Cyclic boronic acid ester and its use

Abstract

The present disclosure relates to cyclic boronic acid esters and salts thereof for use as immunoproteasome inhibitors. The present disclosure further relates to pharmaceutical compositions, methods of preparation, crystals and polymorphs, and methods of treatment related thereto.

Description

Technical Field

[0001] Cross - Reference to Related Applications This application claims priority to U.S. Provisional Patent Application No. 63 / 357,093, filed Jun. 30, 2022, which is hereby incorporated by reference in its entirety.

[0002] The present disclosure relates to cyclic boronic esters and salts thereof for use as immunoproteasome inhibitors. The present disclosure further relates to pharmaceutical compositions, methods of preparation, crystals and polymorphs, and methods of treatment related thereto.

Background Art

[0003] The immunoproteasome is a large proteolytic machinery derived from the constitutive proteasome and is expressed in both immune and non-immune cells. The immunoproteasome plays an important role in the immune system as it degrades proteins into short peptides that can be processed to fit into the groove of major histocompatibility complex (MHC) class I molecules. This presentation of peptides on MHC I enables recognition by CD8 T cells of the adaptive immune system. Such recognition can help CD8 T cells destroy pathogen-infected cells. In addition to its role in pathogen recognition and clearance, the immunoproteasome is also known to influence the progression of inflammatory diseases through its ability to regulate T cell polarization and inflammation and neoplastic transformation. See, for example, 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 pages; 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 known as 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 co-localize with MHC class I-expressing muscle fibers. See Bhattarai, S., et al. 2016, “The immunoproteasomes are key to regulating myokines and MHC class I expression in idiopathic inflammatory myopathies,” J Autoimmunity, 75:118-129. Furthermore, the expression of LMP2 and LMP7 has also been shown to be upregulated in colitis lesions. See, e.g., same reference; 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 have been associated with psoriasis based on analysis of patient samples. See, e.g., Kraemer, 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 that reduces inflammation, cell infiltration, and tissue damage in a mouse model of skin injury, suggesting that LMP7 inhibition could be a potential treatment for inflammatory skin diseases such as psoriasis, cutaneous erythematosus, and systemic sclerosis. See Ah Kioon, M.D. et al. 2021. “Noncytotoxic Inhibition of the Immunoproteasome Regulates Human Immune Cells In Vitro and Suppresses Cutaneous Inflammation in the Mouse,” J Immunol. 206:1631-1641. ONX-0914 (also known as PR-957), a selective inhibitor of LMP7, has been used as a therapeutic agent for autoimmune diseases such as colitis in animal models. See, for example, Kimura 2015 (supra). Studies on ONX-0914 have also suggested its potential to attenuate 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. 185(1):634-641. ONX-0914 has been reported to attenuate experimental arthritis by blocking inflammatory cytokine expression. See, for example, Kimura 2015 (supra). 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 Immunoproteasome Subunit LMP7 with ONX0914 Ameliorates Graft-versus-Host Disease in an MHC-Matched Minor Histocompataibility 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, September 2021, 49(9)810-821. In murine models of rheumatoid arthritis and systemic lupus erythematosus (SLE), KZR-616 blocked disease progression at tolerogenic doses without affecting normal T cell-dependent immune responses. See the same reference. KZR-616 is currently being evaluated in a Phase 2 clinical trial in patients with SLE and lupus nephritis. See the same reference.

[0006] Furthermore, the selective LMP2 inhibitors UK-101 and IPSI-001 have been shown to exhibit antitumor activity against multiple myeloma. See, e.g., the cited references. Similarly, PR-924, a selective inhibitor of LMP7, inhibited proliferation and induced apoptosis in multiple myeloma (MM) cell lines and primary patient MM cells without significantly affecting normal peripheral blood mononuclear cells. See Singh, A.V. 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, for example, in WO 2009 / 154737, certain boronic acid compounds have been disclosed as effective immunoproteasome inhibitors. Despite these promising candidates, additional boronic acid-based immunoproteasome inhibitors are needed, particularly since boronic acids are known to be amorphous and can be difficult to manufacture on a large scale or to purify in the final product. Furthermore, certain boronic acids are prone to hydrolysis and oxidation due to the presence of the boronic acid functional group. This inherent chemical instability can result in potential chemical instability during the manufacture and storage of the drug substance and formulations. Accordingly, there is a need for additional compounds that exhibit similar properties in vivo but can be more readily or efficiently manufactured and / or stored. The preparation of pharmaceutical salts of the compounds of interest is a common strategy for attempting to find more stable compounds for manufacture and storage. Surprisingly, it has been found that cyclic boronic acid esters are formed when attempting to make acid salts of certain boronic acid immunoproteasome inhibitor compounds. Furthermore, some of these esters have been shown to be more stable than the corresponding acids, have higher crystallinity, or both.

[0008] Accordingly, in one aspect, provided herein are cyclic boronic acid esters and salts thereof for use in the treatment of conditions associated with LMP2 and / or LMP7. Summary of the Invention Means for Solving the Problems

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

[0010] Embodiment 1. A compound of formula (I) or a pharmaceutically acceptable salt thereof

Chemical formula

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

[0012] Embodiment 3. The 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 is:

Chemical formula

[0014] Compound according to any one of the preceding embodiments, wherein Y is a monocyclic or bicyclic 6- or 7-membered heterocycle which may be substituted.

[0015] Compound according to any one of the preceding embodiments, wherein Y is selected from piperidinyl, azepanyl and 7-azabicyclo[2.2.1]heptan-7-yl, each of which may be substituted.

[0016] Embodiment 7. Y is:

Chemical formula

[0017] Compound according to any one of the preceding embodiments, wherein X is a citric acid boronic acid ester.

[0018] Embodiment 9. X is:

Chemical formula

[0019] Embodiment 10. A compound prepared by reacting a compound of 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:

Chemical formula

[0020] Embodiment 11. The compound according to Embodiment 10, wherein A is a monocyclic or bicyclic 5- or 6-membered heterocyclic ring which may be substituted.

[0021] Embodiment 12. A is:

Chemical formula

[0022] Embodiment 13. The compound according to any one of Embodiments 10 to 12, wherein Y is a monocyclic or bicyclic 6- or 7-membered heterocyclic ring which may be substituted.

[0023] Embodiment 14. Y is:

Chemical formula

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

[0025] Embodiment 16. The following:

Chemical formula

Chemical formula

[0026] Embodiment 17. The following:

Chemical formula

[0027] Embodiment 18. A boronic acid ester of ((R)-1-(((((R)-1-(2-cyano-4-methyl-4-((R)-2-methylmorpholino)penta-2-enoyl)azepan-3-yl)oxy)carbonyl)amino)-2-phenylethyl)boronic acid or a pharmaceutically acceptable salt thereof, which is a boronic acid ester selected from citric acid esters, pinacol esters, malic acid esters, salicylic acid esters, lactic acid esters, and tartaric acid esters.

[0028] Embodiment 19. A boronic acid ester of ((R)-1-(((((R)-1-((E)-2-cyano-4-methyl-4-((R)-2-methylmorpholino)penta-2-enoyl)azepan-3-yl)oxy)carbonyl)amino)-2-phenylethyl)boronic acid or a pharmaceutically acceptable salt thereof, which is a boronic acid ester selected from citric acid esters, pinacol esters, malic acid esters, salicylic acid esters, lactic acid esters, and tartaric acid esters.

[0029] Embodiment 20. A boronic acid ester of [(1R)-1-[([[7-(2-cyano-2-[2-methyl-2-[(2S)-2-methylmorpholin-4-yl]propylidene]acetyl)-7-azabicyclo[2.2.1]heptan-1-yl]methoxy]carbonyl)amino]-2-phenylethyl]boronic acid or a pharmaceutically acceptable salt thereof, which is a boronic acid ester selected from citric acid esters, pinacol esters, malic acid esters, salicylic acid esters, lactic acid esters, and tartaric acid esters.

[0030] Embodiment 21. A boronic acid ester of ((R)-1-(((((R)-1-(2-cyano-4-(3,3-difluoropyrrolidin-1-yl)-4-methylpenta-2-enoyl)piperidin-2-yl)methoxy)carbonyl)amino)-2-phenylethyl)boronic acid or a pharmaceutically acceptable salt thereof, which is a boronic acid ester selected from citric acid esters, pinacol esters, malic acid esters, salicylic acid esters, lactic acid esters, and tartaric acid esters.

[0031] Boronic acid ester according to any one of Embodiments 18 to 21, wherein the ester is a citrate ester.

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

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

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

[0035] Embodiment 26. The boronic acid ester according to Embodiment 25, wherein the ester is at least about 99% pure.

[0036] Crystal Form I, which is a crystalline form of the citrate ester of ((R)-1-(((((R)-1-((E)-2-cyano-4-methyl-4-((R)-2-methylmorpholino)penta-2-enoyl)azepan-3-yl)oxy)carbonyl)amino)-2-phenylethyl)boronic acid, characterized by an X-ray powder diffractogram comprising at least three peaks selected from the peaks of 2-theta of 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.

[0037] Embodiment 28. Crystal Form I according to Embodiment 27, characterized by an X-ray powder diffractogram substantially the same as that of FIG. 6.

[0038] Embodiment 29. Crystal Form I according to Embodiment 27 or 28, characterized by a DSC thermogram having a peak endotherm at about 192.7 °C.

[0039] Embodiment 30. Crystal Form I according to any one of Embodiments 27 to 29, characterized by a DSC thermogram showing the start of melting at about 179.5 °C.

[0040] Embodiment 31. Crystal Form I according to any one of Embodiments 27 to 30, characterized by a DSC thermogram substantially the same as that of FIG. 7.

