Improved synthesis of CRAC channel inhibitors

Abstract

Provided herein is an improved synthetic method for producing CRAC channel inhibitors, which provides a method for producing highly pure CRAC channel inhibitors for clinical trials.

Description

[Technical Field]

[0001] Calcium plays an essential role in cellular function and survival. For example, calcium is a key element in the transmission of signals into and within cells. Cellular responses to growth factors, neurotransmitters, hormones, and various other signaling molecules are initiated through calcium-dependent processes. [Background technology]

[0002] Virtually all cell types express cytoplasmic Ca in some way. 2+ Depending on the signal generated, it regulates cellular functions or triggers specific responses. 2+ Signals regulate a wide range of cellular functions, ranging from short-term responses such as contraction and secretion to long-term regulation of cell growth and proliferation. Typically, these signals involve the release of Ca from intracellular stores such as the endoplasmic reticulum (ER). 2+ Release and Ca transport across the plasma membrane 2+ In one example, cell activation begins with the binding of an agonist to a surface membrane receptor, which binds to phospholipase C (PLC) via a G-protein mechanism. PLC activation leads to the production of inositol 1,4,5-triphosphate (IP3), which in turn activates IP3 receptors to release Ca from the ER. 2+ This then causes the release of Ca from the ER. 2+ A decrease in ATP signals the activation of plasma membrane store-operated calcium (SOC) channels.

[0003] Store-operated calcium (SOC) entry is a process in cellular physiology that controls such diverse functions, including but not limited to, intracellular Ca 2+These include store refilling (Non-Patent Document 1), activation of enzymatic activity (Non-Patent Document 2), gene transcription (Non-Patent Document 3), cell proliferation (Non-Patent Document 4), and cytokine release (Non-Patent Document 5). In some non-excitable cells, such as blood cells, immune cells, hematopoietic cells, T lymphocytes, and mast cells, SOC influx occurs via calcium release-activated calcium (CRAC) channels, a type of SOC channel.

[0004] The calcium entry mechanism has been termed store-operated calcium entry (SOCE). Stromal interaction molecule (STIM) proteins are essential components of SOC channel function and act as sensors to detect calcium depletion from intracellular stores and activate SOC channels. [Prior art documents] [Non-patent literature]

[0005] [Non-Patent Document 1] Putney et al., Cell, 75, 1993, 1993 [Non-patent document 2] Fagan et al., J. Biol. Chem. 275:26530~26537, 2000 [Non-patent document 3] Lewis, Annu.Rev.Immunol.19:497~521, 2001 [Non-patent document 4] Nunez et al., J.Physiol.571.1, 57–73, 2006 [Non-Patent Document 5] Winslow et al., Curr. Opin. Immunol. 15:299-307, 2003 Summary of the Invention [Means for solving the problem]

[0006] In one embodiment, a CRAC channel inhibitor of formula (I):

[0007] [ka] (In the formula, R 1 , R 2 and R 3 is hydrogen, halogen and C1-C3 alkyl (hydrogen, halogen, -OH, -OR 4 , -CN, -N(R 4 independently selected at each occurrence from -N,N-,N-dimethylformamide, - ... or two R's 1 groups, together with the atoms to which they are attached, form a carbocyclic ring; n is 0, 1, 2 or 3; m is 0, 1, 2, 3, 4 or 5; R 4 is hydrogen; and C 1~6 Alkyl, C 2~6 Alkenyl and C 2~6 alkynyl (each independently selected at each occurrence from halogen, —CN, —NO 2 , —OH, —NH 2 and —OCH 3 ) or a pharmaceutically acceptable salt thereof, comprising the steps of: In the presence of a base, a catalyst and a solvent, a compound of formula (IA)

[0008] [ka] with a compound of formula (IB)

[0009] [ka] (Wherein, X is -B(OH)2, -BF3K

[0010] [ka] is selected from Y is selected from Cl, Br and I. Provided herein is a process comprising reacting

[0011] In some embodiments, the base is selected from the group consisting of potassium carbonate, sodium carbonate, potassium bicarbonate, sodium bicarbonate, piperidine, pyridine, 1,8-diazabicyclo[5.4.0]undec-7-ene, sodium tert-butoxide, potassium tert-butoxide, cesium carbonate, potassium phosphate, sodium hydroxide, N,N-diisopropylethylamine, and triethylamine. In some embodiments, the base is potassium phosphate.

[0012] In some embodiments, the catalyst is selected from Pd(acac)2, [Pd(allyl)Cl]2, Pd(MeCN)2Cl2, Pd(dba)2, Pd(TFA)2, Pd2(dba)3, Pd2(dba)3·CHCl3, Pd(PPh3)4, Pd(OAc)2, Pd(PCy3)2Cl2, Pd(PPh3)2Cl2, Pd[P(o-tol)3]2Cl2, Pd(amphos)Cl2, Pd(dppf)Cl2, Pd(dppf)Cl2·CH2Cl2, Pd(dtbpf)Cl2, Pd(MeCN)4(BF4), PdCl2, XPhos-Pd-G3, Pd-PEPPSI™-IPr, Pd-PEPPSI™-SIPr, and Pd-PEPPSI™-IPent. In some embodiments, the catalyst is Pd(PPh3)4.

[0013] In some embodiments, the solvent is selected from water, ethyl acetate, dichloromethane, tetrahydrofuran, diethyl ether, dimethylformamide, dimethyl sulfoxide, methanol, ethanol, acetone, acetonitrile, 1,4-dioxane, hexane, and methyl tert-butyl ether. In some embodiments, the solvent is 1,4-dioxane.

[0014] In some embodiments, the compound of Formula (IA), the compound of Formula (IB), the base, the catalyst, and the solvent are Within 16 hours, At temperatures between about 75°C and about 80°C, It is stirred.

[0015] In some embodiments, the process further comprises precipitating the compound of formula (I) and isolating it by filtration.

[0016] In some embodiments, the process provides a compound of formula (I) in synthetic yield of greater than about 75%.

[0017] In some embodiments, the compound of formula (IA)

[0018] [ka] is a compound of formula (IC) in the presence of a base and a solvent

[0019] [ka] It is synthesized by reacting with a boronating agent.

[0020] In some embodiments, the boronating agent is selected from 2-isopropoxy-4,4,5,5-tetramethyl-1,3,2-dioxaborolane, 2-methoxy-4,4,5,5-tetramethyl-1,3,2-dioxaborolane, and 2-ethoxy-4,4,5,5-tetramethyl-1,3,2-dioxaborolane. In some embodiments, the boronating agent is 2-isopropoxy-4,4,5,5-tetramethyl-1,3,2-dioxaborolane.

[0021] In some embodiments, the base is selected from isopropylmagnesium chloride, isopropylmagnesium lithium chloride, methylmagnesium bromide, methylmagnesium chloride, methylmagnesium iodide, ethylmagnesium chloride, ethylmagnesium bromide, isopropylmagnesium bromide, methyllithium, ethyllithium, isopropyllithium, n-butyllithium, and tert-butyllithium. In some embodiments, the base is isopropylmagnesium lithium chloride.

[0022] In some embodiments, the solvent is selected from water, ethyl acetate, dichloromethane, tetrahydrofuran, diethyl ether, dimethylformamide, dimethyl sulfoxide, methanol, ethanol, acetone, acetonitrile, 1,4-dioxane, hexane, and methyl tert-butyl ether. In some embodiments, the solvent is tetrahydrofuran.

[0023] In some embodiments, the compound of Formula (IC), the boronating agent, the base, and the solvent are Within two hours, At temperatures between approximately 0°C and approximately 25°C, It is stirred.

[0024] In some embodiments, the process further comprises precipitating the compound of formula (IA) and isolating it by filtration.

[0025] In some embodiments, the process provides a compound of formula (IA) in greater than about 70% synthetic yield.

[0026] In some embodiments, a compound of formula (IC)

[0027] [ka] is a compound of formula (ID) in the presence of an acid and a solvent

[0028] [ka] It is synthesized by reacting with a brominating agent.

[0029] In some embodiments, the brominating agent is selected from N-bromosuccinimide, tribromoisocyanuric acid, 1,3-dibromo-5,5-dimethylhydantoin, and bromine. In some embodiments, the brominating agent is 1,3-dibromo-5,5-dimethylhydantoin.

[0030] In some embodiments, the acid is selected from hydrochloric acid, sulfuric acid, nitric acid, acetic acid, hydrobromic acid, phosphoric acid, formic acid, and trifluoroacetic acid, hi some embodiments, the acid is sulfuric acid.

[0031] In some embodiments, the solvent is selected from water, ethyl acetate, dichloromethane, tetrahydrofuran, diethyl ether, dimethylformamide, dimethyl sulfoxide, methanol, ethanol, acetone, acetonitrile, 1,4-dioxane, hexane, and methyl tert-butyl ether. In some embodiments, the solvent is acetonitrile.

[0032] In some embodiments, the compound of Formula (ID), the brominating agent, the acid, and the solvent are Within 12 hours, At temperatures between approximately 0°C and approximately 15°C, It is stirred.

[0033] In some embodiments, the process further comprises extracting the compound of formula (IC) and isolating it by concentration. In some embodiments, the process provides the compound of formula (IC) in greater than about 80% synthetic yield.

[0034] In some embodiments, a compound of formula (IB)

[0035] [ka] is a compound of formula (IE) in the presence of a base

[0036] [ka] with a compound of formula (IF)

[0037] [ka] wherein Z is selected from Cl, Br and I. It is synthesized by reacting with

[0038] In some embodiments, the base is selected from the group consisting of potassium carbonate, sodium carbonate, potassium bicarbonate, sodium bicarbonate, piperidine, pyridine, 1,8-diazabicyclo[5.4.0]undec-7-ene, sodium tert-butoxide, potassium tert-butoxide, cesium carbonate, potassium phosphate, sodium hydroxide, N,N-diisopropylethylamine, and triethylamine. In some embodiments, the base is pyridine.

[0039] In some embodiments, the compound of Formula (IE), the compound of Formula (IF), and the base are Within two hours, At temperatures between approximately 20°C and 25°C, It is stirred.

[0040] In some embodiments, the process further comprises precipitating the compound of formula (IB) and isolating it by filtration.

[0041] In some embodiments, the process provides the compound of formula (IB) in greater than about 80% synthetic yield.

[0042] In some embodiments, the compound of formula (IF)

[0043] [ka] is a compound of formula (IG) in the presence of a solvent

[0044] [ka] is synthesized by reacting with an acyl halide preparative agent.

[0045] In some embodiments, the acyl halide modifier is selected from oxalyl chloride, thionyl chloride, phosphoryl chloride, phosphorus trichloride, phosphorus pentachloride, phosgene, diphosgene, triphosgene, and cyanuric chloride. In some embodiments, the acyl halide modifier is oxalyl chloride.

[0046] In some embodiments, the solvent is selected from water, ethyl acetate, dichloromethane, tetrahydrofuran, diethyl ether, dimethylformamide, dimethyl sulfoxide, methanol, ethanol, acetone, acetonitrile, 1,4-dioxane, hexane, and methyl tert-butyl ether. In some embodiments, the solvent is tetrahydrofuran.

[0047] In some embodiments, the compound of Formula (IG), the acyl halide coordinating agent, and the solvent are Within 16 hours, At temperatures between approximately 20°C and 25°C, It is stirred.

[0048] In another embodiment, a CRAC channel inhibitor of formula (II):

[0049] [ka] or a pharmaceutically acceptable salt thereof, comprising the steps of: In the presence of a base, a catalyst and a solvent, a compound of formula (II-A)

[0050] [ka] with a compound of formula (IB)

[0051] [ka] Provided herein is a process comprising reacting

[0052] In some embodiments, the base is selected from the group consisting of potassium carbonate, sodium carbonate, potassium bicarbonate, sodium bicarbonate, piperidine, pyridine, 1,8-diazabicyclo[5.4.0]undec-7-ene, sodium tert-butoxide, potassium tert-butoxide, cesium carbonate, potassium phosphate, sodium hydroxide, N,N-diisopropylethylamine, and triethylamine. In some embodiments, the base is potassium phosphate.

[0053] In some embodiments, the catalyst is selected from Pd(acac)2, [Pd(allyl)Cl]2, Pd(MeCN)2Cl2, Pd(dba)2, Pd(TFA)2, Pd2(dba)3, Pd2(dba)3·CHCl3, Pd(PPh3)4, Pd(OAc)2, Pd(PCy3)2Cl2, Pd(PPh3)2Cl2, Pd[P(o-tol)3]2Cl2, Pd(amphos)Cl2, Pd(dppf)Cl2, Pd(dppf)Cl2·CH2Cl2, Pd(dtbpf)Cl2, Pd(MeCN)4(BF4), PdCl2, XPhos-Pd-G3, Pd-PEPPSI™-IPr, Pd-PEPPSI™-SIPr, and Pd-PEPPSI™-IPent. In some embodiments, the catalyst is Pd(PPh3)4.

[0054] In some embodiments, the solvent is selected from water, ethyl acetate, dichloromethane, tetrahydrofuran, diethyl ether, dimethylformamide, dimethyl sulfoxide, methanol, ethanol, acetone, acetonitrile, 1,4-dioxane, hexane, and methyl tert-butyl ether. In some embodiments, the solvent is 1,4-dioxane.

[0055] In some embodiments, the compound of Formula (II-A), the compound of Formula (II-B), the base, the catalyst, and the solvent are Within 16 hours, At temperatures between about 75°C and about 80°C, It is stirred.

