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WO2023248010A2 - Modulateurs ciblés de jak3 pour le traitement de maladies inflammatoires et auto-immunes - Google Patents

Modulateurs ciblés de jak3 pour le traitement de maladies inflammatoires et auto-immunes Download PDF

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WO2023248010A2
WO2023248010A2 PCT/IB2023/000382 IB2023000382W WO2023248010A2 WO 2023248010 A2 WO2023248010 A2 WO 2023248010A2 IB 2023000382 W IB2023000382 W IB 2023000382W WO 2023248010 A2 WO2023248010 A2 WO 2023248010A2
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nmr
mhz
carbocyclyl
aliphatic
compound
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WO2023248010A3 (fr
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Julian LAUX
Jan-Hinrich Guse
Stefan Laufer
Michael W. BURNET
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Synovo GmbH
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Synovo GmbH
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/12—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains three hetero rings
    • C07D471/14—Ortho-condensed systems
    • 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
    • A61P37/02—Immunomodulators

Definitions

  • Targeted modulators of JAK3 for treatment of inflammatory and autoimmune diseases Targeted modulators of JAK3 for treatment of inflammatory and autoimmune diseases
  • Inhibitors of Janus kinases are efficient treatments of autoimmune diseases. However, they are associated with idiosyncratic side-effects such as venous thromboembolism (VTE), major adverse cardiovascular events (MACE), and malignancy. Malignancy may be a mechanismbased side effect due to reduced immune surveillance due to the central mode of action of JAK inhibitors on T-cells. To date, these effects seem to be associated with the JAK1 activity of clinical substances, although the exact cause is unknown.
  • VTE venous thromboembolism
  • MACE major adverse cardiovascular events
  • malignancy may be a mechanismbased side effect due to reduced immune surveillance due to the central mode of action of JAK inhibitors on T-cells. To date, these effects seem to be associated with the JAK1 activity of clinical substances, although the exact cause is unknown.
  • Clinical JAK1 inhibitors have a very low dose in use which we attribute to the requirement not to inhibit mecanical JAK signaling", specifically via the IL-10 receptor which signals through JAK1 (Fig. 1).
  • JAK1 is required for the signaling of a range of "pro-inflammatory" cytokines (e.g. IL-6, IL-12, IFNy, IL-2) and the primary mode of action is considered to be modulation of these signals.
  • JAK3 inhibitors based on Michael acceptor cyano-derivatives of dihydroimidazo pyrrolo pyridines that are selective JAK3 inhibitors which are stabilized for systemic use in vivo and which are targeted toward immune cells, notably myeloid cells through the optimization of physical properties and conjugation to macrolide carriers.
  • R1 a substituted macrolide, attached directly or by a linker
  • R1 any residue suitable to target a specific function in an organism, may it be naturally occurring or artificially introduced, containing, for example, but not being limited to bicyclononin or dibenzocylooctin residues.
  • R1 is as defined above
  • R2 any residue, my it be the same or an other as Rl, suitable to target a specific function in an organism, may it be naturally occurring or artificially introduced;
  • Rl and R2 are connected to form a carbocycle or a heterocycle containing at least one of the atoms O, N, or S, of 3 - 10 atoms, saturated or unsaturated, and optionally substituted with 0 - 6 substituents of the list O-R4, N(R4Rs), S-R4, R4, N3, F, Cl, Br, I, macrolide
  • R6 H or oc-cladinosyl
  • R7, R8 alternatively trans-O-R9, trans referring to the glycosidic bond at the anomeric center, and cis-N(R9R10), cis referring to the glycosidic bond at the anomeric center
  • R9 H or CH3 or Linker
  • R10 CH3 or Linker a compound wherein
  • R1 linker-macrolide
  • FIG. 1 depicts JAK1, 2, 3, and TYK2 signaling receptors, and shows the role of JAK1 in IL-10 signaling (see highlight, adapted from h ftps armrey.a .org/content/Jg/g S Bharadwaj, et al., Pharmacological Reviews April 2020, 72 (2) 486-526).
  • FIG. 2 shows effects of substances on TNFoc and IL-10 production in human buffy coat derived PBMNCs.
  • FIG. 5 shows effects of substances on progression of body weight and clinical score in DSS induced colitis. Increased weight is indicative of improved recovery. Reduced score, likewise indicates positive treatment effects. Legend order reflects the effect of the treatment.
  • FIG. 6 shows effects of compound 52 on body weight and score in mice with progressive EAE.
  • Compound 52 was applied only after onset of signs.
  • the normal mode of action of JAK inhibitors is to prevent proliferation of pathological T-cells.
  • the chemicals used may include, for example, solvents, reagents, catalysts, protecting group and deprotecting group reagents and the like.
  • the methods described may also additionally comprise steps, either before or after the steps described specifically herein, to add or remove suitable protecting groups in order to ultimately allow synthesis of the compound of the formulae described herein.
  • these compounds are suitable for use as medicaments and in particular for the treatment of degenerative diseases of the brain such as Alzheimer's disease.
  • the compound of the invention is administered to the subject using a pharmaceutically-acceptable formulation, e.g., a pharmaceutically-acceptable formulation that provides sustained delivery of the compound of the invention to a subject for at least 12 hours, 24 hours, 36 hours, 48 hours, one week, two weeks, three weeks, or four weeks after the pharmaceutically-acceptable formulation is administered to the subject.
  • these pharmaceutical compositions are suitable for topical or oral administration to a subject.
  • the pharmaceutical compositions of the present invention may be specially formulated for administration in solid or liquid form, including those adapted for the following: (1) oral administration, for example, drenches (aqueous or non-aqueous solutions or suspensions), tablets, boluses, powders, granules, pastes; (2) parenteral administration, for example, by subcutaneous, intramuscular or intravenous injection as, for example, a sterile solution or suspension; (3) topical application, for example, as a cream, ointment or spray applied to the skin; (4) intravaginally or intrarectally, for example, as a pessary, cream or foam; or (5) aerosol, for example, as an aqueous aerosol, liposomal preparation or solid particles containing the compound.
  • phrases "pharmaceutically acceptable” refers to those compound of the inventions of the present invention, compositions containing such compounds, and/or dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit/risk ratio.
  • pharmaceutically acceptable salts or “pharmaceutically acceptable carrier” is meant to include salts of the active compounds which are prepared with relatively nontoxic acids or bases, depending on the particular substituents found on the compounds described herein.
  • base addition salts can be obtained by contacting the neutral form of such compounds with a sufficient amount of the desired base, either neat or in a suitable inert solvent.
  • pharmaceutically acceptable base addition salts include sodium, potassium, calcium, ammonium, organic amino, or magnesium salt, or a similar salt.
  • acid addition salts can be obtained by contacting the neutral form of such compounds with a sufficient amount of the desired acid, either neat or in a suitable inert solvent.
  • Examples of pharmaceutically acceptable acid addition salts include those derived from inorganic acids like hydrochloric, hydrobromic, nitric, carbonic, monohydrogencarbonic, phosphoric, monohydrogenphosphoric, dihydrogenphosphoric, sulfuric, monohydrogensulfuric, hydroiodic, or phosphorous acids and the like, as well as the salts derived from relatively nontoxic organic acids like acetic, propionic, isobutyric, maleic, malonic, benzoic, succinic, suberic, fumaric, lactic, mandelic, phthalic, benzenesulfonic, p-tolylsulfonic, citric, tartaric, methanesulfonic, and the like.
  • inorganic acids like hydrochloric, hydrobromic, nitric, carbonic, monohydrogencarbonic, phosphoric, monohydrogenphosphoric, dihydrogenphosphoric, sulfuric, monohydrogensulfuric, hydroiodic, or phosphorous acids and the like
  • salts of amino acids such as arginate and the like, and salts of organic acids like glucuronic or galactunoric acids and the like (see, e.g., Berge et al., Journal of Pharmaceutical Science 66:1-19 (1977)).
  • Certain specific compounds of the present invention contain both basic and acidic functionalities that allow the compounds to be converted into either base or acid addition salts.
  • Other pharmaceutically acceptable carriers known to those of skill in the art are suitable for the present invention.
  • substances which can serve as pharmaceutical carriers are sugars, such as lactose, glucose and sucrose; starches such as corn starch and potato starch; cellulose and its derivatives such as sodium carboxymethycellulose, ethylcellulose and cellulose acetates; powdered tragancanth; malt; gelatin; talc; stearic acids; magnesium stearate; calcium sulfate; vegetable oils, such as peanut oils, cotton seed oil, sesame oil, olive oil, corn oil and oil of theobroma; polyols such as propylene glycol, glycerine, sorbitol, manitol, and polyethylene glycol; agar; alginic acids; pyrogen-free water; isotonic saline; and phosphate buffer solution; skim milk powder; as well as other non-toxic compatible substances used in pharmaceutical formulations such as Vitamin C, estrogen and echinacea, for example.
  • sugars such as lactose, glucose and sucrose
  • wetting agents and lubricants such as sodium lauryl sulfate, as well as coloring agents, flavoring agents, lubricants, excipients, tableting agents, stabilizers, anti-oxidants and preservatives, can also be present.
