SOCE inhibitors and their therapeutic uses

Abstract

The present invention provides SOCE inhibitors useful as therapeutic agents in a variety of applications. The present invention also relates to pharmaceutical compositions, products and kits comprising such SOCE inhibitors, and methods of using SOCE inhibitors to treat a variety of diseases.

Description

[0001] Related Applications

[0002] This application claims priority from European Patent Application No. EP20175509.7 filed on May 19, 2020, the entire contents of which are incorporated herein by reference. Background of the Invention

[0004] Store-operated calcium entry (SOCE) is a central mechanism for cellular calcium signaling and maintaining cellular calcium homeostasis. 2+ Increase in concentration and replenishment of intracellular Ca 2+ Intracellular Ca induced by SOCE 2+ The increase in concentration is induced by the activation of multiple plasma membrane receptors and is induced by intracellular Ca 2+ depletion of the Ca pool, which then 2+ The opening of the channel triggers the extracellular Ca 2+ Inflow.

[0005] There are two major families of proteins involved in SOCE: the matrix-interacting molecule family (STIM1 and STIM2) and the ORAI (Orai1, Orai2, and Orai3) family. TRPC (transient receptor potential canonical) channels from the large family of TRP channels have also been described as Ca channels involved in SOCE. 2+ Permeable channel. Endoplasmic reticulum (ER) Ca 2+ Depletion of the Ca pool is sensed by STIM triggering translocation of this protein to the ER-plasma membrane junction, where STIM1 interacts with Orai / TRPC channels and subsequently allows extracellular Ca to 2+ Influx. SOCE plays an important role in many physiological processes in almost all cell types. The opening of SOCE channels leads to the activation of many different downstream signaling pathways, which regulate, among other things, cytokine production, gene expression, and cell growth, proliferation, differentiation, migration, and even apoptosis.

[0006] Dysregulated SOCE is implicated in a wide range of human pathologies, including immunodeficiency, autoimmunity, skeletal and vascular diseases, cardiopulmonary and neurodegenerative disorders, allergy, asthma, thrombosis, pancreatitis, inflammatory bowel disease, cardiovascular disorders and cancer, making SOC channels attractive targets for the treatment of these disorders.

[0007] The strongest rationale for SOCE inhibitors is for the treatment of inflammatory and immune disorders, which are typically chronic disorders (e.g., rheumatoid arthritis, psoriasis, multiple sclerosis, and asthma) and cancer. As an example, SOCE plays an important role in cancer development and progression, including tumor cell proliferation, migration, metastasis, invasion, and resistance to apoptosis. 2+ Dysregulation of influx allows cancer cells to gain an adaptive advantage that leads to tumor development, angiogenesis and metastasis of the entire organism. SOCE, more specifically STIM1 and Orai1, was first reported to play a role in breast cancer migration and metastasis. It has been reported in many other types of cancer, such as melanoma, esophageal cancer, pancreatic cancer, prostate cancer, liver cancer and kidney cancer, hepatocellular carcinoma, gastric cancer and colorectal cancer. There is undoubtedly interest in developing molecules that regulate SOCE.

[0008] Since SOCE was described almost 30 years ago, many molecules that inhibit this calcium influx process have been identified. The discovery of ORAI and STIM, the main components of SOCE, has greatly helped to strengthen the interest in SOCE as a drug target and has led to the development of SOC channel inhibitors a decade and a half ago. Several classes of SOCE inhibitors (mainly ORAI inhibitors) have been developed, which are promising for further drug development. However, only a few of them have reached clinical trials, mainly because of the challenges associated with SOCE inhibitors, such as the pharmacology, safety and toxicological properties of the compounds.

[0009] A frequently mentioned concern is the ubiquitous expression of SOCE components (Orai1 and STIM1) and the presence of this Ca 2+ The wide range of cellular functions of influx may lead to many undesirable effects of SOCE inhibition in multiple tissues. In vivo experimental data in mouse models with global Orai1 or STIM1 deletion and the clinical phenotype of SCID (severe combined immunodeficiency) patients carrying loss of function or invalid mutations in ORAI1 or STIM1 confirm that complete inhibition of SOCE may have harmful effects. However, in addition to immune dysfunction, the clinical phenotype of SCID patients seems to be limited to skeletal muscle, sweat glands, tooth enamel and ocular smooth muscle. In addition, heterozygous patients with invalid or loss of any function and mutation in ORAI or STIM1 are mostly asymptomatic. In summary, it is suggested that partial reduction of SOCE can be well tolerated and these SOCE channel blockers do not adversely affect function.

[0010] Therefore, there is still a need in the art to fully reduce Ca 2+ SOCE modulators that flow into but still have significant functional biological effects without inducing side effects. Summary of the invention

[0011] The present invention relates to novel SOCE inhibitors, their use as therapeutic agents, pharmaceutical compositions thereof and methods of treatment using SOCE inhibitors. More specifically, the present invention is based on the development of novel small molecules that exhibit an inhibitory effect on calcium signaling in different cell lines, but do not affect other cellular processes, such as cell survival, cell proliferation and cell migration.

[0012] Therefore, the present invention provides an aromatic azole compound having the chemical formula (I) or a pharmaceutically acceptable salt, solvate or hydrate thereof, or a derivative thereof, or a prodrug thereof:

[0013]

[0014] in:

[0015] R1 is 1, 2, 3, 4 or 5 substituents, wherein each substituent is independently selected from H, OH, halogen, NH2, alkoxy, aryloxy, OCH2OR, wherein R is alkyl, and O-THP, wherein THP is tetrahydropyranyl;

[0016] A is CH2 or O;

[0017] If A is CH2, then n=0, 1 or 2, and if A is O, then n=2 or 3;

[0018] Z is O, NH, NHCO or CONH, NR, wherein R is alkyl, NHSO2 or SO2NH;

[0019] X is one of the following groups:

[0020]

[0021] in:

[0022] R2 is H, Cl, Br or CF3;

[0023] R3 is 1, 2, 3 or 4 substituents, wherein each substituent is independently selected from H, OH, CF3, F, Cl, NH2, COOH and CONH2;

[0024] R4 is 1, 2 or 3 substituents, each of which is independently selected from H, F, CF3 and alkyl; and

[0025] R5 is 1 or 2 substituents, wherein each substituent is independently selected from H, F and CF3.

[0026] In the aromatic azole compound, the second benzene ring may be substituted at the ortho, meta or para position. In certain embodiments, in the aromatic azole compound, the second benzene ring is substituted at the meta or para position.

[0027] In certain embodiments, the aromatic azole compound has the formula (I) wherein Z=O.

[0028] In certain embodiments, the aromatic azole compound wherein Z═O has the formula (II):

[0029]

[0030] wherein R1, A, n and X are as described above.

[0031] In the aromatic azole compound of formula (II), the second benzene ring may be substituted at the ortho position, meta position or para position. In certain embodiments, in the aromatic azole compound, the second benzene ring is substituted at the meta position or para position.

[0032] In certain embodiments, the aromatic azole compound wherein Z═O has the formula (III):

[0033]

[0034] wherein R1, A, n, R2 and R3 are as described above.

[0035] In the aromatic azole compound of formula (III), the second benzene ring may be substituted at the ortho, meta or para position. In certain embodiments, in the aromatic azole compound, the second benzene ring is substituted at the meta or para position.

[0036] In certain embodiments, the aromatic azole compound has a chemical formula of one of the compounds shown in any one of Tables A, B and C, particularly Table A.

[0037] In certain embodiments, the aromatic azole compound is selected from the group consisting of:

[0038]

[0039] In other embodiments, the aromatic azole compound has the formula (I) wherein Z = CONH.

[0040] In certain embodiments, the aromatic azole compound wherein Z═CONH has the formula (II′):

[0041]

[0042] wherein R1, A, n and X are as described above.

[0043] In the aromatic azole compound of formula (II'), the second benzene ring may be substituted at the ortho, meta or para position. In certain embodiments, in the aromatic azole compound, the second benzene ring is substituted at the meta or para position.

[0044] In certain embodiments, the aromatic azole compound wherein Z=CONH has the formula (III')

[0045]

[0046] wherein R1, A, n, R2 and R3 are as described above.

[0047] In the aromatic azole compound of formula (III'), the second benzene ring may be substituted at the ortho, meta or para position. In certain embodiments, in the aromatic azole compound, the second benzene ring is substituted at the meta or para position.

[0048] In certain embodiments, the aromatic azole compound has the chemical formula of one of the amide analogs shown in Table 8 (7a, 7b, 7c, and 7d).

[0049] In other embodiments, the aromatic azole compound has the formula (I) wherein Z=SO2NH.

[0050] In certain embodiments, the aromatic azole compound wherein Z=SO2NH has the formula (II")

[0051]

[0052] wherein R1, A, n and X are as described above.

[0053] In the aromatic azole compound of formula (II″), the second benzene ring may be substituted at the ortho, meta or para position. In certain embodiments, in the aromatic azole compound, the second benzene ring is substituted at the meta or para position.

[0054] In certain embodiments, the aromatic azole compound wherein Z=SO2NH has the formula (III"),

[0055]

[0056] wherein R1, A, n, R2 and R3 are as described above.

[0057] In the aromatic azole compound of formula (III″), the second benzene ring may be substituted at the ortho, meta or para position. In certain embodiments, in the aromatic azole compound, the second benzene ring is substituted at the meta or para position.

[0058] In certain embodiments, the aromatic azole compound has the chemical formula of one of the sulfonamide analogs shown in Table 9 (9a, 9b, 9c, and 9d).

[0059] The aromatic azole compound as described herein, wherein the aromatic azole compound is a SOCE inhibitor.

[0060] The present invention also provides an aromatic azole compound as defined above for use as a therapeutic agent.

[0061] The present invention also provides an aromatic azole compound as defined above for use in treating diseases associated with SOCE dysregulation or dysfunction.

[0062] In certain embodiments, the disease associated with SOCE dysregulation or dysfunction is selected from the group consisting of inflammatory diseases, immunodeficiency diseases, autoimmune diseases, allergies, cardiovascular diseases, cardiopulmonary diseases, vascular diseases, neurodegenerative diseases, skeletal muscle diseases, thrombosis, and cancer.

[0063] In particular, the disease associated with SOCE dysregulation or dysfunction may be selected from the group consisting of inflammatory bowel disease, pancreatitis, rheumatoid arthritis, multiple sclerosis, asthma, psoriasis and cancer.

[0064] The present invention also provides a pharmaceutical composition comprising an effective amount of the aromatic azole compound as defined above and a pharmaceutically acceptable carrier or excipient.

[0065] The present invention also provides pharmaceutical compositions for use as therapeutic agents, in particular for the treatment of diseases associated with SOCE dysregulation or dysfunction, such as those defined herein.

[0066] The present invention also relates to the use of an aromatic azole compound as defined above for the preparation of a medicament, in particular for the treatment of diseases associated with SOCE dysregulation or dysfunction, such as those defined herein.

[0067] The present invention also relates to a method for treating a disease associated with SOCE dysregulation or dysfunction in a subject, the method comprising the step of administering to the subject a therapeutically effective amount of an aromatic azole compound as defined above. The disease associated with SOCE dysregulation or dysfunction is as defined herein.

[0068] These and other objects, advantages and features of the present invention will become apparent to those of ordinary skill in the art from a reading of the following detailed description of the preferred embodiments.

[0069] BRIEF DESCRIPTION OF THE DRAWINGS

[0070] Figure 1 .Chemical scheme for the preparation of N-phenylalkylazole SOCE inhibitors with a benzimidazole, indazole, pyrazole and triazole platform without free hydroxyl functionalities on the terminal side chains.

[0071] Figure 2 .Chemical scheme for the preparation of N-phenylalkylazole SOCE inhibitors with a benzimidazole, indazole, pyrazole and triazole platform bearing free hydroxyl functionalities on the terminal side chains.

[0072] Figure 3 SOCE inhibition by 6αa, GSK-7975-A, and SKF-93365 in B cell lines. 2+ When the compound 6αa (DAD3-473), SOCE inhibitor GSK-7975A and SOCE inhibitor SKF-93365 were added, thapsigargin was used to inhibit ER Ca 2+ SOCE inhibition in JOK B cells after pool depletion. Each compound was added at a final concentration of 5 mM (A) or 25 mM (B).

[0073] Figure 4. SOCE inhibition by 6αa, GSK-7975-A and SKF-93365 in B cell lines. When the compound 6αa (DAD 3-473), the SOCE inhibitor GSK-7975A and the SOCE inhibitor SKF-93365 of the present invention were added at different times before the addition of thapsigargin, the inhibition of ER Ca 2+ SOCE of JOK B cells after pool depletion. Each compound was incubated at a final concentration of 25 mM for 5 min (AB), 15 min (CD) or 30 min (EF).

[0074] Figure 5. Effects of 6αa, GSK-7975-A and SKF-93365 on B cell (JOK) growth, apoptosis and cell cycle. JOK cells were treated with increasing concentrations of the compound of the present invention 6αa (DAD3-473) (A, D and G), SOCE inhibitor GSK-7975A (B, E and H) or SOCE inhibitor SKF-93365 (C, F and I) for 24 hours. Cell proliferation, cell death and apoptosis were determined using CCK-8 cell proliferation assay, LIVE / DEAD cell viability assay and annexin V / FITC-PI staining, respectively. The data represent mean ± SEM (n = 3). The values ​​of control cells were considered to be 100%. The cell cycle distribution results of cells treated with 6αa (J) and SKF-96365 (K) at the specified concentrations, where the treatment endpoint was 48 hours, PI staining was used, and FACS analysis was subsequently performed. The data represent mean ± SEM (n = 2). Statistical analysis was performed using a two-tailed unpaired t-test.

[0075] Figure 6.In vitro effects of 6αa, GSK-7975-A and SKF-93365 on transepithelial migration of B cells. In each experimental method, JOK cells were treated with 2 different concentrations (5μM and 20μM) of SOCE inhibitors GSK-7975A (A), SOCESKF-93365 (B) and the compound of the present invention 6αa (DAD3-473) (C) for 24 hours. The effects of different inhibitors on transepithelial migration were evaluated after 24 hours. The histograms represent individual values ​​for each experimental condition and the mean + SEM of n observations. The data were normalized to the mean obtained for cells treated with DMSO control. The data were analyzed by non-parametric Mann Withney analysis, *P < 0.05, **P < 0.01 and ***P < 0.001.

[0076] Figure 7 .6αa, GSK-7975-A and SKF-93365 in vitro effects on B cell death. JOK cells were treated with two different concentrations of three SOCE inhibitors (5μM and 20μM) or with control DMSO for 24 hours. The percentage of live cells, necrotic cells or apoptotic cells treated with GSK-7975A (A), SKF-93365 (B) and 6αa (DAD3-473) (C) was normalized to the DMSO treatment condition. The histogram shows the amount of apoptotic cells (annexin / PI positive cells) detected under each experimental condition after treatment with GSK-7975A (D), SKF-93365 (E) and 6αa (DAD3-473) (F). Data are expressed as mean ± SEM of n observations (n ​​= 2). Data were analyzed using nonparametric Mann Withney analysis, *P < 0.05, **P < 0.01 and ***P < 0.001.

[0077] Figure 8.6αa, GSK-7975-A and SKF-93365 in vitro effects on HUVEC cell death. HUVEC cells were treated with three SOCE inhibitors (5μM and 20μM) at two different concentrations (5μM and 20μM) or with control DMSO for 24 hours. Cell death was analyzed by flow cytometry after annexin / propidium iodide labeling. The percentages of live cells, necrotic cells and apoptotic cells treated with GSK-7975A (A), SKF-93365 (B) and 6αa (DAD3-473) (C) were normalized to DMSO treatment conditions. The histogram shows the amount of apoptotic cells (annexin / PI positive cells) detected under each experimental condition after treatment with GSK-7975A (D), SKF-93365 (E) and 6αa (DAD3-473) (F). Data are expressed as mean ± SEM of n observations (n ​​= 2). Data were analyzed using nonparametric Mann Withney analysis, *P < 0.05, **P < 0.01 and ***P < 0.001.

[0078] Fig. 9 .Effects of 6αa, GSK-7975-A and SKF-93365 on the proliferation of pancreatic cancer cells (PANC-1). In each experimental method, PANC-1 cells were treated with (A) SOCE inhibitor GSK-7975A, (B) SOCE inhibitor SKF-93365 and (C) compound 6αa (DAD3-473) used at 2 different concentrations (5mM and 20mM) for 24 hours. The proliferation of Panc-1-Wt cells was evaluated using the MTS assay. The histogram represents the average value ± SEM of n observations and the single value of each experimental condition. The data were normalized to the average value of untreated cells. The data were analyzed by non-parametric Mann Withney analysis, *P < 0.05, **P < 0.01 and ***P < 0.001.

[0079] Fig.10 .6αa, GSK-7975-A and SKF-93365 in vitro effects on pancreatic cancer cell cytotoxicity. In each experimental method, PANC-1 cells were treated with (A) SOCE inhibitor GSK-7975A, (B) SOCE inhibitor SKF-93365 and (C) compound 6αa (DAD3-473) used at 2 different concentrations (5pM and 20pM) for 24 hours. Cytotoxic effects were assessed using the cytotoxic green assay. The histograms represent individual values ​​for each experimental condition and the mean + SEM of n observations. The data were normalized to the mean of untreated cells. The data were analyzed by nonparametric Mann Withney analysis, *P < 0.05, **P < 0.01 and ***P < 0.001.

[0080] Fig.11 .6αa, GSK-7975-A and SKF-93365 in vitro effects on pancreatic cancer cell death. PANC-1 cells were treated with 2 different concentrations (5 and 20 pM) of (A) GSK-7975A, (B) SKF-93365 and (C) 6αa (DAD3-473) or with control DMSO for 24 hours. Cell death was analyzed by flow cytometry using annexin / propidium iodide labeling. The percentages of live cells, necrotic cells and apoptotic cells treated with SOCE inhibitors were normalized to the values ​​obtained with DMSO treatment conditions. Data are expressed as mean + SEM of n observations (n ​​= 4). DETAILED DESCRIPTION

[0081] DETAILED DESCRIPTION OF CERTAIN PREFERRED EMBODIMENTS

[0082] As described above, the present invention provides SOCE inhibitors, pharmaceutical compositions thereof, and uses thereof in various therapeutic applications.

[0083] I-SOCE inhibitors

[0084] The present invention provides several SOCE inhibitors. As used herein, the term "store-operated calcium entry" (or "SOCE") refers to a mechanism by which calcium ions are released from intracellular calcium stores to induce calcium influx across the plasma membrane. The terms "SOCE inhibitor" and "SOCE blocker" are used interchangeably herein; and refer to a compound that reduces, blocks, inhibits, or eliminates the activation of Ca2+ after calcium store depletion. 2+ Influx or Ca 2+ A compound, molecule, or agent that induces influx of a substance, regardless of the specific mechanism of action used to achieve that result. 2+ Influx" and "Ca 2+ "Influx" is used interchangeably herein and refers to the Ca 2+ From the extracellular medium into the cytoplasm of the cell. The movement of calcium from intracellular organelles that serve as calcium sinks into the cytoplasm is also known as "calcium release" from the sink.

[0085] A. SOCE inhibitors

[0086] In particular, the present invention provides N-phenylalkylazole derivatives that show inhibitory effects on calcium signaling but do not significantly affect other cellular processes, such as cell survival, cell proliferation and cell migration. N-phenylalkylazole derivatives include one of the following: benzimidazole, indazole, pyrazole and triazole groups and have or do not have free hydroxyl functional groups on the terminal chain. More specifically, the present invention provides aromatic azole compounds of formula (I):

[0087]

[0088] in:

[0089] R1 is 1, 2, 3, 4 or 5 substituents, each of which is independently selected from H, OH, halogen (F, Cl, Br or I), NH2, alkoxy, aryloxy, OCH2OR, where R is alkyl, and O-THP, where THP is tetrahydropyranyl;

[0090] A is CH2 or O;

[0091] If A is CH2, then n=0, 1 or 2, and if A is O, then n=2 or 3;

[0092] Z is O, NH, NHCO, NR, wherein R is alkyl, NHSO2 or SO2NH;

[0093] X is one of the following groups:

[0094]

[0095] in:

[0096] R2 is H, Cl, Br or CF3;

[0097] R3 is 1, 2, 3 or 4 substituents, wherein each substituent is independently selected from H, OH, CF3, F, Cl, NH2, COOH and CONH2;

[0098] R4 is 1, 2 or 3 substituents, each of which is independently selected from H, F, CF3 and alkyl; and

[0099] R5 is 1 or 2 substituents, wherein each substituent is independently selected from H, F and CF3.

[0100] As used herein, the term "alkyl" refers to a monovalent straight or branched chain saturated hydrocarbon group of 1 to 10 carbon atoms (C1-C10 alkyl), for example, 1 to 8 carbon atoms (C1-C8 alkyl) or 1 to 5 carbon atoms (C1-C5 alkyl). Representative saturated straight chain alkyl groups include methyl, methyl, ethyl, n-propyl, n-butyl, n-pentyl, n-hexyl, n-heptyl, n-octyl, n-nonyl and n-decyl; while saturated branched chain alkyl groups include isopropyl, sec-butyl, isobutyl, tert-butyl, isopentyl, 2-methylbutyl, 3-methylbutyl, 2-methylpentyl, 3-methylpentyl, 4-methyl-pentyl, 2-methylhexyl, 3-methylhexyl, 4-methylhexyl, 5-methylhexyl, 2,3-dimethyl-butyl, 2,3-dimethylpentyl, 2,4-dimethylpentyl, 2,3-dimethylhexyl, 2,4-dimethylhexyl, 2,5-dimethyl Alkyl groups may be optionally substituted as defined below.

[0101] As used herein, the term "optionally substituted" means that the particular group being described may have one or more hydrogen substituents replaced by non-hydrogen substituents. In the context of the present invention, an alkyl group is substituted to the extent that such substitution is chemically meaningful. Examples of substituents include, but are not limited to, nitro (-NO2), sulfo (-SO4-), cyano (-CN), halogen (F, Br, Cl, I), amine (-NR"2, wherein each R" is independently H or alkyl), hydroxyl (-OH), aldehyde (-CHO), ketone (R i -CO-R ii ), ester (-R i -COO-R ii or -R i -OCO-R ii ), amide (-R i -CO-NR ii R iii or R ii -NR iii -CO-R i ), carboxylic acid (-COOH or -COOM, where M is a suitable cation such as sodium or potassium) or sulfonic acid (-SO3H or -Ri-SO3H) groups.

[0102] As used herein, the term "alkoxy" refers to a straight or branched chain -OR group, wherein R is an alkyl group. Preferred alkoxy groups include methoxy, ethoxy, n-propoxy, isopropoxy, tert-butoxy, and the like.

[0103] As used herein, the term "aryloxy" refers to a straight or branched -OAr group, wherein Ar is an aryl group. The term "aryl" refers to an aromatic group, such as phenyl, biphenyl or naphthyl, wherein the phenyl, biphenyl or naphthyl may be optionally substituted with one, two or three groups independently selected from nitro, sulfo, cyano, halogen, amine, hydroxyl, aldehyde, ketone, ester, amide, carboxylic acid or sulfonic acid groups (as described above). In certain embodiments, a preferred aryloxy group is a phenoxy group.

[0104] The second benzene ring of the aromatic azole compound of formula (I) may be substituted at the ortho position, meta position or para position. In certain embodiments, the second benzene ring of the aromatic azole compound of formula (I) is substituted at the meta position or para position.

[0105] In other embodiments, the aromatic azole compound of formula (I) is Z=O, that is, has formula (II):

[0106]

[0107] wherein R1, A, n and X are as described above.

[0108] The second benzene ring of the aromatic azole compound of formula (II) may be substituted at the ortho, meta or para position. In certain embodiments, the second benzene ring of the aromatic azole compound of formula (II) is substituted at the meta or para position.

[0109] In certain embodiments, the aromatic azole compound has the chemical formula (III):

[0110]

[0111] wherein R1, A, n, R2 and R3 are as described above.

[0112] The second benzene ring of the aromatic azole compound of formula (III) may be substituted at the ortho position, meta position or para position. In certain embodiments, the second benzene ring of the aromatic azole compound of formula (III) is substituted at the meta position or para position.

[0113] In certain embodiments, the aromatic azole compound is selected from the group consisting of compounds shown in Table A, Table B, and Table C.

[0114] Table A. Chemical structures of 1-[4-(phenylalkoxy)phenylethyl]-1H-benzo[d]imidazole 6α and substituted 1-[4-(phenylalkoxy)-phenylethyl]-1H-indazole 6αf, 6α(x,y).

[0115]

[0116] Table B. Chemical structures of 1-[4-(phenylalkoxy)phenylethyl]-1H-pyrazole 6βc and substituted 1-[4-(phenylalkoxy)phenylethyl]-1H-1,2,4-triazole 6β(j-1).

[0117]

[0118] Table C. Chemical structures of 1-(4-hydroxyphenylalkyl)-1H-azoles 12α.

[0119]

[0120] In certain preferred embodiments, the aromatic azole compound is selected from the group consisting of:

[0121]

[0122] In certain embodiments, the aromatic azole compound of formula (I) is Z═CONH, ie, has formula (II′).

[0123] In certain embodiments, the aromatic azole compound has the chemical formula (I), wherein Z=CONH and X is:

[0124]

[0125] Wherein R2 is H, Cl, Br or CF3, and R3 is 1, 2, 3 or 4 substituents, wherein each substituent is independently selected from H, OH, CF3, F, Cl, NH2, COOH and CONH2. The aromatic azole compound has the chemical formula (III').

[0126] In certain embodiments, the aromatic azole compound has the chemical formula of one of the amide analogs shown in Table 8 (7a, 7b, 7c, and 7d).

[0127] In certain embodiments, the aromatic azole compound has the chemical formula (I), wherein Z=SO2NH, ie, has the chemical formula (II").

[0128] In certain embodiments, the aromatic azole compound has the chemical formula (I), wherein Z=SO2NH and X is:

[0129]

[0130] Wherein R2 is H, Cl, Br or CF3, and R3 is 1, 2, 3 or 4 substituents, wherein each substituent is independently selected from H, OH, CF3, F, Cl, NH2, COOH and CONH2. The aromatic azole compound has the chemical formula (III").

[0131] In certain embodiments, the aromatic azole compound has the chemical formula of one of the sulfonamide analogs shown in Table 9 (9a, 9b, 9c, and 9d).

[0132] B. Preparation of SOCE inhibitors

[0133] The SOCE inhibitors according to the present invention can be prepared using any of a variety of suitable methods known in the art. An exemplary synthetic reaction scheme is shown in Figure 1 and 2 and described in the following experimental section. The synthetic schemes are merely illustrations of some methods by which the compounds of the present invention can be synthesized, and those skilled in the art can easily make various modifications to these synthetic reaction schemes. In particular, when referring to specific acids, bases, reagents, coupling agents, solvents, etc., it should be understood that other bases, acids, reagents, coupling agents, solvents, etc. known in the art may also be used, and are therefore included within the scope of the present invention. Changes in reaction conditions and parameters such as temperature, pressure, reaction duration, etc. that can be used as known in the art are also within the scope of the present invention. The starting materials and reagents for preparing SOCE inhibitors can be purchased from commercial suppliers or prepared by the following conventional procedures.

[0134] The starting materials and intermediates of the synthetic reaction schemes can be isolated and purified if desired using conventional techniques, including but not limited to filtration, distillation, crystallization, chromatography, etc. The purified materials can be characterized using conventional means, including physical constants and spectral data.

[0135] The compounds (SOCE inhibitors) obtained using the general reaction scheme may not be of sufficient purity. They can be purified by using any method known in the art for purifying organic compounds, such as crystallization, chromatography, and the like.

[0136] C. SOCE inhibitor salts, solvates, hydrates, derivatives and prodrugs

[0137] In certain embodiments, the SOCE inhibitors of the present invention are provided as a pharmaceutically acceptable salt, solvate, or hydrate.

