WO2022057930A1 - Benzimidazole compound having endothelial lipase inhibition effect, and application - Google Patents

Benzimidazole compound having endothelial lipase inhibition effect, and application Download PDF

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WO2022057930A1
WO2022057930A1 PCT/CN2021/119412 CN2021119412W WO2022057930A1 WO 2022057930 A1 WO2022057930 A1 WO 2022057930A1 CN 2021119412 W CN2021119412 W CN 2021119412W WO 2022057930 A1 WO2022057930 A1 WO 2022057930A1
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alkyl
aryl
compound
nmr
400mhz
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孙雅泉
张立洁
曹金明
杨康
李琛瑀
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盐城师范学院
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Definitions

  • the invention belongs to the technical field of medicine, in particular to a benzimidazole compound with endothelial lipase inhibitory effect and application thereof.
  • Cardiovascular disease is a common major health risk, and atherosclerosis is the leading cause of heart attack and stroke.
  • Atherosclerosis is a complex disease involving many cell types and molecular factors (Ross, R., Nature, 362(6423):801-809 (1993)).
  • Epidemiological studies have shown an inverse relationship between high-density protein (HDL) content and atherosclerosis risk, with HDL self-tissue transporting endogenous cholesterol to the liver and mediating selective cholesterol-producing tissue (Gordon, DJ et al. N.Eng.J.Med., 321(19):1311-1316(1989)).
  • HDL high-density protein
  • HDL metabolism is affected by several members of the phospholipase and triglyceride (TG) lipase protein family, which hydrolyze triglycerides, phospholipids (PL) and cholesterol lipids (CE) to generate fatty acids for intestinal absorption, energy produced or stored.
  • TG lipases lipoprotein lipase (LPL) affects the metabolism of HDL cholesterol by hydrolyzing triglycerides in triglyceride-rich lipoproteins, transferring lipids and lipoproteins to HDL, and is responsible for Hydrolysis of chylomicrons and very low density lipoproteins (VLDL) in muscle and adipose tissue.
  • VLDL very low density lipoproteins
  • Liver esterase hydrolyzes HDL triglycerides and phospholipids to generate smaller lipid-consuming HDL particles and plays a role in HDL cholesterol absorption (Jin, W. et al., Trends Endocrinol. Metab., 13(4). ): 174-178 (2002); Wong, H. et al., J. Lipid Res., 43: 993-999 (2002)).
  • Endothelial esterases also known as EDL, EL, LIPG, endothelial-derived lipases, and endothelial-derived lipases
  • EDL Endothelial esterase
  • EL endothelial-derived lipases
  • endothelial-derived lipases endothelial-derived lipases
  • endothelial lipase also exhibits in vitro triglyceride lipase activity and was found to hydrolyze HDL more efficiently than other lipoproteins (McCoy, MG et al. J. Lipid Res., 43: 921-929 (2002)).
  • Overexpression of the human endosebase gene in mouse liver significantly reduces HDL cholesterol and plasma concentrations of its major protein lipoprotein AI (apoA-I) (Jaye, M. et al. Nat. Genet., 21:424-428 (1999) )).
  • apoA-I major protein lipoprotein AI
  • the first object of the present invention is to provide a benzimidazole compound with endothelial lipase inhibitory effect and a tautomeric form and a physiologically tolerated salt thereof, wherein the structure of the benzimidazole compound is as shown in the general formula (I ) as shown:
  • R2 is selected from substituted aryl, arylalkyl, haloalkyl, wherein the substituent in substituted aryl is ortho- or meta-substituted halogen, C1-C8 alkyl, C3-C6 cycloalkyl, -ORc, nitro group in ortho position; or, if R3 is -C(O)RaRb, then R2 is selected from ortho, meta or para substituted aryl, ortho, meta Or para-substituted aromatic heterocyclic group, arylalkyl, haloalkyl, wherein the substituted aryl or the substituent in the aromatic heterocyclic ring is selected from halogen, C1-C8 alkyl, -ORc, nitro; R4, R5 , R6 are independently selected from H, -ORc, C1-C8 alkyl, cyano; R' is ortho, meta or para substituted H, halogen,
  • R2 is selected from unsubstituted or substituted aryl, unsubstituted or substituted aromatic heterocyclyl, C3-C6 cycloalkyl, -ORc, C2-C8 alkyl, arylalkyl, haloalkyl, Wherein the substituent in the substituted aryl or aromatic heterocyclic group is selected from ortho, meta or para substituted halogen, C1-C8 alkyl, ORc, nitro; R3 is H, -C(O)RaRb, -ORc, C1-C8 alkyl, C3-C6 cycloalkyl; R4, R5, R6 are independently selected from H, -ORc, C1-C8 alkyl, cyano; R' is H, halogen, -ORc, C1-C8 alkyl; R" is ortho, meta or para substituted H, halogen, -ORc, C1-C8 alkyl; n is 2-4;
  • R2 is selected from unsubstituted or substituted aryl, unsubstituted or substituted aromatic heterocyclyl, C3-C6 cycloalkyl, -ORc, C2-C8 alkyl, arylalkyl, haloalkyl, Wherein the substituent in the substituted aryl or aromatic heterocyclic group is selected from ortho, meta or para substituted halogen, C1-C8 alkyl, ORc, nitro; R3 is H, -C(O)RaRb, -ORc, C1-C8 alkyl, C3-C6 cycloalkyl; R4, R5, R6 are independently selected from H, -ORc, C1-C8 alkyl, cyano; R' is H, halogen, -ORc, C1-C8 alkyl; R"' is ortho, meta or para substituted H, halogen, -ORc, C1-C8 alkyl;
  • Ra and Rb are independently selected from H, C1-C4 alkyl, and Rc is H, C1-C8 alkyl.
  • the arylalkyl group is a C1-C8 alkyl group containing an unsubstituted or substituted aryl group; the substituents in the substituted aryl group are selected from ortho-, meta- or para-substituted Halogen, C1-C8 alkyl, ORc, nitro.
  • the aromatic heterocyclic ring in the aromatic heterocyclic group can be selected from thiophene, furan and pyridine.
  • the benzimidazole compounds are specifically selected as the following compounds:
  • Another object of the present invention is to provide the use of a benzimidazole compound and its tautomeric form and a physiologically tolerated salt thereof in the preparation of a drug for inhibiting endothelial lipase, wherein the structural formula of the benzimidazole compound is as follows: As shown in (I),
  • R1 is hydrogen, (C1-C6)-alkyl, (C1-C6)-haloalkyl, (C1-C6)alkoxy, (C1-C6)-alkylene-aryl, (C1-C6) )-alkylene-heterocycle, (C1-C6)-alkylene-(C3-C12)-cycloalkyl, (C8-C14)-bicycle, in which aryl, heterocycle, cycloalkyl or dicycle
  • the ring may be mono- or polysubstituted by the following preferred groups: halogen, (C1-C6)-alkyl, (C1-C3)-alkoxy, hydroxyl, (C1-C6)-alkylmercapto, amino, ( C1-C6)-Alkyloxy, Di-(C2-C12)Alkylamino, Mono-(C1-C6)-Alkylaminocarbonyl, Di-(C2-C8)-Alkylhydr
  • R2 is -(C1-C6)-alkyl, (C1-C6)-alkoxy, (C1-C3)-haloalkoxy, (C1-C6)-alkyleneamino, di-(C2-C12) -Alkylamino, -CO-(C1-C6)-Alkyl, -COOR7, -CO-NR8R9, -O-CONR8R9, -O-CO-(C1-C6)-Alkylene-CO-O-( C1-C6)-alkyl, -O-CO-(C1-C6)-alkylene-CO-OH or -O-CO-(C1-C6)-alkylene-CO-NR8R9, aryl, hetero Ring, -(C2-C12) cycloalkyl; wherein aryl, heterocycle, cycloalkyl or bicycle may be mono- or polysubstituted by the following preferred groups: halogen, (C1-
  • R3, R4, R5, R6 are identically or differently hydrogen, (C1-C6)-alkyl, (C3-C12)-cycloalkyl, (C1-C4)-alkylene-aryl, (C1-C4 )-alkylene-(C3-C12)-cycloalkyl, halogen, (C1-C6)-alkyl, (C1-C3)-alkoxy, hydroxyl, (C1-C6)-alkylmercapto, amino , (C1-C6)-alkyloxy, di-(C2-C12) alkylamino, mono-(C1-C6)-alkylaminocarbonyl, di-(C2-C8)-alkylhydrocarbonyl, (C1-C6)-alkoxycarbonyl, (C1-C6)-alkylcarbonyl, cyano, nitro, trifluoromethyl, trifluoromethoxy, pentafluorothio, (C1-C6)-al
  • R7 is hydrogen, (C1-C10) alkyl, (C1-C4) alkylene-CN, (C1-C4) alkylene-aryl, (C1-C4)-alkylene-heterocycle, (C1 -C4)-alkylene-(C3-C12)-cycloalkyl, (C8-C14)-bicycle, wherein aryl, heterocycle, cycloalkyl or bicycle can be mono- or bicyclic by the following preferred groups Polysubstituted: Halogen, (C1-C6)-Alkyl, (C1-C6)-Alkoxy, Hydroxyl, (C1-C6)-Alkylmercapto, Amino, (C1-C6)-Alkylamino, Di- (C2-C12)-Alkylamino, Mono-(C1-C6)-Alkylaminocarbonyl, Di-(C2-C8)-Alkylaminocarbonyl, (C1-C6)
  • R8, R9 are identically or differently hydrogen, (C1-C6)-alkyl, aryl, (C3-C12)-cycloalkyl, (C1-C4)-alkylene-aryl, (C1-C4) -Alkylene-(C3-C12)-cycloalkyl.
  • the present invention relates to compounds of formula I in the form of their salts, solvates, racemates, racemic mixtures and pure enantiomers, as well as their diastereomers and mixtures thereof.
  • the alkyl or alkylene groups in substituents R1, R2, R3, R4, R5, R6, R7, R8 and R9 may be straight or branched.
  • Halogen is fluorine, chlorine, bromine or iodine, especially fluorine or chlorine.
  • haloalkyl is an alkyl mono-, poly- or fully substituted with halogen; preferred halogens are fluorine and chlorine.
  • a cycloalkyl group refers to a saturated or partially unsaturated (with one or two double bond) ring system containing one or more rings and containing only carbon atoms, such as cyclopropyl cyclopentyl, cyclopentyl, cyclopentenyl, cyclohexyl or adamantyl.
  • the cycloalkyl group may be mono- or polysubstituted by the following suitable groups, for example: F, Cl, Br, I, CF3, NO2, N3, CN, COOH, COO ( C1-C6) alkyl, CONH2, CONH(C1-C6) alkyl, CON[(C1-C6) alkyl]2, cycloalkyl, (C1-C10) alkyl, (C2-C6)-alkene base, (C2-C6)-alkynyl, O-(C1-C6)-alkyl, O-CO-(C1-C6)-alkyl, O-CO-(C1-C6)-aryl, O- CO-(C1-C6)-heterocycle; PO3H2, SO3H, SO2-NH2, SO2NH(C1-C6)-alkyl, SO2N[(C1-C6)-alkyl]2, S-(C1-C6)-alkane base, S-(CH
  • a bicyclic ring is a partially unsaturated bicyclic ring system having 8-14 ring atoms and having only carbon atoms as ring atoms.
  • This definition includes ring systems containing a fused benzene ring core. Examples which may be mentioned are tetrahydronaphthyl, ⁇ - or ⁇ -tetralone, indanyl or indan-1-one groups.
  • Preferred bicyclic groups are tetrahydronaphthyl and indanyl.
  • Bicyclic groups may be mono- or polysubstituted by suitable groups such as F, Cl, Br, I, CF3, NO2, N3, CN, COOH, COO(C1-C6)-alkyl, CONH2, CONH (C1-C6)-Alkyl, CON[(C1-C6)-Alkyl]2, Cycloalkyl, (C1-C10)Alkyl, (C2-C6)-Alkenyl, (C2-C6)- Alkynyl, O-(C1-C6)-Alkyl, O-CO-(C1-C6)-Alkyl, O-CO-(C1-C6)-Aryl, O-CO-(C1-C6)- Heterocycle; PO3H2, SO3H, SO2-NH2, SO2NH(C1-C6)-alkyl, SO2N[(C1-C6)-alkyl]2, S-(C1-C6)-alkyl, S-(CH2) n-aryl, S
  • aryl or heterocyclic group can be replaced by F, Cl, Br, OH, CF3, NO2, CN, OCF3, O-(C1-C6)-alkyl, (C1-C6)-alkyl, NH2 up to two substituted; or by C(NH)(NH2), NH2, NH-(C1-C6)-alkyl, N((C1-C6)-alkyl)2, NH(C1-C7)-acyl, NH-CO -(C1-C6)-Alkyl, NH-COO-(C1-C6)-Alkyl, NH-CO-Aryl, NH-CO-Heterocycle, NH-COO-Aryl, NH-COO-Heterocycle , NH-CO-NH-(C1-C6)-alkyl, NH-CO-NH-aryl, NH-CO-NH-heterocycle, N(C1-C6)-alkyl-CO-(C1-C6-
  • the aryl or heterocyclyl group can be represented by F, Cl, Br, I, OH, CF3, NO2, CN, OCF3, O-(C1-C6)-Alkyl, (C1-C6)-Alkyl, NH2, NH(C1-C6)-Alkyl, N((C1-C6)- Alkyl)2, SO2-CH3, COOH, COO-(C1-C6)-alkyl, CONH2 mono-substituted to tri-substituted.
  • Aryl groups refer to phenyl or naphthyl groups.
  • Aryl groups may be mono- or polysubstituted by suitable groups such as F, C, Br, I, CF3, NO2, CN, COOH, COO(C1-C6)-alkyl, CONH2, CONH(C1 -C6)-Alkyl, CON[(C1-C6)-Alkyl]2, (C3-C10)-Cycloalkyl, (C1-C10)-Alkyl, (C2-C6)-Alkenyl, ( C2-C6)-alkynyl, O-(C1-C6)-alkyl, O-CO-(C1-C6)-alkyl, O-CO-(C1-C6)-aryl; PO3H2, SO3H, SO2 -NH2, SO2NH(C1-C6)-alkyl, SO2N[((C1-C6)-alkyl]2, S-(C1-C6)-alkyl, S-(CH2)n-aryl, S- (CH2)n-hetero
  • aryl or heterocyclic group can be replaced by F, CI, Br, OH, CF3, NO2, CN, OCF3, O-((C1-C6)-alkyl, (C1-C6)-alkyl, NH2 Disubstituted at most; or by C(NHNH2), NH2, NH-(C1-C6)-alkyl, N((C1-C6)-alkyl)2, NH(C1-C7)-acyl, NH-CO- (C1-C6)-Alkyl, NH-COO(C1-C6)-Alkyl, NH-CO-Aryl, NH-CO-Heterocycle, NH-COO-Aryl, NH-COO-Heterocycle, NH -CO-NH-((C1-C6)-alkyl, NH-CO-NH-aryl, NH-CO-NH-heterocycle, N(C1-C6)-alkyl-CO-((C1-
  • a heterocycle is a mono- or bicyclic ring system having 5-12 ring atoms, wherein at least one atom in the ring system is a heteroatom selected from N, O and S.
  • the definition also includes ring systems in which a heterocycle is fused to a benzene ring core.
  • (C5-C7)-heterocycle is a monocyclic ring system;
  • (C8-C12)-heterocycle is a bicyclic ring system.
  • Suitable "heterocycle” or “heterocyclic groups” are azacinyl, benzimidazolyl, benzofuranyl, benzothienyl, benzothienyl, benzoxyl, benzothiazolyl, benzene Triazolyl, benzotetrazolyl, benzisoxazolyl, benzisothiazolyl, benzimidazolinyl, carbazolyl, 4aH-carbazolyl, carbazolyl, quinazolinyl, quinoline Linyl, 4H-quinazinyl, quinoxalinyl, quinuclidinyl, chromanyl, chromenyl, cinnolinyl, decahydroquinolinyl, 2H,6H-1,5,2-dithiazine base, dihydrofuro[2,3-b]tetrahydrofuran, furanyl, furanyl, imidazolidinyl, imid
  • Peridyl represents 2-, 3- and 4-pyridyl.
  • Thienyl represents 2- and 3-thienyl.
  • Furyl represents 2- and 3-furyl.
  • N-oxides of these compounds such as 1-oxo-2-, -3 or -4-pyridyl heterocyclic or heterocyclic groups which may be mono- or polysubstituted by suitable groups such as: F, C1, Br, I, CF3, NO2, N3, CN, COOH, COO(C1-C6) alkyl, CONH2, CONH(C1-C6) alkyl, CON[(C1-C6) alkyl]2, (C1-C6)-alkyl, (C2-C6)-alkenyl, (C2-C6)-alkynyl, O-(C1-C6)-alkyl, wherein one, more or All hydrogens can be replaced by fluorine; PO3H2, SO3H, SO2-NH2, SO2NH(C1-C6)-alkyl, SO2N[(C1-C6)-alkyl]2, S-(C1-C6)-alkyl, S -(CH2)n-Phenyl, SO
  • suitable groups such as
  • Heteroaryl is a mono- or bicyclic aromatic ring system having 5 to 12 ring atoms, wherein at least one atom in the ring system is a heteroatom selected from N, O and S.
  • the definition also includes ring systems in which a heteroaryl group is fused to a benzene ring.
  • heteroaryl rings or “heteroaryl groups” are benzimidazolyl, benzofuranyl, benzothienyl, benzoxazolyl, benzothiazolyl, benzotriazolyl , benzotetrazolyl, benzisoxazolyl, benzisothiazolyl, quinolinyl, furanyl, furanyl, imidazolyl, 1H-indazolyl, indolyl, 1,2,3- oxadiazolyl, 1,2,4-oxadiazolyl, 1,2,5-oxadiazolyl, 1,3,4-oxadiazolyl, pyrimidinyl, pyrazinyl, pyrazolyl, pyridine base, pyrrolyl, thiazolyl, 1,2,3-thiadiazolyl, 1,2,4-thiadiazolyl, 1,2,5-thiadiazolyl, 1,3,4-thiadiazole base and thienyl.
  • Heteroaryl rings or heteroaryl groups may be mono- or polysubstituted with suitable groups, such as: F, Cl, Br, I, CF3, NO2, N3, CN, COOH, COO(C1-C6)alkyl, CONH2 , CONH(C1-C6) alkyl, CON[(C1-C6)-alkyl]2, (C1-C6)-alkyl, (C2-C6)-alkenyl, (C2-C6)-blockyl , O-(C1-C6)-alkyl, wherein one or more or all hydrogens in the alkyl can be replaced by fluorine; PO3H2, SO3H, SO2-NH2, SO2NH(C1-C6)-alkyl, SO2N[ (C1-C6)-Alkyl]2, S-(C1-C6)-Alkyl, S-(CH2)n-Phenyl, SO-(C1-C6)-Alkyl, SO-(CH2)n- Pheny
  • the benzimidazole compounds that can be used to prepare endothelial lipase inhibitory drugs are specifically selected from the following compounds:
  • Suitable pharmaceutically acceptable acid addition salts of the compounds of this invention are salts of inorganic acids such as hydrochloric, hydrobromic, phosphoric, metaphosphoric, nitric and sulfuric acids, and organic acids such as acetic, benzenesulfonic, benzoic, citric, Salts of ethanesulfonic acid, fumaric acid, gluconic acid, glycolic acid, isethionic acid, lactic acid, lactobionic acid, maleic acid, malic acid, methanesulfonic acid, succinic acid, p-toluenesulfonic acid and tartaric acid, suitable Salts of pharmaceutically acceptable bases are ammonium, alkali metal (eg sodium and potassium) and alkaline earth metal (eg magnesium and calcium) and tromethamine (2-amino-2-
  • suitable Salts of pharmaceutically acceptable bases are ammonium, alkali metal (eg sodium and potassium) and alkaline earth metal (eg magnesium and calcium) and trome
  • Salts with non-pharmaceutically acceptable anions such as trifluoroacetate are also within the scope of the present invention as useful intermediates for the preparation or purification of pharmaceutically acceptable salts and/or for non-therapeutic uses such as in vitro application.
  • physiologically functional derivative refers to any physiologically tolerable derivative of a compound of formula (I), such as an ester, which, when administered to a mammal such as a human, is capable of (directly or indirectly) ) to form a compound of formula I or an active metabolite thereof.
  • Physiologically functional derivatives also include prodrugs of the compounds of the present invention, eg, as described in H. Okada et al., Chem. Pharm, Bull. 1994, 42, 57-61. These prodrugs can be metabolized in vivo to form the compounds of the invention, and these prodrugs can themselves be active or inactive.
  • the compounds of the present invention may also exist in various polymorphic forms, such as amorphous, crystalline and polymorphic forms. All polymorphic forms of the compounds of the present invention are encompassed within the framework of the present invention and are a further aspect of the present invention
  • the compounds of the invention of general formula I have a surprising inhibitory effect on endothelial lipase (EL).
  • EL endothelial lipase
  • a preferred substrate for EL is HDL, which has anti-atherosclerotic activity, and a reduction in HDL levels leads to the progression of atherosclerosis and its sequelae, such as coronary heart disease, and in addition to the development of metabolic syndrome and its sequelae, diabetes mellitus.
  • inhibition of EL generally results in the prevention of atherosclerotic conditions and indirectly reduces the prevalence of the disease in populations at increased risk of diabetes.
  • the compounds of formula I have improved solubility in aqueous media and at least as high activity as compared to compounds of similar structure.
  • Preferred compounds of the present invention also have improved metabolic stability compared to compounds of the prior art.
  • the compounds of the present invention show advantages in serum stability.
  • the compounds of the present invention are particularly suitable for the treatment and/or prevention of the following diseases:
  • Dyslipidemia and its sequelae such as atherosclerosis, coronary heart disease, cerebrovascular disease, etc., especially (but not limited to) those conditions characterized by one or more of the following factors: high plasma triglyceride concentrations, high Postprandial plasma triglyceride concentration; low HDL cholesterol concentration; low apolipoprotein A concentration; high LDL cholesterol concentration; low density LDL cholesterol particles; high apolipoprotein B concentration;
  • metabolic syndrome Various other conditions that may be associated with metabolic syndrome, such as: obesity (overweight), including central obesity; thrombotic, hypercoagulable and prothrombotic stages (arterial and venous); hypertension; Heart failure, such as but not limited to heart failure following myocardial infarction, hypertensive heart disease, or cardiomyopathy; diabetes, especially type 2 diabetes, including prevention of its associated sequelae (hyperglycemia, glucose intolerance, pancreatic ⁇ -cell loss, macrovascular and microvascular disorders)
  • Atherosclerosis such as, but not limited to, coronary arteriosclerosis, including angina pectoris or myocardial infarction, stroke; restenosis or reocclusion of blood vessels; chronic inflammatory bowel disease diseases, such as Crohn's disease and ulcerative colitis; pancreatitis; other inflammatory states; retinopathy; adipocyte tumors; adipocyte carcinomas, such as liposarcoma; , liver, biliary and pancreatic cancers, endocrine tumors, lung, kidney and urinary tract, reproductive tract cancers, prostate cancer, etc.; acute and chronic myeloproliferative diseases and lymphomas; angiogenesis; neurodegenerative diseases; Alzheimer's disease multiple sclerosis; Parkinson's disease; erythrosquamous skin diseases such as psoriasis; acne vulgaris; other skin diseases and dermatological conditions modulated by PPARs; eczema and neuroderma
  • atherosclerosis such as, but not limited to, coronary arterio
  • a daily dose generally ranging from 0.3 mg to 100 mg (usually 3 mg- 50 mg)/day/kg body weight, eg 3-10 mg/kg/day.
  • Intravenous doses may be, for example, 0.3 mg-1.0 mg/kg, which may suitably be used as an infusion of 10 ng-100 ng/kg/minute, and suitable infusion solutions for these purposes may contain, for example, 0.1 ng-10 mg per milliliter, Usually 1 ng-10 mg, a single dose may contain eg 1 mg-10 g of the active ingredient.
  • ampoules for injection may contain, for example, 1 mg-100 mg
  • single-dose formulations, such as tablets or capsules, which may be administered orally may contain, for example, 0.05-1000 mg, usually 0.5-600 g.
  • the compounds of the present invention can be used in the form of compounds of formula I for the treatment of the above-mentioned conditions, but they are preferably in the form of pharmaceutical combinations with a pharmaceutically acceptable carrier, which of course must be pharmaceutically acceptable, that is to say in combination with .
  • the carrier must of course be pharmaceutically acceptable, that is to say compatible with the other ingredients of the composition and not harmful to the patient's health.
  • Carriers can be solid, liquid and colloids, preferably with the compound formulated in a single dose, eg, as a tablet, which may contain from 0.05% to 95% by weight of the active ingredient.
  • Other pharmaceutically active substances, including other compounds of the present invention may also be present.
  • the pharmaceutical compositions of the present invention can be prepared by one of the known methods of pharmacy, which essentially involve admixing the ingredients with pharmaceutically acceptable carriers and/or excipients.
  • oral eg sublingual
  • parenteral eg subcutaneous, intramuscular, intradermal or intravenous
  • Coated formulations and coated sustained release formulations are also encompassed within the scope of the present invention.
  • Acid- and gastric-resistant formulations are preferred.
  • Suitable gastro-resistant coatings include cellulose phthalate.
  • a tablet may be prepared by compressing or molding a powder or granules of the compound, optionally with one or more other ingredients.
  • Compressed tablets may be prepared by mixing the compound in a free-flowing form such as a powder or granules, optionally with binders, glidants, inert diluents and/or one (or more) surface active/dispersing agent(s) in a suitable It is prepared by mixing and tableting in a machine. Molded tablets may be made by molding in a suitable machine the powdered compound moistened with an inert liquid diluent.
  • compositions suitable for oral (sublingual) administration include lozenges containing a compound of formula I with a flavoring agent (usually sucrose) and acacia or tragacanth, and in an inert base such as gelatin and glycerol or sucrose. and gum arabic) containing pastilles of the compounds.
  • a flavoring agent usually sucrose
  • acacia or tragacanth in an inert base
  • an inert base such as gelatin and glycerol or sucrose. and gum arabic
  • compositions suitable for parenteral administration preferably comprise sterile aqueous preparations of the compounds of formula I, preferably in the blood of the target lover, etc. These preparations are preferably administered intravenously, but may also be administered by subcutaneous, intramuscular or intradermal injection
  • these formulations can preferably be prepared by mixing the compound with water and sterilizing the resulting solution with blood and the like.
  • the injectable compositions of the present invention generally contain 0.1 to 5% by weight of the active compound.
  • compositions suitable for rectal administration are preferably in the form of single-dose suppositories.
  • Such formulations may be prepared by admixing a compound of formula I with one or more conventional solid carriers such as cocoa butter and shaping the resulting mixture.
  • Suitable pharmaceutical compositions for topical application to the skin are preferably in the form of ointments, creams, lotions, pastes, sprays, aerosols or oils.
  • Useful carriers include petroleum ether, lanolin, polyethylene glycols, alcohols, and combinations of two or more of these.
  • the active ingredient is generally present at a concentration of 0.1-15% by weight, eg, 0.5-2%, by weight of the composition.
  • compositions suitable for transdermal administration may be in the form of a single patch suitable for prolonged intimate contact with the epidermis of a patient.
  • patches suitably contain the active ingredient in an optionally buffered aqueous solution dissolved and/or dispersed in an adhesive or dispersed in a polymer.
  • Suitable active ingredient concentrations are from about 1% to 35%, preferably 3% to 15%.
  • Particular means of releasing the active ingredient may be by electrotransport or iontophoresis, eg as described in Pharmaceutical Research, 2(6):318 (1986).
  • the compounds of the present invention may be administered alone or in combination with one or more other pharmacologically active active ingredients.
  • the compounds of the present invention can be administered together with active ingredients having pharmacological effects similar thereto.
  • active ingredients having pharmacological effects similar thereto are: blood sugar-lowering drugs, antidiabetic drugs, active ingredients for the treatment of dyslipidemia, anti-atherosclerotic drugs, anti-obesity drugs, anti-inflammatory active ingredients, active ingredients for the treatment of malignant tumors , antithrombotic active ingredients, active ingredients in the treatment of hypertension, active ingredients in the treatment of heart failure, active ingredients in the treatment and/prevention of complications caused by or related to diabetes, active ingredients in the treatment of neurodegenerative diseases, treatment of central Active ingredients for neurological disorders, active ingredients for the treatment of drug dependence, nicotine and alcohol dependence, analgesics.
  • the combination of active ingredients can be administered to the patient by administering the active ingredients separately or as a combination product in which the active ingredients are coexisted in one pharmaceutical formulation.
  • the active ingredients preferably include: sulfonylureas; biguanides; meglitinides; oxadiazolidinediones; thiazolidinediones; glucosidase inhibitors; glycogen phosphorylase inhibitors; Glucagon antagonist; glucokinase agonist; fructose-1,6-bisphosphatase inhibitor.
  • the general formula 1 can be synthesized by the following method, and all chemical raw materials can be purchased through commercial channels.
  • the synthetic method includes the following routes:
  • Or method 2 generate polysubstituted benzimidazoles by reacting 1H benzimidazole with R1X:
  • Or method four the reaction of o-amino-substituted aniline and carbonyl compound generates polysubstituted benzimidazole.
  • the corresponding o-amino-substituted aniline can be prepared by the reaction of o-nitro compounds and different amines according to the literature method to obtain the o-nitro-substituted aniline, and then reduced by the literature method to obtain the o-amino-substituted aniline:
  • the second method is to prepare benzimidazole derivatives by reacting o-phenylenediamine with carboxylic acid.
  • the fourth method is to generate polysubstituted benzimidazole by reacting o-nitro-substituted aniline with aldehyde.
  • phospholipase specific substrate 12- (4,4-difluoro5,7-dimethyl-4-bora-3a,4a-diaza-s-indacene-3-deca Monoacyl)-sn-glycero-3-phosphocholine (manufacturer Molecular Probes) to define the enzymatic activity and inhibitory effect of endothelial lipase.
  • Enzymatic hydrolysis of the A1 ester bond of this phospholipid releases the fluorescent dye Bodipy-labeled fatty acids, which can be detected after separation by thin-layer chromatography on TLC plates (silica gel 60, Merck), or directly in the reaction vessel by measuring fluorescence test.
  • the decrease in enzyme activity was a function of the concentration of inhibitor used.
  • the inhibitor concentration at which half of the maximal enzyme activity observed is referred to as the IC50.
  • the IC50 values of the compounds of each example are shown in Table 1:
  • Solubility in aqueous systems can be tested by different methods. Examples of suitable dissolution precipitation methods ("kinetic solubility”) and methods for studying the dissolution of solid samples until equilibrium (“thermodynamic solubility”) are established.
  • a solution of the test compound in DMSO (2.5 mM; 0.5 ⁇ l) was transferred to 200 uL of an aqueous assay solution (eg, phosphate buffered saline, 10x, 1 M, Sigma, adjusted to 10 mM, pH 7.4) in a 96-well titer plate, The turbidity was also measured with a turbidimeter (eg Nephelostar Galaxy, BMG Labtech) at the resulting theoretical concentration of the test compound of 6.25 uM.
  • the test compound concentration in the aqueous test solution was then increased to 12.5 ⁇ M by further addition of DMSO solution (2.5 mM; 0.5 ⁇ L), and the turbidity measurement was repeated.
  • DMSO solution (1uL, 2.5mM; 0.5 ⁇ L, 10mM; then 9 ⁇ 1 ⁇ L, 10mM; then 9 ⁇ 1 ⁇ L, 10mM was added between the completion of the two detection processes to obtain theoretical concentrations of 25 ⁇ M, 50 ⁇ M, 100uM, 150 ⁇ M, 200 ⁇ M, 250 ⁇ M, 300 ⁇ M, 350 ⁇ M, 400uM , 450uM and 500 ⁇ M and check for turbidity.
  • the turbidity value from the turbidimeter is plotted against the theoretical concentration of the test compound in the aqueous test solution. Once significant turbidity was detected at the theoretical concentration (eg, 5 times the control value for an aqueous test solution), the following concentration levels were used as solubility limits for the compounds to be tested in solution. Therefore, the maximum possible detection range is shown as values ⁇ 625uM, 6.25-500 ⁇ M and >500uM.
  • Preferred benzimidazoles exhibit a kinetic solubility in phosphate buffer (pH 7.4) of at least 12.5 ⁇ M; more preferably at least 50 ⁇ M, even more preferably at least 250 ⁇ M.
  • the overall UV absorbance obtained from the HPLC UV detector for serial dilutions of the test compound (500uM, 100uM, 50uM, 10uM and 1uM) in DMSO showed a linear correlation with concentration as a calibration line.
  • the test compound (500 ug) was shaken together with the aqueous test solution (250 uL) in a sealed vial (capacity: 1.5 mL) for 16 hours (Eppendorf thermoshaker, 1400 rpm, 25°C, covered and protected from light). The samples were then centrifuged at maximum speed and the supernatant was finally filtered. A sample of the filtered supernatant was directly analyzed with an HPLC UV detector (see above). Another sample was analyzed after dilution (1 vol of supernatant, 39 vol of test solution).
  • the concentration of the test compound in the undiluted supernatant was calculated from the bulk UV absorbance obtained for the supernatant samples according to the established calibration line and expressed as the solubility of the test compound in the respective aqueous test solutions.
  • aqueous test solutions are deionized water or aqueous phosphate buffers with various pH values (eg pH 1.2; pH 4.0; pH 6.8; pH 7.4; pH 9.0), which can be obtained from commercial solutions (Phosphate Buffered Saline, 10x, Sigma) was prepared by dilution and adjustment with phosphoric acid or sodium hydroxide solutions according to standard methods.
  • Preferred compounds of the invention exhibit solubility in phosphate buffer (pH 7.4) of at least 12.5 ⁇ M; more preferably at least 50 ⁇ M, even more preferably at least 250 ⁇ M.

Abstract

The present invention relates to the technical field of medicines. Disclosed are a benzimidazole compound having an endothelial lipase inhibition effect, and an application. The benzimidazole compound of the present invention has an excellent inhibition effect on endothelial lipase, can effectively treat atherosclerosis and sequelae thereof, such as coronary heart disease, and also promotes the treatment of metabolic syndrome and sequelae thereof, such as diabetes. The benzimidazole compound of the present invention has good solubility in an aqueous medium, good biological activity and good metabolic stability, and shows an advantage in respect of serum stability.

Description

一种具有内皮脂肪酶抑制作用的苯并咪唑类化合物及应用A benzimidazole compound with endothelial lipase inhibitory effect and application 技术领域technical field
本发明属于医药技术领域，具体涉及一种具有内皮脂肪酶抑制作用的苯并咪唑类化合物及应用。The invention belongs to the technical field of medicine, in particular to a benzimidazole compound with endothelial lipase inhibitory effect and application thereof.
背景技术Background technique
心血管疾病是普遍的主要健康风险，动脉粥样硬化为心脏病发作及中风的主要原因。动脉粥样硬化涉及许多细胞类型及分子因素的复杂疾病(Ross,R.,Nature,362(6423):801-809(1993))。流行病学研究表明高密度蛋白(HDL)含量与动脉粥样硬化风险之间的反比关系，其中高密度蛋白自组织输送内源性胆固醇至肝脏以及介导选择性胆固醇生成组织(Gordon,D.J.等N.Eng.J.Med.,321(19):1311-1316(1989))。Cardiovascular disease is a common major health risk, and atherosclerosis is the leading cause of heart attack and stroke. Atherosclerosis is a complex disease involving many cell types and molecular factors (Ross, R., Nature, 362(6423):801-809 (1993)). Epidemiological studies have shown an inverse relationship between high-density protein (HDL) content and atherosclerosis risk, with HDL self-tissue transporting endogenous cholesterol to the liver and mediating selective cholesterol-producing tissue (Gordon, DJ et al. N.Eng.J.Med., 321(19):1311-1316(1989)).
HDL代谢受磷脂酶及三酸甘油酯(TG)脂酶蛋白质家族等若干成员的影响，它水解三酸甘油酯、磷脂(PL)及胆甾醇脂(CE)，生成脂肪酸以便于肠吸收、能量产生或储存。在TG脂酶中，脂蛋白脂酶(LPL)由水解富含三酸甘油酯之脂蛋白中的三酸甘油酯，使脂质及脂蛋白元转移至HDL而影响HDL胆固醇的代谢，且负责水解肌肉及脂肪组织中的乳糜微粒及极低密度脂蛋白(VLDL)。肝酯酶(HL)水解HDL三酸甘油酯及磷脂，生成较小的脂质消耗HDL粒子，且在HDL胆固醇吸收中起作用(Jin,W.等人，Trends Endocrinol.Metab.,13(4):174-178(2002)；Wong,H.等人,J.Lipid Res.,43:993-999(2002))。HDL metabolism is affected by several members of the phospholipase and triglyceride (TG) lipase protein family, which hydrolyze triglycerides, phospholipids (PL) and cholesterol lipids (CE) to generate fatty acids for intestinal absorption, energy produced or stored. Among TG lipases, lipoprotein lipase (LPL) affects the metabolism of HDL cholesterol by hydrolyzing triglycerides in triglyceride-rich lipoproteins, transferring lipids and lipoproteins to HDL, and is responsible for Hydrolysis of chylomicrons and very low density lipoproteins (VLDL) in muscle and adipose tissue. Liver esterase (HL) hydrolyzes HDL triglycerides and phospholipids to generate smaller lipid-consuming HDL particles and plays a role in HDL cholesterol absorption (Jin, W. et al., Trends Endocrinol. Metab., 13(4). ): 174-178 (2002); Wong, H. et al., J. Lipid Res., 43: 993-999 (2002)).
内皮酯酶(亦称为EDL、EL、LIPG、内皮源脂酶及内皮细胞源脂酶)在内皮细胞中合成，此为区分其与其他家族成员的特征。重组内皮脂酶蛋白质具有相当大的磷脂酶活性，但已报道对三酸甘油酯脂质具有较小水解活性(Hirata,K.等J.Biol.Chem.,274(20):14170-14175(1999)；Jaye,M.等Nat.Genet.,21:424-428(1999))。然而，内皮脂酶除显示其HDL磷脂酶活性外，也显示离体三酸甘油酯脂酶活性，且发现内皮脂酶比其他脂蛋白更有效地水解HDL(McCoy,M.G.等J.LipidRes.,43:921-929(2002))。人类内皮脂酶基因在小鼠肝脏中过度表达明显降低HDL胆固醇及其主要蛋白质脂蛋白元A-I(apoA-I)的血浆浓度(Jaye,M.等Nat.Genet.,21:424-428(1999))。Endothelial esterases (also known as EDL, EL, LIPG, endothelial-derived lipases, and endothelial-derived lipases) are synthesized in endothelial cells, a feature that distinguishes them from other family members. The recombinant endosebase protein has considerable phospholipase activity, but has been reported to have less hydrolytic activity on triglyceride lipids (Hirata, K. et al. J. Biol. Chem., 274(20): 14170-14175 ( 1999); Jaye, M. et al. Nat. Genet., 21:424-428 (1999)). However, in addition to its HDL phospholipase activity, endothelial lipase also exhibits in vitro triglyceride lipase activity and was found to hydrolyze HDL more efficiently than other lipoproteins (McCoy, MG et al. J. Lipid Res., 43: 921-929 (2002)). Overexpression of the human endosebase gene in mouse liver significantly reduces HDL cholesterol and plasma concentrations of its major protein lipoprotein AI (apoA-I) (Jaye, M. et al. Nat. Genet., 21:424-428 (1999) )).
已报到可调节内皮脂酶表现的化合物有多种，例如Eli Lilly Co.的3-侧氧基-1,3-二氢-吲唑-2-甲酰胺(WO2004/093872,US2006/0211755A1)、3-侧氧基-3-H-苯并[d]异噁唑-2-甲酰胺(WO2004/094393,美国专利第7,217,727号)及苯并异噻唑-3-酮-2-甲酰胺(WO2004/094394,美国专利第7,595,403号)；Sanofi-Aventis的酰基吲唑衍生物(WO2007/042178、US 2008/0287448A1)及咪唑并吡啶-2-酮衍生物(WO2007/110215,US2009/0076068A1)及咪唑并吡啶-3-酮衍生物(WO2007/110216,US2009/0054478A1)；ShionogiCo.,Ltd)的亲环衍生物(WO2009/123164)、酮酰胺衍生物(WO2009/133834)、乙酰胺衍生物(WO20/10/44441,US 2011/0251386A1)、噁二唑衍生物(WO2011074560,US2012253040A1)、苯并噻唑及氮亲苯并噻唑噻唑阿衍生物(WO2012081563)及胺基衍生物(WO2012173099)。充分了解内皮脂酶抑制剂对于人类健康的潜能以及其他脂酶抑制剂需要更多研究。因此，明确需要能够抑制脂酶(尤其内皮脂酶)的活性的新型化合物，其对于该脂酶活性相关的疾病或病症构成有效治疗。Various compounds have been reported that can modulate the expression of endothelial lipase, such as 3-oxy-1,3-dihydro-indazole-2-carboxamide of Eli Lilly Co. (WO2004/093872, US2006/0211755A1), 3-Pendant oxy-3-H-benzo[d]isoxazole-2-carboxamide (WO2004/094393, US Pat. No. 7,217,727) and benzisothiazol-3-one-2-carboxamide (WO2004 /094394, US Pat. No. 7,595,403); acyl indazole derivatives of Sanofi-Aventis (WO2007/042178, US 2008/0287448A1) and imidazopyridin-2-one derivatives (WO2007/110215, US2009/0076068A1) and imidazoles Pyridin-3-one derivatives (WO2007/110216, US2009/0054478A1); cyclophilic derivatives of Shionogi Co., Ltd) (WO2009/123164), ketoamide derivatives (WO2009/133834), acetamide derivatives (WO20 /10/44441, US 2011/0251386A1), oxadiazole derivatives (WO2011074560, US2012253040A1), benzothiazole and nitrogenophilic benzothiazole thiazolium derivatives (WO2012081563) and amino derivatives (WO2012173099). More research is needed to fully understand the potential of endothelial lipase inhibitors for human health and other lipase inhibitors. Therefore, there is a clear need for novel compounds capable of inhibiting the activity of lipases, especially endothelial lipases, which constitute effective treatments for diseases or disorders associated with this lipase activity.
发明内容SUMMARY OF THE INVENTION
本发明的第一个目的是提供一种具有内皮脂肪酶抑制作用的苯并咪唑类化合物及其互变异构形式和生理学耐受的盐，所述苯并咪唑类化合物结构如通式(I)所示：The first object of the present invention is to provide a benzimidazole compound with endothelial lipase inhibitory effect and a tautomeric form and a physiologically tolerated salt thereof, wherein the structure of the benzimidazole compound is as shown in the general formula (I ) as shown:
式中，In the formula,
当R1为时，若R3为H，则R2选自取代芳基、芳基烷基、卤代烷基，其中取代芳基中的取代基为邻位或者间位取代的卤素、C1-C8烷基、C3-C6环烷基、-ORc、邻位的硝基；或者，若R3为-C(O)RaRb，则R2选自邻位、间位或者对位取代的芳基，邻位、间位或者对位取代的芳杂环基，芳基烷基，卤代烷基，其中取代的芳基或者芳杂环中的取代基选自卤素、C1-C8烷基、-ORc、硝基；R4、R5、R6分别独立的选自H、-ORc、C1-C8烷基、氰基；R’为邻位、间位或者对位取代的H、卤素、-ORc、C1-C8烷基；When R1 is, if R3 is H, then R2 is selected from substituted aryl, arylalkyl, haloalkyl, wherein the substituent in substituted aryl is ortho- or meta-substituted halogen, C1-C8 alkyl, C3-C6 cycloalkyl, -ORc, nitro group in ortho position; or, if R3 is -C(O)RaRb, then R2 is selected from ortho, meta or para substituted aryl, ortho, meta Or para-substituted aromatic heterocyclic group, arylalkyl, haloalkyl, wherein the substituted aryl or the substituent in the aromatic heterocyclic ring is selected from halogen, C1-C8 alkyl, -ORc, nitro; R4, R5 , R6 are independently selected from H, -ORc, C1-C8 alkyl, cyano; R' is ortho, meta or para substituted H, halogen, -ORc, C1-C8 alkyl;
当R1为时，R2选自未取代或取代的芳基、未取代或取代的芳杂环基、C3-C6环烷基、-ORc、C2-C8烷基、芳基烷基、卤代烷基，其中取代的芳基或者芳杂环基中的取代基选自邻位、间位或者对位取代的卤素、C1-C8烷基、ORc、硝基；R3为H、-C(O)RaRb、-ORc、C1-C8烷基、C3-C6环烷基；R4、R5、R6分别独立的选自H、-ORc、C1-C8烷基、氰基；R’为H、卤素、-ORc、C1-C8烷基；R”为邻位、间位或者对位取代的H、卤素、-ORc、C1-C8烷基；n为2-4；When R1 is, R2 is selected from unsubstituted or substituted aryl, unsubstituted or substituted aromatic heterocyclyl, C3-C6 cycloalkyl, -ORc, C2-C8 alkyl, arylalkyl, haloalkyl, Wherein the substituent in the substituted aryl or aromatic heterocyclic group is selected from ortho, meta or para substituted halogen, C1-C8 alkyl, ORc, nitro; R3 is H, -C(O)RaRb, -ORc, C1-C8 alkyl, C3-C6 cycloalkyl; R4, R5, R6 are independently selected from H, -ORc, C1-C8 alkyl, cyano; R' is H, halogen, -ORc, C1-C8 alkyl; R" is ortho, meta or para substituted H, halogen, -ORc, C1-C8 alkyl; n is 2-4;
当R1为时，R2选自未取代或取代的芳基、未取代或取代的芳杂环基、C3-C6环烷基、-ORc、C2-C8烷基、芳基烷基、卤代烷基，其中取代的芳基或者芳杂环基中的取代基选自邻位、间位或者对位取代的卤素、C1-C8烷基、ORc、硝基；R3为H、-C(O)RaRb、-ORc、C1-C8烷基、C3-C6环烷基；R4、R5、R6分别独立的选自H、-ORc、C1-C8烷基、氰基；R’为H、卤素、-ORc、C1-C8烷基；R”’为邻位、间位或者对位取代的H、卤素、-ORc、C1-C8烷基；When R1 is, R2 is selected from unsubstituted or substituted aryl, unsubstituted or substituted aromatic heterocyclyl, C3-C6 cycloalkyl, -ORc, C2-C8 alkyl, arylalkyl, haloalkyl, Wherein the substituent in the substituted aryl or aromatic heterocyclic group is selected from ortho, meta or para substituted halogen, C1-C8 alkyl, ORc, nitro; R3 is H, -C(O)RaRb, -ORc, C1-C8 alkyl, C3-C6 cycloalkyl; R4, R5, R6 are independently selected from H, -ORc, C1-C8 alkyl, cyano; R' is H, halogen, -ORc, C1-C8 alkyl; R"' is ortho, meta or para substituted H, halogen, -ORc, C1-C8 alkyl;
Ra、Rb分别独立的选自H、C1-C4烷基，Rc为H、C1-C8烷基。Ra and Rb are independently selected from H, C1-C4 alkyl, and Rc is H, C1-C8 alkyl.
在本发明的一种实施方式中，涉及到的“*”均是指连接位点。In one embodiment of the present invention, all references to "*" refer to the attachment site.
在本发明的一种实施方式中，芳基烷基为含未取代或取代的芳基的C1-C8烷基；取代的芳基中的取代基选自邻位、间位或者对位取代的卤素、C1-C8烷基、ORc、硝基。In one embodiment of the present invention, the arylalkyl group is a C1-C8 alkyl group containing an unsubstituted or substituted aryl group; the substituents in the substituted aryl group are selected from ortho-, meta- or para-substituted Halogen, C1-C8 alkyl, ORc, nitro.
在本发明的一种实施方式中，芳杂环基中的芳杂环可选噻吩、呋喃、吡啶。In one embodiment of the present invention, the aromatic heterocyclic ring in the aromatic heterocyclic group can be selected from thiophene, furan and pyridine.
