LT4552B - Inhibitors of farnesyl protein transferase - Google Patents

Abstract

This invention relates to compounds which inhibit a farnesyltransferase and RAS protein farnesylation; it makes them suitable for use as agents against cancer. These compounds are also suitable for treatment of non cancerous diseases related to a signal transmission proceeding through RAS and diseases related with other proteins than RAS, which are also modified after the translation by the farnesyltransferase ferment. Compounds may also act as inhibitors of other prenyl transferase and therefore they may be effective for treating diseases related to other prenyl modifications of proteins.

Description

The present invention relates to compounds which inhibit farnesyl protein transferase and find farnesylation of the protein and are therefore useful as anticancer agents. These compounds are also useful for the treatment of non-cancerous signaling pathways that act via ras and those associated with non-ras proteins that are also modified after translation by the enzyme farnesyl protein transferase. These compounds may also act as inhibitors of other prenyltransferases and therefore may be effective in treating diseases associated with other prenyl-modifications of the protein.

The mammalian ras gene family comprises three genes: H-ras, K-ras and N-ras. Ras proteins are a family of binding and hydrolyzing GTP proteins that regulate cell growth and differentiation. Excessive production of normal ras proteins or mutations that inhibit their GTPase activity can lead to uncontrolled cell division.

Transforming ras activity depends on the localization of the protein to the plasma membrane. This membrane binding occurs through a series of post-translational modifications of cytosolic ras proteins. The first and necessary step in this sequence is the farnesylation of these proteins. The reaction is catalyzed by the enzyme farnesyl protein transferase (FPT), and farnesyl pyrophosphate (FPP) is the donor farnesyl group in this reaction. Ras at the C-terminus is a portion of a sequence called "Cys-Aaai-Aaa ₂ -Xaa" box (CAAX box), where Cys is cysteine, Aaa is an aliphatic amino acid, and Xaa is serine or methionine. Farnesylation occurs at the cysteine residue (cys-186) of the CAAX boxing by attaching the prenyl group to the protein via a thioether linkage.

According to the present invention, compounds of formulas I, II, III and IV:

R ⁴ , R ⁵

R ^S , R ⁷

R ¹ , R ² , R ³

R ¹ , R ² , R ³

IV, their enantiomers, diastereomers and pharmaceutically acceptable salts, their prodrugs and solvates inhibit farnesyl protein transferase, an enzyme involved in the expression of ras oncogene. In the formulas I-IV and in the description of the invention, the above symbols means:

m, n, r, s and t are 0 or 1;

p is O, 1 or 2;

V, W and X are selected from the group consisting of oxygen, hydrogen, R ¹ , R ² or R ³ ;

Z and Y are selected from the group consisting of CHR ⁹ , SO 2, SO 3, CO, CO 2, O, NR ¹⁰ , SO ² NR ¹¹ , CONR ¹² ,

N '

II c, CN / CN N

II

-C-N - I

R ¹³

O

II

-N — ΟΙ

R ¹⁴

NRis

-SO ₂ 0

II

-CN-NI AND ¹⁶ R ¹⁷ or Z may be absent;

- SO ₂ - N

NI AND ¹⁸ R ¹⁹

O .NR ²⁰ R ²¹ N. NR ²² \ -S R ⁶ , R ⁷ , R ⁹ , R ¹⁰ , R ¹¹ , R ¹² , R ¹³ , R ¹⁴ , R ¹⁵ , R ¹⁶ R ¹⁷ , R ¹⁸ , R ¹⁹ , R ²⁰ , R ²¹ , R ²² , R ²⁴ , R ²⁵ , R ²⁶ , R ²⁷ , R ²⁸ , R ²⁹ , R ³⁰ R ³¹ , R ³² , R ³³ , R ³⁴ , R ³⁵ , R ³⁶ R ³⁷ and R ³⁸ is selected from the group consisting of alkyl, aryl or aryl substituted;

R ⁴ , R ⁵ are selected from the group consisting of hydrogen, halogen, nitro, cyano and UR ²³ ;

U is selected from the group consisting of sulfur, oxygen, NR ²⁴ , CO, SO, SO 2, CO2, NR ²⁵ CO 2, NR ²⁶ CONR ²⁷ , NR ²⁸ SO 2, NR ²⁹ SO 2 NR ³⁰ , SO 2 NR ³¹ , NR ³² CO, CONR ³³ , PO2R ³⁴ and PO ₃ R ³⁵ or U are absent;

R ¹ , R ² and R ³ are selected from the group consisting of hydrogen, alkyl, alkoxycarbonyl, substituted alkyl, alkenyl, alkenyl substituted, alkynyl, alkynyl substituted, aralkyl, cycloalkyl, aryl, aryl substituted, heterocyclic, heterocyclic substituents, cyano groups, carboxy groups, carbamyl (e.g., CONH ₂ ) or carbamyl substituents selected from CONH-alkyl, CONHaryl, CONH-aralkyl, or substituted with two nitrogen atoms selected from alkyl, aryl or aralkyl;

R ⁸ and R ²³ are selected from the group consisting of hydrogen, alkyl, substituted alkyl, alkenyl, alkenyl substituted, alkynyl, alkynyl substituted, aralkyl, cycloalkyl, aryl, aryl substituted, heterocyclic, heterocyclic substituted;

any two of R ¹ , R ² and R ³ may be joined together to form a cycloalkyl group;

R, S and T are selected from the group consisting of CH 2, CO and CH (CH ₂ ) _P Q wherein Q is NR ³⁶ R ³⁷ , OR ³⁸ or CN; and A, B, C and D are carbon, oxygen, sulfur or nitrogen; provided that

When m is zero, V and W cannot both be oxygen, or

2) W and X together can be oxygen only when Z is absent or Z is O, NR ¹⁰ , CHR ⁹ ,

O - N - C - - N - SO ₂ -

I I

R ¹⁴ R ¹⁵

In formulas I, II and V, and X together may be oxygen O - N - C - '- N - SO ₂ only if Y is in O, NR ¹⁰ , CHR ⁹ , ^{R 14 R 15} in formulas III and IV, or

3) R ²³ may be hydrogen unless U is SO, SO 2, NR ²⁵ CO2 or NR ²⁸ SO ₂ ; or

4) R ⁸ may be hydrogen unless Z is SO ₂ , CO ₂ or

- N - SO,

O, NR ²⁰ \\ // —S—.

R ²¹ N. NR ²² \\ // —S—

R ¹⁵

Definitions of the various terms used in the description of the present invention are given below. The following definitions apply to the terms used throughout the specification, except in limited specific cases, either individually or as part of a larger group.

The term "alkyl" refers to straight or branched chain unsubstituted hydrocarbon groups having from 1 to 20 carbon atoms, preferably from 1 to 7 carbon atoms. The term "lower alkyl" refers to unsubstituted alkyl groups having from 1 to 4 carbon atoms.

The term "substituted alkyl" means an alkyl group containing, for example, 1-4 substituents such as halogen, trifluoromethyl, trifluoromethoxy, hydroxy, alkoxy, cycloalkoxy, heterocycloxy, oxo, alkanoyl, aryloxy, alkanoyloxy, amino, aryloxy, amino, , cycloalkylamino, heterocycloamino, disubstituted amines wherein 2 amino substituents are selected from alkyl, aryl or aralkyl; alkanoylamino, aroylamino, aralkanoilaminogrupė, substituted alkanoylamino, substituted arylamino, substituted aralkanoilaminogrupė, mercapto, alkylthio, arylthio aralkiltiogrupė, cikloalkiltiogrupė, hetrociklotiogrupė alkylthiono group arylthiono group aralkiltiono group alkilsulfoniias, arylsulfonyl, aralkylsulfonyl sulfonamidogrupė eg., SO ₂ NH ₂ , substituted sulfonamido, nitro, cyano, carboxy, carbamyl, e.g., CONH ₂ , substituted carbamyl, e.g. CONH-alkyl, CONH-aryl, CONH-aralkyl, or two substituents on a nitrogen atom selected from alkyl, aryl or aralkyl; alkoxycarbonyl, aryl, substituted aryl, guanidino and heterocycles such as indolyl, imidazolyl, furyl, thienyl, thiazolyl, pyrrolidyl, pyridyl, pyrimidyl and the like.

As mentioned above, if the substituent is further substituted, they are halogen, alkyl, alkoxy, aryl or aralkyl.

The term "halogen" or "Hal" refers to fluorine, chlorine, bromine and iodine.

The term "aryl" refers to monocyclic or bicyclic aromatic hydrocarbon groups having from 6 to 12 carbon atoms in the ring, such as phenyl, naphthyl, biphenyl and diphenyl groups, and may be substituted in all of them.

The term "aralkyl" refers to an aryl group attached directly through an alkyl group such as benzyl.

The term "substituted aryl" means an aryl group containing, for example,

1-4 substituents, such as alkyl, substituted alkyl, halo, trifluoromethoxy, trifluoromethyl, hydroxy, alkoxy cikloalkiloksigrupė, heterociklooksigrupė, alkanoyl, alkanoyloxy, amino, alkylamino aralkilaminogrupė, cikloalkilaminogrupė, heterocikloaminogrupė, dialkylamino, mercapto, alkylthio, alkanoylamino cikloalkiltiogrupė, hetrociklotiogrupė , ureido, nitro, cyano, carboxy, carboxyalkyl, carbamyl, alkoxycarbonyl, alkylthio, arylthio, alkylsulfonyl, sulfonamido, aryloxy, and the like. The substituents may also be substituted such as halogen, hydroxyl, alkyl, alkoxy, aryl, substituted alkyl or aralkyl.

The term "alkenyl" means straight or branched chain hydrocarbon groups having from 2 to 20 carbon atoms, preferably from 2 to 15 carbon atoms, and most preferably from 2 to 8 carbon atoms having from 1 to 4 double bonds.

The term "substituted alkenyl" means an alkenyl group containing, for example, 1-2 substituents, such as halogen, hydroxyl, alkoxy, alkanoyl, alkanoyloxy, amino, alkylamino, dialkylamino, alkanoylamino, mercapto, alkylthio, alkylthio, alkylthio, alkylthio, a cyano group, a carboxy group, a carbamyl, a substituted carbamyl, a guanidino group and a heterocyclic group such as indolyl, imidazolyl, furyl, thienyl, thiazolyl, pyrrolidyl, pyridyl, pyrimidyl and the like.

The term "alkynyl" refers to straight or branched chain hydrocarbon groups having from 2 to 20 carbon atoms, preferably from 2 to 15 carbon atoms, and most preferably from 2 to 8 carbon atoms having from 1 to 4 triple bonds.

The term "substituted alkynyl" means an alkynyl group containing, for example, a substituent such as halogen, hydroxyl, alkoxy, alkanoyl, alkanoyloxy, amino, alkylamino, dialkylamino, alkanoylamino, mercapto, alkylthio, alkylthiono, alkylthio, , carbamyl, substituted carbamyl, guanidino, and a heterocyclic group such as imidazolyl, furyl, thienyl, thiazolyl, pyrrolidyl, pyridyl, pyrimidyl and the like.

The term "cycloalkyl" refers to saturated cyclic hydrocarbon ring systems, preferably having 1 to 3 rings and 3 to 7 carbon atoms per ring, which may be fused to an unsaturated C ₃ -C ₇ carbocyclic ring which may be substituted. Examples of such groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclodecyl, cyclododecyl and adamantyl. Exemplary substituents include one or more alkyl groups as described above or one or more of the groups described above as alkyl substituents.

The terms "heterocycle," heterocyclic, "and" heterocyclo "refer to a fully saturated or unsaturated, aromatic or non-aromatic cyclic group, such as a 4-7 membered monocyclic, 7-11 membered bicyclic, or 10-15 membered tricyclic ring system. containing at least one heteroatom in the ring containing at least one carbon atom and optionally substituted. Each heteroatom-containing heterocyclic ring may contain 1, 2, 3 or 4 heteroatoms selected from nitrogen, oxygen and sulfur, and optionally nitrogen and sulfur heteroatoms may be oxidized and nitrogen heteroatoms may be quaternized. The heterocyclic group may be attached to any heteroatom or carbon atom.

Examples of monocyclic heterocyclic groups include pyrrolidinyl, pyrrolyl, indolyl, pyrazolinyl, oxetanyl, imidazolinyl, imidazolidinyl, oxazolyl, oxazolidinyl, isoxazolinyl, isoxazolyl, thiazolyl, thiadiazolyl, thiazolyl , piperazinyl, 2-oxopiperazinyl, 2-oxopyrrolidinyl, 2-oxopyrrolidinyl, 2-oxazepinyl, azepinyl, 4-piperidonyl, pyridyl, N-oxopyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, tetrahydrothiopyranyl, tetrahydropyranyl, monomer, , 3-dioxolane and tetrahydro-1,1-dioxothienyl, dioxanyl, isothiazolidinyl, thietanyl, thiranyl, triazinyl and triazolyl and the like.

Examples of bicyclic heterocyclic groups include benzothiazolyl, benzoxazolyl, benzothienyl, quinuclidinyl, quinolinyl, quinolinyl-oxide, tetrahydroisoquinolinyl, isoquinolinyl, benzimidazolyl, benzopyranyl, indolizinyl, benzofuryl, chromonyl, coumarinyl, coumarinyl, coumarinol, , 3-c] pyridinyl, furo [3,1-b] pyridinyl or furo [2,3-b] pyridinyl), dihydroisoindolyl, dihydroquinazolinyl (such as 3,4-dihydro-4-oxoquinazolinyl), benzisothiazolyl, benzisoxazolyl, benzodiazinyl, benzofurazanyl, , benzotriazolif, benzpyrazolyl, dihydrobenzothienyl, dihydrobenzothiopyranyl, dihydrobenzothiopyranyl sulfone, dihydrobenzopyranyl, indolinyl, isochromanyl, isoindolinyl, naphthyridinyl, phthalazinyl, piperonyl, purine.

Exemplary substituents include one or more alkyl groups as described above or one or more of the groups described above as alkyl substituents.

Also included are smaller heterocycles such as epoxides and aziridines.

The term "heteroatoms" includes oxygen, sir and nitrogen.

The ABC ring and the ABCD fused ring with diazepine ring can be monocyclic or bicyclic, e.g. of naphthyl or quinolyl nature.

The compounds of formulas I-IV may form salts which are also encompassed by the present invention. Pharmaceutically acceptable (i.e., non-toxic, physiologically acceptable) salts are preferred, although other salts, e.g. isolating or purifying the compounds of the present invention.

The compounds of formulas I-IV may form salts with alkali metals such as sodium, potassium and lithium, with alkaline earth metals such as calcium and magnesium, with organic bases such as dicyclohexylamine, tributylamine, pyridine, and amino acids such as arginine, lysine and so on. Such salts may be obtained, for example, by substitution of the protons of the carboxylic acid (if present in a carboxylic acid) with the desired ion in the precipitating medium or in aqueous medium, followed by evaporation of the water. Other salts may be obtained by methods known to those skilled in the art.

The compounds of formulas I-IV may form salts with various organic and inorganic acids. Such salts include salts formed with hydrochloric, hydroxymethanesulfonic, hydrobromic, methanesulfonic, sulfuric, acetic, trifluoro-acetic, maleic, benzenesulfonic, toluenesulfonic, and citrates, tartrates, , benzoates, ascorbates, salicylates, etc.). Such salts may be obtained by treating compounds I-IV with an equivalent amount of the acid in which the salt is deposited, or in aqueous medium, followed by evaporation of the water.

In addition, zwitterions ("inner salts") may be obtained.

The compounds of formulas I-IV may also have prodrug forms. Any compound that can be converted in vivo to a bioactive agent (i.e., a compound of formulas I-IV) is a prodrug also encompassed by the present invention.

For example, the compounds of formulas I-IV may contain a carboxylic acid ester group. The carboxylic acid ester may conveniently be obtained by esterification of any carboxylic acid functional group present in the described ring structure (s).

various forms of prodrugs are well known to those skilled in the art. Examples of such prodrug derivatives include:

a) Design of Prodrugs edited by H. Bundgaard, (Elsevier, 1985) and Methods in Enzymology, Vol.42, p. 309-396, edited by K. Widder, et al., (Academic Press, 1985);

b) A Textbook of Drug Design and Development, edited by KrosgaardLarsen and H. Bundgaard, Chapter 5, Design and Application of Prodrugs, by H. Bundgaard, p. 113-191 (1991);

c) H. Bundgaard, Advanced Drug Delivery Revision, 8, 1-38 (1992);

d) H. Bundgaard, et al., Journal of Pharmaceutical Sciences, 77, 285 (1988); and

e) N. Kakeya, et al., Chem. Phar. Bull., 32, 692 (1984),

In addition, it should be understood that solvates (e.g. hydrates) of the compounds of formulas I-IV are also encompassed by the present invention. Methods for the preparation of solvates are known to those skilled in the art.

Preferred groups

Within the compounds of the present invention, the following groups are preferred:

Compounds of formulas I, II, II and IV wherein m is zero.

More preferred are compounds of formulas I, II, II and IV wherein m is zero and n is a unit.

Most preferred are compounds of formula I wherein m, r, s and t are zero, n is a unit, and ABCD is a carbocyclic ring, e.g. benzo-ring.

Utility and utilization

The compounds of formulas I-IV are inhibitors of S-farnesyl protein transferase. Therefore, they are suitable for the treatment of various cancers, including but not limited to:

carcinoma including urinary, bladder, breast, colon, kidney, liver, lung (Including small cell lung cancer), ovarian, prostate, testicular, pancreas, esophagus, stomach, gall bladder, neck, thyroid and skin (including scaly cortex) ) carcinoma:

lymphoid haematopoietic tumors including leukemia, acute lymphocytic leukemia, acute lymphoblastic leukemia, B-cell lymphoma, T-cell lymphoma, non-Hodkin lymphoma, squamous cell lymphoma, and Burkett's lymphoma;

hematopoietic tumors of the myelinic nature, including acute and chronic myelogenous leukemias, myelodysplastic syndrome, and promyelocytic leukemia;

tumors of the central and peripheral nervous system, including astrocytoma, neuroblastoma, glioma, and schwanoma;

tumors of mesenchymal origin, including fibrosarcoma, rhabdomyosarcoma and osteosarcoma;

other tumors including melanoma, xenoderma pigmentation, keratoactantoma, seminoma, thyroid follicular cancer and teratocarcinoma.

The compounds of formulas I-IV are particularly suitable for the treatment of tumors with a high content of ras, such as colon, lung and pancreatic tumors, and tumors in which prenyltransferase contributes to tumor survival, tumor growth or tumor development. Administration of a composition comprising one (or a combination) of the compounds of the present invention reduces tumor growth, reduces tumor mass, or causes tumor regression.

The compounds of formulas I-IV may also inhibit tumor angiogenesis and thus affect tumor growth. Such anti-angiogenic properties of the compounds of Formulas I-IV may also be useful in the treatment of certain forms of blindness associated with retinal vascularization.

Compounds of Formulas I-IV may also be useful in non-malignant disorders that may be involved in signal transduction pathways such as neurofibromatosis, atherosclerosis, pulmonary fibrosis, arthritis, psoriasis, glomerulonephritis, restenosis following angioplasty or vascular surgery, hypertrophic scar formation. , polycystic kidney disease and endotoxic shock. The compounds of formulas I-IV may also be useful as antifungal agents.

Compounds of formulas I-IV can induce or inhibit apoptosis, a physiological process of cell death that is critical to normal development and homeostasis. Changes in the apoptotic pathways contribute to the pathogenesis of various human diseases. Compounds of Formulas I-IV, as modulators of apoptosis, will be useful in the treatment of a variety of human diseases associated with apoptosis abnormalities, including cancer (more specifically, but not limited to follicular lymphomas, carcinomas with p53, hormone-dependent breast, prostate and ovarian tumors), and antitumor lesions such as plain adenomatous polyposis, viral infections (including, but not limited to, herpes virus, smallpox virus, Epstein-Barr virus, Sindbis virus and adenovirus), autoimmune diseases (including but not limited to systemic lupus erythematosus, glomerulonephritis, rheumatoid arthritis, psoriasis, inflammatory bowel disease and autoimmune diabetes mellitus, neurodegenerative disorders (including, but not limited to, Alzheimer's disease, AIDS-related dementia, Parkinson's disease, amyotrophic lateral sclerosis, nuggetic retinitis, pigmentosa) cerebellar degeneration), AIDS, myelodysplastic syndromes, hypoplastic anemia associated with ischemic lesions myocardial infarction, stroke and reperfusion injury, arrhythmia, atherosclerosis, toxin or alcoholic liver disease, hematologic anemia (including but not limited to) musculoskeletal degenerative diseases (including, but not limited to, osteoporosis and arthritis), aspirin-sensitive rhinosinusitis, cystic fibrosis, multiple sclerosis, kidney disease, and cancer pain.

Compounds of formulas I-IV may also be useful in the treatment of diseases involving farnesyltransferase substrates other than ras (e.g., nuclear laminates, transducin, rhodopsin kinase, cGMP phosphodiesterase, TC21, phosphoryl kinase, Rap2, RhoB, RhoE, PRL1). shortly after translation, it modifies farnesyl protein transferase enzyme.

The compounds of formulas I-IV may also act as inhibitors of other prenyltransferases (e.g., geranylgeranyltransferase I and II) and therefore may be effective in the treatment of diseases associated with other protein (e.g., rap, rab, rac and rho gene products, etc.). .) prenyl modifications (e.g., geranylgeranylation). For example, they may find application as drugs against hepatitis delta virus (HDV) infections, which follows recent data that geranylgeranylation of the major isoform of HDV delta antigen is required for productive viral infection [J. S. Glen, et al., Science, 256: 1331 (1992)].

The compounds of the present invention may also be useful in combination with well-known anticancer and cytotoxic agents and treatments, including radiotherapy. When the dosage form is in a dosage form, the combinations of the present invention are used in the following dosage regimens, and the other pharmaceutically active agent is used within its usual dosage range. The compounds of formulas I-IV may be used alternately with known anti-cancer or cytotoxic agents and other therapies, including radiotherapy, if the combination formulation is insufficiently active.

Farnesyltransferase assays were performed according to V. Manne et al., Drug Development Research, 34, 121-137 (1995). The compounds described in Examples 1-431 inhibited farnesyltransferase and have IC ₅₀ values in the range of 0.1 nM to 100 μΜ.

Dosage forms of the compounds of the present invention may be formulated with a pharmaceutical solvent or diluent for oral, intravenous, intraperitoneal, subcutaneous, intra-abdominal, intravenous, rectal, vaginal or topical administration. For oral administration, slow-release formulations such as biosc or prodrugs. Pharmaceutical compositions may be formulated in a classical manner using solid or liquid solvents, diluents, and additives suitable for the intended route of administration. The compounds may be administered orally in the form of tablets, capsules, granules, powders, and the like. in drug form. These compounds may be administered at a dose of 0.05-200 mg / kg / day, preferably less than 100 mg / kg / day, as a single dose or as a divided dose in 2 to 4 doses.

