Imidazole derivatives as inhibitors prenyltransferase, pharmaceutical composition and methods of treatment based on them

 

(57) Abstract:

The invention relates to imidazole derivative of the formula (I)

or its pharmaceutically acceptable salt. The invention relates also to a pharmaceutical composition having inhibitory activity against prenyltransferase, to methods of treatment using these compounds. The technical result is to provide new compounds and pharmaceutical compositions on their basis for the treatment of diseases such as fibrosis, benign prostatic hyperplasia, atherosclerosis, restenosis, breast cancer, colon cancer, pancreatic cancer, prostate cancer, lung cancer, ovarian cancer, cancer of the skin and cancer of blood-forming organs. 5 C. and 13 C.p. f-crystals, 1 table.

The level of technology

The Ras family of proteins plays an important role in the transmission path of the signal, modulating cell growth. The protein is produced in the ribosome is released into the cytosol and post-translational modified. The first stage in a series of post-translational modifications is the alkylation of Cys168farnesyl or geranyl-geranyl the pyrophosphate in the reaction catalyzed by enzymes prenyltransferase, such as farnesyltransferase and geranyl-geranium is 098 (1989)), and terminal Cys is transformed into methyl ester (Clark, S., et al., Proc. Nat'l Acad. Sci. (USA) 85:4643-4647 (1988)). Some forms of Ras are also reversible palmitoylated on cysteine residues immediately N-terminal to Cys168(Buss, JE, et al., Mol Cell Biol. 6:116-122 (1986)). I believe that such modifications increase the hydrophobic C-terminal part of the Ras that is the cause of their localization on the surface of the cell membrane. Localization of Ras to the cell membrane is required for signal transmission (Willumsen, VM, et al., Science 310:583-586 (1984).

Oncogenic forms of Ras are detected in a relatively large number of cancer cases, including more than 50% of cases of colorectal cancer and more than 90% of cases of pancreatic cancer (Bos JL, Cancer Research 49:4682-4689 (1989)). Such observations suggest that interfering with the function of Ras mediawindow signal may be useful in the treatment of cancer.

Previously it was shown that C-terminal tetrapeptide Ras have motive "SHAH" (where C is cysteine, a is an aliphatic amino acid and X is any amino acid). It was shown that tetrapeptide having a similar structure, are inhibitors prenyltransferase (Reiss, et al., Cell 62:81-88 (1990)). Weak action of these previously known inhibitors by Vardanian (James, GL, et al., Science 260:1937-1942 (1993); Kohl, NE, et al., Nat'l Acad. Sci. USA 91:9141-9145 (1994), de Solms, SJ, et al. Proc. J. Med. Chem. 38:3967-3971 (1995); Nagasu, T., et al., Cancer Research 55:5310-5314 (1995); Lerner, EC, et al., J. Biol. Chem. 270:26802-26806 (1995); Lerner, EC, et al., J. Biol. Chem. 270:26770 (1995); and James, et al., Proc. Natl. Acad. Sci. USA 93:4454 (1996)).

It was recently revealed that the inhibitor prenyltransferase can block the growth of Ras-dependent tumors in "Nude" mice (Kohl, NE, et al., Proc. Nat'l Acad. Sci. USA 91:9141-9145 (1994)). In addition, it was shown that over 70% of large samples of lines of tumor cells is inhibited by inhibitors prenyltransferase with selectivity for not transformed epithelial cells (Sepp-Lorenzino, I, et al., Cancer Research, 55:5302-5309 (1995)). Inhibition of farnesiana described as a treatment for Delta viral hepatitis infection (Casey, P, et al., WO 97/31641).

DESCRIPTION OF THE INVENTION

In one aspect this invention relates to the compound of formula (I):

where n1 is 0 or 1;

X independently is (CHR11)n3(CH2)n4Z (CH2)n5;

Z is Oh, N(R12), S or a bond;

n3 is independently 0 or 1;

n4 and n5 each independently 0, 1, 2 or 3;

Y independently has the/SUP>R25);

R2, R11and R12each independently is H or optionally substituted alkyl group selected from the group comprising (C1-6)alkyl or aryl where the specified optionally substituted group optionally substituted by one or more R3or R30;

R3independently is H or optionally substituted by a group selected from the group comprising (C1-6)alkyl, (C2-6)alkenyl, (C2-6)-quinil, (C3-6)cycloalkyl, (C3-6)cycloalkyl(C1-6)alkyl, (C5-7)cyanoacetyl, (C5-7)cycloalkenyl(C1-6)alkyl, aryl, aryl(C1-6)alkyl, heterocyclyl and heterocyclyl(C1-6) alkyl where the specified optionally substituted group optionally substituted by one or more R30;

R4and R5each independently is H or optionally substituted by a group selected from the group comprising (C1-6)-alkyl, (C3-6)cycloalkyl, aryl and heterocyclyl where the specified optionally substituted group optionally substituted by one or more RR6independently is H or optionally substituted by a group selected from the group comprising (C1-6)alkyl, (C2-6)-alkenyl, (C3-6)cycloalkyl, (C3-6)cycloalkyl (C1-6)alkyl, (C5-7)-cycloalkenyl, (C5-7) cycloalkenyl(C1-6)alkyl, aryl, aryl(C1-6)-alkyl, heterocyclyl and heterocyclyl(C1-6)alkyl where the specified optionally substituted group optionally substituted by one or more substituents, each of which is independently selected from the group comprising HE, (C1-6)alkyl, (C1-6)alkoxy, N(R8R9), -COOH, CON(R8R9and halogen, where R8and R9each independently is H, (C1-6)alkyl, (C2-6)alkenyl, (C2-6)quinil, aryl or aryl (C1-6) alkyl;

R7independently is H, =O, =S or optionally substituted by a group selected from the group comprising (C1-6)alkyl, (C2-6)alkenyl, (C3-6)cycloalkyl, (C3-6)cycloalkyl(C1-6)alkyl, (B>)alkyl, heterocyclyl and heterocyclyl (C1-6) alkyl where the specified optionally substituted group optionally substituted by one or more substituents, each of which is independently selected from the group comprising HE, (C1-6)alkyl, (C1-6)alkoxy, -N(R8R9), -COOH, -CON(R8R9and halogen;

R10is C;

or if n1=0, R6and R7taken together with the carbon atoms to which they are attached, may form an aryl or cyclohexyl;

R21independently is H or optionally substituted by a group selected from the group comprising (C1-6)alkyl and aryl (C1-6)alkyl where the specified optionally substituted group optionally substituted by one or more substituents independently selected from the group comprising R8and R30;

R22is H, (C1-6) alkylthio, (C3-6) cycloalkyl, R8-CO - or Vice formula:

R24and R25each independently is H, (C1-6)alkyl or aryl (C1-6)alkyl;

R , -S(O)n7N(R8R9), -N(R8R9), -CN, -NO2, -CO2R8, -CON(R8R9), -NCO-R8or halogen;

n6 and n7 each independently 0, 1 or 2;

where the specified heterocyclyl is azepines, benzimidazolyl, benzisoxazole, benzofurazanyl, benzopyranyl, benzothiophene, benzofuran, benzothiazole, benzothiazyl, benzoxazolyl, bromanil, cinnoline, dihydrobenzofuran, dihydrobenzofuranyl, dihydrobenzofuranyl, dihydrobenzofuranyl, furyl, imidazolidinyl, imidazolyl, imidazolyl, indolinyl, indolyl, isopropanol, isoindolines, ethenolysis, isothiazolinones, isothiazolin, isothiazolinones, morpholinyl, naphthyridine, oxadiazole, 2-oxazinyl, 2-oxopiperidine, 2-oxopiperidine, 2-oxopyrrolidin, piperidyl, piperazinil, pyridyl, pyridyl N-oxide, honokalani, tetrahydrofuryl, tetrahydroisoquinoline, tetrahydroquinoline, thiomorpholine, thiomorpholine sulfoxide, thiazolyl, thiazolyl, cyanophoric, theNational or thienyl; and

where the specified aryl is phenyl or naphthyl;

provided that;

if n1=1, R10is s and Ror if n1=1, R10is s and R7is =O, -N, or =S, R10and R6taken together, may form

where X1X2and X3each independently is H, halogen, -NO2, -NCO-R8, -CO2R8, -CN, or-CON(R8R9); and

if R1is N(R24R25), n3 is 1, n4 and n5 each are equal to O, Z is a bond and R3and R11taken together, form

where n2 is equal to 1-6, and X4and X5each independently is H, (C1-6)alkyl or aryl, or X4and X5taken together can form a (C3-6)cycloalkyl;

or its pharmaceutically acceptable salt.

A preferred group of compounds of formula (I), designated as group a is the group in which

R1is

or N(R24R25); and

X is CH(R11)n3(CH2)n4or Z, where Z is O, S or N(R12);

or parmacek group, is the group in which

R1is

X is CH (R11)n3(CH2)n4; and

n1 is 0;

or their pharmaceutically acceptable salt.

Another preferred group of compounds of the formula designated as group C is the group in which

R1is

n3, n4 and n5 each are equal to 0;

Z is a bond;

Y is, independently for each case, WITH or CS; and

n1 is 0;

or their pharmaceutically acceptable salt.

Another preferred group of compounds of formula (I), designated as group D is the group in which R1is

R6is N;

n1 is equal to 1;

R7and R10taken together, form

n3 is 1 and R11is N;

Z is O or a bond;

n5 is 0; and

Y is CO, CH2or communication;

or their pharmaceutically acceptable salt.

Another preferred group of compounds of formula (I), designated as group E, Aven, 0;

n3 is 1;

n4 0;

n5 is 0;

Y is CO or CS;

z is a bond; and

R3and R11taken together, form

or their pharmaceutically acceptable salt.

Another preferred group of compounds of formula (I), designated as group F is the group in which

R1is

R7is H or=0;

n1 is equal to 1;

R6and R10taken together, form

n3 is 1 and R11is N;

n5 is 0;

Y is CO or CH2; and

Z is O or a bond;

or their pharmaceutically acceptable salt.

In another aspect, this invention relates to pharmaceutical compositions containing one or more compounds of the formula (I) such as defined above, or its pharmaceutically acceptable salt, and a pharmaceutically acceptable carrier.

In another aspect, this invention relates to a method of inhibiting prenyltransferase (for example, farnesyltransferase or geranylgeranyltransferase) in a patient, such is icesta the compounds of formula (I), such as defined above, or its pharmaceutically acceptable salt. In another aspect, this invention relates to a method of treating restenosis or proliferative diseases tissue (e.g. tumor) in a patient by administration to the patient a therapeutically effective amount of the compounds of formula (I) or its pharmaceutically acceptable salt. Examples of proliferative tissue diseases include diseases associated with benign (i.e. not malignant) cell proliferation, such as fibrosis, benign prostatic hyperplasia, atherosclerosis and restenosis, and malignant cell proliferation, such as cancer (e.g., ras-mutated tumors). Examples treat tumors include, but are not limited to, breast cancer, colon, pancreas, prostate, lung, ovarian, epidermal and blood-forming organs (Sepp-Lorenzino, I, et al., Cancer research 55:5302 (1995)).

In another aspect this invention relates to the use of one or more compounds of the formula (I), such as described above, or their pharmaceutically acceptable salts, to associate with prenyltransferases, as shown in in vitro and in vivo tests.

DETAILED DESCRIPTION OF THE INVENTION

In General, Conn the military methods of making compounds of formula (I) are presented as aspects of the present invention and is illustrated reactions and examples presented in this description.

In the above structural formulas, and in the context of this application the terms used have the following meanings, unless otherwise indicated.

The term "alkyl" includes alkyl groups having the specified number of carbon atoms in a straight or branched configuration. Examples of such alkyl groups include methyl, ethyl, propyl, isopropyl, butyl, verbatim, tertiary butier, pentyl, isopentyl, hexyl, isohexyl and the like. If included in the definition of the term "C0-alkyl", it denotes a simple covalent bond.

The term "cycloalkyl includes monocyclohexyl group or bicycloalkyl group having the specified number of carbon atoms. Examples of such cycloalkyl groups include cyclopropyl, cyclobutyl, cyclohexyl and the like.

The term "alkenyl" includes hydrocarbon group having one or more double bonds and the specified number of carbon atoms in a straight or branched configuration. Examples of such alkenyl groups include ethynyl, propenyl, Isopropenyl, butenyl, verbotener, tertiary butanol, pentanol, isopentanol, hexanol, isohexanol and the like.

TAROM carbon atoms, having one or more double bond, but not enough double bonds to ensure that the group has become aromatic. Examples of such cycloalkenyl groups include cyclopentenyl, cyclohexenyl, cycloheptenyl and the like.

The term "quinil includes alkyline group, i.e. hydrocarbon group having one or more triple bond, having the specified number of carbon atoms in a straight or branched configuration. Examples of such etkinlik groups include ethinyl, PROPYNYL, butynyl, pentenyl, isopentenyl, hexenyl, sogecine and the like.

The term "alkylthio" includes allylthiourea, i.e., hydrocarbon groups connected to the molecule via a sulfur atom, having the specified number of carbon atoms in a straight or branched configuration. Examples of such alkylthio include methylthio, ethylthio, propylthio, isopropylthio, butylthio, verbality, tertiary, butylthio, pentylthio, isopentyl, hexylthio, isohexyl and the like.

The term "cycloalkyl" includes monotically and bicycloalkyl with the specified number of carbon atoms. Examples of such cycloalkylation include cyclopentyl, cyclohexylthio and the like.

The term is nfiguration. Examples of such alkoxygroup include methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, tertiary, butoxy, pentox, isopentane, hexose, isohexane and the like.

The term "aryl" includes aromatic rings are known in the art, which can be monocyclic or bicyclic, such as phenyl and naphthyl.

The term "heterocyclyl" in the context of the present invention is a 5-7 membered monocyclic or 8-11 membered bicyclic, or 11 to 15-membered tricyclic ring which is either saturated or not saturated, and which consists of carbon atoms and contains from one to four heteroatoms, independently selected from the group comprising N, O and S. the term includes any bicyclic group in which the above specified heterocyclic ring condensed with the benzene ring, where the heterocyclic ring may be attached to any heteroatom or carbon atom. Examples of such heterocyclic groups include, but are not limited to, azepine, benzimidazolyl, benzisoxazole, benzofurazanyl, benzopyranyl, benzothiophene, benzofuran, benzothiazole, benzothiazyl, benzoxazolyl, bromanil, cinnoline, dihydrobenzofuran, dinil, imidazolyl, indolinyl, indolyl, isopropanol, isoindolines, ethenolysis, isothiazolinones, isothiazolin, isothiazolinones, morpholinyl, naphthyridine, oxadiazole, 2-oxazinyl, 2-oxopiperidine, 2-oxopiperidine, 2-oxopyrrolidin, piperidyl, piperazinil, pyridyl, pyridyl N-oxide, honokalani, tetrahydrofuryl, tetrahydroisoquinoline, tetrahydroquinoline, thiomorpholine, thiomorpholine sulfoxide, thiazolyl, thiazolyl, cyanophoric, theNational, thienyl and the like.

Specialist in the field of chemistry it is clear that certain combinations of substituents containing a heteroatom listed in this invention, identify the connections that will be less stable under physiological conditions. Therefore, such compounds are less preferred.

The term "halogen" or "halo" includes the halogen atoms fluorine, chlorine, bromine and iodine.

If presents the chemical structure there is an arrow coming out of it, the arrow indicates the place of attachment. For example, the structure

is Pintilei group. If next to the arrow builds value in brackets, this value specifies where in the connection is the place of connection. For example, in the General formula (I): the Ute

we get the following structure:

Also, in the General formula (I) such as defined above, if R3and R11taken together, form

we get the following structure:

If the line is shown passing through the cyclic group, this line indicates that the Deputy can be attached to a cyclic group in any available place of connection. For Example,

means the Deputy "X" can be attached in the ortho, meta or para position. Further, if the line is shown passing through the bicyclic or tricyclic group, this means that the Deputy can be attached to the bicyclic or tricyclic group in any available place of connection in any ring. Also, if the arrow is shown passing through the cyclic group, such as the arrow shows that the place of attachment of the cyclic group to the connection may be any connection point in the cyclic group. Further, if the arrow is shown passing through the bicyclic or tricyclic group, this arrow shows that the place of attachment of bicyclic what th or tricyclic group.

Some compounds in accordance with this invention may have at least one center of asymmetry. More centers of asymmetry may be present in the molecule depending on the nature of the various substituents in the molecule. Each of these centers of asymmetry gives two optical isomers and it is implied that all such optical isomers, as separated, purified or partially purified optical isomers, racemic mixture, or diastereomer mixture, included in the scope of this invention.

Compounds in accordance with this invention can usually be isolated in the form of their pharmaceutically acceptable acid additive salts such as salts with inorganic and organic acids. Examples of such acids include hydrochloric, nitric, sulfuric, phosphoric, formic, acetic, triperoxonane, propionic, maleic, succinic, D-tartaric, L-tartaric, malonic, methanesulfonyl and the like. In addition, certain compounds containing acidic functional groups such as carboxy, can be allocated in the form of their inorganic salts, in which the counterion may be selected from sodium, potassium, lithium, calcium, magnesium and the like, and organic base is of ivalent the compounds of formula (I) and about 1 equivalent or more appropriate corresponding acid, salt which is desired. Methods of processing and secretion of the obtained salts are well known specialist in this field.

Compounds in accordance with this invention can be administered orally, parenterally (e.g., intramuscular, intraperitoneal, intravenous or subcutaneous injection, or implant), intranasal, vaginal, rectal, sublingual, or topical and can be prepared in preparative form with pharmaceutically acceptable carriers to get dosage forms appropriate for each route of administration. Therefore, the scope of the present invention is included a pharmaceutical composition containing as active ingredient at least one compound of formula (I) in combination with a pharmaceutically acceptable carrier.

Solid dosage forms for oral administration include capsules, tablets, pills, powders and granules. In such solid dosage forms the active compound is mixed with at least one inert pharmaceutically acceptable carrier such as sucrose, lactose or starch. Such dosage forms can also contain, as is the normal practice, additional substances other than dosage forms may also contain buffering agents. Tablets and pills can additionally be prepared with intersolubility shells.

Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups, elixirs containing inert diluents commonly used in the art, such as water. In addition to these inert diluents, compositions can also contain adjuvants, such as wetting agents, emulsifiers and suspendresume agents, sweeteners, flavorings and fragrances.

Formulation for parenteral administration in accordance with this invention include sterile aqueous and non-aqueous solutions, suspensions or emulsions. Examples of nonaqueous solvents or carriers include propylene glycol, polyethylene glycol, vegetable oils such as olive oil and corn oil, gelatin and organic esters, suitable for injection, such as etiloleat. These dosage forms may also contain adjuvants such as preservatives, wetting agents, emulsifying agents and dispersing agents. They can be sterilized, for example, by filtration through catching bacteria filter, adding the obtained in the form of sterile solid compositions, which can be dissolved in sterile water or some other sterile environments for injection immediately before use.

Compositions for rectal or vaginal injection are preferably suppositories which may contain, in addition to the active ingredient, excipients, such as coconut oil or paraffin for suppositories.

Compositions for intranasal or sublingual introduction also get with standard fillers, which are well known in the art.

In General, the effective dose of the active ingredient in the compositions in accordance with this invention may vary; however, it is necessary that the amount of active ingredient was such to get a suitable dosage form. The selected dosage depends upon the desired therapeutic effect, the route of administration and duration of treatment that falls within the scope of specialist knowledge in this area. In General, dosage is from 0.0001 to 100 mg/kg body weight daily for the introduction of man and other animals, such as mammals.

The preferred dose is from 0.01 to 10.0 mg/kg body weight daily and can be entered by emeniem can be and have been assessed in relation to the actions dependent on the anchor substrate growth lines of tumor cells in humans according to the next test.

Cells were seeded in 96-cell tablet on day 0 and treated on day 1 within 96 hours following concentrations of the compounds in accordance with this invention; 50,25, 12,5, 6,25, 3,12, 1,56, 0,78, 0,39 and 0,00 μm. At the end of this period, quantitative analysis of cell proliferation is performed using a colorimetric test based on the removal of tetrazolium salt WST1 by mitochondrial dehydrogenase in viable cells, leading to the formation of formazan. These experiments repeated twice in octuplicate, thus determining the range of concentrations of the compounds, including the value of the IC50.

By the above method will carry out the analysis with the following lines of tumor cells: prostate: DU145 adenocarcinoma with WT ras-resistant L744-832; rectum: NT, adenocarcinoma with nematanthus type ras (WT), sensitive to L744-832; pancreas: MIA Race-2 carcinoma with Ki-ras mutation; light: A, carcinoma with Ki-ras mutation. (see tab.1)

It should be understood that although this invention is described in conjunction with the detailed description presented below is intended to illustrate and not limit the scope of this invention, which is defined by the formula l)-5,6,7,8-tetrahydroimidazo[1.2A]pyrazin

Connection 2: 8-butyl-2-(2-hydroxyphenyl)-7-(imidazol-4-yl-propyl)-5,6,7,8-tetrahydroimidazo[1.2A]pyrazin

Connection 3: 8-butyl-7-(4-imidazolidinyl)-2-(2-methoxyphenyl)-5,6,7,8-tetrahydroimidazo[1.2A]pyrazin

Compound 4: 7-(2-(imidazol-4-yl)-1-oxoethyl)-2-(2-methoxyphenyl)-8-(1-methylpropyl)-5,6,7,8-tetrahydroimidazo[1,2]-pyrazin

Compound 5: 2-(2-methoxyphenyl)-8-(1-methylpropyl)-7-(1-oxo-2-(1-phenylmethyl)imidazol-5-yl)ethyl)-5,6,7,8-tetrahydroimidazo [1.2A]pyrazin

Compound 6: 2-(2-methoxyphenyl)-8-(1-methylpropyl)-7-(2-(1-phenylmethyl)imidazol-5-yl)ethyl)-5,6,7,8-tetrahydroimidazo-[1.2A]pyrazin

Connection 7: 7-(2-(1-(4-cyanovinylene)imidazol-5-yl)1-oxoethyl)-2-(2-methoxyphenyl)-8-(1-methylpropyl)-5,6,7,8-tetrahydroimidazo[1.2A]pyrazin

Compound 8: 7-((1H-imidazol-4-yl)methyl)-2-(2-methoxyphenyl) -8-(1-methylpropyl)-5,6,7,8-tetrahydroimidazo[1,2]-pyrazin

Compound 9: 7-((4-imidazolyl)carbonyl)-2-(2-methoxyphenyl)-8-(1-methylpropyl)-5,6,7,8-tetrahydroimidazo[1.2A]pyrazin

Connection 10: 7-(1-(4-cyanovinylene)imidazol-5-yl)methyl-2-(2-methoxyphenyl)-8-(1-methylpropyl)-5,6,7,8-tetrahydroimidazo-[1,2 a]feast-imidazo[1,2 a][1,4]benzodiazepine

Connection 12: 7-(2-(4-cyanovinylene)-imidazol-5-yl)-1-oxoethyl)-2-(2-methoxyphenyl)-5,6,1,8-tetrahydroimidazo[1,2]-pyrazin

The connection 13: 7-(2-amino-1-oxo-3-thiopropyl)-8-(mercaptoethyl)-2-(2-methoxyphenyl)-5,6,7,8-tetrahydroimidazo-[1,2]-pyrazin disulfide

The connection 14: 5-butyl-7-(2-(4-cyanopyrimidine-5-yl)-1-oxoethyl)-2-phenyl-5,6,7,8-tetrahydroimidazo[1,2]-pyrazin

The connection 15: 6-butyl-7-(2-(4-cyanopyrimidine-5-yl)-1-oxoethyl)-2-(2-methoxyphenyl)-5,6,7,8-tetrahydroimidazo-[1.2A]pyrazin

The connection 16: 6-butyl-7-(2-(4-cyanopyrimidine-5-yl)-1-oxoethyl)-2-phenyl-5,6,7,8-tetrahydroimidazo[1,2]-pyrazin

The connection 17: 5-butyl-7-(2-(1-(4-cyanovinylene)imidazol-5-yl)-1-oxoethyl)-2-(2-methoxyphenyl)-5,6,7,8-tetrahydroimidazo-[1.2A]pyrazin

Connection 18; 7-(2-(1-(4-cyanovinylene)imidazol-5-yl)1-oxoethyl)-8-(cyclohexylmethyl)-2-(2-methoxyphenyl)-5,6,7,8-tetrahydroimidazo[1.2A]pyrazin

The connection 19: 5-butyl-7-(2-(1H-imidazol-5-yl)-1-oxoethyl)2-(2-methoxyphenyl)-5,6,7,8-tetrahydroimidazo[1.2A]pyrazin

Connection 20: 7-(2-(4-cyanovinylene)imidazol-5-yl)-1-oxoethyl)-2-(2-fenil anothermodel)imidazol-5-yl)-1-oxoethyl)-5,6,7,8-tetrahydroimidazo[1,2]-pyrazin

The connection 22: 1,2-dihydro-1-((1H-imidazol-4-yl)methyl)4-(2-methoxyphenyl)imidazo[1,2][1,4]benzodiazepine

Connection 23: 1-(2-(1-(4-cyanovinylene)imidazol-4-yl)-1-oxoethyl)-1,2-dihydro-4-(2-methoxyphenyl)imidazo[1,2][1,4]-benzodiazepine

Compound 24: 9-bromo-1-(2-(1-(4-cyanovinylene)imidazol-4-yl)-1-oxoethyl)-1,2-dihydro-4-(2-methoxyphenyl)imidazo[1,2]-[1,4]-benzodiazepine

Compound 25: 9-chloro-1-(2-(1-(4-cyanovinylene)imidazol-4-yl)-1-oxoethyl)-1,2-dihydro-4-(2-methoxyphenyl)imidazo[1,2]-[1,4]-benzodiazepine

Compound 26: 10-bromo-1-(2-(1-(4-cyanovinylene)imidazol-4-yl)-1-oxoethyl)-1,2-dihydro-4-(2-methoxyphenyl)imidazo[1,2]-[1,4]-benzodiazepine

Connection 27: 1-(2-(1-(4-cyanovinylene)imidazol-4-yl)1-oxoethyl)-1,2-dihydro-8-fluoro-4-(2-methoxyphenyl)imidazo-[1,2]-[1,4]benzodiazepine

Compound 28: 1,2-dihydro-1-(2-(imidazol-1-yl)-1-oxoethyl)-4-(2-methoxyphenyl)imidazo[1,2 a][1,4]benzodiazepine

Compound 29: 1,2-dihydro-4-(2-methoxyphenyl)-1-(2-(pyridin-3-yl)-1-oxoethyl)imidazo[1,2 a][1,4]benzodiazepine

Compound 30: 1,2-dihydro-4-(2-methoxyphenyl)-1-(2-(pyridin-4-yl)-1-oxoethyl)imidazo[1,2 a][1,4]benzodiazep is imidazo[1,2 a][1,4]-benzodiazepine

Connection 32: 1-(2-(1-((4-cyano)phenylmethyl)imidazol-5-yl)-1-oxoethyl)-9,10-debtor-1,2-dihydro-4-(2-methoxyphenyl)-imidazo[1,2][1,4]benzodiazepine

Compound 33: 4-(2-bromophenyl)-1-(2-(1-[(4-cyano)phenyl-methyl]imidazol-5-yl) -1-oxoethyl)-1,2-dihydro-8-torimodose-[1,2 a][1,4]benzodiazepine

Connection 34: 1-(2-(1-((4-cyano)phenylmethyl)imidazo-5-yl)1-oxoethyl)-1,2-dihydro-10-fluoro-4-(2-methoxyphenyl)imidazol-[1,2 a][1,4]benzodiazepine

Connection 35: 1-(2-(1-((4-cyano-3-methoxy)phenylmethyl)imidazo-5-yl)-1-oxoethyl)-1,2-dihydro-8-fluoro-4-(2-methoxyphenyl)-imidazol[1,2 a][1,4]benzodiazepine

The connection 36: 10-bromo-1-(2-(1-((4-cyano-3-methoxy)phenylmethyl) imidazo-5-yl)-1-oxoethyl)-1,2-dihydro-4-(2-methoxyphenyl)-imidazol[1,2 a][1,4]benzodiazepine

Connection 37: 1-(2-(1-((4-cyano-3-methoxy)phenylmethyl)-imidazo-5-yl)-1-oxoethyl)-1,2-dihydro-8-fluoro-4-phenylimidazol-[1,2 a][1,4]benzodiazepine

Compound 38: 4-(2-bromophenyl)-1-(2-(1-((4-cyano-3-methoxy)-phenylmethyl)imidazo-5-yl)-1-oxoethyl)-1,2-dihydro-8-ftalimidina-[1,2 a][1,4]benzodiazepine

Connection 39: 1-(2-(1-((3-methoxy)phenylmethyl)imidazo-5-yl)-1-oxoethyl)-1,2-dihydro-8-fluoro-4-(2-methoxyphenyl)imidazol-[1,2 a][1,4]benzodi is-(2-methoxyphenyl)imidazo-[1,2][1,4]benzodiazepine

EXPERIMENTS

In the following examples and diagrams used in a variety of substituents, as defined above. Variations of substituents in the schemes and examples do not necessarily coincide with those defined in the claims.

Example 1. 8-butyl-7-(3-(imidazol-5-yl)-1-oxopropyl)-2-(2-methoxyphenyl)-5,6,7,8-tetrahydroimidazo[1.2A]pyrazin

Synthesis example 1 carried out according to scheme 1 as shown below

Scheme 1

1.a. H2/Pd coal/SPLA,

1.b. (VOS)2O/K2CO3/5% aq. HCl/Meon

1.with. Cs2CO3, Br-CHR5CO R4then NH4SLA/xylene

1.d. Br-CHR6CO2Et/K2CO3/DMF

1.e. H2/Pd coal/SPLA

1.f. NR3/THF

1.g. Connection ii/DCC/HOAt/DMF

1.h. TN/iPr3SiH

Stage 1.a. 3-(1H-imidazol-5-yl)propionic acid

Rocanova acid (compound i, in which R2is N) (1,38 g, 10.0 mmol) dissolved in 5% aqueous HCl (20 ml) and Meon, containing 10% Pd on coal (100 mg) and the mixture shaken overnight at a pressure of H2

Stage 1.b. 3-(1-((1,1-dimethylmethoxy)carbonyl)imidazol-5-yl)propionic acid

The crude product from step 1.A. (10.0 mmol) is dissolved in N2About (10 ml) containing K2CO3(2.76 g, 20 mmol) and the obtained mixture is added di-tert-butyl dicarbonate (2,18 g, 10.0 mmol) in acetonitrile (20 ml). The reaction mixture is vigorously stirred for about 3 hours, then add H2About (10 ml) and the mixture is concentrated to about1/2volume. The mixture is acidified with citric acid and extracted with EtOAc (2×25 ml). Water extracts dried over Na2SO4, filtered and concentrated to a solid, which is dried under reduced pressure to obtain 1.89 g (79%). NMR (300 MHz, DMSO-d6in, 30°C) 12, 0-12,2 (1H, s), 8,0-8,2(1H, s), 7,2-7,3(1H, s), 2,65-2/8(2H, t), 2,45-2, 65(2H, t), 1,5-1,7(N, C).

Stage 1.c. 2-(1-(S)-(((phenylmethoxy)carbonyl)amino)-pentyl)-4-(2-methoxyphenyl)imidazol

Cbz-(L)-Norleucine (compound iii in which R3is n-bootrom) (10.6 g, 40.0 mmol) and Cs2CO3(6.25 g, 20.0 mmol) are combined in 2:1/DMF:N2O (65 ml) and the mixture paramashiva the t in DMF (75 ml) and add 2-bromo-2'-methoxyacetophenone (9,16 g, 40.0 mmol) in DMF (50 ml). The mixture is stirred for 15 minutes at room temperature, then concentrated under reduced pressure. Received ketoester dissolved in xylene (250 ml), filtered, add NH4OAc (50.0 g, 0.36 mol) and the mixture is refluxed for about 3 hours with removal of excess NH4OAc and capture water using traps Dean-stark. The reaction mixture was concentrated under reduced pressure. Add a saturated solution of NaHCO3(100 ml) and the product extracted with CH2Cl2(3×50 ml). The combined layers of CH2Cl2dried over Na2SO2, filtered and concentrated in vacuo to obtain the first batch 6.23 g (so pl.=118=121°C) specified in the connection header. The mother liquor is purified flash chromatography on silica gel using 2:3/EtOAc:hexane as eluent. Purified fractions of product are combined and concentrated to obtain a second party 3,26 g (so pl.=119-122°C), the total output is 9,49 g (60%) specified in the connection header. NMR (300 MHz, DMSO-d6, 30°C) 11,7-11, 9 (1H, s), 8,0-of 8.15 (1H, d), and 7.5 to 7.7 (1H, m), between 7.4 to 7.5 (1H, s), and 7.1 to 7.4 (6N, m), 6,9-7,1 (2H, m), 4.95 points with 5.2 (2H, HF), 4,6-4,8 (1H, HF), 3,8-4,0 (3H, s), 1,6-2,0 (2H, -(2-methoxyphenyl)imidazol

The product from step 1.c. (compound iv in which R3is n-bootrom, R4is 2-methoxyphenyl and R5is N) (9,40 g of 23.9 mmol) dissolved in DMF (50 ml) and treated with K2CO3(6,90 g, 50.0 mmol) and ethylbromoacetate (4,17 ml of 75.0 mmol), and the mixture is heated to a temperature of 55°C for about 2 hours. The mixture is concentrated and then dissolved in a simple ether (100 ml) and washed once with saturated solution of NaHCO3(50 ml) and once with saturated NaCl solution (50 ml). The ether layer is dried over Na2SO4, filtered and concentrated to an oil (11.5 g, 100%), which is used without further purification. Mass spectrum 480,3 MH+, NMR (300 MHz, DMSO-d6, 30°C) 8,04-to 8.12 (1H, DD), 7,65 is 7.85 (1H, t wide), with 7.5 and 7.6 (1H, s), 7,25 to 7.4(5H, m) and 7.1-of 7.25(1H, m), of 7.0, and 7.1(1H, d), 6,9-7,05 (1H, t), 4,9-of 5.15 (2H, HF), 5,0-5,2 (2H, s), 4,5-4,7 (1H, HF), 4,05 to 4.2 (2H, q), 3,8-4,0 (3H, s), of 1.8-2.0 (2H, m), 1,2-1,4 (4H, m), 1,15-1,25 (3H, t), 0,75-0,95 (3H, t).

Stage 1.e. 8-butyl-6-oxo-2-(2-methoxyphenyl)imidazo-[1.2A]pyrazin

The product from step 1.d. (compound v in which R3is n-bootrom, R4is 2-methoxyphenyl and R5and R6are N) (11.5g, of 23.9 mmol) dissolved in SPLA (100 ml), steriade for about 3 hours at room temperature. The catalyst was removed by filtration through a 3 cm layer of diatomaceous earth and the filtrate is heated at a temperature of about 70°C for about 2 hours. The mixture is concentrated to a solid under reduced pressure, dissolved in CH2Cl2(100 ml) and washed with saturated solution of NaHCO3(125 ml). The layer of CH2Cl2dried over Na2SO4filter and add 275 ml of hexane. The product is filtered and dried to constant weight to obtain 6,21 g (87%) of product, So pl.=200-202°C NMR (300 MHz, DMSO-d6, 30°C) TO 8.5 AND 8.6 (1H, s), with 8.0 and 8.1 (1H, d), 7,4-7,6 (1H, s), 7,1-7,3 (1H, t), of 7.0, and 7.1 (1H, d), 6,9-7,1 (1H, t), 4,55-4,8 (2H, HF), 4,55-4,7 (1H, t), 3,8-4,0 (3H, s), 1,75-of 1.95 (2H, m), 1,1-1,5 (4H, m), to 0.8-0.9 (3H, t).

