Biphenyl compounds as SOCE modulators, compositions and uses thereof

Abstract

Compounds of formula (I) capable of modulating store-operated calcium entry (SOCE) The present disclosure also relates to compositions and uses of compounds of formula (I) for treating disease conditions that depend on increased / decreased SOCE activity.

Description

Technical Field

[0001] The present disclosure relates to novel biphenyl 1,4-disubstituted 1,2,3-triazole compounds capable of regulating calcium influx operated by the endoplasmic reticulum (also known as store-operated calcium entry (SOCE)), and compositions and uses thereof. Background Art

[0002] Calcium (Ca 2+ ) is a ubiquitous messenger that acts as a universal signaling molecule to encode information between and within cells, regulating a wide range of cellular functions, from short-term responses (such as contraction and secretion) to long-term transcriptional control, cell division, and cell death (Jeremy T. Smyth et al.; 2010. J. Cell. Mol. Med. Vol 14, No 10, pp. 2337-2349; Lewis Richard S. 2011 Cold Spring Harb Perspect Biol; 3: a003970). The huge gradient across the plasma membrane and the extremely low concentration of Ca in the cytosol 2+ (Ca 2+ The content in organelles and extracellular medium is 10 5 times) then becomes an excellent opportunity to use this ion as a specific second messenger. 2+ The signal encodes information through its precise spatial location, amplitude, duration, and frequency of rise in the cell. High concentrations of calcium ions are present in intracellular organelles (particularly in the endoplasmic reticulum (ER) and / or sarcoplasmic reticulum (SR)), and the Ca2+ molecules located on these membranes 2+ Opening of channels (e.g., RyR, IP3R) allows this ion to flow out of the deposits and initiate cellular signaling. 2+ Ca 2+ The pump is present on the SR / ER membrane, but given the activity of the plasma membrane efflux machinery, this organelle is expected to be rapidly depleted of Ca 2+ This is not the case because in cells there is a crosstalk between the ER and the plasma membrane, mediated by the so-called store-operated Ca 2+ The term SOCE refers to the ability of cells to sense a decrease in calcium concentration in the ER and induce the entry of this ion across the plasma membrane into the cell (Putney JW. 2011. Frontiers in Bioscience (Academic Edition) 3: 980-984).

[0003] SOCE and electrophysiological current I CRACThe exact molecular mechanism behind this phenomenon was elucidated between 2005 and 2006, when the main component of the SOCE mechanism, Ca 2+ -release activated -Ca 2+ (CRAC) channels were discovered. CRAC channels are assembled from two basic protein complexes: Orai proteins that form ion channel pores on the plasma membrane and stroma interaction molecules (STIM) proteins that act as calcium sensors on the ER. (Berna-Erro A et al., Redondo PC, Rosado JA. 2012 Medicine and Biology 740: 349-382; Soboloff J, Rothberg BS, Madesh M, Gill DL. 2012 Nature Reviews. Molecular Cell Biology 13: 549-565; Lacruz RS, Feske S. 2015. Annals of the New York Academy of Sciences 1356: 45-79). In addition to STIM and Orai, it should be emphasized that other key proteins are involved in the SOCE mechanism, including transient receptor potential channels (TRPCs) (Ong HL, Ambudkar IS. 2015. Cell Calcium 58: 376-386).

[0004] STIM proteins are single transmembrane proteins that are highly conserved across species. Two members of this family have been described, STIM1 and STIM2, of which the former appears to be more expressed (Roos et al., 2005; J Cell Biol.; 169(3):435-45). Limited RNAi screening of Drosophila S2 cells was used to identify Drosophila STIM as having a fundamental role in SOCE activation, and similar conclusions were drawn almost simultaneously for human STIM1 and STIM2 in HeLa cell screening (Jeremy T. Smyth et al.; 2010. J. Cell. Mol. Med. Vol 14, No 10, pp.2337-2349, Lewis Richard S. 2011 Cold Spring Harb Perspect Biol; 3: a003970). STIM1 was identified as the Ca2+ of SOCE. 2+ sensor because it is specialized to respond to ER Ca 2+ STIM1 localization is crucial for SOCE: when Ca 2+When the store is full, STIM1 is localized in tubular structures throughout the ER membrane, but when the store is depleted, it moves to punctate structures at the site of contact between the ER and the plasma membrane. This relocation of STIM1 within the ER to the plasma membrane allows for direct or indirect interaction and activation of Orai channels. Orai channels are located on the plasma membrane, and three members of this family have been described (Orai1, Orai2, and Orai3), of which Orai1 is the most abundant and associates with I CRAC Closely related (Jeremy T. Smyth et al.; 2010. J. Cell. Mol. Med. Vol 14, No 10, pp. 2337-2349; Lewis Richard S. 2011 Cold Spring Harb Perspect Biol, 3: a003970; Feske S. et al., 2005 J Exp Med 202(5): 651-62; Nature 11; 441(7090): 179-85).

[0005] Examples of key experiments to illustrate SOCE include Figure 1 Briefly, emptying of ER / SR stores leads to the opening of channels located in the plasma membrane, Ca 2+ Both phenomena can be induced by adding Ca to the extracellular solution after depletion of intracellular stores. 2+ This simple yet powerful in vitro assay remains effective in revealing the phenomena under screening.

[0006] The CRAC current was originally identified in lymphocytes and mast cells and has been characterized in different cell lines, such as DT40 B cells, hepatocytes, dendritic cells, megakaryocytes, and Madin-Darby canine kidney cells. In lymphocytes and mast cells, activation of the T cell receptor or Fc receptor initiates the release of Ca from intracellular stores by the second messenger inositol (1,4,5)-triphosphate (IP3). 2+ ions, leading to Ca 2+ Ions flow in through CRAC channels in the plasma membrane.

[0007] CRAC channels also mediate key functions from secretion to gene expression and cell growth and form processes necessary for activation of adaptive immune responses. It has been shown that Ca2+ triggered by stimulation of the T cell antigen receptor (TCR) 2+ The oscillations only involve the influx pathway of reservoir-operated CRAC channels. Therefore, the Ca influx mediated by reservoir-operated CRAC channels 2+Ion influx is the basis of lymphocyte activation. (Anant B. Parekh and James W. Putney Jr. 2005, Physiol Rev 85:757–810.; Hogan Gp et al. 2010, Annu. Rev. Immunol. 28:491–533; Patrick G Hogan and Anjana Rao 2015, Biochem Biophys Res Commun 24, 460(1):40–49.; Feske S, Okamura H, Hogan PG, Rao A. 2003, Biochem Biophys Res Commun, 311(4):1117-32.) In contrast, the reservoir-operated Ca 2+ cells identified in endothelial cells, smooth muscle cells, epidermal cells, and prostate cancer cell lines 2+ The currents showed altered biophysical characteristics, suggesting different molecular origins. These lines of evidence suggest that intracellular Ca 2+ It plays an important role in various cellular functions and its concentration is determined by Ca2+ on the plasma membrane and ER. 2+ Ca influx through the channel 2+ .

[0008] In skeletal muscle from patients with Duchenne muscular dystrophy (DMD) and mdx mice (a popular model for studying DMD that has a point mutation in the DMD gene), loss of the cytoskeletal protein dystrophin has been shown to be essential for maintaining normal calcium influx. In particular, loss of dystrophin has been reported to increase STIM1, ORAI1, and TRPC1 reservoir-dependent influx, suggesting that SOCE is involved in this lethal pathology (Onopiuk M. 2015 Arch Biochem Biophys, 569: 1-9; Sabourin J. 2012 Cell Calcium, 6: 445-456).

[0009] Furthermore, the critical role played by CRAC channels in human health has been highlighted by a growing number of genetic studies that have led to the identification of patients with loss- or gain-of-function STIM1 / Orai1 mutations who are affected by serious health problems such as muscle deficiency, immune deficiency, autoimmunity, and bleeding disorders (Feske S. 2010 European Journal of Physiology, 460:417-435).

[0010] Regarding loss-of-function mutations, at least three unrelated families have been described that do not express Orai1 on the plasma membrane of T lymphocytes and lack the reservoir-operated Ca2+ gene due to different mutations, including frameshift mutations.2+ Influx of STIM1 into the body is inhibited, and thus T lymphocytes cannot be activated (Feske S et al., 1996 European Journal of Immunology 26:2119-2126.; McCarl CA et al., 2009. J Allergy Clin Immunol. 124(6):1311-1318.e7.). It is worth noting that a family of STIM1 mutations that result in the non-expression of this protein has been reported, which is characterized by T cell immunodeficiency (Picard C et al., 2009, N Engl J Med. 7, 360(19):1971-80.; Byun M et al., 2010, The Journal of Experimental Medicine, 207:2307-2312; Fuchs S et al., 2012 Journal of Immunology (Baltimore, Md.: 1950) 188:1523-1533). Finally, while immunodeficiency is a hallmark of the disease, these patients also exhibit lymphoproliferative disorders, autoimmunity, congenital myopathies, anhidrosis, enamel defects, and thrombotic disorders due to defective platelet activation. While some mutations result in reduced activity that may be pharmacologically potentiated, most mutations result in significantly reduced protein expression, making pharmacological approaches potentially applicable to these conditions. Currently, the following loss-of-function mutations in STIM1 and Orai1 have been reported in the literature: p.P165Q, p.R429C, p.R426C, and p.E128RfsX9 for STIM1, and p.R91W, p.A103E, p.L194P, p.A88SfsX25, and p.H165PfsX1 for Orai1.

[0011] Gain-of-function mutations in STIM1 or Orai1 primarily affect skeletal muscle and platelets, but it appears to be a multi-organ disease (Lacruz RS, Feske S. 2015. Annals of the New York Academy of Sciences 1356: 45-79). The prevalence of these diseases is unknown, but their overall prevalence may be approximately 1 in 250,000. Given the rarity of this disease, compared to other myopathies, it has not been systematically addressed clinically and there is currently no disease registry. Both STIM1 and Orai1 mutations are associated with three separate but overlapping conditions: tubular aggregation myopathy, Stormorken syndrome, and York platelet syndrome. Tubular aggregation myopathy is characterized by a variable combination of myalgia, cramps, and muscle stiffness, with or without weakness, predominantly in the proximal distribution, and the presence of tubular aggregates, which are regularly arranged tubules derived from the sarcoplasmic reticulum ( J et al., 2013. American Journal of Human Genetics 92:271-278; Nesin V et al., 2014. Proceedings of the National Academy of Sciences of the United States of America 111:4197-4202; Endo Y et al., 2015. Human Molecular Genetics 24:637-648.). Stormorken syndrome is characterized by myopathic signs, but may also include mild bleeding tendencies due to platelet dysfunction, thrombocytopenia, anemia, asplenia, congenital miosis, ichthyosis, headaches, and recurrent stroke-like episodes (Stormorken H et al., 1995. Thromb Haemost 74:1244-1251). Finally, York platelet syndrome considers blood dyscrasias as the main phenotype. The gain-of-function mutations of STIM1 and Orai1 reported in the literature are as follows: p.N80T, p.H72Q, p.G81D, p.D84G, p.D84E, p.L96V, p.F108L, p.F108I, p.H109R, p.H109N, p.I115F, p.R304W, p.R304G for STIM1; p.S97C, p.G98S, p.V107M, p.L138F, p.T184M, p.P245L for Orai1. In short, the mutations of STIM1 mainly exist in the EF hand Ca 2+ The binding motif is most likely to change the protein's Ca 2 + ion affinity, with the exception of mutations in the helical domain on the cytoplasmic side of the protein, which may affect the dimerization / oligomerization of STIM1, the putative trigger for Orai1 channel opening. The mutations in Orai1 are located in the transmembrane domain, a position that may lead to its hypothesized involvement in channel lining.

[0012] All these data suggest that SOCE modulators could be used to treat diseases caused by aberrant SOCE.A key limitation in the study of SOCE and its physiological and pathophysiological roles is the lack of potent and selective modulators.

[0013] Synta66 (GSK1349571A; 3-fluoropyridine-4-carboxylic acid (2',5'-dimethoxybiphenyl-4-yl)amide) is a compound developed by Synta Pharmaceuticals and GSK. CRAC IC50 About 1 μM (Di Sabatino A. 2009. Journal of Immunology (Baltimore, Md.: 1950) 183: 3454-3462; Ng, SW Journal of Biological Chemistry, 2008, 283, 31348-31355; WO2005009954; WO2005009539). In addition, it is reported to reduce the production of T cell cytokines, in particular, it inhibits the production of IFN-γ, IL-2 and IL-17, but not IL-8 (Di Sabatino A. 2009. Journal of Immunology (Baltimore, Md.: 1950) 183: 3454-3462). Interestingly, in vascular smooth muscle cells, the potency is two orders of magnitude higher (IC 50 About 30 nM) (Li, J. BJP, 2011, 164, 382-393).

[0014] The detailed mechanism of action of this compound is unclear, although siRNA knockdown of Orai1 in mast cells suggests that it may be selective for Orai1 (Ng, SW Journal of Biological Chemistry, 2008, 283, 31348-31355). Furthermore, experiments in vascular smooth muscle cells showed that it did not interfere with STIM1 aggregation, raising the possibility that the drug does not target STIM1 mechanisms (Li, J. BJP, 2011, 164, 382-393).

[0015] Synta66 reportedly does not affect metabotropic glutamate, muscarinic acetylcholine and GABA B receptors, GABA A, AMPA and NMDA receptors, ligand-gated ion channels such as tetrodotoxin-sensitive Na + channels, and N- and P / Q-type voltage-gated Ca 2+ channels (Di Sabatino A. 2009. Journal of Immunology (Baltimore, Md.: 1950)). However, it does not inhibit endogenous TRPC1 / 5 or overexpressed TRPC5 channels (Li, J. BJP, 2011, 164, 382-393).

[0016] Synta66 is increasingly being used to investigate the physiological roles of CRAC channels in vitro and in animal models; however, its specificity for different Orai isoforms is not optimal.

[0017] WO 2017 / 212414 discloses 5-(trifluoromethyl)-1H-pyrazoles as SOCE modulators, which have a benzene ring in the 1-position with a triazole in the para-position.

[0018] Young Ae Cho et al., Organic Letters (2009) 11(19): 4330-4333, disclosed the synthesis of 4'-(4-phenyl-1H-1,2,3-triazol-1-yl)-[1,1'-biphenyl]-4-carbonitrile.

[0019] K. Bolla et al., Tetrahedron (2011) 67(31): 5556-5563 discloses the synthesis of 4'-(4-phenyl-1H-1,2,3-triazol-1-yl)-[1,1'-biphenyl]-4-carbonitrile, 1-(4'-methoxy-[1,1'-biphenyl]-4-yl)-4-phenyl-1H-1,2,3-triazole and 2-(4-(4-phenyl-1H-1,2,3-triazol-1-yl)phenyl)pyridine.

[0020] M. Gilandoust et al., Bioorganics & Medicinal Chemistry Letters (2018) 28(13): 2314-2319 discloses 1-(2'-ethoxy-4'-fluoro-[1,1'-biphenyl]-4-yl)-4-phenyl-1H-1,2,3-triazole, 2-fluoro-5-(4-(4-phenyl-1H-1,2,3-triazol-1-yl)phenyl)pyridine, 1-(3'-(methylsulfonyl)-[1,1'-biphenyl]-4-yl)-4-phenyl-1H-1,2,3-triazole, 5-(4-(4-phenyl-1H-1,2,3-triazol-1-yl)phenyl)pyridine as cytotoxic agents against human breast cancer cells. -1,2,3-triazole, 1-(5'-chloro-2'-fluoro-[1,1'-biphenyl]-4-yl)-4-phenyl-1H-1,2,3-triazole, 1-(5'-fluoro-2'-methoxy-[1,1'-biphenyl]-4-yl)-4-phenyl-1H-1,2,3-triazole and 1-([1,1'-biphenyl]-4-yl)-4-phenyl-1H-1,2,3-triazole.

