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EP-4735424-A1 - PROCESSES FOR MAKING IRAK4 INHIBITORS

EP4735424A1EP 4735424 A1EP4735424 A1EP 4735424A1EP-4735424-A1

Abstract

The present disclosure relates generally to processes for preparing compounds that are inhibitors of the kinase IRAK4 and the synthetic intermediates prepared thereby.

Inventors

  • AMMANN, Stephen, E.
  • NEVILLE, Sean, T.
  • REICHWEIN, JOHN
  • RUEDEN, ERIK
  • YOUNG, May, G.
  • YU, CHIA-YUN
  • ANGELES, ANGIE, R.
  • CHIN, Matthew, R.
  • COTTELL, JEROMY, J.
  • DOXSEE, Ian, J.
  • FUNG, Peter, C.
  • HOANG, Brittanie, T.
  • LAU, STEPHEN
  • MUNDAL, Devon, A.

Assignees

  • GILEAD SCIENCES, INC.

Dates

Publication Date
20260506
Application Date
20240628

Claims (1)

  1. Attorney Docket No.: 1473-WO-PCT 37JD-350642-WO What is Claimed is: 1. A process for preparing Compound I, or a salt thereof: I comprising II with Compound III, or a under conditions suitable to 2. The process of claim 1, wherein the process further comprises contacting Compound I with citric acid to provide Compound I citric acid salt: . 3. A citric acid salt of I. SMRH:4890-6661-4220.1 Attorney Docket No.: 1473-WO-PCT 37JD-350642-WO 4. A methanesulfonic acid salt of Compound II: II. 5. A process for preparing II comprising contacting a thereof; with a compound of Formula V under conditions suitable to X is halo; R 1 is a protecting group; R 2 is hydrogen or -B(OR 3 )2; and each R 3 is independently hydrogen or C 1-6 alkyl, or two R 3 cyclize to form a cyclic boronate ester. 6. The process of claim 5, wherein the conditions further comprise a deprotection step. 7. The process of claim 6, wherein the deprotection step comprises converting a compound of Formula IIA to Compound II: 60 SMRH:4890-6661-4220.1 Attorney Docket No.: 1473-WO-PCT 37JD-350642-WO 8. The process of any one n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, or benzyl. 9. The process of claim 8, wherein the deprotection step comprises methane sulfonic acid. 10. The process of claim 9, wherein the process provides Compound II methanesulfonic acid salt: . 11. The process of any one of 2. 12. The process of any one of claims 5-11, wherein R 2 . 13. The process of any one of claims 5-12, wherein a catalyst, a ligand, and 14. The process of claim 13, wherein the catalyst is a palladium(II) or palladium(0) salt. 15. The process of any one of claims 13-14, wherein the ligand is 2-dicyclohexylphosphino-2′,4′,6′- triisopropylbiphenyl (XPhos), 2-dicyclohexylphosphino-2′,6′-diisopropoxybiphenyl (RuPhos), a dialkylbiaryl phosphine ligand, a monodentate phosphine ligand, or a bidentate phosphine ligand. 16. The process of any one of claims 13-15, wherein the base is an inorganic base, an alkoxide base, a tertiary amine, or a nitrogen-containing heteroaryl base. 17. The process of any one of claims 5-10, wherein R 2 is hydrogen. 18. The process of claim 17, wherein the conditions comprise a catalyst, a ligand, and an acid. 19. The process of claim 18, wherein the catalyst is a palladium catalyst or a palladium precatalyst. 20. The process of claim 18 or 19, wherein the ligand is a monodentate phosphine or a bidentate phosphine. 