在本发明的一种实施方式中，所述苯并咪唑类化合物具体选择如下化合物：In one embodiment of the present invention, the benzimidazole compounds are specifically selected as the following compounds:
本发明的另一个目的是提供一种苯并咪唑类化合物及其互变异构形式和生理学耐受的盐在制备内皮脂肪酶抑制药物中的应用，所述苯并咪唑类化合物的结构式如式(I)所示，Another object of the present invention is to provide the use of a benzimidazole compound and its tautomeric form and a physiologically tolerated salt thereof in the preparation of a drug for inhibiting endothelial lipase, wherein the structural formula of the benzimidazole compound is as follows: As shown in (I),
其中，R1是氢、(C1-C6)-烷基、(C1-C6)-卤代烷基、(C1-C6)烷氧基、(C1-C6)-亚烷基-芳基、(C1-C6)-亚烷基-杂环、(C1-C6)-亚烷基-(C3-C12)-环烷基、(C8-C14)-二环,其中芳基、杂环、环烷基或二环可以被下述优选的基团单或多取代:卤素、(C1-C6)-烷基、(C1-C3)-烷氧基、羟基、(C1-C6)-烷基巯基、氨基、(C1-C6)-烷基氧基、二-(C2-C12)烷基氨基、单-(C1-C6)-烷基氨基羰基、二-(C2-C8)-烷基氫基羰基、(C1-C6)-烷氧基羰基、(C1-C6)-烷基羰基、氰基、硝基、三氟甲基、三氟甲氧基、五氟硫基、(C1-C6)-烷基磺酰基、氨基磺酰基；Wherein, R1 is hydrogen, (C1-C6)-alkyl, (C1-C6)-haloalkyl, (C1-C6)alkoxy, (C1-C6)-alkylene-aryl, (C1-C6) )-alkylene-heterocycle, (C1-C6)-alkylene-(C3-C12)-cycloalkyl, (C8-C14)-bicycle, in which aryl, heterocycle, cycloalkyl or dicycle The ring may be mono- or polysubstituted by the following preferred groups: halogen, (C1-C6)-alkyl, (C1-C3)-alkoxy, hydroxyl, (C1-C6)-alkylmercapto, amino, ( C1-C6)-Alkyloxy, Di-(C2-C12)Alkylamino, Mono-(C1-C6)-Alkylaminocarbonyl, Di-(C2-C8)-Alkylhydrocarbonyl, (C1 -C6)-alkoxycarbonyl, (C1-C6)-alkylcarbonyl, cyano, nitro, trifluoromethyl, trifluoromethoxy, pentafluorosulfanyl, (C1-C6)-alkylsulfonyl Acyl, aminosulfonyl;
R2是-(C1-C6)-烷基、(C1-C6)-烷氧基、(C1-C3)-卤代烷氧基、(C1-C6)-亚烷基氨、二-(C2-C12)-烷基氨、-CO-(C1-C6)-烷基、-COOR7、-CO-NR8R9、-O-CONR8R9、-O-CO-(C1-C6)-亚烷基-CO-O-(C1-C6)-烷基、-O-CO-(C1-C6)-亚烷基-CO-OH或-O-CO-(C1-C6)-亚烷基-CO-NR8R9、芳基、杂环、-(C2-C12)环烷基；其中芳基、杂环、环烷基或二环可以被下述优选的基团单或多取代:卤素、(C1-C6)-烷基、(C1-C3)-烷氧基、羟基、(C1-C6)-烷基巯基、氨基、(C1-C6)-烷基氧基、二-(C2-C12)烷基氨基、单-(C1-C6)-烷基氨基羰基、二-(C2-C8)-烷基氫基羰基、(C1-C6)-烷氧基羰基、(C1-C6)-烷基羰基、氰基、硝基、三氟甲基、三氟甲氧基、五氟硫基、(C1-C6)-烷基磺酰基、氨基磺酰基；R2 is -(C1-C6)-alkyl, (C1-C6)-alkoxy, (C1-C3)-haloalkoxy, (C1-C6)-alkyleneamino, di-(C2-C12) -Alkylamino, -CO-(C1-C6)-Alkyl, -COOR7, -CO-NR8R9, -O-CONR8R9, -O-CO-(C1-C6)-Alkylene-CO-O-( C1-C6)-alkyl, -O-CO-(C1-C6)-alkylene-CO-OH or -O-CO-(C1-C6)-alkylene-CO-NR8R9, aryl, hetero Ring, -(C2-C12) cycloalkyl; wherein aryl, heterocycle, cycloalkyl or bicycle may be mono- or polysubstituted by the following preferred groups: halogen, (C1-C6)-alkyl, ( C1-C3)-alkoxy, hydroxyl, (C1-C6)-alkylmercapto, amino, (C1-C6)-alkyloxy, di-(C2-C12)alkylamino, mono-(C1- C6)-Alkylaminocarbonyl, Di-(C2-C8)-Alkylhydrocarbonyl, (C1-C6)-Alkoxycarbonyl, (C1-C6)-Alkylcarbonyl, Cyano, Nitro, Tri Fluoromethyl, trifluoromethoxy, pentafluorothio, (C1-C6)-alkylsulfonyl, aminosulfonyl;
R3、R4、R5、R6相同或不同地是氢、(C1-C6)-烷基、(C3-C12)-环烷基、(C1-C4)-亚烷基-芳基、(C1-C4)-亚烷基-(C3-C12)-环烷基、卤素、(C1-C6)-烷基、(C1-C3)-烷氧基、羟基、(C1-C6)-烷基巯基、氨基、(C1-C6)-烷基氧基、二-(C2-C12)烷基氨基、单-(C1-C6)-烷基氨基羰基、二-(C2-C8)-烷基氫基羰基、(C1-C6)-烷氧基羰基、(C1-C6)-烷基羰基、氰基、硝基、三氟甲基、三氟甲氧基、五氟硫基、(C1-C6)-烷基磺酰基、氨基磺酰基；R3, R4, R5, R6 are identically or differently hydrogen, (C1-C6)-alkyl, (C3-C12)-cycloalkyl, (C1-C4)-alkylene-aryl, (C1-C4 )-alkylene-(C3-C12)-cycloalkyl, halogen, (C1-C6)-alkyl, (C1-C3)-alkoxy, hydroxyl, (C1-C6)-alkylmercapto, amino , (C1-C6)-alkyloxy, di-(C2-C12) alkylamino, mono-(C1-C6)-alkylaminocarbonyl, di-(C2-C8)-alkylhydrocarbonyl, (C1-C6)-alkoxycarbonyl, (C1-C6)-alkylcarbonyl, cyano, nitro, trifluoromethyl, trifluoromethoxy, pentafluorothio, (C1-C6)-alkane sulfonyl, aminosulfonyl;
R7是氢、(C1-C10)烷基、(C1-C4)亚烷基-CN、(C1-C4)亚烷基-芳基、(C1-C4)-亚烷基-杂环、(C1-C4)-亚烷基-(C3-C12)-环烷基、(C8-C14)-二环,其中芳基、杂环、环烷基或二环可以被下述优选的基团单或多取代：卤素、(C1-C6)-烷基、(C1-C6)-烷氧基、羟基、(C1-C6)-烷基巯基、氨基、(C1-C6)-烷基氨基、二-(C2-C12)-烷基氨基、单-(C1-C6)-烷基氨基羰基、二-(C2-C8)-烷基氨基羰基、(C1-C6)-烷氧基羰基、(C1-C6)-烷基羰基、氰基、三氟甲基、三氟甲氧基、硝基(C1-C6)-烷基磺酰基、氨基磺酰基；R7 is hydrogen, (C1-C10) alkyl, (C1-C4) alkylene-CN, (C1-C4) alkylene-aryl, (C1-C4)-alkylene-heterocycle, (C1 -C4)-alkylene-(C3-C12)-cycloalkyl, (C8-C14)-bicycle, wherein aryl, heterocycle, cycloalkyl or bicycle can be mono- or bicyclic by the following preferred groups Polysubstituted: Halogen, (C1-C6)-Alkyl, (C1-C6)-Alkoxy, Hydroxyl, (C1-C6)-Alkylmercapto, Amino, (C1-C6)-Alkylamino, Di- (C2-C12)-Alkylamino, Mono-(C1-C6)-Alkylaminocarbonyl, Di-(C2-C8)-Alkylaminocarbonyl, (C1-C6)-Alkoxycarbonyl, (C1- C6)-alkylcarbonyl, cyano, trifluoromethyl, trifluoromethoxy, nitro(C1-C6)-alkylsulfonyl, aminosulfonyl;
R8、R9相同或不同地是氢、(C1-C6)-烷基、芳基、(C3-C12)-环烷基、(C1-C4)-亚烷基-芳基、(C1-C4)-亚烷基-(C3-C12)-环烷基。R8, R9 are identically or differently hydrogen, (C1-C6)-alkyl, aryl, (C3-C12)-cycloalkyl, (C1-C4)-alkylene-aryl, (C1-C4) -Alkylene-(C3-C12)-cycloalkyl.
本发明涉及其盐、溶剂化物、外消旋物、外消旋混合物和纯对映异构体形式的式I化合物以及它们的非对映异构体及其混合物。The present invention relates to compounds of formula I in the form of their salts, solvates, racemates, racemic mixtures and pure enantiomers, as well as their diastereomers and mixtures thereof.
在本发明的一种实施方式中，在取代基R1、R2、R3、R4、R5、R6、R7、R8和R9中的烷基或亚烷基基团可以是直链或支链的。卤素是氟、氯、溴或碘，特别是氟或氯。In one embodiment of the present invention, the alkyl or alkylene groups in substituents R1, R2, R3, R4, R5, R6, R7, R8 and R9 may be straight or branched. Halogen is fluorine, chlorine, bromine or iodine, especially fluorine or chlorine.
在本发明的一种实施方式中，卤代烷基是被卤素单、多或全取代的烷基；优选的卤素是氟和氯。In one embodiment of the invention haloalkyl is an alkyl mono-, poly- or fully substituted with halogen; preferred halogens are fluorine and chlorine.
在本发明的一种实施方式中，环烷基基团是指包含一个或多个环并且仅仅包含碳原子的饱和或部分不饱和(具有一个或两个双键)的环系统，例如环丙基、环戊基、环戊烯基、环己基或金刚烷基。In one embodiment of the invention, a cycloalkyl group refers to a saturated or partially unsaturated (with one or two double bond) ring system containing one or more rings and containing only carbon atoms, such as cyclopropyl cyclopentyl, cyclopentyl, cyclopentenyl, cyclohexyl or adamantyl.
在本发明的一种实施方式中，环烷基基团可以被下述合适的基团单或多取代，例如：F、Cl、Br、I、CF3、NO2、N3、CN、COOH、COO(C1-C6)烷基、CONH2、CONH(C1-C6)烷基、CON[(C1-C6)烷基]2、环烷基、(C1-C10)烷基、(C2-C6)-链烯基、(C2-C6)-炔基、O-(C1-C6)-烷基、O-CO-(C1-C6)-烷基、O-CO-(C1-C6)-芳基、O-CO-(C1-C6)-杂环；PO3H2、SO3H、SO2-NH2、SO2NH(C1-C6)-烷基、SO2N[(C1-C6)烷基]2、S-(C1-C6)-烷基、S-(CH2)n-芳基、S-(CH2)n-杂环、SO-(C1-C6)-烷基、SO-(CH2)n-芳基、SO-(CH2)-杂环、SO2-(C1-C6)-烷基、SO2-(CH2)n-芳基、SO2-(CH2)n-杂环、SO2-NH(CH2)n-芳基、SO2-NH(CH2)n-杂环、SO2-N((C1-C6)-烷基)(CH2)n-芳基、SO2-N((C1-C6)-烷基)(CH2)n-杂环、SO2-N((CH2)n芳基)2、SO2-N((CH2)n-(杂环)2；其中n可以是0-6；并且所述芳基或杂环基团可以被F、Cl、Br、OH、CF3、NO2、CN、OCF3、O-(C1-C6)-烷基、(C1-C6)-烷基、NH2最多二取代；或者被C(NH)(NH2)、NH2、NH-(C1-C6)-烷基、N((C1-C6)烷基)2、NH(C1-C7)-酰基、NH-CO-(C1-C6)-烷基、NH-COO-(C1-C6)-烷基、NH-CO-芳基、NH-CO-杂环、NH-COO-芳基、NH-COO-杂环、NH-CO-NH-(C1-C6)-烷基、NH-CO-NH-芳基、NH-CO-NH-杂环、N(C1-C6)-烷基-CO-(C1-C6)-烷基、N(C1-C6)-烷基-COO-(C1-C6)-烷基、N(C1-C6)-烷基-CO-芳基、N(C1-C6)-烷基-CO-杂环、N(C1-C6)-烷基-COO-芳基、N(C1-C6)-烷基-COO-杂环、N(C1-C6)-烷基-CO-NH-(C1-C6)-烷基、N(C1-C6)-烷基-CO-NH-芳基、N(C1-C6)-烷基-CO-NH-杂环、N((C1-C6)-烷基)-CO-N((C1-C6)-烷基)2、N((C1-C6)-烷基)-CO-N((C1-C6)-烷基)-芳基、N((C1-C6)-烷基)-CO-N((C1-C6)-烷基)-杂环、N((C1-C6)-烷基)-CO-N(芳基)2，N((C1-C6)-烷基)-CO-N-(杂环)2、N(芳基)-CO-(C1-C6)-烷基、N(杂环)-CO-(C1-C6)-烷基、N(芳基)-COO-(C1-C6)-烷基、N(杂环)-COO-(C1-C6)-烷基、N(芳基)-CO-芳基、N(杂环)-CO-芳基、N(芳基)-COO-芳基、N(杂环)-COO-芳基、N(芳 基)-CO-NH-(C1-C6)-烷基、N(杂环)-CO-NH-(C1-C6)-烷基、N(芳基)-CO-NH-芳基、N(杂环)-CO-NH-芳基、N(芳基)-CO-N-((C1-C6)-烷基)2、N(杂环)-CO-N-((C1-C6)-烷基)2、N(芳基)-CO-N-((C1-C6)-烷基)-芳基、N(杂环)-CO-N((C1-C6)-烷基)-芳基、N(芳基)-CO-N-(芳基)2、N(杂环)-CO-N-(芳基)2、芳基、O-(CH2)n-芳基、O-(CH2)-杂环，其中n可以是0-6，其中所述芳基或杂环基可以被F、Cl、Br、I、OH、CF3、NO2、CN、OCF3、O-((C1-C6)-烷基、(C1-C6)-烷基、NH2、NH(C1-C6)-烷基、N((C1-C6)-烷基)2、SO2-CH3、COOH、COO-(C1-C6)-烷基、CONH2所单到三取代。In one embodiment of the present invention, the cycloalkyl group may be mono- or polysubstituted by the following suitable groups, for example: F, Cl, Br, I, CF3, NO2, N3, CN, COOH, COO ( C1-C6) alkyl, CONH2, CONH(C1-C6) alkyl, CON[(C1-C6) alkyl]2, cycloalkyl, (C1-C10) alkyl, (C2-C6)-alkene base, (C2-C6)-alkynyl, O-(C1-C6)-alkyl, O-CO-(C1-C6)-alkyl, O-CO-(C1-C6)-aryl, O- CO-(C1-C6)-heterocycle; PO3H2, SO3H, SO2-NH2, SO2NH(C1-C6)-alkyl, SO2N[(C1-C6)-alkyl]2, S-(C1-C6)-alkane base, S-(CH2)n-aryl, S-(CH2)n-heterocycle, SO-(C1-C6)-alkyl, SO-(CH2)n-aryl, SO-(CH2)-heterocycle Ring, SO2-(C1-C6)-Alkyl, SO2-(CH2)n-Aryl, SO2-(CH2)n-Heterocycle, SO2-NH(CH2)n-Aryl, SO2-NH(CH2) n-heterocycle, SO2-N((C1-C6)-alkyl)(CH2)n-aryl, SO2-N((C1-C6)-alkyl)(CH2)n-heterocycle, SO2-N ((CH2)naryl)2, SO2-N((CH2)n-(heterocycle)2; wherein n can be 0-6; and the aryl or heterocyclic group can be replaced by F, Cl, Br , OH, CF3, NO2, CN, OCF3, O-(C1-C6)-alkyl, (C1-C6)-alkyl, NH2 up to disubstituted; or by C(NH)(NH2), NH2, NH- (C1-C6)-Alkyl, N((C1-C6)Alkyl)2, NH(C1-C7)-Acyl, NH-CO-(C1-C6)-Alkyl, NH-COO-(C1- C6)-alkyl, NH-CO-aryl, NH-CO-heterocycle, NH-COO-aryl, NH-COO-heterocycle, NH-CO-NH-(C1-C6)-alkyl, NH -CO-NH-aryl, NH-CO-NH-heterocycle, N(C1-C6)-alkyl-CO-(C1-C6)-alkyl, N(C1-C6)-alkyl-COO- (C1-C6)-Alkyl, N(C1-C6)-Alkyl-CO-Aryl, N(C1-C6)-Alkyl-CO-Heterocycle, N(C1-C6)-Alkyl-COO -Aryl, N(C1-C6)-Alkyl-COO-Heterocycle, N(C1-C6)-Alkyl-CO-NH-(C1-C6)-Alkyl, N(C1-C6)-Alkyl Base-CO-NH-Aryl, N(C1-C6)-Alkyl-CO-NH-Heterocycle, N((C1-C6)-Alkyl)-CO-N((C1-C6)-Alkyl )2, N(( C1-C6)-Alkyl)-CO-N((C1-C6)-Alkyl)-Aryl, N((C1-C6)-Alkyl)-CO-N((C1-C6)-Alkyl )-heterocycle, N((C1-C6)-alkyl)-CO-N(aryl)2, N((C1-C6)-alkyl)-CO-N-(heterocycle)2, N( Aryl)-CO-(C1-C6)-Alkyl, N(Heterocycle)-CO-(C1-C6)-Alkyl, N(Aryl)-COO-(C1-C6)-Alkyl, N (Heterocycle)-COO-(C1-C6)-Alkyl, N(Aryl)-CO-Aryl, N(Heterocycle)-CO-Aryl, N(Aryl)-COO-Aryl, N (Heterocycle)-COO-aryl, N(aryl)-CO-NH-(C1-C6)-alkyl, N(heterocycle)-CO-NH-(C1-C6)-alkyl, N( Aryl)-CO-NH-aryl, N(heterocycle)-CO-NH-aryl, N(aryl)-CO-N-((C1-C6)-alkyl)2, N(heterocycle )-CO-N-((C1-C6)-alkyl)2, N(aryl)-CO-N-((C1-C6)-alkyl)-aryl, N(heterocycle)-CO- N((C1-C6)-Alkyl)-aryl, N(aryl)-CO-N-(aryl)2, N(heterocycle)-CO-N-(aryl)2, aryl, O-(CH2)n-aryl, O-(CH2)-heterocycle, wherein n can be 0-6, wherein the aryl or heterocycle can be replaced by F, Cl, Br, I, OH, CF3, NO2, CN, OCF3, O-((C1-C6)-Alkyl, (C1-C6)-Alkyl, NH2, NH(C1-C6)-Alkyl, N((C1-C6)-Alkyl) 2. SO2-CH3, COOH, COO-(C1-C6)-alkyl, CONH2 are mono- to tri-substituted.
二环是具有8-14个环原子并且仅仅由碳原子作为环原子的部分不饱和的二环系统。该定义包括含有稠合的苯环核心的环系统。可以提及的例子如四氢萘基、α-或β-四氢萘酮、茚满基或茚满-1-酮基基团。优选的二环基团是四氢萘基和茚满基。A bicyclic ring is a partially unsaturated bicyclic ring system having 8-14 ring atoms and having only carbon atoms as ring atoms. This definition includes ring systems containing a fused benzene ring core. Examples which may be mentioned are tetrahydronaphthyl, α- or β-tetralone, indanyl or indan-1-one groups. Preferred bicyclic groups are tetrahydronaphthyl and indanyl.
二环基团可以被合适的下述基团单或多取代，例如：F、Cl、Br、I、CF3、NO2、N3、CN、COOH、COO(C1-C6)-烷基、CONH2、CONH(C1-C6)-烷基、CON[(C1-C6)-烷基]2、环烷基、(C1-C10)烷基、(C2-C6)-链烯基、(C2-C6)-炔基、O-(C1-C6)-烷基、O-CO-(C1-C6)-烷基、O-CO-(C1-C6)-芳基、O-CO-(C1-C6)-杂环；PO3H2、SO3H、SO2-NH2、SO2NH(C1-C6)-烷基、SO2N[(C1-C6)-烷基]2、S-(C1-C6)-烷基、S-(CH2)n-芳基、S-(CH2)-杂环、SO-(C1-C6)-烷基，SO-(CH2)n-芳基、SO(CH2)n-杂环、SO2-(C1-C6)-烷基，SO2-(CH2)n-芳基、SO2-(CH2)n-杂环、SO2-NH(CH2)n-芳基、SO2-NH(CH2)n-杂环、SO2-N((C1-C6)-烷基)(CH2)芳基、SO2-N((C1-C6)-烷基)(CH2)n-杂环、SO2-N((CH2)n-芳基)2、SO2-N((CH2)n-(杂环)2，其中n可以是0-6；Bicyclic groups may be mono- or polysubstituted by suitable groups such as F, Cl, Br, I, CF3, NO2, N3, CN, COOH, COO(C1-C6)-alkyl, CONH2, CONH (C1-C6)-Alkyl, CON[(C1-C6)-Alkyl]2, Cycloalkyl, (C1-C10)Alkyl, (C2-C6)-Alkenyl, (C2-C6)- Alkynyl, O-(C1-C6)-Alkyl, O-CO-(C1-C6)-Alkyl, O-CO-(C1-C6)-Aryl, O-CO-(C1-C6)- Heterocycle; PO3H2, SO3H, SO2-NH2, SO2NH(C1-C6)-alkyl, SO2N[(C1-C6)-alkyl]2, S-(C1-C6)-alkyl, S-(CH2) n-aryl, S-(CH2)-heterocycle, SO-(C1-C6)-alkyl, SO-(CH2)n-aryl, SO(CH2)n-heterocycle, SO2-(C1-C6 )-alkyl, SO2-(CH2)n-aryl, SO2-(CH2)n-heterocycle, SO2-NH(CH2)n-aryl, SO2-NH(CH2)n-heterocycle, SO2-N ((C1-C6)-Alkyl)(CH2)Aryl, SO2-N((C1-C6)-Alkyl)(CH2)n-Heterocycle, SO2-N((CH2)n-Aryl)2 , SO2-N((CH2)n-(heterocycle)2, where n can be 0-6;
且所述芳基或杂环基可以被F、Cl、Br、OH、CF3、NO2、CN、OCF3、O-(C1-C6)-烷基、(C1-C6)-烷基、NH2最多二取代；或者被C(NH)(NH2)、NH2，NH-(C1-C6)-烷基、N((C1-C6)-烷基)2、NH(C1-C7)-酰基、NH-CO-(C1-C6)-烷基、NH-COO-(C1-C6)-烷基、NH-CO-芳基、NH-CO-杂环、NH-COO-芳基、NH-COO-杂环、NH-CO-NH-(C1-C6)-烷基、NH-CO-NH-芳基、NH-CO-NH-杂环、N(C1-C6)-烷基-CO-(C1-C6)-烷基、N(C1-C6)-烷基-COO-(C1-C6)-烷基、N(C1-C6)-烷基-CO-芳基、N(C1-C6)-烷基-CO-杂环、N(C1-C6)-烷基-COO-芳基、N(C1-C6)-烷基-COO-杂环、N(C1-C6)-烷基-CO-NH-(C1-C6)-烷基、N(C1-C6)-烷基-CO-NH-芳基、N(C1-C6)-烷基-CO-NH-杂环、N((C1-C6)-烷基)-CO-N((C1-C6)-烷基)2、N((C1-C6)-烷基)-CO-N((C1-C6)-烷基)-芳基、N((C1-C6)-烷基)-CO-N((C1-C6)-烷基)-杂环、N((C1-C6)-烷基)-CO-N-(芳基)2、N((C1-C6)-烷基)-CO-N-(杂环)2、N(芳基)-CO-(C1-C6)-烷基、N(杂环)-CO-(C1-C6)-烷基、N(芳基)-COO-(C1-C6)-烷基、N(杂环)-COO-(C1-C6)-烷基、N(芳基)-CO-芳基、N(杂环)-CO-芳基、N(芳基)-COO芳基、N(杂环)-COO-芳基、N(芳基)-CO-NH-(C1-C6)-烷基、N(杂环)-CO-NH-(C1-C6)-烷基、N(芳基)-CO-NH-芳基、N(杂环)-CO-NH-芳基、N(芳基)-CO-N-(C1-C6)-烷基)2、N(杂环)-CO-N-((C1-C6)-烷基)2、N(芳基)-CO-N((C1-C6)-烷基)-芳基、N(杂环)-CO-N((C1-C6)-烷基)-芳基、N(芳基)-CO-N-(芳基)2、N(杂环)-CO-N-(芳基)2、芳基、O-(CH2)n-芳基、O-(CH2)n-杂环，其中n可以是0-6，其中所述芳基或杂环基园可以被F、Cl、Br、I、OH、CF3、NO2、CN、OCF3、O-(C1-C6)-烷基、(C1-C6)-烷基、NH2、NH(C1-C6)-烷基、N((C1-C6)-烷基)2、SO2-CH3、COOH、COO-(C1-C6)-烷基、CONH2所单取代到三取代。And the aryl or heterocyclic group can be replaced by F, Cl, Br, OH, CF3, NO2, CN, OCF3, O-(C1-C6)-alkyl, (C1-C6)-alkyl, NH2 up to two substituted; or by C(NH)(NH2), NH2, NH-(C1-C6)-alkyl, N((C1-C6)-alkyl)2, NH(C1-C7)-acyl, NH-CO -(C1-C6)-Alkyl, NH-COO-(C1-C6)-Alkyl, NH-CO-Aryl, NH-CO-Heterocycle, NH-COO-Aryl, NH-COO-Heterocycle , NH-CO-NH-(C1-C6)-alkyl, NH-CO-NH-aryl, NH-CO-NH-heterocycle, N(C1-C6)-alkyl-CO-(C1-C6 )-Alkyl, N(C1-C6)-Alkyl-COO-(C1-C6)-Alkyl, N(C1-C6)-Alkyl-CO-Aryl, N(C1-C6)-Alkyl -CO-heterocycle, N(C1-C6)-alkyl-COO-aryl, N(C1-C6)-alkyl-COO-heterocycle, N(C1-C6)-alkyl-CO-NH- (C1-C6)-Alkyl, N(C1-C6)-Alkyl-CO-NH-Aryl, N(C1-C6)-Alkyl-CO-NH-Heterocycle, N((C1-C6) -Alkyl)-CO-N((C1-C6)-Alkyl)2, N((C1-C6)-Alkyl)-CO-N((C1-C6)-Alkyl)-Aryl, N ((C1-C6)-Alkyl)-CO-N((C1-C6)-Alkyl)-Heterocycle, N((C1-C6)-Alkyl)-CO-N-(Aryl)2, N((C1-C6)-alkyl)-CO-N-(heterocycle)2, N(aryl)-CO-(C1-C6)-alkyl, N(heterocycle)-CO-(C1- C6)-alkyl, N(aryl)-COO-(C1-C6)-alkyl, N(heterocycle)-COO-(C1-C6)-alkyl, N(aryl)-CO-aryl , N(heterocycle)-CO-aryl, N(aryl)-COO-aryl, N(heterocycle)-COO-aryl, N(aryl)-CO-NH-(C1-C6)-alkane base, N(heterocycle)-CO-NH-(C1-C6)-alkyl, N(aryl)-CO-NH-aryl, N(heterocycle)-CO-NH-aryl, N(aryl) base)-CO-N-(C1-C6)-alkyl)2, N(heterocycle)-CO-N-((C1-C6)-alkyl)2, N(aryl)-CO-N( (C1-C6)-Alkyl)-Aryl, N(Heterocycle)-CO-N((C1-C6)-Alkyl)-Aryl, N(Aryl)-CO-N-(Aryl) 2. N(heterocycle)-CO-N-(aryl)2, aryl, O-(CH2)n-aryl, O-(CH2)n-heterocycle, where n can be 0-6, where The aryl or heterocyclyl group can be represented by F, Cl, Br, I, OH, CF3, NO2, CN, OCF3, O-(C1-C6)-Alkyl, (C1-C6)-Alkyl, NH2, NH(C1-C6)-Alkyl, N((C1-C6)- Alkyl)2, SO2-CH3, COOH, COO-(C1-C6)-alkyl, CONH2 mono-substituted to tri-substituted.
芳基基团是指苯基或萘基基团。Aryl groups refer to phenyl or naphthyl groups.
芳基基团可以被合适的下述基团单或多取代，例如：F、C、Br、I、CF3、NO2、CN、COOH、COO(C1-C6)-烷基、CONH2、CONH(C1-C6)-烷基、CON[(C1-C6)-烷基]2、(C3-C10)-环烷基、(C1-C10)-烷基、(C2-C6)-链烯基、(C2-C6)-炔基、O-(C1-C6)-烷基、O-CO-(C1-C6)-烷基、O-CO-(C1-C6)-芳基；PO3H2、SO3H、SO2-NH2、SO2NH(C1-C6)-烷基、SO2N[((C1-C6)-烷基]2、S-(C1-C6)-烷基、S-(CH2)n-芳基、S-(CH2)n-杂环、SO-(C1-C6)-烷基、SO-(CH2)n-芳基、SO-(CH2)n-杂环、SO2-(C1-C6)-烷基、SO2-(CH2)n-芳基、SO2-(CH2)n-杂环、SO2-NH(CH2)n-芳基、SO2-NH(CH2)n-杂环、SO2-N((C1-C6)-烷基)(CH2)n-芳基、SO2-N((C1-C6)-烷基)(CH2)n-杂环、SO2-N(CH2)n-芳基)2、SO2-N(CH2)n-(杂环)2；其中n可以是0-6；Aryl groups may be mono- or polysubstituted by suitable groups such as F, C, Br, I, CF3, NO2, CN, COOH, COO(C1-C6)-alkyl, CONH2, CONH(C1 -C6)-Alkyl, CON[(C1-C6)-Alkyl]2, (C3-C10)-Cycloalkyl, (C1-C10)-Alkyl, (C2-C6)-Alkenyl, ( C2-C6)-alkynyl, O-(C1-C6)-alkyl, O-CO-(C1-C6)-alkyl, O-CO-(C1-C6)-aryl; PO3H2, SO3H, SO2 -NH2, SO2NH(C1-C6)-alkyl, SO2N[((C1-C6)-alkyl]2, S-(C1-C6)-alkyl, S-(CH2)n-aryl, S- (CH2)n-heterocycle, SO-(C1-C6)-alkyl, SO-(CH2)n-aryl, SO-(CH2)n-heterocycle, SO2-(C1-C6)-alkyl, SO2-(CH2)n-aryl, SO2-(CH2)n-heterocycle, SO2-NH(CH2)n-aryl, SO2-NH(CH2)n-heterocycle, SO2-N((C1-C6 )-Alkyl)(CH2)n-Aryl, SO2-N((C1-C6)-Alkyl)(CH2)n-Heterocycle, SO2-N(CH2)n-Aryl)2, SO2-N (CH2)n-(heterocycle)2; wherein n can be 0-6;
并且所述芳基或杂环基团可以被F、CI、Br、OH、CF3、NO2、CN、OCF3、O-((C1-C6)-烷基、(C1-C6)-烷基、NH2最多二取代；或者被C(NHNH2)、NH2、NH-(C1-C6)-烷基、N((C1-C6)-烷基)2、NH(C1-C7)-酰基、NH-CO-(C1-C6)-烷基、NH-COO(C1-C6)-烷基、NH-CO-芳基、NH-CO-杂环、NH-COO-芳基、NH-COO-杂环、NH-CO-NH-((C1-C6)-烷基、NH-CO-NH-芳基、NH-CO-NH-杂环、N(C1-C6)-烷基-CO-((C1-C6)-烷基、N(C1-C6)-烷基-COO-(C1-C6)-烷基、N(C1-C6)-烷基-CO-芳基、N(C1-C6)-烷基-CO-杂环、N(C1-C6)-烷基-COO-芳基、N(C1-C6)-烷基-COO-杂环、N(C1-C6)-烷基-CO-NH-(C1-C6)-烷基、N(C1-C6)-烷基-CO-NH-芳基、N(C1-C6)-烷基-CO-NH-杂环、N((C1-C6)-烷基)-CO-N-(C1-C6)-烷基)2、N((C1-C6)-烷基)-CO-N((C1-C6)-烷基)-芳基、N((C1-C6)-烷基)-CO-N(C1-C6)-烷基)-杂环、N((C1-C6)-烷基)-CO-N-(芳基)2、N((C1-C6)-烷基)-CO-N(杂环)2、N(芳基)-CO-(C1-C6)-烷基、N(杂环)-CO-(C1-C6)-烷基、N(芳基)-COO-(C1-C6)-烷基、N(杂环)-COO-(C1-C6)-烷基、N(芳基)-CO-芳基、N(杂环)-CO-芳基、N(芳基)-COO-芳基、N(杂环)-COO-芳基、N(芳基)-CO-NH-(C1-C6)-烷基、N(杂环)-CO-NH-(C1-C6)-烷基、N(芳基)-CO-NH-芳基、N(杂环)-CO-NH-芳基、N(芳基)-CO-N((C1-C6)-烷基) 2、N(杂环)-CO-N-((C1-C6)-烷基)2、N(芳基)-CO-N((C1-C6)-烷基)-芳基、N(杂环)-CO-N((C1-C6)-烷基)-芳基，N(芳基)-CO-N(芳基)2，N(杂环)-CO-N-(芳基)2、芳基、O-(CH2)n-芳基、O-(CH2)n-杂环，其中n可以是0-6，其中所述芳基或杂环基团可以被F、C、Br、I、OH，CF3、NO2、CN、OCF3、O-(C1-C6)-烷基、(C1-C6)-烷基、NH2、NH(C1-C6)-烷基、N((C1-C6)-烷基)2、SO2-CH3、COOH、COO-(C1-C6)-烷基、CONH2所单-到三取代。And the aryl or heterocyclic group can be replaced by F, CI, Br, OH, CF3, NO2, CN, OCF3, O-((C1-C6)-alkyl, (C1-C6)-alkyl, NH2 Disubstituted at most; or by C(NHNH2), NH2, NH-(C1-C6)-alkyl, N((C1-C6)-alkyl)2, NH(C1-C7)-acyl, NH-CO- (C1-C6)-Alkyl, NH-COO(C1-C6)-Alkyl, NH-CO-Aryl, NH-CO-Heterocycle, NH-COO-Aryl, NH-COO-Heterocycle, NH -CO-NH-((C1-C6)-alkyl, NH-CO-NH-aryl, NH-CO-NH-heterocycle, N(C1-C6)-alkyl-CO-((C1-C6 )-Alkyl, N(C1-C6)-Alkyl-COO-(C1-C6)-Alkyl, N(C1-C6)-Alkyl-CO-Aryl, N(C1-C6)-Alkyl -CO-heterocycle, N(C1-C6)-alkyl-COO-aryl, N(C1-C6)-alkyl-COO-heterocycle, N(C1-C6)-alkyl-CO-NH- (C1-C6)-Alkyl, N(C1-C6)-Alkyl-CO-NH-Aryl, N(C1-C6)-Alkyl-CO-NH-Heterocycle, N((C1-C6) -Alkyl)-CO-N-(C1-C6)-Alkyl)2, N((C1-C6)-Alkyl)-CO-N((C1-C6)-Alkyl)-Aryl, N ((C1-C6)-Alkyl)-CO-N(C1-C6)-Alkyl)-Heterocycle, N((C1-C6)-Alkyl)-CO-N-(Aryl)2, N ((C1-C6)-Alkyl)-CO-N(heterocycle)2, N(aryl)-CO-(C1-C6)-alkyl, N(heterocycle)-CO-(C1-C6) -Alkyl, N(aryl)-COO-(C1-C6)-alkyl, N(heterocycle)-COO-(C1-C6)-alkyl, N(aryl)-CO-aryl, N (Heterocycle)-CO-aryl, N(aryl)-COO-aryl, N(heterocycle)-COO-aryl, N(aryl)-CO-NH-(C1-C6)-alkyl , N(heterocycle)-CO-NH-(C1-C6)-alkyl, N(aryl)-CO-NH-aryl, N(heterocycle)-CO-NH-aryl, N(aryl) )-CO-N((C1-C6)-alkyl) 2, N(heterocycle)-CO-N-((C1-C6)-alkyl) 2, N(aryl)-CO-N(( C1-C6)-Alkyl)-aryl, N(heterocycle)-CO-N((C1-C6)-alkyl)-aryl, N(aryl)-CO-N(aryl)2, N(heterocycle)-CO-N-(aryl)2, aryl, O-(CH2)n-aryl, O-(CH2)n-heterocycle, where n can be 0-6, wherein the Aryl or heterocyclic groups can be represented by F, C, Br, I, OH, CF3, NO2, CN, OCF3, O-(C1-C6)-alkyl, (C1-C6)-alkyl, NH2, NH(C1-C6)-alkyl, N((C1-C6)- Alkyl)2, SO2-CH3, COOH, COO-(C1-C6)-alkyl, CONH2 mono- to tri-substituted.
杂环是具有5-12个环原子的单-或二环的环系统，其中环系统中至少一个原子是选自N、O和S的杂原子。该定义还包括其中杂环与苯环核心稠合的环系统。(C5-C7)-杂环是单环系统；(C8-C12)-杂环是二环系统。A heterocycle is a mono- or bicyclic ring system having 5-12 ring atoms, wherein at least one atom in the ring system is a heteroatom selected from N, O and S. The definition also includes ring systems in which a heterocycle is fused to a benzene ring core. (C5-C7)-heterocycle is a monocyclic ring system; (C8-C12)-heterocycle is a bicyclic ring system.
合适的“杂环”或“杂环基团”是吖辛因基、苯并咪唑基、苯并呋喃基、苯并噻吩基、苯并噻吩基、苯并噁基、苯并噻唑基、苯并三唑基、苯并四唑基、苯并异噁唑基、苯并异噻唑基、苯并咪唑啉基、咔唑基、4aH-咔唑基、咔啉基、喹唑啉基、喹啉基、4H-喹嗪基、喹喔啉基、奎宁环基、色满基、色烯基、噌啉基、十氢喹啉基、2H，6H-1，5，2-二噻嗪基、二氢呋喃并[2，3-b]四氢呋喃、呋喃基、呋咱基、咪唑烷基、咪唑啉基、咪唑基、1H-吲唑基、二氢吲哚基、吲嗪基、吲哚基、3H-吲哚基、异苯并呋喃基、异色满基、异吲唑基、异二氢吲哚基、异吲哚基、异喹啉基(苯并咪唑基)、异噻唑基、异噁唑基、吗啉基、萘啶基、八氢异喹啉基、噁二唑基、1，2，3-噁二唑基、1，2，4-噁二唑基、1，2，5-噁二唑基、1，3，4-噁二唑基、噁唑烷基、噁唑基、噁唑烷基、嘧啶基、菲啶基、菲咯啉基、吩嗪基、吩噻溱基、吩噻噁基(phenoxathiinyl)、吩噁嗪基、2，3-二氮杂萘基、哌嗪基、哌啶基、蝶啶基、嘌呤基、吡喃基、吡嗪基、吡唑烷基、呲唑啉基、吡唑基、哒嗪基、呲啶并噁唑、吡啶并咪唑、吡并噻唑、吡啶基、吡啶基、嘧啶基、吡咯烷基、吡咯啉基、2H-吡咯基、吡咯基、四氢呋喃基、四氢异喹啉基、四氢喹啉基、6H-1，2，5-噻二嗪基、噻唑基、1，2，3-塞二唑基、1，2，4塞二唑基、1，2，5-噻二唑基、1，3，4-噻二唑基、噻吩基、三唑基、四唑基和呫吨基。Suitable "heterocycle" or "heterocyclic groups" are azacinyl, benzimidazolyl, benzofuranyl, benzothienyl, benzothienyl, benzoxyl, benzothiazolyl, benzene Triazolyl, benzotetrazolyl, benzisoxazolyl, benzisothiazolyl, benzimidazolinyl, carbazolyl, 4aH-carbazolyl, carbazolyl, quinazolinyl, quinoline Linyl, 4H-quinazinyl, quinoxalinyl, quinuclidinyl, chromanyl, chromenyl, cinnolinyl, decahydroquinolinyl, 2H,6H-1,5,2-dithiazine base, dihydrofuro[2,3-b]tetrahydrofuran, furanyl, furanyl, imidazolidinyl, imidazolinyl, imidazolyl, 1H-indazolyl, indoline, indolizinyl, indium dolyl, 3H-indolyl, isobenzofuranyl, isochromanyl, isoindazolyl, isoindolyl, isoindolyl, isoquinolinyl (benzimidazolyl), isothiazole base, isoxazolyl, morpholinyl, naphthyridinyl, octahydroisoquinolinyl, oxadiazolyl, 1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl, 1 , 2,5-oxadiazolyl, 1,3,4-oxadiazolyl, oxazolidinyl, oxazolyl, oxazolidinyl, pyrimidinyl, phenanthridine, phenanthroline, phenazinyl , phenothiazinyl, phenoxathiinyl, phenoxazinyl, 2,3-diazanaphthyl, piperazinyl, piperidinyl, pteridyl, purinyl, pyranyl, pyrazine pyrazolidinyl, pyrazolidinyl, pyridazinyl, pyrazolyl, pyridazinyl, pyridoloxazole, pyridoimidazole, pyridothiazole, pyridyl, pyridyl, pyrimidinyl, pyrrolidinyl, pyrrolinyl , 2H-pyrrolyl, pyrrolyl, tetrahydrofuranyl, tetrahydroisoquinolinyl, tetrahydroquinolinyl, 6H-1,2,5-thiadiazinyl, thiazolyl, 1,2,3-sedadiazole base, 1,2,4-xadiazolyl, 1,2,5-thiadiazolyl, 1,3,4-thiadiazolyl, thienyl, triazolyl, tetrazolyl and xanthyl.
呲啶基代表2-、3-和4-吡啶基。噻吩基代表2-和3-塞吩基。呋喃基代表2-和3-呋喃基。Peridyl represents 2-, 3- and 4-pyridyl. Thienyl represents 2- and 3-thienyl. Furyl represents 2- and 3-furyl.
还包括这些化合物相应的N-氧化物，例如1-氧化-2-、-3或-4-吡突基杂环或杂环基团可以被下述合适的基团单或多取代，例如：F、C1、Br、I、CF3、NO2、N3、CN、COOH、COO(C1-C6)烷基、CONH2、CONH(C1-C6)烷基、CON[(C1-C6)烷基]2、(C1-C6)-烷基、(C2-C6)-链烯基，(C2-C6)-炔基、O-(C1-C6)-烷基，其中所述烷基的一个、多个或全部氢可以被氟取代；PO3H2、SO3H、SO2-NH2、SO2NH(C1-C6)-烷基、SO2N[(C1-C6)-烷基]2、S-(C1-C6)-烷基、S-(CH2)n-苯基、SO-(C1-C6)-烷基、SO-(CH2)n-苯基、SO2-(C1-C6)-烷基、SO2-(CH2)n-苯基；其中n可以是0-6；且苯基基团可以被F、Cl、Br、OH、CF3、NO2、CN、OCF3、O-(C1-C6)-烷基、(C1-C6)-烷基、NH2最多二取代；或者被C(NH)(NH2)、NH2、NH-(C1-C6)-烷基、N((C1-C6)-烷基)2、NH(C1-C7)-酰基、苯基、O-(CH2)n-苯基，其中n可以是0-6，其中苯环可以被F、Cl、Br、I、OH、CF3、NO2、CN、OCF3、O(C1-C6)-烷基、(C1-C6)-烷基、NH2、NH(C1-C6)-烷基、N((C1-C6)-烷基)2、SO2-CH3、COOH、COO-(C1-C6)-烷基、CONH2单到三取代。Also included are the corresponding N-oxides of these compounds, such as 1-oxo-2-, -3 or -4-pyridyl heterocyclic or heterocyclic groups which may be mono- or polysubstituted by suitable groups such as: F, C1, Br, I, CF3, NO2, N3, CN, COOH, COO(C1-C6) alkyl, CONH2, CONH(C1-C6) alkyl, CON[(C1-C6) alkyl]2, (C1-C6)-alkyl, (C2-C6)-alkenyl, (C2-C6)-alkynyl, O-(C1-C6)-alkyl, wherein one, more or All hydrogens can be replaced by fluorine; PO3H2, SO3H, SO2-NH2, SO2NH(C1-C6)-alkyl, SO2N[(C1-C6)-alkyl]2, S-(C1-C6)-alkyl, S -(CH2)n-Phenyl, SO-(C1-C6)-Alkyl, SO-(CH2)n-Phenyl, SO2-(C1-C6)-Alkyl, SO2-(CH2)n-Phenyl ; where n can be 0-6; and the phenyl group can be replaced by F, Cl, Br, OH, CF3, NO2, CN, OCF3, O-(C1-C6)-alkyl, (C1-C6)-alkane base, NH2 up to disubstituted; or by C(NH)(NH2), NH2, NH-(C1-C6)-alkyl, N((C1-C6)-alkyl)2, NH(C1-C7)- Acyl, phenyl, O-(CH2)n-phenyl, where n can be 0-6, where the benzene ring can be replaced by F, Cl, Br, I, OH, CF3, NO2, CN, OCF3, O(C1- C6)-Alkyl, (C1-C6)-Alkyl, NH2, NH(C1-C6)-Alkyl, N((C1-C6)-Alkyl)2, SO2-CH3, COOH, COO-(C1 -C6)-Alkyl, CONH2 mono- to tri-substituted.
杂芳基是具有5到12个环原子的单-或双环的芳香族环系统，其中环系统中至少一个原子是选自N、O和S的杂原子。该定义还包括杂芳基与苯环稠合的环系统。Heteroaryl is a mono- or bicyclic aromatic ring system having 5 to 12 ring atoms, wherein at least one atom in the ring system is a heteroatom selected from N, O and S. The definition also includes ring systems in which a heteroaryl group is fused to a benzene ring.
合适的“杂芳基环”或“杂芳基基团”的实例是苯并咪唑基、苯并呋喃基、苯并噻吩基、苯并噁唑基、苯并噻唑基、苯并三唑基、苯并四唑基、苯并异噁唑基、苯并异噻唑基、喹啉基、呋喃基、呋咱基、咪唑基、1H-吲唑基、吲哚基、1，2，3-噁二唑基、1，2，4-噁二唑基、1，2，5-噁二唑基、1，3，4-噁二唑基、嘧啶基、吡嗪基、吡唑基、吡啶基、吡咯基、噻唑基、1，2，3-塞二唑基、1，2，4-噻二唑基、1，2，5-噻二唑基、1，3，4-噻二唑基和噻吩基。Examples of suitable "heteroaryl rings" or "heteroaryl groups" are benzimidazolyl, benzofuranyl, benzothienyl, benzoxazolyl, benzothiazolyl, benzotriazolyl , benzotetrazolyl, benzisoxazolyl, benzisothiazolyl, quinolinyl, furanyl, furanyl, imidazolyl, 1H-indazolyl, indolyl, 1,2,3- oxadiazolyl, 1,2,4-oxadiazolyl, 1,2,5-oxadiazolyl, 1,3,4-oxadiazolyl, pyrimidinyl, pyrazinyl, pyrazolyl, pyridine base, pyrrolyl, thiazolyl, 1,2,3-thiadiazolyl, 1,2,4-thiadiazolyl, 1,2,5-thiadiazolyl, 1,3,4-thiadiazole base and thienyl.
杂芳基环或杂芳基基团可被合适基团单或多取代，如：F、Cl、Br、I、CF3、NO2，N3、CN、COOH、COO(C1-C6)烷基、CONH2、CONH(C1-C6)烷基、CON[(C1-C6)-烷基]2、(C1-C6)-烷基、(C2-C6)-链烯基、(C2-C6)-块基、O-(C1-C6)-烷基，其中所述烷基中一个或多个或全部氢可以被氟代替；PO3H2、SO3H、SO2-NH2，SO2NH(C1-C6)-烷基、SO2N[(C1-C6)-烷基]2、S-(C1-C6)-烷基、S-(CH2)n-苯基、SO-(C1-C6)-烷基、SO-(CH2)n-苯基SO2-(C1-C6)-烷基、SO2-(CH2)n-苯基；其中n可以是0-6；并且所述苯基基团可以被F、Cl、Br、OH、CF3、NO2、CN、OCF3、O-(C1-C6)-烷基、(C1-C6)-烷基、NH2最多二取代；或者被C(NH)(NH2)、NH2、NH-(C1-C6)-烷基、N((C1-C6)-烷基)2，NH(C1-C7)-酰基、苯基、O-(CH2)n-苯基，其中n可以是0-6，其中所述苯环可以被F、Cl、Br、I、OH、CF3、NO2、CN、OCF3、O-(C1-C6)-烷基、(C1-C6)-烷基、NH2、NH(C1-C6)-烷基、N((C1-C6)-烷基)2、SO2-CH3、COOH、COO-(C1-C6)-烷基、CONH2单到三取代。Heteroaryl rings or heteroaryl groups may be mono- or polysubstituted with suitable groups, such as: F, Cl, Br, I, CF3, NO2, N3, CN, COOH, COO(C1-C6)alkyl, CONH2 , CONH(C1-C6) alkyl, CON[(C1-C6)-alkyl]2, (C1-C6)-alkyl, (C2-C6)-alkenyl, (C2-C6)-blockyl , O-(C1-C6)-alkyl, wherein one or more or all hydrogens in the alkyl can be replaced by fluorine; PO3H2, SO3H, SO2-NH2, SO2NH(C1-C6)-alkyl, SO2N[ (C1-C6)-Alkyl]2, S-(C1-C6)-Alkyl, S-(CH2)n-Phenyl, SO-(C1-C6)-Alkyl, SO-(CH2)n- Phenyl SO2-(C1-C6)-alkyl, SO2-(CH2)n-phenyl; where n can be 0-6; and the phenyl group can be replaced by F, Cl, Br, OH, CF3, NO2, CN, OCF3, O-(C1-C6)-alkyl, (C1-C6)-alkyl, NH2 up to disubstituted; or by C(NH)(NH2), NH2, NH-(C1-C6) - alkyl, N((C1-C6)-alkyl)2, NH(C1-C7)-acyl, phenyl, O-(CH2)n-phenyl, where n can be 0-6, wherein the The benzene ring can be replaced by F, Cl, Br, I, OH, CF3, NO2, CN, OCF3, O-(C1-C6)-alkyl, (C1-C6)-alkyl, NH2, NH(C1-C6) -Alkyl, N((C1-C6)-alkyl)2, SO2-CH3, COOH, COO-(C1-C6)-alkyl, CONH2 mono- to tri-substituted.
