Treatment of acute respiratory distress syndrome and other disorders involving cytokine storm using BTK inhibitors

Abstract

To provide a pharmaceutical composition for use in the treatment of a disease selected from sepsis, secondary hemophagocytic lymphohistiocytosis, cytokine release syndrome, and systemic inflammatory response syndrome in a mammal in need thereof.SOLUTION: Provided is a pharmaceutical composition comprising a BTK inhibitor that is a compound of Formula (I) or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier or excipient.SELECTED DRAWING: None

Description

[Technical Field]

[0001] cross reference This application claims priority to U.S. Provisional Application No. 63 / 013,784, filed April 22, 2020, the contents of which are incorporated herein by reference for all purposes.

[0002] Summary of the Invention Disclosed herein are methods for treating a disease selected from acute respiratory distress syndrome (ARDS), sepsis, sepsis-induced acute lung injury, diffuse alveolar damage (DAD), macrophage activation syndrome (MAS), secondary hemophagocytic lymphohistiocytosis (sHIH), cytokine release syndrome (CRS), and systemic inflammatory response syndrome (SIRS), comprising administering to a mammal in need thereof a pharmaceutical composition comprising a small molecule Bruton's tyrosine kinase (BTK) inhibitor (BTKi) and a pharmaceutically acceptable carrier or excipient. In some embodiments, the disease is caused by or associated with COVID-19. [Background technology]

[0003] Emerging clinical data suggest that inflammatory immune responses are dysregulated in many severe COVID-19 patients. Severe COVID-19 patients exhibit venous thrombotic complications, complement activation, and high levels of D-dimers, small protein fragments produced during fibrinolysis (Non-Patent Document 1), which are strongly associated with high mortality rates. Furthermore, some COVID-19 patients suffer from a "cytokine storm" (Non-Patent Document 2), which may contribute to the development of acute lung injury (ALI) and acute respiratory distress syndrome (ARDS) (Non-Patent Document 3).

[0004] A significant increase in neutrophil migration into the lungs is a hallmark of ARDS. Several studies have shown a correlation between the number of neutrophils in the alveolar space and the severity of ARDS disease (Non-Patent Document 4). In COVID-19 patients, increased neutrophil counts and neutrophil-to-lymphocyte ratios appear to indicate increased disease severity and poor clinical prognosis (Non-Patent Document 5). Resident alveolar macrophages and recruited macrophages also appear to play an important role in the inflammatory response process occurring in ARDS patients (Non-Patent Document 6), and growing evidence continues to link monocyte / macrophage hyperactivation and the associated cytokine storm with severe COVID-19 disease-related complications (Non-Patent Document 7).

[0005] Thus, there is a need for new methods of treating diseases caused by or associated with COVID-19, such as ARDS, sepsis, sepsis-induced acute lung injury, DAD, macrophage activation syndrome (MAS), sHIH, CRS, and SIRS.

[0006] The enzyme BTK is a member of the Tec family of non-receptor tyrosine kinases. BTK is an immune target expressed in most hematopoietic cells, including B cells, as well as innate immune cells such as neutrophils, macrophages, and mast cells. This enzyme is also expressed in platelets, which are involved in inflammatory responses, supporting complement production and promoting cytokine release, coagulation, and neutrophil NET formation (Non-Patent Document 8). BTK plays a role in B cell development and activation and regulates immune cell function through various signaling pathways, including those involving B cell receptors, Fc receptors, integrins, Toll-like receptors, and chemokine receptors (Non-Patent Document 9). Furthermore, BTK mediates neutrophil degranulation in damaged tissues. BTK plays an important role in the granulation, migration, and retention of cells (Non-Patent Document 10), as well as the activation and differentiation of monocytes / macrophages (Non-Patent Document 9). BTK inhibition regulates various inflammatory immune cell activities, such as proliferation, differentiation, and cytokine production, without depleting immune cells (Non-Patent Document 9).

[0007] Without wishing to be bound by theory, BTK inhibitors may be useful in the treatment of ARDS, sepsis, sepsis-induced acute lung injury, DAD, macrophage activation syndrome (MAS), sHIH, CRS, and SIRS due to their potential in modulating various immune responses. BTK inhibitors are protective in rodent models of ALI and ARDS, and attenuation of lung pathology, inflammation, and pulmonary dysfunction has been observed in rodents administered BTK inhibitors. Within the lung, BTKi treatment reduced the activation of alveolar macrophages and systemic neutrophils, and substantially reduced the influx of additional monocytes and neutrophils. BTK inhibition also prevented the release of inflammatory cytokines, neutrophil NET formation, and matrix metalloproteinases, which contribute to the pathogenesis of acute lung injury (Non-Patent Document 11; Non-Patent Document 6; Non-Patent Document 12). In a liver model, BTKi treatment was able to inhibit neutrophil activation and migration at sites of tissue inflammation and tissue injury, reversing the potentially harmful effects of neutrophil accumulation (Non-Patent Document 10). Antithrombotic effects were also observed after BTK inhibition due to inhibition of inflammatory platelet mechanisms. Fortunately, BTK inhibition preserves the normal hemostatic function of platelets (Non-Patent Document 8). [Prior art documents] [Non-patent literature]

[0008] [Non-Patent Document 1] Thachil J, et al.ISTH interim guidance on recognition and management of coagulopathy in COVID-19.J Thromb Hemostasis.2020.https: / / doi.org / 10.1111 / JTH.14810 [Non-patent document 2] Mehta P, et al. COVID-19: consider cytokine storm syndromes and immunosuppression. The Lancet.2020.395 (10229):1033-1034. https: / / doi.org / 10.1016 / S0140-6736(20)30628-0 [Non-licensed document 3] Murphy S,et al.Care for Critically Ill Patients With COVID-19.JAMA Insights.2020.https: / / doi.org / 10.1001 / jama.2020.3633

Non-licensed Document 4

Non-licensed Document 5

Non-licensed Document 6

Non-licensed Document 7

[0009] Disclosed herein are methods for treating a disease selected from ARDS, sepsis, sepsis-induced acute lung injury, DAD, macrophage activation syndrome (MAS), sHIH, CRS, and SIRS, comprising administering to a mammal in need thereof a pharmaceutical composition comprising a small molecule BTK inhibitor and a pharmaceutically acceptable carrier or excipient. In some embodiments of the disclosure, the BTK inhibitor is a compound of Formula (I) or a pharmaceutically acceptable salt thereof: [ka]

[0010] During the ceremony, Z 2 -N- or CR 2 where R 2 is selected from hydrogen and alkyl; R 3 and R 4is independently selected from hydrogen, methyl, chloro, fluoro, cyclopropyl, hydroxy, methoxy, cyano, trifluoromethyl, and trifluoromethoxy; R 6 and R 7 is independently selected from hydrogen, methyl, methoxy, fluoro, chloro, trifluoromethyl, trifluoromethoxy, and cyano; -Z-EWG- is -alkylene-NR'CO-, -alkylene-NR'SO2-, [ka] is selected from, where [ka] are each independently substituted with 0, 1, or 2 substituents independently selected from alkyl, hydroxy, and halo; -alkylene-NR'CO-, -alkylene-NR'SO2-, [ka] The carbonyl or sulfonyl group in -C(CN)=CHR c It is bound to; R' is independently selected from hydrogen and alkyl; R c is alkyl, haloalkoxy, substituted alkyl, cycloalkyl, cycloalkylene -NR d R e , and cycloalkylene-alkylene-NR d R e Selected from; R d and R e are independently selected from hydrogen, alkyl, cycloalkyl, and 3- to 6-membered saturated monocyclic heterocyclyl, The heterocycle contains 1 or 2 heteroatoms independently selected from N, O, and S; the heterocycle is substituted with 0, 1, or 2 substituents independently selected from hydroxy, alkyl, and fluoro.

[0011] Compounds of formula (I) are disclosed in PCT / US2012 / 038092, published as WO 2012 / 158764, and PCT / US2013 / 058614, published as WO 2014 / 039899.

[0012] In some embodiments, the BTK inhibitor is a compound of Formula (I) or a pharmaceutically acceptable salt thereof, wherein Z 2 is -N-.

[0013] In some embodiments, the BTK inhibitor is a compound of Formula (I) or a pharmaceutically acceptable salt thereof, wherein: -Z-EWG- [ka] where [ka] is independently substituted with 0, 1, or 2 substituents independently selected from alkyl, hydroxy, and halo; [ka] The carbonyl group in is -C(CN)=CHR c is bonded to.

[0014] In some embodiments, the BTK inhibitor is a compound of Formula (I) or a pharmaceutically acceptable salt thereof, wherein: Z 2 is -N-; -Z-EWG- [ka] is.

[0015] In some embodiments, the BTK inhibitor is a compound of Formula (I) or a pharmaceutically acceptable salt thereof, wherein: Z 2is -N-; -Z-EWG- [ka] is.

[0016] In some embodiments, the BTK inhibitor is selected from the (E)-isomer, the (Z)-isomer, and a mixture of the (E)- and (Z)-isomers of any of the compounds shown in Table 1 below, or a pharmaceutically acceptable salt of any of the foregoing compounds.

[0017] [Table 1-1] [Table 1-2] [Table 1-3] [Table 1-4] [Table 1-5]

[0018] In some embodiments, the BTK inhibitor is a compound of Formula (I) or a pharmaceutically acceptable salt thereof, wherein: Z 2 is -N-; -Z-EWG- [ka] is.

