Imidazodiazepine and its method of use

Abstract

We provide TRPC5 inhibitors for use in treating or reducing the risk of developing kidney disease, diabetic retinopathy, anxiety disorders, depression, or cancer. [Solution] Compounds according to formula (I) or (II), and pharmaceutical compositions containing them are disclosed. A therapeutic method using a compound of formula (I) or (II) to treat, for example, kidney disease is also disclosed. JPEG2026086459000081.jpg3992

Description

[Background technology]

[0001] Proteinuria is a condition in which an excess amount of protein from the blood leaks into the urine. Proteinuria can progress from a loss of 30 mg of protein in the urine per 24 hours (called microalbuminuria) to over 300 mg per day (called macroalbuminuria), before the amount of protein in the urine reaches 3.5 grams or more per 24 hours, or 25 times the normal amount. Proteinuria occurs when there is dysfunction in the glomeruli of the kidneys and causes fluid accumulation in the body (edema). Long-term protein leakage has been shown to lead to kidney failure. Nephrotic syndrome (NS) accounts for about 12% of common end-stage renal disease cases in the United States, which cost more than $3 billion annually. About 5 out of 100,000 children are diagnosed with NS each year, and currently 15 out of 100,000 children are living with NS. Even in patients who respond well to treatment, the relapse rate is very high. About 90% of children with nephrotic syndrome respond to treatment, but an estimated 75% relapse. Therefore, there is a need for more effective methods to treat kidney diseases, such as proteinuria, or to reduce the risk of developing them.

[0002] Mammalian TRP channel proteins form six-transmembrane, cation-permeable channels that can be grouped into six subfamilies based on amino acid sequence homology (TRPC, TRPV, TRPM, TRPA, TRPP, and TRPML). Recent studies of TRP channels indicate that they are involved in numerous fundamental cellular functions and are thought to play a crucial role in the pathophysiology of many diseases. Many TRPs are expressed in the kidney along various parts of the nephron, and there is growing evidence that these channels are involved in hereditary and acquired kidney injury. For example, TRPC6, TRPM6, and TRPP2 are involved in hereditary focal segmental glomerulosclerosis (FSGS), hypomagnesemia with secondary hypocalcemia (HSH), and polycystic kidney disease (PKD), respectively. TRPC5 has also been reported to contribute to the underlying mechanisms of the regulation of the innate fear response. (J Neurosci. 2014 Mar 5;34(10):3653-3667).

[0003] Therefore, further inhibitors of TRPC5 are needed. [Overview of the project]

[0004] This invention is at least in part based on the discovery that transient receptor latent cation channel, subfamily C, member 5 (TRPC5) activity eliminates actin stress fibers, reduces focal adhesion formation, and provides a motile, migratory podocyte phenotype.

[0005] In one embodiment, the present invention relates to a low-molecular-weight TRPC5 modulator.

[0006] In some embodiments, the present invention relates to low-molecular-weight TRPC5 inhibitors and the use of such inhibitors in methods of treating or reducing the risk of developing kidney disease (e.g., proteinuria, microalbuminuria, macroalbuminuria), anxiety disorders, depression, or cancer, and includes administering them to subjects who need them.

[0007] In some embodiments, the present invention relates to low-molecular-weight TRPC5 agonists and the use of such agonists in methods for treating obesity or reducing the risk of developing obesity.

[0008] The interaction between small molecule ligands and proteins can result in agonist or antagonist (inhibitory) activity. The structural determinants of agonist or antagonist activity are often not well understood. Antagonism of closely related molecules, and even enantiomers, against the activity of their biological targets has been observed in multiple cases over decades of research. This is particularly common in membrane signaling proteins such as ion channels and GPCRs (X. Huang et al., ACS Med. Chem. Lett. 2018, 9, 679-684; R. Recio et al., Eur J Med Chem 2017, 138, 644-660; Y. Kim et al., Eur J Med Chem 2016, 123, 180-190). Examples of this behavior include the regulation of calcium channels such as DHP receptors (GCRovnyak et al., J Med Chem. 1995, 38(1):119-29, from Neil's email), and cardiac calcium channels (RS Kass, Circ Res 1987, 61(4 Pt 2), I1-5 and others (RPHof et al., J Cardiovasc Pharmacol. 1985, 7(4):689-93)). These references highlight how small structural features can govern whether a compound can act as an agonist or antagonist. Very recently, such a phenomenon was explained in TRPC1 / 4 / 5 channels (HNRubaiy et al., Br J Pharmacol. 2018, 175(5):830-839. doi:10.1111 / bph.14128. Epub 2018 Jan). 25). According to such literature reports, it has been found that formulas I and II described herein include both agonists and inhibitors. Those skilled in the art can easily determine whether a compound of formula I or formula II is a TRPC5 agonist or inhibitor by testing it with the FLIPR assay described herein, or any other assay capable of determining whether a compound is a TRPC5 inhibitor or a TRPC5 agonist.

[0009] The above treatment methods are effective for a variety of subjects including mammals, such as humans and other mammals, such as mice, rats, rabbits, and monkeys, as well as domestic and farm mammals, such as cats, dogs, goats, sheep, pigs, cows, or horses.

[0010] In some embodiments, the compound of the present invention is a compound of formula (I) or (II), or a pharmaceutically acceptable salt thereof:

[0011] [Chemical Formula] (wherein, A and A’ are independently selected from CR and N, R is L-R 1 and L is absent, CH2, O, SO2, or NR 2 and R 1 is selected from optionally substituted alkyl, optionally substituted aryl, and optionally substituted heteroaryl, each R 2 is independently H or alkyl, R 3 is optionally substituted alkyl, optionally substituted alkylene-OR 2 optionally substituted cycloalkylene-OR 2 optionally substituted alkylene-N(R 7 )2, optionally substituted cycloalkylene-N(R 7 )2, optionally substituted alkylene-C(O)N(R 2 )2, optionally substituted cycloalkylene-C(O)N(R 2 )2, optionally substituted alkylene-S(O)2N(R 2 )2, and optionally substituted cycloalkylene-S(O)2N(R 2 )2, R 4 is selected from alkyl, optionally substituted alkylene-aryl, and optionally substituted alkylene-heteroaryl, each R 5H, N(R 2 )2, OR 2 Selected independently from, Each R 7 This is independently selected from H, alkyl, (alkyl)C(O)-, (aryl)C(O)-, (alkyl)S(O)2-, and (aryl)S(O)2. X is -C(O)-, CH2, CHR 6 , C(R 6 )2, Each R 6 This is independently selected from H, alkyl, and optionally substituted alkylene-OH groups. X' is -C(O)-, CH2, CHR 3’ , C(R 3’ )2 or X' is R 3 Together with other elements, they form a 5- or 6-membered ring. Each R 3’ This is an optionally substituted alkyl, optionally substituted alkylene-OR 2 , optionally substituted cycloalkylene-OR 2 , optionally substituted alkylene-N(R 7 )2, optionally substituted cycloalkylene-N(R 7 )2, optionally substituted alkylene-C(O)N(R 2 )2, optionally substituted cycloalkylene-C(O)N(R 2 )2, optionally substituted alkylene-S(O)2N(R 2 )2, and optionally substituted cycloalkylene-S(O)2N(R 2 ) Selected independently from 2, and Z does not exist, CH2, CHR 5 , O, -NR 2 -, or -SO2-, However, not both X and X' are -C(O)-, and if Z is O, NR, or SO2, R 5 (is H).

[0012] In one embodiment, the present invention is characterized by a composition comprising one compound of formula (I) or (II) or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.

[0013] In one embodiment, the present invention features a method for treating or reducing the risk of developing kidney disease, diabetic retinopathy, anxiety, depression, or cancer, comprising administering a therapeutically effective amount of a compound of formula (I) or (II) to a subject in need. In a particular embodiment, kidney disease is treated or the risk of developing kidney disease is reduced. In a particular embodiment, kidney disease is treated. In certain embodiments, the renal disease is selected from the group consisting of focal segmental glomerulosclerosis (FSGS), diabetic nephropathy, Alport syndrome, hypertensive renal disease, nephrotic syndrome, steroid-resistant nephrotic syndrome, minimal change disease, membranous nephropathy, idiopathic membranous nephropathy, membranoproliferative glomerulonephritis (MPGN), immune complex-mediated MPGN, complement-mediated MPGN, lupus nephritis, post-infectious glomerulonephritis, thin basement membrane disease, mesangial proliferative glomerulonephritis, primary amyloidosis, c1q nephropathy, rapidly progressive GN, anti-GBM disease, C3 glomerulonephritis, hypertensive nephrosclerosis, and IgA nephropathy. In certain embodiments, the renal disease is proteinuria. In certain embodiments, the renal disease is microalbuminuria or macroalbuminuria.

[0014] In some embodiments, the present invention features a method for treating obesity or a method for reducing the risk of developing it.

[0015] In certain embodiments, the subject is a mammal. In certain embodiments, the mammal is a human.

[0016] In some embodiments, the present invention comprises administering a compound of formula (I) or (II) to a mammal and evaluating the effect of the compound on calcium transport, wherein the compound that reduces or inhibits calcium transport is a therapeutic agent for treating or reducing the risk of developing kidney disease, anxiety, depression, or cancer.

[0017] The present invention offers several advantages. The preventive and therapeutic methods described herein are effective in treating kidney diseases, such as proteinuria, with minimal side effects, if any. Furthermore, the methods described herein are effective in identifying compounds that treat or reduce the risk of developing kidney diseases, anxiety disorders, depression, or cancer.

[0018] Other characteristics, purposes, and advantages of the present invention will become apparent from the modes for carrying out the invention and the claims. [Modes for carrying out the invention]

[0019] definition The term "acyl" is recognized in the art and refers to a group represented by the general formula hydrocarbyl C(O)-, preferably alkyl C(O)-.

[0020] The term "acylamino" is recognized in the art and refers to an amino group substituted with an acyl group, which can be represented, for example, by the formula hydrocarbyl C(O)NH-.

[0021] The term "acyloxy" is recognized in the art and refers to a group represented by the general formula hydrocarbyl C(O)O-, preferably alkyl C(O)O-.

[0022] The term "alkoxy" refers to an alkyl group, preferably a lower alkyl group, which has an oxygen atom bonded to it. Typical alkoxy groups include methoxy, trifluoromethoxy, ethoxy, propoxy, and tert-butoxy.

[0023] The term "alkoxyalkyl" refers to an alkyl group substituted with an alkoxy group and can be represented by the general formula alkyl-O-alkyl.

[0024] The term "alkenyl," as used herein, refers to an aliphatic group comprising at least one double bond and is intended to include both "unsubstituted alkenyls" and "substituted alkenyls," the latter referring to an alkenyl moiety having substituents that substitute hydrogens on one or more carbons of the alkenyl group. Such substituents may occur on one or more carbons that are not included in the double bond. Furthermore, such substituents include all those intended for alkyl groups, as described below, unless stability is suppressed. For example, substitution of an alkenyl group with one or more alkyl, carbocykryl, aryl, heterocyclyl, or heteroaryl groups is intended.

[0025] An "alkyl" group or "alkane" is a fully saturated linear or branched non-aromatic hydrocarbon. Typically, linear or branched alkyl groups have 1 to about 20 carbon atoms, preferably 1 to about 10, unless otherwise defined. Examples of linear and branched alkyl groups include methyl, ethyl, n-propyl, iso-propyl, n-butyl, sec-butyl, tert-butyl, pentyl, hexyl, pentyl, and octyl. C1-C6 linear or branched alkyl groups are also referred to as "lower alkyl" groups.

[0026] Furthermore, the term “alkyl” (or “lower alkyl” as used herein, in the examples and claims) is intended to include both “unsubstituted alkyl” and “substituted alkyl,” the latter referring to an alkyl moiety having substituents that substitute hydrogens on one or more carbons of a hydrocarbon skeleton. Such substituents may include, unless otherwise specified, halogens (e.g., fluoro), hydroxyl, carbonyl (e.g., carboxyl, alkoxycarbonyl, formyl, or acyl), thiocarbonyl (e.g., thioester, thioacetate, or thioformate), alkoxy, phosphoryl, phosphate, phosphonate, phosphinate, amino, amide, amidine, imine, cyano, nitro, azide, sulfhydryl, alkylthio, sulfate, sulfonate, sulfamoyl, sulfonamide, sulfonyl, heterocyclyl, aralkyl, or aromatic or heteroaromatic moieties. In preferred embodiments, the substituent of the substituted alkyl is C 1-6 Alkyl, C 3-6 The substituents are selected from cycloalkyl, halogen, carbonyl, cyano, or hydroxyl. In more preferred embodiments, the substituents of the substituted alkyl are selected from fluoro, carbonyl, cyano, or hydroxyl. Those skilled in the art will understand that the substituted portion on the hydrocarbon chain may be substituted itself where appropriate. For example, substituents of the substituted alkyl may include amino, azide, imino, amide, phosphoryl (including phosphonates and phosphinates), sulfonyl (including sulfates, sulfonamides, sulfamoyl, and sulfonates), and silyl groups, as well as substituted and unsubstituted forms such as ether, alkylthio, carbonyl (including ketones, aldehydes, carboxylates, and esters), -CF3, -CN, etc. Exemplary substituted alkyls are described below. Cycloalkyls may be further substituted with alkyl, alkenyl, alkoxy, alkylthio, aminoalkyl, carbonyl-substituted alkyl, -CF3, -CN, etc.

[0027] Unless otherwise specified, “alkylene,” either by itself or as part of another substituent, refers to a saturated linear or branched divalent group having the number of carbon atoms listed and derived from the removal of two hydrogen atoms from the corresponding alkane. Examples of linear and branched alkylene groups include -CH2-(methylene), -CH2-CH2-(ethylene), -CH2-CH2-CH2-(propylene), -C(CH3)2-, -CH2-CH(CH3)-, -CH2-CH2-CH2-CH2-, -CH2-CH2-CH2-CH2-CH2-(pentylene), -CH2-CH(CH3)-CH2-, and -CH2-C(CH3)2-CH2-.

[0028] "C x-y The term "C" means, when used with chemical moieties such as acyl, acyloxy, alkyl, alkenyl, alkynyl, or alkoxy, to mean a group containing x to y carbon atoms in the chain. For example, "C x-y The term "alkyl" refers to substituted or unsubstituted saturated hydrocarbon groups, including haloalkyl groups, which include linear and branched alkyl groups containing x to y carbon atoms in the chain. Preferred haloalkyl groups include trifluoromethyl, difluoromethyl, 2,2,2-trifluoroethyl, and pentafluoroethyl. C0 alkyl indicates a hydrogen atom at the terminal position of the group, and a bond if the group is internal. 2-y "Alkenil" and "C 2-y The term "alkynyl" refers to a substituted or unsubstituted unsaturated aliphatic group that is similar in length and possible substitutions to the alkyl group described above, but each contains at least one double or triple bond.

[0029] As used herein, the term "alkylamino" refers to an amino group substituted with at least one alkyl group.

[0030] The term "alkylthio," as used herein, refers to a thiol group substituted with an alkyl group, and may be represented by the general formula alkylS-.

[0031] The term "alkynyl," as used herein, refers to an aliphatic group containing at least one triple bond and is intended to include both "unsubstituted alkynyls" and "substituted alkynyls," the latter referring to an alkynyl moiety having substituents on one or more carbon atoms of the alkynyl group that replace hydrogen. Such substituents may occur on one or more carbon atoms that are included in or not included in the triple bond. Furthermore, such substituents include all those intended for alkyl groups as described above, except in cases where stability is suppressed. For example, substitution of an alkynyl group with one or more alkyl, carbocykryl, aryl, heterocyclyl, or heteroaryl groups is intended.

[0032] The term "amide" as used herein refers to the base

[0033] [ka] This refers to, and in the formula, each R A However, independently, they represent hydrogen or a hydrocarbyl group, or two R A However, together with the N atoms to which they are bonded, they complete a heterocycle with 4 to 8 atoms in the ring structure.

[0034] The terms "amine" and "amino" are recognized in the art and include both unsubstituted and substituted amines, as well as their salts.

[0035] [ka] For example, it refers to the part that can be represented by, in the formula, each R A However, independently, they represent hydrogen or a hydrocarbyl group, or two R A However, together with the N atoms to which they are bonded, they complete a heterocycle with 4 to 8 atoms in the ring structure.

[0036] As used herein, the term "aminoalkyl" refers to an alkyl group substituted with an amino group.

[0037] As used herein, the term "aralkyl" refers to an alkyl group substituted with an aryl group.

[0038] As used herein, the term "aryl" includes substituted or unsubstituted monocyclic aromatic groups, where each atom of the ring is carbon. Preferably, the ring is a 6- to 10-membered ring, more preferably a 6-membered ring. The term "aryl" also includes polycyclic ring systems having two or more cyclic rings, where two or more carbons are common to two adjacent rings, and at least one of the rings is aromatic, for example, the other cyclic rings may be cycloalkyl, cycloalkenyl, aryl, heteroaryl, and / or heterocyclyl. Examples of aryl groups include benzene, naphthalene, phenanthrene, phenol, and aniline.

[0039] The term "carbamate" is recognized in the art and is based on

[0040] [ka] This refers to, and in the formula, each R A However, R independently represents hydrogen, or a hydrocarbyl group such as an alkyl group, or both R A However, together with the intervening atoms (multiple atoms are possible), they complete a heterocycle with a ring structure containing 4 to 8 atoms.

[0041] The terms “carbocyclic ring” and “carbocyclic formula,” as used herein, refer to a saturated or unsaturated ring in which each atom of the ring is carbon. The term “carbocyclic ring” includes both aromatic and non-aromatic carbocyclic rings. Non-aromatic carbocyclic rings include both cycloalkane rings in which all carbon atoms are saturated, and cycloalkene rings containing at least one double bond. “Carbocyclic rings” include 5- to 7-membered monocyclic rings and 8- to 12-membered bicyclic rings. Each ring in a bicyclic carbocyclic ring may be selected from saturated, unsaturated, and aromatic rings. A carbocyclic ring includes a bicyclic molecule in which one, two, or three or more atoms are shared between two rings. The term “fusion carbocyclic ring” refers to a bicyclic carbocyclic ring in which each ring shares two adjacent atoms with the other ring. Each ring in a fusion carbocyclic ring may be selected from saturated, unsaturated, and aromatic rings. In exemplary embodiments, an aromatic ring, such as phenyl, may be fused to a saturated or unsaturated ring, such as cyclohexane, cyclopentane, or cyclohexene. Any combination of saturated, unsaturated, and aromatic bicyclic rings is included in the definition of a carbocyclic ring, provided that valence is permitted. Exemplary “carbocyclic rings” include cyclopentane, cyclohexane, bicyclo[2.2.1]heptane, 1,5-cyclooctadiene, 1,2,3,4-tetrahydronaphthalene, bicyclo[4.2.0]octa-3-ene, naphthalene, and adamantane. Exemplary fused carbocyclic rings include decalin, naphthalene, 1,2,3,4-tetrahydronaphthalene, bicyclo[4.2.0]octane, 4,5,6,7-tetrahydro-1H-indene, and bicyclo[4.1.0]hepta-3-ene. A “carbocyclic ring” may be substituted at any one or more positions that can support hydrogen atoms.

[0042] The "cycloalkyl" group is a cyclic hydrocarbon that is completely saturated. "Cycloalkyl" includes monocyclic and bicyclic rings. Typically, monocyclic cycloalkyls have 3 to about 10 carbon atoms, more typically 3 to 8 carbon atoms, unless otherwise defined. The second ring of a bicyclic cycloalkyl can be selected from saturated, unsaturated, and aromatic rings. Cycloalkyls include bicyclic molecules in which one, two, or three or more atoms are shared between the two rings. The term "fusion cycloalkyl" refers to a bicyclic cycloalkyl in which each ring shares two adjacent atoms with the other ring. The second ring of a fusion bicyclic cycloalkyl can be selected from saturated, unsaturated, and aromatic rings. The "cycloalkenyl" group is a cyclic hydrocarbon containing one or more double bonds.

[0043] As used herein, the term "carbocykrylalkyl" refers to an alkyl group substituted with a carbocyclic group.

[0044] The term "carbonate" is recognized in the relevant technical field, -OCO2-R A It refers to the base, and in the formula, R A This represents a hydrocarbyl group.

[0045] As used herein, the term "carboxyl" refers to the group represented by the formula -CO2H.

[0046] The term "ester" as used herein means -C(O)OR A It refers to the base, and in the formula, R A This represents a hydrocarbyl group.

[0047] As used herein, the term "ether" refers to a hydrocarbyl group bonded to another hydrocarbyl group via oxygen. Therefore, the ether substituent of a hydrocarbyl group can be hydrocarbyl-O-. Ethers may be symmetric or asymmetric. Examples of ethers include, but are not limited to, heterocyclic-O-heterocyclic and aryl-O-heterocyclic groups. Ethers also include "alkoxyalkyl" groups, which can be represented by the general formula alkyl-O-alkyl.

[0048] The terms "halo" and "halogen" as used herein mean halogens, including chloro, fluoro, bromo, and iodine.

[0049] As used herein, the terms "hetallalkyl" and "hetallalkyl" refer to alkyl groups substituted with hetalil groups.

[0050] As used herein, the term "heteroalkyl" refers to a saturated or unsaturated chain of carbon atoms and at least one heteroatom, where no two heteroatoms are adjacent.

[0051] The terms "hetalial" and "hetalial" include substituted or unsubstituted aromatic monocyclic structures, preferably 5- to 7-membered rings, more preferably 5- to 6-membered rings, where the ring structure contains at least one heteroatom, preferably one to four heteroatoms, more preferably one or two heteroatoms. The terms "hetalial" and "hetalial" also include polycyclic ring systems having two or more cyclic rings, where two or more carbons are common to two adjacent rings, and at least one of these rings is heteroaromatic, for example, the other cyclic rings may be cycloalkyl, cycloalkenyl, aryl, heteroaryl, and / or heterocyclyl. Examples of heteroaryl groups include pyrrole, furan, thiophene, imidazole, oxazole, thiazole, pyrazole, pyridine, pyrazine, pyridazine, and pyrimidine.

[0052] As used herein, the term "heteroatom" means an atom of any element other than carbon or hydrogen. Preferred heteroatoms are nitrogen, oxygen, and sulfur.

[0053] The terms “heterocyclyl,” “heterocyclic,” and “heterocyclic formula” refer to substituted or unsubstituted non-aromatic ring structures, preferably 3- to 10-membered rings, more preferably 3- to 7-membered rings, where these ring structures contain at least one heteroatom, preferably one to four heteroatoms, more preferably one or two heteroatoms. The terms “heterocyclyl” and “heterocyclic formula” also include polycyclic ring systems having two or more cyclic rings, where two or more carbons are common to two adjacent rings, and at least one of these rings is heterocyclic, for example, the other cyclic rings may be cycloalkyl, cycloalkenyl, aryl, heteroaryl, and / or heterocyclyl. Examples of heterocyclyl groups include piperidine, piperazine, pyrrolidine, tetrahydropyran, tetrahydrofuran, morpholine, lactone, and lactam.

[0054] The terms "heterocyclylalkyl" or "heterocycloalkyl" as used herein refer to alkyl groups substituted with heterocyclic groups.

[0055] As used herein, the term "hydrocarbyl" refers to a group that typically has at least one carbon-hydrogen bond and is primarily a carbon skeleton, but is bonded via a carbon atom that may optionally contain a heteroatom, and does not have =O or =S substituents. Therefore, groups such as methyl, ethoxyethyl, 2-pyridyl, and trifluoromethyl are considered hydrocarbyl for the purposes of this application, but substituents such as acetyl (which has an =O substituent on the bonded carbon) and ethoxy (bonded via oxygen rather than carbon) are not. Examples of hydrocarbyl groups include, but are not limited to, aryl, heteroaryl, carbocyclic, heterocyclyl, alkyl, alkenyl, alkynyl, and combinations thereof.

[0056] As used herein, the term "hydroxyalkyl" refers to an alkyl group substituted with a hydroxyl group.

[0057] When used with chemical moieties such as acyl, acyloxy, alkyl, alkenyl, alkynyl, or alkoxy, the term “lower” means that the substituent contains 10 or fewer, preferably 6 or fewer, nonhydrogen atoms. “Lower alkyl” refers to an alkyl group containing, for example, 10 or fewer, preferably 6 or fewer carbon atoms. In certain embodiments, the acyl, acyloxy, alkyl, alkenyl, alkynyl, or alkoxy substituents as defined herein are lower acyl, lower acyloxy, lower alkyl, lower alkenyl, lower alkynyl, or lower alkoxy substituents, whether they appear alone or in combination with other substituents, for example, hydroxyalkyl and aralkyl (in this case, for example, when counting the carbon atoms of the alkyl substituent, atoms in the aryl group are not counted).

