Targeted modulators of JAK3 for treatment of inflammatory and autoimmune diseases

Technical Field: Pharmaceuticals

DETAILED DESCRIPTION OF THE INVENTION

Technical Problem

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.

Clinical JAK1 inhibitors (Tofacitinib, Ruxolitinib) have a very low dose in use which we attribute to the requirement not to inhibit „anti-inflammatory 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.

We observed that at higher doses/concentrations of clinical JAK1 inhibitors like tofacitinib or ruxolitinib, levels of TNFoc, which is pro-inflammatory, may rise (Fig. 2). This is probably dose limiting. We attribute this to an inhibition of IL-10 signaling via the IL-10 receptor, which signals through JAK1. IL-10 production and signaling would normally provide feedback control to the production of TNFoc and thus help dampen excessive inflammatory responses.

We set out to limit these issues at two levels: 1, by making JAK3 specific inhibitors; and 2, by targeting the JAK3 inhibitors to immune cells. By doing this, our goal was to increase systemic IL-10 production and reduce TNFoc production to counter auto-immune phenomena.

Solution to Problem

We describe here a class of 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.

Advantageous Effects of Invention

Previous generations of compounds in this field were potent and selective inhibitors of JAK3 in vitro, however, they were insufficiently stable or bioactive to warrant development as pharmaceuticals and were considered probes or tool compounds for biochemical research. The substances reported here exhibit in vivo activity in disease models in the range of 0.1 to 10 mg/kg and linear dose response. In particular, they simultaneously reduce levels of TNFoc while increasing levels of IL-10. The linearity of response, stability and oral bioavailability make them useful for treatment of autoimmune diseases.

SUMMARY

Compounds are described that contain a combination of 2 or more of the following moieties: a nitrile-containing Michael acceptor, a l,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin and a targeting factor to increase myeloid cell uptake and exposure.

A compound as formula 1 wherein

X = OR1, NR1, CHR1 lf X = ORl,

R1 = H, C1-C12 alkyl or cycloalkyl or alkenyl or cycloalkenyl or alkynyl or cycloalkynyl or aryl, each optionally substituted with 0 - 6 substituents of the list O-R4, N(R4Rs), S-R4, R4, (=0), (=N-R4), -COOH, COOCH3, COOC2H5, N3, F, Cl, Br, I, macrolide and

0 - 4 of the carbons in the carbon chain or in the cycloalkyl residue substituted by -O- or -S- or -N(R4)-

OR

R1 = a substituted macrolide, attached directly or by a linker

OR

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.

AND R2 is a free electron pair lf X = NRl, CHR1,

R1 is as defined above

AND R2 = H, C1-C6 alkyl or cycloalkyl or alkenyl or cycloalkenyl or alkynyl or cycloalkynyl, each optionally substituted with 0 - 5 substituents of the list O-R4, N(R4Rs), S-R4, R4, (=0), (=N-R4), -COOH, COOCH3, COOC2H5, N3, F, Cl, Br, I and

0 - 2 of the carbons in the carbon chain or in the cycloalkyl residue substituted by -O- or -S- or -N(R4)-

OR

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;

OR

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

R3 = aryl or heteroaryl or Cl-C8 alkyl, Cycloalkylalkyl, cycloalkyl, bicycloalkyl, tricycloalkyl, spirocycloalkyl, each saturated or unsaturated, with 0 - 5 substituents of the list O-R4, N(R4Rs), S-R4, R4, (=0), (=N-R4), -COOH, COOCH3, COOC2H5, N3, F, Cl, Br, I and

0 - 2 of the carbons in the carbon chain or in the cycloalkyl or bicycloalkyl or tricycloalkyl or spirocycloalkyl residue substituted by -O- or -S- or -N(R4)-

R4, R5 = independent of each other, H, Cl-C6-a Ikyl or cycloalkyl or alkenyl or cycloalkenyl or alkynyl or cycloalkynyl, each optionally substituted with 0 - 5 substituents of the list OH, OCH3, NH2, NHCH3, N(CH3)2, SH, (=0), (=N-R4), -COOH, C00CH3, COOC2H5, N3, F, Cl, Br, I linker = a linear sequence of 0-30 atoms of the list C, O, N, S, substituted or unsubstituted, containing cyclic elements or being a straight chain, counted along the shortest way from one end to the other.

Macrolide means a structure selected from: Y = -N(CH3)-CH2- or -CHz-NfCHzCHzCHs)-, representing derivatives of azithromycin or gamithromycin, respectively

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

X = OR1 or NR1 and

R1 = linker-macrolide or

C1-C12 alkyl or cycloalkyl or alkenyl or cycloalkenyl or alkynyl or cycloalkynyl, each optionally substituted with 0 - 6 substituents of the list O-R4, N(R4Rs), S-R4, R4, (=0), (=N-R4), -COOH, C00CH3, COOC2H5, F, Cl, Br, I, and 0 - 4 of the carbons in the carbon chain or in the cycloalkyl residue substituted by -O- or -S- or -N(R4)-; and containing at least one group suitable for "click" reactions, for example, but not being limited to azide or bicyclononin or dibenzcyclooctin a compound, wherein

X = NRl and

R1 = linker-macrolide or -CH2-C(=O)O-CH3 a compound, wherein

R1 = C1-C8 alkyl, optionally substituted with 0-3 substituents of the list (=0), -NH2, NH(Boc), NH(Z), NH(Fmoc), and with at least one substituent containing -N3 (azide), bicyclononin or dibenzocyclooctin a compound wherein

R3 = aryl or heteroaryl or spirobicycloalkanes with 5-7 atomes or cyclopropyl or cyclobutyl or bicyclo[W.1.0]alkanes with W = 1-4 and being connected through one of the atoms of the 3- membered ring; optionally substituted with one or two substituents of the list -OH, -OCH3, -NH2, -NHCH3, - N(CH3)2, -SH, -SCH3, (=0), C1-C3 alkyl or alkenyl, and

0-2 carbon atoms of the cyclopropyl or cyclobutyl or bicyclo[W.1.0]alkane or spirobicycloalkane being substituted by -O- or -S- or -NH- or -N(CH3)- a compound wherein

R3 = cyclopropyl or cyclobutyl or a bicyclo [1.0.W]alkane with W = 1-4 and being connected through one of the atoms of the 3- membered ring; optionally substituted with one or two substituents of the list -OH, -0CH3, -NH2, -NHCH3, - N(CH3)2, -SH, -SCH3, (=0), C1-C3 alkyl or alkenyl, and

0-2 carbon atoms of the cyclopropyl or cyclobutyl or bicyclo[W.1.0]alkane being substituted by -O- or -S- or -NH- or -N(CH3)- a compound wherein

R3 = C1-C8 alkyl, Cycloalkylalkyl, cycloalkyl, bicycloalkyl, tricycloalkyl, spirocycloalkyl, each saturated or unsaturated, with 0 - 5 substituents of the list O-R4, S-R4, R4, (=0), C00CH3, COOC2H5, N3, F, Cl, Br, I and 0 - 2 of the carbons in the carbon chain or in the cycloalkyl or bicycloalkyl or tricycloalkyl or spirocycloalkyl residue substituted by -O- or -S- and at least one of the carbons in the carbon chain or in the cycloalkyl or bicycloalkyl or tricycloalkyl or spirocycloalkyl residue substituted by -N(CH3)- or at least one substituent being -N(CH3)2

The compound of formula 2

Formula 2

The compound of formula 3

Formula 3

Either used directly as treatment or as an active metabolite of compounds of claims 1-8, wherein

R3 = aryl or heteroaryl or Cl-C8 alkyl, Cycloalkylalkyl, cycloalkyl, bicycloalkyl, tricycloalkyl, spirocycloalkyl, each saturated or unsaturated, with 0 - 5 substituents of the list O-R4, N(R4Rs), S-R4, R4, (=0),

(=N-R4), -COOH, C00CH3, COOC2H5, N3, F, Cl, Br, I and

0 - 2 of the carbons in the carbon chain or in the cycloalkyl or bicycloalkyl or tricycloalkyl or spirocycloalkyl residue substituted by -O- or -S- or -N(R4)-

R4, R5 = independent of each other, H, Cl-C6-a Ikyl or cycloalkyl or alkenyl or cycloalkenyl or alkynyl or cycloalkynyl, each optionally substituted with 0 - 5 substituents of the list OH, 0CH3, NH2, NHCH3, N(CH3)2, SH, (=0), (=N-R4), -COOH, C00CH3, COOC2H5, N3, F, Cl, Br, I

In another embodiment is a compound as formula 1

X = OR1, NR1, CHR1 lf X = ORl,

R1 = H, C1-C12 alkyl or cycloalkyl or alkenyl or cycloalkenyl or alkynyl or cycloalkynyl, each optionally substituted with 0 - 6 substituents of the list O-R4, N(R4Rs), S-R4, R4, (=0), (=N-R4), -COOH, C00CH3, COOC2H5, N3, F, Cl, Br, I, macrolide and

0 - 4 of the carbons in the carbon chain or in the cycloalkyl residue substituted by -O- or -S- or -N(R4)-

Brief Description of the Drawings 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. 3 shows tail plasma TNFoc, IL-6 and IL-10 concentrations vs untreated control (n = 9) for mice treated with compound 46 10 mg/kg p.o.

FIG. 4 shows tail plasma TNFoc and IL-10 concentrations vs untreated control (n = 8) for mice treated with 15 pmol/kg JAK3 inhibitors or the clinical JAK1 inhibitors Tofacitinib or Ruxolitinib and 30 minutes later challenged with LPS.

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. These data suggest that there was an initial lag phase after starting the compound after which effects became more apparent. This may be the period required to obtain a change in the overall number of proliferated pathogenic T-cells.

Description of Embodiments

The compounds described in this section can be prepared by methods known in the art, as well as by the synthetic routes disclosed herein. Detailed routes including various intermediates are illustrated in the examples herein.

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.

As can be appreciated by the skilled artisan, the synthetic routes herein are not intended to comprise a comprehensive list of all means by which the compounds described and claimed in this application may be synthesized. Further methods will be evident to those of ordinary skill in the art. Additionally, the various synthetic steps described above may be performed in an alternate sequence or order to give the desired compounds.

In one aspect, 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. In an embodiment, 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.

In certain embodiments, these pharmaceutical compositions are suitable for topical or oral administration to a subject. In other embodiments, as described in detail below, 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.

The phrase "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.

The term "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. When compounds of the present invention contain relatively acidic functionalities, 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. Examples of pharmaceutically acceptable base addition salts include sodium, potassium, calcium, ammonium, organic amino, or magnesium salt, or a similar salt. When compounds of the present invention contain relatively basic functionalities, 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. Also included are 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.

Some examples of 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. 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.

Preferably, 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.

Combinations of substituents and variables envisioned by this invention are only those that result in the formation of stable compounds. The term "stable", as used herein, 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).

The term "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.

Examples

General

Unless stated otherwise, solvents, reagents and other materials were of commercial quality and used without further purification. Preparative column chromatography was either performed manually with glass columns and ACROS Organics™ 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). Two different gradients were used depending on the analyte: 20 % B for 5 min, to 100 % B in 20 min, 100 % B for 4 min, to 20 % B in 1 min, 20 % B for 5 min (method A), or: 5 % B for 5 min, to 100 % B in 20 min, 100 % B for 4 min, to 5 % B in 1 min, 5 % B for 5 min (method B). The flow rate for both methods was 1.3 ml/min. Nitrogen gas was used for the nebulization and evaporation of the mobile phase. Pressure was set at 3.3 bar and the drift tube temperature of the ELSD was 75 °C. Measurements of samples from in vivo studies were performed by reverse-phase HPLC on an Agilent series system using the 1260 HiP Degasser, the 1260 BinPump, the 1260 HiP ALS and the 1290 Thermostat, using Agilent C18 2.7 pm columns. For detection, the system was connected to an AB SCIEX API 4000 MS using a TurboSpray ion source (settings: source voltage 45 V, ion spray voltage 4.5 kV, temperature 300 °C, gas flow 5 l/min). NMR spectra were either recorded on a Bruker Avance 400 Mhz, a Bruker Avance III HDX 400 Mhz or a Bruker Avance III 300 Mhz. Chemical shifts are reported in ppm relative to TMS and calibrated against the residual proton peak of the respective solvent. Standard mass spectra were obtained as ESIMS (pos. mode) from a Thermo Finnigan LCQ Deca XP system (settings: ESI voltage 3.0 kV, capillary voltage 9 V, capillary temperature 275 °C, gas flow 7 l/min).

HRMS measurements were made using a Bruker maXis 4G ESI-TOF from Daltonik at the Institute of Organic Chemistry, Eberhard-Karls-University Tuebingen, using ESI+ mode and the following settings: Capillary voltage 4.5 kV, source temperature 200 °C, gas flow 6 l/min, nebulizer gas pressure 1.2 bar, end plate offset - 0.5 kV and an m/z range of 80 to 1350 m/z. All final compounds show > 95 % purity according to analytical HPLC. In case of E/Z mixtures obtained from Knoevenagel condensations, purity is calculated from the sum of both isomer peak areas.

Example 1: Synthesis of4-Chloro-l-tosyl-lH-pyrrolo[2,3-b]pyridine

In a 2 I three-necked round bottomed flask, 25 g of 4-chloro-7-azaindole (163,9 mmol, 1.0 equiv) was dissolved in 700 ml of dry THF. The solution was cooled with ice/water and stirred under argon. Then, 7,6 g of NaH (60 % dispersion in mineral oil, 196,6 mmol, 1.2 equiv) was added portionwise and left to stir for 15 min. Afterwards, 33 g tosyl chloride (172 mmol, 1.05 equiv) was dissolved in 120 ml of dry THF and added dropwise. After complete addition, the cooling bath was removed and stirring continued at ambient temperature for 2 h until TLC and MS controls indicated full consumption of 4-chloro-7-azaindole. After quenching by addition of 25 ml saturated NH4CI solution, the mixture was diluted with EtOAc and transferred to a separatory funnel. Two portions of 200 ml IM K2CO3 and one portion of 200 ml brine were used to wash the organic phase. Afterwards it was dried over NazSC and evaporated under reduced pressure. Cold MeOH was added to the obtained solid and it was lightly ground with a glass rod. After decantation of the solvent and evaporation of residues under reduced pressure, 46 g (92 %) of the title compound were obtained as a brown solid. ¹ H-NMR: (300 MHz, CDCI3) 68.20 (d, J = 5.3 Hz, 1H), 7.96 (d, J = 8.3 Hz, 2H), 7.66 (d, J = 4.0 Hz, 1H), 7.15 (d, J = 8.2 Hz, 2H), 7.06 (d, J = 5.3 Hz, 1H), 6.57 (d, J = 4.0 Hz, 1H), 2.23 (s, 3H). ¹³ C-NMR: (75 MHz, CDCI3) 6 147.49, 145.56, 145.23, 136.68, 135.07, 129.76, 128.11, 126.92, 122.17, 119.01, 103.30, 21.60. MS (ESI) m/z: 307,33 [M+H] ⁺ ; HPLC t _re t = 0,6 min (as a salt) or 14,0 min (free base) (method A)

Example 2: Synthesis of4-Chloro-5-nitro-l-tosyl-lH-pyrrolo[2,3-b]pyridine

37,5 g of example 1 (122,2 mmol, 1.0 equiv) and 21,6 g of tetramethylammonium nitrate (158,9 mmol, 1.3 equiv) were dissolved in 600 ml DCM in a 1 1 three-necked round bottomed flask and stirred. Cooling to an internal temperature of 0-5 °C for the whole reaction was achieved by submersion in an ice/water bath. The flask was then saturated with argon. Over the course of 8 h, 22,4 ml of trifluoroacetic anhydride (158,9 mmol, 1.3 equiv) were added dropwise. Stirring continued overnight while allowing the mixture to reach ambient temperature. As both TLC and MS indicated substantial leftovers of educt (example 1), the mixture was cooled again and an additional 10 ml of trifluoroacetic acid were added over 8 h. Again, stirring overnight was carried out at ambient temperature. The yellow solution was diluted with DCM and washed, in this order, with water, sat. NaHCOs and NazCOs solutions and brine. The resulting red organic phase was dried over NazSC and evaporated under reduced pressure. The solid was suspended in MeOH and stored at -20 °C overnight. The suspension was filtrated, the solids washed with small amounts of cold MeOH and dried in vacuo. 26 g (61 %) of the title compound were obtained as a beige powder. ¹ H-NMR: (300 MHz, CDCI3) 6 8.91 (d, J = 3.9 Hz, 1H), 8.04 - 7.95 (m, J = 7.8, 4.0 Hz, 2H), 7.86 (d, J = 3.9 Hz, 1H), 7.28 - 7.20 (m, 2H), 6.79 - 6.71 (m, J = 3.8 Hz, 1H), 2.32 (s, 3H). ¹³ C-NMR: (75 MHz, CDCI3) 6 147.13, 146.55, 142.20, 140.50, 134.31, 131.20, 130.09, 129.98, 128.53, 122.94, 104.47, 21.79. MS (ESI) m/z: 352,2 [M + H] ⁺ ; HPLC t _re t = 20,9 min (method A) General procedure A for nucleophilic substitution at position 4:

In a sufficiently large round bottomed flask 1.0 equiv of 4-Chloro-5-nitro-l-tosyl-lH- pyrrolo[2,3-b]pyridine (Example 1) were suspended in IPrOH (0.2 M) and stirred. 1.4 equiv of EtsN and 1.25 equiv (unless noted otherwise) of amine were added and the mixture is heated to reflux. After confirmation of full consumption of starting material by TLC and/or MS, a 2:1 mixture of H2O and sat. NH4CI solution (35 ml per 1 g of 4-Chloro-5-nitro-l-tosyl-lH- pyrrolo[2,3-b]pyridine was added portionwise to the hot mixture, leading to precipitation. Stirring at about 80 °C oil bath temperature continued for 5 min. Afterwards, the mixture was stirred for at least 30 min in an ice bath. Filtration, aqueous washing and drying of the precipitate led to the desired products, which most of the time were usable without further purification.

Example 3: N-cyclohexyl-5-nitro-l-tosyl-lH-pyrrolo[2,3-b]pyridin-4-amin e: 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. ^X H-NMR (300 MHz, CDCI3) 69.01 (s, 1H), 7.98 (d, J = 8.2 Hz, 2H), 7.51 (d, J = 4.0 Hz, 1H), 7.21 (d, 2H), 6.62 (d, J = 4.0 Hz, 1H), 3.97 - 3.77 (m, 1H), 2.31 (s, 3H), 2.10- 1.96 (m, 2H), 1.86- 1.69 (m, 2H), 1.50- 1.12 (m, 6H). ¹³ C-NMR (75 MHz, CDCI3) 6 148.87, 146.43, 145.88, 144.94, 134.89, 129.82, 128.60, 126.54, 123.57, 107.63, 106.72, 52.85, 33.49, 25.34, 24.35, 21.79. MS (ESI) m/z: 415,33 [M + H] ⁺ ; HPLC t _re t = 21,7 min (method A)

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. ^T H NMR (300 MHz, DMSO) 6 8.89 (s, 1H), 8.85 (d, J = 7.9 Hz, 1H), 7.99 (d, J = 8.4, 2.1 Hz, 2H), 7.81 - 7.74 (m, 1H), 7.41 (d, J = 8.2 Hz, 2H), 7.08 - 6.99 (m, 1H), 4.34 - 4.22 (m, 1H), 3.88 - 3.75 (m, 2H), 3.56 (t, J = 11.2 Hz, 2H), 2.33 (s, 3H), 2.02 - 1.90 (m, J = 12.4 Hz, 2H), 1.74 - 1.57 (m, J = 19.6, 9.6 Hz, 2H). ¹³ C-NMR (75 MHz, DMSO) 6 148.03, 146.01, 145.25, 144.13, 134.12, 130.07, 127.99, 126.37, 124.15, 107.45, 107.14, 64.96, 49.29, 32.76, 21.13. MS (ESI) m/z: 417.4 [M + H] ⁺ ; HPLC t _re t = 17.6 min (method A)

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. ¹ H NMR (300 MHz, CDCI3) 6 9.08 - 8.96 (m, J = 11.6 Hz, 2H), 8.05 - 7.89 (m, J = 11.3, 8.4 Hz, 2H), 7.56 - 7.44 (m, J = 11.5, 4.1 Hz, 1H), 7.23 (t, J = 9.5 Hz, 2H), 6.69 - 6.58 (m, J = 10.6, 4.2 Hz, 1H), 3.94 (s, 1H), 2.77 - 2.62 (m, 2H), 2.36 - 2.17 (m, J = 19.2, 9.6 Hz, 8H), 2.11 - 1.98 (m, J = 6.1 Hz, 2H), 1.78 - 1.63 (m, 2H). ¹³ C-NMR: (75 MHz, CDCI3) 6 148.75, 146.18, 145.86, 144.82, 134.68, 129.73, 128.47, 126.58, 123.70, 107.50, 106.51, 53.34, 50.15, 46.15, 32.54, 21.69. MS (ESI) m/z: 430.45 [M + H] ⁺ ; HPLC tret = 13.1 min (method B).

Example 6: N-(cyclopropylmethyl)-5-nitro-l-tosyl-lH-pyrrolo[2,3-b]pyrid in-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. ^T H NMR (300 MHz, DMSO) 6 8.87 (s, 1H), 7.99 (d, J = 8.3 Hz, 2H), 7.72 (d, 7 = 4.1 Hz, 1H), 7.41 (d, 7 = 8.3 Hz, 2H), 7.09 (d, 7 = 4.2 Hz, 1H), 3.60 - 3.53 (m, 2H), 2.33 (s, 3H), 1.25 - 1.10 (m, 7 = 12.3, 7.3 Hz, 1H), 0.59 - 0.51 (m, 2H), 0.39 - 0.33 (m, 7 = 4.8 Hz, 2H). ¹³ C-NMR (75 MHz, DMSO) 6 148.19, 146.23, 145.47, 145.40, 134.44, 130.23, 128.22, 126.30, 123.83, 123.70, 108.09, 49.42, 40.63, 40.35, 40.08, 39.80, 39.52, 39.24, 38.96, 21.40, 10.89, 3.61. MS (ESI) m/z: 387.33 [M + H] ⁺ ; HPLC t _re t = 20.7 min (method B).

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. ^T H NMR (400 MHz, DMSO) 6 8.89 (s, 1H), 8.82 (d, 7 = 8.1 Hz, 1H), 8.03 - 7.98 (m, 2H), 7.81 (d, 7 = 4.2 Hz, 1H), 7.44 (d, 7 = 8.1 Hz, 2H), 7.14 (d, 7 = 4.3 Hz, 1H), 4.35 - 4.26 (m, 7 = 8.3 Hz, 1H), 2.39 - 2.33 (m, 5H), 2.10 - 1.99 (m, 7 = 9.4 Hz, 4H), 1.82 - 1.68 (m, 7 = 21.1, 10.2 Hz, 2H). ¹³ C-NMR (101 MHz, DMSO) 6 146.01 (s), 145.16 (s), 144.30 (s), 134.12 (s), 130.33 (d, 7 = 10.5 Hz), 130.02 (s), 127.90 (s), 126.49 (s), 124.12 (s), 107.36 (s), 49.52 (s), 30.84 (t, 7 = 24.6 Hz), 28.49 (d, 7 = 9.5 Hz), 21.06 (s). MS (ESI) m/z: 451.33 [M + H] ⁺ ; HPLC t _re t = 18.3 min (method A).

Example 8: N-cyclopropyl-5-nitro-l-tosyl-lH-pyrrolo[2,3-b]pyridin-4-ami ne-. 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. ^T H NMR (300 MHz, CDCI3) 6 8.98 (s, 1H), 8.87 (s, 1H), 7.97 (d, 7 = 8.3 Hz, 2H), 7.48 (d, 7 = 4.1 Hz, 1H), 7.21 (d, 7 = 8.2 Hz, 2H), 7.15 (d, 7 = 4.1 Hz, 1H), 3.04 - 2.89 (m, 7 = 6.6, 3.0 Hz, 1H), 2.30 (s, 3H), 0.97 (q, 7 = 6.7 Hz, 2H), 0.78 - 0.73 (m, 2H). ¹³ C-NMR (75 MHz, CDCI ₃ ) 6 148.77, 146.85, 145.84, 145.81, 134.84, 129.79, 128.48, 126.56, 123.30, 108.90, 107.42, 27.21, 21.73, 10.14. MS (ESI) m/z: 373.40 [M + H] ⁺ ; HPLC t _re t = 18.5 min (method A).

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. ¹ H-NMR (300 MHz, DMSO) 6 8.98 (s, 1H), 8.00 (d, J = 8.4 Hz, 2H), 7.60 - 7.34 (m, 9H), 2.36 (s, 3H). ¹³ C-NMR (75 MHz, DMSO) 6 148.34, 146.28, 144.95, 143.33, 139.13, 134.42, 130.34, 129.68, 128.17, 127.74, 126.94, 124.09, 109.36, 106.31, 99.73, 21.37. MS (ESI) m/z: 409.40 [M + H] ⁺ ; HPLC t _re t = 20.1 min (method A).