Method of obtaining

Z, = CO, SO ₂ , CO ₂ , CONR ₅ , SO ₃ , SO ₂ NR _5i C (NCN) NR ₅ Stage

The first step is carried out by treating anthranilic acid with an equivalent of phosgene such as phosgene or triphosgene in a water-organic solvent mixture at room temperature to 50 ° C.

stage

The product is treated with amino acid hydrochloride or amino acid ester hydrochloride pyridine at elevated temperature, preferably refluxing. Step 2 of Scheme 1 can be carried out in two steps: condensation of the isatoic acid anhydride with an amino acid in an organic solvent such as pyridine from 0 ° C to reflux, and the gaura anthranoylamino acid is cyclized under standard amide bond conditions such as HOBt / carbodiimide in a solvent such as DMF from 0 ° C to room temperature. Some of the compounds of Scheme 1 in which Ri = halogen are not commercially available. Compounds 3, 4 or 5 of Scheme 1 wherein Ri = halogen can be prepared from compounds 3, 4 or 5 of Scheme 1 where Ri = hydrogen by halogenation, for example by treatment with bromine in an organic solvent such as acetic acid, from 0 °. C to room temperature. Compound 3 wherein R 1 is aryl or heteroaryl may be prepared from compound 3 wherein R 1 is bromo, iodo or trifluoromethanesulfonyloxy by palladium-catalyzed copulation with an aryl or heteroaryl metalloid derivative such as phenylboronic acid in a mixture of water and an organic solvent, e.g. THF / DMF / water in the presence of a base such as sodium carbonate, from room temperature to 90 ° C. (Alternatively, the compound of Scheme 1 in which R 1 = aryl or heteroaryl is also prepared from the compound of Scheme 5 in which Rt is bromo, iodo or trifluoromethanesulfonyloxy, in a deoxygenated organic solvent (e.g., phenylboronic acid or tributylstanylpyridine). THF) or in a water-organic solvent system such as NaHCO ₃ / toluene in the presence of a palladium catalyst such as tetrakis (triphenylphosphine) palladium, from room temperature to 100 ° C. Alternatively, such Suzuki or Stille copulation may be performed with Scheme 1 Compound 1, or Scheme 1 Compound 4, or Scheme 1 Compound 5, wherein the unacylated benzodiazepine nitrogen may be blocked, e.g. trifluoroacetyl group and then deprotected. Compound 3, wherein Rt is an alkoxy group, is prepared by alkylation of the corresponding hydroxy linker under standard conditions. Compound 3 wherein R 1 is alkylaminoalkyl aryl is prepared from reductive amination of compound 3 where R 1 is arylaldehyde under standard conditions.

stage

Compound 3 is then treated with a reducing agent such as lithium aluminum hydride or borane in an inert solvent such as tetrahydrofuran from room temperature to the boiling point of the solvent. If R, or R ₂ is a functional group, e.g. CO ₂ R which is reduced, e.g. lithium aluminum hydride up to, e.g. CH ₂ OH, such groups will be reduced in step 3. Compound 4 or 6, wherein R 1 is CN, can be prepared from compound 4 or 6, where R 1 = halogen, by exchange reaction with CuCN in an inert solvent such as NMP at elevated temperature. Compound 4, wherein R 1 is CO ₂ H, can be prepared from hydrolysis of compound 4, wherein R 1 = CN, e.g. heating with aqueous sodium hydroxide in a suitable solvent such as ethanol at 100 ^° C; thereafter, the product wherein R R = CONRsRe can be prepared under standard amide bond conditions.

stage

The product is then acylated or sulfonylated under standard conditions from -78 ° C to room temperature (e.g., by treatment with acid halide R ₃ COX where X is Cl or Br, in an inert organic solvent such as acetonitrile, or in a mixture of water and organic solvent, e.g. NaOH / dichloroethane; O-phenyl ester in an inert organic solvent such as acetonitrile; carboxylic acid in the presence of a copolymer such as DCC or EDC; in an inert organic solvent such as DMF; in halogen formate such as ethyl, isopropyl or 4- nitrophenyl chloroformate, in an inert organic solvent such as dichloromethane, from 0 ° C to room temperature, if necessary in the presence of a base such as diisopropylethylamine, to form carbamates, and some of them, such as 4-nitrophenylcarbamate, are treated with an amine, e.g. Ν, Ν'-trimethylethylenediamine, from room temperature to 110 ° C, in the presence of ureas; by the action of a carboxylic acid ride or sulfonyl anhydride such as succinic anhydride or trifluoromethanesulfonyl anhydride in an inert solvent such as ethyl acetate, dichloromethane or pyridine, from 0 ° C to room temperature, if necessary in the presence of a base such as diisopropylamine; treating the isocyanate with an inert solvent such as THF; with a carbamyl chloride R ₅ R ₆ NHCOX where X is Cl or Br in an inert solvent such as acetonitrile in the presence of a base such as diisopropylethylamine / dimethylaminopyridine; with a sulfonic acid halide anhydride R ₃ SO ₂ X wherein X is Cl or Br in a mixture of water and an organic solvent, e.g. NaOH / CH ₂ Cl ₂ ; acting on halosulfonate ROSO ₂ Cl, where X is Cl or Br, in an inert solvent such as CH ₂ Cl ₂ ; with sulfamoyl chloride R _{5 in} ReNSO ₂ X, where X is Cl or Br, in an inert solvent such as acetonitrile in the presence of a base such as diisopropylethylamine / dimethylaminopyridine; with N-cyanothiourea NH (CN) C (S) NR ₅ R 6 in the presence of a copolymer such as carbodiimide in an inert solvent such as DMF at about room temperature; treating with a cyanocarbonimidate such as diphenylcyanocarbonimidate in a suitable solvent such as DMF in the presence of a base such as diisopropylethylamine at room temperature to 80 ° C followed by treatment with an amine such as methylamine at about room temperature). Compound 5 wherein R ₍ is a halogen, e.g. bromine) can be prepared from compound 5 wherein R 1 = H by the action of a halogenating agent such as tetrabutylammonium perbromide in an inert solvent such as chloroform at about room temperature. ₂ is CH ₂ OH, the acylation can be carried out to give the diamide ester, this ester can be cleaved with e.g. sodium methoxide in methanol and the resulting alcohol oxidized to an acid such as Jones reagent, followed by cleavage with N1 an amide such as KOH in aqueous methanol under reflux, and the acid can be copolymerized with amines under standard peptide copolymer conditions to form compound 5 of Scheme 1 wherein R ₁ or R ₂ is carboxamide If R ₁ or R ₂ is CH ₂ O-Prot , the protecting group may be removed, e.g., Boc by treatment with an acid such as TFA in an inert solvent such as dichloromethane to form compound 5 or 6 wherein Ri a or R ₂ is CH ₂ OH Compound 5 wherein R ₁ or R ₂ is aryloxyalkyl is prepared from compound 5 wherein R 1 or R ₂ is CH ₂ OH by converting an alcohol group to a leaving group such as triflate, e.g. by treatment with triflic acid anhydrides in dichloromethane at -40 ° C and replacement with an aralkoxide salt, e.g. in dichloromethane from -40 ° C to room temperature. Compound 5 wherein R ₁ or R ₂ is CH ₂ NH ₂ is prepared from compound 5 wherein R ₁ or R ₂ is CH ₂ OH by converting an alcohol group to a leaving group such as triflate, e.g. by treatment with triflic acid anhydride in dichloromethane at -40 ° C, and by reaction with ammonia, e.g. in dichloromethane from -40 ° C to room temperature. This amine can then be copolymerized with carboxylic acids under standard amide linkage conditions. If compound 5 is sulfinylated with a beta-haloalkylsulfonyl halide, this halide can be cleaved by a base such as diisopropylethylamine and then attached to the resulting unsaturated sulfonamide by nucleophiles such as dimethylamine or sodium imidazolate, in a reaction with an organic solvent such as to boiling point. If compound 5 is acylated or sulfonylated with an acylating or sulfonylating agent containing a leaving group, e.g. chloride or bromide, such a leaving group may be replaced by nucleophiles, e.g. amines such as dimethylamine or N-methylpiperazine in an inert solvent such as THF or DMF, if necessary in the presence of a base such as diisopropylethylamine, at a temperature from 0 ° C to 110 ° C.

stage

This can be followed by reductive alkylation of various products in the presence of an acid, e.g. acetic acid, reducing agent, e.g. NaBH (OAc) ₃ , in an inert organic solvent, e.g. in dichloroethane at about room temperature. Reductive alkylation can also be carried out using hydrogen and a catalyst such as Pd on carbon in a solvent such as ethanol in the presence of an acid such as acetic acid at about room temperature.

The compound of Scheme 1 wherein Ri = halogen can then be converted into a metal derivative and cleaved, e.g. water to form a compound wherein R 1 = H or decomposition with carbon dioxide to form a compound wherein R 1 = CO ₂ H; this acid can be copolymerized with amines under standard peptide copulation conditions to form compounds of Scheme 1 wherein R 1 is carboxamide. The compound of Scheme 1 wherein Ri = halogen can be converted to a metal derivative and cleaved with a ketone such as cyclohexanone and then reduced to an alcohol, e.g. with trifluoroacetic acid and sodium borohydride to form a compound wherein Ri = e.g. cyclohexyl. The compound of Scheme 1 wherein the imidazole has a 2-dimethylaminomethyl group can be prepared under standard Manich conditions. The compound of Scheme 1 wherein R 1 = OH can be prepared from the compound of Scheme 1 wherein R 1 = OMe by dealkylation, e.g. exposed to BBr ₃ . The compound of Scheme 1 in which R 1 = arylOalkyl may be prepared from the reaction of Scheme 1 in which R 1 = HOalkyl by Mitsunobu reaction with an aryl alcohol. The compound of Scheme 1 in which R ₃ = aryl-NH ₂ or heteroaryl-NH _{2 1} can be prepared from the compound of Scheme 1 in which R ₃ = aryl-NO ₂ or heteroaryl-NO ₂ by reduction (e.g. SnCl ₂ ) under standard conditions. This product can be further acylated, sulfonylated, or reductively aminated under standard conditions.

scheme

= CO, SO _{2 In the} scheme, the starting material is reduced by hydrogenation in the presence of platinum oxide. The reaction is carried out in alcohol, e.g. in ethanol at about room temperature.

and Stage 3

The product is then monoacylated or monosulfonylated under standard conditions from -78 ° C to room temperature (e.g. by treatment with acid halogen R ₂ COX where X is Cl or Br, in an inert organic solvent such as acetonitrile, or a mixture of water and organic solvent, e.g. NaOH / methylene chloride; or by reaction with a sulfonyl halide R ₃ SO ₂ X, where X is Cl or Br, in an organic solvent such as CH ₂ Cl ₂ in the presence of a base such as triethylamine). This product is then subjected to a reductive alkylation reaction as described in Scheme 1, final step.

in Scheme, compound 1 is blocked with a suitable group, for example tert-butoxycarbonyl. This reaction is carried out in an inert organic solvent, e.g. THF, at about room temperature. Compound 2, wherein R 1 is an amino group, can be selectively acylated, e.g. treating isobutyl chloroformate with an inert solvent such as methylene chloride in the presence of a base such as diisopropylethylamine at about room temperature. Compound 2 wherein R 1 is R ₅ CONH and the other R 1 is Br is prepared by bromination of a compound wherein R 1 is R ₅ CONH, e.g. tetrabutylammonium tribromide in an inert solvent such as chloroform at about room temperature. Compound 2 is then treated with a compound of formula R ₃ COCl in the presence of pyridine in an inert organic solvent such as dichloroethane from 0 ° C to room temperature. Compound 3 is then deprotected by treatment with, for example, trifluoroacetic acid in an inert organic solvent such as dichloroethane at about room temperature. The compound 4 is then subjected to a reductive alkylation reaction according to the steps described in Scheme 1.

scheme

In Scheme I, compound 1 is treated with a compound of formula R ₂ COCO ₂ Me in the presence of an organic acid, e.g. acetic acid, and a reducing agent such as NaCNBH3 or NaBH (OAc) 3 in an inert organic solvent such as dichloroethane at about room temperature. The intermediate is then deprotected by treatment with, for example, trifluoroacetic acid in an inert organic solvent, e.g. CH ₂ Cl ₂ at about room temperature and cyclized by heating, e.g. 60 ° C to form compound 2. Compound 2 is then subjected to a reductive alkylation reaction as shown in Scheme 1 to give compound 3. Compound 3 can be reduced, e.g. lithium aluminum hydride to form compound 4, which can be converted to compound 6 as described in Scheme 12. Alternatively, Compound 2 is reduced to Compound 5 as depicted in Scheme 1 and Compound 5 is treated as depicted in Scheme 1.

7 _y = CO, SO ₂ , CO ₂ , CONR ₅ , SO ₃ , SO ₂ NR ₅

P rot

In Scheme I, Compound 1 is blocked by treatment with, for example, triphenylmethyl chloride or Boc anhydride in an inert organic solvent, e.g.

acetonitrile or tetrahydrofuran, from room temperature to the boiling point of the solvent. Compound 2 is then treated with a compound of formula R ₄ -L wherein L is a leaving group such as triflate in the presence of a base such as diisopropylethylamine in an inert organic solvent such as tetrahydrofuran at -78 ° C to room temperature. R ₄ may be a protecting group, e.g. phthalimide which can be cleaved e.g. hydrazine. The reaction of Scheme 5 with R ₄ -L can be carried out with compound 1 and directly obtain compound 3 without bulging / deprotection.

scheme

NC

N CO, RH ²

HO. ^ S, 'S ΌΗ

R,

Z ₁ = CO, SO ₂

In Scheme R, cyanoacetylamino acid is treated with dithiandiol in a suitable solvent such as ethanol in the presence of bases such as piperidine and triethylamine at room temperature to 80 ° C. The intermediate is then cyclized in a suitable solvent such as pyridine in the presence of a catalyst such as pyridine hydrochloride at an elevated temperature such as 130 ° C. Compound 2 is then treated as described in Scheme 1.

scheme

Z, = CO, SO ₂ , CO ₂ , CONR ₅ , SO ₂ NR ₅ u, = co, so ₂ , co ₂ , conr ₅ , so ₂ nr _5, compound 1 is reduced (e.g. Fe, SnCl ₂ or TiCl _3). ) under standard conditions. Compound 2 is acylated or sulfonylated under standard conditions (e.g., anhydride and acylation catalysts such as DMAP, acid halogen anhydride, carboxylic acid, standard peptide copolymer, alkoxycarbonyl chloride, isocyanate, sulfonyl halide or standard sulfamyl) (e.g., by treatment with an aldehyde and a reducing agent such as NaCNBH ₃ or Na (OAc) ₃ BH in an organic solvent such as dichloroethane or DMF in the presence of an acid such as acetic acid at 0 ° C to room temperature).

scheme

Compound 1 of Scheme R ₄ is treated with ethylenediamine, product 2 is reduced, selectively acylated or sulfonylated, and reductive alkylation affords compound 3 as shown in Scheme 1. Alternatively, Scheme 8, Step 1 may be carried out in Step 2, in which ethylenediamine is condensed with a halogen heterocycle, either on its own or in an organic solvent at a higher temperature, and the resulting amino acid cyclized under standard amide bond formation conditions, e.g. using HOBt / carbodiimide in an organic solvent such as DMF or pyridine from 0 ° C to room temperature. Some compounds of Scheme 8 in which FG = halogen are not commercially available. Scheme 8, wherein R 1 = halogen, can be prepared from Scheme 8, compound 2, wherein R 1 = hydrogen, by halogenation, for example by treatment with bromine in an organic solvent such as acetic acid, from 0 ° C to room temperature. Compound 2, wherein R 1 = aryl or heteroaryl, can be prepared from compound 2, wherein R 1 is halogen or trifluoromethanesulfonyloxy, using standard Suzuki or Stille copolymers as described in Scheme 1, Step 2. The product is then reduced, acylated or sulfonylated and subjected to reductive alkylation as described in Scheme 1. Compound 2 of Scheme 8 itself can be subjected to a reductive alkylation reaction using an imidazole-containing aldehyde as shown in Scheme 1 to give the desired compound.

scheme (imidazole aldehydes)

Some imidazole aldehydes are made this way. A Vittig reaction with an imidazole-containing aldehyde is carried out using a compound of the formula triethylphosphonacetate in the presence of a base such as sodium hydride in an inert organic solvent such as dimethoxyethane from about 0 ° C to room temperature. The product is hydrogenated in alcohol, e.g. ethanol at about room temperature and reduced with DIBAL, such as dichloroethane, at about -78 ° C. Alternatively, some aminoalkyl-containing imidazolylalkanols prepared by known methods (e.g., Buschauer, et al., Arch. Pharm., 315, 563 (1982)) are blocked with the Boc group as shown in Scheme 3, Step 1 and oxidized, e.g. . Svvern terms.

scheme

In the scheme, the starting material is exposed to an aluminum magnesium bromide in the presence of lithium hexamethyldisilazide in an inert solvent, e.g. THF, from about -78 ° C to room temperature. The product is blocked, e.g. Teoc group, in a mixture of water and organic solvent, e.g. in aqueous dioxane at about room temperature. The blocked product is oxidized by the action of e.g. OsO ₄ / NalO _{4 in} aqueous dioxane at about room temperature. This product is then subjected to a reductive alkylation reaction as shown in Scheme 1 and then deprotected with tetrabutylammonium fluoride from room temperature to 50 ° C in THF.

scheme

in the scheme, the starting material is reduced e.g. lithium aluminum hydride in an inert organic solvent, e.g. ethylene glycol in dimethyl ether from 0 ° C to the reflux temperature of the solvent.

scheme

No, CO, SO _2, CO _2, CONR _S, SO _3, SO ₂ NR ₅ scheme 1 step monoprotected benzodiazepine such as shown in Scheme 3 is coupled with, if necessary, protected by an imidazole group-containing carboxylic acid using standard amide bond of methods such as isobutyl chloroformate in an organic solvent such as THF from -30 ° C to room temperature. In Scheme 12, Step 2, the resulting amide is reduced, for example, with borane in an organic solvent such as THF from room temperature to the reflux temperature of the solvent. Compound 3 of Scheme 12 may have a nitro group which can be reduced, e.g. TiCl ₃ , to the amino group, which may then be acylated or sulfonylated as described in Scheme 7. In Scheme 12, Step 3, the amino protecting group is cleaved (e.g., Boc is cleaved with an acid such as TFA in an organic solvent such as methylene chloride). The compound of Scheme 12, Step 4, is treated under standard conditions with various active acylating or sulfonylating agents to form compounds of the present invention, such as acids under the carbodiimide reaction conditions, or acid chloro anhydrides to form amides; carbonates or chloroformates to form carbamates; carbamyl chlorides or isocyanates to form ureas; sulfonyl chlorides to form sulfonamides; halogen sulfonates to form sulfamates; sulfamoyl chlorides to form sulfonylureas. Alternatively, the compound obtained in Step 4 of Scheme 12 is treated with aldehydes under standard reductive amination conditions as described in Scheme 1 Step 5 to form the compounds of the present invention. If the imidazole group is blocked then it is unblocked.

scheme

(e.g. Prot = Boc) in Scheme 1, a monoblocked benzodiazepine such as in Scheme 3 is subjected to reductive alkylation using an imidazole-containing aldehyde and a reducing agent such as NaCNBH ₃ or Na (OAc) ₃ BH in an organic solvent such as dichloroethane or DMF in the presence of an acid such as acetic acid at 0 ° C to room temperature. The product is then treated as described in Scheme 12. Product 2 can be connected to a solid substrate, e.g. polystyrene resins, and the reactions of Scheme 1 can be performed with the resin-bound material. When detached from the base, e.g. treating with an acid such as trifluoroacetic acid in the presence of a binder such as triethylsilane at about room temperature affords Scheme 1 Compound 6.

scheme

e.g., Scheme 1 or Scheme 3 is a reductive amination reaction of an aminobenzoic acid using N-blocked aminoaldehyde under standard conditions, e.g. by treatment with a hydride reagent such as sodium triacetoxyborohydride or sodium cyanoborohydride in a suitable solvent such as methylene chloride or methanol in the presence of an acid such as acetic acid, from 0 ° C to about room temperature. Product is unblocked, e.g. Boc is cleaved by treatment with an acid such as TFA or HCl, if necessary in the presence of a binder such as dimethylsulfide, in a suitable solvent such as methylene chloride or dioxane at about room temperature, or Fmoc is cleaved by treatment with a secondary amine in tetrahydrofuran at about room temperature. The product is then cyclized under standard amide bond formation conditions such as diphenylphosphoryl azide in an organic solvent such as DMF. The product is then treated as described in Scheme 1.

scheme

In Scheme 1, Scheme 1, the benzodiazepindione is sulfonylated with chlorosulfonic acid, and the resulting sulfonyl chloride is condensed with an amine. The product is then treated as described in Scheme 1.

scheme

In Scheme 1, Scheme 1, the benzodiazepine of Scheme 1 can be reductively alkylated at two positions using an imidazole-containing aldehyde and a reducing agent such as NaCNBFfo or Na (OAc) 3BH in an organic solvent such as dichloroethane or DMF in the presence of an acid such as acetic acid. 0 ° C to room temperature.

in Scheme 1, Step 1, the benzodiazepine of Scheme 1 can be treated with R ₃ -L in an inert solvent such as DMF, THF or methylene chloride in the presence of a base such as diisopropylethylamine or potassium carbonate, from 0 ° C to 100 ° C, where L is a leaving group, such as chloride, bromide, methanesulfonate, 4-methylbenzenesulfonate or triflate, and R ₃ is a substituted alkyl group, a substituted aryl group, or a substituted heterocyclic group. This product is then treated as described in Scheme 1.

scheme

CH ₃

NH-Prot

R

ch ₃

NH-Prot

CH ₂ OAc

NH-Prot

CHO

NH-Prot

e.g. Scheme 1 or 3

stage

The first step is carried out by treating a pyridine having a protected amino group and a methyl group with an oxidizing agent such as hydrogen peroxide in a suitable solvent such as aqueous acetic acid or trifluoroacetic acid at room temperature to 75 ° C.

stage

The product is acylated with an acylating agent such as acetic anhydride and regrouped by heating from room temperature to 90 ° C in a suitable solvent such as acetic acid.

stage

The product is deacylated, e.g. aqueous NaOH, from room temperature to 50 ° C and oxidized to aldehyde, e.g. MnO ₂ in a suitable solvent such as tetrahydrofuran at about room temperature.

stage

The product is subjected to a reductive amination reaction using an amino acid ester under standard conditions, e.g. by hydrogenation in an inert solvent such as methanol or by treatment with a hydride reagent such as sodium triacetoxyborohydride in a suitable solvent such as a mixture of methylene chloride and acetic acid at about room temperature.

stage

The product is unblocked and cyclized, e.g. at room temperature to 100 ° C with polyphosphoric acid.

stage

The product is sulfonylated as described in Scheme 1, Step 4.

stage

The product is reduced as described in Scheme 1, Step 3. The product is then treated as described in Scheme 1, Step 5.

R,

R, • N CO ₂ H

Br. NH-Prot Scheme eg Scheme 14

R-,

The first step is carried out by reacting a pyrimidine containing a halogen and a carboxy group, if necessary, with a monoblocked diamine in a suitable solvent such as water in the presence of a catalyst such as CuSO ₄ , from room temperature to 100 ° C. The product is then treated as described in Scheme 14.

scheme

stage

The first step is carried out using reductive amination of the nitrobenzaldehyde with an amino acid ester under standard conditions, e.g. by reaction with a hydride reagent such as triacetoxyborohydride in a suitable solvent such as a mixture of methylene chloride and acetic acid at about room temperature.

stage

The product is sulfonylated as described in Scheme 1, Step 4.

stage

The nitro group of the product is reduced to the amino group under standard conditions such as reaction with SnCl ₂ or TiCl ₃ . The compound wherein Ri = Br can be prepared from the compound wherein Ri = H by bromination, for example by treatment with tetrabutylammonium perbromide in an inert solvent such as chloroform at about room temperature.

stage

The product is cyclized by heating with CuCN in an inert solvent such as N-methylpyrrolidinone from room temperature to 195 ° C. A compound wherein Ri = CN is prepared from a compound wherein Ri = halogen under the same conditions.

stage

The product is alkylated with blocked (if necessary) imidazolylalkanol under Mitsunobu conditions. Subsequently, if necessary, the product is treated as described in Scheme 5.

scheme

Scheme compound 3 may be selectively reduced e.g. acting as a reducing agent such as borane in an inert organic solvent such as tetrahydrofuran at about room temperature. The reductive amination reaction of product 2 is then carried out as described in Scheme 1.

scheme

stage

The reductive amination of compound 4 of Scheme 20 may be carried out first as described in Scheme 1, Step 5.

stage

The esterified (if necessary) ester of this product is hydrolyzed, e.g. by reaction with an alkaline hydroxide in a suitable solvent such as aqueous alcohol, from room temperature to the boiling point of the solvent.

stage

The product is cyclized under standard amide bond conditions, e.g. with BOP in an inert solvent such as DMF in the presence of a base (if necessary) such as diisopropylethylamine at about room temperature.

