Methods for treating acute pancreatitis

Abstract

Provided herein are compositions and methods related to the treatment of acute pancreatitis (AP) in subjects having accompanying Systemic Inflammatory Response Syndrome (SIRS). The present disclosure provides a method for treating AP including administering a therapeutically effective amount of an intracellular calcium signaling inhibitor to a subject, wherein said subject optionally has accompanying systemic inflammatory response syndrome (SIRS).

Description

PATENTATTORNEY DOCKET NO. CM1740-1 WO (449399-766)METHODS FOR TREATING ACUTE PANCREATITISCROSS-REFERENCE TO RELATED APPLICATIONS[OOOlJThis application claims the benefit of priority under 35 U.S.C. §119(e) to U.S. Provisional Application No. 63 / 713,941, filed October 30, 2024. The contents of the prior application are considered part of and are hereby incorporated by reference in their entirety.BACKGROUND

[0002] Acute pancreatis (AP) is a complex inflammatory syndrome that currently has no approved therapies, leaving a significant unmet medical need for patients and hospital systems.SUMMARY OF THE INVENTION

[0003] In an aspect, the disclosure provides for a method of treating acute pancreatitis (AP) in a subject in need thereof, comprising administering a therapeutically effective amount of an intracellular Calcium signaling inhibitor to said subject, wherein said subject optionally has accompanying systemic inflammatory response syndrome (SIRS).

[0004] In some embodiments, the acute pancreatitis comprises pancreatic necrosis or necrotizing pancreatitis. In some embodiments, the administering comprises a reduction the incidence of necrotizing pancreatitis. In some embodiments, the administering further comprises reducing the incidence of severe respiratory failure, severe renal failure, and / or severe cardiovascular failure in the subject. In some embodiments, the severe respiratory failure is new onset persistent respiratory failure or new onset severe respiratory failure. In some embodiments, the administering further comprises reducing the incidence of severe organ failure in the subject. In some embodiments, the administering further comprises a reduction in the length of a hospital stay. In some embodiments, the subject has a recovery rate of about 50% to about 100%. In some embodiments, the subject presents with a high hematocrit level, peripancreatic fluid, and / or abdominal guarding or tenderness. In further embodiments, the administering comprises lowering the hematocrit level.

[0005] In some embodiments, the intracellular Calcium signaling inhibitor is N-(5-(6-Chloro- 2,2-difluorobenzo[d][l,3]dioxol-5-yl)pyrazin-2-yl)-2-fluoro-6-methylbenzamide, or a pharmaceutically acceptable salt or pharmaceutically acceptable solvate thereof. In some embodiments, the intracellular Calcium signaling inhibitor is administered in a concentration of about 0.5 mg / kg to about 2.0 mg / kg. In some embodiments, the intracellular Calcium signaling inhibitor is administered in a concentration of about 0.5 mg / kg. In some embodiments, the intracellular Calcium signaling inhibitor is administered in a concentration of about 1.0 mg / kg. In some embodiments. In some embodiments, the intracellular Calcium signaling inhibitor isPATENTATTORNEY DOCKET NO. CM1740-1 WO (449399-766) administered in a concentration of about 2.0 mg / kg. In some embodiments, the method comprise administering one or more medical treatments.INCORPORATION BY REFERENCE[0006JA11 publications, patents, and patent applications mentioned in this specification are herein incorporated by reference to the same extent as if each individual publication, patent, or patent application was specifically and individually indicated to be incorporated by reference.BRIEF DESCRIPTION OF THE DRAWINGS

[0007] The novel features of the invention are set forth with particularity in the appended claims. A better understanding of the features and advantages of the present invention will be obtained by reference to the following detailed description that sets forth illustrative embodiments, in which the principles of the invention are utilized, and the accompanying drawings of which: [0008JFIG. 1 is the Phase 2b CARPO trial design and key outcomes for AP patients with SIRS. [0009JFIG. 2 shows the baseline characteristics for the AP treatment groups.[0010JFIG. 3 is a plot of time to solid food tolerance and hematocrit analysis with patients treated with Auxora (last six bars from the left) or placebo (first two bars from the left).

[0011] FIG. 4 shows a reduction in the incidence of severe organ failure for patients treated with high and median dose Auxora.[0012JFIG. 5 shows the reduction in the incidence of new onset persistent respiratory7failure after treatment with Auxora.

[0013] FIG. 6 shows the reduction in the incidence of new onset necrotizing pancreatitis and a reduction in hospital stay after treatment with Auxora.[0014JFIG. 7 shows TESAE related to the high dose Auxora group.

[0015] FIG. 8 shows higher versus lower risk of organ failure.

[0016] FIG. 9 shows trial profile.

[0017] FIGs. 10A-10B shows dose response relationship of zegocractin to outcome. FIG. 10A shows time to solide food tolerance (high haematocrit patients). FIG. 10B shows new-onset severe respiratory failure.[0018JFIG. 11 shows a win-ratio for placebo versus 2.0 mg zegocractin. One patient in the placebo group died after consent had been withdrawn, and 1 patient in the zegocractin group did not have a baseline hematocrit and has been excluded.DETAILED DESCRIPTION OF THE INVENTION

[0019] Methods and compositions disclosed herein are used for modulating intracellular calcium to treat or prevent acute pancreatitis (AP) in a subject with accompanying Inflammatory Response Syndrome (SIRS). In some aspects, methods and compounds providedPATENTATTORNEY DOCKET NO. CM1740-1 WO (449399-766) herein modulate CRAC channel activity. In another aspect, methods and compounds provided herein reduce the number of functional CRAC channels. In some aspects, methods and compounds described herein are CRAC channel blockers or CRAC channel modulators.

[0020] Calcium plays a vital role in cell function and survival. Specifically, calcium is a key element in the transduction of signals into and within cells. Cellular responses to growth factors, neurotransmitters, hormones and a variety of other signal molecules are initiated through calcium-dependent processes.

[0021] Almost all cell ty pes depend in some manner upon the generation of cytoplasmic Ca2+signals to regulate cell function, or to trigger specific responses. Cytosolic Ca2+signals control a wide array of cellular functions ranging from short-term responses such as contraction and secretion to longer-term regulation of cell growth and proliferation. Usually, these signals involve some combination of release of Ca2+from intracellular stores, such as the endoplasmic reticulum (ER), and influx of Ca2across the plasma membrane. In one example, cell activation begins with an agonist binding to a surface membrane receptor, which is coupled to phospholipase C (PLC) through a G-protein mechanism. PLC activation leads to the production of inositol 1,4,5-triphosphate (IP?), which in turn activates the IP? receptor causing release of Ca2+from the ER. The fall in ER Ca2+then signals to activate plasma membrane store-operated calcium (SOC) channels.

[0022] Store-operated calcium (SOC) influx is a process in cellular physiology that controls such diverse functions such as, but not limited to. refilling of intracellular Ca21stores (Putney et al. Cell, 75, 199-201, 1993), activation of enzymatic activity (Fagan et al., J. Biol. Chem. 275:26530-26537, 2000), gene transcription (Lewis, Annu. Rev. Immunol. 19:497-521, 2001), cell proliferation (Nunez et al., J. Physiol. 571.1, 57-73, 2006), and release of cytokines (Winslow et al., Curr. Opin. Immunol. 15:299-307. 2003). In some nonexcitable cells, e.g., blood cells, immune cells, hematopoietic cells, T lymphocytes and mast cells, pancreatic acinar cells (PACs), epithelial and ductal cells of other glands (e.g. salivary glands), endothelial and endothelial progenitor cells (e.g., pulmonary endothelial cells), SOC influx occurs through calcium release-activated calcium (CRAC) channels, a type of SOC channel.

[0023] The calcium influx mechanism has been referred to as store-operated calcium entry (SOCE). Stromal interaction molecule (STIM) proteins are an essential component of SOC channel function, serving as the sensors for detecting the depletion of calcium from intracellular stores and for activating SOC channels.Calcium Homeostasis

[0024] Cellular calcium homeostasis is a result of the summation of regulatory systems involved in the control of intracellular calcium levels and movements. Cellular calciumPATENTATTORNEY DOCKET NO. CM1740-1 WO (449399-766) homeostasis is achieved, at least in part, by calcium binding and by movement of calcium into and out of the cell across the plasma membrane and within the cell by movement of calcium across membranes of intracellular organelles including, for example, the endoplasmic reticulum, sarcoplasmic reticulum, mitochondria and endocytic organelles including endosomes and lysosomes.

[0025] Movement of calcium across cellular membranes is earned out by specialized proteins. For example, calcium from the extracellular space can enter the cell through various calcium channels and a sodium / calcium exchanger and is actively extruded from the cell by calcium pumps and sodium / calcium exchangers. Calcium can also be released from internal stores through inositol trisphosphate or ryanodine receptors and can be taken up by these organelles bymeans of calcium pumps.

[0026] Calcium can enter cells by any of several general classes of channels, including but not limited to, voltage-operated calcium (VOC) channels, ligand-gated calcium channels, store- operated calcium (SOC) channels, and sodium / calcium exchangers operating in reverse mode. VOC channels are activated by membrane depolarization and are found in excitable cells like nerve and muscle and are for the most part not found in nonexcitable cells. Under some conditions, Ca2+can enter cells viaNa+-Ca2+exchangers operating in reverse mode.

[0027] Endocytosis provides another process by which cells can take up calcium from the extracellular medium through endosomes. In addition, some cells, e.g.. exocrine cells, can release calcium via exocytosis.

[0028] Cytosolic calcium concentration is tightly regulated with resting levels usually estimated at approximately 0. 1 pM in mammalian cells, whereas the extracellular calcium concentration is ty pically about 2 rnM. This tight regulation facilitates transduction of signals into and within cells through transient calcium flux across the plasma membrane and membranes of intracellular organelles. There is a multiplicity of intracellular calcium transport and buffer systems in cells that serve to shape intracellular calcium signals and maintain the low resting cytoplasmic calcium concentration. In cells at rest, the principal components involved in maintaining basal calcium levels are calcium pumps and leak pathways in both the endoplasmic reticulum and plasma membrane. Disturbance of resting cytosolic calcium levels can affect transmission of calcium-dependent signals and give rise to defects in a number of cellular processes. For example, cell proliferation involves a prolonged calcium signaling sequence. Other cellular processes that involve calcium signaling include, but are not limited to, secretion, transcription factor signaling, and fertilization.

[0029] Cell-surface receptors that activate phospholipase C (PLC) create cytosolic Ca2+signals from intra- and extra-cellular sources. An initial transient rise of [Ca2+]i (intracellular calciumPATENTATTORNEY DOCKET NO. CM1740-1 WO (449399-766) concentration) results from the release of Ca2+from the endoplasmic reticulum (ER), which is triggered by the PLC product, inositol- 1, 4, 5-trisphosphate (IP3), opening IP3 receptors in the ER (Streb et al. Nature, 306, 67-69, 1983). A subsequent phase of sustained Ca2+entry across the plasma membrane then ensues, through specialized store operated calcium (SOC) channels (in the case of non-excitable cells like immune PAC cells, the SOC channels are calcium release- activated calcium (CRAC) channels) in the plasma membrane. Store-operated Ca2+ entry (SOCE) is the process in which the emptying of Ca2+stores itself activates Ca2+channels in the plasma membrane to help refill the stores (Putney, Cell Calcium, 7, 1-12, 1986; Parekh et al., Physiol. Rev. 757-810; 2005). SOCE does more than simply provide Ca2+ for refilling stores, but can itself generate sustained Ca2+signals that control such essential functions as gene expression, cell metabolism and exocytosis (Parekh and Putney, Physiol. Rev. 85, 757-810 (2005).

[0030] In lymphocytes and mast cells, activation of antigen or Fc receptors, respectively causes the release of Ca2+from intracellular stores, which in turn leads to Ca2influx through CRAC channels in the plasma membrane. In some immune cells, including monocyte / macrophage, neutrophils, or dendritic cells, release of Ca2+from intracellular stores and Ca2+influx through CRAC channels in the plasma membrane may result without Fc receptor activation. The subsequent rise in intracellular Ca2+activates calcineurin, a phosphatase that regulates the transcription factor NF AT. In resting cells, NF AT is phospho ylated and resides in the cytoplasm, but when dephosphorylated by calcineurin, NF AT translocates to the nucleus and activates different genetic programs depending on stimulation conditions and cell type. In response to infections and during transplant rejection, NF AT partners with the transcription factor AP-1 (Fos-Jun) in the nucleus of “effector"’ T cells, thereby trans-activating cytokine genes, genes that regulate T cell proliferation and other genes that orchestrate an active immune response (Rao et al., Annu Rev Immunol., 1997;15:707-47). In contrast, in T cells recognizing self-antigens, NFAT is activated in the absence of AP-1, and activates a transcriptional program known as “anergy” that suppresses autoimmune responses (Macian et al., Transcriptional mechanisms underlying lymphocyte tolerance. Cell. 2002 Jun 14; 109(6):719-31). In a subclass of T cells known as regulators’ T cells which suppress autoimmunity mediated by self-reactive effector T cells, NFAT partners with the transcription factor FOXP3 to activate genes responsible for suppressor function (Wu et al., Cell, 2006 Jul 28;126(2):375-87; Rudensky AY, Gavin M, Zheng Y. Cell. 2006 Jul 28;126(2):253-256).

[0031] The endoplasmic reticulum (ER) carries out a variety processes. The ER has a role as both a Ca2+sink and an agonist-sensitive Ca2+store, and protein folding / processing takes place within its lumen. In the latter case, numerous Ca2+-dependent chaperone proteins ensure thatPATENTATTORNEY DOCKET NO. CM1740-1 WO (449399-766) newly synthesized proteins are folded correctly and sent off to their appropriate destination. The ER is also involved in vesicle trafficking, release of stress signals, regulation of cholesterol metabolism, and apoptosis. Many of these processes require intraluminal Ca2+and protein misfolding, ER stress responses, and apoptosis can all be induced by depleting the ER of Ca2+for prolonged periods of time. Because it contains a finite amount of Ca2+, it is clear that ER Ca2+content must fall after release of that Ca2+during stimulation. However, to preserve the functional integrity of the ER, it is vital that the Ca2+content does not fall too low or is maintained at least at a low level. Replenishment of the ER with Ca2+is therefore a central process to all eukary otic cells. Because a fall in ER Ca2+content activates store-operated Ca2+channels in the plasma membrane, a major function of this Ca2+entry pathway is believed to be maintenance of ER Ca21levels that are necessary for proper protein synthesis and folding. However, store-operated Ca2+channels have other important roles.

[0032] The understanding of store-operated calcium entry' was provided by electrophysiological studies which established that the process of emptying the stores activated a Ca2+current in mast cells called Ca2+release-activated Ca2+current or ICRAC. ICRAC is non-voltage activated, inwardly rectifying, and remarkably selective for Ca2+. It is found in several cell types mainly of hematopoietic origin. ICRAC is not the only store-operated current, and it is now apparent that store-operated influx encompasses a family of Ca2+‘permeable channels, with different properties in different cell types. ICRAC was the first store-operated Ca2+current to be described and remains a popular model for studying store-operated influx.

[0033] Store-operated calcium channels can be activated by' any procedure that empties ER Ca2+stores; it does not seem to matter how the stores are emptied, the net effect is activation of store-operated Ca2+entry'. Physiologically, store emptying is evoked by an increase in the levels of IPs or other Ca2+-releasing signals followed by Ca2+release from the stores. But there are several other methods for emptying stores. These methods include the following:1) elevation of IPs in the cytosol (following receptor stimulation or, dialyzing the cytosol with IPs itself or related congeners like the nonmetabolizable analog Ins(2,4,5)Ps);2) application of a Ca2+ionophore (e.g.. ionomycin) to permeabilize the ER membrane;3) dialyzing the cytoplasm with high concentrations of Ca2+chelators (e.g., EGTA or BAPTA), which chelate Ca2+that leaks from the stores and hence prevent store refilling;4) exposure to the sarcoplasmic / endoplasmic reticulum Ca2+-ATPase (SERCA) inhibitors like thapsigargin, cyclopiazonic acid, and di-tert-butylhydroquinone;5) sensitizing the IPs receptors to resting levels of InsP3 with agents like thimerosal; and6) loading membrane-permeable metal Ca2+chelators like N,N,N’,N’-tetrakis(2- pyridylmethyljethylene diamine (TPEN) directly into the stores.PATENTATTORNEY DOCKET NO. CM1740-1 WO (449399-766)

[0034] Through mass action. TPEN lowers free intraluminal Ca2+concentration without changing total store Ca2+such that the store depletion-dependent signal is generated.

[0035] These methods of emptying stores are not devoid of potential problems. The key feature of store-operated Ca2+entry is that it is the fall in Ca2+content within the stores and not the subsequent rise in cytoplasmic Ca2+concentration that activates the channels. However, ionomycin and SERCA pump blockers generally cause a rise in cytoplasmic Ca2+concentration as a consequence of store depletion, and such a rise in Ca2+could open Ca2+-activated cation channels permeable to Ca2+. One way to avoid such problems is to use agents under conditions where cytoplasmic Ca2+has been strongly buffered with high concentrations of Ca2+chelator such as EGTA or BAPTA.Store-Operated Calcium Entry

[0036] Reduced calcium concentration in intracellular calcium stores such as the endoplasmic reticulum resulting from release of calcium therefrom provides a signal for influx of calcium from the extracellular medium into the cell. This influx of calcium, which produces a sustained ‘“plateau” elevation of cytosolic calcium concentration, generally does not rely on voltage-gated plasma membrane channels and does not involve activation of calcium channels by calcium. This calcium influx mechanism is referred to as capacitive calcium entry (CCE), calcium release-activated, store-operated or depletion-operated calcium entry'. Store-operated calcium entry can be recorded as an ionic current with distinctive properties. This current is referred to as Isoc (store-operated current) or ICRAC (calcium release-activated current).

[0037] Electrophysiological analysis of store-operated or calcium release-activated currents reveal distinct biophysical properties (see, e.g., Parekh and Penner (1997) Physiol. Rev. 77:901- 930) of these currents. For example, the current can be activated by depletion of intracellular calcium stores (e.g., by non-physiological activators such as thapsigargin, CPA, ionomycin and BAPTA, and physiological activators such as IP?) and can be selective for divalent cations, such as calcium, over monovalent ions in physiological solutions or conditions, can be influenced by' changes in cytosolic calcium levels, and can show altered selectivity and conductivity in the presence of low extracellular concentrations of divalent cations. The current may also be blocked or enhanced by 2- APB (depending on concentration) and blocked by SKF96365 and Gd3+and generally can be described as a calcium current that is not strictly voltage-gated.

[0038] Patch-clamp studies in mast cells and Jurkat leukemic T cells have established the CRAC entry mechanism as an ion channel with distinctive biophysical characteristics, including a high selectivity for Ca2+paired with an exceedingly low conductance. Furthermore, the CRAC channel was shown to fulfill the rigorous criteria for being store-operated, which is the activation solely by the reduction of Ca2+in the ER rather than by cytosolic Ca2+or otherPATENTATTORNEY DOCKET NO. CM1740-1 WO (449399-766) messengers generated by PLC (Prakriya et al., In Molecular and Cellular Insights into Ion Channel Biology (ed. Robert Maue) 121-140 (Elsevier Science, Amsterdam. 2004)).Regulation of Store-Operated Calcium Entry by Intracellular Calcium Stores

[0039] Store-operated calcium entry' is regulated by the level of calcium within an intracellular calcium store. Intracellular calcium stores can be characterized by sensitivity to agents, which can be physiological or pharmacological, which activate release of calcium from the stores or inhibit uptake of calcium into the stores. Different cells have been studied in characterization of intracellular calcium stores, and stores have been characterized as sensitive to various agents, including, but not limited to, IP3 and compounds that effect the IP3 receptor, thapsigargin, ionomycin and / or cyclic ADP-ribose (cADPR) (see, e.g., Berridge (1993) Nature 361 :315-325; Churchill and Louis (1999) Am. J. Physiol. 276 :C426-C434; Dargie et al. (1990) Cell Regul. 1 :279-290; Gerasimenko et al. (1996) Cell 84 :473-480; Gromoda et al. (1995) FEBS Lett. 360 :303-306; Guse et al. (1999) Nature 398 :70-73).

[0040] Accumulation of calcium within endoplasmic reticulum and sarcoplasmic reticulum (SR; a specialized version of the endoplasmic reticulum in striated muscle) storage organelles is achieved through sarcoplasmic-endoplasmic reticulum calcium ATPases (SERCAs), commonly referred to as calcium pumps. During signaling (i.e., when endoplasmic reticulum channels are activated to provide for calcium release from the endoplasmic reticulum into the cytoplasm), endoplasmic reticulum calcium is replenished by the SERCA pump with cytoplasmic calcium that has entered the cell from the extracellular medium (Yu and Hinkle (2000) J. Biol. Chem. 275:23648-23653; Hofer et a / . ( 1998) EMBO .1 17: 1986-1995).

[0041] Calcium release channels associated with IP3 and ry anodine receptors provide for controlled release of calcium from endoplasmic and sarcoplasmic reticulum into the cytoplasm resulting in transient increases in cytoplasmic calcium concentration. IP3 receptor-mediated calcium release is triggered by IP formed by the breakdow n of plasma membrane phosphoinositides through the action of phospholipase C, which is activated by binding of an agonist to a plasma membrane G protein-coupled receptor or tyrosine kinase. Ry anodine receptor-mediated calcium release is triggered by an increase in cytoplasmic calcium and is referred to as calcium-induced calcium release (CICR). The activity of ryanodine receptors (which have affinity for ryanodine and caffeine) may also be regulated by cyclic ADP-ribose.

