EP4583976A1 - Dérivés hétérocycliques comme inhibiteurs de janus kinase - Google Patents

Dérivés hétérocycliques comme inhibiteurs de janus kinase

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Publication number
EP4583976A1
EP4583976A1 EP23767907.1A EP23767907A EP4583976A1 EP 4583976 A1 EP4583976 A1 EP 4583976A1 EP 23767907 A EP23767907 A EP 23767907A EP 4583976 A1 EP4583976 A1 EP 4583976A1
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EP
European Patent Office
Prior art keywords
pyrazolo
ethyl
methoxy
dihydro
benzo
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.)
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EP23767907.1A
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German (de)
English (en)
Inventor
Alessandro ACCETTA
Alberto CUZZOLIN
Fabio Rancati
Andrea Rizzi
Ivaylo Jivkov Elenkov
Milan MESI
Claudio FIORELLI
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Chiesi Farmaceutici SpA
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Chiesi Farmaceutici SpA
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Publication of EP4583976A1 publication Critical patent/EP4583976A1/fr
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D519/00—Heterocyclic compounds containing more than one system of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring system not provided for in groups C07D453/00 or C07D455/00
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • 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

Definitions

  • the JAK family consists of non-receptor tyrosine protein kinases and has four main members, JAK1, JAK2, JAK3, and TYK2. More than 50 cytokines and growth factors bind to type I and II receptors noncovalently associated with different combinations of JAK kinases.
  • the signalling triggered by the ligands consists in tyrosine phosphorylation of receptors by JAK and recruitment of one or more STATs proteins. Tyrosine-phosphorylated STATs dimerize and are then transported into the nucleus through the nuclear membrane to regulate specific genes. JAKs have seven homology domains (the JAK homology domain, JH).
  • JH1 is the first JH, known as the kinase domain, and is composed of approximately 250 amino acid residues.
  • JH1 encodes a kinase protein that constitutes the kinase structure domain that phosphorylates a substrate;
  • JH2 is a pseudokinase domain which regulates the activity of the kinase domain.
  • JAK3 is expressed in the bone marrow and lymphatic system, as well as endothelial cells and vascular smooth muscle cells; other members are expressed in almost all tissues (Hu X et al., Signal Transduct Target Ther. 2021, 26;6(l):402).
  • JAK/STAT signalling Many cellular processes are downstream JAK/STAT signalling: hematopoiesis, immune balance, tissue repair, inflammation, apoptosis, and adipogenesis. Different biological responses are regulated by specific pairing of JAK isoforms. JAK1/JAK3 combination mediates IL-2, -4, -7, -9, -15, and -21 signalling that is relevant for growth/maturation of lymphoid cells, differentiation/homeostasis of T-cells/NK cells, B-cell class switching and other inflammatory processes.
  • JAK2 frequently associates with itself (JAK2/ JAK2) controlling the signalling of various cytokines and growth factors, such as IL-3, IL-5, granulocyte macrophage colony-stimulating factor (GM-CSF), erythropoietin (EPO), and thrombopoietin (TPO) (Hodge et al., Clin Exp Rheumatol 2016; 34(2):318-28).
  • cytokines and growth factors such as IL-3, IL-5, granulocyte macrophage colony-stimulating factor (GM-CSF), erythropoietin (EPO), and thrombopoietin (TPO)
  • JAK/STAT pathways in immune fitness.
  • overexpression or mutations involving some JAK isoforms as well as aberrant JAK/STAT signalling drive malignancies of hematopoietic and lymphoid tissues as well as inflammatory disorders.
  • FDA Food and Drug Administration
  • EU- approved JAK inhibitors are in clinical use.
  • aryl or heteroaryl monocyclic ring systems include, for instance, phenyl, thienyl, pyrrolyl, pyrazolyl, imidazolyl, isoxazolyl, oxazolyl, isothiazolyl, thiazolyl, pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, triazinyl, furanyl radicals and the like.
  • physiological acceptable anions selected among chloride, bromide, iodide, trifluoroacetate, formate, sulfate, phosphate, methanesulfonate, nitrate, maleate, acetate, citrate, fumarate, tartrate, oxalate, succinate, benzoate, p-toluenesulfonate, pamoate and naphthalene disulfonate may be present.