[0041] Embodiment 32. Crystal Form I according to any one of Embodiments 27 to 31, characterized by a mass loss of less than about 0.5 wt% from about 25 °C to about 150 °C by thermogravimetric analysis.

[0042] Embodiment 33. Crystal Form I according to any one of Embodiments 27 to 32, characterized by a TGA thermogram substantially the same as that of FIG. 7.

[0043] Crystal Form II of the Citric Acid Ester of (I-1-(((((R)-1-((E)-2-Cyano-4-methyl-4-((R)-2-methylmorpholino)penta-2-enoyl)azepan-3-yl)oxy)carbonyl)amino)-2-phenylethyl)boronic Acid, characterized by an X-ray powder diffractogram containing at least three peaks selected from the 2-θ peaks of 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.

[0044] Embodiment 35. Crystal Form II according to Embodiment 34, characterized by an X-ray powder diffractogram substantially the same as that of FIG. 8.

[0045] Embodiment 36. Crystal Form II according to Embodiment 34 or 35, characterized by a DSC thermogram having a peak endotherm at about 173.7 °C.

[0046] Embodiment 37. Crystal Form II according to any one of Embodiments 34 to 36, characterized by a DSC thermogram showing the start of melting at about 164.9 °C.

[0047] Embodiment 38. Crystal Form II according to any one of Embodiments 34 to 37, characterized by a DSC thermogram substantially the same as that of FIG. 9.

[0048] Embodiment 39. Crystal Form II according to any one of Embodiments 34 to 38, characterized by a mass loss of about 5.6 wt% from about 25 °C to about 110 °C by thermogravimetric analysis.

[0049] Embodiment 40. Crystal Form II according to any one of Embodiments 34 to 39, characterized by a TGA thermogram substantially the same as that of FIG. 9.

[0050] Crystal Form I according to any one of Embodiments 27 to 33, prepared by contacting Crystal Form II according to any one of Embodiments 34 to 40 with an alcohol or an alcohol mixture.

[0051] Embodiment 42. A citrate crystal form of ((R)-1-(((((R)-1-((E)-2-cyano-4-methyl-4-((R)-2-methylmorpholino)penta-2-enoyl)azepan-3-yl)oxy)carbonyl)amino)-2-phenylethyl)boronic acid, wherein the crystal form is Crystal Form III, and an X-ray powder diffractogram characterized by including at least three peaks selected from the 2-θ peaks of 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.

[0052] Embodiment 43. Crystal Form III according to Embodiment 42, characterized by an X-ray powder diffractogram substantially the same as that of FIG. 10.

[0053] Embodiment 44. Crystal Form III according to Embodiment 42 or 43, characterized by a DSC thermogram having a peak endotherm at about 176.5°C.

[0054] Embodiment 45. Crystal Form III according to any one of Embodiments 42 to 44, characterized by a DSC thermogram having a broad endotherm from about 37.9°C to about 100°C.

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

[0056] Embodiment 47. Crystal Form III according to any one of Embodiments 42 to 46, characterized by a DSC thermogram substantially the same as that of FIG. 11.

[0057] Embodiment 48. Crystal Form III according to any one of Embodiments 42 to 47, characterized by a mass loss of about 3.1 wt% from about 25 °C to about 105 °C by thermogravimetric analysis.

[0058] Embodiment 49. Crystal Form III according to any one of Embodiments 42 to 48, characterized by a TGA thermogram substantially similar to that of Figure 11.

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

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

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

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

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

[0064] Embodiment 55. A pharmaceutical composition comprising at least one crystal form of the citrate ester of ((R)-1-(((((R)-1-((E)-2-cyano-4-methyl-4-((R)-2-methylmorpholino)penta-2-enoyl)azepan-3-yl)oxy)carbonyl)amino)-2-phenylethyl)boronic acid according to any one of Embodiments 27 to 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 such inhibition a therapeutically effective amount of a compound according to any one of Embodiments 1 to 17, at least one boronic acid ester according to any one of Embodiments 18 to 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 to 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 such inhibition a therapeutically effective amount of a compound according to any one of Embodiments 1 to 17, at least one boronic acid ester according to any one of Embodiments 18 to 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 to 52.

[0067] Embodiment 58. A method of treating a disease selected from autoimmune disorders, inflammatory disorders, and blood disorders 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 to 17, at least one boronic acid ester according to any one of Embodiments 18 to 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 to 52.

[0068] Embodiment 59. The method according to embodiment 58, wherein the disease is selected from lupus, rheumatoid arthritis and arthritis including 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 valve stenosis, restenosis, fibrosis, infectious disease, ischemia, cardiovascular disease, hepatitis, cirrhosis, non-alcoholic steatohepatitis, liver inflammation, Alzheimer's disease (AD), amyotrophic lateral sclerosis (ALS), Huntington's disease, polymyositis, 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 to 17, at least one boronic acid ester according to any one of embodiments 18 to 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)penta-2-enoyl)azepan-3-yl)oxy)carbonyl)amino)-2-phenylethyl)boronic acid according to any one of embodiments 27 to 52.

[0070] Embodiment 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 embodiments 1 to 17, at least one boronic acid ester according to any one of embodiments 18 to 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)penta-2-enoyl)azepan-3-yl)oxy)carbonyl)amino)-2-phenylethyl)boronic acid according to any one of embodiments 27 to 52.

[0071] Embodiment 62. Thus, a use of a composition as a medicament for treating a disease in a subject in need of treatment, wherein the composition comprises administering to the patient a therapeutically effective amount of a compound according to any one of Embodiments 1 to 17, at least one boronic acid ester according to any one of Embodiments 18 to 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)penta-2-enoyl)azepan-3-yl)oxy)carbonyl)amino)-2-phenylethyl)boronic acid according to any one of Embodiments 27 to 52; the disease being selected from autoimmune disorders, inflammatory disorders, and hematological disorders.

[0072] Embodiment 63. The use according to Embodiment 62, wherein the disease is selected from arthritis including lupus, 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, Sjögren's syndrome, bronchitis, conjunctivitis, pancreatitis, cholecystitis, bronchiectasis, aortic valve stenosis, restenosis, fibrosis, infectious diseases, ischemia, cardiovascular diseases, hepatitis, cirrhosis, non-alcoholic steatohepatitis, liver inflammation, Alzheimer's disease (AD), amyotrophic lateral sclerosis (ALS), Huntington's disease, polymyositis, myofibrillar myopathy, graft-versus-host disease (GVHD), and multiple myeloma.

Brief Description of the Drawings

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Mode for Carrying Out the Invention

[0074] Definition Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which the claimed subject matter belongs. It is to be understood that the foregoing general description and the following detailed description are exemplary and explanatory only and are not restrictive of any claimed subject matter. The expression content is controlled to the extent that any material incorporated herein as part of this specification conflicts with the disclosure content. In this application, unless otherwise specified, the use of the singular form includes the plural form. As used in this specification and the appended claims, the singular forms "a", "an", and "the" include plural referents unless the context clearly dictates otherwise. In this application, the use of "or" means "and / or" unless the context requires otherwise. Further, the use of the term "including" and other forms such as "include", "includes", and "included" is not limiting.

[0075] References herein to "some embodiments", "an embodiment", "one embodiment" or "other embodiments" mean 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.

[0076] As used herein, ranges and amounts can be expressed as “about” a particular value or range. About includes the exact amount. Thus, “about 5 μL” means “about 5 μL” and “5 μL”. In general, the term “about” includes amounts that are expected to be within experimental error, such as within 15%, 10%, or 5% for example.

[0077] The section headings used herein are for organization only and should in no way be construed as limiting the subject matter described.

[0078] “Alkyl” refers to a non-branched or branched saturated hydrocarbon chain. As used herein, alkyl has 1 to 20 carbon atoms (i.e., C1-C 20 alkyl), 1 to 10 carbon atoms (i.e., C1-C 10 alkyl), 1 to 6 carbon atoms (i.e., C1-C6 alkyl) or 1 to 3 carbon atoms (i.e., C1-C3 alkyl). Examples of alkyl groups include methyl, ethyl, propyl, isopropyl, n-butyl, sec-butyl, iso-butyl, tert-butyl, pentyl, 2-pentyl, isopentyl, neopentyl, hexyl, 2-hexyl, 3-hexyl and 3-methylpentyl. When an alkyl residue having a specific number of carbons is named by chemical name or identified by molecular formula, all positional isomers having that number of carbons can be included; thus, for example, “butyl” includes n-butyl (i.e., -(CH2)3CH3), isobutyl (i.e., -CH2CH(CH3)2), sec-butyl (i.e., -CH(CH3)CH2CH3) and tert-butyl (i.e., -C(CH3)3); “propyl” includes n-propyl (i.e., -(CH2)2CH3) and isopropyl (i.e., -CH(CH3)2).

[0079] “Methylene” refers to the -CH2- group.

[0080] “Carbonyl” refers to the -C(=O)- group.

