TREATMENT OF MEMBRANOUS NEPHROPATHY, IGG4-RELATED DISEASE, AND ANTIPHOSPHOLIPID SYNDROME USING BTK INHIBITOR 2-[(3R)-3-[4-AMINO-3-(2-FLUORO-4-PHENOXY-PHENYL)PYRAZOLO[3,4-d]PYRIMIDIN-1-YL]PIPERIDINE-1-CARBONYL]-4-METHYL-4-[4-(OXETAN-3-YL)PIPERAZIN-1-YL]PENT-2-ENENITRILE

Abstract

To provide methods of treating a disease chosen from membranous nephropathy, IgG4-related diseases, and antiphospholipid syndrome in a mammal.SOLUTION: The present disclosure provides methods of treating a disease chosen from membranous nephropathy (MN), IgG4-related diseases, and antiphospholipid syndrome (APS) in a mammal using a therapeutically effective amount of, the BTK inhibitor 2-[(3R)-3-[4-amino-3-(2-fluoro-4-phenoxy-phenyl)pyrazolo[3,4-d]pyrimidin-1-yl]piperidine-1-carbonyl]-4-methyl-4-[4-(oxetan-3-yl)piperazin-1-yl]pent-2-enenitrile or a pharmaceutically acceptable salt thereof.SELECTED DRAWING: None

Description

[Technical Field]

[0001] This application claims the benefit of priority to U.S. Provisional Application No. 62 / 957,724 (filed January 6, 2020) and U.S. Provisional Application No. 63 / 039,200 (filed June 15, 2020), the contents of each of which are incorporated herein by reference in their entirety.

[0002] The present disclosure provides a therapeutically effective amount of a compound having the structure: [ka] The present invention provides a method for treating a disease selected from membranous nephropathy (MN), IgG4-related disease, and antiphospholipid syndrome (APS) using 2-[(3R)-3-[4-amino-3-(2-fluoro-4-phenoxy-phenyl)pyrazolo[3,4-d]pyrimidin-1-yl]piperidine-1-carbonyl]-4-methyl-4-[4-(oxetan-3-yl)piperazin-1-yl]pent-2-enenitrile (also referred to herein as Compound (I), PRN1008, and rilzabrutinib), or a pharmaceutically acceptable salt thereof, having the formula: [ka] indicates that compound (I) or a pharmaceutically acceptable salt thereof may be the (E) isomer, the (Z) isomer, or a mixture of the (E) and (Z) isomers. [Background technology]

[0003] Compound (I) is disclosed in Example 31 of Patent Document 1 (filed September 6, 2013). The disclosed synthesis requires purification by column chromatography and provides Compound (I) that upon removal of the solvent produces a foam that can be crushed to obtain a powder.

[0004] Compound (I) is also known as PRN1008 and rilzabrutinib. Compound (I) and its pharmaceutically acceptable salts are potent Bruton's tyrosine kinase (BTK) inhibitors. The enzyme BTK is a member of the Tec family of non-receptor tyrosine kinases. BTK is expressed in most hematopoietic cells, including B cells, mast cells, and macrophages. BTK plays a role in the development and activation of B cells. BTK activity is associated with a variety of conditions, including B cell-related hematologic cancers (e.g., non-Hodgkin's lymphoma and B cell chronic lymphocytic leukemia) and immune-mediated diseases (e.g., rheumatoid arthritis, graft-versus-host disease, Sjogren's syndrome, pemphigus, It has been implicated in the pathology of several disorders and conditions such as IBD, lupus, and asthma. [Prior art documents] [Patent documents]

[0005] [Patent Document 1] PCT Application No. PCT / US2013 / 058614 Summary of the Invention [Means for solving the problem]

[0006] In some embodiments of the present disclosure, at least about 80% by weight, at least about 85% by weight, at least about 90% by weight, at least about 95% by weight, at least about 96% by weight, at least about 97% by weight, or at least about 99% by weight of Compound (I) or a pharmaceutically acceptable salt thereof is the (E) isomer. The ratio of the (E) to (Z) isomers can be calculated by methods well known in the art. One such method is the HPLC total area normalization method.

[0007] In some embodiments, the mammal treated with Compound (I) or a pharmaceutically acceptable salt thereof is naive to immunosuppressive therapy. In some embodiments, the mammal treated with Compound (I) or a pharmaceutically acceptable salt thereof is naive to any immunosuppressive therapy. In some embodiments, the mammal is a human.

[0008] In some embodiments, the mammal has been previously treated with immunosuppressive therapy. In some embodiments, the mammal is a human.

[0009] In some embodiments, the present disclosure provides methods of using Compound (I) or a pharmaceutically acceptable salt thereof as a replacement therapy for immunosuppressive therapy for a disease selected from membranous nephropathy (MN), IgG4-related disease, and antiphospholipid syndrome (APS). In some embodiments, the present disclosure provides methods of using Compound (I) or a pharmaceutically acceptable salt thereof as a replacement therapy for a disease selected from a disease selected from membranous nephropathy (MN), IgG4-related disease, and antiphospholipid syndrome (APS), wherein the immunosuppressant is used as a first-line or second-line treatment for the disease. In some embodiments, Compound (I) or a pharmaceutically acceptable salt thereof is used in place of immunosuppressive therapy. In some embodiments, Compound (I) or a pharmaceutically acceptable salt thereof is used in combination with immunosuppressive therapy. In some embodiments, the present disclosure provides a method of using Compound (I) or a pharmaceutically acceptable salt thereof as replacement therapy for a disease selected from membranous nephropathy (MN), IgG4-related disease, and antiphospholipid syndrome (APS), wherein an immunosuppressant is used as a first-line or second-line maintenance therapy for the disease. In some embodiments, Compound (I) or a pharmaceutically acceptable salt thereof is used in place of an immunosuppressant. In some embodiments, Compound (I) or a pharmaceutically acceptable salt thereof is used in combination with an immunosuppressant.

[0010] In some embodiments, the present disclosure provides a method for eliminating or reducing the therapeutic dose of immunosuppressive therapy used in chronic maintenance therapy in the treatment of a disease selected from membranous nephropathy (MN), IgG4-related disease, and antiphospholipid syndrome (APS) in a mammal in need of such treatment, wherein the immunosuppressive therapy is used as a first-line or second-line treatment, the method comprising administering a therapeutically effective amount of Compound (I) or a pharmaceutically acceptable salt thereof to the mammal in need of such treatment. In some embodiments, Compound (I) or a pharmaceutically acceptable salt thereof is used in place of immunosuppressive therapy. In some embodiments, Compound (I) or a pharmaceutically acceptable salt thereof is used in combination with immunosuppressive therapy. Used in combination.

[0011] In some embodiments, the present disclosure provides methods of using Compound (I) or a pharmaceutically acceptable salt thereof as replacement therapy for corticosteroid therapy for a disease selected from membranous nephropathy (MN), IgG4-related disease, and antiphospholipid syndrome (APS). In some embodiments, the present disclosure provides methods of using Compound (I) or a pharmaceutically acceptable salt thereof as replacement therapy for a disease selected from membranous nephropathy (MN), IgG4-related disease, and antiphospholipid syndrome (APS), where a corticosteroid is used as a first-line or second-line treatment for the disease. In some embodiments, Compound (I) or a pharmaceutically acceptable salt thereof is used in place of a corticosteroid. In some embodiments, Compound (I) or a pharmaceutically acceptable salt thereof is used in combination with a corticosteroid. In some embodiments, the present disclosure provides methods of using Compound (I) or a pharmaceutically acceptable salt thereof as replacement therapy for a disease selected from membranous nephropathy (MN), IgG4-related disease, and antiphospholipid syndrome (APS), wherein a corticosteroid is used as a first-line or second-line maintenance therapy for the disease. In some embodiments, Compound (I) or a pharmaceutically acceptable salt thereof is used in place of a corticosteroid. In some embodiments, Compound (I) or a pharmaceutically acceptable salt thereof is used in combination with a corticosteroid. In some embodiments, the corticosteroid is a glucocorticoid.

