Cyclic boronic acid esters and uses thereof

Abstract

The present disclosure relates to cyclic boronic acid esters and salts thereof useful as immunoproteasome inhibitors. The disclosure further relates to pharmaceutical compositions, methods of preparation, crystal and polymorph forms, and methods of treatment related thereto.

Description

CROSS-REFERENCE TO RELATED APPLICATIONS

[0001] This application claims priority to U.S. Provisional Application No. 63 / 357,093, filed on June 30, 2022, which is hereby incorporated by reference in its entirety. Field of the Invention

[0002] The present disclosure relates to cyclic boronate esters and salts thereof useful as immunoproteasome inhibitors. The present disclosure further relates to pharmaceutical compositions, methods of preparation, crystalline and polymorphic forms, and methods of treatment related thereto. Background Art

[0003] Immunoproteasome is a large proteolytic mechanism derived from constitutive proteasome and expressed in both immune cells and non-immune cells. Immunoproteasome plays a key role in the immune system because it degrades proteins into short peptides that can be processed into grooves suitable for major histocompatibility complex (MHC) class I molecules. This display of peptides on MHC I allows recognition by CD8 T cells of the adaptive immune system. This recognition can help CD8 T cells destroy cells infected by pathogens. In addition to the role of immunoproteasome in pathogen recognition and removal, it is also known that immunoproteasome affects inflammatory disease progression by its ability to regulate T cell polarization and inflammation and neoplastic transformation. See, e.g., Kimura, H. et al., 2015. “New Insights into the Function of the Immunoproteasome in Immune and Nonimmune Cells,” J Immunology Research, Vol. 2015, Article ID 541984, 8 p.; Ogorevc, E., 2018. “A patent review of immunoproteasome inhibitors,” Expert Opin. on Therapeutic Patents, Vol. 28, No. 7, 517-540.

[0004] Two important immunoproteasome subunits are called large multifunctional peptidase 2 (LMP2 or iβ1) and large multifunctional peptidase 7 (LMP7 or iβ5). See, e.g., Kimura 2015. Both subunits are involved in pathways associated with various autoimmune, inflammatory, and hematological disorders. For example, both LMP2 and LMP7 are upregulated in sporadic inclusion body myositis, immune-mediated necrotizing myopathy, and dermatomyositis muscle biopsies, and colocalize with myofibers expressing MHC class I. See Bhattarai, S. et al. 2016, "The immunoproteasomes are key to regulating myokines and MHC class Iexpression in idiopathic inflammatory myopathies," J Autoimmunity, 75: 118-129. Additionally, LMP2 and LMP7 expression have been shown to be upregulated in colitis lesions. See, e.g., supra; Schmidt, N. et al. 2010. "Targeting the proteasome: partial inhibition of the proteasome by bortezomib or deletion of the immunosubunit LMP7 attenuates experimental colitis," Gut 59:896-906. Genetic variations in the immunoproteasome subunits LMP2 and LMP7 are associated with psoriasis based on analysis of patient samples. See, e.g. U. et al. 2007. “Strong associations of psoriasis with antigen processing LMP and transport genes TAP differ by gender and phenotype,” Genes and Immunity 8, 513-51.

[0005] Various immunoproteasome inhibitors are known, for example, PKS3053 is a selective inhibitor of LMP7, which reduces inflammation, cell infiltration, and tissue damage in a mouse model of skin injury, suggesting that LMP7 inhibition may be a potential therapy for inflammatory skin diseases such as psoriasis, cutaneous lupus erythematosus, and systemic sclerosis. See Ah Kioon, MD et al. 2021. "Noncytotoxic Inhibition of the Immunoproteasome Regulates Human Immune Cells In Vitro and Suppresses Cutaneous Inflammation in the Mouse [Non-cytotoxic inhibition of immunoproteasomes regulates human immune cells in vitro and suppresses cutaneous inflammation in mice]," J Immunol. [Journal of Immunology] 206: 1631-1641. ONX-0914 (also known as PR-957), a selective LMP7 inhibitor, has been used as a treatment for autoimmune diseases (such as colitis) in animal models. See, for example, Kimura 2015 (above). Studies on ONX-0914 also suggest the potential to alleviate inflammatory bowel disease (IBD) including Crohn's disease and ulcerative colitis. See Basler M. et al. 2010 "Prevention of Experimental Colitis by a Selective Inhibitor of the Immunoproteasome," J Immunol. [Journal of Immunology] 185 (1): 634-641. ONX-0914 has been reported to alleviate experimental arthritis by blocking inflammatory cytokine expression. See, e.g., Kimura 2015 (above). ONX-0914 has also been found to improve graft-versus-host disease (GVHD) in certain mouse models.See Zilberberg, J. et al. 2015 "Inhibition of the ImmunoproteasomeSubunit LMP7 with ONX0914Ameliorates Graft-versus-Host Disease in an MHC-Matched Minor Histocompatibility Antigen-Disparate Murine Model," Biol. Blood Marrow Transplant., 21(9): 1555-64. KZR-616 is a tripeptide epoxyketone that selectively and irreversibly inhibits LMP7 and LMP2. See Fang, Y. et al. 2021, “Role of Epoxide Hydrolases and Cytochrome P450s on Metabolism of KZR-616, a First-in-Class Selective Inhibitor of the Immunoproteasome,” Drug Metabolism and Disposition, Sep 2021, 49(9) 810-821. In mouse models of rheumatoid arthritis and systemic lupus erythematosus (SLE), KZR-616 blocked disease progression at well-tolerated doses without affecting normal T cell-dependent immune responses. See ibid. KZR-616 is currently being evaluated in a Phase 2 clinical trial in patients with SLE and lupus nephritis. See ibid.

[0006] Additionally, selective LMP2 inhibitors UK-101 and IPSI-001 have been shown to exhibit antitumor activity against multiple myeloma. See, e.g., supra. Similarly, PR-924, a selective inhibitor of LMP7, inhibits growth and triggers apoptosis in multiple myeloma (MM) cell lines and primary patient MM cells without significantly affecting normal peripheral blood mononuclear cells. See Singh, AV et al. 2011, "PR-924, a selective inhibitor of LMP7, blocks multiple myeloma cell growth both in vitro and in vivo," Br. J. Haematol, 152(2): 155-63.

[0007] As disclosed in WO 2009 / 154737 and elsewhere, certain boronic acid-based compounds have been disclosed as effective immunoproteasome inhibitors. Despite these promising candidates, there is still a need for additional boronic acid-based immunoproteasome inhibitors, particularly because it is known that boronic acids can be amorphous and difficult to manufacture on a large scale or to update the purity of the final product. Additionally, due to the presence of the boronic acid functional group, certain boronic acids are susceptible to hydrolysis and oxidation. This inherent chemical instability may lead to potential chemical instability during the manufacture and storage of drug substances and drug products. Therefore, there is a need for additional compounds that exhibit similar properties in vivo but can be manufactured and / or stored more easily or efficiently. The preparation of pharmaceutical salts of compounds of interest is a common strategy to try to find more stable compounds for manufacture and storage. It was unexpectedly found that when attempting to make acid salts of certain boronic acid immunoproteasome inhibitor compounds, cyclic boronate esters were formed. In addition, some of these esters have been shown to be more stable than the corresponding acids, have greater crystallinity, or both.

[0008] Thus, in one aspect, provided herein are cyclic boronate esters and salts thereof for use in treating disorders associated with LMP2 and / or LMP7. Summary of the invention

[0009] In certain embodiments, described herein are cyclic boronates that are useful as immunoproteasome inhibitors.

[0010] Example 1. A compound having formula (I) or a pharmaceutically acceptable salt thereof, in A is an optionally substituted monocyclic or bicyclic heterocycle containing at least one nitrogen atom bonded to a methylene unit; Y is an optionally substituted monocyclic or bicyclic heterocycle containing at least one nitrogen atom bonded to a carbonyl group; X is a borate ester bonded to a methylene unit via a boron atom and selected from the group consisting of citrate, pinacol ester, malate, salicylate, lactate, and tartrate; and n is 0 or 1.

[0011] Embodiment 2. The compound according to embodiment 1, wherein A is an optionally substituted monocyclic or bicyclic 5-membered or 6-membered heterocycle.

[0012] Embodiment 3. A compound according to any one of the preceding embodiments, wherein A is selected from optionally substituted pyrrolidinyl and optionally substituted morpholinyl.

[0013] Embodiment 4. A compound according to any one of the preceding embodiments, wherein A is selected from:

[0014] Embodiment 5. A compound according to any one of the preceding embodiments, wherein Y is an optionally substituted monocyclic or bicyclic 6- or 7-membered heterocycle.

[0015] Embodiment 6. A compound according to any one of the preceding embodiments, wherein Y is selected from piperidinyl, azepanyl and 7-azabicyclo[2.2.1]hept-7-yl, each of which is optionally substituted.

[0016] Embodiment 7. A compound according to any one of the preceding embodiments, wherein Y is selected from:

[0017] Embodiment 8. A compound according to any one of the preceding embodiments, wherein X is boron citrate.

[0018] Embodiment 9. A compound according to any one of the preceding embodiments, wherein X is selected from:

[0019] Embodiment 10. A compound prepared by reacting a compound having formula (i) or a pharmaceutically acceptable salt thereof with a reagent selected from citric acid, malic acid, salicylic acid, lactic acid, tartaric acid and pinacol, wherein formula (i) is: in, A is an optionally substituted monocyclic or bicyclic heterocycle containing at least one nitrogen atom bonded to a methylene unit; Y is an optionally substituted monocyclic or bicyclic heterocycle containing at least one nitrogen atom bonded to the carbonyl group; and n is 0 or 1.

[0020] Embodiment 11. The compound according to embodiment 10, wherein A is an optionally substituted monocyclic or bicyclic 5- or 6-membered heterocycle.

[0021] Embodiment 12. The compound according to embodiment 10 or 11, wherein A is selected from:

[0022] Embodiment 13. A compound according to any one of embodiments 10-12, wherein Y is an optionally substituted monocyclic or bicyclic 6- or 7-membered heterocycle.

[0023] Embodiment 14. A compound according to any one of embodiments 10-13, wherein Y is selected from

[0024] Embodiment 15. The compound according to any one of embodiments 10-14, wherein the agent is citric acid.

[0025] Embodiment 16. A compound selected from:

[0026] Embodiment 17. The compound according to embodiment 16, which is selected from

[0027] Example 18. A boric acid ester of ((R)-1-(((((R)-1-(2-cyano-4-methyl-4-((R)-2-methylmorpholino)pent-2-enoyl)azepan-3-yl)oxy)carbonyl)amino)-2-phenylethyl)boronic acid or a pharmaceutically acceptable salt thereof, wherein the ester is selected from citrate, pinacol, malate, salicylate, lactate, and tartrate.

[0028] Example 19. A boric acid ester of ((R)-1-(((((R)-1-((E)-2-cyano-4-methyl-4-((R)-2-methylmorpholino)pent-2-enoyl)azepan-3-yl)oxy)carbonyl)amino)-2-phenylethyl)boronic acid or a pharmaceutically acceptable salt thereof, wherein the ester is selected from citrate, pinacol, malate, salicylate, lactate, and tartrate.

[0029] Example 20. A boric acid ester of [(1R)-1-[([[7-(2-cyano-2-[2-methyl-2-[(2S)-2-methylmorpholin-4-yl]propylidene]acetyl)-7-azabicyclo[2.2.1]hept-1-yl]methoxy]carbonyl)amino]-2-phenylethyl]boronic acid or a pharmaceutically acceptable salt thereof, wherein the ester is selected from citrate, pinacol ester, malate, salicylate, lactate, and tartrate.

[0030] Example 21. A boric acid ester of ((R)-1-(((((R)-1-(2-cyano-4-(3,3-difluoropyrrolidin-1-yl)-4-methylpent-2-enoyl)piperidin-2-yl)methoxy)carbonyl)amino)-2-phenylethyl)boronic acid or a pharmaceutically acceptable salt thereof, wherein the ester is selected from citrate, pinacol, malate, salicylate, lactate, and tartrate.

[0031] Embodiment 22. The borate ester of any of embodiments 18-21, wherein the ester is a citrate ester.

[0032] Embodiment 23. A boronate ester of ((R)-1-(((((R)-1-(2-cyano-4-methyl-4-((R)-2-methylmorpholino)pent-2-enoyl)azepan-3-yl)oxy)carbonyl)amino)-2-phenylethyl)boronic acid or a pharmaceutically acceptable salt thereof, wherein the ester is converted to its corresponding acid upon exposure to physiological conditions.

[0033] Example 24. A boric acid ester of ((R)-1-(((((R)-1-(2-cyano-4-methyl-4-((R)-2-methylmorpholino)pent-2-enoyl)azepan-3-yl)oxy)carbonyl)amino)-2-phenylethyl)boronic acid or a pharmaceutically acceptable salt thereof, wherein the ester is stable at 40°C and 75% relative humidity for at least three weeks.

[0034] Example 25. A boric acid ester of ((R)-1-(((((R)-1-((E)-2-cyano-4-methyl-4-((R)-2-methylmorpholino)pent-2-enoyl)azepan-3-yl)oxy)carbonyl)amino)-2-phenylethyl)boronic acid or a pharmaceutically acceptable salt thereof wherein the ester is a citrate and is at least about 95% pure.

[0035] Embodiment 26. The boric acid ester of embodiment 25, wherein the ester is at least about 99% pure.

[0036] Example 27. A crystalline form of ((R)-1-(((((R)-1-((E)-2-cyano-4-methyl-4-((R)-2-methylmorpholino)pent-2-enoyl)azepan-3-yl)oxy)carbonyl)amino)-2-phenylethyl)boronic acid citrate, wherein the crystalline form is Form I, characterized in that the X-ray powder diffraction pattern comprises at least three peaks selected from the group consisting of peaks at approximately 6.6±0.2, 11.2±0.2, 13.2±0.2, 13.8±0.2, 14.3±0.2, 15.6±0.2, 16.8±0.2, 17.5±0.2, 18.5±0.2, and 19.0±0.2 2-θ.

[0037] Embodiment 28. The crystalline form I according to embodiment 27, characterized in that the X-ray powder diffraction pattern is Figure 6 The X-ray powder diffraction patterns in are basically similar.

[0038] Embodiment 29. Form I according to Embodiment 27 or 28, characterized in that the DSC thermogram has a peak endotherm at about 192.7°C.

[0039] Embodiment 30. Form I according to any one of Embodiments 27-29, characterized in that the DSC thermogram shows a melting onset at about 179.5°C.

[0040] Embodiment 31. The crystalline form I according to any one of embodiments 27-30, characterized in that the DSC thermogram is Figure 7 The DSC thermograms in are basically similar.

[0041] Embodiment 32. Form I according to any one of Embodiments 27-31, characterized in that the mass loss between about 25°C and about 150°C by thermogravimetric analysis is less than about 0.5 wt.%.

[0042] Embodiment 33. The crystalline form I according to any one of embodiments 27-32, characterized in that the TGA thermogram is Figure 7 The TGA thermograms in are basically similar.

[0043] Example 34. A crystalline form of (I-1-((((((R)-1-((E)-2-cyano-4-methyl-4-((R)-2-methylmorpholino)pent-2-enoyl)azepan-3-yl)oxy)carbonyl)amino)-2-phenylethyl)boronic acid citrate, wherein the crystalline form is Form II, characterized in that the X-ray powder diffraction pattern comprises at least three peaks selected from the group consisting of peaks at approximately 6.1±0.2, 8.1±0.2, 10.6±0.2, 11.0±0.2, 11.9±0.2, 14.0±0.2, 14.7±0.2, 16.6±0.2, 43.7±0.2, and 18.4±0.2 2-θ.

[0044] Embodiment 35. Form II according to embodiment 34, characterized in that the X-ray powder diffraction pattern is Figure 8 The X-ray powder diffraction patterns in are basically similar.