  • acidic groups such as COOH groups
  • physiological cation salts may be present as well, for instance including alkaline or alkaline earth metal ions.
  • Compounds of formula (I) when they contain one or more stereogenic center may exist as optical stereoisomers. Where the compounds of the invention have at least one stereogenic center, they may accordingly exist as enantiomers. Where the compounds of the invention possess two or more stereogenic centers, they may additionally exist as diastereoisomers. It is to be understood that all such single enantiomers, diastereoisomers and mixtures thereof in any proportion are encompassed within the scope of the present invention.
  • the absolute configuration (R) or (S) for carbon bearing a stereogenic center is assigned on the basis of Cahn-Ingold-Prelog nomenclature rules based on groups’ priorities.
  • Atropisomers as conformers that interconvert with a half-life of more than 1000 seconds at a given temperature (Oki M, Topics in Stereochemistry 14, 1-82, 1983).
  • Atropisomers differ from other chiral compounds in that in many cases they can be equilibrated thermally whereas in the other forms of chirality isomerization is usually only possible 35 chemically. Separation of atropisomers is possible by chiral resolution methods such as selective crystallization. In an atropo-enantioselective or atroposelective synthesis one atropisomer is formed at the expense of the other.
  • Atroposelective synthesis may be carried out by use of chiral auxiliaries like a Corey Bakshi Shibata (CBS) catalyst, an asymmetric catalyst derived from proline, or by approaches based on thermodynamic equilibration when an isomerization reaction favors one atropisomer over the other.
  • CBS Corey Bakshi Shibata
  • Racemic forms of compounds of formula (I) as well as the individual atropisomers (substantially free of its corresponding enantiomer) and stereoisomer-enriched atropisomer mixtures are included in the scope of the present invention.
  • the invention further concerns the corresponding deuterated derivatives of compounds of formula (I).
  • V is a divalent group selected from C(O)O, C(O)N(R 6 ), N(R 6 )C(O)O
  • Q is selected from the group consisting of (C 1 -C 6 )alkoxycarbonyl, -(CH 2 ) m NR 4 R 5 , (C 3 - C 8 )cycloalkyl and (C 3 -C 6 )heterocycloalkyl; wherein said (C 3 -C 8 )cycloalkyl and (C 3 - 15 C 6 )heterocycloalkyl are optionally substituted by one or more substituent group selected from the group consisting of (C 1 -C 6 )alkoxycarbonyl(CH 2 ) m , that is preferably (C 1 -C 6 )alkoxycarbonyl (when m is zero), (C3-C8)cycloalkyl-oxycarbonyl, NC-(C1-
  • Preferred, in the above group are compounds of formula I-1 wherein K is O; represented by the formula (Ia) Ia wherein V is C(O)N(R 6 ), Q is (C 3 -C 6 )heterocycloalkyl, preferably a piperidine moiety, substituted by a group selected from (C 1 -C 6 )alkoxycarbonyl, (C 3 -C 8 )cycloalkyl-oxycarbonyl, NC-(C 1 -C 6 ) alkoxycarbonyl, (C 1 - C 6 )haloalkyl-oxycarbonyl, (C 1 -C 6 )alkyl(C 3 -C 8 )heterocycloalkyl-oxycarbonyl, (C 1 - C 6 )hydroxyalkyl -oxycarbonyl, (C 1 -C 6 )alkoxy(C 1 -C 6 )alkyl -oxycarbonyl and (C 1 - C 6 )alkylthi
  • Particularly preferred compounds in this embodiment are: - c]pyridine-3-carboxamido)ethyl)piperidine-4-carboxylate
  • Example C hemical Name A further preferred embodiment in the above group of compounds of formula (I) is that wherein V is a divalent group C(O)O; Q is selected from the group consisting of (C 1 -C 6 )alkoxycarbonyl, -(CH 2 ) m NR 4 R 5 , and (C 3 - C 6 )heterocycloalkyl optionally substituted by one or more group selected from (C 1 -C 10 )alkyl and halogen; n and m are in each occurrence independently 0 or an integer selected from 1, 2, 3 and 4; R 4 and R 5, the same or different, are selected from the group consisting of -H, (C 1 -C 6 )alkyl, single enantiomers, diastereoisomers and mixtures thereof or a pharmaceutically acceptable salt or solvate thereof
  • V is a divalent group selected from N(R6)C(O)O
  • Q is selected from the group consisting of (C 1 -C 6 )alkoxycarbonyl
  • 20 n is an integer selected from 1, 2, 3 and 4
  • R6 is in each occurrence independently selected from the group consisting of H, (C 1 -C 6 )alkyl; single enantiomers, diastereoisomers and mixtures thereof or a pharmaceutically acceptable salt or solvate thereof.
