Benzimidazole compounds and their use for treating alzheimer's disease or huntington's disease

文档序号：213431 发布日期：2021-11-05 浏览：13次中文

阅读说明：本技术 苯并咪唑化合物及其用于治疗阿兹海默症或亨丁顿氏症的用途 (Benzimidazole compounds and their use for treating alzheimer's disease or huntington's disease ) 是由陈志豪陈炯东王惠钧黄开发石全于 2019-08-30 设计创作，主要内容包括：本发明提供了一种如式(I)所示的苯并咪唑化合物,该化合物是有效的人类麸酸胺环化酶抑制剂。本发明还提供了一种含有该等化合物中之一化合物及医药上可接受载体的医药组合物以及一种藉由对需要治疗阿兹海默症或亨丁顿氏症的个体投予有效量的该化合物来治疗阿兹海默症或亨丁顿氏症的方法。(The present invention provides a benzimidazole compound of formula (I) which is a potent inhibitor of human neuraminidase. The invention also provides a pharmaceutical composition comprising one of the compounds and a pharmaceutically acceptable carrier, and a method of treating alzheimer's disease or huntington's disease by administering to a subject in need thereof an effective amount of the compound.)

1. A compound of formula (I):

wherein R is₁Is H or C_1-6An alkyl group;

R₂is a group comprising a benzene ring fused to a 5-membered heteroaromatic ring, R₂Through the benzene ring to N;

R₃、R₄、R₅、R₆and R₇Independently is optionally selected from halogen, nitro, cyano, amino, OH, CF₃、-COOH、-COOC_1-6Alkyl radical, C_1-6Alkoxy radical, C_1-6Alkyl radical, C_2-6Alkenyl radical, C_2-6Alkynyl, C_3-10Cycloalkyl radicalsH, halogen, nitro, cyano, amino, OH, CF substituted by one or more substituents of heterocycloalkyl, aryl and heteroaryl₃、C_1-6Alkoxy radical, C_1-6Alkyl radical, C_2-6Alkenyl radical, C_2-6Alkynyl, C_3-10Cycloalkyl, heterocycloalkyl, aryl or heteroaryl,

wherein R is₃、R₄、R₅、R₆And R₇At least one of which is heteroaryl; and

each C occurring second or third_1-6Alkoxy radical, C_1-6Alkyl radical, C_2-6Alkenyl radical, C_2-6Alkynyl, C_3-10Cycloalkyl, heterocycloalkyl, aryl and heteroaryl are all optionally substituted by halogen, nitro, cyano, amino, OH, CF₃、C_1-6Alkoxy radical, C_1-6Alkyl radical, C_2-6Alkenyl radical, C_2-6Alkynyl, C_3-10Cycloalkyl, heterocycloalkyl, aryl, or heteroaryl;

x is CH₂Or C ═ O;

y is CH₂Or C ═ O.

2. The compound of claim 1, wherein Y is CH₂。

3. The compound of claim 2, wherein R is₁Is H, X is C ═ O, and R₂Is composed of

4. A compound according to claim 3, wherein R is₃、R₄、R₅And R₆Independently is H, CH₃Cl or F.

5. A compound according to claim 4, wherein R is₇Is selected from

Andheteroaryl of the group, wherein R₈Is H, halogen, nitro, cyano, amino, OH, CF₃、-COOH、-COOC_1-6Alkyl radical, C_1-6Alkoxy radical, C_1-6Alkyl radical, C_2-6Alkenyl radical, C_2-6Alkynyl, C_3-10Cycloalkyl, heterocycloalkyl, aryl or heteroaryl,

each C_1-6Alkoxy radical, C_1-6Alkyl radical, C_2-6Alkenyl radical, C_2-6Alkynyl, C_3-10Cycloalkyl, heterocycloalkyl, aryl and heteroaryl are all optionally substituted by halogen, nitro, cyano, amino, OH, CF₃、C_1-6Alkoxy radical, C_1-6Alkyl radical, C_2-6Alkenyl radical, C_2-6Alkynyl, C_3-10Cycloalkyl, heterocycloalkyl, aryl or heteroaryl.

6. A compound according to claim 5, wherein R is₈Is H, F, Cl, CH₃、CF₃Ethyl, n-propyl,

7. A compound according to claim 6, wherein R is₇Is selected from

And

the group consisting of.

8. A compound according to claim 1, wherein Y is C ═ O.

9. The compound of claim 8, wherein R is₁Is H, X is C ═ O, and R₂Is composed of

10. The compound of claim 9, wherein R is₃、R₄、R₅And R₆Independently H, CH3, Cl or F.

11. The compound of claim 10, wherein R is₇Is selected from

Andheteroaryl of the group consisting of, wherein R₈Is H, halogen, nitro, cyano, amino, OH, CF₃、-COOH、-COOC_1-6Alkyl radical, C_1-6Alkoxy radical, C_1-6Alkyl radical, C_2-6Alkenyl radical, C_2-6Alkynyl, C_3-10Cycloalkyl, heterocycloalkyl, aryl or heteroaryl,

12. The compound of claim 11, wherein R is₈Is H, F, Cl, CH₃、CF₃Ethyl, n-propyl,

13. A compound according to claim 12, wherein said compound is selected from the group consisting of,characterized in that R is₇Is selected from

And

the group consisting of.

14.14. The compound of claim 1, wherein R is₁Is H and X is C ═ O.

15. The compound of claim 1, wherein R is₂Is composed of

16. The compound of claim 1, wherein R is₃、R₄、R₅And R₆Independently is H, CH₃Cl or F.

17. The compound of claim 1, wherein R is₇Is selected from

18. The compound of claim 17, wherein R is₈Is H, F, Cl, CH₃、CF₃Ethyl, n-propyl,

19. The compound of claim 18, wherein R is₇Is selected from

And

the group consisting of.

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

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

and

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

and

23. a pharmaceutical composition comprising a compound of claim 1 and a pharmaceutically acceptable carrier.

24. 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.

Technical Field

The present invention relates to a benzimidazole compound, particularly for use in the treatment of alzheimer's disease or huntington's disease.

Background

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, on the other hand, causes uncontrolled movements of the arms, legs, head, face and upper body. HD can also lead to a decline in thought and reasoning abilities, including memory, attention, judgment, planning, and organizational abilities.

Both AD and HD are caused by abnormal aggregation of proteins or peptides. In fact, AD is a cognitive dysfunction caused by aggregated mutant β -amyloid peptide (a β), while HD is caused by the toxic effects of aggregated mutant huntingtin protein (HTT).

Human glutaminyl cyclase (QC) catalyzes the cyclization of the N-terminal residue of glutaminic acid (glutamine) or glutamic acid (glutamate) to form pyroglutamate (pGlu) on a β and HTT. pGlu-modified a β and pGlu-modified HTT thus formed are aggregated, neurotoxic, and resistant to proteolysis, and can initiate pathological cascades (pathological cascades), leading to the development of AD or HD.

Inhibition of human QC has been found to reduce aggregation of a β and HTT in cultured macrophages and drosophila and mouse models. See j.pharmacol.exp.ther.2017,362, 119-130; med.chem.2017,60, 2573-2590; nat. Med.2008,14(10),1106-1111 and nat. chem. Bio.2015,11, 347-354.

Human QC is therefore an emerging drug marker for the treatment of AD or HD.

Currently, only a few drug candidates that inhibit QC are in clinical trials for treating AD or HD. There is a need to develop new QC inhibitors.

Early studies showed that QC is a zinc-dependent enzyme. Therefore, compounds capable of chelating zinc ions at the active site of QC (e.g., benzimidazole compounds) are potential QC inhibitors.

Disclosure of Invention

It has been found that certain novel benzimidazole compounds are QC inhibitors, and unexpectedly, the compounds exhibit high potency in inhibiting QC and are therefore useful in the treatment of AD or HD.

In one aspect, the invention relates to benzimidazole compounds of the following formula (I):

x and Y are independently CH₂Or C ═ O; r₁Is H or C_1-6An alkyl group; r₂Comprising a phenyl ring fused to a 5-membered heteroaromatic ring (e.g. as) A group of (A), R₂Through the benzene ring to N; r₃、R₄、R₅、R₆And R₇Independently is optionally selected from halogen (e.g. F, Cl, Br or I), nitro, cyano, amine, OH, CF₃、-COOH、-COOC_1-6Alkyl radical, C_1-6Alkoxy radical, C_1-6Alkyl radical, C_2-6Alkenyl radical, C_2-6Alkynyl, C_3-10H substituted with one or more substituents of cycloalkyl, heterocycloalkyl, aryl and heteroaryl, halogen (e.g. F, Cl, Br or I), nitro, cyano, amino, OH, CF₃、C_1-6Alkoxy radical, C_1-6Alkyl radical, C_2-6Alkenyl radical, C_2-6Alkynyl, C_3-10Cycloalkyl, heterocycloalkyl, aryl or heteroaryl, wherein R₃、R₄、R₅、R₆And R₇At least one of which is heteroaryl, and wherein each C in the second or third occurrence is_1-6Alkoxy radical, C_1-6Alkyl radical, C_2-6Alkenyl radical, C_2-6Alkynyl, C_3-10Cycloalkyl, heterocycloalkyl, aryl and heteroaryl are all optionally substituted with halogen (e.g., F, Cl, Br or I), nitro, cyano, amino, OH, CF₃、C_1-6Alkoxy radical, C_1-6Alkyl radical, C_2-6Alkenyl radical, C_2-6Alkynyl, C_3-10Cycloalkyl, heterocycloalkyl, aryl or heteroaryl.

Wherein R is₇Examples of the heteroaryl group include Andwherein R is₈Is H, halogen (e.g. F, Cl, Br or I), nitro, cyano, amino, OH, CF₃、-COOH、-COOC_1-6Alkyl radical, C_1-6Alkoxy radical, C_1-6Alkyl radical, C_2-6Alkenyl radical, C_2-6Alkynyl, C_3-10Cycloalkyl, heterocycloalkyl, aryl or heteroaryl, each C_1-6Alkoxy radical, C_1-6Alkyl radical, C_2-6Alkenyl radical, C_2-6Alkynyl, C_3-10Cycloalkyl, heterocycloalkyl, aryl and heteroaryl are all optionally substituted with halogen (e.g., F, Cl, Br or I), nitro, cyano, amino, OH, CF₃、C_1-6Alkoxy radical, C_1-6Alkyl radical, C_2-6Alkenyl radical, C_2-6Alkynyl, C_3-10Cycloalkyl, heterocycloalkyl, aryl or heteroaryl.

Wherein R is₇Included And

wherein R is₈Including H, F, Cl, CH₃、CF₃Ethyl, n-propyl, And

the above compounds can be divided into two subsets. In a subset, Y is CH₂And in another subset, Y is C ═ O. In each subset of features, the preferred compound is R₁Is H; x is C ═ O; r₂Is composed ofR₃、R₄、R₅And R₆Independently is H or F; r₇Is composed of Wherein R is₈Listed in the preceding paragraph. In particularly preferred compounds, R₇Also listed in the preceding paragraph.

As used herein, the term "alkyl" refers to a saturated, straight or branched hydrocarbon group, such as-CH₃or-CH (CH)₃)₂. The term "alkoxy" means an-O (C1-6 alkyl) radical, e.g. -OCH₃and-OCH (CH)₃)₂. The term "alkenyl" refers to a straight or branched hydrocarbon group containing at least one double bond, such as-CH ═ CH-CH₃. The term "alkynyl" refers to a straight or branched hydrocarbon group containing at least one reference bond, e.g., -C.ident.C-CH₃. The term "cycloalkyl" refers to a saturated mono-, di-, or paramethylcyclic hydrocarbon group, such as cyclohexyl. The term "heterocycloalkyl" refers to a saturated mono-, di-, or heterocyclic group having at least one ring heteroatom (e.g., N, O and S), such as 4-tetrahydropyran. The term "aryl" refers to a hydrocarbon group having one or more aromatic rings. Examples of the aryl group include phenyl, phenylene, naphthyl, naphthylene, pyrenyl, anthryl and phenanthrenyl. The term "heteroaryl" refers to a group having one or more aromatic rings containing at least one heteroatom (e.g., N, O and S), and examples of heteroaryl include furyl (furyl), furanyl (furylene), fluorenyl (fluoroenyl), pyrrolyl (pyrryl), thienyl (thienyl), oxazolyl (oxazolyl), imidazolyl (imidazoyl), thiazolyl (thiazoyl), pyridyl (pyridyl), pyrimidinyl (pyrimidinyl), quinazolinyl (quinazolyl), quinolyl (quinolyl), isoquinolyl (isoquinolyl), and indolyl (indolyl). The term "amino" refers to-NH₂A radical of formula (I), -NH (C1-6 alkyl) or-N (C1-6 alkyl) 2, e.g. -NHCH₃and-NHCH (CH)₃)₂。

Unless otherwise indicated, reference herein to alkoxy, alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl includes substituted and unsubstituted groups. Substituents on alkoxy, alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl include, but are not limited to, halogen, nitro, cyano, amino, OH, CF₃-COOH, -COOC1-6 alkyl, C1-6 alkoxy, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10 cycloalkyl, heterocycloalkyl, aryl or heteroaryl.

Where applicable, the compounds described above include the compounds themselves, as well as salts, prodrugs, stereoisomers and tautomers of the compounds. For example, a salt may be formed between an anion and a positively charged group (e.g., amine group) on a compound of formula (I). Suitable anions include chloride, bromide, iodide, sulfate, nitrate, phosphate, citrate, methanesulfonate, trifluoroacetate, acetate, malate, toluenesulfonate, tartrate, fumarate, glutaminate, glucuronate, lactate, glutarate and maleate. Likewise, salts may also be formed between a cation and a negatively charged group (e.g., carboxylate) on a compound of formula (I). Suitable cations include sodium, potassium, magnesium, calcium and ammonium cations such as tetramethylammonium. The compounds also include salts containing a quaternary nitrogen atom. Examples of prodrugs include esters and other pharmaceutically acceptable derivatives that are capable of providing the active compound upon administration to a subject. Stereoisomers of compounds of formula (I) may include cis and trans isomers, optical isomers such as (R) and (S) enantiomers, non-enantiomers, geometric isomers, rotational isomers, atropisomers, conformational isomers and mixtures of the foregoing isomers. Tautomers of such compounds include isomers that exhibit more than one type of isomerism.

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

The carrier in the pharmaceutical composition must be "acceptable" in that it is compatible with (and preferably capable of stabilizing) the active ingredient of the composition and not deleterious to the subject to be treated. Examples of carriers include colloidal silica, magnesium stearate, cellulose, sodium lauryl sulfate, and D & C yellow No. 10.

A method of treating AD or HD is also within the scope of the invention. The method comprises administering to a subject in need of treatment for alzheimer's disease or huntington's disease an effective amount of a compound of formula (I).

The term "treatment" refers to the administration or administration of the compound, or a salt, prodrug, stereoisomer, or tautomer of the compound, to an individual for the purpose of imparting a therapeutic effect, i.e., curing, alleviating, altering, affecting, ameliorating, or preventing AD or HD, symptoms of AD or HD, or a predisposition to AD or HD.

An "effective amount" is the amount of the compound or a salt, prodrug, stereoisomer, or tautomer of the compound that is required to impart the desired effect to the individual. As recognized by those of ordinary skill in the art, effective amounts vary depending on the route of administration, excipient usage, and the potential for co-usage with other therapeutically effective treatments (e.g., with other active agents).

Compositions having a compound of formula (I) or a salt, prodrug, stereoisomer or tautomer of the compound may be administered parenterally or orally. The term "parenteral" as used herein refers to subcutaneous, intradermal, intravenous, intraperitoneal, intramuscular, intraarticular, intraarterial, intrasynovial, intrasternal, intrathecal, intralesional or intracranial injection, as well as any suitable infusion 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, corn starch and the like. Lubricating agents, such as magnesium stearate, are also commonly added. For oral administration in capsule form, useful diluents include lactose and dried corn starch. When aqueous suspensions or emulsions are administered orally, the active ingredient may be suspended or dissolved in the oily 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 accompanying drawings and the description below. Other features, objects, and advantages of the invention will be apparent from the description and from the claims.

[ embodiment ] A method for producing a semiconductor device

The following are disclosed in detail as the benzimidazole compounds of formula (I) shown above.

The compounds of the invention having a chiral center may exist as stereoisomers. Stereoisomers of compounds of formula (I) may include cis and trans isomers, optical isomers such as (R) and (S) enantiomers, non-enantiomers, geometric isomers, rotamers, atropisomers, conformational isomers, and tautomers of such compounds, including compounds exhibiting more than one type of isomerism; and mixtures of the above isomers (e.g., mixtures of racemates and non-enantiomers). All such isomeric forms are contemplated. Furthermore, the compounds of formula (I) in the present invention may exhibit tautomerism.

Notably, the compounds of formula (I) may have an enantiomeric excess (enantiomeric excesses) of 90% or more (e.g.. gtoreq.95% and. gtoreq.99%).

Table 1 below shows 117 exemplary compounds of formula (I):

TABLE 1

Of the 117 compounds listed above, compound 9 and compound 10 are the two enantiomers of compound 8; compound 33 and compound 34 are the two enantiomers of compound 13; compound 35 and compound 36 are the two enantiomers of compound 16; compound 53 and compound 54 are the two enantiomers of compound 25; furthermore, compound 55 and compound 56 are two enantiomers of compound 28.

Compound 9, compound 34, compound 36, compound 54, and compound 56 are preferred.

Methods for synthesizing compounds of formula (I) are well known in the art. It is noted that the procedure for the preparation of up to 67 compounds (i.e., compounds 1-67) is illustrated in example 1 below.

The compounds so prepared can first be screened for efficacy in inhibiting the activity of the enzyme putaminyl cyclase (QC) using an in vitro assay. In vitro assays are illustrated in example 2 below. In addition, the compounds prepared can then be evaluated using in vivo assays. The in vivo assay is illustrated in example 3 below. Selected compounds may be further tested to verify the efficacy of the compounds in treating AD or HD. Based on the results obtained, the appropriate dosage range and administration route can be studied and determined.

All reagents and solvents were purchased from commercial suppliers and no further purification was required unless otherwise indicated. All anhydrous reactions were carried out under nitrogen atmosphere using dry solvents. All reactions were monitored by thin layer chromatography using a Merck Silica gel 60F254 glass back plate. Column chromatography was performed on Merck silica gel 60(0.040-0.063mm, 230-. The purity of the final compound was determined on a Hitachi 2000 series HPLC system operating at 25 ℃ with a reverse phase C18 column (Agilent ZORBAX eclipse XDB-C185 μm, 4.6 mm. times.150 mm). Mobile phase a was acetonitrile. Mobile phase B was 10mM NH4OAc in water containing 0.1% formic acid. The gradient system started from A/B (10%/90%) at 0 min and reached A/B (90%/10%) at 45 min. The flow rate of the mobile phase is0.5mL/min, the injection volume of the sample was 5. mu.L. The peak was detected at 254 nm. Purity of all test compounds>95 percent. LC/MS data were measured on an Agilent MSD-1100ESI-MS/MS system. All compounds tested were tested at UV254nm unless otherwise stated. The measurement was performed by VarianMercury-300 and VarianMercury-400 spectrometers¹H NMR spectrum and chemical shifts (δ) are reported in parts per million (ppm) relative to the resonance of the solvent peak. Multiplicity is described using the following abbreviations: s (singlet), d (doublet), t (triplet), q (quartet), quin (quintet), m (multiplet) or br (broad).

Without further elaboration, it is believed that one skilled in the art can, based on the description above, utilize the present invention to its fullest extent. Accordingly, the specific examples described in examples 1-3 below are to be construed as merely illustrative, and not limitative of the remainder of the disclosure in any way whatsoever. All publications cited herein are incorporated by reference.

Example 1: preparation and characterization of Compounds

Compounds 1-67 were prepared by synthetic methods 1-18 shown in schemes 1-18 below, respectively.

Synthesis method 1

Compounds 1-4, each having a 1, 3-thiazol-2-yl ring, were prepared according to the synthetic procedure shown in scheme 1 below. Coupling of (4-formylphenyl) boronic acid 118 with 2-bromothiazole derivatives 119a-d under Suzuki-coupling conditions affords 4- (1, 3-thiazol-2-yl) benzaldehyde derivatives 120 a-d. 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 1H-benzimidazol-5-amine 121 in acetic acid. The reaction mixture was stirred at room temperature for 2 hours and then treated to give aminoacetonitrile 122a-d, which was hydrogenated in acetic acid using raney nickel (raney nickel) catalyst at 5-10 ℃ to give diamine 123 a-d. In the final step, 1' -Carbonyldiimidazole (CDI) was added to a solution of diamines 123a-d in THF, followed by stirring at 75 deg.C for 18 hours. Purifying by column chromatography to obtain compounds 1-4.