[0058] The terms “polycyclyl,” “polycyclic,” and “polycyclic formula” refer to two or more rings (e.g., cycloalkyl, cycloalkenyl, aryl, heteroaryl, and / or heterocyclyl) in which two or more atoms are common to two adjacent rings, for example, the rings are “fusion rings.” Each of the rings in a polycyclic compound may be substituted or unsubstituted. In certain embodiments, each ring in a polycyclic compound contains 3 to 10 atoms, preferably 5 to 7 atoms, within the ring.

[0059] The term "silyl" refers to the silicon portion formed by the bonding of three hydrocarbyl moieties.

[0060] The term “substituted” refers to a portion having substituents that replace hydrogens on one or more carbons of a skeleton. “Substituting” or “substituted with ~” will be understood to imply that such substitutions are subject to the permissible valencies of the substituted atom and substituent, and that the substitution results in a stable compound that does not naturally undergo transformations such as rearrangement, cyclization, or exclusion. As used in the present invention, the term “substituted” is considered to include all permissible substituents of an organic compound. In a broad range of embodiments, permissible substituents include acyclic and cyclic, branched and unbranched, carbocyclic and heterocyclic, aromatic and non-aromatic substituents of the organic compound. There may be one or more permissible substituents for a given organic compound, and they may be the same or different. For the purposes of the present invention, heteroatoms such as nitrogen may have hydrogen substituents and / or any permissible substituents of the organic compounds described herein that satisfy the valency of the heteroatom. Substituents may include any substituents described herein, such as halogens, hydroxyls, carbonyls (e.g., carboxyls, alkoxycarbonyls, formyls, or acyls), thiocarbonyls (e.g., thioesters, thioacetates, or thioformates), alkoxyls, phosphoryls, phosphates, phosphonates, phosphinates, aminos, amides, amidines, imines, cyanos, nitros, azides, sulfhydryls, alkylthios, sulfates, sulfonates, sulfamoyls, sulfonamides, sulfonyls, heterocyclyls, aralkyls, or aromatic or heteroaromatic moieties. In preferred embodiments, the substituent of the substituted alkyl is C 1-6 Alkyl, C 3-6 The substituents are selected from cycloalkyl, halogen, carbonyl, cyano, or hydroxyl. In more preferred embodiments, the substituents of the substituted alkyl are selected from fluoro, carbonyl, cyano, or hydroxyl. Those skilled in the art will understand that, where appropriate, the substituents themselves may be substituted. Unless otherwise specifically stated as “unsubstituted”, references to chemical moieties herein are understood to include substituted variants. For example, references to an “aryl” group or moiety implicitly include both substituted and unsubstituted variants.

[0061] The term "sulfate" is recognized in the art and refers to the -OSO3H group or its pharmaceutically acceptable salts.

[0062] The term "sulfonamide" is recognized in the art and has a general formula

[0063] [ka] This refers to the group represented by, and in the formula, each R A However, independently, R represents hydrogen or an alkyl or other hydrocarbyl, or both R. A However, together with the intervening atoms (multiple atoms are possible), they complete a heterocycle with a ring structure containing 4 to 8 atoms.

[0064] The term "sulfoxide" is recognized in the relevant technical field, and -S(O)-R A It refers to the base, and in the formula, R A This represents hydrocarbyl.

[0065] The term "sulfonate" is recognized in the relevant technical field, SO 3H This refers to the compound, or a pharmaceutically acceptable salt thereof.

[0066] The term "sulfone" is recognized in the art, and -S(O)2-R A It refers to the base, and in the formula, R A This represents hydrocarbyl.

[0067] As used herein, the term "thioalkyl" refers to an alkyl group substituted with a thiol group.

[0068] The term "thioester" as used herein refers to -C(O)SR A or -SC(O)R A It refers to the base of, and in the formula, R A This represents hydrocarbyl.

[0069] As used herein, the term "thioether" is equivalent to "ether," in which oxygen is substituted with sulfur.

[0070] The term "urea" is recognized in the relevant technical field, and the general formula

[0071] [ka] It can be expressed by, in the formula, each R A However, R independently represents hydrogen or a hydrocarbyl such as an alkyl group, or together with another and intervening atom(s). A Any appearance of completes a heterocycle having 4 to 8 atoms in its ring structure.

[0072] A "protecting group" refers to a group of atoms that, when bonded to a reactive functional group in a molecule, mask, reduce, or prevent the reactivity of that functional group. Typically, protecting groups can be selectively removed during the course of synthesis if desired. Examples of protecting groups can be found in Greene and Wuts, Protective Groups in Organic Chemistry, 3rd Ed., 1999, John Wiley & Sons, NY, and Harrison et al., Compendium of Synthetic Organic Methods, Vols. 1-8, 1971-1996, John Wiley & Sons, NY. Representative nitrogen protecting groups include, but are not limited to, formyl, acetyl, trifluoroacetyl, benzyl, benzyloxycarbonyl ("CBZ"), tert-butoxycarbonyl ("Boc"), trimethylsilyl ("TMS"), 2-trimethylsilyl-ethanesulfonyl ("TES"), trityl and substituted trityl groups, allyloxycarbonyl, 9-fluorenylmethyloxycarbonyl ("FMOC"), and nitro-veratryloxycarbonyl ("NVOC"). Representative hydroxyl protecting groups include, but are not limited to, those in which the hydroxyl group is acylated (esterified) or alkylated, such as benzyl and trityl ethers, as well as alkyl ethers, tetrahydropyranyl ethers, trialkylsilyl ethers (e.g., TMS or TIPS groups), glycol ethers (e.g., ethylene glycol and propylene glycol derivatives), and allyl ethers.

[0073] As used herein, a therapeutic agent that “prevents” a disorder or condition means a compound that reduces or delays the occurrence of a disorder or condition in a treated sample compared to an untreated control sample in a statistical sample, or reduces the severity of one or more symptoms of a disorder or condition compared to an untreated control sample.

[0074] The term “to treat” includes prophylactic and / or therapeutic measures. The term “prophylactic or therapeutic” measure is recognized in the art and includes the administration of one or more of the composition in question to a host. If it is administered before the clinical manifestations of an undesirable condition (e.g., disease or other undesirable condition in a host animal), the treatment is prophylactic (i.e., it protects the host from the onset of the undesirable condition), whereas if it is administered after the appearance of an undesirable condition, the treatment is therapeutic (i.e., it aims to reduce, improve or stabilize an existing undesirable condition or its side effects).

[0075] The phrases “combined administration” and “administered in combination” refer to any form of administration of two or more different therapeutic compounds such that a second compound is administered while a previously administered therapeutic compound is still effective in the body (for example, the two compounds may be effective simultaneously in the patient, and a synergistic effect of the two compounds may be involved). For example, different therapeutic compounds may be administered simultaneously or sequentially, in the same formulation or in separate formulations. In certain embodiments, different therapeutic compounds may be administered to each other within 1 hour, 12 hours, 24 hours, 36 hours, 48 ​​hours, 72 hours, or 1 week. Thus, an individual receiving such treatment may benefit from the combined effects of the different therapeutic compounds.

[0076] The term "prodrug" is intended to encompass compounds that, under physiological conditions, are converted into the therapeutic activators of the present invention. A common method for preparing prodrugs is to include one or more selected moieties that have been hydrolyzed under physiological conditions to reveal the desired molecule. In other embodiments, prodrugs are converted by the enzymatic activity of a host animal. For example, esters or carbonates (e.g., esters or carbonates of alcohols or carboxylic acids) are preferred prodrugs of the present invention. In certain embodiments, some or all of the compounds of the present invention in the above formulations may be replaced with corresponding suitable prodrugs, for example, hydroxyl in the parent compound being presented as an ester or carbonate, or carboxylic acids present in the parent compound being presented as esters.

[0077] As used herein, "low molecular weight" refers to small organic or inorganic molecules with a molecular weight of less than approximately 3,000 daltons. Generally, low molecular weight molecules useful in the present invention have a molecular weight of less than 3,000 daltons (Da). Small molecules may be, for example, at least about 100 Da to about 3,000 Da (e.g., about 100 to about 3,000 Da, about 100 to about 2,500 Da, about 100 to about 2,000 Da, about 100 to about 1,750 Da, about 100 to about 1,500 Da, about 100 to about 1,250 Da, about 100 to about 1,000 Da, about 100 to about 750 Da, about 100 to about 500 Da, about 200 to about 1,500, about 500 to about 1,000, about 300 to about 1,000 Da, or about 100 to about 250 Da).

[0078] In some embodiments, “low molecular weight” typically refers to organic, inorganic, or organometallic compounds having a molecular weight of less than approximately 1000. In some embodiments, the low molecular weight is an organic compound with a size of approximately 1 nm. In some embodiments, the low molecular weight drugs of the present invention include oligopeptides and other biomolecules having a molecular weight of less than approximately 1000.

[0079] An "effective dose" is an amount sufficient to produce a beneficial or desired result. For example, a therapeutic dose is an amount that achieves a desired therapeutic effect. This amount may be the same as or different from the prophylactic effective dose, and is the amount necessary to prevent the onset of the disease or symptoms of the disease. An effective dose may be administered in one or more doses, applications, or applications. The therapeutic effective dose of a composition depends on the composition selected. The composition may be administered at least once a day to at least once a week (including every other day). Those skilled in the art will understand that certain factors, including but not limited to the severity of the disease or disorder, previous treatments, general health, and / or the age of the subject, and other pre-existing diseases, may influence the dose and timing required to effectively treat the subject. Furthermore, the treatment of a subject with the compositions described herein in terms of the therapeutic effective dose may include a single treatment or a series of treatments.

[0080] The compound of the present invention One aspect of the present invention provides a small molecule modulator of TRPC5. In some embodiments, the present invention provides a small molecule inhibitor of TRPC5. In some embodiments, the present invention provides a small molecule agonist of TRPC5.

[0081] In some embodiments, the compound of the present invention is a compound of formula (I) or (II), or a pharmaceutically acceptable salt thereof:

[0082] [ka] (In the formula, A and A' are selected independently from CR and N. R stands for LR 1 And, L does not exist; CH2, O, SO2, or NR 2 And, R 1 is selected from optionally substituted alkyl, optionally substituted aryl, and optionally substituted heteroaryl, and if L is not present, R 1 Further selections are made from H, Each R2 is independently H or alkyl, R 3 is optionally substituted alkyl, optionally substituted alkylene-OR 2 , optionally substituted cycloalkylene-OR 2 , optionally substituted alkylene-N(R 7 )2, optionally substituted cycloalkylene-N(R 7 )2, optionally substituted alkylene-C(O)N(R 2 )2, optionally substituted cycloalkylene-C(O)N(R 2 )2, optionally substituted alkylene-S(O)2N(R 2 )2, and optionally substituted cycloalkylene-S(O)2N(R 2 )2, and is selected from R 4 is selected from alkyl, optionally substituted alkylene-aryl, and optionally substituted alkylene-heteroaryl, each R 5 is independently selected from H, N(R 2 )2, OR 2 , each R 7 is independently selected from H, alkyl, (alkyl)C(O)-, (aryl)C(O)-, (alkyl)S(O)2-, and (aryl)S(O)2, X is -C(O)-, CH2, CHR 6 , C(R 6 )2, each R 6 is independently selected from H, alkyl, and optionally substituted alkylene-OH, X' is -C(O)-, CH2, CHR 3’ , C(R 3’ )2, or X' together with R 3 forms a 5- or 6-membered ring, each R 3’ is optionally substituted alkyl, optionally substituted alkylene-OR 2 , optionally substituted cycloalkylene-OR 2 , optionally substituted alkylene-N(R 7) 2. Independently selected from optionally substituted cycloalkylene-N(R 7 ) 2. Optionally substituted alkylene-C(O)N(R 2 ) 2. Optionally substituted cycloalkylene-C(O)N(R 2 ) 2. Optionally substituted alkylene-S(O)2N(R 2 ) 2. And optionally substituted cycloalkylene-S(O)2N(R 2 ) 2, and Z is absent, CH2, CHR 5 , O, -NR 2 -, or -SO2-, and provided that both X and X' are not -C(O)-, and when Z is O, NR, or SO2, R 5 is H).

[0083] In some embodiments, the compound is a compound of formula (I). In some embodiments, the compound is a compound of formula (II).

[0084] In some embodiments, at least one of A and A' is CR.

[0085] In some embodiments, A is N. In some embodiments, A is CR.

[0086] In some embodiments, A' is N. In some embodiments, A' is CR.

[0087] In some embodiments, A' is N and A is CR.

[0088] In some embodiments, R is L-R 1 is.

[0089] In some embodiments, L is absent. In some embodiments, when L is absent, R 1L is further selected from H. In some embodiments, L is CH2. In some embodiments, L is O. In some embodiments, L is SO2. In some embodiments, L is NR 2 That is the case.

[0090] In some embodiments, R 1 is an arbitrarily substituted aryl. In some embodiments, R 1 R is an optionally substituted phenyl. In some embodiments, R 1 is a substituted phenyl molecule. In some embodiments, the substituted phenyl molecule is substituted with one or more substituents independently selected from halogens, -CF3, -C(H)F2, and -OCF3.

[0091] In some embodiments, R 1 is an optionally substituted alkyl group. In some embodiments, the alkyl group is selected from methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, and tert-butyl.

[0092] In some embodiments, R 1 R is an optionally substituted heteroaryl. In some embodiments, R 1 This is a substituted heteroaryl compound substituted with one or more substituents independently selected from halogen, -CF3, -C(H)F2, and -OCF3.

[0093] In some embodiments, L is O and R 1 These are 3-chlorophenyl, 3-fluorophenyl, 3-trifluoromethoxyphenyl, isopropyl, or n-propyl.

[0094] In some embodiments, R 2 is H. In some embodiments, R 2 is alkyl. In some embodiments, R 2R is selected from methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, and tert-butyl. In some embodiments, R 2 It is methyl.

[0095] In some embodiments, R 3 R is an optionally substituted alkyl group. In some embodiments, R 3 is an optionally substituted alkylene-OR 2 In some embodiments, R 3 This is an optionally substituted cycloalkylene-OR 2 In some embodiments, R 3 This is an arbitrarily substituted alkylene-N(R 7 )2. In some embodiments, R 3 This is an optionally substituted cycloalkylene-N(R 7 )2. In some embodiments, R 3 This is an optionally substituted alkylene-C(O)N(R 2 )2. In some embodiments, R 3 This is an optionally substituted cycloalkylene-C(O)N(R 2 )2. In some embodiments, R 3 This is an optionally substituted alkylene-S(O)2N(R 2 )2. In some embodiments, R 3 This is an optionally substituted cycloalkylene-S(O)2N(R 2 )2. In some embodiments, R 3 These are methyl, 2-hydroxyethyl, 2,3-dihydroxypropyl, 2,2-difluoro-3-hydroxypropyl, 3-hydroxypropyl, 3-methoxypropyl, 3-hydroxycyclobutyl, or 3-hydroxycyclopentyl.

[0096] In some embodiments, R 7 One example is H, and also R 7A second example is alkyl, (alkyl)C(O)-, (aryl)C(O)-, (alkyl)S(O)2-, or (aryl)S(O)2-. In some embodiments, R 7 One example is alkyl, and also R 7 A second example is H, (alkyl)C(O)-, (aryl)C(O)-, (alkyl)S(O)2-, or (aryl)S(O)2-. In some embodiments, R 7 Both examples are H. In some embodiments, R 7 Both examples are alkyl groups.

[0097] In some embodiments, R 3 teeth,

[0098] [ka] Selected from. In some embodiments, R 3 teeth,

[0099] [ka] That is the case.

[0100] In some embodiments, R 3 teeth,

[0101] [ka] Selected from.

[0102] In some embodiments, R 3 teeth,

[0103] [ka] Selected from.

[0104] In some embodiments, R 4 is alkyl. In some embodiments, R 4R is selected from methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, and tert-butyl. In some embodiments, R 4 R is selected from n-butyl, iso-butyl, and tert-butyl. In some embodiments, R 4 It is n-butyl.

[0105] In some embodiments, R 4 is an optionally substituted alkylene-aryl. In some embodiments, the alkylene of the alkylene-aryl is substituted. In some embodiments, the aryl of the alkylene-aryl is substituted. In some embodiments, the substituted aryl is substituted with a halogen, -CF3, -C(H)F2, or -OCF3. In some embodiments, the aryl of the alkylene-aryl is an optionally substituted phenyl. In some embodiments, the phenyl is substituted with one or more halogens. In some embodiments, the alkylene of the alkylene-aryl is methylene. In some embodiments, R 4 This is an arbitrarily substituted alkylene heteroaryl.

[0106] In some embodiments, R 4 These are n-butyl, 4-chlorobenzyl, or 2-(4-chlorophenyl)ethane-2-yl.

[0107] In some embodiments, R 4 teeth

[0108] [ka] In some embodiments, R 4 teeth

[0109] [ka] In some embodiments, R 4 teeth

[0110] [ka] That is the case.

[0111] Several embodiments, each R 5 is H. In some embodiments, one R 5 R is hydrogen, and the other R is hydrogen. 5 is -O-alkyl. In some embodiments, one R 5 R is hydrogen, and the other R is hydrogen. 5 is -OMe. In some embodiments, one R 5 R is hydrogen, and the other R is hydrogen. 5 is -OH. In some embodiments, one R 5 R is hydrogen, and the other R is hydrogen. 5 is -NMe2. In some embodiments, one R 5 R is hydrogen, and the other R is hydrogen. 5 It is -NH2.

[0112] In some embodiments, X is -C(O)-. In some embodiments, X is CH2. In some embodiments, X is -CHR 6 - is. In some embodiments, X is -C(R 6 )2-. In some embodiments, R 6 is alkyl. In some embodiments, R 6 R is selected from methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, and tert-butyl. In some embodiments, R 6 is methyl. In some embodiments, R 6 is an optionally substituted alkylene-OH. In some embodiments, R 6 R is an optionally substituted ethylene-OH. In some embodiments, R 6 R is a substituted ethylene-OH. In some embodiments, R 6 H is H.

[0113] In some embodiments, X' is -C(O)-. In some embodiments, X' is CH2.

[0114] In some embodiments, X' is -CHR 3’ - is. In some embodiments, X' is -C(R 3’ )2-. In some embodiments, R 3’ is alkyl. In some embodiments, R 3’ R is selected from methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, and tert-butyl. In some embodiments, R 3’ is methyl. In some embodiments, R 3’ is an optionally substituted alkylene-OH. In some embodiments, R 3’ R is an optionally substituted ethylene-OH. In some embodiments, R 3’ This is a substituted ethylene-OH group.

[0115] In some embodiments, Z is absent. In some embodiments, Z is CH2. In some embodiments, Z is -N(alkyl)-. In some embodiments, Z is selected from -N(n-butyl)-, -N(iso-butyl)-, and -N(tert-butyl)-. In some embodiments, Z is -SO2-. In some embodiments, Z is absent, and each R 5 It is hydrogen.

[0116] In some embodiments, the compound is

[0117] [ka] Selected from.

[0118] In some embodiments, the compound is

[0119] [ka] That is the case.

[0120] In some embodiments, the compound is

[0121] [ka] That is the case.

[0122] In some embodiments, the compound is

[0123] [ka] Selected from.

[0124] In some embodiments, the compound is

[0125] [ka]

[0126] [ka] Selected from.

[0127] In some embodiments, the compound is

[0128] [ka] Selected from.

[0129] In some embodiments, the compound is

[0130] [ka] That is the case.

[0131] In some embodiments, the compound is

[0132] [ka] That is the case.

[0133] In some embodiments, the compound is

[0134] [ka] That is the case.

[0135] In some embodiments, the compound is

[0136] [ka] That is the case.

[0137] In some embodiments, the compound is

[0138] [ka] That is the case.

[0139] In certain embodiments, the compounds of the present invention may be racemic. In certain embodiments, the compounds of the present invention may be rich in one enantiomer. For example, the compounds of the present invention may have more than 30% ee, more than 40% ee, more than 50% ee, more than 60% ee, more than 70% ee, more than 80% ee, more than 90% ee, or even more than 95% ee.

[0140] The compounds of the present invention have multiple stereocenters. Therefore, the compounds of the present invention may be rich in one or more diastereomers. For example, the compounds of the present invention may have more than 30% de, more than 40% de, more than 50% de, more than 60% de, more than 70% de, more than 80% de, more than 90% de, or even more than 95% de. In certain embodiments, the compounds of the present invention have substantially one isomer configuration in one or more stereocenters and multiple isomer configurations in the remaining stereocenters.

[0141] In certain embodiments, the steric center enantiomer excess is at least 40%ee, 50%ee, 60%ee, 70%ee, 80%ee, 90%ee, 92%ee, 94%ee, 95%ee, 96%ee, 98%ee or higher.

[0142] As used herein, single bonds depicted without stereochemistry do not represent the stereochemistry of a compound.

[0143] As used herein, hash or bold non-wedge bonds indicate a relative but not absolute stereochemical configuration (e.g., not distinguishing between enantiomers of a given diastereomer).

[0144] As used herein, hash or bold wedge bonds represent absolute stereochemical configurations.

[0145] In certain embodiments, therapeutic preparations of the compounds of the present invention may be rich in providing primarily one enantiomer of the compound. Enantiomer-rich mixtures may, for example, contain at least 60 mole percent, or more preferably at least 75, 90, 95, or even 99 mole percent, of one enantiomer. In certain embodiments, a compound rich in one enantiomer may be substantially free of the other enantiomer, by which it means that the substance in question accounts for less than 10%, or less than 5%, or less than 4%, or less than 3%, or less than 2%, or less than 1%, compared to the amount of the other enantiomers in the composition or compound mixture. For example, if a composition or compound mixture contains 98 grams of the first enantiomer and 2 grams of the second enantiomer, it is considered to contain 98 mole percent of the first enantiomer and only 2% of the second enantiomer.

[0146] In certain embodiments, the therapeutic preparation may be rich in providing primarily one diastereomer of the compound of the present invention. A diastereomer-rich mixture may, for example, contain at least 60 mole percent, or more preferably at least 75, 90, 95, or even 99 mole percent, of one diastereomer.

[0147] Treatment method Non-selective Ca 2+ Permeable transient receptor potential (TRP) channels function as sensors that translate extracellular cues into the intracellular environment in a variety of cellular processes, including actin remodeling and cell migration (Greka et al., Nat Neurosci 6, 837-845, 2003; Ramsey et al., Annu Rev Physiol 68, 619-647, 2006; Montell, Pflugers Arch 451, 19-28, 2005; Clapham, Nature 426, 517-524, 2003). Dynamic rearrangement of the actin cytoskeleton is spatiotemporally regulated Ca 2+ These changes are influx-dependent (Zheng and Poo, Annu Rev Cell Dev Biol 23, 375-404, 2007); Brandman and Meyer, Science 322, 390-395, 2008); Collins and Meyer, Dev Cell 16, 160-161, 2009), and the small GTPases RhoA and Rac1 function as important modulators of these changes (Etienne-Manneville and Hall, Nature 420, 629-635, 2002); Raftopoulou and Hall, Dev Biol 265, 23-32, 2004). RhoA induces the formation of stress fibers and focal adhesions, while Rac1 mediates the formation of lamellipodia (Etienne-Manneville and Hall, Nature 420, 629-635, 2002). Transient receptor potential cation channels, subfamily C, member 5 (TRPC5) act in conjunction with TRPC6 to stimulate Ca in renal podocytes and fibroblasts. 2+Regulates influx, actin remodeling, and cell motility. Ca mediated by TRPC5 2+ Influx increases Rac1 activity, but via TRPC6 Ca 2+ Influx promotes RhoA activity. Gene silencing of the TRPC6 channel eliminates stress fibers, reduces focal contact, and results in a phenotype of motile, migratory cells. In contrast, gene silencing of the TRPC5 channel facilitates stress fiber formation and results in a phenotype of contractile cells. The results described herein reveal a conserved signaling mechanism in which the TRPC5 and TRPC6 channels control a tightly regulated balance of cytoskeletal dynamics through differential binding to Rac1 and RhoA.

