Tricyclic Janus Kinase (JAK) Inhibitors and Their Use in the Treatment of Autoimmune Diseases

Abstract

The present invention relates to compounds of formula (1) or (2): [Formula 1] JPEG2022546760000052.jpg3374 In the formula, R 1 and R 3 is a purine or purine analogue, and R 2 and R 4 is a small functional group. The present invention also relates to intermediates in the synthesis of compounds of Formula 1 or Formula 2. Compounds of Formula 1 or Formula 2 are Janus kinase inhibitors and are therefore useful in the treatment of diseases, particularly autoimmune diseases, cancer, Alzheimer's disease, or for preventing allograft or xenograft rejection.

Description

[Background technology]

[0001] The Janus kinase (JAK) family consists of four members: JAK1, JAK2, JAK3, and TYK2. These members mediate cell proliferation, survival, development, and differentiation through cytokine-activated cell signaling. Therefore, Janus kinase inhibitors have a wide range of applications, from cancer to autoimmune diseases and Alzheimer's disease. Known JAK inhibitors include tofacitinib, delgocitinib, PF-06651600, baricitinib, upadacitinib, and filgotinib.

[0002] Tofacitinib is an FDA-approved pan-JAK kinase inhibitor (primarily JAK1 and JAK3) for the treatment of rheumatoid arthritis and ulcerative colitis. It is in clinical trials for psoriatic arthritis (Phase 3), psoriasis (Phase 3), Crohn's disease (Phase 2), kidney transplantation (Phase 2), and many others.

[0003] Delgocitinib (JTE-052) is another pan-JAK kinase inhibitor and a phase 2 compound for treating atopic dermatitis and chronic hand eczema.

[0004] PF-06651600 is a selective JAK3 inhibitor currently in Phase 3 for alopecia areata and Phase 2 for ulcerative colitis, Crohn's disease, rheumatoid arthritis and non-segmental vitiligo.

[0005] Baricitinib is a JAK1 and JAK2 inhibitor approved for treating rheumatoid arthritis.

[0006] Upadacitinib is a selective JAK1 inhibitor that is being investigated in clinical trials for rheumatoid arthritis (Phase 3), Crohn's disease (Phase 2), ulcerative colitis (Phase 2), atopic dermatitis (Phase 2), psoriatic arthritis (Phase 3), and axial spondyloarthritis (Phase 2).

[0007] Filgotinib is also a selective JAK1 inhibitor. It is in Phase 3 trials for rheumatoid arthritis, Crohn's disease, and ulcerative colitis. It is also being investigated in Phase 2 trials for small intestinal CD, CD with fistulas, Sjögren's syndrome, ankylosing spondylitis, cutaneous lupus, lupus nephropathy, and uveitis.

[0008] Based on the above-mentioned state of the art, the object of the present invention is to provide means and methods for providing further JAK inhibitors with a novel tricyclic scaffold (Figure 1). This object is achieved by the subject matter of the independent claims herein.

[0009] explanation Terms and Definitions The term Janus kinase refers to a non-receptor tyrosine kinase that transduces cytokine-mediated signals via the JAK-STAT pathway. Janus kinase can be abbreviated as "JAK." Four JAK family members are known: Janus kinase 1 (JAK1), Janus kinase 2 (JAK2), Janus kinase 3 (JAK3), and tyrosine kinase 2 (TYK2). Human Janus kinase 1 is encoded by the gene JAK1, human Janus kinase 2 is encoded by the gene JAK2, human Janus kinase 3 is encoded by the gene JAK3, and human tyrosine kinase 2 is encoded by the gene TYK2.

[0010] The term allograft refers to an organ, tissue, or cells transplanted from a donor to a recipient of the same species. Such organs are also called homologous organs or allografts, for example, allogeneic kidneys.

[0011] The term xenograft refers to organs, tissues or cells transplanted from a donor into a recipient of a different species.

[0012] As used herein, the term treating or treatment of any disease or disorder (e.g., cancer) refers, in one embodiment, to ameliorating the disease or disorder (e.g., slowing, halting, or alleviating the onset of the disease or at least one of its clinical symptoms). In another embodiment, "treating" or "treatment" refers to alleviating or improving at least one physical parameter, including those not discernible by the patient. In yet another embodiment, "treating" or "treatment" refers to physical modulation of the disease or disorder (e.g., stabilization of discernible symptoms), physiological modulation (e.g., stabilization of physical parameters), or both. Methods for assessing the treatment and / or prevention of disease are generally known in the art unless specifically described herein. Summary of the Invention [Means for solving the problem]

[0013] A first aspect of the present invention relates to a compound of formula 1 or formula 2, or a salt thereof: [ka] During the ceremony R 1 and R 3 teeth [ka] is selected from R 2 and R 4 teeth [ka] is selected from z is 1, 2, 3 or 4; x and p are 1 or 2; y and q are 1 or 2.

[0014] The compounds of Formula 1 or Formula 2 are potent Janus kinase inhibitors characterized by a tricyclic or polycyclic scaffold. 1 or R 3 contains a purine or purine analogue, and R 2 or R 4 The compound of formula 1 contains a small functional group. The purine or purine analog and the small functional group can interact with and inhibit Janus kinase, where the purine or purine analog is assumed to bind to the hinge region of Janus kinase. In particular, compared with known bicyclic JAK inhibitors such as delgocitinib, the JAK inhibitors of the present invention, such as KMC420, exhibit enhanced activity and increased selectivity in various Janus kinases. Enhanced activity can be achieved particularly with the compound of formula 1, while increased selectivity can be achieved with the compound of formula 2.

[0015] In particular, tricyclic JAK inhibitors (Formula 1) are more soluble in water than polycyclic JAK inhibitors (Formula 2).

[0016] In certain embodiments, the compound is a compound of Formula 1.

[0017] In certain embodiments, z is 1 or 2.

[0018] In certain embodiments, z, x, y, p, and q are 1.

[0019] In certain embodiments, R 1 and R 3 teeth, [ka] is selected from.

[0020] In certain embodiments, R 2 and R 4 teeth, [ka] is selected from.

[0021] In certain embodiments, R 2 and R 4 teeth, [ka] is selected from.

[0022] Compounds according to the invention can be synthesized as shown in Schemes 2 to 4 (see the Examples section). The second, third and fourth aspects of the invention relate to intermediates in the synthesis of compounds according to the first aspect of the invention.

[0023] A second aspect of the present invention relates to an intermediate of formula 3 or formula 4, or a salt thereof: [ka] During the ceremony R 5 , R 6 , R 7 and R 8 teeth, -H, - a protecting group that is cleavable under acidic conditions, - a protecting group that is cleavable under basic conditions, - a protecting group that is cleavable under reducing conditions, hydrogenolytically cleavable protecting groups, - a protecting group that can be cleaved using a metal catalyst is selected from z, x, y, p and q are defined as above.

[0024] The compounds according to the present invention are 1 (Equation 1) or R 3 (Formula 2) contains a purine or purine analog at position R 2 (Equation 1) or R 4The N atom in the intermediate of formula 3 or formula 4 can be protected to synthesize the compound of the present invention. Suitable protecting groups include those cleavable under acidic conditions, such as Boc or Ts, those cleavable under basic conditions, such as Fmoc, Ac, or Ac-CF3, those cleavable under reducing conditions, such as Ts, those cleavable hydrogenically, such as Bn or Cbz, and those cleavable using a metal catalyst, such as Alloc or Troc.