Example 86: N-((lR,5S,6r)-bicyclo[3.1.0]hexan-6-yl)-5-nitro-l-tosyl-lH-p yrrolo[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. ¹ H-NMR (400 MHz, CDCI3) 6 9.06 (s, 1H), 8.82 (s, 1H), 8.05 (d, J = 8.4 Hz, 2H), 7.57 (d, J = 4.1 Hz, 1H), 7.29 (d, J = 8.2 Hz, 2H), 7.08 (d, J = 4.1 Hz, 1H), 2.76 - 2.72 (m, J = 1.9 Hz, 1H), 2.38 (s, 3H), 2.02 (dd, J = 13.0, 7.9 Hz, 2H), 1.85 (ddd, J = 21.6, 10.2 Hz, 2H), 1.71 (td, 1H), 1.59 (bs, 2H), 1.25 - 1.12 (m, 1H). ¹³ C-NMR (101 MHz, CDCI3) 6 148.83, 146.58, 145.91, 145.81, 135.09, 129.81, 128.59, 126.69, 123.29, 108.92, 106.77, 34.32, 28.56, 27.19, 21.75, 21.60. MS (ESI) m/z: 413.20 [M + H] ⁺ ; HPLC tret = 21.2 min (method A).

General procedure B for reduction of aromatic nitro groups to amines:

1.0 equiv of the nitro compound were weighed in a round bottomed flask and dissolved in EtOAc (0.075 M). The stirred mixture was thoroughly purged with argon; connection of the system to a washing flask and a subsequent water column before the gas outlet ensured a mild overpressure inside the reaction flask. 0.1 mass equiv Pt/C (5 %) were added and the system was once again purged with argon. Afterwards, the system was purged with H2, the washing flask acting as a reservoir, and stirred at ambient temperature until TLC and/or MS indicated full conversion of educt. Consumption of H2 could be measured semi-quantitatively by observing the height of the water column. If necessary, used up 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. ^X H-NMR (300 MHz, CDCI ₃ ) 6 7.91 (d, J = 8.4 Hz, 2H), 7.72 (s, 1H), 7.36 (d, J = 4.2 Hz, 1H), 7.13 (d, J = 8.3 Hz, 2H), 6.46 (d, J = 4.2 Hz, 1H), 3.66 - 3.53 (m, J = 11.6, 8.2 Hz, 1H), 2.25 (s, 3H), 2.08 (s, 1H), 2.00 - 1.94 (m, J = 7.3 Hz, 2H), 1.75 - 1.66 (m, 2H), 1.35 - 1.16 (m, 6H). ¹³ C- NMR (75 MHz, CDCI3) 6 146.07, 144.60, 140.56, 137.40, 135.69, 129.42, 127.86, 122.99, 122.26, 107.96, 104.89, 52.26, 34.27, 25.59, 24.80, 21.57. MS (ESI) m/z: 385.14 [M + H] ⁺ ; HPLC tret = 14.4 min (method A)

Example 11: N4-(tetrahydro-2H-pyran-4-yl)-l-tosyl-lH-pyrrolo[2,3-b]pyrid ine-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. H -NMR (300 MHz, CDCI3) 67.92 (d, J = 8.4 Hz, 2H), 7.76 (s, 1H), 7.39 (d, J = 4.2 Hz, 1H), 7.17 - 7.12 (m, J = 8.3 Hz, 3H), 6.44 (d, J = 4.2 Hz, 1H), 4.73 - 4.64 (m, J = 6.2 Hz, 1H), 3.95 - 3.89 (m, 2H), 3.44 (t, J = 16.0, 6.2 Hz, 2H), 2.26 (s, 3H), 1.92 (s, 2H), 1.53 - 1.44 (m, 2H). ¹³ C NMR (75 MHz, CDCI3) 6 145.96, 144.80, 140.07, 137.77, 135.67, 129.53, 127.98, 123.53, 122.82, 108.39, 104.46, 66.58, 49.75, 34.47, 21.66. MS (ESI) m/z: 387.4 [M + H] ⁺ ; HPLC tret = 10.4 min (method B)

Example 12: N4-(l-methylpiperidin-4-yl)-l-tosyl-lH-pyrrolo[2,3-b]pyridin e-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. ^T H NMR (300 MHz, CDCI3) 6 7.93 (t, J = 7.6 Hz, 2H), 7.73 (s, 1H), 7.38 (d, J = 4.1 Hz, 1H), 7.13 (d, J = 8.5 Hz, 2H), 6.44 (d, J = 4.2 Hz, 1H), 4.66 (d, J = 8.3 Hz, 1H), 3.69 - 3.45 (m, 1H), 2.88 (s, 1H), 2.79 - 2.67 (m, J = 11.6 Hz, 2H), 2.28 - 2.20 (m, J = 7.6 Hz, 6H), 2.10 (t, J = 10.5 Hz, 2H), 2.03 - 1.90 (m, J = 10.0 Hz, 3H), 1.58 - 1.43 (m, 2H). ¹³ C-NMR NMR (75 MHz, CDCI3) 6 146.00, 144.72, 140.35, 137.59, 135.66, 129.49, 127.93, 123.32, 122.66, 108.20, 104.66, 54.24, 49.99, 46.19, 33.41, 21.64. MS (ESI) m/z: 400.5 [M + H] ⁺ ; HPLC tret = 8.4 min (method B).

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. ^T H NMR (300 MHz, DMSO) 67.88 (d, J = 8.3 Hz, 2H), 7.57 (s, 1H), 7.42 (d, J = 4.2 Hz, 1H), 7.33 (d, J = 8.1 Hz, 2H), 6.81 (d, J = 4.2 Hz, 1H), 5.47 (t, J = 5.6 Hz, 1H), 4.32 (s, 2H), 3.39 - 3.27 (m, 2H), 2.29 (s, 3H), 1.11 - 1.01 (m, 1H), 0.51 - 0.42 (m, 2H), 0.32 - 0.18 (m, 2H). ¹³ C-NMR (75 MHz, DMSO) 6 144.72, 143.57, 137.20, 135.03, 132.73, 129.53, 127.32, 125.90, 122.34, 107.78, 106.00, 48.88, 21.04, 11.29, 3.37. MS (ESI) m/z: 357.27 [M + H] ⁺ ; HPLC t _re t = 11.7 min (method A).

Example 14: N4-(4,4-difluorocyclohexyl)-l-tosyl-lH-pyrrolo[2,3-b]pyridin e-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. ^T H NMR (300 MHz, CDCI ₃ ) 6 7.94 (d, J = 8.3 Hz, 2H), 7.45 - 7.39 (m, J = 4.2 Hz, 2H), 7.18 (d, J = 8.3 Hz, 2H), 6.50 (d, J = 4.2 Hz, 1H), 4.63 (d, J = 8.6 Hz, 1H), 3.90 - 3.74 (m, J = 8.5 Hz, 1H), 2.29 (s, 3H), 2.07 - 1.98 (m, J = 9.5 Hz, 4H), 1.90 - 1.78 (m, 4H), 1.62 - 1.50 (m, J = 20.4, 10.3 Hz, 2H). ¹³ C- NMR (75 MHz, CDCI3) 6 172.56, 146.44, 144.62, 139.32, 135.53, 135.18, 129.22, 127.61, 127.39, 122.98, 107.57, 104.33, 49.85, 31.53, 28.84, 20.80. MS (ESI) m/z: 421.33 [M + H] ⁺ ; HPLC tret = 17.7 min (method A).

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. ^T H NMR (300 MHz, CDCI3) 6 7.90 (d, J = 8.3 Hz, 2H), 7.70 (d, J = 11.5 Hz, 1H), 7.34 (d, J = 4.1 Hz, 1H), 7.12 (d, J = 8.1 Hz, 2H), 6.93 (d, J = 4.1 Hz, 1H), 5.02 (s, 1H), 2.84 - 2.68 (m, J = 4.0, 2.5 Hz, 2H), 2.23 (s, 3H), 1.21 - 1.15 (m, J = 8.3, 5.1 Hz, 1H), 0.83 - 0.71 (m, 2H), 0.61 - 0.52 (m, 2H). ¹³ C-NMR (75 MHz, CDCI3) 6 145.99, 144.67, 141.63, 136.96, 135.73, 129.48, 127.85, 122.80, 122.33, 109.13, 105.85, 26.64, 21.61, 9.65. MS (ESI) m/z: 343.33 [M + H] ⁺ ; HPLC t _re t = 10.5 min (method A).

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. H -NMR (400 MHz, CDCI3) 6 7.95 (d, J = 8.4 Hz, 2H), 7.71 (s, 1H), 7.40 (d, J = 4.1 Hz, 1H), 7.16 (d, J = 8.3 Hz, 2H), 6.87 (d, J = 4.1 Hz, 1H), 4.92 (bs, 1H), 2.94 (bs, 2H), 2.54 - 2.50 (m, 1H), 2.28 (s, 3H), 1.91 (dd, J = 12.7, 8.0 Hz, 2H), 1.75 (ddd, J = 20.7, 10.8 Hz, 2H), 1.63 (td, J = 12.9, 8.4 Hz, 1H), 1.42 (bs, 2H), 1.15 - 1.03 (m, J = 19.7, 8.3 Hz, 1H). ¹³ C-NMR (101 MHz, CDCI3) 6 145.97, 144.60, 141.51, 136.95, 135.89, 129.45, 127.84, 122.71, 122.26, 109.04, 105.31, 34.10, 28.31, 27.17, 21.91, 21.55. MS (ESI) m/z: 383.33 [M + H] ⁺ ; HPLC t _re t = 14.3 min (method A).

Alternative procedure C for reduction of nitro groups: In a round bottomed flask, 1.0 equiv of the nitro compound were dissolved in EtOH (0.1 M) and stirred at ambient temperature. A solution of 6.0 equiv of NazSzC in H2O (0.8 M) was added portionwise. Stirring continued at 70 °C until TLC and/or MS indicated full consumption of starting material, usually overnight. The EtOH was mostly evaporated under reduced pressure and the resulting aqueous mixture poured into a separatory funnel containing DCM. After washing twice with DCM, the combined organic phases were dried over Na2SO4 and evaporated in vacuo to yield the product as a solid. If needed, further purification was carried out by manual column chromatography or flash chromatography.

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 %). ^T H NMR (300 MHz, CDCI3) 6 7.92 (d, J = 7.0 Hz, 2H), 7.86 (s, 1H), 7.29 (d, J = 4.1 Hz, 1H), 7.20 - 7.11 (m, 3H), 6.93 (t, J = 7.6 Hz, 1H), 6.80 (d, J = 7.6 Hz, 2H), 5.98 (s, 1H), 5.89 (d, J = 4.1 Hz, 1H), 2.26 (s, 3H). ¹³ C-NMR (75 MHz, CDCI3) 6 144.91, 144.30, 141.69, 136.48, 135.72, 132.33, 129.62, 129.28, 129.07, 127.94, 124.29, 122.44, 119.36, 114.22, 104.50, 21.68. MS (ESI) m/z: 379.33 [M + H] ⁺ ; HPLC t _re t = 15.2 min (method A).

General procedure D for imidazole ring closure:

In a round bottomed flask, the vicinal diamine obtained in the previous step was dissolved in DMF (0.2 M). 1.2 equiv 5-(hydroxymethyl)furan-2-carbaldehyde were added at ambient temperature and the mixture was stirred for 15 min. Subsequently, 3% (V/V) water and 0.7 to 1.0 equiv KHSOs were added. At times, further addition of KHSOs was necessary during the course of the reaction to drive conversion to product, which was controlled by MS. To the reaction mixture, 0.2 M K2CO3 solution (2 equiv) were added, resulting in brownish precipitate. The solids were filtered, dried under reduced pressure and purified either by manual column chromatography or flash chromatography.

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. ^T H NMR (300 MHz, CDCI3) 68.88 (s, 1H), 8.10 (d, J = 8.2 Hz, 2H), 7.83 (d, J = 4.0 Hz, 1H), 7.33 - 7.16 (m, J = 8.5 Hz, 2H), 6.91 (d, J = 4.0 Hz, 1H), 6.87 (d, J = 3.4 Hz, 1H), 6.41 (d, J = 3.3 Hz, 1H), 4.71 (s, 2H), 2.32 (s, 3H), 2.21 - 2.09 (m, J = 0.9 Hz, 2H), 1.98 - 1.67 (m, J = 17.0 Hz, 5H), 1.61 - 1.23 (m, 5H). ¹³ C-NMR (75 MHz, CDCI3) 6 157.14, 145.27, 144.46, 143.31, 142.77, 138.06, 136.82, 135.22, 133.10, 129.61, 128.24, 124.75, 114.52, 109.53, 107.69, 104.60, 57.13, 30.66, 26.90, 25.61, 24.80, 21.62. MS (ESI) m/z: 491.4 [m + H] ⁺ ; HPLC t _re t = 19.6 min (method A)

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. ¹ H-NMR (300 MHz, CDCI3) 6 8.79 (s, 1H), 8.02 (d, J = 8.4 Hz, 2H), 7.75 (d, J = 4.0 Hz, 1H), 7.18 (d, J = 8.9 Hz, 2H), 6.98 (d, J = 4.1 Hz, 1H), 6.87 (d, J = 3.4 Hz, 1H), 6.36 (d, J = 3.4 Hz, 1H), 5.13 - 4.93 (m, 1H), 4.64 (s, 2H), 4.14 - 3.99 (m, 3H), 3.43 (t, J = 11.4 Hz, 2H), 2.26 (s, 3H), 1.96 (s, 1H), 1.80 - 1.66 (m, J = 13.0, 4.3 Hz, 2H), 1.22 - 1.10 (m, 1H). ¹³ C-NMR (75 MHz, CDCI3) 6 157.07, 145.39, 144.17, 143.58, 142.85, 138.26, 137.05, 135.28, 132.88, 129.70, 128.33, 125.11, 114.68, 109.80, 107.83, 104.90, 67.33, 57.31, 53.34, 30.54, 21.70. MS (ESI) m/z: 493.3 [M + H] ⁺ ; HPLC t _re t = 16.6 min (method A)

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. The mixture was diluted with CHCI3 and 60 ml of 15 % KOH were added. After transfer into a separatory funnel, the aqueous phase was extracted several times with ChCH. The combined organics were concentrated under reduced pressure, washed once with sparing amounts of water and dried over NazSOzi. They were then evaporated in vacuo and the crude product was purified using flash chromatography with EtOAc/MeOH (automatic gradient). Yield: 3.21 g (42 %) of example 19 as a beige solid. ^T H NMR (400 MHz, DMSO) 6 8.77 (s, 1H), 8.06 (d, J = 4.1 Hz, 1H), 8.02 (d, J =

8.4 Hz, 2H), 7.39 (d, J = 8.2 Hz, 2H), 7.27 (d, J = 4.1 Hz, 1H), 7.11 (d, J = 3.4 Hz, 1H), 6.59 (d, J =

3.4 Hz, 1H), 4.94 - 4.81 (m, 1H), 4.54 (s, 2H), 2.99 (d, J = 11.4 Hz, 2H), 2.54 - 2.39 (m, 3H), 2.29 (s, 3H), 2.28 (s, 3H), 2.16 - 2.06 (m, 2H), 1.91 (d, J = 8.6 Hz, 2H). ¹³ C-NMR (101 MHz, DMSO) 6 157.97, 145.52, 144.29, 142.60, 142.04, 137.37, 136.96, 134.67, 132.45, 129.88, 127.72, 125.49, 114.58, 109.02, 107.46, 105.25, 55.77, 54.42, 53.73, 45.88, 29.39, 20.99. MS (ESI) m/z: 506.38 [M + H] ⁺ ; HPLC t _re t = 12.9 min (method B).

Example 20: (5-(l-(cyclopropylmethyl)-6-tosyl-l,6-dihydroimidazo[4,5-d]p yrrolo[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. ¹ H NMR (400 MHz, DMSO) 6 8.73 (s, 1H), 8.03 (d, J = 8.4 Hz, 2H), 7.97 (d, J = 4.1 Hz, 1H), 7.39 (d, J = 8.1 Hz, 2H), 7.23 (dd, J = 3.7, 2.7 Hz, 2H), 6.58 (d, J = 3.4 Hz, 1H), 5.47 (s, 1H), 4.67 (d, J = 7.0 Hz, 2H), 4.54 (s, 2H), 2.29 (s, 3H), 1.33 - 1.15 (m, 1H), 0.44 - 0.34 (m, J = 7 A, 3.4, 2.0 Hz, 4H). ¹³ C-NMR (101 MHz, DMSO) 6 157.68, 145.35, 143.77, 143.35, 142.19, 136.72, 136.23, 134.69, 134.02, 129.78, 127.60, 125.45, 113.93, 109.07, 107.00, 102.31, 55.65, 49.16, 20.92, 11.40, 3.11. MS (ESI) m/z: 463.33 [M + H] ⁺ ; HPLC t _re t = 21.8 min (method A).

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. ^X H NMR (400 MHz, DMSO) 6 8.77 (s, 1H), 8.10 (d, J = 4.1 Hz, 1H), 8.03 (d, J = 8.4 Hz, 2H), 7.41 (d, J = 8.1 Hz, 2H), 7.15 (d, J = 3.4 Hz, 1H), 7.06 (bs, 1H), 6.59 (d, J = 3.4 Hz, 1H), 5.18 - 5.04 (m, 1H), 4.55 (s, 2H), 2.52 - 2.49 (m, 1H), 2.46 - 2.39 (m, J = 11.2 Hz, 1H), 2.32 (s, 3H), 2.25 - 2.19 (m, J = 4.6 Hz, 3H), 2.10 - 2.04 (m, 4H). ¹³ C-NMR (101 MHz, DMSO) 6 157.99, 145.47, 144.17, 142.46, 142.07, 137.33, 136.74, 134.61, 132.60, 129.84, 127.69, 125.64, 123.55, 114.63, 108.93, 107.24, 103.81, 55.70, 53.49, 31.57, 26.20, 20.96. MS (ESI) m/z: 527.47 [M + H] ⁺ ; HPLC t _re t = 22.9 min (method A).

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. H -NMR (400 MHz, DMSO) 6 8.66 (s, 1H), 8.02 (d, J = 8.4 Hz, 2H), 7.88 (d, J = 4.0 Hz, 1H), 7.35 (d, J = 8.1 Hz, 2H), 7.24 (d, J = 3.4 Hz, 1H), 7.15 (d, J = 4.0 Hz, 1H), 6.53 (d, J = 3.4 Hz, 1H), 5.41 (t, J = 5.9 Hz, 1H), 4.54 (d, J = 5.7 Hz, 2H), 3.84 - 3.77 (m, 1H), 2.32 (s, 3H), 1.43 - 1.39 (m, J = 6.7 Hz, 2H), 0.93 - 0.89 (m, 2H). ¹³ C-NMR (101 MHz, DMSO) 6 157.76, 145.28, 145.04, 142.81, 142.21, 136.61, 135.73, 135.03, 134.73, 129.55, 127.54, 124.88, 114.51, 108.71, 107.61, 103.68, 55.80, 26.89, 20.96, 9.93. MS (ESI) m/z: 449.47 [M + H] ⁺ ; HPLC t _re t = 16.7 min (method A).

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. ^X H-NMR (300 MHz, CDCI ₃ ) 68.82 (s, 1H), 7.97 (d, J = 8.4 Hz, 2H), 7.63 - 7.52 (m, 3H), 7.45 (d, J = 4.0 Hz, 1H), 7.41 - 7.33 (m, 2H), 7.21 - 7.13 (m, 2H), 6.14 (d, J = 3.4 Hz, 1H), 5.89 (d, J = 3.5 Hz, 1H), 5.72 (d, J = 4.5 Hz, 1H), 4.53 (s, 2H), 3.22 (s, 1H), 2.21 (s, 3H). ¹³ C-NMR (75 MHz, CDCI ₃ ) 6 157.04, 145.25, 144.13, 143.46, 143.10, 137.85, 136.27, 136.20, 135.43, 135.28, 130.57, 130.32, 129.68, 128.17, 128.05, 125.14, 113.71, 109.23, 107.59, 101.28, 57.29, 21.67. MS (ESI) m/z: 485.40 [M + H] ⁺ ; HPLC t _re t = 16.6 min (method A).

Example 88: (5-(l-((lR,5S,6r)-bicyclo[3.1.0]hexan-6-yl)-6-tosyl-l,6-dihy droimidazo[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. ^X H-NMR (400 MHz, CDCI3) 6 8.75 (s, 1H), 8.08 (d, J = 8.4 Hz, 2H), 7.65 (d, J = 4.0 Hz, 1H), 7.22 (d, J = 8.2 Hz, 2H), 6.94 (d, J = 3.4 Hz, 1H), 6.74 (d, J = 4.0 Hz, 1H), 6.38 (d, J = 3.4 Hz, 1H), 4.67 (s, 2H), 2.86 - 2.81 (m, 1H), 2.29 (s, 3H), 2.15 - 2.12 (m, J = 3.5 Hz, 1H), 1.97 (dd, J = 12.8, 8.0 Hz, 2H), 1.78 (ddd, J = 21.1, 10.0 Hz, 2H), 1.64 - 1.57 (m, 1H), 1.53 (bs, 2H), 1.09 - 0.95 (m, J = 11.8, 8.6 Hz, 1H). ¹³ C-NMR (101 MHz, CDCI3) 6 157.22, 145.55, 145.22, 143.61, 143.00, 137.55, 135.93, 135.55, 134.95, 129.63, 128.23, 124.91, 114.31, 109.58, 107.97, 102.87, 57.20, 34.10, 28.77, 27.74, 21.61, 21.23. MS (ESI) m/z: 489.36 [M + H] ⁺ : HPLC t _re t = 20.1 min (method B).

General procedure E for Dess-Martin-Oxidation of furylic alcohols:

The products obtained in the previous step were dissolved in DCM (0.2 M) and cooled in an ice bath. 1.2 equiv Dess-Martin-Periodinane were added and the ice bath removed, allowing the stirred mixture to slowly reach ambient temperature. Reaction progress was monitored by TLC and/or MS. After complete conversion, saturated NaHCOs solution was added. Phases were separated in a separatory funnel. After extraction of the aqueous phase with four to five portions of DCM, the combined organics were dried over NazSC and DCM was removed in vacuo. Further purification was carried out either by manual column chromatography or flash chromatography.

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. ^X H-NMR (400 MHz, DMSO) 6 9.74 (s, 1H), 8.78 (s, 1H), 8.03 (d, J = 8.2 Hz, 2H), 7.96 (d, J = 4.0 Hz, 1H), 7.68 (t, J = 6.5 Hz, 1H), 7.39 - 7.32 (m, J = 8.7 Hz, 3H), 7.11 (d, J = 4.0 Hz, 1H), 5.01 - 4.88 (m, J = 12.0 Hz, 1H), 2.31 (s, 3H), 2.24 - 2.18 (m, J = 11.4 Hz, 2H), 2.00 - 1.90 (m, 4H), 1.79 - 1.73 (m, J = 7.8 Hz, 1H), 1.58 - 1.44 (m, 3H). ¹³ C-NMR (101 MHz, DMSO) 6 178.01, 152.66, 148.31, 145.20, 142.33, 142.23, 137.74, 136.71, 134.56, 133.05, 129.57, 127.67, 125.09, 123.08, 115.32, 107.20, 104.53, 57.01, 30.28, 25.14, 24.16, 21.00. MS (ESI) m/z: 489.09 [M + H]; HPLC t _re t = 20.5 min (method A).

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. ¹ H- NMR: (400 MHz, DMSO) 6 9.76 (s, 1H), 8.85 (s, 1H), 8.11 (d, J = 4.1 Hz, 1H), 8.04 (d, J = 8.4 Hz, 2H), 7.76 (d, J = 3.8 Hz, 1H), 7.47 (d, J = 3.8 Hz, 1H), 7.41 (d, J = 8.3 Hz, 2H), 7.15 (d, J = 4.1 Hz, 1H), 5.31 - 5.20 (m, 1H), 4.11 (dd, J = 11.4, 4.6 Hz, 2H), 3.61 - 3.53 (m, J = 11.2 Hz, 2H), 2.47 - 2.39 (m, J = 11.6, 7.3 Hz, 2H), 2.31 (s, 3H), 1.98 (dd, J = 12.6, 4.4 Hz, 2H). ¹³ C-NMR (101 MHz, DMSO) 6 178.83, 152.88, 145.62, 142.65, 137.99, 136.89, 134.42, 131.07, 130.33, 129.93, 127.77, 126.25, 125.76, 120.38, 115.70, 107.38, 105.04, 66.31, 53.23, 30.20, 21.02. MS (ESI) m/z: 491.4 [M + H] ⁺ ; HPLC t _re t = 17.2 min (method A).

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. ^T H NMR (400 MHz, DMSO) 6 9.76 - 9.74 (m, 1H), 8.83 (s, 1H), 8.11 (d, J = 4.1 Hz, 1H), 8.03 (d, J = 8.4 Hz, 2H), 7.76 (d, J = 3.8 Hz, 1H), 7.45 (d, J = 3.8 Hz, 1H), 7.42 (d, J = 8.4 Hz, 2H), 7.31 (d, J = 4.0 Hz, 1H), 5.05 - 4.94 (m, 1H), 3.05 (d, J = 7.2 Hz, 2H), 2.50 (dd, J = 3.6, 1.8 Hz, 4H), 2.33 (s, 6H), 2.04 - 1.94 (m, J = 10.4 Hz, 2H). ¹³ C-NMR (101 MHz, DMSO) 6 178.85, 152.90, 148.06, 145.67, 142.82, 142.24, 137.98, 137.00, 134.59,

132.76, 129.98, 127.78, 125.75, 123.30, 115.73, 107.52, 105.39, 69.80, 54.33, 45.73, 29.29, 21.06. MS (ESI) m/z: 504.6 [M + H] ⁺ ; HPLC t _re t = 15.0 min (method A).

