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EP-4735446-A1 - SALTS AND SOLID FORMS OF A COMPOUND THAT MODULATES IRAK4

EP4735446A1EP 4735446 A1EP4735446 A1EP 4735446A1EP-4735446-A1

Abstract

The present disclosure relates to salts and solid forms of a compound that are inhibitors of the kinase IRAK4 and their uses as therapeutic agents for treating diseases, disorders, or conditions modulated by IRAK4, such as inflammatory bowel disease (IBD), systemic lupus erythematosus (SLE), psoriasis, or rheumatoid arthritis.

Inventors

  • AMMANN, STEPHEN E.
  • FUNG, Peter C.
  • HOANG, Brittanie T.
  • HORSTMAN, Elizabeth M.
  • LAU, STEPHEN
  • MORRISON, HENRY G.
  • MUNDAL, Devon A.
  • YOUNG, May G.
  • YU, CHIA-YUN

Assignees

  • GILEAD SCIENCES, INC.

Dates

Publication Date
20260506
Application Date
20240628

Claims (1)

  1. Attorney Docket No.: 1471-WO-PCT 37JD-350600-WO CLAIMS: 1. A crystalline form of Compound I: I, (Compound I Form by an X-ray powder diffractogram comprising on a diffractometer using Cu- Kα radiation. 2. The crystalline form of claim 1, further characterized by: i) one or more peaks at 19.1 °2θ ± 0.2°, 22.7± 0.2°, or 15.1 ± 0.2°; ii) a diffractogram substantially as shown in FIG.1; iii) a differential scanning calorimetry (DSC) curve comprising an endotherm at about 155.3 °C (onset temperature) and an endotherm at about 174.7 °C (onset temperature); iv) a differential scanning calorimetry (DSC) curve substantially as shown in FIG.2; v) thermogravimetric analysis (TGA) showing a weight loss of about 1.0 wt% up to about 150 °C; or vi) thermogravimetric analysis (TGA) comprising a thermogram substantially as shown in FIG.3. 3. A crystalline form of Compound I: I, (Compound I Form by an X-ray powder diffractogram comprising peaks (±0.2°) at 7.5, 14.6, and 17.8 °2θ as determined on a diffractometer using Cu-Kα radiation. 4. The crystalline form of claim 3, further characterized by: i) one or more peaks at 22.8 °2θ ± 0.2°, 26.7 ± 0.2°, or 22.0 ± 0.2°; ii) a diffractogram substantially as shown in FIG.4; iii) a differential scanning calorimetry (DSC) curve comprising an endotherm at about 190.7 °C (onset temperature); Attorney Docket No.: 1471-WO-PCT 37JD-350600-WO iv) a differential scanning calorimetry (DSC) curve substantially as shown in FIG.5; v) thermogravimetric analysis (TGA) showing a weight loss of about 1.0 wt% up to about 200 °C; or vi) thermogravimetric analysis (TGA) comprising a thermogram substantially as shown in FIG. 6. 5. A crystalline form of Compound I: I, (Compound I Form by an X-ray powder diffractogram comprising as on a diffractometer using Cu-Kα radiation. 6. The crystalline form of claim 5, further characterized by: i) one or more peaks at 17.3 °2θ ± 0.2°, 11.7 ± 0.2°, or 21.7 ± 0.2°; ii) a diffractogram substantially as shown in FIG.8; iii) a differential scanning calorimetry (DSC) curve comprising an endotherm at about 192.0 °C (onset temperature); iv) a differential scanning calorimetry (DSC) curve substantially as shown in FIG.9; v) thermogravimetric analysis (TGA) showing a weight loss of about 0.8 wt% up to about 200 °C; vi) thermogravimetric analysis (TGA) comprising a thermogram substantially as shown in FIG. 10; or vii) a dynamic vapor sorption (DVS) curve substantially as shown in FIG.11. 7. A crystalline form of Compound I: I, (Compound I Form and characterized by an X- ray powder diffractogram comprising peaks (±0.2°) at 11.8, 25.9, and 20.7 °2θ as determined on a diffractometer using Cu-Kα radiation. Attorney Docket No.: 1471-WO-PCT 37JD-350600-WO 8. The crystalline form of claim 7, further characterized by: i) one or more peaks at 16.8 °2θ ± 0.2°, 23.1 ± 0.2°, or 18.5 ± 0.2°; ii) a diffractogram substantially as shown in FIG.12; iii) a differential scanning calorimetry (DSC) curve comprising an endotherm at about 70.5 °C (onset temperature), an endotherm at about 151.6 °C (onset temperature), and an endotherm at about 189.1 °C (onset temperature); iv) a differential scanning calorimetry (DSC) curve substantially as shown in FIG.13; v) thermogravimetric analysis (TGA) showing a weight loss of about 3.6 wt% up to about 100 °C; vi) thermogravimetric analysis (TGA) comprising a thermogram substantially as shown in FIG. 14; or vii) a dynamic vapor sorption (DVS) curve substantially as shown in FIG.15. 9. The crystalline form of claim 7, comprising about 1 mole equivalent of water. 