Stage 1.f. 8-butyl-2-(2-methoxyphenyl)-5,6,7,8-tetrahydro-imidazo[1.2A]pyrazin

The product from step 1.e. (6,13 g of 20.5 mmol (compound vi, where R3is n-bootrom, R4is 2-methoxyphenyl and R5and R6are H) was dissolved in THF (100 ml) and treated with 1M NR3/THF (82,0 ml, 82,0 mmol) at room temperature for about 2 hours, and then refluxed for about 3 hours. The mixture is cooled to room temperature and dropwise we use Tim portions addition of solid K2CO3. The product is extracted with EtOAc (3×50 ml). Layers EtOAc combine, dried over Na2SO4filter and concentrate under reduced pressure. The residue is dissolved in Meon (about 50 ml), add concentrated HCl (1.75 ml) and the solution again concentrated under reduced pressure. The product is crystallized from MeOH/Et2O obtaining 6,76 g (92%) of the desired product. Mass spectrum 286,3 MN+, NMR (300 MHz, DMSO-d6, 30°C) 10,0-11,5 (2H, broad), 8,05-of 8.15 (1H, DD), an 8.0 and 8.1 (1H, s), 7,35 is 7.5 (1H, t), 7,15-7,3 (1H, d), 7,0-to 7.15 (1H, t), 4,8-of 4.95 (1H, m), 4,4-the 4.65 (2H, m), 3,9-4,0 (3H, s), 3,65 to 3.8 (1H, m), 3,5-of 3.65 (1H, m), 2,45-to 2.65 (1H, m), 2,1 to 2.35 (1H, m), 1,5-1,7 (2H, m), 1,25-1,5 (2H, m), 0,85-1,0 (3H, t).

Stage 1.g. 8-butyl-7-(3-(((1,1-dimethylmethoxy)carbonyl)-imidazole-5-yl)-1-oxopropyl)-2-(2-methoxyphenyl)-5,6,7,8-tetrahydroimidazo[1.2A]pyrazin

DCC (309 mg, 1.50 mmol) and the product from step 1.b. (compound ii in which R2is N) (720 mg, 3.00 mmol) dissolved in THF (10 ml) and stirred for 30 minutes at room temperature. Solids filtered off, add the product from step 1.f. (compound vii in which R3is n-bootrom, R4is 2-methoxyphenyl and R5, R6and R7ago resin and purified flash chromatography on silica gel, using EtOAc as eluent. Fraction of the product combine, concentrate to obtain a glassy mass and dried to constant weight. Output = 500 mg (99%). Mass spectrum 508,2 (MN+).

Stage 1.h. 8-butyl-7-(3-(imidazol-5-yl)-1-oxopropyl)-2-(2-methoxyphenyl)-5,6,7,8-tetrahydroimidazo[1.2A]pyrazin

The product from step 1.g. (450 mg, 0.89 mmol) was dissolved in Meon (5 ml), added 4N HCl and the reaction mixture was stirred at room temperature for about 1/2 hour. The solvents are removed under reduced pressure to obtain 420 mg of the crude product. Part of the crude product (100 mg) purified preparative HPLC on a column of RAININC18(Varian Analytical, Walnut Creek, CA) using a gradient of 10-30% CH3CN/aq. HCl (pH 2,0) for 45 minutes with UV determination at 254 nm. Fraction of the product are concentrated to about 1/2 volume and lyophilized with obtaining the pure product (47 mg, 47%) as the dihydrochloride. Mass spectrum 508,2 MN.

Example 2: 8-butyl-2-(2-hydroxyphenyl)-7-(imidazol-4-yl-propyl)-5,6,7,8-tetrahydroimidazo[1.2A]pyrazin

The product from step 1.h. (compound viii where R1, R2, R5, R6and R7are H, R3is n-bootrom, R3in THF (10.0 ml, 10.0 mmol) with stirring. The mixture is refluxed for 2 hours, then cooled. Added dropwise 4N solution of HCl and a mixture of short time refluxed and then alkalinized portions careful addition of solid K2CO3. The product is extracted with EtOAc (3×10 ml) and then extracted again with 0.5% aqueous TN (4×10 ml). The crude product is purified preparative HPLC on a column of RAININC18using a gradient of 0-25% CH3CN/0.1% aq. TN for 45 minutes with UV determination at 254 nm. Fraction of the product are concentrated to about 1/2 volume and lyophilized, then lyophilized twice from dilute HCl to obtain the pure product (41 mg, 13%) as the dihydrochloride. Mass spectrum 380,3 MN+. NMR (300 MHz, DMSO-d6, 30°C) FROM 9.0 TO 9.1 (1H, s), 7,9-with 8.05 (2H, m), 7,45-of 7.55 (1H, s), 7,2-7,3 (1H, t), 7,05-to 7.15 (1H, d), the 6.9 to 7.0 (1H, t), 4,5-6,0 (3-4H, with a wide), 4,0-4,4 (), 1,5-1,7 (2H, m), 1,25-1,5 (2H, m), of 0.8-1.0 (3H, t).

Example 3: 8-butyl-7-(4-imidazolidinyl)-2-(2-methoxyphenyl)-5,6,7,8-tetrahydroimidazo[1.2A]pyrazin

The product from step 1.h. (475 mg, 0,973 mmol) dissolved in Meon (10 ml) and add a solution of NaOH (80 mg, 2.0 mmol) in N2O (1 ml) at room TempStorage in THF (10 ml), dried over Na2SO4filter and concentrate under reduced pressure to about 2 ml and add 1M NR3/THF (8.0 ml). The mixture is refluxed for about 3 hours and quenched by adding 5% aqueous HCl with a short reflux. The reaction mixture is cooled to room temperature, alkalinized by careful addition of solid NaHCO3and extracted with CH2Cl2(2×10 ml). Layers CH2Cl2dried over Na2SO4filter and concentrate under reduced pressure. The residue is purified preparative HPLC on a column of RAININC18using a gradient of 0-25% CH3CN/aq. HCl (pH 2.0) for 45 minutes with UV determination at 270 nm. Fraction of the product are concentrated to about 1/2 volume and lyophilized with obtaining the pure product (64 mg, 15%) as the dihydrochloride. Mass spectrum 394,3 MN+. NMR (300 MHz, DMSO-d6, 30°C) FROM 9.0 TO 9.1 (1H, s), 8,0-8,2 (2H, d), of 7.9 and 8.1 (1H, s), between 7.4 to 7.5 (1H, s), 7,35 is 7.5 (1H, t), 7,1-7,3 (1H, d), 7,0-7,2 (1H, t), of 5.0-7.0 (3H, broad), 4.1 and 4.5 (3H, m), 3,9-4,0 (3H, s), 3,2-3,7 (2H, d broad), of 2.7-3.0 (2H, broad), 2,6-2,9 (2H, t), 1,9-2,2 (4H, m), 1,0-1,7 (4H, m), of 0.8-1.0 (3H, t).

Example 4: 7-(2-(imidazol-4-yl)-1-oxoethyl)- schemes 1 and 4, replacing stage 1.A. 1.b. stages 4.A. -4.with.

Scheme 4

4.a. HCl/MeOH;

4.b. Chlorotriphenylmethane/Et3N/DMF;

4.with. Of 2.5 N NaOH/MeOH

Stage 4.A. Methyl 4-imidazolate

A solution of hydrate of sodium salt of 4-imidazolinone acid (compound ix in which R2is N) (3.0 g, to 18.1 mmol) in Meon (50 ml) is cooled to a temperature of about 0°C and anhydrous HCl gas is bubbled into the mixture for about 15 minutes, keeping the reaction temperature below 5°C. the Reaction mixture is stirred for about 1/2 hour at room temperature and then the solvents are removed under reduced pressure to obtain oil, which solidified upon maturation. Mass spectrum 141,0 MN+. NMR (300 MHz, DMSO-d6, 30°C) FROM 9.0 TO 9.2 (1H, s), 7,4-7,6 (1H, s), 3,85-3,95 (2N, 3), up 3.6-3.7 (3H, s).

Stage 4.b. Methyl 1-triphenylmethyl-4-imidazolate

A solution of product from step 4. A. (3.2 g, 17.5 mmol) in DMF (50 ml) is treated with chlorotriphenylmethane (4,88 g, 17.5 mmol) and Et3N (5,4 ml of 38.5 mmol) and the reaction mixture was stirred at room temperature for about 6 hours. DMF is evaporated under reduced pressure and the residue partitioned between EtOAc and saturated NaCl. SML product as a viscous oil (of 6.96 g, 104%), which crystallized upon maturation. Mass spectrum 383,3 MH+.

Stage 4.with. 1-triphenylmethyl-4-imidazolinone acid, sodium salt

The product from step 4.b. (2.0 g, of 5.24 mmol) was dissolved in Meon (20 ml) and add 2.5 N NaOH (2.1 ml) at room temperature and the mixture is stirred over night. The solvents are removed under reduced pressure to get crude product (2.08 g, 102%), which is used in a later stage without further purification.

Stage 4.d.-4.i. carried out by the method of stages 1.c.-1.h. example 1, using as starting compound Cbz-(L)-Ile-OH instead of Cbz-(L)-Nle-HE and receiving (2-(2-methoxyphenyl)-8-(1-methylpropyl)-5,6,7,8-tetrahydro-(7-(2-(1-triphenylimidazole-4-yl)-1-oxoethyl)imidazo[1.2A]pyrazin)(compound viii in which R1, R2, R5, R6and R7are H, R3is isobutyl and R4is 2-methoxyphenyl).

Stage 4.j. 7-(2-(imidazol-4-yl)-1-oxoethyl)-2-(2-methoxyphenyl)-8-(1-methylpropyl)-5,6,7,8-tetrahydroimidazo[1.2A]pyrazin

The product from step 4.i. (150 mg, 0.24 mmol) is treated with TN (1.0 ml) containing iPr3SiH (51 μl, 0.25 mmol) at room temperature for about 2, the product purified preparative HPLC on a column of RAININC18using a gradient from 20% to 70% of CH3CN/0.1% of TN for 45 minutes. Fraction of the product combine, concentrate, and re-lyophilized of diluted HCl to obtain the product (53 mg, 57%) as the dihydrochloride. Mass spectrum 394,3 MH+.

Example 5: 2-(2-methoxyphenyl)-8-(1-methylpropyl)-7-(1-oxo-2-(1-phenylmethyl)-imidazol-5-yl)ethyl)-5,6,7,8-tetrahydroimidazo[1.2A]pyrazin

Synthesis example 5 is conducted according to schemes 1 and 5, replacing the stage 1.A. 1.b. on stage 5.A. -5.with.

Scheme 5

5. a. R1-Br/CH3CN;

5.b. Meon, boiling under reflux;

5.with. 5% aqueous HCl, boiling under reflux

Stage 5. A. Methyl 1-phenylmethyl-3-triphenylmethyl-5-imidazole-acetate

Methyl 1-triphenylmethyl-4-imidazolate with stage 4.b. (1.12 g, with 2.93 mmol) dissolved in CH3CN (15 ml) and add benzylbromide (349 μl, of 2.93 mmol) at room temperature. The mixture is refluxed for about 3 hours and stand at room temperature overnight. The solvents are removed under reduced pressure and the residue used without further purification in stage 5.b.

Stage 5.b. methyl 1-phenylmethyl-5-imide is for 1 hour. The solvents are removed under reduced pressure. The residue is triturated with hexane (2×20 ml) and EtOAc (2×20 ml). The residue is used without further purification in stage 5.with.

Stage 5.with. 1-phenylmethyl-5-imidazolinone acid

The product from step 5.b. dissolved in 5% aqueous HCl and refluxed for about 3 hours, then concentrated under reduced pressure. The crude product is purified preparative HPLC on a column of RAININC18using a gradient from 5% to 35% of CH3CN/0.1% of TN for 45 minutes. Fraction of the product combine, concentrate, and re-lyophilized of diluted HCl to obtain the product (360 mg, 49%) as hydrochloride. Mass spectrum 217,1 MN+. NMR (300 MHz, DMSO-d6, 30°C) AND 8.4 AND 8.6 (1H, s), 7,3-7,5 (3H, m), 7,1-7,3 (3H, m), 5,2-5,4 (2H, s), of 3.5-3.7 (2H, s).

Stage 5.d.-5.g. carried out by the method of stages 1.c.-1.f. example 1, using as starting compound Cbz-(L)-Ile-OH instead of Cbz-(L)-Nle-HE and receiving (2-(2-methoxyphenyl)-8-(1-methylethyl)-5,6,7,8-tetrahydroimidazo[1.2A]pyrazin) (compound vii in which R3is isobutyl, R4is 2-methoxyphenyl and R5, R6and R7are N).

Stage 5.h. 2-(2-metoc">DCC (2-6 mg, 1.00 mmol), HOSu (115 mg, 1.00 mmol), NMM (220 μl, 2.0 mmol), the product from step 5.g. (179 mg, 0.50 mmol) and the product from step 5.with. (330 mg, 1.00 mmol) dissolved in DMF (10 ml) and stirred at room temperature overnight and then heated to a temperature of about 50°C for about 8 hours. The mixture is concentrated to a resin and purified preparative HPLC on a column of RAININC18using a gradient from 25 to 40% of CH3CN/0.1% aqueous TN for 30 minutes. Fraction of the product combine, concentrate, and re-lyophilized of diluted HCl to obtain the product (96 mg, 40%) as hydrochloride. Mass spectrum 484,3 MN+.

Example 6: 2-(2-methoxyphenyl)-8-(1-methylpropyl)-7-(2-(1-phenylmethyl)imidazol-5-yl)ethyl)-5,6,7,8-tetrahydroimidazo[1,2]-pyrazin

The product of example 6 is obtained from the product from step 5.h. according to the method of example 3. Mass spectrum 470,4 MN+. NMR (300 MHz, DMSO-d6, 30°C) 9,15-OF 9.4 (1H, s), 8,05 to 8.2 (2H, DD), to 7.9 and 8.1 (1H, d), and 7.5 and 7.6 (1H, s), 7,25-7,5 (6N, m), 7,15-of 7.25 (1H, DD), 7,05-to 7.15 (1H, m), 5,5-5,6 (2H, s), 4,6-5,4 (3H, broad), 4,0-4,3 (2H, m), 3,8-4,0 (4H, m), 3,1-3,5 (2H, m), 2,6-9,95 (4H, m), 1,95-2,15 (1H, m), of 1.3-1.5 (1H, m), of 1.1-1.3 (1H, m), 0,85-1,0 (3H, d), from 0.7 to 0.85 (3H, t).

Example 7: 7-(2-(1-(4-cyanovinylene)imidazol-5-yl)-1-oxoethyl)-2-(2-methoxyphenyl)-8-(1-methylpropyl)-Mei-4-yl)-1-oxoethyl)imidazo[1,2]-pyrazin) (compound viii, in which R1, R2, R5, R6and R7are H, R3is isobutyl and R4is 2-methoxyphenyl) from example 4, stage 4.i. (135 mg, 0.21 mmol) dissolved in CH3CN (3.0 ml) and add-bromo-p-tolunitrile (42 mg, 0.21 mmol) and the mixture is refluxed for about 3 hours. The solvents are removed under reduced pressure and add Meon (3.0 ml). The mixture is refluxed for about 1 hour and the solvents removed under reduced pressure. The crude product is purified preparative HPLC on a column of RAININC18using a gradient from 5% to 35% of CH3CN/0.1% aqueous TN for 45 minutes. Fraction of the product combine, concentrate, and re-lyophilized of diluted HCl to obtain the product (9.8 mg, 8%) as hydrochloride. Mass spectrum 509,3 MN+.

Example 8: 7-((1H-imidazol-4-yl)methyl)-2-(2-methoxyphenyl)-8-(1-methylpropyl)-5,6,7,8-tetrahydroimidazo[1.2A]pyrazin

Synthesis example 8 is carried out on schemes 1 and 8, replacing the stage 1.A. 1.b. stages 8.A. -8.b. and stage 1.D. 1.h. stages 8.with. and 8.d.

Scheme 8

8. A. (C6H5)33/CH3Cl2;

8.d. TN/iPr3SiH

Stage 8.A. 4-hydroxymethyl-1-triphenylimidazole

4-Hydroxymethylimidazole hydrochloride (compound xiii in which R2is N) (2.50 g, to 18.6 mmol) and Et3N (2,59 g of 18.6 mmol) are combined in DMF (30 ml) and stirred at room temperature. Added dropwise a solution of chlorotriphenylmethane (5.19 g of 18.6 mmol) in DMF (25 ml) at room temperature and the resulting mixture was stirred at room temperature for about 23 hours and then poured into ice water (300 ml). The product is filtered, washed with cold water (75 ml) and triturated with p-dioxane (30 ml). The product is filtered and dried under reduced pressure to obtain the product (4,96 g, 78%). NMR (300 MHz, DMSO-d6, 30°C) 7,3-7,5 (N, m), 7,25-to 7.35 (1H, d), 7,0-7,2 (6N, m), 6,7-of 6.75 (1H, s), 4,15 to 4.2 (2H, m).

Stage 8.b. 1-triphenylimidazole-4-carboxaldehyde

The product from step 8.A. (2,04 g, 6,00 mmol) suspended in DMSO (10.0 ml) and add Et3N (3.34 ml, 24,0 mmol) and SO3-pyridine complex (2,39 g, 15.0 mmol) at room temperature. The mixture is heated to a temperature of about 110°C for about 1 hour and then cooled. The mixture is then poured into 15 ml) and extracted with 2×100 ml of CH2Cl3. Merged layers CH2Cl2washed with 5% citric acid solution (100 ml), dried over Na2SO4filter and concentrate under reduced pressure. The residue is crystallized from Meon and N2O. Output = 1,08 g (53%).

Stage 8.with. 7-((1-triphenylimidazole-4-yl)methyl)-2-(2-methoxyphenyl)-8-(1-methylpropyl)-5,6,7,8-tetrahydroimidazo-[1.2A]pyrazin

8-(1-methylpropyl)-2-(2-methoxyphenyl)-8-(1-methylpropyl)-5,6,7,8-tetrahydroimidazo[1,2 a]pyrazine the dihydrochloride (compound vi in which R3is 1-methylpropyl, R4is 2-methoxyphenyl and R5-R7are N) (from step 4.g.) (179 mg, 0.50 mmol) and the product from step 8.b. (compound xiv, in which R2is N) (338 mg, 1.00 mmol) are combined in 1,2-dichloroethane (2.0 ml). Added NaBH(SLA)3(212 mg, 1.00 mmol) and the reaction mixture was stirred at room temperature for about 1 hour. The reaction mixture was poured into a column with silica gel and elute the product with EtOAc eluent. Fraction of the product are combined and concentrated to obtain the product as a white foam (150 mg, 49%). Mass spectrum 608,2 MN+.