[0019] In some embodiments, the BTK inhibitor is a compound of Formula (I) or a pharmaceutically acceptable salt thereof, wherein: Z 2 is -N-; -Z-EWG- [ka] is.

[0020] In some embodiments, the BTK inhibitor is selected from the (E)-isomer, the (Z)-isomer, and a mixture of the (E)- and (Z)-isomers of any of the compounds shown in Table 2 below, or a pharmaceutically acceptable salt of any of the foregoing compounds.

[0021] [Table 2-1] [Table 2-2] [Table 2-3] [Table 2-4] [Table 2-5] [Table 2-6] [Table 2-7] [Table 2-8]

[0022] In some embodiments, the BTK inhibitor is a compound of Formula (I) or a pharmaceutically acceptable salt thereof, wherein: Z 2 is -N-; -Z-EWG- [ka] where [ka] is substituted with 0, 1, or 2 substituents independently selected from alkyl, hydroxy, and halo; [ka] The carbonyl group in is -C(CN)=CHR c It is bound to; R c is alkyl.

[0023] In some embodiments, the BTK inhibitor is a compound of Formula (I) or a pharmaceutically acceptable salt thereof, wherein: Z 2 is -N-; -Z-EWG- [ka] where [ka] is substituted with 0, 1, or 2 substituents independently selected from alkyl, hydroxy, and halo; [ka] The carbonyl group in is -C(CN)=CHR c It is bound to; R c is t-butyl.

[0024] In some embodiments of the present disclosure, the BTK inhibitor is selected from the (E) isomer, the (Z) isomer, and a mixture of the (E) and (Z) isomers of (R)-2-(3-(4-amino-3-(2-fluoro-4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)piperidine-1-carbonyl)-4,4-dimethylpent-2-enenitrile (compound (IA)), or a pharmaceutically acceptable salt of either compound. A non-fluorinated analog of compound (IA) is disclosed in Example 3 of WO 2012 / 158764. Compound (IA) has the following structure: [ka]

[0025] In some embodiments, the BTK inhibitor is a substantially pure (E) or (Z) isomer of (R)-2-(3-(4-amino-3-(2-fluoro-4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)piperidine-1-carbonyl)-4,4-dimethylpent-2-enenitrile (compound (IA)), or a pharmaceutically acceptable salt thereof.

[0026] In some embodiments, the BTK inhibitor is a compound of Formula (I) or a pharmaceutically acceptable salt thereof, wherein: Z 2 is -N-; -Z-EWG- [ka] where [ka] is substituted with 0, 1, or 2 substituents independently selected from alkyl, hydroxy, and halo; [ka] The carbonyl group in is -C(CN)=CHR c It is bound to; R c is a substituted alkyl.

[0027] In some embodiments, the BTK inhibitor is a compound of Formula (I) or a pharmaceutically acceptable salt thereof, wherein: Z 2 is -N-; -Z-EWG- [ka] where [ka] is substituted with 0, 1, or 2 substituents independently selected from alkyl, hydroxy, and halo; [ka] The carbonyl group in is -C(CN)=CHR c It is bound to; R c is -C(CH3)2-(4-R 8 -piperazin-1-yl), wherein R 8 is selected from hydrogen, alkyl, alkoxyalkyl, haloalkyl, alkylsulfonyl, alkoxycarbonyl, acyl, and oxetan-3-yl; The piperazinyl ring is further optionally substituted with one or two independently selected alkyl.

[0028] In some embodiments, the BTK inhibitor is a compound of Formula (I) or a pharmaceutically acceptable salt thereof, wherein: Z 2 is -N-; -Z-EWG- [ka] where [ka] is substituted with 0, 1, or 2 substituents independently selected from alkyl, hydroxy, and halo; [ka] The carbonyl group in is -C(CN)=CHR c It is bound to; R c is -C(CH3)2-(4-R 8 -piperazin-1-yl), wherein R 8is selected from hydrogen, alkyl, alkoxyalkyl, haloalkyl, alkylsulfonyl, alkoxycarbonyl, acyl, and oxetan-3-yl; The piperazinyl ring is further optionally substituted with one or two independently selected alkyl.

[0029] In some embodiments, the BTK inhibitor is selected from the (E)-isomer, the (Z)-isomer, and a mixture of the (E)- and (Z)-isomers of any of the compounds shown in Table 3 below, or a pharmaceutically acceptable salt of any of the foregoing compounds.

[0030] [Table 3-1] [Table 3-2] [Table 3-3] [Table 3-4]

[0031] In some embodiments, the BTK inhibitor is a compound of Formula (I) or a pharmaceutically acceptable salt thereof, wherein: Z 2 is -N-; -Z-EWG- [ka] where [ka] is substituted with 0, 1, or 2 substituents independently selected from alkyl, hydroxy, and halo; [ka] The carbonyl group in is -C(CN)=CHR c It is bound to; R c is -C(CH3)2-(4-R 8 -piperazin-1-yl), where R 8 is oxetan-3-yl.

[0032] In some embodiments of the present disclosure, the BTK inhibitor is selected from the (E)-isomer, the (Z)-isomer, and a 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 (compound (IB)); and / or a pharmaceutically acceptable salt of any of the foregoing compounds.

[0033] Compound (IB) is also known as PRN1008 or rilzabrutinib and has the following chemical structure: [ka]

[0034] At the alkene carbon in compound (IB) [ka] The line indicates that compound (IB) or a pharmaceutically acceptable salt thereof can be the (E) isomer, the (Z) isomer, or a mixture of the (E) and (Z) isomers.

[0035] Compound (IB) is disclosed in Example 31 of PCT Application No. PCT / US2013 / 058614, filed September 6, 2013, and published as WO 2014 / 039899. The disclosed synthesis shows that compound (IB) requires purification by column chromatography and, after removal of the solvent, produces a foam that can be crushed to obtain a powder.

[0036] Compound (IA), Compound (IB), and pharmaceutically acceptable salts of either compound are potent inhibitors of Bruton's tyrosine kinase (BTK). Compound (IB) is an oral inhibitor of the BTK pathway. It is a reversible covalent inhibitor designed to be rapidly cleared from the circulation, with baseline BTK activity (measured by occupancy) returning within a few days. Compound (IB) is currently in clinical trials for the treatment of both pemphigus vulgaris (PV) and immune thrombocytopenia (ITP).

[0037] BTKi offers an alternative immunomodulatory approach for the treatment of COVID-19 patients. Immunomodulation with BTK inhibitors, such as compounds of formula (I), e.g., compound (IA) or compound (IB), can be beneficial for treating ARDS and inflammation in COVID-19 patients. BTKi can offer an anti-inflammatory approach to target underlying tissue inflammation and the accumulation of harmful neutrophils and macrophages in the lungs. BTKi can also exert antithrombotic effects through inhibition of platelet inflammatory mechanisms while preserving the normal hemostatic function of platelets.

[0038] In some embodiments of the present disclosure, at least about 80% (w / w), at least about 85% (w / w), at least about 90% (w / w), at least about 95% (w / w), at least about 96% (w / w), at least about 97% (w / w), or at least about 99% (w / w) of Compound (IA) or Compound (IB), or a pharmaceutically acceptable salt of either, is the (E) isomer. The ratio of the (E) to (Z) isomers is generally known in the art. The area ratio can be calculated by well-known methods, such as the HPLC total area normalization method, as a non-limiting example of one such method.

[0039] In some embodiments, the present disclosure provides methods of using at least one compound selected from compounds of formula (I) and pharmaceutically acceptable salts thereof as an alternative to corticosteroid therapy for treating a disease selected from acute respiratory distress syndrome (ARDS), sepsis, sepsis-induced acute lung injury, diffuse alveolar damage (DAD), macrophage activation syndrome (MAS), secondary hemophagocytic lymphohistiocytosis (sHIH), cytokine release syndrome (CRS), and systemic inflammatory response syndrome (SIRS).

[0040] In some embodiments, the present disclosure provides a method of using at least one compound selected from the compounds of Formula (I) and pharmaceutically acceptable salts thereof as an alternative therapeutic agent for treating a disease selected from acute respiratory distress syndrome (ARDS), sepsis, sepsis-induced acute lung injury, diffuse alveolar damage (DAD), macrophage activation syndrome (MAS), secondary hemophagocytic lymphohistiocytosis (sHIH), cytokine release syndrome (CRS), and systemic inflammatory response syndrome (SIRS). In some embodiments, a corticosteroid is used as a first- or second-line therapy for treating the disease. In some embodiments, at least one compound is used in place of a corticosteroid. In some embodiments, at least one compound is used in combination with a corticosteroid. In some embodiments, a corticosteroid is used as a first- or second-line maintenance therapy for the disease. In some embodiments, at least one compound is used in place of a corticosteroid. In some embodiments, at least one compound is used in combination with a corticosteroid.

[0041] In some embodiments, the present disclosure provides a method for eliminating or reducing the therapeutic dose of a corticosteroid used in chronic maintenance therapy in the treatment of a disease selected from acute respiratory distress syndrome (ARDS), sepsis, sepsis-induced acute lung injury, diffuse alveolar damage (DAD), macrophage activation syndrome (MAS), secondary hemophagocytic lymphohistiocytosis (sHIH), cytokine release syndrome (CRS), and systemic inflammatory response syndrome (SIRS) in a mammal in need thereof, comprising administering to the mammal a therapeutically effective amount of at least one compound selected from the compounds of Formula (I) and pharmaceutically acceptable salts thereof. In some embodiments, a corticosteroid is used as a first-line or second-line treatment. In some embodiments, at least one compound is used in place of a corticosteroid. In some embodiments, at least one compound is used in combination with a corticosteroid.