  • Solubilizing agents including for example, cremaphore and beta-cyclodextrins can also be used in the pharmaceutical compositions herein.
  • the neutral forms of the compounds may be regenerated by contacting the salt with a base or acid and isolating the parent compound in the conventional manner.
  • the parent form of the compound differs from the various salt forms in certain physical properties, such as solubility in polar solvents, but otherwise the salts are equivalent to the parent form of the compound for the purposes of the present invention.
  • Initial dosages also can be estimated from in vivo data, such as animal models. Animal models useful for testing the efficacy of compounds to treat or prevent the various diseases described above are well-known in the art.
  • Dosage amounts will typically be in the range of from about 0.0001 or 0.001 or 0.01 mg/kg/day to about 100 mg/kg/day, but can be higher or lower, depending upon, among other factors, the activity of the compound, its bioavailability, the mode of administration, and various factors discussed above. Dosage amount and interval can be adjusted individually to provide plasma levels of the compound(s) which are sufficient to maintain therapeutic or prophylactic effect. In cases of local administration or selective uptake, such as local topical administration, the effective local concentration of active compound(s) cannot be related to plasma concentration. Skilled artisans will be able to optimize effective local dosages without undue experimentation.
  • the compound(s) can be administered once per day, a few or several times per day, or even multiple times per day, depending upon, among other things, the indication being treated and the judgment of the prescribing physician.
  • the compound(s) will provide therapeutic or prophylactic benefit without causing substantial toxicity. Toxicity of the compound(s) can be determined using standard pharmaceutical procedures. The dose ratio between toxic and therapeutic (or prophylactic) effect is the therapeutic index. Compounds(s) that exhibit high therapeutic indices are preferred.
  • the recitation of a listing of chemical groups in any definition of a variable herein includes definitions of that variable as any single group or combination of listed groups.
  • the recitation of an embodiment for a variable herein includes that embodiment as any single embodiment or in combination with any other embodiments or portions thereof.
  • the recitation of an embodiment herein includes that embodiment as any single embodiment or in combination with any other embodiments or portions thereof.
  • Another object of the present invention is the use of a compound as described herein (e.g., of any formulae herein) in the manufacture of a medicament for use in the treatment of a disorder or disease herein.
  • Another object of the present invention is the use of a compound as described herein (e.g., of any formulae herein) for use in the treatment of a disorder or disease herein.
  • Many compounds of this invention have one or more double bonds, or one or more asymmetric centers. Such compounds can occur as racemates, racemic mixtures, single enantiomers, individual diastereomers, diastereomeric mixtures, and cis- or trans- or E- or Z- double isomeric forms.
  • stable refers to compounds which possess stability sufficient to allow manufacture and which maintains the integrity of the compound for a sufficient period of time to be useful for the purposes detailed herein (e.g., treating a disease).
  • suitable for click reaction refers to a moiety such as an azide group or an alkyne group, that is activated such that the reaction with an azide group to form a triazole ring occurs below 40°C without copper catalysis.
  • This includes, but is not limited to the bicyclo[6,l,0]non-4-in-9-yl (BCN) group or the Dibenzoazacyclooctin (DBCO) group.
  • Preparative column chromatography was either performed manually with glass columns and ACROS OrganicsTM 60-200 pm silica or by using an Interchim PuriFlash 5.020 automated flash chromatography system with pre-packed Interchim columns containing either 15 pm or 50 pm silica. Gradients for flash chromatography were calculated automatically via the accompanying "TLC to Flash and Prep Chromatography" software. TLC was performed using Merck TLC Silica gel 60 F254 plates. For detection, we used UV light at 254 nm or cerium molybdate staining solution.
  • the purity and tret of intermediates and final compounds were determined on a Varian ProStar210 system coupled with a SEDEX LT-ELSD 80 LT and using a Dr. Maisch ReproSil-Purl20 C18-Aq column (75 x 3 mm, 5 pm).
  • the mobile phase was composed of water containing 0.05 % formic acid (eluent A) and methanol containing 0.05 % formic acid (eluent B).
  • Example 3 N-cyclohexyl-5-nitro-l-tosyl-lH-pyrrolo[2,3-b]pyridin-4-amine: Obtained from 5.03 g of example 2 and 2.06 ml of cyclohexylamine following general procedure A with a reaction time of 1 h. No further purification needed after filtration and wash. Yield: 5.65 g (95 %) of example 3 as a red solid.
  • Example 4 5-nitro-N-(tetrahydro-2H-pyran-4-yl)-l-tosyl-lH-pyrrolo[2,3-b]pyridin-4-amine Obtained from 13.0 g of example 2 and 4.78 ml 4-aminotetrahydropyran following general procedure A with a reaction time of 2 h. No further purification needed after filtration and wash. Yield: 14.57 g (95 %) of example 4 as a bright yellow solid.
  • Example 5 N-(l-methylpiperidin-4-yl)-5-nitro-l-tosyl-lH-pyrrolo[2,3-b]pyridin-4-amine: Obtained from 8.35 g of example 2 and 3.58 ml of l-methylpiperidin-4-amine following general procedure A with a reaction time of 2 h. No further purification was needed after filtration and wash. Yield: 8.9 g (87 %) of example 5 as a yellow solid.
  • Example 6 N-(cyclopropylmethyl)-5-nitro-l-tosyl-lH-pyrrolo[2,3-b]pyridin-4-amine Obtained from 8.14 g of example 2 and 2.48 ml of cyclopropylmethanamine following general procedure A with a reaction time of 1 h. No further purification needed after filtration and wash. Yield: 8.35 g (93 %) as yellow solid.
  • Example 7 N-(4,4-difluorocyclohexyl)-5-nitro-l-tosyl-lH-pyrrolo[2,3-b]pyridin-4-amine Obtained from 1.95 g of example 2 and 1.0 g of 4,4-Difluorocyclohexylamine (1.05 equiv) following general procedure A with a reaction time of 3 h. No further purification needed after filtration and wash. Yield: 2.18 g (87 %) as yellow solid.
  • Example 8 N-cyclopropyl-5-nitro-l-tosyl-lH-pyrrolo[2,3-b]pyridin-4-amine-. Obtained from 2.03 g of example 2 and 501 pl of cyclopropylamine following general procedure A with a reaction time of 1.5 h. No further purification needed after filtration and wash. Yield: 1.83 g (85 %) as yellow solid.
  • Example 9 5-nitro-N-phenyl-l-tosyl-lH-pyrrolo[2,3-b]pyridin-4-amine Obtained from 5.17 g of example 2 and 5.5 ml of Aniline (4.1 equiv) following general procedure A with a reaction time of 1 h. After filtration and wash, the crude product was suspended in a small amount of EtzO and stored at -20 °C for 1 h, after which the red supernatant was discarded. The orange solid was dried in vacuo to yield 5.32 g (88 %) of the tile compound.
  • Example 86 N-((lR,5S,6r)-bicyclo[3.1.0]hexan-6-yl)-5-nitro-l-tosyl-lH-pyrrolo[2,3-b]pyridin- 4-amine: Obtained from 5.76 g of example 2 and 1,59 g of bicyclo[3.1.0]hexan-6-amine following general procedure A with a reaction time of 30 min. After filtration and wash, the crude product was subjected to flash chromatography (cyclohexane/acetone, automatic gradient). Two fractions were collected, the larger of which was identified as the isomerically pure trans product by x-ray crystallography. Yield: 5.0 g (75 %) as yellow crystals.
  • H2 was refilled. Leftover H2 was removed from the closed reaction flask by purge with argon and solids were filtrated over a Celite pad. The pad was washed with EtOAc and the filtrate evaporated under reduced pressure to yield the product as a solid. No further purification steps were necessary.
  • Example 10 N4-cyclohexyl-l-tosyl-lH-pyrrolo[2,3-b]pyridine-4,5-diamine: Obtained from 5.65 g of example 3 following general procedure B. Yield: 5.24 g (quant.) of example 10 as a purple foam.
  • Example 11 N4-(tetrahydro-2H-pyran-4-yl)-l-tosyl-lH-pyrrolo[2,3-b]pyridine-4,5-diamine Obtained from 14.1 g of example 4 following general procedure B. Yield: 13.08 g (quant.) of example 11 as lilac foam.
  • Example 12 N4-(l-methylpiperidin-4-yl)-l-tosyl-lH-pyrrolo[2,3-b]pyridine-4,5-diamine Obtained from 8.85 g of example 5 following general procedure B. Yield: 8.07 g (98 %) of example 12 as a pink to lilac foam.
  • Example 13 N4-(cyclopropylmethyl)-l-tosyl-lH-pyrrolo[2,3-b]pyridine-4,5-diamine Obtained from 8.35 g of example 6 following general procedure B. Yield: 7.56 g (98 %) as dark yellow foam.
