KR20210089129A - Benzimidazole compounds and their use for treating Alzheimer's disease or Huntington's disease - Google Patents

Abstract

.The benzimidazole compounds of formula (I) shown below are disclosed. The compound is a potent inhibitor of human glutaminyl cyclase. Also disclosed are pharmaceutical compositions comprising one of such compounds and a pharmaceutically acceptable carrier, as well as methods of treating Alzheimer's disease or Huntington's disease by administering to a subject in need thereof an effective amount of said compound:

.

Description

Benzimidazole compounds and their use for treating Alzheimer's disease or Huntington's disease

Alzheimer's disease (AD) and Huntington's disease (HD) are both incurable degenerative brain diseases.

More specifically, AD is the most common form of dementia, while HD causes uncontrolled movements of the arms, legs, head, face, and upper body. HD also causes a decline in thinking and reasoning skills, including memory, concentration, judgment, and the ability to plan and organize.

Both AD and HD are caused by abnormal aggregation of proteins or peptides. Indeed, AD is caused by the dysfunction of aggregated mutant β amyloid peptide (Aβ), whereas HD is caused by the toxic function of aggregated mutant huntingtin protein (HTT).

Human glutaminyl cyclase (QC) catalyzes the cyclization reaction of the N-terminal residues of glutamine or glutamate to form pyroglutamate (pGlu) on Aβ and HTT. The pGlu-modified Aβ and pGlu-modified HTT thus formed are cohesive, neurotoxic, and resistant to proteolysis. This can initiate a pathological cascade, resulting in the development of AD or HD.

Human QC inhibition has been shown to reduce aggregation of both Aβ and HTT in cultured macrophage cells and in Drosophila and mouse models. Literature [J. Pharmacol. Exp. Ther. 2017, 362, 119-130; J. Med. Chem. 2017, 60, 2573-2590]; [Nat. Med. 2008, 14(10), 1106-1111]; and [Nat. Chem. Bio. 2015, 11, 347-354].

Therefore, human QC is an emerging drug target for the treatment of AD or HD.

Currently, only a few QC inhibitory drug candidates are in clinical trials for the treatment of AD or HD. The development of new QC inhibitors is required.

Previous studies have shown that QC is a zinc-dependent enzyme. Thus, compounds capable of chelating zinc at the active site of QC, such as benzimidazole compounds, are potential QC inhibitors.

Certain benzimidazole compounds have been found to be QC inhibitors. Unexpectedly, the compounds show high potency in inhibiting QC and thus can be used to treat AD or HD.

In one aspect, the present invention relates to a benzimidazole compound of formula (I):

<Formula (I)>

.

.

)로서, R₂는 페닐 고리를 통해 N에 연결되고; R₃, R₄, R₅, R₆, 및 R₇은 독립적으로, 할로 (예컨대, F, Cl, Br, 또는 I), 니트로, 시아노, 아미노, OH, CF₃, -COOH, -COOC_{1 -6} 알킬, C_1-6 알콕실, C_1-6 알킬, C_2-6 알케닐, C_2-6 알키닐, C_3-10 시클로알킬, 헤테로시클로알킬, 아릴, 및 헤테로아릴로부터 선택되는 하나 이상의 치환기로 선택적으로 치환되는, H, 할로 (예컨대, F, Cl, Br, 또는 I), 니트로, 시아노, 아미노, OH, CF₃, C_1-6 알콕실, C_1-6 알킬, C_2-6 알케닐, C_2-6 알키닐, C_3-10 시클로알킬, 헤테로시클로알킬, 아릴, 또는 헤테로아릴이고, 여기서, R₃, R₄, R₅, R₆, 및 R₇ 중 적어도 하나는 헤테로아릴이고, 여기서, C_1-6 알콕실, C_1-6 알킬, C_2-6 알케닐, C_2-6 알키닐, C_3-10 시클로알킬, 헤테로시클로알킬, 아릴, 및 헤테로아릴은 각각 제2 또는 제3의 경우에 할로 (예컨대, F, Cl, Br, 또는 I), 니트로, 시아노, 아미노, OH, CF₃, C_1-6 알콕실, C_1-6 알킬, C_2-6 알케닐, C_2-6 알키닐, C_3-10 시클로알킬, 헤테로시클로알킬, 아릴, 또는 헤테로아릴로 선택적으로 치환된다. X and Y are independently CH ₂ or C=O; R ₁ is H or C _1-6 alkyl; R ₂ is a moiety containing a phenyl ring fused to a 5-membered heteroaryl ring (eg,

), R ₂ is connected to N via a phenyl ring; R ₃ , R ₄ , R ₅ , R ₆ , and R ₇ are independently halo (eg, F, Cl, Br, or I), nitro, cyano, amino, OH, CF ₃ , -COOH, -COOC _1-6 alkyl, C _1-6 alkoxyl, C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _3-10 cycloalkyl, heterocycloalkyl, selected from aryl, and heteroaryl H, halo (eg F, Cl, Br, or I), nitro, cyano, amino, OH, CF ₃ , C _1-6 alkoxyl, C _1-6 alkyl, optionally substituted with one or more substituents , C _2-6 alkenyl, C _2-6 alkynyl, C _3-10 cycloalkyl, heterocycloalkyl, aryl, or heteroaryl, wherein R ₃ , R ₄ , R ₅ , R ₆ , and R _{7 .} at least one is heteroaryl, wherein: C _1-6 alkoxyl, C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _3-10 cycloalkyl, heterocycloalkyl, aryl, and heteroaryl at the second or third instance, respectively, is halo (eg, F, Cl, Br, or I), nitro, cyano, amino, OH, CF ₃ , C _1-6 alkoxyl, C _1-6 optionally substituted with alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _3-10 cycloalkyl, heterocycloalkyl, aryl, or heteroaryl.

을 포함하고, 여기서, R₈은 H, 할로 (예컨대, F, Cl, Br, 또는 I), 니트로, 시아노, 아미노, OH, CF₃, -COOH, -COOC_{1 -6} 알킬, C_1-6 알콕실, C_1-6 알킬, C_2-6 알케닐, C_2-6 알키닐, C_3-10 시클로알킬, 헤테로시클로알킬, 아릴, 또는 헤테로아릴이고, C_1-6 알콕실, C_1-6 알킬, C_2-6 알케닐, C_2-6 알키닐, C_3-10 시클로알킬, 헤테로시클로알킬, 아릴, 및 헤테로아릴은 각각 할로 (예컨대, F, Cl, Br, 또는 I), 니트로, 시아노, 아미노, OH, CF₃, C_1-6 알콕실, C_1-6 알킬, C_2-6 알케닐, C_2-6 알키닐, C_3-10 시클로알킬, 헤테로시클로알킬, 아릴, 또는 헤테로아릴로 선택적으로 치환된다. Examples of heteroaryl designated by R _{7 include}

It includes, where, R ₈ is H, halo (e.g., F, Cl, Br, or I), nitro, cyano, _{amino, OH, CF 3, -COOH,} -COOC 1 -6 alkyl, C _{1- 6} alkoxyl, C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _3-10 cycloalkyl, heterocycloalkyl, aryl, or heteroaryl, C _1-6 alkoxyl, C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _3-10 cycloalkyl, heterocycloalkyl, aryl, and heteroaryl are each halo (eg, F, Cl, Br, or I) , nitro, cyano, amino, OH, CF ₃ , C _1-6 alkoxyl, C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _3-10 cycloalkyl, heterocycloalkyl , aryl, or heteroaryl.

가 있다. R₈로 구체적으로 지정된 것 중에는 H, F, Cl, CH₃, CF₃, 에틸, n-프로필,

Among those specifically designated as R ₇

there is Among those specifically designated as R ₈ are H, F, Cl, CH ₃ , CF ₃ , ethyl, n-propyl,

가 있다.

there is

이고; R₃, R₄, R₅, 및 R₆는 독립적으로 H 또는 F이고; R₇은

이고, 여기서, R₈로의 지정은 선행 문단에 기술되어 있다. 특히 바람직한 화합물에서, R₇로의 지정 또한 선행 문단에 기술되어 있다. The compounds described above can be classified into two subsets. In one subset, Y is CH ₂ , and in another subset, Y is C=O. Preferred compounds in each subset are R ₁ is H; X is C=O; R ₂ is

ego; R ₃ , R ₄ , R ₅ , and R ₆ are independently H or F; R ₇ is

, where _{the designation to R 8} is described in the preceding paragraph. In particularly preferred compounds, _{the designation to R 7 is} also described in the preceding paragraph.

The term “alkyl” herein refers to a saturated, linear, or branched hydrocarbon moiety, such as —CH ₃ or —CH(CH ₃ ) ₂ . The term “alkoxy” refers to an —O(C _1-6 alkyl) radical, such as —OCH ₃ and —OCH(CH ₃ ) ₂ . The term "alkenyl" refers to a linear or branched hydrocarbon moiety containing at least one double bond, such as, for example, -CH=CH-CH _{3 .} The term “alkynyl” refers to a linear or branched hydrocarbon moiety containing at least one triple bond, such as, _{for example, —C≡C—CH 3 .} The term “cycloalkyl” refers to a saturated mono-, di-, or tri-cyclic hydrocarbon moiety, such as cyclohexyl. The term “heterocycloalkyl” refers to saturated mono-, di-, or tri-cyclic having at least one ring heteroatom (eg, N, O, and S), such as, for example, 4-tetrahydropyranyl. refers to a moiety. The term “aryl” refers to a hydrocarbon moiety having one or more aromatic rings. Examples of aryl include phenyl, phenylene, naphthyl, naphthylene, pyrenyl, anthryl, and phenanthryl. The term “heteroaryl” refers to a moiety having one or more aromatic rings containing at least one heteroatom (eg, N, O, and S). Examples of heteroaryl include furyl, furylene, fluorenyl, pyrrolyl, thienyl, oxazolyl, imidazolyl, thiazolyl, pyridyl, pyrimidinyl, quinazolinyl, quinolyl, isoquinolyl, and indole. Includes reel. The term “amino” refers to a radical of —NH ₂ , —NH(C _1-6 alkyl), or —N(C _1-6 alkyl) ₂ , such as, for example, —NHCH3 and —NHCH(CH ₃ ) _{2 .} do.

References herein to alkoxy, alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl include both substituted and unsubstituted moieties, unless otherwise stated. Alkoxy, alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and the substituent on the heteroaryl group include halo, nitro, cyano, _{amino, OH, CF 3, -COOH,} -COOC 1 -6 alkyl, C _1-6 alkoxyl, C _1-6 alkyl, C _2-6 alkenyl, C _{2 -6-alkynyl,} C _3-10 cycloalkyl, heterocycloalkyl, aryl, or a heteroaryl group include, but are not limited to, .

The compounds described above include the compounds themselves, as well as salts, prodrugs, stereoisomers, and tautomers thereof, where applicable. For example, a salt may be formed between a positively charged group (eg, amino) and an anion on a compound of formula (I). Suitable anions are chloride, bromide, iodide, sulfate, nitrate, phosphate, citrate, methanesulfonate, trifluoroacetate, acetate, maleate, tosylate, tartrate, fumrate, glutamate, glucuro nates, lactates, glutarates, and maleates. Similarly, salts may also be formed between a negatively charged group (eg, carboxylate) on a compound of formula (I) and a cation. Suitable cations include sodium ion, potassium ion, magnesium ion, calcium ion, and ammonium cation such as tetramethylammonium ion. The compounds also include the above salts containing a quaternary nitrogen atom. Examples of prodrugs include esters and other pharmaceutically acceptable derivatives that, when administered to a subject, are capable of providing the active compound. Stereoisomers of compounds of formula (I) include cis and trans isomers, optical isomers, such as ( R ) and ( S ) enantiomers, diastereomers, geometric isomers, rotational isomers, atropisomers, conformational isomers, and mixtures thereof includes Tautomers of a compound include those exhibiting more than one type of isomerism.

In another aspect, the present invention relates to a pharmaceutical composition comprising a compound of formula (I) and a pharmaceutically acceptable carrier.

Carriers in pharmaceutical compositions must be "acceptable" in the sense of being compatible with the active ingredient of the composition (preferably capable of stabilizing the active ingredient) and not deleterious to the subject to be treated. Examples of carriers include colloidal silicon dioxide, magnesium stearate, cellulose, sodium lauryl sulfate, and D&C Yellow 10.

Methods of treating AD or HD are also included within the scope of the present invention. The method comprises administering to a subject in need thereof an effective amount of a compound of formula (I).

The term "treating" is intended to confer a therapeutic effect, i.e. cure, alleviate, alter, affect, AD or HD, symptoms of AD or HD, or tendency to develop AD or HD; Refers to the application or administration of a compound or a salt, prodrug, stereoisomer, or tautomer thereof to a subject for the purpose of amelioration or prevention.

An “effective amount” is the amount of a compound or a salt, prodrug, stereoisomer, or tautomer thereof necessary to confer a desired effect in a subject. As will be appreciated by those skilled in the art, the effective amount will vary depending on the route of administration, the excipient regimen, and the possibility of co-use with other therapeutic treatments, such as the use of other active agents.

A composition having a compound of formula (I) or a salt, prodrug, stereoisomer, or tautomer thereof may be administered parenterally or orally. As used herein, the term "parenteral" refers to subcutaneous, intradermal, intravenous, intraperitoneal, intramuscular, intraarticular, intraarterial, intrasynovial, intrasternal, intrathecal, intralesional, or intracranial injections as well. Rather, it refers to any suitable implantation technique.

Compositions for oral administration may be in any orally acceptable dosage form, such as capsules, tablets, emulsions, and aqueous suspensions, dispersions, and solutions. In the case of tablets, commonly used carriers include lactose and corn starch, among others. Glidants such as magnesium stearate are also typically added. For oral administration in capsule form, useful diluents include lactose and dried corn meal. When aqueous suspensions or emulsions are administered orally, the active ingredient may be suspended or dissolved in the oil phase in combination with emulsifying or suspending agents. If desired, sweetening, flavoring or coloring agents may be added.

The details of one or more embodiments of the invention are set forth in the description that follows. Other features, objects, and advantages of the invention will become apparent from the description and from the claims.

Hereinafter, the benzimidazole compounds of formula (I) given above are disclosed in detail.

Compounds of the invention having chiral centers may exist as stereoisomers. Stereoisomers of compounds of formula (I) include cis and trans isomers, optical isomers such as ( R ) and ( S ) enantiomers, diastereomers, geometric isomers, including compounds exhibiting more than one type of isomerism; rotational isomers, atropisomers, conformational isomers, and tautomers of compounds; and mixtures thereof (eg, racemates and diastereomers). All of the above isomeric forms are contemplated. In addition, the compounds of formula (I) in the present invention may exhibit tautomerism.

In particular, the compounds of formula (I) may have an enantiomeric excess of at least 90% (eg ≥95% and ≥99%).

117 exemplary compounds of Formula (I) are shown in Table 1 below:

Of the 117 compounds listed above, compounds 9 and 10 are two enantiomers of compound 8; compounds 33 and 34 are two enantiomers of compound 13; compounds 35 and 36 are two enantiomers of compound 16; compounds 53 and 54 are two enantiomers of compound 25; Compounds 55 and 5 6 are two enantiomers of compound 28.

Compounds 9, 34, 36, 54, and 56 are preferred.

Methods for synthesizing compounds of formula (I) are well known in the art. It is noted that a method for preparing as many as 67 compounds, compound 1-67, is described in Example 1 below.

The compounds thus prepared can first be screened using in vitro assays for their potency in inhibiting the activity of glutaminyl cyclase (QC). The in vitro assay is described in Example 2 below. Additionally, the prepared compounds can then be evaluated using in vivo assays. An in vivo assay is described in Example 3 below. Selected compounds can be further tested to demonstrate their efficacy in treating AD or HD. Based on the results, an appropriate dosage range and route of administration can be investigated and determined.

All reagents and solvents were purchased from commercial suppliers and were used without further purification unless otherwise noted. All anhydrous reactions were performed under nitrogen atmosphere using a dry solvent. All reactions were monitored by thin layer chromatography using Merck Silica gel 60 F _{254 glass backed plates.} Column chromatography was performed with Merck silica gel 60 (0.040-0.063 mm, 230-400 mesh). The purity of the final compound was determined on a Hitachi 2000 series HPLC system (Agilent ZORBAX Eclipse XDB-C18 5 μm, 4.6 mm×150 mm) equipped with a _{reversed-phase C 18 column, operating at 25° C.} . Mobile phase A was acetonitrile. Mobile phase B was a 10 mM NH ₄ OAc aqueous solution containing 0.1% formic acid. The gradient system was A/B (90%/10%) at 45 min, starting from A/B (10%/90%) at 0 min. The flow rate of the mobile phase was 0.5 mL/min and the injection volume of the sample was 5 μl. The peak peaked at 254 nm. All compounds tested are >95% pure. LC/MS data were measured on an Agilent MSD-1100 ESI-MS/MS system. ¹ H NMR spectra were measured by Varian Mercury-300 and Varian Mercury-400 spectrometers, and chemical shifts (δ) were reported in parts per million (ppm) versus resonance of the solvent peak. Multiplicity is reported by the following abbreviations: s (singlet), d (doublet), t (triplet), q (quartet), quin (quintet), m (multiplet), or br (wide). .

Without further detailed description, it is considered that those skilled in the art will be able to fully utilize the present invention based on the above description. Therefore, the specific embodiments described in Examples 1-3 below are to be construed as illustrative only and not in any way limiting the remainder of the disclosure. All publications cited herein are incorporated by reference.

Example 1 : Compound preparation and characterization

Compound 1-67 was prepared by Synthesis Method 1-18 shown in Scheme 1-18, respectively.

Synthesis Method 1

Compounds 1-4 each having a 1,3-thiazol-2-yl ring were prepared according to the synthesis method shown in Scheme 1 below. 4-(1,3-thiazol-2-yl)benzaldehyde derivative by coupling (4-formylphenyl)boronic acid 118 with 2-bromothiazole derivative 119a-d under Suzuki-coupling conditions 120a-d were obtained. The core structure of the imidazolidinone ring was constructed in the following three steps. TMSCN was added to a solution of benzaldehyde 120a-d and 1 H -benzamidazol-5-amine 121 in acetic acid. After the reaction mixture was stirred at room temperature for 2 hours, it was worked -up to obtain aminoacetonitrile 122a-d , which was hydrogenated using a Raney Nickel catalyst in acetic acid at 5-10° C. to obtain diamine 123a-d obtained. In the final step, 1,1'-carbonyldiimidazole (CDI) was added to a solution of diamine 123a-d in THF, followed by stirring at 75° C. for 18 hours. After purification by column chromatography, compound 1-4 was obtained.

Synthesis Method 2

A precursor of 4-(2-cyclopropyl-1,3-thiazol-4-yl)benzaldehyde 127 was synthesized under two different Suzuki coupling conditions shown in Scheme 2 below. The starting material, which is 2,4-dibromo-1,3-thiazole 124 , was selectively coupled at the 2 position with cyclopropylboronic acid 125 _{using Pd(OAc) 2 as catalyst.} The resulting product 126 was coupled at the 4-position with (4-formylphenyl)boronic acid 118 using Pd(dppf)Cl ₂ as a catalyst to a precursor 127 having a 1,3-thiazol-4-yl ring. was obtained. Then, the above precursor was subjected to the method presented in Synthesis Method 1 for the formation of imidazolidinone to obtain the final compound (Compound 5).

