MX2008008984A

MX2008008984A - Cis-4, 5-biaryl-2-heterocyclic-imidazolines as mdm2 inhibitors

Info

Publication number: MX2008008984A
Application number: MXMX/A/2008/008984A
Authority: MX
Inventors: Evan Webber Stephen; Fotouhi Nader; Thanh Vu Binh; Jay Haley Gregory; B Simonsen Kalus
Original assignee: Hoffmannla Roche Inc
Priority date: 2006-01-18
Filing date: 2008-07-11
Publication date: 2008-09-26

Abstract

There are provided compounds of the formula (I), wherein R, V1, V2 and Ring A are described herein. The compounds exhibit anticancer activity.

Description

- - CIS-4,5-BIARIL-2-HETEROCICLICO-IMIDAZOLINAS AS MDM2 INHIBITORS DESCRIPTION OF THE INVENTION The present invention relates to at least one compound selected from a compound of the formula I I and its pharmaceutically acceptable salts, wherein Vi, V2, R and ring A have the meanings described in this application. It is believed that these compounds inhibit the interaction of the MDM2 protein with a p53-type peptide and have antiproliferative activity. P53 is a tumor suppressor protein that plays a central role in protecting against the development of cancer. It protects cell integrity and prevents the propagation of permanently damaged clones of the cells, inducing the arrest of their growth or their apoptosis. At the molecular level, p53 is a transcription factor that can activate a panel of genes involved in cell cycle regulation and apoptosis. P53 is a potent inhibitor of the cell cycle, which is tightly regulated by MDM2 at the cellular level. No. Ref .: 194524 - - The MDM2 and p53 form a feedback control loop. MDM2 can bind to p53 and inhibit its ability to transactivate genes regulated by p53. In addition, MDM2 intervenes in the degradation of ubiquitin, mediated by p53. The p53 can activate the expression of the MDM2 gene, thereby increasing the cellular level of the MDM2 protein. This feedback control loop ensures that both MDM2 and p53 are maintained at a low level within normal proliferating cells. MDM2 is also a cofactor for E2F, which plays a central role in regulating the cell cycle. In many malignancies, the ratio between MDM2 and p53 (E2F) is deregulated. It has been observed that molecular defects, which frequently appear at the pl6INK4 / pl9ARF site, for example, affect the degradation of the DM2 protein. Inhibition of MDM2-p53 in neoplastic cells with wild type p53 leads to p53 accumulation, disruption of the cell cycle and / or apoptosis. Accordingly, MDM2 antagonists may offer a novel anticancer therapy strategy as individual agents or in combination with a broad spectrum of other antineoplastic therapies. The viability of this strategy has been confirmed using different macromolecular tools for the inhibition of the MDM2-p53 interaction (eg antibodies, oligonucleotides). - antisense, peptides). MDM2 also binds to E2F through a conserved region of p53 binding and activates transcription of cyclin A dependent on E2F, suggesting that MDM2 antagonists may have effects on p53 mutant cells. Wells et al., J. Org. Chem. 37, 2158-2161, 1972, describe the synthesis of the imidazolines. Hunter et al., Can. J. Chem., Vol. _50, pp. 669-77, 1972, describe the obtainment of amarine and isoamarin compounds, previously studied in relation to chemiluminescence (McCapra et al., Photochem., And Photobiol.4, 1111-1121, 1965). Zupanc et al., Bull. Soc. Chem. & Tech. (Yugoslavia) 27/28, 71-80, 1980-81, describe the use of triaryl imidazolines as starting materials for obtaining EDTA derivatives. In EP 363 061 to Matsumoto, imidazoline derivatives are described which are useful as immunomodulators. It is indicated that these compounds have a low toxicity. The treatment and / or prevention of rheumatoid arthritis, multiple sclerosis, systemic lupus, erythematodes and rheumatic fever are mentioned. In WO 00/78725 of Choueiry et al. A method for obtaining substituted amidine compounds is disclosed and it is indicated that the imidazoline-like compounds are useful for the treatment of diabetes or related diseases, which involve a disorder in the elimination of glucose.

- - In US 6,617,346 Bl (published September 9, 2003), US 6,734,302 B2 (published May 11, 2004), US20040259884 Al (published December 23, 2003). 2004), US20040259867 Al (published December 23, 2004) describes related cis-imidazolines. The present invention provides cis-imidazolines which are small molecule inhibitors of the MDM2-p53 interaction. In tests carried out without cells and with cells, it is observed that the compounds of the present invention inhibit the interaction of the MDM2 protein with a p53-type peptide. Therefore, the activity of the MDM2 antagonists is likely to be associated with this mechanism of action. These compounds can be potent and selective anticancer agents. The present invention provides at least one compound of the formula I and pharmaceutically acceptable salts and esters thereof, wherein - -The ring A is: Xi is selected from the group consisting of lower alkoxy and lower alkoxy substituted by trifluoromethyl or fluorine; X2 is selected from the group consisting of hydrogen, thioalkyl, lower alkyl, lower alkoxy, morpholino and -NX3X4; X3 and X independently from each other are selected from the group consisting of hydrogen, lower alkyl, lower alkyl substituted by lower alkoxy or cyano and lower alkoxy; Y and Z independently of each other are chosen between - - group consisting of: carbon and nitrogen; Vi and V2 independently of each other are selected from the group consisting of halogen, cyano and acetylene; R is selected from the group consisting of piperidinyl substituted by a five- or six-membered heterocycle, piperidinyl substituted by -NX3X4 and wherein n is the number 1 or 2, R can be one or more substituents selected from the group consisting of hydrogen, oxo, lower alkyl substituted by R, -C (0) R3 and - - -S02-lower alkyl; R2 is selected from the group consisting of hydroxy, lower alkoxy, trifluoromethyl, -cyano, -NH-S02-lower alkyl, -NH-C (0) -lower alkyl, -C (0) -lower alkyl, -C (0 ) R4, -C (0) -NX3X4, -S02-lower alkyl, -S02-NX3X4, R3 is selected from the group consisting of a five-membered heterocycle, lower alkyl, lower alkoxy and lower alkyl substituted by lower alkoxy; and R is selected from the group consisting of hydroxy, lower alkoxy, morpholino and -NX3X4. Preferred are the compounds of the formula I, wherein 2 independently of each other are chosen from -Cl and -Br.

Also preferred are compounds of the formula I, wherein R is piperazinyl substituted by oxo or lower alkyl substituted by R2. Compounds are also preferred, in which two hydrogen atoms of the imidazoline ring are in the cis configuration, one with respect to the other. The compounds may be in racemic form or they may be optically active. The preferred absolute stereochemistry for position 4 and 5 of the imidazoline ring is S and R, respectively. Also preferred are compounds of formula I, wherein ring A is: where Xi is ethoxy; X2 is hydrogen, -O-C1-C6 alkyl, -S-C1-C6 alkyl, -C1-C6 alkyl or -CF3 and Z and Y are both nitrogen; - - Vi and V2 are -Cl; R is wherein Ri is oxo, -C (O) -alkyl (C1-C6), -C (O) -dimethyl-isoxazole, -S (0) 2 -alkyl (C1-C6) or -alkyl (C1-C6) ), which is unsubstituted or substituted once by -OH, -S (0) 2- (C1-C6) alkyl, -C (O) -morpholino, -C (O) -N [alkyl (Cl-C6) ] 2, wherein each alkyl independently of the others is unsubstituted or substituted once by cyano or methoxy, -C (O) -NH- (C1-C6) alkyl, wherein the alkyl is unsubstituted or substituted once per methoxy, -C (0) -NH2, -C (O) -N- (C1-C4 alkyl) (C1-C4 alkoxy) or - - -NH-S (0) 2-C 1 -C 6 alkyl and n = 1; and the pharmaceutically acceptable salts thereof. Particularly preferred compounds are for example: cis-4- [(4,5-bis- (4-chloro-phenyl) -2- (2-ethoxy-pyridin-3-yl) -4,5-dihydro-imidazole-1 -carbonyl] -piperazin-2-one, cis-2- { 4- [4, 5-bis- (4-chloro-phenyl) -2- (2-ethoxy-pyridin-3-yl) -4, 5-dihydro-imidazole-1-carbonyl] -piperazin-1-i1.} -N, N-dimethyl-acetamide, cis- [4,5-bis- (4-chloro-phenyl) -2- (2-ethoxy-pyridin-3-yl) -4,5-dihydro-imidazol-1-yl] - [4- (2-methanesulfonyl-ethyl) -piperazin-1-yl] -ethanone, cis-2-. { 4- [4,5-bis- (4-chloro-phenyl) -2- (2-ethoxy-pyridin-3-yl) -4,5-dihydro-imidazole-1-carbonyl] -piperazin-1-yl} -1-morpholin-4-yl-ethanone, cis-4- [4,5-bis- (4-chloro-phenyl) -2- (4-ethoxy-2-trifluoromethyl-pyrimidin-5-yl) -4, 5-dihydro-imidazole-1-carbonyl] -piperazin-2-one, cis- [4, 5-bis- (4-chloro-phenyl) -2- (4-ethoxy-2-trifluoromethyl-pyrimidin-5-yl ) -4,5-dihydro-imidazol-1-yl] - [4- (2-methanesulfonyl-ethyl) -piperazin-1-yl] -methanone, cis-2-. { 4- [4,5-bis- (4-chloro-phenyl) -2- (4-ethoxy-2-trifluoromethyl-pyrimidin-5-yl) -, 5-dihydro-imidazole-1-carbonyl] -piperazin-1 -il} -1-morpholin-1-ethanone, cis-4- [4, 5-bis- (4-chloro-phenyl) -2- (2,4-diethoxy-pyrimidin- - - -yl) -4,5-dihydro-imidazole-1-carbonyl] -piperazin-2-one, cis-2-. { 4- [4,5-bis- (4-chloro-phenyl) -2- (2, -dietoxy-pyrimidin-5-yl) -4,5-dihydro-imidazole-1-carbonyl] -piperazin-1-yl } -N, N-dimethyl-acetamide, cis- [4,5-bis- (4-chloro-phenyl) -2- (2, -dietoxy-pyrimidin-5-yl) -4,5-dihydro-imidazole-1 -yl] - [4- (2-methanesulfonyl-ethyl) -piperazin-1-yl] -methanone, cis-2-. { 4- [4,5-bis- (4-chloro-phenyl) -2- (2,4-diethoxy-pyrimidin-5-yl) -4,5-dihydro-imidazole-1-carbonyl] -piperazin-1- il} -1-morpholin-4-yl-ethanone, cis-4- [4, 5-bis- (4-chloro-phenyl) -2- (4-ethoxy-2-methylsulfanyl-pyrimidin-5-yl) -4, 5-dihydro-imidazole-1-carbonyl] -piperazin-2-one, cis-2-. { - [4,5-bis- (4-chloro-phenyl) -2- (4-ethoxy-2-methylsulfanyl-pyrimidin-5-yl) -, 5-dihydro-imidazole-1-carbonyl] -piperazin-1- il} -N, N-dimethyl-acetamide, cis- [4,5-bis- (4-chloro-phenyl) -2- (4-ethoxy-2-methylsulfanyl-pyrimidin-5-yl) -4,5-dihydro- imidazol-1-yl] - [4- (2-methanesulfonyl-ethyl) -piperazin-1-yl] -methanone, cis-2-. { 4- [4,5-bis- (4-chloro-phenyl) -2- (4-ethoxy-2-methylsulfanyl-pyrimidin-5-yl) -4,5-dihydro-imidazole-1-carbonyl] -piperazine- 1-il} -1-morpholin-4-yl-ethanone, cis-4- [4, 5-bis- (4-chloro-phenyl) -2- (4-ethoxy-2-methyl-pyrimidin-5-yl) -4, 5-dihydro-imidazole-1-carbonyl] -piperazin-2-one, cis-2-. { 4- [4,5-bis- (4-chloro-phenyl) -2- (4-ethoxy-2-methyl-pyrimidin-5-yl) -4,5-dihydro-imidazole-1-carbonyl] -piperazine- 1-il} -N, N-dimethyl-acetamide, cis- [4,5-bis- (4-chloro-phenyl) -2- (4-ethoxy-2-methyl-pyrimidin-5-yl) -4,5-dihydro- imidazol-1-yl] - [4- (2-methanesulfonyl-ethyl) -piperazin-1-yl] -methanone, cis-2-. { 4- [4,5-bis- (4-chloro-phenyl) -2- (4-ethoxy-2-methyl-pyrimidin-5-yl) -4,5-dihydro-imidazole-1-carbonyl] -piperazine- 1-il} -l-morpholin-4-yl-ethanone, cis-4- [2- (2-tert-butyl-4-ethoxy-pyrimidin-5-yl) -4,5-bis- (4-chloro-phenyl) hydrochloride ) -4,5-dihydro-imidazole-1-carbonyl] -piperazin-2-one, cis-2-hydrochloride. { 4- [2- (2-tert-Butyl-4-ethoxy-pyrimidin-5-yl) -4,5-bis- (4-chloro-phenyl) -4,5-dihydro-imidazole-1-carbonyl] - piperazin-1-il} -N, N-dimethyl acetamide, cis- [2- (2-tert-butyl-4-ethoxy-pyrimidin-5-yl) -4,5-bis- (-chloro-phenyl) -4,5-hydrochloride -dihydro-imidazol-1-yl] - [4- (2-methanesulfonyl-ethyl) -piperazin-1-yl] -methanone, cis-2-. { 4- [2- (2-tert-Butyl-4-ethoxy-pyrimidin-5-yl) -4,5-bis- (4-chloro-phenyl) -4,5-dihydro-imidazole-1-carbonyl] - piperazin-1-il} -1-morpholin-yl-ethanone, cis- [2- (2-tert-butyl-4-ethoxy-pyrimidin-5-yl) -4,5-bis- (4-chloro-phenyl) -4,5 -dihydro-imidazol-1-yl] - (-dimethylamino-piperidin-1-yl) -methanone, cis- [2- (2-tert-butyl-4-ethoxy-pyrimidin-5-yl) -4, 5- bis- (4- - - chloro-phenyl) -, 5-dihydro-imidazol-1-yl] - (4-pyrrolidin-1-yl-piperidin-1-yl) -methanone, cis-1 -. { 4- [2- (2-tert-Butyl-4-ethoxy-pyrimidin-5-yl) -4,5-bis- (-chloro-phenyl) -4,5-dihydro-imidazole-1-carbonyl] -piperazine -1-il} -etanone, cis- [2- (2-tert-butyl-4-ethoxy-pyrimidin-5-yl) -4,5-bis- (4-chloro-phenyl) -4,5-dihydro-imidazole-1- il] - (4-methyl-piperazin-1-yl) -methanone, cis- [2- (2-tert-butyl-4-ethoxy-pyrimidin-5-yl) -4,5-bis- (4-chloro) phenyl) -4,5-dihydro-imidazol-1-yl] - [4- (3-methanesulfonyl-propyl) -piperazin-1-yl] -methanone, cis- [2- (2-tert-butyl-4 -ethoxy-pyrimidin-5-yl) -4,5-bis- (4-chloro-phenyl) -4,5-dihydro-imidazol-1-yl] - [4- (2-hydroxy-ethyl) -piperazine- 1-yl] -methanone, 2-. { 4- [(4S, 5R) -2- (2-tert-Butyl-4-ethoxy-pyrimidin-5-yl) -4,5-bis- (4-chloro-phenyl) -4,5-dihydro-imidazole -l-carbonyl] -piperazin-1-yl} -1-morpholin-4-yl-ethanone, 4- [(4S, 5R) -2- (2-tert-butyl-4-ethoxy-pyrimidin-5-yl) -4,5-bis- (4-chloro) phenyl) -4,5-dihydro-imidazole-l-carbonyl] -piperazin-2-one, cis-4- [, 5-bis- (4-chloro-phenyl) -2- (4,6-hydrochloride dietoxy-pyridin-3-yl) -4,5-dihydro-imidazole-1-carbonyl] -piperazin-2-one, cis- [4,5-bis- (4-chloro-phenyl) -2- hydrochloride ( 4,6-diethoxy-pyridin-3-yl) -4,5-dihydro-imidazol-1-yl] - [4- (2- hydroxy-ethyl) -piperazin-1-yl] -methanone, 2-. { 4- [(4S, 5R) -4, 5-bis- (-chloro-phenyl) -2- (3-ethoxy-thiophen-2-yl) -4,5-dihydro-imidazole-1-carbonyl] -piperazine -1-il} -N-tert-buty1-acetamide, 2-. { 4 - [(4S, 5R) -4, 5-bis- (-chloro-phenyl) -2- (3-ethoxy-thiophen-2-yl) -4,5-dihydro-imidazole-1-carbonyl] -piperazine -1-il} -acetamide, 2-. { 4 - [(4S, 5R) -4, 5-bis- (-chloro-phenyl) -2- (3-ethoxy-thiophen-2-yl) -4,5-dihydro-imidazole-1-carbonyl] -piperazine -1-i1} -N, N-bis- (2-methoxy-ethyl) -acetamide, 2-. { 4- [(4S, 5R) -4, 5-bis- (4-chloro-phenyl) -2- (3-ethoxy-thiophen-2-yl) -4,5-dihydro-imidazole-1-carbonyl] - piperazin-1-il} -N-methoxy-N-methyl-acetamide, 2-. { 4- [(4S, 5R) -4, 5-bis- (4-chloro-phenyl) -2- (3-ethoxy-thiophen-2-yl) -, 5-dihydro-imidazole-1-carbonyl] -piperazine -1-il} -N-isopropyl-N-methyl-acetamide, 2-. { 4- [(4S, 5R) -4, 5-bis- (4-chloro-phenyl) -2- (3-ethoxy-thiophen-2-yl) -4,5-dihydro-imidazole-1-carbonyl] - piperazin-1-il} -N- (2-cyano-ethyl) -N-methyl-acetamide, cis-2-. { - [4,5-bis- (4-chloro-phenyl) -2- (3-ethoxy-thiophen-2-yl) -4,5-dihydro-imidazole-1-carbonyl] -piperazin-1-yl} -N- (2-methoxy-1-methyl-ethyl) -acetamide, [(4S, 5R) -4,5-bis- (4-chloro-phenyl) -2- (3-ethoxy-thiophen-2-yl) ) -4,5-dihydro-imidazol-1-yl] - [4- (3, 5-dimethyl-isoxazole-4-carbonyl) -piperazin-1-yl] -methanone, - - [(4S, 5R) -4,5-bis- (4-chloro-phenyl) -2- (3-ethoxy-thiophen-2-yl) -4,5-dihydro-imidazol-1-yl] - (4 -etanesulfonyl-piperazin-1-yl) -methanone, N- (2- {4- [(4S, 5R) -4,5-bis- (4-chloro-phenyl) -2- (3-ethoxy- thiophen-2-yl) -4,5-dihydro-imidazole-1-carbonyl] -piperazin-1-yl] -ethyl) -methanesulfonamide, [(4S, 5R) -4, 5-bis- (4- chloro-phenyl) -2- (3-ethoxy-thiophen-2-yl) -4,5-dihydro-imidazol-1-yl] - [4- (3-methanesulfonyl-propyl) -piperazin-1-yl] - methanone, [(4S, 5R) -4, 5-bis- (4-chloro-phenyl) -2- (3-ethoxy-thiophen-2-yl) -4,5-dihydro-imidazol-1-yl] - [4- (2-methanesulfonyl-ethyl) -piperazin-1-yl] -methanone and 2-. { 4- [(4S, 5R) -4, 5-bis- (4-chloro-phenyl) -2- (3-ethoxy-thiophen-2-yl) -4,5-dihydro-imidazole-1-carbonyl] - piperazin-1-il} -1-morpholin-4-yl-ethanone. "Effective amount" means an amount that is effective to prevent, alleviate or ameliorate the symptoms of a disease or prolong the survival of the treated subject. "Halogen" means fluorine, chlorine, bromine or iodine. "Heteroatom" means an atom chosen from N, O and S.