[0138] The term "pharmaceutically acceptable salt" refers to salts that are suitable for contact with the tissues of humans and lower animals without excessive toxicity, irritation, allergic reactions, etc., and that are commensurate with a reasonable benefit / risk ratio within the scope of reasonable medical judgment. The preparation of pharmaceutically acceptable salts is well known in the art. When there is an acidic group in the structure of a pharmaceutically active compound (e.g., a compound of the present invention), a pharmaceutically acceptable salt can be prepared by contacting the compound with a non-toxic inorganic base (including potassium hydroxide, sodium hydroxide, calcium hydroxide, ammonium hydroxide, lithium hydroxide, iron hydroxide, copper hydroxide, and magnesium hydroxide). In some embodiments, a pharmaceutically acceptable salt can be prepared by contacting the compound with a non-toxic organic base (including but not limited to arginine, betaine, histidine, N-methylglucamine, lysine, L-glucosamine, etc.). In some embodiments, when basic groups are present in the structure of a pharmaceutically active compound such as the compounds of the present invention, pharmaceutically acceptable salts can be prepared by contacting the compound with a non-toxic acid such as hydrochloric acid, hydrobromic acid, sulfuric acid, acetic acid, phosphoric acid, tartaric acid, citric acid, fumaric acid, nitric acid, gluconic acid, malic acid, glutamic acid and succinic acid.

[0139] As used herein, the term "solvate" refers to a solvent addition form containing a stoichiometric or non-stoichiometric amount of solvent. Some compounds tend to capture a fixed molar ratio of solvent molecules in the crystalline solid state, thereby forming a solvate. If the solvent is water, the solvate form is called a "hydrate"; when the solvent is an alcohol, the solvate formed is called an alcoholate. Hydrates are formed by the combination of one or more water molecules with a molecule of a substance, where the water retains its molecular state as H2O. Pharmaceutical solvates or hydrates of the compounds of the present invention can be formed by freeze-drying a solution of the compound in water or any other suitable solvent (e.g., methanol, ethanol, DMSO, acetic acid, isopropanol, ethyl acetate, ethanolamine). General methods for preparing solvates and hydrates are well known in the art.

[0140] The present invention also encompasses derivatives of the SOCE inhibitors described herein. As used herein, a "derivative of a SOCE inhibitor" as described herein is a compound having a structure derived from a parent compound (one of the SOCE inhibitors disclosed herein) and having a structure sufficiently similar to those disclosed herein, and based on this similarity, one skilled in the art would expect to exhibit the same or similar activity and utility as the parent compound, or induce the same or similar activity and utility as the parent compound as a precursor. Exemplary derivatives include esters, amides, salts of esters or amides, pegylated derivatives of the parent compound, and N-oxides of the parent compound.

[0141] The present invention also encompasses prodrugs of the SOCE inhibitors described herein. As used herein, the term "prodrug of a SOCE inhibitor" refers to a compound that is rapidly converted in vivo to the parent compound of the chemical formula provided herein by reacting with an enzyme, gastric acid under physiological conditions or by oxidation, reduction, hydrolysis or enzymatic reaction in a living body. Examples of prodrugs include compounds in which the carboxyl group is esterified. Such prodrugs can be prepared according to methods well known in the art.

[0142] D. Biological properties of SOCE inhibitors

[0143] The compounds provided herein were tested for their ability to inhibit SOCE and the results are presented in Tables 4-7 in the Experimental section below.

[0144] The effects of compounds or agents on intracellular calcium can be achieved by providing calcium and / or Ca to cells (including cytosol and intracellular organelles or complement). 2+ Various methods for direct or indirect assessment or measurement of movement into, within or out of a cell, organelle, calcium store or portion thereof (e.g., membrane) can be monitored. A variety of methods can be used to assess calcium levels and calcium cation movement or flux. The specific method used and the conditions used will depend on whether a specific aspect of intracellular calcium is monitored or assessed. For example, in some aspects, reagents and conditions can be used to specifically assess store-operated calcium influx, resting cytosolic calcium levels, calcium buffering and calcium levels, and uptake or release of intracellular organelles and calcium stores. Alternatively, the effect of a compound or agent on intracellular calcium can be monitored or assessed using, for example, cells, intracellular organelles or calcium store compartments, membranes (including, for example, isolated membranes, patches or lipid bilayers), or cell-free assay systems (e.g., outside-out membrane vesicles).

[0145] Assays that can be used to study the inhibitory effects of SOCE inhibitors in vitro or ex vivo are known in the art, see, for example: Vetter, Adv. Exp. Med. Biol., 2012, 740:45-82; Zhang et al., Methods Mol. Biol., 2018, 1843:1-16; Zhang et al., Methods Mol. Biol., 2018, 1843:17-39; Redondo et al., Methods Mol. Biol., 2018, 1843:69-82; Riva et al., J. Med. Chem., 2018, 61:9756-9783; Pan et al., J. Vis. Exp., 2012, 60:3415; Pan et al., Methods Mol. Biol., 2018, 1843:55-62; Oh-Hara et al., Methods Mol. Biol., 2018, 1843:69-82; Riva et al., J. Med. Chem., 2018, 61:9756-9783; Pan et al., J. Vis. Exp., 2012, 60:3415; Pan et al., Methods Mol. Biol., 2018, 1843:55-62; Oh-Hara et al., Methods Mol. Biol., 2018, 1843:69-82; and Lu, "Calcium Entry Channels in Non-Excitable Cells", Boca Raton (FL); CRC Press / Taylor&Francis, 2018, Chapter 6; Stauderman, Cell Calcium, 2018, 74: 147-159; and Sadaghiani et al., Chem. Biol., 2014, 21: 1278-1292.

[0146] Processes regulated by store-operated calcium entry include, but are not limited to, calcium sodium activation, calcineurin activation, mast cell degranulation and release of inflammatory mediators, activation of calcium-dependent transcription factors (e.g., nuclear factor of activated T cells (NFAT), nuclear factor kappa B (NFκB), and / or c-Jun N-terminal kinase (JNK)), NFAT dephosphorylation, NFAT nuclear translocation, NFAT-dependent gene regulation, expression, release and / or activity of molecules regulated by such transcription factors (e.g., cytokine expression, release, or active cytokine release).

[0147] Therefore, the inhibitory effect of a compound on SOCE can be evaluated by detecting the effect on calcium influx-mediated events. For example, the activity of calcium-regulated proteins (such as calmodulin and calcineurin) can be detected or measured; the regulation, localization and / or activity of calcium-regulated transcription factors (such as NFAT, JNK and NFκB); and the effect on gene expression, such as genes regulated by calcium-regulated transcription factors, such as cytokine gene expression (such as IL-2, IL-3, IL-4, IL-5, IL-8, IL-13), and tumor necrosis factor α (TNFα), granulocyte colony stimulating factor (GCSF) and γ-interferon (g-IFN) and / or the expression of reporter genes connected to the promoters or regulatory elements of these genes. The effect on intracellular calcium can also be evaluated by detecting or measuring the secretion and / or release of peptides and proteins, such as the secretion of cytokines (such as IL-2), and the degranulation and release of inflammatory mediators (such as histamine and β-hexosaminidase).

[0148] Therapeutic uses of II-SOCE inhibitors

[0149] Due to their biological activity, the SOCE inhibitors of the present invention are useful as therapeutic agents. Dysregulated SOCE is involved in a large number of human diseases, including immunodeficiency diseases (Feske et al., Nature, 2006, 441: 179-185), autoimmune diseases (Bhuvaneshwari et al., Curr. Drug Targets, 2020, 21(1), doi: 10.2174 / 1389450120666190926150258), cardiovascular diseases (Groschner et al., Adv. Exp. Med. Biol., 2017, 993: 473-503), bone diseases (Michelucci et al., Cell Calcium, 2018, 76: 101-115), and cardiopulmonary diseases (Rode et al., Physiology, 2018, 33: 261-268; Spinelli et al., Am. J. Physiol. Cell Physiol., 2016, 310: C402-413), neurodegenerative diseases (Wegierski et al., Cell Calcium, 2018, 74: 101-111), allergies (Peters-Golden et al., Clin. Exp. Allergy, 2006, 36: 689-703), asthma (Kaur et al., Pulm. Pharmacol. Ther., 2015, 35: 67-74), thrombosis (Braun et al., Blood, 2008, 113: 2056-2063; Mammadova-Bach et al., Cell Calcium, 2019, 77: 39-48), pancreatitis (Gerasimenko et al., PNAS USA, 2013, 110: 13186-13191), inflammatory bowel disease (Feske et al, Nature Rev. Immunol., 2007, 7: 690-702) and cancer (Yang et al., Cancer Cell, 2009, 15: 124-134; Hanahan et al., Cell, 2000, 100: 57-70; Xi et al, Int. J. Cancer, 2016, 138: 2067-2077; Chen et al. al., Cancers, 2019, 11: E899; Bong et al., Biochim.Biophys.Acta Mol.Cell Res., 2018, 1865: 1786-1794; Chalmers et al., CellCalcium, 2018, 74: 160-167). .

[0150] A. Indications

[0151] Therefore, the present invention relates to a SOCE inhibitor as described herein for use as a therapeutic agent for treating a disease associated with SOCE dysregulation or dysfunction in a subject. The present invention also relates to the use of a SOCE inhibitor as described herein in the preparation of a medicament for treating a disease associated with SOCE dysregulation or dysfunction. The present invention also relates to a method for treating a disease associated with SOCE dysregulation or dysfunction in a subject, comprising the step of administering to a subject in need thereof a therapeutically effective amount of a SOCE inhibitor as described herein.

[0152] As used herein, the term "subject" refers to a human or another mammal (e.g., primate, mouse, rat, rabbit, dog, cat, horse, cow, pig, camel, etc.). In many embodiments of the present invention, the subject is a human. In this embodiment, the subject is often referred to as an "individual" or "patient". The terms "individual" and "patient" do not indicate a specific age.

[0153] The term "treat" is used herein to characterize a method or process intended to (1) delay or prevent the onset of a disease or condition; (2) slow or stop the progression, aggravation, or worsening of the symptoms of a disease or condition; (3) ameliorate the symptoms of a disease or condition; or (4) cure a disease or condition. Treatment can be administered prior to the onset of a disease or condition for a prophylactic or preventive effect. Alternatively or additionally, treatment can be administered after the onset of a disease or condition for a therapeutic effect.

[0154] As used herein, the term "therapeutically effective amount" refers to an amount of a compound (herein a SOCE inhibitor) that is effective to achieve a desired biological or medical response or outcome at the necessary dosage and time period. The therapeutically effective amount of a compound may vary according to factors such as the disease state, age, sex and weight of the subject, the ability of the compound to elicit a desired response in the subject, and the route of administration. The therapeutically effective amount for an individual may be determined according to methods known in the art. The dosage regimen may be adjusted to provide the best therapeutic response. Adjusting the dosage based on these or other methods to achieve maximum efficacy is well known in the art and is within the capabilities of a trained physician. A therapeutically effective amount is also an amount in which the therapeutic beneficial effects outweigh any toxic or deleterious effects of the compound. A therapeutically effective amount may consist of a single dose or multiple doses. Thus, the administration of the SOCE inhibitors of the invention described herein may be constant or periodic over a certain period of time and at specific intervals, such as hourly, daily, weekly (or at some other multi-day interval), monthly, annually (e.g., in a timed release form). Alternatively, delivery may occur multiple times over a given period of time, such as twice a week or more, twice a month or more, etc. Delivery may be continuous delivery over a period of time, such as intravenous delivery.

[0155] "Therapeutically desirable biological or medical response or outcome" is understood to mean an improved treatment, cure, prevention or amelioration of a disease, condition or side effect, or a reduction in the rate of progression of a disease or condition in a subject, as compared to a corresponding subject not administered the amount. The term "therapeutically desirable biological or medical response" also includes an enhancement of normal physiological function.

[0156] As used herein, the term "disease associated with SOCE dysregulation or dysfunction" refers to any disease, disorder or condition characterized by an impairment, disorder, perturbation or imbalance of the cellular calcium signaling mechanism of SOCE. The disease may be congenital or acquired. The term also encompasses all pathologies associated with deletion, null or gain-of-function mutations of STIM / ORAI.

[0157] Examples of disease categories known to be associated with SOCE dysregulation or dysfunction include, but are not limited to, inflammatory diseases, immune system diseases, cardiovascular diseases, cardiopulmonary diseases, vascular diseases, neurodegenerative diseases, skeletal muscle diseases, thrombosis, and cancer.

[0158] In certain embodiments, the SOCE inhibitors described herein are used to treat or prevent inflammatory diseases. As used herein, the term "inflammatory disease" refers to a disease, condition, or disorder characterized by inflammation of body tissues or having an inflammatory component. Inflammatory diseases can be caused or triggered by a dysregulation of the normal immune response. Examples of inflammatory conditions that can be treated using the SOCE inhibitors described herein include, but are not limited to, diseases of many body systems, such as:

[0159] - Inflammatory diseases of the musculoskeletal system, including myositis, rheumatoid arthritis, osteoarthritis, gout, gouty arthritis, acute pseudogout, Reiter's syndrome, ankylosing spondylitis, psoriatic arthritis, dermatomyositis, and bone diseases associated with increased bone resorption;

[0160] - Inflammatory diseases of the pulmonary system, including pleurisy, pulmonary fibrosis or nodules, restrictive lung disease, chronic obstructive pulmonary disease (COPD), and acute respiratory distress syndrome (ARDS);

[0161] - Inflammatory diseases of the cardiovascular system, including aortic stenosis, restenosis, arrhythmias, coronary arteritis, myocarditis, pericarditis, Raynaud's phenomenon, systemic vasculitis, angiogenesis, atherosclerosis, ischemic heart disease, thrombosis and myocardial infarction;

[0162] - Inflammatory diseases of the gastrointestinal system, including motility disorders, dysphagia, inflammatory bowel disease (e.g., Crohn's disease, ulcerative colitis, indeterminate colitis, necrotizing enterocolitis, ileitis, infectious colitis, and Barrett's syndrome), and pancreatitis;

[0163] - Inflammatory diseases of the genitourinary system, including interstitial cystitis, renal tubular acidosis, vaginitis, and urosepsis;

[0164] - Inflammatory diseases of the skin, including purpura, vasculitis scleroderma, sclerodermatitis, eczema, and psoriasis;

[0165] - Inflammatory diseases of the nervous system, including central nervous system disorders, cranial and peripheral neuropathies, peripheral neuropathies, radiculopathy, spinal cord or cauda equina compression with sensory and motor loss, and multiple sclerosis (MS);

[0166] - Inflammatory diseases of the central nervous system, including chronic demyelinating diseases of the nervous system, cognitive impairment, multiple sclerosis (MS), AIDS-related neurodegeneration, Alzheimer's disease, infectious meningitis, encephalomyelitis, Parkinson's disease, Huntington's disease, amyotrophic lateral sclerosis, and viral or autoimmune encephalitis:

[0167] - Inflammatory diseases of the ophthalmic system, including iridocyclitis, keratoconjunctivitis sicca, uveitis, corneal dystrophy, trachoma, onchocerciasis, sympathetic ophthalmia and endophthalmitis;

[0168] - Inflammatory diseases of the blood system, including chronic anemia and thrombocytopenia;

[0169] - Inflammatory diseases of the renal system, including renal amyloidosis, glomerulonephritis, nephropathy, and renal failure; and

[0170] - Other inflammatory diseases, such as tuberculosis, leprosy, sarcoidosis, syphilis, Sjögren's syndrome, cystitis, fibromyalgia, fibrosis, septic shock, endotoxic shock, surgical complications, systemic lupus erythematosus (SLE), transplant-related arterial disease, graft-versus-host reaction, allograft rejection, chronic transplant rejection.

[0171] In certain embodiments, the SOCE inhibitors described herein are used to treat or prevent immune disorders. The terms "immune disorder" and "immune system disease" are used interchangeably herein and refer to diseases or disorders or abnormalities caused by dysfunction or malfunction of the immune system as a whole or any of its components, including autoimmune disorders. Immune disorders can be congenital or acquired, characterized in that components of the immune system are affected or the immune system or its components are overactive. Immune disorders include those diseases, disorders or conditions with immune components and those diseases, disorders or conditions caused substantially or entirely by immune system-mediated mechanisms. Because many immune disorders are caused by inflammation or lead to inflammation, there is some overlap between disorders that are considered to be immune disorders and disorders that are considered to be inflammatory disorders. For the purposes of the present invention, in the case of such overlapping disorders, it can be considered to be an immune disorder or an inflammatory disorder.

[0172] In particular, the terms "immune system disease" and "immune disorder" refer to a range of disorders of the immune system, including immunodeficiency disorders, autoimmune disorders, and overactive immune responses (allergic disorders).

[0173] Thus, in certain embodiments, the SOCE inhibitors described herein are used to treat or prevent immunodeficiency disorders. As used herein, the term "immunodeficiency disorder" refers to a disease, disorder, or condition that occurs when the body's immune response is reduced or absent. When the disease is congenital or hereditary, it is called a primary immunodeficiency disease; when the disease is acquired, it is called a secondary immunodeficiency disease. Examples of primary immunodeficiency diseases that can be treated using the SOCE inhibitors described herein include, but are not limited to, X-linked agammaglobulinemia (XLA), common variable immunodeficiency (CVID), severe combined immunodeficiency (SCID) (known as lymphocytosis or "baby in the bubble" disease), DiGeorge syndrome, and Wiskott-Aldrich syndrome. Secondary immunodeficiency disorders occur when an external source (such as a toxic chemical or infection) invades the body (e.g., severe burns, chemotherapy, radiation, diabetes, malnutrition, immunosuppressive drugs). Examples of secondary immunodeficiency diseases that may be treated using the SOCE inhibitors described herein include, but are not limited to, AIDS, immune complex diseases such as viral hepatitis, cancers of the bone marrow and blood cells (leukemia, lymphoma, multiple myeloma).

[0174] In certain embodiments, the SOCE inhibitors described herein are used to treat or prevent autoimmune disorders. As used herein, the term "autoimmune disorder" refers to a disease or disorder or abnormality that occurs when the immune system mistakenly attacks and destroys its own body cells, tissues and / or organs. Examples of autoimmune disorders that can be treated using the SOCE inhibitors described herein include, but are not limited to:

[0175] - Autoimmune disorders of the skin such as psoriasis, dermatitis herpetiformis, pemphigus vulgaris, alopecia areata, bullous pemphigoid and vitiligo;

[0176] - Autoimmune disorders of the gastrointestinal system, such as coeliac disease, inflammatory bowel disease (e.g. Crohn's disease), ulcerative colitis, primary biliary cirrhosis and autoimmune hepatitis, primary sclerosis, cholangitis and autoimmune pancreatitis;

[0177] - Autoimmune disorders of the endocrine glands, such as type 1 diabetes, autoimmune thyroiditis, Graves' disease, Hashimoto's thyroiditis, autoimmune oophoritis, orchitis, and adrenal autoimmune disorders, e.g. Addison's disease;

[0178] - Autoimmune disorders of various organs, including, for example, connective tissue and musculoskeletal system diseases (e.g., rheumatoid arthritis, systemic lupus erythematosus, scleroderma, polymyositis, dermatomyositis, spondyloarthropathies such as ankylosing spondylitis and psoriatic arthritis), graft-versus-host disease (GVHD);

[0179] - autoimmune disorders of the neuromuscular system, such as multiple sclerosis (MS), myasthenia gravis, Eaton-Lambert myasthenic syndrome, autoimmune neuropathies (e.g. Guillain-Barre disease), autoimmune uveitis, juvenile myositis, autoimmune retinopathy, acute inflammatory demyelinating polyneuropathy, chronic inflammatory demyelinating polyneuropathy, chronic inflammatory demyelinating polyradiculoneuropathy, encephalomyelitis, neuromyotonia, stiffness syndromes and paraneoplastic neurological disorders;

[0180] - Autoimmune disorders of the blood, such as autoimmune hemolytic anemia, pernicious anemia, autoimmune thrombocytopenia; and autoimmune lymphoproliferative syndrome;

[0181] - Autoimmune disorders of the blood vessels, such as transient arthritis, antiphospholipid syndrome, vasculitic syndromes, for example Wegener's granulomatosis and Behcet's disease; cryoglobulinemia, systemic necrotizing vasculitis, giant cell arteritis, polyarteritis nodosa, heartburn syndrome, hypersensitivity vasculitis, Takayasu's arteritis, Kawasaki disease, and cryoglobulinemia;

[0182] - Autoimmune disorders of the eye, such as autoimmune uveitis Meniere's disease and autoimmune inner ear diseases;

[0183] - Autoimmune disorders of the kidney, such as glomerulonephritis; and

[0184] -Autoimmune diseases of the exocrine glands, such as Sjögren's syndrome, Raynaud's phenomenon, Ig1-related diseases.

[0185] In other embodiments, the SOCE inhibitors described herein are used to treat or prevent allergic disorders. As used herein, the term "allergic disorder" refers to a disease, condition or disorder associated with an allergic response to a normally harmless substance. These substances may be present in the environment (e.g., indoor air pollutants and aeroallergens), or they may be non-environmental (e.g., those causing skin diseases or food allergies). Examples of allergic disorders include, but are not limited to, rhinitis (such as allergic rhinitis, e.g., hay fever), sinusitis, rhinosinusitis, allergic conjunctivitis, chronic or recurrent otitis media, drug and vaccine reactions, insect sting reactions, latex allergy, conjunctivitis, urticaria (including chronic idiopathic urticaria), allergic and anaphylactoid reactions, atopic dermatitis, contact dermatitis, pruritus, asthma, allergic bronchitis, allergic bronchopulmonary aspergillosis, seasonal allergies, and food allergies.

[0186] In particular, in certain embodiments, the SOCE inhibitors described herein are used to treat or prevent asthma.As used herein, the term "asthma" refers to a pulmonary disease, disorder or condition characterized by reversible airway obstruction, airway inflammation, and increased airway responsiveness to various stimuli.

[0187] In certain embodiments, the SOCE inhibitors described herein are used to treat or prevent cardiovascular disease. As used herein, the term "cardiovascular disease" refers to structural and functional abnormalities of the heart and blood vessels, which may be congenital or acquired. Examples of cardiovascular diseases that can be treated using the SOCE inhibitors described herein include, but are not limited to, atherosclerosis, restenosis, coronary artery disease, arrhythmias, diabetic vascular disease, heart failure, hypertension, hypertrophy, diseases of the aorta and its branches, disorders of the peripheral vascular system, aneurysms, endocarditis, pericarditis, valvular heart disease, ischemic damage associated with myocardial infarction, stroke, vascular thrombosis, rheumatic heart disease, pulmonary embolism, hypertension, and vascular thrombosis.

[0188] In certain embodiments, the SOCE inhibitors described herein are used to treat or prevent cardiopulmonary disease. As used herein, the term "cardiopulmonary disease" refers to a range of serious conditions that affect the heart and lungs. Examples of cardiopulmonary diseases that can be treated using the SOCE inhibitors described herein include, but are not limited to, chronic obstructive pulmonary disease (COPD), congestive heart failure (CCF), bronchiectasis, bronchitis, emphysema, and pneumonia.

[0189] In certain embodiments, the SOCE inhibitors described herein are used to treat or prevent neurodegenerative diseases. The term "neurodegenerative disease" as used herein refers to a series of conditions that primarily affect neurons in the human brain. Examples of neurodegenerative diseases that can be treated using the SOCE inhibitors described herein include, but are not limited to, Alzheimer's disease, Parkinson's disease, Huntington's disease, amyotrophic lateral sclerosis (ALS), AIDS-related dementia, retinitis pigmentosa, spinal muscular atrophy, Batten's disease, hypoxic / ischemic injury, stroke, and cerebellar degeneration.

[0190] In certain embodiments, the SOCE inhibitors described herein are used to treat or prevent vascular diseases. As used herein, the term "vascular disease" refers to a class of diseases of the blood vessels - arteries and veins of the body's circulatory system. Examples of vascular diseases that can be treated using the SOCE inhibitors described herein include, but are not limited to, erythromelalgia, peripheral arterial disease (PAD), renal artery stenosis, Buerger's disease, Raynaud's disease, disseminated intravascular coagulation (DIC), cerebrovascular disease, abdominal aortic aneurysm (AAA), carotid artery disease (CAD), arteriovenous malformation (AVM), critical limb ischemia (CLI), pulmonary embolism, deep vein thrombosis (DVT), chronic venous insufficiency (CVI), atherosclerosis, stenosis and varicose veins.

[0191] In certain embodiments, the SOCE inhibitors described herein are used to treat or prevent skeletal muscle diseases. The term "skeletal muscle disease" refers to a class of diseases that affect muscle function and / or cause muscle pain. Examples of skeletal diseases that can be treated using the SOCE inhibitors described herein include, but are not limited to, muscular dystrophy, myopathy, dermatomyositis, polymyositis, rhabdomyolysis, neuromuscular junction disease, fibromyalgia, malignant paraganglioma, and malignant hyperthermia due to anesthesia.

[0192] In certain embodiments, the SOCE inhibitors described herein are used to treat or prevent thrombosis. As used herein, the term "thrombosis" refers to a class of diseases characterized by the formation of blood clots within blood vessels that hinder blood flow through the circulatory system. Examples of thrombosis that can be treated using the SOCE inhibitors described herein include, but are not limited to, venous thrombosis (e.g., superficial vein thrombosis, deep vein thrombosis (DVT), venous thromboembolism (VTE), cerebral venous sinus thrombosis, mesenteric vein thrombosis, renal vein thrombosis, portal vein thrombosis, jugular vein thrombosis, Paget-Schroeter's disease, Budd-Chilly syndrome); arterial thrombosis (stroke; myocardial infarction; limb ischemia; and hepatic artery thrombosis).

[0193] In certain embodiments, the SOCE inhibitors described herein are used to treat or prevent allelic conditions caused by dominant mutations in STIM1: tubular aggregate myopathy, Stormorken syndrome (a complex phenotype including myopathy, hyposplenism, hypocalcemia, and bleeding diathesis), and the platelet dysfunction disorder, York platelet syndrome.

[0194] In certain embodiments, the SOCE inhibitors described herein are used to treat or prevent thrombocytopenia or idiopathic thrombocytopenia.

[0195] In certain embodiments, the SOCE inhibitors described herein are used to treat or prevent cancer. Examples of cancer include, but are not limited to:

[0196] -Breast cancer, prostate cancer, liver cancer, lung cancer, colon cancer, cervical cancer, kidney cancer, lung cancer, bladder cancer, nasopharyngeal cancer, epidermoid cancer, esophageal cancer, gastric cancer, pancreatic cancer, thyroid cancer, cervical cancer, skin cancer, etc.;

[0197] - Tumors of mesenchymal origin, including rhabdomyosarcoma (an aggressive and highly malignant cancer that develops from skeletal muscle cells that have failed to fully differentiate);

[0198] - Hematopoietic tumors of the lymphoid lineage, including leukemia, acute lymphoblastic leukemia, acute lymphoblastic leukemia, Hodgkin's lymphoma, non-Hodgkin's lymphoma, B-cell lymphoma, T-cell lymphoma, hairy cell lymphoma, and Burkitt's lymphoma;

[0199] - Myeloid hematopoietic neoplasms, including acute and chronic myeloid leukemia, myelodysplastic syndrome and promyelocytic leukemia;

[0200] - Tumors of the central and peripheral nervous system, including astrocytomas, neuroblastomas, gliomas, and schwannomas; and

[0201] - Other tumors, including melanoma, follicular thyroid carcinoma, Kaposi's sarcoma, osteosarcoma, seminoma, teratoma, and keratinocyte squamous cell carcinoma.

[0202] In certain preferred embodiments, the SOCE inhibitors described herein are used to treat or prevent a disease selected from the group consisting of rheumatoid arthritis, multiple sclerosis, asthma, psoriasis, inflammatory bowel disease, hepatitis, pancreatitis, metabolic disorders (such as diabetes) and cancer.

[0203] B. Application

[0204] The SOCE inhibitor (optionally after formulation with one or more suitable pharmaceutically acceptable carriers or excipients) can be administered to a subject in need by any suitable route. Various delivery systems are known and can be used to administer the SOCE inhibitor of the present invention, including tablets, capsules, injectable solutions, encapsulation in liposomes, microparticles, microcapsules, etc. Methods of administration include, but are not limited to, cutaneous, intradermal, intramuscular, intraperitoneal, intralesional, intravenous, subcutaneous, intranasal, pulmonary, epidural, ocular and oral routes. The SOCE inhibitor of the present invention or a composition thereof can be administered by any convenient or other suitable route, such as by infusion or bolus, by adsorption through the epithelial or mucocutaneous lining (e.g., mucosa, rectal and intestinal mucosa, etc.). Administration can be systemic or local. Parenteral administration can be directed to a given tissue of a patient, such as by catheterization.