10. A crystalline form of Compound I: I, (Compound I Form and characterized by an X- ray powder diffractogram comprising peaks (±0.2°) at 4.9, 5.6, and 7.4 °2θ as determined on a diffractometer using Cu-Kα radiation. 11. The crystalline form of claim 10, further characterized by: i) one or more peaks at 8.4 °2θ ± 0.2°, 12.3 ± 0.2°, or 27.2 ± 0.2°; ii) a diffractogram substantially as shown in FIG.16; iii) a differential scanning calorimetry (DSC) curve comprising an endotherm at about 47.0 °C (onset temperature), an endotherm at about 111.1 °C (onset temperature), and an endotherm at about 122.9 °C (onset temperature); iii) a differential scanning calorimetry (DSC) curve substantially as shown in FIG.17; v) thermogravimetric analysis (TGA) showing a weight loss of about 5.2 wt% up to about 140 °C; vi) thermogravimetric analysis (TGA) comprising a thermogram substantially as shown in FIG. 18; or vii) a dynamic vapor sorption (DVS) curve substantially as shown in FIG.19. Attorney Docket No.: 1471-WO-PCT 37JD-350600-WO 12. The crystalline form of claim 10, comprising about 1.25 mole equivalents of water. 13. A crystalline form of a mono-citrate salt of Compound I: I, (Compound I mono- Form I is characterized by an X-ray powder diffractogram °2θ as determined on a diffractometer using Cu-Kα radiation. 14. The crystalline form of claim 13, further characterized by: i) one or more peaks at 19.6 °2θ ± 0.2°, 15.6 ± 0.2°, or 8.1 ± 0.2°; ii) a diffractogram substantially as shown in FIG.39; iii) a differential scanning calorimetry (DSC) curve comprising an endotherm at about 145.2 °C (onset temperature) and an endotherm at about 186.6 °C (onset temperature); iv) a differential scanning calorimetry (DSC) curve substantially as shown in FIG.40; v) thermogravimetric analysis (TGA) showing a weight loss of about 0.6 wt% up to about 150 °C; vi) thermogravimetric analysis (TGA) comprising a thermogram substantially as shown in FIG. 41; vii) a dynamic vapor sorption (DVS) curve substantially as shown in FIG.42. 15. The crystalline form of claim 13, comprising about 1 mole equivalent of citric acid. 16. A crystalline form of Compound I: I, (Compound I Form by an X-ray powder diffractogram comprising peaks (±0.2°) at 21.2, 12.3, and 10.7 °2θ as determined on a diffractometer using Cu-Kα radiation; or Attorney Docket No.: 1471-WO-PCT 37JD-350600-WO (Compound I Form VII), wherein Compound I Form VII is a water:tetrahydrofuran (THF) solvate and characterized by an X-ray powder diffractogram comprising peaks (±0.2°) at 4.0, 25.8, and 6.9 °2θ as determined on a diffractometer using Cu-Kα radiation; or (Compound I Form VIII), wherein Compound I Form VIII is a water:acetonitrile (ACN) solvate and characterized by an X-ray powder diffractogram comprising peaks (±0.2°) at 8.0, 25.8, and 6.1 °2θ as determined on a diffractometer using Cu-Kα radiation; or (Compound I Form IX), wherein Compound I Form IX is a water:2-methyl tetrahydrofuran (Me- THF) solvate and characterized by an X-ray powder diffractogram comprising peaks (±0.2°) at 9.4, 4.5, and 18.3 °2θ as determined on a diffractometer using Cu-Kα radiation; or (Compound I Form X), wherein Compound I Form X is an isopropyl alcohol (IPA) solvate and characterized by an X-ray powder diffractogram comprising peaks (±0.2°) at 4.0, 7.0, and 8.2 °2θ as determined on a diffractometer using Cu-Kα radiation; or (Compound I Form XI), wherein Compound I Form XI is a methyl isobutyl ketone (MIBK) solvate and characterized by an X-ray powder diffractogram comprising peaks (±0.2°) at 4.0, 6.9, and 14.5 °2θ as determined on a diffractometer using Cu-Kα radiation; or (Compound I Form XII), wherein Compound I Form XII is characterized by an X-ray powder diffractogram comprising peaks (±0.2°) at 7.7, 11.7 and 26.1 °2θ as determined on a diffractometer using Cu-Kα radiation; or (Compound I Form XIII), wherein Compound I Form XIII is characterized by an X-ray powder diffractogram comprising peaks (±0.2°) at 7.6, 14.6, and 17.9 °2θ as determined on a diffractometer using Cu-Kα radiation; or (Compound I mono-citrate Form II), wherein Compound I mono-citrate Form II is a mono-citrate salt and characterized by an X-ray powder diffractogram comprising peaks (±0.2°) at 5.6, 7.0, and 24.2 °2θ as determined on a diffractometer using Cu-Kα radiation; or (Compound I mono-citrate Form III), wherein Compound I mono-citrate Form III is a mono-citrate salt and characterized by an X-ray powder