[0042] In some embodiments of the present disclosure, at least one compound selected from the compounds of Formula (I) and pharmaceutically acceptable salts thereof is administered in combination with a non-corticosteroidal immunosuppressant and / or anti-inflammatory agent. In some embodiments, the at least one compound is selected from interferon alpha, interferon gamma, cyclophosphamide, tacrolimus, mycophenolate mofetil, methotrexate, dapsone, sulfasalazine, azathioprine, an anti-CD20 agent (e.g., rituximab, ofatumumab, obinutuzumab, or veltuzumab, or a biosimilar of any of the above), an anti-TNα agent (e.g., etanercept, infliximab, golimumab, adalimumab, or certolizumab pegol, or a biosimilar of any of the above), an anti-TNα agent (e.g., rituximab, ofatumumab, obinutuzumab, or veltuzumab pegol, or a biosimilar of any of the above), an anti-TNα agent (e.g., etanercept, infliximab, golimumab, adalimumab, or certolizumab pegol, or a biosimilar of any of the above), an anti-TNα agent (e.g., rituximab, ofatumumab, obinutuzumab, veltuzumab ... anti-IL6 agents directed against a ligand or its receptor (e.g., tocilizumab, sarilumab, olokizumab, elsililumab, or siltuximab, or a biosimilar of any of the above); anti-IL17 agents directed against a ligand or its receptor (e.g., secukinumab, ustekinumab, brodalumab, or ixekizumab, or a biosimilar of any of the above); anti-IL1 agents directed against a ligand or its receptor (e.g., rilonacept, canakinumab, or anakinra, or a biosimilar of any of the above), anti-IL2 agents directed against a ligand or its receptor (e.g., basiliximab or daclizumab, or a biosimilar of either), anti-CD2 agents (e.g., alefacept or a biosimilar of either), anti-CD3 agents (e.g., muromonab-cd3 or a biosimilar of either), anti-CD80 / 86 agents (e.g., abatacept or belatacept, or a biosimilar of either), anti-sphingosine-1-phosphate receptor agents (e.g., fingolimod or a biosimilar of either), anti It is administered in combination with an active pharmaceutical ingredient selected from a C5 agent (e.g., eculizumab or a biosimilar thereof), an anti-integrin alpha4 agent (e.g., natalizumab or a biosimilar thereof), an anti-alpha4beta7 agent (e.g., vedolizumab or a biosimilar 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 biosimilar of any of the above), leflunomide, and teriflunomide.

[0043] In some embodiments of the present disclosure, at least one compound selected from the group consisting of compounds of Formula (I) and pharmaceutically acceptable salts thereof is administered in combination with at least one antiviral agent, such as remdesivir, which can include, for example, entry inhibitors, uncoating inhibitors, reverse transcriptase inhibitors, integrase inhibitors, and protease inhibitors. [Brief explanation of the drawings]

[0044] [Figure 1] This study design demonstrates dose-dependent inhibition of glomerular basement membrane (GBM) glomerulonephritis in a mouse model. The mouse anti-GBM glomerulonephritis model encompasses antibody-mediated autoimmunity and is histologically and mechanistically similar to glomerulonephritis in humans. This model also involves renal deposition of immune complexes (ICs) targeting the glomerular basement membrane. [Figure 2]1 shows dose-dependent inhibition of serum blood urea nitrogen (BUN) levels by PRN1008 treatment in a mouse anti-GBM glomerulonephritis model. BUN levels represent a measure of renal function. [Figure 3] 1 shows dose-dependent inhibition of severe proteinuria by PRN1008 treatment in a murine anti-GBM glomerulonephritis model. [Figure 4] 1 shows reduction of proteinuria with PRN1008 treatment in a mouse anti-GBM glomerulonephritis model. [Figure 5] 1 shows dose-dependent inhibition of kidney weight gain, a surrogate indicator of renal inflammation, by PRN1008 treatment in a murine anti-GBM glomerulonephritis model. [Figure 6] We demonstrate that PRN1008 significantly reduced renal pathology in a murine anti-GBM glomerulonephritis model, superior to a steroid comparator (Dex). In Figures 1-6, Dex refers to dexamethasone, a potent synthetic member of the glucocorticoid class of steroid hormones. [Figure 7] 1 shows the BioMAP Diversity PLUS panel used in interpreting BioMAP biomarker activity in relation to biological pathways and in vivo correlation and prediction. [Figure 8-1] The BioMAP profile of PRN1008 is shown. [Figure 8-2] Continued from Figure 8-1. [Figure 8-3] Continued from Figure 8-2. [Figure 9] Figure 9A shows that neutrophil migratory activity was significantly reduced in animals treated with Compound (IA) compared to vehicle controls for arrested crawling cells. Figure 9B shows representative photomicrographs of neutrophil (eGFP, green) recruitment to the necrotic area (propidium iodide, red) 4 hours after burn injury obtained using spinning disk time-lapse microscopy. DETAILED DESCRIPTION OF THE INVENTION

[0045] definition As used herein, the entity "a" or "an" means one or more of that entity; for example, "a compound" means 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.

[0046] As used herein, the term "about" means "approximately," "in the region of," "roughly," or "around." When used in conjunction with a numerical range, the term "about" modifies that range by extending the boundaries above and below the stated numerical values. In general, the term "about" is used herein to modify a numerical value above and below the stated value by a variance of 10%.

[0047] As used herein, "small molecule" means an organic compound having a molecular weight of less than 500 g / mol, where the atoms of the compound include carbon, hydrogen, oxygen, nitrogen, phosphorus, and sulfur.

[0048] As used herein, "Compound (IA)" refers to the (E) isomer, the (Z) isomer, or a mixture of the (E) and (Z) isomers of (R)-2-(3-(4-amino-3-(2-fluoro-4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)piperidine-1-carbonyl)-4,4-dimethylpent-2-enenitrile, having the structure shown below. [ka]

[0049] As used herein, “Compound (IB)” means the (E) isomer, the (Z) isomer, or a 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, having the structure shown below, or a pharmaceutically acceptable salt thereof. [ka]

[0050] At the alkene carbon in compound (IA) or compound (IB) [ka] The lines indicate that compound (IA) or compound (IB), or a pharmaceutically acceptable salt of either, can be the (E) isomer, the (Z) isomer, or a mixture of the (E) and (Z) isomers.

[0051] All polymorphs and hydrates of Compound (IA) and Compound (IB) are within the scope of this specification and the claims appended hereto.

[0052] Those skilled in the art will understand 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.

[0053] As used herein, "substantially pure" with respect to a geometric or isomeric form refers to a compound, such as Compound (IA) or Compound (IB), in which greater than 70% by weight of the compound is present as a given isomeric form. For example, the phrase "Compound (IA) is a substantially pure (E) isomer" means that Compound (IA) has at least 70% by weight or mole% of the (E) isomeric form, and the phrase "Compound (IA) is a substantially pure (Z) isomer" means that Compound (IA) has at least 70% by weight or mole% of the (Z) isomeric form. The above equally applies to Compound (IB). In some embodiments, at least 80% by weight or mole% of Compound (IA) or Compound (IB) is the (E) form, or at least 80% by weight or mole% of Compound (IA) or Compound (IB) is the (Z) form. In some embodiments, at least 85% by weight or mole% of Compound (IA) or Compound (IB) is in the (E) form, or at least 85% by weight or mole% of Compound (IA) or Compound (IB) is in the (Z) form. In some embodiments, at least 90% by weight or mole% of Compound (IA) or Compound (IB) is in the (E) form, or at least 90% by weight or mole% of Compound (IA) or Compound (IB) is in the (Z) form. In some embodiments, at least 95% by weight or mole% of Compound (IA) or Compound (IB) is in the (E) form, or at least 95% by weight or mole% of Compound (IA) or Compound (IB) is in the (Z) form. In some embodiments, at least 97% by weight or mole% or at least 98% by weight or mole% of Compound (IA) or Compound (IB) is in the (E) form, or at least 97% by weight or mole% or at least 98% by weight or mole% of Compound (IA) or Compound (IB) is in the (Z) form. In some embodiments, at least 99% by weight or mole percent of Compound (IA) or Compound (IB) is the (E) form, or at least 99% by weight or mole percent of Compound (IA) or Compound (IB) 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.

[0054] As used herein, "acute" refers to a disease with a rapid onset and / or short course.

[0055] 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. These salts include, but are not limited to, the following: They are formed by inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, etc.; or by acids such as 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, benzoic ... 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 sulfate, gluconic acid, glutamic acid, hydroxynaphthoic acid, salicylic acid, stearic acid, and muconic acid; or Salts formed when an acidic proton present in the parent compound is replaced by a metal ion, for example, an alkali metal ion, alkaline earth ion, or aluminum ion, or coordinates to an organic base such as ethanolamine, diethanolamine, triethanolamine, tromethamine, N-methylglucamine, etc. It will be understood that pharmaceutically acceptable salts are non-toxic.

[0056] Further information regarding suitable pharmaceutically acceptable salts can be found in Remington's Pharmaceutical Sciences, 17th ed., Mack Publishing Company, Easton, PA, 1985, the portion thereof regarding suitable pharmaceutically acceptable salts is incorporated herein by reference. Berge et al., Pharmaceutical Salts, Journal of Pharmaceutical Sciences, 1, Volume 66, Number 1, January 1997.