[0148] Ca of the actin cytoskeleton 2+ Dependent remodeling is a dynamic process that drives cell migration (Wei et al., Nature 457, 901-905, 2009). RhoA and Rac1 function as switches involved in the rearrangement of the cytoskeleton of migrating cells (Etienne-Manneville and Hall, Nature 420, 629-635, 2002; Raftopoulou and Hall, Dev Biol 265, 23-32, 2004). Rac1 activation mediates a motile cell phenotype, while RhoA activity promotes a contractile phenotype (Etienne-Manneville and Hall, Nature 420, 629-635, 2002). Ca 2+ It plays a central role in small-scale GTPase regulation (Aspenstrom et al., Biochem J 377, 327-337, 2004). Ca 2+ Spatially and temporally restricted flicker is abundant near the tip of migrating cells (Wei et al., Nature 457, 901-905, 2009). Therefore, Ca 2+Microdomains have been added as a key event at the forefront of local bursts of Rac1 activity (Gardiner et al., Curr Biol 12, 2029-2034, 2002; Machacek et al., Nature 461, 99-103, 2009). To date, Ca, which is involved in GTPase regulation, has been identified. 2+ The source of the influx is largely unknown. TRP (transient receptor latent) channels are temporally and spatially restricted Ca25 channels associated with cell migration in fibroblasts and nerve growth cones. 2+ They generate signals. Specifically, TRPC5 channels are known regulators of nerve growth cone guidance 1, and their activity in neurons depends on PI3K and Rac1 activity (Bezzerides et al., Nat Cell Biol 6, 709-720, 2004).

[0149] Podocytes are nerve-like cells derived from the metanephrine mesenchyme of the renal glomeruli and are essential for the formation of the renal filtration apparatus (Somlo and Mundel, Nat Genet. 24, 333-335, 2000; Fukasawa et al., J Am Soc Nephrol 20, 1491-1503, 2009). Podocytes possess a sophisticated repertoire of cytoskeletal adaptations to environmental cues (Somlo and Mundel, Nat Genet 24, 333-335, 2000; Garg et al., Mol Cell Biol 27, 8698-8712, 2007; Verma et al., J Clin Invest 116, 1346-1359, 2006; Verma et al., J Biol Chem 278, 20716-20723, 2003; Barletta et al., J Biol Chem 278, 19266-19271, 2003; Holzman et al., Kidney Int 56, 1481-1491, 1999; Ahola et al., Am J Pathol 155,907-913,1999; Tryggvason and Wartiovaara, N Engl J Med 354,1387-1401,2006; Schnabel and Farquhar, J Cell Biol 111,1255-1263,1990; Kurihara et al., Proc Natl Acad Sci USA 89,7075-7079,1992). Early events of podocyte damage include dysregulation of the actin cytoskeleton (Faul et al., Trends Cell Biol 17,428-437,2007; Takeda et al., J Clin Invest 108,289-301,2001; Asanuma et al., Nat Cell Biol 8,485-491,2006) and Ca 2+It is characterized by homeostasis (Hunt et al., J Am Soc Nephrol 16, 1593-1602, 2005; Faul et al., Nat Med 14, 931-938, 2008). These changes are associated with the development of proteinuria, loss of albumin into the urinary lumen, and ultimately renal failure (Tryggvason and Wartiovaara, N Engl J Med 354, 1387-1401, 2006). The vasoactive hormone angiotensin II is involved in Ca in podocytes. 2+ It induces inflow, and prolonged treatment leads to the loss of stress fibers (Hsu et al., J Mol Med 86, 1379-1394, 2008). Ca 2+ While a link between cell influx and cytoskeletal reorganization is recognized, the mechanism by which podocytes sense and convert extracellular cues that regulate cell shape and motility remains unknown. Although TRP standard 6 (TRPC6) channel mutations are associated with podocyte damage (Winn et al., Science 308, 1801-1804, 2005; Reiser et al., Nat Genet 37, 739-744, 2005; Moller et al., J Am Soc Nephrol 18, 29-36, 2007; Hsu et al., Biochim Biophys Acta 1772, 928-936, 2007), little is known about the specific pathways that control this process. Furthermore, TRPC6 is closely homologous to the other six members of the TRPC channel family (Ramsey et al., Annu Rev Physiol 68, 619-647, 2006; Clapham, Nature 426, 517-524, 2003). The TRPC5 channel antagonizes the activity of the TRPC6 channel and regulates a tightly controlled balance of cytoskeletal dynamics through differential binding to a separate, small GTPase.

[0150] Proteinuria Proteinuria is a pathological condition in which proteins are present in urine. Albuminuria is a type of proteinuria. Microalbuminuria occurs when the kidneys leak small amounts of albumin into the urine. In a normally functioning body, albumin is retained in the bloodstream by the kidneys and thus is not normally present in urine. Microalbuminuria is diagnosed by a 24-hour urine collection (20 - 200 μg / min) or, more commonly, by at least two high concentrations (30 - 300 mg / L). Microalbuminuria can be a precursor to diabetic nephropathy. Albumin levels exceeding these values are called macroalbuminuria. For example, subjects in certain conditions such as diabetic nephropathy can progress from microalbuminuria to macroalbuminuria and may reach the nephrotic range (more than 3.5 g / 24 hours) when the kidney disease reaches an advanced stage.

[0151] Causes of Proteinuria Proteinuria can be associated with many conditions, including focal segmental glomerulosclerosis, IgA nephropathy, diabetic nephropathy, lupus nephritis, membranoproliferative glomerulonephritis, rapidly progressive (crescentic) glomerulonephritis, and membranous glomerulonephritis.

[0152] A. Focal Segmental Glomerulosclerosis (FSGS) Focal segmental glomerulosclerosis (FSGS) is a disease that attacks the filtering system (glomeruli) of the kidneys, causing severe scarring. FSGS is one of the many causes of the disease known as nephrotic syndrome, which occurs when proteins in the blood leak into the urine (proteinuria).

[0153] There are few treatment options available for patients with FSGS. Many patients are treated with steroid therapy, most of which has very severe side effects. Some patients have been shown to respond positively not only to blood pressure medications that lower protein levels in the urine but also to immunosuppressive drugs. To date, there is no generally accepted effective treatment or cure, and there is no FDA-approved drug for treating FSGS. Therefore, a more effective way to reduce or suppress proteinuria is desired.

[0154] B. IgA nephropathy IgA nephropathy (also known as IgA nephritis, IgAN, Berger's disease, and synpharyngitic glomerulonephritis) is a type of glomerulonephritis (inflammation of the glomeruli of the kidneys). IgA nephropathy is the most common type of glomerulonephritis worldwide. Primary IgA nephropathy is characterized by the deposition of IgA antibodies in the glomeruli. There are other diseases associated with glomerular IgA deposition, the most common of which is Henoch-Schönlein purpura (HSP), which many consider to be a systemic form of IgA nephropathy. Henoch-Schönlein purpura presents with a characteristic purpuric skin rash, arthritis, and abdominal pain, and occurs more commonly in young adults (16-35 years of age). HSP is associated with a more benign prognosis than IgA nephropathy. In IgA nephropathy, progression to chronic renal failure is slower in 25-30% of cases over 20 years.

[0155] C. Diabetic nephropathy Diabetic nephropathy, also known as Kimmel-Steel-Wilson syndrome and capillary glomerulonephritis, is a progressive renal disease caused by vascular damage to the capillaries of the renal glomeruli. It is characterized by nephrotic syndrome and diffuse glomerulosclerosis. It is caused by long-term diabetes and is a major cause of dialysis. The earliest detectable change in the course of diabetic nephropathy is glomerular thickening. At this stage, the kidneys may begin to produce more serum albumin in the urine than normal. As diabetic nephropathy progresses, the number of glomeruli destroyed by tuberous glomerulosclerosis increases, and the amount of albumin excreted in the urine increases.

[0156] D. lupus nephritis Lupus nephritis is a kidney disorder that is a complication of systemic lupus erythematosus (SLU) disease. Lupus nephritis occurs when antibodies and complement accumulate in the kidneys, causing inflammation. It often leads to proteinuria and can rapidly progress to kidney failure. Nitrogenous waste products accumulate in the bloodstream. SLU) disease causes various disorders of the internal structure of the kidneys, including interstitial nephritis. Lupus nephritis affects approximately 3 in 10,000 people.

[0157] E. Membranoproliferative glomerulonephritis I / II / III Membranoproliferative glomerulonephritis is a type of glomerulonephritis caused by deposition in the renal glomerular mesangium and basement membrane thickening, complement activation, and glomerular damage. There are three types of membranoproliferative glomerulonephritis. Type I is caused by immune complexes deposited in the kidney and is thought to be associated with the classical complement pathway. Type II is similar to Type I but is thought to be associated with the secondary complement pathway. Type III is very rare and is characterized by mixed subepithelial deposition and the typical pathological findings of Type I disease.

[0158] F. Progressive (crescent-shaped) glomerulonephritis Progressive (crescent-type) glomerulonephritis (PG) is a renal syndrome that, if left untreated, rapidly progresses to acute renal failure and death within months. In 50% of cases, PG is associated with an underlying condition such as Goodpasture syndrome, systemic lupus erythematosus, or Wegener's granulomatosis, while the remaining cases are idiopathic. Regardless of the underlying condition, PG involves severe damage to the glomeruli of the kidney, many of which contain characteristic crescent-shaped scars. Patients with PG have hematuria and proteinuria, and may also have hypertension and edema. The clinical presentation is consistent with nephritis syndrome, but the degree of proteinuria can exceed 3 g / 24 hours, a range associated with nephrotic syndrome. Untreated disease can progress to decreased urine output (oliguria), which is associated with decreased renal function.

[0159] G. Membranephritis Membraneolephritis (MGN) is a progressively worsening kidney disease that primarily affects patients aged 30 to 50, usually of Caucasian descent. It can develop into nephrotic syndrome. MGN is caused by the circulation of immune complexes. Current research indicates that the majority of immune complexes are formed through the in situ binding of antibodies against antigens to the glomerular basement membrane. These antigens can be endogenous to the basement membrane or deposited from the systemic circulation.

[0160] H. Obesity Experimentally induced TrpC5 deficiency in mice has been shown to cause a positive energy balance leading to excessive weight gain (Y Gao et al., Cell Rep 2017, 18(3), pp. 583-92). Therefore, TrpC5 agonism may lead to a reduction in obesity.

[0161] Measurement of urinary protein levels Urine protein levels can be measured using methods known in the art. Until recently, accurate measurement of protein required a 24-hour urine collection. In a 24-hour collection, the patient urinates and places it in a refrigerated container until going to the toilet. The patient is instructed to begin urine collection after the first toilet use in the morning. All remaining urine droplets for the day are collected in the container. The following morning, the patient adds the first urination after waking up, completing the collection.

[0162] Recently, researchers have discovered that a single urine sample can provide the necessary information. The new method compares the amount of albumin in a urine sample to the amount of creatinine, a waste product of normal muscle breakdown. This measurement is called the urinary albumin-creatinine ratio (UACR). Urine samples containing more than 30 milligrams of albumin per gram of creatinine (30 mg / g) are flagged as potentially problematic. If a clinical test exceeds 30 mg / g, another UACR test must be performed 1-2 weeks later. If the second test also shows high levels of protein, the person has persistent proteinuria, a sign of impaired renal function, and additional tests are needed to assess renal function.

[0163] A test that measures the amount of creatinine in the blood also indicates whether the kidney in question is efficiently removing waste products. Too much creatinine in the blood is a sign of damage to a person's kidneys. Doctors can use creatinine measurements to estimate how efficiently the kidneys filter blood. This calculation is called the estimated glomerular filtration rate, or eGFR. Chronic kidney disease is present when the eGFR is less than 60 milliliters / minute (mL / min).

[0164] TRPC5 TRPCs are a family of transient receptor potential cation channels in animals. TRPC5 is a subtype of the TRPC family of transient receptor potential ion channels in mammals. Three examples of TRPC5 are highlighted in Table 1 below.

[0165] [Table 1]

[0166] Accordingly, in certain embodiments, the present invention provides a method for treating renal disease or reducing the risk of developing it, comprising administering a therapeutically effective amount of the TRPC5 inhibitor compound of the present invention (e.g., a TRPC5 inhibitor compound of formula I or II), or a pharmaceutical composition containing the compound, to a subject in need.

[0167] In some embodiments, the kidney disease is selected from the group consisting of focal segmental glomerulosclerosis (FSGS), diabetic nephropathy, Alport syndrome, hypertensive kidney disease, nephrotic syndrome, steroid-resistant nephrotic syndrome, minimal change disease, membranous nephropathy, idiopathic membranous nephropathy, membranoproliferative glomerulonephritis (MPGN), immune complex-mediated MPGN, complement-mediated MPGN, lupus nephritis, post-infectious glomerulonephritis, thin basement membrane disease, mesangial proliferative glomerulonephritis, primary amyloidosis, c1q nephropathy, rapidly progressive GN, anti-GBM disease, C3 glomerulonephritis, hypertensive nephrosclerosis, and IgA nephropathy. In some embodiments, the kidney disease is proteinuria. In some embodiments, the kidney disease is microalbuminuria or macroalbuminuria.

[0168] The present invention also provides a method for treating anxiety, depression, or cancer, or reducing the risk of developing them, comprising administering a therapeutically effective amount of the TRPC5 inhibitor compound of the present invention (e.g., a TRPC5 inhibitor compound of formula I or II), or a pharmaceutical composition containing the compound, to a subject in need.

[0169] In certain embodiments, the present invention provides a method of treating obesity or reducing the risk of its development, comprising administering to a subject in need thereof a therapeutically effective amount of a TRPC5 agonist compound of the present invention (e.g., a TRPC5 agonist compound of Formula I or II), or a pharmaceutical composition comprising the compound.

[0170] Subject to be treated In one aspect of the present invention, the subject is selected based on having or being at risk of developing a renal disease, anxiety, depression, or cancer.

[0171] Subjects having or at risk of developing proteinuria include those with diabetes, hypertension, or a particular family background. In the United States, diabetes is the main cause of end-stage renal disease (ESRD). In both type 1 and type 2 diabetes, albumin in the urine is one of the first signs of kidney function deterioration. As kidney function declines, the amount of albumin in the urine increases. Another risk factor for developing proteinuria is hypertension. Proteinuria in hypertensive humans is an indicator of kidney function decline. If hypertension is not controlled, a human may progress to complete renal failure. African Americans have higher blood pressure than Caucasians even when their blood pressure is slightly elevated, and thus have a higher likelihood of developing kidney problems. Other groups at risk of proteinuria are American Indians, Hispanic / Latino, Pacific Islander Americans, the elderly, and overweight subjects.

[0172] In one aspect of the present invention, subjects are selected based on having proteinuria or being at risk of developing proteinuria. Subjects having proteinuria or being at risk of developing proteinuria are subjects having one or more symptoms of the condition. The symptoms of proteinuria are known to those skilled in the art and include, but are not limited to, a large amount of protein in the urine, which may appear foamy in the toilet. As a large amount of protein is lost, edema may occur, causing swelling in the hands, feet, abdomen, or face. These are signs of significant protein loss and indicate that kidney disease is progressing. Clinical testing is the only way to determine whether protein is present in a subject's urine before widespread kidney damage occurs.

[0173] This method is effective for a variety of subjects, including mammals, such as humans, and other animals, such as laboratory animals, such as mice, rats, rabbits, or monkeys, or domestic and farm animals, such as cats, dogs, goats, sheep, pigs, cows, or horses. In some embodiments, the subject is a mammal. In some embodiments, the subject is a human. [Examples]

[0174] The present invention is further illustrated in the following embodiments, which do not limit the scope of the invention as described in the claims.

[0175] Example 1: Synthesis Method The following shows the synthesis route to an exemplary compound of the present invention.

[0176] Preparation of intermediate A

[0177] [ka]

[0178] 2,4,5-tribromo-1-[(4-chlorophenyl)methyl]-1H-imidazole A mixture of 2,4,5-tribromo-1H-imidazole (120 g, 393.75 mmol, 1 equivalent), 1-(bromomethyl)-4-chlorobenzene (100 g, 486.67 mmol, 1.236 equivalents), and Cs2CO3 (200 g, 613.84 mmol, 1.559 equivalents) in DMF (1000 mL) was stirred at room temperature for 16 hours. SiO (500 mL) and H2O (300 mL) were added to the reaction mixture. The organic layer was washed with H2O (2 x 300 mL) and brine (300 mL), dried over anhydrous Na2SO4, and filtered. The filtrate was concentrated to obtain 2,4,5-tribromo-1-[(4-chlorophenyl)methyl]-1H-imidazole (170 g, crude) as a pale yellow solid.

[0179] 4,5-Dibromo-1-[(4-chlorophenyl)methyl]-2-[3-(trifluoromethoxy)phenoxy]-1H-imidazole A mixture of 2,4,5-tribromo-1-[(4-chlorophenyl)methyl]-1H-imidazole (175 g, 407.61 mmol, 1 equivalent), 3-(trifluoromethoxy)phenol (87.5 g, 491.27 mmol, 1.205 equivalents), and DMF (1000 mL)K2CO3 (175 g, 1266.23 mmol, 3.106 equivalents) in DMF (1000 mL) was stirred at 100°C for 16 hours. The reaction mixture was cooled to room temperature, and siRNA (750 mL) and H2O (500 mL) were added. The organic layer was washed with H2O (2 x 300 mL) and brine (150 mL), then dried over anhydrous Na2SO4 and filtered. The filtrate was concentrated to obtain the crude product, which was purified by silica gel column chromatography and eluted with PE:siRNA (20:1~10:1) to obtain 4,5-dibromo-1-[(4-chlorophenyl)methyl]-2-[3-(trifluoromethoxy)phenoxy]-1H-imidazole (200g, 93.19%) as a pale yellow solid.

[0180] 4-Bromo-1-[(4-chlorophenyl)methyl]-2-[3-(trifluoromethoxy)phenoxy]-1H-imidazole-5-carboxylate methyl (intermediate A) To a stirred solution of 4,5-dibromo-1-[(4-chlorophenyl)methyl]-2-[3-(trifluoromethoxy)phenoxy]-1H-imidazole (10.52 g, 19.98 mmol, 1 equivalent) in THF (100 mL), n-BuLi (25.8 mL, 64.57 mmol, 1 equivalent) was added dropwise at -78°C. The resulting mixture was stirred at -78°C for 30 minutes, and then CO2 (g) was bubbling through the mixture at -78°C for 50 minutes. The reaction mixture was stirred at -78°C for 30 minutes. HATU (36.8 g, 96.86 mmol, 1.5 equivalents), MeOH (180 mL), and TEA (70 mL) were added to the above solution, and the resulting mixture was stirred at room temperature for 12 hours. The reaction mixture was filtered, and the filtrate was concentrated to obtain the crude product. This was purified by silica gel column chromatography and eluted with PE:EA (20:1~5:1) to obtain 4-bromo-1-[(4-chlorophenyl)methyl]-2-[3-(trifluoromethoxy)phenoxy]-1H-imidazole-5-carboxylate methyl (26 g, 79.63%) as a white solid. 1 ¹H NMR (400 MHz, chloroform-d): δ 7.46-7.40 (m, 1H), 7.36-7.30 (m, 2H), 7.22 (dd, J = 8.4, 2.4 Hz, 3H), 7.13 (dtd, J = 9.9, 2.1, 1.1 Hz, 2H), 5.52 (s, 2H), 3.89 (s, 3H).

[0181] The preparation of intermediates C, E, G, I, J, K, L, M, and N, shown in the table below, is initiated with appropriate halides and phenols, following the methods and protocols described for the synthesis of intermediate A.

[0182] [Table 2-1]

[0183] [Table 2-2]

[0184] [Table 2-3]

[0185] 4-Bromo-1-[(4-chlorophenyl)methyl]-2-[3-(trifluoromethoxy)phenoxy]-1H-imidazole-5-carboxylic acid (intermediate B) A mixture of methyl 4-bromo-1-[(4-chlorophenyl)methyl]-2-[3-(trifluoromethoxy)phenoxy]-1H-imidazole-5-carboxylate (8 g, 15.82 mmol, 1 equivalent) in THF (50 mL) and H2O (50 mL) was mixed with LiOH (3.8 g, 158.21 mmol, 10 equivalents) and stirred at room temperature for 10 hours. The resulting mixture was extracted with EA (4 x 200 mL). The combined organic layer was washed with water (1 x 100 mL) and dried on anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue / crude product was purified by reverse-phase flash under the following conditions (column: spherical C18 column, 20-40 μm, 120 g; mobile phase A: water (0.1% AcOH); mobile phase B: ACN; flow rate: 60 mL / min; gradient: 80-90% B, 254 nm at 15 min), yielding 4-bromo-1-[(4-chlorophenyl)methyl]-2-[3-(trifluoromethoxy)phenoxy]-1H-imidazole-5-carboxylic acid (7.5 g, 96.42%) as a white solid. 1 H NMR(400MHz, DMSO-d6)δ13.41(s, 1H), 7.59(t, J = 8.3Hz, 1H), 7.42(dd, J = 8.7, 2.1Hz, 3H), 7.37(dt, J = 8.2, 1.5Hz, 1H), 7.33-7.29(m, 1H), 7.29-7.24(m, 2H), 5.51(s, 2H)

[0186] The preparation of intermediates D, F, and H, shown in the table below, is initiated with the appropriate intermediate and follows the method and protocol described for the synthesis of intermediate B.

[0187] [Table 3]

[0188] Preparation of Compound 1

[0189] [ka]

[0190] 4-[(2-[[(tert-butoxy)carbonyl]amino]ethyl)(methyl)amino]-1-[(4-chlorophenyl)methyl]-2-[3-(trifluoromethoxy)phenoxy]-1H-imidazole-5-carboxylate methyl A mixture of 4-bromo-1-[(4-chlorophenyl)methyl]-2-[3-(trifluoromethoxy)phenoxy]-1H-imidazole-5-carboxylate methyl (2 g, 3.96 mmol, 1 equivalent), N-[2-(methylamino)ethyl]carbamate tert-butyl (1.4 g, 7.91 mmol, 2.00 equivalent), xanthophos (686.6 mg, 1.19 mmol, 0.3 equivalent), Pd2(dba)3 (362.2 mg, 0.40 mmol, 0.1 equivalent), and Cs2CO3 (3.9 g, 11.87 mmol, 3 equivalents) in dioxane (30 mL, 89.53 equivalents) was stirred at 100°C for 14 hours. The reaction mixture was filtered, and the filtrate was concentrated to obtain the crude product. This was purified by silica gel column chromatography and eluted with PE:EA (10:1~3:2) to obtain 4-[(2-[[(tert-butoxy)carbonyl]amino]ethyl)(methyl)amino]-1-[(4-chlorophenyl)methyl]-2-[3-(trifluoromethoxy)phenoxy]-1H-imidazole-5-carboxylate methyl (630 mg, 26.59%) as a pale yellow oil. 1H NMR(400MHz, chloroform-d)δ7.41(t, J = 8.2 Hz, 1H), 7.34-7.26(m, 3H), 7.18(t, J = 8.7Hz, 2H), 7.09 (d,J = 8.4Hz, 1H), 5.39(s, 2H), 5.28(s, 1H), 3.78(s, 3H), 3.38(dd, J = 18.5, 5.7Hz, 4H), 2.94(s, 3H), 1.43(s, 9H)

[0191] 4-[(2-aminoethyl)(methyl)amino]-1-[(4-chlorophenyl)methyl]-2-[3-(trifluoromethoxy)phenoxy]-1H-imidazole-5-carboxylate methyl In 30 mL of DCM, a stirred solution of 4-[(2-[[(tert-butoxy)carbonyl]amino]ethyl)(methyl)amino]-1-[(4-chlorophenyl)methyl]-2-[3-(trifluoromethoxy)phenoxy]-1H-imidazole-5-carboxylate methyl (700 mg, 1.17 mmol, 1 equivalent) was added dropwise with TFA (10 mL) at room temperature. The resulting mixture was then stirred at room temperature for 2 hours. The reaction mixture was basicized to pH 10 with K2CO3, extracted with ethyl acetate (5 x 50 mL), then washed with brine (2 x 50 mL), dried over anhydrous Na2SO4, and filtered. The filtrate was concentrated to obtain 4-[(2-aminoethyl)(methyl)amino]-1-[(4-chlorophenyl)methyl]-2-[3-(trifluoromethoxy)phenoxy]-1H-imidazole-5-carboxylate methyl (500 mg, crude product) as a pale yellow oil.