21. The process of any one of claims 18-20, wherein the acid is a carboxylic acid or a sulfonic acid. 61 SMRH:4890-6661-4220.1 Attorney Docket No.: 1473-WO-PCT 37JD-350642-WO 22. A process for preparing Compound I, or a salt thereof: I comprising with a compound of V under conditions suitable to the conditions do not comprise microwave radiation; wherein: X is halo; R 2 is hydrogen or -B(OR 3 )2; and each R 3 is independently hydrogen or C 1-6 alkyl, or two R 3 cyclize to form a cyclic boronate ester. 23. The process of claim 22, wherein the process further comprises contacting Compound I with citric acid to provide Compound I citric acid salt: . 24. The process of a a ligand, and a base. 62 SMRH:4890-6661-4220.1 Attorney Docket No.: 1473-WO-PCT 37JD-350642-WO 25. The process of claim 22, wherein the conditions comprise palladium(II) acetate, 2- dicyclohexylphosphino-2′,4′,6′-triisopropylbiphenyl (XPhos), and potassium phosphate tribasic. 26. The process of any one of claims 22-25, wherein the conditions comprise 2- methyltetrahydrofuran and water at a temperature of from about 70 °C to 80 °C. 27. A process for preparing a compound of Formula VI, or a salt thereof: comprising contacting a thereof; with trifluoroacetic under conditions suitable to provide a compound of Formula VIII: wherein X is halo; and to provide a compound of Formula VI. 28. A process for preparing a compound of Formula VI, or a salt thereof: comprising contacting a thereof; SMRH:4890-6661-4220.1 Attorney Docket No.: 1473-WO-PCT 37JD-350642-WO with a dehydrating agent under conditions suitable to provide a compound of Formula VI; wherein X is halo; provided that the dehydrating agent is other than trifluoroacetic anhydride. 29. The process of claim 28, wherein the dehydrating agent is cyanuric chloride, a carboxylic acid anhydride (such as acetic anhydride), a sulfonic acid anhydride (such as trifluoromethanesulfonic anhydride), an alkyl chloroformate (such as ethyl chloroformate), phosphorus oxychloride, or phosphorus pentoxide. 30. The process of claim 28 or 29, wherein the process further comprises a hydrolyzing step. 31. The process of claim 27 or 30, wherein the hydrolyzing comprises an inorganic base or an alkoxide base. 32. The process of claim 28, wherein the conditions comprise a base. 33. The process of claim 32, wherein the base is an amine base. 34. A process for preparing a compound of Formula IX, or a salt thereof: IX comprising with a compound of V under conditions suitable to X is halo; R 2 is hydrogen or -B(OR 3 )2; and each R 3 is independently hydrogen or C1-6 alkyl, or two R 3 cyclize to form a cyclic boronate ester. 64 SMRH:4890-6661-4220.1 Attorney Docket No.: 1473-WO-PCT 37JD-350642-WO 35. The process of claim 34, wherein the compound of Formula V is represented by a compound of Formula VA: 36. The process of any one of 37. A process for preparing Compound I, or a salt thereof: I comprising IX under conditions 38. The process of claim 37, wherein the conditions comprise a dehydrating agent, and optional hydrolysis step. 39. A compound, or a salt thereof, selected from: 65 SMRH:4890-6661-4220.1