Schematic of N23

Rh /

P rot

R,

NU - (CH ₂ ) CO l \ T

R,

Z 1 = CO, so ₂ , SO ₂ NR ₅

R, Scheme 2 may be directly deprotected as described in Scheme 12, Step 3, and treated as described in Scheme 12, Step 4. Alternatively, compound 5 of Scheme 12 may be prepared by reduction, e.g. lithium aluminum hydride or borane, Scheme 23, compound 3, wherein Zi is not CO.

scheme

7., = S0 ₂ , Compound _{5 of} Scheme _{5 of} SO ₂ NR ₅ can be treated with an imidazole-containing aldehyde and an alkali metal cyanide such as NaCN in the presence of an acid such as acetic acid in a suitable solvent such as methanol / acetonitrile at about room temperature. , and the resulting compound 2. Compound 2 can be reduced, e.g. lithium aluminum hydride in a suitable solvent such as ether at about room temperature to give Compound 3 wherein R 1 is halogen, e.g. bromine may be prepared from compound 3 in which R 1 = H by the action of a halogenating agent, e.g. tetrabutylammonium perbromide in an inert solvent such as chloroform at about room temperature. The reductive amination reaction of compound 3 can be carried out under standard conditions to give compound 4.

scheme

in Scheme 1, Scheme 1, the N- (2-nitroaryl) -amino acid ester obtained by treatment of the amino acid with 1-fluoro-2-nitrobenzene followed by esterification is reduced, e.g. hydrogen in the presence of palladium catalyst in a suitable solvent such as ethyl acetate at about room temperature. The resulting amine is cyclized to compound 2 under reduction conditions. Compound 2 is acylated or sulfonylated as described in Scheme 1, Step 4. Compound 3 is reduced, e.g. borane in a suitable solvent such as methanol at about room temperature. Compound 3 wherein R is halogen, e.g. bromine may be prepared from compound 3 in which R 1 = H by the action of a halogenating agent, e.g. tetrabutylammonium perbromide in an inert solvent such as chloroform at about room temperature. Reductive amination of compound 4 with an imidazole-containing aldehyde is carried out as described in Scheme 1, Step 5.

scheme

In Scheme 1, compound 1 is treated with a methylating agent such as Ν, Ν, Ν ', Ν'-tetramethyldiaminomethane in a suitable solvent such as acetic anhydride and DMF at about room temperature. Compound 2 is then treated with 1,2-phenylenediamine in a suitable solvent such as toluene at about 115 ° C under dehydrogenation conditions, e.g. with a Dean-Stark trap with hydroquinone added. Compound 3 is then reduced and subjected to a reductive amine reaction as described in Scheme 1, Step 5.

The following are working examples of the present invention, which are preferred embodiments of the invention. All temperatures are given in degrees Celsius (° C) unless otherwise stated. These examples are merely illustrative of the invention and are not intended to be limiting thereof.

2,3,4,5-Tetrahydro-1- (1H-imidazol-4-ylmethyl) -4- (1-naphthalenylcarbonyl) -1H1,4-benzodiazepine (hydrochloride)

A. 1,4-Benzodiazepine-2,5-dione

A stirred solution of isatoic anhydride (16.4 g, 0.1 mol) and glycine ethyl ester hydrochloride in 40 ml of pyridine was refluxed for 7 hours. The resulting suspension is cooled to 0 ° C for 18 hours. The precipitate is collected and washed with ethanol and ether to give compound A, which is a yellowish solid.

B. 2,3,4,5-Tetrahydro-1 H -1,4-benzodiazepine is added slowly to a stirred suspension of lithium aluminum hydride (LAH, 3.5 g, 90 mmol) in THF (100 mL) at room temperature under argon atmosphere. solid compound A (3.5 g, 20 mmol). After addition of this compound, the resulting suspension was refluxed under argon for 18 h, cooled to 0 ° C, and a mixture of NH ₄ OH (5 mL, almost) and 30 mL of THF was added via a dropping funnel. The resulting suspension was stirred for 1 h. and filtered off. Concentration of the filtrate in vacuo afforded compound B as an oil.

C. 2,3,4,5-Tetrahydro-4- (1-naphthalenylcarbonyl) -1H-1,4-benzodiazepine

A mixture of Compound B (500 mg, 3.37 mmol) and naphthalenecarboxylic acid phenyl ester (750 mg, 3.02 mmol) in a small amount of acetonitrile was added with a catalytic amount of dimethylaminopyridine (DMAP) at 110 ° C under argon for 18 h. The mixture is cooled to room temperature. The product was isolated by flash chromatography (1: 1 ethyl acetate: hexanes) to give Compound C as a white solid (520 mg).

D. 2,3,4,5-Tetrahydro-1- (1H-imidazol-4-ylmethyl) -4- (1-naphthalenylcarbonyl) -1H-1,4-benzodiazepine (hydrochloride)

To a stirred solution of compound C (200 mg, 0.66 mmol) and 4-formylimidazole (110 mg, 1.15 mmol) in dichloroethane (2 mL) and acetic acid (1.0 mL) was added NaBH (OAc) ₃ immediately. (190 mg). The mixture was stirred for 30 min. and diluted with ethyl acetate (25 mL) followed by NH ₄ OH (3 mL, almost). The mixture was stirred at room temperature for 18 hours. and poured into a mixture of ethyl acetate (50 mL) and saturated NaHCO ₃ (50 mL). The organic layer was separated and the aqueous layer was extracted with ethyl acetate (50 mL). The combined organic extracts were washed with saturated NH ₄ Cl solution (50 mL), dried over Na ₂ SO _4, and concentrated in vacuo. The residue was dissolved in methanol (2 mL) and 1N HCl in ether (2 mL) was added. Evaporation of the solvent in vacuo gave a residue which was dried in vacuo to give Example 1 as a yellowish solid (240 mg). MS: (M + H) ⁺ 383 ⁺

Analysis calculated for C ₂₄ H _{2 2} N ₄ O -1.75 HCl -2.5 H ₂ O.

Found: C, 58.67; H, 5.90; N, 11.41; Cl, 12.63.

Found: C, 58.48; H, 6.10; N, 11.32; Cl, 12.46.

8-Chloro-2,3,4,5-tetrahydro-1- (1H-imidazol-4-ylmethyl) -4- (1-naphthalenecarbonyl) -1H-1,4-benzodiazepine (hydrochloride)

A. 8-Chloro-1,4-benzodiazepine-2,5-dione

A solution of 7-chloroisatoic acid anhydride (34 g, 0.17 mol) and glycine ethyl ester hydrochloride (24 g, 0.17 mol) in anhydrous pyridine (120 ml) was heated to 80 ° C for 1 h. and refluxed overnight. The resulting suspension was stirred at room temperature for 3 hours. The precipitate was filtered off, washed with water and dried to give 4.4 g of compound A, a white solid. The filtrate is evaporated, the solid obtained is washed with water and dried to give a further 27.2 g of compound A, which is a white solid (85% overall yield). MS (M + H) 211.

B. 8-Chloro-2,3,4,5-tetrahydro-1H-1,4-benzodiazepine

To compound A (1.4 g, 6.6 mmol) in ethylene glycol dimethyl ether (20 mL) was added borane-THF (1.0 M THF, 20 mL). The clear solution is refluxed for 6 hours. The solvent is evaporated and the residue is treated with saturated sodium bicarbonate. The aqueous solution was extracted with methylene chloride. The organic solution was washed with saturated sodium bicarbonate and brine, dried (sodium sulfate), and evaporated to give an oil (1.0 g). The crude product was purified by chromatography (10% methanol in methylene chloride) to give Compound B as a slightly yellow solid (0.56 g, 46%). MS (M + H) 183.

C. 8-Chloro-2,3,4,5-tetrahydro-4- (1-naphthalenylcarbonyl) -1H-1,4-benzodiazepine

A solution of Compound J (0.154 g, 0.84 mmol) in methylene chloride (4 mL) and sodium hydroxide (1N, 4 mL) at 0 ° C was added dropwise to a solution of 1-naphthoyl chloride (0.12 mL, 0.84 mmol) in methylene chloride (1 mL). The solution is stirred for 1 hour, the organic layer is separated and the aqueous layer is extracted with methylene chloride. The combined organic layers were dried (sodium sulfate) and the solvent was evaporated. The resulting oil was chromatographed (silica gel, 5% methanol, 0.5% ammonium hydroxide, 94.5% methylene chloride) to give Compound C as a yellow solid (0.26 g, 90%). MS (M-H) - 335.

D. 8-Chloro-2,3,4,5-tetrahydro-1- (1H-imidazol-4-ylmethyl) -4- (1-naphthalenylcarbonyl) -1H-1,4-benzodiazepine (hydrochloride)

Compound D is prepared from Compound C according to the procedure for the preparation of Compound D in Example 1. Chromatography (silica gel, 5% methanol, 0.5% ammonium hydroxide, 94.5% methylene chloride) followed by preparative HPLC and conversion to the hydrochloride salt afforded Example 2 as an off-white solid. Lyd. mp: 160-162 ° C.

MS: (M + H) ⁺ 383 ⁺

Analysis calculated for C24H21N4OCI HCI -1.85 -2.5 H ₂ O.

Found: C, 59.51; H, 4.76; N, 11.57.

Found: C, 59.42; H, 4.84; N, 11.48.

example

1,2,3,4-Tetrahydro-4 - [(3H-imidazol-4-yl) methyl] -1 - (- naphthalen-1-ylcarbonyl) quinoxaline (dihydrochloride)

A, 1,2,3,4-Tetrahydroquinoxaline To a solution of quinoxaline (2.75 g, 21 mmol) in absolute EtOH (100 mL) was added Pt (IV) O ₂ (Adams catalyst, 200 mg) and the mixture hydrogenated (1 atm). .) at room temperature for 6 hours. The mixture was filtered through celite (Celite) and the filtrate concentrated to give 2.74 g of Compound A as an off-white solid (97%) MS (M + H) 135.

B. 1,2,3,4-Tetrahydro-1- (naphthalen-1-ylcarbonyl) quinoxaline

To a solution of compound J (1.0 g, 7.45 mmol) and triethylamine (TEA, 2.1 mL, 14.9 mmol) in CH ₂ Cl ₂ (100 mL) at -78 ° C was added naphthalenecarboxylic acid anhydride (1.12 ml, 7.45 mmol). After 2 or. remove the cooling bath, stir the mixture at room temperature for 1 hour. and concentrate. The residue was purified by flash chromatography (silica gel, 95: 5: 0.1 CHCl _3: MeOH: NH ₄ OH) to give compound B, which is an off-white solid (2.04 g, 95%). MS (M + H) 289.

C, 1,2,3,4-Tetrahydro-4 - [(3H-imidazol-4-yl) methyl] -1 - (- naphthalen-1-ylcarbonyl) quinoxaline (dihydrochloride)

Compound C is prepared from Compound B according to the procedure for Preparation D of Example 1. Chromatography (silica gel, 10% ethanol / ethyl acetate) gives a clear yellow oil which is converted to the hydrochloride using 4N HCl in dioxane (4 mL, room temperature, 2 h); The compound of Example 3 is obtained which is an off-white solid. MS: (M + H) ⁺ 289 ⁺

Analysis calculated for C ₂₃ H ₂ O ₄ O · 0.9 HCl.

Excluded; C, 63.10; H, 5.04; N, 12.47.

Found: C, 63.10; H, 5.39; N, 12.47.

example

2,3,4,5-Tetrahydro-4- (1H-imidazol-4-yl-methyl) -1- (1-naphthalenylcarbonyl) -1H1,4-benzodiazepine (dihydrochloride)

A. 2,3,4,5-Tetrahydro-4 - [(1,1-dimethylethoxy) carbonyl] -1H-1,4-benzodiazepine is added di-t-butyl dicarbonate (400 mg) to a stirred solution of Example 1 Compound B (300 mg). mg). The mixture was stirred at room temperature for 18 hours and quenched by the addition of saturated NaHCO ₃ solution. The solvent was evaporated and the residue was chromatographed (flash chromatography, silica gel, 1: 2 ethyl acetate: hexanes). Obtained as an oil, Compound A (350 mg).

B. 2,3,4,5-Tetrahydro-1- (1-naphthalenylcarbonyl) -4 - [(1,1-dimethylethoxy) carbonyl] -1H-1,4-benzodiazepine

To a stirred solution of compound A (350 mg, 1.4 mmol) in methylene chloride at 0 ° C under argon was added 1-naphthalenecarboxylic acid chloro anhydride (0.22 mL, 1.4 mmol) followed by pyridine (0.25 mL). . The mixture is stirred for 2 hours. Then saturated NaHCO ₃ and the mixture was stirred for 18 h. at room temperature. The resulting solution was poured into a mixture of methylene chloride and saturated NaHCO ₃ . The organic layer was separated, washed with 10% HCl (2 x 25 mL), dried (MgSO ₄ ), and concentrated in vacuo to give compound B (450 mg, 80%) as an oil.

C. 2,3,4,5-Tetrahydro-1- (1-naphthalenylcarbonyl) -1H-1,4-benzodiazepine

Compound B was dissolved in a mixture of methylene chloride and TFA (10 mL, 1:10). The solution was stirred at room temperature for 2 h. The solvent was evaporated in vacuo, the residue was diluted with CHCl ₃ and basified with 10N NaOH. The organic layer was separated, dried (MgSO ₄ ) Compound C (310 mg, 92%) as an oil.

D. Preparation of 2,3,4,5-Tetrahydro-4- (1H-imidazol-4-ylmethyl) -1- (1-naphthalenylcarbonyl) -1H-1,4-benzodiazepine (dihydrochloride) as a slightly yellow solid. from compound C according to the procedure for the preparation of compound D as described in Example 1.

Analysis calculated for C ₂₄ H _{2 2} N ₄ O -2.0 HCl -1.3 H ₂ O.

Found: C, 60.20; H, 5.60; N, 11.70; Cl, 14.82.

Found: C, 60.21; H, 5.60; N, 11.48; Cl, 14.68.

2,3,4,5-Tetrahydro-1- (1H-imidazol-4-yl-methyl) -2-methyl-4- (1-naphthalenylcarbonyl) -1H-1,4-benzodiazepine (hydrochloride)

A. 2-M Ethyl-1,4-benzodiazepin-3-one

The Boc derivative of Compound A is prepared from 2-amino-N - [(1,1-dimethylethoxy) carbonyl] phenylmethylamine and methyl pyruvate according to the synthesis procedure for Compound D described in Example 1. The resulting oil was dissolved in a mixture of methylene chloride and TFA (8 mL, 1: 1), and the solution was stirred at room temperature for 1 h. and concentrated in vacuo. The residue was partitioned between ether and 10% HCl, the aqueous layer was basified to pH 11 with 10N NaOH and extracted with ethyl acetate (2 x 50 mL). The combined organic extracts were dried over MgSO ₄ and concentrated to give Compound A as a solid (250 mg, 28%). Lyd. m.p. 149-151 ° C. MS (M + H) 177.

B. 2-Methyl-1,4-benzodiazepine

To a suspension of LAH (160 mg, 4.21 mmol) in anhydrous THF (5 mL) is added a solution of Compound A (181 mg, 1.03 mmol) at room temperature. This solution was refluxed for 5 h, cooled to 0 ° C, and diluted with THF (20 mL). Saturated NaCl solution (0.5 mL) was added dropwise and the mixture was stirred at room temperature for 18 hours. and filtered through a MgSO ₄ layer. The MgSO ₄ layer was washed with ethyl acetate and the combined filtrates concentrated in vacuo. Compound B is obtained which is a semi-solid (160 mg, 96%). MS (M + H) 163.

C. 2-Methyl-4- (1-naphthalenylcarbonyl) -1,4-benzodiazepine

Compound C is prepared from Compound B according to the procedure described in Example 2 for the preparation of Compound C. Chromatography (flash chromatography, silica gel, 1: 1 ethyl acetate: hexanes) gives compound C as a solid. Lyd. mp: 75 ° C. MS (M + H) 317.

D. 2,3,4,5-Tetrahydro-1- (1H-imidazol-4-ylmethyl) -2-methyl-4- (1-naphthalenylcarbonyl) -1H-1,4-benzodiazepine (hydrochloride) Example Compound (slightly yellowish) solid) is prepared from Compound C according to the procedure for the preparation of Compound D as described in Example 1. Lyd. mp: 165 ° C (foam). MS (M + H) 397.

Analysis calculated for C25H24N4O HCl -2.4 -1.0 -0.5 H ₂ O CH ₃ OH. Found: C, 59.12; H, 5.92; N, 10.84; Cl, 16.42.

Found: C, 59.09; H, 5.58; N, 10.48; Cl, 16.28.

example

2,3,4,5-Tetrahydro-4- (1-naphthalenylcarbonyl) -1 - [[1- (phenylmethyl) -1H-imidazol-5-yl] methyl] -1H-1,4-benzodiazepine (hydrochloride)

A. 2,3,4,5-Tetrahydro-4- (1-naphthalenylcarbonyl) -1 - [[1- (triphenylmethyl) -1Himidazol-4-yl] methyl] -1H-1,4-benzodiazepine

To a solution of the compound of Example 1 (90 mg, 0.21 mmol) in acetonitrile (1 mL) at room temperature under argon was added TEA (0.14 μΙ, 1 mmol) followed by triphenylmethyl chloride (56 mg, 0.2 mmol). The mixture is refluxed for 2 hours, cooled to room temperature and stirred in the oven. The precipitate was filtered off and concentrated the filtrate to give Compound A (110 mg, 92%). MS (M + H) <^+> = 625.

B. 2,3,4,5-Tetrahydro-4- (1-naphthalenylcarbonyl) -1 - [[1- (phenylmethyl) -1Himidazol-5-yl] methyl] -1H-1,4-benzodiazepine (hydrochloride) To a solution of benzyl alcohol (18 μΙ, 0.18 mmol) in THF (1 mL) at −78 ° C was added trifluoromethanesulfonic anhydride (30 μΙ, 0.18 mmol) and DIPEA (35 μΙ, 2 mmol) under argon. After 20 minutes A solution of Compound A (100 mg, 0.15 mmol) in THF (1 mL) was added dropwise. For 3 hours. Allow to warm to room temperature and stir for 14 hours. Acetic acid (1.5 mL) and water (1 mL) were added and the mixture was refluxed for 30 min, cooled to room temperature and evaporated. The residue is dissolved in chloroform, washed with saturated NaHCO ₃ solution, dried (MgSO ₄ ) and concentrated. The residue was chromatographed (flash chromatography, silica gel, 9: 1 CHCI _3: MeOH). The pure product was dissolved in ethyl acetate and HCl gas was bubbled through the solution for 30 sec. Evaporation afforded Example 6 (33 mg, 33% overall yield).

MS (M + H) <^+> = 473. IR (KBr) 2853, 1630, 1508 cm ^-1 .

example

2,3,4,5-Tetrahydro-1- (1H-imidazol-4-ylmethyl) -4- (1-naphthalenylsulfonyl) -1H1,4-benzodiazepine (hydrochloride)

A. 2,3,4,5-Tetrahydro-4- (1-naphthalenylsulfonyl) -1H-1,4-benzodiazepine

Compound A is prepared from Example 1 Compound B and 1-naphthalenesulfonyl chloride according to the procedure described in Example 2 for the preparation of Compound C. Recrystallization from methanol gives compound A, which is a solid. Lyd. mp: 165-166 ° C. MS (M + H) 339.

B. 2,3,4,5-Tetrahydro-1- (1H-imidazol-4-ylmethyl) -4- (1-naphthalenylsulfonyl) -1H-1,4-benzodiazepine (hydrochloride) Example compound (white solid) from Compound A according to the procedure for the preparation of Compound D as described in Example 1. Lyd. 140 ° C (foam).

MS (M + H) 419.

Analysis calculated for G ₂₃ H ₂₂ N ₄ O ₂ S -1.5 HCl -1.0 H ₂ O.

Found: C, 56.34: H, 5.22; N, 11.43; Cl, 10.85; S, 6.54.

Found: C, 56.70; H, 5.16; N, 11.04; Cl, 10.72; S, 6.54.

(S) -2,3,4,5-Tetrahydro-1- (1H-imidazol-4-ylmethyl) -3- [2- (methylthio) ethyl] -4- (1-naphthalenylcarbonyl) -1H-1,4-benzodiazepine (hydrochloride) Example compound (yellow solid) is prepared from isatoic anhydride and L-methionine methyl ester hydrochloride according to the reaction sequence described for the following compounds: Example 1 Compound A; Compound B of Example 1, except that ethylene glycol dimethyl ether was used as solvent; The compound C of Example 2; For the compound of Example 1, D. Lyd. m.p. 78-80 ° C.

MS (M + H) 457.

Analysis calculated for C ₂₇ H ₂₈ N ₄ OS -1.6 HCl -2.3 H ₂ O.

Found: C, 58.28; H, 6.20; N, 10.07; S, 5.76. Cl, 10.19.

Found;

C, 58.02; H, 5.87; N, 12.23; S, 4.95; Cl, 10.27.

2,3,4,5-Tetrahydro-1- (1H-imidazol-4-yl-methyl) -N-methyl-N-phenyl-4H-1,4-benzodiazepine-4-carboxamide (hydrochloride)

A. 2,3,4,5-Tetrahydro-N-methyl-N-phenyl-4H-1,4-benzodiazepine-4-carboxamide

To a stirred solution of Example 1 Compound B (0.5 g, 3.35 mmol) in THF in NaHCO ₃ (1.68 g, 20 mmol) was added N-methyl-N-phenylcarbamoyl chloride (480 mg, 2.83 mmol). . The mixture was stirred at room temperature for 18 hours and then filtered. Concentration of the filtrate in vacuo and recrystallization of the residue from methanol gave compound A as a white solid (720 mg, 76%). Lyd. mp: 159-160 ° C.

B. 2,3,4,5-Tetrahydro-1- (1H-imidazol-4-ylmethyl) -N-methyl-N-phenyl-4H-1,4-benzodiazepine-4-carboxamide (hydrochloride) Example compound (white solid) ) is prepared from Compound A according to the procedure for the preparation of Compound D as described in Example 1. Lyd. temp .; 145 ° C (shrinks).

MS (M + H) 362.

Analysis calculated for C21H23N5O HCl -1.8 -1.0 H ₂ O.

Found: C, 56.67; H, 6.07; N, 15.74; Cl, 14.34.

Found: C, 57.08; H, 6.03; N, 15.40; Cl, 14.53.

2-1,2,3,4,5-Tetrahydro-1- (1H-imidazol-4-ylmethyl) -1H-1,4-benzodiazepin-4yl] sulfonyl] benzoic acid methyl ester (hydrochloride), the title compound (white solid) is prepared from methoxycarbonylbenzenesulfonyl chloride and Example 2 Compound B as described in the reaction sequence to afford the following compounds: Example 2 Compound C; For Example 1, Compound D. MS (M + H) 427.

Analysis calculated for C ₂ i H ₂₂ N ₄ O ₄ S -1.1 HCl -1.0 H ₂ O.

Found: C, 56.04; H, 5.22; N, 11.56; S, 6.62. Cl, 8.05.

Found: C, 52.20; H, 5.11; N, 10.40; S, 7.20; Cl, 8.09.

7-Bromo-2,3,4,5-tetrahydro-1- (1H-imidazol-4-ylmethyl) -2-methyl-4- (1-naphthalenylcarbonyl) -1H-1,4-benzodiazepine (hydrochloride)

A. 7-Bromo-1,4-benzodiazepine-2,5-dione

Compound A was prepared from 6-bromoacetic acid anhydride according to the procedure for preparation of Compound A described in Example 1.

B. Example compound 7-Bromo-2,3,4,5-tetrahydro-1- (1H-imidazol-4-ylmethyl) -4- (1-naphthalenecarbonyl) -1H-1,4-benzodiazepine (hydrochloride) (solid) was prepared from Compound A as described in the reaction sequence to afford the following compounds: Example 2 Compound B; The compound C of Example 2; Example 1 Compound D. Chromatography of this compound (5% methanol, 0.5% ammonium hydroxide, 94.5% methylene chloride) followed by preparative HPLC and conversion to the hydrochloride salt afforded Example 11. Lyd. mp: 160-162 ° C.