在本发明的一种实施方式中，可用于制备内皮脂肪酶抑制药物的苯并咪唑类化合物具体选自如下化合物：In one embodiment of the present invention, the benzimidazole compounds that can be used to prepare endothelial lipase inhibitory drugs are specifically selected from the following compounds:
由于可药用盐在水中的溶解度高于最初或基本的化合物，因此其特别适于医药用途。这些盐必须具有可药用的阴离子或阳离子。本发明化合物适宜的可药用的酸加成盐是无机酸例如盐酸、氢溴酸、磷酸、偏磷酸、硝酸和硫酸的盐，以及有机酸例如乙酸、苯磺酸、苯甲酸、柠檬酸、乙磺酸、富马酸、萄糖酸、羟乙酸、羟乙磺酸、乳酸、乳糖酸、马来酸、苹果酸、甲磺酸、琥珀酸、对甲苯磺酸和酒石酸的盐，合适的可药用碱的盐是铵盐、碱金属盐(例如钠盐和钾盐)和碱土金属盐(例如镁盐和钙盐)以及氨基丁三醇(2-氨基-2-羟基甲基-1，3-丙二醇)、二乙醇胺、赖氨酸或乙二胺的盐。Pharmaceutically acceptable salts are particularly suitable for medicinal use due to their higher solubility in water than the original or basic compound. These salts must have a pharmaceutically acceptable anion or cation. Suitable pharmaceutically acceptable acid addition salts of the compounds of this invention are salts of inorganic acids such as hydrochloric, hydrobromic, phosphoric, metaphosphoric, nitric and sulfuric acids, and organic acids such as acetic, benzenesulfonic, benzoic, citric, Salts of ethanesulfonic acid, fumaric acid, gluconic acid, glycolic acid, isethionic acid, lactic acid, lactobionic acid, maleic acid, malic acid, methanesulfonic acid, succinic acid, p-toluenesulfonic acid and tartaric acid, suitable Salts of pharmaceutically acceptable bases are ammonium, alkali metal (eg sodium and potassium) and alkaline earth metal (eg magnesium and calcium) and tromethamine (2-amino-2-hydroxymethyl-1 , 3-propanediol), diethanolamine, lysine or ethylenediamine.
具有不可药用的阴离子的盐类例如三氟乙酸盐也涵盖于本发明的范围之内，作为制备或纯化可药用盐的有用中间体和/或用于非治疗性的用途，例如体外应用。Salts with non-pharmaceutically acceptable anions such as trifluoroacetate are also within the scope of the present invention as useful intermediates for the preparation or purification of pharmaceutically acceptable salts and/or for non-therapeutic uses such as in vitro application.
本发明所用的术语“有生理学功能的衍生物”是指式(I)的化合物的任何生理学可耐受的衍生物，例如酯，当其施用于哺乳动物例如人时，能够(直接或间接地)形成式I化合物或其活性代谢物。The term "physiologically functional derivative" as used in the present invention refers to any physiologically tolerable derivative of a compound of formula (I), such as an ester, which, when administered to a mammal such as a human, is capable of (directly or indirectly) ) to form a compound of formula I or an active metabolite thereof.
有生理学功能的衍生物也包括本发明化合物的前药，例如H.Okada等人，Chem.Pharm，Bull.1994，42，57-61中所述。这些前药可以在体内代谢形成本发明的化合物，这些前药本身可以有活性或者无活性。Physiologically functional derivatives also include prodrugs of the compounds of the present invention, eg, as described in H. Okada et al., Chem. Pharm, Bull. 1994, 42, 57-61. These prodrugs can be metabolized in vivo to form the compounds of the invention, and these prodrugs can themselves be active or inactive.
本发明的化合物也可以以各种多形的形式存在，例如以无定形、结晶和多晶形式存在。所有本发明化合物的多晶形式均涵盖于本发明框架之内，并且是本发明的另一个方面The compounds of the present invention may also exist in various polymorphic forms, such as amorphous, crystalline and polymorphic forms. All polymorphic forms of the compounds of the present invention are encompassed within the framework of the present invention and are a further aspect of the present invention
在下文中，所有提及“式I化合物”处均涉及如上所述的式I化合物及其如本文所述的盐、溶剂合物和有生理学功能的衍生物。In the following, all references to "compounds of formula I" refer to compounds of formula I as described above and their salts, solvates and physiologically functional derivatives as described herein.
用途功效：Use effect:
通式I的本发明化合物具有对内皮脂肪酶(EL)令人惊奇的抑制作用。EL优选的底物是具有抗动脉粥样硬化活性的HDL，HDL水平的降低导致动脉粥样硬化及其后遗症如冠心病的进展，另外还促进代谢综合症和其后遗症糖尿病的发展。因此，抑制EL通常导致对动脉粥样硬化病症的预防，并间接地降低具有糖尿病增高风险的人群的患病概率。The compounds of the invention of general formula I have a surprising inhibitory effect on endothelial lipase (EL). A preferred substrate for EL is HDL, which has anti-atherosclerotic activity, and a reduction in HDL levels leads to the progression of atherosclerosis and its sequelae, such as coronary heart disease, and in addition to the development of metabolic syndrome and its sequelae, diabetes mellitus. Thus, inhibition of EL generally results in the prevention of atherosclerotic conditions and indirectly reduces the prevalence of the disease in populations at increased risk of diabetes.
还发现通式I的本发明化合物抑制作用相比其他脂肪酶具有选择性。The compounds of the invention of general formula I have also been found to inhibit selectively over other lipases.
值得注意的是，式I化合物与类似结构的化合物相比，在水性介质中具有改善的溶解度，同时具有至少是同样高的活性。优选的本发明化合物与现有技术中的化合物相比，还具有改善的代谢稳定性。此外，本发明化合物在血清稳定性方面显示出优势。Notably, the compounds of formula I have improved solubility in aqueous media and at least as high activity as compared to compounds of similar structure. Preferred compounds of the present invention also have improved metabolic stability compared to compounds of the prior art. Furthermore, the compounds of the present invention show advantages in serum stability.
本发明化合物特别适合于治疗和/或预防如下疾病：The compounds of the present invention are particularly suitable for the treatment and/or prevention of the following diseases:
1.血脂异常及其后遗症，例如动脉粥样硬化、冠心病、脑血管病等，特别是(但不限于)那些特征在于一种或多种下列因素的病症：高血浆甘油三酯浓度、高餐后血浆甘油三酯浓度；低HDL胆固醇浓度；低载脂蛋白A浓度；高LDL胆固醇浓度；低密度LDL胆固醇颗粒；高载脂蛋白B浓度；1. Dyslipidemia and its sequelae, such as atherosclerosis, coronary heart disease, cerebrovascular disease, etc., especially (but not limited to) those conditions characterized by one or more of the following factors: high plasma triglyceride concentrations, high Postprandial plasma triglyceride concentration; low HDL cholesterol concentration; low apolipoprotein A concentration; high LDL cholesterol concentration; low density LDL cholesterol particles; high apolipoprotein B concentration;
2.可能与代谢综合症相关的各种其他病症，例如：肥胖症(超重)，包括向心性肥胖；血栓、高凝性和趋于血栓阻塞性的阶段(动脉和静脉的)；高血压；心力竭，例如(但不限于)继心肌梗塞、高血压心脏病或心肌病之后的心力衰竭；糖尿病，特别是2型糖尿病，包括预防与其相关的后遗症(高血糖、葡萄糖不耐受、胰腺β-细胞损失、大血管和微血管的病症)2. Various other conditions that may be associated with metabolic syndrome, such as: obesity (overweight), including central obesity; thrombotic, hypercoagulable and prothrombotic stages (arterial and venous); hypertension; Heart failure, such as but not limited to heart failure following myocardial infarction, hypertensive heart disease, or cardiomyopathy; diabetes, especially type 2 diabetes, including prevention of its associated sequelae (hyperglycemia, glucose intolerance, pancreatic β-cell loss, macrovascular and microvascular disorders)
3.涉及炎症反应或细胞分化的其他病症或病况，例如：动脉粥样硬化，例如(但不限于)冠状动脉硬化，包括心绞痛或心肌梗塞、中风；血管再狭窄或再闭塞；慢性炎性肠病，例如克罗恩病和溃疡性结肠炎；胰腺炎；其他炎症状态；视网膜病；脂肪细胞肿瘤；脂肪细胞癌，例如脂肪肉瘤；实体肿瘤和赘生物，例如(但不限于)胃肠道、肝脏、胆道和胰腺的癌症，内分泌肿瘤，肺、肾和泌尿道、生殖道的癌症，前列腺癌等；急性和慢性骨髓增殖性疾病和淋巴瘤；血管生成；神经变性疾病；阿尔茨海默病；多发性硬化症；帕金森病；红斑鳞屑性皮肤病，例如银屑病；寻常痤疮；受PPAR调节的其他皮肤病和皮肤病学的病症；湿疹和神经性皮炎；皮炎，例如脂溢性皮炎或光照性皮炎；角膜炎和角化病，例如脂溢性角化病、老年角化病、光化性角化病、光诱导的角化病或毛囊角化病；瘢痕疙瘩和瘢痕疙瘩预防；疣，包括性病湿疣或尖锐湿疣；人乳头瘤病毒(HPV)感染，例如性病乳头瘤病，病毒性疣，例如传染性软疣、粘膜白斑；丘疹性皮肤病，例如扁平苔藓；皮肤癌，例如基底细胞癌、黑色素瘤或皮肤的T细胞淋巴瘤；局限的良性上皮肿瘤，例如皮肤角化病、表皮痣；冻疮；高血压；综合征；多囊卵巢综合征(PCOS)；哮喘；骨关节炎；红斑狼疮(LE)或炎性关节病，例如风湿性关节炎；脉管炎；消瘦(恶病质)；痛风；缺血/再灌注综合征；急性呼吸窘迫综合征(ARDS)。3. Other disorders or conditions involving inflammatory responses or cellular differentiation, such as: atherosclerosis, such as, but not limited to, coronary arteriosclerosis, including angina pectoris or myocardial infarction, stroke; restenosis or reocclusion of blood vessels; chronic inflammatory bowel disease diseases, such as Crohn's disease and ulcerative colitis; pancreatitis; other inflammatory states; retinopathy; adipocyte tumors; adipocyte carcinomas, such as liposarcoma; , liver, biliary and pancreatic cancers, endocrine tumors, lung, kidney and urinary tract, reproductive tract cancers, prostate cancer, etc.; acute and chronic myeloproliferative diseases and lymphomas; angiogenesis; neurodegenerative diseases; Alzheimer's disease multiple sclerosis; Parkinson's disease; erythrosquamous skin diseases such as psoriasis; acne vulgaris; other skin diseases and dermatological conditions modulated by PPARs; eczema and neurodermatitis; dermatitis such as seborrhea Atopic dermatitis or photodermatitis; keratitis and keratosis, such as seborrheic keratosis, senile keratosis, actinic keratosis, light-induced keratosis, or follicular keratosis; keloids and scars Pimple prevention; warts, including venereal warts or condyloma acuminatum; human papillomavirus (HPV) infections, such as venereal papilloma, viral warts, such as molluscum contagiosum, leukoplakia; papular skin diseases, such as lichen planus; skin Carcinomas, such as basal cell carcinoma, melanoma, or T-cell lymphoma of the skin; localized benign epithelial tumors, such as keratosis skin, epidermal nevi; frostbite; hypertension; syndromes; polycystic ovary syndrome (PCOS); asthma ; Osteoarthritis; Lupus erythematosus (LE) or inflammatory joint diseases such as rheumatoid arthritis; Vasculitis; Wasting (cachexia); Gout;
制剂：preparation:
本发明的化合物达到所需生物学效应所必需的量取决于多种因素，例如所选择的具体化合物、预期用途、施用方式和患者的临床状况，日剂量一般为0.3mg-100mg(通常3mg-50mg)/天/千克体重，例如3-10mg/kg/天。静脉内剂量可以为例如0.3mg-1.0mg/kg，其可以适宜地以10ng-100ng/kg/分钟输注使用，用于这些目的的适宜的输注液可以含有例如每毫0.1ng-10mg、通常1ng-10mg，单次剂量可以含有如1mg-10g活性成份。因此，注射用安瓿可以含有例如1mg-100mg，可以口服施用的单剂量制剂如片剂或胶囊剂可以含有例如0.05-1000mg，通常0.5-600g。The amount of the compounds of the present invention necessary to achieve the desired biological effect depends on a variety of factors, such as the particular compound chosen, the intended use, the mode of administration and the clinical condition of the patient, with a daily dose generally ranging from 0.3 mg to 100 mg (usually 3 mg- 50 mg)/day/kg body weight, eg 3-10 mg/kg/day. Intravenous doses may be, for example, 0.3 mg-1.0 mg/kg, which may suitably be used as an infusion of 10 ng-100 ng/kg/minute, and suitable infusion solutions for these purposes may contain, for example, 0.1 ng-10 mg per milliliter, Usually 1 ng-10 mg, a single dose may contain eg 1 mg-10 g of the active ingredient. Thus, ampoules for injection may contain, for example, 1 mg-100 mg, and single-dose formulations, such as tablets or capsules, which may be administered orally, may contain, for example, 0.05-1000 mg, usually 0.5-600 g.
本发明的化合物可以以化合物本身形式使用式I化合物治疗上述病症，但是它们优先为含有可药用的载体的药物组合形式，该载体当然是必须是可药用的，也就是说可与组合形式。该载体当然必须是可药用的，也就是说可与组合物中的其它成份相容并且对患者的健康无害。载体可以是固体、液体和胶状体，优先与化合物一起配制成单剂量，例如制成片剂，其可以含有0.05重量％-95重量％的活性成份。也可以存在包括其它本发明化合物在内的其它药学活性物质。本发明的药物组合物可以通过已知的制药方法之一制备，这些方法基本上包括将各成份与可药用的载体和/或赋形剂混合。The compounds of the present invention can be used in the form of compounds of formula I for the treatment of the above-mentioned conditions, but they are preferably in the form of pharmaceutical combinations with a pharmaceutically acceptable carrier, which of course must be pharmaceutically acceptable, that is to say in combination with . The carrier must of course be pharmaceutically acceptable, that is to say compatible with the other ingredients of the composition and not harmful to the patient's health. Carriers can be solid, liquid and colloids, preferably with the compound formulated in a single dose, eg, as a tablet, which may contain from 0.05% to 95% by weight of the active ingredient. Other pharmaceutically active substances, including other compounds of the present invention, may also be present. The pharmaceutical compositions of the present invention can be prepared by one of the known methods of pharmacy, which essentially involve admixing the ingredients with pharmaceutically acceptable carriers and/or excipients.
本发明的药物组合物是适合于口服、直肠、局部、经口(例如舌下)和胃肠外(例如皮下、肌内、皮内或静脉内)给药的组合物，但是最适宜的施用方式每一个体情况中取决于所治疗的病症的性质与严重性以及在每种情况中所用式I化合物的类型。包衣制剂和包衣缓释制剂也涵盖于本发明的范围内。优选耐酸和耐胃液的制剂。适宜的耐胃液的包衣包括邻苯二甲醋酸纤维互。聚醋酸乙烯邻苯二甲酸酯、羟丙基甲基纤维素邻苯二甲酸酯和甲基丙烯酸甲酯的阴离子聚合物。The pharmaceutical compositions of the present invention are compositions suitable for oral, rectal, topical, oral (eg sublingual) and parenteral (eg subcutaneous, intramuscular, intradermal or intravenous) administration, but administration is most suitable The manner in each individual case depends on the nature and severity of the condition being treated and the type of compound of formula I used in each case. Coated formulations and coated sustained release formulations are also encompassed within the scope of the present invention. Acid- and gastric-resistant formulations are preferred. Suitable gastro-resistant coatings include cellulose phthalate. Anionic polymer of polyvinyl acetate phthalate, hydroxypropyl methylcellulose phthalate and methyl methacrylate.
适合于口服施用的药物制剂可以是分开的单位形式，例如胶囊剂、扁囊剂、锭剂或片剂，其各自含有一定量的式I化合物；粉末或颗粒的形式；在水性或非水性液体中的溶液或者混悬液的形式；或者水包油型或油包水型乳剂的形式。如已经提及的那样，这些组合物可以通过任何适宜的制药方法来制备，所述方法包括其中将活性成分与载体(可以包含一种或多种其他成份)相接触的步骤。制备组合物一般是将活性成份与液体载体或/和精细粉碎的固体载体进行均匀和匀质的混合。如 果需要，将该产品成型。因此，例如片剂可以通过将化合物的粉末或颗粒与任选的一种或多种其他成份压制或成型来制备。压制片剂可以通过将自由流动形式例如粉末或颗粒形式的化合物任选地与粘合剂、助流剂、惰性稀释剂和/或一种(或多种)表面活性剂/分散剂在合适的机器中混合、压片来制备。成型片可以通过将用惰性液体稀释剂润湿的粉末关的化合物在合适的机器中进行成型来制备。Pharmaceutical formulations suitable for oral administration may be in discrete unit form such as capsules, cachets, lozenges or tablets, each containing an amount of a compound of formula I; in the form of powders or granules; in aqueous or non-aqueous liquids. in the form of a solution or suspension; or in the form of an oil-in-water or water-in-oil emulsion. As already mentioned, these compositions can be prepared by any suitable method of pharmacy which includes a step in which the active ingredient is brought into contact with the carrier, which may contain one or more other ingredients. The compositions are generally prepared by uniform and homogenous admixture of the active ingredient with liquid carriers or/and finely divided solid carriers. If desired, shape the product. Thus, for example, a tablet may be prepared by compressing or molding a powder or granules of the compound, optionally with one or more other ingredients. Compressed tablets may be prepared by mixing the compound in a free-flowing form such as a powder or granules, optionally with binders, glidants, inert diluents and/or one (or more) surface active/dispersing agent(s) in a suitable It is prepared by mixing and tableting in a machine. Molded tablets may be made by molding in a suitable machine the powdered compound moistened with an inert liquid diluent.
适合于经口(舌下)给药的药物组合物包括有式I化合物与矫味剂(通常为蔗糖)和阿拉伯胶或黄著树胶的锭剂，以及在惰性基质(例如明胶和甘油或蔗糖和阿拉伯胶)中包含所碠化合物的软锭剂。Pharmaceutical compositions suitable for oral (sublingual) administration include lozenges containing a compound of formula I with a flavoring agent (usually sucrose) and acacia or tragacanth, and in an inert base such as gelatin and glycerol or sucrose. and gum arabic) containing pastilles of the compounds.
适合于胃肠外施用的药物组合物优先包含式I化合物的无菌水性制剂，其优先与目标爱者的血液等，这些制剂优选静脉内施用，但也可以通过皮下、肌内或皮内注射施用，这些制剂可以优选通过将化合物与水混合并且使所得溶液无菌和与血液等来制备。本发明的可注射组合物一般包含0.1-5重量％的活性化合物。Pharmaceutical compositions suitable for parenteral administration preferably comprise sterile aqueous preparations of the compounds of formula I, preferably in the blood of the target lover, etc. These preparations are preferably administered intravenously, but may also be administered by subcutaneous, intramuscular or intradermal injection For administration, these formulations can preferably be prepared by mixing the compound with water and sterilizing the resulting solution with blood and the like. The injectable compositions of the present invention generally contain 0.1 to 5% by weight of the active compound.
适合于直肠施用的药物组合物优选单剂量的栓剂形式。可以通过式I化合物与一种或多种常规固体载体如可可脂混合，然后将所得混合物成型来制备这类制剂。Pharmaceutical compositions suitable for rectal administration are preferably in the form of single-dose suppositories. Such formulations may be prepared by admixing a compound of formula I with one or more conventional solid carriers such as cocoa butter and shaping the resulting mixture.
局部应用于皮肤的合适的药物组合物优选软膏剂、霜剂、洗剂、糊剂、喷雾剂、气雾剂或油剂的形式。可用的载体包括石油醚、羊毛脂、聚乙二醇、醇类以及两种或两种以上这些物质的组合。活性成份一般以组合物重量的0.1-15重量％、例如0.5-2％的浓度存在。Suitable pharmaceutical compositions for topical application to the skin are preferably in the form of ointments, creams, lotions, pastes, sprays, aerosols or oils. Useful carriers include petroleum ether, lanolin, polyethylene glycols, alcohols, and combinations of two or more of these. The active ingredient is generally present at a concentration of 0.1-15% by weight, eg, 0.5-2%, by weight of the composition.
也可以进行经皮给药。适合经皮施用的药物组合物可以是适合与患者表皮长期紧密接触的单个贴剂形式。该类贴剂适宜地含有在任选地缓冲的水性溶液中的活性成分，其溶解和/或分散在粘合剂中或分散在聚合物中。适宜的活性成分浓度为约1％至35％，优选为3％-15％。特别的释放活性成分的方式可以通过电转运或离子电渗疗法，例如Pharmaceutical Research,2(6):318(1986)中所述。Transdermal administration is also possible. Pharmaceutical compositions suitable for transdermal administration may be in the form of a single patch suitable for prolonged intimate contact with the epidermis of a patient. Such patches suitably contain the active ingredient in an optionally buffered aqueous solution dissolved and/or dispersed in an adhesive or dispersed in a polymer. Suitable active ingredient concentrations are from about 1% to 35%, preferably 3% to 15%. Particular means of releasing the active ingredient may be by electrotransport or iontophoresis, eg as described in Pharmaceutical Research, 2(6):318 (1986).
值得注意的是式I化合物对脂类代谢病症的有利作用。它们积极地影响HDL与LDL的比例，并且特别是增加HDL的水平，适合于预防和治疗血脂异常和代谢综合征以及它们的多种后遗症，例如动脉粥样硬化、冠心病心力总衰竭、甩脱症和糖尿病。Of note is the beneficial effect of compounds of formula I on disorders of lipid metabolism. They positively affect the ratio of HDL to LDL, and in particular increase the level of HDL, and are suitable for the prevention and treatment of dyslipidemia and metabolic syndrome and their various sequelae, such as atherosclerosis, coronary heart disease, total heart failure, rejection disease and diabetes.
与其它药物的组合：In combination with other medicines:
本发明的化合物可以单独或者与一种或多种其他药理学活性的活性成分组合施用。具体而言，本发明化合物可以和具有与其相似的药理学作用的活性成份一起施用。所述的这类药物的实例有：降低血糖的药物、抗糖尿病的药物、治疗血脂异常的活性成份、抗动脉粥样硬化的药物、抗肥胖药物、抗炎活性成分、治疗恶性肿瘤的活性成分、抗血栓形成的活性成分、治疗高血压的活性成分、治疗心力衰竭的活性成分、治疗和/预防由糖尿病引起或与糖尿病有关的并发症的活性成分、治疗神经变性疾病的活性成分、治疗中枢神经系统疾病的活性成分、治疗药物依赖、烟碱依赖和酒精依赖的活性成分、镇痛药。The compounds of the present invention may be administered alone or in combination with one or more other pharmacologically active active ingredients. In particular, the compounds of the present invention can be administered together with active ingredients having pharmacological effects similar thereto. Examples of such drugs are: blood sugar-lowering drugs, antidiabetic drugs, active ingredients for the treatment of dyslipidemia, anti-atherosclerotic drugs, anti-obesity drugs, anti-inflammatory active ingredients, active ingredients for the treatment of malignant tumors , antithrombotic active ingredients, active ingredients in the treatment of hypertension, active ingredients in the treatment of heart failure, active ingredients in the treatment and/prevention of complications caused by or related to diabetes, active ingredients in the treatment of neurodegenerative diseases, treatment of central Active ingredients for neurological disorders, active ingredients for the treatment of drug dependence, nicotine and alcohol dependence, analgesics.
它们可以与本发明的式I化合物组合，特别是用于效果的协同提高。可以通过对患者分别施用活性成分或者以多种活性成分共存于一种药物制剂中的组合产品形式来施用活性成分组合。They can be combined with the compounds of the formula I according to the invention, in particular for a synergistic enhancement of the effect. The combination of active ingredients can be administered to the patient by administering the active ingredients separately or as a combination product in which the active ingredients are coexisted in one pharmaceutical formulation.
所述活性成分优选地包括：磺酰脲类；双胍类；氯茴苯酸类；噁二唑烷二酮类；噻唑烷二酮类；葡萄糖苷酶抑制剂；糖原磷酸化酶抑制剂；胰高血糖素拮抗剂；葡萄糖激酶激动剂；果糖-1，6-二磷酸酶抑制剂。The active ingredients preferably include: sulfonylureas; biguanides; meglitinides; oxadiazolidinediones; thiazolidinediones; glucosidase inhibitors; glycogen phosphorylase inhibitors; Glucagon antagonist; glucokinase agonist; fructose-1,6-bisphosphatase inhibitor.
制备方法：Preparation:
通式1可以通过如下方法进行合成，所有的化学原料可以通过商业途径购买。所述合成方法包括如下几种路线：The general formula 1 can be synthesized by the following method, and all chemical raw materials can be purchased through commercial channels. The synthetic method includes the following routes:
方法一：由邻苯二胺与不同的羰基化合物反应合成苯并咪唑：Method 1: Synthesize benzimidazole by reacting o-phenylenediamine with different carbonyl compounds:
或者方法二：由1H苯并咪唑与R1X反应生成多取代苯并咪唑：Or method 2: generate polysubstituted benzimidazoles by reacting 1H benzimidazole with R1X:
或者方法三：由邻硝基取代苯胺与醛反应生成多取代苯并咪唑。相应的邻硝基取代苯胺可按文献方法由邻硝基化合物与不同的胺反应制备：Or method three: the reaction of o-nitro-substituted aniline with aldehyde generates polysubstituted benzimidazole. The corresponding o-nitro-substituted anilines can be prepared by reacting o-nitro compounds with different amines according to literature methods:
或者方法四：由邻氨基取代苯胺与羰基化合物反应生成多取代苯并咪唑。相应的邻氨基取代苯胺可按文献方法由邻硝基化合物与不同的胺反应制备得到邻硝取代苯胺，再经文献方法还原得到邻氨基取代苯胺：Or method four: the reaction of o-amino-substituted aniline and carbonyl compound generates polysubstituted benzimidazole. The corresponding o-amino-substituted aniline can be prepared by the reaction of o-nitro compounds and different amines according to the literature method to obtain the o-nitro-substituted aniline, and then reduced by the literature method to obtain the o-amino-substituted aniline:
具体实施方式detailed description
实施例1苯并咪唑类化合物的合成The synthesis of embodiment 1 benzimidazole compounds
由邻苯二胺与不同的羰基化合物反应合成苯并咪唑的方法Method for synthesizing benzimidazole by reacting o-phenylenediamine with different carbonyl compounds
方法一、由邻苯二胺与醛在光照下，以3,6-(吡啶-2-基)1,2,4,5-四嗪为催化剂进行反应。Method 1: 3,6-(pyridin-2-yl)1,2,4,5-tetrazine is used as a catalyst for the reaction between o-phenylenediamine and aldehyde under illumination.
将邻苯二胺(1.08g,10mmol)，PYTZ(20mg)溶于200ml乙醇中，搅拌下缓慢加入醛(10mmol)，置于10.5A氙灯下反应3-5h，反应完全后，浓缩至20mL，过滤，干燥得纯品。Dissolve o-phenylenediamine (1.08g, 10mmol) and PYTZ (20mg) in 200ml of ethanol, slowly add aldehyde (10mmol) under stirring, place under a 10.5A xenon lamp to react for 3-5h, after the reaction is complete, concentrate to 20mL, Filter and dry to obtain pure product.
按照此合成方案，邻苯二胺与不同的醛合成了以下产物。Following this synthetic scheme, the following products were synthesized from o-phenylenediamine with various aldehydes.
化合物1. 2-(2-吡啶基)-1H-苯并咪唑:1H NMR(400MHz,DMSO-d6,ppm)δ13.12(s,1H),8.77-8.70(m,1H),8.39-8.32(m,1H),8.03-7.97(m,1H),7.72(d,1H),7.58-7.49(m,2H),7.29-7.18(m,2H)；MS calcd for:C12H9N3[M+H]+169.0869,found169.0990. Compound 1. 2-(2-pyridyl)-1H-benzimidazole: 1H NMR (400MHz, DMSO-d6, ppm) δ 13.12(s, 1H), 8.77-8.70(m, 1H), 8.39-8.32 (m,1H),8.03-7.97(m,1H),7.72(d,1H),7.58-7.49(m,2H),7.29-7.18(m,2H); MS calcd for:C12H9N3[M+H] +169.0869,found169.0990.
化合物2. 2-(4-吡啶基)-1H-苯并咪唑：1H NMR(400MHz,DMSO-d6,ppm)δ13.27(s,1H),8.77(d,2H),8.11(d,2H),7.68(d,2H),7.28(s,2H)；MS calcd for:C12H9N3[M+H]+169.0869,found 169.0990. Compound 2. 2-(4-pyridyl)-1H-benzimidazole: 1H NMR (400MHz, DMSO-d6, ppm) δ13.27(s,1H), 8.77(d,2H), 8.11(d,2H) ), 7.68(d, 2H), 7.28(s, 2H); MS calcd for: C12H9N3[M+H]+169.0869, found 169.0990.
化合物3. 2-(3-氯苯基)-1H-苯并咪唑：1HNMR(400MHz,DMSO-d6,ppm):δ13.05(s,1H),8.28-8.21(m,1H),8.20-8.13(m,1H),7.70(d,1H),7.64-7.53(m,3H),7.33-7.17(m,2H)；MS calcd for:C13H9ClN2[M+H]+229.0527,found 229.0662. Compound 3. 2-(3-Chlorophenyl)-1H-benzimidazole: 1HNMR (400MHz, DMSO-d6, ppm): δ13.05(s,1H), 8.28-8.21(m,1H), 8.20- 8.13(m, 1H), 7.70(d, 1H), 7.64-7.53(m, 3H), 7.33-7.17(m, 2H); MS calcd for: C13H9ClN2[M+H]+229.0527, found 229.0662.
化合物4. 2-(2-甲基苯基)-1H-苯并咪唑：1HNMR(400MHz,DMSO-d6,ppm):δ12.67(s,1H),7.81-7.74(m,1H),7.71(d,1H),7.55(d,1H),7.44-7.32(m,3H),7.23(t,2H),2.63(s,3H)；MS calcd for:C14H12N2[M+H]+209.1073,found209.1200. Compound 4. 2-(2-methylphenyl)-1H-benzimidazole: 1HNMR (400MHz, DMSO-d6, ppm): δ12.67(s,1H), 7.81-7.74(m,1H), 7.71 (d,1H),7.55(d,1H),7.44-7.32(m,3H),7.23(t,2H),2.63(s,3H); MS calcd for:C14H12N2[M+H]+209.1073,found209 .1200.
化合物6. 2-(3-甲基苯基)-1H-苯并咪唑：1HNMR(400MHz,DMSO-d6,ppm):δ12.87(s,1H),8.04(s,1H),7.98(d,1H),7.60(d,2H),7.44(t,1H),7.32(d,1H),7.21(d,2H),2.43(s,3H)；MS calcd for:C14H12N2[M+H]+209.1073,found 209.1198.Compound 6. 2-(3-methylphenyl)-1H-benzimidazole: 1HNMR (400MHz, DMSO-d6, ppm): δ12.87(s,1H), 8.04(s,1H), 7.98(d ,1H),7.60(d,2H),7.44(t,1H),7.32(d,1H),7.21(d,2H),2.43(s,3H); MS calcd for:C14H12N2[M+H]+ 209.1073, found 209.1198.
化合物7. 2-(3-硝基苯基)-1H-苯并咪唑：1HNMR(400MHz,DMSO-d6,ppm):δ13.34(s,1H),9.10-9.04(m,1H),8.70-8.62(m,1H),8.42-8.34(m,1H),7.90(t,1H),7.77(d,1H),7.64(d,1H),7.4-7.21(m,2H)；MS calcd for:C13H9N3O2[M+H]+240.0768,found 240.0910.Compound 7. 2-(3-nitrophenyl)-1H-benzimidazole: 1HNMR (400MHz, DMSO-d6, ppm): δ13.34(s,1H), 9.10-9.04(m,1H), 8.70 -8.62(m,1H),8.42-8.34(m,1H),7.90(t,1H),7.77(d,1H),7.64(d,1H),7.4-7.21(m,2H); MS calcd for :C13H9N3O2[M+H]+240.0768,found 240.0910.
化合物8. 2-苯基-1H-苯并咪唑：1HNMR(400MHz,DMSO-d6,ppm):δ12.97(s,1H),8.24-8.22(m,2H),7.70(s,1H),7.59-7.55(m,3H),7.52-7.47(m,1H),7.23(m,2H)；MScalcd for:C13H10N2[M+H]+195.0917,found 195.1029.Compound 8. 2-phenyl-1H-benzimidazole: 1HNMR (400MHz, DMSO-d6, ppm): δ12.97(s,1H), 8.24-8.22(m,2H), 7.70(s,1H), 7.59-7.55(m,3H),7.52-7.47(m,1H),7.23(m,2H); MScalcd for:C13H10N2[M+H]+195.0917,found 195.1029.
化合物9. 2-己基-1H-苯并咪唑：1HNMR(400MHz,DMSO-d6,ppm):δ12.16(s,1H),7.45(s,2H),7.13-7.08(m,2H),2.08(m,2H),1.81-1.73(m,2H),1.35-1.30(m,4H),0.87(m,3H)；MS calcd for:C12H16N2[M+H]+189.1386,found 189.1502Compound 9. 2-hexyl-1H-benzimidazole: 1HNMR (400MHz, DMSO-d6, ppm): δ 12.16 (s, 1H), 7.45 (s, 2H), 7.13-7.08 (m, 2H), 2.08 (m,2H),1.81-1.73(m,2H),1.35-1.30(m,4H),0.87(m,3H); MS calcd for:C12H16N2[M+H]+189.1386,found 189.1502
化合物10. 2-苯基-1H-苯并[d]咪唑-4-甲酰胺:1H NMR(400MHz,DMSO-d6)δ13.42(s,1H),9.37(s,1H),8.27(d,1H),8.26–8.22(m,1H),7.88(d,1H),7.79(s,1H),7.76(d,1H),7.64–7.53(m,3H),7.36(t,1H)；HRMS calcd for C14H11N3O[M-1]-236.0902,found236.0945. Compound 10. 2-Phenyl-1H-benzo[d]imidazole-4-carboxamide: 1H NMR (400MHz, DMSO-d6) δ 13.42(s,1H), 9.37(s,1H), 8.27(d ,1H),8.26–8.22(m,1H),7.88(d,1H),7.79(s,1H),7.76(d,1H),7.64–7.53(m,3H),7.36(t,1H); HRMS calcd for C14H11N3O[M-1]-236.0902,found236.0945.
化合物11 2-苯乙基-1H-苯并[d]咪唑-4-甲酰胺:1H NMR(400MHz,DMSO-d6)δ12.75(s,1H),9.33(s,1H),7.80(d,1H),7.68(s,1H),7.64(d,1H),7.33–7.23(m,5H),7.19(d,1H),3.26–3.19(m,2H),3.19–3.12(m,2H)；HRMS calcd for C16H15N3O[M-1]-264.1215,found 264.1261.Compound 11 2-phenethyl-1H-benzo[d]imidazole-4-carboxamide: 1H NMR (400MHz, DMSO-d6)δ12.75(s,1H), 9.33(s,1H), 7.80(d ,1H),7.68(s,1H),7.64(d,1H),7.33–7.23(m,5H),7.19(d,1H),3.26–3.19(m,2H),3.19–3.12(m,2H) ); HRMS calcd for C16H15N3O[M-1]-264.1215, found 264.1261.
化合物12. 2-(邻甲苯基)-1H-苯并[d]咪唑-4-甲酰胺:1H NMR(400MHz,DMSO-d6)δ13.37(s,1H),9.37(d,1H),8.08(d,1H),8.04(d,1H),7.88(d,1H),7.79(d,1H),7.74(d,1H),7.49(t,1H),7.41–7.33(m,2H),2.45(s,3H)；HRMS calcd for C15H13N3O[M+H]+252.1137,found252.1128.Compound 12. 2-(o-Tolyl)-1H-benzo[d]imidazole-4-carboxamide: 1H NMR (400MHz, DMSO-d6)δ13.37(s,1H), 9.37(d,1H), 8.08(d,1H), 8.04(d,1H), 7.88(d,1H), 7.79(d,1H), 7.74(d,1H), 7.49(t,1H), 7.41–7.33(m,2H) ,2.45(s,3H); HRMS calcd for C15H13N3O[M+H]+252.1137,found252.1128.
化合物13. 2-(间甲苯基)-1H-苯并[d]咪唑-4-甲酰胺：1H NMR(400MHz,DMSO-d6)δ13.15(s,1H),9.34(d,1H),7.90(dd,1H),7.84(dt,1H),7.76(d,1H),7.76–7.72(m,1H),7.50–7.45(m,1H),7.45–7.44(m,1H),7.44–7.40(m,1H),7.38(t,1H),2.65(s,3H)；HRMScalcd for C15H13N3O[M+H]+252.1137,found 252.1132.Compound 13. 2-(m-Tolyl)-1H-benzo[d]imidazole-4-carboxamide: 1H NMR (400MHz, DMSO-d6)δ13.15(s,1H), 9.34(d,1H), 7.90(dd,1H),7.84(dt,1H),7.76(d,1H),7.76–7.72(m,1H),7.50–7.45(m,1H),7.45–7.44(m,1H),7.44– 7.40(m, 1H), 7.38(t, 1H), 2.65(s, 3H); HRMScalcd for C15H13N3O[M+H]+252.1137, found 252.1132.
化合物14. 2-(2-硝基苯基)-1H-苯并[d]咪唑-4-甲酰胺:1H NMR(400MHz,DMSO-d6)δ8.91(s,1H),8.36(dd,1H),8.09(dd,1H),7.91–7.82(m,2H),7.76(td,1H),7.56(dt,1H),7.24(d,1H),7.22(d,1H),6.67(s,2H),6.59(td,1H).HRMS calcd for C14H10N4O3[M+H]+283.0831,found 283.0829.Compound 14. 2-(2-nitrophenyl)-1H-benzo[d]imidazole-4-carboxamide: 1H NMR (400MHz, DMSO-d6)δ8.91(s,1H), 8.36(dd, 1H), 8.09(dd, 1H), 7.91–7.82(m, 2H), 7.76(td, 1H), 7.56(dt, 1H), 7.24(d, 1H), 7.22(d, 1H), 6.67(s ,2H),6.59(td,1H).HRMS calcd for C14H10N4O3[M+H]+283.0831,found 283.0829.
化合物15 2-(3-硝基苯基)-1H-苯并[d]咪唑-4-甲酰胺:1H NMR(400MHz,DMSO-d6)δ13.80(s,1H),9.25(s,1H),9.07(s,1H),8.72(d,1H),8.39(dd,1H),7.93(d,1H),7.89(d,1H),7.87–7.84(m,1H),7.81(d,1H),7.42(t,1H)；HRMS calcd for C14H10N4O3[M-1]-281.0753,found281.0833.Compound 15 2-(3-nitrophenyl)-1H-benzo[d]imidazole-4-carboxamide: 1H NMR (400MHz, DMSO-d6)δ13.80(s,1H), 9.25(s,1H ), 9.07(s, 1H), 8.72(d, 1H), 8.39(dd, 1H), 7.93(d, 1H), 7.89(d, 1H), 7.87–7.84(m, 1H), 7.81(d, 1H),7.42(t,1H); HRMS calcd for C14H10N4O3[M-1]-281.0753,found281.0833.
化合物16. 2-(4-硝基苯基)-1H-苯并[d]咪唑-4-甲酰胺:1H NMR(400MHz,DMSO-d6)δ13.80(s,1H),9.25(d,1H),8.52(d,1H),8.51(s,1H),8.47(s,1H),8.46(d,1H),7.94(dd,1H),7.89(d,1H),7.82(dd,1H),7.43(t,1H)；HRMS calcd for C14H10N4O3[M+H]+283.0831,found283.0334. Compound 16. 2-(4-Nitrophenyl)-1H-benzo[d]imidazole-4-carboxamide: 1H NMR (400MHz, DMSO-d6)δ13.80(s,1H), 9.25(d, 1H), 8.52(d, 1H), 8.51(s, 1H), 8.47(s, 1H), 8.46(d, 1H), 7.94(dd, 1H), 7.89(d, 1H), 7.82(dd, 1H) ),7.43(t,1H);HRMS calcd for C14H10N4O3[M+H]+283.0831,found283.0334.
化合物17 2-(2-氯苯基)-1H-苯并[d]咪唑-4-甲酰胺:1H NMR(400MHz,DMSO-d6)δ13.28(s,1H),9.29(d,1H),8.00(dd,1H),7.94–7.90(m,1H),7.83–7.79(m,1H),7.79–7.76(m,1H),7.71(dd,1H),7.61(dd,1H),7.57(dd,1H),7.41(t,1H)；HRMS calcd forC14H10ClN3O[M-1]-270.0512,found270.0576. Compound 17 2-(2-Chlorophenyl)-1H-benzo[d]imidazole-4-carboxamide: 1H NMR (400MHz, DMSO-d6)δ13.28(s,1H), 9.29(d,1H) ,8.00(dd,1H),7.94-7.90(m,1H),7.83-7.79(m,1H),7.79-7.76(m,1H),7.71(dd,1H),7.61(dd,1H),7.57 (dd,1H),7.41(t,1H);HRMS calcd forC14H10ClN3O[M-1]-270.0512,found270.0576.
化合物18. 2-(3-氯苯基)-1H-苯并[d]咪唑-4-甲酰胺:1H NMR(400MHz,DMSO-d6)δ13.53(s,1H),9.28(d,1H),8.32(q,J＝1.4Hz,1H),8.23(d,1H),7.91(d,1H),7.78(s,1H),7.76(d,,1H),7.64(d,1H),7.64–7.62(m,1H),7.39(t,1H；HRMS calcd for C14H10ClN3O[M-1]-270.0512,found270.0574.Compound 18. 2-(3-Chlorophenyl)-1H-benzo[d]imidazole-4-carboxamide: 1H NMR (400MHz, DMSO-d6)δ13.53(s,1H), 9.28(d,1H ),8.32(q,J＝1.4Hz,1H),8.23(d,1H),7.91(d,1H),7.78(s,1H),7.76(d,,1H),7.64(d,1H), 7.64–7.62(m, 1H), 7.39(t, 1H; HRMS calcd for C14H10ClN3O[M-1]-270.0512, found270.0574.
化合物19. 2-(4-氯苯基)-1H-苯并[d]咪唑-4-甲酰胺:1H NMR(400MHz,DMSO-d6)δ13.49(s,1H),9.31(d,1H),8.28(s,1H),8.26(s,1H),7.90(d,1H),7.82(d,1H),7.76(d,1H),7.69(s,1H),7.67(s,1H),7.38(t,1H)；HRMS calcd for C14H10ClN3O[M-1]-270.0512,found270.0571.Compound 19. 2-(4-Chlorophenyl)-1H-benzo[d]imidazole-4-carboxamide: 1H NMR (400MHz, DMSO-d6)δ13.49(s,1H), 9.31(d,1H) ),8.28(s,1H),8.26(s,1H),7.90(d,1H),7.82(d,1H),7.76(d,1H),7.69(s,1H),7.67(s,1H) ,7.38(t,1H); HRMS calcd for C14H10ClN3O[M-1]-270.0512,found270.0571.
化合物20. 2-(吡啶-3-基)-1H-苯并[d]咪唑-4-甲酰胺:1H NMR(400MHz,DMSO-d6)δ13.61(s,1H),9.43(d,1H),9.29(s,1H),8.74(d,1H),8.60(d,1H),7.92(d,1H),7.87–7.81(m,1H),7.78(s,1H),7.63(dd,1H),7.40(t,1H))；HRMS calcd for C13H10N4O[M-1]-237.0855,found237.0904. Compound 20. 2-(Pyridin-3-yl)-1H-benzo[d]imidazole-4-carboxamide: 1H NMR (400MHz, DMSO-d6) δ 13.61(s,1H), 9.43(d,1H) ), 9.29(s, 1H), 8.74(d, 1H), 8.60(d, 1H), 7.92(d, 1H), 7.87–7.81(m, 1H), 7.78(s, 1H), 7.63(dd, 1H),7.40(t,1H)); HRMS calcd for C13H10N4O[M-1]-237.0855,found237.0904.
化合物21 2-(4-氟苯基)-1H-苯并[d]咪唑-4-甲酰胺:1H NMR(400MHz,DMSO-d6)δ13.49(s,1H),9.31(d,1H),8.28(s,1H),8.26(s,1H),7.90(d,1H),7.82(d,1H),7.76(d,1H),7.69(s,1H),7.67(s,1H),7.38(t,1H)；HRMS calcd for C14H10FN3O[M-1]-254.0808,found254.0868.Compound 21 2-(4-Fluorophenyl)-1H-benzo[d]imidazole-4-carboxamide: 1H NMR (400MHz, DMSO-d6)δ13.49(s,1H), 9.31(d,1H) ,8.28(s,1H),8.26(s,1H),7.90(d,1H),7.82(d,1H),7.76(d,1H),7.69(s,1H),7.67(s,1H), 7.38(t,1H); HRMS calcd for C14H10FN3O[M-1]-254.0808, found254.0868.
化合物22. 2-(呋喃-2-基)-1H-苯并[d]咪唑-4-甲酰胺:1H NMR(400MHz,DMSO-d6)δ13.43(s,1H),9.39–9.00(m,1H),8.07–7.97(m,1H),7.87(d,1H),7.79(s,1H),7.71(d,1H),7.37(d,1H),7.34(d,1H),6.79(d,1H)；HRMS calcd for C12H9N3O2[M+H]+228.0773,found 228.0772.Compound 22. 2-(Furan-2-yl)-1H-benzo[d]imidazole-4-carboxamide: 1H NMR (400 MHz, DMSO-d6) δ 13.43 (s, 1H), 9.39–9.00 (m ,1H),8.07–7.97(m,1H),7.87(d,1H),7.79(s,1H),7.71(d,1H),7.37(d,1H),7.34(d,1H),6.79( d,1H); HRMS calcd for C12H9N3O2[M+H]+228.0773, found 228.0772.
化合物23. 2-(噻吩-2-基)-1H-苯并[d]咪唑-4-甲酰胺:1H NMR(400MHz,DMSO-d6)δ13.45(s,1H),9.15(s,1H),7.95(d,1H),7.85(dd,2H),7.79(s,1H),7.72(d,1H),7.35(t,1H),7.29(t,1H)；HRMS calcd for C12H9N3OS[M-1]-242.0466,found 242.0515.Compound 23. 2-(Thien-2-yl)-1H-benzo[d]imidazole-4-carboxamide: 1H NMR (400MHz, DMSO-d6)δ13.45(s,1H), 9.15(s,1H ),7.95(d,1H),7.85(dd,2H),7.79(s,1H),7.72(d,1H),7.35(t,1H),7.29(t,1H); HRMS calcd for C12H9N3OS[M -1]-242.0466,found 242.0515.