[0192] 1-[(4-chlorophenyl)methyl]-4-methyl-2-[3-(trifluoromethoxy)phenoxy]-1H,4H,5H,6H,7H,8H-imidazo[4,5-e][1,4]diazepine-8-one To a stirred mixture of methyl 4-[(2-aminoethyl)(methyl)amino]-1-[(4-chlorophenyl)methyl]-2-[3-(trifluoromethoxy)phenoxy]-1H-imidazole-5-carboxylate (370 mg, 0.74 mmol, 1 equivalent) in 15 mL of dioxane, NaH (59.3 mg, 1.48 mmol, 2.00 equivalents, 60%) was added under a nitrogen atmosphere at 0°C for 0.5 hours. The resulting mixture was stirred at 100°C for a further 4 hours. Ethyl acetate (100 mL) and brine (50 mL) were added to the resulting mixture, and the aqueous layer was then extracted with ethyl acetate (100 mL). The combined organic layer was dried over anhydrous Na₂SO₄ and filtered. The filtrate was concentrated to obtain the crude product, which was purified by reverse-phase flushing under the following conditions (column: spherical C18 column, 20-40 μm, 120 g; mobile phase A: water (0.1% HOAc), mobile phase B: ACN; flow rate: 60 mL / min; gradient: 40%B to 70%B in 30 minutes, 254 nm) to obtain 1-[(4-chlorophenyl)methyl]-4-methyl-2-[3-(trifluoromethoxy)phenoxy]-1H,4H,5H,6H,7H,8H-imidazo[4,5-e][1,4]diazepine-8-one (23 mg, 6.64%) as a pale yellow oil. 1 ¹H NMR (400MHz, chloroform-d): δ 7.37 (q, J = 10.5, 9.4Hz, 1H), 7.27 (d, J = 11.1Hz, 5H), 7.19 (d, J = 8.5Hz, 1H), 7.07 (d, J = 8.3Hz, 1H), 5.80 (s, 1H), 5.53 (s, 2H), 3.54-3.33 (m, 4H), 3.03 (s, 3H)

[0193] 1-[(4-chlorophenyl)methyl]-4-methyl-7-[3-(oxan-2-yloxy)propyl]-2-[3-(trifluoromethoxy)phenoxy]-1H,4H,5H,6H,7H,8H-imidazo[4,5-e][1,4]diazepine-8-one A mixture of 1-[(4-chlorophenyl)methyl]-4-methyl-2-[3-(trifluoromethoxy)phenoxy]-1H,4H,5H,6H,7H,8H-imidazo[4,5-e][1,4]diazepine-8-one (23 mg, 0.05 mmol, 1 equivalent), 2-(3-bromopropoxy)oxane (22.0 mg, 0.10 mmol, 2 equivalents), and K2CO3 (20.4 mg, 0.15 mmol, 3 equivalents) in DMF (5 mL) was stirred at room temperature for 8 hours. ELISA (50 mL) and H2O (50 mL) were added to the reaction mixture. The organic layer was washed with brine (2 x 30 mL) and concentrated to obtain a residue, which was purified by reverse-phase flush under the following conditions (column: spherical C18 column, 20-40 μm, 40 g; mobile phase A: water (0.1% HOAc), mobile phase B: ACN; flow rate: 40 mL / min; gradient: 50%B-70%B at 30 min, 254 nm) to obtain 1-[(4-chlorophenyl)methyl]-4-methyl-7-[3-(oxan-2-yloxy)propyl]-2-[3-(trifluoromethoxy)phenoxy]-1H,4H,5H,6H,7H,8H-imidazo[4,5-e][1,4]diazepine-8-one (10 mg, 33.33%) as a pale yellow oil.

[0194] 1-[(4-chlorophenyl)methyl]-7-(3-hydroxypropyl)-4-methyl-2-[3-(trifluoromethoxy)phenoxy]-1H,4H,5H,6H,7H,8H-imidazo[4,5-e][1,4]diazepine-8-one (compound 1) To a stirred solution of 1-[(4-chlorophenyl)methyl]-4-methyl-7-[3-(oxan-2-yloxy)propyl]-2-[3-(trifluoromethoxy)phenoxy]-1H,4H,5H,6H,7H,8H-imidazo[4,5-e][1,4]diazepine-8-one (10 mg) in THF (5 mL), 2 M HCl (5 mL) was added dropwise at room temperature. The resulting mixture was then stirred at room temperature for 1 hour. The reaction mixture was basicized to pH 10 with K2CO3, extracted with ethyl acetate (3 x 50 mL), then washed with brine (2 x 20 mL), dried over anhydrous Na2SO4, and filtered. The filtrate was concentrated to obtain the crude product, which was purified by preparative chiral HPLC (column: XBridge preparative C18 OBD column, 5 μm, 19*150 mm; mobile phase A: water (0.1% FA), mobile phase B: ACN; flow rate: 20 mL / min; gradient: 50%B to 85%B in 7 mins; 254 & 220 nm; RT: 6.5 mins) to obtain 1-[(4-chlorophenyl)methyl]-7-(3-hydroxypropyl)-4-methyl-2-[3-(trifluoromethoxy)phenoxy]-1H,4H,5H,6H,7H,8H-imidazo[4,5-e][1,4]diazepine-8-one (2.2 mg, 25.53%) as a pale yellow oil. 1 H NMR(400MHz, methanol-d4)δ7.50(t, J = 8.2Hz, 1H), 7.33-7.26(m, 2H), 7.23-7.15(m, 5H), 5.47(s, 2H), 3.59-3.54(m, 2H), 3.53-3.41(m, 6H), 3.01(s, 3H), 1.79-1.70(m, 2H). Molecular formula C 24 H 24 Calculated [M+H] of ClF3N4O4 + :525, observed value:525.

[0195] Preparation of Compound 2

[0196] [ka]

[0197] 4-Bromo-1-[(4-chlorophenyl)methyl]-N-(3-hydroxypropyl)-2-[3-(trifluoromethoxy)phenoxy]-1H-imidazole-5-carboxamide A mixture of 3-aminopropan-1-ol (77.3 mg, 1.03 mmol, 1.5 equivalents) and 4-bromo-1-[(4-chlorophenyl)methyl]-2-[3-(trifluoromethoxy)phenoxy]-1H-imidazole-5-carbonyl chloride (350 mg, 0.69 mmol, 1 equivalent) in DCM (20 mL) and TEA (0.5 mL, 4.71 mmol, 5.0 equivalents) was stirred at room temperature for 16 hours. The reaction mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography and eluted with PE:Â (1:1~1:2) to obtain 4-bromo-1-[(4-chlorophenyl)methyl]-N-(3-hydroxypropyl)-2-[3-(trifluoromethoxy)phenoxy]-1H-imidazole-5-carboxamide (220 mg, 58.43%) as a pale yellow solid. 1 H NMR(300MHz,chloroform-d)δ7.43(td, J = 8.0, 7.5, 1.0Hz, 1H), 7.34-7.28(m, 4H), 7.26(d, J = 2.4Hz, 2H), 7.24(s, 1H), 7.22-7.18(m, 1H), 7.16-7.08(m, 2H), 5.58(s, 2H), 3.61(dt, J = 9.8, 6.0Hz, 4H), 1.78(p, J = 5.8Hz, 2H).

[0198] 4-Bromo-1-[(4-chlorophenyl)methyl]-N-[3-(oxan-2-yloxy)propyl]-2-[3-(trifluoromethoxy)phenoxy]-1H-imidazole-5-carboxamide To a mixture of 4-bromo-1-[(4-chlorophenyl)methyl]-N-(3-hydroxypropyl)-2-[3-(trifluoromethoxy)phenoxy]-1H-imidazole-5-carboxamide (1.00 g, 1.82 mol, 1 equivalent) in DCM (30 mL), 3,4-dihydro-2H-pyran (306.6 mg, 3.64 mol, 2.0 equivalents) and p-toluenesulfonic acid (15.7 mg, 0.09 mmol, 0.05 equivalents) were added. The resulting mixture was stirred at room temperature for 16 hours. The reaction mixture was concentrated to obtain a crude product, which was purified by silica gel column chromatography and eluted with PE:Â(5:1~3:1) to obtain 4-bromo-1-[(4-chlorophenyl)methyl]-N-[3-(oxan-2-yloxy)propyl]-2-[3-(trifluoromethoxy)phenoxy]-1H-imidazole-5-carboxamide (1.00g, 86.71%) as a pale yellow oil. 1 ¹H NMR (300 MHz, chloroform-d): δ 7.52-7.05 (m, 8H), 6.92 (s, 1H), 5.56 (s, 2H), 4.58 (dd, J = 4.7, 2.6 Hz, 1H), 4.12-3.30 (m, 9H), 2.01-1.33 (m, 5H).

[0199] 2-(1-[4-bromo-1-[(4-chlorophenyl)methyl]-2-[3-(trifluoromethoxy)phenoxy]-1H-imidazole-5-yl]-N-[3-(oxan-2-yloxy)propyl]formamide)ethyl acetate To a mixture of 4-bromo-1-[(4-chlorophenyl)methyl]-N-[3-(oxan-2-yloxy)propyl]-2-[3-(trifluoromethoxy)phenoxy]-1H-imidazole-5-carboxamide (1000 mg, 1.58 mmol, 1 equivalent) in DMF (20 mL) and NaH (126.4 mg, 3.16 mmol, 2.0 equivalents), 2-bromoethyl acetate (527.8 mg, 3.16 mmol, 2.0 equivalents) was added dropwise at 0°C. The resulting mixture was warmed to room temperature and stirred at room temperature for 16 hours. H2O (100 mL) was added to the reaction mixture, and the resulting mixture was extracted with ethyl acetate (3 × 100 mL). The organic layer was washed with brine (100 mL), dried anhydrous, and filtered. The filtrate was concentrated to obtain a residue, which was purified by silica gel column chromatography and eluted with PE:Â (5:1~3:1) to obtain ethyl acetate 2-(1-[4-bromo-1-[(4-chlorophenyl)methyl]-2-[3-(trifluoromethoxy)phenoxy]-1H-imidazole-5-yl]-N-[3-(oxan-2-yloxy)propyl]formamide) as a pale yellow oil (970 mg, 87.08%). 1 H NMR(300MHz, chloroform-d)δ7.45-7.35(m, 4H), 7.34-7.30(m, 8H), 7.09(d, J = 15.8Hz, 8H), 6.93(s, 1H), 5.57(d, J = 5.3Hz, 2H), 5.17(s, 6H), 4.53(d, J = 27.3Hz, 1H), 4.25(q, J = 7.7, 6.9Hz, 2H), 3.96-3.18(m, 9H), 1.96-1.70(m, 3H), 1.31(d, J = 3.1Hz, 4H).

[0200] 2-(1-[4-bromo-1-[(4-chlorophenyl)methyl]-2-[3-(trifluoromethoxy)phenoxy]-1H-imidazole-5-yl]-N-[3-(oxan-2-yloxy)propyl]formamide)-N-methylacetamide A mixture of methylamine (3.00 mL) in 2M methanol and ethyl acetate (970 mg, 1.35 mmol, 1 equivalent) of 2-(1-[4-bromo-1-[(4-chlorophenyl)methyl]-2-[3-(trifluoromethoxy)phenoxy]-1H-imidazole-5-yl]-N-[3-(oxan-2-yloxy)propyl]formamide) was irradiated with microwave radiation at 60°C for 1 hour. The reaction mixture was cooled to room temperature and concentrated under reduced pressure. The residue was purified by silica gel column chromatography and eluted with PE:SiO (1:6~1:9) to obtain 2-(1-[4-bromo-1-[(4-chlorophenyl)methyl]-2-[3-(trifluoromethoxy)phenoxy]-1H-imidazole-5-yl]-N-[3-(oxan-2-yloxy)propyl]formamide)-N-methylacetamide (600 mg, 63.17%) as a colorless oil. 1 H NMR(300MHz, DMSO-d6)δ8.07-7.88(m, 1H), 7.61-7.47(m, 1H), 7.38(d, J = 1.6Hz, 6H), 7.24(dd, J = 27.9, 9.7Hz, 5H), 5.12(s, 2H), 4.49(d, J = 30.7Hz, 2H), 4.15(s, 1H), 3.79-3.55(m, 1H), 3.39(s, 6H), 3.27(d, J = 4.1Hz, 0H), 2.60(dd, J = 13.1, 4.4Hz, 5H), 1.87-1.26(m, 14H).

[0201] 1-[(4-chlorophenyl)methyl]-4-methyl-7-[3-(oxan-2-yloxy)propyl]-2-[3-(trifluoromethoxy)phenoxy]-1H,4H,5H,6H,7H,8H-imidazo[4,5-e][1,4]diazepine-5,8-dione Toluene (10.0 mL) contains 2-(1-[4-bromo-1-[(4-chlorophenyl)methyl]-2-[3-(trifluoromethoxy)phenoxy]-1H-imidazole-5-yl]-N-[3-(oxan-2-yloxy)propyl]formamide)-N-methylacetamide (500 mg, 0.71 mmol, 1 equivalent), Pd2(dba)3·CHCl3 (73.5 mg, 0.07 mmol, 0.1 equivalent), P(o-Tol)3 (43.2 mg, 0.14 mmol, 0.2 equivalent), and Cs2C O3 A mixture of (462.9 mg, 1.42 mmol, 2.0 equivalents) was irradiated with microwave radiation at 120°C for 4 hours. The reaction mixture was cooled to room temperature and concentrated under reduced pressure. The residue was purified by silica gel column chromatography and eluted with PE:SiO (3:1~1:1) to obtain 1-[(4-chlorophenyl)methyl]-4-methyl-7-[3-(oxan-2]-yloxy)propyl]-2-[3-(trifluoromethoxy)phenoxy]-1H,4H,5H,6H,7H,8H-imidazo[4,5-e][1,4]diazepine-5,8-dione (300 mg, 67.79%) as a pale yellow oil.

[0202] 1-[(4-chlorophenyl)methyl]-7-(3-hydroxypropyl)-4-methyl-2-[3-(trifluoromethoxy)phenoxy]-1H,4H,5H,6H,7H,8H-imidazo[4,5-e][1,4]diazepine-5,8-dione (compound 2) A mixture of 1-[(4-chlorophenyl)methyl]-4-methyl-7-[3-(oxan-2-yloxy)propyl]-2-[3-(trifluoromethoxy)phenoxy]-1H,4H,5H,6H,7H,8H-imidazo[4,5-e][1,4]diazepine-5,8-dione (300 mg, 0.48 mmol, 1 equivalent) in THF (10 mL) and HCl (6 M) (20 mL) was stirred at room temperature for 2 hours. The reaction mixture was concentrated to obtain a residue. The residue was basicized to pH 9 with saturated K2CO3 (aq), and the mixture was then extracted with ethyl acetate (3 x 100 mL). The organic layer was washed with brine (50 mL) and concentrated to obtain the crude product, which was purified by reverse-phase flush under the following conditions (column: spherical C18 column, 20-40 μm, 120 g; mobile phase A: water (0.1% HOAc), mobile phase B: ACN; flow rate: 60 mL / min; gradient: 50%B-60%B at 15 min, 254 nm) to obtain 1-[(4-chlorophenyl)methyl]-7-(3-hydroxypropyl)-4-methyl-2-[3-(trifluoromethoxy)phenoxy]-1H,4H,5H,6H,7H,8H-imidazo[4,5-e][1,4]diazepine-5,8-dione (220 mg, 84.78%) as a pale yellow oil. 1 H NMR(300MHz, DMSO-d6)δ7.59-7.54(m, 1H), 7.42-7.26(m, 7H), 5.44(s, 2H), 4.48(t, J = 5.1Hz, 1H), 4.05(s, 2H), 3.51(t, J = 7.1Hz, 2H), 3.39-3.33(m, 2H), 3.20(s, 3H), 1.69-1.60(m, 2H). Molecular formula C 24 H 22 Calculated [M+H] of ClF3N4O5 + :539, observed value:539.

[0203] The preparation of compounds 3-5, shown in the table below, begins with a suitable intermediate E and follows the method and protocol described for the synthesis of compound 2.

[0204] [Table 4]

[0205] Preparation of compounds 6 and 7

[0206] [ka]

[0207] 1-[(1R)-1-(4-chlorophenyl)ethyl]-2-(3-fluorophenoxy)-7-(3-hydroxypropyl)-4-methyl-1H,4H,5H,6H,7H,8H-imidazo[4,5-e][1,4]diazepine-5,8-dione and 1-[(1S)-1-(4-chlorophenyl)ethyl]-2-(3-fluorophenoxy)-7-(3-hydroxypropyl)-4-methyl-1H,4H,5H,6H,7H,8H-imidazo[4,5-e][1,4]diazepine-5,8-dione Crude product 1-(1-(4-chlorophenyl)ethyl)-2-(3-fluorophenoxy)-7-(3-hydroxypropyl)-4-methyl-1,4,6,7-tetrahydroimidazo[4,5-e][1,4]diazepine-5,8-dione (200 mg) was purified by chiral HPLC under the following conditions (column: CHIRALPAK IE, 2*25 cm, 5 μm; mobile phase A: 0.1% hexane--HPLC, mobile phase B: EtOH--HPLC; flow rate: 17 mL / min; gradient: 50B~50B at 11 min; 220 / 254 nm; RT1: 7.423; RT2: 9.034) to obtain separated enantiomer compound 6 (RT 7.423 min, 73 mg, 23.14%) and compound 7 (RT 9.034 min, 77 mg, 24.41%).

[0208] Characterization of Compounds 6: 1H NMR(400MHz, methanol-d4)δ7.44-7.41(m, 2H), 7.38-7.31(m, 3H), 6.98-6.93(m, 1H), 6.87-6.82(m, 2H), 6.25(q, J = 7.2Hz, 1H), 4.16(s, 2H), 3.73-3.63(m, 2H), 3.56(t, J = 6.1Hz, 2H), 3.32(s, 3H), 2.00(d, J = 7.2Hz, 3H), 1.85(p, J = 6.6Hz, 2H). Molecular formula C 24 H 24 Calculated [M+H] of ClFN4O4 + :487, observed value:487.

[0209] Characterization of Compounds 7: 1 H NMR(400MHz, methanol-d4)δ7.43-7.41(m, 2H), 7.40-7.30(m, 3H), 6.98-6.95(m, 1H), 6.87-6.82(m, 2H), 6.25(q, J = 7.2Hz, 1H), 4.17(s, 2H), 3.68(t, J = 6.8, 2H), 3.56(t, J = 6.1Hz, 2H), 3.32(s, 3H), 2.00(d, J = 7.2Hz, 3H), 1.85(p, J = 6.7Hz, 2H). Molecular formula C 24 H 24 Calculated [M+H] of ClFN4O4 + :487, observed value:487.

[0210] Preparation of compound 8

[0211] [ka]

[0212] 1-[(4-chlorophenyl)methyl]-7-(3-methoxypropyl)-4-methyl-2-[3-(trifluoromethoxy)phenoxy]-1H,4H,5H,6H,7H,8H-imidazo[4,5-e][1,4]diazepine-5,8-dione (compound 8) To a mixture of 1-[(4-chlorophenyl)methyl]-7-(3-hydroxypropyl)-4-methyl-2-[3-(trifluoromethoxy)phenoxy]-1H,4H,5H,6H,7H,8H-imidazo[4,5-e][1,4]diazepine-5,8-dione (120 mg, 0.22 mmol, 1 equivalent) in DMF (20 mL), NaH (44.5 mg, 1.11 mmol, 5 equivalents, 60 wt%) was added under a nitrogen atmosphere at 0°C for 0.5 hours. CH3I (94.8 mg, 0.67 mmol, 3 equivalents) was added to the above mixture at 0°C. The resulting mixture was stirred for a further 16 hours at 80°C. The mixture was basicized to pH 10 with K2CO3 (aq), extracted with ethyl acetate (5 x 50 mL), and the organic layer was washed with brine (2 x 50 mL) and concentrated under reduced pressure. The residue was purified by reverse-phase flushing under the following conditions (column: XBridge preparative OBD C18 column 30*150 mm 5 μm; mobile phase A: water (0.05% TFA), mobile phase B: ACN; flow rate: 60 mL / min; gradient: 45%B~80%B at 7 min; 220 nm; RT: 6.55 min) to obtain 1-[(4-chlorophenyl)methyl]-7-(3-methoxypropyl)-4-methyl-2-[3-(trifluoromethoxy)phenoxy]-1H,4H,5H,6H,7H,8H-imidazo[4,5-e][1,4]diazepine-5,8-dione (34.1 mg, 27.70%) as a pale yellow oil. 1 H NMR(400MHz, methanol-d4)δ7.52(t, J = 8.2Hz, 1H), 7.36-7.28(m, 6H), 7.20(d, J = 8.1Hz, 1H), 5.50(s, 2H), 4.05(s, 2H), 3.63(t, J = 6.9Hz, 2H), 3.37-3.32(m, 5H), 3.29(s, 3H), 1.89-1.82(m, 2H). Molecular formula C 25 H 24 Calculated [M+H] of ClF3N4O5 + :553, observed value:553.

[0213] Preparation of compound 9

[0214] [ka]

[0215] 4-Bromo-1-[(4-chlorophenyl)methyl]-N-[(2,2-dimethyl-1,3-dioxolan-4-yl)methyl]-2-[3-(trifluoromethoxy)phenoxy]-1H-imidazole-5-carboxamide To a mixture of (2,2-dimethyl-1,3-dioxolan-4-yl)methaneamine (617.2 mg, 4.71 mmol, 2.0 equivalents) in DCM (30 mL) and TEA (1.0 mL, 9.69 mmol, 3.0 equivalents), 4-bromo-1-[(4-chlorophenyl)methyl]-2-[3-(trifluoromethoxy)phenoxy]-1H-imidazole-5-carbonyl chloride (1.2 g, 2.35 mmol, 1 equivalent) in DCM (20 mL) was added dropwise at 0°C. The resulting mixture was warmed to room temperature and stirred at room temperature for 16 hours. The reaction mixture was concentrated under reduced pressure and purified by silica gel column chromatography. Elution with PE:HCl (3:1~2:1) yielded 4-bromo-1-[(4-chlorophenyl)methyl]-N-[(2,2-dimethyl-1,3-dioxolan-4-yl)methyl]-2-[3-(trifluoromethoxy)phenoxy]-1H-imidazole-5-carboxamide (1.30 g, 91.37%) as a pale yellow oil. 1 H NMR(300MHz, chloroform-d)δ7.46-7.38(m, 1H), 7.35-7.29(m, 2H), 7.27-7.16(m, 3H), 7.15-7.08(m, 2H), 7.01(t, J = 5.6Hz, 1H), 5.59(s, 2H), 4.32(qd, J = 6.2, 3.8Hz, 1H), 4.07(dd, J = 8.4, 6.4Hz, 1H), 3.71-3.62(m, 2H), 3.57(dt, J = 14.1, 5.8Hz, 1H), 1.47(s, 3H), 1.38(s, 3H).

[0216] 2-(1-[4-bromo-1-[(4-chlorophenyl)methyl]-2-[3-(trifluoromethoxy)phenoxy]-1H-imidazole-5-yl]-N-[(2,2-dimethyl-1,3-dioxolan-4-yl)methyl]formamide)ethyl acetate To a mixture of 4-bromo-1-[(4-chlorophenyl)methyl]-N-[(2,2-dimethyl-1,3-dioxolan-4-yl)methyl]-2-[3-(trifluoromethoxy)phenoxy]-1H-imidazole-5-carboxamide (1 g, 1.65 mol, 1 equivalent) in DMF (20 mL), NaH (99.2 mg, 2.48 mmol, 1.5 equivalents, 60 wt%) was added under a nitrogen atmosphere at 0°C for 0.5 hours. To the above mixture, 2-ethyl bromo (0.3 mL, 1.80 mmol, 1.636 equivalents) was added at 0°C. The resulting mixture was stirred at room temperature for a further 16 hours. Ethyl acetate (300 mL) and brine (100 mL) were added to the resulting mixture, and the aqueous layer was then extracted with ethyl acetate (100 mL). The combined organic layer was dried over anhydrous Na₂SO₄ and filtered. The filtrate was concentrated to obtain the crude product, which was purified by silica gel column chromatography and eluted with PE:EA (20:1~4:1) to obtain ethyl acetate 2-(1-[4-bromo-1-[(4-chlorophenyl)methyl]-2-[3-(trifluoromethoxy)phenoxy]-1H-imidazole-5-yl]-N-[(2,2-dimethyl-1,3-dioxolan-4-yl)methyl]formamide) as a pale yellow oil (1.1g, 96.3%).

