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    • 专利摘要:
    The present invention provides compounds of Formula (I) and Formula (II) and pharmaceutically acceptable salts and esters thereof, wherein the symbols are defined herein, inhibit the interaction of the MDM2 protein with the p53-like peptide, and have the appropriate activity: [Formula I]
    公开号:KR20040068277A
    申请号:KR10-2004-7009563
    申请日:2002-12-09
    公开日:2004-07-30
    发明作者:콩노만；리우에밀리아이준；부빈덴
    申请人:에프. 호프만-라 로슈 아게；
    IPC主号:
    专利说明:

    Cis-2,4,5-triphenyl-imidazoline and its use in tumor treatment {CIS-2,4,5-TRIPHENYL-IMIDAZOLINES AND THEIR USE IN THE TREATMENT OF TUMORS}
    [1] p53 is a tumor protein that plays a pivotal role in protection against the development of cancer. It escorts cell integrity and prevents the proliferation of permanently damaged clones of cells by induction of growth arrest or apoptosis. At the molecular level, p53 is a transcription factor that activates a panel of genes that are important in the regulation of cell cycle and apoptosis. p53 is a potent cell cycle inhibitor that is tightly engineered by MDM2 at the cellular level. MDM2 and p53 form a feedback control loop. MDM2 can bind p53 and inhibit its ability to transactivate p53 regulatory genes. MDM2 also mediates the ubiquitin dependent degradation of p53. p53 can activate the expression of the MDM2 gene, thereby raising cellular levels of MDM2 protein. The feedback loop ensures that both MDM2 and p53 are kept at low levels in normal proliferating cells. MDM2 is also a cofactor for E2F and plays a pivotal role in cell cycle regulation.
    [2] The ratio of MDM2 to p53 (E2F) is dysregulated in many cancers. For example, molecular defects that often occur at the p16INK4 / p19ARF locus have been shown to affect MDM2 proteolysis. Inhibition of MDM2-p53 interaction in tumor cells with wild type p53 leads to accumulation of p53, cell cycle arrest and / or apoptosis. Thus, MDM2 antagonists provide a novel approach to cancer therapy as a single agent or in combination with a broad spectrum of other antitumor therapies. The viability of this strategy has resulted in the use of different polymer tools (eg, antibodies, antisense oligonucleotides, peptides) for the inhibition of MDM2-p53 interactions. MDM2 also binds to E2F through constant binding regions, such as p53, and activates E2F-dependent transcription of Cycline A, suggesting that MDM2 antagonists affect p53 mutant cells.
    [3] Wells et al. J. Org. Chem., 1972, 37, 2158-2161 report the synthesis of imidazolines. Hunter et al., Can. J. Chem., 1972, Vol. 50, pgs. 669-77 report the preparation of the amarin and isomarin compounds studied in the prior art for chemiluminescence (McCapra et al. Photochem. And Photobiol. 1965, 4, 1111-1121). See Zupanc et al. Bull. Soc. chem. & Tech. (Yugoslavia) 1980-81, 27/28, 71-80 report the use of triaryl imidazolines as starting material in the preparation of EDTA derivatives. EP 363 061 to Matsumoto reports imidazoline derivatives useful as immunomodulators. The compounds appear to have low toxicity. The treatment and / or prevention of rheumatoid arthritis, multiple sclerosis, systemic lupus erythema and rheumatic fever are important. WO 00/78725 to Choueiry reports a method for the preparation of substituted amidine compounds, indicating that imidazoline-type compounds may be useful for the treatment of diabetes or related diseases associated with lack of glucose degradation.
    [4] The present invention provides one or more compounds of Formula (I) and pharmaceutically acceptable salts and esters thereof:
    [5]
    [6] [In the meal,
    [7] R is -C = OR 1 ,
    [8] Where R 1 is C 1 -C 6 alkyl, -C = CHCOOH, -NHCH 2 CH 2 R2, -N (CH 2 CH 2 0H) CH 2 CH 2 0H, -N (CH 3 ) CH 2 CH 2 NCH 3 , -N (CH 3 ) CH 2 CH 2 N (CH 3 ) CH 3 , saturated 4-, 5- and 6-membered rings, and one or more hetero atoms selected from S, N and 0, and C 1 -C 6 alkyl, -C = OR 5 , -OH, C 1 -C 6 alkyl optionally substituted with hydroxy, -NH 2 , -NC 1 -C 6 alkyl, -SO 2 CH 3 , = O, -CH Saturated and unsaturated 5- and 6- optionally substituted with C 1 -C 6 alkyl optionally substituted with 5- and 6-membered rings comprising 2 C═OCH 3 and at least one hetero atom selected from S, N and 0 Is selected from a circle ring, where
    [9] R 5 is H, C 1 -C 6 alkyl, -NH 2 , -NC 1 -C 6 alkyl, C 1 -C 6 alkyl optionally substituted with hydroxy, and C 1 -C 6 alkyl optionally substituted with NH 2 Is selected from,
    [10] R 2 is selected from —N (CH 3 ) CH 3 , —NCH 2 CH 2 NH 2 , —NH 2 , morpholinyl and piperazinyl,
    [11] X 1 , X 2 and X 3 are independent from -OH, C 1 -C 2 alkyl, C 1 -C 6 alkoxy, -Cl, -Br, -F, -CH 2 0CH 3 and -CH 2 0CH 2 CH 3 Or one of X 1 , X 2 or X 3 is H and the other two are hydroxy, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, Cl, Br, F, -CF 3 ,- CH 2 0CH 3 , -CH 2 0CH 2 CH 3 , -OCH 2 CH 2 R 3 , -OCH 2 CF 3 , and -OR 4 or one of X 1 , X 2 or X 3 is H and the other Two are taken together with a bond between them from two carbon atoms and an optionally substituted benzene ring to form a 5- or 6-membered saturated ring comprising at least one hetero atom selected from S, N and 0, wherein
    [12] R 3 is from an unsaturated 5- and 6-membered ring comprising at least one hetero atom selected from -F, -OCH 3 , -N (CH 3 ) CH 3 , -Cl, -Br, and S, N and 0; Is selected,
    [13] R 4 is a 3- to 5-membered saturated ring,
    [14] Y 1 and Y 2 are independently selected from —Cl, —Br, —NO 2 , —C═N, and —C═CH].
    [15] The invention also provides one or more compounds of formula (II) and pharmaceutically acceptable salts and esters thereof:
    [16]
    [17] [In the meal,
    [18] R is -C = OR 1 ,
    [19] R 1 comprises C 1 -C 6 alkyl, saturated 5- and 6-membered rings, and at least one hetero atom selected from S, N and 0, and C 1 -C 2 alkyl, C 1 -C 3 alcohol, Saturated 5- and 6-membered optionally substituted with a group selected from 5- and 6-membered rings comprising at least one hetero atom selected from -N (CH 3 ) CH 3 , -C═OCH 3 and S, N and 0; Selected from rings,
    [20] X 4 is C 1 -C 2 alkyl, C 1 -C 6 alkoxy, fluoroethoxy, -Cl, -Br, -F, -OCH 2 C = OOQ, -OC 1 -C 6 alkyl, -OCH 2- Cyclopropyl, -CH 2 0CH 2 -phenyl, saturated and unsaturated 5- and 6-membered rings, saturated and unsaturated 5- and 6-membered rings comprising one or more hetero atoms selected from S, N and 0 and ,
    [21] Wherein Q is selected from H and C 1 -C 6 alkyl,
    [22] Y 1 and Y 2 are independently selected from -Cl, -Br, -NO 2 , -C = N and -C = H,
    [23] Provided that when Y 1 and Y 2 are both -Cl and R 1 is -CH 3 or phenyl, X 4 is not -Cl].
    [24] Another subject of the present invention is to provide a pharmaceutical composition containing said compounds and the use of said compounds in medicinal therapies, in particular in the treatment of tumors.
    [25] Another subject of the present invention is to provide a method for preparing the compounds.
    [26] The present invention provides cis-imidazoline, which is a small molecule inhibitor of MDM2-p53 interaction. In cell-free and cell-based assays, the compounds of the present invention have been shown to inhibit the interaction of MDM2 protein with p53-like peptides having about 100 times greater intensity than p53-derived peptides. In cell based assays, the compounds exhibit dynamic activity. Incubation of wild type p53 and cancer cells induces accumulation of p53 protein, induction of p21 gene regulated by p53, and cell cycle arrest on G1 and G2, resulting in potent antiproliferative activity against wild type p53 in vitro. In contrast, these activities are not observed at comparable compound concentrations in mutant p53 and cancer cells. Thus, the activity of MDM2 antagonists is associated with its mechanism of action. The compounds may be potent and selective anticancer agents.
    [27] Unless otherwise indicated, the following definitions apply to the description and define the meaning and scope of the various terms used to describe the invention herein.
    [28] "Effective amount" means an effective amount that prevents, alleviates or alleviates the signs of a disease or prolongs the survival of a subject to be treated.
    [29] "Halogen" means fluorine, chlorine, bromine or iodine.
    [30] "Hetero atom" means an atom selected from N, 0 and S.
    [31] "IC 50 " refers to the concentration of a particular compound required for 50% inhibition of a particular measured activity. IC 50 may in particular be measured as described subsequently.
    [32] "Alkyl" refers to a straight or branched chain saturated aliphatic hydrocarbon. "Lower alkyl" groups refer to C 1 -C 6 alkyl groups and include methyl, ethyl, propyl, isopropyl, butyl, t-butyl, 2-butyl, pentyl, hexyl, and the like. In general, lower alkyl is preferably C 1 -C 4 alkyl, more preferably C 1 -C 3 alkyl.
    [33] "Alkoxy" refers to -O-alkyl. "Lower alkoxy" refers to -OC 1 -C 6 alkyl.
    [34] The term "saturated 4-, 5- and 6-membered rings" for R 1 preferably means cyclopentyl and cyclohexyl.
    [35] Term for R 1 "S, N, and saturated containing one or more heteroatoms selected from 0, and unsaturated 5-and 6-membered ring" is preferably a morpholinyl, piperazinyl, piperadinyl, thiophenyl , Saturated and unsaturated ring systems such as isoxazolyl, furanyl and piperazinyl, more preferably piperazinyl.
    [36] The term "unsaturated 5- and 6-membered ring comprising at least one hetero atom" for R 3 preferably means imidazolyl.
    [37] The term "3- to 5-membered saturated ring" for R 4 preferably means an aliphatic ring, for example cyclopentyl.
    [38] "Pharmaceutically acceptable ester" means a conventionally esterified compound of formula (I) having a carboxyl group, which ester retains the biological effects and characteristics of formula (I) and the corresponding active carboxylic acid in vivo (in organic) Separated by.
    [39] Information on the use and esters of esters for the delivery of pharmaceutical compounds is given in Design of Prodrugs. Edited by Bundgaard H (Elsevier, 1985). See also, H. Ansel et al., Pp. Pharmaceutical Dosage Forms and Drug Delivery Systems (6th Ed. 1995). 108-109; Krogsgaard-Larsen, et al., Pp. Textbook of Drug Design and Development (2d Ed. 1996). 152].
    [40] "Pharmaceutically acceptable salt" means a conventional acid addition salt or base addition salt that retains the biological effects and properties of the compounds of the present invention and is formed from non-toxic organic or inorganic acids, or organic or inorganic bases. Illustrative acid addition salts include those derived from inorganic acids such as hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, sulfamic acid, phosphoric acid and nitric acid and p-toluenesulfonic acid, salicylic acid, methanesulfonic acid, oxalic acid, succinic acid, citric acid, malic acid, lactic acid And those derived from organic acids such as fumaric acid and the like. Illustrative base addition salts include quaternary ammonium hydroxides such as ammonium, potassium, sodium and, for example, tetramethylammonium hydroxide. Chemical modification of pharmaceutical compounds (ie, drugs) into salts to improve the physical and chemical stability, hygroscopicity, flowability and solubility of the compounds is well known to pharmacologists. References are made, for example, in [H. Ansel et al., Pharmaceutical Dosage Forms and Drug Delivery Systems (6th Ed. 1995), pP. 196 and 1456-1467.
    [41] “Pharmaceutically acceptable,” eg, pharmaceutically acceptable carrier, excipient, etc. means that the subject is administered a physiologically acceptable and substantially nontoxic to the subject.
    [42] As in substituted alkyl, "substitution" means that the substitution may occur at one or more positions, and unless otherwise indicated, the substituents at each substitution site are independently selected from the specified selection range.
    [43] A "therapeutically effective amount" means an amount of one or more designated compounds that significantly inhibits proliferation and / or prevents differentiation of human tumor cells, including human tumor cell lines.
    [44] The present invention relates to compounds of formula (I) and pharmaceutically acceptable salts and esters thereof:
    [45] [Formula I]
    [46]
    [47] [In the meal,
    [48] R is -C = OR 1 ,
    [49] Wherein R 1 is C 1 -C 6 alkyl, -C = CHCOOH, -NHCH 2 CH 2 R 2 , -N (CH 2 CH 2 0H) CH 2 CH 2 0H, -N (CH 3 ) CH 2 CH 2 NCH 3 , —N (CH 3 ) CH 2 CH 2 N (CH 3 ) CH 3 , saturated 4-, 5- and 6-membered rings, and one or more hetero atoms selected from S, N and 0, and C 1 -C 6 alkyl, -C = OR 5 , -OH, C 1 -C 6 alkyl optionally substituted with hydroxy, -NH 2 , -NC 1 -C 6 alkyl, -SO 2 CH 3 , = O,- Saturated and unsaturated 5- and 6- optionally substituted with C 1 -C 6 alkyl optionally substituted with 5 and 6-membered rings comprising at least one hetero atom selected from CH 2 C═OCH 3 and S, N and 0; Is selected from a circle ring, where
    [50] R 5 is H, C 1 -C 6 alkyl, -NH 2 , -NC 1 -C 6 alkyl, C 1 -C 6 alkyl optionally substituted with hydroxy, and C 1 -C 6 alkyl optionally substituted with NH 2 Is selected from,
    [51] R 2 is selected from —N (CH 3 ) CH 3 , —NCH 2 CH 2 NH 2 , —NH 2 , morpholinyl and piperazinyl,
    [52] X 1 , X 2 and X 3 are independent from -OH, C 1 -C 2 alkyl, C 1 -C 6 alkoxy, -Cl, -Br, -F, -CH 2 0CH 3 and -CH 2 0CH 2 CH 3 Or one of X 1 , X 2 or X 3 is H and the other two are hydroxy, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, Cl, Br, F, -CF 3 ,- CH 2 0CH 3 , -CH 2 0CH 2 CH 3 , -OCH 2 CH 2 R 3 , -OCH 2 CF 3 , and -OR 4 or one of X 1 , X 2 or X 3 is H and the other Two are taken together with a bond between them from two carbon atoms and an optionally substituted benzene ring to form a 5- or 6-membered saturated ring comprising at least one hetero atom selected from S, N and 0, wherein
    [53] R 3 is from an unsaturated 5- and 6-membered ring comprising at least one hetero atom selected from -F, -OCH 3 , -N (CH 3 ) CH 3 , -Cl, -Br, and S, N and 0; Is selected,
    [54] R 4 is a 3- to 5-membered saturated ring,
    [55] Y 1 and Y 2 are independently selected from —Cl, —Br, —NO 2 , —C═N, and —C═CH].
    [56] In a preferred embodiment, the invention comprises compounds of formula I, wherein Y 1 and Y 2 are each independently selected from -Cl and -Br.
    [57] In another embodiment, the invention provides that R 1 is morpholinyl, piperazinyl, piperadinyl, cyclopentyl, cyclohexyl, thiophenyl, isoxazolyl and furanyl, and C 1 -C 3 alkyl, —C 1 -C 2 alkoxy, -C = OCH 3 , -SO 2 CH 3 , -C = O, -OH, -CH 2 NH 2 , -C = OCH 2 NH 2 , -C = OCH 2 0H, -C = 0C (OH) CH 2 OH, -CH 2 C (OH) -CH 2 OH, -C = ON (CH 2- ) 2 , -C = ONH 2 , and -C = ON (CH 3 ) CH 3 Piperazinyl substituted with one or more groups, -C = OCH (CH 3 ) 2 , -CH 2 C = OCH 3 , -CH 2 CH (OH) CH 3 , -CH (CH 3 ) CH (OH) CH 3 And -CH 2 CH 2 0H.
    [58] In a more preferred embodiment, the invention provides that one of the groups X 1 , X 2 and X 3 is H and the other two are hydroxy, C 1 -C 5 alkoxy, Cl, Br, F, —CH 2 0CH 3 , -CH 2 0CH 2 CH 3 , C 1 -C 2 alkyl, -OCH 2 CH 2 R 3 and -OR 4 , wherein R 3 is -F, -OCH 3 , -N (CH 3 ) CH 3 , S, Is an unsubstituted 5-membered ring comprising at least one hetero atom selected from N and O, R 4 is cyclopentyl, more preferably R 3 is imidazolyl), or X 1 , One of X 2 or X 3 is H and the other two are taken together with a bond between them from two carbon atoms and an optionally substituted benzene ring and comprise one or more hetero atoms selected from S, N and 0; It relates to a compound of formula (I) which forms a circular saturated ring.
    [59] Preferably, when one of X 1 , X 2 or X 3 is H, the other two are independently selected from —OCH 3 and —CH 2 0CH 2 CH 3 .
    [60] More preferably, when one of X 1 , X 2 or X 3 is H, one or both of the other two are —OC 1 alkyl, —OC 2 alkyl or —OC 3 alkyl.
    [61] Another embodiment of the invention is a 6-membered saturated ring wherein X 3 is H and X 1 and X 2 are taken together with two carbon atoms such that the bond between the substituted benzene rings comprises one hetero atom O It relates to a compound of formula (I) which forms.
    [62] In another embodiment of the invention, one of X 1 , X 2 or X 3 is H in the meta position and the group in the ortho position is selected from C 1 -C 5 alkoxy and —OCH 2 CF 3 and in the para position And to a compound of formula (I) wherein the group of is lower alkoxy. Preferably, the X 1 , X 2 or X 3 group in the ortho position is selected from ethoxy, isopropoxy and —OCH 2 CF 3 and the group in the para position is selected from methoxy and ethoxy. In this preferred embodiment, R 1 is selected from piperazinyl and substituted piperazinyl.
    [63] In one embodiment of the invention, one of the groups X 1 , X 2 or X 3 is H in the meta position, the group at the ortho position is C 1 -C 6 alkoxy and the group at the para position is -Cl, -Br or- Or one of the groups X 1 , X 2 or X 3 is H in the para position, the other two other groups are C 1 -C 6 alkoxy in the ortho position and the group in the meta position is —C 1 , —Br Or -F.
    [64] Another embodiment of the invention relates to compounds of Formula II and pharmaceutically acceptable salts and esters thereof:
    [65] [Formula 2]
    [66]
    [67] [In the meal,
    [68] R is -C = OR 1 ,
    [69] R 1 comprises C 1 -C 6 alkyl, saturated 5- and 6-membered rings, and at least one hetero atom selected from S, N and 0, and C 1 -C 2 alkyl, C 1 -C 3 alcohol, Saturated 5- and 6-membered optionally substituted with a group selected from 5- and 6-membered rings comprising at least one hetero atom selected from -N (CH 3 ) CH 3 , -C═OCH 3 and S, N and 0; Selected from rings,
    [70] X 4 is C 1 -C 2 alkyl, C 1 -C 6 alkoxy, fluoroethoxy, -Cl, -Br, -F, -OCH 2 C = OOQ, -OC 1 -C 6 alkyl, -OCH 2- Cyclopropyl, -CH 2 0CH 2 -phenyl, saturated and unsaturated 5- and 6-membered rings, saturated and unsaturated 5- and 6-membered rings comprising one or more hetero atoms selected from S, N and 0 and ,
    [71] Wherein Q is selected from H and C 1 -C 6 alkyl,
    [72] Y 1 and Y 2 are independently selected from -Cl, -Br, -NO 2 , -C = N and -C = H,
    [73] Provided that when Y 1 and Y 2 are both -Cl and R 1 is -CH 3 or phenyl, X 4 is not -Cl].
    [74] In a preferred embodiment, the invention provides that X 4 is selected from —CH 3 , C 1 -C 6 alkoxy, —Cl, —Br, —OCH 2 C═OOQ, phenyl and pyrrolidinyl, more preferably X 4 And -CH 3 , C 1 -C 6 alkoxy, -OCH 2 C═OOQ, phenyl and pyrrolidinyl, wherein -Q is H or —CH 2 CH 3 .
    [75] In another embodiment of the invention, R 1 is substituted with -CH (CH 3 ) CH 3 , piperazinyl, and -CH 3 , -CH 2 CH 2 0H, and -C = OCH 3 It relates to a compound of formula (II) selected from ferrazinyl, piperadinyl, and piperadinyl substituted with a group selected from -pyrrolidinyl, piperadinyl and N (CH 3 ) CH 3 .
    [76] More preferably, C 1 -C 6 alkyl in the compound of formula II is selected from C 1 alkyl, C 2 alkyl and C 3 alkyl.
    [77] More preferably, the present invention relates to compounds of formula (II), wherein Y 1 and Y 2 are independently selected from -Cl and -Br.
    [78] Another preferred embodiment of the invention is that X 4 is C 1 -C 6 alkoxy at the ortho position, more preferably C 1 -C 6 alkoxy is selected from ethoxy, isopropoxy and 2-fluoroethoxy To a compound of formula (I). In a preferred embodiment, R 1 is selected from piperazinyl and substituted piperazinyl.
    [79] The present invention relates to compounds of formula (I) selected from the group:
    [80] a) 1- [4,5-bis- (4-chloro-phenyl) -2- (2,4-dimethoxy-phenyl) -4,5-dihydroimidazol-1-yl] -2-methyl- Propane-1-one;
    [81] b) 1- [4,5-bis- (4-chloro-phenyl) -2- (2,4-dimethoxy-phenyl) -4,5-dihydroimidazol-1-yl] ethanone;
    [82] c) 1- [4,5-bis- (4-chloro-phenyl) -2- (2,4-dimethoxy-phenyl) -4,5-dihydroimidazol-1-yl] -2,2- Dimethyl-propan-1-one;
    [83] d) [4,5-bis- (4-chloro-phenyl) -2- (2,4-dimethoxy-phenyl) -4,5-dihydro-imidazol-1-yl] -cyclopentyl-methanone ;
    [84] e) [4,5-bis- (4-chloro-phenyl) -2- (2,4-dimethoxy-phenyl) -4,5-dihydro-imidazol-1-yl] -cyclohexyl-methanone ;
    [85] f) [4,5-bis- (4-chloro-phenyl) -2- (2,4-dimethoxy-phenyl) -4,5-dihydro-imidazol-1-yl] -thiophen-2- Mono-methanone;
    [86] g) [4,5-bis- (4-chloro-phenyl) -2- (2,4-dimethoxy-phenyl) -4,5-dihydro-imidazol-1-yl] -isoxazole-5- Mono-methanone;
    [87] h) [4,5-bis- (4-chloro-phenyl) -2- (2,4-dimethoxy-phenyl) -4,5-dihydro-imidazol-1-yl] -furan-2-yl Methanone;
    [88] i) 1- [4,5-bis- (4-chloro-phenyl) -2- (2,3-dimethoxy-phenyl) -4,5-dihydro-imidazol-1-yl] -2-methyl -Propan-1-one;
    [89] j) [4,5-bis- (4-chloro-phenyl) -2- (2,4-dimethoxy-phenyl) -4,5-dihydro-imidazol-1-yl]-(4-methyl- Piperazin-1-yl) -methanone;
    [90] k) [4,5-bis- (4-chloro-phenyl) -2- (2,4-dimethoxy-phenyl) -4,5-dihydro-imidazol-1-yl] -piperazin-1- Mono-methanone;
    [91] l) [4,5-bis- (4-chloro-phenyl) -2- (2-fluoro-6-methoxy-phenyl) -4,5-dihydroimidazol-1-yl]-[4- (2-hydroxy-ethyl) -piperazin-1-yl) -methanone;
    [92] m) 1- {4- [4,5-bis- (4-bromo-phenyl) -2- (2,4-dimethoxy-phenyl) -4,5-dihydroimidazole-1-carbonyl] -Piperazin-1-yl} -ethanone;
    [93] n) [4,5-bis- (4-bromo-phenyl) -2- (2,4-dimethoxy-phenyl) -4,5-dihydro-imidazol-1-yl]-[4- ( 2-hydroxy-ethyl) -piperazin-1-yl] -methanone;
    [94] o) [4,5-bis- (4-chloro-phenyl) -2- (2-isopropoxy-4-methoxy-phenyl) -4,5-dihydroimidazol-1-yl]-[4 -(2-hydroxy-ethyl) -piperazin-1-yl] -methanone hydrochloride;
    [95] p) [4,5-bis- (4-chloro-phenyl) -2- (2-ethoxy-4-methoxy-phenyl) -4,5-dihydroimidazol-1-yl]-(4- Methanesulfonyl-piperazin-1-yl) -methanone;
    [96] q) [4,5-bis- (4-chloro-phenyl) -2- (2-ethoxy-4-methoxy-phenyl) -4,5-dihydroimidazol-1-yl]-[4- (2-hydroxy-ethyl) -piperazin-1-yl] -methanone;
    [97] r) [4,5-bis- (4-chloro-phenyl) -2- (2-ethoxy-4-methoxy-phenyl) -4,5-dihydroimidazol-1-yl] -morpholine- 4-yl-methanone;
    [98] s) [4,5-bis- (4-chloro-phenyl) -2- (2-ethoxy-4-methoxy-phenyl) -4,5-dihydroimidazol-1-yl]-(4- Methyl-piperazin-1-yl) -methanone;
    [99] t) 1- {4- [4,5-bis- (4-chloro-phenyl) -2- (2-ethoxy-4-methoxy-phenyl) -4,5-dihydroimidazole-1-car Carbonyl] -piperazin-1-yl} -ethanone;
    [100] u) 4- [4,5-bis- (4-chloro-phenyl) -2- (2-ethoxy-4-methoxy-phenyl) -4,5-dihydroimidazole-1-carbonyl]- Piperazin-2-one;
    [101] v) [4,5-bis- (4-chloro-phenyl) -2- (2-isopropoxy-4-methoxy-phenyl) -4,5-dihydroimidazol-1-yl] -piperazine -1-yl-methanone;
    [102] w) 1- {4- [4,5-bis- (4-chloro-phenyl) -2- (2-isopropoxy-4-methoxy-phenyl) -4,5-dihydro-imidazole-1 -Carbonyl] -piperazin-1-yl} -ethanone;
    [103] x) [4,5-bis- (4-chloro-phenyl) -2- (2-isopropoxy-4-methoxy-phenyl) -4,5-dihydroimidazol-1-yl]-(4 Methanesulfonyl-piperazin-1-yl) -methanone;
    [104] y) [4,5-bis- (4-chloro-phenyl) -2- (2-isopropoxy-4-methoxy-phenyl) -4,5-dihydroimidazol-1-yl]-(2 , 5-dimethyl-piperazin-1-yl) -methanone;
    [105] z) 4,5-bis- (4-chloro-phenyl) -2- (2-isopropoxy-4-methoxy-phenyl) -4,5-dihydroimidazole-1-carboxylic acid bis- ( 2-hydroxy-ethyl) -amide;
    [106] aa) [4,5-bis- (4-chloro-phenyl) -2- (2-isopropoxy-4-methoxy-phenyl) -4,5-dihydroimidazol-1-yl]-(4 -Ethyl-piperazin-1-yl) -methanone;
    [107] bb) [1,4 '] bipiperidinyl-1'-yl- [4,5-bis- (4-chloro-phenyl) -2- (2-isopropoxy-4-methoxy-phenyl) -4 , 5-dihydro-imidazol-1-yl] -methanone;
    [108] cc) [4,5-bis- (4-chloro-phenyl) -2- (2-isopropoxy-4-methoxy-phenyl) -4,5-dihydroimidazol-1-yl]-(4 -Pyrrolidin-1-yl-piperidin-1-yl) -methanone;
    [109] dd) [4,5-bis- (4-chloro-phenyl) -2- (2-isopropoxy-4-methoxy-phenyl) -4,5-dihydroimidazol-1-yl]-(4 -Dimethylamino-piperidin-1-yl) -methanone;
    [110] ee) [4,5-bis- (4-chloro-phenyl) -2- (2-isopropoxy-4-methoxy-phenyl) -4,5-dihydroimidazol-1-yl] -morpholine -4-yl-methanone;
    [111] ff) [4,5-bis- (4-chloro-phenyl) -2- (2-isopropoxy-4-methoxy-phenyl) -4,5-dihydroimidazol-1-yl]-(4 -Isopropyl-piperazin-1-yl) -methanone;
    [112] gg) 4- [4,5-bis- (4-chloro-phenyl) -2- (2-isopropoxy-4-methoxy-phenyl) -4,5-dihydro-imidazole-1-carbonyl ] -Piperazin-2-one;
    [113] hh) [4,5-bis- (4-chloro-phenyl) -2- (2-isopropoxy-4-methoxy-phenyl) -4,5-dihydroimidazol-1-yl]-(4 -Hydroxymethyl-piperidin-1-yl) -methanone;
    [114] ii) [4,5-bis- (4-chloro-phenyl) -2- (2-isopropoxy-4-methoxy-phenyl) -4,5-dihydroimidazol-1-yl]-[4 -(2-hydroxy-ethyl) -piperidin-1-yl] -methanone;
    [115] jj) [4,5-bis- (4-chloro-phenyl) -2- (2-isopropoxy-4-methoxy-phenyl) -4,5-dihydroimidazol-1-yl]-(3 -Methyl-piperazin-1-yl) -methanone;
    [116] kk) 1- {4- [4,5-bis- (4-chloro-phenyl) -2- (2-isopropoxy-4-methoxy-phenyl) -4,5-dihydro-imidazole-1 -Carbonyl] -2-methyl-piperazin-1-yl} -ethanone;
    [117] ll) [4,5-bis- (4-chloro-phenyl) -2- (2-isopropoxy-4-methoxy-phenyl) -4,5-dihydroimidazol-1-yl]-(4 Methanesulfonyl-3-methyl-piperazin-1-yl) -methanone;
    [118] mm) [4,5-bis- (4-chloro-phenyl) -2- (2-isopropoxy-4-methoxy-phenyl) -4,5-dihydroimidazol-1-yl]-(4 -Hydroxy-piperidin-1-yl) -methanone;
    [119] nn) (4-aminomethyl-piperidin-1-yl)-[4,5-bis- (4-chloro-phenyl) -2- (2-isopropoxy-4-methoxy-phenyl) -4 , 5-dihydro-imidazol-1-yl] -methanone;
    [120] oo) [4,5-bis- (4-bromo-phenyl) -2- (2-ethoxy-4-methoxy-phenyl) -4,5-dihydroimidazol-1-yl]-[4 -(2-hydroxy-ethyl) -piperazin-1-yl] -methanone;
    [121] pp) [4,5-bis- (4-bromo-phenyl) -2- (2-ethoxy-4-methoxy-phenyl) -4,5-dihydroimidazol-1-yl] -piperazine -1-yl-methanone;
    [122] qq) [4,5-bis- (4-bromo-phenyl) -2- (2-ethoxy-4-methoxy-phenyl) -4,5-dihydroimidazol-1-yl]-(4 Methanesulfonyl-piperazin-1-yl) -methanone;
    [123] rr) 1- {4- [4,5-bis- (4-bromo-phenyl) -2- (2-ethoxy-4-methoxy-phenyl) -4,5-dihydroimidazole-1- Carbonyl] -piperazin-1-yl} -ethanone;
    [124] ss) [4,5-bis- (4-bromo-phenyl) -2- (2-ethoxy-4-methoxy-phenyl) -4,5-dihydroimidazol-1-yl]-(4 -Methyl-piperazin-1-yl) -methanone;
    [125] tt) 4- [4,5-bis- (4-bromo-phenyl) -2- (2-ethoxy-4-methoxy-phenyl) -4,5-dihydroimidazole-1-carbonyl] Piperazine-1-carbaldehyde;
    [126] uu) [4,5-bis- (4-bromo-phenyl) -2- (2-ethoxy-4-methoxy-phenyl) -4,5-dihydroimidazol-1-yl]-(4 -Pyrrolidin-1-yl-piperidin-1-yl) -methanone;
    [127] vv) [4,5-bis- (4-bromo-phenyl) -2- (2-ethoxy-4-methoxy-phenyl) -4,5-dihydroimidazol-1-yl]-(4 -Dimethylamino-piperidin-1-yl) -methanone;
    [128] ww) [4,5-bis- (4-bromo-phenyl) -2- (2-ethoxy-4-methoxy-phenyl) -4,5-dihydroimidazol-1-yl]-(4 -Isopropyl-piperazin-1-yl) -methanone;
    [129] xx) 4- [4,5-bis- (4-bromo-phenyl) -2- (2-ethoxy-4-methoxy-phenyl) -4,5-dihydroimidazole-1-carbonyl] Piperazin-2-one; And
    [130] yy) [4,5-bis- (4-bromo-phenyl) -2- (2-isopropoxy-4-methoxy-phenyl) -4,5-dihydroimidazol-1-yl] -pipe Razin-1-yl-methanone.