  • Example 14 N4-(4,4-difluorocyclohexyl)-l-tosyl-lH-pyrrolo[2,3-b]pyridine-4,5-diamine Obtained from 3.43 g of example 7 following general procedure B. Due to impurities, most likely from the educt, purification by flash chromatography (cyclohexane/acetone, automatic gradient) was performed after the filtration step. Yield: 2.51 g (78 %) as greyish foam.
  • Example 15 N4-cyclopropyl-l-tosyl-lH-pyrrolo[2,3-b]pyridine-4,5-diamine Obtained from 1.65 g of example 8 following general procedure B. Yield: 1.51 g (100 %) as pale pink solid.
  • Example 87 N4-((lR,5S,6r)-bicyclo[3.1.0]hexan-6-yl)-l-tosyl-lH-pyrrolo[2,3-b]pyridine-4,5- diamine: Obtained from 3.7 g of example 86 following general procedure B. Yield: 3.36 g (98 %) as a solid.
  • Example 16 N4-phenyl-l-tosyl-lH-pyrrolo[2,3-b]pyridine-4,5-diamine Obtained from 5.32 g of example 9 following procedure C with stirring overnight. No further purification. Yield: 4.8 g (98 %).
  • Example 17 (5-(l-cyclohexyl-6-tosyl-l,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-2- yl)furan-2-yl)methanol: Obtained from 4.97 g of example 10 following general procedure. Flash chromatography with DCM/MeOH (automatic gradient). Yield: 5.21 g (82 %) as a light brown powder.
  • Example 18 (5-(l-(tetrahydro-2H-pyran-4-yl)-6-tosyl-l,6-dihydroimidazo[4,5-d]pyrrolo[2,3- b]pyridin-2-yl)furan-2-yl)methanol: Obtained from 14.0 g of example 11 using general procedure D. Manual column chromatography with DCM DCM/EtOAc 1:2. Yield: 7.56 g (42 %) of example 18 as yellow to white solid.
  • Example 19 (5-(l-(l-methylpiperidin-4-yl)-6-tosyl-l,6-dihydroimidazo[4,5-d]pyrrolo[2,3- b]pyridin-2-yl)furan-2-yl)methanol Obtained from 6 g of example 12 following general procedure D. MS spectra taken from reaction control samples showed an m/z of 522, suggesting N-oxidation of the methylpiperidine due to KHSO5. Before workup, the mixture was treated with 15 ml of a solution of TiCH (12 %) in HCI. After 2 h of stirring at ambient temperature, MS showed no remainder of the 522 m/z peak.
  • Example 20 (5-(l-(cyclopropylmethyl)-6-tosyl-l,6-dihydroimidazo[4,5-d]pyrrolo[2,3- b]pyridin-2-yl)furan-2-yl)methanol Obtained from 7.56 g of example 14 following general procedure D. No further purification. Yield: 8.38 g (85 %) as brown solid.
  • Example 21 (5-(l-(4,4-difluorocyclohexyl)-6-tosyl-l,6-dihydroimidazo[4,5-d]pyrrolo[2,3- b]pyridin-2-yl)furan-2-yl)methanol: Obtained from 2.4 g of example 14 following general procedure D. Flash chromatography (cyclohexane/acetone, automatic gradient). Yield: 2.05 g (68 %) as brown foam.
  • Example 22 (5-(l-cyclopropyl-6-tosyl-l,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-2- yl)furan-2-yl)methanol: Obtained from 1.45 g of example 15 following general procedure D. Flash chromatography (cyclohexane/acetone, automatic gradient). Yield: 1.11 g (54 %) as brown solid.
  • Example 23 (5-(l-phenyl-6-tosyl-l,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-2-yl)furan-2- yl)methanol: Obtained from 4.35 g of example 16 following general procedure D. Flash chromatography (cyclohexane/acetone, automatic gradient). Yield: 3.38 g (61 %) as brown solid.
  • Example 88 (5-(l-((lR,5S,6r)-bicyclo[3.1.0]hexan-6-yl)-6-tosyl-l,6-dihydroimidazo[4,5- d]pyrrolo[2,3-b]pyridin-2-yl)furan-2-yl)methanol: Obtained from 3.3 g of example 87 following general procedure D. Flash chromatography (cyclohexane/acetone, automatic gradient). Yield: 2.29 g (54 %) as brown solid.
  • Example 24 5-(l-cyclohexyl-6-tosyl-l,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-2- yl)furan-2-carbaldehyde Obtained from 5.2 g example 17 following general procedure E with a reaction time of 3 h. Flash chromatography with cyclohexane/acetone (automatic gradient). Yield: 3.73 g (72 %) of example 24 as a brown solid.
  • Example 25 5-(l-(tetrahydro-2H-pyran-4-yl)-6-tosyl-l,6-dihydroimidazo[4,5-d]pyrrolo[2,3- b]pyridin-2-yl)furan-2-carbaldehyde: Obtained from 2.02 g of example 18 following general procedure E with stirring overnight. After workup, the product was carried on to the next step without further purification. Yield: 1.9 g (90 %) of crude example 25 as an orange solid.
  • Example 26 5-(l-(l-methylpiperidin-4-yl)-6-tosyl-l,6-dihydroimidazo[4,5-d]pyrrolo[2,3- b]pyridin-2-yl)furan-2-carbaldehyde Obtained from 1.34 g of example 19 following general procedure E with stirring overnight. Manual column chromatography (EtOAc EtOAc/MeOH 9:1). Yield: 935 mg (70 %) as yellow powder.
  • Example 27 5-(l-(cyclopropylmethyl)-6-tosyl-l,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin- 2-yl)furan-2-carbaldehyde Obtained from 5.18 g of example 20 following general procedure E with stirring overnight. Flash chromatography (cyclohexane/acetone, automatic gradient). Yield: 4.33 g (80 %) as yellow solid.
  • Example 29 5-(l-cyclopropyl-6-tosyl-l,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-2- yl)furan-2-carbaldehyde: Obtained from 1.02 g of example 22 following general procedure E with overnight stirring. Flash chromatography (cyclohexane/acetone, automatic gradient). Yield: 800 mg (79 %) as pale brown solid.
  • Example 30 5-(l-phenyl-6-tosyl-l,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-2-yl)furan-2- carbaldehyde: Obtained from 1.75 g of example 23 following general procedure E with a reaction time of 3 h. Flash chromatography (cyclohexane/acetone, automatic gradient). Yield: 1.35 g (78 %) as brown solid.
  • Example 89 5-(l-((lR,5S,6r)-bicyclo[3.1.0]hexan-6-yl)-6-tosyl-l,6-dihydroimidazo[4,5- d]pyrrolo[2,3-b]pyridin-2-yl)furan-2-carbaldehyde: Obtained from 1.35 g of example 88 following general procedure E. Flash chromatography (cyclohexane/acetone, automatic gradient). Yield: 1.3 g (96 %) as a solid.
  • the aldehyde from the previous step was dissolved or suspended in a 1 M solution of KOH in MeOH.
  • the mixture was stirred at ambient temperature. After indication of complete consumption of educt by TLC and/or MS, saturated NH4CI solution was added to quench.
  • the mixture was transferred to a separatory funnel and EtOAc and water were added until clear, separate phases appeared.
  • the organic phase was washed two to three times with water and subsequently brine, dried over Na2SO4 and reduced in vacuo. Purification of this residue, if necessary, was carried out either by manual column chromatography or flash chromatography.
  • Example 31 5-(l-cyclohexyl-l, 6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-2-yl)furan-2- carbaldehyde: Obtained from 3.63 g of example 24 following general procedure F with a reaction time of 45 min. Flash chromatography with cyclohexane/acetone (automatic gradient). Yield: 988 mg (40 %) of example 31 as an orange solid.
  • Example 32 5-(l-(tetrahydro-2H-pyran-4-yl)-l,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin- 2-yl)furan-2-carbaldehyde: Obtained from 1.75 g of example 25 following general procedure F with a reaction time of 1 h. No further purification after workup with water/EtOAc. Yield: 1.04 g (83 %) as an orange powder.
  • Example 33 5-(l-(l-methylpiperidin-4-yl)-l,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-2- yl)furan-2-carbaldehyde: Obtained from 890 mg of example 26 following general procedure F with a reaction time of 1 h. No further purification after workup with water/EtOAc. Yield: 395 mg (64 %) as yellow powder.
  • Example 34 5-(l-(cyclopropylmethyl)-l,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-2- yl)furan-2-carbaldehyde: Obtained from 3.3 g of example 27 following general procedure F. Since TLC and MS indicated slow conversion of product to side products, the reaction was quenched after 20 minutes. Flash chromatography (cyclohexane/acetone, automatic gradient). Yield: 618 mg (28 %) as orange solid.
  • Example 35 5-(l-(4,4-difluorocyclohexyl)-l,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-2- yl)furan-2-carbaldehyde: Obtained from 300 mg of example 28 following general procedure F with a reaction time of 2 h. No further purification after workup with water/EtOAc. Yield: 187 mg (88 %) as solid.
  • Example 36 5-(l-cyclopropyl-l,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-2-yl)furan-2- carbaldehyde: Obtained from 700 mg of example 29 following general procedure F with a reaction time of 1.5 h. Flash chromatography (cyclohexane/acetone, automatic gradient). Yield: 133 mg (30 %) as orange solid.