[0056] In some embodiments, the process further comprises precipitating the compound of formula (II) and isolating it by filtration.

[0057] In some embodiments, the process provides a compound of formula (II) in synthetic yield of greater than about 75%.

[0058] In some embodiments, the compound of formula (II-A)

[0059] [ka] is reacted with a compound of formula (II-C) in the presence of a base and a solvent.

[0060] [ka] It is synthesized by reacting with a boronating agent.

[0061] In some embodiments, the boronating agent is selected from 2-isopropoxy-4,4,5,5-tetramethyl-1,3,2-dioxaborolane, 2-methoxy-4,4,5,5-tetramethyl-1,3,2-dioxaborolane, and 2-ethoxy-4,4,5,5-tetramethyl-1,3,2-dioxaborolane. In some embodiments, the boronating agent is 2-isopropoxy-4,4,5,5-tetramethyl-1,3,2-dioxaborolane.

[0062] In some embodiments, the base is selected from isopropylmagnesium chloride, isopropylmagnesium lithium chloride, methylmagnesium bromide, methylmagnesium chloride, methylmagnesium iodide, ethylmagnesium chloride, ethylmagnesium bromide, isopropylmagnesium bromide, methyllithium, ethyllithium, isopropyllithium, n-butyllithium, and tert-butyllithium. In some embodiments, the base is isopropylmagnesium lithium chloride.

[0063] In some embodiments, the solvent is selected from water, ethyl acetate, dichloromethane, tetrahydrofuran, diethyl ether, dimethylformamide, dimethyl sulfoxide, methanol, ethanol, acetone, acetonitrile, 1,4-dioxane, hexane, and methyl tert-butyl ether. In some embodiments, the solvent is tetrahydrofuran.

[0064] In some embodiments, the compound of Formula (II-C), the boronating agent, the base, and the solvent are Within two hours, At temperatures between approximately 0°C and approximately 25°C, It is stirred.

[0065] In some embodiments, the process further comprises precipitating the compound of formula (II-A) and isolating it by filtration.

[0066] In some embodiments, the process provides the compound of formula (II-A) in greater than about 70% synthetic yield.

[0067] In some embodiments, a compound of formula (II-C)

[0068] [ka] is a compound of formula (II-D) in the presence of an acid and a solvent.

[0069] [ka] It is synthesized by reacting with a brominating agent.

[0070] In some embodiments, the brominating agent is selected from N-bromosuccinimide, tribromoisocyanuric acid, 1,3-dibromo-5,5-dimethylhydantoin, and bromine. In some embodiments, the brominating agent is 1,3-dibromo-5,5-dimethylhydantoin.

[0071] In some embodiments, the acid is selected from hydrochloric acid, sulfuric acid, nitric acid, acetic acid, hydrobromic acid, phosphoric acid, formic acid, and trifluoroacetic acid, hi some embodiments, the acid is sulfuric acid.

[0072] In some embodiments, the solvent is selected from water, ethyl acetate, dichloromethane, tetrahydrofuran, diethyl ether, dimethylformamide, dimethyl sulfoxide, methanol, ethanol, acetone, acetonitrile, 1,4-dioxane, hexane, and methyl tert-butyl ether. In some embodiments, the solvent is acetonitrile.

[0073] In some embodiments, the compound of Formula (II-D), the brominating agent, the acid, and the solvent are Within 12 hours, At temperatures between approximately 0°C and approximately 15°C, It is stirred.

[0074] In some embodiments, the process further comprises extracting the compound of formula (II-C) and isolating it by concentration.

[0075] In some embodiments, the process provides the compound of formula (II-C) in greater than about 80% synthetic yield.

[0076] In some embodiments, a compound of formula (II-B)

[0077] [ka] is reacted with a compound of formula (II-E) in the presence of a base

[0078] [ka] with a compound of formula (II-F)

[0079] [ka] wherein Z is selected from Cl, Br and I. It is synthesized by reacting with

[0080] In some embodiments, the base is selected from the group consisting of potassium carbonate, sodium carbonate, potassium bicarbonate, sodium bicarbonate, piperidine, pyridine, 1,8-diazabicyclo[5.4.0]undec-7-ene, sodium tert-butoxide, potassium tert-butoxide, cesium carbonate, potassium phosphate, sodium hydroxide, N,N-diisopropylethylamine, and triethylamine. In some embodiments, the base is pyridine.

[0081] In some embodiments, the compound of Formula (II-E), the compound of Formula (II-F), and the base are Within two hours, At temperatures between approximately 20°C and 25°C, It is stirred.

[0082] In some embodiments, the process further comprises precipitating the compound of formula (II-B) and isolating it by filtration.

[0083] In some embodiments, the process provides the compound of formula (II-B) in greater than about 80% synthetic yield.

[0084] In some embodiments, a compound of formula (II-F)

[0085] [ka] is a compound of formula (II-G) in the presence of a solvent.

[0086] [ka] It is synthesized by reacting with an acyl halide preparative agent.

[0087] In some embodiments, the acyl halide modifier is selected from oxalyl chloride, thionyl chloride, phosphoryl chloride, phosphorus trichloride, phosphorus pentachloride, phosgene, diphosgene, triphosgene, and cyanuric chloride. In some embodiments, the acyl halide modifier is oxalyl chloride.

[0088] In some embodiments, the solvent is selected from water, ethyl acetate, dichloromethane, tetrahydrofuran, diethyl ether, dimethylformamide, dimethyl sulfoxide, methanol, ethanol, acetone, acetonitrile, 1,4-dioxane, hexane, and methyl tert-butyl ether. In some embodiments, the solvent is tetrahydrofuran.

[0089] In some embodiments, the compound of Formula (II-G), the acyl halide adjusting agent, and the solvent are Within 16 hours, At temperatures between approximately 20°C and 25°C, It is stirred.

[0090] Incorporation by Reference All publications, patents, and patent applications mentioned in this specification are herein incorporated by reference to the same extent as if each individual publication, patent, or patent application was specifically and individually indicated to be incorporated by reference. DETAILED DESCRIPTION OF THE INVENTION

[0091] definition Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood in the field to which the claimed subject matter belongs.If there are multiple definitions for terms in this specification, the definition in this section shall prevail.Patents, patent applications, publications, and published nucleotide and amino acid sequences (for example, sequences available in GenBank or other databases) mentioned in this specification are incorporated by reference.When referring to a URL or other such identifier or address, it is understood that such identifiers may change and specific information on the Internet may change, but equivalent information can be found by searching the Internet.Reference thereto evidences the availability and public dissemination of such information.

[0092] It is to be understood that the foregoing general description and the following detailed description are exemplary and explanatory only and are not restrictive of any claimed subject matter. In this application, the use of the singular includes the plural unless specifically stated otherwise. It must be noted that as used in this specification and the appended claims, the singular forms "a," "an," and "the" include plural referents unless the context clearly dictates otherwise. In this application, the use of "or" means "and / or" unless specifically stated otherwise. Furthermore, the use of the term "including," as well as other forms such as "include," "includes," and "included," is not limiting.

[0093] The section headings used herein are for organizational purposes only and are not to be construed as limiting the subject matter described.

[0094] Definitions of standard chemical terms can be found in references including, but not limited to, Carey and Sundberg, "ADVANCED ORGANIC CHEMISTRY 4TH ED.", A(2000) and B(2001), Plenum Press, New York. Unless otherwise indicated, conventional methods of mass spectroscopy, NMR, HPLC, protein chemistry, biochemistry, recombinant DNA techniques and pharmacology, within the skill of the art, are used.

[0095] The term "CRAC channel inhibitors" refers to specific plasma membrane Ca channels that slowly replenish reduced calcium levels in the endoplasmic reticulum. 2+ It refers to an inhibitor that suppresses the calcium release-activated channel (CRAC), an ion channel.

[0096] The terms "inhibits," "inhibiting," or "inhibitor" of CRAC channel activity, as used herein, refer to the inhibition of store-operated calcium channel activity or calcium release-activated calcium channel activity.

[0097] As used herein, C1-C X are C1~C2, C1~C3...C1~C x Includes C1~C x refers to the number of carbon atoms that make up the moiety it represents (excluding optional substituents).

[0098] An "alkyl" group refers to an aliphatic hydrocarbon group. The alkyl group may or may not contain unsaturated units. The alkyl moiety may be a "saturated alkyl" group, which means that the alkyl moiety does not contain any unsaturated units (i.e., carbon-carbon double bonds or carbon-carbon triple bonds). The alkyl group may also be an "unsaturated alkyl" moiety, which means that the alkyl group contains at least one unsaturated unit. The alkyl moiety, whether saturated or unsaturated, may be branched, linear, or cyclic.

[0099] An "alkyl" group can have 1 to 6 carbon atoms (wherever an "alkyl" group appears herein, a numerical range such as "1 to 6" refers to each integer in the given range; for example, "1 to 6 carbon atoms" means that the alkyl group can consist of 1 carbon atom, 2 carbon atoms, 3 carbon atoms, etc., up to and including 6 carbon atoms, although the definition herein also encompasses appearances of the term "alkyl" without a specified numerical range). The alkyl group of the compounds described herein can be represented as "C1-C6 alkyl" or similar designations. By way of example only, "C1-C6 alkyl" indicates that there are 1 to 6 carbon atoms in the alkyl chain, i.e., the alkyl chain is selected from the group consisting of methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, t-butyl, n-pentyl, isopentyl, neopentyl, hexyl, propen-3-yl (allyl), cyclopropylmethyl, cyclobutylmethyl, cyclopentylmethyl, and cyclohexylmethyl. Alkyl groups can be substituted or unsubstituted. Depending on the structure, alkyl groups can be monoradicals or diradicals (i.e., alkylene groups).

[0100] The term "alkenyl" refers to a type of alkyl group in which the first two atoms of the alkyl group form a double bond that is not part of an aromatic group. That is, an alkenyl group begins with the atom -C(R)=CR, where R refers to the remainder of the alkenyl group, which may be the same or different. Non-limiting examples of alkenyl groups include -CH=CH, -C(CH)=CH, -CH=CHCH, -CH=C(CH), and -C(CH)=CHCH. The alkenyl moiety may be branched, straight-chained, or cyclic (in which case it is also known as a "cycloalkenyl" group). Alkenyl groups can have 2 to 6 carbons. Alkenyl groups can be substituted or unsubstituted. Depending on the structure, alkenyl groups can be monoradicals or diradicals (i.e., alkenylene groups).

[0101] The term "alkynyl" refers to a type of alkyl group in which the first two atoms of the alkyl group form a triple bond. That is, an alkynyl group begins with the atom -C≡CR, where R refers to the remainder of the alkynyl group. Non-limiting examples of alkynyl groups include -C≡CH, -C≡CCH3, -C≡CCH2CH3, and -C≡CCH2CH2CH3. The "R" portion of the alkynyl moiety can be branched, straight-chain, or cyclic. Alkynyl groups can have 2 to 6 carbons. Alkynyl groups can be substituted or unsubstituted. Depending on the structure, alkynyl groups can be monoradicals or diradicals (i.e., alkynylene groups).

[0102] "Carbocycle" refers to a saturated, unsaturated, or aromatic ring in which each atom of the ring is carbon. Carbocycles can be monocyclic or polycyclic and can include 3- to 10-membered monocyclic rings, 6- to 12-membered bicyclic rings, and 6- to 12-membered bridged rings. Each ring in a bicyclic carbocycle can be selected from saturated, unsaturated, and aromatic rings. In some embodiments, a carbocycle is aryl. In some embodiments, a carbocycle is cycloalkyl. In some embodiments, a carbocycle is cycloalkenyl. In exemplary embodiments, an aromatic ring, such as phenyl, can be fused to a saturated or unsaturated ring, such as cyclohexane, cyclopentane, or cyclohexene. Where valence permits, any combination of saturated, unsaturated, and aromatic bicyclic rings is included in the definition of carbocycle. Exemplary carbocycles include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclohexenyl, adamantyl, phenyl, indanyl, and naphthyl. Unless stated otherwise specifically in the specification, carbocycles are optionally substituted with one or more substituents such as those substituents described herein.

[0103] The term "halo" or alternatively "halogen" means fluoro, chloro, bromo and iodo.

[0104] The compounds disclosed herein may, in some embodiments, be, for example, 2 H, 3 H, 11 C. 13 C and / or 14 The compound described herein is used with various enriched isotopes, which are rich in C content. In a specific embodiment, the compound described herein is deuterated at at least one position. Such deuterated forms can be prepared by the procedures described in U.S. Patent Nos. 5,846,514 and 6,334,997. As described in U.S. Patent Nos. 5,846,514 and 6,334,997, deuteration can improve metabolic stability and / or efficacy, thereby increasing the duration of action of the drug.

[0105] Unless otherwise stated, structures depicted herein are also meant to include compounds which differ only in the presence of one or more isotopically enriched atoms. For example, the replacement of hydrogen by deuterium or tritium, or 13 C or 14 Compounds having the presented structure, except for the replacement of a carbon with a C-rich carbon, are within the scope of this disclosure.

[0106] The compounds of the present disclosure optionally contain unnatural proportions of atomic isotopes at one or more of the atoms that constitute such compounds. For example, the compounds may contain deuterium ( 2 H), tritium ( 3 H), iodine-125( 125 I) or carbon-14 ( 14 It may be labeled with an isotope such as C. 2 H, 11 C. 13 C. 14 C. 15 C. 12 N, 13 N, 15 N, 16 N, 16 O. 17 O. 14 F, 15 F, 16 F, 17 F, 18 F, 33 S, 34 S, 35 S, 36 S, 35 Cl, 37 Cl, 79 Br, 81 Br, 125 All isotopic substitutions with I are contemplated. All isotopic variations of the compounds described herein, whether radioactive or not, are encompassed within the scope of the present disclosure.