[0042] Thus, the calcium levels in the stores, and in the cytoplasm, fluctuate. For example, ER free calcium concentration can decrease from a range of about 60-400 pM to about 1-50 pM when HeLa cells are treated with histamine, an agonist of PLC-linked histamine receptors (Miyawaki et al. (1997) Nature 388:882-887). Store-operated calcium entry is activated as the free calcium concentration of the intracellular stores is reduced. Depletion of store calcium, asPATENTATTORNEY DOCKET NO. CM1740-1 WO (449399-766) well as a concomitant increase in cytosolic calcium concentration, can thus regulate store- operated calcium entry into cells.Cytoplasmic Calcium Buffering

[0043] Agonist activation of signaling processes in cells can involve dramatic increases in the calcium permeability' of the endoplasmic reticulum, for example, through opening of IP3 receptor channels, and the plasma membrane through store-operated calcium entry. These increases in calcium permeability are associated with an increase in cytosolic calcium concentration that can be separated into two components: a “spike” of calcium release from the endoplasmic reticulum during activation of the IP3 receptor and a plateau phase which is a sustained elevation of calcium levels resulting from entry of calcium into the cytoplasm from the extracellular medium. Upon stimulation, the resting intracellular free calcium concentration of about 100 nM can rise globally to greater than 1 pM and higher in microdomains of the cell. The cell modulates these calcium signals with endogenous calcium buffers, including physiological buffering by organelles such as mitochondria, endoplasmic reticulum and Golgi. Mitochondrial uptake of calcium through a uniporter in the inner membrane is driven by the large negative mitochondrial membrane potential, and the accumulated calcium is released slowly7through sodium-dependent and -independent exchangers, and, under some circumstances, the permeability' transition pore (PTP). Thus, mitochondria can act as calcium buffers by taking up calcium during periods of cellular activation and can slowly release it later. Uptake of calcium into the endoplasmic reticulum is regulated by the sarcoplasmic and endoplasmic reticulum calcium ATPase (SERCA). Uptake of calcium into the Golgi is mediated by a P-type calcium transport ATPase (PMR1 / ATP2C1). Additionally, there is evidence that a significant amount of the calcium released upon IP3 receptor activation is extruded from the cell through the action of the plasma membrane calcium ATPase. For example, plasma membrane calcium ATPases provide the dominant mechanism for calcium clearance in human T cells and Jurkat cells, although sodium / calcium exchange also contributes to calcium clearance in human T cells. Within calcium-storing organelles, calcium ions can be bound to specialized calcium-buffering proteins, such as, for example, calsequestrins, calreticulins and calnexins. Additionally, there are calcium-buffering proteins in the cytosol that modulate calcium spikes and assist in redistribution of calcium ions. Thus, proteins and other molecules that participate in any of these and other mechanisms through which cytosolic calcium levels can be reduced are proteins that are involved in, participate in and / or provide for cytoplasmic calcium buffering. Thus, cytoplasmic calcium buffering helps regulate cytoplasmic Ca2+levels during periods of sustained calcium influx through SOC channels or bursts of Ca2+release. Large increases in cytoplasmic Ca2+levels or store refilling deactivate SOCE.PATENTATTORNEY DOCKET NO. CM1740-1 WO (449399-766) Downstream Calcium Entry-Mediated Events

[0044] In addition to intracellular changes in calcium stores, store-operated calcium entry affects a multitude of events that are consequent to or in addition to the store-operated changes. For example Ca2+influx results in the activation of a large number of calmodulin-dependent enzymes including the serine phosphatase calcineurin. Activation of calcineurin by an increase in intracellular calcium results in acute secretory processes such as mast cell degranulation. Activated mast cells release preformed granules containing histamine, heparin, TNFa and enzymes such as |3-hexosaminidase. Some cellular events, such as B and T cell proliferation, require sustained calcineurin signaling, which requires a sustained increase in intracellular calcium. A number of transcription factors are regulated by calcineurin, including NFAT (nuclear factor of activated T cells). MEF2 and NFKB. NFAT transcription factors play important roles in many cell types, including immune cells. In immune cells NFAT mediates transcription of a large number of molecules, including cytokines, chemokines and cell surface receptors. Transcriptional elements for NFAT have been found within the promoters of cytokines such as IL -2, IL-3, IL-4, IL-5, IL-8, IL-13, as well as tumor necrosis factor alpha (TNFa), granulocyte colony-stimulating factor (G-CSF), and gamma-interferon (y-IFN).

[0045] The activity of NFAT proteins is regulated by their phosphorylation level, which in turn is regulated by both calcineurin and NFAT kinases. Activation of calcineurin by an increase in intracellular calcium levels results in dephosphorylation of NFAT and entry into the nucleus. Rephosphorylation of NFAT masks the nuclear localization sequence of NFAT and prevents its entry’ into the nucleus. Because of its strong dependence on calcineurin-mediated dephosphorylation for localization and activity, NFAT is a sensitive indicator of intracellular free calcium levels.CRAC channels and Immune Responses

[0046] CRAC channels are located in the plasma membrane and open in response to the release of Ca2+ from endoplasmic reticulum stores. In immune cells, stimulation of cell surface receptors activates CRAC channels, leading to Ca2+ entry7and cytokine production. Cells of both the adaptive and innate immune system (e g., T-cells, neutrophils and macrophages) are known to be regulated by CRAC channels. CRAC channels also play a role in the activation of endothelial cells, which are involved in the pathogenesis of ALI / ARDS. The normal pulmonary endothelium maintains a tight barrier between endothelial cells, the pulmonary7interstitium, and the alveolar space, thereby enabling gas exchange. In inflammatory7conditions, stimulation of receptors on pulmonary endothelial cells leads to activation of Ca2+ entry via CRAC channels. The Ca2+ entry leads to loss of barrier function, which in turn causes leakage of protein-rich fluid into the alveolus, impaired gas exchange, and hypoxemia.PATENTATTORNEY DOCKET NO. CM1740-1 WO (449399-766)

[0047] Stimulation of T cell receptors causes depletion of intracellular Ca2+ stores and subsequent opening of the CRAC (Ca2+-release-activated Ca2+) channels. A sustained increase in intracellular Ca2+ concentration activates the calcineurin / NFAT (nuclear factor of activated T cells) pathway and turns on transcriptional programs of various cytokines. Orail and STIM1 are identified as a long-sought pore component of CRAC channels and as an endoplasmic reticulum (ER) Ca2+ sensor, respectively. STIM1 senses Ca2+ depletion in ER after stimulation of T cell receptors, translocates to plasma membrane (PM) proximal ER, binds to and activates Orai l. Human patients deficient in Orail or STIM1 have severe combined immune deficiency. Calcium Channel Inhibitors

[0048] Disclosed herein are a number of Calcium channel inhibitors consistent with the methods, compositions, administration regimens and compositions for use disclosed herein. In some embodiments, a Calcium channel inhibitor comprises a SOC inhibitor. In some embodiments, a Calcium channel inhibitor is a SOC inhibitor. In some embodiments, the SOC comprises a CRAC. In some embodiments the SOC inhibitor comprises a CRAC inhibitor. In some embodiments the Calcium channel inhibitor is a CRAC inhibitor. In some embodiments, the Calcium channel inhibitor inhibits a channel comprising STIM1 protein. In some embodiments, the CRAC comprises an Orail protein. In some embodiments, the CRAC inhibitor comprises an Orail protein inhibitor. In some embodiments, the Calcium channel inhibitor inhibits a channel comprising Orail protein. In some embodiments, the CRAC comprises an Orai2 protein. In some embodiments, the CRAC inhibitor comprises an Orai2 protein inhibitor. In some embodiments, the Calcium channel inhibitor inhibits a channel comprising Orai2 protein.

[0049] In some embodiments the compound is a compound having the structure of:PATENTsalt, pharmaceutically acceptable solvate, or pharmaceutically acceptable prodrug thereof. In some embodiments the compound is selected form a list of compounds consisting: N-(5-(6- chloro-2,2-difluorobenzo[tf][l,3]dioxol-5-yl)pyrazin-2-yl)-2-fluoro-6-methylbenzamide. In some aspects the intracellular Calcium signaling inhibitor is a compound of 7V-(5-(6-chloro-2,2- difluorobenzo[< / ][l,3]dioxol-5-yl)pyrazin-2-yl)-2-fluoro-6-methylbenzamide or a pharmaceutically acceptable salt, pharmaceutically acceptable solvate, or pharmaceutically acceptable prodrug thereof.PATENTATTORNEY DOCKET NO. CM1740-1WO (449399-766)

[0050] The chemical compound N-(5-(6-Chloro-2,2-difluorobenzo[d][l,3]dioxol-5-yl)pyrazin-2- yl)-2-fluoro-6-methylbenzamide, is herein referred to as CM4620, and is also known by its development name Zegocractin. This compound serves as the active pharmaceutical ingredient (API) in various formulations, including those described herein, and is recognized for its activity' as a calcium release-activated calcium (CRAC) channel inhibitor.

[0051] The chemical structure for N-(5-(6-Chloro-2,2-difluorobenzo[d][l,3]dioxol-5- yl)pyrazin-2-yl)-2-fluoro-6-methylbenzamide (CM4620) is as follows:N-(5-(6-Chloro-2,2-difluorobenzo[d][l,3]dioxol-5-yl)pyrazin-2-yl)-2-fluoro-6- methylbenzamide (CM4620).

[0052] In some aspects, the CM4620 is administered as an IV infusion. In some aspects, the CM4620 is supplied as a translucent, white to yellowish, sterile, non-pyrogenic emulsion containing the active pharmaceutical ingredient CM4620. The injectable emulsion of CM4620 is herein referred to as Auxora. In some aspects, the CM4620 is supplied as a translucent, white to yellowish, sterile, non-pyrogenic emulsion containing 1.6 mg / mL of the active pharmaceutical ingredient CM4620. In some aspects, the emulsion includes egg phospholipids, medium chain triglycerides, glycerin, edetate disodium salt dehydrate (EDTA), sodium hydroxide (as needed to adjust pH), and sterile water for injection.

[0053] In some embodiments, the intracellular Calcium signaling inhibitor is a CRACT inhibitor. In some aspects the intracellular Calcium signaling inhibitor is chosen from among the compounds, Ar-(5-(6-ethoxy-4-methylpyridin-3-yl)pyrazin-2-yl)-2,6-difluorobenzamide, N- (5-(2-ethyl-6-methylbenzo[< / |oxazol-5-yl)pyridin-2-yl)-3,5-difluoroisonicotinamide. A-(4-(l- ethyl-3-(thiazol-2-yl)-17 / -pyrazol-5-yl)phenyl)-2-fluorobenzamide, jV-(5-(l-ethyl-3- (triflouromethyl)-17 / -pyrazol-5-yl)pyrazin-2-yl)-2,4,6-trifluorobenzamide, 4-chloro-l-methyl- A-(4-(l-methyl-3-(trifluoromethyl)-lTZ-pyrazol-5-yl)phenyl)-17 / -pyrazole-5-carboxamide, N- (4-(3-(difluoromethyl)-5-methyl-177-pyrazol-I-yl)-3-fluorophenyl)-2,6-difluorobenzamide, N- (4-(3-(difluoromethyl)-5-methyl-17f-pyrazol-I-yl)-3-fluorophenyl)-2,4,6-trifluorobenzamide, AA4-(3-(difl uoromethyl)- 1 -methyl- l / / -pyrazol-5-yl)-3-lluorophenyl)-2.4.6-tri fluorobenzamide,PATENTATTORNEY DOCKET NO. CM1740-1 WO (449399-766) 4-chloro-2 / -(3-fluoro-4-(l-methyl-3-(trifluoromethyl)-lH-pyrazol-5-yl)phenyl)-l -methyl- \H- pyrazole-5-carboxamide, 3-fluoro-4-(l-methyl-3-(trifluoromethyl)-l / 7 — pyrazol-5-yl)-JV-((3- methylisothiazol-4-yl)methyl)aniline, jV-(5-(7-chloro-2,3-dihydro-[l,4]dioxino[2,3-b]pyridin-6- yl)pyridin-2-yl)-2,6-difluorobenzamide, jV-(2,6-difluorobenzyl)-5-(l-ethyl-3-(thiazol-2-yl)-177- pyrazol-5-yl)pyrimidin-2-amine, 3,5-difluoro-7V-(3-fluoro-4-(3-methyl-l-(thiazol-2-yl)-177- pyrazol-4-yl)phenyl)isonicotinamide, 5-(l-methyl-3-(trifluoromethyl)-17 / -pyrazol-5-yl)-7V- (2,4,6-trifluorobenzyl)pyridin-2-amine, JV-(5-(l-ethyl-3-(trifluoromethyl)-17 / -pyrazol-5- yl)pyridin-2-yl)-2,4,6-trifluorobenzamide, 7V-(5-(5-chl oro-2 -methylbenzo[d]oxazol-6- yl)pyrazin-2-yl)-2,6-difluorobenzamide, 7V-(5-(6-ethoxy-4-methylpyridin-3-yl)thiazol-2-yl)- 2,3,6-trifluorobenzamide, Ar-(5-(l-ethyl-3-(trifluoromethyl)-17 / -pyrazol-5-yl)pyridin-2-yl)- 2,3,6-trifluorobenzamide, 2.3.6-trifluoro-jV-(3-fluoro-4-(l-methyl-3-(trifluoromethyl)-17 / - pyrazol-5-yl)phenyl)benzamide, 2,6-difluoro-N-(4-(5-methyl-2-(trifluoromethyl)oxazol-4- yl)phenyl)benzamide, or7V-(5-(6-chloro-2,2-difluorobenzo[<7][l,3]dioxol-5-yl)pyrazin-2-yl)-2- fluoro-6-methylbenzamide, 2,6-difluoro-N-(5-(2-methylbenzo[d]oxazol-6-yl)pyrazin-2- yl)benzamide, 2,3.6-trifluoro-N-(3-fluoro-4-(l-methyl-3-(trifluoromethyl)-lH-pyrazol-5- yl)phenyl)benzamide, N-(5-(2,5-dimethylbenzo[d]oxazol-6-yl)thiazol-2-yl)-2,3,6- trifluorobenzamide, N-(4-(l-ethyl-3-(thiazol-2-yl)-lH-pyrazol-5-yl)phenyl)-2 -fluorobenzamide, N-(4-(2-((6-chloropyridin-3-yl)oxy)-4-methylthiazol-5-yl)phenyl)-2-fluorobenzamide, or a pharmaceutically acceptable salt, pharmaceutically acceptable solvate, or pharmaceutically acceptable prodrug thereof. Each of these compounds is an example of a Calcium channel inhibitor, a SOC inhibitor, or a CRAC inhibitor.

[0054] In some embodiments, the intracellular Calcium signaling inhibitor is jV-(5-(6-ethoxy-4- methylpyridin-3-yl)pyrazin-2-yl)-2,6-difluorobenzamide, 7V-(5-(2-ethyl-6- melhylbenzo|<7|oxazol-5-yl)pyri din-2 -yl)-3.5-difluoroisonicotinamide. JV-(4-(l-ethyl-3-(thiazol- 2-yl)-17 / -pyrazol-5-yl)phenyl)-2 -fluorobenzamide, A^-(5-(l-ethyl-3-(triflouromethyl)-lE7- pyrazol-5-yl)pyrazin-2-yl)-2,4,6-trifluorobenzamide, A^-(4-(3-(difluoromethyl)-5-methyl-177- pyrazol-l-yl)-3-fluorophenyl)-2,6-difluorobenzamide, W-(4-(3-(difluoromethyl)-5-methyl-lEZ- pyrazol-l-yl)-3-fluorophenyl)-2,4,6-trifluorobenzamide, W-(4-(3-(difluoromethyl)-l-methyl- l / / -pyrazol-5-yl)-3-fluorophenyl)-2,4,6-trifluorobenzamide, 3-fluoro-4-( 1 -methyl-3- (trifluoromethyl)-lTf — pyrazol-5-yl)-7V-((3-methylisothiazol-4-yl)methyl)aniline, TV-(5-(7- chloro-2,3-dihydro-[l,4]dioxino[2,3-b]pyridin-6-yl)pyridin-2-yl)-2,6-difluorobenzamide, N- (2,6-difluorobenzyl)-5-(l-ethyl-3-(thiazol-2-yl)-127-pyrazol-5-yl)pyrimidin-2-amine, 3,5- difluoro-7V-(3-fluoro-4-(3-methyl-l-(thiazol-2-yl)-l / / -pyrazol-4-yl)phenyl)isoni cotinamide, N- (5-(l-ethyl-3-(trifluoromethyl)-17 / -pyrazol-5-yl)pyridin-2-yl)-2,4,6-trifluorobenzamide, N-(5- (6-ethoxy-4-methylpyridin-3-yl)thiazol-2-yl)-2,6-difluorobenzamide, V-(5-(l-ethyl-3-PATENTATTORNEY DOCKET NO. CM1740-1 WO (449399-766) (trifluoromethyl)- 17 / -pyrazol-5-yl)pyridin-2-yl)-2, 3, 6-trifluorobenzamide, 2.3.6-trifluoro-7V-(3- fluoro-4-(l-methyl-3-(trifluoromethyl)-17 / -pyrazol-5-yl)phenyl)benzamide, 2.6-difluoro-N-(4- (5-methyl-2-(trifluoromethyl)oxazol-4-yl)phenyl)benzamide, 2,6-difluoro-N-(5-(2- methylbenzo[d]oxazol-6-yl)pyrazin-2-yl)benzamide, N-(4-(l-ethyl-3-(thiazol-2-yl)-lH-pyrazol- 5-yl)phenyl)-2-fluorobenzamide, N-(4-(2-((6-chloropyridin-3-yl)oxy)-4-methylthiazol-5- yl)phenyl)-2-fluorobenzamide, N-(5-(2.5-dimethylbenzo[d]oxazol-6-yl)thiazol-2-yl)-2,3,6- trifluorobenzamide, or JV-(5-(6-chloro-2,2-difluorobenzo[J][l,3]dioxol-5-yl)pyrazin-2-yl)-2- fluoro-6-methylbenzamide, or a pharmaceutically acceptable salt, pharmaceutically acceptable solvate, or pharmaceutically acceptable prodrug thereof. In some embodiments, the intracellular Calcium signaling inhibitor is 2,6-difluoro-N-(4-(5-methyl-2-(trifluoromethyl)oxazol-4- yl)phenyl)benzamide, N-(5-(7-chloro-2,3-dihydro-[1.4]dioxino[2,3- b]pyridin-6-yl)pyridin-2- yl)-2,6-difluorobenzamide, N-(2,6-difluorobenzyl)-5-(l -ethyl-3-(thiazol-2-yl)-l H-pyrazol-5- yl)pyrimidin-2-amine, 3,5-difluoro-N-(3-fluoro-4-(3-methyl-l-(thiazol-2-yl)-lHpyrazol-4- yl)phenyl)isonicotinamide, N-(5-(2-ethyl-6-methylbenzo[d]oxazol-5-yl)pyridin-2-yl)-3,5- difluoroisonicotinamide, or 7V-(5-(6-chl oro-2, 2-difluorobenzo[< / ][ 1,3] di oxol-5-yl)pyrazin-2-yl)- 2-fluoro-6-methylbenzamide, or a pharmaceutically acceptable salt, pharmaceutically acceptable solvate, or pharmaceutically acceptable prodrug thereof. In some embodiments, the intracellular Calcium signaling inhibitor is N-(5-(6-Chloro-2,2-difluorobenzo[d][l,3]dioxol-5- yl)pyrazin-2-yl)-2-fluoro-6-methylbenzamide or a pharmaceutically acceptable salt, pharmaceutically acceptable solvate, or pharmaceutically acceptable prodrug thereof.

[0055] Disclosed herein, in some embodiments, are CRAC inhibitors. In some embodiments, the CRAC inhibitor comprises SK&F 96365. In some embodiments, the CRAC inhibitor comprises Econazole. In some embodiments, the CRAC inhibitor comprises L-651582. In some embodiments, the CRAC inhibitor comprises a carboxanilide compound. In some embodiments, the CRAC inhibitor comprises a biaryl carboxanilide compound. In some embodiments, the CRAC inhibitor comprises a heterocyclic carboxanilide compound. In some embodiments, the CRAC inhibitor comprises RP4010. In some embodiments, the CRAC inhibitor comprises Synta-66 (N-(2'.5'-dimethoxy[l,r-biphenyl]-4-yl)-3-fluoro-4-pyridinecarboxamide). In some embodiments, the CRAC inhibitor comprises ML-9 (l-(5-chloronaphthalene-l- sulfonyl)homopiperazine). In some embodiments, the CRAC inhibitor comprises capsaicin (8- methyl-N-vanillyl-(trans)-6-nonenamide). In some embodiments, the CRAC inhibitor comprises NPPB (5-nitro-2-(3-phenylpropylamino)-benzoic acid). In some embodiments, the CRAC inhibitor comprises DES (diethylstilbestrol). In some embodiments, the CRAC inhibitor comprises BEL (bromenol lactone, or E-6-(bromoethylene)tetrahydro-3-(l-naphthyl)-2H-pyran- 2-one). In some embodiments, the CRAC inhibitor comprises Carboxyamidotriazole (CAI). InPATENTATTORNEY DOCKET NO. CM1740-1 WO (449399-766) some embodiments, the CRAC inhibitor comprises R02959 (2,6-difluoro-N-{5-[4-methyl-l-(5- methyl-thiazol-2-yl)-l,2,5,6-tetrahydro-pyridin-3-yl]-pyrazin-2-yl}-benzamide). In some embodiments, the CRAC inhibitor comprises a Tanshinone IIA sulfonate. In some embodiments, the CRAC inhibitor comprises sodium Tanshinone IIA sulfonate. In some embodiments, the CRAC inhibitor comprises MRS 1845. Each of these compounds is also an example of a Calcium channel inhibitor, or of a SOC inhibitor.

[0056] Disclosed herein, in some embodiments, are CRAC inhibitors. In some embodiments, the CRAC inhibitor comprises a lanthanide. In some embodiments, the CRAC inhibitor comprises lanthanide trivalent ion. In some embodiments, the CRAC inhibitor comprises La?+(lanthanum). In some embodiments, the CRAC inhibitor comprises Gd3+(gadolinium). Each of these compounds is also an example of a Calcium channel inhibitor, or of a SOC inhibitor.

[0057] Disclosed herein, in some embodiments, are CRAC inhibitors. In some embodiments, the CRAC inhibitor comprises an imidazole. In some embodiments, the CRAC inhibitor comprises imidazole antimycotic SKF-96365. In some embodiments, the CRAC inhibitor comprises econazole. In some embodiments, the CRAC inhibitor comprises miconazole. Each of these compounds is also an example of a Calcium channel inhibitor, or of a SOC inhibitor.

[0058] Disclosed herein, in some embodiments, are CRAC inhibitors. In some embodiments, the CRAC inhibitor comprises a diphenylboronate. In some embodiments, the CRAC inhibitor comprises 2-Aminoethyldiphenyl borate (2-APB). In some embodiments, the CRAC inhibitor comprises DPB162-AE. In some embodiments, the CRAC inhibitor comprises DPB163-AE. Each of these compounds is also an example of a Calcium channel inhibitor, or of a SOC inhibitor.

[0059] Disclosed herein, in some embodiments, are CRAC inhibitors. In some embodiments, the CRAC inhibitor comprises a pyrazole. In some embodiments, the CRAC inhibitor comprises a bis(trifluoromethyl)pyrazole. In some embodiments, the CRAC inhibitor comprises BTP1. In some embodiments, the CRAC inhibitor comprises BTP2. In some embodiments, the CRAC inhibitor comprises YM-58483. In some embodiments, the CRAC inhibitor comprises BTP3. Each of these compounds is also an example of a Calcium channel inhibitor, or of a SOC inhibitor.