MS (M + H) 461.

Analysis calculated for C ₂₄ H ₂ iBrN ₄ O · 1.5 HCl.

Found: C, 55.86; H, 4.39; N, 10.86.

Found: C, 55.84; H, 4.49; N, 10.71.

example

2,3,4,5-Tetrahydro-1- (1H-imidazol-4-ylmethyl) -4- (1-naphthalenecarbonyl) -7-phenyl-1H-1,4-benzodiazepine (hydrochloride)

A. A solution of 7-phenyl-1,4-benzodiazepine-2,5-dione compound A (0.834 g, 3.1 mmol) in 20 mL of 1: 1 DMF: THF is degassed with nitrogen. Palladium tetrakistriphenylphosphine is added. After half an hour, a solution of anhydrous sodium carbonate (0.37 g, 3.5 mmol) in water (6 mL) and phenylboronic acid (1.00 g, 8.3 mmol) was added. The suspension was stirred at room temperature overnight, then at 80-90 ° C for 2 days. The suspension is filtered. The precipitate was washed with water and ethyl acetate to give Compound A as a slightly gray solid (0.65 g, 84%). LC-MS (M + H) ⁺ 253.

B. 7-Phenyl-1,4-benzodiazepine To a suspension of Example 11 Compound A (0.62 g, 2.5 mmol) in THF was added LAH THF (1.0 M THF, T mL). The suspension is stirred for 3 hours. and boil under reflux for 2 hours. After cooling to room temperature, sodium hydroxide (1 N, 5 ml) was added followed by 10 ml of saturated sodium potassium tartrate. The aqueous solution was extracted with methylene chloride. The organic phase is dried (sodium sulfate) and evaporated. The resulting oil was purified by chromatography (10% methanol in methylene chloride) to give Compound B as a yellowish solid (0.46 g, 58%). LC-MS (M + H) ⁺ 225.

C. 2,3,4,5-Tetrahydro-1- (1H-imidazol-4-ylmethyl) -4- (1-naphthalenylcarbonyl) -7-phenyl-1H-1,4-benzodiazepine (hydrochloride) Example compound (solid) prepared from Compound B according to the reaction sequence described to give the following compounds: Example C; Example 1 Compound D. Chromatography of this compound (5% methanol, 0.5% ammonium hydroxide, 94.5% methylene chloride) followed by preparative HPLC and conversion to the hydrochloride salt afforded Example 12. Lyd. mp: 158-160 ° C.

MS (M + H) 459.

Analysis calculated for C30H26N4O -2.0 HCIO, 58H ₂ O.

Found: C, 66.50; H, 5.42; N, 10.34. ·

Found: C, 66.56; H, 5.64; N, 10.00.

2,3,4,5-Tetrahydro-1- (1H-imidazol-2-ylmethyl) -4- (1-naphthalenylcarbonyl) -1H1,4-benzodiazepine (hydrochloride)

To a solution of compound C (50 mg, 0.085 mmol) in Example 1 in dichloroethane (5 mL) was added 2-imidazolecarboxaldehyde (33 mg, 0.34 mmol), NaBH (OAc) ₃ (72 mg, 0.34 mmol) and glacial acetic acid. (0.2 mL). The mixture is stirred for 16 hours. Saturated aqueous sodium bicarbonate solution (0.5 ml) is added and the solution is evaporated to dryness. The residue was dissolved in a mixture (50/50) of 0.1% TFA in methanol and 0.1% TFA in water and applied to a YMC C18 column (S-5, ODS 30x250 mm). Purification by HPLC is carried out under the following conditions: solvent A: 0.1% TFA in 90% water and 10% methanol; solvent B; 0.1% TFA in 90% methanol and 10% water: 10-90% B in solution A over 30 min. The highest peak fractions are pooled and lyophilized to give a white solid. 1M HCl (6 mL) was added and the solution was concentrated to a glass. Repeat this step to obtain 25 mg (66%) of Example 13 as a white glassy solid.

MS (M + H) ⁺ 383.

¹ H-NMR (CD ₃ OD, 270 MHz) δ 8.11 (2H, m), 7.7-7.1 (10H, m), 6.71 (0.5H, t, J = 7.05 Hz), 6.07 (0.5H, d, J = 7.05Hz), 5.01 (1H, m), 4.7-4.0 (2H, m), 3.6-3, 4 (4H, m), 3.1 (1H, m).

2,3,4,5-Tetrahydro-1- [3- (1H-imidazol-2-yl) propyl] -4- (1-naphthalenylcarbonyl) 1H-1,4-benzodiazepine (dihydrochloride)

A. Ethyl 3- [imidazol-2-yl] -propionic acid ethyl ester into cooled (0 ° C) sodium hydride (1.86 g, 45.8 mmol, 60% dispersion in mineral oil, washed with THF and dried over N ₂ ). solution in 1,2-dimethoxyethane (DME, 20 mL) over 15 min. triethylphosphonacetate (12 g, 54.1 mmol) dissolved in DME (10 mL) was added dropwise. The solution is stirred for 1 hour. at room temperature, followed by the addition of 2-imidazoleacetaldehyde (4 g, 41.6 mmol) in 20 mL of DME. The solution was stirred and refluxed (85 ° C) for 15 minutes, then cooled to 60 ° C and held for 1 hour. Upon cooling, the solution is concentrated to 1/2 initial volume and filtered. The solid was recrystallized from a mixture of methanol, ethyl acetate and hexanes to give 5.1 g (74%) of compound A as a white crystalline solid. MS (M + H) ⁺ 167.

B. 3- [Imidazol-2-yl] -propionic acid ethyl ester

A solution of Compound A (4.01 g, 24.2 g) in absolute ethanol (100 mL, heated to dissolve) was hydrogenated using Pd / C (0.5 g) at room temperature for 16 h. After removal of H _{2 in} vacuo, the catalyst is separated by filtration through a pad of celite. Concentration of the filtrate in vacuo afforded 4.0 g (100%) of Compound B as a white crystalline solid. MS (M + H) &lt; ⁺ &gt; 169 ⁺ .

C. Ethyl 3- [N-triphenylmethyl-imidazol-2-yl] -propionic acid

Compound C is prepared from Compound B according to the procedure described in Example 6 for the preparation of Compound A using methylene chloride as solvent. Treatment of the aqueous solution and recrystallization from a mixture of ethyl acetate and hexane affords compound C, which is a white crystalline solid. MS (M + H) ⁺ 411 ⁺ .

D. 3- [N-Triphenylmethylimidazol-2-yl] propanal

A stirred solution of Compound C (300 mg, 0.73 mmol) in dichloromethane (3 mL) is cooled to -78 ° C and a pre-cooled (-70 ° C) 1M DIBAL solution in dichloromethane (0.73 mmol, 0, 73 ml). After stirring for 1 hour. additional pre-cooled (-70 ° C) DIBAL solution (0.3 mL, 0.3 mmol) was added. After stirring for a further 2 h, saturated NH ₄ Cl solution (10 mL) was added followed by 0.1 N HCl (20 mL). After stirring for 5 min, methylene chloride (30 mL) was added. The layers were separated and the aqueous layer was washed with methylene chloride. The combined organic layers were dried over MgSO ₄ , filtered, and concentrated to give 266 mg (99%) of Compound D as a white solid. ¹ H-NMR (CD ₃ OD, 270 MHz) δ 9.4 (1H, s), 7.38 (10H, m), 7.05 (7H, m), 2.7-2.2 (4H, m).

E. 2,3,4,5-Tetrahydro-1- [3- (1-triphenylmethylimidazol-2-yl) propyl] -4- (1-naphthalenylcarbonyl) -1H-1,4-benzodiazepine

Compound E was prepared from Compound D and Example 1 Compound C according to the procedure described in Example 1 for the preparation of Compound D with stirring for 16 hours. Chromatography (flash chromatography, silica gel, 9: 1 methylene chloride: methanol) affords E (74%) as a glass. MS (M + H) ⁺ 653.3.

F. 2,3,4,5-Tetrahydro-1- [3- (1H-imidazol-2-yl) propyl] -4- (1-naphthalenylcarbonyl) -1H-1,4-benzodiazepine (dihydrochloride)

A mixture of E (110 mg, 0.18 mmol) in TFA (5 mL), methylene chloride (5 mL), and triethylsilane (0.1 mL) was stirred for 2 h. at room temperature and concentrated. Hexane is added to the residue while stirring and the mixture is decanted. The residue is dissolved in a mixture of 0.1% TFA in methanol and 0.1% TFA in water (50/50), applied to a YMC C18 column (S-5, ODS 30x250 mm) and purified by HPLC under the following conditions: solvent A 0.1% TFA in a mixture of 90% water and 10% methanol; solvent B: 0.1% TFA in a mixture of 90% methanol and 10% water; 0-100% B in solvent A over 30 min. The highest peak fractions are pooled and lyophilized to an oily residue. 1M aqueous HCl (6 mL) was added and the solution was concentrated to a glass residue. Repeat this step to obtain 50 mg (84%) of Example 14 as a white solid.

MS (M + H) ⁺ 411.

¹ H-NMR (CD ₃ OD, 300 MHz) δ 8.05-7.95 (2H, m), 7.6-7.05 (12H, m), 6.71 (0.5H, m), 6.02 (0.5H, m), 4.4 (2H, m), 3.6-3.0 (8H, m), 2.2-2.0 (2H, m).

1- [3-Amino-3- (1H-imidazol-2-yl) propyl] -2,3,4,5-tetrahydro-4- (1-naphthalenylcarbonyl) -1H-1,4-benzodiazepine (trihydrochloride)

A. N- [2- (Trimethylsilyl) ethoxymethyl] imidazole

Imidazole (3.0 g, 44 mmol) was added in small portions to a mixture of NaH (2.1 g, 51 mmol, 60% dispersion in mineral oil, washed with hexanes) and DMF (60 mL). The mixture is stirred under N _{2 for} 1 h, then added dropwise

2- (trimethylsilyl) ethoxymethyl chloride (SEM-CI). The mixture was stirred for 1 h and quenched with water (5 mL). The mixture was poured into water (80 mL) and extracted with ethyl acetate. The organic layer was washed with saturated aqueous NH4Cl, saturated aqueous NaCl, dried (MgSO _4), filtered and concentrated to provide 6.3 g (72%) of Compound A, which is a clear liquid. MS (M + H) ⁺ 199.

B. N- [2- (Trimethylsilyl) ethoxymethyl] imidazole-2-carboxaldehyde in n-BuLi in hexane was added to a cooled (-40 ° C) mixture of Compound A (3.0 g, 15.1 mmol) in THF (75 mL). (2.5M, 6.4 mL, 15.1 mmol). After 15 minutes DMF (1.4 mL, 18.1 mmol) was added and the mixture was stirred for 3 h before saturated aqueous NH ₄ Cl (30 mL) was added. The mixture is extracted with ethyl acetate, the organic phase is washed with saturated aqueous NH ₄ Cl, saturated NaCl, dried over MgSO ₄ , filtered, and concentrated to give 3.1 g of compound B (92%) as a yellowish oil. MS (2M + H) ⁺ 453.2.

C. 1-Amino-1- [N- [2- (trimethylsilyl) ethoxymethyl] imidazol-2-yl] -but-3-ene to cooled (-78 ° C) compound B (1.22 g, 5.4) mmol) in THF (10 mL) A solution of lithium bistrimethylsilylamide in THF (1M, 5.6 mL, 5.6 mmol) was pre-cooled by syringe under Ar atmosphere. The mixture was warmed to -20 ° C and held for 1 h, then cooled again to -78 ° C. A pre-cooled (-78 ° C) solution of aluminum magnesium bromide (1M, in ethyl ether, 7.45 mL, 7.45 mmol) is added to this mixing syringe. The mixture was warmed to room temperature and stirred under Ar for 16 h. The mixture was quenched with 1N aqueous NaOH (20 mL) and extracted with ethyl ether. The organic layer was washed with saturated NaCl, dried over MgSO ₄ , filtered, and concentrated to a yellow residue. This residue is chromatographed on a silica gel flash column (5 x 20 cm), eluting with a mixture of methylene chloride and methanol (9: 1) followed by a mixture of ammonium hydroxide, methanol and chloroform (1: 5: 94). 0.55 g (38%) of C is obtained, which is an orange liquid. MS (M + H) ⁺ 267.

D. 1 - [(Triethylsilyl) ethoxycarbonylamino] -1- [N- [2-trimethylsilyl) ethoxymethyl] imidazol-2-yl] -but-3-ene

To a stirred suspension of Compound C (450 mg, 1.7 mmol) in water (2 mL) was added a solution of TEA (0.32 mL, 2.3 mmol) in dioxane (2 mL) followed by 2 (triethylsilyl) ethoxycarbonyl succinimide. The mixture was stirred at room temperature for 16 hours. Ethyl ether (30 mL) and 1N aqueous KHSO ₄ (30 mL) were added. The layers were separated and the aqueous layer was washed with ethyl ether. The combined organic layers were dried over MgSO ₄ , filtered, and concentrated. The residue is chromatographed on a silica gel flash column (5 x 20 cm), eluting with a mixture of methylene chloride and methanol (9: 1). 531 mg (84%) of D. is obtained in the form of a glass. MS (M + H) ⁺ 412.

E. 3 - [(Triethylsilyl) ethoxycarbonylamino] -3- [N- [2-trimethylsilyl) ethoxymethyl] imidazol-2-yl] -propanal

Sodium periodate (94 mg, 0.37 mmol) and osmium tetroxide (2 mg dissolved in 0.5 mL water and 0.5 mL dioxane) were added to a stirred mixture of Compound D in dioxane (5 mL) and water (5 mL). The mixture is stirred for 18 hours. Methylene chloride is added, the layers are separated and the aqueous layer is washed with methylene chloride. The combined organic layers were dried over MgSO ₄ , filtered, and concentrated. The residue is chromatographed on a silica gel flash column (5 x 20 cm), eluting with a mixture of methylene chloride and methanol (9: 1). 90 mg (90%) of compound E are obtained in the form of a glass.

F. 1 - [[(Triethylsilyl) ethoxycarbonylamino] -3- (1- (trimethylsilyl) ethoxymethylimidazol-2-yl] propyl] -2,3,4,5-tetrahydro-4- (1-naphthalenylcarbonyl) -1H-1,4 benzodiazepine

Compound F is prepared from Compound E and Example 1 Compound C according to the procedure for Preparation Compound D described in Example 1 with stirring for 16 hours. Chromatography (flash chromatography, silica gel, 9: 1 methylene chloride: methanol) affords F (44%) as a glass. MS (M + H) ⁺ 700.

G. 1- [3-Amino-3- (1H-imidazol-2-yl] propyl] -2,3,4,5-tetrahydro-4- (1-naphthalenylcarbonyl) -1H-1,4-benzodiazepine (trihydrochloride)

To a solution of compound F (20 mg, 0.029 mmol) in TFA (3 mL) was added tetrabutylammonium fluoride (44 mg, 0.17 mmol) and the solution was heated at 50 ° C for 16 h. After cooling, the solvent was evaporated in vacuo and the residue was dissolved in a mixture of 0.1% TFA in methanol and 0.1% TFA in water (50/50) and applied to a YMC C18 column (S-5, ODS 30x250 mm). Purification by HPLC is carried out under the following conditions: solvent A: 0.1% TFA in a mixture of 90% water and 10% methanol; solvent B: 0.1% TFA in a mixture of 90% methanol and 10% water; 0-100% B in solvent A over 30 min. The highest peak fractions are pooled and lyophilized to an oily residue. 1M aqueous HCl (6 mL) was added and the solution was concentrated to a white solid. Repeat this step to give 9 mg (58%) of Example 15 as a white solid.

MS (M + H) &lt; ⁺ &gt;

¹ H-NMR (CD ₃ OD, 270 MHz) δ 8.05-7.95 (2H, m), 7.7-7.05 (10H, m), 6.71 (0.5H, m), 6.02 (0.5H, m), 4.4 (2H, m), 4.0 (1H, m), 3.6-3.0 (7H, m), 2.9 (1H, m) .

2,3,4,5-Tetrahydro-1- (1H-imidazol-4-ylmethyl) -3-methyl-4- (1-naphthalenylcarbonyl) -1H-1,4-benzodiazepine (hydrochloride) Example Compound (yellow solid) ) is prepared from isatoic anhydride and D, L-alanine ethyl ester hydrochloride according to the procedure described in Example 8. Lyd. mp: 180-185 ° C.

MS (M + H) &lt; ⁺ &gt; 397.

Analysis calculated for C25H24N4O-HCl -1.3 1.3H ₂ O.

Found: C, 64.26; H, 6.02; N, 11.99; Cl, 9.86.

Found: C, 64.33; H, 5.82; N, 11.70; Cl, 9.65.

(S) -2,3,4,5-Tetrahydro-1- (1H-imidazol-4-ylmethyl) -3- [2- (methylthio) ethyl] -4- (1-naphthalenylmethyl) -1H-1,4-benzodiazepine (hydrochloride) to a suspension of ethylene glycol dimethyl ether (anhydrous, 20 mL) and lithium aluminum hydride (17 mg, 0.45 mmol) under argon at 0 ° C was slowly added a mixture of compound 8 (75 mg, 0.15 mmol) in ethylene glycol dimethyl ether . The mixture was allowed to warm to room temperature and stirred for 30 min. and reflux (85 ° C) for 18 hours. The mixture was cooled to 0 ° C and quenched by successive addition of a mixture of tetrahydrofuran and water (1 mL), aqueous sodium hydroxide (2 mL, 1N) and water (1 mL). The precipitate formed is filtered off and the filtrate is concentrated in vacuo to give an amber oil. This material was dissolved in methanol (2 mL), treated with a solution of hydrochloric acid (1 mL, anhydrous, 2M, in ether) and concentrated in vacuo to afford Example 17 as a yellow solid. Lyd. mp: 115-120 ° C.

MS (M + H) ⁺ 443.

Analysis calculated for C27H30N4S HCI -2.4 -2.6 H ₂ O.

Excluded; C, 56.21; H, 6.57; N, 9.71; Cl, 14.75. Found: C, 56.20; H, 6.55; N, 9.85; Cl, 14.81.

example

2,3,4,5-Tetrahydro-1- (1H-imidazol-4-ylmethyl) -9-methyl-4- (1-naphthalenylcarbonyl) -1H-1,4-benzodiazepine (dihydrochloride) Example Compound (yellowish solid) prepared from 8-methylsilicic acid anhydride and glycine ethyl ester hydrochloride according to the reaction sequence described to give the following compounds of Example 1 by boiling under reflux for 16 hours; The compound of Example 17, except that THF is used as a solvent; boiling with 4-nitrophenyl ester of 1-naphthalenecarboxylic acid in toluene in the presence of DMAP; For Example 1, Compound D.

MS (M + H) &lt; ⁺ &gt; 397.

Analysis calculated for C25H24N4O -2 HCl.

Found: C, 63.96; H, 5.58; N, 11.93.

Found: C, 62.83; H, 5.77; N, 11.13.

example

2,3,4,5-Tetrahydro-4- (1H-imidazol-4-ylmethyl) -9-methyl-1- (1-naphthalenylcarbonyl) -1H-1,4-benzodiazepine (dihydrochloride) Example compound is prepared from 9-methyl -2,3,4,5-tetrahydro-1,4-benzodiazepine according to the reaction sequence described for the preparation of the following compounds: Compound A of Example 4; coupled with chloro-anhydrides of 1-naphthalenecarboxylic acid using triethylamine in methylene chloride: Boc is cleaved in 4N HCl in dioxane; Example 1 for compound D; Chromatography (silica gel, flash chromatography, 9/1 CHCl 3 / CH 3 OH) followed by treatment with 1M HCl in ether and purification with ether afforded Example 19 as a yellow solid.

MS (M + H) &lt; ⁺ &gt; 397.

¹ H-NMR (270 MHz, CD ₃ OD) δ 9.12-8.9 (m, 1H), 8.5-8.23 (m, 1H), 8.1-7.9 (m,

3H), 7.9-7.0 (m, 7H), 5.7-5.28 (m, 1H), 4.85-4.1 (m, 3H), 4.0-3.05 ( m, 4H), 2.92,55 (m, 1H), 1.9-1.75 (s, 3H).

1 - [[2- (2-Aminoethyl) -1H-imidazol-4-yl] methyl] -2,3,4,5-tetrahydro-4- (1-naphthalenylcarbonyl) -1H-1,4-benzodiazepine (trihydrochloride)

A. [2- (2 - [[(1,1-Dimethyl) -ethoxycarbonyl] amino] ethyl) -1 - [(1,1-dimethyl) ethoxycarbonyl] -imidazol-4-yl] methanol [2- (2 -Aminoethyl) -1H-imidazol-4-yl] methanol hydrochloride was prepared as described (Buschauer, et al., Arch. Pharm., 315, 563 (1982)). To a suspension of 1.0 g of this crude material (considered 4.7 mmol) in 10 mL of DMF was added 2 mL (14.1 mmol) of triethylamine and the suspension was stirred for 0.5 h. Thereafter, 3.1 g (14.1 mmol) of BOC anhydride were added to the reaction mixture and stirred at room temperature overnight. The reaction mixture is evaporated to dryness and the residue is subjected to flash chromatography over a 100 cm ³ silica gel column. Elution with ethyl acetate gave 1.27 g (3.7 mmol, 79%) of Compound A as a viscous yellow oil.

B. [2- (2 - [[(1,1-Dimethyl) ethoxycarbonyl] amino] ethyl) -1 - [(1,1-dimethyl) ethoxycarbonyl] -imidazol-4-yl] carboxaldehyde

To a solution of 1.2 g (3.5 mmol) of Compound A in 10 ml of chloroform is added 0.9 g (10 mmol) of manganese dioxide. The reaction mixture was heated at 50 ° C with vigorous stirring. After 1, 2 there are 4 or. 0.3 g of MnO ₂ were added after heating. After 6 hours At 50 [deg.] C., the mixture is cooled to room temperature and subjected to flash chromatography on a 150 cm <^3> silica gel column without elution. Elution with 50% ethyl acetate in hexane afforded 673 mg (57%) of Compound B as a white crystalline solid.

C. 1 - [[2- (2-Aminoethyl) -1H-imidazol-4-yl] methyl] -2,3,4,5-tetrahydro-4- (1-naphthalenylcarbonyl) -1H-1,4-benzodiazepine (trihydrochloride) )

The reductive amination reaction of compound C of Example 1 with compound B is carried out according to the procedure for the synthesis of compound D as described in Example 1. The resulting oil is subjected to flash chromatography (silica gel, 50% ethyl acetate in hexanes) to give a white foam analogue of compound C, bisBoc. A solution of this material (94 mg, 0.15 mmol) in 3 mL of 4N HCl in dioxane was stirred at room temperature for 3 h. Evaporation of the solvent gave a white foam which was purified by HPLC on a YMC S5 ODS (30 x 250 mm) column. A gradient elution of 0 to 100% solvent B (A: 10% methanol: water + 0.1% TFA, B: 10% water: methanol + 0.1% TFA) is used to give an oil residue which is converted into its HCl. salt by adding methanolic HCl and evaporating the solvent. The residue was stripped of methanol twice more to give 53 mg (0.10 mmol, 66%) of Example 20 as a white solid. Lyd. mp: 165 ° C.

MS (M + H) &lt; ⁺ &gt;

Analysis calculated for C26H27N5O -3 HCl.

Found: C, 58.38; H, 5.65; N, 13.09.

Found: C, 59.01; H, 6.15; N, 13.03.

Example 1 - [[2- (2-Aminomethyl) -1H-imidazol-4-yl] methyl] -2,3,4,5-tetrahydro-4- (1-naphthalenylcarbonyl) -1H-1,4-benzodiazepine (trihydrochloride) Compound (white solid) is prepared from chloroacetonitrile and Compound C of Example 1 according to the procedure described in Example 20; melt mp: 155-160 ° C.

MS (M + H) ⁺ 412,

Analysis calculated for C25H25N5O -3 HCl.

Found: C, 57.65; H, 5.42; N, 13.45.