[0025] In certain embodiments, R 5 , R 6 , R 7 and R 8 teeth -H, - [ka] - [ka] - [ka] - [ka] - [ka] is selected from z, x, y, p and q are defined as above.

[0026] In particular, orthogonal protection facilitates the synthesis of compounds according to Formula 1 and Formula 2. Orthogonally protected intermediates contain two protecting groups that are cleavable by different reaction conditions from each other.

[0027] In certain embodiments, -R 5and R 6 Both, as well as R 7 and R 8 are both -H, or -R 5 and R 7 or R 6 and R 8 is -H and the other R is a protecting group, or -R 5 and R 7 Both, as well as R 6 and R 8 are protecting groups, and R 5 and R 7 Cleavage of the protecting group at R 6 and R 8 This is different from the cleavage of the protecting group in

[0028] In certain embodiments, -R 5 and R 7 or R 6 and R 8 is -H and the other R is a protecting group, or -R 5 and R 7 Both, as well as R 6 and R 8 are protecting groups, and R 5 and R 7 Cleavage of the protecting group at R 6 and R 8 This is different from the cleavage of the protecting group in

[0029] In certain embodiments, R 5 and R 7 Both, as well as R 6 and R 8 are protecting groups, and R 5 and R 7 Cleavage of the protecting group at R 6 and R 8 This is different from the cleavage of the protecting group in

[0030] A third aspect of the present invention relates to an intermediate according to formula 3 or formula 4, or a salt thereof, wherein: R 5 and R 7 or R 6 and R 8 On the other hand, [ka] is selected from The other R is -H, - protecting groups that are cleavable under acidic conditions, in particular Boc, Ts, protecting groups cleavable under basic conditions, in particular Fmoc, Ac, Ac-CF3, protecting groups cleavable under reducing conditions, in particular Ts, hydrogenolytically cleavable protecting groups, in particular Bn, Cbz, - protecting groups that can be cleaved using metal catalysts, in particular Alloc, Troc, is selected from z, x, y, p and q are defined as above.

[0031] As mentioned above, the orthogonal protection strategy is 1 or R 3 Purine or purine analogues in, and R 2 or R 4 If a purine or purine analogue is attached first, an intermediate according to the third aspect of the invention is obtained.

[0032] In certain embodiments, R 5 and R 7 or R 6 and R 8 On the other hand, [ka] is selected from The other R is -H, - protecting groups that are cleavable under acidic conditions, in particular Boc, Ts, protecting groups cleavable under basic conditions, in particular Fmoc, Ac, Ac-CF3, protecting groups cleavable under reducing conditions, in particular Ts, hydrogenolytically cleavable protecting groups, in particular Bn, Cbz, - protecting groups that can be cleaved using metal catalysts, in particular Alloc, Troc, is selected from z, x, y, p and q are defined as above.

[0033] A fourth aspect of the present invention relates to an intermediate of formula 3 or formula 4, or a salt thereof, wherein R 5 and R 7 or R 6 and R 8 On the other hand, [ka] is selected from The other R is -H, - protecting groups that are cleavable under acidic conditions, in particular Boc, Ts, protecting groups cleavable under basic conditions, in particular Fmoc, Ac, Ac-CF3, protecting groups cleavable under reducing conditions, in particular Ts, hydrogenolytically cleavable protecting groups, in particular Bn, Cbz, - protecting groups that can be cleaved using metal catalysts, in particular Alloc, Troc, is selected from z, x, y, p and q are defined as above.

[0034] As mentioned above, the orthogonal protection strategy is 1 or R 3 Purine or purine analogues in, and R 2 or R 4 If the small functional group is attached first, an intermediate according to the fourth aspect of the invention is obtained.

[0035] In certain embodiments, R5 and R 7 or R 6 and R 8 On the other hand, [ka] is selected from The other R is -H, - protecting groups that are cleavable under acidic conditions, in particular Boc, Ts, protecting groups cleavable under basic conditions, in particular Fmoc, Ac, Ac-CF3, protecting groups cleavable under reducing conditions, in particular Ts, hydrogenolytically cleavable protecting groups, in particular Bn, Cbz, - protecting groups that can be cleaved using metal catalysts, in particular Alloc, Troc, is selected from z, x, y, p and q are defined as above.

[0036] A fifth aspect of the present invention relates to an intermediate of formula 5 or formula 6: [ka] During the ceremony, R 9 and R 10 teeth, -H, - protecting groups that are cleavable under acidic conditions, in particular Boc, Ts, protecting groups cleavable under basic conditions, in particular Fmoc, Ac, Ac-CF3, protecting groups cleavable under reducing conditions, in particular Ts, hydrogenolytically cleavable protecting groups, in particular Bn, Cbz, - protecting groups that can be cleaved using metal catalysts, in particular Alloc, Troc, is selected from z, y, and q are defined as above.

[0037] In certain embodiments of the first, second, third, fourth or fifth aspect of the invention, the compounds or intermediates are enantiomers.

[0038] The compounds and intermediates disclosed herein contain one or more chiral C atoms. Therefore, the compounds and intermediates can be obtained as racemates. The activity and selectivity against Janus kinase can be increased by using only one enantiomer.

[0039] According to a sixth aspect of the invention, there is provided a compound according to the first aspect of the invention for use in the treatment of disease.

[0040] As shown in Table 1 (see the Examples section), compounds according to the invention inhibit all four members of the JAK family, particularly JAK1. A variety of diseases are associated with the activity of kinases of the JAK family.

[0041] JAKs are associated with cytokine receptors. When a ligand binds to a cytokine receptor, the JAK family of kinases is activated by phosphorylation. Phosphorylated JAKs phosphorylate STAT proteins downstream of the JAK-STAT signaling pathway. These STAT proteins function as nuclear transcription factors. The JAK-STAT signaling pathway is involved in the expression of cytokines, interferons, or interleukins. Therefore, diseases, particularly those involving cytokines, interferons, or interleukins, such as autoimmune diseases, can be treated by inhibiting JAKs.

[0042] In a particular embodiment of the sixth aspect of the invention, an enantiomer or a racemate, in particular an enantiomer, is used.

[0043] According to a seventh aspect of the invention, there is provided a compound according to the first aspect of the invention for use in the treatment of autoimmune diseases, cancer, Alzheimer's disease, asthma, or for use in the prevention of allograft or xenograft rejection.

[0044] In particular in the treatment of cancer, the compounds of the present invention can also be used to aid anti-cancer therapy by modifying the tumor microenvironment to allow better access of anti-tumor drugs, such as antibodies or antibody-drug conjugates, to malignant cells.

[0045] In certain embodiments, the compounds according to the first aspect are used in the treatment of rheumatoid arthritis, ulcerative colitis, psoriatic arthritis, psoriasis, Crohn's disease, atopic dermatitis, chronic hand eczema, non-segmental vitiligo, axial spondyloarthritis, small intestinal CD, CD with fistulas, Sjogren's syndrome, ankylosing spondylitis, cutaneous lupus, lupus nephropathy, uveitis, myelofibrosis and Alzheimer's disease, asthma, or for the prevention of allograft, particularly renal allograft, rejection.

[0046] In certain embodiments, the compounds according to the first aspect are used in the treatment of rheumatoid arthritis, ulcerative colitis, psoriatic arthritis, psoriasis, Crohn's disease, atopic dermatitis, chronic hand eczema, non-segmental vitiligo, axial spondyloarthritis, small intestinal CD, fistulizing CD, Sjogren's syndrome, ankylosing spondylitis, cutaneous lupus, lupus nephropathy, uveitis, asthma and Alzheimer's disease.