[0081] The term "heterocyclyl" or "heterocyclic ring" refers to a saturated or unsaturated cyclic alkyl group having one or more ring heteroatoms independently selected from nitrogen, oxygen, and sulfur. The term "heterocyclyl" includes heterocycloalkenyl groups (i.e., heterocyclyl groups having at least one double bond), bridged heterocyclyl groups, fused heterocyclyl groups, and spiro - heterocyclyl groups. Heterocyclyl may be monocyclic, or a plurality of rings may be fused, bridged, or spiro, and may contain one or more oxo (C=O) or N - oxide (N - O -) moieties. Any non - aromatic ring containing at least one heteroatom is considered heterocyclyl regardless of the bond (i.e., it can be bonded via a carbon atom or a heteroatom). Further, the term heterocyclyl is intended to encompass any non - aromatic ring containing at least one heteroatom, and this ring may be fused to an aryl ring or a heteroaryl ring regardless of the bond to the remainder of the molecule. As used herein, heterocyclyl 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, heterocyclyl 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 heterocyclyl groups include azepanyl, 7 - azabicyclo[2.2.1]heptan - 7 - yl, dioxolanyl, thienyl[1.3]dithianyl, decahydroisoquinolyl, imidazolinyl, imidazolidinyl, isothiazolidinyl, isoxazolidinyl, morpholinyl, octahydroindolyl, octahydroisoindolyl, 2 - oxopiperazinyl, 2 - oxopiperidinyl, 2 - oxopyrrolidinyl, oxazolidinyl, piperidinyl, piperazinyl, 4 - piperidinyl, pyrrolidinyl, pyrazolidinyl, quinuclidinyl, thiazolidinyl, tetrahydrofuryl, trithianyl, tetrahydropyranyl, thiomorpholinyl, thiomorpholinyl, 1 - oxo - thiomorpholinyl, and 1,1 - dioxo - thiomorpholinyl.

[0082] As used herein, the term "optionally substituted" when referring to a heterocyclic group refers to a heterocyclic group in which one or more hydrogen atoms on carbon or on a heteroatom are substituted with an alkyl group, halo, cyano or hydroxy.

[0083] "Cyano" refers to the group -CN.

[0084] "Halogen" or "halo" includes fluoro, chloro, bromo and iodo.

[0085] "Hydroxy" refers to the group -OH.

[0086] Certain commonly used alternative chemical names may be used. For example, divalent groups such as a divalent "alkyl" group, a divalent "phenyl" group, a divalent "heteroaryl" group, a divalent "heterocyclyl" group, etc. may also be referred to as an "alkylene" group, a "phenylene" group, a "heteroarylene" group, or a "heterocyclylene" group, respectively.

[0087] The term "optional" or "optionally" means that the subsequently described event or circumstance may or may not occur, and that the description includes both the case where the event or circumstance occurs and the case where it does not occur.

[0088] "Pharmaceutically acceptable" refers to compounds, salts, compositions, dosage forms, and other materials useful in preparing pharmaceutical compositions suitable for human pharmaceutical use.

[0089] The term "pharmaceutically acceptable salt" of a given compound refers to a salt that retains the biological effectiveness and properties of the given compound and that is not biologically or otherwise undesirable.

[0090] The compounds described herein or their pharmaceutically acceptable salts may contain asymmetric centers and, thus, can give rise to enantiomers, diastereomers, and other stereoisomeric forms that can be defined as (R)- or (S)- for amino acids, or as (D)- or (L)- from the perspective of absolute stereochemistry. This disclosure is meant to include all such possible isomers, as well as their racemic and optically pure forms. The optically active (+) and (-), (R)- and (S)-, or (D)- and (L)- isomers may be prepared using a chiral synthon or chiral reagent or resolved using conventional techniques such as chromatography and fractional crystallization. Conventional techniques for the preparation / isolation of individual enantiomers include chiral synthesis from an appropriate optically pure precursor or resolution of a racemate (or a racemate of a salt or derivative) using, for example, chiral high performance liquid chromatography (HPLC).

[0091] "Tautomers" refer to alternative forms of a compound where the position of protons is different, such as enol-keto and imine-enamine tautomers, or tautomeric forms of heteroaryl groups containing ring atoms bonded to both a ring-NH- moiety and a ring=N moiety, such as pyrazole, imidazole, benzimidazole, triazole, and tetrazole. All tautomeric forms of the compounds described herein are intended to be included.

[0092] "Stereoisomers" refer to compounds that are composed of the same atoms bonded by the same bonds but have different three-dimensional structures and are not interchangeable. This disclosure contemplates various stereoisomers and mixtures thereof and includes "enantiomers", which refer to two stereoisomers that are mirror images of each other and cannot be superimposed on each other.

[0093] "Diastereoisomers" are stereoisomers that have at least two asymmetric atoms but are not mirror images of each other.

[0094] As used herein, the terms "pharmaceutically acceptable carrier", "pharmaceutically acceptable excipient", or "excipient" include 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. The use thereof in therapeutic compositions is contemplated, except where any conventional media or agent is incompatible with the active ingredient. Auxiliary active ingredients can also be incorporated into the compositions.

[0095] The "effective amount" or dose of a compound or composition refers to the amount of the compound or composition that results in the intended outcome. 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 (lethal dose for 50% of the population) and the ED 50 (therapeutically effective dose in 50% of the population).

[0096] The "therapeutically effective amount" or dose of a compound or composition refers to the amount of the compound or composition that results in the alleviation or inhibition of symptoms or the prolongation of survival in a subject (i.e., a human patient). The result may require multiple administrations of the compound or composition.

[0097] "Treating" or "treatment" of a disease in a subject refers to: 1) preventing the occurrence of the disease in a patient who has a predisposition to the disease or who has not yet shown symptoms of the disease; 2) inhibiting the disease or halting its onset; or 3) ameliorating or regressing the disease. As used herein, "treatment" or "treating" is an approach to obtain a beneficial or desired result, including clinical outcomes. For the purposes of this disclosure, beneficial or desired results include, but are not limited to, one or more of the following: reducing one or more symptoms resulting from the disease or disorder, reducing the severity of the disease or disorder, stabilizing the disease or disorder (e.g., preventing or delaying worsening of the disease or disorder), delaying the occurrence or recurrence of the disease or disorder, delaying or retarding the progression of the disease or disorder, improving the condition of the disease or disorder, effecting remission (partial or total) of the disease or disorder, reducing the dosage of one or more other drugs required to treat the disease or disorder, enhancing the effect of another drug 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. A reduction in the pathological consequences of the disease or disorder is also encompassed by "treatment". The methods of the present invention contemplate any one or more of these aspects of treatment.

[0098] As used herein, the terms "subject" and "patient" mean any mammal. In some embodiments, the mammal is a human. Neither term requires, nor is limited to, a situation characterized by the management (e.g., regular or intermittent) of a healthcare provider (e.g., a physician, registered nurse, clinical nurse, physician assistant, nursing assistant, or hospice worker).

[0099] As used herein, the term "pharmaceutical composition" or "pharmaceutical" refers to a composition suitable for pharmaceutical use in a subject.

[0100] Although the various features of the present invention can be described in the context of a single embodiment, the features can also be provided separately or in any suitable combination. Conversely, although the present invention may be described herein in the context of separate embodiments for clarity, the present invention may also be implemented in a single embodiment.

[0101] Compound In one aspect, a compound of formula (I) or a pharmaceutically acceptable salt thereof:

Chemical formula

[0102] 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 substituted with at least one alkyl and / or halo. In some embodiments, A is an optionally substituted monocyclic 5- or 6-membered heterocycle substituted with at least one alkyl and / or halo. In some embodiments, A is selected from optionally substituted pyrrolidinyl and optionally substituted morpholinyl. In some embodiments, A is optionally substituted pyrrolidinyl or morpholinyl substituted with at least one alkyl and / or halo. In some embodiments, A is:

Chemical formula

Chemical formula

[0103] In some embodiments, Y is an optionally substituted monocyclic or bicyclic 6- or 7-membered heterocyclic ring. In some embodiments, Y is an optionally substituted monocyclic or bicyclic 7-membered heterocyclic ring. In some embodiments, Y is an optionally substituted monocyclic or bicyclic 6- or 7-membered heterocyclic ring substituted with at least one alkyl and / or halo. In some embodiments, Y is a monocyclic or bicyclic 6- or 7-membered heterocyclic ring and is unsubstituted. In some embodiments, Y is selected from piperidinyl, azepanyl, and 7-azabicyclo[2.2.1]heptan-7-yl, each of which may be optionally substituted. In some embodiments, Y is selected from piperidinyl, azepanyl, and 7-azabicyclo[2.2.1]heptan-7-yl, each of which is unsubstituted. In some embodiments, Y is:

Chemical formula

[0104] In some embodiments, X is selected from citrate esters and pinacol esters. In some embodiments, X is a citric acid boronic ester. In some embodiments, X is:

Chemical formula

[0105] In some embodiments, X is:

Chemical formula

Chemical formula

[0106] In some embodiments, n is 0. In some embodiments, n is 1.

[0107] In one aspect, provided herein is a compound prepared by reacting a compound of 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 [Chemical formula] (wherein 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; and n is 0 or 1) is.

[0108] 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 substituted with at least one alkyl and / or halo. In some embodiments, A is an optionally substituted monocyclic 5- or 6-membered heterocycle substituted with at least one alkyl and / or halo. In some embodiments, A is selected from optionally substituted pyrrolidinyl and optionally substituted morpholinyl. In some embodiments, A is optionally substituted pyrrolidinyl or morpholinyl substituted with at least one alkyl and / or halo. In some embodiments, A is: [Chemical formula] selected from. In some embodiments, A is [Chemical formula] is as follows.

[0109] In some embodiments, Y is a monocyclic or bicyclic 6- or 7-membered heterocyclic ring which may be substituted. In some embodiments, Y is a monocyclic or bicyclic 7-membered heterocyclic ring which may be substituted. In some embodiments, Y is a monocyclic or bicyclic 6- or 7-membered heterocyclic ring which may be substituted with at least one alkyl and / or halo. In some embodiments, Y is a monocyclic or bicyclic 6- or 7-membered heterocyclic ring which is unsubstituted. In some embodiments, Y is selected from piperidinyl, azepanyl and 7-azabicyclo[2.2.1]heptan-7-yl, each of which may be substituted. In some embodiments, Y is selected from piperidinyl, azepanyl and 7-azabicyclo[2.2.1]heptan-7-yl, each of which is unsubstituted. In some embodiments, Y is:

Chemical formula

[0110] In some embodiments, n is 0. In some embodiments, n is 1.