[0045] Embodiment 36. Form II according to Embodiment 34 or 35, characterized in that the DSC thermogram has a peak endotherm at about 173.7°C.

[0046] Embodiment 37. Form II according to any one of Embodiments 34-36, characterized in that the DSC thermogram shows a melting onset at about 164.9°C.

[0047] Embodiment 38. Form II according to any one of Embodiments 34-37, characterized in that the DSC thermogram is Fig. 9 The DSC thermograms in are basically similar.

[0048] Embodiment 39. Form II according to any one of embodiments 34-38, characterized in that the mass loss between about 25° C. and about 110° C. by thermogravimetric analysis is about 5.6 wt.%.

[0049] Embodiment 40. The crystalline form II according to any one of embodiments 34-39, characterized in that the TGA thermogram is Fig. 9 The TGA thermograms in are basically similar.

[0050] Embodiment 41. Form I according to any one of embodiments 27-33, which is prepared by contacting Form II according to any one of embodiments 34-40 with an alcohol or an alcohol mixture.

[0051] Example 42. A crystalline form of ((R)-1-(((((R)-1-((E)-2-cyano-4-methyl-4-((R)-2-methylmorpholino)pent-2-enoyl)azepan-3-yl)oxy)carbonyl)amino)-2-phenylethyl)boronic acid citrate, wherein the crystalline form is Form III, characterized in that the X-ray powder diffraction pattern comprises at least three peaks selected from the group consisting of peaks at approximately 5.9±0.2, 6.9±0.2, 9.4±0.2, 10.5±0.2, 11.1±0.2, 12.3±0.2, 12.7±0.2, 13.8±0.2, 14.3±0.2, and 15.2±0.2 2-θ.

[0052] Embodiment 43. The crystalline form III according to embodiment 42, characterized in that the X-ray powder diffraction pattern is Fig.10 The X-ray powder diffraction patterns in are basically similar.

[0053] Embodiment 44. Form III according to Embodiment 42 or 43, characterized in that the DSC thermogram has a peak endotherm at about 176.5°C.

[0054] Embodiment 45. The crystalline form III according to any one of embodiments 42-44, characterized in that the DSC thermogram has a broad endothermic peak from about 37.9°C to about 100°C.

[0055] Embodiment 46. Form III according to Embodiment 45, wherein the broad endothermic peak has a peak at about 70.4°C.

[0056] Embodiment 47. Form III according to any one of Embodiments 42-46, characterized in that the DSC thermogram is Fig.11 The DSC thermograms in are basically similar.

[0057] Embodiment 48. Form III according to any one of Embodiments 42-47, characterized in that the mass loss between about 25° C. and about 105° C. is about 3.1 wt.% by thermogravimetric analysis.

[0058] Embodiment 49. The crystalline form III according to any one of embodiments 42-48, characterized in that the TGA thermogram is Fig.11 The TGA thermograms in are basically similar.

[0059] Embodiment 50. Form III according to any one of embodiments 42-49, prepared by a method comprising contacting an alkyl ester, ether and / or toluene with Form II according to any one of embodiments 34-40.

[0060] Embodiment 51. Form III prepared by the method according to Embodiment 50, wherein the alkyl ester is isopropyl acetate.

[0061] Embodiment 52. Form III prepared by the method according to Embodiment 50 or 51, wherein the method further comprises separating Form III from the alkyl ester.

[0062] Embodiment 53. A pharmaceutical composition comprising at least one compound according to any one of Embodiments 1-17 and a pharmaceutically acceptable excipient.

[0063] Embodiment 54. A pharmaceutical composition comprising at least one borate ester according to any one of embodiments 18-26 and a pharmaceutically acceptable excipient.

[0064] Embodiment 55. A pharmaceutical composition comprising at least one crystalline form of the citrate ester of ((R)-1-(((((R)-1-((E)-2-cyano-4-methyl-4-((R)-2-methylmorpholino)pent-2-enoyl)azepan-3-yl)oxy)carbonyl)amino)-2-phenylethyl)boronic acid according to any one of Embodiments 27-52 and a pharmaceutically acceptable excipient.

[0065] Embodiment 56. A method of inhibiting large multifunctional protease 2 (LMP2) in a subject, the method comprising administering to the subject in need of said inhibition a therapeutically effective amount of a compound according to any one of embodiments 1-17, at least one boronic acid ester according to any one of embodiments 18-26, or at least one crystalline form of a citrate ester of ((R)-1-(((((R)-1-((E)-2-cyano-4-methyl-4-((R)-2-methylmorpholino)pent-2-enoyl)azepan-3-yl)oxy)carbonyl)amino)-2-phenylethyl)boronic acid according to any one of embodiments 27-52.

[0066] Embodiment 57. A method of inhibiting large multifunctional protease 7 (LMP7) in a subject, the method comprising administering to the subject in need of said inhibition a therapeutically effective amount of a compound according to any one of embodiments 1-17, at least one boronic acid ester according to any one of embodiments 18-26, or at least one crystalline form of a citrate ester of ((R)-1-(((((R)-1-((E)-2-cyano-4-methyl-4-((R)-2-methylmorpholino)pent-2-enoyl)azepan-3-yl)oxy)carbonyl)amino)-2-phenylethyl)boronic acid according to any one of embodiments 27-52.

[0067] Embodiment 58. A method of treating a disease selected from an autoimmune disorder, an inflammatory disorder, and a hematological disorder in a patient in need of such treatment, the method comprising administering to the patient a therapeutically effective amount of a compound according to any one of embodiments 1-17, at least one boronic acid ester according to any one of embodiments 18-26, or at least one crystalline form of a citrate ester of ((R)-1-(((((R)-1-((E)-2-cyano-4-methyl-4-((R)-2-methylmorpholino)pent-2-enoyl)azepan-3-yl)oxy)carbonyl)amino)-2-phenylethyl)boronic acid according to any one of embodiments 27-52.

[0068] Embodiment 59. The method of embodiment 58, wherein the disease is selected from lupus, arthritis including rheumatoid arthritis and psoriatic arthritis, scleroderma, ankylosing spondylitis, Duchenne muscular dystrophy (DMD), Becker muscular dystrophy (BMD), idiopathic inflammatory myopathy (IIM), polymyositis, sporadic inclusion body myositis, dermatomyositis, immune-mediated necrotizing myopathy (IMNM), psoriasis, multiple sclerosis, inflammatory bowel disease, Behcet's disease, ulcerative colitis, Crohn's disease, Sjogren's syndrome, bronchitis, conjunctivitis, pancreatitis, cholecystitis, bronchiectasis, aortic stenosis, restenosis, fibrosis, infection, ischemia, cardiovascular disease, hepatitis, cirrhosis, steatohepatitis, liver inflammation, Alzheimer's disease (AD), amyotrophic lateral sclerosis (ALS), Huntington's disease, body myositis, myofibrillar myopathy, graft versus host disease (GVHD), and multiple myeloma.

[0069] Embodiment 60. Use of a composition as a medicament for inhibiting large multifunctional protease 2 (LMP2) in a subject, wherein the composition comprises a therapeutically effective amount of a compound according to any one of embodiments 1-17, at least one boronic acid ester according to any one of embodiments 18-26, or at least one crystalline form of the citrate ester of ((R)-1-(((((R)-1-((E)-2-cyano-4-methyl-4-((R)-2-methylmorpholino)pent-2-enoyl)azepan-3-yl)oxy)carbonyl)amino)-2-phenylethyl)boronic acid according to any one of embodiments 27-52.

[0070] Example 61. Use of a composition as a medicament for inhibiting large multifunctional protease 7 (LMP7) in a subject, wherein the composition comprises a therapeutically effective amount of a compound according to any one of Examples 1-17, at least one boronate ester according to any one of Examples 18-26, or at least one crystalline form of a citrate ester of ((R)-1-(((((R)-1-((E)-2-cyano-4-methyl-4-((R)-2-methylmorpholino)pent-2-enoyl)azepan-3-yl)oxy)carbonyl)amino)-2-phenylethyl)boronic acid according to any one of Examples 27-52.

[0071] Embodiment 62. Use of a composition as a medicament for treating a disease in a subject in need thereof, wherein the composition comprises administering to the patient a therapeutically effective amount of a compound according to any one of embodiments 1-17, at least one boronic acid ester according to any one of embodiments 18-26, or at least one crystalline form of a citrate ester of ((R)-1-(((((R)-1-((E)-2-cyano-4-methyl-4-((R)-2-methylmorpholino)pent-2-enoyl)azepan-3-yl)oxy)carbonyl)amino)-2-phenylethyl)boronic acid according to any one of embodiments 27-52; and wherein the disease is selected from an autoimmune disorder, an inflammatory disorder, and a hematological disorder.

[0072] Embodiment 63. The use according to embodiment 62, wherein the disease is selected from lupus, arthritis including rheumatoid arthritis and psoriatic arthritis, scleroderma, ankylosing spondylitis, Duchenne muscular dystrophy (DMD), Becker muscular dystrophy (BMD), idiopathic inflammatory myopathy (IIM), polymyositis, sporadic inclusion body myositis, dermatomyositis, immune-mediated necrotizing myopathy (IMNM), psoriasis, multiple sclerosis, inflammatory bowel disease, Behcet's disease, ulcerative colitis, Crohn's disease, Sjogren's syndrome, bronchitis, conjunctivitis, pancreatitis, cholecystitis, bronchiectasis, aortic stenosis, restenosis, fibrosis, infection, ischemia, cardiovascular disease, hepatitis, cirrhosis, steatohepatitis, liver inflammation, Alzheimer's disease (AD), amyotrophic lateral sclerosis (ALS), Huntington's disease, body myositis, myofibrillar myopathy, graft-versus-host disease (GVHD), and multiple myeloma. BRIEF DESCRIPTION OF THE DRAWINGS

[0073] Figure 1 An exemplary NMR spectrum of the pinacol ester of ((R)-1-(((((R)-1-(2-cyano-4-methyl-4-((R)-2-methylmorpholino)pent-2-enoyl)azepan-3-yl)oxy)carbonyl)amino)-2-phenylethyl)boronic acid is provided.

[0074] Figure 2The NMR spectrum of the citrate ester of [(1R)-1-[([[7-(2-cyano-2-[2-methyl-2-[(2S)-2-methylmorpholin-4-yl]propylidene]acetyl)-7-azabicyclo[2.2.1]hept-1-yl]methoxy]carbonyl)amino]-2-phenylethyl]boronic acid is provided.

[0075] Figure 3 The NMR spectrum of boronic acid 3 from Example 5 is provided.

[0076] Figure 4 The NMR spectrum of the citrate ester of ((R)-1-(((((R)-1-(2-cyano-4-(3,3-difluoropyrrolidin-1-yl)-4-methylpent-2-enoyl)piperidin-2-yl)methoxy)carbonyl)amino)-2-phenylethyl)boronic acid is provided.

[0077] Figure 5 The NMR spectrum of the salicylate of ((R)-1-(((((R)-1-(2-cyano-4-(3,3-difluoropyrrolidin-1-yl)-4-methylpent-2-enoyl)piperidin-2-yl)methoxy)carbonyl)amino)-2-phenylethyl)boronic acid is provided.

[0078] Figure 6 An X-ray powder diffraction pattern of Form I of citrate ester of ((R)-1-(((((R)-1-((E)-2-cyano-4-methyl-4-((R)-2-methylmorpholino)pent-2-enoyl)azepan-3-yl)oxy)carbonyl)amino)-2-phenylethyl)boronic acid is provided.

[0079] Figure 7 Provided are the TGA thermogram and DSC thermogram of Form I of the citrate ester of ((R)-1-(((((R)-1-((E)-2-cyano-4-methyl-4-((R)-2-methylmorpholino)pent-2-enoyl)azepan-3-yl)oxy)carbonyl)amino)-2-phenylethyl)boronic acid.

[0080] Figure 8 An X-ray powder diffraction pattern of Form II of citrate ester of ((R)-1-(((((R)-1-((E)-2-cyano-4-methyl-4-((R)-2-methylmorpholino)pent-2-enoyl)azepan-3-yl)oxy)carbonyl)amino)-2-phenylethyl)boronic acid is provided.

[0081] Fig. 9Provided are the TGA thermogram and DSC thermogram of Form II of the citrate ester of ((R)-1-(((((R)-1-((E)-2-cyano-4-methyl-4-((R)-2-methylmorpholino)pent-2-enoyl)azepan-3-yl)oxy)carbonyl)amino)-2-phenylethyl)boronic acid.

[0082] Fig.10 An X-ray powder diffraction pattern of Form III of citrate ester of ((R)-1-(((((R)-1-((E)-2-cyano-4-methyl-4-((R)-2-methylmorpholino)pent-2-enoyl)azepan-3-yl)oxy)carbonyl)amino)-2-phenylethyl)boronic acid is provided.

[0083] Fig.11 Provided are the TGA thermogram and DSC thermogram of Form III of the citrate ester of ((R)-1-(((((R)-1-((E)-2-cyano-4-methyl-4-((R)-2-methylmorpholino)pent-2-enoyl)azepan-3-yl)oxy)carbonyl)amino)-2-phenylethyl)boronic acid.

[0084] Fig.12 An X-ray powder diffraction pattern of Form IV of citrate ester of ((R)-1-(((((R)-1-((E)-2-cyano-4-methyl-4-((R)-2-methylmorpholino)pent-2-enoyl)azepan-3-yl)oxy)carbonyl)amino)-2-phenylethyl)boronic acid is provided.

[0085] Fig.13 Provided are the TGA thermogram and DSC thermogram of Form IV of the citrate ester of ((R)-1-(((((R)-1-((E)-2-cyano-4-methyl-4-((R)-2-methylmorpholino)pent-2-enoyl)azepan-3-yl)oxy)carbonyl)amino)-2-phenylethyl)boronic acid.

[0086] Fig.14 An X-ray powder diffraction pattern of Form V of citrate ester of ((R)-1-(((((R)-1-((E)-2-cyano-4-methyl-4-((R)-2-methylmorpholino)pent-2-enoyl)azepan-3-yl)oxy)carbonyl)amino)-2-phenylethyl)boronic acid is provided.

[0087] Fig.15 Provided are the TGA thermogram and DSC thermogram of Form V of citrate ester of ((R)-1-(((((R)-1-((E)-2-cyano-4-methyl-4-((R)-2-methylmorpholino)pent-2-enoyl)azepan-3-yl)oxy)carbonyl)amino)-2-phenylethyl)boronic acid. DETAILED DESCRIPTION definition

[0088] Unless otherwise defined, all technical terms and scientific terms used herein have the same meanings as those generally understood by those skilled in the art to which the claimed subject belongs. It should be understood that the foregoing general description and the following specific embodiments are only exemplary and explanatory, and do not limit any subject matter claimed. To the extent that any material incorporated herein by reference is inconsistent with the explicit content of this disclosure, the explicit content shall prevail. In this application, unless otherwise explicitly stated, the use of the singular includes the plural. It must be noted that, unless the context clearly stipulates otherwise, as used in this specification and the appended claims, the singular forms "a / an" and "the" include plural indicators. In this application, unless the context requires otherwise, the use of "or" means "and / or". In addition, the use of the term "including" and other forms such as "include", "includes" and "included" is not restrictive.

[0089] Reference in this specification to "some embodiments," "embodiments," "one embodiment," or "other embodiments" means that a particular feature, structure, or characteristic described in connection with the embodiments is included in at least some embodiments, but not necessarily all embodiments of the invention.

[0090] As used herein, ranges and amounts can be expressed as "about" a particular value or range. About also includes an exact amount. Thus, "about 5 μL" means "about 5 μL" as well as "5 μL". Typically, the term "about" includes amounts that are expected to be within experimental error, such as, for example, within 15%, 10%, or 5%.