[0057] Treatment decisions often follow formal or informal algorithmic guidelines. Treatment options can often be ranked or prioritized into treatment modalities, i.e., first-line treatment, second-line treatment, third-line treatment, etc. First-line treatment refers to the first treatment to be tried. Its preference over other options is usually (1) officially recommended based on clinical trial evidence of its best available combination in terms of efficacy, safety, and tolerability; or (2) selected based on the physician's clinical experience. If the first-line treatment cannot solve the problem or causes intolerable side effects, additional (second-line) treatments, followed by third-line treatments, etc., can be used instead or added to the treatment regimen. Therefore, as used herein, "first-line" treatment refers to the treatment that is usually given when someone is diagnosed with a particular disease or condition. First-line treatment may be classified as standard treatment.

[0058] As used herein, "maintenance therapy" refers to the initial therapy administered to a patient with a disease. Maintenance therapy refers to a treatment, treatment regimen, or course of treatment implemented following a course of treatment. Maintenance therapy can be used to halt, slow, or even reverse disease progression, maintain improvements in health achieved by initial treatment, and / or increase the benefits achieved by initial treatment.

[0059] "Pharmaceutically acceptable carrier or excipient" means 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 and human pharmaceutical use. As used herein, "pharmaceutically acceptable carrier or excipient" means one or more pharmaceutically acceptable carriers or excipients.

[0060] As used herein, "treating," "treat," or "treatment" means (1) inhibiting the disease, i.e., halting or reducing the occurrence of the disease or its clinical symptoms; or (2) Relieving the disease, including causing regression of the disease or its clinical symptoms.

[0061] As used herein, a "therapeutically effective amount" refers to the amount of a compound of the present disclosure that, when administered to a mammal, particularly 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 being treated.

[0062] As used herein, "QD" means once daily.

[0063] As used herein, "BID" means twice a day.

[0064] As used herein, "mammal" means animals such as dogs, cats, and humans.

[0065] Acute respiratory distress syndrome (ARDS) is a condition characterized by shortness of breath, rapid breathing, and / or bluish skin coloration. It is a type of respiratory failure involving inflammation within the lungs. ARDS impairs the lungs' ability to exchange oxygen and carbon dioxide. Causes of ARDS can include sepsis, pancreatitis, trauma, pneumonia, and aspiration. In some embodiments of the present disclosure, ARDS is caused by or associated with coronavirus disease 2019 (COVID-19). ARDS caused by COVID-19 is the leading cause of death in patients infected with the COVID-19 virus (Mehta 2020; Ryan 2020).

[0066] Secondary hemophagocytic lymphohistiocytosis (sHLH) is a hyperinflammatory syndrome characterized by fulminant (i.e., severe and sudden onset) and fatal hypercytokinemia (an immune response involving highly elevated levels of various cytokines, demonstrating a positive feedback loop between cytokines and immune cells) accompanied by multiple organ failure (Mehta 2020). sHLH is an acquired form of hemophagocytic lymphohistiocytosis (HLH) triggered by infection, malignancy, autoimmune disease, or other immune challenge. Symptoms of critical care patients with sHLH include fever, organ dysfunction, lymphadenopathy, and potentially hepatomegaly and / or splenomegaly. In some embodiments of the present disclosure, sHLH is caused by or associated with COVID-19.

[0067] Sepsis (also known as septicemia and blood poisoning) is an inflammatory immune response caused by an infection. Sepsis is a life-threatening condition that exists when the body causes damage to its own tissues and organs during infection. Infections can be caused by bacteria (most common), fungi, viruses, and protozoa. Symptoms of sepsis can include fever, increased heart rate, low blood pressure, increased respiratory rate, and confusion. In some embodiments of the present disclosure, the sepsis is caused by or associated with COVID-19.

[0068] Systemic inflammatory response syndrome (SIRS), also known as acute inflammatory syndrome, is an inflammatory condition affecting the entire body. SIRS is the body's response to infectious or non-infectious challenges. SIRS has both pro- and anti-inflammatory components. SIRS is associated with systemic inflammation, organ dysfunction, and organ failure and is a subset of cytokine storm, in which various cytokines are dysregulated. It is also closely related to sepsis, in which patients meet the criteria for SIRS and have suspected or proven infection. Complications of SIRS can include acute kidney injury, shock, and multiple organ dysfunction syndrome. Causes of SIRS can include microbial infection, malaria, trauma, burns, pancreatitis, ischemia, hemorrhage, surgical complications, adrenal insufficiency, pulmonary embolism, aortic aneurysm, cardiac tamponade, anaphylaxis, and drug overdose. In some embodiments of the present disclosure, SIRS is caused by or associated with COVID-19.

[0069] Cytokine release syndrome (CRS) or cytokine storm syndrome (CSS) is a form of SIRS that can be triggered by various factors, such as infections and certain drugs. When CRS occurs as a result of drug administration, it is also known as an infusion-related reaction (IRR) or infusion reaction. This syndrome occurs when large numbers of leukocytes are activated and release inflammatory cytokines, which then activate additional leukocytes. CRS can be an adverse effect of some monoclonal antibody drugs and adoptive T-cell therapy drugs. Symptoms of CRS can include fever, fatigue, loss of appetite, muscle and joint pain, nausea, vomiting, diarrhea, rash, tachypnea, tachycardia, hypotension, seizures, headache, confusion, delirium, hallucinations, tremors, and dyscoordination. In some embodiments of the present disclosure, CRS is caused by or associated with COVID-19.

[0070] Sepsis-induced acute lung injury (ALI) is characterized by edema, inflammatory cell infiltration, and impaired gas exchange. Patients' conditions can be exacerbated by hypoxia, which can lead to multiple organ failure. Approximately 40% of sepsis patients develop ALI. In some embodiments of the present disclosure, septic ALI is caused by or associated with COVID-19.

[0071] Diffuse alveolar damage (DAD) is a response to injury in lung tissue. It consists of intraalveolar exudates (often described as hyaline membranes) and hyperplasia of type II pneumocytes, which may be cytologically pleomorphic (King 2007). DAD has been observed in autopsies of individuals deceased from AIDS / HIV-1 infection, and possible etiologies include viral or opportunistic infections (e.g., Pneumocystis pneumoniae (P. jirovecii)), adult respiratory distress syndrome, and oxygen toxicity. Clinically, it is characterized by respiratory distress and diffuse pulmonary infiltrates (Kattan et al. 2012). DAD is considered the gold standard pathological finding for ARDS in postmortem examinations and lung biopsies (Maley et al. 2020). In some embodiments of the present disclosure, DAD is caused by or associated with COVID-19.

[0072] Macrophage activation syndrome (MAS) is a form of hemophagocytic lymphohistiocytosis (HLH) associated with rheumatoid conditions. It is characterized by hemophagocytosis and cytokine overproduction resulting from the activation and uncontrolled proliferation of T lymphocytes and macrophages. In some embodiments of the present disclosure, MAS is caused by or associated with COVID-19. Patients with severe COVID-19-associated pneumonia may exhibit features of systemic hyperinflammation, collectively referred to as macrophage activation syndrome (MAS), also known as secondary hemophagocytic lymphohistiocytosis (sHLH), or cytokine storm. This is distinct from HLH associated with an immunodeficiency state known as primary HLH, and the treatment strategies for both conditions are fundamentally different. COVID-19 infection with MAS typically occurs in patients with adult respiratory distress syndrome (ARDS), and historically, non-survival in ARDS has been associated with persistent elevated IL-6 and IL-1 levels (McGonagle et al. 2020).

[0073] As used herein, "acyl" refers to a -COR group, e.g., acetyl, propionyl, benzoyl, or pyridinylcarbonyl, where R is selected from alkyl, haloalkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heteroaryl, heteroaralkyl, heterocyclyl, and heterocyclylalkyl, and further wherein the aryl, heteroaryl, or heterocyclyl ring, alone or as part of another group, e.g., an aralkyl, is optionally substituted with one, two, or three substituents independently selected from alkyl, alkoxy, halo, haloalkoxy, hydroxyl, carboxy, or alkoxycarbonyl. When R is alkyl, this group is also referred to herein as alkylcarbonyl.

[0074] As used herein, "alkyl" means a linear saturated monovalent hydrocarbon radical of one to six carbon atoms or a branched saturated monovalent hydrocarbon radical of three to six carbon atoms, e.g., methyl, ethyl, propyl, 2-propyl, butyl (including all isomeric forms), or pentyl (including all isomeric forms).

[0075] As used herein, "alkylene" refers to a linear saturated divalent hydrocarbon radical of 1 to 6 carbon atoms or a branched saturated divalent hydrocarbon radical of 3 to 6 carbon atoms, e.g., methylene, ethylene, propylene, 1-methylpropylene, 2-methylpropylene, butylene, or pentylene.

[0076] As used herein, "alkylthio" refers to the group --SR where R is alkyl, e.g., methylthio or ethylthio.

[0077] As used herein, "alkylsulfonyl" refers to an -SO2 group where R is alkyl, e.g., methylsulfonyl or ethylsulfonyl.

[0078] As used herein, "alkoxy" refers to an --OR group where R is alkyl, e.g., methoxy, ethoxy, propoxy, or 2-propoxy, n-, iso-, or tert-butoxy.