[0205] In certain embodiments, the SOCE inhibitors of the invention or pharmaceutical compositions thereof are administered alone according to the methods of treatment of the invention. In other embodiments, the SOCE inhibitors of the invention or compositions thereof are administered in combination with at least one additional therapeutic agent or therapeutic procedure. The SOCE inhibitors or compositions thereof may be administered prior to, concurrently with, and / or after the administration of the additional therapeutic agent or procedure.

[0206] Therapeutic procedures that may be performed in combination with administration of the SOCE inhibitors of the invention or compositions thereof include, but are not limited to, surgery, catheterization, and other invasive therapeutic procedures.

[0207] The therapeutic agent that can be administered in combination with the SOCE inhibitor of the present invention or a composition thereof can be selected from a variety of biologically active compounds, including compounds known to have beneficial effects in treating or preventing diseases associated with SOCE dysregulation or dysfunction as defined above; compounds that increase the availability and / or activity of SOCE inhibitors; and compounds that are generally beneficial to the health of the subject. Examples of such biologically active compounds include, but are not limited to, anti-inflammatory agents, immunomodulators, analgesics, antimicrobials, antibacterial agents, antibiotics, antioxidants, preservatives, and the like. As will be appreciated by one of ordinary skill in the art, in embodiments where the SOCE inhibitor of the present invention is administered with an additional therapeutic agent, the SOCE inhibitor and the therapeutic agent can be administered by the same route (e.g., oral) or by different routes (e.g., oral and intravenous).

[0208] In embodiments where the disease associated with SOCE dysregulation or dysfunction involves an autoimmune, allergic, or inflammatory disorder, the additional therapeutic agent may be a steroidal or nonsteroidal anti-inflammatory drug. Examples of suitable nonsteroidal anti-inflammatory drugs (NSAIDs) that can be used in combination with the SOCE inhibitors described herein include, but are not limited to, aspirin, ibuprofen, diclofenac, naproxen, benoxaprofen, flurbiprofen, fenoprofen, flubufen, ketoprofen, indoprofen, piroprofen, carprofen, oxaprozin, pramoprofen, muroprofen, trioxaprofen, suprofen, aminoprofen, tiaprofenic acid, and fenprofenic acid. acid), fluprofen, bucloxic acid, indomethacin, sulindac, tolmetin, zomepirac, tiopinac, zidometacin, acemetacin, fentiazac, clidanac, oxpinac, mefenamic acid, meclofenamic acid, flufenamic acid, niflumicacid, tolfenamic acid acid, diflurisal, flufenisal, piroxicam, sudoxicam, isoxicam; salicylic acid derivatives, including aspirin, sodium salicylate, choline magnesium trisalicylate, salsalate, diflunisal, salicylic acid, sulfasalazine, and olsalazine; para-aminophenol derivatives, including acetaminophen and phenacetin;Indole and indene acetates, including indomethacin, sulinacri and etodolac; heteroaryl acetates, including tolmetin, diclofenac and ketorolac; anthranilic acids (fenamates), including mefenamic acid and mefenamic acid; enolic acids, including oxicams (piloxicam, tenoxicam), and pyrazolidinediones (phenylbutazone, oxyphenthartazone); and alkanones, including nabumetone; and pharmaceutically acceptable salts thereof and mixtures thereof. ;

[0209] In embodiments where the disease associated with SOCE dysregulation or dysfunction involves an allergic condition, the additional therapeutic agent may be an antihistamine. Examples of antihistamines that can be used in combination with the SOCE inhibitors described herein include, but are not limited to, loratadine, cetirizine, fexofenadine, desloratadine, diphenhydramine, chlorpheniramine, chlorcyclizine, pyrilamine, promethazine, terfenadine, doxepin, and doxycycline. pin, carbinoxamine, clemastine, tripelennamine, brompheniramine, hydroxyzine, cyclizine, meclizine, cyproheptadine, phenindamine, acrivastine, azelastine, levocabastine, and mixtures thereof. Other examples of suitable antihistamines can be found in Goofman and Gilman, "The Pharmacological Basis of Therapeutics," 2001, 10 th Ed., pp.651-657.

[0210] Examples of immunosuppressants that can be used in combination with the SOCE inhibitors described herein include, but are not limited to, glucocorticoids, corticosteroids (such as Prednisone or Solumedrol), T cell blockers (such as cyclosporin A and FK506), purine analogs (such as azathioprine (Imuran)), pyrimidine analogs (such as cytosine arabinoside), alkylating agents (such as nitrogen mustard, phenylalanine mustard, buslfan and cyclophosphamide), folic acid antagonists (such as aminopterin and methotrexate), antibiotics (such as rapamycin, actinomycin D, mitomycin C ( C), puramycin and chloramphenicol), human immunoglobulin G (IgG), antilymphocyte globulin (ALG), and antibodies (such as anti-CD3 (OKT3), anti-CD4 (OKT4), anti-CD5, anti-CD7, anti-interleukin 2 receptor, anti-α / βTCR, anti-intercellular adhesion molecule 1 (anti-ICAN-1), anti-CD20 (Rituxan), anti-interleukin 12 and immunotoxin antibodies).

[0211] In embodiments where the disease associated with SOCE dysregulation or dysfunction involves cancer, the other therapeutic agent may be an anticancer agent. Examples of anticancer agents that can be used in combination with the SOCE inhibitors described herein include drugs that are conventionally classified into one of the following groups: alkylating agents, purine antagonists, pyrimidine antagonists, alkaloids, intercalating antibiotics, aromatase inhibitors, antimetabolites, mitotic inhibitors, growth factor inhibitors, cell cycle inhibitors, enzymes, topoisomerase inhibitors, biological response modifiers, antihormones, and antiandrogens. Examples of the anticancer agent include, but are not limited to, BCNU, cisplatin, gemcitabine, hydroxyurea, paclitaxel, temozolomide, topotecan, fluorouracil, vincristine, vinblastine, procarbazine, decarbazine, altretamine, methotrexate, mercaptopurine, thioguanine, fludarabine phosphate, phosphate), cladribine, pentostatin, cytarabine, azacitidine, etoposide, teniposide, irinotecan, docetaxel, doxorubicin, daunorubicin, dactinomycin, idarubicin, plicomycin camycin, mitomycin, bleomycin, tamoxifen, flutamide, leuprolide, goserelin, aminogluthimide, anastrozole, amsacrine, asparaginase, mitoxantrone, mitotane, and amifostine.Other examples of such anti-cancer agents include therapeutic antibodies used to treat cancer, including but not limited to anti-CD52 antibodies such as alemtuzumab (CAMPATH) used to treat chronic lymphocytic leukemia. TM ); anti-VEGF antibodies, including bevacizumab (AVASTIN) for the treatment of colorectal cancer and breast cancer TM ); anti-CD33 antibodies, including gemtuzumab ozogamicin (MYLOTARG for the treatment of acute myeloid leukemia TM ); anti-CD20 antibodies, including ibritumomab (ZEVALIN) for the treatment of lymphoma TM ) for the treatment of Hodgkin lymphoma (RITUXAN TM ); Tositumomab (BEXXAR) for the treatment of Hodgkin lymphoma TM ) and ARZERRA for chronic lymphocytic leukemia TM ); anti-EGFR antibodies, such as cetuximab (ERBITUX) for the treatment of colorectal cancer, head and neck cancer, and squamous cell carcinoma TM ) and panitumumab (VECTIBEX) for colorectal cancer TM ); anti-Her2 antibodies, including trastuzumab (HERCEPTIN) for the treatment of breast cancer and gastric cancer TM ); and anti-CTLA4 antibodies, including ipilimumab (YERVOY) for the treatment of melanoma TM ).

[0212] It is within the capabilities of those skilled in the art to select therapeutic agents to design appropriate combinations with SOCE inhibitors for the treatment or prevention of diseases associated with SOCE dysregulation or dysfunction.

[0213] III-Pharmaceutical Compositions

[0214] As described above, the SOCE inhibitors described herein can be administered per se or as a pharmaceutical composition. Thus, the present invention provides a pharmaceutical composition comprising an effective amount of a SOCE inhibitor and at least one pharmaceutically acceptable carrier or excipient. In some embodiments, the composition further comprises one or more additional bioactive agents.

[0215] As used herein, the term "pharmaceutically acceptable carrier or excipient" refers to a carrier medium that does not interfere with the effectiveness of the biological activity of the active ingredient and is not unduly toxic to the host at the concentration at which it is administered. The term includes solvents, dispersions, media, coatings, antibacterial and antifungal agents, isotonic and adsorption delaying agents, and the like. The use of such media and agents for pharmaceutically active substances is well known in the art (see, for example, Remington's Pharmaceutical Sciences, EW Martin, 18 th Ed., 1990, Mack Publishing Co.: Easton, PA, the entire contents of which are incorporated herein by reference). In certain embodiments, the pharmaceutically acceptable carrier or excipient is a veterinarily acceptable carrier or excipient.

[0216] SOCE inhibitors and pharmaceutical compositions thereof can be administered in any amount and using any route of administration effective to achieve the desired preventive and / or therapeutic effect. The optimal pharmaceutical formulation may vary depending on the route of administration and the desired dose. Such formulations may affect the physical state, stability, in vivo release rate, and in vivo clearance rate of the administered active ingredient.

[0217] The pharmaceutical compositions of the present invention can be formulated in dosage unit form for ease of administration and uniformity of dosage. The expression "unit dosage form" as used herein refers to a physically discrete unit of a SOCE inhibitor of the present invention for a patient to be treated. However, it should be understood that the total daily dose of the composition will be determined by the attending physician within the scope of sound medical judgment.

[0218] A. Preparation

[0219] Injectable preparations, such as sterile injectable aqueous or oily suspensions, can be prepared according to known techniques using suitable dispersants or wetting agents and suspending agents. Sterile injectable preparations can also be sterile injectable solutions, suspensions or emulsions in nontoxic parenterally acceptable diluents or solvents, such as solutions in 2,3-butanediol. Acceptable vehicles and solvents that can be used are water, Ringer's solution, USP and isotonic sodium chloride solution. In addition, sterile non-volatile oils are generally used as solutions or suspension media. For this purpose, any mild non-volatile oil can be used, including synthetic monoglycerides or diglycerides. Fatty acids (such as oleic acid) can also be used to prepare injectable preparations. Sterile liquid carriers can be used for sterile liquid form compositions for parenteral administration.

[0220] Injectable preparations can be sterilized, for example, by filtering through a bacteria-retaining filter or by incorporating a sterilizing agent in the form of a sterile solid composition, which can be dissolved or dispersed in sterile water or other sterile injectable media before use. Liquid pharmaceutical compositions as sterile solutions or suspensions can be administered, for example, by intravenous, intramuscular, intraperitoneal or subcutaneous injection. Injection can be by single bolus or by gradual infusion. When necessary or desired, the composition can include a local anesthetic to alleviate pain at the injection site.

[0221] In order to prolong the effect of active ingredient, it is usually necessary to slow down the absorption of ingredients from subcutaneous or intramuscular injection. The absorption of active ingredient applied parenterally can be delayed by dissolving or suspending the ingredient in an oil vehicle. Injectable reservoir forms are prepared by forming a microencapsulated matrix of active ingredient in a biodegradable polymer (e.g., polylactide-polyglycolide). According to the ratio of active ingredient to polymer and the property of the specific polymer used, the release rate of the ingredient can be controlled. Examples of other biodegradable polymers include poly (orthoesters) and poly (anhydrides). Depot injectable preparations can also be prepared by embedding active ingredient in liposomes or microemulsions compatible with body tissues.

[0222] Liquid dosage forms for oral administration include, but are not limited to, pharmaceutically acceptable emulsions, microemulsions, solutions, suspensions, syrups, elixirs and pressurized compositions. In addition to SOCE inhibitors, liquid dosage forms may also contain inert diluents commonly used in the art, such as water or other solvents, solubilizers and emulsifiers, such as ethanol, isopropanol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, dimethylformamide, oils (particularly cottonseed oil, peanut oil, corn oil, germ oil, olive oil, castor oil and sesame oil), glycerol, tetrahydrofurfuryl alcohol, polyethylene glycol and fatty acid esters of sorbitan and mixtures thereof. In addition to inert diluents, oral compositions may also contain adjuvants such as wetting agents, suspending agents, preservatives, sweeteners, flavoring agents and aromatics, thickeners, colorants, viscosity modifiers, stabilizers or osmotic modifiers. Examples of suitable liquid carriers for oral administration include water (possibly containing additives as described above, for example, cellulose derivatives, such as sodium carboxymethylcellulose solution), alcohols (including monohydric alcohols and polyhydric alcohols, such as glycols) and their derivatives, and oils (for example, fractionated coconut oil and peanut oil). For pressurized compositions, the liquid carrier may be a halogenated hydrocarbon or other pharmaceutically acceptable propellant.

[0223] Solid dosage forms for oral administration include, for example, capsules, tablets, pills, powders, and granules. In this solid dosage form, the SOCE inhibitor of the present invention can be mixed with at least one inert, pharmaceutically acceptable excipient or carrier (such as sodium citrate or dicalcium phosphate) and one or more of the following: (a) fillers or extenders, such as starch, lactose, sucrose, glucose, mannitol and silicic acid; (b) binders, such as carboxymethyl cellulose, alginates, gelatin, polyvinyl pyrrolidone, sugars and acacia; (c) humectants, such as glycerol; (d) disintegrants, such as agar, calcium carbonate, potato or tapioca starch, alginic acid, certain silicates and sodium carbonate; (e) solution retarding agents, such as paraffin; absorption promoters, such as quaternary ammonium compounds; (g) wetting agents, such as cetyl alcohol and glyceryl monostearate; (h) absorbents, such as kaolin and bentonite; and (i) lubricants, such as talc, calcium stearate, magnesium stearate, solid polyethylene glycol, sodium lauryl sulfate and mixtures thereof. Other excipients suitable for solid formulations include surface modifiers, such as nonionic and anionic surface modifiers. Representative examples of surface modifiers include, but are not limited to, poloxamer 188, benzalkonium chloride, calcium stearate, cetearyl alcohol, cetomacrogol emulsifying wax, sorbitan esters, colloidal silicon dioxide, phosphates, sodium lauryl sulfate, magnesium aluminum silicate, and triethanolamine. In the case of capsules, tablets, and pills, the dosage form may also include a buffer.

[0224] Solid compositions of similar types can also be used as fillers in soft and hard filled gelatin capsules using excipients such as lactose or milk sugar and high molecular weight polyethylene glycols. Solid dosage forms of tablets, dragees, capsules, pills and granules can be prepared with coatings and shells (e.g., enteric coatings, release-controlling coatings and other coatings well known in the art of pharmaceutical formulation). They can optionally contain opacifiers and can also be compositions so that they optionally release the active ingredient only in or preferably in a certain part of the intestinal tract in a delayed manner. Examples of embedding compositions that can be used include polymeric substances and waxes.

[0225] In certain embodiments, it may be desirable to apply the compositions of the invention locally to the area in need of treatment. This can be achieved, for example, but not limited to, by local infusion during surgery, topical application, by injection, by catheter, by suppository, or by a skin patch or stent or another implant.

[0226] For topical administration, the composition is preferably formulated as a gel, ointment, lotion or cream, which may contain a carrier such as water, glycerol, alcohol, propylene glycol, fatty alcohol, triglyceride, fatty acid ester or mineral oil. Other topical carriers include liquid petroleum, isopropyl palmitate, polyethylene glycol, alcohol (95%), polyoxyethylene monolaurate (5%) or sodium lauryl sulfate (5%). Other materials such as antioxidants, wetting agents, viscosity stabilizers and the like may be added as necessary.

[0227] In addition, in some cases, it is expected that the compositions of the present invention can be placed in a transdermal device placed on, in or under the skin. Such devices include patches, implants and injections that release active ingredients through passive or active release mechanisms. Transdermal administration includes all administrations across the body surface and the linings of body passages (including epithelial and mucosal tissues). Such administration can be carried out using the compositions of the present invention in the form of lotions, creams, foams, patches, suspensions, solutions and suppositories (rectal and vaginal).

[0228] Transdermal administration can be achieved by using a transdermal patch containing an active ingredient (i.e., a SOCE inhibitor) and a carrier that is non-toxic to the skin, and allows the ingredients for systemic absorption to be delivered to the bloodstream via the skin. The carrier can take any form, such as creams and ointments, pastes, gels, and occlusive devices. Creams and ointments can be viscous liquids or semisolid emulsions of oil-in-water or water-in-oil type. Pastes composed of absorbent powders dispersed in petroleum or hydrophilic petroleum containing the active ingredient may be suitable. A variety of occlusive devices can be used to release the active ingredient into the bloodstream, such as a semipermeable membrane covering a reservoir containing the active ingredient with or without a carrier, or a matrix containing the active ingredient.

[0229] Suppository formulations can be made from traditional materials, including cocoa butter (with or without the addition of wax to alter the melting point of the suppository), and glycerin. Water-soluble suppository bases, such as polyethylene glycols of various molecular weights, can also be used.

[0230] Materials and methods for preparing various formulations are known in the art and can be adapted for use in the practice of the present invention. Suitable formulations for delivery of antibodies can be found, for example, in "Remington's Pharmaceutical Sciences", EW Martin, 18 th Ed., 1990, Mack Publishing Co.: Easton, PA.

[0231] B. Other Bioactive Agents

[0232] In certain embodiments, the SOCE inhibitor of the present invention is the sole active ingredient in the pharmaceutical composition of the present invention. In other embodiments, the pharmaceutical composition further comprises one or more bioactive agents. Examples of suitable bioactive agents include, but are not limited to, anti-inflammatory agents, immunomodulators, analgesics, antimicrobials, antibacterial agents, antibiotics, antioxidants, preservatives, and combinations thereof.

[0233] In such pharmaceutical compositions, the SOCE inhibitor and at least one additional therapeutic agent can be combined in one or more formulations for simultaneous, separate or sequential administration of the SOCE inhibitor and the therapeutic agent. More specifically, the compositions of the invention can be formulated in such a way that the SOCE inhibitor and the therapeutic agent can be administered together or independently of each other. For example, the SOCE inhibitor and the therapeutic agent can be formulated together in a single composition. Alternatively, they can be maintained (e.g., in different compositions and / or containers) and administered separately.

[0234] C. Drug packaging or kit

[0235] In another aspect, the invention provides a pharmaceutical pack or kit comprising one or more containers (eg, vials, ampoules, test tubes, flasks or bottles) containing one or more of the ingredients of the pharmaceutical compositions of the invention, allowing for administration of the SOCE inhibitors of the invention.

[0236] The different components of a pharmaceutical package or test kit can be provided in solid (e.g., lyophilized) or liquid form. Each component is generally suitable for being provided as an aliquot in its respective container or in a concentrated form. A package or test kit according to the present invention may include a medium for reconstructing the lyophilized components. The individual containers of the test kit are preferably kept tightly closed for commercial sale.

[0237] In certain embodiments, the package or kit includes one or more additional therapeutic agents. Optionally, associated with the container may be a notice or package insert in a form prescribed by a governmental agency regulating the manufacture, use or sale of drugs or biological products, which reflects the agency's approval of manufacture, use or sale for human administration. The instructions of the package insert may include instructions for use of the pharmaceutical composition according to the methods of treatment disclosed herein.

[0238] An identifier, such as a barcode, radio frequency, ID tag, etc., may be present in or on the reagent kit. For example, the identifier may be used to uniquely identify the reagent kit for purposes of quality control, inventory control, tracking movement between workstations, etc.

[0239] Example

[0240] The following examples describe some preferred modes for preparing and implementing the present invention. However, it should be understood that these examples are for illustrative purposes only and are not intended to limit the scope of the present invention. In addition, unless the description in the examples is presented in the past tense, text similar to the rest of the specification is not intended to imply that an experiment was actually performed or data was actually obtained.

[0241] I. Chemical synthesis of SOCE inhibitors

[0242] The route for the preparation of N-phenylalkylazole derivatives with or without a free hydroxyl functionality on the terminal side chain attached to the azole heterocyclic platform is shown below.

[0243] Part 1

[0244] A chemical scheme for the preparation of N-phenylalkylazole SOCE inhibitors bearing a platform of benzimidazole, indazole, pyrazole, and triazole on the terminal side chain without free hydroxyl functionalities is presented in Figure 1 middle.

[0245] Example 1

[0246]

[0247] 2-(4-(4-Methoxyphenethyloxy)phenyl)ethan-1-ol (3a). To a solution of 2-(4-hydroxyphenyl)ethanol 1a (3.75 g, 27.14 mmol) in 15 ml of dry N,N-dimethylformamide (DMF) was added portionwise 11.25 g potassium carbonate KCO (8.43 mmol, 3 eq.) at room temperature under vigorous magnetic stirring (550 rpm). After 30 minutes, 5.838 g of 4-methoxyphenethyl bromide 2a (27.14 mmol) was added dropwise at 25°C over 30 minutes and stirring was continued for 24 hours (monitored by thin layer chromatography on 0.2 mm silica gel plates 60F-254 Merck using CHCl / MeOH 95:5 v / v as eluent). Deionized water (150 ml) was added directly to the crude reaction mixture and stirring was maintained until complete precipitation. The insoluble material was recovered by filtration in a Buchner funnel (porosity N°4), and the precipitate was washed successively with deionized water (3x50 ml) and then with hexane (2x50 ml). The resulting precipitate was stirred in hexane (50 ml), and the suspension was concentrated under reduced pressure using a rotary evaporator. The resulting solid was concentrated under high vacuum (10 -3 Further drying at 400 torr gave the desired compound 3a as a white powder in 41% yield. Compound 3a was found to be pure enough for subsequent use without further purification. Mp = 73-74°C.

[0248] 1H NMR(300MHz,DMSO-d6)δ=1.96(m,2H,CH2,H-2′),2.65(td,J=7.1,5.1Hz,4H,CH2,H-2,H-3′),3.55(q,J=6.6Hz,2H,CH2,H-1),3.71(s,3H,OCH3),3.89(t,J=6.4Hz,CH2,2H,H-1′),4.61(t,J=5.2Hz,1H,OH),6.83(t,J=7.7Hz,4H,H-2 a ,H-6 a ,H-2,H-6 b ,Ar),7.12(t,J=8.6Hz,4H,H-3,H-5,H-3,H-5,Ar).

[0249] 13 C NMR(75MHz,DMSO-d6)δ=30.6(C-3′),30.7(C-2′),38.2(C-2),55.0(OCH3),62.5(C-1),66.5(C-1′),113.8(C-3 b ,C-5 b ),114.2(C-3 a ,C-5 a ),129.3(C-2 b ,C-6 b ),129.8(C-2 a ,C-6 a ),131.3(C-1 a ),133.2(C-1 b ),156.9(C-4 a ),157.5(C-4 b ).

[0250] HRMS,m / z=295.1310found(calculated for C 18 H 22 O3Na[M+Na] + requires295.1311).

[0251] 4-(4-Methoxyphenethoxy)phenethyl methanesulfonate (4a). A solution of methanesulfonyl chloride (2.55 g, 22.2 mmol, 2 eq.) in anhydrous dichloromethane (CH2Cl2) (3.5 ml) was added dropwise to a cooled solution (0°C, ice bath) of 2-(4-(4-methoxy-phenethoxy)phenyl)ethan-1-ol 3a (3.027 g, 11.1 mmol) and triethylamine TEA (1.12 g, 27.75 mmol, 2.5 eq.) in 8 ml of dry CH2Cl2 under magnetic stirring (500 rpm) for 15 minutes. Stir further at room temperature for 8 hours. The crude reaction mixture was transferred to a separatory funnel. The organic layer was washed successively with deionized water (3×100 ml) and saturated sodium bicarbonate NaHCO3 (3×100 ml). After decantation, the organic layer was dried over anhydrous MgSO4, filtered on a paper filter, and the filtrate was concentrated under reduced pressure in a rotary evaporator. After standing, the viscous oil gradually crystallized to give the desired compound as a white powder in 78% yield. Mp = 51-52°C.

[0252] 1 H NMR (300MHz, DMSO-d6) δ = 2.93 (dt, J = 10.4, 6.8Hz, 4H, CH2, H-2, H-2′). 3.10 (s, 3H, SCH3), 3.72 (s, 3H, OCH3), 4.11 (t, J=6.9Hz, 2H, CH2, H-1), 4.35 (t, J=6.8Hz, 2H, CH2, H-1′), 6.79-6.98 (m, 4H, H-3 a , H-5 a , H-3 b , H-5 b , Ar), 7.19 (d, J=8.6Hz, 2H, H-2 b , H-6 b , Ar), 7.24 (d, J=8.7Hz, 2H, H-2 a , H-6 a , Ar).

[0253] 13 C NMR (75MHz, DMSO-d6) δ=33.9(C-2), 34.1(C-2′), 36.6(SCH3), 55.1(OCH3), 68.4(C-1′), 70.9(C-1), 113.8(C-3 a , C-5 a ), 114.4(C-3 b , C-5 b ), 128.8(C-1 a ), 129.9(C-2 b, C-6 b ), 130.0(C-2 a , C-6 a ), 130.2(C-1 b ), 157.3(C-4 a ), 157.8(C-4 b ).

[0254] HRMS, m / z=373.1086 found (calculated for C 18 H 22 O5NaS[M+Na] + requires373.1084).

[0255] 1-[4-(4-methoxyphenethoxy)phenethyl]-1H-benzo[d]imidazole (6αa). To a vigorously stirred (550rpm) solution of benzimidazole 5αa (2mmol) in 3.4ml DMF was added a dispersion of 60% sodium hydride in mineral oil (0.081g, 2mmol) in batches, and the resulting suspension was stirred for 5 minutes. After a one-time addition of 4-(4-methoxyphenethoxy)phenethyl methanesulfonate 4a (1mmol), the reaction mixture was heated at 60°C for 12 hours. After cooling to room temperature, deionized water (34ml) was added to the reaction mixture, the flask was shaken manually, and then stored at 4°C (refrigerator) for 6 hours until precipitation was complete. The insoluble material was recovered by filtration in a Buchner funnel (porosity N°4), and the precipitate was washed with deionized water (3x17ml) and hexane (3x7ml) in sequence. Under high vacuum (10 -3 The solid was further dried at 400 torr to obtain 0.307 g of the desired compound 6αa as a white powder with a yield of 77%. Mp = 116-118°C.

[0256] 1 H NMR (300MHz, DMSO-d6) δ = 2.92 (t, J = 6.9Hz, 2H, CH2, H-2'), 3.03 (t, J = 7.2Hz, 2H, CH2, H-2”), 3.72 (s, 3 H, OCH3), 4.07 (t, J=6.9Hz, 2H, CH2, H-1'), 4.43 (t, J=7.2Hz, 2H, CH2, H-1"), 6.79 (d, J=8.1Hz, 2H, H-3 b , H-5 b , Ar), 6.86 (d, J=8.6Hz, 2H, H-3 a , H-5 a , Ar), 7.04 (d, J=8.1Hz, 2H, H-2 b , H-6b , Ar), 7.21 (ddd, J = 10.5, 6.0, 2.7 Hz, 4H, H-2 a , H-6 a , H-6, H-7, Ar), 7.55 - 7.65 (m, 2H, H-5, H-8, Ar), 8.00 (s, 1H, H-2).

[0257] 13 C NMR (75 MHz, DMSO-d6) δ = 34.1 (C-2’), 34.5 (C-2”), 45.7 (C-1”), 55.0 (OCH3), 68.3 (C-1’), 110.5 (C-5), 113.8 (C-3 b , C-5 b ), 114.4 (C-3 a , C-5 a ), 119.4 (C-8), 121.4 (C-6), 122.2 (C-7), 129.8 (C-2 b , C-6 b ), 129.9 (C-2 a , C-6 a ), 130.0 (C-1 a ), 130.2 (C-1 b ), 133.6 (C-9), 143.3 (C-4), 143.9 (C-2), 157.1 (C-4 a ), 157.8 (C-4 b ).