[0217] 2-(1-[4-bromo-1-[(4-chlorophenyl)methyl]-2-[3-(trifluoromethoxy)phenoxy]-1H-imidazole-5-yl]-N-[(2,2-dimethyl-1,3-dioxolan-4-yl)methyl]formamide)-N-methylacetamide A mixture of methylamine (5 mL) in 2 M methanol and ethyl acetate (1.2 g, 1.74 mmol, 1 equivalent) (2-[4-bromo-1-[(4-chlorophenyl)methyl]-2-[3-(trifluoromethoxy)phenoxy]-1H-imidazole-5-yl]-N-[(2,2-dimethyl-1,3-dioxolan-4-yl)methyl]formamide) was irradiated with microwave radiation at 60°C for 1 hour. The mixture was cooled to room temperature. The reaction mixture was concentrated to obtain a crude product, which was purified by silica gel column chromatography and eluted with PE:EA (1:1~1:8) to obtain 2-(1-[4-bromo-1-[(4-chlorophenyl)methyl]-2-[3-(trifluoromethoxy)phenoxy]-1H-imidazole-5-yl]-N-[(2,2-dimethyl-1,3-dioxolan-4-yl)methyl]formamide)-N-methylacetamide (0.92 g, 78.37%) as a white solid.

[0218] 1-[(4-chlorophenyl)methyl]-7-[(2,2-dimethyl-1,3-dioxolan-4-yl)methyl]-4-methyl-2-[3-(trifluoromethoxy)phenoxy]-1H,4H,5H,6H,7H,8H-imidazo[4,5-e][1,4]diazepine-5,8-dione A mixture of 2-(1-[4-bromo-1-[(4-chlorophenyl)methyl]-2-[3-(trifluoromethoxy)phenoxy]-1H-imidazole-5-yl]-N-[(2,2-dimethyl-1,3-dioxolan-4-yl)methyl]formamide)-N-methylacetamide (1 g, 1.48 mmol, 1 equivalent), Pd2(dba)3·CHCl3 (150 mg, 0.14 mmol, 0.098 equivalents), P(o-Tol)3 (90 mg, 0.30 mmol, 0.200 equivalents), and Cs2CO3 (1 g, 3.07 mmol, 2.074 equivalents) in toluene (15 mL) was irradiated with microwave radiation at 120 °C for 4 hours. The mixture was cooled to room temperature. The reaction mixture was filtered, and the filtrate was concentrated to obtain the crude product. This was purified by silica gel column chromatography and eluted with PE:EA (4:1~2:3) to obtain 1-[(4-chlorophenyl)methyl]-7-[(2,2-dimethyl-1,3-dioxolan-4-yl)methyl]-4-methyl-2-[3-(trifluoromethoxy)phenoxy]-1H,4H,5H,6H,7H,8H-imidazo[4,5-e][1,4]diazepine-5,8-dione (470 mg, 53.39%) as a pale yellow oil.

[0219] 1-[(4-chlorophenyl)methyl]-7-(2,3-dihydroxypropyl)-4-methyl-2-[3-(trifluoromethoxy)phenoxy]-1H,4H,5H,6H,7H,8H-imidazo[4,5-e][1,4]diazepine-5,8-dione (compound 9) To a stirred solution of 1-[(4-chlorophenyl)methyl]-7-[(2,2-dimethyl-1,3-dioxolan-4-yl)methyl]-4-methyl-2-[3-(trifluoromethoxy)phenoxy]-1H,4H,5H,6H,7H,8H-imidazo[4,5-e][1,4]diazepine-5,8-dione (600 mg, 1.01 mol, 1 equivalent) in THF (15 mL), HCl (15 mL) in H2O (15.0 mL) was added dropwise at room temperature. The resulting mixture was then stirred at room temperature for 2 hours. The mixture was basicized to pH 10 with K2CO3 (aq), extracted with ethyl acetate (5 x 50 mL), and the organic layer was washed with brine (2 x 50 mL) and concentrated under reduced pressure. The residue was purified by reverse-phase flushing under the following conditions (column: spherical C18 column, 20-40 μm, 330 g; mobile phase A: water (0.1% HOAc), mobile phase B: ACN; flow rate: 80 mL / min; gradient: 60%B to 95%B at 35 min, 254 nm) to obtain 1-[(4-chlorophenyl)methyl]-7-(2,3-dihydroxypropyl)-4-methyl-2-[3-(trifluoromethoxy)phenoxy]-1H,4H,5H,6H,7H,8H-imidazo[4,5-e][1,4]diazepine-5,8-dione (520 mg, 92.92%) as a white solid. 1 H NMR(300MHz, DMSO-d6)δ7.57(t, J = 8.3Hz, 1H), 7.41-7.35(m, 7H), 5.44(d, J = 1.8Hz, 2H), 4.81(d, J = 5.3Hz, 1H), 4.63(t, J = 5.7Hz, 1H), 4.25-4.01(m, 2H), 3.83-3.62(m, 1H), 3.55-3.48(m, 1H), 3.43-3.40(m, 1H), 3.32-3.24(m, 2H), 3.19(s, 3H). Molecular formula C 24 H 22 Calculated [M+H] of ClF3N4O6 + :555, observed value:555.

[0220] Preparation of compound 10

[0221] [ka]

[0222] 4-Bromo-1-[(4-chlorophenyl)methyl]-2-[3-(trifluoromethoxy)phenoxy]-1H-imidazole-5-carboxylic acid A mixture of methyl 4-bromo-1-[(4-chlorophenyl)methyl]-2-[3-(trifluoromethoxy)phenoxy]-1H-imidazole-5-carboxylate (2.5 g, 4.94 mmol, 1 equivalent) and LiOH (1.2 g, 49.44 mmol, 10 equivalents) in THF (50 mL) and H2O (50 mL) was stirred at room temperature for 10 hours. The resulting mixture was extracted with EA (4 x 200 mL). The combined organic layer was washed with water (1 x 100 mL) and dried on anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue / crude product was purified by reverse-phase flash under the following conditions (column: spherical C18 column, 20-40 μm, 120 g; mobile phase A: water (0.1% AcOH); mobile phase B: ACN; flow rate: 60 mL / min; gradient: 80-90% B, 254 nm at 15 min), yielding 4-bromo-1-[(4-chlorophenyl)methyl]-2-[3-(trifluoromethoxy)phenoxy]-1H-imidazole-5-carboxylic acid (2.1 g, 86.40%) as a white solid. 1 H NMR(400MHz, DMSO-d6)δ13.41(s, 1H), 7.59(t, J = 8.3Hz, 1H), 7.42(dd, J = 8.7, 2.1Hz, 3H), 7.37(dt, J = 8.2, 1.5Hz, 1H), 7.33-7.29(m, 1H), 7.29-7.24(m, 2H), 5.51(s, 2H).

[0223] 4-Bromo-1-[(4-chlorophenyl)methyl]-N-(2-hydroxyethyl)-2-[3-(trifluoromethoxy)phenoxy]-1H-imidazole-5-carboxamide To a mixture of 4-bromo-1-[(4-chlorophenyl)methyl]-2-[3-(trifluoromethoxy)phenoxy]-1H-imidazole-5-carboxylic acid (1.1 g, 2.24 mmol, 1 equivalent) and one drop of DMF in 20 mL of DCM, oxalic dichloride (0.9 g, 6.71 mmol, 3 equivalents) was added dropwise at 0°C. The mixture was stirred at room temperature for 3 hours. The resulting mixture was concentrated under vacuum. The solid was dissolved in 30 mL of DCM to obtain solution A for the next reaction. A mixture of 2-aminoethane-1-ol (0.4 g, 6.71 mmol, 3 equivalents) and triethylamine (0.7 g, 6.71 mmol, 3 equivalents) in 10 mL of DCM was cooled to 0°C, and solution A was added dropwise at 0°C under a nitrogen atmosphere. The mixture was stirred at room temperature for 3 hours. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography and eluted with PE / EA (2 / 1~1 / 1) to obtain 4-bromo-1-[(4-chlorophenyl)methyl]-N-(2-hydroxyethyl)-2-[3-(trifluoromethoxy)phenoxy]-1H-imidazole-5-carboxamide (0.91 g, 76.06%) as a white solid. 1 H NMR(400MHz, DMSO-d6)δ7.99(t, J = 5.6Hz, 1H), 7.58(t, J = 8.3Hz, 1H), 7.45-7.37(m, 2H), 7.38-7.26(m, 5H), 5.39(s, 2H), 4.77(t, J = 5.4Hz, 1H), 3.47(q, J = 6.1Hz, 2H), 3.35-3.27(m, 2H).

[0224] 4-Bromo-1-[(4-chlorophenyl)methyl]-N-[2-(oxan-2-yloxy)ethyl]-2-[3-(trifluoromethoxy)phenoxy]-1H-imidazole-5-carboxamide 3,4-dihydro-2H-pyran (0.0g, 0.34 mmol, 0.2 equivalents) was added to a stirred mixture of 4-bromo-1-[(4-chlorophenyl)methyl]-N-(2-hydroxyethyl)-2-[3-(trifluoromethoxy)phenoxy]-1H-imidazole-5-carboxamide (0.9g, 1.68 mmol, 1 equivalent) and 4-methylbenzene-1-sulfonic acid (0.0g, 0.17 mmol, 0.1 equivalent) in 50 mL of DCM under a nitrogen atmosphere at room temperature. The mixture was reacted at room temperature for 10 hours. The resulting mixture was quenched with water (100 mL) and extracted with DCM (4 × 100 mL). The combined organic layer was washed with water (1 × 100 mL) and dried on anhydrous Na₂SO₄. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography and eluted with PE / EA(4 / 1) to obtain 4-bromo-1-[(4-chlorophenyl)methyl]-N-[2-(oxan-2-yloxy)ethyl]-2-[3-(trifluoromethoxy)phenoxy]-1H-imidazole-5-carboxamide (0.8g, 76.81%) as a yellow oil. 1 H NMR(400MHz, DMSO-d6)δ8.09(d, J = 5.6Hz, 1H), 7.60-7.55(m, 1H), 7.43-7.38(m, 2H), 7.36-7.25(m, 5H), 5.38(s, 2H), 4.59(d, J = 4.0Hz, 1H), 3.76-3.66(m, 2H), 3.42(dq, J = 10.2, 5.9, 5.4Hz, 4H), 1.50-1.41(m, 6H).

[0225] 2-(1-[4-bromo-1-[(4-chlorophenyl)methyl]-2-[3-(trifluoromethoxy)phenoxy]-1H-imidazole-5-yl]-N-[2-(oxan-2-yloxy)ethyl]formamide)ethyl acetate To a stirred solution of 4-bromo-1-[(4-chlorophenyl)methyl]-N-[2-(oxan-2-yloxy)ethyl]-2-[3-(trifluoromethoxy)phenoxy]-1H-imidazole-5-carboxamide (0.64 g, 1.03 mmol, 1 equivalent) in DMF (15 mL), NaH (0.1 g, 4.14 mmol, 4 equivalents) was gradually added under a nitrogen atmosphere at 0°C. The mixture was stirred at 0°C for 30 minutes, and 2-bromoethyl acetate (0.7 g, 4.14 mmol, 4 equivalents) was added. The mixture was stirred at room temperature for 16 hours. The resulting mixture was quenched with water (100 ml) and extracted with EA (3 × 100 ml). The combined organic layer was washed with water (1 × 100 mL) and dried on anhydrous Na₂SO₄. After filtration, the filtrate was concentrated under reduced pressure to obtain the crude compound. The crude product was purified by reverse-phase flush under the following conditions (column: spherical C18 column, 20-40 μm, 120 g; mobile phase A: water (0.1% AcOH); mobile phase B: ACN; flow rate: 60 mL / min; gradient: 60-80% B, 254 nm at 35 min), yielding ethyl acetate 2-(1-[4-bromo-1-[(4-chlorophenyl)methyl]-2-[3-(trifluoromethoxy)phenoxy]-1H-imidazole-5-yl]-N-[2-(oxan-2-yloxy)ethyl]formamide) as a yellow oil (400 mg, 54.87%).

[0226] 2-(1-[4-bromo-1-[(4-chlorophenyl)methyl]-2-[3-(trifluoromethoxy)phenoxy]-1H-imidazole-5-yl]-N-[2-(oxan-2-yloxy)ethyl]formamide)-N-methylacetamide 2-(1-[4-bromo-1-[(4-chlorophenyl)methyl]-2-[3-(trifluoromethoxy)phenoxy]-1H-imidazole-5-yl]-N-[2-(oxan-2-yloxy)ethyl]formamide)ethyl acetate (0.4 g, 0.57 mmol, 1 equivalent) and CH3NH2·MeOH (6 mL, 30%) were added to a 20 mL container at room temperature. The mixture was reacted under microwave irradiation at 60°C for 1 hour. The resulting mixture was cooled to room temperature and concentrated under vacuum. The residue was purified by silica gel column chromatography and eluted with PE / EA(1 / 1) to obtain 2-(1-[4-bromo-1-[(4-chlorophenyl)methyl]-2-[3-(trifluoromethoxy)phenoxy]-1H-imidazole-5-yl]-N-[2-(oxan-2-yloxy)ethyl]formamide)-N-methylacetamide (0.28 g, 71.52%) as a yellow oil. 1 H NMR(400MHz, chloroform-d)δ7.42(d, J = 8.5Hz, 1H), 7.33(d, J = 8.6Hz, 3H), 7.14(dd, J = 31.1, 7.5Hz, 4H), 5.17(s, 2H), 4.41(s, 1H), 4.17(s, 2H), 3.75(d, J = 53.6Hz, 4H), 3.51(s, 2H), 2.82(s, 3H), 1.73(d, J = 36.0Hz, 6H).

[0227] 1-[(4-chlorophenyl)methyl]-4-methyl-7-[2-(oxan-2-yloxy)ethyl]-2-[3-(trifluoromethoxy)phenoxy]-1H,4H,5H,6H,7H,8H-imidazo[4,5-e][1,4]diazepine-5,8-dione 2-(1-[4-bromo-1-[(4-chlorophenyl)methyl]-2-[3-(trifluoromethoxy)phenoxy]-1H-imidazole-5-yl]-N-[2-(oxan-2-yloxy)ethyl]formamide)-N-methylacetamide (280 mg, 0.41 mmol, 1 equivalent), Pd2(dba)3 (55.9 mg, 0.06 mmol, 0.150 equivalents), Cs2CO3 (397.7 mg, 1.22 mmol, 3.008 equivalents), and tris(2-methylphenyl)phosphane (37.23 mg, 0.12 mmol, 0.301 equivalents) were added to a 20 mL container at room temperature. The mixture was heated at 120 °C for 4 hours under microwave conditions. The mixture was cooled to room temperature. The residue was purified by silica gel column chromatography and eluted with PE / EA(1 / 1) to obtain 1-[(4-chlorophenyl)methyl]-4-methyl-7-[2-(oxan-2-yloxy)ethyl]-2-[3-(trifluoromethoxy)phenoxy]-1H,4H,5H,6H,7H,8H-imidazo[4,5-e][1,4]diazepine-5,8-dione (110 mg, 44.51%) as a yellow oil.

[0228] 1-[(4-chlorophenyl)methyl]-7-(2-hydroxyethyl)-4-methyl-2-[3-(trifluoromethoxy)phenoxy]-1H,4H,5H,6H,7H,8H-imidazo[4,5-e][1,4]diazepine-5,8-dione (compound 10) A mixture of 1-[(4-chlorophenyl)methyl]-4-methyl-7-[2-(oxan-2-yloxy)ethyl]-2-[3-(trifluoromethoxy)phenoxy]-1H,4H,5H,6H,7H,8H-imidazo[4,5-e][1,4]diazepine-5,8-dione (120 mg, 200 mmol, 1 equivalent) and 2M HCl (20 mL) in THF (20 mL) was stirred at room temperature for 1 hour. The reaction was monitored by LC-MS. The resulting mixture was extracted with EA (3 x 200 mL). The combined organic layer was washed with water (1 x 200 mL) and dried on anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The crude product (88 mg) was purified by preparative HPLC under the following conditions (column: XBridge preparative C18 OBD column, 5 μm, 19*150 mm; mobile phase A: water (0.05% TFA), mobile phase B: ACN; flow rate: 20 mL / min; gradient: 35%B~60%B at 12 min; 254 nm; RT: 11.70 min) to obtain 1-[(4-chlorophenyl)methyl]-7-(2-hydroxyethyl)-4-methyl-2-[3-(trifluoromethoxy)phenoxy]-1H,4H,5H,6H,7H,8H-imidazo[4,5-e][1,4]diazepine-5,8-dione (60 mg, 73.28%) as a yellow semi-solid. 1 H NMR(400MHz, methanol-d4)δ7.52(t, J = 8.3Hz, 1H), 7.34-7.27(m, 6H), 7.20(d, J = 8.3Hz, 1H), 5.51(s, 2H), 4.14(s, 2H), 3.74(t, J = 5.5Hz, 2H), 3.67(t, J = 5.6Hz, 2H), 3.33(s, 3H). Molecular formula C 23 H 20 Calculated [M+H] of ClF3N4O5 + :525, observed value:525.

[0229] The preparation of compounds 11-14, shown in the table below, is initiated with a suitable amine and follows the method and protocol described for the synthesis of compound 10.

[0230] [Table 5]

[0231] Preparation of compounds 15 and 16:

[0232] [ka]

[0233] 1-[(4-chlorophenyl)methyl]-7-[(1R,3R)-3-hydroxycyclopentyl]-4-methyl-2-[3-(trifluoromethoxy)phenoxy]-1H,4H,5H,6H,7H,8H-imidazo[4,5-e][1,4]diazepine-5,8-dione and 1-[(4-chlorophenyl)methyl]-7-[(1S,3S)-3-hydroxycyclopentyl]-4-methyl-2-[3-(trifluoromethoxy)phenoxy]-1H,4H,5H,6H,7H,8H-imidazo[4,5-e][1,4]diazepine-5,8-dione The crude product 1-(4-chlorobenzyl)-7-((trans-3-hydroxycyclopentyl)-4-methyl-2-(3-(trifluoromethoxy)phenoxy)-1,4,6,7-tetrahydroimidazo[4,5-e][1,4]diazepine-5,8-dione was purified by chiral preparative HPLC under the following conditions (column: CHIRALPAK IC, 2*25cm, 5μm; mobile phase A: 0.1% hexane--HPLC, mobile phase B: EtOH--HPLC; flow rate: 20 mL / min; gradient: 20B~20B at 18 min; 220 / 254 nm; RT1: 12.901; RT2: 15.068), yielding compound 15 (RT 12.901 min, 23.8 mg, 16.08%) and compound 16 (RT 15.068 minutes, 22.0 mg, 14.87%) was obtained.

[0234] Characterization of compound 15: 1H NMR(400MHz, methanol-d4)δ7.52(t, J = 8.3Hz, 1H), 7.43-7.24(m, 6H), 7.20(d, J = 8.4Hz, 1H), 5.51(s, 2H), 5.17(p, J = 8.5Hz, 1H), 4.40(s, 1H), 3.93(s, 2H), 3.33(s, 3H), 2.10-2.09(m, 2H), 1.99-1.97(m, 2H), 1.68-1.59(m, 2H). Molecular formula C 26 H 24 Calculated [M+H] of ClF3N4O5 + :565, observed value:565.

[0235] Characterization of compound 16: 1 H NMR(400MHz, methanol-d4)δ7.52(t, J = 8.3Hz, 1H), 7.36-7.27(m, 6H), 7.20(d, J = 8.4Hz, 1H), 5.51(s, 2H), 5.18(p, J = 8.5Hz, 1H), 4.40(s, 1H), 3.93(s, 2H), 3.33(s, 3H), 2.10-2.08(m, 2H), 1.87-1.77(m, 2H), 1.68-1.59(m, 2H). Molecular formula C 26 H 24 Calculated [M+H] of ClF3N4O5 + :565, observed value:565.

[0236] Preparation of compounds 17 and 18:

[0237] [ka]

[0238] 2-amino-4-[(tert-butyldimethylsilyl)oxy]butanoic acid To a stirred solution of 2-amino-4-hydroxybutanoic acid (5.0 g, 41.97 mmol, 1 equivalent) in MeCN (150 mL) and DBU (6.6 mL, 43.25 mmol, 1.05 equivalents), TBSCl (6.6 g, 44.07 mmol, 1.05 equivalents) was slowly added at 0°C. The resulting mixture was warmed to room temperature and stirred at room temperature for 16 hours. The reaction mixture was filtered, and the filter cake was washed with MeCN (3 x 50 mL). The combined filtrate was concentrated to obtain 2-amino-4-[(tert-butyldimethylsilyl)oxy]butanoic acid (8.5 g, crude product). 1 ¹H NMR (300MHz, methanol-d4): δ 3.89 (t, J = 6.1Hz, 2H), 3.79 (t, J = 5.9Hz, 1H), 3.74-3.55 (m, 2H), 0.95 (s, 9H), 0.14 (s, 6H).

[0239] 2-amino-4-[(tert-butyldimethylsilyl)oxy]methyl butanoate A mixture of 2-amino-4-[(tert-butyldimethylsilyl)oxy]butanoic acid (5 g, 21.42 mmol, 1 equivalent) in toluene (200 mL) and MeOH (50 mL) was mixed with trimethylsilyldiazomethane (60 mL, 0.53 mmol, 0.025 equivalents) at room temperature. The resulting mixture was stirred at room temperature for 16 hours. The reaction mixture was concentrated to obtain methyl 2-amino-4-[(tert-butyldimethylsilyl)oxy]butanoate (5 g, crude product) as a pale yellow oil.

[0240] 2-([4-bromo-1-[(4-chlorophenyl)methyl]-2-[3-(trifluoromethoxy)phenoxy]-1H-imidazole-5-yl]formamide)-4-[(tert-butyldimethylsilyl)oxy]methyl butanoate A mixture of 4-bromo-1-[(4-chlorophenyl)methyl]-2-[3-(trifluoromethoxy)phenoxy]-1H-imidazole-5-carboxylic acid (1.1 g, 2.24 mmol, 1 equivalent) and (COCl)2 (0.6 mL, 4.73 mmol, 3.148 equivalents) in DCM (20.0 mL) and DMF (5 drops) was stirred at room temperature for 1 hour. The resulting mixture was concentrated to obtain a crude product. To the crude product, 2-amino-4-[(tert-butyldimethylsilyl)oxy]methyl butanoate (1.1 g, 4.45 mmol, 1.987 equivalents), TEA (1.6 mL, 15.37 mmol, 5 equivalents), and DCM (25.0 mL) were added, and the resulting mixture was then stirred at room temperature for 4 hours. The reaction mixture was purified by silica gel column chromatography and eluted with PE:EA (20:1~5:1) to obtain 2-([4-bromo-1-[(4-chlorophenyl)methyl]-2-[3-(trifluoromethoxy)phenoxy]-1H-imidazole-5-yl]formamide)-4-[(tert-butyldimethylsilyl)oxy]methyl butanoate (1.2g, 74.38%) as a pale yellow oil. 1 H NMR(400MHz, DMSO-d6)δ8.51(d, J = 7.6Hz, 1H), 7.68-7.53(m, 1H), 7.44-7.23(m, 7H), 5.47-5.26(m, 2H), 4.55(ddd, J = 9.5, 7.5, 4.3Hz, 1H), 3.70(dd, J = 7.1, 4.7Hz, 2H), 3.34(s, 3H), 2.08-1.89(m, 2H), 0.85(s, 9H), 0.01(d, J = 5.2Hz, 7H).