    [131] In another embodiment, the invention relates to compounds of formula I, selected from the group:
    [132] a) 1- {4- [4,5-bis- (4-bromo-phenyl) -2- (2-isopropoxy-4-methoxy-phenyl) -4,5-dihydro-imidazole- 1-carbonyl] -piperazin-1-yl] -ethanone;
    [133] b) [4,5-bis- (4-bromo-phenyl) -2- (2-isopropoxy-4-methoxy-phenyl) -4,5-dihydroimidazol-1-yl]-( 4-methanesulfonyl-piperazin-1-yl) -methanone;
    [134] c) [4,5-bis- (4-bromo-phenyl) -2- (2-isopropoxy-4-methoxy-phenyl) -4,5-dihydroimidazol-1-yl]-( 4-methyl-piperazin-1-yl) -methanone;
    [135] d) [4,5-bis- (4-bromo-phenyl) -2- (2-isopropoxy-4-methoxy-phenyl) -4,5-dihydroimidazol-1-yl] -mor Folin-1-yl-methanone;
    [136] e) [1,4 '] bipiperidinyl-1'-yl- [4,5-bis- (4-bromo-phenyl) -2- (2-isopropoxy-4-methoxy-phenyl)- 4,5-dihydro-imidazol-1-yl] -methanone;
    [137] f) [4,5-bis- (4-bromo-phenyl) -2- (2-isopropoxy-4-methoxy-phenyl) -4,5-dihydroimidazol-1-yl]-( 4-ethyl-piperazin-1-yl) -methanone;
    [138] g) 4- [4,5-bis- (4-bromo-phenyl) -2- (2-isopropoxy-4-methoxy-phenyl) -4,5-dihydro-imidazole-1-car Carbonyl] -piperazin-2-one;
    [139] h) [4,5-bis- (4-cyano-phenyl) -2- (2-isopropoxy-4-methoxy-phenyl) -4,5-dihydroimidazol-1-yl] -pipe Razin-1-yl-methanone;
    [140] i) 1- (4- {4,5-bis- (4-chloro-phenyl) -2- [4-methoxy-2- (2-methoxy-ethoxy) phenyl] -4,5-dihydro -Imidazol-1-carbonyl} -piperazin-1-yl) -ethanone;
    [141] j) 1- (4- {4,5-bis- (4-chloro-phenyl) -2- [2- (2-fluoro-ethoxy) -4-methoxy-phenyl] -4,5-di Hydro-imidazol-1-carbonyl} -piperazin-1-yl) -ethanone;
    [142] k) 4- {4,5-bis- (4-chloro-phenyl) -2- [2- (2-fluoro-ethoxy) -4-methoxy-phenyl] -4,5-dihydro-imi Dazol-1-carbonyl} -piperazin-2-one;
    [143] l) [4,5-bis- (4-chloro-phenyl) -2- (2-ethoxy-4-methoxy-phenyl) -4,5-dihydroimidazol-1-yl] -piperazine- 1-yl-methanone hydrochloride;
    [144] m) 4,5-bis- (4-chloro-phenyl) -2- (2-ethoxy-4-methoxy-phenyl) -4,5-dihydroimidazole-1-carboxylic acid methyl- (2 -Methylamino-ethyl) -amide, trifluoroacetic acid salt;
    [145] n) 4,5-bis- (4-chloro-phenyl) -2- (2-ethoxy-4-methoxy-phenyl) -4,5-dihydroimidazole-1-carboxylic acid (2-dimethyl Amino-ethyl) -methyl-amide, trifluoroacetic acid salt;
    [146] o) 4,5-bis- (4-chloro-phenyl) -2- (2-ethoxy-4-methoxy-phenyl) -4,5-dihydroimidazole-1-carboxylic acid (2-dimethyl Amino-ethyl) -amide, trifluoroacetic acid salt;
    [147] p) 4,5-bis- (4-chloro-phenyl) -2- (2-ethoxy-4-methoxy-phenyl) -4,5-dihydroimidazole-1-carboxylic acid (2-amino -Ethyl) -amide, trifluoroacetic acid salt;
    [148] q) [4,5-bis- (4-chloro-phenyl) -2- (2-ethoxy-4-methoxy-phenyl) -4,5-dihydroimidazol-1-yl]-(4- Pyrrolidin-1-yl-piperidin-1-yl) -methanone hydrochloride;
    [149] r) [4,5-bis- (4-chloro-phenyl) -2- (4-methoxy-2-propoxy-phenyl) -4,5-dihydroimidazol-1-yl] -piperazine- 1-yl-methanone, trifluoro acetic acid salt;
    [150] s) [4,5-bis- (4-chloro-phenyl) -2- (2-isopropoxy-4-methoxy-phenyl) -4,5-dihydroimidazol-1-yl]-(4 -Methyl-piperazin-1-yl) -methanone hydrochloride;
    [151] t) 4,5-bis- (4-chloro-phenyl) -2- (2-isopropoxy-4-methoxy-phenyl) -4,5-dihydroimidazole-1-carboxylic acid (2- Morpholin-4-yl-ethyl) -amide hydrochloride;
    [152] u) 4,5-bis- (4-chloro-phenyl) -2- (2-isopropoxy-4-methoxy-phenyl) -4,5-dihydroimidazole-1-carboxylic acid (2- Piperazin-1-yl-ethyl) -amide hydrochloride;
    [153] v) [4,5-bis- (4-chloro-phenyl) -2- (2-isobutoxy-4-methoxy-phenyl) -4,5-dihydroimidazol-1-yl] -piperazine- 1-yl-methanone hydrochloride;
    [154] w) [4,5-bis- (4-chloro-phenyl) -2- (2-isopropoxy-4-methoxy-phenyl) -4,5-dihydroimidazol-1-yl]-(3 -Methyl-piperazin-1-yl) -methanone hydrochloride;
    [155] x) {4,5-bis- (4-chloro-phenyl) -2- [4-methoxy-2- (2-methoxy-ethoxy) -phenyl] -4,5-dihydro-imidazole- 1-yl] -piperazin-1-yl-methanone, trifluoroacetic acid salt;
    [156] y) {4,5-bis- (4-chloro-phenyl) -2- [2- (2-fluoro-ethoxy) -4-methoxy-phenyl] -4,5-dihydro-imidazole- 1-yl} -piperazin-1-yl-methanone;
    [157] z) {4,5-bis- (4-chloro-phenyl) -2- [2- (2-fluoro-ethoxy) -4-methoxy-phenyl] -4,5-dihydro-imidazole- 1-yl}-(4-pyrrolidin-1-yl-piperidin-1-yl) -methanone hydrochloride;
    [158] aa) 2-amino-1- {4- [4,5-bis- (4-chloro-phenyl) -2- (2-isopropoxy-4-methoxyphenyl) -4,5-dihydro-imi Dazol-1-carbonyl] -piperazin-1-yl] -ethanone;
    [159] bb) 1- {4- [4,5-bis- (4-chloro-phenyl) -2- (2-isopropoxy-4-methoxy-phenyl) -4,5-dihydro-imidazole-1 -Carbonyl] -piperazin-1-yl} -2-hydroxy-ethanone;
    [160] cc) 1- {4- [4,5-bis- (4-chloro-phenyl) -2- (2-isopropoxy-4-methoxy-phenyl) -4,5-dihydro-imidazole-1 -Carbonyl] -piperazin-1-yl} -2,3-dihydroxy-propan-1-one;
    [161] dd) [4,5-bis- (4-chloro-phenyl) -2- (2-isopropoxy-4-methoxy-phenyl) -4,5-dihydroimidazol-1-yl]-[4 -(2,3-dihydroxy-propyl) -piperazin-1-yl] -methanone;
    [162] ee) 4- [4,5-bis- (4-chloro-phenyl) -2- (2-isopropoxy-4-methoxy-phenyl) -4,5-dihydro-imidazole-1-carbonyl ] -Piperazine-1-carboxylic acid dimethylamide;
    [163] ff) 4- [4,5-bis- (4-chloro-phenyl) -2- (2-isopropoxy-4-methoxy-phenyl) -4,5-dihydro-imidazole-1-carbonyl ] -Piperazine-1-carboxylic acid amide;
    [164] gg) [4,5-bis- (4-chloro-phenyl) -2- (2,4-diethoxy-phenyl) -4,5-dihydro-imidazol-1-yl] -piperazin-1- Mono-methanone;
    [165] hh) [4,5-bis- (4-chloro-phenyl) -2- (2,4-diethoxy-phenyl) -4,5-dihydro-imidazol-1-yl] morpholin-4-yl Methanone;
    [166] ii) [4,5-bis- (4-chloro-phenyl) -2- (2,4-diethoxy-phenyl) -4,5-dihydro-imidazol-1-yl]-[4- (2 -Hydroxy-ethyl) -piperazin-1-yl] -methanone;
    [167] jj) [4,5-bis- (4-chloro-phenyl) -2- (2,4-diethoxy-phenyl) -4,5-dihydro-imidazol-1-yl]-(4-methyl- Piperazin-1-yl) -methanone;
    [168] kk) 1- {4- [4,5-bis- (4-chloro-phenyl) -2- (2,4-diethoxy-phenyl) -4,5-dihydroimidazole-1-carbonyl]- Piperazin-1-yl} -ethanone;
    [169] ll) [4,5-bis- (4-chloro-phenyl) -2- (2,4-diethoxy-phenyl) -4,5-dihydro-imidazol-1-yl]-(4-methanesulphate Ponyl-piperazin-1-yl) -methanone;
    [170] mm) [4,5-bis- (4-chloro-phenyl) -2- (2,4-diethoxy-phenyl) -4,5-dihydro-imidazol-1-yl]-(4-pyrroli Din-1-yl-piperidin-1-yl) -methanone;
    [171] nn) [4,5-bis- (4-bromo-phenyl) -2- (2,4-diethoxy-phenyl) -4,5-dihydro-imidazol-1-yl]-(4-methyl -Piperazin-1-yl) -methanone;
    [172] oo) [4,5-bis- (4-bromo-phenyl) -2- (2,4-diethoxy-phenyl) -4,5-dihydro-imidazol-1-yl]-(4-ethyl -Piperazin-1-yl) -methanone;
    [173] pp) [4,5-bis- (4-bromo-phenyl) -2- (2,4-diethoxy-phenyl) -4,5-dihydro-imidazol-1-yl] -morpholine-1 -Yl-methanone;
    [174] qq) 4- [4,5-bis- (4-chloro-phenyl) -2- (2,4-diethoxy-phenyl) -4,5-dihydro-imidazole-1-carbonyl] -piperazine -1-carboxylic acid amide;
    [175] rr) 4- [4,5-bis- (4-chloro-phenyl) -2- (2,4-diethoxy-phenyl) -4,5-dihydro-imidazole-1 -carbonyl] -piperazine -1-carboxylic acid dimethylamide;
    [176] ss) [4,5-bis- (4-chloro-phenyl) -2- (4-dimethylamino-2-ethoxy-phenyl) -4,5-dihydro-imidazol-1-yl] -piperazine -1-yl-methanone;
    [177] tt) [4,5-bis- (4-chloro-phenyl) -2- (2-ethoxy-4-ethyl-phenyl) -4,5-dihydroimidazol-1-yl] -piperazine-1 -Yl-methanone;
    [178] uu) [4,5-bis- (4-chloro-phenyl) -2- (2-ethoxy-4-methyl-phenyl) -4,5-dihydroimidazol-1-yl] -piperazine-1 -Yl-methanone;
    [179] vv) [4,5-bis- (4-chloro-phenyl) -2- (4-ethyl-2-isopropoxy-phenyl) -4,5-dihydroimidazol-1-yl] -piperazine- 1-yl-methanone;
    [180] ww) [4,5-bis- (4-chloro-phenyl) -2- (2-isopropoxy-4-methyl-phenyl) -4,5-dihydroimidazol-1-yl] -piperazine- 1-yl-methanone;
    [181] xx) 1- {4- [4,5-bis- (4-chloro-phenyl) -2- (4-dimethylamino-2-ethoxyphenyl) -4,5-dihydro-imidazole-1-car Carbonyl] -piperazin-1-yl] -ethanone; And
    [182] yy) [4,5-bis- (4-chloro-phenyl) -2- (2-ethoxy-5-methyl-phenyl) -4,5-dihydroimidazol-1-yl] -piperazine-1 -Yl-methanone, trifluoroacetic acid salt.
    [183] In another embodiment, to compounds of formula I selected from the following group of the invention:
    [184] a) [4,5-bis- (4-chloro-phenyl) -2- (2-ethoxy-4-fluoro-phenyl) -4,5-dihydroimidazol-1-yl]-(4- Pyrrolidin-1-yl-piperidin-1-yl) -methanone;
    [185] b) [4,5-bis- (4-chloro-phenyl) -2- (2-ethoxy-4-fluoro-phenyl) -4,5-dihydroimidazol-1-yl]-(4- Dimethylamino-piperidin-1-yl) -methanone;
    [186] c) [4,5-bis- (4-chloro-phenyl) -2- (2-ethoxy-4-fluoro-phenyl) -4,5-dihydroimidazol-1-yl] -piperazine- 1-yl-methanone;
    [187] d) [4,5-bis- (4-chloro-phenyl) -2- (4-fluoro-2-isopropoxy-phenyl) -4,5-dihydroimidazol-1-yl]-(4 -Pyrrolidin-1-yl-piperidin-1-yl) -methanone;
    [188] e) [4,5-bis- (4-chloro-phenyl) -2- (4-fluoro-2-isopropoxy-phenyl) -4,5-dihydroimidazol-1-yl]-(4 -Dimethylamino-piperidin-1-yl) -methanone;
    [189] f) [4,5-bis- (4-chloro-phenyl) -2- (4-fluoro-2-isopropoxy-phenyl) -4,5-dihydroimidazol-1-yl]-(4 -Methyl-piperazin-1-yl) -methanone;
    [190] g) [4,5-bis- (4-chloro-phenyl) -2- (4-fluoro-2-isopropoxy-phenyl) -4,5-dihydroimidazol-1-yl] -piperazine -1-yl-methanone;
    [191] h) [4,5-bis- (4-chloro-phenyl) -2- (4-fluoro-2-isopropoxy-phenyl) -4,5-dihydroimidazol-1-yl]-(4 Methanesulfonyl-piperazin-1-yl) -methanone;
    [192] i) 4- [4,5-bis- (4-chloro-phenyl) -2- (4-fluoro-2-isopropoxy-phenyl) -4,5-dihydroimidazole-1-carbonyl] Piperazin-2-one;
    [193] j) [4,5-bis- (4-chloro-phenyl) -2-chroman-8-yl-4,5-dihydro-imidazol-1-yl] -piperazin-1-yl-methanone ;
    [194] k) 4- [4,5-bis- (4-bromo-phenyl) -2- (2-ethoxy-4-fluoro-phenyl) -4,5-dihydroimidazole-1-carbonyl] Piperazin-2-one;
    [195] l) [4,5-bis- (4-bromo-phenyl) -2- (2-ethoxy-4-fluoro-phenyl) -4,5-dihydroimidazol-1-yl] -morpholine -4-yl-methanone;
    [196] m) [4,5-bis- (4-bromo-phenyl) -2- (2-ethoxy-4-fluoro-phenyl) -4,5-dihydroimidazol-1-yl]-(4 -Pyrrolidin-1-yl-piperidin-1-yl-methanone;
    [197] n) [4,5-bis- (4-bromo-phenyl) -2- (2-ethoxy-4-fluoro-phenyl) -4,5-dihydroimidazol-1-yl]-(4 -Dimethylamino-piperidin-1-yl) -methanone;
    [198] o) [4,5-bis- (4-bromo-phenyl) -2- (2-ethoxy-4-fluoro-phenyl) -4,5-dihydroimidazol-1-yl] -piperazine -1-yl-methanone;
    [199] p) [4,5-bis- (4-chloro-phenyl) -2- (2-cyclopentyloxy-4-methoxy-phenyl) -4,5-dihydro-imidazol-1-yl] -pipe Razin-1-yl-methanone;
    [200] q) {4,5-bis- (4-chloro-phenyl) -2- [2- (2-dimethylamino-ethoxy) -4-methoxy-phenyl] -4,5-dihydro-imidazole- 1-yl} -piperazin-1-yl-methanone;
    [201] r) {4,5-bis- (4-chloro-phenyl) -2- [2- (2-imidazol-1-yl-ethoxy) -4-methoxyphenyl] -4,5-dihydro- Imidazol-1-yl} -piperazin-1-yl-methanone;
    [202] s) [2- (4-Chloro-2-ethoxy-phenyl) -4,5-bis- (4-chloro-phenyl) -4,5-dihydroimidazol-1-yl] -piperazine-1 -Yl-methanone hydrochloride;
    [203] t) [2- (4-chloro-2-ethoxy-phenyl) -4,5-bis- (4-chloro-phenyl) -4,5-dihydroimidazol-1-yl]-(4-methyl -Piperazin-1-yl) -methanone hydrochloride;
    [204] u) [2- (4-chloro-2-ethoxy-phenyl) -4,5-bis- (4-chloro-phenyl) -4,5-dihydroimidazol-1-yl]-(4-py Ralidin-1-yl-piperidin-1-yl) -methanone hydrochloride;
    [205] v) 2- (4-Chloro-2-ethoxy-phenyl) -4,5-bis- (4-chloro-phenyl) -4,5-dihydroimidazol-1-yl] -morpholin-4- Mono-methanone;
    [206] w) 1- {4- [2- (4-chloro-2-ethoxy-phenyl) -4,5-bis- (4-chloro-phenyl) -4,5-dihydroimidazole-1-carbonyl ] -Piperazin-1-yl} -ethanone;
    [207] x) [2- (4-chloro-2-ethoxy-phenyl) -4,5-bis- (4-chloro-phenyl) -4,5-dihydroimidazol-1-yl]-[4- ( 2-hydroxy-ethyl) -piperazin-1-yl] -methanone hydrochloride;
    [208] y) 4- [2- (4-chloro-2-ethoxy-phenyl) -4,5-bis- (4-chloro-phenyl) -4,5-dihydroimidazole-1-carbonyl] -pipe Razin-2-one;
    [209] z) [4,5-bis- (4-chloro-phenyl) -2- (4-ethoxy-2-isopropoxy-phenyl) -4,5-dihydroimidazol-1-yl] -piperazine -1-yl-methanone;
    [210] aa) [4,5-bis- (4-chloro-phenyl) -2- (2-ethoxy-5-methoxy-phenyl) -4,5-dihydroimidazol-1-yl] -piperazine- 1-yl-methanone, trifluoroacetic acid salt;
    [211] bb) [4,5-bis- (4-chloro-phenyl) -2- (2-ethoxy-5-methoxy-phenyl) -4,5-dihydroimidazol-1-yl]-(4- Methanesulfonyl-piperazin-1-yl) -methanone;
    [212] cc) [4,5-bis- (4-chloro-phenyl) -2- (2-ethoxy-5-methoxy-phenyl) -4,5-dihydroimidazol-1-yl]-[4- (2-hydroxy-ethyl) -piperazin-1-yl] -methanone hydrochloride;
    [213] dd) [4,5-bis- (4-chloro-phenyl) -2- (2,5-diethoxy-phenyl) -4,5-dihydro-imidazol-1-yl] -piperazin-1- Mono-methanone hydrochloride;
    [214] ee) [4,5-bis- (4-chloro-phenyl) -2- (2,5-diethoxy-phenyl) -4,5-dihydro-imidazol-1-yl]-(4-methanesulphate) Ponyl-piperazin-1-yl) -methanone;
    [215] ff) [4,5-bis- (4-chloro-phenyl) -2- (4-ethoxy-2-isopropoxy-phenyl) -4,5-dihydroimidazol-1-yl]-[4 -(2-hydroxy-ethyl) -piperazin-1-yl] -methanone;
    [216] gg) 4- [4,5-bis- (4-chloro-phenyl) -2- (4-ethoxy-2-isopropoxy-phenyl) -4,5-dihydroimidazole-1-carbonyl] Piperazin-2-one;
    [217] hh) [4,5-bis- (4-chloro-phenyl) -2- (5-ethoxy-2-isopropoxy-phenyl) -4,5-dihydroimidazol-1-yl] -piperazine -1-yl-methanone;
    [218] ii) [4,5-bis- (4-chloro-phenyl) -2- (5-ethoxy-2-isopropoxy-phenyl) -4,5-dihydroimidazol-1-yl]-(4 Methanesulfonyl-piperazin-1-yl) -methanone;
    [219] jj) [4,5-bis- (4-chloro-phenyl) -2- (5-ethoxy-2-isopropoxy-phenyl) -4,5-dihydroimidazol-1-yl]-[4 -(2-hydroxy-ethyl) -piperazin-1-yl] -methanone hydrochloride;
    [220] kk) 1- {4- [4,5-bis- (4-chloro-phenyl) -2- (4-ethoxy-2-isopropoxy-phenyl) -4,5-dihydro-imidazole-1 -Carbonyl] -piperazin-1-yl} -ethanone;
    [221] ll) 1- {4- [4,5-bis- (4-chloro-phenyl) -2- (5-ethoxy-2-propoxy-phenyl) -4,5-dihydro-imidazole-1- Carbonyl] -piperazin-1-yl] -ethanone;
    [222] mm) [4,5-bis- (4-chloro-phenyl) -2- (4-ethoxy-2-isopropoxy-phenyl) -4,5-dihydroimidazol-1-yl]-(4 -Pyrrolidin-1-yl-piperidin-1-yl) -methanone;
    [223] nn) [4,5-bis- (4-chloro-phenyl) -2- (2-isopropoxy-4-methoxy-phenyl) -4,5-dihydroimidazol-1-yl] -piperazine -1-yl-methanone, trifluoroacetic acid salt;
    [224] oo) [4,5-bis- (4-chloro-phenyl) -2- (2,4-diisopropoxy-phenyl) -4,5-dihydroimidazol-1-yl] -piperazine-1 -Yl-methanone;
    [225] pp) [4,5-bis- (4-chloro-phenyl) -2- (2,5-diisopropoxy-phenyl) -4,5-dihydroimidazol-1-yl] -piperazin-1 -Yl-methanone hydrochloride;
    [226] qq) 1- [4,5-bis- (4-chloro-phenyl) -2- (2-methoxy-5-morpholin-4-yl-methylphenyl) -4,5-dihydro-imidazole-1 -Yl] -2-methyl-propan-1-one;
    [227] rr) 1- [4,5-bis- (4-chloro-phenyl) -2- (3-hydroxymethyl-5-methoxy-phenyl) -4,5-dihydro-imidazol-1-yl] -2-methyl-propan-1-one;
    [228] ss) 1- [4,5-bis- (4-chloro-phenyl) -2- (3-hydroxymethyl-5-methoxymethyl-phenyl) -4,5-dihydro-imidazol-1-yl ] -Ethanone;
    [229] tt) 1- [4,5-bis- (4-chloro-phenyl) -2- (3-methoxy-5-methoxymethyl-phenyl) -4,5-dihydro-imidazol-1-yl] -2-methyl-propan-1-one;
    [230] uu) 3- [4,5-bis- (4-chloro-phenyl) -1-isobutyryl-4,5-dihydro-1H-imidazol-2-yl] -5-methoxymethyl-benzoic acid;
    [231] vv) 1- [4,5-bis- (4-chloro-phenyl) -2- (5-ethoxymethyl-2,4-dimethoxy-phenyl) -4,5-dihydro-imidazole-1- Il] -2-methyl-propan-1-one;
    [232] ww) [4,5-bis- (4-chloro-phenyl) -2- (2-ethoxy-6-methoxy-phenyl) -4,5-dihydroimidazol-1-yl] -piperazine- 1-yl-methanone; And
    [233] xx) [4,5-bis- (4-chloro-phenyl) -2- (5-ethoxymethyl-2,4-dimethoxy-phenyl) -4,5-dihydro-imidazol-1-yl] Piperazin-1-yl-methanone.
    [234] In another embodiment, the invention relates to compounds of formula I, selected from the group:
    [235] a) [4,5-bis- (4-chloro-phenyl) -2- (2-isopropoxy-4-methoxy-phenyl) -4,5-dihydroimidazol-1-yl]-[4 -(2-hydroxy-propyl) -piperazin-1-yl] -methanone;
    [236] b) [4,5-bis- (4-chloro-phenyl) -2- (2-isopropoxy-4-methoxy-phenyl) -4,5-dihydroimidazol-1-yl] -threo [ 4- (2-hydroxy-1-methyl-propyl) -piperazin-1-yl] methanone;
    [237] c) [4,5-bis- (4-chloro-phenyl) -2- (2-isopropoxy-4-methoxy-phenyl) -4,5-dihydroimidazol-1-yl] -erythro [ 4- (2-hydroxy-1-methyl-propyl) -piperazin-1-yl] methanone;
    [238] d) 1- {4- [4,5-bis- (4-chloro-phenyl) -2- (2-isopropoxy-4-methoxy-phenyl) -4,5-dihydro-imidazole-1 -Carbonyl] -piperazin-1-yl} -propan-2-one;
    [239] e) [4,5-bis- (4-chloro-phenyl) -2- (2-isopropoxy-4-methoxy-phenyl) -4,5-dihydroimidazol-1-yl]-[1 , 4] diazepan-1-yl-methanone;
    [240] f) 4- [4,5-bis- (4-chloro-phenyl) -2- (2-isopropoxy-4-methoxy-phenyl) -4,5-dihydro-imidazole-1-carbonyl ] -1-methyl-piperazin-2-one;
    [241] g) 1- {4- [4,5-bis- (4-chloro-phenyl) -2- (2-isopropoxy-4-methoxy-phenyl) -4,5-dihydro-imidazole-1 -Carbonyl] -piperazin-1-yl} -2-methyl-propan-1-one;
    [242] h) 4- [4,5-bis- (4-chloro-phenyl) -2- (2-isopropoxy-4-methoxy-phenyl) -4,5-dihydro-imidazole-1-carbonyl ] -Piperazine-1-carbaldehyde;
    [243] i) 4- {4,5-bis- (4-chloro-phenyl) -2- [4-methoxy-2- (2,2,2-trifluoro-ethoxy) phenyl] -4,5- Dihydro-imidazol-1-carbonyl} -piperazin-2-one;
    [244] j) 4- {4,5-bis- (4-bromo-phenyl) -2- [4-methoxy-2- (2,2,2-trifluoro-ethoxy) phenyl] -4,5 -Dihydro-imidazol-1-carbonyl} -piperazin-2-one;
    [245] k) [4,5-bis- (4-ethynyl-phenyl) -2- (2-isopropoxy-4-methoxy-phenyl) -4,5-dihydro-imidazol-1-yl]- (4-pyrrolidin-1-yl-piperidin-1-yl) -methanone;
    [246] l) 1- {4- [2- (5-chloro-2-isopropoxy-phenyl) -4,5-bis- (4-chloro-phenyl) -4,5-dihydro-imidazole-1- Carbonyl] -piperazin-1-yl} -ethanone; And
    [247] m) [5- (4-chloro-phenyl) -4- (4-ethynyl-phenyl) -2- (2-isopropoxy-4-methoxy-phenyl) -4,5-dihydro-imidazole -1-yl]-(4-pyrrolidin-1-yl-piperidin-1-yl) methanone.
    [248] In another embodiment, the present invention is directed to compounds of formula II:
    [249] a) 1- [4,5-bis- (4-chloro-phenyl) -2- (2-methoxy-phenyl) -4,5-dihydro-imidazol-1-yl] -2-methyl-propane -1-one;
    [250] b) 1- [4,5-bis- (4-chloro-phenyl) -2-p-tolyl-4,5-dihydro-imidazol-1-yl] -ethanone;
    [251] c) {4- [4,5-bis- (4-chloro-phenyl) -1-isobutyryl-4,5-dihydro-1H-imidazol-2-yl] phenoxy} -acetic acid ethyl ester;
    [252] d) {4- [4,5-bis- (4-chloro-phenyl) -1-isobutyryl-4,5-dihydro-1H-imidazol-2-yl] phenoxy} -acetic acid;
    [253] e) 2-methyl-1- [2,4,5-tris- (4-chloro-phenyl) -4,5-dihydro-imidazol-1-yl] -propan-1-one;
    [254] f) 1- [4,5-bis- (4-chloro-phenyl) -2- (4-methoxy-phenyl) -4,5-dihydro-imidazol-1-yl] -ethanone;
    [255] g) [2- (2-Chloro-phenyl) -4,5-bis- (4-chloro-phenyl) -4,5-dihydro-imidazol-1-yl] -piperazin-1-yl-methane On;
    [256] h) [2- (3-Bromo-phenyl) -4,5-bis- (4-chloro-phenyl) -4,5-dihydro-imidazol-1-yl] -piperazin-1-yl- Methanone;
    [257] i) [2-biphenyl-3-yl-4,5-bis- (4-chloro-phenyl) -4,5-dihydro-imidazol-1-yl]-(4-methyl-piperazine-1 -Yl) -methanone;
    [258] j) [4,5-bis- (4-chloro-phenyl) -2- (3-pyrrolidin-1-yl-phenyl) -4,5-dihydroimidazol-1-yl] -piperazine- 1-yl-methanone;
    [259] k) [4,5-bis- (4-bromo-phenyl) -2- (2-methoxy-phenyl) -4,5-dihydro-imidazol-1-yl]-[4- (2- Hydroxy-ethyl) -piperazin-1-yl] -methanone;
    [260] l) 1- [5- (4-chloro-phenyl) -2- (4-methoxy-phenyl) -4- (4-nitro-phenyl) -4,5-dihydro-imidazol-1-yl] -Methyl-propan-1-one;
    [261] m) 1- [4- (4-chloro-phenyl) -2- (4-methoxy-phenyl) -5- (4-nitro-phenyl) -4,5-dihydro-imidazol-1-yl] -2-methyl-propan-1-one;
    [262] n) 1- [4,5-bis- (4-chloro-phenyl) -2- (2-isopropoxy-phenyl) -4,5-dihydro-imidazol-1-yl] -2-methyl- Propane-1-one;
    [263] o) [4,5-bis- (4-chloro-phenyl) -2- (2-isopropoxy-phenyl) -4,5-dihydro-imidazol-1-yl]-(4-pyrrolidine -1-yl-piperidin-1-yl) -methanone;
    [264] p) [4,5-bis- (4-chloro-phenyl) -2- (2-isopropoxy-phenyl) -4,5-dihydro-imidazol-1-yl] -piperazin-1-yl Methanone;
    [265] q) [4,5-bis- (4-chloro-phenyl) -2- (2-isopropoxy-phenyl) -4,5-dihydro-imidazol-1-yl]-(4-dimethylamino- Piperidin-1-yl) -methanone;
    [266] r) [1,4 '] bipiperidinyl-1'-yl- [4,5-bis- (4-chloro-phenyl) -2- (2-isopropoxy-phenyl) -4,5-dihydro -Imidazol-1-yl] -methanone;
    [267] s) [4,5-bis- (4-chloro-phenyl) -2- (2-isopropoxy-phenyl) -4,5-dihydro-imidazol-1-yl]-[4- (2- Hydroxy-ethyl) -piperazin-1-yl] -methanone;
    [268] t) {4,5-bis- (4-chloro-phenyl) -2- [2- (2-methyl-butoxy-phenyl] -4,5-dihydroimidazol-1-yl} -piperazine- 1-yl-methanone;
    [269] u) [4,5-bis- (4-chloro-phenyl) -2- (2-pentyloxy-phenyl) -4,5-dihydro-imidazol-1-yl] -piperazin-1-yl- Methanone;
    [270] v) [4,5-bis- (4-chloro-phenyl) -2- (3-ethoxy-phenyl) -4,5-dihydro-imidazol-1-yl] -piperazin-1-yl- Methanone, trifluoroacetate;
    [271] w) [4,5-bis- (4-chloro-phenyl) -2- (3-isopropoxy-phenyl) -4,5-dihydro-imidazol-1-yl] -piperazin-1-yl Methanone, trifluoroacetic acid salt;
    [272] x) 1- {4- [4,5-bis- (4-bromo-phenyl) -2- (2-ethoxy-phenyl) -4,5-dihydro-imidazole-1-carbonyl]- Piperazin-1-yl} -ethanone;
    [273] y) [4,5-bis- (4-bromo-phenyl) -2- (2-ethoxy-phenyl) -4,5-dihydro-imidazol-1-yl]-[4- (2- Hydroxy-ethyl) -piperazin-1-yl] -methanone;
    [274] z) 1- {4- [4,5-bis- (4-bromo-phenyl) -2- (2-isopropoxy-phenyl) -4,5-dihydroimidazole-1-carbonyl]- Piperazin-1-yl} -ethanone; And
    [275] aa) [4,5-bis- (4-bromo-phenyl) -2- (2-isopropoxy-phenyl) -4,5-dihydro-imidazol-1-yl]-[4- (2 -Hydroxy-ethyl) -piperazin-1-yl] -methanone.