[0258] HRMS m / z = 395.1732 found (calculated for C 24 H 24 N2O2Na [M+Na] + requires 395.1730), 373.1912 found (calculated for C 24 H 25 N2O2 [M+H] + requires 373.1911).

[0259] Example 2

[0260]

[0261] 1-(4-(4-methoxyphenethoxy)phenethyl)-1H-indazole (6αb). To a vigorously stirred solution of indazole 5αb (0.571 mmol) in 1 ml of DMF (550 rpm) was added a dispersion of 60% sodium hydride in mineral oil (0.023 g, 2 mmol), and the resulting suspension was stirred for 5 minutes. After a single addition of 4-(4-methoxyphenethoxy)phenethyl methanesulfonate 4a (0.286 mmol), the reaction mixture was heated at 60°C for 24 hours. After cooling to room temperature, deionized water (10 ml) was added to the reaction mixture. Extraction was performed with ethyl acetate (3×10 ml), and the collected extracts were transferred to a separatory funnel. The organic phase was washed with brine (3×10 ml). After decantation, the organic layer was dried over anhydrous MgSO4, filtered on a paper filter, and the filtrate was concentrated under reduced pressure in a rotary evaporator. The crude residue was purified by preparative chromatography (Combi Flash R f Purification was performed on a prepacked silica gel column 60F-254 (Merck) using a step gradient of cyclohexane / acetonitrile (0-25%) at 200 psi with a DAD 200 / 360 nm detector. The elution was combined for 60 minutes and the solvent was removed in vacuo to give 14 mg (13% yield) of pure desired compound 6αb as a white powder. Mp = 124-126°C.

[0262] 1 H NMR (300MHz, DMSO-d6) δ = 3.07 (t, J = 7.2Hz, 2H, CH2, H-2'), 3.74 (s, 3H, OCH3), 4. 57(t, J=7.2Hz, 2H, CH2, H-1'), 4.92 (s, 2H, CH2, OCH2), 6.82 (d, J=8.5Hz, 2H, H-3 b , H-5 b , Ar), 6.92 (t, J=5.7Hz, 2H, H-3 a , H-5 a , Ar), 7.14-6.99(m, 3H, H-5, H-2 b , H-6 b , Ar), 7.31 (dd, J=12.2, 5.6Hz, 3H, H-8, H-2 a , H-6 a , Ar), 7.52 (d, J=8.5Hz, 1H, H-6, Ar), 7.72 (d, J=8.1Hz, 1H, H-7, Ar), 8.04 (s, 1H, H-2, Ar).

[0263] 1313C NMR (75 MHz, DMSO-d6) δ = 34.8 (C-2’), 49.8 (C-1’), 55.3 (OCH3), 69.1 (OCH2), 109.7 (C-5), 114.0 (C-3 a , C-5 a ), 114.8 (C-3 b , C-5 b ), 120.4 (C-8), 120.9 (C-6), 123.5 (C-1 a ), 126.1 (C-7), 129.2 (C-1 b ), 129.6 (C-2 a , C-6 a ), 129.9 (C-2 b , C-6 b ), 130.7 (C-9), 132.8 (C-3), 139.4 (C-4), 157.1 (C-4 a ), 159.1 (C-4 b ).

[0264] HRMS, m / z = 395.1732 found (calculated for C 24 H 24 N2O2Na [M+Na] + requires 395.1730), 373.1913 found (calculated for C 24 H 25 N2O2 [M+H] + requires 373.1911), 411.1473 found (calculated for C 24 H 24 N2O2K [M+K] + requires 411.1469).

[0265] Example 3

[0266]

[0267] 2-Trifluoromethyl-1H-benzo[d]imidazole (5αc). O-phenylenediamine (1 g, 9.25 mmol) and trifluoroacetic acid TFA (1.581, 13.87 mmol, 1.5 equiv) were heated to reflux for 24 h under vigorous magnetic stirring (500 rpm). After cooling to room temperature, the reaction mixture was carefully and stepwise transferred to a saturated sodium carbonate solution (100 ml). Extraction was performed with ethyl acetate (3×50 ml), and the collected extracts were transferred to a separatory funnel. The organic phase was washed with brine (3×50 ml). After decantation, the organic layer was dried over anhydrous MgSO4, filtered on a paper filter, and the filtrate was concentrated under reduced pressure on a rotary evaporator. The resulting solid was concentrated under high vacuum (10 -3 The mixture was further dried at 400 °C (240 °C) to give the desired compound 5αc as a brown powder with a yield of 97%. The purity of compound 5αc was sufficient for subsequent use without further purification. Mp = 213-218 °C.

[0268] 1 H NMR (300MHz, DMSO-d6) δ=7.38 (dd, J=6.2, 3.2Hz, 2H, H-5, H-6, Ar), 7.72 (dt, J=6.7, 3.3Hz, 2H, H-4, H-7, Ar), 12.53 (br s, 1H, NH).

[0269] 13 C NMR (75MHz, DMSO-d6) δ = 117.3 (C-4, C-7), 120.9 (CF3), 124.1 (C-5, C-6), 139.8 (C-3a, C-7a), 140.3 (C-2).

[0270] 19 F NMR (282MHz, DMSO-d6) δ = -62.8.

[0271] HRMS, m / z=209.0295found(calculated for C8H5N2F3Na[M+Na] + requires209.0297).

[0272] 1-(4-(4-methoxyphenethoxy)phenethyl)-2-trifluoromethyl-1H-benzo[d]imidazole (6αc). To a vigorously stirred (550 rpm) solution of 2-trifluoromethylbenzimidazole 5αc (0.571 mmol) in 1 ml of DMF was added a dispersion of sodium hydride 60% in mineral oil (0.023 g, 2 mmol), and the suspension was stirred for 5 minutes. After a single addition of 4-(4-methoxyphenethoxy)phenethyl methanesulfonate 4a (0.286 mmol), the reaction mixture was heated at 60°C for 24 hours. After cooling to room temperature, deionized water (10 ml) was added to the reaction mixture. Extraction was performed with ethyl acetate (3×10 ml), and the collected extracts were transferred to a separatory funnel. The organic phase was washed with brine (3×10 ml). After decantation, the organic layer was dried over anhydrous MgSO4, filtered on a paper filter, and the filtrate was concentrated under reduced pressure in a rotary evaporator. The crude residue was purified by preparative chromatography (CombiFlash R f Purification was performed on a prepacked column of silica gel 60F-254 (Merck) at 200 psi with DAD 200 / 360 nm detector using a step gradient of CH2Cl2 / MeOH (0-1%). The reaction mixture was combined for 60 minutes and the solvent was removed in vacuo to give 62.5 mg (50% yield) of pure desired compound 6αc as a viscous white oil.

[0273] 1 H NMR (300MHz, DMSO-d6) δ = 2.92 (t, J = 6.9Hz, 2H, CH2, H-2”), 3.02 (t, J = 7.5Hz, 2H, CH2, H-2’), 3.72 (s, 3 H, OCH3), 4.07 (t, J=6.9Hz, 2H, CH2, H-1'), 4.54 (t, J=7.5Hz, 2H, CH2, H-1"), 6.80 (d, J=8.6Hz, 2H, H-3 b , H-5 b , Ar), 6.86 (d, J=8.6Hz, 2H, H-3 a , H-5 a , Ar), 7.03 (d, J=8.6Hz, 2H, H-2 b , H-6 b , Ar), 7.20 (d, J=8.6Hz, 2H, H-2 a , H-6 a , Ar), 7.40 (dddd, J=19.9, 8.2, 7.2, 1.2Hz, 2H, H-6, H-7, Ar), 7.70-7.76 (m, 1H, H-8, Ar), 7.78-7.84 (m, 1H, H-5, Ar).

[0274] 13 13C NMR (75 MHz, DMSO-d6) δ = 34.1 (C-2’), 34.6 (C-2”), 46.4 (C-1”), 55.1 (OCH3), 68.4 (C-1’), 112.1 (C-5), 113.8 (C-3 b , C-5 b ), 114.6 (C-3 a , C-5 a ), 120.9 (C-8), 123.6 (C-6), 125.3 (C-7), 129.2 (C-1 a ), 129.9 (C-2 b , C-6 b ), 130.0 (C-2 a , C-6 a ), 130.2 (C-1 b ), 135.2 (C-9), 140.4 (C-4), 157.4 (C-4 a ), 157.9 (C-4 b ).

[0275] 19 19F NMR (282 MHz, DMSO-d6) δ = -60.8.

[0276] HRMS m / z = 463.1604 found (calculated for C 25 H 23 N2O2F3Na [M+Na] + requires 463.1604), 373.1912 found (calculated for C 25 H 24 N2O2F3 [M+H] + requires 373.1911), 479.1341 found (calculated for C 25 H 23 N2O2F3K [M+K] + requires 479.1343).

[0277] Example 4

[0278]

[0279] 5-Fluoro-1H-benzo[d]imidazole (5αd). To a mixture of 4-fluoro-o-phenylenediamine (0.5 g, 3.96 mmol) in 2.5 ml of 5.5 M HCl solution was added formic acid (0.273 g, 5.95 mmol, 1.5 equiv). The resulting reaction mixture was heated under reflux with vigorous magnetic stirring (500 rpm) for 4 hours. After cooling to room temperature, 10 ml of 28-30% ammonia was carefully added dropwise to the reaction mixture over 10 minutes. Extraction was performed with ethyl acetate (4×50 ml), and the collected extracts were transferred to a separatory funnel. The organic phase was washed with deionized water (4×50 ml). After decantation, the organic layer was dried over anhydrous MgSO4, filtered on a paper filter, and the filtrate was concentrated under reduced pressure in a rotary evaporator. 10 ml of hexane was added to the resulting solid, and the suspension was ground for 10 minutes. The insoluble material was recovered by filtration on a Buchner funnel (porosity N° 4) and concentrated under high vacuum (10 -3 The mixture was further dried at 400 °C to give the desired compound 5αd as a purple powder in 89% yield. Mp = 142-145 °C.

[0280] 1 H NMR (300MHz, DMSO-d6) δ=7.05 (td, J=9.3, 2.5Hz, 1H, H-6, Ar), 7.39 (m, 1H, H-3, Ar), 7.58 (m, 1H, H-7, Ar), 8.25 (s, 1H, H-2, Ar), 12.53 (br s, 1H, NH).

[0281] 13 C NMR (75MHz, DMSO-d6) δ = 109.7 (C-4), 110.0 (C-6), 143.3 (C-3a), 157.3 (C-2), 159.6 (C-5).

[0282] 19 F NMR (282MHz, DMSO-d6) δ = -121.4.

[0283] HRMS, m / z=137.0507found(calculated for C7H6N2F[M+H] + requires137.05095).

[0284] 5-Fluoro-1-(4-(4-methoxyphenethoxy)phenethyl)-2-trifluoromethyl-1H-benzo[d]imidazole (6αd). To a vigorously stirred (550 rpm) solution of 5-fluoro-benzimidazole 5αd (0.571 mmol) in 1 ml of DMF was added a dispersion of sodium hydride 60% in mineral oil (0.023 g, 2 mmol) and the resulting suspension was stirred for 5 minutes. After a single addition of 4-(4-methoxyphenethoxy)phenethyl methanesulfonate 4a (0.286 mmol), the reaction mixture was heated at 60°C for 12 hours. After cooling to room temperature, deionized water (10 ml) was added to the reaction mixture. Extraction was performed with ethyl acetate (2×10 ml), and the collected extracts were transferred to a separatory funnel. The organic phase was washed with brine (2×10 ml). After decantation, the organic layer was dried over anhydrous MgSO4, filtered on a paper filter, and the filtrate was concentrated under reduced pressure on a rotary evaporator. The crude residue was purified by preparative chromatography (Combi Flash R f Purification was performed by eluting with a step gradient of CH2Cl2 / MeOH (0-0.5%) on a prepacked column of silica gel 60F-254 (Merck) at 200 psi with DAD 200 / 360 nm detector. The reaction mixture was combined for 60 minutes and the solvent was removed in vacuo to give 63 mg (56% yield) of pure desired compound 6αd as a white powder. Mp = 121-123°C.

[0285] 1 H NMR (300MHz, DMSO-d6) δ=2.93 (t, J=6.9Hz, 2H, CH2, H-2"),), 3.02 (td, J=7.2, 2.8Hz, 2H, CH2, H-2'), 3.7 2(s, 3H, OCH3), 4.08 (t, J=6.9Hz, 2H, CH2, H-1'), 4.43 (q, J=7.4Hz, 2H, CH2, H-1”), 6.77-6.83 (m, 2H, H-3 b , H-5 b , Ar), 6.86 (d, J=8.6Hz, 2H, 2H, H-3 a , H-5 a , Ar), 6.98-7.15(m, 3H, H-7, H-2 b , H-6 b , Ar), 7.21 (d, J=8.6Hz, 2H, H-2 a , H-6 a,Ar),7.46(ddd,J=28.2,9.6,2.5Hz,1H,H-8,Ar),7.62(dt,J=8.8,5.1Hz,1H,H-5,Ar),8.07(d,J=10.7Hz,1H,H-2,Ar).

[0286] 13 C NMR(75MHz,DMSO-d6)δ=34.0(C-2’),34.5(d,J=8.8Hz)(C-2”),45.8(d,J=10.8Hz)(C-1”),55.0(OCH3),68.3(C-1’),97.1,97.4,104.6,104.9,109.5,109.7,110.2,110.5,111.3,111.4,113.7(C-3 b ,C-5 b ),114.4(C-3 a ,C-5 a ),120.1,120.2,129.7(C-2 b ),129.8(C-6 b ),129.9(C-2 a ,C-6 a ),129.9(C-1 a ),130.2(C-1 b ),139.7(C-9),145.2(d,J=69.5Hz)(C-2),159.7(d,J=41.9Hz)(C-6),157.1(C-4 a ),157.8(C-4 b ).

[0287] 19 F NMR(282MHz,DMSO-d6)δ=-122.0(td,J=9.7,4.8Hz),-119.8(td,J=9.6,5.0Hz).

[0288] HRMS m / z=413.1639found(calcuIated for C 24 H 23 N2O2FNa[M+Na] + requires413.1636),391.1819found(calculated for C 24 H 24 N2O2F[M+H] +requires 391.1816), 429.1379found(calculated for C 24 H 23 N2O2FK[M+K] + requires 429.1375).

[0289] Example 5

[0290]

[0291] 4-Chloro-1-(4-(4-methoxyphenethoxy)phenethyl)-6-(trifluoromethyl)-1H-benzo[d]imidazole (6αe). Compound 6αe was prepared from 4-(4-methoxyphenethoxy)phenethyl methanesulfonate 4a and 4-chloro-5-trifluoromethylbenzimidazole 5αe according to the procedure described in Example 1 for the preparation of 6αa in 25% yield (0.115 g). Mp = 119-121°C.

[0292] 1 H NMR (300MHz, DMSO-d6) δ = 2.91 (t, J = 6.8Hz, 2H, CH2, H-2”), 3.04 (t, J = 6.9Hz, 2H, CH2, H-2’), 3.72 (s, 3 H, OCH3), 4.05 (t, J=6.9Hz, 2H, CH2, H-1'), 4.58 (t, J=6.9Hz, 2H, CH2, H-1"), 6.77 (d, J=8.6Hz, 2H, H-3 b , H-5 b , Ar), 6.86 (d, J=8.6Hz, 2H, H-3 a , H-5 a , Ar), 7.02 (d, J=8.6Hz, 2H, H-2 b , H-6 b , Ar), 7.20 (d, J=8.6Hz, 2H, H-2 a , H-6 a , Ar), 7.54-7.63 (m, 1H, H-8, Ar), 7.92 (dd, J=1.6, 0.8Hz, 1H, H-5, Ar), 8.37 (s, 1H, H-2, Ar).

[0293] 19 F NMR (282MHz, DMSO-d6) δ = -51.0.

[0294] HRMS m / z=497.1220found(calculated for C 25 H22 N2O2F3 35 CI Na[M+Na] + requires 497.1214), 475.1397found(calculated for C 25 H 23 N2O2F3 35 CI[M+H] + requires475.1395),513.0959found(calculated for C 25 H 22 N2O2F3 35 CIK[M+K] + requires513.0954).

[0295] Example 6

[0296]

[0297] 2,6-Difluoro-N-(2-(trifluoromethyl)-1H-benzo[d]imidazol-5-yl)benzamide (5αg). To a solution of 5-amino-2-trifluoromethylbenzimidazole 5αf (0.5 g, 2.48 mmol) in 2 ml of dry acetonitrile (MeCN) and cooled at 0°C (ice bath) was added triethylamine TEA (4.97 mmol, 2 eq.) dropwise under vigorous magnetic stirring (500 rpm), and stirring was then continued at 0°C for 10 minutes. A solution of 2,6-difluorobenzoyl chloride (2.48 mmol, 1 eq.) in 0.5 ml of dry acetonitrile was added dropwise to the mixture for 3 minutes. The resulting reaction mixture was mixed at room temperature for 7 days (monitored by thin layer chromatography on 0.2 mm silica gel plates 60 F254 Merck using CH2Cl2 / MeOH 9:1 v / v as eluent). The solvent of the reaction mixture was removed under reduced pressure in a rotary evaporator, and 10 ml of deionized water and 20 ml of ethyl acetate were poured into the crude residue in sequence. The resulting mixture was transferred to a separatory funnel and after separation of the organic layer; extraction from the aqueous layer was performed with 3×75 ml of AcOEt. The collected organic layer was dried over magnesium sulfate and filtered on a paper filter. The filtrate was concentrated in vacuo to give the desired compound 5αg in a yield of 78% as a brown powder. The purity of compound 5αg was sufficient for subsequent use without further purification. Mp=159-162°C.

[0298] 1H NMR (300MHz, DMSO-d6) δ = 7.28 (t, J = 8.0Hz, 2H, H-3”, H5”, Ar), 7.59 (m, 2H, H-6, H -7, Ar), 7.75 (d, J=8.8Hz, 1H, H-4”, Ar), 8.32 (d, J=1.9Hz, 1H, H-4, Ar), 10.99 (br s, 1H, NH).

[0299] 13 C NMR (75MHz, DMSO-d6) δ = 112.0 (C-4, Ar), 112.3 (C-3”, C-5”, Ar), 1152 (C-7, Ar), 115.5 (C-1”, Ar), 115.8 (CF3), 117.3 (C-6, Ar), 120.8 (C-4”, Ar), 132.2 (C-5, Ar), 135.4 (C-7 a , Ar), 140.6(C-3 a , Ar), 157.3 (C=O, C-2), 1582 (C-2″, C-6″, Ar), 160.5 (C=N, C-2, Ar).

[0300] 19 F NMR (282MHz, DMSO-d6) δ = -114.0), -62.7 (CF3).

[0301] HRMS, m / z=364.0481 found (calculated for C 15 H8N3F5Na[M+Na] + requires364.0480).

[0302] N-(1-(4-(4-methoxyphenethoxy)phenethyl)-2-(trifluoromethyl)-1H-benzo[d]imidazol-5-yl)-2,6-difluorobenzamide (6αf). Compound 6αc was prepared in 26% yield from 2,6-difluoro-N-(2-(trifluoromethyl)-1H-benzo[d]imidazol-5-yl)benzamide 5ag (0.176 g, 0.52 mmol, 1.45 equiv) and 4-(4-methoxyphenethoxy)phenethyl methanesulfonate 4a (0.125 g, 0.356 mmol, 1 equiv) according to the procedure described in Example 3 for the preparation of 6αc. Mp = 69-70°C.

[0303] 1H NMR(300MHz,DMSO-d6)δ=2.93(tt,J=7.0,2.9Hz,2H,CH2,H-2”),3.04(m,2H,CH2,H-2′),3.72(s). H,OCH3),4.08(tt,J,6.9,2.5Hz,2H,CH2,H-1'),4.53(q,J,7.4Hz,2H,CH2,H-1”),6.84Hz-3Hz. a ,H-5 a ,H-3 b ,H-5 b ,Ar),7.02(m,2H,H-3 c ,H-5 c ,Ar),7.24(m,4H,H-2 a ,H-6 a ,H-2 b ,H-6 b ,Ar),7.64(m,3H,H-6,H-7,H-4 c ,Ar),8.28(dd,J,16.4,1.8Hz,1H,H-4,Ar),10.97(d,J,35.8Hz,1H,NH).

[0304] 13 C NMR(75MHz,DMSO-d6)δ=34.1(C-2'),34.6(C-2”),46.6(C-1'),55.1(OCH3),68.4(C-1”),10)1.9(C-4),17(C-4)(C-3)). c ,C-5 c ,Ar),112.1(CF3),112.5(C-1) c ,Ar),113.8(C-3 a ,C-5 a ,Ar),114.6(C-3 b ,C-5 b ,Ar),114.7(C-7,Ar),118.6(C-6,Ar),129.1(C-2 b ,C-6 b ,Ar),129.8(C-2 a ,C-6 a ,Ar),130.0(C-7a,Ar),130.2(C-1 a ,Ar),134.8(C-5,Ar),136.3(C-4 c ,Ar),137.2(C-3a,Ar),140.5(C-2,Ar),157.4(C-2c , C-6 c , Ar), 157.9, 158.2, 158.4, 160.6 (C=O, C-2”').

[0305] 19 F NMR (282MHz, DMSO-d6) δ = -114.(), -113.9, -60).7(CF3).

[0306] HRMS, m / z=618.1786 found (calculated for C 32 H 26 N3F5Na[M+Na] + requires618.17865).

[0307] Example 7

[0308]

[0309] 1-(4-(2-phenoxyethoxy)phenethyl)-1H-benzo[d]imidazole (6αk). Compound 6αk was prepared from 4-(2-phenoxyethoxy)phenethyl methanesulfonate 4k and benzimidazole 5αa according to the procedure described in Example 1 for the preparation of 6αa in 34% yield (0.125 g). Mp = 141-143°C.

[0310] 1 H NMR (300MHz, DMSO-d6) δ = 3.05 (t, J = 7.2Hz, 2H, CH2, H-2'), 4.35-4.18 (m, 4.H, CH2, H-1″, H-2”), 4.45 (t, J = 7.2Hz, 2H, CH2, H-1’), 7.01-6.81 (m, 5H, H-3 b , H-4 b , H-5 b , H-6, H-7, Ar), 7.08 (d, J=8.6Hz, 2H, H-5, H-8, Ar), 7.24 (dddd, J=29.2, 27.6, 13.7, 7.5Hz, 4H, H-3 a , H-5 a , H-2 b , H-6 b , Ar), 7.67-7.58(m, 2H, H-2 a , H-6 a , Ar), 8.02 (s, 1H, H-2, Ar).

[0311] 1313C NMR (75 MHz, DMSO-d6) δ = 34.5 (C-2’), 45.6 (C-1’), 66.2 (C-2”), 66.25 (C-1”), 110.4 (C-5), 114.4 (C-3 b , C-5 b ), 114.5 (C-3 a , C-5 a ), 119.3 (C-8), 120.7 (C-6), 121.3 (C-7), 122.1 (C-4 b ), 129.5 (C-2 b , C-6 b ), 129.8 (C-2 a , C-6 a ), 130.3 (C-1 a ), 133.6 (C-4), 143.4 (C-9), 143.9 (C-2), 157.0 (C-1 b ), 158.3 (C-4 a ).

[0312] HRMS m / z = 381.1569 found (calculated for C 23 H 22 N2O2Na [M+Na] + requires 381.1573), 359.1753 found (calculated for C 23 H 23 N2O2 [M+H] + requires 359.1754).

[0313] Example 8

[0314]

[0315] 2-(Trifluoromethyl)-1H-benzo[d]imidazol-5-ylcarbamic acid tert-butyl ester (5αh). Under vigorous magnetic stirring (500rpm), triethylamine TEA (0.2369g, 326ml, 2.34mmol) was added dropwise to a solution of 5-amino-2-(trifluoromethyl)benzimidazole 5αf (0.470g, 2.34mmol) in 8ml dichloromethane, followed by di-tert-butyl carbonate (t-BuOC)2O (0.510g, 538ml, 2.34mmol) and stirred at 30°C for 5 days (monitored by thin layer chromatography using 0.2mm silica gel plate 60-F254 Merck). The reaction mixture was concentrated under reduced pressure using a rotary evaporator and the crude residue was purified by chromatography (Combi Flash R f Purification was performed by eluting with a stepwise gradient of cyclohexane / AcOEt (0-50%) on a prepacked column of silica gel 60F-254 (Merck) at 200 psi with DAD 200 / 360 nm detector. The elution was combined for 60 minutes and the solvent was removed in vacuo to give the pure desired compound 5αh as a white powder in 84% yield. Mp = 210-212°C.

[0316] 1 H NMR (300MHz, DMSO-d6) δ = 1.5 ((s, 9H, (CH3)3), 7.36 (d, J = 8.9Hz, 1H, H-6), 7.62 (d, J =8.8Hz, 1H, H-7), 7.94 (d, J = 1.9Hz, 1H, H-4), 9.52 (s, 1H, H-1′), 13.70 (s, 1H, H-1).

[0317] 13 C NMR (75MHz, DMSO-d6) δ=28.2(CH3)3), 79.2(C-4″), 117.3(C-7), 120.9(CF3), 152.9(C-2″).

[0318] 19 F NMR (282MHz, DMSO-d6) δ = -62.6.

[0319] HRMS, m / z=324.0934 found (calculated for C 13 H 15 N3O2F5Na[M+Na] + requires324.0930).

[0320] tert-Butyl 1-(4-(4-methoxyphenethoxy)phenethyl)-2-(trifluoromethyl)-1H-benzo[d]imidazol-5-ylcarbamate (6αl). To a solution of tert-butyl 2-(trifluoromethyl)-1H-benzo[d]imidazol-5-ylcarbamate 5αh (1.2 mmol) in 3.5 ml of dry DMF was added potassium bicarbonate NaHCO3 (3.6 mmol, 3 eq) in portions and stirring was continued for 30 minutes. After addition of 4-(4-methoxyphenethoxy)phenethyl methanesulfonate 4a (1.2 mmol), the mixture was heated at 60°C for 3 days (monitored by thin layer chromatography using 0.2 mm silica gel plate 60-F254 Merck). After cooling to room temperature, 35 ml of deionized water was poured into the reaction mixture and the resulting solution was transferred to a separatory funnel. The mixture was extracted with ethyl acetate (4 x 25 ml), and the collected extracts were washed with deionized water (4 x 25 ml), brine (2 x 45 ml), dried over anhydrous MgSO4 and filtered on a paper filter. The filtrate was concentrated under reduced pressure using a rotary evaporator, and the crude residue was purified by chromatography (Combi Flash R f Purification was performed by eluting with a step gradient of cyclohexane / AcOEt (0-50%) on a prepacked column of silica gel 60F-254 (Merck) at 200 psi with DAD 200 / 360 nm detector. The elution was combined for 60 minutes and the solvent was removed in vacuo to give the pure desired compound 6α1 as a beige viscous paste in 73% yield. Mp < 50°C.

[0321] 1 H NMR (300MHz, DMSO-d6) δ=1.50 (d, J=5.1Hz, 9H, (CH3)3), 2.93 (m, 2H, CH2, H-2”), 3.01 (t, J=7.4Hz, 2H.CH2, H -2'), 3.73 (s, 3H, OCH3), 4.08 (t, J=6.9Hz, 2H, CH2, H-1'), 4.45 (t, J=7.4Hz, 2H, CH2, H-1"), 6.84 (m, 4H, H-3 a , H-5 a , H-3 b , H-5 b , Ar), 7.01 (dd, J=8.6, 4.2Hz, 2H, H-2 a , H-6 a , Ar), 7.22 (m, 2H, H-2 b , H-6 b),7.35(dd,J=8.9,1.9Hz,1H,H-6,Ar),7.68(d,J=8.9Hz,1H,H-7,Ar),7.93(d,J=15.8Hz,1H,H-4),9.57(s,1H,NH).

[0322] 13 C NMR(75MHz,DMSO-d6)δ=28.1(CH3)3,34.0)(C-2’),34.6(C-2”),46.2(C-1’),55.0(OCH3),68.4(C-1”),79.3(CO),111.8(C-4),113.7(CF3),114.5(C-3 b ,C-5 b ),114.6(C-3 a ,C-5 a ),116.1(C-7),120.9(C-6),129.6(C-2 a ,C-1 a ).129.8(C-7 a ),129.9(C-1 a ),130.1(C-1 b ),135.4(C-5),135.9(C-3 a ),137.5(C-2),152.8(C=O),157.3(C-4 a ),157.8(C-4 b ).