  • Example 37 5-(l-phenyl-l,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-2-yl)furan-2- carbaldehyde: Obtained from 1.1 g of example 30 following general procedure F with a reaction time of 4 h. No further purification after workup with water/EtOAc. Yield: 310 mg (41 %) as yellow solid.
  • Example 90 5-(l-((lR,5S,6r)-bicyclo[3.1.0]hexan-6-yl)-l,6-dihydroimidazo[4,5-d]pyrrolo[2,3- b]pyridin-2-yl)furan-2-carbaldehyde: Obtained from 650 mg of example 89 following general procedure F, substitution KOH with CS2CO3, with a reaction time of 4 h. After extractive workup, HPLC indicated sufficient purity and the product was carried on to the next step without further purification. Yield: 342 mg (77 %) as an orange solid.
  • Example 38 (E)-2-cyano-3-(5-(l-cyclohexyl-l,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-2- yl)furan-2-yl)-N,N-dimethylacrylamide Obtained from 620 mg of example 31 and 229 mg of 2-cyano-N,N-dimethylacetamide (1.1 equiv) in 10 ml of MeOH following general procedure G at 60 °C oil-bath temperature. TLC and MS showed complete conversion of educts after 30 min. The mixture was stored at -20 °C overnight and the resulting precipitate collected by filtration and washed sparingly with cold MeOH. No further purification was necessary.
  • Example 39 (E)-2-cyano-N,N-dimethyl-3-(5-(l-(tetrahydro-2H-pyran-4-yl)-l,6- dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-2-yl)furan-2-yl)acrylamide Obtained from 680 mg of example 32 and 249 mg of 2-cyano-N,N-dimethylacetamide (1.1 equiv) in 10 ml MeOH following general procedure G at 60 °C oil bath temperature. TLC and MS indicated full conversion of educts after 2 h. The mixture was stored at -20 °C overnight and the resulting precipitate collected by filtration and washed sparingly with cold MeOH.
  • Example 40 methyl (E)-N-(2-cyano-3-(5-(l-cyclohexyl-l,6-dihydroimidazo[4,5-d]pyrrolo[2,3- b]pyridin-2-yl)furan-2-yl)acryloyl)-N-methylglycinate Obtained from 700 mg of example 31 and 425 mg of example 41 (1.2 equiv) in 11 ml MeOH following general procedure G at 60 °C oil bath temperature. TLC and MS indicated consumption of educts after 2 h. The solvents were evaporated under reduced pressure and the crude product was purified by column chromatography (EtOAc EtOAc/MeOH 9:1). Yield: 470 mg (46 %) as red solid.
  • Example 42 methyl (E)-N-(2-cyano-3-(5-(l-(tetrahydro-2H-pyran-4-yl)-l,6- dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-2-yl)furan-2-yl)acryloyl)-N-methylglycinate Obtained from 980 mg of example 32 and 595 mg of example 41 (1.2 equiv) in 14 ml MeOH following general procedure G at 60 °C oil bath temperature. Full consumption of starting material was observed after 3 h. The mixture was stored at -20 °C overnight and the resulting precipitate was filtrated and washed sparingly with cold MeOH. No further purification was necessary.
  • Example 43 (E)-2-cyano-3-(5-(l-cyclohexyl-l,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-2- yl)furan-2-yl)-N-(2-(dimethylamino)ethyl)-N-methylacrylamide Obtained from 1.0 g of example 31 and 506 mg of example 44 (1.0 equiv) in 15 ml MeOH following general procedure G at 60 °C oil bath temperature. Full consumption of educts was observed after 1 h. Manual column chromatography (EtOAc EtOAc/MeOH 6:1), during which part of product was lost due to beaker malfunction.
  • Example 45 (E)-2-cyano-N-(2-(dimethylamino)ethyl)-N-methyl-3-(5-(l-(tetrahydro-2H-pyran- 4-yl)-l,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-2-yl)furan-2-yl)acrylamide Obtained from 105 mg of example 32 and 52.5 mg of example 44 (1.0 equiv) in 1.5 ml MeOH following general procedure G at 60 °C oil bath temperature with a reaction time of 1 h. The mixture was stored at -20 °C overnight and the precipitate was collected by filtration and washed sparingly with cold MeOH. No further purification was necessary.
  • Example 46 (E)-2-cyano-3-(5-(l-cyclohexyl-l,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-2- yl)furan-2-yl)-N-(2-(((2S,3R,6R)-2-(((2R,3S,4R,5R,8R,10R,llR,12S,13S,14R)-2-ethyl-3,4,10- trihydroxy-13-(((2R,4R,5S,6S)-5-hydroxy-4-methoxy-4,6-dimethyltetrahydro-2H-pyran-2- yl)oxy)-3,5,6,8,10,12,14-heptamethyl-15-oxo-l-oxa-6-azacyclopentadecan-ll-yl)oxy)-3- hydroxy-6-methyltetrahydro-2H-pyran-4-yl)(methyl)amino)eth
  • Example 48 (E)-2-cyano-N-(2-(((2S,3R,6R)-2-(((2R,3S,4R,5R,8R,10R,llR,12S,13S,14R)-2-ethyl- 3,4,10-trihydroxy-13-(((2R,4R,5S,6S)-5-hydroxy-4-methoxy-4,6-dimethyltetrahydro-2H-pyran- 2-yl)oxy)-3,5,6,8,10,12,14-heptamethyl-15-oxo-l-oxa-6-azacyclopentadecan-ll-yl)oxy)-3- hydroxy-6-methyltetrahydro-2H-pyran-4-yl)(methyl)amino)ethyl)-N-methyl-3-(5-(l- (tetrahydro-2H-pyran-4-yl)-l,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]
  • Example 49 (E)-2-cyano-N,N-dimethyl-3-(5-(l-(l-methylpiperidin-4-yl)-l,6- dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-2-yl)furan-2-yl)acrylamide Obtained from 83 mg of example 33 and 29 mg 2-cyano-N,N-dimethylacetamide (1.1 equiv) in 1 ml MeOH following general procedure G at 60 °C oil bath temperature with a reaction time of 1 h. Purification by storage at -20 °C overnight and subsequent filtration of precipitate and washing with cold MeOH. Yield: 70 mg (66 %) as an orange solid.
  • Example 50 (E)-2-cyano-N-(2-(((2S,3R,6R)-2-(((2R,3S,4R,5R,8R,10R,HR,12S,13S,14R)-2-ethyl- 3,4,10-trihydroxy-13-(((2R,4R,5S,6S)-5-hydroxy-4-methoxy-4,6-dimethyltetrahydro-2H-pyran- 2-yl)oxy)-3,5,6,8,10,12,14-heptamethyl-15-oxo-l-oxa-6-azacyclopentadecan-ll-yl)oxy)-3- hydroxy-6-methyltetrahydro-2H-pyran-4-yl)(methyl)amino)ethyl)-N-methyl-3-(5-(l-(l- methylpiperidin-4-yl)-l,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-2
  • Example 51 (E)-2-cyano-N-(2-(dimethylamino)ethyl)-N-methyl-3-(5-(l-(l-methylpiperidin-4- yl)-l,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-2-yl)furan-2-yl)acrylamide Obtained from 78 mg of example 33 and 38 mg of example 44 (1.0 equiv) in 1 ml MeOH following general procedure G at 60 °C oil bath temperature with a reaction time of 1 h. Flash chromatography (EtOAc/MeOH, automatic gradient). Yield: 35 mg (32 %) as red solid.
  • Example 52 methyl (E)-N-(2-cyano-3-(5-(l-(l-methylpiperidin-4-yl)-l,6-dihydroimidazo[4,5- d]pyrrolo[2,3-b]pyridin-2-yl)furan-2-yl)acryloyl)-N-methylglycinate Obtained from 225 mg of example 33 and 110 mg of example 41 in 2.3 ml MeOH following general procedure G at 60 °C oil bath temperature with a reaction time of 2 h. Purification by storage at -20 °C overnight and subsequent filtration of precipitate and washing with cold MeOH. Yield: 177 mg (55 %) as red solid.
  • Example 53 (E)-2-(morpholine-4-carbonyl)-3-(5-(l-(tetrahydro-2H-pyran-4-yl)-l,6- dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-2-yl)furan-2-yl)acrylonitrile Obtained from 105 mg of example 32 and 49 mg of N-cyanoacetylmorpholine (1.0 equiv) in 1 ml MeOH following general procedure G at ambient temperature overnight. P Purification by storage at -20 °C overnight and subsequent filtration of precipitate and washing with cold MeOH. Yield: 109 mg (74 %) as orange solid.
  • Example 54 (E)-2-(4-methylpiperazine-l-carbonyl)-3-(5-(l-(tetrahydro-2H-pyran-4-yl)-l,6- dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-2-yl)furan-2-yl)acrylonitrile Obtained from 84 mg of example 32 and 44 mg of example 55 in 1 ml MeOH following general procedure G at 60 °C oil bath temperature with a reaction time of 7 h. Purification by storage at -20 °C overnight and subsequent filtration of precipitate and washing with cold MeOH. Yield: 70 mg (58 %) as orange solid.