"IC50" indicates the concentration of a particular compound, which is required to inhibit a measured specific activity by 50%. The IC50 can be measured, for example, in the manner described below. "Alkyl" means a saturated aliphatic hydrocarbon, - - linear or branched chain. The "alkyl" preferably has 14 carbon atoms, more preferably 12, more preferably 8 carbon atoms. "Cycloalkyl" means a monovalent, non-aromatic, partially or fully saturated cyclic hydrocarbon radical containing 3 to 8 carbon atoms. Preferred examples of cycloalkyl groups are cyclopropyl, cyclobutyl and cyclopentyl. "A five- or six-membered heterocycle" means a cyclic, aromatic or non-aromatic hydrocarbon having 5 or 6 links, in which from one to three carbon atoms, preferably one or two, have been replaced by independently chosen heteroatoms among themselves oxygen, nitrogen and sulfur. Preferred examples of a five or six membered heterocycle include, but are not limited to: pyrrolidine, pyrazolidine, imidazolidine, imidazole, pyrazole, triazole, oxazolidine, isoxazolidine, oxazole, isoxazole, thiazolidine, piperidine, piperazine, morpholine, and the like. "Lower alkyl" denotes C 1 -C 6 alkyl groups and includes 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 and more preferably C 1 -C 3 alkyl. "Alkoxy" means -O-alkyl. "Lower alkoxy" means -O-lower alkyl.