[0111] In some embodiments, the reagent is selected from citric acid esters and pinacol esters. In some embodiments, the reagent is citric acid.

[0112] It is understood that in the description herein, any description, modification, embodiment or aspect of a part can be combined with any description, modification, embodiment or aspect of another part as if every possible combination were specifically and individually recited. For example, all the descriptions, modifications, embodiments, or aspects provided herein regarding ring A of formula (I) and formula (i) can be combined with all the descriptions, modifications, embodiments, or aspects of X or Y or n, as if all the combinations were specifically and individually recited.

[0113] In some embodiments, a compound selected from the compounds of Table 1 or a pharmaceutically acceptable salt thereof is provided. The specific compounds described in this disclosure including Table 1 are presented as specific stereoisomers and / or in non-stereochemical forms, but it is understood that any or all stereochemical forms including any enantiomeric or diastereomeric forms, and any tautomeric or other forms of any of the compounds of this disclosure including Table 1 are described herein.

[0114]

Table 1

[0115]

Table 2

[0116]

Table 3

[0117]

Table 4

[0118]

Table 5

[0119] In some embodiments, the compound is

Chemical formula

[0120] In one aspect, provided herein is a boronic acid ester of ((R)-1-(((((R)-1-(2-cyano-4-methyl-4-((R)-2-methylmorpholino)penta-2-enoyl)azepan-3-yl)oxy)carbonyl)amino)-2-phenylethyl)boronic acid or a pharmaceutically acceptable salt thereof, wherein the boronic acid ester is selected from citrate esters, pinacol esters, malate esters, salicylate esters, lactate esters, and tartrate esters. In some embodiments, the ester is selected from pinacol esters and citrate esters. In some embodiments, the ester is a citrate ester.

[0121] In one aspect, provided herein is a boronic acid ester of ((R)-1-(((((R)-1-((E)-2-cyano-4-methyl-4-((R)-2-methylmorpholino)penta-2-enoyl)azepan-3-yl)oxy)carbonyl)amino)-2-phenylethyl)boronic acid or a pharmaceutically acceptable salt thereof, wherein the boronic acid ester is selected from citrate esters, pinacol esters, malate esters, salicylate esters, lactate esters, and tartrate esters. In some embodiments, the ester is selected from pinacol esters and citrate esters. In some embodiments, the ester is a citrate ester.

[0122] In one aspect, provided herein is a boronic acid ester of [(1R)-1-[([[7-(2-cyano-2-[2-methyl-2-[(2S)-2-methylmorpholin-4-yl]propylidene]acetyl)-7-azabicyclo[2.2.1]heptan-1-yl]methoxy]carbonyl)amino]-2-phenylethyl]boronic acid or a pharmaceutically acceptable salt thereof, wherein the boronic acid ester is selected from citrate esters, pinacol esters, malate esters, salicylate esters, lactate esters, and tartrate esters. In some embodiments, the ester is a citrate ester.

[0123] In one aspect, provided herein is a boronic 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 boronic acid ester is selected from citrate ester, pinacol ester, malate ester, salicylate ester, lactate ester, and tartrate ester. In some embodiments, the ester is a citrate ester.

[0124] In one aspect, provided herein is a boronic 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, which converts to its corresponding acid when exposed to physiological conditions. In some embodiments, the ester is selected from pinacol ester and citrate ester. In some embodiments, the ester is a citrate ester.

[0125] In one aspect, provided herein is a boronic 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, which is stable at 40 °C and 75% relative humidity for at least 3 weeks. In some embodiments, the ester is selected from pinacol ester and citrate ester. In some embodiments, the ester is a citrate ester.

[0126] In one aspect, provided herein is a boronic acid ester of ((R)-1-(((((R)-1-((E)-2-cyano-4-methyl-4-((R)-2-methylmorpholino)penta-2-enoyl)azepan-3-yl)oxy)carbonyl)amino)-2-phenylethyl)boronic acid or a pharmaceutically acceptable salt thereof, which 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.

[0127] In one aspect, provided herein is a crystalline form of a citrate ester of ((R)-1-(((((R)-1-((E)-2-cyano-4-methyl-4-((R)-2-methylmorpholino)penta-2-enoyl)azepan-3-yl)oxy)carbonyl)amino)-2-phenylethyl)boronic acid. In some embodiments, the crystalline form is selected from Form I, Form II, Form III, Form IV, and Form V.

[0128] In some embodiments, the crystalline form of the citrate ester of ((R)-1-(((((R)-1-((E)-2-cyano-4-methyl-4-((R)-2-methylmorpholino)penta-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 diffractogram comprising at least three peaks selected from the 2-θ peaks of 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. In some embodiments, Form I is characterized by an X-ray powder diffractogram substantially the same as that of FIG. 6.

[0129] 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 the onset of melting at about 179.5 °C. In some embodiments, Form I is characterized by a DSC thermogram substantially similar to that of FIG. 7.

[0130] In some embodiments, Form I is characterized by a mass loss of less than about 0.5 wt% from about 25 °C to about 150 °C by thermogravimetric analysis. In some embodiments, Form I is characterized by a TGA thermogram substantially similar to the thermogram of FIG. 7.

[0131] In some embodiments, the crystalline form of the citrate ester of ((R)-1-(((((R)-1-((E)-2-cyano-4-methyl-4-((R)-2-methylmorpholino)penta-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 diffractogram comprising at least three peaks selected from the 2-θ peaks of 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. In some embodiments, Form II is characterized by an X-ray powder diffractogram substantially similar to that of FIG. 8.

[0132] 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 the onset of melting at about 164.9 °C. In some embodiments, Form II is characterized by a DSC thermogram substantially similar to that of FIG. 9.

[0133] In some embodiments, Form II is characterized by a mass loss of about 5.6 wt% from about 25 °C to about 110 °C by thermogravimetric analysis. In some embodiments, Form II is characterized by a TGA thermogram substantially similar to the thermogram of FIG. 9.

[0134] In some embodiments, Form I is prepared by contacting crystalline Form II with an alcohol or alcohol mixture. In some embodiments, Form I is prepared by contacting crystalline Form III with an alcohol or 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.

[0135] In some embodiments, the crystalline form of the citrate ester of ((R)-1-(((((R)-1-((E)-2-cyano-4-methyl-4-((R)-2-methylmorpholino)penta-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 diffractogram comprising at least three peaks selected from the 2-θ peaks of 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. In some embodiments, Form III is characterized by an X-ray powder diffractogram substantially similar to that of FIG. 10.

[0136] 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 has a peak at about 70.4 °C. In some embodiments, Form III is characterized by a DSC thermogram substantially similar to that of FIG. 11.

[0137] In some embodiments, Form III is characterized by a mass loss of about 3.1 wt% from about 25 °C to about 105 °C by thermogravimetric analysis. In some embodiments, Form III is characterized by a TGA thermogram substantially similar to the thermogram of FIG. 11.

[0138] In some embodiments, Form III is prepared by a method that includes contacting a crystalline Form II with 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.

[0139] In some embodiments, the method further includes isolating Form III from the alkyl ester, the 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.

[0140] In some embodiments, the crystalline form of the citrate ester of ((R)-1-(((((R)-1-((E)-2-cyano-4-methyl-4-((R)-2-methylmorpholino)penta-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 diffractogram substantially similar to that of FIG. 12. In some embodiments, Form IV is characterized by a DSC thermogram substantially similar to the thermogram of FIG. 13. In some embodiments, Form IV is characterized by a TGA thermogram substantially similar to the thermogram of FIG. 13.

[0141] In some embodiments, the crystalline form of the citrate ester of ((R)-1-(((((R)-1-((E)-2-cyano-4-methyl-4-((R)-2-methylmorpholino)penta-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 diffractogram substantially similar to that of FIG. 14. In some embodiments, Form V is characterized by a DSC thermogram substantially similar to the thermogram of FIG. 15. In some embodiments, Form V is characterized by a TGA thermogram substantially similar to the thermogram of FIG. 15.

[0142] Pharmaceutical composition In another aspect, pharmaceutical compositions of the compounds and their pharmaceutically acceptable salts described herein are provided herein. Thus, the present disclosure includes pharmaceutical compositions comprising at least one compound of formula (I) or a pharmaceutically acceptable salt thereof described herein and a pharmaceutically acceptable excipient. The present disclosure further includes pharmaceutical compositions comprising at least one boronic acid or a pharmaceutically acceptable salt thereof described herein and a pharmaceutically acceptable excipient. The present disclosure further includes pharmaceutical compositions comprising at least one crystalline form of the citrate ester of ((R)-1-(((((R)-1-((E)-2-cyano-4-methyl-4-((R)-2-methylmorpholino)penta-2-enoyl)azepan-3-yl)oxy)carbonyl)amino)-2-phenylethyl)boronic acid described herein or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable excipient.

[0143] The pharmaceutical compositions according to the present disclosure can take forms suitable for oral, systemic (e.g., transdermal, intranasal, or suppository), parenteral (e.g., intramuscular, intravenous or subcutaneous) or topical (e.g., application to the skin) administration. In some embodiments, administration is oral using a convenient once-daily dosing regimen that can be adjusted according to the degree of pain. The compositions can take the form of tablets, pills, capsules, semi-solids, powders, sustained release formulations, solutions, suspensions, elixirs, aerosols, or any other suitable composition.

[0144] Any compound described in this specification can be used in the preparation of pharmaceutical compositions by combining the compound as an active ingredient with pharmaceutically acceptable excipients. 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, 21 st ed. (2005), which is incorporated herein by reference.