[0241] 2-(1-[4-bromo-1-[(4-chlorophenyl)methyl]-2-[3-(trifluoromethoxy)phenoxy]-1H-imidazole-5-yl]-N-methylformamide)-4-[(tert-butyldimethylsilyl)oxy]methyl butanoate A mixture of 2-([4-bromo-1-[(4-chlorophenyl)methyl]-2-[3-(trifluoromethoxy)phenoxy]-1H-imidazole-5-yl]formamide)-4-[(tert-butyldimethylsilyl)oxy]methyl butanoate (1.2 g, 1.66 mmol, 1 equivalent) in DMF (20 mL) was mixed with NaH (100 mg, 2.50 mmol, 1.502 equivalents, 60 wt%) at 0°C under a nitrogen atmosphere for 0.5 hours. CH3I (0.2 mL, 3.21 mmol, 1.930 equivalents) was added to the above mixture at 0°C. The resulting mixture was stirred at room temperature for a further 16 hours. Ethyl acetate (300 mL) and brine (300 mL) were added to the resulting mixture, and the aqueous layer was then extracted with ethyl acetate (200 mL). The combined organic layer was dried over anhydrous Na2SO4 and filtered. The filtrate was purified by silica gel column chromatography and eluted with PE:EA (20:1~6:1) to obtain 2-(1-[4-bromo-1-[(4-chlorophenyl)methyl]-2-[3-(trifluoromethoxy)phenoxy]-1H-imidazole-5-yl]-N-methylformamide)-4-[(tert-butyldimethylsilyl)oxy]methyl butanoate (880 mg, 71.93%) as a pale yellow oil.

[0242] 2-(1-[4-bromo-1-[(4-chlorophenyl)methyl]-2-[3-(trifluoromethoxy)phenoxy]-1H-imidazole-5-yl]-N-methylformamide)-4-[(tert-butyldimethylsilyl)oxy]-N-methylbutanamide A mixture of methylamine (5 mL) in 2 M methanol and 2-(1-[4-bromo-1-[(4-chlorophenyl)methyl]-2-[3-(trifluoromethoxy)phenoxy]-1H-imidazole-5-yl]-N-methylformamide)-4-[(tert-butyldimethylsilyl)oxy]methyl butanoate (1.1 g, 1.50 mmol, 1 equivalent) was irradiated with microwave radiation at 60°C for 1 hour. The reaction mixture was purified by silica gel column chromatography and eluted with PE:EA (1:1~1:8) to obtain 2-(1-[4-bromo-1-[(4-chlorophenyl)methyl]-2-[3-(trifluoromethoxy)phenoxy]-1H-imidazole-5-yl]-N-methylformamide)-4-[(tert-butyldimethylsilyl)oxy]-N-methylbutanamide (550 mg, 50.07%) as a pale yellow oil. 1 H NMR(300MHz, DMSO-d6)δ7.70(s, 1H), 7.58(t, J = 8.2Hz, 1H), 7.46-7.21(m, 6H), 5.16(s, 2H), 4.94(s, 1H), 3.60(s, 3H), 2.88(s, 3H), 2.60(d, J = 4.5Hz, 3H), 2.03(d, J = 8.7Hz, 1H), 1.90(d, J = 12.3Hz, 1H), 0.86(s, 9H), 0.02(d, J = 2.7Hz, 6H).

[0243] 6-[2-[(tert-butyldimethylsilyl)oxy]ethyl]-1-[(4-chlorophenyl)methyl]-4,7-dimethyl-2-[3-(trifluoromethoxy)phenoxy]-1H,4H,5H,6H,7H,8H-imidazo[4,5-e][1,4]diazepine-5,8-dione A mixture of 2-(1-[4-bromo-1-[(4-chlorophenyl)methyl]-2-[3-(trifluoromethoxy)phenoxy]-1H-imidazole-5-yl]-N-methylformamide)-4-[(tert-butyldimethylsilyl)oxy]-N-methylbutanamide (450 mg, 610 mmol, 1 equivalent), Pd2(dba)3·CHCl3 (63.45 mg, 0.06 mmol, 0.100 equivalents), P(o-Tol)3 (37.35 mg, 0.12 mmol, 0.200 equivalents), and Cs2CO3 (400 mg, 1.23 mmol, 2.003 equivalents) in toluene (8 mL) was irradiated with microwave radiation at 120 °C for 4 hours. The mixture was cooled to room temperature. The reaction mixture was filtered, and the filtrate was concentrated to obtain the crude product. This was purified by silica gel column chromatography and eluted with PE:EA (2:1~2:3) to obtain 6-[2-[(tert-butyldimethylsilyl)oxy]ethyl]-1-[(4-chlorophenyl)methyl]-4,7-dimethyl-2-[3-(trifluoromethoxy)phenoxy]-1H,4H,5H,6H,7H,8H-imidazo[4,5-e][1,4]diazepine-5,8-dione (220 mg, 54.95%) as a pale yellow oil.

[0244] (6S)-1-[(4-chlorophenyl)methyl]-6-(2-hydroxyethyl)-4,7-dimethyl-2-[3-(trifluoromethoxy)phenoxy]-1H,4H,5H,6H,7H,8H-imidazo[4,5-e][1,4]diazepine-5,8-dione and (6R)-1-[(4-chlorophenyl)methyl]-6-(2-hydroxyethyl)-4,7-dimethyl-2-[3-(trifluoromethoxy)phenoxy]-1H,4H,5H,6H,7H,8H-imidazo[4,5-e][1,4]diazepine-5,8-dione To a stirred solution of 6-[2-[(tert-butyldimethylsilyl)oxy]ethyl]-1-[(4-chlorophenyl)methyl]-4,7-dimethyl-2-[3-(trifluoromethoxy)phenoxy]-1H,4H,5H,6H,7H,8H-imidazo[4,5-e][1,4]diazepine-5,8-dione (200 mg, 310 mmol, 1 equivalent) in THF (10 mL), 6 M HCl (10 mL) was added dropwise at room temperature. The resulting mixture was stirred at room temperature for 2 hours. The reaction mixture was basicized to pH 10 with K2CO3, extracted with ethyl acetate (3 x 100 mL), then washed with brine (2 x 50 mL), dried over anhydrous Na2SO4, and filtered. The filtrate was concentrated to obtain the crude product, which was purified by preparative chiral HPLC (column: CHIRALPAK IG, 20*250 mm, 5 μm; mobile phase A: hexane 0.1% DEA--HPLC, mobile phase B: EtOH--HPLC; flow rate: 20 mL / min; gradient: 20B~20B at 18 min; 220 / 254 nm; RT1: 10.297; RT2: 13.612) to obtain compound 17 (RT 10.297 min, 20.2 mg, 12.24%) and compound 18 (RT 13.612 min, 18.2 mg, 11.03%) as pale yellow oil.

[0245] Characterization of compound 17: 1 H NMR(300MHz, DMSO-d6)δ7.63-7.50(m, 1H), 7.46-7.24(m, 7H), 5.65-5.32(m, 2H), 4.72-4.59(m, 1H), 4.41-4.30(m, 1H), 3.55-3.43(m, 0.8H), 3.42-3.36(m, 0.7H), 3.23(s, 3H), 3.08-3.01(m, 1H), 3.00-2.90(m, 0.3H), 2.84(s, 2.2H), 2.25-2.14(m, 0.7H), 2.07-1.93(m, 0.7H), 1.61-1.49(m, 0.7H). Molecular formula C 24 H 22 Calculated [M+H] of ClF3N4O5 + :539, observed value:539.

[0246] Characterization of compound 18:1 H NMR(300MHz, DMSO-d6)δ7.63-7.53(m, 1H), 7.47-7.23(m, 7H), 5.64-5.32(m, 2H), 4.72-4.59(m, 1H), 4.39-4.27(m, 1H), 3.55-3.42(m, 0.8H), 3.42-3.36(m, 0.8H), 3.23(s, 3H), 3.08-3.01(m, 1H), 3.00-2.89(m, 0.5H), 2.84(s, 2.2H), 2.27-2.13(m, 0.7H), 2.08-1.94(m, 0.7H), 1.62-1.49(m, 0.5H). Molecular formula C 24 H 22 Calculated [M+H] of ClF3N4O5 + :539, observed value:539.

[0247] Preparation of compounds 19 and 20:

[0248] [ka]

[0249] 4-Bromo-1-[(4-chlorophenyl)methyl]-2-(3-fluorophenoxy)-N-(3-hydroxypropyl)-1H-imidazole-5-carboxamide To a mixture of 4-bromo-1-[(4-chlorophenyl)methyl]-2-(3-fluorophenoxy)-1H-imidazole-5-carboxylic acid (2 g, 4.70 mmol, 1 equivalent) and one drop of DMF in 30 mL of DCM, oxalyl dichloride (1.8 g, 14.10 mmol, 3 equivalents) was added dropwise at 0°C. The mixture was stirred at room temperature for 3 hours. The resulting mixture was concentrated under vacuum. The solid was dissolved in 30 mL of DCM to obtain solution A. A mixture of 3-aminopropan-1-ol (1.8 g, 23.49 mmol, 5 equivalents) and triethylamine (2.4 g, 23.49 mol, 5 equivalents) in 5 mL of DCM was cooled to 0°C, and solution A was added dropwise at 0°C under a nitrogen atmosphere. The mixture was stirred at room temperature for 3 hours. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography and eluted with PE / EA (2 / 1~1 / 1) to obtain 4-bromo-1-[(4-chlorophenyl)methyl]-2-(3-fluorophenoxy)-N-(3-hydroxypropyl)-1H-imidazole-5-carboxamide (1.65 g, 72.74%) as a white solid.

[0250] 4-Bromo-1-[(4-chlorophenyl)methyl]-2-(3-fluorophenoxy)-N-[3-(oxan-2-yloxy)propyl]-1H-imidazole-5-carboxamide 4-Methylbenzene-1-sulfonic acid (0.059 g, 0.34 mmol, 0.100 equivalent) was added at room temperature to a stirred mixture of 4-bromo-1-[(4-chlorophenyl)methyl]-2-(3-fluorophenoxy)-N-(3-hydroxypropyl)-1H-imidazole-5-carboxamide (1.65 g, 3.42 mmol, 1 equivalent) and 3,4-dihydro-2H-pyran (1.4427 g, 17.15 mmol, 5.018 equivalents) in 50 mL of DCM. The mixture was stirred at room temperature for 16 hours. The resulting mixture was washed with saturated NaHCO3 aqueous solution. The DCM layer was concentrated under reduced pressure. The residue was purified by silica gel column chromatography and eluted with PE / EA (6 / 1~3 / 1) to obtain 4-bromo-1-[(4-chlorophenyl)methyl]-2-(3-fluorophenoxy)-N-[3-(oxan-2-yloxy)propyl]-1H-imidazole-5-carboxamide (1.65 g, 85.16%) as a white solid.

[0251] 2-(1-[4-bromo-1-[(4-chlorophenyl)methyl]-2-(3-fluorophenoxy)-1H-imidazole-5-yl]-N-[3-(oxan-2-yloxy)propyl]formamide)ethyl propanoate To a stirred solution of 4-bromo-1-[(4-chlorophenyl)methyl]-2-(3-fluorophenoxy)-N-[3-(oxan-2-yloxy)propyl]-1H-imidazole-5-carboxamide (2.5 g, 4.41 mmol, 1 equivalent) in DMF (15 mL), NaH (0.7 g, 17.64 mmol, 4 equivalents, 60%) was gradually added at 0°C under a nitrogen atmosphere. The mixture was stirred at 0°C for 30 minutes, and ethyl 2-bromopropanoate (3.1936 g, 17.64 mmol, 4.000 equivalents) was added. The mixture was stirred at room temperature for 16 hours. The resulting mixture was quenched with water (100 mL) and extracted with EA (3 × 100 mL). The combined organic layer was washed with water (1 × 100 mL) and dried on anhydrous Na₂SO₄. After filtration, the filtrate was concentrated under reduced pressure to obtain the crude compound. The crude product was purified by reverse-phase flush under the following conditions (column: spherical C18 column, 20-40 μm, 120 g, mobile phase A: water (0.1% AcOH), mobile phase B: ACN, flow rate: 60 mL / min, gradient: 60-80% B, 254 nm at 35 min) to obtain ethyl 2-(1-[4-bromo-1-[(4-chlorophenyl)methyl]-2-(3-fluorophenoxy)-1H-imidazole-5-yl]-N-[3-(oxan-2-yloxy)propyl]formamide)propanoate (1.38 g, 46.91%) as a yellow oil.

[0252] 2-(1-[4-bromo-1-[(4-chlorophenyl)methyl]-2-(3-fluorophenoxy)-1H-imidazole-5-yl]-N-[3-(oxan-2-yloxy)propyl]formamide)-N-methylpropanamide To a 20 mL container, ethyl 2-(1-[4-bromo-1-[(4-chlorophenyl)methyl]-2-(3-fluorophenoxy)-1H-imidazole-5-yl]-N-[3-(oxan-2-yloxy)propyl]formamide)propanoate (1.3 g, 1 equivalent) and methylamine in methanol (6 mL, 30%) were added at room temperature. The mixture was reacted under microwave conditions at 60°C for 1 hour. The resulting mixture was cooled to room temperature and concentrated under vacuum. The residue was purified by silica gel column chromatography and eluted with PE / EA(1 / 1) to obtain 2-(1-[4-bromo-1-[(4-chlorophenyl)methyl]-2-(3-fluorophenoxy)-1H-imidazole-5-yl]-N-[3-(oxan-2-yloxy)propyl]formamide)-N-methylpropanamide (1.2g, 94.43%) as a yellow oil.

[0253] 1-[(4-chlorophenyl)methyl]-2-(3-fluorophenoxy)-4,6-dimethyl-7-[3-[(2R)-oxan-2-yloxy]propyl]-1H,4H,5H,6H,7H,8H-imidazo[4,5-e][1,4]diazepine-5,8-dione 2-(1-[4-bromo-1-[(4-chlorophenyl)methyl]-2-(3-fluorophenoxy)-1H-imidazole-5-yl]-N-[3-(oxan-2-yloxy)propyl]formamide)-N-methylpropanamide (1.1936 g, 1.83 mol, 1 equivalent), Pd2(dba)3 (0.2 g, 0.18 mmol, 0.1 equivalent), Cs2CO3 (1.1966 g, 3.67 mmol, 2.006 equivalents), and tris(2-methylphenyl)phosphane (0.1 g, 0.37 mmol, 0.2 equivalents) were added to a 20 mL container at room temperature. The mixture was heated under microwave conditions at 120 °C for 5 hours. The mixture was then cooled to room temperature. The residue was purified by silica gel column chromatography and eluted with PE / EA(1 / 1) to obtain 1-[(4-chlorophenyl)methyl]-2-(3-fluorophenoxy)-4,6-dimethyl-7-[3-[(2R)-oxan-2-yloxy]propyl]-1H,4H,5H,6H,7H,8H-imidazo[4,5-e][1,4]diazepine-5,8-dione (340 mg, 32.52%) as a yellow oil.

[0254] (6S)-1-[(4-chlorophenyl)methyl]-2-(3-fluorophenoxy)-7-(3-hydroxypropyl)-4,6-dimethyl-1H,4H,5H,6H,7H,8H-imidazo[4,5-e][1,4]diazepine-5,8-dione and (6R)-1-[(4-chlorophenyl)methyl]-2-(3-fluorophenoxy)-7-(3-hydroxypropyl)-4,6-dimethyl-1H,4H,5H,6H,7H,8H-imidazo[4,5-e][1,4]diazepine-5,8-dione A mixture of 1-[(4-chlorophenyl)methyl]-2-(3-fluorophenoxy)-4,6-dimethyl-7-[3-[(2R)-oxan-2-yloxy]propyl]-1H,4H,5H,6H,7H,8H-imidazo[4,5-e][1,4]diazepine-5,8-dione (200 mg, 0.35 mmol, 1 equivalent) and HCl (2 M; 20 mL) in THF (20 mL) was stirred at room temperature for 1 hour. The resulting mixture was extracted with EA (3 x 200 mL). The combined organic layer was washed with water (1 x 200 mL) and dried on anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The crude product (170 mg) was purified by preparative HPLC under the following conditions (column: XBridge preparative C18 OBD column, 5 μm, 19*150 mm; mobile phase A: water (0.05% TFA), mobile phase B: ACN; flow rate: 20 mL / min; gradient: 40%B to 70%B in 7 mins; 254 nm; RT: 6.32 mins) to obtain 1-[(4-chlorophenyl)methyl]-2-(3-fluorophenoxy)-7-(3-hydroxypropyl)-4,6-dimethyl-1H,4H,5H,6H,7H,8H-imidazo[4,5-e][1,4]diazepine-5,8-dione (140 mg). The racemic mixture was separated by chiral HPLC under the following conditions (column: CHIRALPAK IF, 2*25cm, 5μm; mobile phase A: 0.1% hexane--HPLC, mobile phase B: EtOH--HPLC; flow rate: 15mL / min; gradient: 50B~50B at 13 min; 220 / 254nm; RT1: 8.349; RT2: 9.504), yielding compound 19 (RT 8.349 min, 20 mg, 11.73%) and compound 20 (RT 9.504 min, 20 mg, 11.73%).

[0255] Characterization of compound 19: 1H NMR(400MHz, methanol-d4)δ7.45(dd, J = 13.8, 6.2Hz, 1H), 7.41-7.29(m, 4H), 7.23-6.99(m, 3H), 5.63-5.53(m, 1H), 5.45-5.38(m, 1H), 4.38(dd, J = 16.4, 8.3Hz, 1H), 3.96(dt, J = 14.8, 7.7Hz, 1H), 3.64(t, J = 7.0Hz, 1H), 3.49(t, J = 6.3Hz, 2H), 3.35(s, 3H), 1.85-1.73(m, 1H), 1.69-1.62(dt, J = 13.5, 6.9Hz, 1H), 1.56(d, J = 7.0Hz, 2H), 1.10(d, J = 7.5Hz, 1H). Molecular formula C 24 H 24 Calculated [M+H] of ClFN4O4 + :487, observed value:487.

[0256] Characterization of compound 20: 1 H NMR(400MHz, methanol-d4)δ7.49-7.40(m, 1H), 7.37-7.29(m, 4H), 7.22-7.00(m, 3H), 5.62-5.53(m, 1H), 5.42-5.39(m, 1H), 4.43-4.33(m, 1H), 3.99-3.92(dt, J = 14.9, 7.7Hz, 1H), 3.64(t, J = 8.0Hz, 1H), 3.49(t, J = 8.0Hz, 2H), 3.35(s, 3H), 1.82-1.75(m, 1H), 1.69-1.62(dt, J = 13.7, 6.9Hz, 1H), 1.56(d, J = 8.0Hz, 2H), 1.10(d, J = 8.0Hz, 1H). Molecular formula C 24 H 24 Calculated [M+H] of ClFN4O4 + :487, observed value:487.

[0257] Preparation of compound 21:

[0258] [ka]

[0259] 1-[(4-chlorophenyl)methyl]-4-[(2-methoxy-2-oxoethyl)(methyl)amino]-2-[3-(trifluoromethoxy)phenoxy]-1H-imidazole-5-carboxylate methyl A mixture of 4-bromo-1-[(4-chlorophenyl)methyl]-2-[3-(trifluoromethoxy)phenoxy]-1H-imidazole-5-carboxylate methyl (1.00 g, 1.98 mol, 1 equivalent), 2-(methylamino)acetate methyl (1019.6 mg, 9.89 mol, 5.0 equivalents), Pd2(dba)3 (452.7 mg, 0.49 mmol, 0.25 equivalents), xanthophos (572.1 mg, 0.99 mmol, 0.50 equivalents), and Cs2CO3 (6.4 g, 19.78 mmol, 10.0 equivalents) in dioxane (100.0 mL) was stirred at 100°C for 16 hours under a nitrogen atmosphere. The reaction mixture was cooled to room temperature, and ethyl acetate (200 mL) and H2O (200 mL) were added. The organic layer was washed with brine (3 x 50 mL), dried over anhydrous sodium 2SO4, and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography and eluted with PE:Â (6:1~4:1) to obtain 1-[(4-chlorophenyl)methyl]-4-[(2-methoxy-2-oxoethyl)(methyl)amino]-2-[3-(trifluoromethoxy)phenoxy]-1H-imidazole-5-carboxylate methyl (150 mg, 14.37%) as a pale yellow oil.

[0260] 4-[(carbamoylmethyl)(methyl)amino]-1-[(4-chlorophenyl)methyl]-2-[3-(trifluoromethoxy)phenoxy]-1H-imidazole-5-carboxylate methyl A mixture of 1-[(4-chlorophenyl)methyl]-4-[(2-methoxy-2-oxoethyl)(methyl)amino]-2-[3-(trifluoromethoxy)phenoxy]-1H-imidazole-5-carboxylate methyl (300 mg, 570 mmol, 1 equivalent) in ammonia solution (10 mL) was irradiated with microwave radiation at 120°C for 4 hours. The reaction mixture was concentrated under reduced pressure. The residue was purified by reverse-phase flushing under the following conditions (column: spherical C18 column, 20-40 μm, 120 g; mobile phase A: water (0.1% HOAc), mobile phase B: ACN; flow rate: 60 mL / min; gradient: 60%B-70%B at 10 min, 254 nm) to obtain methyl 4-[(carbamoylmethyl)(methyl)amino]-1-[(4-chlorophenyl)methyl]-2-[3-(trifluoromethoxy)phenoxy]-1H-imidazole-5-carboxylate (230 mg, 39.46%) as an off-white solid.

[0261] 1-[(4-chlorophenyl)methyl]-4-methyl-2-[3-(trifluoromethoxy)phenoxy]-1H,4H,5H,6H,7H,8H-imidazo[4,5-e][1,4]diazepine-6,8-dione A mixture of methyl 4-[(carbamoylmethyl)(methyl)amino]-1-[(4-chlorophenyl)methyl]-2-[3-(trifluoromethoxy)phenoxy]-1H-imidazole-5-carboxylate (120 mg, 0.23 mmol, 1 equivalent) in dioxane (20 mL) and NaH (18.7 mg, 0.47 mmol, 2.0 equivalents, 60 wt%) was refluxed for 15 minutes. 0.5 mL of HOAc was added to the reaction mixture, and the resulting mixture was stirred at room temperature for 16 hours. The reaction mixture was concentrated under reduced pressure. The residue was purified by reverse-phase flushing under the following conditions (column: spherical C18 column, 20-40 μm, 120 g; mobile phase A: water (0.1% HOAc), mobile phase B: ACN; flow rate: 60 mL / min; gradient: 60%B-70%B at 15 min, 254 nm) to obtain 1-[(4-chlorophenyl)methyl]-4-methyl-2-[3-(trifluoromethoxy)phenoxy]-1H,4H,5H,6H,7H,8H-imidazo[4,5-e][1,4]diazepine-6,8-dione (45 mg, 40.00%) as an off-white solid.

[0262] 1-[(4-chlorophenyl)methyl]-4-methyl-7-[3-(oxan-2-yloxy)propyl]-2-[3-(trifluoromethoxy)phenoxy]-1H,4H,5H,6H,7H,8H-imidazo[4,5-e][1,4]diazepine-6,8-dione A mixture of 1-[(4-chlorophenyl)methyl]-4-methyl-2-[3-(trifluoromethoxy)phenoxy]-1H,4H,5H,6H,7H,8H-imidazo[4,5-e][1,4]diazepine-6,8-dione (100 mg, 0.21 mmol, 1 equivalent), 2-(3-bromopropoxy)oxane (139.2 mg, 0.62 mmol, 3.0 equivalents), and K2CO3 (86.2 mg, 0.62 mmol, 3.0 equivalents) in DMF (15.0 mL) was stirred at 50°C for 16 hours. The reaction mixture was cooled to room temperature and H2O (100 mL) was added. The resulting mixture was extracted with  (3 × 50 mL). The combined organic layer was washed with brine (2 × 50 mL) and dried on anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography and eluted with PE:EA (6:1~3:1) to obtain 1-[(4-chlorophenyl)methyl]-4-methyl-7-[3-(oxan-2-yloxy)propyl]-2-[3-(trifluoromethoxy)phenoxy]-1H,4H,5H,6H,7H,8H-imidazo[4,5-e][1,4]diazepine-6,8-dione (120 mg, 92.6:1%) as a pale yellow oil. 1 H NMR(400MHz, chloroform-d)δ7.43(t, J = 8.3Hz, 1H), 7.27(d, J = 8.7Hz, 5H), 7.17(dd, J = 33.5, 8.4Hz, 2H), 5.58(s, 2H), 4.60(d, J = 14.8Hz, 2H), 3.88(s, 2H), 3.85-3.72(m, 2H), 3.63(dt, J = 10.4, 5.6Hz, 1H), 3.58-3.47(m, 2H), 3.13(s, 3H), 2.04-1.58(m, 8H).