    [276] The compounds according to the invention exhibit strong antitumor activity against various tumor cell lines. The antitumor activity indicates that the compounds of the invention and their pharmaceutically acceptable salts may be antitumor agents.
    [277] One embodiment of the invention is also a pharmaceutical composition containing a compound according to the invention as an active ingredient and a pharmaceutically acceptable carrier. Preferably, the pharmaceutical composition according to the present invention is suitable for oral or parenteral administration.
    [278] Pharmaceutical compositions can be administered orally, for example in the form of tablets, coated tablets, dragees, hard or soft gelatin capsules, solutions, emulsions or suspensions. Administration can also be performed rectally, eg using suppositories; Topically or percutaneously, for example with ointments, creams, gels or solutions; Or parenterally, for example, using injection solutions.
    [279] For the preparation of tablets, coated tablets, dragees or hard gelatin capsules, the compounds of the present invention may be mixed with pharmaceutically inert, inorganic or organic excipients. Examples of suitable excipients for tablets, dragees or hard gelatin capsules include lactose, corn starch or derivatives thereof, talc or stearic acid or salts thereof.
    [280] Suitable excipients for soft gelatin capsules include, for example, vegetable oils, waxes, fats, semisolid or liquid polyols, and the like; Depending on the nature of the active ingredient, no excipients may be required for the soft gelatin capsules.
    [281] For the preparation of solutions and syrups, excipients that can be used include, for example, water, polyols, saccharose, inert sugars and glucose.
    [282] For injectable solutions, excipients that can be used include water, alcohols, polyols, glycerin and vegetable oils.
    [283] For suppository, topical or transdermal administration, excipients that can be used include, for example, natural or hardened oils, waxes, fats and semisolid or liquid polyols.
    [284] Pharmaceutical compositions may also include preservatives, solubilizers, stabilizers, wetting agents, emulsifiers, sweeteners, colorants, exploitants, salts for osmotic pressure changes, buffers, coatings or antioxidants. They may also contain other therapeutically valuable agents.
    [285] In summary, pharmaceutical formulations for oral administration may be granules, tablets, sugar coated tablets, capsules, pills, suspensions or emulsions, and other materials for parenteral administration, eg intravenous, intramuscular or subcutaneous administration, For example, it may be used in the form of a sterile aqueous solution which may contain a salt or glucose which makes the solution isotonic. Antitumor agents may also be administered in the form of suppositories or pessaries or applied locally in the form of lotions, solutions, creams, ointments or fine powders.
    [286] The invention also relates to the use of a compound as described above for the manufacture of a medicament, preferably a medicament for the treatment or control of a cell proliferative disorder, most preferably a medicament for the treatment or control of a cancer.
    [287] For example, they are useful for the treatment or control of breast, colon, lung or prostate cancer.
    [288] A further embodiment of the invention relates to a method for treating cell proliferative disorder comprising administering a therapeutically effective amount of a compound of the present invention to a patient in need thereof. More preferably, the method according to the invention is a method wherein the cell proliferative disorder is cancer, and most preferably the cancer is breast cancer, colon cancer, lung cancer and prostate cancer.
    [289] Finally, the present invention relates to compounds of formula (I) and formula (II) for therapeutic use.
    [290] Compounds of the invention are advantageously illustrated with an IC 50 of about 70 hM to about 100 mM.
    [291] A therapeutically effective amount of a compound according to the invention means an amount of the compound effective to prevent, alleviate or alleviate the signs of the disease to be treated or to prolong the lifespan. Definition of a therapeutically effective amount is a technique in the art.
    [292] Therapeutically effective amounts or dosages of the compounds according to the invention are variable at a wide range of limits and can be determined by methods known in the art. The dosage is adjusted to the individual requirements in each particular case, including the particular compound (s) to be administered, the route of administration, the condition to be treated and the patient to be treated. In general, for oral or parenteral administration to adult humans weighing about 70 kg, the upper limit may be exceeded if indicated, but the daily dosage may be from about 10 mg to about 10,000 mg, preferably about 200 mg. To about 1,000 mg is suitable. The daily dose may be administered as a single dose or as separate doses, or for parenteral administration, and may be supplied as a continuous infusion.
    [293] Compounds of the present invention can be prepared according to the following scheme according to the provided process. Starting compounds are known in the art or are commercially available. The following definitions are provided as applicable to the synthetic schemes:
    [294] V 1 , V 2 , V 3 , V 4 , V 5 are each hydrogen, -OV 6 , -SV 7 , NV 8 V 9 , -CONV 8 V 9 , -COOV 10 , halogen, nitro, trifluoromethyl, Independently selected from C 1 -C 6 alkyl, which may be optionally substituted with V 11 and cycloalkyl;
    [295] V 1 , V 2 may together form part of a heterocycle having one or more hetero atoms, which may be substituted with V 10 .
    [296] V 2 , V 3 together may form part of a heterocycle having one or more hetero atoms, which may be substituted with V 10 .
    [297] Y 1 , Y 2 are each -Cl, -Br, nitro, cyano; And -C = CH are independently selected.
    [298] V, is selected from COV 12 and CONV 13 V 14 ,
    [299] V 6 is selected from hydrogen, C 1 -C 6 alkyl, which may be optionally substituted with V 11 and cycloalkyl;
    [300] V 7 is selected from the group of hydrogen and C 1 -C 6 alkyl;
    [301] V 8 , V 9 are each independently selected from hydrogen, C 1 -C 6 alkyl and cycloalkyl;
    [302] V 8 , V 9 may together form part of a heterocycle having one or more hetero atoms;
    [303] V 10 is selected from the group of hydrogen, C 1 -C 6 alkyl and cycloalkyl;
    [304] V 11 is selected from the group of —CONV 8 V 9 , —NV 8 V 9 , —COOV 10 , aryl, halogen, C 1 -C 6 alkoxy, morpholinyl and heterocycle;
    [305] V 12 is selected from the group of hydrogen, C 1 -C 6 alkyl, cycloalkyl, aryl, heterocycle, and heteroaryl;
    [306] V 13 and V 14 are independently selected from the group of C 1 -C 6 alkyl, cycloalkyl, C 1 -C 4 alkyl substituted with V 11; or
    [307] V 13 and V 14 may together form part of a heterocycle such as morpholine, piperidine, pyrrolidine and piperazine; Piperazine may be substituted with acyl, alkylsulfonyl, CONH 2 , CONV 8 V 9 , keto, hydroxy substituted with C 1 -C 6 alkyl, hydroxyalkyl, acyl, hydroxy and amino;
    [308] Piperidine can be substituted with dialkyl amines, pyrrolidine or piperidine.
    [309]
    [310] Compounds of formula (2), which are known compounds or prepared by known methods, are converted to compounds of formula (3) using hydrogen chloride gas over a period of several hours to several weeks in ethanol. Subsequently, the compound of formula 3 is reacted with a compound of formula 4 at a temperature of 60 to 100 ° C. in a solvent such as ethanol to obtain a compound of formula 5.
    [311] When V is COV 12 , the compound of formula 5 is reacted with a compound of formula ClCOV 12 (known compound or compound prepared by a known method) in the presence of a base such as triethylamine at a temperature of 0 ° C. to 25 ° C. The compound of formula 1 is obtained.
    [312] When V is CONV 13 V 14 , wherein NHV 13 V 14 is a known compound or a compound prepared by a known method, the compound of formula 5 is reacted with phosgene in the presence of triethylamine at 0 ° C., Treatment with a compound of formula HNV 13 V 14 yields a compound of formula 1.
    [313]
    [314] As shown in Scheme II, when the V 15 substituted piperazine is not commercially available (V 15 may be acyl, hydroxyl substituted acyl, amino, protected amino and sulfonyl), the compound of formula 7 It is prepared as follows: A compound of formula 5 is reacted with phosgene and triethylamine and then treated with piperazine to give a compound of formula 6. The compound of formula 6 is reacted with V 15 X to give a compound of formula 7.
    [315] As shown in Scheme III, the compound of formula 8 may be prepared by the reaction of phosgene and triethylamine from the compound of formula 6 followed by the treatment of NHV 8 V 9 , a known compound or a compound prepared by a known method. have.
    [316]
    [317] Meso-1,2-diamine (Y 1 = Y 2 ) of formula (4) can be prepared according to literature procedures (see, Jennerwein, M. et al. Cancer Res. Clin. Oncol. 1988, 114, 347-58; Vogtle , F .; Goldschmitt, E. Chem. Ber. 1976, 109, 1-40).
    [318] Y 1 If it is desired to prepare a compound of formula 4, Y 2 , modifications can be made to existing procedures. Mixtures of equimolar amounts of benzaldehyde and meso-1,2-bis- (2-hydroxy-phenyl) -ethane-1,2-diamine can be used to obtain a mixture of 1,2-diamine (Scheme IV) Knoelker, HJ, et al. Tetrahedron Letters 1998, 39, P. 9407. Subsequently, di-t-butyldicarbonate is reacted with dimethylaminopyridine in the presence of the compound of formula 9 to obtain HPLC purification. Compound 9 is then converted to the compound of formula 4 by treatment with hydrobromic acid in hot acetic acid.
    [319]
    [320] If it is desired to prepare a compound of formula 2 that is not commercially available, a number of synthetic methods known in the art may be employed. Suitable methods for the synthesis of benzonitrile are provided in the examples. The following reaction illustrates part of the method.
    [321] Compound of Formula 11 (V 16 may be any suitable group such as V 1 , V 2 , V 3 , V 4 or V 5 ) may be a compound of Formula 10 and V 6 X (X = Cl, Br, I) Can be prepared by alkylation using conventional methods (Scheme V). Phenoxide anions are produced by bases such as cesium carbonate or potassium carbonate. The reaction is generally carried out during acetone reflux. V 6 can also be introduced using Mitsunobu reactions (eg, references Hughes, DL Org. React. 1992, 42, 335-656).
    [322]
    [323] Compounds of formula 12 (V 16 may be any suitable group such as V 1 , V 2 , V 3 , V 4 or V 5 ) are described in the literature (Karmarkar, S. N; Kelkar, SL; Wadia, MS Synthesis). 1985, 510-512; Bergeron, RJ et al., J. Med. Chem. 1999, 42, 95-108). The V group can then be introduced using V 6 X (X = Cl, Br, I), or using the Mitsunobu reaction to afford benzonitrile 13 (Scheme VI).
    [324]
    [325] Compounds of formula 15 may be prepared by bromination or iodide of phenol 14 (Scheme VII) (V 16 may be any suitable group such as V 1 , V 2 , V 3 , V 4 or V 5 ). Reaction conditions such as N-brosuccinamide / tetrahydrofuran or iodine / thallium (I) acetate can be used (see, eg, Carreno, MC; Garcia Ruano, JL; Sanz, G .; Toledo, MA; Urbano, A. Synlett 1997, 1241-1242; Cambie, RC; Rutledge, PS; Smith-Palmer, T .; Woodgate, PDJ Chem. Soc., Perkin Trans. 1 1976, 1161-4). The V 5 group can be introduced using V 6 X (X = Cl, Br, I) or Mitsunobu reaction. Methods for the conversion of aromatic halides to the corresponding nitriles are known in the art (see, eg, Okano T .; Iwahara, M .; Kiji, J., Synlett 1998, 243). Cyanation of halide 15 (X ′ = Br, I) can be achieved using a catalyst such as tetrakis (triphenylphosphine) palladium (0) and using zinc cyanide. Solvents such as dimethylformamide can be used and the reaction temperature is 80-110 ° C.
    [326]
    [327] In Scheme VIII, amination of aromatic halide 16 with HNV 7 V 8 and a palladium catalyst is used to provide benzonitrile of formula 17 (see, eg, Harris, MC; Geis, O .; Buchwald, SLJ Org Chem. 1999, 64, 6019).
    [328]
    [329] Compounds of formula 13 (V 16 may be any suitable group such as V 1 , V 2 , V 3 , V 4 or V 5 ) may be prepared by nucleophilic substitution of 2-halobenzonitrile 18 IX). (See, eg, X = F: Wells, KM; Shi, Y.-J .; Lynch, JE; Humphrey, GR; Volante, RP; Reider, PJ Tetrahedron Lett. 1996, 37, 6439-6442; X = NO 2 : Harrison, CR; Lett, RM; McCann, SF; Shapiro, R .; Stevenson, TM WO 92/03421, 1992).
    [330]
    [331] To prepare the benzonitrile of formula 21 wherein V 1 , V 2 , V 3 , V 4 or V 5 = OV 6 , continuous alkylation of diol 19 with suitable V 6 X (X = Cl, Br, I) is used. do. Bromide 20 is then converted to nitrile 21 using zinc cyanide and a Pd (O) catalyst (Scheme X).
    [332]
    [333] Specific examples below are described in U.S. Pat. See the example provided in Provisional Application Serial No. 60 / 341,729. Examples of such temporary applications are incorporated herein by reference.
    [334] The present invention includes the following examples. For the structural formulas shown, it will be understood that the oxygen and nitrogen atoms with available electrons, as indicated in the compound name, have hydrogen bonded to them. The following examples detail preferred methods for the preparation of the compounds of the present invention, but the present invention is not limited thereto.
    [335] Example 1
    [336] 1- [4,5-bis- (4-chloro-phenyl) -2- (2,4-dimethoxy-phenyl) -4,5-dihydro-imidazol-1-yl] -2-methyl-propane -1-on
    [337]
    [338] Hydrogen chloride gas was passed a solution of 2,4-dimethoxy-benzonitrile (5.20 g, 32 mmol) in anhydrous ethanol (200 mL, 0 ° C.) at 0 ° C. After 7 hours, the hydrogen chloride gas was stopped and the reaction mixture was stirred at rt overnight. The solvent was removed and the residue was triturated in diethyl ether to give ethyl 2,4-dimethoxy-benzimidate hydrochloride (4.5 g, 57%). Used without further purification.
    [339] Meso-1,2-bis- (4-chloro-phenyl) -ethane-1,2-diamine (1.21 g, 4.30 mmol, Jennerwein, M. et al Cancer Res. Clin. Oncol 1988, 114, 347-8 Vogtle, F .; Goldschmitt, E. Chem. Ber. 1976, 109, 1-40) and ethyl 2,4-dimethoxy-benzimidate hydrochloride (1.58 g, 6.43 mmol) Solution in ethanol (30 mL) was heated to reflux for 16 h. The reaction mixture was basified with aqueous sodium bicarbonate solution (10 mL) and extracted with ethyl acetate. The organic extract was washed with brine and dried over anhydrous sodium sulfate. The solid was then filtered off and the filtrate was concentrated in vacuo. The crude residue was purified by flash chromatography eluting with 2-6% methanol in methylene chloride (Biotage system, KP-Sil ™ 32-63 μm, 60 μs silica gel) to give 4,5-bis- (4-chloro- Phenyl) -2- (2,4-dimethoxyphenyl) -4,5-dihydro-1H-imidazole (1.10 g, 60%) was obtained.
    [340] Isobutyryl chloride (19 μl, 0.18 mmol) was added to triethylamine (25 μl, 0.18 mmol) and 4,5-bis- (4-chloro-phenyl) -2- (2,4-dimethoxy-phenyl)- To a solution of 4,5-dihydro-1H-imidazole (70 mg, 0.164 mmol) was added. The reaction mixture was stirred at rt for 2 h. It was diluted with methylene chloride, washed with water and brine and dried over sodium sulfate. The solvent was removed under reduced pressure and the residue was chromatographed on silica gel with 0.5-1% methanol in methylene chloride to give 1- [4,5-bis- (4-chloro-phenyl) -2- (2,4-dimeth Methoxy-phenyl) -4,5-dihydroimidazol-1-yl] -2-methyl-propan-1-one was obtained. HR-MS (EI, m / z) Calcd for C 27 H 26 N 2 0 3 Cl 2 (M + ) 496.1320, found 496.1319
    [341] Example 2
    [342] In a similar manner to Example 1, the following compounds were prepared.
    [343] a) 1- [4,5-bis- (4-chloro-phenyl) -2- (2,4-dimethoxy-phenyl) -4,5-dihydro-imidazol-1-yl] ethanone. HR-MS (EI, m / z) calcd for C 25 H 22 N 2 0 3 Cl 2 (M + ) 468.1007, found 468.1020,
    [344]
    [345] b) 1- [4,5-bis- (4-chloro-phenyl) -2- (2,4-dimethoxy-phenyl) -4,5-dihydro-imidazol-1-yl] -2,2 -Dimethyl-propan-1-one. HR-MS (EI, m / z) calcd for C 28 H 28 N 2 0 3 Cl 2 (M + ) 510.1477, found 510.1476,
    [346] c) [4,5-bis- (4-chloro-phenyl) -2- (2,4-dimethoxy-phenyl) -4,5-dihydro-imidazol-1-yl] cyclopentyl-methanone. HR-MS (EI, m / z) calcd for C 29 H 28 N 2 0 3 Cl 2 (M + ) 522.1477, found 522.1470,
    [347] d) [4,5-bis- (4-chloro-phenyl) -2- (2,4-dimethoxy-phenyl) -4,5-dihydro-imidazol-1-yl] -cyclohexyl-methanone . HR-MS (EI, m / z) calculated for C 3O H 3O N 2 0 3 Cl 2 (M +) 536.1633, measured 536.1633,
    [348] e) [4,5-bis- (4-chloro-phenyl) -2- (2,4-dimethoxy-phenyl) -4,5-dihydro-imidazol-1-yl] thiophen-2-yl Methanone. HR-MS (EI, m / z) C 28 H 2O N 2 0 3 Cl 2 S calcd 534.0572, measured value for [(M-2H) +] 534.0566,
    [349] f) [4,5-bis- (4-chloro-phenyl) -2- (2,4-dimethoxy-phenyl) -4,5-dihydro-imidazol-1-yl] -isoxazole-5- Sun-methanone. HR-MS (EI, m / z) Calcd for C 27 H 21 N 3 0 4 Cl 2 (M + ) 521.0909, found 521.0892,
    [350] g) [4,5-bis- (4-chloro-phenyl) -2- (2,4-dimethoxy-phenyl) -4,5-dihydro-imidazol-1-yl] -furan-2-yl Methanone. HR-MS (EI, m / z) calcd for C 28 H 2 O N 2 0 4 Cl 2 [(M-2H) + ] 518.0800, found 518.0802,
    [351] h) 1- [4,5-bis- (4-chloro-phenyl) -2- (2-methoxy-phenyl) -4,5-dihydro-imidazol-1-yl] -2-methyl-propane -1-one. HR-MS (EI, m / z) calcd for C 26 H 25 N 2 0 2 Cl 2 [(M + H) + ] 467.1289, found 467.1295
    [352]
    [353] i) 1- [4,5-bis- (4-chloro-phenyl) -2-p-tolyl-4,5-dihydro-imidazol-1-yl] -ethanone. HR-MS (EI, m / z) Calcd for C 24 H 2 O N 2 0Cl 2 (M + ) 422.0953, found 422.0950
    [354] j) {4- [4,5-bis- (4-chloro-phenyl) -1-isobutyryl-4,5-dihydro-1H-imidazol-2-yl] phenoxy} -acetic acid ethyl ester. HR-MS (ES, m / z) calcd for C 29 H 29 N 2 0 4 Cl 2 [(M + H) + ] 539.1499, found 539.1506. Starting ethyl (4-cyano-phenoxy) -acetates are prepared from 4-hydroxy-benzonitrile and ethyl bromoacetate, see Kirkiacharian, S .; Goma, JR et al. Pharm. Fr. 1989, 47, 16-23.
    [355] k) {4- [4,5-bis- (4-chloro-phenyl) -l-isobutyryl-4,5-dihydro-lH-imidazol-2-yl] phenoxy} -acetic acid is {4 By hydrolysis of-[4,5-bis- (4-chloro-phenyl) -1-isobutyryl-4,5-dihydro-1H-imidazol-2-yl] -phenoxy} -acetic acid ethyl ester Manufactured. HR-MS (ES, m / z) Calcd for C 27 H 25 N 2 0 4 Cl 2 (M + ) 511.1186, found 511.1191
    [356] l) 2-methyl-1- [2,4,5-tris- (4-chloro-phenyl) -4,5-dihydro-imidazol-1-yl] -propan-1-one. HR-MS (FAB, m / z) calc'd for C 25 H 22 N 2 0Cl 3 [(M + H) + ] 471.0797, found 471.0814
    [357] m) 1- [4,5-bis- (4-chloro-phenyl) -2- (4-methoxy-phenyl) -4,5-dihydro-imidazol-1-yl] ethanone. HR-MS (FAB, m / z) Calcd for C 24 H 21 N 2 0 2 Cl 2 [(M + H) + ] 439.0980, found 439.0967
    [358]
    [359] n) 1- [4,5-bis- (4-chloro-phenyl) -2- (2,3-dimethoxy-phenyl) -4,5-dihydro-imidazol-1-yl] -2-methyl -Propan-1-one. HR-MS (ES, m / z) Calcd for C 27 H 27 N 2 0 3 Cl 2 [(M + H) + ] 497.1393, found 497.1398
    [360] Example 3
    [361] [4,5-bis- (4-chloro-phenyl) -2- (2,4-dimethoxy-phenyl) -4,5-dihydro-imidazol-1-yl]-(4-methyl-piperazine -1-yl) -methanone
    [362]
    [363] Phosgene (1.31 mL, 2.53 mmol, 1.93 M in toluene) was cooled (O < 0 > C) triethylamine (0.37 mL, 2.64 mmol) and 4,5-bis- (4-chloro-phenyl) -2- (2, 4-dimethoxy phenyl) -4,5-dihydro-1H-imidazole (225 mg, 0.53 mmol, Example 1) was added dropwise to a mixture in THF (5 mL). The reaction mixture was stirred for 2.5 hours and evaporated. The residue was kept under high vacuum for 30 minutes and redissolved in methylene chloride (10 mL). The slurry was added dropwise to a solution of methylene chloride (5 mL) of N-methylpiperazine (1.05 g, 10.48 mmol). After 1 hour, the reaction was worked up with aqueous sodium bicarbonate and extracted with methylene chloride. The organic extract was washed with water and brine and dried over sodium sulfate. Evaporation of the solvent and chromatography of the residue on silica gel with 1-4% methanol in methylene chloride 4,5-bis- (4-chloro-phenyl) -2- (2,4-dimethoxy-phenyl)- 4,5-dihydro-imidazol-1-yl]-(4-methyl-piperazin-1-yl) -methanone was obtained. HR-MS (ES, m / z) calcd for C 29 H 31 N 4 0 3 Cl 2 [(M + H) + ] 553.1768, found 553.1773.
    [364] Example 4
    [365] In a similar manner to Examples 1 and 3, the following compounds were prepared.
    [366] a) [2- (2-chloro-phenyl) -4,5-bis- (4-chloro-phenyl) -4,5-dihydro-imidazol-1-yl] piperazin-1-yl-methanone . HR-MS (ES, m / z) calcd for C 26 H 24 N 4 0Cl 3 [(M + H) + ] 513.1009, measured 513.1013
    [367]
    [368] b) [2- (3-Bromo-phenyl) -4,5-bis- (4-chloro-phenyl) -4,5-dihydro-imidazol-1-yl] piperazin-1-yl-methane On. HR-MS (ES, m / z) calcd for C 26 H 24 N 4 OCl 2 Br [(M + H) + ] 557.0505, found 557.0506
    [369] c) [2-biphenyl-3-yl-4,5-bis- (4-chloro-phenyl) -4,5-dihydro-imidazol-1-yl]-(4-methyl-piperazine-1 -Day) -methanone. HR-MS (ES, m / z) calcd for C 33 H 31 N 4 0Cl 2 [(M + H) + ] 569.1870, found 569.1875
    [370] d) [4,5-bis- (4-chloro-phenyl) -2- (3-pyrrolidin-1-yl-phenyl) -4,5-dihydro-imidazol-1-yl] -piperazine -1-yl-methanone was synthesized from 3-pyrrolidinobenzonitrile (described in the preceding patent). HR-MS (ES, m / z) calcd for C 30 H 32 N 5 0Cl 2 [(M + H) + ] 548.1979, found 548.1980
    [371] e) [4,5-bis- (4-chloro-phenyl) -2- (2,4-dimethoxy-phenyl) -4,5-dihydro-imidazol-1-yl] piperazin-1-yl Methanone. HR-MS (ES, m / z) calcd for C 28 H 29 N 4 0 3 Cl 2 [(M + H) + ] 539.1610, found 539.1613
    [372]
    [373] f) [4,5-bis- (4-chloro-phenyl) -2- (2-fluoro-6-methoxy-phenyl) -4,5-dihydro-imidazol-1-yl]-[4 -(2-hydroxy-ethyl) -piperazin-1-yl] -methanone. HR-MS (ES, m / z) C 29 H 3O N 4 0 3 FCl 2 [(M + H) +] calcd for 571.1674, measured 571.1678
    [374] g) 1- {4- [4,5-bis- (4-bromo-phenyl) -2- (2,4-dimethoxy-phenyl) -4,5-dihydroimidazole-1-carbonyl] -Piperazin-1-yl} -ethanone. HR-MS (ES, m / z) Calcd for C 30 H 31 N 4 0 4 Br 2 [(M + H) + ] 669.0707, found 669.0710
    [375] h) [4,5-bis- (4-bromo-phenyl) -2- (2,4-dimethoxy-phenyl) -4,5-dihydro-imidazol-1-yl]-[4- ( 2-hydroxy-ethyl) -piperazin-1-yl] -methanone. HR-MS (ES, m / z) calc'd for C 30 H 33 N 4 0 4 Br 2 [(M + H) + ] 671.0863, found 671.0870
    [376] i) [4,5-bis- (4-bromo-phenyl) -2- (2-methoxy-phenyl) -4,5-dihydro-imidazol-1-yl]-[4- (2- Hydroxy-ethyl) -piperazin-1-yl] -methanone. HR-MS (ES, m / z) calc'd for C 29 H 31 N 4 0 3 Br 2 [(M + H) + ] 641.0758, found 641.0765
    [377]
    [378] Example 5
    [379] 1- [5- (4-chloro-phenyl) -2- (4-methoxy-phenyl) -4- (4-nitro-phenyl) -4,5-dihydroimidazol-1-yl] -2- Methyl-propan-1-one and 1- [4- (4-chloro-phenyl) -2- (4-methoxyphenyl) -5- (4-nitro-phenyl) -4,5-dihydro-imidazole -1-yl] -2-methyl-propan-1-one
    [380] Meso-1,2-bis- (2-hydroxy-phenyl) -ethane-1,2-diamine (5.38 g, 22 mmol, Vogltle, F .; Goldschmitt, E. Chem. Ber. 1976, 109, 4-nitrobenzaldehyde (3.33 g, 22 mmol) and 4-chlorobenzaldehyde (3.31 g, 23.5 mmol) were added to a solution in acetonitrile (50 mL) according to the procedure described in 1-40]. The reaction mixture was heated at light reflux for 12 h. Cool to room temperature and remove the solvent in vacuo. The residue was suspended in 3 N sulfuric acid and the reaction mixture was heated at reflux for 2 hours. Upon cooling to room temperature, the byproduct salicyaldehyde was removed by extraction with diethyl ether (1 × 10 mL). The clear aqueous layer was neutralized with 5% sodium hydroxide to precipitate the diamine product (pH> 9). Crude 1- (4-chloro-phenyl) -2- (4-nitro-phenyl) -ethane-1,2-diamine (4.61 g) was collected by filtration, washed with water and dried under vacuum overnight.
    [381] Di-t-butyldicarbonate (6.77 g, 31 mmol) was dissolved in crude 1- (4-chloro-phenyl) -2- (4-nitro-phenyl) -ethane-1,2-diamine (2.92 g). To a solution in acetonitrile (100 mL) was added in an ice bath. Dimethylaminopyridine (122 mg, 1 mmol) was added and the ice bath was removed. After 1 hour, additional dimethylaminopyridine (122 mg, 1 mmol) was added. After a few minutes, the mixture was warmed to 50 ° C. over 10 minutes. Evaporation of solvents and reverse phase HPLC purification of the crude mixture gave 4- (4-chlorophenyl) -2- (4-nitro-phenyl) -2-oxo-cyclopentane-1, 3-dicarboxylic acid di-tert- Butyl ester (1.19 g) was obtained.
    [382] Hydro of 4- (4-chloro-phenyl) -5- (4-nitro-phenyl) -2-oxo-cyclopentane-1, 3-dicarboxylic acid di-tert-butyl ester (1.0 g, 2.0 mmol) The mixture in bromic acid (4.37 mL, 48%) and acetic acid (3.21 mL) was heated at reflux overnight. After cooling to room temperature, water was added. The mixture was washed with diethyl ether and then basified with 10 N NaOH. The aqueous layer was extracted with methylene chloride. The organic extract was washed with brine, dried over magnesium sulfate and evaporated to give 1- (4-chloro-phenyl) -2- (4-nitro-phenyl) -ethane-1,2-diamine (464 mg, 80%). Obtained.
    [383] 1- (4-chloro-phenyl) -2- (4-nitro-phenyl) -ethane-1,2-diamine (200 mg, 0.685 mmol) and ethyl 4-methoxy-benzimidate hydrochloride (148 mg, 0.686 mmol) was added triethylamine (0.11 mL, 0.79 mmol) to a solution in ethanol (5 mL). The reaction mixture was heated at reflux for 12 h. The solvent was removed to give a clear oil. Then collected in methylene chloride (2 mL) and aqueous sodium carbonate. The product was extracted with methylene chloride (2 x 20 mL). The organic layer was washed with brine (1 × 5 mL), dried (Na 2 SO 4 ) and concentrated. The crude residue was purified by Biotage flash chromatography eluting with 70% ethyl acetate in hexanes to give 4- (4-chloro-phenyl) -2- (4-methoxy-phenyl) -5- (4-nitro-phenyl) -4,5-dihydro-1H-imidazole (103 mg, 37%) was obtained.
    [384] Isobutyryl chloride (32 μl, 0.30 mmol) was added triethylamine (71 μl, 0.51 mmol) and 4- (4-chloro-phenyl) -2- (4-methoxy-phenyl) -5- (4-nitro -Phenyl) -4,5-dihydro-1H-imidazole (103 mg, 0.25 mmol) was added to the solution. The reaction mixture was stirred at rt for 2 h and then diluted with methylene chloride and aqueous sodium. The organic layer was washed with water and brine and dried over sodium sulfate. The solvent was removed under reduced pressure and the residue chromatography on silica gel with 10-40% ethyl acetate in hexanes gave two products:
    [385] a) 1- [5- (4-chloro-phenyl) -2- (4-methoxy-phenyl) -4- (4-nitro-phenyl) -4,5-dihydroimidazol-1-yl]- 2-methyl-propan-1-one (48 mg, 40%). HR-MS (ES, m / z) Calcd for C 26 H 25 N 3 0 4 Cl [(M + H) + ] 478.1528, found 478.1533
    [386]
    [387] b) 1- [4- (4-Chloro-phenyl) -2- (4-methoxy-phenyl) -5- (4-nitro-phenyl) -4,5-dihydroimidazol-1-yl]- 2-methyl-propan-1-one (31 mg, 26%). HR-MS (ES, m / z) Calcd for C 26 H 25 N 3 0 4 Cl [(M + H) + ] 478.1528, found 478.1533
    [388] Example 6
    [389] 1- [4,5-bis- (4-chloro-phenyl) -2- (2-isopropoxy-phenyl) -4,5-dihydro-imidazol-1-yl] -2-methyl-propane- 1-on
    [390]
    [391] A mixture of 2-cyanophenol (5.0 g, 42 mmol), cesium carbonate (27.1 g, 82.9 mmol) and 2-iodopropane (7.63 mL, 76 mmol) in acetone (80 mL) was vigorously stirred at 60 ° C. Heated. After 45 minutes, the grey-brown mixture was decanted off and the acetone layer was concentrated in vacuo. Water was added to dissolve the solids and the mixture was extracted with diethyl ether (3 x 200 mL). The organic layer was washed with water, 1 N ammonium hydroxide and brine and dried over anhydrous sodium sulfate. The solid was then filtered off and the filtrate was concentrated in vacuo. Purification of the crude residue by flash chromatography (Biotage system, KP-Sil ™ , 32-63 μm, 60 μs silica gel) eluted with 5% ethyl acetate in hexanes to give 2-isopropoxy-benzonitrile (6.6 g , 97%) was obtained as a colorless liquid.