[0047] In certain embodiments, the compounds according to the first aspect are used in the treatment of rheumatoid arthritis, ulcerative colitis, psoriatic arthritis, psoriasis, Crohn's disease, atopic dermatitis, chronic hand eczema, non-segmental vitiligo, axial spondyloarthritis, small intestinal CD, fistulizing CD, Sjogren's syndrome, ankylosing spondylitis, cutaneous lupus, lupus nephropathy, uveitis and Alzheimer's disease.

[0048] In certain embodiments, the compounds according to the first aspect are used in the treatment of rheumatoid arthritis, ulcerative colitis, psoriatic arthritis, psoriasis, Crohn's disease, atopic dermatitis, chronic hand eczema, non-segmental vitiligo, axial spondyloarthritis, small intestinal CD, fistulizing CD, Sjogren's syndrome, ankylosing spondylitis, cutaneous lupus, lupus nephropathy, and uveitis.

[0049] In particular embodiments of the seventh aspect of the invention, enantiomers or racemates, especially enantiomers, are used.

[0050] In another embodiment, the present invention relates to a pharmaceutical composition comprising at least one compound of the present invention or a pharmaceutically acceptable salt thereof and at least one pharmaceutically acceptable carrier, diluent or excipient.

[0051] As used herein, the term "pharmaceutical composition" refers to a compound of the present invention or a pharmaceutically acceptable salt thereof, comprising at least one pharmaceutically acceptable carrier. In certain embodiments, the pharmaceutical composition according to the present invention is provided in a form suitable for topical, parenteral, or injectable administration.

[0052] As used herein, the term pharmaceutically acceptable carrier includes any solvents, dispersion media, coatings, surfactants, antioxidants, preservatives (e.g., antibacterial, antifungal), isotonic agents, absorption delaying agents, salts, preservatives, drugs, drug stabilizers, binders, excipients, disintegrants, lubricants, sweeteners, flavoring agents, dyes, and the like, and combinations thereof, as known to those skilled in the art (see, e.g., Remington: the Science and Practice of Pharmacy, ISBN 0857110624).

[0053] Those skilled in the art will recognize that any drug specifically mentioned can exist as a pharmaceutically acceptable salt of said drug.Pharmaceutically acceptable salts include ionized drug and oppositely charged counterion.Non-limiting examples of pharmaceutically acceptable anionic salt forms include acetate, benzoate, besylate, bitartrate, bromide, carbonate, chloride, citrate, edetate, edisylate, embonate, estolate, fumarate, gluceptate, gluconate, hydrobromide, hydrochloride, iodide, lactate, lactobionate, malate, maleate, mandelate, mesylate, methyl bromide, methyl sulfate, mucate, napsylate, nitrate, pamoate, phosphate, diphosphate, salicylate, disalicylate, stearate, succinate, sulfate, tartrate, tosylate, triethiodide and valerate. Non-limiting examples of pharmaceutically acceptable cationic salt forms include aluminum, benzathine, calcium, ethylenediamine, lysine, magnesium, meglumine, potassium, procaine, sodium, tromethamine, and zinc.

[0054] A further aspect of the invention relates to a method for preparing a compound of Formula 1 or Formula 2.

[0055] The synthesis of compounds of formula 1 or formula 2 begins with a diketone, which is an educt for preparing the bicyclic or tricyclic intermediate of formula 5 or formula 6 according to the fifth aspect of the invention.

[0056] In certain embodiments, the method for preparing an intermediate of formula 5 or formula 6 comprises: a diketone of formula 6 or 7, [ka] providing a diketone wherein z is 1 or 2, particularly 1; - carrying out a condensation reaction using a compound of formula 8 and a diketone of formula 6 or formula 7, followed by reduction to give an intermediate of formula 9 or formula 10, [ka] During the ceremony, B is a protecting group, in particular Boc; y is 1 or 2, in particular 1; q is 1 or 2, in particular 1; obtaining an intermediate wherein z is 1 or 2, in particular 1, allylation, in particular using allyl bromine and potassium carbonate as base, to give intermediates of formula 11 or 12, [ka] During the ceremony, B is a protecting group, in particular Boc; y is 1 or 2, in particular 1; q is 1 or 2, in particular 1; obtaining an intermediate wherein z is 1 or 2, in particular 1, - removing the protecting group and carrying out an intramolecular reductive amination, in particular by using NaBH3CN, to give an intermediate of formula 5 or formula 6.

[0057] With respect to intermediates of formula 5 or formula 6, reference is made to the fifth aspect of the invention.

[0058] Starting from an intermediate of formula 5 or formula 6, an intermediate of formula 3 or formula 4 according to the second aspect of the invention can be obtained.

[0059] In certain embodiments, the method for preparing an intermediate of formula 3 or formula 4 comprises: - providing an intermediate of formula 5 or formula 6, - ozonolysis followed by two reductive aminations, in particular with benzylamine and NaBH3CN, to give intermediates of formula 3 or 4.

[0060] Purine or purine analogue (R 1 and R 3 ) coupling, and R 2 and R 4Intermediates of formula 3 or formula 4 may contain orthogonal protecting groups to allow for the coupling of small functional groups as described for

[0061] With respect to intermediates of formula 3 or formula 4, reference is made to the second aspect of the invention.

[0062] Ozonolysis followed by two reductive aminations is typically carried out to provide intermediates of formula 3 or 4 where x and p are 1.

[0063] Intermediates of formula 3 or 4 where x and p are 2 can be obtained by hydroazidation or ozonolysis of olefins, followed by selective aldehyde reduction, tosylation, and displacement with sodium cyanide as described in Li, et al. J. Am. Chem. Soc. 2019141239415-9421.

[0064] Intermediates of formula 3 or formula 4 described in the third and fourth aspects of the present invention may be obtained by standard methods.

[0065] In particular, intermediates of formula 3 or formula 4 described in the third aspect of the present invention can be obtained by selective deprotection followed by nucleophilic substitution with chloropurine or analogues thereof.

[0066] Finally, the compound of formula 1 or formula 2 described in the first aspect of the present invention can be converted to R by deprotection followed by amide bond formation. 2 and R 4 The hydroxybenzoates are obtained by coupling small functional groups as described for [Brief explanation of the drawings]

[0067] [Figure 1] Known JAK inhibitors, tofacitinib, JTE-052 (delgocitinib), or PF-066051600, are shown in comparison to JAK inhibitors according to the present invention (KMC420 and KMC423).