Scheme 1

Synthesis method 2

One precursor, 4- (2-cyclopropyl-1, 3-thiazol-4-yl) benzaldehyde 127, was synthesized under two different suzuki coupling conditions as shown in scheme 2 below. The starting material 2, 4-dibromo-1, 3-thiazole 124 was selectively coupled at the 2-position with cyclopropylboronic acid 125 using pd (oac)2 as a catalyst. The resulting product 126 was coupled at the 4-position with (4-formylphenyl) boronic acid 118 using pd (dppf) Cl2 as a catalyst to give precursor 127 having a 1, 3-thiazol-4-yl ring. This precursor was then applied to the procedure shown in synthesis method 1 to form the imidazolidinone to give the final compound (compound 5).

Scheme 2

Synthesis method 3

Compounds 6-8, each having a 3-thiazol-5-yl ring, were prepared in eight steps as shown in scheme 3 below. After the substitution reaction using HMTA and then refluxing in an ethanol solution of hydrochloric acid, the commercially available starting material, 4- (bromoacetyl) -benzonitrile 130, is converted to 4- (aminoacetyl) benzonitrile hydrochloride 131. Compound 131 is then acetylated with a variable anhydride 132a-c to give amide 133a-c, followed by treatment with Lawson's reagent at reflux in THF or toluene to give (1, 3-thiazol-5-yl) benzonitrile analog 134 a-c. Benzonitrile analogs 134a-c are reduced by DIBAL-H to form benzaldehyde precursors 135 a-c. These precursors were then applied to the procedure shown in synthesis method 1 to form the imidazolidinone to give compounds 6-8.

Scheme 3

Synthesis method 4

Compounds 11 and 29-32, each having a thiophen-2-yl ring, were prepared by the synthetic procedure shown in scheme 4 below. Under Suzuki coupling conditions, 4-bromobenzaldehyde 138a-d is coupled with 2-substituted thiophene 139a or 139b, respectively, to give benzaldehyde precursors 140 a-e. These precursors were then applied to the procedure shown in synthesis method 1 to form the imidazolidinone, giving compounds 11 and 29-32.

Scheme 4

Synthesis method 5

Compound 12 having a thiophen-2-yl ring was prepared by the synthetic procedure shown in scheme 5. 4-acetylbenzonitrile 143 was subjected to alpha-methylation in Dimethylacetamide (DMA) using FeCl3.6H2O and K2S2O 8. The resulting α -methylene product 144 is reacted with cyclopropanecarboxaldehyde under Stetter conditions to form 1, 4-dicarbonyl compound 146. The dicarbonyl compound is then treated with lawson's reagent in toluene at reflux to give 4- (5-cyclopropylthiophen-2-yl) benzonitrile 147, and the 4- (5-cyclopropylthiophen-2-yl) benzonitrile 147 is reduced with DABAL-H to form benzaldehyde precursor 148. This precursor was then applied to the procedure shown in synthesis method 1 to form the imidazolidinone to give compound 12.

Scheme 5

Synthesis method 6

Compounds 13 and 22-24, each having a thiophen-2-yl ring, were prepared by the synthetic procedure shown in scheme 6. 4-bromobenzaldehyde 138a-d was each coupled with thiophene under two different Suzuki coupling conditions to form 4- (thiophen-2-yl) -benzaldehyde 152 a-d. Benzaldehyde is iodinated via N-iodosuccinimide (NIS) to produce iodinated products 153a-d, which iodinated products 153a-d are trifluoromethylated using difluoro- (fluoro-sulfonyl) acetic acid methyl ester 154 and copper iodide to give precursors 155 a-d. These precursors were then applied to the procedure shown in synthesis method 1 to form the imidazolidinone, giving compounds 13 and 22-24.

Scheme 6

Synthesis method 7

Compounds 14-16 and 25-28, each having a thiophen-3-yl ring, were prepared by the synthetic procedure shown in scheme 7. Various (4-formylphenyl) boronic acids were coupled with 3-bromothiophene derivatives 158a-c under Suzuki-Miyaura coupling conditions. The resulting products 159a-g were then applied to the procedure outlined in synthetic method 1 to form the imidazolidinones to give compounds 14-16 and 25-28.

Scheme 7

Synthesis method 8

Compound 17 having a thiophen-3-yl ring was prepared by the synthetic procedure shown in scheme 8 below. The starting material 159a is selectively brominated with bromine or NBS in acetic acid to yield a 2-brominated thiophene product 162, which 2-brominated thiophene product 162 is coupled with cyclopropyl-boronic acid under suzuki coupling conditions to form 4- (2-cyclopropyl-thiophen-3-yl) benzaldehyde 163. This benzaldehyde was then applied to the procedure shown in synthetic method 1 to form the imidazolidinone to give compound 17.

Scheme 8

Synthesis method 9

Compound 18 having a 1,2, 4-oxadiazol-3-yl ring is prepared by the synthetic procedure outlined in scheme 9. Starting material 4-formylbenzonitrile 166 is protected by monoethylene glycol (MEG) to form acetal 167, and the acetal 167 is reacted with hydroxylamine hydrochloride to give amidoxime 168. The amidoxime is acetylated with cyclopropanecarbonyl chloride and then refluxed in toluene to form 1,2, 4-oxadiazole 170, which is deprotected under acidic conditions. The resulting product 171 was reacted with TMSCN and 1H-benzimidazol-5-amine 121 in acetic acid for 2 hours at room temperature and then worked up to give aminoacetonitrile 172. The aminoacetonitrile was hydrogenated with Pd/C catalyst overnight at room temperature in acetic acid to give diamine 173. In the final step, 1' -carbonyldiimidazole was added to a solution of diamine 173 in THF, followed by stirring at 75 ℃ for 18 hours. After purification by column chromatography, compound 18 is finally obtained.

Scheme 9

Synthesis method 10

Compound 19, having a 1, 2-oxazol-3-yl ring, was prepared by the synthetic procedure shown in scheme 10. The starting material cyclopropanecarboxaldehyde 174 is reacted with hydroxylamine hydrochloride to give oxime 175 which is treated first with N-chlorosuccinimide (NCS) and then at room temperature with 4-ethynylbenzaldehyde 176 in DMF to form the 1, 2-oxazole precursor 177. This precursor was then applied to the procedure shown in synthesis method 9 to form the imidazolidinone to give compound 19.

Scheme 10

Synthesis method 11

Compounds 20 and 21, each having a 2H-tetrazol-5-yl ring, were prepared by the synthetic procedure shown in scheme 11. Starting material 4-formylbenzonitrile 166 is reacted at reflux with sodium azide and ammonium chloride in DMF to form tetrazole compound 180, and tetrazole compound 180 is substituted with variable alkyl halides to give precursors 181 a-b. These precursors were then applied to the procedure shown in synthesis method 9 to form imidazolidinone, giving compounds 20 and 21.

Scheme 11

Synthesis method 12

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

Scheme 12

Synthesis method 13

Compound 38 having a 1, 3-thiazol-4-yl ring was prepared by the synthetic procedure shown in scheme 13. Intermediate 4-bromo-2-cyclopropyl-1, 3-thiazole 126, prepared according to synthesis method 2, was coupled with (4-acetylphenyl) boronic acid 184 under suzuki coupling conditions. The resulting coupling product 188 is oxidized to glyoxal 189 using selenium dioxide. Compound 38 is formed from glyoxal 189 and benzimidazolyl urea 187 via a cycloaddition reaction. The procedure was the same as that shown in synthesis method 12.

Scheme 13

Synthesis method 14

Compounds 39 and 40, each having a 1, 3-thiazol-5-yl ring, were prepared by the synthetic procedure shown in scheme 14. Intermediate 1, 3-thiazol-5-yl benzonitrile 134b-c prepared according to Synthesis method 3 was acetylated with methylmagnesium bromide. The acetyl product 190b-c obtained is oxidized to glyoxal 191b-c with selenium dioxide. Compounds 39 and 40 are formed from glyoxal 191b-c and benzimidazolyl urea 187 via a cycloaddition reaction. The procedure was the same as that shown in synthesis method 12.

Scheme 14

Synthesis method 15

Compounds 41-52, each having a 2H-tetrazol-5-yl ring, were prepared by the synthetic procedure shown in scheme 15. Starting material 143 is reacted with sodium azide and ammonium chloride in DMF at reflux to form tetrazole 192, which tetrazole 192 is substituted with a variable alkyl halide to provide precursor 193 a-1. These precursors were then applied to the procedure shown in synthesis 12 to form hydantoins, giving compounds 41-52.

Scheme 15

Synthesis method 16

Compound 57 having a 1, 3-thiazol-5-yl ring was prepared by the synthetic procedure shown in scheme 16. The starting material 131 was acetylated with adamantane-1-carbonyl chloride 195 to give amide 196. Subsequently, amide 196 was mixed with lawson's reagent in THF at reflux to give (1, 3-thiazol-5-yl) -benzonitrile 197, and (1, 3-thiazol-5-yl) -benzonitrile 197 was reduced with DIBAL-H to form benzaldehyde 198. Benzaldehyde 198 was then applied to the procedure shown in synthetic method 1 to form the imidazolidinone to give compound 57.

Scheme 16

Synthesis method 17

Compounds 58-65, each having a thiophen-3-yl ring, were prepared by the synthetic procedure shown in scheme 17. 118g of 2, 3-difluoro-4-formylphenylboronic acid was coupled with 3-bromothiophene derivatives 158a-b and 158d-i under Suzuki-Miyaura coupling conditions. The resulting products 201a-h were then applied to the procedure shown in synthetic method 1 to form imidazolidinones to give compounds 58-65.

Scheme 17

Synthesis method 18

Compound 66 is prepared by the hydrolysis of compound 64 in methanolic potassium hydroxide solution, shown in scheme 18. Compound 67 was prepared by reduction of compound 64 with LAH in dry THF, also shown in the scheme.

Scheme 18

The following are detailed procedures for preparing compounds 1-67 according to the above-described synthetic methods 1-18 and analytical data for intermediates and final products produced in the procedures.

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

(4-formylphenyl) boronic acid 118(0.30g, 2.0mmol), 2-bromo-1, 3-thiazole 119a (0.33g, 2.0mmol), Pd (PPh) under nitrogen₃)4(0.12g, 0.1mmol), aqueous potassium carbonate (0.4M, 5mL), ethanol (5mL) and toluene (2mL) were added to a 50mL flask. The reaction mixture was stirred at 115 ℃ for 24 hours and then cooled to room temperature. After removal of the solvent, the crude residue was purified by silica gel column chromatography using EA/hexane (1/5) as eluent. Product 120a was obtained as a white solid in 95% yield.

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

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

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

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

4. 4- [4- (trifluoromethyl) -1, 3-thiazol-2-yl ] benzaldehyde (Compound 120d)

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

5. (1H-benzimidazol-5-ylamino) [4- (1, 3-thiazol-2-yl) phenyl ] acetonitrile (Compound 122a)

Compound 120a (1.06g, 5.62mmol) was added to a solution of 1H-benzoimidazol-5-amine 121(0.68g, 5.11mmol) in acetic acid (20mL) and stirred at room temperature for 20 min. TMSCN (1mL) was added dropwise to the reaction mixture and stirring continued for 2 h. 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 (10mL) and water. The diluted solution was adjusted to pH 6-7 with ammonia under ice bath. The neutralized solution was extracted with ethyl acetate (20mL × 4), dried over sodium sulfate, filtered and concentrated under reduced pressure to give a thick dark yellow solid. The solid was dissolved in ethyl acetate (15mL) and brine (15 mL). The mixture was stirred at room temperature for 2 minutes, forming a pale yellow precipitate. The light yellow precipitate was filtered 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 solids were combined to the desired product 122a in 96% yield.

6. (1H-benzimidazol-5-ylamino) [4- (4-methyl-1, 3-thiazol-2-yl) phenyl ] acetonitrile (Compound 122b)

(1H-benzimidazol-5-ylamino) [4- (4-methyl-1, 3-thiazol-2-yl) phenyl ] acetonitrile 122b was prepared by adding 1H-benzimidazol-5-ylamino 121, TMSCN and compound 120 b. The procedure was the same as for the synthesis of compound 122 a. Product 122b was obtained as a pale yellow solid in 97% yield.

7. (1H-benzimidazol-5-ylamino) [4- (4-cyclopropyl-1, 3-thiazol-2-yl) phenyl ] acetonitrile (Compound 122c)

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

8. (1H-benzimidazol-5-ylamino) {4- [4- (trifluoromethyl) -1, 3-thiazol-2-yl ] phenyl } acetonitrile (Compound 122d)

(1H-benzimidazol-5-ylamino) {4- [4- (trifluoromethyl) -1, 3-thiazol-2-yl ] phenyl } -acetonitrile 122d was prepared by adding 1H-benzimidazol-5-amine 121, TMSCN and compound 120 d. The procedure was the same as for the synthesis of compound 122 a. Product 122d was obtained as a pale yellow solid in 96% yield.

9. N1- (1H-Benzimidazol-5-yl) -1- [4- (1, 3-thiazol-2-yl) phenyl ] ethane-1, 2-diamine (Compound 123a)

Compound 122a (5.0g, 15.08mmol) was dissolved in acetic acid (200mL) and then stirred at 10 ℃ for 5 minutes. The raney nickel reagent was added to the stirred solution and refilled with hydrogen three times. The reaction mixture was stirred at 10 ℃ under hydrogen 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 product was purified by silica gel column chromatography using methanol/dichloromethane (1/19) as eluent. Product 123a was obtained as a yellow viscous liquid in 60% yield.

10. N1- (1H-Benzimidazol-5-yl) -1- [4- (4-methyl-1, 3-thiazol-2-yl) phenyl ] ethane-1, 2-diamine (Compound 123b)

Hydrogenation of compound 122b using raney nickel reagent as a catalyst produced N1- (1H-benzoimidazol-5-yl) -1- [4- (4-methyl-1, 3-thiazol-2-yl) phenyl ] ethane-1, 2-diamine 123 b. The procedure was the same as for the synthesis of compound 123 a. Product 123b was obtained as a yellow viscous liquid in 50% yield.

11. N1- (1H-Benzimidazol-5-yl) -1- [4- (4-cyclopropyl-1, 3-thiazol-2-yl) phenyl ] ethane-1, 2-diamine (Compound 123c)

Compound 122c was hydrogenated using raney nickel reagent as a catalyst to produce N1- (1H-benzoimidazol-5-yl) -1- [4- (4-cyclopropyl-1, 3-thiazol-2-yl) phenyl ] ethane-1, 2-diamine 123 c. The procedure was the same as for the synthesis of compound 123 a. Product 123c was obtained as a yellow viscous liquid in 54% yield.

12. N1- (1H-Benzimidazol-5-yl) -1- {4- [4- (trifluoromethyl) -1, 3-thiazol-2-yl ] phenyl } ethane-1, 2-diamine (Compound 123d)

Hydrogenation of compound 122d using raney nickel reagent as a catalyst produced N1- (1H-benzoimidazol-5-yl) -1- {4- [4- (trifluoromethyl) -1, 3-thiazol-2-yl ] phenyl } ethane-1, 2-diamine 123 d. The procedure was the same as for the synthesis of compound 123 a. Product 123d was obtained as a yellow viscous liquid in 40% yield.

13. 1- (1H-benzimidazol-5-yl) -5- [4- (1, 3-thiazol-2-yl) phenyl ] imidazolidin-2-one (Compound 1)

A solution of compound 123a (4.56g, 13.6mmol) in dry THF (100mL) was added dropwise to a solution of 1,1' -carbonyldiimidazole (2.21g, 20.5mmol) and trimethylamine (7.5mL) in dry THF (100mL) at room temperature via an additional funnel. The resulting mixture was heated to 75 ℃ and stirred for 18 hours. After cooling to room temperature, the reaction mixture was concentrated under reduced pressure. The crude residue was purified by silica gel column chromatography using methanol/dichloromethane (1/19) as eluent. The product (compound 1) was obtained as a white solid in 70% yield.¹HNMR(400MHz,CD3OD)δ3.39(dd,1H,J＝7.0,9.2Hz),4.02(dd,1H,J＝9.2,9.2Hz),5.55(dd,1H,J＝7.0,9.2Hz),7.31(d,1H,J＝8.8Hz),7.48(d,1H,J＝8.8Hz),7.52(d,2H,J＝8.2Hz),7.56(s,1H),7.57(s,1H),7.82(d,1H,J＝3.6Hz),7.88(d,2H,J＝8.2Hz),8.06(s,1H)；LC/MS(ESI)m/z:362.1[M+H]⁺。

14. 1- (1H-benzimidazol-5-yl) -5- [4- (4-methyl-1, 3-thiazol-2-yl) phenyl ] imidazolidin-2-one (Compound 2)

Preparation of 1- (1H-benzimidazol-5-yl) -5- [4- (4-methyl-1, 3-thiazol-2-yl) phenyl from the cycloaddition reaction of 1,1' -carbonyldiimidazole and the Compound 123b]Imidazolidin-2-one (Compound 2). The procedure was the same as for the synthesis of compound 1. The product (compound 2) was obtained as a white solid in 66% yield.¹HNMR(400MHz,DMSO-d₆)δ2.37(s,3H),3.13(dd,1H,J＝6.6,8.8Hz),3.87(dd,1H,J＝8.8,9.2Hz),5.58(dd,1H,J＝6.6,9.2Hz),7.01(s,1H),,7.27(s,2H),7.40(s,1H),7.46(d,2H,J＝8.2Hz),7.57(s,1H),7.83(d,2H,J＝8.2Hz),8.07(s,1H)；LC/MS(ESI)m/z:376.2[M+H]⁺。

15. 1- (1H-benzimidazol-5-yl) -5- [4- (4-cyclopropyl-1, 3-thiazol-2-yl) phenyl ] imidazolidin-2-one (Compound 3)

Preparation of 1- (1H-benzimidazol-5-yl) -5- [4- (4-cyclopropyl-1, 3-thiazol-2-yl) phenyl from the cycloaddition reaction of 1,1' -carbonyldiimidazole and the Compound 123c]Imidazolidin-2-one (Compound 3). The procedure was the same as for the synthesis of compound 1. The product (compound 3) was obtained as a white solid in 71% yield.¹HNMR(400MHz,DMSO-d₆)δ0.80-0.84(m,2H),0.85-0.90(m,2H),2.05-2.09(m,1H),3.12(dd,1H,J＝6.4,8.8Hz),3.87(dd,1H,J＝8.8,9.2Hz),5.57(dd,1H,J＝6.4,9.2Hz),7.02(s,1H),7.26(s,2H),7.39(d,1H,J＝8.4Hz),7.45(d,2H,J＝7.8Hz),7.55(s,1H),7.79(d,2H,J＝7.8Hz),8.07(s,1H),12.27(s,1H)；LC/MS(ESI)m/z:402.2[M+H]⁺。

16. 1- (1H-Benzoimidazol-5-yl) -5- {4- [4- (trifluoromethyl) -1, 3-thiazol-2-yl ] phenyl } imidazolidin-2-one (Compound 4)

Preparation of 1- (1H-Benzimidazol-5-yl) -5- {4- [4- (trifluoromethyl) -1, 3-thiazol-2-yl ] by cycloaddition of carbonyldiimidazole and Compound 123d]Phenyl } imidazolidin-2-one (Compound 4). The procedure was the same as for the synthesis of compound 1. The product (compound 4) was obtained as a white solid in 67% yield.¹H NMR(300MHz,DMSO-d₆)δ3.14(dd,1H,J＝6.3,8.7Hz),3.89(dd,1H,J＝8.7,9.0Hz),5.62(dd,1H,J＝6.3,9.0Hz),7.02(d,1H,J＝8.7Hz),7.28(s,1H),7.40(d,1H,J＝8.7Hz),7.52(d,2H,J＝8.1Hz),7.57(s,1H),7.92(d,2H,J＝8.1Hz),8.08(s,1H),8.50(s,1H),12.21(s,1H)；LC/MS(ESI)m/z:430.2[M+H]⁺。

17. 4-bromo-2-cyclopropyl-1, 3-thiazole (Compound 126)

Palladium acetate (0.025g, 0.11mmol) and 4, 5-bis-diphenylphosphine-9, 9-dimethylxanthene (Xantphos, 0.066g, 0.11mmol) were added to THF (22mL) and degassed under argon. Then, the reaction mixture was stirred at room temperature for 5 minutes. 2, 4-dibromo-1, 3-thiazole 124(1.09g, 4.50mmol), cyclopropylboronic acid 125(0.58g, 6.70mmol) and potassium phosphate (2.86g) were added to the reaction mixture and purged with argon. The reaction mixture was stirred at 70 ℃ for 15 hours. After cooling to room temperature, the reaction mixture was filtered and washed with dichloromethane. The filtrate was concentrated under reduced pressure and purified by silica gel column chromatography using hexane as the eluent. Product 126 was obtained as a colorless oil in 81% yield.