Example 27: 5-(l-(cyclopropylmethyl)-6-tosyl-l,6-dihydroimidazo[4,5-d]py rrolo[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. ^T H NMR (400 MHz, CDCI ₃ ) 6 9.71 (s, 1H), 8.89 (s, 1H), 8.09 (d, J = 8.4 Hz, 2H), 7.79 (d, J = 4.0 Hz, 1H), 7.39 (s, 2H), 7.25 (d, J = 8.1 Hz, 2H), 6.84 (d, J = 4.0 Hz, 1H), 4.68 (d, J = 6.9 Hz, 2H), 2.14 (s, 3H), 1.43 - 1.31 (m, 1H), 0.59 - 0.40 (m, 4H). ¹³ C-NMR (101 MHz, CDCI3) 6 176.98, 152.93, 149.89, 145.34, 143.26, 142.17, 138.49, 136.85, 135.44,

134.76, 129.66, 128.29, 125.51, 122.43, 114.72, 107.38, 101.39, 50.54, 30.86, 21.61, 11.71, 3.78. MS (ESI) m/z: 461.33 [M + H] ⁺ ; HPLC t _re t = 22.7 min (method A). Example 28: 5-(l-(4,4-difluorocyclohexyl)-6-tosyl-l,6-dihydroimidazo[4,5 -d]pyrrolo[2,3- b]pyridin-2-yl)furan-2-carbaldehyde: Obtained from 2.04 g of example 21 following general procedure E with stirring overnight. Flash chromatography (cyclohexane/acetone, automatic gradient). Yield: 1.84 g (90 %) as brown solid. ^X H-NMR NMR (400 MHz, DMSO) 6 9.77 (s, 1H), 8.84 (s, 1H), 8.13 (d, J = 4.1 Hz, 1H), 8.03 (d, 2H), 7.75 (d, J = 3.8 Hz, 1H), 7.46 (d, J = 3.8 Hz, 1H), 7.41 (d, J = 8.1 Hz, 2H), 7.07 (s, 1H), 5.22 - 5.12 (m, J = 14.3, 10.0 Hz, 1H), 2.47 - 2.36 (m, J = 11.0 Hz, 2H), 2.32 (s, 3H), 2.29 - 2.10 (m, 6H). ¹³ C-NMR (101 MHz, DMSO) 6 179.14, 153.12, 147.97, 145.79, 142.97, 142.44, 138.16, 137.00, 134.73, 130.11, 127.94, 126.08, 122.79, 115.94, 107.52, 104.09, 54.02, 32.07, 31.80, 30.80, 26.46, 21.20. MS (ESI) m/z: 525.40 [M + H] ⁺ ; HPLC tret = 20.0 min (method A).

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. ^T H NMR (400 MHz, DMSO) 69.76 (s, 1H), 8.78 (s, 1H), 8.05 - 8.02 (m, 2H), 7.99 (d, J = 4.0 Hz, 1H), 7.77 (d, J = 3.8 Hz, 1H), 7.58 (d, J = 3.8 Hz, 1H), 7.42 (d, J = 8.1 Hz, 2H), 7.24 (d, J = 4.0 Hz, 1H), 3.96 - 3.89 (m, 1H), 2.33 (s, 3H), 1.46 - 1.40 (m, 2H), 0.99 - 0.94 (m, 2H). ¹³ C-NMR (101 MHz, DMSO) 6 178.86, 152.62, 148.04, 145.55, 143.98, 142.47, 140.47, 137.57, 135.87, 135.48, 134.66, 129.95, 127.70, 125.49, 115.73, 107.80, 104.15, 30.69, 21.06, 9.94. MS (ESI) m/z: 447.33 [M + H] ⁺ ; HPLC t _re t = 17.1 min (method A).

Example 30: 5-(l-phenyl-6-tosyl-l,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]p yridin-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. H -NMR (300 MHz, CDCI ₃ ) 69.56 (s, 1H), 8.94 (s, 1H), 8.00 (d, 2H), 7.62 ( m, J = 9.0, 3.8, 2.1 Hz, 3H), 7.51 (d, J = 4.0 Hz, 1H), 7.44 - 7.39 (m, 2H), 7.22 - 7.17 (m, 2H), 7.08 (d, J = 3.8 Hz, 1H), 6.41 (d, J = 3.8 Hz, 1H), 5.78 (d, J = 4.0 Hz, 1H), 2.28 (s, 3H). ¹³ C- NMR (75 MHz, CDCI3) 6 177.86, 152.83, 147.66, 144.97, 143.32, 142.07, 138.24, 136.01, 135.55, 135.12, 134.98, 130.38, 129.96, 129.32, 127.86, 127.48, 124.96, 118.88, 113.86, 107.23, 100.90, 21.30. MS (ESI) m/z: 483.40 [M + H] ⁺ ; HPLC t _re t = 8.5 min (method A).

Example 89: 5-(l-((lR,5S,6r)-bicyclo[3.1.0]hexan-6-yl)-6-tosyl-l,6-dihyd roimidazo[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. ^T H-NMR (400 MHz, CDCI3) 6 9.80 (s, 1H), 8.91 (s, 1H), 8.11 (d, J = 8.3 Hz, 2H), 7.83 (d, J = 3.9 Hz, 1H), 7.43 (d, J = 3.7 Hz, 1H), 7.38 (d, J = 3.7 Hz, 1H), 7.29 - 7.25 (m, J = 8.2 Hz, 2H), 7.05 (d, J = 3.9 Hz, 1H), 3.55 - 3.50 (m, 1H), 2.35 (s, 3H), 2.31 (dd, J = 12.8, 8.1 Hz, 2H), 1.94 (ddd, J = 21.2, 10.2 Hz, 2H), 1.88 - 1.81 (m, J = 13.1, 8.5 Hz, 1H), 1.77 (bs, 2H), 1.49 - 1.38 (m, 1H). ¹³ C-NMR (101 MHz, CDCI3) 6 177.51, 153.48, 149.55, 145.33, 143.92, 143.44, 138.60, 136.42, 135.55, 135.45, 129.72, 128.33, 125.31, 122.02, 114.76, 108.17, 103.07, 34.62, 29.12, 27.74, 21.69, 21.51. MS (ESI) m/z: 487.33 [M + H] ⁺ ; HPLC t _re t = 22.5 min (method B).

General procedure F for Tosyl Cleavage:

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. ^T H NMR (400 MHz, DMSO) 6 12.12 (s, 1H), 9.74 (s, 1H), 8.70 (s, 1H), 7.76 (d, J = 3.7 Hz, 1H), 7.58 - 7.55 (m, 1H), 7.38 (d, J =

3.7 Hz, 1H), 6.86 - 6.80 (m, J = 3.3, 1.8 Hz, 1H), 4.95 (dt, J = 16.5, 8.4, 4.2 Hz, 1H), 2.42 - 2.27 (m, 2H), 2.03 - 1.84 (m, 4H), 1.80 - 1.65 (m, J = 22.2 Hz, 1H), 1.59 - 1.42 (m, 3H). ¹³ C-NMR (101 MHz, DMSO) 6 178.38, 152.49, 149.12, 144.72, 140.35, 136.28, 134.81, 133.00, 124.09, 123.66, 114.64, 104.03, 99.80, 56.62, 30.22, 25.22, 24.28. MS (ESI) m/z: 335.42 [M + H]; HPLC tret = 14.9 min (method A).

Example 32: 5-(l-(tetrahydro-2H-pyran-4-yl)-l,6-dihydroimidazo[4,5-d]pyr rolo[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. ^T H NMR (300 MHz, DMSO) 6 11.92 (s, 1H), 9.57 (s, 1H), 8.51 (s, 1H), 7.57 (d, J = 3.8 Hz, 1H), 7.41 (d, J = 2.6 Hz, 1H), 7.23 (d, J = 3.7 Hz, 1H), 6.66 (d, J =

1.7 Hz, 1H), 5.12 - 4.95 (m, 1H), 4.05 - 3.90 (m, 2H), 3.88 - 3.79 (m, 1H), 2.53 - 2.37 (m, 1H), 2.37 - 2.29 (m, 1H), 1.85 - 1.72 (m, J = 9.1 Hz, 2H), 1.04 - 0.95 (m, 1H). ¹³ C-NMR (75 MHz, DMSO) 6 178.82, 152.73, 148.89, 144.75, 140.62, 136.46, 135.02, 132.77, 124.47, 123.61, 114.95, 104.31, 100.38, 66.53, 52.99, 30.17. MS (ESI) m/z: 337.4 [M + H] ⁺ ; HPLC t _re t = 12.6 min (method A).

Example 33: 5-(l-(l-methylpiperidin-4-yl)-l,6-dihydroimidazo[4,5-d]pyrro lo[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. ^T H NMR (400 MHz, DMSO) 6 12.07 (s, 1H), 9.74 (s, 1H), 8.68 (s, 1H), 7.76 (d, J = 3.7 Hz, 1H), 7.63 - 7.55 (m, 1H), 7.40 (d, J = 3.7 Hz, 1H), 6.99 (s, 1H), 5.04 - 4.92 (m, 1H), 3.03 (d, J = 10.9 Hz, 2H), 2.75 - 2.64 (m, 2H), 2.58 - 2.47 (m, 4H), 2.31 - 2.28 (m, 3H). ¹³ C-NMR (101 MHz, DMSO) 6 178.35, 152.42, 148.77, 144.45, 140.38, 136.11, 134.81, 132.51, 124.02, 123.37, 114.55, 104.15, 100.44, 54.46, 53.73, 45.85, 29.17. MS (ESI) m/z: 350.64 [M + H] ⁺ ; HPLC t _re t = 12.7 min (method A).

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. H -NMR (400 MHz, DMSO) 6 11.85 (s, 1H), 9.69 (s, 1H), 8.62 (s, 1H), 7.57 (d, J = 3.8 Hz, 1H), 7.39 - 7.35 (m, 2H), 6.75 - 6.71 (m, J = 3.3, 1.8 Hz, 1H), 4.71 (d, J = 7.0 Hz, 2H), 1.50- 1.39 (m, 1H), 0.51 -0.43 (m, 4H). ¹³ C-NMR (101 MHz, DMSO) 6 177.08, 152.11, 149.65, 144.80, 139.80, 135.71, 134.21, 134.16, 123.67, 122.97, 113.28, 103.62, 96.42, 49.59, 11.32, 3.08. MS (ESI) m/z: 307.33 [M + H] ⁺ ; HPLC t _re t = 15.1 min (method A).

Example 35: 5-(l-(4,4-difluorocyclohexyl)-l,6-dihydroimidazo[4,5-d]pyrro lo[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. ^T H NMR (400 MHz, DMSO) 6 12.16 (s, 1H), 9.77 (s, 1H), 8.70 (s, 1H), 7.75 (d, J = 3.7 Hz, 1H), 7.64 - 7.57 (m, 2H), 7.42 (d, J = 3.8 Hz, 1H), 5.23 - 5.12 (m, 1H), 2.31 - 2.24 (m, J = 13.3 Hz, 4H), 2.18 - 2.09 (m, 4H). ¹³ C NMR (101 MHz, DMSO) 6 178.80, 152.72, 152.31, 148.61, 144.71, 140.75, 136.32, 136.06, 134.94, 132.69, 124.48, 122.87, 114.86, 104.21, 99.17, 53.52, 32.01, 31.77, 31.52, 26.30, 26.20. MS (ESI) m/z: 371.46 [M + H] ⁺ ; HPLC t _re t = 19.7 min (method A). Example 36: 5-(l-cyclopropyl-l,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyri din-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. ^X H NMR (300 MHz, DMSO) 6 11.91 (s, 1H), 9.74 (s, 1H), 8.61 (s, 1H), 7.70 (d, J = 4.7, 3.8 Hz, 1H), 7.53 - 7.41 (m, J = 5.9, 3.9 Hz, 2H), 6.91 - 6.83 (m, 1H), 3.90 (dt, J = 7.3, 3.8 Hz, 1H), 1.51 - 1.36 (m, 2H), 1.04 - 0.94 (m, J = 7.5 Hz, 2H). ¹³ C-NMR (75 MHz, DMSO) 6 178.12, 152.28, 148.89, 144.89, 141.66, 135.87, 135.20, 133.68, 123.72,

123.25, 114.33, 104.36, 98.62, 30.51, 9.87. MS (ESI) m/z: 293.46 [M + H] ⁺ ; HPLC t _re t = 11.8 min (method A).

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. ^T H-NMR (400 MHz, DMSO) 6 12.05 - 12.02 (m, 1H), 9.63 (s, 1H), 8.80 (s, 1H), 7.78 - 7.75 (m, J = 6.1, 2.2 Hz, 4H), 7.57 (d, J = 3.8 Hz, 1H), 7.37 - 7.34 (m, 2H), 6.45 (d, J = 3.8 Hz, 1H), 5.66 -5.63 (m, 1H). ¹³ C-NMR (101 MHz, DMSO) 6178.32, 152.11, 148.35, 145.33,

140.26, 136.14, 135.94, 135.09, 133.90, 130.25, 130.07, 127.99, 124.30, 123.45, 113.32, 103.86, 96.17. MS (ESI) m/z: 329.53 [M + H] ⁺ ; HPLC t _re t = 15.2 min (method A).

Example 90: 5-(l-((lR,5S,6r)-bicyclo[3.1.0]hexan-6-yl)-l,6-dihydroimidaz o[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. ¹ H-NMR : (400 MHz, CDCI3) 6 11.73 (bs, 1H), 9.71 (s, 1H), 8.71 (s, 1H), 7.41 - 7.31 (m, 2H), 6.89 - 6.82 (m, 2H), 3.36

- 3.33 (m, 1H), 2.56 (s, 1H), 2.24 (dd, J = 12.2, 8.2 Hz, 2H), 1.91 - 1.85 (m, J = 9.7 Hz, 2H), 1.80

- 1.75 (m, 2H), 1.16 - 1.10 (m, 1H). ¹³ C-NMR: (101 MHz, CDCI3) 6 177.52, 153.22, 150.17, 145.25, 142.59, 136.27, 135.99, 134.55, 123.72, 121.96, 113.96, 105.43, 99.18, 34.59, 29.02, 27.82, 21.52. MS (ESI) m/z: 333.43 [M + H] ⁺ ; HPLC t _re t= 19.5 min (method A).

General procedure G for Knoevenagel-condensation:

Products obtained from the tosyl deprotection step were dissolved in MeOH or IPrOH (0.2 M) and 0.1 equiv piperidine. The corresponding cyanoacetamide (1.0 to 1.1 equiv) was added and the stirred solution was heated to 50-70 °C, either in an oil bath or a shaking incubator, or left at ambient temperature. Reaction times ranged between 1-3 h and complete conversion was determined by TLC and MS. Products were either isolated by filtration after storage at -20 °C or by flash chromatography. Oftentimes, mixtures of E/Z isomers were obtained, leading to complex NMR spectra.

Example 38: (E)-2-cyano-3-(5-(l-cyclohexyl-l,6-dihydroimidazo[4,5-d]pyrr olo[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. Yield: 460 mg (58 %) of example 38 as yellow solid. ^T H NMR (400 MHz, DMSO) 6 12.08 (s, 1H), 8.69 (s, 1H), 7.78 (s, 1H), 7.52 (d, J = 28.3 Hz, 2H), 7.39 (s, 1H), 6.83 (s, 1H), 5.03 - 4.86 (m, 1H), 3.35 (s, 6H), 2.38 - 2.32 (m, 2H), 2.15 - 1.98 (m, J = 17.8 Hz, 2H), 1.96 - 1.87 (m, 2H), 1.83 - 1.69 (m, 1H), 1.63 - 1.43 (m, J = 37.3 Hz, 3H). ¹³ C-NMR (101 MHz, DMSO) 6 162.73, 149.50,

148.39, 144.62, 140.49, 136.26, 135.32, 135.02, 132.76, 124.03, 121.74, 116.30, 116.24, 104.08, 100.29, 100.23, 56.07, 30.02, 29.96, 24.88, 24.22. ESI-HRMS: [M + H] ⁺ calculated for C24H24N6O2: 429.20335, found 429.20374; HPLC t _re t = 21.1 min (method A).

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)a crylamide 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. No further purification was necessary. Yield: 350 mg (40 %) as an orange solid. ^T H NMR (400 MHz, DMSO) 6 11.95 (s, 1H), 8.60 - 8.47 (m, J = 5.4 Hz, 1H), 7.62 (s, 1H), 7.48 - 7.39 (m, 1H), 7.29 (dd, J = 9.2, 3.7 Hz, 2H), 6.75 - 6.61 (m, J = 20.2 Hz, 1H), 5.27 (q, 1H), 3.98 - 3.88 (m, 2H), 3.57 - 3.43 (m, J = 11.4 Hz, 2H), 3.26 (s, 3H), 3.06 - 2.95 (m, 1H), 2.88 - 2.76 (m, J = 11.0 Hz, 2H), 2.32 (s, 1H), 1.98 - 1.64 (m, 3H). ¹³ C-NMR (101 MHz, DMSO) 6 162.61, 149.39, 148.47,

144.40, 140.15, 136.11, 135.20, 134.99, 132.40, 123.99, 122.16, 116.07, 115.87, 104.13, 101.39, 100.51, 65.97, 51.82, 30.34, 29.44. ESI-HRMS: [M + H] ⁺ calculated for C23H22N6O3: 431.18262, found 431.18322; [M + H] ⁺ ; HPLC t _re t = 19.1 min (method A). Example 40: methyl (E)-N-(2-cyano-3-(5-(l-cyclohexyl-l,6-dihydroimidazo[4,5-d]p yrrolo[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. ¹ H NMR (400 MHz, DMSO) 6 12.08 (s, 1H), 8.67 (d, J = 8.2 Hz, 1H), 7.87 - 7.73 (m, 1H), 7.58 - 7.53 (m, J = 6.0, 3.0 Hz, 1H), 7.39 (d, J = 3.6 Hz, 1H), 7.32 (dd, J = 26.1, 3.8 Hz, 1H), 6.88 - 6.80 (m, J = 9.0, 3.2, 1.8 Hz, 1H), 5.01 - 4.87 (m, 1H), 3.69 (s, 3H), 3.23 (s, 3H), 3.09 (s, 1H), 1.98 (s, 1H), 1.92 - 1.89 (m, 2H), 1.80 - 1.71 (m, 2H), 1.65 - 1.41 (m, 4H), 1.25 - 1.06 (m, J = 9.7, 6.5, 3.0 Hz, 2H). ¹³ C-NMR (101 MHz, DMSO) 6 168.82, 163.54, 162.23, 149.36, 148.87, 144.49, 140.41, 136.17, 134.94, 132.72, 124.06, 119.80, 116.36, 115.70, 115.46, 104.05, 100.29, 69.65, 56.03, 51.77, 36.54, 29.88, 24.80, 24.15. ESI-HRMS: [M + H] ⁺ calculated for C26H26N6O4: 487.20883, found 487.20970; HPLC t _re t= 19.8 and 20.7 min (E/Z mixture, method A).

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)a cryloyl)-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. Yield: 796 mg (56 %) as an orange solid. ^T H NMR (400 MHz, DMSO) 6 12.08 (s, 1H), 8.69 (s, 1H), 7.88 - 7.70 (m, J = 24.6, 13.4 Hz, 1H), 7.61 - 7.56 (m, J = 2.7 Hz, 1H), 7.53 - 7.43 (m, J = 13.7 Hz, 1H), 7.43 - 7.32 (m, 1H), 6.92 - 6.81 (m, 1H), 5.46 - 5.05 (m, 1H), 4.36 - 4.19 (m, 1H), 4.17 - 4.03 (m, J = 16.2, 11.4, 4.7 Hz, 2H), 3.73 - 3.62 (m, 3H), 3.59 - 3.55 (m, J = 6.4 Hz, 3H), 3.28 - 3.23 (m, 1H), 3.09 (t, J = 28.2 Hz, 1H), 2.74 - 2.58 (m, 2H), 2.54 - 2.49 (m, 1H), 2.06 - 1.86 (m, J = 15.7 Hz, 2H). ¹³ C-NMR (101 MHz, DMSO) 6 178.79, 163.78, 152.75, 149.66, 144.66, 140.46, 136.39, 135.26, 132.75, 124.41, 116.57, 115.91, 114.94, 104.46, 100.87, 100.38, 66.55, 66.28, 52.18, 48.67, 36.77, 30.20, 29.74. ESI- HRMS: [M + Na] ⁺ calculated for C25H24N6O5 : 511.17004, found 511.17050; HPLC t _re t = 16.7 and 18.5 min (E/Z mixture, method A). Example 43: (E)-2-cyano-3-(5-(l-cyclohexyl-l,6-dihydroimidazo[4,5-d]pyrr olo[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. Yield: 225 mg (15 %) as an orange solid. ¹ H NMR (400 MHz, DMSO) 6 12.10 (s, 1H), 8.68 (s, 1H), 7.89 (d, J = 7.9, 0.9 Hz, 2H), 7.58 (d, J = 7.7, 1.7 Hz, 2H), 7.17 - 7.08 (m, 1H), 4.98 - 4.88 (m, 1H), 3.46 (t, J = 6.6 Hz, 2H), 3.33 (t, J = 6.7 Hz, 2H), 2.92 (s, 3H), 2.64 - 2.56 (m, J = 12.0, 5.4 Hz, 2H), 2.34 (s, 6H), 2.13 - 2.03 (m, 2H), 1.24 - 1.12 (m, 6H). ¹³ C-NMR (101 MHz, DMSO) 6 163.38, 149.61, 144.71, 144.11, 140.68, 139.90, 136.35, 135.11, 132.92, 130.99, 129.34, 127.95, 124.29, 116.49, 104.26, 100.43, 93.66,

56.28, 55.04, 45.55, 44.26, 35.28, 30.11, 25.06. ESI-HRMS: [M + H] ⁺ calculated for C27H31N7O2 : 486.26120, found 486.26138; HPLC t _re t = 15.5 and 16.2 min (E/Z mixture, method A).

Example 45: (E)-2-cyano-N-(2-(dimethylamino)ethyl)-N-methyl-3-(5-(l-(tet rahydro-2H-pyran- 4-yl)-l,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-2-yl)fu ran-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. Yield: 70 mg (46 %) as an orange to red solid. ^T H NMR (400 MHz, CDCI3) 6 12.25 (s, 1H), 8.83 (s, 1H), 7.67 (s, 1H), 7.53 - 7.45 (m, 1H), 7.38 (d, J = 3.7 Hz, 1H), 7.23 (d, J = 3.7 Hz, 1H), 7.10 - 7.05 (m, J = 2.2 Hz, 1H), 5.53 - 5.40 (m, 1H), 4.22 (dd, J = 11.5, 4.7 Hz, 2H), 3.74 (t, J = 11.6 Hz, 2H), 3.62 (t, J = 6.2 Hz, 2H), 3.20 (s, 3H), 2.89 (qd, J = 12.5, 5.1 Hz, 2H), 2.58 (t, J = 6.6 Hz, 2H), 2.28 (s, 6H), 2.02 (dd, J = 12.6, 4.6 Hz, 2H). ¹³ C-NMR: (101 MHz, DMSO) 6 149.66, 148.53, 144.62, 140.44, 136.31, 135.17, 132.64, 124.31, 122.23, 116.38, 116.19, 104.36, 102.00, 100.71, 66.24, 56.08, 52.12,

45.28, 44.91, 35.54, 29.70. ESI-HRMS: [M + H] ⁺ calculated for C26H29N7O3 : 488.24046, found 488.24070; HPLC t _re t = 14.2 and 15.4 min (E/Z mixture, method A).