    [392] Hydrogen chloride gas was passed through a solution of 2-isopropoxy-benzonitrile (6.6 g, 40.9 mmol) in anhydrous ethanol (75 mL) in a pressurized tube at 0 ° C. After 30 minutes, the hydrogen chloride gas was stopped. The reaction vessel was sealed and stirred for 3 d at room temperature. The pressure was released only after cooling the tube to 0 ° C. The solvent was removed to give a cloudy yellow oil (10.1 g). It was triturated in diethyl ether (100 mL) to give a white solid. Ethyl 2-isopropoxy-benzimidate hydrochloride (9.17 g, 92%) was collected by filtration, extracted with diethyl ether (3 × 25 mL) and dried in vacuo. It was used without further purification.
    [393] Triethylamine (0.88 mL, 6.26 mmol) in a solution in ethanol (3.5 mL) meso-1,2-bis- (4-chloro-phenyl) -ethane-1,2-diamine (0.80 g, 2.85 mmol, literature (Vogt1e, F .; Goldschmitt, E. Chem. Ber. 1976, 109, 1-40) and ethyl 2-isopropoxy-benzimidate hydrochloride (0.86 g, 3.52 mmol) Added. The reaction mixture was refluxed overnight. After cooling to room temperature, the reaction mixture was diluted with methylene chloride and washed with 1N HCl and 5% aqueous sodium bicarbonate. The organic layer was washed with brine and dried over anhydrous sodium sulfate. Evaporation of the solvent and chromatography of the residue on silica gel with 2% methanol in methylene chloride, gave 4,5-bis- (4-chloro-phenyl) -2- (2-isopropoxy-phenyl) -4,5 -Dihydro-1H-imidazole (0.86 g, 71%) was obtained.
    [394] Isobutyryl chloride (8.1 μl, 0.077 mmol) was converted to triethylamine (10.8 μl, 0.077 mmol) and 4,5-bis- (4-chloro-phenyl) -2- (2-isopropoxy-phenyl) -4 To a solution of, 5-dihydro 1H-imidazole (30 mg, 0.071 mmol) in methylene chloride (3 mL) was added. The reaction mixture was stirred at rt for 3 h. Then diluted with methylene chloride, washed with water and brine and dried over sodium sulfate. The solvent was removed under reduced pressure and chromatography of the residue on silica gel with 25% ethyl acetate in hexanes gave 1- [4,5-bis- (4-chloro-phenyl) -2- (2-isopropoxyphenyl ) -4,5-dihydro-imidazol-1-yl] -2-methyl-propan-1-one was obtained. HR-MS (ES, m / z) Calcd for C 28 H 29 N 2 0 2 Cl 2 [(M + H) + ] 495.1601, found 495.1606
    [395] Example 7
    [396] [4,5-bis- (4-chloro-phenyl) -2- (2-isopropoxy-phenyl) -4,5-dihydro-imidazol-1-yl]-(4-pyrrolidine-1 -Yl-piperidin-1-yl) -methanone
    [397]
    [398] Phosgene (2.95 mL, 5.69 mmol, 1.93 M in toluene) was converted to triethylamine (1.3 mL, 9.4 mmol) and 4,5-bis- (4-chloro-phenyl) -2- (2-isopropoxy-phenyl) To a mixture of -4,5-dihydro-1H-imidazole (0.80 g, 1.88 mmol, Example 6) in methylene chloride (15 mL) was added dropwise at 0 ° C. The reaction mixture was stirred for 30 minutes at 0 ° C. and evaporated. The residue was kept under high vacuum for 30 minutes. Chromatography of the residue with 60-80% methylene chloride in hexane gives 4,5-bis- (4chloro-phenyl) -2- (2-isopropoxy-phenyl) -4,5-dihydro-imidazole- 1-carbonyl chloride (0.71 g, 77%) was obtained.
    [399] 4,5-bis- (4-chloro-phenyl) -2- (2-isopropoxy-phenyl) -4,5-dihydro-imidazole-1-carbonyl chloride (200 mg, 0.41 mmol) To a solution of ethylamine (0.23 mL, 1.64 mmol) and 4- (1-pyrrolidinyl) -piperidine (0.11 g, 0.70 mmol) in methylene chloride (8 mL) was added at 0 ° C. over 15 minutes. After 30 minutes, the reaction was worked up with water. The mixture was extracted with methylene chloride and washed with water and brine. The organic extract was dried over sodium sulphate and evaporated. Chromatography of the residue on silica gel with 1-2% methanol in methylene chloride gave [4,5-bis- (4-chlorophenyl) -2- (2-isopropoxy-phenyl) -4,5-di Hydro-imidazol-1-yl]-(4-pyrrolidin-1-yl-piperidin-1-yl) -methanone (0.18 g, 72%) was obtained as off-white foam. HR-MS (ES, m / z) calcd for C 34 H 39 N 4 0 2 Cl 2 [(M + H) + ] 605.2445, found 605.2448
    [400] Example 8
    [401] In a similar manner to Examples 6 and 7, the following compounds were prepared.
    [402] a) [4,5-bis- (4-chloro-phenyl) -2- (2-isopropoxy-phenyl) -4,5-dihydro-imidazol-1-yl] -piperazin-1-yl Methanone. HR-MS (ES, m / z) calcd for C 29 H 31 N 4 0 2 Cl 2 [(M + H) + ] 537.1819, found 537.1828
    [403]
    [404] b) [4,5-bis- (4-chloro-phenyl) -2- (2-isopropoxy-phenyl) -4,5-dihydro-imidazol-1-yl]-(4-dimethylamino- Piperidin-1-yl) -methanone. HR-MS (ES, m / z) calcd for C 32 H 37 N 4 0 2 Cl 2 [(M + H) + ] 579.2288, found 579.2293
    [405] c) [1,4 '] bipiperidinyl-1'-yl- [4,5-bis- (4-chloro-phenyl) -2- (2-isopropoxy-phenyl) -4,5-dihydro -Imidazol-1-yl] -methanone. HR-MS (ES, m / z) Calcd for C 35 H 41 N 4 0 2 Cl 2 [(M + H) + ] 619.2601, found 619.2606
    [406] d) [4,5-bis- (4-chloro-phenyl) -2- (2-isopropoxy-phenyl) -4,5-dihydro-imidazol-1-yl]-[4- (2- Hydroxy-ethyl) -piperazin-1-yl] -methanone. HR-MS (ES, m / z) calcd for C 31 H 35 N 4 0 3 Cl 2 [(M + H) + ] 581.2081, found 581.2082
    [407] e) {4,5-bis- (4-chloro-phenyl) -2- [2- (2-methyl-butoxy) -phenyl] -4,5-dihydroimidazol-1-yl} -piperazine -1-yl-methanone. HR-MS (ES, m / z) Calcd for C 31 H 35 N 4 0 2 Cl 2 [(M + H) + ] 565.2132, found 565.2140
    [408] f) [4,5-bis- (4-chloro-phenyl) -2- (2-pentyloxy-phenyl) -4,5-dihydro-imidazol-1-yl] -piperazin-1-yl- Methanone. HR-MS (ES, m / z) calcd for C 31 H 35 N 4 0 2 Cl 2 [(M + H) + ] 565.2132, found 565.2138
    [409] g) [4,5-bis- (4-chloro-phenyl) -2- (3-ethoxy-phenyl) -4,5-dihydro-imidazol-1-yl] piperazin-1-yl-methane On, trifluoroacetic acid salt. HR-MS (ES, m / z) Calcd for C 28 H 29 N 4 0 2 Cl 2 [(M + H) + ] 523.1662, found 523.1666
    [410] h) [4,5-bis- (4-chloro-phenyl) -2- (3-isopropoxy-phenyl) -4,5-dihydro-imidazol-1-yl] -piperazin-1-yl -Methanone, trifluoroacetic acid salt. HR-MS (ES, m / z) calcd for C 29 H 31 N 4 0 2 Cl 2 [(M + H) + ] 537.1819, found 537.1824
    [411] i) 1- {4- [4,5-bis- (4-bromo-phenyl) -2- (2-ethoxy-phenyl) -4,5-dihydro-imidazole-1-carbonyl]- Piperazin-1-yl} -ethanone. HR-MS (ES, m / z) Calcd for C 30 H 31 N 4 0 3 Br 2 [(M + H) + ] 653.0758, found 653.0771
    [412] j) [4,5-bis- (4-bromo-phenyl) -2- (2-ethoxy-phenyl) -4,5-dihydro-imidazol-1-yl]-[4- (2- Hydroxy-ethyl) -piperazin-1-yl] -methanone. HR-MS (ES, m / z) C 3O H 33 N 4 0 3 Br 2 [(M + H) +] calcd for 655.0914, measured 655.0928
    [413] k) 1- {4- [4,5-bis- (4-bromo-phenyl) -2- (2-isopropoxy-phenyl) -4,5-dihydro-imidazole-1-carbonyl] Piperazin-1-yl} -ethanone. HR-MS (ES, m / z) calc'd for C 31 H 33 N 4 0 3 Br 2 [(M + H) + ] 667.0914, found 667.0920
    [414] l) [4,5-bis- (4-bromo-phenyl) -2- (2-isopropoxy-phenyl) -4,5-dihydro-imidazol-1-yl]-[4- (2 -Hydroxy-ethyl) -piperazin-1-yl] -methanone. HR-MS (ES, m / z) calcd for C 31 H 35 N 4 0 3 Br 2 [(M + H) + ] 669.1071, found 669.1069
    [415] Example 9
    [416] [4,5-bis- (4-chloro-phenyl) -2- (2-isopropoxy-4-methoxy-phenyl) -4,5-dihydroimidazol-1-yl]-[4- ( 2-hydroxy-ethyl) -piperazin-1-yl] -methanone hydrochloride
    [417]
    [418] A mixture of 2-hydroxy-4-methoxybenzaldehyde (25.0 g, 164 mmol), sodium acetate (26.4 g, 322 mmol), nitroethane (23 g, 307 mmol) in acetic acid (45 mL) at reflux for 6 hours Heated during. The mixture was then cooled to room temperature and poured into ice water. The solid was filtered off, washed with water and dried. Recrystallization of the crude solid in ethyl acetate gave 2-hydroxy-4-methoxy-benzonitrile as a brown solid (15.9 g, 65%).
    [419] Cesium carbonate (51.5 g, 158 mmol) was added to a solution of 2-hydroxy-4-methoxybenzonitrile (11.8 g, 79 mmol) in acetone (100 mL). 2-iodopropane (12.5 mL, 125 mmol) was added. The mixture was heated at reflux for 3 hours. Water was added and the mixture was extracted with diethyl ether (4 x 100 mL). The combined organic extracts were washed with diluted ammonium hydroxide and brine and dried (MgSO 4 ). Evaporation of the solvent and chromatography of the residue on silica gel with 5% diethyl ether in hexanes gave 2-isopropoxy-4-methoxybenzonitrile (13.2 g, 87%).
    [420] Hydrogen chloride gas was passed through a solution of 2-isopropoxy-4-methoxybenzonitrile (13.2 g, 69 mmol) in pure ethanol (200 mL) for 1 hour at −10 ° C. in a pressure vessel. The tube was sealed and stirred for 7 d at room temperature. The tube was cooled to -10 ° C and additional ethanol (100 mL) was added. Hydrogen chloride gas was passed through it at -10 ° C for 30 minutes. The tube was resealed and stirred for 7 d at room temperature. Evaporation of the solvent and trituration of the residue in diethyl ether gave ethyl 2-isopropoxy-4-methoxy-benzimidate hydrochloride as a white solid (17.5 g, 99%). It was used without further purification.
    [421] Ethyl 2-isopropoxy-4-methoxy-benzimidate hydrochloride (8.21 g, 30 mmol), meso-1,2-bis- (4-chloro-phenyl) -ethane-1,2-diamine (7.59 g, 27 mmol, prepared according to the procedure described in Vogttle, F .; Goldschmitt, E. Chem. Ber. 1976, 109, 1-40) and ethanol (200.35 mL, 60 mmol) in triethylamine (200 mL) was heated at reflux for 24 h. Additional ethyl 2-isopropoxy-4-methoxy-benzimidate hydrochloride (1.64 g, 6 mmol) was added and the reaction mixture was further heated at reflux for 24 h. Aqueous sodium bicarbonate was added and it was extracted with methylene chloride (3 x). The combined organic extracts were washed with water and brine and dried over sodium sulfate. Chromatography of the residue on silica gel with 0.5-2% methanol in methylene chloride followed by recrystallization with diethyl ether in pentane 4,5-bis- (4-chlorophenyl) -2- (2-isopropoxy- 4-methoxy-phenyl) -4,5-dihydro-1H-imidazole (9 g, 73%) was obtained.
    [422] Phosgene (12 mL, 23 mmol, 1.93 M in toluene) was charged with triethylamine (3.75 mL, 26.9 mmol) and 4,5-bis- (4-chloro-phenyl) -2- (2-isopropoxy-4- To a mixture of methoxy-phenyl) -4,5-dihydro-1H-imidazole (3.50 g, 7.69 mmol) in methylene chloride (80 mL) was added dropwise at 0 ° C. The reaction mixture was stirred for 30 minutes at 0 ° C. and evaporated. The residue was kept under high vacuum for 30 minutes. Methylene chloride (50 mL) was added to the residue, and the solution was added dropwise to a solution of 2-piperazin-1-yl ethanol (10 g) in methylene chloride (200 mL) at 0 ° C. over 15 minutes. After 30 minutes, the reaction was worked up with water. The mixture was extracted with methylene chloride and extracted with water and brine. The organic extract was dried over sodium sulphate and evaporated. Chromatography of the residue on silica gel with 1-2% methanol in methylene chloride gave [4,5-bis- (4-chloro-phenyl) -2- (2-isopropoxy-4-methoxy-phenyl) -4,5-Dihydro-imidazol-1-yl]-[4- (2-hydroxy-ethyl) -piperazin-1-yl] -methanone was obtained as a light yellow foam (4.07 g, 87 %).
    [423] [4,5-bis- (4-chloro-phenyl) -2- (2-isopropoxy-4-methoxy-phenyl) -4,5-dihydroimidazol-1-yl]-[4- ( 2-hydroxy-ethyl) -piperazin-1-yl] -methanone (2.20 g, 3.60 mmol) was dissolved in dilute hydrochloric acid (0.23 N, 20 mL). The light yellow solution was filtered and lyophilized to [4,5-bis- (4-chloro-phenyl) -2- (2-isopropoxy-4-methoxyphenyl) -4,5-dihydro-imidazole- 1-yl]-[4- (2-hydroxy-ethyl) -piperazin-1-yl] -methanone hydrochloride was obtained as off-white powder (2.26 g, 97%). HR-MS (ES, m / z) Calcd for C 32 H 37 N 4 0 4 Cl 2 [(M + H) + ] 611.2187, found 611.2195
    [424] Example 10
    [425] In a similar manner to Example 9, the following compounds were prepared.
    [426] a) [4,5-bis- (4-chloro-phenyl) -2- (2-ethoxy-4-methoxy-phenyl) -4,5-dihydroimidazol-1-yl]-(4- Methanesulfonyl-piperazin-1-yl) -methanone. HR-MS (ES, m / z) C 3O H 33 N 4 0 5 SCl 2 [(M + H) +] calcd for 631.1543, measured 631.1549
    [427]
    [428] b) [4,5-bis- (4-chloro-phenyl) -2- (2-ethoxy-4-methoxy-phenyl) -4,5-dihydroimidazol-1-yl]-[4- (2-hydroxy-ethyl) -piperazin-1-yl] -methanone. HR-MS (ES, m / z) Calcd for C 31 H 35 N 4 0 4 Cl 2 [(M + H) + ] 597.2030, found 597.2038
    [429] c) [4,5-bis- (4-chloro-phenyl) -2- (2-ethoxy-4-methoxy-phenyl) -4,5-dihydroimidazol-1-yl] -morpholine- 1-yl-methanone. HR-MS (m / z) C 29 H 3O N 3 0 4 Cl 2 [(M + H) +] calcd for 554.1608, measured 554.1614
    [430] d) [4,5-bis- (4-chloro-phenyl) -2- (2-ethoxy-4-methoxy-phenyl) -4,5-dihydroimidazol-1-yl]-(4- Methyl-piperazin-1-yl) -methanone. HR-MS (ES, m / z) C 3O H 33 N 4 0 3 Cl 2 [(M + H) +] calculated 567.1924, measured 567.1929 for
    [431] e) 1- {4- [4,5-bis- (4-chloro-phenyl) -2- (2-ethoxy-4-methoxy-phenyl) -4,5-dihydroimidazole-1-car Carbonyl] -piperazin-1-yl} -ethanone. HR-MS (ES, m / z) Calcd for C 31 H 33 N 4 0 4 Cl 2 [(M + H) + ] 595.1874, Found 595.1882
    [432] f) 4- [4,5-bis- (4-chloro-phenyl) -2- (2-ethoxy-4-methoxy-phenyl) -4,5-dihydro-imidazole-1-carbonyl] Piperazine-2-one. HR-MS (ES, m / z) calcd for C 29 H 29 N 4 0 4 Cl 2 [(M + H) + ] 567.1561, found 567.1571
    [433] g) [4,5-bis- (4-chloro-phenyl) -2- (2-isopropoxy-4-methoxy-phenyl) -4,5-dihydroimidazol-1-yl] -piperazine -1-yl-methanone. HR-MS (ES, m / z) C 3O H 33 N 4 0 3 Cl 2 [(M + H) +] calcd for 567.1924, measured 567.1927
    [434] h) 1- {4- [4,5-bis- (4-chloro-phenyl) -2- (2-isopropoxy-4-methoxy-phenyl) -4,5-dihydro-imidazole-1 -Carbonyl] -piperazin-1-yl] -ethanone. HR-MS (ES, m / z) Calcd for C 32 H 35 N 4 0 4 Cl 2 [(M + H) + ] 609.2030, found 609.2036
    [435] i) [4,5-bis- (4-chloro-phenyl) -2- (2-isopropoxy-4-methoxy-phenyl) -4,5-dihydroimidazol-1-yl]-(4 Methanesulfonyl-piperazin-1-yl) -methanone to [4,5-bis- (4-chloro-phenyl) -2- (2-isopropoxy-4-methoxy-phenyl) -4, Prepared by sulfonation of 5-dihydro-imidazol-1-yl] -piperazin-1-yl-methanone (Example 10g). HR-MS (ES, m / z) calc'd for C 31 H 35 N 4 0 5 SCl 2 [(M + H) + ] 645.1700, found 645.1710
    [436] j) [4,5-bis- (4-chloro-phenyl) -2- (2-isopropoxy-4-methoxy-phenyl) -4,5-dihydro-imidazol-1-yl]-( 2,5-dimethyl-piperazin-1-yl) -methanone. HR-MS (ES, m / z) calcd for C 32 H 37 N 4 0 3 Cl 2 [(M + H) + ] 595.2237, found 595.2240
    [437] k) 4,5-bis- (4-chloro-phenyl) -2- (2-isopropoxy-4-methoxy-phenyl) -4,5-dihydroimidazole-1-carboxylic acid bis- ( 2-hydroxy-ethyl) -amide. HR-MS (ES, m / z) C 3O H 34 N 3 0 5 Cl 2 [(M + H) +] calcd for 586.1870, measured 586.1878
    [438] l) [4,5-bis- (4-chloro-phenyl) -2- (2-isopropoxy-4-methoxy-phenyl) -4,5-dihydroimidazol-1-yl]-(4 -Ethyl-piperazin-1-yl) -methanone. HR-MS (ES, m / z) Calcd for C 32 H 37 N 4 0 3 Cl 2 [(M + H) + ] 595.2237, found 595.2241
    [439] m) [1,4 '] bipiperidinyl-1'-yl- [4,5-bis- (4-chloro-phenyl) -2- (2-isopropoxy-4-methoxyphenyl) -4, 5-dihydro-imidazol-1-yl] -methanone. HR-MS (ES, m / z) Calcd for C 36 H 43 N 4 0 3 Cl 2 [(M + H) + ] 649.2707, found 649.2712
    [440] n) [4,5-bis- (4-chloro-phenyl) -2- (2-isopropoxy-4-methoxy-phenyl) -4,5-dihydroimidazol-1-yl]-(4 -Pyrrolidin-1-yl-piperidin-1-yl) -methanone. HR-MS (ES, m / z) calcd for C 35 H 41 N 4 0 3 Cl 2 [(M + H) + ] 635.2550, found 635.2559
    [441] o) [4,5-bis- (4-chloro-phenyl) -2- (2-isopropoxy-4-methoxy-phenyl) -4,5-dihydroimidazol-1-yl]-(4 -Dimethylamino-piperidin-1-yl) -methanone. HR-MS (ES, m / z) calcd for C 33 H 39 N 4 0 3 Cl 2 [(M + H) + ] 609.2394, found 609.2395
    [442] p) [4,5-bis- (4-chloro-phenyl) -2- (2-isopropoxy-4-methoxy-phenyl) -4,5-dihydroimidazol-1-yl] -morpholine -1-yl-methanone. HR-MS (ES, m / z) C 3O H 32 N 3 0 4 Cl 2 [(M + H) +] calcd for 568.1765, measured 568.1768
    [443] q) [4,5-bis- (4-chloro-phenyl) -2- (2-isopropoxy-4-methoxy-phenyl) -4,5-dihydroimidazol-1-yl]-(4 -Isopropyl-piperazin-1-yl) -methanone. HR-MS (ES, m / z) calcd for C 33 H 39 N 4 0 3 Cl 2 [(M + H) + ] 609.2394, found 609.2395. N-isopropyl piperazine used in the synthesis of the compounds is described by Renau, Thomas E .; Sanchez, Joseph P. et al. J. Med. Chem. 1996, 39, 729-35.
    [444] r) 4- [4,5-bis- (4-chloro-phenyl) -2- (2-isopropoxy-4-methoxy-phenyl) -4,5-dihydroimidazole-1-carbonyl] Piperazine-2-one. HR-MS (ES, m / z) C 3O H 31 N 4 0 4 Cl 2 [(M + H) +] calcd for 581.1717, measured 581.1723
    [445] s) [4,5-bis- (4-chloro-phenyl) -2- (2-isopropoxy-4-methoxy-phenyl) -4,5-dihydro-imidazol-1-yl]-( 4-hydroxymethyl-piperidin-1-yl) -methanone. HR-MS (ES, m / z) calcd for C 32 H 36 N 3 0 4 Cl 2 [(M + H) + ] 596.2078, found 596.2081
    [446] t) [4,5-bis- (4-chloro-phenyl) -2- (2-isopropoxy-4-methoxy-phenyl) -4,5-dihydroimidazol-1-yl]-[4 -(2-hydroxy-ethyl) -piperidin-1-yl] -methanone. HR-MS (ES, m / z) Calcd for C 33 H 38 N 3 0 4 Cl 2 [(M + H) + ] 610.2234, found 610.2236
    [447] u) [4,5-bis- (4-chloro-phenyl) -2- (2-isopropoxy-4-methoxy-phenyl) -4,5-dihydroimidazol-1-yl]-(3 -Methyl-piperazin-1-yl) -methanone. HR-MS (ES, m / z) calcd for C 31 H 35 N 4 0 3 Cl 2 [(M + H) + ] 581.2081, found 581.2081
    [448] v) 1- {4- [4,5-bis- (4-chloro-phenyl) -2- (2-isopropoxy-4-methoxy-phenyl) -4,5-dihydro-imidazole-1 -Carbonyl] -2-methyl-piperazin-1-yl] -ethanone. HR-MS (ES, m / z) Calcd for C 33 H 37 N 4 0 4 Cl 2 [(M + H) + ] 623.2187, found 623.2190
    [449] w) [4,5-bis- (4-chloro-phenyl) -2- (2-isopropoxy-4-methoxy-phenyl) -4,5-dihydroimidazol-1-yl]-(4 Methanesulfonyl-3-methyl-piperazin-1-yl) methanone is [4,5-bis- (4-chloro-phenyl) -2- (2-isopropoxy-4-methoxy-phenyl ) -4,5-dihydro-imidazol-1-yl]-(3-methyl-piperazin-1-yl) -methanone (Example 10u). HR-MS (ES, m / z) C 32 H 37 N 4 0 5 SCl 2 [(M + H) +] calcd for 659.1856, measured 659.1856
    [450] x) [4,5-bis- (4-chloro-phenyl) -2- (2-isopropoxy-4-methoxy-phenyl) -4,5-dihydroimidazol-1-yl]-(4 -Hydroxy-piperidin-1-yl) -methanone. HR-MS (ES, m / z) calcd for C 31 H 34 N 3 0 4 Cl 2 [(M + H) + ] 582.1921, found 582.1926
    [451] y) (4-aminomethyl-piperidin-1-yl)-[4,5-bis- (4-chloro-phenyl) -2- (2-isopropoxy-4-methoxy-phenyl) -4 , 5-dihydro-imidazol-1-yl] -methanone. HR-MS (ES, m / z) calcd for C 32 H 37 N 4 0 3 Cl 2 [(M + H) + ] 595.2237, found 595.2243
    [452] z) [4,5-bis- (4-bromo-phenyl) -2- (2-ethoxy-4-methoxy-phenyl) -4,5-dihydroimidazol-1-yl]-[4 -(2-hydroxy-ethyl) -piperazin-1-yl] -methanone. HR-MS (ES, m / z) calc'd for C 31 H 35 N 4 0 4 Br 2 [(M + H) + ] 685.1020, found 685.1031
    [453] aa) [4,5-bis- (4-bromo-phenyl) -2- (2-ethoxy-4-methoxy-phenyl) -4,5-dihydroimidazol-1-yl] -piperazine -1-yl-methanone. HR-MS (ES, m / z) calc'd for C 29 H 31 N 4 0 3 Br 2 [(M + H) + ] 641.0758, found 641.0762
    [454] bb) [4,5-bis- (4-bromo-phenyl) -2- (2-ethoxy-4-methoxy-phenyl) -4,5-dihydroimidazol-1-yl]-(4 -Methanesulfonyl-piperazin-1-yl) -methanone is prepared using [4,5-bis- (4-bromo-phenyl) -2- (2-ethoxy-4) using methods known in the art. -Methoxy-phenyl) -4,5-dihydroimidazol-1-yl] -piperazin-1-yl-methanone (Example 10aa) was prepared by sulfonation. HR-MS (ES, m / z) C 3O H 33 N 4 0 5 SBr 2 [(M + H) +] calcd for 719.0533, measured 719.0540
    [455] cc) 1- {4- [4,5-bis- (4-bromo-phenyl) -2- (2-ethoxy-4-methoxy-phenyl) -4,5-dihydroimidazole-1- Carbonyl] -piperazin-1-yl} -ethanone. HR-MS (ES, m / z) calcd for C 31 H 33 N 4 0 4 Br 2 [(M + H) + ] 683.0863, found 683.0866
    [456] dd) [4,5-bis- (4-bromo-phenyl) -2- (2-ethoxy-4-methoxy-phenyl) -4,5-dihydroimidazol-1-yl]-(4 -Methyl-piperazin-1-yl) -methanone. HR-MS (ES, m / z) C 3O H 33 N 4 0 3 Br 2 [(M + H) +] calcd for 655.0914, measured 655.0917
    [457] ee) 4- [4,5-bis- (4-bromo-phenyl) -2- (2-ethoxy-4-methoxy-phenyl) -4,5-dihydroimidazole-1-carbonyl] Piperazine-1-carbaldehyde. HR-MS (ES, m / z) C 3O H 31 N 4 0 4 Br 2 [(M + H) +] calcd for 669.0707, measured 669.0713
    [458] ff) [4,5-bis- (4-bromo-phenyl) -2- (2-ethoxy-4-methoxy-phenyl) -4,5-dihydroimidazol-1-yl]-(4 -Pyrrolidin-1-yl-piperidin-1-yl) -methanone. HR-MS (ES, m / z) calc'd for C 34 H 39 N 4 0 3 Br 2 [(M + H) + ] 709.1384, found 709.1401
    [459] gg) [4,5-bis- (4-bromo-phenyl) -2- (2-ethoxy-4-methoxy-phenyl) -4,5-dihydroimidazol-1-yl]-(4 -Dimethylamino-piperidin-1-yl) -methanone. HR-MS (ES, m / z) C 32 H 37 N 4 0 3 Br 2 [(M + H) +] calcd for 683.1227, measured 683.1250
    [460] hh) [4,5-bis- (4-bromo-phenyl) -2- (2-ethoxy-4-methoxy-phenyl) -4,5-dihydroimidazol-1-yl]-(4 -Isopropyl-piperazin-1-yl) -methanone. HR-MS (ES, m / z) calc'd for C 32 H 37 N 4 0 3 Br 2 [(M + H) + ] 683.1227, found 683.1231
    [461] ii) 4- [4,5-bis- (4-bromo-phenyl) -2- (2-ethoxy-4-methoxy-phenyl) -4,5-dihydroimidazole-1-carbonyl] Piperazine-2-one. HR-MS (ES, m / z) Calcd for C 29 H 29 N 4 0 4 Br 2 [(M + H) + ] 655.0550, found 655.0557
    [462] jj) [4,5-bis- (4-bromo-phenyl) -2- (2-isopropoxy-4-methoxy-phenyl) -4,5-dihydroimidazol-1-yl] -pipe Razin-1-yl-methanone. HR-MS (ES, m / z) C 3O H 33 N 4 0 3 Br 2 [(M + H) +] calcd for 655.0914, measured 655.0918
    [463] kk) 1- {4- [4,5-bis- (4-bromo-phenyl) -2- (2-isopropoxy-4-methoxy-phenyl) -4,5-dihydro-imidazole- 1-carbonyl] -piperazin-1-yl} -ethanone. HR-MS (ES, m / z) calc'd for C 32 H 35 N 4 0 4 Br 2 [(M + H) + ] 697.1020 found 697.1028
    [464] ll) [4,5-bis- (4-bromo-phenyl) -2- (2-isopropoxy-4-methoxy-phenyl) -4,5-dihydroimidazol-1-yl]-( 4-Methanesulfonyl-piperazin-1-yl) -methanone is [4,5-bis- (4-bromo-phenyl) -2- (2-isopropoxy-4-methoxy-phenyl)- 4,5-Dihydro-imidazol-1-yl] -piperazin-1-yl-methanone (Example 10jj) was prepared by sulfonation using a known method. HR-MS (ES, m / z) Calcd for C 31 H 35 N 4 0 5 SBr 2 [(M + H) + ] 733.0690, found 733.0696
    [465] mm) [4,5-bis- (4-bromo-phenyl) -2- (2-isopropoxy-4-methoxy-phenyl) -4,5-dihydroimidazol-1-yl]-( 4-Methyl-piperazin-1-yl) -methanone. HR-MS (ES, m / z) calc'd for C 31 H 35 N 4 0 3 Br 2 [(M + H) + ] 669.1071, found 669.1078
    [466] nn) [4,5-bis- (4-bromo-phenyl) -2- (2-isopropoxy-4-methoxy-phenyl) -4,5-dihydroimidazol-1-yl] -mor Polin-1-yl-methanone. HR-MS (ES, m / z) C 3O H 32 N 3 0 4 Br 2 [(M + H) +] calcd for 656.0754, measured 656.0762
    [467] oo) [1,4 '] bipiperidinyl-1'-yl- [4,5-bis- (4-bromo-phenyl) -2- (2-isopropoxy-4-methoxy-phenyl)- 4,5-dihydro-imidazol-1-yl] -methanone. HR-MS (ES, m / z) calc'd for C 36 H 43 N 4 0 3 Br 2 [(M + H) + ] 737.1697, found 737.1707
    [468] pp) [4,5-bis- (4-bromo-phenyl) -2- (2-isopropoxy-4-methoxy-phenyl) -4,5-dihydroimidazol-1-yl]-( 4-ethyl-piperazin-1-yl) -methanone. HR-MS (ES, m / z) Calcd for C 32 H 37 N 4 0 3 Br 2 [(M + H) + ] 683.1227, found 683.1232
    [469] qq) 4- [4,5-bis- (4-bromo-phenyl) -2- (2-isopropoxy-4-methoxy-phenyl) -4,5-dihydroimidazole-1-carbonyl ] -Piperazine-2-one. HR-MS (ES, m / z) C 3O H 31 N 4 0 4 Br 2 [(M + H) +] calcd for 669.0707, measured 669.0718
    [470] rr) [4,5-bis- (4-cyano-phenyl) -2- (2-isopropoxy-4-methoxy-phenyl) -4,5-dihydroimidazol-1-yl] -pipe Razin-1-yl-methanone. HR-MS (ES, m / z) calc'd for C 32 H 33 N 6 0 3 [(M + H) + ] 549.2609, found 549.2614
    [471] ss) 1- (4- {4,5-bis- (4-chloro-phenyl) -2- [4-methoxy- (2-methoxy-ethoxy) -phenyl] -4,5-dihydro- Imidazole-1-carbonyll-piperazin-1-yl) -ethanone. HR-MS (ES, m / z) calc'd for C 32 H 35 N 4 0 5 Cl 2 [(M + H) + ] 625.1979, found 625.1987
    [472] tt) 1- (4- {4,5-bis- (4-chloro-phenyl) -2- [2- (2-fluoro-ethoxy) -4-methoxy-phenyl] -4,5-di Hydro-imidazole-1-carbonyl} -piperazin-1-yl) -ethanone. HR-MS (ES, m / z) calcd for C 31 H 32 N 4 0 4 FCl 2 [(M + H) + ] 613.1779, found 613.1775
    [473] uu) 4- {4,5-bis- (4-chloro-phenyl) -2- [2- (2-fluoro-ethoxy) -4-methoxy-phenyl] -4,5-dihydro-imi Dazol-1-carbonyl} -piperazin-2-one. HR-MS (ES, m / z) calcd for C 29 H 28 N 4 0 4 FCl 2 [(M + H) + ] 585.1466, found 585.1475
    [474] Example 11
    [475] In a similar manner to Example 9, the following compounds were prepared.