Synthesis Method 3

Compound 6-8 , each having a 3-thiazol-5-yl ring, was prepared in 8 steps as shown in Scheme 3 below. After carrying out the substitution reaction using HMTA, then refluxing in a solution of hydrochloric acid in ethanol, the commercially available starting material 4-(bromoacetyl)-benzonitrile 130 was reacted with 4-(aminoacetyl)benzonitrile hydrochloride. 131 was converted. Compound 131 was then acetylated with various anhydrides 132a-c to give amides 133a-c , which were then treated with Lawesson's reagent in THF or toluene under reflux (1,3-thiazol-5-yl) The benzonitrile analogues 134a-c were obtained. The benzonitrile analog 134a-c was reduced with DIBAL-H to form the benzaldehyde precursor 135a-c. Then, the above precursor was subjected to the method presented in Synthesis Method 1 for the formation of imidazolidinone to obtain compound 6-8.

Synthesis Method 4

Compounds 11 and 29-32 each having a thiophen-2-yl ring were prepared by the synthesis method shown in Scheme 4 below. 4-Bromobenzaldehyde 138a-d was coupled with a 2-substituted thiophene 139a or 139b under Suzuki coupling conditions, respectively, to obtain benzaldehyde precursor 140a-e. Then, the above precursor was subjected to the method presented in Synthesis Method 1 for the formation of imidazolidinone to obtain compounds 11 and 29-32.

Synthesis Method 5

Compound 12 having a thiophen-2-yl ring was prepared by the synthesis method shown in Scheme 5 below. The 4-acetyl-benzonitrile in 143-dimethylacetamide (DMA) using the FeCl ₃ .6H ₂ O and K ₂ S ₂ O ₈ was screen α- methylene. The resulting α-methylene product 144 was reacted with cyclopropanecarbaldehyde under Stetter conditions to form 1,4-dicarbonyl compound 146. Then, the dicarbonyl compound was treated with Lawson's reagent under reflux in toluene to give 4-(5-cyclopropylthiophen-2-yl)benzonitrile 147 , which was reduced with DABAL-H to give the benzaldehyde precursor 148 formed. Then, the above precursor was subjected to the method presented in Synthesis Method 1 for the formation of imidazolidinone to obtain compound 12.

Synthesis Method 6

Compounds 13 and 22-24 each having a thiophen-2-yl ring were prepared by the synthesis method shown in Scheme 6 below. 4-Bromobenzaldehyde 138a-d was each coupled with thiophene under two different Suzuki coupling conditions to form 4-(thiophen-2-yl)-benzaldehyde 152a-d . The benzaldehyde was iodinated with N -iodosuccinimide (NIS) to give the iodinated products 153a-d , which were prepared with methyl difluoro-(fluoro-sulfonyl) acetate 154 and copper iodide. was used for trifluoromethylation to obtain precursor 155a-d. Then, the above precursor was subjected to the method presented in Synthesis Method 1 for the formation of imidazolidinone to obtain compounds 13 and 22-24.

Synthesis Method 7

Compounds 14-16 and 25-28 having a thiophen-3-yl ring were prepared by the synthetic method shown in Scheme 7 below. Various (4-formylphenyl) boronic acids were coupled with the 3-bromothiophene derivative 158a-c under Suzuki-Miyaura coupling conditions. The resulting product 159a-g was then subjected to the method given in Synthesis Method 1 for the formation of imidazolidinone to obtain compounds 14-16 and 25-28.

Synthesis Method 8

Compound 17 having a thiophen-3-yl ring was prepared by the synthetic method shown in Scheme 8 below. Selective bromination of starting material 159a with bromine or NBS in acetic acid gives the 2-brominated thiophene product 162 , which is coupled with cyclopropyl-boronic acid under Suzuki coupling conditions to 4-(2-cyclo Propyl-thiophen-3-yl)benzaldehyde 163 was formed. Compound 6-8 was obtained by applying the benzaldehyde to the method presented in Synthesis Method 1 for the formation of imidazolidinone.

Synthesis Method 9

Compound 18 having a 1,2,4-oxadiazol-3-yl ring was prepared by the synthetic method shown in Scheme 9 below. The starting material, 4-formylbenzonitrile 166 , was protected with monoethylene glycol (MEG) to form acetal 167 , which was reacted with hydroxylamine hydrochloride to give amidoxime 168. Amidoxime was acetylated with cyclopropanecarbonyl chloride followed by reflux in toluene to form 1,2,4-oxadiazole 170 , which was then deprotected under acidic conditions. The resulting product 171 was reacted with TMSCN and 1 H -benzamidazol-5-amine 121 in acetic acid at room temperature for 2 hours, followed by workup to obtain aminoacetonitrile 172. The diamine 173 was obtained by hydrogenation of aminoacetonitrile over Pd/C catalyst in acetic acid at room temperature overnight. In the final step, 1,1'-carbonyldiimidazole was added to a solution of diamine 173 in THF, followed by stirring at 75° C. for 18 hours. Finally, after purification by column chromatography, compound 18 was obtained.

Synthesis Method 10

Compound 19 having a 1,2-oxazol-3-yl ring was prepared by the synthetic method shown in Scheme 10 below. A starting material, which is cyclopropanecarbaldehyde 174 , is reacted with hydroxylamine hydrochloride to give oxime 175 , which is first treated with N -chlorosuccinimide (NCS) and then 4-ethynylbenzaldehyde 176 in DMF at room temperature was treated to form a 1,2-oxazole precursor 177. Then, the above precursor was subjected to the method presented in Synthesis Method 9 for the formation of imidazolidinone to obtain compound 19.

Synthesis Method 11

Compounds 20 and 21 each having a 2 H -tetrazol-5-yl ring were prepared by the synthetic method shown in Scheme 11 below. The starting material, 4-formylbenzonitrile 166 , was reacted with sodium azide and ammonium chloride in DMF under reflux to form tetrazole compound 180 , which was substituted with various alkyl halides to give precursors 181a-b . Then, the above precursor was subjected to the method presented in Synthesis Method 9 for the formation of imidazolidinone to obtain compounds 20 and 21.

Synthesis Method 12

Compound 37 having a 1,3-thiazol-2-yl ring was prepared by the synthetic method shown in Scheme 12 below. (4-acetylphenyl)boronic acid 184 was coupled with 2-bromo-4-(trifluoromethyl)-1,3-thiazole 119d under Suzuki coupling conditions. The resulting product 185 was oxidized with selenium dioxide to obtain glyoxal 186. Glyoxal was mixed with benzamidazolylurea 187 in HCl/AcOH (1/40 v/v) and then refluxed overnight. After removal of the solvent under reduced pressure, the residue was treated with an excess solution of ammonia in methanol for several hours. The crude product was purified by column chromatography to obtain compound 37.

Synthesis Method 13

Compound 38 having a 1,3-thiazol-4-yl ring was prepared by the synthetic method shown in Scheme 13 below. The intermediate prepared according to Synthesis Method 2, which is 4-bromo-2-cyclopropyl-1,3-thiazole 126 , was coupled with (4-acetylphenyl)boronic acid 184 under Suzuki coupling conditions. The resulting coupling product 188 was oxidized with selenium dioxide to obtain glyoxal 189. Compound 38 was prepared from glyoxal 189 and benzamidazolylurea 187 through cycloaddition reaction. The method was identical to that presented in Synthesis Method 12.

Synthesis Method 14

Compounds 39 and 40 each having a 1,3-thiazol-5-yl ring were prepared by the synthetic method shown in Scheme 14 below. The intermediate prepared according to Synthesis Method 3, which is 1,3-thiazol-5- ylbenzonitrile 134b- c, was acetylated with methylmagnesium bromide. The resulting acetyl product 190b -c was oxidized to glyoxal 191b-c with selenium dioxide. Compounds 39 and 40 were prepared from glyoxal 191b-c and benzamidazolylurea 187 through cycloaddition reaction. The method was identical to that presented in Synthesis Method 12.

Synthesis Method 15

Compounds 41-52 each having a 2 H -tetrazol-5-yl ring were prepared by the synthesis method shown in Scheme 15 below. Starting material 143 was reacted with sodium azide and ammonium chloride in DMF under reflux to form tetrazole 192 , which was substituted with various alkyl halides to give precursor 193a-l . Then, the above precursor was subjected to the method presented in Synthesis Method 12 for hydantoin formation to obtain compounds 41-52.

Synthesis Method 16

Compound 57 having a 1,3-thiazol-5-yl ring was prepared by the synthetic method shown in Scheme 16 below. The starting material 131 was acetylated with adamantane-1-carbonyl chloride 195 to give the amide 196. The amide 196 was then mixed with Lawson's reagent under reflux in THF to give (1,3-thiazol-5-yl)-benzonitrile 197 , which was reduced with DIBAL-H to form benzaldehyde 198. Benzaldehyde 198 was subjected to the method presented in Synthesis Method 1 for the formation of imidazolidinone to obtain compound 57.

Synthesis Method 17

Compound 58-65 having a thiophen-3-yl ring was prepared by the synthetic method shown in Scheme 17 below. 118 g of 2,3-difluoro-4-formylphenylboronic acid was coupled with the 3-bromothiophene derivatives 158a-b and 158d-i under Suzuki-Miyaura coupling conditions. The resulting product 201a-h was then subjected to the method presented in Synthesis Method 1 for the formation of imidazolidinone to obtain compounds 58-65.

Synthesis Method 18

Compound 66 was prepared via hydrolysis of compound 64 in a solution of potassium hydroxide in methanol as shown in Scheme 18. Compound 67 was prepared via reduction of compound 64 by LAH in dry THF, also shown in this scheme.

The detailed method for preparing compound 1-67 according to the synthesis method 1-18 described above and the analytical data of the intermediate and final product produced in this method are presented below.

4-(1,3-thiazol-2-yl) benzaldehyde (Compound 120a)

(4-formylphenyl)boronic acid 118 (0.30 g, 2.0 mmol), 2-bromo-1,3-thiazole 119a (0.33 g, 2.0 mmol), Pd(PPh ₃ ) ₄ (0.12 g, 0.1 mmol) ), aqueous potassium carbonate solution (0.4 M, 5 mL), ethanol (5 mL) and toluene (2 mL) were added to a 50 mL flask under nitrogen. The reaction mixture was stirred at 115° C. for 24 h and then cooled to room temperature. After removal of the solvent, the crude residue was purified by column chromatography on silica gel using EA/hexane (1/5) as eluent. The product 120a was obtained in 95% yield as a white solid.

4-(4- methyl -1,3-thiazol-2-yl) benzaldehyde (Compound 120b)

4-(4-methyl-1,3-thiazol-2-yl)benzaldehyde 120b to Suzuki of (4-formylphenyl)boronic acid 118 and 2-bromo-4-methyl-1,3-thiazole 119b prepared from coupling. The method was the same as for the synthesis of compound 120a. The product 120b was obtained in 90% yield as a white solid.

4-(4- cyclopropyl -1,3-thiazol-2-yl) benzaldehyde (Compound 120c)

4-(4-cyclopropyl-1,3-thiazol-2-yl)benzaldehyde 120c to (4-formylphenyl)boronic acid 118 and 2-bromo-4-cyclopropyl-1,3-thiazole 119c from the Suzuki coupling of The method was the same as for the synthesis of compound 120a. The product 120c was obtained in 92% yield as a white solid.

4-[4-(trifluoro methyl )-1,3-thiazole-2- Work ] benzaldehyde (Compound 120d)

4-[4-(trifluoromethyl)-1,3-thiazol-2-yl]benzaldehyde 120d to (4-formylphenyl)boronic acid 118 and 2-bromo-4-(trifluoromethyl) Prepared from Suzuki coupling of -1,3-thiazole 119d. The method was the same as for the synthesis of compound 120a. The product 120d was obtained in 90% yield as a white solid.

(One H - Benzamidazole -5- ilamino )[4-(1,3-thiazol-2-yl)phenyl] acetonitrile (Compound 122a)

To a solution of 1 H -benzamidazol-5-amine 121 (0.68 g, 5.11 mmol) in acetic acid (20 mL) was added compound 120a (1.06 g, 5.62 mmol) and stirred at room temperature for 20 min. TMSCN (1 mL) was added dropwise to the reaction mixture and stirred continuously for 2 hours. After completion of the reaction, the reaction mixture was concentrated under reduced pressure to obtain a viscous liquid. The viscous liquid was diluted with ethyl acetate (10 mL) and water. The diluted solution was adjusted to pH 6-7 with ammonia in an ice bath. The neutralized solution was extracted with ethyl acetate (20 mL x 4), dried over sodium sulfate, filtered and concentrated under reduced pressure to give a viscous dark yellow solid. The solid was dissolved in ethyl acetate (15 mL) and brine (15 mL). The mixture was stirred at room temperature for 2 minutes to form a pale yellow precipitate. The pale yellow precipitate was filtered off and washed with water. The filtrate was dried over sodium sulfate and concentrated under reduced pressure to give a pale yellow solid. The pale yellow solid was combined as the desired product 122a in 96% yield.

(One H -benzamidazol-5-ylamino) [4-(4-Methyl-1,3-thiazol-2-yl)phenyl]acetonitrile (Compound 122b)

( 1H -benzamidazol-5-ylamino)[4-(4-methyl-1,3-thiazol-2-yl)phenyl]acetonitrile 122b to 1H -benzamidazol-5-amine 121 ; Prepared from addition of TMSCN and compound 120b. The method was the same as for the synthesis of compound 122a. The product 122b was obtained in 97% yield as a pale yellow solid.

(One H - Benzamidazole -5- ilamino )[4-(4-Cyclopropyl-1,3-thiazol-2-yl)phenyl]acetonitrile (Compound 122c)

( 1H -benzamidazol-5-ylamino)[4-(4-cyclopropyl-1,3-thiazol-2-yl)phenyl]acetonitrile 122c to 1H -benzamidazol-5-amine 121 , TMSCN and addition of compound 120c. The method was the same as for the synthesis of compound 122a. The product 122c was obtained in 95% yield as a pale yellow solid.

(One H - Benzamidazole -5- ilamino ) {4- [4- (trifluoro methyl )-1,3-thiazol-2-yl]phenyl}acetonitrile (compound 122d)

( 1H -benzamidazol-5-ylamino){4-[4-(trifluoromethyl)-1,3-thiazol-2-yl]phenyl}-acetonitrile 122d to 1H -benzamidazole Prepared from the addition of 5-amine 121 , TMSCN and compound 120d. The method was the same as for the synthesis of compound 122a. The product 122d was obtained in 96% yield as a pale yellow solid.

N ^One -(One H - Benzamidazole -5-yl)-1-[4-(1,3-thiazol-2-yl)phenyl]ethane-1,2- diamine (Compound 123a)

Compound 122a (5.0 g, 15.08 mmol) was dissolved in acetic acid (200 mL) and then stirred at 10° C. for 5 min. Raney Nickel reagent was added to the stirred solution and hydrogen was refilled 3 times. The reaction mixture was stirred under hydrogen at 10° C. for 8 hours. The catalyst was removed by filtration through celite. The filtrate was concentrated under reduced pressure to give the crude product. The crude residue was purified by column chromatography on silica gel using methanol/dichloromethane (1/19) as eluent. The product 123a was obtained in 60% yield as a yellow viscous liquid.

N ^One -(One H - Benzamidazole -5- Work )-1-[4-(4-methyl-1,3-thiazol-2-yl)phenyl]ethane-1,2-diamine (compound 123b)

N ¹ -(1 H -benzamidazol-5-yl)-1-[4-(4-methyl-1,3-thiazol-2-yl) from hydrogenation of compound 122b using Raney Nickel reagent as catalyst Phenyl]ethane-1,2-diamine 123b was prepared. The method was the same as for the synthesis of compound 123a. The product 123b was obtained in 50% yield as a yellow viscous liquid.

N ^One -(One H - Benzamidazole -5- Work )-1-[4-(4-Cyclopropyl-1,3-thiazol-2-yl)phenyl]ethane-1,2-diamine (Compound 123c)

N ¹ -(1 H -benzamidazol-5-yl)-1-[4-(4-cyclopropyl-1,3-thiazol-2-yl) from hydrogenation of compound 122c using Raney Nickel reagent as catalyst ) phenyl] ethane-1,2-diamine 123c was prepared. The method was the same as for the synthesis of compound 123a. The product 123c was obtained in 54% yield as a yellow viscous liquid.

N ^One -(One H - Benzamidazole -5- Work )-1-{4-[4-(trifluoro methyl )-1,3-thiazol-2-yl]phenyl}ethane-1,2-diamine (compound 123d)

N ¹ -(1 H -benzamidazol-5-yl)-1-{4-[4-(trifluoromethyl)-1,3-thiazole from hydrogenation of compound 122d using Raney Nickel reagent as catalyst -2-yl]phenyl}-ethane-1,2-diamine 123d was prepared. The method was the same as for the synthesis of compound 123a. The product 123d was obtained in 40% yield as a yellow viscous liquid.

1-(1 H - Benzamidazole -5-yl)-5-[4-(1,3-thiazol-2-yl)phenyl] imidazolidine -2-one (Compound 1)

To a solution of 1,1′-carbonyl diimidazole (2.21 g, 20.5 mmol) and trimethylamine (7.5 mL) in anhydrous THF (100 mL) in anhydrous THF (100 mL) of compound 123a (4.56 g, 13.6 mmol) The solution was added dropwise by addition funnel at room temperature. The resulting mixture was heated to 75° C. and stirred for 18 h. After cooling to room temperature, the reaction mixture was concentrated under reduced pressure. The crude residue was purified by column chromatography on silica gel using methanol/dichloromethane (1/19) as eluent. The product (compound 1 ) was obtained in 70% yield as a white solid.

1-(1 H - Benzamidazole -5- Work )-5-[4-(4-methyl-1,3-thiazol-2-yl)phenyl]imidazolidin-2-one (Compound 2)

1-(1 H -benzamidazol-5-yl)-5-[4-(4-methyl-1,3-thiazole from the cycloaddition reaction of 1,1'-carbonyl diimidazole and compound 123b) -2-yl)phenyl]imidazolidin-2-one (compound 2 ) was prepared. The method was the same as the synthesis of compound 1. The product (compound 2 ) was obtained as a white solid in 66% yield.

1-(1 H - Benzamidazole -5- Work )-5-[4-(4-cyclopropyl-1,3-thiazol-2-yl)phenyl]imidazolidin-2-one (Compound 3)

1-(1 H -benzamidazol-5-yl)-5-[4-(4-cyclopropyl-1,3-thia) from the cycloaddition reaction of 1,1'-carbonyl diimidazole and compound 123c Zol-2-yl)phenyl]imidazolidin-2-one (Compound 3 ) was prepared. The method was the same as the synthesis of compound 1. The product (compound 3 ) was obtained as a white solid in 71% yield.