Example 46: (E)-2-cyano-3-(5-(l-cyclohexyl-l,6-dihydroimidazo[4,5-d]pyrr olo[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-dimeth yltetrahydro-2H-pyran-2- yl)oxy)-3,5,6,8,10,12,14-heptamethyl-15-oxo-l-oxa-6-azacyclo pentadecan-ll-yl)oxy)-3- hydroxy-6-methyltetrahydro-2H-pyran-4-yl)(methyl)amino)ethyl )-N-methylacrylamide Obtained from 100 mg of example 31 and 257 mg of example 47 (1.0) in 1 ml MeOH following general procedure G at 60 °C oil bath temperature with a reaction time of 1 h. Manual column chromatography (EtOAc EtOAc/MeOH 4:1). Yield: 255 mg (73 %) as a yellow solid. ^X H-NMR (400 MHz, DMSO) 6 12.08 (s, 1H), 8.67 (s, 1H), 7.70 (s, 1H), 7.57 - 7.52 (m, J = 9.1, 6.3 Hz, 2H), 7.46 (s, 1H), 7.38 (d, J = 3.6 Hz, 1H), 4.96 - 4.82 (m, J = 20.8 Hz, 4H), 4.77 - 4.72 (m, 1H), 4.59 (s, 1H), 4.34 - 4.25 (m, 3H), 4.11 - 4.03 (m, 2H), 4.01 - 3.90 (m, J =

3.4 Hz, 2H), 3.78 (s, 1H), 3.62 (d, J = 7.0 Hz, 1H), 3.50 (s, 3H), 3.42 (d, J = 7.5 Hz, 2H), 3.23 (t, J = 4.7 Hz, 3H), 3.06 - 3.03 (m, 1H), 2.94 - 2.89 (m, 2H), 2.69 (s, 1H), 2.41 - 2.30 (m, 6H), 2.26 - 2.17 (m, 6H), 2.11 (s, 1H), 2.04 - 2.00 (m, J = 11.4 Hz, 2H), 1.94 - 1.87 (m, 5H), 1.79 - 1.72 (m, 4H), 1.60 - 1.45 (m, 9H), 1.22 (s, 3H), 1.17 - 1.16 (m, 3H), 1.14 (s, 1H), 1.11 - 1.10 (m, J = 3.2 Hz, 2H), 1.05 (d, J = 5.0 Hz, 4H), 1.01 - 0.99 (m, 3H), 0.95 - 0.93 (m, 2H), 0.87 - 0.82 (m, 6H), 0.79 - 0.75 (m, 3H). ¹³ C NMR (101 MHz, DMSO) 6 177.27, 149.58, 148.43, 144.70, 140.58, 136.31, 135.11, 132.87, 124.19, 121.68, 116.41, 104.20, 100.35, 99.62, 94.65, 77.44, 77.09, 76.20, 73.73, 73.64, 72.82, 72.34, 69.83, 68.56, 67.05, 65.67, 64.91, 56.19, 55.83, 48.82, 48.70, 45.80, 44.96, 41.70, 40.99, 38.26, 35.76, 34.59, 30.66, 30.34, 30.06, 29.58, 28.99, 25.03, 24.31, 22.00, 21.69, 21.38, 20.98, 18.37, 17.54, 14.82, 14.71, 10.94, 10.89, 9.12, 8.71, 6.82. ESI-HRMS: [M + H] ⁺ calculated for C62H94N8O14 : 1175.69623, found 1175.69397; HPLC t _re t = 18.0 and 18.4 min (E/Z mixture, method A).

Example 48: (E)-2-cyano-N-(2-(((2S,3R,6R)-2-(((2R,3S,4R,5R,8R,10R,llR,12 S,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-azacyc lopentadecan-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]pyridin-2-yl)furan-2- yl)acrylamide: Obtained from 98 mg of example 32 and 220 mg of example 47 (0.9 equiv) in

1.5 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 over a weekend and subsequent filtration of precipitate and washing with cold MeOH. Yield: 144 mg (42 %) as orange platelets. ^T H NMR (400 MHz, DMSO) 6 12.07 (s, 1H), 8.69 (s, 1H), 7.71 (s, 1H), 7.58 (dd, 1H), 7.48 - 7.44 (m, 2H), 6.91 - 6.87 (m, 1H), 5.47 - 5.36 (m, J = 11.5, 5.8 Hz, 1H), 4.90 (s, 1H), 4.85 (d, J = 3.0 Hz, 1H), 4.73 (d, J = 8.2 Hz, 1H), 4.63 (s, 1H), 4.32 - 4.24 (m, J = 8.3 Hz, 3H), 4.13 - 4.05 (m, 4H), 3.99 - 3.90 (m, 2H), 3.82 - 3.78 (m, 1H), 3.68 - 3.64 (m, J = 8.8, 4.3 Hz, 3H), 3.22 (s, 6H), 3.04 (d, J = 6.5 Hz, 1H), 2.94 - 2.86 (m, J = 15.7, 6.7 Hz, 2H), 2.71 - 2.61 (m, J = 11.9, 7.4 Hz, 5H), 2.49 - 2.47 (m, 2H), 2.40 (s, 1H), 2.36 - 2.31 (m, 1H), 2.27 - 2.15 (m, 5H), 2.00 (dd, J = 7.5 Hz, 2H), 1.92 - 1.80 (m, 3H), 1.79 - 1.62 (m, 3H), 1.53 - 1.43 (m, J = 15.5 Hz, 4H), 1.20 (s, 3H), 1.18 - 1.14 (m, J = 5.8 Hz, 4H), 1.12 - 1.09 (m, 4H), 1.07 - 1.03 (m, J = 5.6 Hz, 5H), 1.00 - 0.98 (m, 3H), 0.95 - 0.91 (m, J = 6.3 Hz, 4H), 0.86 - 0.75 (m, J = 19.0, 9.0 Hz, 9H). ¹³ C NMR (101 MHz, DMSO) 6 177.27, 149.67, 148.63, 144.64, 140.42, 136.32, 135.21, 132.67, 124.32, 122.27, 116.40, 104.39, 102.08, 100.75, 99.63, 94.65, 83.64, 77.44, 77.08, 76.31, 74.92, 73.65, 72.71, 72.35, 69.33, 68.60, 66.27, 64.85, 61.57, 52.09, 48.70, 48.56, 44.94, 41.71, 41.02, 36.58, 35.67, 34.61, 29.71, 27.60, 26.03, 22.06, 21.69, 20.99, 20.91, 18.37, 17.58, 14.81, 10.88, 8.73, 6.69. ESI-HRMS: [M + H] ⁺ calculated for CeiHgzNsOis : 1177.67549, found 1177.67436; HPLC tret = 17.7 min (method A).

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)a crylamide 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. ^T H NMR (400 MHz, DMSO) 6 12.05 (s, 1H), 8.68 (s, 1H), 7.76 (s, 1H), 7.60 - 7.53 (m, J = 2.9 Hz, 1H), 7.48 (d, J = 3.7 Hz, 1H), 7.41 (d, J = 3.7 Hz, 1H), 7.08 - 7.02 (m, J = 3.1, 1.9 Hz, 1H), 5.12 - 4.96 (m, 1H), 3.10 - 2.90 (m, 6H), 2.76 - 2.60 (m, J = 24.7, 12.4, 4.1 Hz, 3H), 2.28 (s, 3H), 2.24 - 2.12 (m, J = 10.8 Hz, 3H), 2.00 (d, J = 7.8 Hz, 2H). ¹³ C-NMR (101 MHz, DMSO) 6 162.84, 149.59, 148.44, 144.58, 140.55, 136.26, 135.30, 135.15, 132.65, 124.15, 122.14, 116.31, 115.97, 104.45, 101.86, 101.01, 54.52, 53.29, 46.22, 34.42, 29.11. ESI-HRMS: [M + H] ⁺ calculated for C24H25N7O2 : 444.21425, found 444.21472; HPLC t _re t = 14.7 min (method A).

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-azacyc lopentadecan-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-yl)furan-2- yl)acrylamide Obtained from 83 mg of example 33 and 204 mg of example 47 (1.0 equiv) in 1 ml MeOH following general procedure G at 60 °C oil bath temperature with a reaction time of 2.5 h. Purification by manual column chromatography (EtOAc EtOAc(MeOH 6:1). Yield: 183 mg (65 %) as an orange solid. ^X H-NMR (400 MHz, DMSO) 6 12.07 (s, 1H), 8.68 (s, 1H), 7.70 (s, 1H), 7.58 - 7.55 (m, 1H), 7.45 (d, J = 3.8 Hz, 1H), 7.42 (d, J = 3.7 Hz, 1H), 7.09 - 7.06 (m, 1H), 5.00 (d, J = 3.8 Hz, 3H), 4.91 - 4.90 (m, 1H), 4.88 - 4.84 (m, 1H), 4.79 - 4.71 (m, 1H), 4.63 - 4.55 (m, J = 17.7 Hz, 1H), 4.10 - 4.02 (m, 2H), 3.99 - 3.93 (m, 1H), 3.76 - 3.70 (m, J = 7.7, 3.8 Hz, 3H), 3.50 (s, 3H), 3.25 - 3.21 (m, J = 5.2 Hz, 4H), 3.19 - 3.12 (m, 7H), 3.05 - 2.99 (m, 3H), 2.95 - 2.87 (m, J = 12.5, 8.8, 3.6 Hz, 7H), 2.73 - 2.65 (m, 4H), 2.36 - 2.29 (m, 4H), 2.08 - 1.97 (m, J = 7.0 Hz, 3H), 1.88 - 1.81 (m, J = 13.6, 7.2, 3.5 Hz, 6H), 1.61 - 1.50 (m, 7H), 1.23 (s, 4H), 1.19 (s, 1H), 1.17 (s, 2H), 1.14 (s, 1H), 1.12 - 1.09 (m, 3H), 1.05 (d, J = 5.4 Hz, 4H), 1.01 - 0.98 (m, J = 7.3 Hz, 2H), 0.96 - 0.90 (m, J = 6.7 Hz, 2H), 0.88 - 0.83 (m, 4H), 0.81 - 0.75 (m, J = 14.8, 7.4 Hz, 4H). ¹³ C NMR (101 MHz, DMSO) 6 177.38, 149.80, 148.44, 144.72, 136.31, 135.24, 132.74, 124.38, 122.24, 116.56, 104.50, 102.25, 101.16, 99.70, 94.66, 82.58, 77.51, 77.08, 75.91, 73.75, 72.93, 72.42, 69.89, 68.67, 67.06, 65.02, 62.69, 55.88, 54.26, 48.76, 45.59, 45.05, 41.73, 41.22, 40.66, 36.08, 34.60, 33.45, 32.19, 30.51, 29.65, 29.08, 28.93, 25.35, 22.03, 21.81, 21.04, 20.86, 18.45, 17.56, 14.93, 14.79, 10.98, 9.16, 8.65, 7.38. MS (ESI) m/z: 1191.27 [M + H] ⁺ ; HPLC tret = 15.6 and 16.0 min (E/Z mixture, method A).

Example 51: (E)-2-cyano-N-(2-(dimethylamino)ethyl)-N-methyl-3-(5-(l-(l-m ethylpiperidin-4- yl)-l,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-2-yl)fura n-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. ^T H NMR (400 MHz, DMSO) 6 12.17 - 11.98 (m, J = 18.4 Hz, 1H), 8.81 - 8.60 (m, 1H), 7.72 - 6.98 (m, 5H), 5.33 - 5.01 (m, J = 55.6, 17.6 Hz, 1H), 4.28 - 3.85 (m, 6H), 3.23 - 2.09 (m, 18H). ¹³ C-NMR (101 MHz, DMSO) 6 163.59, 150.07, 149.35, 144.99, 141.28, 137.16, 136.84, 135.86, 133.83, 123.38, 121.01, 116.29, 115.95, 105.31, 102.81, 102.30, 56.52, 55.22, 54.39, 46.60, 45.67, 29.76, 29.68, 29.30. ESI-HRMS: [M + H] ⁺ calculated for C27H32N8O2 : 501.27210, found 501.27228; HPLC tret = 9,6 and 10,0 min (E/Z mixture, method B)

Example 52: methyl (E)-N-(2-cyano-3-(5-(l-(l-methylpiperidin-4-yl)-l,6-dihydroi midazo[4,5- d]pyrrolo[2,3-b]pyridin-2-yl)furan-2-yl)acryloyl)-N-methylgl ycinate 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. ^X H-NMR (400 MHz, CDCI ₃ ) 6 8.71 (s, 1H), 7.80 - 7.72 (m, 1H), 7.45 (d, J = 3.3 Hz, 1H), 7.42 (s, 1H), 7.38 - 7.35 (m, 1H), 7.29 - 7.23 (m, 1H), 5.12 - 4.99 (m, 1H), 4.23

- 4.12 (m, 2H), 3.88 (s, 3H), 3.79 (s, 3H), 3.36 - 3.30 (m, 2H), 3.18 - 3.11 (m, 2H), 2.90 - 2.83 (m, J = 9.5 Hz, 2H), 2.43 (s, 3H), 2.12 - 2.05 (m, J = 12.3 Hz, 2H). ¹³ C-NMR (101 MHz, CDCI3) 6 168.98, 160.20, 155.48, 141.16, 139.88, 135.34, 132.38, 128.66, 126.73, 126.02, 124.69, 115.10, 113.44, 107.95, 106.44, 96.32, 92.53, 45.98, 43.28, 41.32, 36.92, 29.34, 20.74, 20.45. ESI-HRMS: [M + H] ⁺ calculated for C26H27N7O4 : 502.21973, found 502.22012; HPLC t _re t = 14.3 min (method A).

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)a crylonitrile 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. ^X H-NMR (400 MHz, DMSO) 6 12.12 (s, 1H), 8.70 (s, 1H), 7.80 (s, 1H), 7.60 (t, J = 3.0 Hz, 1H), 7.49 (dd, J = 12.8, 3.8 Hz, 2H), 6.90 - 6.88 (m, J = 3.3, 1.9 Hz, 1H), 5.48 - 5.38 (m, 1H), 3.71 - 3.58 (m, J = 20.0, 9.8 Hz, 12H), 2.70 - 2.63 (m, 2H), 2.04 - 1.97 (m, J = 12.6, 4.9 Hz, 2H). ¹³ C-NMR (101 MHz, DMSO) 6 162.14, 149.63, 148.81, 144.62, 140.37, 136.35, 135.72, 135.21, 132.63, 124.32, 122.84, 116.44, 116.19, 104.37, 100.88, 100.78, 66.19, 65.93, 52.05, 46.55, 29.67. ESI-HRMS: [M + H] ⁺ calculated for C25H24N6O4 : 473.19318, found 473.19354; HPLC t _re t = 19.7 min (method A)

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)a crylonitrile 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. ^X H-NMR (400 MHz, DMSO) 6 12.23 (s, 1H), 8.82 (s, 1H), 7.89 (s, 1H), 7.72 (s, 1H), 7.60 (dd, J = 11.2, 3.6 Hz, 2H), 7.01 (s, 1H), 5.61 - 5.49 (m, 1H), 4.27 - 4.18 (m, 2H), 3.76 - 3.69 (m, 4H), 2.86 - 2.74 (m, 2H), 2.63 (s, 6H), 2.34 (s, 3H), 2.15 - 2.11 (m, 2H). ¹³ C-NMR (101 MHz, DMSO) 6 161.98, 149.65, 148.70, 144.63, 140.40, 136.33, 135.46, 135.20, 132.66, 124.31, 122.60, 116.41, 116.18, 104.37, 101.28, 100.75, 66.21, 54.22, 52.11, 45.44, 45.15, 29.69. ESI-HRMS: [M + H] ⁺ calculated for C26H27N7O3: 486.22481, found 486.22558; HPLC t _re t = 16.4 min (method A).

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. ^X H NMR (400 MHz, DMSO) 6 12.10 (s, 1H), 8.69 (s, 1H), 7.79 (s, 1H), 7.57 (s, 1H), 7.51 (d, J = 3.5 Hz, 1H), 7.41 (d, J = 3.5 Hz, 1H), 6.84 (s, 1H), 5.04 - 4.85 (m, J = 12.0 Hz, 1H), 3.69 - 3.57 (m, J = 7.8 Hz, 8H), 2.42 - 2.30 (m, J = 10.6 Hz, 2H), 2.07 - 1.98 (m, J = 10.5 Hz, 2H), 1.98 - 1.85 (m, J = 11.3 Hz, 2H), 1.82 - 1.47 (m, J = 44.4, 37.2, 11.2 Hz, 4H). ¹³ C-NMR (101 MHz, DMSO) 6 162.09, 149.58, 148.61, 144.66, 140.55, 136.36, 135.76, 135.13, 132.79, 124.20, 122.34, 116.47, 116.01, 104.17, 101.11, 100.45, 65.91, 56.04, 30.00, 24.92, 24.28. ESI-HRMS: [M + H] ⁺ calculated for C26H26N6O3: 471.21392, found 471.21436; HPLC tret = 21.2 min (method A).

Example 57: (E)-2-cyano-3-(5-(l-(4,4-difluorocyclohexyl)-l,6-dihydroimid azo[4,5- d]pyrrolo[2,3-b]pyridin-2-yl)furan-2-yl)-N,N-dimethylacrylam ide 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. ^T H NMR (400 MHz, CDCI3) 6 11.97 (s, 1H), 8.70 (s, 1H), 7.52 (s, 1H), 7.28 (s, 1H), 7.27 - 7.22 (m, J = 3.8 Hz, 1H), 7.06 - 7.04 (m, J = 2.3 Hz, 1H), 6.80 (s, 1H), 5.29 - 5.16 (m, J = 12.4, 6.1 Hz, 1H), 3.10 - 2.99 (m, 2H), 2.92 - 2.81 (m, J = 17.4 Hz, 6H), 2.77 - 2.69 (m, J = 12.4, 5.7 Hz, 2H), 2.21 - 2.09 (m, J = 15.9 Hz, 4H). ¹³ C-NMR (101 MHz, CDCI3) 6 163.05, 149.64, 149.59, 144.95, 140.47, 136.81, 136.49, 135.55, 133.16, 123.52, 122.06, 116.31, 115.69, 104.74, 101.82, 100.23, 100.15, 53.44, 31.83, 29.32, 26.21. ESI-HRMS: [M + H] ⁺ calculated for C24H22F2N6O2: 465.18451, found 465.18520; HPLC t _re t = 15.4 and 17.4 min (E/Z mixture, method A).

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)a crylonitrile 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. Yield: 67 mg (48 %) as bright yellow solid. ¹ H-NMR (400 MHz, CDCI ₃ ) 6 11.82 (s, 1H), 8.80 (s, 1H), 7.58 (s, 1H), 7.39 (d, J = 41.0 Hz, 2H), 7.20 (s, 1H), 7.03 (s, 1H), 5.49 - 5.35 (m, 1H), 4.17 (d, J = 7.7 Hz, 2H), 3.69 (t, J = 11.9 Hz, 2H), 3.57 (s, 4H), 2.92 - 2.79 (m, J = 8.5 Hz, 2H), 1.98 (d, J = 9.5 Hz, 2H), 1.69 - 1.57 (m, 6H). ¹³ C-NMR (101 MHz, CDCI3) 6 162.44, 150.18, 149.61, 144.87, 141.19, 136.55, 135.90, 133.94, 123.78, 121.79, 116.59, 116.10, 105.50, 103.05, 102.21, 67.22, 52.80, 30.16, 25.81, 24.39. ESI-HRMS: [M + H] ⁺ calculated for C26H26N6O3 : 471.21392, found 471.21473; HPLC t _re t = 20.1 min (method A).

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. ¹ H-NMR (400 MHz, CDCI3) 6 12.00 (s, 1H), 8.81 (s, 1H), 7.63 (s, 1H), 7.45 - 7.36 (m, 2H), 7.23 (s, 1H), 6.83 (s, 1H), 4.98 - 4.86 (m, J = 12.1 Hz, 1H), 3.56 (s, 4H), 2.46 - 2.39 (m, J = 12.0 Hz, 2H), 2.06 - 1.92 (m, 4H), 1.68 - 1.39 (m, 10H). ¹³ C-NMR (101 MHz, CDCI3) 6 162.37, 150.18, 149.16, 145.01, 141.57, 137.09, 136.69, 135.80, 134.18, 123.46, 120.40, 116.28, 116.01, 105.28, 103.41, 101.34, 57.18, 53.10, 30.63, 26.05, 25.76, 24.90, 24.40. ESI-HRMS: [M + H] ⁺ calculated for C27H28N6O2 : 469.23465, found 469.23521; HPLC t _re t = 21.9 min (method A).

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)acry lonitrile 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. ^X H NMR (400 MHz, CDCI3) 6 11.81 (s, 1H), 8.89 (s, 1H), 7.70 (s, 1H), 7.48 (d, J = 35.0 Hz, 2H), 7.30 (d, J = 10.6 Hz, 1H), 7.12 (s, 1H), 5.50 (s, 1H), 4.26 (d, J = 7.3 Hz, 2H), 4.02 - 3.92 (m, 4H), 3.83 - 3.72 (m, J = 11.1 Hz, 2H), 3.01 - 2.87 (m, J = 8.4 Hz, 2H), 2.77 (s, 3H), 2.36 (s, 1H), 2.06 (d, J = 8.4 Hz, 2H). ¹³ C-NMR (101 MHz, CDCI3) 6 163.12, 150.18, 150.03, 145.17, 140.94, 137.35, 137.06, 136.07, 133.88, 123.63, 122.51, 116.66, 116.10, 105.40, 102.28, 101.97, 67.23, 52.87, 30.24, 27.54. ESI-HRMS: [M + H] ⁺ calculated for C25H24N6O3S : 489.17034, found 489.17085; HPLC t _re t = 15.1 and 16.0 min (E/Z mixture, method A).

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. ^X H-NMR (400 MHz, CDCI3) 6 11.62 (s, 1H), 8.77 (s, 1H), 7.67 (s, 1H), 7.42 (d, J = 3.6 Hz, 2H), 7.25 (d, J = 3.4 Hz, 1H), 6.72 (d, J = 2.4 Hz, 1H), 4.85 (d, J = 6.6 Hz, 2H), 3.34 - 2.92 (m, J = 51.1 Hz, 6H), 1.37 - 1.26 (m, J = 4.9 Hz, 1H), 0.55 - 0.25 (m, 4H). ¹³ C-NMR (101 MHz, CDCI3) 6 163.55, 150.13, 149.62, 144.79, 141.33, 137.11, 135.91, 135.77, 135.15, 124.06, 122.24, 116.33, 115.59, 104.97, 102.15, 97.64, 50.21, 39.34,

36.99, 12.08, 3.66. ESI-HRMS: [M + H] ⁺ calculated for C22H20N6O2 : 401.17205, found 401.17250; HPLC t _re t = 13.9 min (method A).

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. ^X H NMR (400 MHz, DMSO) 6 11.99 (s, 1H), 8.63 (s, 1H), 7.69 (s, 1H), 7.43 (d, J = 3.5 Hz, 2H), 7.29 (d, J = 3.7 Hz, 1H), 6.81 - 6.74 (m, J = 11.4 Hz, 1H), 4.99 - 4.85 (m, J = 11.9 Hz, 1H), 3.87 - 3.70 (m, J = 14.8 Hz, 4H), 2.66 (s, 3H), 2.46 (s, 1H), 2.40 - 2.30 (m, 2H), 2.02 - 1.88 (m, 4H), 1.75 (d, J = 10.7 Hz, 1H), 1.63 - 1.43 (m, J = 31.3, 17.0 Hz, 3H). ¹³ C NMR (101 MHz, DMSO) 6 162.22, 149.50, 148.50, 144.07, 140.61, 135.73, 135.70, 134.95,

132.99, 131.50, 123.78, 121.71, 116.12, 115.60, 104.26, 101.40, 100.37, 56.02, 48.83, 29.87, 26.59, 24.88, 24.19. ESI-HRMS: [M + H] ⁺ calculated for C ₂ 6H ₂ 6N6O ₂ S : 487.19107, found 487.19119; HPLC t _re t = 17.3 and 19.5 min (E/Z mixture, method A).

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. Total yield: 149 mg (69 %) as red solid. ¹ H NMR (300 MHz, DMSO) 6 12.10 (s, 1H), 8.77 - 8.66 (m, J = 5.8 Hz, 1H), 7.77 (s, 1H), 7.58 (s, 1H), 7.51 (d, J = 3.7 Hz, 1H), 7.41 (d, J = 3.7 Hz, 1H), 6.86 (s, 1H), 5.05 - 4.72 (m, 2H), 3.99 - 3.72 (m, J = 35.5, 21.2 Hz, 3H), 2.53 (s, 1H), 2.44 - 2.33 (m, J = 10.3 Hz, 2H), 2.12 - 2.02 (m, 2H), 1.99 - 1.76 (m, J = 41.2, 10.1 Hz, 5H), 1.68 - 1.41 (m, J = 30.9, 16.9 Hz, 6H). ¹³ C-NMR (75 MHz, DMSO) 6 161.75, 149.64, 148.44, 144.67, 140.59, 136.35, 135.19, 135.12, 132.81, 124.16, 121.93, 116.37, 116.01, 104.18, 101.93, 100.41, 65.12, 56.09, 33.85, 30.01, 24.95, 24.30. ESI-HRMS: [M + H] ⁺ calculated for C27H28N6O3 : 485.22957, found 485.22985; HPLC t _re t = 17.0 min (method A).

Example 66: (E)-2-cyano-3-(5-(l-cyclopropyl-l,6-dihydroimidazo[4,5-d]pyr rolo[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. ^X H NMR (400 MHz, DMSO) 6 11.98 (s, 1H), 8.64 (s, 1H), 7.78 (s, 1H), 7.52 - 7.49 (m, 3H), 6.94 - 6.88 (m, 1H), 4.06 - 3.94 (m, 1H), 3.18 - 2.97 (m, 6H), 1.46 - 1.38 (m, 2H), 0.96 - 0.91 (m, 2H). ¹³ C-NMR (101 MHz, DMSO) 6 162.92, 149.41, 148.33, 144.91, 141.89, 135.88, 135.34, 135.15, 133.86, 124.07, 121.99, 116.05, 115.19, 104.47, 101.71, 98.71, 37.39, 27.42, 9.72. ESI-HRMS: [M + H] ⁺ calculated for C21H18N6O2 : 387.15640, found 387.15668; HPLC t _re t = 14.0 min (method A).