[0323] 19 F NMR(282MHz,DMSO-d6)δ=-60.6.

[0324] HRMS,m / z=578.2235found(calculated for C 30 H 32 N3O4F3Na[M+Na] + requires578.2237).

[0325] 5-amino-1-(4-(4-methoxyphenethyloxy)phenethyl)-6-(trifluoromethyl)-1H-benzo[d]imidazole hydrochloride (6αm). At room temperature, under vigorous magnetic stirring (500rpm), 1.1ml 6M HCl solution (24 equivalents) was added dropwise to a solution of tert-butyl 1-(4-(4-methoxyphenethyloxy)phenethyl)-2-(trifluoromethyl)-1H-benzo[d]imidazole-5-ylcarbamate 6αl (0.155g, 0.277mmol) in 2.1ml dioxane. Stirring was continued for 3 days (monitored by thin layer chromatography using 0.2mm silica gel plate 60-F254Merck). The reaction mixture was concentrated under reduced pressure using a rotary evaporator. 5ml of dry ether Et2O was poured into the crude residue, and the suspension was ground for 10 minutes to obtain a fine powder. The insoluble material was recovered by filtration on a Buchner funnel (porosity N° 4), washed with Et2O (2×5 ml) and concentrated under high vacuum (10 -3 The desired hydrochloride 6αm was obtained as a white powder with a yield of 26%. Mp = 210-212°C.

[0326] 1 H NMR (300MHz, DMSO-d6) δ=2.93 (td, J=7.0, 2.1Hz, 2H), 3.03 (q, J=7.0Hz, 2H), 3.72 (s, 3H), 4.08 (td, J=6.9, 4.7Hz, 2H), 4.5 4 (dt, J=24.4, 7.5Hz, 2H), 6.85 (m, 4H), 7.04 (t, J=8.2Hz, 2H), 7.24 (ddd, J=9.7, 8.6, 1.4Hz, 2H), 7.50 (m, 1H), 7.85 (m, 1H).

[0327] 13 C NMR (75MHz, DMSO-d6) δ=34.0(C-2″), 34.5(C-2′), 46.4(C-1′), 55.0(OCH3), 68.4(C-1″), 103.7(C-4), 113.4(CF3), 113.7(C-3 a , C-5 a ), 114.6(C-3 b , C-5 b ), 118.0(C-7), 120.5(C-6), 121.9(C-7a), 128.1(C-1 a ), 129.0(C-1 b ), 129.7(C-2 b , C-6 b ), 129.9(C-2 a, C-6 a ), 130.1(C-3a), 137.9(C-2), 140.3(C-5), 157.3(C-4 a ), 157.8(C-4 b ).

[0328] 19 F NMR (282MHz, DMSO-d6) δ = -61.0.

[0329] Example 9

[0330]

[0331] 1-(4-(4-methoxyphenethoxy)phenethyl)-3-(trifluoromethyl)-1H-1,2,4-triazole (6βa). Compound 6βa was prepared from 4-(4-methoxyphenethoxy)phenethyl methanesulfonate 4a and 3-(trifluoromethyl)-1H-1,2,4-triazole 5βa according to the procedure described in Example 1 for the preparation of 6αa in 44% yield (0.171 g). Mp = 83-85°C.

[0332] 1 H NMR (300MHz, DMSO-d6) δ = 2.93 (t, J = 6.9Hz, 2H, CH2, H-2'), 3.06 (t, J = 7.2Hz, 2H, CH2, H-2”), 3.72 (s, 3H, O CH3), 4.08 (t, J=6.9Hz, 2H, CH2, H-1'), 4.48 (t, J=7.2Hz, 2H, CH2, H-1"), 6.84 (dd, J=10.4, 8.6Hz, 4H, H-3 a , H-5 a , H-3 b , H-5 b , Ar), 7.05 (d, J=8.6Hz, 2H, H-2 b , H-6 b , Ar), 7.21 (d, J=8.6Hz, 2H, H-2 a , H-6 a , Ar), 8.63 (d, J=0.9Hz, 1H, H-5).

[0333] 13 C NMR (75MHz, DMSO-d6) δ = 34.1 (C-2'), 34.1 (C-2"), 51.0 (C-1"), 55.0 (OCH3), 68.3 (C-1'), 113.7 (C-3 a , C-5 a ), 114.5(C-3b , C-5 b ), 129.1(C-1 a ), 129.6(C-2 b , C-6 b ), 129.9(C-2 a , C-6 a ), 130.2(C-1 b ), 146.4(C-5), 157.2(C-4 a ), 157.8(C-4 b ).

[0334] 19 F NMR (282MHz, DMSO-d6) δ = -63.8.

[0335] HRMS m / z=428.1554found(calculated for C 21 H 22 N3O2F3Na[M+Na] + requires428.1556).

[0336] Example 10

[0337]

[0338] 1-(4-(4-methoxyphenethoxy)phenethyl)-1H-1,2,4-triazole (6βb). Compound 6βb was prepared from 4-(4-methoxyphenethoxy)phenethyl methanesulfonate 4a and 1H-1,2,4-triazole 5βb according to the method used to prepare 6αa in Example 1 in a yield of 31% (0.102 g). Mp < 50°C.

[0339] 1 H NMR (300MHz, DMSO-d6) δ = 2.93 (t, J = 6.9Hz, 2H, CH2, H-2”), 3.02 (t, J = 7.1Hz, 2H, CH2, H-2’), 3.72 (s, 3 H, OCH3), 4.08 (t, J=6.9Hz, 2H, CH2, H-1'), 4.36 (t, J=7.1Hz, 2H, CH2, H-1"), 6.81 (d, J=8.6Hz, 2H, H-3 a , H-5 a , Ar), 6.86 (d, J=8.6Hz, 2H, H-3 b , H-5 b , Ar), 7.02 (d, J=8.6Hz, 2H, H-2 b , H-6 b, Ar), 7.22 (d, J = 8.6 Hz, 2H, H-2 a , H-6 a , Ar), 7.94 (s, H-5, Ar), 8.29 (s, H-3, Ar).

[0340] 13 C NMR (75 MHz, DMSO-d6) δ = 34.4 (C-2”), 34.7 (C-2’), 50.4 (C-1’), 55.4 (OCH3), 68.7 (C-1”), 114.1 (C-3 a , C-5 a ), 114.8 (C-3 b , C-5 b ), 129.9 (C-1 a ), 130.0 (C-2 a , C-6 a ), 130.3 (C-2 b , C-6 b ), 130.7 (C-1 b ), 144.3 (C-5), 151.5 (C-3), 157.4 (C-4 a ), 158.1 (C-4 b ).

[0341] HRMS m / z = 346.1528 found (calculated for C 19 H 21 N3O2Na [M+Na] + requires 346.1526), 324.1706 found (calculated for C 19 H 22 N3O2 [M+H] + requires 324.1707).

[0342] Example 11

[0343]

[0344] 2,6-Difluoro-N-(1H-pyrazol-3-yl)benzamide (5βd). To a vigorously stirred (500 rpm) solution of 3-aminopyrazole 5βc (0.5 g, 6.017 mmol) in 4.17 ml of dry acetonitrile cooled at 0°C (ice bath) was added dropwise triethylamine TEA (1.63 ml, 1.21 g, 12.034 mmol, 2 eq) for 10 min. Stirring was continued at 0°C for 10 min and then a solution of 2,6-difluorobenzoyl chloride (6.017 mmol, 1 eq) in 1.67 ml of dry MeCN was added dropwise for 3 min. Stirring was carried out at room temperature for 24 h (monitored by thin layer chromatography on 0.2 mm silica gel plates 60-F254 Merck using CH2Cl2 / MeOH 9:1 v / v as eluent). The reaction mixture was concentrated under reduced pressure using a rotary evaporator and 2 ml of deionized water and 4 ml of ethyl acetate were added to the crude residue. The resulting solution was transferred to a separatory funnel and the two phases were separated after decantation. The aqueous phase was washed with ethyl acetate (2×4 ml). The collected organic extracts were washed with deionized water (3×15 ml) in turn, dried over MgSO4 and filtered on a paper filter. The filtrate was concentrated under reduced pressure in a rotary evaporator to obtain a clear yellow viscous paste. The paste was ground in dichloromethane to produce a fine powder, which was washed with 15 ml of deionized water. The white powder was recovered by filtration on a Buchner funnel and concentrated under high vacuum (10 -2 The mixture was further dried at 400°C (250°C).

[0345] 1 H NMR (300MHz, DMSO-d6) δ = 6.63 (t, J = 2.1Hz, 1H, = CH, H-4), 7.20 (t, J = 8.0Hz, 2H, H-2"', H-6"'), 7. 55 (tt, J=8.4, 6.6Hz, 1H, H-4”'), 7.70 (t, J=1.8Hz, 1H, =CH, H-5), 11.24 (s1, 1H, H-1”), 12.50 (br s, 1H, H-1).

[0346] 13 C NMR (75MHz, DMSO-d6) δ=96.5 (=CH, C-4), 112.1 (C-3”, C-5”, Ar), 115.3 (C-1”’, Ar), 128.9 (=CH, C-5), 131.9 (C-4”, Ar), 146.5 (C=N, C-3), 157.4 (C-2”, C-6”, Ar), 160.6 (C-1”, Ar).

[0347] 19F NMR (282MHz, DMSO-d6) δ = -114.1, -114.0.

[0348] HRMS, m / z=246.0446 found (calculated for C 10 H7N3OF2Na[M+Na] + requires246.0449).

[0349] N-(1-(4-(4-methoxyphenethoxy)phenethyl)-1H-pyrazol-3-yl)-2,6-difluorobenzamide (6βc). Compound 6βc was prepared from 4-(4-methoxyphenethoxy)phenethyl methanesulfonate 4a (0.07, 0.2 mmol) and 2,6-difluoro-N-(1H-pyrazol-3-yl)benzamide 5βd (0.09 g, 0.4 mmol, 2 equiv) according to the procedure described in Example 6 for the preparation of 6αf in 21% yield as a white powder. Mp = 210-212°C.

[0350] 1 H NMR (300MHz, DMSO-d6) δ = 2.97 (dt, J = 17.9, 7.0Hz, 4H, CH2, H-2', H-2”), 3.73 (s, 3H, OCH3), 4.10 (t, J = 6. 9Hz, 2H, CH2, H-1'), 4.22 (t, J=6.8Hz, 2H, CH2, H-1″), 6.52 (d, J=2.3Hz, 1H, HC=, H-4, Ar), 6.86 (m, 4H, H-3 a , H-5 a , H-3 b , H-5 b , Ar), 7.06 (d, J=8.6Hz, 2H, H-2 b , H-6 b , Ar), 7.20 (m, 4H, H-2 a , H-6 a , H-3 c , H-5 c , Ar), 7.54 (d, J=2.4Hz, 2H, HC=, H-5, H-4 c Ar), 11.23 (br s, 1H, NH).

[0351] 1313C NMR (75 MHz, DMSO-d6) δ = 34.1 (C-2’), 35.0 (C-2”), 52.6 (C-1’), 55.0 (OCH3), 68.3 (C-1”), 96.6 (C═, C-4, Ar), 111.7 (C-3 C , C-5 C , Ar), 112.0 (C-1 c , Ar), 113.7 (C-3 a , C-5 a , Ar), 114.4 (C-3 b , C-5 b , Ar), 129.6 (C-2 a , C-6 a , Ar, C═, C-5, Ar), 129.9 (C-2 b , C-6 b , Ar), 130.1 (C-1 a , Ar), 130.2 (C-1 b , Ar), 130.5 (C-4 c , Ar), 131.8 (C═N, C-3, Ar), 146.1 (C-4 a , Ar), 157.0 (C-4 b , Ar), 157.3 (C-2 c , C-6 c , Ar), 157.8, 160.6 (C═O, C-2”’).

[0352] 19 19F NMR (282 MHz, DMSO-d6) δ = -114.1, -113.9.

[0353] HRMS, m / z = 500.1758 found (calculated for C 27 H 25 N3O3F2Na [M+Na] + requires 500.1756).

[0354] Example 12

[0355] General procedure for O-alkylation of 2-(4-hydroxyphenyl)ethanol 1a, 2-(3-hydroxyphenyl)ethanol 1b or 2-(2-hydroxyphenyl)ethanol 1c for the preparation of compound 3. To a solution of 2-(4-hydroxyphenyl)ethanol 1a or 2-(3-hydroxyphenyl)ethanol 1b or 2-(2-hydroxyphenyl)ethanol 1c (3.75 g, 27.14 mmol) in 15 ml of dry DMF was added portionwise 11.25 g of potassium carbonate KCO (8.43 mmol, 3 eq.) at room temperature under vigorous magnetic stirring (550 rpm). After 30 minutes, alkyl halide 2 (27.14 mmol) was added dropwise at 25° C. over 30 minutes and stirring was then continued for 24 hours (monitored by thin layer chromatography using 0.2 mm silica gel plates 60-F254 Merck, using CHCl / MeOH 95:5 v / v as eluent). Deionized water (150 ml) was added directly to the crude reaction mixture and stirred until complete precipitation. Insoluble material was recovered by filtration in a Buchner funnel (porosity N°4), and the precipitate was washed successively with deionized water (3 x 50 ml) and then with hexane (2 x 50 ml). The resulting precipitate was stirred in hexane (50 ml), and the suspension was concentrated under reduced pressure using a rotary evaporator; the resulting solid was concentrated under high vacuum (10 -3 Further drying at 400 torr gave the desired compound 3. Compound 3 was subsequently used without further purification.

[0356] 2-(4-(3-phenylpropoxy)phenyl)ethan-1-ol (3b). Compound 3b was prepared from 4-hydroxyphenylethanol 1a and 1-bromo-3-phenylpropane 2b according to the general procedure above in 95% yield as a white powder. Mp = 51-52°C.

[0357]

[0358] 1 H NMR (300MHz, DMSO-d6) δ=2.01 (dt, J=8.6, 6.3Hz, 2H, CH2, H-2′), 2.65 (t, J=7.1Hz, 2H, CH2, H-3′), 2.73 (t, J=7.7Hz, 2H, CH2, H-2), 3.55 (t, J=7.1Hz, 2H, CH2, H-1), 3.91 (t, J=6.3Hz, 2H, H-1′), 4.40-4.78 (br m, 1H, OH), 6.82 (d, J=8.4Hz, 2H, H-3 a , H-5 a , Ar), 7.11 (d, J=8.4Hz, 2H, H-2 a , H-6 a , Ar), 7.15-7.33(m, 5H, H-2b , H-3 b , H-4 b , H-5 b , H-6 b , Ar).

[0359] 13 C NMR (75MHz, DMSO-d6) δ=30.4(C-2′), 30.7(C-3′), 38.2(C-2), 62.4(C-1), 66.6(C-1′), 114.2(C-3 a , C-5 a ), 125.8(C-4 b ), 128.3(C-2 b , C-6 b ), 128.4(C-3 b , C-5 b ), 129.8(C-2 a , C-6 a ), 131.3(C-1 a ), 141.4(C-1 b ), 156.9(C-4 a ).

[0360] HRMS, m / z=279.1361 found (calculated for C 17 H 20 O2Na[M+Na] + requires279.1362).

[0361] 2-(4-(3-(4-methoxyphenyl)propoxy)phenyl)ethan-1-ol (3c). Compound 3c was prepared from 4-hydroxyphenylethanol 1a and 1-(3-bromopropyl)-4-methoxybenzene 2c according to the general procedure above in 85% yield as a white powder. Mp = 82-85°C.

[0362]

[0363] 1 H NMR (300MHz, DMSO-d6) δ = 1.96 (m, 2H, CH2, H-2′), 2.65 (td, J = 7.1, 5.1Hz, 4H, CH2, H-2, H-3′), 3.55 (q, J = 6.6Hz, 2 H, CH2, H-1), 3.71 (s, 3H, OCH3), 3.89 (t, J=6.4Hz, 2H, H-1′), 24.61 (t, J=5.2Hz, 1H, OH), 6.83 (t, J=7.7Hz, 4H, H-2 a, H-6 a , H-2 b , H-6 b , Ar), 7.12 (t, J=8.6Hz, 4H, H-3 a , H-5 a , H-3 b , H-5 b , Ar).

[0364] 13 C NMR (75MHz, DMSO-d6) δ=30.6(C-3′), 30).7(C-2′), 38.2(C-2), 55.0(OCH3), 62.5(C-1), 66.5(C-1′), 113.8(C-3 b , C-5 b ), 114.2(C-3 a , C-5 a ), 129.3(C-2 b , C-6 b ), 129.8(C-2 a , C-6 a ), 131.3(C-1 a ), 133.2(C-1 b ), 156.9(C-4 a ), 157.5(C-4 b ).

[0365] HRMS, m / z=309.1467 found (calculated for C 18 H 22 O3Na[M+Na] + requires309.1465).

[0366] 2-(4-((4-methoxybenzyl)oxy)phenyl)ethan-1-ol (3d). Compound 3d was prepared from 4-hydroxyphenylethanol 1a and 4-methoxybenzyl chloride 2d according to the general procedure above in 89% yield as a white powder. Mp = 95-98°C.

[0367]

[0368] 1H NMR (300MHz, DMSO-d6) δ = 2.64 (t, J = 7.2Hz, 2H, CH2, H-2), 3.54 (td, J = 7.1, 5.1Hz, 2H, CH2, H-2 1), 3.75 (s, 3H, OCH3), 4.60 (t, J=5.2Hz, 1H, OH), 4.97 (s, 2H, OCH2), 6.89 (d, J=8.6Hz, 2H, H-3 b , H-5 b , Ar), 6.94 (d, J=8.7Hz, 2H, H-3 a , H-5 a , Ar), 7.11 (d, J=8.7Hz, 2H, H-2 b , H-6 b , Ar), 7.36 (d, J=8.6Hz, 2H, H-2 a , H-6 a , Ar).

[0369] 13 C NMR (75MHz, DMSO-d6) δ = 38.2 (C-2), 55.1 (OCH3), 62.5 (C-1), 68.9 (OCH2), 113.8 (C-3 b , C-5 b ), 114.6(C-3 a , C-5 a ), 129.2(C-1 b ), 129.4(C-2 a , C-6 a ), 129.8(C-2 b , C-6 b ), 131.5(C-1 a ), 156.7(C-4 a ), 158.9(C-4 b ).

[0370] HRMS, m / z=281.1150found(calculated for C 16 H 18 O3Na[M+Na] + requires281.1151).

[0371] 2-(2-(3-Phenylpropoxy)phenyl)ethan-1-ol (3e). Compound 3e was prepared from 2-hydroxyphenylethanol 1b and 1-bromo-3-phenylpropane 2b according to the general procedure above in 53% yield as a light yellow oil.

[0372]

[0373] 1 H NMR(300MHz,DMSO-d6)δ=1.93-2.14(m,2H,CH2,H-2’),2.77(td,J=7.2,1.9Hz,4H,CH2,H-2,H-3’),3.60(1d,J=7.3,5.1Hz,2H,CH2,H-1),3.94(t,J=6.2Hz,2H,CH2,H-1’),4.59(t,J=5.3Hz,1H,OH),6.76-6.94(m,2H,H-2 a ,H-5 a ,Ar),7.06-7.39(m,7H,H-3 a ,H-4 a ,H-2 b ,H-3 b ,H-4 b ,H-5 b ,H-6 b ,Ar).

[0374] 13 C NMR(75MHz,DMSO-d6)δ=30.7(C-2’),31.7(C-3’),33.9(C-2),61.0(C-1’),66.5(C-1),111.5(C-2 a ),120.2(C-3 a ),126.0(C-4 b ),127.3(C-1 b ),127.4(C-4 a ),128.5(C-2 b ,C-3 b ,C-5 b ,C-6 b ),130.6(C-5 a ),141.5(C-1 a ),156.6(C-6 a ).

[0375] HRMS m / z=279.1355found(calculated for C 17 H 20 O2Na[M+Na] + requires279.1356).

[0376] 2-(2-(3-(4-methoxyphenyl)propoxy)phenyl)ethan-1-ol (3f). Compound 3f was prepared from 2-hydroxyphenylethanol 1b and 1-(3-bromopropyl)-4-methoxybenzene 2c according to the general procedure described above in 64% yield as a light yellow oil.

[0377]

[0378] 1 H NMR (300MHz, DMSO-d6) δ=1.92-2.08 (m, 2H, CH2, H-2'), 2.74 (dt, J=17.0, 7.7Hz, 4H, CH2, H-2, H-3'), 3.59 (td, J=7.4 , 5.1Hz, 2H, CH2, H-1'), 3.72 (OCH3) 3.92 (1, J=6.2Hz, 2H, CH2, H-1), 4.59 (t, J=5.3Hz, 1H, OH), 6.75-6.95 (m, 4H, H-2 a , H-5 a , H-3 b , H-5 b , Ar), 7.13 (td, J=9.0, 4.9, 1.9Hz, 4H, H-3 a , H-4 a , H-2 b , H-6 b , Ar).

[0379] 13 C NMR (75MHz, DMSO-d6) δ = 30.6 (C-3'), 30.8 (C-2), 33.8 (C-2'), 55.0 (OCH3), 60.9 (C-1'), 66.4 (C-1), 111.4 (C-2 a ), 113.8(C-3 b , C-5 b ), 120.1(C-3 a ), 127.2(C-1 b ), 127.3(C-4 a ), 129.3(C-2 b , C-6 b ), 130.5(C-5 a ), 133.3(C-1 a ), 156.6(C-4 b ), 157.5(C-6 a ).

[0380] HRMS m / z=309.1461found(calculated for C18 H 22 O3Na[M+Na] + requires309.1461).

[0381] 2-(2-((4-methoxybenzyl)oxy)phenyl)ethan-1-ol (3g). Compound 3g was prepared from 2-hydroxyphenylethanol 1b and 4-methoxybenzyl chloride 2d according to the general procedure above in 90% yield as a slightly yellowish color.

[0382]

[0383] 1 H NMR (300MHz, DMSO-d6) δ = 2.74 (t, J = 7.3Hz, 2H, CH2, H-2), 3.52-3.61 (m, 2H, CH2, H-1), 3.76 (s, OCH3), 4.57 (t, J=5.3Hz, 1H, OH), 5.02 (s, 2H, CH2, OCH2), 6.85 (td, J=7.4, 1.2Hz, 1H, H-3 a , Ar), 6.95 (d, J=8.7Hz, 2H, H-3 b , H-5 b , Ar), 7.01 (dd, J=8.7, 1.2Hz, 1H, H-4 a ), 7.15 (ddd, J=7.3, 4.3, 2.5Hz, 2H, H-2 a , H-5 a , Ar), 7.38 (d, J=8.6Hz, 2H, H-2 b , H-6 b , Ar).

[0384] 13 C NMR (75MHz, DMSO-d6) δ = 33.8 (C-2), 55.1 (OCH3), 60.8 (C-1), 69.0 (OCH2), 112.0 (C-2 a ), 113.9(C-2 b , C-6 b ), 120.3(C-3 a ), 127.2(C-4 a ), 127.4(C-1 a ), 129.1(C-3 b , C-5 b ), 129.3(C-1 b ), 130.5(C-5 a ), 156.3(C-6 a), 158.9(C-4 b ).

[0385] HRMS m / z=281.1151found(calculated for C 16 H 18 O3Na[M+Na] + requires281.1148).

[0386] 2-(3-(3-Phenylpropoxy)phenyl)ethan-1-ol (3h). Compound 3h was prepared from 2-hydroxyphenylethanol 1c and 1-bromo-3-phenylpropane 2b according to the general procedure above in 78% yield as a light yellow oil.

[0387]

[0388] 1 H NMR (300MHz, DMSO-d6) δ = 1.92-2.09 (m, 2H, CH2, H-2'), 2.71 (dt, J = 14.7, 7.2Hz, 4H, CH2, H-2, H-3'), 3.59 (td, J=7.1, 5.1Hz, 2H, CH2, H-1'), 3.94 (t, J=6.4Hz, 2H, CH2, H-1), 4.60 (t, J=5.2Hz, 1H, OH), 6.67-6.86 (m, 2H, H-2 a , H-4 a , Ar), 7.08-7.37(m, 7H, H-3 a , H-6 a , H-2 b , H-3 b , H-4 b , H-5 b , H-6 b , Ar).

[0389] 13 C NMR (75MHz, DMSO-d6) δ = 30.4 (C-2'), 31.5 (C-3'), 39.0 (C-2), 62.1 (C-1'), 66.4 (C-1), 111.8 (C-2 a ), 115.1(C-4 a ), 121.1(C-6 a ), 125.8(C-3 a ), 128.3(C-2 b , C-3 b , C-5 b , C-6 b ), 129.1(C-4b ), 141.1(C-1 b ), 141.4(C-1 a ), 158.5(C-5 a ).

[0390] HRMS m / z=279.1355found(calculated for C 17 H 20 O2Na[M+Na] + requires279.1356).

[0391] 2-(3-(3-(4-methoxyphenylpropoxy)phenyl)ethan-1-ol (3i). Compound 3i was prepared from 2-hydroxyphenylethanol 1c and 1-(3-bromopropyl)-4-methoxybenzene 2c according to the general procedure above in 99% yield as a white powder. Mp = 53-55°C.

[0392]

[0393] 1 H NMR (300MHz, DMSO-d6) δ=1.96 (dq, J=8.4, 6.5Hz, 2H, CH2, H-2'), 2.67 (td, J=7.9, 7.5, 4.2Hz, 4H, CH2, H-2, H-3'), 3.59 (t, J=7.1Hz, 2H, CH2, H-1'), 3.71 (s, 3H, OCH3), 3.91 (t, J=6.3Hz, 2H, CH2, H-1), 4.61 (s, 1H, OH), 6.68-6.80 (m, 3H, H-2 a , H-4 a , H-6 a , Ar), 6.85 (d, J=8.6Hz, 2H, H-3 b , H-5 b , Ar), 7.06-7.24(m, 3H, H-3 a , H-2 b , H-6 b , Ar).

[0394] 13 C NMR (75MHz, DMSO-d6) δ = 30.6 (C-2'), 30.7 (C-3'), 39.1 (C-2), 55.1 (OCH3), 62.2 (C-1'), 66.5 (C-1), 111.9 (C-2 a ), 113.9(C-2 b , C-6 b ), 115.2(C-4a ), 121.2(C-6 a ), 129.2(C-3 a ), 129.4(C-3 b , C-5 b ), 133.3(C-1 b ), 141.2(C-1 a ), 157.5(C-5 a ), 158.6(C-4 b ).

[0395] HRMS m / z=309.1461found(calculated for C 18 H 22 O3Na[M+Na] + requires309.1461),325.1197found(calculated for C 18 H 22 O3K[M+K] + requires 325.1200).

[0396] 2-(4-((4-methoxybenzyl)oxy)phenyl)ethan-1-ol (3j). Compound 3j was prepared from 2-hydroxyphenylethanol 1c and 1-(3-bromopropyl)-4-methoxybenzene 2d according to the general procedure above in 98% yield as a white powder. Mp = 62-64°C.

[0397]

[0398] 1 H NMR (300MHz, DMSO-d6) δ = 2.68 (t, J = 7.1Hz, 2H, CH2, H-2), 3.59 (t, J = 7.1Hz, 2H, CH2, H-1), 3 .75 (s, 3H, OCH3), 4.62 (s, 1H, OH), 4.97 (s, 2H, OCH2), 6.81 (ddd, J=14.3, 6.1, 4.4Hz, 3H, H-2 a , H-4 a , H-6 a , Ar), 6.94 (d, J=8.6Hz, 2H, H-3 b , H-5 b , Ar), 7.17 (t, J=7.8Hz, 1H, H-3 a , Ar), 7.36 (d, J=8.5Hz, 2H, H-2 b , H-6 b , Ar).

[0399] 13 C NMR (75MHz, DMSO-d6) δ = 39.0 (C-2), 55.4 (OCH3), 62.4 (C-1), 69.1 (OCH2), 112.4 (C-2 a ), 114.1(C-3 b , C-5 b ), 115.8(C-4 a ), 121.6(C-6 a ), 129.4(C-1 a ), 129.5(C-3 a ), 129.8(C-2 b , C-6 b ), 141.3(C-1 b ), 158.6(C-5 a ), 159.2(C-4 b ).