1-(1 H - Benzamidazole -5- Work )-5-{4-[4-(trifluoro methyl )-1,3-thiazol-2-yl]phenyl}imidazolidin-2-one (Compound 4)

1-(1 H -benzamidazol-5-yl)-5-{4-[4-(trifluoromethyl)-1,3-thiazole from the cycloaddition reaction of carbonyl diimidazole and compound 123d -2-yl]phenyl}-imidazolidin-2-one (Compound 4 ) was prepared. The method was the same as the synthesis of compound 1. The product (compound 4 ) was obtained as a white solid in 67% yield.

4- Bromo -2- cyclopropyl -1,3-thiazole (compound 126)

Palladium acetate (0.025 g, 0.11 mmol) and Xantphos (0.066 g, 0.11 mmol) were added under argon in degassed THF (22 mL). The reaction mixture was then stirred at room temperature for 5 minutes. 2,4-dibromo-1,3-thiazole 124 (1.09 g, 4.50 mmol), cyclopropylboronic acid 125 (0.58 g, 6.70 mmol) and potassium phosphate (2.86 g) are added to the reaction mixture, argon was flushed with The reaction mixture was stirred at 70° C. for 15 h. After cooling to room temperature, the reaction mixture was filtered and washed with dichloromethane. The filtrate was concentrated under reduced pressure and purified by column chromatography on silica gel using hexane as eluent. the product 126 as a colorless oil It was obtained in 81% yield.

4-(2- cyclopropyl -1,3-thiazol-4-yl) benzaldehyde (Compound 127)

(4-formylphenyl)boronic acid 118 (0.33 g, 2.2 mmol), 4-bromo-2-cyclopropyl-1,3-thiazole 126 (0.41 g, 2.0 mmol), Pd(dppf)Cl ₂ ( 0.08 g, 0.1 mmol), potassium carbonate (0.41 g) and 1,2-dimethoxyethane (20 mL) were added to a 50 mL round bottom flask under nitrogen. The reaction mixture was stirred at 80° C. for 16 h, then cooled to room temperature. The reaction mixture was partitioned between ethyl acetate and water. The organic layer was collected, dried over sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel using hexane/ether (10/1) as eluent. The product 127 was obtained in 55% yield as a white solid.

(One H - Benzamidazole -5- ilamino )[4-(2-Cyclopropyl-1,3-thiazol-4-yl)phenyl]acetonitrile (Compound 128)

( 1H -benzamidazol-5-ylamino)[4-(2-cyclopropyl-1,3-thiazol-4-yl)phenyl]acetonitrile 128 to 1H -benzamidazol-5-amine 121 , TMSCN and addition of compound 127. The method was the same as for the synthesis of compound 122a. The product 128 was obtained in 93% yield as a pale yellow solid.

N ^One -(One H - Benzamidazole -5- Work )-1-[4-(2-Cyclopropyl-1,3-thiazol-4-yl)phenyl]ethane-1,2-diamine (Compound 129)

N ¹ -(1 H -benzamidazol-5-yl)-1-[4-(2-cyclopropyl-1,3-thiazol-4-yl) from hydrogenation of compound 128 using Raney Nickel reagent as catalyst ) phenyl] ethane-1,2-diamine 129 was prepared. The method was the same as for the synthesis of compound 123a. The product 129 was obtained in 52% yield as a yellow viscous liquid.

1-(1 H - Benzamidazole -5- Work )-5-[4-(2-cyclopropyl-1,3-thiazol-4-yl)phenyl]imidazolidin-2-one (Compound 5)

1-(1 H -benzamidazol-5-yl)-5-[4-(2-cyclopropyl-1,3 from cycloaddition of 1,1'-carbonyl diimidazole and product ( 129)) -thiazol-4-yl)phenyl]imidazolidin-2-one (Compound 5 ) was prepared. The method was the same as the synthesis of compound 1. The product (compound 5 ) was obtained as a white solid in 73% yield.

4- Glycylbenzonitrile hydrochloride (Compound 131)

4-(Bromoacetyl)benzonitrile 130 (22.4 g, 100 mmol) and hexamethylenetetramine (HMTA, 15.4 g, 110 mmol) were dissolved in chloroform (900 mL). The reaction mixture was stirred at room temperature overnight. The precipitate was filtered and washed with ethanol and ether. The resulting solid was suspended in a mixture of HCl/ethanol (48 mL/240 mL) and stirred at 75° C. overnight. When the solution was still warm, the precipitate was filtered off. The filtrate was concentrated to remove the solvent. A portion of acetone (100 mL) was added and stirred for 1 h. The precipitate was filtered and washed with acetone and ether. The product 131 was obtained in quantum yield and without further purification as an off-white solid.

N -[2-(4- cyanophenyl )-2- oxoethyl ]Acetamide (Compound 133a)

Triethylamine (21 mL) was added to a suspension solution of compound 131 (10 g, 50.85 mmol) in dichloromethane (330 mL) and stirred at room temperature for 10 min. Acetic anhydride (7.79 g, 76.28 mmol) was diluted in dichloromethane (20 mL) and then added to the reaction solution by addition funnel in an ice bath for 30 min. The resulting mixture was then stirred for 1 h at room temperature. The reaction was quenched with water and extracted with dichloromethane. The organic layer was collected, dried over sodium sulfate, filtered and concentrated under reduced pressure. The crude residue was purified by column chromatography on silica gel using ethyl acetate/hexanes (1/2) as eluent. The product 133a was obtained in 70% yield as a yellow solid.

N -[2-(4- cyanophenyl )-2- oxoethyl ] Cyclopropanecarboxamide (Compound 133b)

N- [2-(4-cyanophenyl)-2-oxoethyl]cyclopropanecarboxamide 133b was prepared from the acetylation of compound 131 with cyclopropanecarboxylic anhydride 132b. The method was the same as for the synthesis of compound 133a. 133b was obtained as a yellow solid in 73% yield.

N -[2-(4- cyanophenyl )-2- oxoethyl ]-2,2,2- trifluoroacetamide (Compound 133c)

N- [2-(4-cyanophenyl)-2-oxoethyl]-2,2,2-trifluoroacetamide 133c was prepared from the acetylation of compound 131 with trifluoroacetic anhydride 132c. The method was the same as for the synthesis of compound 133a. 133c was obtained as a yellow solid in 73% yield.

4-(2- methyl -1,3-thiazol-5-yl)benzonitrile (Compound 134a)

Compound 133a (0.3 g, 1.48 mmol) and Lawson's reagent (0.9 g, 2.22 mmol) were dissolved in THF (20 mL). The reaction mixture was refluxed and stirred for 17 h. After removal of the solvent, the crude residue was purified by column chromatography on silica gel using ethyl acetate/hexanes (1/10) as eluent. 134a was obtained in 70% yield as a yellow solid.

4-(2- cyclopropyl -1,3-thiazol-5-yl)benzonitrile (compound 134b)

4-(2-cyclopropyl-1,3-thiazol-5-yl)benzonitrile 134b was prepared from the cyclization reaction of compound 133b with Lawson's reagent in THF. The method was the same as for the synthesis of compound 134a. The product 134b was obtained as a yellow solid in 67% yield.

4-[2-( trifluoromethyl )-1,3-thiazol-5-yl]benzonitrile (Compound 134c)

4-[2-(trifluoromethyl)-1,3-thiazol-5-yl]benzonitrile 134c was prepared from the cyclization of Lawson's reagent and compound 133c in toluene. The method was the same as for the synthesis of compound 134a. The product 134c was obtained as a yellow solid in 65% yield.

4-(2- methyl -1,3-thiazol-5-yl) benzaldehyde (Compound 135a)

To a solution of compound 134a (1.57 g, 7.86 mmol) in anhydrous toluene (100 mL) cooled at -70°C was added a solution of DIBAL-H in (1.2 M, 13.1 mL) dropwise using an addition funnel. The reaction mixture was stirred under argon at -70° C. for 1 h, _{then quenched with 1 N HCl (aq)} (20 mL). The reaction mixture was continuously stirred at room temperature overnight. The reaction mixture was partitioned between ethyl acetate and water. The organic layer was collected, washed with brine, dried over sodium sulfate, filtered and concentrated under reduced pressure. The crude residue was purified by column chromatography on silica gel using ethyl acetate/hexanes (1/5) as eluent. The product 135a was obtained in 63% yield as a yellow solid.

4-(2- cyclopropyl -1,3-thiazol-5-yl) benzaldehyde (Compound 135b)

4-(2-cyclopropyl-1,3-thiazol-5-yl)benzaldehyde 135b was prepared from reduction of compound 134b with DIBAL-H reagent. The method was the same as for the synthesis of compound 135a. The product 135b was obtained as a yellow solid in 66% yield.

4-[2-( trifluoromethyl )-1,3-thiazol-5-yl] benzaldehyde (Compound 135c)

4-[2-(trifluoromethyl)-1,3-thiazol-5-yl]benzaldehyde 135c was prepared from reduction of compound 134c with DIBAL-H reagent. The method was the same as for the synthesis of compound 135a. The product 135c was obtained as a yellow solid in 65% yield.

(One H - Benzamidazole -5- ilamino )[4-(2-methyl-1,3-thiazole-5- Work )phenyl] acetonite reel (compound 136a)

1 H - benz imidazol-5-amine 121, from the addition of TMSCN and compound 135a (1 H - benz imidazol-5-ylamino) - [4- (2-methyl-1,3-thiazol-5-yl )phenyl]acetonitrile 136a was obtained. The method was the same as for the synthesis of compound 122a. The product 136a was obtained in 90% yield as a pale yellow solid.

(One H - Benzamidazole -5- ilamino )[4-(2-Cyclopropyl-1,3-thiazol-5-yl)phenyl]acetonitrile (Compound 136b)

1 H - benz imidazol-5-amine 121, from the addition of TMSCN and compound 135b (1 H - benz imidazol-5-ylamino) - [4- (2-cyclopropyl-1,3-thiazol-5 yl)phenyl]acetonitrile 136b was obtained. The method was the same as for the synthesis of compound 122a. The product 136b was obtained as a pale yellow solid in 92% yield.

(One H - Benzamidazole -5- ilamino ) {4- [2- (trifluoro methyl )-1,3-thiazol-5-yl]phenyl}acetonitrile (compound 136c)

1 H - benz imidazol-5-amine 121, TMSCN and a compound from the addition of 135c (1 H - benz imidazol-5-yl-amino) {4- [2- (trifluoromethyl) -1,3-thiazol Zol-5-yl]phenyl}-acetonitrile 136c was obtained. The method was the same as for the synthesis of compound 122a. The product 136c was obtained in 90% yield as a pale yellow solid.

N ^One -(One H - Benzamidazole -5- Work )-1-[4-(2-methyl-1,3-thiazole-5- Work )phenyl]ethane-1,2-diamine (compound 137a)

N ¹ -(1 H -benzamidazol-5-yl)-1-[4-(2-methyl-1,3-thiazol-5-yl) from hydrogenation of compound 136a using Raney Nickel reagent as catalyst Phenyl]ethane-1,2-diamine 137a was prepared. The method was the same as for the synthesis of compound 123a. The product 137a was obtained in 50% yield as a yellow viscous liquid.

N ^One -(One H - Benzamidazole -5- Work )-1-[4-(2-cyclopropyl-1,3-thiazole-5- Work )phenyl]ethane-1,2-diamine (compound 137b)

N ¹ -(1 H -benzamidazol-5-yl)-1-[4-(2-cyclopropyl-1,3-thiazol-5-yl) from hydrogenation of compound 136b using Raney Nickel reagent as catalyst ) phenyl] ethane-1,2-diamine 137b was prepared. The method was the same as for the synthesis of compound 123a. The product 137b was obtained in 54% yield as a yellow viscous liquid.

N ^One -(One H - Benzamidazole -5- Work )-1-{4-[2-(trifluoro methyl )-1,3-thiazol-5-yl]phenyl}ethane-1,2-diamine (compound 137c)

N ¹ -(1 H -benzamidazol-5-yl)-1-{4-[2-(trifluoromethyl)-1,3-thiazole from hydrogenation of compound 136c using Raney Nickel reagent as catalyst -5-yl]phenyl}-ethane-1,2-diamine 137c was prepared. The method was the same as for the synthesis of compound 123a. The product 137c was obtained in 50% yield as a yellow viscous liquid.

1-(1 H - Benzamidazole -5- Work )-5-[4-(2-methyl-1,3-thiazole-5- Work )phenyl] imidazoline Din-2-one (Compound 6)

1-(1 H -benzamidazol-5-yl)-5-[4-(2-methyl-1,3-thiazole from the cycloaddition reaction of 1,1'-carbonyl diimidazole and compound 137a) -5-yl)phenyl]imidazolidin-2-one (Compound 6 ) was prepared. The method was the same as the synthesis of compound 1. The product (compound 6 ) was obtained as a white solid in 71% yield.

1-(1 H - Benzamidazole -5- Work )-5-[4-(2-cyclopropyl-1,3-thiazol-5-yl)phenyl]imidazolidin-2-one (Compound 7)

1-(1 H -benzamidazol-5-yl)-5-[4-(2-cyclopropyl-1,3-thia) from the cycloaddition reaction of 1,1'-carbonyl diimidazole and compound 137b Zol-5-yl)phenyl]imidazolidin-2-one (Compound 7 ) was prepared. The method was the same as the synthesis of compound 1. The product (compound 7 ) was obtained as a white solid in 74% yield.

1-(1 H - Benzamidazole -5- Work )-5-{4-[2-(trifluoro methyl )-1,3-thiazol-5-yl]phenyl}imidazolidin-2-one (Compound 8)

1-(1 H -benzamidazol-5-yl)-5-{4-[2-(trifluoromethyl)-1 from the cycloaddition reaction of 1,1'-carbonyl diimidazole and compound 137c ,3-thiazol-5-yl]phenyl}-imidazolidin-2-one (Compound 8 ) was prepared. The method was the same as the synthesis of compound 1. The product (compound 8 ) was obtained in 70% yield as a white solid.

(5 S )-1-(1 H - Benzamidazole -5- Work )-5-{4-[2-(trifluoro methyl )-1,3-thiazol-5-yl]phenyl}-imidazolidin-2-one (Compound 9)

(5 R )-1-(1 H - Benzamidazole -5-day)-5-{4-[2-( trifluoromethyl )-1,3-thiazol-5-yl]phenyl}-imidazolidin-2-one (Compound 10)

The enantiomers (compounds 9 and 10 ) were separated from compound 8 by HPLC using CHIRALPAK IC. Each of the isomeric fractions was collected, whereby the optically pure isomers (compounds 9 and 10 ) were obtained by removing the solvent under reduced pressure.

4-(5- methylthiophene -2 days) benzaldehyde (Compound 140a)

4-Bromobenzaldehyde 138a (1.85 g, 10.0 mmol), 2-methylthiophene 139a (1.96 g, 20.0 mmol), potassium acetate (1.96 g, 20.0 mmol) and palladium acetate (0.002 g, 0.01 mmol) in dimethylacet dissolved in amide (DMA). The reaction mixture was purged with argon and stirred at 150° C. for 4 hours. The reaction mixture was cooled to room temperature and extracted with dichloromethane. The organic layer was collected, washed with brine, dried over sodium sulfate, filtered and concentrated under reduced pressure. The crude residue was purified by column chromatography on silica gel using pentane/ether (1/4) as eluent. The product 140a was obtained in 92% yield as a white solid.

(One H - Benzamidazole -5- ilamino )[4-(5-methylthiophene-2- Work )phenyl] acetonitrile (Compound 141a)

( 1H -benzamidazol-5-ylamino)[4-(5-methylthiophen-2-yl)phenyl]acetonitrile 141a was mixed with 1H -benzamidazol-5-amine 121 , TMSCN and compound 140a prepared from addition. The method was the same as for the synthesis of compound 122a. The product 141a was obtained in 90% yield as a pale yellow solid.

N ^One -(One H - Benzamidazole -5- Work )-1-[4-(5-methylthiophene-2- Work )phenyl]ethane-1,2-diamine (compound 142a)

N ¹ -(1 H -benzamidazol-5-yl)-1-[4-(5-methylthiophen-2-yl)phenyl]ethane-1 from hydrogenation of compound 141a using Raney Nickel reagent as catalyst ,2-diamine 142a was prepared. The method was the same as for the synthesis of compound 123a. The product 142a was obtained in 55% yield as a yellow viscous liquid.

1-(1 H - Benzamidazole -5- Work )-5-[4-(5-methylthiophene-2- Work )phenyl] imidazolidine -2-one (compound 11)

1-(1 H -benzamidazol-5-yl)-5-[4-(5-methylthiophen-2-yl) from the cycloaddition reaction of 1,1'-carbonyl diimidazole and compound 142a Phenyl]imidazolidin-2-one (Compound 11 ) was prepared. The method was the same as the synthesis of compound 1. The product (compound 11 ) was obtained as a white solid in 63% yield.

4- Acryloylbenzonitrile (Compound 144)

4-acetyl-benzonitrile 143 (0.73 g, 5.0 mmol) , FeCl 3 .6H 2 O (0.14 g, 0.5 mmol), K 2 S 2 O 8 (2.7 g, 10.0 mmol) and DMA (20 mL) successively was added to the round bottle flask. The reaction mixture was stirred at 110° C. for 4 hours. Upon completion of the reaction (monitored by TLC), the resulting mixture was diluted with ether and washed with brine. The organic layer was dried over sodium sulfate, filtered and concentrated under reduced pressure. The crude residue was purified by column chromatography on silica gel using ethyl acetate/ether (1/4) as eluent. The product 144 was obtained in 40% yield as an off-white solid.

4-(4- oxopentanoyl ) benzonitrile (compound 146)

Product 144 (2.0 g, 12.7 mmol), cyclopropanecarbaldehyde (1.2 mL, 15.3 mmol), triethylamine (1.2 mL, 8.6 mmol) and 2-(2-hydroxyethyl)-3-methyl-4- Benzylthiazolium chloride 145 (0.65 g, 15.2 mmol) was added sequentially to the round bottle flask. The reaction mixture was stirred at 70° C. overnight. Upon completion of the reaction (monitored by TLC), the resulting mixture was partitioned between ether and water. The organic layer was washed with water, 2 M HCl and brine. After drying over sodium sulfate, filtration and concentration in vacuo, the crude residue was purified by column chromatography on silica gel using ethyl acetate/hexanes (1/3) as eluent. The product 146 was obtained in 50% yield as a yellow liquid.

4-(5- Cyclopropylthiophene -2-yl)benzonitrile (Compound 147)

4-(5-cyclopropylthiophen-2-yl)benzonitrile 147 was prepared from the cyclization of product 146 with Lawson's reagent in THF. The experimental method was the same as the synthesis of compound 134a. The product 147 was obtained in 75% yield as a yellow solid.

4-(5- Cyclopropylthiophene -2 days) benzaldehyde (Compound 148)

4-(5-cyclopropylthiophen-2-yl)benzaldehyde 148 was prepared from reduction of compound 147 with DIBAL-H reagent. The experimental method was the same as the synthesis of compound 135a. The product 148 was obtained in 64% yield as a yellow solid.