化合物24. 2-环己基-1H-苯并[d]咪唑-4-甲酰胺:1H NMR(400MHz,DMSO-d6)δ12.62(s,1H),9.38(d,1H),7.80(dd,1H),7.67(d,1H),7.62(dd,1H),7.26(t,1H),2.94(t，1H),2.12–2.07(m,1H),2.05(d,1H),1.83(q,1H),1.79(q,1H),1.74–1.69(m,1H),1.66(d,1H),1.63(d,1H),1.44(dt,1H),1.38(dt,1H),1.30(tt,1H)；HRMS calcd for C14H17N3O[M-1]-242.1372,found242.1406.Compound 24. 2-Cyclohexyl-1H-benzo[d]imidazole-4-carboxamide: 1H NMR (400MHz, DMSO-d6)δ12.62(s,1H), 9.38(d,1H), 7.80(dd ,1H),7.67(d,1H),7.62(dd,1H),7.26(t,1H),2.94(t,1H),2.12–2.07(m,1H),2.05(d,1H),1.83( q,1H),1.79(q,1H),1.74–1.69(m,1H),1.66(d,1H),1.63(d,1H),1.44(dt,1H),1.38(dt,1H),1.30 (tt,1H);HRMS calcd for C14H17N3O[M-1]-242.1372,found242.1406.
化合物25. 2-戊基-1H-苯并[d]咪唑-4-甲酰胺:1H NMR(400MHz,DMSO-d6)δ12.73(s,1H),9.40(s,1H),7.85(d,1H),7.72(s,1H),7.68(d,1H),7.31(t,1H),2.94(t,2H),1.89–1.82(m,2H),1.40(d,2H),1.38(d,2H),0.95–0.91(m,3H)；HRMS calcd for C13H17N3O[M+H]+232.1450,found 232.1445.Compound 25. 2-pentyl-1H-benzo[d]imidazole-4-carboxamide: 1H NMR (400MHz, DMSO-d6) δ 12.73(s,1H), 9.40(s,1H), 7.85(d ,1H),7.72(s,1H),7.68(d,1H),7.31(t,1H),2.94(t,2H),1.89–1.82(m,2H),1.40(d,2H),1.38( d,2H),0.95–0.91(m,3H); HRMS calcd for C13H17N3O[M+H]+232.1450, found 232.1445.
方法二、由邻苯二胺与羧酸反应制备苯并咪唑衍生物。The second method is to prepare benzimidazole derivatives by reacting o-phenylenediamine with carboxylic acid.
在四口烧瓶中，依次加入PPA 5g、邻苯二胺(5mmol,0.54g)、羧酸5mmol，回流2h。冷至室温，加入10％NaOH溶液7.5mL，搅拌，过滤，干燥得到纯品。用该法合成两种化合物。In a four-necked flask, PPA 5g, o-phenylenediamine (5mmol, 0.54g), and carboxylic acid 5mmol were successively added, and refluxed for 2h. Cool to room temperature, add 7.5 mL of 10% NaOH solution, stir, filter, and dry to obtain pure product. Two compounds were synthesized by this method.
化合物26 2-甲基-1H-苯并咪唑：1H NMR(400MHZ,CD3OD,ppm)δ7.46-7.50(m,2H),7.17-7.27(m,2H),2.57(s,3H)；MS calcd for:C8H8N2[M+H]+133.0760,found 133.0704。Compound 26 2-methyl-1H-benzimidazole: 1H NMR (400MHZ, CD3OD, ppm) δ 7.46-7.50(m, 2H), 7.17-7.27(m, 2H), 2.57(s, 3H); MS calcd for: C8H8N2[M+H]+133.0760, found 133.0704.
化合物27. 2-(四氢呋喃-2-基)-1H-苯并咪唑：1HNMR(400MHZ,CD3OD,ppm)δ7.53-7.55(m,2H),7.21-7.24(m,2H),5.15-5.19(m,1H)4.13-4.18(m,1H),3.96-4.01(m,1H),2.44-2.52(m,1H),2.15-2.23(m,1H),2.04-2.11(m,2H)；MS calcd for:C11H12N2O[M+H]+189.1022,found189.0953。Compound 27. 2-(tetrahydrofuran-2-yl)-1H-benzimidazole: 1HNMR (400MHZ, CD3OD, ppm) δ 7.53-7.55 (m, 2H), 7.21-7.24 (m, 2H), 5.15-5.19 (m,1H)4.13-4.18(m,1H), 3.96-4.01(m,1H), 2.44-2.52(m,1H), 2.15-2.23(m,1H), 2.04-2.11(m,2H); MS calcd for: C11H12N2O[M+H]+189.1022, found189.0953.
方法三、由1H苯并咪唑与R1X反应生成多取代苯并咪唑 Method 3. Generation of polysubstituted benzimidazoles from the reaction of 1H benzimidazole and R1X
合成通法：所有1H苯并咪唑来自上述合成。将1H苯并咪唑(4mmol)溶于120mL DMF，加入Cs2 CO3(9.6mmol,3.6g),升温到80℃，加入苄氯(12mmol,6.1g),反应1-2h。降温，过滤，洗涤，用乙酸乙酯重结晶或者柱层析得到纯品。用此方法合成以下化合物。General Synthesis: All 1H benzimidazoles were from the above synthesis. 1H benzimidazole (4mmol) was dissolved in 120mL DMF, Cs2CO3 (9.6mmol, 3.6g) was added, the temperature was raised to 80°C, benzyl chloride (12mmol, 6.1g) was added, and the reaction was performed for 1-2h. Cool down, filter, wash, recrystallize with ethyl acetate or column chromatography to obtain pure product. The following compounds were synthesized by this method.
化合物28. 1-苄基-2-(吡啶-2-基)-苯并[d]咪唑:黄色晶体，产率83％。m.p.118.3℃。1H NMR(400MHz,DMSO-d6,ppm)δ8.73-8.68(m,1H),8.40-8.35(m,1H),8.03-7.97(m,1H),7.79-7.74(m,1H),7.61-7.57(m,1H),7.55-7.50(m,1H),7.30-7.26(m,2H),7.26-7.17(m,3H),7.16-7.11(m,2H),6.24(s,2H)；13C NMR(100MHz,DMSO-d6,ppm)δ150.49,149.73,149.32,142.69,138.23,138.02,136.98,128.99,127.71,127.18,124.88,123.87,123.06,120.11,111.80,48.43；MS calcd for:C19H15N3[M+H]+286.1339,found286.1414.Compound 28. 1-benzyl-2-(pyridin-2-yl)-benzo[d]imidazole: yellow crystals, 83% yield. m.p. 118.3°C. 1H NMR(400MHz,DMSO-d6,ppm)δ8.73-8.68(m,1H),8.40-8.35(m,1H),8.03-7.97(m,1H),7.79-7.74(m,1H),7.61 -7.57(m,1H),7.55-7.50(m,1H),7.30-7.26(m,2H),7.26-7.17(m,3H),7.16-7.11(m,2H),6.24(s,2H) ; 13C NMR (100MHz, DMSO-d6, ppm) δ150.49,149.73,149.32,142.69,138.23,138.02,136.98,128.99,127.71,127.18,124.88,123.87,123.06,120.11,111.80,48.43; MS calcd for: C19H15N3 [ M+H]+286.1339,found286.1414.
化合物29. 1-苄基-2-(吡啶-3-基)-苯并[d]咪唑:棕色晶体，产率83％。m.p.126.1℃-127.7℃。1H NMR(400MHz,CDCl3,ppm)δ8.92(dd,J＝2.2,0.7Hz,1H),8.71(dd,J＝4.9,1.7Hz,1H),8.07-7.97(m,1H),7.89(d,J＝7.9Hz,1H),7.43-7.27(m,7H),7.14-7.01(m,2H),5.47(s,2H)；13C NMR(100MHz，CD3OD,ppm)δ150.22,148.97,142.09,137.30,136.38,128.73,127.60,126.58,125.77,123.95,123.70,123.05,118.77,110.94；MScalcd for:C19H15N3[M+H]+286.1339,found286.1229.Compound 29. 1-benzyl-2-(pyridin-3-yl)-benzo[d]imidazole: brown crystals, 83% yield. m.p.126.1°C-127.7°C. 1H NMR (400MHz, CDCl3, ppm) δ 8.92 (dd, J=2.2, 0.7Hz, 1H), 8.71 (dd, J=4.9, 1.7Hz, 1H), 8.07-7.97 (m, 1H), 7.89 ( d, J=7.9Hz, 1H), 7.43-7.27 (m, 7H), 7.14-7.01 (m, 2H), 5.47 (s, 2H); 13C NMR (100MHz, CD3OD, ppm) δ 150.22, 148.97, 142.09, 137.30, 136.38, 128.73, 127.60, 126.58, 125.77, 123.95, 123.70, 123.05, 118.77, 110.94; MScalcd for: C19H15N3[M+H]+286.1339, found286.1229.
化合物30. 1-苄基-2-(吡啶-4-基)-苯并[d]咪唑:棕色粉末，产率81％。m.p.95.2℃-96.1℃。1H NMR(400MHz,CDCl3,ppm)δ8.30(d,J＝6.9Hz,2H),7.93-7.82(m,1H),7.66-7.55(m,2H),7.42-7.38(m,2H),7.36(d,J＝1.8Hz,1H),7.32(s,1H),7.30(d,J＝4.0Hz,2H),7.07(dd,J＝7.5,1.8Hz,2H),5.68(s,2H)；13C NMR(100MHz,CDCl3,ppm)δ146.29,145.32,145.11,143.27,137.52,134.72,132.92,130.00,129.57,128.56,126.46,125.69,124.44,48.73；MS calcd for:C19H15N3[M+H]+286.1339,found 286.1415.Compound 30. 1-benzyl-2-(pyridin-4-yl)-benzo[d]imidazole: brown powder, 81% yield. m.p.95.2°C-96.1°C. 1H NMR (400MHz, CDCl3, ppm) δ8.30 (d, J=6.9Hz, 2H), 7.93-7.82 (m, 1H), 7.66-7.55 (m, 2H), 7.42-7.38 (m, 2H), 7.36(d,J＝1.8Hz,1H),7.32(s,1H),7.30(d,J＝4.0Hz,2H),7.07(dd,J＝7.5,1.8Hz,2H),5.68(s,2H) ); 13C NMR (100MHz, CDCl3, ppm) δ146.29, 145.32, 145.11, 143.27, 137.52, 134.72, 132.92, 130.00, 129.57, 128.16, 126.46, 125.69, 124.44, 48.73; MS [M+H15 for:Ccalc+] 286.1339, found 286.1415.
化合物31. 1-苄基-2-(2-氯苯基)-苯并[d]咪唑:黄色晶体，产率82％。m.p.109.2℃-110.7℃。1H NMR(400MHz,DMSO-d6,ppm)δ7.74(d,J＝13.5Hz,1H),7.68(d,J＝8.8Hz,1H),7.61(d,J＝15.9Hz,2H),7.51(d,J＝22.4Hz,2H),7.24(d,J＝31.1Hz,5H),6.96(d,J＝9.4Hz,2H),5.33(s,2H)；13C NMR(100MHz,DMSO-d6,ppm)δ151.11,143.10,136.79,135.17,133.68,132.91,132.35,130.22,129.03,128.05,127.89,127.17,123.32,122.60,119.96,111.68,47.66；MS calcd for:C20H15ClN2[M+H]+319.0997,found 319.1072.Compound 31. 1-benzyl-2-(2-chlorophenyl)-benzo[d]imidazole: yellow crystals, 82% yield. m.p.109.2°C-110.7°C. 1H NMR(400MHz,DMSO-d6,ppm)δ7.74(d,J=13.5Hz,1H),7.68(d,J=8.8Hz,1H),7.61(d,J=15.9Hz,2H),7.51 (d, J=22.4Hz, 2H), 7.24 (d, J=31.1Hz, 5H), 6.96 (d, J=9.4Hz, 2H), 5.33 (s, 2H); 13C NMR (100MHz, DMSO-d6 , ppm) δ151.11,143.10,136.79,135.17,133.68,132.91,132.35,130.22,129.03,128.05,127.89,127.17,123.32,122.60,119.96,111.68,47.66; MS calcd for: C20H15ClN2 [M + H] +319.0997, found 319.1072.
化合物32 1-苄基-2-(3-氯苯基)-苯并[d]咪唑:白色晶体，产率85％，m.p.96.0-97.1℃。1H NMR(400MHz,CDCl3,ppm)δ7.87(d,J＝8.0Hz,1H),7.73(t,J＝1.8Hz,1H),7.55-7.50(m,1H),7.48-7.42(m,1H),7.38(d,J＝7.9Hz,1H),7.36-7.30(m,4H),7.30-7.26(m,1H),7.26-7.22(m,1H),7.12-7.06(m,2H),5.45(s,2H)；13C NMR(100MHz,CDCl3,ppm)δ152.61,143.07,136.15,134.88,131.85,130.04,129.99,129.55,129.17,127.97,127.17,1 25.97,123.45,122.94,120.19,110.57,48.44；MS calcd for:C20H15ClN2[M+H]+319.0997,found 319.1072。Compound 32 1-benzyl-2-(3-chlorophenyl)-benzo[d]imidazole: white crystals, 85% yield, m.p. 96.0-97.1°C. 1H NMR (400MHz, CDCl3, ppm) δ7.87 (d, J=8.0Hz, 1H), 7.73 (t, J=1.8Hz, 1H), 7.55-7.50 (m, 1H), 7.48-7.42 (m, 1H), 7.38(d, J=7.9Hz, 1H), 7.36-7.30(m, 4H), 7.30-7.26(m, 1H), 7.26-7.22(m, 1H), 7.12-7.06(m, 2H) ,5.45(s,2H);13C NMR(100MHz,CDCl3,ppm)δ152.61,143.07,136.15,134.88,131.85,130.04,129.99,129.55,129.17,127.97,127.17,1 25.97,123.45,122 48.44; MS calcd for: C20H15ClN2[M+H]+319.0997, found 319.1072.
化合物33. 1-苄基-2-(4-氯苯基)-苯并[d]咪唑:棕色粉末，产率87％。m.p.137.5-138.0℃。1H NMR(400MHz,DMSO-d6,ppm)δ7.75(d,J＝12.3Hz,3H),7.60(d,J＝13.5Hz,2H),7.50(d,J＝19.2Hz,1H),7.27(d,J＝36.6Hz,5H),7.00(d,J＝8.3Hz,2H),5.61(s,2H)；13C NMR(100MHz,DMSO-d6,ppm)δ152.58,143.08,137.30,136.46,135.20,131.29,129.39,129.29,128.00,126.57,123.38,122.84,119.83,111.66,47.93；MS calcd for:C20H15ClN2[M+H]+319.0997,found319.1072.Compound 33. 1-benzyl-2-(4-chlorophenyl)-benzo[d]imidazole: brown powder, 87% yield. m.p.137.5-138.0°C. 1H NMR(400MHz,DMSO-d6,ppm)δ7.75(d,J=12.3Hz,3H),7.60(d,J=13.5Hz,2H),7.50(d,J=19.2Hz,1H),7.27 (d, J=36.6Hz, 5H), 7.00 (d, J=8.3Hz, 2H), 5.61 (s, 2H); 13C NMR (100MHz, DMSO-d6, ppm) δ 152.58, 143.08, 137.30, 136.46, 135.20 ,131.29,129.39,129.29,128.00,126.57,123.38,122.84,119.83,111.66,47.93; MS calcd for:C20H15ClN2[M+H]+319.0997,found319.1072.
化合物34. 1-苄基-2-(邻甲苯基)-苯并[d]咪唑:白色晶体，产率88％，m.p.119.5-120.4℃。1H NMR(400MHz,DMSO-d6,ppm)δ7.75-7.69(m,1H),7.57-7.51(m,1H),7.49-7.31(m,4H),7.29-7.18(m,5H),6.94-6.88(m,2H),5.31(s,2H),2.10(s,3H)；13C NMR(100MHz,DMSO-d6,ppm)δ153.40,143.15,138.16,137.09,135.22,130.92,130.43,130.29,129.04,127.98,127.07,126.22,122.94,122.39,119.70,111.56,47.48,19.77；MS calcdfor:C21H18N2[M+H]+299.1543,found 299.1619。Compound 34. 1-benzyl-2-(o-tolyl)-benzo[d]imidazole: white crystals, 88% yield, m.p. 119.5-120.4°C. 1H NMR(400MHz,DMSO-d6,ppm)δ7.75-7.69(m,1H),7.57-7.51(m,1H),7.49-7.31(m,4H),7.29-7.18(m,5H),6.94 -6.88(m, 2H), 5.31(s, 2H), 2.10(s, 3H); 13C NMR (100MHz, DMSO-d6, ppm) δ 153.40, 143.15, 138.16, 137.09, 135.22, 130.92, 130.43, 130.29, 129.04 , 127.98, 127.07, 126.22, 122.94, 122.39, 119.70, 111.56, 47.48, 19.77; MS calcdfor: C21H18N2[M+H]+299.1543, found 299.1619.
化合物35. 1-苄基-2-(间甲苯基)-苯并[d]咪唑:白色晶体，产率88％，m.p.109.7-110.1℃。1H NMR(400MHz,DMSO-d6,ppm)δ7.73(d,J＝17.3Hz,1H),7.56(s,1H),7.49(d,J＝16.8Hz,2H),7.41(d,J＝15.1Hz,1H),7.35(d,J＝7.5Hz,1H),7.27(d,J＝42.1Hz,5H),7.02(d,J＝8.3Hz,2H),5.59(s,2H),2.36(s,3H)；13C NMR(100MHz,DMSO-d6,ppm)δ153.86,143.15,138.58,137.55,136.40,130.92,130.21,129.26,129.11,127.95,126.59,126.48,123.12,122.65,119.70,111.56,47.96,21.42；MS calcd for:C21H18N2[M+H]+299.1543,found 299.1620。 Compound 35. 1-benzyl-2-(m-tolyl)-benzo[d]imidazole: white crystals, 88% yield, m.p. 109.7-110.1°C. 1H NMR(400MHz,DMSO-d6,ppm)δ7.73(d,J=17.3Hz,1H),7.56(s,1H),7.49(d,J=16.8Hz,2H),7.41(d,J= 15.1Hz, 1H), 7.35 (d, J=7.5Hz, 1H), 7.27 (d, J=42.1Hz, 5H), 7.02 (d, J=8.3Hz, 2H), 5.59 (s, 2H), 2.36 (s,3H);13C NMR(100MHz,DMSO-d6,ppm)δ153.86,143.15,138.58,137.55,136.40,130.92,130.21,129.26,129.11,127.95,126.59,126.48,123.12,122.564,199 , 21.42; MS calcd for: C21H18N2[M+H]+299.1543, found 299.1620.
化合物36. 1-苄基-2-(对甲苯基)-苯并[d]咪唑:白色晶体，产率87％。m.p.123.7-124.7℃。1H NMR(400MHz,DMSO-d6,ppm)δ7.72(d,J＝8.6Hz,1H),7.63(d,J＝8.1Hz,2H),7.45(d,J＝8.7Hz,1H),7.28(d,J＝56.6Hz,7H),7.01(d,J＝8.3Hz,2H),5.58(s,2H),2.38(s,3H)；13C NMR(100MHz,DMSO-d6,ppm)δ153.84,143.18,140.01,137.48,136.38,129.83,129.41,127.93,126.53,123.02,122.62,119.64,47.90,21.41；MS calcdfor:C21H18N2[M+H]+299.1543,found299.1612。 Compound 36. 1-benzyl-2-(p-tolyl)-benzo[d]imidazole: white crystals, 87% yield. m.p.123.7-124.7°C. 1H NMR(400MHz,DMSO-d6,ppm)δ7.72(d,J=8.6Hz,1H),7.63(d,J=8.1Hz,2H),7.45(d,J=8.7Hz,1H),7.28 (d, J=56.6Hz, 7H), 7.01 (d, J=8.3Hz, 2H), 5.58 (s, 2H), 2.38 (s, 3H); 13C NMR (100MHz, DMSO-d6, ppm) δ153. 84,143.18,140.01,137.48,136.38,129.83,129.41,127.93,126.53,123.02,122.62,119.64,47.90,21.41; MS calcdfor:C21H18N2[M+H]+299.1543,found29.9.9.
化合物37. 1-苄基-2-(2-硝基苯基)-苯并[d]咪唑:淡黄色晶体，产率85％，m.p.166.3-166.9℃。1H NMR(400MHz,DMSO-d6,ppm)δ8.31-8.16(m,1H),7.90-7.82(m,2H),7.77-7.73(m,1H),7.72-7.67(m,1H),7.56-7.44(m,1H),7.34-7.18(m,5H),7.15-7.01(m,2H),5.43(s,2H)；13C NMR(100MHz,DMSO-d6,ppm)δ149.66,149.42,143.13,136.68,135.51,134.08,132.67,132.05,129.04,128.08,127.34,125.40,123.44,122.68,119.90,111.74,47.96；MS calcd for:C20H15N3O2[M+H]+330.1237,found 330.1320。Compound 37. 1-benzyl-2-(2-nitrophenyl)-benzo[d]imidazole: pale yellow crystals, 85% yield, m.p. 166.3-166.9°C. 1H NMR(400MHz,DMSO-d6,ppm)δ8.31-8.16(m,1H),7.90-7.82(m,2H),7.77-7.73(m,1H),7.72-7.67(m,1H),7.56 -7.44 (m, 1H), 7.34-7.18 (m, 5H), 7.15-7.01 (m, 2H), 5.43 (s, 2H); 13C NMR (100MHz, DMSO-d6, ppm) δ 149.66, 149.42, 143.13, 136.68, 135.51, 134.08, 132.67, 132.05, 129.04, 128.08, 127.34, 125.40, 123.44, 122.68, 119.90, 111.74, 47.96; MS calcd for: C20H15N3O2[M+H]+330.1
化合物38. 1-苄基-2-(3-硝基苯基)-苯并[d]咪唑:黄色粉末，产率87％。m.p.167.2-167.9℃。1H NMR(400MHz,DMSO-d6,ppm)δ8.54-8.49(m,1H),8.41-8.34(m,1H),8.24-8.18(m,1H),7.87-7.77(m,2H),7.60-7.54(m,1H),7.35-7.23(m,5H),7.08-7.00(m,2H),5.68(s,2H)；13C NMR(100MHz,DMSO-d6,ppm)δ151.38,148.41,142.98,137.21,136.70,135.71,131.03,129.34,128.07,126.62,124.90,124.11,123.82,123.10,120.07,111.82,48.07；MS calcd for:C20H15N3O2[M+H]+330.1237,found 330.1302。Compound 38. 1-benzyl-2-(3-nitrophenyl)-benzo[d]imidazole: yellow powder, 87% yield. m.p.167.2-167.9°C. 1H NMR(400MHz,DMSO-d6,ppm)δ8.54-8.49(m,1H),8.41-8.34(m,1H),8.24-8.18(m,1H),7.87-7.77(m,2H),7.60 -7.54 (m, 1H), 7.35-7.23 (m, 5H), 7.08-7.00 (m, 2H), 5.68 (s, 2H); 13C NMR (100MHz, DMSO-d6, ppm) δ 151.38, 148.41, 142.98, 137.21, 136.70, 135.71, 131.03, 129.34, 128.07, 126.62, 124.90, 124.11, 123.82, 123.10, 120.07, 111.82, 48.07;
化合物39. 1-苄基-2-(4-硝基苯基)-苯并[d]咪唑:黄色粉末，产率89％。m.p.184.1-184.4℃。1H NMR(400MHz,DMSO-d6,ppm)δ8.40-8.32(m,2H),8.08-8.02(m,2H),7.82-7.76(m,1H),7.60-7.54(m,1H),7.34-7.21(m,5H),7.03-6.98(m,2H),5.68(s,2H)；13CNMR(100MHz,CDCl3,ppm)δ156.27,153.19,147.88,141.86,141.45,135.55,134.07,132.83,131.39,129.20,128.72,127.94,124.92,116.67,52.82；MS calcd for:C20H15N3O2[M+H]+330.1237,found330.1323。Compound 39. 1-benzyl-2-(4-nitrophenyl)-benzo[d]imidazole: yellow powder, 89% yield. m.p.184.1-184.4°C. 1H NMR(400MHz,DMSO-d6,ppm)δ8.40-8.32(m,2H),8.08-8.02(m,2H),7.82-7.76(m,1H),7.60-7.54(m,1H),7.34 -7.21 (m, 5H), 7.03-6.98 (m, 2H), 5.68 (s, 2H); 13CNMR (100MHz, CDCl3, ppm) δ156.27, 153.19, 147.88, 141.86, 141.45, 135.55, 134.07, 132.83, 131.39, 129.20, 128.72, 127.94, 124.92, 116.67, 52.82; MS calcd for: C20H15N3O2[M+H]+330.1237, found330.1323.
化合物40. 1-苄基-2-苯基-苯并[d]咪唑:白色晶体，产率89％。m.p.138.0-139.7℃。1H NMR(400MHz,DMSO-d6,ppm)δ7.77-7.69(m,3H),7.57-7.50(m,3H),7.49-7.45(m,1H),7.34-7.20(m,5H),7.06-6.96(m,2H),5.60(s,2H)；13C NMR(100MHz,DMSO-d6,ppm)δ153.74,143.16,137.42,136.37,130.63,130.31,129.52,129.27,127.96,126.57,123.17,122.69,119.75,111.59,47.92；MS calcd for:C20H16N2[M+H]+285.1386,found 285.1450。Compound 40. 1-benzyl-2-phenyl-benzo[d]imidazole: white crystals, 89% yield. m.p.138.0-139.7°C. 1H NMR(400MHz,DMSO-d6,ppm)δ7.77-7.69(m,3H),7.57-7.50(m,3H),7.49-7.45(m,1H),7.34-7.20(m,5H),7.06 -6.96 (m, 2H), 5.60 (s, 2H); 13C NMR (100MHz, DMSO-d6, ppm) δ 153.74, 143.16, 137.42, 136.37, 130.63, 130.31, 129.52, 129.27, 127.96, 126.57, 123.17, 122.69 119.75, 111.59, 47.92; MS calcd for: C20H16N2[M+H]+285.1386, found 285.1450.
化合物41. 1-苄基-2-戊基-苯并[d]咪唑:白色晶体，产率84％。m.p.60.2-61.1℃。1H NMR(400MHz,CDCl3,ppm)δ7.77(d,J＝7.8Hz,1H),7.33-7.29(m,1H),7.29-7.25(m,2H),7.24-7.20(m,1H),7.20-7.15(m,2H),7.07-6.99(m,2H),5.33(s,2H),2.88-2.76(m,2H),1.90-1.76(m,2H),1.44-1.25(m,4H),0.86(t,J＝7.1Hz,3H)；13C NMR(100MHz,CDCl3,ppm)δ155.58,142.78,136.14,135.45,128.98,127.86,126.15,121.95,119.32,109.45,46.90,31.67,27.65,27.39,22.39,13.96；MS calcd for:C19H22N2[M+H]+279.1856,found279.1927。Compound 41. 1-benzyl-2-pentyl-benzo[d]imidazole: white crystals, 84% yield. m.p.60.2-61.1°C. 1H NMR (400MHz, CDCl3, ppm) δ7.77(d, J=7.8Hz, 1H), 7.33-7.29(m, 1H), 7.29-7.25(m, 2H), 7.24-7.20(m, 1H), 7.20-7.15(m, 2H), 7.07-6.99(m, 2H), 5.33(s, 2H), 2.88-2.76(m, 2H), 1.90-1.76(m, 2H), 1.44-1.25(m, 4H) The , 22.39, 13.96; MS calcd for: C19H22N2[M+H]+279.1856, found279.1927.
化合物42. 1-苄基-2-甲基-苯并[d]咪唑:白色粉末，产率83％。m.p.65.3-66.7℃；1H NMR(400MHz,DMSO-d6,ppm)δ7.58-7.52(m,1H),7.50-7.44(m,1H),7.37-7.30(m,2H),7.30-7.24(m,1H),7.18-7.10(m,4H),5.48(s,2H),2.52(s,3H)；13C NMR(100MHz,DMSO-d6,ppm)δ152.35,142.81,137.49,135.83,129.24,127.98,127.12,122.10,118.75,110.51,46.68,14.11；MS calcd for:C15H14N2[M+H]+223.1230,found 223.1225。Compound 42. 1-benzyl-2-methyl-benzo[d]imidazole: white powder, 83% yield. mp65.3-66.7℃;1H NMR(400MHz,DMSO-d6,ppm)δ7.58-7.52(m,1H),7.50-7.44(m,1H),7.37-7.30(m,2H),7.30-7.24( m, 1H), 7.18-7.10 (m, 4H), 5.48 (s, 2H), 2.52 (s, 3H); 13C NMR (100MHz, DMSO-d6, ppm) δ 152.35, 142.81, 137.49, 135.83, 129.24, 127.98 , 127.12, 122.10, 118.75, 110.51, 46.68, 14.11; MS calcd for: C15H14N2[M+H]+223.1230, found 223.1225.
化合物43. 1-苄基-2-(四氢呋喃-2-基)-苯并[d]咪唑:白色粉末，产率92％，m.p.93.2-94.1℃。1H NMR(400MHz,DMSO-d6,ppm)δ7.68-7.63(m,1H),7.42-7.38(m,1H),7.34-7.29(m,2H),7.28-7.24(m,1H),7.21-7.13(m,4H),5.70-5.48(m,2H),5.29-5.18(m,1H),3.83(t,J＝6.8Hz,2H),2.67-2.55(m,1H),2.26-2.16(m,1H),2.08-1.89(m,2H)；13CNMR(100MHz,DMSO-d6,ppm)δ154.22,142.19,137.50,129.10,127.92,127.19,122.99,122.22,119.77,111.18,72.99,68.55,47.04,29.57,25.99；MS calcd for:C18H18N2O[M+H]+279.1492,found 279.1495。Compound 43. 1-benzyl-2-(tetrahydrofuran-2-yl)-benzo[d]imidazole: white powder, 92% yield, m.p. 93.2-94.1°C. 1H NMR(400MHz,DMSO-d6,ppm)δ7.68-7.63(m,1H),7.42-7.38(m,1H),7.34-7.29(m,2H),7.28-7.24(m,1H),7.21 -7.13(m, 4H), 5.70-5.48(m, 2H), 5.29-5.18(m, 1H), 3.83(t, J=6.8Hz, 2H), 2.67-2.55(m, 1H), 2.26-2.16 (m, 1H), 2.08-1.89 (m, 2H); 13CNMR (100MHz, DMSO-d6, ppm) δ 154.22, 142.19, 137.50, 129.10, 127.92, 127.19, 122.99, 122.22, 119.77, 111.18, 72.99, 68.55, 47 , 29.57, 25.99; MS calcd for: C18H18N2O[M+H]+279.1492, found 279.1495.
化合物44. 1-苯乙基-2-(吡啶-2-基)-苯并[d]咪唑:白色粉末，产率53％，m.p.96.2℃，暂无文献报道合成方法；1H NMR(400MHz,DMSO-d6,ppm)δ7.65-7.58(m,2H),7.41(d,J＝8.1Hz,2H),7.27(d,J＝7.9Hz,2H),7.25-7.15(m,2H),7.15-7.08(m,3H),6.95-6.89(m,2H),4.42(t,J＝7.4Hz,2H),2.95(t,J＝7.4Hz,2H),2.35(s,3H)；13C NMR(100MHz,DMSO-d6,ppm)δ150.46,149.83,149.26,142.54,138.65,137.81,136.63,129.25,128.77,126.86,124.75,123.63,122.80,119.98,111.41,46.74,36.35；MS calcd for:C20H17N3[M+H]+300.1495,found 300.1509。Compound 44. 1-Phenethyl-2-(pyridin-2-yl)-benzo[d]imidazole: white powder, yield 53%, mp96.2°C, no synthetic method reported in literature; 1H NMR (400MHz, DMSO-d6,ppm)δ7.65-7.58(m,2H),7.41(d,J=8.1Hz,2H),7.27(d,J=7.9Hz,2H),7.25-7.15(m,2H), 7.15-7.08(m,3H),6.95-6.89(m,2H),4.42(t,J=7.4Hz,2H),2.95(t,J=7.4Hz,2H),2.35(s,3H); 13C NMR (100MHz, DMSO-d6, ppm) δ150.46,149.83,149.26,142.54,138.65,137.81,136.63,129.25,128.77,126.86,124.75,123.63,122.80,119.98,111.41,46.74,36.35; MS calcd for: C20H17N3 [ M+H]+300.1495, found 300.1509.
化合物45. 1-苯乙基-2-(吡啶-3-基)-苯并[d]咪唑:白色粉末，产率52％，m.p.113.7-114.6℃，1H NMR(400MHz,DMSO-d6,ppm)δ8.73-8.62(m,2H),7.92-7.83(m,1H),7.79-7.68(m,2H),7.54-7.45(m,1H),7.39-7.24(m,2H),7.16-7.07(m,3H),6.85-6.76(m,2H),4.55(t,J＝7.0Hz,2H),2.99(t,J＝7.0Hz,2H)；13C NMR(100MHz,DMSO-d6,ppm)δ151.08,150.62,149.80,143.15,138.07,136.85,135.80,128.98,128.75,127.02,123.87,123.25,122.67,119.84,111.70,46.14,35.31；MS calcd for:C20H17N3[M+H]+300.1495,found 300.1886。Compound 45. 1-Phenethyl-2-(pyridin-3-yl)-benzo[d]imidazole: white powder, 52% yield, mp 113.7-114.6°C, 1H NMR (400MHz, DMSO-d6, ppm )δ8.73-8.62(m,2H),7.92-7.83(m,1H),7.79-7.68(m,2H),7.54-7.45(m,1H),7.39-7.24(m,2H),7.16- 7.07 (m, 3H), 6.85-6.76 (m, 2H), 4.55 (t, J=7.0Hz, 2H), 2.99 (t, J=7.0Hz, 2H); 13C NMR (100MHz, DMSO-d6, ppm ) δ151.08,150.62,149.80,143.15,138.07,136.85,135.80,128.98,128.75,127.02,123.87,123.25,122.67,119.84,111.70,46.14,35.31; MS calcd for: C20H17N3 [M + H] + 300.1495, found 300.1886 .
化合物46 1-苯乙基-2-(吡啶-4-基)-苯并[d]咪唑:白色粉末，产率52％，m.p.124.7℃；1H NMR(400MHz,DMSO-d6,ppm)δ8.74-8.64(m,2H),7.81-7.68(m,2H),7.56-7.47(m,2H),7.41-7.26(m,2H),7.18-7.05(m,3H),6.88-6.80(m,2H),4.61(t,J＝7.1Hz,2H),2.99(t,J＝7.0Hz,2H)；13CNMR(100MHz,DMSO-d6,ppm)δ151.11,150.37,143.03,138.00,135.98,129.05,128.77,127.05,123.73,123.59,122.86,120.05,111.84,46.15,35.40；MS calcd for:C20H17N3[M+H]+300.1495,found 300.1500。 Compound 46 1-phenethyl-2-(pyridin-4-yl)-benzo[d]imidazole: white powder, 52% yield, mp 124.7°C; 1H NMR (400MHz, DMSO-d6, ppm) δ8. 74-8.64(m, 2H), 7.81-7.68(m, 2H), 7.56-7.47(m, 2H), 7.41-7.26(m, 2H), 7.18-7.05(m, 3H), 6.88-6.80(m , 2H), 4.61 (t, J=7.1Hz, 2H), 2.99 (t, J=7.0Hz, 2H); 13CNMR (100MHz, DMSO-d6, ppm) δ151.11, 150.37, 143.03, 138.00, 135.98, 129.05, 128.77, 127.05, 123.73, 123.59, 122.86, 120.05, 111.84, 46.15, 35.40; MS calcd for: C20H17N3[M+H]+300.1495, found 300.1500.
化合物47. 1-苯乙基-2-(2-氯苯基)-苯并[d]咪唑:黄色晶体，产率55％，m.p.103.7℃；1H NMR(400MHz,DMSO-d6,ppm)δ7.76(d,J＝7.7Hz,1H),7.69(d,J＝7.4Hz,1H),7.60-7.45(m,3H),7.40-7.24(m,3H),7.19-7.08(m,3H),6.86-6.76(m,2H),4.53(t,J＝7.0Hz,2H),2.99(t,J＝7.0Hz,2H)；13C NMR(100MHz,DMSO-d6,ppm)δ150.92,143.00,138.22,134.82,132.67,132.12,130.12,129.86,129.01,128.88,127.69,126.99,123.10,122.40,119.86,111.56,45.95,35.27；MS calcd for:C21H17ClN2[M+H]+333.1153,found333.1619。Compound 47. 1-phenethyl-2-(2-chlorophenyl)-benzo[d]imidazole: yellow crystal, yield 55%, mp 103.7°C; 1H NMR (400MHz, DMSO-d6, ppm) δ7 .76(d,J=7.7Hz,1H),7.69(d,J=7.4Hz,1H),7.60-7.45(m,3H),7.40-7.24(m,3H),7.19-7.08(m,3H) ), 6.86-6.76 (m, 2H), 4.53 (t, J=7.0Hz, 2H), 2.99 (t, J=7.0Hz, 2H); 13C NMR (100MHz, DMSO-d6, ppm) δ150.92, 143.00, 138.22,134.82,132.67,132.12,130.12,129.86,129.01,128.88,127.69,126.99,123.10,122.40,119.86,111.56,45.95,35.27; MS calcd for: C21H17ClN2 [M + H] + 333.1153, found333.1619.
化合物48. 1-苯乙基-2-(3-氯苯基)-苯并[d]咪唑:白色粉末，产率49％，m.p.114.8℃；1H NMR(400MHz,DMSO-d6,ppm)δ7.80-7.65(m,2H),7.61-7.45(m,3H),7.40-7.24(m,3H),7.20-7.07(m,3H),6.86-6.76(m,2H),4.53(t,J＝7.0Hz,2H),2.99(t,J＝7.0Hz,2H)；13CNMR(100MHz,DMSO-d6,ppm)δ152.25,142.99,138.12,135.73,133.64,130.79,129.82,129.27,129.01,128.76,128.05,126.95,123.20,122.64,119.80,111.72,46.17,35.24；MS calcd for:C21H17ClN2[M+H]+333.1153,found 333.1620。Compound 48. 1-Phenethyl-2-(3-chlorophenyl)-benzo[d]imidazole: white powder, 49% yield, mp 114.8°C; 1H NMR (400MHz, DMSO-d6, ppm) δ7 .80-7.65(m, 2H), 7.61-7.45(m, 3H), 7.40-7.24(m, 3H), 7.20-7.07(m, 3H), 6.86-6.76(m, 2H), 4.53(t, J=7.0Hz, 2H), 2.99 (t, J=7.0Hz, 2H); 13CNMR (100MHz, DMSO-d6, ppm) δ 152.25, 142.99, 138.12, 135.73, 133.64, 130.79, 129.82, 129.27, 129.01, 128.76, 128.05, 126.95, 123.20, 122.64, 119.80, 111.72, 46.17, 35.24; MS calcd for: C21H17ClN2[M+H]+333.1153, found 333.1620.
化合物49. 1-苯乙基-2-(4-氯苯基)-苯并[d]咪唑:白色晶体，产率54％，m.p.128.7℃；1H NMR(400MHz,DMSO-d6,ppm)δ7.77-7.63(m,2H),7.62-7.48(m,4H),7.35-7.29(m,1H),7.28-7.22(m,1H),7.19-7.07(m,3H),6.96-6.82(m,2H),4.52(t,J＝7.2Hz,2H),2.99(t,J＝7.2Hz,2H)；13CNMR(100MHz,DMSO-d6,ppm)δ143.01,139.42,138.12,135.86,134.79,131.32,129.73,129.07,128.79,127.02,123.08,122.56,119.70,111.63,46.11,35.35；MS calcd for:C21H17ClN2[M+H]+333.1153,found333.1585。Compound 49. 1-phenethyl-2-(4-chlorophenyl)-benzo[d]imidazole: white crystal, yield 54%, mp 128.7°C; 1H NMR (400MHz, DMSO-d6, ppm) δ7 .77-7.63(m,2H),7.62-7.48(m,4H),7.35-7.29(m,1H),7.28-7.22(m,1H),7.19-7.07(m,3H),6.96-6.82( m, 2H), 4.52 (t, J=7.2Hz, 2H), 2.99 (t, J=7.2Hz, 2H); 13CNMR (100MHz, DMSO-d6, ppm) δ 143.01, 139.42, 138.12, 135.86, 134.79, 131.32 , 129.73, 129.07, 128.79, 127.02, 123.08, 122.56, 119.70, 111.63, 46.11, 35.35; MS calcd for: C21H17ClN2[M+H]+333.1153, found333.1585.
化合物50. 1-苯乙基-2-(邻甲苯基)-苯并[d]咪唑:白色粉末，产率47％，m.p.127.2-128.9℃；1H NMR(400MHz,DMSO-d6,ppm)δ7.78-7.63(m,2H),7.49-7.34(m,3H),7.33-7.22(m,3H),7.19-7.12(m,3H),6.87-6.78(m,2H),4.25(t,J＝7.3Hz,2H),2.92(t,J＝7.2Hz,2H),2.05(s,3H)；13C NMR(100MHz,DMSO-d6,ppm)δ153.17,143.10,138.23,137.87,134.83,130.64,130.35,130.09,129.01,128.85,126.96,126.02,122.69,122.18,119.62,111.45,45.63,35.29,19.69；MS calcd for:C22H20N2[M+H]+313.1699,found313.1712。Compound 50. 1-Phenethyl-2-(o-tolyl)-benzo[d]imidazole: white powder, 47% yield, mp 127.2-128.9°C; 1H NMR (400MHz, DMSO-d6, ppm) δ7 .78-7.63(m,2H),7.49-7.34(m,3H),7.33-7.22(m,3H),7.19-7.12(m,3H),6.87-6.78(m,2H),4.25(t, J=7.3Hz, 2H), 2.92 (t, J=7.2Hz, 2H), 2.05 (s, 3H); 13C NMR (100MHz, DMSO-d6, ppm) δ 153.17, 143.10, 138.23, 137.87, 134.83, 130.64, 130.35, 130.09, 129.01, 128.85, 126.96, 126.02, 122.69, 122.18, 119.62, 111.45, 45.63, 35.29, 19.69; MS calcd for: C22H20N2[M+H]+313.1699, found313.17.
化合物51. 1-苯乙基-2-(间甲苯基)-苯并[d]咪唑:白色粉末，产率41％，m.p.72.1℃；1H NMR(400MHz,DMSO-d6,ppm)δ7.78-7.58(m,2H),7.42-7.37(m,1H),7.37-7.31(m,2H),7.31-7.26(m,1H),7.26-7.22(m,2H),7.19-7.14(m,3H),6.98-6.85(m,2H),4.48(t,J＝7.3Hz,2H),2.98(t,2H),2.37(s,3H)；13C NMR(100MHz,DMSO-d6,ppm)δ153.83,143.07,138.26,135.77,130.78,130.59,130.15,129.07,128.83,126.94,126.56,122.83,122.39,119.58,111.51,46.09,35.35,21.40；MS calcd for:C22H20N2[M+H]+313.1699,found 313.2117。Compound 51. 1-phenethyl-2-(m-tolyl)-benzo[d]imidazole: white powder, 41% yield, mp 72.1°C; 1H NMR (400MHz, DMSO-d6, ppm) δ 7.78 -7.58(m,2H),7.42-7.37(m,1H),7.37-7.31(m,2H),7.31-7.26(m,1H),7.26-7.22(m,2H),7.19-7.14(m, 3H), 6.98-6.85(m, 2H), 4.48(t, J=7.3Hz, 2H), 2.98(t, 2H), 2.37(s, 3H); 13C NMR (100MHz, DMSO-d6, ppm) δ153 .83,143.07,138.26,135.77,130.78,130.59,130.15,129.07,128.83,126.94,126.56,122.83,122.39,119.58,111.51,46.09,35.35,21.40; MS calcd for: C22H20N2 [M + H] + 313.1699, found 313.2117 .
化合物52. 1-苯乙基-2-(对甲苯基)-苯并[d]咪唑:白色晶体，产率56％，m.p.104.7℃；1H NMR(400MHz,DMSO-d6,ppm)δ7.68-7.51(m,2H),7.41(d,J＝8.1Hz,2H),7.27(d,J＝7.9Hz,2H),7.25-7.21(m,1H),7.20(t,J＝1.7Hz,1H),7.19-7.15(m,1H),7.14-7.11(m,2H),7.03-6.83(m,2H),4.42(t,J＝7.4Hz,1H),2.95(t,J＝7.4Hz,2H),2.35(s,3H)；13C NMR(100MHz,DMSO-d 6,ppm)δ153.72,143.06,139.64,138.23,135.88,129.60,129.45,129.09,128.84,127.00,122.74,122.33,119.51,111.44,46.06,35.41,21.43；MScalcd for:C22H20N2[M+H]+313.1699,found313.1717。Compound 52. 1-phenethyl-2-(p-tolyl)-benzo[d]imidazole: white crystal, yield 56%, mp 104.7°C; 1H NMR (400MHz, DMSO-d6, ppm) δ7.68 -7.51(m, 2H), 7.41(d, J=8.1Hz, 2H), 7.27(d, J=7.9Hz, 2H), 7.25-7.21(m, 1H), 7.20(t, J=1.7Hz, 1H), 7.19-7.15(m, 1H), 7.14-7.11(m, 2H), 7.03-6.83(m, 2H), 4.42(t, J=7.4Hz, 1H), 2.95(t, J=7.4Hz) , 2H), 2.35(s, 3H); 13C NMR (100MHz, DMSO-d 6, ppm) δ 153.72, 143.06, 139.64, 138.23, 135.88, 129.60, 129.45, 129.09, 128.84, 127.00, 122.74, 112.33, 119.51 , 46.06, 35.41, 21.43; MScalcd for: C22H20N2[M+H]+313.1699, found313.1717.
化合物53. 1-苯乙基-2-(2-硝基苯基)-苯并[d]咪唑:淡黄色晶体，产率51％，m.p.130.5-131.8℃；1H NMR(400MHz,CDCl3,ppm)δ8.17(dd,J＝8.2,1.1Hz,1H),7.84-7.78(m,1H),7.67-7.60(m,1H),7.57-7.51(m,1H),7.50-7.45(m,1H),7.41-7.31(m,2H),7.23-7.12(m,3H),6.87(dd,J＝7.6,1.4Hz,1H),6.82-6.76(m,2H),4.21(t,J＝7.0Hz,2H),3.06(t,J＝7.0Hz,2H)；13C NMR(100MHz,CDCl3,ppm)δ149.70,148.37,143.20,137.55,134.53,133.2,132.96,130.73,128.77,126.91,125.91,124.55,123.27,122.53,120.37,110.16,46.39,35.27；MS calcd for:C21H17N3O2[M+H]+344.1394,found 344.1447。Compound 53. 1-phenethyl-2-(2-nitrophenyl)-benzo[d]imidazole: pale yellow crystal, yield 51%, mp 130.5-131.8°C; 1H NMR (400MHz, CDCl3, ppm )δ8.17(dd,J=8.2,1.1Hz,1H),7.84-7.78(m,1H),7.67-7.60(m,1H),7.57-7.51(m,1H),7.50-7.45(m, 1H), 7.41-7.31(m, 2H), 7.23-7.12(m, 3H), 6.87(dd, J=7.6, 1.4Hz, 1H), 6.82-6.76(m, 2H), 4.21(t, J= 7.0Hz, 2H), 3.06 (t, J=7.0Hz, 2H); 13C NMR (100MHz, CDCl3, ppm) δ 149.70, 148.37, 143.20, 137.55, 134.53, 133.2, 132.96, 130.73, 128.77, 126.91, 125.91, 1255. , 123.27, 122.53, 120.37, 110.16, 46.39, 35.27; MS calcd for: C21H17N3O2[M+H]+344.1394, found 344.1447.
化合物54. 1-苯乙基-2-(3-硝基苯基)-苯并[d]咪唑:淡黄色晶体，产率43％，m.p.103.0℃；1H NMR(400MHz,DMSO-d6,ppm)δ8.32(dd,J＝2.3,0.9Hz,1H),8.12-8.06(m,1H),8.01-7.92(m,4H),7.83-7.72(m,2H),7.42-7.30(m,2H),7.12-6.98(m,3H),4.61(t,J＝6.8Hz,2H),2.99(t,J＝6.8Hz,2H)；13C NMR(100MHz,DMSO-d6,ppm)δ162.78,148.86,143.04,138.02,135.55,132.98,132.22,131.20,130.54,129.03,128.61,126.85,124.72,122.85,121.31,111.84,36.25,31.24；MS calcd for:C21H17N3O2[M+H]+344.1394,found344.1402。Compound 54. 1-phenethyl-2-(3-nitrophenyl)-benzo[d]imidazole: pale yellow crystal, yield 43%, mp 103.0°C; 1H NMR (400MHz, DMSO-d6, ppm )δ8.32(dd,J=2.3,0.9Hz,1H),8.12-8.06(m,1H),8.01-7.92(m,4H),7.83-7.72(m,2H),7.42-7.30(m, 2H), 7.12-6.98 (m, 3H), 4.61 (t, J=6.8Hz, 2H), 2.99 (t, J=6.8Hz, 2H); 13C NMR (100MHz, DMSO-d6, ppm) δ 162.78, 148.86 , 143.04,138.02,135.55,132.98,132.22,131.20,130.54,129.03,128.61,126.85,124.72,122.85,121.31,111.84,36.25,31.24; MS calcd for: C21H17N3O2 [M + H] + 344.1394, found344.1402.