[0107] In certain embodiments, the compounds disclosed herein comprise: 1 Some or all of the H atoms 2The deuterium atoms are replaced by H atoms. Methods for synthesizing deuterium-containing compounds are known in the art and include, by way of non-limiting example only, the following synthetic methods:

[0108] Deuterium-substituted compounds are synthesized using a variety of methods, such as those described in Dean, Dennis C.; ed., Recent Advances in the Synthesis and Applications of Radiolabeled Compounds for Drug Discovery and Development. [In: Curr., Pharm. Des., 2000;6(10)] 2000, 110; George W.; Varma, Rajender S., The Synthesis of Radiolabeled Compounds via Organometallic Intermediates, Tetrahedron, 1989, 45(21), 6601-21; and Evans, E. Anthony. Synthesis of radiolabeled compounds, J. Radioanal. Chem., 1981, 64(1-2), 9-32.

[0109] Deuterated starting materials are readily available and, when subjected to the synthetic methods described herein, result in the synthesis of deuterated compounds. Many deuterated reagents and building blocks are commercially available from chemical suppliers such as Aldrich Chemical Co.

[0110] Deuterium transfer reagents suitable for use in nucleophilic substitution reactions, such as iodomethane-d3 (CD3I), are readily available and can be used to transfer a deuterated carbon atom to a reaction substrate under nucleophilic substitution reaction conditions. The use of CD3I is illustrated, by way of example only, in the following reaction scheme.

[0111] [ka]

[0112] A deuterium transfer reagent, such as lithium aluminum deuteride (LiAlD4), is used to transfer deuterium to the reaction substrate under reducing conditions. The use of LiAlD4 is illustrated in the following reaction scheme, by way of example only.

[0113] [ka]

[0114] As illustrated by way of example only in the reaction scheme below, deuterium gas and a palladium catalyst are used to reduce unsaturated carbon-carbon linkages and to effect reductive displacement of aryl carbon-halogen bonds.

[0115] [ka]

[0116] The term "non-polar solvent" refers to a solvent that does not have a large electric dipole moment. As used herein, examples of "non-polar solvents" include, but are not limited to, pentane, cyclopentane, hexane, cyclohexane, benzene, carbon tetrachloride, toluene, 1,4-dioxane, diethyl ether, and chloroform.

[0117] The term "aprotic polar solvent" refers to a solvent that lacks an acidic hydrogen atom. Essentially, an "aprotic polar solvent" is a solvent that lacks an acidic hydrogen atom. N They do not promote hydrogen bonding interactions that favor type 2 reactions. Examples of "polar aprotic solvents," as used herein, include, but are not limited to, chloroform, N-methylpyrrolidone, tetrahydrofuran, ethyl acetate, acetone, dimethylformamide, acetonitrile, dimethyl sulfoxide, propylene carbonate, and dichloromethane.

[0118] The term "protic polar solvent" refers to a solvent that has labile or acidic hydrogen atoms. "Protic polar solvents" promote hydrogen bonding interactions. Examples of "polar aprotic solvents," as used herein, include, but are not limited to, water, acetic acid, formic acid, methanol, ethanol, n-propanol, and t-butanol.

[0119] The term "acid" refers to a molecule having a dissociable hydrogen atom or an acidic hydrogen atom. Examples of "acid" as used herein include, but are not limited to, trifluoroacetic acid, 2,2,2-trifluoroethanol, sulfuric acid, nitric acid, hydrofluoric acid, hydrobromic acid, hydroiodic acid, trifluoromethanesulfonic acid, perchloric acid, phosphoric acid, chloric acid, methanesulfonic acid, p-toluenesulfonic acid, acetic acid, formic acid, and hydrochloric acid.

[0120] The term "base" refers to a molecule that can abstract a hydrogen atom from another molecule. Examples of "bases" as used herein include, but are not limited to, lithium hydroxide, sodium hydroxide, potassium hydroxide, ammonium hydroxide, potassium acetate, sodium acetate, tripotassium phosphate, sodium butoxide, potassium butoxide, sodium carbonate, potassium carbonate, cesium carbonate, sodium bicarbonate, potassium bicarbonate, calcium hydroxide, and triethylamine.

[0121] The term "coupling reaction" refers to a chemical reaction in which two fragments are brought together by a metal catalyst, "catalyst," or "coupling catalyst." Examples of "coupling reactions," as used herein, include, but are not limited to, Suzuki, Negishi, Stille, or Liebeskind-Srogl coupling reactions. Examples of "coupling catalysts," as used herein, include, but are not limited to, catalysts derived from copper, palladium, nickel, or iron. The term "palladium-based catalyst" refers to a palladium-derived coupling catalyst used in a coupling reaction. "Palladium-based catalysts," as used herein, include, but are not limited to, Pd(PPh3)4, Pd(OAc)2, Pd(dppf)Cl2, Pd(dtpbf)Cl2, Pd(dba)2, Pd(PCy3)2, Pd(dppe)Cl2, Pd(t-Bu3P)2, PdCl2[P(o-Tol)3]2, benzylbis(triphenylphosphine)palladium(II) chloride, (A-Phos)2Cl2Pd, Na2PdCl4, and PdCl2(PPh3)4.

[0122] The term "brominating agent" refers to a chemical reagent typically used to add a bromine atom to an organic reactant. Examples of "brominating agents," as used herein, include, but are not limited to, bromine, bromine 1,4-dioxane complex, bromotrichloromethane, 1,2-dibromo-1,1,2,2-tetrachloroethane, carbon tetrabromide, tetrabutylammonium tribromide, trimethylphenylammonium tribromide, benzyltrimethylammonium tribromide, pyridinium bromide perbromide, 4-dimethylaminopyridinium bromide perbromide, 1-butyl-3-methylimidazolium tribromide, 1,8-diazabicyclo[5.4.0]-7-undecene trihydrobromide, N-bromo Included are succinimide, N-bromophthalimide, N-bromosaccharin, N-bromoacetamide, 2-bromo-2 cyano-N,N-dimethylacetamide, 1,3-dibromo-5,5-dimethylhydantoin, dibromoisocyanuric acid, bromoisocyanuric acid monosodium hydrate, boron tribromide, phosphorus tribromide, bromodimethylsulfonium bromide, 5,5-dibromoMeldrum's acid, 2,4,4,6-tetrabromo-2,5-cyclohexadienone, bis(2,4,6-trimethylpyridine)-bromonium hexafluorophosphate, and trimethylsilyl bromide.

[0123] The term "boronating agent" generally refers to a chemical reagent used to impart boron-containing functional groups to an organic reactant. Examples of "boronating agents," as used herein, include, but are not limited to, tetrahydroxydiboron, catecholborane, 4,4,5,5-tetramethyl-1,3,2-dioxaborolane, 4,6,6-trimethyl-1,3,2-dioxaborinane, diisopropylamineborane, bis(neopentylglycolato)diboron, bis(catecholato)diboron, bis(hexyleneglycolato)diboron, bis(pinacolato)diboron, bis[(pinacolato)boryl]methane, 4 -(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5-(trifluoromethyl)-1-(triisopropylsilyl)-1H-pyrrolo[2,3-b]pyridine, HB(trip)2, 2-isopropoxy-4,4,5,5-tetramethyl-1,3,2-dioxaborolane, 2-methoxy-4,4,5,5-tetramethyl-1,3,2-dioxaborolane, and 2-ethoxy-4,4,5,5-tetramethyl-1,3,2-dioxaborolane.

[0124] The term "acyl halide preparing agent" refers to a chemical reagent typically used to impart an acyl halide functional group to an organic reactant. Examples of "acyl halide preparing agents" as used herein include, but are not limited to, oxalyl chloride, thionyl chloride, phosphoryl chloride, phosphorus trichloride, phosphorus pentachloride, phosgene, diphosgene, triphosgene, and cyanuric chloride.

[0125] The compounds described herein may be formed as and / or used as pharmaceutically acceptable salts. Types of pharmaceutically acceptable salts include, but are not limited to: (1) salts of a compound in free base form with a pharmaceutically acceptable inorganic acid (e.g., hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, metaphosphoric acid, etc.); or organic acid (e.g., acetic acid, propionic acid, hexanoic acid, cyclopentanepropionic acid, glycolic acid, pyruvic acid, lactic acid, malonic acid, succinic acid, malic acid, maleic acid, fumaric acid, trifluoroacetic acid, tartaric acid, citric acid, benzoic acid, 3-(4-hydroxybenzoyl)benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, 1,2-ethanedisulfonic acid, 2-hydroxyethanesulfonic acid, benzenesulfonic acid, toluenesulfonic acid, 2-naphthalenesulfonic acid, 4-methylbicyclo[2.2 (2) acid addition salts formed by reacting an acidic proton present in the parent compound with a metal ion, such as an alkali metal ion (e.g., lithium, sodium, potassium), an alkaline earth ion (e.g., magnesium or calcium), or an aluminum ion; (3) acid addition salts formed by reacting an acidic proton present in the parent compound with an acidic acid such as oct-2-ene-1-carboxylic acid, glucoheptonic acid, 4,4'-methylenebis-(3-hydroxy-2-ene-1-carboxylic acid), 3-phenylpropionic acid, trimethylacetic acid, tertiary butylacetic acid, lauryl sulfuric acid, gluconic acid, glutamic acid, hydroxynaphthoic acid, salicylic acid, stearic acid, muconic acid, butyric acid, phenylacetic acid, phenylbutyric acid, valproic acid, etc.; (4) salts formed when an acidic proton present in the parent compound is replaced with a metal ion, such as an alkali metal ion (e.g., lithium, sodium, potassium), an alkaline earth ion (e.g., magnesium or calcium), or an aluminum ion. In some cases, the compounds described herein may form coordination complexes with organic bases, such as, but not limited to, ethanolamine, diethanolamine, triethanolamine, tromethamine, N-methylglucamine, dicyclohexylamine, and tris(hydroxymethyl)methylamine. In other cases, the compounds described herein may form salts with amino acids such as, but not limited to, arginine, lysine, etc. Acceptable inorganic bases used to form salts with compounds containing acidic protons include, but are not limited to, aluminum hydroxide, calcium hydroxide, potassium hydroxide, sodium carbonate, sodium hydroxide, and the like.

[0126] When referring to pharmaceutically acceptable salts, it should be understood to include solvent addition forms or crystalline forms thereof, particularly solvates or polymorphs.Solvates contain either stoichiometric or non-stoichiometric amounts of solvent and can be formed during the crystallization process with pharmaceutically acceptable solvents such as water, ethanol, etc.Hydrates are formed when the solvent is water, or alcoholates are formed when the solvent is alcohol.Solvates of the compounds described herein can be conveniently prepared or formed during the processes described herein.In addition, the compounds provided herein can exist in unsolvated and solvated forms.In general, solvated forms are considered equivalent to unsolvated forms in the compounds and methods provided herein.

[0127] Furthermore, the compounds described herein include crystalline forms, also known as polymorphs. Polymorphs include different crystal packing arrangements of the same elemental composition of a compound. Polymorphs typically have different X-ray diffraction patterns, melting points, densities, hardnesses, crystal shapes, optical properties, stability, and solubility. Various factors, such as recrystallization solvents, crystallization rates, and storage temperatures, can result in the predominance of a single crystalline form.

[0128] The synthetic method disclosed herein is a method for producing CRAC channel inhibitors.In some embodiments, this method produces kilogram amounts.This method can improve previous synthetic routes by eliminating the existence of multiple undesired impurities.

[0129] Improved process for synthesizing CRAC channel inhibitors Provided herein is a process useful for preparing CRAC channel inhibitors and their intermediates.In particular, provided herein is a process and method for producing N-(5-(6-chloro-2,2-difluorobenzo[d][1,3]dioxol-5-yl)pyrazin-2-yl)-2-fluoro-6-methylbenzamide (compound 3.1) or its pharmaceutically acceptable salt, as shown in Scheme 1.

[0130] [ka]

[0131] In some embodiments, the present process provides an improvement over previously disclosed processes. In some embodiments, the process of the present disclosure, shown in Scheme 1, provides an improvement over the process disclosed in PCT / US2020 / 031506, shown in Scheme 2.

[0132] [ka]

[0133] The disclosed process affords compound 3.1 from compounds 1.1 and 2.1 in six synthetic steps, as opposed to the seven steps required for the process of PCT / US2020 / 031506. The fewer total steps results in reduced solvent usage and minimized waste and environmental impact. In particular, the disclosed process avoids several solvents and reagents of concern, such as dichloromethane.

[0134] In the process of PCT / US2020 / 031506, the preparation of compound 2.2 from compound 2.1 was subjected to over-bromination, resulting in a dibrominated impurity. Therefore, this process yielded compound 2.2 in 75% yield and 87% purity. In contrast, the process of the present disclosure yields compound 2.2 in 82% yield and 97% purity, avoiding the production of the dibrominated impurity. Furthermore, this process is completed in 12 hours, as opposed to the 3-day reaction time required for the process of PCT / US2020 / 031506.

[0135] In the process of PCT / US2020 / 031506, the preparation of boronated Suzuki coupling partner compound 4.3 required wasteful protection and deprotection schemes, resulting in the production of dehalogenated impurities. In contrast, the process of the present disclosure avoids the production of dehalogenated impurities while simultaneously providing boronated Suzuki coupling partner compound 2.3. This improvement significantly simplified the purification of compound 3.1, resulting in the acquisition of compound 3.1 in quantitative purity.