    [476] a) [4,5-bis- (4-chloro-phenyl) -2- (2-ethoxy-4-methoxy-phenyl) -4,5-dihydroimidazol-1-yl] -piperazine- 1-yl-methanone hydrochloride. HR-MS (ES, m / z) C 29 H 31 N 4 0 3 calculated for Cl 2 [(M + H) +] 553.1768, measured 553.1773
    [477]
    [478] b) 4,5-bis- (4-chloro-phenyl) -2- (2-ethoxy-4-methoxy-phenyl) -4,5-dihydroimidazole-1-carboxylic acid methyl- (2 -Methylamino-ethyl) -amide, trifluoroacetic acid salt. HR-MS (ES, m / z) calcd for C 29 H 33 N 4 0 3 Cl 2 [(M + H) + ] 555.1924, found 555.1929.
    [479] c) 4,5-bis- (4-chloro-phenyl) -2- (2-ethoxy-4-methoxy-phenyl) -4,5-dihydroimidazole-1-carboxylic acid (2-dimethyl Amino-ethyl) -methyl-amide, trifluoroacetic acid salt. HR-MS (ES, m / z) C 3O H 35 N 4 0 3 Cl 2 [(M + H) +] calcd for 569.2081, measured 569.2085
    [480] d) 4,5-bis- (4-chloro-phenyl) -2- (2-ethoxy-4-methoxy-phenyl) -4,5-dihydroimidazole-1-carboxylic acid (2-dimethyl Amino-ethyl) -amide, trifluoroacetic acid salt. HR-MS (ES, m / z) calcd for C 29 H 33 N 4 0 3 Cl 2 [(M + H) + ] 555.1924, found 555.1940.
    [481] e) 4,5-bis- (4-chloro-phenyl) -2- (2-ethoxy-4-methoxy-phenyl) -4,5-dihydroimidazole-1-carboxylic acid (2-amino -Ethyl) -amide, trifluoroacetic acid salt. HR-MS (m / z) calc'd for C 27 H 29 N 4 0 3 Cl 2 [(M + H) + ] 527.1611, found 527.1621
    [482] f) [4,5-bis- (4-chloro-phenyl) -2- (2-ethoxy-4-methoxy-phenyl) -4,5-dihydro-imidazol-1-yl]-(4 -Pyrrolidin-1-yl-piperidin-1-yl) -methanone hydrochloride. HR-MS (ES, m / z) Calcd for C 34 H 39 N 4 0 3 Cl 2 [(M + H) + ] 621.2394, found 621.2400
    [483] g) [4,5-bis- (4-chloro-phenyl) -2- (4-methoxy-2-propoxy-phenyl) -4,5-dihydroimidazol-1-yl] -piperazine- 1-yl-methanone, trifluoroacetic acid salt. HR-MS (ES, m / z) C 3O H 33 N 4 0 3 Cl 2 [(M + H) +] calcd 1567.1924, measurements for 567.1932
    [484] h) [4,5-bis- (4-chloro-phenyl) -2- (2-isopropoxy-4-methoxy-phenyl) -4,5-dihydroimidazol-1-yl]-(4 -Methyl-piperazin-1-yl) -methanone hydrobromide. HR-MS (ES, m / z) Calcd for C 31 H 35 N 4 0 3 Cl 2 [(M + H) + ] 581.2081, found 581.2086
    [485] i) 4,5-bis- (4-chloro-phenyl) -2- (2-isopropoxy-4-methoxy-phenyl) -4,5-dihydroimidazole-1-carboxylic acid (2- Morpholin-1 -yl-ethyl) -amide hydrochloride. HR-MS (ES, m / z) Calcd for C 32 H 37 N 4 0 4 Cl 2 [(M + H) + ] 611.2187, found 611.2197
    [486] j) 4,5-bis- (4-chloro-phenyl) -2- (2-isopropoxy-4-methoxy-phenyl) -4,5-dihydroimidazole-1-carboxylic acid (2- Piperazin-1-yl-ethyl) -amide hydrochloride. HR-MS (ES, m / z) calcd for C 32 H 38 N 5 0 3 Cl 2 [(M + H) + ] 610.2346, found 610.2348.
    [487] k) [4,5-bis- (4-chloro-phenyl) -2- (2-isobutoxy methoxy-phenyl) -4,5-dihydroimidazol-1-yl] -piperazin-1-yl -Methanone hydrochloride. HR-MS (ES, m / z) calcd for C 31 H 35 N 4 0 3 Cl 2 [(M + H) + ] 581.2081, found 581.2081
    [488] l) [4,5-bis- (4-chloro-phenyl) -2- (2-isopropoxy-4-methoxy-phenyl) -4,5-dihydroimidazol-1-yl]-(3 -Methyl-piperazin-1-yl) -methanone hydrochloride. HR-MS (ES, m / z) Calcd for C 31 H 35 N 4 0 3 Cl 2 [(M + H) + ] 581.2081, found 581.2084
    [489] m) {4,5-bis- (4-chloro-phenyl) -2- [4-methoxy-2- (2-methoxy-ethoxy) -phenyl] -4,5-dihydro-imidazole- 1-yl} -piperazin-1-yl-methanone, trifluoroacetic acid salt. HR-MS (ES, m / z) C 3O H 33 N 4 0 4 Cl 2 [(M + H) +] calcd for 583.1874, measured 583.1875
    [490] n) {4,5-bis- (4-chloro-phenyl) -2- [2- (2-fluoro-ethoxy) -4-methoxy-phenyl] -4,5-dihydro-imidazole- 1-yl} -piperazin-1-yl-methanone. HR-MS (ES, m / z) C 29 H 3O N 4 0 3 FCl 2 [(M + H) +] calcd for 571.1674, measured 571.1676
    [491] o) {4,5-bis- (4-chloro-phenyl) -2- [2- (2-fluoro-ethoxy) -4-methoxy-phenyl] -4,5-dihydro-imidazole- 1-yl}-(4-pyrrolidin-1-yl-piperidin-1-yl) -methanone hydrochloride. HR-MS (ES, m / z) calc'd for C 34 H 38 N 4 0 3 FCl 2 [(M + H) + ] 639.2300, found 639.2303
    [492] Example 12
    [493] 2-amino-1- {4- [4,5-bis- (4-chloro-phenyl) -2- (2-isopropoxy-4-methoxy-phenyl) -4,5-dihydro-imidazole -1-carbonyl] -piperazin-1-yl] -ethanone
    [494]
    [495] [4,5-bis- (4-chloro-phenyl) -2- (2-isopropoxy-4-methoxy-phenyl) -4,5-dihydroimidazol-1-yl] -piperazine-1 Methanone (52 mg, 0.092 mmol, Example 10) was added to a solution of N- (t-butoxycarbonyl) glycine (21 mg, 0.119 mmol) in THF (12 mL), followed by diisopropyl carbox Added to bodyamide (19.7 μl, 0.125 mmol). After 3 hours, the reaction mixture was concentrated and then diluted with methylene chloride. The mixture was washed with aqueous sodium bicarbonate, water and brine and dried over sodium sulfate. Evaporation of the solvent and chromatography of the residue on silica with 1-2% methanol in methylene chloride gave (2- {4- [4,5-bis- (4-chloro-phenyl) -2- (2-isopro). Foxy-4-methoxy-phenyl) -4,5-dihydro-imidazole-1-carbonyl] -piperazin-1-yl} -2-oxo-ethyl) -carbamic acid tert-butyl ester (54 mg , 81%) was obtained.
    [496] Trifluoroacetic acid (2 mL, 26 mmol) was added (2- {4- [4,5-bis- (4-chloro-phenyl) -2- (2-isopropoxy-4-methoxy-phenyl)- Methylenechloride (6 mL of 4,5-dihydro-imidazole-1-carbonyl} -piperazin-1-yl] -2-oxo-ethyl) -carbamic acid tert-butyl ester (40 mg, 0.054 mmol) ) In solution. The reaction mixture was stirred for 2.5 hours and diluted with methylene chloride. The mixture was washed with aqueous sodium carbonate, water and brine and dried over sodium sulfate. Evaporation of the solvent and chromatography of the residue on silica gel with 5-10% methanol in methylene chloride, gave 2-amino-1- {4- [4,5-bis- (4-chloro-phenyl) -2- ( 2-isopropoxy-4-methoxy-phenyl) -4,5-dihydro-imidazole-1-carbonyl] -piperazin-1-yl} -ethanone (22 mg, 65%) was obtained. . HR-MS (ES, m / z) calc'd for C 32 H 36 N 5 0 4 Cl 2 [(M + H) + ] 624.2139, found 624.2147
    [497] Example 13
    [498] In a similar manner to that described in Example 12, the following compounds were prepared.
    [499] a) 1- {4- [4,5-bis- (4-chloro-phenyl) -2- (2-isopropoxy-4-methoxy-phenyl) -4,5-dihydro-imidazole-1 -Carbonyl] -piperazin-1-yl} -2-hydroxy-ethanone. HR-MS (ES, m / z) calc'd for C 32 H 35 N 4 0 5 Cl 2 [(M + H) + ] 625.1979, found 625.1984
    [500]
    [501] b) 1- {4- [4,5-bis- (4-chloro-phenyl) -2- (2-isopropoxy-4-methoxy-phenyl) -4,5dihydro-imidazole-1- Carbonyl] -piperazin-1-yl} -2,3-dihydroxy-propan-1-one.HR-MS (ES, m / z) C 33 H 37 N 4 0 6 Cl 2 [(M + H) + calculated on 655.2085, measured 655.2090
    [502] Example 14
    [503] [4,5-bis- (4-chloro-phenyl) -2- (2-isopropoxy-4-methoxy-phenyl) -4,5-dihydroimidazol-1-yl]-[4- ( 2,3-dihydroxy-propyl) -piperazin-1-yl] -methanone
    [504]
    [505] [4,5-bis- (4-chloro-phenyl) -2- (2-isopropoxy-4-methoxy-phenyl) -4,5-dihydro-imidazol-1-yl] -piperazine- 1-yl-methanone (50 mg, 0.088 mmol, Example 10 g) was dissolved in anhydrous methanol (10 mL). Glycidol (0.15 mL, 2.26 mmol) was added and the reaction was heated at 40 ° C. for 20 h. The mixture was cooled to rt and concentrated in vacuo. Chromatography of the residue on silica gel with 1-6% methanol in methylene chloride gave [4,5-bis- (4-chloro-phenyl) -2- (2-isopropoxy-4-methoxy-phenyl) -4,5-dihydro-imidazol-1-yl]-[4- (2,3-dihydroxy-propyl) -piperazin-1-yl] methanone (25 mg, 44%) was obtained. . HR-MS (ES, m / z) Calcd for C 33 H 39 N 4 0 5 Cl 2 [(M + H) + ] 641.2292, found 641.2300
    [506] Example 15
    [507] 4- [4,5-bis- (4-chloro-phenyl) -2- (2-isopropoxy-4-methoxy-phenyl) -4,5-dihydroimidazole-1-carbonyl] -pipe Razine-1-carboxylic acid dimethylamide
    [508]
    [509] Phosgene (0.26 mL, 0.5 mmol, 1.93 M in toluene) was dissolved in 4,5-bis (4-chloro-phenyl) -2- (2-isopropoxy-4-methoxy-phenyl) -4,5-di Solution of methylene chloride (10 mL) of hydro-imidazol-1-yl] -piperazin-1-yl-methanone (60 mg, 0.11 mmol, Example 10g) and triethylamine (97 μl, 0.70 mmol) Added to. The reaction mixture was stirred for 1 hour. The solvent was evaporated and the residue was dried under high vacuum for 30 minutes. The residue was dissolved in methylene chloride (10 mL). Dimethylamine (0.993 mL, 1.986 mmol, 2 M in THF) was added and the reaction mixture was stirred overnight. The mixture was washed with brine and the aqueous layer was extracted with methylene chloride. The combined organic extracts were dried (MgSO 4 ) and evaporated. Purification of the residue by reverse phase HPLC gave 4- [4,5-bis- (4-chloro-phenyl) -2- (2-isopropoxy-4-methoxy-phenyl) -4,5-dihydro-imid Dazole-1-carbonyl] -piperazine-carboxylic acid dimethylamide (48 mg, 68%) was obtained. HR-MS (ES, m / z) calcd for C 33 H 38 N 5 0 4 Cl 2 [(M + H) + ] 638.2296, found 638.2299
    [510] Example 16
    [511] 4- [4,5-bis- (4-chloro-phenyl) -2- (2-isopropoxy-4-methoxy-phenyl) -4,5-dihydroimidazole-1-carbonyl] -pipe Razine-1-carboxylic acid amide
    [512]
    [513] The named compounds were prepared in a similar manner as described in Example 15. HR-MS (m / z) calc'd for C 31 H 34 N 5 0 4 Cl 2 [(M + H) + ] 610.1983, found 610.1985
    [514] Example 17
    [515] [4,5-bis- (4-chloro-phenyl) -2- (2,4-diethoxy-phenyl) -4,5-dihydro-imidazol-1-yl] piperazin-1-yl-methane On trifluoroacetate salt
    [516]
    [517] A mixture of 2,4-diethoxybenzaldehyde (5.0 g, 25.7 mmol), sodium acetate (4.23 g, 51.6 mmol), nitroethane (3.86 g, 51.4 mmol) in acetic acid (7 mL) was heated at reflux for 6 hours. . The mixture was then cooled and poured onto ice water. The solid was filtered off, washed with water and dried. Chromatography of the residue on silica gel with 2-5% ethyl acetate in hexanes and subsequent recrystallization in ethyl acetate gave 2,4-ethoxybenzonitrile (1.86 g, 38%).
    [518] Hydrogen chloride gas was passed through a solution of 2,4-diethoxybenzonitrile (1.86 g, 9.7 mmol) in pure ethanol (20 mL) for 1 hour at −10 ° C. in a pressure vessel. The tube was sealed and stirred at room temperature for 12 d. Evaporation of the solvent and trituration of the residue in diethyl ether gave ethyl 2,4-diethoxy-benzimidate hydrochloride (2.53 g, 95%).
    [519] Ethyl 2,4-diethoxy-benzimidate hydrochloride (0.76 g, 2.79 mmol), meso-1,2-bis- (4-chloro-phenyl) -ethane-1,2-diamine (0.65 mg, 2.327 mmol , Prepared according to the procedure described in Vogttle, F .; Goldschmitt, E. Chem. Ber. 1976, 109, 1-40) and a mixture of triethylamine (0.489 mL, 3.49 mmol) in ethanol (10 mL). Was heated at reflux for 4 h. Solvent was removed to yield a yellow paste. Aqueous sodium bicarbonate was added and extracted with methylene chloride. The combined organic extracts were washed with water and brine and dried over sodium sulfate. Chromatography of the residue on silica gel using 70% ethyl acetate-hexane to give 4,5-bis- (4-chloro-phenyl) -2- (2,4-diethoxy-phenyl) -4,5-dihydro -1H-imidazole (0.50 g, 47%) was obtained.
    [520] Phosgene (0.558 mL, 1.1 mmol, 1.93 M in toluene) was charged with triethylamine (0.216 mL, 1.54 mmol) and 4,5-bis- (4-chloro-phenyl) -2- (2,4-diethoxyphenyl) To a solution of -4,5-dihydro-1H-imidazole (0.10 g, 0.22 mmol) in methylene chloride (10 mL) was added dropwise at 0 ° C. The reaction mixture was stirred at 0 ° C. for 1 h and evaporated. The residue was left to stand for 30 minutes under high vacuum. Methylene chloride (5 mL) was added to the residue and the solution was added dropwise to a solution of piperazine (0.38 g, 4.4 mmol) in methylene chloride (5 mL) at 0 ° C. over 15 minutes. After 1 hour, the reaction was worked up with aqueous sodium bicarbonate. The mixture was extracted with methylene chloride and washed with water and brine. The organic extract was extracted over sodium sulfate and evaporated. Purification by HPLC [4,5-bis- (4-chloro-phenyl) -2- (2,4-diethoxyphenyl) -4,5-dihydro-imidazol-1-yl] -piperazine- 1-yl-methanone, trifluoroacetic acid salt (4.07 g, 87%) was obtained. HR-MS (ES, m / z) C 3O H 33 N 4 0 3 Cl 2 [(M + H) +] calculated 567.1924, measured 567.1928 for
    [521] Example 18
    [522] In a similar manner to Example 17, the following compounds were prepared.
    [523] a) [4,5-bis- (4-chloro-phenyl) -2- (2,4-diethoxy-phenyl) -4,5-dihydro-imidazol-1-yl] -morpholin-4- Sun-methanone. HR-MS (ES, m / z) C 3O H 32 N 3 0 4 Cl 2 [(M + H) +] calcd for 568.1765, measured 568.1766
    [524]
    [525] b) [4,5-bis- (4-chloro-phenyl) -2- (2,4-diethoxy-phenyl) -4,5-dihydro-imidazol-1-yl]-[4- (2 -Hydroxy-ethyl) -piperazin-1-yl] -methanone. HR-MS (ES, m / z) calcd for C 32 H 37 N 4 0 4 Cl 2 [(M + H) + ] 611.2187, found 611.2203
    [526] c) [4,5-bis- (4-chloro-phenyl) -2- (2,4-diethoxy-phenyl) -4,5-dihydro-imidazol-1-yl]-(4-methyl- Piperazin-1-yl) -methanone. HR-MS (ES, m / z) Calcd for C 31 H 35 N 4 0 3 Cl 2 [(M + H) + ] 581.2081, found 581.2087
    [527] d) 1- {4- [4,5-bis- (4-chloro-phenyl) -2- (2,4-diethoxy-phenyl) -4,5-dihydro-imidazole-1-carbonyl] -Piperazin-1-yl} -ethanone. HR-MS (ES, m / z) calc'd for C 32 H 35 N 4 0 4 Cl 2 [(M + H) + ] 609.2030, found 609.2035
    [528] e) [4,5-bis- (4-chloro-phenyl) -2- (2,4-diethoxy-phenyl) -4,5-dihydro-imidazol-1-yl] (4-methanesulfonyl -Piperazin-1-yl) -methanone is [4,5-bis (4-chloro-phenyl) -2- (2,4-diethoxy-phenyl) -4,5-dihydro-imidazole-1 -Yl] -piperazin-1-yl-methanone (Example 17) was prepared by sulfonation. HR-MS (ES, m / z) calc'd for C 31 H 35 N 4 0 5 SCl 2 [(M + H) + ] 645.1700, found 645.1704
    [529] f) [4,5-bis- (4-chloro-phenyl) -2- (2,4-diethoxy-phenyl) -4,5-dihydro-imidazol-1-yl] (4-pyrrolidine -1-yl-piperidin-1-yl) -methanone. HR-MS (ES, m / z) Calcd for C 35 H 41 N 4 0 3 Cl 2 [(M + H) + ] 635.2550, found 635.2561
    [530] g) [4,5-bis- (4-bromo-phenyl) -2- (2,4-diethoxy-phenyl) -4,5-dihydro-imidazol-1-yl] (4-methyl- Piperazin-1-yl) -methanone. HR-MS (ES, m / z) calc'd for C 31 H 35 N 4 0 3 Br 2 [(M + H) + ] 669.1071, found 669.1074
    [531] h) [4,5-bis- (4-bromo-phenyl) -2- (2,4-diethoxy-phenyl) -4,5-dihydro-imidazol-1-yl] (4-ethyl- Piperazin-1-yl) -methanone. HR-MS (ES, m / z) calc'd for C 32 H 37 N 4 0 3 Br 2 [(M + H) + ] 683.1227, found 683.1228
    [532] i) [4,5-bis- (4-bromo-phenyl) -2- (2,4-diethoxy-phenyl) -4,5-dihydro-imidazol-1-yl] morpholine-1- Sun-methanone. HR-MS (ES, m / z) C 3O H 32 N 3 0 4 Br 2 [(M + H) +] calcd for 656.0754, measured 656.0760
    [533] Example 19
    [534] In a similar manner to that described in Example 15, the following compounds were prepared [4,5-bis- (4-chloro-phenyl) -2- (2,4-diethoxy-phenyl) -4,5-dihydro-imidazole -1-yl] -piperazin-1-yl-methanone (Example 17).
    [535] a) 4- [4,5-bis- (4-chloro-phenyl) -2- (2,4-diethoxy-phenyl) -4,5-dihydro-imidazole-1-carbonyl] -piperazine -1-carboxylic acid amide. HR-MS (ES, m / z) calc'd for C 31 H 34 N 5 0 4 Cl 2 [(M + H) + ] 610.1983, found 610.1983
    [536]
    [537] b) 4- [4,5-bis- (4-chloro-phenyl) -2- (2,4-diethoxy-phenyl) -4,5-dihydro-imidazole-1-carbonyl] -piperazine -1-carboxylic acid dimethylamide. HR-MS (ES, m / z) Calcd for C 33 H 38 N 5 0 4 Cl 2 [(M + H) + ] 638.2296, found 638.2297
    [538] Example 20
    [539] [4,5-bis- (4-chloro-phenyl) -2- (4-dimethylamino-2-ethoxy-phenyl) -4,5-dihydroimidazol-1-yl] -piperazin-1- Sun-methanone
    [540]
    [541] Iodine (6.35 g, 25 mmol) in methylene chloride (300 mL) was added to methylene chloride (300) of thallium (I) acetate (7.90 g, 30 mmol) and 3-dimethylaminophenol (3.43 g, 25 mmol) over 3 hours. mL) was added dropwise to the stirred suspension. The resulting mixture was stirred at rt for 24 h and filtered. Evaporation of the solvent and chromatography of the residue on silica gel with 0-5% diethyl ether in hexanes gave 5-dimethylamino-2-iodophenol (2.35 g, 36%).
    [542] A mixture of 5-dimethylamino-2-iodophenol (0.90 g, 3.42 Mmol), cesium carbonate (2.79 g, 8.55 mmol) and iodoethane (0.81 mL, 10 mmol) in acetone (5 mL) was refluxed. Heated for 2 hours. The reaction mixture was cooled to room temperature and water was added. The mixture was extracted with diethyl ether (3 x). The combined organic extracts were washed with brine, dried over magnesium sulfate and evaporated. Chromatography of the residue on silica gel with hexanes gave N, N-dimethyl-2-ethoxy-4-iodo-aniline (0.75 g, 76%).
    [543] N, N-dimethyl-2-ethoxy-4-iodo-aniline (0.75 g, 2.58 mmol) was dissolved in DMF (4 mL). Zinc cyanide (0.18 g, 1.54 mmol) was added. Argon was passed through the mixture for 10 minutes. Tetrakis (triphenylphosphine) palladium (148 mg, 0.13 mmol) was added and the mixture was heated at 110 ° C. for 24 hours. The reaction mixture was cooled down and poured with water. The mixture was extracted with ethyl acetate, washed with brine and dried over magnesium sulfate. Evaporation of the solvent and chromatography of the residue on silica gel with 20% ethyl acetate in hexanes gave N, N-dimethyl-2-ethoxy-4-cyano-aniline (187 mg, 38%).
    [544] Hydrogen chloride gas was passed through a solution of N, N-dimethyl-2-ethoxy-4-cyano-aniline (0.185 g, 0.97 mmol) in ethanol (5 mL) at 0 ° C. for 30 minutes. The pressure tube was sealed and stirred at room temperature for 2 d. After the tube was cooled to 0 ° C., the pressure was released. Evaporation of the solvent and trituration of the residue in diethyl ether gave ethyl 4- (N, N-dimethylamino) -2-ethoxy-benzimidate hydrochloride as a white powder (0.25 g, 95%).
    [545] Triethylamine (0.28 mL, 2.0 mmol) was added 4- (N, N-dimethylamino) -2-ethoxy-benzimidate hydrochloride (250 mg, 0.92 mmol) and meso-1,2-bis- (4 -Chloro-phenyl) -ethane-1,2-diamine (190 mg, 0.68 mmol, prepared according to the procedure described in Vogltle, F .; Goldschmitt, E. Chem. Ber. 1976, 109, 1-40) To a mixture in ethanol (5 mL). The mixture was heated at reflux overnight. The reaction was worked up with sodium bicarbonate and extracted with methylene chloride. The organic extract was washed with brine and dried over sodium sulfate. Evaporation of the solvent and chromatography of the residue on silica gel with 10-30% methanol in methylene gave {4- [4,5-bis- (4-chloro-phenyl) -4,5-dihydro-1H-imide Dazol-2-yl] -3-ethoxyphenyl} -dimethyl-amine was obtained as a white foam (0.18 g, 59%).
    [546] Phosgene (0.47 mL, 0.91 mmol, 1.93 M in toluene) was added [4- [4,5-bis- (4-chloro-phenyl) -4,5-dihydro-1H-imidazol-2-yl] -3 To a stirred solution of -ethoxy-phenyl} -dimethylamine (83 mg, 0.18 mmol) and triethylamine (0.14 mL, 1 mmol) in THF (3 mL) was added at 0 ° C. over 5 minutes. The mixture was stirred for 1 hour and evaporated. The residue was dissolved in methylene chloride (2 mL) and added dropwise to a stirred solution of piperazine (0.239 g, 2.77 mmol) in methylene chloride (2 mL) at room temperature for 1 hour. The mixture was diluted with aqueous sodium bicarbonate and extracted with methylene chloride. The organic extract was washed with brine and dried over sodium sulfate. Evaporation of the solvent and chromatography of the residue on silica gel with 0-10% methanol in methylene chloride gave [4,5-bis- (4-chloro-phenyl) -2- (4-dimethylamino-2-ethoxy -Phenyl) -4,5-dihydro-imidazol-1-yl] -piperazin-1-yl-methanone was obtained as a white foam (68 mg, 66%). HR-MS (ES, m / z) C 3O H 34 N 5 0 2 Cl 2 [(M + H) +] calcd for 566.2084, measured 566.2088
    [547] Example 21
    [548] In the same manner as in Example 20, the following compounds were prepared.
    [549] a) [4,5-bis- (4-chloro-phenyl) -2- (2-ethoxy-4-ethyl-phenyl) -4,5-dihydro-imidazol-1-yl] -piperazine- 1-yl-methanone. HR-MS (ES, m / z) C 3O H 33 N 4 0 2 Cl 2 [(M + H) +] calcd for 551.1975, measured 551.1984
    [550]
    [551] b) [4,5-bis- (4-chloro-phenyl) -2- (2-ethoxy-4-methyl-phenyl) -4,5-dihydro-imidazol-1-yl] -piperazine- 1-yl-methanone. HR-MS (ES, m / z) calcd for C 29 H 31 N 4 0 2 Cl 2 [(M + H) + ] 537.1819, found 537.1824
    [552] c) [4,5-bis- (4-chloro-phenyl) -2- (4-ethyl-2-isopropoxy-phenyl) -4,5-dihydroimidazol-1-yl] -piperazine- 1-day methanone. HR-MS (ES, m / z) Calcd for C 31 H 35 N 4 0 2 Cl 2 [(M + H) + ] 565.2132, found 565.2135
    [553] d) [4,5-bis- (4-chloro-phenyl) -2- (2-isopropoxy-4-methyl-phenyl) -4,5-dihydroimidazol-1-yl] -piperazine- 1-yl-methanone. HR-MS (ES, m / z) C 3O H 33 N 4 0 2 Cl 2 [(M + H) +] calcd for 551.1975, measured 551.1980
    [554] e) 1- {4- [4,5-bis- (4-chloro-phenyl) -2- (4-dimethylamino-2-ethoxy-phenyl) -4,5-dihydro-imidazole-1- Carbonyl] -piperazin-1-yl} -ethanone. HR-MS (ES, m / z) calc'd for C 32 H 36 N 5 0 3 Cl 2 [(M + H) + ] 608.2190, found 608.2201
    [555] Example 22
    [556] In the same manner as in Example 20, the following compounds were prepared.