[0021] A. Baschieri et al., Organometallics (2014) 33(21): 6154-6164 discloses the synthesis of 4'-(4-(pyridin-2-yl)-1H-1,2,3-triazol-1-yl)-[1,1'-biphenyl]-4-amine and 4'-(4-(pyridin-2-yl)-1H-1,2,3-triazol-1-yl)-[1,1'-biphenyl]-4-ol as intermediates for the production of luminescent compounds.

[0022] US 2014 / 005231 discloses N-(4'-(4-phenyl-1H-1,2,3-triazol-1-yl)-[1,1'-biphenyl]-2-yl)-2-(trifluoromethyl)benzamide and N-(5-fluoro-4'-(4-phenyl-1H-1,2,3-triazol-1-yl)-[1,1'-biphenyl]-2-yl)-2-(trifluoromethyl)benzamide as fungicides and nematicides for controlling plant diseases.

[0023] EP 2578581 discloses the synthesis of 4-[4-(4-biphenyl-1H-1,2,3-triazol-1-yl]pyridine-2,6-dicarboxylic acid as an intermediate for the production of luminescent compounds.

[0024] It is noteworthy that, except for the compounds disclosed in WO 2017 / 212414, the biphenyl 1,4-disubstituted 1,2,3-triazole compounds disclosed in the above-mentioned prior art documents are not indicated as SOCE modulators.

[0025] There is an unmet need for small molecule modulators with high potency and specificity for STIM1 and / or Orai1 to regulate the activity of CRAC channels, particularly for the treatment of diseases and disorders associated with SOCE. Summary of the Invention

[0026] The object of the present disclosure is to provide new compounds capable of modulating SOCE.

[0027] According to the invention, the above objects are achieved thanks to the subject matter particularly mentioned in the appended claims, which are to be understood as forming an integral part of the present disclosure.

[0028] The present invention provides a class of compounds as novel SOCE modulators and their use in therapy. More specifically, the present invention provides a class of biphenyl 1,4-disubstituted 1,2,3-triazole compounds.

[0029] The present disclosure discloses compounds of formula (I):

[0030]

[0031] in

[0032] Ring Hy is selected from

[0033] Ring Hz is selected from an aryl or heteroaryl group;

[0034] A1, A2, A3, A4 and A5 are the same as or different from each other and are independently selected from H, CF3, Br, I, Cl, F, OH, OR1, SR1, NH2, NHR1, NR1R2, S(O)R1, S(O)2R1, NHCOR1, NHSO2R1, CONHR1, CONR1R2, SO2NHR1, COOH, COOR1, NO2, CN, a 5-6 membered O-heterocyclic group;

[0035] A1 and A2, or A2 and A3, or A3 and A4, or A4 and A5 may together form a 5-6 membered O-heterocyclic group fused to the benzene ring to which it is attached;

[0036] B1, B2, B3, B4 and B5 are the same or different and are independently selected from H, CH2COOH, COOH, COOR3, CN, CF3, Br, I, Cl, F, 1H-tetrazol-5-yl;

[0037] R1 and R2 are the same as or different from each other and are independently selected from unsubstituted or substituted C 1-8 Alkyl groups, unsubstituted or substituted C 2-8 Alkenyl groups, unsubstituted or substituted C 2-8 Alkynyl groups, unsubstituted or substituted C 3-6 Cycloalkyl, unsubstituted or substituted aryl, unsubstituted or substituted heterocyclic group, (CH2) n -C 1-8 Alkyl, (CH2) n -C 2-8 Alkenyl, (CH2) n -C 2-8 Alkynyl group, (CH2) n -cycloalkyl, (CH2) n -aryl and (CH2) n -heteroaryl, wherein n is an integer from 1 to 4;

[0038] R3 is selected from unsubstituted or substituted C 1-8 Alkyl groups, unsubstituted or substituted C 2-8 Alkenyl groups, unsubstituted or substituted C 2-8 Alkynyl groups, unsubstituted or substituted C 3-6 Cycloalkyl, unsubstituted or substituted aryl, unsubstituted or substituted heterocyclic group, (CH2) m -C 1-8 Alkyl, (CH2)m -C 2-8 Alkenyl, (CH2) m -C 2-8 Alkynyl group, (CH2) m -cycloalkyl, (CH2) m -aryl and (CH2) m -heteroaryl, wherein m is an integer from 1 to 4;

[0039] Pharmaceutically acceptable hydrates and / or solvates and / or salts thereof.

[0040] The present disclosure discloses biphenyl 1,4-disubstituted 1,2,3-triazole compounds of formula (I) for use as pharmaceuticals, preferably having specific activity against SOCE.

[0041] The present disclosure also discloses compounds of formula (I) for use in the in vivo treatment of pathological conditions associated with loss or gain of function STIM1 / Orai1 mutations, muscular dystrophy, inflammatory diseases, wherein SOCE modulation is beneficial.

[0042] The present disclosure also provides a pharmaceutical composition comprising at least one compound of formula (I) and a pharmaceutically acceptable carrier. The pharmaceutical composition may further comprise one or more other therapeutic agents. BRIEF DESCRIPTION OF THE DRAWINGS

[0043] The invention will now be described in detail purely by way of illustrative and non-limiting examples with reference to the accompanying drawings, in which:

[0044] - Figure 1 :Representative description of store-operated calcium entry (SOCE)

[0045] When cells are exposed to Ca-free 2+ solution before and during the experiment. In the absence of Ca 2+ In the case of intracellular Ca 2 + Stores were depleted with the SERCA poison 2,5-tert-butylhydroquinone (tBHQ, 50 μM; Sigma-Aldrich, Italy), and 2 mM calcium was then added back to the extracellular fluid.

[0046] - Figure 2 : Calcium responses to SOCE modulators

[0047] (A) HEK cells were seeded in 6-well plates coated with poly-d-lysine and incubated overnight. After 24 h, the cells were loaded with 5 μM Fura-2 AM and placed in a 5% flask containing 0 mM Ca. 2+ The stock was depleted using 50 μM tBHQ and the extracellular fluid was depleted by adding only 2 mM Ca 2+Calcium influx was stimulated by RT-PCR (Ctrl) or in combination with the following: an inactive compound (4-(1-(2',5'-dimethoxy-[1,1'-biphenyl]-4-yl)-1H-1,2,3-triazol-4-yl)-3-fluoropyridine) and the compounds that negatively regulate SOCE, 3-(1-(3'-methoxy-[1,1'-biphenyl]-4-yl)-1H-1,2,3-triazol-4-yl)benzoic acid, 3-(1-(4-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)phenyl)-1H-1,2,3-triazol-4-yl)benzoic acid, and 3-(1-(2',3'-dimethoxy-[1,1'-biphenyl]-4-yl)-1H-1,2,3-triazol-4-yl)benzoic acid. Calcium responses are expressed as changes in fluorescence intensity before and after addition of selected modulators.

[0048] (B) Calcium responses of HEK cells to varying concentrations of 3-(1-(2',3'-dimethoxy-[1,1'-biphenyl]-4-yl)-1H-1,2,3-triazol-4-yl)benzoic acid and 3-(1-(4-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)phenyl)-1H-1,2,3-triazol-4-yl)benzoic acid (0.1-0.3-1-3-10-30-100 μM) were measured using Fura-2 AM assay. Concentration-response curves represent the AUC% of the two compounds compared to the positive control.

[0049] - Figure 3 :SOCE in KI-STIM1 I115F Enhanced myotube

[0050] tBHQ in wild type (WT) or KI-STIM1 I115F SOCE was induced in mouse myotubes. Traces are the average of at least 180 myotubes from 6 plates on two different experimental days. At all time points, myotubes from 4 animals (2 males, 2 females) were used per condition.

[0051] - Figure 4 : In KI-STIM1 I115F Evaluation of the effects of 3-(1-(3'-methoxy-[1,1'-biphenyl]-4-yl)-1H-1,2,3-triazol-4-yl)benzoic acid in mouse myotubes

[0052] 3-(1-(3'-methoxy-[1,1'-biphenyl]-4-yl)-1H-1,2,3-triazol-4-yl)benzoic acid (10 μM) impairs KI-STIM1 I115FSOCE in mouse myotubes. Specifically, the compound is able to restore overactivation of the STIM1 mutant protein. Traces are the average of at least 180 myotubes from six plates on two different experimental days.

[0053] - Figure 5 : SOCE is enhanced in myotubes of mdx mice

[0054] tBHQ induces SOCE in myotubes from wild-type (WT) or mdx mice. Traces are the average of at least 180 myotubes from 6 plates on two different experimental days. Myotubes from 4 animals (2 males, 2 females) were used per condition at all time points.

[0055] - Figure 6 :Evaluation of the effects of 3-(1-(4-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)phenyl)-1H-1,2,3-triazol-4-yl)benzoic acid in myotubes of mdx mice

[0056] 3-(1-(3'-Methoxy-[1,1'-biphenyl]-4-yl)-1H-1,2,3-triazol-4-yl)benzoic acid (10 μM) impairs SOCE in mdx mouse myotubes. Specifically, the compound is able to restore the overactivation of the DMD mutant protein. Traces are the average of at least 180 myotubes from six plates on two different experimental days.

[0057] - Figure 7 :Targeting vector F118.3 TV

[0058] The exchanged bases (indicated by asterisks) in exon 3 of Stim1 (indicated by arrows) were inserted together with the neomycin resistance expression cassette flanked by FRT. The long arm of homology is 5.3 kb in length, while the short arm of homology is 2.8 kb in length (LA and SA; indicated by boxes). The restriction endonucleases used for confirmation are indicated. The targeting vector can be linearized with NotI before electroporation. DETAILED DESCRIPTION

[0059] In the following description, numerous specific details are given to provide a thorough understanding of the embodiments. The embodiments may be practiced without one or more of the specific details, or with other methods, components, materials, etc. In other cases, well-known structures, materials, or operations are not shown or described in detail to avoid obscuring aspects of the embodiments.

[0060] References throughout this specification to "one embodiment" or "an embodiment" mean that a particular feature, structure, or characteristic described in connection with that embodiment is included in at least one embodiment. Thus, appearances of the phrases "in one embodiment" or "in an embodiment" in various places throughout this specification are not necessarily all referring to the same embodiment. Furthermore, the particular features, structures, or characteristics may be combined in any suitable manner in one or more embodiments.

[0061] The headings provided herein are for convenience only and do not interpret the scope or meaning of the embodiments.

[0062] As used herein, the term "alkyl" refers to a monovalent straight or branched chain group derived from an unsaturated hydrocarbon of 1 to 8 carbons. The alkyl groups of the present invention may be optionally substituted.

[0063] As used herein, the term "alkenyl" refers to a monovalent straight or branched chain group derived from a hydrocarbon of 2 to 8 carbons having at least one carbon-carbon double bond. The alkenyl groups of the present invention may be optionally substituted.

[0064] As used herein, the term "alkynyl" refers to a monovalent straight or branched chain group derived from a hydrocarbon of 2 to 8 carbons having at least one carbon-carbon triple bond. The alkynyl groups of the present invention may be optionally substituted.

[0065] As used herein, the term "aryl" refers to a monocyclic or bicyclic carbocyclic ring system having at least one optionally substituted aromatic ring. The aryl group may be fused to a cyclohexane, cyclohexene, cyclopentane, or cyclopentene ring, in which case the aryl group may be attached via the ring to which it is attached or via the aromatic ring itself. The aryl groups of the present invention may be optionally substituted.

[0066] As used herein, the term "heteroaryl" refers to an aryl group as defined above containing one, two, three or four heteroatoms independently selected from nitrogen, oxygen and sulfur. Preferably, the heteroaryl group is represented by benzimidazolyl, benzofuranyl, benzothiazolyl, benzothienyl, benzoxazolyl, furyl, imidazolinyl, imidazolyl, indolyl, isoquinolyl, isothiazolidinyl, isothiazolyl, isoxazolyl, oxadiazolyl, oxazolidinyl, oxazolyl, pyrazolidinyl, pyrazinyl, pyrazolyl, pyrazolinyl, pyridazinyl, pyridyl, pyrimidinyl, pyrimidyl, pyrrolyl, quinolyl, quinoxalinyl, tetrahydrofuranyl, tetrahydroisoquinolyl, tetrahydroquinolyl, tetrazolyl, thiadiazolyl, thiazolidinyl, thiazolyl, thienyl, triazolyl, etc. More preferably, the heteroaryl group represents a nitrogen-containing heterocycle, such as pyridyl, triazolyl, and the like.

[0067] As used herein, the term "cycloalkyl" refers to a monovalent saturated cyclic or bicyclic hydrocarbon of 3 to 6 carbon atoms. The cycloalkyl groups of the present invention may be optionally substituted.

[0068] As used herein, the term "halogen" refers to F, Cl, Br, or I.

[0069] As used herein, the term "heterocycle" refers to a 4-, 5-, 6- or 7-membered ring comprising one, two or three heteroatoms independently selected from nitrogen, oxygen and sulfur. The 4- and 5-membered rings have 0, 1 or 2 double bonds, and the 6- and 7-membered rings have 0, 1, 2 or 3 double bonds. The nitrogen and sulfur atoms may optionally be oxidized, and the nitrogen atom may optionally be quaternized. The term "heterocycle" also includes bicyclic, tricyclic and tetracyclic groups in which the heterocycle is fused to one or two rings selected from an aromatic ring, a cyclohexane ring, a cyclohexene ring, a cyclopentane ring, a cyclopentene ring or other monocyclic rings. This type of heterocycle can be connected by its fused ring or by the heterocycle itself. Heterocycles include, but are not limited to, acridinyl, benzimidazolyl, benzofuranyl, benzothiazolyl, benzothiophenyl, benzoxazolyl, biotinyl, cinnamyl, dihydrofuranyl, dihydroindolinyl, dihydropyranyl, dihydrothiophenyl, dithiazolyl, dioxanyl, dioxolyl, furanyl, homopiperidinyl, imidazolidinyl, imidazolinyl, imidazolyl, indolyl, isoquinolinyl, isothiazolidinyl, isothiazolyl, isoxazolyl, morpholinyl, oxadiazolyl, oxazole Alkyl, oxazolyl, piperazinyl, piperidinyl, pyranyl, pyrazolidinyl, pyrazinyl, pyrazolyl, pyrazolinyl, pyridazinyl, pyridyl, pyrimidinyl (pyrimidinyl), pyrimidinyl (pyrimidyl), pyrrolidinyl, pyrrolinyl, pyrrolyl, quinolyl, quinoxalinyl, tetrahydrofuranyl, tetrahydroisoquinolyl, tetrahydroquinolyl, tetrazolyl, thiadiazolyl, thiazolidinyl, thiazolyl, thienyl, thiomorpholinyl, triazolyl etc.Heterocyclic group of the present invention can be optionally substituted.Preferably, heterocyclic group is selected from nitrogen-containing heterocycle, such as pyridyl, triazolyl, and oxygen-containing heterocycle, such as dioxanyl (dioxanyl), dioxolane (dioxolanyl).

[0070] As used herein, the term "pharmaceutically acceptable salts" refers to those salts which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of humans and lower animals without excessive toxicity, irritation, allergic response, etc., and are commensurate with a reasonable benefit / risk ratio.

[0071] As used herein, the term "pharmaceutically acceptable hydrate and / or solvate" refers to a crystalline form of a substance that contains one or more water and / or solvent molecules.