[0091] The section headings used herein are for organizational purposes only and are not to be construed as limiting the subject matter described.

[0092] "Alkyl" refers to an unbranched or branched saturated hydrocarbon chain. As used herein, an alkyl group has 1 to 20 carbon atoms (i.e., C 1 -C 20 alkyl), 1 to 10 carbon atoms (i.e., C 1 -C 10 alkyl), 1 to 6 carbon atoms (i.e., C 1 -C 6 alkyl) or 1 to 3 carbon atoms (i.e., C 1 -C 3Alkyl). Examples of alkyl groups include methyl, ethyl, propyl, isopropyl, n-butyl, sec-butyl, isobutyl, tert-butyl, pentyl, 2-pentyl, isopentyl, neopentyl, hexyl, 2-hexyl, 3-hexyl, and 3-methylpentyl. When an alkyl residue having a particular number of carbon atoms is designated by chemical name or identified by molecular formula, all positional isomers having that number of carbon atoms are contemplated; thus, for example, "butyl" includes n-butyl (i.e., -(CH 2 ) 3 CH 3 ), isobutyl (i.e., -CH 2 CH(CH 3 ) 2 ), sec-butyl (i.e., -CH(CH 3 )CH 2 CH 3 ), and tert-butyl (i.e., -C(CH 3 ) 3 ); and "propyl" includes n-propyl (i.e., -(CH 2 ) 2 CH 3 ) and isopropyl (i.e., -CH(CH 3 ) 2 ).

[0093] "Methylene" refers to -CH 2 -group.

[0094] "Carbonyl" refers to a -C(=O)- group.

[0095] The term "heterocyclic radical" or "heterocycle" refers to a saturated or unsaturated cyclic alkyl radical having one or more ring heteroatoms independently selected from nitrogen, oxygen and sulfur. The term "heterocyclic radical" includes heterocyclic alkenyl (i.e., heterocyclic radicals with at least one double bond), bridged heterocyclic radicals, fused heterocyclic radicals and spiro heterocyclic radicals. The heterocyclic radical can be a single ring or multiple rings, wherein multiple rings can be fused, bridged or spiral, and can include one or more oxo (C=O) or N-oxide (NO-) parts. Any non-aromatic ring containing at least one heteroatom is considered to be a heterocyclic radical, regardless of attachment (i.e., can be bonded by carbon atoms or heteroatoms). In addition, the term heterocyclic radical is intended to encompass any non-aromatic ring containing at least one heteroatom, which ring can be fused to an aryl or heteroaryl ring, regardless of attachment to the rest of the molecule. As used herein, a heterocyclic radical has 1 to 10 ring carbon atoms, 1 to 8 carbon atoms, 1 to 6 carbon atoms, or 1 to 4 carbon atoms. As used herein, a heterocyclyl group has 1 to 5 ring heteroatoms, 1 to 4 heteroatoms, 1 to 3 heteroatoms, or 1 to 2 heteroatoms independently selected from nitrogen, sulfur, and oxygen. Examples of heterocyclic groups include azepanyl, 7-azabicyclo[2.2.1]hept-7-yl, dioxolanyl, thienyl[1,3]dithianyl, decahydroisoquinolinyl, imidazolinyl, imidazolidinyl, isothiazolidinyl, isoxazolidinyl, morpholinyl, octahydroindolyl, octahydroisoindolyl, 2-oxopiperazinyl, 2-oxopiperidinyl, 2-oxopyrrolidinyl, oxazolidinyl, piperidinyl, piperazinyl, 4-piperidonyl, pyrrolidinyl, pyrazolidinyl, quinuclidinyl, thiazolidinyl, tetrahydrofuranyl, trithianyl, tetrahydropyranyl, thiomorpholinyl, thimorpholinyl, 1-oxo-thiomorpholinyl, and 1,1-dioxo-thiomorpholinyl.

[0096] As used herein, when referring to a heterocyclic group, the term "optionally substituted" refers to a heterocyclic group in which one or more hydrogen atoms on carbon or on a heteroatom are replaced by alkyl, halogen, cyano or hydroxy.

[0097] "Cyano" refers to the radical -CN.

[0098] "Halogen" or "halo" includes fluorine, chlorine, bromine, and iodine.

[0099] "Hydroxy" refers to the radical -OH.

[0100] Certain commonly used alternative chemical names may be used. For example, divalent groups such as divalent "alkyl", divalent "phenyl", divalent "heteroaryl", divalent "heterocyclyl", etc. may also be referred to as "alkylene", "phenylene", "heteroarylene", or "heterocyclylene", respectively.

[0101] The term "optional" or "optionally" means that the subsequently described event or circumstance may or may not occur, and that the description includes instances where said event or circumstance occurs and instances where it does not.

[0102] "Pharmaceutically acceptable" refers to compounds, salts, compositions, dosage forms, and other materials that are useful in preparing pharmaceutical compositions suitable for human pharmaceutical use.

[0103] The term "pharmaceutically acceptable salt" of a given compound refers to salts that retain the biological effectiveness and properties of the given compound and which are not biologically or otherwise undesirable.

[0104] The compounds described herein, or their pharmaceutically acceptable salts, may contain asymmetric centers and may therefore give rise to enantiomers, diastereomers, and other stereoisomeric forms which may be defined with respect to absolute stereochemistry as (R)- or (S)-, or, for amino acids, as (D)- or (L)-. The disclosure is intended to include all such possible isomers and their racemic and optically pure forms. Optically active (+) and (-), (R)- and (S)-, or (D)- and (L)-isomers may be prepared using chiral synthons or chiral reagents, or resolved using conventional techniques (e.g., chromatography and fractional crystallization). Conventional techniques for preparing / isolating individual enantiomers include chiral synthesis from suitable optically pure precursors or resolution of the racemate (or racemate of a salt or derivative) using, for example, chiral high pressure liquid chromatography (HPLC).

[0105] "Tautomers" refers to alternative forms of a compound that differ in the position of a proton, such as enol-keto and imine-enamine tautomers, or tautomeric forms of heteroaryl groups containing ring atoms attached to both the ring-NH- portion and the ring=N portion, such as pyrazole, imidazole, benzimidazole, triazole, and tetrazole. All tautomeric forms of the compounds described herein are intended to be included.

[0106] "Stereoisomers" refer to compounds made up of the same atoms bonded by the same bonds but with different three-dimensional structures that are not interchangeable. The present disclosure contemplates various stereoisomers and mixtures thereof, and includes "enantiomers," which refer to two stereoisomers whose molecules are non-superimposable mirror images of one another.

[0107] "Diastereomers" are stereoisomers that have at least two asymmetric atoms, but which are not mirror images of each other.

[0108] As used herein, "pharmaceutically acceptable carrier" or "pharmaceutically acceptable excipient" or "excipient" includes any and all solvents, dispersion media, coatings, antibacterial and antifungal agents, isotonic and absorption delaying agents, and the like. The use of such media and agents for pharmaceutically active substances is well known in the art. Unless any conventional media or agent is incompatible with the active ingredient, its use in the therapeutic composition is contemplated. Supplementary active ingredients may also be incorporated into the composition.

[0109] An "effective amount" or dose of a compound or composition is that amount of the compound or composition that results in the desired result. The effective amount can be determined by standard pharmaceutical procedures in cell cultures or experimental animals, including but not limited to determining the LD 50 (a dose lethal to 50% of the population) and ED 50 (the dose that is therapeutically effective in 50% of the population).

[0110] A "therapeutically effective amount" or dosage of a compound or composition refers to that amount of the compound or composition that results in a reduction or inhibition of symptoms or a prolongation of survival in a subject (ie, a human patient). Multiple doses of the compound or composition may be required as a result.

[0111] "Treating" or "treatment" of a disease of a subject refers to 1) preventing the disease from occurring in a patient who is susceptible to the disease or who does not yet show symptoms of the disease; 2) inhibiting the disease or preventing its development; or 3) ameliorating the disease or causing regression of the disease. As used herein, "treatment" or "treating" is a method for obtaining a beneficial or desired result (including a clinical result). For the purposes of this disclosure, a beneficial or desired result includes, but is not limited to, one or more of the following: reducing one or more symptoms caused by a disease or disorder, reducing the extent of the disease or disorder, stabilizing the disease or disorder (e.g., preventing or delaying the deterioration of the disease or disorder), delaying the occurrence or recurrence of the disease or disorder, delaying or slowing the progression of the disease or disorder, improving the disease or disorder state, providing relief from the disease or disorder (whether partial or complete), reducing the dose of one or more other agents required to treat the disease or disorder, enhancing the effect of another agent used to treat the disease or disorder, delaying the progression of the disease or disorder, improving the quality of life, and / or prolonging the survival of the subject. "Treatment" also encompasses reducing the pathological consequences of the disease or disorder. The methods of the present invention contemplate any one or more of these therapeutic aspects.

[0112] As used herein, the terms "subject" and "patient" mean any mammal. In some embodiments, the mammal is a human. None of these terms require or are limited to situations characterized by supervision (e.g., continuous or intermittent) by a medical professional (e.g., a physician, a registered nurse, a licensed nurse, a physician's assistant, a caregiver, or a hospice staff member).

[0113] As used herein, the term "pharmaceutical composition" or "medicament" refers to a composition suitable for pharmaceutical use in a subject.

[0114] Although various features of the present invention may be described in the context of a single embodiment, these features may also be provided separately or in any suitable combination. Conversely, although the invention may be described herein in the context of separate embodiments for clarity, the invention may also be implemented in a single embodiment. Compound

[0115] In one aspect, provided herein is a compound having formula (I) or a pharmaceutically acceptable salt thereof: in A is an optionally substituted monocyclic or bicyclic heterocycle containing at least one nitrogen atom bonded to a methylene unit; Y is an optionally substituted monocyclic or bicyclic heterocycle containing at least one nitrogen atom bonded to a carbonyl group; X is a borate ester bonded to a methylene unit via a boron atom and selected from the group consisting of citrate, pinacol ester, malate, salicylate, lactate, and tartrate; and n is 0 or 1.

[0116] In some embodiments, A is an optionally substituted monocyclic or bicyclic 5- or 6-membered heterocycle. In some embodiments, A is an optionally substituted monocyclic or bicyclic 5- or 6-membered heterocycle. In some embodiments, A is an optionally substituted monocyclic or bicyclic 5- or 6-membered heterocycle by at least one alkyl and / or halogen. In some embodiments, A is an optionally substituted monocyclic 5- or 6-membered heterocycle by at least one alkyl and / or halogen. In some embodiments, A is selected from optionally substituted pyrrolidinyl and optionally substituted morpholinyl. In some embodiments, A is optionally substituted pyrrolidinyl or morpholinyl by at least one alkyl and / or halogen. In some embodiments, A is selected from: In some embodiments, A is

[0117] In some embodiments, Y is an optionally substituted monocyclic or bicyclic 6- or 7-membered heterocycle. In some embodiments, Y is an optionally substituted monocyclic or bicyclic 7-membered heterocycle. In some embodiments, Y is an optionally substituted monocyclic or bicyclic 6- or 7-membered heterocycle substituted with at least one alkyl and / or halogen. In some embodiments, Y is an unsubstituted monocyclic or bicyclic 6- or 7-membered heterocycle. In some embodiments, Y is selected from piperidinyl, azepanyl, and 7-azabicyclo [2.2.1] hept-7-yl, each of which is optionally substituted. In some embodiments, Y is selected from piperidinyl, azepanyl, and 7-azabicyclo [2.2.1] hept-7-yl, each of which is unsubstituted. In some embodiments, Y is selected from:

[0118] In some embodiments, X is selected from citrate esters and pinacol esters. In some embodiments, X is borate citrate. In some embodiments, X is selected from:

[0119] In some embodiments, X is selected from: In some embodiments, X is

[0120] In some embodiments, n is 0. In some embodiments, n is 1.

[0121] In one aspect, provided herein is a compound prepared by reacting a compound having formula (i) or a pharmaceutically acceptable salt thereof with a reagent selected from citric acid, malic acid, salicylic acid, lactic acid, tartaric acid and pinacol, wherein formula (i) is: in, A is an optionally substituted monocyclic or bicyclic heterocycle containing at least one nitrogen atom bonded to a methylene unit; Y is an optionally substituted monocyclic or bicyclic heterocycle containing at least one nitrogen atom bonded to the carbonyl group; and n is 0 or 1.

[0122] In some embodiments, A is an optionally substituted monocyclic or bicyclic 5- or 6-membered heterocycle. In some embodiments, A is an optionally substituted monocyclic or bicyclic 5- or 6-membered heterocycle. In some embodiments, A is an optionally substituted monocyclic or bicyclic 5- or 6-membered heterocycle by at least one alkyl and / or halogen. In some embodiments, A is an optionally substituted monocyclic 5- or 6-membered heterocycle by at least one alkyl and / or halogen. In some embodiments, A is selected from optionally substituted pyrrolidinyl and optionally substituted morpholinyl. In some embodiments, A is optionally substituted pyrrolidinyl or morpholinyl by at least one alkyl and / or halogen. In some embodiments, A is selected from: In some embodiments, A is

[0123] In some embodiments, Y is an optionally substituted monocyclic or bicyclic 6- or 7-membered heterocycle. In some embodiments, Y is an optionally substituted monocyclic or bicyclic 7-membered heterocycle. In some embodiments, Y is an optionally substituted monocyclic or bicyclic 6- or 7-membered heterocycle substituted with at least one alkyl and / or halogen. In some embodiments, Y is an unsubstituted monocyclic or bicyclic 6- or 7-membered heterocycle. In some embodiments, Y is selected from piperidinyl, azepanyl, and 7-azabicyclo [2.2.1] hept-7-yl, each of which is optionally substituted. In some embodiments, Y is selected from piperidinyl, azepanyl, and 7-azabicyclo [2.2.1] hept-7-yl, each of which is unsubstituted. In some embodiments, Y is selected from:

[0124] In some embodiments, n is 0. In some embodiments, n is 1.

[0125] In some embodiments, the agent is selected from citrate esters and pinacol esters. In some embodiments, the agent is citric acid.

[0126] In the description herein, it should be understood that each description, variation, embodiment or aspect of a part can be combined with each description, variation, embodiment or aspect of other parts, just as each combination described is specifically and individually listed. For example, each description, variation, embodiment or aspect of Ring A provided herein with Formula (I) and Formula (i) can be combined with each description, variation, embodiment or aspect of X or Y or n, just as each combination is specifically and individually listed.

[0127] In some embodiments, a compound or a pharmaceutically acceptable salt thereof is provided that is selected from the compounds in Table 1. Although certain compounds described in the present disclosure (including in Table 1) are presented as specific stereoisomers and / or in non-stereochemical forms, it should be understood that any or all stereochemical forms of any of the compounds of the present disclosure (including in Table 1) are described herein, including any enantiomeric or diastereomeric forms and any tautomeric or other forms. Table 1.

[0128] In some embodiments, the compound is

[0129] In one aspect, provided herein is a boric acid ester of ((R)-1-(((((R)-1-(2-cyano-4-methyl-4-((R)-2-methylmorpholino)pent-2-enoyl)azepan-3-yl)oxy)carbonyl)amino)-2-phenylethyl)boronic acid or a pharmaceutically acceptable salt thereof, wherein the ester is selected from citrate, pinacol ester, malate, salicylate, lactate, and tartrate. In some embodiments, the ester is selected from pinacol ester and citrate. In some embodiments, the ester is a citrate.

[0130] In one aspect, provided herein is a boric acid ester of ((R)-1-(((((R)-1-((E)-2-cyano-4-methyl-4-((R)-2-methylmorpholino)pent-2-enoyl)azepan-3-yl)oxy)carbonyl)amino)-2-phenylethyl)boronic acid or a pharmaceutically acceptable salt thereof, wherein the ester is selected from citrate, pinacol ester, malate, salicylate, lactate, and tartrate. In some embodiments, the ester is selected from pinacol ester and citrate. In some embodiments, the ester is a citrate.