Found: C, 57.41; H, 5.18; N, 13.17.

example

N- [2,3,4,5-Tetrahydro-1- (1H-imidazol-4-ylmethyl) -4- (1-naphthalenylcarbonyl) 1H-1,4-benzodiazepin-8-yl] acetamide (dihydrochloride)

A. 2- [2 - [[(1,1-Dimethyl) -ethoxycarbonyl] amino] ethylamino] -4-nitrobenzoic acid to 2 - [[(1,1-dimethyl) -ethoxycarbonyl] amino] acetaldehyde (6.0 g) , 38 mmol), a solution of 4-nitroanthranilic acid (3.8 g, 19 mmol) and acetic acid (2.0 mL) in methanol (150 mL) was added portionwise to sodium cyanoborohydride (2.3 g, 38 mmol). The mixture was stirred at room temperature for 16 h, concentrated in vacuo, quenched with 1N HCl (100 mL) and extracted with CH ₂ Cl ₂ (3 x 100 mL). The combined organic extracts were dried (MgSO ₄ ), filtered and concentrated in vacuo. The residue was purified by flash chromatography (19/1 / 0.05 CHCl ₃ / MeOH / AcOH) to give Compound A (4.4 g, 72%) as a solid. MS: (M + H) ⁺ 326.

B. 2 - [(2-Amino] ethylamino] -4-nitrobenzoic acid to compound B (2.8 g, 8.6 mmol) at room temperature was added to anhydrous HCl in dioxane (4M, 20 mL, 80 mmol) and the mixture was stirred for 2 h. Concentrate the solution in vacuo and purify the residue with diethyl ether to give Compound B (2.1 g, 84%) as a solid, MS: (M + H) ⁺ 226.

C. 8-Nitro-2,3-dihydro-1H-1,4-benzodiazepin-5-one To a solution of compound B (1.0 g, 3.4 mmol) in DMF (12 mL) was added diphenylphosphorylazide (1) at room temperature. , 1 mL, 5.0 mmol). The mixture was stirred for 10 min, N-methylmorpholine (1.3 mL, 12 mmol) was added and the mixture was stirred at room temperature for 5 h. The reaction was then quenched with 10% LiCl / 10% NaHCO ₃ (100 mL) and the aqueous solution was extracted with ethyl acetate (5 x 50 mL). The combined organic extracts were washed with 10% LiCl (2x60 mL), dried (MgSO ₄ ), filtered, and concentrated in vacuo. The residue was triturated with petroleum ether and diethyl ether to give Compound C (0.42 g, 61%) as a solid. MS: (M + CH ₃ CN + H) ⁺ 249.

D. 8-Nitro-2,3,4,5-tetrahydro-1H-1,4-benzodiazepine

A solution of Compound C (0.42 g, 2.0 mmol) in THF (5 mL) was added dropwise at 0 ° C to borane dimethyl sulfide (10 M, 1.2 mL, 12 mmol). The mixture is warmed to room temperature and refluxed for 2 hours. The mixture was then cooled to 0 ° C, methanol (10 mL) was carefully added, and the solution was saturated with anhydrous HCl. The mixture was refluxed for 1 h, concentrated in vacuo and the residue triturated with diethyl ether. Compound D (0.34 g, 65%) was obtained as a solid. MS: (M + H) &lt; ⁺ &gt; 194.

E. 8-Nitro-2,3,4,5-tetrahydro-4- (1-naphthalenylcarbonyl) -1H-1,4-benzodiazepine

Compound E is prepared from compound D and 1-naphthalenecarboxylic acid anhydride according to the procedure described in Example 2 for the synthesis of compound C with stirring for 16 hours. MS: (M + CH ₃ CN + H) ⁺ 389.

F. 2,3,4,5-Tetrahydro-1- (1H-imidazol-4-ylmethyl) -4- (1-naphthalenylcarbonyl) -8-nitro-1H-1,4-benzodiazepine

Compound F is prepared from Compound E according to the procedure described in Example 1 for the synthesis of Compound D, except that the solvent is methanol and the free base is used in the following reaction. MS (M + H) &lt; ⁺ &gt;

G. 2,3,4,5-Tetrahydro-1- (1H-imidazol-4-ylmethyl) -4- (1-naphthalenylcarbonyl) -8-amino-1 H -1,4-benzodiazepine, Compound F (0.13 g, 0.29 mmol) in ethanol, water and nearly. To a mixture of HCl (500/50/1) (26 mL) was added iron powder (0.15 g, 2.6 mmol) at room temperature. The mixture was refluxed for 3 h, cooled to room temperature, filtered and the filtrate concentrated in vacuo, the residue was dissolved in CH 2 Cl 2 (100 mL), washed with 1N NaOH (100 mL) and the aqueous layer was re-extracted with CH 2 Cl 2 (2x100 mL). The combined organic extracts were dried (MgSO ₄ ), filtered, and concentrated in vacuo to give G (0.60 g, 52%) as a solid. Compound G is used without further purification.

H. N- [2,3,4,5-Tetrahydro-1- (1H-imidazol-4-ylmethyl) -4- (1-naphthalenylcarbonyl) -1H-1,4-benzodiazepin-8-yl] acetamide (dihydrochloride)

To a solution of compound G (0.050 g, 0.13 mmol) and acetic anhydride (0.024 mL, 0.25 mmol) in CH ₂ Cl ₂ (2 mL) was added 4-dimethylaminopyridine (0.005 g) at room temperature. The mixture was stirred for 16 h, quenched with 10% NaHCO ₃ (1 mL) and MeOH (0.50 mL), and stirred at room temperature for 15 min. The mixture was diluted with water (5 mL) and the solution was extracted with CH ₂ Cl ₂ (3x50 mL). The combined organic extracts were dried (MgSO ₄ ), filtered, and concentrated in vacuo. The residue was purified by flash chromatography (19/1 / 0.01 CHCl ₃ / MeOH / NH ₄ OH) and the required fractions concentrated in vacuo. The residue was dissolved in MeOH (5 mL), treated with 1N HCl (2 mL), filtered through a millipolar filter, and lyophilized to give Example 22 (0.018 g, 32%) as a solid. MS (M + H) ⁺ 440.

Analysis calculated for C26H25N5O2 -1.16 HCI -2.0 CH ₃ OH.

Found: C, 59.35; H, 5.80; N, 12.74.

Found: C, 59.35; H, 5.81; N, 12.22.

2,3,4,5-Tetrahydro-1- (1H-imidazol-4-ylmethyl) -4- (1-naphthalenylcarbonyl) -1H-pyrido [2,3-e] -1,4-diazepine (trihydrochloride)

A. 2,3,4,5-Tetrahydro-1H-pyrido [2,3-e] -1,4-diazepin-5-one

A solution of 2-chloronicotinamide (4.0 g, 25.5 mmol) in ethylenediamine (25 mL) was refluxed for 24 h. To this solution was added 5N NaOH (5.1 mL, 25.5 mmol) and the mixture was concentrated in vacuo. The crude material was chromatographed (silica gel, 5-20% CH3OH / CHCl3) to give Compound A (339 mg, 8%) as a yellowish solid. MS (M + H + CH ₃ CN) ⁺ 205.

B, 2,3,4,5-Tetrahydro-1 H -pyrido [2,3-b] -1,4-diazepine is added to a solution of compound A (100 mg, 0.61 mmol) in dry toluene (15 mL) with diisobutylaluminum hydride ( 1M in hexanes, 3.1 mL, 3.1 mmol). The mixture is refluxed for 36 hours. After 12 and after 24 or. DiBAH is added again (3.1 ml each). After 36 or so. the reaction mixture is cooled to room temperature and quenched with methanol. A viscous gel is formed which is dissolved in 1N HCl. The mixture was extracted with EtOAc (15 mL) and the organic layer was separated. The aqueous layer was basified with 5N NaOH and extracted with 10% i-PrOH / CH ₂ Cl ₂ (5 x 15 mL). The organic layers were combined, dried over Na ₂ SO ₄ and concentrated in vacuo to give Compound B (79 mg, 87%) which was used crude. MS (M + H + CH ₃ CN) ⁺ 191.

C. 2,3,4,5-Tetrahydro-4- (1-naphthalenylcarbonyl) -1H-pyrido [2,3-e] -1,4-diazepine, Compound B (79 mg, 0.53 mmol), 1-naphthalenecarboxylic acid (115.5 mg, 0.67 mmol), EDC (128.4 mg, 0.67 mmol) and HOBt (90.5 mg, 0.67 mmol) in anhydrous DMF (2 mL) were added diisopropylethylamine (0.1 ml, 0.67 mmol). After 3 or. the reaction mixture was diluted with EtOAc (5 mL) and washed with 10% LiCl. The organic layer was washed with 1N HCl and separated. The aqueous layer was basified with 5N NaOH and extracted with EtOAc (5x5 mL). The five organic layers were combined, dried over Na ₂ SO _4, and concentrated. The crude material was chromatographed (silica gel, 0-5% CH ₃ OH / CHCl ₃ ) to give Compound C (96 mg, 60%) as a brown oil. MS (M + H + CH ₃ CN) ⁺ 345.

D. 2,3,4,5-Tetrahydro-1- (1H-imidazol-4-ylmethyl) -4- (1-naphthalenylcarbonyl) -1H-pyrido [2,3-e] -1,4-diazepine (trihydrochloride) a solution of compound C (30 mg, 0.10 mmol) and 4-formylimidazole (14.5 mg, 0.50 mmol) in dichloroethane (0.5 mL) and acetic acid (0.25 mL) was added NaBH (OAc) ₃ ( 29.7 mg, 0.14 mmol). The mixture was stirred at room temperature for 12 hours. and at 80 ° C for 12 hours. 4-Formylimidazole (14.5 mg, 0.50 mmol) and NaBH (OAc) ₃ (30 mg, 0.14 mmol) were added again and the reaction mixture was heated at 80 ° C for a further 24 h. The reaction mixture was cooled to room temperature, diluted with EtOAc (2 mL) and NH ₄ OH (almost 2 mL) was added. After stirring for 3 h, NaHCO ₃ (saturated solution, 3 mL) and EtOAc (5 mL) were added. The layers were separated and the aqueous layer was extracted with EtOAc (3x5 mL). The organic layers were combined and washed with NH ₄ Cl (saturated solution, 5 mL), dried over Na ₂ SO _4, and concentrated in vacuo. The crude material was dissolved in methanol (2 mL) and purified by HPLC (YMC S5 ODS 30x250 mm column, solvent A: 10% MeOH / H ₂ O w / w 0.1% TFA, solvent B: 90% MeOH / H ₂ O mass / 0.1% TFA, gradient: 0-100% B in Solvent A over 60 min at 25 mL / min, controlled at 220 nm). The fractions containing product are mixed, concentrated in vacuo, and the residue is dissolved in 1N

HCl and lyophilized, redissolved in water and lyophilized. Example 23 is obtained as a fluffy solid (4 mg, 8%). ¹ H-NMR (CD ₃ OD, 400 MHz) δ 8.87 (d, J 1 = 1.3, 0.5H), 8.70 (d, J 1 = 1.3 0.5H), 8.06 ( dd, J 1 = 1.7, J ₂ = 5.6, 0.5H), 7.96 (d, J 1 = 6.8, 0.5H), 7.83-7.91 (m, 2 , 5H), 7.60 (d, J ₁ = 1.3, 0.5H), 7.52 (dd, J 1 = 1.7, J ₂ = 7.3, 0.5H), 7.34- 7.49 (m, 4H), 7.26 (dd, J 1 = 1.3, J ₂ = 7.6, 0.5H), 7.11 (dd, J 1 = 1.3, J ₂ = 7,1,0,5H), 7.05 (dd, Ji = 5.6, J ₂ = 7.3, 0.5H), 6.57 (d, J = 7.3, 0.5H) 6.52 (dd, J = 5.6, J ₂ = 7.7, 0.5H), 5.01 (d, J = 1.3, 1H), 4.95 (d, Ji = 1 , 3, 1H), 4.39-4.57 (m, 1.5H), 4.084.13 (m, 1H), 3.88-3.94 (m, 1H), 3.53-3.65 (m, 1.5H), 3.42-3.45 (m, 1H); MS (M + H) &lt; ⁺ &gt; 384.

example

2,3,4,5-Tetrahydro-1- (1H-imidazol-4-ylmethyl) -4- (1-naphthalenylcarbonyl) -1H-naphtho [2,3-e] -1,4-diazepine (dihydrochloride)

A. 2H-3,1-Naphthoxazine-2,4 (1 H) -dione in a ice-cooled suspension of 25 g (10.7 mmol) of 80% 2-amino-3-naphthalenecarboxylic acid and 2.5 g (8.5 mmol) of triphosgene. of acetonitrile under argon was added dropwise 0.35 mL (25 mmol) of triethylamine. Stir until the ice bath reaches room temperature and then stir overnight at room temperature. 2 ml of methanol are then added to the resulting suspension and stirred for an additional hour. Filtration of the solid gave 2.5 g (assuming a 100% yield) of Compound A, which was a brownish powder.

B. 2,3,4,5-Tetrahydro-1- (1H-imidazol-4-ylmethyl) -4- (1-naphthalenylcarbonyl) -1H-naphtho [2,3-e] -1,4-diazepine (dihydrochloride) Example compound (off-white amorphous solid) is prepared from Compound A according to the reaction sequence to give Compound A of Example 1, boiling for 10 hours; Compound B of Example 2, except that THF is used as solvent and the product: bornan complex is cleaved by boiling with aqueous HCl; Compound C of Example 2, except that 50% ethyl acetate in hexane was used for chromatography; Example 1 Compound D, and the product was purified by preparative HPLC (YMC S5 ODS (30 x 250 mm column, gradient elution 40 to 100% solvent B (A: 10% methanol: water + 0.1% TFA, B: 10% water: methanol) + 0.1% TFA) and converted to the HCl salt with HCl-MeOH.

Analysis calculated for C ₂₈ H ₂₄ N ₄ O -1.5 HCl -0.25 H ₂ O.

Found: C, 68.39; H, 5.33; N, 11.39.

Found: C, 68.41; H, 5.46; N, 11.31.

2,3,4,5-Tetrahydro-1- (1H-imidazol-4-ylmethyl) -4- (1-naphthalenylcarbonyl) -8nitro-1H-1,4-benzodiazepine (dihydrochloride)

To a solution of Example 22 Compound E (0.50 g, 1.43 mmol), 4-formylimidazole (0.41 g, 4.3 mmol) and AcOH (4 mL) in CH ₂ Cl ₂ (4 mL) was added sodium triacetoxyborohydride ( 0.91 g, 4.3 mmol). After stirring for 15 h, the mixture was diluted with CH ₂ Cl ₂ (10 mL), NH ₄ OH (5 mL) and NaHCO ₃ (5 mL) and stirred for 30 min. The layers were separated and the aqueous layer was extracted with CH ₂ Cl ₂ ( ₂ x 50 mL). The combined organic layers were dried over MgSO ₄ , filtered, and concentrated. The product was purified by chromatography on a silica gel column eluting with 19/1 CHCl ₃ / CH ₃ OH to give Example 25 (0.52 g, 85%) as a yellowish solid. (The compound of Example 25 is also the compound F of Example 22).

MS (M + H) &lt; ⁺ &gt;

2,3,4,5-Tetrahydro-1- (1H-imidazol-4-ylmethyl) -4- (1-naphthalenylcarbonyl) -8amino-1H-1,4-benzodiazepine (dihydrochloride)

To a solution of Example 25 (0.10 g, 0.23 mmol) in AcOH / H ₂ O (2 mL, 1: 1) was added 16% aqueous TiCl ₃ (2 mL). After stirring for 15 min, the reaction mixture was basified with 1N NaOH and NaHCO ₃ and stirred for 30 min. The layers were separated and the aqueous layer was extracted with CHCl ₃ / CH ₃ OH (9/1). The combined organic layers were dried over MgSO ₄ , filtered, and concentrated to give 0.92 g (73%) of Example 26. A 20 mg sample of this material is treated with 1M HCl in ether (2 mL). A yellowish solid is formed which is triturated several times with ether, dried in vacuo to give Example 26 (23 mg) as a yellowish solid. (The compound of Example 26 is also the compound of Example 22, G).

MS (M + H) &lt; ⁺ &gt; 398.

N- [2,3,4,5-Tetrahydro-1- (1H-imidazol-4-ylmethyl) -4- (1-naphthalenylcarbonyl) -1H-1,4-benzodiazepin-8-yl] benzamide (dihydrochloride) To a solution of Example 26 (0.042 g, 0.10 mmol) in CH ₂ Cl ₂ (1 mL) and triethylamine (0.01 g, 0.016 mL) at 0 ° C was added benzoyl chloride (0.016 g, 0.013 mL). After stirring for 2 h, the mixture was diluted with NaHCO ₃ (2 mL) and CHCl ₃ (10 mL). The layers were separated and the aqueous layer was extracted with CHCl ₃ (2 x 20 mL). The combined organic layers were dried over MgSO ₄ , filtered, and concentrated. The residue was purified by flash column chromatography on silica gel eluting with CHCl ₃ / CH ₃ OH (9/1). The product was treated with 1M HCl in ether (2 mL). A yellowish solid is formed which is triturated several times with ether, dried in vacuo to give Example 27 (0.015 g, 28%) as a yellowish solid.

MS (M + H) ⁺ 502.

IR: (KBr) 3434, 2930, 1611, 1508, 1424, 1263 cm @ ^-1 .

example

Example of N- [2,3,4,5-Tetrahydro-1- (1H-imidazol-4-ylmethyl) -4- (1-naphthalenylcarbonyl) -1H-1,4-benzodiazepin-8-yl] cyclohexanamide (dihydrochloride) The compound is prepared from the compound of Example 26 and cyclohexanecarbonyl chloride according to the procedure described in Example 27. The crude product is exposed directly to HCl / ether. The yellow solid, which is formed by repeated trituration with ether, is dried in vacuo to give Example 28 as a yellow solid. Yield 90%. MS (M + H) ⁺ 508.

IR: (KBr) 3434, 2930, 1611, 1508, 1424, 1263 cm @ ^-1 .

2,3,4,5-Tetrahydro-1- [2- (1H-imidazol-4-yl) ethyl] -4- (1-naphthalenylcarbonyl) -1H1,4-benzodiazepine (dihydrochloride)

A. 2,3,4,5-Tetrahydro-1- [1-oxo-2- (1-triphenylmethyl-imidazol-4-yl) -ethyl] -4 - [(1,1-dimethylethoxy) carbonyl] -1H-1 , 4-Benzodiazepine

To a solution of 250 mg (0.68 mmol) of N-triphenylmethyl-4-imidazolactic acid and 94 μΙ (0.68 mmol) of triethylamine in 3 mL of THF at -30 ° C was added 97 μΙ (0.75 mmol) of isobutyl chloroformate. Stir for 10 min and add a solution of 253 mg (1.02 mmol) of Example 4 Compound A in 1 mL THF. After warming to room temperature, the mixture was stirred for 7 h, then diluted with ethyl acetate. The solution was washed with saturated NaCl, saturated NaHCO ₃ , again with saturated NaCl, dried (MgSO ₄ ) and concentrated. The resulting oil was subjected to flash chromatography (silica gel, 75% ethyl acetate: hexanes) to give 195 mg (0.33 mmol, 48%) of Compound A as a white foamy solid.

B. 2,3,4,5-Tetrahydro-1- [2- (1H-imidazol-4-yl) ethyl] -4- (1,1-dimethylethoxy) carbonyl] -1H-1,4-benzodiazepine

To a solution of 100 mg (0.17 mmol) of Compound A in 1 mL of THF under argon was added 1 mL (1 mmol) of 1M borane in THF. When the foaming ceases, the mixture is heated to 60 ° C for 1 hour. and cooled to room temperature. Comes with machine. HCl (0.5 mL), warm to 60 ° C for 1 h. and evaporated to dryness. The residue was diluted with water, washed twice with ethyl acetate, basified with 40% KOH in water and extracted with methylene chloride (3x). The combined methylene chloride extracts were washed with saturated NaCl (2x), dried (MgSO ₄ ) and evaporated to give 39 mg of a viscous oil. This material was subjected to flash chromatography (silica gel, CHCl ₃ : MeOH: NH ₄ OH 80: 20: 2) to give 16 mg (0.066 mmol, 40%) of compound B as an oil.

C. 2,3,4,5-Tetrahydro-1- [2- (1H-imidazol-4-yl) ethyl] -4- (1-naphthalenylcarbonyl) -1H-1,4-benzodiazepine (dihydrochloride)

Compound C is prepared from Compound B (30 mg, 0.12 mmol) according to the procedure for preparation of Compound C described in Example 23 with stirring for 18 hours. The mixture is evaporated to dryness, and the residue is chromatographed on flash silica gel (10% methanol: chloroform) to give 33 mg of material which is purified by preparative HPLC over a YMC S5 ODS (30 x 250 mm) column. A gradient elution of 30 to 100% solvent B (A: 10% methanol: water + 0.1% TFA, B: 10% water: methanol + 0.1% TFA) gives a clear glassy residue which is converted to the HCl salt with HCl-MeOH; 20 mg (0.04 mmol, 36%) of Example 29 is obtained which is a solid foam.

MS (M + H) &lt; ⁺ &gt; 397.

Analysis calculated for C25H24N4O · HCl 2 -1.5 H ₂ O.

Found: C, 60.48; H, 5.89; N, 11.28.

Found: C, 60.69; H, 5.63; N, 11.12.

2,3,4,5-Tetrahydro-1- [2- (1H-imidazol-4-yl) ethyl] -4- (1-naphthalenylcarbonyl) -7-phenyl-1H-1,4-benzodiazepine (dihydrochloride)

A. 2,3,4,5-Tetrahydro-4 - [(1,1-dimethylethoxy) carbonyl] -7-phenyl-1H-1,4-benzodiazepine in Example 12 Compound B (5.2 g, 23 mmol) in THF (50 mL) was added di-tert-butyl dicarbonate (6.1 g, 28 mmol). The mixture was stirred at room temperature for 2 hours and concentrated in vacuo. The residue was purified by flash chromatography (silica gel, ethyl acetate) to give compound A as an oil (5.7 g, 91%). MS: (M + H) ⁺ 325.

B. Example of 2,3,4,5-Tetrahydro-1- [2- (1H-imidazol-4-yl) ethyl] -4- (1-naphthalenylcarbonyl) -7-phenyl-1H-1,4-benzodiazepine (dihydrochloride) Compound A is prepared from Compound A according to the following 3-step procedure used to prepare the following compounds: Compound A of Example 29; Example 29 Compound B under reflux for 4 hours. and excess borane by decomposition with methanol: Compound B of Example 3 under stirring at room temperature for 2 hours. and flash chromatography on silica gel eluting with 10% methanol in chloroform followed by preparative HPLC (YMC S5 ODS (30 x 250 mm) column: gradient elution from 40 to 100% solvent B (A: 10% methanol: water + 0). 1% TFA, B: 10% water: methanol + 0.1% TFA), the clear glass residue is converted to the HCl salt by treatment with HCl-MeOH to give Example 30 as a foamy solid.

MS (M + H) ⁺ 473.

Analysis calculated for C ₂ iH 8N ₃ O ₄ -2.15 HCl -1 H ₂ O.

Found: C, 65.44; H, 5.69; N, 9.85.

Found: C, 65.56; H, 5.26; N, 9.40.

Example 7 7-Bromo-2,3,4,5-tetrahydro-1- [2- (1H-imidazol-4-yl) ethyl] -4- (1-naphthalenylcarbonyl) -1H-1,4-benzodiazepine (dihydrochloride) is prepared. from 7-bromo-1,4-benzodiazepine (prepared according to the synthesis procedure for compound B described in Example 11) according to the procedures used to obtain the following compounds: Compound A of Example 4; Example 29 to compound A with stirring for 2 hours. and ethyl acetate for chromatography; Example 29 Compound B, under borane reduction, was refluxed for 3 hours and treated with HCl at 60 ° C for 2 hours. and chloroform used in chromatography: methanol: NH ₄ OH (90: 10: 1); Compound C of Example 23 was chromatographed on silica gel with 20% methanol in chloroform and preparative HPLC using a 40-100% gradient B, MS (M + H) ⁺ 475.

