WO2024105070A1 - Dérivés de pyrido oxazolidinone utilisés en tant qu'inhibiteurs d'alk5 - Google Patents

Dérivés de pyrido oxazolidinone utilisés en tant qu'inhibiteurs d'alk5 Download PDF

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WO2024105070A1
WO2024105070A1 PCT/EP2023/081822 EP2023081822W WO2024105070A1 WO 2024105070 A1 WO2024105070 A1 WO 2024105070A1 EP 2023081822 W EP2023081822 W EP 2023081822W WO 2024105070 A1 WO2024105070 A1 WO 2024105070A1
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formula
mmol
compound
pyridin
alkyl
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PCT/EP2023/081822
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Daniele PALA
Daniela PIZZIRANI
Paolo RONCHI
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Chiesi Farmaceutici S.P.A.
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D498/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D498/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
    • C07D498/04—Ortho-condensed systems
    • 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

Definitions

  • the present invention generally relates to compounds inhibiting the transforming growth factor P (TGF P) type I receptor (ALK5) (hereinafter ALK5 inhibitors), methods of preparing such compounds, pharmaceutical compositions containing them and therapeutic use thereof; the compounds of the invention may be useful for instance in the treatment of many diseases, disorder, or condition associated with ALK5 signaling pathway.
  • TGF P transforming growth factor P
  • ALK5 inhibitors transforming growth factor P type I receptor
  • TGF P Transforming Growth Factor P
  • TGF P The Transforming Growth Factor P (TGF P) is a protein belonging to the TGF P superfamily. It is involved in several processes, both cellular, such as proliferation, migration and differentiation, and biological, including wound healing, immunosuppression, cancerogenesis and extracellular matrix production.
  • the TGF P superfamily also includes, among others, other members known as activins (Acts) (see e.g., Hinck AP, FEBS Letters 586 (2012); 1860-1870).
  • Acts activins
  • the binding of the peptide initiates the TGF P signalling cascade through the formation of a heterotetrameric complex composed of two different serine/threonine kinases receptors: type 1 (TGFPR1/ALK5) and type 2 (TGFPR2).
  • TGFPR1/ALK5 is recruited and activated through the phosphorylation of its intracellular domain by TGFPR2, leading in turn to the phosphorylation of the receptor-activated (R)-Smad family, resulting in the activation of target gene transcription (see e.g., Sheppard D., Proc Am Thorac Soc. (2006) ;(3):413- 417).
  • R receptor-activated
  • ALKA type I receptor for activin
  • TGFP expression is increased in fibrotic lung diseases, such as idiopathic pulmonary fibrosis (IPF), and in chronic inflammatory conditions, such as chronic obstructive pulmonary disease and asthma (see e.g., Thomas BJ et al., Am J Respir Cell Mol Biol. (2016); (55):759-766).
  • fibrotic lung diseases such as idiopathic pulmonary fibrosis (IPF)
  • chronic obstructive pulmonary disease and asthma see e.g., Thomas BJ et al., Am J Respir Cell Mol Biol. (2016); (55):759-766.
  • TGFP is expressed in several cell types, like epithelial cells, endothelial cells, connective tissue cells, macrophages and fibroblasts. These cell populations may produce excess of TGFP in IPF human lung tissue.
  • TGFP signalling inhibition obtained by employing knockout (KO) animals can inhibit fibrosis development through TGFP-linked mechanisms (see e.g., Bonniaud P et al., Am J Respir Crit Care Med (2005); 171 :889-898; 34).
  • TGFP plays a key role in the development and functionality of cardiac valves. It is therefore clear the importance of a selective regulation of TGFp pathway to target the pathological effects avoiding the suppression of the signalling needed for a correct homeostasis.
  • the answer to this crucial point could be addressed by using the inhalation route to deliver an antiTGFp drug.
  • the inhalatory route would allow the treatment of the affected lung compartment bypassing the issue of the heart exposure.
  • ALK5 and/or ALK4 receptor inhibitors Various compounds have been described in the literature as ALK5 and/or ALK4 receptor inhibitors.
  • inhibition of ALK5 receptor may be useful for the treatment of fibrosis and disease, disorder and conditions that result from fibrosis.