    [557] a) [4,5-bis- (4-chloro-phenyl) -2- (2-ethoxy methyl-phenyl) -4,5-dihydro-imidazol-1-yl] -piperazin-1-yl -Methanone, trifluoroacetic acid salt. HR-MS (ES, m / z) calcd for C 32 H 31 N 4 0 2 Cl 2 [(M + H) + ] 537.1819, found 537.1826
    [558]
    [559] b) [4,5-bis- (4-chloro-phenyl) -2- (2-ethoxy-4-fluoro-phenyl) -4,5-dihydro-imidazol-1-yl]-(4 -Pyrrolidin-1-yl-piperidin-1-yl) -methanone. HR-MS (ES, m / z) calc'd for C 33 H 36 N 4 0 2 Cl 2 F [(M + H) + ] 609.2194, found 609.2204
    [560] c) [4,5-bis- (4-chloro-phenyl) -2- (2-ethoxy-4-fluoro-phenyl) -4,5-dihydro-imidazol-1-yl]-(4 -Dimethylamino-piperidin-1-yl) -methanone. HR-MS (ES, m / z) Calcd for C 31 H 34 N 4 0 2 Cl 2 F [(M + H) + ] 583.2038, found 583.2041
    [561] d) [4,5-bis- (4-chloro-phenyl) -2- (2-ethoxy-4-fluoro-phenyl) -4,5-dihydro-imidazol-1-yl] -piperazine -1-yl-methanone. HR-MS (ES, m / z) Calcd for C 28 H 28 N 4 0 2 Cl 2 F [(M + H) + ] 541.1568, found 541.1571
    [562] e) [4,5-bis- (4-chloro-phenyl) -2- (4-fluoro-2-isopropoxy-phenyl) -4,5-dihydroimidazol-1-yl]-(4 -Pyrrolidin-1-yl-piperidin-1-yl) -methanone. HR-MS (ES, m / z) calc'd for C 34 H 38 N 4 0 2 FCl 2 [(M + H) + ] 623.2351, found 623.2360
    [563] f) [4,5-bis- (4-chloro-phenyl) -2- (4-fluoro-2-isopropoxy-phenyl) -4,5-dihydroimidazol-1-yl]-(4 -Dimethylamino-piperidin-1-yl) -methanone. HR-MS (ES, m / z) Calcd for C 32 H 36 N 4 0 2 FCl 2 [(M + H) + ] 597.2194, found 597.2197
    [564] g) [4,5-bis- (4-chloro-phenyl) -2- (4-fluoro-2-isopropoxy-phenyl) -4,5-dihydro-imidazol-1-yl]-( 4-Methyl-piperazin-1-yl) -methanone. HR-MS (ES, m / z) C 3O H 32 N 4 0 2 FCl 2 [(M + H) +] calcd for 569.1881, measured 569.1887
    [565] h) [4,5-bis- (4-chloro-phenyl) -2- (4-fluoro-2-isopropoxy-phenyl) -4,5-dihydroimidazol-1-yl] -piperazine -1-yl-methanone. HR-MS (ES, m / z) C 29 H 3O N 4 0 2 FCl 2 [(M + H) +] calcd for 551.1725, measured 551.1726
    [566] i) [4,5-bis- (4-chloro-phenyl) -2- (4-fluoro-2-isopropoxy-phenyl) -4,5-dihydroimidazol-1-yl]-(4 Methanesulfonyl-piperazin-1-yl) -methanone. HR-MS (ES, m / z) C 3O H 32 N 4 0 4 SFCl 2 [(M + H) +] calcd for 633.1500, measured 633.1506
    [567] j) 4- [4,5-bis- (4-chloro-phenyl) -2- (4-fluoro-2-isopropoxy-phenyl) -4,5-dihydroimidazole-1-carbonyl] Piperazine-2-one. HR-MS (ES, m / z) calcd for C 29 H 28 N 4 0 3 FCl 2 [(M + H) + ] 569.1517, found 569.1529
    [568] k) [4,5-bis- (4-chloro-phenyl) -2-chroman-8-yl-4,5-dihydro-imidazol-1-yl] piperazin-1-yl-methanone 8-Bromo-Chroman (2,6-dibromo-phenol) from Thomas, GH et al. Tetrahedron Lett. 1998. 39, 2219-22). HR-MS (ES, m / z) Calcd for C 29 H 29 N 4 0 2 Cl 2 [(M + H) + ] 535.1662, found 535.1672
    [569] l) 4- [4,5-bis- (4-bromo-phenyl) -2- (2-ethoxy-4-fluoro-phenyl) -4,5-dihydroimidazole-1-carbonyl] Piperazine-2-one. HR-MS (ES, m / z) calc'd for C 28 H 26 N 4 0 3 FBr 2 [(M + H) + ] 643.0350, found 643.0349
    [570] m) [4,5-bis- (4-bromo-phenyl) -2- (2-ethoxy-4-fluoro-phenyl) -4,5-dihydro-imidazol-1-yl] -mor Polin-1-yl-methanone. HR-MS (ES, m / z) calc'd for C 28 H 27 N 3 0 3 FCl 2 [(M + H) + ] 630.0398, found 630.0414
    [571] n) [4,5-bis- (4-bromo-phenyl) -2- (2-ethoxy-4-fluoro-phenyl) -4,5-dihydro-imidazol-1-yl]-( 4-pyrrolidin-1-yl-piperidin-1-yl) -methanone. HR-MS (ES, m / z) Calcd for C 33 H 36 N 4 0 2 FBr 2 [(M + H) + ] 697.1184, found 697.1188
    [572] o) [4,5-bis- (4-bromo-phenyl) -2- (2-ethoxy-4-fluoro-phenyl) -4,5-dihydro-imidazol-1-yl]-( 4-dimethylamino-piperidin-1-yl) -methanone. HR-MS (ES, m / z) calc'd for C 31 H 34 N 4 0 2 FBr 2 [(M + H) + ] 671.1027, found 671.1036
    [573] p) [4,5-bis- (4-bromo-phenyl) -2- (2-ethoxy-4-fluoro-phenyl) -4,5-dihydro-imidazol-1-yl] -pipe Razin-1-yl-methanone. HR-MS (ES, m / z) calc'd for C 28 H 28 N 4 0 2 FBr 2 [(M + H) + ] 629.0558, found 629.0569
    [574] Example 23
    [575] [4,5-bis- (4-chloro-phenyl) -2- (2-cyclopentyloxy-4-methoxy-phenyl) -4,5-dihydroimidazol-1-yl] -piperazine-1 -Day-methanone
    [576]
    [577] THF of 2-hydroxy-4-methoxy-benzonitrile (90 mg, 0.60 mmol, Example 9), cyclopentanol (55 mg, 0.64 mmol) and triphenylphosphine (167 mg, 0.64 mmol) (3 To the solution in mL) was added diethyl azodicarboxate (0.16 mL, 0.860 mmol, 85%) at -78 ° C. The cooling bath was removed and the reaction was allowed to warm to room temperature over 1.5 hours. The reaction mixture was concentrated in vacuo and the residue was purified by flash chromatography (Biotage system, KP-Sil ™ 32-63 μm, 60 μs silica gel) eluted with 0-8% diethyl ether in hexane. Toxybenzonitrile was obtained as a clear liquid (125 mg, 90%).
    [578] Hydrogen chloride gas was passed through a solution of 2-cyclopentyloxy-4-methoxy-benzonitrile (0.12 g, 0.55 mmol) in pure ethanol (15 mL) in a pressurized tube at 0 ° C. for 1 hour. The tube was sealed and stirred at room temperature for 3 d. Evaporation of the solvent and trituration of the residue in diethyl ether gave ethyl 2-cyclopentyloxy-4-methoxy-benzimidate hydrochloride (0.17 g, 100%).
    [579] Ethyl 2-cyclopentyloxy-4-methoxy-benzimidate hydrochloride (0.16 g, 0.57 mmol), meso-1,2-bis- (4-chloro-phenyl) -ethane-1,2-diamine (0.17 g, 0.56 mmol, a mixture in ethanol (2 ml), prepared according to the procedure described in Vogltle, F .; Goldschmitt, E. Chem. Ber. 1976, 1091-40], was heated under reflux for 18 hours. Solvent was removed to yield a yellow paste. Aqueous sodium bicarbonate was added and extracted with methylene chloride. The combined organic extracts were washed with water and brine and dried over sodium sulfate. Chromatography of the residue on silica gel with 0-5% methanol in methylene chloride 4,5-bis- (4-chloro-phenyl) -2- (2-cyclopentyloxy-4-methoxy-phenyl) -4 , 5-dihydro-1H-imidazole was obtained.
    [580] Phosgene (0.48 mL, 0.925 mmol, 1.93 M in toluene) was charged with triethylamine (0.14 mL, 1.0 mmol) and 4,5-bis- (4-chloro-phenyl) -2- (2-cyclopentyloxy-4- To a mixture of methoxy-phenyl) -4,5-dihydro-1H-imidazole (89 mg, 0.185 mmol) in THF (2 mL) was added dropwise at 0 ° C. The reaction mixture was stirred at 0 ° C. for 1 h and evaporated. The residue was left to stand for 30 minutes under high vacuum. After methylene chloride (2 ml) was added to the residue, the solution was added dropwise to a solution of piperazine (0.24 g, 2.78 mmol) in methylene chloride (2 mL) at 0 ° C. After 1 hour, the reaction was worked up using aqueous sodium bicarbonate. The mixture was extracted with methylene chloride and washed with water and brine. The organic layer was extracted with 0.5 N HCl (2 × 50 mL). The combined aqueous layer was cooled to 0 ° C. and basified with 2N NaOH. The mixture was extracted with methylene chloride (3 x 50 mL). The organic extract was dried over sodium sulphate and evaporated. Flash chromatography of the residue on silica gel using 3-6% methanol in methylene chloride gave [4,5-bis- (4-chloro-phenyl) -2- (2-cyclopentyloxy-4-methoxy- Phenyl) -4,5-dihydro-imidazol-1-yl] -piperazin-1-yl-methanone (89 mg, 81%) was obtained. HR-MS (ES, m / z) Calcd for C 32 H 35 N 4 0 3 Cl 2 [(M + H) + ] 593.2081, found 593.2084
    [581] Example 24
    [582] The following compounds were prepared in a similar manner to Example 23 and Example 9.
    [583] a) [4,5-bis- (4-chloro-phenyl) -2- [2- (2-dimethylamino-ethoxy) -4-methoxy-phenyl] -4,5-dihydro-imidazole- 1-yl] -piperazin-1-yl-methanone. HR-MS (ES, m / z) Calcd for C 31 H 36 N 5 0 3 Cl 2 [(M + H) + ] 596.2190, found 596.2196
    [584]
    [585] b) {4,5-bis- (4-chloro-phenyl) -2- [2- (2-imidazol-1-yl-ethoxy) -4-methoxy-phenyl] -4,5-dihydro -Imidazol-1-yl] -piperazin-1-yl-methanone. HR-MS (ES, m / z) Calcd for C 32 H 33 N 6 0 3 Cl 2 [(M + H) + ] 619.1986, found 619.1988
    [586] Example 25
    [587] [2- (4-Chloro-2-ethoxy-phenyl) -4,5-bis- (4-chloro-phenyl) -4,5-dihydro-imidazol-1-yl] -piperazine-1- Mono-methanone hydrochloride
    [588]
    [589] To a solution of 4-chloro-2-fluoro-benzonitrile (1.0 g, 6.428 mmol) in ethanol (10 mL) was added sodium ethoxide solution (4.8 mL, 12.86 mmol, 21 wt% in ethanol). The reaction mixture was heated at light reflux for 12 h. Solvent was removed and the residue was partitioned between water (10 mL) and diethyl ether (20 mL). The layers were separated and the product was extracted with diethyl ether (20 mL). The organic layer was washed with brine (5 mL) and dried over anhydrous sodium sulfate. The solid was filtered off and the filtrate was concentrated in vacuo. Flash chromatography of the residue by flash chromatography eluting with 5% ethyl acetate in hexane (Biotage system, KP-Sil ™ 32-63 μm, 60 μs silica gel) gave 4-chloroethoxy-benzonitrile (0.67 g, 57%) was obtained.
    [590] [2- (4-Chloro-2-ethoxy-phenyl) -4,5-bis- (4-chloro-phenyl) -4,5-dihydro-imidazol-1-yl] -piperazine-1- Mono-methanone hydrochloride was prepared from 4-chloro-2-ethoxy-benzonitrile in a similar manner as described in Example 23. HR-MS (ES, m / z) calcd for C 28 H 28 N 4 0 2 Cl 3 [(M + H) + ] 557.1273, found 557.1277
    [591] Example 26
    [592] In a similar manner to those described in Example 23 and Example 25, the following compounds were prepared.
    [593] a) [2- (4-Chloro-2-ethoxy-phenyl) -4,5-bis- (4-chloro-phenyl) -4,5-dihydro-imidazol-1-yl]-(4- Methyl-piperazin-1-yl) -methanone hydrochloride. HR-MS (ES, m / z) C 29 H 3O N 4 0 2 Cl 2 [(M + H) +] calcd for 571.1429, measured 571.1438
    [594]
    [595] b) [2- (4-Chloro-2-ethoxy-phenyl) -4,5-bis- (4-chloro-phenyl) -4,5-dihydro-imidazol-1-yl]-(4- Pyrrolidin-1-yl-piperidin-1-yl) -methanone hydrochloride. HR-MS (ES, m / z) calc'd for C 33 H 36 N 4 0 2 C l3 [(M + H) + ] 625.1899, found 625.1908
    [596] c) [2- (4-Chloro-2-ethoxy-phenyl) -4,5-bis- (4-chloro-phenyl) -4,5-dihydro-imidazol-1-yl] -morpholine- 1-yl-methanone. HR-MS (ES, m / z) calcd for C 28 H 27 N 3 0 3 Cl 3 [(M + H) + ] 558.1113, found 558.1118
    [597] d) 1- {4- [2- (4-chloro-2-ethoxy-phenyl) -4,5-bis- (4-chloro-phenyl) -4,5-dihydroimidazole-1-carbonyl ] -Piperazin-1-yl} -ethanone. HR-MS (ES, m / z) C 3O H 3O N 4 0 3 Cl 3 [(M + H) +] calculated 599.1378, measured 599.1388 for
    [598] e) [2- (4-chloro-2-ethoxy-phenyl) -4,5-bis- (4-chloro-phenyl) -4,5-dihydro-imidazol-1-yl]-[4- (2-hydroxy-ethyl) -piperazin-1-yl] -methanone hydrochloride. HR-MS (ES, m / z) C 3O H 32 N 4 0 3 Cl 3 [(M + H) +] calcd for 601.1535, measured 601.1543
    [599] f) 4- [2- (4-chloro-2-ethoxy-phenyl) -4,5-bis- (4-chloro-phenyl) -4,5-dihydroimidazole-1-carbonyl] -pipe Razin-2-one. HR-MS (ES, m / z) calcd for C 28 H 26 N 4 0 3 Cl 3 [(M + H) + ] 571.1065, found 571.1071
    [600] Example 27
    [601] [4,5-bis- (4-chloro-phenyl) -2- (4-ethoxy-2-isopropoxy-phenyl) -4,5-dihydroimidazol-1-yl] -piperazine-1 -Day-methanone
    [602]
    [603] To a solution of 4-bromo-benzene-1,3-diol (1.50 g, 7.94 mmol) in acetone (10 mL) potassium carbonate (1.1 g, 7.94 mmol) and 2-iodopropane (1.58 mL, 15.87 mmol) Was added. The reaction mixture was heated at light reflux for 12 h. The solvent was removed to give a white paste. Then it was taken up in diethyl ether (50 mL). The white solid was filtered off and the filtrate was concentrated. The residue was purified by Biotage flash chromatography eluting with 10% ethyl acetate in hexanes to give 4-bromo-3-isopropoxy-phenol (0.77 g, 42%).
    [604] To a solution of 4-bromo-3-isopropoxy-phenol (0.50 g, 2.16 mmol) in acetone (3 mL) was added potassium carbonate (0.30 g, 2.16 mmol) and ethyl iodide (0.35 mL, 4.33 mmol). Added. The reaction mixture was heated at light reflux for 12 h. The solvent was removed to give a white paste. It was then taken up in diethyl ether (50 mL). The white solid was filtered off and the filtrate was concentrated. Purification of the residue by Biotage flash chromatography eluting with 10% ethyl acetate in hexanes gave 1-bromo-4-ethoxy-2-isopropoxy-benzene (0.48 g, 86%).
    [605] Zinc cyanide (217 mg, 1.85 mmol) was added to a solution of 1-bromo-4-ethoxy-2-isopropoxy-benzene (0.48 g, 1.85 mmol) in DMF (5 mL). The reaction was degassed by passing the mixture through argon for 2 hours and then tetrakis (triphenylphosphine) -palladium (0) (0.21 g, 0.185 mmol) was added. The reaction mixture was heated at 100-105 ° C. under argon for 12 hours. The reaction mixture was poured into diethyl ether (50 mL) and saturated sodium bicarbonate solution (5 mL). The product was extracted with diethyl ether (2 x 30 mL). The organic layer was washed with water (1 x 10 mL) and brine (1 x 10 mL), dried (sodium sulfate) and concentrated. Purification of the crude by Biotage flash chromatography eluting with 10-15% ethyl acetate in hexanes gave 4-ethoxy-2-isopropoxy-benzonitrile as a clear oil (0.31 g, 81%).
    [606] Hydrogen chloride gas was passed through a solution of 4-ethoxy-2-isopropoxybenzonitrile (0.30 g, 1.46 mmol) in pure ethanol (100 mL) in a pressurized tube at 0 ° C. for 45 minutes. The tube was sealed and stirred for 4 d at room temperature. The pressure was released only after the tube had cooled to 0 ° C. Evaporation of the solvent and trituration of the residue in diethyl ether gave ethyl 4-ethoxy-2-isopropoxy-benzimidate hydrochloride, which was used without further purification.
    [607] Crude ethyl 4-ethoxy-2-isopropoxy-benzimidate hydrochloride and meso-1,2-bis- (4-chloro-phenyl) -ethane-1,2-diamine (0.41 g, 1.46 mmol, Prepared according to the procedure described in Vogttle, F .; Goldschmitt, E. Chem. Ber. 1976, 109, 1-40) and a solution of triethylamine (0.205 mL, 1.46 mmol) in ethanol (25 mL). Heated at reflux for 3 hours. Solvent was removed to yield a yellow paste. Aqueous sodium bicarbonate was added and extracted with methylene chloride. The combined organic extracts were washed with water and brine and dried over sodium sulfate. Chromatography of the residue on silica gel with 70% ethyl acetate-hexane gave 4,5-bis- (4-chloro-phenyl) -2- (4-ethoxy-2-isopropoxy-phenyl) -4, 5-dihydro-1H-imidazole (0.50 g, 47%) was obtained.
    [608] Phosgene (0.325 mL, 0.64 mmol, 1.93 M in toluene) was charged with triethylamine (0.126 mL, 0.896 mmol) and 4,5-bis- (4-chloro-phenyl) -2- (4-ethoxy-2-iso To the solution of propoxy-phenyl) -4,5-dihydro-1H-imidazole (60 mg, 0.128 mmol) in methylene chloride (5 mL) was added dropwise at 0 ° C. The reaction mixture was stirred for 30 minutes at 0 ° C. and evaporated. The residue was kept under high vacuum for 30 minutes. Methylene chloride (5 mL) was added to the residue and the solution was added dropwise to a solution of piperazine (0.22 mg, 2.56 mmol) in methylene chloride (5 mL) at 0 ° C. for 15 minutes. After 1 hour, the reaction was worked up with aqueous sodium bicarbonate. The mixture was extracted with methylene chloride and washed with water and brine. The organic extract was dried over sodium sulphate and evaporated. Purification using reverse phase HPLC gave [4,5-bis- (4-chloro-phenyl) -2- (4-ethoxy-2-isopropoxy-phenyl) -4,5-dihydro-imidazole-1- Il] -piperazin-1-yl-methanone (6.5 mg, 8%) was obtained. HR-MS (ES, m / z) Calcd for C 31 H 35 N 4 0 3 Cl 2 [(M + H) + ] 581.2081, found 581.2086
    [609] Example 28
    [610] In a similar manner to Example 27, the following compounds were prepared.
    [611] a) [4,5-bis- (4-chloro-phenyl) -2- (2-ethoxy-5-methoxy-phenyl) -4,5-dihydro-imidazol-1-yl] -piperazine -1-yl-methanone, trifluoroacetic acid salt. HR-MS (ES, m / z) Calcd for C 29 H 31 N 4 0 3 Cl 2 [(M + H) + ] 553.1768, found 553.1776
    [612]
    [613] b) [4,5-bis- (4-chloro-phenyl) -2- (2-ethoxy-5-methoxy-phenyl) -4,5-dihydroimidazol-1-yl]-(4- Methanesulfonyl-piperazin-1-yl) -methanone is converted to [4,5-bis- (4-chloro-phenyl) -2- (2-ethoxy-4-methoxy-phenyl) -4,5- Dihydroimidazol-1-yl] -piperazin-1-yl-methanone (Example 28a) was prepared by sulfonation. HR-MS (ES, m / z) C 3O H 33 N 4 0 5 SCl 2 [(M + H) +] calcd for 631.1543, measured 631.1548
    [614] c) [4,5-bis- (4-chloro-phenyl) -2- (2-ethoxy-4-methoxy-phenyl) -4,5-dihydroimidazol-1-yl]-[4- (2-hydroxy-ethyl) -piperazin-1-yl] -methanone hydrochloride. HR-MS (ES, m / z) Calcd for C 31 H 35 N 4 0 4 Cl 2 [(M + H) + ] 597.2030, found 597.2037
    [615] d) [4,5-bis- (4-chloro-phenyl) -2- (2,5-diethoxy-phenyl) -4,5-dihydro-imidazol-1-yl] piperazin-1-yl Methanone hydrochloride. HR-MS (ES, m / z) C 3O H 33 N 4 0 3 Cl 2 [(M + H) +] calculated 567.1924, measured 567.1928 for
    [616] e) [4,5-bis- (4-chloro-phenyl) -2- (2,5-diethoxy-phenyl) -4,5-dihydro-imidazol-1-yl] (4-methanesulfonyl -Piperazin-1-yl) -methanone with [4,5-bis- (4-chloro-phenyl) -2- (2,5-diethoxy-phenyl) -4,5-dihydro-imidazole- Prepared by sulfonation of 1-yl] -piperazin-1-yl] methanone (Example 28d). HR-MS (ES, m / z) calc'd for C 31 H 35 N 4 0 5 SCl 2 [(M + H) + ] 645.1700, found 645.1714
    [617] f) [4,5-bis- (4-chloro-phenyl) -2- (4-ethoxy-2-isopropoxy-phenyl) -4,5-dihydroimidazol-1-yl]-[4 -(2-hydroxy-ethyl) -piperazin-1-yl] -methanone. HR-MS (ES, m / z) Calcd for C 33 H 39 N 4 0 4 Cl 2 [(M + H) + ] 625.2343, found 625.2350
    [618] g) 4- [4,5-bis- (4-chloro-phenyl) -2- (4-ethoxy-2-isopropoxy-phenyl) -4,5-dihydroimidazole-1-carbonyl] Piperazine-2-one. HR-MS (ES, m / z) Calcd for C 31 H 33 N 4 0 4 Cl 2 [(M + H) + ] 595.1874, Found 595.1879
    [619] h) [4,5-bis- (4-chloro-phenyl) -2- (5-ethoxy-2-isopropoxy-phenyl) -4,5-dihydroimidazol-1-yl] -piperazine -1-yl-methanone. HR-MS (ES, m / z) Calcd for C 31 H 35 N 4 0 3 Cl 2 [(M + H) + ] 581.2081, found 581.2088
    [620] i) [4,5-bis- (4-chloro-phenyl) -2- (5-ethoxy-2-isopropoxy-phenyl) -4,5-dihydroimidazol-1-yl]-(4 Methanesulfonyl-piperazin-1-yl) -methanone to [4,5-bis- (4-chloro-phenyl) -2- (5-ethoxy-2-isopropoxy-phenyl) -4, Prepared by sulfonation of 5-dihydro-imidazol-1-yl] -piperazin-1-yl-methanone (Example 28h). HR-MS (ES, m / z) calcd for C 32 H 37 N 4 0 5 SCl 2 [(M + H) + ] 659.1856, found 659.1864
    [621] j) [4,5-bis- (4-chloro-phenyl) -2- (5-ethoxy-2-isopropoxy-phenyl) -4,5-dihydroimidazol-1-yl]-[4 -(2-hydroxy-ethyl) -piperazin-1-yl] -methanone hydrochloride. HR-MS (ES, m / z) Calcd for C 33 H 39 N 4 0 4 Cl 2 [(M + H) + ] 625.2343, found 625.2352
    [622] k) 1- {4- [4,5-bis- (4-chloro-phenyl) -2- (4-ethoxy-2-isopropoxy-phenyl) -4,5-dihydroimidazole-1- Carbonyl] -piperazin-1-yl} -ethanone. HR-MS (ES, m / z) Calcd for C 33 H 37 N 4 0 4 Cl 2 [(M + H) + ] 623.2187, found 623.2194
    [623] l) 1- {4- [4,5-bis- (4-chloro-phenyl) -2- (5-ethoxy-2-isopropoxy-phenyl) -4,5-dihydroimidazole-1- Carbonyl] -piperazin-1-yl} -ethanone. HR-MS (ES, m / z) calcd for C 33 H 37 N 4 0 4 Cl 2 [(M + H) + ] 623.2187, found 623.2195
    [624] m) [4,5-bis- (4-chloro-phenyl) -2- (4-ethoxy-2-isopropoxy-phenyl) -4,5-dihydroimidazol-1-yl]-(4 -Pyrrolidin-1-yl-piperidin-1-yl) -methanone. HR-MS (ES, m / z) calcd for C 36 H 43 N 4 0 3 Cl 2 [(M + H) + ] 649.2707, found 649.2717
    [625] n) [4,5-bis- (4-chloro-phenyl) -2- (2-isopropoxy-5-methoxy-phenyl) -4,5-dihydroimidazol-1-yl] -piperazine -1-yl-methanone, trifluoroacetic acid salt. HR-MS (ES, m / z) C 3O H 33 N 4 0 3 Cl 2 [(M + H) +] calculated 567.1924, measured 567.1929 for
    [626] o) [4,5-bis- (4-chloro-phenyl) -2- (2,4-diisopropoxy-phenyl) -4,5-dihydro-imidazol-1-yl] -piperazine- 1-yl-methanone. HR-MS (ES, m / z) Calcd for C 32 H 37 N 4 0 3 Cl 2 [(M + H) + ] 595.2237, found 595.2244
    [627] p) [4,5-bis- (4-chloro-phenyl) -2- (2,5-diisopropoxy-phenyl) -4,5-dihydro-imidazol-1-yl] -piperazine- 1-yl-methanone hydrochloride. HR-MS (ES, m / z) C 32 H 37 N 4 0 3 Cl 2 [(M + H) +] calcd for 595.2237, measured 595.2243
    [628] Example 29
    [629] 1- [4,5-bis- (4-chloro-phenyl) -2- (2-methoxy-5-morpholin-4-yl-methyl-phenyl) -4,5-dihydro-imidazole-1 -Yl] -2-methyl-propan-1-one
    [630]
    [631] 4- {3- [4,5-bis- (4-chloro-phenyl) -4,5-dihydro-1H-imidazol-1-yl] -4-methoxy-benzyl} morpholine (100 mg, Triethylamine (0.10 mL, 0.712 mmol) and isobutyryl chloride (42 in order) in a solution in methylene chloride (10 mL) of 0.20 mmol, US temporary application, as incorporated herein by reference, as in Example 31 mL, 0.392 mmol) was added. The reaction mixture was stirred for 12 hours. The solvent was removed under reduced pressure. Saturated sodium bicarbonate (2 mL) and methylene chloride (20 mL) were added and the layers were separated. The aqueous layer was extracted with methylene chloride (1 x 100 mL). The combined organic extracts were evaporated. Purification of the crude residue by Biotage flash chromatography, eluting with 0-5% methanol in ethyl acetate, yielded 1- [4,5-bis- (4-chloro-phenyl) -2- (2-methoxy-5- Morpholin-4-ylmethylphenyl) -4,5-dihydro-imidazol-1-yl] -2-methyl-propan-1-one was obtained. HR-MS (ES, m / z) calc'd for C 31 H 34 N 3 0 3 Cl 2 [(M + H) + ] 566.1972, found 566.1977
    [632] Example 30
    [633] In a similar manner as described in Example 29, the following compounds were prepared.
    [634] a) 1- [4,5-bis- (4-chloro-phenyl) -2- (3-hydroxymethyl-5-methoxy-phenyl) -4,5-dihydro-imidazol-1-yl] -2-methyl-propan-1-one is substituted with {3- [4,5-bis- (4-chloro-phenyl) -4,5-dihydro-1H-imidazol-2-yl] -5-methoxy Prepared as in US Provisional Application, Example 33, incorporated herein by reference from -phenyl} -methanol. HR-MS (ES, m / z) Calcd for C 27 H 27 N 2 0 3 Cl 2 [(M + H) + ] 497.1393, found 497.1402
    [635]
    [636] b) 1- [4,5-bis- (4-chloro-phenyl) -2- (3-hydroxymethyl-5-methoxymethyl-phenyl) -4,5-dihydro-imidazol-1-yl ] -Ethanone is sodium {3- [4,5-bis- (4-chloro-phenyl) -4,5-dihydro-1H-imidazol-2-yl] -5-methoxymethyl-phenyl}- From methanol, it was prepared as in US Provisional Application, Example 35, which is incorporated herein by reference. HR-MS (EI, m / z) calcd for C 26 H 24 N 2 0 3 Cl 2 (M + ) 482.1164, found 482.1161
    [637] c) 1- [4,5-bis- (4-chloro-phenyl) -2- (3-methoxy-5-methoxymethyl-phenyl) -4,5-dihydro-imidazol-1-yl] 2-Methyl-propan-1-one to 4,5-bis- (4-chloro-phenyl) -2- (3-methoxy-5-methoxymethyl-phenyl) -4,5-dihydro-1H From imidazole, as prepared in US Provisional Application Example 34, incorporated herein by reference. HR-MS (m / z) calc'd for C 28 H 29 N 2 0 3 Cl 2 [(M + H) + ] 511.1550, found 511.1556
    [638] d) 3- [4,5-bis- (4-chloro-phenyl) -1-isobutyryl-4,5-dihydro-1H-imidazol-2-yl] -5-methoxymethyl-benzoic acid From 3- [4,5-bis- (4-chloro-phenyl) -4,5-dihydro-1H-imidazol-2-yl] -5-methoxymethyl-benzoate, incorporated herein by reference US Provisional Application, which was prepared as in Example 40. HR-MS (ES, m / z) Calcd for C 28 H 27 N 2 0 4 Cl 2 [(M + H) + ] 525.1343, found 525.1347
    [639] e) 1- [4,5-bis- (4-chloro-phenyl) -2- (5-ethoxymethyl-2,4-dimethoxy-phenyl) -4,5-dihydro-imidazole-1- Il] -2-methyl-propan-1-one to 4,5-bis- (4-chloro-phenyl) -2- (5-ethoxymethyl-2,4-dimethoxy-phenyl) -4,5- US, which is incorporated herein by reference, from dihydro-1H-imidazole Prepared as in Interim Application Example 32.
    [640] Example 31
    [641] [4,5-bis- (4-chloro-phenyl) -2- (2-ethoxy-6-methoxy-phenyl) -4,5-dihydro-imidazol-1-yl] -piperazine-1 -Day-methanone
    [642]
    [643] Phosgene (0.147 mL, 0.283 mmol, 1.93 M in toluene) was dissolved in 4,5-bis- (4-chloro-phenyl) -2- (2-ethoxy-6-methoxy-phenyl) -4,5-dihydro To a stirred solution of -1H-imidazole (described in the prior art patent) (25 mg, 0.0566 mmol) and triethylamine (39 mL, 0.283 mmol) in THF (2 mL) was added at 0 ° C. for 5 minutes. The mixture was stirred for 3 hours and evaporated. The residue was dissolved in methylene chloride (2 mL) and added dropwise to a stirred solution of piperazine (24 mg, 0.283 mmol) in methylene chloride (2 mL) at room temperature for 3 hours. The mixture was diluted with aqueous sodium bicarbonate and extracted with methylene chloride. The organic layer was washed with brine and dried over sodium sulfate. Evaporation of the solvent and chromatography of the residue on silica gel with 0-10% methanol in methylene chloride gave [4,5-bis- (4-chloro-phenyl) -2- (2-ethoxy-6-methoxy -Phenyl) -4,5-dihydro-imidazol-1-yl] -piperazin-1-yl-methanone (19 mg, 61%) was obtained. HR-MS (ES, m / z) calcd for C 29 H 31 N 4 0 3 Cl 2 [(M + H) + ] 553.1768, found 553.1770
    [644] Example 32
    [645] [4,5-bis- (4-chloro-phenyl) -2- (5-ethoxymethyl-2,4-dimethoxy-phenyl) -4,5-dihydroimidazol-1-yl] -piperazine -1-yl-methanone
    [646]
    [647] In a manner analogous to that described in Example 31, the compound referred to was prepared as 4,5-bis- (4-chloro-phenyl) -2- (5-ethoxymethyl-2,4-dimethoxy-phenyl) -4,5 Prepared from -dihydro-1H-imidazole (described in the prior art patent). HR-MS (ES, m / z) Calcd for C 31 H 35 N40 4 Cl 2 [(M + H) + ] 597.2030, found 597.2034
    [648] Example 33
    [649] [4,5-bis- (4-chloro-phenyl) -2- (2-isopropoxy-4-methoxy-phenyl) -4,5-dihydroimidazol-1-yl]-[4- ( 2-hydroxy-propyl) -piperazin-1-yl] -methanone
    [650]
    [651] The compound is [4,5-bis- (4-chloro-phenyl) -2- (2-isopropoxy-4-methoxy-phenyl) -4,5-dihydro-imidazol-1-yl]- Piperazin-1-yl-methanone (Example 10 g) was prepared by treating in propylene oxide and methanol for 7 hours at 45 ° C. in a sealed tube. HR-MS (ES, m / z) Calcd for C 33 H 38 N 4 0 4 Cl 2 [(M + H) + ] 625.2343, found 625.2350
    [652] Example 34
    [653] In a similar manner to that described in Example 33, the following compounds were prepared.