[0136] Additionally, the disclosed process avoids the use of highly undesirable reagents such as trifluoroacetic acid, further minimizing the environmental impact of the disclosed process. Additionally, the disclosed process does not require column chromatography, thus avoiding the use of silica gel.

[0137] In some embodiments, the processes described herein provide compound 3.1 in higher overall yield (e.g., 45% overall yield compared to 33% overall yield for the process of PCT / US2020 / 031506).

[0138] In one embodiment, a CRAC channel inhibitor of formula (I):

[0139] [ka] (In the formula, R 1 , R 2 and R3 is hydrogen, halogen and C1-C3 alkyl (hydrogen, halogen, -OH, -OR 4 , -CN, -N(R 4 independently selected at each occurrence from -N,N-,N-dimethylformamide, - ... or two R's 1 groups, together with the atoms to which they are attached, form a carbocyclic ring; n is 0, 1, 2 or 3; m is 0, 1, 2, 3, 4 or 5; R 4 is hydrogen; and C 1~6 Alkyl, C 2~6 Alkenyl and C 2~6 alkynyl (each independently selected at each occurrence from halogen, —CN, —NO 2 , —OH, —NH 2 and —OCH 3 ) or a pharmaceutically acceptable salt thereof.

[0140] In another embodiment, CRAC channel inhibitors of formula (IA), (IB), (IC), (ID), (IE), (IF) and (IG):

[0141] [ka] or a salt of any one thereof.

[0142] In certain embodiments, with respect to a compound or salt of any one of Formulas (I), (IA), (IB), (IC), (ID), (IE), (IF), and (IG), R 1 , R 2 and R 3 is hydrogen, halogen and C1-C3 alkyl (hydrogen, halogen, -OH, -OR 4 , -CN, -N(R 4)2 and —NO2), each occurrence independently selected from —N—, ...

[0143] In certain embodiments, with respect to a compound or salt of any one of Formulas (I), (IA), (IB), (IC), and (ID), n is 0, 1, 2, or 3. In certain embodiments, with respect to a compound or salt of any one of Formulas (I), (IA), (IB), (IC), and (ID), n is 0, 1, or 2. In certain embodiments, with respect to a compound or salt of any one of Formulas (I), (IA), (IB), (IC), and (ID), n is 0 or 1. In certain embodiments, with respect to a compound or salt of any one of Formulas (I), (IA), (IB), (IC), and (ID), n is 1.

[0144] In certain embodiments, with respect to a compound or salt of any one of Formulas (I), (IA), and (IB), m is 0, 1, 2, 3, or 4. In certain embodiments, with respect to a compound or salt of any one of Formulas (I), (IA), and (IB), m is 0, 1, 2, or 3. In certain embodiments, with respect to a compound or salt of any one of Formulas (I), (IA), and (IB), m is 0, 1, or 2. In certain embodiments, with respect to a compound or salt of any one of Formulas (I), (IA), and (IB), m is 2.

[0145] In certain embodiments, with respect to a compound or salt of any one of Formulas (I), (IA), (IB), (IC), (ID), (IE), (IF), and (IG), R 4 is hydrogen; and C 1~6 Alkyl, C 2~6 Alkenyl and C 2~6 and each occurrence is independently selected from alkynyl, each of which may be optionally substituted at each occurrence with halogen, -CN, -NO2, -OH, -NH2, and -OCH3.

[0146] In another aspect, there is provided a process for synthesizing CRAC channel inhibitors of formula (I), (IA), (IB), (IC), (ID), (IE), (IF) and (IG), comprising: In the presence of a base, a catalyst and a solvent, a compound of formula (IA)

[0147] [ka] with a compound of formula (IB)

[0148] [ka] (In the formula, X is -B(OH)2, -BF3K

[0149] [ka] is selected from Y is selected from Cl, Br and I. Provided herein is a process comprising reacting

[0150] In some embodiments, X is -B(OH), -BF,

[0151] [ka] In some embodiments, X is selected from: In some embodiments, X is -B(OH)2. In some embodiments, X is -BF3K. In some embodiments, X is

[0152] [ka] In some embodiments, X is

[0153] [ka] In some embodiments, X is

[0154] [ka] is.

[0155] In some embodiments, Y is selected from Cl, Br, and I. In some embodiments, Y is Cl. In some embodiments, Y is Br. In some embodiments, Y is I.

[0156] In some embodiments, the base is selected from the group consisting of potassium carbonate, sodium carbonate, potassium bicarbonate, sodium bicarbonate, piperidine, pyridine, 1,8-diazabicyclo[5.4.0]undec-7-ene, sodium tert-butoxide, potassium tert-butoxide, cesium carbonate, potassium phosphate, sodium hydroxide, N,N-diisopropylethylamine, and triethylamine. In some embodiments, the base is potassium carbonate. In some embodiments, the base is sodium carbonate. In some embodiments, the base is potassium bicarbonate. In some embodiments, the base is sodium bicarbonate. In some embodiments, the base is piperidine. In some embodiments, the base is pyridine. In some embodiments, the base is 1,8-diazabicyclo[5.4.0]undec-7-ene. In some embodiments, the base is sodium tert-butoxide. In some embodiments, the base is potassium tert-butoxide. In some embodiments, the base is cesium carbonate. In some embodiments, the base is potassium phosphate. In some embodiments, the base is sodium hydroxide. In some embodiments, the base is N,N-diisopropylethylamine. In some embodiments, the base is triethylamine.

[0157] In some embodiments, the catalyst is selected from Pd(acac)2, [Pd(allyl)Cl]2, Pd(MeCN)2Cl2, Pd(dba)2, Pd(TFA)2, Pd2(dba)3, Pd2(dba)3·CHCl3, Pd(PPh3)4, Pd(OAc)2, Pd(PCy3)2Cl2, Pd(PPh3)2Cl2, Pd[P(o-tol)3]2Cl2, Pd(amphos)Cl2, Pd(dppf)Cl2, Pd(dppf)Cl2·CH2Cl2, Pd(dtbpf)Cl2, Pd(MeCN)4(BF4), PdCl2, XPhos-Pd-G3, Pd-PEPPSI™-IPr, Pd-PEPPSI™-SIPr, and Pd-PEPPSI™-IPent. In some embodiments, the catalyst is Pd(acac)2. In some embodiments, the catalyst is [Pd(allyl)Cl]2. In some embodiments, the catalyst is Pd(MeCN)2Cl2. In some embodiments, the catalyst is Pd(dba)2. In some embodiments, the catalyst is Pd(TFA)2. In some embodiments, the catalyst is Pd2(dba)3. In some embodiments, the catalyst is Pd2(dba)3·CHCl3. In some embodiments, the catalyst is Pd(PPh3)4. In some embodiments, the catalyst is Pd(OAc)2. In some embodiments, the catalyst is Pd(PCy3)2Cl2. In some embodiments, the catalyst is Pd(PPh3)2Cl2. In some embodiments, the catalyst is Pd[P(o-tol)3]2Cl2. In some embodiments, the catalyst is Pd(amphos)Cl2. In some embodiments, the catalyst is Pd(dppf)Cl2. In some embodiments, the catalyst is Pd(dppf)Cl2·CH2Cl2. In some embodiments, the catalyst is Pd(dtbpf)Cl2. In some embodiments, the catalyst is Pd(MeCN)4(BF4)2. In some embodiments, the catalyst is PdCl2. In some embodiments, the catalyst is XPhos-Pd-G3. In some embodiments, the catalyst is Pd-PEPPSI™-IPr. In some embodiments, the catalyst is Pd-PEPPSI™-SIPr. In some embodiments, the catalyst is Pd-PEPPSI™-IPent.

[0158] In some embodiments, the solvent is selected from water, ethyl acetate, dichloromethane, tetrahydrofuran, diethyl ether, dimethylformamide, dimethyl sulfoxide, methanol, ethanol, acetone, acetonitrile, 1,4-dioxane, hexane, and methyl tert-butyl ether. In some embodiments, the solvent is water. In some embodiments, the solvent is ethyl acetate. In some embodiments, the solvent is dichloromethane. In some embodiments, the solvent is tetrahydrofuran. In some embodiments, the solvent is diethyl ether. In some embodiments, the solvent is dimethylformamide. In some embodiments, the solvent is dimethyl sulfoxide. In some embodiments, the solvent is methanol. In some embodiments, the solvent is ethanol. In some embodiments, the solvent is acetone. In some embodiments, the solvent is acetonitrile. In some embodiments, the solvent is 1,4-dioxane. In some embodiments, the solvent is hexane. In some embodiments, the solvent includes methyl tert-butyl ether.

[0159] In some embodiments, the compound of Formula (IA), the compound of Formula (IB), the base, the catalyst, and the solvent are Within 16 hours, At temperatures between about 75°C and about 80°C, It is stirred.

[0160] In some embodiments, the process further comprises precipitating the compound of formula (I) and isolating it by filtration.

[0161] In some embodiments, the process provides the compound of formula (I) in a synthetic yield of greater than about 60%. In some embodiments, the process provides the compound of formula (I) in a synthetic yield of greater than about 65%. In some embodiments, the process provides the compound of formula (I) in a synthetic yield of greater than about 70%. In some embodiments, the process provides the compound of formula (I) in a synthetic yield of greater than about 75%. In some embodiments, the process provides the compound of formula (I) in a synthetic yield of greater than about 80%.

[0162] In some embodiments, the compound of formula (IA)

[0163] [ka] is a compound of formula (IC) in the presence of a base and a solvent

[0164] [ka] It is synthesized by reacting with a boronating agent.

[0165] In some embodiments, the boronating agent is selected from 2-isopropoxy-4,4,5,5-tetramethyl-1,3,2-dioxaborolane, 2-methoxy-4,4,5,5-tetramethyl-1,3,2-dioxaborolane, and 2-ethoxy-4,4,5,5-tetramethyl-1,3,2-dioxaborolane. In some embodiments, the boronating agent is 2-isopropoxy-4,4,5,5-tetramethyl-1,3,2-dioxaborolane. In some embodiments, the boronating agent is 2-methoxy-4,4,5,5-tetramethyl-1,3,2-dioxaborolane. In some embodiments, the boronating agent is 2-ethoxy-4,4,5,5-tetramethyl-1,3,2-dioxaborolane.

[0166] In some embodiments, the base is selected from isopropylmagnesium chloride, isopropylmagnesium lithium chloride, methylmagnesium bromide, methylmagnesium chloride, methylmagnesium iodide, ethylmagnesium chloride, ethylmagnesium bromide, isopropylmagnesium bromide, methyllithium, ethyllithium, isopropyllithium, n-butyllithium, and tert-butyllithium. In some embodiments, the base is isopropylmagnesium chloride. In some embodiments, the base is isopropylmagnesium lithium chloride. In some embodiments, the base is methylmagnesium bromide. In some embodiments, the base is methylmagnesium chloride. In some embodiments, the base is methylmagnesium iodide. In some embodiments, the base is ethylmagnesium chloride. In some embodiments, the base is ethylmagnesium bromide. In some embodiments, the base is isopropylmagnesium bromide. In some embodiments, the base is methyllithium. In some embodiments, the base is ethyllithium. In some embodiments, the base is isopropyllithium. In some embodiments, the base is n-butyllithium. In some embodiments, the base is tert-butyllithium.

[0167] In some embodiments, the solvent is selected from water, ethyl acetate, dichloromethane, tetrahydrofuran, diethyl ether, dimethylformamide, dimethyl sulfoxide, methanol, ethanol, acetone, acetonitrile, 1,4-dioxane, hexane, and methyl tert-butyl ether. In some embodiments, the solvent is water. In some embodiments, the solvent is ethyl acetate. In some embodiments, the solvent is dichloromethane. In some embodiments, the solvent is tetrahydrofuran. In some embodiments, the solvent is diethyl ether. In some embodiments, the solvent is dimethylformamide. In some embodiments, the solvent is dimethyl sulfoxide. In some embodiments, the solvent is methanol. In some embodiments, the solvent is ethanol. In some embodiments, the solvent is acetone. In some embodiments, the solvent is acetonitrile. In some embodiments, the solvent is 1,4-dioxane. In some embodiments, the solvent is hexane. In some embodiments, the solvent includes methyl tert-butyl ether.

[0168] In some embodiments, the compound of Formula (IC), the boronating agent, the base, and the solvent are Within two hours, At temperatures between approximately 0°C and approximately 25°C, It is stirred.

[0169] In some embodiments, the process further comprises precipitating the compound of formula (IA) and isolating it by filtration.

[0170] In some embodiments, the process provides a compound of formula (IA) in a synthetic yield of greater than about 60%. In some embodiments, the process provides a compound of formula (IA) in a synthetic yield of greater than about 65%. In some embodiments, the process provides a compound of formula (IA) in a synthetic yield of greater than about 70%. In some embodiments, the process provides a compound of formula (IA) in a synthetic yield of greater than about 75%.

[0171] In some embodiments, a compound of formula (IC)

[0172] [ka] is a compound of formula (ID) in the presence of an acid and a solvent

[0173] [ka] It is synthesized by reacting with a brominating agent.

[0174] In some embodiments, the brominating agent is selected from N-bromosuccinimide, tribromoisocyanuric acid, 1,3-dibromo-5,5-dimethylhydantoin, and bromine. In some embodiments, the brominating agent is N-bromosuccinimide. In some embodiments, the brominating agent is tribromoisocyanuric acid. In some embodiments, the brominating agent is 1,3-dibromo-5,5-dimethylhydantoin. In some embodiments, the brominating agent is bromine.