  • V is a divalent group selected from C(O)N(R 6 );
  • Q is (C 3 -C 6 )heterocycloalkyl substituted by one (C 1 -C 6 )alkoxycarbonyl(CH 2 ) m ;
  • n is an integer selected from 1, 2, 3 and 4;
  • R 6 is in each occurrence independently selected from the group consisting of H, (C1-C6)alkyl; single enantiomers, diastereoisomers and mixtures thereof or a pharmaceutically acceptable salt or solvate thereof.
  • Preferred compounds showed a drop of at least 10 fold or more in the functional activity 5 (such as inhibition of pSTAT6 in BEAS cells stimulated with IL-13) of the predicted carboxylic acid metabolite. More preferred compounds showed a drop even higher than 100 fold, even more preferred higher than 200 fold. Even more preferred are compounds according to the invention that, in addition to the previous properties, show an high clearance at least in in-vitro stability assays in human and/or mice representative tissues as for example liver microsomes, and/or hepatocytes, and/or plasma, with an half-life less than or equal to 30 min using well established and validated assays. Those assays were adapted from literature methods (Kevin J.
  • I-2 Compounds of formula (I-1) can be prepared according to scheme 1 starting from intermediates of formula IIa (or IIb, or IIc) by removing of PG 1 by mean of procedures well known to those skilled in the art.
  • a suitable protective group for protecting secondary amines of intermediates IIa (or IIb, or IIc) can be carbamate type protective groups such as Boc (tert- butoxycarbonyl). Boc group can be easily removed by treating Boc protected intermediate IIa (or IIb, or IIc) in acidic conditions with an organic or an inorganic strong acid.
  • Boc group can be cleaved by treating the intermediates with trifluoroacetic acid neat or in mixture with an organic solvent such as DCM, DCE, THF or similar, typically at room temperature overnight.
  • the group Q' present in intermediates of formula IIa is a group of formula Q that can undergo a single step functional group interconversion to generate a compound of formula I-1.
  • Example 43, 44 and 45 were prepared from example 29, 30 and 9 respectively by transesterification with an appropriate alcohol to provide the desired ester.
  • a transesterification reaction can be carried out by reacting parent ester with an excess of the desired alcohol, in the presence of a strong inorganic acid such as sulfuric acid or hydrochloric acid, by heating at high temperature or up to boiling point of the alcohol.
  • Intermediate IIa (or IIb, or IIc) can be obtained by direct introduction of pyrazolo[1,5- a]pyrimidin-3-yl moiety through a metal/palladium catalyzed cross coupling reaction such as Suzuki coupling, Stille coupling or similar (Strategic application of named reactions in organic synthesis, L. Kurti, B. Czako, Ed. 2005) by reaction of intermediate IIIa (or respectively IIIb or IIIc) with intermediate VI.
  • a metal/palladium catalyzed cross coupling reaction such as Suzuki coupling, Stille coupling or similar (Strategic application of named reactions in organic synthesis, L. Kurti, B. Czako, Ed. 2005) by reaction of intermediate IIIa (or respectively IIIb or IIIc) with intermediate VI.
  • a suitable palladium catalyzed cross coupling for introducing pyrazolo[1,5-a]pyrimidin-3-yl moiety can be performed by reacting intermediate IIIa (or IIIb, or IIIc) with the corresponding boronic acid or boron pinacolate (intermediate VI, where A is dihydroxyboryl or 4,4,5,5-tetramethyl-1,3,2-dioxaborolanyl) in the presence of a palladacycle precatalyst as XPhos-Pd-G3 [(2-Dicyclohexylphosphino-2′,4′,6′-triisopropyl-1,1′-biphenyl)[2-(2′- amino-1,1′-biphenyl)]palladium(II) methanesulfonate], or in the presence of Pd catalyst such as tetrakistriphenylphosphinepalladium(0) or PdCl 2 (dppf)
  • Boronic acid and boronic pinacolate esters are generally commercially available or may be readily prepared by those skilled in the art starting from commercially available reagents.