diffractogram comprising peaks (±0.2°) at 6.3, 18.8, and 7.7 °2θ as determined on a diffractometer using Cu-Kα radiation; or (Compound I mono-citrate Form IV), wherein Compound I mono-citrate Form IV is a mono-citrate salt characterized by an X-ray powder diffractogram comprising peaks (±0.2°) at 26.8, 25.7, and 25.1 °2θ as determined on a diffractometer using Cu-Kα radiation; or (Compound I hemi-citrate Form I), wherein Compound I hemi-citrate Form I is a hemi-citrate salt characterized by an X-ray powder diffractogram comprising peaks (±0.2°) at 6.1, 7.4, and 17.1 °2θ as determined on a diffractometer using Cu-Kα radiation; or (Compound I mono-HCl Form I), wherein Compound I mono-HCl Form I is a mono-hydrochloride (HCl) salt and characterized by an X-ray powder diffractogram comprising peaks (±0.2°) at 6.9, 20.7, and 16.9 °2θ as determined on a diffractometer using Cu-Kα radiation; or Attorney Docket No.: 1471-WO-PCT 37JD-350600-WO (Compound I mono-maleate Form I), wherein Compound I mono-maleate Form I is a mono-maleate salt and characterized by an X-ray powder diffractogram comprising peaks (±0.2°) at 7.4, 6.1, and 23.2 °2θ as determined on a diffractometer using Cu-Kα radiation; or (Compound I hemi-fumarate Form I), wherein Compound I hemi-fumarate Form I is a hemi- fumarate salt and characterized by an X-ray powder diffractogram comprising peaks (±0.2°) at 7.7, 6.8, and 13.0 °2θ as determined on a diffractometer using Cu-Kα radiation; or (Compound I mono-fumarate Form I), wherein Compound I mono-fumarate Form I is a mono- fumarate salt and characterized by an X-ray powder diffractogram comprising peaks (±0.2°) at 6.1, 7.8, and 18.7 °2θ as determined on a diffractometer using Cu-Kα radiation; or (Compound I hemi-L-tartrate Form I), wherein Compound I hemi-L-tartrate Form I is a hemi-L- tartrate salt and characterized by an X-ray powder diffractogram comprising peaks (±0.2°) at 8.5, 5.2 and 18.6 °2θ as determined on a diffractometer using Cu-Kα radiation; or (Compound I mono-ESA Form I), wherein Compound I mono-ethanesulfonic acid (ESA) Form I is a mono-ESA salt and characterized by an X-ray powder diffractogram comprising peaks (±0.2°) at 6.4, 10.9, and 19.0 °2θ as determined on a diffractometer using Cu-Kα radiation; or (Compound I hemi-glycolate Form I), wherein Compound I hemi-glycolate Form I is a hemi- glycolate and characterized by an X-ray powder diffractogram comprising peaks (±0.2°) at 6.2, 8.0, and 22.9 °2θ as determined on a diffractometer using Cu-Kα radiation; or (Compound I sulfate Form I), wherein Compound I sulfate Form I is a sulfate salt and characterized by an X-ray powder diffractogram comprising peaks (±0.2°) at 5.5, 4.9, and 11.1 °2θ as determined on a diffractometer using Cu-Kα radiation; or (Compound I phosphate Form I), wherein Compound I phosphate Form I is a phosphate salt characterized by an X-ray powder diffractogram comprising peaks (±0.2°) at 4.8, 9.7, and 16.9 °2θ as determined on a diffractometer using Cu-Kα radiation; or (Compound I hemi-HCl Form I), wherein Compound I hemi-HCl Form I is a hemi-hydrochloride (HCl) salt characterized by an X-ray powder diffractogram comprising peaks (±0.2°) at 5.6, 9.2, and 11.2 °2θ as determined on a diffractometer using Cu-Kα radiation; or (Compound I co-crystal Form I), wherein Compound I co-crystal Form I is a co-crystal of Compound I and 4-(((S)-1-cyanoethyl)amino)-6-(3-cyanopyrrolo[1,2-b]pyridazin-7-yl)-N-((R)-2-fluoro-3- hydroxy-3-methylbutyl)nicotinamide and is characterized by an X-ray powder diffractogram comprising peaks (±0.2°) at 19.1, 10.3, and 9.4 °2θ as determined on a diffractometer using Cu-Kα radiation. 17. A pharmaceutical composition comprising a crystalline form of any one of claims 1-16 and a pharmaceutically acceptable carrier. Attorney Docket No.: 1471-WO-PCT 37JD-350600-WO 18. A method of treating an inflammatory condition, in a patient in need thereof, comprising administering to said patient a therapeutically effective amount of a crystalline form of any one of claims 1- 16 or a pharmaceutical composition of claim 17. 19. The method of claim 18, wherein the inflammatory condition is selected from inflammatory bowel disease (IBD), systemic lupus erythematosus (SLE), psoriasis, and rheumatoid arthritis. 20. The method of claim 19, wherein the inflammatory condition is IBD. 21. The method of claim 19, wherein the inflammatory condition is rheumatoid arthritis.