[0079] As used herein, "alkoxyalkyl" refers to a linear monovalent hydrocarbon radical of 1 to 6 carbon atoms or a branched monovalent hydrocarbon radical of 3 to 6 carbon atoms, substituted with at least one alkoxy group, e.g., one or two alkoxy groups, e.g., 2-methoxyethyl, 1-, 2-, or 3-methoxypropyl, or 2-ethoxyethyl.

[0080] As used herein, "alkoxycarbonyl" refers to a -C(O)OR group where R is alkyl, e.g., methoxycarbonyl or ethoxycarbonyl.

[0081] As used herein, "aralkyl" refers to the group -(alkylene)-R, where R is aryl.

[0082] As used herein, "aryl" refers to a monovalent monocyclic or bicyclic aromatic hydrocarbon radical of 6 to 10 ring atoms, e.g., phenyl or naphthyl.

[0083] As used herein, "carboxy" refers to --COOH.

[0084] As used herein, "cycloalkyl" refers to a cyclic saturated monovalent hydrocarbon group of 3 to 10 carbon atoms in which one or two carbon atoms may be replaced by an oxo group, e.g., cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl.

[0085] As used herein, "cycloalkylalkyl" refers to the group -(alkylene)-R where R is cycloalkyl, e.g., cyclopropylmethyl, cyclobutylmethyl, cyclopentylethyl, or cyclohexylmethyl.

[0086] As used herein, "cycloalkylene" refers to a cyclic saturated divalent hydrocarbon group of 3 to 10 carbon atoms in which one or two carbon atoms may be replaced by an oxo group, e.g., cyclopropylene, cyclobutylene, cyclopentylene, or cyclohexylene.

[0087] As used herein, "halo" means fluoro, chloro, bromo, or iodo.

[0088] As used herein, "haloalkyl" refers to an alkyl group as defined above (including those substituted with different halogens) that is substituted with one or more halogen atoms, e.g., 1 to 5 halogen atoms, e.g., fluorine or chlorine, such as -CH2Cl, -CF3, -CHF2, -CH2CF3, -CF2CF3, or -CF(CH3)2.

[0089] As used herein, "haloalkoxy" refers to the group --OR where R is haloalkyl.

[0090] As used herein, "heteroaralkyl" refers to the group -(alkylene)-R, where R is heteroaryl.

[0091] As used herein, "heteroaryl" refers to a monovalent monocyclic or bicyclic aromatic group of 5 to 10 ring atoms in which one or more, e.g., two or three, ring atoms are heteroatoms independently selected from N, O, and S, and the remaining ring atoms are carbon. Non-limiting examples include pyrrolyl, thienyl, thiazolyl, imidazolyl, furanyl, indolyl, isoindolyl, oxazolyl, isoxazolyl, benzothiazolyl, benzoxazolyl, quinolinyl, isoquinolinyl, pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, triazolyl, and tetrazolyl.

[0092] As used herein, "heterocyclyl" refers to a heterocyclic group in which one or two ring atoms are N, O, and S(O) n (where n is an integer from 0 to 2), and the remaining ring atoms are C. The heterocyclyl ring is optionally fused to an aryl or heteroaryl ring, provided that the aryl and heteroaryl rings are monocyclic. A heterocyclyl ring fused to a monocyclic aryl or heteroaryl ring is also referred to herein as a "bicyclic heterocyclyl" ring. Furthermore, one or two ring carbon atoms in the heterocyclyl ring may optionally be replaced with a -CO- group. Non-limiting examples of heterocyclyl include pyrrolidino, piperidino, homopiperidino, 2-oxopyrrolidinyl, 2-oxopiperidinyl, morpholino, piperazino, tetrahydropyranyl, and thiomorpholino. When a heterocyclyl ring is unsaturated, it may contain one or two ring double bonds, provided that the ring is not aromatic. When a heterocyclyl group contains at least one nitrogen atom, it is also referred to herein as heterocycloamino, and is a subset of the heterocyclyl group. When a heterocyclyl group is a saturated ring that is not fused to an aryl or heteroaryl ring as described above, it is also referred to herein as saturated monocyclic heterocyclyl.

[0093] As used herein, "heterocyclylalkyl" refers to an -(alkylene)-R group where R is a heterocyclyl, e.g., tetrahydrofuranylmethyl, piperazinylmethyl, or morpholinylethyl.

[0094] As used herein, "hydroxyalkyl" means a linear monovalent hydrocarbon radical of 1 to 6 carbon atoms or a branched monovalent hydrocarbon radical of 3 to 6 carbon atoms substituted with one or two hydroxy groups, provided that if two hydroxy groups are present, they are not both on the same carbon atom. Non-limiting examples include hydroxymethyl, 2-hydroxyethyl, 2-hydroxypropyl, 3-hydroxypropyl, 1-(hydroxymethyl)-2-methylpropyl, 2-hydroxybutyl, 3-hydroxybutyl, 4-hydroxybutyl, 2,3-dihydroxypropyl, 1-(hydroxymethyl)-2-hydroxyethyl, 2,3-dihydroxybutyl, 3,4-dihydroxybutyl, and 2-(hydroxymethyl)-3-hydroxypropyl, preferably 2-hydroxyethyl, 2,3-dihydroxypropyl, and 1-(hydroxymethyl)-2-hydroxyethyl.

[0095] As used herein, "oxo" or "carbonyl" refers to a C=(O) group.

[0096] As used herein, "substituted alkyl" refers to an alkyl group substituted with one, two, or three substituents independently selected from hydroxyl, alkoxy, carboxy, cyano, carboxy, alkoxycarbonyl, alkylthio, alkylsulfonyl, halo, -CONRR, -NRR, and heterocyclyl (e.g., heterocycloamino), wherein each R is independently selected from hydrogen, alkyl, cycloalkyl, hydroxyalkyl, and alkoxyalkyl; each R' is independently selected from hydrogen, alkyl, and cycloalkyl; The heterocyclyl group is optionally substituted with one or two groups independently selected from acyl, alkyl, alkylthio, alkylsulfonyl, alkoxy, alkoxyalkyl, alkoxycarbonyl, halo, haloalkyl, heterocyclyl, hydroxyl, and -CONR*R''; R *is selected from hydrogen, alkyl, cycloalkyl, and hydroxyalkyl; R'' is selected from hydrogen, alkyl, and cycloalkyl.

[0097] Formulation and Administration In general, compounds of the present disclosure are administered in therapeutically effective amounts by any of the accepted modes of administration (e.g., oral administration) for agents that provide similar utilities. 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, which 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.

[0098] Suitable dosage levels can also be about 0.01 to about 250 mg / kg per day, such as about 0.05 to about 100 mg / kg per day, and further for example, about 0.1 to about 50 mg / kg per day. Within this range, the dosage can be about 0.05 to about 0.5, such as about 0.5 to about 5, and further for example, about 5 to about 50 mg / kg per day. For oral administration, the composition can be provided in the form of tablets containing 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 compound of the present disclosure, i.e., the active ingredient, administered will depend on numerous factors, including 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.

[0099] Generally, the compounds of the present disclosure are administered as pharmaceutical compositions by any one of the following routes: oral administration, systemic administration (e.g., transdermal administration, intranasal administration, or administration by suppository), or parenteral administration (e.g., intramuscular administration, intravenous administration, or subcutaneous administration).The preferred mode of administration is oral administration using a convenient daily dosage regimen that can be adjusted according to the disease state.The composition can take the form of a tablet, pill, capsule, semisolid, powder, sustained-release formulation, solution, suspension, elixir, aerosol, or any other suitable composition.

[0100] 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, are preferred) and the bioavailability of the drug substance. Recently, pharmaceutical formulations for drugs exhibiting particularly low bioavailability have been developed based on the principle that bioavailability can be increased by increasing the surface area, i.e., by reducing particle size. For example, U.S. Pat. No. 4,107,288 describes a pharmaceutical formulation having particles in the size range of 10 to 1,000 nm, in which the active substance is supported in a crosslinked matrix of macromolecules. U.S. Pat. No. 5,145,684 describes the preparation of a pharmaceutical formulation in which the drug substance is milled into nanoparticles (average particle size 400 nm) in the presence of a surface modifier, followed by dispersion in a liquid medium, yielding a pharmaceutical formulation exhibiting significantly higher bioavailability. The portions of both patents relating to pharmaceutical formulations are incorporated herein by reference.

[0101] Generally, the composition comprises a compound of the present disclosure combined with a pharmaceutically acceptable excipient. Pharmaceutically acceptable excipients are non-toxic, facilitate administration, and do not adversely affect the therapeutic effect of the compound of the present disclosure. These excipients can be any solid excipient, liquid excipient, semi-solid excipient, or gaseous excipient in the case of an aerosol composition, that is generally available to those skilled in the art.

[0102] Solid pharmaceutical excipients include starch, cellulose, talc, glucose, lactose, sucrose, gelatin, malt, rice, wheat flour, chalk, silica gel, magnesium stearate, sodium stearate, glyceryl monostearate, sodium chloride, dried skim milk, etc. Liquid and semi-solid excipients can be selected from glycerin, 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. Preferred liquid carriers, particularly for injectable solutions, include water, saline, aqueous dextrose, and glycols.

[0103] Compressed gases can be used to disperse the compounds of the present disclosure in aerosol form. Suitable inert gases for this purpose include nitrogen, carbon dioxide, and the like.

[0104] Other suitable pharmaceutical excipients and their formulations are described in Remington's Pharmaceutical Sciences, edited by E. W. Martin (Mack Publishing Company, 20th ed., 2000), which is incorporated herein by reference in its entirety with respect to pharmaceutical excipients and their formulations.