  • Intermediates of formula IIIa may be obtained from intermediate IVa by means of amide coupling with the corresponding amine Va.
  • An amide coupling can be performed by reacting the amine and the acid in an organic solvent like DMF, DCM, or THF, in the presence of a coupling agent like HATU((1-[Bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate), HBTU (O-(Benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate) or COMU ((1-Cyano-2-ethoxy-2-oxoethylidenaminooxy)dimethylamino- morpholino-carbenium) and in the presence of an organic base like DIPEA, TEA, or pyridine.
  • a coupling agent like HATU((1-[Bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b
  • Intermediate of formula IIIb may be obtained from intermediate IVa and an alcohol intermediate Vb through a two steps / one pot process that involves: 1) Acylazide formation and Curtius rearrangement to give an isocyanate intermediate and 2) one pot reaction of isocyanate 35 with alcohol Vb to form the corresponding carbamate.
  • the corresponding acyl azide of intermediate IIIb can be prepared by reaction with an azide source as azido(trimethyl)silane, in the presence of a suitable coupling agents such as T3P and with an organic base like TEA or DIPEA, in an organic solvent such as 2-methyl-THF, DMF or toluene.
  • intermediate IIIb may be prepared from intermediate IVb and intermediate Vb by a two steps / one pot process that involve: 1) isocyanate formation and 2) one pot reaction with alcohol Vb to form the corresponding carbamate.
  • Intermediate IVb can be reacted with bis(trichloromethyl) carbonate in an organic solvent as DCM or THF, at low temperature like dry ice temperature (-78oC), in the presence of an organic base like TEA or DIPEA for times up to 1 or 2 hours to form the corresponding isocyanate; addition of intermediate Vb and reaction at room temperature lead to the formation of carbamate of formula IIIb.
  • intermediate IIa may be obtained from intermediate VIIa and intermediate Va by an amide coupling using the same procedure described above for intermediate IIIa from IVa and Va.
  • intermediate IIc may be obtained from intermediate VIIa and intermediate Vb by esterification reaction promoted by a coupling agent like EDC (1-etil-3-(3- dimetilamminopropil)carbodiimmide) or DIC (N, N′-diisopropilcarbodiimmide), in an organic solvent as DCM or THF, in the presence of an organic base like DMAP or pyridine, at room temperature for few hours (typically 2-4 hours).
  • EDC 1-etil-3-(3- dimetilamminopropil)carbodiimmide
  • DIC N, N′-diisopropilcarbodiimmide
  • Intermediate VIIa can be obtained from intermediate IVa and VI by a Suzuki coupling in a similar way to that described above for the reaction of intermediate IIIa (or respectively IIIb or IIIc) with an intermediate VI.
  • Intermediate IVa (or IVb) can be prepared according to scheme 2.
  • Intermediate IVa (or IVb) can be prepared by means of N-arylation of intermediate VIIIa (or VIIIb) with a halide intermediate IX by using copper catalyzed Ullmann type reaction.
  • An Ullmann reaction between a NH heteroaryl and an aryl/heteroaryl halide can be performed in the presence of a suitable copper(I) catalyst/promoter such as CuI, Cu 2 O or CuTC (copper thiophene carboxylate), ligandless or with a suitable ligand such as N,N-dimethylglicine, proline, phenantroline or dimethylcyclohexane-1,2-diamine (DMCHA), in the presence of an inorganic base such as K 2 CO 3 or Cs 2 CO 3 , by heating (typically 90-150oC) in a polar organic solvent such as DMSO, DMF or DMA, overnight or longer.