[0131] In one aspect, provided herein is a boric acid ester of [(1R)-1-[([[7-(2-cyano-2-[2-methyl-2-[(2S)-2-methylmorpholin-4-yl]propylidene]acetyl)-7-azabicyclo[2.2.1]hept-1-yl]methoxy]carbonyl)amino]-2-phenylethyl]boronic acid or a pharmaceutically acceptable salt thereof, wherein the ester is selected from citrate, pinacol ester, malate, salicylate, lactate, and tartrate. In some embodiments, the ester is a citrate.

[0132] In one aspect, provided herein is a boric acid ester of ((R)-1-(((((R)-1-(2-cyano-4-(3,3-difluoropyrrolidin-1-yl)-4-methylpent-2-enoyl)piperidin-2-yl)methoxy)carbonyl)amino)-2-phenylethyl)boronic acid or a pharmaceutically acceptable salt thereof, wherein the ester is selected from citrate, pinacol ester, malate, salicylate, lactate, and tartrate. In some embodiments, the ester is a citrate.

[0133] In one aspect, provided herein is a boric acid ester of ((R)-1-(((((R)-1-(2-cyano-4-methyl-4-((R)-2-methylmorpholino)pent-2-enoyl)azepan-3-yl)oxy)carbonyl)amino)-2-phenylethyl)boronic acid or a pharmaceutically acceptable salt thereof, wherein the ester is converted to its corresponding acid upon exposure to physiological conditions. In some embodiments, the ester is selected from a pinacol ester and a citrate ester. In some embodiments, the ester is a citrate ester.

[0134] In one aspect, provided herein is a boric acid ester of ((R)-1-(((((R)-1-(2-cyano-4-methyl-4-((R)-2-methylmorpholino)pent-2-enoyl)azepan-3-yl)oxy)carbonyl)amino)-2-phenylethyl)boronic acid or a pharmaceutically acceptable salt thereof, wherein the ester is stable at 40° C. and 75% relative humidity for at least three weeks. In some embodiments, the ester is selected from a pinacol ester and a citrate ester. In some embodiments, the ester is a citrate ester.

[0135] In one aspect, provided herein is a boric acid ester of ((R)-1-(((((R)-1-((E)-2-cyano-4-methyl-4-((R)-2-methylmorpholino)pent-2-enoyl)azepan-3-yl)oxy)carbonyl)amino)-2-phenylethyl)boronic acid or a pharmaceutically acceptable salt thereof, wherein the ester is a citrate ester and is at least about 95% pure. In some embodiments, the ester is at least about 96% pure. In some embodiments, the ester is at least about 97% pure. In some embodiments, the ester is at least about 98% pure. In some embodiments, the ester is at least about 99% pure.

[0136] In one aspect, provided herein is a crystalline form of ((R)-1-(((((R)-1-((E)-2-cyano-4-methyl-4-((R)-2-methylmorpholino)pent-2-enoyl)azepan-3-yl)oxy)carbonyl)amino)-2-phenylethyl)boronic acid citrate. In some embodiments, the crystalline form is selected from Form I, Form II, Form III, Form IV, and Form V.

[0137] In some embodiments, the crystalline form of the citrate of ((R)-1-(((((R)-1-((E)-2-cyano-4-methyl-4-((R)-2-methylmorpholino)pent-2-enoyl)azepan-3-yl)oxy)carbonyl)amino)-2-phenylethyl)boronic acid is Form I. In some embodiments, Form I is characterized by an X-ray powder diffraction pattern comprising at least three peaks selected from peaks at about 6.6±0.2, 11.2±0.2, 13.2±0.2, 13.8±0.2, 14.3±0.2, 15.6±0.2, 16.8±0.2, 17.5±0.2, 18.5±0.2, and 19.0±0.2 2-theta. In some embodiments, Form I is characterized by an X-ray powder diffraction pattern comprising at least three peaks selected from peaks at about 6.6±0.2, 11.2±0.2, 13.2±0.2, 13.8±0.2, 14.3±0.2, 15.6±0.2, 16.8±0.2, 17.5±0.2, 18.5±0.2, and 19.0±0.2 2-theta. Figure 6 The X-ray powder diffraction patterns in are basically similar.

[0138] In some embodiments, Form I is characterized by a DSC thermogram having a peak endotherm at about 192.7°C. In some embodiments, Form I is characterized by a DSC thermogram showing a melting onset at about 179.5°C. In some embodiments, Form I is characterized by a DSC thermogram having a peak endotherm at about 192.7°C. Figure 7 The DSC thermograms in are basically similar.

[0139] In some embodiments, Form I is characterized by a mass loss of less than about 0.5 wt.% between about 25°C and about 150°C by thermogravimetric analysis. In some embodiments, Form I is characterized by a TGA thermogram with Figure 7 The TGA thermograms in are basically similar.

[0140] In some embodiments, the crystalline form of the citrate of ((R)-1-(((((R)-1-((E)-2-cyano-4-methyl-4-((R)-2-methylmorpholino)pent-2-enoyl)azepan-3-yl)oxy)carbonyl)amino)-2-phenylethyl)boronic acid is Form II. In some embodiments, Form II is characterized by an X-ray powder diffraction pattern comprising at least three peaks selected from peaks at about 6.1±0.2, 8.1±0.2, 10.6±0.2, 11.0±0.2, 11.9±0.2, 14.0±0.2, 14.7±0.2, 16.6±0.2, 43.7±0.2, and 18.4±0.2 2-θ. In some embodiments, Form II is characterized by an X-ray powder diffraction pattern comprising at least three peaks selected from peaks at about 6.1±0.2, 8.1±0.2, 10.6±0.2, 11.0±0.2, 11.9±0.2, 14.0±0.2, 14.7±0.2, 16.6±0.2, 43.7±0.2, and 18.4±0.2 2-θ. Figure 8 The X-ray powder diffraction patterns in are basically similar.

[0141] In some embodiments, Form II is characterized by a DSC thermogram having a peak endotherm at about 173.7°C. In some embodiments, Form II is characterized by a DSC thermogram showing a melting onset at about 164.9°C. In some embodiments, Form II is characterized by a DSC thermogram having a peak endotherm at about 173.7°C. Fig. 9 The DSC thermograms in are basically similar.

[0142] In some embodiments, Form II is characterized by a mass loss of about 5.6 wt.% between about 25°C and about 110°C by thermogravimetric analysis. In some embodiments, Form II is characterized by a TGA thermogram with Fig. 9 The TGA thermograms in are basically similar.

[0143] In some embodiments, Type I is prepared by contacting Form II with an alcohol or an alcohol mixture. In some embodiments, Type I is prepared by contacting Form III with an alcohol or an alcohol mixture. In some embodiments, the alcohol is EtOH. In some embodiments, the alcohol mixture comprises EtOH. In some embodiments, the alcohol mixture comprises EtOH and IPA.

[0144] In some embodiments, the crystalline form of the citrate of ((R)-1-(((((R)-1-((E)-2-cyano-4-methyl-4-((R)-2-methylmorpholino)pent-2-enoyl)azepan-3-yl)oxy)carbonyl)amino)-2-phenylethyl)boronic acid is Form III. In some embodiments, Form III is characterized by an X-ray powder diffraction pattern comprising at least three peaks selected from peaks at about 5.9±0.2, 6.9±0.2, 9.4±0.2, 10.5±0.2, 11.1±0.2, 12.3±0.2, 12.7±0.2, 13.8±0.2, 14.3±0.2, and 15.2±0.2 2-θ. In some embodiments, Form III is characterized by an X-ray powder diffraction pattern comprising at least three peaks selected from peaks at about 5.9±0.2, 6.9±0.2, 9.4±0.2, 10.5±0.2, 11.1±0.2, 12.3±0.2, 12.7±0.2, 13.8±0.2, 14.3±0.2, and 15.2±0.2 2-θ. Fig.10 The X-ray powder diffraction patterns in are basically similar.

[0145] In some embodiments, Form III is characterized by a DSC thermogram having a peak endotherm at about 176.5°C. In some embodiments, Form III is characterized by a DSC thermogram having a broad endotherm from about 37.9°C to about 100°C. In some embodiments, the broad endotherm peaks at about 70.4°C. In some embodiments, Form III is characterized by a DSC thermogram having a peak endotherm from about 176.5°C. Fig.11 The DSC thermograms in are basically similar.

[0146] In some embodiments, Form III is characterized by a mass loss of about 3.1 wt.% between about 25°C and about 105°C by thermogravimetric analysis. In some embodiments, Form III is characterized by a TGA thermogram with Fig.11 The TGA thermograms in are basically similar.

[0147] In some embodiments, Form III is prepared by a process comprising contacting an alkyl ester, an ether, and / or toluene with Form II. In some embodiments, the alkyl ester is selected from ethyl acetate and isopropyl acetate. In some embodiments, the alkyl ester is isopropyl acetate. In some embodiments, the ether is methyl tert-butyl ether.

[0148] In some embodiments, the method further comprises separating Form III from an alkyl ester, an ether and / or toluene. In some embodiments, the alkyl ester is selected from ethyl acetate and isopropyl acetate. In some embodiments, the alkyl ester is isopropyl acetate. In some embodiments, the ether is methyl tert-butyl ether.

[0149] In some embodiments, the crystalline form of the citrate ester of ((R)-1-(((((R)-1-((E)-2-cyano-4-methyl-4-((R)-2-methylmorpholino)pent-2-enoyl)azepan-3-yl)oxy)carbonyl)amino)-2-phenylethyl)boronic acid is Form IV. In some embodiments, Form IV is characterized by an X-ray powder diffraction pattern similar to Fig.12 In some embodiments, Form IV is characterized by a DSC thermogram that is substantially similar to Fig.13 In some embodiments, Form IV is characterized by a TGA thermogram that is substantially similar to Fig.13 The TGA thermograms in are basically similar.

[0150] In some embodiments, the crystalline form of the citrate ester of ((R)-1-(((((R)-1-((E)-2-cyano-4-methyl-4-((R)-2-methylmorpholino)pent-2-enoyl)azepan-3-yl)oxy)carbonyl)amino)-2-phenylethyl)boronic acid is Form V. In some embodiments, Form V is characterized by an X-ray powder diffraction pattern similar to Fig.14 In some embodiments, Form V is characterized by a DSC thermogram that is substantially similar to Fig.15 In some embodiments, the V-type is characterized by a TGA thermogram that is substantially similar to Fig.15 The TGA thermograms in are basically similar. Pharmaceutical composition

[0151] In another aspect, provided herein are pharmaceutical compositions of compounds described herein and pharmaceutically acceptable salts thereof. Thus, the present disclosure includes pharmaceutical compositions comprising at least one compound of formula (I) as described herein or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable excipient. The present disclosure further includes pharmaceutical compositions comprising at least one boronic acid as described herein or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable excipient. The present disclosure additionally includes pharmaceutical compositions comprising at least one crystalline form of a citrate ester of ((R)-1-(((((R)-1-((E)-2-cyano-4-methyl-4-((R)-2-methylmorpholino)pent-2-enoyl)azepan-3-yl)oxy)carbonyl)amino)-2-phenylethyl)boronic acid as described herein or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable excipient.

[0152] Pharmaceutical compositions according to the present disclosure can be in a form suitable for oral, systemic (e.g., transdermal, intranasal or by suppository), parenteral (e.g., intramuscular, intravenous or subcutaneous) or topical (e.g., applied to the skin) administration. In some embodiments, administration is oral using a conventional daily dosing regimen, which can be adjusted according to the degree of pain. The composition can take the form of a tablet, a pill, a capsule, a semisolid, a powder, a sustained release formulation, a solution, a suspension, an elixir, an aerosol, or any other suitable composition.

[0153] Any of the compounds described herein can be used to prepare a pharmaceutical composition by combining the compound as an active ingredient with a pharmaceutically acceptable excipient. Pharmaceutical formulations can be prepared by known pharmaceutical methods. Suitable formulations can be found, for example, in Remington: The Science and Practice of Pharmacy, Lippincott Williams & Wilkins, 21st edition (2005), which is incorporated herein by reference.

[0154] The pharmaceutical composition can conveniently be present in unit dosage form. Such dosage forms can be prepared by any method well known in the pharmaceutical field. The amount of active ingredient that can be combined with excipients to produce a single dosage form will vary according to the subject being treated and the specific mode of administration. The amount of active ingredient that can be combined with excipients to produce a single dosage form will generally be the amount of the compound that produces the therapeutic effect. Typically, this amount range will be about 1% to about 99%, for example, about 5% to about 70%, including about 10% to about 30% of the active ingredient.

[0155] In the solid dosage forms for oral administration (capsules, tablets, pills, dragees, powders, granules, etc.) of the present disclosure, the active ingredient can be mixed with one or more pharmaceutically acceptable carriers, such as sodium citrate or dicalcium phosphate and / or any of the following: fillers or extenders, such as starch, lactose, sucrose, glucose, mannitol and / or silicic acid; binders, such as, for example, carboxymethyl cellulose, alginates, gelatin, polyvinyl pyrrolidone, sucrose and / or acacia; wetting agents, such as glycerol; disintegrants, such as agar, calcium carbonate, potato or tapioca starch, alginic acid, certain silicates and sodium carbonate; dissolution retardants, such as paraffin; wetting agents, such as, for example, cetyl alcohol, glyceryl monostearate and nonionic surfactants; absorbents, such as kaolin and bentonite; lubricants, such as talc, calcium stearate, magnesium stearate, solid polyethylene glycol, sodium lauryl sulfate and mixtures thereof; and coloring agents. In the case of capsules, tablets and pills, the pharmaceutical compositions may also comprise buffering agents. Methods of treatment and use as a medicament

[0156] The compounds described herein, or their pharmaceutically acceptable salts, and pharmaceutical compositions comprising such compounds or their pharmaceutically acceptable salts can be used in methods of administration and treatment as provided herein. These compounds and pharmaceutical compositions can also be used in in vitro methods, such as administering the compounds or pharmaceutical compositions to cells for screening purposes and / or in vitro methods for quality control assays. Similarly, the compounds described herein, or their pharmaceutically acceptable salts, and pharmaceutical compositions comprising such compounds or their pharmaceutically acceptable salts can be used as medicaments for treatment as provided herein.

[0157] In one aspect, provided herein is a method of inhibiting a large multifunctional protease 2 (LMP2) in a subject, the method comprising administering to the subject in need of said inhibition a therapeutically effective amount of at least one compound described herein or a pharmaceutically acceptable salt thereof. Accordingly, the present disclosure includes a method of inhibiting a large multifunctional protease 2 (LMP2) in a subject, the method comprising administering to the subject in need of said inhibition a therapeutically effective amount of at least one compound having formula (I) as described herein or a pharmaceutically acceptable salt thereof.

[0158] The present disclosure further includes a method of inhibiting large multifunctional protease 2 (LMP2) in a subject, comprising administering to the subject in need of said inhibition a therapeutically effective amount of at least one boronic acid or a pharmaceutically acceptable salt thereof as described herein.

[0159] The present disclosure additionally includes a method of inhibiting large multifunctional protease 2 (LMP2) in a subject, the method comprising administering to the subject in need of said inhibition a therapeutically effective amount of at least one crystalline form of a citrate ester of ((R)-1-(((((R)-1-((E)-2-cyano-4-methyl-4-((R)-2-methylmorpholino)pent-2-enoyl)azepan-3-yl)oxy)carbonyl)amino)-2-phenylethyl)boronic acid as described herein, or a pharmaceutically acceptable salt thereof.