Analysis calculated for C ₂₅ H ₂₃ N ₄ OBr -2 HCl -0.35 H ₂ O.

Found: C, 55.41; H, 4.67; N, 9.79.

Found: C, 55.55; H, 4.53; N, 10.00.

1 - [[1- (2-Aminoethyl) -1H-imidazol-5-yl] methyl] -2,3,4,5-tetrahydro-4- (1-naphthalenylcarbonyl) -7-phenyl-1 H -1,4-benzodiazepine (trihydrochloride)

A. 1 - [[1 - [(1,1-Dimethylethoxy) carbonyl] -1H-imidazol-4-yl] methyl] -2,3,4,5-tetrahydro-4- (1-naphthalenylcarbonyl) - 7-phenyl-1H-1,4-benzodiazepine

A solution of 150 mg (0.33 mmol) of Example 12, 144 mg (0.66 mmol) of di-t-butyl dicarbonate and 5 mg of dimethylaminopyridine in 2 mL of methylene chloride was stirred under argon overnight. The crude mixture was subjected to flash chromatography (silica gel, 50% ethyl acetate in hexanes) to afford 142 mg (0.25 mmol, 77%) of Compound A as a white foam.

B. 1 - [[1- (2- (N-Phthalimidoethyl) -1H-imidazol-5-yl] methyl] -2,3,4,5-tetrahydro-4- (1-naphthalenylcarbonyl) -7-phenyl-1 H- 1,4-Benzodiazepine

A solution of 0.5 g (2.6 mmol) of N-hydroxyethylphthalimide and 315 μΙ (3.9 mmol) of pyridine in 5 mL of methylene chloride under argon was added dropwise to a solution of 527 μ 3 (3.1 mmol) of trifluoromethanesulfonic anhydride in 5 mL of methylene chloride. Stirring is continued for another 0.5 h, followed by -1 h at room temperature. A large amount of friable sediment forms. The reaction mixture was hydrolyzed by adding ice and stirred for 10 min. The organic layer was washed with 5% NaHSO ₄ and saturated NaCl, dried (MgSO ₄ ), and evaporated the solvent to give 615 mg (1.9 mmol, 73%) of trifluoromethanesulfonate as a white solid. A solution of this trifluoromethanesulfonate (44 mg, 0.13 mmol) and 75 mg (0.13 mmol) of Compound A in 1.5 mL of methylene chloride was stirred overnight under argon. The crude mixture was subjected to flash chromatography (silica gel, ethyl acetate followed by 10% methanol in chloroform) to give 41 mg (0.065 mmol, 50%) of Compound B as a white foam.

C. 1 - [[1- (2-Aminoethyl) -1H-imidazol-5-yl] methyl] -2,3,4,5-tetrahydro-4- (1-naphthalenylcarbonyl) -7-phenyl-1H-1, A solution of 4-benzodiazepine (trihydrochloride) mg (0.095 mmol) in Compound C and 100 μΙ hydrazine in 0.5 mL methanol was stirred overnight under argon. The resulting precipitate is filtered off and the clear colorless filtrate is chromatographed on preparative HPLC over a YMC S5 ODS (30 x 250 mm) column. A gradient elution of 25 to 100% solvent B (A: 10% methanol: water + 0.1% TFA, B: 10% water: methanol + 0.1% TFA) gives a white solid which is converted to the HCl salt, HCl MeOH to give 11 mg (0.18 mmol, 19%) of Example 32 which is an amorphous yellowish solid.

MS (M + H) ⁺ 502.

¹ H-NMR (270 MHz, CD ₃ OD, rotamer / conformer mixture): δ 3.00 (1H, m),

3.43 (2H, m), 3.57 (2H, m), 4.09 (1H, m), 4.20 (1H, m), 4.50 (1H, m), 4.59 (1H ,

m), 4.72 (2H, m), 5.02 (1H, m), 6.09 (1H, s), 7.03 (1H, m), 7.22-8.05 (13H, m) ), 9.12 and 9.18 (1H, m).

IR (KBr): 764, 781, 1144, 1487, 1510, 1609, 2924, 3418 cm @ ^-1 .

2,3,4,5-Tetrahydro-1- (1H-imidazol-4-ylmethyl) -7-phenyl-1H-1,4-benzodiazepine, 4-carboxylic acid (phenylmethyl ester)

A. 2,3,4,5-Tetrahydro-1- (1H-imidazol-4-ylmethyl) -4 - [(1,1-dimethylethoxy) carbonyl] -7-phenyl-1H-1,4-benzodiazepine

A solution of Example 30 Compound A (4.6 g, 14 mmol) and 4-formylimidazole (2.7 g, 28 mmol) in 1: 1 methylene chloride / AcOH (40 mL) was treated with sodium triacetoxyborohydride (4.5 g) at room temperature. 21 mmol). The mixture was stirred at room temperature for 16 hours. and concentrated in vacuo. The residue was dissolved in methylene chloride (100 mL) and 1/1 1N NaOH / NH ₄ OH (100 mL) and the mixture was stirred at room temperature for 16 h. The organic layer was separated and the aqueous layer was extracted with methylene chloride (3 x 50 mL). The combined organic extracts were dried (MgSO ₄ ), filtered and concentrated in vacuo. Purification of the residue by flash chromatography (19/1 CHCl ₃ / MeOH) afforded Compound A (5.7 g, 100%) as a solid. MS: (M + H) ⁺ 405.

B. 2,3,4,5-Tetrahydro-1- (1H-imidazol-4-ylmethyl) -7-phenyl-1H-1,4-benzodiazepine, to compound A (2.0 g, 5.0 mmol) was added with anhydrous HCl (4M, 20 mL, 80 mmol) in dioxane. The mixture was stirred at room temperature for 4 hours. and concentrated in vacuo. The residue was dissolved in water (10 mL) and 1N NaOH (15 mL) was added. The solution was extracted with methylene chloride (4 x 75 mL), the combined organic extracts dried (MgSO ₄ ), filtered and concentrated in vacuo to give Compound B (1.45 g, 97%) as a solid. MS: (M + H) ⁺ 305.

C. 2,3,4,5-Tetrahydro-1- (1H-imidazol-4-ylmethyl) -7-phenyl-1H-1,4-benzodiazepine-4-carboxylic acid (phenylmethyl ester) in Compound B (O, To a solution of 2 M, 1.0 mL, 0.16 mmol) in DMF was added pnitrophenylbenzyl carbonate (0.04 g, 0.16 mmol). The mixture was stirred at room temperature for 3 h, diluted with ethyl acetate (50 mL) and washed with 10% LiCl (50 mL). The aqueous layer was extracted with ethyl acetate (2 x 50 mL). The organic fractions were combined, washed with 10% LiCl (2 x 50 mL), dried (MgSO ₄ ), filtered and concentrated in vacuo. After purification of the residue by flash chromatography (19/1 / 0.05)

CHCl 3 / MeOH / AcOH) to give Example 33 (0.07 g, 93%) as a white solid.

MS (M + H) ⁺ 439.

Analysis calculated for C27H26N4O2 0.05 H ₂ O.

Found: C, 72.52; H, 6.08; N, 12.53.

Found: C, 72.51; H, 5.85; N, 12.47.

example e

N

H

N

O OCF ₃

2,3,4,5-Tetrahydro-1- (1H-imidazol-4-ylmethyl) -7-phenyl-4- [2- (trifluoromethoxy) benzoyl] -1H-benzodiazepine

A solution of HOAt (0.014 g, 0.10 mmol) in DMF (0.5 mL) was added at room temperature to the o-trifluoromethoxybenzoic acid (0.021 g, 0.10 mmol). To this mixture was added a solution of Example 33 Compound B (0.2 M, 0.50 mL, 0.16 mmol) in DMF and diisopropylcarbodiimide (DIC, 0.013 mL, 0.10 mmol, 1.0 equiv.), And the mixture was stirred at room temperature. at 16 hours. The mixture is purified by ion-exchange chromatography over a solid phase extraction column using the following sequence of operations:

1) Varian solid phase extraction column (1.5 g, SCX cation exchanger) is conditioned with 10 mL MeOH / CH ₂ Cl ₂ ;

2) Inject the mixture into the column using a 10 ml syringe to maintain a constant system pressure;

3) washing the column with 3x7.5 mL of MeOH / CH ₂ Cl ₂ (1: 1);

4) washing the column with 1x 7.5 mL of 0.01 N ammonia in MeOH;

5) Elute the column with 7.5 mL of 1.0 N ammonia in MeOH and collect the eluate on a weighed collector.

The solution containing the product is concentrated using the Savant Speed Vac system (approximately 2 mm Hg, 20 hours). The residue is dissolved in a mixture of CH ₃ CN (1 ml) and water (1 ml) and lyophilized; Example 34 (0.42 g, 85%) is obtained which is a white lyophilisate.

MS (M + H) &lt; ⁺ &gt; 493.

Analysis calculated for C ₂ 7 H ₂₃ N ₄ O ₂ F ₃ -0.68 H ₂ O.

Found: C, 64.25; H, 4.86; N, 11.29. Found: C, 64.24; H, 4.83; N, 11.40.

1,2,3,5-Tetrahydro-1- (1H-imidazol-4-ylmethyl) -N-methyl-N, 7-diphenyl-4H-1,4-benzodiazepine-4-carboxamide (dihydrochloride)

A. 7-Phenyl-1,2,3,5-tetrahydro-N-methyl-N-phenyl-4H-1,4-benzodiazepine-4-carboxamide in stirring 115 mg (0.5 mmol) of Example 12 Compound B in 3 mL CH ₂ Cl ₂ and 2.5 mL of 1N NaOH at 0 ° C for 3 min. a solution of 94 mg (0.55 mmol) of N-methyl-N-phenylcarbamyl chloride in 1.5 mL of CH ₂ Cl _{2 was added} . After 1.5 or. the reaction mixture is diluted with CH ₂ Cl ₂ and water and the layers are separated. The aqueous layer was extracted with CH ₂ Cl ₂ (2x), the combined organic layers dried (Na ₂ SO ₄ ), and concentrated to give 177 mg (99%) of compound A as a glass.

B. 1,2,3,5-Tetrahydro-1- (1H-imidazol-4-ylmethyl) -N-methyl-N, 7-diphenyl-4H-1,4-benzodiazepine-4-carboxamide (dihydrochloride) from compound A according to the synthesis procedure for compound D described in Example 1. Chromatographic purification (silica gel, 7% methanol, 0.5% ammonium hydroxide, 93% methylene chloride) followed by conversion to the hydrochloride salt gave the powdered compound of Example 35; melt temp .; 97-102 ° C.

MS (M + H) &lt; ⁺ &gt; 438 ⁺ .

Analysis calculated for C ₂₇ H ₂₇ N ₅ O · 1.2 HCl · 0.75 H ₂ O · 0.25 C ₄ H ₁₀ O. Calculated: C, 65.51; H, 6.32; N, 13.64; Cl, 8.29.

Found: C, 65.55; H, 5.98; N, 13.50; Cl, 8.42.

2,3,4,5-Tetrahydro-1- (1H-imidazol-4-ylmethyl) -4- (1-naphthalenecarbonyl) -7- (1-pyridine Isulfonyl) -1H-1,4-benzodiazepine ( monohydrochloride)

A. 2,3,4,5-Tetrahydro-7- (1-piperidinylsulfonyl) -1H-1,4-benzodiazepine-2,5-dione

A stirred solution of Example 1 Compound A (400 mg, 2.3 mmol) in 10 mL of chlorosulfonic acid was heated at 100 ° C for 6 h. Pour the solution into a mixture of ice and water. The aqueous suspension is extracted with ethyl acetate. The combined organic extracts were dried and filtered. The filtrate was mixed with piperidine (0.2 mL) at 0 ° C. The reaction was run for 30 min. The resulting solution was washed with 10% HCl, saturated NH ₄ Cl solution, dried and concentrated. The residue was triturated with ether to give Compound A as a white solid (250 mg, 34%). (MH) '322.

B. 2,3,4,5-Tetrahydro-7- (1-piperidinylsulfonyl) -1H-1,4-benzodiazepine

To a stirred suspension of LAH (200 mg, 5 mmol) was added compound A (185 mg, 0.57 mmol) in portions. After compounding, the mixture was heated at 80 ° C under argon for 4 h. The mixture was then cooled to 0 ° C and ethyl acetate (20 mL) was added followed by NH ₄ OH (0.3 mL). The mixture was stirred at room temperature for 18 hours. The resulting suspension is filtered. Concentration of the filtrate gave compound B which was an oil (90 mg, 53%). (MH) 295.

C. 2,3,4,5-Tetrahydro-1- (1H-imidazol-4-ylmethyl) -4- (1'-naphthalenylcarbonyl) -7- (1-piperidinylsulfonyl) -1H-1,4-benzodiazepine (monohydrochloride) Example 2 is prepared from Compound B using the 2-step procedure described for Example 2, Compound C, followed by Example 1, for Compound D.

MS (M + H) &lt; ⁺ &gt; 530 ⁺ .

Analysis calculated for C ₂ 9H3iN ₅ O ₃ S · HCl -1.1 · 0.2 toluene 0.5 C4H10O. Found: C, 62.22; H, 6.27; N, 11.20; S, 5.13; Cl, 6.23.

Found: C, 62.38; H, 6.45; N, 11.18; S, 5.23; Cl, 6.29.

2,3,4,5-Tetrahydro-1- (1H-imidazol-4-ylmethyl) -4- (1-naphthalenylcarbonyl) -7-pyridazole-2-yl-1H-1,4-benzodiazepine (trihydrochloride) )

A. 2,3,4,5-Tetrahydro-1- (1-triphenylmethyl-imidazol-4-ylmethyl) -4- (1-naphthalenylcarbonyl) -7-bromo-1H-1,4-benzodiazepine into the compound of Example 11 (6). , 83 mmol, 3.15 g) and triethylamine (34 mmol, 4.7 mL) in acetonitrile (100 mL) were added triphenylmethyl chloride (6.83 mmol, 1.9 mL).

g), and the reaction mixture is stirred for 2 hours. The resulting homogeneous yellow solution was concentrated under reduced pressure and purified by flash chromatography to give 3.9 g (81%) of Compound A as a white solid. MS (M + H) ⁺ 703.

B. 2,3,4,5-Tetrahydro-1- (1H-imidazol-4-ylmethyl) -4- (1-naphthalenylcarbonyl) -7pyridin-2-yl-1H-1,4-benzodiazepine (trihydrochloride)

Compound A (0.28 mmol, 200 mg), 2- (tert-butylstanyl) pyridine (1.4 mmol,

A mixture of 520 mg) and Pd (PPh ₃ ) ₄ (40 mg, 0.034 mmol) in degassed THF (3 mL) was heated at 75 ° C for 18 h. The reaction mixture was cooled to room temperature, diluted with 30 mL of MeOH and treated with 2.0 mL of TFA. The mixture was stirred for 12 h, concentrated, purified by preparative HPLC and converted to the HCl salt to afford 46 mg (30% of both steps) of Example 37 as a yellow solid.

MS (M + H) ⁺ 460 ⁺ .

Analysis calculated for C29H25N5O -3.09 HCl.

Found: C, 60.07; H, 4.95; N, 12.24.

Found: C, 60.72; H, 5.09; N, 12.16.

7- (2-Furanyl) -2,3,4,5-tetrahydro-1- (1H-imidazol-4-ylmethyl) -4- (1-naphthalenecarbonyl) -1H-1,4-benzodiazepine (dihydrochloride) Example Compound (green solid) was prepared (11% yield) from Example 37 Compound A and 2- (tributylstanyl) furan according to the procedure described in Example 37 for the preparation of Compound B.

MS: (M + H) &lt; ⁺ &gt; 449 ⁺ .

2,3,4,5-Tetrahydro-1- (1H-imidazol-4-ylmethyl) -4- (1-naphthalenylcarbonyl) -7- (2-thienyl) -1H-1,4-benzodiazepine (dihydrochloride) Example Compound ( green solid) prepared (10% yield) from Example 37 Compound A and 2- (tributylstanyl) thiophene according to the procedure described in Example 37 for the preparation of Compound B.

MS: (M + H) ⁺ 465.

2,3,4,5-Tetrahydro-1- (1H-imidazol-4-ylmethyl) -4- (1-naphthalenylcarbonyl) -7- (4-pyridine) -1H-1,4-benzodiazepine (trihydrochloride) 2,3,4,5-Tetrahydro-4- (1-naphthalenylcarbonyl) -7-bromo-1H-1,4-benzodiazepine (prepared according to the procedure described in Example 11, 0.26 mmol, 100 mg) and NEt ₃ (1). , 04 mmol, 150 μΙ) solution of CH ₂ Cl ₂ (5 mL) was added trifluoroacetic anhydride (0.4 mmol, 60 μΙ) and the homogeneous colorless solution was kept at room temperature for 1 h. The reaction mixture was concentrated and the residue was passed through a short silica gel column (gradient elution: 30% ethyl acetate / hexanes to pure ethyl acetate). A white solid is obtained in the form of a fluff which is used without further purification in the subsequent step. This material was dissolved in toluene (2.0 mL) along with 4- (tributylstanyl) pyridine (0.52 mmol, 190 mg) and Pd (PPh ₃ ) 4 (30 mg, 0.026 mmol), and 15 min. argon is passed through the solution. The brown homogeneous solution is heated at 115 ° C for 20 hours to give a black heterogeneous solution. The reaction mixture was concentrated, the residue was dissolved in MeOH / 2N NaOH (aq) (5 mL: 5 mL) and the solution was stirred at room temperature for 30 min. The MeOH was evaporated under reduced pressure, the reaction mixture was partitioned between 10% isopropanol / CH ₂ Cl ₂ and 2N NaOH / saturated NaCl (1: 1, 10 mL) and extracted 2x with 10% isopropanol / CH ₂ Cl ₂ (2x5 mL). The combined organic phases were dried over Na ₂ SO ₄ , concentrated, and the residue was passed through a short silica gel column (eluted with 95: 5: 1 CHCl ₃ : MeOH: TEA) to remove polar impurities, and the crude material was dissolved in 1,2-dichloroethane: AcOH (1: 1, total 2 mL) was treated with 4-formylimidazole (62 mg, 0.65 mmol) and NaBH (OAc) ₃ (0.78 mmol, 165 mg) and the mixture was heated at 55 ° C for 2 h. The reaction mixture was concentrated, partitioned between 10% isopropanol / CH ₂ Cl ₂ and 2N NaOH / saturated NaCl (1: 1, 10 mL) and extracted with 2x10% isopropanol / CH ₂ Cl ₂ (2x5 mL). The combined organic phase is concentrated, the residue is dissolved in MeOH / TFA (5 mL: 0.5 mL) and purified by preparative HPLC (YMC S5 ODS 30x250 mm: retention time = 19-21 min; gradient elution from 0 to 100% buffer B). 30 min; buffer A = MeOH: H ₂ O: TFA (10: 90: 0.1); buffer B = MeOH: H ₂ O: TFA (90: 10: 0.1); 25 mL / min). The trifluoroacetate salt is converted to the HCl salt by lyophilization with 1M HCl (2x5 mL) to give 75 mg (50% yield over 4 steps) of Example 40 as a shiny yellow solid. MS: (M + H) ⁺ 460.

2,3,4,5-Tetrahydro-1- [3- (1H-imidazol-2-yl) propyl] -4- (1-naphthalenylcarbonyl) 7-phenyl-1H-1,4-benzodiazepine (dihydrochloride)

A. 3- [lmidazol-2-yl] propanoic acid (ethyl ester) in a cooled (0 ° C) solution of sodium hydride (1.86 g, 45.8 mmol, 60% dispersion in mineral oil, washed with THF and dried over N ₂ ) 1,2-dimethoxyethane (DME, 20 mL) over 15 min. triethylphosphonacetate (12 g, 54.1 mmol) dissolved in DME (10 mL) was added dropwise. The solution is stirred for 1 hour. at room temperature, followed by the addition of 2-imidazoleacetaldehyde (4 g, 41.6 mmol) in 20 mL of DME. The solution was stirred and refluxed (85 ° C) for 15 minutes, then cooled to 60 ° C and held for 1 hour. Upon cooling, the solution is concentrated to 1/2 volume and filtered. The solid was recrystallized from methanol / ethyl acetate / hexanes to give 5.1 g (74%) of compound A as a white crystalline solid. MS (M + H) ⁺ 167 ⁺ .

B. 3- [lmidazol-2-yl] propanoic acid (ethyl ester)

A solution of Compound A (4.01 g, 24.2 mmol) in absolute ethanol (100 mL, heated to dissolve) was hydrogenated using Pd / C (0.5 g) at room temperature for 16 h. After removal of H _{2 in} vacuo, the catalyst is filtered through a pad of celite. Concentration of the filtrate in vacuo afforded 4.0 g (100%) of Compound B as a white crystalline solid. MS (M + H) &lt; ⁺ &gt; 169 ⁺ .

C. 3- [N-Triphenylmethyl-1-imidazol-2-yl] -propionic acid (ethyl ester)

Compound B is prepared from Compound A according to the procedure described in Example 6 for the synthesis of Compound A using methylene chloride as the solvent and triethylamine as the base. After treatment of the aqueous solution, recrystallization from ethyl acetate / hexanes gives compound B, which is a white microcrystalline material MS (M + H) ⁺ 411 ⁺ .

D. 3- [N-Triphenylmethyl-imidazol-2-yl] -propan-1-ol

A solution of Compound C (0.80 g, 1.95 mmol) in THF (15 mL) was cooled to 0 ° C under argon and a solution of 1M lithium aluminum hydride (2 mL, 2 mmol) was added dropwise with stirring. The reaction mixture was stirred at room temperature for 16 hours. Water (2 mL) was added slowly and the solution concentrated. Water (40 mL) and ethyl ether (60 mL) were added and the layers separated. The ether layer was dried (MgSO ₄ ) and concentrated. The residue is chromatographed (flash chromatography on silica gel, 10: 1 methylene chloride: methanol). The product-containing fractions were combined and concentrated to give 680 mg (95%) of Compound D as a white crystalline solid. MS (M + H) &lt; ^{+ &gt};.

E. 3- [N-Triphenylmethyl-imidazol-2-yl] -propanal

A solution of oxalyl chloride (0.3 mL, 0.6 mmol) in 2 mL of methylene chloride under argon was cooled to -63 ° C over 10 min. DMSO (0.056 mL, 0.8 mmol) in methylene chloride (0.5 mL) was added followed by the addition of Compound D (147 mg, 0.4 mmol) over 15 min, keeping the reaction temperature below -50 ° C. ) solution of methylene chloride (6 mL). The resulting clear solution was stirred for 50 min. At -63 ° C. A solution of triethylamine (0.25 mL, 1.8 mmol) in methylene chloride (1 mL) was added over a period of 15 min, keeping the temperature below -50 ° C. The mixture was stirred for 15 min, then 1M potassium bisulfate (4.5 mL), water (20 mL) and ethyl ether (60 mL) were added. Separate the layers, basify the aqueous layer with half-saturated aqueous sodium bicarbonate and wash with ethyl acetate (3x30 mL).

The combined organic layers were dried (MgSO ₄ ) and concentrated to give 146 mg (> 99%) of Compound E as a yellowish gum.

F. 2,3,4,5-Tetrahydro-4- (1-naphthalenylcarbonyl) -7-phenyl-1H-1,4-benzodiazepine

To a stirred solution of EDC (3.0 g, 15.63 mmol), HOBt (2.1 g, 15.63 mmol) and 1-naphthalenecarboxylic acid (2.42 g, 14.06 mmol) in DMF (20 mL) was added v A solution of compound B (3.5 g, 15.63 mmol) and N, N-diisopropylethylamine (2.73 mL, 15.63 mmol) in DMF (10 mL). The mixture was stirred for 4 h, poured into water (200 mL) and the product extracted with ethyl acetate (2 x 100 mL). The combined ethyl acetate layers were washed with water (3 x 200 mL), saturated NaCl (100 mL), dried (MgSO ₄ ), concentrated and chromatographed (silica gel, 50% ethyl acetate / hexane). The fractions containing the desired compound are collected and concentrated to give compound F, which is a clear oil (4.4 g, 93%), (M + H) ⁺ 379 ⁺ .