  • the present invention relates to compounds of formula (I) wherein Ri is selected from the group consisting of Al and A2
  • I ⁇ 2 is selected from the group consisting of phenyl optionally substituted by one or more halogen atoms; pyridyl optionally substituted by one or more -(Ci-Ce)alkyl; and thiazolyl optionally substituted by one or more -(Ci-Ce)alkyl;
  • Ri is H or is selected from the group consisting of -NH2, -NHC(O)-(Ci-Ce)alkyl and -NHC(O)- (Ci-Ce)alkylene-NRARB; RA is -(Ci-Ce)alkyl;
  • RB is -(Ci-Ce)alkyl; and pharmaceutically acceptable salts thereof.
  • the invention refers to a pharmaceutical composition
  • a pharmaceutical composition comprising a compound of formula (I) and pharmaceutically acceptable salts thereof in admixture with one or more pharmaceutically acceptable carrier or excipient.
  • the invention refers to a compound of formula (I) and pharmaceutically acceptable salts, or to a pharmaceutical composition comprising a compound of formula (I) and pharmaceutically acceptable salts thereof, for use as a medicament.
  • the invention refers to a compound of formula (I) and pharmaceutically acceptable salts thereof, or to a pharmaceutical composition comprising a compound of formula (I) and pharmaceutically acceptable salts thereof, for use in preventing and/or treating a disease, disorder or condition mediated by ALK5 receptor in a mammal.
  • the invention refers to a compound of formula (I) and pharmaceutically acceptable salts thereof, or to a pharmaceutical composition comprising a compound of formula (I) and pharmaceutically acceptable salts thereof, for use in the prevention and/or treatment of fibrosis and/or diseases, disorders, or conditions that involve fibrosis.
  • the invention refers to a compound of formula (I) and pharmaceutically acceptable salts thereof, or to a pharmaceutical composition comprising a compound of formula (I) and pharmaceutically acceptable salts thereof, for use in the prevention and/or treatment idiopathic pulmonary fibrosis (IPF).
  • IPF idiopathic pulmonary fibrosis
  • the compound of formula (I) of the present invention is intended to include also pharmaceutically acceptable salts thereof.
  • the compound of formula (I) of the present invention is intended to include also the compounds of formula (la) and (lb).
  • pharmaceutically acceptable salts refers to derivatives of compounds of formula (I) wherein the parent compound is suitably modified by converting any of the free acid or basic group, if present, into the corresponding addition salt with any base or acid conventionally intended as being pharmaceutically acceptable.
  • Suitable examples of said salts may thus include mineral or organic acid addition salts of basic residues such as amino groups, as well as mineral or organic basic addition salts of acid residues such as carboxylic groups.
  • Cations of inorganic bases which can be suitably used to prepare salts comprise ions of alkali or alkaline earth metals such as potassium, sodium, calcium or magnesium.
  • Those obtained by reacting the main compound, functioning as a base, with an inorganic or organic acid to form a salt comprise, for example, salts of hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, methane sulfonic acid, camphor sulfonic acid, acetic acid, oxalic acid, maleic acid, fumaric acid, succinic acid and citric acid.
  • halogen or “halogen atoms” or “halo” as used herein includes fluorine, chlorine, bromine, and iodine atom.
  • (C x -C y )alkyl wherein x and y are integers, refers to a straight or branched chain alkyl group having from x to y carbon atoms.
  • x is 1 and y is 6, for example, the term includes methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, t-butyl, n-pentyl and n- hexyl.
  • a dash that is not between two letters or symbols is meant to represent the point of attachment for a substituent.
  • the compounds of the invention are active as inhibitors of ALK5 receptor, they are potent and show improved properties such as a low metabolic stability, a low systemic exposure, a good inhalatory profile and a good selectivity across the kinome.
  • the state of the art does not describe or suggest pyrido oxazolidinone derivatives of general formula (I) of the present invention having an inhibitory activity on receptor ALK5 which represents a solution to the aforementioned need.
  • the present invention refers to a series of compounds represented by the general formula (I) as herein below described in details, which are endowed with an inhhibitory activity on receptor ALK5 receptor.
  • the inhibitory action on receptor ALK5 can be effective in the treatment of those diseases where these receptors play a relevant role in the pathogenesis such as fibrosis and disease, disorder, and condition from fibrosis.
  • the compounds of formula (I) of the present invention are able to act as antagonists of ALK5 receptor, particularly appreciated by the skilled person when looking at a suitable and efficacious compounds useful for the treatment of fibrosis, in particular idiopathic pulmonary fibrosis.