[0012] In some embodiments, the present disclosure provides a method for eliminating or reducing the therapeutic dose of corticosteroid therapy used in chronic maintenance therapy in the treatment of a disease selected from membranous nephropathy (MN), IgG4-related disease, and antiphospholipid syndrome (APS) in a mammal in need of such treatment, wherein the corticosteroid therapy is used as a first-line or second-line treatment, the method comprising administering a therapeutically effective amount of Compound (I) or a pharmaceutically acceptable salt thereof to the mammal in need of such treatment. In some embodiments, Compound (I) or a pharmaceutically acceptable salt thereof is used in place of corticosteroid therapy. In some embodiments, Compound (I) or a pharmaceutically acceptable salt thereof is used in combination with corticosteroid therapy. In some embodiments, the corticosteroid therapy is a glucocorticoid.

[0013] In some embodiments of the present disclosure, Compound (I) or a pharmaceutically acceptable salt thereof is administered in combination with a non-corticosteroid immunosuppressant and / or an anti-inflammatory agent.

[0014] In some embodiments of the present disclosure, Compound (I) or a pharmaceutically acceptable salt thereof is selected from the group consisting of interferon alpha, interferon gamma, cyclophosphamide, tacrolimus, mycophenolate mofetil, methotrexate, dapsone, sulfasalazine, azathioprine, anti-CD20 agents (e.g., rituximab, dupilumab, ofatumumab, obinutuzumab, or veltuzumab, or a biosuccessor version of any of the foregoing), anti-TNF alpha agents (e.g., etanercept, infliximab, golimumab, adalimumab, or certolizumab pegol, or a biosuccessor version of any of the foregoing), anti-I ligands or their receptors, L-4 agents (e.g., dupilumab or biosuccessor versions thereof), anti-IL-6 agents directed against a ligand or its receptor (e.g., tocilizumab, sarilumab, olokizumab, elsililumab, or siltuximab, or biosuccessor versions of any of the foregoing), anti-IL-17 agents directed against a ligand or its receptor (e.g., secukinumab, ustekinumab, brodalumab, or ixekizumab, or biosuccessor versions of any of the foregoing), anti-IL-23 agents directed against a ligand or its receptor (e.g., guselkumab or risanki ...4 agents directed against a ligand or its receptor (e.g., dupilumab or biosuccessor versions thereof), anti-IL-6 agents directed against a ligand or its receptor (e.g., tocilizumab, sarilumab, olokizumab, elsililumab, or siltuximab, or biosuccessor versions of any of the foregoing), anti-IL-17 agents directed against a ligand or its receptor (e.g., secukinumab, ustekinumab, brodalumab, or ixekizumab, or biosuccessor versions of any of the foregoing), anti-IL-23 agents directed against a ligand or its receptor (e.g., guselkumab or risankizumab, or biosuccessor versions thereof), anti-IL-23 agents directed against a ligand or its receptor (e.g., guselkumab or risankizumab, or biosuccessor versions thereof), anti-IL-23 agents directed against a ligand or its receptor (e.g., guselkumab or ris anti-IL-12 / 23 agents directed against a ligand or its receptor (e.g., ustekinumab or a biosuccessor version thereof), anti-IL-12 agents directed against a ligand or its receptor (e.g., rilonacept, canakinumab, or anakinra, or a biosuccessor version of any of the foregoing), anti-IL-2 agents directed against a ligand or its receptor (e.g., basiliximab or daclizumab, or a biosuccessor version of any of the foregoing), anti-CD2 agents (e.g., alefacept or a biosuccessor version thereof), anti-CD3 agents (e.g., muromonab-cd3 or a biosuccessor version thereof), anti-CD80 / 86 agents (e.g., abatacept or belatacept, or a biosuccessor version thereof), an anti-sphingosine-1-phosphate receptor agent (e.g., fingolimod or a biosequencer version thereof), an anti-C5 agent (e.g., eculizumab or a biosequencer version thereof), an anti-integrin alpha4 agent (e.g., natalizumab or a biosequencer version thereof), an anti-α4β7 agent (e.g., vedolizumab or a biosequencer version thereof), an anti-mTOR agent (e.g., sirolimus or everolimus), an anti-calcineurin agent (e.g., tacrolimus), an anti-BAFF / BlyS agent (e.g., belimumab, VAY736, or blisibimod, or a biosequencer version of any of the foregoing), leflunomide, and teriflunomide.

[0015] Embodiments: Non-limiting embodiments of the present disclosure include: 1. A method of treating a disease selected from membranous nephropathy (MN), IgG4-related disease (IgG4-RD), and antiphospholipid syndrome (APS) in a mammal, comprising: the (E) isomer, (Z) isomer, and mixtures of the (E) and (Z) isomers of 2-[(3R)-3-[4-amino-3-(2-fluoro-4-phenoxy-phenyl)pyrazolo[3,4-d]pyrimidin-1-yl]piperidine-1-carbonyl]-4-methyl-4-[4-(oxetan-3-yl)piperazin-1-yl]pent-2-enenitrile; and / or A pharmaceutically acceptable salt of any of the foregoing compounds. a compound selected from: Pharmaceutically acceptable carrier or excipient The method comprises administering to the mammal a pharmaceutical composition comprising:

[0016] 2. The method of embodiment 1, wherein the disease is acute.

[0017] 3. The method of embodiment 1 or 2, wherein the disease is IgG4-RD disease flare.

[0018] 4. The method of any one of embodiments 1-3, wherein the pharmaceutical composition is administered orally.

[0019] 5. The method of any one of embodiments 1 to 4, wherein the pharmaceutical composition is administered daily.

[0020] 6. The method of any one of embodiments 1 to 5, wherein the pharmaceutical composition is administered orally daily.

[0021] 7. The method of any one of embodiments 1 to 6, wherein the pharmaceutical composition is administered in place of immunosuppressive therapy.

[0022] 8. The method of any one of embodiments 1-7, wherein the pharmaceutical composition is administered in place of corticosteroid therapy.

[0023] 9. The method of any one of embodiments 1 to 6, wherein the pharmaceutical composition is administered in combination with immunosuppressive therapy.

[0024] 10. The method of any one of embodiments 1 to 6, wherein the pharmaceutical composition is administered in combination with corticosteroid therapy.

[0025] 11. The method of any one of embodiments 1-6 or 8-10, wherein the pharmaceutical composition is administered in combination with a non-corticosteroid immunosuppressant and / or an anti-inflammatory agent.

[0026] 12. The method of any one of embodiments 1 or 4-6, wherein the pharmaceutical composition is administered in place of immunosuppressive maintenance therapy.

[0027] 13. The method of any one of embodiments 1 or 4-6, wherein the pharmaceutical composition is administered in place of corticosteroid maintenance therapy.