18. 4- (2-cyclopropyl-1, 3-thiazol-4-yl) benzaldehyde (Compound 127)

(4-formylphenyl) boronic acid 118(0.33g, 2.2mmol), 4-bromo-2-cyclopropyl-1, 3-thiazole 126(0.41g, 2.0mmol), Pd (dppf) Cl2(0.08g, 0.1mmol), potassium carbonate (0.41g) and 1, 2-dimethoxyethane were reacted under nitrogen(20mL) was added to a 50mL round bottom flask. The reaction mixture was stirred at 80 ℃ for 16 hours and 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 silica gel column chromatography using hexane/diethyl ether (10/1) as eluent. Product 127 was obtained as a white solid in 55% yield.¹HNMR(300MHz,CDCl3)δ1.10-1.16(m,4H),2.32-2.39(m,1H),7.40(s,1H),7.89(d,2H,J＝8.4Hz),8.03(d,2H,J＝8.4Hz),10.01(s,1H)；LC/MS(ESI)m/z:230.1[M+H]⁺。

19. (1H-benzimidazol-5-ylamino) [4- (2-cyclopropyl-1, 3-thiazol-4-yl) phenyl ] acetonitrile (Compound 128)

(1H-benzimidazol-5-ylamino) [4- (2-cyclopropyl-1, 3-thiazol-4-yl) phenyl ] acetonitrile 128 is prepared by adding 1H-benzimidazol-5-amine 121, TMSCN and compound 127. The procedure was the same as for the synthesis of compound 122 a. Product 128 was obtained as a pale yellow solid in 93% yield.

20. N1- (1H-Benzimidazol-5-yl) -1- [4- (2-cyclopropyl-1, 3-thiazol-4-yl) phenyl ] ethane-1, 2-diamine (Compound 129)

Hydrogenation of compound 128 using raney nickel reagent as a catalyst produced N1- (1H-benzoimidazol-5-yl) -1- [4- (2-cyclopropyl-1, 3-thiazol-4-yl) phenyl ] ethane-1, 2-diamine 129. The procedure was the same as for the synthesis of compound 123 a. Product 129 was obtained as a yellow viscous liquid in 52% yield.

21. 1- (1H-benzimidazol-5-yl) -5- [4- (2-cyclopropyl-1, 3-thiazol-4-yl) phenyl ] imidazolidin-2-one (Compound 5)

Preparation of 1- (1H-benzimidazol-5-yl) -5- [4- (2-cyclopropyl-1, 3-thiazol-4-yl) phenyl from the cycloaddition reaction of 1,1' -carbonyldiimidazole and product (129)]Imidazolidin-2-one (Compound 5). The procedure was the same as for the synthesis of compound 1. The product (compound 5) was obtained as a white solid in 73% yield.¹HNMR(300MHz,DMSO-d₆)δ0.93-0.98(m,2H),1.08-1.16(m,2H),2.34-2.42(m,1H),3.13(dd,1H,J＝6.6,9.0Hz),3.85(dd,1H,J＝8.7,9.0Hz),5.52(dd,1H,J＝6.6,8.7Hz),6.98(s,1H),7.25(d,1H,J＝8.1Hz),7.37-7.40(m,3H),7.54(s,1H),7.72(s,1H),7.80(d,2H,J＝8.1Hz),8.07(s,1H),12.24(s,1H)；LC/MS(ESI)m/z:402.2[M+H]⁺。

22. 4-Glycimidobenzonitrile hydrochloride (Compound 131)

4- (Bromoacetyl) benzonitrile 130(22.4g, 100mmol) and hexamethylenetetramine (HMTA, 15.4g, 110mmol) were dissolved in chloroform (900 mL). The reaction mixture was stirred at room temperature overnight. The precipitate was filtered and washed with ethanol and diethyl ether. The resulting solid was suspended in a mixture of HCl/ethanol (48mL/240mL) and then stirred at 75 ℃ overnight. The precipitate was filtered while the solution was still warm. The filtrate was concentrated to remove the solvent. Some acetone (100mL) was added and stirred for 1 hour. The precipitate was filtered and washed with acetone and diethyl ether. Product 131 was obtained as an off-white solid in quantum yield without further purification.¹HNMR(300MHz,DMSO-d₆)δ4.62(s,2H),8.06(d,2H,J＝8.4Hz),8.16(d,2H,J＝8.4Hz),8.59(s,2H)；LC/MS(ESI)m/z:161.1[M+H]⁺。

23. N- [2- (4-cyanophenyl) -2-oxoethyl ] acetamide (Compound 133a)

Triethylamine (21mL) was added to a suspension of compound 131(10g, 50.85mmol) in dichloromethane (330mL) and stirred at room temperature for 10 min. Acetic anhydride (7.79g, 76.28mmol) was diluted in dichloromethane (20mL) and then added to the reaction solution over 30 minutes through an additional funnel under ice bath. The resulting mixture was stirred continuously at room temperature for 1 hour. 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 silica gel column chromatography using ethyl acetate/hexane (1/2) as eluent. Product 133a was obtained as a yellow solid in 70% yield.

24. N- [2- (4-cyanophenyl) -2-oxoethyl ] cyclopropanecarboxamide (Compound 133b)

Preparation of N- [2- (4-cyanophenyl) -2-oxoethyl by acetylation of Compound 131 with cyclopropanecarboxylic anhydride 132b]Cyclopropanecarboxamide 133 b. The procedure was the same as for the synthesis of compound 133 a. Product 133b was obtained as a yellow solid in 73% yield.¹H NMR(400MHz,DMSO-d₆)δ0.65-0.68(m,4H),1.70(m,1H),4.64(d,2H,J＝5.4Hz),8.01(d,2H,J＝8.4Hz),8.10(d,2H,J＝8.4Hz),8.51(t,1H,d,J＝5.4Hz)；LC/MS(ESI)m/z:229.1[M+H]⁺。

25. N- [2- (4-cyanophenyl) -2-oxoethyl ] -2,2, 2-trifluoroacetamide (compound 133c)

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

26. 4- (2-methyl-1, 3-thiazol-5-yl) benzonitrile (Compound 134a)

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

27. 4- (2-cyclopropyl-1, 3-thiazol-5-yl) benzonitrile (Compound 134b)

Cyclization of compound 133b with lawson's reagent in THF produces 4- (2-cyclopropyl-1, 3-thiazol-5-yl) benzonitrile 134 b. The procedure was the same as for the synthesis of compound 134 a. Product 134b was obtained as a yellow solid in 67% yield.¹HNMR(300MHz,CDCl3)δ1.10-1.21(m,4H),2.31-2.35(m,1H),7.59(d,2H,J＝8.4Hz),7.66(d,2H,J＝8.4Hz),7.84(s,1H)；LC/MS(ESI)m/z:227.1[M+H]⁺。

28. 4- [2- (trifluoromethyl) -1, 3-thiazol-5-yl ] benzonitrile (compound 134c)

Preparation of 4- [2- (trifluoromethyl) -1, 3-thiazol-5-yl radical by cyclization of compound 133c with Lawson's reagent in toluene]Benzonitrile 134 c. The procedure was the same as for the synthesis of compound 134 a. Product 134c was obtained as a yellow solid in 65% yield.¹HNMR(400MHz,CDCl3)δ7.68(d,2H,J＝8.8Hz),7.74(d,2H,J＝8.8Hz),8.15(s,1H)；LC/MS(ESI)m/z:255.1[M+H]⁺。

29. 4- (2-methyl-1, 3-thiazol-5-yl) benzaldehyde (Compound 135a)

A solution of DIBAL-H in toluene (1.2M, 13.1mL) was added dropwise to a solution of compound 134a (1.57g, 7.86mmol) in dry toluene (100mL) cooled at-70 ℃ using an additional funnel. The reaction mixture was stirred at-70 ℃ under argon for 1 hour and then quenched with 1N HCl (aq) (20 mL). The reaction mixture was stirred continuously 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 silica gel column chromatography using ethyl acetate/hexane (1/5) as eluent. Product 135a was obtained as a yellow solid in 63% yield.

30. 4- (2-cyclopropyl-1, 3-thiazol-5-yl) benzaldehyde (Compound 135b)

Compound 134b is reduced with DIBAL-H reagent to produce 4- (2-cyclopropyl-1, 3-thiazol-5-yl) benzaldehyde 135 b. The procedure was the same as for the synthesis of compound 135 a. Product 135b was obtained as a yellow solid in 66% yield.¹HNMR(300MHz,CDCl3)δ1.13-1.20(m,4H),2.31-2.35(m,1H),7.65(d,2H,J＝6.9Hz),7.87-7.89(m,3H),9.99(s,1H)；LC/MS(ESI)m/z:230.1[M+H]⁺。

31. 4- [2- (trifluoromethyl) -1, 3-thiazol-5-yl ] benzaldehyde (Compound 135c)

Compound 134c was reduced with DIBAL-H reagent to prepare 4- [2- (trifluoromethyl) -1, 3-thiazol-5-yl ] benzaldehyde 135 c. The procedure was the same as for the synthesis of compound 135 a. Product 135c was obtained as a yellow solid in 65% yield.

32. (1H-benzimidazol-5-ylamino) [4- (2-methyl-1, 3-thiazol-5-yl) phenyl ] acetonitrile (Compound 136a)

(1H-benzimidazol-5-ylamino) [4- (2-methyl-1, 3-thiazol-5-yl) phenyl ] acetonitrile 136a was prepared by adding 1H-benzimidazol-5-amine 121, TMSCN and compound 135 a. The procedure was the same as for the synthesis of compound 122 a. Product 136a was obtained as a pale yellow solid in 90% yield.

33. (1H-benzimidazol-5-ylamino) [4- (2-cyclopropyl-1, 3-thiazol-5-yl) phenyl ] acetonitrile (Compound 136b)

(1H-benzimidazol-5-ylamino) [4- (2-cyclopropyl-1, 3-thiazol-5-yl) phenyl ] acetonitrile 136b was prepared by adding 1H-benzimidazol-5-amine 121, TMSCN and compound 135 b. The procedure was the same as for the synthesis of compound 122 a. Product 136b was obtained as a pale yellow solid in 92% yield.

34. (1H-benzimidazol-5-ylamino) {4- [2- (trifluoromethyl) -1, 3-thiazol-5-yl ] phenyl } acetonitrile (Compound 136c)

(1H-benzimidazol-5-ylamino) {4- [2- (trifluoromethyl) -1, 3-thiazol-5-yl ] phenyl } -acetonitrile 136c was prepared by the addition of 1H-benzimidazol-5-amine 121, TMSCN and compound 135 c. The procedure was the same as for the synthesis of compound 122 a. Product 136c was obtained as a pale yellow solid in 90% yield.

35. N1- (1H-Benzimidazol-5-yl) -1- [4- (2-methyl-1, 3-thiazol-5-yl) phenyl ] ethane-1, 2-diamine (Compound 137a)

Hydrogenation of compound 136a using raney nickel reagent as a catalyst produced N1- (1H-benzoimidazol-5-yl) -1- [4- (2-methyl-1, 3-thiazol-5-yl) phenyl ] ethane-1, 2-diamine 137 a. The procedure was the same as for the synthesis of compound 123 a. Product 137a was obtained as a yellow viscous liquid in 50% yield.

36. N1- (1H-Benzimidazol-5-yl) -1- [4- (2-cyclopropyl-1, 3-thiazol-5-yl) phenyl ] ethane-1, 2-diamine (Compound 137b)

Hydrogenation of compound 136a using raney nickel reagent as a catalyst produced N1- (1H-benzoimidazol-5-yl) -1- [4- (2-cyclopropyl-1, 3-thiazol-5-yl) phenyl ] ethane-1, 2-diamine 137 b. The procedure was the same as for the synthesis of compound 123 a. Product 137b was obtained as a yellow viscous liquid in 54% yield.

37. N1- (1H-Benzimidazol-5-yl) -1- {4- [2- (trifluoromethyl) -1, 3-thiazol-5-yl ] phenyl } ethane-1, 2-diamine (Compound 137c)

Hydrogenation of compound 136a using raney nickel reagent as a catalyst produced N1- (1H-benzoimidazol-5-yl) -1- {4- [2- (trifluoromethyl) -1, 3-thiazol-5-yl ] phenyl } ethane-1, 2-diamine 137 c. The procedure was the same as for the synthesis of compound 123 a. Product 137c was obtained as a yellow viscous liquid in 50% yield.

38. 1- (1H-benzimidazol-5-yl) -5- [4- (2-methyl-1, 3-thiazol-5-yl) phenyl ] imidazolidin-2-one (Compound 6)

Preparation of 1- (1H-benzimidazol-5-yl) -5- [4- (2-methyl-1, 3-thiazol-5-yl) phenyl from the cycloaddition reaction of 1,1' -carbonyldiimidazole and the Compound 137a]Imidazolidin-2-one (Compound 6). The procedure was the same as for the synthesis of compound 1. The product (compound 6) was obtained as a white solid in 71% yield.¹HNMR(400MHz,CD3OD)δ2.64(s,3H),3.30-3.36(m,1H),3.97(dd,1H,J＝8.6,9.2Hz),5.48(dd,1H,J＝7.6,8.6Hz),7.29(d,1H,J＝8.8Hz),7.39(d,2H,J＝8.0Hz),7.45-7.46(m,3H),7.55(s,1H),7.76(s,1H),8.06(s,1H)；LC/MS(ESI)m/z:376.3[M+H]⁺。

39. 1- (1H-benzimidazol-5-yl) -5- [4- (2-cyclopropyl-1, 3-thiazol-5-yl) phenyl ] imidazolidin-2-one (Compound 7)

Preparation of 1- (1H-benzimidazol-5-yl) -5- [4- (2-cyclopropyl-1, 3-thiazol-5-yl) phenyl from the cycloaddition reaction of 1,1' -carbonyldiimidazole and the Compound 137b]Imidazolidin-2-one (Compound 7). The procedure was the same as for the synthesis of compound 1. The product (compound 7) was obtained as a white solid in 74% yield.¹HNMR(400MHz,DMSO-d₆)δ0.92-0.95(m,2H),1.06-1.11(m,2H),2.32-2.39(m,1H),3.10(dd,1H,J＝6.4,9.2Hz),3.84(dd,1H,J＝8.4,9.2Hz),5.53(dd,1H,J＝6.4,8.4Hz),6.99(s,1H),7.26(s,1H),7.37-7.39(m,3H),7.50(d,2H,J＝8.0Hz),7.54(s,1H),7.88(s,1H),8.07(s,1H),12.23(s,1H)；LC/MS(ESI)m/z:402.2[M+H]+。

40. 1- (1H-Benzoimidazol-5-yl) -5- {4- [2- (trifluoromethyl) -1, 3-thiazol-5-yl ] phenyl } imidazolidin-2-one (Compound 8)

Preparation of 1- (1H-benzimidazol-5-yl) -5- {4- [2- (trifluoromethyl) -1, 3-thiazol-5-yl ] by cycloaddition of 1,1' -carbonyldiimidazole and Compound 137c]Phenyl } -imidazolidin-2-one (Compound 8). The procedure was the same as for the synthesis of compound 1. The product (compound 8) was obtained as a white solid in 70% yield.¹HNMR(400MHz,CD3OD)δ3.37(dd,1H,J＝7.2,8.8Hz),4.01(dd,1H,J＝8.8,9.2Hz),5.56(dd,1H,J＝7.2,9.2Hz),7.31(d,1H,J＝8.0Hz),7.47(d,1H,J＝8.0Hz),7.50(d,2H,J＝8.4Hz),7.58(s,1H),7.63(d,2H,J＝8.4Hz),8.07(s,1H),8.18(s,1H)；LC/MS(ESI)m/z:430.2[M+H]⁺。

41. (5S) -1- (1H-benzimidazol-5-yl) -5- {4- [2- (trifluoromethyl) -1, 3-thiazol-5-yl ] phenyl } -imidazolidin-2-one (Compound 9)

42. (5R) -1- (1H-benzimidazol-5-yl) -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. The isomeric fractions were collected separately and the solvent was removed under reduced pressure to give optically pure isomers (compounds 9 and 10).¹HNMR(400MHz,CD3OD)δ3.37(dd,1H,J＝7.2,8.8Hz),4.01(dd,1H,J＝8.8,9.2Hz),5.56(dd,1H,J＝7.2,9.2Hz),7.31(d,1H,J＝8.0Hz),7.47(d,1H,J＝8.0Hz),7.50(d,2H,J＝8.4Hz),7.58(s,1H),7.63(d,2H,J＝8.4Hz),8.07(s,1H),8.18(s,1H)；LC/MS(ESI)m/z:430.2[M+H]⁺。

43. 4- (5-Methylthiophen-2-yl) benzaldehyde (Compound 140a)

4-bromobenzaldehyde 138a (1.85g, 10.0mmol), 2-methylthiophene 139a (1.96g, 20.0mmol), potassium acetate (1.96g, 20.0mmol) and palladium acetate (0.002g, 0.01mmol) were dissolved in Dimethylacetamide (DMA). The reaction mixture was purged with argon and stirred at 150 ℃ 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 silica gel column chromatography using pentane/diethyl ether (1/4) as eluent. Product 140a was obtained as a white solid in 92% yield.

44. (1H-benzimidazol-5-ylamino) [4- (5-methylthiophen-2-yl) phenyl ] acetonitrile (Compound 141a)

(1H-benzimidazol-5-ylamino) [4- (5-methylthiophen-2-yl) phenyl ] acetonitrile 141a was prepared by adding 1H-benzimidazol-5-amine 121, TMSCN and compound 140 a. The procedure was the same as for the synthesis of compound 122 a. Product 141a was obtained as a light yellow solid in 90% yield.

45. N1- (1H-Benzimidazol-5-yl) -1- [4- (5-methylthiophen-2-yl) phenyl ] ethane-1, 2-diamine (Compound 142a)

Compound 141a was hydrogenated using raney nickel reagent as a catalyst to produce N1- (1H-benzoimidazol-5-yl) -1- [4- (5-methylthiophen-2-yl) phenyl ] ethane-1, 2-diamine 142 a. The procedure was the same as for the synthesis of compound 123 a. Product 142a was obtained as a yellow viscous liquid in 55% yield.

46. 1- (1H-benzimidazol-5-yl) -5- [4- (5-methylthiophen-2-yl) phenyl ] imidazolidin-2-one (Compound 11)

Preparation of 1- (1H-benzimidazol-5-yl) -5- [4- (5-methylthiophen-2-yl) phenyl from the cycloaddition reaction of 1,1' -carbonyldiimidazole and the Compound 142a]Imidazolidin-2-one (Compound 11). The procedure was the same as for the synthesis of compound 1. The product (compound 11) was obtained as a white solid in 63% yield.¹HNMR(400MHz,CD3OD)δ2.44(s,3H),3.39(dd,1H,J＝7.6,8.8Hz),3.97(dd,1H,J＝8.8,9.2Hz),5.40(dd,1H,J＝7.6,9.2Hz),6.67(d,1H,J＝3.0Hz),7.05(d,1H,J＝3.0Hz),7.26(d,1H,J＝8.8Hz),7.33(d,2H,J＝8.0Hz),7.45-7.47(m,3H),7.52(s,1H),7.99(s,1H)；LC/MS(ESI)m/z:375.3[M+H]⁺。

47. 4-acryloyl benzonitrile (compound 144)

4-Acetylbenzonitrile 143(0.73g, 5.0mmol), FeCl3.6H2O (0.14g, 0.5mmol), K2S2O8(2.7g, 10.0mmol), and DMA (20mL) were added sequentially to the flask. The reaction mixture was stirred at 110 ℃ for 4 hours. After 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 silica gel column chromatography using ethyl acetate/diethyl ether (1/4) as eluent. Product 144 was obtained as an off-white solid in 40% yield.

48. 4- (4-Oxopentanyl) benzonitrile (Compound 146)

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

49. 4- (5-Cyclopropylthiophen-2-yl) benzonitrile (Compound 147)

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

50. 4- (5-Cyclopropylthiophen-2-yl) benzaldehyde (Compound 148)

Compound 147 is reduced with DIBAL-H reagent to produce 4- (5-cyclopropylthiophen-2-yl) benzaldehyde 148. The procedure was the same as for the synthesis of compound 135 a. Product 148 was obtained as a yellow solid in 64% yield.

51. (1H-benzimidazol-5-ylamino) [4- (5-cyclopropylthiophen-2-yl) phenyl ] acetonitrile (Compound 149)

(1H-benzimidazol-5-ylamino) [4- (5-cyclopropylthiophen-2-yl) phenyl ] acetonitrile 149 was prepared by addition of 1H-benzimidazol-5-amine 121, TMSCN and compound 148. The procedure was the same as for the synthesis of compound 122 a. Product 149 was obtained as a pale yellow solid in 91% yield.