  • a suitable copper(I) catalyst/promoter such as CuI, Cu 2 O or CuTC (copper thiophene carboxylate)
  • ligandless or with a suitable ligand such as N,N-dimethylglicine, proline, phenantroline or dimethylcyclohe
  • Intermediate IX may be obtained from intermediate X in a two steps process that involves PG 1 introduction (Boc group introduction) and halogenation or inverting the sequence of the steps. Insertion of Boc group can be carried out by reacting the anilino intermediate with Boc 2 O in an organic solvent like THF or DCM, in the presence of an organic base like DMAP or pyridine, at room temperature for several hours up to overnight (typically 12 hours).
  • intermediate IVa where K is S and PG 1 is H
  • intermediate VIIIa may be obtained from intermediate VIIIa by means of a multistep synthetic sequence reported in scheme 3.
  • Intermediate VIIIa and intermediate XII can undergo an aromatic nucleophilic substitution (SNAr) to give 5 intermediate XI, for example by reacting them in an organic solvent like DMF or 1,4-dioxane, in the presence of an organic base like DBU or DIPEA, at RT for few hours (typically 4 hours); addition of methyl halide like MeI at the end of SNAr reaction can lead to in situ methylation of the carboxylic acid and formation of intermediate XI.
  • SNAr aromatic nucleophilic substitution
  • Intermediate XI can be reacted with mercaptoethanol under Pd-catalyzed C-S coupling conditions to give intermediate XII.
  • C-S coupling can be performed by reacting aryl bromide XI and mercaptoethanol in the presence of a suitable catalytic system like as Pd 2 (dba) 3 / Xantphos or another suitable palladium source / phosphine source, in an organic solvent as 1,4-dioxane, toluene or DMA, in the presence of an organic base like DIPEA or DBU, at temperature up to 100oC for few hours (typically 3 -5 hours).
  • a suitable catalytic system like as Pd 2 (dba) 3 / Xantphos or another suitable palladium source / phosphine source
  • intermediate IIIa' (or IIIb') can be prepared from esterification with an alcohol of formula r-OH with the corresponding acid of formula XVIIa (or XVIIb) by using similar conditions to those reported in scheme 1 for the transformation of intermediates VIIa and Vb into IIc.
  • Intermediates IIIa' (or IIIb') can be converted to compound of formula I-1 by using similar methods reported in scheme 1 to convert intermediate IIIa (or IIIb) to compound of formula I-1.
  • IIa can be transformed in IIa’ by a two steps process can allow transformation of group Q’ to Q’’.
  • ester hydrolysis of Q’ of IIa generates an acid intermediate that can be submitted to an esterification with a proper alcohol (r-OH) to give intermediate IIa’.
  • Intermediate IVa and intermediate XVIII can be reacted, to give intermediate XIX, in the presence of a suitable ligand palladacyle system such as XPhos-Pd-G3 (2- Dicyclohexylphosphino-2′,4′,6′-triisopropyl-1,1′-biphenyl)[2-(2′-amino-1,1′- biphenyl)]palladium(II) methanesulfonate) or RuPhos-Pd-G3 (2-Dicyclohexylphosphino-2′,6′- diisopropoxy-1,1′-biphenyl)[2-(2′-amino-1,1′-biphenyl)]palladium(II) methanesulfonate) or in general a suitable Pd source (for example Pd 2 (dba) 3 or Pd(OAc) 2 ) with a suitable phosphine ligand such as
  • effective amount in reference to a compound of formula (I) or a pharmaceutically acceptable salt thereof or other pharmaceutically active agent means an amount of the compound sufficient to treat the patient's condition but low enough to avoid serious side effects and it can nevertheless be routinely determined by the skilled artisan.
  • the compounds of formula (I) or pharmaceutically acceptable salts thereof may be administered once or according to a dosing regimen wherein a number of doses are administered at varying intervals of time for a given period of time. Typical daily dosages may vary depending upon the particular route of administration chosen.
  • Suppositories for rectal administration of the compounds of the invention can be prepared by mixing the compound with a suitable excipient such as cocoa butter, salicylates and polyethylene glycols.
  • Formulations for vaginal administration can be in the form of cream, gel, paste, foam, or spray formula containing, in addition to the active ingredient, such as suitable carriers, are also known.