G. 2,3,4,5-Tetrahydro-1- [3- (1-triphenylmethyl-imidazol-2-yl) -propyl] -4- (1-naphthalenylcarbonyl) -7-phenyl-1H-1,4-benzodiazepine

Compound E (109 mg, 0.29 mmol) and compound F (100 mg, 0.26 mmol) were dissolved in 1,2-dichloroethane (10 mL). Acetic acid (0.1 mL) was added followed by sodium triacetoxyborohydride (84 mg, 0.40 mmol). The mixture was stirred at 50 ° C for 2 hours. Saturated NaHCO ₃ (10 mL) was added and the mixture was concentrated and partitioned between ethyl acetate (50 mL) and water (20 mL). The organic layer was separated, dried (MgSO ₄ ), concentrated and chromatographed (silica gel, 40% ethyl acetate / hexane). The fractions containing the desired compound are collected and concentrated to give compound G, which is a clear glass material (100 mg, 47%), (M + H) ⁺ 729 ⁺ .

H. 2,3,4,5-Tetrahydro-1- [3- (1H-imidazol-2-yl) propyl] -4- (1-naphthalenylcarbonyl) -7-phenyl-1H-1,4-benzodiazepine (dihydrochloride)

A solution of compound G (70 mg, 0.096 mmol) in methylene chloride (7 mL), TFA (7 mL), and triethylsilane (0.36 mg, 0.50 mL, 0.31 mmol) was stirred for 30 min. at room temperature. The mixture was concentrated and the residue was dissolved in methylene chloride (60 mL) and concentrated. This procedure is repeated five times to give the crude product which is a white sticky solid (quantitative yield). This crude material was purified by preparative HPLC (YMC S-5 ODS-A column, 30 x 250 mm; solvent A, 0.1% TFA in 90% water / 10% methanol; solvent B, 0.1% TFA in 10% water and 90%). % methanol in the mixture; 20-100% B in 60 min; flow rate 25 mL / min). The fractions containing the desired product are mixed, concentrated and lyophilized. The lyophilisate was dissolved in methanol (0.5 mL) and 1N HCl (5 mL).

This mixture is concentrated and lyophilized. Repeat this procedure to give Example 41 as a white solid (15 mg, 28%).

MS (M + H) &lt; ⁺ &gt; 487 ⁺ .

¹ H-NMR (CD ₃ OD, 400 MHz) δ 8.05-7.00 (16H, m), 6.20 (1H, m), 4.47-4.26 (2H, dd, J = 15 , 0), 4.17 (1H, m), 4.08 (1H, m), 3.48 (1H, m), 3.43 (1H, m), 3.33 (1H, m) ), 3.12 (1H, t), 3.06 (1H, t), 2.98 (1H, m), 2.16 (1H, sq), 2.04 (1H, s) .

example

Br

7-Bromo-2,3,4,5-tetrahydro-4- (1H-imidazol-4-ylmethyl) -1- (1-naphthalenylcarbonyl) -1H-1,4-benzodiazepine (dihydrochloride) Example Compound (off-white solid) ) prepared from 7-bromo-1,4-benzodiazepine (prepared according to the synthesis procedure for compound B described in Example 1) using the procedure described for the preparation of such compounds; Example 4 for compound A; Compound B of Example 4; Example 4 for compound C; For compound D of Example 1, purification using methylene chloride as a solvent by preparative HPLC (YMC S-5 ODS 30x250 mm; gradient elution from 0 to 100% buffer B over 45 min; buffer A = MeOH: H ₂ O: TFA (10:90 : 0.1); buffer B = MeOH: H ₂ O: TFA (90: 10: 0.1); 25 mL / min) and converted to the HCl salt by lyophilization from 1M HCl. MS (M + H) ⁺ 462. ¹ H-NMR (CD ₃ OD): 3.5 (ppm, 2H), 3.80 (m, 2H), 4.80 (ppm, 2H), 5.30 (m, 2H), 6.60 (m, 1H), 7.15-8.15 (m, 11H), 9.10 (s, 1H).

example

8-Chloro-2,3,4,5-tetrahydro-4- (1H-imidazol-4-ylmethyl) -1- (1-naphthalenylcarbonyl) -1H-1,4-benzodiazepine (dihydrochloride) Example Compound (off-white solid) prepared from Example 2 Compound B according to the procedure described in Example 42, MS (M + H) ⁺ 459. ¹ H-NMR (CD ₃ OD): 3.40-3.80 (m.p., 4H), 4.4 ( pi, 2H), 4.7 (pi, 2H), 5.20 (pi, 2H), 6.65 (d, 1H), 7.00-8.15 (m, 16H), 9, 00 (s, 1H).

example

2,3,4,5-Tetrahydro-4- (1H-imidazol-4-ylmethyl) -1- (1-naphthalenylcarbonyl) -7-phenyl-1H-1,4-benzodiazepine (hydrochloride) Example compound (off-white solid) ) is prepared from Example 12 Compound B according to the procedure described in Example 42. MS (M + H) ⁺ 459. ¹ H-NMR (CD ₃ OD): 3.40-3.80 (m.p., 4H), 4.4 (pi, 2H), 4.7 (pi). , 2H), 5.20 (pi, 2H), 6.65 (d, 1H), 7.00-8.15 (m, 16H), 9.00 (s, 1H).

2,3,4,5-Tetrahydro-1,4-bis (1H-imidazol-4-ylmethyl) -7-phenyl-1H-1,4-benzodiazepine (dihydrochloride) Example compound (off-white solid) is prepared from the sample. of compound B according to the procedure for the synthesis of compound D described in Example 1 using methylene chloride as a solvent, 4.3 equivalents of 4-formylimidazole, 4.3 equivalents of sodium triacetoxyborohydride and stirring for 4 hours.

MS (M + H) ⁺ 385. ¹ H-NMR (CD ₃ OD): 3.5 (m.p., 4H), 4.60 (pi, 2H), 4.9 (pi, 4H), 7.2-8.0 (m, 10H), 8.90 (s, 1H), 9.05 (s, 1H).

2,3,4,5-Tetrahydro-1- (1H-imidazol-4-ylmethyl) -4- (1-naphthalenylmethyl) -7-phenyl-1H-1,4-benzodiazepine (trifluoroacetate)

To a suspension of Example 12 (0.25 g, 0.55 mmol) in THF (10 mL) was added lithium aluminum hydride (1M THF, 15 mL, 15 mmol). This suspension was refluxed for 5 hours, cooled to 0 ° C and treated with 20% aqueous NaOH (10 mL) and H ₂ O (10 mL). The mixture was saturated with NaCl and extracted with CH ₂ Cl ₂ (2 x 50 mL). Drying over Na ₂ SO ₄ and evaporation of the solvent afforded a solid (0.21 g) which was dissolved in MeOH / TFA (10: 1) and purified by preparative HPLC (YMC S5 ODS 30x250 mm; gradient elution 0-100% buffer B). 45 min; buffer A = MeOH: H ₂ O: TPA (10: 90: 0.1); buffer B = MeOH: H ₂ O: TFA (90: 10: 0.1); 25 mL / min); Example 46 is obtained (50 mg) which is an off-white solid.

MS (M + H) ⁺ 445.

Analysis calculated for C ₃ H ₂₈ N ₄ 0 · 2 HCl · 0.3 H ₂ O

Found: C, 68.90; H, 5.90; N, 10.71.

Found: C, 68.94; H, 5.78; N, 10.43.

2,3,4,5-Tetrahydro-1- (1H-imidazol-4-ylmethyl) -7-methoxy-4- (1-naphthalenylcarbonyl) -! The H-1,4-benzodiazepine (dihydrochloride) sample compound (off-white solid) is prepared from

6-hydroxyisanoic acid anhydride according to the procedure for the preparation of the following compounds: Example A Compound A was refluxed for 18 hours and the residue was washed with water; producing methyl ether by stirring with 1.3 equivalents of methyl iodide in DMF in K2CO3 at room temperature for 12 hours; Example 1 Compound B, 20% NaOH and water followed by extraction with CH ₂ Cl ₂ : Example 2 Compound C, without product chromatography; Example D Compound D using methylene chloride with stirring for 5 hours. and purification by flash chromatography (94.5: 5: 0.5, CH ₂ Cl ₂ : MeOH: NH ₄ OH) before the hydrochloride salt was prepared.

Analysis calculated for C ₂₄ H ₂₄ N ₄ O 2 · 2 HCl 0.61 H ₂ O.

Found: C, 60.50; H, 5.53; N, 11.29.

Found: C, 60.51; H, 5.59; N, 11.14.

example

CO ₂ H

100

2,3,4,5-Tetrahydro-1- (1H-imidazol-4-ylmethyl) -4- (1-naphthalenylcarbonyl) -1H-1,4-benzodiazepine-7-carboxylic acid (dihydrochloride)

A solution of Example 11 (0.12 g, 0.26 mmol) in THF (10 mL) at -78 ° C was added n-BuLi (2.5 M THF, 0.22 mL, 0.55 mmol). The resulting brown solution was stirred for 4 min. At -78 ° C for 20 min. CO _{2 is added} and the mixture is diluted with a mixture of acetic acid and water (2: 1, 2 ml). The solvent is evaporated off, the residue is dissolved in methylene chloride and the solution is washed with saturated NaCl solution, dried (Na ₂ SO ₄ ) and evaporated. The residue was purified by preparative HPLC (YMC S5 ODS 30x250 mm; gradient elution 0 to 100% buffer B over 45 min; buffer A = MeOH: H ₂ O: TFA (10: 90: 0.1); buffer B = MeOH H ₂ O: TFA (90: 10: 0.1); 25 mL / min) and the product was converted to the HCl salt by lyophilization from 1M HCl (5 mL). Example 48 (50 mg, 45%) is obtained which is an off-white solid.

MS (M + H ⁺ ) 427.

¹ H-NMR (CD 3 OD): 3.05 (ppm, 1H), 3.20 (m, 1H), 4.00 (ppm, 1H), 4.20 (ppm, 1H), 4.40 (pi.d, 1H), 4.50 (ss, 1H), 4.65 (s, 1H), 5.05 (s, 1H), 6.60 (d, 1H), 7 , 19-8.20 (m, 11H), 8.85 (s, 1H), 8.95 (s, 1H).

example

2,3,4,5-Tetrahydro-1- (1H-imidazol-5-ylmethyl) -4- (1-naphthalenylcarbonyl) -7-cyclohexyl-1H-1,4-benzodiazepine (2.5 hydrochloride)

A solution of 101 {Example 11 (0.68 g, 1.4 mmol) in THF (15 mL) was added at -78 ° C with n-BuLi (2.5 M in THF, 1.4 mL, 3.5 mmol). The resulting brown solution was stirred for 5 min. At -78 ° C, followed by cyclohexanone (1.5 mL, 14.4 mmol). After stirring at -78 ° C for 10 min, quench the reaction with saturated NH ₄ Cl (3 mL) and saturated NaHCO ₃ (10 mL). The aqueous solution is extracted with CH ₂ Cl ₂ . The organic phase is dried (Na ₂ SO ₄ ) and evaporated. The residue was purified by chromatography (silica gel, 10% CH ₃ OH, 0.5% AcOH CH ₂ Cl ₂ ) to give the crude alcohol (80 mg) as well as 25% of Example 50. To a solution of the crude alcohol (40 mg) in CH ₂ Cl ₂ (15 mL) at -78 ° C was added TFA (3 mL). The resulting blue solution was treated with solid NaBH ₄ (0.7 g, 18.5 mmol). The mixture was warmed to room temperature and quenched with NH ₄ OH (10 mL). The solution was diluted with CH ₂ Cl ₂ (20 mL) and washed with aqueous NaOH (1N, 10 mL) and saturated NaCl (10 mL). Drying of Na ₂ SO 4 and evaporation of the solvent afforded a solid which was converted to its HCl salt by lyophilization from 1M HCl to give Example 49 as a yellow solid (30 mg). MS (M + H ⁺ ) 465.

¹ H-NMR (CD ₃ OD): 1.50 - 2.40 (m, 10H), 2.89 (m, 1H), 3.20 (m, 2H), 4.00 (s, 1H ), 4.20 (p.s.s, 1H), 4.40 (p.s.d. 1H), 4.50 (p.s.s, 1H), 4.65 (s, 1H), 4.95 (s) 1H), 6.15 (d, 1H), 7.19-8.10 (m, 11H), 8.85 (s, 1H), 8.95 (s, 1H).

example .Me

7-Butyl-2,3,4,5-tetrahydro-1- (1H-imidazol-4-ylmethyl) -4- (1-naphthalenylcarbonyl) -1H-1,4-benzodiazepine (dihydrochloride)

Preparation of Example 102 is described in Example 49.

MS (M + H ⁺ ) 439.

¹ H-NMR (CD ₃ OD): 0.5-2.40 (m, 9H), 2.9 (m, 2H). 3.20 (m, 2H), 4.00 (m.p., 1H), 4.20 (m.s, 1H), 4.40 (m.p., 1H), 4.50 (m.p. 1H), 4.65 (s, 1H), 4.95 (s, 1H), 6.00 (ss, 1H), 7.19-8.10 (m, 11H), 8.85 ( s, 1H), 8.95 (s, 1H).

1 - [[2- (2-Aminoethyl) -1H-imidazol-4-yl] methyl] -2,3,4,5-tetrahydro-4- (1-naphthalenylcarbonyl) -7-phenyl-1H-1,4- benzodiazepine (trihydrochloride) sample compound is prepared according to the following two-step procedure. Reductive alkylation of tetrahydro-4- (1-naphthalenylcarbonyl) -7-phenyl-1H-1,4-benzodiazepine (prepared according to the procedure described in Example 12) with the compound B of Example 20 according to the procedure for the preparation of the compound D described in Example 1 is carried out. The crude mixture was purified by flash chromatography (silica gel, 60% ethyl acetate in hexanes) to give the bis-Boc analog. Deprotection and purification according to the purification procedure of Compound C described in Example 20 affords Example 51 as an off-white powder.

MS (M + H) ⁺ 502.

Analysis calculated for C 32 H 31 N ₅ O · 3 HCl 0.5 H ₂ O.

Found: C, 61.99; H, 5.69; N, 11.29.

Found: C, 61.68; H, 6.07; N, 11.22.

example

103

1 - [[2- (2-Aminomethyl) -1H-imidazol-4-yl] methyl] -2,3,4,5-tetrahydro-4- (1-naphthalenylcarbonyl) -7-phenyl-1H-1,4- benzodiazepine (trihydrochloride) Example compound prepared from tetrahydro-4- (1-naphthalenylcarbonyl) 7-phenyl-1H-1,4-benzodiazepine and [2- (2 - [[(1,1-dimethyl) ethoxycarbonyl] amino] methyl] ) -1 - [(1,1-dimethyl) -ethoxycarbonyl] -imidazol-4-yl] carboxaldehyde (see Example 21) according to the procedure described in Example 51.

MS (M + H) &lt; ⁺ &gt; 488.

Analysis calculated for C31H29N5O3 HCl.

Found: C, 62.37; H, 5.40; N, 11.73.

Found: C, 62.13; H, 5.67; N, 11.73.

example

2,3,4,5-Tetrahydro-1- (1H-imidazol-4-ylmethyl) -4- (1-naphthalenylcarbonyl) -8 [N, N-bis (phenylmethyl) amino] -1H-1, 4-Benzodiazepine (trihydrochloride)

104

Sodium triacetoxyborohydride (0.079 g, 0.37) was added to a solution of Example 26 (0.50 g, 0.12 mmol), benzaldehyde (0.04 g, 0.37 mmol) and AcOH (1 mL) in CH 2 Cl 2 (1 mL). mmol). After stirring for 16 h, the reaction mixture was diluted with CH ₂ Cl ₂ (10 mL), NH ₄ OH (3 mL) and NaHCO ₃ (3 mL) and stirred for 30 min. The layers were separated and the aqueous layer was re-extracted with CH 2 Cl 2 (2 x 50 mL). The combined organic layers were dried over MgSO ₄ , filtered, and concentrated. The residue was treated with HCl / ether to give a yellow solid which was triturated several times with ether and dried in vacuo to afford Example 53 (0.43 g, 60%).

MS (M + H) ⁺ 579.

1 H-NMR (270 MHz, CD ₃ OD): δ 8.8 (d, 1H, J = 20 Hz), 8.04-7.9 (m, 2H), 7.67.2 (m, 18H) ), 7.0 (s, 0.5H), 5.87 (s, 0.5H), 4.95-4.8 (m, 5H), 4.5-4.1 (m, 3H), 3.85 (m, 1H), 3.4-3.2 (m, 2H), 3.0 (m, 1H).

N- [2,3,4,5-Tetrahydro-1- (1H-imidazol-4-ylmethyl) -4- (1-naphthalenylcarbonyl) -1H-1,4-benzodiazepin-8-yl] phenylsulfonamide (dihydrochloride) To a solution of Example 26 (0.50 g, 0.12 mmol) and triethylamine (0.019 mL, 0.13 mmol) in CH ₂ Cl ₂ (1 mL) was added benzenesulfonamide (0.024 g, 0.13 mmol). After stirring for 16 h, the reaction mixture was diluted with CHCl ₃ (10 mL) and NaHCO ₃ (3 mL) and stirred for 30 min. The layers were separated and the aqueous layer was re-extracted with CHCl ₃ (2 x 20 mL). The combined organic layers were dried over MgSO ₄ , filtered, and concentrated. Remain

Treatment with HCl / ether gave a yellow solid which was triturated several times with ether and dried in vacuo to afford Example 54 (0.642 g, 83%) as a brownish solid.

MS (M + H) &lt; ⁺ &gt; 538.

¹ H-NMR (270 MHz, CD ₃ OD): δ 8.8 (d, 1H, J = 20 Hz), 8.1-7.23 (m, 13H), 7.1 (d, 0.5H) , J = 8Hz), 7.0 (d, 0.5H, J = 8Hz), 6.9 (d, 0.5H, J = 8Hz), 6.62 (d, 0.5H, J = 8Hz), 6.12 (d, 0.5H, J = 8Hz), 5.71 (d, 0.5H, J = 8Hz), 4.55 (m, 1H), 4.553.9 ( m, 3H), 3.45-3.25 (m, 2H), 3.0-2.8 (m, 2H).

N-Phenyl-2,3,4,5-tetrahydro-1- (1H-imidazol-4-ylmethyl) -4- (1-naphthalenylcarbonyl) -1H-1,4-benzodiazepine-7-carboxamide (dihydrochloride) A mixture of 50 mg, 0.11 mmol), PyBROP (0.28 g, 0.6 mmol), DMAP (0.04 g, 0.3 mmol) and DIEA (0.3 g, 2.3 mmol) in DMF ( 5 ml) was stirred for 5 min, aniline (1 ml, 11 mmol) was added and the resulting homogeneous solution was stirred for two days. After evaporation of DMF, the residue was purified by preparative HPLC (YMC S5 ODS 30x250 mm: Rt = 2223 min; gradient elution from 0 to 100% buffer B over 45 min; buffer A = MeOH: H ₂ O: TFA (10:90 Buffer B = MeOH: H ₂ O: TFA (90: 10: 0.1); 25 mL / min) and converted to the HCl salt by lyophilization from 1M HCl (5 mL). Example 55 (40 mg, 34%) is obtained as a yellow solid.

MS (M + H) ⁺ 502.

106 ¹ H-NMR (CD 3 OD): 3.10 (ppm, 1H), 3.25 (m, 1H), 4.10 (p.s, 1H), 4.25 (p.s.

1H), 4.45 (dd, 1H), 4.55 (dd, 1H), 4.60 (s, 1H), 5.10 (s, 1H), 6.64 (d, 1H) ), 7.19-8.20 (m, 16H), 8.85 (s, 1H), 8.95 (s, 1H).

example

N- [2,3,4,5-Tetrahydro-1- (1H-imidazol-4-ylmethyl) -4- (1-naphthalenylcarbonyl) -1H-1,4-benzodiazepin-8-yl] -3-methylbenzamide ( dihydrochloride) is prepared from m-toluoyl chloride and the compound of Example 26 according to the procedure described in Example 27 by stirring for 16 hours. The HCl salt is prepared directly from the crude product to give Example 56 (94% yield) as a brown solid.

MS (M + H) &lt; ⁺ &gt; 516.

¹ H-NMR (270 MHz, CD ₃ OD): δ 8.8 (d, 1H, J = 20 Hz), 8.15-7.2 (m, 14H), 6.8 (d, 0.5H) , J = 7Hz), 5.95 (d, 0.5H, J = 7Hz), 4.98 (s, 1H), 4.7-4.19 (m, 3H), 4.19-3 , 9 (m, 1H), 3.52-3.2 (m, 1.5H), 3.25-3.15 (m, 0.5H), 3.1-2.8 (m, 1H) , 2.46-2.33 (m, 3H).

example

107

HN

N- [2,3,4,5-Tetrahydro-1- (1H-imidazol-4-ylmethyl) -4- (1-naphthalenylcarbonyl) 1H-1,4-benzodiazepin-8-yl] -4-methylbenzamide (dihydrochloride) ) Example compound is prepared from p-toluoyl chloride and Example 26 according to the procedure described in Example 56.

MS (M + H) &lt; ⁺ &gt; 516.

¹ H-NMR (270 MHz, CD ₃ OD): δ 8.8 (d, 1H, J = 20 Hz), 8.15-7.72 (m, 5H), 7.77.2 (m, 9H) ), 6.77 (d, 0.5H, J = 7Hz), 5.92 (d, 0.5H, J = 7Hz), 4.98 (s, 1H), 4.7-4.19 (m, 3H), 4.12-3.9 (m, 1H), 3.52-3.2 (m, 1.5H), 3.25-3.15 (m, 0.5H), 3 , 1-2.8 (m, 1H), 2.46-2.33 (m, 3H).

example

Cl

HN

3-Chloro-N- [2,3,4,5-tetrahydro-1- (1H-imidazol-4-ylmethyl) -4- (1-naphthalenylcarbonyl) -1H-1,4-benzodiazepin-8-yl] benzamide (dihydrochloride) )

Example 108 is prepared from 3-chlorobenzoyl chloride and Example 26 according to the procedure described in Example 56.

MS (M + H) ⁺ 536.

¹ H-NMR (270 MHz, CD ₃ OD): δ 8.87 (d, 1H, J = 20 Hz), 8.05-7.82 (m, 4H), 7.75-7.2 (m , 10H), 6.8 (d, 0.5H, J = 8Hz), 5.9 (d, 0.5H, J = 8Hz), 4.96 (s, 1H), 4.65-3 , 9 (m, 4H), 3.4-3.3 (m, 2H), 3.05-2.9 (m, 1H).

7-Bromo-2,3,4,5-tetrahydro-1 - [[2 - [(dimethylamino) methyl] -1H-imidazol-4-yl] methyl] -4- (1-naphthalenylcarbonyl) -1H-1,4 benzodiazepine (dihydrochloride)

A suspension of Example 11 (100 mg, 0.22 mmol), paraformaldehyde (10 mg, 0.33 mmol) and dimethylamine (40% in water, 0.041 mL) was stirred in acetic acid at 90 ° C for 18 h. The mixture was partitioned between ethyl acetate and saturated NaHCC> 3. The organic layer was separated, dried and concentrated in vacuo. The residue was purified by flash chromatography (30% MeOH, 69% ethyl acetate and 1% NH4OH) to give a solid which was dissolved in methanol. 1N HCl in ether was added and evaporation of the solvent gave Example 59 as a yellow solid (30 mg, 23%).