[0068] example Synthesis of diamine 1 Diamine 1 was synthesized as shown in Scheme 1. Diallyl-1,3-cyclopentanedione 3 was available by palladium-catalyzed allylation of 1,3-cyclopentanedione 2 (Schwartz, C.E.; Curran, D.P., A.J. Am. Chem. Soc. 1990, 112(25), 9272-9284). Simultaneous ring closure was achieved by one-pot tandem ozonolysis and reductive amination with benzylamine and NaBH(OAc)3 (Kyasa, S.; Fisher, T.; Dussault, P., Synthesis 2011, 2011(21), 3475-3481) to give benzyl-protected diamine 4. Subsequent deprotection with palladium on charcoal and hydrogen gas afforded diamine 1. Its structure was confirmed by crystallization of the HCl salt. [ka]

[0069] Scheme 1: Synthesis of diamine 1

[0070] Synthesis of orthogonally protected diamine 9 The synthesis of tricyclic diamine 9 bearing two different protecting groups is shown in Scheme 2. Proline-catalyzed Knoevenagel condensation of 1,3-cyclopentanedione 2 with Boc-protected aminoacetaldehyde, followed by in situ reduction with Hantzsch ester, afforded mono-alkylated dione 5 (Ramachary, DB; Kishor, M., Org. Biomol. Chem. 2008, 6(22), 4176), which was then subjected to palladium-catalyzed allylation to give an equilibrium mixture of C-allylated product 6 and O-allylated product 7. Removal of Boc, followed by intramolecular reductive amination with NaBH3CN and Boc reprotection, afforded bicyclic ketone 8. Finally, ozonolysis followed by two reductive aminations with benzylamine and NaBH3CN afforded 9, a useful derivative of 1 bearing two orthogonally protected secondary amines. [ka]

[0071] Scheme 2: Synthesis of orthogonally protected diamine 9

[0072] Synthesis of JAK inhibitors KMC420 and KMC423 (inhibitors of formula 1) KMC420 and KMC423 (see also Figure 1) were obtained from intermediate 9 as shown in Scheme 3. Selective deprotection of the benzyl protecting group followed by nucleophilic substitution with 6-chloro-7-deazapurine gave compound 10. Boc deprotection followed by amide bond formation with either cyanoacetic acid or acrylic acid gave the two JAK inhibitors KMC420 and KMC423, respectively. [ka]

[0073] Scheme 3: Synthesis of novel JAK inhibitors KMC420 and KMC423

[0074] Synthesis of JAK inhibitors according to formula 2 The JAK inhibitors of formula 2 are synthesized according to the reaction scheme shown in Scheme 4.

[0075] Similar to the synthesis of 9, tetracyclic orthogonally protected diamine 15 can be obtained according to Scheme 4. Proline-catalyzed Knoevenagel condensation of 1,3-indanedione 11 with Boc-protected aminoacetaldehyde, followed by in situ reduction with Hantzsch ester, afforded monoalkylated dione 12 (Ramachary, DB; Kishor, M., Org. Biomol. Chem. 2008, 6(22), 4176). Allylation with allyl bromine and potassium carbonate as base afforded product 13. Removal of the Boc group, followed by intramolecular reductive amination with NaBH3CN and Boc reprotection, afforded tricyclic ketone 14. Finally, ozonolysis followed by two reductive aminations with benzylamine and NaBH3CN afforded 15, a useful derivative of 16 bearing two orthogonally protected secondary amines. [ka]

[0076] Scheme 4: Synthesis of benzodiamine analogue 15 and its kinase inhibitors.

[0077] JAK inhibition Activity studies reveal that KMC420 and KMC423 are potent kinase inhibitors (Table 1). [Table 1]

[0078] The enzyme assay was performed using ATP (K m In the presence of 100 nM Ulight-CAGAGAIETDKEYYTVKD (100 nM), JAK1 was detected as described in Zhou, YJ. et al. (1997), Proc. Natl. Acad. Sci. USA, 94:13850-13855; JAK2 as described in Brizzi, M.F. et al. (1996), J. Biol. Chem., 271:3562-3567; JAK3 as described in Yamaoka, K. et al. (2004), Gen. Biol., 5:253; and TYK2 as described in Ide, H. et al. (2008), Biochem. Biophys. Res. Commun., 369:292-296.

[0079] Detailed Description of the Synthesis of Compounds According to the Invention tert-Butyl (2-(2-hydroxy-5-oxocyclopent-1-en-1-yl)ethyl)carbamate (5) [ka]

[0080] To a suspension of 1,3-cyclopentadione (3.32 g, 33.8 mmol, 1.0 equiv.), Hantzsch ester (11.1 g, 43.8 mmol, 1.3 equiv.), and crude N-Boc-2-aminoacetaldehyde (6.98 g, 43.8 mmol, 1.3 equiv.) in anhydrous DCM (110 mL) was added proline (1.01 g, 8.8 mmol, 0.3 equiv.), and the mixture was stirred for 25 h at 22 °C. After the reaction was completed, the solvent was evaporated under reduced pressure, and the residue was purified using flash column chromatography (SiO:hexane / EtOAc 2:8 to pure EtOAc) to give the desired title product 5 (7.15 g, 29.6 mmol, 88%) as a white powder. R f =0.35(9:1 DCM / MeOH); mp:170-171℃; 1 H-NMR (400MHz, CDCl3): δ=3.11(t,J=7.1Hz,2H),2.52(s,4H),2.42(t,J=7.1Hz,2H),1.45(s,9H); 13 C-NMR (100MHz, CDCl3): δ=157.9,115.3,80.9,40.0,30.4,28.4,21.5; HRMS(ESI):m / z calculated for C 12 H 20 O4N + [M+H] + 242.1387,found 242.1386.

[0081] tert-Butyl 3a-allyl-4-oxohexahydrocyclopenta[b]pyrrole-1(2H)-carboxylate (8) [ka]

[0082] To a suspension of compound 5 (4.82 g, 20.0 mmol, 1.0 equiv.) and allyl acetate (2.2 mL, 20.4 mmol, 1.0 equiv.) in anhydrous THF (40 mL) was added Pd(PPh3)4 (0.23 g, 0.2 mmol, 0.01 equiv.) under an argon atmosphere and stirred at 22 °C for 4.5 h. The solvent was evaporated and purified by column chromatography (SiO2:8:2 hexane / EtOAc) to give the C- and O-alkylated intermediates as an inseparable mixture. This mixture was then redissolved in DCM (40 mL), and TFA (10 mL) was added slowly at 0 °C. The solution was then stirred at 22 °C for 12 h. The volatiles were evaporated under reduced pressure, and excess TFA was removed by coevaporation with toluene (3 × 30 mL) to give the imine intermediate as a brownish oil. The residue was dissolved in MeOH (200 mL), and NaBHCN (1.26 g, 20.0 mmol, 1.0 equiv) was added at 0 °C. The solution was warmed to 22 °C and then stirred at that temperature for 24 h. The reaction was then quenched with aqueous NaOH (3 M, 20 mL), and the solvent was reduced to approximately one-quarter. The aqueous phase was extracted with diethyl ether (3 × 150 mL), dried over NaSO, filtered, and evaporated to dryness. This intermediate was dissolved in DCM (200 mL), and triethylamine (4.2 mL, 30.1 mmol, 1.5 equiv) and BocO (4.80 g, 22.0 mmol, 1.1 equiv) were added at 0 °C. The solution was stirred at 22 °C for 16 h. Evaporation of the solvent followed by purification by column chromatography (SiO2:9:1 to 8:2 hexane / EtOAc) afforded the title compound 8 (2.44 g, 9.2 mmol, 46%) as a colorless crystalline compound. R f = 0.30 (hexane / EtOAc: 9:1); mp:46-47℃; 1 H-NMR (400MHz, CDCl3): δ=5.75-5.65(m,1H),5.12-5.08(m,2H),4.18-4.09(m,1H),3.60(b r,1H),3.11(br,1H),2.40-2.21(m,5H),2.14-2.01(m,2H),1.82-1.74(m,1H),1.48(s,9H); 13 C-NMR (100MHz, CDCl3): δ=221.6,221.0,154.0,132.8,119.1,79.7,63.7,60.4,59.7,45.9,38.2,36.8,32.9,32.5,28.5,26.4,25.3; HR-MS(ESI):m / z calculated for C 15 H 23 O3NNa + [M+Na] + 288.1570,found 288.1572.