  • Example 56 (E)-3-(5-(l-cyclohexyl-l,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-2-yl)furan- 2-yl)-2-(morpholine-4-carbonyl)acrylonitrile Obtained from 94 mg of example 31 and 43 mg N-cyanoacetylmorpholine (1.0 equiv) in 1 ml MeOH following general procedure G at 65 °C oil bath temperature with a reaction time of 3 h. Purification by storage at -20 °C over a weekend and subsequent filtration of precipitate and washing with cold MeOH. Yield: 60 mg (46 %) as orange solid.
  • Example 57 (E)-2-cyano-3-(5-(l-(4,4-difluorocyclohexyl)-l,6-dihydroimidazo[4,5- d]pyrrolo[2,3-b]pyridin-2-yl)furan-2-yl)-N,N-dimethylacrylamide Obtained from 140 mg of example 35 and 45 mg of 2-cyano-N,N-dimethylacetamide (1.05 equiv) in 1.5 ml MeOH following general procedure G at 60 °C oil bath temperature with a reaction time of 2 h. Flash chromatography (EtOAc/MeOH, automatic gradient). Yield: 75 mg (42 %) as orange solid.
  • Example 58 (E)-2-(piperidine-l-carbonyl)-3-(5-(l-(tetrahydro-2H-pyran-4-yl)-l,6- dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-2-yl)furan-2-yl)acrylonitrile Obtained from 100 mg of example 32 and 45 mg of 3-oxo-3-(piperidin-l-yl)propanenitrile (1.0 equiv) in 1 ml MeOH following general procedure G at 70 °C oil bath temperature with a reaction time of 2 h. Purification by storage at -20 °C overnight and subsequent filtration of precipitate and washing with cold MeOH.
  • Example 59 (E)-3-(5-(l-cyclohexyl-l,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-2-yl)furan- 2-yl)-2-(piperidine-l-carbonyl)acrylonitrile: Obtained from 105 mg of example 31 and 48 mg of 3-oxo-3-(piperidin-l-yl)propanenitrile (1.0 equiv) in 1 ml MeOH following general procedure G at 65 °C oil bath temperature with a reaction time of 2 h. Flash chromatography (cyclohexane/acetone, automatic gradient). Yield: 55 mg (37 %) as orange solid.
  • Example 60 (E)-3-(5-(l-(tetrahydro-2H-pyran-4-yl)-l,6-dihydroimidazo[4,5-d]pyrrolo[2,3- b]pyridin-2-yl)furan-2-yl)-2-(thiomorpholine-4-carbonyl)acrylonitrile Obtained from 67 mg of example 32 and 34 mg of example 61 (1.0 equiv) in 1 ml MeOH following general procedure G at 60 °C oil bath temperature with a reaction time of 1.5 h. Purification by storage at -20 °C overnight and subsequent filtration of precipitate and washing with cold MeOH. Yield: 33 mg (34 %) as orange solid.
  • Example 62 (E)-2-cyano-3-(5-(l-(cyclopropylmethyl)-l,6-dihydroimidazo[4,5-d]pyrrolo[2,3- b]pyridin-2-yl)furan-2-yl)-N,N-dimethylacrylamide: Obtained from 83 mg of example 34 and 30 mg of 2-cyano-N,N-dimethylacetamide (1.0 equiv) in 1 ml MeOH following general procedure G at 60 °C oil bath temperature with a reaction time of 1.5 h. Purification by storage at -20 °C overnight and subsequent filtration of precipitate and washing with cold MeOH. Yield: 78 mg (72 %) as orange solid.
  • Example 63 (E)-3-(5-(l-cyclohexyl-l,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-2-yl)furan- 2-yl)-2-(thiomorpholine-4-carbonyl)acrylonitrile Obtained from 120 mg of example 31 and 61 mg of example 61 (1.0 equiv) in 1.5 ml MeOH following general procedure G at 60 °C oil bath temperature with a reaction time of 1.5 h. Purification by storage at -20 °C over a weekend and subsequent filtration of precipitate and washing with cold MeOH. Yield: 80 mg (46 %) as orange solid.
  • Example 64 (E)-3-(5-(l-cyclohexyl-l,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-2-yl)furan- 2-yl)-2-(4-hydroxypiperidine-l-carbonyl)acrylonitrile Obtained from 149 mg of example 31 and 75 mg of example 65 in 1.5 ml MeOH following general procedure G at 55 °C oil bath temperature with a reaction time of 1 h. Purification by storage at -20 °C overnight and subsequent filtration of precipitate and washing with cold MeOH. The filtrate was concentrated in vacuo, subjected to flash chromatography (EtOAc/MeOH, automatic gradient) and then added to the collected solid.
  • Example 66 (E)-2-cyano-3-(5-(l-cyclopropyl-l,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin- 2-yl)furan-2-yl)-N,N-dimethylacrylamide Obtained from 110 mg of example 36 and 42 mg of 2-cyano-N,N-dimethylacetamide (1.0 equiv) in 1 ml MeOH following general procedure G at 60 °C oil bath temperature with a reaction time of 1.5 h. Flash chromatography (EtOAc/MeOH, automatic gradient). Yield: 75 mg (52 %) as orange solid.
  • Example 67 (E)-2-cyano-N,N-dimethyl-3-(5-(l-phenyl-l,6-dihydroimidazo[4,5-d]pyrrolo[2,3- b]pyridin-2-yl)furan-2-yl)acrylamide Obtained from 220 mg of example 37 and 85 mg of 2- cyano-N,N-dimethylacetamide (1.0 equiv) in 2 ml MeOH following general procedure G in a screw-cap tube at 60 °C incubator temperature with a reaction time of 1 h. Purification by storage at -20 °C overnight and subsequent filtration of precipitate and washing with cold MeOH. Yield: 124 mg (44 %) as orange solid.
  • Example 68 (E)-2-(morpholine-4-carbonyl)-3-(5-(l-phenyl-l,6-dihydroimidazo[4,5- d]pyrrolo[2,3-b]pyridin-2-yl)furan-2-yl)acrylonitrile Obtained from 35 mg of example 37 and 16 mg of N-cyanoacetylmorpholine (1.0 equiv) in 2 ml EtOH following general procedure G in a screw-cap tube at 60 °C incubator temperature with a reaction time of 3 h. Flash chromatography (EtOAc/MeOH, automatic gradient). Yield: 35 mg (70 %) as yellow solid.
  • Example 69 methyl (E)-N-(2-cyano-3-(5-(l-phenyl-l,6-dihydroimidazo[4,5-d]pyrrolo[2,3- b]pyridin-2-yl)furan-2-yl)acryloyl)-N-methylglycinate Obtained from 41 mg of example 37 and 21 mg of example 41 in 0.5 ml MeOH following general procedure G in a screw-cap tube at 60 °C incubator temperature overnight. Flash chromatography (EtOAc/MeOH, automatic gradient). Yield: 28 mg (47 %) as orange solid.
  • Example 70 (E)-2-(4-methylpiperazine-l-carbonyl)-3-(5-(l-phenyl-l,6-dihydroimidazo[4,5- d]pyrrolo[2,3-b]pyridin-2-yl)furan-2-yl)acrylonitrile Obtained from 40 mg of example 37 and 21 mg of example 55 in 1 ml EtOH following general procedure G in a screw-cap tube at 60 °C incubator temperature overnight. Flash chromatography (EtOAc/MeOH, automatic gradient). Yield: 40 mg (70 %) as orange platelets.
  • Example 71 (E)-3-(5-(l-(cyclopropylmethyl)-l,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin- 2-yl)furan-2-yl)-2-(4-methylpiperazine-l-carbonyl)acrylonitrile Obtained from 80 mg of example 34 and 40 mg of example 55 in 3 ml of MeOH following general procedure G at 60 °C oil bath temperature with a reaction time of 4 h. Flash chromatography (EtOAc/MeOH, automatic gradient). Yield: 91 mg (77 %) as red solid.
  • Example 72 methyl (E)-N-(2-cyano-3-(5-(l-(cyclopropylmethyl)-l,6-dihydroimidazo[4,5- d]pyrrolo[2,3-b]pyridin-2-yl)furan-2-yl)acryloyl)-N-methylglycinate Obtained from 97 mg of example 34 and 60 mg of example 41 (1.1 equiv) in 1 ml MeOH following general procedure G in a screw-cap tube at 60 °C incubator temperature with a reaction time of 2 h. Flash chromatography (EtOAc/MeOH, automatic gradient). Yield: 112 mg (77 %) as orange solid.
  • Example 73 (E)-3-(5-(l-(cyclopropylmethyl)-l,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin- 2-yl)furan-2-yl)-2-(piperidine-l-carbonyl)acrylonitrile Obtained from 107 mg of example 34 and 48 mg of 3-oxo-3-(piperidin-l-yl)propanenitrile (1.0 equiv) in 1 ml MeOH following general procedure G in a screw-cap tube at 60 °C incubator temperature with a reaction time of 1.5 h. Flash chromatography (cyclohexane/IPrOH, automatic gradient). Yield: 100 mg (71 %) as orange solid.