[0072] In one embodiment, the present disclosure provides a compound of formula (I):

[0073]

[0074] in

[0075] Ring Hy is selected from

[0076] Ring Hz is selected from an aryl or heteroaryl group;

[0077] A1, A2, A3, A4 and A5 are the same as or different from each other and are independently selected from H, CF3, Br, I, Cl, F, OH, OR1, SR1, NH2, NHR1, NR1R2, S(O)R1, S(O)2R1, NHCOR1, NHSO2R1, CONHR1, CONR1R2, SO2NHR1, COOH, COOR1, NO2, CN, a 5-6 membered O-heterocyclic group;

[0078] A1 and A2, or A2 and A3, or A3 and A4, or A4 and A5 may together form a 5-6 membered O-heterocyclic group fused to the benzene ring to which it is attached;

[0079] B1, B2, B3, B4 and B5 are the same or different and are independently selected from H, CH2COOH, COOH, COOR3, CN, CF3, Br, I, Cl, F, 1H-tetrazol-5-yl;

[0080] R1 and R2 are the same as or different from each other and are independently selected from unsubstituted or substituted C 1-8 Alkyl groups, unsubstituted or substituted C 2-8 Alkenyl groups, unsubstituted or substituted C 2-8 Alkynyl groups, unsubstituted or substituted C 3-6 Cycloalkyl, unsubstituted or substituted aryl, unsubstituted or substituted heterocyclic group, (CH2) n -C 1-8 Alkyl, (CH2) n -C 2-8 Alkenyl, (CH2) n -C 2-8 Alkynyl group, (CH2) n -cycloalkyl, (CH2) n -aryl and (CH2) n -heteroaryl, wherein n is an integer from 1 to 4;

[0081] R3 is selected from unsubstituted or substituted C 1-8 Alkyl groups, unsubstituted or substituted C 2-8 Alkenyl groups, unsubstituted or substituted C 2-8 Alkynyl groups, unsubstituted or substituted C 3-6 Cycloalkyl, unsubstituted or substituted aryl, unsubstituted or substituted heterocyclic group, (CH2) m -C 1-8 Alkyl, (CH2) m -C 2-8Alkenyl, (CH2) m -C 2-8 Alkynyl group, (CH2) m -cycloalkyl, (CH2) m -aryl and (CH2) m -heteroaryl, wherein m is an integer from 1 to 4;

[0082] and pharmaceutically acceptable hydrates and / or solvates and / or salts thereof, except for the following: 4'-(4-phenyl-1H-1,2,3-triazol-1-yl)-[1,1'-biphenyl]-4-carbonitrile; 1-(4'-methoxy-[1,1'-biphenyl]-4-yl)-4-phenyl-1H-1,2,3-triazole; 2-(4-(4-phenyl-1H-1,2,3-triazol-1-yl)phenyl)pyridine; 1-(2'-ethoxy-4'-fluoro-[1,1'-biphenyl]-4-yl)-4-phenyl-1 H-1,2,3-triazole; 2-fluoro-5-(4-(4-phenyl-1H-1,2,3-triazol-1-yl)phenyl)pyridine; 1-(3'-(methylsulfonyl)-[1,1'-biphenyl]-4-yl)-4-phenyl-1H-1,2,3-triazole; 5-(4-(4-phenyl-1H-1,2,3-triazol-1-yl)phenyl)nicotinamide; 1-(2'-chloro-[1,1'-biphenyl]-4-yl)-4-phenyl-1H-1,2,3-triazole; 1-(5'-chloro-2'-fluoro-[1 ,1'-biphenyl]-4-yl)-4-phenyl-1H-1,2,3-triazole; 1-(5'-fluoro-2'-methoxy-[1,1'-biphenyl]-4-yl)-4-phenyl-1H-1,2,3-triazole; 1-([1,1'-biphenyl]-4-yl)-4-phenyl-1H-1,2,3-triazole; 4'-(4-(pyridin-2-yl)-1H-1,2,3-triazol-1-yl)-[1,1'-biphenyl]-4-amine; 4'-(4-(pyridin-2-yl)-1H-1,2, 3-Triazol-1-yl)-[1,1'-biphenyl]-4-ol; N-(4'-(4-phenyl-1H-1,2,3-triazol-1-yl)-[1,1'-biphenyl]-2-yl)-2-(trifluoromethyl)benzamide; N-(5-fluoro-4'-(4-phenyl-1H-1,2,3-triazol-1-yl)-[1,1'-biphenyl]-2-yl)-2-(trifluoromethyl)benzamide; 4-[4-(4-biphenyl-1H-1,2,3-triazol-1-yl)pyridine-2,6-dicarboxylic acid.

[0083] In one or more embodiments, when R1, R2 and R, if present, are independently selected from substituted C 1-8 Alkyl groups, substituted C 2-8 Alkenyl groups, substituted C 2-8Alkynyl groups, substituted C 3-6 When the alkyl group is a cycloalkyl group, a substituted aryl group, or a substituted heterocyclic group, one or more substituents are independently selected from halogen, CH3, CH2F, CHF2, CF3, OR2, CN, COOR4, CONR4R5, NR4R5, NHCOR4, NHSO2R4, S(O)R4, S(O)2R4 and SO2NHR4,

[0084] wherein R4 and R5 are the same or different and are independently selected from H, an unsubstituted or substituted C1-C8 alkyl group having one or more halogen atoms, and an unsubstituted or substituted C3-C6 cycloalkyl group having one or more halogen atoms.

[0085] In one or more preferred embodiments, R1, R2 and R3 are selected from unsubstituted methyl, ethyl, tert-butyl, isopropyl, phenyl and benzyl.

[0086] In one or more preferred embodiments, ring Hz is selected from

[0087] In one or more preferred embodiments, the A1 substituent is selected from H, F, OMe, and a 5-6 membered O-heterocyclic group.

[0088] In one or more preferred embodiments, the A2 substituent is selected from H, OMe, SMe, OH, and a 5-6 membered O-heterocyclic group.

[0089] In one or more preferred embodiments, the A3 substituent is selected from H, OMe, and a 5-6 membered O-heterocyclic group.

[0090] In one or more preferred embodiments, the A4 substituent is selected from H, OMe, and a 5-6 membered O-heterocyclic group.

[0091] In one or more preferred embodiments, the A5 substituent is selected from H, OMe, and a 5-6 membered O-heterocyclic group.

[0092] In one or more preferred embodiments, the two adjacent groups at positions A1, A2, A3, A4 or A5 together form a 5-6 membered O-heterocyclic group fused to the benzene ring to which they are connected, and the heterocyclic group fused to the benzene ring is selected from dihydrobenzodioxinyl or benzodioxolyl.

[0093] In one or more preferred embodiments, the B1 substituent is selected from H and F.

[0094] In one or more preferred embodiments, the B2 substituent is selected from H, CH2COOH, COOH, COOMe, CN and 1H-tetrazol-5-yl.

[0095] In one or more preferred embodiments, B3 is H.

[0096] In one or more preferred embodiments, the B4 substituent is selected from H, CH2COOH, COOH, COOMe, CN and 1H-tetrazol-5-yl.

[0097] In one or more preferred embodiments, the B5 substituent is selected from H and F.

[0098] Compared to the compounds described in this invention, Synta66 exhibited considerable cytotoxicity at 10 μM, with residual cell viability of 76% after 24 hours. Under the same conditions, the biphenyl 1,4-disubstituted 1,2,3-triazole SOCE modulators were non-cytotoxic, with cell viability exceeding 90% after 24 hours. Furthermore, the biphenyl modulators maintained comparable potency to Synta66 in inhibiting SOCE activity, with IC values ​​of 0.001 in both cases. 50 The values ​​are all in the nanomolar range.

[0099] In one embodiment, the present description relates to compounds of formula (I) and pharmaceutical compositions comprising the same for use as medicaments.

[0100]

[0101] wherein the residues A1, A2, A3, A4, A5, B1, B2, B3, B4, B5, Hy and Hz have the meanings indicated above, with the exception of the following: 1-(2'-ethoxy-4'-fluoro-[1,1'-biphenyl]-4-yl)-4-phenyl-1H-1,2,3-triazole; 2-fluoro-5-(4-(4-phenyl-1H-1,2,3-triazol-1-yl)phenyl)pyridine; 1-(3'-(methylsulfonyl)-[1,1'-biphenyl]-4-yl)-4-phenyl-1H-1,2,3-triazole; 5-(4-(4-phenyl-1H-1,2,3-triazol-1-yl)phenyl)pyridine; 1-(5'-chloro-2'-fluoro-[1,1'-biphenyl]-4-yl)-4-phenyl-1H-1,2,3-triazole; 1-(5'-fluoro-2'-methoxy-[1,1'-biphenyl]-4-yl)-4-phenyl-1H-1,2,3-triazole; 1-([1,1'-biphenyl]-4-yl)-4-phenyl-1H-1,2,3-triazole.

[0102] In one embodiment, the present disclosure relates to compounds of formula (I) for use in treating disease conditions that depend on increased / decreased SOCE activity.

[0103]

[0104] wherein the residues A1, A2, A3, A4, A5, B1, B2, B3, B4, B5, Hy and Hz have the meanings indicated above.

[0105] Therefore, the compounds of formula (I) are useful in the prevention or treatment of:

[0106] - Diseases associated with loss- or gain-of-function STIM1 / Orai1 mutations, including but not limited to, immunodeficiency (T-cell immunodeficiency, lymphoproliferative disorders, autoimmunity, congenital myopathies, anhidrosis, tooth enamel and thrombotic disorders due to platelet activation defects), tubular aggregation myopathy (TAM), Stormorken syndrome, and York platelet syndrome.

[0107] -Muscular dystrophy, including Duchenne muscular dystrophy;

[0108] - Inflammatory diseases, including mild and severe acute pancreatitis, chronic pancreatitis, and post-ERCP pancreatitis.

[0109] The compounds of formula (I) can be administered in a variety of ways suitable for the condition to be treated. Suitable routes include oral, parenteral (including subcutaneous, intramuscular, intravenous, intraarterial, intradermal, intrathecal and epidural), transdermal, rectal, nasal, topical (including buccal and sublingual), vaginal, intraperitoneal, intrapulmonary and intranasal.

[0110] The compound of formula (I) can be formulated into pharmaceutical compositions in the form of tablets, capsules, aqueous solutions, granules, powders, suspensions, creams, syrups, gels, emulsions, and the like.

[0111] The dosage depends on a variety of factors, including the patient's age, weight, and condition, as well as the route of administration. Although the daily dose may vary from person to person, the compound will be given to adults in a single daily dose of 0.0001-50 mg / kg body weight or repeated daily doses of 0.01 to 1 mg / kg.

[0112] Tablets contain a mixture of a compound of formula (I) and non-toxic pharmaceutical excipients suitable for preparing tablets. Exemplary excipients may include: inert diluents such as sodium carbonate, lactose, glucose, cellulose, etc.; granulating disintegrants such as corn starch, glycolate, alginic acid; binders such as gelatin or gum arabic; lubricants such as magnesium silica or calcium stearate, stearic acid, or talc. To prepare suppositories, a mixture of, for example, fatty acid glycerides or cocoa butter is first melted and the compound of formula (I) is uniformly dissolved by stirring. The homogeneous mixture is then cooled into a mold of a suitable size. Liquid preparations, including solutions, suspensions, and emulsions, contain a mixture of a compound of formula (I) and excipients suitable for preparing aqueous suspensions, such as sodium carboxymethylcellulose, methylcellulose, resins, sodium alginate, and natural or synthetic gums. Finally, liquid preparations may contain suitable colorants, flavorings, stabilizers, preservatives, and thickeners as needed.

[0113] The compounds of the present invention may also be co-administered with one or more other therapeutic agents. In a preferred embodiment, the other therapeutic agents include, but are not limited to, nonsteroidal anti-inflammatory drugs (such as indomethacin) and steroidal anti-inflammatory drugs.

[0114] Furthermore, more than one compound according to formula (I) may be co-administered.

[0115] Compounds of formula (I) include, but are not limited to, the compounds shown in Table 1.

[0116] Table 1

[0117]

[0118]

[0119]

[0120]

[0121]

[0122]

[0123]

[0124]

[0125]

[0126] General synthesis of compounds of formula (I)

[0127] The following route shows a method for preparing the formula (I) compound of this specification sheet. For a more detailed description of each reaction step, see the Examples below. Those skilled in the art will appreciate that other synthetic routes can be used to synthesize compounds of the present invention. Although specific starting materials and reagents are described in the route and discussed below, other starting materials and reagents can be easily substituted to provide various derivatives and / or reaction conditions. In addition, many compounds prepared by the following methods can be further modified according to the disclosure using conventional chemistry well known to those skilled in the art.

[0128] In detail, the compound of formula (IV)

[0129]

[0130] wherein C is selected from 2-methoxyphenyl, 3-methoxyphenyl, phenyl, 3-methylthiophenyl, 2,4-dimethoxyphenyl, 3,5-dimethoxyphenyl, benzo[d][1,3]dioxol, dihydrobenzo[b][1,4]dioxin, 2,3-dimethoxyphenyl, 2,6-dimethoxyphenyl, 3,4-dimethoxyphenyl, 2-fluoro-5-methoxyphenyl and 3-hydroxyphenyl, can be prepared as outlined in Scheme a below:

[0131] Route a

[0132]

[0133] Compounds of formula IV were synthesized using a Suzuki cross-coupling reaction. Boronic acids are commercially available or can be synthesized using methods known in the art. Aryl bromide 1 (Intermediate 1) was prepared by a copper(I)-catalyzed azide-alkyne 1,3-dipolar cycloaddition reaction generated in situ with sodium ascorbate. A click reaction between 1-azido-4-bromobenzene and 3-ethynylbenzoic acid afforded Intermediate 1.

[0134] Compound of formula (V)

[0135]

[0136] wherein D is selected from pyridin-4-yl, pyridin-3-yl, pyridin-2-yl, 3-fluoropyridin-4-yl, 3-carboxyphenyl, 2-carboxy-pyridin-4-yl and (2-methoxycarbonyl)pyridin-4-yl, can be prepared as outlined in Scheme b below:

[0137] Route B

[0138]

[0139] Compounds of Formula V are synthesized via an in situ generated copper(I)-catalyzed azide-alkyne 1,3-dipolar cycloaddition reaction using sodium ascorbate. Alkynes are commercially available or can be synthesized using methods known in the art. Azide 3 is synthesized as described in Scheme b. (2,5-Dimethoxyphenyl)boronic acid and 4-bromoaniline react in a Suzuki cross-coupling reaction to afford intermediate 2. A diazotization-azidation protocol then provides azide 3 (intermediate 3), which undergoes click chemistry with various alkynes.

[0140] Compound of formula (VI)

[0141]

[0142] wherein E is selected from (1H-tetrazol-5-yl)phenyl, (carboxymethyl)phenyl and 3-cyanophenyl, can be prepared as outlined in Scheme c below:

[0143] Route c

[0144]

[0145] Compounds of Formula VI are synthesized via a copper(I)-catalyzed azide-alkyne 1,3-dipolar cycloaddition generated in situ from sodium ascorbate. Alkynes are commercially available or can be synthesized according to methods known in the art. Azide 5 was synthesized as described in Scheme c. (2,3-Dihydrobenzo[b][1,4]dioxin-6-yl)boronic acid and 4-bromoaniline react in a Suzuki cross-coupling reaction to afford intermediate 4. A diazotization-azidation protocol then affords azide 5 (intermediate 5), which undergoes click chemistry with various alkynes.

[0146] Compound of formula (VII)

[0147]

[0148] wherein F is selected from 2-methoxyphenyl, 3-methoxyphenyl, phenyl, 3-methylthiophenyl, 2,4-dimethoxyphenyl, 3,5-dimethoxyphenyl, benzo[d][1,3]dioxol, dihydrobenzo[b][1,4]dioxin, 2,3-dimethoxyphenyl, 2,6-dimethoxyphenyl, 3,4-dimethoxyphenyl, 2-fluoro-5-methoxyphenyl and 3-hydroxyphenyl, can be prepared as outlined in Scheme d below:

[0149] Route d

[0150]

[0151] Compounds of Formula VII were synthesized using a Suzuki cross-coupling reaction. Boronic acids are commercially available or can be synthesized according to methods known in the art. Aryl bromide 7 was prepared from 4-bromobenzaldehyde and reacted in the presence of a Bestmann-Ohira reagent to afford intermediate 6. Compound 7 was then reacted with 3-azidobenzoic acid via an azide-alkyne 1,3-dipolar cycloaddition catalyzed by copper(I) generated in situ from sodium ascorbate.