[0060] Disclosed herein, in some embodiments, are CRAC inhibitors. In some embodiments, the CRAC inhibitor comprises a Pyr compound. Disclosed herein, in some embodiments, are CRAC inhibitors. In some embodiments, the CRAC inhibitor comprises N-(4-(3,5- bis(trifluoromethyl)- IH-pyrazol- 1 -yl)phenyl)-4-methyl- 1 ,2,3-thiadiazole-5-carboxamide (Pyr2 / BTP2 / YM58483). In some embodiments, the CRAC inhibitor comprises ethyl l-(4- (2,3,3-trichloroacrylamido)phenyl)-5-(trifluoromethyl)-lH-pyrazole-4-carboxylate (Pyr3). InPATENTATTORNEY DOCKET NO. CM1740-1 WO (449399-766) some embodiments, the CRAC inhibitor comprises N-(4-(3,5-bis(trifluoromethyl)-lH-pyrazol- l-yl)phenyl)-3-fluoroisonicotinamide (Pyr6). In some embodiments, the CRAC inhibitor comprises N-(4-(3,5-bis(trifluoromethyl)-lH-pyrazol-l-yl)phenyl)-4- methylbenzenesulfonamide (PyrlO). In some embodiments, the CRAC inhibitor comprises 2- aminoethoxy diphenylborate (2 -APB). In some embodiments, the CRAC inhibitor comprises 2,2’-((((oxybis(methylene))bis(3,l-phenylene))bis(phenylboranediyl))bis(oxy)) bis(ethan-l- amine) (DPB162-AE); 2,2’-((((oxybis(methylene))bis(4,l- phenylene))bis(phenylboranediyl))bis(oxy)) bis(ethan-l -amine) (DPB163-AE). Each of these compounds is also an example of a Calcium channel inhibitor, or of a SOC inhibitor.

[0061] Disclosed herein, in some embodiments, are CRAC inhibitors. In some embodiments, the CRAC inhibitor comprises a GSK compound. In some embodiments, the CRAC inhibitor comprises GSK-5498A. In some embodiments, the CRAC inhibitor comprises GSK-5503A (2,6-difluoro-N-(l-(2-phenoxybenzyl)-lH-pyrazol-3-yl)benzamide). In some embodiments, the CRAC inhibitor comprises GSK-7975A (2,6-difluoro-N-(l-(4-hydroxy-2- (trifluoromethyl)benzy’l)-lH-pyrazol-3-yl)benzamide). Each of these compounds is also an example of a Calcium channel inhibitor, or of a SOC inhibitor.

[0062] Disclosed herein, in some embodiments, are CRAC inhibitors. In some embodiments, the CRAC inhibitor comprises a polyunsaturated fatty acid (PUFA). In some embodiments, the CRAC inhibitor comprises an 18-C PUFA. In some embodiments, the CRAC inhibitor comprises linoleic acid. Each of these compounds is also an example of a Calcium channel inhibitor, or of a SOC inhibitor.

[0063] Disclosed herein, in some embodiments, are CRAC inhibitors. In some embodiments, the CRAC inhibitor comprises l-phenyl-3-(l-phenylethyl)urea. In some embodiments, the CRAC inhibitor comprises a l-phenyl-3-(l-phenylethyl)urea derivative. In some embodiments, the CRAC inhibitor comprises a l-phenyl-3-(l-phenylethyl)urea derivative comprising Compound 22. In some embodiments, the CRAC inhibitor comprises a l-phenyl-3-(l-phenylethyl)urea derivative comprising Compound 23. Each of these compounds is also an example of a Calcium channel inhibitor, or of a SOC inhibitor.

[0064] Disclosed herein, in some embodiments, are CRAC inhibitors. In some embodiments, the CRAC inhibitor comprises a cholestatic bile acid. In some embodiments, the CRAC inhibitor comprises taurolithocholic acid (TLCA; 2-[4-[(3R,5R,8R,9S,10S,13R,14S,17R)-3-hydroxy- 10,13-dimethyl-2,3,4,5,6,7,8,9,Il,12,I4,15,16,17-tetradecahydro-lH- cyclopenta[a]phenanthren-17-yl]pentanoylamino]ethanesulfonic acid). In some embodiments, the CRAC inhibitor comprises lithocholic acid (LCA; (4R)-4- [(3R,5R,8R,9S,10S,13R,14S,17R)-3-Hydroxy-10,13-dimethyl-PATENTATTORNEY DOCKET NO. CM1740-1 WO (449399-766) 2,3,4,5,6,7,8,9,l l,12,14.15,16,17-tetradecahydro-lH-cyclopenta[a]phenanthren-17-yl]pentanoic acid). In some embodiments, the CRAC inhibitor comprises cholic acid (CA; (R)-4- ((3R,5S,7R,8R,9S,10S,12S,13R,14S,17R)-3,7,12-trihydroxy-10,13-dimethylhexadecahydro- lH-cyclopenta[a]phenanthren-17-yl)pentanoic acid). In some embodiments, the CRAC inhibitor comprises taurocholic acid (TCA; 2-{[(3a,5p,7a,12a)-3,7,12-trihydroxy-24- oxocholan-24-yl] amino} ethanesulfonic acid)). Each of these compounds is also an example of a Calcium channel inhibitor, or of a SOC inhibitor.

[0065] Disclosed herein, in some embodiments, are CRAC inhibitors. In some embodiments, the CRAC inhibitor comprises FCC2121 (4-[3-(diphenylmethyl)-l,2,4-oxadiazol-5- yl]piperidineyl]piperidine). In some embodiments, the CRAC inhibitor comprises FCC2122 (3- (4-methyl-1.5-diphenyl-lH-pyrazol-3-yl)-2-phenylpropanoic acid). In some embodiments, the CRAC inhibitor comprises FC-2399 (2-(4-Chloro-phenyl)-3-[l-(4-chloro-phenyl)-5-methyl-lH- pyrazol-3-yl]-propionic acid). Each of these compounds is also an example of a Calcium channel inhibitor, or of a SOC inhibitor.

[0066] Disclosed herein, in some embodiments, are CRAC inhibitors. In some embodiments, the CRAC inhibitor comprises any one of N-[l-({2-Chloro-5- [(cyclopropylmethyl)oxy]phenyl}methyl)-lH-pyrazol-3-yl]-2,6-difluorobenzamide; N-{l-[(2,4- Dichlorophenyl)methyl]-lH-pyrazol-3-yl}-2,6-difluorobenzamide; 2-Bromo-N-{l-[(2,4- dichlorophenyl)methyl]-lH-pyrazol-3-yl}-6-fluorobenzamide; 2-Chloro-N-{l-[(2.4- dichlorophenyl)methyl]-lH-pyrazol-3-yl}-6-fluorobenzamide; 2.6-Dichloro-N-{ l-[(2.4- dichlorophenyl)methyl]-lH-pyrazol-3-yl} benzamide; N-{l -[(2,4-dichlorophenyl)methyl]-lH- pyrazol-3-yl}-3,5-difluoro-4-pyridinecarboxamide; N-[l-({5-chloro-2- [(phenylmethyl)oxy]phenyl}methyl)-lH-pyrazol-3-yl]-2,6-25 difluorobenzamide; N-{ l-[(2,6- dichlorophenyl)methyl]-lH-pyrazol-3-yl}-2,6-difluorobenzamide; N-[l-({5-chloro-2-[(2- methylpropyl)oxy]phenyl}methyl)-lH-pyrazol-3-yl]-2,6-difluorobenzamide; N-(l-{[2-bromo- 5-(methyloxy)phenyl]methyl}-lH-pyrazol-3-yl)-2,6-difluorobenzamide; N-(l-{[5-chloro-2- (methyloxy)phenyl]methyl}-lH-pyrazol-3-yl)-2,6-difluorobenzamide; 2,6-Difluoro-N-(l-{[2- (phenyloxy)phenyl]methyl}-lH-pyrazol-3-yl)benzamide; N-[l-({5-bromo-2- [(phenylmethyl)oxy]phenyl}methyl)-lH-pyrazol-3-yl]-2,6-difluorobenzamide; 2,6-Difluoro-N- [l-({2-[(trifluoromethyl)oxy]phenyl}methyl)-lH-pyrazol-3-yl]benzamide; 2,6-Difluoro-N-(l- {[4-[(phenylmethyl)oxy]-2-(trifluoromethyl)phenyl]methyl}-lH-pyrazol-3-yl)benzamide; N- {l-[(2-Bromo-6-chlorophenyl)methyl]-lH-pyrazol-3-yl}-2,6-difluorobenzamide; 2,6-Difluoro- / V-[l-({2-[(phenylmethyl)oxy]phenyl}methyl)-lH-pyrazol-3-yl]benzamide; N / -[l-({2-chloro- 5-[(2-methylpropyl)oxy]phenyl}methyl)-lH-pyrazol-3-yl]-2,6-difluorobenzamide; N-(l-{[4- [(cyclopropylmethyl)oxy]-2-(trifluoromethyl)phenyl]methyl}-lH-pyrazol-3-yl)-2,6-PATENTATTORNEY DOCKET NO. CM1740-1 WO (449399-766) difluorobenzamide; 2,6-Difluoro-N-(l-{[4-iodo-2-(trifluoromethyl)phenyl]methyl}-lH-pyrazol- 3-yl)benzamide; 2,6-Difluoro-N-(l-{[4-methyl-2-(trifluoromethyl)phenyl]methyl}-lH-pyrazol- 3-yl)benzamide; N-(l-{[4-cyclopropyl-2-(trifluoromethyl)phenyl]methyl}-lH-pyrazol-3-yl)- 2,6-difluorobenzamide; 2,6-Difluoro-N-{l-[(4-iodo-2-methylphenyl)methyl]-lH-pyrazol-3- yljbenzamide; N-(l-{[4-chloro-2-(trifluoromethyl)phenyl]methyl}-lH-pyrazol-3-yl)-2,6- difluorobenzamide; 2-Fluoro-N-(l-{[4-iodo-2-(trifluoromethyl)phenyl] methyl}-lH-pyrazol-3- yl)benzamide; 2-Chloro-N-(l-{ t4-cyclopropyl-2-(trifluoromethyl) phenylJmethylJ-lH-pyrazol- 3-yl)benzamide; N-(l - { [4-cyclopropyl-2-(trifluoromethyl) phenyl]methyl} -lH-pyrazol-3-yl)-2- fluorobenzamide; 2,6-Difluoro-N-(l-{[5-iodo-2-(trifluoromethyl)phenyl]methyl}-lH-pyrazol- 3-yl)benzamide; 2,6-Difluoro-N-(l-{[2-fluoro-6-(trifluoromethyl)phenyl]methyl}-lH-pyrazol- 3-yl)benzamide; or 2,6-Difluoro-N-(l-{[4-hydroxy-2-(trifluoromethyl)phenyl]methyl}-lH- pyrazol-3-yl)benzamide. Each of these compounds is also an example of a Calcium channel inhibitor, or of a SOC inhibitor.

[0067] Disclosed herein, in some embodiments, are CRAC inhibitors. In some embodiments, the CRAC inhibitor comprises any one of N-[4-(3,5-dicyclopropyl-lH-pyrazol-l-yl)phenyl]-lH- benzo[d]imidazole-6-carboxamide; N-[4-(3,5-dicyclopropyl-lH-pyrazol-l-yl)phenyl]-lH- benzo[d][l,2,3]triazole-6-carboxamide; N-[4-(3,5-dicyclopropyl-lH-pyrazol-l- yl)phenyl]quinoline-6-carboxamide; N-[4-(3,5-dicyclopropyl-lH-pyrazol-l-yl)phenyl] quinoxaline-6-carboxamide; 2-(lH-benzo[d]imidazol-l-yl)-N-[4-(3,5-dicyclopropyl-lH- pyrazol-l-yl)phenyl]acetamide; 2-(lH-benzo[d][l,2,3] triazol-l-yl)-N-[4-(3.5-dicyclopropyl- lH-pyrazol-l-yl)phenyl] acetamide; N-[4-(3,5-dicyclopropyl-lH-pyrazol-l-yl)phenyl]-2-(lH- indol-3-yl)acetamide; N-[4-(3,5-dicyclopropyl-lH-pyrazol-l-yl)phenyl]-2-(imidazo[l,2- a]pyridin-2-yl) acetamide; N-[4-(3,5-dicyclopropyl-lH-pyrazol-l-yl)phenyl]-2-(quinolin-6- yl)acetamide; N-[4-(3,5-dicyclopropyl-lH-pyrazol-l-yl)phenyl]-2-(quinolin-6-yl)acetamide; 2- (lH-benzo[d][l,2,3]triazol-l-yl)-N-(4-(3,5-dicyclopropyl-lH-pyrazol-l-yl)-3-fluorophenyl) acetamide; N-[4-(3,5-dicyclopropyl-lH-pyrazol-l-yl)-3-fluorophenyl]-2-(quinolin-6-yl) acetamide; N-[6-(3,5-dicyclopropyl-lH-pyrazol-l-yl)pyridin-3-yl]quinoline-6-carboxamide; N- [6-(3,5-dicyclopropyl-lH-pyrazol-l-yl)pyridin-3-yl]quinoxaline-6-carboxamide; 2-(lH- benzo[d][l,2,3]tnazol-l-yl)-N-[6-(3,5-dicyclopropyl-lH-pyrazol-l-yl)pyridin-3-yl] acetamide; N-[6-(3,5-dicyclopropyl-lH-pyrazol-l-yl)pyridin-3-yl]-2-(quinolin-6-yl) acetamide; N-{4-[5- cyclopropyl-3-(trifluoromethyl)-lH-pyrazol-l-yl]phenyl}quinoline-6-carboxamide; N-{4-[5- cyclopropyl-3-(trifluoromethyl)-lH-pyrazol-l-yl]phenyl}quinoxaline-6-carboxamide; 2-(lH- benzo[d]imidazol-l-yl)-N-{4-[5-cyclopropyl-3-(trifluoromethyl)-lH-pyrazol-l-yl] phenyl] acetamide; 2-(lH-benzo[d][l,2,3]triazol-l-yl)-N-{4-[5-cyclopropyl-3-(trifluoromethyl)- IH-pyrazol-l-yl] phenyl} acetamide; 2-(2H-benzo[d][l,2,3]triazol-2-yl)-N-{4-[5-cyclopropyl-3-PATENTATTORNEY DOCKET NO. CM1740-1 WO (449399-766) (trifluoromethyl)- lH-pyrazol-l-yl]phenyl} acetamide; 2-(3H-[l,2,3]triazolo[4,5-b]pyridin-3-yl)- N-{4-[5-cyclopropyl-3-(trifluoromethyl)-lH-pyrazol-l-yl] phenyl} acetamide; (S)-2-(3H- [l,2,3]triazolo[4,5-b]pyridin-3-y])-N-{4-[5-cyclopropyl-3-(trifluoromethyl)-lH-pyrazol-l- yl]phenyl}propanamide; 2-(6-amino-9H-purin-9-yl)-N-{4-[5-cyclopropyl-3-(trifluoromethyl)- 1 H-pyrazol- 1 -y 1] phenyl } acetamide; N -(4-(5-cy clopropyl-3-(trifluoromethyl)- IH-py razol- 1 - yl)phenyl)-2-(l,3-dimethyl-2,6-dioxo-2,3-dihydro-lH-purin-7(6H)-yl)acetamide; N-{4-[5- cyclopropyl-3-(tnfluoromethyl)-lH-pyrazol-l-yl) phenyl)-2-(imidazo[ 1,2-aJ pyridin-2-yl) acetamide; N-{4-[5-cyclopropyl-3-(trifluoromethyl)-lH-pyrazol-l-yl]phenyl}-2-(quinolin-6- yl)acetamide; N-{4-[5-cyclopropyl-3-(trifluoromethyl)-lH-pyrazol-l-yl]phenyl}-2-(quinolin-6- yl)propanamide; N-{4-[5-cyclopropyl-3-(trifluoromethyl)-lH-pyrazol-l-yl]-3-fluorophenyl}- lH-benzo[d] [l,2,3]triazole-6-carboxamide; 2-(lH-benzo[d][1.2.3]triazol-l-yl)-N-{4-[5- cyclopropyl-3-(trifluoromethyl)-lH-pyrazol-l-yl]-3-fluorophenyl}acetamide; N-{6-[5- cyclopropyl-3-(trifluoromethyl)-lH-pyrazol-l-yl]pyridin-3-yl}-lH-benzo[d][l,2,3] triazole-5- carboxamide; 2-(lH-benzo[d][l,2,3]triazol-l-yl)-N-{6-[5-cyclopropyl-3-(trifluoromethyl)-lH- pyrazol-I-yl]pyridin-3-yl} acetamide; 2-(2H-benzo[d][l,2,3]triazol-2-yl)-N-{6-[5-cyclopropyl- 3-(trifluoromethyl)-lH-pyrazol-l-yl]pyridin-3-yl} acetamide; N-{6-[5-cyclopropyl-3- (trifluoromethyl)-lH-pyrazol-l-yl]pyridin-3-yl}-2-(quinolin-6-yl)acetamide; 2-(lH- benzo[d][l,2,3]triazol-l-yl)-N-{6-[4-chloro-5-cyclopropyl-3-(trifluoromethyl)-lH-pyrazol-l- yl]pyridin-3-yl}acetamide; 4-[5-cyclopropyl-3-(trifluoromethyl)-lH-pyrazol-l-yl]-3-fluoro-N- (quinolin-6-ylmethyl)benzamide; or l-[4-(3,5-dicyclopropyl-lH-pyrazol-l-yl)phenyl]-3- (quinolin-6-yl)urea. Each of these compounds is also an example of a Calcium channel inhibitor, or of a SOC inhibitor.

[0068] Disclosed herein, in some embodiments, are CRAC inhibitors. In some embodiments, the CRAC inhibitor comprises any one of 4-[6-(2-chloro-6-fluoro-phenyl)-5H-pyrrolo[3,2- d]pyrimidin-2-yl]-3,N,N-trimethyl-benzenesulfonamide; 6-(2-Chloro-phenyl)-2-(2-methyl-5- trifluoromethyl-2H-pyrazol-3-yl)-5H-pyrrolo[2,3-b]pyrazine; 4-[6-(2-Chloro-phenyl)-5H- pyrrolo[2,3-b]pyrazin-2-yl]-3-methyl-benzoic acid methyl ester; 4-(6-(2-Chlorophenyl)-5H- pyrrolo[2,3-b]pyrazin-2-yl)-N,N,3-trimethylbenzenesulfonamide; 6-(2-chloro-6-fluorophenyl)- 2-(l-methyl-3-(trifluoromethyl)-lH-pyrazol-5-yl)-5H-pyrrolo[2,3-b]pyrazine; 6-Cyclohexyl-2- (l-methyl-3-(trifluoromethyl)-lH-pyrazol-5-yl)-5H-pyrrolo[2,3-b]pyrazine; or 4-(6- Cyclohexyl-5H-pyrrolo[2,3-b]pyrazin-2-yl)-N,N,3-trimethylbenzenesulfonamide. Each of these compounds is also an example of a Calcium channel inhibitor, or of a SOC inhibitor.