  • Example 74 (E)-2-cyano-3-(5-(l-cyclohexyl-l,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-2- yl)furan-2-yl)-N-(3-(((2S,3R,4S,6R)-2-(((2R,3S,4R,5R,8R,10R,llR,12S,13S,14R)-2-ethyl-3,4,10- trihydroxy-13-(((2R,4R,5S,6S)-5-hydroxy-4-methoxy-4,6-dimethyltetrahydro-2H-pyran-2- yl)oxy)-3,5,6,8,10,12,14-heptamethyl-15-oxo-l-oxa-6-azacyclopentadecan-ll-yl)oxy)-3- hydroxy-6-methyltetrahydro-2H-pyran-4-yl)(methyl)a
  • Example 98 (E)-3-(5-(l-((lR,5S,6r)-bicyclo[3.1.0]hexan-6-yl)-l,6-dihydroimidazo[4,5- d]pyrrolo[2,3-b]pyridin-2-yl)furan-2-yl)-2-(morpholine-4-carbonyl)acrylonitrile: Obtained from 80 mg of example 90 and 37 mg of N-cyanoacetylmorpholine (1.0 equiv.) following general procedure G in 2 ml of absolute EtOH. Flash chromatography (EtOAc/MeOH, automatic gradient). Yield: 56 mg (50 %) as an orange solid.
  • Example 99 (E)-3-(5-(l-((lR,5S,6r)-bicyclo[3.1.0]hexan-6-yl)-l,6-dihydroimidazo[4,5- d]pyrrolo[2,3-b]pyridin-2-yl)furan-2-yl)-2-cyano-N-(3-(((2S,3S,4R,6R)-2- (((2R,3S,4R,5R,8R,10R,llR,12S,13S,14R)-2-ethyl-3,4,10-trihydroxy-13-(((2R,4R,5S,6S)-5- hydroxy-4-methoxy-4,6-dimethyltetrahydro-2H-pyran-2-yl)oxy)-3,5,6,8,10,12,14- heptamethyl-15-oxo-l-oxa-6-azacyclopentadecan-ll-yl)oxy)-4-hydroxy-6-
  • Example 100 (E)-3-(5-(l-((lR,5S,6r)-bicyclo[3.1.0]hexan-6-yl)-l,6-dihydroimidazo[4,5- d]pyrrolo[2,3-b]pyridin-2-yl)furan-2-yl)-2-cyano-N-(2-((2-(((2S,3S,4R,6R)-2- (((2R,3S,4R,5R,8R,10R,llR,12S,13S,14R)-2-ethyl-3,4,10-trihydroxy-13-(((2R,4R,5S,6S)-5- hydroxy-4-methoxy-4,6-dimethyltetrahydro-2H-pyran-2-yl)oxy)-3,5,6,8,10,12,14- heptamethyl-15-oxo-l-oxa-6-azacyclopentadecan-ll-yl)oxy)-4-hydroxy
  • Example 101 2-cyano-3-(5-(l-cyclohexyl-l,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-2- yl)furan-2-yl)-N-(4-(((2S,3S,4R,6R)-2-(((2R,3S,4R,5R,8R,10R,llR,12S,13S,14R)-2-ethyl-3,4,10- trihydroxy-13-(((2R,4R,5S,6S)-5-hydroxy-4-methoxy-4,6-dimethyltetrahydro-2H-pyran-2- yl)oxy)-3,5,6,8,10,12,14-heptamethyl-15-oxo-l-oxa-6-azacyclopentadecan-ll-yl)oxy)-4- hydroxy-6-methyltetrahydro-2H-pyran-3-yl)(methyl)amino)buty
  • Example l02 2-cyano-N-(4-(((2S,3S,4R,6R)-2-(((2R,3S,4R,5R,8R,10R,llR,12S,13S,14R)-2- ethyl-3,4,10-trihydroxy-13-(((2R,4R,5S,6S)-5-hydroxy-4-methoxy-4,6-dimethyltetrahydro-2H- pyran-2-yl)oxy)-3,5,6,8,10,12,14-heptamethyl-15-oxo-l-oxa-6-azacyclopentadecan-ll- yl)oxy)-4-hydroxy-6-methyltetrahydro-2H-pyran-3-yl)(methyl)amino)butyl)-N-methyl-3-(5-(l- (l-methylpiperidin-4-yl)-l,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyr
  • Example 103 2-cyano-3-(5-(l-cyclohexyl-l,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-2- yl)furan-2-yl)-N-(4-(((2S,3R,4S,6R)-2-(((2R,3S,4R,5R,8R,10R,llR,12S,13S,14R)-2-ethyl-3,4,10- trihydroxy-13-(((2R,4R,5S,6S)-5-hydroxy-4-methoxy-4,6-dimethyltetrahydro-2H-pyran-2- yl)oxy)-3,5,6,8,10,12,14-heptamethyl-15-oxo-l-oxa-6-azacyclopentadecan-ll-yl)oxy)-3- hydroxy-6-methyltetrahydro-2H-pyran-4-yl)(methyl)amino)but
  • Example 104 2-Cyano-3-(5-(l-cyclohexyl-l,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-2- yl)furan-2-yl)-N-(2-(((2S,3R,4S,6R)-2-(((2R,3S,4R,5R,8R,10R,llR,12S,13S,14R)-2-ethyl-3,4,10- trihydroxy-13-(((2R,4R,5S,6S)-5-hydroxy-4-methoxy-4,6-dimethyltetrahydro-2H-pyran-2- yl)oxy)-3,5,6,8,10,12,14-heptamethyl-15-oxo-l-oxa-6-azacyclopentadecan-ll-yl)oxy)-3- hydroxy-6-methyltetrahydro-2H-pyran-4-yl)(methyl)amino)
  • Example 105 2-Cyano-3-(5-(l-cyclohexyl-l,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-2- yl)furan-2-yl)acrylic acid: Obtained from 100 mg of example 31 and 25,4 mg of cyanoacetic acid following general procedure G in MeOH. Flash chromatography (EtOAc/MeOH, automatic gradient). Yield: 83 mg (69 %) as yellow solid.
  • Example 106 2-cyano-N,N-dimethyl-3-(5-(l-(tetrahydro-2H-pyran-4-yl)-l,6- dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-2-yl)furan-2-yl)propanamide: 50 mg of example 39 (0.12 mmol, 1.0 equiv) and 5 mg of NaBH4 (0.13 mmol, 1.1 equiv) were dissolved in 1 ml MeOH and stirred at ambient temperature. TLC and MS indicated full conversion of educt after 30 min. H2O was added dropwise to convert excess NaHB4 and the organic solvent was evaporated under reduced pressure. The mixture was diluted with sat.
  • Example 107 methyl-N-(2-cyano-3-(5-(l-cyclohexyl-l,6-dihydroimidazo[4,5-d]pyrrolo[2,3- b]pyridin-2-yl)furan-2-yl)propanoyl)-N-methylglycinate: 72 mg of example 39 (0.17 mmol, 1.0 equiv) and 7,2 mg of NaBH4 (0.19 mmol, 1.1 equiv) were dissolved in 1 ml MeOH and stirred at ambient temperature. TLC and MS indicated full conversion of educt after 30 min. H2O was added dropwise to convert excess NaHB4 and the organic solvent was evaporated under reduced pressure. The mixture was diluted with sat.
  • Example 77 2R,3S,4R,5R,8R,10R,llR,12S,13S,14R)-2-ethyl-3,4,10-trihydroxy-13- (((2R,4R,5S,6S)-5-hydroxy-4-methoxy-4,6-dimethyltetrahydro-2H-pyran-2-yl)oxy)- 3,5,6,8,10,12,14-heptamethyl-ll-(((lR,2S,4R,6R)-4-methyl-3,7-dioxabicyclo[4.1.0]heptan-2- yl)oxy)-l-oxa-6-azacyclopentadecan-15-one.
  • Example 79 methyl methylglycinate: In an ice-cooled round bottomed flask, 25 g (281 mmol, 1.0 equiv) of sarcosine were dissolved in 350 ml of MeOH. 21.4 ml SOCI2 (295 mmol, 1.05 equiv) were added dropwise. After complete addition, the mixture was stirred for 30 min at 0 °C. At this point, the ice bath was removed and the mixture was heated to reflux for 3 h. The reflux condenser was removed and the mixture was concentrated under the hood. To the crude product, a sparing amount of MeOH and a larger amount of EtzO were added. After vigorous stirring for about 10 min, the product was left to crystallize overnight.
  • Example 41 methyl N-(2-cyanoacetyl)-N-methylglycinate: In a round bottomed flask, 8.25 g (97 mmol, 1.0 equiv) of cyanoacetic acid were dissolved in 250 ml DCM. The flask was fitted with a septum connected to a gas bubbler, purged with argon and put on an ice bath. 3 ml of DMF were added by syringe, followed by 8.7 ml of oxalyl chloride (101.9 mmol, 1.05 equiv), after which gas development was observed. The mixture was stirred on ice for 40 min.