[0152] Compound of formula (VIII)

[0153]

[0154] wherein G is selected from pyridin-4-yl, pyridin-3-yl, pyridin-2-yl, 3-fluoropyridin-4-yl, 3-carboxyphenyl, 2-carboxy-pyridin-4-yl and (2-methoxycarbonyl)pyridin-4-yl, can be prepared as outlined in Scheme e below:

[0155] Route e

[0156]

[0157] Compounds of Formula VIII are synthesized via a copper(I)-catalyzed azide-alkyne 1,3-dipolar cycloaddition generated in situ from sodium ascorbate. Azides are synthesized according to methods known in the art, and alkyne 9 is prepared as described in Scheme e. (2,5-Dimethoxyphenyl)boronic acid and 4-bromobenzaldehyde react in a Suzuki cross-coupling reaction to afford intermediate 8. 8 is then reacted in the presence of a Bestmann-Ohira reagent to afford alkyne 9 (intermediate 9).

[0158] The chemical reactions described in the following examples can be readily adapted to prepare many other SOCE modulators of the present invention, and alternative methods for preparing compounds of formula (I) are within the common knowledge of those skilled in the art.

[0159] For example, the synthesis of non-exemplified compounds according to the present invention can be successfully carried out by modifications obvious to those skilled in the art, for example, by appropriately protecting interfering groups, by using other suitable reagents known in the art other than those described, and / or by making routine modifications to the reaction conditions. Alternatively, other reactions disclosed herein or known in the art will be considered suitable for preparing other compounds of the present invention.

[0160] Example 1: Synthesis of 3-(1-(4-bromophenyl)-1H-1,2,3-triazol-4-yl)benzoic acid (Intermediate 1)

[0161] To the suspension of 1-azido-4-bromobenzene (2.78g, 14.04mmol) in water (26mL) and t-BuOH (26mL), 3-ethynylbenzoic acid (2.05g, 14.04mmol) was added. Then, 1.4mL of 1M sodium ascorbate aqueous solution and copper sulfate pentahydrate (34.9mg, 0.14mmol) were added and the mixture was stirred vigorously for 48h. Volatiles were then removed and the crude product was purified by column chromatography using petroleum ether / ethyl acetate 2:8 and ethyl acetate / methanol 8:2 as eluents to obtain compound 1 as a yellow solid (4.22g, 12.27mmol, 87%).

[0162] Analyze the data:

[0163] 1 H-NMR (300MHz, DMSO-d6): δ9.54(s,1H),8.51(s,1H),8.14(d,J=7.7Hz,1H), 7.98-7.94(m,3H),7.86-7.83(d,J=8.8Hz,2H),7.60(t,J=7.7Hz,1H).MS:M-1 343.

[0164] Example 2: Synthesis of 2',5'-dimethoxy-[1,1'-biphenyl]-4-amine (Intermediate 2)

[0165] Under nitrogen atmosphere, 4- bromoaniline (2g, 11.63mmol) is dissolved in DMF (23mL) and ethanol (23mL).(2,5-dimethoxyphenyl)boric acid (3.17g, 17.44mmol), Pd(OAc)2(26.1mg, 0.116mmol) and K2CO3(3.2g, 23.26mmol) are added successively. The mixture is stirred at 80 DEG C for 3h, and spends the night at room temperature. The reactant is vacuum filtered on a diatomaceous earth pad, rinsed with ethanol and evaporated. The crude product is purified by column chromatography using petroleum ether / ethyl acetate 7:3 as eluent to obtain compound 2 as a yellow solid (2.61g, 11.40mmol, 98%).

[0166] Analyze the data:

[0167] 1 H-NMR (300MHz, CDCl3): δ7.39(d,J=6.9Hz,2H),6.97-6.88(m,2H),6.84(s,1H),6.70(d,J=6.9Hz,2H),3.82(s,3H),3.76(s,3H).MS:M+1 230.

[0168] Example 3: Synthesis of 4'-azido-2,5-dimethoxy-1,1'-biphenyl (Intermediate 3)

[0169] HCl 37% (3.5 mL) was added to a solution of 2', 5'-dimethoxy-[1,1'-biphenyl]-4-amine (2g, 8.73mmol) in water (40 mL), and the resulting mixture was cooled at 0 ° C. Then, NaNO2 (0.60g, 8.73mmol) in water (2 mL) was added. After 10 min, NaN3 (0.68g, 10.48mmol) in water (2 mL) was added dropwise. The reactant was stirred at room temperature for 5h, diluted with EtOAc and washed with water (2x). The organic layer was dried over sodium sulfate and volatiles were removed in vacuo. The crude material was purified by column chromatography using petroleum ether / ethyl acetate 98:2 as eluent to obtain compound 3 as an orange solid (1.33g, 5.24mmol, 60%).

[0170] Analyze the data:

[0171] 1 H-NMR (300MHz, CDCl3): δ8.31(d,J=7.1Hz,2H),7.75(d,J=7.1Hz,2H),6.92-6.83(m,3H),3.85(s,3H),3.79(s,3H).

[0172] Example 4: Synthesis of 4-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)aniline (Intermediate 4)

[0173] 4- bromoaniline (0.5g, 2.91mmol) is dissolved in DMF (5mL) and ethanol (5mL) under a nitrogen atmosphere. (2,3- dihydrobenzo [b] [1,4] dioxin-6-yl) boronic acid (0.52g, 2.91mmol), Pd (OAc) 2 (19.6mg, 0.029mmol) and K 2 CO 3 (0.80g, 5.82mmol) are added sequentially. The mixture is stirred at 80 ° C for 6h and spent the night at room temperature. The reactant is vacuum filtered on a diatomaceous earth pad, rinsed with ethanol and evaporated. The crude product is purified by column chromatography using petroleum ether / ethyl acetate 8: 2 as eluent to obtain compound 4 as an orange solid (0.65g, 2.86mmol, 98%).

[0174] Analyze the data:

[0175] 1 H-NMR (300MHz, CDCl3): δ7.37(d,J=7.9Hz,2H),7.09(s,1H),7.04(d,J=8.2Hz ,1H),6.93(d,J=8.2Hz,1H),6.72(d,J=7.9Hz,2H),4.26-4.23(m,4H).MS:M+1 228.

[0176] Example 5: Synthesis of 6-(4-azidophenyl)-2,3-dihydrobenzo[b][1,4]dioxin (Intermediate 5)

[0177] To 2', 5'-dimethoxy-[1,1'-biphenyl]-4-amine (475mg, 2.09mmol) water (9mL) solution, HCl 37% (831 μ L) was added, and the resulting mixture was cooled at 0 ° C. Then, NaNO2 (144mg, 2.09mmol) in water (2mL) was added, and after 10min, NaN3 (163mg, 2.51mmol) in water (2mL) was added dropwise. The reactant was stirred at room temperature for 1h, diluted with EtOAc and washed with water (1x) and HCl 3N aqueous solution (1x). The organic layer was dried over sodium sulfate and volatiles were removed in vacuo. The crude material was purified by column chromatography using petroleum ether / ethyl acetate 98:2 as eluent to obtain compound 5 as a dark yellow solid (386mg, 1.53mmol, 73%).

[0178] Analyze the data:

[0179] 1 H-NMR (300MHz, CDCl3): δ7.50(d,J=6.8Hz,2H),7.10-7.07(m,4H),6.92(d,J=7.7Hz,1H),4.28-4.22(m,4H).

[0180] Example 6: Synthesis of 1-bromo-4-ethynylbenzene (Intermediate 6)

[0181] Under nitrogen, K is added to a solution of 4-bromobenzaldehyde (2.15g, 11.62mmol) in MeOH (22mL) successively CO (3.21g, 23.24mmol) and dimethyl (1-diazo-2-oxopropyl) phosphonate (2.61g, 17.43mmol). The mixture is stirred at room temperature overnight, then the solvent is removed in vacuo, water is added, and CH for water layer is Cl (5x) extracted. The collected organic layer is dried over sodium sulfate and evaporated. The thick material is purified by column chromatography, using petroleum ether / ethyl acetate 9:1 and petroleum ether / ethyl acetate 8:2 as eluents, to obtain compound 6, which is an orange solid (1.12g, 6.26mmol, 54%).

[0182] Analyze the data:

[0183] 1 H-NMR (300MHz, CDCl3): δ7.45 (d, J=8.5Hz, 2H), 7.34 (d, J=8.5Hz, 2H), 3.11 (s, 1H). MS: M+1 180.

[0184] Example 7: Synthesis of 3-(4-(4-bromophenyl)-1H-1,2,3-triazol-1-yl)benzoic acid (Intermediate 7)

[0185] 3-azidobenzoic acid (0.89g, 5.52mmol) is added to a suspension of 1-bromo-4-ethynylbenzene (1g, 5.52mmol) in water (6mL) and t-BuOH (6mL).Then, 55 μL of 1M sodium ascorbate aqueous solution and copper sulfate pentahydrate (13.7mg, 0.055mmol) are added, the mixture is vigorously stirred and spent the night.Then volatile matter is removed, and thick material is purified by column chromatography, using petroleum ether / ethyl acetate 3:7 and ethyl acetate as eluent, to obtain compound 7, which is light yellow solid (1.23g, 3.59mmol, 65%).

[0186] Analyze the data:

[0187] 1 H-NMR (300MHz, DMSO-d6): δ9.50(s,1H),8.46(s,1H),8.19(d,J=7.6Hz,1H),8.06(d,J=7.6Hz,1H),7.92(d,J=8.5Hz,2H),7.78-7.69(m,3H).MS:M-1 343.

[0188] Example 8: Synthesis of 2',5'-dimethoxy-[1,1'-biphenyl]-4-carbaldehyde (Intermediate 8)

[0189] Under nitrogen atmosphere, (2,5-dimethoxyphenyl) boronic acid (540mg, 2.97mmol), Pd (OAc) (11.2mg, 0.05mmol) and K CO (933mg, 6.75mmol) are added to a solution of 4-bromobenzaldehyde (500mg, 2.70mmol) in DMF (8mL) and water (2mL) successively. The mixture is stirred at 50 DEG C for 3h. The reactant is vacuum filtered on a diatomaceous earth pad, diluted with ether and washed with water (3x). The organic phase is dried over sodium sulfate and evaporated. The crude product is purified by column chromatography using petroleum ether / ethyl acetate 98:2 as eluent to give compound 8 as an orange solid (647mg, 2.67mmol, 99%).

[0190] Analyze the data:

[0191] 1 H-NMR (300MHz, CDCl3): δ10.06 (s, 1H), 7.89 (d, J = 7.7Hz, 2H), 7.69 (d, J = 7.7Hz, 2H), 7.08-6.91 (m, 3H), 3.79 (s, 3H), 3.73 (s, 3H). MS: M+1 243.

[0192] Example 9: Synthesis of 4'-ethynyl-2,5-dimethoxy-1,1'-biphenyl (Intermediate 9)

[0193] Under nitrogen, KCO (727 mg, 5.26 mmol) and dimethyl (1-diazo-2-oxopropyl) phosphonate (759 mg, 3.95 mmol) were added to a solution of 2', 5'-dimethoxy-[1,1'-biphenyl]-4-carbaldehyde (636 mg, 2.63 mmol) in MeOH (6 mL) successively. The mixture was stirred at room temperature overnight, then the solvent was removed, water was added and CHCl was used to extract the aqueous layer (3x). The organic layer was collected, dried over sodium sulfate and evaporated. The crude material was purified by column chromatography using petroleum ether / ethyl acetate 98:2 as eluent to give compound 9 as a white solid (514 mg, 2.16 mmol, 82%).

[0194] Analyze the data:

[0195] 1 H-NMR (300MHz, CDCl3): δ7.59-7.49(m,4H),6.93-6.85(m,3H),3.86(s,3H),3.76(s,3H),3.10(s,1H).MS:M+1 239.

[0196] Example 10: Synthesis of 3-(1-([1,1'-biphenyl]-4-yl)-1H-1,2,3-triazol-4-yl)benzoic acid (10) become

[0197] Under a nitrogen atmosphere, 3- (1- (4- bromophenyl) -1H-1,2,3- triazole -4- bases) benzoic acid (100mg, 0.29mmol) was dissolved in DMF (500μL) and ethanol (500μL). Phenylboronic acid (79mg, 0.44mmol), Pd (OAc) (1.96mg, 0.0029mmol) and KCO (80mg, 0.58mmol) were added sequentially. The mixture was stirred at 80°C for 3h and spent the night at room temperature. The reactant was vacuum filtered on a diatomaceous earth pad, rinsed with ethanol and evaporated. The crude product was purified by column chromatography using petroleum ether / ethyl acetate 4: 6 as eluent to give compound 10 as a yellow solid (39.5mg, 0.12mmol, 40%).

[0198] Analyze the data:

[0199] 1H-NMR (300MHz, DMSO-d6): δ9.52(s,1H),8.61(s,1H),8.20(d,J=6.9Hz,1H),8.09(d,J=8.3Hz,2H),7.98-7 .85(m,3H),7.77(d,J=8.3Hz,2H),7.63(t,J=7.5Hz,1H),7.54-7.50(m,2H),7.43(d,J=7.5Hz,1H).MS:M+1 342.

[0200] Example 11: 3-(1-(3'-(methylthio)-[1,1'-biphenyl]-4-yl)-1H-1,2,3-triazol-4-yl)benzene Synthesis of formic acid (11)

[0201] The title compound was synthesized according to the procedure described in Example 10. The crude product was purified by column chromatography using ethyl acetate / methanol 9:1 as eluent to afford compound 11 as a white solid (89.8 mg, 0.23 mmol, 80%).

[0202] Analyze the data:

[0203] 1 H-NMR (300MHz, DMSO-d6): δ9.55(s,1H),8.55(s,1H),8.18(d,J=7.9Hz,1H),8.08(d,J=9.3Hz,2H),7.97-7.95(m,3 H),7.60(d,J=9.3Hz,2H),7.52(d,J=7.9Hz,1H),7.45(t,J=7.9Hz,1H),7.31(d,J=6.2Hz,1H),2.58(s,3H).MS:M+1 388.

[0204] Example 12: 3-(1-(2'-methoxy-[1,1'-biphenyl]-4-yl)-1H-1,2,3-triazol-4-yl)benzene Synthesis of acid (12)

[0205] The title compound was synthesized according to the procedure described in Example 10. The crude product was purified by column chromatography using ethyl acetate as eluent to afford compound 12 as a yellow solid (72 mg, 0.19 mmol, 67%).

[0206] Analyze the data:

[0207] 1H-NMR (300MHz, DMSO-d6): δ9.45(s,1H),8.56(s,1H),8.18(d,J=6.9Hz,1H),8.03-7.95(m,3H),7.7 4(d,J=8.3Hz,2H),7.53(t,J=6.9Hz,1H),(d,J=8.3Hz,2H),7.24-7.14(m,2H),3.82(s,3H).MS:M+1 372.

[0208] Example 13: 3-(1-(3'-methoxy-[1,1'-biphenyl]-4-yl)-1H-1,2,3-triazol-4-yl)benzene Synthesis of acid (13)

[0209] The title compound was synthesized according to the procedure described in Example 10. The crude product was purified by column chromatography using ethyl acetate / methanol 9:1 as eluent to afford compound 13 as a white solid (73 mg, 0.20 mmol, 68%).

[0210] Analyze the data:

[0211] 1 H-NMR (300MHz, DMSO-d6):9.45(s,1H),8.54(s,1H),8.19(d,J=7.4Hz,1H),8.05(d,J=7.8Hz,2H),7.94-7.91(m,3H),7.6 4(t,J=7.4Hz,1H),7.42(d,J=6.8Hz,1H),7.32(d,J=6.8Hz,1H),7.28(s,1H),6.98(d,J=7.4Hz,1H),3.84(s,3H).MS:M+1 372.