52. N1- (1H-Benzimidazol-5-yl) -1- [4- (5-cyclopropylthiophen-2-yl) phenyl ] ethane-1, 2-diamine (Compound 150)

Compound 149 is hydrogenated using raney nickel reagent as a catalyst to produce N1- (1H-benzoimidazol-5-yl) -1- [4- (5-cyclopropylthiophen-2-yl) phenyl ] ethane-1, 2-diamine 150. The procedure was the same as for the synthesis of compound 123 a. Product 150 was obtained as a yellow viscous liquid in 53% yield.

53. 1- (1H-benzimidazol-5-yl) -5- [4- (5-cyclopropylthiophen-2-yl) phenyl ] imidazolidin-2-one (Compound 12)

Preparation of 1- (1H-benzimidazol-5-yl) by cycloaddition of 1,1' -carbonyldiimidazole and Compound 150) -5- [4- (5-Cyclopropylthiophen-2-yl) phenyl]Imidazolidin-2-one (Compound 12). The procedure was the same as for the synthesis of compound 1. The product (compound 12) was obtained as a white solid in 69% yield.¹HNMR(400MHz,CD3OD)δ0.67-0.71(m,2H),0.96-1.01(m,2H),2.03-2.09(m,1H),3.36(dd,1H,J＝6.8,8.8Hz),3.97(dd,1H,J＝8.8,9.2Hz),5.45(dd,1H,J＝6.8,9.2Hz),6.69(d,1H,J＝3.6Hz),7.08(d,1H,J＝3.6Hz),7.29(d,1H,J＝8.8Hz),7.36(d,2H,J＝8.4Hz),7.46-7.49(m,3H),7.54(s,1H),8.06(s,1H)；LC/MS(ESI)m/z:401.3[M+H]⁺。

54. 4- (Thiophen-2-yl) benzaldehyde (Compound 152a)

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

55. 4- (5-Iodothien-2-yl) benzaldehyde (Compound 153a)

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

56. 4- [5- (trifluoromethyl) thiophen-2-yl ] benzaldehyde (Compound 155a)

A mixture of compound 153a (0.31g, 1.0mmol), difluoro (fluorosulfonyl) acetic acid methyl ester 154(0.96g, 5.0mmol), copper iodide (0.23g, 1.2mmol), N-methylpyrrolidine (NMP, 1.2mL) and DMF (10mL) was stirred at 70 ℃ for 13 hours. The reaction mixture was quenched with saturated aqueous ammonium chloride (15mL), diluted with water (10mL), 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 silica gel column chromatography using ethyl acetate/hexane (1/6) as eluent. Product 155a was obtained as a yellow solid in 70% yield.

57. (1H-benzimidazol-5-ylamino) {4- [5- (trifluoromethyl) thiophen-2-yl ] phenyl } acetonitrile (Compound 156a)

(1H-benzimidazol-5-ylamino) {4- [5- (trifluoromethyl) thiophen-2-yl ] phenyl } -acetonitrile 156a was prepared by adding 1H-benzimidazol-5-amine 121, TMSCN and compound 155 a. The procedure was the same as for the synthesis of compound 122 a. Product 156a was obtained as a pale yellow solid in 88% yield.

58. N1- (1H-Benzimidazol-5-yl) -1- {4- [5- (trifluoromethyl) thiophen-2-yl ] phenyl } ethane-1, 2-diamine (Compound 157a)

Hydrogenation of compound 156a using raney nickel reagent as a catalyst produced N1- (1H-benzimidazol-5-yl) -1- {4- [5- (trifluoromethyl) thiophen-2-yl ] phenyl } ethane-1, 2-diamine 157 a. The procedure was the same as for the synthesis of compound 123 a. Product 157a was obtained as a yellow viscous liquid in 49% yield.

59. 1- (1H-Benzimidazol-5-yl) -5- {4- [5- (trifluoromethyl) thiophen-2-yl ] phenyl } imidazolidin-2-one (Compound 13)

Preparation of 1- (1H-benzimidazol-5-yl) -5- {4- [5- (trifluoromethyl) thiophen-2-yl ] starting from 1,1' -carbonyldiimidazole by cycloaddition reaction with Compound 157a]Phenyl } -imidazolidin-2-one (Compound 13). The procedure was the same as for the synthesis of compound 1. The product (compound 13) was obtained as a white solid in 67% yield.¹H NMR(300MHz,CD3OD)δ3.36(dd,1H,J＝6.9,9.3Hz),3.99(dd,1H,J＝9.3,9.3Hz),5.51(dd,1H,J＝6.9,9.3Hz),7.29-7.32(m,2H),7.43-7.48(m,4H),7.55-7.60(m,3H),8.06(s,1H)；LC/MS(ESI)m/z:429.2[M+H]⁺。

60. 4- (Thien-3-yl) benzaldehyde (Compound 159a)

3-bromothiophene 158a (1.96g, 12.0mmol), (4-formylphenyl) boronic acid 118(2.70g, 18.0mmol), ethylene glycol dimethyl ether (17mL), water (10mL) and sodium bicarbonate (3.02g, 36.0mmol) were placed in a 50mL round bottom flask. After addition of Pd (PPh3)4(0.69g, 0.6mmol) at room temperature, the reaction mixture was refluxed for 5 hours. 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 silica gel column chromatography using toluene/hexane (2/1) as eluent. Product 159a was obtained as a light yellow oil in 95% yield.

61. 4- (5-Methylthiophen-3-yl) benzaldehyde (Compound 159b)

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

62. 4- [5- (trifluoromethyl) thiophen-3-yl ] benzaldehyde (Compound 159c)

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

63. (1H-benzimidazol-5-ylamino) [4- (thien-3-yl) phenyl ] acetonitrile (Compound 160a)

(1H-benzimidazol-5-ylamino) [4- (thiophen-3-yl) phenyl ] acetonitrile 160a was prepared by adding 1H-benzimidazol-5-amine 121, TMSCN and compound 159 a. The procedure was the same as for the synthesis of compound 122 a. Product 160a was obtained as a pale yellow solid in 92% yield.

64. (1H-benzimidazol-5-ylamino) [4- (5-methylthiophen-3-yl) phenyl ] acetonitrile (Compound 160b)

(1H-benzimidazol-5-ylamino) [4- (5-methylthiophen-3-yl) phenyl ] acetonitrile 160b was prepared by adding 1H-benzimidazol-5-amine 121, TMSCN and compound 159 b. The procedure was the same as for the synthesis of compound 122 a. Product 160b was obtained as a pale yellow solid in 90% yield.

65. (1H-benzimidazol-5-ylamino) {4- [5- (trifluoromethyl) thiophen-3-yl ] phenyl } acetonitrile (Compound 160c)

(1H-benzimidazol-5-ylamino) {4- [5- (trifluoromethyl) thiophen-3-yl ] phenyl } -acetonitrile 160c was prepared by adding 1H-benzimidazol-5-amine 121, TMSCN and compound 159 c. The procedure was the same as for the synthesis of compound 122 a. Product 160c was obtained as a pale yellow solid in 85% yield.

66. N1- (1H-benzimidazol-5-yl) -1- [4- (thien-3-yl) phenyl ] ethane-1, 2-diamine (Compound 161a)

Hydrogenation of compound 160a using raney nickel reagent as a catalyst produces N1- (1H-benzimidazol-5-yl) -1- [4- (thiophen-3-yl) phenyl ] ethane-1, 2-diamine 161 a. The procedure was the same as for the synthesis of compound 123 a. The product was obtained as a yellow viscous liquid in 53% yield.

67. N1- (1H-benzimidazol-5-yl) -1- [4- (5-methylthiophen-3-yl) phenyl ] ethane-1, 2-diamine (Compound 161b)

Hydrogenation of compound 160b using raney nickel reagent as a catalyst produces N1- (1H-benzoimidazol-5-yl) -1- [4- (5-methylthiophen-3-yl) phenyl ] ethane-1, 2-diamine 161 b. The procedure was the same as for the synthesis of compound 123 a. Product 161b was obtained as a yellow viscous liquid in 50% yield.

68. N1- (1H-Benzimidazol-5-yl) -1- {4- [5- (trifluoromethyl) thiophen-3-yl ] phenyl } ethane-1, 2-diamine (Compound 161c)

Hydrogenation of compound 160c using raney nickel reagent as a catalyst produced N1- (1H-benzimidazol-5-yl) -1- {4- [5- (trifluoromethyl) thiophen-3-yl ] phenyl } ethane-1, 2-diamine 161 c. The procedure was the same as for the synthesis of compound 123 a. Product 161c was obtained as a yellow viscous liquid in 51% yield.

69. 1- (1H-benzimidazol-5-yl) -5- [4- (thien-3-yl) phenyl ] imidazolidin-2-one (Compound 14)

Preparation of 1- (1H-benzimidazol-5-yl) -5- [4- (thien-3-yl) phenyl by cycloaddition of 1,1' -carbonyldiimidazole with Compound 161a]Imidazolidin-2-one (Compound 14). The procedure was the same as for the synthesis of compound 1. The product (compound 14) was obtained as a white solid in 73% yield.¹HNMR(300MHz,CD3OD)δ3.38(dd,1H,J＝6.9,9.0Hz),3.99(dd,1H,J＝9.0,9.3Hz),5.48(dd,1H,J＝6.9,9.3Hz),7.05(s,1H),7.30(d,1H,J＝8.4Hz),7.37-7.48(m,4H),7.54-7.60(m,3H),7.68(s,1H),8.06(s,1H)；LC/MS(ESI)m/z:361.3[M+H]⁺。

70. 1- (1H-benzimidazol-5-yl) -5- [4- (5-methylthiophen-3-yl) phenyl ] imidazolidin-2-one (Compound 15)

Preparation of 1- (1H-benzimidazol-5-yl) -5- [4- (5-methylthiophen-3-yl) phenyl from the cycloaddition reaction of 1,1' -carbonyldiimidazole and the Compound 161b]Imidazolidin-2-one (Compound 15). The procedure was the same as for the synthesis of compound 1. The product (compound 15) was obtained as a white solid in 75% yield.¹HNMR(300MHz,CD3OD)δ2.40(s,3H),3.30(dd,1H,J＝7.5,9.0Hz),3.90(dd,1H,J＝9.0,9.0Hz),5.38(dd,1H,J＝7.5,9.0Hz),6.95(s,1H),7.17(s,1H),7.26-7.31(m,3H),7.42-7.45(m,3H),7.55(s,1H),8.03(s,1H)；LC/MS(ESI)m/z:375.1[M+H]⁺。

71. 1- (1H-Benzimidazol-5-yl) -5- {4- [5- (trifluoromethyl) thiophen-3-yl ] phenyl } imidazolidin-2-one (Compound 16)

Preparation of 1- (1H-benzimidazol-5-yl) -5- {4- [5- (trifluoromethyl) thiophen-3-yl ] starting from 1,1' -carbonyldiimidazole and Compound 161c by cycloaddition]Phenyl } -imidazolidin-2-one (compound 16). The procedure was the same as for the synthesis of compound 1. The product (compound 16) was obtained as a white solid in 67% yield.¹H NMR(300MHz,CD3OD)δ3.36(dd,1H,J＝6.9,9.0Hz),3.99(dd,1H,J＝9.0,9.3Hz),5.50(dd,1H,J＝6.9,9.3Hz),7.30(d,1H,J＝8.1Hz),7.41-7.47(m,3H),7.56-7.58(m,3H),7.81(s,2H),8.05(s,1H)；LC/MS(ESI)m/z:429.1[M+H]⁺。

72. 4- (5-bromothien-3-yl) benzaldehyde (Compound 162)

A solution of bromine (5.0g, 32.0mmol) in 50mL of glacial acetic acid was added dropwise to a solution of compound 159a (6.0g, 32.0mmol) in 65mL of glacial acetic acid. The resulting yellow solution was stirred at room temperature for 2 days. The reaction mixture was diluted with 300mL of water and extracted with ethyl acetate (100 mL. times.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 silica gel column chromatography using ethyl acetate/hexane (1/9) as eluent. Product 162 was obtained as a yellow solid in 73% yield.

73. 4- (5-Cyclopropylthiophen-3-yl) benzaldehyde (Compound 163)

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

74. (1H-benzimidazol-5-ylamino) [4- (5-cyclopropylthiophen-3-yl) phenyl ] acetonitrile (Compound 164)

(1H-benzimidazol-5-ylamino) [4- (5-cyclopropylthiophen-3-yl) phenyl ] acetonitrile 164 is prepared by adding 1H-benzimidazol-5-amine 121, TMSCN and compound 163. The procedure was the same as for the synthesis of compound 122 a. Product 164 was obtained as a pale yellow solid in 81% yield.

75. N1- (1H-Benzimidazol-5-yl) -1- [4- (5-cyclopropylthiophen-3-yl) phenyl ] ethane-1, 2-diamine (Compound 165)

Compound 164 is hydrogenated using raney nickel reagent as a catalyst to produce N1- (1H-benzimidazol-5-yl) -1- [4- (5-cyclopropylthiophen-3-yl) phenyl ] ethane-1, 2-diamine 165. The procedure was the same as for the synthesis of compound 123 a. Product 165 was obtained as a yellow viscous liquid in 49% yield.

76. 1- (1H-benzimidazol-5-yl) -5- [4- (5-cyclopropylthiophen-3-yl) phenyl ] imidazolidin-2-one (Compound 17)

Preparation of 1- (1H-benzimidazol-5-yl) -5- [4- (5-cyclopropylthiophen-3-yl) phenyl from the cycloaddition reaction of 1,1' -carbonyldiimidazole and Compound 165]Imidazolidine-2-ketones (compound 17). The procedure was the same as for the synthesis of compound 1. The product (compound 17) was obtained as a white solid in 65% yield.¹HNMR(300MHz,CD3OD)δ0.59-0.63(m,2H),0.91-0.96(m,2H),2.00-2.09(m,1H),3.39(dd,1H,J＝6.9,9.0Hz),4.00(dd,1H,J＝9.0,9.3Hz),5.50(dd,1H,J＝6.9,9.3Hz),6.69(d,1H,J＝5.4Hz),7.05(d,1H,J＝5.4Hz),7.32(dd,1H,J＝1.8,8.7Hz),7.41-7.45(m,3H),7.46(d,2H,J＝8.1Hz),7.58(d,1H,J＝1.8Hz),8.06(s,1H)；LC/MS(ESI)m/z:401.2[M+H]⁺。

77. 4- (1, 3-Dioxolan-2-yl) benzonitrile (Compound 167)

4-formyl benzonitrile 166(7.68g, 58.6mmol), catalytic amount of p-TsOH (PTSA), and toluene (150mL) were added sequentially to a round-bottomed flask equipped with a Dean-Stark trap. After stirring at room temperature for 5 minutes, monoethylene glycol (MEG) (13mL, 234.3mmol) was added dropwise. The reaction mixture was refluxed for 3 hours and cooled to room temperature. After removing the toluene under reduced pressure, saturated Na2CO3(aq) was added to quench the reaction 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 hexane in an ice bath to form product 167 in quantum yield as a yellow solid.

78. 4- (1, 3-Dioxolan-2-yl) -N' -hydroxybenzoylimidic amide (Compound 168)

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

79. N' - [ (cyclopropylcarbonyl) oxy ] -4- (1, 3-dioxolan-2-yl) benzoylimine amide (Compound 169)

Pyridine (1.4mL, 17.30mmol) and cyclopropanecarbonyl chloride (0.02mL, 11.20mmol) were added dropwise to a suspension of compound 168(1.8g, 8.65mmol) in DCM (100mL) at room temperature under nitrogen. The reaction mixture was stirred at room temperature for 4 hours and 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 silica gel column chromatography using DCM/methanol (9/1) as eluent to give the product 169 as a white solid in 60% yield.

80. 5-cyclopropyl-3- [4- (1, 3-dioxolan-2-yl) phenyl ] -1,2, 4-oxadiazole (Compound 170)

Raw material 169(1.1g, 3.98mmol) 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 silica gel column chromatography using EA/hexane (1/4) as eluent to give product 170 as a white solid in 70% yield.

81. 4- (5-cyclopropyl-1, 2, 4-oxadiazol-3-yl) benzaldehyde (compound 171)

Concentrated HCl was added dropwise to a solution of compound 170(1.2g, 4.64mmol) in THF/H2O (4/1, 30 mL). The reaction mixture was stirred at 65 ℃ for 6 hours and 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 silica gel column chromatography using EA/hexane (1/9) as eluent to afford product 171 as a white solid in 97% yield.

82. (1H-benzimidazol-5-ylamino) [4- (5-cyclopropyl-1, 2, 4-oxadiazol-3-yl) phenyl ] acetonitrile (Compound 172)

(1H-benzimidazol-5-ylamino) [4- (5-cyclopropyl-1, 2, 4-oxadiazol-3-yl) phenyl ] -acetonitrile 172 is prepared by adding 1H-benzimidazol-5-amine 121, TMSCN and compound 171. The procedure was the same as for the synthesis of compound 122 a. Product 172 was obtained as a pale yellow solid in 86% yield.

83. N1- (1H-Benzimidazol-5-yl) -1- [4- (5-cyclopropyl-1, 2, 4-oxadiazol-3-yl) phenyl ] ethane-1, 2-diamine (Compound 173)

Compound 172 was hydrogenated using Pd/C as a catalyst to produce N1- (1H-benzoimidazol-5-yl) -1- [4- (5-cyclopropyl-1, 2, 4-oxadiazol-3-yl) phenyl ] ethane-1, 2-diamine 173. The procedure was the same as for the synthesis of compound 123 a. Product 173 was obtained as a yellow viscous liquid in 55% yield.

84. 1- (1H-Benzimidazol-5-yl) -5- [4- (5-cyclopropyl-1, 2, 4-oxadiazol-3-yl) phenyl ] imidazolidin-2-one (Compound 18)

Preparation of 1- (1H-benzimidazol-5-yl) -5- [4- (5-cyclopropyl-1, 2, 4-oxadiazol-3-yl) phenyl from the cycloaddition reaction of 1,1' -carbonyldiimidazole and Compound 173]Imidazolidin-2-one (compound 18). The procedure was the same as for the synthesis of compound 1. The product (compound 18) was obtained as a white solid in 68% yield.¹HNMR(300MHz,DMSO-d₆)δ1.12-1.19(m,2H),1.21-1.28(m,2H),2.31-2.38(m,1H),3.13(dd,1H,J＝6.3,8.7Hz),3.89(dd,1H,J＝8.7,9.0Hz),5.60(dd,1H,J＝6.3,9.0Hz),6.98-7.03(m,1H),7.19(br.s,1H),7.35-7.59(m,4H),7.88(d,2H,J＝7.8Hz),8.07(s,1H),12.23(s,1H)；LC/MS(ESI)m/z:387.1[M+H]⁺。

85. 4- (3-cyclopropyl-1, 2-oxazol-5-yl) benzaldehyde (compound 177)

Cyclopropanecarboxaldehyde 174(1.0g, 14.26mmol), hydroxylamine hydrochloride (0.99g, 14.26mmol) and potassium carbonate (2.17g, 15.68mmol) were dissolved in H2O (25 mL). The reaction mixture was stirred at 85 ℃ for 3 hours and 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 any further purification. A catalytic amount of pyridine was added to a solution of compound 175 and NCS (1.9g, 14.26mmol) in DMF (30mL) under argon. The reaction mixture was stirred at room temperature for 2 hours. After cooling to 0 deg.C, 4-ethynylbenzaldehyde 176(1.9g, 14.26mmol) and triethylamine (3mL) were added. The reaction mixture was stirred continuously at room temperature 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 silica gel column chromatography using EA/hexane (1/8) as eluent to give product 177 as a yellow solid in 54% overall yield.

86. (1H-benzimidazol-5-ylamino) [4- (5-cyclopropyl-1, 2-oxazol-3-yl) phenyl ] acetonitrile (Compound 178)

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

87. N1- (1H-Benzimidazol-5-yl) -1- [4- (5-cyclopropyl-1, 2-oxazol-3-yl) phenyl ] ethane-1, 2-diamine (Compound 179)

Compound 178 was hydrogenated using Pd/C as a catalyst to produce N1- (1H-benzimidazol-5-yl) -1- [4- (5-cyclopropyl-1, 2-oxazol-3-yl) phenyl ] ethane-1, 2-diamine 179. The procedure was the same as for the synthesis of compound 123 a. Product 179 was obtained as a yellow viscous liquid in 49% yield.