Stage 8.d. 7-((1H-imidazol-4-yl)methyl)-the s viii, in which R1is triphenylmethyl, R3is isobutyl, R4is 2-methoxyphenyl and R2, R5-R7are H, and X and Y form a bond) (160 mg, 0.26 mmol) is treated with TN (10 ml) containing iPr3SiH (0,20 ml, 1.0 mmol) for about 45 minutes at room temperature in an atmosphere of N2. The solvents are removed under reduced pressure and the product purified preparative HPLC on a column of RAININC18using a gradient of 20-40% CH3CN/0.1% of TN for 45 minutes. Fraction of the product are concentrated to about 1/2 volume and lyophilized. Product re-lyophilized of diluted HCl to obtain the pure product (77 mg, 66%). Mass spectrum 366,2 MH+.

Example 9: 7-((4-imidazolyl)carbonyl)-2-(2-methoxyphenyl)-8-(1-methylpropyl)-5,6,7,8-tetrahydroimidazo[1.2A]pyrazin

The compound of example 9 prepared as in schemes 1 and 4 according to the method of example 4, using as starting compound, the imidazole-4-carboxylic acid instead of the imidazole-4-acetic acid in stage 4.A. Mass spectrum 380,3 MN+.

Example 10: 7-(1-(4-cyanovinylene)imidazol-5-yl)methyl-2-(2-methoxyphenyl)-8-(1-methylpropyl)-5,6,7,8-tetrahydroimidazo, R3is isobutyl, R4is 2-methoxyphenyl and R2, R5, R6and R7are H, and X and Y form a bond) (150 mg, 0.25 mmol) dissolved in CH2Cl2(2.0 ml). Add-bromo-p-tolunitrile (49 mg, 0.25 mmol) and the mixture is refluxed for about 1 hour. Add Meon (3.0 ml) and the mixture is again refluxed for 1 hour. The solvents are removed under reduced pressure, add Et2O (10 ml) and the product extracted with 1.0% of TN (2×15 ml). The crude product is purified preparative HPLC on a column of RAININC18using a gradient from 20-50% CH3CN/0.1% of TN for 40 minutes. Fraction of the product concentrate to about1/2volume and lyophilized. Product re-lyophilized of diluted HCl to obtain the pure product (52 mg, 35%). Mass spectrum 481,4 MN+.

Example 11: 5-(2-(1-(4-cyanovinylene)-imidazol-5-yl)-1-oxoethyl)-5,6-dihydro-2-phenyl-1H-imidazo[1,2 a][1,4]benzodiazepine

Synthesis example 11 is carried by circuits 5 and 11.

Scheme 11

11. A. Cbz-Osu/K2CO3/CH3CN/N2O;

11.with. HBr/SPLA;

11. d. 2-perbenzoate/Et3N/CH2Cl2/, then boiling under reflux in DMF;

11. that is, NR3/THF;

11. f. 1-chloroethylphosphonic/CH2Cl2

11.g. MeOH/HCl;

11.h. Trt-Cl/Et3N/DMF;

11.i. R1Br/EtOAc, then the Meon;

11.j. MeOH/H2O/NaOH;

11.k. DCC/HOAt/DMF/connection xix/ Et3N

Stage 11.a. (N-(phenylmethoxy)carbonyl)-N-(phenylmethyl)-glycine

A solution of Cbz-Osu (6,18 g, 24/8 mmol) in CH3CN (55 ml) was added to a solution of N-benzylglycine hydrochloride (compound xv in which R3is N) (5,00 g of 24.8 mmol) and K2CO3(6,84 g of 49.6 mmol) in H2O (35 ml) and the mixture vigorously stirred for about 2 hours. The mixture is concentrated to about 35 ml and washed with Et2O (2×25 ml). The aqueous layer was acidified to about pH 1 by careful addition of concentrated HCl and the product extracted with EtOAc (2×50 ml). Layers EtOAc combined and dried over Na2SO4filter and concentrate under reduced pressure to a clear, colourless oil (yield of 7.40 g, 99.7 per cent). NMR (300 MHz, DMSO-d

The product from step 11.A. (7,18 g, 24,0 mmol) dissolved in DMF (50 ml) and add Cs2CO3(3,91 g, 12,0 mmol) in N2O (20 ml) and the mixture is stirred until homogeneity. The solvents are removed under reduced pressure, the residue is dissolved in DMF (25 ml) and add 2-bromo-2'-methoxyacetophenone (4,78 g of 24.0 mmol) in DMF (25 ml). The mixture is stirred for about 30 minutes at room temperature, then concentrated under reduced pressure. Received ketoester dissolved in xylene (125 ml) and filtered. Add NH4OAc (28,0 g, 0.36 mol) and the mixture is refluxed for about 2 hours with removal of excess NH4OAC and release of N2On using the trap Dean-stark. The reaction mixture is cooled and washed with saturated solution of NaHCO3(100 ml), dried over Na2SO4, filtered and concentrated in vacuo to obtain to 9.70 g (102%) of the compound that is used without further purification. Mass spectrum 398,2 MH+.

Stage 11.with. 2-(N-(phenylmethyl)amino)methyl)-4-phenylimidazol

The product from step 11b. (compound xvi in which R3and R5are H and R4is 2-methoxyphenyl) (9.7 g, the keys Et2O (100 ml) and the product is filtered, washed with Et2O and dried under reduced pressure to obtain the product (7.70 g, 75%) as a whitish-grayish solid. Mass spectrum 264,3 MN+, NMR (300 MHz, DMSO-d6, 30°C) 8,5-11,0 (3H, broad), of 8.1 to 8.2 (1H, s), 7,8-7,9 (2H, m), 7,55-the 7.65 (2H, m), 7,45-of 7.55 (2H, m), 7,35 and 7.5 (4H, m), 4,5-4,7 (2H, s), a 4.3 to 4.5 (2H, s).

Stage 11.d. 6-oxo-2-phenyl-5-(phenylmethyl)-1H-imidazo-[1,2 a][1,4]benzodiazepine

The product from step 11.with. (4,25 g, 10.0 mmol) suspended in THF (35 ml) and add Et3N (4.9 ml of 35.0 mmol) at room temperature. Add 2-perbenzoate (1,19 ml, 10.0 mmol) and the mixture is stirred for about 1 hour at room temperature. The solvents are removed under reduced pressure and the residue is placed in CH2Cl2(50 ml) and washed with saturated NaCl solution (2×25 ml). The layer of CH2Cl2dried over Na2SO4filter and concentrate under reduced pressure. The residue is dissolved in DMF (35 ml), add K2CO3(to 1.38 g, 10.0 mmol) and the mixture is refluxed for about 1 hour. The solvents are removed under reduced pressure, the intermediate compound is dissolved in EtOAc (50 m SO4, filtered and concentrated to about 25 ml Add Et2O (25 ml) and the product is filtered (1,46 g). Royal solutions of purified flash chromatography on silica gel using 1:1/hexane:EtOAc as eluent to obtain the second party a pale orange foam (0,63 g), which is used in the following stages. Total yield=57%. Mass spectrum 366,2 MH+, NMR (300 MHz, DMSO-d6, 30°C) 8,25-8,35 (1H, s), 7, 95-8,05 (1H, DD), about 7.6 to 7.9 (4H, m), 7,5-7,7 (1H, t), 7,3-7,5 (2H, t), 7,2-7,4 (6N, m), between 4.6-5.0 (2H, broad), 4,4-4,6 (2H, s).

Stage 11.E. 2-phenyl-5-(phenylmethyl)-1H-imidazo[1,2 a]-[1,4]benzodiazepine

The product from step 11.A. (compound xvii in which R3and R5are H and R4is 2-methoxyphenyl) (0,63 g of 1.73 mmol) was dissolved in THF and added 1M borane/THF complex (16.0 ml, 16.0 mmol) at room temperature. The mixture is refluxed for about 1 hour and then cooled. Added 4N HCl (12 ml) and the mixture is refluxed for 1/2 hour. The mixture is cooled to room temperature, concentrated to about 12 ml under reduced pressure and then neutralized by careful addition of solid NaHCO3. The product is extracted 2 times with EtOAc, dried over methanol (10 ml) and treated with concentrated HCl (0.5 ml) to turn the product in hydrochloride. The solution is concentrated and the product is obtained by crystallization from MeOH/Et2O. Output=444 mg (60%). Mass spectrum 352,2 MN+, NMR (300 MHz, DMSO-d6, 30°C) TO 8.5 AND 8.6 (1H, s), of 7.9 to 8.0 (2H, d), 7,65 was 7.9 (5H, m), 7,4-7,6 (6N, m), 7.3 to 7.4 (1H, t), 4,5-6,5 (H2O), 4,4-4,6(2H, s), 4,2-4,3 (2H, s), 4,1-of 4.25 (2H, s).

Stage 11.f. 2-phenyl-1H-imidazo[1,2 a][1,4]benzodiazepine

The product from step 11.E. (compound xviii in which R3, R5, R6and R7are H and R4is 2-methoxyphenyl) (382 mg, 0.90 mmol) partitioned between a saturated solution of NaHCO3and CH2Cl2. Layer CH2Cl2dried over Na2SO4filter and add 1-chloroethylphosphonic (108 μl, 1.00 mol) at room temperature. The mixture is stirred over night at room temperature. The layer of CH2Cl2washed with a saturated solution of NaHCO3, dried over Na2SO4filter and concentrate under reduced pressure. The residue is dissolved in Meon (5.0 ml) and stirred at room temperature for about 1 hour. The methanol solution is treated with concentrated HCl (0.5 ml) to turn the product is 62%). Mass spectrum 262,2 MN+, NMR (300 MHz, DMSO-d6, 30°C) 10,7-11,1 (1-2H, broad), an 8.5 and 8.6 (1H, s), 8,1-8,6 (1-2H, broad), 7,9-with 8.05 (2H, DD), 7,7-a 7.85 (3H, m), 7,55-the 7.65 (1H, m), 7,45-of 7.55 (2H, t), 7,3 was 7.45 (1H, m), 4,2-4,4 (2H, s), 4,1-4,3 (2H, s).

Stage 11.g. Methyl 4-imidazolate

The dihydrate sodium salt of 4-imidazolinone acid (15.3 g, 83.1 mmol) suspended in toluene (100 ml) and concentrated to remove water remaining from the hydrogenation. The residue is dissolved in Meon (235 ml) and the solution cooled in a bath of ice/water in the atmosphere N2. Add gaseous HCl for 20 minutes, and the resulting solution was stirred for 2 hours at room temperature. The mixture is concentrated to dryness. The residue re-dissolved in Meon (235 ml), filtered and the solution is cooled in a bath of ice/water in the atmosphere N2. Add gaseous HCl for 20 minutes and the resulting solution was stirred for 2 hours at room temperature. Add toluene (150 ml) and the mixture is concentrated to dryness and dried to obtain the product (16.6 g, 113%), which is used in the next stage without further purification. Mass spectrum 141,2 MH+, NMR (300 MHz, DMSO-d6, 30°C) 8,8-8,9 (1H, s), 7,5-7,7 (1H, s), of 3.7-3.9 (2H, s), up 3.6-3.7 (3H, s).

Stage 11.h. Methyl 1-triphosphate N2and in an exothermic reaction the mixture was added Et2N (35,6 ml, 241 mmol). After cooling to room temperature, add chlorotriphenylmethane (23,2 g, 83.1 mmol) and the mixture is stirred over night at room temperature. The mixture is then poured into H2O (300 ml) and extracted once with 300 ml of EtOAc and once with 150 ml of EtOAc. The combined EtOAc layers are washed with saturated solution of NaHCO3(300 ml), dried over Na2SO4, filtered and concentrated to an oil, which crystallizes from obtaining reddish-brown solid (30,9 g, 97%). Mass spectrum 382,9 MN+.

Stage 11.i. methyl 1-(cianfanelli)-5-imidazolate

The product from step 11.h. (15.0 g, is 39.2 mmol) dissolved in EtOAc (80 ml) while heating, add-bromo-p-tolunitrile (of 7.69 g of 39.2 mmol) and the mixture is heated at a temperature of 65 to 70°C for 2.5 hours. The first batch is filtered off, washed with EtOAc and dried to 9.27, the Filtrate is concentrated to about 80 ml and heated at a temperature of 65 to 70°C for another 14 hours. The second part is filtered off, washed with EtOAc and dried to 9.40, the Filtrate is concentrated to about 30 ml and heated at a temperature of 65 to 70°C for 48 hours. The third batch is filtered, PR is the principal refrigerator for 1/2 hour. The solvent distil under reduced pressure and the resulting solid is triturated with EtOAc (250 ml). The obtained solid is suspended in CH2Cl2(500 ml), add a saturated solution of NaHCO3(500 ml) and the mixture is stirred for 3 hours. The aqueous layer was removed and the layer of CH2Cl2dried over Na2SO2filter and concentrate under reduced pressure to obtain oil, which crystallizes upon maturation (8,08 g, 81%) Mass spectrum 256,2 MN+.

Stage 11.j. 1-(cianfanelli)-5-imidazole hydrochloride

The product from step 11.i. (8.0 g, 31,3 mmol) dissolved in THF (200 ml) and added 2N NaOH (16,7 ml, 33.4 mmol). The mixture is stirred for 48 hours at room temperature. The solution is neutralized to pH of 2.0 by the addition of 2N HCl and the solution concentrated under reduced pressure to a tan solid. The residue is stirred with Meon (200 ml), the solids removed by filtration and the filtrate concentrated under reduced pressure and dried to obtain the product (5,85 g, 67%). Mass spectrum 242,1 MN+, NMR (300 MHz, DMSO-d6, 30°C) of 9.3 and 9.4 (1H, s), 7,8-of 7.95 (2H, d), 7,55 to 7.7 (1H, s), 7,4-7,6 (2H, d), 5.5 to 5.7 (2H, s), 3,8-4,0 (2H, s).

The product from step 11.j. (77 mg, 0.24 mmol) are combined with DCC (49 mg, 0.24 mmol), HOAt (33 mg, 0.24 mmol), NMM (110 μl, 1.0 mmol) and the product from step 11.f. (75,0 mg, 0,225 mmol) in DMF (3.0 ml) and the reaction mixture stirred for 3 days at room temperature. The solvents are removed under reduced pressure and the crude product purified preparative HPLC on a column of RAININC18using a gradient of 15-40% CH3CN/0.1% of TN for 45 minutes. Fraction of the product are concentrated to about 1/2 volume and lyophilized. Product re-lyophilized twice from dilute HCl to obtain the pure product (71 mg, 61%). Mass spectrum 485,3 MN+. NMR (300 MHz, DMSO-d6, 30°C) OF 9.3 AND 9.4 (1H, d), 8.6 out of 8.8 (1H, d), 8,0-of 8.15 (2H, d), of 7.3 to 8.0 (N, m), 5.5 to 5.7 (2H, s), 4,9-5,1 (1H, s), 4.75 V-4,9 (1H, s), 4,65-4,8 (1H, s), 4,45-4,6 (1H, s), 4,25-4,4 (1H, s), 4,15 of 4.3 (1H, s).

Example 12: 7-(2-(4-cyanovinylene)-imidazol-5-yl)-1-oxoethyl)-2-(2-methoxyphenyl)-5,6,7,8-tetrahydroimidazo-[1.2A]pyrazin

Stage 12.A. -12.d. carried out according to scheme 1, stage 1.c.-1.f., using as starting compound Cbz-Gly-OH instead of Cbz-(L)-Ile-OH in stage 12.A. Stage 12.f. carried out according to scheme 1, step 1.D., substituting the product from step 11.j. the product from step 1.b. Mass spectrum 453,3 MN+. NMR (300 MHz, DMSO-d67 (2H, C), 4,9-5,1 (2H, broad), 4,15-4,4 (2H, broad), 4,05 to 4.2 (2H, s), 3,9-4,1 (2H, broad), 3,9-4,0 (3H, s).

Example 13: 7-(2-amino-1-oxo-3-thiopropyl)-8-(mercaptoethyl)-2-(2-methoxyphenyl)-5,6,7,8-tetrahydroimidazo-[1.2A]pyrazin disulfide

Stage 13.A. - 13.d. carried out according to scheme 1, stage 1.c.-1.f., using Cbz-(L)-Asp(Obz)-HE instead of Cbz-(L)-Nle-HE's on stage 13.A. and on the stage 13.d. use 6.0 mmol NR31.0 mmol of compound vi (in which R3is-CH2CO2N, R4is 2-methoxyphenyl and R5and R6are H). Also, the dried EtOAc layer on the stage 13.d. concentrated to solids and used without conversion into the hydrochloride.

Stage 13.E. -13.j. carried out according to scheme 13:

Scheme 13

13.e. (Vos)2O/NaOH/THF/N2O

13.f. (C6H5)3P/DEAD/Trt-SH/THF

13.g. 20% OF TN/CH2Cl2

13.h. Boc-(L)-Cys(Trt)-OH/EDC/HOAt/NMM/THF

13.i. TN/iPr3SiH/CH2Cl2

13.j. the air at pH 7,2-7,5

Stage 13.e. 7-((1,1-dimethylmethoxy)carbonyl)-8-(2-hydroxy-ethyl)-2-(2-methoxyphenyl)-5,6,7,8-tetrahydroimidazo-[1,2]-pyrazin

is 2-hydroxyethyl, R4is 2-methoxyphenyl and R5, R6and R7are H) from the stage 13.d. (3,70 g of 13.6 mmol) dissolved in THF (50 ml) and add N2O (10 ml). Add di-tert-BUTYLCARBAMATE (3.25 g, 14.9 mmol) and the reaction mixture is vigorously stirred for about 3 hours while maintaining the pH of the reaction mixture at about 8.5 by the addition of 2.5 N NaOH solution. The solvents are removed under reduced pressure, and the residue partitioned between EtOAc (25 ml) and N2O (25 ml). The product is extracted with 2×25 ml EtOAc and the combined extracts dried over Na2SO4filter and concentrate. The crude product is purified flash chromatography on silica gel using 3:2/EtOAc:hexane as eluent. Combined fractions of the product are concentrated to a white foam and dried to obtain 2,95 g (58%) of the desired product. Mass spectrum 374,3 MH+. NMR (300 MHz, DMSO-d6, 30°C) TO 7.95-WITH 8.05 (1H, DD), 1,45-of 7.55 (1H, s), 7,1-of 7.25 (1H, m), of 7.0, and 7.1 (1H, m), the 6.9 to 7.0 (1H, m), 5,1-5,3 (1H, m), 4,1-4,4 (1H, d broad), 4,0-to 4.15 (1H, m), 3,8-4,0 (1H, m), 3,85 to-3.9 (3H, s), of 3.5-3.7 (2H, t), 3,2-3,5 (1H, t broad), 3,25-3,25 (1H, s), 1.8-to 2.2 (2H, m), 1,35-1,5 (N, C).