[0028] 14. The method of any one of embodiments 1, 2, or 4-6, wherein the pharmaceutical composition is administered in combination with immunosuppressive maintenance therapy.

[0029] 15. The method of any one of embodiments 1, 2, or 4-6, wherein the pharmaceutical composition is administered in combination with corticosteroid maintenance therapy.

[0030] 16. The method of any one of embodiments 13-15, wherein the pharmaceutical composition is administered in combination with a non-corticosteroid immunosuppressant and / or an anti-inflammatory agent.

[0031] 17. The pharmaceutical composition comprises a compound that is a substantially pure (E) or (Z) isomer of 2-[(3R)-3-[4-amino-3-(2-fluoro-4-phenoxy-phenyl)pyrazolo[3,4-d]pyrimidin-1-yl]piperidine-1-carbonyl]-4-methyl-4-[4-(oxetan-3-yl)piperazin-1-yl]pent-2-enenitrile, and / or a pharmaceutically acceptable salt of said compound; and Pharmaceutically acceptable carrier or excipient 17. The method of any one of embodiments 1 to 16, comprising:

[0032] 18. The method of any one of embodiments 1-17, wherein at least about 85% weight / weight of the 2-[(3R)-3-[4-amino-3-(2-fluoro-4-phenoxy-phenyl)pyrazolo[3,4-d]pyrimidin-1-yl]piperidine-1-carbonyl]-4-methyl-4-[4-(oxetan-3-yl)piperazin-1-yl]pent-2-enenitrile or at least about 85% weight / weight of the pharmaceutically acceptable salt of 2-[(3R)-3-[4-amino-3-(2-fluoro-4-phenoxy-phenyl)pyrazolo[3,4-d]pyrimidin-1-yl]piperidine-1-carbonyl]-4-methyl-4-[4-(oxetan-3-yl)piperazin-1-yl]pent-2-enenitrile is the (E) isomer.

[0033] 19. The method of any one of embodiments 1 to 18, wherein the mammal is a human.

[0034] 20. The method of any one of embodiments 1-19, wherein the IgG4-related disease is characterized by an IgG4-RD Responder Index (RI) greater than or equal to 2 in at least one organ system.

[0035] 21. The method of any one of embodiments 1 to 20, wherein the IgG4-related disease is characterized by a serum IgG4 concentration greater than 1.5 times the upper limit of normal.

[0036] 22. IgG4-related diseases include IgG4-related sialadenitis, IgG4-related eye disease (IgG4-ROD), IgG4-related pharyngitis, IgG4-related thyroid disease, IgG4-related hypophysitis, IgG4-related pachymeningitis, IgG4-related leptomeningitis, IgG4-related pancreatitis, IgG4-related lung disease, IgG4-related pleuritis, IgG4-related hepatopathy, IgG4-related sclerosing cholangitis, IgG4-related cholecystitis, IgG4-related aortitis, IgG4-related periaortitis, IgG4-related periarteritis, IgG4-related pericarditis, 22. The method of any one of embodiments 1 to 21, wherein the disease is selected from IgG4-related mediastinitis, IgG4-related retroperitoneal fibrosis, IgG4-related mesenteritis, IgG4-related mastitis, IgG4-related kidney disease (IgG4-RKD), IgG4-related prostatitis, IgG4-related perivascular fibrosis, IgG4-related paratesticular pseudotumor, IgG4-related epididymo-orchitis, IgG4-related lymphadenopathy, IgG4-related skin disease, and IgG4-related perineural disease, or a flare-up of any of the aforementioned IgG4-related diseases.

[0037] 23. The method of embodiment 1, wherein the pharmaceutical composition is administered in combination with an active pharmaceutical ingredient selected from interferon alpha, interferon gamma, cyclophosphamide, tacrolimus, mycophenolate mofetil, methotrexate, dapsone, sulfasalazine, azathioprine, an anti-CD20 agent, an anti-TNF alpha agent, an anti-IL-6 agent directed against a ligand or its receptor, an anti-IL-17 agent directed against a ligand or its receptor, an anti-IL-1 agent directed against a ligand or its receptor, an anti-IL-2 agent directed against a ligand or its receptor, an anti-CD2 agent, an anti-CD3 agent, an anti-CD80 / 86 agent, an anti-sphingosine-1-phosphate receptor agent, an anti-C5 agent, an anti-mTOR agent, an anti-calcineurin agent, an anti-BAFF / BlyS agent, leflunomide, and teriflunomide.

[0038] 24. The method of embodiment 1, wherein the pharmaceutical composition is administered in combination with rituximab, ofatumumab, obinutuzumab, or veltuzumab, or a biosuccessor version of any of the foregoing.

[0039] 25. The method of any one of embodiments 1-6, 9-11, or 14-24, wherein the mammal is naive to immunosuppressive therapy.

[0040] 26. The method of any one of embodiments 1-6, 9-11, or 14-24, wherein the mammal is naive to any immunosuppressive therapy.

[0041] 27. The method of any one of embodiments 1 to 24, wherein the mammal has previously been treated with immunosuppressive therapy. [Brief explanation of the drawings]

[0042] [Figure 1] Figure 1 illustrates the study design for examining dose-dependent inhibition using Compound (I) (PRN1008) treatment in an anti-GBM (anti-glomerular basement membrane) mouse glomerulonephritis model. The mouse anti-GBM glomerulonephritis model involves antibody-mediated autoimmunity, and this model is histologically and mechanistically similar to glomerulonephritis in humans. This model also involves renal deposition of immune complexes (ICs) that target the glomerular basement membrane. [Figure 2] Figure 2 shows the dose-dependent inhibition of serum blood urea nitrogen (BUN) levels with Compound (I) (PRN1008) treatment in a mouse anti-GBM glomerulonephritis model. BUN levels provide a measure of renal function. [Figure 3] 3A and 3B show dose-dependent inhibition of severe proteinuria with Compound (I) (PRN1008) treatment in a murine anti-GBM glomerulonephritis model. [Figure 4] FIG. 4 shows reduced proteinuria with Compound (I) (PRN1008) treatment in a mouse anti-GBM glomerulonephritis model. [Figure 5] Figure 5 shows dose-dependent inhibition of kidney weight gain with Compound (I) (PRN1008) treatment in a mouse anti-GBM glomerulonephritis model. Kidney weight gain is a surrogate for kidney inflammation. [Figure 6]Figure 6 shows that compound (I) (PRN1008) significantly reduces renal pathology in a murine anti-GBM glomerulonephritis model and is superior to a steroid control drug (Dex). In Figures 1-6, Dex refers to dexamethasone, a potent synthetic member of the glucocorticoid class of steroid hormones. [Figure 7] FIG. 7 shows the inhibition of B cell activation, as measured by anti-IgM-induced CD69 expression, on CD20+ B cells from human whole blood treated with increasing concentrations of Compound (I) (rilzabrutinib), as measured by flow cytometry (n=4). [Figure 8] Figures 8A and 8B show the inhibition of IgG and IgM production by Compound (I) (rizabrutinib). Rilzabrutinib-treated enriched B cells were stimulated for 7 days with CpG (n=4), TNP-LPS (n=4-6), or anti-CD40+ IL-21 (n=2-7). Measurement of IgG and IgM indicated that both T cell-dependent and T cell-independent antibody production were inhibited by rizabrutinib. Curves show the results of a representative experiment. DETAILED DESCRIPTION OF THE INVENTION

[0043] Definition: As used herein, "a" or "an" entity refers to one or more of that entity; for example, "a compound" refers to one or more compounds, or at least one compound, unless otherwise specified. Thus, the terms "a" (or "an"), "one or more," and "at least one" are used interchangeably herein.