[0175] In some embodiments, the acid is selected from hydrochloric acid, sulfuric acid, nitric acid, acetic acid, hydrobromic acid, phosphoric acid, formic acid, and trifluoroacetic acid. In some embodiments, the acid is hydrochloric acid. In some embodiments, the acid is sulfuric acid. In some embodiments, the acid is nitric acid. In some embodiments, the acid is acetic acid. In some embodiments, the acid is hydrobromic acid. In some embodiments, the acid is phosphoric acid. In some embodiments, the acid is formic acid. In some embodiments, the acid is trifluoroacetic acid.

[0176] In some embodiments, the solvent is selected from water, ethyl acetate, dichloromethane, tetrahydrofuran, diethyl ether, dimethylformamide, dimethyl sulfoxide, methanol, ethanol, acetone, acetonitrile, 1,4-dioxane, hexane, and methyl tert-butyl ether. In some embodiments, the solvent is water. In some embodiments, the solvent is ethyl acetate. In some embodiments, the solvent is dichloromethane. In some embodiments, the solvent is tetrahydrofuran. In some embodiments, the solvent is diethyl ether. In some embodiments, the solvent is dimethylformamide. In some embodiments, the solvent is dimethyl sulfoxide. In some embodiments, the solvent is methanol. In some embodiments, the solvent is ethanol. In some embodiments, the solvent is acetone. In some embodiments, the solvent is acetonitrile. In some embodiments, the solvent is 1,4-dioxane. In some embodiments, the solvent is hexane. In some embodiments, the solvent includes methyl tert-butyl ether.

[0177] In some embodiments, the compound of Formula (ID), the brominating agent, the acid, and the solvent are Within 12 hours, At temperatures between approximately 0°C and approximately 15°C, It is stirred.

[0178] In some embodiments, the process further comprises extracting the compound of formula (IC) and isolating it by concentration.

[0179] In some embodiments, the process provides a compound of formula (IC) in a synthetic yield of greater than about 70%. In some embodiments, the process provides a compound of formula (IC) in a synthetic yield of greater than about 75%. In some embodiments, the process provides a compound of formula (IC) in a synthetic yield of greater than about 80%. In some embodiments, the process provides a compound of formula (IC) in a synthetic yield of greater than about 85%.

[0180] In some embodiments, a compound of formula (IB)

[0181] [ka] is a compound of formula (IE) in the presence of a base

[0182] [ka] with a compound of formula (IF)

[0183] [ka] (In the formula, Z is selected from Cl, Br and I. It is synthesized by reacting with

[0184] In some embodiments, Z is selected from Cl, Br, and I. In some embodiments, Z is Cl. In some embodiments, Z is Br. In some embodiments, Z is I.

[0185] In some embodiments, the base is selected from the group consisting of potassium carbonate, sodium carbonate, potassium bicarbonate, sodium bicarbonate, piperidine, pyridine, 1,8-diazabicyclo[5.4.0]undec-7-ene, sodium tert-butoxide, potassium tert-butoxide, cesium carbonate, potassium phosphate, sodium hydroxide, N,N-diisopropylethylamine, and triethylamine. In some embodiments, the base is potassium carbonate. In some embodiments, the base is sodium carbonate. In some embodiments, the base is potassium bicarbonate. In some embodiments, the base is sodium bicarbonate. In some embodiments, the base is piperidine. In some embodiments, the base is pyridine. In some embodiments, the base is 1,8-diazabicyclo[5.4.0]undec-7-ene. In some embodiments, the base is sodium tert-butoxide. In some embodiments, the base is potassium tert-butoxide. In some embodiments, the base is cesium carbonate. In some embodiments, the base is potassium phosphate. In some embodiments, the base is sodium hydroxide. In some embodiments, the base is N,N-diisopropylethylamine. In some embodiments, the base is triethylamine.

[0186] In some embodiments, the compound of Formula (IE), the compound of Formula (IF), and the base are Within two hours, At temperatures between approximately 20°C and 25°C, It is stirred.

[0187] In some embodiments, the process further comprises precipitating the compound of formula (IB) and isolating it by filtration.

[0188] In some embodiments, the process provides a compound of formula (IB) in greater than about 70% synthetic yield. In some embodiments, the process provides a compound of formula (IB) in greater than about 75% synthetic yield. In some embodiments, the process provides a compound of formula (IB) in greater than about 80% synthetic yield. In some embodiments, the process provides a compound of formula (IB) in greater than about 85% synthetic yield.

[0189] In some embodiments, the compound of formula (IF)

[0190] [ka] is a compound of formula (IG) in the presence of a solvent

[0191] [ka] It is synthesized by reacting with an acyl halide preparative agent.

[0192] In some embodiments, the acyl halide preparing agent is selected from oxalyl chloride, thionyl chloride, phosphoryl chloride, phosphorus trichloride, phosphorus pentachloride, phosgene, diphosgene, triphosgene, and cyanuric chloride. In some embodiments, the acyl halide preparing agent is oxalyl chloride. In some embodiments, the acyl halide preparing agent is thionyl chloride. In some embodiments, the acyl halide preparing agent is phosphorus trichloride. In some embodiments, the acyl halide preparing agent is phosphorus pentachloride. In some embodiments, the acyl halide preparing agent is phosgene. In some embodiments, the acyl halide preparing agent is diphosgene. In some embodiments, the acyl halide preparing agent is triphosgene. In some embodiments, the acyl halide preparing agent is cyanuric chloride.

[0193] In some embodiments, the solvent is selected from water, ethyl acetate, dichloromethane, tetrahydrofuran, diethyl ether, dimethylformamide, dimethyl sulfoxide, methanol, ethanol, acetone, acetonitrile, 1,4-dioxane, hexane, and methyl tert-butyl ether. In some embodiments, the solvent is water. In some embodiments, the solvent is ethyl acetate. In some embodiments, the solvent is dichloromethane. In some embodiments, the solvent is tetrahydrofuran. In some embodiments, the solvent is diethyl ether. In some embodiments, the solvent is dimethylformamide. In some embodiments, the solvent is dimethyl sulfoxide. In some embodiments, the solvent is methanol. In some embodiments, the solvent is ethanol. In some embodiments, the solvent is acetone. In some embodiments, the solvent is acetonitrile. In some embodiments, the solvent is 1,4-dioxane. In some embodiments, the solvent is hexane. In some embodiments, the solvent includes methyl tert-butyl ether.

[0194] In some embodiments, the compound of Formula (IG), the acyl halide coordinating agent, and the solvent are Within 16 hours, At temperatures between approximately 20°C and 25°C, It is stirred.

[0195] In one embodiment, a CRAC channel inhibitor of formula (IE):

[0196] [ka] (In the formula, R 1 , R 2 and R 3 is hydrogen, halogen and C1-C3 alkyl (hydrogen, halogen, -OH, -OR 4 , -CN, -N(R 4 independently selected at each occurrence from -N,N-,N-dimethylformamide, - ... or two R's 1 groups, together with the atoms to which they are attached, form a carbocyclic ring; R 4 is hydrogen; and C 1~6 Alkyl, C 2~6 Alkenyl and C 2~6 alkynyl (each independently selected at each occurrence from halogen, —CN, —NO 2 , —OH, —NH 2 and —OCH 3 ) or a pharmaceutically acceptable salt thereof, comprising the steps of: In the presence of a base, a catalyst and a solvent, a compound of formula (IE-A)

[0197] [ka] with a compound of formula (IE-B)

[0198] [ka] (Wherein, X is -B(OH)2, -BF3K

[0199] [ka] is selected from Y is selected from Cl, Br and I. Provided herein is a process comprising reacting

[0200] In some embodiments, X is -B(OH), -BF,

[0201] [ka] In some embodiments, X is selected from: In some embodiments, X is -B(OH)2. In some embodiments, X is -BF3K. In some embodiments, X is

[0202] [ka] In some embodiments, X is

[0203] [ka] In some embodiments, X is

[0204] [ka] is.

[0205] In some embodiments, Y is selected from Cl, Br, and I. In some embodiments, Y is Cl. In some embodiments, Y is Br. In some embodiments, Y is I.

[0206] In some embodiments, the base is selected from the group consisting of potassium carbonate, sodium carbonate, potassium bicarbonate, sodium bicarbonate, piperidine, pyridine, 1,8-diazabicyclo[5.4.0]undec-7-ene, sodium tert-butoxide, potassium tert-butoxide, cesium carbonate, potassium phosphate, sodium hydroxide, N,N-diisopropylethylamine, and triethylamine. In some embodiments, the base is potassium carbonate. In some embodiments, the base is sodium carbonate. In some embodiments, the base is potassium bicarbonate. In some embodiments, the base is sodium bicarbonate. In some embodiments, the base is piperidine. In some embodiments, the base is pyridine. In some embodiments, the base is 1,8-diazabicyclo[5.4.0]undec-7-ene. In some embodiments, the base is sodium tert-butoxide. In some embodiments, the base is potassium tert-butoxide. In some embodiments, the base is cesium carbonate. In some embodiments, the base is potassium phosphate. In some embodiments, the base is sodium hydroxide. In some embodiments, the base is N,N-diisopropylethylamine. In some embodiments, the base is triethylamine.

[0207] In some embodiments, the catalyst is selected from Pd(acac)2, [Pd(allyl)Cl]2, Pd(MeCN)2Cl2, Pd(dba)2, Pd(TFA)2, Pd2(dba)3, Pd2(dba)3·CHCl3, Pd(PPh3)4, Pd(OAc)2, Pd(PCy3)2Cl2, Pd(PPh3)2Cl2, Pd[P(o-tol)3]2Cl2, Pd(amphos)Cl2, Pd(dppf)Cl2, Pd(dppf)Cl2·CH2Cl2, Pd(dtbpf)Cl2, Pd(MeCN)4(BF4), PdCl2, XPhos-Pd-G3, Pd-PEPPSI™-IPr, Pd-PEPPSI™-SIPr, and Pd-PEPPSI™-IPent. In some embodiments, the catalyst is Pd(acac)2. In some embodiments, the catalyst is [Pd(allyl)Cl]2. In some embodiments, the catalyst is Pd(MeCN)2Cl2. In some embodiments, the catalyst is Pd(dba)2. In some embodiments, the catalyst is Pd(TFA)2. In some embodiments, the catalyst is Pd2(dba)3. In some embodiments, the catalyst is Pd2(dba)3·CHCl3. In some embodiments, the catalyst is Pd(PPh3)4. In some embodiments, the catalyst is Pd(OAc)2. In some embodiments, the catalyst is Pd(PCy3)2Cl2. In some embodiments, the catalyst is Pd(PPh3)2Cl2. In some embodiments, the catalyst is Pd[P(o-tol)3]2Cl2. In some embodiments, the catalyst is Pd(amphos)Cl2. In some embodiments, the catalyst is Pd(dppf)Cl2. In some embodiments, the catalyst is Pd(dppf)Cl2·CH2Cl2. In some embodiments, the catalyst is Pd(dtbpf)Cl2. In some embodiments, the catalyst is Pd(MeCN)4(BF4)2. In some embodiments, the catalyst is PdCl2. In some embodiments, the catalyst is XPhos-Pd-G3. In some embodiments, the catalyst is Pd-PEPPSI™-IPr. In some embodiments, the catalyst is Pd-PEPPSI™-SIPr. In some embodiments, the catalyst is Pd-PEPPSI™-IPent.

[0208] In some embodiments, the solvent is selected from water, ethyl acetate, dichloromethane, tetrahydrofuran, diethyl ether, dimethylformamide, dimethyl sulfoxide, methanol, ethanol, acetone, acetonitrile, 1,4-dioxane, hexane, and methyl tert-butyl ether. In some embodiments, the solvent is water. In some embodiments, the solvent is ethyl acetate. In some embodiments, the solvent is dichloromethane. In some embodiments, the solvent is tetrahydrofuran. In some embodiments, the solvent is diethyl ether. In some embodiments, the solvent is dimethylformamide. In some embodiments, the solvent is dimethyl sulfoxide. In some embodiments, the solvent is methanol. In some embodiments, the solvent is ethanol. In some embodiments, the solvent is acetone. In some embodiments, the solvent is acetonitrile. In some embodiments, the solvent is 1,4-dioxane. In some embodiments, the solvent is hexane. In some embodiments, the solvent includes methyl tert-butyl ether.

[0209] In some embodiments, the compound of formula (IE-A), the compound of formula (IE-B), the base, the catalyst, and the solvent are Within 16 hours, At temperatures between about 75°C and about 80°C, It is stirred.

[0210] In some embodiments, the process further comprises precipitating the compound of formula (IE) and isolating it by filtration.

[0211] In some embodiments, the process provides a compound of formula (IE) in a synthetic yield of greater than about 60%. In some embodiments, the process provides a compound of formula (IE) in a synthetic yield of greater than about 65%. In some embodiments, the process provides a compound of formula (IE) in a synthetic yield of greater than about 70%. In some embodiments, the process provides a compound of formula (IE) in a synthetic yield of greater than about 75%. In some embodiments, the process provides a compound of formula (IE) in a synthetic yield of greater than about 80%.

[0212] In some embodiments, a compound of formula (IE-A)

[0213] [ka] is a compound of formula (IE-C) in the presence of a base and a solvent.

[0214] [ka] It is synthesized by reacting with a boronating agent.