- "Pharmaceutically acceptable ester" means a compound of the formula I having a carboxyl group, esterified in a conventional manner, the esters retain the biological efficacy and properties of the compounds of the formula I and decompose "in vivo" (in the body ), regenerating the corresponding active carboxylic acid. You can find information regarding esters and the use of esters for the generation of pharmaceutical compounds in Design of Prodrugs, Bundgaard, H. (coord.), (Elsevier, 1985). See also, H. Ansel et al., Pharmaceutical Dosage Forms and Drug Delivery Systems (6th ed., 1995) on pp. 108-109; Krogsgaard-Larsen et al., Textbook of Drug Design and Development (2nd ed.1996) on pp. 152-191. "Pharmaceutically acceptable salt" denotes conventional salts of acid addition or base addition, which retain the biological efficacy and properties of the compounds of the present invention and are formed with suitable non-toxic organic or inorganic acids or organic bases or inorganic Examples of acid addition salts include salts derived from inorganic acids, such as hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, sulfamic acid, phosphoric acid and nitric acid and those derived from organic acids, such as the acid p-Toluenesulfonic, salicylic acid, acid - methanesulfonic acid, oxalic acid, succinic acid, citric acid, malic acid, lactic acid, fumaric acid and the like. Examples of base addition salts include salts derived from ammonium, potassium, sodium and quaternary ammonium hydroxides, for example tet ramethalmmonium hydroxide. The chemical modification of a pharmaceutical compound (ie, a drug) to obtain a salt is a technique that pharmaceutical chemists know well and apply to obtain better physical and chemical properties, such as stability, hygroscopicity, fluidity and solubility of the substances. compounds See, eg H. Ansel et al., Pharmaceutical Dosage Forms and Drug Delivery Systems (6th ed., 1995) on pp. 196 and 1456-1457; or Richard J. Bastin et al., Organic Process Research & Development _, 427-435, 2000. "Pharmaceutically acceptable", for example a vehicle, a pharmaceutically acceptable excipient, etc., means that it is pharmacologically acceptable and non-toxic to the subject, to which the particular compound is administered. "Substituted" means that the substitution may take place in one or more positions and, unless otherwise indicated, that the substituents of each substitution site are chosen independently from the options - - concrete. "Therapeutically effective amount" means an amount of at least one compound mentioned, which significantly inhibits proliferation and / or prevents the differentiation of a human neoplastic cell, including human neoplastic cell lines. The compounds of the present invention exemplified as advantageous possess IC50 values between 0.030 μM and 7 μM. The compounds of the present invention are useful for the treatment or control of cell proliferation disorders, in particular oncological disorders. These compounds and formulations containing the compounds may be useful for the treatment or control of solid tumors, for example breast, colon, lung and prostate tumors. A therapeutically effective amount of a compound according to this invention means an amount of compound that is effective to prevent, alleviate or ameliorate the symptoms of the disease or prolong the survival of the treated subject. The determination of the therapeutically effective amount is for those skilled in the art. The therapeutically effective amount or dose of a compound of this invention may vary within - broad limits and can be determined by a manner known in the art. Such dosage can be adjusted to the individual requirements of each particular case, including the specific compound (s) to be administered, the route of administration, the pathological condition to be treated, as well as the patient. In general, in the case of oral or parenteral administration to adult humans weighing approximately 70 kg, a daily dosage of 10 mg to 10,000 mg, preferably 200 mg to 1,000 mg, may be appropriate, although the upper limit may be exceeded, if it is considered indicated. The daily dosage can be administered in a single dose or it can be divided into sub-doses, or for parenteral administration it can be administered in the form of continuous infusion. The present invention further provides pharmaceutical compositions containing at least one compound of formula I, or a pharmaceutically acceptable salt or ester thereof and a pharmaceutically acceptable carrier or excipient. The compounds of the present invention can be obtained according to the following scheme 1, in which unless otherwise explicitly indicated, all substituents, variables, reagents or agents, have the meanings indicated in this application or that are well known to those skilled in the art. Reaction scheme 1 The synthesis begins with the formation reaction of ester 2 with meso-1,2-bis- (4-chlorophenyl) -ethane-1,2-diamine 1 (obtained according to the procedure described by Jennerwein, M. et al., Cancer Res. Clin. Oncol. 114, 347-58, 1988; Vogtle, F., Goldschmitt, E., Chem. Ber. 109, 1-40, 1976) using as a catalyst trimethyl aluminum, in a solvent for example toluene, and heating under reflux (Moormann, A. E. et al., J. Med. Chem. 33, 614-626, 1990). Esters 2 are obtained by applying procedures already known in the art. By treatment of the imidazoline 3 with phosgene in the presence of a base, for example triethylamine, the racemic carbamoyl chloride 4 is obtained. By reaction of the racemic carbamoyl chloride 4 with appropriate amine groups R, the compounds of the formula I are obtained form of racemic mixtures. Many compounds with amine R groups are commercial products. If desired, the amine R groups can be obtained by applying synthetic procedures already known in the art. Appropriate processes for obtaining these amine R groups are given in the examples. If it is desired to obtain optically active compounds of the formula I, the enantiomers of the carbamoyl chloride rac-4 can be separated by carrying out a chiral chromatography. The chiral stationary phase R, R-Whelk-01, supplied by Regis Technologies can be used. The reaction of the desired enantiomer 5A with appropriate amine groups R provides optically active compounds of the formula I. The optically active compounds of the formula I can also be obtained by the chiral separation of the racemic mixtures of the compounds of the formula I. the chiral stationary phase Diacel ChiralPak OD or AD. The absolute stereochemistry of the preferred enantiomer of formula I is determined based on the crystal structure of its complex with human MDM2 (Vassilev et al., Science 303, 844-848, 2004. The following examples and references are given to help a better understanding of the present invention, the true scope of which is defined in the appended claims Example 1 cis-4- [(4,5-bis- (4-chloro-phenyl) -2- (2-ethoxy-pyridin-3 -yl) -4,5-dihydro-imidazole-1-carbonyl] -piperazin-2-one To a solution of 2-chloronicotinic acid (5 g, 31.7 mmol, Aldrich) in dimethylformamide (50 ml) is added potassium carbonate (6,579 g, 47.6 mmol) and ethyl iodide. (3.8 ml, 47.7 mmol), respectively. The reaction mixture was stirred at room temperature for 3 d. Water is added (~50 mL) and extract the product with ethyl ether (2 x 75 mL). The organic phases are combined, washed with brine (1 x 50 ml) and dried with anhydrous magnesium sulfate. They separate The solids were filtered off and the filtrate was concentrated under reduced pressure to obtain ethyl 2-chloronicotinate as a yellow oil. It is then dissolved in ethanol (50 ml) and sodium ethoxide (17.8 ml, 47.6 mmol, 21% in ethanol, Aldrich) is added dropwise. When the sodium ethoxide is added, precipitation is observed. The reaction mixture was stirred at room temperature for 12 h. The reaction mixture was concentrated and the residue was partitioned between methylene chloride (150 ml) and water (50 ml). The aqueous phase is extracted with methylene chloride (1 x 50 mL). The organic phases are combined, washed with brine (1 x 20 ml) and dried with anhydrous magnesium sulfate. The solids are separated by filtration and the filtrate is concentrated in vacuo. The residue was purified by flash chromatography (120 g of silica gel, 10 to 30% ethyl acetate in hexane) to obtain ethyl 2-ethoxynicotinate as an orange oil (4.04 g, yield: 65% the 2 steps). With a syringe, trimethyl aluminum (1156 ml, 2.312 mmol, 2 M solution in toluene, Aldrich) is introduced into a flask and cooled to 0 ° C. A mixture of meso-1,2-bis- (4-chlorophenyl) -ethane-1,2-diamine (650 mg, 2.312 mmol, obtained according to the procedure described by Jennerwein) is added dropwise over a period of 30 min. , M. et al., Cancer Res. Clin. Oncol. 114, 347-58, 1988; Vogtle, F., Goldschmitt, E., Chem. Ber. 109, 1-40, 1976) in about 8 ml. toluene Once the addition is complete, the cooling bath is removed and the mixture is stirred at room temperature for 15 min, at 50-60 ° C for 30 min and then at 80-90 ° C for 30 min. When the temperature returns to 60 ° C, a solution of ethyl 2-ethoxynicotinate (418.9 mg, 2.312 mmol) in toluene (5 ml) is added. The reaction mixture was heated at reflux for 2 h. The reaction mixture was then cooled in an ice bath at 10 ° C and a 1 M solution of Rochelle's salt (10 ml) was added. The ice bath is removed and the biphasic mixture is stirred vigorously for 30 min. Ethyl acetate (20 ml) is added and stirring is continued overnight. The phases are separated and the organic phase is washed with brine (lx) and dried with anhydrous magnesium sulfate. The solids are separated by filtration and the filtrate is concentrated in vacuo to obtain a yellow oil (950 mg). The crude product was purified by flash chromatography (40 g, eluting with 15% ethyl acetate in hexane, 50% ethyl acetate in hexane, then ethyl acetate), yielding 4,5-bis- (4- chloro-phenyl) -2- (2-ethoxy-pyridin-3-yl) -4,5-dihydro-1H-imidazole as a white solid (481 mg, 51%). To a solution of 4,5-bis- (4-chloro-f-enyl) -2- (2-ethoxy-pyridin-3-yl) -4,5-dihydro-1H-imidazole (475 mg, 1152 mmol) and triethylamine (321 μl, 2,304 mmol) in methylene chloride (6 ml) cooled to 0 ° C is added phosgene (895 μl, 1728 mmol, % solution in toluene, Fluka). The reaction mixture was stirred at 0 ° C for 30 min, then concentrated to dryness. The residue is taken up in ethyl acetate and the solids are separated by filtration. The filtrate is concentrated to give the crude 5-bis- (4-chloro-phenyl) -2- (2-ethoxy-pyridin-3-yl) -4,5-dihydro-imidazole-l-carbonyl chloride. , as a yellow solid (450 mg). To a solution of 4,5-bis- (4-chloro-phenyl) -2- (2-ethoxy-pyridin-3-yl) -4,5-dihydro-imidazole-1-carbonyl chloride (100 mg, 0.211) mmoles) in methylene chloride (3 ml) were added at room temperature triethylamine (88 μl) and 2-piperazinone (31.7 mg, 0.317 mmol, Tyger Scientific), respectively. The reaction mixture was stirred at room temperature for 1 h. The reaction is monitored by thin layer chromatography (silica gel, 15% methanol in ethyl acetate). The reaction mixture was concentrated to dryness and the crude residue was purified by high performance liquid chromatography (C18-silica gel, eluting with a gradient of acetonitrile from 5 to 95% in water), yielding cis-4- [ (4, 5-bis- (4-chloro-phenyl) -2- (2-ethoxy-pyridin-3-yl) -4,5-dihydro-imidazole-1-carbonyl] -piperazin-2-one in the form of white solid (98 mg, 86%). HR-MS (ES, m / z) calculated from C27H26N503C12 [(M + H) +] = 538.1407, found = 538. 1408 - - Example 2 cis-2-. { 4- [4,5-bis- (4-chloro-phenyl) -2- (2-ethoxy-pyridin-3-yl) -4,5-dihydro-imidazole-1-carbonyl] -piperazin-1-yl} -N, N-dimethyl acetamide The 4,5-bis- (-chloro-phenyl) -2- (2-ethoxy-pyridin-3-yl) -4,5-dihydro-imidazole-l-carbonyl chloride (Example 1) is reacted with the N, N-dimethyl-2-piperazin-1-yl-acetamide (Oakwood Products), obtaining cis-2-. { 4- [4,5-bis- (4-chloro-phenyl) -2- (2-ethoxy-pyridin-3-yl) -4,5-dihydro-imidazole-1-carbonyl] -piperazin-1-yl} -N, N-dimethyl acetamide in a manner similar to that described in example 1. HRMS (ES, m / z) calculated from C3? H35N6? 3Cl2 [(M + H) +] = 609.2142, found = 609.2146. Example 3 cis- [4,5-bis- (4-chloro-phenyl) -2- (2-ethoxy-pyridin-3-yl) -4,5-dihydro-imidazol-1-yl] - [4- ( 2-methanesulfonyl-ethyl) -piperazin-1-yl] -methanone Methyl vinyl sulfone (1.8 ml, 20.1 mmol) is added to - - a solution of 1- (tert-butyloxycarbonyl) piperazine (1.50 g, 8 mmol) in methanol (84 ml). The reaction mixture was stirred at room temperature for 4 h and concentrated, forming a white solid. Purification of the solid by flash column chromatography (silica gel, eluting with 1 to 5% methanol in methylene chloride) gives 1-tert-butyloxycarbonyl-4- (2-methanesulfonylethyl) piperazine as a white solid ( 2.29 g, 95%). Hydrochloric acid (42 ml, 168 mmol, 4 M in 1,4-dioxane) is added to a cooled solution of 1-tert-butyloxycarbonyl-4- (2-methanesulfonylethyl) piperazine (2.29 g, 7.8 mmol) in 1, 4-dioxane (42 ml). The mixture is stirred at room temperature overnight and then concentrated to give l- (2-methanesulfonylethyl) piperazine dihydrochloride as a white solid (2.05 g). The 4,5-bis- (4-chloro-phenyl) -2- (2-ethoxy-pyridin-3-yl) -4,5-dihydro-imidazole-1-carbonyl chloride is reacted (example 1) with l- (2-methanesulfonylethyl) piperazine dihydrochloride, obtaining cis- [4,5-bis- (4-chloro-phenyl) -2- (2-ethoxy-pyridin-3-yl) -4,5-dihydro-imidazol-1-yl] - [4- (2-methanesulfonyl-ethyl) -piperazin-1-yl] -methanone in a manner similar to that described in Example 1. EM-HR (EN , m / z) calculated from C 30 H 34 N 5 O 4 S Cl 2 [(M + H) +] = 630.1703, found = 603.1705.

- Example 4 cis-2-. { 4- [4,5-bis- (4-chloro-phenyl) -2- (2-ethoxy-pyridin-3-yl) -4,5-dihydro-imidazole-1-carbonyl] -piperazin-1-yl} -l-morpholin-4-yl-ethanone The 4,5-bis- (4-chloro-phenyl) -2- (2-ethoxy-pyridin-3-yl) -4,5-dihydro-imidazole-1-carbonyl chloride (Example 1) is reacted with l-morpholin-4-yl-2-piperazin-1-yl-ethanone (Oakwood Products), yielding cis-2-. { 4- [4,5-bis- (-chloro-phenyl) -2- (2-ethoxy-pyridin-3-yl) -4,5-dihydro-imidazole-1-carbonyl] -piperazin-1-yl} -l-morpholin-4-yl-ethanone in a manner similar to that described in Example 1. HR-MS (ES, m / z) calculated for C33H37N6? 4Cl2 t (M + H) +] = 651.2248, found = 651.2250. Example 5 cis-4- [4,5-bis- (4-chloro-phenyl) -2- (4-ethoxy-2-trifluoromethyl-pyrimidin-5-yl) -4,5-dihydro-imidazole-1-carbonyl ] -piperazin-2-one The 4-hydroxy-2-trifluoromethyl acid is dissolved pyrimidine-5-carboxylic acid (1 g, 4.828 mmole, Oakwood Products) in dimethylformamide (10 ml) and potassium carbonate (1668 g, 12,070 mmol) is added. After stirring at room temperature for 15 min, iodoethane (0.966 ml, 12.070 mmol) was added and the reaction mixture was stirred at room temperature for 3 d. Water is added and the product is extracted with ethyl acetate (2x). The organic phases are washed with water (lx), brine (lx) and dried with anhydrous sodium sulfate. The solids are separated by filtration and the filtrate is concentrated in vacuo. Purification of the residue by flash column chromatography (silica gel, eluting with a gradient of 5 to 50% ethyl acetate in hexanes) affords ethyl 4-ethoxy-2-trifluoromethyl-pyrimidine-5-carboxylate (852). mg, 67%). The ethyl 4-ethoxy-2-trifluoromethyl-pyrimidine-5-carboxylate is reacted with meso-1,2-bis- (4-chlorophenyl) -ethane-1,2-diamine in a manner similar to that described in Example 1, obtaining cis-4- [4, 5-bis- (4-chloro-phenyl) -2- (4-ethoxy-2-trifluoromethyl-pyrimidin-5-yl) -4,5-dihydro-1H -imidazole HRMS (ES, m / z) calculated for C22H? 8N4OF3Cl2 [(M + H) +] = 481.0805, found = 481.0806. By applying the procedure described in example 1, cis-4- [4,5-bis- (4-chloro-phenyl) -2- (4-ethoxy-2-trifluoromethyl-pyrimidin-5-yl) -4 is reacted , 5-dihydro-lH-imidazole with phosgene, obtaining cis-4- [4,5-bis- (4-chloro- - - phenyl) -2- (4-ethoxy-2-trifluoromethyl-pyrimidin-5-yl) -4,5-dihydro-imidazole-1-carbonyl. The carbonyl chloride is then reacted with 2-piperazinone, yielding cis-4- [4,5-bis- (4-chloro-phenyl) -2- (4-ethoxy-2-trifluoromethyl-pyrimidin-5- il) -4,5-dihydro-imidazole-1-carbonyl] -piperazin-2-one. HRMS (ES, m / z) calculated for C27H24N603F3C12 [(M + H) +] = 607.1234, found = 607.1231. Example 6 cis- [4,5-bis- (4-chloro-phenyl) -2- (4-ethoxy-2-trifluoromethyl-pyrimidin-5-yl) -4,5-dihydro-imidazol-1-yl] - [4- (2-methanesulfonyl-ethyl) -piperazin-1-yl] -methanone The cis-4 - [4,5-bis- (4-chloro-phenyl) -2- (4-ethoxy-2-trifluoromethyl-pyrimidin-5-yl) -4,5-dihydro-imide chloride is reacted zol -1 -carboni lo (example 5) with the di- (2-methanesul fonylethyl) piperazine dihydrochloride (example 3), obtaining cis- [4,5-bis- (4-chloro-phenyl) -2 - (-toxy-2-trifluoromethyl-pyrimidin-5-yl) -4,5-dihydro- - - imidazol-1-yl] - [4- (2-methanesulfonyl-ethyl) -piperazin-1-yl] -methanone in a manner similar to that described in example 1. EM-HR (ES, m / z) calculated from C30H32N6O4SF3Cl2 [(M + H) +] = 699.1530, found = 699.1533. Example 7 cis-2-. { 4- [4,5-bis- (4-chloro-phenyl) -2- (4-ethoxy-2-trifluoromethyl-pyrimidin-5-yl) -4,5-dihydro-imidazol-1 -carbonyl] -piperazine- 1-il} -l-morpholin-4-yl-ethanone The cis -4- [4,5-bis- (-chloro-phenyl) -2- (4-ethoxy-2-trifluoromethyl-pyrimidin-5-yl) -4,5-dihydro-imidazole- chloride is reacted l-carbonyl (example 5) with 1-mor folin-4 -i 1-2 -pipera zin-1 -i 1-et anona (Oakwood Products), obtaining cis-2-. { - [4,5-bis- (4-chloro-phenyl) -2- (4-ethoxy-2-trifluoromethyl-pyrimidin-5-yl) -4,5-dihydro-imidazole-1-carbonyl] -piperazin-1 -il} 1-morpholin-4-yl-ethanone in a manner similar to that described in Example 1. HR-MS (ES, m / z) calculated from C33H35N704F3C12 [(M + H) +] = 720.2074, found 720.2075.