[0069] Disclosed herein, in some embodiments, are CRAC inhibitors. In some embodiments, the CRAC inhibitor comprises any one of 2,6-Difluoro-N-(6-(5-(4-methyl-5-oxo-4,5-dihydro-l,3,4- oxadiazol-2-yl)-3-(trifluoromethyl)-lH-pyrazol-l-yl)pyridin-3-yl)benzamide; 2-Fluoro-6-PATENTATTORNEY DOCKET NO. CM1740-1 WO (449399-766) methyl-N-(6-(5-(4-methyl-5-oxo-4,5-dihydro-l,3,4-oxadiazol-2-yl)-3-(trifluoromethyl)-lH- pyrazol-l-yl)pyridin-3-yl)benzamide; 5-(3-Cyclopropyl-l-(5-(2,6- difluorobenzyl)amino)pyridin-2-yl)-lH-pyrazol-5-yl)-3-methyl-l,3,4-oxadiazol-2(3H)-one; N- (6-(3-(Difluoromethyl)-5-(4-methyl-5-oxo-4,5-dihydro-l,3,4-oxadiazol-2-yl)-lH-pyrazol-l- yl)pyridin-3-yl)-2,6-difluorobenzamide; 5-(l-(5-(2,6-Difluorobenzyl)amino)pyridin-2-yl)-5- (fluoromethyl)-lH-pyrazol-3-yl)-3-methyl-l,3,4-oxadiazol-2(3H)-one; Methyl 3-(l-(5-((2,6- difluorobenzyl) amino)pyridin-2-yl)-5-(trifluoromethyl)-lH-pyrazol-3-yl)-5-methyl-4,5- dihydroisoxazole-5-carboxylate; Methyl 3-(l-(5-(2-chloro-6-fluorobenzyl)amino)pyridin-2-yl)- 5-(trifluoromethyl)-lH-pyrazol-3-yl)-5-methyl-4,5-dihydroisoxazole-5-carboxylate; 2,6- Difluoro-W-(6-(3-(4-methyl-5-oxo-4,5-dihydro-l,3,4-oxadiazol-2-yl)-5-(trifluoromethyl)-lH- pyrazol-l-yl)pyridin-3-yl)benzamide; 2-Chloro-6-fluoro-N-(6-(3-(4-methyl-5-oxo-4,5-dihydro-1.3.4-oxadiazol-2-yl)-5-(trifluoromethyl)-\H-pyrazol-l -yl)pyridin-3-yl)benzamide; 2-Fluoro-6- methyl- / v-(6-(3-(4-methyl-5-oxo-4,5-dihydro-l,3,4-oxadiazol-2-yl)-5-(trifluoromethyl)-lH- pyrazol-l-yl)pyridin-3-yl)benzamide; N-(6-(5-(Difluoromethyl)-3-(4-methyl-5-oxo-4,5- dihydro-l,3,4-oxadiazol-2-yl)-lH-pyrazol-l-yl)pyridin-3-yl)-2,6-difluorobenzamide; 5-(l- (5((2,6-Difluorobenzyl) amino)pyri din-2 -yl)-5-(difluoromethyl)- lH-pyrazol-3-yl)-3-methyl-1.3.4-oxadiazol-2(3H)-one; 5-(l-(5-((2,6-Difluorobenzyl)amino) pyridin-2-yl)-3- (difluoromethyl)-lH-pyrazol-5-yl)-3-methyl-l,3,4-oxadiazol-2(3H)-one; N-(6-(3-(5,5- Dimethyl-4-oxo-4,5-dihydroisoxazol-3-yl)-5-(trifluoromethyl)-lH-pyrazol-l-yl)pyridin-3-yl)- 2,6-difluorobenzamide; 2-Chloro-N-(6-(3-(5.5-dimethyl-4-oxo-4,5-dihydroisoxazol-3-yl)-5- (trifluoromethyl)-lH-pyrazol- 1 -yl)pyridin-3-yl)-6-fluorobenzamide; 2,6-Difluoro-N-(6- (r,4’,4,-trimethyl-5’-oxo-5-(trifluoromethyl)-4’,5’-dihydro-lH,lH’-[3,3’-bipyrazol]-l- yl)pyridin-3-yl)benzamide; 2-Chloro-6-fluoro-N-(6-(l,4,4’-trimethyl-5’-oxo-5- (trifluoromethyl)-4’.5.-dihydro-lH,l’H-[3,3’-bipyrazol]-l-yl)pyridin-3-yl)benzamide; 2- Fluoro-6-methyl-N-(6-(l,4,4’-trimethyl-5’-oxo-5-(trifluoromethyl)-4’,5’-dihydro-lH,rH-[3,3’- bipyrazol]-l-yl)pyri din-3 -yl)benzamide; 2,6-Difluoro-N-(6-(3-(4-methyl-5-oxo-4,5-dihydro-1.2.4-oxadiazol-3-yl)-5-(trifluoromethyl)-lH-pyrazol-l-yl)pyridin-3-yl)benzamide; N-(6-(3-(4- Acetyl-5,5-dimethyl-4,5-dihydro-l,3,4-oxadiazol-2-yl)-5-trifluoromethyl)-lH-pyrazol-l- yl)pyridin-3-yl)-2,6-difluorobenzamide; N-(6-(3-(4,4-Dimethyl-4,5-dihydrooxazol-2-yl)-5- (trifluoromethyl)-lH-pyrazol-l-yl)pyridin-3-yl)-2,6-difluorobenzamide; 5-(l-(5-(2,6- Difluorobenzyl)amino)pyridin-2-yl)-5-(trifluoromethyl)-lH-pyrazol-3-yl)-3-methyl-l,3,4- oxadiazol-2(3H)-one; 5-(l-(5-((2-Chloro-6-fluorobenzyl)amino)pyridin-2-yl)-5- (trifluoromethyl)-lH-pyrazol-3-yl)-3-methyl-1.3.4-oxadiazol-2(3iy)-one; 1’454(2.6- Difluorobenzy l)amino)py ridin-2-y 1)- 1 ,4,4-trimethyl-5 ’ -(trifluoromethyl)- 1 H, 1’H- [3 ,3 ’ - bipyrazol]-5(4H)-one; r-(5-(2-Chloro-6-fluorobenzyl)amino)pyridin-2-yl)-l,4,4-trimethyl-5’-PATENTATTORNEY DOCKET NO. CM1740-1 WO (449399-766) (trifluoromethyl)- lH,l’H-[3,3’-bipyrazol]-5(4H)-one; 3-(l-(5-(2,6- Difluorobenzyl)amino)pyridin-2-yl)-5-(trifluoromethyl)-lH-pyrazol-3-yl)-4-methyl- 1.2.4- oxadiazol-5(4H)-one; l-(5-(l-(5-(2,6-Difluorobenzyl)amino)pyridin-2-yl)-5-(trifluoromethyl)- lH-pyrazol-3-yl)-2,2-dimethyl-l,3,4-oxadiazol-3(2H)-yl)ethanone; N-(2,6-Difluorobenzyl)-6- (3-(4,4-dimethyl-4,5-dihydrooxazol-2-yl)-5-(trifluoromethyl)-lH-pyrazol-l-yl)pyridin-3-amine; N-(6-(5-Cyclopropyl-3-(4-methyl-5-oxo-4,5-dihydro-l,3,4-oxadiazol-2-yl)-lH-pyrazol-l- yl)pyridin-3-yl)-2,6-difluorobenzamide; N-(6-(3-Cyclopropyl-5-(4-methyl-5-oxo-4,5-dihydro-1.3.4-oxadiazol-2-yl)-lH-pyrazol-l-yl)pyridin-3-yl)-2,6-difluorobenzamide; 2,6-Difluoro-N-(6- (5-methyl-3-(4-methyl-5-oxo-4,5-dihydro-l,3,4-oxadiazol-2-yl)-lH-pyrazol-l-yl)pyridin-3- yl)benzamide; 5-(l-(5-((2,6-Difluorobenzyl) amino )pyridin-2-yl)-5-methyl-lH-pyrazol-3-yl)-3- methyl-l,3,4-oxadiazol-2(3H)-one; (3-(I-(5-((2,6-Difluorobenzyl)amino)pyridin-2-yl)-5- (trifluoromethyl)-lH-pyrazol-3-yl)-5-methyl-4,5-dihydroisoxazol-5-yl)methanol; (3-(l-(5-((2- Chloro-6-fluorobenzyl)amino)pyridin-2-yl)-5-(trifluoromethyl)-lH-pyrazol-3-yl)-5-methyl-4,5- dihydroisoxazol-5-yl)methanol; Methyl 3-(l-(5-(2,6-difluorobenzamido)pyridin-2-yl)-5- (trifluoromethyl)-lH-pyrazol-3-yl)-5-methyl-4.5-dihydroisoxazole-5-carboxylate; 2.6-Difluoro- N-(6-(3-(5-(hydroxymethyl)-5-methyl-4,5-dihydroisoxazol-3-yl)-5-(trifluoromethyl)-lH- pyrazol-l-yl)pyridin-3-yl)benzamide; 3-(l-(5-(2, 6-Difluorobenzamido)pyri din-2 -yl)-5- (trifluoromethyl)-lH-pyrazol-3-yl)-5-methyl-4,5-dihydroisoxazole-5-carboxamide; 2,6- Difluoro-N-(5-(3-(4-methyl-5-oxo-4,5-dihydro-l,3,4-oxadiazol-2-yl)-5-(trifluoromethyl)-lH- pyrazol-l-yl)pyridin-2-yl)benzamide; 2-Chloro-6-fluoro-N-(5-(3-(4-methyl-5-oxo-4,5-dihydro-1.3.4-oxadiazol-2-yl)-5-(trifluoromethyl)-lH-pyrazol-l -yl)pyridin-2-yl)benzamide; 2-Fluoro-6- methyl-N-(5-(3-(4-methyl-5-oxo-4,5-dihydro-l,3,4-oxadiazol-2-yl)-5-(trifluoromethyl)-lH- pyrazol- l-yl)pyri din-2 -yl)benzami de; 2-Fluoro-N-(5-(3-(4-methyl-5-oxo-4,5-dihydro-l,3,4- oxadiazol-2-yl)-5-(trifluoromethyl)-lH-pyrazol-l-yl)pyridin-2-yl)benzamide; 2,3-Difluoro-N- (5-(3-(4-methyl-5-oxo-4,5-dihydro-l,3,4-oxadiazol-2-yl)-5-(trifluoromethyl)-lH-pyrazol-l- yl)pyridin-2-yl)benzamide; 2,4,5-Trifluoro-N-(5-(3-(4-methyl-5-oxo-4,5-dihydro-l,3,4- oxadiazol-2-yl)-5-(trifluoromethyl)-lH-pyrazol-l-yl)pyridin-2-yl)benzamide; 2,3,4-Trifluoro- N-(5-(3-(4-methyl-5-oxo-4,5-dihydro-l,3,4-oxadiazol-2-yl)-5-(trifluoromethyl)-lH-pyrazol-l- yl)pyridin-2-yl)benzamide; 2,4-Difluoro-N-(5-(3-(4-methyl-5-oxo-4,5-dihydro-l,3,4-oxadiazol- 2-yl)-5-(trifluoromethyl)-lH-pyrazol-l-yl)pyridin-2-yl)benzamide; 2,3-Dimethyl-N-(5-(3-(4- methyl-5-oxo-4,5-dihydro-l,3,4-oxadiazol-2-yl)-5-(trifluoromethyl)-lH-pyrazol-l-yl)pyridin-2- yl)benzamide; 2-Chloro-N-(5-(3-(4-methyl-5-oxo-4,5-dihydro-l,3,4-oxadiazol-2-yl)-5- (trifluoromethyl)-lH-pyrazol-l-yl)pyridin-2-yl)benzamide; 2-Methyl-N-(5-(3-(4-methyl-5-oxo- 4,5-dihydro-l,3,4-oxadiazol-2-yl)-5-(trifluoromethyl)-lH-pyrazol-l-yl)pyridin-2-yl)benzamide; 4-Ethyl-N-(5-(3-(4-methyl-5-oxo-4,5-dihydro-l,3,4-oxadiazol-2-yl)-5-(trifluoromethyl)-l / / -PATENTATTORNEY DOCKET NO. CM1740-1 WO (449399-766) pyrazol- l-yl)pyri din-2 -yl)benzami de; N-(5-(3-(4-Methyl-5-oxo-4,5-dihydro-13,4-oxadiazol-2- yl)-5-(trifluoromethyl)-lH-pyrazol-l-yl)pyri din-2 -yl)-2 -naphthamide; 5-(l -(6-((2,6- Difluorobenzyl)amino)pyridin-3-yl)-5-(trifluoromethyl)-lH-pyrazol-3-yl)-3-methyl-l,3,4- oxadiazol-2(3H)-one; 5-(l-(6-((2-Chloro-6-fluorobenzyl)amino)pyridin-3-yl)-5- (trifluoromethyl)-lH-pyrazol-3-yl)-3-methyl-l,3,4-oxadiazol-2(3H)-one; 5-(l-(6-(2-Fluoro-6- methylbenzyl)amino)pyridm-3-yl)-5-(trifluoromethyl)-lH-pyrazol-3-yl)-3-methyl-l,3,4- oxadiazol-2(3H)-one; N-(2,6-Difluorophenyl)-6-(3-(4-methyl-5-oxo-4,5-dihydro-l,3,4- oxadiazol-2-yl)-5-(trifluoromethyl)-lH-pyrazol-l-yl)nicotinamide; or N-(2-Chloro-6- fluorophenyl)-6-(3-(4-methyl-5-oxo-4,5-dihydro-l,3,4-oxadiazol-2-yl)-5-(trifluoromethyl)-lH- pyrazol-l-yl)nicotinamide. Each of these compounds is also an example of a Calcium channel inhibitor, or of a SOC inhibitor.

[0070] Disclosed herein, in some embodiments, are Calcium channel inhibitors, SOC inhibitors, or CRAC inhibitors. In some embodiments, the Calcium channel inhibitor, SOC inhibitor, or CRAC inhibitor comprises a small molecule such as a small molecule that interferes with the Calcium channel's activity’, the SOC channel's activity, or the CRAC channel’s activity. In some embodiments, the Calcium channel inhibitor, SOC inhibitor, or CRAC inhibitor comprises a polypeptide such as a mutated or nonfunctional form of a component of a Calcium channel, of a SOC channel, or of a CRAC channel that may interfere with the Calcium channel's activity, the SOC channel’s activity, or the CRAC channel’s activity.Further Forms of Compounds

[0071] The compounds described herein may in some cases exist as diastereomers, enantiomers, or other stereoisomeric forms. The compounds presented herein include all diastereomeric, enantiomeric, and epimeric forms as well as the appropriate mixtures thereof. Separation of stereoisomers may be performed by chromatography or by the forming diastereomeric and separation by recrystallization, or chromatography, or any combination thereof. (Jean Jacques, Andre Collet, Samuel H. Wilen, “Enantiomers, Racemates and Resolutions”, John Wiley And Sons, Inc., 1981, herein incorporated by reference for this disclosure). Stereoisomers may also be obtained by stereoselective synthesis.

[0072] In some situations, compounds may exist as tautomers. All tautomers are included within the formulas described herein.

[0073] The methods and compositions described herein include the use of amorphous forms as well as crystalline forms (also known as polymorphs). The compounds described herein may be in the form of pharmaceutically acceptable salts. As well, active metabolites of these compounds having the same type of activity are included in the scope of the present disclosure. In addition, the compounds described herein can exist in unsolvated as well as solvated formsPATENTATTORNEY DOCKET NO. CM1740-1 WO (449399-766) with pharmaceutically acceptable solvents such as water, ethanol, and the like. The solvated forms of the compounds presented herein are also considered to be disclosed herein.

[0074] In some embodiments, compounds described herein may be prepared as prodrugs. A “prodrug” refers to an agent that is converted into the parent drug in vivo. Prodrugs are often useful because, in some situations, they may be easier to administer than the parent drug. They may. for instance, be bioavailable by oral administration whereas the parent is not. The prodrug may also have improved solubility in pharmaceutical compositions over the parent drug. An example, without limitation, of a prodrug would be a compound described herein, which is administered as an ester (the “prodrug”) to facilitate transmittal across a cell membrane where water solubility is detrimental to mobility but which then is metabolically hydrolyzed to the carboxylic acid, the active entity, once inside the cell where water-solubility is beneficial. A further example of a prodrug might be a short peptide (polyaminoacid) bonded to an acid group where the peptide is metabolized to reveal the active moiety. In certain embodiments, upon in vivo administration, a prodrug is chemically converted to the biologically, pharmaceutically or therapeutically active form of the compound. In certain embodiments, a prodrug is enzymatically metabolized by one or more steps or processes to the biologically, pharmaceutically or therapeutically active form of the compound.

[0075] To produce a prodrug, a pharmaceutically active compound is modified such that the active compound will be regenerated upon in vivo administration. The prodrug can be designed to alter the metabolic stability or the transport characteristics of a drug, to mask side effects or toxicity, to improve the flavor of a drug or to alter other characteristics or properties of a drug. In some embodiments, by virtue of know ledge of pharmacodynamic processes and drug metabolism in vivo, once a pharmaceutically active compound is determined, prodrugs of the compound are designed, (see, for example, Nogrady (1985) Medicinal Chemistry A Biochemical Approach, Oxford University Press, New York, pages 388-392; Silverman (1992), The Organic Chemistry of Drug Design and Drug Action, Academic Press, Inc., San Diego, pages 352-401, Saulnier et al., (1994), Bioorganic and Medicinal Chemistry Letters, Vol. 4, p. 1985; Rooseboom et al.. Pharmacological Reviews, 56:53-102, 2004; Miller et al., J. Med. Chem. Vol.46. no. 24, 5097-5116, 2003; Aesop Cho, “Recent Advances in Oral Prodrug Discovery”, Annual Reports in Medicinal Chemistry, Vol. 41, 395-407, 2006).

[0076] Prodrug forms of the herein described compounds, wherein the prodrug is metabolized in vivo to produce a compound as set forth herein, are included within the scope of the claims. In some cases, some of the herein-described compounds may be a prodrug for another derivative or active compound.PATENTATTORNEY DOCKET NO. CM1740-1 WO (449399-766)

[0077] Prodrugs are often useful because, in some situations, they may be easier to administer than the parent drug. They may. for instance, be bioavailable by oral administration whereas the parent is not. The prodrug may also have improved solubility7in pharmaceutical compositions over the parent drug. Prodrugs may be designed as reversible drug derivatives, for use as modifiers to enhance drug transport to site-specific tissues. In some embodiments, the design of a prodrug increases the effective water solubility. See, e.g.. Fedorak et al., Am. J. Physiol., 269:G210-218 (1995); McLoed et al.. Gastroenterol, 106:405-413 (1994); Hochhaus et al., Biomed. Chrom., 6:283-286 (1992); J. Larsen and H. Bundgaard, Int. J. Pharmaceutics, 37, 87 (1987); J. Larsen et al., Int. J. Pharmaceutics, 47, 103 (1988); Sinkula et al., J. Pharm. Sci., 64: 181-210 (1975); T. Higuchi and V. Stella, Pro-drugs as Novel Delivery Systems, Vol. 14 of the A.C.S. Symposium Series; and Edward B. Roche, Bioreversible Carriers in Drug Design, American Pharmaceutical Association and Pergamon Press, 1987, all incorporated herein for such disclosure).

[0078] Sites on the aromatic ring portion of compounds described herein can be susceptible to various metabolic reactions, therefore incorporation of appropriate substituents on the aromatic ring structures, such as, by way of example only, halogens can reduce, minimize or eliminate this metabolic pathway.

[0079] The compounds described herein may be labeled isotopically (e.g. with a radioisotope) or by other means, including, but not limited to, the use of chromophores or fluorescent moieties, bioluminescent labels, photoactivatable or chemiluminescent labels.

[0080] Compounds described herein include isotopically-labeled compounds, which are identical to those recited in the various formulae and structures presented herein, but for the fact that one or more atoms are replaced by an atom having an atomic mass or mass number different from the atomic mass or mass number usually found in nature. Examples of isotopes that can be incorporated into the present compounds include isotopes of hydrogen, carbon, nitrogen, oxygen, fluorine and chlorine, such as, for example, 2H, 3H, 13C, 14C, 15N, 180, 170, 35S, 18F, 36C1, respectively. Certain isotopically-labeled compounds described herein, for example those into which radioactive isotopes such as 3H and 14C are incorporated, are useful in drug and / or substrate tissue distribution assays. Further, substitution with isotopes such as deuterium, i.e., 2H, can afford certain therapeutic advantages resulting from greater metabolic stability, such as, for example, increased in vivo half-life or reduced dosage requirements.

[0081] In additional or further embodiments, the compounds described herein are metabolized upon administration to an organism in need to produce a metabolite that is then used to produce a desired effect, including a desired therapeutic effect.PATENTATTORNEY DOCKET NO. CM1740-1 WO (449399-766)

[0082] Compounds described herein may be formed as, and / or used as, pharmaceutically acceptable salts. The type of pharmaceutical acceptable salts, include, but are not limited to: (1) acid addition salts, formed by reacting the free base form of the compound with a pharmaceutically acceptable: inorganic acid, such as, for example, hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, metaphosphoric acid, and the like; or with an organic acid, such as, for example, acetic acid, propionic acid, hexanoic acid, cyclopentanepropionic acid, glycolic acid, pyruvic acid, lactic acid, malonic acid, succinic acid, malic acid, maleic acid, fumaric acid, trifluoroacetic 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-hydroxy ethanesulfonic acid, benzenesulfonic acid, toluenesulfonic acid. 2-naphthalenesulfonic acid, 4-methylbicyclo-[2.2.2]oct-2-ene-l- carboxylic acid, glucoheptonic acid, 4,4’-methylenebis-(3-hydroxy-2-ene-l -carboxylic acid), 3- phenylpropionic acid, trimethylacetic acid, tertiary but l acetic acid, lauryl sulfuric acid, gluconic acid, glutamic acid, hydroxynaphthoic acid, salicylic acid, stearic acid, muconic acid, butyric acid, phenylacetic acid, phenylbutyric acid, valproic acid, and the like; (2) salts formed when an acidic proton present in the parent compound is replaced by a metal ion, e.g., an alkali metal ion (e.g. lithium, sodium, potassium), an alkaline earth ion (e.g. magnesium, or calcium), or an aluminum ion. In some cases, compounds described herein may coordinate with an organic base, such as, but not limited to, ethanolamine, diethanolamine, triethanolamine, tromethamine. N-methylglucamine. di cyclohexyl amine, tris(hydroxymethyl)methylamine. In other cases, compounds described herein may form salts with amino acids such as, but not limited to, arginine, lysine, and the like. Acceptable inorganic bases used to form salts with compounds that include an acidic proton, include, but are not limited to, aluminum hydroxide, calcium hydroxide, potassium hydroxide, sodium carbonate, sodium hydroxide, and the like.

[0083] It should be understood that a reference to a pharmaceutically acceptable salt includes the solvent addition forms or crystal forms thereof, particularly solvates or polymorphs.Solvates contain either stoichiometric or non-stoichiometric amounts of a solvent, and may be formed during the process of crystallization with pharmaceutically acceptable solvents such as water, ethanol, and the like. Hydrates are formed when the solvent is water, or alcoholates are formed when the solvent is alcohol. Solvates of compounds described herein can be conveniently prepared or formed during the processes described herein. In addition, the compounds provided herein can exist in unsolvated as well as solvated forms. In general, the solvated forms are considered equivalent to the unsolvated forms for the purposes of the compounds and methods provided herein.PATENTATTORNEY DOCKET NO. CM1740-1 WO (449399-766)

[0084] In some embodiments, compounds described herein, are in various forms, including but not limited to, amorphous forms, milled forms, injectable emulsion forms, and nano-particulate forms. In addition, compounds described herein include crystalline forms, also known as polymorphs. Polymorphs include the different crystal packing arrangements of the same elemental composition of a compound. Polymorphs usually have different X-ray diffraction patterns, melting points, density, hardness, crystal shape, optical properties, stability, and solubility. Various factors such as the recrystallization solvent, rate of crystallization, and storage temperature may cause a single crystal form to dominate.

[0085] Throughout the specification, groups and substituents thereof can be chosen to provide stable moieties and compounds.Synthesis of Compounds

[0086] In some embodiments, the synthesis of compounds described herein are accomplished using means described in the chemical literature, using the methods described herein, or by a combination thereof. In addition, solvents, temperatures and other reaction conditions presented herein may vary.

[0087] In other embodiments, the starting materials and reagents used for the synthesis of the compounds described herein are synthesized or are obtained from commercial sources, such as, but not limited to, Sigma- Aldrich, Fischer Scientific (Fischer Chemicals), and Acros Organics.

[0088] In further embodiments, the compounds described herein, and other related compounds having different substituents are synthesized using techniques and materials described herein as well as those that are recognized in the field, such as described, for example, in Fieser and Fieser’s Reagents for Organic Synthesis, Volumes 1-17 (John Wiley and Sons, 1991); Rodd’s Chemistry of Carbon Compounds, Volumes 1-5 and Suppiementals (Elsevier Science Publishers, 1989); Organic Reactions. Volumes 1-40 (John Wiley and Sons, 1991), Larock’s Comprehensive Organic Transformations (VCH Publishers Inc., 1989), March, Advanced Organic Chemistry 4th Ed., (Wiley 1992); Carey and Sundberg, Advanced Organic Chemistry 4th Ed., Vols. A and B (Plenum 2000, 2001), and Green and Wuts, Protective Groups in Organic Synthesis 3rd Ed., (Wiley 1999) (all of which are incorporated by reference for such disclosure).

[0089] The recovery rate of the subject after administration of the intracellular Calcium signaling inhibitor can be any suitable value known by one of skill in the art. The recovery' rate of the subject is also applicable to combination therapy, wherein the intracellular Calcium signaling inhibitor is administered with an effective amount of a corticosteroid or immunosuppressive drug described herein. In some embodiments, the subject has a recovery rate of greater than about 35%. In some embodiments, the subject has a recovery' rate of greaterPATENTATTORNEY DOCKET NO. CM1740-1 WO (449399-766) than about 50%. In some embodiments, the subject has a recovery rate of greater than about 75%. In some embodiments, the subject has a recovery rate of greater than about 90%. In some embodiments, the subject has a recovery rate of about 35% to about 100%. In some embodiments, the subject has a recovery rate of about 35% to about 95%. In some embodiments, the subject has a recovery' rate of about 50% to about 100%. In some embodiments, the subject has a recovery rate of about 50% to about 95%.