[0215] In some embodiments, the boronating agent is selected from 2-isopropoxy-4,4,5,5-tetramethyl-1,3,2-dioxaborolane, 2-methoxy-4,4,5,5-tetramethyl-1,3,2-dioxaborolane, and 2-ethoxy-4,4,5,5-tetramethyl-1,3,2-dioxaborolane. In some embodiments, the boronating agent is 2-isopropoxy-4,4,5,5-tetramethyl-1,3,2-dioxaborolane. In some embodiments, the boronating agent is 2-methoxy-4,4,5,5-tetramethyl-1,3,2-dioxaborolane. In some embodiments, the boronating agent is 2-ethoxy-4,4,5,5-tetramethyl-1,3,2-dioxaborolane.

[0216] In some embodiments, the base is selected from isopropylmagnesium chloride, isopropylmagnesium lithium chloride, methylmagnesium bromide, methylmagnesium chloride, methylmagnesium iodide, ethylmagnesium chloride, ethylmagnesium bromide, isopropylmagnesium bromide, methyllithium, ethyllithium, isopropyllithium, n-butyllithium, and tert-butyllithium. In some embodiments, the base is isopropylmagnesium chloride. In some embodiments, the base is isopropylmagnesium lithium chloride. In some embodiments, the base is methylmagnesium bromide. In some embodiments, the base is methylmagnesium chloride. In some embodiments, the base is methylmagnesium iodide. In some embodiments, the base is ethylmagnesium chloride. In some embodiments, the base is ethylmagnesium bromide. In some embodiments, the base is isopropylmagnesium bromide. In some embodiments, the base is methyllithium. In some embodiments, the base is ethyllithium. In some embodiments, the base is isopropyllithium. In some embodiments, the base is n-butyllithium. In some embodiments, the base is tert-butyllithium.

[0217] In some embodiments, the solvent is selected from water, ethyl acetate, dichloromethane, tetrahydrofuran, diethyl ether, dimethylformamide, dimethyl sulfoxide, methanol, ethanol, acetone, acetonitrile, 1,4-dioxane, hexane, and methyl tert-butyl ether. In some embodiments, the solvent is water. In some embodiments, the solvent is ethyl acetate. In some embodiments, the solvent is dichloromethane. In some embodiments, the solvent is tetrahydrofuran. In some embodiments, the solvent is diethyl ether. In some embodiments, the solvent is dimethylformamide. In some embodiments, the solvent is dimethyl sulfoxide. In some embodiments, the solvent is methanol. In some embodiments, the solvent is ethanol. In some embodiments, the solvent is acetone. In some embodiments, the solvent is acetonitrile. In some embodiments, the solvent is 1,4-dioxane. In some embodiments, the solvent is hexane. In some embodiments, the solvent includes methyl tert-butyl ether.

[0218] In some embodiments, the compound of Formula (IE-C), the boronating agent, the base, and the solvent are Within two hours, At temperatures between approximately 0°C and approximately 25°C, It is stirred.

[0219] In some embodiments, the process further comprises precipitating the compound of formula (IE-A) and isolating it by filtration.

[0220] In some embodiments, the process provides a compound of formula (IE-A) in a synthetic yield of greater than about 60%. In some embodiments, the process provides a compound of formula (IE-A) in a synthetic yield of greater than about 65%. In some embodiments, the process provides a compound of formula (IE-A) in a synthetic yield of greater than about 70%. In some embodiments, the process provides a compound of formula (IE-A) in a synthetic yield of greater than about 75%.

[0221] In some embodiments, a compound of formula (IE-C)

[0222] [ka] is a compound of formula (IE-D) in the presence of an acid and a solvent

[0223] [ka] It is synthesized by reacting with a brominating agent.

[0224] In some embodiments, the brominating agent is selected from N-bromosuccinimide, tribromoisocyanuric acid, 1,3-dibromo-5,5-dimethylhydantoin, and bromine. In some embodiments, the brominating agent is N-bromosuccinimide. In some embodiments, the brominating agent is tribromoisocyanuric acid. In some embodiments, the brominating agent is 1,3-dibromo-5,5-dimethylhydantoin. In some embodiments, the brominating agent is bromine.

[0225] In some embodiments, the acid is selected from hydrochloric acid, sulfuric acid, nitric acid, acetic acid, hydrobromic acid, phosphoric acid, formic acid, and trifluoroacetic acid. In some embodiments, the acid is hydrochloric acid. In some embodiments, the acid is sulfuric acid. In some embodiments, the acid is nitric acid. In some embodiments, the acid is acetic acid. In some embodiments, the acid is hydrobromic acid. In some embodiments, the acid is phosphoric acid. In some embodiments, the acid is formic acid. In some embodiments, the acid is trifluoroacetic acid.

[0226] In some embodiments, the solvent is selected from water, ethyl acetate, dichloromethane, tetrahydrofuran, diethyl ether, dimethylformamide, dimethyl sulfoxide, methanol, ethanol, acetone, acetonitrile, 1,4-dioxane, hexane, and methyl tert-butyl ether. In some embodiments, the solvent is water. In some embodiments, the solvent is ethyl acetate. In some embodiments, the solvent is dichloromethane. In some embodiments, the solvent is tetrahydrofuran. In some embodiments, the solvent is diethyl ether. In some embodiments, the solvent is dimethylformamide. In some embodiments, the solvent is dimethyl sulfoxide. In some embodiments, the solvent is methanol. In some embodiments, the solvent is ethanol. In some embodiments, the solvent is acetone. In some embodiments, the solvent is acetonitrile. In some embodiments, the solvent is 1,4-dioxane. In some embodiments, the solvent is hexane. In some embodiments, the solvent includes methyl tert-butyl ether.

[0227] In some embodiments, the compound of Formula (IE-D), the brominating agent, the acid, and the solvent are Within 12 hours, At temperatures between approximately 0°C and approximately 15°C, It is stirred.

[0228] In some embodiments, the process further comprises extracting the compound of formula (IE-C) and isolating it by concentration.

[0229] In some embodiments, the process provides a compound of formula (IE-C) in a synthetic yield of greater than about 70%. In some embodiments, the process provides a compound of formula (IE-C) in a synthetic yield of greater than about 75%. In some embodiments, the process provides a compound of formula (IE-C) in a synthetic yield of greater than about 80%. In some embodiments, the process provides a compound of formula (IE-C) in a synthetic yield of greater than about 85%.

[0230] In some embodiments, a compound of formula (IE-B)

[0231] [ka] is a compound of formula (IE) in the presence of a base

[0232] [ka] with a compound of formula (IE-F)

[0233] [ka] wherein Z is selected from Cl, Br and I. It is synthesized by reacting with

[0234] In some embodiments, Z is selected from Cl, Br, and I. In some embodiments, Z is Cl. In some embodiments, Z is Br. In some embodiments, Z is I.

[0235] In some embodiments, the base is selected from the group consisting of potassium carbonate, sodium carbonate, potassium bicarbonate, sodium bicarbonate, piperidine, pyridine, 1,8-diazabicyclo[5.4.0]undec-7-ene, sodium tert-butoxide, potassium tert-butoxide, cesium carbonate, potassium phosphate, sodium hydroxide, N,N-diisopropylethylamine, and triethylamine. In some embodiments, the base is potassium carbonate. In some embodiments, the base is sodium carbonate. In some embodiments, the base is potassium bicarbonate. In some embodiments, the base is sodium bicarbonate. In some embodiments, the base is piperidine. In some embodiments, the base is pyridine. In some embodiments, the base is 1,8-diazabicyclo[5.4.0]undec-7-ene. In some embodiments, the base is sodium tert-butoxide. In some embodiments, the base is potassium tert-butoxide. In some embodiments, the base is cesium carbonate. In some embodiments, the base is potassium phosphate. In some embodiments, the base is sodium hydroxide. In some embodiments, the base is N,N-diisopropylethylamine. In some embodiments, the base is triethylamine.

[0236] In some embodiments, the compound of Formula (IE), the compound of Formula (IE-F), and the base are Within two hours, At temperatures between approximately 20°C and 25°C, It is stirred.

[0237] In some embodiments, the process further comprises precipitating the compound of formula (IE-B) and isolating it by filtration.

[0238] In some embodiments, the process provides a compound of formula (IE-B) in a synthetic yield of greater than about 70%. In some embodiments, the process provides a compound of formula (IE-B) in a synthetic yield of greater than about 75%. In some embodiments, the process provides a compound of formula (IE-B) in a synthetic yield of greater than about 80%. In some embodiments, the process provides a compound of formula (IE-B) in a synthetic yield of greater than about 85%.

[0239] In some embodiments, a compound of formula (IE-F)

[0240] [ka] is a compound of formula (IE-G) in the presence of a solvent

[0241] [ka] It is synthesized by reacting with an acyl halide preparative agent.

[0242] In some embodiments, the acyl halide preparing agent is selected from oxalyl chloride, thionyl chloride, phosphoryl chloride, phosphorus trichloride, phosphorus pentachloride, phosgene, diphosgene, triphosgene, and cyanuric chloride. In some embodiments, the acyl halide preparing agent is oxalyl chloride. In some embodiments, the acyl halide preparing agent is thionyl chloride. In some embodiments, the acyl halide preparing agent is phosphorus trichloride. In some embodiments, the acyl halide preparing agent is phosphorus pentachloride. In some embodiments, the acyl halide preparing agent is phosgene. In some embodiments, the acyl halide preparing agent is diphosgene. In some embodiments, the acyl halide preparing agent is triphosgene. In some embodiments, the acyl halide preparing agent is cyanuric chloride.

[0243] In some embodiments, the solvent is selected from water, ethyl acetate, dichloromethane, tetrahydrofuran, diethyl ether, dimethylformamide, dimethyl sulfoxide, methanol, ethanol, acetone, acetonitrile, 1,4-dioxane, hexane, and methyl tert-butyl ether. In some embodiments, the solvent is water. In some embodiments, the solvent is ethyl acetate. In some embodiments, the solvent is dichloromethane. In some embodiments, the solvent is tetrahydrofuran. In some embodiments, the solvent is diethyl ether. In some embodiments, the solvent is dimethylformamide. In some embodiments, the solvent is dimethyl sulfoxide. In some embodiments, the solvent is methanol. In some embodiments, the solvent is ethanol. In some embodiments, the solvent is acetone. In some embodiments, the solvent is acetonitrile. In some embodiments, the solvent is 1,4-dioxane. In some embodiments, the solvent is hexane. In some embodiments, the solvent includes methyl tert-butyl ether.

[0244] In some embodiments, the compound of Formula (IE-G), the acyl halide coordinating agent, and the solvent are Within 16 hours, At temperatures between approximately 20°C and 25°C, It is stirred.

[0245] In another embodiment, a CRAC channel inhibitor of formula (II):

[0246] [ka] or a pharmaceutically acceptable salt thereof, comprising the steps of: In the presence of a base, a catalyst and a solvent, a compound of formula (II-A)

[0247] [ka] with a compound of formula (IB)

[0248] [ka] Provided herein is a process comprising reacting

[0249] In some embodiments, the base is selected from the group consisting of potassium carbonate, sodium carbonate, potassium bicarbonate, sodium bicarbonate, piperidine, pyridine, 1,8-diazabicyclo[5.4.0]undec-7-ene, sodium tert-butoxide, potassium tert-butoxide, cesium carbonate, potassium phosphate, sodium hydroxide, N,N-diisopropylethylamine, and triethylamine. In some embodiments, the base is potassium carbonate. In some embodiments, the base is sodium carbonate. In some embodiments, the base is potassium bicarbonate. In some embodiments, the base is sodium bicarbonate. In some embodiments, the base is piperidine. In some embodiments, the base is pyridine. In some embodiments, the base is 1,8-diazabicyclo[5.4.0]undec-7-ene. In some embodiments, the base is sodium tert-butoxide. In some embodiments, the base is potassium tert-butoxide. In some embodiments, the base is cesium carbonate. In some embodiments, the base is potassium phosphate. In some embodiments, the base is sodium hydroxide. In some embodiments, the base is N,N-diisopropylethylamine. In some embodiments, the base is triethylamine.

[0250] In some embodiments, the catalyst is selected from Pd(acac)2, [Pd(allyl)Cl]2, Pd(MeCN)2Cl2, Pd(dba)2, Pd(TFA)2, Pd2(dba)3, Pd2(dba)3·CHCl3, Pd(PPh3)4, Pd(OAc)2, Pd(PCy3)2Cl2, Pd(PPh3)2Cl2, Pd[P(o-tol)3]2Cl2, Pd(amphos)Cl2, Pd(dppf)Cl2, Pd(dppf)Cl2·CH2Cl2, Pd(dtbpf)Cl2, Pd(MeCN)4(BF4), PdCl2, XPhos-Pd-G3, Pd-PEPPSI™-IPr, Pd-PEPPSI™-SIPr, and Pd-PEPPSI™-IPent. In some embodiments, the catalyst is Pd(acac)2. In some embodiments, the catalyst is [Pd(allyl)Cl]2. In some embodiments, the catalyst is Pd(MeCN)2Cl2. In some embodiments, the catalyst is Pd(dba)2. In some embodiments, the catalyst is Pd(TFA)2. In some embodiments, the catalyst is Pd2(dba)3. In some embodiments, the catalyst is Pd2(dba)3·CHCl3. In some embodiments, the catalyst is Pd(PPh3)4. In some embodiments, the catalyst is Pd(OAc)2. In some embodiments, the catalyst is Pd(PCy3)2Cl2. In some embodiments, the catalyst is Pd(PPh3)2Cl2. In some embodiments, the catalyst is Pd[P(o-tol)3]2Cl2. In some embodiments, the catalyst is Pd(amphos)Cl2. In some embodiments, the catalyst is Pd(dppf)Cl2. In some embodiments, the catalyst is Pd(dppf)Cl2·CH2Cl2. In some embodiments, the catalyst is Pd(dtbpf)Cl2. In some embodiments, the catalyst is Pd(MeCN)4(BF4)2. In some embodiments, the catalyst is PdCl2. In some embodiments, the catalyst is XPhos-Pd-G3. In some embodiments, the catalyst is Pd-PEPPSI™-IPr. In some embodiments, the catalyst is Pd-PEPPSI™-SIPr. In some embodiments, the catalyst is Pd-PEPPSI™-IPent.