  • the pharmaceutical composition can be in the form of creams, ointments, liniments, lotions, emulsions, suspensions, gels, solutions, pastes, powders, sprays, and drops suitable for administration to the skin, eye, ear or nose. Topical administration may also involve transdermal administration via means such as transdermal patches.
  • Compounds of the invention may exhibit profile suitable for oral route administration.
  • a JAKi should preferably possess additional properties that may further limit the systemic exposure after inhalation.
  • a way to limit systemic exposure, after local administration, might be to design soft-drug that means the introduction of specific moieties, like for example esters in the present invention, which favour a controlled rapid systemic metabolism (in the liver and/or in the blood) into predicted functionally less active, or even negligibly active, metabolites compared to parent compound.
  • one way resulted in the optimization of 'suitably designed esters derivatives' which having corresponding predicted carboxylic acid metabolites showing a drop in functional activity (like cell based activity).
  • such optimized esters can be substrates of liver and/or blood esterases that may be beneficial for achieving an enhanced clearance in-vivo.
  • preferred compounds of the invention showed one or more of the following properties: high biochemical activity on target, strong functional activity (like cell based activity), a rapid clearance in representative assays (stability in liver microsomes and/or hepatocytes, plasma stability) and drop in the functional activity of the predicted carboxylic acid metabolite so that they can have potential for giving compounds with an improved safety.
  • NMR spectra were obtained on a Bruker Avance III 600 (5 mm RT inverse probe head), Bruker DRX 500, Bruker Avance AV 400 (5 mm RT direct probehead) or Bruker DPX 300 spectrometers using standard Bruker pulse sequences.
  • NMR spectra were recorded with Varian MR-400 spectrometer operating at 400 Mhz or a Varian Unity Inova 400 spectrometer with a 5 mm inverse detection triple resonance probe operating at 400 MHz.
  • DMSO-d 6 or CDCl 3 were used as solvents. Chemical shifts are given in relative to internal standard tetramethylsilane or solvent residual peak. All experiments were recorded at 298 K, unless stated differently.
  • HPLC-MDAP Method 1 Agilent 1290 Infinity II Purification System; Column: Waters XBridge® (C18, 100 mm x 19 mm i.d., 5 ⁇ m), mobile phase A: 0.1% (v/v) formic acid in water, mobile phase B: acetonitrile; .
  • Step 2 tert-Butyl 6-bromo-7-methoxy-3,4-dihydroquinoline- -carboxylate (Intermediate 4)
  • a solution of intermediate 4-1 (228 mg, 0.86 mmol) in EtOAc (10 mL) was cooled to 0°C.
  • 1,3-dibromo-5,5-dimethyl-imidazolidine-2,4-dione (124 mg, 43.3 mmol) was added portion wise over 15 min.
  • RM was stirred at 0 °C for 20 min, then quenched with 10 % (w/w) aq. K 2 CO 3 (20 mL).
  • the organic layer was separated, washed with sat. aq.
  • Step 2 tert-butyl 7-iodo-6-methoxy-2,3-dihydro-4H-benzo[b][1,4]oxazine-4-carboxylate (Intermediate 5)
  • Intermediate 5-step 1 (5.9g, 22.1 mmol) was dissolved in DMF (60mL), then N- Iodohydroxysuccinimide (12.7g, 111 mmol) added and RM stirred at 40°C overnight. RM was quenched in cold water and extracted with EtOAc. Combined organic layers were evaporated to dryness and the residue purified by chromatography on silica gel by gradient elution from 1:1 to 3:2 DCM-Hexane to afford the title compound (7.38g).
  • Reaction mixture was refluxed for 3 h., diluted with EtOAc (25 mL), washed with sat. aq. NaHCO 3 (3x15 mL) and sat. aq. NaCl (15 mL). Organic layer was dried over Na 2 SO 4 and concentrated in vacuo. The residue was purified by flash chromatography on Si cartridge by eluting with 0-35 % DCM/MeOH/NH 4 OH (90:15:1.5) in DCM to afford the desired product.