Description

Attorney Docket No.: 1471-WO-PCT 37JD-350600-WO SALTS AND SOLID FORMS OF A COMPOUND THAT MODULATES IRAK4 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 63/511,597, filed June 30, 2023, the contents of which are hereby incorporated by reference in its entirety. FIELD [0002] The present disclosure relates generally to salts and solid forms of a compound that are inhibitors of the kinase IRAK4. The disclosure also relates to pharmaceutical compositions comprising such salts and solid forms and methods of using the same. BACKGROUND [0003] Interleukin-1 receptor-associated kinase-4 (IRAK4) is a serine-threonine kinase that 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. Attorney Docket No.: 1471-WO-PCT 37JD-350600-WO SUMMARY [0005] Provided herein are salts and solid forms of a compound that are useful as inhibitors of IRAK4. Also disclosed herein are pharmaceutical compositions comprising salts and solid forms of Compound I and methods of using the same in the treatment of diseases, disorders, or conditions modulated by IRAK4. [0006] Some embodiments provide for a crystalline form of Compound I: (Compound I Form I), X-ray powder diffractogram comprising peaks (±0.2°) at 7.5, 12.3, and 7.2 °2θ as determined on a diffractometer using Cu-Kα radiation. [0007] Some embodiments provide for a crystalline form of Compound I (Compound I Form II), wherein Compound I Form II is characterized by an X-ray powder diffractogram comprising peaks (±0.2°) at 7.5, 14.6, and 17.8 °2θ as determined on a diffractometer using Cu-Kα radiation. [0008] Some embodiments provide for a crystalline form of Compound I (Compound I Form IV), wherein Compound I Form IV is characterized by an X-ray powder diffractogram comprising peaks (±0.2°) at 10.1, 10.7, and 17.9 °2θ as determined on a diffractometer using Cu-Kα radiation. [0009] Some embodiments provide for a crystalline form of Compound I (Compound I Form V), wherein Compound I Form V is a monohydrate and characterized by an X-ray powder diffractogram comprising peaks (±0.2°) at 11.8, 25.9, and 20.7 °2θ as determined on a diffractometer using Cu-Kα radiation. [0010] Some embodiments provide for a crystalline form of Compound I (Compound I Form VI), wherein Compound I Form VI is a monohydrate and characterized by an X-ray powder diffractogram comprising peaks (±0.2°) at 4.9, 5.6, and 7.4 °2θ as determined on a diffractometer using Cu-Kα radiation. [0011] Some embodiments provide for a crystalline form of a mono-citrate salt of Compound I (Compound I mono-citrate Form I), wherein Compound I mono-citrate Form I is characterized by an X-ray powder diffractogram comprising peaks (±0.2°) at 5.7, 7.0, and 22.7 °2θ as determined on a diffractometer using Cu- Kα radiation. [0012] Some embodiments provide for a crystalline form of Compound I (Compound I Form III), wherein Compound I Form III is characterized by an X-ray powder diffractogram comprising peaks (±0.2°) at