[0145] Pharmaceutical compositions can conveniently be provided in unit dosage form. Such dosage forms can be prepared by any method well known in the pharmaceutical arts. The amount of the active ingredient that can be combined with excipients to produce a single dosage form will vary depending on the subject being treated and the particular mode of administration. The amount of the active ingredient that can be combined with excipients to produce a single dosage form is generally the amount of the compound that produces a therapeutic effect. Generally, this amount ranges from about 1% to about 99% of the active ingredient, such as from about 5% to about 70% (including from about 10% to about 30%).

[0146] In the solid dosage forms of the present disclosure for oral administration (such as capsules, tablets, pills, dragees, powders, granules, etc.), the active ingredient may be mixed with one or more pharmaceutically acceptable carriers, such as sodium citrate or dicalcium phosphate and / or fillers or extenders such as starch, lactose, sucrose, glucose, mannitol and / or silicic acid; binders such as carboxymethylcellulose, alginate, gelatin, polyvinylpyrrolidone, 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; solution retardants such as paraffin; wetting agents such as cetyl alcohol, glycerol monostearate and nonionic surfactants; absorbents such as kaolin and bentonite clay; 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 composition may also contain buffering agents.

[0147] Therapeutic methods and use as medicaments The compounds or pharmaceutically acceptable salts thereof described herein, and pharmaceutical compositions containing such compounds or pharmaceutically acceptable salts thereof, can be used in the methods of administration and treatment as provided herein. The compounds and pharmaceutical compositions can also be used in in vitro methods, such as in vitro methods of administering the compound or pharmaceutical composition to cells for screening purposes and / or quality control assays. Similarly, the compounds or pharmaceutically acceptable salts thereof described herein, and pharmaceutical compositions containing such compounds or pharmaceutically acceptable salts thereof, can be used as therapeutic medicaments provided herein.

[0148] In one aspect, provided herein is a method of inhibiting large multifunctional protease 2 (LMP2) in a subject, the method comprising administering to the subject in need thereof 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 large multifunctional protease 2 (LMP2) in a subject, the method comprising administering to the subject in need thereof a therapeutically effective amount of at least one compound of formula (I) described herein or a pharmaceutically acceptable salt thereof.

[0149] The present disclosure includes a method of inhibiting large multifunctional protease 2 (LMP2) in a subject, the method further comprising administering to the subject in need thereof a therapeutically effective amount of at least one boronic acid described herein or a pharmaceutically acceptable salt thereof.

[0150] The present disclosure further includes a method of inhibiting large multifunctional protease 2 (LMP2) in a subject, the method comprising administering to the subject in need thereof a therapeutically effective amount of at least one crystalline form of the citrate ester of (((R)-1-(((((R)-1-((E)-2-cyano-4-methyl-4-((R)-2-methylmorpholino)penta-2-enoyl)azepan-3-yl)oxy)carbonyl)amino)-2-phenylethyl)boronic acid described herein or a pharmaceutically acceptable salt thereof.

[0151] In one aspect, provided herein is a method of inhibiting large multifunctional protease 7 (LMP7) in a subject, the method comprising administering to the subject in need thereof 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 large multifunctional protease 7 (LMP7) in a subject, the method comprising administering to the subject in need thereof a therapeutically effective amount of at least one compound of formula (I) described herein or a pharmaceutically acceptable salt thereof.

[0152] The present disclosure further includes a method for inhibiting large multifunctional protease 7 (LMP7) in a subject, comprising administering to the subject in need of such inhibition a therapeutically effective amount of at least one boronic acid described herein or a pharmaceutically acceptable salt thereof.

[0153] The present disclosure further includes a method for inhibiting large multifunctional protease 7 (LMP7) in a subject, comprising administering to the subject in need of such inhibition a therapeutically effective amount of at least one crystalline form of the citrate ester of ((R)-1-(((((R)-1-((E)-2-cyano-4-methyl-4-((R)-2-methylmorpholino)penta-2-enoyl)azepan-3-yl)oxy)carbonyl)amino)-2-phenylethyl)boronic acid described herein or a pharmaceutically acceptable salt thereof.

[0154] Inhibition of LMP2 and / or LMP7 can be evaluated and demonstrated by a variety of methods known in the art. Kits and commercially available assays can be utilized to determine whether LMP2 and / or LMP7 is inhibited and to what extent.

[0155] 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 at least one compound described herein or a pharmaceutically acceptable salt thereof in an effective amount. Non-limiting examples of diseases associated with LMP2 and / or LMP7 include arthritis including lupus, 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, Behçet's disease, ulcerative colitis, Crohn's disease, Sjögren's syndrome, bronchitis, conjunctivitis, pancreatitis, cholecystitis, bronchiectasis, aortic valve stenosis, restenosis, fibrosis, infectious diseases, ischemia, cardiovascular diseases, hepatitis, cirrhosis, nonalcoholic steatohepatitis, liver inflammation, Alzheimer's disease (AD), amyotrophic lateral sclerosis (ALS), Huntington's disease, polymyositis, myofibrillar myopathy, graft-versus-host disease (GVHD) and multiple myeloma.

[0156] In another aspect, provided herein is a method for treating a disease selected from the group consisting of autoimmune disorders, inflammatory disorders, and hematological disorders in a patient in need thereof, the method comprising administering to the patient a therapeutically effective amount of at least one compound described herein or a pharmaceutically acceptable salt thereof. Thus, the present disclosure includes a method for treating a disease selected from the group consisting of autoimmune disorders, inflammatory disorders, and hematological disorders in a patient in need thereof, the method comprising administering to the patient a therapeutically effective amount of at least one compound of formula (I) described herein or a pharmaceutically acceptable salt thereof.

[0157] The present disclosure further includes a method for treating a disease selected from the group consisting of autoimmune disorders, inflammatory disorders, and hematological disorders in a patient in need thereof, the method comprising administering to the patient a therapeutically effective amount of at least one boronic acid described herein or a pharmaceutically acceptable salt thereof.

[0158] The present disclosure further provides a method for performing such treatment in a patient in need of treatment of a disease selected from autoimmune disorders, inflammatory disorders, and hematological disorders, the method comprising administering to the patient a therapeutically effective amount of at least one crystalline form of the citrate ester of ((R)-1-(((((R)-1-((E)-2-cyano-4-methyl-4-((R)-2-methylmorpholino)penta-2-enoyl)azepan-3-yl)oxy)carbonyl)amino)-2-phenylethyl)boronic acid described herein or a pharmaceutically acceptable salt thereof.

[0159] In some embodiments, the disease is selected from arthritis including lupus, 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, Behçet's disease, ulcerative colitis, Crohn's disease, Sjögren's syndrome, bronchitis, conjunctivitis, pancreatitis, cholecystitis, bronchiectasis, aortic valve stenosis, restenosis, fibrosis, infectious diseases, ischemia, cardiovascular diseases, hepatitis, cirrhosis, non-alcoholic steatohepatitis, liver inflammation, Alzheimer's disease (AD), amyotrophic lateral sclerosis (ALS), Huntington's disease, polymyositis, myofibrillar myopathy, graft-versus-host disease (GVHD), and multiple myeloma.

[0160] In another aspect, the present disclosure provides the use of a composition as a medicament for inhibiting large multifunctional protease 2 (LMP2) in a subject, the composition comprising a therapeutically effective amount of a compound described herein or a pharmaceutically acceptable salt thereof. Accordingly, the present disclosure provides the use of a composition as a medicament for inhibiting large multifunctional protease 2 (LMP2) in a subject, the composition comprising a therapeutically effective amount of at least one compound of formula (I) described herein or a pharmaceutically acceptable salt thereof.

[0161] 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 boronic ester described herein or a pharmaceutically acceptable salt thereof.

[0162] 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 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 described herein or a pharmaceutically acceptable salt thereof.

[0163] In one aspect, the present disclosure provides 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 compound described herein or a pharmaceutically acceptable salt thereof. Accordingly, the present disclosure 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 compound of formula (I) described herein or a pharmaceutically acceptable salt thereof.

[0164] 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 boronic ester described herein or a pharmaceutically acceptable salt thereof.

[0165] The present disclosure further relates to 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 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 as described herein or a pharmaceutically acceptable salt thereof.

[0166] In one aspect, it 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; the disease is selected from autoimmune disorders, inflammatory disorders, and hematological disorders. Thus, the present disclosure provides the use of a composition as a medicament for treating a disease in a subject in need thereof, which comprises administering to the patient a therapeutically effective amount of at least one compound of formula (I) described herein or a pharmaceutically acceptable salt thereof; the disease is selected from autoimmune disorders, inflammatory disorders, and hematological disorders.

[0167] The present disclosure further provides the 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 boronic acid ester described herein or a pharmaceutically acceptable salt thereof; the disease is selected from autoimmune disorders, inflammatory disorders, and hematological disorders.

[0168] The present disclosure further relates to the use of a composition as a medicament for treating a target disease, wherein the composition comprises 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 described herein or a pharmaceutically acceptable salt thereof; and the disease is selected from autoimmune disorders, inflammatory disorders, and hematological disorders.

[0169] In some embodiments, the disease is selected from arthritis including lupus, 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, Sjögren's syndrome, bronchitis, conjunctivitis, pancreatitis, cholecystitis, bronchiectasis, aortic valve stenosis, restenosis, fibrosis, infectious diseases, ischemia, cardiovascular diseases, hepatitis, cirrhosis, non-alcoholic steatohepatitis, liver inflammation, Alzheimer's disease (AD), amyotrophic lateral sclerosis (ALS), Huntington's disease, polymyositis, myofibrillar myopathy, graft-versus-host disease (GVHD), and multiple myeloma.