88. 1- (1H-benzimidazol-5-yl) -5- [4- (5-cyclopropyl-1, 2-oxazol-3-yl) phenyl ] imidazolidin-2-one (Compound 19)

Preparation of 1- (1H-benzimidazol-5-yl) -5- [4- (5-cyclopropyl-1, 2-oxazol-3-yl) phenyl from the cycloaddition of 1,1' -carbonyldiimidazole and Compound 179]Imidazolidin-2-one (Compound 19). The procedure was the same as for the synthesis of compound 1. The product (compound 19) was obtained as a white solid in 58% yield.¹H NMR(400MHz,DMSO-d₆)δ0.75-0.79(m,2H),0.99-1.04(m,2H),1.98-2.02(m,1H),3.13(dd,1H,J＝6.3,9.0Hz),3.88(dd,1H,J＝8.7,9.0Hz),5.59(dd,1H,J＝6.3,8.7Hz),6.68(s,1H),7.01(s,1H),7.26(d,1H,J＝8.4Hz),7.40(d,1H,J＝8.4Hz),7.49(d,2H,J＝7.8Hz),7.56(s,1H),7.72(d,2H,J＝7.8Hz),7.79(s,1H),8.08(s,1H)；LC/MS(ESI)m/z:386.2[M+H]⁺。

89. 4- (2H-tetrazol-5-yl) benzaldehyde hydrochloride (Compound 180)

Sodium azide (0.72g, 11mmol) and ammonium chloride (0.14g, 2.5mmol) were added to a solution of 4-formylbenzonitrile 166(1.31g, 10.0mmol) in DMF (10mL) under nitrogen. 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 1n hcl (aq). After filtration, the precipitate was washed with water and ether to give product 180 as a yellow solid in 94% yield.

90. 4- (2-propyl-2H-tetrazol-5-yl) benzaldehyde (Compound 181a)

Potassium carbonate (2.76g, 20mmol) and 1-bromopropane (2.46g, 20mmol) were added to a suspension of compound 180(2.1g, 10.0mmol) in acetonitrile (20mL) under nitrogen. The reaction mixture was stirred at 50 ℃ overnight and 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 silica gel column chromatography using EA/hexane (1/4) as eluent to give the product 181a as a yellow solid in 76% yield.

91. 4- [2- (Propan-2-yl) -2H-tetrazol-5-yl ] benzaldehyde (Compound 181b)

Isopropanol (1.2g, 20.0mmol) was added to a solution of compound 180(2.1g, 10.0mmol) in trifluoromethanesulfonic acid (20mL) under nitrogen. The reaction mixture was stirred at room temperature for 1 hour. The reaction mixture was poured into water and treated with saturated NaHCO3(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 silica gel column chromatography using EA/hexane (1/4) as eluent to give the product 181b as a yellow solid in 54% yield.

92. (1H-benzimidazol-5-ylamino) [4- (2-propyl-2H-tetrazol-5-yl) phenyl ] acetonitrile (Compound 182a)

(1H-benzimidazol-5-ylamino) [4- (2-propyl-2H-tetrazol-5-yl) phenyl ] acetonitrile 182a was prepared by adding 1H-benzimidazol-5-amine 121, TMSCN and compound 181 a. The procedure was the same as for the synthesis of compound 122 a. Product 182a was obtained as a pale yellow solid in 86% yield.

93. (1H-benzimidazol-5-ylamino) {4- [2- (propan-2-yl) -2H-tetrazol-5-yl ] phenyl } acetonitrile (Compound 182b)

(1H-benzimidazol-5-ylamino) {4- [2- (propan-2-yl) -2H-tetrazol-5-yl ] phenyl } -acetonitrile 182b was prepared by adding 1H-benzimidazol-5-amine 121, TMSCN and compound 181 b. The procedure was the same as for the synthesis of compound 122 a. Product 182b was obtained as a pale yellow solid in 81% yield.

94. N1- (1H-Benzimidazol-5-yl) -1- [4- (2-propyl-2H-tetrazol-5-yl) phenyl ] ethane-1, 2-diamine (Compound 183a)

Hydrogenation of compound 182a using Pd/C as a catalyst produced N1- (1H-benzimidazol-5-yl) -1- [4- (2-propyl-2H-tetrazol-5-yl) phenyl ] ethane-1, 2-diamine 183 a. The procedure was the same as for the synthesis of compound 123 a. Product 183a was obtained as a yellow viscous liquid in 50% yield.

95. N1- (1H-Benzimidazol-5-yl) -1- {4- [2- (propan-2-yl) -2H-tetrazol-5-yl ] phenyl } ethane-1, 2-diamine (Compound 183b)

Hydrogenation of compound 182b using Pd/C as a catalyst produced N1- (1H-benzimidazol-5-yl) -1- {4- [2- (propan-2-yl) -2H-tetrazol-5-yl ] phenyl } ethane-1, 2-diamine 183 b. The procedure was the same as for the synthesis of compound 123 a. Product 183b was obtained as a yellow viscous liquid in 45% yield.

96. 1- (1H-Benzimidazol-5-yl) -5- [4- (2-propyl-2H-tetrazol-5-yl) phenyl ] imidazolidin-2-one (Compound 20)

Preparation of 1- (1H-benzimidazol-5-yl) -5- [4- (2-propyl-2H-tetrazol-5-yl) phenyl from the cycloaddition reaction of 1,1' -carbonyldiimidazole with Compound 183a]Imidazolidin-2-one (Compound 20). The procedure was the same as for the synthesis of compound 1. The product (compound 20) was obtained as a white solid in 60% yield.¹HNMR(300MHz,DMSO-d₆)δ0.83(t,3H,J＝7.2Hz),1.87-1.99(m,2H),3.14(dd,1H,J＝6.3,8.7Hz),3.89(dd,1H,J＝8.7,9.0Hz),4.64(t,2H,J＝7.2Hz),5.60(dd,1H,J＝6.3,9.0Hz),7.01(s,1H),7.26(d,1H,J＝8.9Hz),7.39(d,1H,J＝8.9Hz),7.52-7.57(m,3H),7.98(d,2H,J＝8.4Hz),8.07(s,1H),12.21(s,1H)；LC/MS(ESI)m/z:389.2[M+H]⁺。

97. 1- (1H-Benzimidazol-5-yl) -5- {4- [2- (propan-2-yl) -2H-tetrazol-5-yl ] phenyl } imidazolidin-2-one (Compound 21)

Preparation of 1- (1H-benzimidazol-5-yl) -5- {4- [2- (propan-2-yl) -2H-tetrazol-5-yl ] by cycloaddition of 1,1' -carbonyldiimidazole and Compound 183b]Phenyl } imidazolidin-2-one (Compound 21). The procedure was the same as for the synthesis of compound 1 to give the product (compound 21) as a white solid in 62% yield.¹HNMR(400MHz,DMSO-d₆)δ1.56(d,6H,J＝6.4Hz),3.14(dd,1H,J＝6.4,8.8Hz),3.89(dd,1H,J＝8.8,9.2Hz),5.09-5.15(m,1H),5.60(dd,1H,J＝6.4,9.2Hz),7.04(s,1H),7.26(d,1H,J＝7.6Hz),7.39(d,1H,J＝8.8Hz),7.52-7.57(m,3H),7.97(d,2H,J＝8.4Hz),8.07(s,1H),12.25(s,1H)；LC/MS(ESI)m/z:389.2[M+H]⁺。

98. 3-fluoro-4- (thiophen-2-yl) benzaldehyde (Compound 152b)

A mixture of tributyl (thien-2-yl) stannane 151(6.62g, 17.7mmol), 4-bromo-3-fluorobenzaldehyde 138b (3.0g, 14.8mmol) and Pd (PPh3)4(0.51g, 0.43mmol) in toluene (160mL) 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 silica gel column chromatography using dichloromethane/hexane (1/9) as eluent. Product 152b was obtained as a pale yellow solid in 70% yield.

99. 2-fluoro-4- (thiophen-2-yl) benzaldehyde (Compound 152c)

2-fluoro-4- (thiophen-2-yl) benzaldehyde 152c was prepared from the Suzuki coupling reaction of 4-bromo-2-fluorobenzaldehyde 138c and tributyl (thiophen-2-yl) stannane 151 using Pd (PPh3)4 as a catalyst. The procedure was the same as for the synthesis of compound 152 b. Product 152c was obtained as a light yellow solid in 68% yield.

100. 2, 6-difluoro-4- (thiophen-2-yl) benzaldehyde (Compound 152d)

2, 6-difluoro-4- (thiophen-2-yl) benzaldehyde (compound 152d) was prepared from the Suzuki coupling reaction of 4-bromo-2, 6-difluorobenzaldehyde 138d and tributyl (thiophen-2-yl) stannane 151 using Pd (PPh3)4 as a catalyst. The procedure was the same as for the synthesis of compound 152 b. Product 152d was obtained as a pale yellow solid in 56% yield.

101. 3-fluoro-4- (5-iodothiophen-2-yl) benzaldehyde (Compound 153b)

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

102. 2-fluoro-4- (5-iodothiophen-2-yl) benzaldehyde (Compound 153c)

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

103. 2, 6-difluoro-4- (5-iodothiophen-2-yl) 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 procedure was the same as for the synthesis of compound 153 a. Product 153d was obtained as a yellow-green solid in 71% yield.

104. 3-fluoro-4- [5- (trifluoromethyl) thiophen-2-yl ] benzaldehyde (Compound 155b)

3-fluoro-4- [5- (trifluoromethyl) thiophen-2-yl ] benzaldehyde 155b was prepared by a trifluoromethylation reaction using difluoro (fluorosulfonyl) acetic acid methyl ester 154 and copper iodide treatment compound 153 b. The procedure was the same as for the synthesis of compound 155 a. Product 155b was obtained as a yellow solid in 70% yield.

105. 2-fluoro-4- [5- (trifluoromethyl) thiophen-2-yl ] benzaldehyde (Compound 155c)

2-fluoro-4- [5- (trifluoromethyl) thiophen-2-yl ] benzaldehyde 155c was prepared by a trifluoromethylation reaction using difluoro (fluorosulfonyl) acetic acid methyl ester 154 and copper iodide treatment compound 153 c. The procedure was the same as for the synthesis of compound 155 a. Product 155c was obtained as a yellow solid in 72% yield.

106. 2, 6-difluoro-4- [5- (trifluoromethyl) thiophen-2-yl ] benzaldehyde (Compound 155d)

2, 6-difluoro-4- [5- (trifluoromethyl) thiophen-2-yl ] benzaldehyde 155d was prepared by a trifluoromethylation reaction using difluoro (fluorosulfonyl) acetic acid methyl ester 154 and copper iodide treated compound 153 d. The procedure was the same as for the synthesis of compound 155 a. Product 155d was obtained as a yellow solid in 67% yield.

107. 1- (1H-Benzimidazol-5-yl) -5- { 3-fluoro-4- [5- (trifluoromethyl) thiophen-2-yl ] phenyl } -imidazolidin-2-one (Compound 22)

Preparation of 1- (1H-benzimidazol-5-yl) -5- { 3-fluoro-4- [5- (trifluoromethyl) thiophen-2-yl ] starting from compound 155b in the three-step synthesis of imidazolidinone]Phenyl } -imidazolidin-2-one (Compound 22). The procedure was the same as for the synthesis of compound 1. The product (compound 22) was obtained as a white solid in 27% overall yield.¹H NMR(300MHz,CD3OD)δ3.36(dd,1H,J＝6.9,9.0Hz),4.01(dd,1H,J＝9.0,9.6Hz),5.54(dd,1H,J＝6.9,9.6Hz),7.27-7.34(m,3H),7.41(d,1H,J＝3.9Hz),7.48-7.51(m,2H),7.59-7.67(m,2H),8.07(s,1H)；LC/MS(ESI)m/z:447.0[M+H]⁺。

108. 1- (1H-Benzimidazol-5-yl) -5- { 2-fluoro-4- [5- (trifluoromethyl) thiophen-2-yl ] phenyl } -imidazolidin-2-one (Compound 23)

Preparation of 1- (1H-benzimidazol-5-yl) -5- { 2-fluoro-4- [5- (trifluoromethyl) thiophen-2-yl ] starting from compound 155c in the three-step synthesis of imidazolidinone]Phenyl } -imidazolidin-2-one (compound 23). The procedure was the same as for the synthesis of compound 1. The product (compound 23) was obtained as a white solid in 25% overall yield.¹H NMR(300MHz,CD3OD)δ3.44(dd,1H,J＝6.0,9.0Hz),4.05(dd,1H,J＝9.0,9.3Hz),5.83(dd,1H,J＝6.0,9.3Hz),7.31-7.51(m,7H),7.60(d,1H,J＝2.1Hz),8.08(s,1H)；LC/MS(ESI)m/z:447.1[M+H]⁺。

109. 1- (1H-Benzimidazol-5-yl) -5- {2, 6-difluoro-4- [5- (trifluoromethyl) thiophen-2-yl ] phenyl } -imidazolidin-2-one (Compound 24)

Preparation of 1- (1H-benzimidazol-5-yl) -5- {2, 6-difluoro-4- [5- (trifluoromethyl) thiophen-2-yl from Compound 155d in the formation of the three-step synthetic imidazolidinone]Phenyl } -imidazolidin-2-one (compound 24). The procedure was the same as for the synthesis of compound 1. The product (compound 24) was obtained as a white solid in 21% overall yield.¹H NMR(300MHz,CD3OD)δ3.65(dd,1H,J＝7.2,9.3Hz),4.05(dd,1H,J＝9.3,10.5Hz),6.01(dd,1H,J＝7.2,10.5Hz),7.23-7.28(m,3H),7.39-7.41(m,1H),7.46-7.50(m,2H),7.57(d,1H,J＝1.8Hz),8.08(s,1H)；LC/MS(ESI)m/z:465.1[M+H]⁺。

110. 3-fluoro-4- [5- (trifluoromethyl) thiophen-3-yl ] benzaldehyde (Compound 159d)

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

111. 2-fluoro-4- [5- (trifluoromethyl) thiophen-3-yl ] benzaldehyde (Compound 159e)

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

112. 2, 6-difluoro-4- [5- (trifluoromethyl) thiophen-3-yl ] benzaldehyde (Compound 159f)

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

113. 2, 3-difluoro-4- [5- (trifluoromethyl) thiophen-3-yl ] benzaldehyde (Compound 159g)

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

114. 1- (1H-Benzimidazol-5-yl) -5- { 3-fluoro-4- [5- (trifluoromethyl) thiophen-3-yl ] phenyl } -imidazolidin-2-one (Compound 25)

Preparation of 1- (1H-benzimidazol-5-yl) -5- { 3-fluoro-4- [5- (trifluoromethyl) thiophen-3-yl ] starting from compound 159d in the formation of the three-step synthetic imidazolidinone]Phenyl } -imidazolidin-2-one (compound 25). The procedure was the same as for the synthesis of compound 1. The product (compound 25) was obtained as a white solid in 25% overall yield.¹H NMR(300MHz,CD3OD)δ3.37(dd,1H,J＝6.9,9.0Hz),4.01(dd,1H,J＝9.0,9.3Hz),5.54(dd,1H,J＝6.9,9.3Hz),7.24-7.34(m,3H),7.49(d,1H,J＝8.7Hz),7.56-7.61(m,2H),7.80(d,1H,J＝0.9Hz),7.90(s,1H),8.08(s,1H)；LC/MS(ESI)m/z:447.0[M+H]⁺。

115. 1- (1H-Benzimidazol-5-yl) -5- { 2-fluoro-4- [5- (trifluoromethyl) thiophen-3-yl ] phenyl } -imidazolidin-2-one (Compound 26)

Preparation of 1- (1H-benzimidazol-5-yl) -5- { 2-fluoro-4- [5- (trifluoromethyl) thiophen-3-yl ] starting from compound 159e in the three-step synthesis of imidazolidinone]Phenyl } -imidazolidin-2-one (compound 26). The procedure was the same as for the synthesis of compound 1. The product (compound 26) was obtained as a white solid in 27% overall yield.¹H NMR(300MHz,CD3OD)δ3.44(dd,1H,J＝6.3,9.0Hz),4.05(dd,1H,J＝9.0,9.6Hz),5.82(dd,1H,J＝6.3,9.6Hz),7.33(dd,1H,J＝1.2,8.7Hz),7.42-7.50(m,4H),7.60(d,1H,J＝2.0Hz),7.86(d,1H,J＝1.2Hz),7.93(d,1H,J＝2.0Hz),8.07(s,1H)；LC/MS(ESI)m/z:447.0[M+H]⁺。

116. 1- (1H-Benzimidazol-5-yl) -5- {2, 6-difluoro-4- [5- (trifluoromethyl) thiophen-3-yl ] phenyl } -imidazolidin-2-one (Compound 27)

Preparation of 1- (1H-benzimidazol-5-yl) -5- {2, 6-difluoro-4- [5- (trifluoromethyl) thiophen-3-yl from Compound 159f in the formation of the three-step synthetic imidazolidinone]Phenyl } -imidazolidin-2-one (compound 27). The procedure was the same as for the synthesis of compound 1. The product (compound 27) was obtained as a white solid in 21% overall yield.¹H NMR(300MHz,CD3OD)δ3.65(dd,1H,J＝7.2,9.3Hz),4.04(dd,1H,J＝9.3,10.2Hz),6.00(dd,1H,J＝7.2,10.2Hz),7.24-7.28(m,3H),7.48(d,1H,J＝8.7Hz),7.56(d,1H,J＝1.8Hz),7.84(s,1H),7.95(d,1H,J＝1.8Hz),8.07(s,1H)；LC/MS(ESI)m/z:465.1[M+H]⁺。

117. 1- (1H-Benzimidazol-5-yl) -5- {2, 3-difluoro-4- [5- (trifluoromethyl) thiophen-3-yl ] phenyl } -imidazolidin-2-one (Compound 28)

Preparation of 1- (1H-benzimidazol-5-yl) -5- {2, 3-difluoro-4- [5- (trifluoromethyl) thiophen-3-yl from compound 159g in the formation of the three-step synthetic imidazolidinone]Phenyl } -imidazolidin-2-one (compound 28). The procedure was the same as for the synthesis of compound 1. The product (compound 28) was obtained as a white solid in 20% overall yield.¹H NMR(300MHz,CD3OD)δ3.46(dd,1H,J＝6.3,9.0Hz),4.07(dd,1H,J＝9.0,9.6Hz),5.87(dd,1H,J＝6.3,9.6Hz),7.23-7.40(m,3H),7.50(d,1H,J＝8.4Hz),7.61(d,1H,J＝1.8Hz),7.82(s,1H),7.97(s,1H),8.09(s,1H)；LC/MS(ESI)m/z:465.1[M+H]⁺。

118. 4- (5-chlorothien-2-yl) benzaldehyde (Compound 140b)

Preparation of 4- (5-chlorothien-2-yl) benzaldehyde 140b from Suzuki coupling of 4-bromobenzaldehyde 138a and 2-chlorothiophene 139 b. The procedure was the same as for the synthesis of compound 140 a. Product 140b was obtained as a yellow solid in 74% yield.

119. 4- (5-chlorothien-2-yl) -3-fluorobenzaldehyde (Compound 140c)

4- (5-chlorothien-2-yl) -3-fluorobenzaldehyde 140c was prepared by suzuki coupling of 4-bromo-3-fluorobenzaldehyde 138b and 2-chlorothiophene 139 b. The procedure was the same as for the synthesis of compound 140 a. Product 140c was obtained as a yellow solid in 69% yield.

120. 4- (5-chlorothien-2-yl) -2-fluorobenzaldehyde (Compound 140d)

Preparation of 4- (5-chlorothien-2-yl) -2-fluorobenzaldehyde 140d from suzuki coupling of 4-bromo-2-fluorobenzaldehyde 138c and 2-chlorothiophene 139 b. The procedure was the same as for the synthesis of compound 140 a. Product 140d was obtained as a yellow solid in 67% yield.

121. 4- (5-chlorothien-2-yl) -2, 6-difluorobenzaldehyde (Compound 140e)

4- (5-chlorothien-2-yl) -2, 6-difluorobenzaldehyde 140e was prepared by suzuki coupling of 4-bromo-2, 6-fluorobenzaldehyde 138d and 2-chlorothiophene 139 b. The procedure was the same as for the synthesis of compound 140 a. Product 140e was obtained as a yellow solid in 60% yield.