[0105] The level of the compound in the formulation can vary within the full range used by those skilled in the art. Typically, the formulation will contain 0.01 to 99.99% by weight of the compound of the present disclosure, with the remainder being suitable pharmaceutical excipients, based on weight percent (wt%) of the total formulation. For example, the compound may be present at a level of about 1 to 80% by weight. With respect to the numerical range 0.01 to 99.99, "about" indicates less than 0.01%. With respect to the numerical range 1 to 80, "about" indicates 0.05 to 1 and 10 to 80, thus encompassing a range of 0.05 to 90% by weight.

[0106] The compounds of the present disclosure can be used in combination with one or more other drugs to treat diseases or conditions for which the compounds of the present disclosure or other drugs can be useful.These other drugs can be administered simultaneously with the compounds of the present disclosure, for example, as a fixed-dose combination, or sequentially with the compounds of the present disclosure, by routes and amounts commonly used therefor.When the compounds of the present disclosure are used simultaneously with one or more other drugs, pharmaceutical compositions in unit dosage form, i.e., fixed-dose formulations, containing these other drugs and the compounds of the present disclosure are 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 schedules, or even non-overlapping schedules.It is also anticipated that when used in combination with one or more other active ingredients, the compounds of the present disclosure and the other active ingredients can be used in lower doses than when each is used alone.

[0107] All publications and patents mentioned in this specification are incorporated herein by reference in their entirety, unless a particular portion of this disclosure is specifically incorporated, to the same extent as if each individual publication or patent was specifically and individually indicated to be incorporated by reference.

[0108] A claim or statement involving "or" or "and / or" between at least two members 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 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.

[0109] 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 may 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 elements is also disclosed, and any element(s) can be excluded from the group. In general, when the present disclosure or aspects of the present disclosure are referred to as including certain elements and / or features, it should be understood that an embodiment of the present disclosure or aspects of the present disclosure consists of or consists essentially of such elements and / or features. For simplicity, the present disclosure may be modified to include at least one limitation found in any other claim that depends from the same base claim. In the specification, the embodiments are not specifically described in those terms. When ranges are presented, the endpoints are included. Furthermore, unless otherwise indicated or otherwise apparent from the context and the understanding of one of ordinary skill in the art, values ​​expressed as ranges can, in various embodiments of the present disclosure, assume any particular value or subrange within the stated range, down to one-tenth of the unit of the lower limit of that range, unless the context clearly dictates otherwise.

[0110] 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 which equivalents are intended to be encompassed by the following claims.

[0111] Example The following examples are intended to be illustrative and in no way intended to limit the scope of the present disclosure. [Example]

[0112] Murine anti-GBM glomerulonephritis model The efficacy of Compound (IB) (also referred to as PRN1008) was tested in a mouse anti-GBM glomerulonephritis model in comparison with the corticosteroid dexamethasone (Dex) according to the design shown in Figure 1. Briefly, mice were pre-sensitized with sheep IgG / FCA to induce glomerulonephritis (Study Day -5). Five days later (Study Day 0), mice received anti-GBM sheep IgG. Treatment with vehicle, Compound (IB), or Dex at various dosing regimens (Compound (IB): 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 Study Day -1, i.e., one day before injection of anti-GBM sheep IgG. Treatment continued until Study Day 10, for a total of 11 days of treatment. Urine protein analysis was performed on study days -6, -4, -1, 1, 3, 6, 8, and 10. After study day 10, mouse serum BUN levels were analyzed as a measure of renal function, and renal histology was performed. In a mouse anti-GBM glomerulonephritis model, dose-dependent inhibition of serum BUN levels (Figure 2), severe proteinuria (Figure 3), and increased kidney weight (a surrogate indicator of renal inflammation) (Figure 5) was observed. Furthermore, treatment with compound (IB) reduced proteinuria throughout the study (Figure 4), and compound (IB) reduced renal pathology (Figure 6), demonstrating favorable results compared to Dex. [Example]

[0113] BioMAP Diversity PLUS Panel The BioMAP Diversity Plus panel (Figure 7) displays a broad phenotypic profile of pharmaceutically active drugs. This panel provides 148 clinically relevant biomarker readouts using 12 individual BioMAP human primary cell-based coculture systems for predictively modeling drug effects across multiple tissues and disease states. Several key activities of PRN1008 exemplified by the BioMAP profile (Figure 8) include antiproliferative activity, inflammation-related activity, immunomodulatory activity, tissue remodeling activity, hemostasis-related activity, and LDLR reduction. The LDLR gene is associated with the low-density lipoprotein receptor, which binds to low-density lipoproteins that transport cholesterol in the blood. Gray arrows indicate antiproliferative activity on endothelial cells, T cells, B cells, coronary artery smooth muscle cells, and fibroblasts. Reductions in MCP-1, sTNFα, eotaxin-3, ICAM-1, IL-1α, and IL-8, as well as increases in sPGE2, are associated with PRN1008's inflammation-related activity. The decrease in CD38, sIgG, sIL-17A, sIL-2, sIL-6, and M-CSF and the increase in CD69 are associated with the immunomodulatory activity of PRN1008. The decrease in MMP-9, uPA, and PAI-I is associated with the tissue remodeling activity of PRN1008. The decrease in thrombomodulin (TM) and the modulation of tissue factor (TF) are associated with the hemostasis-related activity of PRN1008. Therefore, the BioMA of PRN1008 P Diversity Plus panel data support its anti-inflammatory and cytokine inhibitory mechanisms. [Example]

[0114] Neutrophil migration test After post-adhesion reinforcement, neutrophils exhibit Mac-1 (an integrin)-dependent migratory activity toward the vascular side of the vessel wall before transmigration (Herter and Zarbock 2013). Previous studies have highlighted the importance of this step for successful neutrophil recruitment (Phillipson et al. 2006). To investigate the effect of Btk inhibition on this step of the leukocyte recruitment cascade, we examined intraluminal crawling after fMLP (N-formylmethionine-leucyl-phenylalanine)-mediated arrest in vivo.

[0115] Neutrophil intravascular crawling was investigated using intravital microscopy as previously described (Phillipson et al. 2006). Briefly, anti-Gr-1 antibody (clone RB6-8C5) labeled with Alexa Fluor 488 (Molecular Probes, Eugene, OR, USA) was injected through a cannulated carotid artery prior to the experiment. After preparation and exteriorization, the cremaster muscle was perfused with fMLP (10 μM) and subjected to time-lapse microscopy for 2 h. The number of adherent cells was determined.

[0116] In animals treated with compound (IA), neutrophil migration activity was significantly reduced compared to vehicle controls for arrested crawling cells (Figure 9A). Compound (IA) was also found to abolish neutrophil recruitment after aseptic liver injury (Figure 9B). Figure 9B shows representative photomicrographs of neutrophil (eGFP, green) recruitment to the necrotic area (propidium iodide, red) 4 hours after burn injury, obtained using spinning disk time-lapse microscopy.

[0117] References Busygina K, et al. Oral Bruton tyrosine kinase inhibitors selectively block atherosclerotic plaque-triggered thrombus formation in humans. Blood. 2018. 131(24):2605-2616. https: / / doi.org / 10.1182 / blood-2017-09-808808 Cao X. COVID-19: immunopathology and its implications for therapy. Nat Rev Immunol. 2020. https: / / doi.org / 10.1038 / s41577-020-0308-3 DePorto AP, et al. Btk inhibitor ibrutinib reduces inflammatory myeloid cell responses in the lung during murine pneumococcal pneumonia. Mol Med. 2019. 25(3). https: / / doi.org / 10.1186 / s10020-018-0069-7 Florence JM, et al. Inhibiting Bruton's tyrosine kinase rescues mice from lethal influenza-induced acute lung injury. Am J Physiol Lung Cell Mol Physiol. 2018. 315(1):L52-L58. https: / / doi.org / 10.1152 / ajplung.00047.2018 Herter JM, et al. PRN473, an inhibitor of Bruton's tyrosine kinase, inhibits neutrophil recruitment via inhibition of macrophage antigen-1 signalling. Br J Pharmacol, 2018, 175(3):429-439. https: / / doi.org / 10.1111 / bph.14090 Herter JM, et al. (2013). Integrin regulation during leukocyte recruitment. J Immunol 190: 4451-4457. Huang X, et al. The Role of Macrophages in the Pathogenesis of ALI / ARDS. Mediators Inflamm. 2018. https: / / doi.org / 10.1155 / 2018 / 1264913 Kattan M, et al. "Respiratory Disorders in Pediatric HIV Infection" in Kendig & Chernick's Disorders of the Respiratory Tract in Children (Eighth Edition), 2012 King T, "Respiratory Tract and Pleura" in Elsevier's Integrated Pathology, 2007 Krupa A,et al. Silencing Bruton's tyrosine kinase in alveolar neutrophils protects mice from LPS / immune complex-induced acute lung injury. Am J Physiol Lung Cell Mol Physiol. 307(6): L435-L448, 2014. Manappallil R, "A Case of Macrophage Activation Syndrome with Acute Respiratory Distress Syndrome" Journal of Clinical and Diagnostic Research. 2016 Sep, Vol-10(9): OD11-OD12 McGonagle D, et al. "The Role of Cytokines including Interleukin-6 in COVID-19 induced Pneumonia and Macrophage Activation Syndrome-Like Disease." Autoimmun Rev. 2020 Apr 3:102537. doi: 10.1016 / j.autrev.2020.102537 Mehta P, et al. COVID-19: consider cytokine storm syndromes and immunosuppression. The Lancet. 2020. 395 (10229):1033-1034. https: / / doi.org / 10.1016 / S0140-6736(20)30628-0 Murphy S, et al. Care for Critically Ill Patients With COVID-19. JAMA Insights. 2020. https: / / doi.org / 10.1001 / jama.2020.3633 Phillipson M et al. (2006). Intraluminal crawling of neutrophils to emigration sites: a molecularly distinct process from adhesion in the recruitment cascade. J Exp Med 203: 2569-2575. Rip J, et al. The role of Bruton's Tyrosine Kinase in immune cell signaling and systemic autoimmunity. Crit Rev Immunol, 38(1):17-62, 2018. https: / / doi.org / 10.1615 / CritRevImmunol.2018025184. Thachil J, et al. ISTH interim guidance on recognition and management of coagulopathy in COVID-19. J Thromb Hemostasis. 2020. https: / / doi.org / 10.1111 / JTH.14810 Zhang D, et al. COVID-19 infection induces readily detectable morphological and inflammation-related phenotypic changes in peripheral blood monocytes, the severity of which correlate with patient outcome. 2020. https: / / doi.org / 10.1101 / 2020.03.24.20042655 Jason H. Maley, B. Taylor Thompson, "ARDS: Are the current definitions useful?", in Evidence-Based Practice of Critical Care (Third Edition), 2020 .