[0170] In some embodiments, administering a compound described herein or a pharmaceutically acceptable salt thereof to a subject in need thereof reduces the degree of a disease associated with LMP2 and / or LMP7 (e.g., those listed above) in the subject. In some embodiments, administering a compound described herein or a pharmaceutically acceptable salt thereof to a subject in need thereof 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 thereof delays the onset 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 thereof 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 thereof 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 thereof improves the quality of life of a subject having 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 thereof prolongs the survival of a subject having a disease associated with LMP2 and / or LMP7.

[0171] Administration and Methods of Administration These compounds can be administered to humans for therapeutic purposes by any suitable route of administration, including oral, nasal, for example, by spray, rectal, intravaginal, parenteral, intracapsular and topical, by powder, ointment or drops (including oral and sublingual). Suitable unit dosage 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 dosage forms, forms for inhalation, topical, transdermal, subcutaneous, intramuscular or intravenous administration, rectal dosage forms and implant tablets. For topical application, the compounds described herein can be used in creams, gels, ointments or lotions.

[0172] Regardless of the administration route selected, the compounds described herein or pharmaceutically acceptable salts thereof are formulated into pharmaceutically acceptable dosage forms by conventional methods known to those of ordinary skill in the art.

[0173] The actual dosage level of the active ingredient in the pharmaceutical compositions of the present disclosure may vary 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.

[0174] The selected dosage level depends on a variety of factors including the activity of the particular compound or salt of the present disclosure being used, the route of administration, the time of administration, the rate of excretion or metabolism of the particular compound or salt being used, the duration of the treatment, other drugs, compounds and / or materials used in combination with the particular compound or salt being used, the age, sex, weight, condition, general health and prior medical history of the patient being treated, and like factors well known in the medical arts. Dosage amounts per day, per week or per month (or other time intervals) can be used.

[0175] A physician who is a person of ordinary skill in the art can readily determine and prescribe the effective amount of the pharmaceutical composition required. For example, the physician can start with a dosage of the compound or salt of the present disclosure used 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.

[0176] Generally, a suitable daily dosage of the compounds of the present disclosure is the amount of the compound that is the lowest dosage effective to produce a therapeutic effect (e.g., inhibiting necrosis). Such effective dosages generally depend on the factors described above. Generally, the dosage of the compounds of the present disclosure for a patient, when used for the indicated effect, is in the range of about 0.0001 to about 100 mg / kg body weight / day. Preferably, the daily dosage is in the range of 0.001 to 50 mg of the compound per kg of body weight, and even more preferably in the range of 0.01 to 10 mg of the compound per kg of body weight.

[0177] If desired, the effective daily dose of the active compound can optionally be administered in unit dosage form as two, three, four, five, six or more sub-doses which are administered separately at appropriate intervals throughout the day.

[0178] When the compounds or salts of the present disclosure are administered to humans as pharmaceuticals, they can be administered by themselves or as pharmaceutical compositions containing, for example, from 0.1% to 99.5% (e.g., from 0.5% to 90%) of the active ingredient in combination with a pharmaceutically acceptable carrier.

[0179] The compounds and salts or pharmaceutical compositions thereof of the present application can be administered once, twice, three times or four times a day using any of the above suitable modes. In addition, administration or treatment with the compound or salt may be continued for several days. For example, generally, the treatment will continue for at least 7 days, 14 days or 28 days during one cycle of treatment. Treatment cycles are well known and generally alternate frequently with a rest period of about 1 to 28 days, generally about 7 days or about 14 days between cycles. In certain embodiments, the treatment cycles may be continuous.

[0180] In certain embodiments, the methods and uses herein involve administering an initial daily dose of about 1 to 800 mg of the compounds or salts described herein to a subject and increasing the dose incrementally until clinical effectiveness is achieved. Increments of about 5, 10, 25, 50 or 100 mg can be used to increase the dose. The dose can be increased daily, every other day, twice a week or once a week.

[0181] The formulations of the present disclosure can be administered orally, parenterally, topically or rectally. They will of course be given in a form suitable for each administration route. For example, they can be administered in the form of tablets or capsules, by injection, inhalation, eye drops, ointments, suppositories, etc., by injection, infusion or inhalation; topically by lotion or ointment; and rectally by suppository. In certain embodiments, the administration is oral.

[0182] The methods of the present disclosure may include the compounds described herein or pharmaceutically acceptable salts thereof, used alone or in combination with one or more additional therapies (e.g., non-drug therapies or therapeutic agents). The dosage of one or more additional therapies (e.g., non-drug therapies or therapeutic agents) may be reduced from the standard dosage when administered alone. For example, the dosage may be determined empirically from drug combinations and permutations or may be estimated by isobolographic analysis.

[0183] The compounds or salts thereof described herein can be administered before, after, or simultaneously with one or more of such additional therapies. When combined, the dosage of the compounds or salts thereof described herein and the dosage of one or more additional therapies (e.g., non-drug treatment agents or therapeutic agents) provide a therapeutic effect (e.g., a synergistic or additive therapeutic effect). The compounds or pharmaceutically acceptable salts thereof described herein and further therapies (e.g., anti-cancer agents) may be administered together, such as in a single pharmaceutical composition, or separately, and if administered separately, this may occur simultaneously or sequentially. Such sequential administration may be close in time or far apart in time.

Examples

[0184] 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.

[0185] The chemical reactions in the described examples can be easily adapted to prepare many 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 compounds not exemplified by the present disclosure can be achieved by modifications apparent to those skilled in the art, such as appropriately protecting interfering groups, using other suitable reagents known in the art other than those described, or by making routine modifications to reaction conditions, reagents, and starting materials. Alternatively, other reactions described herein or known in the art will be recognized as having applicability for preparing other compounds of the present disclosure.

[0186] The following abbreviations may be relevant to the present application.

[0187] [Table 6]

[0188] Example 1: Preparation of the Citric Acid Ester of ((R)-1-(((((R)-1-((E)-2-Cyano-4-methyl-4-((R)-2-methylmorpholino)penta-2-enoyl)azepan-3-yl)oxy)carbonyl)amino)-2-phenylethyl)boronic Acid Step 1: Synthesis of Starting Material 1 (SM1) [Chemical Structure] Isobutyraldehyde (733 g) in DCM (3500 mL) was brominated with bromine (1686 g) at 0 - 5 °C. The reaction mixture was quenched with an aqueous Na2SO3 solution and washed with water and brine. The DCM solution was stored at 0 - 10 °C. (R)-2-Methylmorpholine (700 g) was dissolved in DCM (1400 mL), cooled to 5 °C, and diisopropylethylamine (1.97 L) was added. After cooling the reaction mixture to 0 - 5 °C, a DCM solution of 2-bromo-2-methylpropanal was added. The layers were separated and the organic phase was washed with water and brine. The organic phase was concentrated to dryness under reduced pressure to obtain (R)-2-methyl-2-(2-methylmorpholino)propanal (802 g) as a pale yellow oil. Yield: 90% and purity: 99.0%. (R)-2-Methyl-2-(2-methylmorpholino)propanal (802 g) and 2-cyanoacetic acid (439 g) were dissolved in toluene (2.4 L), and subsequently ammonium acetate (18 g) was added. The reaction mixture was heated at 80 ± 5 °C for 22 h, then cooled to 20 ± 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 ± 5 °C to constant weight to obtain SM1 (790 g) as a white solid. Yield: 70% and purity: 98.5%.

[0189] Step 2: Synthesis of Intermediate 3

Chemical Structure

[0190] Step 3: Synthesis of Intermediate 5

Chemical Structure

[0191] Step 4: Synthesis of Boronic Acid 1

Chemical Structure

[0192] Step 5: Synthesis of Citric Acid Ester of Boronic Acid 1

Chemical Structure

[0193]

Table 7

[0194] Example 2: Preparation of the pinacol ester of ((R)-1-(((((R)-1-(2-cyano-4-methyl-4-((R)-2-methylmorpholino)penta-2-enoyl)azepan-3-yl)oxy)carbonyl)amino)-2-phenylethyl)boronic acid.

Chem.

[0195] The pinacol ester of ((R)-1-(((((R)-1-(2-cyano-4-methyl-4-((R)-2-methylmorpholino)penta-2-enoyl)azepan-3-yl)oxy)carbonyl)amino)-2-phenylethyl)boronic acid is prepared by combining boronic acid 1 with pinacol in dichloromethane. The reaction mixture is stirred at ambient temperature and then washed with water. The layers are separated and the organic phase is concentrated to dryness to give ester N. Predicted MS [M+1]: 609. An exemplary NMR spectrum is shown in Figure 1.

[0196] 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]heptan-1-yl]methoxy]carbonyl)amino]-2-phenylethyl]boronic acid.

[0197] Step 1: Synthesis of Intermediate 2

Chem.