(One H - Benzamidazole -5- ilamino )[4-(5-cyclopropylthiophene-2- Work )phenyl] aceto Nitrile (Compound 149)

( 1H -benzamidazol-5-ylamino)[4-(5-cyclopropylthiophen-2-yl)phenyl]acetonitrile 149 was replaced with 1H -benzamidazol-5-amine 121 , TMSCN and compound 148 was prepared from the addition of The experimental method was the same as the synthesis of compound 122a. The product 149 was obtained in 91% yield as a pale yellow solid.

N ^One -(One H - Benzamidazole -5- Work )-1-[4-(5-cyclopropylthiophene-2- Work )phenyl]ethane-1,2-diamine (compound 150)

N ¹ -(1 H -benzamidazol-5-yl)-1-[4-(5-cyclopropylthiophen-2-yl)phenyl]ethane- from hydrogenation of compound 149 using Raney Nickel reagent as catalyst 1,2-diamine 150 was prepared. The method was the same as for the synthesis of compound 123a. The product 150 was obtained in 53% yield as a yellow viscous liquid.

1-(1 H - Benzamidazole -5- Work )-5-[4-(5-Cyclopropylthiophen-2-yl)phenyl]imidazolidin-2-one (Compound 12)

1-(1 H -benzamidazol-5-yl)-5-[4-(5-cyclopropylthiophen-2-yl) from cycloaddition of 1,1'-carbonyl diimidazole and product 150 )phenyl]imidazolidin-2-one (Compound 12 ) was prepared. The experimental method was the same as the synthesis of compound 1. The product (compound 12 ) was obtained as a white solid in 69% yield.

4-(thiophen-2-yl) benzaldehyde (Compound 152a)

4-Bromobenzaldehyde 138a (1.85 g, 10.0 mmol), thiophene (6.72 g, 80.0 mmol), potassium acetate (1.96 g, 20.0 mmol) and palladium acetate (0.002 g, 0.01 mmol) in DMA (50 mL) dissolved. The reaction mixture was purged with argon and stirred at 130° C. for 20 hours. The reaction mixture was cooled to room temperature and the solvent was removed in vacuo. The crude residue was purified by column chromatography on silica gel using pentane/ether (1/4) as eluent. The product 152a was obtained in 60% yield as a pale yellow solid.

4-(5- iodothiophene -2 days) benzaldehyde (Compound 153a)

Compound 152a (0.94 g, 5.0 mmol) and N -iodosuccinimide (2.81 g, 12.5 mmol) were added to a 500 mL flask. After flushing the flask with nitrogen, chloroform (200 mL) and acetic acid (16 mL) were added. The reaction mixture was stirred at room temperature for 8 hours. The reaction mixture was washed with saturated sodium thiosulfate solution (75 mL), saturated sodium bicarbonate solution (75 mL), and water (75 mL). The organic layer was collected, dried over sodium sulfate, filtered and concentrated in vacuo. The crude residue was purified by column chromatography on silica gel using dichloromethane/hexane (1/1) as eluent. The product 153a was obtained in 75% yield as a yellow solid.

4-[5-( trifluoromethyl )thiophen-2-yl] benzaldehyde (Compound 155a)

Compound 153a (0.31 g, 1.0 mmol), methyl difluoro(fluorosulfonyl)acetate 154 (0.96 g, 5.0 mmol), copper iodide (0.23 g, 1.2 mmol), N -methylpyrrolidine (NMP) , 1.2 mL) and DMF (10 mL) was stirred at 70° C. for 13 h. The reaction mixture was quenched with saturated aqueous ammonium chloride (15 mL), diluted with water (10 mL), filtered through celite and extracted with ethyl acetate. The organic layer was collected, dried over sodium sulfate, filtered and concentrated in vacuo. The crude residue was purified by column chromatography on silica gel using ethyl acetate/hexanes (1/6) as eluent. The product 155a was obtained in 70% yield as a yellow solid.

(One H - Benzamidazole -5- ilamino ) {4- [5- (trifluoro methyl )thiophen-2-yl]phenyl}acetonitrile (compound 156a)

( 1H -benzamidazol-5-ylamino){4-[5-(trifluoromethyl)thiophen-2-yl]phenyl}-acetonitrile 156a to 1H -benzamidazol-5-amine 121 , TMSCN and addition of compound 155a. The experimental method was the same as the synthesis of compound 122a. The product 156a was obtained in 88% yield as a pale yellow solid.

N ^One -(One H - Benzamidazole -5- Work )-1-{4-[5-(trifluoro methyl )thiophen-2-yl]phenyl}ethane-1,2-diamine (compound 157a)

N ¹ -(1 H -benzamidazol-5-yl)-1-{4-[5-(trifluoromethyl)thiophen-2-yl] from hydrogenation of compound 156a using Raney Nickel reagent as catalyst Phenyl}ethane-1,2-diamine 157a was prepared. The method was the same as for the synthesis of compound 123a. The product 157a was obtained in 49% yield as a yellow viscous liquid.

1-(1 H - Benzamidazole -5- Work )-5-{4-[5-(trifluoro methyl ) thiophen-2-yl] phenyl} imidazolidin-2-one (compound 13)

1-(1 H -benzamidazol-5-yl)-5-{4-[5-(trifluoromethyl)thiophene from the cycloaddition reaction of 1,1'-carbonyl diimidazole and compound 157a Prepared -2-yl]phenyl}-imidazolidin-2-one (Compound 13 ). The experimental method was the same as the synthesis of compound 1. The product (compound 13 ) was obtained as a white solid in 67% yield.

4-(thiophen-3-yl) benzaldehyde (Compound 159a)

3-bromothiophene 158a (1.96 g, 12.0 mmol), (4-formylphenyl)boronic acid 118 (2.70 g, 18.0 mmol), ethylene glycol dimethyl ether (17 mL), water (10 mL) and sodium bicarbonate ( 3.02 g, 36.0 mmol) was placed in a 50 mL round bottom flask. After addition of Pd(PPh ₃ ) ₄ (0.69 g, 0.6 mmol) at room temperature, the reaction mixture was refluxed for 5 h. The resulting mixture was extracted with ethyl acetate and water. The organic layer was collected, washed with brine, dried over sodium sulfate, filtered and concentrated under reduced pressure. The crude residue was purified by column chromatography on silica gel using toluene/hexane (2/1) as eluent. The product 159a was obtained in 95% yield as a pale yellow oil.

4-(5-Methylthiophene-3- Work ) benzaldehyde (Compound 159b)

4-(5-methylthiophen-3-yl)benzaldehyde 159b was prepared from Suzuki-Miyaura coupling of (4-formylphenyl)boronic acid 118 and 3-bromo-5-methylthiophene 158b. The experimental method was the same as the synthesis of compound 159a. The product 159b was obtained in 92% yield as a pale yellow oil.

4-[5-( trifluoromethyl )thiophen-3-yl] benzaldehyde (Compound 159c)

4-[5-(trifluoromethyl)thiophene from Suzuki-Miyaura coupling of (4- formylphenyl )boronic acid 118 and 3-bromo-(5-trifluoromethyl)-thiophene 158c -3-yl]benzaldehyde 159c was prepared. The experimental method was the same as the synthesis of compound 159a. The product 159c as a pale yellow oil was obtained in 85% yield.

(One H - Benzamidazole -5- ilamino )[4-(thiophen-3-yl)phenyl] acetonitrile (Compound 160a)

Prepared (1 H -benzamidazol-5-ylamino)[4-(thiophen-3-yl)phenyl]acetonitrile 160a from addition of 1 H -benzamidazol-5-amine 121 , TMSCN and compound 159a did. The experimental method was the same as the synthesis of compound 122a. The product 160a was obtained in 92% yield as a pale yellow solid.

(One H - Benzamidazole -5- ilamino )[4-(5-methylthiophene-3- Work )phenyl] acetonitrile (Compound 160b)

( 1H -benzamidazol-5-ylamino)[4-(5-methylthiophen-3-yl)phenyl]acetonitrile 160b was mixed with 1H -benzamidazol-5-amine 121 , TMSCN and compound 159b prepared from addition. The experimental method was the same as the synthesis of compound 122a. The product 160b was obtained in 90% yield as a pale yellow solid.

(One H - Benzamidazole -5- ilamino ) {4- [5- (trifluoro methyl )thiophen-3-yl]phenyl}acetonitrile (compound 160c)

( 1H -benzamidazol-5-ylamino){4-[5-(trifluoromethyl)thiophen-3-yl]phenyl}-acetonitrile 160c to 1H -benzamidazol-5-amine 121 , TMSCN and addition of compound 159c. The experimental method was the same as the synthesis of compound 122a. The product 160c was obtained in 85% yield as a pale yellow solid.

N ^One -(One H - Benzamidazole -5- Work )-1-[4-(thiophene-3- Work )phenyl]ethane-1,2- diamine (Compound 161a)

N ¹ -(1 H -benzamidazol-5-yl)-1-[4-(thiophen-3-yl)phenyl]ethane-1,2- from hydrogenation of compound 160a using Raney Nickel reagent as catalyst Diamine 161a was prepared. The method was the same as for the synthesis of compound 123a. The product was obtained in 53% yield as a yellow viscous liquid.

N ^One -(One H - Benzamidazole -5- Work )-1-[4-(5-methylthiophene-3- Work )phenyl]ethane-1,2-diamine (compound 161b)

N ¹ -(1 H -benzamidazol-5-yl)-1-[4-(5-methylthiophen-3-yl)phenyl]ethane-1 from hydrogenation of compound 160b using Raney Nickel reagent as catalyst ,2-diamine 161b was prepared. The method was the same as for the synthesis of compound 123a. The product 161b was obtained in 50% yield as a yellow viscous liquid.

N ^One -(One H - Benzamidazole -5- Work )-1-{4-[5-(trifluoro methyl )thiophen-3-yl]phenyl}ethane-1,2-diamine (compound 161c)

N ¹ -(1 H -benzamidazol-5-yl)-1-{4-[5-(trifluoromethyl)thiophen-3-yl] from hydrogenation of compound 160c using Raney Nickel reagent as catalyst Phenyl}ethane-1,2-diamine 161c was prepared. The method was the same as for the synthesis of compound 123a. The product 161c was obtained in 51% yield as a yellow viscous liquid.

1-(1 H - Benzamidazole -5- Work )-5-[4-(thiophene-3- Work )phenyl] imidazolidine -2-one (compound 14)

1-(1 H -benzamidazol-5-yl)-5-[4-(thiophen-3-yl)phenyl] imi from the cycloaddition reaction of 1,1'-carbonyl diimidazole and compound 161a Dazolidin-2-one (Compound 14 ) was prepared. The method was the same as the synthesis of compound 1. The product (compound 14 ) was obtained as a white solid in 73% yield.

1-(1 H - Benzamidazole -5-day)-5-[4-(5- methylthiophene -3-yl)phenyl] imidazolidine -2-one (compound 15)

1-(1 H -benzamidazol-5-yl)-5-[4-(5-methylthiophen-3-yl) from cycloaddition reaction of 1,1'-carbonyl diimidazole and compound 161b Phenyl]imidazolidin-2-one (Compound 15 ) was prepared. The method was the same as the synthesis of compound 1. The product (compound 15 ) was obtained as a white solid in 75% yield.

1-(1 H - Benzamidazole -5- Work )-5-{4-[5-(trifluoro methyl )thiophen-3-yl]phenyl}imidazolidin-2-one (Compound 16)

1-(1 H -benzamidazol-5-yl)-5-{4-[5-(trifluoromethyl)thiophene from the cycloaddition reaction of 1,1'-carbonyl diimidazole and compound 161c -3-yl]phenyl}-imidazolidin-2-one (Compound 16 ) was prepared. The method was the same as the synthesis of compound 1. The product (compound 16 ) was obtained as a white solid in 67% yield.

4-(5- bromothiophene -3 days) benzaldehyde (Compound 162)

Bromine (5.0 g, 32.0 mmol) in 50 mL of glacial acetic acid was added dropwise to a solution of compound 159a (6.0 g, 32.0 mmol) in 65 mL glacial acetic acid. The resulting yellow solution was stirred at room temperature for 2 days. The reaction mixture was diluted with 300 mL of water and extracted with ethyl acetate (100 mL×2). The combined organic layers were washed with saturated aqueous sodium bicarbonate, dried over sodium sulfate, filtered and concentrated under reduced pressure. The crude residue was purified by column chromatography on silica gel using ethyl acetate/hexanes (1/9) as eluent. The product 162 was obtained as a yellow solid in 73% yield.

4-(5- Cyclopropylthiophene -3 days) benzaldehyde (Compound 163)

Palladium acetate (0.025 g, 0.11 mmol) and xantphos (0.066 g, 0.11 mmol) were added under argon in degassed THF (22 mL). The reaction mixture was then stirred at room temperature for 5 minutes. 4-(5-Bromothiophen-3-yl)benzaldehyde 162 (0.73 g, 3.0 mmol), cyclopropylboronic acid 125 (0.58 g, 6.70 mmol) and potassium phosphate (2.86 g) are added to the reaction mixture, argon was flushed with The reaction mixture was stirred at 70° C. for 15 h. After cooling to room temperature, the reaction mixture was filtered and washed with dichloromethane. The filtrate was concentrated under reduced pressure and purified by column chromatography on silica gel using hexane as eluent. the product 163 as a yellow solid It was obtained in 84% yield.

(One H - Benzamidazole -5- ilamino )[4-(5-cyclopropylthiophene-3- Work )phenyl] aceto Nitrile (Compound 164)

( 1H -benzamidazol-5-ylamino)[4-(5-cyclopropylthiophen-3-yl)phenyl]acetonitrile 164 was replaced with 1H -benzamidazol-5-amine 121 , TMSCN and compound 163 was prepared from the addition of The method was the same as for the synthesis of compound 122a. The product 164 was obtained as a pale yellow solid in 81% yield.

N ^One -(One H - Benzamidazole -5- Work )-1-[4-(5-cyclopropylthiophene-3- Work )phenyl]ethane-1,2-diamine (compound 165)

N ¹ -(1 H -benzamidazol-5-yl)-1-[4-(5-cyclopropylthiophen-3-yl)phenyl]ethane- from hydrogenation of compound 164 using Raney Nickel reagent as catalyst 1,2-diamine 165 was prepared. The method was the same as for the synthesis of compound 123a. The product 165 was obtained in 49% yield as a yellow viscous liquid.

1-(1 H - Benzamidazole -5- Work )-5-[4-(5-Cyclopropylthiophen-3-yl)phenyl]imidazolidin-2-one (Compound 17)

1-(1 H -benzamidazol-5-yl)-5-[4-(5-cyclopropylthiophen-3-yl) from the cycloaddition reaction of 1,1'-carbonyl diimidazole and compound 165 )phenyl]imidazolidin-2-one (Compound 17 ) was prepared. The method was the same as the synthesis of compound 1. The product (compound 17 ) was obtained in 65% yield as a white solid.

4-(1,3- dioxolane -2-yl)benzonitrile (Compound 167)

To a round bottom flask equipped with a Dean-Stark trap were successively added 4-formylbenzonitrile 166 (7.68 g, 58.6 mmol), catalytic amounts of p- TsOH (PTSA) and toluene (150 mL). . After stirring at room temperature for 5 minutes, monoethylene glycol (MEG) (13 mL, 234.3 mmol) was added dropwise. The reaction mixture was refluxed for 3 hours and cooled to room temperature. After removal of toluene under reduced pressure, the reaction was quenched by addition of _{saturated Na 2} CO _{3 (aq) and partitioned between DCM and water.} The organic phase was collected, washed with brine, dried over sodium sulfate, filtered and concentrated under reduced pressure. The viscous residue was treated with hexanes in an ice bath to give the product 167 as a yellow solid in quantum yield.

4-(1,3- dioxolane -2 days)- N '- Hydroxybenzenecarboximidamide (Compound 168)

To a solution of compound 167 (7.6 g, 43.4 mmol) in ethanol/water (2/1, 75 mL) at room temperature was added hydroxylamine hydrochloride (10.6 g, 151.8 mmol) and sodium carbonate (9.2 g, 86.8 mmol) . The reaction mixture was stirred at 100° C. for 2 hours. After concentration under reduced pressure, the residue was poured into water (50 mL) and stirred for 30 min. The precipitate was filtered and washed with cold water to give the product 168 as a white solid in 83% yield.

N '-[( Cyclopropylcarbonyl ) oxy ]-4-(1,3- dioxolane -2 days) Benzenecarboximidamide (Compound 169)

To a suspension of compound 168 (1.8 g, 8.65 mmol) in DCM (100 mL) under nitrogen at room temperature was added pyridine (1.4 mL, 17.30 mmol) and cyclopropanecarbonyl chloride (0.02 mL, 11.20 mmol) dropwise. The reaction mixture was stirred at room temperature for 4 h, then partitioned between DCM and water. The organic phase was collected, washed with brine, dried over sodium sulfate, filtered and concentrated under reduced pressure. The crude residue was purified by column chromatography on silica gel using DCM/methanol (9/1) as eluent to give the product 169 as a white solid in 60% yield.

5- cyclopropyl -3-[4-(1,3- dioxolane -2-yl)phenyl]-1,2,4- oxadiazole (Compound 170)

Starting material 169 (1.1 g, 3.98 mmol) was dissolved in toluene (40 mL). The reaction mixture was refluxed for 15 hours and then cooled to room temperature. After removal of the solvent under reduced pressure, the crude residue was purified by column chromatography on silica gel using EA/hexane (1/4) as eluent to give the product 170 as a white solid in 70% yield.

4-(5- cyclopropyl -1,2,4- oxadiazole -3 days) benzaldehyde (Compound 171)

To a solution of 170 (1.2 g, 4.64 mmol) in _{THF/H 2} O (4/1, 30 mL) was added concentrated HCl dropwise. The reaction mixture was stirred at 65° C. for 6 h, then cooled to room temperature. The reaction mixture was partitioned between DCM and water. The organic phase was collected, washed with brine, dried over sodium sulfate, filtered and concentrated under reduced pressure. The crude residue was purified by column chromatography on silica gel using EA/hexanes (1/9) as eluent to give the product 171 as a white solid in 97% yield.

(One H - Benzamidazole -5- ilamino )[4-(5-Cyclopropyl-1,2,4-oxadiazol-3-yl)phenyl]acetonitrile (Compound 172)

1 H - benz imidazol-5 from the addition of the amine 121, TMSCN and Compound 171 (1 H - benz imidazol-5-ylamino) - [4- (5-cyclopropyl-1,2,4-oxadiazole -3-yl)phenyl]-acetonitrile 172 was obtained. The method was the same as for the synthesis of compound 122a. The product 172 was obtained in 86% yield as a pale yellow solid.

N ^One -(One H - Benzamidazole -5- Work )-1-[4-(5-Cyclopropyl-1,2,4-oxadiazol-3-yl)phenyl]ethane-1,2-diamine (Compound 173)

N ¹ -(1 H -benzamidazol-5-yl)-1-[4-(5-cyclopropyl-1,2,4-oxadiazole- from hydrogenation of compound 172 using Pd/C as catalyst) 3-yl)phenyl]ethane-1,2-diamine 173 was prepared. The method was the same as for the synthesis of compound 123a. The product 173 was obtained in 55% yield as a yellow viscous liquid.