  • RM was stirred at -78°C for 1 h. Ethyl 2-hydroxyacetate (79 ⁇ L, 0.83 mmol) and TEA (58.1 ⁇ L, 0.42 mmol) were added and RM stirred overnight reaching RT. RM was quenched with sat. aq. NaHCO 3 and water, then extracted with DCM (4 ⁇ 10 mL). Combined organic layers were washed with sat. aq. NaCl, dried over Na 2 SO 4 and solvent evaporated in vacuo. The residue was purified by flash chromatography on Si cartridge by eluting with 0-40 % EtOAc in DCM to afford the title product (92 mg).
  • Step 3 (R)-1-(2-Fluoroethyl)pyrrolidin-3-yl (R)-1-(2- (((benz xy)carbonyl)amino)ethyl)pyrrolidine-3-carboxylate (Intermediate 17)
  • Intermediate 17-2 (135 mg, 0.46 mmol)
  • Intermediate 16 (73.8 mg, 0.55 mmol)
  • 2,4,6-trichlorobenzoyl chloride 86.6 ⁇ L, 0.55 mmol
  • TEA 129 ⁇ L, 0.92 mmol
  • DMAP (14.1 mg, 0.25 mmol
  • RM was poured in a mixture of EtOAc and water (10 mL each) and pH adjusted from 5.5 to 3.5 using aq. 1.0 M HCl. Aqueous layer was basified with 2M NaOH to pH 9.5 and extracted with EtOAc (2x10 mL). Combined organic layers were washed with sat. aq. NH 4 Cl (2x), sat. aq. NaCl, dried over Na 2 SO 4 and solvent removed in vacuo to afford the title product (162 mg).
  • RM was diluted with sat.aq. NaHCO 3 , DCM (5 mL) and the pH adjusted to 9.5. Aqueous layer was extracted with DCM/i-PrOH (3:1; 4x5 mL) and the combined organic layers were passed through a phase separator and solvents removed in vacuo. The residue was purified by flash chromatography on Si cartridge by eluting with 0-70 % DCM/MeOH/NH 4 OH (90:5:0.5) in DCM to afford the title product (28 mg).
  • RM was partitioned between EtOAc (10 mL) and water (5 mL). The organic layer was washed with sat. aq. NaCl (5 mL) and solvent removed in vacuo. The residue was purified by flash chromatography on Si cartridge by eluting with 0-20 % DCM/MeOH/NH 4 OH (90:9:0.5) in DCM to afford the title product (6.6 mg).
  • RM was diluted with EtOAc (15 mL), washed with sat. aq. NaHCO 3 (3x10 mL) and sat. aq. NaCl (10 mL). Organic layer was dried over Na2SO4 and concentrated in vacuo. The residue was purified by flash chromatography on Si cartridge by eluting with 0-70 % DCM/MeOH (9:1) in DCM to afford the title product (28 mg).
  • Example 55 1-(4-(tert-Butoxycarbonyl)-6-methoxy-3,4-dihydro-2H-benzo[b][1,4]oxazin-7-yl)-6- (pyrazolo[1,5-a]pyrimidin-3-yl pyrazolo[4,3-c]pyridine-3-carboxylic acid (Example 55- Intermediate 1) To a previously degassed mixture of aqueous potassium phosphate (1.0 M, 2.17 mL, 2.2 mmol) and THF (5 mL), intermediate 7 (500 mg, 1.1 mmol), 3-(4,4,5,5-tetramethyl-1,3,2- dioxaborolan-2-yl)pyrazolo[1,5-a]pyrimidine (372 mg, 1.5 mmol) and XPhos-PdG3 (46 mg, 54 ⁇ mol) were added and RM stirred at 70 o C for 1.5h.
  • aqueous potassium phosphate 1.0 M, 2.17 mL,
  • RM was diluted with water (15 mL) and basified to pH 10. RM was washed with EtOAc (2x20 mL) and aqueous layer filtered through a pad of diatomaceous earth and washed with water (100 mL). A mixture of MEK (methylethyl ketone) and i-BMK (isobutylmethyl ketone) (5:1 - 150 mL) was added and pH adjusted to 4.5. Organic layer was separated, dried over Na 2 SO 4 , filtered, and evaporated to dryness to give the title product (560 mg) that was used in the next synthetic steps without further purification.