Stage 13.f. 7-((1,1-dimethylmethoxy)carbonyl)-2-(2-methoxyphenyl)-5,6,7,8-tetrahydro-8-(2-((triphenylmethyl)thio)ethyl)-imidazo[1,2]POST">2and added dropwise diethylazodicarboxylate (at 2.45 ml, 15,54 mmol) in such a way that the temperature of the reaction mixture was maintained at <3°C. the Stirring is continued for 1/2 hour at a temperature of 0°C. are added dropwise, the mixture triphenylmethanol (4.30 g, 15,54 mmol) and the product from step 13.E. (2,90 g, to 7.77 mmol) in THF (25 ml). The resulting mixture is stirred for about 1 hour at a temperature of approximately 0°C and then warmed to room temperature. The mixture is concentrated under reduced pressure, and the residue is dissolved in a simple ether (40 ml) and stand over night. The solid is filtered off and the filtrate is concentrated and then purified flash chromatography on silica gel using 4:1/hexane:EtOAc and then 4:1/hexane:EtOAc as eluents. Fraction of the product are combined and concentrated under reduced pressure to obtain a pale yellow foam (5.49 g, 111%), which is used without further purification. Mass spectrum 632,4 MN+.

Stage 13.g. 2-(2-methoxyphenyl)-5,6,7,8-tetrahydro-8-(2-((triphenylmethyl)thio)ethyl)imidazo-[1.2A]pyrazin

The product from step 13.f. (2.50 g, of 3.96 mmol) dissolved in CH2Cl2(16.0 ml) and treated with TN (4.0 ml) at room temperature in an atmosphere of N3(150 ml) and the product extracted with CH2Cl2(2×50 ml), dried over Na2SO2filter and concentrate under reduced pressure. The crude product is purified flash chromatography on silica gel using 9:1/hexane:EtOAc and then 100% EtOAc as eluents. Fraction of the product are combined and concentrated under reduced pressure to obtain a white foam (1.35 g, 64%), which is used without further purification. Mass spectrum 532,4 MH+.

Stage 13.h. 7-(2-(((1,1-dimethylmethoxy)carbonyl)amino)-1-oxo-3-((triphenylmethyl)thio)propyl)-2-(2-methoxyphenyl)-5,6,1,8-tetrahydro-8-(2-((triphenylmethyl)thio)ethyl)imidazo-[1.2A]pyrazin

A mixture of the product from step 13.g. (compound xxi in which R2, R3, R5, R6and R7are H, R4is 2-methoxyphenyl and n is 1) (1,30 g, 2.45 mmol), Boc-(L)-Cys(Trt)-OH (1,14 g, 2.45 mmol), NMM (270 μl, 2.45 mmol) and HOAt (333 mg, 2.45 mmol) in THF (20 ml) was treated with EDC (470 mg, 2.45 mmol) at room temperature in an atmosphere of N2. The reaction mixture is stirred overnight and then concentrated under reduced pressure. Add a saturated solution of NaHCO3(25 ml) and product extracted with a 3:2 mixture g is complementary and concentrated under reduced pressure to obtain a white foam (2,31 g, 97%), which is used without further purification. Mass spectrum 977,6 MN+.

Stage 13.i. 7-(2-amino-1-oxo-3-thiopropyl)-8-(mercapto-ethyl)-2-(2-methoxyphenyl)-5,6,1, 8-tetrahydroimidazo-[1.2A]pyrazin

A solution of product from step 13.h. (2.25 g, 2.31 mmol) (compound xxii, in which each of R1, R2, R3, R5, R6and R7is H, R4is 2-methoxyphenyl, Y is =O and n = 1) in CH2Cl2(16.0 ml) is treated with TN (4,0 ml) for about 1/2 hour. Add (iPr)3SiH (1,42 ml, 6,93 mmol) and the reaction mixture is stirred for a further 1 hour. The mixture is concentrated under reduced pressure and the product is then extracted by rubbing with a 0.1% solution of TN (3×20 ml). The extracts are filtered and lyophilized to obtain 1.40 g (98%) of a white solid with a purity (HPLC) of about 92%. The crude product is then purified preparative HPLC on a column of RAININC18using a gradient of 10-30% CH3CN/0.1% of TN for 45 minutes. Fraction of the product combine, concentrate under reduced pressure to about 1/2 volume and is used in the next stage without further purification. Mass spectrum 393,2 MN+.

An aqueous solution of the product from step 13.i. (the crude solution, 0.45 mmol) were diluted to 100 ml 0.1% of TN and neutralized with 5% solution of NH4OH. Add methanol (100 ml) to obtain a homogeneous solution. The mixture is stirred overnight, while maintaining a pH of about 7.2 and 7.5. The solution is concentrated to about 25 ml, alkalinized by adding pure NaHCO3and the product extracted with CH2Cl2(3×25 ml). Extracts poured into a column of silica gel and elute the product with 90:9:1/CH2Cl2:Meon:SPLA. Fraction of the product are combined and concentrated under reduced pressure. The residue is dissolved in 0.5% HCl solution (10 ml) and lyophilized and then re-lyophilized of H2O (10 ml) to give 43 mg (9%) of pure product. Mass spectrum 391,2 MH+. NMR (300 MHz, DMSO-d6, 30°C) OF 8.8 TO 9.2(2H, broad), of 7.9 to 8.1 (2H, m), 7,3-7,5 (1H, t), 7,15-7,3 (1H, d), 7,0-7,2 (1H, t), 6,05 and 6.25 (1H, m), 4,85-5,0 (1H, broad), 4,7-4,9 (1H, d), 4,2-of 4.35 (1H, d), 4,0-4,2 (1H, m), 3,9-4,0 (3H, s), 3,55-3,7 (1H, d), 3,3-3,55 (1H, overlapped, H2O peak), 2,9-3,1 (1H, t), 2.4 to 2.8 (4H, m).

Example 14: 5-butyl-7-(2-(4-cyanopyrimidine-5-yl)-1-oxoethyl)-2-phenyl-5,6,7,8-tetrahydroimidazo[1.2A]pyrazin

Stage 14.A. -14.d. spend according shat on stage 14.b. Stage 14.E. carried out according to scheme 1, step 1.g., substituting the product from step 11.j. the product from step 1.b. Mass spectrum 479,3 MH+.

Example 15: 6-butyl-7-(2-(4-cyanovinylene)imidazol-5-yl)-1-oxoethyl)-2-(2-methoxyphenyl)-5,6,7,8-tetrahydroimidazo-[1.2A]pyrazin

The compound from example 15 get analogously to example 14 except that the stage 1.d., 1.e. 1.f. replace on stage 15.A. and 15.b.

Scheme 15

15. A. R7COCHBr6/K2CO3/DMF

15.b. H2/Pd coal/SPLA

Stage 15.A. 1-(2-oxohexyl)-2-(1-(((phenylmethoxy) carbonyl)amino)methyl)-4-(2-methoxyphenyl)imidazol

1-H-2-(1-(((phenylmethoxy)carbonyl)amino)methyl)-4-(2-methoxyphenyl)imidazole (compound iv in which R3and R5are H and R4is 2-methoxyphenyl) (790 mg, 2.34 mmol), 1-chloro-2-hexanone (473 mg, 3,51 mmol) and K2CO3(469 mg, and 4.68 mmol) are combined in DMF (4 ml) and stirred at room temperature for 42 hours. The reaction mixture was diluted with saturated NaHCO3(25 ml) and extracted with Et2O (2×50 ml). The combined extracts Et2O dried over Na2SO2Cl2as eluent. The fractions of pure product are combined and concentrated under reduced pressure to obtain a pale yellow oil (650 mg, 64%), which solidified upon maturation. Mass spectrum 463,3 MN+.

Stage 15.b. 6-butyl-2-(2-methoxyphenyl)-5,6,7,8-tetrahydroimidazo[1.2A]pyrazin

The product from step 15.A. (compound xxiv in which R3, R5and R6are H, R5is 2-methoxyphenyl and R7is n-bootrom) (650 mg, 1,49 mmol) dissolved in SPLA (25 ml) containing 10% Pd on coal (65 mg) and the mixture hydronaut under pressure Hz 2,109 kg/cm2(30 pounds/square inch) for about 6 hours. The catalyst was removed by filtration through diatomaceous earth and the filtrate concentrated under reduced pressure to obtain a pale yellow oil, which crystallizes upon maturation (430 mg, 101%).

Stage 15.with. 6-butyl-7-(2-(4-cyanovinylene)imidazol-5-yl)-1-oxoethyl)-2-(2-methoxyphenyl)-5,6,7,8-tetrahydroimidazo-[1.2A]pyrazin

The compound of example 15 get on stage 15.with. according to the method of stage 1.D., substituting the product from step 15.b. the product from step 1.f. Mass spectrum 509,3 MH+.

Example 16: 6-inania example 16 receive according to the method of example 15, using as starting compound 2-bromoacetophenone instead of 2-bromo-2'-methoxyacetophenone in stage 1.c. Mass spectrum 509,4 MH+.

Example 17: 5-butyl-7-(2-(1-(4-cyanovinylene)imidazol-5-yl)-1-oxoethyl)-2-(2-methoxyphenyl)-5,6,7,8-tetrahydroimidazo-[1.2A]pyrazin

The compound of example 17 receive according to the method of example 14, using as starting compound 2-bromoacetophenone instead of 2-bromo-2'-methoxyacetophenone in stage 1.e. Mass spectrum 509, 3 MH+.

Example 18: 7-(2-(1-(4-cyanovinylene)imidazol-5-yl)-1-oxoethyl)-8-(cyclohexylmethyl)-2-(2-methoxyphenyl)-5,6,7,8-tetrahydroimidazo[1.2A]pyrazin

Stage 18.A. -18.d. carried out similarly to scheme 1, stage 1.c.-1.f. Using Cbz-(L)-cyclohexylamine instead of Cbz-(L)-Nle-OH in stage 18.A. Stage 18.E. carried out according to scheme 1, step 1.g., substituting the product from step 11.j. the product from step 1.b. Mass spectrum 549,4 MH+. NMR (300 MHz, DMSO-d6, 30°C) 9,15-A 9.25 (1H, s), 8,05-of 8.15 (1H, d), with 8.0 and 8.1 (1H, s), 7,8-7,9 (2H, d), and 7.6 to 7.7 (1H, s), and 7.5 and 7.6 (2H, d), between 7.4 to 7.5 (1H, t), 7,15-7,3 (1H, d), 7,05-to 7.15 (1H, t), 5,85-6,05 (1H, DD), of 5.5 to 5.6 (2H, s), 4.1 and 4.5 (5H, m), 3,9-4,1 (3H, s), 3.75 to a 3.9 (1H, m), 1.85 to 2.1 a (3H, m), 1,4-1,8 (41-1, m), 0,8-1,4 (7H, m).

The connection 19: 5-butyl-7-(2-(1H-imidazol-5-yl)-1-oxoethyl)-2-(2-methoxyphenyl)-5,6,7,8-tetrahydroimidazo[1,26,7,8-tetrahydroimidazo-[1.2A]pyrazin (compound vii, in which R3, R5and R7are H, R4is 2-methoxyphenyl and R6is n-bootrom), as described in example 14 instead of 2-(2-methoxyphenyl)-8-(1-methyl-propyl)-5,6,7,8-tetrahydroimidazo[1,2 a]pyrazine on stage 19.E. Mass spectrum 394,3 MH+.

Example 20: 7-(2-(4-cyanovinylene)imidazol-5-yl)-1-oxoethyl) -2-(2-phenylmethoxy)phenyl)-5,6,7,8-tetrahydroimidazo[1,2]-pyrazin

The source material for the stage 20.A. get a similar scheme 1, stage 1.with.-1.f., using Cbz-(Gly)-OH instead of Cbz-(L)-Nle-HE. Stage 20.in. carried out according to scheme 1, step 1.g., substituting the product from step 11.j. the product from step 1.b.

Scheme 20

20.A. BBr3/CH2Cl2/hexane, then (Vos)2O/NaOH/THF/H2ABOUT

20.b. NaH/R8Br/DMF

20.with. TN/iPr3SiH

Stage 20.A. 7-((1,1-dimethylmethoxy)carbonyl)-2-(2-hydroxy-phenyl)-5,6,1,8-tetrahydroimidazo[1,2]-pyrazin

2-(2-methoxyphenyl)-5,6,1,8-tetrahydroimidazo[1.2A]pyrazin (compound vii in which R3, R5, R6and R7are H and R4is 2-methoxyphenyl) (5.30 g, 23,1 mmol) is dissolved in the SUB>/hexane (80,3 ml of 80.3 mmol) in CH2Cl2(500 ml) at a temperature of approximately 0°C. the Mixture is heated to room temperature and stirred over night. Demetilirovanie intermediate compound is extracted with N2About (3×240 ml) and the combined aqueous layers washed with Et2O (100 ml). The solution is brought to pH 8 by the addition of 2.5 N NaOH and add di-tert-BUTYLCARBAMATE (of 5.55 g of 25.4 mmol) in THF (200 ml). The solution is vigorously stirred for about 2 hours, maintaining the pH of the solution to 8.0 to 8.5. The mixture is concentrated to about 700 ml) and extracted with CH2Cl2(2×100 ml). The combined layers of CH2Cl2dried over Na2SO4filter and concentrate under reduced pressure to obtain the product (7,10 g, 97%) as a reddish brown solid. Mass spectrum 316,2 MN+. NMR (300 MHz, DMSO-d6, 30°C) the 7.65 to 7.7 (1H, s), and 7.6 to 7.7 (1H, DD), 7,0-to 7.15 (1H, m), 6.75 in-6,9 (2H, m), 4,6-4,7 (2H, s), 4,0-4,2 (2H, t), 3.75 to 3,9 (2H, t), 3,3-3,4 (H2O), 1,4-1.55V (N, C).

Stage 20.b. 7-((1,1-dimethylmethoxy)carbonyl)-2-(phenylmethoxy)-5,6,7,8-tetrahydroimidazo[1.2A]pyrazin

60% dispersion of NaH in mineral oil (76 mg, 1.9 mmol) was washed with hexane (2×5.0 ml) and add RA is Noah temperature. The reaction mixture is stirred for about 10 minutes and then add benzylbromide (188 μl, was 1.58 mmol) and the reaction mixture was stirred at room temperature for about 2 hours. The mixture was poured into saturated NaCl solution (40 ml) and extracted with Et2O (2×50 ml). Layers Et2O unite, dried over Na2SO4filter and concentrate under reduced pressure to obtain the product (430 mg, 67%) as a viscous yellow oil, which crystallizes upon maturation. Mass spectrum 406,3 MN+.

Stage 20.with. 2-(2-(phenylmethoxy)phenyl)-5,6,7,8-tetrahydroimidazo[1.2A]pyrazin

The product from step 20.b. (250 mg, 0.62 mmol) is treated with TN (15.0 ml) containing iPr3SiH (505 μl, 2,47 mmol) at room temperature for about 1 hour in an atmosphere of N2. The solvents are removed under reduced pressure and the residue triturated with Et2O (2×20 ml), filtered and dried. The rest is used in the next stage without further purification.

Stage 20.d. 7-(2-(4-cyanovinylene)imidazol-5-yl)-1-oxo-ethyl)-2-(2-phenylmethoxy)phenyl)-5,6,7,8-tetrahydroimidazo[1,2-a]-pyrazin

The compound of example 20 is obtained from the product from step 20.d. and the product from step 11.j is ethyl)-imidazol-5-yl)-1-oxoethyl)-5,6,1, 8 tetrahydroimidazo[1,2]-pyrazin

The compound of example 21 receive according to the method of example 20 using n-butylated instead of benzylbromide on stage 20.b. Mass spectrum 495,4 MH+.

Example 22: 1,2-dihydro-1-((1H-imidazol-4-yl)methyl)-4-(2-methoxyphenyl)imidazo[1,2][1,4]benzodiazepine

The source material for the stage 22.A. get similar to scheme 1, step 1.c. using Cbz-(Gly)-HE instead of Cbz-(L)-Nle-HE. Stage 22.d. and 22.with. carried out by the method of stages 8.with. and 8.d..

Scheme 22

22.A. 2-florantyrone/K2CO3/DMF

22.b. HBr/HOAc

22.with. NMP (boiling under reflux)

Stage 22.A. 1-((2-forfinal)methyl)-2-(1-(S)-(((phenylmethoxy)carbonyl)amino)methyl)-4-(2-methoxyphenyl)imidazol

1H-2-(1-(S)-(((phenylmethoxy)carbonyl)amino)methyl)-4-(2-methoxyphenyl)imidazole (1,69 g, 5.00 mmol) dissolved in DMF (20 ml) and treated with K2CO3(to 1.38 g, 10.0 mmol) and 2-terbisil-bromide (1,21 ml, 10.0 mmol) and the mixture is heated to a temperature of about 50°C for about 2 hours. The mixture is concentrated under reduced pressure. The residue is placed in EtOAc (50 ml), washed once with saturated solution of NaHCO3(25 ml) and once with a saturated solution is e crystallizes during maturation. Mass spectrum 446,2 MH+. NMR (300 MHz, DMSO-d6, 30°C) 8,05-of 8.15 (1H, d), 8,75-8,9 (1H, t), with 7.5 and 7.6 (1H, s), 7,1-7,5 (N, m), 6,9-7,1 (3H, m), 5.3 to the 5.45 (2H, s), 4,9-5,1 (2H, s), 4,3 is 4.45 (2H, s), 3,8-3,9 (3H, s).