- - Example 8 cis-4- [4,5-bis- (4-chloro-phenyl) -2- (2, -dietoxy-pyrimidin-5-yl) -4,5-dihydro-imidazole-1-carbonyl] -piperazine -2-one To a solution of ethyl 4-chloro-5-pyrimidine carboxylate (5 g, 21,488 mol, Aldrich) in ethanol (50 ml) is added dropwise the sodium ethoxide (12 ml, 32.232 mmol, 21% solution ethanol, Aldrich). Precipitation is observed when sodium ethoxide is added. The reaction mixture was stirred at room temperature for 12 h. The reaction mixture is then heated to -60 ° C for 2 h. The reaction mixture is diluted with ethyl acetate, it is washed with water, brine and dried with magnesium sulfate. The solids are separated by filtration and the filtrate is concentrated in vacuo. The residue was purified by flash chromatography (120 g of silica gel, gradient of ethyl acetate of 10 to 50% in hexane), yielding ethyl 2,4-diethoxy-pyrimidine-5-carboxylate (1679 g) and Ethyl 4-ethoxy-2-methylsulfanyl-pyrimidine-5-carboxylate (1764 g). The ethyl 2 -dietoxy-pyrimidine-5-carboxylate is reacted with meso-l, 2-bis- (4-chlorophenyl) -ethane-l, 2-diamine in a manner similar to that described in example 1 , obtaining the cis-4- - - [4,5-bis- (4-chlorophenyl) -2- (2,4-diethoxy-pyrimidin-5-yl) -4,5-dihydro-1H-imidazole. HRMS (ES, m / z) calculated for C23H23N402C12 [(M + H) +] = 457.1193, found = 457.1193. Applying the procedure described in example 1, cis-4- [4,5-bis- (4-chloro-phenyl) -2- (2,4-diethoxy-pyrimidin-5-yl) -, 5- is reacted dihydro-lH-imidazole with phosgene, obtaining cis-4- [4,5-bis- (4-chloro-phenyl) -2- (2,4-diethoxy-pyrimidin-5-yl) -4,5-chloride. -dihydro-imidazole-1-carbonyl.

This carbonyl chloride is then reacted with 2-piperazinone (Alfa), yielding cis-4- [4,5-bis- (4-chloro-phenyl) -2- (2, -dietoxy-pyrimidin-5- il) -4,5-dihydro-imidazole-1-carbonyl] -piperazin-2-one. HRMS (ES, m / z) calculated for C28H29N604C12 [(M + H) +] = 583.1622, found = 583.1621. Example 9 cis-2-. { 4- [4,5-bis- (4-chloro-phenyl) -2- (2,4-diethoxy-pyrimidin-5-yl) -4,5-dihydro-imidazole-1-carbonyl] -piperazin-1- il} -N, N-dimethyl acetamide The cis-4 - [4, 5-bis- (4-chloro-phenyl) -2- (2,4-diethoxy-pyrimidin-5-yl) -4,5-dihydro-imidazole-1 chloride is reacted -carbonyl (example 8) with N, N-dimethyl-2-piperazin-l-yl-acetamide (Oakwood - - Products), obtaining cis-2-. { 4- [4,5-bis- (4-chloro-phenyl) -2- (2, -dietoxy-pyrimidin-5-yl) -4,5-dihydro-imidazole-1-carbonyl] -piperazin-1-yl } -N, N-dimethyl acetamide in a manner similar to that described in Example 1. HR-HR (ES, 'm / z) calculated from C 32 H 37 N 704 C 12 [(M + H) +] = 654.2357, found = 654.2355. Example 10 cis- [4,5-bis- (4-chloro-phenyl) -2- (2,4-diethoxy-pyrimidin-5-yl) -4,5-dihydro-imidazol-1-yl] - [4 - (2-methanesulfonyl-ethyl) -piperazin-1-yl] -methanone The cis-4- [4,5-bis- (4-chloro-phenyl) -2- (2,4-diethoxy-pyrimidin-5-yl) -4,5-dihydro-imidazole-1 chloride is reacted -carbonyl (example 8) with l- (2-methanesulfonylethyl) -piperazine dihydrochloride (example 3), obtaining cis- [4,5-bis- (4-chloro-phenyl) -2- (2, 4) -dietoxy-pyrimidin-5-yl) -4,5-dihydro-imidazol-1-yl] - [4- (2-methanesulfonyl-ethyl) -piperazin-1-yl] -methanone in a manner similar to that described in Example 1. HR-MS (ES, m / z) calculated from C3? H37N605SCl2 [(M + H) +] = 675.1918, found = 675.1914.

- Example 11 cis-2-. { 4- [4,5-bis- (4-chloro-phenyl) -2- (2,4-diethoxy-pyrimidin-5-yl) -4,5-dihydro-imidazole-1-carbonyl] -piperazin-1- il} -l-morpholin-4-yl-ethanone The cis-4- [4,5-bis- (4-chloro-phenyl) -2- (2,4-diethoxy-pyrimidin-5-yl) -4,5-dihydro-imidazole-1 chloride is reacted -carbonyl (example 8) with l-morpholin-4-yl-2-piperazin-1-yl-ethanone (Oakwood Products), yielding cis-2-. { 4- [4,5-bis- (4-chloro-phenyl) -2- (2,4-diethoxy-pyrimidin-5-yl) -4,5-dihydro-imidazole-1-carbonyl] -piperazin-1- il} -l-morpholin-4-yl-ethanone in a manner similar to that described in Example 1. HR-MS (ES, m / z) calculated from C 34 H 40 N 7 O 5 Cl 2 [(M + H) +] = 696.2463, found = 696.2463. Example 12 cis-4- [4,5-bis- (4-chloro-phenyl) -2- (4-ethoxy-2-methylsulfanyl-pyrimidin-5-yl) -4,5-dihydro-imidazole-1-carbonyl ] -piperazin-2-one - - The ethyl 4-ethoxy-2-methylsulfanyl-pyrimidine-5-carboxylate (Example 8) is reacted with meso-l, 2-bis- (4-chlorophenyl) -ethane-1,2-diamine in a similar manner to that described in Example 1, obtaining cis-4- [4, 5-bis- (4-chloro-phenyl) -2- (4-ethoxy-2-methyl-sulfanyl-pyrimidin-5-yl) -4 , 5-dihydro-lH-imidazole. HRMS (ES, m / z) calculated for C22H2? N4OSCl2 [(M + H) +] = 459.0808, found = 459.0808. By applying the procedure described in Example 1, cis-4- [4,5-bis- (4-chloro-phenyl) -2- (4-ethoxy-2-methylsulfanyl-pyrimidin-5-yl) -4 is reacted , 5-dihydro-lH-imidazole with phosgene, obtaining cis-4- [4,5-bis- (4-chloro-phenyl) -2- (4-ethoxy-2-methylsulfanyl-pyrimidin-5-yl chloride. -4,5-dihydro-imidazole-1-carbonyl. This carbonyl chloride is then reacted with 2-piperazinone (Alfa), yielding cis-4- [4,5-bis- (4-chloro-phenyl) -2- (4-ethoxy-2-methylsulfanyl-pyrimidine. -5-yl) -4,5-dihydro-imidazole-1-carbonyl] -piperazin-2-one. HRMS (ES, m / z) calculated for C2H27N6? 3SCl2 [(M + H) +] = 585.1237, found: 585.1236. Example 13 cis-2-. { 4- [4,5-bis- (4-chloro-phenyl) -2- (4-ethoxy-2-methylsulfanyl-pyrimidin-5-yl) -4,5-dihydro-irnidazole-1-carbonyl] -piperazine- l-il } -N, N-dimethyl acetamide The cis-4- [4,5-bis- (4-chloro-) chloride is reacted - - phenyl) -2- (4-ethoxy-2-methylsulfani 1-pyridin-5-yl) -4,5-dihydro-imidazol-1 -carbonyl (example 12) with N, N-dimethyl -2-piperazin-l-yl-acetamide (Oakwood Products), obtaining cis-2-. { 4 - [4,5-bis- (4-chloro-phenyl) -2- (4-ethoxy-2-methylsulfanyl-pyrimidin-5-yl) -4,5-dihydro-imidazole-1-carbonyl] -piperazine- l-il } -N, N-dimethyl acetamide in a manner similar to that described in example 1. HR-MS (ES, m / z) calculated from C3? H36N703SCl2 [(M + H) +] = 656.1972, found = 656.1973. Example 14 cis- [4,5-bis- (4-chloro-phenyl) -2- (4-ethoxy-2-methylsulfanyl-pyrimidin-5-yl) -4,5-dihydro-imidazol-1-yl] - [4- (2-methanesulfonyl-ethyl) -piperazin-1-yl] -methanone The cis-4- [4,5-b-sis (4-chloro-phenyl) -2- (4-ethoxy-2-methylsulfanyl-pyrimidin-5-yl) -4,5-dihydro chloride is reacted -imido zol-1-carboni lo (example 12) with the dihydrochloride of 1- (2-methanesulfonylethyl) -piperazine (example 3), obtaining the cis- [4,5-bis- - - (4-chloro-phenyl) -2- (4-ethoxy-2-methylsulfanyl-pyrimidin-5-yl) -4,5-dihydro-imide zol-1-yl] - [4- (2-methanesulfonyl-ethyl) -piperazin-1-yl] -methanone in a manner similar to that described in Example 1. HR-MS (ES, m / z) calculated from C 30 H 35 N 6 O 4 S 2 Cl 2 [(M + H) +] = 677.1533, found 677.1532. Example 15 cis-2-. { 4- [4,5-bis- (4-chloro-phenyl) -2- (4-ethoxy-2-methylsulfanyl-pyrimidin-5-yl) -4,5-dihydro-imidazole-1-carbonyl] -pipera zin - 1-il} -l-morpholin-4-yl-ethanone The cis-4 - [, 5-bis- (4-chloro-phenyl) -2- (4-ethoxy-2-methylsulfanyl-pyrimidin-5-yl) -4,5-dihydro-imide zol is reacted -1-carbonyl (example 12) with 1-morpholin-4-yl-2-piperazin-1-yl-ethanone (Oakwood Products), yielding cis-2 -. { 4 - [4, 5 -bi s- (4-chloro-phenyl) -2- (4-ethoxy-2-methylsulfanyl-pyrimidin-5-yl) -4,5-dihydro-imide zol-1 -carbonyl] - pipera zin-1-il} -1-morpholin-4-yl-ethanone in a manner similar to - - described in Example 1. HR-MS (ES, m / z) calculated from C33H38N704SC12 [(M + H) +] = 698.2078, found 698.2078. E x takes 16 cis-4- [4,5-bis- (4-chloro-phenyl) -2- (4-ethoxy-2-met i 1 -pyrimidin-5-yl) -4,5-dihydro-imide zol- 1 -carbonyl] -pipera zin-2 -one The ethyl 4-ethoxy-2-met i 1-pyrimidine-5-carboxylate is reacted (obtained according to the procedure described by Baxter, R.L. et al., J.

Chem. Soc. Perkin Trans. I 2963-2966, 1990; and Dostert, P. et al., Eur. J. Med. Chem. 11_, 437-444, 1982) with meso-1,2-bis- (4-chlorophenyl) -ethane-1,2-diamine in a similar manner to the one described in Example 1, obtaining cis-4 - [4, 5-bis - (-chloro-phenyl-1) -2- (4-ethoxy-2-methyl-pyrimidin-5-yl) -4,5- dihydro-lH-imidazole.

HRMS (ES, m / z) calculated for C22H2? N4OSCl2 [(M + H) +] = 459. 0808, found = 459.0808. Applying the procedure described in the example 1 cis-4 - [4,5-bis- (-chlorophenyl) -2- (4-ethoxy-2-methyl-pyrimidin-5-yl) -4,5-dihydro-1H-imidazole is reacted with phosgene , yielding cis-4- [4,5-bis- (4-chloro-phenyl) -2- (-ethoxy-2-methyl-1-pyrimidin-5-yl) -4,5-dihydro-imide chloride zol- 1 -carbonyl. This carbonyl chloride is then reacted with 2-piperazinone (Alfa), yielding cis-4- [4,5-bis- (4-chloro-phenyl) -2- (4-ethoxy-2-methyl- pyrimidin-5-yl) -4,5-dihydro-imidazole-1-carbonyl] -piperazin-2-one. HRMS (ES, m / z) calculated from C2 H27N603C12 [(M + H) +] = 553.1516, found = 553.1515. Example 17 cis-2-. { 4- [4,5-bis- (4-chloro-phenyl) -2- (4-ethoxy-2-methyl-pyrimidin-5-yl) -4,5-dihydro-imidazole-1-carbonyl] -piperazine- l-il } -N, -dimethyl-acetamide The cis-4 - [4, 5-bis- (4-chloro-phenyl) -2- (4-ethoxy-2-methyl-pyrimidin-5-yl) -4,5-dihydro chloride is reacted -imidazole- 1 -carbonyl (example 16) with the N, N-dimet i 1-2-pipera zin-1-yl-acetamide (Oakwood - - Products), yielding cis-4 - [4,5-bis- (4-chlorophenyl) -2- (4-ethoxy-2-methyl-pyrimidin-5-yl) -4,5-dihydro-imide zol- 1 -carbonyl] -pipera zin-1-yl} -N, N-dimethyl-a.tatamide in a manner similar to that described in Example 1. HR-MS (ES, m / z) calculated from C3? H36N703Cl2 [(M + H) +] = 624.2251, found = 624.2253. Example 18 cis- [4, 5-bis- (4-chloro-phenyl) -2- (4-ethoxy-2-methyl-pyrimidin-5-yl) -4,5-dihydro-imide zol-1-yl] - [4- (2-methanesulfonyl-ethyl) -piperazin-1-yl] -methanone The cis- [5-bis- (4-chloro-phenyl) -2- (4-ethoxy-2-methyl-pyrimidin-5-yl) -4,5-dihydro-imidazole-1 chloride is reacted -carbonyl (example 16) with the dihydrochloride of the 1- (2-methanesulfonyl-1-ethyl) piperazine (example 3), obtaining cis- [4,5-bis- (4-chlorophenyl) -2- (4 -ethoxy-2-methyl-pyrimidin-5-yl) -4,5-dihydro-imidazol-1-yl] - [4- (2-methanesulfonyl-ethyl) -piperazin-1-yl] -methanone in a similar manner to the one described in Example 1. HR-MS (ES, m / z) calculated from C3oH34N604SCl2 [(M + H) +] = 645.1812, found 645.1814. Example 19 cis-2-. { 4- [4,5-bis- (4-chloro-phenyl) -2- (4-ethoxy-2-methyl-pyrimidin-5-yl) -4,5-dihydro-imidazole-1-carbonyl] -piperazine- 1-il} -l-morpholin-4-yl-ethanone The chloride of ci s-4 - [4,5-b-s- (4-chloro-phenyl) -2- (4-ethoxy-2-methyl-pyrimidin-5-yl) -4,5-dihydro is reacted -imidazole-1-carbonyl (example 16) with l-morpholin-4 -i 1-2 -pipera zin-1-yl-ethanone (Oa wood Products), obtaining cis-2 -. { 4 - [4, 5-bi s- (4-chloro-phenyl) -2- (4-ethoxy-2-methyl-pyrimidin-5-yl) -4,5-dihydro-imide zol-1 -carbonyl] - pipera zin-1-il} -l-morpholin-4-yl-ethanone in a manner similar to that described in Example 1. HR-MS (ES, m / z) calculated from C33H38N704C12 [(M + H) +] = 666.2357, found = 666.2358.