化合物55. 1-苯乙基-2-(4-硝基苯基)-苯并[d]咪唑:黄色晶体，产率49％，m.p.153.9-154.8℃；1H NMR(400MHz,DMSO-d6,ppm)δ8.36-8.25(m,2H),7.85-7.70(m,4H),7.40-7.27(m,2H),7.17-7.08(m,3H),6.91-6.79(m,2H),4.61(t,J＝7.0Hz,2H),2.99(t,J＝7.0Hz,2H)；13CNMR(100MHz,DMSO-d6,ppm)δ151.54,148.15,143.10,137.97,137.05,136.04,130.80,129.08,128.76,127.07,124.04,123.63,120.04,111.89,46.26,35.40；MScalcd for:C21H17N3O2[M+H]+344.1394,found344.1397。Compound 55. 1-Phenethyl-2-(4-nitrophenyl)-benzo[d]imidazole: yellow crystal, yield 49%, mp 153.9-154.8°C; 1H NMR (400MHz, DMSO-d6, ppm)δ8.36-8.25(m,2H),7.85-7.70(m,4H),7.40-7.27(m,2H),7.17-7.08(m,3H),6.91-6.79(m,2H),4.61 (t, J=7.0Hz, 2H), 2.99 (t, J=7.0Hz, 2H); 13CNMR (100MHz, DMSO-d6, ppm) δ 151.54, 148.15, 143.10, 137.97, 137.05, 136.04, 130.80, 129.08, 128.76 , 127.07, 124.04, 123.63, 120.04, 111.89, 46.26, 35.40; MScalcd for: C21H17N3O2[M+H]+344.1394, found344.1397.
化合物56. 1-苯乙基-2-苯基-苯并[d]咪唑:白色粉末，产率51％，m.p.90.8-92.1℃；1H NMR(400MHz,CDCl3,ppm)δ7.90-7.77(m,1H),7.49-7.38(m,6H),7.36-7.26(m,2H),7.22-7.13(m,3H),6.94-6.84(m,2H),4.43(t,2H),3.04(t,2H)；13C NMR(100MHz,CDCl3,ppm)δ153.98,143.17,137.38,135.33,130.40,129.64,129.28,128.76,128.63,126.96,122.85,122.50,120.11,110.12,46.18,35.85；MS calcd for:C21H18N2[M+H]+299.1543,found299.1941。Compound 56. 1-Phenethyl-2-phenyl-benzo[d]imidazole: white powder, 51% yield, mp 90.8-92.1°C; 1H NMR (400MHz, CDCl3, ppm) δ 7.90-7.77 ( m,1H),7.49-7.38(m,6H),7.36-7.26(m,2H),7.22-7.13(m,3H),6.94-6.84(m,2H),4.43(t,2H),3.04( t, 2H); 13C NMR (100MHz, CDCl3, ppm) δ153.98, 143.17, 137.38, 135.33, 130.40, 129.64, 129.28, 128.76, 128.63, 126.96, 122.85, 122.50, 120.11, 110.5 calcfor; C21H18N2[M+H]+299.1543, found299.1941.
化合物57. 1-苯乙基-2-戊基-苯并[d]咪唑:黄色粉末，产率49％，m.p.81.6-81.9℃；1H NMR(400MHz,CDCl3,ppm)δ7.78-7.69(m,1H),7.32-7.20(m,6H),6.96(d,J＝6.7Hz,2H),4.26(t,J＝7.0Hz,2H),3.03(t,J＝7.0Hz,2H),2.42(t,2H),1.80-1.63(m,2H),1.38-1.21(m,4H),0.88(t,J＝6.4Hz,3H)；13C NMR(100MHz,CDCl3,ppm)δ155.41,142.80,137.77,134.65,128.83,128.78,127.03,121.81,119.28,109.20,45.28,35.92,31.74,27.22,27.09,22.41,14.04；MS calcd for:C20H24N2[M+H]+293.2012,found293.2029。Compound 57. 1-Phenethyl-2-pentyl-benzo[d]imidazole: yellow powder, 49% yield, mp 81.6-81.9°C; 1H NMR (400MHz, CDCl3, ppm) δ 7.78-7.69 ( m,1H),7.32-7.20(m,6H),6.96(d,J=6.7Hz,2H),4.26(t,J=7.0Hz,2H),3.03(t,J=7.0Hz,2H), 2.42(t, 2H), 1.80-1.63(m, 2H), 1.38-1.21(m, 4H), 0.88(t, J=6.4Hz, 3H); 13C NMR (100MHz, CDCl3, ppm) δ 155.41, 142.80, 137.77, 134.65, 128.83, 128.78, 127.03, 121.81, 119.28, 109.20, 45.28, 35.92, 31.74, 27.22, 27.09, 22.41, 14.04; MS calcd for: C20H24N2[M+H]+2929.20
化合物58. 1-苯乙基-2-甲基-苯并[d]咪唑:白色粉末，产率73％，m.p.83.4-84.2℃；1H NMR(400MHz,DMSO-d6,ppm)δ7.54-7.47(m,2H),7.29-7.05(m,7H),4.39(t,J＝7.1Hz,2H),3.02(t,J＝7.1Hz,2H),2.20(s,3H)；13CNMR(100MHz,DMSO-d6,ppm)δ152.18,142.75,138.74,135.26,129.42,128.85,127.03,121.82,118.62,110.32,45.19,35.50,13.57；MScalcd for:C16H16N2[M+H]+237.1386,found 237.1711。Compound 58. 1-Phenethyl-2-methyl-benzo[d]imidazole: white powder, 73% yield, mp 83.4-84.2°C; 1H NMR (400MHz, DMSO-d6, ppm) δ7.54- 7.47(m, 2H), 7.29-7.05(m, 7H), 4.39(t, J=7.1Hz, 2H), 3.02(t, J=7.1Hz, 2H), 2.20(s, 3H); 13CNMR(100MHz) ,DMSO-d6,ppm)δ152.18,142.75,138.74,135.26,129.42,128.85,127.03,121.82,118.62,110.32,45.19,35.50,13.57; MScalcd for:C16H16N2[M+H]+237.138found
化合物59. 1-苯乙基-2-(四氢呋喃-2-基)-苯并[d]咪唑:白色晶体，产率91％，m.p.103.4℃；1H NMR(400MHz,DMSO-d6,ppm)δ7.66-7.54(m,2H),7.32-7.25(m,2H),7.25-7.20(m,2H),7.20-7.15(m,3H),4.97(t,J＝6.9,6.0Hz,1H),4.61-4.42(m,2H),3.90-3.71(m,2H),3.07(t,J＝7.5Hz,2H),2.67-2.55(m,1H),2.14-1.83(m,3H)；13CNMR(100MHz,DMSO-d6,ppm)δ153.89,142.06,138.81,135.75,129.35,128.91,127.01,122.79,119.70,110.88,72.72,68.37,45.38,35.95,29.11,26.04；MS calcd for:C19H20N2O[M+H]+293.1648,found293.2041。Compound 59. 1-Phenethyl-2-(tetrahydrofuran-2-yl)-benzo[d]imidazole: white crystals, 91% yield, mp 103.4°C; 1H NMR (400MHz, DMSO-d6, ppm) δ7 .66-7.54(m, 2H), 7.32-7.25(m, 2H), 7.25-7.20(m, 2H), 7.20-7.15(m, 3H), 4.97(t, J=6.9, 6.0Hz, 1H) , 4.61-4.42(m, 2H), 3.90-3.71(m, 2H), 3.07(t, J=7.5Hz, 2H), 2.67-2.55(m, 1H), 2.14-1.83(m, 3H); 13CNMR (100MHz,DMSO-d6,ppm)δ153.89,142.06,138.81,135.75,129.35,128.91,127.01,122.79,119.70,110.88,72.72,68.37,45.38,35.95,29.11,26.04; ]+293.1648, found293.2041.
化合物60. 1-苯丙基-2-(吡啶-2-基)-苯并[d]咪唑：白色晶体，产率83％，m.p.79.1-80.9℃；1H NMR(400MHz,DMSO-d6,ppm)δ8.65-8.59(m,1H),8.32(d,J＝8.0Hz,1H),8.05-7.95(m,1H),7.74(d,J＝7.5Hz,1H),7.63(d,J＝7.6Hz,1H),7.54-7.47(m,1H),7.37-7.23(m,4H),7.22-7.14(m,3H),4.82(t,2H),2.66(t,J＝7.5Hz,2H),2.18-2.05(m,2H)；13C NMR(100MHz,DMSO-d6,ppm)δ150.46,149.27,142.59,141.53,137.85,136.87,128.77,128.70,126.33,124.74,124.67,123.63,122.80,120.04,111.28,44.96,32.74,31.67；MS calcd for:C21H19N3[M+H]+314.1652,found 314.1645。Compound 60. 1-Phenylpropyl-2-(pyridin-2-yl)-benzo[d]imidazole: white crystal, yield 83%, mp 79.1-80.9°C; 1H NMR (400MHz, DMSO-d6, ppm )δ8.65-8.59(m,1H),8.32(d,J=8.0Hz,1H),8.05-7.95(m,1H),7.74(d,J=7.5Hz,1H),7.63(d,J =7.6Hz,1H),7.54-7.47(m,1H),7.37-7.23(m,4H),7.22-7.14(m,3H),4.82(t,2H),2.66(t,J=7.5Hz, 2H), 2.18-2.05 (m, 2H); 13C NMR (100MHz, DMSO-d6, ppm) δ 150.46, 149.27, 142.59, 141.53, 137.85, 136.87, 128.77, 128.70, 126.33, 124.74, 124.67, 120.64, 12 , 111.28, 44.96, 32.74, 31.67; MS calcd for: C21H19N3[M+H]+314.1652, found 314.1645.
化合物61. 1-苯丙基-2-(吡啶-3-基)-苯并[d]咪唑：黄色晶体，产率83％，m.p.97.5-98.3℃；1HNMR(400MHZ,CD3OD,ppm)δ8.76-8.77(1H,m),8.60-8.61(1H,m),7.95-7.98(1H,m),7.61-7.63(1H,m),7.44-7.47(2H,m),7.25-7.30(1H,m),7.22-7.25(1H,m),7.09-7.14(2H,m),7.03-7.07(1H,m)；13CNMR(100MHz,CD3OD,ppm)δ150.22,148.97,142.09,137.30,136.38,128.73,127.60,126.58,125.77,123.95,123.70,123.05,118.77,110.94；MS calcd for:C21H19N3[M+H]+314.1652,found314.1538。 Compound 61. 1-Phenylpropyl-2-(pyridin-3-yl)-benzo[d]imidazole: yellow crystal, yield 83%, mp97.5-98.3℃;1HNMR(400MHZ,CD3OD,ppm)δ8. 76-8.77(1H,m), 8.60-8.61(1H,m), 7.95-7.98(1H,m), 7.61-7.63(1H,m), 7.44-7.47(2H,m), 7.25-7.30(1H ,m),7.22-7.25(1H,m),7.09-7.14(2H,m),7.03-7.07(1H,m); 13CNMR(100MHz,CD3OD,ppm)δ150.22,148.97,142.09,137.30,136.38,128.73 , 127.60, 126.58, 125.77, 123.95, 123.70, 123.05, 118.77, 110.94; MS calcd for: C21H19N3[M+H]+314.1652, found314.1538.
化合物62. 1-苯丙基-2-(吡啶-4-基)-苯并[d]咪唑：白色晶体，产率81％，m.p.115.3-116.4℃；1HNMR(400MHz,CDCl3,ppm)δ8.70(dd,J＝4.4,1.6Hz,2H),7.93-7.75(m,1H),7.64-7.46(m,2H),7.37-7.33(m,3H),7.33-7.31(m,1H),7.31-7.27(m,2H),7.17-7.06(m,2H),4.27(t,2H),2.66(t,J＝7.2Hz,2H),2.29-2.12(m,2H)；13CNMR(100MHz,CDCl3,ppm)δ150.34,143.06,139.92,138.11,135.81,128.73,128.33,126.60,123.65,123.26,122.98,120.48,110.22,44.07,32.74,31.16；MS calcd for:C21H19N3[M+H]+314.1652,found314.1652。Compound 62. 1-Phenylpropyl-2-(pyridin-4-yl)-benzo[d]imidazole: white crystal, yield 81%, mp115.3-116.4℃;1HNMR(400MHz,CDCl3,ppm)δ8. 70(dd,J=4.4,1.6Hz,2H),7.93-7.75(m,1H),7.64-7.46(m,2H),7.37-7.33(m,3H),7.33-7.31(m,1H), 7.31-7.27(m, 2H), 7.17-7.06(m, 2H), 4.27(t, 2H), 2.66(t, J=7.2Hz, 2H), 2.29-2.12(m, 2H); 13CNMR(100MHz, CDCl3, ppm) δ150.34,143.06,139.92,138.11,135.81,128.73,128.33,126.60,123.65,123.26,122.98,120.48,110.22,44.07,32.74,31.16; MS calcd for: C21H19N3 [M + H] + 314.1652, found314 .1652.
化合物63. 1-苯丙基-2-(2-氯苯基)-苯并[d]咪唑：黄色粉末，产率82％，m.p.104.6-105.2℃；1H NMR(400MHz,DMSO-d6,ppm)δ7.74-7.68(m,1H),7.68-7.59(m,4H),7.56-7.49(m,1H),7.36-7.24(m,2H),7.23-7.09(m,3H),7.03-6.95(m,2H),4.07(t,J＝7.4Hz,2H),2.44(t,J＝7.6Hz,2H),1.98-1.81(m,2H)；13CNMR(100MHz,DMSO-d6,ppm)δ150.76,143.03,141.01,135.10,133.50,132.78,132.26,130.37,130.13,128.75,128.39,127.91,126.33,123.11,122.39,119.88,111.24,43.73,32.37,30.93；MS calcd for:C22H19ClN2[M+H]+347.1310,found 347.1319。Compound 63. 1-Phenylpropyl-2-(2-chlorophenyl)-benzo[d]imidazole: yellow powder, 82% yield, mp 104.6-105.2°C; 1H NMR (400MHz, DMSO-d6, ppm )δ7.74-7.68(m,1H),7.68-7.59(m,4H),7.56-7.49(m,1H),7.36-7.24(m,2H),7.23-7.09(m,3H),7.03- 6.95 (m, 2H), 4.07 (t, J=7.4Hz, 2H), 2.44 (t, J=7.6Hz, 2H), 1.98-1.81 (m, 2H); 13CNMR (100MHz, DMSO-d6, ppm) δ150.76,143.03,141.01,135.10,133.50,132.78,132.26,130.37,130.13,128.75,128.39,127.91,126.33,123.11,122.39,119.88,111.24,43.73,32.37,30.93; MS calcd for: C22H19ClN2 [M + H] +347.1310, found 347.1319.
化合物64. 1-苯丙基-2-(3-氯苯基)-苯并[d]咪唑：白色晶体，产率85％，m.p.109.5-112.2℃；1H NMR(400MHz,CDCl3,ppm)δ7.85-7.80(m,1H),7.72(t,J＝1.8Hz,1H),7.53-7.45(m,2H),7.38(t,J＝7.8Hz,1H),7.34-7.30(m,3H),7.30-7.27(m,2H),7.24-7.18(m,1H),7.11-7.06(m,2H),4.23(t,J＝6.9Hz,2H),2.62(t,J＝7.4Hz,2H),2.21-2.11(m,2H)；13CNMR(100MHz,CDCl3,ppm)δ152.00,142.99,140.10,135.57,134.84,130.01,129.87,129.48,128.64,128.24,127.19,126.41,123.12,122.67,120.17,110.10,44.13,32.80,31.03；MS calcd for:C22H19ClN2[M+H]+347.1310,found 347.1320。 Compound 64. 1-Phenylpropyl-2-(3-chlorophenyl)-benzo[d]imidazole: white crystal, 85% yield, mp 109.5-112.2°C; 1H NMR (400MHz, CDCl3, ppm)δ7 .85-7.80(m, 1H), 7.72(t, J=1.8Hz, 1H), 7.53-7.45(m, 2H), 7.38(t, J=7.8Hz, 1H), 7.34-7.30(m, 3H ), 7.30-7.27(m, 2H), 7.24-7.18(m, 1H), 7.11-7.06(m, 2H), 4.23(t, J=6.9Hz, 2H), 2.62(t, J=7.4Hz, 2H),2.21-2.11(m,2H);13CNMR(100MHz,CDCl3,ppm)δ152.00,142.99,140.10,135.57,134.84,130.01,129.87,129.48,128.64,128.24,127.19,126,41,1203.7. 110.10, 44.13, 32.80, 31.03; MS calcd for: C22H19ClN2[M+H]+347.1310, found 347.1320.
化合物65. 1-苯丙基-2-(4-氯苯基)-苯并[d]咪唑：白色晶体，产率87％，m.p.138.7-139.2℃；1H NMR(400MHz,CDCl3,ppm)δ7.84-7.78(m,1H),7.56(d,J＝8.3Hz,2H),7.42(d,J＝8.4Hz,2H),7.32(dd,J＝4.2,3.6Hz,1H),7.30-7.19(m,5H),7.07(d,J＝7.1Hz,2H),4.25-4.16(m,2H),2.60(t,J＝7.3Hz,2H),2.20-2.09(m,2H)；13CNMR(100MHz,CDCl3,ppm)δ152.36,143.05,140.11,135.94,135.61,130.49,129.05,128.65,128.29,126.42,122.99,122.60,120.07,110.05,43.99,32.75,31.03；MS calcd for:C22H19ClN2[M+H]+347.1310,found 347.1306。Compound 65. 1-Phenylpropyl-2-(4-chlorophenyl)-benzo[d]imidazole: white crystal, 87% yield, mp 138.7-139.2°C; 1H NMR (400MHz, CDCl3, ppm)δ7 .84-7.78(m,1H),7.56(d,J=8.3Hz,2H),7.42(d,J=8.4Hz,2H),7.32(dd,J=4.2,3.6Hz,1H),7.30- 7.19 (m, 5H), 7.07 (d, J=7.1Hz, 2H), 4.25-4.16 (m, 2H), 2.60 (t, J=7.3Hz, 2H), 2.20-2.09 (m, 2H); (100MHz, CDCl3, ppm) δ152.36,143.05,140.11,135.94,135.61,130.49,129.05,128.65,128.29,126.42,122.99,122.60,120.07,110.05,43.99,32.75,31.03; MS calcd for: C22H19ClN2 [M + H ]+347.1310, found 347.1306.
化合物66. 1-苯丙基-2-(邻甲苯基)-苯并[d]咪唑：黄色粉末，产率87％，m.p.70.6-71.2℃；1H NMR(400MHz,DMSO-d6,ppm)δ7.72-7.65(m,1H),7.62-7.55(m,1H),7.51-7.43(m,1H),7.43-7.37(m,2H),7.34(d,J＝7.7Hz,1H),7.30-7.23(m,2H),7.22-7.09(m,3H),7.01-6.94(m,2H),4.06(t,2H),2.42(t,J＝7.6Hz,2H),2.16(s,3H),1.95-1.80(m,2H)；13CNMR(100MHz,DMSO-d6,ppm)δ153.04,143.12,141.02,137.79,135.07,130.83,130.35,130.15,128.74,128.40,126.32,126.23,122.69,122.17,119.62,111.10,43.57,32.40,30.95,19.82；MS calcd for:C23H22N2[M+H]+327.1856,found 327.1858。 Compound 66. 1-Phenylpropyl-2-(o-tolyl)-benzo[d]imidazole: yellow powder, 87% yield, mp70.6-71.2°C; 1H NMR (400MHz, DMSO-d6, ppm)δ7 .72-7.65(m, 1H), 7.62-7.55(m, 1H), 7.51-7.43(m, 1H), 7.43-7.37(m, 2H), 7.34(d, J=7.7Hz, 1H), 7.30 -7.23(m, 2H), 7.22-7.09(m, 3H), 7.01-6.94(m, 2H), 4.06(t, 2H), 2.42(t, J=7.6Hz, 2H), 2.16(s, 3H) The , 111.10, 43.57, 32.40, 30.95, 19.82; MS calcd for: C23H22N2[M+H]+327.1856, found 327.1858.
化合物67. 1-苯丙基-2-(间甲苯基)-苯并[d]咪唑：白色粉末，产率88％，m.p.68.3-69.7℃；1H NMR(400MHz,DMSO-d6,ppm)δ7.70-7.63(m,1H),7.61-7.54(m,1H),7.52(s,1H),7.49-7.31(m,3H),7.31-7.20(m,4H),7.19-7.15(m,1H),7.11-7.06(m,2H),4.27(t,2H),2.54(t,2H),2.39(s,3H),2.09-1.99(m,2H)；13CNMR(100MHz,DMSO-d6,ppm)δ153.46,143.10,141.06,138.48,136.05,130.67,130.10,128.98,128.75,128.61,126.47,126.38,122.79,122.34,119.59,111.15,44.08,32.48,31.11,21.47；MS calcd for:C 23H22N2[M+H]+327.1856,found 327.1870。Compound 67. 1-Phenylpropyl-2-(m-tolyl)-benzo[d]imidazole: white powder, 88% yield, mp 68.3-69.7°C; 1H NMR (400MHz, DMSO-d6, ppm) δ7 .70-7.63(m, 1H), 7.61-7.54(m, 1H), 7.52(s, 1H), 7.49-7.31(m, 3H), 7.31-7.20(m, 4H), 7.19-7.15(m, 1H), 7.11-7.06(m, 2H), 4.27(t, 2H), 2.54(t, 2H), 2.39(s, 3H), 2.09-1.99(m, 2H); 13CNMR(100MHz, DMSO-d6, ppm) δ153.46,143.10,141.06,138.48,136.05,130.67,130.10,128.98,128.75,128.61,126.47,126.38,122.79,122.34,119.59,111.15,44.08,32.48,31.11,21.47; MS calcd for: C 23H22N2 [M +H]+327.1856, found 327.1870.
化合物68. 1-苯丙基-2-(对甲苯基)-苯并[d]咪唑：白色粉末,产率88％，m.p.90.6-91.6℃；1H NMR(400MHz,DMSO-d6,ppm)δ7.67(dd,J＝7.0,1.5Hz,1H),7.59(d,J＝8.1Hz,3H),7.31(dd,J＝10.2,4.6Hz,2H),7.29-7.21(m,4H),7.21-7.15(m,1H),7.13-7.07(m,2H),4.27(t,2H),2.53(t,2H),2.41(s,3H),2.09-1.97(m,2H)；13CNMR(100MHz,DMSO-d6,ppm)δ153.44,143.11,141.13,139.70,136.11,129.75,129.42,128.80,128.68,126.41,122.74,122.33,119.56,111.17,44.03,32.43,31.13,21.44；MS calcd for:C23H22N2[M+H]+327.1856,found 327.1877。Compound 68. 1-Phenylpropyl-2-(p-tolyl)-benzo[d]imidazole: white powder, 88% yield, mp90.6-91.6℃; 1H NMR (400MHz, DMSO-d6, ppm)δ7 .67(dd,J＝7.0,1.5Hz,1H),7.59(d,J＝8.1Hz,3H),7.31(dd,J＝10.2,4.6Hz,2H),7.29-7.21(m,4H), 7.21-7.15(m, 1H), 7.13-7.07(m, 2H), 4.27(t, 2H), 2.53(t, 2H), 2.41(s, 3H), 2.09-1.97(m, 2H); 13CNMR( 100MHz, DMSO-d6, ppm) δ153.44,143.11,141.13,139.70,136.11,129.75,129.42,128.80,128.68,126.41,122.74,122.33,119.56,111.17,44.03,32.43,31.13,21.44; MS calcd for: C23H22N2 [ M+H]+327.1856, found 327.1877.
化合物69. 1-苯丙基-2-(2-硝基苯基)-苯并[d]咪唑：黄色晶体，产率85％，m.p.92.7-93.5℃；1H NMR(400MHz,CDCl3,ppm)δ8.18(dd,J＝7.7,1.6Hz,1H),7.78(dd,J＝7.1,4.2Hz,1H),7.75-7.65(m,2H),7.56(dd,J＝7.1,1.8Hz,1H),7.31-7.25(m,2H),7.23-7.16(m,4H),7.02(d,J＝7.0Hz,2H),4.00(t,2H),2.56(t,J＝7.5Hz,2H),2.13-2.01(m,2H)；13CNMR(100MHz,CDCl3,ppm)δ149.27,148.74,143.14,140.21,134.90,133.34,132.59,131.01,128.55,128.18,126.28,124.98,123.19,122.48,120.28,110.03,43.93,32.82,30.73；MS calcd for:C22H19N3O2[M+Na]+380.1369,found 380.1376。Compound 69. 1-Phenylpropyl-2-(2-nitrophenyl)-benzo[d]imidazole: yellow crystals, 85% yield, mp 92.7-93.5°C; 1H NMR (400MHz, CDCl3, ppm) δ8.18(dd,J=7.7,1.6Hz,1H),7.78(dd,J=7.1,4.2Hz,1H),7.75-7.65(m,2H),7.56(dd,J=7.1,1.8Hz, 1H), 7.31-7.25(m, 2H), 7.23-7.16(m, 4H), 7.02(d, J=7.0Hz, 2H), 4.00(t, 2H), 2.56(t, J=7.5Hz, 2H) The , 43.93, 32.82, 30.73; MS calcd for: C22H19N3O2[M+Na]+380.1369, found 380.1376.
化合物70. 1-苯丙基-2-(3-硝基苯基)-苯并[d]咪唑：淡黄色晶体，产率87％，m.p.99.6-101.8℃；1H NMR(400MHz,CDCl3,ppm)δ8.54(t,J＝1.9Hz,1H),8.39-8.28(m,1H),8.07-7.96(m,1H),7.89-7.79(m,1H),7.64(t,J＝8.0Hz,1H),7.41-7.31(m,3H),7.26-7.22(m,2H),7.21-7.18(m,1H),7.08(dd,J＝13.4,6.6Hz,2H),4.25(t,J＝6.9Hz,2H),2.65(t,J＝7.3Hz,2H),2.25-2.16(m,2H)；13CNMR(100MHz,CDCl3,ppm)δ150.68,148.25,142.86,139.85,135.16,132.09,129.98,128.65,128.24,126.47,124.40,1 23.95,123.62,123.04,120.32,110.24,4.21,32.74,31.15；MS calcd for:C22H19N3O2[M+Na]+380.1369,found380.1366。Compound 70. 1-Phenylpropyl-2-(3-nitrophenyl)-benzo[d]imidazole: pale yellow crystal, yield 87%, mp 99.6-101.8°C; 1H NMR (400MHz, CDCl3, ppm )δ8.54(t,J=1.9Hz,1H),8.39-8.28(m,1H),8.07-7.96(m,1H),7.89-7.79(m,1H),7.64(t,J=8.0Hz ,1H),7.41-7.31(m,3H),7.26-7.22(m,2H),7.21-7.18(m,1H),7.08(dd,J=13.4,6.6Hz,2H),4.25(t,J =6.9Hz,2H),2.65(t,J=7.3Hz,2H),2.25-2.16(m,2H);13CNMR(100MHz,CDCl3,ppm)δ150.68,148.25,142.86,139.85,135.16,132.09,129.98, 128.65, 128.24, 126.47, 124.40, 1 23.95, 123.62, 123.04, 120.32, 110.24, 4.21, 32.74, 31.15; MS calcd for: C22H19N3O2[M+Na]+380.1369, found380.1366.
化合物71. 1-苯丙基-2-(4-硝基苯基)-苯并[d]咪唑：黄色晶体，产率89％，m.p.143.4-145.2℃；1H NMR(400MHz,DMSO-d6,ppm)δ8.35-8.29(m,2H),8.03-7.97(m,2H),7.72(dd,J＝13.4,7.7Hz,2H),7.39-7.27(m,2H),7.23(t,J＝7.2Hz,2H),7.16(t,J＝7.3Hz,1H),7.11(d,J＝6.9Hz,2H),4.34(t,2H),2.55(t,2H),2.11-1.98(m,2H)；13CNMR(100MHz,CDCl3,ppm)δ150.83,148.28,143.12,139.86,136.63,135.82,130.05,128.72,128.34,126.59,123.90,123.07,120.45,110.25,44.06,32.67,31.10；MS calcd for:C22H19N3O2[M+Na]+380.1369,found380.1363。Compound 71. 1-Phenylpropyl-2-(4-nitrophenyl)-benzo[d]imidazole: yellow crystals, 89% yield, mp 143.4-145.2°C; 1H NMR (400MHz, DMSO-d6, ppm)δ8.35-8.29(m,2H),8.03-7.97(m,2H),7.72(dd,J=13.4,7.7Hz,2H),7.39-7.27(m,2H),7.23(t,J ＝7.2Hz, 2H), 7.16(t, J＝7.3Hz, 1H), 7.11(d, J＝6.9Hz, 2H), 4.34(t, 2H), 2.55(t, 2H), 2.11-1.98(m ,2H);13CNMR(100MHz,CDCl3,ppm)δ150.83,148.28,143.12,139.86,136.63,135.82,130.05,128.72,128.34,126.59,123.90,123.07,120.45,110.25,4.1;3calcd MS31,4.06,3calcd C22H19N3O2[M+Na]+380.1369, found380.1363.
化合物72. 1-苯丙基-2-苯基-苯并[d]咪唑：白色粉末，产率89％，m.p.79.4-81.9℃；1H NMR(400MHz,DMSO-d6,ppm)δ7.73-7.67(m,3H),7.61(dd,J＝7.1,1.2Hz,1H),7.56-7.49(m,3H),7.32-7.22(m,4H),7.20-7.15(m,1H),7.12-7.08(m,2H),4.28(t,2H),2.54(t,2H),2.10-1.98(m,2H)；13CNMR(100MHz,DMSO-d6,ppm)δ153.33,143.10,141.11,136.11,130.90,130.08,129.53,129.17,128.82,128.68,126.43,122.42,119.67,111.27,44.07,32.43,31.12；MS calcd for:C22H20N2[M+H]+313.1699,found 313.1787。Compound 72. 1-Phenylpropyl-2-phenyl-benzo[d]imidazole: white powder, 89% yield, mp 79.4-81.9°C; 1H NMR (400MHz, DMSO-d6, ppm) δ 7.73- 7.67(m,3H),7.61(dd,J=7.1,1.2Hz,1H),7.56-7.49(m,3H),7.32-7.22(m,4H),7.20-7.15(m,1H),7.12- 7.08 (m, 2H), 4.28 (t, 2H), 2.54 (t, 2H), 2.10-1.98 (m, 2H); 13CNMR (100MHz, DMSO-d6, ppm) δ 153.33, 143.10, 141.11, 136.11, 130.90, 130.08, 129.53, 129.17, 128.82, 128.68, 126.43, 122.42, 119.67, 111.27, 44.07, 32.43, 31.12; MS calcd for: C22H20N2[M+H]+313.1699, found 313.1787.
化合物73. 1-苯丙基-2-戊基-苯并[d]咪唑：黄色粉末，产率84％，m.p.91.3-92.1℃；1H NMR(400MHz,CDCl3,ppm)δ7.75-7.70(m,1H),7.32-7.24(m,2H),7.24-7.19(m,2H),7.19-7.14(m,4H),4.02(t,J＝5.2Hz,2H),2.74-2.63(m,4H),2.14-2.03(m,2H),1.87-1.78(m,2H),1.44-1.27(m,4H),0.91(s,3H)；13CNMR(100MHz,CDCl3,ppm)δ155.10,142.76,140.42,134.98,128.66,128.32,126.41,121.74,119.20,109.22,42.83,32.96,31.76,31.09,27.57,27.46,22.47,14.07；MS calcd for:C21H26N2[M+H]+307.2169,found307.2187。Compound 73. 1-Phenylpropyl-2-pentyl-benzo[d]imidazole: yellow powder, 84% yield, mp 91.3-92.1°C; 1H NMR (400MHz, CDCl3, ppm) δ 7.75-7.70 ( m, 1H), 7.32-7.24(m, 2H), 7.24-7.19(m, 2H), 7.19-7.14(m, 4H), 4.02(t, J=5.2Hz, 2H), 2.74-2.63(m, 4H), 2.14-2.03 (m, 2H), 1.87-1.78 (m, 2H), 1.44-1.27 (m, 4H), 0.91 (s, 3H); 13CNMR (100MHz, CDCl3, ppm) δ 155.10, 142.76, 140.42 found
化合物74. 1-苯丙基-2-甲基-苯并[d]咪唑：黄色晶体，产率82％，m.p.91.4-92.1℃；1H NMR(400MHz,DMSO-d6,ppm)δ7.54(d,J＝7.5Hz,1H),7.43(dd,J＝6.7,1.8Hz,1H),7.31-7.25(m,2H),7.23-7.18(m,3H),7.18-7.13(m,2H),4.17(t,J＝7.4Hz,2H),2.63(t,2H),2.51(s,3H),2.06-1.95(m,2H)；13CNMR(100MHz,DMSO-d6,ppm)δ152.00,142.86,141.47,135.55,128.83,128.65,126.42,121.83,118.69,110.13,43.11,32.66,31.21,13.89；MS calcd for:C17H18N2[M+H]+251.1543,found 251.1568。Compound 74. 1-Phenylpropyl-2-methyl-benzo[d]imidazole: yellow crystals, 82% yield, mp 91.4-92.1°C; 1H NMR (400MHz, DMSO-d6, ppm) δ 7.54 ( d, J=7.5Hz, 1H), 7.43 (dd, J=6.7, 1.8Hz, 1H), 7.31-7.25 (m, 2H), 7.23-7.18 (m, 3H), 7.18-7.13 (m, 2H) , 4.17 (t, J=7.4Hz, 2H), 2.63 (t, 2H), 2.51 (s, 3H), 2.06-1.95 (m, 2H); 13CNMR (100MHz, DMSO-d6, ppm) δ152.00, 142.86, 141.47, 135.55, 128.83, 128.65, 126.42, 121.83, 118.69, 110.13, 43.11, 32.66, 31.21, 13.89; MS calcd for: C17H18N2[M+H]+251.1543, found 251.1568.
化合物75 1-苯丙基-2-(四氢呋喃-2-基)-苯并[d]咪唑：白色晶体,产率81％，m.p.115.3-116.4℃；1H NMR(400MHz,DMSO-d6,ppm)δ7.64-7.59(m,1H),7.50(d,J＝7.6Hz,1H),7.33-7.25(m,2H),7.24-7.15(m,5H),5.18(t,J＝7.2,6.3Hz,1H),4.36-4.27(m,2H),3.87-3.70(m,2H),2.72-2.57(m,3H),2.26-2.10(m,2H),2.09-1.89(m,3H)；13CNMR(100MHz,DMSO-d6,ppm)δ153.80,141.56,135.92,128.85,128.69,126.41,122.80,121.99,119.71,110.72,72.85,68.38,43.37,32.74,31.51,29.38,26.06；MS calcd for:C20H22N2O[M+H]+307.1805,found307.1819。Compound 75 1-Phenylpropyl-2-(tetrahydrofuran-2-yl)-benzo[d]imidazole: white crystal, 81% yield, mp 115.3-116.4°C; 1H NMR (400MHz, DMSO-d6, ppm) δ7.64-7.59(m,1H),7.50(d,J=7.6Hz,1H),7.33-7.25(m,2H),7.24-7.15(m,5H),5.18(t,J=7.2,6.3 Hz, 1H), 4.36-4.27(m, 2H), 3.87-3.70(m, 2H), 2.72-2.57(m, 3H), 2.26-2.10(m, 2H), 2.09-1.89(m, 3H); 13CNMR (100MHz, DMSO-d6, ppm) δ153.80,141.56,135.92,128.85,128.69,126.41,122.80,121.99,119.71,110.72,72.85,68.38,43.37,32.74,31.51,29.38,26.06; MS calcd for: C20H22N2O [ M+H]+307.1805, found307.1819.
化合物76. 1-苄基-2-苯基-1H-苯并[d]咪唑-4-甲酰胺：深黄色固体,产率89％.m.p.118.3℃；1H NMR(400MHz,CDCl3)δ9.78(s,1H),8.19(dd,J＝7.2,1.5Hz,1H),7.72(t,J＝1.6Hz,1H),7.70(t,J＝2.0Hz,1H),7.57–7.44(m,3H),7.42–7.28(m,5H),7.10(dd,J＝2.5,1.4Hz,1H),7.09(dd,J＝2.2,1.2Hz,1H),6.15–5.83(m,1H),5.51(s,2H).13CNMR(101MHz,CDCl3)δ167.44,154.31,136.30,135.80,130.50,129.37,129.23,128.94,128.08,125.92,124.70,122.96,122.77,114.38,77.26,48.66；HRMS calcd for:C21H17N3O[M+H]+328.1444,found 328.1443.Compound 76. 1-benzyl-2-phenyl-1H-benzo[d]imidazole-4-carboxamide: dark yellow solid, yield 89%.mp 118.3°C; 1H NMR (400MHz, CDCl3) δ 9.78 (s, 1H), 8.19 (dd, J=7.2, 1.5Hz, 1H), 7.72 (t, J=1.6Hz, 1H), 7.70 (t, J=2.0Hz, 1H), 7.57–7.44 (m, 3H), 7.42–7.28 (m, 5H), 7.10 (dd, J=2.5, 1.4Hz, 1H), 7.09 (dd, J=2.2, 1.2Hz, 1H), 6.15–5.83 (m, 1H), 5.51 (s, 2H) .13CNMR (101MHz, CDCl3) δ167.44,154.31,136.30,135.80,130.50,129.37,129.23,128.94,128.08,125.92,124.70,122.96,122.77,114.38,77.26,48.66; HRMS calcd for: C21H17N3O [ M+H]+328.1444,found 328.1443.
化合物77 1,2-二苄基-1H-苯并[d]咪唑-4-甲酰胺：白色粉末,产率90％.m.p.206-207℃；1H NMR(400MHz,CDCl3)δ9.74(s,1H),8.14(dd,J＝7.3,1.4Hz,1H),7.39–7.15(m,10H),6.97–6.88(m,2H),5.98–5.92(m,1H),5.24(s,2H),4.27(s,2H).13CNMR(101MHz,CDCl3)δ167.49,153.87,140.75,135.49,135.21,129.08,128.93,128.52,128.13,127.25,126.17,124.18,122.5,122.48,113.49,47.42,34.39；HRMS calcd for:C22H19N3O[M+H]+342.1601,found342.1604.Compound 77 1,2-Dibenzyl-1H-benzo[d]imidazole-4-carboxamide: white powder, yield 90%.mp206-207℃;1H NMR(400MHz,CDCl3)δ9.74(s ,1H),8.14(dd,J=7.3,1.4Hz,1H),7.39-7.15(m,10H),6.97-6.88(m,2H),5.98-5.92(m,1H),5.24(s,2H) The calcd for:C22H19N3O[M+H]+342.1601,found342.1604.
化合物78. 1-苄基-2-苯乙基-1H-苯并[d]咪唑-4-甲酰胺:淡黄色粉末,产率93％.m.p.118.3℃；1H NMR(400MHz,CDCl3)δ9.77(s,1H),8.12(dd,J＝7.5,1.2Hz,1H),8.01(s,1H),7.41–7.19(m,8H),7.19–7.12(m,2H),6.99–6.92(m,2H),5.22(s,2H),2.96(s,2H),2.88(s,2H)；13CNMR(101MHz,CDCl3)δ167.71,162.60,155.04,140.49,135.58,129.15,128.64,128.42,128.16,126.52,126.09,124.04,122.32,122.13,113.39,47.00,33.57,29.44；HRMS calcd for:C23H21N3O[M+H]+356.1757,found 356.1756.Compound 78. 1-benzyl-2-phenethyl-1H-benzo[d]imidazole-4-carboxamide: pale yellow powder, yield 93%.mp 118.3℃; 1H NMR (400MHz, CDCl3)δ9. 77(s,1H),8.12(dd,J=7.5,1.2Hz,1H),8.01(s,1H),7.41-7.19(m,8H),7.19-7.12(m,2H),6.99-6.92( m, 2H), 5.22 (s, 2H), 2.96 (s, 2H), 2.88 (s, 2H); 126.52,126.09,124.04,122.32,122.13,113.39,47.00,33.57,29.44; HRMS calcd for:C23H21N3O[M+H]+356.1757,found 356.1756.
化合物79.1-苄基-2-(邻甲苯基)-1H-苯并[d]咪唑-4-甲酰胺:白色粉末，产率79％.m.p.207.9-208.6℃；1H NMR(400MHz,CDCl3)δ10.04–9.50(m,1H),8.19(dd,J＝7.6,1.2Hz,1H),7.46–7.43(m,1H),7.42(t,J＝1.5Hz,1H),7.37(d,J＝2.8Hz,1H),7.35(d,J＝1.9Hz,1H),7.33(d,J＝1.6Hz,1H),7.30(dd,J＝7.4,1.3Hz,1H),7.27(d,J＝2.4Hz,1H),7.25(d,J＝1.4Hz,1H)，7.24(d,J＝1.5Hz,1H),6.98–6.91(m,2H),5.94(s,1H),5.27(s,2H),2.22(s,3H).13CNMR(101MHz,CDCl3)δ167.38,153.83,141.12,135.47,135.05,130.88,130.38,129.88,129.10,128.92,128.06,126.51,125.93,124.47,122.77,114.38,48.22,19.90；HRMS calcd for:C22H19N3O[M+H]+342.1601,found 342.1601.Compound 79. 1-Benzyl-2-(o-tolyl)-1H-benzo[d]imidazole-4-carboxamide: white powder, 79% yield.mp 207.9-208.6°C; 1H NMR (400MHz, CDCl3)δ10 .04–9.50 (m, 1H), 8.19 (dd, J=7.6, 1.2Hz, 1H), 7.46–7.43 (m, 1H), 7.42 (t, J=1.5Hz, 1H), 7.37 (d, J =2.8Hz,1H),7.35(d,J=1.9Hz,1H),7.33(d,J=1.6Hz,1H),7.30(dd,J=7.4,1.3Hz,1H),7.27(d,J ＝2.4Hz, 1H), 7.25(d, J＝1.4Hz, 1H), 7.24(d, J＝1.5Hz, 1H), 6.98–6.91(m, 2H), 5.94(s, 1H), 5.27(s ,2H),2.22(s,3H).13CNMR(101MHz,CDCl3)δ167.38,153.83,141.12,135.47,135.05,130.88,130.38,129.88,129.10,128.92,128.06,126.51,125.94.7,112.4. ,19.90;HRMS calcd for:C22H19N3O[M+H]+342.1601,found 342.1601.
化合物80. 1-苄基-2-(间甲苯基)-1H-苯并[d]咪唑-4-甲酰胺：白色粉末,产率53％.m.p.192.8-193.5℃；1H NMR(400MHz,CDCl3)δ9.87–9.54(m,1H),8.19(dd,J＝7.3,1.4Hz,1H),7.55(d,J＝2.1Hz,1H),7.45(dt,J＝7.0,2.0Hz,1H),7.41–7.36(m,2H),7.36–7.28(m,5H),7.10(d,J＝1.9Hz,1H),7.08(d,J＝1.4Hz,1H),5.99(d,J＝3.9Hz,1H),5.49(s,2H),2.40(s,3H).13CNMR(101MHz,CDCl3)δ167.45,154.54,141.21,138.86,136.30,135.94,131.27,130.22,129.25,129.20,128.75,128.05,126.23,125.98,124.64,122.88,122.74,114.34,48.69,21.44；HRMS calcd for:C22H19N3O[M+H]+342.1601,found342.1598.Compound 80. 1-benzyl-2-(m-tolyl)-1H-benzo[d]imidazole-4-carboxamide: white powder, yield 53%.mp 192.8-193.5℃; 1H NMR (400MHz, CDCl3 )δ9.87–9.54(m,1H),8.19(dd,J=7.3,1.4Hz,1H),7.55(d,J=2.1Hz,1H),7.45(dt,J=7.0,2.0Hz,1H) ), 7.41–7.36 (m, 2H), 7.36–7.28 (m, 5H), 7.10 (d, J=1.9Hz, 1H), 7.08 (d, J=1.4Hz, 1H), 5.99 (d, J= 3.9Hz,1H),5.49(s,2H),2.40(s,3H).13CNMR(101MHz,CDCl3)δ167.45,154.54,141.21,138.86,136.30,135.94,131.27,130.22,129.25,129.20,128.075,128 126.23,125.98,124.64,122.88,122.74,114.34,48.69,21.44; HRMS calcd for:C22H19N3O[M+H]+342.1601,found342.1598.
化合物81 1-苄基-2-(对甲苯基)-1H-苯并[d]咪唑-4-甲酰胺:白色粉末,产率74％.m.p.234.1-234.7℃；1H NMR(400MHz,CDCl3)δ9.95–9.46(m,1H),8.18(dd,J＝7.1,1.5Hz,1H),7.70–7.56(m,2H),7.45–7.27(m,7H),7.19–7.05(m,2H),5.98(d,J＝4.0Hz,1H),5.49(s,2H),2.43(s,3H).13CNMR(101MHz,CDCl3)δ167.49,154.51,140.83,136.32,135.90,129.64,129.26,129.21,128.03,126.43,125.92,124.60,122.78,122.64,114.29,48.65,21.49；HRMS calcd for:C22H19N3O[M+H]+342.1601,found 342.1593.Compound 81 1-benzyl-2-(p-tolyl)-1H-benzo[d]imidazole-4-carboxamide: white powder, yield 74%.mp234.1-234.7℃;1H NMR (400MHz, CDCl3) δ9.95–9.46 (m, 1H), 8.18 (dd, J=7.1, 1.5Hz, 1H), 7.70–7.56 (m, 2H), 7.45–7.27 (m, 7H), 7.19–7.05 (m, 2H) ),5.98(d,J=4.0Hz,1H),5.49(s,2H),2.43(s,3H).13CNMR(101MHz,CDCl3)δ167.49,154.51,140.83,136.32,135.90,129.64,129.26,129.21, 128.03, 126.43, 125.92, 124.60, 122.78, 122.64, 114.29, 48.65, 21.49; HRMS calcd for: C22H19N3O[M+H]+342.1601, found 342.1593.
化合物82. 1-苄基-2-(2-氯苯基)-1H-苯并[d]咪唑-4-甲酰胺:淡黄色粉末,产率72％.m.p.208.2-208.9℃；1H NMR(400MHz,CDCl3)δ9.61(s,1H),8.19(dd,J＝7.5,1.2Hz,1H),7.57(dd,J＝8.1,1.3Hz,1H),7.53–7.46(m,2H),7.42(dd,J＝8.1,1.3Hz,1H),7.40–7.37(m,1H),7.37–7.32(m,1H),7.27(s,1H),7.24(d,J＝2.1Hz,1H),7.23(d,J＝1.5Hz,1H),6.99–6.92(m,2H),5.97(s,1H),5.30(s,2H).13CNMR(101MHz,CDCl3)δ167.36,151.51,141.08,135.25,135.07,134.25,132.30,131.80,130.06,129.28,128.92,128.13,127.14,126.64,124.65,123.14,122.98,114.64,77.27,48.55；HRMS calcd for:C21H16ClN3O[M+H]+362.1055,found 362.1051.Compound 82. 1-benzyl-2-(2-chlorophenyl)-1H-benzo[d]imidazole-4-carboxamide: pale yellow powder, yield 72%.mp 208.2-208.9℃; 1H NMR ( 400MHz, CDCl3)δ9.61(s,1H),8.19(dd,J=7.5,1.2Hz,1H),7.57(dd,J=8.1,1.3Hz,1H),7.53–7.46(m,2H), 7.42(dd,J=8.1,1.3Hz,1H),7.40-7.37(m,1H),7.37-7.32(m,1H),7.27(s,1H),7.24(d,J=2.1Hz,1H) ,7.23(d,J＝1.5Hz,1H),6.99-6.92(m,2H),5.97(s,1H),5.30(s,2H).13CNMR(101MHz,CDCl3)δ167.36,151.51,141.08,135.25, 135.07,134.25,132.30,131.80,130.06,129.28,128.92,128.13,127.14,126.64,124.65,123.14,122.98,114.64,77.27,48.55; HRMS calcd for: C21H16ClN3O [M + H] + 362.1055, found 362.1051.