  • Example 44 2-cyano-N-(2-(dimethylamino)ethyl)-N-methylacetamide: 180 mg of methyl-2- cyanoacetate (1.82 mmol, 1.0 equiv) and 236 pip of N,N,N'-trimethylethane-l,2-diamine were stirred overnight at ambient temperature. The brown mixture was taken up in EtzO and water, transferred to a separatory funnel and the aqueous phase was washed two times with EtzO. The organic phase was discarded and the aqueous phase was dried in vacuo, yielding 245 mg (80 %) of the tile compound as a dark oil with no further purification steps taken.
  • Example 65 3-(4-hydroxypiperidin-l-yl)-3-oxopropanenitrile
  • 4-hydroxypiperidine 15.68 mmol, 1.0 equiv
  • 1.67 ml of ethyl cyanoacetate 15.68 mmol, 1.0 equiv
  • 11 mg of sodium ethoxide (0.157 mmol, 0.01 equiv)
  • Flash chromatography (cyclohexane/acetone, automatic gradient). Yield: 800 mg (30 %) as red oil.
  • Example 55 3-(4-methylpiperazin-l-yl)-3-oxopropanenitrile
  • 2.21 ml of N-methylpiperazine (20.0 mmol, 1.0 equiv) and 1.78 ml of methyl cyanoacetate (20.0 mmol, 1.0 equiv) were stirred overnight and allowed to reach ambient temperature. Volatile residues were then evaporated under reduced pressure and the crude solid was suspended in EtzO and triturated with a glass rod. After decanting with EtzO three times, the solid was collected by filtration and dried in vacuo. Yield: 2.36 g (71 %) as brown solid.
  • Example 61 3-oxo-3-thiomorpholinopropanenitrile
  • 2.07 ml of ethyl cyanoacetate (19.4 mmol, 1.0 equiv) and 13 mg of sodium ethoxide (0.194 mmol, 0.01 equiv) were dissolved in 6 ml EtOH and stirred at 65 °C overnight. Volatiles were removed under reduced pressure and the residue was subjected to flash chromatography (EtOAc/MeOH, automatic gradient). HPLC still showed impurities but the product was successfully used in further reactions without additional purification.
  • Example 80 2-cyano-3-(5-(l-cyclohexyl-l,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-2- yl)furan-2-yl)-N,N-dimethylpropanamide
  • 100 mg of example 38 (0.23 mmol, 1.0 equiv) and 10 mg of NaBH4 (0.26 mmol, 1.1 equiv) were dissolved in 1 ml MeOH and gently shaken at ambient temperature. TLC and MS indicated full conversion of educt after 30 min. H2O was added dropwise to convert excess NaHB4 and the organic solvent was evaporated under reduced pressure. The mixture was diluted with sat.
  • Example 76 (2R,3S,4R,5R,8R,10R,llR,12S,13S,14R)-2-ethyl-3,4,10-trihydroxy-13- (((2R, 4R, 5S, 6S)-5-hydroxy-4-methoxy-4, 6-dimethyltetrahydro-2H-pyran-2-yl)oxy)-l 1 - (((2S,3R,6R)-3-hydroxy-6-methyl-4-(methyl(3-(methylamino)propyl)amino)tetrahydro-2H- pyran-2-yl)oxy)-3,5,6,8,10,12,14-heptamethyl-l-oxa-6-azacyclopentadecan-15-one
  • 519 mg of example 77 (0.738 mmol, 1.0 equiv) were suspended in excess Nl,N3-dimethylpropane-l,3-diamine (about 0.5 ml) and left in
  • Example 75 2-cyano-N-(3-(((2S, 3R, 6R)-2-(((2R, 35, 4R, 5R, 8R, 10R,ll R,12S, 135, 14R)-2-ethyl- 3,4,10-trihydroxy-13-(((2R,4R,5S,6S)-5-hydroxy-4-methoxy-4,6-dimethyltetrahydro-2H-pyran- 2-yl)oxy)-3,5,6,8,10,12,14-heptamethyl-15-oxo-l-oxa-6-azacyclopentadecan-ll-yl)oxy)-3- hydroxy-6-methyltetrahydro-2H-pyran-4-yl)(methyl)amino)propyl)-N-methylacetamide: In a round-bottomed flask, 44 mg of cyanoacetic acid, (0.519 mmol, 1.1 equiv), 197 mg of HATU (0.519 mmol, 1.1
  • Example 81 benzyl (2-((2-(((2S,6R)-2-(((2R,3S,4R,5R,8R,10R,HR,12S,13S,14R)-2-ethyl-3,4,10- trihydroxy-13-(((2R,4R,5S,6S)-5-hydroxy-4-methoxy-4,6-dimethyltetrahydro-2H-pyran-2- yl)oxy)-3,5,6,8,10,12,14-heptamethyl-15-oxo-l-oxa-6-azacyclopentadecan-ll-yl)oxy)-4- hydroxy-6-methyltetrahydro-2H-pyran-3-yl)(methyl)amino)ethyl)(methyl)amino)-2- oxoethyl)(methyl)carbamate 579 mg of N-benzyloxycarbonyl-N-methylglycine (2.59 mmol, 1.05 equiv), 9
  • Example 82 N-(2-(((2S,6R)-2-(((2R,3S,4R,5R,8R,10R,llR,12S,13S,14R)-2-ethyl-3,4,10- trihydroxy-13-(((2R,4R,5S,6S)-5-hydroxy-4-methoxy-4,6-dimethyltetrahydro-2H-pyran-2- yl)oxy)-3,5,6,8,10,12,14-heptamethyl-15-oxo-l-oxa-6-azacyclopentadecan-ll-yl)oxy)-4- hydroxy-6-methyltetrahydro-2H-pyran-3-yl)(methyl)amino)ethyl)-N-methyl-2-methyl-2-
  • Example 83 2-cyano-N-(2-((2-(((2S,6R)-2-(((2R,3S,4R,5R,8R,10R,HR,12S,13S,14R)-2-ethyl- 3,4,10-trihydroxy-13-(((2R,4R,5S,6S)-5-hydroxy-4-methoxy-4,6-dimethyltetrahydro-2H-pyran- 2-yl)oxy)-3,5,6,8,10,12,14-heptamethyl-15-oxo-l-oxa-6-azacyclopentadecan-ll-yl)oxy)-4- hydroxy-6-methyltetrahydro-2H-pyran-3-yl)(methyl)amino)ethyl)(methyl)amino)-2-oxoethyl)- N-methylacetamide: 52.7 mg of cyanoacetic acid (0.62 mmol, l.O equiv), 247 mg of HATU
  • Example 84 (E)-2-cyano-3-(5-(l-cyclohexyl-l,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-2- yl)furan-2-yl)-N-(2-((2-(((2S,6R)-2-(((2R,3S,4R,5R,8R,10R,llR,12S,13S,14R)-2-ethyl-3,4,10- trihydroxy-13-(((2R,4R,5S,6S)-5-hydroxy-4-methoxy-4,6-dimethyltetrahydro-2H-pyran-2- yl)oxy)-3,5,6,8,10,12,14-heptamethyl-15-oxo-l-oxa-6-azacyclopentadecan-ll-yl)oxy)-4- hydroxy-6-methyltetrahydro-2H-pyran-3-yl)(methyl)amino)e
  • Example 85 (E)-2-cyano-N-(3-(((2S,6R)-2-(((2R,3S,4R,5R,8R,10R,llR,12S,13S,14R)-2-ethyl- 3,4,10-trihydroxy-13-(((2R,4R,5S,6S)-5-hydroxy-4-methoxy-4,6-dimethyltetrahydro-2H-pyran- 2-yl)oxy)-3,5,6,8,10,12,14-heptamethyl-15-oxo-l-oxa-6-azacyclopentadecan-ll-yl)oxy)-4- hydroxy-6-methyltetrahydro-2H-pyran-3-yl)(methyl)amino)propyl)-N-methyl-3-(5-(l-(l- methylpiperidin-4-yl)-l,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-2-y
  • Example 92 was obtained as another product in the synthesis of example 91 (see above).
  • Example 93 2-cyano-N-(4-(((2S,3S,4R,6R)-2-(((2R,3S,4R,5R,8R,10R,llR,12S,13S,14R)-2-ethyl- 3,4,10-trihydroxy-13-(((2R,4R,5S,6S)-5-hydroxy-4-methoxy-4,6-dimethyltetrahydro-2H-pyran- 2-yl)oxy)-3,5,6,8,10,12,14-heptamethyl-15-oxo-l-oxa-6-azacyclopentadecan-ll-yl)oxy)-4- hydroxy-6-methyltetrahydro-2H-pyran-3-yl)(methyl)amino)butyl)-N-methylacetamide: 26 mg of cyanoacetic acid (0.31 mmol, 1.05 equiv.), 117 mg of HATU (1.05 equiv.) and 43 pl of Ets
  • Example 94 was obtained as another product during the synthesis of example 78 (see above). After separation by chromatography, 1,25 g (19 %) were obtained as a white solid.