    [654] a) [4,5-bis- (4-chloro-phenyl) -2- (2-isopropoxy-4-methoxy-phenyl) -4,5-dihydroimidazol-1-yl] -threo [ 4- (2-hydroxy-1-methyl-propyl) -piperazin-1-yl] -methanone .HR-MS (ES, m / z) C 34 H 4O N 4 0 4 Cl 2 [(m + H) + calculated on 639.2500, measured 639.2508
    [655]
    [656] b) [4,5-bis- (4-chloro-phenyl) -2- (2-isopropoxy-4-methoxy-phenyl) -4,5-dihydroimidazol-1-yl] -erythro [ 4- (2-hydroxy-1-methyl-propyl) -piperazin-1-yl] -methanone. HR-MS (ES, m / z) C 34 H 4O N 4 0 4 Cl 2 [(M + H) +] calculated 639.2500, measured 639.2507 for
    [657] Example 35
    [658] 1- {4- [4,5-bis- (4-chloro-phenyl) -2- (2-isopropoxy-4-methoxy-phenyl) -4,5-dihydroimidazole-1-carbonyl ] -Piperazin-1-yl} -propan-2-one
    [659]
    [660] [4,5-bis- (4-chloro-phenyl) -2- (2isopropoxy-4-methoxy-phenyl) -4,5-dihydro-imidazol-1-yl] -piperazin-1 The compound was prepared by treating -yl-methanone (Example 10g) with chloroacetone and triethylamine overnight at 40 ° C. HR-MS (ES, m / z) Calcd for C 33 H 36 N 4 0 4 Cl 2 [(M + H) + ] 623.2187, found 623.2194
    [661] Example 36
    [662] In a similar manner to that described in Example 9, the following compounds were prepared.
    [663] a) [4,5-bis- (4-chloro-phenyl) -2- (2-isopropoxy-4-methoxy-phenyl) -4,5-dihydroimidazol-1-yl]-[1 , 4] diazepan-1-yl-methanone. HR-MS (ES, m / z) Calcd for C 31 H 34 N 4 0 3 Cl 2 [(M + H) + ] 581.2081, found 581.2086
    [664]
    [665] b) 4- [4,5-bis- (4-chloro-phenyl) -2- (2-isopropoxy-4-methoxy-phenyl) -4,5-dihydroimidazole-1-carbonyl] -1-methyl-piperazin-2-one. HR-MS (ES, m / z) Calcd for C 31 H 32 N 4 0 4 Cl 2 [(M + H) + ] 595.1874, Found 595.1880
    [666] c) 1- {4- [4,5-bis- (4-chloro-phenyl) -2- (2-isopropoxy-4-methoxy-phenyl) -4,5-dihydro-imidazole-1 -Carbonyl] -piperazin-1-yl} -2-methyl-propan-1-one. HR-MS (ES, m / z) Calcd for C 34 H 38 N 4 0 4 Cl 2 [(M + H) + ] 637.2343, found 637.2348
    [667] d) 4- [4,5-bis- (4-chloro-phenyl) -2- (2-isopropoxy-4-methoxy-phenyl) -4,5-dihydroimidazole-1-carbonyl] Piperazine-1-carbaldehyde. HR-MS (ES, m / z) Calcd for C 31 H 32 N 4 0 4 Cl 2 [(M + H) + ] 595.1874, Found 595.1882
    [668] Example 37
    [669] In a similar manner to that described in Example 9, the following compounds were prepared.
    [670] a) 4- {4,5-bis- (4-chloro-phenyl) -2- [4-methoxy-2- (2,2,2-trifluoro-ethoxy) -phenyl] -4,5 -Dihydro-imidazole-1-carbonyl] -piperazin-2-one
    [671]
    [672] The compound is 4,5-bis- (4-chloro-phenyl) -2- [4-methoxy-2- (2,2,2-trifluoro-ethoxy) -phenyl-4,5-dihydro From -1H-imidazole, prepared as in US Provisional Application, Example 47a, which is incorporated herein by reference. HR-MS (ES, m / z) calcd for C 29 H 25 N 4 0 4 F 3 Cl 2 [(M + H) + ] 621.1278, found 621.1285
    [673] b) 4- {4,5-bis- (4-bromo-phenyl) -2- [4-methoxy-2- (2,2,2-trifluoro-ethoxy) -phenyl] -4, 5-dihydro-imidazol-1-carbonyl} -piperazin-2-one was added to 4,5-bis- (4-bromo-phenyl) -2- [4-methoxy-2- (2,2 , 2-trifluoro-ethoxy) -phenyl] -4,5-dihydro-1H-imidazole, prepared as in US Provisional Application, Example 47b, which is incorporated herein by reference. HR-MS (ES, m / z) Calcd for C 29 H 25 N 4 0 4 F 3 Br 2 [(M + H) + ] 709.0268, found 709.0280
    [674] c) [4,5-bis- (4-ethynyl-phenyl) -2- (2-isopropoxy-4-methoxy-phenyl) -4,5-dihydroimidazol-1-yl]-( 4-Pyrrolidin-1-yl-piperidin-1-yl) -methanone is 4,5-bis- (4-ethynyl-phenyl) -2- (2-isopropoxy-4-methoxy From -phenyl) -4,5-dihydro-1H-imidazole, as in US Provisional Application, Example 47d, which is incorporated herein by reference. HR-MS (ES, m / z) calc'd for C 29 H 25 N 4 0 4 F 3 Br 2 [(M + H) + ] 615.3330, found 615.3319
    [675] d) 1- {4- [2- (5-chloro-2-isopropoxy-phenyl) -4,5-bis- (4-chloro-phenyl) -4,5-dihydroimidazole-1-car Carbonyl) -piperazin-1-yl} -ethanone to 2- (5-chloro-2-isopropoxy-phenyl) -4,5-bis- (4-chloro-phenyl) -4,5-dihydro From -1H-imidazole, prepared as in US Provisional Application, Example 46, which is incorporated herein by reference. HR-MS (ES, m / z) Calcd for C 31 H 31 N 3 0 3 Cl 3 [(M + H) + ] 613.1535, found 613.1543
    [676] Example 38
    [677] In a similar manner to that described in Example 3, the following compounds were added to 4- (4-chloro-phenyl) -5- (4-ethynyl-phenyl) -2- (2-isopropoxy-4-methoxyphenyl)- US, which is incorporated herein by reference, from 4,5-dihydro-1H-imidazole Provisional application, made as in Example 47e:
    [678] a) [5- (4-Chloro-phenyl) -4- (4-ethynyl-phenyl) -2- (2-isopropoxy-4-methoxy-phenyl) -4,5-dihydro-imidazole -1-yl]-(4-pyrrolidin-1-yl-piperidin-1-yl) -methanone. HR-MS (ES, m / z) calc'd for C 37 H 41 N 4 0 3 Cl [(M + H) + ] 625.2940, found 625.2943
    [679]
    [680] b) 4- {4,5-bis- (4-bromo-phenyl) -2- [4-methoxy-2- (2,2,2-trifluoro-ethoxy) -phenyl] -4, 5-dihydro-imidazole-1-carbonyl} -piperazin-2-one [4- (4-chloro-phenyl) -5- (4-ethynyl-phenyl) -2- (2-isopropoxy -4-methoxy-phenyl) -4,5-dihydro-imidazol-1-yl]-(4-pyrrolidin-1-yl) -methanone. HR-MS (ES, m / z) calc'd for C 37 H 41 N 4 0 3 Cl [(M + H) + ] 625.2940, found 625.2943
    [681] Example 39
    [682] In vitro Activity Assay
    [683] The ability of compounds to inhibit the interaction between p53 and MDM2 protein is measured by ELISA (Enzyme-Linked Immuno Sorbent Assay), where the recombinant GST-tag MDM2 is a peptide similar to the MDM2 interaction region of p53. (Boettger et al., J. Mol. Bio. 1997, Vol. 269, pgs. 744-756). The peptide is immobilized on the surface of a 96 well plate via N-terminal biotin that binds to streptavidin-coated wells. MDM2 is added to each well in the presence of anti-MDM2 mouse monoclonal antibody (SMP-14, Santa Cruz Biotech). After removal of unbound MDM2 protein, peroxidase-binding secondary antibodies (anti-mouse IgG, Roche Molecular Biochemicals) were added and the amount of peptide bound MDM2 was added to the peroxidase substrate (MTB Microwell Peroxydase Substrate System, Kirkegaard & Perry). Colorimetric determination with the addition of Labs).
    [684] The test plates were coated with streptavidin (5 mg / ml in PBS) for 2 hours, then washed with PBS (phosphate buffered saline), and 2 mg / ml bovine serum albumin (Sigma) and 0.05% Tween 20 (Sigma) It was prepared by blocking overnight at 4 ° C. with 150 ml of blocking buffer contained in PBS. Biotinylated peptide (1 mM) was added to each well with 50 ml of blocking buffer and washed strongly after 1 hour incubation. Test compounds were diluted in separate 96 well plates and added in duplicate to compound incubation plates containing a mix of MDM2 protein and anti-MDM2 antibody. After 20 minutes incubation, the contents of the plate were transferred to the test plate and incubated for one more hour. Secondary anti-mouse IgG antibodies were placed in advanced test plates and washed three times with 0.05% Tween 20 in PBS. Finally, peroxidase substrate was added to each well and the absorbance was read at 450 nm using a plate reader (MR7000, Dynatech). Inhibitory activity of the test compounds was assessed as the percentage of bound MDM2 in treated versus untreated wells and the IC50 calculated.
    权利要求:
    Claims (38)
    [1" claim-type="Currently amended] Compounds of Formula (I) and pharmaceutically acceptable salts and esters thereof:
    [Formula I]
    [In the meal,
    R is -C = OR 1 ,
    Wherein R 1 is C 1 -C 6 alkyl, -C = CHCOOH, -NHCH 2 CH 2 R 2 , -N (CH 2 CH 2 0H) CH 2 CH 2 0H, -N (CH 3 ) CH 2 CH 2 NCH 3 , —N (CH 3 ) CH 2 CH 2 N (CH 3 ) CH 3 , saturated 4-, 5- and 6-membered rings, and one or more hetero atoms selected from S, N and 0, and C 1 -C 6 alkyl, -C = OR 5 , -OH, C 1 -C 6 alkyl optionally substituted with hydroxy, -NH 2 , -NC 1 -C 6 alkyl, -SO 2 CH 3 , = O,- Saturated and unsaturated 5- and 6- optionally substituted with C 1 -C 6 alkyl optionally substituted with 5 and 6-membered rings comprising at least one hetero atom selected from CH 2 C═OCH 3 and S, N and 0; Is selected from a circle ring, where
    R 5 is H, C 1 -C 6 alkyl, -NH 2 , -NC 1 -C 6 alkyl, C 1 -C 6 alkyl optionally substituted with hydroxy, and C 1 -C 6 alkyl optionally substituted with NH 2 Is selected from,
    R 2 is selected from —N (CH 3 ) CH 3 , —NCH 2 CH 2 NH 2 , —NH 2 , morpholinyl and piperazinyl,
    X 1 , X 2 and X 3 are independent from -OH, C 1 -C 2 alkyl, C 1 -C 6 alkoxy, -Cl, -Br, -F, -CH 2 0CH 3 and -CH 2 0CH 2 CH 3 Or one of X 1 , X 2 or X 3 is H and the other two are hydroxy, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, Cl, Br, F, -CF 3 ,- CH 2 0CH 3 , —CH 2 0CH 2 CH 3 , —OCH 2 CH 2 R 3, —OCH 2 CF 3 , and —OR 4 , or one of X 1 , X 2 or X 3 is H and the other two A dog is taken with two carbon atoms and a bond between them from an optionally substituted benzene ring to form a 5- or 6-membered saturated ring comprising at least one hetero atom selected from S, N and 0, wherein
    R 3 is from an unsaturated 5- and 6-membered ring comprising at least one hetero atom selected from -F, -OCH 3 , -N (CH 3 ) CH 3 , -Cl, -Br, and S, N and 0; Is selected,
    R 4 is a 3- to 5-membered saturated ring,
    Y 1 and Y 2 are independently selected from —Cl, —Br, —NO 2 , —C═N, and —C═CH].
    [2" claim-type="Currently amended] The compound of claim 1, wherein Y 1 and Y 2 are independently selected from —Cl and —Br.
    [3" claim-type="Currently amended] The compound of claim 1, wherein R 1 is morpholinyl, piperazinyl, piperadinyl, cyclopentyl, cyclohexyl, thiophenyl, isoxazolyl, and furanyl, C 1 -C 3 alkyl, —C 1 -C 2 alkoxy, -C = OCH 3 , -SO 2 CH 3 , -C = O, -OH, -CH 2 NH 2 , -C = OCH 2 NH 2 , -C = OCH 2 0H, -C = OC (OH ) CH 2 0H, -CH 2 C (OH) -CH 2 0H, -C = ON (CH 2- ) 2, -C = ONH 2 and -C = ON (CH 3 ) CH 3 with one or more groups Substituted piperazinyl, -C = OCH (CH 3 ) 2 , -CH 2 C = OCH 3 , -CH 2 CH (OH) CH 3 , -CH (CH 3 ) CH (OH) CH 3 and -CH 2 A compound selected from CH 2 0H.
    [4" claim-type="Currently amended] The compound of claim 1, wherein one of the groups X 1 , X 2 and X 3 is H and the other two are hydroxy, C 1 -C 6 alkoxy, Cl, Br, F, —CH 2 0CH 3 , —CH 2 0CH 2 CH 3 , C 1 -C 2 alkyl, —OCH 2 CH 2 R 3 and —OR 4 are independently selected from where R 3 is —F, —OCH 3 , —N (CH 3 ) CH 3 , and S, Is selected from unsaturated five-membered rings containing at least one hetero atom selected from N and 0, wherein R 4 is cyclopentyl or one of the groups X 1 , X 2 or X 3 is H and the other two are 2 Taken together with bonds therebetween from two carbon atoms and an optionally substituted benzene ring to form a five-membered saturated ring comprising at least one hetero atom selected from S, N and 0.
    [5" claim-type="Currently amended] The compound of claim 4, wherein one of X 1 , X 2 and X 3 is H, and the other two are independently selected from —OCH 3 and —CH 2 0CH 2 CH 3 .
    [6" claim-type="Currently amended] The compound of claim 4, wherein one of X 1 , X 2 or X 3 is H and one or both of the others is —OC 1 alkyl, —OC 2 alkyl or —OC 3 alkyl.
    [7" claim-type="Currently amended] The compound of claim 4, wherein R 3 is imidazolyl.
    [8" claim-type="Currently amended] The compound of claim 1, wherein X 3 is H and the groups X 1 and X 2 are taken together with a bond between them from two carbon atoms and an optionally substituted benzene ring to form a six-membered saturated ring comprising a hetero atom O Compound.
    [9" claim-type="Currently amended] The compound of claim 1, wherein one of the groups X 1 , X 2 or X 3 is H in the meta position, the group in the ortho position is selected from C 1 -C 6 alkoxy and —OCH 2 CF 3 , the group in the para position C 1 -C 6 alkoxy.
    [10" claim-type="Currently amended] The compound of claim 9, wherein the X 1 , X 2 or X 3 group at the ortho position is selected from ethoxy, isopropoxy and —OCH 2 CF 3 and the group at the para position is selected from methoxy and ethoxy.
    [11" claim-type="Currently amended] The compound of claim 10, wherein R 1 is selected from piperazinyl and substituted piperazinyl.
    [12" claim-type="Currently amended] The compound of claim 1, wherein one of the groups X 1 , X 2 or X 3 is H in the meta position, the group in the ortho position is C 1 -C 6 alkoxy and the group in the para position is —Cl, —Br or —F Or one of the groups X 1 , X 2 or X 3 is H in the para position, the remaining two groups in the ortho position are C 1 -C 6 alkoxy and the group in the meta position is —Cl, —Br or —F Phosphorus compounds.
    [13" claim-type="Currently amended] Compounds of Formula II and pharmaceutically acceptable salts and esters thereof:
    [Formula II]
    [In the meal,
    R is -C = OR 1 ,
    R 1 comprises C 1 -C 6 alkyl, saturated 5- and 6-membered rings, and at least one hetero atom selected from S, N and 0, and C 1 -C 2 alkyl, C 1 -C 3 alcohol, Saturated 5- and 6-membered optionally substituted with a group selected from 5- and 6-membered rings comprising at least one hetero atom selected from -N (CH 3 ) CH 3 , -C═OCH 3 and S, N and 0; Selected from rings,
    X 4 is C 1 -C 2 alkyl, C 1 -C 6 alkoxy, fluoroethoxy, -Cl, -Br, -F, -OCH 2 C = OOQ, -OC 1 -C 6 alkyl, -OCH 2- Cyclopropyl, -CH 2 0CH 2 -phenyl, saturated and unsaturated 5- and 6-membered rings, saturated and unsaturated 5- and 6-membered rings comprising one or more hetero atoms selected from S, N and 0 and ,
    Wherein Q is selected from H and C 1 -C 6 alkyl,
    Y 1 and Y 2 are independently selected from -Cl, -Br, -NO 2 , -C = N and -C = H,
    Provided that when Y 1 and Y 2 are both -Cl and R 1 is -CH 3 or phenyl, X 4 is not -Cl.
    [14" claim-type="Currently amended] The compound of claim 13, wherein X 4 is selected from —CH 3 , C 1 -C 5 alkoxy, —Cl, —Br, —OCH 2 C═OOQ, phenyl and pyrrolidinyl,
    Wherein Q is H or —CH 2 CH 3 .
    [15" claim-type="Currently amended] The compound of claim 14, wherein X 4 is selected from —CH 3 , C 1 -C 6 alkoxy, —OCH 2 C═OOQ, phenyl and pyrrolidinyl, wherein Q is H or —CH 2 CH 3 .
    [16" claim-type="Currently amended] The piperazinyl, pipepe according to claim 13, wherein R 1 is substituted with -CH (CH 3 ) CH 3 , piperazinyl and -CH 3 , -CH 2 CH 2 0H and -C = OCH 3 . Radiinyl and piperadinyl substituted with a group selected from pyrrolidinyl, piperadinyl and -N (CH 3 ) CH 3 .
    [17" claim-type="Currently amended] The compound of claim 13, wherein C 1 -C 6 alkyl is selected from C 1 alkyl, C 2 alkyl, and C 3 alkyl.
    [18" claim-type="Currently amended] The compound of claim 13, wherein Y 1 and Y 2 are independently selected from —Cl and —Br.
    [19" claim-type="Currently amended] 19. The compound of claim 18, wherein X 4 is C 1 -C 6 alkoxy at the ortho position.
    [20" claim-type="Currently amended] 20. The compound of claim 19, wherein C 1 -C 6 alkoxy is selected from ethoxy, isopropoxy and 2-fluoroethoxy.
    [21" claim-type="Currently amended] The compound of claim 20, wherein R 1 is selected from piperazinyl and substituted piperazinyl.
    [22" claim-type="Currently amended] The compound of claim 1 selected from:
    a) 1- [4,5-bis- (4-chloro-phenyl) -2- (2,4-dimethoxy-phenyl) -4,5-dihydroimidazol-1-yl] -2-methyl- Propane-1-one;
    b) 1- [4,5-bis- (4-chloro-phenyl) -2- (2,4-dimethoxy-phenyl) -4,5-dihydroimidazol-1-yl] ethanone;
    c) 1- [4,5-bis- (4-chloro-phenyl) -2- (2,4-dimethoxy-phenyl) -4,5-dihydroimidazol-1-yl] -2,2- Dimethyl-propan-1-one;
    d) [4,5-bis- (4-chloro-phenyl) -2- (2,4-dimethoxy-phenyl) -4,5-dihydro-imidazol-1-yl] -cyclopentyl-methanone ;
    e) [4,5-bis- (4-chloro-phenyl) -2- (2,4-dimethoxy-phenyl) -4,5-dihydro-imidazol-1-yl] -cyclohexyl-methanone ;
    f) [4,5-bis- (4-chloro-phenyl) -2- (2,4-dimethoxy-phenyl) -4,5-dihydro-imidazol-1-yl] -thiophen-2- Mono-methanone;
    g) [4,5-bis- (4-chloro-phenyl) -2- (2,4-dimethoxy-phenyl) -4,5-dihydro-imidazol-1-yl] -isoxazole-5- Mono-methanone;
    h) [4,5-bis- (4-chloro-phenyl) -2- (2,4-dimethoxy-phenyl) -4,5-dihydro-imidazol-1-yl] -furan-2-yl Methanone;
    i) 1- [4,5-bis- (4-chloro-phenyl) -2- (2,3-dimethoxy-phenyl) -4,5-dihydro-imidazol-1-yl] -2-methyl -Propan-1-one;
    j) [4,5-bis- (4-chloro-phenyl) -2- (2,4-dimethoxy-phenyl) -4,5-dihydro-imidazol-1-yl]-(4-methyl- Piperazin-1-yl) -methanone;
    k) [4,5-bis- (4-chloro-phenyl) -2- (2,4-dimethoxy-phenyl) -4,5-dihydro-imidazol-1-yl] -piperazin-1- Mono-methanone;
    l) [4,5-bis- (4-chloro-phenyl) -2- (2-fluoro-6-methoxy-phenyl) -4,5-dihydroimidazol-1-yl]-[4- (2-hydroxy-ethyl) -piperazin-1-yl) -methanone;
    m) 1- {4- [4,5-bis- (4-bromo-phenyl) -2- (2,4-dimethoxy-phenyl) -4,5-dihydroimidazole-1-carbonyl] -Piperazin-1-yl} -ethanone;
    n) [4,5-bis- (4-bromo-phenyl) -2- (2,4-dimethoxy-phenyl) -4,5-dihydro-imidazol-1-yl]-[4- ( 2-hydroxy-ethyl) -piperazin-1-yl] -methanone;
    o) [4,5-bis- (4-chloro-phenyl) -2- (2-isopropoxy-4-methoxy-phenyl) -4,5-dihydroimidazol-1-yl]-[4 -(2-hydroxy-ethyl) -piperazin-1-yl] -methanone hydrochloride;
    p) [4,5-bis- (4-chloro-phenyl) -2- (2-ethoxy-4-methoxy-phenyl) -4,5-dihydroimidazol-1-yl]-(4- Methanesulfonyl-piperazin-1-yl) -methanone;
    q) [4,5-bis- (4-chloro-phenyl) -2- (2-ethoxy-4-methoxy-phenyl) -4,5-dihydroimidazol-1-yl]-[4- (2-hydroxy-ethyl) -piperazin-1-yl] -methanone;
    r) [4,5-bis- (4-chloro-phenyl) -2- (2-ethoxy-4-methoxy-phenyl) -4,5-dihydroimidazol-1-yl] -morpholine- 4-yl-methanone;
    s) [4,5-bis- (4-chloro-phenyl) -2- (2-ethoxy-4-methoxy-phenyl) -4,5-dihydroimidazol-1-yl]-(4- Methyl-piperazin-1-yl) -methanone;
    t) 1- {4- [4,5-bis- (4-chloro-phenyl) -2- (2-ethoxy-4-methoxy-phenyl) -4,5-dihydroimidazole-1-car Carbonyl] -piperazin-1-yl} -ethanone;
    u) 4- [4,5-bis- (4-chloro-phenyl) -2- (2-ethoxy-4-methoxy-phenyl) -4,5-dihydroimidazole-1-carbonyl]- Piperazin-2-one;
    v) [4,5-bis- (4-chloro-phenyl) -2- (2-isopropoxy-4-methoxy-phenyl) -4,5-dihydroimidazol-1-yl] -piperazine -1-yl-methanone;
    w) 1- {4- [4,5-bis- (4-chloro-phenyl) -2- (2-isopropoxy-4-methoxy-phenyl) -4,5-dihydro-imidazole-1 -Carbonyl] -piperazin-1-yl} -ethanone;
    x) [4,5-bis- (4-chloro-phenyl) -2- (2-isopropoxy-4-methoxy-phenyl) -4,5-dihydroimidazol-1-yl]-(4 Methanesulfonyl-piperazin-1-yl) -methanone;
    y) [4,5-bis- (4-chloro-phenyl) -2- (2-isopropoxy-4-methoxy-phenyl) -4,5-dihydroimidazol-1-yl]-(2 , 5-dimethyl-piperazin-1-yl) -methanone;
    z) 4,5-bis- (4-chloro-phenyl) -2- (2-isopropoxy-4-methoxy-phenyl) -4,5-dihydroimidazole-1-carboxylic acid bis- ( 2-hydroxy-ethyl) -amide;
    aa) [4,5-bis- (4-chloro-phenyl) -2- (2-isopropoxy-4-methoxy-phenyl) -4,5-dihydroimidazol-1-yl]-(4 -Ethyl-piperazin-1-yl) -methanone;
    bb) [1,4 '] bipiperidinyl-1'-yl- [4,5-bis- (4-chloro-phenyl) -2- (2-isopropoxy-4-methoxy-phenyl) -4 , 5-dihydro-imidazol-1-yl] -methanone;
    cc) [4,5-bis- (4-chloro-phenyl) -2- (2-isopropoxy-4-methoxy-phenyl) -4,5-dihydroimidazol-1-yl]-(4 -Pyrrolidin-1-yl-piperidin-1-yl) -methanone;
    dd) [4,5-bis- (4-chloro-phenyl) -2- (2-isopropoxy-4-methoxy-phenyl) -4,5-dihydroimidazol-1-yl]-(4 -Dimethylamino-piperidin-1-yl) -methanone;
    ee) [4,5-bis- (4-chloro-phenyl) -2- (2-isopropoxy-4-methoxy-phenyl) -4,5-dihydroimidazol-1-yl] -morpholine -4-yl-methanone;
    ff) [4,5-bis- (4-chloro-phenyl) -2- (2-isopropoxy-4-methoxy-phenyl) -4,5-dihydroimidazol-1-yl]-(4 -Isopropyl-piperazin-1-yl) -methanone;
    gg) 4- [4,5-bis- (4-chloro-phenyl) -2- (2-isopropoxy-4-methoxy-phenyl) -4,5-dihydro-imidazole-1-carbonyl ] -Piperazin-2-one;
    hh) [4,5-bis- (4-chloro-phenyl) -2- (2-isopropoxy-4-methoxy-phenyl) -4,5-dihydroimidazol-1-yl]-(4 -Hydroxymethyl-piperidin-1-yl) -methanone;
    ii) [4,5-bis- (4-chloro-phenyl) -2- (2-isopropoxy-4-methoxy-phenyl) -4,5-dihydroimidazol-1-yl]-[4 -(2-hydroxy-ethyl) -piperidin-1-yl] -methanone;
    jj) [4,5-bis- (4-chloro-phenyl) -2- (2-isopropoxy-4-methoxy-phenyl) -4,5-dihydroimidazol-1-yl]-(3 -Methyl-piperazin-1-yl) -methanone;
    kk) 1- {4- [4,5-bis- (4-chloro-phenyl) -2- (2-isopropoxy-4-methoxy-phenyl) -4,5-dihydro-imidazole-1 -Carbonyl] -2-methyl-piperazin-1-yl} -ethanone;
    ll) [4,5-bis- (4-chloro-phenyl) -2- (2-isopropoxy-4-methoxy-phenyl) -4,5-dihydroimidazol-1-yl]-(4 Methanesulfonyl-3-methyl-piperazin-1-yl) -methanone;
    mm) [4,5-bis- (4-chloro-phenyl) -2- (2-isopropoxy-4-methoxy-phenyl) -4,5-dihydroimidazol-1-yl]-(4 -Hydroxy-piperidin-1-yl) -methanone;
    nn) (4-aminomethyl-piperidin-1-yl)-[4,5-bis- (4-chloro-phenyl) -2- (2-isopropoxy-4-methoxy-phenyl) -4 , 5-dihydro-imidazol-1-yl] -methanone;
    oo) [4,5-bis- (4-bromo-phenyl) -2- (2-ethoxy-4-methoxy-phenyl) -4,5-dihydroimidazol-1-yl]-[4 -(2-hydroxy-ethyl) -piperazin-1-yl] -methanone;
    pp) [4,5-bis- (4-bromo-phenyl) -2- (2-ethoxy-4-methoxy-phenyl) -4,5-dihydroimidazol-1-yl] -piperazine -1-yl-methanone;
    qq) [4,5-bis- (4-bromo-phenyl) -2- (2-ethoxy-4-methoxy-phenyl) -4,5-dihydroimidazol-1-yl]-(4 Methanesulfonyl-piperazin-1-yl) -methanone;
    rr) 1- {4- [4,5-bis- (4-bromo-phenyl) -2- (2-ethoxy-4-methoxy-phenyl) -4,5-dihydroimidazole-1- Carbonyl] -piperazin-1-yl} -ethanone;
    ss) [4,5-bis- (4-bromo-phenyl) -2- (2-ethoxy-4-methoxy-phenyl) -4,5-dihydroimidazol-1-yl]-(4 -Methyl-piperazin-1-yl) -methanone;
    tt) 4- [4,5-bis- (4-bromo-phenyl) -2- (2-ethoxy-4-methoxy-phenyl) -4,5-dihydroimidazole-1-carbonyl] Piperazine-1-carbaldehyde;
    uu) [4,5-bis- (4-bromo-phenyl) -2- (2-ethoxy-4-methoxy-phenyl) -4,5-dihydroimidazol-1-yl]-(4 -Pyrrolidin-1-yl-piperidin-1-yl) -methanone;
    vv) [4,5-bis- (4-bromo-phenyl) -2- (2-ethoxy-4-methoxy-phenyl) -4,5-dihydroimidazol-1-yl]-(4 -Dimethylamino-piperidin-1-yl) -methanone;
    ww) [4,5-bis- (4-bromo-phenyl) -2- (2-ethoxy-4-methoxy-phenyl) -4,5-dihydroimidazol-1-yl]-(4 -Isopropyl-piperazin-1-yl) -methanone;
    xx) 4- [4,5-bis- (4-bromo-phenyl) -2- (2-ethoxy-4-methoxy-phenyl) -4,5-dihydroimidazole-1-carbonyl] Piperazin-2-one; And
    yy) [4,5-bis- (4-bromo-phenyl) -2- (2-isopropoxy-4-methoxy-phenyl) -4,5-dihydroimidazol-1-yl] -pipe Razin-1-yl-methanone.