[0044] As used herein, the term "about" means approximately, in the range of, roughly, or approximately. When the term "about" is used in conjunction with a numerical range, it modifies that range by expanding the boundaries around the stated numerical values. In general, the term "about" is used herein to modify a numerical value around the stated value by a variance of 10%.

[0045] As used herein, “Compound (I)” refers to a compound having the following structure: [ka] The term "(E) isomer, (Z) isomer, or mixture of the (E) and (Z) isomers of 2-[(3R)-3-[4-amino-3-(2-fluoro-4-phenoxy-phenyl)pyrazolo[3,4-d]pyrimidin-1-yl]piperidine-1-carbonyl]-4-methyl-4-[4-(oxetan-3-yl)piperazin-1-yl]pent-2-enenitrile, or a pharmaceutically acceptable salt thereof, wherein the carbon atom at the alkene carbon in compound (I) is [ka] means that compound (I) or a pharmaceutically acceptable salt thereof is an (E) isomer, a (Z) isomer, or It is noted that the (E) and (Z) isomers may be a mixture.

[0046] All polymorphic forms and hydrates of Compound (I) are within the scope of this disclosure and the claims appended hereto.

[0047] Those skilled in the art will appreciate that when a compound is designated as the (R) isomer, the compound may contain the corresponding (S) stereoisomer as an impurity, i.e., less than about 1% by weight of the (S) stereoisomer, and vice versa.

[0048] As used herein, "substantially pure" in reference to a geometric or isomeric form refers to a compound, such as Compound (I), in which greater than 70% by weight of the compound is present in a given isomeric form. For example, the phrase "a solid form of Compound (I) is a substantially pure (E) isomer of Compound (I)" refers to a solid form of Compound (I) that is at least 70% by weight of the (E) isomer form, and the phrase "a solid form of Compound (I) is a substantially pure (Z) isomer of Compound (I)" refers to a solid form of Compound (I) that is at least 70% by weight of the (Z) isomer form. In some embodiments, at least 80% by weight of the solid form of Compound (I) is the (E) form, or at least 80% by weight of the solid form of Compound (I) is the (Z) form. In some embodiments, at least 85% by weight of the solid form of Compound (I) is the (E) form, or at least 85% by weight of the solid form of Compound (I) is the (Z) form. In some embodiments, at least 90% by weight of the solid form of Compound (I) is the (E) form, or at least 90% by weight of the solid form of Compound (I) is the (Z) form. In some embodiments, at least 95% by weight of the solid form of Compound (I) is the (E) form, or at least 95% by weight of the solid form of Compound (I) is the (Z) form. In some embodiments, at least 97% or 98% by weight of the solid form of Compound (I) is the (E) form, or at least 97% or 98% by weight of the solid form of Compound (I) is the (Z) form. In some embodiments, at least 99% by weight of the solid form of Compound (I) is the (E) form, or at least 99% by weight of the solid form of Compound (I) is the (Z) form. The relative amounts of the (E) and (Z) isomers in a solid mixture can be determined according to standard methods and techniques known in the art.

[0049] As used herein, "acute" refers to a disease that has a rapid onset and / or a short course (eg, disease flare-ups).

[0050] As used herein, a "pharmaceutically acceptable salt" of a compound means a salt that is pharmaceutically acceptable and that possesses the desired pharmacological activity of the parent compound. Such salts include, but are not limited to: Formed with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, etc.; or with formic acid, acetic acid, propionic acid, hexanoic acid, cyclopentanepropionic acid, glycolic acid, pyruvic acid, lactic acid, malonic acid, succinic acid, malic acid, maleic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, 3-(4-hydroxybenzoyl)benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, 1,2-ethanedisulfonic acid, 2-hydroxyethanesulfonic acid , acid addition salts formed with organic acids such as benzenesulfonic acid, 4-chlorobenzenesulfonic acid, 2-naphthalenesulfonic acid, 4-toluenesulfonic acid, camphorsulfonic acid, glucoheptonic acid, 4,4'-methylenebis-(3-hydroxy-2-ene-1-carboxylic acid), 3-phenylpropionic acid, trimethylacetic acid, tert-butylacetic acid, lauryl sulfuric acid, gluconic acid, glutamic acid, hydroxynaphthoic acid, salicylic acid, stearic acid, muconic acid, and the like; or If any of the acidic protons present in the parent compound are metal ions, e.g., alkali metal ions, salts formed when cations are replaced by cations, alkaline earth ions, or aluminum ions; or Coordination with ethanolamine, diethanolamine, triethanolamine, tromethamine, N-methylglucamine, etc. It is understood that the pharmaceutically acceptable salts are non-toxic.

[0051] Further information regarding suitable pharmaceutically acceptable salts can be found in Remington's Pharmaceutical Sciences, 17th Edition, Mack Publishing Company, Easton, PA, 1985, the section regarding suitable pharmaceutically acceptable salts being incorporated herein by reference. See also Berge et al., Pharmaceutical Salts, Journal of Pharmaceutical Sciences, 1, Vol. 66, No. 1, January 1997.

[0052] Treatment decisions often follow formal or informal algorithmic guidelines. Treatment options are often ranked into a continuum or can be prioritized: first-line therapy, second-line therapy, third-line therapy, etc. A first-line therapy is the first treatment tried. Its preference over other options is usually either (1) officially recommended based on clinical trial evidence for the best available combination of efficacy, safety, and tolerability, or (2) selected based on the physician's clinical experience. If the first-line therapy either fails to resolve the problem or produces unacceptable side effects, an additional (second-line) therapy may be substituted or added to the treatment plan, followed by a third-line therapy, etc. Thus, as used herein, "first-line" therapy typically refers to the treatment given when someone is diagnosed with a particular diagnosis or condition and can be classified as standard care.

[0053] As used herein, "maintenance therapy" refers to a treatment, treatment regimen, or course of therapy given to a patient with a disease after an initial course of treatment. Maintenance therapy can be used to halt, slow, or even reverse disease progression, maintain health improvements achieved by initial treatment, and / or enhance gains achieved by initial therapy.

[0054] A "pharmaceutically acceptable carrier or excipient" refers to a carrier or excipient that is generally safe, non-toxic, and not biologically or otherwise undesirable and is useful in preparing pharmaceutical compositions, and includes carriers or excipients that are acceptable for veterinary as well as human pharmaceutical use. As used herein, "pharmaceutically acceptable carrier or excipient" refers to one or more pharmaceutically acceptable carriers or excipients.

[0055] As used herein, "treating," "treat," or "treatment" of a disease means: (1) inhibiting the disease, i.e., halting or reducing the occurrence of the disease or its clinical symptoms; or (2) Relieving the disease, i.e., causing regression of the disease or its clinical symptoms. Includes.

[0056] As used herein, a "therapeutically effective amount" means the amount of a compound of the present disclosure that, when administered to a mammal, e.g., a human, for treating a disease, is sufficient to effect such treatment for the disease. The "therapeutically effective amount" varies depending on the compound, the disease and its severity, and the age, weight, etc., of the mammal to be treated.