Claims

1. 1. A method for treating a disease selected from acute respiratory distress syndrome, sepsis, sepsis-induced acute lung injury, diffuse alveolar damage, macrophage activation syndrome, secondary hemophagocytic lymphohistiocytosis, cytokine release syndrome, and systemic inflammatory response syndrome, comprising administering to a mammal in need thereof a pharmaceutical composition comprising a small molecule Bruton's tyrosine kinase (BTK) inhibitor and a pharmaceutically acceptable carrier or excipient.

2. 10. The method of claim 1, wherein the BTK inhibitor is a compound of formula (I) or a pharmaceutically acceptable salt thereof: 【Chemistry 1】 During the ceremony, Z ２ is -N- or CR ２ where R ２ is selected from hydrogen and alkyl; R ３ and R ４ is independently selected from hydrogen, methyl, chloro, fluoro, cyclopropyl, hydroxy, methoxy, cyano, trifluoromethyl, and trifluoromethoxy; R ６ and R ７ is independently selected from hydrogen, methyl, methoxy, fluoro, chloro, trifluoromethyl, trifluoromethoxy, and cyano; -Z-EWG- is -alkylene-NR'CO-, -alkylene-NR'SO ２ -, 【Chemistry 2】 is selected from, where 【Transformation 3】 are each independently substituted with 0, 1, or 2 substituents independently selected from alkyl, hydroxy, and halo; -Alkylene-NR'CO-, -Alkylene-NR'SO ２ -, 【Chemistry 4】 The carbonyl or sulfonyl group in the formula is -C(CN)=CHR ｃ is bound to; R' is independently selected from hydrogen and alkyl; R ｃ is alkyl, haloalkoxy, substituted alkyl, cycloalkyl, cycloalkylene -NR ｄ R ｅ , and cycloalkylene-alkylene-NR ｄ R ｅ Selected from: R ｄ and R ｅ is independently selected from hydrogen, alkyl, cycloalkyl, and 3- to 6-membered saturated monocyclic heterocyclyl, heterocyclyl contains 1 or 2 heteroatoms independently selected from N, O, and S; The heterocyclyl is substituted with 0, 1, or 2 substituents independently selected from hydroxy, alkyl, and fluoro.

3. Z ２ The method of claim 1 or 2, wherein is -N-.

4. -Z-EWG- is 【Transformation 5】 where 【Transformation 6】 is independently substituted with 0, 1, or 2 substituents independently selected from alkyl, hydroxy, and halo; 【Transformation 7】 The carbonyl group in is -C(CN)=CHR ｃ The method according to any one of claims 1 to 3, wherein the

5. -Z-EWG- is 【Transformation 8】 The method according to any one of claims 1 to 4, wherein

6. BTK inhibitors (R)-2-(3-(4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)piperidine-1-carbonyl)-3-cyclopropylacrylonitrile; 2-((R)-3-(4-amino-3-(4-(3,4-dichlorophenoxy)-3-methoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)piperidine-1-carbonyl)-3-cyclopropylacrylonitrile; (R)-2-(3-(4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)piperidine-1-carbonyl)-4,4-dimethylpent-2-enenitrile; (R)-2-(3-(4-amino-3-(4-(3,4-dichlorophenoxy)-3-methoxyphenyl)-1H-pyrazolo-[3,4-d]pyrimidin-1-yl)piperidine-1-carbonyl)-4,4-dimethylpent-2-enenitrile; (R)-2-(3-(4-amino-3-(4-(2-fluorophenoxy)phenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)piperidine-1-carbonyl)-3-cyclopropylacrylonitrile; (R)-2-(3-(4-amino-3-(4-(3-fluorophenoxy)phenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)piperidine-1-carbonyl)-3-cyclopropylacrylonitrile; (R)-2-(3-(4-amino-3-(4-(2,3-difluorophenoxy)phenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)piperidine-1-carbonyl)-3-cyclopropylacrylonitrile; (R)-2-(3-(4-amino-3-(4-(2,6-difluorophenoxy)phenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)piperidine-1-carbonyl)-3-cyclopropylacrylonitrile; (R)-2-(3-(4-amino-3-(4-(3,5-difluorophenoxy)phenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)piperidine-1-carbonyl)-3-cyclopropylacrylonitrile; (R)-2-(3-(4-amino-3-(4-(2,5-difluorophenoxy)phenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)piperidine-1-carbonyl)-3-cyclopropylacrylonitrile; (R)-2-(3-(4-amino-3-(2-fluoro-4-(phenoxy)phenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)piperidine-1-carbonyl)-3-cyclopropylacrylonitrile; (R)-2-(3-(4-amino-5-(4-phenoxyphenyl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)piperidine-1-carbonyl)-3-cyclopropylacrylonitrile; and (R)-2-(3-(4-amino-3-(4-(2,3-difluorophenoxy)-2-fluorophenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)piperidine-1-carbonyl)-4-methylpent-2-enenitrile; or a pharmaceutically acceptable salt of any of the foregoing compounds, wherein the compound is selected from the (E)-isomer, the (Z)-isomer, and a mixture of the (E)- and (Z)-isomers.

7. -Z-EWG- is 【Chemistry 9】 The method according to any one of claims 1 to 4, wherein

8. BTK inhibitors 2-(2-((4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)methyl)pyrrolidine-1-carbonyl)-4,4-dimethylpent-2-enenitrile; (R)-2-(2-((4-amino-3-(4-(3-fluorophenoxy)phenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)methyl)pyrrolidine-1-carbonyl)-3-cyclopropylacrylonitrile; (R)-2-(2-((4-amino-3-(4-(2,6-difluorophenoxy)phenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)methyl)pyrrolidine-1-carbonyl)-3-cyclopropylacrylonitrile; (R)-2-(2-((4-amino-3-(2-fluoro-4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)methyl)pyrrolidine-1-carbonyl)-3-cyclopropylacrylonitrile; (R)-2-(2-((4-amino-3-(4-(2,3-difluorophenoxy)phenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)methyl)pyrrolidine-1-carbonyl)-3-cyclopropylacrylonitrile; (R)-2-(2-((4-amino-3-(4-(3,5-difluorophenoxy)phenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)methyl)pyrrolidine-1-carbonyl)-3-cyclopropylacrylonitrile; (R)-2-(2-((4-amino-3-(4-(2-fluorophenoxy)phenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)methyl)pyrrolidine-1-carbonyl)-3-cyclopropylacrylonitrile; (S)-2-{2-[4-amino-5-(4-phenoxy-phenyl)-pyrrolo[2,3-d]pyrimidin-7-ylmethyl]-pyrrolidine-1-carbonyl}-3-cyclopropyl-acrylonitrile; (S)-2-(2-((4-amino-6-methyl-5-(4-phenoxyphenyl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)methyl)pyrrolidine-1-carbonyl)-3-cyclopropylacrylonitrile; (S)-2-(2-((4-amino-6-methyl-5-(4-phenoxyphenyl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)methyl)pyrrolidine-1-carbonyl)-4-(dimethylamino)-4-methylpent-2-enenitrile; (S)-2-(2-((4-amino-3-(2-fluoro-4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)methyl)pyrrolidine-1-carbonyl)-3-cyclopropylacrylonitrile; (R)-2-(2-((4-amino-3-(4-(2,3-difluorophenoxy)-2-fluorophenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)methyl)pyrrolidine-1-carbonyl)-3-cyclopropylacrylonitrile; (S)-2-(2-((4-amino-3-(4-(2,3-difluorophenoxy)-2-fluorophenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)methyl)pyrrolidine-1-carbonyl)-3-cyclopropylacrylonitrile; 2-((S)-2-((4-amino-3-(2-fluoro-4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)methyl)pyrrolidine-1-carbo (nyl)-4-(ethylamino)-4-methylpent-2-enenitrile; 2-((R)-2-((4-amino-3-(2-fluoro-4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)methyl)pyrrolidine-1-carbonyl)-4-(ethylamino)-4-methylpent-2-enenitrile; 2-((S)-2-((4-amino-3-(2-fluoro-4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)methyl)pyrrolidine-1-carbonyl)-4-(cyclopropylamino)-4-methylpent-2-enenitrile; 2-((S)-2-((4-amino-3-(2-fluoro-4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)methyl)pyrrolidine-1-carbonyl)-4-(2-methoxyethylamino)-4-methylpent-2-enenitrile; (R)-2-(2-((4-amino-3-(2-fluoro-4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)methyl)pyrrolidine-1-carbonyl)-3-(1-aminocyclopropyl)acrylonitrile; 2-[(2S)-2-[[4-amino-3-(2-fluoro-4-phenoxy-phenyl)pyrazolo[3,4-d]pyrimidin-1-yl]methyl]pyrrolidine-1-carbonyl]-4-methyl-4-morpholino-pent-2-enenitrile; 2-[(2R)-2-[[4-amino-3-(2-fluoro-4-phenoxy-phenyl)pyrazolo[3,4-d]pyrimidin-1-yl]methyl]pyrrolidine-1-carbonyl]-4-methyl-4-morpholino-pent-2-enenitrile; 2-[(2R)-2-[[4-amino-3-(2-fluoro-4-phenoxy-phenyl)pyrazolo[3,4-d]pyrimidin-1-yl]methyl]pyrrolidine-1-carbonyl]-4-methyl-4-(1-piperidyl)pent-2-enenitrile; 2-[(2S)-2-[[4-amino-3-(2-fluoro-4-phenoxy-phenyl)pyrazolo[3,4-d]pyrimidin-1-yl]methyl]pyrrolidine-1-carbonyl]-4-methyl-4-(1-piperidyl)pent-2-enenitrile; and 2-[(2S)-2-[[4-amino-3-(2-fluoro-4-phenoxy-phenyl)pyrazolo[3,4-d]pyrimidin-1-yl]methyl]-pyrrolidine-1-carbonyl]-3-(3-methyloxetan-3-yl)prop-2-enenitrile; or a pharmaceutically acceptable salt of any of the foregoing compounds, wherein the compound is selected from the (E)-isomer, the (Z)-isomer, and a mixture of the (E)- and (Z)-isomers.