[0160] In one aspect, provided herein is a method of inhibiting a large multifunctional protease 7 (LMP7) in a subject, the method comprising administering to the subject in need of said inhibition a therapeutically effective amount of at least one compound described herein or a pharmaceutically acceptable salt thereof. Accordingly, the present disclosure includes a method of inhibiting a large multifunctional protease 7 (LMP7) in a subject, the method comprising administering to the subject in need of said inhibition a therapeutically effective amount of at least one compound having formula (I) as described herein or a pharmaceutically acceptable salt thereof.

[0161] The present disclosure further includes a method of inhibiting large multifunctional protease 7 (LMP7) in a subject, the method comprising administering to the subject in need of said inhibition a therapeutically effective amount of at least one boronic acid or a pharmaceutically acceptable salt thereof as described herein.

[0162] The present disclosure additionally includes a method of inhibiting large multifunctional protease 7 (LMP7) in a subject, the method comprising administering to the subject in need of said inhibition a therapeutically effective amount of at least one crystalline form of a citrate ester of ((R)-1-(((((R)-1-((E)-2-cyano-4-methyl-4-((R)-2-methylmorpholino)pent-2-enoyl)azepan-3-yl)oxy)carbonyl)amino)-2-phenylethyl)boronic acid as described herein, or a pharmaceutically acceptable salt thereof.

[0163] Inhibition of LMP2 and / or LMP7 can be assessed and confirmed by a variety of methods known in the art.Kits and commercially available assays can be used to determine whether and to what extent LMP2 and / or LMP7 are inhibited.

[0164] In another aspect, provided herein is a method for treating a disease associated with LMP2 and / or LMP7 in a subject in need thereof, the method comprising administering to the subject an effective amount of at least one of the compounds described herein or a pharmaceutically acceptable salt thereof. Non-limiting examples of diseases associated with LMP2 and / or LMP7 include rheumatoid arthritis and psoriatic arthritis, scleroderma, ankylosing spondylitis, Duchenne muscular dystrophy (DMD), Becker muscular dystrophy (BMD), idiopathic inflammatory myopathy (IIM), polymyositis, sporadic inclusion body myositis, dermatomyositis, immune-mediated necrotizing myopathy (IMNM), psoriasis, multiple sclerosis, inflammatory bowel disease, Behcet's disease, ulcerative colitis, Crohn's disease, Sjogren's syndrome, bronchitis, conjunctivitis, pancreatitis, cholecystitis, bronchiectasis, aortic stenosis, restenosis, fibrosis, infection, ischemia, cardiovascular disease, hepatitis, cirrhosis, steatohepatitis, liver inflammation, Alzheimer's disease (AD), amyotrophic lateral sclerosis (ALS), Huntington's disease, body myositis, myofibrillar myopathy, graft versus host disease (GVHD), and multiple myeloma.

[0165] In another aspect, provided herein is a method for treating a disease selected from an autoimmune disorder, an inflammatory disorder, and a hematological disorder in a patient in need of such treatment, the method comprising administering to the patient a therapeutically effective amount of at least one compound described herein, or a pharmaceutically acceptable salt thereof. Accordingly, the present disclosure includes a method for treating a disease selected from an autoimmune disorder, an inflammatory disorder, and a hematological disorder in a patient in need of such treatment, the method comprising administering to the patient a therapeutically effective amount of at least one compound as described herein having formula (I), or a pharmaceutically acceptable salt thereof.

[0166] The present disclosure further includes a method for treating a disease selected from an autoimmune disorder, an inflammatory disorder, and a hematological disorder in a patient in need of such treatment, the method comprising administering to the patient a therapeutically effective amount of at least one boronic acid or a pharmaceutically acceptable salt thereof as described herein.

[0167] The present disclosure additionally includes a method for treating a disease selected from an autoimmune disorder, an inflammatory disorder, and a hematological disorder in a patient in need of such treatment, the method comprising administering to the patient a therapeutically effective amount of at least one crystalline form of a citrate ester of ((R)-1-(((((R)-1-((E)-2-cyano-4-methyl-4-((R)-2-methylmorpholino)pent-2-enoyl)azepan-3-yl)oxy)carbonyl)amino)-2-phenylethyl)boronic acid as described herein, or a pharmaceutically acceptable salt thereof.

[0168] In some embodiments, the disease is selected from lupus, arthritis including rheumatoid arthritis and psoriatic arthritis, scleroderma, ankylosing spondylitis, Duchenne muscular dystrophy (DMD), Becker muscular dystrophy (BMD), idiopathic inflammatory myopathy (IIM), polymyositis, sporadic inclusion body myositis, dermatomyositis, immune-mediated necrotizing myopathy (IMNM), psoriasis, multiple sclerosis, inflammatory bowel disease, Behcet's disease, ulcerative colitis, Crohn's disease, Sjogren's syndrome, bronchitis, conjunctivitis, pancreatitis, cholecystitis, bronchiectasis, aortic stenosis, restenosis, fibrosis, infection, ischemia, cardiovascular disease, hepatitis, cirrhosis, steatohepatitis, liver inflammation, Alzheimer's disease (AD), amyotrophic lateral sclerosis (ALS), Huntington's disease, body myositis, myofibrillar myopathy, graft versus host disease (GVHD), and multiple myeloma.

[0169] In another aspect, provided herein is the use of a composition as a medicament for inhibiting large multifunctional protease 2 (LMP2) in a subject, wherein the composition comprises a therapeutically effective amount of a compound described herein or a pharmaceutically acceptable salt thereof. Thus, the present disclosure includes the use of a composition as a medicament for inhibiting large multifunctional protease 2 (LMP2) in a subject, wherein the composition comprises a therapeutically effective amount of at least one compound as described herein having formula (I) or a pharmaceutically acceptable salt thereof.

[0170] The present disclosure further includes the use of a composition as a medicament for inhibiting large multifunctional protease 2 (LMP2) in a subject, wherein the composition comprises a therapeutically effective amount of at least one boronate ester as described herein or a pharmaceutically acceptable salt thereof.

[0171] The present disclosure additionally includes the use of a composition as a medicament for inhibiting large multifunctional protease 2 (LMP2) in a subject, wherein the composition comprises a therapeutically effective amount of at least one crystalline form of a citrate ester of ((R)-1-(((((R)-1-((E)-2-cyano-4-methyl-4-((R)-2-methylmorpholino)pent-2-enoyl)azepan-3-yl)oxy)carbonyl)amino)-2-phenylethyl)boronic acid as described herein, or a pharmaceutically acceptable salt thereof.

[0172] In one aspect, provided herein is the use of a composition as a medicament for inhibiting a large multifunctional protease 7 (LMP7) in a subject, wherein the composition comprises a therapeutically effective amount of at least one of the compounds described herein or a pharmaceutically acceptable salt thereof. Thus, the present disclosure includes the use of a composition as a medicament for inhibiting a large multifunctional protease 7 (LMP7) in a subject, wherein the composition comprises a therapeutically effective amount of at least one compound of formula (I) as described herein or a pharmaceutically acceptable salt thereof.

[0173] The present disclosure further includes the use of a composition as a medicament for inhibiting large multifunctional protease 7 (LMP7) in a subject, wherein the composition comprises a therapeutically effective amount of at least one boronate ester or a pharmaceutically acceptable salt thereof as described herein.

[0174] The present disclosure additionally includes the use of a composition as a medicament for inhibiting large multifunctional protease 7 (LMP7) in a subject, wherein the composition comprises a therapeutically effective amount of at least one crystalline form of a citrate ester of ((R)-1-(((((R)-1-((E)-2-cyano-4-methyl-4-((R)-2-methylmorpholino)pent-2-enoyl)azepan-3-yl)oxy)carbonyl)amino)-2-phenylethyl)boronic acid as described herein, or a pharmaceutically acceptable salt thereof.

[0175] In one aspect, provided herein is the use of a composition as a medicament for treating a disease in a subject in need thereof, wherein the composition comprises administering to the patient a therapeutically effective amount of at least one of the compounds described herein or a pharmaceutically acceptable salt thereof; and wherein the disease is selected from an autoimmune disorder, an inflammatory disorder, and a hematological disorder. Thus, the present disclosure includes the use of a composition as a medicament for treating a disease in a subject in need thereof, wherein the composition comprises administering to the patient a therapeutically effective amount of at least one compound of formula (I) as described herein or a pharmaceutically acceptable salt thereof; and wherein the disease is selected from an autoimmune disorder, an inflammatory disorder, and a hematological disorder.

[0176] The present disclosure further includes use of a composition as a medicament for treating a disease in a subject, wherein the composition comprises a therapeutically effective amount of at least one borate ester or a pharmaceutically acceptable salt thereof as described herein; and wherein the disease is selected from an autoimmune disorder, an inflammatory disorder, and a hematological disorder.

[0177] The present disclosure additionally includes use of a composition as a medicament for treating a disease in a subject, wherein the composition comprises a therapeutically effective amount of at least one crystalline form of a citrate ester of ((R)-1-(((((R)-1-((E)-2-cyano-4-methyl-4-((R)-2-methylmorpholino)pent-2-enoyl)azepan-3-yl)oxy)carbonyl)amino)-2-phenylethyl)boronic acid as described herein, or a pharmaceutically acceptable salt thereof; and wherein the disease is selected from an autoimmune disorder, an inflammatory disorder, and a hematological disorder.

[0178] In some embodiments, the disease is selected from lupus, arthritis including rheumatoid arthritis and psoriatic arthritis, scleroderma, ankylosing spondylitis, Duchenne muscular dystrophy (DMD), Becker muscular dystrophy (BMD), idiopathic inflammatory myopathy (IIM), polymyositis, sporadic inclusion body myositis, dermatomyositis, immune-mediated necrotizing myopathy (IMNM), psoriasis, multiple sclerosis, inflammatory bowel disease, Behcet's disease, ulcerative colitis, Crohn's disease, Sjogren's syndrome, bronchitis, conjunctivitis, pancreatitis, cholecystitis, bronchiectasis, aortic stenosis, restenosis, fibrosis, infection, ischemia, cardiovascular disease, hepatitis, cirrhosis, steatohepatitis, liver inflammation, Alzheimer's disease (AD), amyotrophic lateral sclerosis (ALS), Huntington's disease, body myositis, myofibrillar myopathy, graft versus host disease (GVHD), and multiple myeloma.

[0179] In some embodiments, administering a compound described herein or a pharmaceutically acceptable salt thereof to a subject in need reduces the extent of a disease associated with LMP2 and / or LMP7 (e.g., those listed above). In some embodiments, administering a compound described herein or a pharmaceutically acceptable salt thereof to a subject in need stabilizes a disease associated with LMP2 and / or LMP7. In some embodiments, administering a compound described herein or a pharmaceutically acceptable salt thereof to a subject in need delays the occurrence or recurrence of a disease associated with LMP2 and / or LMP7. In some embodiments, administering a compound described herein or a pharmaceutically acceptable salt thereof to a subject in need slows down the progression of a disease associated with LMP2 and / or LMP7. In some embodiments, administering a compound described herein or a pharmaceutically acceptable salt thereof to a subject in need delays the progression of a disease associated with LMP2 and / or LMP7. In some embodiments, administering a compound described herein or a pharmaceutically acceptable salt thereof to a subject in need increases the quality of life of a subject suffering from a disease associated with LMP2 and / or LMP7. In some embodiments, administering a compound described herein or a pharmaceutically acceptable salt thereof to a subject in need prolongs the survival of a subject suffering from a disease associated with LMP2 and / or LMP7. Dosage and administration method

[0180] The compounds can be administered to humans for treatment by any suitable route of administration, including oral, intranasal (e.g., by spray), rectal, intravaginal, parenteral, intracisternal, and topical (e.g., by powders, ointments, or drops, including buccal and sublingual). Suitable unit administration forms include oral forms, such as tablets, soft or hard gel capsules, powders, granules, and oral solutions or suspensions, sublingual, buccal, intratracheal, intraocular, and intranasal administration forms, forms for inhalation, topical, transdermal, subcutaneous, intramuscular, or intravenous administration, rectal administration forms, and implants. For topical administration, the compounds described herein can be used in creams, gels, ointments, or lotions.

[0181] Regardless of the route of administration chosen, the compounds described herein, or pharmaceutically acceptable salts thereof, are formulated into pharmaceutically acceptable dosage forms by conventional methods known to those skilled in the art.

[0182] Actual dosage levels of the active ingredients in the pharmaceutical compositions of the present disclosure may be varied so as to obtain an amount of the active ingredient that is effective to achieve the desired therapeutic response for a particular patient, composition, and mode of administration without being toxic to the patient.

[0183] The selected dosage level will depend on a variety of factors, including the activity of the specific compound or salt of the disclosure employed, the route of administration, the time of administration, the rate of excretion or metabolism of the specific compound or salt employed, the duration of the treatment, other drugs, compounds and / or materials used in combination with the specific compound or salt employed, the age, sex, weight, condition, general health and previous medical history of the patient being treated, and similar factors well known in the medical arts. Daily, weekly or monthly dosages (or other time intervals) may be used.

[0184] A physician with ordinary skills in the art can easily determine and prescribe the effective amount of the desired pharmaceutical composition. For example, the physician can start the dosage of the compound or salt of the disclosure employed in the pharmaceutical composition at a level lower than that required to achieve the desired therapeutic effect, and then gradually increase the dosage until the desired effect is achieved.

[0185] Typically, the suitable daily dose of the compound of the present disclosure will be the amount of the compound at the lowest dose that effectively produces a therapeutic effect (e.g., inhibiting necrosis). This effective dose will generally depend on the above factors. Typically, when used for the indicated effect, the dosage range of the compound of the present disclosure for the patient will be about 0.0001 to about 100 mg / kg body weight / day. Preferably, the daily dose range will be 0.001 to 50 mg compound / kg body weight, and even more preferably 0.01 to 10 mg compound / kg body weight.

[0186] If desired, the effective daily dose of active compound may be administered as two, three, four, five, six or more sub-doses divided at appropriate intervals throughout the day, alternatively, in unit dosage forms.

[0187] When the compounds or salts of the present disclosure are administered to humans as medicines, they can be given per se or as a pharmaceutical composition containing, for example, 0.1% to 99.5% (such as 0.5% to 90%) of the active ingredient in combination with a pharmaceutically acceptable carrier.

[0188] The compounds and salts of the present application or their pharmaceutical compositions can be administered once, twice, three times or four times a day using any of the above-mentioned suitable modes. In addition, the administration or treatment with the compound or salt can last for several days; for example, for a treatment cycle, the treatment will usually last for at least 7 days, 14 days or 28 days. The treatment cycle is well known, and there is often a rest period of about 1 to 28 days, usually about 7 days or about 14 days, alternating between cycles. In certain embodiments, the treatment cycle can also be continuous.

[0189] In certain embodiments, the methods and uses herein include administering to a subject an initial daily dose of about 1 to 800 mg of a compound or salt described herein and increasing the dose in increments until clinical efficacy is achieved. The dose may be increased in increments of about 5, 10, 25, 50, or 100 mg. The dose may be increased every day, every two days, twice a week, or once a week.

[0190] The formulations disclosed herein can be administered orally, parenterally, topically or rectally. Of course, the formulations are administered in a form suitable for each route of administration. For example, they are administered in tablet or capsule form; by injection, inhalation, eye lotion, ointment, suppository, infusion, inhalation, etc.; topically by lotion or ointment; and rectally by suppository. In certain embodiments, administration is oral.

[0191] The method of the present disclosure may include a compound described herein or a pharmaceutically acceptable salt thereof, used alone or in combination with one or more additional therapies (e.g., non-drug treatments or therapeutic agents). When administered alone, the dosage of one or more of the additional therapies (e.g., non-drug treatments or therapeutic agents) may be reduced from the standard dosage. For example, the dosage may be determined empirically based on drug combinations and permutations, or may be inferred by an equivalence analysis.