Use 20 cis-4 - [2- (2-t-ert-butyl-4-ethoxy-pyrimidin-5-yl) -4,5-bis- (4-chloro-phenyl) -4,5-hydrochloride -dihydro-imidazole-1-carbonyl] -piperazin-2-one, A solution of ethyl 4-hydroxy-2-tert-butyl-pyrimidine-5-carboxylate (3 g, 13.377 mmol, obtained by a method similar to that described for the preparation of 2-yl-4-hydroxy) is slowly added. -ethyl ethyl imidine-5-carboxylate, Dostert, P. et al., Eur. J. Med. Chem. 1 1, 437-444, 1982) in dimethylformamide (10 ml) to a suspension of sodium hydride (800 mg, 60% in mineral oil, Aldrich) in dimethylformamide cooled to 0 ° C. After the addition, the ice bath is removed and the reaction mixture is stirred at room temperature for 2 h. The reaction mixture was stirred at room temperature for 4 h, then the reaction was quenched with a saturated solution of ammonium chloride. Extract with ethyl acetate (2x). They wash - - organic extracts with brine (lx), dried over anhydrous sodium sulfate and concentrated. Purification of the crude residue by flash column chromatography (120 g of silica gel, elution with a gradient of ethyl acetate of 5 to 60% in hexane) yields 4-ethoxy-2-tert-but i 1- pyidine imidine-5-ethylcarboxylate (1.12 g, 30%).

The ethyl 2-tert-butyl-4-ethoxy-pyrimidine-5-carboxylate is reacted with the meso-1,2-bi s- (4-chlorophenyl) -ethane-1,2-diamine in a similar manner to that described in Example 1, obtaining cis-4- [2- (2-tert-butyl-4-ethoxy-pyrimidin-5-yl) -4,5-bis- (4-chloro-phenyl) -4 , 5-dihydro-lH-imidazole. HRMS (ES, m / z) calculated for C22H2? N4OSCl2 [(M + H) +] = 459.0808, found = 459.0808. By applying the procedure described in example 1, cis-4 - [2 - (2-tert-butyl-4-ethoxy-pyrimidin-5-yl) -4,5-bis- (4-chloro-phenyl) is reacted ) -4,5-dihydro-lH-imidazole with phosgene, obtaining the chloride of ci s-4 - [2 - (2 - 1 ert-but i 1-4 -et oxy-pyrimidin-5-yl) -4 , 5-bis- (4-chloro-phenyl) -4,5-dihydro-imidazole-1-carbonyl. This carbonyl chloride is reacted with 2-pipera z inona (Alfa), obtaining cis-4- [2- (2-tert-butyl-4-ethoxy-pyrimidin-5-yl) -4,5-bis. - (4-chloro-phenyl) -4,5-dihydro-imidazol-1 -carbonyl] - - - piperazin-2-one, hydrochloride. HRMS (ES, m / z) calculated for C 30 H 33 N 6 O 3 Cl 2 [(M + H) +] = 595.1986, found = 595.1985. E xemplo 21 cis-2-hydrochloride. { 4 - [2- (2-tert-butyl-4-ethoxy-pyrimidin-5-yl) -4,5-bis- (4-chloro-phenyl) -4,5-dihydro-imidazole-1-carbonyl] -piperazin-1-il} -N, N-dimethyl-acet amide, The cis-4 - [2- (2-tert-butyl-4-ethoxy-pyrimidin-5-yl) -4,5-bis- (4-chloro-phenyl) -4,5-dihydro chloride is reacted -imidazol- 1 -carbonyl (example 20) with N, N-dimet i 1-2 -pipera zin-1-yl-acetamide (Oakwood Products), obtaining cis-2-. { 4- [2- (2-tert-butyl-4-ethoxy-pyrimidin-5-yl) -4,5-bis- (4-chloro-phenyl) -4,5-dihydro-imidazole-1-carbonyl] -piperazin-l-il} -N, N-dimethyl acet amide, hydrochloride, in a manner similar to that described in example 1. HR-MS (ES, m / z) calculated from C34H42N703C12 [(M + H) +] = 666.2721, found = 666.2721.

- - Example 22 cis- [2- (2-tert-butyl-4-ethoxy-pyrimidin-5-yl) -4,5-bis- (4-chloro-phenyl) -4,5-dihydro-imide zol hydrochloride - 1-yl] - [4- (2-methanesulfonyl-ethyl) -piperazin-1-yl] -methanone, The cis-4 - [2- (2-tert-butyl-4-ethoxy-pyrimidin-5-yl) -4,5-bis- (-chloro-phenyl) -4,5-dihydrochloride is reacted imide zol-1-carbonyl (example 20) with the dihydrochloride of 1- (2-methyl-anosul-foni-1-ethyl) piperazine (example 3), obtaining cis- [2- (2-tert-butyl-4- ethoxy-pyrimidin-5-yl) -4,5-bis- (4-chloro-phenyl) -4,5-dihydro-imide zol-1-yl] - [4- (2-methanesulfonyl-ethyl) -pipera zin -l-yl] -metanone, hydrochloride, in a manner similar to that described in Example 1. HR-MS (ES, m / z) calculated from C33H4? N604SCl2 [(M + H) +] = 687.2282, found = 687.2286.

- Example 23 cis-2-. { 4- [2- (2-tert-Butyl-4-ethoxy-pyrimidin-5-yl) -4,5-bis- (4-chloro-phenyl) -4,5-dihydro-imidazole-1-carbonyl] -pipera zin- 1-il} -l-morpholin-4-i 1-ethanone The cis-4 - [2- (2-tert-butyl-4-ethoxy-pyrimidin-5-yl) -4,5-bis- (4-chloro-phenyl) -, 5-dihydrochloride is reacted imidazole-1-carbonyl (Example 20) with l-morpholin-4 -i 1-2 -piperazin-1-yl-ethanone (Oa wood Products), obtaining cis-2-. { - [2- (2-tert-butyl-4-ethoxy-pyrimidin-5-yl) -4,5-bis- (4-chloro-phenyl) -4,5-dihydro-imidazole-1-carbonyl] - pipera zin-l-il} -1-morpholin-4-yl-ethanone in a manner similar to that described in example 1. HRMS (ES, m / z) calculated from C36H44N704C12 [(M + H) +] = 708.2827, found 708.2830.

- - Example 24 cis- [2- (2-tert-butyl-4-ethoxy-pyrimidin-5-yl) -4,5-bis- (4-chloro-phenyl) -4,5-dihydro-imidazol-1-yl ] - (4-dimethylamino-piperidin-1-yl) -metanone The cis-4- [2- (2-tert-butyl-4-ethoxy-pyrimidin-5-yl) -4,5-bis- (4-chloro-phenyl) -4,5-dihydro chloride is reacted -imidazole-1-carbonyl (example 20) with 4-dimethylamino-piperidine (Aldrich), obtaining cis- [2- (2-tert-butyl-4-ethoxy-pyrimidin-5-yl) -4,5- bis- (4-chloro-phenyl) -4,5-dihydro-imidazol-1-yl] - (4-dimethylamino-piperidin-1-yl) -methanone in a manner similar to that described in example 1. EM- HR (ES, m / z) calculated from C33H4? N6? 2Cl2 [(M + H) +] = 623.2663, found = 623.2665. Example 25 cis- [2- (2-tert-butyl-4-ethoxy-pyrimidin-5-yl) -4,5-bis- (4-chloro-phenyl) -, 5-dihydro-imidazol-1-yl] - (4-pyrrolidin-1-yl-piperidin-1-yl) -metanone The cis-4- [2- (2-tert-butyl-4-ethoxy-pyrimidin-5-yl) -4,5-bis- (4-chloro-phenyl) -4,5-dihydro chloride is reacted -imidazole-1-carbonyl (example 20) with 4-pyrrolidin-1-yl- - piperidine (Aldrich), obtaining cis- [2- (2-tert-butyl-4-ethoxy-pyrimidin-5-yl) -4,5-bis- (4-chloro-phenyl) -4,5-dihydro -imidazol-1-yl] - (4-pyrrolidin-1-yl-piperidin-1-yl) -methanone in a manner similar to that described in Example 1. HR-HR (ES, m / z) calculated for C35H42N602C12 [(M + H) +] = 649.2819, found = 649.2822. Example 26 cis-l-. { 4- [2- (2-tert-buty1-4-ethoxy-pyrimidin-5-yl) -4,5-bis- (4-chloro-phenyl) -4,5-dihydro-imidazole-1-carbonyl] - piperazin-1-il} -etanone The cis-4- [2- (2-tert-butyl-4-ethoxy-pyrimidin-5-yl) -4,5-bis- (4-chloro-phenyl) -4,5-dihydro chloride is reacted -imidazole-1-carbonyl (example 20) with 1-acetyl-piperazine (Aldrich), obtaining cis-1-. { 4- [2- (2-tert-Butyl-4-ethoxy-pyrimidin-5-yl) -4,5-bis- (4-chloro-phenyl) -4,5-dihydro-imidazole-1-carbonyl] - piperazin-1-il} -etanone in a manner similar to that described in example 1. HR-MS (ES, m / z) calculated from C32H37N603C12 [(M + H) +] = 623.2299, found = 623.2303.

Example 27 cis- [2- (2-tert-butyl-4-ethoxy-pyrimidin-5-yl) -4,5-bis- (4-chloro-phenyl) -4,5-dihydro-imidazole-1- il] - (4-methyl-piperazin-1-yl) -metanone The cis-4- [2- (2-tert-butyl-4-ethoxy-pyrimidin-5-yl) -4,5-bis- (4-chloro-phenyl) -4,5-dihydro chloride is reacted -imidazole-1-carbonyl (example 20) with 1-methyl-piperazine (Aldrich), obtaining cis- [2- (2-tert-butyl-4-ethoxy-pyrimidin-5-yl) -4,5- bis- (4-chloro-phenyl) -4,5-dihydro-imidazol-1-yl] - (4-methyl-piperazin-1-yl) -methanone in a manner similar to that described in Example 1. HR (ES, m / z) calculated from C32H3 N < 5? 2 Cl2 [(M + H) +] = 595.2350, found = 595.2351. Example 28 cis- [2- (2-tert-butyl-4-ethoxy-pyrimidin-5-yl) -4,5-bis- (4-chloro-phenyl) -4,5-dihydro-imidazol-1-yl ] - [4- (3-methanesulfonyl-propyl) -piperazin-1-yl] -methanone The 1- (3-methanesulfonyl) dihydrochloride is obtained propyl) -piperazine from the 3-methanesulfonyl-propyl 1-tert-butyloxycarbonyl-piperazine and methanesulfonate (obtained according to the method proposed by Baerlocher, FJ et al., Aust. J. Chem. 52, 167-172 , 1999,) in a manner similar to that described for the preparation of the N- (2-methoxy-l-methyl-ethyl) -2-piperazin-1-yl-acetamide dihydrochloride (example 40). The cis-4- [2- (2-tert-butyl-4-ethoxy-pyrimidin-5-yl) -4,5-bis- (4-chloro-phenyl) -4,5-dihydro chloride is reacted -imidazole-1-carbonyl (example 20) with 1- (3-methanesulfonyl-propyl) -piperazine dihydrochloride, obtaining cis- [2- (2-tert-butyl-4-ethoxy-pyrimidin-5-yl) ) -4,5-bis- (4-chloro-phenyl) -4,5-dihydro-imidazol-1-yl] - [4- (3-methanesulfonyl-propyl) -piperazin-1-yl] -methanone from a Similar to that described in Example 1. HR-MS (ES, m / z) calculated from C34H43N6? 4SCl2 [(M + H) +] = 701.2438, found = 701.2439. Example 29 cis- [2- (2-tert-butyl-4-ethoxy-pyrimidin-5-yl) -4,5-bis- (4-chloro-phenyl) -4,5-dihydro-imidazole-1- il] - [4- (2-hydroxy-ethyl) -piperazin-1-yl] -methanone The cis-4- [2- (2-tert-butyl-) chloride is reacted - - 4-ethoxy-pyrimidin-5-yl) -4,5-bis- (4-chloro-phenyl) -4,5-dihydro-imidazole-1-carbonyl (example 20) with 2-piperazin-1-yl- ethanol (Aldrich), yielding cis- [2- (2-tert-butyl-4-ethoxy-pyrimidin-5-yl) -4,5-bis- (4-chloro-phenyl) -4,5-dihydro- imidazol-1-yl] - [4- (2-hydroxy-ethyl) -piperazin-1-yl] -methanone in a manner similar to that described in Example 1. HR-MS (ES, m / z) calculated from C32H39N603C12 [(M + H) +] = 625.2455, found = 625.2457. Example 30 2-. { 4- [(4S, 5R) -2- (2-tert-Butyl-4-ethoxy-pyrimidin-5-yl) -4,5-bis- (4-chloro-phenyl) -4,5-dihydro-imidazole -l-carbonyl] -piperazin-1-yl} -1-morpholin-4-yl-ethanone By chiral chromatography on a ChiralPak OD column, the enantiomers are separated from that of cis-2-. { 4- [2- (2-tert-Butyl-4-ethoxy-pyrimidin-5-yl) -4,5-bis- (4-chloro-phenyl) -4,5-dihydro-imide zol-1 -carbonyl] -piperazin-1-il} -1-morpholin-4-yl-ethanone (example 23). Eluent: 60% ethanol in hexane. The first peak of material that leaves the column corresponds to the desired enantiomer, 2-. { - [(4 S, 5R) -2- (2-tert-butyl-4-ethoxy-pyrimidin-5-yl) -4,5-bis- (4-chloro-f-enyl) -4,5-dihydro - imide zol-1- carbonyl] -pipera zin-l-il} -1-morph olin-4-yl-ethanone. LRMS = 708.0 [(M + H) +]. EXAMPLE 31 4- [(4S, 5R) -2- (2-tert-Butyl-4-ethoxy-pyrimidin-5-yl) -4,5-bis- (4-chloro-phenyl) -4,5-dihydro -imidazol-1 -carbonyl] -pipera zin-2 -one The enantiomers of cis-4- [2- (2-tert-butyl-4-ethoxy-pyrimidin-5-yl) -4,5-bis- (-chlorophenyl) -4,5-dihydro-imide zol are separated - 1 -carbonyl] -pipera zin-2-one (example 20) by chiral chromatography on a ChiralPak OD column. Eluent: 60% ethanol in hexane. The first peak of material leaving the column corresponds to the desired enantiomer, 4- [(4S, 5R) -2- (2-tert-butyl-4-ethoxy-pyrimidin-5-yl) -4,5-bis - (4-chloro-phenyl) -4,5-dihydro-imidazole-1-carbonyl] -piperazin-2-one. LR-MS = 595.2 [(M + H) +] - - Example 32 cis-4- [4,5-bis- (4-chloro-phenyl) -2- (4,6-diethoxy-pyridin-3-yl) -4,5-dihydro-imidazole-1-carbonyl hydrochloride ] -piperazin-2-one, The 2,4-diethoxy-5-carbethoxypyridine is reacted (obtained from the 2, -dichloro-5-carbetoxypyridine and sodium ethoxide applying the procedure described by Nesnow, S. et al., J. Med. Chem. 16, 524, 1973) with meso-l, 2-bis- (-chlorophenyl) - ethane-1,2-diamine in a manner similar to that described in example 1, obtaining cis-4- [4,5-bis- (4-chlorophenyl) -2- (4,6-diethoxy-pyridine) -3-yl) -4,5-dihydro-lH-imidazole. Applying the procedure described in example 1, cis-4- [4,5-bis- (4-chloro-f-enyl) -2- (4,6-diethoxy-pyridin-3-yl) -4 is reacted, 5-dihydro-lH-imidazole with phosgene, obtaining cis-4- [, 5-bis- (4-chloro-f-enyl) -2- (4,6-diethoxy-pyridin-3-yl) -4 chloride , 5-dihydro-imidazole-1-carbonyl. This carbonyl chloride is then reacted with 2-piperazinone (Alfa), obtaining the hydrochloride of cis-4- [4,5-bis- (4-chloro-phenyl) -2- (4,6-diethoxy). pyridin-3-yl) -4,5-dihydro-imidazole-1-carbonyl] -piperazin-2-one.