[0083] For the generation of rotamers in NMR measurements, analytical aliquots were deprotected using a mixture of DCM and TFA (1:1, 1.0 mL). 1 H-NMR(400MHz,CDCl3):δ=10.11(br,1H;NH2 + ), 9.71(br, 1H;NH2 + ),5.67-5.57(m,1H),5.18-5.14(m,2H),4.12(br,1H),3.32(br,1H),3.16(br,1 H),2.67-2.57(m,1H),2.52-2.36(m,2H),2.32-2.20(m,4H),2.06-1.99(m,1H); 13 C-NMR (100MHz, CDCl3): δ=217.4,131.4,120.6,64.1,59.5,45.3,38.5,36.5,33.9,23.1;

[0084] tert-Butyl 6-benzyloctahydrocyclopenta[2,1-b:5,1-b']dipyrrole-3(3aH)-carboxylate (9) [ka]

[0085] A stream of O3 / O2 (≈3 g O3 / h) was introduced into a solution of compound 8 (1.06 g, 4.00 mmol, 1.0 equiv.) in DCM and MeOH (1:1, 40 mL) at −78 °C for 30 min. The characteristic blue color indicated the end of ozonolysis, and excess ozone was removed with a stream of O2. Dimethyl sulfide (3.00 mL, 41.0 mmol, 10 equiv.) was added, and the cooling bath was removed. The reaction mixture was allowed to warm to 22 °C and stirred at that temperature for 8 h. The solvent was then evaporated, and the residue was redissolved in MeOH (40 mL). Benzylamine (440 μL, 4.03 mmol, 1.0 equiv) was added and stirred at 22 °C for 1 h. After that, acetic acid (230 μL, 4.02 mmol, 1.0 equiv) and sodium cyanoborohydride (251 mg, 3.99 mmol, 1.0 equiv) were added sequentially. The mixture was stirred at 22 °C for 16.5 h and then quenched using aqueous NaOH (2 M, 20 mL). The reaction volume was reduced to approximately one-third of the original volume, and the crude product was extracted with diethyl ether (3 × 100 mL). The combined organic phases were dried over NaSO, filtered, and concentrated under reduced pressure. The crude product was purified by column chromatography (SiO: hexane / EtOAc + 0.1% triethylamine 8:2 to 1:1) to give the title compound 9 (956 mg, 2.79 mmol, 70%) as a colorless oil. R f = 0.13-0.38 (SiO2; DCM / MeOH: 50:1 + NEt3 droplets); 1 H-NMR(400MHz,CD2Cl2):δ=7.32-7.21(m,5H),3.89(d,J=13.1Hz,1H),3.70-3.63(m,2H),3.29(d,J=13.1Hz,1H),3.08(dt,J=11.1,6.0Hz,1H ),2.79(t,J=7.8Hz,1H),2.60-2.56(m,1H),2.24-2.18(m,1H),2.05-1 .94(m,3H),1.90-1.72(m,3H),1.63-1.57(m,1H),1.55-1.44(m,10H); 13C-NMR(100MHz,CD2Cl2):δ=154.3(br),154.1(br),140.4,129.1,128.5,127.1,78.9,77.5,69.3,61.1(br),6 0.3(br),59.5,54.1,47.7(br),47.2(br),37.5(br),37.0(br),36.8,32.0(br),30.9(br),30.6,28.7,28.5; HR-MS(ESI):m / z calculated for C 21 H 31 O2N2 + [M+H] + 343.2380,found 343.2371

[0086] For the generation of rotamers in NMR measurements, analytical aliquots were deprotected using a mixture of DCM and TFA (1:1, 1.0 mL). 1 H-NMR(400MHz,CD3OD):δ=7.57-7.47(m,5H),4.48-4.41(m,2H),3.97(br,2H),3.64-3.58(m,1H),3.50- 3.41(m,2H),3.35-3.27(m,1H),2.50-2.43(m,1H),2.41-2.18(m,4H),2.07(br,2H),1.85(br,1H),ppm; 13 C-NMR(100MHz,CD3OD):δ=163.1(q,J=34Hz,COOCF3 - ),131.9,131.5,131.2,130.4,118.3(q,J=294Hz,COOCF3 - ),78.7(br),70.1,62.6(br),59.5(br),56.0(br),47.3(br),37.7,35.2(br),30.0,29.5(br),ppm;

[0087] tert-Butyl 6-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)octahydrocyclopenta[2,1-b:5,1-b']dipyrrole-3(3aH)-carboxylate (10) [ka]

[0088] To a solution of compound 9 (829 mg, 2.42 mmol, 1.0 equiv.) in methanol (24.0 mL, 0.10 M) was added acetic acid (280 μL, 4.90 mmol, 2.0 equiv.) and Pd / C (10% Pd; 83 mg, 10 m / m%). The flask was placed under vacuum and flushed with hydrogen gas three times. The reaction mixture was then stirred at 22 °C under a hydrogen atmosphere (1 atm, balloon) for 3 days until the starting material was completely consumed. The reaction mixture was filtered through Celite, and the solvent was evaporated to dryness. The intermediate was redissolved in anhydrous NMP (5.0 mL, 0.48 M), and then triethylamine (1.0 mL, 7.17 mmol, 3.0 equiv.) and 6-chloro-7-deazapurine (409 mg, 2.66 mmol, 1.1 equiv.) were added under argon, heated to 110 °C, and stirred at that temperature for 14 h. The solution was diluted with deionized water (50 mL) and extracted with DCM (3 × 30 mL). The combined organic phases were dried over NaSO, filtered, and the solvent was reduced. Flash column chromatography (SiO:DCM / MeOH 50:1 to 20:1) afforded the title compound 10 (603 mg, 1.63 mmol, 67%) as a slightly brownish powder. R f =0.23(SiO2;50:1 DCM / MeOH); mp:219-222℃; 1 H-NMR(400MHz,CD2Cl2):δ=11.24(br,1H),8.27(s,1H),7.09(d,J=3.7Hz,1H),6.55(d,,J=3.7Hz,1H),4.48-4.46(m,1H),4. 25-4.20(m,1H),3.96-3.91(m,1H),3.71-3.70(m,2H),3.34-3.27(m,1H),2.25-2.23(m,1H),2.14-1.74(m,8H),1.45(s,9H); 13C-NMR(100MHz,CD2Cl2):δ=155.1,154.1,151.8,151.6,120.5,103.4,101.9, 79.3,70.2,69.1,61.4,49.2,47.5,47.1,36.3,35.9,33.9,33.4,32.9,28.7; HR-MS(ESI):m / z calculated for C 20 H 28 O2N5 + [M+H] + 370.2238,found 370.2245

[0089] 3-(6-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)octahydrocyclopenta[2,1-b:5,1-b']dipyrrol-3(3aH)-yl)-3-oxopropanenitrile (KMC 420) [ka]

[0090] Compound 10 (66.5 mg, 0.18 mmol, 1.0 equiv.) was dissolved in a mixture of DCM and TFA (1:1, 2 mL), and the solution was stirred for 2 h at 22° C. After deprotection was complete, volatile compounds were evaporated under reduced pressure.