  • the compounds of formula (I) of the present invention show a notable potency with respect to their inhibitory activity on receptor ALK5, with a pKi greater than 7.5, confirming that they are able to inhibit the ALK5 receptor involved in fibrosis and diseases that result from fibrosis.
  • the compounds of the present invention are endowed with a high potency, they could be administered in human at a lower dosage respect to the compounds of the prior art, thus reducing the adverse events that typically occur administering higher dosages of a drug.
  • the compounds of the present invention are also characterized by a good inhalatory profile, that permits to act effectively on the lung compartment and have, at the same time, a low metabolic stability, that allows to minimize the drawbacks associated with the systemic exposure, such as safety and tolerability issues.
  • the compounds of the present invention are particularly appreciated by the skilled person when looking at a suitable and efficacious compounds useful for the treatment of fibrosis, in particular idiopathic pulmonary fibrosis, administered by the inhalation route and characterized by a good inhalatory profile, that corresponds to a good activity on the lung, a good lung retention and to a low metabolic stability, that minimizes the systemic exposure and correlated safety issues.
  • the present invention relates to a compound of general formula (I) wherein Ri is selected from the group consisting of Al and A2
  • Al A2 I ⁇ 2 is selected from the group consisting of phenyl optionally substituted by one or more halogen atoms; pyridyl optionally substituted by one or more -(Ci-Ce)alkyl; and thiazolyl optionally substituted by one or more -(Ci-Ce)alkyl;
  • R is H or is selected from the group consisting of -NH2, -NHC(O)-(Ci-Ce)alkyl and - NHC(O)-(Ci-C 6 )alkylene-NR A RB;
  • RA is -(Ci-Ce)alkyl
  • RB is -(Ci-Ce)alkyl; and pharmaceutically acceptable salts thereof.
  • the present invention refers to a compound of formula (I), wherein Ri is Al
  • Al represented by the formula (la) wherein Rz is selected from the group consisting of phenyl optionally substituted by one or more halogen atoms; pyridyl optionally substituted by one or more -(Ci-Ce)alkyl; and thiazolyl optionally substituted by one or more -(Ci-Ce)alkyl;
  • Rs is H or is selected from the group consisting of -NH2, -NHC(O)-(Ci-Ce)alkyl and -NHC(O)- (Ci-Ce)alkylene-NRARB;
  • RA is -(Ci-Ce)alkyl
  • RB is -(Ci-Ce)alkyl; and pharmaceutically acceptable salts thereof.
  • the invention refers to at least one of the compounds of Formula (la) listed in the Table 1 below and pharmaceutically acceptable salts thereof. These compounds are particularly active on receptor ALK5, as shown in Table 3.
  • Table 1 List of preferred compounds of Formula (la)
  • the present invention refers to a compound of formula (I), wherein Ri is A2
  • the invention refers to at least one of the compounds of Formula (lb) listed in the Table 2 below and pharmaceutically acceptable salts thereof. These compounds are particularly active on receptor ALK5, as shown in Table 3.
  • the present invention refers to a compound of formula (I), wherein Rz is phenyl substituted by a chlorine and a fluorine atom.
  • the present invention refers to a compound of formula (I), wherein Rz is -(5-chloro-2-fluorophenyl).
  • the present invention refers to a compound of formula (I), wherein Rz is pyridyl substituted by a methyl.
  • the present invention refers to a compound of formula (I), wherein Rz is -(6-methylpyridin-2-yl). In a more preferred embodiment, the present invention refers to a compound of formula (I), wherein Rz is thiazolyl substituted by a methyl.
  • the present invention refers to a compound of formula (I), wherein Rz is -(4-methylthiazol-2-yl).
  • the compounds of the invention can be prepared from readily available starting materials using the following general methods and procedures outlined in detail in the Schemes shown below, or by using slightly modified processes readily available to those of ordinary skill in the art. Although a particular embodiment of the present invention may be shown or described herein, those skilled in the art will recognize that all embodiments or aspects of the present invention can be obtained using the methods described herein or by using other known methods, reagents and starting materials. When typical or preferred process conditions (i.e., reaction temperatures, times, mole ratios of reactants, solvents, pressures, etc.) are given, other process conditions can also be used unless otherwise stated.