[0212] Example 14: 3-(1-(3'-hydroxy-[1,1'-biphenyl]-4-yl)-1H-1,2,3-triazol-4-yl)benzoic acid Synthesis of (14)

[0213] The title compound was synthesized according to the procedure described in Example 10. The crude product was purified by column chromatography using ethyl acetate / methanol 9:1 and ethyl acetate / methanol 8:2 as eluents to afford compound 14 as a dark yellow solid (19 mg, 0.05 mmol, 18%).

[0214] Analyze the data:

[0215] 1H-NMR (300MHz, CD3OD): δ8.96(s,1H),8.59(s,1H),8.15(s,1H),8.03(d,J=7.8Hz,1H),7.92(d,J=7. 4Hz,1H),7.58(d,J=7.8Hz,1H),7.18-7.15(m,3H),7.04-6.99(m,2H),6.82(d,J=5.8Hz,2H).MS:M-1 356.

[0216] Example 15: 3-(1-(2',4'-dimethoxy-[1,1'-biphenyl]-4-yl)-1H-1,2,3-triazol-4-yl) Synthesis of benzoic acid (15)

[0217] The title compound was synthesized according to the procedure described in Example 10. The crude product was purified by column chromatography using ethyl acetate / methanol 9:1 as eluent to afford compound 15 as a light yellow solid (100 mg, 0.25 mmol, 86%).

[0218] Analyze the data:

[0219] 1 H-NMR (300MHz, DMSO-d6): δ9.47(s,1H),8.56(s,1H),8.17(d,J=8.2Hz,1H),7.99-7.95(m,3H),7.69(d,J=9.2Hz,2H ),7.62(t,J=8.2Hz,1H)7.32(d,J=8.2Hz,1H),6.71(s,1H),6.66(d,J=6.2Hz,1H),3.83(s,3H),3.81(s,3H).MS:M+1 402.

[0220] Example 16: 3-(1-(3',5'-dimethoxy-[1,1'-biphenyl]-4-yl)-1H-1,2,3-triazol-4-yl) Synthesis of benzoic acid (16)

[0221] The title compound was synthesized according to the procedure described in Example 10. The crude product was purified by column chromatography using ethyl acetate / methanol 9:1 as eluent to afford compound 16 as a white solid (100 mg, 0.25 mmol, 86%).

[0222] Analyze the data:

[0223] 1H-NMR (300MHz, DMSO-d6): δ9.51(s,1H),8.56(s,1H),8.17(d,J=7.4Hz,1H),8.06(d,J=8.2Hz,2H),7 .95-7.93(m,3H),7.61(t,J=7.4Hz,1H),6.89(s,2H),6.55(s,1H),3.83(s,3H),3.73(s,3H).MS:M+1 402.

[0224] Example 17: 3-(1-(4-(Benzo[d][1,3]dioxol-5-yl)phenyl)-1H-1,2,3-triazole- Synthesis of 4-aminobenzoic acid (17)

[0225] The title compound was synthesized according to the procedure described in Example 10. The crude product was purified by column chromatography using ethyl acetate / methanol 9:1 as eluent to afford compound 17 as a yellow solid (37 mg, 0.10 mmol, 33%).

[0226] Analyze the data:

[0227] 1 H-NMR (300MHz, DMSO-d6): δ9.51(s,1H),8.54(s,1H),8.17(d,J=7.4Hz,1H),8.03(d,J=8.5Hz,2H),7.95(d,J=7.9Hz,1H),7 .87(d,J=8.5Hz,2H),7.61(t,J=7.4Hz,1H),7.42(s,1H),7.27(d,J=7.9Hz,1H),7.04(d,J=7.4Hz,1H),6.09(s,2H).MS:M+1 386.

[0228] Example 18: 3-(1-(4-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)phenyl)-1H-1,2, Synthesis of 3-triazol-4-yl)benzoic acid (18)

[0229] The title compound was synthesized according to the procedure described in Example 10. The crude product was purified by column chromatography using ethyl acetate / methanol 9:1 as eluent to afford compound 18 as a white solid (87 mg, 0.22 mmol, 75%).

[0230] Analyze the data:

[0231] 1H-NMR (300MHz, DMSO-d6): δ9.50(s,1H),8.55(s,1H),8.03-7.94(m,4H),7.86(d,J=7.9Hz,2H ),7.62(t,J=8.2Hz,1H),7.27-7.23(m,2H),6.97(d,J=8.2Hz,1H),4.29-4.22(m,4H).MS:M+1 400.

[0232] Example 19: 3-(1-(3',4'-dimethoxy-[1,1'-biphenyl]-4-yl)-1H-1,2,3-triazol-4-yl) Synthesis of benzoic acid (19)

[0233] The title compound was synthesized according to the procedure described in Example 10. The crude product was purified by column chromatography using ethyl acetate / methanol 9:1 and ethyl acetate / methanol 8:2 as eluents to afford compound 19 as a light yellow solid (50 mg, 0.12 mmol, 43%).

[0234] Analyze the data:

[0235] 1 H-NMR (300MHz, DMSO-d6): δ9.47(s,1H),8.55(s,1H),8.17(d,J=7.1Hz,1H),8.03(d,J=8.2Hz,2H),7.97-7. 90(m,3H),7.62(t,J=7.9Hz,1H),7.33-7.29(m,2H),7.07(d,J=7.9Hz,1H),3.99(s,3H),3.88(s,3H).MS:M+1 402.

[0236] Example 20: 3-(1-(2',3'-dimethoxy-[1,1'-biphenyl]-4-yl)-1H-1,2,3-triazol-4-yl) Synthesis of benzoic acid (20)

[0237] The title compound was synthesized according to the procedure described in Example 10. The crude product was purified by column chromatography using ethyl acetate / methanol 9:1 and ethyl acetate / methanol 8:2 as eluents to afford compound 20 as a yellow solid (88 mg, 0.22 mmol, 76%).

[0238] Analyze the data:

[0239] 1H-NMR (300MHz, DMSO-d6): δ9.46(s,1H),8.57(s,1H),8.18(d,J=6.8Hz,1H),8.05(d,J=7.1Hz,2H),7.98(d,J=6.8Hz,1H) ,7.74(d,J=7.1Hz,2H),7.64(t,J=6.8Hz,1H),7.18-7.14(m,2H),7.03(t,J=7.3Hz,1H)3.88(s,3H),3.77(s,3H).MS:M+1 402.

[0240] Example 21: 3-(1-(4-(2,3-dihydrobenzo[b][1,4]dioxin-5-yl)phenyl)-1H-1,2, Synthesis of 3-triazol-4-yl)benzoic acid (21)

[0241] The title compound was synthesized according to the procedure described in Example 10. The crude product was purified by column chromatography using petroleum ether / ethyl acetate 1:9 and ethyl acetate / methanol 9:1 as eluents to afford compound 21 as a light yellow solid (88 mg, 0.22 mmol, 76%).

[0242] Analyze the data:

[0243] 1 H-NMR (300MHz, DMSO-d6): δ9.44(s,1H),8.55(s,1H),8.15(d,J=5.9Hz,1H),8.03-7.97(m,3H ),7.67(d,J=8.5Hz,2H),7.61(t,J=7.5Hz,1H),6.94-6.93(m,3H),4.32-4.28(m,4H).MS:M+1 400.

[0244] Example 22: 3-(1-(2',6'-dimethoxy-[1,1'-biphenyl]-4-yl)-1H-1,2,3-triazol-4-yl) Synthesis of benzoic acid (22)

[0245] The title compound was synthesized according to the procedure described in Example 10. The crude product was purified by column chromatography using ethyl acetate / methanol 9:1 and ethyl acetate / methanol 8:2 as eluents to afford compound 22 as a light yellow solid (60 mg, 0.15 mmol, 52%).

[0246] Analyze the data:

[0247] 1H-NMR (300MHz, DMSO-d6): δ9.40(s,1H),8.55(s,1H),8.15(d,J=6.9Hz,1H),7.97-7.95(m,4H),7.84(d,J=6.9Hz ,1H),7.62-7.58(m,1H),7.47(d,J=8.2Hz,1H),7.35(t,J=8.2Hz,1H),6.79(d,J=8.2Hz,1H),3.71(s,6H).MS:M+1 402.

[0248] Example 23: 3-(1-(2'-fluoro-5'-methoxy-[1,1'-biphenyl]-4-yl)-1H-1,2,3-triazole-4-yl Synthesis of benzoic acid (23)

[0249] The title compound was synthesized according to the procedure described in Example 10. The crude product was purified by column chromatography using ethyl acetate / methanol 9:1 as eluent to afford compound 23 as a white solid (52 mg, 0.13 mmol, 46%).

[0250] Analyze the data:

[0251] 1 H-NMR (300MHz, DMSO-d6): δ9.45(s,1H),8.54(s,1H),8.16(d,J=7.1Hz,1H),8.08(d,J=7.8Hz,2H),7.95(d,J=7.1Hz,1H), 7.82(d,J=7.8Hz,2H),7.64-7.59(m,1H),7.27(t,J=7.1Hz,1H),7.13-7.12(m,1H),7.01-6.98(m,1H),3.81(s,3H).MS:M+1 390.

[0252] Example 24: 3-(1-(2',5'-dimethoxy-[1,1'-biphenyl]-4-yl)-1H-1,2,3-triazol-4-yl) Synthesis of benzoic acid (24)

[0253] 3-ethynylbenzoic acid (42 mg, 0.29 mmol) was added to a suspension of 4'-azido-2,5-dimethoxy-1,1'-biphenyl (74 mg, 0.29 mmol) in water (460 μL) and t-BuOH (460 μL). 29 μL of 1M sodium ascorbate aqueous solution and copper sulfate pentahydrate (0.72 mg, 0.0029 mmol) were then added and the mixture was stirred vigorously overnight. Volatiles were then removed and the crude product was purified by column chromatography using petroleum ether / ethyl acetate 6:4 as eluent to give compound 24 as a pale yellow solid (49 mg, 0.12 mmol, 42%).

[0254] Analyze the data:

[0255] 1 H-NMR (300MHz, CDCl3): δ9.20(s,1H),8.66(s,1H),8.28(d,J=8.0Hz,1H),8.04(d,J=6.6Hz,2H),7.73(d,J =6.6Hz,2H),7.67-7.53(m,2H),7.08(d,J=8.0Hz,1H),7.01-6.92(m,2H),3.82(s,3H),3.79(s,3H).MS:M+1 402.

[0256] Example 25: 4-(1-(2',5'-dimethoxy-[1,1'-biphenyl]-4-yl)-1H-1,2,3-triazol-4-yl) Synthesis of picolinic acid (25)

[0257] Methyl 4-(1-(2',5'-dimethoxy-[1,1'-biphenyl]-4-yl)-1H-1,2,3-triazol-4-yl)picolinate was synthesized according to the procedure described in Example 24. The crude product was purified by column chromatography using petroleum ether / ethyl acetate 4:6 as eluent to give methyl 4-(1-(2',5'-dimethoxy-[1,1'-biphenyl]-4-yl)-1H-1,2,3-triazol-4-yl)picolinate as a yellow solid (39 mg, 0.09 mmol, 32%).

[0258] Compound (39 mg, 0.09 mmol) was dissolved in acetone (390 μ L) and water (390 μ L). NaOH (7.2 mg, 0.18 mmol) was added, and the mixture was stirred at room temperature for 1 h. Volatiles were then removed and the crude product was purified by column chromatography using ethyl acetate / methanol 7: 3 as eluent to obtain compound 25 as a light yellow solid (21 mg, 0.05 mmol, 58%).

[0259] Analyze the data:

[0260] 1 H-NMR (300MHz, DMSO-d6): δ9.72 (s, 1H), 8.70-8.56 (m, 3H), 8.01 (d, J = 8.0Hz, 2H), 7. 75(d,J=8.0Hz,2H),7.75(s,1H),6.96(m,2H),3.76(s,3H),3.73(s,3H).MS:M+1403.

[0261] Example 26: 4-(1-(2',5'-dimethoxy-[1,1'-biphenyl]-4-yl)-1H-1,2,3-triazole-4-yl Synthesis of 2-(4-(2-amino-3-fluoropyridine)-1-yl)-3-fluoropyridine (26)

[0262] The title compound was synthesized according to the procedure described in Example 24. The crude product was purified by column chromatography using petroleum ether / ethyl acetate 6:4 as eluent to afford compound 26 as a yellow solid (34 mg, 0.09 mmol, 31%).

[0263] Analyze the data:

[0264] 1 H-NMR (300MHz, CDCl3): δ8.60-8.50(m,3H),8.31(d,J=6.1Hz,1H),7.85(d,J=8.5Hz, 2H),7.73(d,J=8.5Hz,2H),6.97-6.89(m,3H),3.83(s,3H),3.75(s,3H).MS:M+1377.

[0265] Example 27: 4-(1-(2',5'-dimethoxy-[1,1'-biphenyl]-4-yl)-1H-1,2,3-triazol-4-yl) Synthesis of pyridine (27)

[0266] The title compound was synthesized according to the procedure described in Example 24. The crude product was purified by column chromatography using petroleum ether / ethyl acetate 4:6 as eluent to afford compound 27 as a white solid (38 mg, 0.11 mmol, 37%).

[0267] Analyze the data:

[0268] 1 H-NMR (300MHz, CDCl3): δ8.36(s,1H),7.82(d,J=7.4Hz,2H),7.73-7.64(m,4H),7.52(s,1H),6.97-6.90(m,4H),3.82(s,3H),3.80(s,3H).MS:M+1 359.

[0269] Example 28: 3-(1-(2',5'-dimethoxy-[1,1'-biphenyl]-4-yl)-1H-1,2,3-triazol-4-yl) Synthesis of pyridine (28)

[0270] The title compound was synthesized according to the procedure described in Example 24. The crude product was purified by column chromatography using petroleum ether / ethyl acetate 5:5, petroleum ether / ethyl acetate 3:7 and petroleum ether / ethyl acetate 2:8 as eluents to afford compound 28 as a yellow solid (68 mg, 0.19 mmol, 65%).

[0271] Analyze the data:

[0272] 1H-NMR (300MHz, CDCl3): δ9.11(s,1H),8.63(s,1H),8.31-8.29(m,2H),7.83(d,J=8.3Hz,2H ),7.72(d,J=8.3Hz,2H),7.43(s,1H),6.97-6.91(m,3H),3.94(s,3H),3.79(s,3H).MS:M+1 359.

[0273] Example 29: 2-(1-(2',5'-dimethoxy-[1,1'-biphenyl]-4-yl)-1H-1,2,3-triazol-4-yl) Synthesis of pyridine (29)

[0274] The title compound was synthesized according to the procedure described in Example 24. The crude product was purified by column chromatography using petroleum ether / ethyl acetate 7:3 as eluent to afford compound 29 as a yellow solid (52 mg, 0.15 mmol, 50%).

[0275] Analyze the data:

[0276] 1 H-NMR (300MHz, CDCl3): δ8.65-8.59(m,2H),8.26(d,J=8.0Hz,1H),7.85-7.78(m,3H),7.70( d,J=8.5Hz,2H),7.25(t,J=6.6Hz,1H),6.95-6.86(m,3H),3.82(s,3H),3.77(s,3H).MS:M+1 359.

[0277] Example 30: 3-(1-(4-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)phenyl)-1H-1,2, Synthesis of 3-triazol-4-yl)benzonitrile (30)

[0278] To Cu (OAc) 2(5.27mg, 0.029mmol) in THF (53 μ L) was added TBTA (tri (benzyltriazolylmethyl) amine) (15mg, 0.029mmol), and the mixture was stirred at room temperature for 30min. A solution of intermediate 3 (150mg, 0.58mmol) in THF (1mL), a solution of 3-ethynylbenzonitrile (74mg, 0.58mmol) in THF (1mL) and 58 μ L 1M sodium ascorbate aqueous solution were added successively. The reactant was stirred at room temperature for 3h. Volatiles were removed and the crude product was purified by column chromatography using ethyl acetate / methanol 9:1 as eluent to give compound 30 as a yellow solid (198mg, 0.52mmol, 90%).