[0057] As used herein, "QD" means once daily.

[0058] As used herein, "BID" means twice a day.

[0059] "Mammal," as used herein, means animals such as dogs, cats, and humans.

[0060] "Membranous nephropathy (MN)" is a kidney disease that affects the kidney's filters (glomeruli) and can lead to protein in the urine, as well as decreased kidney function and swelling. It is also known as membranous glomerulopathy and glomerulonephritis. Without wishing to be bound by theory, it is believed that treatment of MN is mediated by autoantibody depletion and inhibition of platelet aggregation. Therefore, BTK inhibitors such as Compound (I) may be useful in treating MN.

[0061] "IgG4-related disease (IgG4-RD)" is a fibroinflammatory condition that can affect almost any organ system. If left untreated, IgG4-RD can lead to severe morbidity and death, including organ damage and organ failure. IgG4-RD is characterized by tissue infiltration of lymphocytes and IgG4-secreting plasma cells, varying degrees of fibrosis (scarring), and a usually rapid response to oral steroids. Common symptoms include severe salivary and lacrimal gland enlargement, orbital disease, autoimmune pancreatitis, retroperitoneal fibrosis, and tubulointerstitial nephritis. In some embodiments, IgG4-RD is characterized by an IgG4-RD responder index (RI) greater than or equal to 2 in at least one organ system. In some embodiments, IgG4-RD is characterized by a serum IgG4 concentration greater than 1.5 times the upper limit of normal. In some embodiments, IgG4-RD is characterized by an IgG4-RD responder index (RI) of greater than or equal to 2 in at least one organ system and a serum IgG4 concentration greater than 1.5 times the upper limit of normal.

[0062] There are no approved drugs for the treatment of IgG4-RD. Treatment is typically with corticosteroids (CS); however, patients often relapse after tapering CS, necessitating chronic CS medication, which results in severe and debilitating side effects. Rituximab has been shown to have effective clinical responses; however, patients also frequently relapse after treatment. While not wishing to be bound by theory, it is believed that multiple mechanisms of action could potentially lead to positive outcomes in IgG4-RD by affecting many of the features driving the disease, including inflammation, allergic components (IgE and eosinophils), monocytes and macrophages (involved in fibrosis), and B cells involved in disease initiation and maintenance. Therefore, BTK inhibitors such as Compound (I) may be useful in the treatment of IgG4-RD.

[0063] When the organ involved is the salivary gland, the IgG4-related disease is called IgG4-related sialadenitis. Non-limiting examples of IgG4-related sialadenitis include IgG4-related submandibular gland disease and IgG4-related parotitis.

[0064] When the organ involved is the orbit, the IgG4-related disease is called IgG4-related ocular disease (IgG4-ROD). Non-limiting examples of IgG4-ROD include IgG4-related dacryoadenitis (lacrimal gland), IgG4-related orbital inflammation (or IgG4-related orbital inflammatory pseudotumor), IgG4-related orbital myositis (extraocular muscles), and IgG4-related pan-orbital inflammation.

[0065] When the organ involved is the paranasal sinus, non-limiting examples of IgG4-related diseases include chronic sinusitis and eosinophilic angiocentric fibrosis (upper respiratory tract and orbit).

[0066] When the organ involved is the pharynx, a non-limiting example of an IgG4-related disease is IgG4-related pharyngitis.

[0067] When the organ involved is the thyroid gland, a non-limiting example of an IgG4-related disease is IgG4-related thyroid disease.

[0068] When the organ involved is the soft tissue of the head and neck, non-limiting examples of IgG4-related diseases include idiopathic cervical fibrosis, sclerosing cervicitis, and cervical fibrosclerosis.

[0069] When the organ involved is the pituitary gland, the IgG4-related disease is called IgG4-related hypophysitis. Non-limiting examples include IgG4-related panhypophysitis (all of the pituitary gland), IgG4-related adenohypophysitis (anterior pituitary gland), and IgG4-related infundibuloneurohypophysitis (posterior pituitary gland and pituitary stalk).

[0070] When the organ involved is the meninges, a non-limiting example of an IgG4-related disease includes idiopathic hypertrophic pachymeningitis.

[0071] When the organ involved is the pancreas, non-limiting examples of IgG4-related diseases include type 1 autoimmune pancreatitis, lymphoplasmacytic sclerosing pancreatitis, and chronic pancreatitis with scattered irregular narrowing of the main pancreatic duct.

[0072] When the organ involved is the lung, non-limiting examples of IgG4-related diseases include pulmonary inflammatory pseudotumor.

[0073] When the organ involved is the pleura, a non-limiting example of an IgG4-related disease includes pleurisy.

[0074] When the organ involved is the liver, non-limiting examples of IgG4-related diseases include IgG4-related hepatopathy and IgG4-related cholecystitis.

[0075] When the organ involved is the bile duct, non-limiting examples of IgG4-related diseases include IgG4-related sclerosing cholangitis.

[0076] When the organ involved is the gallbladder, a non-limiting example of an IgG4-related disease includes IgG4-related cholecystitis.

[0077] When the organ involved is the aorta, non-limiting examples of IgG4-related diseases include IgG4-related aortitis and IgG4-related periaortitis.

[0078] When the organ involved is a bifurcation of the aorta (including the coronary, renal, or iliac arteries), non-limiting examples of IgG4-related diseases include IgG4-related periarteritis.

[0079] When the organ involved is the breast, non-limiting examples of IgG4-related diseases include IgG4-related mastitis.

[0080] When the organ involved is the kidney, the IgG4-related disease is called IgG4-related kidney disease (IgG4-RKD). Non-limiting examples of IgG4-KD include IgG4-related tubulointerstitial nephritis (IgG4-TIN), membranous glomerulonephritis secondary to IgG4-related disease, and IgG4-related pyelitis (renal pelvis).

[0081] When the organ involved is the prostate, non-limiting examples of IgG4-related diseases include IgG4-related prostatitis.

[0082] When the organ involved is the vas deferens, a non-limiting example of an IgG4-related disease includes IgG4-related perivasal fibrosis.

[0083] When the organ involved is the scrotum, non-limiting examples of IgG4-related diseases include IgG4-related paratesticular pseudotumor and IgG4-related epididymo-orchitis.

[0084] When the organ involved is a lymph node, a non-limiting example of an IgG4-related disease includes IgG4-related lymphadenopathy.

[0085] When the organ involved is the skin, non-limiting examples of IgG4-related diseases include IgG4-related skin diseases such as eosinophilic angiolymphocytosis and cutaneous pseudolymphoma.

[0086] When the organ involved is a nerve, non-limiting examples of IgG4-related diseases include IgG4-related perineural diseases.

[0087] In some embodiments of the present disclosure, the IgG4-related disease is acute (eg, IgG4-related disease flare-up).

[0088] Antiphospholipid syndrome (APS), sometimes known as Hughes syndrome, is a disorder of the immune system that results in an increased risk of blood clots. Therefore, people with APS are at higher risk of developing conditions such as deep vein thrombosis (DVT) (a blood clot usually occurring in the lower extremities), arterial thrombosis (a blood clot in the arteries) that can lead to stroke or heart attack, and blood clots in the brain, which can cause problems with movement, speech, vision, and memory. While not wishing to be bound by theory, autoantibodies produced by plasma cells are thought to be important in the pathology of APS. Thrombotic events and pregnancy morbidity are also mediated by immune infiltration. Therefore, BTK inhibitors such as Compound (I) may be useful in treating APS.