化合物83. 1-苄基-2-(3-氯苯基)-1H-苯并[d]咪唑-4-甲酰胺:白色粉末,产率92％.m.p.188.3-188.8℃；1H NMR(400MHz,DMSO-d6)δ9.15(d,J＝3.3Hz,1H),7.95(dd,J＝7.6,1.1Hz,1H),7.87(t,J＝1.9Hz,1H),7.83(d,J＝3.3Hz,1H),7.80–7.75(m,2H),7.67(ddd,J＝8.1,2.2,1.2Hz,1H),7.59(t,J＝7.8Hz,1H),7.44–7.38(m,1H),7.34–7.25(m,3H),7.07–7.00(m,2H),5.69(s,2H).13CNMR(101MHz,DMSO-d6)δ166.21,152.73,140.57,136.86,136.75,134.07,131.73,131.34,130.81,129.44,129.36,129.12,128.36,128.18,126.68,124.19,123.57,123.41,115.46,48.31；HRMS calcd for:C21H16ClN3O[M+H]+362.1055,found 362.1053.Compound 83. 1-benzyl-2-(3-chlorophenyl)-1H-benzo[d]imidazole-4-carboxamide: white powder, yield 92%.mp 188.3-188.8°C; 1H NMR (400MHz) ,DMSO-d6)δ9.15(d,J＝3.3Hz,1H),7.95(dd,J＝7.6,1.1Hz,1H),7.87(t,J＝1.9Hz,1H),7.83(d,J = 3.3Hz, 1H), 7.80–7.75 (m, 2H), 7.67 (ddd, J=8.1, 2.2, 1.2Hz, 1H), 7.59 (t, J=7.8Hz, 1H), 7.44–7.38 (m, 1H),7.34–7.25(m,3H),7.07–7.00(m,2H),5.69(s,2H).13CNMR(101MHz,DMSO-d6)δ166.21,152.73,140.57,136.86,136.75,134.07,131.73, 131.34, 130.81, 129.44, 129.36, 129.12, 128.36, 128.18, 126.68, 124.19, 123.57, 123.41, 115.46, 48.31; HRMS calcd for: C21H16ClN3O[M+H]+362.1055, found3
化合物84. 1-苄基-2-(4-氯苯基)-1H-苯并[d]咪唑-4-甲酰胺:淡黄色粉末,产率64％.m.p.215.9-216.5℃；1H NMR(400MHz,DMSO-d6)δ9.18(d,J＝3.4Hz,1H),7.95(dd,J＝7.6,1.1Hz,1H),7.89–7.81(m,3H),7.75(dd,J＝8.1,1.1Hz,1H),7.69–7.61(m,2H),7.39(t,J＝7.9Hz,1H),7.33–7.24(m,3H),7.05–6.99(m,2H),5.69(s,2H).13CNMR(101MHz,DMSO-d6)δ166.25,153.16,140.65,136.84,136.74,135.82,131.54,129.56,129.36,128.58,128.16,126.67,124.12,123.45,123.27,115.43,48.26；HRMS calcd for:C21H16ClN3O[M+H]+362.1055,found362.1058.Compound 84. 1-benzyl-2-(4-chlorophenyl)-1H-benzo[d]imidazole-4-carboxamide: pale yellow powder, yield 64%.mp215.9-216.5℃;1H NMR( 400MHz, DMSO-d6)δ9.18(d,J=3.4Hz,1H),7.95(dd,J=7.6,1.1Hz,1H),7.89-7.81(m,3H),7.75(dd,J=8.1 ,1.1Hz,1H),7.69-7.61(m,2H),7.39(t,J=7.9Hz,1H),7.33-7.24(m,3H),7.05-6.99(m,2H),5.69(s, 2H) .13CNMR (101MHz, DMSO-d6) δ166.25,153.16,140.65,136.84,136.74,135.82,131.54,129.56,129.36,128.58,128.16,126.67,124.12,123.45,123.27,115.43,48.26; HRMS calcd for: C21H16ClN3O [M+H]+362.1055,found362.1058.
化合物85. 1-苄基-2-(3-硝基苯基)-1H-苯并[d]咪唑-4-甲酰胺:黄色粉末,产率80％.m.p.225.9-226.5℃；1H NMR(400MHz,CDCl3)δ9.59(s,1H),8.60(t,J＝2.0Hz,1H),8.37(ddd,J＝8.3,2.3,1.1Hz,1H),8.25(dd,J＝7.4,1.3Hz,1H),8.08–7.99(m,1H),7.68(t,J＝8.0Hz,1H),7.49(dd,J＝8.2,1.3Hz,1H),7.48–7.38(m,1H),7.42–7.30(m,3H),7.13–7.05(m,2H),5.99(s,1H),5.55(s,2H).13CNMR(101MHz,CDCl3)δ167.01,151.43,148.48,136.54,135.15,134.91,131.09,130.10,129.48,128.50,125.80,125.40,125.00,124.41,123.90,123.20,114.44,48.80；HRMS calcd for:C21H16N4O3[M+H]+373.1295,found373.1290.Compound 85. 1-benzyl-2-(3-nitrophenyl)-1H-benzo[d]imidazole-4-carboxamide: yellow powder, yield 80%.mp225.9-226.5℃;1H NMR( 400MHz, CDCl3)δ9.59(s,1H),8.60(t,J=2.0Hz,1H),8.37(ddd,J=8.3,2.3,1.1Hz,1H),8.25(dd,J=7.4,1.3 Hz, 1H), 8.08–7.99 (m, 1H), 7.68 (t, J=8.0Hz, 1H), 7.49 (dd, J=8.2, 1.3Hz, 1H), 7.48–7.38 (m, 1H), 7.42 –7.30(m,3H),7.13–7.05(m,2H),5.99(s,1H),5.55(s,2H).13CNMR(101MHz,CDCl3)δ167.01,151.43,148.48,136.54,135.15,134.91,131.09 ,130.10,129.48,128.50,125.80,125.40,125.00,124.41,123.90,123.20,114.44,48.80; HRMS calcd for:C21H16N4O3[M+H]+373.1295,found373.1290.
化合物86. 1-苄基-2-(4-硝基苯基)-1H-苯并[d]咪唑-4-甲酰胺:深黄色粉末,产率78％.m.p.250.6-251.3℃；1H NMR(400MHz,CDCl3)δ9.58(s,1H),8.39–8.30(m,2H),8.25(dd,J＝7.0,1.8Hz,1H),7.95–7.87(m,2H),7.50–7.32(m,5H),7.12–7.05(m,2H),5.96(s,1H),5.54(s,2H).13CNMR(101MHz,CDCl3)δ166.94,140.96,136.58,135.38,130.30,129.50,128.47,125.68,125.48,124.08,124.03,123.27,114.48,48.79；HRMS calcd for:C21H16N4O3[M+H]+373.1295,found 373.1289.Compound 86. 1-benzyl-2-(4-nitrophenyl)-1H-benzo[d]imidazole-4-carboxamide: dark yellow powder, yield 78%.mp250.6-251.3℃;1H NMR (400MHz, CDCl3)δ9.58(s,1H),8.39-8.30(m,2H),8.25(dd,J=7.0,1.8Hz,1H),7.95-7.87(m,2H),7.50-7.32( m,5H),7.12–7.05(m,2H),5.96(s,1H),5.54(s,2H).13CNMR(101MHz,CDCl3)δ166.94,140.96,136.58,135.38,130.30,129.50,128.47,125.68, 125.48, 124.08, 124.03, 123.27, 114.48, 48.79; HRMS calcd for: C21H16N4O3[M+H]+373.1295, found 373.1289.
化合物87. 1-苄基-2-(3-氟苯基)-1H-苯并[d]咪唑-4-甲酰胺:白色固体,产率45％.m.p.189.7-191.5℃；1H NMR(400MHz,CDCl3)δ9.68(s,1H),8.21(dd,J＝7.1,1.6Hz,1H),7.52–7.28(m,8H),7.23(ddt,J＝8.3,4.6,2.7Hz,1H),7.12–7.04(m,2H),5.99(s,1H),5.52(s,2H).13CNMR(101MHz,CDCl3)δ167.25,163.98,152.80(d,J＝2.9Hz),141.00,136.35,135.51,131.31,130.70,130.61,129.33,128.23,125.85,124.99,124.92,124.89,123.35,122.95,117.68,117.47,116.77,116.54,114.43,77.24,48.69；HRMS calcd for:C21H16FN3O[M+H]+346.1350,found 346.1353.Compound 87. 1-benzyl-2-(3-fluorophenyl)-1H-benzo[d]imidazole-4-carboxamide: white solid, 45% yield.mp 189.7-191.5°C; 1H NMR (400MHz) , CDCl3)δ9.68(s,1H),8.21(dd,J=7.1,1.6Hz,1H),7.52–7.28(m,8H),7.23(ddt,J=8.3,4.6,2.7Hz,1H) ,7.12–7.04(m,2H),5.99(s,1H),5.52(s,2H).13CNMR(101MHz,CDCl3)δ167.25,163.98,152.80(d,J=2.9Hz),141.00,136.35,135.51, 131.31,130.70,130.61,129.33,128.23,125.85,124.99,124.92,124.89,123.35,122.95,117.68,117.47,116.77,116.54,114.43,77.24,48.69; HRMS calcd for: C21H16FN3O [M + H] + 346.1350, found 346.1353.
化合物88. 1-苄基-2-(4-氟苯基)-1H-苯并[d]咪唑-4-甲酰胺:白色固体,产率65％.m.p.227.0-227.5℃；1H NMR(400MHz,CDCl3)δ9.71(s,1H),8.20(dd,J＝7.1,1.6Hz,1H),7.72–7.67(m,2H),7.41–7.32(m,5H),7.22–7.15(m,2H),7.11–7.06(m,2H),5.97(s,1H),5.49(s,2H).13CNMR(101MHz,CDCl3)δ167.31,153.32,141.06,136.33,135.64,131.47,131.39,129.32,128.19,125.82,124.86,123.1 2,122.80,116.30,116.08,114.31,77.24,48.64；HRMS calcd for:C21H16FN3O[M+H]+346.1350,found 346.1344.Compound 88. 1-benzyl-2-(4-fluorophenyl)-1H-benzo[d]imidazole-4-carboxamide: white solid, 65% yield.mp 227.0-227.5°C; 1H NMR (400MHz) , CDCl3)δ9.71(s,1H),8.20(dd,J=7.1,1.6Hz,1H),7.72–7.67(m,2H),7.41–7.32(m,5H),7.22–7.15(m, 2H),7.11–7.06(m,2H),5.97(s,1H),5.49(s,2H).13CNMR(101MHz,CDCl3)δ167.31,153.32,141.06,136.33,135.64,131.47,131.39,129.32,128.19, 125.82, 124.86, 123.1 2, 122.80, 116.30, 116.08, 114.31, 77.24, 48.64; HRMS calcd for: C21H16FN3O[M+H]+346.1350, found 346.1344.
化合物89. 1-苄基-2-(吡啶-2-基)-1H-苯并[d]咪唑-4-甲酰胺:黄色固体,产率31％.m.p.℃；1H NMR(400MHz,CDCl3)δ9.87–9.59(m,1H),8.65(dt,J＝4.8,1.3Hz,1H),8.44(d,J＝7.9Hz,1H),8.18(dd,J＝7.6,1.0Hz,1H),7.87(td,J＝7.8,1.8Hz,1H),7.50(dd,J＝8.2,1.0Hz,1H),7.40–7.33(m,2H),7.29–7.22(m,3H),7.19–7.13(m,2H),6.25(s,2H),6.16(s,1H).13CNMR(101MHz,CDCl3)δ167.47,149.90,148.85,140.64,137.07,136.98,136.89,128.73,127.63,126.78,125.04,124.94,124.40,123.46,122.84,114.69,49.24；HRMScalcd for:C20H16N4O[M+H]+329.1397,found 329.1398.Compound 89. 1-benzyl-2-(pyridin-2-yl)-1H-benzo[d]imidazole-4-carboxamide: yellow solid, 31% yield.mp°C; 1H NMR (400MHz, CDCl3) δ9.87–9.59(m,1H),8.65(dt,J=4.8,1.3Hz,1H),8.44(d,J=7.9Hz,1H),8.18(dd,J=7.6,1.0Hz,1H) ,7.87(td,J=7.8,1.8Hz,1H),7.50(dd,J=8.2,1.0Hz,1H),7.40-7.33(m,2H),7.29-7.22(m,3H),7.19-7.13 (m,2H),6.25(s,2H),6.16(s,1H).13CNMR(101MHz,CDCl3)δ167.47,149.90,148.85,140.64,137.07,136.98,136.89,128.73,127.63,126.78,125.04,124.94 124.40, 123.46, 122.84, 114.69, 49.24; HRMScalcd for: C20H16N4O[M+H]+329.1397, found 329.1398.
化合物90. 1-苄基-2-(吡啶-3-基)-1H-苯并[d]咪唑-4-甲酰胺:黄色固体,产率39％.m.p.℃；1H NMR(400MHz,CDCl3)δ9.80–9.53(m,1H),8.97(d,J＝2.1Hz,1H),8.76(dd,J＝4.9,1.7Hz,1H),8.22(dd,J＝7.4,1.3Hz,1H),8.03(dt,J＝7.9,2.0Hz,1H),7.47–7.41(m,2H),7.41–7.30(m,4H),7.07(dd,J＝7.4,1.9Hz,2H),6.25–6.01(m,1H),5.53(s,2H).13CNMR(101MHz,CDCl3)δ167.20,151.31,151.25,149.84,141.09,136.68,136.39,135.31,129.40,128.34,125.75,125.11,123.63,123.56,123.03,114.43,48.66；HRMS calcd for:C20H16N4O[M+H]+329.1397,found 329.1390. Compound 90. 1-benzyl-2-(pyridin-3-yl)-1H-benzo[d]imidazole-4-carboxamide: yellow solid, yield 39%.mp°C; 1H NMR (400MHz, CDCl3) δ9.80–9.53(m,1H),8.97(d,J=2.1Hz,1H),8.76(dd,J=4.9,1.7Hz,1H),8.22(dd,J=7.4,1.3Hz,1H) , 8.03 (dt, J=7.9, 2.0Hz, 1H), 7.47–7.41 (m, 2H), 7.41–7.30 (m, 4H), 7.07 (dd, J=7.4, 1.9Hz, 2H), 6.25–6.01 (m,1H),5.53(s,2H).13CNMR(101MHz,CDCl3)δ167.20,151.31,151.25,149.84,141.09,136.68,136.39,135.31,129.40,128.34,125.75,125.11,123.63,123.5.3 ,48.66;HRMS calcd for:C20H16N4O[M+H]+329.1397,found 329.1390.
化合物91. 1-苄基-2-(呋喃-2-基)-1H-苯并[d]咪唑-4-甲酰胺:淡黄色粉末,产率42％.m.p.208.1-208.8℃；1H NMR(400MHz,CDCl3)δ9.64(s,1H),8.17(dd,J＝7.5,1.1Hz,1H),7.61(dd,J＝1.8,0.8Hz,1H),7.45(dd,J＝8.1,1.1Hz,1H),7.37–7.31(m,2H),7.31–7.27(m,2H),7.26(s,1H),7.17(dd,J＝3.4,0.8Hz,1H),7.16–7.10(m,2H),6.60(dd,J＝3.5,1.8Hz,1H),5.77(s,2H).13CNMR(101MHz,CDCl3)δ167.29,144.67,141.23,136.04,135.88,129.05,128.02,126.27,125.00,123.10,122.56,114.13,113.84,112.21,77.23,48.68；HRMS calcd for:C19H15N3O2[M+H]+318.1237,found318.1236.Compound 91. 1-benzyl-2-(furan-2-yl)-1H-benzo[d]imidazole-4-carboxamide: pale yellow powder, yield 42%.mp 208.1-208.8℃; 1H NMR ( 400MHz, CDCl3)δ9.64(s,1H),8.17(dd,J=7.5,1.1Hz,1H),7.61(dd,J=1.8,0.8Hz,1H),7.45(dd,J=8.1,1.1 Hz, 1H), 7.37–7.31 (m, 2H), 7.31–7.27 (m, 2H), 7.26 (s, 1H), 7.17 (dd, J=3.4, 0.8Hz, 1H), 7.16–7.10 (m, 2H),6.60(dd,J=3.5,1.8Hz,1H),5.77(s,2H).13CNMR(101MHz,CDCl3)δ167.29,144.67,141.23,136.04,135.88,129.05,128.02,126.27,125.00,123.10, 122.56,114.13,113.84,112.21,77.23,48.68; HRMS calcd for:C19H15N3O2[M+H]+318.1237,found318.1236.
化合物92. 1-苄基-2-(噻吩-2-基)-1H-苯并[d]咪唑-4-甲酰胺:棕黄色粉末,产率35％.m.p.212.3-212.9℃；1H NMR(400MHz,CDCl3)δ9.95–9.40(m,1H),8.19(dd,J＝7.5,1.2Hz,1H),7.54(dd,J＝5.1,1.0Hz,1H),7.40(dd,J＝8.1,1.2Hz,1H),7.39–7.31(m,5H),7.15–7.07(m,3H),6.07(s,1H),5.65(s,2H).13CNMR(101MHz,CDCl3)δ167.34,148.28,141.03,136.59,135.43,131.22,129.71,129.33,128.58,128.17,125.79,124.97,123.15,122.53,113.79,48.48；HRMS calcd for:C19H15N3OS[M+H]+334.1009,found334.1020.Compound 92. 1-benzyl-2-(thiophen-2-yl)-1H-benzo[d]imidazole-4-carboxamide: tan powder, yield 35%.mp212.3-212.9℃;1H NMR( 400MHz, CDCl3)δ9.95-9.40(m,1H),8.19(dd,J=7.5,1.2Hz,1H),7.54(dd,J=5.1,1.0Hz,1H),7.40(dd,J=8.1 ,1.2Hz,1H),7.39–7.31(m,5H),7.15–7.07(m,3H),6.07(s,1H),5.65(s,2H).13CNMR(101MHz,CDCl3)δ167.34,148.28,141.03 ,136.59,135.43,131.22,129.71,129.33,128.58,128.17,125.79,124.97,123.15,122.53,113.79,48.48; HRMS calcd for:C19H15N3OS[M+H]+334.1009,found33
化合物93. 1-苄基-2-环己基-1H-苯并[d]咪唑-4-甲酰胺:白色固体,产率96％.m.p.242.5-243.2℃；1H NMR(400MHz,CDCl3)δ9.87(s,1H),8.10(dd,J＝7.5,1.2Hz,1H),7.38–7.21(m,6H),7.07–6.99(m,2H),5.40(s,2H),2.88(s,1H),1.84–1.72(m,4H),1.40–1.28(m,6H).13CNMR(101MHz,CDCl3)δ167.82,159.84,135.73,135.37,129.11,128.10,126.05,123.82,122.09,122.04,113.49,47.02,36.48,33.32,26.08,25.71；HRMS calcdfor:C21H23N3O[M+H]+334.1914,found 334.1916.Compound 93. 1-benzyl-2-cyclohexyl-1H-benzo[d]imidazole-4-carboxamide: white solid, yield 96%.mp242.5-243.2℃;1H NMR(400MHz,CDCl3)δ9. 87(s, 1H), 8.10(dd, J=7.5, 1.2Hz, 1H), 7.38-7.21(m, 6H), 7.07-6.99(m, 2H), 5.40(s, 2H), 2.88(s, 1H),1.84–1.72(m,4H),1.40–1.28(m,6H).13CNMR(101MHz,CDCl3)δ167.82,159.84,135.73,135.37,129.11,128.10,126.05,123.82,122.09,122.04,113.49 ,36.48,33.32,26.08,25.71; HRMS calcdfor:C21H23N3O[M+H]+334.1914,found 334.1916.
化合物94. 1-(3-苯丙基)-2-(吡啶-2-基)-1H-苯并[d]咪唑-4-甲酰胺:黄色粉末,产率45％.m.p.184.3-185.4℃；1H NMR(400MHz,CDCl3)δ9.75(d,J＝4.2Hz,1H),8.59(dd,J＝5.0,1.6Hz,1H),8.39(d,J＝7.9Hz,1H),8.18(dd,J＝7.5,1.1Hz,1H),7.84(td,J＝7.8,1.8Hz,1H),7.48–7.43(m,1H),7.40(d,J＝7.7Hz,1H),7.38–7.33(m,1H),7.29(t,J＝7.4Hz,2H),7.22(d,J＝7.2Hz,1H),7.18(d,J＝1.6Hz,1H),7.16(s,1H),6.24(d,J＝4.2Hz,1H),4.97–4.64(m,2H),2.73(t,J＝7.4Hz,2H),2.25(p,J＝7.5Hz,2H).13CNMR(101MHz,CDCl3)δ167.61,149.81,148.82,140.83,140.55,136.85,128.49,128.39,126.18,124.90,124.71,124.19,123.14,122.78,113.98,45.38,33.06,31.32；HRMS calcd for:C22H20N4O[M+H]+357.1710,found 357.1722.Compound 94. 1-(3-phenylpropyl)-2-(pyridin-2-yl)-1H-benzo[d]imidazole-4-carboxamide: yellow powder, 45% yield.mp 184.3-185.4°C ;1H NMR(400MHz,CDCl3)δ9.75(d,J=4.2Hz,1H),8.59(dd,J=5.0,1.6Hz,1H),8.39(d,J=7.9Hz,1H),8.18( dd, J=7.5, 1.1Hz, 1H), 7.84 (td, J=7.8, 1.8Hz, 1H), 7.48–7.43 (m, 1H), 7.40 (d, J=7.7Hz, 1H), 7.38–7.33 (m, 1H), 7.29 (t, J=7.4Hz, 2H), 7.22 (d, J=7.2Hz, 1H), 7.18 (d, J=1.6Hz, 1H), 7.16 (s, 1H), 6.24 (d, J=4.2Hz, 1H), 4.97–4.64 (m, 2H), 2.73 (t, J=7.4Hz, 2H), 2.25 (p, J=7.5Hz, 2H). 13CNMR (101MHz, CDCl3) δ167.61,149.81,148.82,140.83,140.55,136.85,128.49,128.39,126.18,124.90,124.71,124.19,123.14,122.78,113.98,45.38,33.06,31.32; HRMS calcd for: C22H20N4O [M + H] + 357.1710, found 357.1722.
化合物95. 1-(3-苯丙基)-2-(吡啶-3-基)-1H-苯并[d]咪唑-4-甲酰胺:黄色粉末,产率53％.m.p.161.7-162.4℃；1H NMR(400MHz,CDCl3)δ9.65–9.59(m,1H),9.01(dd,J＝2.3,0.9Hz,1H),8.80(dd,J＝4.9,1.7Hz,1H),8.22(dd,J＝7.3,1.4Hz,1H),7.98(dt,J＝7.9,2.0Hz,1H),7.54–7.40(m,3H),7.37–7.24(m,2H),7.29–7.16(m,1H),7.15–7.07(m,2H),6.01(s,1H),4.35–4.26(m,2H),2.67(t,J＝7.3Hz,2H),2.28–2.16(m,2H).13CNMR(101MHz,CDCl3)δ167.20,151.08,150.56,149.83,141.08,139.70,136.58,135.87,128.74,128.24,126.59,124.88,123.58,123.21,122.99,113.93,44.41,32.70,31.20；HRMS calcd for:C22H20N4O[M+H]+357.1710,found 357.1711.Compound 95. 1-(3-phenylpropyl)-2-(pyridin-3-yl)-1H-benzo[d]imidazole-4-carboxamide: yellow powder, yield 53%.mp 161.7-162.4°C ;1H NMR(400MHz,CDCl3)δ9.65-9.59(m,1H),9.01(dd,J=2.3,0.9Hz,1H),8.80(dd,J=4.9,1.7Hz,1H),8.22(dd , J=7.3, 1.4Hz, 1H), 7.98 (dt, J=7.9, 2.0Hz, 1H), 7.54–7.40 (m, 3H), 7.37–7.24 (m, 2H), 7.29–7.16 (m, 1H) ), 7.15–7.07(m, 2H), 6.01(s, 1H), 4.35–4.26(m, 2H), 2.67(t, J=7.3Hz, 2H), 2.28–2.16(m, 2H).13CNMR( 101MHz, CDCl3) δ167.20,151.08,150.56,149.83,141.08,139.70,136.58,135.87,128.74,128.24,126.59,124.88,123.58,123.21,122.99,113.93,44.41,32.70,31.20; HRMS calcd for: C22H20N4O [M + H]+357.1710, found 357.1711.
化合物96. 1-(3-苯丙基)-2-(邻甲苯基)-1H-苯并[d]咪唑-4-甲酰胺:黄色粉末,产率67％.m.p.192.7-194.6℃；1H NMR(400MHz,CDCl3)δ9.67(s,1H),8.18(dd,J＝7.4,1.3Hz,1H),7.49–7.42(m,2H),7.42–7.37(m,2H),7.36–7.29(m,2H),7.23(dd,J＝8.1,6.3Hz,2H),7.21–7.16(m,1H),7.04–6.95(m,2H),5.91(s,1H),4.10–4.01(m,2H),2.50(t,J＝7.5Hz,2H),2.25(s,3H),2.06–1.97(m,2H).13CNMR(101MHz,CDCl3)δ167.52,153.44,141.15,140.04,137.98,134.83,130.87,130.30,129.85,129.44,128.60,128.10,126.35,126.00,124.30,122.76,122.52,113.72,43.85,32.68,30.87,19.86；HRMS calcd for:C24H23N3O[M+H]+370.1914,found370.2371.Compound 96. 1-(3-Phenylpropyl)-2-(o-tolyl)-1H-benzo[d]imidazole-4-carboxamide: yellow powder, yield 67%.mp 192.7-194.6℃; 1H NMR (400MHz, CDCl3) δ 9.67 (s, 1H), 8.18 (dd, J=7.4, 1.3 Hz, 1H), 7.49–7.42 (m, 2H), 7.42–7.37 (m, 2H), 7.36–7.29 (m, 2H), 7.23 (dd, J=8.1, 6.3 Hz, 2H), 7.21–7.16 (m, 1H), 7.04–6.95 (m, 2H), 5.91 (s, 1H), 4.10–4.01 (m , 2H), 2.50(t, J=7.5Hz, 2H), 2.25(s, 3H), 2.06–1.97(m, 2H).13CNMR(101MHz,CDCl3)δ167.52,153.44,141.15,140.04,137.98,134.83, 130.87,130.30,129.85,129.44,128.60,128.10,126.35,126.00,124.30,122.76,122.52,113.72,43.85,32.68,30.87,19.86; HRMS calcd for: C24H23N3O [M + H] + 370.1914, found370.2371.
化合物97. 1-(3-苯丙基)-2-(间甲苯基)-1H-苯并[d]咪唑-4-甲酰胺:淡黄色粉末,产率80％.m.p.168.9-171.2℃；1H NMR(400MHz,CDCl3)δ9.87–9.48(m,1H),8.17(dd,J＝7.6,1.1Hz,1H),7.54–7.50(m,1H),7.46–7.40(m,2H),7.40–7.33(m,3H),7.29–7.24(m,2H),7.23–7.14(m,1H),7.10–7.03(m,2H),5.96(s,1H),4.30–4.23(m,2H),2.61(t,J＝7.3Hz,2H),2.44(s,3H),2.22–2.08(m,2H).13CNMR(101MHz,CDCl3)δ167.53,153.94,140.05,138.84,135.82,131.04,130.08,129.71,128.74,128.63,128.24,126.42,126.18,124.39,122.69,122.55,113.76,44.33,32.78,31.05,21.50；HRMS calcd for:C24H23N3O[M+H]+370.1914,found370.1922.Compound 97. 1-(3-phenylpropyl)-2-(m-tolyl)-1H-benzo[d]imidazole-4-carboxamide: pale yellow powder, yield 80%.mp168.9-171.2℃; 1H NMR(400MHz, CDCl3)δ9.87-9.48(m,1H),8.17(dd,J=7.6,1.1Hz,1H),7.54-7.50(m,1H),7.46-7.40(m,2H), 7.40–7.33 (m, 3H), 7.29–7.24 (m, 2H), 7.23–7.14 (m, 1H), 7.10–7.03 (m, 2H), 5.96 (s, 1H), 4.30–4.23 (m, 2H) ), 2.61(t, J=7.3Hz, 2H), 2.44(s, 3H), 2.22–2.08(m, 2H).13CNMR(101MHz,CDCl3)δ167.53,153.94,140.05,138.84,135.82,131.04,130.08, 129.71,128.74,128.63,128.24,126.42,126.18,124.39,122.69,122.55,113.76,44.33,32.78,31.05,21.50; HRMS calcd for:C24H23N3O[M+H]+370.1922.1914
化合物98. 2-环己基-1-(3-苯丙基)-1H-苯并[d]咪唑-4-甲酰胺:白色固体,产率90％.m.p.198.8-199.9℃；1H NMR(400MHz,CDCl3)δ9.78(d,J＝3.9Hz,1H),8.01(dd,J＝7.4,1.3Hz,1H),7.30–7.24(m,3H),7.21(d,J＝5.5Hz,1H),7.19(d,J＝4.7Hz,1H),7.15–7.11(m,2H),5.85(d,J＝4.0Hz,1H),4.13–3.95(m,2H),2.66(t,J＝7.3Hz,2H),2.56(tt,J＝11.6,3.4Hz,1H),2.09(dq,J＝9.9,7.4Hz,2H),1.89–1.55(m,9H),1.24(s,H).13CNMR(101MHz,CDCl3)δ167.84,159.35,140.10,135.00,128.77,128.32,126.57,123.60,122.00,121.71,113.02,77.24,42.71,36.21,32.78,31.96,31.22,26.10,25.73；HRMScalcd for:C23H27N3O[M+H]+362.2227found 362.2218.Compound 98. 2-Cyclohexyl-1-(3-phenylpropyl)-1H-benzo[d]imidazole-4-carboxamide: white solid, yield 90%.mp 198.8-199.9℃;1H NMR (400MHz) , CDCl3)δ9.78(d,J=3.9Hz,1H),8.01(dd,J=7.4,1.3Hz,1H),7.30–7.24(m,3H),7.21(d,J=5.5Hz,1H) ), 7.19(d, J=4.7Hz, 1H), 7.15-7.11(m, 2H), 5.85(d, J=4.0Hz, 1H), 4.13-3.95(m, 2H), 2.66(t, J= 7.3Hz, 2H), 2.56 (tt, J=11.6, 3.4Hz, 1H), 2.09 (dq, J=9.9, 7.4Hz, 2H), 1.89–1.55 (m, 9H), 1.24 (s, H). 13CNMR (101MHz, CDCl3) δ167.84,159.35,140.10,135.00,128.77,128.32,126.57,123.60,122.00,121.71,113.02,77.24,42.71,36.21,32.78,31.96,31.22,26.10,25.73; HRMScalcd for: C23H27N3O [M +H]+362.2227found 362.2218.
化合物99. 1-(3-苯丙基)-2-(噻吩-2-基)-1H-苯并[d]咪唑-4-甲酰胺:白色固体,产率80％.m.p.198.9-200.1℃；1H NMR(400MHz,CDCl3)δ9.55(s,1H),8.09(dd,J＝7.2,1.5Hz,1H),7.46(dd,J＝5.1,1.0Hz,1H),7.35–7.29(m,2H),7.29–7.24(m,3H),7.23–7.17(m,2H),7.12(dd,J＝7.0,1.7Hz,2H),7.04(dd,J＝5.1,3.7Hz,1H),5.86(s,1H),4.37–4.30(m,2H),2.71(t,J＝7.3Hz,2H),2.23–2.13(m,2H).13CNMR(101MHz,CDCl3)δ167.35,140.94,140.01,136.18,131.51,129.27,128.76,128.47,128.30,128.09,126.60,124.72,122.78,122.42,113.33,44.30,32.92,31.18；HRMS calcd for:C21H19N3OS[M+H]+362.1322found 362.1326.Compound 99. 1-(3-Phenylpropyl)-2-(thiophen-2-yl)-1H-benzo[d]imidazole-4-carboxamide: white solid, 80% yield.mp 198.9-200.1°C ;1H NMR(400MHz,CDCl3)δ9.55(s,1H),8.09(dd,J=7.2,1.5Hz,1H),7.46(dd,J=5.1,1.0Hz,1H),7.35-7.29(m , 2H), 7.29–7.24 (m, 3H), 7.23–7.17 (m, 2H), 7.12 (dd, J=7.0, 1.7Hz, 2H), 7.04 (dd, J=5.1, 3.7Hz, 1H), 5.86(s,1H),4.37-4.30(m,2H),2.71(t,J=7.3Hz,2H),2.23-2.13(m,2H).13CNMR(101MHz,CDCl3)δ167.35,140.94,140.01,136.18 ,131.51,129.27,128.76,128.47,128.30,128.09,126.60,124.72,122.78,122.42,113.33,44.30,32.92,31.18;
化合物100. 2-(3-氟苯基)-1-(3-苯基丙基)-1H-苯并[d]咪唑-4-甲酰胺:淡黄色固体,产率95％.m.p.169.7-170.5℃；1H NMR(400MHz,CDCl3)δ9.72–9.66(m,1H),8.20(dd,J＝7.5,1.2Hz,1H),7.69–7.61(m,2H),7.52–7.37(m,2H),7.38–7.13(m,5H),7.14–7.07(m,2H),5.99(d,J＝4.0Hz,1H),4.31–4.22(m,2H),2.66(t,J＝7.2Hz,2H),2.26–2.13(m,2H).13CNMR(101MHz,CDCl3)δ167.41,152.65,141.01,139.86,135.84,131.35,131.26,128.70,128.30,126.54,124.57,122.76,122.73,116.23,116.01,113.80,44.22,32.70,31.06；HRMS calcd for:C23H20FN3O[M+H]+374.1663found 374.1665.Compound 100. 2-(3-Fluorophenyl)-1-(3-phenylpropyl)-1H-benzo[d]imidazole-4-carboxamide: pale yellow solid, 95% yield.mp169.7- 170.5℃;1H NMR(400MHz,CDCl3)δ9.72-9.66(m,1H),8.20(dd,J=7.5,1.2Hz,1H),7.69-7.61(m,2H),7.52-7.37(m, 2H), 7.38–7.13 (m, 5H), 7.14–7.07 (m, 2H), 5.99 (d, J=4.0Hz, 1H), 4.31–4.22 (m, 2H), 2.66 (t, J=7.2Hz) ,2H),2.26–2.13(m,2H).13CNMR(101MHz,CDCl3)δ167.41,152.65,141.01,139.86,135.84,131.35,131.26,128.70,128.30,126.54,124.57,122.76,116.12.73 ,44.22,32.70,31.06; HRMS calcd for:C23H20FN3O[M+H]+374.1663found 374.1665.
化合物101. 2-(4-氟苯基)-1-(3-苯基丙基)-1H-苯并[d]咪唑-4-甲酰胺:白色固体,产率95.7％.m.p.170.7-171.8℃；1H NMR(400MHz,CDCl3)δ9.59(s,1H),8.10(dd,J＝7.5,1.2Hz,1H),7.60–7.53(m,2H),7.39(dd,J＝8.1,1.2Hz,1H),7.36–7.28(m,1H),7.24–7.15(m,3H),7.12–7.05(m,2H),7.03–6.95(m,2H),5.97(s,1H),4.28–4.09(m,2H),2.18–2.01(m,2H).13CNMR(101MHz,CDCl3)δ167.37,162.53,152.60,140.61,139.83,135.72,131.41,131.32,128.70,128.29,126.55,124.72,122.88,122.64,116.25,116.04,113.87,44.26,32.69,31.03；HRMS calcd for:C23H20FN3O[M+H]+374.1663found 374.1668.Compound 101. 2-(4-Fluorophenyl)-1-(3-phenylpropyl)-1H-benzo[d]imidazole-4-carboxamide: white solid, 95.7% yield.mp170.7-171.8 ℃;1H NMR(400MHz,CDCl3)δ9.59(s,1H),8.10(dd,J=7.5,1.2Hz,1H),7.60-7.53(m,2H),7.39(dd,J=8.1,1.2 Hz, 1H), 7.36–7.28 (m, 1H), 7.24–7.15 (m, 3H), 7.12–7.05 (m, 2H), 7.03–6.95 (m, 2H), 5.97 (s, 1H), 4.28– 4.09(m,2H),2.18–2.01(m,2H).13CNMR(101MHz,CDCl3)δ167.37,162.53,152.60,140.61,139.83,135.72,131.41,131.32,128.70,128.29,126.55,122.68,122.84 116.25, 116.04, 113.87, 44.26, 32.69, 31.03; HRMS calcd for: C23H20FN3O[M+H]+374.1663found 374.1668.
方法四、由邻硝基取代苯胺与醛反应生成多取代苯并咪唑。The fourth method is to generate polysubstituted benzimidazole by reacting o-nitro-substituted aniline with aldehyde.
N-取代-2-硝基-4-取代基-苯胺的合成方法：The synthetic method of N-substituted-2-nitro-4-substituent-aniline:
合成通法：(以苯丙胺和3-氟-4-硝基苯甲醚为原料为例，)在1L烧瓶中加入3-氟-4-硝基苯甲醚(13.69g,0.08mol)、碳酸钾(33.17g,0.24mol)、乙腈360mL、苯丙胺(12.98g,0.096mol)，回流2h冷至室温，倒入500mL纯水中，析出橘黄色固体，抽滤，干燥为纯品。General synthesis method: (taking amphetamine and 3-fluoro-4-nitroanisole as raw materials as examples,) in a 1L flask, add 3-fluoro-4-nitroanisole (13.69g, 0.08mol), carbonic acid Potassium (33.17 g, 0.24 mol), acetonitrile 360 mL, amphetamine (12.98 g, 0.096 mol), refluxed for 2 h, cooled to room temperature, poured into 500 mL of pure water, an orange solid was precipitated, suction filtered, and dried to obtain pure product.
化合物102 3-(苄基氨基)-4-硝基苄腈:橘黄色固体,产率97.23％.m.p.151.5-152.6℃；1H NMR(400MHz,CDCl3)δ:8.42(d,J＝6.2Hz,1H),8.28(d,J＝8.7Hz,1H),7.44–7.38(m,2H),7.38–7.31(m,3H),7.13(d,J＝1.6Hz,1H),6.90(dd,J＝8.7,1.7Hz,1H),4.55(d,J＝5.6Hz,2H)；HRMS caled for C14H11N3O2[M+H]+254.0924,found 254.0926.Compound 102 3-(benzylamino)-4-nitrobenzonitrile: orange solid, yield 97.23%.mp151.5-152.6℃;1H NMR(400MHz,CDCl3)δ:8.42(d,J=6.2Hz, 1H), 8.28(d, J=8.7Hz, 1H), 7.44–7.38 (m, 2H), 7.38–7.31 (m, 3H), 7.13 (d, J=1.6Hz, 1H), 6.90 (dd, J ＝8.7,1.7Hz,1H),4.55(d,J＝5.6Hz,2H);HRMS caled for C14H11N3O2[M+H]+254.0924,found 254.0926.
化合物103. 4-硝基-3-((3-苯丙基)氨基)苄腈:橘黄色固体，95.23％.m.p.93.2-94.7℃.1H NMR(400MHz,CDCl3)δ8.24(dd,J＝8.7,2.0Hz,1H),8.05(d,J＝5.4Hz,1H),7.37–7.29(m,2H),7.23(dd,J＝15.7,7.0Hz,3H),7.06(s,1H),6.85(dd,J＝8.9,1.7Hz,1H),3.30(q,J＝6.7,6.3Hz,2H),2.79(td,J＝7.4,2.0Hz,2H),2.09(pd,J＝7.2,1.9Hz,2H)；HRMScalcd for C16H15N3O2[M+H]+282.1237,found 282.1237.Compound 103. 4-Nitro-3-((3-phenylpropyl)amino)benzonitrile: orange solid, 95.23%.mp93.2-94.7℃.1H NMR(400MHz,CDCl3)δ8.24(dd,J =8.7,2.0Hz,1H),8.05(d,J=5.4Hz,1H),7.37–7.29(m,2H),7.23(dd,J=15.7,7.0Hz,3H),7.06(s,1H) ,6.85(dd,J＝8.9,1.7Hz,1H),3.30(q,J＝6.7,6.3Hz,2H),2.79(td,J＝7.4,2.0Hz,2H),2.09(pd,J＝7.2 ,1.9Hz,2H); HRMScalcd for C16H15N3O2[M+H]+282.1237,found 282.1237.
化合物104 5-甲氧基-2-硝基-N-(3-苯基丙基)苯胺:亮黄色固体，91.64％.m.p.151.5-152.6℃.1H NMR(400MHz,CDCl3)δ8.36(d,J＝6.1Hz,1H),8.14(d,J＝9.5Hz,1H),7.35–7.27(m,2H),7.25–7.16(m,3H),6.22(dd,J＝9.5,2.6Hz,1H),6.05(d,J＝2.5Hz,1H),3.80(s,3H),3.28(td,J＝7.1,5.4Hz,2H),2.78(t,J＝7.4Hz,2H),2.07(p,J＝7.3Hz,2H；HRMS calcd for C16H18N2O3[M+H]+287.1390,found 287.1390. Compound 104 5-Methoxy-2-nitro-N-(3-phenylpropyl)aniline: bright yellow solid, 91.64%.mp151.5-152.6℃.1H NMR(400MHz,CDCl3)δ8.36(d , J=6.1Hz, 1H), 8.14 (d, J=9.5Hz, 1H), 7.35–7.27 (m, 2H), 7.25–7.16 (m, 3H), 6.22 (dd, J=9.5, 2.6Hz, 1H), 6.05(d, J=2.5Hz, 1H), 3.80(s, 3H), 3.28(td, J=7.1, 5.4Hz, 2H), 2.78(t, J=7.4Hz, 2H), 2.07( p,J=7.3Hz,2H; HRMS calcd for C16H18N2O3[M+H]+287.1390, found 287.1390.
合成通法：向250mL反应瓶中加入1mmol化合物Ⅰ,1mmol合适的醛，15mL DMSO，9mmol保险粉溶解在10mL水中形成的溶液。在80℃下反应TLC跟踪反应至结束。降至室温，加入50mL纯水、0℃搅拌2h、过滤、20mL纯水洗涤滤饼，丙酮重结晶，真空干燥。General synthesis method: add 1 mmol of compound I, 1 mmol of suitable aldehyde, 15 mL of DMSO, 9 mmol of hydrosulfite to a solution of 10 mL of water into a 250 mL reaction flask. The reaction was followed by TLC to completion at 80°C. Drop to room temperature, add 50 mL of pure water, stir at 0°C for 2 h, filter, wash the filter cake with 20 mL of pure water, recrystallize from acetone, and dry in vacuo.
用此方法合成以下化合物：The following compounds were synthesized using this method:
化合物105. 1-苄基-2-(吡啶-2-基)-1H-苯并[d]咪唑-6-甲腈:1H NMR(400MHz,CDCl3)δ8.70–8.65(m,1H),8.46(d,1H),7.92–7.86(m,2H),7.65(d,1H),7.54(dd,1H),7.40(d,1H),7.31–7.26(m,3H),7.19–7.14(m,2H),6.22(s,2H)；HRMS calcd for C20H14N4[M+H]+311.1291,found 311.1291. Compound 105. 1-Benzyl-2-(pyridin-2-yl)-1H-benzo[d]imidazole-6-carbonitrile: 1H NMR (400 MHz, CDCl3) δ 8.70–8.65 (m, 1H), 8.46(d,1H), 7.92–7.86(m,2H), 7.65(d,1H), 7.54(dd,1H), 7.40(d,1H), 7.31–7.26(m,3H), 7.19–7.14( m,2H),6.22(s,2H); HRMS calcd for C20H14N4[M+H]+311.1291,found 311.1291.
化合物106. 1-苄基-2-(吡啶-4-基)-1H-苯并[d]咪唑-6-甲腈:1H NMR(400MHz,CDCl3)δ8.78(m,1H),8.54(dd,1H),8.15(dt,J＝7.9,2.0Hz,1H),7.89–7.94(m,1H),7.74(d,2H),7.45(dd,1H),7.45–7.38(m,3H),7.06–7.11(m,2H),5.79(s,2H)；HRMS calcd forC20H14N4[M+H]+311.1291,found 311.1289.Compound 106. 1-benzyl-2-(pyridin-4-yl)-1H-benzo[d]imidazole-6-carbonitrile: 1H NMR (400MHz, CDCl3) δ 8.78 (m, 1H), 8.54 ( dd, 1H), 8.15 (dt, J=7.9, 2.0Hz, 1H), 7.89–7.94 (m, 1H), 7.74 (d, 2H), 7.45 (dd, 1H), 7.45–7.38 (m, 3H) ,7.06–7.11(m,2H),5.79(s,2H); HRMS calcd forC20H14N4[M+H]+311.1291,found 311.1289.
化合物108 1-苄基-2-苯基-1H-苯并[d]咪唑-6-甲腈:1H NMR(400MHz,CDCl3)δ7.90(d,J＝8.3Hz,1H),7.74～7.68(m,2H),7.58～7.54(m,1H),7.54～7.50(m,3H),7.48(d,1H),7.42～7.30(m,3H),7.08(dd,2H),5.49(s,2H)；HRMS calcd for C21H15N3[M+H]+310.1339,found310.1335.Compound 108 1-benzyl-2-phenyl-1H-benzo[d]imidazole-6-carbonitrile: 1H NMR (400MHz, CDCl3) δ7.90 (d, J=8.3Hz, 1H), 7.74～7.68 (m,2H),7.58～7.54(m,1H),7.54～7.50(m,3H),7.48(d,1H),7.42～7.30(m,3H),7.08(dd,2H),5.49(s ,2H);HRMS calcd for C21H15N3[M+H]+310.1339,found310.1335.
化合物109 1-苄基-2-苯乙基-1H-苯并[d]咪唑-6-甲腈:1H NMR(400MHz,CDCl3)δ7.94(d,J＝8.3Hz,1H),7.51(d,J＝8.2Hz,2H),7.34–7.29(m,3H),7.25–7.19(m,3H),7.15–7.09(m,2H),6.97–6.90(m,2H),5.21(s,2H),3.31(dd,2H),3.18(dd,2H)；HRMS calcd forC21H15N3[M+H]+338.1652,found 338.1648. Compound 109 1-benzyl-2-phenethyl-1H-benzo[d]imidazole-6-carbonitrile: 1H NMR (400MHz, CDCl3) δ 7.94 (d, J=8.3Hz, 1H), 7.51 ( d, J＝8.2Hz, 2H), 7.34-7.29(m,3H), 7.25-7.19(m,3H), 7.15-7.09(m,2H), 6.97-6.90(m,2H), 5.21(s, 2H), 3.31(dd, 2H), 3.18(dd, 2H); HRMS calcd forC21H15N3[M+H]+338.1652, found 338.1648.
化合物110 1-苄基-2-(3-氟苯基)-1H-苯并[d]咪唑-6-甲腈:1H NMR(400MHz,CDCl3)δ7.84(dd,J＝8.4,0.7Hz,1H),7.55–7.44(m,2H),7.44–7.35(m,3H),7.35–7.23(m,3H),7.20–7.16(m,1H),7.05–6.95(m,2H),5.43(s,2H)；HRMS calcd for C21H14FN3[M+H]+328.1245,found 328.1241.Compound 110 1-benzyl-2-(3-fluorophenyl)-1H-benzo[d]imidazole-6-carbonitrile: 1H NMR (400 MHz, CDCl3) δ 7.84 (dd, J=8.4, 0.7 Hz ,1H),7.55–7.44(m,2H),7.44–7.35(m,3H),7.35–7.23(m,3H),7.20–7.16(m,1H),7.05–6.95(m,2H),5.43 (s,2H); HRMS calcd for C21H14FN3[M+H]+328.1245, found 328.1241.
化合物111 1-苄基-2-(4-氟苯基)-1H-苯并[d]咪唑-6-甲腈:1H NMR(400MHz,CDCl3)δ7.88–7.78(m,1H),7.67–7.57(m,2H),7.50(dd,1H),7.46(d,1H),7.35–7.26(m,3H),7.17–7.05(m,2H),7.05–6.92(m,2H),5.40(s,2H)；HRMS calcd for C21H14FN3[M+H]+328.1245,found 328.1243.Compound 111 1-benzyl-2-(4-fluorophenyl)-1H-benzo[d]imidazole-6-carbonitrile: 1H NMR (400MHz, CDCl3) δ 7.88–7.78 (m, 1H), 7.67 –7.57(m,2H),7.50(dd,1H),7.46(d,1H),7.35–7.26(m,3H),7.17–7.05(m,2H),7.05–6.92(m,2H),5.40 (s,2H); HRMS calcd for C21H14FN3[M+H]+328.1245, found 328.1243.
化合物112 1-苄基-2-(对甲苯基)-1H-苯并[d]咪唑-6-甲腈:1H NMR(400MHz,CDCl3)δ7.91(d,J＝8.4Hz,1H),7.66–7.60(m,2H),7.57(dd,1H),7.52(d,),7.42–7.35(m,3H),7.32(d,2H),7.13–7.03(m,2H),5.50(s,2H),2.44(s,3H)；HRMS calcd for C22H17N3[M+H]+324.1495,found 324.1498. Compound 112 1-benzyl-2-(p-tolyl)-1H-benzo[d]imidazole-6-carbonitrile: 1H NMR (400MHz, CDCl3) δ 7.91 (d, J=8.4Hz, 1H), 7.66–7.60 (m, 2H), 7.57 (dd, 1H), 7.52 (d,), 7.42–7.35 (m, 3H), 7.32 (d, 2H), 7.13–7.03 (m, 2H), 5.50 (s) ,2H),2.44(s,3H); HRMS calcd for C22H17N3[M+H]+324.1495,found 324.1498.