  • MEK methylethyl ketone
  • i-BMK isobutylmethyl ketone
  • Compound testing Serial dilutions of compounds in pure DMSO are prepared from 10 mM DMSO stock solutions. Compounds were tested in 384-well plate for 11 consecutive 5-fold dilutions starting from 20 ⁇ M highest concentration (20 ⁇ M – 2 pM). 200 nL of compound were transferred from mother plate to test plate by using Mosquito (TTP labtech). Assay was performed in 384-well Perkin Elmer test plate in 20 ⁇ L assay volume (kinase reaction) and 40 ⁇ L total volume (stopping reagent and antibody detection reagents).

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  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • General Chemical & Material Sciences (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Engineering & Computer Science (AREA)
  • Immunology (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Nitrogen And Oxygen Or Sulfur-Condensed Heterocyclic Ring Systems (AREA)
  • Epidemiology (AREA)
  • Pulmonology (AREA)
  • Medicinal Preparation (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
  • Steroid Compounds (AREA)
  • Pain & Pain Management (AREA)
  • Rheumatology (AREA)

Abstract

La présente invention concerne un composé de formule générale (I) inhibant la famille des janus kinase (JAK) des protéines kinases à tyrosine non réceptrices (JAK1, JAK2, JAK3 et TYK2) ; des méthodes de préparation de tels composés, des compositions pharmaceutiques les contenant et leur utilisation thérapeutique. Les composés de l'invention peuvent être utiles dans le traitement de maladies ou de pathologies associées à un dérèglement des kinases non réceptrices de la famille JAK ; en particulier pour le traitement de diverses maladies inflammatoires, notamment l'asthme, la BPCO et d'autres maladies respiratoires.
EP23767907.1A 2022-09-09 2023-09-08 Dérivés hétérocycliques comme inhibiteurs de janus kinase Pending EP4583976A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
EP22194841 2022-09-09
PCT/EP2023/074692 WO2024052513A1 (fr) 2022-09-09 2023-09-08 Dérivés hétérocycliques comme inhibiteurs de janus kinase

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EP4583976A1 true EP4583976A1 (fr) 2025-07-16

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EP (1) EP4583976A1 (fr)
JP (1) JP2025530239A (fr)
KR (1) KR20250060914A (fr)
CN (1) CN119968375A (fr)
AR (1) AR130426A1 (fr)
AU (1) AU2023336561A1 (fr)
CA (1) CA3266831A1 (fr)
CL (1) CL2025000636A1 (fr)
CO (1) CO2025004441A2 (fr)
GE (1) GEAP202516731A (fr)
IL (1) IL319348A (fr)
MX (1) MX2025002632A (fr)
PE (1) PE20251394A1 (fr)
TW (1) TW202421149A (fr)
WO (1) WO2024052513A1 (fr)

Family Cites Families (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2010508315A (ja) * 2006-10-30 2010-03-18 ノバルティス アーゲー 抗炎症剤としてのヘテロ環式化合物
EP2463289A1 (fr) * 2010-11-26 2012-06-13 Almirall, S.A. Dérivés imidazo[1,2-b]pyridazine en tant qu'inhibiteur JAK
CR20190310A (es) * 2016-12-29 2019-08-21 Hoffmann La Roche Compuestos de pirazolopirimidina y métodos de uso de los mismos
KR20230157431A (ko) * 2021-03-15 2023-11-16 키에시 파르마슈티시 엣스. 피. 에이. 야누스 키나아제 억제제로서 헤테로사이클릭 유도체
US20240209001A1 (en) * 2021-03-15 2024-06-27 Chiesi Farmaceutici S.p. A. Heterocyclic derivatives as janus kinase inhibitors

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GEAP202516731A (en) 2025-06-10
JP2025530239A (ja) 2025-09-11
IL319348A (en) 2025-05-01
CL2025000636A1 (es) 2025-07-04
CO2025004441A2 (es) 2025-04-28
AU2023336561A1 (en) 2025-04-17
CA3266831A1 (fr) 2024-03-14
KR20250060914A (ko) 2025-05-07
CN119968375A (zh) 2025-05-09
AR130426A1 (es) 2024-12-04
TW202421149A (zh) 2024-06-01
MX2025002632A (es) 2025-04-02
WO2024052513A1 (fr) 2024-03-14
PE20251394A1 (es) 2025-05-22

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