[0279] Analyze the data:

[0280] 1H-NMR (300MHz, DMSO-d6): δ9.45(s,1H),8.35(s,1H),8.30(d,J=7.7Hz,1H),7.94(d,J=7.9Hz,2H),7.88 -7.86(m,3H),7.73(t,J=7.4Hz,1H),7.26-7.23(m,2H),6.97(d,J=7.4Hz,1H),4.31-4.28(m,4H).MS:M+1 381.

[0281] Example 31: 5-(3-(1-(4-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)phenyl)-1H- Synthesis of 1,2,3-triazol-4-yl)phenyl)-1H-tetrazolyl (31)

[0282] Compound 30 (100mg, 0.26mmol) is dissolved in DMF (3mL), NaN (20mg, 0.31mmol) and NH4Cl (16mg, 0.31mmol) are added sequentially. The mixture is stirred at 120 DEG C for 48h. Then, HCl 3N is added dropwise until pH 6. The water layer is extracted with ethyl acetate (6x), and the organic phase is collected, dried over sodium sulfate and evaporated. The crude product is purified by column chromatography, using petroleum ether / ethyl acetate 2:8 and ethyl acetate as eluents, to obtain compound 31 as a dark yellow solid (39mg, 0.09mmol, 35%).

[0283] Analyze the data:

[0284] 1 H-NMR (300MHz, CD3OD): δ8.94(s,1H),8.42(s,1H),7.95(d,J=8.2Hz,2H),7.76(d,J=8.2Hz,2H),7.66( t,J=7.1Hz,1H),7.37-7.33(m,2H),7.17-7.15(m,2H),6.98(d,J=7.1Hz,1H),4.30-4.27(m,4H).MS:M+1 424.

[0285] Example 32: 2-(3-(1-(4-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)phenyl)-1H- Synthesis of 1,2,3-triazol-4-yl)phenyl)acetic acid (32)

[0286] The title compound was synthesized according to the procedure described in Example 30. The crude product was purified by column chromatography using ethyl acetate and ethyl acetate / methanol 8:2 as eluents to afford compound 32 as a dark yellow solid (98 mg, 0.24 mmol, 41%).

[0287] Analyze the data:

[0288] 1H-NMR (300MHz, DMSO-d6): δ9.21(s,1H),8.02(s,1H),7.87-7.80(m,4H),7.40(d,J=7.9H z,2H),7.26(t,J=8.5Hz,1H),7.25-7.20(m,3H),5.51(s,2H),4.30-4.27(m,4H).MS:M+1 414.

[0289] Example 33: Synthesis of 3-(4-([1,1'-biphenyl]-4-yl)-1H-1,2,3-triazol-1-yl)benzoic acid (33) become

[0290] 3-(4-(4-bromophenyl)-1H-1,2,3-triazol-1-yl)benzoic acid (100 mg, 0.29 mmol) was dissolved in DMF (500 μL) and ethanol (500 μL) under a nitrogen atmosphere. Phenylboronic acid (79 mg, 0.44 mmol), Pd(OAc)2 (1.96 mg, 0.0029 mmol) and K2CO3 (80 mg, 0.58 mmol) were added sequentially. The mixture was stirred at 80 ° C for 3 h and spent the night at room temperature. The reactant was vacuum filtered on a celite pad, rinsed with ethanol and evaporated. The crude product was purified by column chromatography using ethyl acetate as eluent to give compound 33 as a white solid (54 mg, 0.16 mmol, 55%).

[0291] Analyze the data:

[0292] 1 H-NMR (300MHz, DMSO-d6): δ9.48 (s, 1H), 8.48 (s, 1H), 8.13-8.03 (m, 5H), 7.83-7.69 (m, 4H), 7.49 (m, 2H), 7.38 (d, J = 7.1Hz, 1H). MS: M+1 342.

[0293] Example 34: 3-(4-(3'-(methylthio)-[1,1'-biphenyl]-4-yl)-1H-1,2,3-triazol-1-yl)benzene Synthesis of formic acid (34)

[0294] The title compound was synthesized according to the procedure described in Example 33. The crude product was purified by column chromatography using petroleum ether / ethyl acetate 5:5 as eluent to afford compound 34 as a light yellow solid (111 mg, 0.29 mmol, 99%).

[0295] Analyze the data:

[0296] 1H-NMR (300MHz, DMSO-d6): δ9.49(s,1H),8.47(s,1H),8.13-8.03(m,4H),7.83(d,J=8.3Hz,2H),7.70(d,J=7.7 Hz,1H),7.58(s,1H),7.51(d,J=7.1Hz,1H),7.43(t,J=7.7Hz,1H),7.28(d,J=7.7Hz,1H),2.56(s,3H).MS:M-1 386.

[0297] Example 35: 3-(4-(2'-methoxy-[1,1'-biphenyl]-4-yl)-1H-1,2,3-triazol-1-yl)benzene Synthesis of acid (35)

[0298] The title compound was synthesized according to the procedure described in Example 33. The crude product was purified by column chromatography using ethyl acetate / methanol 9:1 as eluent to afford compound 35 as a white solid (24 mg, 0.06 mmol, 22%).

[0299] Analyze the data:

[0300] 1 H-NMR (300MHz, DMSO-d6): δ9.41(s,1H),8.51(s,1H),8.19(d,J=7.7Hz,1H),8.00(d,J=7 .7Hz,1H),7.71-7.62(m,3H),7.37-7.35(m,3H),7.13-7.05(m,3H),3.81(s,3H).MS:M+1 372.

[0301] Example 36: 3-(4-(3'-methoxy-[1,1'-biphenyl]-4-yl)-1H-1,2,3-triazol-1-yl)benzene Synthesis of acid (36)

[0302] The title compound was synthesized according to the procedure described in Example 33. The crude product was purified by column chromatography using ethyl acetate / methanol 9:1 as eluent to afford compound 36 as a white solid (66 mg, 0.18 mmol, 61%).

[0303] Analyze the data:

[0304] 1 H-NMR (300MHz, DMSO-d6): δ9.53 (s, 1H), 8.50 (s, 1H), 8.25 (d, J = 7.7Hz, 1H), 8.07-8.05 (m,3H),7.84-7.75(m,3H),7.40-7.27(m,3H),6.96(d,J=7.7,1H),3.84(s,3H).MS:M+1 372.

[0305] Example 37: 3-(4-(2',4'-dimethoxy-[1,1'-biphenyl]-4-yl)-1H-1,2,3-triazol-1-yl) Synthesis of benzoic acid (37)

[0306] The title compound was synthesized according to the procedure described in Example 33. The crude product was purified by column chromatography using ethyl acetate / methanol 9:1 as eluent to afford compound 37 as a yellow solid (114 mg, 0.28 mmol, 98%).

[0307] Analyze the data:

[0308] 1 H-NMR (300MHz, DMSO-d6): δ9.41(s,1H),8.47(s,1H),8.13(d,J=7.4Hz,1H),8.04(d,J=7.4Hz,1H),7.96(d,J=7.1Hz,2H) ,7.71(d,J=6.6Hz,1H),7.55(d,J=7.1Hz,2H),7.27(t,J=7.4Hz,1H),6.67-6.61(m,2H),3.80(s,3H),3.78(s,3H).MS:M+1 402.

[0309] Example 38: 3-(4-(3',5'-dimethoxy-[1,1'-biphenyl]-4-yl)-1H-1,2,3-triazol-1-yl) Synthesis of benzoic acid (38)

[0310] The title compound was synthesized according to the procedure described in Example 33. The crude product was purified by column chromatography using ethyl acetate / methanol 9:1 as eluent to afford compound 38 as a yellow solid (115 mg, 0.29 mmol, 99%).

[0311] Analyze the data:

[0312] 1 H-NMR (300MHz, DMSO-d6): δ9.50(s,1H),8.50(s,1H),8.14(d,J=7.1Hz,1H),8.06-8.04(m,3H),7.82(d ,J=8.2Hz,2H),7.70(t,J=7.1Hz,1H),6.94-6.87(m,2H),6.52(s,1H),3.82(s,3H),3.78(s,3H)MS:M+1 402.

[0313] Example 39: 3-(4-(4-(Benzo[d][1,3]dioxol-5-yl)phenyl)-1H-1,2,3-triazole- Synthesis of 1-methyl)benzoic acid (39)

[0314] The title compound was synthesized according to the procedure described in Example 33. The crude product was purified by column chromatography using diethyl ether / ethyl acetate 1:9 as eluent to afford compound 39 as a light yellow solid (65 mg, 0.17 mmol, 58%).

[0315] Analyze the data:

[0316] 1 H-NMR (300MHz, DMSO-d6): δ9.48(s,1H),8.49(s,1H),8.22(d,J=8.2Hz,1H),8.05-7.94(m,3H),7.7 9-7.74(m,3H),7.33(s,1H),7.23(t,J=8.2Hz,1H),7.02(d,J=8.2Hz,1H),6.11(s,2H).MS:M+1386.

[0317] Example 40: 3-(4-(4-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)phenyl)-1H-1,2, Synthesis of 3-triazol-1-yl)benzoic acid (40)

[0318] The title compound was synthesized according to the procedure described in Example 33. The crude product was purified by column chromatography using ethyl acetate as eluent to afford compound 40 as a light yellow solid (115 mg, 0.29 mmol, 99%).

[0319] Analyze the data:

[0320] 1 H-NMR (300MHz, DMSO-d6): δ9.49(s,1H),8.49(s,1H),8.22(d,J=8.0Hz,1H),8.02(d,J=8.5Hz ,2H),7.79-7.77(m,3H),7.27-7.22(m,3H),6.95(d,J=8.0Hz,1H),4.34-4.28(m,4H).MS:M+1 400.

[0321] Example 41: 3-(4-(3',4'-dimethoxy-[1,1'-biphenyl]-4-yl)-1H-1,2,3-triazol-1-yl) Synthesis of benzoic acid (41)

[0322] The title compound was synthesized according to the procedure described in Example 33. The crude product was purified by column chromatography using ethyl acetate / methanol 9:1 and ethyl acetate / methanol 8:2 as eluents to afford compound 41 as a white solid (65 mg, 0.16 mmol, 56%).

[0323] Analyze the data:

[0324] 1H-NMR (300MHz, DMSO-d6): δ9.41(s,1H),8.49(s,1H),8.16(d,J=7.9Hz,1H),8.08-8.02(m,3H),7.79(d,J=8 .0Hz,2H),7.71(t,J=7.9Hz.1H),7.30-7.27(m,2H),7.06(d,J=7.9Hz,1H),3.88(s,3H),3.82(s,3H).MS:M+1 402.

[0325] Example 42: 3-(4-(2',3'-dimethoxy-[1,1'-biphenyl]-4-yl)-1H-1,2,3-triazol-1-yl) Synthesis of benzoic acid (42)

[0326] The title compound was synthesized according to the procedure described in Example 33. The crude product was purified by column chromatography using ethyl acetate / methanol 9:1 and ethyl acetate / methanol 8:2 as eluents to afford compound 42 as a white solid (88 mg, 0.22 mmol, 76%).

[0327] Analyze the data:

[0328] 1 H-NMR (300MHz, DMSO-d6): δ9.53(s,1H),8.56(s,1H),8.18-8.07(m,4H),7.77(t,J=7.6Hz,1H),7 .66(d,J=7.3Hz,2H),7.21-7.15(m,2H),7.03(d,J=7.6Hz,1H),3.91(s,3H),3.62(s,3H).MS:M+1 402.

[0329] Example 43: 3-(4-(4-(2,3-dihydrobenzo[b][1,4]dioxin-5-yl)phenyl)-1H-1,2, Synthesis of 3-triazol-1-yl)benzoic acid (43)

[0330] The title compound was synthesized according to the procedure described in Example 33. The crude product was purified by column chromatography using ethyl acetate / methanol 9:1 and ethyl acetate / methanol 8:2 as eluents to afford compound 43 as a light yellow solid (105 mg, 0.26 mmol, 91%).

[0331] Analyze the data:

[0332] 1 H-NMR (300MHz, DMSO-d6): δ9.42(s,1H),8.49(s,1H),8.11-7.99(m,4H),7.70(t, J=7.2Hz,1H),7.63(d,J=7.4Hz,2H),6.93-6.90(m,3H),4.29-4.26(m,4H).MS:M+1 400.

[0333] Example 44: 3-(4-(2',6'-dimethoxy-[1,1'-biphenyl]-4-yl)-1H-1,2,3-triazol-1-yl) Synthesis of benzoic acid (44)

[0334] The title compound was synthesized according to the procedure described in Example 33. The crude product was purified by column chromatography using ethyl acetate, ethyl acetate / methanol 9:1 and ethyl acetate / methanol 8:2 as eluents to afford compound 44 as a light yellow solid (53 mg, 0.13 mmol, 46%).

[0335] Analyze the data:

[0336] 1 H-NMR (300MHz, DMSO-d6): δ9.40 (s, 1H), 8.55 (s, 1H), 8.15 (d, J = 7.4Hz, 1H), 8.06 (d, J = 7. 4Hz,1H),7.96-7.92(m,3H),7.72-7.70(m,4H),7.29(t,J=7.4Hz,1H),3.69(s,6H).MS:M+1 402.

[0337] Example 45: 3-(4-(2'-fluoro-5'-methoxy-[1,1'-biphenyl]-4-yl)-1H-1,2,3-triazole-1- Synthesis of benzoic acid (45)

[0338] The title compound was synthesized according to the procedure described in Example 33. The crude product was purified by column chromatography using petroleum ether / ethyl acetate 2:8 as eluent to afford compound 45 as a yellow solid (46 mg, 0.12 mmol, 41%).

[0339] Analyze the data:

[0340] 1 H-NMR (300MHz, DMSO-d6): δ9.49 (s, 1H), 8.50 (s, 1H), 8.24 (d, J = 7.9Hz, 1H), 8.08-8.06 (m, 3H), 7. 80-7.70(m,3H),7.25(t,J=7.1Hz,1H),7.12-7.11(m,1H),6.99-6.98(m,1H),3.78(s,3H).MS:M+1 390.

[0341] Example 46: 3-(4-(2',5'-dimethoxy-[1,1'-biphenyl]-4-yl)-1H-1,2,3-triazol-1-yl) Synthesis of benzoic acid (46)

[0342] 3-azidobenzoic acid (68mg, 0.42mmol) is added to a suspension of 4'-ethynyl-2,5-dimethoxy-1,1'-biphenyl (100mg, 0.42mmol) in water (425 μL) and t-BuOH (425 μL). Then, 42 μL 1M sodium ascorbate aqueous solution and copper sulfate pentahydrate (1.04mg, 0.0042mmol) are added and the mixture is vigorously stirred overnight. Volatiles are then removed, and the crude product is purified by column chromatography using petroleum ether / ethyl acetate 3:7 as eluent to obtain compound 46 as a light yellow solid (167mg, 0.42mmol, 99%).

[0343] Analyze the data:

[0344] 1 H-NMR (300MHz, (CD3)2CO): δ9.18(s,1H),8.58(s,1H),8,26(d,J=8.0Hz,1H),8.15(d,J=8.0Hz,1H),8.05(d,J=6.9Hz,2H) ,7.77(t,J=8.0Hz,1H),7.65(d,J=6.9Hz,2H),7.04(d,J=9.0Hz,1H),6.97-6.89(m,2H),3.80(s,3H),3.76(s,3H).MS:M+1 402.

[0345] Example 47: 4-(4-(2',5'-dimethoxy-[1,1'-biphenyl]-4-yl)-1H-1,2,3-triazol-1-yl) Synthesis of methyl picolinate (47)

[0346] The title compound was synthesized according to the procedure described in Example 46. The crude product was purified by column chromatography using petroleum ether / ethyl acetate 4:6 as eluent to afford compound 47 as a light yellow solid (107 mg, 0.26 mmol, 61%).