Stage 22.b. 2-(aminomethyl)-1-((2-forfinal)methyl)-4-(2-methoxyphenyl)imidazol

1-((2-forfinal)methyl)-2-(1-(S)-((phenylmethoxy)carbonyl)-amino)methyl)-4-(2-methoxyphenyl)imidazol (compound xxvi, in which R2, R3, R5and R6are H and R4is 2-methoxyphenyl) (2,22 g, 4,99 mmol) dissolved in 30% HBr/SPLA (25 ml) and the reaction mixture is stirred for about 1 hour at room temperature. Add Et2O (100 ml) and the resulting suspension is stirred for about 15 minutes and the product is filtered and washed with Et2O (100 ml). The product is neutralized by adding a saturated solution of NaHCO3(50 ml) and the product extracted with CH2Cl2(2×25 ml). The combined layers of CH2Cl2unite, dried over Na2SO4filter and concentrate under reduced pressure to a viscous oil (1.26 g, 81%), which solidified upon maturation. Mass spectrum 312,2 MN.

Stage 22.with. 1,2-dihydro-4-(2-methoxyphenyl)imide,26 g, of 4.05 mmol) are added to NMP (20 ml) containing K2CO3(1.12 g, 8,10 mmol) and the reaction mixture is refluxed for about 11 hours. The solvent is distilled off under reduced pressure and add H2O (50 ml). The crude product is filtered and purified flash chromatography on silica gel using CH2Cl2and then 19:1/Meon:CH2Cl2as eluents. Fraction of the product are combined and concentrated under reduced pressure and then triturated with EtOAc to obtain the product as a reddish brown solid (329 mg, 28%). Mass spectrum 292,3 MN+. NMR (300 MHz, DMSO-d6, 30°C) TO 7.95 AND 8.1 (1H, DD), 7,6-the 7.65 (1H, s), 7,1-7,2 (1H, m), 6,9-7,1 (4H, m), 6,5-of 6.65 (2H, m), 5,2-5,4 (2H, s), 4.4 to 4.5 (2H, s), 3,8-4,0 (3H, s).

Stage 22.d. 1,2-dihydro-4-(2-methoxyphenyl)-1-((1-(triphenyl-methyl)imidazol-4-yl)methyl)imidazo[1,2-C][1,4]benzodiazepine

According to the method stage 8.with. a mixture of the product from step 22.with. (compound xxvii, in which R2, R3, R5and R6are H and R4is 2-methoxyphenyl) (146 mg, 0.50 mmol) and 1-triphenylimidazole-4-carboxaldehyde (stage 8.b.) (338 mg, 1.00 mmol) in CH2Cl2(212 mg, 1.00 mmol) and the mixture is stirred for about 1 hour. Add EtOAc (25 ml) and concentrated NH4OAc (3.0 ml) and the mixture is stirred for about 1.5 hours. Add a saturated solution of NaHCO3and the mixture extracted with EtOAc (3×25 ml). The combined EtOAc layers are dried, filtered and concentrated under reduced pressure. The product was then purified flash chromatography on silica gel using 1:1:1/CH2Cl2:EtOAc:hexane, then EtOAc as eluent. Combined fractions of the product are concentrated and dried to 210 mg (68%) under reduced pressure. Mass spectrum 614,3 MH+.

Stage 22.E. 1,2-dihydro-4-(2-methoxyphenyl)-1-((1-(triphenylmethyl)imidazol-4-yl)methyl)imidazo[1,2-C][1,4]benzodiazepine

The product from step 22.d. remove protection according to the method of stage 1.h. to obtain 104 mg (70%) of product. Mass spectrum 372,3 MN+. NMR (300 MHz, DMSO-d6, 30°C) FROM 9.0 TO 9.2 (1H, s), 8,05-of 8.15 (1H, s), of 7.9 to 8.0 (1H, d), 7,7-7,8 (1H, s), 7.3 to at 7.55 (4H, m), 7,1-7,3 (2H, m), of 7.0, and 7.1 (1H, t), 5,6-5,8 (2H, s), 4, 55-4,75 (4H, s), 3,9-4,1 (3H, s), 2,7-4,0 (N2O wide).

Example 23: 1-(2-(1-(4-cyanovinylene)imidazol-4-yl)-1-oxoethyl)-1,2-dihydro-4-(2-methoxyphenyl)imidazo[1,2][1,4]-benzodiazepine

1,2-dihydro-4-(2-methoxyphenyl)imidazo[1,2][1,4]benzodiazepine (compound xxvii, in which R2, R3, R5and R6are H and R4is 2-methoxyphenyl) (stage 22.with.) combine with DCC (103 mg, 0.50 mmol), HOAt (68 mg, 0.50 mmol), NMM (55 μl, 0.50 mmol) and 1-(4-cyanovinylene)-5-imidazolinone acid (the product from step 11.j.) (160 mg, 0.50 mmol) in DMF (3.0 ml) and the reaction mixture was stirred over night at room temperature. The reaction mixture is heated to a temperature of about 70°C and then concentrated under reduced pressure. The crude material is purified preparative HPLC on a column of RAININC18exercising the first transmission using a gradient of 10-40% CH3CN/0.1% of TN for 45 minutes, then a second pass using a gradient of 20-35% CH3CN/0.1% of TN for 45 minutes. Fraction of the product are combined and concentrated to dryness. The product is converted into the dihydrochloride by passing 9:1/N2O:Meon solution through ion-exchange column (AG 1 x2, 200-400 mesh, 100 ml layer of 0.6 mEq/ml, chloride, Biorad, Inc., Hercules, CA). Fraction of the product again concentrated under reduced pressure and lyophilized of H2O (10 ml) to give 21 mg (10%) W-4-yl)-1-oxoethyl)-1,2-dihydro-4-(2-methoxyphenyl)imidazo[1,2]-[1,4]-benzodiazepine

The compound of example 24 receive according to figure 22, figure 24 and figure 1, stage 1.g.

Scheme 24

Stage 24.A. 9-bromo-1,2-dihydro-4-(2-methoxyphenyl)-1H-imidazo[1,2][1,4]-benzodiazepine

The product from step 22.with. (291 mg, 1.00 mmol) is dissolved in acetic acid (10 ml) and added dropwise Br2(52 μl) with stirring. Add methanol (10 ml) to keep the solution homogeneous. After adding the solvent is evaporated under reduced pressure and the residue purified preparative HPLC on a column of RAININC18using a gradient of 20-50% CH3CN/0.1% of TN for 45 minutes with UV determination at 254 nm. Fraction of the product are concentrated to 1/2 volume and lyophilized. Liofilizovannye product is converted into the hydrochloride by passing 20% methanol solution through the ion exchange column (BioRad AG 1 x2, 200-400 mesh, 0.6 mEq/ml, 100 ml, chloride). Fraction of the product combine, concentrate, and lyophilized of N2O obtaining the pure product (110 mg, 24%) as the dihydrochloride. Mass spectrum 370,0 MN+. NMR (300 MHz, DMSO-d6, 30°C) 8,05-of 8.15 (1H, s), of 7.9 to 8.0 (1H, d), between 7.4 to 7.5 (1H, t), 7.3 to 7.4 (1H, s), 7,2-7,3 (1H, DD), 7,15-of 7.25 (1H, d), 7,05-to 7.15 (1H, t), 6,65 to 6.75 (1H, d), 5,55-5,7 (2H, s), 4,8-of 4.95 (2H, s), 3,9-4,0 (3H, s).

1,2][1,4]-benzodiazepine

The product from step 24.A. (72 mg, 0,177 mmol) dissolved in DMF (3 ml). To the resulting solution was added NMM (98 μl, 0.89 mmol), 1-(4-cyanovinylene)-5-imidazolinone acid (the product from step 11.j.) (128 mg, 0.36 mmol), HOAt (49 mg, 0.36 mmol) and DCC (74 mg, 0.36 mmol). The reaction mixture was stirred over night at room temperature and then heated to a temperature of 70°C for one hour. The reaction mixture is heated at a temperature of 70°C for 1 hour and concentrated under reduced pressure. The residue is purified preparative HPLC on a column of RAININC18using the gradient 25-60% CH3CN/0.1% of TN for 45 minutes with UV determination at 254 nm. Required a second purification using a gradient 44-80% CH3CN/0,2% NH4OAc for 45 minutes. Fraction of the product concentrate and lyophilized with obtaining the pure product (11 mg, 9%) in the form of acetate. Mass spectrum 593,2, 595,3 MN+.

Example 25: 9-chloro-1-(2-(1-(4-cyanovinylene)imidazol-4-yl)-1-oxoethyl)-1,2-dihydro-4-(2-methoxyphenyl)imidazo[1,2][1,4]-benzodiazepine

The compound of example 25 receive according to figure 22, figure 24 and figure 1, stage 1.g.

Stage 25.A. 9-chloro-1,2-dihydro-4-(2-methoxyphenyl)-1H-imidazo[1,2][1,4]-benzodi the ml) adding 5% saturated with HCl (3.0 ml) and concentrating to obtain a solid substance. The residue is dissolved in methanol (5 ml) and add SPLA (1,0 μl) and N-chlorosuccinimide (133 mg, 1.0 mmol). The mixture is stirred at room temperature overnight and concentrated under reduced pressure. The residue is partitioned between saturated NaHCO3and CHCl3and layer CHCl3injected into a column of silica gel. Column elute first 3:1/CHCl3:EtOAc, then 1:1/CHCl3:EtOAc to obtain the crude product. The crude material is then purified preparative HPLC on a column of RAININC18using the gradient 25-60% CH3CN/0.1% of TN for 45 minutes with UV determination at 254 nm. The fractions of pure product are combined and lyophilized to obtain 94 mg (17%) of product in the form of TN-salt. Mass spectrum 326,2 MH+. NMR (300 MHz, DMSO-d6, 30°C) TO 8.0 AND 8.1 (1H, s), 7,7-7,8 (1H, DD), to 7.4 and 7.5 (1H, t), 7,2-7,3 (1H, s), 7,15-7,3 (1H, d), 7,1-7,2 (1H, DD), 7,05-to 7.15 (1H, t), 6,7-6,8 (1H, d), 5,55-the 5.65 (2H, s), 4,7-4,8 (2H, s), 3,9-4,0 (3H, s).

Stage 25.b. 9-chloro-1-(2-(1-(4-cyanovinylene)imidazol-4-yl)-1-oxoethyl)-1,2-dihydro-4-(2-methoxyphenyl)imidazo-[1,2][1,4]-benzodiazepine

The product from step 25.A. (72 mg, 0.13 mmol) dissolved in DMF (1.5 ml). This POST">1is (4-cyanovinylene) and R2is H) (92 mg, 0.26 mmol) and TFFH (69 mg, 0.26 mmol). The reaction mixture was stirred over night at room temperature and then heated to a temperature of 70°C for one hour. The solution is cooled to room temperature and add 1-(4-cyanovinylene)-5-imidazolinone acid (the product from step 11.j.) (92 mg, 0.26 mmol) and TFFH (60 mg, 0.26 mmol). The reaction mixture was stirred over night at room temperature, then concentrated under reduced pressure. The residue is purified preparative HPLC on a column of RAININC18using the gradient 25-60% CH3CN/0.1% of TN for 45 minutes with UV determination at 254 nm. Fraction of the product concentrate and lyophilized. Liofilizovannye product is converted into the hydrochloride by passing a 30% methanolic solution through the ion exchange column (BioRad AG 1-X2, 200-400 mesh, 0.6 mEq/ml, 100 ml, chloride). Fraction of the product combine, concentrate, and lyophilized of H2O obtaining the pure product (59 mg, 73%) as the dihydrochloride. Mass spectrum 594,3 MH+. NMR (300 MHz, DMSO-d6, 30°C) TO 9.2 AND 9.3 (1H, s), with 8.0 and 8.1 (1H, s), is 7.9 and 8.1 (1H, d), 7,8-7,9 (2H, d), 7,7-a 7.85 (2H, m), and 7.6 to 7.75 (1H, DD), 7,5-7,7 (1H, s), 7,4-of 7.55 (2H, d), 7,35 is 7.5 (1H, t), 7,15-7,3 (1H, d), 7,0-7, the l-4-yl)-1-oxoethyl)-1,2-dihydro-4-(2-methoxyphenyl)imidazo[1,2]-[1,4]benzodiazepine

Stage 26.A. -26.with. carried out by the method of stages 22.A. -22.S., using 4-bromo-2-florantyrone instead of 2-terbisil bromide on stage 26.A. The product from step 26.with. isolated in the form of the dihydrochloride by mixing a methanol suspension with 20% excess of concentrated hydrochloric acid and filtering the obtained solid substance. Mass spectrum 370,1, 372,1 MN+.

Stage 26.d. 10-bromo-1-(2-(1-(4-cyanovinylene)imidazol-4-yl)-1-oxoethyl)-1,2-dihydro-4-(2-methoxyphenyl)imidazo[1,2][1,4]-benzodiazepine

The product from step 26.with. (100 mg, 0.23 mmol) suspended in DMF (1.5 ml) and added the product from step 11.j. (125 mg, 0.45 mmol), TFFH (119 mg, 0.45 mmol) and NMM (110 μl, 1.0 mmol). The reaction mixture was stirred at room temperature for about 45 minutes and stand at room temperature overnight. The crude mixture was concentrated under reduced pressure and the residue purified preparative HPLC on a column of RAININC18using a gradient of 20-50% CH3CN/0.1% of TN for 45 minutes with UV determination at 254 nm. Spend a second purification using socratous system containing 44% of CH3CN/0.2% aqueous NH4The OAc. Fraction of the product concentrate and lyophilized. Liofilizovannye products% CH3CN/1% of TN and then converted into the hydrochloride by passing a 30% methanolic solution through the ion exchange column (BioRad AG 1-X2, 200-400 mesh, 0.6 mEq/ml, 100 ml, chloride). Fraction of the product combine, concentrate, and lyophilized from 20% CH2CN/H2O obtaining the pure product (45 mg, 30%) as the dihydrochloride. Mass spectrum 593,2, 595,2 MH+. NMR (300 MHz, DMSO-d6, 30°C) TO 9.1 AND 9.3 (1H, s), is 7.9 and 8.1 (3H, m), 7,8-7,9 (2H, d), 7,7-7,8 (1H, DD), about 7.6 to 7.7 (1H, d), and 7.5 and 7.6 (1H, s), between 7.4 to 7.5 (2H, d), 7,3 was 7.45 (1H, t), 7,1-of 7.25 (1H, s), to 7.0, and 7.1 (1H, t), 4,4-6,2 (2H, DD), 5,4-5,7 (4H, m), 3,9-4,0 (3H, s), of 3.5-3.9 (2H, DD).

Example 27: 1-(2-(1-(4-cyanovinylene)imidazol-4-yl)-1-oxoethyl)-1,2-dihydro-8-fluoro-4-(2-methoxyphenyl)imidazo[1,2][1,4]-benzodiazepine

Stage 27.A. -27.with. carried out by the method of stages 22.A. -22.S., using 2,6-differenziale instead of 2-ftorangidridy on stage 27.A.

Stage 27.d. 1-(2-(1-(4-cyanovinylene)imidazol-4-yl)-1-oxoethyl)-1,2-dihydro-8-fluoro-4-(2-methoxyphenyl)imidazo-[1,2][1,4]benzodiazepine

The product from step 21.with. (124 mg, 0.40 mmol) suspended in DMF (2 ml) and added the product from step 11j. (111 mg, 0.40 mmol), TFFH (106 mg, 0.40 mmol) and NMM (88 μl, 0.8 mmol). The reaction mixture was stirred at room temperature for about 1.5 hours. Add the second portion at room temperature over night. The crude mixture was concentrated under reduced pressure and the residue purified preparative HPLC on a column of RAININC18using a gradient of 20-50% CH3CN/0.1% of TN for 45 minutes with UV determination at 254 nm. Fraction of the product are combined and lyophilized. TN salt is converted into the hydrochloride by passing a 40% methanolic solution through the ion exchange column (BioRad AG 1-x2, 200-400 mesh, 0.6 mEq/ml, 100 ml, chloride). Fraction of the product combine, concentrate, and lyophilized of N2O obtaining the pure product (126 mg, 59%) as the dihydrochloride. Mass spectrum 533,3, MN+. NMR (300 MHz, DMSO-d6, 30°C) TO 9.2 AND 9.3 (1H, s), 8,2-8,4 (1H, s), is 7.9 and 8.1 (1H, d), 7,8-7,9 (2H, d), 7,55 to 7.7 (3H, m), 7,35-of 7.55 (4H, m), 7,15-of 7.25 (1H, d), 7,0-to 7.15 (1H, t), 4,5-6,3 (2H, DD), 5,5-5,7 (2H, DD), 3,9-4,1 (3H, s), 3.6 and 4.0 (2H, DD).

Example 28: 1,2-dihydro-1-(2-(imidazol-1-yl)-1-oxoethyl)-4-(2-methoxyphenyl)imidazo[1,2 a][1,4]benzodiazepine

A solution of product from step 22.with. (146 mg, 0.50 mmol) in DMF (2 ml) is treated with chloracetamide (44 μl, 0.55 mmol) in DMF (0.5 ml) and the mixture is stirred at room temperature for 1/2 hour. Add imidazole (204 mg, 3.00 mmol) and the mixture is heated to a temperature of 50°C for 3 hours and then stand at room temperature for NINC18using a gradient of 10-50% CH3CN/0.1% of TN for 25 minutes with UV determination at 254 nm. Fraction of the product are combined and concentrated under reduced pressure. TN salt is converted into the hydrochloride by passing a 30% methanolic solution through the ion exchange column (BioRad AG 1-x2, 200-400 mesh, 0.6 mEq/ml, 100 ml, chloride). Fraction of the product combine, concentrate to a volume of about 10 ml and lyophilized of H2O obtaining the pure product (127 mg, 54%) as the dihydrochloride. Mass spectrum 400,2, MN+. NMR (300 MHz, DMSO-d6, 30°C) FROM 9.1 TO 9.2 (1H, s), of 8.1 to 8.2 (1H, s), 7,9-with 8.05 (1H, d), 7,8-7,9 (1H, d), 7,5-7,8 (5H, m), 7,35 is 7.5 (1H, m), 7,15-of 7.25 (1H, d), 7,0-to 7.15 (1H, t), 6,2 to 6.35 (1H, d), the 6.0-x 6.15 (1H, d), 5,5-5,7 (1H, d), 5,35 to 5.5 (1H, d), 4.95 points-of 5.15 (1H, d), 4,6-4,8 (1H, d), 3,9-4,0 (3H, s).