- Example 33 cis- [4,5-bis- (4-chlorophenyl) -2- (4,6-diethoxy-pyridin-3-yl) -4,5-dihydro-imidazol-1-yl] hydrochloride] - [4- (2-hydroxy-ethyl) -piperazin-1-yl] -methanone, The cis-4- [4,5-bis- (4-chloro-phenyl) -2- (4,6-diethoxy-pyridin-3-yl) -4,5-dihydro-imidazol-1 chloride is reacted -carbonyl (example 32) with 2-piperazin-1-yl-ethanol (Aldrich), obtaining cis- [4,5-bis- (4-chloro-phenyl) -2- (4-6) hydrochloride dietoxy-pyridin-3-yl) -4,5-dihydro-imidazol-1-yl] - [4- (2-hydroxy-ethyl) -piperazin-1-yl] -methanone in a manner similar to that described in example 1. Example 34 2-. { 4- [(4S, 5R) -4, 5-bis- (4-chloro-phenyl) -2- (3-ethoxy-thiophen-2-yl) -4,5-dihydro-imidazole-1-carbonyl] - piperazin-1-il} -N-tert-butyl-acetamide The N-tert-butyl-2-piperazin-1-yl-acetamide dihydrochloride is obtained from the 1-tert- - butyloxycarbonyl-piperazine, chloroacetyl chloride and N-tert-butylamine in a manner similar to that described for the preparation of N- (2-methoxy-1-methyl-ethyl) -2-piperazin-1-yl- dihydrochloride acetamide (example 40). The ethyl 3-ethoxy-thiophene-2-carboxylate (obtained from 3-hydroxy-thiophene-2-carboxylic acid) is reacted with meso-1,2-bis- (4-chlorofenyl) -ethane -1,2-diamine in a manner similar to that described in Example 1, yielding cis-4, 5-bis- (4-chlorophenyl) -2- (3-ethoxy-thiophen-2-yl) -4, 5-dihydro-lH-imidazole. Applying the procedure described in the example 1 cis-4, 5-bis- (4-chloro-f-en-1) -2- (3-ethoxy-thiophen-2-yl) -4,5-dihydro-1H-imidazole is reacted with phosgene, obtaining the chloride of ci s- 4, 5-bi s - (4-chloro-phenyl) -2- (3-ethoxy-thiophen-2-yl) -4,5-dihydro-imide zol-1 -carbonyl lo. The enantiomers of cis-4,5-bis- (-chloro-f-enyl) -2- (3-ethoxy-thiophen-2-yl) -4,5-dihydro-imide zol-1 -carbonyl are separated from each other. by chiral chromatography using a Modcol spring column (50 mm x 70 cm) with R filling, R-Whelk-01 spherical Kromasil silica gel (Regis Technologies, eluent: 30% methylene chloride in hexane, flow rate: 85 ml / min), yielding 2- chloride. { 4- [(4S, 5R) -4,5-bis- (4-chloro-phenyl) -2- (3-ethoxy-) - thiophen-2-yl) -4,5-dihydro-imide zol-1 -carboni as desired.

The 2- chloride is reacted. { - [(4S, 5R) -4,5-bis- (4-chloro-phenyl) -2- (3-ethoxy-thiophen-2-yl) -4,5-dihydro-imidazole-1-carbonyl with dihydrochloride of N-tert-butyl-2-piperazin-1-yl-acetamide, obtaining 2-. { 4- [(4S, 5R) -4, 5-bis- (4-chloro-phenyl) -2- (3-ethoxy-thiophen-2-yl) -4,5-dihydro-imidazole-1-carbonyl] - piperazin-1-il} -N-tert-butyl acetamide in a manner similar to that described in example 1. EM-LR = 642.3 [(M + H) +]. Example 35 2-. { 4- [(4S, 5R) -4, 5-bis- (4-chloro-phenyl) -2- (3-ethoxy-thiophen-2-yl) -4,5-dihydro-imidazole-1-carbonyl] -piperazine -l-il} -acetamide ral The 2- chloride is reacted. { 4- [(4S, 5R) -4,5-bis- (4-chloro-phenyl) -2- (3-ethoxy-thiophen-2-yl) -4,5-dihydro-imidazole-1-carbonyl (example 34) with the hydrochloride of 2-piperazin-1-yl-acetamide (Matrix), obtaining 2-. { 4- [(4S, 5R) -4, 5-bis- (4-chloro-phenyl) -2- (3-ethoxy-thiophen-2-yl) -4,5-dihydro-imidazole-1-carbonyl] - piperazin-1-il} -acetamide in a manner similar to that described in example 1. EM-LR = 586.2 [(M + H) +].

Example 36 2-. { 4- [(4S, 5R) -4, 5-bis- (4-chloro-phenyl) -2- (3-ethoxy-thiophen-2-yl) -4,5-dihydro-imidazole-1-carbonyl] - piperazin-1-il} -N, N-bis- (2-methoxy-ethyl) -acetamide The N, N-bis- (2-methoxy-ethyl) -2-piperazin-1-yl-acetamide dihydrochloride is obtained from 1-tert-butyloxycarbonyl-piperazine, chloroacetyl chloride and N, N-bis - (2-methoxy-ethyl) amine in a manner similar to that described for the preparation of the N- (2-methoxy-1-methyl-ethyl) -2-piperazin-1-yl-acetamide dihydrochloride (example 40) . The 2- chloride is reacted. { 4- [(4S, 5R) -4, 5-bis- (4-chloro-phenyl) -2- (3-ethoxy-thiophen-2-yl) -4,5-dihydro-imidazole-1-carbonyl (example 34) with the dihydrochloride of N, N-bis- (2-methoxy-ethyl) -2-piperazin-1-yl-acetamide, obtaining 2-. { 4- [(4S, 5R) -4,5-bis- (-chloro-phenyl) -2- (3-ethoxy-thiophen-2-yl) -4,5-dihydro-imidazole-1-carbonyl] -piperazine -1-il} -N, N-bis- (2-methoxy-ethyl) -acetamide in a manner similar to that described in example 1. MS-LR = 702.3 [(M + H) +].

- - Example 37 2-. { 4- [(4S, 5R) -4, 5-bis- (-chloro-phenyl) -2- (3-ethoxy-thiophen-2-yl) -4,5-dihydro-imidazole-1-carbonyl] -piperazine -1-il} -N-methoxy-N-methyl-acetamide The dihydrochloride of N-methoxy-N-met i 1-2 -pipera zin-1-yl-acetamide is obtained from 1-tert-but i loxycarboni 1 -piperazine, chloroacetyl chloride and N- methoxy-N-methylamine in a manner similar to that described for the preparation of the N- (2-methoxy-1-met-il-et i 1) -2-piperazin-1-yl-acetylamide dihydrochloride (eg 40). The 2 - chloride is reacted. { - [(4 S, 5R) -4,5-bis- (4-chloro-phenyl) -2- (3-ethoxy-thiophen-2-yl) -4,5-dihydro-imidazol-1 -carboni lo ( example 34) with the dihydrochloride of N-methoxy-N-met i 1-2 -piperazin-1-i-acetamide, obtaining 2-. { - [(4 S, 5R) -4, 5-bis- (-chloro-phenyl) -2- (3-ethoxy-thiophen-2-yl) -4,5-dihydro-imide zol-1 -carbonyl] - pipera zin-1-il} -N-methoxy-N-methyl-acetamide in a manner similar to that described in example 1. EM-LR = 630.3 [(M + H) +].

- - Example 38 2-. { 4- [(4S, 5R) -4, 5-bis- (4-chloro-phenyl) -2- (3-ethoxy-thiophen-2-yl) -4,5-dihydro-imidazole-1-carbonyl] - piperazin-1-il} -N-isopropyl-N-methyl-acetamide The N-isopropyl-N-methyl-2-piperazin-1-yl-acetamide dihydrochloride is obtained from 1-tert-butyloxycarbonyl-piperazine, chloroacetyl chloride and N-isopropyl-N-methylamine in a similar manner to that described for the preparation of the N- (2-methoxy-l-methyl-ethyl) -2-piperazin-1-yl-acetamide dihydrochloride (example 40). The 2 - chloride is reacted. { 4 - [(4 S, 5R) -4,5-bis- (4-chloro-phenyl) -2- (3-ethoxy-thiophen-2-yl) -4,5-dihydro-imide zol-1 -carboni (Example 34) with the dihydrochloride of N-i sopropi 1-N-met il-2-piperazin 1 -i 1-acet amide, obtaining 2 -. { 4 - [(4 S, 5R) -, 5-bi s- (4-chloro-phenyl) -2- (3-ethoxy-thiophen-2-yl) -4,5-dihydro-imidazol-1 -carbonyl] -pipe zin-1-il} -N-isopropyl-N-met i 1-acet amide in a manner similar to that described in example 1. EM-LR = 642.3 [(M + H) +].

- Example 39 2-. { 4- [(4S, 5R) -4, 5-bis- (4-chloro-phenyl) -2- (3-ethoxy-thiophen-2-yl) -4,5-dihydro-imidazole-1-carbonyl] - piperazin-l-il} -N- (2-cyano-ethyl) -N-methyl-acetamide The N- (2-Cyano-et i 1) -N-met il-2-piperazin-1-yl-acet amide dihydrochloride is obtained from 1-tert-butyloxycarbonyl-piperazine, chloroacetyl chloride and N- (2-cyanoethyl) -N-methylamine in a manner similar to that described for the preparation of the dihydrochloride of N- (2-methoxy-1-met i 1 -et il) -2-piperaz in- 1-yl-acetamide (example 40). The 2 - chloride is reacted. { - [(4 S, 5R) -4,5-bis- (4-chloro-phenyl) -2- (3-ethoxy-thiophen-2-yl) -4,5-dihydro-imide zol-1-carbonyl ( Example 34) with the N- (2-cyano-et i 1) -N-met i 1-2 -piperazin-1-yl-acet amide dihydrochloride, obtaining 2-. { 4- [(4S, 5R) -4,5-bis- (4-chloro-phenyl) -2- (3-ethoxy-thiophen-2-yl) -4,5-dihydro-imidazol-1 -carbonyl] - piperazin-1-il} -N- (2-cyano-ethyl) -N-met-il-acetamide in a manner similar to that described in example 1. EM-LR = 653.2 [(M + H) +].