[0090] In some embodiments, a second dose of the intracellular Calcium signaling inhibitor is administered about 24 hours after a first dose. In some embodiments, a third dose of the intracellular Calcium signaling inhibitor is administered about 48 hours after a first dose. In some embodiments, the concentration of the first dose is greater than the concentration of the second and third dose. In some embodiments, the concentration of the first dose is the same as the concentration of the second and third dose.

[0091] The intracellular Calcium signaling inhibitor can be administered in any suitable concentration known by one of skill in the art. In some embodiments, the intracellular Calcium signaling inhibitor is administered in a concentration of about 0. 1 mg / kg to about 5 mg / kg. In some embodiments, the intracellular Calcium signaling inhibitor is administered in a concentration of about 0.5 mg / kg to about 3 mg / kg. In some embodiments, the intracellular Calcium signaling inhibitor is administered in a concentration of about 0.5 mg / kg to about 2.5 mg / kg. In some embodiments, the intracellular Calcium signaling inhibitor is administered in a concentration of about 1 mg / kg to about 2.0 mg / kg. In some embodiments, the intracellular Calcium signaling inhibitor is administered in a concentration of about 1.5 mg / kg to about 2.0 mg / kg. In some embodiments, the intracellular Calcium signaling inhibitor is administered in a concentration of about 1.6 mg / kg to about 2.0 mg / kg. In some embodiments, the first dose is administered in a concentration of about 2.0 mg / kg, and the second and third dose is administered in a concentration of about 1.6 mg / kg. In some embodiments, the concentration of the intracellular Calcium signaling inhibitor is increased or decreased when the subject’s P / F ratio similar to the P / F ratio prior to administration.

[0092] In some embodiments, the intracellular Calcium signaling inhibitor is delivered to achieve a tissue level concentration that is equal to, about, or greater than the in vitro IC50 value determined for the compound. In some embodiments the Calcium signaling inhibitor is delivered to achieve a tissue level concentration that is 1.5x. 2x, 3x, 4x, 5x, 6x, 7x, 8x, 9x, lOx, l lx, 12x, 13x, 14x, 15x. 16x, 17x, 18x, 19x, 20x, 2 lx, 22x, 23x, 24x, 25x, 26x, 27x, 28x, 29x,30x, 31x, 32x. 33x, 34x. 35x, 36x, 37x, 38x, 39x. 40x, 41x, 42x, 43x, 44x. 45x, 46x. 47x, 48x,49x, 50x, 51x, 52x, 53x, 54x, 55x, 56x, 57x, 58x, 59x, 60x, 61x, 62x, 63x, 64x, 65x, 66x, 67x,68x, 69x, 70x, 71x, 72x, 73x, 74x, 75x, 76x, 77x, 78x, 79x, 80x, 81x, 82x, 83x, 84x, 85x, 86x,PATENTATTORNEY DOCKET NO. CM1740-1 WO (449399-766) 87x, 88x, 89x, 90x, 91x. 92x, 93x, 94x, 95x, 96x, 97x, 98x, 99x, lOOx, or any non-integer multiple ranging from lx to lOOx of the in vitro IC50 value determined for the compound.

[0093] In some embodiments the Calcium signaling inhibitor is delivered to achieve a tissue level concentration that ranges from lx to lOOx, 2x to 80x, 3x to 60x, 4x to 50x, 5x to 45x, 6x to 44x, 7x to 43x, 8x to 43x, 9x to 41x, or lOx to 40x, or any non-integer within said range, of the in vitro IC50 value determined for the compound.

[0094] In some embodiments the Calcium signaling inhibitor is delivered to achieve a tissue level concentration that is IpM, 2pM, 3pM, 4pM, 5pM, 6pM, 7 M, 8pM, 9pM, lOpM, 1 IpM, 12pM, 13pM, 14pM, 15pM, 16pM, 17pM, 18pM, 19pM, 20pM, 21pM, 22pM, 23pM, 24pM, 25pM. 26pM, 27pM, 28pM, 29pM, 30pM, 31pM, 32pM, 33pM, 34pM, 35pM, 36pM. 37pM, 38pM. 39pM. 40pM, 41pM, 42pM, 43pM, 44pM. 45pM, 46pM, 47pM, 48pM, 49pM. 50pM. 51 pM, 52pM, 53pM, 54pM, 55pM, 56pM, 57pM, 58pM, 59pM, 60pM, 61 pM, 62pM, 63pM, 64pM, 65pM, 66pM, 67pM, 68pM, 69pM, 70pM, 71pM, 72pM, 73pM, 74pM, 75pM, 76pM, 77pM, 78pM, 79pM, 80pM, 81pM, 82pM, 83pM, 84pM, 85pM, 86pM, 87pM, 88pM. 89pM, 90pM. 91pM, 92pM, 93pM, 94pM, 95pM, 96pM. 97pM, 98pM, 99pM, lOOpM. or any non- integer multiple ranging from about IpM to about lOOpM.

[0095] In some embodiments the Calcium signaling inhibitor is delivered to achieve a tissue level concentration that ranges from IpM to lOOpM, 2pM to 90pM, 3pM to 80pM, 4pM to 70pM. 5pM to 60pM, 6pM to 50pM. 7pM to 40pM, 8pM to 30pM. 9pM to 20pM. or lOpM to 40pM, or any integer or non-integer within said range.

[0096] In some embodiments the Calcium signaling inhibitor is delivered to achieve a tissue level concentration that ranges from 9.5 pM to 10.5 pM, 9 pM to 11 pM, 8 pM to 12 pM, 7 pM to 13 pM, 5 pM to 15 pM, 2 pM to 20 pM or 1 pM to 50 pM, or any integer or non-integer within said range.

[0097] In one embodiment is a method for treating a patient having cytokine storm syndrome comprising administering to the patient in need a therapeutically effective amount of N-(5-(6- Chloro-2,2-difluorobenzo[d][l,3]dioxol-5-yl)pyrazin-2-yl)-2-fluoro-6-methylbenzamide. In another embodiment, the patient is administered N-(5-(6-Chloro-2.2- difluorobenzo[d][l,3]dioxol-5-yl)pyrazin-2-yl)-2-fluoro-6-methylbenzamide via intravenously. In a further embodiment is a method for inhibiting the release of multiple key cytokines comprising administering to the patient a therapeutically effective amount of N-(5-(6-Chloro- 2,2-difluorobenzo[d][l,3]dioxol-5-yl)pyrazin-2-yl)-2-fluoro-6-methylbenzamide. In a further embodiment is a method for inhibiting release of IL-2, IL-6, IL-17, and / or TNFa comprising administering an effective amount of N-(5-(6-Chloro-2,2-difluorobenzo[d][l,3]dioxol-5- yl)pyrazin-2-yl)-2-fluoro-6-methylbenzamide. In yet another embodiment is a method ofPATENTATTORNEY DOCKET NO. CM1740-1 WO (449399-766) inhibiting excessive or uncontrolled release of proinflammatory cytokines comprising administering an effective amount of N-(5-(6-Chloro-2,2-difluorobenzo[d][l,3]dioxol-5- yl)pyrazin-2-yl)-2-fluoro-6-methylbenzamide.

[0098] N-(5-(6-Chloro-2,2-difluorobenzo[d][l,3]dioxol-5-yl)pyrazin-2-yl)-2-fluoro-6- methylbenzamide (Compound 1) is an example of a composition described herein, and inhibits calcium release-activated calcium (CRAC) channels. A pharmaceutical composition comprising Compound 1 has been demonstrated to be safe and potentially efficacious in critically ill patients with acute pancreatitis. Its rapid onset may be beneficial for acute settings. It may prevent the development of acute pancreatitis in subjects presenting with accompanying systemic inflammatory response syndrome (SIRS).

[0099] Compound 1 is a potent and selective small molecule inhibitor of CRAC channels. CRAC channels are found on many cell types, including immune cells, where aberrant activation of these channels may play a key role in the pathobiology of acute and chronic inflammatory syndromes.[OOlOOJIn some embodiments, the baseline measurement is obtained by performing an assay such as an immunoassay, a colorimetric assay, or a fluorescence assay, on the sample obtained from the subject. In some embodiments, the baseline measurement is obtained by an immunoassay, a colorimetric assay, or a fluorescence assay. In some embodiments, the baseline measurement is obtained by PCR. In some embodiments, the PCR comprises RT-qPCR or RT- qPCR. For example, quantitation or confirmation of viral particles such as SARS-Cov-2 nucleic acids may be obtained using an RT-PCR assay of a nasal swab, pharyngeal swab, or respiratory tract aspirate.[001011 In some embodiments, the baseline measurement is obtained directly in or on the subject. In some embodiments, the baseline measurement is obtained with a nasal cannula. In some embodiments, the baseline measurement is obtained with pulse oximetry. In some embodiments, the baseline measurement is obtained with a thermometer. In some embodiments, the baseline measurement is obtained by making a visual inspection of the subject. In some embodiments, the baseline measurement is obtained with a medical imaging device.

[0102] Some embodiments of the methods described herein include obtaining a sample from a subject. In some embodiments, the baseline measurement is obtained from the subject prior to administration of a composition described herein. In some embodiments, the baseline measurement is obtained in a sample obtained from the subject. In some embodiments, the sample is obtained from the subject prior to administration or treatment of the subject with a composition described herein. In some embodiments, a baseline measurement is obtained in a sample obtained from the subject prior to administering the composition to the subject.PATENTATTORNEY DOCKET NO. CM1740-1 WO (449399-766)

[0103] In some embodiments, the sample comprises a fluid. In some embodiments, the sample is a fluid sample. In some embodiments, the fluid sample is bronchoalveolar lavage fluid (BAL) sample. In some embodiments, the sample comprises a nasal sample. In some embodiments, the sample comprises a pharyngeal sample. In some embodiments, the sample comprises a swab (e.g., a nasal swab or a pharyngeal swab). In some embodiments, the sample comprises an aspirate. In some embodiments, the sample comprises a respiratory tract sample (e.g., a respiratory tract aspirate). In some embodiments, the sample comprises or consists of a blood, plasma, or serum sample. In some embodiments, the sample is a blood sample. In some embodiments, the sample is a plasma sample. In some embodiments, the sample is a serum sample. In some embodiments, the sample comprises a tissue. In some embodiments, the sample is a tissue sample. In some embodiments, the sample comprises or consists of lung tissue. In some embodiments, the sample comprises or consists of one or more lung cells. The lung cells may be epithelial cells or endothelial cells. In some embodiments, the sample comprises or consists of one or more endothelial cells such as pulmonary' endothelial cells. In some embodiments, the sample comprises or consists of one or more epithelial cells such as alveolar epithelial cells.

[0104] Some embodiments of the methods described herein include obtaining the measurement from a subject. For example, the measurement may be obtained from the subject after treating the subject. In some embodiments, the CRAC inhibitor is administered to a subject at 0 hour (start of the first infusion of CRAC inhibitor) with an initial dose and a subsequent different dose may be administered at 24 hours and 48 hours after 0 hour. In some embodiments, the subsequence does of the CRAC inhibitor may be administered 72 hours after 0 hour. In some embodiments, the measurement is obtained in samples collected at aforementioned 24 hours. In some embodiments, the measurement is obtained in samples collected at aforementioned 48 hours. In some embodiments, the measurement is obtained in samples collected at aforementioned 72 hours. In some embodiments, the measurement is obtained in a second sample described herein (such as a blood, plasma, serum, or lung sample) obtained from the subject after the composition is administered to the subject. In some embodiments, the measurement is an indication that the disorder has been treated. In some embodiments, the measurement is obtained directly from the subject. In some embodiments, the measurement is obtained noninvasively, such as by using an imaging device.

[0105] In some embodiments, the Calcium channel inhibitor (e.g., Auxora) is administered at a dosage of about 0.5 mg / kg, 1.0 mg / kg, 1.5 mg / kg, 2 mg / kg, 5 mg / kg, 10 mg / kg, 15 mg / kg, 20 mg / kg, 25 mg / kg, 30 mg / kg, 35 mg / kg, 40 mg / kg, 45 mg / kg, 50 mg / kg, 55 mg / kg, 60 mg / kg, 65 mg / kg, 70 mg / kg, 75 mg / kg, 80 mg / kg, 85 mg / kg, 90 mg / kg, 95 mg / kg, 100 mg / kg, 125 mg / kg,PATENTATTORNEY DOCKET NO. CM1740-1 WO (449399-766) 150 mg / kg, 175 mg / kg, 200 mg / kg, 225 mg / kg, 250 mg / kg, or any numbers between any two forgoing values.

[0106] In some embodiments, the intracellular Calcium signaling inhibitor is delivered to achieve a tissue level concentration that is equal to, about, or greater than the in vitro IC50 value determined for the compound. In some embodiments the Calcium signaling inhibitor is delivered to achieve a tissue level concentration that is 1.5x. 2x, 3x, 4x, 5x, 6x, 7x, 8x, 9x. lOx, l lx. 12x, 13x, 14x, 15x. 16x, 17x, 18x. 19x, 20x. 2 lx, 22x, 23x. 24x, 25x. 26x, 27x. 28x, 29x,30x, 31x, 32x, 33x, 34x, 35x, 36x, 37x, 38x, 39x, 40x, 41x, 42x, 43x, 44x, 45x, 46x, 47x, 48x,49x, 50x, 5 lx, 52x, 53x, 54x, 55x, 56x, 57x, 58x, 59x, 60x, 61x, 62x, 63x, 64x, 65x, 66x, 67x,68x, 69x, 70x, 71x, 72x. 73x, 74x, 75x, 76x, 77x, 78x, 79x, 80x, 81x, 82x, 83x, 84x. 85x, 86x,87x, 88x, 89x. 90x, 91x. 92x, 93x, 94x, 95x, 96x. 97x, 98x, 99x, lOOx. or any non-integer multiple ranging from lx to l OOx of the in vitro IC50 value determined for the compound.

[0107] In some embodiments the Calcium signaling inhibitor is delivered to achieve a tissue level concentration that ranges from lx to lOOx, 2x to 80x, 3x to 60x, 4x to 50x, 5x to 45x, 6x to 44x. 7x to 43x, 8x to 43x, 9x to 4 lx, or lOx to 40x, or any non-integer within said range, of the in vitro IC50 value determined for the compound.

[0108] In some embodiments the Calcium signaling inhibitor is delivered to achieve a tissue level concentration that is IpM, 2pM, 3pM, 4pM, 5pM, 6pM, 7pM, 8pM, 9pM, lOpM, 1 IpM, 12pM. 13pM, 14pM, 15pM, 16pM, 17pM, 18pM, 19pM, 20pM, 21pM, 22pM, 23pM. 24pM, 25pM. 26pM. 27 pM, 28pM, 29pM, 30pM, 31pM. 32pM, 33pM, 34pM, 35pM, 36pM. 37pM. 38pM, 39pM, 40pM, 41 pM, 42pM, 43pM, 44pM, 45pM, 46pM, 47pM, 48pM, 49pM, 50pM, 51pM, 52pM, 53pM, 54pM, 55pM, 56pM, 57pM, 58pM, 59pM, 60pM, 61pM, 62pM, 63pM, 64pM, 65pM, 66pM, 67pM, 68pM, 69pM, 70pM, 71pM, 72pM, 73pM, 74pM, 75pM, 76pM, 77pM. 78pM, 79pM, 80pM, 81pM, 82pM, 83pM. 84pM, 85pM, 86pM, 87pM, 88pM. 89pM. 90pM, 91pM, 92pM, 93pM, 94pM, 95pM, 96pM, 97pM, 98pM, 99pM, lOOpM, or any non- integer multiple ranging from about IpM to about lOOpM.

[0109] In some embodiments the Calcium signaling inhibitor is delivered to achieve a tissue level concentration that ranges from IpM to lOOpM, 2pM to 90pM, 3pM to 80pM, 4pM to 70pM, 5pM to 60pM, 6pM to 50pM. 7pM to 40pM. 8pM to 30pM. 9pM to 20pM. or lOpM to 40pM, or any integer or non-integer within said range.

[0110] In some embodiments the Calcium signaling inhibitor is delivered to achieve a tissue level concentration that ranges from 9.5 pM to 10.5 pM, 9 pM to 11 pM, 8 pM to 12 pM, 7 pM to 13 pM, 5 pM to 15 pM, 2 pM to 20 pM or 1 pM to 50 pM, or any integer or non-integer within said range.Pharmaceutical CompositionsPATENTATTORNEY DOCKET NO. CM1740-1 WO (449399-766)

[0111] Provided herein can be pharmaceutical compositions comprising at least one of the Calcium signaling inhibitors described herein. In some cases, the pharmaceutical compositions comprise at least one of the Calcium signaling inhibitors and at least one of the compounds for treating AP disclosed herein.

[0112] Pharmaceutical compositions provided herein can be introduced as oral forms, transdermal forms, oil formulations, edible foods, food substrates, aqueous dispersions, emulsions, injectable emulsions, solutions, suspensions, elixirs, gels, syrups, aerosols, mists, powders, capsule, tablets, nanoparticles, nanoparticle suspensions, nanoparticle emulsions, lozenges, lotions, pastes, formulated sticks, balms, creams, and / or ointments.

[0113] In some embodiments, the pharmaceutical composition additionally comprises at least one of an excipient, a solubilizer, a surfactant, a disintegrant. and a buffer. In some embodiments, the pharmaceutical composition is free of pharmaceutically acceptable excipients. The term “pharmaceutically acceptable excipient”, as used herein, means one or more compatible solid or encapsulating substances, which are suitable for administration to a subject. The term "‘compatible”, as used herein, means that the components of the composition are capable of being commingled with the subject compound, and with each other, in a manner such that there is no interaction, which would substantially reduce the pharmaceutical efficacy of the composition under ordinary use situations. In some embodiments, the pharmaceutically acceptable excipient is of sufficiently high purity and sufficiently low toxicity to render them suitable for administration preferably to an animal, preferably mammal, being treated.

[0114] Some examples of substances, which can sen e as pharmaceutically acceptable excipients include: amino acids such as alanine, arginine, asparagine, aspartic acid, cysteine, glutamine, glutamic acid, glycine, histidine, isoleucine, leucine, lysine, methionine, phenylalanine, proline, serine, threonine, tryptophan, tyrosine, and valine. In some embodiments, the amino acid is arginine. In some embodiments, the amino acid is L-arginine; monosaccharides such as glucose (dextrose), arabinose, mannitol, fructose (levulose), and galactose; cellulose and its derivatives such as sodium carboxymethyl cellulose, ethyl cellulose, and methyl cellulose; solid lubricants such as talc, stearic acid, magnesium stearate and sodium stearyl fumarate; polyols such as propylene glycol, glycerin, sorbitol, mannitol, and polyethylene glycol; emulsifiers such as the polysorbates; wetting agents such as sodium lauryl sulfate, Tween®, Span, alkyl sulphates, and alkyl ethoxylate sulphates; cationic surfactants such as cetrimide. benzalkonium chloride, and cetylpyridinium chloride; diluents such as calcium carbonate, microcrystalline cellulose, calcium phosphate, starch, pregelatinized starch, sodium carbonate, mannitol, and lactose; binders such as starches (com starch and potato starch),PATENTATTORNEY DOCKET NO. CM1740-1 WO (449399-766) gelatin, sucrose hydroxypropyl cellulose (HPC), polyvinylpyrrolidone (PVP), and hydroxypropyl methyl cellulose (HPMC); disintegrants such as starch, and alginic acid; super- disintegrants such as ac-di-sol, croscarmellose sodium, sodium starch glycolate and crospovidone.

[0115] Glidants such as silicon dioxide; coloring agents such as the FD&C dyes; sweeteners and flavoring agents, such as aspartame, saccharin, menthol, peppermint, and fruit flavors; preservatives such as benzalkonium chloride, PHMB, chlorobutanol, thimerosal. phenylmercuric, acetate, phenylmercuric nitrate, parabens, and sodium benzoate; tonicity adjustors such as sodium chloride, potassium chloride, mannitol, and glycerin; antioxidants such as sodium bisulfite, acetone sodium bisulfite, sodium formaldehyde, sulfoxy late, thiourea, and EDTA; pH adjuster such as NaOH. sodium carbonate, sodium acetate. HC1, and citric acid; cryoprotectants such as sodium or potassium phosphates, citric acid, tartaric acid, gelatin, and carbohydrates such as dextrose, mannitol, and dextran; surfactants such as sodium lauryl sulfate. For example, cationic surfactants such as cetrimide (including tetradecyl trimethyl ammonium bromide with dodecyl and hexadecyl compounds), benzalkonium chloride, and cetylpyridinium chloride. Some examples of anionic surfactants are alkylsulphates, alkylethoxylate sulphates, soaps, carxylate ions, sulfate ions, and sulfonate ions. Some examples of non-ionic surfactants are polyoxyethylene derivatives, polyoxypropylene derivatives, polyol derivatives, polyol esters, polyoxyethylene esters, poloxamers, glocol, glycerol esters, sorbitan derivatives, polyethylene glycol (such as PEG-40. PEG-50, or PEG-55) and esters of fatty alcohols; organic materials such as carbohydrates, modified carbohydrates, lactose (including a-lactose, monohydrate spray dried lactose or anhydrous lactose), starch, pregelatinized starch, sucrose, mannitol, sorbital, cellulose (including powdered cellulose and microcrystalline cellulose); inorganic materials such as calcium phosphates (including anhydrous dibasic calcium phosphate, dibasic calcium phosphate or tribasic calcium phosphate); co-processed diluents; compression aids; anti-tacking agents such as silicon dioxide and talc.

[0116] In some embodiments, the pharmaceutical compositions described herein are provided in unit dosage form. As used herein, a “unit dosage form’?is a composition containing an amount of the at least one of the Calcium signaling inhibitors and / or the at least one of the compounds for treating AP that is suitable for administration to a subject in a single dose, according to good medical practice. The preparation of a single or unit dosage form however, does not imply that the dosage form is administered once per day or once per course of therapy. Such dosage forms are contemplated to be administered once, twice, thrice or more per day and may be administered as infusion over a period of time (e.g., from about 30 minutes to about 2-6PATENTATTORNEY DOCKET NO. CM1740-1 WO (449399-766) hours), or administered as a continuous infusion, and may be given more than once during a course of therapy, though a single administration is not specifically excluded.Certain Terminology

[0117] Unless defined otherw ise, all technical and scientific terms used herein have the same meaning as is commonly understood to which the claimed subject matter pertains. In the event that there are a plurality of definitions for terms herein, those in this section prevail. Where reference is made to a URL or other such identifier or address, it is understood that such identifiers can change and particular information on the internet can come and go, but equivalent information can be found by searching the internet. Reference thereto evidences the availability and public dissemination of such information.