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. ^T H NMR (400 MHz, DMSO) 6 11.97 (s, 1H), 8.79 - 8.72 (m, 1H), 7.82 - 7.63 (m, 6H), 7.57 - 7.48 (m, 1H), 7.35 - 7.27 (m, 2H), 5.65 - 5.55 (m, J = 16.1, 3.2 Hz, 1H), 3.34 (s, 6H). ¹³ C-NMR (101 MHz, DMSO) 6 162.59, 149.03, 147.15, 145.31, 140.35, 135.90, 135.17, 135.04, 133.97, 130.29, 130.11, 127.99, 124.27, 120.21, 115.70, 114.55, 113.62, 103.84, 102.72, 96.16, 37.37. ESI-HRMS: [M + H] ⁺ calculated for C24H18N6O2 : 423.15640, found 423.15676; HPLC t _re t = 16.5 min (method A).

Example 68: (E)-2-(morpholine-4-carbonyl)-3-(5-(l-phenyl-l,6-dihydroimid azo[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. ¹ H- NMR (400 MHz, DMSO) 6 11.98 (s, 1H), 8.74 (s, 1H), 7.82 - 7.60 (m, 6H), 7.55 (d, J = 9.5 Hz, 1H), 7.36 - 7.23 (m, 2H), 5.59 (d, J = 17.8, 1.8 Hz, 1H), 3.75 - 3.39 (m, 8H). ¹³ C-NMR (101 MHz, DMSO) 6 161.84, 148.97, 147.25, 145.31, 140.31, 136.18, 135.90, 135.43, 135.03, 133.97, 130.33, 130.11, 127.98, 124.28, 120.46, 114.57, 113.59, 103.83, 101.97, 96.16, 65.85, 46.47. ESI-HRMS: [M + Na] ⁺ calculated for C26H20N6O3 : 487.14891, found 487.14961; HPLC tret = 16.8 min (method A).

Example 69: methyl (E)-N-(2-cyano-3-(5-(l-phenyl-l,6-dihydroimidazo[4,5-d]pyrro lo[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. ^X H-NMR (400 MHz, DMSO) 6 12.04 (s, 2H), 8.83 (s, 1H), 7.81 - 7.75 (m, 7H), 7.38 - 7.36 (m, 1H), 6.50 (d, J = 3.8 Hz, 1H), 5.69 - 5.66 (m, J = 4.0, 2.2 Hz, 1H), 4.37 - 4.24 (m, 1H), 3.76 (s, 3H), 3.28 (s, 3H). ¹³ C-NMR (101 MHz, DMSO) 6 169.19, 163.42, 152.32, 148.93, 145.31, 140.28, 136.18, 135.93, 135.37, 133.98, 130.10,

129.99, 127.98, 124.27, 115.38, 114.64, 111.96, 110.22, 103.83, 97.04, 96.17, 52.70, 52.04,

28.99. ESI-HRMS: [M + H] ⁺ calculated for C26H20N6O4 : 481.16188, found 481.16229; HPLC t _re t = 15.7 and 16.7 min (E/Z/ mixture, method A).

Example 70: (E)-2-(4-methylpiperazine-l-carbonyl)-3-(5-(l-phenyl-l,6-dih ydroimidazo[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. ¹ H-NMR (300 MHz, MeOD) 6 8.98 (s, 1H), 7.99 - 7.94 (m, J = 5.0, 2.2 Hz, 2H), 7.93 (s, 1H), 7.85 - 7.80 (m, 2H), 7.77 (s, 1H), 7.63 (d, J = 3.9 Hz, 1H), 7.46 (d, J = 3.4 Hz, 1H), 6.76 (d, J = 3.9 Hz, 1H), 6.02 (d, J = 3.4 Hz, 1H), 3.96 - 3.89 (m, 4H), 2.79 - 2.73 (m, 4H), 2.59 (s, 3H). ¹³ C-NMR (75 MHz, MeOD) 6 163.33, 150.53, 147.99, 145.78, 142.05, 137.88, 137.00, 136.53, 136.17, 134.66, 131.21, 130.94, 128.61, 124.90, 120.32, 116.32, 115.86, 105.54, 103.34, 97.68, 54.99, 45.95. ESI-HRMS: [M + H] ⁺ calculated for C27H23N7O2 : 478.19860, found 478.19891; HPLC t _re t = 11.0 min (method A).

Example 71: (E)-3-(5-(l-(cyclopropylmethyl)-l,6-dihydroimidazo[4,5-d]pyr rolo[2,3-b]pyridin- 2-yl)furan-2-yl)-2-(4-methylpiperazine-l-carbonyl)acrylonitr ile 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. ¹ H-NMR (300 MHz, DMSO) 6 11.81 (s, 1H), 8.43 (s, 1H), 7.55 (s, 1H), 7.37 - 7.26 (m, 3H), 6.73 - 6.65 (m, J = 1.5 Hz, 1H), 4.67 (d, J = 6.9 Hz, 2H), 3.47 - 3.21 (m, 4H), 2.31 - 2.14 (m, 4H), 1.99 (s, 3H), 0.93 - 0.89 (m, 1H), 0.25 - 0.06 (m, 4H). ¹³ C-NMR (75 MHz, DMSO) 6 161.95, 149.21, 149.15, 144.91, 140.06, 135.78, 135.30, 134.42, 134.38, 124.32, 122.89, 116.40, 115.23, 103.84, 100.76, 96.99, 54.19, 49.11, 45.54, 45.47, 12.00, 3.10. ESI-HRMS: [M + H] ⁺ calculated for C25H25N7O2 : 456.21425, found 456.21429; HPLC t _re t = 2.1 min (method A).

Example 72: methyl (E)-N-(2-cyano-3-(5-(l-(cyclopropylmethyl)-l,6-dihydroimidaz o[4,5- d]pyrrolo[2,3-b]pyridin-2-yl)furan-2-yl)acryloyl)-N-methylgl ycinate 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. ^X H-NMR (300 MHz, DMSO) 6 12.03 (s, 1H), 8.66 (s, 1H), 7.86 (s, 1H), 7.60 - 7.48 (m, J = 9.1, 6.3 Hz, 3H), 6.95 - 6.89 (m, 1H), 4.88 (d, J = 12.6 Hz, 2H), 4.12 (d, J = 7.4 Hz, 2H), 3.70 (s, 3H), 3.28 (s, 3H), 1.03 (d, J = 6.1 Hz, 1H), 0.47 - 0.33 (m, 4H). ¹³ C-NMR (75 MHz, DMSO) 6 169.23, 163.66, 149.47, 149.09, 144.91, 144.78, 140.01, 135.80, 134.45, 124.31, 116.04, 115.80, 115.28, 103.83, 100.10, 97.16, 97.01, 52.73, 51.82, 49.22, 25.45, 11.99, 3.07. ESI-HRMS: [M + H] ⁺ calculated for C24H22N6O4 : 459.17753, found 459.17752; HPLC t _re t = 15.8 min (method A).

Example 73: (E)-3-(5-(l-(cyclopropylmethyl)-l,6-dihydroimidazo[4,5-d]pyr rolo[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. ^X H-NMR (300 MHz, CDCI ₃ ) 6 11.39 (s, 1H), 8.78 (s, 1H), 7.59 (s, 1H), 7.44 - 7.35 (m, 2H), 7.23 (d, J = 3.8 Hz, 1H), 6.71 (d, J = 2.5 Hz, 1H), 4.85 (d, J = 6.8 Hz, 2H), 3.65 - 3.53 (m, J = 18.4 Hz, 4H), 1.64 (s, 6H), 0.86 - 0.73 (m, J = 15.2, 8.2 Hz, 1H), 0.49 - 0.32 (m, 4H). ¹³ C-NMR (75 MHz, CDCI3) 6 162.97, 150.52, 150.09, 145.72, 141.55, 137.03, 136.98, 135.95, 135.66, 124.24, 122.32, 116.90, 115.83, 105.21, 103.04, 98.00, 50.60, 26.28, 25.91, 24.89, 12.52, 4.08. ESI-HRMS: [M + H] ⁺ calculated for C25H24N6O2 : 441.20335, found 441.20352; HPLC t _re t = 15.9 and 18.8 min (E/Z mixture, method A).

Example 74: (E)-2-cyano-3-(5-(l-cyclohexyl-l,6-dihydroimidazo[4,5-d]pyrr olo[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-dimeth yltetrahydro-2H-pyran-2- yl)oxy)-3,5,6,8,10,12,14-heptamethyl-15-oxo-l-oxa-6-azacyclo pentadecan-ll-yl)oxy)-3- hydroxy-6-methyltetrahydro-2H-pyran-4-yl)(methyl)amino)propy l)-N-methylacrylamide Obtained from 73 mg of example 75 and 211 mg of example 31 in 1.5 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: 129 mg (50 %) as orange solid. ^X H-NMR (400 MHz, DMSO) 6 12.08 (s, 1H), 8.69 - 8.67 (m, J = 2.1 Hz, 1H), 7.75 (s, 1H), 7.57 - 7.53 (m, 2H), 7.47 (d, J = 3.7 Hz, 1H), 7.39 (d, J = 3.8 Hz, 1H), 5.01 - 4.85 (m, 4H), 4.80 - 4.73 (m, 1H), 4.60 - 4.53 (m, 1H), 4.42 - 4.17 (m, 3H), 4.11 - 4.02 (m, J = 14.9, 6.5 Hz, 2H), 3.96 - 3.60 (m, J = 74.2, 37.1, 24.6 Hz, 3H), 3.50 (s, 1H), 3.43 - 3.39 (m, 2H), 3.38 (s, 1H), 3.36 (s, 1H), 3.34 (d, J = 1.4 Hz, 1H), 3.23 (t, 3H), 3.17 (s, 2H), 3.05 - 2.99 (m, 2H), 2.93 - 2.88 (m, 2H), 2.68 (s, 1H), 2.48 - 2.45 (m, 2H), 2.40 - 2.29 (m, 5H), 2.26 - 2.20 (m, J = 10.8 Hz, 2H), 2.06 - 1.99 (m, 3H), 1.96 - 1.86 (m, 6H), 1.78 - 1.69 (m, J = 10.5 Hz, 5H), 1.61 - 1.45 (m, J = 30.7, 17.5 Hz, 9H), 1.22 - 1.20 (m, 2H), 1.17 (s, 1H), 1.15 (s, 1H), 1.10 (s, 3H), 1.08 (s, 2H), 1.06 (s, 2H), 1.04 - 0.98 (m, 7H), 0.87 - 0.79 (m, 6H), 0.78 - 0.73 (m, 3H). ¹³ C-NMR (101 MHz, DMSO) 6 178.48, 177.22, 149.59, 148.50, 144.66, 140.51, 136.31, 135.12, 132.79, 124.10, 121.75, 116.31, 115.88, 114.72, 104.14, 100.34, 99.60, 94.50, 77.37, 76.94, 73.50, 72.29, 65.49, 64.88, 56.06, 54.03, 48.63, 48.58, 45.70, 44.89, 41.62, 38.21, 36.85, 34.49, 30.26, 30.00, 28.97, 27.35, 25.27, 24.95, 24.29, 21.88, 21.65, 20.92, 20.78, 18.32, 17.47, 17.41, 15.12, 14.79, 10.85, 8.53. ESI-HRMS: [M + H] ⁺ calculated for CesHgeNsO : 1189.71188, found 1189.71202; HPLC t _re t = 14.9 and 15.1 min (E/Z mixture, method A). Example 97: 3-(5-(l-((lR,5S,6r)-bicyclo[3.1.0]hexan-6-yl)-l,6-dihydroimi dazo[4,5- d]pyrrolo[2,3-b]pyridin-2-yl)furan-2-yl)-2-cyano-N,N-dimethy lacrylamide: Obtained from 82 mg of example 90 and 28 mg of 2-cyano-N,N-dimethylacetamide following general procedure G in 2 ml of absolute EtOH. Flash chromatography (EtOAc/MeOH, automatic gradient). Yield: 55 mg (52 %) as an orange to yellow solid. ¹ H-NMR: (400 MHz, CDCI3) 6 11.79 (s, 1H), 8.80 (s, 1H), 7.80 (s, 1H), 7.47 (bs, 1H), 7.36 (d, J = 3.7 Hz, 1H), 7.33 (d, J = 3.7 Hz, 1H), 6.93 (d, J = 2.3 Hz, 1H), 3.80 - 3.76 (m, 1H), 3.34 - 3.19 (m, 3H), 3.15 - 3.00 (m, 3H), 2.21 (dd, J = 12.6, 7.9 Hz, 2H), 1.93 (ddd, 2H), 1.80 - 1.75 (m, J = 7.9 Hz, 2H), 1.62 - 1.49 (m, J = 16.3, 11.5, 6.3 Hz, 1H), 1.30 - 1.22 (m, J = 16.3, 7.9 Hz, 1H). ¹³ C-NMR: (101 MHz, CDCI3) 6

163.6, 150.2, 149.5, 145.3, 143.0, 137.4, 137.0, 136.0, 134.9, 123.3, 121.4, 116.3, 114.8, 105.4, 102.7, 99.5, 34.3, 29.8, 28.7, 27.9, 21.3. ESI-HRMS: [M + Na] ⁺ calculated for C24H22N6O2: 449.16964, measured 449.16983; HPLC t _re t = 20.4 min (method B)

Example 98: (E)-3-(5-(l-((lR,5S,6r)-bicyclo[3.1.0]hexan-6-yl)-l,6-dihydr oimidazo[4,5- d]pyrrolo[2,3-b]pyridin-2-yl)furan-2-yl)-2-(morpholine-4-car bonyl)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. ¹ H-NMR: (400 MHz, CDCI3) 6 11.02 (s, 1H), 8.68 (s, 1H), 7.74 (s, 1H), 7.38 (d, J = 3.1 Hz, 1H), 7.35 - 7.31 (m, 2H), 6.89 (d, J = 3.3 Hz, 1H), 3.79 - 3.64 (m, J = 13.5, 12.1 Hz, 9H), 2.15 (dd, J = 12.2, 8.2 Hz, 2H), 1.87 (ddd, J =

19.6, 9.8 Hz, 2H), 1.72 (bs, 2H), 1.57 - 1.45 (m, J = 19.1, 10.9 Hz, 1H), 1.30 - 1.16 (m, 1H). ¹³ C NMR: (101 MHz, CDCI3) 6 162.9, 150.1, 149.3, 144.6, 142.9, 137.7, 136.2, 136.0, 134.3,

123.6, 122.0, 116.2, 115.1, 105.5, 101.7, 99.2, 66.6, 34.2, 28.5, 27.8, 21.2. ESI-HRMS: [M + Na] ⁺ calculated for C26H24N6O3: 491.18021, measured 491.18064; HPLC t _re t = 20.2 min (method B)

Example 99: (E)-3-(5-(l-((lR,5S,6r)-bicyclo[3.1.0]hexan-6-yl)-l,6-dihydr oimidazo[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-trihyd roxy-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-h ydroxy-6-methyltetrahydro- 2H-pyran-3-yl)(methyl)amino)propyl)-N-methylacrylamide: Obtained from 57 mg of example 90 and 150 mg of example 75 following general procedure G in 2 ml MeOH at 60 °C oil bath temperature with a reaction time of 3 h. Flash chromatography (EtOAc / MeOH, automatic gradient). Yield: 122 mg (61 %) as yellow solid. ^X H-NMR (400 MHz, CDCI3) 6 11.42 (bs, 1H), 8.74 (s, 1H), 7.73 (s, 1H), 7.44 (s, 1H), 7.32 (d, J = 17.6 Hz, 2H), 6.89 (s, 1H), 5.03 - 4.96 (m, 2H), 4.72 (d, J = 8.3 Hz, 1H), 4.35 - 4.28 (m, 1H), 4.14 - 4.01 (m, 2H), 3.98 - 3.91 (m, 1H), 3.75

- 3.59 (m, 4H), 3.45 (dd, J = 13.9, 6.9 Hz, 4H), 3.33 - 3.26 (m, 4H), 3.24 - 3.19 (m, 2H), 3.08 - 2.98 (m, 3H), 2.70 (bs, 3H), 2.58 - 2.47 (m, J = 16.5 Hz, 4H), 2.33 - 2.26 (m, J = 12.8 Hz, 5H),

2.21 - 2.15 (m, 2H), 1.92 - 1.80 (m, 8H), 1.78 - 1.72 (m, 4H), 1.50 (d, J = 11.4 Hz, 3H), 1.35 -

I.29 (m, J = 16.0 Hz, 7H), 1.20 - 1.15 (m, 12H), 1.09 - 1.05 (m, 7H), 0.91 - 0.82 (m, 9H). ¹³ C-

NMR: (101 MHz, CDCI3) 6 178.50, 163.38, 150.15, 149.43, 149.28, 145.13, 142.80, 137.01, 136.49, 135.94, 134.67, 123.68, 116.30, 114.75, 105.37, 102.89, 100.47, 99.13, 95.19, 85.58, 78.16, 74.44, 73.82, 73.00, 71.08, 70.01, 68.78, 66.42, 65.86, 65.82, 63.45, 62.52, 54.59,

49.52, 49.38, 45.52, 43.06, 41.87, 40.38, 37.15, 36.47, 34.98, 34.25, 29.74, 28.61, 27.84,

27.77, 27.55, 26.86, 26.77, 22.23, 22.05, 21.72, 21.61, 21.30, 18.37, 16.52, 15.32, 15.22,

II.27, 11.22, 9.43, 7.63. ESI-HRMS: [M + H] ⁺ calculated for C63H94N8O14: 1187.69623, found

1187.69593. HPLC t _re t = 18.0 and 18.8 min (E/Z mixture, method B).

Example 100: (E)-3-(5-(l-((lR,5S,6r)-bicyclo[3.1.0]hexan-6-yl)-l,6-dihydr oimidazo[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-trihyd roxy-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-h ydroxy-6-methyltetrahydro- 2H-pyran-3-yl)(methyl)amino)ethyl)(methyl)amino)-2-oxoethyl) -N-methylacrylamide: Obtained from 98 mg of example 90 and 274 mg of example 83 following general procedure G in 3 ml absolute EtOH at 60 °C oil bath temperature with a reaction time of 3 h. Flash chromatography (EtOAc / MeOH, automatic gradient). Yield: 191 mg (53 %) as yellow to orange solid. ¹ H-NMR (400 MHz, CDCI3) 6 11.34 (bs, 1H), 8.73 (s, 1H), 7.69 (s, 1H), 7.44 (s, 1H), 7.33 - 7.23 (m, 2H), 6.90 (s, 1H), 5.08 - 4.96 (m, 2H), 4.73 (d, J = 8.5 Hz, 1H), 4.36 - 4.24 (m, J = 31.2 Hz, 2H), 4.11 (s, 1H), 4.03 - 3.93 (m, 2H), 3.76 (s, 1H), 3.69 - 3.62 (m, J = 20.9 Hz, 2H), 3.46 (dd, J = 13.4, 6.4 Hz, 4H), 3.32 (s, 6H), 3.26 - 3.18 (m, 2H), 3.06 - 2.96 (m, 6H), 2.79

- 2.68 (m, 3H), 2.62 - 2.53 (m, 4H), 2.37 - 2.29 (m, J = 15.7 Hz, 4H), 2.21 - 2.14 (m, 2H), 1.92

- 1.83 (m, J = 8.3 Hz, 4H), 1.72 (s, 3H), 1.63 - 1.41 (m, 6H), 1.38 - 1.30 (m, J = 18.7 Hz, 8H),

1.21 - 1.19 (m, J = 1.8 Hz, 2H), 1.19 - 1.16 (m, J = 6.0 Hz, 9H), 1.11 - 1.06 (m, 6H), 0.96 - 0.83 (m, 10H). ¹³ C-NMR (176 MHz, CDCI3) 6 178.84, 178.77, 167.31, 167.08, 164.30, 164.23, 149.99, 149.31, 144.92, 142.79, 142.75, 137.67, 136.25, 135.89, 134.50, 123.72, 121.68, 116.13, 114.76, 105.36, 101.70, 101.62, 100.60, 100.42, 99.12, 94.96, 94.85, 85.07, 84.36, 78.15, 78.10, 77.85, 77.54, 74.25, 73.87, 73.74, 73.58, 72.86, 72.74, 70.44, 69.80, 66.52,

66.44, 65.89, 65.72, 64.86, 62.89, 62.80, 62.56, 54.75, 54.54, 50.73, 50.28, 49.35, 48.48,

46.82, 45.87, 45.57, 42.69, 42.31, 42.16, 42.01, 40.88, 38.69, 36.92, 36.75, 36.29, 35.21,

34.75, 34.71, 34.15, 34.08, 29.72, 28.47, 27.74, 26.58, 22.29, 22.22, 21.75, 21.55, 21.26,

21.17, 18.29, 18.25, 16.41, 15.02, 14.88, 11.22, 8.96, 8.84, 7.38. ESI-HRMS: [M + H] ⁺ calculated for C65H97N9O15: 1244.71769, found 1244.71656; HPLC t _re t = 16.3 min (method B).

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-dimeth yltetrahydro-2H-pyran-2- yl)oxy)-3,5,6,8,10,12,14-heptamethyl-15-oxo-l-oxa-6-azacyclo pentadecan-ll-yl)oxy)-4- hydroxy-6-methyltetrahydro-2H-pyran-3-yl)(methyl)amino)butyl )-N-methylacrylamide: Obtained from 37 mg of example 31 and 98 mg of example 93 following general procedure G in MeOH. Flash chromatography (EtOAc/MeOH, automatic gradient). Yield: 130 mg (97 %) as a yellow solid. ¹ H-NMR (400 MHz, CDCI3) 6 11.55 (bs, 1H), 8.80 (s, 1H), 7.72 (s, 1H), 7.51 - 7.41 (m, 2H), 7.29 - 7.23 (m, 1H), 6.89 - 6.82 (m, 1H), 5.04 - 4.92 (m, J = 21.6 Hz, 3H), 4.73 (d, J = 9.4 Hz, 1H), 4.31 (s, 1H), 4.17 - 4.09 (m, 1H), 4.03 - 3.91 (m, J = 30.5 Hz, 2H), 3.67 (s, 1H), 3.59 (d, J = 5.3 Hz, 1H), 3.48 - 3.39 (m, J = 12.2, 7.8 Hz, 3H), 3.25 (d, J = 29.6 Hz, 4H), 3.06 - 2.98 (m, J = 10.7 Hz, 3H), 2.85 - 2.66 (m, J = 22.3 Hz, 6H), 2.64 - 2.61 (m, 1H), 2.55 - 2.44 (m, 6H), 2.29 (s, 4H), 2.03 (s, 6H), 1.91 - 1.82 (m, J = 15.6 Hz, 4H), 1.63 (s, 3H), 1.55 - 1.43 (m, J = 22.5 Hz, 8H), 1.36 - 1.29 (m, 7H), 1.18 - 1.12 (m, 11H), 1.07 (s, 6H), 0.93 - 0.81 (m, J = 21.2, 11.7 Hz, 9H). ¹³ C-NMR (101 MHz, CDCI3) 6 178.6, 163.2, 150.1, 149.3, 144.9,

141.4, 137.3, 136.8, 135.8, 134.1, 123.6, 120.6, 116.2, 115.9, 105.2, 103.2, 101.1, 100.6, 95.2, 85.4, 78.4, 78.1, 77.4, 74.4, 73.9, 73.0, 70.6, 70.1, 66.3, 65.8, 65.7, 62.5, 57.2, 56.9,

50.4, 49.4, 45.6, 43.0, 41.9, 40.5, 38.7, 37.0, 36.4, 34.9, 30.9, 30.7, 27.8, 26.7, 25.8, 25.6, 24.9, 22.2, 21.7, 21.6, 21.2, 18.4, 16.6, 15.3, 11.2, 9.4, 7.5. ESI-HRMS: [M + H] ⁺ calculated for C64H98N8O14 : 1203.72753, measured 1203.72736; HPLC t _re t = 19.8 min (method B).

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-metho xy-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)a mino)butyl)-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 40 mg of example 33 and 101 mg of example 93 following general procedure G in MeOH. Flash chromatography (EtOAc/MeOH, automatic gradient). Yield: 110 mg (79 %) as an orange to yellow solid. ^X H-NMR (400 MHz, CDCI3) 6 11.54 (bs, 1H), 8.82 (s, 1H), 7.72 (s, 1H), 7.43 (d, J = 27.9 Hz, 2H), 7.30 (d, J = 5.5 Hz, 1H), 7.18 (s, 1H), 5.03 (d, J = 18.7 Hz, 3H), 4.75 (d, J = 6.1 Hz, 1H), 4.34 (s, 1H), 4.18 - 4.12 (m, 1H), 4.06 - 3.94 (m, J = 31.5 Hz, 2H), 3.72 - 3.60 (m, J = 28.4 Hz, 2H), 3.50 - 3.44 (m, J = 6.7 Hz, 3H), 3.36 - 3.21 (m, J = 31.6 Hz, 4H), 3.06 (s, 3H), 2.89 - 2.65 (m, J = 57.9, 25.8 Hz, 8H), 2.54 (s, 4H), 2.40 - 2.21 (m, 8H), 2.08 - 1.82 (m, J = 42.7 Hz, 10H), 1.66 (s, 3H), 1.57 - 1.41 (m, 6H), 1.35 (d, J = 11.5 Hz, 7H), 1.22 - 1.15 (m, 11H), 1.11 - 1.06 (m, 6H), 0.96 - 0.80 (m, 9H). ¹³ C-NMR (101 MHz, CDCI3) 6 178.7, 163.3, 150.2, 149.4, 144.9, 141.3, 137.2, 136.8, 135.9, 133.9, 123.6, 120.9,

116.3, 116.0, 105.4, 103.1, 102.2, 100.6, 95.1, 85.4, 78.1, 77.4, 74.4, 73.9, 73.0, 70.7, 70.1,

66.3, 65.9, 65.8, 62.5, 56.9, 55.4, 54.6, 49.4, 46.7, 45.6, 43.0, 42.0, 40.5, 37.0, 36.4, 34.9,

30.4, 30.2, 29.9, 29.7, 27.8, 26.8, 25.6, 22.2, 21.8, 21.6, 21.3, 18.3, 16.6, 15.3, 15.2, 11.2, 9.4, 7.5. ESI-HRMS: [M + H] ⁺ calculated for C64H100N9O14: 1218.73843, measured 1218.73942; HPLC tret = 14.7 and 14.9 min (E/Z mixture, method B).