[0251] In some embodiments, the solvent is selected from water, ethyl acetate, dichloromethane, tetrahydrofuran, diethyl ether, dimethylformamide, dimethyl sulfoxide, methanol, ethanol, acetone, acetonitrile, 1,4-dioxane, hexane, and methyl tert-butyl ether. In some embodiments, the solvent is water. In some embodiments, the solvent is ethyl acetate. In some embodiments, the solvent is dichloromethane. In some embodiments, the solvent is tetrahydrofuran. In some embodiments, the solvent is diethyl ether. In some embodiments, the solvent is dimethylformamide. In some embodiments, the solvent is dimethyl sulfoxide. In some embodiments, the solvent is methanol. In some embodiments, the solvent is ethanol. In some embodiments, the solvent is acetone. In some embodiments, the solvent is acetonitrile. In some embodiments, the solvent is 1,4-dioxane. In some embodiments, the solvent is hexane. In some embodiments, the solvent includes methyl tert-butyl ether.

[0252] In some embodiments, the compound of Formula (II-A), the compound of Formula (II-B), the base, the catalyst, and the solvent are Within 16 hours, At temperatures between about 75°C and about 80°C, It is stirred.

[0253] In some embodiments, the process further comprises precipitating the compound of formula (II) and isolating it by filtration.

[0254] In some embodiments, the process provides a compound of formula (II) in a synthetic yield of greater than about 60%. In some embodiments, the process provides a compound of formula (II) in a synthetic yield of greater than about 65%. In some embodiments, the process provides a compound of formula (II) in a synthetic yield of greater than about 70%. In some embodiments, the process provides a compound of formula (II) in a synthetic yield of greater than about 75%. In some embodiments, the process provides a compound of formula (I) in a synthetic yield of greater than about 80%.

[0255] In some embodiments, the compound of formula (II-A)

[0256] [ka] is reacted with a compound of formula (II-C) in the presence of a base and a solvent.

[0257] [ka] It is synthesized by reacting with a boronating agent.

[0258] In some embodiments, the boronating agent is selected from 2-isopropoxy-4,4,5,5-tetramethyl-1,3,2-dioxaborolane, 2-methoxy-4,4,5,5-tetramethyl-1,3,2-dioxaborolane, and 2-ethoxy-4,4,5,5-tetramethyl-1,3,2-dioxaborolane. In some embodiments, the boronating agent is 2-isopropoxy-4,4,5,5-tetramethyl-1,3,2-dioxaborolane. In some embodiments, the boronating agent is 2-methoxy-4,4,5,5-tetramethyl-1,3,2-dioxaborolane. In some embodiments, the boronating agent is 2-ethoxy-4,4,5,5-tetramethyl-1,3,2-dioxaborolane.

[0259] In some embodiments, the base is selected from isopropylmagnesium chloride, isopropylmagnesium lithium chloride, methylmagnesium bromide, methylmagnesium chloride, methylmagnesium iodide, ethylmagnesium chloride, ethylmagnesium bromide, isopropylmagnesium bromide, methyllithium, ethyllithium, isopropyllithium, n-butyllithium, and tert-butyllithium. In some embodiments, the base is isopropylmagnesium chloride. In some embodiments, the base is isopropylmagnesium lithium chloride. In some embodiments, the base is methylmagnesium bromide. In some embodiments, the base is methylmagnesium chloride. In some embodiments, the base is methylmagnesium iodide. In some embodiments, the base is ethylmagnesium chloride. In some embodiments, the base is ethylmagnesium bromide. In some embodiments, the base is isopropylmagnesium bromide. In some embodiments, the base is methyllithium. In some embodiments, the base is ethyllithium. In some embodiments, the base is isopropyllithium. In some embodiments, the base is n-butyllithium. In some embodiments, the base is tert-butyllithium.

[0260] In some embodiments, the solvent is selected from water, ethyl acetate, dichloromethane, tetrahydrofuran, diethyl ether, dimethylformamide, dimethyl sulfoxide, methanol, ethanol, acetone, acetonitrile, 1,4-dioxane, hexane, and methyl tert-butyl ether. In some embodiments, the solvent is water. In some embodiments, the solvent is ethyl acetate. In some embodiments, the solvent is dichloromethane. In some embodiments, the solvent is tetrahydrofuran. In some embodiments, the solvent is diethyl ether. In some embodiments, the solvent is dimethylformamide. In some embodiments, the solvent is dimethyl sulfoxide. In some embodiments, the solvent is methanol. In some embodiments, the solvent is ethanol. In some embodiments, the solvent is acetone. In some embodiments, the solvent is acetonitrile. In some embodiments, the solvent is 1,4-dioxane. In some embodiments, the solvent is hexane. In some embodiments, the solvent includes methyl tert-butyl ether.

[0261] In some embodiments, the compound of Formula (II-C), the boronating agent, the base, and the solvent are Within two hours, At temperatures between approximately 0°C and approximately 25°C, It is stirred.

[0262] In some embodiments, the process further comprises precipitating the compound of formula (II-A) and isolating it by filtration.

[0263] In some embodiments, the process provides a compound of formula (II-A) in a synthetic yield of greater than about 60%. In some embodiments, the process provides a compound of formula (II-A) in a synthetic yield of greater than about 65%. In some embodiments, the process provides a compound of formula (II-A) in a synthetic yield of greater than about 70%. In some embodiments, the process provides a compound of formula (II-A) in a synthetic yield of greater than about 75%.

[0264] In some embodiments, a compound of formula (II-C)

[0265] [ka] is a compound of formula (II-D) in the presence of an acid and a solvent.

[0266] [ka] It is synthesized by reacting with a brominating agent.

[0267] In some embodiments, the brominating agent is selected from N-bromosuccinimide, tribromoisocyanuric acid, 1,3-dibromo-5,5-dimethylhydantoin, and bromine. In some embodiments, the brominating agent is N-bromosuccinimide. In some embodiments, the brominating agent is tribromoisocyanuric acid. In some embodiments, the brominating agent is 1,3-dibromo-5,5-dimethylhydantoin. In some embodiments, the brominating agent is bromine.

[0268] In some embodiments, the acid is selected from hydrochloric acid, sulfuric acid, nitric acid, acetic acid, hydrobromic acid, phosphoric acid, formic acid, and trifluoroacetic acid. In some embodiments, the acid is hydrochloric acid. In some embodiments, the acid is sulfuric acid. In some embodiments, the acid is nitric acid. In some embodiments, the acid is acetic acid. In some embodiments, the acid is hydrobromic acid. In some embodiments, the acid is phosphoric acid. In some embodiments, the acid is formic acid. In some embodiments, the acid is trifluoroacetic acid.

[0269] In some embodiments, the solvent is selected from water, ethyl acetate, dichloromethane, tetrahydrofuran, diethyl ether, dimethylformamide, dimethyl sulfoxide, methanol, ethanol, acetone, acetonitrile, 1,4-dioxane, hexane, and methyl tert-butyl ether. In some embodiments, the solvent is water. In some embodiments, the solvent is ethyl acetate. In some embodiments, the solvent is dichloromethane. In some embodiments, the solvent is tetrahydrofuran. In some embodiments, the solvent is diethyl ether. In some embodiments, the solvent is dimethylformamide. In some embodiments, the solvent is dimethyl sulfoxide. In some embodiments, the solvent is methanol. In some embodiments, the solvent is ethanol. In some embodiments, the solvent is acetone. In some embodiments, the solvent is acetonitrile. In some embodiments, the solvent is 1,4-dioxane. In some embodiments, the solvent is hexane. In some embodiments, the solvent includes methyl tert-butyl ether.

[0270] In some embodiments, the compound of Formula (II-D), the brominating agent, the acid, and the solvent are Within 12 hours, At temperatures between approximately 0°C and approximately 15°C, It is stirred.

[0271] In some embodiments, the process further comprises extracting the compound of formula (II-C) and isolating it by concentration.

[0272] In some embodiments, the process provides a compound of formula (II-C) in a synthetic yield of greater than about 70%. In some embodiments, the process provides a compound of formula (II-C) in a synthetic yield of greater than about 75%. In some embodiments, the process provides a compound of formula (II-C) in a synthetic yield of greater than about 80%. In some embodiments, the process provides a compound of formula (II-C) in a synthetic yield of greater than about 85%.

[0273] In some embodiments, a compound of formula (II-B)

[0274] [ka] is a compound of formula (II-E)

[0275] [ka] in the presence of a base, a compound of formula (II-F)

[0276] [ka] wherein Z is selected from Cl, Br and I. It is synthesized by reacting with

[0277] In some embodiments, the base is selected from the group consisting of potassium carbonate, sodium carbonate, potassium bicarbonate, sodium bicarbonate, piperidine, pyridine, 1,8-diazabicyclo[5.4.0]undec-7-ene, sodium tert-butoxide, potassium tert-butoxide, cesium carbonate, potassium phosphate, sodium hydroxide, N,N-diisopropylethylamine, and triethylamine. In some embodiments, the base is potassium carbonate. In some embodiments, the base is sodium carbonate. In some embodiments, the base is potassium bicarbonate. In some embodiments, the base is sodium bicarbonate. In some embodiments, the base is piperidine. In some embodiments, the base is pyridine. In some embodiments, the base is 1,8-diazabicyclo[5.4.0]undec-7-ene. In some embodiments, the base is sodium tert-butoxide. In some embodiments, the base is potassium tert-butoxide. In some embodiments, the base is cesium carbonate. In some embodiments, the base is potassium phosphate. In some embodiments, the base is sodium hydroxide. In some embodiments, the base is N,N-diisopropylethylamine. In some embodiments, the base is triethylamine.

[0278] In some embodiments, the compound of Formula (II-E), the compound of Formula (II-F), and the base are Within two hours, At temperatures between approximately 20°C and 25°C, It is stirred.

[0279] In some embodiments, the process further comprises precipitating the compound of formula (II-B) and isolating it by filtration.

[0280] In some embodiments, the process provides a compound of formula (II-B) in a synthetic yield of greater than about 70%. In some embodiments, the process provides a compound of formula (II-B) in a synthetic yield of greater than about 75%. In some embodiments, the process provides a compound of formula (II-B) in a synthetic yield of greater than about 80%. In some embodiments, the process provides a compound of formula (II-B) in a synthetic yield of greater than about 85%.

[0281] In some embodiments, a compound of formula (II-F)

[0282] [ka] is a compound of formula (II-G) in the presence of a solvent.

[0283] [ka] It is synthesized by reacting with an acyl halide preparative agent.

[0284] In some embodiments, the acyl halide preparing agent is selected from oxalyl chloride, thionyl chloride, phosphoryl chloride, phosphorus trichloride, phosphorus pentachloride, phosgene, diphosgene, triphosgene, and cyanuric chloride. In some embodiments, the acyl halide preparing agent is oxalyl chloride. In some embodiments, the acyl halide preparing agent is thionyl chloride. In some embodiments, the acyl halide preparing agent is phosphorus trichloride. In some embodiments, the acyl halide preparing agent is phosphorus pentachloride. In some embodiments, the acyl halide preparing agent is phosgene. In some embodiments, the acyl halide preparing agent is diphosgene. In some embodiments, the acyl halide preparing agent is triphosgene. In some embodiments, the acyl halide preparing agent is cyanuric chloride.

[0285] In some embodiments, the solvent is selected from water, ethyl acetate, dichloromethane, tetrahydrofuran, diethyl ether, dimethylformamide, dimethyl sulfoxide, methanol, ethanol, acetone, acetonitrile, 1,4-dioxane, hexane, and methyl tert-butyl ether. In some embodiments, the solvent is water. In some embodiments, the solvent is ethyl acetate. In some embodiments, the solvent is dichloromethane. In some embodiments, the solvent is tetrahydrofuran. In some embodiments, the solvent is diethyl ether. In some embodiments, the solvent is dimethylformamide. In some embodiments, the solvent is dimethyl sulfoxide. In some embodiments, the solvent is methanol. In some embodiments, the solvent is ethanol. In some embodiments, the solvent is acetone. In some embodiments, the solvent is acetonitrile. In some embodiments, the solvent is 1,4-dioxane. In some embodiments, the solvent is hexane. In some embodiments, the solvent includes methyl tert-butyl ether.