[0192] The compound described herein or its salt can be administered before, after or simultaneously with one or more of such additional therapies. When combined, the dosage of the compound described herein or its salt and the dosage of one or more additional therapies (e.g., non-drug treatments or therapeutic agents) provide a therapeutic effect (e.g., a synergistic or cumulative therapeutic effect). The compound described herein or its pharmaceutically acceptable salt and additional therapies (such as anticancer agents) can be administered together, such as in a single pharmaceutical composition, or separately, and when administered separately, this can occur simultaneously or sequentially. This sequential administration can be closer or farther apart in time. Examples

[0193] The examples and preparations provided below further illustrate and exemplify the compounds of the present disclosure.It should be understood that the scope of the present disclosure is not limited in any way by the scope of the following examples.

[0194] The chemical reactions in the described examples can be easily adapted to prepare a variety of other compounds described herein, and alternative methods for preparing the compounds of the present disclosure are considered to be within the scope of the present disclosure. For example, the synthesis of non-exemplary compounds according to the present disclosure can be carried out by modifications obvious to those skilled in the art, such as by appropriately protecting interfering groups, by utilizing other suitable reagents other than those known in the art, or by conventional modifications to reaction conditions, reagents and starting materials. Alternatively, other reactions described herein or known in the art will be considered to have adaptability for preparing other compounds of the present disclosure.

[0195] The following abbreviations may be used in connection with this application. abbreviation

[0196] Example 1: Preparation of citrate ester of ((R)-1-(((((R)-1-((E)-2-cyano-4-methyl-4-((R)-2-methylmorpholino)pent-2-enoyl)azepan-3-yl)oxy)carbonyl)amino)-2-phenylethyl)boronic acid.

[0197] Step 1: Synthesis of starting material 1 (SM1)

[0198] Isobutyraldehyde (733 g) in DCM (3500 mL) was brominated with bromine (1686 g) at 0°C to 5°C. The reaction was stirred with aqueous Na 2 SO 3The product is quenched and washed with water and brine. The DCM solution is stored at 0°C to 10°C. (R)-2-methylmorpholine (700g) is dissolved in DCM (1400mL), cooled to 5°C, and diisopropylethylamine (1.97L) is added. The reactant is cooled to 0°C to 5°C, followed by addition of a DCM solution of 2-bromo-2-methylpropanal. Each layer is separated, and the organic phase is washed with water and brine. The organic phase is concentrated to dryness under reduced pressure to give (R)-2-methyl-2-(2-methylmorpholino) propanal (802g) in a light yellow oil. Yield: 90% yield and purity: 99.0%. (R)-2-methyl-2-(2-methylmorpholino) propanal (802g) and 2-cyanoacetic acid (439g) are dissolved in toluene (2.4L), followed by addition of ammonium acetate (18g). The reactant was heated to 80°C ± 5°C for 22 hours, then cooled to 20°C ± 5°C and acetonitrile (1.6 L) was added to form a solid. The solid was collected by filtration and rinsed with acetonitrile. The solid was dried under vacuum at 40°C ± 5°C to constant weight to give SM1 (790 g) as a white solid. Yield: 70% yield and purity: 98.5%.

[0199] Step 2: Synthesis of intermediate 3

[0200] Starting material 1 (SM1) was reacted with starting material 2 (SM2) (which can be prepared according to methods disclosed in the literature), BOP-Cl and triethylamine in CH 2 Cl 2 Combine the reactants with water K 2 CO 3 and washed with NaCl to produce intermediate 3.

[0201] Step 3: Synthesis of intermediate 5

[0202] Intermediate 3 is reacted with intermediate 4 (which is obtained from KingChem Life Science and can be prepared by known methods, for example, as described in U.S. Pat. No. 11,225,493), triphosgene and pyridine in CH 2 Cl 2 The reaction mixture was then combined with water, aqueous HCl and MeOH to give intermediate 5.

[0203] Step 4: Synthesis of boronic acid 1

[0204] Intermediate 5 was reacted with i-BuB(OH) 2Combined in aqueous HCl, MeOH and heptane. The mixture was then mixed with aqueous NaCO 3 , CH 2 Cl 2 , aqueous NaCl, and MTBE were mixed to produce boronic acid 1 (i.e., ((R)-1-(((((R)-1-((E)-2-cyano-4-methyl-4-((R)-2-methylmorpholino)pent-2-enoyl)azepan-3-yl)oxy)carbonyl)amino)-2-phenylethyl)boronic acid).

[0205] Step 5: Synthesis of citrate ester of boronic acid 1

[0206] At 15 ℃-20 ℃, a solution of anhydrous citric acid (1.05 equivalents) in ethanol (EtOH, 5mL) is added to a solution of boric acid 1 (1.0g) in isopropyl acetate (IPAC, 5mL), and stirred for 5min to a clear solution. Then, the solution is heated to 30 ℃-35 ℃ and stirred until crystals are formed. The slurries are stirred for about 2h at 30 ℃-35 ℃, and then slowly cooled to 15 ℃-20 ℃ and stirred for 2h. The resulting slurries are filtered, and the solid is washed with ethanol / IPAC (1 / 1.2mL). Then, the solid is dried under vacuum at 30 ℃-35 ℃, producing a mixture (1.0g, 77% yield, 99% purity) of the citrate esters (esters A-1 to D-1) shown above as off-white solids. MS[M+1]: 683 (SFC-MS). 1 The H NMR results are shown in Table 1 below. Table 1. *Signal assignment cannot be confirmed.

[0207] Example 2: Preparation of the pinacol ester of ((R)-1-(((((R)-1-(2-cyano-4-methyl-4-((R)-2-methylmorpholino)pent-2-enoyl)azepan-3-yl)oxy)carbonyl)amino)-2-phenylethyl)boronic acid.

[0208] The pinacol ester of ((R)-1-(((((R)-1-(2-cyano-4-methyl-4-((R)-2-methylmorpholino)pent-2-enoyl)azepan-3-yl)oxy)carbonyl)amino)-2-phenylethyl)boronic acid was prepared by combining boronic acid 1 with pinacol in dichloromethane. The reaction was stirred at ambient temperature and then washed with water. The layers were separated and the organic phase was concentrated to dryness to give ester N. Predicted MS [M+1]: 609. An exemplary NMR spectrum is shown in Figure 1 middle.

[0209] Example 3: Preparation of the citrate ester of [(1R)-1-[([[7-(2-cyano-2-[2-methyl-2-[(2S)-2-methylmorpholin-4-yl]propylidene]acetyl)-7-azabicyclo[2.2.1]hept-1-yl]methoxy]carbonyl)amino]-2-phenylethyl]boronic acid.

[0210] Step 1: Synthesis of intermediate 2

[0211] In a 100-mL round-bottom flask, starting material 1 (1 g, 4.144 mmol, 1 equivalent) and oxolane (THF, 10 mL) were placed. Then, BH 3 .THF (1M) (16.6mL, 4.0 equiv.). The resulting solution was stirred at room temperature for 1 overnight. Then, the reactant was quenched by adding 20mL MeOH at 0°C. The resulting mixture was concentrated under vacuum. The residue was applied to a silica gel column using ethyl acetate / petroleum ether (1:20). This produced 900mg (95.54%) of intermediate 2 as a colorless oil.

[0212] Step 2: Synthesis of intermediate 3

[0213] Into a 100-mL 3-neck round-bottom flask purged and maintained with a nitrogen inert atmosphere, intermediate 2 (470 mg, 2.068 mmol, 1 eq.), DCM (10 mL), DIPEA (801.71 mg, 6.203 mmol, 3.00 eq.) was placed. After that, a solution of ditrichloromethyl carbonate (490.84 mg, 1.654 mmol, 0.80 eq.) in DCM (2 mL) was added dropwise at 0°C with stirring. A solution of DMAP (126.30 mg, 1.034 mmol, 0.50 eq.) in DCM (1 mL) was added thereto at 0°C. The resulting solution was stirred at 0°C in an ice / salt bath for 2 hours. The reaction mixture solution was used directly in the next step.

[0214] Step 3: Synthesis of intermediate 4

[0215] Into a 100-mL 3-neck round-bottom flask purged and maintained with an inert atmosphere of nitrogen, intermediate 3a (683.50 mg, 2.036 mmol, 1.00 equiv), DCM (10 mL) and DIPEA (789.48 mg, 6.109 mmol, 3.00 equiv) were placed. After this, a solution of intermediate 3 (590 mg, 2.036 mmol, 1 equiv) in DCM (10 mL) was added dropwise at 0°C with stirring. The resulting solution was stirred at room temperature for 1 hour. The resulting mixture was washed with 1×30 mL of water. The mixture was dried over anhydrous sodium sulfate and concentrated under vacuum. The crude product was purified by flash preparative HPLC under the following conditions: column, C18 silica gel; mobile phase, ACN / H in 45 min. 2 O=5 / 95increase to ACN / H 2 O=100 / 0; detector, 220 nm. This resulted in 700 mg (62.22%) of intermediate 4 as a light yellow solid.

[0216] Step 4: Synthesis of intermediate 5

[0217] Into a 250-mL round bottom flask was placed intermediate 4 (1.434 g, 2.595 mmol, 1 eq), DCM (30 mL) and TFA (5 mL). The resulting solution was stirred at room temperature for 1 hour. The resulting mixture was concentrated under vacuum. This produced 1.15 g (97.94%) of intermediate 5 as a yellow oil.

[0218] Step 5: Synthesis of intermediate 6

[0219] Into a 250-mL round-bottom flask was placed intermediate 5 (1.15 g, 2.542 mmol, 1 eq), DCM (30 mL), DIPEA (1.31 g, 10.136 mmol, 3.99 eq), 2-cyanoacetic acid (0.43 g, 5.055 mmol, 1.99 eq) and HATU (2.90 g, 7.627 mmol, 3.00 eq). The resulting solution was stirred at room temperature for 1 hour. The resulting mixture was washed with 1×30 mL of water. The mixture was dried over anhydrous sodium sulfate and concentrated under vacuum. The crude product was purified by flash preparative HPLC under the following conditions: column, C18 silica gel; mobile phase, ACN / H in 45 min. 2 O=5 / 95increase to ACN / H 2O=90 / 10; detector, 220 nm. This resulted in 900 mg (68.16%) of intermediate 6 as a yellow solid.

[0220] Step 6: Synthesis of 2-bromo-2-methylpropanal

[0221] In a 1L 3-necked round-bottom flask, 2-methylpropanal (50 g, 693.43 mmol, 1.00 equiv), ether (500 mL) and AlCl 3 The mixture was stirred at 0 ° C for 10 minutes under stirring for 2 hours. The resulting solution was stirred at room temperature overnight. Then, the reactant was quenched by adding 100 mL of water / ice. The pH value of the solution was adjusted to 10-12 with sodium carbonate. The resulting solution was extracted with 3 × 100 mL of ether and the organic layers were combined and dried over anhydrous sodium sulfate and concentrated under vacuum. The crude product was purified by distillation under reduced pressure (170 mm Hg) and fractions were collected at 70 ° C-77 ° C. This produced 21.0 g (20.0%) of 2-bromo-2-methylpropanal as a colorless oil.

[0222] Step 7: Synthesis of 2-methyl-2-[(2S)-2-methylmorpholin-4-yl]propanal

[0223] Into a 50-mL round-bottom flask was placed (2S)-2-methylmorpholine (500 mg, 4.943 mmol, 1 equivalent), ethoxyethane (10 mL), 2-bromo-2-methylpropanal (1119.66 mg, 7.415 mmol, 1.5 equivalents) and TEA (1500.61 mg, 14.830 mmol, 3.00 equivalents). The resulting solution was stirred at room temperature for 3 days. The resulting mixture was washed with 1×10 mL of water. The mixture was dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was applied to a silica gel column using ethyl acetate / hexane (1:10). This produced 600 mg (70.88%) of 2-methyl-2-[(2S)-2-methylmorpholine-4-yl]propanal as a yellow oil.

[0224] Step 8: Synthesis of Intermediate 7

[0225] Into a 50-mL round-bottom flask was placed intermediate 6 (170 mg, 0.327 mmol, 1 eq), DCM (5 mL), 2-methyl-2-[(2S)-2-methylmorpholin-4-yl]propanal (168.12 mg, 0.982 mmol, 3.00 eq), pyrrolidine (116.38 mg, 1.636 mmol, 5.00 eq) and TMSCl (177.78 mg, 1.636 mmol, 5.00 eq). The resulting solution was stirred at room temperature for 1 hour. The resulting mixture was washed with 1×10 mL of water. The mixture was dried over anhydrous sodium sulfate and concentrated under vacuum. The crude product was purified by flash preparative HPLC under the following conditions: column, C18 silica gel; mobile phase, ACN / H in 45 min. 2 O=5 / 95increase to ACN / H 2 O=100 / 0; detector, 220 nm. This resulted in 140 mg (63.59%) of intermediate 7 as a light yellow solid.

[0226] Step 9: Synthesis of boronic acid 2

[0227] Into a 100-mL round-bottom flask was placed intermediate 7 (140 mg, 0.208 mmol, 1 eq), MeOH (4 mL), (2-methylpropyl)boric acid (63.65 mg, 0.624 mmol, 3.00 eq), hexane (4 mL), and 1N HCl (4 mL). The resulting solution was stirred at room temperature for 1 hour. The methanol layer was diluted with 25 mL of water and dried by lyophilization to give a crude product. The crude product was purified by preparative HPLC under the following conditions: column, XBridge Prep OBD C18 column, 30*150 mm5um; mobile phase, water (10 MMOL / L NH 4 HCO 3 ) and ACN (25% phase B to 55% in 8 min); detector, UV 254 / 220 nm. This gave 39.2 mg (34.98%) of boronic acid 2 as a white solid. LC-MS m / z:539(M+1); 1H NMR (300MHz, methanol-d4) δ7.23(m,5H),7.03(s,1H),4.75(s,2H),4.42(s,1H),3.79(m,3H),3.24(t,J=7.6Hz,1H),2.92- 2.64(m,4H),2.48-2.35(m,1H),2.15-2.02(m,1H),1.91(m,4H),1.73-1.60(m,4H),1.40-1.22(m,6H),1.12(m,3H).

[0228] Step 10: Synthesis of citrate ester of boronic acid 2

[0229] To prepare the citrate ester, a solution of anhydrous citric acid (345 mg, 1.0 equiv.) in EtOH (5.0 mL) was added to a solution of boronic acid 2 (1.0 g) in dichloromethane (20 mL) at 15°C-20°C. The solution was concentrated to 5-6 mL under vacuum at a temperature below 18°C. The concentrated solution was then slowly added to n-heptane (30.0 mL) to produce a slurry, which was stirred for 30 min. The resulting solid was filtered and washed with n-heptane (2 mL) and dried under vacuum to give a mixture of citrate borate esters (esters EH) (970 mg, 75% yield, purity 97.1%, determined by HPLC). MS[M+1]: 695,330 (SFC-MS). NMR is shown in Figure 2 middle.

[0230] Example 4: Preparation of [(1R)-1-[([[7-(2-cyano-2-[2-methyl-2-[(2S)-2-methylmorpholin-4-yl]propylidene]acetyl)-7-azabicyclo[2.2.1]hept-1-yl]methoxy]carbonyl)amino]-2-phenylethyl]boronic acid solvate-citrate crystals.

[0231] [(1R)-1-[([[7-(2-cyano-2-[2-methyl-2-[(2S)-2-methylmorpholin-4-yl]propylidene]acetyl)-7-azabicyclo[2.2.1]hept-1-yl]methoxy]carbonyl)amino]-2-phenylethyl]boronic acid solvate-citrate crystals were obtained by reaction crystallization of boronic acid 2 with 1.1 equivalents of citric acid in acetonitrile, or by reactive crystallization of boronic acid 2 with 1.1 equivalents of citric acid in EtOH / ACN (1:1 or 1:2). After the reaction crystallization, cooling to 0°C-10°C produced a wet cake showing good crystallinity. SFC / MS of the wet cake showed the [M+1] peak of [(1R)-1-[([[7-(2-cyano-2-[2-methyl-2-[(2S)-2-methylmorpholin-4-yl]propylidene]acetyl)-7-azabicyclo[2.2.1]hept-1-yl]methoxy]carbonyl)amino]-2-phenylethyl]boronic acid citrate at 695. Although the wet cake showed good crystallinity, its crystallinity decreased dramatically when it was air-dried for several minutes and became amorphous.