[0347] Analyze the data:

[0348] 1 H-NMR (300MHz, (CD3)2CO): δ9.38 (s, 1H), 8.93 (d, J = 4.6Hz, 1H) 8.65 (s, 1H), 8.26 (d, J = 9.0Hz, 1H) 8.05 (d, J = 8.3Hz, 2H),7.67(d,J=8.3Hz,2H),7.05(d,J=9.0Hz,1H),6.95-6.91(m,2H),4.03(s,3H),3.81(s,3H),3,77(s,3H).MS:M+1 417.

[0349] Example 48: 4-(4-(2',5'-dimethoxy-[1,1'-biphenyl]-4-yl)-1H-1,2,3-triazol-1-yl) Synthesis of picolinic acid (48)

[0350] Compound 47 (49 mg, 0.12 mmol) was dissolved in acetone (490 μ L) and water (490 μ L). NaOH (9.6 mg, 0.24 mmol) was added, and the mixture was stirred at room temperature for 2 h. Volatiles were then removed, and the crude product was purified by column chromatography using ethyl acetate / methanol 8: 2 and ethyl acetate / methanol 7: 3 as eluents to obtain compound 48 as a pale yellow solid (36 mg, 0.09 mmol, 75%).

[0351] Analyze the data:

[0352] 1 H-NMR (300MHz, DMSO-d6): δ9.71 (s, 1H), 8.70-8.62 (m, 3H), 8.02 (d, J = 8.0Hz, 2H), 7.63 (d ,J=8.0Hz,2H),7.09(d,J=9.6Hz,1H),6.94-6.92(m,2H),3.80(s,3H),3.76(s,3H).MS:M+1 403.

[0353] Example 49: 4-(4-(2',5'-dimethoxy-[1,1'-biphenyl]-4-yl)-1H-1,2,3-triazole-1- Synthesis of 3-fluoropyridine (49)

[0354] The title compound was synthesized according to the procedure described in Example 46. The crude product was purified by column chromatography using petroleum ether / ethyl acetate 7:3 as eluent to afford compound 49 as a yellow solid (95 mg, 0.25 mmol, 60%).

[0355] Analyze the data:

[0356] 1 H-NMR (300MHz, CDCl3): δ8.75(s,1H),8.64(d,J=6.0Hz,1H),8.48(s,1H),8.22(d,J=6.0Hz,1H), 7.96(d,J=8.3Hz,2H),7.66(d,J=8.3Hz,2H),6.96-6.89(m,3H),3.82(s,3H),3.76(s,3H).MS:M+1 377.

[0357] Example 50: 4-(4-(2',5'-dimethoxy-[1,1'-biphenyl]-4-yl)-1H-1,2,3-triazol-1-yl) Synthesis of pyridine (50)

[0358] The title compound was synthesized according to the procedure described in Example 46. The crude product was purified by column chromatography using petroleum ether / ethyl acetate 9:1 as eluent to afford compound 50 as a yellow solid (119 mg, 0.33 mmol, 79%).

[0359] Analyze the data:

[0360] 1 H-NMR (300MHz, DMSO-d6): δ9.55(s,1H),8.85(s,1H),8.04-8.01(m,2H),7.99(d,J=8.3Hz,2H), 7.66(d,J=8.3Hz,2H),7.06(d,J=6.9Hz,1H)6.94-9.93(m,3H),3.77(s,3H),3.74(s,3H).MS:M+1 359.

[0361] Example 51: 3-(4-(2',5'-dimethoxy-[1,1'-biphenyl]-4-yl)-1H-1,2,3-triazol-1-yl) Synthesis of pyridine (51)

[0362] The title compound was synthesized according to the procedure described in Example 46. The crude product was purified by column chromatography using petroleum ether / ethyl acetate 5:5 as eluent to afford compound 51 as a light yellow solid (117 mg, 0.33 mmol, 78%).

[0363] Analyze the data:

[0364] 1 H-NMR (300MHz, CDCl3): δ9.08 (s, 1H), 8.72 (s, 1H), 8.27-8.21 (m, 2H), 7.95 (d, J = 8.3Hz, 2H), 7.65 (d,J=8.3Hz,2H),7.53(t,J=5.2Hz,1H),6.96-6.88(m,3H),3.82(s,3H),3.78(s,3H).MS:M+1359.

[0365] Bioassay

[0366] Figure 1 The current method used to exemplify store-operated Ca 2+ In short, emptying the ER / SR stores leads to the opening of plasma membrane channels, Ca 2+ can flow back into the cell through this channel, and both phenomena can be induced by adding Ca to the extracellular solution after the intracellular stores are depleted. 2+ This simple yet powerful experimental approach remains effective for uncovering phenomena in screening.

[0367] Cell culture and animal models

[0368] Human embryonic kidney HEK cells were obtained from ATCC ( CRL-1573 TM , Rockville, MD, USA) and cultured in Dulbecco's modified Eagle's medium (DMEM; Sigma-Aldrich, Italy) supplemented with 10% heat-inactivated FBS (Gibco, Italy), 50 mg / mL l-glutamine (Sigma-Aldrich, Italy), 10 U / mL penicillin, and 100 mg / mL streptomycin (Sigma-Aldrich, Italy) at 37°C in a humidified atmosphere of 5% CO2. For the experiments, cells were plated at 5 × 10 4 The concentration of 50 μg / mL was plated on glass coverslips (24 mm diameter coverslips in 6-well plates).

[0369] To demonstrate the effects of these compounds and develop therapeutic strategies for gain-of-function rare genetic diseases, we generated a K-STIM1 mutant carrying the p.I115F knock-in point mutation on a C57Bl / 6N background. I115F In addition, to evaluate the effects of these compounds on Duchenne muscular dystrophy, we used dystrophin-deficient mdx mice (C57BL / 10ScSn-Dmdmdx / J) purchased from The Jackson Laboratory.

[0370] Animal care and maintenance adhered to institutional guidelines and complied with national and international laws and policies. Mice were housed in ventilated cages under a 12-h light / dark cycle in a monitored room at 22 ± 1°C with free access to food and water and were weaned according to sex at 23 days of age. These procedures were approved by the local Animal Health and Ethics Committee (Università del Piemonte Orientale) and authorized by national authorities (Istituto Superiore di Sanità; authorization number N.194 / 2019-PR).

[0371] KI-STIM1 established in the C57Bl / 6N background I115F Obtained from PolyGene transgenics (CH, https: / / www.polygene.ch / ). Briefly, this knock-in mouse model was generated by homologous recombination in electroporated embryonic stem (ES) cells transfected with the c.343A>T mutation (corresponding to the substitution of isoleucine to phenylalanine; I115F) located in exon 3 of the Stim1 gene on chromosome 7.

[0372] The linearized targeting vector F118.3 TV ( Figure 7 ) was used for electroporation, and the vector carried an FRT-flanked neomycin resistance expression cassette inserted into an unsuspected region of Stim1 intron 3.

[0373] The integrity of the targeting vector was confirmed by sequencing and restriction analysis of the exon region using the following restriction enzymes: HindIII (7.2 kb / 2.9 kb / 1.7 kb / 1.2 kb), PstI (8.3 kb / 2.7 kb / 1.3 kb / 0.7 kb), PvuII (3.5 kb / 2.8 kb / 2.5 kb / 1.1 kb / 0.9 kb / 0.8 kb / 0.6 kb / 0.4 kb / 0.3 kb / 0.15 kb) and BglII (5.5 kb / 2.9 kb / 2.2 kb / 1.3 kb / 1.0 kb / 0.05 kb). G418 selection was used to maintain stable transfection, and the clones obtained were analyzed and verified by PCR and Southern blot using the restriction enzyme BstEII and a 3' external probe (LA probe). The probe is 463 bp in size and was generated using the following primers:

[0374] F118.20 5'-TGCCAGTTTCCCTATCAG-3' (SEQ ID No.: 1);

[0375] F118.21 5'-CCTAAGGATGGGGATGTAACC-3 (SEQ ID No.: 2).

[0376] Selected ES clones were injected into 49 blastocysts of gray C57Bl / 6N mice. Forty-one surviving blastocysts were transferred into two CD-1 foster mice. The resulting chimeras were mated with gray Flp-null mice. Progeny from the chimeras were screened for Flp-mediated deletion of the neomycin expression cassette and the presence of the corresponding remaining FRT site.

[0377] Mice were ear-marked at weaning, and tissues were used for genotyping using the PCRBIO Rapid Extraction PCR Kit (PCR Biosystems, UK). DNA was extracted according to the manufacturer's instructions (5× PCRBIO Rapid Extraction Buffer A, 10× PCRBIO Rapid Extraction Buffer B).

[0378] Wild type and KI-STIM1 I115FPrimary myoblasts were cultured from the following muscles: gastrocnemius, tibialis anterior, quadriceps femoris, extensor digitorum longus, soleus, biceps brachii, and diaphragm. Each muscle was placed in a 60 mm dish containing phosphate-buffered saline (PBS), removed from the tendon, separated longitudinally, and then cut into small pieces. The small pieces were then separated from the tendon. (Protease, Streptomyces griseus, 25KU) were incubated with shaking at 37°C for 1 hour and irradiated with Dulbecco's modified Eagle's medium (DMEM; Sigma-Aldrich, Italy) supplemented with 10% heat-inactivated FBS (Gibco, Italy), 50 mg / mL L-glutamine (Sigma-Aldrich, Italy), 10 U / mL penicillin and 100 mg / mL streptomycin (Sigma-Aldrich, Italy), and 1% chicken embryo extract (Sigma-Aldrich, Italy). The tissue was then cut into small pieces, passed through 10 mL and 5 mL pipettes, and the supernatant obtained was filtered through a 40 μm filter and centrifuged at 1200 rpm for 10 minutes at room temperature. The pellet was resuspended, and the myoblasts were placed in DMEM supplemented with 10% heat-inactivated fetal bovine serum (Gibco, Italy), 50 mg / mL L-glutamine (Sigma-Aldrich, Italy), 10 U / mL penicillin and 100 mg / mL streptomycin (Sigma-Aldrich, Italy), and 1% chicken embryo extract (Sigma-Aldrich, Italy) in a humidified atmosphere of 5% CO2 in a 100 mm dish for 90 min to release debris.

[0379] The supernatant was then centrifuged and plated in 2% gelatin-treated 35 mm culture dishes in DMEM (Sigma-Aldrich, Italy) supplemented with 20% heat-inactivated fetal bovine serum (Gibco, Italy), 10% horse serum (Gibco, Italy), 50 mg / mL L-glutamine (Sigma-Aldrich, Italy), 10 U / mL penicillin and 100 mg / mL streptomycin (Sigma-Aldrich, Italy), 1% chicken embryo extract (Sigma-Aldrich, Italy), and 10 ng / mL FGF (Peprotech, UK) and cultured at 37°C in a humidified atmosphere of 5% CO2 for 6-7 days with medium changes every 24-36 hours. To differentiate into myotubes, myoblasts were transferred to differentiation medium consisting of DMEM containing 5% horse serum and 1% penicillin-streptomycin for 24 hours.

[0380] For the experiment, myotubes were plated at 20 × 104 After plating on glass coverslips (24 mm diameter coverslips in 6-well plates) at a concentration of 1:1, the cells were maintained in the same medium for an additional 24 hours and then maintained in DMEM supplemented with 10% heat-inactivated FBS (Gibco, Italy), 50 mg / mL L-glutamine (Sigma-Aldrich, Italy), 10 U / mL penicillin, and 100 mg / mL streptomycin (Sigma-Aldrich, Italy) at 37°C in a humidified atmosphere of 5% CO2. Experiments were performed 6-7 days after P2 and P3 extraction.

[0381] Through Fura-2 Ca 2+ Measuring biological evaluation of compounds targeting SOCE

[0382] Compound testing was performed on Hek cells using Fura-2 AM in single cell analysis on coverslips. In Krebs-Ringer buffer (KRB, 135mM NaCl, 5mM KCl, 0.4mM KH2PO4, 1mM MgSO4, 5.5mM glucose, 20mM HEPES, pH 7.4) containing 2mM CaCl2, in the presence of 0.02% Pluronic-127 and 10μM sulfinpyrazone (all from Life Technologies, Italy), Hek cells were loaded with 5μM Fura-2 AM (30min, room temperature). Subsequently, the cells were washed and incubated with KRB for another 30min to delipidate Fura-2 AM. To measure store-operated calcium influx, the intracellular Ca 2+ Monitoring cytosolic Ca upon store depletion 2+ When cells were exposed to Ca-free 2+ solution before and during the experiment. 2+ In the case of intracellular Ca 2+ Storage of vesicular Ca was inhibited by 2,5-tert-butylhydroquinone (tBHQ, 50 μM; Sigma-Aldrich, Italy). 2+ The pump was exhausted. 2 mM Ca was added again. 2+SOCE can be assessed. During the experiment, the coverslip was mounted in a collection chamber and placed on the stage of a Leica DMI6000 epifluorescence microscope equipped with an S Fluor × 40 / 1.3 objective. Fura-2 was excited by alternating 340 and 380 nm using a Polychrome IV monochromator (Till Photon-ics, Germany), and the probe emission light was filtered through a 520 / 20 bandpass filter and collected by a cooled CCD camera (Hamamatsu, Japan). The fluorescence signal was collected and processed using MetaFluor software (Molecular Device, Sun-Nyvale, CA, USA). In order to quantify Ca 2+ The difference in transient amplitude was normalized using the formula ΔF / F0 to compare the values.

[0383] The percentage of SOCE modulation by the compound was determined based on the values ​​of tBHQ-induced calcium influx in HEK cells. Data were analyzed using Microsoft Excel and GraphPad Prism. Examples are shown in Table 2.

[0384] Table 2

[0385]

[0386]

[0387] Table 3

[0388]

[0389]

[0390] From STIM1 mutant mouse model (KI-STIM1 I115F Pharmacological modulation of SOCE in myotubes

[0391] Myotubes were generated from four animals per condition. We also analyzed whether SOCE in WT myotubes was altered during the lifespan of these animals. To this end, we used the classical Ca 2+ In-flow scheme, in which no Ca 2+ The reservoir was depleted with tBHQ in a buffer containing Ca. 2+ The cells were perfused in a solution (2 mM).

[0392] The WT and KI-STIM1 I115F Mouse myotubes were loaded with 5 μM Fura-2 AM and placed in a 0 mM Ca 2+The cells were depleted with 50 μM tBHQ and 10 min later, the cells were incubated in a Ca-containing medium in the presence or absence of the selected compound (3-(1-(3'-methoxy-[1,1'-biphenyl]-4-yl)-1H-1,2,3-triazol-4-yl)benzoic acid). 2+ Solution (2mM) was perfused. Figure 3 As shown in Figure 2, compared with WT, the expression of KI-STIM1 I115F Myotubes from WT animals showed significantly enhanced SOCE at 1 month. This increased SOCE was maintained at all time points examined (1, 3, 6, and 12 months). Interestingly, SOCE from WT myotubes appeared higher in young animals (1 month) and decreased at later time points.

[0393] The effects of the compound 3-(1-(4-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)phenyl)-1H-1,2,3-triazol-4-yl)benzoic acid on myotubes are shown in Figure 4. Figure 4 It can be observed that the compound is able to restore the hyperactivation of STIM1 mutant protein ( Figure 4 ).

[0394] Pharmacological modulation of SOCE in myotubes from a DMD mouse model (mdx)

[0395] Myotubes were generated from four animals per condition. We analyzed whether SOCE was increased in myotubes from mxd mice compared to myotubes from WT mice. To this end, we used the classical Ca 2+ In-flow scheme, in which no Ca 2+ The reservoir was depleted with tBHQ in a buffer containing Ca. 2+ The cells were perfused in a solution (2 mM).