[0400] HRMS m / z=281.1149found(calculated for C 16 H 18 O3Na[M+Na] + requires281.1148),297.0888found(calculated for C 16 H 18 O3K[M+K] + requires297.0888).

[0401] 2-(4-(2-Phenoxyethoxy)phenyl)ethan-1-ol (3k). Compound 3k was prepared from 4-hydroxyphenylethanol 1a and 2-phenoxyethyl bromide 2e according to the general procedure above in 90% yield as a white powder. Mp = 143-145°C.

[0402]

[0403] 1 H NMR (300MHz, DMSO-d6) δ = 2.66 (t, J = 7.1Hz, 2H, CH2, H-2), 3.56 (t, J = 7.1Hz, 2H, CH2, H-1), 4.28 (s, 4H, CH2, H-1', H-2'), 4.60 (s, 1H, OH), 6.84-7.05 (m, 5H, H-2 a , H-6 a , H-2 b , H-4 b , H-6 b, Ar), 7.13 (d, J = 8.2 Hz, 2H, H-3 a , H-5 a , Ar), 7.30 (t, J = 7.8 Hz, 2H, H-3 b , H-5 b , Ar).

[0404] 13 C NMR (75 MHz, DMSO-d6) δ = 38.2 (C-2), 62.4 (C-1), 66.3 (C-2’), 66.3 (C-1’), 114.3 (C-3 a , C-5 a ), 114.5 (C-3 b , C-5 b ), 120.8 (C-4 b ), 129.6 (C-2 a , C-6 a ), 129.9 (C-2 b , C-6 b ), 131.7 (C-1 a ), 156.6 (C-4 a ), 158.3 (C-4 b ).

[0405] HRMS m / z = 281.1147 found (calculated for C 16 H 18 O3Na [M+Na] + requires 281.1148), 297.0883 found (calculated for C 16 H 18 O3K [M+K] + requires 297.0887).

[0406] Example 13

[0407] General procedure for the mesylation of O-alkyl-phenylethanol 3(bk) in the preparation of phenethyl mesylate derivatives 4(bk). A solution of methanesulfonyl chloride (1.55 g, 13.52 mmol, 2 eq.) in anhydrous CH2Cl2 (3.5 ml) was added dropwise to a cooled solution (0°C, ice bath) of phenethyl-1-ol derivative 3 (6.76 mmol) and triethylamine TEA (1.71 g, 16.9 mmol, 2.5 eq.) in 8 ml of dry CH2Cl2 under magnetic stirring (500 rpm) over 15 min. It was further stirred at room temperature for 8 h. The crude reaction mixture was transferred to a separatory funnel. The organic layer was washed successively with deionized water (3×100 ml), saturated sodium bicarbonate NaHCO3 (3×100 ml). After decantation, the organic layer was dried over anhydrous MgSO4, filtered on a paper filter, and the filtrate was concentrated under reduced pressure in a rotary evaporator. If the crude residue crystallizes, it is triturated in deionized water (3 x 50 ml). If a viscous oil is obtained, it is triturated in 8 ml of di-iso-propyl ether, resulting in crystallization, and the resulting material is washed with deionized water (3 x 45 ml). The resulting solid is then placed under high vacuum (10 -3 The mixture was dried under 400 °C (240 °F) to give the desired compound 3. Compound 3 was subsequently used without further purification.

[0408] 4-(3-Phenylpropoxy)phenethyl methanesulfonate (4b). Compound 4b was prepared from 2-(4-(3-phenylpropoxy)phenyl)ethan-1-ol 3b and methanesulfonyl chloride according to the general procedure above in 67% yield as a white powder. Mp = 51-52°C.

[0409]

[0410] 1 H NMR (300MHz, DMSO-d6) δ = 1.87-2.09 (m, 2H, CH2, H-2′), 2.73 (t, J = 7.7Hz, 2H, CH2, H-3′), 2.92 (t, J = 6.8Hz, 2H, CH2, H-2), 3.09 (s, 3H, SO2CH3), 3.94 (t, J=6.3Hz, 2H, CH2, H-1), 4.36 (t, J=6.8Hz, 2H, CH2, H-1′), 6.87 (d, J=8.4, 2H, H-3 a , H-5 a , Ar), 7.10-7.35(m, 7H, H-2 a , H-6 a , H-2 b , H-3 b , H-4 b , H-5 b , H-6b , Ar).

[0411] 13 C NMR (75MHz, DMSO-d6) δ=30.5(C-2′), 31.6(C-3′), 34.0(C-2), 36.7(SO2CH3), 66.7(C-1′), 71.0(C-1), 114.6(C-3 a , C-5 a ), 126.0(C-4 b ), 128.5(C-2 b , C-6 b , C-3 b , C-5 b ), 128.8(C-1 a ), 130.2(C-2 a , C-6 a ), 141.5(C-1 b ), 157.5(C-4 a ).

[0412] HRMS, m / z=357.1137 found (calculated for C 18 H 22 O4SNa[M+Na] + requires357.1138).

[0413] 4-(3-(4-methoxyphenyl)propoxy)phenethyl methanesulfonate (4c). Compound 4c was prepared from 2-(4-(3-(4-methoxyphenyl)propoxy)phenyl)ethan-1-ol 3c and methanesulfonyl chloride according to the general procedure above in 68% yield as a white powder. Mp = 117-120°C.

[0414]

[0415] 1 H NMR (300MHz, DMSO-d6) δ = 1.82-2.06 (m, 2H, CH2, H-2′), 2.58-2.72 (m, 2H, CH2, H-3′), 2.92 (t, J = 6.8Hz, 2H, CH2, H-2), 3.10 (s, 3H, SO2CH3), 3.71 (s, 3H, OCH3), 3.92 (t, J=6.4Hz, 2H, CH2, H-1), 4.36 (t, J=6.8Hz, 2H, CH2, H-1′), 6.83-6.89 (m, 4H, H-3 a , H-5 a , H-3 b , H-5b , Ar), 7.14 (d, J=8.6Hz, 2H, H-2 b , H-6 b , Ar), 7.20 (d, J=8.4, 2H, H-2 a , H-6 a , Ar).

[0416] 13 C NMR (75MHz, DMSO-d6) δ=30.5(C-2′), 30.6(C-3′), 33.8(C-2), 36.6(SO2CH3), 55.0(OCH3), 66.6(C-1′), 70.9(C-1), 113.8(C-3 b , C-5 b ), 114.4(C-3 a , C-5 a ), 128.6(C-1 a ), 129.3(C-2 b , C-6 b ), 130.0(C-2 a , C-6 a ), 133.2(C-1 b ), 157.4(C-4 b ).

[0417] HRMS, m / z=387.1242 found (calculated for C 19 H 24 O5SNa[M+Na] + requires387.1242);269.1542found(calculated for C 18 H 21 O2[M-OSO2Me] + requires269.1543).

[0418] 4-((4-methoxybenzyl)oxy)phenethyl methanesulfonate (4d). Compound 4d was prepared from 2-(4-((4-methoxybenzyl)oxy)phenyl)ethan-1-ol 3d and methanesulfonyl chloride according to the general procedure above in 91% yield as a white powder. Mp = 100-103°C.

[0419]

[0420] 1H NMR (300MHz, DMSO-d6) δ = 2.92 (t, J = 6.8Hz, 2H, CH2, H-2), 3.10 (s, 3H, SO2CH3), 3.75 ( s, 3H, OCH3), 4.35 (t, J=6.8Hz, 2H, CH2, H-1), 4.99 (s, 2H, OCH2), 6.79-7.02 (m, 4H, H-3 a , H-5 a , H-3 b , H-5 b , Ar), 7.20 (d, J=8.6Hz, 2H, H-2 b , H-6 b , Ar), 7.37 (d, J=8.6Hz, 2H, H-2 a , H-6 a , Ar).

[0421] 13 C NMR (75MHz, DMSO-d6) δ = 33.9 (C-2), 36.6 (SO2CH3), 55.1 (OCH3), 68.9 (OCH2), 70.9 (C-1), 113.8 (C-3 b , C-5 b ), 114.8(C-3 a , C-5 a ), 128.8(C-1 b ), 129.0(C-1 a ), 129.5(C-2 b , C-6 b ), 130.0(C-2 a , C-6 a ), 157.2(C-4 a ), 159.0(C-4 b ).

[0422] HRMS, m / z=359.0929 found (calculated for C 17 H 20 O5SNa[M+Na] + requires359.0930).

[0423] Embodiment 14

[0424] Table 1. Other O-alkyl-phenyl methanesulfonates 4 derived from O-alkyl-phenylethanol 3, which were synthesized according to the procedure described in the previous examples.

[0425]

[0426] Embodiment 15

[0427] Table 2. Other N-phenylalkylazole SOCE inhibitors 6α, 6β synthesized from 5α or 5β and O-alkyl-phenylethyl methanesulfonate 4.

[0428]

[0429]

[0430] Example 16

[0431]

[0432] 1-(2-Bromoethyl)-4-(methoxymethoxy)benzene (2f). To a solution of 4-(2-bromoethyl)phenol 1d (1.507 g, 7.497 mmol) in 25 ml of dry acetonitrile was added 3.108 g of potassium carbonate KCO (22.49 mmol, 3 eq.) in portions at room temperature under vigorous magnetic stirring (550 rpm). After 30 minutes, a solution of chloromethoxymethane MeOCHCl (1.508 g, 18.74 mmol, 2.5 eq.) in 15 ml of dry acetonitrile was added dropwise over 15 minutes, and the resulting reaction mixture was heated at 34°C for 24 hours (monitored by thin layer chromatography using 0.2 mm silica gel plate 60-F254 Merck, using CHCl / MeOH 95:5 v / v as eluent). After cooling to room temperature, the reaction mixture was concentrated under reduced pressure using a rotary evaporator. Into the crude residue, 100 ml of deionized water was poured, then extracted with CH2Cl2 (3×30 ml), and the collected extracts were transferred to a separatory funnel. The organic phase was washed with brine (2x50 ml) in turn, dried over anhydrous MgSO4, filtered in filter paper and the filtrate was concentrated in vacuo. Into the crude residue, 15 ml of cyclohexane was poured to produce a precipitate of unreacted 4-(2-bromoethyl)phenol 1d, which was removed by filtration in a Buchner funnel (porosity N°4) and cyclohexane was removed from the filtrate in vacuo to obtain the desired compound 2f in a yield of 64%, which was a translucent mobile oil. It was found that compound 2f was pure enough to be used for subsequent use without purification.

[0433] 1 H NMR (300MHz, CDCl3) δ=3.12 (t, J=7.6Hz, 2H, H-2), 3.49 (s, 3H, H-4″), 3.54 (dd, J=8.0, 7.3Hz, 2H, H-2 1), 5.17 (s, 2H, H-2″), 7.01 (d, J=8.7Hz, 2H, H-3′, H-5′, Ar), 7.14 (d, J=8.7Hz, 2H, H-2′, H-6′, Ar).

[0434] 13 C NMR (75MHz, CDCl3) δ=33.3(C-1), 38.7(C-2), 56.0(C-4″), 94.6(C-2″), 116.5(C-3′, C-5′), 129.8(C-2′, C-6′), 132.4(C-1′), 156.3(C-4′).

[0435] 1-(4-(Methoxymethoxy)phenethyl)-1H-benzo[d]imidazole (6αad). To a vigorously stirred (550 rpm) solution of benzimidazole 5αa (0.385 g, 3.26 mmol, 2 eq) in 6 ml of dry DMF was added potassium carbonate K2CO3 (0.677 g, 4.89 mmol, 3 eq) in portions. After magnetic stirring for 30 min, 1-(2-bromoethyl)-4-(methoxymethoxy)-benzene 2f (0.4 g, 1.63 mmol, 1 eq) and potassium iodide KI (0.054 g, 0.33 mmol, 0.2 eq) were added to the reaction mixture and the resulting reaction mixture was stirred at 60°C for 72 h (monitored by thin layer chromatography using 0.2 mm silica gel plates 60-F254 Merck, using CH2Cl2 / MeOH 95:5 v / v as eluent). After cooling to room temperature, 60 ml of deionized water was poured into the reaction mixture and the resulting mixture was transferred to a separatory funnel. Extraction was performed with ethyl acetate (2×30 ml), and the collected extracts were washed with brine (3×20 ml) in sequence, dried over anhydrous MgSO4 and filtered through filter paper. The filtrate was concentrated under reduced pressure using a rotary evaporator, and the crude residue was purified by chromatography (Combi Flash R f Purification was performed on a prepacked column of silica gel 60F-254 (Merck) at 200 psi with DAD 200 / 360 nm detector using a step gradient of cyclohexane / AcOEt (0-80%). The elution was combined for 60 minutes and the solvent was removed in vacuo to give the pure desired compound 6αad as an ivory viscous paste in 44% yield.

[0436] 1 H NMR (300MHz, CDCl3) δ=3.08 (t, J=7.0Hz, 2H, H-2′), 3.47 (s, 3H, H-4″), 4.36 (t, J=7.0Hz, 2H, H-1′), 5.14 (s, 2H, H-2″), 6.93 (s, 4H, H-2 a , H-3 a , H-5 a H-6 a), 7.29 (m, 2H, H-5, H-6, Ar), 7.38 (m, 1H, H-7, Ar), 7.62 (s, 1H, H-2), 7.81 (m, 1H, H-4, Ar).

[0437] 13 C NMR (75MHz, CDCl3) δ = 35.6 (C-2′), 47.0 (C-1′), 56.1 (C-4″), 94.6 (C-2″), 109.6 (C-7), 116.8 (C-3 a , C-5 a ), 120.6(C-4), 122.2(C-5), 122.9(C-6), 123.0(C-7a), 129.8(C-2 a , C-6 a ), 130.9(C-1 a ), 133.7(C-3a), 143.1(C-2), 156.4(C-4 a ).

[0438] Embodiment 17

[0439]

[0440] 1-(4-(Methoxymethoxy)phenethyl)-1H-indazole (6αae). To a vigorously stirred (550 rpm) solution of indazole 5αb (0.289 g, 2.45 mmol, 1.5 eq.) in 4 ml of dry DMF was added portionwise a dispersion of sodium hydride 60% in mineral oil (0.261 g, 6.53 mmol, 4 eq.). After 30 min of magnetic stirring, 1-(2-bromoethyl)-4-(methoxy-methoxy)benzene 2f (0.4 g, 3 mmol, 1 eq.) and potassium iodide KI (0.054 g, 0.33 mmol, 0.2 eq.) were added to the reaction mixture and the resulting reaction mixture was stirred at 80° C. for 5 days (monitored by thin layer chromatography using 0.2 mm silica gel plates 60-F254 Merck using CH2Cl2 / MeOH 95:5 v / v as eluent). After cooling to room temperature, 40 ml of deionized water was poured into the reaction mixture and the resulting mixture was transferred to a separatory funnel. Extraction was performed with ethyl acetate (2×20 ml), and the collected extracts were washed with brine (3×15 ml) in turn, dried over anhydrous MgSO4 and filtered through filter paper. The filtrate was concentrated under reduced pressure in a rotary evaporator and the crude residue was purified by chromatography (Combi Flash R fPurification was performed by eluting with a stepwise gradient of cyclohexane / AcOEt (0-20%) on a prepacked column of silica gel 60F-254 (Merck) at 200 psi with DAD 200 / 360 nm detector. After 60 min of elution, the solvent was removed in vacuo to give the pure desired compound 6αae as a translucent viscous oil in 54% yield.

[0441] 1 H NMR (300MHz, CDCl3) δ = 3.20 (m, 2H, H-2′), 3.49 (s, 3H, H-4″), 4.59 (m, 2H, H-1′), 5.16 (s, 2H, H-2″), 6.96 (m, 2H, H-3 a , H-5 a , Ar), 7.07 (m, 2H, H-2 a , H-6 a , Ar), 7.14 (ddd, J=7.9, 6.6, 1.2Hz, 1H, H-5, Ar), 7.27 (dq, J=8.7, 1.1Hz, 1H, H-7, Ar), 7.34 (ddd, J =8.5, 6.6, 1.1Hz, 1H, H-6, Ar), 7.74 (dt, J=8.1, 1.0Hz, 1H, H-4, Ar), 8.04 (d, J=0.9Hz, 1H, H-3, Ar).

[0442] 13 C NMR (75MHz, CDCl3) δ=35.6(C-2′), 50.7(C-1′), 56.0(C-4″), 94.6(C-2″), 109.0(C-7), 116.6(C-3 a , C-5 a ), 120.5(C-4), 121.1(C-5), 124.0(C-3a), 126.2(C-6), 129.9(C-2 a , C-6 a ), 131.9(C-1 a ), 133.1(C-3), 139.6(C-7a), 156.1(C-4 a ).

[0443] Embodiment 18

[0444]

[0445] 1-(4-(Methoxymethoxy)-2-(trifluoromethyl)-1H-benzo[d]imidazole (6αaf). To a vigorously stirred (550 rpm) solution of 2-trifluoromethylbenzimidazole 5αc (0.516 g, 2.77 mmol, 2 eq) in 4 ml DMF was added potassium carbonate K2CO3 (0.677 g, 4.89 mmol, 3 eq) in portions. After magnetic stirring for 30 min, 1-(2-bromoethyl)-4-(methoxymethoxy)benzene 2f (0.34 g, 1.63 mmol, 1 eq) was added to the reaction mixture and the resulting reaction mixture was stirred at 60°C for 72 h (monitored by thin layer chromatography using 0.2 mm silica gel plates 60-F254 Merck, using CH2Cl2 / MeOH 95:5 v / v as eluent). After cooling to room temperature, 40 ml of deionized water was poured into the reaction mixture and the resulting mixture was transferred to a separatory funnel. Extraction was performed with ethyl acetate (2×20 ml), and the collected extracts were washed with brine (3×20 ml) in sequence, dried over anhydrous MgSO4 and filtered through filter paper. The filtrate was concentrated under reduced pressure using a rotary evaporator, and the crude residue was purified by chromatography (Combi Flash R f Purification was performed on a prepacked column of silica gel 60F-254 (Merck) at 200 psi with DAD 200 / 360 nm detector using a step gradient of cyclohexane / AcOEt (0-20%). The reaction mixture was combined for 60 minutes and the solvent was removed in vacuo to give the pure desired compound 6αad as a translucent viscous oil in 50% yield.

[0446] 1 H NMR (300MHz, CDCl3) δ = 3.07 (m, 2H, H-2′), 3.46 (s, 3H, H-4″), 4.46 (m, 2H, H-1′), 5.14 (s, 2H, H-2″), 6.97 (m, 2H, H-3 a , H-5 a , Ar), 7.06 (m, 2H, H-2 a , H-6 a , Ar), 7.36 (m, 3H, H-5, H-6, H-7, Ar), 7.88 (m, 1H, H-4, Ar).

[0447] 13 C NMR (75MHz, CDCl3) δ=35.7(C-2′), 46.8(C-1′), 56.0(C-4″), 94.5(C-2″), 110.5(CF3), 116.8(C-3 a , C-5 a), 121.8(C-4, C-7), 123.7(C-5, C-6), 125.4(C-7a), 129.8(C-2 a , C-6 a ), 130.3(C-1 a ), 135.3(C-3a), 141.2(C-2), 156.5(C-4 a ).

[0448] 19 F NMR (282MHz, CDCl3) δ = 62.0

[0449] Part 2

[0450] The chemical scheme for the preparation of N-phenylalkylazole SOCE inhibitors with a platform of benzimidazole, indazole, pyrazole and triazole with free hydroxyl functional groups on the terminal side chains is as follows Figure 2 shown.

[0451] Embodiment 19

[0452]

[0453] 4-(Methylsulfonyloxy)phenylmethyl methanesulfonate (7). To a vigorously stirred (550 rpm) solution of 4-hydroxyphenylethanol 1b (2 g, 16.11 mmol) in 45 ml of anhydrous dichloromethane cooled at 0°C (ice bath) was added triethylamine TEA (4.7 ml, 33.8 mmol, 2.1 eq) continuously for 10 minutes. Then methanesulfonyl chloride (2.62 ml, 33.8 mmol, 2.1 eq) was slowly added. After the addition was complete, the reaction mixture was stirred at room temperature for 18 hours. Deionized water (90 ml) was poured into the reaction mixture and after magnetic stirring for 10 minutes, the reaction mixture was transferred to a separatory funnel. Extraction was performed with 2×45 ml of CH2Cl2 and the collected extracts were washed with brine (2×45 ml), dried over anhydrous MgSO4 and filtered on a paper filter. The filtrate was concentrated under reduced pressure using a rotary evaporator, and the resulting solid material was dried in vacuo to give the desired compound 7 as a mobile light yellow oil in a yield of 41%. Compound 7 was subsequently used without further purification.

[0454] 1 H NMR (300MHz, DMSO-d6) δ = 3.16 (s, 3H, CH3, H-1b), 3.68 (s, 3H, CH3, H-1a), 4.60 (s, 2H, CH2, H-1), 7.29 (m, 2H, H-3′, H-5′, Ar), 7.46 (m, 2H, H-2′, H-6′, Ar).

[0455] 13 C NMR (75MHz, DMSO-d6) δ = 37.5 (C-1 a ), 45.1(C-1 b ), 52.6(C-1), 122.3(C-3′, C-5′), 130.3(C-2′, C-6′), 136.9(C-1′), 149.0(C-4′).

[0456] HRMS, m / z=302.9973 found (calculated for C9H 12 O6S2Na[M+Na] + requires302.9973).

[0457] 4-((1H-Benzo[d]imidazol-1-yl)methyl)phenyl methanesulfonate (8αa). To a vigorously stirred (550 rpm) solution of benzimidazole 5αa (0.337 g, 2.85 mmol, 2 equivalents) in 4 ml of anhydrous DMF was added in portions a dispersion of sodium hydride 60% in mineral oil (0.112 g, 2.85 mmol) and the resulting suspension was stirred for 10 minutes. After adding 4-(methylsulfonyloxy)benzyl methanesulfonate 7 (0.4 g, 1.43 mmol) in 4 portions, the reaction mixture was heated at 60°C for 24 hours. After cooling to room temperature, deionized water (40 ml) was added to the reaction mixture. After standing at 4°C (refrigerator) for 8 hours, a precipitate gradually formed, and the resulting insoluble material was collected by filtration in a Buchner funnel (porosity N°4), washed successively with 3×5 ml of deionized water, 3×15 ml of cyclohexane, and heated at 25°C under high reduced pressure (10 -2 The desired product 8αa was obtained as a white powder with a yield of 47%. Mp = 104-108°C.

[0458] 1 H NMR (300MHz, DMSO-d6) δ = 3.35 (s, 3H, CH3), 5.55 (s, 2H, CH2, H-1′), 7.22 (m, 2H, H-3″, H-5″), 7.33 (m, 2H, H-2″, H-6″), 7.43 (m, 2H, H-5, H-6), 7.55 (m, 1H, H-7), 7.67 (m, 1H, H-4), 8.42 (s, 1H, H-2).

[0459] 13C NMR (75MHz, DMSO-d6) δ = 37.4 (CH3), 46.8 (C-1′), 110.6 (C-7), 119.5 (C-4), 121 .7(C-2″, C-6″), 122.5(C-3″, C-5″), 129.1(C-5, C-6), 133.6(C-1″), 136.2(C-7 a ), 143.5(C-3 a ), 144.2(C-2), 148.5(C-4″).

[0460] HRMS, m / z=325.0621 found (calculated for C 15 H 14 N2O3SNa[M+Na] + requires325.0617).

[0461] 1-(4-Hydroxyphenylmethyl)-1H-benzo[d]imidazole (9αa). A solution of PEG 200 (9.8 mg, 0.2 eq.) in deionized water (6 ml) was stirred vigorously at 90°C under magnetic stirring (550 rpm). The pH of the reaction mixture was adjusted to pH 10 by adding (0.5 ml) sodium hydroxide NaOH 1N. After stirring at room temperature for 10 minutes, 4-((1H-benzo[d]imidazol-1-yl)methyl)phenyl methanesulfonate 8αa (0.074 g, 0.245 mmol) was added in portions and vigorously stirred magnetically at 90°C for 7 days (monitored by thin layer chromatography using 0.2 mm silica gel plates 60-F254 Merck, using CH2Cl2 / MeOH 95:5 v / v as eluent). After cooling to room temperature, deionized water (40 ml) was added directly to the reaction mixture. The resulting mixture was transferred to a separatory funnel and extracted with ethyl acetate (3×30 ml), then the collected organic extracts were washed with brine (3×30 ml), dried over anhydrous MgSO4 and filtered on filter paper. The filtrate was concentrated under reduced pressure in a rotary evaporator to produce a slightly yellow viscous oil. The product was then purified by chromatography (Combi Flash R f Purification was performed by elution with a step gradient of cyclohexane / AcOEt (0-30%) on a prepacked column of silica gel 60F-254 (Merck) at 200 psi with DAD 200 / 360 nm detector. The elution was combined for 60 minutes and the solvent was removed in vacuo to give the pure desired compound 9αa in 46% yield as a white powder. Mp = 102-106°C. Mp = 242-246°C.

[0462] 11H NMR (300 MHz, DMSO-d6) δ = 5.34 (s, 2H, CH2, H-1′), 6.71 (m, 2H, H-3″, H-5″, Ar), 7.18 (td, J = 6.3, 3.0 Hz, 4H, H-2″, H-6″, H-5, H-6, Ar), 7.51 (m, 1H, H-7, Ar), 7.63 (m, 1H, H-4, Ar), 8.34 (s, 1H, H-2, Ar), 9.42 (br s, 1H, OH).

[0463] 13 13C NMR (75 MHz, DMSO-d6) δ = 47.3 (C-1′), 110.8, (C-7), 115.3 (C-3″, C-5″), 119.4 (C-4), 121.4 (C-5, C-6), 122.2 (C-1″), 127.0 (C-2″, C-6″), 133.6 (C-7 a ), 143.5 (C-3a ) , 144.0 (C-2), 157.0 (C-4″).

[0464] HRMS, m / z = 247.0840 found (calculated for C 14 H 12 N2ONa [M + Na] + requires 247.0842).

[0465] Example 20

[0466]

[0467] 4-((2-(Trifluoromethyl)-1H-benzo[d]imidazol-1-yl)methyl)phenyl methanesulfonate (8αc). To a vigorously stirred (550 rpm) solution of 2-trifluoromethylbenzimidazole 5αc (0.197 g, 2.85 mmol, 2 equiv) in 4 ml of dry DMF was added sodium hydride 60% (0.114 g, 2.85 mmol) in portions and the resulting suspension was stirred for 10 minutes. After adding 4-(methylsulfonyloxy)-benzene methanesulfonic acid methyl ester 7 (0.5 g, 1.78 mmol) in 4 portions, the reaction mixture was heated at 60°C for 7 days (monitored by thin layer chromatography using 0.2 mm silica gel plate 60F-254 Merck). After cooling to room temperature, deionized water (40 ml) was added to the reaction mixture. The reaction mixture was transferred to a separatory funnel. Extraction was performed with 2×30 ml of ethyl acetate, and the collected extracts were washed with brine (2×30 ml), dried over anhydrous MgSO4, and filtered on a paper filter. The filtrate was concentrated under reduced pressure in a rotary evaporator, and the crude residue was purified on a pre-packed silica gel column 60F-254 (Merck) (Combi Flash Rf 200 psi device with DAD200 / 360 nm detector) using a step gradient elution of cyclohexane / AcOEt (0-10%). The mixture was combined for 60 minutes and the solvent was removed in vacuo to obtain the pure desired compound 8αc in a yield of 36% as a white powder. Mp=102-106°C.

[0468] 1 H NMR (300MHz, DMSO-d6) δ = 3.35 (s, 3H, CH3), 5.75 (s, 2H, CH2, H-1′), 7.20 (m, 2H, H-3″, H- 5″), 7.32(m, 2H, H-2″, H-6″), 7.44(m, 2H, H-5, H-6), 7.70(m, 1H, H-7), 7.88(m, 1H, H-4).