[0263] 1-[(4-chlorophenyl)methyl]-7-(3-hydroxypropyl)-4-methyl-2-[3-(trifluoromethoxy)phenoxy]-1H,4H,5H,6H,7H,8H-imidazo[4,5-e][1,4]]diazepine-6,8-dione A mixture of 1-[(4-chlorophenyl)methyl]-4-methyl-7-[3-(oxan-2-yloxy)propyl]-2-[3-(trifluoromethoxy)phenoxy]-1H,4H,5H,6H,7H,8H-imidazo[4,5-e][1,4]diazepine-6,8-dione (45 mg, 0.07 mmol, 1 equivalent) in THF (10 mL) and 6M HCl (10 mL) was stirred at room temperature for 2 hours. The reaction mixture was concentrated under reduced pressure. The residue was basicized to pH 9 with saturated K2CO3 (aq). The resulting mixture was extracted with ethyl acetate (3 x 50 mL), the combined organic layer was washed with brine (50 mL), and concentrated to obtain the crude product. This was purified by preparative HPLC under the following conditions (column: XSelect CSH preparative C18 OBD column, 5 μm, 19 x 150 mm; mobile phase A: water (0.1% FA), mobile phase B: ACN; flow rate: 20 mL / min; gradient: 50% B to 87% B at 7 min; 254 nm; RT: 6.58 min) to obtain 1-[(4-chlorophenyl)methyl]-7-(3-hydroxypropyl)-4-methyl-2-[3-(trifluoromethoxy)phenoxy]-1H,4H,5H,6H,7H,8H-imidazo[4,5-e][1,4]diazepine-6,8-dione (3.9 mg, 9.52%) as an off-white solid. 1 H NMR(400MHz, chloroform-d)δ7.54-7.45(m, 1H), 7.43-7.28(m, 2H), 7.24-7.02(m, 5H), 5.57(s, 2H), 4.04(t, J = 6.0Hz, 2H), 3.90(s, 2H), 3.50(t, J = 5.5Hz, 2H), 3.15(s, 3H), 1.80(p, J = 5.7Hz, 2H). Molecular formula C 24 H 22 Calculated [M+H] of ClF3N4O5 + :539, observed value:539.

[0264] Preparation of compounds 22 and 23:

[0265] [ka]

[0266] 1-[(4-chlorophenyl)methyl]-4-[2-(methoxycarbonyl)pyrrolidine-1-yl]-2-[3-(trifluoromethoxy)phenoxy]-1H-imidazole-5-carboxylate methyl A mixture of 4-bromo-1-[(4-chlorophenyl)methyl]-2-[3-(trifluoromethoxy)phenoxy]-1H-imidazole-5-carboxylate methyl (1.5 g, 2.97 mmol, 1 equivalent), Pd2(dba)3 (280 mg, 0.31 mmol, 0.103 equivalents), xanthophos (520 mg, 0.90 mmol, 0.303 equivalents), pyrrolidine-2-carboxylate methyl (800.0 mg, 6.19 mmol, 2.088 equivalents), and Cs2CO3 (4.9 g, 15.04 mmol, 5.070 equivalents) in dioxane (40 mL) was stirred at 100°C for 14 hours. The reaction mixture was filtered, and the filtrate was concentrated to obtain the crude product. This was purified by silica gel column chromatography and eluted with PE:EA (20:1~4:1) to obtain methyl 1-[(4-chlorophenyl)methyl]-4-[2-(methoxycarbonyl)pyrrolidine-1-yl]-2-[3-(trifluoromethoxy)phenoxy]-1H-imidazole-5-carboxylate (830 mg, 50.51%) as a pale yellow oil.

[0267] 4-(2-carbamoylpyrrolidine-1-yl)-1-(4-chlorobenzyl)-2-(3-(trifluoromethoxy)phenoxy)-1H-imidazole-5-carboxylate methyl A mixture of 1-[(4-chlorophenyl)methyl]-4-[2-(methoxycarbonyl)pyrrolidine-1-yl]-2-[3-(trifluoromethoxy)phenoxy]-1H-imidazole-5-carboxylate methyl (1.65 g, 2.98 mmol, 1 equivalent) in an ammonia solution (7.0 M in methanol) (10 mL) was irradiated with microwave radiation at 140°C for 10 hours. The reaction mixture was cooled to room temperature and concentrated to obtain a residue, which was purified by flash chromatography on a silica gel column. Elution with 70% ethyl acetate in petroleum ether yielded 4-(2-carbamoylpyrrolidine-1-yl)-1-(4-chlorobenzyl)-2-(3-(trifluoromethoxy)phenoxy)-1H-imidazole-5-carboxylate methyl (300 mg, 24% yield) as a pale yellow semi-solid. 1 H NMR(400MHz, chloroform-d)δ7.41(t, J = 8.3Hz, 1H), 7.34-7.24(m, 4H), 7.23-7.18(m, 3H), 7.12-7.07(m, 1H), 6.52(s, 1H), 5.41(q, J = 15.4Hz, 2H), 4.53(dd, J = 8.2, 5.2Hz, 1H), 3.87-3.69(m, 4H), 3.32(dt, J = 10.5, 7.1Hz, 1H), 2.28-2.09(m, 2H), 2.05-1.83(m, 2H).

[0268] 5-[(4-chlorophenyl)methyl]-4-[3-(trifluoromethoxy)phenoxy]-1,3,5,8-tetraazatricyclo[8.3.0.0^[2,6]]trideca-2(6),3-diene-7,9-dione A mixture of 4-(2-carbamoylpyrrolidine-1-yl)-1-[(4-chlorophenyl)methyl]-2-[3-(trifluoromethoxy)phenoxy]-1H-imidazole-5-carboxylate methyl (185 mg, 340 mmol, 1 equivalent) in dioxane (40 mL) was mixed with NaH (96.1 mg, 2.40 mmol, 7.0 equivalents, 60 wt%) at 0°C, and the reaction mixture was refluxed for 15 minutes. The reaction mixture was cooled to room temperature and concentrated under reduced pressure. The residual product was purified by reverse-phase flash under the following conditions (column: spherical C18 column, 20-40 μm, 120 g; mobile phase A: water (0.1% HOAc), mobile phase B: ACN; flow rate: 60 mL / min; gradient: 65%B-85%B at 15 min, 254 nm) to obtain 5-[(4-chlorophenyl)methyl]-4-[3-(trifluoromethoxy)phenoxy]-1,3,5,8-tetraazatricyclo[8.3.0.0^[2,6]]trideca-2(6),3-diene-7,9-dione (115 mg, 66.09%) as an off-white solid. 1 H NMR(400MHz, DMSO-d6)δ10.52(s, 1H), 7.58(t, J = 8.3Hz, 1H), 7.47(d, J = 2.7Hz, 1H), 7.44-7.36(m, 3H), 7.36-7.27(m, 3H), 5.52(dd, J = 91.6, 15.5Hz, 2H), 3.81(dd, J = 8.3, 5.2Hz, 1H), 3.51(dt, J = 10.1, 7.3Hz, 1H), 3.32(d, J = 7.1Hz, 1H), 2.50(s, 1H), 2.12-1.96(m, 1H), 1.81(qt, J = (12.3, 6.6Hz, 2H).

[0269] 5-[(4-chlorophenyl)methyl]-8-[3-(oxan-2-yloxy)propyl]-4-[3-(trifluoromethoxy)phenoxy]-1,3,5,8-tetraazatricyclo[8.3.0.0^[2,6]]trideca-2(6),3-diene-7,9-dione A mixture of 5-[(4-chlorophenyl)methyl]-4-[3-(trifluoromethoxy)phenoxy]-1,3,5,8-tetraazatricyclo[8.3.0.0^[2,6]]trideca-2(6),3-diene-7,9-dione (150 mg, 300 mmol, 1 equivalent), 2-(3-bromopropoxy)oxane (198.1 mg, 890 mmol, 3,000 equivalents), and K2CO3 (122.7 mg, 0.89 mmol, 3.0 equivalents) in DMF (15.0 mL) was stirred at 50°C for 16 hours. The reaction mixture was cooled to room temperature, and  (100 mL) and H2O (100 mL) were added. The organic layer was washed with brine (2 x 30 mL), concentrated under reduced pressure, and purified by reverse-phase flush under the following conditions (column: spherical C18 column, 20-40 μm, 120 g; mobile phase A: water (0.1% HOAc), mobile phase B: ACN; flow rate: 60 mL / min; gradient: 90%B-98%B at 10 min, 254 nm) to obtain 5-[(4-chlorophenyl)methyl]-8-[3-(oxan-2-yloxy)propyl]-4-[3-(trifluoromethoxy)phenoxy]-1,3,5,8-tetraazatricyclo[8.3.0.0^[2,6]]trideca-2(6),3-diene-7,9-dione (185 mg, 96.31%) as a pale yellow oil. 1 H NMR(400MHz, chloroform-d)δ7.43(t, J = 8.3Hz, 1H), 7.30(s, 4H), 7.27-7.19(m, 2H), 7.13(d, J = 8.3Hz, 1H), 5.73(d, J = 14.9Hz, 1H), 5.43(d, J = 15.1Hz, 1H), 4.65-4.49(m, 1H), 4.15(ddt, J = 19.0, 13.7, 7.1Hz, 1H), 3.98-3.61(m, 4H), 3.46(tt, J = 16.5, 7.6Hz, 4H), 2.85(dt, J = 12.2, 6.3Hz, 1H), 2.18-2.02(m, 2H), 1.99-1.77(m, 3H), 1.76-1.48(m, 6H).

[0270] (10R)-5-[(4-chlorophenyl)methyl]-8-(3-hydroxypropyl)-4-[3-(trifluoromethoxy)phenoxy]-1,3,5,8-tetraazatricyclo[8.3.0.0^[2,6]]trideca-2(6),3-diene-7,9-dione and (10S)-5-[(4-chlorophenyl)methyl]-8-(3-hydroxypropyl)-4-[3-(trifluoromethoxy)phenoxy]-1,3,5,8-tetraazatricyclo[8.3.0.0^[2,6]]trideca-2(6),3-diene-7,9-dione A mixture of 5-[(4-chlorophenyl)methyl]-8-[3-(oxan-2-yloxy)propyl]-4-[3-(trifluoromethoxy)phenoxy]-1,3,5,8-tetraazatricyclo[8.3.0.0^[2,6]]trideca-2(6),3-diene-7,9-dione (160 mg, 250 mmol, 1 equivalent) in THF (5 mL) and 2 M HCl (5 mL) was stirred at room temperature for 2 hours. Saturated NaHCO3 (aq) was added to the reaction mixture to adjust the pH to 9, ethyl acetate (100 mL) was added, and the organic layer was washed with brine (2 × 50 mL) and concentrated under reduced pressure. The residue was purified by preparative HPLC under the following conditions (column: XBridge Shield RP18 OBD column 30*150 mm, 5 μm; mobile phase A: water (0.1% FA), mobile phase B: ACN; flow rate: 60 mL / min; gradient: 50%B to 80%B in 7 mins; 254 nm; RT: 6.45 mins) to obtain a racemic 5-[(4-chlorophenyl)methyl]-8-(3-hydroxypropyl)-4-[3-(trifluoromethoxy)phenoxy]-1,3,5,8-tetraazatricyclo[8.3.0.0^[2,6]]trideca-2(6),3-diene-7,9-dione (110 mg, 78.99%) as a colorless oil. 90 mg of this substance was subjected to chiral preparative HPLC (column: CHIRALPAK AD-H, 2.0 cm ID*25 cm L; mobile phase A: hexane 0.1% DEA--HPLC, mobile phase B: EtOH--HPLC; flow rate: 20 mL / min; gradient: 15B~15B at 15 min; 220 / 254 nm; RT1: 9.279; RT2: 10.54) to obtain compound 22 (RT 9.279 min, 17.7 mg, 19.67%) and compound 23 (RT 10.54 min, 19.11%).

[0271] Characterization of compound 22: 1H NMR(400MHz, methanol-d4)δ7.55-7.51(m, 1H), 7.36-7.27(m, 6H), 7.23-7.20(m, 1H), 5.70(d, J = 16.0Hz, 1H), 5.52(d, J = 16.0Hz, 1H), 4.13-4.05(m, 1H), 3.90-3.83(m, 1H), 3.75-3.73(m, 1H), 3.69-3.62(m, 1H), 3.58-3.51(m, 2H), 3.45-3.41(m, 1H), 2.80-2.72(m, 1H), 2.19-2.10(m, 1H), 2.05-1.92(m, 2H), 1.91-1.68(m, 2H). Molecular formula C 26 H 24 Calculated [M+H] of ClF3N4O5 + :565, observed value:565.

[0272] Characterization of compound 23: 1 H NMR(400MHz, methanol-d4)δ7.55-7.51(m, 1H), 7.35-7.28(m, 6H), 7.23-7.21(m, 1H), 5.70(d, J = 16.0Hz, 1H), 5.52(d, J = 16.0Hz, 1H), 4.13-4.06(m, 1H), 3.90-3.82(m, 1H), 3.77-3.73(m, 1H), 3.69-3.62(m, 1H), 3.55-3.51(m, 2H), 3.46-3.41(m, 1H), 2.79-2.70(m, 1H), 2.19-2.10(m, 1H), 2.04-1.94(m, 2H), 1.79-1.70(m, 2H). Molecular formula C 26 H 24 Calculated [M+H] of ClF3N4O5 + :565, observed value:565.

[0273] Preparation of compounds 24 and 25: The preparation of the racemic mixtures of compounds 24 and 25 is carried out starting from intermediate I, following the methods and protocols described for the synthesis of compounds 22 and 23.

[0274] [ka]

[0275] (10R)-5-butyl-4-(3-fluorophenoxy)-8-(3-hydroxypropyl)-1,3,5,8-tetraazatricyclo[8.3.0.0^[2,6]]trideca-2(6),3-diene-7,9-dione and (10S)-5-butyl-4-(3-fluorophenoxy)-8-(3-hydroxypropyl)-1,3,5,8-tetraazatricyclo[8.3.0.0^[2,6]]trideca-2(6),3-diene-7,9-dione Crude 5-butyl-4-(3-fluorophenoxy)-8-(3-hydroxypropyl)-1,3,5,8-tetraazatricyclo[8.3.0.0^[2,6]]trideca-2(6),3-diene-7,9-dione was purified by chiral HPLC (column: XBridge shielded RP18 OBD column, 5 μm, 19*150 mml; mobile phase A: water (10 MMOL / L NH4HCO3), mobile phase B: ACN; flow rate: 20 mL / min; gradient: 45%B~70%B at 7 min; 220 nm; RT1: 15.00 min, RT2: 17.33 min) to obtain compound 24 (RT=15.00 min, 20.3 mg, 8.09%) and compound 25 (RT=17.33 min, 18.9 mg, 7.53%).

[0276] Characterization of compound 24: 1H NMR(400MHz, メタノール-d4)δ7.51-7.40(m, 1H), 7.19-7.08(m, 2H), 7.09-6.99(m, 1H), 4.41(dt, J = 13.5, 6.8Hz, 1H), 4.26(dt, J = 13.7, 7.4Hz, 1H), 4.13(ddd, J = 13.4, 7.7, 5.8Hz, 1H), 3.88(dt, J = 13.6, 7.3Hz, 1H), 3.75(dd, J = 8.2, 4.7Hz, 1H), 3.70-3.50(m, 3H), 3.42(dd, J = 10.7, 5.8Hz, 1H), 2.77(dq, J = 12.2, 6.0Hz, 1H), 2.16(dq, J = 12.7, 7.8Hz, 1H), 1.98(h, J = 6.1Hz, 2H), 1.79(dq, J = 14.5, 7.1Hz, 4H), 1.38(p, J = 7.4Hz, 2H), 0.98(t, J = 7.4Hz, 3H). Molecular formula C 22 H 27 Calculation of FN4O4[M+H] + :431, View value: 431.

[0277] Evaluation of properties of compound 25: 1H NMR(400MHz, methanol-d4)δ7.49-7.38(m, 1H), 7.19-7.10(m, 2H), 7.03(d, J = 7.8Hz, 1H), 4.41(dt, J = 13.6, 6.8Hz, 1H), 4.26(dt, J = 13.9, 7.4Hz, 1H), 4.17-4.08(m, 1H), 3.88(dt, J = 13.5, 7.2Hz, 1H), 3.75(dd, J = 8.2, 4.7Hz, 1H), 3.70-3.52(m, 3H), 3.43(dt, J = 11.0, 5.8Hz, 1H), 2.77(dq, J = 12.3, 6.1Hz, 1H), 2.16(dq, J = 12.6, 7.8Hz, 1H), 1.99(hept, J = 6.1Hz, 2H), 1.80(dp, J = 14.6, 7.1Hz, 4H), 1.35(dd, J = 17.2, 9.9Hz, 2H), 0.98(t, J = 7.4Hz, 3H). Molecular formula C 22 H 27 Calculated [M+H] of FN4O4 + :431, observed value:431.

[0278] The following compounds were prepared using the same procedure as for the preparation of compounds 22 and 23.

[0279] [Table 6-1]

[0280] [Table 6-2]

[0281] [Table 6-3]

[0282] [Table 6-4]

[0283] Preparation of compounds 34 and 35:

[0284] [ka]

[0285] 4-[2-([[(tert-butoxy)carbonyl]amino]methyl)pyrrolidine-1-yl]-1-[(4-chlorophenyl)methyl]-2-[3-(trifluoromethoxy)phenoxy]-1H-imidazole-5-carboxylate methyl A mixture of methyl 4-bromo-1-[(4-chlorophenyl)methyl]-2-[3-(trifluoromethoxy)phenoxy]-1H-imidazole-5-carboxylate (intermediate A, 6g, 11.87 mmol, 1 equivalent), tert-butyl N-[(pyrrolidine-2-yl)methyl]carbamate (4.8g, 23.73 mmol, 2.00 equivalents), xanthophos (2.1g, 3.56 mmol, 0.3 equivalents), Pd2(dba)3 (1.1g, 1.19 mmol, 0.1 equivalents), and Cs2CO3 (19.3g, 59.33 mmol, 5 equivalents) in 100 mL of dioxane was stirred at 100°C for 16 hours. The reaction mixture was filtered, and the filtrate was concentrated to obtain the crude product, which was purified by silica gel column chromatography and eluted with PE:EA (20:1~1:1) to obtain 4-[2-([[(tert-butoxy)carbonyl]amino]methyl)pyrrolidine-1-yl]-1-[(4-chlorophenyl)methyl]-2-[3-(trifluoromethoxy)phenoxy]-1H-imidazole-5-carboxylate methyl (3.4g, 45.84%) as a pale yellow oil. 1H NMR(400MHz, chloroform-d)δ7.42(t, J = 8.2Hz, 1H), 7.31(d, J = 8.2Hz, 2H), 7.23(q, J = 9.0, 8.4Hz, 4H), 7.10(d, J = 8.3Hz, 1H), 5.45(d, J = 15.8Hz, 1H), 5.33(d, J = 15.4Hz, 1H), 5.02(s, 1H), 4.16(dt, J = 23.2, 6.8Hz, 1H), 3.76(s, 4H), 3.30(s, 2H), 3.11(s, 1H), 1.97(d, J = 41.7Hz, 2H), 1.75(d, J = 6.8Hz, 2H), 1.43(s, 9H).

[0286] 4-[2-(aminomethyl)pyrrolidine-1-yl]-1-[(4-chlorophenyl)methyl]-2-[3-(trifluoromethoxy)phenoxy]-1H-imidazole-5-carboxylate methyl A stirring solution of 4-[2-([[(tert-butoxy)carbonyl]amino]methyl)pyrrolidine-1-yl]-1-[(4-chlorophenyl)methyl]-2-[3-(trifluoromethoxy)phenoxy]-1H-imidazole-5-carboxylate methyl (3.4 g, 5.44 mmol, 1 equivalent) in HCl (4 M) (30 mL, 987.36 mmol, 181.51 equivalents) was stirred at room temperature for 2 hours. The reaction mixture was then converted to K2CO3. The pH was reduced to 10, extracted with ethyl acetate (5 x 150 mL), then the organic layer was washed with brine (2 x 150 mL), dried on anhydrous sodium 2SO4, and filtered. The filtrate was concentrated to obtain 4-[2-(aminomethyl)pyrrolidine-1-yl]-1-[(4-chlorophenyl)methyl]-2-[3-(trifluoromethoxy)phenoxy]-1H-imidazole-5-carboxylate methyl (2.85 g, crude product) as a pale yellow oil. 1H NMR(400MHz, chloroform-d)δ7.39(t, J = 8.3Hz, 1H), 7.34-7.28(m, 3H), 7.19(t, J = 7.6Hz, 3H), 7.07(d, J = 8.3Hz, 1H), 5.44(d, J = 15.5Hz, 1H), 5.32(d, J = 15.4Hz, 1H), 4.25-4.08(m, 2H), 3.92-3.66(m, 5H), 3.11(ddd, J = 10.9, 6.8, 3.2Hz, 1H), 2.81(d, J = 4.9Hz, 2H), 2.04-1.86(m, 2H), 1.75(td, J = 12.2, 7.8Hz, 2H).

[0287] 5-[(4-chlorophenyl)methyl]-4-[3-(trifluoromethoxy)phenoxy]-1,3,5,8-tetraazatricyclo[8.3.0.0^[2,6]]trideca-2(6),3-dien-7-one To a mixture of 4-[2-(aminomethyl)pyrrolidine-1-yl]-1-[(4-chlorophenyl)methyl]-2-[3-(trifluoromethoxy)phenoxy]-1H-imidazole-5-carboxylate methyl (2.75 g, 5.24 mmol, 1 equivalent) in dioxane (50 mL), NaH (1.5 g, 36.67 mmol, 7.00 equivalent, 60%) was added at 0°C, and the reaction mixture was refluxed for 15 minutes. The reaction mixture was cooled to room temperature and concentrated to obtain the residue. The residual product was purified by silica gel column chromatography and eluted with PE:EA (1:2~0:1) to obtain 5-[(4-chlorophenyl)methyl]-4-[3-(trifluoromethoxy)phenoxy]-1,3,5,8-tetraazatricyclo[8.3.0.0^[2,6]]trideca-2(6),3-dien-7-one (1.5g, 58.09%) as a white solid. 1H NMR(400MHz, chloroform-d)δ7.38(t, J = 8.3Hz, 1H), 7.26(s, 5H), 7.18(dd, J = 8.4, 2.3Hz, 1H), 7.06(d, J = 8.3Hz, 1H), 5.67(d, J = 14.9Hz, 2H), 5.40(d, J = 14.9Hz, 1H), 3.68-3.38(m, 4H), 3.22-3.09(m, 1H), 2.18(dt, J = 12.8, 6.4Hz, 1H), 1.93(tdd, J = 21.4, 11.8, 6.7Hz, 2H), 1.61(qd, J = 11.5, 7.9Hz, 1H),

[0288] 5-[(4-chlorophenyl)methyl]-8-[3-(oxan-2-yloxy)propyl]-4-[3-(trifluoromethoxy)phenoxy]-1,3,5,8-tetraazatricyclo[8.3.0.0^[2,6]]trideca-2(6),3-dien-7-one To a mixture of 5-[(4-chlorophenyl)methyl]-4-[3-(trifluoromethoxy)phenoxy]-1,3,5,8-tetraazatricyclo[8.3.0.0^[2,6]]trideca-2(6),3-dien-7-one (350 mg, 0.71 mmol, 1 equivalent) in DMF (40 mL), NaH (85.2 mg, 2.13 mmol, 3 equivalents, 60%) was added at 0°C under a nitrogen atmosphere for 0.5 hours. To the above mixture, 2-(3-bromopropoxy)oxane (475.3 mg, 2.13 mmol, 3.00 equivalents) was added at 0°C. The resulting mixture was stirred at 50°C for a further 16 hours. Ethyl acetate (300 mL) and brine (100 mL) were added to the resulting mixture, and then the aqueous layer was extracted with ethyl acetate (200 mL). The combined organic layers were dried over anhydrous Na2SO4 and filtered. The filtrate was concentrated to obtain the crude product, which was purified by silica gel column chromatography and eluted with PE:EA (10:1~1:1) to obtain 5-[(4-chlorophenyl)methyl]-8-[3-(oxan-2-yloxy)propyl]-4-[3-(trifluoromethoxy)phenoxy]-1,3,5,8-tetraazatricyclo[8.3.0.0^[2,6]]trideca-2(6),3-dien-7-one (300 mg, 66.52%) as a pale yellow oil.