[0091] The dry residue was suspended in DCM (2 mL) and N,N-diisopropylethylamine (156 μL, 0.89 mmol, 4.9 equiv.) was added to form a clear solution. Cyanoacetic acid (30.8 mg, 0.36 mmol, 2.0 equiv.), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (69.0 mg, 0.36 mmol, 2.0 equiv.) as the HCl salt, and Oxima (51.0 mg, 0.36 mmol, 2.0 equiv.) were then added sequentially, and the reaction was stirred at 22 °C for 21 h. The organic phase was diluted with EtOAc (30 mL) and washed with saturated NaHCO (2 × 30 mL) solution. The combined organic phases were dried over NaSO, filtered, and reduced. RP-HPLC (gradient: 0-20% D in 40 min) afforded the final compound KMC420 as a TFA salt (18.0 mg, 0.04 mmol, 23%; purity >98%). UPLC:t R =2.17 minutes; RP-HPLC: R =19-28 minutes; 1 H-NMR (400MHz, D2O): δ=8.22(s,1H),7.41(s,1H),6.92(s,1H),4.45(br,1H),4. 28-4.27(m,1H),4.05-3.75(m,4.5H),3.62-3.42(br,1.5H),2.46-1.95(m,8H); 13 C-NMR(100MHz,D2O):δ=163.1,162.7,147.6,142.0,124.2,115.7,104.6 ,71.3,70.4,69.0,48.4,47.2,34.5,33.8,33.3,32.9,31.6,26.0,25.2;

[0092] Rotation was hindered, so some 13 The C signal was split and the quaternary carbon signal could not be resolved. HR-MS(ESI):m / z calculated for C 18 H 21 NO + [M+H] + 337.1771,found 337.1768.

[0093] 1-(6-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)octahydrocyclopenta[2,1-b:5,1-b']dipyrrol-3(3aH)-yl)prop-2-en-1-one (KMC423) [ka]

[0094] Compound 10 (49.9 mg, 0.14 mmol, 1.0 equiv) was dissolved in a mixture of DCM and TFA (1:1, 1 mL), and the solution was stirred at 22 °C for 2 h. The volatiles were evaporated under reduced pressure, and the dry residue was suspended in DCM (1 mL). DIPEA (23 μL, 0.13 mmol, 1.0 equiv) was added to form a clear solution, followed by the sequential addition of acrylic acid (175 μL, 2.55 mmol, 19 equiv), EDCl (58.8 mg, 0.31 mmol, 2.3 equiv), and DMAP (2.8 mg, 0.02 mmol, 0.2 equiv), and the reaction was stirred at 22 °C for 19.5 h. The organic phase was diluted with DCM (5 mL) and washed with saturated Na2CO3 solution (3 × 5 mL), and the aqueous phase was then extracted with DCM (3 × 5 mL). The combined organic phases were dried over Na2SO4, filtered, and reduced. RP-HPLC (gradient: 0 to 50% D in 40 min) afforded the final compound KMC423 as the TFA salt (19.0 mg, 0.04 mmol, 31%; purity >99%). UPLC:t R =2.40 minutes; RP-HPLC: R =20-23 minutes; 1 H-NMR(400MHz,CD3OD):δ=8.25(d,J=2.5Hz,1H),7.39(d,J=3.4Hz,1H),6.97(d,J=3.6Hz,1H),6.70-6.61(m,1H),6.29(dt,J=16.8,1.8Hz ,1H),5.78(ddd,J=10.4,6.1,1.8Hz,1H),4.43(br,1H),4.32(br,1H),4.14-3.96(m,2H),3.69(br,1H),3.48(br,1H),2.46-1.95(m,8H); 13 C-NMR(100MHz,CD3OD):δ=166.3,166.3,162.3(q,J=34.7Hz,COOCF3 - ),143.2,130.1,129.6,128.8,128.5,1225.3,105.7,72.3,69.9,69.3,48.9,47.7,36.4,36.0,35.0,33.4;

[0095] Rotation was hindered, so some 13 The C signal was split and the quaternary carbon signal could not be resolved. HR-MS(ESI):m / z calculated for C 18 H 22 N5O + [M+H] + 324.1819,found 324.1820.

[0096] tert-Butyl (2-(1,3-dioxo-2,3-dihydro-1H-inden-2-yl)ethyl)carbamate (12) [ka]

[0097] To a suspension of 1,3-indadione (2.93 g, 20.0 mmol, 1.0 equiv.), Hantzsch ester (5.07 g, 20.0 mmol, 1.0 equiv.), and crude N-Boc-2-aminoacetaldehyde (3.18 g, 20.0 mmol, 1.0 equiv.) in DCM (65 mL) was added proline (460 mg, 4 mmol, 0.2 equiv.), and the mixture was stirred at 22 °C for 19.5 h. After the reaction was complete, the solvent was evaporated under reduced pressure, and the product was purified by flash column chromatography (SiO:hexane / EtOAc 9:1 to pure EtOAc), followed by recrystallization from a hot hexane / EtOAc mixture (8 / 2, 100 mL) to give the desired title compound 12 (2.99 g, 10.3 mmol, 52%) as an off-white powder. R f=0.18(Hex / EtOAc:8 / 2); mp:97-99℃; 1 H-NMR (400MHz, CDCl3): δ=7.94-7.98(m,2H),7.80-7.85(m,2H),4.9(br,1H;NH), 3.36(q,J=6.2Hz,2H),3.06(t,J=6.4Hz,1H),2.11(q,J=6.5Hz,2H),1.35(s,9H); 13 C-NMR (100MHz, CDCl3): δ=200.3,157.9,142.1,135.7,123.3,79.2,50.1,38.3,28.3,26.9; HR-MS(ESI):m / z calculated for C 16 H 19 O4NNa + [M+Na] + 312.1206,found 312.1190.

[0098] tert-Butyl (2-(2-allyl-1,3-dioxo-2,3-dihydro-1H-inden-2-yl)ethyl)carbamate (13) [ka]

[0099] To a yellow suspension of compound 12 (1.46 g, 5.0 mmol, 1 equiv.), K2CO3 (1.39 g, 10.1 mmol, 2 equiv.), and tetrabutylammonium hydrogen sulfate (TBAHS) (0.26 g, 0.75 mmol, 0.15 equiv.) in anhydrous acetonitrile (35 mL), allyl bromide (0.9 mL, 10.4 mmol, 2.1 equiv.) was added dropwise under an argon atmosphere. The mixture was stirred at 22 °C for 19 h. After the reaction was complete, excess K2CO3 was filtered off and the solvent was reduced. The residue was partitioned between deionized water and DCM, and the aqueous layer was extracted with DCM (3 × 25 mL). The combined organic phase was dried over MgSO4, filtered, and reduced. Purification by MPLC (24 g SiO2: hexane / EtOAc 1:0 to 1:1) afforded the title compound 13 (1.48 g, 4.49 mmol, 90%) as a yellowish powder. R f =0.31 (hexane / EtOAc: 8 / 2); mp:63-65℃; 1 H-NMR (400MHz, CDCl3): δ=7.98-7.94(m,2H),7.85-7.80(m,2H),5.50-5.40(m,1H),5.04-4.87(m,2 H),4.27(br,1H;NH),3.04-2.99(m,2H),2.52(d,J=7.5Hz,1H),2.06(t,J=7.2Hz,2H),1.29(s,9H); 13 C-NMR (100MHz, CDCl3): δ=203.3,155.2,142.0,135.8,131.1,123.2,119.7,79.2,56.8,28.3,39.6,36.7,34.2; HR-MS(ESI):m / z=calculated for C 19 H 23 O4NNa + [M+Na] + 352.1519,found 352.1509.