[0198] Step 2: Synthesis of Intermediate 3

Chemical Structure

[0199] Step 3: Synthesis of Intermediate 4

Chemical Structure

[0200] Step 4: Synthesis of Intermediate 5

Chemical Structure

[0201] Step 5: Synthesis of Intermediate 6

Chemical Structure

[0202] Step 6: Synthesis of 2-bromo-2-methylpropanal

Chemical formula

[0203] Step 7: Synthesis of 2-methyl-2-[(2S)-2-methylmorpholin-4-yl]propanal

Chemical formula

[0204] Step 8: Synthesis of Intermediate 7

Chemical Structure

[0205] Step 9: Synthesis of Boronic Acid 2

Chemical Structure

[0206] Step 10: Synthesis of the citrate ester of boronic acid 2

Chemical formula

[0207] Example 4: Preparation of Solvate-Citrate Crystal of [(1R)-1-[([7-(2-Cyano-2-[2-methyl-2-[(2S)-2-methylmorpholin-4-yl]propylidene]acetyl)-7-azabicyclo[2.2.1]heptan-1-yl]methoxy]carbonyl)amino]-2-phenylethyl]boronic Acid

[0208] The solvate-citrate crystal of [(1R)-1-[([7-(2-Cyano-2-[2-methyl-2-[(2S)-2-methylmorpholin-4-yl]propylidene]acetyl)-7-azabicyclo[2.2.1]heptan-1-yl]methoxy]carbonyl)amino]-2-phenylethyl]boronic Acid was obtained by reaction crystallization of boronic acid 2 with 1.1 equivalents of citric acid in acetonitrile or by reaction crystallization of boronic acid 2 with 1.1 equivalents of citric acid in an EtOH / ACN (1:1 or 1:2) mixture. After reaction crystallization, a wet cake showing good crystallinity was obtained by cooling to 0-10 °C. The SFC / MS of the wet cake showed a [(1R)-1-[([7-(2-Cyano-2-[2-methyl-2-[(2S)-2-methylmorpholin-4-yl]propylidene]acetyl)-7-azabicyclo[2.2.1]heptan-1-yl]methoxy]carbonyl)amino]-2-phenylethyl]boronic acid citrate peak of 695 [M+1]. The wet cake showed good crystallinity, but when air-dried for several minutes, the crystallinity decreased rapidly and it became amorphous.

[0209] Example 5: Preparation of Citrate 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

[0210] Steps 1 and 2: Synthesis of Intermediates 1 and 2 [Chemical formula] The reaction was carried out in a three-necked round-bottom flask under N₂. Bromine was added dropwise to a solution of starting material 1 (isobutyraldehyde) in DCM with magnetic stirring. The reaction mixture was stirred at 0 ± 5 °C for at least 15 minutes. A sample was taken for GC analysis. Then, the solution was washed with aqueous Na₂SO₃, saturated aqueous NaHCO₃, and brine. The solution was used in the next step without further purification. The reaction was carried out in a three-necked round-bottom flask under N₂. The solution from step 1 was added dropwise to a solution of 3,3-difluoropyrrolidine hydrochloride (starting material 2a) and DIPEA in DCM with magnetic stirring. The reaction mixture was reacted at 0 ± 5 °C for at least 17 hours, monitored by GC analysis, worked up, and concentrated to a syrup.

[0211] Step 3: Synthesis of Intermediate 3

Chemical formula

[0212] Step 4: Synthesis of Intermediate 4

Chemical formula

[0213] Step 5: Synthesis of Intermediate 5

Chemical formula

[0214] Step 6: Synthesis of Boronic Acid 3

Chemical Structure

[0215] Step 7: Synthesis of the Citric Acid Ester of Boronic Acid 3

Chemical Structure

[0216] Example 6: Preparation of the salicylic 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. [Chemical formula]

[0217] The salicylic 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 can be prepared by putting boronic acid 3 (500 mg) into isopropyl acetate (2.5 mL) and adding a solution of salicylic acid (1.1 equivalents) in isopropyl acetate (1.25 mL). The resulting mixture was stirred at 20 - 25 °C for 2 hours. n-Heptane (25 mL) was added to the reaction mixture to form a solid precipitate, which was stirred at 20 - 25 °C for 30 minutes. The solid was filtered, washed with n-heptane (1 mL), and dried using nitrogen on the filter to obtain 610 mg of the salicylic acid ester as a yellow solid. MS[M+1]: 635 (SFC-MS). The NMR is shown in Figure 5.

[0218] Example 7: Polymorphs 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. Form I - Form I was obtained by slurrying Form II in EtOH and IPA at room temperature and 50 °C. Form I could 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 at 60 °C for 7 days. The prepared Form I was plate-like crystals with good crystallinity (Figure 6). This showed a 0.5% weight loss in the TGA profile and endothermic peaks at 179 / 193 °C in the DSC profile (Figure 7). The characterization data indicated that it was an anhydrate.

[0219] Form II - Form II is a solvate with acetonitrile. Form II was prepared from the HCl 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 equiv) in water (5 V). Then the layers were separated and 10% brine (5 V) was added to the organic phase. The pH was adjusted to about 6 - 7 using 1N HCl. The layers were separated again, the organic phase was dried over Na2SO4, filtered, and the cake was washed with EtOAc (2 V). The solution was concentrated and redissolved in DCM (5 V) at < 20 °C. HCl (1 equiv) in EtOAc was added to the reaction and stirred at about 20 °C for 30 min. MTBE (20 V) and DCM (5 V) were added to the solution at 20 °C and stirred at about 20 °C for about 2 h. The mixture was filtered and the cake was washed with MTBE / DCM = 2 / 1 (2 V). The cake was slurried with EtOAc (10 V) and MTBE (10 V) at about 20 °C and then stirred at about 20 °C for about 2 h. The organic layer was filtered and the cake was washed with EtOAc / MTBE = 1 / 1 (2 V). The cake was dried under vacuum at about 20 °C for 4 h to obtain the HCl salt as a pale yellow solid.

[0220] Next, the HCl salt (8 g) was added to DCM (160 mL), and H2O (10 V) was added to the mixture. The pH was adjusted to about 7 with 9% NaHCO3. The layers were separated, and the organic phase was washed once with brine. The DCM solution was dried over Na2SO4, concentrated, and exchanged with EtOH (44 mL) under vacuum to obtain boronic acid 1. Citric acid (3.14 g) in an EtOH solution (80 mL) was added to boronic acid 1, and when n-heptane (32 mL) was charged into the system, a turbid solution was obtained. The mixture was stirred at about 15 - 20 °C overnight (at least 16 hours). Next, n-heptane (88 mL) and IPAc (16 mL) were charged into the reaction mixture, and it was stirred for about 3 hours. The reaction mixture was filtered, and the cake was washed with EtOH / n-heptane (1:2). The cake was dried under vacuum to obtain the citrate ester, which was then recrystallized in MeCN. More specifically, the citrate ester (8.3 g) was added to MeCN (830 mL, 10 V), stirred at about 40 - 45 °C for about 2 hours, and then cooled to about 15 - 20 °C over at least about 3 hours. Additional MeCN (5 V) and MTBE (3 V) were charged into the reaction mixture, and it was stirred at about 40 - 45 °C for about 20 hours. The solution was filtered, and the cake was washed with MeCN / MTBE (5:1, 1 V). The cake was dried under vacuum to obtain Form II. The XRPD is shown in Figure 8. The TGA and DSC thermograms are shown in Figure 9.

[0221] Form III - Form III is a hydrate formed by dehydration of Form II. Form III was also obtained by slurrying Form II in MTBE, toluene, EA, and IPAc at room temperature or about 50 °C. The XRPD is shown in Figure 10. The TGA and DSC thermograms are shown in Figure 11.

[0222] Form IV - Form IV was a hydrate formed by slurrying Form II in MEK at room temperature. The XRPD is shown in Figure 12. The TGA and DSC thermograms are shown in Figure 13.

[0223] Form V - Form V is a hydrate obtained from Form IV. After initially passing through a metastable form and then air - drying for 20 minutes, it was converted to Form V. Form V was also prepared by slurrying Form I in MEK at a cycle of about 50 °C / 25 °C (8 hours / cycle) for about 24 hours. The resulting suspension was filtered and dried briefly with compressed air to obtain Form V. XRPD is shown in Figure 14. TGA and DSC thermograms are shown in Figure 15.

[0224] Example 8: Stability of the boronic acid ester of ((R)-1-(((((R)-1-((E)-2-cyano-4-methyl-4-((R)-2-methylmorpholino)penta-2-enoyl)azepan-3-yl)oxy)carbonyl)amino)-2-phenylethyl)boronic acid.

[0225] 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 tested by diluting a 10 mg / mL ACN solution of the ester 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 an ACN solution of the citrate ester of boronic acid 1 was added to SGF, the ester was immediately completely converted to boronic acid 1. When an ACN solution of the citrate ester of boronic acid 1 was added to SIF, about 8% of the ester remained and most of the ester was immediately converted to boronic acid 1.

[0226] For the pinacol and pinandiol esters of boronic acid 1, the same series of experiments were conducted except that additional ACN was added when diluting the compound in SIF to maintain it in solution (final ACN concentration in the diluted solution in SIF 20% - 30%). It was found that when added to SGF and SIF, the pinacol ester of boronic acid 1 was immediately completely converted to boronic acid 1, and the pinandiol ester (Intermediate 5 of Example 1) was only partially converted to boronic acid 1 (the ratio of boronic acid 1:Intermediate 5 was 65:35 in SGF and 37:63 in SIF).

[0227] Stability in Open Disk Experiments: To compare the stability of the citrate ester of boronic acid 1 with 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, an open dish stability test was conducted in an open glass vial at 40 °C / 75% RH.

[0228] The results (shown in the table below) indicated that boronic acid 1, its HCl salt, and the pinacol and pinanediol esters of boronic acid 1 all decomposed significantly after two weeks, while the citrate ester of boronic acid 1 was stable for at least four weeks. Furthermore, the citrate ester showed acceptable stability for at least six months under the conditions of 5 °C, 25 °C / 60% RH, and 40 °C / 75% RH.

[0229]

Table 8

[0230] Discussion: Boronic acid 1 is amorphous and difficult to produce in high purity. In contrast, its corresponding citrate ester is a crystalline material and is produced on a large scale with high purity (> 99% area). Furthermore, boronic acid 1 is susceptible to hydrolysis and oxidation. Due to the presence of the boronic acid functional group in boronic acid 1, the molecule can be easily oxidized by peroxides and also by oxygen present in the environment or dissolved in the solution. This inherent chemical instability can lead to chemical instability during production and storage. The citrate ester of boronic acid 1 showed much improved chemical stability as shown in the above stability studies. Furthermore, citrate is easily converted to boronic acid 1 in an aqueous medium under physiological conditions (e.g., SGF and SIF).