[0089] Formulation and Administration: In general, compounds of the present disclosure will be administered in therapeutically effective amounts by any of the accepted modes of administration for agents that serve similar utilities (e.g., oral administration). Therapeutically effective amounts of compounds of the present disclosure can range from about 0.01 to about 500 mg / kg of patient body weight per day, and can be administered in single or multiple doses. Suitable dosage levels can be from about 0.1 to about 250 mg / kg per day, e.g., from about 0.5 to about 100 mg / kg per day.

[0090] Suitable dosage levels may also be from about 0.01 to about 250 mg / kg per day, such as from about 0.05 to about 100 mg / kg per day, and further such as from about 0.1 to about 50 mg / kg per day. Within this range, dosages may be from about 0.05 to about 0.5, such as from about 0.5 to about 5, and further such as from about 5 to about 50 mg / kg per day. For oral administration, the compositions may be provided in the form of tablets containing from about 1 to about 1000 milligrams of active ingredient, particularly about 1, 5, 10, 15, 20, 25, 50, 75, 100, 150, 200, 250, 300, 400, 500, 600, 750, 800, 900, and 1000 milligrams of active ingredient. The actual amount of a compound of the present disclosure, i.e., the active ingredient, to be administered will depend on a number of factors, such as the severity of the disease being treated, the age and relative health of the patient, the potency of the compound utilized, the route and form of administration, and other factors.

[0091] Generally, the compounds of the present disclosure are administered as pharmaceutical compositions by any one of the following routes: oral, systemic (e.g., transdermal, intranasal, or via suppository), or parenteral (e.g., intramuscular, intravenous, or subcutaneous) administration. In some embodiments, the pharmaceutical compositions are administered orally using a convenient daily dosing regimen, which can be adjusted according to the severity of the condition. The compositions can take the form of tablets, pills, capsules, semisolids, powders, sustained-release formulations, solutions, suspensions, elixirs, aerosols, or any other suitable compositions.

[0092] The choice of formulation depends on various factors, such as the mode of drug administration (e.g., for oral administration, formulations in the form of tablets, pills, or capsules, including enteric-coated or delayed-release tablets, pills, or capsules) and the bioavailability of the drug substance. Recently, pharmaceutical formulations have been developed specifically for drugs exhibiting poor bioavailability, based on the principle that bioavailability can be increased by increasing surface area, i.e., by reducing particle size. For example, U.S. Pat. No. 4,107,288 describes a pharmaceutical formulation having particles with a size ranging from 10 to 1,000 nm, in which the active substance is supported on a crosslinked matrix of polymers. U.S. Pat. No. 5,145,684 describes the preparation of a pharmaceutical formulation in which a drug substance is milled to nanoparticles (average particle size 400 nm) in the presence of a surface modifier, which are then dispersed in a liquid medium to obtain a pharmaceutical formulation exhibiting significantly higher bioavailability. The disclosures of these two patents are incorporated by reference for their portions relating to pharmaceutical formulations.

[0093] The compositions generally comprise the compounds of the present disclosure in combination with pharmaceutically acceptable excipients. Pharmaceutically acceptable excipients are non-toxic, auxiliary to administration, and do not adversely affect the therapeutic benefits of the compounds of the present disclosure. Such excipients can be any solid, liquid, semi-solid, or, in the case of aerosol compositions, gaseous excipients commonly available to those skilled in the art.

[0094] Solid pharmaceutical excipients include starch, cellulose, talc, glucose, lactose, sucrose, gelatin, corn starch, rice, wheat flour, chalk, silica gel, magnesium stearate, sodium stearate, glycerol monostearate, sodium chloride, dried skim milk, etc. Liquid and semi-solid excipients can be selected from glycerol, propylene glycol, water, ethanol, and various oils, including those of petroleum, animal, vegetable, or synthetic origin, such as peanut oil, soybean oil, mineral oil, sesame oil, etc. For example, liquid carriers for injectable solutions include water, saline, aqueous dextrose, and glycols.

[0095] Compressed gases can be used to dispense the compounds of the present disclosure in aerosol form. Suitable inert gases for this purpose include nitrogen, carbon dioxide, and the like.

[0096] Other suitable pharmaceutical excipients and their formulations are described in Remington's Pharmaceutical Sciences, edited by E. W. Martin (Mack Publishing Company, 20th Edition, 2000), which is incorporated herein by reference in its entirety with respect to the portions relating to pharmaceutical excipients and their formulations.

[0097] The level of the compound in the formulation can vary well within the range used by those skilled in the art. Typically, the formulation contains about 0.01 to 99.99% by weight (wt%) of a compound of the present disclosure based on the total formulation, with the balance being suitable pharmaceutical excipients. For example, the compound may be present at about 1 to 80% by weight. For the numerical range 0.01 to 99.99, "about" indicates less than 0.01%. For the numerical range 1 to 80, "about" indicates 0.05 for 1 and 10 for 80, thus encompassing the range of 0.05 to 90% by weight.

[0098] The compounds of the present disclosure can be used in combination with one or more other drugs in the treatment of diseases or conditions for which the compounds of the present disclosure or other drugs may be useful.Therefore, such other drugs can be administered simultaneously with the compounds of the present disclosure, for example, in a fixed-dose combination, or sequentially, by commonly used routes and amounts.When the compounds of the present disclosure are used simultaneously with one or more other drugs, a unit dosage form containing such other drugs and the compounds of the present disclosure, i.e., a fixed-dose compound pharmaceutical composition, is preferred.However, combination therapy can also include therapy in which the compounds of the present disclosure and one or more other drugs are administered on different overlapping or non-overlapping schedules.When used in combination with one or more other active ingredients, it is conceivable that situations may arise in which the compounds of the present disclosure and the other active ingredients can be used in lower doses than when each is used alone.

[0099] All publications and patents mentioned in this specification are herein incorporated by reference in their entirety to the same extent as if each individual publication or patent was specifically and individually indicated to be incorporated by reference.

[0100] A claim or description including "or" or "and / or" between at least one member of a group is deemed to be satisfied when one, more than one, or all of the group members are present in, employed in, or otherwise relevant to a given product or process, unless indicated to the contrary or otherwise clear from the context. The present disclosure includes embodiments in which exactly one member of the group is present in, employed in, or otherwise relevant to a given product or process. The present disclosure includes embodiments in which more than one, or all of the group members are present in, employed in, or otherwise relevant to a given product or process.

[0101] Furthermore, the present disclosure encompasses all variations, combinations, and permutations in which at least one limitation, element, clause, and descriptive term from at least one of the enumerated claims is introduced into another claim. For example, any claim that depends on another claim can be modified to include at least one limitation found in any other claim that depends from the same base claim. Where elements are presented as a list, e.g., in Markush group format, each subgroup of those elements is also disclosed, and any element can be removed from the group. It should be understood that, generally, when a disclosure, or an aspect of a disclosure, is referred to as including certain elements and / or features, an embodiment of the disclosure or aspect of the disclosure consists of or consists essentially of such elements and / or features. For purposes of brevity, these embodiments are not specifically described in these terms herein. Where ranges are presented, the endpoints are included. Furthermore, unless otherwise indicated or clear from the context and the understanding of one of ordinary skill in the art, values ​​expressed as ranges can take any particular value or subrange within the ranges set forth in various embodiments of this disclosure, down to one-tenth of the unit of the lower limit of that range, unless the context clearly dictates otherwise.