    [23" claim-type="Currently amended] The compound of claim 1 selected from the group:
    a) 1- {4- [4,5-bis- (4-bromo-phenyl) -2- (2-isopropoxy-4-methoxy-phenyl) -4,5-dihydro-imidazole- 1-carbonyl] -piperazin-1-yl] -ethanone;
    b) [4,5-bis- (4-bromo-phenyl) -2- (2-isopropoxy-4-methoxy-phenyl) -4,5-dihydroimidazol-1-yl]-( 4-methanesulfonyl-piperazin-1-yl) -methanone;
    c) [4,5-bis- (4-bromo-phenyl) -2- (2-isopropoxy-4-methoxy-phenyl) -4,5-dihydroimidazol-1-yl]-( 4-methyl-piperazin-1-yl) -methanone;
    d) [4,5-bis- (4-bromo-phenyl) -2- (2-isopropoxy-4-methoxy-phenyl) -4,5-dihydroimidazol-1-yl] -mor Folin-1-yl-methanone;
    e) [1,4 '] bipiperidinyl-1'-yl- [4,5-bis- (4-bromo-phenyl) -2- (2-isopropoxy-4-methoxy-phenyl)- 4,5-dihydro-imidazol-1-yl] -methanone;
    f) [4,5-bis- (4-bromo-phenyl) -2- (2-isopropoxy-4-methoxy-phenyl) -4,5-dihydroimidazol-1-yl]-( 4-ethyl-piperazin-1-yl) -methanone;
    g) 4- [4,5-bis- (4-bromo-phenyl) -2- (2-isopropoxy-4-methoxy-phenyl) -4,5-dihydro-imidazole-1-car Carbonyl] -piperazin-2-one;
    h) [4,5-bis- (4-cyano-phenyl) -2- (2-isopropoxy-4-methoxy-phenyl) -4,5-dihydroimidazol-1-yl] -pipe Razin-1-yl-methanone;
    i) 1- (4- {4,5-bis- (4-chloro-phenyl) -2- [4-methoxy-2- (2-methoxy-ethoxy) phenyl] -4,5-dihydro -Imidazol-1-carbonyl} -piperazin-1-yl) -ethanone;
    j) 1- (4- {4,5-bis- (4-chloro-phenyl) -2- [2- (2-fluoro-ethoxy) -4-methoxy-phenyl] -4,5-di Hydro-imidazol-1-carbonyl} -piperazin-1-yl) -ethanone;
    k) 4- {4,5-bis- (4-chloro-phenyl) -2- [2- (2-fluoro-ethoxy) -4-methoxy-phenyl] -4,5-dihydro-imi Dazol-1-carbonyl} -piperazin-2-one;
    l) [4,5-bis- (4-chloro-phenyl) -2- (2-ethoxy-4-methoxy-phenyl) -4,5-dihydroimidazol-1-yl] -piperazine- 1-yl-methanone hydrochloride;
    m) 4,5-bis- (4-chloro-phenyl) -2- (2-ethoxy-4-methoxy-phenyl) -4,5-dihydroimidazole-1-carboxylic acid methyl- (2 -Methylamino-ethyl) -amide, trifluoroacetic acid salt;
    n) 4,5-bis- (4-chloro-phenyl) -2- (2-ethoxy-4-methoxy-phenyl) -4,5-dihydroimidazole-1-carboxylic acid (2-dimethyl Amino-ethyl) -methyl-amide, trifluoroacetic acid salt;
    o) 4,5-bis- (4-chloro-phenyl) -2- (2-ethoxy-4-methoxy-phenyl) -4,5-dihydroimidazole-1-carboxylic acid (2-dimethyl Amino-ethyl) -amide, trifluoroacetic acid salt;
    p) 4,5-bis- (4-chloro-phenyl) -2- (2-ethoxy-4-methoxy-phenyl) -4,5-dihydroimidazole-1-carboxylic acid (2-amino -Ethyl) -amide, trifluoroacetic acid salt;
    q) [4,5-bis- (4-chloro-phenyl) -2- (2-ethoxy-4-methoxy-phenyl) -4,5-dihydroimidazol-1-yl]-(4- Pyrrolidin-1-yl-piperidin-1-yl) -methanone hydrochloride;
    r) [4,5-bis- (4-chloro-phenyl) -2- (4-methoxy-2-propoxy-phenyl) -4,5-dihydroimidazol-1-yl] -piperazine- 1-yl-methanone, trifluoro acetic acid salt;
    s) [4,5-bis- (4-chloro-phenyl) -2- (2-isopropoxy-4-methoxy-phenyl) -4,5-dihydroimidazol-1-yl]-(4 -Methyl-piperazin-1-yl) -methanone hydrochloride;
    t) 4,5-bis- (4-chloro-phenyl) -2- (2-isopropoxy-4-methoxy-phenyl) -4,5-dihydroimidazole-1-carboxylic acid (2- Morpholin-1 -yl-ethyl) -amide hydrochloride;
    u) 4,5-bis- (4-chloro-phenyl) -2- (2-isopropoxy-4-methoxy-phenyl) -4,5-dihydroimidazole-1-carboxylic acid (2- Piperazin-1-yl-ethyl) -amide hydrochloride;
    v) [4,5-bis- (4-chloro-phenyl) -2- (2-isobutoxy-4-methoxy-phenyl) -4,5-dihydroimidazol-1-yl] -piperazine- 1-yl-methanone hydrochloride;
    w) [4,5-bis- (4-chloro-phenyl) -2- (2-isopropoxy-4-methoxy-phenyl) -4,5-dihydroimidazol-1-yl]-(3 -Methyl-piperazin-1-yl) -methanone hydrochloride;
    x) {4,5-bis- (4-chloro-phenyl) -2- [4-methoxy-2- (2-methoxy-ethoxy) -phenyl] -4,5-dihydro-imidazole- 1-yl] -piperazin-1-yl-methanone, trifluoroacetic acid salt;
    y) {4,5-bis- (4-chloro-phenyl) -2- [2- (2-fluoro-ethoxy) -4-methoxy-phenyl] -4,5-dihydro-imidazole- 1-yl} -piperazin-1-yl-methanone;
    z) {4,5-bis- (4-chloro-phenyl) -2- [2- (2-fluoro-ethoxy) -4-methoxy-phenyl] -4,5-dihydro-imidazole- 1-yl]-(4-pyrrolidin-1-yl-piperidin-1-yl) -methanone hydrochloride;
    aa) 2-amino-1- {4- [4,5-bis- (4-chloro-phenyl) -2- (2-isopropoxy-4-methoxyphenyl) -4,5-dihydro-imi Dazol-1-carbonyl] -piperazin-1-yl] -ethanone;
    bb) 1- {4- [4,5-bis- (4-chloro-phenyl) -2- (2-isopropoxy-4-methoxy-phenyl) -4,5-dihydro-imidazole-1 -Carbonyl] -piperazin-1-yl} -2-hydroxy-ethanone;
    cc) 1- {4- [4,5-bis- (4-chloro-phenyl) -2- (2-isopropoxy-4-methoxy-phenyl) -4,5-dihydro-imidazole-1 -Carbonyl] -piperazin-1-yl} -2,3-dihydroxy-propan-1-one;
    dd) [4,5-bis- (4-chloro-phenyl) -2- (2-isopropoxy-4-methoxy-phenyl) -4,5-dihydroimidazol-1-yl]-[4 -(2,3-dihydroxy-propyl) -piperazin-1-yl] -methanone;
    ee) 4- [4,5-bis- (4-chloro-phenyl) -2- (2-isopropoxy-4-methoxy-phenyl) -4,5-dihydro-imidazole-1-carbonyl ] -Piperazine-1-carboxylic acid dimethylamide;
    ff) 4- [4,5-bis- (4-chloro-phenyl) -2- (2-isopropoxy-4-methoxy-phenyl) -4,5-dihydro-imidazole-1-carbonyl ] -Piperazine-1-carboxylic acid amide;
    gg) [4,5-bis- (4-chloro-phenyl) -2- (2,4-diethoxy-phenyl) -4,5-dihydro-imidazol-1-yl] -piperazin-1- Mono-methanone;
    hh) [4,5-bis- (4-chloro-phenyl) -2- (2,4-diethoxy-phenyl) -4,5-dihydro-imidazol-1-yl] morpholin-4-yl Methanone;
    ii) [4,5-bis- (4-chloro-phenyl) -2- (2,4-diethoxy-phenyl) -4,5-dihydro-imidazol-1-yl]-[4- (2 -Hydroxy-ethyl) -piperazin-1-yl] -methanone;
    jj) [4,5-bis- (4-chloro-phenyl) -2- (2,4-diethoxy-phenyl) -4,5-dihydro-imidazol-1-yl]-(4-methyl- Piperazin-1-yl) -methanone;
    kk) 1- {4- [4,5-bis- (4-chloro-phenyl) -2- (2,4-diethoxy-phenyl) -4,5-dihydroimidazole-1-carbonyl]- Piperazin-1-yl} -ethanone;
    ll) [4,5-bis- (4-chloro-phenyl) -2- (2,4-diethoxy-phenyl) -4,5-dihydro-imidazol-1-yl]-(4-methanesulphate Ponyl-piperazin-1-yl) -methanone;
    mm) [4,5-bis- (4-chloro-phenyl) -2- (2,4-diethoxy-phenyl) -4,5-dihydro-imidazol-1-yl]-(4-pyrroli Din-1-yl-piperidin-1-yl) -methanone;
    nn) [4,5-bis- (4-bromo-phenyl) -2- (2,4-diethoxy-phenyl) -4,5-dihydro-imidazol-1-yl]-(4-methyl -Piperazin-1-yl) -methanone;
    oo) [4,5-bis- (4-bromo-phenyl) -2- (2,4-diethoxy-phenyl) -4,5-dihydro-imidazol-1-yl]-(4-ethyl -Piperazin-1-yl) -methanone;
    pp) [4,5-bis- (4-bromo-phenyl) -2- (2,4-diethoxy-phenyl) -4,5-dihydro-imidazol-1-yl] -morpholine-1 -Yl-methanone;
    qq) 4- [4,5-bis- (4-chloro-phenyl) -2- (2,4-diethoxy-phenyl) -4,5-dihydro-imidazole-1-carbonyl] -piperazine -1-carboxylic acid amide;
    rr) 4- [4,5-bis- (4-chloro-phenyl) -2- (2,4-diethoxy-phenyl) -4,5-dihydro-imidazole-1 -carbonyl] -piperazine -1-carboxylic acid dimethylamide;
    ss) [4,5-bis- (4-chloro-phenyl) -2- (4-dimethylamino-2-ethoxy-phenyl) -4,5-dihydro-imidazol-1-yl] -piperazine -1-yl-methanone;
    tt) [4,5-bis- (4-chloro-phenyl) -2- (2-ethoxy-4-ethyl-phenyl) -4,5-dihydroimidazol-1-yl] -piperazine-1 -Yl-methanone;
    uu) [4,5-bis- (4-chloro-phenyl) -2- (2-ethoxy-4-methyl-phenyl) -4,5-dihydroimidazol-1-yl] -piperazine-1 -Yl-methanone;
    vv) [4,5-bis- (4-chloro-phenyl) -2- (4-ethyl-2-isopropoxy-phenyl) -4,5-dihydroimidazol-1-yl] -piperazine- 1-yl-methanone;
    ww) [4,5-bis- (4-chloro-phenyl) -2- (2-isopropoxy-4-methyl-phenyl) -4,5-dihydroimidazol-1-yl] -piperazine- 1-yl-methanone;
    xx) 1- {4- [4,5-bis- (4-chloro-phenyl) -2- (4-dimethylamino-2-ethoxyphenyl) -4,5-dihydro-imidazole-1-car Bonyll-piperazin-1-yl] -ethanone; And
    yy) [4,5-bis- (4-chloro-phenyl) -2- (2-ethoxy-5-methyl-phenyl) -4,5-dihydroimidazol-1-yl] -piperazine-1 -Yl-methanone, trifluoroacetic acid salt.
    [24" claim-type="Currently amended] The compound of claim 1 selected from the group:
    a) [4,5-bis- (4-chloro-phenyl) -2- (2-ethoxy-4-fluoro-phenyl) -4,5-dihydroimidazol-1-yl]-(4- Pyrrolidin-1-yl-piperidin-1-yl) -methanone;
    b) [4,5-bis- (4-chloro-phenyl) -2- (2-ethoxy-4-fluoro-phenyl) -4,5-dihydroimidazol-1-yl]-(4- Dimethylamino-piperidin-1-yl) -methanone;
    c) [4,5-bis- (4-chloro-phenyl) -2- (2-ethoxy-4-fluoro-phenyl) -4,5-dihydroimidazol-1-yl] -piperazine- 1-yl-methanone;
    d) [4,5-bis- (4-chloro-phenyl) -2- (4-fluoro-2-isopropoxy-phenyl) -4,5-dihydroimidazol-1-yl]-(4 -Pyrrolidin-1-yl-piperidin-1-yl) -methanone;
    e) [4,5-bis- (4-chloro-phenyl) -2- (4-fluoro-2-isopropoxy-phenyl) -4,5-dihydroimidazol-1-yl]-(4 -Dimethylamino-piperidin-1-yl) -methanone;
    f) [4,5-bis- (4-chloro-phenyl) -2- (4-fluoro-2-isopropoxy-phenyl) -4,5-dihydroimidazol-1-yl]-(4 -Methyl-piperazin-1-yl) -methanone;
    g) [4,5-bis- (4-chloro-phenyl) -2- (4-fluoro-2-isopropoxy-phenyl) -4,5-dihydroimidazol-1-yl] -piperazine -1-yl-methanone;
    h) [4,5-bis- (4-chloro-phenyl) -2- (4-fluoro-2-isopropoxy-phenyl) -4,5-dihydroimidazol-1-yl]-(4 Methanesulfonyl-piperazin-1-yl) -methanone;
    i) 4- [4,5-bis- (4-chloro-phenyl) -2- (4-fluoro-2-isopropoxy-phenyl) -4,5-dihydroimidazole-1-carbonyl] Piperazin-2-one;
    j) [4,5-bis- (4-chloro-phenyl) -2-chroman-8-yl-4,5-dihydro-imidazol-1-yl] piperazin-1-yl-methanone;
    k) 4- [4,5-bis- (4-bromo-phenyl) -2- (2-ethoxy-4-fluoro-phenyl) -4,5-dihydroimidazole-1-carbonyl] Piperazin-2-one;
    l) [4,5-bis- (4-bromo-phenyl) -2- (2-ethoxy-4-fluoro-phenyl) -4,5-dihydroimidazol-1-yl] -morpholine -4-yl-methanone;
    m) [4,5-bis- (4-bromo-phenyl) -2- (2-ethoxy-4-fluoro-phenyl) -4,5-dihydroimidazol-1-yl]-(4 -Pyrrolidin-1-yl-piperidin-1-yl-methanone;
    n) [4,5-bis- (4-bromo-phenyl) -2- (2-ethoxy-4-fluoro-phenyl) -4,5-dihydroimidazol-1-yl]-(4 -Dimethylamino-piperidin-1-yl) -methanone;
    o) [4,5-bis- (4-bromo-phenyl) -2- (2-ethoxy-4-fluoro-phenyl) -4,5-dihydroimidazol-1-yl] -piperazine -1-yl-methanone;
    p) [4,5-bis- (4-chloro-phenyl) -2- (2-cyclopentyloxy-4-methoxy-phenyl) -4,5-dihydro-imidazol-1-yl] -pipe Razin-1-yl-methanone;
    q) {4,5-bis- (4-chloro-phenyl) -2- [2- (2-dimethylamino-ethoxy) -4-methoxy-phenyl] -4,5-dihydro-imidazole- 1-yl} -piperazin-1-yl-methanone;
    r) {4,5-bis- (4-chloro-phenyl) -2- [2- (2-imidazol-1-yl-ethoxy) -4-methoxyphenyl] -4,5-dihydro- Imidazol-1-yl} -piperazin-1-yl-methanone;
    s) [2- (4-Chloro-2-ethoxy-phenyl) -4,5-bis- (4-chloro-phenyl) -4,5-dihydroimidazol-1-yl] -piperazine-1 -Yl-methanone hydrochloride;
    t) [2- (4-chloro-2-ethoxy-phenyl) -4,5-bis- (4-chloro-phenyl) -4,5-dihydroimidazol-1-yl]-(4-methyl -Piperazin-1-yl) -methanone hydrochloride;
    u) [2- (4-chloro-2-ethoxy-phenyl) -4,5-bis- (4-chloro-phenyl) -4,5-dihydroimidazol-1-yl]-(4-py Ralidin-1-yl-piperidin-1-yl) -methanone hydrochloride;
    v) 2- (4-Chloro-2-ethoxy-phenyl) -4,5-bis- (4-chloro-phenyl) -4,5-dihydroimidazol-1-yl] -morpholin-4- Mono-methanone;
    w) 1- {4- [2- (4-chloro-2-ethoxy-phenyl) -4,5-bis- (4-chloro-phenyl) -4,5-dihydroimidazole-1-carbonyl ] -Piperazin-1-yl} -ethanone;
    x) [2- (4-chloro-2-ethoxy-phenyl) -4,5-bis- (4-chloro-phenyl) -4,5-dihydroimidazol-1-yl]-[4- ( 2-hydroxy-ethyl) -piperazin-1-yl] -methanone hydrochloride;
    y) 4- [2- (4-chloro-2-ethoxy-phenyl) -4,5-bis- (4-chloro-phenyl) -4,5-dihydroimidazole-1-carbonyl] -pipe Razin-2-one;
    z) [4,5-bis- (4-chloro-phenyl) -2- (4-ethoxy-2-isopropoxy-phenyl) -4,5-dihydroimidazol-1-yl] -piperazine -1-yl-methanone;
    aa) [4,5-bis- (4-chloro-phenyl) -2- (2-ethoxy-5-methoxy-phenyl) -4,5-dihydroimidazol-1-yl] -piperazine- 1-yl-methanone, trifluoroacetic acid salt;
    bb) [4,5-bis- (4-chloro-phenyl) -2- (2-ethoxy-5-methoxy-phenyl) -4,5-dihydroimidazol-1-yl]-(4- Methanesulfonyl-piperazin-1-yl) -methanone;
    cc) [4,5-bis- (4-chloro-phenyl) -2- (2-ethoxy-5-methoxy-phenyl) -4,5-dihydroimidazol-1-yl]-[4- (2-hydroxy-ethyl) -piperazin-1-yl] -methanone hydrochloride;
    dd) [4,5-bis- (4-chloro-phenyl) -2- (2,5-diethoxy-phenyl) -4,5-dihydro-imidazol-1-yl] -piperazin-1- Mono-methanone hydrochloride;
    ee) [4,5-bis- (4-chloro-phenyl) -2- (2,5-diethoxy-phenyl) -4,5-dihydro-imidazol-1-yl]-(4-methanesulphate) Ponyl-piperazin-1-yl) -methanone;
    ff) [4,5-bis- (4-chloro-phenyl) -2- (4-ethoxy-2-isopropoxy-phenyl) -4,5-dihydroimidazol-1-yl]-[4 -(2-hydroxy-ethyl) -piperazin-1-yl] -methanone;
    gg) 4- [4,5-bis- (4-chloro-phenyl) -2- (4-ethoxy-2-isopropoxy-phenyl) -4,5-dihydroimidazole-1-carbonyl] Piperazin-2-one;
    hh) [4,5-bis- (4-chloro-phenyl) -2- (5-ethoxy-2-isopropoxy-phenyl) -4,5-dihydroimidazol-1-yl] -piperazine -1-yl-methanone;
    ii) [4,5-bis- (4-chloro-phenyl) -2- (5-ethoxy-2-isopropoxy-phenyl) -4,5-dihydroimidazol-1-yl]-(4 Methanesulfonyl-piperazin-1-yl) -methanone;
    jj) [4,5-bis- (4-chloro-phenyl) -2- (5-ethoxy-2-isopropoxy-phenyl) -4,5-dihydroimidazol-1-yl]-[4 -(2-hydroxy-ethyl) -piperazin-1-yl] -methanone hydrochloride;
    kk) 1- {4- [4,5-bis- (4-chloro-phenyl) -2- (4-ethoxy-2-isopropoxy-phenyl) -4,5-dihydro-imidazole-1 -Carbonyl] -piperazin-1-yl} -ethanone;
    ll) 1- {4- [4,5-bis- (4-chloro-phenyl) -2- (5-ethoxy-2-propoxy-phenyl) -4,5-dihydro-imidazole-1- Carbonyl] -piperazin-1-yl] -ethanone;
    mm) [4,5-bis- (4-chloro-phenyl) -2- (4-ethoxy-2-isopropoxy-phenyl) -4,5-dihydroimidazol-1-yl]-(4 -Pyrrolidin-1-yl-piperidin-1-yl) -methanone;
    nn) [4,5-bis- (4-chloro-phenyl) -2- (2-isopropoxy-5-methoxy-phenyl) -4,5-dihydroimidazol-1-yl] -piperazine -1-yl-methanone, trifluoroacetic acid salt;
    oo) [4,5-bis- (4-chloro-phenyl) -2- (2,4-diisopropoxy-phenyl) -4,5-dihydroimidazol-1-yl] -piperazine-1 -Yl-methanone;
    pp) [4,5-bis- (4-chloro-phenyl) -2- (2,5-diisopropoxy-phenyl) -4,5-dihydroimidazol-1-yl] -piperazin-1 -Yl-methanone hydrochloride;
    qq) 1- [4,5-bis- (4-chloro-phenyl) -2- (2-methoxy-5-morpholin-4-yl-methylphenyl) -4,5-dihydro-imidazole-1 -Yl] -2-methyl-propan-1-one;
    rr) 1- [4,5-bis- (4-chloro-phenyl) -2- (3-hydroxymethyl-5-methoxy-phenyl) -4,5-dihydro-imidazol-1-yl] -2-methyl-propan-1-one;
    ss) 1- [4,5-bis- (4-chloro-phenyl) -2- (3-hydroxymethyl-5-methoxymethyl-phenyl) -4,5-dihydro-imidazol-1-yl ] -Ethanone;
    tt) 1- [4,5-bis- (4-chloro-phenyl) -2- (3-methoxy-5-methoxymethyl-phenyl) -4,5-dihydro-imidazol-1-yl] -2-methyl-propan-1-one;
    uu) 3- [4,5-bis- (4-chloro-phenyl) -1-isobutyryl-4,5-dihydro-1H-imidazol-2-yl] -5-methoxymethyl-benzoic acid;
    vv) 1- [4,5-bis- (4-chloro-phenyl) -2- (5-ethoxymethyl-2,4-dimethoxy-phenyl) -4,5-dihydro-imidazole-1- Il] -2-methyl-propan-1-one;
    ww) [4,5-bis- (4-chloro-phenyl) -2- (2-ethoxy-6-methoxy-phenyl) -4,5-dihydroimidazol-1-yl] -piperazine- 1-yl-methanone; And
    xx) [4,5-bis- (4-chloro-phenyl) -2- (5-ethoxymethyl-2,4-dimethoxy-phenyl) -4,5-dihydro-imidazol-1-yl] Piperazin-1-yl-methanone.
    [25" claim-type="Currently amended] The compound of claim 1 selected from the group:
    a) [4,5-bis- (4-chloro-phenyl) -2- (2-isopropoxy-4-methoxy-phenyl) -4,5-dihydroimidazol-1-yl]-[4 -(2-hydroxy-propyl) -piperazin-1-yl] -methanone;
    b) [4,5-bis- (4-chloro-phenyl) -2- (2-isopropoxy-4-methoxy-phenyl) -4,5-dihydroimidazol-1-yl] -threo [ 4- (2-hydroxy-1-methyl-propyl) -piperazin-1-yl] methanone;
    c) [4,5-bis- (4-chloro-phenyl) -2- (2-isopropoxy-4-methoxy-phenyl) -4,5-dihydroimidazol-1-yl] -erythro [ 4- (2-hydroxy-1-methyl-propyl) -piperazin-1-yl] methanone;
    d) 1- {4- [4,5-bis- (4-chloro-phenyl) -2- (2-isopropoxy-4-methoxy-phenyl) -4,5-dihydro-imidazole-1 -Carbonyl] -piperazin-1-yl} -propan-2-one;
    e) [4,5-bis- (4-chloro-phenyl) -2- (2-isopropoxy-4-methoxy-phenyl) -4,5-dihydroimidazol-1-yl]-[1 , 4] diazepan-1-yl-methanone;
    f) 4- [4,5-bis- (4-chloro-phenyl) -2- (2-isopropoxy-4-methoxy-phenyl) -4,5-dihydro-imidazole-1-carbonyl ] -1-methyl-piperazin-2-one;
    g) 1- {4- [4,5-bis- (4-chloro-phenyl) -2- (2-isopropoxy-4-methoxy-phenyl) -4,5-dihydro-imidazole-1 -Carbonyl] -piperazin-1-yl} -2-methyl-propan-1-one;
    h) 4- [4,5-bis- (4-chloro-phenyl) -2- (2-isopropoxy-4-methoxy-phenyl) -4,5-dihydro-imidazole-1-carbonyl ] -Piperazine-1-carbaldehyde;
    i) 4- {4,5-bis- (4-chloro-phenyl) -2- [4-methoxy-2- (2,2,2-trifluoro-ethoxy) phenyl] -4,5- Dihydro-imidazol-1-carbonyl} -piperazin-2-one;
    j) 4- {4,5-bis- (4-bromo-phenyl) -2- [4-methoxy-2- (2,2,2-trifluoro-ethoxy) phenyl] -4,5 -Dihydro-imidazol-1-carbonyl} -piperazin-2-one;
    k) [4,5-bis- (4-ethynyl-phenyl) -2- (2-isopropoxy-4-methoxy-phenyl) -4,5-dihydro-imidazol-1-yl]- (4-pyrrolidin-1-yl-piperidin-1-yl) -methanone;
    l) 1- {4- [2- (5-chloro-2-isopropoxy-phenyl) -4,5-bis- (4-chloro-phenyl) -4,5-dihydro-imidazole-1- Carbonyl] -piperazin-1-yl} -ethanone; And
    m) [5- (4-chloro-phenyl) -4- (4-ethynyl-phenyl) -2- (2-isopropoxy-4-methoxy-phenyl) -4,5-dihydro-imidazole -1-yl]-(4-pyrrolidin-1-yl-piperidin-1-yl) methanone.
    [26" claim-type="Currently amended] A compound according to claim 13 selected from the group:
    a) 1- [4,5-bis- (4-chloro-phenyl) -2- (2-methoxy-phenyl) -4,5-dihydro-imidazol-1-yl] -2-methyl-propane -1-one;
    b) 1- [4,5-bis- (4-chloro-phenyl) -2-p-tolyl-4,5-dihydro-imidazol-1-yl] -ethanone;
    c) {4- [4,5-bis- (4-chloro-phenyl) -1-isobutyryl-4,5-dihydro-1H-imidazol-2-yl] phenoxy} -acetic acid ethyl ester;
    d) {4- [4,5-bis- (4-chloro-phenyl) -1-isobutyryl-4,5-dihydro-1H-imidazol-2-yl] phenoxy} -acetic acid;
    e) 2-methyl-1- [2,4,5-tris- (4-chloro-phenyl) -4,5-dihydro-imidazol-1-yl] -propan-1-one;
    f) 1- [4,5-bis- (4-chloro-phenyl) -2- (4-methoxy-phenyl) -4,5-dihydro-imidazol-1-yl] -ethanone;
    g) [2- (2-Chloro-phenyl) -4,5-bis- (4-chloro-phenyl) -4,5-dihydro-imidazol-1-yl] -piperazin-1-yl-methane On;
    h) [2- (3-Bromo-phenyl) -4,5-bis- (4-chloro-phenyl) -4,5-dihydro-imidazol-1-yl] -piperazin-1-yl- Methanone;
    i) [2-biphenyl-3-yl-4,5-bis- (4-chloro-phenyl) -4,5-dihydro-imidazol-1-yl]-(4-methyl-piperazine-1 -Yl) -methanone;
    j) [4,5-bis- (4-chloro-phenyl) -2- (3-pyrrolidin-1-yl-phenyl) -4,5-dihydroimidazol-1-yl] -piperazine- 1-yl-methanone;
    k) [4,5-bis- (4-bromo-phenyl) -2- (2-methoxy-phenyl) -4,5-dihydro-imidazol-1-yl]-[4- (2- Hydroxy-ethyl) -piperazin-1-yl] -methanone;
    l) 1- [5- (4-chloro-phenyl) -2- (4-methoxy-phenyl) -4- (4-nitro-phenyl) -4,5-dihydro-imidazol-1-yl] -Methyl-propan-1-one;
    m) 1- [4- (4-chloro-phenyl) -2- (4-methoxy-phenyl) -5- (4-nitro-phenyl) -4,5-dihydro-imidazol-1-yl] -2-methyl-propan-1-one;
    n) 1- [4,5-bis- (4-chloro-phenyl) -2- (2-isopropoxy-phenyl) -4,5-dihydro-imidazol-1-yl] -2-methyl- Propane-1-one;
    o) [4,5-bis- (4-chloro-phenyl) -2- (2-isopropoxy-phenyl) -4,5-dihydro-imidazol-1-yl]-(4-pyrrolidine -1-yl-piperidin-1-yl) -methanone;
    p) [4,5-bis- (4-chloro-phenyl) -2- (2-isopropoxy-phenyl) -4,5-dihydro-imidazol-1-yl] -piperazin-1-yl Methanone;
    q) [4,5-bis- (4-chloro-phenyl) -2- (2-isopropoxy-phenyl) -4,5-dihydro-imidazol-1-yl]-(4-dimethylamino- Piperidin-1-yl) -methanone;
    r) [1,4 '] bipiperidinyl-1'-yl- [4,5-bis- (4-chloro-phenyl) -2- (2-isopropoxy-phenyl) -4,5-dihydro -Imidazol-1-yl] -methanone;
    s) [4,5-bis- (4-chloro-phenyl) -2- (2-isopropoxy-phenyl) -4,5-dihydro-imidazol-1-yl]-[4- (2- Hydroxy-ethyl) -piperazin-1-yl] -methanone;
    t) {4,5-bis- (4-chloro-phenyl) -2- [2- (2-methyl-butoxy-phenyl] -4,5-dihydroimidazol-1-yl} -piperazine- 1-yl-methanone;
    u) [4,5-bis- (4-chloro-phenyl) -2- (2-pentyloxy-phenyl) -4,5-dihydro-imidazol-1-yl] -piperazin-1-yl- Methanone;
    v) [4,5-bis- (4-chloro-phenyl) -2- (3-ethoxy-phenyl) -4,5-dihydro-imidazol-1-yl] -piperazin-1-yl- Methanone, trifluoroacetate;
    w) [4,5-bis- (4-chloro-phenyl) -2- (3-isopropoxy-phenyl) -4,5-dihydro-imidazol-1-yl] -piperazin-1-yl Methanone, trifluoroacetic acid salt;
    x) 1- {4- [4,5-bis- (4-bromo-phenyl) -2- (2-ethoxy-phenyl) -4,5-dihydro-imidazole-1-carbonyl]- Piperazin-1-yl} -ethanone;
    y) [4,5-bis- (4-bromo-phenyl) -2- (2-ethoxy-phenyl) -4,5-dihydro-imidazol-1-yl]-[4- (2- Hydroxy-ethyl) -piperazin-1-yl] -methanone;
    z) 1- {4- [4,5-bis- (4-bromo-phenyl) -2- (2-isopropoxy-phenyl) -4,5-dihydroimidazole-1-carbonyl]- Piperazin-1-yl} -ethanone; And
    aa) [4,5-bis- (4-bromo-phenyl) -2- (2-isopropoxy-phenyl) -4,5-dihydro-imidazol-1-yl]-[4- (2 -Hydroxy-ethyl) -piperazin-1-yl] -methanone.
    [27" claim-type="Currently amended] A pharmaceutical composition comprising the compound according to any one of claims 1 to 26 as an active ingredient and a pharmaceutically acceptable carrier.
    [28" claim-type="Currently amended] 28. A pharmaceutical composition according to claim 27 suitable for oral or parenteral administration.
    [29" claim-type="Currently amended] Use of a compound of any one of claims 1 to 26 for the manufacture of a medicament.
    [30" claim-type="Currently amended] The use of claim 29 for the manufacture of a medicament for the treatment or control of a cell proliferative disorder.
    [31" claim-type="Currently amended] 31. Use according to claim 29 or 30 for the treatment or control of cancer.
    [32" claim-type="Currently amended] 32. The use according to any of claims 29 to 31 for the treatment or control of a breast, colon, lung or prostate tumor.
    [33" claim-type="Currently amended] 27. A method of treating a cell proliferative disorder comprising administering a therapeutically effective amount of the compound of any one of claims 1 to 26 to a patient in need thereof.
    [34" claim-type="Currently amended] The method of claim 33, wherein the cell proliferative disorder is cancer.
    [35" claim-type="Currently amended] The method of claim 34, wherein the cancer is a breast, colon, lung or prostate tumor.
    [36" claim-type="Currently amended] 27. A compound according to any one of claims 1 to 26 for treatment.
    [37" claim-type="Currently amended] 27. A process for the preparation of a compound of any one of claims 1 to 26, as shown in Schemes I-X.
    [38" claim-type="Currently amended] The present invention described above.
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    同族专利:
    公开号 | 公开日
    AT389400T|2008-04-15|
    AU2002366278B2|2007-07-19|
    MXPA04005906A|2004-09-13|
    US20030153580A1|2003-08-14|
    WO2003051359A1|2003-06-26|
    JP2005511766A|2005-04-28|
    CA2469187C|2012-07-17|
    DE60225719D1|2008-04-30|
    KR100650966B1|2006-11-30|
    PA8561901A1|2003-11-12|
    RU2004122414A|2005-06-27|
    RU2305095C2|2007-08-27|
    PE20030895A1|2003-10-25|
    CN100486969C|2009-05-13|
    ES2301717T3|2008-07-01|
    US6734302B2|2004-05-11|
    CA2469187A1|2003-06-26|
    JP4477351B2|2010-06-09|
    EP1458380A1|2004-09-22|
    CN1606439A|2005-04-13|
    UY27585A1|2003-06-30|
    AU2002366278A1|2003-06-30|
    DE60225719T2|2009-04-23|
    BR0215157A|2004-10-19|
    TW200301112A|2003-07-01|
    EP1458380B1|2008-03-19|
    PL370823A1|2005-05-30|
    KR20060096513A|2006-09-11|
    引用文献:
    公开号 | 申请日 | 公开日 | 申请人 | 专利标题
    法律状态:
    2001-12-18|Priority to US34171401P
    2001-12-18|Priority to US60/341,714
    2002-06-21|Priority to US39087402P
    2002-06-21|Priority to US60/390,874
    2002-12-09|Application filed by 에프. 호프만-라 로슈 아게
    2002-12-09|Priority to PCT/EP2002/013904
    2004-07-30|Publication of KR20040068277A
    2006-11-30|Application granted
    2006-11-30|Publication of KR100650966B1
    优先权:
    申请号 | 申请日 | 专利标题
    US34171401P| true| 2001-12-18|2001-12-18|
    US60/341,714|2001-12-18|
    US39087402P| true| 2002-06-21|2002-06-21|
    US60/390,874|2002-06-21|
    PCT/EP2002/013904|WO2003051359A1|2001-12-18|2002-12-09|Cis-2,4,5- triphenyl-imidazolines and their use in the treatment of tumors|
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