Example 29: 1,2-dihydro-4-(2-methoxyphenyl)-1-(2-(pyridin-3-yl)-1-oxoethyl)imidazo[1,2 a][1,4]benzodiazepine

A solution of product from step 22.with. (102 mg, 0.35 mmol) in DMF (1.5 ml) is treated with 3-peridiocally acid hydrochloride (69,4 mg, 0.40 mmol), NMM (110 μl, 1.00 mmol) and TFFH (106 mg, 0.40 mmol) and the mixture is stirred at room temperature for 14 hours. To the reaction mixture an additional amount of 3-peridiocally acid hydrochloride (26,0 mg, 0.15 mmol), NMM(33 μl, 0.30 mmol) and TFFH (40 mg, 0.15 to much under reduced pressure. Add a saturated solution of NaHCO3(5 ml) and the product extracted with CH2Cl2(2×5 ml). CH2Cl2distilled off under reduced pressure and the residue is dissolved in 10% aqueous CH3CN pH is increased to 2 by the addition of TN. The crude product is purified preparative HPLC on a column of RAININC18using a gradient of 10-50% CH3CN/0.1% of TN for 25 minutes with UV determination at 254 nm. Fraction of the product are combined and concentrated under reduced pressure. TN salt is converted into the hydrochloride by passing a 30% methanolic solution through the ion exchange column (BioRad AG 1-X2, 200-400 mesh, 0.6 mEq/ml, 100 ml, chloride). Fraction of the product combine, concentrate to a volume of about 10 ml and lyophilized of N2About obtaining the pure product (123 mg, 73%) as the dihydrochloride. Mass spectrum 411,1, MH+.

Example 30: 1,2-dihydro-4-(2-methoxyphenyl)-1-(2-(pyridin-4-yl)-1-oxoethyl)imidazo[1,2 a][1,4]benzodiazepine

The compound of example 30 receive according to the method of example 29 except using 4-peridiocally acid hydrochloride instead of 3-peridiocally acid hydrochloride on the stage 30.A. Mass spectrum 411,1, MN+. NMR (300 MHz, DMSO-5-of 7.25 (1H, d), 7,0-to 7.15 (1H, t), 6,2-6,4 (1H, d), 5,7-to 5.85 (1H, d), 5,5-the 5.65 (1H, d), 4,5-4,7 (1H, d), 3,7-4,2 (2H, m), 3,9-4,0 (3H, s).

Example 31: 1-(2-(1-benzylimidazole-5-yl)-1-oxoethyl)-1,2-dihydro-8-fluoro-4-(2-methoxyphenyl)imidazo[1,2 a][1,4]benzodiazepine

Stage 31.A. -31.with. carried out by the method of stages 22.A. -22.S., using 2,6-differenziale instead of 2-ftorangidridy on the stage 31.A.

Stage 31.d. 1-(2-(1-benzylimidazole-5-yl)-1-oxoethyl)-1,2-dihydro-8-fluoro-4-(2-methoxyphenyl)imidazo[1,2 a][1,4]-benzodiazepine

The product from step 31.with. combined with the product from step 5.with. (1-phenylmethyl-5-imidazolinone acid) and purified by the method of stage 25. b. Mass spectrum 508,5, MH+. NMR (300 MHz, DMSO-d6, 30°C) TO 9.1 AND 9.3 (1H, s), and 8.2 and 8.3 (1H, s), of 7.9 to 8.0 (1H, DD), of 7.2 to 7.7 (10H, m), 7,15-of 7.25 (1H, d), 7,0-to 7.15 (1H, t), of 6.1 and 6.3 (1H, d), 5,65 to 5.8 (1H, d), 5,3-5,6 (3H, m), 4,45-4,6 (1H, d), 3,9-4,0 (3H, s), 3,6-3,9 (2H, HF).

Example 32: 1-(2-(1-((4-cyano)phenylmethyl)imidazol-5-yl)-1-oxoethyl)-9,10-debtor-1,2-dihydro-4-(2-methoxyphenyl)imidazo-[1,2][1,4]benzodiazepine

Stage 32.A. -32.with. carried out by the method of stages 22.A. -22.S., using 2,4,5-triterpenoid instead of 2-ftorangidridy on stage 32.A.

Stage 32.d. 1-(2-(1-((4-cyano)phenylmethyl)imidazol-5-yl)-1-oxoethyl)-9,10-debtor-1,2-dihydro-4-(2-methoxyphenyl)imidazo-[1,2] [1,4]benzodiazepinas hydrochloride) and purified according to the method of stage 25.b. Mass spectrum 551,4, MH+. NMR (300 MHz, DMSO-d6, 30°C) TO 9.1 AND 9.3 (1H, s), is 7.9 and 8.1 (3H, m), 7,75-7,9 (3H, m), 7,55-the 7.65 (1H, s), 7,45-of 7.55 (2H, d), 7,35-7,45 (1H, m), 7,15-of 7.25 (1H, d), 7,0-to 7.15 (1H, t).

Example 33: 4-(2-bromophenyl)-1-(2-(1-[(4-cyano)phenylmethyl]-imidazol-5-yl)-1-oxoethyl)-1,2-dihydro-8-torimodose-[1,2 a][1,4]benzodiazepine

Stage 33.A. 2,2'-dibromoethane

Bromine (40,3 g, 0.25 mol) is added dropwise to a solution of 2'-bromoacetophenone (50.0 g, 0.25 mol) in acetic acid (500 ml) for 1.5 hours at a temperature of 15-20°C. Then the solution is heated to room temperature and concentrate under reduced pressure to get crude product which is used without further purification.

Stage 33.b. conduct similar to stage 1.c. using the product from step 33.A. instead of 2-bromo-2'-methoxyacetophenone and Cbz-Glycine instead of Cbz-(L)-Norleucine.

Stage 33.with.-33.E. carried out by the method of stages 22.A. -22.S., using 2,6-differenziale instead of 2-terbisil-bromide on stage 33.with. and 1,8-diazabicyclo[5.4.0]undec-7-ene instead of K2CO3at stage 33.E.

Stage 33.f. 4-(2-bromophenyl)-1-(2-(1-[(4-cyano)phenylmethyl]-imidazol-5-yl)-1-oxoethyl)-1,2-dihydro-8-torimodose-[1,2 a][1,4]benzodiazepine

Product with stat by the method of stage 25.b. Mass spectrum 581,1, 583,1 MH+.

Example 34: 1-(2-(1-((4-cyano)phenylmethyl)imidazo-5-yl)-1-oxoethyl)-1,2-dihydro-10-fluoro-4-(2-methoxyphenyl)imidazol-[1,2 a][1,4]benzodiazepine

Stage 34.A. -34.with. carried out by the method of stages 22.A. -22.S., using 2.4-differenziale instead of 2-forensicsdata on the stage 31.A.

Stage 34.d. 1-(2-(1-((4-cyano)phenylmethyl)imidazo-5-yl)-1-oxoethyl)-1,2-dihydro-10-fluoro-4-(2-methoxyphenyl)imidazol-[1,2 a][1,4]benzodiazepine

The product from step 34.with. combined with the product from step 11.j. (1-(cianfanelli)-5-imidazolinone acid hydrochloride) and purified according to the method of stage 25.b. Mass spectrum 533,2, MN+.

Example 35: 1-(2-(1-((4-cyano-3-methoxy)phenylmethyl)-imidazo-5-yl)-1-oxoethyl)-1,2-dihydro-8-fluoro-4-(2-methoxyphenyl)-imidazol[1,2 a][1,4]benzodiazepine

Stage 35.A. -35.f. carried out according to the scheme 35.

Scheme 35

A. Meon/HCl

b. NaNO2/aq. HCl/KI

C. Zn(CN)2/(Ph3R)4Pd/DMF

d. MeI/NaH/DMF

E. LiBH4/THF

f. SOBr2/CH2Cl2

Stage 35.A. Methyl 4-amino-3-hydroxybenzoate

A solution of 4-amino-3-hydroxybenzoic acid is minutes (about 60 g). Stirring is continued overnight and then the solution is concentrated under reduced pressure. The residue is triturated with EtOAc (200 ml) and dried to obtain brown solid (24.5 g, 92%), which is used without further purification. Mass spectrum 168,2, NMR (300 MHz, DMSO-d6, 30°C) OF 9.3 AND 9.4 (1H, s), 7,2-7,3 (2H, m), 6,55-of 6.65 (1H, d), 5,3-5,4 (2H, s (broad)), 3,6-3,8 (3H, s).

Stage 35.b. methyl 3-hydroxy-4-identit

A solution of the product from stage 35.A. (24.5 g, 146 mmol) in THF (77 ml) was diluted with 3N HCl (232 ml) and cooled in an ice bath to a temperature of 8°With sediment. Add NaNO2(11.1 g, 161 mmol) in H2O (75 ml) for 6 minutes at a temperature of an ice bath. Stirring is continued for 25 minutes and then add a solution of KI (97,1 g, 585 mmol) in H2O (75 ml) in one portion and stirred for 15 minutes. Add EtOAc (550 ml) and the layers separated. The EtOAc layer was washed with H2O (500 ml) and saturated salt solution (550 ml), dried over Na2SO2filter and concentrate to obtain a black solid. The crude product is purified by chromatography on silica gel using CH2Cl2as eluent to obtain 19.7 g (48%) Belov is 5 (3H, C).

Stage 35.with. methyl 4-cyano-3-hydroxybenzoic

A solution of the product from stage 35.b. (25,3 g, to 91.1 mmol) and ZnCN2(of 7.48 g of 63.7 mmol) in DMF (100 ml) is treated, in an atmosphere of N2, (Ph3P)4Pd (2.0 g, 1.82 mmol) and heated at a temperature of about 80°C for 4 hours. The solution is then cooled to room temperature and partitioned between EtOAc (400 ml) and N2O (400 ml). The EtOAc layer was washed with a saturated solution of salt (4×200 ml), dried over Na2SO4filter and concentrate under reduced pressure. The crude product is purified by chromatography on silica gel using CH2Cl2and then with 2.5% MeOH/CH2Cl2as eluents. Fractions concentrated to obtain a light orange solid and dried to constant weight in a vacuum to obtain the product (13.4 g, 83%), which is used at the stage 35.d. without further purification. NMR (300 MHz, DMSO-d6, 30°C) OF 7.7 AND 7.8 (1H, m), and 7.5 and 7.6 (1H, d), between 7.4 to 7.5 (1H, m), 3,8-3,9 (3H, s).

Stage 35.d. methyl 4-cyano-3-methoxybenzoate

60% NaH in mineral oil (of 6.02 g, 151 mmol) was washed with 3 portions of hexane (20 ml) and suspended in DMF (100 ml) at room temperature. Add the Reaction mixture was stirred over night at room temperature. The reaction mixture was diluted with EtOAc (400 ml) and washed with 5% citric acid (2×150 ml) and saturated salt solution (150 ml). The EtOAc layer is dried over Na2SO4, filtered and concentrated to obtain a solid product (13,4 g, 93%), which is used at the stage 35. that is, without further purification. NMR (300 MHz, DMSO-d6, 30°C) 7, 62-7,72 (3H, m), 4,0-4,1(3H, s), 3,9-4,0 (3H, s).

Stage 35.E. 4-hydroxymethyl-2-methoxybenzonitrile

The product from step 35.d. (13.3 g, 70,0 mmol) in THF (200 ml) is treated with 2M LiBH4(75 ml, 150 mmol) in an atmosphere of N2and the resulting solution was refluxed for 3 hours. The reaction mixture is cooled to room temperature and treated carefully with excess 4N HCl to absorb the excess reagent. Type H2About (50 ml) and EtOAc (100 ml) and the layers separated. The aqueous layers are re-extracted with EtOAc (2×50 ml) and EtOAc layers are combined and washed with a saturated solution of salt (3×100 ml), dried (Na2SO4), filtered and concentrated under reduced pressure to obtain white solid (10.7 g, 94%). NMR (300 MHz, DMSO-d6, 30°C) 7,5-7,8 (1H, d), of 7.0, and 7.1 (1H, s), 6,94-7,0 (1H, m), 4.75 V to 4.8 (2H, s), 3,9-4,0 (3H, s), and 1.9-2.1 (1H, s (broad)).

Stage 2Cl2(3.0 ml), treated with SOBr2(480 μl, 6.13 mmol), stirred for about 1/2 hour and then concentrated. The residue re-dissolved in CH2Cl2(100 ml), washed with saturated solution of NaHCO3(50 ml), dried (Na2SO4), filtered and concentrated to obtain a light yellow solid (1.22 g, 88%). NMR (300 MHz, DMSO-d6, 30°C) A 7.5 AND 7.6 (1H, d, j=8 Hz), 7,02-was 7.08 (1H, DD, j=8 Hz, j=1 Hz)), 7,0-7,02 (1H, d, j=1 Hz)), 4,45 to 4.5 (2H, s), 3.95 to 4,0 (3H, s).

Stage 35.g.-35.i. carried out by the method of stages 5.A. -5.S., using the product from step 35.f. instead of benzylbromide on stage 5.A.

Stage 35.j. 1-(2-(1-((4-cyano-3-methoxy)phenylmethyl)-imidazo-5-yl)-1-oxoethyl)-1,2-dihydro-8-fluoro-4-(2-methoxyphenyl)-imidazol[1,2 a][1,4]benzodiazepine

The product from step 31.with. combined with the product from step 35.i. (1-((4-cyano-3-methoxyphenyl)methyl)-5-imidazolinone acid hydrochloride) and purified according to the method of stage 25.b. Mass spectrum 563,2 MH+.

Example 36: 10-bromo-1-(2-(1-((4-cyano-3-methoxy)phenylmethyl)-imidazo-5-yl)-1-oxoethyl)-1,2-dihydro-4-(2-methoxyphenyl)-imidazol[1,2 a][1,4]benzodiazepine

Stage 36.A. -36.with. carried out by the method of stages 22.A. -22.S., using 2,4-dibromostyrene VM is 5-yl)-1-oxoethyl)-1,2-dihydro-4-(2-methoxyphenyl)-imidazol[1,2 a][1,4]benzodiazepine

The product from step 36.with. (10-bromo-1,2-dihydro-4-(2-methoxyphenyl)imidazo[1,2-C][1,4]benzodiazepine) combined with the product from step 35.i. (1-((4-cyano-3-methoxyphenyl)methyl)-5-imidazolinone acid hydrochloride) and purified according to the method of stage 25.b. Mass spectrum 623,1, 625,1 MH+.

Example 37: 1-(2-(1-((4-cyano-3-methoxy) phenylmethyl)-imidazo-5-yl)-1-oxoethyl)-1,2-dihydro-8-fluoro-4-phenylimidazol-[1,2 a][1,4]benzodiazepine

The product from step 31.with. (1,2-dihydro-8-fluoro-4-(2-methoxyphenyl)imidazo[1,2-C][1,4]benzodiazepine) combined with the product from step 35.i. (1-((4-cyano-3-methoxyphenyl)methyl)-5-imidazolinone acid hydrochloride) and purified according to the method of stage 25.b. Mass spectrum 533,3 MN+.

Example 38: 4-(2-bromophenyl)-1-(2-(1-((4-cyano-3-methoxy)-phenylmethyl)imidazo-5-yl)-1-oxoethyl)-1,2-dihydro-8-ftalimidina-[1,2 a][1,4]benzodiazepine

The product from step 33.E. (4-(2-bromophenyl)-1,2-dihydro-8-fluoro-imidazo[1,2-C][1,4]benzodiazepine) combined with the product from step 35.i. (1-((4-cyano-3-methoxyphenyl)methyl)-5-imidazolinone acid hydrochloride) and purified according to the method of stage 25.b. Mass spectrum 611,1, 613,1 MH+.

Example 39: 1-(2-(1-((3-methoxy)phenylmethyl)imidazo-5-yl)-1-oxoethyl)-1,2-dihydro-8-fluoro-4-(2-methoxyphenyl)imidazol-[1,2 a][1,4]benzodiazep is avramidi on stage 5.A.

Stage 39.d. 1-(2-(1-((3-methoxy)phenylmethyl)imidazo-5-yl)-1-oxoethyl)-1,2-dihydro-8-fluoro-4-(2-methoxyphenyl)imidazol-[1,2 a][1,4]benzodiazepine

The product from step 31.with. (1,2-dihydro-8-fluoro-4-(2-methoxyphenyl)imidazo[1,2-C][1,4]benzodiazepine) combined with the product from step 39.with. (1-((3-methoxyphenyl)methyl)-5-imidazolinone acid hydrochloride) and purified according to the method of stage 25.b. Mass spectrum 538,4 MN+.

Example 40: 1-(2-(5-((4-cyano)phenylmethyl)imidazol-1-yl)-1-oxoethyl)-2,5-dihydro-8-fluoro-4-(2-methoxyphenyl)imidazo-[1,2][1,4]benzodiazepine

Stage 40.A. -40.d. carried out according to the circuit 40 as follows:

Scheme 40

A. EtMgBr/4-cyanobenzaldehyde/Et2O/CH2Cl2

b. TN/Et3SiH/(boiling under reflux)

C. Trt-Cl/Et3N/THF

d. BrCH2COBr/DMF

that is, the intermediate compound xxxvi, then Meon

Stage 40.a. (R,S)-4-(hydroxy-(1-trityl-1H-imidazol-4-yl)-methyl)benzonitrile

A solution of 1-trityl-4-itimidate (3,53 g, 8,10 mmol) in CH2Cl2(35 ml) is cooled to a temperature of about -3°C in an atmosphere of N2and added dropwise 3M EtMgBr in Et2O, sahraei about 0°C and then one portion add 4-cyanobenzaldehyde (1.18 g, of 9.00 mmol) and the reaction mixture was stirred at room temperature for about 1 hour. The reaction mixture was then again cooled to a temperature of about 0°C and add 5% HCl (30 ml). The reaction mixture is stirred for about 15 minutes and then extracted with CH2Cl2(2×25 ml). Merged layers CH2Cl2washed with saturated NaHCO3, dried over Na2SO4, filtered and then concentrated under reduced pressure. The residue is triturated with EtOAc (25 ml) and the product is filtered (2,92 g, 82%). Mass spectrum 442,3 MN+. NMR (300 MHz, DMSO-d6, 30°C) 7,7-7,8 (2H, d), and 7.5 and 7.6 (2H, d), 7,3-7,5 (N, m), 7,25 of 7.3 (1H, s), 7,0-7,15 (6N, m), 6.75 in-6,8 (1H, s). 5.9 to make 6.90 (1H, m). 5,6-5,7 (1H, m).