化合物113 1-苄基-2-(2-氯苯基)-1H-苯并[d]咪唑-6-甲腈:黄色粉末,产率67％.m.p.95.6-96.7℃；1H NMR(400MHz,CDCl3)δ7.95–7.89(m,1H),7.57(d,J＝7.5Hz,3H),7.51(dd,J＝7.9,6.4Hz,2H),7.43–7.35(m,3H),7.29–7.26(m,3H),5.28(s,2H)；HRMScalcd for C21H14ClN3[M+H]+344.0949,found 344.0957. Compound 113 1-benzyl-2-(2-chlorophenyl)-1H-benzo[d]imidazole-6-carbonitrile: yellow powder, yield 67%.mp95.6-96.7℃;1H NMR (400MHz, CDCl3)δ7.95–7.89(m,1H),7.57(d,J=7.5Hz,3H),7.51(dd,J=7.9,6.4Hz,2H),7.43–7.35(m,3H),7.29– 7.26(m,3H),5.28(s,2H); HRMScalcd for C21H14ClN3[M+H]+344.0949, found 344.0957.
化合物114 1-苄基-2-(3-氯苯基)-1H-苯并[d]咪唑-6-甲腈:白色粉末，产率76％，m.p.186.4-189.1℃；1H NMR(400MHz,CDCl3)δ7.84(dd,J＝8.4,0.7Hz,1H),7.68(t,J＝1.9Hz,1H),7.51(dd,J＝8.4,1.5Hz,1H),7.48(ddt,J＝4.8,2.9,1.4Hz,2H),7.44(ddd,J＝8.1,2.1,1.1Hz,1H),7.36(d,J＝7.8Hz,1H),7.34–7.28(m,3H),7.04–6.95(m,2H),5.41(s,2H)；HRMS calcd for C21H14ClN3[M+H]+344.0949,found 344.0959.Compound 114 1-benzyl-2-(3-chlorophenyl)-1H-benzo[d]imidazole-6-carbonitrile: white powder, 76% yield, mp 186.4-189.1°C; 1H NMR (400MHz, CDCl3)δ7.84(dd,J=8.4,0.7Hz,1H),7.68(t,J=1.9Hz,1H),7.51(dd,J=8.4,1.5Hz,1H),7.48(ddt,J= 4.8, 2.9, 1.4Hz, 2H), 7.44 (ddd, J=8.1, 2.1, 1.1Hz, 1H), 7.36 (d, J=7.8Hz, 1H), 7.34–7.28 (m, 3H), 7.04–6.95 (m,2H),5.41(s,2H); HRMS calcd for C21H14ClN3[M+H]+344.0949, found 344.0959.
化合物115 1-苄基-2-(4-氯苯基)-1H-苯并[d]咪唑-6-甲腈:黄色粉末,收率87％.m.p.199.5-200.9℃；1H NMR(400MHz,CDCl3)δ7.91(d,J＝8.3Hz,1H),7.68–7.62(m,2H),7.58(dd,J＝8.4,1.5Hz,1H),7.54(d,J＝1.3Hz,1H),7.51–7.45(m,2H),7.41–7.34(m,3H),7.10–7.04(m,2H),5.47(s,2H)；HRMS calcd for C21H14ClN3[M+H]+344.0949,found344.0948.Compound 115 1-benzyl-2-(4-chlorophenyl)-1H-benzo[d]imidazole-6-carbonitrile: yellow powder, yield 87%.mp199.5-200.9℃;1H NMR (400MHz, CDCl3)δ7.91(d,J=8.3Hz,1H),7.68–7.62(m,2H),7.58(dd,J=8.4,1.5Hz,1H),7.54(d,J=1.3Hz,1H) ,7.51–7.45(m,2H),7.41–7.34(m,3H),7.10–7.04(m,2H),5.47(s,2H); HRMS calcd for C21H14ClN3[M+H]+344.0949,found344.0948 .
化合物116. 1-苄基-2-(2-氨基苯基)-1H-苯并[d]咪唑-6-甲腈:黄色粉末，收率71％.m.p.97.7-98.6℃；1H NMR(400MHz,DMSO-d6)δ8.21(d,J＝1.4Hz,1H),7.90(d,J＝8.3Hz,1H),7.70(dd,J＝8.3,1.5Hz,1H),7.29(s,1H),7.27(d,J＝2.1Hz,2H),7.26–7.23(m,2H),7.07–6.99(m,2H),6.93–6.86(m,1H),6.66(td,J＝7.5,1.0Hz,1H),5.56(s,2H)；HRMS calcd for C21H16N4[M+H]+325.1448,found 325.1448. Compound 116. 1-benzyl-2-(2-aminophenyl)-1H-benzo[d]imidazole-6-carbonitrile: yellow powder, yield 71%.mp97.7-98.6℃;1H NMR (400MHz) ,DMSO-d6)δ8.21(d,J＝1.4Hz,1H),7.90(d,J＝8.3Hz,1H),7.70(dd,J＝8.3,1.5Hz,1H),7.29(s,1H ), 7.27(d, J=2.1Hz, 2H), 7.26–7.23 (m, 2H), 7.07–6.99 (m, 2H), 6.93–6.86 (m, 1H), 6.66 (td, J=7.5, 1.0 Hz,1H),5.56(s,2H); HRMS calcd for C21H16N4[M+H]+325.1448, found 325.1448.
化合物117. 1-苄基-2-(呋喃-2-基)-1H-苯并[d]咪唑-6-甲腈:淡黄色粉末,产率82％.m.p.192.3-193.8℃；1H NMR(400MHz,CDCl3)δ7.93–7.84(m,1H),7.61–7.52(m,3H),7.44–7.33(m,4H),7.12(td,J＝7.1,6.3,2.7Hz,3H),5.64(s,2H)；HRMS calcd forC19H13N3O[M+H]+300.1131,found 300.1131.Compound 117. 1-benzyl-2-(furan-2-yl)-1H-benzo[d]imidazole-6-carbonitrile: pale yellow powder, yield 82%.mp 192.3-193.8°C; 1H NMR ( 400MHz, CDCl3) δ 7.93–7.84 (m, 1H), 7.61–7.52 (m, 3H), 7.44–7.33 (m, 4H), 7.12 (td, J=7.1, 6.3, 2.7Hz, 3H), 5.64 (s,2H);HRMS calcd forC19H13N3O[M+H]+300.1131,found 300.1131.
化合物118. 1-苄基-2-(噻吩-2-基)-1H-苯并[d]咪唑-6-甲腈:白色粉末,产率80％.m.p.221.9-223.4℃；1H NMR(400MHz,CDCl3)δ7.86(d,J＝8.4Hz,1H),7.63(d,J＝1.7Hz,1H),7.59(d,J＝1.4Hz,1H),7.54(dd,J＝8.4,1.5Hz,1H),7.38–7.30(m,3H),7.25(d,J＝3.6Hz,1H),7.14(d,J＝2.1Hz,1H),7.13(t,J＝1.8Hz,1H),6.62(dd,J＝3.6,1.8Hz,1H),5.75(s,2H)；HRMS calcd for C19H13N3S[M+H]+316.0903,found 316.0907.Compound 118. 1-benzyl-2-(thiophen-2-yl)-1H-benzo[d]imidazole-6-carbonitrile: white powder, yield 80%.mp221.9-223.4℃;1H NMR (400MHz ,CDCl3)δ7.86(d,J＝8.4Hz,1H),7.63(d,J＝1.7Hz,1H),7.59(d,J＝1.4Hz,1H),7.54(dd,J＝8.4,1.5 Hz, 1H), 7.38–7.30 (m, 3H), 7.25 (d, J=3.6Hz, 1H), 7.14 (d, J=2.1Hz, 1H), 7.13 (t, J=1.8Hz, 1H), 6.62(dd,J=3.6,1.8Hz,1H),5.75(s,2H); HRMS calcd for C19H13N3S[M+H]+316.0903, found 316.0907.
化合物119. 1-苄基-2-乙基-1H-苯并[d]咪唑-6-甲腈:淡黄色粉末,产率43％.m.p.118.8-119.5℃；1H NMR(400MHz,CDCl3)δ7.72(d,J＝8.4Hz,1H),7.47–7.37(m,2H),7.30–7.20(m,3H),6.98–6.90(m,2H),5.28(s,2H),2.84(q,J＝7.5Hz,2H),1.36(t,J＝7.5Hz,3H)；HRMS calcd for C17H15N3[M+H]+262.1339,found 262.1342.Compound 119. 1-benzyl-2-ethyl-1H-benzo[d]imidazole-6-carbonitrile: pale yellow powder, yield 43%.mp 118.8-119.5℃; 1H NMR (400MHz, CDCl3)δ7 .72(d,J=8.4Hz,1H),7.47-7.37(m,2H),7.30-7.20(m,3H),6.98-6.90(m,2H),5.28(s,2H),2.84(q , J=7.5Hz, 2H), 1.36(t, J=7.5Hz, 3H); HRMS calcd for C17H15N3[M+H]+262.1339, found 262.1342.
化合物120. 1-苄基-2-丁基-1H-苯并[d]咪唑-6-甲腈:黄色固体,产率45％.m.p.127.4-128.6℃；1H NMR(400MHz,CDCl3)δ7.72(d,J＝8.2Hz,1H),7.46–7.37(m,2H),7.31–7.22(m,3H),7.02–6.84(m,2H),5.29(s,2H),2.94–2.68(m,2H),1.89–1.63(m,2H),1.34(dt,J＝14.7,7.4Hz,2H),0.85(t,J＝7.3Hz,3H)；HRMS calcd for C19H19N3[M+H]+290.1652,found 290.1649.Compound 120. 1-benzyl-2-butyl-1H-benzo[d]imidazole-6-carbonitrile: yellow solid, yield 45%.mp127.4-128.6℃;1H NMR (400MHz,CDCl3)δ7. 72(d,J=8.2Hz,1H),7.46-7.37(m,2H),7.31-7.22(m,3H),7.02-6.84(m,2H),5.29(s,2H),2.94-2.68( m,2H),1.89–1.63(m,2H),1.34(dt,J=14.7,7.4Hz,2H),0.85(t,J=7.3Hz,3H); HRMS calcd for C19H19N3[M+H]+ 290.1652, found 290.1649.
化合物121. 6-甲氧基-2-苯基-1-(3-苯丙基)-1H-苯并[d]咪唑:浅黄色粉末，产率87％.m.p.106.5-108.0℃；1H NMR(400MHz,CDCl3)δ8.03(d,J＝9.0Hz,1H),7.67(d,J＝7.3Hz,2H),7.45(dq,J＝14.9,7.3Hz,3H),7.31–7.13(m,4H),7.06(d,J＝7.2Hz,2H),6.91(d,J＝8.8Hz,1H),6.82(s,1H),4.32(t,J＝8.0Hz,2H),3.81(s,3H),2.70–2.54(m,2H)；HRMS calcd for C23H22N2O[M+H]+343.1805,found 343.1807.Compound 121. 6-Methoxy-2-phenyl-1-(3-phenylpropyl)-1H-benzo[d]imidazole: pale yellow powder, 87% yield.mp 106.5-108.0°C; 1H NMR (400MHz, CDCl3)δ8.03(d,J＝9.0Hz,1H),7.67(d,J＝7.3Hz,2H),7.45(dq,J＝14.9,7.3Hz,3H),7.31–7.13(m ,4H),7.06(d,J＝7.2Hz,2H),6.91(d,J＝8.8Hz,1H),6.82(s,1H),4.32(t,J＝8.0Hz,2H),3.81(s ,3H),2.70–2.54(m,2H); HRMS calcd for C23H22N2O[M+H]+343.1805, found 343.1807.
化合物122. 2-苄基-6-甲氧基-1-(3-苯丙基)-1H-苯并[d]咪唑:粉色粉末，产率83％.m.p.194.9-195.7℃；1H NMR(400MHz,DMSO-d6)δ7.78(dd,J＝9.1,1.8Hz,1H),7.41(d,J＝2.5Hz,1H),7.29(q,J＝6.9,6.2Hz,5H),7.26–7.10(m,6H),4.35(t,J＝7.7Hz,2H),3.15(t,J＝7.9Hz,2H),2.71(t,J＝7.8Hz,2H),2.00(t,J＝7.9Hz,2H)；13CNMR(101MHz,DMSO-d6)δ158.40,152.67,141.13,139.62,133.02,129.03,128.90,128.85,128.71,127.13,126.54,124.99,116.01,115.79,96.05,56.64,44.28,32.56,32.15,30.39,27.22；HRMScalcd for C24H24N2O[M+H]+357.1961,found 357.1953. Compound 122. 2-benzyl-6-methoxy-1-(3-phenylpropyl)-1H-benzo[d]imidazole: pink powder, 83% yield.mp 194.9-195.7°C; 1H NMR ( 400MHz, DMSO-d6)δ7.78(dd,J=9.1,1.8Hz,1H),7.41(d,J=2.5Hz,1H),7.29(q,J=6.9,6.2Hz,5H),7.26– 7.10(m, 6H), 4.35(t, J=7.7Hz, 2H), 3.15(t, J=7.9Hz, 2H), 2.71(t, J=7.8Hz, 2H), 2.00(t, J=7.9 hz, 2H); 13CNMR (101MHz, DMSO-d6) δ158.40,152.67,141.13,139.62,133.02,129.03,128.90,128.85,128.71,127.13,126.54,124.99,116.01,115.79,96.05,56.64,44.28,32.56,32.15 , 30.39, 27.22; HRMScalcd for C24H24N2O[M+H]+357.1961, found 357.1953.
化合物123 6-甲氧基-2-苯乙基-1-(3-苯丙基)-1H-苯并[d]咪唑:黄色粉末，产率90％.m.p.141.7-144.2℃；1H NMR(400MHz,CDCl3)δ7.77(dd,J＝9.0,1.9Hz,1H),7.25–7.09(m,5H),7.00(d,J＝7.4Hz,2H),6.95–6.89(m,1H),6.76–6.69(m,2H),4.20(t,J＝7.8Hz,2H),3.79(d,J＝1.9Hz,3H),2.48(s,2H),2.02(h,J＝7.8Hz,2H).13CNMR(101MHz,CDCl3)δ148.66,146.96,139.92,133.22,133.02,130.51,128.61,128.25,127.91,126.38,117.93,117.67,115.47,94.38,77.25,56.06,44.74,32.40,30.17；HRMS calcd for C25H26N2O[M+H]+371.2118,found 371.2118. Compound 123 6-Methoxy-2-phenethyl-1-(3-phenylpropyl)-1H-benzo[d]imidazole: yellow powder, yield 90%.mp 141.7-144.2°C; 1H NMR ( 400MHz, CDCl3)δ7.77(dd,J=9.0,1.9Hz,1H),7.25-7.09(m,5H),7.00(d,J=7.4Hz,2H),6.95-6.89(m,1H), 6.76–6.69(m, 2H), 4.20(t, J=7.8Hz, 2H), 3.79(d, J=1.9Hz, 3H), 2.48(s, 2H), 2.02(h, J=7.8Hz, 2H ) .13CNMR (101MHz, CDCl3) δ148.66,146.96,139.92,133.22,133.02,130.51,128.61,128.25,127.91,126.38,117.93,117.67,115.47,94.38,77.25,56.06,44.74,32.40,30.17; HRMS calcd for C25H26N2O [M+H]+371.2118, found 371.2118.
化合物124 6-甲氧基-1-(3-苯丙基)-2-(邻甲苯基)-1H-苯并[d]咪唑:粉色粉末，产率88％.m.p.88.2-91.5℃；1H NMR(400MHz,CDCl3)δ7.72(d,J＝8.8Hz,1H),7.44(td,J＝7.4,1.7Hz,1H),7.40–7.34(m,2H),7.34–7.29(m,1H),7.28–7.26(m,1H),7.26–7.17(m,2H),7.08–7.01(m,2H),6.96(dd,J＝8.8,2.4Hz,1H),6.73(d,J＝2.3Hz,1H),4.02–3.94(m,2H),3.88(s,3H),2.52(t,J＝7.5Hz,2H),2.25(s,3H),2.07–1.98(m,2H)；13CNMR(101MHz,CDCl3)δ156.52,152.52,140.44,138.01,137.56,135.13,130.50,130.25,130.14,129.75,128.54,128.18,126.23,125.76,120.43,111.24,93.62,55.97,43.34,32.68,30.60,19.74；HRMS calcd for C24H24N2O[M+H]+357.1961,found 357.1953. Compound 124 6-Methoxy-1-(3-phenylpropyl)-2-(o-tolyl)-1H-benzo[d]imidazole: pink powder, 88% yield.mp 88.2-91.5°C; 1H NMR (400MHz, CDCl3) δ 7.72 (d, J=8.8Hz, 1H), 7.44 (td, J=7.4, 1.7Hz, 1H), 7.40–7.34 (m, 2H), 7.34–7.29 (m, 1H) ), 7.28–7.26 (m, 1H), 7.26–7.17 (m, 2H), 7.08–7.01 (m, 2H), 6.96 (dd, J=8.8, 2.4Hz, 1H), 6.73 (d, J=2.3 13CNMR (101MHz, CDCl3) δ156.52,152.52,140.44,138.01,137.56,135.13,130.50,130.25,130.14,129.75,128.54,128.18,126.23,125.76,120.43,111.24,93.62,55.97,43.34,32.68,30.60,19.74; HRMS calcd for C24H24N2O[M+H]+357.1961,found 357.1953.
化合物125 6-甲氧基-1-(3-苯丙基)-2-(间甲苯基)-1H-苯并[d]咪唑:灰色粉末，产率83％.m.p.150.8-152.3℃；1H NMR(400MHz,CDCl3)δ7.61(d,J＝8.8Hz,1H),7.45(td,J＝1.7,0.9Hz,1H),7.31(dt,J＝7.5,1.7Hz,1H),7.26(t,J＝7.5Hz,1H),7.23–7.17(m,3H),7.16–7.09(m,1H),7.06–6.98(m,2H),6.85(dd,J＝8.8,2.4Hz,1H),6.62(d,J＝2.4Hz,1H),4.18–4.04(m,2H),3.77(s,3H),2.53(t,J＝7.3Hz,2H),2.34(s,3H),2.07(dq,J＝10.0,7.4Hz,2H)；13CNMR(101MHz,CDCl3)δ156.57,153.13,140.43,138.62,137.63,136.20,130.53,130.28,130.02,128.58,128.50,128.32,126.31,125.91,120.42,111.39,93.72,55.96,43.91,32.78,30.80,21.45；HRMS calcd for C24H24N2O[M+H]+357.1961,found357.1951.Compound 125 6-Methoxy-1-(3-phenylpropyl)-2-(m-tolyl)-1H-benzo[d]imidazole: grey powder, 83% yield.mp 150.8-152.3°C; 1H NMR (400MHz, CDCl3) δ 7.61 (d, J=8.8Hz, 1H), 7.45 (td, J=1.7, 0.9Hz, 1H), 7.31 (dt, J=7.5, 1.7Hz, 1H), 7.26 ( t, J=7.5Hz, 1H), 7.23–7.17 (m, 3H), 7.16–7.09 (m, 1H), 7.06–6.98 (m, 2H), 6.85 (dd, J=8.8, 2.4Hz, 1H) ,6.62(d,J＝2.4Hz,1H),4.18–4.04(m,2H),3.77(s,3H),2.53(t,J＝7.3Hz,2H),2.34(s,3H),2.07( dq, J=10.0, 7.4Hz, 2H); 13CNMR (101MHz, CDCl3) δ 156.57, 153.13, 140.43, 138.62, 137.63, 136.20, 130.53, 130.28, 130.12, 128.58, 128.50, 128.32, 12, 9.41, 11, 12, 9.41 93.72, 55.96, 43.91, 32.78, 30.80, 21.45; HRMS calcd for C24H24N2O[M+H]+357.1961, found357.1951.
化合物126 6-甲氧基-1-(3-苯丙基)-2-(对甲苯基)-1H-苯并[d]咪唑:黄色粉末，产率87％.m.p.145.9-147.5℃；1H NMR(400MHz,CDCl3)δ7.71(d,J＝8.8Hz,1H),7.59–7.52(m,2H),7.32–7.27(m,4H),7.26–7.21(m,1H),7.16–7.09(m,2H),6.94(dd,J＝8.8,2.4Hz,1H),6.71(d,J＝2.4Hz,1H),4.24–4.13(m,2H),3.87(s,3H),2.62(t,J＝7.3Hz,2H),2.46(s,3H),2.16(dq,J＝9.9,7.5Hz,2H)；13CNMR(101MHz,CDCl3)δ156.52,153.07,140.44,139.57,137.56,136.19,129.42,129.00,128.58,128.35,127.67,126.29,120.32,111.34,93.71,55.96,43.86,32.76,30.80,21.45；HRMS calcd for C24H24N2O[M+H]+357.1961,found 357.1952. Compound 126 6-Methoxy-1-(3-phenylpropyl)-2-(p-tolyl)-1H-benzo[d]imidazole: yellow powder, 87% yield.mp 145.9-147.5°C; 1H NMR(400MHz, CDCl3)δ7.71(d,J=8.8Hz,1H),7.59-7.52(m,2H),7.32-7.27(m,4H),7.26-7.21(m,1H),7.16-7.09 (m, 2H), 6.94 (dd, J=8.8, 2.4Hz, 1H), 6.71 (d, J=2.4Hz, 1H), 4.24–4.13 (m, 2H), 3.87 (s, 3H), 2.62 ( t, J=7.3Hz, 2H), 2.46 (s, 3H), 2.16 (dq, J=9.9, 7.5Hz, 2H); 13CNMR (101MHz, CDCl3) δ 156.52, 153.07, 140.44, 139.57, 137.56, 136.19, 129.42 ,129.00,128.58,128.35,127.67,126.29,120.32,111.34,93.71,55.96,43.86,32.76,30.80,21.45; HRMS calcd for C24H24N2O[M+H]+357.1961,found5 357.19
化合物127 2-(2-氯苯基)-6-甲氧基-1-(3-苯丙基)-1H-苯并[d]咪唑:黄色粉末，产率64％.m.p.111.1-112.1℃；1H NMR(400MHz,CDCl3)δ8.10(d,J＝9.1Hz,1H),7.77(dd,J＝7.6,1.7Hz,1H),7.55–7.37(m,5H),7.24–7.10(m,3H),7.08–6.94(m,3H),6.82(d,J＝2.3Hz,1H),4.15(t,J＝7.8Hz,2H),3.82(s,3H),2.52(t,J＝7.2Hz,2H),2.01(p,J＝7.2Hz,2H).13CNMR(101MHz,CDCl3)δ159.03,145.92,139.56,133.96,133.60,133.26,132.46,130.18,128.65,128.23,128.15,126.46,125.94,122.04,118.18,117.11,94.04,56.24,44.81,32.20,30.06；HRMS calcd for C23H21ClN2O[M+H]+377.1415,found 377.1418. Compound 127 2-(2-Chlorophenyl)-6-methoxy-1-(3-phenylpropyl)-1H-benzo[d]imidazole: yellow powder, yield 64%.mp111.1-112.1℃ ;1H NMR(400MHz,CDCl3)δ8.10(d,J=9.1Hz,1H),7.77(dd,J=7.6,1.7Hz,1H),7.55-7.37(m,5H),7.24-7.10(m ,3H),7.08–6.94(m,3H),6.82(d,J=2.3Hz,1H),4.15(t,J=7.8Hz,2H),3.82(s,3H),2.52(t,J= 7.2Hz, 2H), 2.01 (p, J=7.2Hz, 2H). 13CNMR (101MHz, CDCl3) δ159.03, 145.92, 139.56, 133.96, 133.60, 133.26, 132.46, 130.18, 128.65, 128.23, 128.15, 126.46, 125.92 122.04, 118.18, 117.11, 94.04, 56.24, 44.81, 32.20, 30.06; HRMS calcd for C23H21ClN2O[M+H]+377.1415, found 377.1418.
化合物128 2-(3-氯苯基)-6-甲氧基-1-(3-苯丙基)-1H-苯并[d]咪唑：灰色粉末，产率92％.m.p.131.2-132.7℃；1H NMR(400MHz,CDCl3)δ7.66–7.58(m,2H),7.44–7.35(m,2H),7.30(t,J＝7.8Hz,1H),7.23–7.19(m,2H),7.17–7.10(m,1H),7.08–7.00(m,2H),6.86(dd,J＝8.8,2.4Hz,1H),6.62(d,J＝2.3Hz,1H),4.24–3.97(m,2H),3.78(s,3H),2.54(t,J＝7.3Hz,2H),2.13–2.02(m,2H)；13CNMR(101MHz,CDCl3)δ156.87,151.26,140.19,137.54,136.25,134.79,132.39,129.98,129.62,129.32,128.64,128.30,127.05,126.41,120.65,111.87,93.63,55.94,43.92,32.72,30.79；HRMS calcd for C23H21ClN2O[M+H]+377.1415,found377.1408. Compound 128 2-(3-Chlorophenyl)-6-methoxy-1-(3-phenylpropyl)-1H-benzo[d]imidazole: grey powder, 92% yield.mp 131.2-132.7°C ;1H NMR(400MHz,CDCl3)δ7.66-7.58(m,2H),7.44-7.35(m,2H),7.30(t,J=7.8Hz,1H),7.23-7.19(m,2H),7.17 –7.10(m,1H),7.08–7.00(m,2H),6.86(dd,J=8.8,2.4Hz,1H),6.62(d,J=2.3Hz,1H),4.24–3.97(m,2H) ), 3.78(s, 3H), 2.54(t, J=7.3Hz, 2H), 2.13–2.02(m, 2H); 13CNMR(101MHz, CDCl3)δ156.87,151.26,140.19,137.54,136.25,134.79,132.39, 129.98,129.62,129.32,128.64,128.30,127.05,126.41,120.65,111.87,93.63,55.94,43.92,32.72,30.79; HRMS calcd for C23H21ClN2O[M+H]+377.1415
化合物129 2-(4-氯苯基)-6-甲氧基-1-(3-苯丙基)-1H-苯并[d]咪唑：白色粉末，90％.m.p.159.1-160.5℃；1H NMR(400MHz,CDCl3)δ7.60(d,J＝8.8Hz,1H),7.52–7.44(m,2H),7.38–7.29(m,2H),7.26–7.11(m,3H),7.05–6.97(m,2H),6.86(dd,J＝8.8,2.4Hz,1H),6.62(d,J＝2.3Hz,1H),4.12–4.03(m,2H),3.77(s,3H),2.54(t,J＝ 7.2Hz,2H),2.06(p,J＝7.3Hz,2H)；13CNMR(101MHz,CDCl3)δ156.80,151.60,140.18,137.52,136.25,135.69,130.34,129.02,128.65,128.34,126.43,120.53,111.76,93.65,55.95,43.80,32.67,30.78；HRMS calcd for C23H21ClN2O[M+H]+377.1415,found 377.1414. Compound 129 2-(4-Chlorophenyl)-6-methoxy-1-(3-phenylpropyl)-1H-benzo[d]imidazole: white powder, 90%.mp 159.1-160.5°C; 1H NMR(400MHz, CDCl3)δ7.60(d,J=8.8Hz,1H),7.52-7.44(m,2H),7.38-7.29(m,2H),7.26-7.11(m,3H),7.05-6.97 (m, 2H), 6.86(dd, J=8.8, 2.4Hz, 1H), 6.62(d, J=2.3Hz, 1H), 4.12–4.03(m, 2H), 3.77(s, 3H), 2.54( t, J=7.2Hz, 2H), 2.06 (p, J=7.3Hz, 2H); 13CNMR (101MHz, CDCl3) δ 156.80, 151.60, 140.18, 137.52, 136.25, 135.69, 130.34, 129.02, 128.65, 128.34, 126.43, 120.53,111.76,93.65,55.95,43.80,32.67,30.78; HRMS calcd for C23H21ClN2O[M+H]+377.1415,found 377.1414.
化合物130 2-(3-氟苯基)-6-甲氧基-1-(3-苯丙基)-1H-苯并[d]咪唑:灰色粉末,产率81％.m.p.104.5-105.6℃；1H NMR(400MHz,CDCl3)δ7.71(d,J＝8.8Hz,1H),7.49–7.38(m,3H),7.35–7.28(m,1H),7.30(s,1H),7.29–7.15(m,2H),7.20–7.09(m,2H),6.96(dd,J＝8.8,2.4Hz,1H),6.71(d,J＝2.3Hz,1H),4.25–4.16(m,2H),3.87(s,3H),2.64(t,J＝7.2Hz,2H),2.23–2.11(m,2H)；13CNMR(101MHz,CDCl3)δ163.94,161.48,156.85,151.39(d,J＝2.4Hz),140.21,137.54,136.27,132.71,130.43,130.34,128.64,128.31,126.41,124.74,124.71,120.65,116.63,116.43,116.17,111.84,93.63,55.94,43.88,32.72,30.78；HRMScalcd for C23H21FN2O[M+H]+361.1711,found 361.1713. Compound 130 2-(3-Fluorophenyl)-6-methoxy-1-(3-phenylpropyl)-1H-benzo[d]imidazole: grey powder, 81% yield.mp 104.5-105.6℃ ;1H NMR(400MHz,CDCl3)δ7.71(d,J=8.8Hz,1H),7.49-7.38(m,3H),7.35-7.28(m,1H),7.30(s,1H),7.29-7.15 (m, 2H), 7.20–7.09 (m, 2H), 6.96 (dd, J=8.8, 2.4Hz, 1H), 6.71 (d, J=2.3Hz, 1H), 4.25–4.16 (m, 2H), 3.87 (s, 3H), 2.64 (t, J=7.2Hz, 2H), 2.23–2.11 (m, 2H); 13CNMR (101MHz, CDCl3) δ 163.94, 161.48, 156.85, 151.39 (d, J=2.4Hz), 140.21,137.54,136.27,132.71,130.43,130.34,128.64,128.31,126.41,124.74,124.71,120.65,116.63,116.43,116.17,111.84,93.63,55.94,43.88,32.72,30.78; HRMScalcd for C23H21FN2O [M + H] +361.1711,found 361.1713.
化合物131 2-(4-氟苯基)-6-甲氧基-1-(3-苯丙基)-1H-苯并[d]咪唑:褐色粉末,产率88％.m.p.137.8-138.6℃；1H NMR(400MHz,CDCl3)δ7.60(d,J＝8.8Hz,1H),7.57–7.47(m,2H),7.26–7.10(m,3H),7.11–6.98(m,4H),6.86(dd,J＝8.8,2.4Hz,1H),6.63(d,J＝2.3Hz,1H),4.12–4.03(m,2H),3.78(s,3H),2.54(t,J＝7.2Hz,2H),2.06(dq,J＝9.6,7.3Hz,2H)；13CNMR(101MHz,CDCl3)δ162.19,156.71,151.84,140.24,137.49,136.17,131.09,131.01,128.64,128.34,126.42,120.45,115.99,115.77,111.60,93.70,77.24,55.96,43.79,32.70,30.78；HRMS calcd for C23H21FN2O[M+H]+361.1711,found 361.1711.Compound 131 2-(4-Fluorophenyl)-6-methoxy-1-(3-phenylpropyl)-1H-benzo[d]imidazole: brown powder, 88% yield.mp 137.8-138.6℃ ;1H NMR(400MHz,CDCl3)δ7.60(d,J=8.8Hz,1H),7.57-7.47(m,2H),7.26-7.10(m,3H),7.11-6.98(m,4H),6.86 (dd, J=8.8, 2.4Hz, 1H), 6.63 (d, J=2.3Hz, 1H), 4.12–4.03 (m, 2H), 3.78 (s, 3H), 2.54 (t, J=7.2Hz, 2H), 2.06 (dq, J=9.6, 7.3Hz, 2H); 13CNMR (101MHz, CDCl3) δ162.19, 156.71, 151.84, 140.24, 137.49, 136.17, 131.09, 131.01, 128.64, 128.34, 126.42, 125.975, 126.42, 125.945 ,111.60,93.70,77.24,55.96,43.79,32.70,30.78; HRMS calcd for C23H21FN2O[M+H]+361.1711,found 361.1711.
化合物132 2-(噻吩-2-基)-6-甲氧基-1-(3-苯丙基)-1H-苯并[d]咪唑：黄色固体，产率95％.m.p.134.7-135.7℃；1H NMR(400MHz,DMSO-d6)δ8.16–8.07(m,1H),7.80(t,J＝2.8Hz,1H),7.71(dd,J＝9.0,2.1Hz,1H),7.46(s,1H),7.35(q,J＝3.5,2.5Hz,1H),7.32–7.25(m,2H),7.21(d,J＝7.2Hz,3H),7.15(d,J＝9.1Hz,1H),4.55(t,J＝7.9Hz,2H),3.90(d,J＝2.0Hz,3H),2.74(t,J＝7.7Hz,2H),2.15(p,J＝7.7Hz,2H)；13CNMR(101MHz,DMSO-d6)δ158.44,144.22,141.02,134.81,133.68,133.16,129.26,128.87,128.82,127.72,126.59,124.72,116.47,116.12,95.73,56.65,45.13,32.25,30.65；HRMS calcd forC21H20N2OS[M+H]+349.1369found 349.1369. Compound 132 2-(thiophen-2-yl)-6-methoxy-1-(3-phenylpropyl)-1H-benzo[d]imidazole: yellow solid, 95% yield.mp 134.7-135.7°C ;1H NMR(400MHz,DMSO-d6)δ8.16-8.07(m,1H),7.80(t,J=2.8Hz,1H),7.71(dd,J=9.0,2.1Hz,1H),7.46(s ,1H),7.35(q,J＝3.5,2.5Hz,1H),7.32–7.25(m,2H),7.21(d,J＝7.2Hz,3H),7.15(d,J＝9.1Hz,1H) ,4.55(t,J=7.9Hz,2H),3.90(d,J=2.0Hz,3H),2.74(t,J=7.7Hz,2H),2.15(p,J=7.7Hz,2H);13CNMR (101MHz, DMSO-d6) δ158.44,144.22,141.02,134.81,133.68,133.16,129.26,128.87,128.82,127.72,126.59,124.72,116.47,116.12,95.73,56.65,45.13,32.25,30.65; HRMS calcd forC21H20N2OS [M +H]+349.1369found 349.1369.
化合物133 2-(呋喃-2-基)-6-甲氧基-1-(3-苯丙基)-1H-苯并[d]咪唑：黄色固体，产率78％.m.p.169.1-171.0℃；1H NMR(400MHz,DMSO-d6)δ8.19(d,J＝1.7Hz,1H),7.68(d,J＝8.9Hz,1H),7.49(dd,J＝5.8,3.0Hz,2H),7.34–7.25(m,2H),7.28–7.14(m,4H),6.93(dd,J＝3.7,1.8Hz,1H),4.65(s,1H),4.65(d,J＝15.3Hz,1H),3.90(s,3H),2.79(t,J＝7.6Hz,2H),2.23–2.06(m,2H).13C NMR(101MHz,DMSO-d6)δ158.65,148.44,141.16,139.7,139.17,134.48,128.87,128.79,126.74,126.56,117.87,116.53,116.03,113.94,95.77,56.69,45.47,32.29,30.55；HRMS calcd for C21H20N2O2[M+H]+333.1598,found 333.1599.Compound 133 2-(furan-2-yl)-6-methoxy-1-(3-phenylpropyl)-1H-benzo[d]imidazole: yellow solid, 78% yield.mp 169.1-171.0°C ;1H NMR(400MHz,DMSO-d6)δ8.19(d,J=1.7Hz,1H),7.68(d,J=8.9Hz,1H),7.49(dd,J=5.8,3.0Hz,2H), 7.34–7.25 (m, 2H), 7.28–7.14 (m, 4H), 6.93 (dd, J=3.7, 1.8Hz, 1H), 4.65 (s, 1H), 4.65 (d, J=15.3Hz, 1H) ,3.90(s,3H),2.79(t,J=7.6Hz,2H),2.23–2.06(m,2H).13C NMR(101MHz,DMSO-d6)δ158.65,148.44,141.16,139.7,139.17,134.48, 128.87, 128.79, 126.74, 126.56, 117.87, 116.53, 116.03, 113.94, 95.77, 56.69, 45.47, 32.29, 30.55; HRMS calcd for C21H20N2O2[M+H]+333.1598, found 333.1
化合物134 2-丁基-6-甲氧基-1-(3-苯丙基)-1H-苯并[d]咪唑:白色粉末,产率94％.m.p.133.8-134.7℃；1H NMR(400MHz,DMSO-d6)δ7.72(d,J＝8.9Hz,1H),7.44(d,J＝2.3Hz,1H),7.35–7.29(m,2H),7.30–7.25(m,2H),7.25–7.19(m,1H),7.16(dd,J＝9.0,2.3Hz,1H),4.45(t,J＝7.7Hz,2H),3.88(s,3H),3.11(tt,J＝12.2,3.5Hz,1H),2.19–2.06(m,2H),1.95(d,J＝12.5Hz,2H),1.87–1.78(m,2H),1.74(d,J＝12.3Hz,1H),1.64(qd,J＝12.4,3.0Hz,2H),1.45–1.21(m,3H).13CNMR(101MHz,DMSO-d6)δ158.47,152.51,139.77,132.14,128.82,128.61,128.50,126.68,124.63,116.89,115.87,94.05,56.19,43.75,32.35,30.49,29.64,24.95,22.34,13.56；HRMS calcd for C21H26N2O[M+H]+323.2118,found 323.2116.Compound 134 2-butyl-6-methoxy-1-(3-phenylpropyl)-1H-benzo[d]imidazole: white powder, yield 94%.mp 133.8-134.7℃;1H NMR (400MHz ,DMSO-d6)δ7.72(d,J=8.9Hz,1H),7.44(d,J=2.3Hz,1H),7.35–7.29(m,2H),7.30–7.25(m,2H),7.25 –7.19(m,1H),7.16(dd,J=9.0,2.3Hz,1H),4.45(t,J=7.7Hz,2H),3.88(s,3H),3.11(tt,J=12.2,3.5 Hz, 1H), 2.19–2.06 (m, 2H), 1.95 (d, J=12.5Hz, 2H), 1.87–1.78 (m, 2H), 1.74 (d, J=12.3Hz, 1H), 1.64 (qd , J=12.4,3.0Hz,2H),1.45–1.21(m,3H).13CNMR(101MHz,DMSO-d6)δ158.47,152.51,139.77,132.14,128.82,128.61,128.50,126.68,124.63,116.89,115.87 94.05, 56.19, 43.75, 32.35, 30.49, 29.64, 24.95, 22.34, 13.56; HRMS calcd for C21H26N2O[M+H]+323.2118, found 323.2116.
化合物135 2-环己基-6-甲氧基-1-(3-苯丙基)-1H-苯并[d]咪唑:黄色粉末,产率96％.m.p.176.5-177.4℃；1H NMR(400MHz,DMSO-d6)δ7.72(d,J＝8.9Hz,1H),7.44(d,J＝2.3Hz,1H),7.37–7.12(m,6H),4.45(t,J＝7.7Hz,2H),3.88(s,3H),3.11(tt,J＝12.2,3.5Hz,1H),2.76(t,J＝7.6Hz,2H),2.18–2.07(m,2H),1.95(d,J＝12.5Hz,2H),1.87–1.78(m,2H),1.78–1.67(m,1H),1.62(td,J＝12.5,3.2Hz,2H),1.45–1.22(m,3H).13CNMR(101MHz,DMSO-d6)δ158.40,156.36,141.17,133.00,128.94,128.78,126.60,125.21,116.04,115.64,96.13,56.68,44.16,34.63,32.05,30.85,30.79,25.52,25.40；HRMScalcd for C23H28N2O[M+H]+349.2274,found 349.2278。 Compound 135 2-Cyclohexyl-6-methoxy-1-(3-phenylpropyl)-1H-benzo[d]imidazole: yellow powder, yield 96%.mp176.5-177.4℃;1H NMR (400MHz ,DMSO-d6)δ7.72(d,J＝8.9Hz,1H),7.44(d,J＝2.3Hz,1H),7.37–7.12(m,6H),4.45(t,J＝7.7Hz,2H) ), 3.88(s, 3H), 3.11(tt, J=12.2, 3.5Hz, 1H), 2.76(t, J=7.6Hz, 2H), 2.18–2.07(m, 2H), 1.95(d, J= 12.5Hz, 2H), 1.87–1.78 (m, 2H), 1.78–1.67 (m, 1H), 1.62 (td, J=12.5, 3.2Hz, 2H), 1.45–1.22 (m, 3H). 13CNMR (101MHz) , DMSO-d6) δ158.40,156.36,141.17,133.00,128.94,128.78,126.60,125.21,116.04,115.64,96.13,56.68,44.16,34.63,32.05,30.85,30.79,25.52,25.40; HRMScalcd for C23H28N2O [M + H ]+349.2274, found 349.2278.
化合物136 6-甲基-1-苯甲基-2-苯基-1H-苯并[d]咪唑：浅黄色粉末，产率93％，m.p.202.4-203℃。1H NMR(400MHz,CDCl3,ppm)δ7.74(d,J＝8.2Hz,1H),7.70-7.63(m,2H),7.50-7.39(m,3H),7.38-7.28(m,3H),7.17-7.07(m,3H),7.00(s,1H),5.42(s,2H),2.44(s,3H)；13CNMR(100MHz,CDCl3,ppm)δ153.74,141.29,136.59,136.37,133.12,130.22,129.77,129.20,129.08,128.72,127.72,125.92,124.32,119.51,110.30,48.26,21.88；MScalcd for:C21H18N2[M+H]+299.1543,found 299.1608。 Compound 136 6-Methyl-1-benzyl-2-phenyl-1H-benzo[d]imidazole: pale yellow powder, 93% yield, m.p. 202.4-203°C. 1H NMR (400MHz, CDCl3, ppm) δ7.74 (d, J=8.2Hz, 1H), 7.70-7.63 (m, 2H), 7.50-7.39 (m, 3H), 7.38-7.28 (m, 3H), 7.17-7.07 (m, 3H), 7.00 (s, 1H), 5.42 (s, 2H), 2.44 (s, 3H); 129.77, 129.20, 129.08, 128.72, 127.72, 125.92, 124.32, 119.51, 110.30, 48.26, 21.88; MScalcd for: C21H18N2[M+H]+299.1543, found 299.1608.
化合物137 2-(4-氯苯基)-6-甲基-1-苯甲基-1H-苯并[d]咪唑：淡黄色粉末，产率89％，m.p.180.9-181.9℃。1H NMR(400MHz,CDCl3,ppm)δ7.74(d,J＝8.2Hz,1H),7.63-7.56(m,2H),7.43-7.30(m,5H),7.17-7.06(m,3H),7.01(t,J＝4.1Hz,1H),5.40(s,2H),2.45(s,3H)； 13CNMR(100MHz,CDCl3,ppm)δ152.52,141.20,136.46,136.37,136.03,133.45,130.44,129.18,129.03,128.68,127.86,125.81,124.54,119.57,110.25,48.25,21.89；MScalcd for:C21H17ClN2[M+H]+333.1153,found 333.1234。Compound 137 2-(4-Chlorophenyl)-6-methyl-1-benzyl-1H-benzo[d]imidazole: pale yellow powder, 89% yield, m.p. 180.9-181.9°C. 1H NMR (400MHz, CDCl3, ppm) δ7.74 (d, J=8.2Hz, 1H), 7.63-7.56 (m, 2H), 7.43-7.30 (m, 5H), 7.17-7.06 (m, 3H), 7.01(t, J=4.1Hz, 1H), 5.40(s, 2H), 2.45(s, 3H); 13CNMR (100MHz, CDCl3, ppm) δ 152.52, 141.20, 136.46, 136.37, 136.03, 133.45, 130.44, 129.18, 129.03, 128.68, 127.86, 125.81, 124.54, 119.57, 110.25, 48.25, 21.89; MScalcd for: C21H17ClN2[M+H]+333.1153, found 333.1234.
化合物138 6-甲基-1-苯甲基-2-(对甲苯基)-1H-苯并[d]咪唑：淡黄色粉末，产率98％，m.p.196.4-197.5℃。1H NMR(400MHz,CDCl3,ppm)δ7.73(d,J＝8.2Hz,1H),7.55(d,J＝8.1Hz,2H),7.37-7.29(m,3H),7.24(d,J＝7.9Hz,2H),7.12(dd,J＝9.3,3.8Hz,3H),6.99(s,1H),5.41(s,2H),2.43(s,3H),2.39(s,3H)；13CNMR(100MHz,CDCl3,ppm)δ153.91,141.27,139.90,136.69,136.38,132.93,129.42,129.08,129.05,127.66,127.27,125.92,124.21,119.39,110.24,48.26,21.86,21.42；MS calcd for:C22H20N2[M+H]+313.1699,found 313.1774。 Compound 138 6-Methyl-1-benzyl-2-(p-tolyl)-1H-benzo[d]imidazole: pale yellow powder, 98% yield, m.p. 196.4-197.5°C. 1H NMR (400MHz, CDCl3, ppm) δ7.73 (d, J=8.2Hz, 1H), 7.55 (d, J=8.1Hz, 2H), 7.37-7.29 (m, 3H), 7.24 (d, J= 7.9Hz,2H), 7.12(dd,J=9.3,3.8Hz,3H), 6.99(s,1H), 5.41(s,2H), 2.43(s,3H), 2.39(s,3H); 13CNMR( 100MHz, CDCl3, ppm) δ153.91,141.27,139.90,136.69,136.38,132.93,129.42,129.08,129.05,127.66,127.27,125.92,124.21,119.39,110.24,48.26,21.86,21.42; MS calcd for: C22H20N2 [M + H]+313.1699, found 313.1774.
化合物139 6-甲基-2-(4-硝基苯基)-1-苯甲基-1H-苯并[d]咪唑:淡黄色粉末，产率62％，m.p.163.0-163.8℃。1H NMR(400MHz,CDCl3,ppm)δ7.73(d,J＝8.2Hz,1H),7.52-7.46(m,2H),7.39-7.28(m,3H),7.12(d,J＝7.0Hz,3H),6.97(s,1H),6.73-6.66(m,2H),5.42(s,2H),2.44(s,3H)；13CNMR(100MHz,CDCl3,ppm)δ154.33,147.91,141.28,136.87,136.42,132.52,130.47,129.03,127.59,125.93,124.01,119.95,119.07,114.81,110.11,50.86,21.83；MS calcd for:C21H17N3O2[M+H]+344.1394,found 344.1397。Compound 139 6-Methyl-2-(4-nitrophenyl)-1-benzyl-1H-benzo[d]imidazole: pale yellow powder, 62% yield, m.p. 163.0-163.8°C. 1H NMR (400MHz, CDCl3, ppm) δ7.73 (d, J=8.2Hz, 1H), 7.52-7.46 (m, 2H), 7.39-7.28 (m, 3H), 7.12 (d, J=7.0Hz, 3H), 6.97(s, 1H), 6.73-6.66(m, 2H), 5.42(s, 2H), 2.44(s, 3H); 13CNMR (100MHz, CDCl3, ppm) δ 154.33, 147.91, 141.28, 136.87, 136.42 ,132.52,130.47,129.03,127.59,125.93,124.01,119.95,119.07,114.81,110.11,50.86,21.83; MS calcd for:C21H17N3O2[M+H]+344.1394,found 344.1397.
化合物140 6-甲基-1-苯甲基-2-(吡啶-4-基)-1H-苯并[d]咪唑:淡黄色粉末，产率76％，m.p.230.8-231.5℃。1H NMR(400MHz,CDCl3,ppm)δ8.69(dd,J＝4.5,1.5Hz,2H),7.77(d,J＝8.3Hz,1H),7.58(dd,J＝4.5,1.6Hz,2H),7.42-7.29(m,3H),7.18(d,J＝8.3Hz,1H),7.10(d,J＝6.7Hz,2H),7.06(s,1H),5.45(d,J＝10.8Hz,2H),2.46(s,3H)；13CNMR(100MHz,CDCl3,ppm)δ150.63,150.36,141.27,137.81,136.69,136.01,134.27,129.29,128.04,125.73,124.99,123.11,120.01,110.30,48.29,21.93；MS calcd for:C20H17N3[M+H]+300.1495,found300.1572。 Compound 140 6-Methyl-1-benzyl-2-(pyridin-4-yl)-1H-benzo[d]imidazole: pale yellow powder, 76% yield, m.p. 230.8-231.5°C. 1H NMR (400MHz, CDCl3, ppm) δ8.69 (dd, J=4.5, 1.5Hz, 2H), 7.77 (d, J=8.3Hz, 1H), 7.58 (dd, J=4.5, 1.6Hz, 2H) ,7.42-7.29(m,3H),7.18(d,J＝8.3Hz,1H),7.10(d,J＝6.7Hz,2H),7.06(s,1H),5.45(d,J＝10.8Hz, 2H),2.46(s,3H);13CNMR(100MHz,CDCl3,ppm)δ150.63,150.36,141.27,137.81,136.69,136.01,134.27,129.29,128.04,125.73,124.99,123.11,120.01,110; MS calcd for: C20H17N3[M+H]+300.1495, found300.1572.