122. 1- (1H-benzimidazol-5-yl) -5- [4- (5-chlorothien-2-yl) phenyl ] imidazolidin-2-one (Compound 29)

In the formation of imidazolidinone from Compound 140b in a three-step SynthesisPreparation of 1- (1H-benzimidazol-5-yl) -5- [4- (5-chlorothien-2-yl) phenyl]Imidazolidin-2-one (Compound 29). The procedure was the same as for the synthesis of compound 1. The product (compound 29) was obtained as a white solid in 28% overall yield.¹HNMR(300MHz,CD3OD)δ3.36(dd,1H,J＝6.9,9.0Hz),3.99(dd,1H,J＝9.0,9.3Hz),5.48(dd,1H,J＝6.9,9.3Hz),6.90(d,1H,J＝3.9Hz),7.12(d,1H,J＝3.9Hz),7.30(d,1H,J＝9.0Hz),7.40(d,2H,J＝8.4Hz),7.45-7.49(m,3H),7.54(d,1H,J＝2.1Hz),8.06(s,1H)；LC/MS(ESI)m/z:395.0[M+H]⁺。

123. 1- (1H-benzimidazol-5-yl) -5- [4- (5-chlorothien-2-yl) -3-fluorophenyl ] imidazolidin-2-one (Compound 30)

Preparation of 1- (1H-benzimidazol-5-yl) -5- [4- (5-chlorothien-2-yl) -3-fluorophenyl from compound 140c in the formation of an imidazolidinone synthesized in three steps]Imidazolidin-2-one (Compound 30). The procedure was the same as for the synthesis of compound 1. The product (compound 30) was obtained as a white solid in 24% overall yield.¹H NMR(400MHz,CD3OD)δ3.36(dd,1H,J＝6.8,9.2Hz),4.00(dd,1H,J＝9.2,9.2Hz),5.52(dd,1H,J＝6.8,9.2Hz),6.95(d,1H,J＝4.0Hz),7.23-7.26(m,3H),7.31(d,1H,J＝8.0Hz),7.49(d,1H,J＝8.4Hz),7.56-7.59(m,2H),8.08(s,1H)；LC/MS(ESI)m/z:413.0[M+H]⁺。

124. 1- (1H-benzimidazol-5-yl) -5- [4- (5-chlorothien-2-yl) -2-fluorophenyl ] imidazolidin-2-one (Compound 31)

Preparation of 1- (1H-benzimidazol-5-yl) -5- [4- (5-chlorothien-2-yl) -2-fluorophenyl from compound 140d in the formation of an imidazolidinone synthesized in three steps]Imidazolidin-2-one (compound 31). The procedure was the same as for the synthesis of compound 1. The product (compound 31) was obtained as a white solid in 25% overall yield.¹H NMR(300MHz,CD3OD)δ3.42(dd,1H,J＝6.6,9.0Hz),4.03(dd,1H,J＝9.0,9.6Hz),5.78(dd,1H,J＝6.6,9.6Hz),6.91(d,1H,J＝4.2Hz),7.17(d,1H,J＝4.2Hz),7.24-7.42(m,4H),7.48(d,1H,J＝8.4Hz),7.58(d,1H,J＝1.8Hz),8.07(s,1H)；LC/MS(ESI)m/z:413.0[M+H]⁺。

125. 1- (1H-benzimidazol-5-yl) -5- [4- (5-chlorothien-2-yl) -2, 6-difluorophenyl ] imidazolidin-2-one (Compound 32)

1- (1H-benzimidazol-5-yl) -5- [4- (5-chlorothien-2-yl) -2, 6-difluorophenyl ] -imidazolidin-2-one (compound 32) was prepared from compound 140e in a three-step synthetic imidazolidinone formation. The procedure was the same as for the synthesis of compound 1. The product (compound 32) was obtained as a white solid in 20% overall yield.

126. (5R) -1- (1H-benzimidazol-5-yl) -5- {4- [5- (trifluoromethyl) thiophen-2-yl ] phenyl } imidazolidin-2-one (Compound 33)

127. (5S) -1- (1H-benzimidazol-5-yl) -5- {4- [5- (trifluoromethyl) thiophen-2-yl ] phenyl } imidazolidin-2-one (Compound 34)

The enantiomers (compounds 33 and 34) were separated from compound 13 by HPLC using CHIRALPAKAD-H. The isomeric fractions were collected separately and the solvent was removed under reduced pressure to give optically pure isomers (compounds 33 and 34).¹HNMR(300MHz,CD3OD)δ3.36(dd,1H,J＝6.9,9.3Hz),3.99(dd,1H,J＝9.3,9.3Hz),5.51(dd,1H,J＝6.9,9.3Hz),7.29-7.32(m,2H),7.43-7.48(m,4H),7.55-7.60(m,3H),8.06(s,1H)；LC/MS(ESI)m/z:429.2[M+H]⁺。

128. (5R) -1- (1H-benzimidazol-5-yl) -5- {4- [5- (trifluoromethyl) thiophen-3-yl ] phenyl } imidazolidin-2-one (Compound 35)

129. (5S) -1- (1H-benzimidazol-5-yl) -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 CHIRALPAKAD-H. The isomeric fractions were collected separately and the solvent was removed under reduced pressure to give optically pure isomers (compounds 35 and 36).¹HNMR(300MHz,CD3OD)δ3.36(dd,1H,J＝6.9,9.0Hz),3.99(dd,1H,J＝9.0,9.3Hz),5.50(dd,1H,J＝6.9,9.3Hz),7.30(d,1H,J＝8.1Hz),7.41-7.47(m,3H),7.56-7.58(m,3H),7.81(s,2H),8.05(s,1H)；LC/MS(ESI)m/z:429.1[M+H]⁺。

130. 1- {4- [4- (trifluoromethyl) -1, 3-thiazol-2-yl ] phenyl } ethanone (Compound 185)

Preparation of 1- {4- [4- (trifluoromethyl) -1, 3-thiazol-2-yl by Suzuki coupling of (4-acetylphenyl) boronic acid 184 and Compound 119d]Phenyl group, 185. The procedure was the same as for the synthesis of compound 120 a. Product 185 was obtained as a white solid in 83% yield.¹H NMR(400MHz,CDCl3)δ2.65(s,3H),7.82(s,1H),8.05(d,2H,J＝8.6Hz),8.09(d,2H,J＝8.6Hz)；LC/MS(ESI)m/z:271.7[M+H]⁺。

131. Oxo {4- [4- (trifluoromethyl) -1, 3-thiazol-2-yl ] phenyl } acetaldehyde (Compound 186)

Compound 185(10.0g, 36.86mmol) and selenium dioxide (6.95g, 62.67mmol) were dissolved in H2O/1, 4-dioxane (8mL/160 mL). The reaction mixture was stirred at 100 ℃ 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 silica gel column chromatography using ethyl acetate/hexane (1/1) as eluent. Product 186 was obtained as a yellow solid in 100% yield.

132. 1- (1H-Benzoimidazol-5-yl) -5- {4- [4- (trifluoromethyl) -1, 3-thiazol-2-yl ] phenyl } imidazolidine-2, 4-dione (Compound 37)

Compound 186(9.0g, 31.55mmol) and 1- (1H-benzimidazol-6-yl) urea 187(5.56g, 31.55mmol) are dissolved in HCl/AcOH (3mL/120 mL). The reaction mixture was stirred at 120 ℃ overnight. After removal of the solvent, the residue was treated with excess methanolic ammonia in an ice bath and stirred at room temperature for 1 hour. The precipitate was filtered and washed with ethyl acetate and water to give the pure product. The filtrate was concentrated and recrystallized from ethyl acetate. The product (compound 37) was collected as a white solid in 45% yield.¹HNMR(300MHz,DMSO-d₆)δ6.13(s,1H),7.27(s,1H),7.43(s,1H),7.55(d,2H,J＝8.4Hz),7.71(s,1H),7.94(d,2H,J＝8.4Hz),8.16(s,1H),8.52(s,1H),11.43(s,1H),12.41(s,1H)；LC/MS(ESI)m/z:444.2[M+H]⁺。

133. 1- [4- (2-cyclopropyl-1, 3-thiazol-4-yl) phenyl ] ethanone (Compound 188)

Preparation of 1- [4- (2-cyclopropyl-1, 3-thiazol-4-yl) phenyl ] boronic acid from Suzuki coupling of (4-acetylphenyl) boronic acid 184 and compound 126 using Pd (dppf) Cl2 as catalyst]And (3) an ethyl ketone 188. The procedure was the same as for the synthesis of compound 127. Product 188 was obtained as a white solid in 57% yield.¹H NMR(400MHz,CDCl3)δ1.09-1.16(m,4H),2.32-2.37(m,1H),2.60(s,3H),7.35(s,1H),7.94(d,2H,J＝8.8Hz),7.97(d,2H,J＝8.8Hz)；LC/MS(ESI)m/z:244.1[M+H]⁺。

134. [4- (2-cyclopropyl-1, 3-thiazol-4-yl) phenyl ] (oxo) acetaldehyde (compound 189)

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

135. 1- (1H-Benzoimidazol-5-yl) -5- [4- (2-cyclopropyl-1, 3-thiazol-4-yl) phenyl ] imidazolidine-2, 4-dione (Compound 38)

Preparation of 1- (1H-benzimidazol-5-yl) -5- [4- (2-cyclopropyl-1, 3-thiazol-4-yl) phenyl from cycloaddition reaction of 1- (1H-benzimidazol-6-yl) urea 187 and compound 189]Imidazolidine-2, 4-dione (compound 38). The procedure was the same as for the synthesis of compound 37. The product (compound 38) was obtained as a white solid in 49% yield.¹HNMR(400MHz,DMSO-d₆)δ1.00-1.03(m,2H),1.08-1.11(m,2H),2.36-2.42(m,1H),6.03(s,1H),7.28(s,1H),7.41(d,2H,J＝8.0Hz),7.48(s,1H),7.69(s,1H),7.77(s,1H),7.83(d,2H,J＝8.0Hz),8.15(s,1H),11.38(s,1H),12.41(s,1H)；LC/MS(ESI)m/z:416.2[M+H]⁺。

136. 1- [4- (2-cyclopropyl-1, 3-thiazol-5-yl) phenyl ] ethanone (Compound 190b)

A solution of methylmagnesium bromide in THF (1M, 2mL) was added dropwise to a solution of compound 134b (0.23g, 1.0mmol) in dry THF (4mL) at 0 deg.C. The reaction mixture was then stirred at room temperature overnight. Adding saturated ammonium chloride waterThe solution was used to quench the reaction. 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 silica gel column chromatography using ethyl acetate/hexane (1/4) as eluent. Product 190b was obtained as a yellow solid in 48% yield.¹H NMR(300MHz,CDCl3)δ1.13-1.19(m,4H),2.30-2.35(m,1H),2.61(s,3H),7.58(d,2H,J＝8.0Hz),7.85(s,1H),7.96(d,2H,J＝8.0Hz)；LC/MS(ESI)m/z:244.1[M+H]⁺。

137. 1- {4- [2- (trifluoromethyl) -1, 3-thiazol-5-yl ] phenyl } ethanone (Compound 190c)

Preparation of 1- {4- [2- (trifluoromethyl) -1, 3-thiazol-5-yl radical by methylation of Compound 134c]Phenyl } ethanone 190 c. The procedure was the same as for the synthesis of compound 190 b. Product 190c was obtained as a yellow solid in 49% yield.¹HNMR(400MHz,CDCl3)δ2.64(s,3H),7.69(d,2H,J＝8.0Hz),8.04(d,2H,J＝8.0Hz),8.17(s,1H)；LC/MS(ESI)m/z:271.7[M+H]⁺。

138. [4- (2-cyclopropyl-1, 3-thiazol-5-yl) phenyl ] (oxo) acetaldehyde (Compound 191b)

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

139. Oxo {4- [2- (trifluoromethyl) -1, 3-thiazol-5-yl ] phenyl } acetaldehyde (Compound 191c)

Oxidation of compound 190c with selenium dioxide produces oxo {4- [2- (trifluoromethyl) -1, 3-thiazol-5-yl ] phenyl } acetaldehyde 191 c. The procedure was the same as for the synthesis of compound 186. Product 191c is obtained as a yellow solid in 100% yield.

140. 1- (1H-Benzoimidazol-5-yl) -5- [4- (2-cyclopropyl-1, 3-thiazol-5-yl) phenyl ] imidazolidine-2, 4-dione (Compound 39)

Preparation of 1- (1H-benzimidazol-5-yl) -5- [4- (2-cyclopropyl-1, 3-thiazol-5-yl) phenyl from the cycloaddition reaction of 1- (1H-benzimidazol-6-yl) urea 187 with Compound 191b]Imidazolidine-2, 4-dione (Compound 39). The procedure was the same as for the synthesis of compound 37. The product (compound 39) was obtained as a white solid in 57% yield.¹HNMR(400MHz,DMSO-d₆)δ0.93-0.99(m,2H),1.01-1.11(m,2H),2.33-2.39(m,1H),6.05(s,1H),7.33(d,1H,J＝8.6Hz),7.41(d,2H,J＝8.0Hz),7.48(d,1H,J＝8.6Hz),7.53(d,2H,J＝8.0Hz),7.70(d,1H,J＝1.2Hz),7.91(s,1H),8.18(s,1H),11.39(s,1H),12.47(s,1H)；LC/MS(ESI)m/z:416.2[M+H]⁺。

141. 1- (1H-Benzoimidazol-5-yl) -5- {4- [2- (trifluoromethyl) -1, 3-thiazol-5-yl ] phenyl } imidazolidine-2, 4-dione (Compound 40)

Preparation of 1- (1H-benzimidazol-5-yl) -5- {4- [2- (trifluoromethyl) -1, 3-thiazol-5-yl ] by cycloaddition of 1- (1H-benzimidazol-6-yl) urea 187 and Compound 191c]Phenyl } -imidazolidine-2, 4-dione (compound 40). The procedure was the same as for the synthesis of compound 37. The product (compound 40) was obtained as a white solid in 30% yield.¹H NMR(400MHz,DMSO-d₆)δ6.12(s,1H),7.35(s,1H),7.47-7.52(m,3H),7.71-7.75(m,3H),8.16(s,1H),8.48(s,1H),11.44(s,1H),12.43(s,1H)；LC/MS(ESI)m/z:444.2[M+H]⁺。

142. 1- [4- (2H-tetrazol-5-yl) phenyl ] ethanone (Compound 192)

Sodium azide (2.15g, 33mmol) and ammonium chloride (0.40g, 7.5mmol) were added to a solution of 4-acetylbenzonitrile 143(4.35g, 30.0mmol) in DMF (30mL) under nitrogen. 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 1n hcl (aq). After filtration, the precipitate was washed with water and diethyl ether to give product 192 as a yellow solid in 94% yield.

143. 1- (1H-Benzimidazol-5-yl) -5- [4- (2-methyl-2H-tetrazol-5-yl) phenyl ] imidazolidine-2, 4-dione (Compound 41)

Preparation of 1- (1H-benzimidazol-5-yl) -5- [4- (2-methyl-2H-tetrazol-5-yl) phenyl from the cycloaddition reaction of 1- (1H-benzimidazol-6-yl) urea 187 with Compound 194a]Imidazolidine-2, 4-dione (Compound 41). The procedure was the same as for the synthesis of compound 37. The product (compound 41) was obtained as a white solid in 17% yield.¹H NMR(400MHz,DMSO-d₆)δ4.38(s,3H),6.12(s,1H),7.28(br s,1H),7.47(br s,1H),7.57(d,2H,J＝8.4Hz),7.72(s,1H),8.00(d,2H,J＝8.4Hz),8.16(s,1H),11.46(br s,1H),12.44(br s,1H)；LC/MS(ESI)m/z:375.1[M+H]⁺。

144. 1- (1H-Benzimidazol-5-yl) -5- [4- (2-propyl-2H-tetrazol-5-yl) phenyl ] imidazolidine-2, 4-dione (Compound 42)

Preparation of 1- (1H-benzimidazol-5-yl) -5- [4- (2-propyl-2H-tetrazol-5-yl) phenyl from the cycloaddition reaction of 1- (1H-benzimidazol-6-yl) urea 187 with Compound 194b]Imidazolidine-2, 4-dione (Compound 42). The procedure was the same as for the synthesis of compound 37. To obtain the product (Compound)42) As a white solid, yield 33%.¹H NMR(300MHz,DMSO-d₆)δ0.84(t,3H,J＝7.5Hz),1.87-1.99(m,2H),4.65(t,2H,J＝6.8Hz),6.12(s,1H),7.34(br s,1H),7.47(br s,1H),7.57(d,2H,J＝8.4Hz),7.71(s,1H),8.00(d,2H,J＝8.4Hz),8.15(s,1H),11.43(s,1H),12.41(s,1H)；LC/MS(ESI)m/z:403.2[M+H]⁺。

145. 1- (1H-Benzimidazol-5-yl) -5- {4- [2- (propan-2-yl) -2H-tetrazol-5-yl ] phenyl } imidazolidine-2, 4-dione (Compound 43)

Preparation of 1- (1H-benzimidazol-5-yl) -5- {4- [2- (propan-2-yl) -2H-tetrazol-5-yl radical from the cycloaddition reaction of 1- (1H-benzimidazol-6-yl) urea 187 with Compound 194c]Phenyl } imidazolidine-2, 4-dione (Compound 43). The procedure was the same as for the synthesis of compound 37. The product (compound 43) was obtained as a white solid in 28% yield.¹HNMR(400MHz,DMSO-d₆)δ1.57(d,6H,J＝6.4Hz),5.09-5.16(m,1H),6.11(s,1H),7.27(brs,1H),7.42(br s,1H),7.57(d,2H,J＝8.4Hz),7.71(s,1H),8.00(d,2H,J＝8.4Hz),8.15(s,1H),11.43(s,1H),12.41(s,1H)；LC/MS(ESI)m/z:403.2[M+H]⁺。

146. 1- (1H-Benzimidazol-5-yl) -5- {4- [2- (2-methylpropyl) -2H-tetrazol-5-yl ] phenyl } imidazolidine-2, 4-dione (Compound 44)

Preparation of 1- (1H-benzimidazol-5-yl) -5- {4- [2- (2-methylpropyl) -2H-tetrazol-5-yl ] by cycloaddition of 1- (1H-benzimidazol-6-yl) urea 187 and Compound 194d]Phenyl } imidazolidine-2, 4-dione (Compound 44). The procedure was the same as for the synthesis of compound 37. The product (compound 44) was obtained as a white solid in 34% yield.¹HNMR(400MHz,DMSO-d₆)δ0.86(d,6H,J＝6.4Hz),2.22-2.29(m,1H),4.53(d,2H,J＝6.8Hz),6.12(s,1H),7.28(br s,1H),7.47(br s,1H),7.57(d,2H,J＝8.0Hz),7.72(s,1H),8.01(d,2H,J＝8.0Hz),8.16(s,1H),11.45(s,1H),12.42(s,1H)；LC/MS(ESI)m/z:417.2[M+H]⁺。

147. 1- (1H-Benzimidazol-5-yl) -5- {4- [2- (cyclopropylmethyl) -2H-tetrazol-5-yl ] phenyl } -imidazolidine-2, 4-dione (Compound 45)

Preparation of 1- (1H-benzimidazol-5-yl) -5- {4- [2- (cyclopropylmethyl) -2H-tetrazol-5-yl ] by cycloaddition of 1- (1H-benzimidazol-6-yl) urea 187 and Compound 194e]Phenyl } -imidazolidine-2, 4-dione (Compound 45). The procedure was the same as for the synthesis of compound 37. The product (compound 45) was obtained as a white solid in 31% yield.¹H NMR(300MHz,DMSO-d₆)δ0.42-0.45(m,2H),0.54-0.58(m,2H),1.33-1.41(m,1H),4.57(d,2H,J＝7.2Hz),6.12(s,1H),7.29(brs,1H),7.46(brs,1H),7.58(d,2H,J＝8.4Hz),7.72(s,1H),8.01(d,2H,J＝8.4Hz),8.15(s,1H),11.43(s,1H),12.41(s,1H)；LC/MS(ESI)m/z:415.1[M+H]⁺。

148. 1- (1H-Benzimidazol-5-yl) -5- {4- [2- (2,2, 2-trifluoroethyl) -2H-tetrazol-5-yl ] phenyl } -imidazolidine-2, 4-dione (Compound 46)

Preparation of 1- (1H-benzimidazol-5-yl) -5- {4- [2- (2,2, 2-trifluoroethyl) -2H-tetrazol-5-yl from the cycloaddition reaction of 1- (1H-benzimidazol-6-yl) urea 187 and Compound 194f]Phenyl } -imidazolidine-2, 4-dione (compound 46). The procedure was the same as for the synthesis of compound 37. The product (compound 46) was obtained as a white solid in 36% yield.¹H NMR(300MHz,DMSO-d₆)δ6.01(q,2H,J＝8.7Hz),6.15(s,1H),7.36(br s,1H),7.48(br s,1H),7.61(d,2H,J＝8.4Hz),7.73(s,1H),8.04(d,2H,J＝8.4Hz),8.17(s,1H),11.49(br s,1H),12.41(br s,1H)；LC/MS(ESI)m/z:443.2[M+H]⁺。

149. 1- (1H-Benzimidazol-5-yl) -5- {4- [2- (prop-2-yn-1-yl) -2H-tetrazol-5-yl ] phenyl } imidazolidine-2, 4-dione (Compound 47)