- - Example 40 cis-2-. { 4- [4,5-bis- (4-chloro-phenyl) -2- (3-ethoxy-thiofen-2-yl) -, 5-dihydro-imide zol-1 -carbonyl] -pipera zin- 1- il} -N- (2-methoxy-1-methyl-ethyl) -acetamide The 2-methoxy-1-methyl-ethylamine (15 mmol, 1.15 eq.) And the diisopropylethylamine (17 mmol, 1.3 eq.) Were diluted with methylene chloride, obtaining a total volume of 8 ml. This amine solution is added in portions by syringe to a solution of chloroacetyl chloride (13 mmol) in methylene chloride (10 ml) cooled to approximately -40 ° C in a sealed vial of 40 ml. The reaction mixture was stirred at reduced temperature for 1 h. The solution is acidified with IN hydrochloric acid and diluted with 10 ml of methylene chloride. The vial is shaken and centrifuged. The organic phase is transferred to 40 ml vials and concentrated in vacuo. The residue is diluted (1.69 g, 10.21 mmol) with 10 ml of dimethylformamide. Tert-butyl piperazine-1-carboxylate (8.67 mmole, 0.85 eq.) And diisopropylethylamine (13.27 mmole, 1.3 eq.). The reaction mixture was stirred at 65 ° C overnight and concentrated in vacuo. The raw residue is dissolved in 10 ml - of dioxane and 10 ml of 4M hydrochloric acid in dioxane. The solution is stirred at room temperature overnight and then centrifuged. The supernatant liquid is separated and the remaining solids are stirred with hexane, then centrifuged. The supernatant liquid is separated, the solids are collected and dried under vacuum, obtaining the N- (2-methoxy-l-methylethyl) -2-piperazin-1-yl-acetamide dihydrochloride. LRMS = 216.4 [(M + H) +]. The 2- chloride is reacted. { 4- [(4S, 5R) -4,5-bis- (4-chloro-phenyl) -2- (3-ethoxy-thiophen-2-yl) -4,5-dihydro-imidazole-1-carbonyl (example 34) with the N- (2-methoxy-1-methylethyl) -2-piperazin-1-yl-acetamide dihydrochloride, obtaining cis-2. { 4- [4,5-bis- (4-chloro-phenyl) -2- (3-ethoxy-thiof en-2-yl) -4,5-dihydro-imide zol-1 -carbonyl] -piperazin-1- il} -N- (2-methoxy-1-methyl-ethyl) -acetamide in a manner similar to that described in Example 1. MS-LR = 658.2 [(M + H) +]. Example 41 [(4S, 5R) -4,5-bis- (4-chloro-phenyl) -2- (3-ethoxy-thiophen-2-yl) -4,5-dihydro-imidazol-1-yl] - [4- (3, 5-dimethyl-isoxazole-4-carbonyl) -piperazin-1-yl] -metanone chiral A 1-tert-solution is introduced into a 40 ml vial. - butyloxycarbonyl-piperazine (4.581 mmol, 0.9 eq.) and diisopropylethylamine (5.09 mmol, 1.0 eq.) in methylene chloride (5 ml). The 3,5-dimethyl-isoxazolecarbonyl chloride (5.09 mmol, 1.0 eq.) Is added to the vial and the reaction mixture is stirred at room temperature overnight. After the reaction is complete, the reaction mixture is diluted with methylene chloride (5 ml) and washed with 4 ml of IN hydrochloric acid and then with 4 ml of 10% potassium carbonate. The organic phase is concentrated in vacuo. The crude residue was dissolved in 5 ml of dioxane and 5 ml of 4M hydrochloric acid in dioxane. The reaction mixture is stirred at room temperature overnight and then centrifuged. The supernatant is separated and the remaining solid is stirred with hexane, then centrifuged. The supernatant liquid is separated, the solids are collected and dried in vacuo to obtain (3,5-dimethyl-1-isoxazol-1-yl) -piperazin-1-yl-methanolamine. LRMS = 210.2 [(M + H) +]. The 2 - chloride is reacted. { 4 - [(4S, 5R) -4,5-bis- (4-chloro-phenyl) -2- (3-ethoxy-thiophen-2-yl) -4,5-dihydro-imidazole-1-carbonyl ( example 34) with (3,5-dimet i l-isoxazol-4-yl) -piperazin-1-yl-methanone, obtaining [(4 S, 5R) -4,5-bis- (4-chloro) - feni 1) -2 - (3- - - ethoxy-thiophen-2-yl) -4,5-dihydro-imide zol-1-yl] - [4- (3,5-dimethyl-isoxazole-4-carbonyl) -piperazin-1-yl] -methanone in a manner similar to that described in example 1. EM-LR = 652.2 [(M + H) +]. Example 42 [(4S, 5R) -4,5-bis- (4-chloro-f-enyl) -2- (3-ethoxy-thiofen-2-yl) -4,5-dihydride or -imide zol- 1-yl] - (4-ethanesulfonyl-piperazin-1-yl) -metanone The ethosul fonyl-piperazine is obtained from 1-tert-but-yloxycarbonyl 1-piperazinone and ethylsulfonyl chloride in a manner similar to that described for the preparation of (3, 5-dimet i-isoxa) zol- 4 -i 1) -piperazin-1-yl-methanone in Example 41. The 2 - chloride is reacted. { 4 - [(4S, 5R) -4,5-bis- (4-chloro-phenyl) -2- (3-ethoxy-thiophen-2-yl) -4,5-dihydro-imidazole-1-carbonyl ( Example 34) with 1-ethanesulfonyl-piperazine, yielding [(4S, 5R) -4,5-bis- (4-chloro-phenyl) -2- (3-ethoxy-thiophen-2-yl) -4, 5-dihydro-imidazol-1-yl] - (4-ethanesulfonyl-piperazin-1-yl) -methanone in a manner similar to that described in example 1. EM-LR = 621.2 [(M + H) +].

- - Example 43 N- (2- { 4- [(S, 5R) -4,5-bis- (4-chloro-phenyl) -2- (3-ethoxy-thiophen-2-yl) -4,5 -dihydro-imidazole-1-carbonyl] -piperazin-1-yl ethyl) -methanesulfonamide Methanesulfonyl chloride (0.7 ml, 9.0 mmol) is added to a cooled solution of tert-butyl 4- (2-amino-ethyl) -piperazine-1-carboxylate (1.33 g), 5.8 mmole) in pyridine (25.0 ml). The reaction mixture was stirred for 12 h and partitioned between an aqueous solution of sodium bicarbonate and methylene chloride. The organic phase is washed with 1M hydrochloric acid, an aqueous solution of sodium bicarbonate, brine, dried with anhydrous magnesium sulfate and concentrated. Purification of the crude residue by flash chromatography through silica gel with 0 to 5% methanol in methylene chloride gives 4- (2-methanesulfonylamino-ethyl) -piperazine-1-carboxylate of tert-butyl (0.70. g, 70%). To a cooled solution of tert-butyl 4- (2-methanesulfonylamino-ethyl) -piperazine-1-carboxylate (0.64 g, 0.2 - - mmoles) in dioxane (20 ml) was added hydrochloric acid (4M in dioxane, 10 ml) and the reaction mixture was stirred at room temperature for 12 h and concentrated, obtaining N- (2-methanesulfonylethyl) dihydrochloride. -piperazine as a white solid (0.55 g, 95%). The 2- chloride is reacted. { 4 - [(S, 5R) -4,5-bis- (4-chloro-phenyl) -2- (3-ethoxy-thiophen-2-yl) -4,5-dihydro-imidazole-1-carbonyl (example 34) with the dihydrochloride of N- (2-met anosul f onile ti 1) -piperazine, obtaining N- (2- { 4 - [(S, 5R) -4,5-bis- (4 - chloro-phenyl) -2- (3-ethoxy-thiophen-2-yl) -4,5-dihydro-imidazol-1-carbonyl] -piperazin-1-yl}. -ethyl) -methanesulfonamide in a manner similar to the one described in example 1. EM-LR = 650.1 [(M + H) +]. Example 44 [(4S, 5R) -4,5-bis- (4-chloro-f-enyl) -2- (3-ethoxy-thiof-2-yl) -4,5-dihydro-imidazol-1-yl ] - [4- (3-me t anosul fonil-propyl) -piperazin-1-yl] -methanone The 2- chloride is reacted. { 4 - [(4S, 5R) -4, 5-bis- (4-chloro-phenyl) -2- (3-ethoxy-thiophen-2-yl) -4, 5- - - dihydro-imidazol-1 -carboni lo (example 34) with the dihydrochloride of 1- (3-met anosul fonyl-propyl) -piperazine (example 28), obtaining [(4 S, 5R) -4.5 -bis- (4-chloro-phenyl) -2- (3-ethoxy-thiophen-2-yl) -4,5-dihydro-imide zol-1-yl] - [4- (3-methanesulfonyl-propyl) -piperazin 1 -i 1] -methanone in a manner similar to that described in example 1. EM-LR = 649.2 [(M + H) +]. Example 45 [(4S, 5R) -4,5-bis- (4-chloro-f-enyl) -2- (3-ethoxy-thiof-2-yl) -4,5-dihydro-imidazol-1-yl ] - [4- (2-methanesulfonyl-ethyl) -piperazin-1-yl] -methanone The 2- chloride is reacted. { 4 - [(4 S, 5R) -4,5-bis- (4-chloro-phenyl) -2- (3-ethoxy-thiophen-2-yl) -4,5-dihydro-imide zol-1 -carboni with 1- (2-methanesulfonylethyl) piperazine dihydrochloride (example 3), obtaining [(4 S, 5R) -4,5-bis- (4-chloro-phenyl) -2- (3-ethoxy) -thiophen-2-yl) -4,5-dihydro-imide zol-1-yl] - [4- (2-methanesulfonyl-et i 1) -pipera zin-1 -i 1] -methanone in a similar manner to that described in example 1. EM-LR = 635.1 [(M + H) +].

- - Example 46 2-. { 4- [(4S, 5R) -4, 5-bis- (4-chloro-phenyl) -2- (3-ethoxy-thiof-2-yl) -4,5-dihydro-imide zol-1 -carbonyl ] -pipera zin-1-il} -l-morpholin-4-yl-et anona The 2- chloride is reacted. { 4- [(4S, 5R) -4,5-bis- (4-chloro-phenyl) -2- (3-ethoxy-thiophen-2-yl) -4,5-dihydro-imidazole-1-carbonyl (example 28) with 1-morpholin-4-yl-2-piperazin-1-yl-ethanone (Oakwood Products), obtaining 2-. { - [(4S, 5R) -4,5-bis- (4-chloro-phenyl) -2- (3-ethoxy-thiophen-2-yl) -4,5-dihydro-imidazole-1-carbonyl] -piperazine -1-il} -1-morpholin-4-yl-ethanone in a manner similar to that described in example 1. EM-LR = 656.3 [(M + H) +]. EXAMPLE 47"In vitro" Activity Test The ability of the compounds to inhibit the interaction between the p53 and MDM2 proteins is measured by HTRF assay (homogeneous time-resolved fluorescence), in which the recombinant MDM2, labeled with GST, is fixed on a peptide that is similar to the region of interaction of p53 with MDM2 (Lane et al.). The fixation of the GST-MDM2 protein and the - - p53 peptide (biotinylated at its N-terminus) is recorded by a FRET (fluorescence resonance energy transfer) assay between the anti-GST antibody labeled with europium (Eu) and the allophycocyanin (APC) conjugated with streptavidin. The assay is carried out in 384-well flat bottom black plates (Costar), in a total volume of 40 μl containing: 90 nM of biotinylated peptide, 160 ng / ml of GST-MDM2, 20 nM of streptavidin-APC (PerkinElmerWallac), 2 nM Eu-labeled anti-GST antibody (PerkinElmer allac), 0.2% bovine serum albumin (BSA), 1 mM dithiothreitol (DTT) and 20 mM Tris-borate-saline buffer (TBS) , as follows: 10 μl of GST-MDM2 (640 ng / ml working solution) in reaction buffer is added to each well. Add 10 μl of the diluted compounds (dilution 1: 5 and el the reaction buffer) to each well, mix by agitation. 20 μl of biotinylated p53 peptide (180 nM working solution) are added in reaction buffer to each well and mixed in the agitator. Incubate at 37 ° C for 1 h. 20 μl of a mixture of streptavidin-APC and anti-GST-labeled anti-GST antibody (6 nM anti-GST labeled with Eu and 60 nM streptavidin-working solution APC) in TBS buffer with 0.2% BSA are added, it is stirred at room temperature for 30 minutes and the result is read with a plate reading apparatus suitable for the TRF between 665 and 615 nm (Victor 5, Perkin Elmer allac). If I dont know - - specifies otherwise, the reagents are purchased from Sigma Chemical Co. The values of the IC50 that indicate the biological activity, which emanates from the compounds that are the object of this invention, are between 0.030 μM and 7 μM. The specific data of the compounds of some examples are the following: Example IC50 (μM) 6 2.890 17 0.677 20 0.046 34 0.110 36 0.054 It is noted that in relation to this date, the best method known by the applicant to carry the practice said invention is that which is clear from the present description of the invention.