[0100] tert-Butyl 3a-allyl-4-oxo-3,3a,4,8b-tetrahydroindeno[1,2-b]pyrrole-1(2H)-carboxylate (14) [ka]

[0101] Compound 13 (1.47 g, 4.46 mmol, 1.0 equiv) was stirred in a solution of HCl in MeOH (7.2 mL, approximately 1.25 M, 2.0 equiv) at 22 °C for 18 h. After the reaction was complete, the volatiles were evaporated and the residue was dissolved in MeOH (45 mL). NaOAc (0.38 g, 4.48 mmol, 1.0 equiv) and NaBHCN (0.28 g, 4.48 mmol, 1.0 equiv) were added and stirred at 22 °C for 16 h. The reaction was quenched with aqueous NaOH (2 M, 10 mL) and the volume was reduced to approximately ¼. The aqueous phase was extracted with EtOAc (3 × 50 mL), and the combined organic phase was washed with brine, dried over NaSO, filtered, and the solvent was evaporated. The residue was then dissolved in DCM (10 mL), and NEt (0.65 mL, 4.50 mmol, 1.0 equiv) and BocO (1.18 g, 5.41 mmol, 1.2 equiv) were added at 0° C. The solution was stirred at 22° C. for 20 h. After the reaction was completed, the solvent was evaporated and the product was purified by column chromatography (SiO:hexane / EtOAc 1:0 to 1:1) to give the title compound 14 (0.74 g, 2.36 mmol, 53%) as a colorless oil. R f =0.35 (hexane / EtOAc: 9 / 1); 1 H-NMR (400MHz, CDCl3): δ=8.02-7.81(m,1H),7.71-7.63(m,2H),7.47-7. 45(m,1H),5.71-5.59(m,1H),5.30-5.18(m,1H),5.15-5.10(m,1H),5.05- 5.00(m,1H),3.81-3.62(m,1H),3.07-2.96(m,1H),2.67-2.62(m,1H),2. 49-2.43(m,1H),2.15-2.11(m,1H),1.96-1.88(m,1H),1.61-1.48(m,9H); 13C-NMR(100MHz,CDCl3):δ=207.7,207.2,154.8,154.1,152.9,152.3,136.1,135.9,133.3,133.1,129.5,129.4,12 8.5,127.2,123.7,123.4,119.2,80.6,80.1,63.9,63.8,61.1,60.1,45.8,45.2,39.4,39.2,34.2,33.7,28.9,28.6

[0102] Rotational obstruction causes some 1 H and 13 The C signal is split. HR-MS(ESI):m / z calculated for C 19 H 23 O3NNa + [M+Na] + 336.1570,found 336.1564.

[0103] For the generation of rotamers in NMR measurements, analytical aliquots were deprotected using a mixture of DCM and TFA (1:1, 1.0 mL). 1 H-NMR(400MHz,D2O):δ=7.95-7.91(m,1H),7.86-7.84(m,2H),7.75-7.71(m,1H),5.67-5.56(m,1H),5.32(s,1H),5.20 -5.04(m,2H),3.53-3.48(m,1H),3.0(dt,J=11.7,6.4Hz,1H),2.75-2.54(m,2H),2.43-2.37(m,1H),2.24-2.16(m,1H); 13 C-NMR(100MHz,D2O):δ=208.8,162.8(q,J=36Hz,COOCF3 - ),145.5,137.8,136.8,131.8,131.8,127.5,124.4,120.1,116.3(q,J=292Hz,COOCF3 - ), 64.0, 59.9, 45.0, 38.4, 32.8

[0104] tert-Butyl 6-benzyl-2,3,5,6,6a,10b-hexahydroindeno[1,2-b:3,2-b']dipyrrole-1(4H)-carboxylate (15) [ka]

[0105] A stream of O3 / O2 (≈3 g O3 / h) was introduced into a solution of compound 14 (683 mg, 2.18 mmol, 1.0 equiv.) in DCM and MeOH (1:1, 22 mL) at -78 °C for 30 min. The characteristic blue color indicated the end of ozonolysis, and excess ozone was removed with a stream of O2. Dimethyl sulfide (1.6 mL, 21.6 mmol, 9.9 equiv.) was added, and the cooling bath was removed. The reaction mixture was allowed to warm to 22 °C and stirred at that temperature for 5 h. The solvent was then evaporated and subsequently coevaporated with toluene. The residue was dissolved in abs. MeOH (22 mL), followed by the addition of benzylamine (238 μL, 2.18 mmol, 1.0 equiv.) and acetic acid (125 μL, 2.19 mmol, 1.0 equiv.) and stirring at 22 °C for 1 h. Sodium cyanoborohydride (274 mg, 4.36 mmol, 2.0 equiv.) was then added, and the solution was stirred at 22 °C for 19.5 h. After the reaction was complete, it was quenched using aqueous NaOH (2 M, 20 mL). The reaction volume was reduced to approximately one-third of the original volume, and the crude product was extracted with diethyl ether (3 × 100 mL). The combined organic phases were dried over NaSO, filtered, and concentrated under reduced pressure. The product was purified by column chromatography (SiO: hexane / EtOAc 8:2 + 0.1% triethylamine) to give the title compound 15 (687 mg, 1.76 mmol, 81%) as a colorless oil. R f = 0.34 (hexane / EtOAc:8 / 2 + NEt3 drops); 1H-NMR(400MHz,CD2Cl2):δ=7.73-7.62(m,1H),7.36-7.22(m,8H),5.09-5.04(m,1H),4.16-4.12(m,1H),3.93-3.90(m,1H),3. 67-3.62(m,2H),3.28-3.22(m,1H),2.86(br,1H),2.61-2.55(m,1H),2.14-2.07(m,1H),2.01-1.88(m,3H)1.57-1.48(m,9H); 13 C-NMR (100MHz, CDCl3): δ=155.2,154.8,145.4,144.9,143.4,143.2,140.0,129.2,128.8,128.7,128.6,128.4,127.8,127.6,127. 3,127.2,126.8,125.9,125.7,79.9,79.4,77.7,77.6,72.4,62.3,61.1,59.2,54.3,46.9,46.5,37.0,36.7,36.5,36.2,28.8,28.7; HR-MS(ESI):m / z calculated for C 25 H 31 O2N2 + [M+H] + 391.2380,found 391.2365.