[0102] Those skilled in the art will recognize, or be able to ascertain using no more than routine experimentation, many equivalents to the specific embodiments of the disclosure described herein. Such equivalents are intended to be encompassed by the following claims. [Example]

[0103] The following examples are intended to be illustrative and are not meant to limit the scope of the disclosure in any way.

[0104] Example 1: Murine anti-GBM glomerulonephritis model Compound (I) (PRN1008) compared with the corticosteroid dexamethasone (Dex) The efficacy of Compound (I), also referred to as Dextromethorphan (Dextromethorphan), was tested in a mouse anti-GBM glomerulonephritis model according to the design shown in Figure 1. Briefly, mice were pre-sensitized with sheep IgG / FCA to induce glomerulonephritis (test day -5). Five days later (test day 0), mice were administered anti-GBM sheep IgG. Treatment with vehicle, Compound (I), or Dex using various dosing regimens (Compound (I): 10 mg / kg, 20 mg / kg, or 40 mg / kg QD or 20 mg / kg BID; Dex: 1 mg / kg QD; vehicle: QD or BID) began on test day -1, one day before injection with anti-GBM sheep IgG. Treatment continued until test day 10, for a total of 11 days of treatment. Urinary protein analysis was performed on test days -6, -4, -1, 1, 3, 6, 8, and 10. After study day 10, mouse serum BUN levels were analyzed as a measure of kidney function, and kidney histology was performed. In the mouse anti-GBM glomerulonephritis model, dose-dependent inhibition of serum BUN levels (Figure 2), severe proteinuria (Figure 3), and increased kidney weight (a surrogate for kidney inflammation) (Figure 5) were observed. Furthermore, treatment with Compound (I) resulted in a decrease in proteinuria over the course of the study (Figure 4), and Compound (I) reduced kidney pathology (Figure 6), providing favorable results compared to Dex.

[0105] Example 2 : An open-label, two-arm comparative study to evaluate the safety and efficacy of compound (I) in IgG4-RD patients resistant to rituximab To evaluate the safety and efficacy of daily oral administration of Compound (I) in patients with IgG4-RD resistant to rituximab, patients were enrolled in an open-label, two-arm study. Patients with an IgG4-RD responder index (RI) greater than or equal to 2 in at least one organ system at screening (i.e., up to 4 days before the start of treatment) and, optionally, serum IgG4 concentrations greater than 1.5 times the upper limit of normal will be treated with Compound (I) for 12 to 52 weeks. After 12 weeks, the safety of daily oral administration of Compound (I) and its ability / effectiveness to induce glucocorticoid-free disease remission in IgG4-RD will be evaluated. Complete remission will be defined as an IgG4-RD RI score of 0 at week 12 and no use of glucocorticoids or other immunosuppressive medications between weeks 4 and 12. After extended treatment for up to 52 weeks, the effect of Compound (I) on IgG4-RD disease flares and glucocorticoid sparing will be evaluated, along with the effect of Compound (I) over time on changes in serum concentrations of IgG4, IgE, IgG, IgM, C3, C4, and other serological parameters.

[0106] Example 3 Assay method for inhibition of B cell antibody production by compound (I) B cells were enriched from TrimaAccel® LRS chamber leukocyte concentrates collected after platelet apheresis procedures from healthy volunteers (Stanford Blood Center, Palo Alto, CA) using the Straight from LRSC CD19 MicroBead Kit (Miltenyi Biotech). 10 concentrations of 3-fold serially diluted rilzabrutinib in DMSO were incubated for 1 hour at 37°C with 5% DMSO. B cells were treated with CO2. Compound (I) (rilzabrutinib)-treated B cells and DMSO controls were then stimulated with trinitrophenyl phosphate conjugated to lipopolysaccharide (TNP-LPS (Santa Cruz Biotechnology)), 5'-cytosine-phosphate-guanine-3' (CpG (ODN2006, Invivogen)), or anti-CD40 (BD Biosciences) + IL21 (R&D Systems) for 7 days at 37°C, 5% CO2. Compound (I) inhibition of antibody production was determined by measuring IgG and IgM in cell culture lysates using human IgG and IgM AlphaLISA kits (Perkin Elmer). IC 50 was calculated without constraints using a "log(inhibitor) vs. response - variable slope (four parameters)" analysis using nonlinear regression in GraphPad Prism.

[0107] Example 4 Blockade of B cell activation, IgM and IgG antibody production using Compound (I) treatment Cut off Compound (I) can inhibit B cell activation, BCR-dependent B cell proliferation, and de novo antibody production. To determine the functional activity of Compound (I), the compound's ability to inhibit B cell activation was assessed by anti-IgM-induced CD69 expression on CD20+ B cells in human whole blood (Figure 7). The potency of Compound (I) (rilzabrutinib) in the B cell activation assay correlated well with BTK target occupancy. IC 50 The IC values ​​determined were 126±32 nM and 233±75 nM for inhibition of CD69 B cell expression and BTK target occupancy, respectively. As a further measure of the effect of Compound (I) on B cell function, the ability of Compound (I) to inhibit B cell receptor (BCR)-induced human B cell proliferation was determined. The IC values ​​of Compound (I) for inhibition of human B cell proliferation were: 50The mean plasma concentration was 5±2.4 nM. Compound (I) did not block antibody-dependent cell-mediated cytotoxicity (ADCC) in combination with an anti-CD20 antibody, demonstrating the potential for combination therapy. (Pirunsarn, A., P. Kijrattanakul, S. Chamnanchanunt, C. Polprasert, and P. Rojnuckarin. 2018. A randomized multicenter trial comparing low-dose prednisolone versus observation for prevention of recurrences in adult immune thrombocytopenia. Clin Appl Thromb Hemost 24: 867-873).

[0108] Compound (I) significantly inhibited IgM and IgG antibody production when stimulated in vitro. Compound (I) inhibited IgG antibody production with an IC of 20±20 nM when stimulated by the T cell-dependent pathway with anti-CD40 in combination with IL-21. 50 and IgM antibody production at an IC of 800 ± 1000 nM. 50 Compound (I) also inhibited IgG and IgM antibody production when stimulated by the TLR-9 agonist CpG via a T-independent pathway with an IgG IC of 50±90 nM. 50 and an IgM IC of 1 ± 1 nM. 50 and inhibited TNP-LPS-stimulated antibody production with an IgG IC of 300±600nM. 50 and IgM IC of 200 ± 600 nM. 50 was inhibited by (Table 1).

[0109] [Table 1]

Claims

1. 1. A method of treating a disease selected from membranous nephropathy (MN), IgG4-related disease (IgG4-RD), and antiphospholipid syndrome (APS) in a mammal in need thereof, comprising: a compound selected from the (E)-isomer, (Z)-isomer, and mixtures of the (E)- and (Z)-isomers of 2-[(3R)-3-[4-amino-3-(2-fluoro-4-phenoxy-phenyl)pyrazolo[3,4-d]pyrimidin-1-yl]piperidine-1-carbonyl]-4-methyl-4-[4-(oxetan-3-yl)piperazin-1-yl]pent-2-enenitrile; and / or a pharmaceutically acceptable salt of any of the foregoing compounds; and Pharmaceutically acceptable carrier or excipient The method comprises administering to the mammal a pharmaceutical composition comprising:

2. 10. The method of claim 1, wherein the disease is acute.