[0232] Example 5:Preparation of citrate ester of ((R)-1-(((((R)-1-(2-cyano-4-(3,3-difluoropyrrolidin-1-yl)-4-methylpent-2-enoyl)piperidin-2-yl)methoxy)carbonyl)amino)-2-phenylethyl)boronic acid.

[0233] Steps 1 and 2: Synthesis of intermediates 1 and 2

[0234] The reaction was carried out in a 3-necked round-bottom flask under N 2 Bromine was added dropwise to a solution of starting material 1 (isobutyraldehyde) in DCM under magnetic stirring. The reaction was stirred at 0°C ± 5°C for at least 15 min. A sample was taken for GC analysis. The solution was then heated with Na 2 SO 3 Aqueous solution, saturated NaHCO 3 The solution was washed with aqueous solution and brine. The solution was used in the next step without further purification.

[0235] The reaction was carried out in a 3-necked round-bottom flask under N 2 The solution from step 1 was added dropwise to a solution of 3,3-difluoropyrrolidine hydrochloride (starting material 2a) and DIPEA in DCM under magnetic stirring. The reaction was allowed to react at 0°C ± 5°C for at least 17 hours and monitored by GC analysis and worked up and concentrated to a syrup.

[0236] Step 3: Synthesis of Intermediate 3

[0237] The reaction was carried out in a bottom flask under N 2 Under magnetic stirring, the intermediate 2, 2-cyanoacetic acid and NH 4 OAc was added sequentially to the reaction flask. The reaction was stirred at 80°C ± 5°C for at least 48 hours. Samples were analyzed by GC and the reaction progress was monitored by the ratio of intermediate 2 / solvent.

[0238] Step 4: Synthesis of intermediate 4

[0239] The reaction was carried out in a 3-necked round-bottom flask under N 2 Under magnetic stirring, intermediate 3, (R)-piperidin-2-ylmethanol in DCM, DIPEA and HATU were added to the reaction flask in sequence. The reaction was stirred at 0°C ± 5°C for at least 4h. The reaction was monitored by LC / MS.

[0240] Step 5: Synthesis of Intermediate 5

[0241] The product (20.0 g) and dichloromethane (250 mL) from step 4 were loaded into a 1000 mL jacketed reactor equipped with an overhead mechanical stirrer. The solution was cooled to 0°C ± 5°C, followed by the addition of DIPEA (31.5 g). Triphosgene (12.2 g) in dichloromethane (60 mL) was added dropwise to the reactant, maintaining the internal temperature at 0°C ± 5°C. The reactant was stirred at 0°C ± 5°C for 20 minutes to give solution A. Starting material 5a (19.07 g) and dichloromethane (300 mL) were added to a separate reactor. The mixture was stirred and cooled to -5°C ± 5°C, followed by the addition of DIPEA (15.14 g) at -5°C ± 5°C. Solution A was added dropwise to the stirred reactant, maintaining the internal temperature at -5°C to 0°C. The reactant was stirred for 5 minutes, and then quenched with water (200 mL) at -5°C to 0°C. The mixture was stirred at -5 ° C to 0 ° C for 10 minutes, and then the phases were separated. The organic phase was washed with water (600 mL). Cold water (300 mL) was added to the organic phase and the pH was adjusted to 2-3 with 1N HCl, maintaining the internal temperature to be 5 ° C ± 5 ° C. The organic phase was separated and washed with cold water (300 mL). The organic phase was concentrated to 150 mL, and methanol (900 mL) was subsequently added. The solution was concentrated to 750 mL under reduced pressure at <15 ° C.

[0242] Step 6: Synthesis of boronic acid 3

[0243] To the solution from step 5 (750 mL) was added n-heptane (750 mL). 1 N HCl (600 mL) was added to the mixture at 5°C ± 5°C, followed by dropwise addition of i-BuB(OH) in MeOH (60 mL) at 5°C ± 5°C. 2 (2.0 equivalents). The reactant was stirred for 2 hours. The phases were separated and the aqueous phase was washed three times with n-heptane (750 mL). Water (600 mL) was added to the aqueous phase and extracted with dichloromethane (600 mL), followed by a second extraction with dichloromethane (300 mL). The dichloromethane extracts were combined and washed twice with water (600 mL). The dichloromethane solution was directly purified by silica gel chromatography eluting with dichloromethane and isopropanol. The fractions containing the product were combined and washed five times with water (30 volumes). The resulting organic solution was concentrated to about 30 V under reduced pressure at less than 15 ° C, and then solvent exchanged to water / acetonitrile (600 mL, 1: 1). Boric acid 3 (23.0 g) was obtained as a white powder after freeze drying. NMR is shown in Figure 3 middle.

[0244] Step 7: Synthesis of citrate ester of boronic acid 3

[0245] To prepare citrate, a solution of anhydrous citric acid (379 mg, 1.05 equiv.) in ethanol (EtOH, 2.5 mL) was charged into a solution of boric acid 3 (1.0 g) in EtOH. The mixture was stirred at 15°C-20°C for 20 min. Methyl tert-butyl ether (MTBE, 40 mL) was added to the solution, and a solid was formed. After stirring at 20°C for 1 h, the slurry was filtered and the wet cake was washed with MTBE (2 mL). After drying under vacuum at room temperature, a mixture of citrate (ester IL) as an off-white solid was obtained (970 mg, 75% yield, purity 84.6%, determined by HPLC). MS[M+1]: 689 (SFC-MS). NMR is shown in Figure 4 middle.

[0246] Example 6: Preparation of salicylate of ((R)-1-(((((R)-1-(2-cyano-4-(3,3-difluoropyrrolidin-1-yl)-4-methylpent-2-enoyl)piperidin-2-yl)methoxy)carbonyl)amino)-2-phenylethyl)boronic acid.

[0247] The salicylate of ((R)-1-(((((R)-1-(2-cyano-4-(3,3-difluoropyrrolidin-1-yl)-4-methylpent-2-enoyl)piperidin-2-yl)methoxy)carbonyl)amino)-2-phenylethyl)boronic acid can be prepared by charging boronic acid 3 (500 mg) in isopropyl acetate (2.5 mL) and adding a solution of salicylic acid (1.1 eq) in isopropyl acetate (1.25 mL). The resulting mixture was stirred at 20-25° C. for 2 h. n-heptane (25 mL) was added to the reactants to form a solid precipitate, which was stirred at 20-25° C. for 30 minutes. The solid was filtered and rinsed with n-heptane (1 mL) and dried on the filter with nitrogen to give 610 mg of salicylate as a yellow solid. MS[M+1]: 635 (SFC-MS). NMR is shown at Figure 5 middle.

[0248] Example 7: Polymorphic forms of the citrate ester of ((R)-1-(((((R)-1-((E)-2-cyano-4-methyl-4-((R)-2-methylmorpholino)pent-2-enoyl)azepan-3-yl)oxy)carbonyl)amino)-2-phenylethyl)boronic acid.

[0249] Form I - Form I was obtained by slurrying Form II in EtOH and IPA at room temperature and 50°C. It can also be formed by slurrying Form III with EtOH at room temperature and 50°C. Form I was found to be stable at 40°C / 75% relative humidity and 60°C for 7 days. Form I was prepared as plate-like crystals with good crystallinity ( Figure 6 ). It shows a weight loss of 0.5% on the TGA characteristic curve and an endothermic peak at 179°C / 193°C on the DSC characteristic curve ( Figure 7 ). Characterization data showed that it is anhydrous.

[0250] Form II - Form II is a solvate with acetonitrile. Form II was prepared from the HCl salt of boronic acid 1. The HCl salt was prepared by dissolving boronic acid 1 (140 g) in EtOAc (10 V) and washing with NaOH (0.2 eq) in water (5 V). The layers were then separated and the organic phase was charged with 10% brine (5 V). The pH was adjusted to about 6-7 with 1 N HCl. The layers were separated again and the organic phase was washed with NaOH (0.2 eq). 2 SO 4 The mixture was dried, filtered and the filter cake was washed with EtOAc (2V). The solution was concentrated and redissolved in DCM (5V) at less than 20°C. HCl (1 equivalent) in EtOAc was loaded into the reactant and stirred for 30min at about 20°C. At 20°C, MTBE (20V) and DCM (5V) were loaded into the solution and stirred for about 2 hours at about 20°C. The mixture was filtered and the filter cake was washed with MTBE / DCM=2 / 1 (2V). At about 20°C, the filter cake was slurried with EtOAc (10V) and MTBE (10V), and then stirred for about 2 hours at about 20°C. The organic layer was filtered and the filter cake was washed with EtOAc / MTBE=1 / 1 (2V). The filter cake was dried under vacuum at about 20°C for 4 hours to obtain the HCl salt as a light yellow solid.

[0251] Then, the HCl salt (8 g) was added to DCM (160 mL) and the mixture was charged with H 2 O (10V). 9% NaHCO 3 The pH was adjusted to about 7. The layers were separated and the organic phase was washed once with brine. The DCM solution was washed with Na 2 SO 4Dried, concentrated, and exchanged with EtOH (44mL) under vacuum to give boric acid 1. Citric acid (3.14g) in EtOH solution (80mL) is added to boric acid 1, and n-heptane (32mL) is loaded into the system to produce a muddy solution. The mixture is stirred overnight (at least 16 hours) at about 15 ℃-20 ℃. Then, n-heptane (88mL) and IPAc (16mL) are loaded into the reactant and stirred for about 3 hours. The reactant is filtered, and the filter cake is washed with EtOH / n-heptane (1:2). The filter cake is dried under vacuum to give citrate, which is then recrystallized in MeCN. More specifically, citrate (8.3g) is added into MeCN (830mL, 10V), and stirred for about 2 hours at about 40 ℃-45 ℃, then cooled to about 15 ℃-20 ℃ through at least about 3 hours. The reaction was charged with additional MeCN (5V) and MTBE (3V) and stirred at about 40°C-45°C for about 20 hours. The solution was filtered and the filter cake was washed with MeCN / MTBE (5:1, 1V). The filter cake was dried under vacuum to give Form II. XRPD is shown in Figure 8 The TGA and DSC thermograms are shown in Fig. 9 middle.

[0252] Form III - Form III is a hydrate formed by dehydration of Form II. Form III is also obtained by slurrying Form II in MTBE, toluene, EA and IPAc at room temperature or at about 50°C. XRPD is shown in Fig.10 The TGA and DSC thermograms are shown in Fig.11 middle.

[0253] Form IV - Form IV is a hydrate formed by slurrying Form II in MEK at room temperature. XRPD is shown in Fig.12 The TGA and DSC thermograms are shown in Fig.13 middle.

[0254] Form V - Form V is a hydrate obtained from Form IV which first undergoes a metastable form and then converts to Form V after air drying for 20 minutes. Form V was also prepared by slurrying Form I in MEK for about 24 hours at about 50°C / 25°C cycles (8 hours / cycle). The resulting suspension was filtered and briefly dried with compressed air to give Form V. XRPD is shown at Fig.14 The TGA and DSC thermograms are shown in Fig.15 middle.

[0255] Example 8:Stability of boronate esters of ((R)-1-(((((R)-1-((E)-2-cyano-4-methyl-4-((R)-2-methylmorpholino)pent-2-enoyl)azepan-3-yl)oxy)carbonyl)amino)-2-phenylethyl)boronic acid.

[0256] Stability in SGF and SIF: The stability of the citrate ester of boronic acid 1 in SGF (simulated gastric fluid, pH 1.2) and SIF (simulated intestinal fluid, pH 6.8) was studied by diluting a 10 mg / mL solution of the ester in ACN with SGF or SIF to achieve a final ester concentration of 0.5 mg / mL. The diluted solution was then analyzed for ester content by UPLC. It was found that when the solution of the citrate ester of boronic acid 1 in ACN was added to SGF, the ester was immediately and completely converted to boronic acid 1. When the solution of the citrate ester of boronic acid 1 in ACN was added to SIF, the ester was immediately and almost completely converted to boronic acid 1, with approximately 8% of the ester remaining.

[0257] The same set of experiments were performed on the pinacol and pinanediol esters of boronic acid 1, except that additional ACN was added when diluted into SIF in order to maintain the compounds in solution (the final ACN concentration in the diluted solution in SIF was 20%-30%). It was found that the pinacol ester of boronic acid 1 was immediately and completely converted to boronic acid 1 when added to SGF and SIF, while the pinanediol ester (Intermediate 5 from Example 1) was only partially converted to boronic acid 1 (with the ratio of boronic acid 1:Intermediate 5 being 65:35 in SGF and 37:63 in SIF).

[0258] Stability in open dish experiments : An open dish stability study was conducted in open glass vials at 40°C / 75% RH to compare the stability of the citrate ester of boronic acid 1 relative to boronic acid 1, the pinacol ester of boronic acid 1, the pinanediol ester of boronic acid 1, and the HCl salt of boronic acid 1.

[0259] The results (shown in the table below) show that Boric acid 1, its HCl salt, and the pinacol and pinanediol esters of Boric acid 1 all significantly degraded after two weeks, while the citrate ester of Boric acid 1 was stable for at least four weeks. In addition, the citrate ester was demonstrated to have acceptable stability for at least 6 months at 5°C, 25°C / 60% RH, and 40°C / 75% RH. Table 2

[0260] discuss:Boric acid 1 is amorphous and difficult to manufacture in high purity. In contrast, its corresponding citrate ester is a crystalline material and has been manufactured on a large scale with high purity (>99% area). In addition, boronic acid 1 is easily hydrolyzed and oxidized. Due to the presence of the boronic acid functional group in boronic acid 1, the molecule can be easily oxidized by peroxides and can even be oxidized by oxygen present in the environment or dissolved in solution. This inherent chemical instability may lead to chemical instability during manufacturing and storage. The citrate ester of boronic acid 1 has demonstrated greatly improved chemical stability, as shown in the above stability studies. In addition, citric acid is easily converted to boronic acid 1 in aqueous media under physiological conditions (e.g., SGF and SIF).

[0261] Although preferred embodiments of the present disclosure have been shown and described herein, it will be clear to those skilled in the art that such embodiments are provided by way of example only. Without departing from the present disclosure, those skilled in the art will now expect many variations, changes and substitutions. It should be understood that different alternatives to the embodiments of the present disclosure described herein may be used to practice the present disclosure. The following claims are intended to define the scope of the present disclosure, and methods and structures within the scope of these claims and their equivalents are thus covered. The disclosures of all patents and scientific literature cited herein are expressly incorporated herein by reference in their entirety. To the extent that any incorporated material is inconsistent with the explicit content of the present disclosure, the explicit content shall prevail.

Claims

1. A compound of formula (I) or a pharmaceutically acceptable salt thereof, in A is an optionally substituted monocyclic or bicyclic heterocycle containing at least one nitrogen atom bonded to a methylene unit; Y is an optionally substituted monocyclic or bicyclic heterocycle containing at least one nitrogen atom bonded to a carbonyl group; X is a borate ester bonded to a methylene unit via a boron atom and selected from the group consisting of citrate, pinacol ester, malate, salicylate, lactate, and tartrate; and n is 0 or 1.

2. The compound according to claim 1, wherein A is an optionally substituted monocyclic or bicyclic 5-membered or 6-membered heterocyclic ring.

3. A compound according to any one of the preceding claims, wherein A is selected from optionally substituted pyrrolidinyl and optionally substituted morpholinyl.