[0286] In some embodiments, the compound of Formula (II-G), the acyl halide adjusting agent, and the solvent are Within 16 hours, At temperatures between approximately 20°C and 25°C, It is stirred. [Example]

[0287] These examples are presented for illustrative purposes only and do not limit the scope of the claims presented herein. The starting materials and reagents used in the synthesis of the compounds described herein are either synthesized or obtained from commercial sources, such as, but not limited to, Sigma-Aldrich, Acros Organics, Fluka, and Fischer Scientific. [Example]

[0288] Synthesis of N-(5-bromopyrazin-2-yl)-2-fluoro-6-methylbenzamide (compound 1.3)

[0289] [ka]

[0290] Step 1: Preparation of 2-fluoro-6-methylbenzoyl chloride (compound 1.2) In a 100 mL three-necked round-bottom flask under N2, compound 1.1 (5.00 g, 32.4 mmol, 1.00 equiv) and DMF (23.7 mg, 324.3 μmol, 0.01 equiv) were dissolved in anhydrous THF (50 mL) at 25 °C. The solution was cooled to 10-15 °C using a cryogenic circulating bath, and oxalyl chloride (4.32 g, 34.0 mmol, 1.05 equiv) was added dropwise. The resulting reaction mixture was stirred at 20-25 °C for 16 h. Upon complete conversion of compound 1.1, the reaction solution was carried on to the next synthetic step without further purification.

[0291] Step 2: Preparation of N-(5-bromopyrazin-2-yl)-2-fluoro-6-methylbenzamide (compound 1.3) To a solution of compound 1.1 in THF was added 5-bromopyrazin-2-amine (5.08 g, 29.2 mmol, 0.9 equiv.) at 25 °C. The reaction mixture was cooled to 0-5 °C using a cryogenic circulating bath, and pyridine (5.13 g, 64.9 mmol, 2.00 equiv.) was added dropwise at 0-5 °C. The resulting reaction mixture was stirred at 20-25 °C for 2 h. Upon complete conversion of compound 1.2, ice water (50 mL) was added to the reaction solution with stirring at 20-25 °C, and the mixture was extracted twice with EtOAc (20 mL, 10 mL). The combined organic phase was dried over Na2SO4, filtered, and concentrated under reduced pressure to give 15.4 g of crude compound 1.3. Crude compound 1.3 (15.4 g) was triturated with MTBE (60 mL) at 25 °C for 3 h, the suspension was filtered, and the filter cake was dried under reduced pressure to give compound 1.3 (9.1 g, 26.4 mmol, 81% yield, 90% purity) as a gray solid. [Example]

[0292] Synthesis of 2-(6-chloro-2,2-difluorobenzo[d][1,3]dioxol-5-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (compound 2.3)

[0293] [ka]

[0294] Step 1: Preparation of 5-bromo-6-chloro-2,2-difluorobenzo[d][1,3]dioxole (Compound 2.2) In a 100 mL three-necked round-bottom flask, compound 2.1 (3.00 g, 15.5 mmol, 1.00 equiv.) was dissolved in ACN (30 mL) and DBDMH (4.90 g, 17.1 mmol, 1.10 equiv.) was added at 25 °C. The solution was cooled to 0-5 °C using a cryogenic circulating bath, and H2SO4 (6.8 g, 70.1 mmol, 4.50 equiv.) was added dropwise. The resulting reaction mixture was stirred at 10-15 °C for 12 h. Upon complete conversion of compound 2.1, ice water (30 mL) was added dropwise to the reaction solution with stirring at 10-15 °C, and the mixture was extracted twice with MTBE (10 mL, 5 mL). The combined organic phase was washed with 1 M NaOH (20 mL). The organic phase was dried over NaSO, filtered, and concentrated under reduced pressure to give compound 2.2 (3.60 g, 12.8 mmol, 82% yield, 97% purity) as a pale yellow liquid, which was carried on to the next synthetic step without purification.

[0295] Step 2: Preparation of 2-(6-chloro-2,2-difluorobenzo[d][1,3]dioxol-5-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (Compound 2.3) In a 100 mL three-necked round-bottom flask under N2, compound 2.2 (3.60 g, 12.8 mmol, 1.00 equiv.) and 2-isopropoxy-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (3.11 g, 16.7 mmol) were dissolved in anhydrous THF (21 mL) at 25 °C. The solution was cooled to 0-5 °C using a cryogenic circulating bath, and isopropylmagnesium lithium chloride (1.30 M solution, 12.8 mL, 1.30 equiv.) was added dropwise. The resulting reaction mixture was stirred at 20-25 °C for 2 h. Upon complete conversion of compound 2.2, ice water (50 mL) was added to the reaction solution while stirring at 20-25 °C. The mixture was filtered through a pad of Celite, the filter cake was washed twice with MTBE (20 mL, 10 mL), and the filtrate was extracted twice with MTBE (10 mL, 5 mL). The combined organic phase was dried over NaSO, filtered, and concentrated under reduced pressure to give compound 2.3 (3.87 g, 9.84 mmol, 76% yield, 81% purity) as a pale yellow waxy solid. Compound 2.3 was carried on to the next synthetic step without purification. [Example]

[0296] Synthesis of N-(5-(6-chloro-2,2-difluorobenzo[d][1,3]dioxol-5-yl)pyrazin-2-yl)-2-fluoro-6-methylbenzamide (compound 3.1)

[0297] [ka]

[0298] In a 100 mL three-necked round-bottom flask, compound 2.3 (3.87 g, 9.84 mmol, 1.00 equiv.) and compound 1.3 (3.56 g, 10.3 mmol, 1.05 equiv.) were dissolved in 1,4-dioxane (38 mL) at 25 °C under N2. K3PO4 (6.27 g, 29.5 mmol, 3.00 equiv.) and Pd(PPh3)4 (568 mg, 492 μmol, 0.05 equiv.) were added in one portion at 25 °C. The resulting reaction mixture was degassed and stirred at 75–80 °C for 16 h. Upon complete conversion of compound 2.3, the solution was concentrated, and the resulting residue was added to MTBE (30 mL) and water (30 mL) and stirred at 40 °C for 30 min. The mixture was extracted twice with MTBE (50 mL, 20 mL). The combined organic phase was dried over NaSO, filtered, and concentrated under reduced pressure to give 4.10 g of crude compound 3.1. Crude compound 3.1 was triturated with IPA / n-hexane (V / V=1:8, 50 mL) at 25 °C for 6 h, the resulting suspension was filtered, and the filter cake was dried under reduced pressure to give compound 3.1 (3.3 g, 7.82 mmol, 79% yield, 100% purity) as an off-white solid.

[0299] While preferred embodiments of the present invention have been shown and described herein, it will be obvious to those skilled in the art that such embodiments are provided by way of example only. Numerous variations, changes, and substitutions will occur to those skilled in the art without departing from the invention. It should be understood that various alternatives to the embodiments of the invention described herein can be used in practicing the invention. It is intended that the following claims define the scope of the invention, and that methods and structures within the scope of these claims and their equivalents be covered thereby.

Claims

1. a CRAC channel inhibitor of formula (II): 【Chemistry 1】 or a pharmaceutically acceptable salt thereof, comprising the steps of: In the presence of a base, a catalyst and a solvent, a compound of formula (II-A) 【Chemistry 2】 with a compound of formula (II-B) 【Transformation 3】 A process comprising the step of reacting with

2. 2. The process of claim 1, wherein the base is selected from the group consisting of potassium carbonate, sodium carbonate, potassium bicarbonate, sodium bicarbonate, piperidine, pyridine, 1,8-diazabicyclo[5.4.0]undec-7-ene, sodium tert-butoxide, potassium tert-butoxide, cesium carbonate, potassium phosphate, sodium hydroxide, N,N-diisopropylethylamine, and triethylamine.

3. The catalyst is Pd(acac) ２ [Pd(allyl)Cl] ２ , Pd(MeCN) ２ Cl ２ , Pd(dba) ２ , Pd(TFA) ２ , Pd ２ (dba) ３ , Pd ２ (dba) ３ CHCl ３ , Pd(PPh ３ ) ４ , Pd(OAc) ２ , Pd(PCy ３ ) ２ Cl ２ , Pd(PPh ３ ) ２ Cl ２ , Pd[P(o-tol) ３ ] ２ Cl ２ , Pd(amphos)Cl ２ , Pd(dppf)Cl ２ , Pd(dppf)Cl ２ ・CH ２ Cl ２ , Pd(dtbpf)Cl ２ , Pd(MeCN) ４ (BF ４ ) ２ , PdCl ２ 3. The process of claim 1 or 2, wherein the Pd-PEPPSI™-IPr is selected from Pd-PEPPSI™-IPr, XPhos-Pd-G3, Pd-PEPPSI™-IPr, Pd-PEPPSI™-SIPr and Pd-PEPPSI™-IPent.

4. 4. The process of any one of claims 1 to 3, wherein the solvent is selected from water, ethyl acetate, dichloromethane, tetrahydrofuran, diethyl ether, dimethylformamide, dimethyl sulfoxide, methanol, ethanol, acetone, acetonitrile, 1,4-dioxane, hexane, and methyl tert-butyl ether.

5. A compound of formula (II-A), a compound of formula (II-B), a base, a catalyst, and a solvent, Within 16 hours, At temperatures between 75°C and 80°C, 5. The process of claim 1, wherein the mixture is stirred.

6. 6. The process according to any one of claims 1 to 5, wherein the compound of formula (II) is obtained in a synthetic yield of more than 75%.

7. Compound of formula (II-A) 【Chemistry 4】 In the presence of a base and a solvent, a compound of formula (II-C) 【Transformation 5】 7. The process of claim 1, wherein the compound is synthesized by reacting a boronating agent with a boronizing agent.

8. the boronating agent is selected from 2-isopropoxy-4,4,5,5-tetramethyl-1,3,2-dioxaborolane, 2-methoxy-4,4,5,5-tetramethyl-1,3,2-dioxaborolane, and 2-ethoxy-4,4,5,5-tetramethyl-1,3,2-dioxaborolane; the base is selected from isopropylmagnesium chloride, isopropylmagnesium lithium chloride, methylmagnesium bromide, methylmagnesium chloride, methylmagnesium iodide, ethylmagnesium chloride, ethylmagnesium bromide, isopropylmagnesium bromide, methyllithium, ethyllithium, isopropyllithium, n-butyllithium, and tert-butyllithium; and 8. The process of claim 7, wherein the solvent is selected from water, ethyl acetate, dichloromethane, tetrahydrofuran, diethyl ether, dimethylformamide, dimethyl sulfoxide, methanol, ethanol, acetone, acetonitrile, 1,4-dioxane, hexane, and methyl tert-butyl ether.

9. A compound of formula (II-C), a boronating agent, a base, and a solvent Within two hours, At temperatures between 0°C and 25°C, 9. The process of claim 7 or 8, wherein the process is stirred.

10. 10. The process according to any one of claims 7 to 9, wherein the compound of formula (II-A) is obtained in a synthetic yield of more than 70%.

11. Compound of formula (II-C) 【Transformation 6】 In the presence of an acid and a solvent, a compound of formula (II-D) 【Transformation 7】 11. The process of claim 7, wherein the compound is synthesized by reacting the compound with a brominating agent.

12. the brominating agent is selected from N-bromosuccinimide, tribromoisocyanuric acid, 1,3-dibromo-5,5-dimethylhydantoin, and bromine; the acid is selected from hydrochloric acid, sulfuric acid, nitric acid, acetic acid, hydrobromic acid, phosphoric acid, formic acid, and trifluoroacetic acid; and 12. The process of claim 11, wherein the solvent is selected from water, ethyl acetate, dichloromethane, tetrahydrofuran, diethyl ether, dimethylformamide, dimethyl sulfoxide, methanol, ethanol, acetone, acetonitrile, 1,4-dioxane, hexane, and methyl tert-butyl ether.

13. a compound of formula (II-D), a brominating agent, an acid, and a solvent, Within 12 hours, At temperatures between 0°C and 15°C, 13. The process of claim 11 or 12, wherein the process is stirred.

14. The process of any one of claims 11 to 13, wherein the compound of formula (II-C) is obtained in a synthetic yield of more than 80%.

15. Compound of formula (II-B) 【Transformation 8】 is a compound of formula (II-E) 【Chemistry 9】 in the presence of a base, 【Chemistry 10】 2. The process of claim 1, wherein the compound is synthesized by reacting

16. 16. The process of claim 15, wherein the base is selected from the group consisting of potassium carbonate, sodium carbonate, potassium bicarbonate, sodium bicarbonate, piperidine, pyridine, 1,8-diazabicyclo[5.4.0]undec-7-ene, sodium tert-butoxide, potassium tert-butoxide, cesium carbonate, potassium phosphate, sodium hydroxide, N,N-diisopropylethylamine, and triethylamine.

17. The compound of formula (II-E), the compound of formula (II-F), and the base are Within two hours, At temperatures between 20°C and 25°C, 17. The process of claim 15 or 16, wherein the process is stirred.

18. The process according to any one of claims 15 to 17, wherein the compound of formula (II-B) is obtained in a synthetic yield of more than 80%.

19. Compound of formula (II-F) 【Chemistry 11】 is a compound of formula (II-G) 【Chemistry 12】 16. The process of claim 15, wherein the compound is synthesized by reacting with an acyl halide preparative agent in the presence of a solvent.

20. the acyl halide modifier is selected from oxalyl chloride, thionyl chloride, phosphoryl chloride, phosphorus trichloride, phosphorus pentachloride, phosgene, diphosgene, triphosgene, and cyanuric chloride; 20. The process of claim 19, wherein the solvent is selected from water, ethyl acetate, dichloromethane, tetrahydrofuran, diethyl ether, dimethylformamide, dimethyl sulfoxide, methanol, ethanol, acetone, acetonitrile, 1,4-dioxane, hexane, and methyl tert-butyl ether.

21. The compound of formula (II-G), an acyl halide preparative agent, and a solvent are Within 16 hours, At temperatures between 20°C and 25°C, 21. The process of claim 19 or 20, wherein the process is stirred.

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