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-dimeth yltetrahydro-2H-pyran-2- yl)oxy)-3,5,6,8,10,12,14-heptamethyl-15-oxo-l-oxa-6-azacyclo pentadecan-ll-yl)oxy)-3- hydroxy-6-methyltetrahydro-2H-pyran-4-yl)(methyl)amino)butyl )-N-methylacrylamide: Obtained from 43 mg of example 31 and 114 mg of example 96 following general procedure G in MeOH. Flash chromatography (EtOAc/MeOH, automatic gradient). Yield: 105 mg (69 %) as a yellow solid. ¹ H-NMR (400 MHz, CDCI3) 6 11.74 (bs, 1H), 8.82 (s, 1H), 7.76 (s, 1H), 7.51 - 7.44 (m, 2H), 7.29 (d, J = 4.0 Hz, 1H), 6.88 - 6.81 (m, J = 9.6 Hz, 1H), 5.02 (d, J = 4.4 Hz, 1H), 4.99 - 4.85 (m, 2H), 4.76 - 4.71 (m, 1H), 4.46 (d, J = 7.0 Hz, 1H), 4.31 (d, J = 3.5 Hz, 1H), 4.13

- 4.01 (m, 1H), 3.74 (s, 1H), 3.67 (d, J = 6.9 Hz, 1H), 3.53 - 3.48 (m, J = 5.9 Hz, 2H), 3.45 (dd, J = 14.0, 7.0 Hz, 3H), 3.31 (s, 3H), 3.28 - 3.22 (m, 2H), 3.07 - 2.99 (m, J = 17.5, 7.8 Hz, 2H), 2.81

- 2.67 (m, 2H), 2.64 - 2.57 (m, J = 12.4, 6.4 Hz, 1H), 2.53 - 2.43 (m, J = 10.6 Hz, 4H), 2.38 - 2.33 (m, 2H), 2.31 (s, 4H), 2.24 (s, 3H), 2.07 - 1.96 (m, J = 14.3, 8.5 Hz, 7H), 1.91 - 1.79 (m, 3H), 1.69 - 1.40 (m, 11H), 1.33 (s, 3H), 1.30 (d, J = 5.9 Hz, 4H), 1.22 - 1.16 (m, J = 13.7, 6.7 Hz, 11H), 1.10 - 1.04 (m, 9H), 0.90 - 0.83 (m, 6H). ¹³ C-NMR (101 MHz, CDCI3) 6 178.4, 163.2, 150.1, 149.4, 144.8, 141.3, 137.6, 136.7, 135.8, 134.1, 123.5, 120.7, 116.2, 115.9, 105.1, 103.0, 102.9, 101.1, 95.1, 83.9, 78.5, 78.2, 77.6, 77.4, 74.5, 73.8, 73.0, 70.9, 70.0, 68.8, 65.9, 65.9, 65.6, 62.2, 57.1, 52.8, 49.5, 45.1, 42.6, 41.7, 37.0, 36.4, 34.9, 30.6, 29.9, 27.6, 26.8,

25.7, 25.5, 24.9, 22.0, 21.6, 21.4, 21.3, 18.4, 16.5, 15.3, 15.2, 11.3, 9.3, 7.7. ESI-HRMS: [M + H] ⁺ calculated for C64H98N ₈ Oi ₄ : 1203.72753, measured 1203.72690; HPLC t _re t = 20.4 and 20.6 min (E/Z mixture, method B).

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-dimeth yltetrahydro-2H-pyran-2- yl)oxy)-3,5,6,8,10,12,14-heptamethyl-15-oxo-l-oxa-6-azacyclo pentadecan-ll-yl)oxy)-3- hydroxy-6-methyltetrahydro-2H-pyran-4-yl)(methyl)amino)ethyl )-N-methylacrylamide: Obtained from 62 mg of example 31 and 160 mg of example 95 following general procedure G in MeOH. Flash chromatography (EtOAc/MeOH, automatic gradient). Yield: 153 mg (70 %) as a yellow solid. ^-NMR (400 MHz, CDCI3) 6 11.87 (bs, 1H), 8.85 - 8.79 (m, J = 4.6 Hz, 1H), 7.72 (bs, J = 28.4 Hz, 1H), 7.51 - 7.41 (m, J = 21.6 Hz, 2H), 7.28 (s, 1H), 6.86 (s, 1H), 5.05 - 4.93 (m, 2H), 4.74 (d, J = 9.2 Hz, 1H), 4.44 (s, 1H), 4.28 (s, 1H), 4.15 - 4.02 (m, 1H), 3.78 - 3.62 (m, J = 27.3 Hz, 3H), 3.58 - 3.50 (m, 2H), 3.48 - 3.41 (m, 2H), 3.37 - 3.22 (m, 7H), 3.08 - 2.97 (m, 2H), 2.85 (bs, 1H), 2.79 - 2.66 (m, 3H), 2.60 - 2.41 (m, 6H), 2.38 - 2.26 (m, 6H), 2.10 - 1.95 (m, J = 6.9 Hz, 7H), 1.90 - 1.77 (m, 3H), 1.70 - 1.44 (m, J = 39.7 Hz, 7H), 1.31 (d, J =

13.7 Hz, 6H), 1.22 - 1.16 (m, 11H), 1.10 - 1.01 (m, J = 14.4 Hz, 9H), 0.91 - 0.82 (m, 6H). ¹³ C- NMR (101 MHz, CDCI3) 6 178.2, 163.5, 150.1, 149.5, 144.9, 141.3, 137.5, 136.8, 135.8, 134.1, 123.5, 120.7, 116.2, 116.0, 105.1, 103.2, 102.7, 101.0, 95.2, 84.3, 78.7, 78.2, 77.6, 77.4, 74.5,

73.8, 73.0, 71.5, 70.0, 68.6, 65.8, 65.7, 62.2, 57.1, 49.5, 45.2, 42.6, 41.6, 37.4, 36.4, 35.0,

30.8, 30.6, 27.5, 26.8, 25.7, 24.9, 22.0, 21.6, 21.3, 18.4, 16.5, 15.3, 15.1, 11.2, 9.5, 7.6. ESI- HRMS: [M + H] ⁺ calculated for C62H ₉₅ N ₈ O14: 1175.69623, measured 1175.69618; HPLC t _re t =

19.8 and 20.4 min (E/Z mixture, method B)

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. ¹ H-NMR (400 MHz, DMSO) 6 11.81 (s, 1H), 8.64 (s, 1H), 7.91 (s, 1H), 7.36 (d, J = 2.6 Hz, 2H), 7.17 (d, J = 3.3 Hz, 1H), 6.81 - 6.73 (m, 1H), 4.97 - 4.86 (m, J = 12.1 Hz, 1H), 3.19 (s, 1H), 2.40 (dd, J = 23.0, 11.1 Hz, 2H), 2.05 - 1.90 (m, 4H), 1.78 (d, J = 11.2 Hz, 1H), 1.51 (td, J = 25.2, 12.3 Hz, 3H). ¹³ C-NMR: (101 MHz, DMSO) 6 164.12, 149.58, 146.70, 143.87, 140.11, 135.41, 134.22, 133.17, 132.16, 122.38, 117.23, 116.91, 114.52, 107.90, 103.42, 99.26, 55.56, 44.32, 29.31, 24.36. MS (ESI) m/z: 402.27 [M + H] ⁺ ; HPLC t _re t = 22,0 min (method B).

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)p ropanamide: 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. NazCCh and DCM and transferred to a separatory funnel. After extraction with DCM (three times), the combined organics were dried over NazSC and evaporated in vacuo to yield 50 mg (quant.) of the title compound as beige solid. ¹ H-NMR: (400 MHz, CDCI3) 6 12.01 (s, 1H), 8.86 (s, 1H), 7.49 (s, 1H), 7.02 - 6.92 (m, J = 9.3, 3.1 Hz, 2H), 6.50 (d, J = 3.2 Hz, 1H), 5.22 - 5.12 (m, 1H), 4.25 (dd, J = 11.7, 4.6 Hz, 2H), 4.07 (t, J = 7.5 Hz, 1H), 3.66 (td, J = 11.6, 6.0 Hz, 2H), 3.44 - 3.40 (m, J = 7.0 Hz, 2H), 3.12 (s, 3H), 3.03 (s, 3H), 2.94 - 2.76 (m, 2H), 2.00 - 1.88 (m, 2H). ¹³ C-NMR: (101 MHz, CDCI3) 6 163.1, 152.3, 145.2, 144.7, 142.6, 136.7, 135.4, 133.6, 123.6, 116.4, 114.1, 110.9, 105.2, 100.9 67.4, 53.4, 37.6, 36.7, 34.4, 30.9, 30.6, 28.6. ESI-HRMS: [M + Na] ⁺ calculated ofr C23H24NeNaO3: 455.18021, measured 455.18105; HPLC t _re t = 17.0 min (method B).

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. Na2COs and DCM and transferred to a separatory funnel. After extraction with DCM (three times), the combined organics were dried over Na2SO4 and evaporated in vacuo to yield 34 mg (47 %) of the title compound as beige solid. ¹ H-NMR: (400 MHz, CDCI3) 6 11.46 (bs, 1H), 8.86 (s, 1H), 7.50 - 7.43 (m, 1H), 6.84 (d, J = 11.4 Hz, 2H), 6.54 - 6.49 (m, 1H), 4.84 - 4.78 (m, J = 13.7 Hz, 1H), 4.22 - 4.13 (m, 1H), 3.75 (s, 3H), 3.63 (s, 2H), 3.49 - 3.43 (m, 2H), 3.20 (s, 3H), 2.47 (s, 2H), 2.06 - 1.99 (m, 4H), 1.91 - 1.85 (m, 1H), 1.58 - 1.49 (m, 3H). ¹³ C-NMR: (101 MHz, CDCI3) 6 168.8, 164.3, 151.9, 145.0, 144.7, 143.1, 136.9, 135.6, 133.8, 123.2, 115.9, 113.9, 110.8, 105.2, 101.1, 70.7, 57.1, 52.5, 50.4, 37.1, 34.3, 30.9, 29.8, 28.6, 25.9, 25.1. ESI-HRMS: [M + H] ⁺ calculated for C26H29N6O4: 489.22448, measured 489.22470; HPLC t _re t = 21.9 min (method B).

Example 77: 2R,3S,4R,5R,8R,10R,llR,12S,13S,14R)-2-ethyl-3,4,10-trihydrox y-13- (((2R,4R,5S,6S)-5-hydroxy-4-methoxy-4,6-dimethyltetrahydro-2 H-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. 15,55 g of azithromycin (20,8 mmol, 1.0 equiv) were dissolved in 105 ml IBuOH and the stirred solution heated to 75 °C. 45 ml of glycidol (685 mmol, 33 equiv) were added dropwise as a 1:1 mixture in IBuOH over 1 h. Stirring continued for 3 h, at which point MS indicated no further conversion of azithromycin. The solution was concentrated to almost dryness under reduced pressure and 300 ml of H2O were added. The suspension was left to stir at ambient temperature overnight and the solids were filtered. Recrystallization in MeOH yielded 3,07 g (21 %) of as fine, colorless to white platelets. ^X H-NMR (400 MHz, CDCI3) 6 5.08 (d, J = 4.8 Hz, 1H), 4.90 (s, 1H), 4.68 (d, J = 9.5 Hz, 1H), 4.18 (d, J = 4.4 Hz, 1H), 4.03 (dq, J = 12.4, 6.1 Hz, 1H), 3.67 - 3.61 (m, 2H), 3.50 - 3.44 (m, J = 15.8 Hz, 2H), 3.42 - 3.38 (m, 1H), 3.37 (s, 3H), 3.33 - 3.30 (m, J = 4.7 Hz, 1H), 3.19 (d, J = 3.0 Hz, 1H), 3.00 (t, J = 10.2 Hz, 1H), 2.95 - 2.90 (m, 1H), 2.81 - 2.66 (m, 2H), 2.54 (d, J = 10.7 Hz, 1H), 2.37 (s, 1H), 2.34 - 2.30 (m, J = 5.2 Hz, 3H), 2.20 (d, J = 11.0 Hz, 1H), 2.04 - 1.95 (m, J = 14.1 Hz, 3H), 1.93 - 1.84 (m, J = 14.7, 7.4 Hz, 1H), 1.74 - 1.61 (m, J = 29.9, 14.7 Hz, 2H), 1.56 (dd, J = 15.2, 4.7 Hz, 1H), 1.51 - 1.41 (m, 1H), 1.35 - 1.27 (m, J = 11.5, 5.1 Hz, 7H), 1.24 - 1.18 (m, 7H), 1.14 (d, J = 6.1 Hz, 3H), 1.11 - 1.06 (m, J = 8.9 Hz, 6H), 0.98 (d, J = 7.2 Hz, 3H), 0.94 - 0.86 (m, J = 15.9, 7.0 Hz, 6H). ¹³ C-NMR (101 MHz, CDCI3) 6 178.23, 97.78, 94.65, 85.88, 77.80, 76.84, 76.53, 73.92, 73.54, 73.02, 72.47, 69.82, 65.21, 62.23, 61.60, 53.75, 51.52, 48.95, 44.89, 41.58, 41.39, 35.97, 34.37, 32.30, 26.97, 26.43, 21.62, 21.26, 21.00, 20.64, 17.98, 15.97, 14.53, 10.96, 8.94, 6.94. MS (ESI) m/z: 704,60 [M + H] ⁺ ; HPLC t ^ret = 14.1 min (method A).

Example 78: (2R,3S,4R,5R,8R,10R,llR,12S,13S,14R)-2-ethyl-3,4,10-trihydro xy-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(2-(methylamino)eth yl)amino)tetrahydro-2H- pyran-2-yl)oxy)-3,5,6,8,10,12,14-heptamethyl-l-oxa-6-azacycl opentadecan-15-one: 6,0 g of (example 77) (8,52 mmol, 1.0 equiv) were dissolved in 10 ml N,N'-dimethylethane-l,2-diamine in a 25 ml round bottomed flask and stirred at 60 °C. After two days, MS indicated full consumption of starting material. The crude product was taken up in silica gel and subjected to column chromatography (EtOAc EtOAc/MeOH 2:1), yielding 4,47 g (66 %) of the title compound as a solid. Another 1,25 g of product with identical m/z but different t _re t and NMR spectra were also isolated, likely to be from opening of the epoxide at the 2' position instead of 3'. ^X H-NMR (400 MHz, DMSO) 6 7.51 (s, 1H), 4.90 (s, 1H), 4.86 (d, J = 4.6 Hz, 1H), 4.75 (dd, J = 10.1, 2.4 Hz, 1H), 4.31 - 4.28 (m, J = 2.3 Hz, 1H), 4.12 - 4.04 (m, 2H), 4.02 (d, J = 7.1 Hz, 1H), 3.86 - 3.83 (m, 3H), 3.53 (d, 2H), 3.43 (s, 1H), 3.25 (s, 3H), 3.16 (s, 1H), 3.07 - 2.99 (m, 1H), 2.84 - 2.76 (m, J = 13.1, 5.9 Hz, 1H), 2.74 - 2.69 (m, J = 5.7 Hz, 2H), 2.66 (d, J = 6.9 Hz, 2H), 2.47 (s, 3H), 2.42 (s, 3H), 2.36 (d, J = 10.4 Hz, 1H), 2.27 (s, 1H), 2.21 (s, 3H), 2.11 - 2.06 (m, J = 6.9, 4.7 Hz, 1H), 1.98 (s, 1H), 1.93 - 1.74 (m, 3H), 1.66 (d, J = 14.2 Hz, 1H), 1.54 - 1.45 (m, 3H), 1.44 - 1.25 (m, 3H), 1.21 (s, 3H), 1.17 (s, 2H), 1.15 (d, J = 1.3 Hz, 1H), 1.11 (s, 3H), 1.09 - 1.05 (m, 5H), 1.00 (s, 3H), 0.96 - 0.92 (m, J = 6.9, 3.2 Hz, 4H), 0.88 - 0.82 (m, 6H), 0.81 - 0.76 (m, J = 7.3 Hz, 3H). ¹³ C-NMR (101 MHz, DMSO) 6 177.11, 99.68, 94.56, 83.43, 77.37, 77.00, 76.29, 74.92, 73.59, 72.60, 72.31, 69.04, 68.65, 65.55, 64.78, 63.21, 61.53, 59.65, 53.90, 48.64, 47.61, 45.68, 44.88, 41.63, 36.82, 35.61, 34.01, 27.56, 26.02, 22.03, 21.62, 20.93, 20.64, 18.30, 17.59, 14.77, 14.00, 10.81, 8.65, 6.60. MS (ESI) m/z: 859,73 [M + H] ⁺ ; HPLC t _re t = 13,7 min (method A) Example 47: 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-azacyc lopentadecan-ll-yl)oxy)-3- hydroxy-6-methyltetrahydro-2H-pyran-4-yl)(methyl)amino)ethyl )-N-methylacetamide: 566 mg cyanoacetic acid (6.66 mmol, 1.1 equiv) and 2.3 g HATU (6.06 mmol, 1.0 equiv) are suspended in 35 ml dry THF and 1 ml EtsN (7 ,T1 mmol, 1.2 equiv) and stirred at ambient temperature for 30 min. 4,8 g of example 78 (6.06 mmol, 1.0 equiv) are added in one portion and the mixture was left to stir for two days, after which TLC and MS confirmed full conversion of starting material. The reaction mixture was diluted with EtOAc, transferred to a separatory funnel and extracted three times with 5 % citric acid solution. The combined aqueous phases were basified by portionwise addition of K2CO3 and extracted with three portions of EtOAc. The combined organics were evaporated under reduced pressure and the crude product was subjected to column chromatography (EtOAc EtOAc/MeOH 8:1), yielding 3.35 g (64 %) of the title compound as an off-white solid. ¹ H NMR (400 MHz, DMSO) 6 7.56 (s, 1H), 4.90 (s, 1H), 4.85 (s, 1H), 4.74 (d, J = 9.7 Hz, 1H), 4.65 (dd, J = 16.7, 2.4 Hz, 1H), 4.41 - 4.27 (m, 3H), 4.13 - 4.02 (m, 2H), 3.98 - 3.91 (m, 1H), 3.78 - 3.63 (m, 2H), 3.58 - 3.47 (m, J = 15.0, 11.1 Hz, 2H), 3.23 (s, 4H), 3.12 - 3.00 (m, J = 16.8, 9.9 Hz, 1H), 2.97 - 2.87 (m, 2H), 2.83 (d, J = 2.7 Hz, 1H), 2.69 (s, 6H), 2.66 - 2.61 (m, 1H), 2.52 - 2.44 (m, 3H), 2.37 (d, J = 9.8 Hz, 1H), 2.29 - 2.17 (m, 5H), 2.08 (s, 1H), 1.98 (s, 1H), 1.94 - 1.81 (m, 2H), 1.79 - 1.26 (m, 7H), 1.21 (d, J = 2.2 Hz, 2H), 1.16 (d, J = 6.4 Hz, 3H), 1.14 - 1.13 (m, 1H), 1.11 (s, 2H), 1.09 - 1.04 (m, 6H), 1.01 (s, 3H), 0.97 - 0.92 (m, J = 4.8 Hz, 4H), 0.87 - 0.82 (m, 4H), 0.78 (t, J = 7.4 Hz, 3H). ¹³ C-NMR (101 MHz, DMSO) 6 177.22, 162.76, 116.14, 99.61, 94.62, 82.85, 77.43, 77.08, 76.32, 74.93, 73.63, 72.68, 72.34, 69.82, 68.71, 65.48, 64.84, 61.58, 59.75, 54.18, 53.69, 48.69, 44.96, 41.73, 41.37, 35.64, 34.62, 30.63, 27.59, 26.05, 24.92, 24.50, 22.07, 21.60, 20.98, 20.71, 18.35, 17.60, 14.84, 14.06, 10.88, 8.79, 6.66. ESI-HRMS: [M + H] ⁺ calculated for C43H78N4O13 : 859.56382, found 859.56332; HPLC t _re t = 14,7 min (method A)

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. The solids were filtrated and dried in vacuo. Yield: 33.5 g (86 %) of the title compound. ^T H NMR (300 MHz, MeOD) 6 4.88 (d, J = 8.5 Hz, 2H), 4.09 (s, 1H), 3.92 (s, 3H), 2.86 (s, 3H). ¹³ C-NMR (75 MHz, MeOD) 6 168.14, 53.41, 48.72, 33.56. MS (ESI) m/z: 104.16 [M + H] ⁺ ; HPLC t _re t = 0.5 min (method B)

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. The ice bath was then removed and 10 g of example 79 (97 mmol, 1.0 equiv) were added. Following that, 27 ml EtsN (194 mmol, 2.0 equiv) were slowly added and the mixture was left to stir overnight. After addition of water and sat. NaHCCh (2:1), the two phases were transferred to a separatory funnel and extracted two times with DCM. The combined organics were dried over NazSC , evaporated under reduced pressure and the crude product was purified by flash chromatography (cyclohexane/acetone, automatic gradient). Yield: 12.5 g (75 %) of the title compound as a brownish oil. ⁿ H NMR (300 MHz, DMSO) 64.10 (d, J = 2.6 Hz, 4H), 3.66 (s, 3H), 3.00 (s, 3H). ¹³ C-NMR (75 MHz, DMSO) 6 169.31, 163.93, 115.82, 51.87, 49.27, 36.38, 24.73. MS (ESI) m/z: 171.13 [M + H] ⁺ ; HPLC t _re t = 1.3 min (method B)

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. H -NMRn (400 MHz, DMSO) 6 3.99 (s, 2H), 3.40 (t, J = 6.7 Hz, 2H), 2.91 (s, 3H), 2.55 - 2.37 (m, 2H), 2.21 (s, 6H). ¹³ C-NMR (75 MHz, DMSO) 6 162.73, 116.15, 56.09, 45.47, 45.26, 35.35, 25.02. MS (ESI) m/z: 170.2 [M + H] ⁺ ; HPLC t _re t =7,8 min (method B)

Example 65: 3-(4-hydroxypiperidin-l-yl)-3-oxopropanenitrile In a round bottomed flask, 1.58 g of 4-hydroxypiperidine (15.68 mmol, 1.0 equiv), 1.67 ml of ethyl cyanoacetate (15.68 mmol, 1.0 equiv) and 11 mg of sodium ethoxide (0.157 mmol, 0.01 equiv) were dissolved in 6 ml of EtOH and stirred over a weekend at ambient temperature, after which TLC and MS indicated consumption of starting material. Flash chromatography (cyclohexane/acetone, automatic gradient). Yield: 800 mg (30 %) as red oil. ^T H NMR (300 MHz, DMSO) 64.74 (d, J = 4.0 Hz, 1H), 3.99 (s, 2H), 3.90 - 3.77 (m, 1H), 3.76 - 3.64 (m, 1H), 3.57 - 3.45 (m, J = 12.8, 4.5 Hz, 1H), 3.20 - 2.97 (m, J = 16.4, 11.2, 3.3 Hz, 2H), 1.81 - 1.61 (m, 2H), 1.49 - 1.19 (m, J = 17.2, 8.9, 3.9 Hz, 2H). ¹³ C-NMR (75 MHz, DMSO) 6 161.10, 116.27, 65.56, 43.43, 33.98, 24.80. MS (ESI) m/z: 169.20 [M + H] ⁺ ; HPLC t _re t = 1.2 min (method B).

Example 55: 3-(4-methylpiperazin-l-yl)-3-oxopropanenitrile In an ice cooled round bottomed flask, 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. ^X H NMR (400 MHz, DMSO) 6 4.01 (s, 2H), 3.44 (t, 2H), 3.32 (t, 2H), 2.31 (t, 2H), 2.25 (t, 2H), 2.18 (s, 3H). ¹³ C-NMR (101 MHz, DMSO) 6 161.27, 115.96, 54.25, 53.90, 45.41, 45.18, 41.51, 24.55. MS (ESI) m/z: 168.27 [M + H] ⁺ ; HPLC t _re t = 0.5 min (method B)

Example 61: 3-oxo-3-thiomorpholinopropanenitrile In a round bottomed flask, 2.0 ml of thiomorpholine (19.4 mmol, 1.0 equiv), 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. Yield: 1.84 g (56 %) as beige solid. ^T H NMR (400 MHz, DMSO) 6 4.03 (s, 2H), 3.76 - 3.68 (m, 2H), 3.62 - 3.55 (m, 2H), 2.68 - 2.60 (m, 2H), 2.60 - 2.53 (m, 2H). ¹³ C-NMR (101 MHz, DMSO) 6 161.45, 115.94, 48.13, 44.25, 24.88. MS (ESI) m/z: 168.93 [M - H]’; HPLC t _re t =13.1 min (method B).