[0118] It is to be understood that the foregoing general description and the following detailed description are exemplary and explanatory only and are not restrictive of any subject matter claimed. In this application, the use of the singular includes the plural unless specifically stated otherwise. It must be noted that, as used in the specification and the appended claims, the singular forms “a." '’an” and ‘“the” include plural referents unless the context clearly dictates otherwise. In this application, the use of “or” means “and / or” unless stated otherwise.Furthermore, use of the term “including” as well as other forms, such as “‘include”, “includes,” and “included,” is not limiting.

[0119] The section headings used herein are for organizational purposes only and are not to be construed as limiting the subject matter described.

[0120] Defmition of standard chemistry terms may be found in reference works, including but not limited to, Carey and Sundberg “Advanced Organic Chemistry74th Ed.” Vols. A (2000) and B (2001), Plenum Press, New York. Unless otherwise indicated, conventional methods of mass spectroscopy, NMR, HPLC. protein chemistry, biochemistry, recombinant DNA techniques and pharmacology.

[0121] Unless specific definitions are provided, the nomenclature employed in connection with, and the laboratory procedures and techniques of, analytical chemistry7, synthetic organic chemistry, and medicinal and pharmaceutical chemistry7described herein are those recognized in the field. Standard techniques can be used for chemical syntheses, chemical analyses, pharmaceutical preparation, formulation, and delivery, and treatment of patients. Standard techniques can be used for recombinant DNA, oligonucleotide synthesis, and tissue culture and transformation (e.g., electroporation, lipofection). Reactions and purification techniques can be performed e.g., using kits of manufacturer's specifications or as commonly accomplished in the art or as described herein. The foregoing techniques and procedures can be generally performedPATENTATTORNEY DOCKET NO. CM1740-1 WO (449399-766) of conventional methods and as described in various general and more specific references that are cited and discussed throughout the present specification.

[0122] It is to be understood that the methods and compositions described herein are not limited to the particular methodology, protocols, cell lines, constructs, and reagents described herein and as such may vary. It is also to be understood that the terminology used herein is for the purpose of describing particular embodiments only, and is not intended to limit the scope of the methods, compounds, compositions described herein.

[0123] The terms “kit” and “article of manufacture” are used as synonyms.

[0124] The term “subject” or “patient” encompasses mammals and non-mammals. Examples of mammals include, but are not limited to, any member of the Mammalian class: humans, nonhuman primates such as chimpanzees, and other apes and monkey species; farm animals such as cattle, horses, sheep, goats, swine; domestic animals such as rabbits, dogs, and cats; laboratory animals including rodents, such as rats, mice and guinea pigs, and the like. Examples of nonmammals include, but are not limited to, birds, fish and the like. In one embodiment of the methods and compositions provided herein, the mammal is a human.

[0125] The terms “treat,” “treating” or “treatment,” as used herein, include alleviating, abating or ameliorating a disease or condition symptoms, preventing additional symptoms, ameliorating or preventing the underlying causes of symptoms, inhibiting the disease or condition, e.g., arresting the development of the disease or condition, relieving the disease or condition, causing regression of the disease or condition, relieving a condition caused by the disease or condition, or stopping the symptoms of the disease or condition either prophylactically and / or therapeutically.As used herein, the term “target protein” refers to a protein or a portion of a protein capable of being bound by, or interacting with a compound described herein, such as a compound with a structure from the group of Compound A. In certain embodiments, a target protein is a STIM protein. In certain embodiments, a target protein is an Orai protein.

[0126] As used herein, “STIM protein” includes but is not limited to, mammalian STIM-1, such as human and rodent (e.g., mouse) STIM-1, Drosophila melanogaster D-STIM. C. elegans C-ST1M, Anopheles gambiae STIM and mammalian ST1M-2, such as human and rodent (e.g., mouse) STIM-2. (see paragraphs

[0211] through

[0270] of US 2007 / 0031814, as well as Table 3 of US 2007 / 0031814, herein incorporated by reference) As described herein, such proteins have been identified as being involved in, participating in and / or providing for store-operated calcium entry or modulation thereof, cytoplasmic calcium buffering and / or modulation of calcium levels in or movement of calcium into, within or out of intracellular calcium stores (e.g., endoplasmic reticulum).PATENTATTORNEY DOCKET NO. CM1740-1 WO (449399-766)

[0127] As used herein, an “Orai protein’" includes Orail (as described in WO 07 / 081804), Orai2 (as described in WO 07 / 081804). or Orai3 (as described in WO 07 / 081804). Orail nucleic acid sequence corresponds to GenBank accession number NM_032790, Orai2 nucleic acid sequence corresponds to GenBank accession number BC069270 and Orai3 nucleic acid sequence corresponds to GenBank accession number NM_152288. As used herein, Orai refers to any one of the Orai genes, e.g., Orail, Orai2. Orai3 (see Table I of WO 07 / 081804). As described herein, such proteins have been identified as being involved in, participating in and / or providing for store-operated calcium entry or modulation thereof, cytoplasmic calcium buffering and / or modulation of calcium levels in or movement of calcium into, within or out of intracellular calcium stores (e.g., endoplasmic reticulum).

[0128] The term “fragment” or “derivative” when referring to a protein (e.g. STIM. Orai) means proteins or polypeptides which retain essentially the same biological function or activity in at least one assay as the native protein(s). For example, the fragments or derivatives of the referenced protein maintains at least about 50% of the activity' of the native proteins, at least 75%, at least about 95% of the activity of the native proteins, as determined e.g. by a calcium influx assay.

[0129] As used herein, amelioration of the symptoms of a particular disease, disorder or condition by administration of a particular compound or pharmaceutical composition refers to any lessening of severity, delay in onset, slowing of progression, or shortening of duration, whether permanent or temporary, lasting or transient that can be attributed to or associated with administration of the compound or composition.

[0130] The term “modulate,” as used herein, means to interact with a target protein either directly or indirectly so as to alter the activity of the target protein, including, by w ay of example only, to inhibit the activity of the target, or to limit or reduce the activity of the target.

[0131] As used herein, the term “modulator” refers to a compound that alters an activity' of a target. For example, a modulator can cause an increase or decrease in the magnitude of a certain activity' of a target compared to the magnitude of the activity in the absence of the modulator. In certain embodiments, a modulator is an inhibitor, which decreases the magnitude of one or more activities of a target. In certain embodiments, an inhibitor completely prevents one or more activities of a target.

[0132] As used herein, “modulation” with reference to intracellular calcium refers to any alteration or adjustment in intracellular calcium including but not limited to alteration of calcium concentration in the cytoplasm and / or intracellular calcium storage organelles, e.g., endoplasmic reticulum, and alteration of the kinetics of calcium fluxes into, out of and within cells. In aspect, modulation refers to reduction.PATENTATTORNEY DOCKET NO. CM1740-1 WO (449399-766)

[0133] As used herein, the term "target activity” refers to a biological activity capable of being modulated by a modulator. Certain exemplary target activities include, but are not limited to, binding affinity, signal transduction, enzymatic activity, tumor growth, inflammation or inflammation-related processes, and amelioration of one or more symptoms associated with a disease or condition.

[0134] The terms “inhibits”, “inhibiting”, or “inhibitor” of SOC channel activity or CRAC channel activity, as used herein, refer to inhibition of store operated calcium channel activity or calcium release activated calcium channel activity.

[0135] The term “acceptable” with respect to a formulation, composition or ingredient, as used herein, means having no persistent detrimental effect on the general health of the subject being treated.

[0136] The term “pharmaceutically acceptable,” as used herein, refers a material, such as a carrier, diluent, or formulation, which does not abrogate the biological activity or properties of the compound, and is relatively nontoxic, i.e., the material may be administered to an individual without causing undesirable biological effects or interacting in a deleterious manner with any of the components of the composition in which it is contained.

[0137] The term “pharmaceutical combination” as used herein, means a product that results from the mixing or combining of more than one active ingredient and includes both fixed and non-fixed combinations of the active ingredients. The term “fixed combination” means that one active ingredient, e.g. a compound with a structure from the group of Compound A and a coagent, are administered to a patient as separate entities either simultaneously, concurrently or sequentially with no specific intervening time limits, wherein such administration provides effective levels of the two compounds in the body of the patient. The latter also applies to cocktail therapy, e.g. the administration of three or more active ingredients.

[0138] The term “pharmaceutical composition” refers to a mixture of a compound with a structure from the group of Compound A, described herein with other chemical components, such as carriers, stabilizers, diluents, surfactants, dispersing agents, suspending agents, thickening agents, and / or excipients. The pharmaceutical composition facilitates administration of the compound to an organism. Multiple techniques of administering a compound exist in the art including, but not limited to: intravenous, oral, aerosol, parenteral, ophthalmic, subcutaneous, intramuscular, pulmonary and topical administration.

[0139] The terms “effective amount” or “therapeutically effective amount,” as used herein, refer to a sufficient amount of an agent or a compound being administered which will relieve to some extent one or more of the symptoms of the disease or condition being treated. The result can be reduction and / or alleviation of the signs, symptoms, or causes of a disease, or any otherPATENTATTORNEY DOCKET NO. CM1740-1 WO (449399-766) desired alteration of a biological system. For example, an “effective amount'’ for therapeutic uses is the amount of the composition that includes a compound with a structure from the group of Compound A, required to provide a clinically significant decrease in disease symptoms. An appropriate “effective” amount in any individual case may be determined using techniques, such as a dose escalation study.

[0140] The terms “enhance” or “enhancing,” as used herein, means to increase or prolong either in potency or duration a desired effect. Thus, in regard to enhancing the effect of therapeutic agents, the term “enhancing” refers to the ability to increase or prolong, either in potency or duration, the effect of other therapeutic agents on a system. An “enhancing-effective amount,” as used herein, refers to an amount adequate to enhance the effect of another therapeutic agent in a desired system.

[0141] The terms “co-administration” or the like, as used herein, are meant to encompass administration of the selected therapeutic agents to a single patient, and are intended to include treatment regimens in which the agents are administered by the same or different route of administration or at the same or different time.

[0142] The term “carrier,” as used herein, refers to relatively nontoxic chemical compounds or agents that facilitate the incorporation of a compound into cells or tissues.

[0143] The term “diluent” refers to chemical compounds that are used to dilute the compound of interest prior to delivery. Diluents can also be used to stabilize compounds because they can provide a more stable environment. Salts dissolved in buffered solutions (which also can provide pH control or maintenance) are utilized as diluents in the art, including, but not limited to a phosphate buffered saline solution.[00144JA “metabolite” of a compound disclosed herein is a derivative of that compound that is formed when the compound is metabolized. The term “active metabolite” refers to a biologically active derivative of a compound that is formed when the compound is metabolized. The term “metabolized,” as used herein, refers to the sum of the processes (including, but not limited to, hydrolysis reactions and reactions catalyzed by enzymes) by which a particular substance is changed by an organism. Thus, enzymes may produce specific structural alterations to a compound. For example, cytochrome P450 catalyzes a variety of oxidative and reductive reactions while uridine diphosphate glucuronyltransferases catalyze the transfer of an activated glucuronic-acid molecule to aromatic alcohols, aliphatic alcohols, carboxylic acids, amines and free sulphydryl groups. Further information on metabolism may be obtained from The Pharmacological Basis of Therapeutics. 9th Edition, McGraw-Hill (1996). Metabolites of the compounds disclosed herein can be identified either by administration of compounds to a hostPATENTATTORNEY DOCKET NO. CM1740-1 WO (449399-766) and analysis of tissue samples from the host, or by incubation of compounds with hepatic cells in vitro and analysis of the resulting compounds.|00145|”Bioavailability" refers to the percentage of the weight of the compound disclosed herein (e.g. a compound from the group of Compound A) that is delivered into the general circulation of the animal or human being studied. The total exposure (AUC(0- »)) of a drug when administered intravenously is usually defined as 100% bioavailable (F%). “Oral bioavailability'’ refers to the extent to which a compound disclosed herein, is absorbed into the general circulation when the pharmaceutical composition is taken orally as compared to intravenous injection.

[0146] “Blood plasma concentration’’ refers to the concentration of a compound with a structure from the group of Compound A, in the plasma component of blood of a subject. It is understood that the plasma concentration of compounds described herein may vary significantly between subjects, due to variability with respect to metabolism and / or possible interactions with other therapeutic agents. In accordance with one embodiment disclosed herein, the blood plasma concentration of the compounds disclosed herein may vary from subject to subject. Likewise, values such as maximum plasma concentration (Cmax) or time to reach maximum plasma concentration (Tmax), or total area under the plasma concentration time curve (AUC(0- oo)) may vary from subject to subject. Due to this variability, the amount necessary' to constitute “a therapeutically effective amount’’ of a compound may vary from subject to subject.

[0147] As used herein, “calcium homeostasis” refers to the maintenance of an overall balance in intracellular calcium levels and movements, including calcium signaling, within a cell.

[0148] As used herein, “intracellular calcium” refers to calcium located in a cell without specification of a particular cellular location. In contrast, “cytosolic” or “cytoplasmic” with reference to calcium refers to calcium located in the cell cytoplasm.

[0149] As used herein, an effect on intracellular calcium is any alteration of any aspect of intracellular calcium, including but not limited to, an alteration in intracellular calcium levels and location and movement of calcium into, out of or within a cell or intracellular calcium store or organelle. For example, an effect on intracellular calcium can be an alteration of the properties, such as, for example, the kinetics, sensitivities, rate, amplitude, and electrophysiological characteristics, of calcium flux or movement that occurs in a cell or portion thereof. An effect on intracellular calcium can be an alteration in any intracellular calcium- modulating process, including, store-operated calcium entry', cytosolic calcium buffering, and calcium levels in or movement of calcium into, out of or within an intracellular calcium store. Any of these aspects can be assessed in a variety of ways including, but not limited to, evaluation of calcium or other ion (particularly cation) levels, movement of calcium or other ionPATENTATTORNEY DOCKET NO. CM1740-1 WO (449399-766) (particularly cation), fluctuations in calcium or other ion (particularly cation) levels, kinetics of calcium or other ion (particularly cation) fluxes and / or transport of calcium or other ion (particularly cation) through a membrane. An alteration can be any such change that is statistically significant. Thus, for example if intracellular calcium in a test cell and a control cell is said to differ, such difference can be a statistically significant difference.

[0150] As used herein, "‘involved in" with respect to the relationship between a protein and an aspect of intracellular calcium or intracellular calcium regulation means that when expression or activity of the protein in a cell is reduced, altered or eliminated, there is a concomitant or associated reduction, alteration or elimination of one or more aspects of intracellular calcium or intracellular calcium regulation. Such an alteration or reduction in expression or activity can occur by virtue of an alteration of expression of a gene encoding the protein or by altering the levels of the protein. A protein involved in an aspect of intracellular calcium, such as, for example, store-operated calcium entry, thus, can be one that provides for or participates in an aspect of intracellular calcium or intracellular calcium regulation. For example, a protein that provides for store-operated calcium entry can be a STIM protein and / or an Orai protein.

[0151] As used herein, a protein that is a component of a calcium channel is a protein that participates in multi-protein complex that forms the channel.

[0152] As used herein, “basal” or “resting” with reference to cytosolic calcium levels refers to the concentration of calcium in the cytoplasm of a cell, such as, for example, an unstimulated cell, that has not been subjected to a condition that results in movement of calcium into or out of the cell or within the cell. The basal or resting cytosolic calcium level can be the concentration of free calcium (i.e., calcium that is not bound to a cellular calcium-binding substance) in the cytoplasm of a cell, such as, for example, an unstimulated cell, that has not been subjected to a condition that results in movement of calcium into or out of the cell.

[0153] As used herein, “movement” with respect to ions, including cations, e.g., calcium, refers to movement or relocation, such as for example flux, of ions into, out of, or within a cell. Thus, movement of ions can be, for example, movement of ions from the extracellular medium into a cell, from within a cell to the extracellular medium, from within an intracellular organelle or storage site to the cytosol, from the cytosol into an intracellular organelle or storage site, from one intracellular organelle or storage site to another intracellular organelle or storage site, from the extracellular medium into an intracellular organelle or storage site, from an intracellular organelle or storage site to the extracellular medium and from one location to another within the cell cytoplasm.

[0154] As used herein, “cation entry” or “calcium entry” into a cell refers to entry of cations, such as calcium, into an intracellular location, such as the cytoplasm of a cell or into the lumenPATENTATTORNEY DOCKET NO. CM1740-1 WO (449399-766) of an intracellular organelle or storage site. Thus, cation entry' can be, for example, the movement of cations into the cell cytoplasm from the extracellular medium or from an intracellular organelle or storage site, or the movement of cations into an intracellular organelle or storage site from the cytoplasm or extracellular medium. Movement of calcium into the cytoplasm from an intracellular organelle or storage site is also referred to as “calcium release” from the organelle or storage site.

[0155] As used herein, “protein that modulates intracellular calcium” refers to any cellular protein that is involved in regulating, controlling and / or altering intracellular calcium. For example, such a protein can be involved in altering or adjusting intracellular calcium in a number of ways, including, but not limited to, through the maintenance of resting or basal cytoplasmic calcium levels, or through involvement in a cellular response to a signal that is transmitted in a cell through a mechanism that includes a deviation in intracellular calcium from resting or basal states. In the context of a “protein that modulates intracellular calcium,” a “cellular” protein is one that is associated with a cell, such as, for example, a cytoplasmic protein, a plasma membrane-associated protein or an intracellular membrane protein. Proteins that modulate intracellular calcium include, but are not limited to, ion transport proteins, calcium-binding proteins and regulatory' proteins that regulate ion transport proteins.

[0156] As used herein, “cell response” refers to any cellular response that results from ion movement into or out of a cell or within a cell. The cell response may be associated with any cellular activity that is dependent, at least in part, on ions such as, for example, calcium. Such activities may include, for example, cellular activation, gene expression, endocytosis, exocytosis, cellular trafficking and apoptotic cell death.

[0157] As used herein, “immune cells” include cells of the immune system and cells that perform a function or activity in an immune response, such as, but not limited to, T-cells, B- cells, lymphocytes, macrophages, dendritic cells, neutrophils, eosinophils, basophils, mast cells, plasma cells, white blood cells, antigen presenting cells and natural killer cells.

[0158] As used herein, “cytokine” refers to small soluble proteins secreted by cells that can alter the behavior or properties of the secreting cell or another cell. Cytokines bind to cytokine receptors and trigger a behavior or property within the cell, for example, cell proliferation, death or differentiation. Exemplary cytokines include, but are not limited to, interleukins (e g., IL-2, IL-3, IL-4, IL-5, IL-6, IL-7, IL-8, IL-9, IL-10, IL-11, IL-12, IL-13, IL-15, IL-16, IL-17, IL-18, IL-la, IL-ip, and IL-1 RA), granulocyte colony stimulating factor (G-CSF), granulocytemacrophage colony stimulating factor (GM-CSF), oncostatin M, erythropoietin, leukemia inhibitory factor (LIF), interferons, B7.1 (also known as CD80), B7.2 (also known as B70,PATENTATTORNEY DOCKET NO. CM1740-1 WO (449399-766)CD86), TNF family members (TNF-a, TNF-P, LT-P, CD40 ligand, Fas ligand, CD27 ligand, CD30 ligand, 4-1BBL, Trail), and MIF.

[0159] “Store operated calcium entry” or “SOCE” refers to the mechanism by which release of calcium ions from intracellular stores is coordinated with ion influx across the plasma membrane.

[0160] “Selective inhibitor of SOC channel activity” means that the inhibitor is selective for SOC channels and does not substantially affect the activity of other types of ion channels.

[0161] “Selective inhibitor of CRAC channel activity” means that the inhibitor is selective for CRAC channels and does not substantially affect the activity7of other types of ion channels and / or other SOC channels.

[0162] As used herein, the term "calcium” may be used to refer to the element or to the divalent cation Ca2+.

[0163] While preferred embodiments of the present invention have been show n and described herein, it will be obvious to those skilled in the art that such embodiments are provided by w ay of example only. Numerous variations, changes, and substitutions will now occur to those skilled in the art without departing from the invention. It should be understood that various alternatives to the embodiments of the invention described herein may be employed in practicing the invention. It is intended that the follow ing claims define the scope of the invention and that methods and structures w ithin the scope of these claims and their equivalents be covered thereby.EXAMPLESExample 1Description of CARPO Trial Design

[0164] The Phase 2b CARPO trial was an international, randomized, double-blind, placebo- controlled, dose-ranging trial intended to establish Auxora's dose-response and efficacy in AP with accompanying SIRS, to assess the time to medically indicated discharge in responders to early tolerance of solid food intake versus non-responders, and to assess the safety and tolerability of varying doses of Auxora in AP and accompanying SIRS.

[0165] The trial reached its target enrollment of 216. Patients were randomized into four groups to receive either high 2.0 mg / kg dose (n=53), medium 1.0 mg / kg dose (n=56), or low 0.5 mg / kg dose (n=52) of Auxora or a matched dose of placebo (n=53) intravenously every 24 hours for a total of three doses. Approximately 216 patients are randomized 1 : 1 : 1 : 1 into one of 4 groups using a computer generated randomization scheme accessed through an interactive voice / web response system (IXRS). Randomization are first stratified by gender (male or female) and then by risk for organ failure in the gender subgroups (higher or low er). Higher risk for organ failurePATENTATTORNEY DOCKET NO. CM1740-1 WO (449399-766) is defined by the presence of both an elevated hematocrit (HCT >44% for men or >40% for women) and hypoxemia (imputed PaO2 / FiO2 <360). Lower risk for organ failure is defined by the absence of either or both an elevated hematocrit and hypoxemia (FIG. 8). The PaO2 / FiO2 are determined using an arterial blood gas or imputed using pulse oximetry. Treatment and observation of patients continued for 30 days. CT scans to evaluate pancreatic inflammation and necrosis were performed at study entry and at 30 days. Patients were stratified by baseline hematocrit, a biomarker for inflammation severity, and were well-matched for all baseline characteristics with the exception that the placebo group had approximately 12% lower proportion of hyper-inflamed patients than the study overall.[ 001661 E / / zc«cy & Safety Data[00167JCARPO endpoints include median time to solid food tolerance (up to a 50 hour reduction for Auxora patients compared to placebo),severe organ failure including both respiratory and renal failure (up to 61.7% relative risk reduction for Auxora patients compared to placebo), solid food tolerance at 48 hours, 72 hours, and 96 hours after the Start of First Infusion of Study Drug (SFISD) and at discharge time to medically indicated discharge, Length of stay in the hospital, length of stay in the ICU for patients admitted to the ICU, rehospitalization for AP by Day 30, change in severity of AP by CTSI score from screening to Day 30, development of pancreatic necrosis >30% and >50%, the persistence of SIRS >48 hours after the SFISD, incidence, severity, and duration of organ failure, mortality by Day 30, change in pain score and opioid use. The data includes an integration of key endpoints of the trial into a win ratio analysis, providing a comprehensive evaluation of Auxora for the treatment of AP with SIRS.