1-(1 H - Benzamidazole -5- Work )-5-[4-(5-Cyclopropyl-1,2,4-oxadiazol-3-yl)phenyl]imidazolidin-2-one (Compound 18)

1-(1 H -benzamidazol-5-yl)-5-[4-(5-cyclopropyl-1,2,4) from the cycloaddition reaction of 1,1'-carbonyl diimidazole and compound 173 -Oxadiazol-3-yl)phenyl]-imidazolidin-2-one (Compound 18 ) was prepared. The method was the same as the synthesis of compound 1. The product (compound 18 ) was obtained in 68% yield as a white solid.

4-(3- cyclopropyl -1,2- oxazole -5 days) benzaldehyde (Compound 177)

Cyclopropanecarboxaldehyde 174 (1.0 g, 14.26 mmol), hydroxylamine hydrochloride (0.99 g, 14.26 mmol) and potassium carbonate (2.17 g, 15.68 mmol _{) were dissolved in H 2} O (25 mL). The reaction mixture was stirred at 85° C. for 3 h, then cooled to room temperature. The reaction mixture was partitioned between ether and water. The organic phase was collected, washed with brine, dried over sodium sulfate, filtered and concentrated under reduced pressure. The crude product 175 was used in the next step without further purification. To a solution of compound 175 and NCS (1.9 g, 14.26 mmol) in DMF (30 mL) under argon was added a catalytic amount of pyridine. The reaction mixture was stirred at room temperature for 2 hours. After cooling to 0° C., 4-ethynylbenzaldehyde 176 (1.9 g, 14.26 mmol) and triethylamine (3 mL) were added. The reaction mixture was stirred at room temperature continuously for 3 hours. The reaction mixture was partitioned between EA and water. The organic phase was collected, washed with brine, dried over sodium sulfate, filtered and concentrated under reduced pressure. The crude residue was purified by column chromatography on silica gel using EA/hexanes (1/8) as eluent to give the product 177 as a yellow solid in 54% total yield.

(One H - Benzamidazole -5- ilamino )[4-(5-cyclopropyl-1,2- oxazole -3-yl)phenyl]acetonitrile (Compound 178)

( 1H -benzamidazol-5-ylamino)[4-(5-cyclopropyl-1,2-oxazol-3-yl)phenyl]acetonitrile 178 to 1H -benzamidazol-5-amine 121 , TMSCN and addition of compound 177. The method was the same as for the synthesis of compound 122a. The product 178 was obtained as a pale yellow solid in 83% yield.

N ^One -(One H - Benzamidazole -5- Work )-1-[4-(5-cyclopropyl-1,2- oxazole -3- Work )phenyl]ethane-1,2-diamine (compound 179)

N ¹ -(1 H -benzamidazol-5-yl)-1-[4-(5-cyclopropyl-1,2-oxazol-3-yl from hydrogenation of compound 178 using Pd/C as catalyst) ) phenyl] ethane-1,2-diamine 179 was prepared. The method was the same as for the synthesis of compound 123a. The product 179 was obtained in 49% yield as a yellow viscous liquid.

1-(1 H - Benzamidazole -5- Work )-5-[4-(5-cyclopropyl-1,2- oxazole -3-yl)phenyl]imidazolidin-2-one (Compound 19)

1-(1 H -benzamidazol-5-yl)-5-[4-(5-cyclopropyl-1,2-oxa from the cycloaddition reaction of 1,1'-carbonyl diimidazole and compound 179) Prepared zol-3-yl)phenyl]imidazolidin-2-one (Compound 19 ). The method was the same as the synthesis of compound 1. The product (compound 19 ) was obtained as a white solid in 58% yield.

4-(2 H - tetrazole -5 days) benzaldehyde hydrochloride (Compound 180)

To a solution of 4-formylbenzonitrile 166 (1.31 g, 10.0 mmol) in DMF (30 mL) under nitrogen was added sodium azide (0.72 g, 11 mmol) and ammonium chloride (0.14 g, 2.5 mmol). The reaction mixture was refluxed overnight and then cooled to room temperature. The reaction mixture was diluted with water and extracted with DCM. The aqueous phase was cooled in ice and acidified by addition of _{1 N HCl (aq).} After filtration, the precipitate was added with water and ether to give the product 180 as a yellow solid in 94% yield.

4-(2-propyl-2 H - tetrazole -5 days) benzaldehyde (Compound 181a)

To a suspension of compound 180 (2.1 g, 10.0 mmol) in acetonitrile (20 mL) under nitrogen was added potassium carbonate (2.76 g, 20 mmol) and 1-bromopropane (2.46 g, 20 mmol). The reaction mixture was stirred at 50° C. overnight, then cooled to room temperature. The reaction mixture was partitioned between EA and water. The organic phase was collected, washed with brine, dried over sodium sulfate, filtered and concentrated under reduced pressure. The crude residue was purified by column chromatography on silica gel using EA/hexanes (1/4) as eluent to give the product 181a as a yellow solid in 76% yield.

4-[2-(propan-2-yl)-2 H - tetrazole -5 days] benzaldehyde (Compound 181b)

Isopropanol (1.2 g, 20.0 mmol) was added under nitrogen to a solution of compound 180 (2.1 g, 10.0 mmol) in trifluoromethanesulfonic acid (20 mL). The reaction mixture was stirred at room temperature for 1 hour. The reaction mixture was poured into water and treated with _{saturated NaHCO 3 (aq) until pH = 8-9.} The mixture was partitioned between DCM and water. The organic phase was collected, washed with brine, dried over sodium sulfate, filtered and concentrated under reduced pressure. The crude residue was purified by column chromatography on silica gel using EA/hexanes (1/4) as eluent to give the product 181b as a yellow solid in 54% yield.

(One H - Benzamidazole -5- ilamino )[4-(2- profile -2 H - tetrazole -5- Work )phenyl] aceto Nitrile (Compound 182a)

1 H - benz imidazol-5-amine 121, from the addition of TMSCN and compound 181a (1 H - benz imidazol-5-ylamino) - [4- (2-propyl -2 H - tetrazol-5-yl) Phenyl]acetonitrile 182a was obtained. The method was the same as for the synthesis of compound 122a. The product 182a was obtained as a pale yellow solid in 86% yield.

(One H - Benzamidazole -5- ilamino ){4-[2-( propane -2- Work )-2 H - tetrazole -5-yl]phenyl}acetonitrile (compound 182b)

1 H - benz imidazol-5-amine 121, from the addition of TMSCN and compound 181b (1 H - benz imidazol-5-yl-amino) {4- [2- (propane-2-yl) -2 H - tetra Zol-5-yl]phenyl}-acetonitrile 182b was obtained. The method was the same as for the synthesis of compound 122a. The product 182b was obtained in 81% yield as a pale yellow solid.

N ^One -(One H - Benzamidazole -5- Work )-1-[4-(2- profile -2 H - tetrazole -5- Work )phenyl]ethane-1,2-diamine (compound 183a)

N ¹ -(1 H -benzamidazol-5-yl)-1-[4-(2-propyl- 2H -tetrazol-5-yl)phenyl from hydrogenation of compound 182a using Pd/C as catalyst ]Ethane-1,2-diamine 183a was prepared. The method was the same as for the synthesis of compound 123a. The product 183a was obtained in 50% yield as a yellow viscous liquid.

N ^One -(One H - Benzamidazole -5- Work )-1-{4-[2-( propane -2- Work )-2 H - tetrazole -5-yl]phenyl}ethane-1,2-diamine (compound 183b)

Using Pd / C as a catalyst from the hydrogenation of compound 182b N ¹ - ⁽¹ H - benz imidazol-5-yl) -1- {4- [2- (propane-2-yl) -2 H - tetrazol -5-yl]phenyl}ethane-1,2-diamine 183b was prepared. The method was the same as for the synthesis of compound 123a. The product 183b was obtained in 45% yield as a yellow viscous liquid.

1-(1 H - Benzamidazole -5- Work )-5-[4-(2- profile -2 H - tetrazole -5- Work )phenyl] imidazole Ridin-2-one (Compound 20)

1-(1H -benzamidazol-5-yl)-5-[4-(2-propyl- 2H -tetrazole-) from the cycloaddition reaction of 1,1'-carbonyl diimidazole and compound 183a 5-yl)phenyl]imidazolidin-2-one (Compound 20 ) was prepared. The method was the same as the synthesis of compound 1. The product (compound 20 ) was obtained in 60% yield as a white solid.

1-(1 H - Benzamidazole -5- Work )-5-{4-[2-( propane -2- Work )-2 H - tetrazole -5-yl]phenyl}imidazolidin-2-one (Compound 21)

1-(1 H -benzamidazol-5-yl)-5-{4-[2-(propan-2-yl)- from the cycloaddition reaction of 1,1'-carbonyl diimidazole and compound 183b Prepared 2H -tetrazol-5-yl]phenyl}-imidazolidin-2-one (Compound 21 ). The method was the same as the synthesis of compound 1. The product (compound 21 ) was obtained as a white solid in 62% yield.

3- fluoro -4- (thiophen-2-yl) benzaldehyde (Compound 152b)

Tributyl(thiophen-2-yl)stannane 151 (6.62 g, 17.7 mmol), 4-bromo-3-fluorobenzaldehyde 138b (3.0 g, 14.8 mmol) and Pd(PPh _{3 ) in toluene (160 mL)} ) ₄ (0.51 g, 0.43 mmol) was refluxed for 16 hours. After cooling to room temperature, the solvent was removed under reduced pressure. The residue was diluted with dichloromethane and filtered through celite. The organic phase was washed with water, dried over sodium sulfate, filtered and concentrated. The crude product was purified by column chromatography on silica gel using dichloromethane/hexanes (1/9) as eluent. The product 152b was obtained in 70% yield as a pale yellow solid.

2- fluoro -4- (thiophen-2-yl) benzaldehyde (Compound 152c)

2-fluoro-4-(thi) from Suzuki coupling of 4-bromo-2-fluorobenzaldehyde 138c and tributyl(thiophen-2-yl)stannane 151 using Pd(PPh ₃ ) _{4 as catalyst} Offen-2-yl)benzaldehyde 152c was prepared. The method was the same as for the synthesis of compound 152b. The product 152c was obtained as a pale yellow solid in 68% yield.

2,6- difluoro -4- (thiophen-2-yl) benzaldehyde (Compound 152d)

2,6-difluoro-4- of 4-bromo-2,6-difluorobenzaldehyde 138d and tributyl(thiophen-2-yl)stannane 151 using Pd(PPh ₃ ) _{4 as catalyst} (thiophen-2-yl)benzaldehyde 152d was prepared. The method was the same as for the synthesis of compound 152b. The product 152d was obtained in 56% yield as a pale yellow solid.

3- fluoro -4-(5- iodothiophene -2 days) benzaldehyde (Compound 153b)

3-Fluoro-4-(5-iodothiophen-2-yl)benzaldehyde 153b was prepared from selective iodination of compound 152b using N -iodosuccinimide. The method was the same as for the synthesis of compound 153a. The product 153b was obtained as a yellow-green solid in 77% yield.

2-fluoro-4-(5-iodo thiophene- 2- Work ) benzaldehyde (Compound 153c)

2-fluoro-4-(5-iodothiophen-2-yl)benzaldehyde 153c was prepared from the selective iodination of compound 152c using N -iodosuccinimide. The method was the same as for the synthesis of compound 153a. The product 153c was obtained in 75% yield as a yellow-green solid.

2,6- difluoro -4-(5- iodothiophene -2 days) benzaldehyde (Compound 153d)

2,6-difluoro-4-(5-iodothiophen-2-yl)benzaldehyde 153d was prepared from the selective iodination of compound 152d using N -iodosuccinimide. The method was the same as for the synthesis of compound 153a. The product 153d was obtained as a yellow-green solid in 71% yield.

3- fluoro -4-[5-( trifluoromethyl )thiophen-2-yl] benzaldehyde (Compound 155b)

3-fluoro-4-[5-(trifluoromethyl)thiophen-2-yl from trifluoromethylation of compound 153b treated with methyl difluoro(fluorosulfonyl)acetate 154 and copper iodide ]Benzaldehyde 155b was prepared. The method was the same as for the synthesis of compound 155a. The product 155b was obtained in 70% yield as a yellow solid.

2- fluoro -4-[5-( trifluoromethyl )thiophen-2-yl] benzaldehyde (Compound 155c)

2-fluoro-4-[5-(trifluoromethyl)thiophen-2-yl from trifluoromethylation of compound 153c treated with methyl difluoro(fluorosulfonyl)acetate 154 and copper iodide ]Benzaldehyde 155c was prepared. The method was the same as for the synthesis of compound 155a. The product 155c was obtained in 72% yield as a yellow solid.

2,6- difluoro -4-[5-( trifluoromethyl )thiophen-2-yl] benzaldehyde (Compound 155d)

2,6-difluoro-4-[5-(trifluoromethyl)thiophene- from trifluoromethylation of compound 153d treated with methyl difluoro(fluorosulfonyl)acetate 154 and copper iodide 2-yl]benzaldehyde 155d was prepared. The method was the same as for the synthesis of compound 155a. The product 155d was obtained as a yellow solid in 67% yield.

1-(1 H - Benzamidazole -5- Work )-5-{3-fluoro-4-[5-(trifluoro methyl )Thiophen-2-yl]phenyl}-imidazolidin-2-one (Compound 22)

1-(1 H -benzamidazol-5-yl)-5-{3-fluoro-4-[5-(trifluoromethyl)thiophene- from compound 155b in 3-step synthesis of imidazolidinone formation 2-yl]phenyl}-imidazolidin-2-one (Compound 22 ) was prepared. The method was the same as the synthesis of compound 1. The product (compound 22 ) was obtained as a white solid in 27% total yield.

1-(1 H - Benzamidazole -5- Work )-5-{2-fluoro-4-[5-(trifluoro methyl )Thiophen-2-yl]phenyl}-imidazolidin-2-one (Compound 23)

1-(1 H -benzamidazol-5-yl)-5-{2-fluoro-4-[5-(trifluoromethyl)thiophene- from compound 155c in 3-step synthesis of imidazolidinone formation 2-yl]phenyl}-imidazolidin-2-one (Compound 23 ) was prepared. The method was the same as the synthesis of compound 1. The product (compound 23 ) was obtained as a white solid in 25% total yield.

1-(1 H - Benzamidazole -5- Work )-5-{2,6- difluoro -4-[5-(trifluoro methyl )Thiophen-2-yl]phenyl}-imidazolidin-2-one (Compound 24)

1-(1 H -benzamidazol-5-yl)-5-{2,6-difluoro-4-[5-(trifluoromethyl) from compound 155d in 3-step synthesis of imidazolidinone formation Thiophen-2-yl]phenyl}imidazolidin-2-one (Compound 24 ) was prepared. The method was the same as the synthesis of compound 1. The product (compound 24 ) was obtained as a white solid in 21% total yield.

3- fluoro -4-[5-( trifluoromethyl )thiophen-3-yl] benzaldehyde (Compound 159d)

3-fluoro-4-[5- from Suzuki-Miyaura coupling of (2-fluoro-4- formylphenyl )boronic acid 118d and 3-bromo-(5-trifluoromethyl)thiophene 158c (trifluoromethyl)thiophen-3-yl]benzaldehyde 159d was prepared. The method was the same as for the synthesis of compound 159a. The product 159d was obtained in 60% yield as a pale yellow solid.

2- fluoro -4-[5-( trifluoromethyl )thiophen-3-yl] benzaldehyde (Compound 159e)

2-fluoro-4-[5- from the Suzuki-Miyaura coupling of (3-fluoro-4- formylphenyl )boronic acid 118e and 3-bromo-(5-trifluoromethyl)thiophene 158c (trifluoromethyl)thiophen-3-yl]benzaldehyde 159e was prepared. The method was the same as for the synthesis of compound 159a. The product 159e was obtained in 53% yield as a pale yellow solid.

2,6- difluoro -4-[5-( trifluoromethyl )thiophen-3-yl] benzaldehyde (Compound 159f)

2,6-difluoro from Suzuki-Miyaura coupling of (3,5-difluoro-4- formylphenyl )boronic acid 118f and 3-bromo-(5-trifluoromethyl)thiophene 158c -4-[5-(trifluoromethyl)thiophen-3-yl]benzaldehyde 159f was prepared. The method was the same as for the synthesis of compound 159a. The product 159f was obtained as a pale yellow solid in 33% yield.

2,3- difluoro -4-[5-( trifluoromethyl )thiophen-3-yl] benzaldehyde (159 g of compound)

2,3-difluoro from Suzuki-Miyaura coupling of 118 g of (2,3-difluoro-4-formylphenyl)boronic acid and 3-bromo-(5-trifluoromethyl)thiophene 158c 159 g of -4-[5-(trifluoromethyl)thiophen-3-yl]benzaldehyde was prepared. The method was the same as for the synthesis of compound 159a. 159 g of the product was obtained as a pale yellow solid in 29% yield.

1-(1 H - Benzamidazole -5- Work )-5-{3-fluoro-4-[5-(trifluoro methyl )Thiophen-3-yl]phenyl}-imidazolidin-2-one (Compound 25)

1-(1 H -benzamidazol-5-yl)-5-{3-fluoro-4-[5-(trifluoromethyl)thiophene- from compound 159d in 3-step synthesis of imidazolidinone formation Prepared 3-yl]phenyl}-imidazolidin-2-one (Compound 25 ). The method was the same as the synthesis of compound 1. The product (compound 25 ) was obtained as a white solid in 25% total yield.

1-(1 H - Benzamidazole -5- Work )-5-{2-fluoro-4-[5-(trifluoro methyl )thiophen-3-yl]phenyl}-imidazolidin-2-one (Compound 26)

1-(1 H -benzamidazol-5-yl)-5-{2-fluoro-4-[5-(trifluoromethyl)thiophene- from compound 159e in 3-step synthesis of imidazolidinone formation 3-yl]phenyl}imidazolidin-2-one (Compound 26 ) was prepared. The method was the same as the synthesis of compound 1. The product (compound 26 ) was obtained as a white solid in 27% total yield.

1-(1 H - Benzamidazole -5- Work )-5-{2,6- difluoro -4-[5-(trifluoro methyl )thiophen-3-yl]phenyl}-imidazolidin-2-one (Compound 27)

1-(1 H -benzamidazol-5-yl)-5-{2,6-difluoro-4-[5-(trifluoromethyl) from compound 159f in 3-step synthesis of imidazolidinone formation Thiophen-3-yl]phenyl}imidazolidin-2-one (Compound 27 ) was prepared. The method was the same as the synthesis of compound 1. The product (compound 27 ) was obtained as a white solid in 21% total yield.