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 In a screw-cap tube, 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. NazCOs and DCM and transferred to a separatory funnel. After extraction with DCM (three times), the combined organics were dried over NazSC and evaporated in vacuo to yield 89 mg (89 %) of the title compound as yellow solid. ^X H-NMR (400 MHz, CDCI3) 6 11.93 (s, 1H), 8.94 - 8.83 (m, 1H), 7.49 (s, 1H), 6.87 (d, J = 2.9 Hz, 2H), 6.51 (d, J = 3.0 Hz, 1H), 4.83 (t, J = 12.1 Hz, 1H), 4.10 (dd, J = 8.0, 6.9 Hz, 1H), 3.45 (qd, J = 15.3, 7.6 Hz, 2H), 3.12 (s, 3H), 3.02 (s, 3H), 2.58 - 2.44 (m, J = 9.5 Hz, 2H), 2.12 - 1.97 (m, J = 13.0 Hz, 4H), 1.89 (s, 1H), 1.61 - 1.47 (m, J = 7.0 Hz, 3H). ¹³ C- NMR (101 MHz, CDCI3) 6 163.16, 152.18, 145.11, 144.64, 143.06, 136.71, 135.54, 133.76, 123.25, 116.34, 113.81, 110.65, 105.23, 100.93, 57.06, 37.58, 36.61, 34.18, 30.86, 28.68, 25.90, 25.04. ESI-HRMS: [M + H] ⁺ calculated for C24H26N6O2 : 431.21900, found 431.21942; HPLC tret = 16.4 min (method A).

Example 76: (2R,3S,4R,5R,8R,10R,llR,12S,13S,14R)-2-ethyl-3,4,10-trihydro xy-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)pro pyl)amino)tetrahydro-2H- pyran-2-yl)oxy)-3,5,6,8,10,12,14-heptamethyl-l-oxa-6-azacycl opentadecan-15-one In a screw-cap tube, 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 a shaking incubator at 105 °C overnight, after which MS indicated full conversion of educt. The mixture was transferred to a round bottomed flask, concentrated under reduced pressure and subjected to flash chromatography (acetone/MeOH, automatic gradient). Yield: 270 mg (46 %) as colorless crystals ^X H-NMR (600 MHz, DMSO) 64.89 (d, J = 2.5 Hz, 1H), 4.86 (d, J = 4.8 Hz, 1H), 4.75 (dd, J = 10.2, 2.7 Hz, 1H), 4.32 - 4.29 (m, J = 2.1 Hz, 1H), 4.09 (dq, J = 12.4, 6.1 Hz, 1H), 3.96 - 3.91 (m, J = 17.0, 7.6, 4.5 Hz, 1H), 3.77 (d, J = 2.4 Hz, 1H), 3.51 (d, J = 7.7 Hz, 1H), 3.43 (s, 2H), 3.25 (s, 3H), 2.89 (d, J = 9.4 Hz, 1H), 2.84 - 2.75 (m, 1H), 2.68 - 2.64 (m, 2H), 2.61 (dt, J = 13.0, 6.6 Hz, 1H), 2.47 - 2.44 (m, J = 7.1 Hz, 2H), 2.43 (s, 3H), 2.38 - 2.34 (m, 1H), 2.27 - 2.22 (m, J = 11.1 Hz, 4H), 2.20 (s, 3H), 2.15 - 2.07 (m, 2H), 1.91 - 1.82 (m, 2H), 1.77 (ddd, J = 14.1, 7.5, 2.6 Hz, 1H), 1.72 - 1.68 (m, 1H), 1.52 - 1.46 (m, 4H), 1.45 - 1.41 (m, J = 13.6 Hz, 2H), 1.38 - 1.34 (m, 1H), 1.27 (dd, J = 14.2, 7.7 Hz, 1H), 1.21 (s, 3H), 1.16 (d, J = 6.2 Hz, 3H), 1.11 (s, 3H), 1.07 (d, J = 7.5 Hz, 3H), 1.05 (d, J = 6.1 Hz, 3H), 1.00 (s, 3H), 0.93 (d, J = 6.8 Hz, 3H), 0.86 (d, J = 7.4 Hz, 3H), 0.83 (d, J = 6.9 Hz, 3H), 0.78 (t, J = 7.4 Hz, 3H). 13C-NMR (75 MHz, DMSO) 6 177.14, 99.66, 94.52, 83.33, 77.37, 76.98, 76.27, 75.15, 73.63, 72.59, 72.30, 68.94, 68.82, 65.47, 64.87, 64.77, 63.03, 61.62, 58.48, 54.91, 49.93, 48.62, 44.93, 42.22, 41.77, 40.15, 36.86, 36.27, 35.63, 34.59, 27.94, 27.60, 26.02, 22.00, 21.75, 20.94, 18.36, 17.74, 15.12, 14.83, 10.92, 8.02, 6.59. MS (ESI) m/z: 806.73 [M + H] ⁺ ; HPLC t _re t = 8.9 min (method B).

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-azacyc lopentadecan-ll-yl)oxy)-3- hydroxy-6-methyltetrahydro-2H-pyran-4-yl)(methyl)amino)propy l)-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 equiv) and 72 pl of EtsN (0.519 mmol, 1.1 equiv) were stirred in 5 ml dry THF at ambient temperature for 1 h. At this point, 380 mg of example 76 (0.471 mmol, 1.0 equiv) were added and the mixture was stirred until TLC and MS indicated full consumption of educts. The mixture was diluted with sat. NaHCCh and DCM and transferred to a separatory funnel. The aqueous phase was extracted four times with DCM, the combined organics were dried over NazSC and evaporated under reduced pressure. The crude product was then purified by flash chromatography (EtOAc/MeOH, automatic gradient). Yield: 340 mg (83 %) as off-color solid. ¹ H-NMR (400 MHz, DMSO) 6 4.92 (s, 2H), 4.86 - 4.82 (m, 1H), 4.13 - 4.05 (m, 2H), 4.04

- 3.99 (m, 1H), 3.96 (s, 1H), 3.87 - 3.81 (m, 1H), 3.74 - 3.69 (m, 1H), 3.54 (d, J = 7.2 Hz, 1H), 3.45 (d, J = 9.9 Hz, 2H), 3.40 (s, 1H), 3.38 (s, 1H), 3.36 (s, 1H), 3.26 (s, 5H), 3.21 - 3.19 (m, J = 5.8 Hz, 1H), 3.09 (d, J = 7.2 Hz, 1H), 2.97 - 2.93 (m, J = 8.9 Hz, 2H), 2.91 (s, 3H), 2.87 - 2.84 (m, J = 9.6 Hz, 1H), 2.82 (s, 2H), 2.28 (d, J = 14.8 Hz, 2H), 1.82 - 1.75 (m, J = 13.0, 6.2 Hz, 2H), 1.70

- 1.61 (m, J = 18.0, 10.3 Hz, 3H), 1.58 - 1.47 (m, 5H), 1.36 (s, 2H), 1.34 - 1.30 (m, J = 8.1 Hz, 3H), 1.26 - 1.22 (m, J = 7.5 Hz, 6H), 1.18 (s, 1H), 1.14 - 1.13 (m, 4H), 1.11 (s, 3H), 1.10 (s, 3H), 1.08 (s, 3H), 1.07 - 1.05 (m, 3H), 0.92 - 0.87 (m, J = 5.6 Hz, 6H), 0.81 (t, J = 7.4 Hz, 4H). ¹³ C NMR (101 MHz, DMSO) 6 177.28, 164.60, 151.91, 134.35, 129.32, 124.89, 121.12, 116.16, 94.51, 77.40, 76.93, 73.52, 72.36, 65.59, 64.96, 54.09, 53.46, 48.66, 47.30, 45.75, 44.94, 41.56, 36.99, 36.05, 35.28, 34.46, 33.17, 30.40, 29.86, 25.02, 24.50, 21.69, 20.93, 20.66, 18.35, 17.37, 14.84, 10.88, 8.69, 8.51, 7.26. MS (ESI) m/z: 873.80 [M + H] ⁺ ; HPLC t _re t = 11.8 min (method B).

Example 81: benzyl (2-((2-(((2S,6R)-2-(((2R,3S,4R,5R,8R,10R,HR,12S,13S,14R)-2-e thyl-3,4,10- trihydroxy-13-(((2R,4R,5S,6S)-5-hydroxy-4-methoxy-4,6-dimeth yltetrahydro-2H-pyran-2- yl)oxy)-3,5,6,8,10,12,14-heptamethyl-15-oxo-l-oxa-6-azacyclo pentadecan-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), 986 mg of HATU (2.59 mmol, 1.05 equiv) and 361 p.1 of triethylamine (2.59 mmol, 1.05 equiv) were dissolved in 13 ml dry THF and stirred at ambient temperature for 1 h. Then, 1.96 g of example 78 (2.47 mmol, 1.0 equiv) were added and the mixture was left to stir overnight. The mixture was concentrated under reduced pressure, taken up in DCM and sat. NaHCCh solution and extracted three times with DCM. The combined organic phases were then dried in vacuo and subjected to flash chromatography (EtOAc/MeOH, automatic gradient). Yield: 1.81 g (= 73 %) as a beige foam. MS (ESI) m/z: 997.87 [M + H] ⁺ ; HPLC t _re t = 14.3 min (method B).

Example 82: N-(2-(((2S,6R)-2-(((2R,3S,4R,5R,8R,10R,llR,12S,13S,14R)-2-et hyl-3,4,10- trihydroxy-13-(((2R,4R,5S,6S)-5-hydroxy-4-methoxy-4,6-dimeth yltetrahydro-2H-pyran-2- yl)oxy)-3,5,6,8,10,12,14-heptamethyl-15-oxo-l-oxa-6-azacyclo pentadecan-ll-yl)oxy)-4- hydroxy-6-methyltetrahydro-2H-pyran-3-yl)(methyl)amino)ethyl )-N-methyl-2-

(methylamino)acetamide: 1.5 g of example 81 (1.504 mmol) were dissolved in 45 ml EtOAc. The stirred mixture was thoroughly purged with argon; connection of the system to a washing flask and a subsequent water column before the gas outlet ensured a mild overpressure inside the reaction flask. 150 mg of Pt/C (5 %) were added and the system was once again purged with argon. Afterwards, the system was purged with H2, the washing flask acting as a reservoir, and stirred at ambient temperature until TLC and MS indicated full conversion of educt. 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 630 mg (= 49 %) as a white solid. No further purification steps were necessary. MS (ESI) m/z: 863.62 [M + H] ⁺ ; HPLC t _re t = 10.1 min (method B).

Example 83: 2-cyano-N-(2-((2-(((2S,6R)-2-(((2R,3S,4R,5R,8R,10R,HR,12S,13 S,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-azacyc lopentadecan-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 (0.65 mmol, 1.05 equiv) and 90.6 pl of EtsN (0.65 mmol, 1.05 equiv) were dissolved in 8 ml dry THF and stirred at ambient temperature for 20 min. Then, 535 mg of example 82 (0.62 mmol, 1.0 equiv) as a solution in dry THF were added and the mixture was left to stir overnight. The mixture was concentrated under reduced pressure, taken up in DCM and sat. NaHCOs solution and transferred to a separatory funnel. The aqueous phase was extracted four times with DCM. Then, the combined organic phases were dried over Na2SC>4 and dried under reduced pressure. No further purification steps were necessary. Yield: 461 mg (80 %) as off-white solid. MS (ESI) m/z: 930.73 [M + H] ⁺ ; HPLC t _re t = 12.1 min (method B).

Example 84: (E)-2-cyano-3-(5-(l-cyclohexyl-l,6-dihydroimidazo[4,5-d]pyrr olo[2,3-b]pyridin-2- yl)furan-2-yl)-N-(2-((2-(((2S,6R)-2-(((2R,3S,4R,5R,8R,10R,ll R,12S,13S,14R)-2-ethyl-3,4,10- trihydroxy-13-(((2R,4R,5S,6S)-5-hydroxy-4-methoxy-4,6-dimeth yltetrahydro-2H-pyran-2- yl)oxy)-3,5,6,8,10,12,14-heptamethyl-15-oxo-l-oxa-6-azacyclo pentadecan-ll-yl)oxy)-4- hydroxy-6-methyltetrahydro-2H-pyran-3-yl)(methyl)amino)ethyl )(methyl)amino)-2-oxoethyl)- N-methylacrylamide: 70 mg of example 31 (0.209 mmol, 1.0 equiv), 195 mg of example 83 (0.209 mmol, 1.0 equiv) and 2.1 pl of piperidine (0.0209 mmol, 0.1 equiv) were dissolved in 1.5 ml of MeOH and stirred at 60 °C for 2 h. The solvent was removed under reduced pressure and the crude product was purified by flash chromatography (EtOAc/MeOH, automatic gradient). Yield: 177 mg (68 %) as a yellow solid. MS (ESI) m/z: 1246.80 [M + H] ⁺ ; HPLC t _re t = 15.3 min (method B). Example 85: (E)-2-cyano-N-(3-(((2S,6R)-2-(((2R,3S,4R,5R,8R,10R,llR,12S,1 3S,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-azacyc lopentadecan-ll-yl)oxy)-4- hydroxy-6-methyltetrahydro-2H-pyran-3-yl)(methyl)amino)propy l)-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: 53 mg of example 33 (0.151 mmol, 1.0 equiv), 132 mg of example 75 (0.151 mmol, 1.0 equiv) and 1.5 pl of piperidine (0.0151 mmol, 0.1 equiv) were dissolved in 3 ml of MeOH and stirred at 60 °C for 6 h. The solvent was removed under reduced pressure and the crude product was purified by flash chromatography (EtOAc/MeOH, automatic gradient). Yield: 145 mg (80 %) as a yellow solid. MS (ESI) m/z: 1204.80 [M + H] ⁺ ; HPLC t _re t = 12.4 and 13.3 min (E/Z mixture, method B).

Example 91: (2R,3S,4R,5R,8R,10R,llR,12S,13S,14R)-2-ethyl-3,4,10-trihydro xy-13-

(((2R, 4R, 58, 68)-5-hydroxy-4-methoxy-4, 6-dimethyltetrahydro-2H-pyran-2-yl)oxy)-l 1 - (((28,38,4R,6R)-4-hydroxy-6-methyl-3-(methyl(4-(methylamino) butyl)amino)tetrahydro-2H- pyran-2-yl)oxy)-3,5,6,8,10,12,14-heptamethyl-l-oxa-6-azacycl opentadecan-15-one: 2,3 g of example 77 (3,27 mmol, 1.0 equiv.), 1,14 ml EtsN (8,18 mmol, 2,5 Aq.) and 0,98 g of N,N'- dimethyl-l,4-diaminobutane (8,18 mmol, 2,5 equiv.) were dissolved in 7 ml iPrOH and stirred at 90 °C overnight, until reaction controls indicated consumption of starting material. The solution was concentrated under reduced pressure and subjected to flash chromatography (EtOAc/MeOH, automatic gradient). Yield: 260 mg (10 %) as a white solid. ¹ H-NMR: (400 MHz, CDCI3) 6 8.38 (bs, 1H), 4.98 - 4.95 (m, 1H), 4.93 - 4.87 (m, 1H), 4.58 (d, J = 9.5 Hz, 1H), 4.29 (bs, 1H), 4.09 - 3.99 (m, J = 5.9 Hz, 1H), 3.95 - 3.85 (m, 2H), 3.58 (s, 1H), 3.52 (d, J = 6.7 Hz, 1H), 3.34 (td, J = 10.1, 4.9 Hz, 1H), 3.23 (s, 3H), 2.89 (d, J = 8.8 Hz, 1H), 2.78 - 2.71 (m, 1H), 2.66

- 2.57 (m, J = 4.4 Hz, 3H), 2.56 - 2.53 (m, 1H), 2.51 - 2.47 (m, J = 5.6 Hz, 2H), 2.43 (s, 3H), 2.40

- 2.38 (m, J = 3.4 Hz, 1H), 2.32 (s, 3H), 2.25 - 2.22 (m, J = 4.2 Hz, 1H), 2.20 (s, 3H), 1.99 - 1.70 (m, 6H), 1.60 - 1.52 (m, J = 10.8 Hz, 1H), 1.47 - 1.33 (m, 7H), 1.26 - 1.19 (m, 7H), 1.10 - 1.05 (m, 11H), 0.98 (s, 6H), 0.87 - 0.81 (m, J = 5.9 Hz, 3H), 0.80 - 0.74 (m, J = 5.1 Hz, 6H). ¹³ C-NMR: (101 MHz, CDCI3) 6 178.1, 99.9, 94.4, 84.2, 73.8, 73.1, 72.3, 69.7, 69.6, 65.7, 65.3, 65.1, 63.3, 62.0, 56.9, 51.1, 48.8, 45.8, 45.1, 42.6, 41.8, 39.9, 36.7, 35.9, 35.2, 34.5, 27.3, 26.4, 26.3, 25.8, 25.0, 24.8, 21.7, 21.3, 21.1, 20.9, 17.9, 16.1, 14.6, 10.8, 8.8, 6.8. MS (ESI) m/z: 820.40 [M + H] ⁺ ;

HPLC tret = 11-3 min (method B) Example 92: (2R,3S,4R,5R,8R,10R,llR,12S,13S,14R)-2-ethyl-3,4,10-trihydro xy-13-

(((2R, 4R, 5S, 6S)-5-hydroxy-4-methoxy-4, 6-dimethyltetrahydro-2H-pyran-2-yl)oxy)-l 1 - (((2S,3R,4S,6R)-3-hydroxy-6-methyl-4-(methyl(4-(methylamino) butyl)amino)tetrahydro-2H- pyran-2-yl)oxy)-3,5,6,8,10,12,14-heptamethyl-l-oxa-6-azacycl opentadecan-15-one: Example 92 was obtained as another product in the synthesis of example 91 (see above). After separation of the two products by flash chromatography, 640 mg (24 %) of example 92 were obtained as a white solid. ¹ H-NMR: (400 MHz, CDCI3) 6 8.25 (bs, 1H), 5.02 (d, J = 4.4 Hz, 1H), 4.60 - 4.54 (m, 1H), 4.40 (d, J = 7.2 Hz, 1H), 4.24 (d, J = 2.7 Hz, 1H), 4.03 (dd, J = 9.0, 6.2 Hz, 1H), 3.61 - 3.57 (m, J = 10.1 Hz, 2H), 3.49 - 3.37 (m, 2H), 3.29 (s, 3H), 3.19 (dd, J = 9.9, 7.4 Hz, 1H), 2.98 (d, J = 9.3 Hz, 1H), 2.72 (dd, J = 7.2, 4.7 Hz, 1H), 2.65 - 2.60 (m, J = 6.4 Hz, 1H), 2.56 - 2.51 (m, 3H), 2.49 - 2.47 (m, 1H), 2.43 (d, J = 10.7 Hz, 2H), 2.36 (s, 4H), 2.26 (s, 4H), 2.18 (s, 3H), 2.04 - 1.81 (m, 5H), 1.74 (d, J = 14.5 Hz, 1H), 1.62 - 1.56 (m, J = 12.3 Hz, 1H), 1.52 - 1.39 (m, J = 14.7 Hz, 7H), 1.26 - 1.22 (m, J = 5.0 Hz, 7H), 1.20 - 1.12 (m, 11H), 1.04 - 0.98 (m, 9H), 0.87 - 0.81 (m, J = 7.4 Hz, 6H). ¹³ C-NMR: (101 MHz, CDCI3) 6 178.6, 103.1, 94.9, 83.9, 78.6,

78.3, 77.7, 77.4, 74.3, 73.5, 73.1, 70.8, 70.3, 68.8, 65.7, 65.5, 63.8, 62.2, 53.6, 51.6, 49.5, 45.2, 42.6, 41.9, 36.8, 36.5, 36.0, 35.0, 29.8, 27.6, 27.2, 26.8, 26.3, 22.1, 21.7, 21.4, 18.4, 16.5, 15.1,

11.3, 9.3, 7.5. MS (ESI) m/z: 820.40 [M + H] ⁺ ; HPLC t _re t = 10.1 min (method B).

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-azacyc lopentadecan-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 EtsN (1,05 equiv.) were dissolved in 5 ml of dry THF and stirred at ambient temperature for 30 min. Then, 240 mg of example 91 (0.29 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. NaHCCh, 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: 235 mg (90 %) as beige solid. ^T H- NMR: (400 MHz, CDCI3) 68.22 (bs, 1H), 4.99 - 4.90 (m, 2H), 4.63 (d, J = 9.6 Hz, 1H), 4.31 -4.24 (m, 1H), 4.12 - 4.04 (m, 1H), 3.99 - 3.92 (m, 1H), 3.90 - 3.84 (m, 1H), 3.60 - 3.56 (m, 1H), 3.52 (d, J = 8.3 Hz, 3H), 3.46 - 3.41 (m, J = 9.6, 7.0, 3.5 Hz, 2H), 3.27 (s, 3H), 3.03 - 2.97 (m, 3H), 2.93 - 2.90 (m, 1H), 2.83 - 2.67 (m, 6H), 2.58 - 2.53 (m, 1H), 2.48 (s, 3H), 2.29 (s, 4H), 2.09 - 1.74 (m, 6H), 1.64 - 1.37 (m, J = 65.4, 17.3 Hz, 8H), 1.33 - 1.25 (m, 7H), 1.18 - 1.13 (m, 11H), 1.03 (s, 6H), 0.90 - 0.81 (m, J = 14.5 Hz, 9H). ¹³ C-NMR: (101 MHz, CDCI3) 6 178.6, 161.8, 114.4, 114.3, 100.5, 100.4, 95.3, 85.7, 85.5, 78.6, 78.1, 77.5, 77.5, 74.9, 74.4, 73.7, 73.7, 73.0, 70.5,

70.1, 66.2, 65.8, 65.7, 63.8, 63.4, 62.2, 56.9, 56.6, 50.7, 49.4, 48.5, 45.5, 43.0, 41.6, 40.4, 40.3,

38.6, 37.0, 36.8, 36.5, 35.9, 35.0, 33.8, 27.7, 26.7, 25.9, 25.5, 25.3, 24.7, 24.5, 22.2, 22.1, 21.7,

21.6, 21.1, 18.4, 16.4, 15.5, 15.3, 11.2, 9.5, 7.5. MS (ESI) m/z: 887.60 [M + H] ⁺ ; HPLC t _re t = 14.3 min (method B).

Example 94: (2R,3S,4R,5R,8R,10R,llR,12S,13S,14R)-2-ehyl-3,4,10-trihydrox y-13-

(((2R, 4R, 5S, 6S)-5-hydroxy-4-methoxy-4, 6-dimethyltetrahydro-2H-pyran-2-yl)oxy)-l 1 - (((2S,3R,4S,6R)-3-hydroxy-6-methyl-4-(methyl(2-(methylamino) ethyl)amino)tetrahydro-2H- pyran-2-yl)oxy)-3,5,6,8,10,12,14-heptamethyl-l-oxa-6-azacycl opentadecan-15-one: 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. ¹ H-NMR: (600 MHz, CDCI3) 67.99 (s, 1H), 5.08 (d, J = 4.7 Hz, 1H), 4.62 (dd, J = 9.7, 1.8 Hz, 1H), 4.33 (d, J = 7.2 Hz, 1H), 4.22 - 4.18 (m, 1H), 4.02 (dt, J = 15.2, 6.1 Hz, 2H), 3.96 - 3.91 (m, 1H), 3.59 (s, 1H), 3.54 (d, J = 7.3 Hz, 1H), 3.47 - 3.38 (m, 2H), 3.27 (s, 3H), 3.20 (dd, J = 9.9, 7.5 Hz, 1H), 2.96 (d, J = 9.4 Hz, 1H), 2.91 (s, 1H), 2.81 (s, 1H), 2.76 - 2.60 (m, 6H), 2.51 - 2.44 (m, 3H), 2.42 (s, 3H), 2.37 - 2.36 (m, J = 0.9 Hz, 1H), 2.29 - 2.27 (m, 1H), 2.25 - 2.22 (m, J = 2.3 Hz, 5H), 2.01 - 1.88

(m, 3H), 1.86 (s, 1H), 1.85 - 1.80 (m, 1H), 1.70 (d, J = 14.6 Hz, 1H), 1.64 (d, J = 12.7 Hz, 1H),

1.50 (dd, J = 15.2, 4.8 Hz, 1H), 1.43 - 1.34 (m, J = 20.0, 14.4, 6.4 Hz, 2H), 1.26 - 1.22 (m, 6H),

1.17 (s, 3H), 1.13 (d, J = 6.0 Hz, 3H), 1.11 (d, J = 7.5 Hz, 3H), 1.01 (s, 3H), 1.01 - 1.00 (m, 1H),

0.97 (d, J = 7.5 Hz, 3H), 0.86 - 0.79 (m, J = 14.8, 6.5 Hz, 6H). ¹³ C-NMR: (101 MHz, DMSO) 6

177.1, 102.4, 94.6, 82.9, 77.5, 76.4, 75.0, 73.7, 72.8, 72.7, 70.5, 68.8, 67.1, 64.8, 64.5, 61.5,

52.7, 51.7, 48.8, 48.5, 48.2, 44.7, 42.0, 41.7, 40.4, 36.6, 35.8, 35.0, 30.8, 29.1, 27.4, 26.1, 22.1, 21.4, 21.0, 18.4, 17.7, 14.8, 10.9, 9.1, 6.8. MS (ESI) m/z: 792.67 [M + H] ⁺ ; HPLC t _re t = 12.5 min (method A).