[0168] All patients would have received a Screening CECT of the abdomen / pancreas before being randomized into the study. CECTs performed as standard of care (SOC) may be used as the Screening CECT but must have been performed in the 24 hours before Consent or after Consent and before Randomization (Section 8.12.12). The SFISD should occur within 8 hours of the patient or LAR providing informed consent. Patients randomized to Group 1 receive 2.0 mg / kg of Auxora intravenously every 24 hours (±1 hour) for a total of three doses. Patients randomized to Group 2 receive 1.0 mg / kg of Auxora intravenously every 24 hours (±1 hour) for a total of three doses. Patients randomized to Group 3 receive 0.5 mg / kg of Auxora intravenously every 24 hours (±1 hour) for a total of three doses. Patients randomized to Group 4 receive emulsion without any active pharmaceutical ingredient. Patients in Group 4 receive one of three randomly assigned dose volumes. 1.25 mL / kg, 0.625 mL / kg. or 0.3125 mL / kg, which are administered intravenously every 24 hours (±1 hour) for a total of three doses.(Section 5.3) The dosing are based on actual body weight obtained at the time of hospitalizationPATENTATTORNEY DOCKET NO. CM1740-1 WO (449399-766) or screening for the study. As described in the pharmacy manual, the upper limit of the volume of Auxora and volume of Placebo that is administered is 156.25 mL. The sponsor, investigators, pharmacists, and patients is blinded to the assigned group. In the event of a medical emergency, investigators are able to receive the treatment assignment if required to provide optimal care of the patient.

[0169] For all 4 groups, a study physician or appropriately trained delegate performed studyspecific assessments at screening, at the baseline assessment, immediately prior to the SFISD, and then every 24 hours until 240 hours after the SFISD, or until discharge if earlier. If patients remain hospitalized at Day 12, assessments is then performed every' 48 hours starting on Day 12 until Day 28, or until discharge if earlier. Patients discharged from the hospital before Day 25 are to return at Day 30 (+5 days) to perform the Day 30 assessments. If patients are discharged on Days 25-29, the Day 30 assessments may be performed prior to discharge.

[0170] Patients are to receive another CECT of the abdomen / pancreas at the Day 30 (±5 days) visit. All CECTs performed as SOC after randomization and before the Day 30 CECT are also captured. A blinded central reader reads the Screening, Day 30, and any SOC CECTs obtained between randomization and the Day 30 visit.

[0171] Patients will complete the modified American Neurogastroenterology' and Motility' Society' (ANMS) Gastrointestinal Cardinal Symptom Index Daily Diary' (mGCSI-DD) worksheet at the baseline assessment, at 96 hours, 168 hours, Day 14 and Day 21 (for patients who remain hospitalized on these days), on the day of discharge, and daily at bedtime after discharge until the Day 30 visit. Patients who are discharged on Days 25-29 are not to complete the mGCSI worksheet after discharge.

[0172] It is recommended that all patients randomized in the study should receive care consistent with the 2018 American Gastroenterological Association (AGA) Institute Technical Review of the Initial Medical Management of Acute Pancreatitis. Patients should receive local SOC for the management of other medical conditions.

[0173] In patients with AP, the AGA strongly recommends early oral feeding (within 24 hours) rather than keeping the patient nil per mouth (Nil per Os, NPO). Patients randomized into the study, therefore, are offered a low fat, >500-calorie solid meal at each mealtime after the infusion of the first dose of study drug if alert and not on mechanical ventilation, or if not NPO for a planned surgery / medical procedure, or if not NPO because of an acute medical condition. If the patient does not wish to eat the solid meal when offered or is unable to tolerate the solid meal, they should then be offered a liquid meal. The same approach should occur at each subsequent mealtime until discharge. When patients eat a solid meal, it should be recorded ifPATENTATTORNEY DOCKET NO. CM1740-1 WO (449399-766) they ate >50% of the meal and if they either vomited or experienced an increase in abdominal pain in the two hours after the meal.

[0174] It is also recommended that all patients randomized in the study should not be discharged from the hospital until solid food is tolerated, abdominal pain has resolved or been adequately controlled, and there is no clinical evidence of infection necessitating continued hospitalization. Tolerating solid food is defined as eating >50% of a low fat, >500-calorie solid meal without an increase in abdominal pain or vomiting. If the patient is not tolerating either solid or liquid meals, tube feedings should be considered.

[0175] All protocol required laboratory testing, except biomarker and PK samples, are performed at the local laboratory. Results from the biomarkers and PK blood samples collected as part of the protocol and being tested at a central lab are not be available to assist the PI or treating physician in managing the patient. CalciMedica may submit amendments to the protocol to modify the planned doses, the dosingschedule, the infusion time, the number of sites in the study, the total number of patientsrandomized in the study, the number of patients randomized in each group, and the number of groups in the study.• New-onset severe respiratory failure occurred in 0% of high dose patients, 0% of medium dose patients, 8.3% of low dose patients, and 8.5% of placebo patients, representing a 100% (p = 0.0027) relative risk reduction when combined high and medium dosed patients were compared to combined low dose and placebo patients.• New-onset persistent respiratory failure developed in 8% of high dose patients, 1.9% of medium dose patients, 10.4% of low dose patients, and 17% of placebo patients, demonstrating a 64.2% (p = 0.0476) relative risk reduction when combined high and medium dosed patients were compared to combined low dose and placebo patients.• New-onset necrotizing pancreatitis, measured on day 30, occurred in 29.7% of high dose patients, 40.8% of medium dose patients, 38.6% of low dose patients, and 37.0% of placebo patients, representing an absolute reduction of 7.3% and a relative risk reduction of approximately 20% for high dose patients compared with placebo patients.• Time to medically indicated discharge was 89.0 hours for high dose patients, 104.5 hours for medium dose patients, 109.5 hours for low dose patients, and 104.0 hours for placebo patients, demonstrating a reduction of 15.0 hours for high dose patients when compared to placebo.• Long hospital stays were reduced in combined high and medium dose patients compared to combined low dose and placebo patients with 18% vs 31% of patients in the hospital longerPATENTATTORNEY DOCKET NO. CM1740-1 WO (449399-766) than 7 days, 5% vs 10% longer than 14 days, and 1% vs 6% longer than 21 days, respectively. There were no high dose patients who stayed in the hospital longer than 21 days.

[0176] When key endpoints — mortality, new-onset severe respiratory failure, new-onset necrotizing pancreatitis, and time to medically indicated discharge — were integrated into a win ratio analysis, the high dose of Auxora outperformed placebo by a similar margin across all endpoints and delivered a win ratio of 1.640 (p = 0.0372).Drug Materials and Management

[0177] Auxora is to be administered as an IV infusion and is supplied as a translucent, white to yellowish, sterile, non-pyrogenic emulsion containing 1.6 mg / mL of the active pharmaceutical ingredient CM4620. Auxora is supplied as an 80 mL fill in a 100 mL single-use glass vial. Auxora contains egg phospholipids, medium chain triglycerides, glycerin, edetate disodium salt dehydrate (EDTA), sodium hydroxide (as needed to adjust pH), and sterile water for injection (Table 1).

[0178] Table 1. Auxora Product Information

[0179] Matching Placebo is to be administered as an IV infusion and is supplied as a translucent, white to yellowish, sterile, non-pyrogenic emulsion carrier containing no active pharmaceutical ingredient. Placebo is supplied as an 80 mL fill in a 100 mL single-use vial. Placebo contains the same ingredients as Auxora except that it does not contain CM4620.

[0180] Auxora and Placebo must be maintained in a secure location with refrigerated temperature conditions of 2 to 8°C (36 to 46°F). Precaution should be taken to ensure that the Auxora and Placebo do not freeze. Temperature logs should be maintained and available during monitor review. When a temperature is noted outside the range of 2°C to 8°C lasting for 24 hours or more, or if the temperature exceeds 20°C (68°F), or is below 0°C (32°F), CalciMedica or its designee must be notified as soon as possible. The stability of Auxora and Placebo has been demonstrated to 24 months and is being evaluated for longer periods in ongoing studies.PATENTATTORNEY DOCKET NO. CM1740-1 WO (449399-766) The Pharmacy Manual will also contain details regarding Auxora and Placebo storage in addition to procedures for managing and reporting temperature excursions.

[0181] The study pharmacist and / or designee will be responsible for the preparation and dispensation of Auxora and Placebo. Prior to administration, Auxora and Placebo both must be transferred to a sterile container a using sterile technique. Specific details on how to prepare Auxora and Placebo, as well as the specific components that will be used to administer both Auxora and Placebo, will be provided in the Pharmacy Manual. The Pharmacy Manual will also contain tables detailing the selected dose level and volume of administration of Auxora and Placebo.

[0182] Both Auxora and Placebo will be administered intravenously over 4 hours at a constant rate of infusion. Auxora will be administered every 24 hours (±1 hours) for three consecutive days for a total of 3 doses in all patients; randomized patients will receive either three additional doses or Auxora or Placebo. The dose and volume of Auxora, and the volume of Placebo, that will be administered will be calculated using the patient weight obtained at the time of hospitalization or during screening. A line into a peripheral or central vein may be used for the infusion. The peripheral IV should be 20 gauge in size or larger. The peripheral IV or central line port should be dedicated when administering Auxora or Placebo other than 0.9% normal saline. Auxora and Placebo are compatible with 0.9% normal saline. The IV tubing used to administer Auxora and Placebo must contain a 1.2 micron filter. The Pharmacy Manual will contain a recommended procedure to prime the IV tubing and flush the tubing, but this may be adapted to local nursing standards. 0.9% normal saline may be used to clear the line to ensure that the volume to be infused (VTBI) is completely administered. If the administration of Auxora or Placebo is stopped because of a technical reason, such as failure of the IV site, or IV pump malfunction, the administration of Auxora or Placebo should be resumed when the technical reason is resolved, and continued at the same rate until the infusion is completed. The total amount of time for the start of infusion to end of infusion of Auxora or Placebo should be recorded.

[0183] The study may be modified at any time the administered doses of Auxora or volumes of Placebo, the days of infusion, the timing of the infusion and the rate of infusion based on review of the safety and tol erabi 1 i ty data by the IDMC. If the administration of Auxora or Placebo is stopped because of a serious adverse event that is considered to be probably or definitely related to Auxora or Placebo, the Medical Monitor must be immediately contacted.

[0184] Although the administration of the infusion should be set up to be completed over four hours, it is expected that there will be minor variability based on the equipment used and calibration of the equipment. The recommended infusion timeframe is 4 hours (± 30 minutes).PATENTATTORNEY DOCKET NO. CM1740-1 WO (449399-766) Infusion outside this timeframe will be evaluated to confirm that the full dose( >90%)was administered. If the full dose was not administered, a protocol deviation will be recorded.EXAMPLE 2 MethodsStudy design and participants

[0185] Adult patients with AP and SIRS were enrolled in the tnal. The diagnosis of AP required characteristic abdominal pain, with a serum lipase >3 times the upper limit of normal or characteristic findings on contrast-enhanced computed tomography (CECT) or magnetic resonance imaging (MRI). SIRS was established by the presence of two or more of the following criteria: temperature <36°C or >38°C, heart rate >90 beats per minute, respiratory rate >20 breaths / minute or arterial carbon dioxide tension <32 mmHg, white blood cell count >12,000 mm3 , or <4,000 mm3 . In addition to SIRS, patients were also required to have one of the following: a high haematocrit (>44% for men or >40% for women), a peripancreatic fluid collection (Balthazar D or E score) or pleural effusion on imaging, or guarding or rebound tenderness on abdominal examination. A full list of exclusion criteria is given in the protocol. All patients, or their legally authorized representatives, gave w ritten informed consent.Randomisation and masking

[0186] Patients were assigned in a 1 : 1 : 1: 1 ratio to placebo, or low (0.5 mg / kg; 0.3125 mL / kg), medium (1.0 mg / kg; 0.625 mL / kg) or high dose (2.0 mg / kg; 1.25 mL / kg) zegocractin (as Auxora™from CalciMedica), infused intravenously over 4 hours once daily for 3 days. Placebo infusions each comprised 1 of 3 random volumes corresponding to each zegocractin dose. Trial products containing placebo or zegocractin were visually identical and packaged in a manner that maintained masking, including all notation and approved labelling. Randomisation was performed centrally for each country using a computer-generated randomisation scheme with a block size of 8 that was accessed through an interactive voice / web response system (IXRS). Randomisation w as stratified first by sex, then by the presence of an elevated haematocrit (>44% for men or >40% for women) and hypoxaemia (PaO2 / FiO2 <360 mmHg). CARPO was a double-blind trial with both participants and study teams (sponsor, investigators, study coordinators, and pharmacists) masked to treatment.Procedures

[0187] Trial treatment was begun w ithin 8 hours of informed consent. After the first trial infusion, patients were offered a low fat, >500 calorie solid meal at each mealtime until discharge, if not nil per os for a medical reason, recording whether they ate >50% of the meal, vomited, or experienced increased abdominal pain in the two hours follow ing the meal. If solidPATENTATTORNEY DOCKET NO. CM1740-1 WO (449399-766) food was not tolerated, liquid food was offered. Throughout the trial, including daily after discharge, patients completed a modified American Neurogastroenterology and Motility Society’ Gastroparesis Cardinal Symptom Index Daily Diary (mGCSI-DD) worksheet, and daily while hospitalised, a pain 10-10 numeric rating scale. CECT or MRI was performed before randomisation, from which the Balthazar CT severity score (A to E) was determined, on day 30, and as required for standard care. All imaging was interpreted centrally by two independent, experienced radiologists blinded to treatment assignments, with differences resolved by consensus. The peripheral oxygen saturation (SpO2) and fraction of inspired oxygen (FiO2) were assessed daily for the first 10 days, and all organ support assessed daily during hospitalisation.Outcomes

[0188] The primary endpoint and secondary endpoint to determine dose-response was time to solid food tolerance, and the development of (new-onset) severe respiratory’ failure, respectively. Time to solid food tolerance was recorded from the start of trial treatment until the patient could eat >50% of a low fat. >500-calorie solid meal, without increasing abdominal pain or vomiting within two hours of that and all subsequent meals. For patients discharged not tolerating solid food, this time was determined using the mGCSI-DD worksheet as 8am on the first of 3 consecutive days when there was no vomiting, no or mild nausea or abdominal pain, and patients finished a normal-sized meal. Severe respiratory failure was defined as the use of invasive mechanical ventilation, or >48 hours of either high flow nasal cannula or non-invasive mechanical ventilation, excluding for a procedure or obstructive sleep apnea. Severe cardiovascular failure was defined as receiving vasopressors or inotropes for >48 hours, and severe renal failure as the initiation of renal replacement therapy. Organ failure was defined as the development of severe respiratory failure and / or severe renal failure and / or severe cardiac failure.

[0189] The development of necrotising pancreatitis was determined from the day 30 CECT, or if unavailable, the last CECT following trial treatment. Time to medically indicated discharge was taken from the start of trial treatment to when the patient tolerated solid food, abdominal pain was controlled or resolved (>50% pain scale reduction from peak level in the first 24 hours and no opioids), and the patient was without infection requiring continued hospitalization. For patients discharged before meeting these criteria, this time was determined using the mGCSI- DD worksheet as for solid food tolerance.

[0190] An independent data and safety monitoring committee evaluated the progress of the trial and examined safety’ end points sequentially after 20, 60, 120, and 140 patients were enrolled and had completed the trial. Safety was evaluated by treatment-emergent adverse events codedPATENTATTORNEY DOCKET NO. CM1740-1 WO (449399-766) per the Medical Dictionary' for Regulatory' Activities (MedDRA) version 26.0. All endpoints were predefined in the protocol and statistical analysis plan (see appendix p 1).Statistical analysis

[0191] Sample size was based on the PYTHON trial, which found the median time to full oral diet in the on demand feeding group was 6 days, and a phase 2a trial of zegocractin, which found 7 of 14 (50%) patients receiving zegocractin tolerated solid food at 72 hours versus 1 of 7 (14%) receiving standard care. A sample size of 216 patients randomised in a 1: 1: 1 : 1 ratio to 4 groups of 54 patients was calculated each would provide 86% power for testing the difference in two populations having a median length of time of 72 and 144 hours, respectively, to tolerating solid food. In addition, it would provide 80% power with a two-sided alpha of 0.05 to detect a 45% response rate for tolerating solid food in a zegocractin group versus 20% in the placebo group at 72 hours.[00192JA11 statistics were compiled from the modified intention-to-treat (mITT) population, comprising all randomised patients receiving any trial treatment. The generalised multiple comparisons and modeling (gMCP-Mod) analysis as described in the statistical analysis plan was the primary statistical method used for determining a dose-response relationship for both time to solid food tolerance and severe respiratory failure, with predefined alpha at 0.15.21,22 The time to solid food analysis was performed in the mITT population and in the prespecified population determined by the additional inclusion criteria of a high haematocrit. The analysis of severe respiratory failure was only performed in the mITT population. The results of the additional secondary' analyses were not adjusted for multiplicity and therefore should not be interpreted to inform definitive treatment effects but characterize a potential composite phase 3 endpoint. An exploratory' win-ratio with the potential to serve as a phase 3 endpoint was calculated for each zegocractin group versus placebo using a hierarchical composite endpoint of mortality', new-onset severe respiratory failure, new-onset necrotising pancreatitis, and time to medically indicated discharge, in that order. Patients were included in the statistical analyses if they received any amount of study drug. Missing data in the response variable after the early termination to Day 30 were not imputed in the win ratio. Statistical analyses were conducted using SAS software, version 9.4 (for further detail on statistical considerations see the appendix p5).PK analysis

[0193] Blood samples for PK analysis will be drawn as soon as possible after the completion of the first infusion of study drug (within +2 hours), prior to the start of second infusion of study drug (within -30 min), and at 72 hours (±2 hours) from the SFISD. If the patient is discharged after the third infusion of study drug and prior to 72 hours from the SFISD, the blood samplePATENTATTORNEY DOCKET NO. CM1740-1 WO (449399-766) will be drawn prior to discharge. A PK sample will also be drawn at Day 30. The date and time that the sample for PK analysis is drawn shall be recorded. All samples for PK analysis should be stored at either -20°C or -80°C until shipment on dry ice to the central laboratory. As with the biomarkers, it is the expectation that all sites participate in the PK sample collection; however, if a site is unable to provide blood for the PK analysis, this will be determined at study start and not considered a protocol deviation for that site. In addition, if a site is participating in PK collection but a patient does not want to provide PK samples this will be documented in the informed consent and not considered a protocol deviation.Enhanced Recovery Strategy for Tolerance of Solid Food

[0194] Patients randomized into the study will be offered a low fat, >500-calorie solid meal at each mealtime after the infusion of the first dose of study drug until discharge if alert and not on mechanical ventilation, or if not NPO for a planned surgei / medical procedure, or if not NPO because of an acute medical condition. See Section 5.2 for specific assessment procedures. Modified ANMS GCSI-Daily Diary (mGCSI-DD)

[0195] The ANMS GCSI Daily Diary was designed to assess gastrointestinal symptoms associated with idiopathic and diabetic gastroparesis. It has been shown to be a reliable tool to evaluate dysmotility in patients with AP (Ma 2016). It will be used to assess gastrointestinal symptoms associated with AP in an exploratory manner. The mGCSI-DD has a 24-hour recall; thus, all items are designed to be self-administered on a daily basis. The patient training for completing the daily diary is provided by the PI or appropriately trained delegate. Patients should understand their disorder: AP, where there is an abnormally delayed emptying of food from the stomach because of inflammation in the pancreas. The mGCSI-DD recording sheet and instructions are reviewed with the patient prior to the patient starting the recording of daily symptoms in the diary. The symptom severity response items are reviewed: "‘For each symptom listed below, please mark with an X the box that best describes the worst severity of each symptom during the past 24 hours. The next question asks you to record the number of times vomiting occurred in the last 24 hours. Please record the number of vomits (throwing up with food or liquid coming out) that occurred in the last 24 hours. Record zero, if you have not vomited during the past 24 hours. If you vomited, write down the number of all vomits. If you vomited once, record one. If you vomited three times during the day, record three.

[0196] If you vomited three times, whether it was during the same trip to the bathroom or three separate trips, record three as the number of episodes of vomiting."’ Patients discharged before Day 25 will complete the daily diary on the day of discharge, and then after discharge, daily at bedtime until the Day 30 visit.Pain Numeric Rating Scale (PNRS)PATENTATTORNEY DOCKET NO. CM1740-1 WO (449399-766)

[0197] In patients who are able to self-report their pain, the Pain Numeric Rating Scale (Appendix 4) will be used to grade the severity of the abdominal pain. It should be recorded if an opioid analgesic had been given in the 2 hours prior to the PNRS determination.Contrast-Enhanced Computed Tomography (CECT) of the Abdomen / Pancreas

[0198] The recommended CECT protocol will consist of:• A non-ionic contrast bolus of 100-150cc will be administered at 3-5cc / second• Slice thicknesses will be 5 mm or less and will be obtained through the pancreas during the pancreatic phase (35 seconds after the start of the non-ionic contrast bolus) and through the entire abdomen during the portal venous phase (50 to 70 seconds after the start of the non-ionic contrast bolus) to visualize the pancreas and surrounding tissue.If CECT is not available (e.g. medical contraindication to contrast medium used in CECT) and another appropriate imaging is available (e.g. MRI, MRCP), please contact medical monitor to discuss whether local SOC imaging can be used for eligibility and Day 30 purposes.CECT contrast protocol may be altered to local SOC. The lack of perfusion of the pancreas on the CECT will be exclusionary. If a CECT had already been performed more than 24 hours but less than 48 hours before Consent, and there is a contraindication to repeating it, the PI should discuss with the medical monitor if the CECT may be used for evaluating the inclusion and exclusion criteria for the study.

[0199] The PI or treating physician may also elect to delay the Day 30 CECT (±5 days) due to patientspecific safety considerations but must inform the Medical Monitor of the decision. The PI or treating physician may also elect not to perform the CECT because of futility considerations, e.g., the patient is unlikely to survive in the next 48 hours but must discuss the decision with the Medical Monitor. The CECT may also be used to make the diagnosis of chronic pancreatitis. Patients with a diagnosis of chronic pancreatitis in the chart or who selfreport chronic pancreatitis but are neither on enzyme replacement nor following up with a gastroenterologist as an outpatient, should be considered for the study after a careful review of a CECT (Appendix 7).