  • Example 95 2-cyano-N-(2-(((2S,3R,4S,6R)-2-(((2R,3S,4R,5R,8R,10R,HR,12S,13S,14R)-2-ethyl- 3,4,10-trihydroxy-13-(((2R,4R,5S,6S)-5-hydroxy-4-methoxy-4,6-dimethyltetrahydro-2H-pyran- 2-yl)oxy)-3,5,6,8,10,12,14-heptamethyl-15-oxo-l-oxa-6-azacyclopentadecan-ll-yl)oxy)-3- hydroxy-6-methyltetrahydro-2H-pyran-4-yl)(methyl)amino)ethyl)-N-methylacetamide: 36 mg of cyanoacetic acid (0.42 mmol, 1.05 equiv.), 161 mg of HATU (1.05 equiv.) and 59 p.1 of
  • Example 96 2-cyano-N-(4-(((2S,3R,4S,6R)-2-(((2R,3S,4R,5R,8R,10R,llR,12S,13S,14R)-2-ethyl- 3,4,10-trihydroxy-13-(((2R,4R,5S,6S)-5-hydroxy-4-methoxy-4,6-dimethyltetrahydro-2H-pyran- 2-yl)oxy)-3,5,6,8,10,12,14-heptamethyl-15-oxo-l-oxa-6-azacyclopentadecan-ll-yl)oxy)-3- hydroxy-6-methyltetrahydro-2H-pyran-4-yl)(methyl)amino)butyl)-N-methylacetamide: 61 mg of cyanoacetic acid (0.72 mmol, 1.05 equiv.), 274 mg of HATU (1.05 equiv.) and 100 pl of Et
  • example 92 (0.69 mmol, 1.0 equiv.) were added at once. The solution was stirred until reaction controls indicated full conversion of starting material. The solution was concentrated under reduced pressure, transferred to a separatory funnel and, after addition of sat. NaHCOs, extracted four times with DCM. The combined organics were dried over NazSC , evaporated under reduced pressure and the crude solid was purified by flash chromatography (EtOAc/MeOH, automatic gradient). Yield: 123 mg (20 %) as a white solid.
  • Plasma samples were diluted with ACN containing 5 nM sulfentrazone and 1 nM terbuthylazine (used as negative and positive internal standards respectively), homogenized in a FastPrep FP-120 instrument and then centrifuged at 14,000 rpm for 7 min at 4° C.
  • Organ samples were treated with 1 pl proteinase K solution (0.5 mg/ml in 20mM phosphate buffer) per mg organ weight and then worked up analogously to the plasma samples.
  • Bile samples were diluted with water, homogenized and then further diluted with ACN plus internal standards, followed by homogenization and centrifugation. Compound concentrations were measured using reverse-phase HPLC with MS detection.
  • a mobile phase comprised of 0.1 % formic acid in water (solvent A) and 0.1 % formic acid in acetonitrile (solvent B).
  • Method 10 % B for 1 min, to 100 % B in 4 min, 100 % B for 2 min, to 10 % B in 1 min, 10 % B for 2 min, stop time 10 min, flow rate 500 pl/min, injection volume 6 pl.
  • a thermostat Using a thermostat, a constant column temperature of 45 °C was maintained, while the samples were kept at 6 °C.
  • JAK3 IC50 values were a described previously (Bauer et al., 2014).57 In short, a 96-well plates was fitted with artificial, tyrosine-rich peptides to act as phosphorylation targets. A fragment (amino acids 781 to 1124) of human JAK3 containing the active site was incubated with 1.4 pM ATP (twice the Km value), leading to phosphorylation of the peptide substrate. By addition of a horseradish peroxidase- conjugated phosphotyrosine antibody followed by 3,3',5,5'-tetra-methylbenzidine, color development proportional to bound antibody was observed.
  • the reaction was stopped after a set time via sulphuric acid and the optical density (OD) was determined at 450 nm.
  • OD optical density
  • kinase was obtained as plasmid cloned in frame with a C-terminal NanoLuc-fusion (NV1471, Promega). Plasmid was transfected into HEK293T cells (ATCC) using FuGENE HD (Promega, E2312) and proteins were allowed to express for 20h. Serially diluted inhibitor and NanoBRET Kinase Tracer K10 (Promega) at a concentration determined previously as the Tracer K10 KD, app (500 nM) were pipetted into white 384-well plates (Greiner 784075) using an Echo acoustic dispenser (Labcyte).
  • the corresponding protein-transfected cells were added and reseeded at a density of 2.5 x 105 cells/mL after trypsinization and resuspending in Opti-MEM without phenol red (Life Technologies). The system was allowed to equilibrate for 2 hours at 37°C/5% CO2 prior to BRET measurements.
  • NanoBRET NanoGio Substrate + Extracellular NanoLuc Inhibitor (Promega, N2540) was added as stated in the manufacturer's protocol, and filtered luminescence was measured on a PHERAstar plate reader (BMG Labtech) equipped with a luminescence filter pair (450 nm BP filter (donor) and 610 nm LP filter (acceptor)).
  • ELISA Materials for ELISA were obtained from Biolegend (ELISA Max Standard Kit, mTNF0, hlL-6, hlL-10, mlL-6, mlL-10) and R&D Systems (Human TNF-alpha DuoSet ELISA, hTNFoc). ELISAs to detect cytokines were performed using Sarstedt 96-well flat-bottom plates. Assay diluent, coating buffer and TMB substrate were purchased from Biolegend. Human peripheral blood leukocytes extracted from human full blood provided by the blood bank, Tuebingen.
  • LPS Lipopolysaccharide
  • LPS 5. enterica typhimurium
  • mice were treated with 15 pmol/kg p.o. of JAK inhibitors or vehicle (0.5 % citric acid in water, 10 ml/kg). After 30 min, 10 mg/kg LPS (5. enterica typhimurium) in phosphate buffered saline was administered intraperitoneally (10 ml/kg). Blood was taken from the tail vein at 60, 90 and 180 min after LPS injection. After 180 min, mice were sacrificed by CO2 inhalation.
  • LPS enterica typhimurium
  • IBD Inflammatory bowel disease
  • DSS dextran sulfate, sodium salt
  • Treatments were given at the same molar dose, 1 pmol/kg to compensate for large differences in molecular weight.
  • the applied amount of substance were as follows:
  • DSS induces sufficient gut dysfunction that animals reach sufficient disease severity to be removed from the study.
  • the number of animals from each group that reach study termination is recorded in the following table.
  • a number of treatment compounds allowed enhanced survival vs. vehicle.
  • Example 102 EAE disease model
  • EAE Experimental autoinflammatory encephalomyelitis
  • MS Multiple Sclerosis
  • Animals are injected with MOG35-55 peptide in Complete Freund's Adjuvant and receive two boost injections of Pertussistoxin within one day of disease induction.
  • mice develop typical symptoms reminiscent of MS: Impaired movement coordination, slow gait, stiffness of limbs and so on.
  • Body weight decreases just prior to the onset of signs and reflects both the onset of systemic inflammation and difficulty feeding and drinking. Additionally, inflammation in peripheral organs can also be observed.
  • EAE experimental autoimmune encephalomyelitis
  • IBD inflammatory bowel disease
  • LPS lipopolysaccharides
  • NaHCO3 sodium bicarbonate
  • R1 and R2 are connected to form a 3- to 10-membered carbocycle or a 3- to 10- membered heterocycle containing at least one of the atoms O, N, or S, wherein the carbocycle or heterocycle is saturated or unsaturated, and is optionally substituted with 0 - 6 substituents of the list O-R4, N(R4Rs), S-R4, R4, N3, F, Cl, Br, I, or macrolide;
  • R9 H, CH3, or a linker
  • RIO CH3 or a linker
  • Rll H, CH3, or a linker; and one of R9, RIO, or Rll is a linker.
  • R1 linker-macrolide
  • R3 aryl, heteroaryl
  • 0-2 carbon atoms of the cyclopropyl, cyclobutyl, bicyclo[W.1.0]alkanyl, or spirobicycloalkanyl is substituted by -0-, -S-, -NH-, or -N(CH3)-.
  • Embodiment 6 The compound of any preceding embodiment, wherein
  • 0-2 carbon atoms of the cyclopropyl, cyclobutyl, or bicyclo[W.1.0]alkanyl is substituted by - 0-, -S-, -NH-, or -N(CH3)-.

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Abstract

L'invention concerne des inhibiteurs de JAK3 qui contiennent une combinaison de 2 ou plus des fractions suivantes : un accepteur de Michael contenant un cyano, une 1,6-dihydroimidazo[4,5-d]pyrrolo [2,3-b]pyridine, et un facteur de ciblage pour augmenter l'absorption et l'exposition de cellules myéloïdes.
PCT/IB2023/000382 2022-06-23 2023-06-23 Modulateurs ciblés de jak3 pour le traitement de maladies inflammatoires et auto-immunes Ceased WO2023248010A2 (fr)

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