化合物141 6-甲基-1-苯乙基-2-苯基-1H-苯并[d]咪唑：黄色粉末，产率89％，m.p.96.6-97.4℃。1H NMR(400MHz,DMSO-d6,ppm)δ7.60-7.46(m,7H),7.21-7.13(m,3H),7.08(dd,J＝8.2,1.1Hz,1H),6.98-6.91(m,2H),4.44(t,J＝7.4Hz,2H),2.99(t,J＝7.4Hz,2H),2.49(s,3H)；13CNMR(100MHz,DMSO-d6,ppm)δ153.19,141.25,138.26,136.07,132.28,131.01,129.84,129.50,129.08,128.96,128.81,126.97,123.96,119.22,111.21,46.01,35.43,21.96；；MS calcd for:C22H20N2[M+H]+313.1699,found 313.1713。Compound 141 6-Methyl-1-phenethyl-2-phenyl-1H-benzo[d]imidazole: yellow powder, 89% yield, m.p. 96.6-97.4°C. 1H NMR(400MHz,DMSO-d6,ppm)δ7.60-7.46(m,7H),7.21-7.13(m,3H),7.08(dd,J=8.2,1.1Hz,1H),6.98-6.91(m , 2H), 4.44 (t, J=7.4Hz, 2H), 2.99 (t, J=7.4Hz, 2H), 2.49 (s, 3H); 13CNMR (100MHz, DMSO-d6, ppm) δ153.19, 141.25, 138.26 ,136.07,132.28,131.01,129.84,129.50,129.08,128.96,128.81,126.97,123.96,119.22,111.21,46.01,35.43,21.96;;
化合物142 2-(4-氯苯基)-6-甲基-1-苯乙基-1H-苯并[d]咪唑：淡黄色粉末，产率91％，m.p.119.7-120.4℃。1H NMR(400MHz,DMSO-d6,ppm)δ7.58-7.55(m,1H),7.55-7.52(m,4H),7.52-7.48(m,2H),7.20-7.13(m,3H),7.09(dd,J＝8.2,1.1Hz,1H),6.94-6.89(m,2H),4.46(t,J＝7.2Hz,2H),2.99(t,J＝7.2Hz,2H),2.49(s,3H)；13CNMR(100MHz,DMSO-d6,ppm)δ152.05,141.20,138.21,136.09,134.64,132.50,131.25,129.84,129.11,129.02,128.79,127.01,124.12,119.29,111.30,46.06,35.37,21.97；MS calcd for:C22H19ClN2[M+H]+347.1310,found347.1370。 Compound 142 2-(4-Chlorophenyl)-6-methyl-1-phenethyl-1H-benzo[d]imidazole: pale yellow powder, 91% yield, m.p. 119.7-120.4°C. 1H NMR(400MHz,DMSO-d6,ppm)δ7.58-7.55(m,1H),7.55-7.52(m,4H),7.52-7.48(m,2H),7.20-7.13(m,3H),7.09 (dd, J=8.2, 1.1Hz, 1H), 6.94-6.89(m, 2H), 4.46(t, J=7.2Hz, 2H), 2.99(t, J=7.2Hz, 2H), 2.49(s, 3H);13CNMR(100MHz,DMSO-d6,ppm)δ152.05,141.20,138.21,136.09,134.64,132.50,131.25,129.84,129.11,129.02,128.79,127.01,12MS4.12,119.21,9,5.3;37. calcd for: C22H19ClN2[M+H]+347.1310, found347.1370.
化合物143 6-甲基-1-苯乙基-2-(对甲苯基)-1H-苯并[d]咪唑:淡黄色粉末，产率70％，m.p.113.8-114.2℃。1H NMR(400MHz,DMSO-d6,ppm)δ7.54(d,J＝8.2Hz,1H),7.49-7.41(m,3H),7.31(d,J＝7.9Hz,2H),7.25-7.15(m,3H),7.07(d,J＝9.3Hz,1H),7.03-6.96(m,2H),4.43(t,J＝14.9Hz,2H),3.01(t,J＝14.9Hz,2H),2.48(s,3H),2.40(s,3H)；13CNMR(100MHz,DMSO-d6,ppm)δ153.24,141.23,139.47,138.32,136.11,132.10,129.56,129.40,129.12,128.83,128.17,126.99,123.86,119.10,111.15,46.01,35.44,21.95,21.42；MScalcd for:C23H22N2[M+H]+327.1856,found 327.1867. Compound 143 6-Methyl-1-phenethyl-2-(p-tolyl)-1H-benzo[d]imidazole: pale yellow powder, 70% yield, m.p. 113.8-114.2°C. 1H NMR(400MHz,DMSO-d6,ppm)δ7.54(d,J=8.2Hz,1H),7.49-7.41(m,3H),7.31(d,J=7.9Hz,2H),7.25-7.15( m, 3H), 7.07(d, J=9.3Hz, 1H), 7.03-6.96(m, 2H), 4.43(t, J=14.9Hz, 2H), 3.01(t, J=14.9Hz, 2H), 2.48(s,3H),2.40(s,3H); 13CNMR(100MHz,DMSO-d6,ppm)δ153.24,141.23,139.47,138.32,136.11,132.10,129.56,129.40,129.12,128.83,128.17,126.99,128.17,123.86 119.10, 111.15, 46.01, 35.44, 21.95, 21.42; MScalcd for: C23H22N2[M+H]+327.1856, found 327.1867.
化合物144 6-甲基-2-(4-硝基苯基)-1-苯乙基-1H-苯并[d]咪唑：黄色粉末，54％，m.p.220.8-221.9℃；1H NMR(400MHz,CDCl3,ppm)δ7.67(d,J＝8.2Hz,1H),7.34-7.29(m,2H),7.28-7.18(m,5H),7.17(s,1H),7.12(d,J＝8.2Hz,1H),7.05-6.98(m,2H),4.40(t,2H),3.09(t,2H),2.53(s,3H)；13CNMR(100MHz,CDCl3,ppm)δ153.91,147.75,137.66,132.36,130.46,128.72,128.68,126.88,123.86,121.56,119.10,114.74,110.13,109.85,46.14,35.91,21.93；MS calcd for:C22H19N3O2[M+H]+358.1550,found 358.2650。 Compound 144 6-Methyl-2-(4-nitrophenyl)-1-phenethyl-1H-benzo[d]imidazole: yellow powder, 54%, mp220.8-221.9℃;1H NMR (400MHz, CDCl3,ppm)δ7.67(d,J=8.2Hz,1H),7.34-7.29(m,2H),7.28-7.18(m,5H),7.17(s,1H),7.12(d,J=8.2 Hz,1H),7.05-6.98(m,2H),4.40(t,2H),3.09(t,2H),2.53(s,3H);13CNMR(100MHz,CDCl3,ppm)δ153.91,147.75,137.66,132.36 ,130.46,128.72,128.68,126.88,123.86,121.56,119.10,114.74,110.13,109.85,46.14,35.91,21.93; MS calcd for:C22H19N3O2[M+H]+358.1550,found 3.8
化合物145 6-甲基-1-苯乙基-2-(吡啶-4-基)-1H-苯并[d]咪唑：灰色粉末，产率84％，m.p.100.5-101.5℃；1H NMR(400MHz,CDCl3,ppm)δ8.61(d,J＝5.3Hz,2H),7.72(d,J＝8.2Hz,1H),7.23(d,J＝6.0Hz,3H),7.19-7.10(m,4H),6.77(d,J＝7.3Hz,2H),4.44(t,J＝6.9Hz,2H),3.04(t,J＝6.8Hz,2H),2.51(s,3H)；13CNMR(100MHz,CDCl3,ppm)δ150.59,149.94,141.28,138.14,137.05,135.59,133.76,128.76,128.62,127.10,124.69,123.31,119.97,110.25,46.15,35.63,22.02；MS calcd for:C21H19N3[M+H]+314.1652,found314.1666。Compound 145 6-Methyl-1-phenethyl-2-(pyridin-4-yl)-1H-benzo[d]imidazole: grey powder, 84% yield, mp 100.5-101.5°C; 1H NMR (400MHz) ,CDCl3,ppm)δ8.61(d,J＝5.3Hz,2H),7.72(d,J＝8.2Hz,1H),7.23(d,J＝6.0Hz,3H),7.19-7.10(m,4H ), 6.77(d, J=7.3Hz, 2H), 4.44(t, J=6.9Hz, 2H), 3.04(t, J=6.8Hz, 2H), 2.51(s, 3H); 13CNMR(100MHz, CDCl3 , ppm) δ150.59,149.94,141.28,138.14,137.05,135.59,133.76,128.76,128.62,127.10,124.69,123.31,119.97,110.25,46.15,35.63,22.02; MS calcd for: C21H19N3 [M + H] +314.1652, found314.1666.
化合物146 6-甲基-2-苯基-1-(3-苯基丙基)-1H-苯并[d]咪唑：淡黄色粉末，产率89％，m.p.89.3-90.2℃；1H NMR(400MHz,DMSO-d6,ppm)δ7.71-7.65(m,2H),7.58-7.47(m,4H),7.35(s,1H),7.29-7.23(m,2H),7.22-7.16(m,1H),7.15-7.05(m,3H),4.23(t,2H),2.55(t,J＝7.4Hz,2H),2.47(s,3H),2.09-1.99(m,2H)；13C NMR(100MHz,DMSO-d6,ppm)δ152.81,141.26,141.13,136.35,132.25,131.01,129.93,129.44,129.14,128.82,128.74,126.45,123.94,119.24,110.94,43.90,32.41,31.05,21.96；MS calcd for:C23H22N2[M+H]+327.1856,found 327.1920。Compound 146 6-methyl-2-phenyl-1-(3-phenylpropyl)-1H-benzo[d]imidazole: pale yellow powder, 89% yield, mp 89.3-90.2°C; 1H NMR ( 400MHz,DMSO-d6,ppm)δ7.71-7.65(m,2H),7.58-7.47(m,4H),7.35(s,1H),7.29-7.23(m,2H),7.22-7.16(m, 1H), 7.15-7.05(m, 3H), 4.23(t, 2H), 2.55(t, J=7.4Hz, 2H), 2.47(s, 3H), 2.09-1.99(m, 2H); 13C NMR( 100MHz, DMSO-d6, ppm) δ152.81,141.26,141.13,136.35,132.25,131.01,129.93,129.44,129.14,128.82,128.74,126.45,123.94,119.24,110.94,43.90,32.41,31.05,21.96; MS calcd for: C23H22N2[M+H]+327.1856, found 327.1920.
化合物147 2-(4-氯苯基)-6-甲基-1-(3-苯基丙基)-1H-苯并[d]咪唑：淡黄色粉末，产率91％，m.p.140.9-142.2℃；1H NMR(400MHz,DMSO-d6,ppm)δ7.74-7.66(m,2H),7.60-7.52(m,3H),7.37(s,1H),7.31-7.23(m,2H),7.22-7.16(m,1H),7.15-7.05(m,3H),4.22(t,2H),2.54(t,2H),2.46(s,3H),2.08-1.97(m,2H)；13CNMR(100MHz,DMSO-d6,ppm)δ151.65,141.16,141.08,136.37,134.80,132.52,131.24,129.80,129.23,128.80,128.75,126.43,124.12,119.30,111.01,43.88,32.34,31.01,21.96；MS calcd for:C23H21ClN2[M+H]+361.1466,found 361.1480。 Compound 147 2-(4-Chlorophenyl)-6-methyl-1-(3-phenylpropyl)-1H-benzo[d]imidazole: pale yellow powder, 91% yield, mp 140.9-142.2 ℃;1H NMR(400MHz,DMSO-d6,ppm)δ7.74-7.66(m,2H),7.60-7.52(m,3H),7.37(s,1H),7.31-7.23(m,2H),7.22 -7.16(m, 1H), 7.15-7.05(m, 3H), 4.22(t, 2H), 2.54(t, 2H), 2.46(s, 3H), 2.08-1.97(m, 2H); 13CNMR(100MHz) , DMSO-d6, ppm) δ151.65,141.16,141.08,136.37,134.80,132.52,131.24,129.80,129.23,128.80,128.75,126.43,124.12,119.30,111.01,43.88,32.34,31.01,21.96; MS calcd for: C23H21ClN2 [M+H]+361.1466, found 361.1480.
化合物148 6-甲基-1-(3-苯基丙基)-2-(对甲苯基)-1H-苯并[d]咪唑:淡黄色粉末，产率71％，m.p.116.8-117.9℃；1H NMR(400MHz,DMSO-d6,ppm)δ7.55(dd,J＝11.2,8.2Hz,3H),7.35-7.23(m,5H),7.22-7.15(m,1H),7.14-7.09(m,2H),7.06(dd,J＝8.2,1.1Hz,1H),4.22(t,2H),2.54(t,2H),2.46(s,3H),2.40(s,3H),2.08-1.97(m,H)；13CNMR(100MHz,DMSO-d6,ppm)δ152.91,141.19,141.14,139.55,136.32,132.11,129.72,129.33,128.80,128.74,128.12,126.42,123.87,119.11,110.87,43.87,32.41,31.07,21.95,21.43；MS calcd for:C24H24N2[M+H]+341.2012,found 341.2019。Compound 148 6-methyl-1-(3-phenylpropyl)-2-(p-tolyl)-1H-benzo[d]imidazole: pale yellow powder, yield 71%, mp 116.8-117.9°C; 1H NMR(400MHz,DMSO-d6,ppm)δ7.55(dd,J=11.2,8.2Hz,3H),7.35-7.23(m,5H),7.22-7.15(m,1H),7.14-7.09(m ,2H),7.06(dd,J＝8.2,1.1Hz,1H),4.22(t,2H),2.54(t,2H),2.46(s,3H),2.40(s,3H),2.08-1.97( m, H);13CNMR(100MHz,DMSO-d6,ppm)δ152.91,141.19,141.14,139.55,136.32,132.11,129.72,129.33,128.80,128.74,128.12,126.42,123.87,119.11,3.70.8 , 21.95, 21.43; MS calcd for: C24H24N2[M+H]+341.2012, found 341.2019.
化合物149 6-甲基-2-(4-硝基苯基)-1-(3-苯基丙基)-1H-苯并[d]咪唑：黄色粉末，产率65％，m.p.240.5-241.4℃；1H NMR(400MHz,CDCl3,ppm)δ7.65(d,J＝8.1Hz,1H),7.44(d,J＝8.5Hz,2H),7.30(d,J＝7.0Hz,3H),7.22(t,J＝7.3Hz,2H),7.14-7.06(m,4H),4.17(t,J＝16.3,8.4Hz,2H),2.62(t,J＝7.4Hz,2H),2.49(s,3H),2.21(m,2H)；13CNMR(100MHz,CDCl3,ppm)δ157.05,153.61,147.76,140.53,135.79,132.20,30.43,128.55,128.38,128.28,126.26,123.73,118.99,114.84,109.77,43.94,32.85,30.95,21.89。Compound 149 6-Methyl-2-(4-nitrophenyl)-1-(3-phenylpropyl)-1H-benzo[d]imidazole: yellow powder, 65% yield, mp 240.5-241.4 ℃;1H NMR(400MHz,CDCl3,ppm)δ7.65(d,J=8.1Hz,1H),7.44(d,J=8.5Hz,2H),7.30(d,J=7.0Hz,3H),7.22 (t, J＝7.3Hz, 2H), 7.14-7.06(m, 4H), 4.17(t, J＝16.3, 8.4Hz, 2H), 2.62(t, J＝7.4Hz, 2H), 2.49(s, 3H),2.21(m,2H);13CNMR(100MHz,CDCl3,ppm)δ157.05,153.61,147.76,140.53,135.79,132.20,30.43,128.55,128.38,128.28,126.26,123.73,118.79,414 32.85, 30.95, 21.89.
化合物150 6-甲基-1-(3-苯基丙基)-2-(吡啶-4-基)-1H-苯并[d]咪唑:灰色粉末，产率88％，m.p.101.3-103.2℃；1H NMR(400MHz,CDCl3,ppm)δ8.68(dd,J＝4.5,1.6Hz,2H),7.74-7.68(m,1H),7.53(dd,J＝4.5,1.6Hz,2H),7.33-7.27(m,3H),7.15-7.08(m,4H),4.23(t,J＝8.9,6.9Hz,2H),2.66(t,J＝7.2Hz,2H),2.52(s,3H),2.23-2.16(m,2H)；13CNMR(100MHz,CDCl3,ppm)δ150.3,149.9,143.6,141.2,140.0,138.2,136.1,133.8,128.7,128.4,126.6,124.65,123.17,119.93,110.04,43.90,32.71,31.11,21.98；MS calcd for:C22H21N3[M+H]+328.1808,found 328.1818。 Compound 150 6-Methyl-1-(3-phenylpropyl)-2-(pyridin-4-yl)-1H-benzo[d]imidazole: grey powder, 88% yield, mp 101.3-103.2°C ; 1H NMR (400MHz, CDCl3, ppm) δ 8.68 (dd, J=4.5, 1.6Hz, 2H), 7.74-7.68 (m, 1H), 7.53 (dd, J=4.5, 1.6Hz, 2H), 7.33 -7.27(m, 3H), 7.15-7.08(m, 4H), 4.23(t, J=8.9, 6.9Hz, 2H), 2.66(t, J=7.2Hz, 2H), 2.52(s, 3H), 2.23-2.16 (m, 2H); 13CNMR (100MHz, CDCl3, ppm) δ150.3, 149.9, 143.6, 141.2, 140.0, 138.2, 136.1, 133.8, 128.7, 128.4, 126.6, 124.65, 123.17, 119.9, 3, 2.10.4 , 31.11, 21.98; MS calcd for: C22H21N3[M+H]+328.1808, found 328.1818.
实施例2生物活性测定Example 2 Biological activity assay
用磷脂酶特异性底物12-＝(4,4-二氟5,7-二甲基-4-硼杂-3a,4a-二氮杂-s-引达省(indacene)-3-十一酰基)-sn-甘油基-3-磷酸胆碱(生产商Molecular Probes)来定义内皮脂酶的酶活性和抑制剂的作用。用酶水解该磷脂的A1酯键，释放出荧光染料Bodipy标记的脂肪酸，其可以通过薄层色谱法在TLC板(硅胶60，Merck)上分离后进行检测，或者直接在反应容器中通过测量荧光进行检测。Using the phospholipase specific substrate 12-=(4,4-difluoro5,7-dimethyl-4-bora-3a,4a-diaza-s-indacene-3-deca Monoacyl)-sn-glycero-3-phosphocholine (manufacturer Molecular Probes) to define the enzymatic activity and inhibitory effect of endothelial lipase. Enzymatic hydrolysis of the A1 ester bond of this phospholipid releases the fluorescent dye Bodipy-labeled fatty acids, which can be detected after separation by thin-layer chromatography on TLC plates (silica gel 60, Merck), or directly in the reaction vessel by measuring fluorescence test.
通过将100ug的1,2-二(4,4-二氟-5,7-二甲基-4-硼杂-3a,4a-二氮杂-s-引达省-3-十一酰基)-sn-甘油基-3-磷酸胆碱(生产商Molecular Probes)溶解于100ul DMSO中，吸收到包含20mg/m1DOP-胆碱(1,2-二油酰基-sn-甘油基3-磷酸胆碱)的2.4mg棕榈酸甘油酯在393μl氯仿中的2.4g棕榈精溶液中来制备底物溶液。转移39.3μl该脂类混合物到新的反应容器中，蒸发溶剂。通过超声处理两次将脂类混合物溶解在4ml 200mM TRIS-HCl,150mM氯化钠，pH＝7.4中。随后的酶促反应在37℃下进行90分钟。为此，将20μl底物溶液与2μl适宜浓度的抑制剂(溶于10％DMSO中，用10％的DMSO溶液作为对照)和2μl酶溶液(条件培养基)一起进行孵育。然后将4μl测试混合物上样到HPTLC板(硅胶60,Merck)上，用洗脱液(乙醚：石油醚：乙酸[78:22:1])分离释放的荧光染料以进行检测。蒸发洗脱液后，在荧光扫描仪中读板。观察未被抑制的反应中荧光染料释放的增加作为酶活性的量度。By adding 100ug of 1,2-bis(4,4-difluoro-5,7-dimethyl-4-bora-3a,4a-diaza-s-inda-3-undecanoyl) -sn-glycero-3-phosphocholine (manufacturer Molecular Probes) was dissolved in 100 ul DMSO and absorbed into a solution containing 20 mg/m1 DOP-choline (1,2-dioleoyl-sn-glycero-3-phosphocholine ) of 2.4 mg of glyceryl palmitate in a solution of 2.4 g of palmitrine in 393 μl of chloroform to prepare a substrate solution. Transfer 39.3 μl of this lipid mixture to a new reaction vessel and evaporate the solvent. The lipid mixture was dissolved in 4 ml of 200 mM TRIS-HCl, 150 mM sodium chloride, pH=7.4 by sonication twice. The subsequent enzymatic reaction was carried out at 37°C for 90 minutes. For this purpose, 20 μl of substrate solution was incubated with 2 μl of inhibitor at the appropriate concentration (dissolved in 10% DMSO, with 10% DMSO solution as control) and 2 μl of enzyme solution (conditioned medium). 4 μl of the test mixture was then loaded onto HPTLC plates (silica gel 60, Merck) and the released fluorescent dye was separated for detection with eluent (diethyl ether:petroleum ether:acetic acid [78:22:1]). After evaporating the eluate, read the plate in a fluorescence scanner. An increase in the release of the fluorescent dye in the uninhibited reaction was observed as a measure of the enzymatic activity.
酶活性的降低与所用抑制剂的浓度呈函数关系。所观察的半数最大酶活性的抑制剂浓度被称为IC50。在这些试验中，各实施例的化合物的IC50值如表1所示：The decrease in enzyme activity was a function of the concentration of inhibitor used. The inhibitor concentration at which half of the maximal enzyme activity observed is referred to as the IC50. In these tests, the IC50 values of the compounds of each example are shown in Table 1:
表1苯并咪唑类化合物的IC50值结果Table 1 IC50 value results of benzimidazole compounds
另外，通过多种试验模型来检测作为活性药物成分的本发明化合物的可用性。通过下述实施例来描述这些试验模型。In addition, the availability of the compounds of the present invention as active pharmaceutical ingredients is tested by various experimental models. These experimental models are described by the following examples.
在水性体系中的溶解度Solubility in Aqueous Systems
物质在水溶剂系统中足够的溶解度对于(可重复的)药物效果而言是重要的必要条件。可以通过不同的方法来检测在水系统中的溶解度。建立了合适的溶解沉淀方法(“动力学溶解度”)的例子和研究固体样品溶解直至平衡的方法(“热力学溶解度”)。Sufficient solubility of substances in aqueous solvent systems is an important prerequisite for (reproducible) drug effects. Solubility in aqueous systems can be tested by different methods. Examples of suitable dissolution precipitation methods ("kinetic solubility") and methods for studying the dissolution of solid samples until equilibrium ("thermodynamic solubility") are established.
a)动力学溶解度：a) Kinetic solubility:
将待测化合物的DMSO溶液(2.5mM；0.5μl)移至在96孔滴定板内的200uL水性试验溶液(例如磷酸盐缓冲盐水,10x,1M，Sigma，调至10mM，pH7.4)中，并用比浊计(例如Nephelostar Galaxy，BMG Labtech)在6.25uM的待测化合物的所得理论浓度下检测浑浊度。然后通过进一步加入DMSO溶液(2.5mM；0.5μL)使水性试验溶液中的待测化合物浓度升高至12.5μM，并重复检测浑浊度。在完成两次检测过程之间进一步加入DMSO溶液(1uL,2.5mM；0.5μL,10mM；然后9×1μL,10mM，获得理 论浓度25μM、50μM、100uM、150μM、200μM、250μM、300μM、350μM、400uM、450uM和500μM并检测浑浊度。A solution of the test compound in DMSO (2.5 mM; 0.5 μl) was transferred to 200 uL of an aqueous assay solution (eg, phosphate buffered saline, 10x, 1 M, Sigma, adjusted to 10 mM, pH 7.4) in a 96-well titer plate, The turbidity was also measured with a turbidimeter (eg Nephelostar Galaxy, BMG Labtech) at the resulting theoretical concentration of the test compound of 6.25 uM. The test compound concentration in the aqueous test solution was then increased to 12.5 μM by further addition of DMSO solution (2.5 mM; 0.5 μL), and the turbidity measurement was repeated. DMSO solution (1uL, 2.5mM; 0.5μL, 10mM; then 9×1 μL, 10mM; then 9 × 1μL, 10mM was added between the completion of the two detection processes to obtain theoretical concentrations of 25μM, 50μM, 100uM, 150μM, 200μM, 250μM, 300μM, 350μM, 400uM , 450uM and 500μM and check for turbidity.
评价：将来自比浊计的浑浊度值对应于待测化合物在水性试验溶液中的理论浓度绘图。一旦在理论浓度检测出显著的浑浊度(例如5倍于水性试验溶液的对照值)，就用以下的浓度水平作为溶液中待测化合物的溶解度界限。因此，最大可能检测范围显示为<625uM、6.25-500μM和>500uM的值。Evaluation: The turbidity value from the turbidimeter is plotted against the theoretical concentration of the test compound in the aqueous test solution. Once significant turbidity was detected at the theoretical concentration (eg, 5 times the control value for an aqueous test solution), the following concentration levels were used as solubility limits for the compounds to be tested in solution. Therefore, the maximum possible detection range is shown as values <625uM, 6.25-500μM and >500uM.
优选的苯并咪唑类化合物显示在磷酸盐缓冲液(pH7.4)中至少12.5μM的动力学溶解度；更加优选至少50μM、甚至更加优选至少250μM的动力学溶解度。Preferred benzimidazoles exhibit a kinetic solubility in phosphate buffer (pH 7.4) of at least 12.5 μM; more preferably at least 50 μM, even more preferably at least 250 μM.
b)热力学溶解度：b) Thermodynamic solubility:
在DMSO中的待测化合物(500uM、100uM、50uM、10uM和1uM)的系列稀释液从HPLCUV检测仪得到的整体的UV吸收显示出与浓度以校准线形式的线性相关。将待测化合物(500ug)与水性试验溶液(250uL)一起在密封的小瓶(容量:1.5mL)中震荡16小时(Eppendorf thermoshaker，1400rpm,25℃，遮盖避光)。然后将样品在最大转速离心，最后过滤上清。过滤的上清的样品直接用HPLC UV检测仪分析(参见上文)。另一份样品在稀释后分析(1份体积的上清,39份体积的试验溶液)。The overall UV absorbance obtained from the HPLC UV detector for serial dilutions of the test compound (500uM, 100uM, 50uM, 10uM and 1uM) in DMSO showed a linear correlation with concentration as a calibration line. The test compound (500 ug) was shaken together with the aqueous test solution (250 uL) in a sealed vial (capacity: 1.5 mL) for 16 hours (Eppendorf thermoshaker, 1400 rpm, 25°C, covered and protected from light). The samples were then centrifuged at maximum speed and the supernatant was finally filtered. A sample of the filtered supernatant was directly analyzed with an HPLC UV detector (see above). Another sample was analyzed after dilution (1 vol of supernatant, 39 vol of test solution).
评价：根据已建立的校准线，从上清样品所得的整体UV吸收计算出未稀释上清中的待测化合物的浓度，并表示为待测化合物在各自水性试验溶液中的溶解度。Evaluation: The concentration of the test compound in the undiluted supernatant was calculated from the bulk UV absorbance obtained for the supernatant samples according to the established calibration line and expressed as the solubility of the test compound in the respective aqueous test solutions.
水性试验溶液的例子是去离子水或具有多种pH值(例如pH 1.2；pH4.0；pH6.8；pH7.4；pH9.0)的水性磷酸盐缓冲液，其可以从商品化的溶液(磷酸盐缓冲生理盐水,10x，Sigma)通过稀释和按标准方法用磷酸或氢氧化钠溶液调节来制备。Examples of aqueous test solutions are deionized water or aqueous phosphate buffers with various pH values (eg pH 1.2; pH 4.0; pH 6.8; pH 7.4; pH 9.0), which can be obtained from commercial solutions (Phosphate Buffered Saline, 10x, Sigma) was prepared by dilution and adjustment with phosphoric acid or sodium hydroxide solutions according to standard methods.
优选的本发明化合物在磷酸盐缓冲液(pH7.4)中显示出至少12.5μM的溶解度；更加优选至少50μM、甚至更加优选至少250μM的溶解度。Preferred compounds of the invention exhibit solubility in phosphate buffer (pH 7.4) of at least 12.5 μM; more preferably at least 50 μM, even more preferably at least 250 μM.

Claims (10)

  1. 一种具有内皮脂肪酶抑制作用的苯并咪唑类化合物及其互变异构形式和生理学耐受的盐，其特征在于，所述苯并咪唑类化合物的结构如通式(I)所示：A benzimidazole compound with endothelial lipase inhibitory effect and its tautomeric form and physiologically tolerated salt, characterized in that the structure of the benzimidazole compound is as shown in general formula (I):
    式中，In the formula,
    当R1为时，若R3为H，则R2选自取代芳基、芳基烷基、卤代烷基，其中取代芳基中的取代基为邻位或者间位取代的卤素、C1-C8烷基、C3-C6环烷基、-ORc、邻位的硝基；或者，若R3为-C(O)RaRb，则R2选自邻位、间位或者对位取代的芳基，邻位、间位或者对位取代的芳杂环基，芳基烷基，卤代烷基，其中取代的芳基或者芳杂环中的取代基选自卤素、C1-C8烷基、-ORc、硝基；R4、R5、R6分别独立的选自H、-ORc、C1-C8烷基、氰基；R’为邻位、间位或者对位取代的H、卤素、-ORc、C1-C8烷基；When R1 is, if R3 is H, then R2 is selected from substituted aryl, arylalkyl, haloalkyl, wherein the substituent in substituted aryl is ortho- or meta-substituted halogen, C1-C8 alkyl, C3-C6 cycloalkyl, -ORc, nitro group in ortho position; or, if R3 is -C(O)RaRb, then R2 is selected from ortho, meta or para substituted aryl, ortho, meta Or para-substituted aromatic heterocyclic group, arylalkyl, haloalkyl, wherein the substituted aryl or the substituent in the aromatic heterocyclic ring is selected from halogen, C1-C8 alkyl, -ORc, nitro; R4, R5 , R6 are independently selected from H, -ORc, C1-C8 alkyl, cyano; R' is ortho, meta or para substituted H, halogen, -ORc, C1-C8 alkyl;
    当R1为时，R2选自未取代或取代的芳基、未取代或取代的芳杂环基、C3-C6环烷基、-ORc、C2-C8烷基、芳基烷基、卤代烷基，其中取代的芳基或者芳杂环基中的取代基选自邻位、间位或者对位取代的卤素、C1-C8烷基、ORc、硝基；R3为H、-C(O)RaRb、-ORc、C1-C8烷基、C3-C6环烷基；R4、R5、R6分别独立的选自H、-ORc、C1-C8烷基、氰基；R’为H、卤素、-ORc、C1-C8烷基；R”为邻位、间位或者对位取代的H、卤素、-ORc、C1-C8烷基；n为2-4；When R1 is, R2 is selected from unsubstituted or substituted aryl, unsubstituted or substituted aromatic heterocyclyl, C3-C6 cycloalkyl, -ORc, C2-C8 alkyl, arylalkyl, haloalkyl, Wherein the substituent in the substituted aryl or aromatic heterocyclic group is selected from ortho, meta or para substituted halogen, C1-C8 alkyl, ORc, nitro; R3 is H, -C(O)RaRb, -ORc, C1-C8 alkyl, C3-C6 cycloalkyl; R4, R5, R6 are independently selected from H, -ORc, C1-C8 alkyl, cyano; R' is H, halogen, -ORc, C1-C8 alkyl; R" is ortho, meta or para substituted H, halogen, -ORc, C1-C8 alkyl; n is 2-4;
    当R1为时，R2选自未取代或取代的芳基、未取代或取代的芳杂环基、C3-C6环烷基、-ORc、C2-C8烷基、芳基烷基、卤代烷基，其中取代的芳基或者芳杂环基中的取代基选自邻位、间位或者对位取代的卤素、C1-C8烷基、ORc、硝基；R3为H、-C(O)RaRb、-ORc、C1-C8烷基、C3-C6环烷基；R4、R5、R6分别独立的选自H、-ORc、C1-C8烷基、氰基；R’为H、卤素、-ORc、C1-C8烷基；R”’为邻位、间位或者对位取代的H、卤素、-ORc、C1-C8烷基；When R1 is, R2 is selected from unsubstituted or substituted aryl, unsubstituted or substituted aromatic heterocyclyl, C3-C6 cycloalkyl, -ORc, C2-C8 alkyl, arylalkyl, haloalkyl, Wherein the substituent in the substituted aryl or aromatic heterocyclic group is selected from ortho, meta or para substituted halogen, C1-C8 alkyl, ORc, nitro; R3 is H, -C(O)RaRb, -ORc, C1-C8 alkyl, C3-C6 cycloalkyl; R4, R5, R6 are independently selected from H, -ORc, C1-C8 alkyl, cyano; R' is H, halogen, -ORc, C1-C8 alkyl; R"' is ortho, meta or para substituted H, halogen, -ORc, C1-C8 alkyl;
    Ra、Rb分别独立的选自H、C1-C4烷基，Rc为H、C1-C8烷基。Ra and Rb are independently selected from H, C1-C4 alkyl, and Rc is H, C1-C8 alkyl.
  2. 根据权利要求1所述的苯并咪唑类化合物，其特征在于，芳基烷基为含未取代或取代的芳基的C1-C8烷基；取代的芳基中的取代基选自邻位、间位或者对位取代的卤素、C1-C8烷基、ORc、硝基。The benzimidazole compound according to claim 1, wherein the arylalkyl group is a C1-C8 alkyl group containing an unsubstituted or substituted aryl group; the substituents in the substituted aryl group are selected from the group consisting of ortho, Meta or para substituted halogen, C1-C8 alkyl, ORc, nitro.
  3. 根据权利要求1所述的苯并咪唑类化合物，其特征在于，芳杂环基中的芳杂环选自噻吩、呋喃、吡啶、吡咯、嘧啶。The benzimidazole compound according to claim 1, wherein the aromatic heterocycle in the aromatic heterocyclic group is selected from thiophene, furan, pyridine, pyrrole and pyrimidine.
  4. 苯并咪唑类化合物及其互变异构形式和生理学耐受的盐在制备内皮脂肪酶抑制药物中的应用，其特征在于，所述苯并咪唑类化合物的结构式如式(I)所示，The application of benzimidazole compounds and their tautomeric forms and physiologically tolerated salts in the preparation of endothelial lipase inhibitory drugs, characterized in that the structural formula of the benzimidazole compounds is shown in formula (I),
    其中，R1是氢、(C1-C6)-烷基、(C1-C6)-卤代烷基、(C1-C6)烷氧基、(C1-C6)-亚烷基-芳基、(C1-C6)-亚烷基-杂环、(C1-C6)-亚烷基-(C3-C12)-环烷基、(C8-C14)-二环，其中芳基、杂环、环烷基或二环可以被下述优选的基团单或多取代：卤素、(C1-C6)-烷基、(C1-C3)-烷氧基、羟基、(C1-C6)-烷基巯基、氨基、(C1-C6)-烷基氧基、二-(C2-C12)烷基氨基、单-(C1-C6)-烷基氨基羰基、二-(C2-C8)-烷基羰基、(C1-C6)-烷氧基羰基、(C1-C6)-烷基羰基、氰基、硝基、三氟甲基、三氟甲氧基、五氟硫基、(C1-C6)-烷基磺酰基、氨基磺酰基；Wherein, R1 is hydrogen, (C1-C6)-alkyl, (C1-C6)-haloalkyl, (C1-C6)alkoxy, (C1-C6)-alkylene-aryl, (C1-C6) )-alkylene-heterocycle, (C1-C6)-alkylene-(C3-C12)-cycloalkyl, (C8-C14)-bicycle, wherein aryl, heterocycle, cycloalkyl or dicycle The ring may be mono- or polysubstituted with the following preferred groups: halogen, (C1-C6)-alkyl, (C1-C3)-alkoxy, hydroxy, (C1-C6)-alkylmercapto, amino, ( C1-C6)-Alkyloxy, Di-(C2-C12)Alkylamino, Mono-(C1-C6)-Alkylaminocarbonyl, Di-(C2-C8)-Alkylcarbonyl, (C1-C6 )-alkoxycarbonyl, (C1-C6)-alkylcarbonyl, cyano, nitro, trifluoromethyl, trifluoromethoxy, pentafluorothio, (C1-C6)-alkylsulfonyl, aminosulfonyl;
    R2是-(C1-C6)-烷基、(C1-C6)-烷氧基、(C1-C3)-卤代烷氧基、(C1-C6)-亚烷基氨、二-(C2-C12)-烷基氨、-CO-(C1-C6)-烷基、-COOR7、-CO-NR8R9、-O-CONR8R9、-O-CO-(C1-C6)-亚烷基-CO-O-(C1-C6)-烷基、-O-CO-(C1-C6)-亚烷基-CO-OH或-O-CO-(C1-C6)-亚烷基-CO-NR8R9、芳基、杂环、-(C2-C12)环烷基；其中芳基、杂环、环烷基或二环可以被下述优选的基团单或多取代:卤素、(C1-C6)-烷基、(C1-C3)-烷氧基、羟基、(C1-C6)-烷基巯基、氨基、(C1-C6)-烷基氧基、二-(C2-C12)烷基氨基、单-(C1-C6)-烷基氨基羰基、二-(C2-C8)-烷基羰基、(C1-C6)-烷氧基羰基、(C1-C6)-烷基羰基、氰基、硝基、三氟甲基、三氟甲氧基、五氟硫基、(C1-C6)-烷基磺酰基、氨基磺酰基；R2 is -(C1-C6)-alkyl, (C1-C6)-alkoxy, (C1-C3)-haloalkoxy, (C1-C6)-alkyleneamino, di-(C2-C12) -Alkylamino, -CO-(C1-C6)-Alkyl, -COOR7, -CO-NR8R9, -O-CONR8R9, -O-CO-(C1-C6)-Alkylene-CO-O-( C1-C6)-alkyl, -O-CO-(C1-C6)-alkylene-CO-OH or -O-CO-(C1-C6)-alkylene-CO-NR8R9, aryl, hetero Ring, -(C2-C12) cycloalkyl; wherein aryl, heterocycle, cycloalkyl or bicycle may be mono- or polysubstituted by the following preferred groups: halogen, (C1-C6)-alkyl, ( C1-C3)-alkoxy, hydroxyl, (C1-C6)-alkylmercapto, amino, (C1-C6)-alkyloxy, di-(C2-C12)alkylamino, mono-(C1- C6)-Alkylaminocarbonyl, Di-(C2-C8)-Alkylcarbonyl, (C1-C6)-Alkoxycarbonyl, (C1-C6)-Alkylcarbonyl, Cyano, Nitro, Trifluoromethyl base, trifluoromethoxy, pentafluorothio, (C1-C6)-alkylsulfonyl, aminosulfonyl;
    R3、R4、R5、R6相同或不同地是氢、(C1-C6)-烷基、(C3-C12)-环烷基、(C1-C4)-亚烷基-芳基、(C1-C4)-亚烷基-(C3-C12)-环烷基、卤素、(C1-C6)-烷基、(C1-C3)-烷氧基、羟基、(C1-C6)-烷基巯基、氨基、(C1-C6)-烷基氧基、二-(C2-C12)烷基氨基、单-(C1-C6)-烷基氨基羰基、二-(C2-C8)-烷基氫基羰基、(C1-C6)-烷氧基羰基、(C1-C6)-烷基羰基、氰基、硝基、三氟甲基、三氟甲氧基、五氟硫基、(C1-C6)-烷基磺酰基、氨基磺酰基；R3, R4, R5, R6 are identically or differently hydrogen, (C1-C6)-alkyl, (C3-C12)-cycloalkyl, (C1-C4)-alkylene-aryl, (C1-C4 )-alkylene-(C3-C12)-cycloalkyl, halogen, (C1-C6)-alkyl, (C1-C3)-alkoxy, hydroxyl, (C1-C6)-alkylmercapto, amino , (C1-C6)-alkyloxy, di-(C2-C12) alkylamino, mono-(C1-C6)-alkylaminocarbonyl, di-(C2-C8)-alkylhydrocarbonyl, (C1-C6)-alkoxycarbonyl, (C1-C6)-alkylcarbonyl, cyano, nitro, trifluoromethyl, trifluoromethoxy, pentafluorothio, (C1-C6)-alkane sulfonyl, aminosulfonyl;
    R7是氢、(C1-C10)烷基、(C1-C4)亚烷基-CN、(C1-C4)亚烷基-芳基、(C1-C4)-亚烷基-杂环、(C1-C4)-亚烷基-(C3-C12)-环烷基、(C8-C14)-二环,其中芳基、杂环、环烷基或二环可以被下述优选的基团单或多取代：卤素、(C1-C6)-烷基、(C1-C6)-烷氧基、羟基、(C1-C6)-烷基巯基、氨基、(C1-C6)-烷基氨基、二-(C2-C12)-烷基氨基、单-(C1-C6)-烷基氨基羰基、二-(C2-C8)-烷基氨基羰基、(C1-C6)-烷氧基羰基、 (C1-C6)-烷基羰基、氰基、三氟甲基、三氟甲氧基、硝基(C1-C6)-烷基磺酰基、氨基磺酰基；R7 is hydrogen, (C1-C10) alkyl, (C1-C4) alkylene-CN, (C1-C4) alkylene-aryl, (C1-C4)-alkylene-heterocycle, (C1 -C4)-alkylene-(C3-C12)-cycloalkyl, (C8-C14)-bicycle, wherein aryl, heterocycle, cycloalkyl or bicycle can be mono- or bicyclic by the following preferred groups Polysubstituted: Halogen, (C1-C6)-Alkyl, (C1-C6)-Alkoxy, Hydroxyl, (C1-C6)-Alkylmercapto, Amino, (C1-C6)-Alkylamino, Di- (C2-C12)-Alkylamino, Mono-(C1-C6)-Alkylaminocarbonyl, Di-(C2-C8)-Alkylaminocarbonyl, (C1-C6)-Alkoxycarbonyl, (C1- C6)-alkylcarbonyl, cyano, trifluoromethyl, trifluoromethoxy, nitro(C1-C6)-alkylsulfonyl, aminosulfonyl;
    R8、R9相同或不同地选自氢、(C1-C6)-烷基、芳基、(C3-C12)-环烷基、(C1-C4)-亚烷基-芳基、(C1-C4)-亚烷基-(C3-C12)-环烷基。R8, R9 are identically or differently selected from hydrogen, (C1-C6)-alkyl, aryl, (C3-C12)-cycloalkyl, (C1-C4)-alkylene-aryl, (C1-C4) )-alkylene-(C3-C12)-cycloalkyl.
  5. 根据权利要求4所述的应用，其特征在于，所述生理学耐受的盐选自：盐酸盐、氢溴酸盐、磷酸盐、偏磷酸盐、硝酸和硫酸盐、乙酸盐、苯磺酸盐、苯甲酸盐、柠檬酸盐、乙磺酸盐、富马酸盐、萄糖酸盐、羟乙酸盐、羟乙磺酸盐、乳酸盐、乳糖酸盐、马来酸盐、苹果酸盐、甲磺酸盐、琥珀酸盐、对甲苯磺酸盐和酒石酸盐、铵盐、碱金属盐、碱土金属盐、氨基丁三醇盐、二乙醇胺盐、赖氨酸盐、乙二胺盐。The use according to claim 4, wherein the physiologically tolerated salt is selected from the group consisting of: hydrochloride, hydrobromide, phosphate, metaphosphate, nitric and sulfate, acetate, benzene sulfonate acid salt, benzoate, citrate, ethanesulfonate, fumarate, gluconate, glycolate, isethionate, lactate, lactobionate, maleate , malate, mesylate, succinate, p-toluenesulfonate and tartrate, ammonium salt, alkali metal salt, alkaline earth metal salt, tromethamine, diethanolamine salt, lysine salt, ethyl Diamine salt.
  6. 苯并咪唑类化合物及其互变异构形式和生理学耐受的盐在制备用于治疗和预防血脂异常的药物的应用；所述血脂异常包括动脉粥样硬化、冠心病、脑血管病；所述苯并咪唑类化合物及为权利要求4中定义的式(I)化合物。Use of benzimidazole compounds and their tautomeric forms and physiologically tolerated salts in the preparation of medicaments for the treatment and prevention of dyslipidemia; the dyslipidemia includes atherosclerosis, coronary heart disease, and cerebrovascular disease; The benzimidazole compound and the compound of formula (I) defined in claim 4.
  7. 苯并咪唑类化合物及其互变异构形式和生理学耐受的盐在制备用于治疗和预防与代谢综合症相关病症的药物中的应用，所述与代谢综合症相关病症包括肥胖症、高血压、心力衰竭、糖尿病；所述苯并咪唑类化合物及为权利要求4中定义的式(I)化合物。Use of benzimidazoles, tautomeric forms and physiologically tolerated salts thereof in the manufacture of a medicament for the treatment and prevention of disorders associated with metabolic syndrome, including obesity, high Blood pressure, heart failure, diabetes; the benzimidazole compound and the compound of formula (I) as defined in claim 4.
  8. 苯并咪唑类化合物及其互变异构形式和生理学耐受的盐在制备用于治疗和预防涉及炎症反应或细胞分化的病症的药物中的应用；所述苯并咪唑类化合物及为权利要求4中定义的式(I)化合物；所述涉及炎症反应或细胞分化的病症包括血管再狭窄或再闭塞、慢性炎性肠病、视网膜病、脂肪细胞肿瘤、实体肿瘤和赘生物、急性和慢性骨髓增殖性疾病和淋巴瘤、血管生成、神经变性疾病；阿尔茨海默病；多发性硬化症；帕金森病；红斑鳞屑性皮肤病、湿疹和神经性皮炎、角膜炎和角化病、人乳头瘤病毒感染、疣、瘢痕疙瘩和瘢痕疙瘩预防、丘疹性皮肤病、皮肤癌、局限的良性上皮肿瘤、冻疮、多囊卵巢综合征、哮喘、红斑狼疮、炎性关节病、痛风、缺血/再灌注综合征、急性呼吸窘迫综合征。Use of benzimidazoles and their tautomeric forms and physiologically tolerated salts in the manufacture of medicaments for the treatment and prevention of disorders involving inflammatory responses or cell differentiation; the benzimidazoles and the claims Compounds of formula (I) as defined in 4; conditions involving inflammatory responses or cellular differentiation include vascular restenosis or reocclusion, chronic inflammatory bowel disease, retinopathy, adipocyte tumors, solid tumors and neoplasms, acute and chronic Myeloproliferative and lymphomas, angiogenesis, neurodegenerative diseases; Alzheimer's disease; multiple sclerosis; Parkinson's disease; erythrosquamous skin diseases, eczema and neurodermatitis, keratitis and keratosis, human Papillomavirus infection, warts, keloids and keloid prevention, papular skin disease, skin cancer, localized benign epithelial tumors, frostbite, polycystic ovary syndrome, asthma, lupus erythematosus, inflammatory joint disease, gout, ischemia / reperfusion syndrome, acute respiratory distress syndrome.
  9. 一种用于抑制内皮脂肪酶的药物组合物，其特征在于，所述药物组合物包含权利要求4中定义的苯并咪唑类化合物及其互变异构形式和生理学耐受的盐，可药用的载体和/或赋形剂。A pharmaceutical composition for inhibiting endothelial lipase, characterized in that the pharmaceutical composition comprises the benzimidazole compounds defined in claim 4 and their tautomeric forms and physiologically tolerated salts, which are pharmaceutically acceptable. carriers and/or excipients used.
  10. 根据权利要求9所述的药物组合物，其特征在于，所述药物组合物的剂型选自胶囊剂、扁囊剂、锭剂、片剂、注射剂、软膏剂、霜剂、洗剂、糊剂、喷雾剂、气雾剂或油剂。The pharmaceutical composition according to claim 9, wherein the dosage form of the pharmaceutical composition is selected from capsules, cachets, lozenges, tablets, injections, ointments, creams, lotions, pastes , spray, aerosol or oil.
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