Preparation of 1- (1H-benzimidazol-5-yl) -5- {4- [2- (prop-2-yn-1-yl) -2H-tetrazol-5-yl from a cycloaddition reaction of 1- (1H-benzimidazol-6-yl) urea 187 with 194g of Compound]Phenyl } imidazolidine-2, 4-dione (Compound 47). The procedure was the same as for the synthesis of compound 37. The product (compound 47) was obtained as a white solid in 36% yield.¹HNMR(300MHz,DMSO-d₆)δ5.75(d,1H,J＝1.5Hz),6.07(d,1H,J＝6.6Hz),6.14(s,1H),7.29(br s,1H),7.47(br s,1H),7.59(d,2H,J＝8.0Hz),7.72(s,1H),8.02(d,2H,J＝8.0Hz),8.16(s,1H),8.24(dd,1H,J＝1.5,6.6Hz),11.47(br s,1H),12.44(s,1H)；LC/MS(ESI)m/z:399.1[M+H]⁺。

150. 1- (1H-Benzimidazol-5-yl) -5- {4- [2- (but-2-yn-1-yl) -2H-tetrazol-5-yl ] phenyl } imidazolidine-2, 4-dione (Compound 48)

Preparation of 1- (1H-benzimidazol-5-yl) -5- {4- [2- (but-2-yn-1-yl) -2H-tetrazol-5-yl from a cycloaddition reaction of 1- (1H-benzimidazol-6-yl) urea 187 with Compound 194H]Phenyl } imidazolidine-2, 4-dione (Compound 48). The procedure was the same as for the synthesis of compound 37. The product (compound 48) was obtained as a white solid in 34% yield.¹HNMR(300MHz,DMSO-d₆)δ1.83(s,3H),5.65(d,2H,J＝1.8Hz),6.13(s,1H),7.34(d,1H,J＝6.6Hz),7.48(d,1H,J＝8.7Hz),7.58(d,2H,J＝7.8Hz),7.72(s,1H),8.02(d,2H,J＝7.8Hz),8.16(s,1H),11.44(s,1H),12.41(s,1H)；LC/MS(ESI)m/z:413.1[M+H]⁺。

151. 1- (1H-Benzimidazol-5-yl) -5- {4- [2- (pent-2-yn-1-yl) -2H-tetrazol-5-yl ] phenyl } imidazolidine-2, 4-dione (Compound 49)

Preparation of 1- (1H-benzimidazol-5-yl) -5- {4- [2- (pent-2-yn-1-yl) -2H-tetrazol-5-yl from the cycloaddition reaction of 1- (1H-benzimidazol-6-yl) urea 187 and Compound 194i]Phenyl } imidazolidine-2, 4-dione (Compound 49). The procedure was the same as for the synthesis of compound 37. The product (compound 49) was obtained as a white solid in 32% yield.¹HNMR(300MHz,DMSO-d₆)δ1.03(t,3H,J＝7.5Hz),2.17-2.26(m,2H),5.65(t,2H,J＝2.1Hz),6.11(s,1H),7.29(brs,1H),7.46(brs,1H),7.58(d,2H,J＝8.4Hz),7.71(s,1H),8.01(d,2H,J＝8.4Hz),8.15(s,1H),11.43(br s,1H),12.42(br s,1H)；LC/MS(ESI)m/z:427.1[M+H]⁺。

152. 1- (1H-benzimidazol-5-yl) -5- {4- [2- (4-chlorobenzyl) -2H-tetrazol-5-yl ] phenyl } imidazolidine-2, 4-dione (compound 50)

Preparation of 1- (1H-benzoimidazol-5-yl) -5- {4- [2- (4-chlorobenzyl) -2H-tetrazol-5-yl group by cycloaddition of 1- (1H-benzoimidazol-6-yl) urea 187 and compound 194j]Phenyl } imidazolidine-2, 4-dione (Compound 50). The procedure was the same as for the synthesis of compound 37. The product (compound 50) was obtained as a white solid in 43% yield.¹H NMR(300MHz,DMSO-d₆)δ5.98(s,2H),6.11(s,1H),7.25(d,1H,J＝8.1Hz),7.36-7.50(m,5H),7.56(d,2H,J＝8.4Hz),7.70(s,1H),7.99(d,2H,J＝8.4Hz),8.15(s,1H),11.44(s,1H),12.41(s,1H)；LC/MS(ESI)m/z:485.1[M+H]⁺。

153. 1- (1H-benzimidazol-5-yl) -5- {4- [2- (4-methoxybenzyl) -2H-tetrazol-5-yl ] phenyl } -imidazolidine-2, 4-dione (compound 51)

Preparation of 1- (1H-benzoimidazol-5-yl) -5- {4- [2- (4-methoxybenzyl) -2H-tetrazole-5-Base of]Phenyl } -imidazolidine-2, 4-dione (Compound 51). The procedure was the same as for the synthesis of compound 37. The product (compound 51) was obtained as a white solid in 22% yield.¹H NMR(300MHz,DMSO-d₆)δ3.71(s,3H),5.86(s,2H),6.15(s,1H),6.91(d,2H,J＝8.4Hz),7.33(d,2H,J＝8.4Hz),7.42(br s,2H),7.55(d,2H,J＝8.1Hz),7.70(s,1H),7.98(d,2H,J＝8.1Hz),8.15(s,1H),11.43(s,1H),12.41(s,1H)；LC/MS(ESI)m/z:481.2[M+H]⁺。

154. 1- (1H-Benzimidazol-5-yl) -5- (4- {2- [ (3-methyl-1, 2-oxazol-5-yl) methyl ] -2H-tetrazol-5-yl } phenyl) imidazolidine-2, 4-dione (Compound 52)

Preparation of 1- (1H-benzimidazol-5-yl) -5- (4- {2- [ (3-methyl-1, 2-oxazol-5-yl) methyl by cycloaddition of 1- (1H-benzimidazol-6-yl) urea 187 and Compound 194l]-2H-tetrazol-5-yl } phenyl) imidazolidine-2, 4-dione (compound 52). The procedure was the same as for the synthesis of compound 37. The product (compound 52) was obtained as a white solid in 52% yield.¹HNMR(400MHz,DMSO-d₆)δ2.20(s,3H),6.12(s,1H),6.24(s,2H),6.51(s,1H),7.27(brs,1H),7.46(brs,1H),7.58(d,2H,J＝8.0Hz),7.71(s,1H),8.00(d,2H,J＝8.0Hz),8.16(s,1H),11.30(brs,1H),12.42(brs,1H)；LC/MS(ESI)m/z:456.1[M+H]⁺。

155. N- [2- (4-cyanophenyl) -2-oxoethyl ] tricyclo [3.3.1.13,7] decane-1-carboxamide (Compound 196)

Preparation of N- [2- (4-cyanophenyl) -2-oxoethyl by acetylation of Compound 131 with adamantane-1-carbonyl chloride 195]Tricyclic [3.3.1.13,7]]Decane-1-carboxamide 196. The experimental procedure was the same as for the synthesis of compound 133 a. Product 196 was obtained as a yellow solid in 53% yield.¹HNMR(400MHz,CDCl3)δ1.71-1.78(m,6H),1.92(s,6H),2.07(s,3H),4.74(d,2H,J＝4.0Hz),6.65(s,1H),7.81(d,2H,J＝8.6Hz),8.07(d,2H,J＝8.6Hz)；LC/MS(ESI)m/z:323.3[M+H]⁺。

156. 4- [2- (tricyclo [3.3.1.13,7] decan-1-yl) -1, 3-thiazol-5-yl ] benzonitrile (compound 197)

Preparation of 4- [2- (tricyclo [3.3.1.13, 7) by cyclization of Compound 196 with Lawson's reagent in THF]Decan-1-yl) -1, 3-thiazol-5-yl]Benzonitrile 197. The experimental procedure was the same as for the synthesis of compound 134 a. Product 197 was obtained as a white solid in 49% yield.¹H NMR(400MHz,CDCl3)δ1.80(s,6H),2.08(s,6H),2.13(s,3H),7.61-7.67(m,4H),7.94(s,1H)；LC/MS(ESI)m/z:321.3[M+H]⁺。

157. 4- [2- (tricyclo [3.3.1.13,7] decan-1-yl) -1, 3-thiazol-5-yl ] benzaldehyde (compound 198)

Preparation of 4- [2- (tricyclo [3.3.1.13, 7) by reduction of compound 197 with DIBAL-H reagent]Decan-1-yl) -1, 3-thiazol-5-yl]Benzaldehyde 198. The experimental procedure was the same as for the synthesis of compound 135 a. Product 198 was obtained as a yellow solid in 83% yield.¹HNMR(300MHz,CDCl3)δ1.81(s,6H),2.10(s,6H),2.14(s,3H),7.70(d,2H,J＝8.4Hz),7.89(d,2H,J＝8.4Hz),7.98(s,1H),10.00(s,1H)；LC/MS(ESI)m/z:324.3[M+H]⁺。

158. (1H-benzimidazol-5-ylamino) {4- [2- (tricyclo [3.3.1.13,7] decan-1-yl) -1, 3-thiazol-5-yl ] phenyl } acetonitrile (Compound 199)

(1H-benzimidazol-5-ylamino) {4- [2- (tricyclo [3.3.1.13,7] decan-1-yl) -1, 3-thiazol-5-yl ] phenyl } acetonitrile 199 was prepared by the addition of 1H-benzimidazol-5-amine 121, TMSCN and compound 198. The experimental procedure was the same as for the synthesis of compound 122 a. Product 199 was obtained as a pale yellow solid in 91% yield.

159. N1- (1H-Benzimidazol-5-yl) -1- {4- [2- (tricyclo [3.3.1.13,7] decan-1-yl) -1, 3-thiazol-5-yl ] phenyl } ethane 1, 2-diamine (Compound 200)

Compound 199 was hydrogenated using raney nickel reagent as a catalyst to produce N1- (1H-benzoimidazol-5-yl) -1- {4- [2- (tricyclo [3.3.1.13,7] decan-1-yl) -1, 3-thiazol-5-yl ] phenyl } ethane 1, 2-diamine 200. The experimental procedure was the same as for the synthesis of compound 123 a. Product 200 was obtained as a yellow viscous liquid in 60% yield.

160. 1- (1H-Benzimidazol-5-yl) -5- {4- [2- (tricyclo [3.3.1.13,7] decan-1-yl) -1, 3-thiazol-5-yl ] phenyl } imidazolidine 2-one (Compound 57)

Preparation of 1- (1H-benzimidazol-5-yl) -5- {4- [2- (tricyclo [3.3.1.13, 7) by cycloaddition of 1,1' -carbonyldiimidazole and Compound 200]Decan-1-yl) -1, 3-thiazol-5-yl]Phenyl } imidazolidine 2-one (Compound 57). The experimental procedure was the same as for the synthesis of compound 1. The product (compound 57) was obtained as a yellow solid. The yield was 78%.¹HNMR(400MHz,CD3OD)δ1.75(s,6H),2.03(s,6H),2.05(s,3H),3.32-3.36(m,1H),3.97(dd,1H,J＝9.2,9.2Hz),5.49(dd,1H,J＝6.8,9.2Hz),7.30(d,1H,J＝8.8Hz),7.40(d,2H,J＝8.4Hz),7.45-7.49(m,3H),7.56(s,1H),7.79(s,1H),8.06(s,1H)；LC/MS(ESI)m/z:496.4[M+H]⁺。

161. 2, 3-difluoro-4- (5-fluorothiophen-3-yl) benzaldehyde (Compound 201a)

2, 3-difluoro-4- (5-fluorothiophen-3-yl) benzaldehyde 201a was prepared from a suzuki-miyaura coupling of 118g of 2, 3-difluoro-4-formylphenylboronic acid and 4-bromo-2-fluorothiophene 158 d. The experimental procedure was the same as for the synthesis of compound 159 a. Product 201a was obtained as a light yellow oil in 42% yield.

162. 4- (5-chlorothien-3-yl) -2, 3-difluorobenzaldehyde (Compound 201b)

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

163. 2, 3-difluoro-4- (5-methylthiophen-3-yl) benzaldehyde (Compound 201c)

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

164. 4- (5-ethylthiophen-3-yl) -2, 3-difluorobenzaldehyde (Compound 201d)

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

165. 2, 3-difluoro-4- [5- (methoxymethyl) thiophen-3-yl ] benzaldehyde (Compound 201e)

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

166. 4- [5- (ethoxymethyl) thiophen-3-yl ] -2, 3-difluorobenzaldehyde (compound 201f)

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

167. 4- (2, 3-difluoro-4-formylphenyl) thiophene-2-carboxylic acid methyl ester (Compound 201g)

201g of methyl 4- (2, 3-difluoro-4-formylphenyl) thiophene-2-carboxylate was prepared by suzuki-miyaura coupling of 118g of 2, 3-difluoro-4-formylphenyl boronic acid and methyl 4-bromothiophene-2-carboxylate 158 i. The experimental procedure was the same as for the synthesis of compound 159 a. 201g of product was obtained as a pale yellow oil in 42% yield.

168. 2, 3-difluoro-4- (thiophen-3-yl) benzaldehyde (Compound 201h)

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

169. (1H-benzimidazol-5-ylamino) [2, 3-difluoro-4- (5-fluorothiophen-3-yl) phenyl ] acetonitrile (Compound 202a)

(1H-benzimidazol-5-ylamino) [2, 3-difluoro-4- (5-fluorothiophen-3-yl) phenyl ] acetonitrile 202a was prepared by adding 1H-benzimidazol-5-amine 121, TMSCN and compound 201 a. The experimental procedure was the same as for the synthesis of compound 122 a. Product 202a was obtained as a pale yellow solid in 85% yield.

170. (1H-benzimidazol-5-ylamino) [4- (5-chlorothien-3-yl) -2, 3-difluorophenyl ] acetonitrile (Compound 202b)

(1H-benzimidazol-5-ylamino) [4- (5-chlorothien-3-yl) -2, 3-difluorophenyl ] acetonitrile 202b was prepared by adding 1H-benzimidazol-5-amine 121, TMSCN and compound 201 b. The experimental procedure was the same as for the synthesis of compound 122 a. Product 202b was obtained as a pale yellow solid in 79% yield.

171. (1H-benzimidazol-5-ylamino) [2, 3-difluoro-4- (5-methylthiophen-3-yl) phenyl ] acetonitrile (Compound 202c)

(1H-benzimidazol-5-ylamino) [2, 3-difluoro-4- (5-methylthiophen-3-yl) phenyl ] acetonitrile 202c was prepared by adding 1H-benzimidazol-5-amine 121, TMSCN and compound 201 c. The experimental procedure was the same as for the synthesis of compound 122 a. Product 202c was obtained as a pale yellow solid in 88% yield.

172. (1H-benzimidazol-5-ylamino) [4- (5-ethylthiophen-3-yl) -2, 3-difluorophenyl ] acetonitrile (Compound 202d)

(1H-benzimidazol-5-ylamino) [4- (5-ethylthiophen-3-yl) -2, 3-difluorophenyl ] acetonitrile 202d was prepared by adding 1H-benzimidazol-5-amine 121, TMSCN and compound 201 d. The experimental procedure was the same as for the synthesis of compound 122 a. Product 202d was obtained as a pale yellow solid in 81% yield.

173. (1H-benzimidazol-5-ylamino) {2, 3-difluoro-4- [5- (methoxymethyl) thiophen-3-yl ] phenyl } acetonitrile (Compound 202e)

(1H-benzimidazol-5-ylamino) {2, 3-difluoro-4- [5- (methoxymethyl) thiophen-3-yl ] phenyl } acetonitrile 202e was prepared by adding 1H-benzimidazol-5-amine 121, TMSCN and compound 201 e. The experimental procedure was the same as for the synthesis of compound 122 a. Product 202e was obtained as a pale yellow solid in 84% yield.

174. (1H-benzimidazol-5-ylamino) {4- [5- (ethoxymethyl) thiophen-3-yl ] -2, 3-difluorophenyl } acetonitrile (Compound 202f)

(1H-benzimidazol-5-ylamino) {4- [5- (ethoxymethyl) thiophen-3-yl ] -2, 3-difluorophenyl } acetonitrile 202f was prepared by adding 1H-benzimidazol-5-amine 121, TMSCN and compound 201 f. The experimental procedure was the same as for the synthesis of compound 122 a. Product 202f was obtained as a pale yellow solid in 90% yield.

175. 4- {4- [ (1H-benzimidazol-5-ylamino) (cyano) methyl ] -2, 3-difluorophenyl } thiophene-2-carboxylic acid methyl ester (Compound 202g)

202g of methyl 4- {4- [ (1H-benzimidazol-5-ylamino) (cyano) methyl ] -2, 3-difluorophenyl } thiophene-2-carboxylate was prepared by adding 1H-benzimidazol-5-amine 121, TMSCN and 201g of compound. The experimental procedure was the same as for the synthesis of compound 122 a. 202g of product was obtained as a pale yellow solid with a yield of 81%.

176. (1H-benzimidazol-5-ylamino) [2, 3-difluoro-4- (thiophen-3-yl) phenyl ] acetonitrile (Compound 202H)

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

177. N1- (1H-benzimidazol-5-yl) -1- [2, 3-difluoro-4- (5-fluorothiophen-3-yl) phenyl ] ethane-1, 2-diamine (Compound 203a)

Compound 202a was hydrogenated using raney nickel reagent as a catalyst to produce N1- (1H-benzoimidazol-5-yl) -1- [2, 3-difluoro-4- (5-fluorothiophen-3-yl) phenyl ] ethane-1, 2-diamine 203 a. The experimental procedure was the same as for the synthesis of compound 123 a. Product 203a was obtained as a yellow viscous liquid in 43% yield.

178. N1- (1H-benzimidazol-5-yl) -1- [4- (5-chlorothien-3-yl) -2, 3-difluorophenyl ] ethane-1, 2-diamine (Compound 203b)

Compound 202b was hydrogenated using raney nickel reagent as a catalyst to produce N1- (1H-benzoimidazol-5-yl) -1- [4- (5-chlorothien-3-yl) -2, 3-difluorophenyl ] ethane-1, 2-diamine 203 b. The experimental procedure was the same as for the synthesis of compound 123 a. Product 203b was obtained as a yellow viscous liquid in 40% yield.

179. N1- (1H-Benzimidazol-5-yl) -1- [2, 3-difluoro-4- (5-methylthiophen-3-yl) phenyl ] ethane-1, 2-diamine (Compound 203c)

Compound 202c was hydrogenated using raney nickel reagent as a catalyst to produce N1- (1H-benzoimidazol-5-yl) -1- [2, 3-difluoro-4- (5-methylthiophen-3-yl) phenyl ] ethane-1, 2-diamine 203 c. The experimental procedure was the same as for the synthesis of compound 123 a. Product 203c was obtained as a yellow viscous liquid in 53% yield.

180. N1- (1H-benzimidazol-5-yl) -1- [4- (5-ethylthiophen-3-yl) -2, 3-difluorophenyl ] ethane-1, 2-diamine (Compound 203d)

Compound 202d was hydrogenated using raney nickel reagent as a catalyst to produce N1- (1H-benzoimidazol-5-yl) -1- [4- (5-ethylthiophen-3-yl) -2, 3-difluorophenyl ] ethane-1, 2-diamine 203 d. The experimental procedure was the same as for the synthesis of compound 123 a. Product 203d was obtained as a yellow viscous liquid in 51% yield.

181. N1- (1H-Benzimidazol-5-yl) -1- {2, 3-difluoro-4- [5- (methoxymethyl) thiophen-3-yl ] phenyl } ethane-1, 2-diamine (Compound 203e)

Compound 202e was hydrogenated using raney nickel reagent as a catalyst to produce N1- (1H-benzoimidazol-5-yl) -1- {2, 3-difluoro-4- [5- (methoxymethyl) thiophen-3-yl ] phenyl } ethane-1, 2-diamine 203 e. The experimental procedure was the same as for the synthesis of compound 123 a. Product 203e was obtained as a yellow viscous liquid in 46% yield.

182. N1- (1H-Benzimidazol-5-yl) -1- {4- [5- (ethoxymethyl) thiophen-3-yl ] -2, 3-difluorophenyl } ethane-1, 2-diamine (Compound 203f)

Compound 202f was hydrogenated using raney nickel reagent as a catalyst to produce N1- (1H-benzoimidazol-5-yl) -1- {4- [5- (ethoxymethyl) thiophen-3-yl ] -2, 3-difluorophenyl } ethane-1, 2-diamine 203 f. The experimental procedure was the same as for the synthesis of compound 123 a. Product 203f was obtained as a yellow viscous liquid in 49% yield.

183. 4- {4- [ 2-amino-1- (1H-benzimidazol-5-ylamino) ethyl ] -2, 3-difluorophenyl } thiophene-2-carboxylic acid methyl ester (compound 203g)

202g of compound was hydrogenated using Raney's nickel reagent as a catalyst to prepare 203g of methyl 4- {4- [ 2-amino-1- (1H-benzimidazol-5-ylamino) ethyl ] -2, 3-difluorophenyl } thiophene-2-carboxylate. The experimental procedure was the same as for the synthesis of compound 123 a. 203g of product was obtained as a yellow viscous liquid in 47% yield.