Stage 40.b. 4-((1H-imidazol-4-yl)methyl)benzonitrile

A solution of product from step 40.A. (1.10 g, 2.49 mmol) is treated with TN (15 ml) and Et3SiH (3.0 ml, of 18.8 mmol). The mixture is refluxed for about 2 hours. The reaction mixture was then concentrated to remove by-products. Add TN (15 ml) and Et3SiH (3.0 ml, of 18.8 mmol) and the mixture refluxed for a further 2 hours and then concentrated. Add fresh reagents and by-products ishodny material. Consumption of starting material are controlled by analytical HPLC using VYDAC column C18(The Nest Group, Southborough, MA) and a gradient from 0 to 70% of CH3CN/0.1% of TN for 25 minutes. The crude product is purified preparative HPLC on a column of RAININC18using a gradient from 0 to 50% of CH3CN/0.1% of TN for 45 minutes. Fraction of the product combine, concentrated to about 1/2 volume and lyophilized with obtaining the pure product. The salt product is alkalinized by addition of a saturated solution of NaHCO3, extracted with CH2Cl2(3×25 ml), dried over Na2SO4filter and concentrate under reduced pressure. Mass spectrum 183,9 MN+. NMR (300 MHz, DMSO-d6, 30°C) AT 7.55-7,58 (1H, d, j=1 Hz), 7.3 to 7.4 (2H, d, j=8 Hz), 6.75 in-6,8 (1H, d, j=1 Hz)), 3,9-4,1 (2H, s).

Stage 40.with. 4-((Titel-1H-imidazol-4-yl)methyl)benzonitrile

The product from step 40.b. (152 mg, 0.83 mmol), chlorotriphenylmethane (231 mg, 0.83 mmol) and Et3N (139 μl, 1.0 mmol) dissolved in THF (4 ml) and stirred in an atmosphere of N2at room temperature for about 2 hours. Add a saturated solution of NaHCO3(5 ml) and the product extracted with EtOAc (2×20 ml). the. accidenly the product was then purified by crystallization from EtOAc and hexane to obtain the pure product (285 mg, 81%). Mass spectrum 426,4 MN+(small line), NMR (300 MHz, DMSO-d6, 30°C) A 7.5 AND 7.6 (2H, d, j=8 Hz)), 7,4 was 7.45 (1H, d, j=1 Hz), 7.3 to 7.4 (11N, m), 7,1-7,2 (6N, m), 6,58-6,62 (1H, d, j=1 Hz)), 3,9-4,0 (2H, s).

Stage 40.d. 1-bromacetyl-1,2-dihydro-8-fluoro-4-(2-methoxyphenyl)imidazo[1,2 a][1,4]benzodiazepine

The product from step 40.with. (108 mg, 0.35 mmol) dissolved in DMF (1.5 ml) and add bromoacetamide (65 μl, 0.75 mmol) at room temperature under stirring. The mixture stand over night and then concentrated under reduced pressure to get crude product, which is used at the stage 40.E. without further purification. Mass spectrum 430,2, 432,2 MN+.

Stage 40.e. (2-(5-((4-cyano)phenylmethyl)imidazol-1-yl)-1-oxoethyl)-2,5-dihydro-8-fluoro-4-(2-methoxyphenyl)imidazo-[1,2][1,4]benzodiazepine

The product from step 40.d. (0.32 mmol) partitioned between saturated NaHCO3(2 ml) and EtOAc (5 ml). The aqueous layer was extracted again with EtOAc (5 ml) and EtOAc layers are combined, dried (Na2SO4), filtered and concentrated to about 2 ml Add the product from step 40.with. (134 mg, 0.32 mmol) and the mixture was stirred at komnata (4 ml) and refluxed for about 1 hour. The reaction mixture is cooled and concentrated under reduced pressure and the crude product purified preparative HPLC on a column of RAININC18using a gradient from 0 to 50% of CH3CN/0.1% of TN for 45 minutes. Fraction of the product are combined and concentrated under reduced pressure. TN salt is converted into the hydrochloride by passing a 30% methanolic solution through the ion exchange column (BioRad AG 1 x2, 200-400 mesh, 0.6 mEq/ml, 100 ml, chloride). Fraction of the product combine, concentrate to a volume of about 10 ml and lyophilized of N2About obtaining the pure product (35 mg, 18%) as the dihydrochloride. Mass spectrum 533,2 MH+.

It should be understood that although this invention is described using detailed descriptions, such description is intended to illustrate and not limit the scope of the invention defined by the claims. Other aspects, advantages and modifications presented in the claims.

1. Imidazole derivatives of the formula (I)

where n1 = 0 or 1;

X independently is (CHR11)n3(CH2)n4Z(CH2)n5;

Z assetsensitive is CO, CH2CS or telephone;

R1is

or N(R24R25);

R11is N;

R3independently is H or optionally substituted by a group selected from the group comprising (C1-C6)alkyl, (C3-C6)cycloalkyl-(C1-C6)alkyl;

R4and R5each independently is H or optionally substituted by aryl, where the specified optionally substituted aryl optionally substituted with one R30;

R6independently is H or optionally substituted C1-C6)alkyl;

where R8is H, (C1-C6)alkyl or aryl(C1-C6)alkyl;

R7independently is in each case H or optionally substituted C1-C6)alkyl;

R10is C;

R21independently is H or optionally substituted aryl(C1-C6)alkyl where the specified optionally substituted group optional the R30;

R24and R25each independently is H;

R30independently is-O-R8, -CN or halogen;

where the specified aryl is phenyl,

provided that if n1=1, R10is s and R6is H, R10and R7taken together, may form

or if n1=1, R10is s and R7is-H, R10and R6taken together, may form

where X1X2and X3each independently is H or halogen,

and if R1is N(R24R25), n3 = 1, n4 and n5 each are 0, Z is a bond and R3and R11taken together, form

where n2 = 1 and X4and X5each independently is H;

or its pharmaceutically acceptable salt, provided that the compound of formula I is not

bis-1,1'-[7-(2-amino-1-oxo-3-thiopropyl)-2-(methoxyphenyl)-8-(1-methylpropyl)-5,6,7,8-tetrahydroimidazo[1.2A]pyrazin]-disulfide;

bis-1,1'-[7-(2-amino-1-oxo-3-thiopropyl)-8-B. the filing)-2-(2-methoxyphenyl)-8-(1-methylethyl)-5,6,7,8-tetrahydroimidazo[1.2A]pyrazin]-disulfide;

bis-1,1'-[7-(2-amino-1-oxo-3-thiopropyl)-8-(1,1-dimethylethyl)-2-(2-methoxyphenyl)-5,6,7,8-tetrahydroimidazo-[1.2A]pyrazin]disulfide;

bis-1,1'-[7-(2-amino-1-oxo-3-thiopropyl)-8-butyl-2,3-diphenyl-5,6,7,8-tetrahydroimidazo[1.2A]pyrazin]disulfide;

bis-1,1'-[7-(2-amino-1-oxo-3-thiopropyl)-8-(1-methylpropyl)-2-(2-(phenylmethoxy)phenyl)-5,6,7,8-tetrahydroimidazo[1.2A] pyrazin]disulfide;

bis-1,1'-[7-(2-amino-1-oxo-3-thiopropyl)-8-(cyclohexylmethyl)-2-(2-methoxyphenyl)-5,6,7,8-tetrahydroimidazo[1.2A]pyrazin]disulfide;

bis-1,1'-[7-(2-amino-1-oxo-3-thiopropyl)-8-hexyl-2-(2-methoxyphenyl)-5,6,7,8-tetrahydroimidazo[1.2A]pyrazin]-disulfide;

bis-1,1'-[7-(2-amino-1-oxo-3-thiopropyl)-8-(cyclohexylmethyl)-2-(2-methoxyphenyl)-5,6,7,8-tetrahydroimidazo[1.2A]pyrazin]disulfide;

bis-1,1'-[7-(2-amino-1-oxo-3-thiopropyl)-8-(2-(4-methoxy-cyclohexyl)methyl)-2-(2-methoxyphenyl)-5,6,7,8-tetrahydroimidazo-[1.2A]pyrazin]disulfide;

[S-(2-amino-3-oxo-3-(8-cyclohexylmethyl)-2-(2-methoxyphenyl)-5,6,7,8-tetrahydroimidazo-[1.2A]pyrazin-7-yl)propyl]-S'-cyclohexyl]disulfide;

[S-(2-amino-3-oxo-3-(8-cyclohexylmethyl)-2-(2-methoxyphenyl)-5,6,7,8-tetrahydroimidazo[1.2A]pyrazin-7-yl)propyl]-S'-ethyl]disulfide;

S-(dimethy/P>

2. Connection on p. 1, in which R1is

or N(R24R25);

X is CH(R11)n3(CH2)n4,

or its pharmaceutically acceptable salt.

3. Connection on p. 2, in which R1is

X is CH(R11)n3(CH2)n4; n1 = 0, or its pharmaceutically acceptable salt.

4. Connection on p. 2, in which R1is

R6is N; n1 = 1; R7and R10taken together, form

n3 = 1 and R11is N; Z is a bond; n5 = 0 and Y is CO, CH2or communications, or its pharmaceutically acceptable salt

5. Connection on p. 2, in which R1is N(R24R25); n1 = 0; n3 = 1; n4 = 0; n5 = 0; Y is CO or CS; Z is a bond and R3and R11taken together, form

or its pharmaceutically acceptable salt.

6. Connection on p. 2, in which R1is

R7is N; n1 = 1; R2and Z is a bond, or its pharmaceutically acceptable salt.

7. Connection on p. 3, which is a

8-butyl-7-(3-(imidazol-5-yl)-1-oxopropyl)-2-(2-methoxyphenyl)-5,6,7,8-tetrahydroimidazo[1.2A]pyrazin;

8-butyl-2-(2-hydroxyphenyl)-7-(imidazol-4-yl-propyl)-5,6,7,8-tetrahydroimidazo[1.2A]pyrazin;

8-butyl-7-(4-imidazolidinyl)-2-(2-methoxyphenyl)-5,6,7,8-tetrahydroimidazo[1.2A]pyrazin;

7-(2-(imidazol-4-yl)-1-oxoethyl)-2-(2-methoxyphenyl)-8-(1-methylpropyl)-5,6,7,8-tetrahydroimidazo[1.2A]pyrazin;

2-(2-methoxyphenyl)-8-(1-methylpropyl)-7-(1-oxo-2-(1-phenylmethyl)imidazol-5-yl)ethyl)-5,6,7,8-tetrahydroimidazo[1.2A]pyrazin;

2-(2-methoxyphenyl)-8-(1-methylpropyl)-7-(2-(1-phenylmethyl)-imidazol-5-yl)ethyl)-5,6,7,8-tetrahydroimidazo[1.2A]pyrazin;

7-(2-(1-(4-cyanovinylene)imidazol-5-yl)-1-oxoethyl)-2-(2-methoxyphenyl)-8-(1-methylpropyl)-5,6,7,8-tetrahydroimidazo[1.2A]pyrazin;

7-((1H-imidazol-4-yl)methyl)-2-(2-methoxyphenyl)-8-(1-methylpropyl)-5,6,7,8-tetrahydroimidazo[1.2A]pyrazin;

7-((4-imidazolyl)carbonyl)-2-(2-methoxyphenyl)-8-(1-methylpropyl)-5,6,7,8-tetrahydroimidazo[1.2A]pyrazin;

7-(1-(4-cyanovinylene)imidazol-5-yl)methyl-2-(2-methoxyphenyl)-8-(1-methylpropyl)-5,6,7,8-tetrahydroimidazo[1,2]-pyrazin;

5-butyl-7-(2-(4-cyanopyrimidine-5-yl)-1-oxoethyl)-2-phenyl-5,6,7,8-tetrahydroimidazo[1.2A]pyrazin;

6-butyl-7-(2-(4-cyanopyrimidine-5-yl)-1-oxoethyl)-2-(2-methoxyphenyl)-5,6,7,8-tetrahydroimidazo[1.2A]pyrazin;

6-butyl-7-(2-(4-cyanopyrimidine-5-yl)-1-oxoethyl)-2-phenyl-5,6,7,8-tetrahydroimidazo[1.2A]pyrazin;

5-butyl-7-(2-(1-(4-cyanovinylene)imidazol-5-yl)-1-oxoethyl)-2-(2-methoxyphenyl)-5,6,7,8-tetrahydroimidazo-[1.2A]pyrazin;

7-(2-(1-(4-cyanovinylene)imidazol-5-yl)-1-oxoethyl)-8-(cyclohexylmethyl)-2-(2-methoxyphenyl)-5,6,7,8-tetrahydroimidazo-[1.2A]pyrazin;

5-butyl-7-(2-(1H-imidazol-5-yl)-1-oxoethyl)-2-(2-methoxyphenyl)-5,6,7,8-tetrahydroimidazo[1.2A]pyrazin;

7-(2-(4-cyanovinylene)imidazol-5-yl)-1-oxoethyl)-2-(2-phenylmethoxy)phenyl)-5,6,7,8-tetrahydroimidazo[1.2A]pyrazin; or

2-(2-butoxyphenyl)-7-(2-(4-cyanovinylene)-imidazol-5-yl)-1-oxoethyl)-5,6,7,8-tetrahydroimidazo[1.2A]pyrazin,

or their pharmaceutically acceptable salts.

8. Connection on p. 4, which is a

1,2-dihydro-1-((1H-imidazol-4-yl)methyl)-4-(2-methoxyphenyl)-imidazo[1,2][1,4]benzodiazepine;

1-(2-(1-(4-cyanovinylene)imidazol-4-yl)-1-oxoethyl)-1,2-dihydro-4-(2-methoxyphenyl)they shall Setenil)imidazo[1,2][1,4]benzodiazepine;

9-chloro-1-(2-(1-(4-cyanovinylene)imidazol-4-yl)-1-oxoethyl)-1,2-dihydro-4-(2-methoxyphenyl)imidazo[1,2][1,4]-benzodiazepine;

10-bromo-1-(2-(1-(4-cyanovinylene)imidazol-4-yl)-1-oxoethyl)-1,2-dihydro-4-(2-methoxyphenyl)imidazo[1,2][1,4]-benzodiazepine;

1-(2-(1-(4-cyanovinylene)imidazol-4-yl)-1-oxoethyl)-1,2-dihydro-8-fluoro-4-(2-methoxyphenyl)imidazo[1,2][1,4]-benzodiazepine,

or its pharmaceutically acceptable salt.

9. Connection on p. 8, which is a

1-(2-(1-(4-cyanovinylene)imidazol-4-yl)-1-oxoethyl)-1,2-dihydro-4-(2-methoxyphenyl)imidazo[1,2][1,4]benzodiazepine;

9-bromo-1-(2-(1-(4-cyanovinylene)imidazol-4-yl)-1-oxoethyl)-1,2-dihydro-4-(2-methoxyphenyl)imidazo[1,2][1,4]benzodiazepine;

9-chloro-1-(2-(1-(4-cyanovinylene)imidazol-4-yl)-1-oxoethyl)-1,2-dihydro-4-(2-methoxyphenyl)imidazo[1,2][1,4]benzodiazepine;

10-bromo-1-(2-(1-(4-cyanovinylene)imidazol-4-yl)-1-oxoethyl)-1,2-dihydro-4-(2-methoxyphenyl)imidazo[1,2][1,4]benzodiazepine;

1-(2-(1-(4-cyanovinylene)imidazol-4-yl)-1-oxoethyl)-1,2-dihydro-8-fluoro-4-(2-methoxyphenyl)imidazo[1,2][1,4] benzodiazepine.

10. Connection on p. 5, which is 7-(2-amino-1-oxo-3-thiopropyl)-8-(mercaptoethyl)-2-(2-methoxyphenyl)-5,6,7,8-heat.6, which is a 5-(2-(1-(4-cyanovinylene)-imidazol-5-yl)-1-oxoethyl)-5,6-dihydro-2-phenyl-1H-imidazo[1,2 a][1,4]benzodiazepine, or its pharmaceutically acceptable salt.

12. Connection on p. 2, which is a

1,2-dihydro-1-(2-(imidazol-1-yl)-1-oxoethyl)-4-(2-methoxyphenyl)imidazo[1,2 a][1,4]benzodiazepine;

1,2-dihydro-4-(2-methoxyphenyl)-1-(2-(pyridin-3-yl)-1-oxoethyl) imidazo[1,2 a][1,4]benzodiazepine or

1,2-dihydro-4-(2-methoxyphenyl)-1-(2-(pyridin-4-yl)-1-oxoethyl) imidazo[1,2 a][1,4]benzodiazepine,

or its pharmaceutically acceptable salt.

13. Connection on p. 2, which is a

or

or its pharmaceutically acceptable salt.

14. Pharmaceutical composition having inhibitory activity against prenyltransferase containing an effective amount of the compounds under item 1 or its pharmaceutically acceptable salt and a pharmaceutically acceptable carrier.

15. A method of treating disease in a patient, in need thereof, comprising the introduction of the indicated patient a therapeutically effective amount of the compounds on p. 1 ileocecectomy hyperplasia of the prostate, atherosclerosis, restenosis, breast cancer, colon cancer, pancreatic cancer, prostate cancer, lung cancer, ovarian cancer, cancer of the skin and cancer of blood-forming organs and infectious Delta viral hepatitis.

16. A method of treating disease in a patient, in need thereof, comprising the administration to a patient a therapeutically effective amount of the compounds under item 1 or its pharmaceutically acceptable salt, where the specified condition is Ras-dependent tumors.

17. Method of inhibiting prenyltransferase in a patient in need thereof, comprising the introduction of the indicated patient a therapeutically effective amount of the compounds under item 1 or its pharmaceutically acceptable salt.

18. Connection on p. 2, which is a

or

or its pharmaceutically acceptable salt.



 

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