[0200] If the findings in the mild-moderate or severe categories are not present on the CECT. please contact the medical monitor to discuss whether the patient would be appropriate for randomization if they meet the other inclusion and none of the exclusion criteria. The ‘equivocal’ criteria do not exclude patients from randomization. The Screening and Day 30 CECTs will be read by a blinded central reader. They will also be read locally and may be used by the PI or treating physician, as needed, for patient management.PATENTATTORNEY DOCKET NO. CM1740-1 WO (449399-766)

[0201] If the patient undergoes additional CECTs at the discretion of the PI or treating physician from randomization to the Day 30 visit, the date of the CECT will be recorded and a blinded central reader will read the images.Systemic Inflammatory Response Syndrome (SIRS)

[0202] The physician, or appropriately trained designee will determine the presence of SIRS at Screening. The most extreme value for each criterion in the 24 hours before consent may be used. SIRS is defined as the presence of at least 2 of the 4 critena: •Temperature < 36°C or > 38°C •Heart rate > 90 beats / minute•Respiratory rate > 20 breaths / minute or arterial carbon dioxide tension (PaCO2)< 32 mmHg•White blood cell count (WBC) >12,000 mm3, or < 4,000 mm3, or > 10% immature (band) formsEXAMPLE 3Zegocractin for Acute Pancreatitis with Systemic Inflammatory Response Syndrome

[0203] Consecutive patients with AP and SIRS were fully screened at 58 sites in the US and India, of whom 216 were enrolled across 37 centres. In the US. 152 patients were randomised, and in India; 53 were assigned to placebo and 163 to either low (N=53), medium (N=56), or high dose (N=54) zegocractin (FIG. 9). The median (interquartile range; IQR) patient age was 43 (34, 57) years and median (IQR) time from the onset of abdominal pain to randomisation was 3 (2, 4) days. Overall, the 4 trial groups were balanced except for statistically fewer patients >65 years of age in the high dose and placebo groups compared to the low and medium groups (Table 2)

[0204] Table 2: Characteristics of the Patients at Baseline.*PATENTATTORNEY DOCKET NO. CM1740-1 WO (449399-766)PATENTATTORNEY DOCKET NO. CM1740-1 WO (449399-766)* Data are for the modified intention-to-treat population. The abbreviation BMI denotes body mass index, ED Emergency Department, HTG hypertriglyceridaemia, IQR interquartile range, N number of patients, SIRS systemic inflammatory response syndrome, and US United States. f>44% for men, >40% for womenJDefined by a score of >2 on the modified Marshall scoring system.

[0205] At least 1 tnal infusion was started in 53 patients in the placebo group and in 52 patients in the low, 56 in the medium, 53 in the high dose zegocractin groups, resulting in a mITT population of 214 patients. 34 patients did not receive all three doses of study drug (Table 3). Trial treatment was stopped early because of adverse events in 3 (5.7%) of 53 patients in the placebo group and in 2 (3.8 %) of 52, 1 (1.8%) of 56 and 2 (3.7%) of 53 patients in the low, medium, and high dose zegocractin groups, respectively. Physician discharge led to early discontinuation of study drug in 2 (3.8%) patients in the placebo group and in 2 (3.8%), 6 (10.7%) and 4 (7.4%) patients in the low, medium, high dose zegocractin groups, respectively (Table 3).

[0206] Table 3: Number of Trial Infusions Received by Each Patient Group.PATENTATTORNEY DOCKET NO. CM1740-1 WO (449399-766)* Modified intention-to-treat population. f All three patients left hospital against medical advice.I Attending physician decision to remove one patient from trial.

[0207] ln the mlTT population, the median time to solid food tolerance was similar following treatment with placebo compared to all doses of zegocractin (Table 4). In the predefined subgroup of 92 (43.0%) patients with a high haematocrit, all doses of zegocractin resulted in a shorter time to solid food tolerance, with medians of 78.0, 64.0 and 67.0 hours for low. medium and high doses, respectively, versus 113.5 hours for placebo; in these patients a dose-response relationship was demonstrated by gMCP-Mod analysis (p=0.057) (FIG. 10A). In the predefined subgroup of 145 (67.8%) patients with screening Balthazar scores of D or E, all doses of zegocractin resulted in a shorter time to solid food tolerance, with medians of 68.5, 68.5, and 66.0 hours for low. medium, and high doses, respectively, versus 112.0 hours for placebo (Table 3). Patients with a low haematocrit, or screening Balthazar scores of A, B, or C, had similar solid food tolerance following zegocractin versus placebo.

[0208] Table 4: Trial Endpoints.*PATENTATTORNEY DOCKET NO. CM1740-1 WO (449399-766)PATENTATTORNEY DOCKET NO. CM1740-1 WO (449399-766)* Data are median values or number of patients. All analyses were performed in the modified intention-to-treat (mITT) population.IQR denotes interquartile ranges. N and no. denote number of patients. f>44% for men, >40% for women. One patient in the 2.0 mg zegocractin group did not have a screening haematocrit.JStratified Cox proportional hazard model with treatment as the independent variable and stratified by sex and haematocrit.§ One patient in the 0.5 mg zegocractin group and one in the 2.0 mg zegocractin group were without a screening Balthazar score.T| Number and percentage of patients with new-onset organ failure among all patients who did not have organ failure at presentation.IICochran-Mantel-Haenszel test zegocractin versus placebo stratified analysis. v Number of patients with CECT / MRI of sufficient quality' to be read accurately by the central panel at both baseline and Day 30, or if unavailable, post-trial treatment standard care CECT / MRI. Patients with new-onset necrotizing pancreatic were the number and percentage of patients who did not have necrotizing pancreatitis at screening determined by the central panel.Upper limit not applicable as 1.0 mg zegocractin group included patients who did not tolerate solid food throughout the 30-day period of the trial.§§ ANOVA model.

[0209] In patients without respiratory failure at screening, none developed severe respiratory failure in the medium (52 patients) and high (50 patients) dose groups, versus 4 (8.5% of 47 patients) and 4 (8.3% of 48 patients) in the placebo and low dose groups, respectively. A doseresponse relationship was demonstrated for zegocractin by gMCP-Mod analysis of new-onset severe respiratory failure (p=0.029) (FIG. 10B).

[0210] Although the statistical analysis plan predefined 11 subgroups allowing for 22 analyses, with two for each binary variable that defined subgroups, because dose-response w as demonstrated for solid food tolerance in the subgroup with a high haematocrit, and was seen in the subgroup of Balthazar D or E, once dose-response was determined for the entire population for severe respiratory failure, further subgroup analyses were not performed.Patients receiving medium or high dose zegocractin had less frequent organ failure, predominantly severe respiratory failure (Table 4). All organ failure occurred in patients who had either a high haematocrit or peripancreatic fluid at screening, except in one. One patient treated with placebo died from multiorgan failure and one patient treated with medium dosePATENTATTORNEY DOCKET NO. CM1740-1 WO (449399-766) zegocractin died secondary to acute coronary syndrome. There were no deaths in the low or high dose groups.

[0211] By day 30, new-onset necrotising pancreatitis in 11 of 37 (29.7%) patients in the high dose group was lower than in 17 of 46 (37%), 17 of 44 (38.6%) and 20 of 49 (40.8%) in the placebo, low dose and medium dose groups, respectively. One patient in both the placebo and high dose groups was found to have imaging consistent with infected pancreatic necrosis at day 30. (Table 4).

[0212] The median time to medically indicated discharge of 89.0 hours in the high dose group was lower than 104.0, 109.5 and 104.5 hours in the placebo, low dose and medium dose groups, respectively (Table 4). The median length of hospital stay of 4.0 days for the high dose group was lower than 5.0, 5.5 and 5.0 days for the placebo, low dose and medium dose groups, respectively (Table 4). The number of patients discharged by days 7, 14 and 21 was consistently higher in the medium and high dose groups versus the low dose and placebo groups (Table S4 in the appendix p 913). No patient in the high dose group was hospitalised more than 21 days.

[0213] In the exploratory stratified win-ratio analysis of the hierarchical composite endpoint, there were 1553 total wins for the high dose group versus 920 for placebo (win-ratio 1.64 [95% CI 1.030 -2.612], p = 0.04, FIG. 11), whereas neither the low (win-ratio 1.123 [95% CI 0.708 - 1.781], p = 0.62) nor the medium dose (win-ratio 1.177 [95% CI 0.740 - 1.871], p = 0.50) group won statistically against placebo.

[0214] The incidence of adverse and serious adverse events was slightly higher in the zegocractin groups overall versus placebo but was similar across the high dose and placebo groups, without a pattern suggestive of a dose-response relationship (Table 5). The low and medium dose groups, among whom adverse events were commoner, were older (Table 2) and pharmacokinetic analysis did not show serious adverse events to be increased by increasing drug exposure. An adverse event led to discontinuation of trial drug in 3 patients in the placebo group and in 2 patients in each zegocractin group. An increase in alanine aminotransferase, aspartate aminotransferase and total bilirubin classified as three serious adverse events in 1 (1.9%) patient in the low dose group were believed by the investigator to be related to trial treatment. Metabolic acidosis and multiorgan failure preceded death in 1 patient in20 the placebo group, and acute coronary syndrome preceded death in 1 patient in the medium dose group, not considered related to the trial treatment.

[0215] Table 5: Summary of adverse events.*PATENTATTORNEY DOCKET NO. CM1740-1 WO (449399-766)PATENTATTORNEY DOCKET NO. CM1740-1 WO (449399-766)* Data compiled from the modified intention-to-treat (mITT) population. N denotes number of patients in each group.Discussion

[0216] In this phase 2 trial gMCP-MOD analysis of the mITT population did not demonstrate a dose-response relationship for the primary outcome of time to solid food tolerance but demonstrated a dose-response relationship for the secondary outcome of severe respiratory failure. An analysis of subgroups defined by the additional inclusion criteria of a high haematocrit or peripancreatic fluid collection (Balthazar D or E score on CECT or MRI at screening) found zegocractin to be associated with a reduction in time to solid food tolerance. All patients but one who developed organ failure had either a high haematocrit or peripancreatic fluid at screening and all organ failure was found to be less frequent in the medium and high dose groups. These findings suggest that the benefit from zegocractin in patients with AP and SIRS is most apparent in those who have additional clinical evidence of severe inflammation and are at risk for organ failure. Organ failure, most frequently respiratory, is a major complication of AP that is a major risk factor for, contributes to, and precedes most mortality from AP. No drug has been shown previously to reduce the development of organ failure in patients with AP. A combination of the cyclooxygenase inhibitors parecoxib and imrecoxib reduced the occurrence and duration of severe AP but did not reduce the development of organ failure or use of mechanical ventilation compared to placebo in patients with predicted severe AP. Use of these two medicines is not an option in many countries as neither the US Food and Drug Administration (FDA) nor European Medicines Agency’ (EMA) has approved imrecoxib and the FDA has not approved parecoxib.

[0217] The 2.0 mg / kg dose of zegocractin was associated with a reduction in necrotising pancreatitis at Day 30, length of stay notably prolonged hospital stays >21 days, and time to medically indicated discharge, compared to other dose groups and placebo. Time to medically indicated discharge is an endpoint designed to standardise discharge criteria for patients with AP across different sites and was first proposed in the PYTHON trial.[00218JA composite endpoint integrating patient outcomes, specifically mortality, new-onset respiratory failure, new-onset necrotizing pancreatitis, and time to medically indicatedPATENTATTORNEY DOCKET NO. CM1740-1 WO (449399-766) discharge, was developed in CARPO as a potential confirmatory trial endpoint and tested using the win ratio method. The comparison of drug doses to placebo was consistent with an advantage of the 2.0 mg / kg dose over the 1.0 and 0.5 mg / kg doses. Additionally, the 2.0 mg / kg dose had a similar safety and tolerability profile to placebo. These safety data add to those of the phase 2 CARDEA trial of zegocractin in COVID-19 pneumonia, which in addition to significant beneficial effects on mortality over 30 days, found fewer adverse events in 130 patients receiving zegocractin at 2.0 mg / kg then 1.6 mg / kg (each given once daily for 3 days) than in 131 patients receiving placebo.

[0219] The CARPO trial has limitations. First, time to solid food tolerance did not demonstrate a dose-response relationship for zegocractin in the whole mITT population,, although aA doseresponse did appear was however seen in data for time to solid food tolerance in patients with a high haematocrit, as well as in data for new-onset severe respiratory failure in the mITT population. These data also met the primary objective of the trial, since a dose-response relationship has been determined in this patient population. Time to solid food tolerance was chosen as the primary endpoint to assess dose-response because every patient enrolled would contribute to the analysis but may have lacked discriminative ability compared to the exploratory secondary end points of organ failure and necrotizing pancreatitis, both of which were improved across the whole mITT population following zegocractin. In addition, time to solid food tolerance may have been subject to the benefits of an enhanced recovery strategy promoting early tolerance in patients treated with placebo. Alternatively, zegocractin may have greater efficacy in patients who have a more23 markedly increased inflammatory state, as indicated by an elevated haematocrit or high (D or E) Balthazar score. Second, trial treatment was incomplete in 34 of 216 patients, although early efficacy of medium and high dose zegocractin, begun within a median of 3 or 2 days from the onset of pain respectively, might have contributed to this, and so leading to early discharge. Third, the absence of adjustments for multiplicity requires caution in the interpretation of endpoint differences between the four trial treatment arms, as without such adjustments, the secondary endpoints are exploratory7. The direction of improvement of all outcomes, however, was associated with the administration of zegocractin, most consistently at high dose, reflected in the win-ratio. As hypothesis generating, these data provide justification for a pivotal phase 3 trial of zegocractin. Fourth, global generalisability is undetermined, wi th short lengths of stay typical of the US health system, despite recruitment of patients with more severe AP. but Nevertheless consistent results with from patients with different ethnicities from the US and India point to a greater impact of 0RAI1 inhibition common to patients with more severe AP, the clinical features of which are similar throughout the world.PATENTATTORNEY DOCKET NO. CM1740-1 WO (449399-766)

[0220] From 1965, three decades of negative randomised trials of drugs in AP prompted search for a mechanism fundamental in AP to target, leading to discovery of a critical role for abnormal pancreatic parenchymal cell overload with calcium, normal signaling of which is essential to exocrine secretion. Since discovery of the role of CRAC channel calcium entry in AP, three further decades of randomised trials of drugs targeting other mechanisms have not resulted in a licensed therapeutic for AP. The findings from CARPO provide credence for the essential role of cellular calcium entry and overload in the development of AP, and confirmpoint to this mechanism as a tractable target, demonstrating a dose-response for zegocractin in patients with AP and SIRS. Furthermore, this trial has identified earmarked patients with AP at higher risk o£24 organ failure who are likely to benefit most from zegocractin, determined suggesting an effective dose, at 2 mg / kg and developed suitable endpoints with a win ratio to evaluate effectiveness, which if established would overcome hurdles that have hindered drug development for AP over so many years.

[0221] Although the invention has been described with reference to the above examples, it will be understood that modifications and variations are encompassed within the spirit and scope of the invention. Accordingly, the invention is limited only by the following claims.

Claims

PATENTATTORNEY DOCKET NO. CM1740-1 WO (449399-766) CLAIMSWHAT IS CLAIMED IS:

1. A method for treating acute pancreatitis (AP) in a subject in need thereof, comprising administering a therapeutically effective amount of an intracellular Calcium signaling inhibitor to said subject, wherein said subject optionally has accompanying systemic inflammatory response syndrome (SIRS).

2. The method of claim 1, wherein the acute pancreatitis comprises pancreatic necrosis or necrotizing pancreatitis.

3. The method of claim 2, wherein the necrotizing pancreatitis is new onset necrotizing pancreatitis.

4. The method of claim 2 or 3, wherein the administering comprises a reduction the incidence of necrotizing pancreatitis.

5. The method of claim 4, wherein the administering comprise at least 10%, at least 20%, at least 30%, at least 40%, or at least 50%, at least 60%. at least 70%, at least 80%, or at least 90% reduction in the incidence of necrotizing pancreatitis.

6. The method of claim 2 or 3, wherein the administering comprises a 1 to 25% reduction in new onset necrotizing pancreatitis.

7. The method of claim 2 or 3, wherein the administering comprises a 1 to 15% reduction in new onset necrotizing pancreatitis.

8. The method of claim 2 or 3, wherein the administering comprises a 1 to 50% reduction in the relative risk of developing new onset necrotizing pancreatitis.

9. The method of claim 2 or 3, wherein the administering comprises a 1 to 25% reduction in the relative risk of developing new onset necrotizing pancreatitis.

10. The method of any one of claims 3-9, wherein the percentage of subjects with pancreatic necrosis affecting greater than or equal to about 30% of the pancreas is reduced after treatment with the intracellular Calcium signaling inhibitor.

11. The method of any of claims 3-9, wherein no subj ects have pancreatic necrosis affecting greater than or equal to about 30% of the pancreas after treatment with the intracellular Calcium signaling inhibitor.

12. The method of any one of claims 1-11, wherein the severity of the necrotizing pancreatitis is evaluated using a computed tomography severity index (CTSI) score.

13. The method of claim 12, wherein a CTSI score range of the subject is from 0 to 10 to 0 to 4.PATENTATTORNEY DOCKET NO. CM1740-1 WO (449399-766)14. The method of any one of claims 1- 13. wherein the administering further comprises reducing the incidence of severe respiratory failure, severe renal failure, and / or severe cardiovascular failure in the subject.

15. The method of claim 14, wherein the severe respiratory failure is new onset persistent respiratory failure or new onset severe respiratory failure.

16. The method of claim 15, wherein the incidence of new onset persistent respiratory failure is reduced by about 10%, about 20%, about 30%, about 40%, about 50%, about 60%, about 70%, about 80%, or about 90% after treatment with the intracellular Calcium signaling inhibitor.

17. The method of claim 15, wherein the administering comprises a 50 to 75% reduction in the relative risk of developing new onset persistent respiratory failure.

18. The method of claim 15, wherein the administering comprises about a 60%, 65%, 70%, or 75% reduction in the development of new onset persistent respiratory failure.

19. The method of claim 15, wherein the incidence of new onset severe respiratory failure is reduced by about 10%, about 20%, about 30%, about 40%. about 50%, about 60%, about 70%, about 80%, or about 90% after treatment with the intracellular Calcium signaling inhibitor.

20. The method of claim 15, wherein the administering comprises a 50 to 100% reduction in the relative risk of developing new onset persistent respiratory failure.

21. The method of claim 15, wherein the administering comprises about a 75%, 80%, 85%, 90%, 95%, or 100% reduction in the development of new onset persistent respiratory failure.

22. The method of claim 15, wherein the incidence of severe renal failure is reduced by at least 10%, at least 20%, at least 30%, at least 40%, at least 50%, at least about 60%, at least about 70%, at least about 80%, or at least about 90% after treatment with the intracellular Calcium signaling inhibitor.

23. The method of claim 15, wherein the incidence of severe cardiovascular failure is reduced by at least 10%, at least 20%, at least 30%, at least 40%, at least 50%, at least about 60%, at least about 70%, at least about 80%, or at least about 90% after with the intracellular Calcium signaling inhibitor.

24. The method of any one of claims 1-23, wherein the administering further comprises reducing the incidence of severe organ failure in the subject.

25. The method of claim 24, wherein the incidence of severe organ failure is reduced by at least 10%, at least 20%, at least 30%, at least 40%, at least 50%, at least about 60%, at least about 70%, at least about 80%, or at least about 90% after treatment with the intracellular Calcium signaling inhibitor.PATENTATTORNEY DOCKET NO. CM1740-1 WO (449399-766)26. The method of any one of claims 1-25. wherein the administering further comprises a reduction in the length of a hospital stay.

27. The method of claim 26, wherein the hospital stay is reduced by 1-30 days.

28. The method of claim 26, wherein the hospital stay is reduced by 1-14 days.

29. The method of claim 26, wherein the hospital stay is reduced by 1, 2, 3, 4, 5, 6, or 7 days.

30. The method of claim 26, wherein the hospital stay is reduced by about 200 hours.31 . The method of claim 26, wherein the hospital stay is reduced by about 150 hours.

32. The method of any one of claims 1-31, wherein the subject has a recovery' rate of greater than about 35%.

33. The method of any one of claims 1-31, wherein the subject has a recovery’ rate of greater than about 50%.

34. The method of any one of claims 1-31, wherein the subject has a recovery' rate of greater than about 75%.

35. The method of any one of claims 1-31, wherein the subject has a recovery’ rate of greater than about 90%.

36. The method of any one of claims 1-31, wherein the subject has a recovery' rate of about 50% to about 100%.

37. The method of any one of claims 1-36, wherein the subject presents with a high hematocrit level, peripancreatic fluid, and / or abdominal guarding or tenderness.

38. The method of any one of claims 1-37, wherein the administering comprises lowering a hematocrit level.

39. The method of claim 38, wherein the hematocrit level is lowered by about 10%, about 20%, about 30%, about 40%, or about 50% of the level prior to the treatment with the intracellular Calcium signaling inhibitor.

40. The method of any' one of claims 1-39, wherein the intracellular Calcium signaling inhibitor is administered in a concentration of about 0.1 mg / kg to about 5 mg / kg.

41. The method of any one of claims 1-39, wherein the intracellular Calcium signaling inhibitor is administered in a concentration of about 0.5 mg / kg to about 2.5 mg / kg.

42. The method of any one of claims 1-39, wherein the intracellular Calcium signaling inhibitor is administered in a concentration of about 1 mg / kg to about 2.0 mg / kg.

43. The method of any one of claims 1-39, wherein the intracellular Calcium signaling inhibitor is administered in a concentration of about 1.5 mg / kg to about 2.0 mg / kg.

44. The method of any one of claims 1-39, wherein the intracellular Calcium signaling inhibitor is administered in a concentration of about 0.5 mg / kg.PATENTATTORNEY DOCKET NO. CM1740-1 WO (449399-766)45. The method of any one of claims 1-39, wherein the intracellular Calcium signaling inhibitor is administered in a concentration of about 1.0 mg / kg.

46. The method of any one of claims 1-39, wherein the intracellular Calcium signaling inhibitor is administered in a concentration of about 2.0 mg / kg.

47. The method of any one of claims 1-46, wherein one, two, or three doses of the intracellular Calcium inhibitor are administered to the subject.

48. The method of claim 47, wherein the first dose is administered in a concentration of about 2.0 mg / kg, and the second and third dose is administered in a concentration of about 1.6 mg / kg.

49. The method of any one of claims 1-48, wherein the intracellular Calcium signaling inhibitor is N-(5-(6-Chloro-2,2-difluorobenzo[d][1.3]dioxol-5-yl)pyrazin-2-yl)-2-fluoro-6- methylbenzamide, or a pharmaceutically acceptable salt or pharmaceutically acceptable solvate thereof.

50. The method of any one of claims 1-49, wherein the method further comprise administering one or more medical treatments.

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