  • process conditions i.e., reaction temperatures, times, mole ratios of reactants, solvents, pressures, etc.
  • PG protective groups
  • the compounds of formula (I) of the present invention have surprisingly been found to effectively inhibit the receptor ALK5.
  • the inhibition of ALK5 may result in efficacious treatment of the diseases or condition wherein the ALK5 receptor is involved.
  • the compounds of formula (I) of the present invention have an inhibitory drug potency, expressed as pICso (negative logarithm of IC50, half maximal inhibitory concentration) and subsequently converted to pKi (negative logarithm of dissociate function Ki), equal or higher than 7.5 on ALK5, as shown in the experimental part.
  • the compounds of the present invention have a pKi on ALK5 between 7.5 and 8.9, more preferably higher or equal than 9.0.
  • the present invention refers to a compound of formula (I) or a pharmaceutically acceptable salt thereof, for use as a medicament.
  • the invention refers to a compound of formula (I) in the preparation of a medicament, preferably for use in the prevention and/or treatment of a disease, disorder or condition associated with ALK5 signaling pathway.
  • the invention refers to a compound of formula (I) or a pharmaceutically acceptable salt thereof, for use in the prevention and/or treatment of a disease, disorder or condition associated with ALK5 signaling pathway.
  • the present invention refers to a compound of formula (I) useful for the prevention and/or treatment of fibrosis and/or diseases, disorders, or conditions that involve fibrosis.
  • fibrosis refers to conditions that are associated with the abnormal accumulation of cells and/or fibronectin and/or collagen and/or increased fibroblast recruitment and include but are not limited to fibrosis of individual organs or tissues such as the heart, kidney, liver, joints, lung, pleural tissue, peritoneal tissue, skin, cornea, retina, musculoskeletal and digestive tract.
  • the compounds of formula (I) of the present invention are useful for the treatment and/or prevention of fibrosis such as pulmonary fibrosis, idiopathic pulmonary fibrosis (IPF), hepatic fibrosis, renal fibrosis, ocular fibrosis, cardiac fibrosis, arterial fibrosis and systemic sclerosis.
  • fibrosis such as pulmonary fibrosis, idiopathic pulmonary fibrosis (IPF), hepatic fibrosis, renal fibrosis, ocular fibrosis, cardiac fibrosis, arterial fibrosis and systemic sclerosis.
  • the compounds of formula (I) of the present invention, or a pharmaceutical composition comprising a compound of formula (I) are useful for the treatment of idiopathic pulmonary fibrosis (IPF).
  • IPF idiopathic pulmonary fibrosis
  • safety and 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) may be administered once or according to a dosing regimen wherein several doses are administered at varying intervals of time for a given period of time. Typical daily dosages may vary depending upon the route of administration chosen.
  • the present invention also refers to a pharmaceutical composition
  • a pharmaceutical composition comprising a compound of formula (I) in admixture with at least one or more pharmaceutically acceptable carrier or excipient.
  • the invention refers to a pharmaceutical composition of compounds of formula (I) in admixture with one or more pharmaceutically acceptable carrier or excipient, for example those described in Remington’s Pharmaceutical Sciences Handbook, XVII Ed., Mack Pub., N.Y., U.S.A.
  • Administration of the compounds of the invention and their pharmaceutical compositions may be accomplished according to patient needs, for example, orally, nasally, parenterally (subcutaneously, intravenously, intramuscularly, intrastemally and by infusion) and by inhalation.
  • the compounds of the present invention are administered orally or by inhalation. More preferably, the compounds of the present invention are administered by inhalation.
  • the pharmaceutical composition comprising the compound of formula (I) is a solid oral dosage form such as tablets, gelcaps, capsules, caplets, granules, lozenges and bulk powders.
  • the pharmaceutical composition comprising the compound of formula (I) is a tablet.
  • the compounds of the invention can be administered alone or combined with various pharmaceutically acceptable carriers, diluents (such as sucrose, mannitol, lactose, starches) and known excipients, including suspending agents, solubilizers, buffering agents, binders, disintegrants, preservatives, colorants, flavorants, lubricants and the like.
  • the pharmaceutical composition comprising a compound of formula (I) is a liquid oral dosage forms such as aqueous and non-aqueous solutions, emulsions and suspensions.