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-azacyc lopentadecan-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 EtsN (1,05 equiv.) were dissolved in 7 ml of dry THF and stirred at ambient temperature for 30 min. Then, 320 mg of example 94 (0.4 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. NaHCCh, 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 (cyclohexane/acetone, automatic gradient). Yield: 167 mg (48 %) as off-white solid. ^X H NMR (400 MHz, CDCI3) 6 8.10 (bs, 1H), 4.97 - 4.86 (m, 1H), 4.58 (d, J = 9.9 Hz, 1H), 4.38 - 4.27 (m, 1H), 4.20 - 4.13 (m, J = 15.9 Hz, 1H), 4.04 - 3.97 (m, 1H), 3.94 - 3.85 (m, 1H), 3.59 - 3.54 (m, 2H), 3.51 (s, 1H), 3.46 - 3.40 (m, 4H), 3.31 (s, 3H), 3.26 (s, 3H), 3.21 - 3.14 (m, 1H), 3.04 - 3.00 (m, 1H), 2.90 (d, J = 2.8 Hz, 1H), 2.85 (s, 1H), 2.78 - 2.60 (m, 3H), 2.51 - 2.39 (m, 3H), 2.26 (s, 6H), 2.01 - 1.71 (m, J = 35.2, 29.3, 13.3 Hz, 5H), 1.58 (d, J = 11.6 Hz, 1H), 1.49 (d, J = 14.3 Hz, 1H), 1.45 - 1.36 (m, J = 3.6 Hz, 1H), 1.25 - 1.22 (m, 6H), 1.16 (d, J = 12.5 Hz, 9H),

I.08 - 1.05 (m, 5H), 1.02 - 0.99 (m, 5H), 0.98 - 0.91 (m, 3H), 0.86 - 0.79 (m, J = 12.5, 4.5 Hz, 6H). ¹³ C-NMR: (101 MHz, CDCI3) 6 178.3, 178.1, 162.8, 162.1, 114.9, 114.0, 103.4, 103.1, 95.5,

95.3, 85.3, 84.5, 79.3, 78.9, 78.1, 78.0, 77.7, 77.6, 77.3, 76.8, 76.0, 75.9, 74.9, 74.8, 74.4, 74.3, 73.6, 73.5, 73.0, 72.2, 71.4, 70.1, 68.5, 68.5, 65.6, 65.6, 65.4, 62.0, 62.0, 59.0, 56.6, 56.5, 52.2, 50.8, 50.1, 49.4, 47.2, 45.1, 42.6, 42.5, 41.2, 40.9, 37.9, 37.4, 36.7, 36.5, 35.0, 34.2, 32.4, 31.0,

27.3, 27.2, 26.7, 25.1, 24.8, 21.9, 21.9, 21.6, 21.3, 21.1, 18.4, 17.1, 16.9, 16.4, 16.2, 15.5, 15.3,

II.1, 9.7, 9.4, 7.5. MS (ESI) m/z: 859.60 [M + H] ⁺ .

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-azacyc lopentadecan-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 EtsN (1,05 equiv.) were dissolved in 11 ml of dry THF and stirred at ambient temperature for 30 min. Then, 560 mg of 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. ¹ H NMR (400 MHz, CDCI3) 68.06 (bs, 1H), 5.00 - 4.95 (m, J = 4.4 Hz, 1H), 4.61 (d, J = 10.0 Hz, 1H), 4.43 - 4.38 (m, 1H), 4.26 - 4.21 (m, 1H), 4.07 - 3.90 (m, 2H), 3.61 (d, J = 5.8 Hz, 2H), 3.55 (s, 1H), 3.50 (s, 1H), 3.43 (dd, J = 14.0, 7.0 Hz, 3H), 3.38 - 3.35 (m, J = 5.5 Hz, 1H), 3.28 (s, 3H), 3.23 - 3.18 (m, 1H), 3.01 - 2.98 (m, 2H), 2.91 (s, 1H), 2.77 (d, J = 6.1 Hz, 2H), 2.70 - 2.62 (m, J = 6.5 Hz, 1H), 2.58 - 2.49 (m, 1H), 2.47 - 2.41 (m, J = 11.5 Hz, 2H), 2.32 (s, 1H), 2.29 (s, 4H), 2.21 (d, J = 10.8 Hz, 3H), 2.05 - 1.90 (m, J = 26.6, 15.0 Hz, 3H), 1.87 - 1.80 (m, J = 13.6, 7.3 Hz, 1H), 1.77 (d, J = 14.7 Hz, 1H), 1.65 - 1.37 (m, 8H), 1.30 - 1.25 (m, 7H), 1.20 - 1.15 (m, J = 14.3, 8.1 Hz, 11H), 1.07 - 0.99 (m, J = 16.6, 7.9 Hz, 9H), 0.89 - 0.82 (m, J = 13.2, 6.5 Hz, 6H). ¹³ C-NMR (101 MHz, CDCI3) 6 178.5, 161.7, 114.3, 114.1, 103.2, 103.1, 95.4, 95.3, 84.5, 84.1, 79.0, 78.9,

78.2, 78.2, 77.8, 77.7, 74.9, 74.5, 73.7, 73.6, 73.1, 73.0, 71.2, 71.0, 70.1, 68.8, 65.8, 65.7, 65.4,

62.1, 53.0, 52.6, 50.6, 49.5, 48.4, 45.1, 42.7, 41.3, 41.2, 37.2, 37.0, 36.6, 35.9, 35.1, 33.9, 30.32,

30.1, 27.4, 26.9, 25.8, 25.5, 25.3, 24.7, 24.7, 22.0, 21.7, 21.4, 21.4, 21.2, 18.5, 16.4, 15.5, 15.4,

15.3, 11.2, 9.5, 9.4, 7.7. MS (ESI) m/z: 887.53 [M + H] ⁺ ; HPLC t _re t = 12.4 min (method B). Example 97 Stability, pharmacokinetics and JAK inhibition.

All animal experiments were carried out in accordance with German law. Seven to eight weeks old BALB/cJ female mice N = 3 per group. Body weights were approximately 20 g per mouse. For i.v. treatment, compounds were dissolved in DMSO and then diluted 40-fold in BALB/c female serum (4 compounds, final DMSO concentration 10 %) for application at 5 ml/kg to reach a dose of 2.4 pmol/kg per substance. The vehicle for p.o. treatment comprised a solution in DMSO that was diluted 40-fold in 0.5 % citric acid (4 compounds, final DMSO concentration 10 %) with each compound being administered at a dose of 12 pmol/kg. The solutions were thoroughly homogenized via vortex mixer and ultrasonic bath. We collected heart blood, bile, brain, ileum, liver, lung, kidneys and spleen. Blood was collected in heparinized tubes and centrifuged for 8 min at 8000 rpm at 4 °C. The supernatant was used to determine plasma concentrations. Both plasma and organ samples were immediately stored at -25 °C until workup for analytics.

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. The procedure used 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. Using a thermostat, a constant column temperature of 45 °C was maintained, while the samples were kept at 6 °C.

Data on half life and bioavailability are provided in the tables below.

To determine JAK3 IC50 values, assays 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. Through inclusion of potential inhibitors to the incubation step at varying concentrations, their inhibitory potencies could be determined by comparison of the resulting OD450 values to those of control reactions.

Table 1. JAK3 Inhibition Values and PK Parameters of cyclohexane series

Compound R = JAK3 ti/2 BA ^C

IC ₅ o [nM]° [min] ^b [%]

FM-381 H-,C X 12 ± 1 23 10

^J "N

(38) ^CH 3

IC50 values are calculated by ELISA. ⁵⁷ “average ± SEM (n = 3). '’biological half-lives are calculated from i.v. PK studies. ^C BA = apparent oral bioavailability. ^d ti/2 and BA could not be calculated due to a lack of quantifiable compound concentrations in PK study samples.

Table 3. JAK3 Inhibition Values and PK Parameters of 1-methylpiperidine series

ICso values are calculated by ELISA. ⁵⁷ “average ± SEM (n = 3). '’biological half-lives are calculated from i.v. PK studies. ^C BA = apparent oral bioavailability. ^d ti/2 and BA could not be calculated due to a lack of quantifiable compound concentrations in PK study samples. Table 4. JAK3 Inhibition Values and PK Parameters of methylcyclopropane series

IC50 values are calculated by ELISA. ⁵⁷ “average ± SEM (n = 3). '’biological half-lives are calculated from i.v. PK studies. ^C BA = apparent oral bioavailability.

Example 98 NanoBRET assay

The assay was performed as described previously (Vasta et al, 2018). In brief: Full-length 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. To measure BRET, 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)). Competitive displacement data were then graphed using GraphPad Prism 8 software using a normalized 3-parameter curve fit with the following equation: Y=100/(l+10 ^A (X-LoglC50)). For the lysed assay format, the HEK293T cells were treated the same way as described above. After the 2 h incubation time with the tracer and compound, 50 ng/mL of digitonin (CAS 11024-24-1) was added using the ECHO acoustic dispenser (Labcyte). After an incubation time of 5 min at RT, NanoBRET NanoGio Substrate was added and luminescence was measured on a PHERAstar plate reader.

Cellular activity and target engagement of JAK3 as determined by nanoBRET

Compound Intact IC ₅ o [nM] ^a ' ^b Lysed IC ₅₀ [nM] ^{o c} Ratio Tofacitinib 892 ± 398 228 ± 34 3.9 38 / 347 ± 177 98 ± 3 3.5 56 877 ± 22 115 ± 2 7.7 49 1029 ± 399 269 ± 11 3.8 52 1361 ± 174 209 ± 11 6.5 62 n.d. ^d 271 ± 9 / 67 9706 474 20.5 46 > 45000 16490 / 74 19860 2201 9.0 85 12564 765 ± 74 16.4 57 597 117 131 ± 11 4.6 66 3807 122 435 ± 85 8.7

“Obtained from BRET signal ratios at eleven inhibitor concentrations. IC50 calculations were done using a normalized 3-parameter curve fit . ^fa n = 4. ^c n = 2. ^Displacement could not be determined for this compound due to interference with the BRET signal.

Example 99 LPS challenge in cells

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.

In vitro stimulation of cells: Human peripheral blood leukocytes were seeded into 96-well flat-bottom plates (Sarstedt) in a concentration of 2.5*105 cells/well and stimulated with 50 ng/ml LPS (E.coli; Sigma). Then, cells were incubated with JAK inhibitors or DMSO in the indicated concentrations for 24 h at 37°C and 5% CO2. Supernatant was taken after centrifugation at 400 rpm and immediately used for determination of cytokine concentrations. IL-10, and TNFoc levels were determined in the supernatants of the in vitro stimulation and in vivo tail plasma samples. ELISA was performed according to manufacturer's instructions and OD was measured using a VersaMax™ Tunable Microplate Reader (Molecular Devices).

Example 100: LPS challenge in mice

Lipopolysaccharide (LPS) is a bacterial cell wall fraction that is highly stimulatory to the innate immune system of most mammals. LPS is used to investigate immune responses and the impact of immune modulators on cytokine production and secretion.

Effect of compound 46. Balb/c female mice (n = 9) were treated with either vehicle or 10 mg/kg p.o. of compound 46 (in 0.5 % citric acid, 10 ml/kg). After 15 min, a solution of 10 mg/kg LPS (5. enterica typhimurium) in phosphate buffered saline (10 ml/kg) was applied intraperitoneally. 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. Data are recorded in Figure 3.

To compare the effects of different analogs, additional BALB/c female mice (n = 8) 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.

Example 101 DSS IBD model

Inflammatory bowel disease (IBD) can be modeled by disrupting the gut wall using a strong polyanion - in this case dextran sulfate, sodium salt (DSS). DSS binds to the phospholipids of the gut membrane and displaces heparin, leading to loss of membrane function. In this study, we used a defined diet that intensifies the effects of IBD and mimics aspects of the modern human diet (too little fiber). Mice were acclimated to the diet for 14 days prior to the start of DSS treatment. Male C57B6 mice (n = 8) received DSS (Dextran sulfate) 2.5% W/V in drinking water for 5 days, after which they received normal drinking water and were observed until day 15 (weight, clinical score, water consumption). Animals were maintained in 12 h light, 22C, maintenance chow ad libitum. Animals were treated daily p.o. with 1 pmol/kg substance in 0.5 % methyl cellulose in water. On day 15, mice were sacrificed by CO2 inhalation and samples of whole blood, colon, spleen and liver were recovered. Where signs of IBD were above a given level (i.e. score 4), animals were removed from the study. All procedures were approved by federal ethics committees. NTC: Non treated control = healthy

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:

NTC= Not treated control, received no DSS

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.

Data on weight and score are recorded in Figures 5 and 6. Higher body weight and faster recovery after removal of DSS suggests better maintenance of gut function. Lower score and faster reduction of score are likewise indicators of improved gut function. By both measures, and survival, compounds 84, 85 and 66 were generally able to improve signs, survival and apparent recovery.

Example 102: EAE disease model

Experimental autoinflammatory encephalomyelitis (EAE) is an animal model of human Multiple Sclerosis (MS), a neurological disorder stemming from loss of neuronal myelin sheaths. 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. Within 8- 10 days, 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.

Substances were tested for their ability to modulate the EAE model in C57BL/6 mice (n = 8) using compound 52. Treatment was i.p. 6 pmol/kg which approximates to 3 mg/kg. Treatment started as soon as animals exhibited signs (typically day 10 after disease induction). Animals in the treatment group had significantly higher body weights (p < 0,001) and lower clinical scores (p < 0,01) compared to vehicle treated animals that were induced for EAE. OTHER EMBODIMENTS

All of the features disclosed in this specification may be combined in any combination. Thus, unless expressly stated otherwise, each feature disclosed is only an example of a generic series of equivalent or similar features.

It is to be understood that while the invention has been described in conjunction with the detailed description thereof, the foregoing description is intended to illustrate and not limit the scope of the invention, which is defined by the scope of the appended claims. Other aspects, advantages, and modifications are within the scope of the following claims.

ABBREVIATIONS

The following abbreviations were used as noted:

DCM: dichloromethane

DMAP: 4-dimethylamino pyridine

DMSO: dimethyl sulfoxide

DSS sodium dextran sulfate

EAE: experimental autoimmune encephalomyelitis

EDCI: N-Ethyl-N'-(3-dimethylaminopropyl)carbodiimide hydrochloride

ELISA enzyme linked immunosorbent assay

ELSD evaporative light scattering detector

Et3N: triethylamine

EtOAc: ethyl acetate

HPLC: high performance liquid chromatography

IBD: inflammatory bowel disease

IL interleukin

JAK Janus kinase

K2CO3: potassium carbonate

LPS: lipopolysaccharides

MeOH: methanol

MOG myelin oligodendrocyte glycoprotein

MS: mass spectrometry

MS: Multiple Sclerosis Na2CO3: sodium carbonate

NaHCO3: sodium bicarbonate

NH4CI: ammonium chloride

NTC: non-treatment control

STAT signal transducer and activator of transcription

THF: tetrahydrofuran

TNFoc tumor necrosis factor oc

TLC: thin layer chromatography

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Embodiment 1

A compound of formula 1 (Formula 1) wherein

X = OR1, NR1, CHR1 lf X = ORl,

R1 = H, C1-C12 alkyl, alkenyl, alkynyl, C3-C12 cycloalkyl, cycloalkenyl, or cycloalkynyl or aryl, wherein each of C1-C12 alkyl, alkenyl, alkynyl, C3-C12 cycloalkyl, cycloalkenyl, or cycloalkynyl is optionally substituted with 0 - 6 substituents of the list O-R4, N(R4Rs), S-R4, R4, (=0), (=N- R4), -COOH, C00CH3, COOC2H5, N3, F, Cl, Br, I, bicyclononinyl, or macrolide and wherein 0 - 4 of the carbons in the C1-C12 alkyl, alkenyl, alkynyl, C3-C12 cycloalkyl, cycloalkenyl, or cycloalkynyl is substituted by -O- or -S- or -N(R4)-; or R1 = a substituted macrolide attached via a linker; and R2 is a free electron pair; lf X = NRl, CHR1,

R1 is as defined above; and R2 = H, C1-C6 alkyl, alkenyl, alkynyl, C3-C6 cycloalkyl, or cycloalkenyl, wherein each of C1-C6 alkyl, alkenyl, alkynyl, C3-C6 cycloalkyl, or cycloalkenyl is optionally substituted with 0 - 5 substituents of the list 0-R4, N(R4R5), S-R4, R4, (=0), (=N-R4), -COOH, C00CH3, COOC2H5, N3, F, Cl, Br, I, bicyclononinyl and

0 - 2 of the carbons in the C1-C6 alkyl, alkenyl, alkynyl, C3-C6 cycloalkyl, or cycloalkenyl is substituted by -O- or -S- or -N(R4)-; or 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;

R3 = aryl, heteroaryl, C1-C8 aliphatic, (C3-C8 carbocyclyl)-(Cl-C8 aliphatic), C3-C8 carbocyclyl, C4-C8 carbobicyclyl, C5-C8 carbotricyclyl, or C5-C8 carbospirocyclyl, wherein each of aryl, heteroaryl, C1-C8 aliphatic, (C3-C8 carbocyclyl)-(Cl-C8 aliphatic), C3-C8 carbocyclyl, C4-C8 carbobicyclyl, C5-C8 carbotricyclyl, or C5-C8 carbospirocyclyl is saturated or unsaturated and is optionally substituted with 0 - 5 substituents of the list O-R4, N(R4Rs), S-R4, R4, (=0), (=N-R4), -COOH, C00CH3, COOC2H5, N3, F, Cl, Br, or I and

0 - 2 of carbon atoms in the C1-C8 aliphatic, (C3-C8 carbocyclyl)-(Cl-C8 aliphatic), C3-C8 carbocyclyl, C4-C8 carbobicyclyl, C5-C8 carbotricyclyl, or C5-C8 carbospirocyclyl is substituted by -O- or -S- or -N(R4)-;

R4, R5 = independent of each other, H, Cl-C6-alkyl, alkenyl, alkynyl, C3-C6 cycloalkyl, or cycloalkenyl, wherein each of , Cl-C6-a I kyl, alkenyl, alkynyl, C3-C6 cycloalkyl, or cycloalkenyl is optionally substituted with 0 - 5 substituents of the list OH, OCH3, NH2, NHCH3, N(CH3)2, SH, (=0), - COOH, COOCH3, COOC2H5, N3, F, Cl, Br, or I; linker = a moiety connecting R1 and the macrolide comprising 0-30 atoms of the list C, O, N, or S, substituted or unsubstituted, containing cyclic elements or being a straight chain, counted along the shortest path from one end of the linker to the other;

Macrolide = one of R7 and R8 = trans-0-R9, trans referring to the glycosidic bond at the anomeric center, and the other of R7 and R8 = cis-N(RlORll), cis referring to the glycosidic bond at the anomeric center;

R9 = H, CH3, or a linker; and

RIO = CH3 or a linker; and

Rll = H, CH3, or a linker; and one of R9, RIO, or Rll is a linker.

Embodiment 2

The compound of embodiment 1, wherein

X = OR1 or NR1 and;

R1 = linker-macrolide or

C1-C12 alkyl, alkenyl, alkynyl, C3-12 cycloalkyl, cycloalkenyl, or cycloalkynyl, each optionally substituted with 0 - 6 substituents of the list O-R4, N(R4R5), S-R4, R4, (=0), (=N- R4), -COOH, C00CH3, COOC2H5, F, Cl, Br, I, and 0 - 4 of the carbons in the C1-C12 alkyl, alkenyl, alkynyl, C3-12 cycloalkyl, cycloalkenyl, or cycloalkynyl is substituted by -O- or -S- or - N(R4)-; and R1 contains at least one group suitable for "click" reactions.

Embodiment 3

The compound of any preceding embodiment, wherein

X = NR1; and

R1 = linker-macrolide or -CH2-C(=O)O-CH3.

Embodiment 4

The compound of any preceding embodiment, wherein

R1 = C1-C8 alkyl, optionally substituted with 0-3 substituents of the list (=0), -NH2, NH(Boc), NH(Z), NH(Fmoc), and with at least one substituent containing -N3, or bicyclononin.

Embodiment 5

The compound of any preceding embodiment, wherein

R3 = aryl, heteroaryl,

5- to 7-membered spirobicycloalkanyl, cyclopropyl, cyclobutyl, or bicyclo[W.1.0]alkanyl with W = 1-4 and R3 being connected through one of the atoms of the 3-membered ring; wherein the aryl, heteroaryl, spirobicycloalkanyl, cyclopropyl, cyclobutyl, or bicyclo[W.1.0]alkanyl is optionally substituted with one or two substituents of the list -OH, - 0CH3, -NH2, -NHCH3, -N(CH3)2, -SH, -SCH3, (=0), C1-C3 alkyl, or alkenyl, and

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

R3 = cyclopropyl, cyclobutyl, bicyclofl. O.W]alkanyl with W = 1-4 and R3 being connected through one of the atoms of the 3-membered ring; optionally substituted with one or two substituents of the list -OH, -0CH3, -NH2, -NHCH3, - N(CH3)2, -SH, -SCH3, (=0), C1-C3 alkyl, or alkenyl, and

0-2 carbon atoms of the cyclopropyl, cyclobutyl, or bicyclo[W.1.0]alkanyl is substituted by - 0-, -S-, -NH-, or -N(CH3)-.

Embodiment 7

The compound of any preceding embodiment, wherein

R3 = C1-C8 aliphatic, (C3-C8 carbocyclyl)-(Cl-C8 aliphatic), C3-C8 carbocyclyl, C4-C8 carbobicyclyl, C5-C8 carbotricyclyl, or C5-C8 carbospirocyclyl, wherein each of C1-C8 aliphatic, (C3-C8 carbocyclyl)-(Cl-C8 aliphatic), C3-C8 carbocyclyl, C4-C8 carbobicyclyl, C5-C8 carbotricyclyl, or C5-C8 carbospirocyclyl is saturated or unsaturated and is optionally substituted with 0 - 5 substituents of the list O-R4, S-R4, R4, (=0), C00CH3, COOC2H5, N3, F, Cl, Br, or I, and wherein 0 - 2 of the carbon atoms in C1-C8 aliphatic, (C3-C8 carbocyclyl)-(Cl- C8 aliphatic), C3-C8 carbocyclyl, C4-C8 carbobicyclyl, C5-C8 carbotricyclyl, or C5-C8 carbospirocyclyl is substituted by -O- or -S-; and at least one of the carbon atoms in the C1-C8 aliphatic, (C3-C8 carbocyclyl)-(Cl-C8 aliphatic), C3-C8 carbocyclyl, C4-C8 carbobicyclyl, C5-C8 carbotricyclyl, or C5-C8 carbospirocyclyl is substituted by -N(CH3)- or at least one substituent is -N(CH3)2.

Embodiment 8

A compound of formula 2 Embodiment 9

A compound of formula 3 wherein the compound of Formula 3 is either used directly as treatment or is an active metabolite of compounds of embodiments 1-8, wherein

R3 = aryl, heteroaryl C1-C8 aliphatic, (C3-C8 carbocyclyl)-(Cl-C8 aliphatic), C3-C8 carbocyclyl, C4-C8 carbobicyclyl, C5-C8 carbotricyclyl, or C5-C8 carbospirocyclyl, wherein each of aryl, heteroaryl, C1-C8 aliphatic, (C3-C8 carbocyclyl)-(Cl-C8 aliphatic), C3-C8 carbocyclyl, C4-C8 carbobicyclyl, C5-C8 carbotricyclyl, or C5-C8 carbospirocyclyl is saturated or unsaturated and is optionally substituted with 0 - 5 substituents of the list O-R4, N(R4R5), S-R4, R4, (=0), (=N-R4), -COOH, C00CH3, COOC2H5, N3, F, Cl, Br, or I and

0 - 2 of the carbons in the C1-C8 aliphatic, (C3-C8 carbocyclyl)-(Cl-C8 aliphatic), C3-C8 carbocyclyl, C4-C8 carbobicyclyl, C5-C8 carbotricyclyl, or C5-C8 carbospirocyclyl is substituted by -O- or -S- or -N(R4)-;

R4, R5 = independent of each other, H, Cl-C6-alkyl, alkenyl, alkynyl, C3-C6 cycloalkyl, or cycloalkenyl, wherein each of Cl-C6-a I ky I, alkenyl, alkynyl, C3-C6 cycloalkyl, or cycloalkenyl is optionally substituted with 0 - 5 substituents of the list OH, 0CH3, NH2, NHCH3, N(CH3)2, SH, (=0), -COOH, C00CH3, COOC2H5, N3, F, Cl, Br, or I.

Embodiment 10

The compound of any preceding embodiment, wherein the compound has increased metabolic stability of R3 relative to a compound comprising an optionally substituted cyclohexyl group at R3.

Embodiment 11

The compound of any preceding embodiment, wherein the compound has cerebral activity.

Embodiment 12

The compound of any preceding embodiment, wherein the compound is suitable to target specific sites or structures in a body.