4. A compound according to any one of the preceding claims, wherein A is selected from:

5. A compound according to any one of the preceding claims, wherein Y is an optionally substituted monocyclic or bicyclic 6- or 7-membered heterocycle.

6. A compound according to any one of the preceding claims, wherein Y is selected from piperidinyl, azepanyl, and 7-azabicyclo[2.2.1]hept-7-yl, each of which is optionally substituted.

7. A compound according to any one of the preceding claims, wherein Y is selected from:

8. A compound according to any one of the preceding claims, wherein X is borate citrate.

9. A compound according to any one of the preceding claims, wherein X is selected from:

10. A compound prepared by reacting a compound having formula (i) or a pharmaceutically acceptable salt thereof with a reagent selected from citric acid, malic acid, salicylic acid, lactic acid, tartaric acid and pinacol, wherein formula (i) is: in, A is an optionally substituted monocyclic or bicyclic heterocycle containing at least one nitrogen atom bonded to a methylene unit; Y is an optionally substituted monocyclic or bicyclic heterocycle containing at least one nitrogen atom bonded to the carbonyl group; and n is 0 or 1.

11. The compound according to claim 10, wherein A is an optionally substituted monocyclic or bicyclic 5-membered or 6-membered heterocyclic ring.

12. The compound according to claim 10 or 11, wherein A is selected from:

13. The compound according to any one of claims 10 to 12, wherein Y is an optionally substituted monocyclic or bicyclic 6- or 7-membered heterocycle.

14. The compound according to any one of claims 10 to 13, wherein Y is selected from 15. The compound according to any one of claims 10 to 14, wherein The reagent is citric acid.

16. A compound selected from:

17. The compound according to claim 16, which is selected from:

18. A boric acid ester of ((R)-1-(((((R)-1-(2-cyano-4-methyl-4-((R)-2-methylmorpholino)pent-2-enoyl)azepan-3-yl)oxy)carbonyl)amino)-2-phenylethyl)boronic acid or a pharmaceutically acceptable salt thereof, wherein the ester is selected from the group consisting of citrate, pinacol, malate, salicylate, lactate, and tartrate.

19. A boric acid ester of ((R)-1-(((((R)-1-((E)-2-cyano-4-methyl-4-((R)-2-methylmorpholino)pent-2-enoyl)azepan-3-yl)oxy)carbonyl)amino)-2-phenylethyl)boronic acid or a pharmaceutically acceptable salt thereof, wherein the ester is selected from the group consisting of citrate, pinacol, malate, salicylate, lactate, and tartrate.

20. A boric acid ester of [(1R)-1-[([[7-(2-cyano-2-[2-methyl-2-[(2S)-2-methylmorpholin-4-yl]propylidene]acetyl)-7-azabicyclo[2.2.1]hept-1-yl]methoxy]carbonyl)amino]-2-phenylethyl]boronic acid or a pharmaceutically acceptable salt thereof, wherein the ester is selected from citrate, pinacol ester, malate, salicylate, lactate, and tartrate.

21. A boric acid ester of ((R)-1-(((((R)-1-(2-cyano-4-(3,3-difluoropyrrolidin-1-yl)-4-methylpent-2-enoyl)piperidin-2-yl)methoxy)carbonyl)amino)-2-phenylethyl)boronic acid or a pharmaceutically acceptable salt thereof, wherein the ester is selected from citrate, pinacol, malate, salicylate, lactate, and tartrate.

22. The borate ester according to any one of claims 18 to 21, wherein The ester is a citrate ester.

23. A boronate ester of ((R)-1-(((((R)-1-(2-cyano-4-methyl-4-((R)-2-methylmorpholino)pent-2-enoyl)azepan-3-yl)oxy)carbonyl)amino)-2-phenylethyl)boronic acid or a pharmaceutically acceptable salt thereof, wherein the ester is converted to its corresponding acid upon exposure to physiological conditions.

24. A boric acid ester of ((R)-1-(((((R)-1-(2-cyano-4-methyl-4-((R)-2-methylmorpholino)pent-2-enoyl)azepan-3-yl)oxy)carbonyl)amino)-2-phenylethyl)boronic acid or a pharmaceutically acceptable salt thereof, wherein the ester is stable at 40°C and 75% relative humidity for at least three weeks.

25. A boric acid ester of ((R)-1-(((((R)-1-((E)-2-cyano-4-methyl-4-((R)-2-methylmorpholino)pent-2-enoyl)azepan-3-yl)oxy)carbonyl)amino)-2-phenylethyl)boronic acid or a pharmaceutically acceptable salt thereof, wherein the ester is a citrate and is at least about 95% pure.

26. The borate ester according to claim 25, wherein The esters are at least about 99% pure.

27. A crystalline form of ((R)-1-(((((R)-1-((E)-2-cyano-4-methyl-4-((R)-2-methylmorpholino)pent-2-enoyl)azepan-3-yl)oxy)carbonyl)amino)-2-phenylethyl)boronic acid citrate, wherein the crystalline form is Form I, characterized in that The X-ray powder diffraction pattern comprises at least three peaks selected from peaks at about 6.6±0.2, 11.2±0.2, 13.2±0.2, 13.8±0.2, 14.3±0.2, 15.6±0.2, 16.8±0.2, 17.5±0.2, 18.5±0.2, and 19.0±0.2 2-theta.

28. The crystalline form I according to claim 27, characterized in that The X-ray powder diffraction pattern was substantially similar to that in FIG6 .

29. The crystalline form I according to claim 27 or 28, characterized in that The DSC thermogram had a peak endotherm at about 192.7°C.

30. The crystalline form I according to any one of claims 27 to 29, characterized in that The DSC thermogram showed a melting onset at about 179.5 °C.

31. The crystalline form I according to any one of claims 27 to 30, characterized in that The DSC thermogram is substantially similar to the DSC thermogram in FIG. 7 .

32. The crystalline form I according to any one of claims 27 to 31, characterized in that The mass loss between about 25° C. and about 150° C. by thermogravimetric analysis is less than about 0.5 wt. %.

33. The crystalline form I according to any one of claims 27 to 32, characterized in that The TGA thermogram is substantially similar to the TGA thermogram in FIG. 7 .

34. A crystalline form of (I-1-((((((R)-1-((E)-2-cyano-4-methyl-4-((R)-2-methylmorpholino)pent-2-enoyl)azepan-3-yl)oxy)carbonyl)amino)-2-phenylethyl)boronic acid citrate, wherein the crystalline form is Form II, characterized in that The X-ray powder diffraction pattern comprises at least three peaks selected from peaks at about 6.1 ± 0.2, 8.1 ± 0.2, 10.6 ± 0.2, 11.0 ± 0.2, 11.9 ± 0.2, 14.0 ± 0.2, 14.7 ± 0.2, 16.6 ± 0.2, 43.7 ± 0.2, and 18.4 ± 0.2 2-theta.

35. The crystalline form II according to claim 34, characterized in that The X-ray powder diffraction pattern was substantially similar to that in FIG. 8 .

36. Form II according to claim 34 or 35, characterized in that The DSC thermogram had a peak endotherm at about 173.7°C.

37. The crystalline form II according to any one of claims 34 to 36, characterized in that The DSC thermogram showed a melting onset at about 164.9°C.

38. The crystalline form II according to any one of claims 34 to 37, characterized in that The DSC thermogram is substantially similar to the DSC thermogram in FIG. 9 .

39. The crystalline form II according to any one of claims 34 to 38, characterized in that The mass loss between about 25° C. and about 110° C. was about 5.6 wt. % by thermogravimetric analysis.

40. The crystalline form II according to any one of claims 34 to 39, characterized in that The TGA thermogram is substantially similar to the TGA thermogram in FIG. 9 .

41. The crystalline form I according to any one of claims 27 to 33, which is prepared by contacting the crystalline form II according to any one of claims 34 to 40 with an alcohol or an alcohol mixture.

42. A crystalline form of ((R)-1-(((((R)-1-((E)-2-cyano-4-methyl-4-((R)-2-methylmorpholino)pent-2-enoyl)azepan-3-yl)oxy)carbonyl)amino)-2-phenylethyl)boronic acid citrate, wherein the crystalline form is Form III, characterized in that The X-ray powder diffraction pattern comprises at least three peaks selected from peaks at about 5.9±0.2, 6.9±0.2, 9.4±0.2, 10.5±0.2, 11.1±0.2, 12.3±0.2, 12.7±0.2, 13.8±0.2, 14.3±0.2, and 15.2±0.2 2-theta.

43. The crystalline form III according to claim 42, characterized in that The X-ray powder diffraction pattern was substantially similar to that in FIG. 10 .

44. The crystalline form III according to claim 44 or 43, characterized in that The DSC thermogram had a peak endotherm at about 176.5°C.

45. The crystalline form III according to any one of claims 42-44, characterized in that The DSC thermogram has a broad endothermic peak from about 37.9°C to about 100°C.

46. ​​Form III according to claim 45, wherein The broad endothermic peak has a peak at about 70.4°C.

47. The crystalline form III according to any one of claims 42-46, characterized in that The DSC thermogram is substantially similar to the DSC thermogram in FIG. 11 .

48. The crystalline form III according to any one of claims 42-47, characterized in that The mass loss between about 25°C and about 105°C was about 3.1 wt.% by thermogravimetric analysis.

49. The crystalline form III according to any one of claims 42-48, characterized in that The TGA thermogram is substantially similar to the TGA thermogram in FIG. 11 .

50. Form III according to any one of claims 42-49, prepared by a process comprising contacting an alkyl ester, ether and / or toluene with Form II according to any one of claims 34-40.

51. The crystalline form III prepared by the method according to claim 50, wherein The alkyl ester is isopropyl acetate.

52. Form III prepared by the method according to claim 50 or 51, wherein The method further comprises separating Form III from the alkyl ester.

53. A pharmaceutical composition comprising at least one compound according to any one of claims 1 to 17 and a pharmaceutically acceptable excipient.

54. A pharmaceutical composition comprising at least one boric acid ester according to any one of claims 18-26 and a pharmaceutically acceptable excipient.

55. A pharmaceutical composition comprising at least one crystalline form of ((R)-1-(((((R)-1-((E)-2-cyano-4-methyl-4-((R)-2-methylmorpholino)pent-2-enoyl)azepan-3-yl)oxy)carbonyl)amino)-2-phenylethyl)boronic acid citrate according to any one of claims 27-52 and a pharmaceutically acceptable excipient.

56. A method of inhibiting large multifunctional protease 2 (LMP2) in a subject, the method comprising administering to the subject in need of such inhibition a therapeutically effective amount of a compound according to any one of claims 1-17, at least one boronic acid ester according to any one of claims 18-26, or at least one crystalline form of the citrate ester of ((R)-1-(((((R)-1-((E)-2-cyano-4-methyl-4-((R)-2-methylmorpholino)pent-2-enoyl)azepan-3-yl)oxy)carbonyl)amino)-2-phenylethyl)boronic acid according to any one of claims 27-52.

57. A method of inhibiting large multifunctional protease 7 (LMP7) in a subject, the method comprising administering to the subject in need of such inhibition a therapeutically effective amount of a compound according to any one of claims 1-17, at least one boronic acid ester according to any one of claims 18-26, or at least one crystalline form of the citrate ester of ((R)-1-(((((R)-1-((E)-2-cyano-4-methyl-4-((R)-2-methylmorpholino)pent-2-enoyl)azepan-3-yl)oxy)carbonyl)amino)-2-phenylethyl)boronic acid according to any one of claims 27-52.

58. A method of treating a disease selected from the group consisting of an autoimmune disorder, an inflammatory disorder, and a hematological disorder in a patient in need of such treatment, the method comprising administering to the patient a therapeutically effective amount of a compound according to any one of claims 1-17, at least one boronic acid ester according to any one of claims 18-26, or at least one crystalline form of the citrate ester of ((R)-1-(((((R)-1-((E)-2-cyano-4-methyl-4-((R)-2-methylmorpholino)pent-2-enoyl)azepan-3-yl)oxy)carbonyl)amino)-2-phenylethyl)boronic acid according to any one of claims 27-52.

59. The method of claim 58, wherein: The disease is selected from lupus, arthritis including rheumatoid arthritis and psoriatic arthritis, scleroderma, ankylosing spondylitis, Duchenne muscular dystrophy (DMD), Becker muscular dystrophy (BMD), idiopathic inflammatory myopathy (IIM), polymyositis, sporadic inclusion body myositis, dermatomyositis, immune-mediated necrotizing myopathy (IMNM), psoriasis, multiple sclerosis, inflammatory bowel disease, Behcet's disease, ulcerative colitis, Crohn's disease, Sjogren's syndrome, bronchitis, conjunctivitis, pancreatitis, cholecystitis, bronchiectasis, aortic stenosis, restenosis, fibrosis, infection, ischemia, cardiovascular disease, hepatitis, cirrhosis, steatohepatitis, liver inflammation, Alzheimer's disease (AD), amyotrophic lateral sclerosis (ALS), Huntington's disease, body myositis, myofibrillar myopathy, graft versus host disease (GVHD), and multiple myeloma.

60. Use of a composition as a medicament for inhibiting large multifunctional protease 2 (LMP2) in a subject, wherein the composition comprises a therapeutically effective amount of a compound according to any one of claims 1-17, at least one boronic acid ester according to any one of claims 18-26, or at least one crystalline form of the citrate ester of ((R)-1-(((((R)-1-((E)-2-cyano-4-methyl-4-((R)-2-methylmorpholino)pent-2-enoyl)azepan-3-yl)oxy)carbonyl)amino)-2-phenylethyl)boronic acid according to any one of claims 27-52.

61. Use of a composition as a medicament for inhibiting large multifunctional protease 7 (LMP7) in a subject, wherein the composition comprises a therapeutically effective amount of a compound according to any one of claims 1-17, at least one boronic acid ester according to any one of claims 18-26, or at least one crystalline form of the citrate ester of ((R)-1-(((((R)-1-((E)-2-cyano-4-methyl-4-((R)-2-methylmorpholino)pent-2-enoyl)azepan-3-yl)oxy)carbonyl)amino)-2-phenylethyl)boronic acid according to any one of claims 27-52.

62. Use of a composition as a medicament for treating a disease in a subject in need thereof, wherein the composition comprises administering to the patient a therapeutically effective amount of a compound according to any one of claims 1-17, at least one boronic acid ester according to any one of claims 18-26, or at least one crystalline form of a citrate ester of ((R)-1-(((((R)-1-((E)-2-cyano-4-methyl-4-((R)-2-methylmorpholino)pent-2-enoyl)azepan-3-yl)oxy)carbonyl)amino)-2-phenylethyl)boronic acid; And wherein the disease is selected from the group consisting of an autoimmune disorder, an inflammatory disorder, and a hematological disorder.

63. The use according to claim 62, wherein The disease is selected from lupus, arthritis including rheumatoid arthritis and psoriatic arthritis, scleroderma, ankylosing spondylitis, Duchenne muscular dystrophy (DMD), Becker muscular dystrophy (BMD), idiopathic inflammatory myopathy (IIM), polymyositis, sporadic inclusion body myositis, dermatomyositis, immune-mediated necrotizing myopathy (IMNM), psoriasis, multiple sclerosis, inflammatory bowel disease, Behcet's disease, ulcerative colitis, Crohn's disease, Sjogren's syndrome, bronchitis, conjunctivitis, pancreatitis, cholecystitis, bronchiectasis, aortic stenosis, restenosis, fibrosis, infection, ischemia, cardiovascular disease, hepatitis, cirrhosis, steatohepatitis, liver inflammation, Alzheimer's disease (AD), amyotrophic lateral sclerosis (ALS), Huntington's disease, body myositis, myofibrillar myopathy, graft versus host disease (GVHD), and multiple myeloma.

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