[0396] Myotubes from 4 wild-type (WT) and 4 mdx mice were loaded with 5 μM Fura-2 AM and placed in a 5% CO2-containing medium. 2+ The cells were depleted with 50 μM tBHQ and 10 min later, the cells were incubated in a Ca-containing medium in the presence or absence of the selected compound (3-(1-(3'-methoxy-[1,1'-biphenyl]-4-yl)-1H-1,2,3-triazol-4-yl)benzoic acid). 2+ Solution (2mM) was perfused. Figure 5 As shown in , myotubes from mdx mice showed significantly enhanced SOCE at 3 months compared to WT.

[0397] The effects of the compound 3-(1-(4-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)phenyl)-1H-1,2,3-triazol-4-yl)benzoic acid on myotubes are shown in Figure 4. Figure 6 It can be observed that the compound can restore the overactivation of SOCE in the DMD mouse model ( Figure 6 ).

Claims

1. A compound of formula (I), or a pharmaceutically acceptable salt thereof: in Ring Hy is selected from Ring Hz is selected from A1, A2, A3, A4 and A5 are the same as or different from each other and are independently selected from H, CF3, Br, I, Cl, F, OH, OR1, SR1, a 5-6 membered O-heterocyclic group; A1 and A2, or A2 and A3, or A3 and A4, or A4 and A5 may together form a 5-6 membered O-heterocyclic group fused to the benzene ring to which they are attached; B1, B2, B3, B4 and B5 are the same or different and are independently selected from H, CH2COOH, COOH, COOR3, CN, CF3, Br, I, Cl, F, 1H-tetrazol-5-yl; R1 is selected from unsubstituted C 1-8 alkyl groups; R3 is selected from unsubstituted C 1-8 alkyl groups; Except for the following: 4'-(4-phenyl-1H-1,2,3-triazol-1-yl)-[1,1'-biphenyl]-4-carbonitrile; 1-(4'-methoxy-[1,1'-biphenyl]-4-yl)-4-phenyl-1H-1,2,3-triazole; 1-(2'-ethoxy-4'-fluoro-[1,1'-biphenyl]-4-yl)-4-phenyl-1H-1,2,3-triazole; 1-(3'-(methylsulfonyl)- [1,1'-biphenyl]-4-yl)-4-phenyl-1H-1,2,3-triazole; 1-(2'-chloro-[1,1'-biphenyl]-4-yl)-4-phenyl-1H-1,2,3-triazole; 1-(5'-chloro-2'-fluoro-[1,1'-biphenyl]-4-yl)-4-phenyl-1H-1,2,3-triazole; 1-(5'-fluoro-2'-methoxy-[1,1'-biphenyl]-4-yl)-4-phenyl-1H-1,2,3-triazole Phenyl-1H-1,2,3-triazole; 1-([1,1'-biphenyl]-4-yl)-4-phenyl-1H-1,2,3-triazole; 4'-(4-(pyridin-2-yl)-1H-1,2,3-triazol-1-yl)-[1,1'-biphenyl]-4-amine; 4'-(4-(pyridin-2-yl)-1H-1,2,3-triazol-1-yl)-[1,1'-biphenyl]-4-ol; N-(4'-( 4-(4-phenyl-1H-1,2,3-triazol-1-yl)-[1,1'-biphenyl]-2-yl)-2-(trifluoromethyl)benzamide; N-(5-fluoro-4'-(4-phenyl-1H-1,2,3-triazol-1-yl)-[1,1'-biphenyl]-2-yl)-2-(trifluoromethyl)benzamide; 4-[4-(4-biphenyl-1H-1,2,3-triazol-1-yl)]pyridine-2,6-dicarboxylic acid.

2. The compound according to claim 1, wherein R1 and R3 are selected from unsubstituted methyl, ethyl, tert-butyl, isopropyl, and pent-2-yl.

3. The compound according to claim 1, wherein A1 is selected from H, F, OMe, and a 5-6 membered O-heterocyclic group.

4. The compound according to claim 1, wherein A2 is selected from H, OMe, SMe, OH, and a 5-6 membered O-heterocyclic group.

5. The compound according to claim 1, wherein A3, A4 and A5 are independently selected from H, OMe, and 5-6 membered O-heterocyclic groups.

6. The compound according to claim 1, wherein two adjacent groups at positions A1, A2, A3, A4 or A5 together form a 5-6 membered O-heterocyclic group fused to the benzene ring to which they are attached, and the heterocyclic group fused to the benzene ring is selected from dihydrobenzodioxinyl or benzodioxolyl.

7. The compound according to claim 1, wherein B1 and B5 are independently selected from H and F.

8. The compound of claim 1, wherein B2 and B4 are independently selected from H, CH2COOH, COOH, COOMe, CN and 1H-tetrazol-5-yl.

9. The compound of claim 1, wherein B3 is H.

10. The compound according to claim 1, which is selected from: 3-(1-([1,1'-biphenyl]-4-yl)-1H-1,2,3-triazol-4-yl)benzoic acid; 3-(1-(3'-(methylthio)-[1,1'-biphenyl]-4-yl)-1H-1,2,3-triazol-4-yl)benzoic acid; 3-(1-(2'-methoxy-[1,1'-biphenyl]-4-yl)-1H-1,2,3-triazol-4-yl)benzoic acid; 3-(1-(3'-methoxy-[1,1'-biphenyl]-4-yl)-1H-1,2,3-triazol-4-yl)benzoic acid; 3-(1-(3'-hydroxy-[1,1'-biphenyl]-4-yl)-1H-1,2,3-triazol-4-yl)benzoic acid; 3-(1-(2',4'-dimethoxy-[1,1'-biphenyl]-4-yl)-1H-1,2,3-triazol-4-yl)benzoic acid; 3-(1-(3',5'-dimethoxy-[1,1'-biphenyl]-4-yl)-1H-1,2,3-triazol-4-yl)benzoic acid; 3-(1-(4-(Benzo[d][1,3]dioxol-5-yl)phenyl)-1H-1,2,3-triazol-4-yl)benzoic acid; 3-(1-(4-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)phenyl)-1H-1,2,3-triazol-4-yl)benzoic acid; 3-(1-(3',4'-dimethoxy-[1,1'-biphenyl]-4-yl)-1H-1,2,3-triazol-4-yl)benzoic acid; 3-(1-(2',3'-dimethoxy-[1,1'-biphenyl]-4-yl)-1H-1,2,3-triazol-4-yl)benzoic acid; 3-(1-(4-(2,3-dihydrobenzo[b][1,4]dioxin-5-yl)phenyl)-1H-1,2,3-triazol-4-yl)benzoic acid; 3-(1-(2',6'-dimethoxy-[1,1'-biphenyl]-4-yl)-1H-1,2,3-triazol-4-yl)benzoic acid; 3-(1-(2'-fluoro-5'-methoxy-[1,1'-biphenyl]-4-yl)-1H-1,2,3-triazol-4-yl)benzoic acid; 3-(1-(2',5'-dimethoxy-[1,1'-biphenyl]-4-yl)-1H-1,2,3-triazol-4-yl)benzoic acid; 4-(1-(2',5'-dimethoxy-[1,1'-biphenyl]-4-yl)-1H-1,2,3-triazol-4-yl)picolinic acid; 4-(1-(2',5'-dimethoxy-[1,1'-biphenyl]-4-yl)-1H-1,2,3-triazol-4-yl)-3-fluoropyridine; 4-(1-(2',5'-dimethoxy-[1,1'-biphenyl]-4-yl)-1H-1,2,3-triazol-4-yl)pyridine; 3-(1-(2',5'-dimethoxy-[1,1'-biphenyl]-4-yl)-1H-1,2,3-triazol-4-yl)pyridine; 2-(1-(2',5'-dimethoxy-[1,1'-biphenyl]-4-yl)-1H-1,2,3-triazol-4-yl)pyridine; 3-(1-(4-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)phenyl)-1H-1,2,3-triazol-4-yl)benzonitrile; 5-(3-(1-(4-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)phenyl)-1H-1,2,3-triazol-4-yl)phenyl)-1H-tetrazole; 2-(3-(1-(4-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)phenyl)-1H-1,2,3-triazol-4-yl)phenyl)acetic acid; 3-(4-([1,1'-biphenyl]-4-yl)-1H-1,2,3-triazol-1-yl)benzoic acid; 3-(4-(3'-(methylthio)-[1,1'-biphenyl]-4-yl)-1H-1,2,3-triazol-1-yl)benzoic acid; 3-(4-(2'-methoxy-[1,1'-biphenyl]-4-yl)-1H-1,2,3-triazol-1-yl)benzoic acid; 3-(4-(3'-methoxy-[1,1'-biphenyl]-4-yl)-1H-1,2,3-triazol-1-yl)benzoic acid; 3-(4-(2',4'-dimethoxy-[1,1'-biphenyl]-4-yl)-1H-1,2,3-triazol-1-yl)benzoic acid; 3-(4-(3',5'-dimethoxy-[1,1'-biphenyl]-4-yl)-1H-1,2,3-triazol-1-yl)benzoic acid; 3-(4-(4-(Benzo[d][1,3]dioxol-5-yl)phenyl)-1H-1,2,3-triazol-1-yl)benzoic acid; 3-(4-(4-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)phenyl)-1H-1,2,3-triazol-1-yl)benzoic acid; 3-(4-(3',4'-dimethoxy-[1,1'-biphenyl]-4-yl)-1H-1,2,3-triazol-1-yl)benzoic acid; 3-(4-(2',3'-dimethoxy-[1,1'-biphenyl]-4-yl)-1H-1,2,3-triazol-1-yl)benzoic acid; 3-(4-(4-(2,3-dihydrobenzo[b][1,4]dioxin-5-yl)phenyl)-1H-1,2,3-triazol-1-yl)benzoic acid; 3-(4-(2',6'-dimethoxy-[1,1'-biphenyl]-4-yl)-1H-1,2,3-triazol-1-yl)benzoic acid; 3-(4-(2'-fluoro-5'-methoxy-[1,1'-biphenyl]-4-yl)-1H-1,2,3-triazol-1-yl)benzoic acid; 3-(4-(2',5'-dimethoxy-[1,1'-biphenyl]-4-yl)-1H-1,2,3-triazol-1-yl)benzoic acid; 4-(4-(2',5'-dimethoxy-[1,1'-biphenyl]-4-yl)-1H-1,2,3-triazol-1-yl)picolinic acid methyl ester; 4-(4-(2',5'-dimethoxy-[1,1'-biphenyl]-4-yl)-1H-1,2,3-triazol-1-yl)picolinic acid; 4-(4-(2',5'-dimethoxy-[1,1'-biphenyl]-4-yl)-1H-1,2,3-triazol-1-yl)-3-fluoropyridine; 4-(4-(2',5'-dimethoxy-[1,1'-biphenyl]-4-yl)-1H-1,2,3-triazol-1-yl)pyridine; 3-(4-(2',5'-dimethoxy-[1,1'-biphenyl]-4-yl)-1H-1,2,3-triazol-1-yl)pyridine.

11. Use of a compound of formula (I) or a pharmaceutically acceptable salt thereof in the preparation of a medicament: in Ring Hy is selected from Ring Hz is selected from A1, A2, A3, A4 and A5 are the same as or different from each other and are independently selected from H, CF3, Br, I, Cl, F, OH, OR1, SR1, a 5-6 membered O-heterocyclic group; A1 and A2, or A2 and A3, or A3 and A4, or A4 and A5 may together form a 5-6 membered O-heterocyclic group fused to the benzene ring to which they are attached; B1, B2, B3, B4 and B5 are the same or different and are independently selected from H, CH2COOH, COOH, COOR3, CN, CF3, Br, I, Cl, F, 1H-tetrazol-5-yl; R1 is selected from unsubstituted C 1-8 alkyl groups; R3 is selected from unsubstituted C 1-8 alkyl groups; Except for the following: 1-(2'-ethoxy-4'-fluoro-[1,1'-biphenyl]-4-yl)-4-phenyl-1H-1,2,3-triazole; 1-(3'-(methylsulfonyl)-[1,1'-biphenyl]-4-yl)-4-phenyl-1H-1,2,3-triazole; 1-(2'-chloro-[1,1'-biphenyl]-4-yl)-4-phenyl-1H-1,2 ,3-triazole; 1-(5'-chloro-2'-fluoro-[1,1'-biphenyl]-4-yl)-4-phenyl-1H-1,2,3-triazole; 1-(5'-fluoro-2'-methoxy-[1,1'-biphenyl]-4-yl)-4-phenyl-1H-1,2,3-triazole; 1-([1,1'-biphenyl]-4-yl)-4-phenyl-1H-1,2,3-triazole.

12. Use of a compound of formula (I) or a pharmaceutically acceptable salt thereof for the preparation of a medicament for treating a disease condition that depends on increased / decreased SOCE activity: in Ring Hy is selected from Ring Hz is selected from A1, A2, A3, A4 and A5 are the same as or different from each other and are independently selected from H, CF3, Br, I, Cl, F, OH, OR1, SR1, a 5-6 membered O-heterocyclic group; A1 and A2, or A2 and A3, or A3 and A4, or A4 and A5 may together form a 5-6 membered O-heterocyclic group fused to the benzene ring to which they are attached; B1, B2, B3, B4 and B5 are the same or different and are independently selected from H, CH2COOH, COOH, COOR3, CN, CF3, Br, I, Cl, F, 1H-tetrazol-5-yl; R1 is selected from unsubstituted C 1-8 alkyl groups; R3 is selected from unsubstituted C 1-8 Alkyl group.

13. Use of a compound of formula (I) or a pharmaceutically acceptable salt thereof in the preparation of a medicament for treating diseases associated with loss-of-function or gain-of-function STIM1 / Orai1 mutations, muscular dystrophy, or inflammatory diseases: in Ring Hy is selected from Ring Hz is selected from A1, A2, A3, A4 and A5 are the same as or different from each other and are independently selected from H, CF3, Br, I, Cl, F, OH, OR1, SR1, a 5-6 membered O-heterocyclic group; A1 and A2, or A2 and A3, or A3 and A4, or A4 and A5 may together form a 5-6 membered O-heterocyclic group fused to the benzene ring to which they are attached; B1, B2, B3, B4 and B5 are the same or different and are independently selected from H, CH2COOH, COOH, COOR3, CN, CF3, Br, I, Cl, F, 1H-tetrazol-5-yl; R1 and R2 are the same as or different from each other and are independently selected from unsubstituted C 1-8 alkyl groups; R3 is selected from unsubstituted C 1-8 Alkyl group.

14. A pharmaceutical composition comprising at least one compound of formula (I), a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier and / or vehicle in Ring Hy is selected from Ring Hz is selected from A1, A2, A3, A4 and A5 are the same as or different from each other and are independently selected from H, CF3, Br, I, Cl, F, OH, OR1, SR1, a 5-6 membered O-heterocyclic group; A1 and A2, or A2 and A3, or A3 and A4, or A4 and A5 may together form a 5-6 membered O-heterocyclic group fused to the benzene ring to which they are attached; B1, B2, B3, B4 and B5 are the same or different and are independently selected from H, CH2COOH, COOH, COOR3, CN, CF3, Br, I, Cl, F, 1H-tetrazol-5-yl; R1 and R2 are the same as or different from each other and are independently selected from unsubstituted C 1-8 alkyl groups; R3 is selected from unsubstituted C 1-8 alkyl groups; Except for the following: 1-(2'-ethoxy-4'-fluoro-[1,1'-biphenyl]-4-yl)-4-phenyl-1H-1,2,3-triazole; 1-(3'-(methylsulfonyl)-[1,1'-biphenyl]-4-yl)-4-phenyl-1H-1,2,3-triazole; 1-(2'-chloro-[1,1'-biphenyl]-4-yl)-4-phenyl-1H-1,2 ,3-triazole; 1-(5'-chloro-2'-fluoro-[1,1'-biphenyl]-4-yl)-4-phenyl-1H-1,2,3-triazole; 1-(5'-fluoro-2'-methoxy-[1,1'-biphenyl]-4-yl)-4-phenyl-1H-1,2,3-triazole; 1-([1,1'-biphenyl]-4-yl)-4-phenyl-1H-1,2,3-triazole.

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