[0469] 13 C NMR (75MHz, DMSO-d6) δ = 37.5 (CH3), 47.0 (C-1′), 112.0 (CF3), 121.0 (C-4, C-7), 122.6 (C-3″, C-5″), 123 .9(C-5, C-6), 125.7(C-2″, C-6″), 128.0(C-1″), 135.2(C-7a), 135.5(C-3a), 140.5(C-2), 148.4(C-4″).

[0470] 19 F NMR (282MHz, DMSO-d6) δ = -60.7.

[0471] HRMS, m / z=393.0493 found (calculated for C 16 H 13 N2O3F3SNa[M+Na] + requires393.0491).

[0472] 1-(4-Hydroxyphenylmethyl)-2-trifluoromethyl-1H-benzo[d]imidazole (9αc). Compound 9αc was synthesized from 4-((2-(trifluoromethyl)-1H-benzo[d]imidazol-1-yl)methyl)phenyl methanesulfonate 8αc (0.70 mmol) according to the procedure for 9αa in Example 16 to give the desired compound 9αc in 15% yield as a white powder. Mp = 188-192°C.

[0473] 1 H NMR (300MHz, DMSO-d6) δ = 5.46 (s, 2H, CH2, H-1′), 6.80 (m, 2H, H-3″, H-5″), 7.02 (m, 2H, H-3″, H-5″), 7.33 (m, 3H, H-4, H-5, H-7), 7.88 (ddd, J=6.1, 3.2, 0.8Hz, 1H, H-6).

[0474] 13 C NMR (75MHz, DMSO-d6) δ = 48.3 (C-1′), 111.4 (CF3), 116.1 (C-3″, C-5″), 121.7 (C-4, C-7) 124.0 (C-2 , C-6), 125.7(C-1″), 126.9(C-7a), 128.2(C-2″, C-6″), 135.7(C-3a), 141.2(C-2), 156.0(C-4″).

[0475] 19 F NMR (282MHz, DMSO-d6) δ = -61.4.

[0476] HRMS, m / z=315.0717 found (calculated for C 15 H 11 N2OF3Na[M+Na] + requires315.0716).

[0477] Embodiment 21

[0478]

[0479] 4-((1H-pyrazol-1-yl)methyl)benzene methanesulfonate (8βa). According to the procedure for 8αa in Example 16, compound 8βa was synthesized from 4-(methylsulfonyloxy)benzene methanesulfonate 7 and pyrazole 5βc in 59% yield as a white powder after 24 hours of reaction time. Mp = 77-80°C.

[0480] 1 H NMR (300MHz, DMSO-d6) δ = 3.12 (s, 3H, CH3), 5.33 (s, 2H, CH2, H-1′), 6.30 (s, 1H, H-4, Ar), 7.24 (d, J = 0.7Hz, 4H, H-2″, H-3″, H-5″, H-6″, Ar), 7.41 (dd, J=2.3, 0.6Hz, 1H, H-5, Ar), 7.56 (dd, J=1.8, 0.7Hz, 1H, H-3, Ar).

[0481] 13 C NMR (75MHz, DMSO-d6) δ = 37.6 (CH3), 55.2 (C-1′), 106.4 (C-4), 122.5 (C-3″, C-5 ″), 129.2(C-1″), 129.5(C-5), 136.4(C-2″, C-6″), 140.1(C-3), 148.9(C-4″).

[0482] HRMS, m / z=275.0461 found (calculated for C 11 H 12 N2O3SNa[M+Na] + requires275.0461).

[0483] 1-(4-Hydroxyphenylmethyl)-1H-pyrazole (9βa). Compound 9βh was synthesized from 4-((1H-pyrazol-1-yl)methyl)benzene methanesulfonate 8βca (0.70 mmol) according to the method used for 9αa in Example 16 to give the desired compound 9βa in 55% yield as a white powder. Yield = 55%. Mp = 116-120°C.

[0484] 1H NMR (300MHz, DMSO-d6) δ = 5.22 (s, 2H, CH2, H-1′), 6.28 (t, J = 2.1Hz, 1H, H-4), 6.65 (m, 2H, H-3″, H- 5″), 7.00 (m, 2H, H-2″, H-6″), 7.41 (dd, J=2.3, 0.6Hz, 1H, H-5), 7.57 (dd, J=1.9, 0.7Hz, 1H, H-3).

[0485] 13 C NMR (75MHz, DMSO-d6) δ=55.6(C-1′), 105.9(C-4), 116.0(C-3″, C-5″), 127.8(C-1″), 129.3(C-2″, C-6″), 129.7(C-5), 139.7(C-3), 156.3(C-4″).

[0486] HRMS, m / z=197.0684 found (calculated for C 10 H 10 N2ONa[M+Na] + requires197.0685).

[0487] Embodiment 22

[0488]

[0489] 4-((1H-1,2,4-triazol-1-yl)methyl)phenyl methanesulfonate (8βb). Compound 8βb was synthesized from 4-(methylsulfonyloxy)benzyl methanesulfonate 7 and triazole 5βb in 69% yield as a white powder according to the procedure used for 80a in Example 16 after 48 hours of reaction time. Mp = 60-64°C.

[0490] 1 H NMR (300MHz, DMSO-d6) δ = 3.14 (s, 3H, CH3), 5.36 (s, 2H, CH2, H-1′), 7.30 (d, J =1.8Hz, 4H, H-2″, H-3″, H-5″, H-6″, Ar), 7.98(s, 1H, H-5), 8.10(s, 1H, H-3).

[0491] 13C NMR (75MHz, DMSO-d6) δ=37.7(CH3), 52.8(C-1′), 122.8(C-3″, C-5″), 129.7(C-1″), 134.2(C-2″, C-6″), 143.3(C-5), 149.3((C-4″), 152.6(C-3).

[0492] HRMS, m / z=276.0415 found (calculated for C 10 H 11 N3O3SNa[M+Na] + requires276.0413).

[0493] Embodiment 23

[0494]

[0495] 2-[4-(2-bromoethyl)phenoxy]tetrahydro-2H-pyran (10). Under vigorous magnetic stirring, 1.5ml 3,4-dihydro-2H-pyran DHP (16.41mmol, 1.1 equivalent) was added dropwise to a solution of 4-hydroxyphenylethyl bromide 1d (3g, 14.92mmol, 1 equivalent) in 12ml CH2Cl2 for 10 minutes. After 5 minutes, pyridinium p-toluenesulfonate PPTS (0.375g, 1.49mmol., 0.1 equivalent) was added to the reaction mixture in batches. Stir at room temperature for 24 hours. The reaction solution was transferred to a separating funnel and the organic layer was washed with saturated sodium bicarbonate NaHCO3 (2x30ml) and brine (2x30ml) successively, and MgSO4 was dried and filtered on filter paper. The filtrate was concentrated under reduced pressure using a rotary evaporator and the resulting oily residue was purified by chromatography (Combi Flash R f Purification was performed on a prepacked column of silica gel 60F-254 (Merck) at 200 psi with DAD 200 / 360 nm detector using a step gradient of cyclohexane / AcOEt (0-20%). The reaction mixture was combined for 60 minutes and the solvent was removed in vacuo to give 3.17 g (56% yield) of pure desired compound 10 as a colorless mobile oil.

[0496] 1H NMR(300MHz,DMSO-d6)δ=1.78(m,3H,H-3″,H-3″,H-4″),1.99(m,2H,H-4″,H-2″),),2.13(m,1H,H-2″),3.23(t,J=7.7Hz,2H,CH2,H-2),3.65(dd,J=8.1,7.3Hz,2H,CH2,H-1),3.73(dtd,J=11.4,4.2,1.5Hz,1H,H-5″),4.04(ddd,J=11.5,9.2,3.3Hz,1H,H-5″),5.52(t,J=3.3Hz,1H,H-1″),7.14(m,2H,H-3′,H-5′),7.24(m,2H,H-2′,H-6′).

[0497] 13 C NMR(75MHz,DMSO-d6)δ=18.9(C-3″),25.3(C-4″),30.5(C-2″),33.3(C-1),38.8(C-2),62.1(C-5″),96.5(C-4″),116.7(C-3′,C-5′),129.7(C-2′,C-6′),132.1(C-1′),156.2(C-4′).

[0498] HRMS,m / z=307.0312 found(calculated for C 13 H 17 BrO2Na[M+Na] + requires307.0310).

[0499] 1-(4-((tetrahydro-2H-pyran-2-yl)oxy)phenethyl)-1H-benzo[d]imidazole (11αa). To a solution of benzimidazole 50a (0.70 mmol, 2 eq.) in 1.2 ml DMF was added a dispersion of NaH 60% in mineral oil (0.027 g, 0.70 mmol, 2 eq.) in portions for 5 min under vigorous stirring (500 rpm). To this mixture were added 2-[4-(2-bromoethyl)phenoxy]tetrahydro-2H-pyran 10 (0.1 g, 0.35 mmol, 1 eq.) and potassium iodide KI (0.006 g, 0.035 mmol, 0.1 eq.) in sequence, and the resulting reaction mixture was heated at 90° C. for 24 h. After cooling to room temperature, 12 ml of deionized water was poured into the reaction mixture, and the flask was shaken manually, and then stored at 4°C (refrigerator) for 6 hours until complete precipitation. The insoluble material was recovered by filtration in a Buchner funnel (porosity N°4), and the precipitate was washed successively with 3 ml of deionized water and then with hexane (3x3 ml). Under high vacuum (10 -3 The solid was further dried at 400 torr to obtain 0.052 g of the desired compound 11αa as a white powder with a yield of 46%. Mp = 101-103°C.

[0500] 1 H NMR (300MHz, DMSO-d6) δ = 1.41-199 (m, 6H, H-3″, H-4″, H-5″), 3.05 (s, 2H, CH2, H-2’), 3.54 (s, 1H, H-6 ″), 3.71 (d, J=26.1Hz, 1H, H-6″), 4.45 (s, 2H, CH2, H-1′), 5.39 (s, 1H, H-1″), 6.91 (d, J=7.8Hz, 2H, H-3 a , H-5 a , Ar), 7.08 (d, J=7.7Hz, 2H, H-2 a , H-6 a , Ar), 7.31-7.13 (m, 2H, H-6, H-7, Ar), 7.62 (d, J=6.5Hz, 2H, H-5, H-8, Ar), 8.04 (s, 1H, H-2, Ar).

[0501] 13 C NMR (75MHz, DMSO-d6) δ = 18.7 (C-4”), 24.7 (C-3”), 29.9 (C-5”), 34.6 (C-6”), 45.6 (C-2’), 61.6 (C-1’), 95.9 (C-1”’), 110.5 (C-5), 116.4 (C-3 a , C-5 a), 119.4(C-8), 121.4(C-6), 122.2(C-7), 129.6(C-2 a , C-6 a ), 131.0(C-1 a ), 133.7(C-9), 143.3(C-4), 143.9(C-2), 155.2(C-4 a ).

[0502] HRMS m / z=345.1573 found(calculated for C 20 H 22 N2O2Na[M+Na] + requires345.1574),323.1754 found(calculated for C 20 H 23 N2O2[M+H] + requires 323.1754), 261.0998 found (calculated for C 15 H 14 N2ONa[M-C5H8O+Na] + requires 323.1754).

[0503] 1-(4-Hydroxyphenylethyl)-1H-benzo[d]imidazole hydrochloride (12a). To a solution of 1-(4-((tetrahydro-2H-pyran-2-yl)oxy)phenyl)-1H-benzo[d]imidazole 110a (0.11 mmol, 1 eq.) in 0.33 ml of tetrahydrofuran was added dropwise 0.33 ml of 3M HCl and the reaction was stirred at room temperature for 5 h under magnetic stirring (monitored by thin layer chromatography on 0.2 mm silica gel plates 60 F254 Merck using cyclohexane / AcOEt 1:1 or CH2Cl2 / MeOH 9:1 v / v as eluent). The solution was concentrated under reduced pressure in a rotary evaporator and the resulting solid was triturated in 1 ml of dry acetone (or finally stirred for 15 minutes). The insoluble material was recovered by filtration on a Buchner funnel (porosity N°4) and washed with dry acetone (3x0.5 ml). The solid was placed under high vacuum (10 -3 The mixture was further dried at 400 °C for 10 min to give 0.025 g of the desired compound 120a as a white powder with a yield of 83%. Mp = 212-214 °C.

[0504] 11H NMR (300 MHz, DMSO-d6) δ = 3.11 (t, J = 7.2 Hz, 2H, CH2, H-2’), 4.68 (t, J = 7.1 Hz, 2H, CH2, H-1’), 6.65 (d, J = 8.4 Hz, 2H, H-3 a , H-5 a , Ar), 6.95 (d, J = 8.3 Hz, 2H, H-2 a , H-6 a , Ar), 7.67 - 7.49 (m, 2H, H-5, H-8, Ar), 8.09 - 7.73 (m, 2H, H-6, H-7, Ar), 9.43 (s, 1H, H-2).

[0505] 13 13C NMR (75 MHz, DMSO-d6) δ = 33.8 (C-2’), 47.8 (C-1’), 113.3 (C-5), 115.1 (C-1 a ), 115.3 (C-3 a , C-5 a ), 125.9 (C-8), 126.2 (C-6), 126.9 (C-7), 129.7 (C-2 a , C-6 a ), 131.0 (C-9), 131.3 (C-4), 141.4 (C-2), 156.2 (C-4 a ).

[0506] HRMS m / z = 261.1001 found (calculated for C 15 H 14 N2ONa [M+Na] + requires 261.0998), 239.1182 found (calculated for C 15 H 15 N2O [M+H] + requires 239.1179).

[0507] Example 24

[0508]

[0509] 2-(4-(4-((tetrahydro-2H-pyran-2-yl)oxy)phenethoxy)phenyl)ethan-1-ol (3k). To a solution of 2-(4-hydrophenyl)ethanol 1a (0.5 g, 3.62 mmol) in 2 ml of dry DMF was added 1.5 g of potassium carbonate K2CO3 (10.86 mmol, 3 eq.) in several portions at room temperature under vigorous magnetic stirring (550 rpm). After 30 min, a solution of 2-[4-(2-bromoethyl)phenoxy]tetrahydro-2H-pyran 10 (1.02 g, 4.34 mmol, 1.2 eq.) in 1.5 ml of DMF was added dropwise at 25 °C over 15 min and stirring was continued for 72 h (monitored by thin layer chromatography on 0.2 mm silica gel plates 60 F254 Merck using cyclohexane / AcOEt 1:1 as eluent). Deionized water (20ml) is added directly to the crude reaction mixture, and the resulting solution is transferred to a separatory funnel. Extracted with EtOAc (3×25ml), the organic layer is washed with deionized water (2×25ml) and brine (2×25ml) in turn, dried over MgSO4 and filtered on filter paper. The filtrate is concentrated under reduced pressure in a rotary evaporator and the resulting oily residue is purified by chromatography (Combi Flash Rf 200psi device with DAD200 / 360nm detector) on a pre-packed column of silica gel 60F-254 (Merck) using a stepwise gradient elution of cyclohexane / AcOEt (0-50%). Merge for 60 minutes, remove the solvent in vacuo, and obtain 0.455g (36% yield) of pure desired compound 3k as a colorless mobile oil.

[0510] 1 H NMR (300MHz, DMSO-d6) δ = 1.94-1.45 (m, 6H, CH2, H-3″, H-4″, H-5″), 2.64 (t, J= 7.1Hz, 2H, CH2, H-2'), 2.94 (t, J=6.9Hz, 2H, CH2, H-2), 3.53 (tt, J=9.5, 4.7Hz, 3H, CH, CH2, H-1', H-1"), 3.82-3.69 (m, 1H, 1"), 4.10 (t, J=6.9Hz, 2H, CH2, H-1 ), 4.58 (t, J = 5.2Hz, 1H, OH), 5.41 (t, J = 3.2Hz, 1H, H-1”), 6.86-6.75 (m, 2H, H-3 a , H-5 a , Ar), 7.00-6.89(m, 2H, H-3 b , H-5 b , Ar), 7.15-7.04(m, 2H, H-2 a , H-6a ,Ar),7.28-7.16(m,2H,H-2 b ,H-6 b ,Ar).

[0511] 13 C NMR(75MHz,DMSO-d6)δ=18.7(C-4”),24.7(C-3”),29.9(C-5”),34.2(C-6”),38.2(C-2’),61.5(C-2),62.4(C-1’),68.3(C-1),95.9(C-1”),114.2(C-3 a ,C-5 a ),116.4(C-3 b ,C-5 b ),129.8(C-2 a ,C-6 a ,C-2 b ,C-6 b ),131.4(C-1 b ),131.4(C-1 a ),155.1(C-4 a ),156.7(C-4 b ).

[0512] HRMS m / z=365.1726 found(calculated for C 21 H 26 O4Na[M+Na] + requires365.1723),381.1465 found(calculated for C 21 H 26 O4K[M+K] + requires 381.1463),281.1153 found(calculated for C 16 H 18 O3Na[M-C5H8O+Na] + requires 281.1148).

[0513] 4-(4-((Tetrahydro-2H-pyran-2-yl)oxy)phenethoxy)phenethyl methanesulfonate (4k). To a solution of 2-(4-(4-((tetrahydro-2H-pyran-2-yl)oxy)phenethoxy)phenyl)ethan-1-ol 3k (0.48 g, 1.37 mmol, 1 eq.) in anhydrous CH2Cl2 (4.7 ml) cooled at 0°C (ice bath) was added a solution of methanesulfonyl chloride (220 μl, 0.326 g, 2.84 mmol, 2.07 eq.) in 0.7 ml anhydrous CH2Cl2 and 483 μl triethylamine TEA (0.379 g, 3.75 mmol, 2.7 eq.) dropwise over 15 min. The resulting reaction mixture was then stirred at room temperature for 2 hours (monitored by thin layer chromatography with 0.2 mm silica gel plates 60 F254 Merck using cyclohexane / AcOEt 1:1 as eluent). Work-up according to the procedure for 4a in Example 1 gave 0.339 g of the desired compound 4k as a light yellow mobile oil (57% yield).

[0514] 1 H NMR (300MHz, DMSO-d6) δ = 1.94-1.41 (m, 6H, H-3″, H-4″, H-5″), 3.01-2.83 (m, 4H, CH2, H-2’, H-2″), 3.09 (s, 3H, SCH3), 3.60-3.45 (m, 1H, CH, H-6″), 3 .83-3.68(m, 1H, CH, H-6″), 4.12(t, J=6.9Hz, 2H, CH2, H-1′), 4.35(t, J=6 .8Hz, 2H, CH2, H-1), 5.42 (t, J=3.1Hz, 1H, CH, H-1″), 6.91-6.82 (m, 2H, H-3 a , H-5 a , Ar), 6.99-6.92(m, 2H, H-3 b , H-5 b , Ar), 7.21 (dd, J=10.9, 8.6Hz, 4H, H-2 a , H-6 a , H-2 b , H-6 b , Ar).

[0515] 13 C NMR (75MHz, DMSO-d6) δ = 18.7 (C-4”), 24.7 (C-3”), 29.9 (C-5”), 34.2 (C-6”) , 38.2(C-2'), 61.5(C-2), 62.4(C-1'), 68.3(C-1), 95.9(C-1”), 114.2(C-3a , C-5 a ), 116.4(C-3 b , C-5 b ), 129.8(C-2 a , C-6 a , C-2 b , C-6 b ), 131.4(C-1 b ), 131.4(C-1 a ), 155.1(C-4 a ), 156.7(C-4 b ).

[0516] HRMS m / z=443.1498 found(calculated for C 22 H 28 O6NaS[M+Na] + requires443.1499),459.1233 found(calculated for C 22 H 28 O6SK[M+K] + requires 459.1238).

[0517] 1-(4-(4-((tetrahydro-2H-pyran-2-yl)oxy)phenethoxy)phenethyl)-1H-benzo[d]imidazole (11αb). Compound 11αb was synthesized from benzimidazole 5αa (0.76 mmol, 2 equiv) and 4-(4-((tetrahydro-2H-pyran-2-yl)oxy)phenethoxy)phenethyl methanesulfonate 4k (0.16 g, 0.38 mmol, 1 equiv) according to the procedure for 11αa in Example 23 to give 0.048 g of the desired compound 11αb as a white powder (28% yield).

[0518] 1H NMR(300MHz,DMSO-d6)δ=1.69(dddd,J=25.8,16.9,15.9,8.3Hz,6H,CH2,H-3”’,H-4″’,H-5″’),2.93(t,J=6.7Hz,2H,CH2,H-2″),3.04(t,J=7.1Hz,2H,CH2,H-2’),3.59-3.45(m,1H,H-6″’),3.85-3.67(m,1H,H-6″’),4.08(t,J=6.8Hz,2H,CH2,H-1″),4.44(t,J=7.1Hz,2H,CH2,H-1’),5.41(s,1H,H-1″’),6.81(d,J=8.4Hz,2H,H-3 a ,H-5 a ,Ar),6.96(d,J=8.4Hz,2H,H-3 b ,H-5 b ,Ar),7.06(d,J=8.4Hz,2H,H-2 a ,H-6 a ,Ar),7.28-7.13(m,4H,H-6,H-7,H-2 b ,H-6 b ,Ar),7.63(dd,J=12.3,5.8Hz,2H,H-5,H-8,Ar),8.01(s,1H,H-2,Ar).

[0519] 13 C NMR(75MHz,DMSO-d6)δ=18.7(C-4”’),24.7(C-3”’),29.9(C-5”’),34.1(C-6”’),34.5(C-2”),45.6(C-2’),61.5(C-1”),68.3(C-1’),95.9(C-1”’),110.4(C-5),114.4(C-3 a ,C-5 a ),116.4(C-3 b ,C-5 b ),119.4(C-8),121.3(C-6),122.2(C-7),129.7(C-2 a ,C-6 a ),129.8(C-2 b ,C-6 b ),130.0(C-1 a ),131.3(C-1 b ),133.6(C-9),143.3(C-4),143.9(C-2),155.1(C-4a ), 157.1(C-4 b ).

[0520] HRMS m / z=465.2144 found(calculated for C 28 H 30 N2O3Na[M+Na] + requires465.2149),443.2328 found(calculated for C 28 H 31 N2O3[M+H] + requires 443.2329), 481.1887 found (calculated for C 28 H 30 N2O3K[M+K] + requires 481.1888).

[0521] 1-(4-(4-Hydroxyphenethoxy)phenethyl)-1H-benzo[d]imidazole hydrochloride (12αb). Compound 12αb was synthesized from 11αb (0.11 mmol) according to the procedure for 12αa in Example 23 to give 0.028 g of the desired compound 12αb as a brown powder (72% yield). Mp = 97-107°C.

[0522] 1 H NMR (300MHz, DMSO-d6) δ = 2.87 (t, J = 6.8Hz, 2H, CH2, H-2″), 3.16 (t, J = 7.0Hz, 2H, CH2, H-2′) , 4.04 (t, J=6.9Hz, 2H, CH2, H-1″), 4.70 (t, J=7.1Hz, 2H, CH2, Hr), 6.70 (d, J=8.3Hz, 2H, H-3 b , H-5 b , Ar), 6.81 (d, J=8.4Hz, 2H, H-3 a , H-5 a , Ar), 7.07 (d, J=8.3Hz, 4H, H-2 a , H-6 a , H-2 b , H-6 b, Ar), 7.59 (dd, J=6.0, 3.1Hz, 2H, H-5, H-6, A), 7.85 (dd, J=6.0, 2.7Hz, 1H, H-7, Ar), 8.00 (dd, J=6.2, 2.7Hz, 1H, H-8, Ar), 9.47 (s, 1H, H-2, Ar).

[0523] HRMS m / z=359.1759 found(calculated for C 23 H 23 N2O2[M+H] + requires359.1754).

[0524] Embodiment 25

[0525]

[0526] 5-Fluoro-1-(4-(4-((tetrahydro-2H-pyran-2-yl)oxy)phenethyloxy)phenethyl)-1H-benzo[d]imidazole (11αc). Compound 11αc was synthesized from 5-fluorobenzimidazole 5αd (0.76 mmol, 2 equiv) and 4-(4-((tetrahydro-2H-pyran-2-yl)oxy)phenethyloxy)phenethyl methanesulfonate 4k (0.16 g, 0.38 mmol, 1 equiv) according to the procedure for 11αa in Example 23 to give 0.111 g of the desired compound 11αc as a white powder (63% yield). Mp = 90-92°C.

[0527] 1 H NMR (300MHz, DMSO-d6) δ = 1.95-1.46 (m, 6H, CH2, H-3"', H-4"', H-5"'), 2.92 (dd, J = 12 .4, 5.5Hz, 2H, CH2, H-2"), 3.02 (td, J=7.2, 2.8Hz, 2H, CH2, H-2'), 3.52 (dt, J=22.2, 8. 1Hz, 1H, H-6"'), 3.82-3.66 (m, 1H, H-6"'), 4.09 (t, J=6.9Hz, 2H, CH2, H-1'), 4.43 (q, J=7.6Hz, 2H, CH2, H-1”), 5.42 (dd, J=8.4, 5.0Hz, 1H, H-1”’), 6.81 (d, J=7.9Hz, 2H, H-3 b , H-5 b , Ar), 7.00-6.86(m, 2H, H-3 a , H-5 a , Ar), 7.13-7.00(m, 3H, H-2b , H-6 b , H-8, Ar), 7.26-7.13 (m, 2H, H-2 a , H-6 a , Ar), 7.46 (ddd, J=28.0, 9.6, 2.5Hz, 1H, H-7, Ar), 7.62 (dt, J=8.9, 5.1Hz, 1H, H-5, Ar), 8.06 (d, J=11.1Hz, 1H, H-2, Ar).

[0528] HRMS m / z=483.2056 found(calculated for C 28 H 29 N2O3FNa[M+Na] + rcquires483.2054), 461.2235 found(calculated for C 28 H 30 N2O3F[M+H] + requires 461.2235), 499.1793 found (calculated for C 28 H 29 N2O3FK[M+K] + requires 499.1794).

[0529] 5-Fluoro-1-(4-(4-hydroxyphenethoxy)phenethyl)-1H-benzo[d]imidazole hydrochloride (12αc). Compound 12αc was synthesized from 11αc (0.11 mmol) according to the procedure for 12αa in Example 23 to give 0.028 g of the desired compound 12αc (41% yield) as a white powder. Mp = 158-160°C.

[0530] 1 H NMR (300MHz, DMSO-d6) δ=2.87 (t, J=6.9Hz, 2H, CH2, H-2”), 3.13 (t, J=7.1Hz, 2H, CH2, H-2’), 4.0 5(t, J=6.9Hz, 2H, CH2, H-1”), 4.66 (dd, J=15.6, 7.8Hz, 2H, CH2, H-1’), 6.70 (d, J=8.5Hz, 2H, H-3 b , H-5 b , Ar), 6.81 (d, J=8.6Hz, 2H, H-3 a , H-5 a , Ar), 7.08 (dd, J=8.4, 4.6Hz, 4H, H-2a , H-6 a , H-2 b , H-6 b , Ar), 7.46 (td, J=9.3, 2.4Hz, 1H, H-8, Ar), 7.88 (dddd, J=49.2, 11.0, 8.9, 3.4Hz, 2H, H-6, H-7, Ar), 9.36 (d, J=3.4Hz, 1H, H-2).

[0531] HRMS m / z=399.1471 found(calculated for C 23 H 21 N2O2FNa[M+Na] + requires399.1479),377.1659 found(calculated for C 23 H 22 N2O2F[M+H] + requires 377.1660).

[0532] Embodiment 26

[0533]

[0534] 5-Fluoro-1-(4-((tetrahydro-2H-pyran-2-yl)oxy)phenethyl)-1H-benzo[d]imidazole (11αd). Compound 11αd was synthesized from 5-fluorobenzimidazole 5αd (0.70 mmol, 2 equiv) and 2-[4-(2-bromoethyl)phenoxy]tetrahydro-2H-pyran 10 (0.1 g, 0.35 mmol, 1 equiv) according to the procedure for 11αa in Example 23 to give 0.047 g of the desired compound 11αd (39% yield) as a light yellow oil.