9. R ｃ The method of any one of claims 1 to 5, wherein is alkyl.

10. R ｃ The method of claim 9, wherein is t-butyl.

11. 11. The method of claim 10, wherein the BTK inhibitor is selected from the (E) isomer, the (Z) isomer, and a mixture of the (E) and (Z) isomers of (R)-2-(3-(4-amino-3-(2-fluoro-4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)piperidine-1-carbonyl)-4,4-dimethylpent-2-enenitrile (compound (IA)), and / or a pharmaceutically acceptable salt of any of the foregoing compounds.

12. The method of claim 10, wherein the compound is a substantially pure (E) or (Z) isomer of (R)-2-(3-(4-amino-3-(2-fluoro-4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)piperidine-1-carbonyl)-4,4-dimethylpent-2-enenitrile (compound (IA)), and / or a pharmaceutically acceptable salt thereof.

13. at least about 85% (w / w) of (R)-2-(3-(4-amino-3-(2-fluoro-4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)piperidine-1-carbonyl)-4,4-dimethylpent-2-enenitrile or (R 13. The method of claim 12, wherein at least about 85% (w / w) of the pharmaceutically acceptable salt of (E)-2-(3-(4-amino-3-(2-fluoro-4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)piperidine-1-carbonyl)-4,4-dimethylpent-2-enenitrile is the (E) isomer.

14. R ｃ The method of claim 5 , wherein is a substituted alkyl.

15. R ｃ is -C(CH ３ ) ２ -(4-R ８ -piperazin-1-yl); R ８ is selected from hydrogen, alkyl, alkoxyalkyl, haloalkyl, alkylsulfonyl, alkoxycarbonyl, acyl, and oxetan-3-yl; The piperazinyl ring is further optionally substituted independently with one or two alkyl groups.

15. The method of claim 14.

16. BTK inhibitors 2-[[(3R)-3-[4-amino-3-(2-fluoro-4-phenoxyphenyl)-1H-pyrazolo[3,4-d]-pyrimidin-1-yl]-piperidin-1-yl]carbonyl]-4-methyl-4-(4-methylpiperazin-1-yl)pent-2-enenitrile; 2-((R)-3-(4-amino-3-(2-fluoro-4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)piperidine-1-carbonyl)-4-methyl-4-(piperazin-1-yl)pent-2-enenitrile; 2-[(3R)-3-[4-amino-3-(2-fluoro-4-phenoxy-phenyl)pyrazolo[3,4-d]-pyrimidin-1-yl]piperidine-1-carbonyl]-4-(4-ethylpiperazin-1-yl)-4-methyl-pent-2-enenitrile; (R)-2-(3-(4-amino-3-(2-fluoro-4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)piperidine-1-carbonyl)-4-(4-isopropylpiperazin-1-yl)-4-methylpent-2-enenitrile; (R)-2-(3-(4-amino-3-(2-fluoro-4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)piperidine-1-carbonyl)-4-(4-(tert-butyl)piperazin-1-yl)-4-methylpent-2-enenitrile; (R)-2-(3-(4-amino-3-(2-fluoro-4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)piperidine-1-carbonyl)-4-(4-(2-methoxyethyl)piperazin-1-yl)-4-methylpent-2-enenitrile; (R)-2-(3-(4-amino-3-(2-fluoro-4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)piperidine-1-carbonyl)-4-methyl-4-(4-(methylsulfonyl)piperazin-1-yl)pent-2-enenitrile; (R)-2-(3-(4-amino-3-(2-fluoro-4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)piperidine-1-carbonyl)-4-methyl-4-(4-(2,2,2-trifluoroethyl)piperazin-1-yl)pent-2-enenitrile; 2-((R)-3-(4-amino-3-(2-fluoro-4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)piperidine-1-carbonyl)-4-methyl-4-((3S,5R)-3,4,5-trimethylpiperazin-1-yl)pent-2-enenitrile; 2-((R)-3-(4-amino-3-(2-fluoro-4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)piperidine-1-carbonyl)-4 -((3S,5R)-3,5-dimethylpiperazin-1-yl)-4-methylpent-2-enenitrile; (R)-2-(3-(4-amino-3-(2-fluoro-4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)piperidine-1-carbonyl)-4-methyl-4-(4-(oxetan-3-yl)piperazin-1-yl)pent-2-enenitrile; (R)-4-(4-acetylpiperazin-1-yl)-2-(3-(4-amino-3-(2-fluoro-4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)piperidine-1-carbonyl)-4-methylpent-2-enenitrile; and (R)-methyl-4-(5-(3-(4-amino-3-(2-fluoro-4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)piperidin-1-yl)-4-cyano-2-methyl-5-oxopent-3-en-2-yl)piperazine-1-carboxylate; or a pharmaceutically acceptable salt of any of the foregoing compounds, wherein the compound is selected from the (E)-isomer, the (Z)-isomer, and a mixture of the (E)- and (Z)-isomers.

17. R ８ The method of claim 15, wherein is oxetan-3-yl.

18. 18. The method of claim 17, wherein the BTK inhibitor is selected from the (E)-isomer, the (Z)-isomer, and a 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 (compound (IB)); and / or a pharmaceutically acceptable salt of any of the foregoing compounds.

19. 18. The method of claim 17, wherein the BTK inhibitor 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 (compound (IB)), or a pharmaceutically acceptable salt thereof.

20. 20. The method of claim 19, wherein at least about 85% (w / w) 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% (w / w) 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.

21. The method of any one of claims 1 to 20, wherein the pharmaceutical composition is administered in place of corticosteroid therapy.

22. The method of any one of claims 1 to 20, wherein the pharmaceutical composition is administered in combination with corticosteroid therapy.

23. The method of any one of claims 1 to 20, wherein the pharmaceutical composition is administered in combination with a non-corticosteroid immunosuppressant and / or an anti-inflammatory agent.

24. The method of any one of claims 1 to 20, wherein the pharmaceutical composition is administered in combination with corticosteroid maintenance therapy.

25. The method of any one of claims 1 to 24, wherein the mammal is a human.

26. 26. The method of any one of claims 1 to 25, 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, anti-CD20 agents, anti-TNα agents, anti-IL6 agents directed against a ligand or its receptor, anti-IL17 agents directed against a ligand or its receptor, anti-IL1 agents directed against a ligand or its receptor, anti-IL2 agents directed against a ligand or its receptor, anti-CD2 agents, anti-CD3 agents, anti-CD80 / 86 agents, anti-sphingosine-1-phosphate receptor agents, anti-C5 agents, anti-mTOR agents, anti-calcineurin agents, anti-BAFF / BlyS agents, leflunomide, and teriflunomide.

27. 27. The method of any one of claims 1 to 26, wherein the pharmaceutical composition is administered in combination with rituximab, ofatumumab, obinutuzumab, or veltuzumab, or a biosimilar of any of the above.

28. The method of any one of claims 1 to 26, wherein the pharmaceutical composition is administered in combination with at least one antiviral agent.

29. 29. The method of claim 28, wherein the antiviral agent comprises at least one agent selected from an entry inhibitor, an uncoating inhibitor, a reverse transcriptase inhibitor, an integrase inhibitor, a transcription inhibitor, and a protease inhibitor.

30. 30. The method of claim 28 or 29, wherein the antiviral agent comprises remdesivir.

Images