3. 3. The method of claim 1 or 2, wherein the disease is IgG4-RD disease exacerbation.

4. The method of any one of claims 1 to 3, wherein the pharmaceutical composition is administered orally.

5. The method of any one of claims 1 to 4, wherein the pharmaceutical composition is administered daily.

6. The method of any one of claims 1 to 5, wherein the pharmaceutical composition is administered orally daily.

7. The method of any one of claims 1 to 6, wherein the pharmaceutical composition is administered in place of immunosuppressive therapy.

8. The method of any one of claims 1 to 7, wherein the pharmaceutical composition is administered in place of corticosteroid therapy.

9. The method of any one of claims 1 to 6, wherein the pharmaceutical composition is administered in combination with immunosuppressive therapy.

10. The method of any one of claims 1 to 6, wherein the pharmaceutical composition is administered in combination with corticosteroid therapy.

11. The method of any one of claims 1 to 6 or 8 to 10, wherein the pharmaceutical composition is administered in combination with a non-corticosteroid immunosuppressant and / or an anti-inflammatory agent.

12. The method of any one of claims 1 or 4-6, wherein the pharmaceutical composition is administered in place of immunosuppressive maintenance therapy.

13. 7. The method of any one of claims 1 or 4 to 6, wherein the pharmaceutical composition is administered in place of corticosteroid maintenance therapy.

14. The method of any one of claims 1, 2, or 4-6, wherein the pharmaceutical composition is administered in combination with immunosuppressive maintenance therapy.

15. 7. The method of any one of claims 1, 2, or 4-6, wherein the pharmaceutical composition is administered in combination with corticosteroid maintenance therapy.

16. The method of any one of claims 13 to 15, wherein the pharmaceutical composition is administered in combination with a non-corticosteroid immunosuppressant and / or an anti-inflammatory agent.

17. The pharmaceutical composition comprises a compound that is a substantially pure (E) or (Z) isomer of 2-[(3R)-3-[4-amino-3-(2-fluoro-4-phenoxy-phenyl)pyrazolo[3,4-d]pyrimidin-1-yl]piperidine-1-carbonyl]-4-methyl-4-[4-(oxetan-3-yl)piperazin-1-yl]pent-2-enenitrile, and / or a pharmaceutically acceptable salt of said compound; and Pharmaceutically acceptable carrier or excipient The method according to any one of claims 1 to 16, comprising:

18. 18. The method of any one of claims 1-17, wherein at least about 85% weight / weight of 2-[(3R)-3-[4-amino-3-(2-fluoro-4-phenoxy-phenyl)pyrazolo[3,4-d]pyrimidin-1-yl]piperidine-1-carbonyl]-4-methyl-4-[4-(oxetan-3-yl)piperazin-1-yl]pent-2-enenitrile or at least about 85% weight / weight of a pharmaceutically acceptable salt of 2-[(3R)-3-[4-amino-3-(2-fluoro-4-phenoxy-phenyl)pyrazolo[3,4-d]pyrimidin-1-yl]piperidine-1-carbonyl]-4-methyl-4-[4-(oxetan-3-yl)piperazin-1-yl]pent-2-enenitrile is the (E) isomer.

19. The method of any one of claims 1 to 18, wherein the mammal is a human.

20. 20. The method of any one of claims 1 to 19, wherein the disease is an IgG4-related disease characterized by an IgG4-RD responder index (RI) greater than or equal to 2 in at least one organ system.

21. The method of any one of claims 1 to 20, wherein the disease is an IgG4-related disease characterized by a serum IgG4 concentration greater than 1.5 times the upper limit of normal.

22. The diseases include IgG4-related sialadenitis, IgG4-related eye disease (IgG4-ROD), IgG4-related pharyngitis, IgG4-related thyroid disease, IgG4-related hypophysitis, IgG4-related pachymeningitis, IgG4-related leptomeningitis, IgG4-related pancreatitis, IgG4-related lung disease, IgG4-related pleuritis, IgG4-related hepatopathy, IgG4-related sclerosing cholangitis, IgG4-related cholecystitis, IgG4-related aortitis, IgG4-related periaortitis, IgG4-related periarteritis, IgG4-related pericarditis, IgG4-related pericardiitis, IgG4-related pericardial inflammation ... The method of any one of claims 1 to 21, wherein the IgG4-related condition is selected from IgG4-related mediastinitis, IgG4-related retroperitoneal fibrosis, IgG4-related mesenteritis, IgG4-related mastitis, IgG4-related kidney disease (IgG4-RKD), IgG4-related prostatitis, IgG4-related perivascular fibrosis, IgG4-related paratesticular pseudotumor, IgG4-related epididymo-orchitis, IgG4-related lymphadenopathy, IgG4-related skin disease, and IgG4-related perineural disease, or a flare-up of any of the IgG4-related diseases.

23. The pharmaceutical composition may be selected from the group consisting of interferon alpha, interferon gamma, cyclophosphamide, tacrolimus, mycophenolate mofetil, methotrexate, dapsone, sulfasalazine, azathioprine, anti-CD20 agents, anti-TNF alpha agents, anti-IL-4 agents directed against a ligand or its receptor, anti-IL-6 agents directed against a ligand or its receptor, anti-IL-12 agents directed against a ligand or its receptor, anti-IL-17 agents directed against a ligand or its receptor, anti-IL-1 agents directed against a ligand or its receptor, anti-IL-2 agents directed against a ligand or its receptor, anti-IL-3 agents directed against a ligand or its receptor, anti-IL-4 agents directed against a ligand or its receptor, anti-IL-5 ...2 agents directed against a ligand or its receptor, anti-IL-17 agents directed against a ligand or its receptor, anti-IL-22 agents directed against a ligand or its receptor, anti-IL-12 agents directed against a ligand or its receptor, anti-IL-12 agents directed against a ligand or its receptor, anti-IL-12 agents directed against a ligand or its receptor, anti-IL-12 agents directed against a ligand or its receptor, anti-IL-12 agents directed against a ligand or its receptor, anti-IL-12 agents directed against a ligand or its receptor, anti-IL-12 agents directed against 10. The method of claim 1, wherein the compound is administered in combination with an active pharmaceutical ingredient selected from an IL-2 agent, an anti-IL-23 agent directed against a ligand or its receptor, an anti-IL-12 / 23 agent directed against a ligand or receptor, an anti-CD2 agent, an anti-CD3 agent, an anti-CD80 / 86 agent, an anti-sphingosine-1-phosphate receptor agent, an anti-C5 agent, an anti-mTOR agent, an anti-calcineurin agent, an anti-BAFF / BlyS agent, leflunomide, and teriflunomide.

24. 10. The method of claim 1, wherein the pharmaceutical composition is administered in combination with rituximab, dupilumab, ofatumumab, obinutuzumab, or veltuzumab, or a biosuccessor version of any of the foregoing.

25. 25. The method of any one of claims 1-6, 9-11, or 14-24, wherein the mammal is naive with respect to immunosuppressive therapy.

26. 25. The method of any one of claims 1-6, 9-11, or 14-24, wherein the mammal is naive to any immunosuppressive therapy.

27. The method of any one of claims 1 to 24, wherein the mammal has previously been treated with immunosuppressive therapy.

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