[0535] 1 H NMR (300MHz, DMSO-d6) δ=1.86-1.42 (m, 6H, CH2, H-3″, H-4″, H-5″), 3.02 (tt, J=17.8, 8.9Hz, 2H, CH2, H-2’), 3.52 (dd, J=9.3, 5.4Hz, 1 H, H-6"), 3.81-3.66 (m, 1H, H-6"), 4.44 (dd, J=14.8, 7.7Hz, 2H, CH2, H-1'), 5.38 (t, J=3.2Hz, 1H, CH, H-1"), 6.89 (d, J=8.4Hz, 2H, H-3 a , H-5 a , Ar), 7.15-6.95(m, 3H, H-8, H-2a , H-6 a , Ar), 7.45 (ddd, J=23.3, 9.6, 2.4Hz, 1H, H-5, Ar), 7.61 (ddd, J=8.8, 4.8, 2.5Hz, 1H, H-7, Ar), 8.08 (d, J=11.1Hz, 1H, H-2).

[0536] 13 C NMR (75MHz, DMSO-d6) δ = 18.8 (C-4”), 24.8 (C-3”), 30.0 (C-5”), 34.7 (C-6”), 45.9 (C-2’), 61.6 (C-1’), 95.9 (C-1”’), 111.4, 116.4 (C-3 a , C-5 a ), 129.7(C-2 a ), 129.8(C-6 a ), 131.0, 145.6(C-2), 155.3(C-4 a ).

[0537] 19 F NMR (282MHz, DMSO-d6) δ = -119.7-119.9(m), -121.9-122.1(m).

[0538] HRMS m / z=363.1482 found(calculated for C 20 H 21 N2O2FNa[M+Na] + requires363.1479),341.1660 found(calculated for C 20 H 22 N2O2F[M+H] + requires 341.1660), 379.1219 found (calculated for C 22 H 21 N2O2FK[M+K] + requires 379.1219).

[0539] 5-Fluoro-1-(4-hydroxyphenylethyl)-1H-benzo[d]imidazole hydrochloride (12αd). Compound 12αd was synthesized from 11αd (0.11 mmol) according to the procedure for 12αa in Example 23 to give 0.017 g of the desired compound 12αd (47% yield) as a beige powder. Mp = 217-219°C.

[0540] 1 H NMR(300MHz,DMSO-d6)δ=3.09(dd,J=15.5,8.4Hz,2H,CH2,H-2’),4.63(dd,J=15.5,7.4Hz,2H,CH2,H-1’),6.64(d,J=8.4Hz,2H,H-3 a ,H-5 a ,Ar),7.00-6.89(m,2H,H-2 a ,H-6 a ,Ar),7.44(qd,J=9.6,2.4Hz,1H,H-8,Ar),7.86(dddd,J=48.3,11.1,8.9,3.4Hz,2H,H-5,H-7,Ar),9.28(d,J=3,0Hz,1H,H-2,Ar).

[0541] 13 C NMR(75MHz,DMSO-d6)δ=33.9(C-1’),47.7(C-2’),100.1,102.2,114.7(C-8),115.3(C-2 a ,C-6 a ),117.2(C-5),127.0(C-9),128.2(C-1 a ),129.7(C-3 a ,C-5 a ),129.7(C-7),143.0(C-2),156.2(C-4 a ).

[0542] 19 F NMR(282MHz,DMSO-d6)δ=-119.8(m),-121.9-122.1(m).

[0543] HRMS m / z=279.0903 found(calculated for C 15 H 13 N2OF Na[M+Na] + requires279.0904),257.1084 found(calculated for C 15 H 14 N2OF[M+H] + requires 257.1085),121.0648 found(calculated for C8H9O[C8H8O+H] +requires 121.0648).

[0544] Embodiment 27

[0545]

[0546] Compound 11αe was synthesized from indazole 5αb (0.70 mmol, 2 eq.) and 2-[4-(2-bromoethyl)phenoxy]tetrahydro-2H-pyran 10 (0.1 g, 0.35 mmol, 1 eq.) according to the method used to prepare 11αa in Example 23 and purified by chromatography (Combi Flash R f Purification was performed on a pre-packed silica gel 60-F254 (Merck) column using a step gradient of cyclohexane / AcOEt (0-25%) at 200 psi with a DAD 200 / 360 nm detector. The elution was combined for 60 minutes and the solvent was removed in vacuo to give the pure desired compound 11αe in 25% yield as a milky white powder. Mp = 86-90°C.

[0547] 1 H NMR (300MHz, DMSO-d6) δ = 1.65 (dddd, J = 18.4, 11, 4, 8.7, 4.7Hz, 4H, H-3 a , H-4 a ), 1.85 (tt, J=6.4, 2.3Hz, 1H, H-2 a ), 1.99(m, 1H, H-2 a ), 3.16 (m, 2H, CH2, H-2′), 3.58 (dtd, J=11.4, 4.2, 1.6Hz, 1H, H-5 a ), 3.90 (ddd, J=11.4, 9.2, 3.3Hz, 1H, H-5 a ), 4.56 (m, 2H, CH2, H-1′), 5.36 (t, J=3.3Hz, 1H, H-1 a ), 6.94 (m, 2H, H-3″, H-5″), 7.05 (m, 2H, H-2″, H-6″), 7.11 (ddd, J=7.9, 6.5, 1.2Hz, 1H, H -5), 7.28 (m, 2H, H-6, H-7), 7.71 (dt, J=8.1, 1.0Hz, 1H, H-4), 8.01 (d, J=0.9Hz, 1H, H-3).

[0548] 13 C NMR (75MHz, DMSO-d6) δ = 19.0 (C-3 a ), 25.4(C-4 a), 30.5(C-2 a ),, 35.7(C-2′), 50.8(C-1′), 62.2(C-5a), 96.6(C-1 a ), 109.1(C-7), 115.6, 116.8(C-3″, C-5″), 120.6(C-5), 121.2(C-41), 124.0( C-3a), 126.3(C-6), 129.8(C-2″, C-6″), 131.5(C-1″), 133.1(C-3), 139.6(C-7 a ), 156.0(C-4″).

[0549] 1-(4-Hydroxyphenylethyl)-1H-indazole hydrochloride (12αe). Compound 12αe was synthesized from 11αe (0.11 mmol) according to the procedure for synthesizing 12αa in Example 23 to give the desired compound 12αe in 21% yield as a beige powder. Mp = 217-219°C.

[0550] 1 H NMR (300MHz, DMSO-d6) δ = 3.00 (t, J = 7.3Hz, 2H, CH2, H-2′), 4.54 (1, J = 7.3Hz, 2H, CH2, H-1′), 6.60 (d, J = 8.1Hz, 2H, H-3″, H-5″, Ar), 6.95 (d, J = 8.0Hz, 2H, H-2″, H-6″, Ar), 7.08 (t, J=7.4Hz, 1H, H-5), 7.30 (t, J=7.6Hz, 1H, H-6) , 7.54 (d, J=8.5Hz, 1H, H-7), 7.72 (d, J=8.1Hz, 1H, H-4), 8.05 (s, 1H, H-3).

[0551] 13 C NMR (75MHz, DMSO-d6) δ=34.8(C-2′), 49.8(C-1′), 109.7(C-7), 115.1(C-3″, C-5″), 120.3(C-4), 120.8(C- 5), 123.4(C-7a), 125.9(C-6), 128.5(C-1″), 129.7(C-2″, C-6″), 132.6(C-3), 139.3(C-7a), 155.9(C-4″).

[0552] Embodiment 28

[0553]

[0554] 1-(4-((Tetrahydro-2H-pyran-2-yl)oxy)phenethyl)-1H-1,2,4-triazole (11βa). Compound 11βa was synthesized from 1H-1,2,4-triazole 5βd (0.70 mmol, 2 equiv) and 2-(4-(2-bromoethyl)phenoxy)tetrahydro-2H-pyran 10 (0.1 g, 0.35 mmol, 1 equiv) according to the procedure used for 11αa in Example 23 to give the desired compound 12βa in 70% yield as a white powder. Mp = 56-60°C.

[0555] 1 H NMR (300MHz, DMSO-d6) δ = 1.63 (m, 3H, CH2, H-3 a , H-4 a ), 1.83 (tt, J=5.3, 2.5Hz, 2H, H-4 a , H-2 a ), 1.96 (dt, J=9.6, 6.7Hz, 1H, H-2 a ), 3.09 (t, J=7.0Hz, 2H, CH2, H-2′), 3.57 (dtd, J=11.2, 4.2, 1.6Hz, 1H, H-5 a ), 3.88 (ddd, J=12.1, 9.1, 3.2Hz, 1H, H-5 a ), 4.33 (t, J=7.0Hz, 2H, CH2, H-1′), 5.35 (t, J=3.4Hz, 1H, H-1 a ), 6.93(m, 4H, H-2″, H-3″, H-5″, H-6″), 7.74(s, 1H, H-5), 7.93(s, 1H, H-3).

[0556] 13 C NMR (75MHz, DMSO-d6) δ = 18.9 (C-3 a ), 25.3(C-4 a ), 30.5(C-2a), 35.5(C-2′), 51.4(C-1′), 62.2(C-5 a ), 96.6(C-1 a ), 116.9(C-3″, C-5″), 129.6(C-2″, C-6″), 130.2(C-1″), 143.3(C-5), 152.1(C-3), 156.2(C-4″).

[0557] 1-(4-Hydroxyphenylethyl)-1H-1,2,4-triazole hydrochloride (12βa). According to the method used for 12αa in Example 23, compound 12βa was synthesized from 11βa (0.11 mmol) to obtain the desired compound 12βa in 70% yield as a white powder. Mp = 172-176°C.

[0558] 1 H NMR (300MHz, DMSO-d6) δ = 2.98 (t, J = 7.1Hz, 2H, CH2, H-2′), 4.38 (t, J = 7.2Hz, 2H, CH2, H-1 ′), 6.64(m, 2H, H-3″, H-5″), 6.91(m, 2H, H-2″, H-6″), 8.15(s, 1H, H-2), 8.58(s, 1H, H-5).

[0559] 13 C NMR (75MHz, DMSO-d6) δ=34.4(C-2′), 50.5(C-1′), 115.2(C-3″, C-5″), 127.5(C-1″), 129.5(C-2″, C-6″), 149.8(C-2), 143.4(C-5), 156.0(C-4″).

[0560] HRMS, m / z=21.0794 found (calculated for C 10 H 13 N3ONa[M+Na] + requires212.0793).

[0561] Embodiment 29

[0562] Table 3. Other N-phenylalkylazole SOCE inhibitors with free or protected hydroxyl functions on the terminal side chain.

[0563]

[0564] II. Biological properties of SOCE inhibitors

[0565] Embodiment 30

[0566] All the "final" molecules described in Part I above and some synthetic intermediates have been tested for their bioactivity on the Calciscreen platform at the University of Brest for their potential SOCE modulating activity on different cell lines.

[0567] Testing the effects of the developed molecules on PLP-B lymphocytes. Store-operated Ca 2+ Influx occurs in the absence of Ca2+ Thapsigargin (Tg) was used to deplete the endoplasmic reticulum Ca 2+ ERCa 2+ The results were compared with those obtained by known SOCE inhibitors SKF-96365, GSK-7975A, and Synta66.

[0568] The effect of the molecule that gave the best results in this test, namely the molecule 6αa, was then evaluated in two cancer cell lines: the HEK 293 and the HEK 651HS1 tumor cell lines.

[0569] Table 4 presents the results obtained for 1-[4-(phenylalkoxy)phenyl]ethyl]-1H-imidazole 6α and substituted 1-[4-(phenylalkoxy)phenylethyl]-1H-indazole 6αf, 6α(x,y) in PLP-B lymphocytes; Table 5 presents the results obtained for 1-[4-(phenylalkoxy)phenylethyl]-1H-pyrazole 6βc and substituted 1-[4-(phenylalkoxy)phenylethyl]-1H-1,2,4-triazole 6β(j-1) in PLP-B lymphocytes; and Table 6 presents the results obtained for 1-(4-hydroxyphenylalkyl)-1H-azole 9α, 9β, 12α, 12β and its precursors 8α, 8β, 11α, 11β in PLP-B lymphocytes. Table 7 presents the results obtained for compound 6αa in cancer cell lines.

[0570] Table 4. Effects of 1-[4-(phenylalkoxy)phenylethyl]-1H-benzimidazole 6α and substituted 1-[4-(phenylalkoxy)phenylethyl]-1H-indazole 6αf, 6α(x,y) on store-operated Ca in PLP-B lymphocytes compared with known standard SOCE inhibitors (SKF-96365, GSK-7975A, Synta66). 2+ In the table below, "white" indicates "no effect", i.e., values ​​of 0-10%; "light grey" indicates "moderate effect", i.e., values ​​of 10%-20%; "medium grey" indicates "significant effect", i.e., values ​​of 20%-50%; and "dark grey" indicates "very significant effect", i.e., values ​​>50%.

[0571]

[0572]

[0573]

[0574] a Percent inhibition (-) or activation. DMSO 100% control. bIC in μM 50 Mean values ​​of three determinations, ± 0.5 μM.

[0575] Table 5. Effects of 1-[4-(phenylalkoxy)phenylethyl]-1H-pyrazole 6βc and substituted 1-[4-(phenylalkoxy)phenylethyl]-1H-1,2,4-triazole 6β(j-1) on store-operated Ca in PLP-B lymphocytes compared with known standard SOCE inhibitors (SKF-96365, GSK-7975A, Synta66). 2+ In the table below, "white" indicates "no effect", i.e., values ​​of 0-10%; "light grey" indicates "moderate effect", i.e., values ​​of 10%-20%; "medium grey" indicates "significant effect", i.e., values ​​of 20%-50%; and "dark grey" indicates "very significant effect", i.e., values ​​>50%.

[0576]

[0577]

[0578]

[0579] a Percent inhibition (-) or activation. DMSO 100% control. b IC in μM 50 Mean values ​​of three determinations, ± 0.5 μM.

[0580] Table 6. Effects of 1-(4-hydroxyphenylalkyl)-1H-pyrrole 9α, 9β, 12α, 12β and their precursors 8α, 8β, 11α, 11β on store-operated Ca2+ in PLP-B lymphocytes compared with known standard SOCE inhibitors (SKF-96365, GSK-7975A, Synta66). 2+ In the table below, "white" indicates "no effect", i.e., values ​​of 0-10%; "light grey" indicates "moderate effect", i.e., values ​​of 10%-20%; "medium grey" indicates "significant effect", i.e., values ​​of 20%-50%; and "dark grey" indicates "very significant effect", i.e., values ​​>50%.

[0581]

[0582]

[0583]

[0584] a Percent inhibition (-) or activation. DMSO 100% control.b IC in μM 50 Mean values ​​of three determinations, ± 0.5 μM.

[0585] Table 7. Effect of compound 6αa on store-operated Ca2+ in HEK293 and HEK651HS1 tumor cell lines compared to known standard SOCE inhibitors (SKF-96365 and GSK-7975A). 2+ In the table below, "white" indicates "no effect", i.e., values ​​of 0-10%; "light gray" indicates "moderate effect", i.e., values ​​of 10%-20%; "medium gray" indicates "significant effect", i.e., values ​​of 20%-50%; and "dark gray" indicates "very significant effect", i.e., values ​​>50%.

[0586]

[0587] a Percent inhibition (-) or activation. DMSO 100% control. b IC in μM 50 Mean values ​​of three determinations, ± 0.5 μM. c ND: Not determined.

[0588] in conclusion

[0589] The goal was to identify inhibitors of SOCE without inhibiting Ca 2+ From the endoplasmic reticulum Ca 2+ Innovative modulators of SOCE released from the pool. Another aim was to select inhibitors with better inhibition of SOCE than SKF-96365. Molecules from the 6α series were found to be the most potent, and the 6αa molecule was found to be the best candidate in the 6α series (Table 6). In summary, compound 6αa is a new SOCE inhibitor with an efficiency superior to or equal to previously described SOCE inhibitors such as GSK-7975A (Table 7).

[0590] III. SOCE inhibition of compound 6αa of the present invention and comparison with GSK-7975A and SKF-93365

[0591] Embodiment 31

[0592] A. Materials and Methods

[0593] Methods for measuring intracellular calcium levels

[0594] Using FlexStation 3 TM Intracellular calcium levels were monitored at 37°C using the FlexStation 3 (Molecular Devices, Berkshire, UK). TMis a fluorescence plate reader for measuring time-resolved intracellular Ca in a 96-well format 2+ concentration, in which cells were loaded with the dual-wavelength fluorescent calcium-sensitive dye Fura-2AM.

[0595] In the absence of Ca 2+ The intracellular Ca was depleted by 2 μM thapsigargin (an inhibitor of the ER SERCA pump) under 2+ To measure intracellular Ca 2+ Next, the cells were returned to a culture medium containing Ca 2+ Hepes buffer was used to measure SOCE. The size of SOCE was estimated as Ca 2+ The maximum value of the normalized fluorescence ratio after the addition of

[0596] Data were stored for subsequent analysis by using Softmaxpro (Molecular Devices), Excel, and Graph Pad Prism software (Graph Pad Software, La Jolla, CA, USA).

[0597] A method for measuring the function of B cells (JOK cells).

[0598] Cell viability assay. JOK cells were treated with test compounds (GSK-7975-A, SKF-93365 and 6αa) or solvent for 48 h. Then, JOK cell viability was assessed using the LIVE / DEAD cell viability assay kit (Abcam). Live and dead cells differentially labeled with fluorescent dyes were analyzed by flow cytometry.

[0599] Cell proliferation assay. Cultured JOK cells were seeded in 96-well culture plates with or without inhibitors. After 48 hours, cell proliferation was assessed using the WST-8 assay (Sigma Aldrich). The absorbance was read at 450 nm on a plate reader.

[0600] Cell cycle analysis. JOK cells were incubated with or without test compounds (GSK-7975-A, SKF-93365 and 6αa) for 48 hours, then washed with cold PBS and fixed with 70% ethanol for 30 minutes at room temperature. Cell cycle was analyzed using propidium iodide (PI). Cell cycle distribution was determined by PI-staining using flow cytometry and analyzed by Kaluza 1.3.

[0601] Apoptosis Assay. Apoptosis of JOK cells was determined by flow cytometry by Annexin V-FITC / PI staining (Biolegend). The percentage of Annexin V-FITC and propidium iodide negative cells was assessed using Kaluza 1.3.

[0602] Migration scheme. The migration chamber (transwell) (Transwell 5.0ml polycarbonate membrane Costar) was coated with 100 μL of fibronectin solution containing BSA (1mg / ml) and LHC basal medium overnight (37°C, 5% CO2). Primary umbilical vein endothelial cells (HUVEC) were seeded in each transwell (100000 / well) and cultured for 24 hours (37°C, 5% CO2). In order to evaluate B cell migration, JOK cells (300000 / well) were added to each transwell upper chamber containing RPMI1640 culture medium (Biowest), which contained 0.5% BSA, and SDF1 (200ng / ml) was added to the lower chamber. Cells were cultured in the presence or absence of test compounds (GSK-7975-A, SKF-93365 and 6αa) or solvents. After 24 hours (37°C, 5% CO2), the migrated cells were collected in the lower chamber and counted by flow cytometry. Calculate the migration percentage for each experimental set.

[0603] Methods for functional assays of pancreatic cancer cells (PANC-1 cells).

[0604] Cell proliferation analysis. For PANC-1 cell proliferation and cell cytotoxicity measurements, 10 6 Cells were seeded in 100 μL DMEM medium in 96-well plates. Compared with DMSO and untreated cells, cells were incubated with 3 different SOCE inhibitors (GSK-7975-A, SKF-93365 and 6αa) at 2 different concentrations (5 and 20 mM) at 37 ° C for 24 hours. Cell proliferation was assessed using a cell titer kit proliferation assay (Promega). Cytotoxicity was assessed using a cytotoxic green cytotoxicity assay (Promega). All kits were used according to the manufacturer's recommendations and using a plate reader.

[0605] Cell apoptosis analysis. For PANC-1 cell apoptosis measurement, 5x10 6 Cells were seeded in 12-well plates.Compared with DMSO and untreated cells, cells were incubated with two different concentrations (5 and 20 mM) of test compounds (GSK-7975-A, SKF-93365 and 6αa) at 37 ° C for 24 hours.After washing, cells were removed from the plate using enzyme-free solution.Cells were centrifuged at 1500 rpm for 5 minutes and suspended in 50 mL PBS containing 1 μL Annexin V-FiTC and 1 μL propidium iodide (PI) at room temperature in the dark for 15 minutes.Flow cytometer (Navios, Beckman Counter) was used to evaluate annexin and PI staining to assess cell apoptosis and necrosis.

[0606] B.Results.

[0607] Effects of drug treatment on intracellular calcium levels in JOK B cells. The results are shown in Figure 3 and 4. Figure 3 4 shows that compound 6αa significantly reduced the amplitude of SOCE compared to the control observed at two different concentrations (5 and 20 μM) of GSK-7975A and SKF-93365, regardless of the incubation time of the drugs ( Figure 3 : 1 hour incubation; Figure 4A-B : 5 minutes incubation; Fig. 4C-D : 15 minutes incubation; Figure 4E-F : 30 min incubation). In the presence of 6αca, GSK-7975A and SKF-93365, no Ca 2+ The magnitude of release from endosomal pools was significantly affected.

[0608] Functional effects of drugs on JOK cells. The results are shown in Figures 5 to 8. Figure 5 shows that the compound 6αa of the present invention significantly reduces JOK proliferation and affects the cell cycle without significantly reducing cell survival. Figure 7 and 8 The results show that the compound 6αa of the present invention does not induce the death of B cells and HUVEC cells. Figure 7 and 8 Compounds of the invention 6αa, GSK-7975A and SKF-93365 at concentrations of 5 or 20 mM did not induce apoptosis or necrosis in cells treated for 48 hours. However, compound 6αa of the invention used at 5 or 20 μM did significantly inhibit transendothelial migration of JOK cells through HUVECs, while GSK-7975A did not.

[0609] The drug has an effect on the function of pancreatic cancer cell PANC-1. The results are shown in Figure 9-11 . Fig. 9 It was shown that the compound 6αa of the present invention significantly reduced PANC-1 proliferation and reduced it to a greater extent than GSK-7975A and SKF-93365. Fig.10 It was shown that the compound 6αa of the present invention induced cytotoxicity in cancer PANC-1 cells, whereas GSK-7975A and SKF-93365 showed no cytotoxic effect on these cancer cells. Fig.11 It was shown that the compound 6αa of the present invention induced PANC-1 cells by apoptosis even at a concentration of 5 μM.

[0610] IV. Synthetic routes for preparing amide or sulfonamide analogs of the SOCE inhibitor 6αa of the present invention

[0611] Embodiment 32

[0612] Synthesis of Common Intermediates. The intermediate (hereinafter Compound 5), which is common to the preparation of the amide analog of Compound 6αa and the preparation of the sulfonamide analog of Compound 6αa, can be synthesized according to the following scheme.

[0613]

[0614] Synthesis of the amide analog of compound 6αa The amide analog of compound 6αa can be synthesized from common intermediate 5 according to the following scheme.

[0615]

[0616] By reacting different acid chlorides with the common intermediate, different amide analogs can be obtained, as shown in Table 8.

[0617] Table 8. Acid chlorides and corresponding amide analogs 7.

[0618]

[0619] Synthesis of sulfonamide analogs of compound 6αa. Sulfonamide analogs of compound 6αa can be synthesized from common intermediate 5 according to the following scheme.

[0620]

[0621] By reacting different sulfonyl chlorides with common intermediates, different sulfonamide analogs can be obtained, as shown in Table 9.

[0622] Table 9. Sulfonyl chlorides and corresponding sulfonamide analogs 9.

[0623]

Claims

1. An aromatic azole compound of formula (I) or a pharmaceutically acceptable salt thereof: in: R1 is 1, 2, 3, 4 or 5 substituents, wherein each substituent is independently selected from H, OH, halogen, NH2, -OR, -OAr, OCH2OR and O-THP; In the -OR, R is an alkyl group of 1 to 10 carbon atoms; In the -OAr, Ar is phenyl, biphenyl or naphthyl; In the OCH2OR, R is an alkyl group of 1 to 10 carbon atoms; In the O-THP, THP is tetrahydropyranyl; A is CH2 or O; If A is CH2, then n=0, 1 or 2, and if A is O, then n=2 or 3; Z is O; X is one of the following groups: in: R2 is H, Cl, Br or CF3; R3 is 1, 2, 3 or 4 substituents, wherein each substituent is independently selected from H, OH, CF3, F, Cl, NH2, COOH and CONH2; R4 is 1, 2 or 3 substituents, wherein each substituent is independently selected from H, F, CF3 and an alkyl group of 1 to 10 carbon atoms; and R5 is 1 or 2 substituents, wherein each substituent is independently selected from H, F and CF3. 2 . The aromatic azole compound according to claim 1 , wherein in the —OR, R is an alkyl group of 1 to 5 carbon atoms.

3. The aromatic azole compound according to claim 2, wherein the -OR is methoxy, ethoxy, n-propoxy, isopropoxy or tert-butoxy.

4. The aromatic azole compound according to claim 1, wherein in OCH2OR, the alkyl group R is an alkyl group of 1 to 5 carbon atoms.

5. The aromatic azole compound according to claim 1, wherein R4 is an alkyl group of 1 to 5 carbon atoms.

6. The aromatic azole compound according to claim 1, wherein the aromatic azole compound has the chemical formula (II): wherein R1, A, n and X are as described in claim 1.

7. The aromatic azole compound according to claim 6, wherein the aromatic azole compound has the chemical formula (III): wherein R1, A, n, R2 and R3 are as described in claim 1.

8. The aromatic azole compound according to claim 1, wherein the aromatic azole compound has a chemical formula of one of the following compounds:

9. The aromatic azole compound according to claim 8, wherein the aromatic azole compound has compounds 6αc (DAD 4-546), 6αt (VAL 1-76), 6αm (VAL 1-77), 6αu (VAL 1-75), 6αv (VAL 1-64), 6αe (DAD4-548), 6αd (DAD 4-547), 6αo (DAD 4-551), 6αp (DAD 4-552), 6αab (DAD 4-553), 6αac (DAD4-566), 6αad (DAD 4-567), 6αd (DAD 4-568), 6αs (DAD4-570), 6αae (DAD 4-569), 6αa (DAD3-473), 6αm (DAD 3-475), 6αn (DAD The chemical formula is one of 6αz (DAD 4-474), 6αz (DAD 4-472), 6αb (DAD 4-573), 6αaa (DAD4-574) and 6αab (DAD 4-575).

10. The aromatic azole compound according to claim 9, wherein the aromatic azole compound is selected from the group consisting of:

11. Use of an aromatic azole compound according to any one of claims 8 to 10 in the preparation of a medicament for treating a disease associated with SOCE disorder or dysfunction, wherein the disease associated with SOCE disorder or dysfunction is selected from the group consisting of inflammatory diseases, immunodeficiency diseases, autoimmune diseases, allergies, cardiovascular diseases, cardiopulmonary diseases, neurodegenerative diseases, skeletal muscle diseases and cancer.

12. Use according to claim 11, wherein the cardiovascular disease is a vascular disease.

13. The use according to claim 12, wherein the vascular disease is thrombosis.

14. The use according to claim 11, wherein the disease associated with SOCE dysregulation or dysfunction is selected from the group consisting of inflammatory bowel disease, pancreatitis, rheumatoid arthritis, multiple sclerosis, asthma, psoriasis and cancer.

15. A pharmaceutical composition comprising an effective amount of at least one aromatic azole compound according to any one of claims 8 to 10 and a pharmaceutically acceptable carrier or excipient.

16. Use of the pharmaceutical composition according to claim 15 in the preparation of a medicament for treating a disease associated with SOCE disorder or dysfunction, wherein the disease associated with SOCE disorder or dysfunction is selected from the group consisting of inflammatory diseases, immunodeficiency diseases, autoimmune diseases, allergies, cardiovascular diseases, cardiopulmonary diseases, neurodegenerative diseases, skeletal muscle diseases and cancer.

17. Use according to claim 16, wherein the cardiovascular disease is a vascular disease.

18. The use according to claim 17, wherein the vascular disease is thrombosis.

19. The use according to claim 16, wherein the disease associated with SOCE dysregulation or dysfunction is selected from the group consisting of inflammatory bowel disease, pancreatitis, rheumatoid arthritis, multiple sclerosis, asthma, psoriasis and cancer.

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