Description

Attorney Docket No.: 1473-WO-PCT 37JD-350642-WO PROCESSES FOR MAKING IRAK4 INHIBITORS CROSS-REFERENCE TO RELATED APPLICATIONS [0001] This application claims the benefit under 35 U.S.C. § 119(e) of United States Provisional Application Serial Number 63/511,558, filed June 30, 2023, the contents of which are hereby incorporated by reference in its entirety. FIELD [0002] The present disclosure relates generally to processes for preparing compounds that are inhibitors of the kinase IRAK4 and the synthetic intermediates prepared thereby. BACKGROUND [0003] Interleukin-1 receptor-associated kinase-4 (IRAK4) is a serine-threonine kinase which acts as a mediator in interleukin-1/Toll-like receptor (IL-1/TLR) signaling cascades. More particularly, IRAK4 is involved in activation of adaptor protein myeloid differentiation primary response gene 88 (MyD88) signaling cascades and is hypothesized to play a role in inflammatory and fibrotic disorders, such as rheumatoid arthritis (RA), inflammatory bowel disease (IBD), gout, Lyme disease, arthritis, psoriasis, pelvic inflammatory disease, systemic lupus erythematosus (SLE), Sjogren's syndrome, viral myocarditis, acute and chronic tissue injury, non-alcoholic steatohepatitis (NASH), alcoholic hepatitis and kidney disease, including chronic kidney disease and diabetic kidney disease. In addition, IRAK4 plays a role in certain cancers and is hypothesized to play a role in inflammation associated with gastrointestinal infections, including C. difficile. Signaling through IL-1R/TLR results in the activation of MyD88 which recruits IRAK4 and IRAK1 to form a signaling complex. This complex then interacts with a series of kinases, adaptor proteins, and ligases, ultimately resulting in the activation of nuclear factor kappa-light- chain-enhancer of activated B cells (NF-κB), activator protein-1 (API), cyclic AMP-responsive element- binding protein (CREB) and the interferon-regulatory factors (IRFs), including IRF5 and IRF7, inducing the generation of pro-inflammatory cytokines and type I interferons. [0004] Therefore, inhibitors of IRAK4 may be useful in the treatment of inflammatory and fibrotic disorders, such as rheumatoid arthritis (RA), inflammatory bowel disease (IBD), gout, Lyme disease, arthritis, psoriasis, pelvic inflammatory disease, systemic lupus erythematosus (SLE), Sjogren's syndrome, inflammation associated with gastrointestinal infections, including C. difficile, viral myocarditis, acute and chronic tissue injury, non-alcoholic steatohepatitis (NASH), alcoholic hepatitis, and kidney disease, including chronic kidney disease and diabetic kidney disease. SUMMARY [0005] Provided herein is a process for preparing Compound I, or a salt thereof: Attorney Docket No.: 1473-WO-PCT 37JD-350642-WO I comprising II with Compound III, or a HO NH2 under conditions suitable to [0006] Also provided is a citric acid salt of Compound I: I. [0007] Also provided is a II. [0008] Also provided is a thereof: II SMRH:4890-6661-4220.1 Attorney Docket No.: 1473-WO-PCT 37JD-350642-WO comprising contacting a compound of Formula IV, or a salt thereof; with a compound of Formula V under conditions suitable to X is halo; R1 is a protecting group; R2 is hydrogen or -B(OR3)2; and each R3 is independently hydrogen or C1-6 alkyl, or two R3 cyclize to form a cyclic boronate ester. [0009] Also provided is a process for preparing Compound I, or a salt thereof: I comprising with a compound of V under conditions suitable to the conditions do not comprise microwave radiation; wherein: 3 SMRH:4890-6661-4220.1 Attorney Docket No.: 1473-WO-PCT 37JD-350642-WO X is halo; R2 is hydrogen or -B(OR3)2; and each R3 is independently hydrogen or C1-6 alkyl, or two R3 cyclize to form a cyclic boronate ester. [0010] Also provided is a process for preparing a compound of Formula VI, or a salt thereof: comprising contacting a thereof; with trifluoroacetic under conditions suitable to provide a compound of Formula VIII: wherein X is halo; and to provide a compound of Formula VI. [0011] Also provided is a process for preparing a compound of Formula VI, or a salt thereof: comprising contacting a thereof; SMRH:4890-6661-4220.1 Attorney Docket No.: 1473-WO-PCT 37JD-350642-WO with a dehydrating agent under conditions suitable to provide a compound of Formula VI; wherein X is halo. [0012] In some embodiments, the dehydrating agent is other than trifluoroacetic anhydride. [0013] Also provided is a process for preparing a compound of Formula IX, or a salt thereof: IX comprising with a compound of V under conditions suitable to X is halo; R2 is hydrogen or -B(OR3)2; and each R3 is independently hydrogen or C1-6 alkyl, or two R3 cyclize to form a cyclic boronate ester. [0014] Also provided is a process for preparing Compound I, or a salt thereof: I comprising 5 SMRH:4890-6661-4220.1 Attorney Docket No.: 1473-WO-PCT 37JD-350642-WO IX under conditions [0015]