  • Such liquid dosage forms can also contain suitable known inert diluents such as water and suitable known excipients such as preservatives, wetting agents, sweeteners, flavorants, as well as agents for emulsifying and/or suspending the compounds of the invention.
  • the pharmaceutical composition comprising the compound of formula (I) is an inhalable preparation such as inhalable powders, propellant-containing metering aerosols or propellant-free inhalable formulations.
  • the powder may be filled in gelatine, plastic or other capsules, cartridges or blister packs or in a reservoir.
  • a diluent or carrier chemically inert to the compounds of the invention e.g., lactose or any other additive suitable for improving the respirable fraction may be added to the powdered compounds of the invention.
  • Inhalation aerosols containing propellant gas such as hydrofluoroalkanes may contain the compounds of the invention either in solution or in dispersed form.
  • the propellant-driven formulations may also contain other ingredients such as co-solvents, stabilizers and optionally other excipients.
  • the propellant-free inhalable formulations comprising the compounds of the invention may be in form of solutions or suspensions in an aqueous, alcoholic or hydroalcoholic medium and they may be delivered by j et or ultrasonic nebulizers known from the prior art or by soft-mist nebulizers.
  • the compounds of the invention can be administered as the sole active agent or in combination with other pharmaceutical active ingredients.
  • the dosages of the compounds of the invention depend upon a variety of factors including among others the particular disease to be treated, the severity of the symptoms, the route of administration and the like.
  • the invention is also directed to a device comprising a pharmaceutical composition comprising a compound of formula (I) according to the invention, in form of a single- or multidose dry powder inhaler or a metered dose inhaler.
  • Compounds of formula (III) may be obtained by oxidation of commercially available pyridines (II) suitably substituted for further elaboration.
  • Oxidation conditions may comprise the use of 3 -chloroperbenzoic acid in a suitable solvent, such as di chloroethane and at an appropriate temperature, as for example 60 °C.
  • Compounds of formula (III) treated under nitration conditions may afford compounds (IV).
  • Typical conditions include heating compounds (III) in the presence of sulfuric acid and nitric acid at high temperature, such as 60 to 90 °C. Reduction of nitro group of compounds (IV) may lead to compounds of formula (V).
  • Such reaction may be carried out in the presence of reductive agents, as for example iron powder, in a suitable polar protic solvent, such as ethanol and at the proper temperature, as 70 °C.
  • a compound of formula (V) may first undergo demethylation followed by proper protection of the free amino group to afford compounds (VII).
  • Demethylation can be carried out under standard conditions represented using boron tribromide in a suitable apolar and aprotic solvent, such dichloromethane, as very well known to the person skilled in the art.
  • the resulting compounds of formula (VI) may be suitably protected at the amine group, as described in “Protective group in organic syntheses, 3rd ed. T. W. Greene, P. G. M. Wuts”, using for example, di-tert butyl dicarbonate in the presence of a base, such as sodium hydroxide and in an apolar solvent, as for example 1,4-di oxane, at room temperature.
  • Compounds (VII) can participate to metal -catalyzed cross coupling reaction to introduce the proper R2 group leading to compounds (VIII).
  • Cross-coupling reactions may be Suzuki coupling, as described in “Transition Metals for 15 Organic Synthesis", 2nd Ed, 1, 2004.
  • Representative Suzuki reaction conditions include reacting compound (VII) with a suitable boronic acid, in the presence of base, such as K2CO3, KF and the like, and Pd catalyst, as PdChfPPhs ⁇ DCM or PdChfPhsP in a mixture of solvents, such as 1,4 dioxane, MeCN and water, at an appropriate temperature, such as, for example, 115 °C under conventional heating or microwave irradiation.
  • base such as K2CO3, KF and the like
  • Pd catalyst as PdChfPPhs ⁇ DCM or PdChfPhsP in a mixture of solvents, such as 1,4 dioxane, MeCN and water, at an appropriate temperature, such as, for example, 115 °C under conventional heating or microwave irradiation.
  • a compound of formula (V) can first partecipate in a metal -catalyzed cross coupling reactions to afford compounds (X).
  • Such reactions may comprise Suzuki cross-coupling as described above or Stille coupling to introduce appropriate R2 groups.