1-(1 H - Benzamidazole -5- Work )-5-{2,3- difluoro -4-[5-(trifluoro methyl )thiophen-3-yl]phenyl}-imidazolidin-2-one (compound 28)

1-(1 H -benzamidazol-5-yl)-5-{2,3-difluoro-4-[5-(trifluoromethyl) from compound 159g in 3-step synthesis of imidazolidinone formation Thiophen-3-yl]phenyl}imidazolidin-2-one (Compound 28 ) was prepared. The method was the same as the synthesis of compound 1. The product (compound 28 ) was obtained as a white solid in 20% total yield.

4-(5- chlorothiophene -2 days) benzaldehyde (Compound 140b)

4-(5-Chlorothiophen-2-yl)benzaldehyde 140b was prepared from Suzuki coupling of 4-bromobenzaldehyde 138a and 2-chlorothiophene 139b. The method was the same as for the synthesis of compound 140a. The product 140b was obtained in 74% yield as a white solid.

4-(5- chlorothiophene -2-yl)-3- Fluorobenzaldehyde (Compound 140c)

4-(5-Chlorothiophen-2-yl)-3-fluorobenzaldehyde 140c was prepared from the Suzuki coupling of 4-bromo-3-fluorobenzaldehyde 138b and 2-chlorothiophene 139b. The method was the same as for the synthesis of compound 140a. The product 140c was obtained as a yellow solid in 69% yield.

4-(5- chlorothiophene -2-yl)-2- Fluorobenzaldehyde (compound 140d)

4-(5-Chlorothiophen-2-yl)-2-fluorobenzaldehyde 140d was prepared from Suzuki coupling of 4-bromo-2-fluorobenzaldehyde 138c and 2-chlorothiophene 139b. The method was the same as for the synthesis of compound 140a. The product 140d was obtained in 67% yield as a yellow solid.

4-(5- chlorothiophene -2-yl)-2,6- difluorobenzaldehyde (Compound 140e)

4- (5-chloro-thiophen-2-yl) -2,6-prepared from a Suzuki coupling of a fluoro-benzaldehyde benzaldehyde 138d to 140e as a 4-bromo-2,6-fluoro and 2-chloro-thiophene-139b did. The method was the same as for the synthesis of compound 140a. The product 140e was obtained in 60% yield as a yellow solid.

1-(1 H - Benzamidazole -5- Work )-5-[4-(5- Chlorothiophene- 2- Work )phenyl] imidazolidine -2-one (Compound 29)

1-(1 H -benzamidazol-5-yl)-5-[4-(5-chlorothiophen-2-yl)phenyl]imidazolidine from compound 140b in three step synthesis of imidazolidinone formation -2-one (Compound 29 ) was prepared. The method was the same as the synthesis of compound 1. The product (compound 29 ) was obtained as a white solid in 28% total yield.

1-(1 H - Benzamidazole -5- Work )-5-[4-(5- Chlorothiophene- 2- Work )-3-Fluorophenyl]imidazolidin-2-one (Compound 30)

1-(1 H -benzamidazol-5-yl)-5-[4-(5-chlorothiophen-2-yl)-3-fluorophenyl from compound 140c in three step synthesis of imidazolidinone formation ]-imidazolidin-2-one (Compound 30 ) was prepared. The method was the same as the synthesis of compound 1. The product (compound 30) was obtained as a white solid in 24% total yield.

1-(1 H - Benzamidazole -5- Work )-5-[4-(5- Chlorothiophene- 2- Work )-2-Fluorophenyl]imidazolidin-2-one (Compound 31)

1-(1 H -benzamidazol-5-yl)-5-[4-(5-chlorothiophen-2-yl)-2-fluorophenyl from compound 140d in 3-step synthesis of imidazolidinone formation ]-imidazolidin-2-one (Compound 31 ) was prepared. The method was the same as the synthesis of compound 1. The product (compound 31) was obtained as a white solid in 25% total yield.

1-(1 H - Benzamidazole -5- Work )-5-[4-(5- Chlorothiophene- 2- Work )-2,6-difluorophenyl]imidazolidin-2-one (Compound 32)

1-(1 H -benzamidazol-5-yl)-5-[4-(5-chlorothiophen-2-yl)-2,6-di from compound 140e in 3-step synthesis of imidazolidinone formation Prepared Fluorophenyl]-imidazolidin-2-one (Compound 32 ). The method was the same as the synthesis of compound 1. The product (compound 32 ) was obtained as a white solid in 20% total yield.

(5 R )-1-(1 H - Benzamidazole -5- Work )-5-{4-[5-(trifluoro methyl ) Thiophen-2-yl] phenyl} imidazolidin-2-one (Compound 33)

(5 S )-1-(1 H - Benzamidazole -5- Work )-5-{4-[5-(trifluoro methyl ) thiophen-2-yl] phenyl} imidazolidin-2-one (compound 34)

The enantiomers (compounds 33 and 34 ) were separated from compound 13 by HPLC using CHIRALPAK AD-H. Each of the isomeric fractions was collected, whereby the optically pure isomers (compounds 33 and 34 ) were obtained by removing the solvent under reduced pressure.

(5 R )-1-(1 H - Benzamidazole -5- Work )-5-{4-[5-(trifluoro methyl ) thiophen-3-yl] phenyl} imidazolidin-2-one (compound 35)

(5 S )-1-(1 H - Benzamidazole -5-day)-5-{4-[5-( trifluoromethyl )thiophen-3-yl]phenyl}imidazolidin-2-one (Compound 36)

The enantiomers (compounds 35 and 36 ) were separated from compound 16 by HPLC using CHIRALPAK AD-H. Each of the isomeric fractions was collected, whereby the optically pure isomers (compounds 35 and 36 ) were obtained by removing the solvent under reduced pressure.

1-{4-[4-( trifluoromethyl )-1,3-thiazol-2-yl]phenyl} Ethanone (Compound 185)

Preparation of 1-{4-[4-(trifluoromethyl)-1,3-thiazol-2-yl]phenyl}ethanone 185 from Suzuki coupling of (4-acetylphenyl)boronic acid 184 and compound 119d did. The method was the same as for the synthesis of compound 120a. The product 185 was obtained in 83% yield as a white solid.

oxo {4-[4-( trifluoromethyl )-1,3-thiazol-2-yl]phenyl}acetaldehyde (compound 186)

Compound 185 (10.0 g, 36.86 mmol) and selenium dioxide (6.95 g, 62.67 mmol) were dissolved in H ₂ O/1,4-dioxane (8 mL/160 mL). The reaction mixture was stirred at 100° C. overnight. The black solid was filtered through celite and washed with ethyl acetate. The filtrate was concentrated under reduced pressure. The residue was purified by column chromatography on silica gel using ethyl acetate/hexanes (1/1) as eluent. The product 186 was obtained in 100% yield as a yellow solid.

1-(1 H - Benzamidazole -5-day)-5-{4-[4-( trifluoromethyl )-1,3-thiazol-2-yl]phenyl}imidazolidine-2,4-dione (Compound 37)

Compound 186 (9.0 g, 31.55 mmol) and 1-(1 H -benzamidazol-6-yl)urea 187 (5.56 g, 31.55 mmol) were dissolved in HCl/AcOH (3 mL/120 mL). The reaction mixture was stirred at 120° C. overnight. After removal of the solvent, the residue was treated with excess ammonia in methanol in an ice bath and stirred at room temperature for 1 h. The precipitate was filtered and washed with ethyl acetate and water to give the pure product. The filtrate was concentrated and recrystallized in ethyl acetate. The product (compound 37 ) was obtained as a white solid in 45% yield.

1-[4-(2- cyclopropyl -1,3-thiazol-4-yl)phenyl] Ethanone (Compound 188)

1-[4-(2-cyclopropyl-1,3-thiazol-4-yl)phenyl] from Suzuki coupling of Pd(dppf)Cl ₂ with (4-acetylphenyl)boronic acid 184 and compound 126 as catalyst Ethanone 188 was prepared. The method was the same as for the synthesis of compound 127. The product 188 was obtained in 57% yield as a white solid.

[4-(2- cyclopropyl -1,3-thiazol-4-yl)phenyl](oxo)acetaldehyde (Compound 189)

[4-(2-cyclopropyl-1,3-thiazol-4-yl)phenyl](oxo)acetaldehyde 189 was prepared from oxidation of compound 188 with selenium dioxide. The method was the same as for the synthesis of compound 186. The product 189 was obtained in 100% yield as a yellow solid.

1-(1 H - Benzamidazole -5-day)-5-[4-(2- cyclopropyl -1,3-thiazol-4-yl)phenyl] imidazolidine -2,4-dione (compound 38)

1-(1 H -benzamidazol-6-yl)-5-[4-(2-cyclopropyl from the cycloaddition reaction of 1-(1 H -benzamidazol-6-yl)urea 187 and compound 189 -1,3-thiazol-4-yl)phenyl]-imidazolidine-2,4-dione (Compound 38 ) was prepared. The method was the same as for the synthesis of compound 37. The product (compound 38 ) was obtained as a white solid in 49% yield.

1-[4-(2- cyclopropyl -1,3-thiazol-5-yl)phenyl] Ethanone (Compound 190b)

To a solution of compound 134b (0.23 g, 1.0 mmol) in dry THF (4 mL) at 0° C. was added dropwise methylmagnesium bromide in THF (1 M, 2 mL). The reaction mixture was then stirred at room temperature overnight. The reaction was quenched by addition of saturated aqueous ammonium chloride solution. The aqueous layer was extracted with ethyl acetate. The organic layer was collected, washed with brine, dried over sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel using ethyl acetate/hexanes (1/4) as eluent. The product 190b was obtained in 48% yield as a yellow solid.

1-{4-[2-(trifluoromethyl)-1,3-thiazol-5-yl]phenyl}ethanone (Compound 190c)

1-{4-[2-(trifluoromethyl)-1,3-thiazol-5-yl]phenyl}ethanone 190c was prepared from the methylation of compound 134c. The method was the same as the synthesis of compound 190b . The product 190c was obtained in 49% yield as a yellow solid.

[4-(2- cyclopropyl -1,3-thiazol-5-yl)phenyl](oxo)acetaldehyde (compound 191b)

[4-(2-cyclopropyl-1,3-thiazol-5-yl)phenyl](oxo)acetaldehyde 191b was prepared from oxidation of compound 190b with selenium dioxide. The method was the same as for the synthesis of compound 186. The product 191b was obtained in 100% yield as a yellow solid.

oxo {4-[2- (trifluoro methyl )-1,3-thiazole-5- Work ]phenyl}acetaldehyde (compound 191c)

Oxo{4-[2-(trifluoromethyl)-1,3-thiazol-5-yl]phenyl}acetaldehyde 191c was prepared from oxidation of compound 190c with selenium dioxide. The method was the same as for the synthesis of compound 186. The product 191c was obtained in 100% yield as a yellow solid.

1-(1 H - Benzamidazole -5- Work )-5-[4-(2-Cyclopropyl-1,3-thiazol-5-yl)phenyl]imidazolidine-2,4-dione (Compound 39)

1-(1 H -benzamidazol-6-yl)-5-[4-(2-cyclopropyl from the cycloaddition reaction of 1-(1 H -benzamidazol-6-yl)urea 187 and compound 191b -1,3-thiazol-5-yl)phenyl]-imidazolidine-2,4-dione (Compound 39 ) was prepared. The method was the same as for the synthesis of compound 37. The product (compound 39 ) was obtained as a white solid in 57% yield.

1-(1 H - Benzamidazole -5- Work )-5-{4-[2-(trifluoro methyl )-1,3-thiazol-5-yl]phenyl}imidazolidine-2,4-dione (compound 40)

1 - (1 H - benz imidazol-6-yl) 1-from the cycloaddition reaction of the urea compound 187 and 191c (1 H - benz imidazol-5-yl) -5- {4- [2- (tri Prepared Fluoromethyl)-1,3-thiazol-5-yl]phenyl}-imidazolidine-2,4-dione (Compound 40 ). The method was the same as for the synthesis of compound 37. The product (compound 40 ) was obtained as a white solid in 30% yield.

1-[4-(2 H - tetrazole -5-yl)phenyl] Ethanone (Compound 192)

To a solution of 4-acetylbenzonitrile 143 (4.35 g, 30.0 mmol) in DMF (30 mL) under nitrogen was added sodium azide (2.15 g, 33 mmol) and ammonium chloride (0.40 g, 7.5 mmol). The reaction mixture was refluxed overnight and then cooled to room temperature. The reaction mixture was diluted with water and extracted with DCM. The aqueous phase was cooled in ice and acidified by addition of _{1 N HCl (aq).} After filtration, the precipitate was added with water and ether to give the product 192 as a yellow solid in 94% yield.

1-(1 H - Benzamidazole -5- Work )-5-[4-(2-methyl-2) H - tetrazole -5-yl)phenyl]imidazolidine-2,4-dione (Compound 41)

1-( 1H -benzamidazol-6-yl)urea 187 and 1-(1H -benzamidazol-5-yl)-5-[4-(2-methyl-) from cycloaddition reaction of compound 194a Prepared 2H -tetrazol-5-yl)phenyl]imidazolidine-2,4-dione (Compound 41 ). The method was the same as for the synthesis of compound 37. The product (compound 41 ) was obtained as a white solid in 17% yield.

1-(1 H - Benzamidazole -5- Work )-5-[4-(2- profile -2 H - tetrazole -5-yl)phenyl]imidazolidine-2,4-dione (Compound 42)

1-( 1H -benzamidazol-6-yl)-5-[4-(2-propyl-) from the cycloaddition reaction of 1-( 1H -benzamidazol-6-yl)urea 187 and compound 194b Prepared 2H -tetrazol-5-yl)phenyl]imidazolidine-2,4-dione (Compound 42 ). The method was the same as for the synthesis of compound 37. The product (compound 42 ) was obtained in 33% yield as a white solid.

1-(1 H - Benzamidazole -5-yl)-5-{4-[2-(propan-2-yl)-2 H - tetrazole -5-yl]phenyl}imidazolidine-2,4-dione (Compound 43)

1-(1 H -benzamidazol-6-yl)-5-{4-[2-(propane) from the cycloaddition reaction of 1-( 1H -benzamidazol-6-yl)urea 187 and compound 194c 2-yl) -2 H-tetrazol-5-yl] phenyl} - an imidazolidin-2,4-dione (compound 43) was prepared. The method was the same as for the synthesis of compound 37. The product (compound 43 ) was obtained as a white solid in 28% yield.

1-(1 H - Benzamidazole -5-day)-5-{4-[2-(2- methylpropyl )-2 H - tetrazole -5-yl]phenyl}imidazolidine-2,4-dione (Compound 44)

1-( 1H -benzamidazol-6-yl)-5-{4-[2-(2) from the cycloaddition reaction of 1-( 1H -benzamidazol-6-yl)urea 187 and compound 194d -methylpropyl) -2 H-tetrazol-5-yl] phenyl} - was already prepared the 2,4dione (compound 44). The method was the same as for the synthesis of compound 37. The product (compound 44 ) was obtained as a white solid in 34% yield.

1-(1 H - Benzamidazole -5-day)-5-{4-[2-( Cyclopropylmethyl )-2 H - tetrazole -5-yl]phenyl}-imidazolidine-2,4-dione (Compound 45)

1-(1 H -benzamidazol-5-yl)-5-{4-[2-(cyclo) from the cycloaddition reaction of 1-(1 H -benzamidazol-6-yl)urea 187 and compound 194e methyl) -2 H-tetrazol-5-yl] phenyl} - was already prepared the 2,4dione (compound 45). The method was the same as for the synthesis of compound 37. The product (compound 45 ) was obtained as a white solid in 31% yield.

1-(1 H - Benzamidazole -5-day)-5-{4-[2-(2,2,2- trifluoroethyl )-2 H - tetrazole -5-yl]phenyl}-imidazolidine-2,4-dione (Compound 46)

1-( 1H -benzamidazol-6-yl)-5-{4-[2-(2) from the cycloaddition reaction of 1-( 1H -benzamidazol-6-yl)urea 187 and compound 194f , 2,2-trifluoroethyl) -2 H-tetrazol-5-yl] phenyl} - was already prepared the 2,4dione (compound 46). The method was the same as for the synthesis of compound 37. The product (compound 46 ) was obtained as a white solid in 36% yield.

1-(1 H - Benzamidazole -5-day)-5-{4-[2-( prop -2-yn-1-yl)-2 H - tetrazole -5-yl]phenyl}imidazolidine-2,4-dione (Compound 47)

1-( 1H -benzamidazol-6-yl)-5-{4-[2-(prop) from the cycloaddition reaction of 1-( 1H -benzamidazol-6-yl)urea 187 and compound 194g 2-a-l-yl) -2 H-tetrazol-5-yl] phenyl} - was already prepared the 2,4dione (compound 47). The method was the same as for the synthesis of compound 37. The product (compound 47 ) was obtained as a white solid in 36% yield.

1-(1 H - Benzamidazole -5- Work )-5-{4-[2-(boot-2- sign -One- Work )-2 H - tetrazole -5-yl]phenyl}imidazolidine-2,4-dione (Compound 48)

1-(1 H -benzamidazol-5-yl)-5-{4-[2-(but) from the cycloaddition reaction of 1-(1 H -benzamidazol-6-yl)urea 187 and compound 194h 2-a-l-yl) -2 H-tetrazol-5-yl] phenyl} - was already prepared the 2,4dione (compound 48). The method was the same as for the synthesis of compound 37. The product (compound 48 ) was obtained as a white solid in 34% yield.

1-(1 H - Benzamidazole -5-day)-5-{4-[2-( pent -2-yn-1-yl)-2 H - tetrazole -5-yl]phenyl}imidazolidine-2,4-dione (Compound 49)

1-( 1H -benzamidazol-5-yl)-5-{4-[2-(pent) from the cycloaddition reaction of 1-(1 H -benzamidazol-6-yl)urea 187 and compound 194i 2-a-l-yl) -2 H-tetrazol-5-yl] phenyl} - was already prepared the 2,4dione (compound 49). The method was the same as for the synthesis of compound 37. The product (compound 49 ) was obtained as a white solid in 32% yield.

1-(1 H - Benzamidazole -5-day)-5-{4-[2-(4- chlorobenzyl )-2 H - tetrazole -5-yl]phenyl}imidazolidine-2,4-dione (Compound 50)

1-(1 H -benzamidazol-6-yl)-5-{4-[2-(4) from the cycloaddition reaction of 1-(1 H -benzamidazol-6-yl)urea 187 and compound 194j -chlorobenzyl) -2 H-tetrazol-5-yl] phenyl} - an imidazolidin-2,4-dione (compound 50) was prepared. The method was the same as for the synthesis of compound 37. The product (compound 50 ) was obtained as a white solid in 43% yield.

1-(1 H - Benzamidazole -5- Work )-5-{4-[2-(4-methoxybenzyl)-2 H - tetrazole -5- Work ]phenyl}-imidazolidine-2,4-dione (compound 51)

1-(1 H -benzamidazol-6-yl)-5-{4-[2-(4) from the cycloaddition reaction of 1-(1 H -benzamidazol-6-yl)urea 187 and compound 194k -methoxybenzyl) -2 H - were prepared imidazolidin-2,4-dione (compound 51) -tetrazol-5-yl] phenyl}. The method was the same as for the synthesis of compound 37. The product (compound 51 ) was obtained as a white solid in 22% yield.