[0289] (10R)-5-[(4-chlorophenyl)methyl]-8-(3-hydroxypropyl)-4-[3-(trifluoromethoxy)phenoxy]-1,3,5,8-tetraazatricyclo[8.3.0.0^[2,6]]trideca-2(6),3-dien-7-one and (10S)-5-[(4-chlorophenyl)methyl]-8-(3-hydroxypropyl)-4-[3-(trifluoromethoxy)phenoxy]-1,3,5,8-tetraazatricyclo[8.3.0.0^[2,6]]trideca-2(6),3-dien-7-one To a stirred solution of 5-[(4-chlorophenyl)methyl]-8-[3-(oxan-2-yloxy)propyl]-4-[3-(trifluoromethoxy)phenoxy]-1,3,5,8-tetraazatricyclo[8.3.0.0^[2,6]]trideca-2(6),3-dien-7-one (300 mg, 0.47 mmol, 1 equivalent) in THF (15 mL), HCl (2 M) (15 mL) was added dropwise at room temperature. The resulting mixture was then stirred at room temperature for 2 hours. The reaction mixture was basicized to pH 10 with K2CO3, extracted with ethyl acetate (3 x 100 mL), and the organic layer was washed with brine (2 x 50 mL), dried over anhydrous Na2SO4, and filtered. The filtrate was concentrated to obtain the crude product, which was purified by preparative chiral HPLC (column: (R,R)Whelk-01, 21.1*250 mm, 5 μm; mobile phase A: Hex--HPLC, mobile phase B: EtOH--HPLC; flow rate: 20 mL / min; gradient: 50B~50B in 14 mins; 220 / 254 nm; RT1: 8.638; RT2: 11.063) to obtain compound 34 (37.8 mg, 14.52%) and compound 35 (51.9 mg, 19.94%).

[0290] Characterization of compound 34: 1 ¹H NMR (400MHz, methanol-d4) chemical shifts: 7.49 (t, J = 8.2Hz, 1H), 7.29 (d, J = 8.2Hz, 2H), 7.26-7.18 (m, 4H), 7.15 (d, J = 8.3Hz, 1H), 5.64 (d, J = 15.3Hz, 1H), 5.34 (d, J = 15.3Hz, 1H), 3.80 (dt, J = 14.3, 7.4Hz, 1H), 3.65-3.38 (m, 6H), 3.25 (dd, J = 13.4, 6.5Hz, 1H), 3.15 (dd, J = 14.8, 7.6Hz, 1H), 2.24 (dt, J = 12.0, 6.0Hz, 1H), 2.02-1.85(m, 2H), 1.76(p, J = 6.5Hz, 2H), 1.69-1.56(m, 1H). Molecular formula C 26 H 26 Calculated [M+H] of ClF3N4O4 + :551, Observed value: 551.

[0291] Characterization of compound 35: 1 ¹H NMR (400MHz, methanol-d4) chemical shifts: 7.49 (t, J = 8.2Hz, 1H), 7.29 (d, J = 8.3Hz, 2H), 7.26-7.18 (m, 4H), 7.15 (d, J = 8.3Hz, 1H), 5.64 (d, J = 15.2Hz, 1H), 5.34 (d, J = 15.3Hz, 1H), 3.80 (dt, J = 14.3, 7.4Hz, 1H), 3.66-3.38 (m, 6H), 3.25 (dd, J = 13.5, 6.4Hz, 1H), 3.15 (dd, J = 14.8, 7.6Hz, 1H), 2.24 (dt, J = 12.3, 6.2Hz, 1H), 2.11-1.85(m, 2H), 1.76(p, J = 6.4Hz, 2H), 1.70-1.58(m, 1H). Molecular formula C 26 H 26 Calculated [M+H] of ClF3N4O4 + :551, Observed value: 551.

[0292] Example 2: Assay Protocol

[0293] I. Human TRPC5-expressing cells. ICLN-1633 cells expressing TRPC5 (HEK-TREx hTRPC5) were generated as follows: Commercially available HekTrex-293 cells were seeded at 0.7 x 10⁶ cells / well in 1x6 well plates 24 hours before transfection using 2 mL of antibiotic-free cell growth medium (1x DMEM / high glucose (Hyclone#SH30022.02); 10% fetal bovine serum (Sigma) 2 mM sodium pyruvate, 10 mM HEPES). The human TRPC5 coding sequence (NM_012471, including the silent T478C mutation) was cloned into pcDNA5 / TO (Invitrogen; catalog number V103320) using hygromycin as a resistance gene, and the plasmid (SEQ ID NO: 1) was grown using T-Rex-293 cells (Invitrogen; catalog number R71007) according to the manufacturer's instructions. On day 2, 2 μg of plasmid DNA and 6 μl of Xtreme-GENE HP reagent (total volume 200 μl) were prepared in Optimem and incubated at room temperature for 15 minutes. Then, this plasmid solution was gently dropped into each well and the plate was gently rotated to mix the complex with the culture medium for approximately 30 seconds. The transfected cells were incubated at 37°C for 24 hours in a 10% CO2 incubator. The transfected cells were harvested and transferred to 2 x 150 mm dishes containing antibiotic-free cell growth medium at 37°C.

[0294] The following day, cell growth medium containing 150 μg / mL hygromycin and 5 μg / mL blastosidine was added to initiate selection to create a stable pool, and the cells were grown. To remove dead cells, the medium containing the selectors was replaced every 1-2 days as needed. After 7 days, the hygromycin concentration was reduced to 75 μg / mL, and cell growth was continued.

[0295] Single clones were selected as follows: A stable pool was diluted to 10 cells / mL and seeded (100 μl / well) into 24x96 well plates (approximately 1 cell / well). Cells were grown in cell growth medium for 7 days. Fresh medium (100 μl) was added, and the cells were grown for a further 1-2 weeks before being cryopreserved or used immediately.

[0296] II. Automated Patch Clamp Assay (Qpatch) Automated electrophysiological assays were performed at room temperature. On the day of the experiment, TRPC5 cells were cultured according to standard operating procedures. Briefly, cells were harvested using TrypLE™ Express, resuspended in serum-free medium, added to the automated platform, and used within 0.5–3 hours. Fresh internal and external saline solutions were prepared prior to the assay. The external solution contained 145 mM NaCl, 4 mM KCl, 2 mM CaCl2, 1 mM MgCl2, 10 mM HEPES, 10 mM glucose, NaOH, pH 7.4, and 310 mOsm / L. The internal solution contained 120 mM L-aspartic acid, 120 mM CsOH, H2O, 20 mM CsCl, 2 mM MgCl2, 8.8 mM CaCl2, 10 mM EGTA, 10 mM HEPES, and 2 mM Na2ATP;CsOH, with a pH of 7.2 and a concentration of 330 mOsm / L. According to WCabuf software, the freed internal Ca was detected. 2+ The concentration was buffered to 1 μM. Compound profiling was performed using the automated electrophysiological platform QPatch 16 from Sophion (Denmark). The series resistance and quality of the seal were continuously monitored during the experiment. Data were analyzed using Sophion QPatch assay software 5.6 (Odense). Data were normalized using the maximum activation obtained during application of the pre-compound agonist as the highest value (1.0) and the maximum inhibition induced by ML-204 as the lowest value (0.0). IC50 values ​​were calculated using the least-squares regression algorithm (Hill equation).

[0297] To monitor the ion current, a voltage ramp from -100mV to +100mV was applied every 10 seconds over 300ms, starting from a holding potential of -60mV. Antagonist mode: After recording a minimum control period of 60 seconds, the channel was activated by applying the TRPC5 agonist, rosiglitazone (30μM), at EC60 concentration. After reaching a steady state, simultaneous application of the test compounds at gradually increasing concentrations was applied, followed by the application of rosiglitazone EC60 and the specific blocker ML-204 (100μM) at saturation concentration.

[0298] III. FLIPR Protocol: Compounds were prepared or supplied as stock solutions up to 10 mM, typically using DMSO as the vehicle. Ten dose-response curves were created using an Echo-550 acoustic dispenser. Compound source plates were prepared by serially diluting compound stocks to create 10 mM, 1 mM, and 0.1 mM solutions in DMSO on Echo-certified LDV plates. Echo then sequentially added 100% DMSO stock solution to the source dose-response plates to create a 4-fold dilution scheme. 100% DMSO was added to the added dose-response plates to a final volume of 5 μl. Next, 300 nl of dose-response stock plates were added to pre-incubation and stimulation assay plates. Then, 50 μl of pre-incubation buffer and 100 μl of stimulation buffer were added to the plates to obtain a final assay concentration range of 30 μM to 0.0001 μM at a final 0.3% DMSO concentration.

[0299] Human ICLN-1633 cells expressing the compound were plated into 384-well black poly-D-lysine coated microplates and maintained in TRPC5 growth medium the day before use in the experiment. TRPC5 expression was induced by applying 1 μg / mL of tetracycline at the time of plating. The medium was removed from the plate and 10 μl of 4 μM Fluo-4 AM (mixed with an equal volume of Pluronic F-127) in Earls buffer solution (EBSS) was added to the cells. The cells were incubated at room temperature, shielded from light, for 60–90 minutes. After the incubation period, the dye was removed and replaced with 10 μl of EBSS. The cells, pre-incubation, and stimulated plates were loaded into FLIPR-II and the assay was initiated. FLIPR measured baseline at 10 seconds, followed by the addition of 10 μl of the 2X compound (or control). The change in fluorescence was monitored for a further 5 minutes. After a 5-minute pre-incubation, 20 μl of 2X riluzole (containing 1X compound or control) was added to the cell plate. The final riluzole stimulation concentration in the assay was 30 μM. After riluzole addition, changes in fluorescence were monitored for a further 5 minutes. A decrease in the riluzole-activated calcium response compared to the control well was reported as an inhibitor. During the pre-incubation phase, an increase in the compound-mediated riluzole response compared to the control riluzole response (without the presence of the test drug), without enhanced calcium influx, was reported as an agonist response.

[0300] Compound inhibition of the TRPC5 calcium response was determined as follows: Fluorescence was monitored for 5 minutes after riluzole addition. For inhibition, the maximum relative fluorescence response (subtracting the control response of a 1 μM internal control compound known to maximally block the TRPC5 calcium response, represented as "REF INHIB" in the following formula) was captured and exported from FLIPR.

[0301] Compound inhibition is calculated using the following formula:

[0302]

number

[0303] The compound activation (agonism) in the TRPC5 calcium response was determined as follows: Fluorescence was monitored for 5 minutes after the initial compound addition. The maximum relative fluorescence response (subtracting the control response with EBSS buffer only) was captured and exported from FLIPR. Compound activation was calculated using the following formula:

[0304]

number

[0305] Example 3: Exemplary Biological Assay Data Table 2: Efficacy range of representative compounds of this disclosure as QPatch, FLIPR inhibitors, and FLIPR agonists.

[0306] Scope of effect: Qpatch assay: A=0.001-1μM; B=1-30μM; C=>30μM; ND=Not tested.

[0307] FLIPR assay (inhibitor and agonist activity): A=0.001-1μM; B=1-10μM; C=>10μM; D=The test result for agonism is positive, but EC 50 This has not been calculated; ND = Not tested.

[0308] The pairs of enantiomers shown in Table 2 (see, for example, compounds 6 and 7; compounds 12 and 13; compounds 15 and 16, etc.) have relative stereochemistry. In other words, two enantiomers were separated from a racemic mixture, but their absolute stereochemistry has not been determined.

[0309] [Table 7-1]

[0310] [Table 7-2]

[0311] [Table 7-3]

[0312] [Table 7-4]

[0313] Sequence ID 1: TRPC5 plasmid sequence The DNA sequence of the TRPC5 plasmid used in Example 2 is shown below. Underlined nucleic acids represent those encoding human TRPC5.

[0314] [ka]

[0315] [ka]

[0316] [ka]

[0317] [ka]

[0318] Embedding by reference All U.S. patents and U.S. and PCT published patent applications cited herein are incorporated herein by reference.

[0319] The doctrine of equality The above specification is sufficient to enable those skilled in the art to carry out the invention. Since the examples are intended as a single description of one aspect of the invention, the scope of the invention should not be limited by the provided examples, and other functionally equivalent embodiments are within the scope of the invention. In addition to those shown and described herein, various modifications of the invention are apparent to those skilled in the art from the above specification and are included in the scope of the appended claims. The advantages and objectives of the invention are not necessarily encompassed by each embodiment of the invention.

Claims

1. Compounds of formula (I) or (II), their tautomers, or pharmaceutically acceptable salts: 【Chemistry 1】 (In the formula, A and A' are selected independently from CR and N, and at least one of A and A' is CR. R stands for L-R １ And, L does not exist, CH ２ , O, SO ２ , or NR ２ And, R １ is selected from optionally substituted alkyl, optionally substituted aryl, and optionally substituted heteroaryl, and if L is not present, R １ Further selections are made from H, Each R ２ is independently H or alkyl, R ３ is selected from optionally substituted alkyl, optionally substituted alkylene - OR ２ , optionally substituted cycloalkylene - OR ２ optionally substituted alkylene - N(R ７ ) ２ optionally substituted cycloalkylene - N(R ７ ) ２ optionally substituted alkylene - C(O)N(R ２ ) ２ optionally substituted cycloalkylene - C(O)N(R ２ ) ２ optionally substituted alkylene - S(O) ２ N(R ２ ) ２ and optionally substituted cycloalkylene - S(O) ２ N(R ２ ) ２ ; R ４ This is selected from alkyl, optionally substituted alkylene-aryl, and optionally substituted alkylene-heteroaryl. Each R ５ H, N(R ２ ) ２ , OR ２ Selected independently from, Each R ７ H, alkyl, (alkyl)C(O)-, (aryl)C(O)-, (alkyl)S(O) ２ - and (aryl) S(O) ２ Selected independently from, X is -C(O)-, CH ２ _CHR ６ , C(R ６ ) ２ And, Each R ６ This is independently selected from H, alkyl, and optionally substituted alkylene-OH groups. X' is -C(O)-, CH ２ _CHR ３’ , C(R ３’ ) ２ Either X' is R ３ Together with other elements, they form a 5- or 6-membered ring. Each R ３’ This is an optionally substituted alkyl, optionally substituted alkylene-OR ２ , optionally substituted cycloalkylene-OR ２ , arbitrarily substituted alkylene-N(R ７ ) ２ , optionally substituted cycloalkylene-N(R ７ ) ２ , optionally substituted alkylene-C(O)N(R ２ ) ２ , optionally substituted cycloalkylene-C(O)N(R ２ ) ２ , arbitrarily substituted alkylene-S(O) ２ N(R) ２ ) ２ , and optionally substituted cycloalkylene-S(O) ２ N(R) ２ ) ２ Selected independently from, and Z does not exist, CH ２ _CHR ５ , O, -NR ２ -, or -SO ２ - and However, not both X and X' are -C(O)-, and Z is O, NR, or SO ２ In the case of R ５ (is H).

2. The compound according to claim 1, wherein the compound is a compound of formula (I).

3. The compound according to claim 1, wherein the compound is a compound of formula (II).

4. A compound according to any one of claims 1 to 3, wherein A is N.

5. A compound according to any one of claims 1 to 3, wherein A is CR.

6. The compound according to any one of claims 1 to 3 or 5, wherein A' is N.

7. The compound according to any one of claims 1 to 5, wherein A' is CR.

8. A compound according to any one of claims 1 to 8, wherein L is absent.

9. L is CH ２ The compound according to any one of claims 1 to 8.

10. A compound according to any one of claims 1 to 8, wherein L is O.

11. L is SO ２ The compound according to any one of claims 1 to 8.

12. L is NR ２ The compound according to any one of claims 1 to 8.

13. R １ The compound according to any one of claims 1 to 12, wherein is optionally substituted with an aryl.

14. R １ The compound according to claim 13, wherein is a phenyl which is optionally substituted.

15. R １ The compound according to claim 14, wherein the compound is a substituted phenyl.

16. The substituted phenyl is halogen, -CF ３ , -C(H)F ２ , and -OCF ３ The compound according to claim 15, substituted with one or more substituents independently selected from the above.

17. R １ The compound according to any one of claims 1 to 12, wherein is an optionally substituted alkyl group.

18. The compound according to claim 17, wherein the alkyl is selected from methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, and tert-butyl.

19. R １ The compound according to any one of claims 1 to 12, wherein is an optionally substituted heteroaryl.

20. R １ However, halogen, -CF ３ , -C(H)F ２ , and -OCF ３ The compound according to claim 19, which is a substituted heteroaryl substituted with one or more substituents independently selected from the above.

21. R ２ The compound according to any one of claims 1 to 7 and 12 to 20, wherein is H.

22. R ２ The compound according to any one of claims 1 to 7 and 12 to 20, wherein is alkyl.

23. R ２ The compound according to claim 22, wherein the compound is selected from methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, and tert-butyl.

24. R ２ The compound according to claim 23, wherein is methyl.

25. R ３ The compound according to any one of claims 1 to 24, wherein is optionally substituted alkyl.

26. R ３ The compound according to any one of claims 1 to 24, wherein is an optionally substituted alkylene-OH.

27. R ３ The compound according to claim 26, wherein the alkylene-OH is substituted.

28. R ３ The compound according to any one of claims 1 to 24, wherein is optionally substituted cycloalkylene-OH.

29. R ３ but, 【Chemistry 2】 A compound according to any one of claims 1 to 26, selected from the above.

30. R ３ is 【Transformation 3】 A compound selected from any one of claims 1 to 24 and 27.

31. R ３ but, 【Chemistry 4】 A compound selected from any one of claims 1 to 24 and 27.

32. R ４ The compound according to any one of claims 1 to 31, wherein the alkyl group is alkyl.

33. R ４ The compound according to claim 32, wherein the compound is selected from methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, and tert-butyl.

34. R ４ The compound according to claim 33, wherein the compound is selected from n-butyl, iso-butyl, and tert-butyl.

35. R ４ The compound according to claim 34, wherein n-butyl is present.

36. R ４ The compound according to any one of claims 1 to 31, wherein the alkylene-aryl compound is optionally substituted.

37. The compound according to claim 36, wherein the alkylene of the alkylene-aryl group is substituted.

38. The compound according to claim 36 or 37, wherein the aryl in alkylene-aryl is substituted.

39. The substituted aryl is halogen, -CF ３ , -C(H)F ２ , or -OCF ３ The compound according to claim 38, substituted with.

40. The compound according to any one of claims 36 to 39, wherein the aryl in the alkylene-aryl is optionally substituted with a phenyl compound.

41. The compound according to claim 40, wherein phenyl is substituted with one or more halogens.

42. The compound according to any one of claims 36 to 41, wherein the alkylene in alkylene-aryl is methylene.

43. R ４ The compound according to any one of claims 1 to 31, wherein the compound is an optionally substituted alkylene heteroaryl.

44. R ４ but, 【Transformation 5】 The compound according to any one of claims 1 to 31 and 36 to 42.

45. R ４ but, 【Transformation 6】 The compound according to any one of claims 1 to 31 and 36 to 41.

46. R ４ but, 【Transformation 7】 The compound according to any one of claims 1 to 31 and 43.

47. Each R ５ The compound according to any one of claims 1 and 3 to 46, wherein is H.

48. One side of the ５ R is -O-alkyl, and the other R is ５ The compound according to any one of claims 1 and 3 to 46, wherein is H.

49. One side of the ５ is -OH, and the other R ５ The compound according to any one of claims 1 and 3 to 46, wherein is H.

50. One side of the ５ ga-NMe ２ , and the other R ５ The compound according to any one of claims 1 and 3 to 46, wherein is H.

51. One side of the ５ ga-NH ２ , and the other R ５ The compound according to any one of claims 1 and 3 to 46, wherein is H.

52. The compound according to any one of claims 1 to 2 and 4 to 51, wherein X is -C(O)-.

53. X is CH ２ The compound according to any one of claims 1 to 2 and 4 to 51.

54. X is -CHR ６ - The compound according to any one of claims 1 to 2 and 4 to 51.

55. X is -C(R ６ ) ２ - The compound according to any one of claims 1 to 2 and 4 to 51.

56. The compound according to any one of claims 1 to 51 and 53 to 55, wherein X' is -C(O)-.

57. X' is CH ２ The compound according to any one of claims 1 to 55.

58. X' is -CHR ３’ - The compound according to any one of claims 1 to 55.

59. X' is -C(R ３’ ) ２ - The compound according to any one of claims 1 to 55.

60. R ３’ The compound according to any one of claims 54-55 and 58-59, wherein is alkyl.

61. R ３’ The compound according to claim 60, wherein the compound is selected from methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, and tert-butyl.

62. R ３’ The compound according to claim 61, wherein is methyl.

63. R ３’ The compound according to any one of claims 54 to 55 and 58 to 59, wherein is optionally substituted alkylene-OH.

64. R ３’ The compound according to claim 63, wherein is optionally substituted ethylene-OH.

65. R ３’ The compound according to claim 64, wherein the ethylene-OH group is substituted.

66. A compound according to any one of claims 1 and 3 to 65, wherein Z is absent.

67. Z is CH ２ The compound according to any one of claims 1 and 3 to 65.

68. The compound according to any one of claims 1 and 3 to 65, wherein Z is -N (alkyl)-.

69. The compound according to claim 68, wherein Z is selected from -N(n-butyl)-, -N(iso-butyl)-, and -N(tert-butyl)-.

70. Z is -SO ２ - The compound according to any one of claims 1 and 3 to 65.

71. The aforementioned compound, 【Transformation 8】 A compound according to claim 1, selected from the following.

72. The aforementioned compound, 【Chemistry 9】 The compound according to claim 1.

73. The aforementioned compound, 【Chemistry 10】 The compound according to claim 1.

74. The aforementioned compound, 【Chemistry 11】 A compound according to claim 1, selected from the following.

75. The aforementioned compound, 【Chemistry 12】 【Chemistry 13】 A compound according to claim 1, selected from the following.

76. The aforementioned compound, 【Chemistry 14】 A compound according to claim 1, selected from the following.

77. The aforementioned compound, 【Chemistry 15】 The compound according to claim 1.

78. The aforementioned compound, 【Chemistry 16】 The compound according to claim 1.

79. The aforementioned compound, 【Chemistry 17】 The compound according to claim 1.

80. The aforementioned compound, [Chemistry 18] The compound according to claim 1.

81. The aforementioned compound, 【Chemistry 19】 The compound according to claim 1.

82. A composition comprising a compound according to any one of claims 1 to 81, a tautomer thereof, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.

83. A method for treating or reducing the risk of developing a kidney disease, diabetic retinopathy, anxiety disorder, depression, or cancer, comprising administering to a subject in need thereof a therapeutically effective amount of a TRPC5 inhibitor compound according to any one of claims 1 to 81 or a composition according to claim 82, wherein the compound in the composition is a TRPC5 inhibitor.

84. The method according to claim 83, which treats kidney disease or reduces the risk of developing kidney disease.

85. The method according to claim 83, wherein a kidney disease is treated.

86. The method according to any one of claims 83 to 85, wherein the renal disease is selected from the group consisting of focal segmental glomerulosclerosis (FSGS), diabetic nephropathy, Alport syndrome, hypertensive renal disease, nephrotic syndrome, steroid-resistant nephrotic syndrome, minimal change disease, membranous nephropathy, idiopathic membranous nephropathy, membranoproliferative glomerulonephritis (MPGN), immune complex-mediated MPGN, complement-mediated MPGN, lupus nephritis, post-infectious glomerulonephritis, thin basement membrane disease, mesangial proliferative glomerulonephritis, amyloidosis (primary), c1q nephropathy, rapidly progressive GN, anti-GBM disease, C3 glomerulonephritis, hypertensive nephrosclerosis, and IgA nephropathy.

87. The method according to any one of claims 83 to 85, wherein the kidney disease is proteinuria.

88. The method according to any one of claims 83 to 85, wherein the kidney disease is microalbuminuria or macroalbuminuria.

89. A method for treating obesity or reducing the risk of developing it, comprising administering to a subject in need of such treatment a therapeutically effective amount of a TRPC5 agonist compound according to any one of claims 1 to 81, or a composition according to claim 82, wherein the compound in the composition is a TRPC5 agonist.

90. The method according to any one of claims 83 to 89, wherein the subject is a mammal.

91. The method according to claim 90, wherein the mammal is a human.

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