Claims

- - CLAIMS Having described the invention as above, the content of the following claims is claimed as property: 1. Compound of the formula I and pharmaceutically acceptable salts and esters thereof, characterized in that ring A is: where Xi is ethoxy; X2 is hydrogen, -O-C1-C6 alkyl, -S-C1-C6 alkyl, - - -alkyl (C1-C6) or -CF3 and Z and Y are both nitrogen; Vi and V2 are -Cl; is wherein Ri is oxo, -C (O) -alkyl (C1-C6), -C (O) -dimethyl-isoxazole, -S (0) 2 -alkyl (C1-C6), or -alkyl (C1-6) C6), which is unsubstituted or substituted once by -OH, -S (0) 2-(C1-C6) alkyl, -C (O) -morpholino, -C (0) -N [alkyl (Cl-C6 )] 2, wherein each alkyl independently of the others is unsubstituted or substituted once by cyano or methoxy, -C (O) -NH- (C1-C6) alkyl, in which the alkyl is unsubstituted or replaced once by - - methoxy, -C (0) -NH2, -C (0) -N- (C1-C4 alkyl) (C1-C4 alkoxy) or -NH-S (0) 2-(C1-C6) alkyl and n = 1; and the pharmaceutically acceptable salts thereof. Compound according to claim 1, characterized in that two hydrogen atoms of the imidazoline ring are in a cis configuration, one with respect to the other. 3. Compound characterized in that it is chosen from the group consisting of: cis-4- [(4, 5-bis- (4-chloro-phenyl) -2- (2-ethoxy-pyridin-3-yl) -4,5 -dihydro-imidazole-1-carbonyl] -piperazin-2-one, cis-2 { 4- [4, 5-bis- (4-chloro-phenyl) -2- (2-ethoxy-pyridin-3 -yl) -4,5-dihydro-imidazole-1-carbonyl] -piperazin-1-yl.} - N, N-dimethyl-acetamide, cis- [4, 5-bis- (4-chloro-phenyl) -2- (2-Ethoxy-pyridin-3-yl) -4,5-dihydro-imidazol-1-yl] - [4- (2-methanesulfonyl-ethyl) -piperazin-1-yl] -methanone, cis- 2- { 4- [4, 5-bis- (4-chloro-phenyl) -2- (2-ethoxy-pyridin-3-yl) -4,5-dihydro-imidazole-1-carbonyl] -piperazine -l-il.}.-l-morpholin-4-yl-ethanone, cis-4- [4,5-bis- (4-chloro-phenyl) -2- (4-ethoxy-2-trifluoromethyl-pyrimidin- 5-yl) -4,5-dihydro-imidazole-l- - - carbonyl] -piperazin-2-one, cis- [4,5-bis- (4-chloro-phenyl) -2- (4-ethoxy-2-trifluoromethyl-pyrimidin-5-yl) -4,5- dihydro-imidazol-1-yl] - [4- (2-methanesulfonyl-ethyl) -piperazin-1-yl] -methanone, cis-2-. { 4- [4,5-bis- (4-chloro-phenyl) -2- (4-ethoxy-2-trifluoromethyl-pyrimidin-5-yl) -4,5-dihydro-imidazole-1-carbonyl] -piperazine- l-il } -l-morpholin-4-yl-ethanone, cis-4- [4,5-bis- (4-chloro-phenyl) -2- (2,4-diethoxy-pyrimidin-5-yl) -4,5- dihydro-imidazole-1-carbonyl] -piperazin-2-one, cis-2-. { 4- [4,5-bis- (4-chloro-phenyl) -2- (2,4-diethoxy-pyrimidin-5-yl) -4,5-dihydro-imidazole-1-carbonyl] -piperazin-1- il} -N, N-dimethyl-acetamide, cis- [4,5-bis- (4-chloro-phenyl) -2- (2,4-diethoxy-pyrimidin-5-yl) -4,5-dihydro-imidazole- l-il] - [4- (2-methanesulfonyl-ethyl) -piperazin-1-yl] -methanone, cis-2-. { 4- [4,5-bis- (4-chloro-phenyl) -2- (2,4-diethoxy-pyrimidin-5-yl) -4,5-dihydro-imidazole-1-carbonyl] -piperazin-1- il) -l-morpholin-4-yl-ethanone, cis-4- [4, 5-bis- (4-chloro-phenyl) -2- (4-ethoxy-2-methylsulfañyl-pyrimidin-5-yl) - 4, 5-dihydro-imidazole-1-carbonyl] -piperazin-2-one and cis-2-. { 4- [4,5-bis- (4-chloro-phenyl) -2- (4-ethoxy-2-methylsulfanyl-pyrimidin-5-yl) -4,5-dihydro-imidazole-1-carbonyl] -piperazine- 1-il} -N, N-dimethyl acetamide. 4. Compound characterized because chosen among the - - group consisting of cis- [4,5-bis- (4-chloro-phenyl) -2- (4-ethoxy-2-methylsulfanyl-pyrimidin-5-yl) -4,5-dihydro-imidazole-1- il] - [4- (2-methanesulfonyl-ethyl) -piperazin-1-yl] -methanone, cis-2-. { 4- [4,5-bis- (4-chloro-phenyl) -2- (4-ethoxy-2-methylsulfanyl-pyrimidin-5-yl) -4,5-dihydro-imidazole-1-carbonyl] -piperazine- 1-il} -1-morpholin-4-yl-ethanone, cis-4- [4,5-bis- (4-chloro-phenyl) -2- (4-ethoxy-2-methyl-pyrimidin-5-yl) -4, 5-dihydro-imidazole-1-carbonyl] -piperazin-2-one, cis-2-. { 4- [4,5-bis- (4-chloro-phenyl) -2- (4-ethoxy-2-methyl-pyrimidin-5-yl) -4,5-dihydro-imidazole-1-carbonyl] -piperazine- 1-il} -N, N-dimethyl-acetamide, cis- [4, 5-bis- (4-chloro-phenyl) -2- (4-ethoxy-2-methyl-pyrimidin-5-yl) -4, 5-dihydro-imidazol-1-yl] - [4- (2-methanesulfonyl-ethyl) -piperazin-1-yl] -methanone, cis-2-. { 4- [4,5-bis- (4-chloro-phenyl) -2- (4-ethoxy-2-methyl-pyrimidin-5-yl) -4,5-dihydro-imidazole-1-carbonyl] -piperazine- 1-il} -l-morpholin-4-yl-ethanone, cis-4- [2- (2-tert-butyl-4-ethoxy-pyrimidin-5-yl) -4,5-bis- (4-chloro-phenyl) hydrochloride ) -4,5-dihydro-imidazole-1-carbonyl] -piperazin-2-one, cis-2-hydrochloride. { 4- [2- (2-tert-Butyl-4-ethoxy-pyrimidin-5-yl) -4,5-bis- (4-chloro-phenyl) -4,5-dihydro-imidazole-1-carbonyl] - piperazin-1-il} -N, N-dimethyl acetamide, - - Cis- [2- (2-tert-Butyl-4-ethoxy-pyrimidin-5-yl) -4,5-bis- (4-chloro-phenyl) -4,5-dihydro-imidazol-l-yl hydrochloride ] - [4- (2-methanesulfonyl-ethyl) -piperazin-1-yl] -methanone, cis-2-. { 4- [2- (2-tert-Butyl-4-ethoxy-pyrimidin-5-yl) -4,5-bis- (4-chloro-phenyl) -4,5-dihydro-imidazole-1-carbonyl] - piperazin-1-il} -l-morpholin-4-yl-ethanone, cis- [2- (2-tert-butyl-4-ethoxy-pyrimidin-5-yl) -4,5-bis- (4-chloro-phenyl) -4, 5-dihydro-imidazol-1-yl] - (4-dimethylamino-piperidin-1-yl) -methanone, cis- [2- (2-tert-butyl-4-ethoxy-pyrimidin-5-yl) -4, 5-bis- (4-chloro-phenyl) -4,5-dihydro-imidazol-1-yl] - (4-pyrrolidin-1-yl-piperidin-1-yl) -methanone and cis-1-. { 4- [2- (2-tert-Butyl-4-ethoxy-pyrimidin-5-yl) -4,5-bis- (4-chloro-phenyl) -4,5-dihydro-imidazole-1-carbonyl] - piperazin-1-il} -etanone. 5. Cararterized compound because it is chosen from the group consisting of cis- [2- (2-tert-butyl-4-ethoxy-pyrimidin-5-yl) -4,5-bis- (4-chloro-phenyl) -4 , 5-dihydro-imidazol-1-yl] - (4-methyl-piperazin-1-yl) -methanone, cis- [2- (2-tert-butyl-4-ethoxy-pyrimidin-5-yl) -4 , 5-bis- (4-chloro-phenyl) -4,5-dihydro-imidazol-1-yl] - [4- (3-methanesulfonyl-propyl) -piperazin-1-yl] -methanone, cis- [2 - (2-tert-Butyl-4-ethoxy-pyrimidin-5-yl) -4,5-bis- (4-chloro-phenyl) -4,5-dihydro-imidazol-1-yl] - [4- ( 2-hydroxy-ethyl) - - - piperazin-1-yl] -methanone, 2-. { 4- [(4S, 5R) -2- (2-tert-Butyl-4-ethoxy-pyrimidin-5-yl) -4,5-bis- (4-chloro-phenyl) -4,5-dihydro-imidazole -1-carbonyl] -piperazin-l-il} -l-morpholin-4-yl-ethanone, 4- [(4S, 5R) -2- (2-tert-butyl-4-ethoxy-pyrimidin-5-yl) -4,5-bis- (4-chloro) phenyl) -4,5-dihydro-imidazole-1-carbonyl] -piperazin-2-one, cis-4- [4,5-bis- (4-chloro-phenyl) -2- (4,6) hydrochloride -dietoxy-pyridin-3-yl) -4,5-dihydro-imidazole-1-carbonyl] -piperazin-2-one, cis- [4,5-bis- (4-chloro-phenyl) -2- hydrochloride (4,6-diethoxy-pyridin-3-yl) -4,5-dihydro-imidazol-1-yl] - [4- (2-hydroxy-ethyl) -piperazin-1-yl] -methanone, 2-. { 4- [(4S, 5R) -4, 5-bis- (4-chloro-phenyl) -2- (3-ethoxy-thiophen-2-yl) -4,5-dihydro-imidazole-1-carbonyl] - piperazin-l-il} -N-tert-buty1-acetamide, 2-. { 4- [(4S, 5R) -4,5-bis- (4-chloro-phenyl) -2- (3-ethoxy-thiophen-2-yl) -4,5-dihydro-imidazole-1-carbonyl] - piperazin-1-il} -acetamide, 2-. { 4- [(4S, 5R) -4, 5-bis- (4-chloro-phenyl) -2- (3-ethoxy-thiophen-2-yl) -4,5-dihydro-imidazole-1-carbonyl] - piperazin-l-il} -N, N-bis- (2-methoxy-ethyl) -acetamide, 2-. { 4- [(4S, 5R) -4, 5-bis- (4-chloro-phenyl) -2- (3-ethoxy-thiophen-2-yl) -4,5-dihydro-imidazole-1-carbonyl] - piperazin-

1-il} -N-methoxy-N-methyl-acetamide, - -

2-. { 4- [(4S, 5R) -4, 5-bis- (4-chlorophenyl) -2- (

3-ethoxy-thiophen-2-yl) -4,5-dihydro-imidazole-1-carbonyl] - piperazin-l-il} -N-isopropyl-N-methyl-acetamide, 2-. {

4- [(4S, 5R) -4,

5-bis- (4-chloro-phenyl) -2- (3-ethoxy-thiophen-2-yl) -4,5-dihydro-imidazole-1-carbonyl] - piperazin-l-il} -N- (2-cyano-ethyl) -N-methyl-acetamide, cis-2-. { 4- [4,5-bis- (4-chloro-phenyl) -2- (3-ethoxy-thiophen-2-yl) -4,5-dihydro-imidazole-1-carbonyl] -piperazin-1-yl} -N- (2-methoxy-1-methyl-ethyl) -acetamide and [(4S, 5R) -4,5-bis- (4-chloro-phenyl) -2- (3-ethoxy-thiophen-2-yl) ) -4,5-dihydro-imidazol-1-yl] - [4- (3, 5-dimethyl-isoxazole-4-carbonyl) -piperazin-1-yl] -methanone. 6. Compound characterized in that it is chosen from the group consisting of [(4S, 5R) -4,5-bis- (4-chloro-phenyl) -2- (3-ethoxy-thiophen-2-yl) -4,5 -dihydro-imidazol-1-yl] - (4-ethanesulfonyl-piperazin-1-yl) -methanone, N- (2 { 4- [(4S, 5R) -4, 5-bis- (4- chloro-phenyl) -2- (3-ethoxy-thiophen-2-yl) -4,5-dihydro-imidazole-1-carbonyl] -piperazin-1-yl}. -ethyl) -methanesulfonamide, [(4S, 5R) -4,5-bis- (4-chloro-phenyl) -2- (3-ethoxy-thiophen-2-yl) -4,5-dihydro-imidazol-1-yl] - [4- (3 - methanesulfonyl-propyl) -piperazin-1-yl] -methanone, [(4S, 5R) -4,5-bis- (4-chloro-phenyl) -2- (3-ethoxy-thiophen-2-yl) -4 , 5-dihydro-imidazol-1-yl] - [4- (2-methanesulfonyl-ethyl) - - - piperazin-1-yl] -methanone and 2-. { 4- [(4S, 5R) -4, 5-bis- (4-chloro-phenyl) -2- (3-ethoxy-thiophen-2-yl) -4,5-dihydro-imidazole-1-carbonyl] - piperazin-l-il} -l-morpholin-4-yl-ethanone. 7. Pharmaceutical composition, characterized in that it contains a compound of the formula I according to claim 1. and a pharmaceutically acceptable carrier. 8. Process for obtaining the compounds according to claim 1, characterized in that a) compound of the formula 3 is reacted with phosgene in the presence of a base, for example triethylamine, obtaining a racemic carbamoyl chloride of the formula 4, b) then the carbamoyl chloride is reacted - racemic of the formula 4 with an amine R, obtaining the corresponding compound of the formula I in the form of a racemic mixture and c) separating the racemic mixture by chiral chromatography, obtaining the specific enantiomers of the formula I; wherein Vi, V2, R and ring A have the meanings defined in claim 1. 9. Compound according to claim 1, characterized in that it is for the use of medicament. Compound according to claim 1, characterized in that it is for the treatment of cancer, in particular of solid tumors, more in particular of breast, colon, lung and prostate tumors. 11. Use of a compound according to claim 1 for the manufacture of medicaments for the treatment of cancer, in particular of solid tumors, more in particular of breast, colon, lung and prostate tumors.