1-(1 H - Benzamidazole -5-day)-5-(4-{2-[(3- methyl -1,2- oxazole -5 days) methyl ]-2 H - tetrazole -5-yl}phenyl)imidazolidine-2,4-dione (Compound 52)

1-(1 H -benzamidazol-5-yl)-5-(4-{2-[(1 H -benzamidazol-6-yl) urea 187 and cycloaddition of compound 194l 3-methyl-1,2-oxazol-5-yl) methyl] -2 H - tetrazol-5-yl} phenyl) imidazole was prepared 2,4dione (compound 52). The method was the same as for the synthesis of compound 37. The product (compound 52 ) was obtained as a white solid in 52% yield.

N - [2-(4-cyanophenyl)-2-oxoethyl]tricyclo[3.3.1.1 ^3,7 ]decane -One- carboxa Mead (Compound 196)

N- [2-(4-cyanophenyl)-2-oxoethyl]tricyclo[3.3.1.1 ^3,7 ]decane-1- via acetylation of adamantane-1-carbonyl chloride 195 with compound 131 Carboxamide 196 was prepared. The experimental method was the same as the synthesis of compound 133a. The product 196 was obtained in 53% yield as a yellow solid.

4-[2-(Trichy) claw [3.3.1.1 ^3,7 ]Det- One- Work )-1,3-thiazole-5- Work ]benzonitrile (compound 197)

4-[2-(tricyclo[3.3.1.1 ^3,7 ]det-1-yl)-1,3-thiazol-5-yl]benzonitrile 197 from the cyclization reaction of compound 196 with Lawson's reagent in THF was prepared. The experimental method was the same as the synthesis of compound 134a. The product 197 was obtained in 49% yield as a white solid.

4- [2-(tricyclo[3.3.1.1 ^3,7 ]Det- One- Work )-1,3-thiazol-5-yl]benzaldehyde (Compound 198)

4-[2-(tricyclo[3.3.1.1 ^3,7 ]det-1-yl)-1,3-thiazol-5-yl]benzaldehyde 198 was prepared from reduction of compound 197 with DIBAL-H reagent . The experimental method was the same as the synthesis of compound 135a. The product 198 was obtained in 83% yield as a white solid.

(One H - Benzamidazole -5- ilamino ){4-[2-(tricy claw [3.3.1.1 ^3,7 ]Det- One- Work )-1,3-thiazol-5-yl]phenyl}acetonitrile (Compound 199)

(1 H -benzamidazol-5-ylamino){4-[2-(tricyclo[3.3.1.1 ^3,7 ]det-1-yl)-1,3-thiazol-5-yl]phenyl} Acetonitrile 199 was prepared from the addition of 1 H -benzamidazol-5-amine 121 , TMSCN and compound 198 . The experimental method was the same as the synthesis of compound 122a. The product 199 was obtained in 91% yield as a pale yellow solid.

N ^One -(One H - Benzamidazole -5-yl)-1-{4-[2-( tricyclo[3.3.1.1 ^3,7 ]Det -1-yl)-1,3-thiazol-5-yl]phenyl}ethane-1,2-diamine (Compound 200)

N ¹ -(1 H -benzamidazol-5-yl)-1-{4-[2-(tricyclo[3.3.1.1 ^3,7 ]det-) from hydrogenation of compound 199 using Raney Nickel reagent as catalyst 1-yl)-1,3-thiazol-5-yl]phenyl}ethane-1,2-diamine 200 was prepared. The method was the same as for the synthesis of compound 123a. The product 200 was obtained in 60% yield as a yellow viscous liquid.

1-(1 H - Benzamidazole -5- Work )-5-{4-[2-(tricy) claw [3.3.1.1 ^3,7 ]Det- One- Work )-1,3-thiazol-5-yl]phenyl}imidazolidin-2-one (Compound 57)

1-(1 H -benzamidazol-5-yl)-5-{4-[2-(tricyclo[3.3.1.1 ³ ) from the cycloaddition reaction of 1,1'-carbonyl diimidazole and compound 200 ^,7 ]Det-1-yl)-1,3-thiazol-5-yl]phenyl}imidazolidin-2-one (Compound 57 ) was prepared. The experimental method was the same as the synthesis of compound 1. The product (compound 57 ) was obtained as a yellow solid in 78% yield.

2,3- difluoro -4-(5- Fluorothiophene -3 days) benzaldehyde (Compound 201a)

2,3-difluoro-4-(5-fluoro) from Suzuki-Miyaura coupling of 118 g of 2,3-difluoro-4-formylphenylboronic acid and 4-bromo-2-fluorothiophene 158d Rothiophen-3-yl)benzaldehyde 201a was prepared. The experimental method was the same as the synthesis of compound 159a. The product 201a was obtained in 42% yield as a pale yellow oil.

4-(5- chlorothiophene -3-yl)-2,3- difluorobenzaldehyde (Compound 201b)

4-(5-chlorothiophen-3-yl)- from Suzuki-Miyaura coupling of 2,3-difluoro-4-formylphenylboronic acid 118 g and 4-bromo-2-chlorothiophene 158e 2,3-difluorobenzaldehyde 201b was prepared. The experimental method was the same as the synthesis of compound 159a. The product 201b was obtained in 45% yield as a pale yellow oil.

2,3- difluoro -4-(5- methylthiophene -3 days) benzaldehyde (Compound 201c)

2,3-difluoro-4-(5-methyl) from Suzuki-Miyaura coupling of 118 g of 2,3-difluoro-4-formylphenylboronic acid and 4-bromo-2-methylthiophene 158b Thiophen-3-yl)benzaldehyde 201c was prepared. The experimental method was the same as the synthesis of compound 159a. The product 201c was obtained in 53% yield as a pale yellow oil.

4-(5-Ethylthiophen-3-yl)-2,3-difluorobenzaldehyde (compound 201d)

4-(5-ethylthiophen- 3-yl)- from Suzuki-Miyaura coupling of 2,3-difluoro-4 -formylphenylboronic acid 118 g and 4-bromo-2-ethylthiophene 158f 2,3-difluorobenzaldehyde 201d was prepared. The experimental method was the same as the synthesis of compound 159a. The product 201d was obtained in 56% yield as a pale yellow oil.

2,3-difluoro-4-[5-(methoxymethyl)thiophen-3-yl]benzaldehyde (Compound 201e)

2,3-difluoro-4- from Suzuki-Miyaura coupling of 118 g of 2,3-difluoro-4-formylphenylboronic acid and 158 g of 4-bromo-2-(methoxymethyl)thiophene [5-(methoxymethyl)thiophen-3-yl]benzaldehyde 201e was prepared. The experimental method was the same as the synthesis of compound 159a. The product 201e as a pale yellow oil was obtained in 49% yield.

4-[5-( ethoxymethyl )thiophen-3-yl]-2,3- difluorobenzaldehyde (Compound 201f)

4-[5-(ethoxymethyl) from Suzuki-Miyaura coupling of 118 g of 2,3-difluoro-4-formylphenylboronic acid and 4-bromo-2-(ethoxymethyl)thiophene 158h Thiophen-3-yl]-2,3-difluorobenzaldehyde 201f was prepared. The experimental method was the same as the synthesis of compound 159a. The product 201f was obtained in 48% yield as a pale yellow oil.

methyl 4-(2,3- difluoro -4- formylphenyl ) thiophene-2- carboxylate (201 g of compound)

From the Suzuki-Miyaura coupling of 118 g of 2,3-difluoro-4-formylphenylboronic acid and methyl 4-bromothiophene-2-carboxylate 158i, methyl 4-(2,3-difluoro- 201 g of 4-formylphenyl)thiophene-2-carboxylate was prepared. The experimental method was the same as the synthesis of compound 159a. 201 g of product as a pale yellow oil was obtained in 42% yield.

2,3- difluoro -4- (thiophen-3-yl) benzaldehyde (Compound 201h)

2,3-difluoro-4-(thiophen-3-yl)benzaldehyde from Suzuki-Miyaura coupling of 118 g of 2,3-difluoro-4-formylphenylboronic acid and 3-bromothiophene 158a 201h was prepared. The experimental method was the same as the synthesis of compound 159a. The product 201h as a pale yellow oil was obtained in 54% yield.

(One H - Benzamidazole -5- ilamino )[2,3- difluoro -4-(5-Fluorothiophen-3-yl)phenyl]acetonitrile (Compound 202a)

( 1H -benzamidazol-5-ylamino)[2,3-difluoro-4-(5-fluorothiophen-3-yl)phenyl]-acetonitrile 202a to 1H -benzamidazole-5 -prepared from the addition of amine 121 , TMSCN and compound 201a. The experimental method was the same as the synthesis of compound 122a. The product 202a was obtained in 85% yield as a pale yellow solid.

(One H - Benzamidazole -5- ilamino )[4-(5- Chlorothiophene- 3- Work )-2,3-difluorophenyl]acetonitrile (compound 202b)

( 1H -benzamidazol-5-ylamino)[4-(5-chlorothiophen-3-yl)-2,3-difluorophenyl]acetonitrile 202b to 1H -benzamidazole-5- Prepared from the addition of amine 121 , TMSCN and compound 201b. The experimental method was the same as the synthesis of compound 122a. The product 202b was obtained as a pale yellow solid in 79% yield.

(One H - Benzamidazole -5- ilamino )[2,3- difluoro -4-(5-Methylthiophen-3-yl)phenyl]acetonitrile (Compound 202c)

( 1H -benzamidazol-5-ylamino)[2,3-difluoro-4-(5-methylthiophen-3-yl)phenyl]acetonitrile 202c to 1H -benzamidazole-5- Prepared from the addition of amine 121 , TMSCN and compound 201c. The experimental method was the same as the synthesis of compound 122a. The product 202c was obtained as a pale yellow solid in 88% yield.

(One H - Benzamidazole -5- ilamino )[4-(5-ethylthiophene-3- Work )-2,3-difluorophenyl]acetonitrile (compound 202d)

( 1H -benzamidazol-5-ylamino)[4-(5-ethylthiophen-3-yl)-2,3-difluorophenyl]-acetonitrile 202d to 1H -benzamidazole-5 -prepared from the addition of amine 121 , TMSCN and compound 201d. The experimental method was the same as the synthesis of compound 122a. The product 202d was obtained as a pale yellow solid in 81% yield.

(One H - Benzamidazole -5- ilamino ){2,3- difluoro -4-[5-(methoxy methyl )thiophen-3-yl]phenyl}acetonitrile (compound 202e)

( 1H -benzamidazol-5-ylamino){2,3-difluoro-4-[5-(methoxymethyl)thiophen-3-yl]phenyl}acetonitrile 202e to H -benzamidazole Prepared from the addition of-5-amine 121 , TMSCN and compound 201 e. The experimental method was the same as the synthesis of compound 122a. The product 202e was obtained in 84% yield as a pale yellow solid.

(One H - Benzamidazole -5- ilamino ){4-[5-( ethoxymethyl ) thiophene-3- Work ]-2,3-difluorophenyl}acetonitrile (compound 202f)

( 1H -benzamidazol-5-ylamino){4-[5-(ethoxymethyl)thiophen-3-yl]-2,3-difluorophenyl}acetonitrile 202f to H -benzamidazole Prepared from the addition of 5-amine 121 , TMSCN and compound 201f. The experimental method was the same as the synthesis of compound 122a. The product 202f was obtained in 90% yield as a pale yellow solid.

methyl 4-{4-[(1 H - Benzamidazole -5- ilamino )(cyano)methyl]-2,3-difluorophenyl}thiophene-2-carboxylate (compound 202g)

202 g of methyl 4-{4-[(1 H -benzamidazol-5-ylamino)(cyano)methyl]-2,3-difluorophenyl}thiophene-2-carboxylate to H - benzami Prepared from the addition of dazol-5-amine 121 , TMSCN and 201 g of compound. The experimental method was the same as the synthesis of compound 122a. 202 g of the product was obtained as a pale yellow solid in 81% yield.

(One H - Benzamidazole -5- ilamino )[2,3- difluoro -4-(thiophene-3- Work )phenyl] aceto Nitrile (Compound 202h)

( 1H -benzamidazol-5-ylamino)[2,3-difluoro-4-(thiophen-3-yl)phenyl]acetonitrile 202h to H -benzamidazol-5-amine 121 , TMSCN and compound 201h . The experimental method was the same as the synthesis of compound 122a. The product 202h was obtained as a pale yellow solid in 92% yield.

N ^One -(One H - Benzamidazole -5- Work )-1-[2,3- difluoro -4-(5-Fluorothiophen-3-yl)phenyl]ethane-1,2-diamine (Compound 203a)

N ¹ -(1 H -benzamidazol-5-yl)-1-[2,3-difluoro-4-(5-fluorothiophen-3) from hydrogenation of compound 202a using Raney Nickel reagent as catalyst -yl)phenyl]ethane-1,2-diamine 203a was prepared. The experimental method was the same as the synthesis of compound 123a. The product 203a was obtained in 43% yield as a yellow viscous liquid.

N ^One -(One H - Benzamidazole -5- Work )-1-[4-(5- Chlorothiophene- 3- Work )-2,3-difluorophenyl]ethane-1,2-diamine (compound 203b)

N ¹ -(1 H -benzamidazol-5-yl)-1-[4-(5-chlorothiophen-3-yl)-2,3- from hydrogenation of compound 202b using Raney Nickel reagent as catalyst Difluorophenyl]ethane-1,2-diamine 203b was prepared. The experimental method was the same as the synthesis of compound 123a. The product 203b was obtained in 40% yield as a yellow viscous liquid.

N ^One -(One H - Benzamidazole -5- Work )-1-[2,3- difluoro -4-(5-Methylthiophen-3-yl)phenyl]ethane-1,2-diamine (Compound 203c)

N ¹ -(1 H -benzamidazol-5-yl)-1-[2,3-difluoro-4-(5-methylthiophen-3) from hydrogenation of compound 202c using Raney Nickel reagent as catalyst -yl)phenyl]ethane-1,2-diamine 203c was prepared. The experimental method was the same as the synthesis of compound 123a. The product 203c was obtained in 53% yield as a yellow viscous liquid.

N ^One -(One H - Benzamidazole -5- Work )-1-[4-(5-ethylthiophene-3- Work )-2,3-difluorophenyl]ethane-1,2-diamine (compound 203d)

N ¹ -(1 H -benzamidazol-5-yl)-1-[4-(5-ethylthiophen-3-yl)-2,3- from hydrogenation of compound 202d using Raney Nickel reagent as catalyst Difluorophenyl]ethane-1,2-diamine 203d was prepared. The experimental method was the same as the synthesis of compound 123a. The product 203d was obtained in 51% yield as a yellow viscous liquid.

N ^One -(One H - Benzamidazole -5- Work )-1-{2,3- difluoro -4-[5-(methoxy methyl )thiophen-3-yl]phenyl}ethane-1,2-diamine (compound 203e)

N ¹ -(1 H -benzamidazol-5-yl)-1-{2,3-difluoro-4-[5-(methoxymethyl) from hydrogenation of compound 202e using Raney Nickel reagent as catalyst Thiophen-3-yl]phenyl}ethane-1,2-diamine 203e was prepared. The experimental method was the same as the synthesis of compound 123a. The product 203e was obtained in 46% yield as a yellow viscous liquid.

N ^One -(One H - Benzamidazole -5- Work )-1-{4-[5-( ethoxymethyl ) thiophene-3- Work ]-2,3-difluorophenyl}ethane-1,2-diamine (compound 203f)

N ¹ -(1 H -benzamidazol-5-yl)-1-{4-[5-(ethoxymethyl)thiophen-3-yl]- from hydrogenation of compound 202f using Raney Nickel reagent as catalyst 2,3-difluorophenyl}ethane-1,2-diamine 203f was prepared. The experimental method was the same as the synthesis of compound 123a. The product 203f was obtained in 49% yield as a yellow viscous liquid.

methyl 4-{4-[2-amino-1-(1) H - Benzamidazole -5- ilamino )ethyl]-2,3-difluorophenyl}thiophene-2-carboxylate (compound 203g)

Methyl 4-{4-[2-amino-1-(1 H -benzamidazol-5-ylamino)ethyl]-2,3-difluorophenyl from hydrogenation of 202 g using Raney Nickel reagent as catalyst } 203 g of thiophene-2-carboxylate was prepared. The experimental method was the same as the synthesis of compound 123a. 203 g of product as a yellow viscous liquid was obtained in 47% yield.

N ^One -(One H - Benzamidazole -5- Work )-1-[2,3- difluoro -4-(thiophen-3-yl)phenyl]ethane-1,2-diamine (compound 203h)

N ¹ -(1 H -benzamidazol-5-yl)-1-[2,3-difluoro-4-(thiophen-3-yl) from hydrogenation of compound 202h using Raney Nickel reagent as catalyst Phenyl]ethane-1,2-diamine 203h was prepared. The experimental method was the same as the synthesis of compound 123a. The product 203h as a yellow viscous liquid was obtained in 58% yield.

1-(1 H - Benzamidazole -5- Work )-5-[2,3- difluoro -4-(5-Fluorothiophen-3-yl)phenyl]imidazolidin-2-one (Compound 58)

1-(1 H -benzamidazol-5-yl)-5-[2,3-difluoro-4-(5-) from the cycloaddition reaction of 1,1'-carbonyl diimidazole and compound 203a Fluorothiophen-3-yl)phenyl]imidazolidin-2-one (Compound 58 ) was prepared. The experimental method was the same as the synthesis of compound 1. The product (compound 58 ) was obtained as a white solid in 71% yield.

1-(1 H - Benzamidazole -5- Work )-5-[4-(5- Chlorothiophene- 3- Work )-2,3-difluorophenyl]imidazolidin-2-one (Compound 59)

1-(1 H -benzamidazol-5-yl)-5-[4-(5-chlorothiophen-3-yl) from the cycloaddition reaction of 1,1'-carbonyl diimidazole and compound 203b -2,3-difluorophenyl]imidazolidin-2-one (Compound 59 ) was prepared. The experimental method was the same as the synthesis of compound 1. The product (compound 59 ) was obtained as a white solid in 74% yield.

1-(1 H - Benzamidazole -5- Work )-5-[2,3- difluoro -4-(5-Methylthiophen-3-yl)phenyl]imidazolidin-2-one (Compound 60)

1-(1 H -benzamidazol-5-yl)-5-[2,3-difluoro-4-(5-) from the cycloaddition reaction of 1,1'-carbonyl diimidazole and compound 203c Methylthiophen-3-yl)phenyl]imidazolidin-2-one (Compound 60 ) was prepared. The experimental method was the same as the synthesis of compound 1. The product (compound 60 ) was obtained in 70% yield as a white solid.