  • Typical Stille coupling conditions involve the use of the proper organostannane, in the presence of a suitable catalyst such as PdChfPhsP ⁇ and a copper salt, like copper iodide, in an appropriate solvent such as DMF or toluene and at an appropriate temperature, such as, for example, 100 °C.
  • compounds (X) can undergo demethylation according to the conditions described above to lead to compounds (VIII).
  • compounds of formula (VIII) can react with a suitable halide under standard Buchwald-Hartwig amination conditions to afford compounds (IX).
  • Typical reaction conditions comprise the use of a base, such as CS2CO3 or sodium /c/V-butoxide, a suitable ligand reagent, as Xantphos, and a suitable catalyst like Pd(OAc)2 or Pd2(dba)3, in an appropriate solvent as, for example, 1,4-di oxane and at an appropriate temperature, such as, for example, 100 °C or 140 °C under conventional heating or microwave irradiation.
  • compounds of formula (I) can be obtained by carbamate ring formation enabled by treating compounds (IX) with 1,1’ -carbonyldiimidazole.
  • Representative reaction conditions include the use of an organic base, such as diisopropylethylamine, triethylamine and the like, in a polar solvent as for instance DMF and at an appropriate temperature, such as 55 °C.
  • 1 H-NMR spectra were performed on a Varian MR-400 spectrometer operating at 400 MHz (proton frequency), equipped with: a self-shielded Z-gradient coil 5 mm IH/nX broadband probe head for reverse detection, deuterium digital lock channel unit, quadrature digital detection unit with transmitter offset frequency shift, or on Agilent VNMRS-500, or on a Bruker Avance 400, or on a Bruker Avance III HD 400 MHz or on a Bruker Fourier 300 MHz; or on a Agilent Inova 600 operating at 600 MHz equipped with 5mm PFG PENTA Probe spectrometers.
  • Method A' Waters ACQUITY UPLC I-Class PLUS System with Waters SQ Detector 2 (ESIMS, capillary voltage: 3000 V, cone voltage: 40 V, de-solvation gas: 1000 L/h, de-solvation temp.: 500 °C), equipped with Acquity UPLC BEH C18 1.7 pm (2.1 x 100 mm), column no. 186002352, using 20 - 100% MeCN in water gradient with 0.1% formic acid (flow: 0.5 mL/min); analysis time: 3.0 min.
  • EIMS Waters ACQUITY UPLC I-Class PLUS System with Waters SQ Detector 2
  • Method B Shimadzu LCMS-2020 Single Quadrupole Liquid Chromatograph Mass Spectrometer, equipped with Acquity UPLC BEH - Waters, 1.7 pm C18 (2.1 x 100 mm), 130 A, column no. 186002352, using 20 - 100% ACN in water gradient with 0.1% formic acid (flow: 0.5 mL/min); analysis time: 6.0 min.
  • LC-MS may be recorded under the following conditions: diode array DAD chromatographic traces, mass chromatograms and mass spectra may be taken on UPLC/PDA/MS Acquity TM system coupled with Micromass ZQTM or Waters SQD single quadrupole mass spectrometer operated in positive and/or negative electron spray ES ionization mode and/or Fractionlynx system used in analytical mode coupled with ZQTM single quadrupole operated in positive and/or negative ES ionisation mode. Quality Control methods used operated under low pH conditions or under high pH conditions:
  • the UV detection range was 210-350 nm and ES+ZES- range was 100 to 1500 AMU.
  • LC-MS measurements may be performed on Dionex UHPLC Ultimate 3000 with DAD detector/Thermo Scientific MSQ Plus system, equipped with Kinetex® 2.6 pm XB-C18 (4.6 x 50mm), 110A, column no. 00B-4496-E0. Detection range: 190 - 350 nm ⁇ 4 nm. Flow: 1.0 mL/min. Column temperature: 25 °C. Autosampler temperature: 20 °C.
  • Example 1 was prepared following the procedure used for the synthesis of Intermediate 18, starting from Intermediate 11 (56 mg, 0.20 mmol) to afford title compound (11 mg, 0.04 mmol, 18% yield).
  • Example 2 was prepared following the procedure used for the synthesis of Intermediate 18, starting from Intermediate 12 (35 mg, 0.11 mmol) to afford title compound (6 mg, 0.02 mmol, 16% yield).
  • Example 3 was prepared following the procedure used for the synthesis of Intermediate 18, starting from Intermediate 14 (56 mg, 0.15 mmol) to afford title compound (22 mg, 0.06 mmol, 66% yield).