[0106] For the generation of rotamers in NMR measurements, analytical aliquots were deprotected using a mixture of DCM and TFA (1:1, 1.0 mL). 1 H-NMR(400MHz,D2O):δ=7.63-7.54(m,8H),7.06-7.04(m,1H),5.30(s,1H),5.24(s,1H),4.83-4.79(m ,1H),4.63-4.60(m,1H),3.66-3.51(m,3H),3.23-3.16(m,1H),2.63-2.54(m,2H),2.49-2.39(m,2H); 13 C-NMR(100MHz,D2O):δ=162.8(q,J=36Hz,COOCF3 -),136.7,136.2,132.2,131.8,130.9,130.5,129.7,126.9,126.1,116.3(q,J=292Hz,COOCF3 - ),79.6,71.6,59.9,58.9,54.4,45.8,35.7,34.0;

[0107] 1,2,3,4,5,6,6a,10b-Octahydroindeno[1,2-b:3,2-b']dipyrrole-1,6-diium dichloride (16) [ka]

[0108] To a solution of compound 15 (324.6 mg, 0.83 mmol, 1.0 equiv.) and acetic acid (95 μL, 1.66 mmol, 2.0 equiv.) in MeOH (10 mL) was added Pd / C (10 wt%) (32 mg, 10 wt%). The mixture was stirred under an H atmosphere (1 atm, balloon) at 22 °C for 20 h, then filtered through Celite and concentrated under reduced pressure. The residue was added to DCM (10 mL) and TFA (5 mL) and stirred at 22 °C for 2 h. After the reaction was complete, the solvent was evaporated, basified with aqueous NaOH (3 M, 10 mL), and extracted with EtOAc (3 × 100 mL). The combined organic phase was dried over NaSO, filtered, and concentrated. The final compound 16 (206 mg, 0.75 mmol, 91%) was precipitated from diethyl ether with HCl (1.25 M in MeOH) as a colorless crystalline solid. 1 H-NMR(400MHz,D2O):δ=7.68-7.62(m,4H),5.36(s,2H),3.62-3.56(m,2H),3.20-3.13(m,2H),2.59-2.53(m,2H),2.44-2.36(m,2H); 13 C-NMR(100MHz,D2O):δ=137.1,131.8,126.5,72.0,59.2,45.5,35.1; HR-MS(ESI):m / z calculated for C 13 H 17 N2+ [M+H] + 201.1386, found 201.1392.

[0109] References Schwartz, C. E.; Curran, D. P., A. J. Am. Chem. Soc. 1990, 112(25), 9272 - 9284 Kyasa, S.; Fisher, T.; Dussault, P., Synthesis 2011, 2011(21), 3475 - 3481 Ramachary, D. B.; Kishor, M., Org. Biomol. Chem. 2008, 6(22), 4176 Zhou, Y - J. et al. (1997), Proc. Natl. Acad. Sci. U.S.A., 94:13850 - 13855 Brizzi, M. F. et al. (1996), J. Biol. Chem., 271:3562 - 3567 Yamaoka, K. et al. (2004), Gen. Biol., 5:253 Ide, H. et al. (2008), Biochem. Biophys. Res. Commun., 369:292 - 296 Li, et al. J. Am. Chem. Soc. 2019 141 239415 - 9421

Claims

1. A compound of formula (1) or (2) or a salt thereof, 【Chemical 1】 During the ceremony, R １ and R ３ is a group represented by the following formula: 【Chemistry 2】 is selected from the group consisting of R ２ and R ４ is a group represented by the following formula: 【Chemistry 3】 is selected from the group consisting of A compound or a salt thereof, wherein z, x, y, p and q are 1.

2. R １ and R ３ is a group represented by the following formula: 【Chemistry 4】 2. The compound of claim 1 selected from the group consisting of:

3. R ２ and R ４ is a group represented by the following formula: 【Chemistry 5】 3. The compound of claim 1 or 2, selected from the group consisting of:

4. An intermediate of formula (3) or (4) or a salt thereof, 【Chemistry 6】 During the ceremony, R ５ , R ６ , R ７ and R ８ but, H. A protecting group cleavable under acidic conditions represented by the following formula: 【Chemistry 7】 A protecting group cleavable under basic conditions represented by the following formula: 【Chemistry 8】 A protecting group that can be cleaved under reducing conditions and is represented by the following formula: 【Chemistry 9】 A hydrogenolytically cleavable protecting group represented by the formula: 【Chemistry 10】 A protecting group that can be cleaved using a metal catalyst, represented by the formula: 【Chemistry 11】 is selected from the group consisting of An intermediate or a salt thereof, wherein z, x, y, p and q are 1.

5. In formula (3), R ５ and R ６ are both -H, or one of R 5 and R 6 is —H, and R ５ and the other of R 6 is said protecting group, or both R 5 and R 6 are said protecting groups, and the reaction conditions for cleavage of said protecting group at R 5 are different from the reaction conditions for cleavage of said protecting group at R 6 ; and In formula (4), Both R 7 and R 8 are —H; or one of R 7 and R 8 is —H and the other of R 7 and R 8 is said protecting group; or R 7 and R ８ are the protecting group, and the reaction conditions for cleavage of the protecting group at R 7 are different from the reaction conditions for cleavage of the protecting group at R 8; The intermediate of claim 4.

6. An intermediate of formula (3) or (4) or a salt thereof, 【Chemistry 12】 During the ceremony, In formula (3), R ５ and one of R 6 is a group represented by the following formula: 【Chemistry 13】 is selected from the group consisting of R ５ and the other of R 6 is H. Boc, or Ts, Fmoc, Ac, or Ac-CF ３ , Ts, Bn, or Cbz, and Alloc, or Troc, and In formula (4), one of R 7 and R 8 is a group represented by the following formula: 【Chemistry 14】 is selected from the group consisting of The other of R 7 and R 8 is H. Boc, or Ts, Fmoc, Ac, or Ac-CF 3 , Ts, Bn, or Cbz, and Alloc, or Troc, is selected from the group consisting of An intermediate or a salt thereof, wherein z, x, y, p and q are 1.

7. An intermediate of formula (3) or (4) or a salt thereof, 【Chemistry 15】 During the ceremony, In formula (3), R ５ and one of R 6 is a group represented by the following formula: 【Chemistry 16】 is selected from the group consisting of R ５ and the other of R 6 is H. Boc, or Ts, Fmoc, Ac, or Ac-CF ３ , Ts, Bn, or Cbz, and Alloc, or Troc, and In formula (4), one of R 7 and R 8 is a group represented by the following formula: 【Chemistry 17】 is selected from the group consisting of The other of R 7 and R 8 is H. Boc, or Ts, Fmoc, Ac, or Ac-CF 3 , Ts, Bn, or Cbz, and Alloc, or Troc, is selected from the group consisting of An intermediate or a salt thereof, wherein z, x, y, p and q are 1.

8. An intermediate of formula (5) or formula (6): 【Chemistry 18】 During the ceremony, R ９ and R １０ but, H. Boc, or Ts, Fmoc, Ac, or Ac-CF ３ , Ts, Bn, or Cbz, and Alloc, or Troc, is selected from the group consisting of An intermediate wherein z, y, and q are 1.

9. The compound according to any one of claims 1 to 3, the intermediate according to claim 4 or 5, the intermediate according to claim 6, the intermediate according to claim 7 or the intermediate according to claim 8, wherein the compound or the intermediate is an enantiomer.

10. i. Treatment of autoimmune diseases, cancer, Alzheimer's disease, or asthma; or ii. Prevention of allograft or xenograft rejection A pharmaceutical composition comprising a compound according to any one of claims 1 to 3 for use in 11. The pharmaceutical composition of claim 10, wherein the autoimmune disease is selected from the group consisting of rheumatoid arthritis, ulcerative colitis, psoriatic arthritis, psoriasis, Crohn's disease, atopic dermatitis, chronic hand eczema, non-segmental vitiligo, axial spondyloarthritis, small intestinal Crohn's disease, fistulizing Crohn's disease, Sjogren's syndrome, ankylosing spondylitis, cutaneous lupus, lupus nephropathy, and uveitis.

12. The pharmaceutical composition described in claim 10, wherein the cancer is myelofibrosis.

13. The pharmaceutical composition described in claim 10, wherein the allograft is an allogeneic kidney.

14. 11. The pharmaceutical composition of claim 10, wherein the compound is an enantiomer or a racemate.

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