1-(1 H - Benzamidazole -5- Work )-5-[4-(5-ethylthiophene-3- Work )-2,3-difluorophenyl]imidazolidin-2-one (Compound 61)

1-(1 H -benzamidazol-5-yl)-5-[4-(5-ethylthiophen-3-yl) from the cycloaddition reaction of 1,1'-carbonyl diimidazole and compound 203d -2,3-difluorophenyl]-imidazolidin-2-one (Compound 61 ) was prepared. The experimental method was the same as the synthesis of compound 1. The product (compound 61 ) was obtained in 70% yield as a white solid.

1-(1 H - Benzamidazole -5- Work )-5-{2,3- difluoro -4-[5-(methoxy methyl )thiophen-3-yl]phenyl}imidazolidin-2-one (Compound 62)

1-(1H -benzamidazol-5-yl)-5-{2,3-difluoro-4-[5-] from the cycloaddition reaction of 1,1'-carbonyl diimidazole and compound 203e (Methoxymethyl)thiophen-3-yl]phenyl}imidazolidin-2-one (Compound 62 ) was prepared. The experimental method was the same as the synthesis of compound 1. The product (compound 62 ) was obtained as a white solid in 76% yield.

1-(1 H - Benzamidazole -5- Work )-5-{4-[5-( ethoxymethyl ) thiophene-3- Work ]-2,3-difluorophenyl}imidazolidin-2-one (Compound 63)

1-(1 H -benzamidazol-5-yl)-5-{4-[5-(ethoxymethyl)thiophene- from the cycloaddition reaction of 1,1'-carbonyl diimidazole and compound 203f 3-yl]-2,3-difluorophenyl}imidazolidin-2-one (Compound 63 ) was prepared. The experimental method was the same as the synthesis of compound 1. The product (compound 63 ) was obtained in 72% yield as a white solid.

methyl 4-{4-[3-(1) H - Benzamidazole -5- Work )-2-oxo imidazolidine -4- Work ]-2,3-difluorophenyl}thiophene-2-carboxylate (Compound 64)

Methyl 4-{4-[3-( 1H -benzamidazol-5-yl)-2-oxoimidazolidine-4 from the cycloaddition reaction of 1,1'-carbonyl diimidazole and compound 203g -yl]-2,3-difluorophenyl}thiophene-2-carboxylate (Compound 64 ) was prepared. The experimental method was the same as the synthesis of compound 1. The product (compound 64 ) was obtained as a white solid in 75% yield.

1-(1 H - Benzamidazole -5- Work )-5-[2,3- difluoro -4-(thiophen-3-yl)phenyl]imidazolidin-2-one (Compound 65)

1-(1 H -benzamidazol-5-yl)-5-[2,3-difluoro-4-(thiophene) from the cycloaddition reaction of 1,1'-carbonyl diimidazole and compound 203h -3-yl)phenyl]imidazolidin-2-one (Compound 65 ) was prepared. The experimental method was the same as the synthesis of compound 1. The product (compound 65 ) was obtained as a white solid in 79% yield.

4-{4-[3-(1 H - Benzamidazole -5-day)-2- Oxoimidazolidine -4-yl]-2,3- difluoro Phenyl}thiophene-2-carboxylic acid (Compound 66)

To a solution of compound 64 (0.45 g, 1.0 mmol) in methanol (10 mL) was added potassium hydroxide (0.07 g, 1.2 mmol). The reaction mixture was stirred at 60° C. for 1.5 h and then cooled to room temperature. The reaction mixture was neutralized to pH 7 with _{1 N HCl (aq).} After removal of the solvent, the crude residue was purified by reverse phase column chromatography on C-18 silica gel using _{methanol/H 2} O (1/1) as eluent to give the product 66 as a white solid in 81% yield. did.

1-(1 H - Benzamidazole -5- Work )-5-{2,3- difluoro -4-[5-(hydroxyl) methyl )thiophen-3-yl]phenyl}imidazolidin-2-one (Compound 67)

A solution of compound 64 (0.45 g, 1.0 mmol) in dry THF (5 mL) was added dropwise to a refluxing, magnetically stirred slurry of LAH (1.5 mmol) in dry THF (7.5 mL). The reaction mixture was kept at reflux for 3 hours, quenched _{by dropwise addition of 1 mL saturated MgSO 4} solution, and filtered through celite. The filtrate was partitioned between ethyl acetate and water. The organic phase was _{dried over MgSO 4} and evaporated on a rotary evaporator. The residue was purified by column chromatography on silica gel using methanol/DCM (1/10) as eluent to give the product 67 as a white solid in 92% yield.

compound 8 of enantiomeric Separation

Chiral separation of compound 8 was completed by HPLC using CHIRALPAK IC. Each of the isomeric fractions was collected, whereby the solvent was removed under reduced pressure to obtain the optically pure isomers (compounds 9 and 10). The results of this separation are presented below:

Column: CHIRALPAK IC (IC00CE-OL002),

Column size: 0.46 cm I.D. x 25 cm L,

Injection: 0.5 ul,

mobile phase: 100% methanol,

flow rate: 1.0 ml/min;

Detection: UV 214 nm,

Temperature: 35℃,

HPLC instrument: Shimadzu LC-20AD (CP-HPLC-06),

Retention E1 (compound 9 ): 5.494 min,

Retention E2 (compound 10 ): 6.379 min.

compound 13 of enantiomeric Separation

Chiral separation of compound 13 was completed by HPLC using CHIRALPAK AD-H. Each of the isomeric fractions was collected, whereby the solvent was removed under reduced pressure to obtain the optically pure isomers (compounds 33 and 34). The results of this separation are presented below:

Column: CHIRALPAK AD-H (ADH0CD-UE022),

Column size: 0.46 cm I.D. x 15 cm L,

Injection: 1.0 ul,

mobile phase: hexane/EtOH=60/40 (v/v),

flow rate: 1.0 ml/min;

Detection: UV 214 nm,

Temperature: 35℃,

HPLC instrument: Shimadzu LC-20AT (CP-HPLC-09),

Retention E1 (compound 33 ): 4.270 min,

Retention E2 (compound 34 ): 5.679 min.

compound 16 of enantiomeric Separation

Chiral separation of compound 16 was completed by HPLC using CHIRALPAK AD-H. Each of the isomeric fractions was collected, whereby the solvent was removed under reduced pressure to give the optically pure isomers (compounds 35 and 36 ). The results of this separation are presented below:

Column: CHIRALPAK AD-H (ADH0CD-UE022),

Column size: 0.46 cm I.D. x 15 cm L,

Injection: 2.0 ul,

mobile phase: hexane/EtOH=70/30 (v/v),

flow rate: 1.0 ml/min;

Detection: UV 214 nm,

Temperature: 35℃,

HPLC instrument: Shimadzu LC-20AD (CP-HPLC-08),

Retention E1 (compound 35 ): 7.273 min,

Retention E2 (compound 36 ): 9.232 min.

compound 25 of enantiomeric Separation

Chiral separation of compound 25 was completed by HPLC using CHIRALPAK AD-H. The isomer fractions were individually collected, whereby the solvent was removed under reduced pressure to give the optically pure isomers (compounds 53 and 54 ). The results of this separation are presented below:

Column: CHIRALPAK AD-H (ADH0CD-UE022),

Column size: 0.46 cm I.D. x 15 cm L,

Injection: 2.0 ul,

mobile phase: hexane/EtOH=70/30 (v/v),

flow rate: 1.0 ml/min;

Detection: UV 214 nm,

Temperature: 35℃,

HPLC instrument: Shimadzu LC-20AD (CP-HPLC-08),

Retention E1 (compound 53 ): 2.166 min,

Retention E2 (compound 54 ): 2.767 min.

compound 28 of enantiomeric Separation

Chiral separation of compound 28 was completed by HPLC using CHIRALPAK AD-H. Each of the isomeric fractions was collected, whereby the solvent was removed under reduced pressure to give the optically pure isomers (compounds 55 and 56 ). The results of this separation are presented below:

Column: CHIRALPAK AD-H (ADH0CD-UE022),

Column size: 0.46 cm I.D. x 15 cm L,

Injection: 2.0 ul,

mobile phase: hexane/EtOH=70/30 (v/v),

flow rate: 1.0 ml/min;

Detection: UV 214 nm,

Temperature: 35℃,

HPLC instrument: Shimadzu LC-20AD (CP-HPLC-08),

Retention E1 (compound 55 ): 3.827 min,

Retention E2 (compound 56 ): 7.914 min.

Example 2 : In vitro activity screening of compounds

QC activity assay

The enzyme activity assay of QC was performed using a fluorescent substrate, ie, L-glutaminyl 2-naphthylamide (Gln-βNA), at 25°C. See Huang et al., Biochem . J. 2008, 411,181-190]. 100 μl reaction mixture was prepared. It contains 300 μM of fluorogenic substrate in 50 mM Tris-HCl (pH 8.0), ˜0.2 units of coenzyme human pyroglutamyl aminopeptidase I (PAP I), where 1 unit equals 1 under assay conditions. defined as the amount of human PAP I required to hydrolyze 1 μmol of pGlu-βNA per minute), and an appropriately diluted aliquot of recombinant QC. The excitation and emission wavelengths were set to 320 nm and 410 nm, respectively. QC was added to initiate the reaction. The enzymatic activity of QC was determined from the amount of free βNA and calculated using a standard curve for βNA under the same assay conditions. Measurements were made using a Synergy H4 microplate reader (BioTek, Winusky, VT, USA).

Enzyme Kinetic Assay

Reaction rate constants were measured at 25°C and pH 8.0 using Gln-βNA as a substrate. See Huang et al., Biochem . J. 2008, 411, 181-190]. The reaction was initiated by adding QC to the 100 μl reaction mixture described above. Initial rates were determined following <10% substrate depletion during the first 2-12 minutes. After the weak substrate inhibition observed, Calle a graph (KaleidaGraph) software (Synergy software (Synergy Software: Pennsylvania Reading)) using the equation by non-linear regression, _{i.e., v 0 = V max [S} ] / (K _The kinetic parameters K _m , V , and K _i were evaluated by fitting m + [S] + [S]2/ K _i ) to the initial rate data , where v ₀ is the initial rate and V _max is the limiting ratio. , [S] is the substrate concentration, K _m is the Michaelis constant, and K _i is the inhibition constant.

QC Inhibition assay

Inhibitory activity assays of QC inhibitors were performed. Literature [Huang et al., J. Biol. Chem . 2011, 286, 12439-12449]. A reaction mixture was prepared containing 300 μM of Gln-βNA and ˜0.2 units of human PAP I. First, the QCs were incubated with the inhibitor at 25° C. for 30 minutes, and then the enzyme-inhibitor mixture was added to the reaction mixture to initiate the reaction, which is a cyclization reaction. The _{IC 50} values were obtained by fitting the initial reaction rate versus the inhibitor concentration using a Kaleidagraph. The K _i value of the inhibitor was calculated according to the equation IC ₅₀ = K _i (1 + [S]/ K _{m ).} Segel, Enzyme Kinetics: Behavior and Analysis of Rapid Equilibrium and Steady-State Enzyme Systems, pp. 100-118. New York: John Wiley & Sons, 1993]. In the above equation, [S] is the substrate (ie, Gln-βNA) concentration and K _m is the Michaelis-Menten constant. The lower the K _i value, the higher the rate of QC inhibition of the inhibitor.

The K _i values of compounds 1-29 , 33-57 , and 59-65 , obtained from the inhibition assays described above, are shown in Table 2 below.

As shown in this table, compounds 1-29 , 33-57 , and 59-65 all have K _i values within the nanomolar range. Note that a low K _i value suggests that the inhibitor has a high rate of QC inhibition. Obviously, these compounds have good inhibitory effects on QC.

QC inhibition has been reported to reduce the aggregation of Aβ and HTT in cultured macrophage cells and in Drosophila and mouse models. Therefore, compounds 1-29 , 33-57 , and 59-65, which are potent QC inhibitors, are drug candidates for the treatment of AD or HD.

Example 3 : In vivo activity of the compound

Compound 37 showed potent potency (K _i = 0.018 μM) and desired pharmacokinetic properties (F % = 11) in inhibiting QC in mice (F % is the fraction of orally administered drug reaching systemic circulation) . Accordingly, compounds were selected for further animal studies in a transgenic mouse model using APP/PS1 mice (Jackson Lab, Maine, USA). Schilling et al., Nat. Med . 2008, 14, 1106-1111] and [Li et al., J. Med . Chem . 2017, 60, 6664-6677]. APP/PS1 mice are dual transgenic mice expressing a chimeric mouse/human amyloid precursor protein (Mo/HuAPP695swe) and a mutant human presenilin 1 (PS1-dE9), both directed to CNS neurons. These two mutations are associated with early-onset Alzheimer's disease. In animal studies, 4-month-old APP/PS1 mice were housed on a 12-hour day/12-hour night cycle, with free access to drinking water and food. Compound 37 was orally administered to APP/PS1 mice for 3.5 months to measure their in vivo activity. After administration, the cognitive function and brain pathology of each mouse were analyzed. The resulting analytical data showed Aβ deposit depletion in brain tissue of APP/PS1 mice.

The same in vivo assay was performed for compound 28 , and as a result, the compound exhibited excellent pharmacokinetic properties (F% = 25) with high inhibitory activity (K _{i = 0.039 μM) and high oral bioavailability in APP/PS1 mice.} appeared to have

These two assays demonstrate both the potency and efficacy of compounds 28 and 37 as QC inhibitors for the treatment of AD.

other embodiments

All of the features disclosed herein can be combined in any combination. Each feature disclosed herein may be replaced by an alternative feature serving the same, equivalent, or similar purpose. Accordingly, unless expressly stated otherwise, each feature disclosed herein is merely an example of a series of equivalent or similar features.

From the above description, those skilled in the art can readily ascertain the essential characteristics of the present invention, and without departing from the spirit and scope thereof, various modifications and variations can be made thereto to adapt the present invention to various uses and conditions. Accordingly, other embodiments are also included within the scope of the following claims.

Claims (24)

A compound of formula (I):
<Formula (I)>

In the above formula,
R ₁ is H or C _1-6 alkyl;
R ₂ is a moiety containing a phenyl ring fused to a 5-membered heteroaryl ring, wherein R ₂ is connected to N through the phenyl ring;
R ₃ , R ₄ , R ₅ , R ₆ , and R ₇ are independently halo, nitro, cyano, amino, OH, CF ₃ , -COOH, -COOC _1-6 alkyl, C _1-6 alkoxyl, H, optionally substituted with one or more substituents selected from C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _{3-10 cycloalkyl, heterocycloalkyl, aryl, and heteroaryl;} halo, nitro, cyano, amino, OH, CF ₃ , C _1-6 alkoxyl, C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _3-10 cycloalkyl, heterocyclo alkyl, aryl, or heteroaryl;
here,
at least one of R ₃ , R ₄ , R ₅ , R ₆ , and R _{7 is heteroaryl;}
C _1-6 alkoxyl, C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _3-10 cycloalkyl, heterocycloalkyl, aryl, and heteroaryl are each a second or third for halo, nitro, cyano, amino, OH, CF ₃ , C _1-6 alkoxyl, C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _3-10 cycloalkyl , optionally substituted with heterocycloalkyl, aryl, or heteroaryl;
X is CH ₂ or C=O;
Y is CH ₂ or C=O. The compound of claim 1 , wherein Y is CH _{2 .} 3. The method of claim 2, wherein R ₁ is H, X is C=O and R ₂ is

A compound that is 4. The _{compound of claim 3} , wherein R 3 , R ₄ , R ₅ , and R ₆ are independently H, CH ₃ , Cl, or F. 5. The method of claim 4, wherein R ₇ is

And heteroaryl is selected from the group consisting of wherein, R ₈ is H, halo, nitro, cyano, _{amino, OH, CF 3, -COOH,} -COOC 1 -6 alkyl, C _1-6 alkoxyl, C _{1 -6} alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _3-10 cycloalkyl, heterocycloalkyl, aryl, or heteroaryl;
C _1-6 alkoxyl, C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _3-10 cycloalkyl, heterocycloalkyl, aryl, and heteroaryl are each halo, nitro, cya no, amino, OH, CF ₃ , C _1-6 alkoxyl, C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _3-10 cycloalkyl, heterocycloalkyl, aryl, or optionally substituted with heteroaryl. 6. The method of claim 5, wherein R ₈ is H, F, Cl, CH ₃ , CF ₃ , ethyl, n-propyl,

A compound that is 7. The method of claim 6, wherein R ₇ is

A compound selected from the group consisting of. The compound of claim 1 , wherein Y is C═O. 9. The method of claim 8, wherein R ₁ is H, X is C=O and R ₂ is

A compound that is _10. The compound of claim 9, wherein R ₃ , R ₄ , R ₅ , and R 6 are independently H, CH ₃ , Cl, or F. 11. The method of claim 10, wherein R ₇ is

And heteroaryl is selected from the group consisting of wherein, R ₈ is H, halo, nitro, cyano, _{amino, OH, CF 3, -COOH,} -COOC 1 -6 alkyl, C _1-6 alkoxyl, C _{1 -6} alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _3-10 cycloalkyl, heterocycloalkyl, aryl, or heteroaryl;
C _1-6 alkoxyl, C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _3-10 cycloalkyl, heterocycloalkyl, aryl, and heteroaryl are each halo, nitro, cya no, amino, OH, CF ₃ , C _1-6 alkoxyl, C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _3-10 cycloalkyl, heterocycloalkyl, aryl, or optionally substituted with heteroaryl. 12. The method of claim 11, wherein R ₈ is H, F, Cl, CH ₃ , CF ₃ , ethyl, n-propyl,

A compound that is 13. The method of claim 12, wherein R ₇ is

A compound selected from the group consisting of. The compound of claim 1 , wherein R ₁ is H and X is C═O. The method of claim 1, wherein R ₂ is

A compound that is The compound of claim 1 , wherein R ₃ , R ₄ , R ₅ , and R ₆ are independently H, CH ₃ , Cl, or F. The method of claim 1, wherein R ₇ is

And heteroaryl is selected from the group consisting of wherein, R ₈ is H, halo, nitro, cyano, _{amino, OH, CF 3, -COOH,} -COOC 1 -6 alkyl, C _1-6 alkoxyl, C _{1 -6} alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _3-10 cycloalkyl, heterocycloalkyl, aryl, or heteroaryl;
C _1-6 alkoxyl, C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _3-10 cycloalkyl, heterocycloalkyl, aryl, and heteroaryl are each halo, nitro, cya no, amino, OH, CF ₃ , C _1-6 alkoxyl, C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _3-10 cycloalkyl, heterocycloalkyl, aryl, or optionally substituted with heteroaryl. 18. The method of claim 17, wherein R ₈ is H, F, Cl, CH ₃ , CF ₃ , ethyl, n-propyl,

A compound that is 19. The method of claim 18, wherein R ₇ is

A compound selected from the group consisting of. The compound of claim 1 , wherein the compound is one of the following compounds:

. 21. The compound of claim 20, wherein the compound is one of the following compounds:

. The compound of claim 1 , wherein the compound is one of the following compounds:

. A pharmaceutical composition comprising a compound of claim 1 and a pharmaceutically acceptable carrier. A method of treating Alzheimer's disease or Huntington's disease by administering to a subject in need thereof an effective amount of a compound of claim 1 .