  • Example 4 was prepared following the procedure used for the synthesis of Intermediate 18, starting from Intermediate 16 (62 mg, 0.14 mmol) and using THF as solvent to afford title compound (12 mg, 0.03 mmol, 18% yield).
  • Example 6 was prepared followed the procedure used for the synthesis of Intermediate 18, starting from Intermediate 20 (200 mg, 0.70 mmol) to afford title compound (8.2 mg, 0.026 mmol, 4% yield).
  • Example 7 was prepared following the procedure used for the synthesis of Intermediate 18, starting from Intermediate 21 (35 mg, 0.105 mmol) to afford title compound (6.33 mg, 0.016 mmol, 17% yield).
  • Example 8 6-(5-chloro-2-fluorophenyl)-l-(quinolin-4-yl)-lH,2H-[l,3]oxazolo[5,4- c]pyridin-2-one
  • Example 8 was prepared following the procedure used for the synthesis of Intermediate 18, starting from Intermediate 22 (53 mg, 0.28 mmol) to afford title compound (25.5 mg, 0.064 mmol, 23% yield).
  • Example 9 was prepared following the procedure used for the synthesis of Intermediate 18, starting from Intermediate 23 (28 mg, 0.089 mmol) to afford title compound (6.4 mg, 0.019 mmol, 21% yield).
  • Example Cl was prepared following the procedure used for the synthesis of Intermediate 18, starting from Intermediate 24 (48 mg, 0.15 mmol). The residue was purified by flash chromatography on Biotage silica cartridge (gradient of elution from 0 to 30% of EtOAc in cHex) to afford title compound (22 mg, 0.06 mmol, 42% yield). LC-MS (ESI): m/z (M+l): 342.1 (Method 1).
  • Example C2 l-(5-aminopyridin-3-yl)-6-(5-chloro-2-fluorophenyl)-lH,2H-
  • Example C2 was prepared following the procedure used for the synthesis of Example 5, starting from Intermediate 26 (42 mg, 0.11 mmol) to afford title compound (13 mg, 0.04 mmol, 33% yield).
  • 'H NMR 400 MHz, Chloroform-d 5 ppm 8.67-8.70 (m, 1H), 8.20-8.27 (m, 2H), 7.98-8.04 (m, 1H), 7.59-7.63 (m, 1H), 7.33-7.41 (m, 1H), 7.20-7.25 (m, 1H), 7.08-7.16 (m, 1H), 3.96-4.11 (m, 2H).
  • the enzymatic activity of compounds of the present invention was monitored measuring the formation of ADP using the ADP-GLO Kinases assay. Following the incubation of the purified enzyme, a substrate and ATP, the produced ADP was converted into ATP, which in turn was converted into light by Ultra-Gio Luciferase. The luminescent signal positively correlated with ADP amount and kinase activity.
  • the kinase reaction was performed by incubating 2.6nM of the purified, commercially available human ALK5 (recombinant TGF pi N-term GST-tagged, 80-end), a final concentration of TGFpi peptide 94.5pM (Promega, T36-58) and ultra-pure ATP (Promega V915B).
  • the ATP concentration was set at the Km value (concentration of substrate which permits the enzyme to achieve half maximal velocity (Vmax)) of ALK5 (0.5pM).
  • Compound and ALK5 kinase were mixed and incubated for 15 mins. Reactions were initiated by addition of ATP at a final concentration in the assay of 0.83 pM.
  • the compounds of the present invention as shown in Table 3, have a pki higher than 7.5 whereas comparative examples Cl and C2 have a pki lower than 5.5.

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Abstract

La présente invention concerne de manière générale des composés de formule (I) inhibant le récepteur de type I du facteur de croissance transformant β (TGF bêta) (ALK5) (ci-après inhibiteurs d'ALK5), des procédés de préparation de tels composés, des compositions pharmaceutiques les contenant et leur utilisation thérapeutique; les composés de l'invention peuvent être utiles par exemple dans le traitement de maladies, de troubles ou d'états nombreux associés à la voie de signalisation ALK5.
PCT/EP2023/081822 2022-11-16 2023-11-15 Dérivés de pyrido oxazolidinone utilisés en tant qu'inhibiteurs d'alk5 WO2024105070A1 (fr)

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