184. N1- (1H-benzimidazol-5-yl) -1- [2, 3-difluoro-4- (thien-3-yl) phenyl ] ethane-1, 2-diamine (Compound 203H)

Compound 202H was hydrogenated using raney nickel reagent as a catalyst to produce N1- (1H-benzoimidazol-5-yl) -1- [2, 3-difluoro-4- (thiophen-3-yl) phenyl ] ethane-1, 2-diamine 203H. The experimental procedure was the same as for the synthesis of compound 123 a. Product 203h was obtained as a yellow viscous liquid in 58% yield.

185. 1- (1H-benzimidazol-5-yl) -5- [2, 3-difluoro-4- (5-fluorothiophen-3-yl) phenyl ] imidazolidin-2-one (Compound 58)

1- (1H-benzimidazol-5-yl) -5- [2, 3-difluoro-4- (5-fluorothiophen-3-yl) phenyl ] imidazolidin-2-one (compound 58) was prepared by cycloaddition of 1,1' -carbonyldiimidazole and compound 203 a. The experimental procedure was the same as for the synthesis of compound 1. The product (compound 58) was obtained as a white solid in 71% yield.

186. 1- (1H-benzimidazol-5-yl) -5- [4- (5-chlorothien-3-yl) -2, 3-difluorophenyl ] imidazolidin-2-one (Compound 59)

Preparation of 1- (1H-benzimidazol-5-yl) -5- [4- (5-chlorothien-3-yl) -2, 3-difluorophenyl from a cycloaddition reaction of 1,1' -carbonyldiimidazole and the Compound 203b]Imidazolidin-2-one (Compound 59). The experimental procedure was the same as for the synthesis of compound 1. The product (compound 59) was obtained as a white solid in 74% yield.¹HNMR(300MHz,CD3OD)δ3.44(dd,1H,J＝6.3,9.3Hz),4.05(dd,1H,J＝9.3,9.6Hz),5.83(dd,1H,J＝6.3,9.6Hz),7.17-7.34(m,4H),7.48-7.51(m,2H),7.60(d,1H,J＝1.8Hz),8.07(d,1H,J＝3.9Hz)；LC/MS(ESI)m/z:431.0[M+H]⁺。

187. 1- (1H-benzimidazol-5-yl) -5- [2, 3-difluoro-4- (5-methylthiophen-3-yl) phenyl ] imidazolidin-2-one (Compound 60)

Preparation of 1- (1H-benzimidazol-5-yl) -5- [2, 3-difluoro-4- (5-methylthiophen-3-yl) phenyl from the cycloaddition reaction of 1,1' -carbonyldiimidazole and Compound 203c]Imidazolidin-2-one (Compound 60). Fruit of Chinese wolfberryThe experimental procedure was the same as for the synthesis of compound 1. The product (compound 60) was obtained as a white solid in 70% yield.¹H NMR(300MHz,CD3OD)δ2.45(s,3H),3.43(dd,1H,J＝6.3,9.0Hz),4.04(dd,1H,J＝9.0,9.3Hz),5.81(dd,1H,J＝6.3,9.3Hz),7.02(s,1H),7.18-7.38(m,4H),7.49(d,1H,J＝8.4Hz),7.59(s,1H),8.07(s,1H)；LC/MS(ESI)m/z:411.3[M+H]⁺。

188. 1- (1H-benzimidazol-5-yl) -5- [4- (5-ethylthiophen-3-yl) -2, 3-difluorophenyl ] imidazolidin-2-one (Compound 61)

Preparation of 1- (1H-benzimidazol-5-yl) -5- [4- (5-ethylthiophen-3-yl) -2, 3-difluorophenyl by cycloaddition of 1,1' -carbonyldiimidazole and the Compound 203d]Imidazolidin-2-one (Compound 61). The experimental procedure was the same as for the synthesis of compound 1. The product (compound 61) was obtained as a white solid in 70% yield.¹H NMR(400MHz,CD3OD)δ1.28(t,3H,J＝7.6Hz),2.83(q,2H,J＝7.6Hz),3.44(dd,1H,J＝6.4,9.2Hz),4.05(dd,1H,J＝9.2,9.6Hz),5.82(dd,1H,J＝6.4,9.6Hz),7.05(s,1H),7.15-7.19(m,1H),7.26-7.34(m,2H),7.41(s,1H),7.50(d,1H,J＝8.8Hz),7.60(s,1H),8.08(s,1H)；LC/MS(ESI)m/z:425.1[M+H]⁺。

189. 1- (1H-Benzimidazol-5-yl) -5- {2, 3-difluoro-4- [5- (methoxymethyl) thiophen-3-yl ] phenyl } imidazolidin-2-one (Compound 62)

Preparation of 1- (1H-benzimidazol-5-yl) -5- {2, 3-difluoro-4- [5- (methoxymethyl) thiophen-3-yl ] from the cycloaddition reaction of 1,1' -carbonyldiimidazole and Compound 203e]Phenyl } imidazolidin-2-one (Compound 62). The experimental procedure was the same as for the synthesis of compound 1. The product (compound 62) was obtained as a white solid in 76% yield.¹HNMR(400MHz,CD3OD)δ3.34(s,3H),3.45(dd,1H,J＝6.8,9.2Hz),4.05(dd,1H,J＝9.2,9.2Hz),4.59(s,2H),5.82(dd,1H,J＝6.4,9.2Hz),7.17-7.21(m,1H),7.28-7.34(m,3H),7.50(d,1H,J＝8.4Hz),7.60(s,1H),7.62(s,1H),8.08(s,1H)；LC/MS(ESI)m/z:441.3[M+H]⁺。

190. 1- (1H-Benzimidazol-5-yl) -5- {4- [5- (ethoxymethyl) thiophen-3-yl ] -2, 3-difluorophenyl } imidazolidin-2-one (Compound 63)

Preparation of 1- (1H-benzimidazol-5-yl) -5- {4- [5- (ethoxymethyl) thiophen-3-yl ] starting from 1,1' -carbonyldiimidazole and cycloaddition of Compound 203f]-2, 3-difluorophenyl } imidazolidin-2-one (compound 63). The experimental procedure was the same as for the synthesis of compound 1. The product (compound 63) was obtained as a white solid in 72% yield.¹HNMR(400MHz,CD3OD)δ1.19(t,3H,J＝7.2Hz),3.45(dd,1H,J＝6.4,9.2Hz),3.54(q,2H,J＝7.2Hz),4.05(dd,1H,J＝9.2,9.6Hz),4.63(s,2H),5.83(dd,1H,J＝6.4,9.6Hz),7.17-7.20(m,1H),7.26-7.34(m,3H),7.50(d,1H,J＝8.4Hz),7.61(m,2H),8.08(s,1H)；LC/MS(ESI)m/z:455.3[M+H]⁺。

191. 4- {4- [3- (1H-benzimidazol-5-yl) -2-oxoimidazolidin-4-yl ] -2, 3-difluorophenyl } thiophene-2-carboxylic acid methyl ester (Compound 64)

Preparation of 4- {4- [3- (1H-benzimidazol-5-yl) -2-oxoimidazolidin-4-yl radical by cycloaddition of 1,1' -carbonyldiimidazole and 203g of Compound]-methyl 2, 3-difluorophenyl } thiophene-2-carboxylate (compound 64). The experimental procedure was the same as for the synthesis of compound 1. The product (compound 64) was obtained as a white solid in 75% yield.¹H NMR(300MHz,DMSO-d₆)δ3.16-3.29(m,1H),3.81(s,3H),3.94(dd,1H,J＝9.0,9.3Hz),5.84(dd,1H,J＝5.4,9.3Hz),7.11(s,1H),7.17(dd,1H,J＝6.9,7.5Hz),7.30(brs,1H),7.43-7.54(m,2H),7.61(s,1H),8.06-8.10(m,1H),8.22(s,1H),8.23(s,1H),12.29(br s,1H)；LC/MS(ESI)m/z:455.1[M+H]⁺。

192. 1- (1H-benzimidazol-5-yl) -5- [2, 3-difluoro-4- (thiophen-3-yl) phenyl ] imidazolidin-2-one (Compound 65)

Preparation of 1- (1H-benzimidazol-5-yl) -5- [2, 3-difluoro-4- (thien-3-yl) phenyl from the cycloaddition reaction of 1,1' -carbonyldiimidazole with Compound 203H]Imidazolidin-2-one (Compound 65). The experimental procedure was the same as for the synthesis of compound 1. The product (compound 65) was obtained as a white solid in 79% yield.¹H NMR(400MHz,CD3OD)δ3.45(dd,1H,J＝6.8,9.2Hz),4.06(dd,1H,J＝9.2,9.6Hz),5.83(dd,1H,J＝6.8,9.6Hz),7.20(m,1H),7.31-7.36(m,3H),7.44-7.52(m,2H),7.61(s,1H),7.66(s,1H),8.08(s,1H)；LC/MS(ESI)m/z:397.1[M+H]⁺。

193. 4- {4- [3- (1H-benzimidazol-5-yl) -2-oxoimidazolidin-4-yl ] -2, 3-difluorophenyl } thiophene-2-carboxylic acid (Compound 66)

Potassium hydroxide (0.07g, 1.2mmol) was added to a solution of compound 64(0.45g, 1.0mmol) in methanol (10 mL). The reaction mixture was stirred at 60 ℃ for 1.5 hours and then cooled to room temperature. The reaction mixture was neutralized to pH7 with 1N HCl (aq). After removal of the solvent, the crude residue was purified by C-18 silica gel reverse phase column chromatography using methanol/H2O (1/1) as eluent to afford product 66 as a white solid in 81% yield.¹HNMR(400MHz,DMSO-d₆)δ3.26(dd,1H,J＝5.6,9.2Hz),3.92(dd,1H,J＝9.2,9.2Hz),4.18(br s,1H),5.80(dd,1H,J＝5.6,9.2Hz),7.12-7.15(m,2H),7.29(brs,1H),7.40-7.46(m,2H),7.52(s,1H),7.61(s,1H),7.67(s,1H),8.09(s,1H)；LC/MS(ESI)m/z:441.0[M+H]⁺。

194. 1- (1H-Benzimidazol-5-yl) -5- {2, 3-difluoro-4- [5- (hydroxymethyl) thiophen-3-yl ] phenyl } imidazolidin-2-one (Compound 67)

A solution of compound 64(0.45g, 1.0mmol) in anhydrous THF (5mL) was added dropwise to a refluxing, magnetically stirred slurry of LAH (1.5mmol) in anhydrous THF (7.5 mL). The reaction mixture was kept at reflux for 3 hours, quenched by the dropwise addition of 1mL of saturated MgSO4 solution, and filtered through celite. The filtrate was partitioned between ethyl acetate and water. The organic phase was dried over MgSO4 and evaporated on a rotary evaporator. The residue was purified by silica gel column chromatography using methanol/DCM (1/10) as eluent to give product 67 as a white solid in 92% yield.

Isolation of the enantiomer of Compound 8

Chiral separation of compound 8 was accomplished by HPLC using CHIRALPAK IC. The isomeric fractions were collected separately and the optically pure isomers (compounds 9 and 10) were obtained by removing the solvent under reduced pressure. The results of such separation are shown below:

pipe column: CHIRALPAK IC (IC00CE-OL002),

the size of the pipe column is as follows: 0.46cm I.D.x 25cm L,

injection amount: 0.5ul of the total amount of the sodium hypochlorite,

mobile phase: the content of the methanol is 100 percent,

flow rate: 1.0 ml/min of the mixture is added,

detection wavelength: the Ultraviolet (UV) wavelength of the light source is 214nm,

temperature: at a temperature of 35c,

HPLC equipment: shimadzu LC-20AD (CP-HPLC-06),

retention time E1 (compound 9): 5.494 the time of the mixing is less than the total time of the mixing,

retention time E2 (compound 10): 6.379 minutes.

Isolation of the enantiomer of Compound 13

Chiral separation of compound 13 was accomplished by HPLC using CHIRALPAKAD-H. The isomeric fractions were collected separately and the optically pure isomers (compounds 33 and 34) were obtained by removing the solvent under reduced pressure. The results of such separation are shown below:

pipe column: CHIRALPAKAD-H (ADH0CD-UE022),

the size of the pipe column is as follows: 0.46cm I.D.x 15cm L,

injection amount: 1.0ul of the total amount of the sodium hypochlorite,

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

flow rate: 1.0 ml/min of the mixture is added,

detection wavelength: the Ultraviolet (UV) wavelength of the light source is 214nm,

temperature: at a temperature of 35c,

HPLC equipment: shimadzu LC-20AD (CP-HPLC-09),

retention time E1 (compound 33): 4.270 the time of the mixing is less than the total time of the mixing,

retention time E2 (compound 34): 5.679 minutes.

Isolation of the enantiomer of Compound 16

Chiral separation of compound 16 was accomplished by HPLC using CHIRALPAKAD-H. The isomeric fractions were collected separately and the optically pure isomers (compounds 35 and 36) were obtained by removing the solvent under reduced pressure. The results of such separation are shown below:

pipe column: CHIRALPAKAD-H (ADH0CD-UE022),

the size of the pipe column is as follows: 0.46cm I.D.x 15cm L,

injection amount: 2.0ul of the total amount of the sodium hypochlorite,

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

flow rate: 1.0 ml/min of the mixture is added,

detection wavelength: the Ultraviolet (UV) wavelength of the light source is 214nm,

temperature: at a temperature of 35c,

HPLC equipment: shimadzu LC-20AD (CP-HPLC-08),

retention time E1 (compound 33): 7.273 the time of the mixing is less than the total time of the mixing,

retention time E2 (compound 34): 9.232 minutes.

Isolation of the enantiomer of Compound 25

Chiral separation of compound 25 was accomplished by HPLC using CHIRALPAKAD-H. The isomeric fractions were collected separately and the optically pure isomers (compounds 53 and 54) were obtained by removing the solvent under reduced pressure. The results of such separation are shown below:

pipe column: CHIRALPAKAD-H (ADH0CD-UE022),

the size of the pipe column is as follows: 0.46cm I.D.x 15cm L,

injection amount: 2.0ul of the total amount of the sodium hypochlorite,

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

flow rate: 1.0 ml/min of the mixture is added,

detection wavelength: the Ultraviolet (UV) wavelength of the light source is 214nm,

temperature: at a temperature of 35c,

HPLC equipment: shimadzu LC-20AD (CP-HPLC-08),

retention time E1 (compound 53): 2.166 the time of the mixing is less than the total time of the mixing,

retention time E2 (compound 54): 2.767 minutes.

Isolation of the enantiomer of Compound 28

Chiral separation of compound 28 was accomplished by HPLC using CHIRALPAKAD-H. The isomeric fractions were collected separately and the optically pure isomers (compounds 55 and 56) were obtained by removing the solvent under reduced pressure. The results of such separation are shown below:

pipe column: CHIRALPAKAD-H (ADH0CD-UE022),

the size of the pipe column is as follows: 0.46cm I.D.x 15cm L,

injection amount: 2.0ul of the total amount of the sodium hypochlorite,

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

flow rate: 1.0 ml/min of the mixture is added,

detection wavelength: the Ultraviolet (UV) wavelength of the light source is 214nm,

temperature: at a temperature of 35c,

HPLC equipment: shimadzu LC-20AD (CP-HPLC-08),

retention time E1 (compound 53): 3.827 the time of the mixing is less than the total time of the mixing,

retention time E2 (compound 54): 7.914 minutes.

Example 2: in vitro activity screening of Compounds

QC Activity assay

Enzymatic activity assays for QC were performed at 25 ℃ using a fluorescent matrix, i.e., L-glutamic acid amine 2-naphthamide (Gln- β NA). See Huang et al, biochem.J.2008,411, 181-190. A100. mu.l reaction mixture was prepared. The reaction mixture contained 300. mu.M of fluorescent matrix, approximately 0.2 units of the helper enzyme human pyroglutamyl-amidoamino-peptide peptidase I (PAPI), one unit of which is defined as the amount of human PAPI required to hydrolyze 1. mu. mol of pGlu-. beta.NA per minute under the same assay conditions, and an appropriately diluted aliquot of recombinant QC in 50mM Tris-HCl, pH 8.0. The excitation and emission wavelengths were set at 320nm and 410nm, respectively. The reaction was initiated by addition of QC. The enzymatic activity of QC is determined by the amount of β NA released and calculated under the same experimental conditions using a standard curve of β NA. Measurements were performed using a Synergy H4 microwell disk reader (BioTek, Winooski, Vermont, USA).

Enzyme kinetic assay

Kinetic constants were determined at pH8.0 and 25 ℃ using Gln- β NA as the matrix. See also Huang et al, biochem.J.2008,411, 181-190. QC was added to 100. mu.l of the above reaction mixture to initiate the reaction. The initial rate was measured during the first 2-12 minutes when less than 10% of the substrate was consumed. Since weak matrix inhibition was observed, kinetic parameters Km, V and Ki were evaluated by fitting equations (i.e. V0 ═ Vmax [ S ]/(Km + [ S ]2/Ki) to initial velocity data by non-linear regression using KaleidaGraph Software (Synergy Software, read, Pennsylvania, USA) where V0 is the initial velocity, Vmax is the limiting rate, [ S ] is the matrix concentration, Km is the Michaelis constant and Ki is the inhibition constant.

QC inhibition assay

Assays for inhibitory activity of QC inhibitors were performed. See Huang et al, J.biol.chem.2011,286, 12439-12449. A reaction mixture containing 300. mu.M Gln- β NA and about 0.2 units human PAPI was prepared. QC is first incubated with the inhibitor for 30 minutes at 25 ℃, and then the enzyme-inhibitor mixture is added to the reaction mixture to initiate the cyclization reaction. IC50 values were obtained by adapting the initial reaction rate using KaleidaGraph comparative inhibitor concentration. The Ki value of the inhibitor was calculated according to the equation IC50 ═ Ki (1+ [ S ]/Km). See Segel, enzyme kinetics: behavior and Analysis of rapidly equilibrating and Steady-State Enzyme Systems (Enzyme Kinetics: Behavior and Analysis of Rapid Equilibrium and Steady-State Enzyme Systems), p.100. sup. 118, New York: John Wiley & Sons, 1993. In this equation, [ S ] is the substrate (i.e., Gln- β NA) concentration and Km is the Michaelis-Menten constant. The lower the Ki value, the higher the QC inhibition of the inhibitor.

Ki values for compounds 1-29, 33-57, and 59-65 obtained from the above inhibition assays are shown in Table 2 below.

TABLE 2

As shown in this table, compounds 1-29, 33-57, and 59-65 all had Ki values in the nanomolar range. Note that low Ki values indicate high QC inhibition. Apparently, these compounds have excellent inhibitory potency against QC.

Inhibition of QC was reported to reduce aggregation of a β and HTT in cultured macrophages and drosophila and mouse models. Thus, compounds 1-29, 33-57, and 59-65, which are potent QC inhibitors, are candidates for treatment of AD or HD.

Example 3: in vivo Activity of Compounds

Compound 37 showed strong potency at inhibiting QC (Ki ═ 0.018 μ M) and the desired pharmacokinetic profile (F ═ 11) in mice (F% is the fraction of orally administered drug reaching the systemic circulation). Therefore, compounds were selected for further animal studies in a transgenic mouse model using APP/PS1 mice (JacksonLab, ME). See Schilling et al nat. med.2008,14, 1106-. APP/PS1 mice are double transgenic mice expressing chimeric mouse/human amyloid precursor protein (Mo/HuAPP695swe) and mutant human presenilin 1(PS1-dE9), both directed against CNS neurons. Both 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 water and food. Compound 37 was orally administered to APP/PS1 mice for 3.5 months to determine its in vivo activity. Each mouse was analyzed for cognitive function and brain pathology after dosing. The resulting analytical data showed depletion of A β deposits in brain tissue of APP/PS1 mice.

The same in vivo assay was performed on compound 28, showing that this compound has high inhibitory activity (Ki 0.039 μ M) and excellent pharmacokinetic properties and desired oral bioavailability (F% ═ 25) in APP/PS1 mice.

The two above experiments demonstrate the efficacy and efficacy of compounds 28 and 37 as QC inhibitors for the treatment of AD.

Other embodiments

All features disclosed in this specification may be combined in any combination. Each feature disclosed in this specification may be replaced by an alternative feature serving the same, equivalent, or similar purpose. Thus, unless expressly stated otherwise, each feature disclosed herein is one example only of a generic series of equivalent or similar features.

From the above description, one having ordinary skill in the art can easily ascertain the essential characteristics of the present invention, and without departing from the spirit and scope thereof, can make various changes and modifications of the invention to adapt it to various usages and conditions. Accordingly, other embodiments are within the scope of the following claims.

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