[0231] Preferred embodiments of the present disclosure have been shown and described herein, but it will be apparent to those skilled in the art that such embodiments are provided by way of example only. Without departing from the present disclosure, numerous variations, modifications, and substitutions will occur to those skilled in the art. It should be understood that various alternative forms of the embodiments of the disclosure described herein may be used in practicing the present disclosure. The following claims define the scope of the present disclosure, and it is intended that methods and structures within the scope of these claims and their equivalents be covered thereby. The disclosures of all patents and scientific documents cited herein are hereby expressly incorporated by reference in their entirety. To the extent that the incorporated material is inconsistent with the explicit content of the present disclosure, the explicit content of the present disclosure shall prevail.

Claims

1. Compound of formula (I) or its pharmaceutically acceptable salt 【Chemistry 1】 (In the formula, A is a substituted monocyclic or bicyclic heterocycle containing at least one nitrogen atom bond to a methylene unit; Y is a substituted monocyclic or bicyclic heterocycle containing at least one nitrogen atom bonded to a carbonyl group; X is a boronic acid ester, which is bonded to the methylene unit via a boron atom, and is selected from citrate esters, pinacol esters, malate esters, salicylate esters, lactic acid esters and tartaric acid esters; and n is either 0 or 1.

2. The compound according to claim 1, wherein A is a monocyclic or bicyclic five- or six-membered heterocycle which may be substituted, and / or Y is a monocyclic or bicyclic six- or seven-membered heterocycle which may be substituted.

3. The compound according to claim 2, wherein A is selected from optionally substituted pyrrolidinyl and optionally substituted morpholinyl, and / or Y is selected from piperidinyl, azepanil, and 7-azabicyclo[2.2.1]heptan-7-yl, each of which may be substituted.

4. A: 【Chemistry 2】 Selected from and / or Y is: 【Transformation 3】 A compound according to claim 3, selected from the above.

5. The compound according to claim 1, wherein X is a citrate boronic acid ester.

6. X: 【Chemistry 4】 A compound according to claim 1, selected from the following.

7. A compound prepared by reacting a compound of 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: 【Transformation 5】 (In the formula, A is a substituted monocyclic or bicyclic heterocycle containing at least one nitrogen atom bond to a methylene unit; Y is a substituted monocyclic or bicyclic heterocycle containing at least one nitrogen atom bonded to a carbonyl group; and n is either 0 or 1.

8. Claim 7 is a monocyclic or bicyclic 5- or 6-membered heterocyclic ring which may be substituted, and / or Y is a monocyclic or bicyclic 6- or 7-membered heterocyclic ring which may be substituted. The compound listed.

9. A: 【Transformation 6】 Selected from, and / or Y 【Transformation 7】 A compound according to claim 7, selected from the above.

10. The compound according to claim 7, wherein the reagent is citric acid.

11. below: 【Transformation 8】 【Chemistry 9】 【Chemistry 10】 【Chemistry 11】 A compound selected from among them.

12. ((R)-1-(((((R)-1-(2-cyano-4-methyl-4-((R)-2-methylmorpholino)penta-2-enoyl)azepan-3-yl)oxy)carbonyl)amino)-2-phenylethyl)boronic acid, ((R)-1-(((((R)-1-((E)-2-cyano-4-methyl-4-((R)-2-methylmorpholino)penta-2-enoyl)azepan-3-yl)oxy)carbonyl)amino)-2-phenylethyl)boronic acid, [(1R)-1-[([[7-(2-cyano-2-[2-methyl-2-[(2S)-2-methylmorpholin-4-yl]propyridene]acetyl)- A boronic acid ester of ((R)-1-(((((R)-1-(2-cyano-4-(3,3-difluoropyrrolidine-1-yl)-4-methylpent-2-enoyl)piperidine-2-yl)methoxy)carbonyl)amino)-2-phenylethyl)boronic acid or a pharmaceutically acceptable salt thereof, wherein the ester is selected from citrate esters, pinacol esters, malate esters, salicylate esters, lactate esters and tartaric acid esters.

13. The boronic acid ester according to claim 12, wherein the ester is a citrate ester.

14. The following structure: 【Chemistry 12】 A compound having or a pharmaceutically acceptable salt thereof.

15. A boronic acid ester of ((R)-1-(((((R)-1-(2-cyano-4-methyl-4-((R)-2-methylmorpholino)penta-2-enoyl)azepan-3-yl)oxy)carbonyl)amino)-2-phenylethyl)boronic acid or a pharmaceutically acceptable salt thereof, which, upon exposure to physiological conditions, is converted to its corresponding acid, is stable at 40°C and 75% relative humidity for at least 3 weeks, and / or is at least about 95% pure.

16. The boronic acid ester according to claim 15, wherein the ester is at least about 99% pure.

17. ((R)-1-(((((R)-1-((E)-2-cyano-4-methyl-4-((R)-2-methylmorpholino)penta-2-enoyl)azepan-3-yl)oxy)carbonyl)amino)-2-phenylethyl)boronic acid citrate ester in crystalline form, with 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 Crystal morphology I is characterized by an X-ray powder diffractogram containing at least three peaks selected from the 2-θ peaks of 2 and 19.0 ± 0.2, a DSC thermogram having a peak endothermic at about 192.7°C, and / or a mass loss of less than about 0.5 wt% between about 25°C and about 150°C by thermogravimetric analysis.

18. Crystal morphology I according to claim 17, characterized by an X-ray powder diffractogram substantially similar to that of Figure 6, and / or a DSC thermogram substantially similar to that of Figure 7, and / or a TGA thermogram substantially similar to that of Figure 7.

19. The crystalline form of the citrate ester of ((R)-1-(((((R)-1-((E)-2-cyano-4-methyl-4-((R)-2-methylmorpholino)penta-2-enoyl)azepan-3-yl)oxy)carbonyl)amino)-2-phenylethyl)boronic acid, with 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 Crystal morphology is crystal morphology II, characterized by an X-ray powder diffractogram containing at least three peaks selected from the 2-θ peaks, a DSC thermogram with a peak endothermic at approximately 173.7°C, a DSC thermogram showing the onset of melting at approximately 164.9°C, and / or a mass loss of approximately 5.6 wt% between approximately 25°C and approximately 110°C as determined by thermogravimetric analysis.

20. Crystal morphology II according to claim 19, characterized by an X-ray powder diffractogram substantially similar to that of Figure 8, and / or a DSC thermogram substantially similar to that of Figure 9, and / or a TGA thermogram substantially similar to that of Figure 9.

21. Crystal form I according to claim 17, which is prepared by contacting crystal form II according to claim 19 with an alcohol or a mixture of alcohols.

22. ((R)-1-(((((R)-1-((E)-2-cyano-4-methyl-4-((R)-2-methylmorpholino)penta-2-enoyl)azepan-3-yl)oxy)carbonyl)amino)-2-phenylethyl)boronic acid citrate ester in crystalline form, with 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. Crystal morphology is crystal morphology III, characterized by an X-ray powder diffractogram containing at least three peaks selected from 2-θ peaks of 8±0.2, 14.3±0.2, and 15.2±0.2; a DSC thermogram having a peak endothermic temperature at approximately 176.5°C; a DSC thermogram having a broad endothermic temperature range of approximately 37.9°C to approximately 100°C; and / or a mass loss of approximately 3.1 wt% from approximately 25°C to approximately 105°C by thermogravimetric analysis.

23. Crystal morphology III according to claim 22, characterized by an X-ray powder diffractogram substantially similar to that of Figure 10, and / or a DSC thermogram substantially similar to that of Figure 11, and / or a TGA thermogram substantially similar to that of Figure 11.

24. The crystal morphology III according to claim 22, wherein the broad endothermic activity has a peak at approximately 70.4°C.

25. Crystalline form III according to claim 22, which is prepared by a method comprising contacting an alkyl ester, an ether and / or toluene with crystalline form II according to claim 19.

26. Crystalline form III prepared by the method of claim 25, wherein the alkyl ester is isopropyl acetate.

27. Crystalline form III prepared by the method of claim 25, further comprising isolating form III from the alkyl ester.

28. A pharmaceutical composition comprising at least one compound according to any one of claims 1 to 11, at least one boronic acid ester according to any one of claims 12 to 16, or at least one crystalline form of a citrate ester of ((R)-1-(((((R)-1-((E)-2-cyano-4-methyl-4-((R)-2-methylmorpholino)penta-2-enoyl)azepan-3-yl)oxy)carbonyl)amino)-2-phenylethyl)boronic acid according to any one of claims 17 to 20, 22 to 24, 26 and 27, and a pharmaceutically acceptable excipient.

29. A compound according to any one of claims 1 to 11, at least one boronic acid ester according to any one of claims 12 to 16, or at least one crystalline form of a citrate ester of ((R)-1-(((((R)-1-((E)-2-cyano-4-methyl-4-((R)-2-methylmorpholino)penta-2-enoyl)azepan-3-yl)oxy)carbonyl)amino)-2-phenylethyl)boronic acid according to any one of claims 17 to 20, 22 to 24, 26 and 27.

30. The aforementioned diseases include lupus, 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, Behçet's disease, ulcerative colitis, and Crohn's disease. The compound according to claim 29, selected from diseases, Sjögren's syndrome, bronchitis, conjunctivitis, pancreatitis, cholecystitis, bronchiectasis, aortic stenosis, restenosis, fibrosis, infection, ischemia, cardiovascular disease, hepatitis, cirrhosis, fatty liver disease, liver inflammation, Alzheimer's disease (AD), amyotrophic lateral sclerosis (ALS), Huntington's disease, somatic myositis, myofibrilary myopathy, graft-versus-host disease (GVHD), and multiple myeloma.

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