MS (M + H) &lt; ⁺ &gt; 518.

example

109

7- (4-Chlorophenyl) -2,3,4,5-tetrahydro-1- (1H-imidazol-4-yl) -4- (1-naphthalenylcarbonyl) -1H-1,4-benzodiazepine (dihydrochloride) Example A ( A solution of 0.142 g, 0.2 mmol) in DMF (5 mL) and THF (10 mL) was degassed under argon for 5 min. Tetrakis (triphenylphosphine) palladium (0.10 g, 0.08 mmol) is added and the solution is degassed under argon for 20 min. A solution of sodium carbonate (0.11 g, 0.8 mmol) in degassed H ₂ O (2 mL) was added followed by 4-chlorobenzeneboronic acid (0.17 g, 1.1 mmol). The resulting solution was heated at 110 ° C for 14 h. The solvent was evaporated, the residue was dissolved in CH ₂ Cl ₂ (15 mL), and the solution was treated with HSiMe ₃ (3 equiv.) And TFA (10 equiv.). The solvent is evaporated and the residue is purified by preparative HPLC and converted to the HCl salt according to the procedure described in Example 48. Example 60 (40 mg, 40%) is obtained as a gray solid.

MS (M + H) &lt; ⁺ &gt; 493.

¹ H-NMR (CD ₃ OD, 300 MHz): δ 2.95 (ppm, 1H), 3.30 (m, 1H), 4.00 (ppm, 1H),

4.20 (m.p., 1H), 4.40 (m.p., 1H), 4.60 (m, 1H), 4.65 (m, 1H), 5.05 (s, 1H), δ , 05 (d, 1H), 7.00 (d, 1H), 7.15-8.10 (m, 13H), 8.85 (s, 1H), 8.95 (s, 1H).

example

110

7- (3-Aminophenyl) -2,3,4,5-tetrahydro-1- (1H-imidazol-4-ylmethyl) -4- (1-naphthalenylcarbonyl) -1H-1,4-benzodiazepine (trihydrochloride) Example Compound ( gray solid) is prepared in 45% yield from Example 37 Compound A and 3-aminobenzeneboronic acid (0.17 g, 1.1 mmol) according to the procedure described in Example 60.

MS (M + H) &lt; ⁺ &gt; 474.

¹ H-NMR (CD ₃ OD, 300 MHz): δ 2.95 (ppm, 1H), 3.30 (m, 1H), 4.00 (ppm, 1H),

4.20 (m.p., 1H), 4.40 (m.p., 1H), 4.60 (m, 1H), 4.65 (m, 1H), 5.05 (s, 1H), δ , 05 (d, 1H), 7.00 (d, 1H), 7.15-8.10 (m, 13H), 8.85 (s, 1H), 8.95 (s, 1H).

1-Methyl-N- [2,3,4,5-tetrahydro-1- (1H-imidazol-4-ylmethyl) -4- (1-naphthalenylcarbonyl) -1H-1,4-benzodiazepin-8-yl] -1H- pyrrole-2-carboxamide (trihydrochloride)

To a solution of 111 mL of EDC (0.071 g, 0.37 mmol), HOAt (0.051 g, 0.37 mmol) and 1-methyl-2-pyrrole carboxylic acid (0.046 g, 0.37 mmol) in DMF (1 mL) was added compound 26 (0.050). g, 0.12 mmol). After stirring for 16 h, the mixture was diluted with CHCl ₃ (10 mL) and NaHCO ₃ (3 mL) and stirred for 30 min. The layers were separated and the aqueous layer was re-extracted with CHCl ₃ (2 x 20 mL). The combined organic layers were dried over MgSO 4, filtered, and concentrated. The residue was purified by chromatography on a silica gel column eluting with CHCl ₃ followed by CHCl ₃ / MeOH (19/1) to give a yellow solid which was triturated with ether several times and dried in vacuo. Example 62 (0.007 g, 11%) is obtained as a brownish solid.

MS (M + H) ⁺ 505.

¹ H-NMR (270 MHz, CD ₃ OD): δ 8.88 (d, 1H, J = 21 Hz), 8.07-7.9 (m, 2.5H), 7.72-7.4 (m, 5H), 7.3 (d, 0.5H, J = 8Hz), 7.23 (d, 0.5H, J = 8Hz), 7.16 (d, 0.5H, J = 8Hz), 7.0 (m, 0.5H), 6.95-6.85 (m, 1H), 6.7 (d, 0.5H, J = 8Hz), 6.15-6, 1 (m, 1H), 5.92 (d, 0.5H, J = 8Hz), 5-4.9 (m, 2H), 4.65-4.15 (m, 4H), 3.98 -3.9 (d, 3H, J = 10), 3.43-3.3 (m, 2.5H), 3.05-2.87 (m, 1H).

example

N- [2,3,4,5-Tetrahydro-1- (1H-imidazol-4-ylmethyl) -4- (1-naphthalenylcarbonyl) -1H-1,4-benzodiazepin-8-yl] -3- Furancarboxamide (dihydrochloride) Example compound (yellow solid) is prepared from Example 26 compound and 3-furancarboxylic acid according to the procedure described in Example 62.

112

MS (M + H) &lt; ⁺ &gt; 492.

¹ H-NMR (270 MHz, CD ₃ OD): δ 8.88 (d, 1H, J = 20 Hz), 8.25 (d, 1H, J = 16 Hz), 8.13-7.38 ( m, 9H), 7.38 (d, 0.5H, J = 6Hz), 7.25 (0.5H, J = 6Hz), 7.19 (d, 0.5H, J = 8Hz) , 6.95 (d, 0.5H, J = 17Hz), 6.72-6.68 (m, 1H), 5.93 (d, 0.5H, J = 8Hz), 5.0- 4.9 (m, 2H), 4.66-3.91 (m, 3.5H), 3.4-3.3 (m, 2H), 3.052.89 (m, 1H).

7- (3-Chlorophenyl) -2,3,4,5-tetrahydro-1- (1H-imidazol-4-ylmethyl) -4- (1-naphthalenylcarbonyl) -1H-1,4-benzodiazepine (dihydrochloride) Example Compound (Gray) The solid was prepared in 55% yield from Example 37 Compound A and 3-chlorobenzeneboronic acid (0.17 g, 1.1 mmol) according to the procedure described in Example 60.

MS (M ⁺ H) ⁺ 493.

¹ H-NMR (CD ₃ OD, 300 MHz): δ 2.95 (ppm, 1H), 3.30 (m, 1H), 4.00 (ss, 1H),

4.20 (m.p., 1H), 4.40 (m.p., 1H), 4.60 (m, 1H), 4.65 (m, 1H), 5.05 (s, 1H), δ , 05 (d, 1H), 7.00 (d, 1H), 7.15-8.10 (m, J13H), 8.85 (s, 1H), 8.95 (s, 1H).

example

113

Me

2-Methyl-N- [2,3,4,5-tetrahydro-1- (1H-imidazol-4-ylmethyl) -4- (1-naphthalenylcarbonyl) -1H-1,4-benzodiazepin-8-yl] benzamide ( dihydrochloride) Example 23 (yellow solid) 23% yield of o-toluoyl chloride and Example 26 according to the procedure described in Example 56.

MS (M + H) &lt; ⁺ &gt; 516.

¹ H-NMR (270 MHz, CD ₃ OD): δ 8.8 (d, 1H, J = 20 Hz), 8.05-7.2 (m, 13.5H), 7.1 (d, 0 , 5H, J = 6Hz), 6.7 (d, 0.5H, J = 8Hz), 5.95 (d, 0.5H, J = 8Hz), 5.1-4.9 (m , 2H), 4.7-3.9 (m, 3H), 3.45-3.3 (m, 2H), 3.8-2.9 (m, 1H), 2.5-2.4 (d, 3H, J =

Hz).

example

HN

114

N-Phenyl-N '- [2,3,4,5-tetrahydro-1- (1H-imidazol-4-ylmethyl) -4- (1-naphthalenylcarbonyl) -1H-1,4-benzodiazepin-8-yl] urea ( dihydrochloride)) To a solution of Example 26 (0.050 g, 0.12 mmol) and triethylamine (0.020 mL, 0.15 mmol) in CH ₂ Cl ₂ (1 mL) was added phenyl isocyanate (0.016 mL, 0.15 mmol). After stirring for 16 h, the reaction mixture was diluted with CHCl 3 (10 mL) and NaHCO ₃ (3 mL) and stirred for 30 min. The layers were separated and the aqueous layer was extracted with CHCl ₃ (2 x 20 mL). The combined organic layers were dried over MgSO ₄ , filtered, and concentrated. The residue was purified by chromatography on silica gel eluting with CHCl3 / CH3OH (19/1). The appropriate fractions are concentrated and the residue is treated with HCl / ether. The solid was triturated several times with ether and dried in vacuo to give Example 66 (0.018 g, 25%) as a yellowish solid.

MS (M + H) ⁺ 517.

¹ H-NMR (400 MHz, CD ₃ OD): δ 8.83 (d, 1H, J = 19 Hz), 8.07-7.89 (m, 2H), 7.68-7.2 (m , 11.5H), 7.07-6.98 (m, 1H), 6.85 (d, 0.5H, J = 6Hz), 6.4 (d, 0.5H, J = 8Hz) , 5.89 (d, 0.5H, J = 8Hz), 5.1-4.9 (m, 1H), 4.69-3.9 (m, 4H), 3.45-3.3 (m, 2H), 3.05-2.88 (m, 1H).

2,3,4,5-Tetrahydro-1- (1H-imidazol-4-ylmethyl) -4- (1-naphthalenylcarbonyl) -7- (3-pyridinyl) -1H-1,4-benzodiazepine (trihydrochloride)

Example 115 Compound (yellow solid) 8% yield is prepared from Example 37 Compound A and 3- (tributylstanyl) pyridine according to the procedure described in Example 37 for the synthesis of Compound B.

MS: (M + H) ⁺ 460.

2,3,4,5-Tetrahydro-1- (1H-imidazol-4-ylmethyl) -9-methoxy-4- (1-naphthalenylcarbonyl) -1H-1,4-diazepine (dihydrochloride) Example compound (yellowish solid) of 8-methoxyisatoic acid anhydride and glycine ethyl ester hydrochloride according to the following sequence of reactions: Compound A of Example 1; reduction is carried out by refluxing a solution of dione with 5 eq. borano-THF in tetrahydrofuran or; cooled to 0 ° C, acidified with 3N HCl, heated at 100 ° C for 30 min, neutralized with 5N NaOH, and then extracted with methylene chloride; Compound C of Example 2; Example 1 Compound D.

MS (M + H) &lt; ⁺ &gt; 413.

IR: (KBr): 2926, 2837, 1732, 1630, 1580, 1474, 1252, 1078, 804, 781 cm @ ^-1 .

example

116

2,3,4,5-Tetrahydro-1- (1H-imidazol-4-ylmethyl) -4- (1-naphthalenylcarbonyl) -7-phenyl-1H-pyrido [2,3-e] -1,4-diazepine ( trihydrochloride)

A. 2,3,4,5-Tetrahydro-7-bromo-1H-pyrido [2,3-e] -1,4-diazepin-5-one

To a solution of Example 23 Compound A (100 mg, 0.61 mmol) in acetic acid (10 mL) was added bromine (32 μΙ, 0.61 mmol). The mixture was stirred for 30 min, then another bromine equivalent (32 μΙ) was added to allow the reaction to complete. After stirring for a further 30 min, the reaction mixture was diluted with 30 mL of H ₂ O and neutralized to pH 7 with 5N NaOH. The mixture was extracted with Et ₂ O (50 mL) followed by CH ₂ Cl ₂ (2 x 100 mL). The organic layers were combined, washed with brine and dried over Na ₂ SO ₄ . Concentration gave compound A, which was a solid (116 mg, 79%). MS (M + CH ₃ CN) ⁺ 283.

B. 2,3,4,5-Tetrahydro-7-phenyl-1H-pyrido [2, 3 _d-e] -1,4-diazepin-5-one

Compound A (27 mg, 0.11 mmol) PHB (OH) ₂ (34 mg, 0.28 mmol) and K5PO ₄ (59 mg, 0.28 mmol) in anhydrous DMF (0.6 mL) and anhydrous THF (0.6 ml) is degassed by bubbling N ₂ for 1 hour. recrystallized Pd (PPh ₃ ) _{4 is} added to this solution and the solution is heated at 65 ° C for 30 hours. The mixture was cooled to room temperature and diluted with CH ₂ Cl ₂ (6 mL). This mixture was extracted with 10% LiCl, and the aqueous layer was extracted once with CH ₂ Cl ₂ (6 mL). The organic layers were mixed and washed with 1N HCl. The organic layer was removed and the aqueous layer was basified with 5N NaOH and extracted with CH ₂ Cl ₂ (3 x 10 mL). These organic layers are washed further

117 times with 10% LiCl, dried over Na ₂ SO ₄ , and concentrated to give Compound B as a white solid (18 mg, 70%). MS (M + H + CH ₃ CN) ⁺ 281.

C. 2,3,4,5-Tetrahydro-7-phenyl-1H-pyrido [2,3-e] -1,4-diazepine

Compound C is prepared according to the procedure described in Example 23 for the preparation of compound B by refluxing for 60 hours. The crude material was chromatographed (flash chromatography, 230-400 mesh, 5-10% MeOH / CHCl ₃ ) to give Compound C as a white solid (34%). MS (M + H + CH ₃ CN) ⁺ 267.

D. 2,3,4,5-Tetrahydro-1- (1H-imidazol-4-ylmethyl) -4- (1-naphthalenylcarbonyl) -7-phenyl-1H-pyrido [2,3-e] -1,4-diazepine (trihydrochloride) Example Compound (fluffy white solid) is prepared in a total 36% yield from Compound C according to the synthesis procedures of Compound 23 of Example 23 and Compound D of Example 23 using a total of 6 aliquots of aldehyde and hydride for complete reaction.

MS (M + H) ⁺ 460.

Analysis calculated with Ο ₂₉ Η ₂₅ Ν ₅ Ο · 3 HCl.

Found: C, 61.22; H, 4.96; N, 12.31.

Found: C, 61.50; H, 5.21; N, 12.29.

(R) -2,3,4,5-Tetrahydro-1- (1H-imidazol-4-ylmethyl) -3- [2- (methylthio) ethyl] -4- (1-naphthalenylcarbonyl) -1H-1,4- benzodiazepine (hydrochloride)

Example 118 (yellow solid) is prepared from isatoic anhydride and L-methionine O-methyl ester hydrochloride according to the described synthesis sequence of Example 1 Compound A by boiling for 18 hours, evaporating the solvent and partitioning between 1N hydrochloric acid and dichloromethane ; Example 17 except that the free base is used; Example 2 Compound C using flash chromatography on silica gel eluting with ethyl acetate: hexane (1: 2); The compound of Example 1, D. Lyd. mp: 145-150 ° C.

MS (M + H) ⁺ 456.

Analysis calculated for C ₂₇ H ₂₈ N ₄ OS 1.6 H ₂ O · 1.3 HCl.

Found: C, 60.86; H, 6.15; N, 10.51; S, 8.65; Cl, 6.02.

Found: C, 60.96; H, 5.67; N, 10.14; S, 8.39; Cl, 5.68.

example

2,3,4,5-Tetrahydro-1- (1H-imidazol-4-ylmethyl) -4- (1-naphthalenylcarbonyl) -3 (phenylmethyl) -1H-1,4-benzodiazepine (hydrochloride) Example Compound (yellow solid) material) is prepared from isatoic anhydride and D, L-phenylalanine O-methyl ester hydrochloride according to the procedure described in Example 70. Lyd. m.p. 78-80 ° C.

MS (M + H) ⁺ 473.

Analysis calculated for C ₃ i H ₂₈ N ₄ O 1.6 H ₂ O · 1.8 HCl.

Found: C, 65.66; H, 5.87; N, 9.88; Cl, 11.25.

Found: C, 65.85; H, 5.68; N, 9.64; Cl, 11.55.

Example 119 < ^z

N

N

H

OH

2,3,4,5-Tetrahydro-3- (2-hydroxyethyl) -1- (1H-imidazol-4-ylmethyl) -4- (1-naphthalenecarbonyl) -1H-1,4-benzodiazepine (trifluoroacetate) Example Compound ( white solid) is prepared from isatoic anhydride and D, L-aspartate O-dimethyl ester hydrochloride according to the procedure described in Example 70, except that 5 eq. lithium aluminum hydride, and the final product is purified by preparative HPLC (gradient of aqueous methanol with 0.1% TFA). Lyd. mp: 155-160 ° C.

MS (M + H) &lt; ⁺ &gt;

Analysis calculated for C26H26N4O2 1.0 _H2O 1.3 TFA.

Found: C, 57.95; H, 4.98; N, 9.45; Cl, 11.25.

Found: C, 58.09; H, 4.71; N, 9.32; Cl, 11.55.

example

MeS

2,3,4,5-Tetrahydro-4- (1H-imidazol-4-ylmethyl) -3- [2- (methylthio) ethyl] -4- (1-naphthalenylcarbonyl) -1H-1,4-benzodiazepine (trifluoroacetate)

Example 120 is prepared from 2,3,4,5-tetrahydro-3- [2 (methylthio) ethyl] -1H-1,4-benzodiazepine (prepared from DL-methionine O-methyl ester hydrochloride according to the procedure described in Example 70) according to the procedure described in Example 70. synthesis of the following compounds: Example 4 Compound A; For the compound C of Example 2, the reaction is carried out without purification of the compound; The compound C of Example 4; Compound D of Example 1 by purification by preparative HPLC (gradient of aqueous methanol with 0.1% TFA). Lyd. mp: 130-135 ° C.

MS (M + H) ⁺ 456.

Analysis calculated for C27H28N4OS · 1.5 H ₂ O · 1.3 TFA.

Found: C, 56.27; H, 5.15; N, 8.87; S, 5.07; F, 11.73.

Found: C, 56.24; H, 4.84; N, 8.74; S, 5.10; F, 12.05.

example

(S) -2,3,4,5-Tetrahydro-1- (1H-imidazol-4-ylmethyl) -4- (1-naphthalenylcarbonyl) -3 (phenylmethyl) -1H-1,4-benzodiazepine (trifluoroacetate) Example compound (white solid) is prepared from isatoic anhydride and L-enylalanine O-methyl ester hydrochloride according to the procedure described in Example 70; the final product is purified by preparative HPLC (gradient of aqueous methanol with 0.1% TFA). Lyd. mp: 152-154 ° C.

MS (M + H) ⁺ 473.

Analysis calculated for C ₃₁ H ₂₃ N ₄ O · 1.0 H ₂ O · 1.2 TFA.

Found: C, 63.94; H, 5.01; N, 8.93; Cl, 10.90.

Found: C, 64.12; H, 4.87; N, 8.73; Cl, 11.01.

Example 121

Br e

N

H

N

N

Y

O

Me

4-Acetyl-7-bromo-2,3,4,5-tetrahydro-1- (1H-imidazo-4-ylmethyl) -3- (phenylmethyl) -1H-1,4-benzodiazepine (hydrochloride)

A. 7-Bromo-2,3,4,5-tetrahydro-3- (phenylmethyl) -1H-1,4-benzodiazepine-2,5dione

Bromizatoic acid anhydride (2.93 g, 12.1 mmol), D, L-phenylalanine O-methyl ester hydrochloride (2.62 g, 12.1 mmol), dimethylaminopyridine (100 mg, catalytic amount) and pyridine (50 mL) ) was heated to reflux (bath temperature -140 ° C) under argon for 48 hours. The solution is concentrated in vacuo to a semi-solid and the residue is suspended in 1N HCl (200 mL) and dichloromethane (200 mL). The resulting precipitate was filtered off, washed with dichloromethane (50 mL) and dried in vacuo at 50 ° C for 18 h. Compound A (1.1 g, 26%) is obtained as a gray solid.

B. 7-Bromo-2,3,4,5-tetrahydro-3- (phenylmethyl) -1H-1,4-benzodiazepine

A solution of Compound A (500 mg, 1.45 mmol) in ethylene glycol dimethyl ether (anhydrous, 50 mL) at 0 ° C under argon was added slowly to a solution of BH ₃ : THF (20 mL, 1M in THF). The solution was allowed to warm to room temperature, then refluxed for 18 h, cooled to 0 ° C, quenched with methanol (5 mL) and concentrated in vacuo to an oil residue. This oil is exposed to 6M HCl (100 mL) water vapor

122 baths for 2 hours. (noticeable partial dissolution of the substance). The mixture was cooled to 0 ° C and basified with solid NaOH to pH 10. The resulting mixture was partitioned between ethyl acetate (200 mL), extracted with ethyl acetate (2 x 100 mL), dried (Na ₂ SO ₄ ) and concentrated in vacuo to give Compound B brown solid (300 mg, 0.94 mmol, 65%).

C. 4-Acetyl-7-bromo-2,3,4,5-tetrahydro-3- (phenylmethyl) -1H-1,4-benzodiazepine

Compound B (200 mg, 0.63 mmol), dichloromethane (5 mL) and aqueous sodium hydroxide (1 mL, 1N) were added and the mixture was cooled to 0 ° C. Acetyl chloride (66 mL, 0.94 mmol) was added to the mixture and stirred for 2 h. At 0 ° C, aqueous sodium hydroxide (20 mL, 1N) and dichloromethane (50 mL) were added, followed by extraction with dichloromethane (50 mL). The organic fractions were combined, dried (Na ₂ SO ₄ ) and concentrated to a crude oil (230 mg, 100%).

D. 4-Acetyl-7-bromo-2,3,4,5-tetrahydro-1- (1H-imidazol-4-ylmethyl) -3- (phenylmethyl) -1H-1,4-benzodiazepine Exemplary compound (white solid) is prepared from Compound C according to the procedure for the preparation of Compound D described in Example 1; the final product is purified by preparative HPLC (gradient of aqueous methanol with 0.1% TFA). Lyd. mp: 112 ° C.

MS (M + H) ⁺ 440.

Analysis calculated for C ₂₂ H ₂₃ N ₄ OBr · 0.5 H ₂ O · 1.3 TFA.

Found: C, 49.53; H, 4.27; N, 9.39; F, 12.42.

Found: C, 49.44; H, 4.07; N, 9.34; F, 12.32.

example

123

2,3,4,5-Tetrahydro-4- (1H-imidazol-4-ylmethyl) -1- (1-naphthalenylcarbonyl) -3 (phenylmethyl) -1H-1,4-benzodiazepine (1.5 hydrochloride) Example compound (a white solid) is prepared from 2,3,4,5-tetrahydro-3- (phenylmethyl) -1H-1,4-benzodiazepine (prepared according to the procedure described in Example 71) using the following procedures to obtain the following compounds: Compound A of Example 4; To compound C of Example 2 by adding a catalytic amount of pyridine and purifying over silica gel eluting with hexane: ethyl acetate (4: 1); Example 4 for compound C; Compound D of Example 1 by purification by preparative HPLC (gradient of aqueous methanol with 0.1% TFA). Lyd. mp 117-120 ° C.

MS (M + H) ⁺ 473.

Analysis calculated for C ₃₁ H ₂₈ N 4 OBr · 0.8 H ₂ O - 1.52 TFA.

Found: C, 61.92; H, 4.75; N, 8.48; F, 13.12.

Found: C, 62.31; H, 4.40; N, 8.09; F, 12.76.

124

7-Bromo-1,2,3,5-tetrahydro-1- (1H-imidazol-4-ylmethyl) -3- (phenylmethyl) -4H-1,4-benzodiazepine-4-carboxamide (trifluoroacetate)

A. 7-Bromo-1,2,3,5-tetrahydro-3- (phenylmethyl) -4H-1,4-benzodiazepine-4-carboxamide Example B (200 mg, 0.63 mmol), THF (20 mL) and trimethylsilyl isocyanate (0.13 mL, 0.95 mmol) was stirred under argon at room temperature for 18 h. To the solution was added water (5 mL) followed by aqueous hydrochloric acid (20 mL, 1N). The mixture was extracted with ethyl acetate (2 x 100 mL), the organic extracts were combined, dried (MgSO ₄ ) and concentrated in vacuo to give Compound A as a yellow solid (200 mg, 88%).

B. 7-Bromo-1,2,3,5-tetrahydro-1- (1H-imidazol-4-ylmethyl) -3- (phenylmethyl) -4H-1,4-benzodiazepine-4-carboxamide (trifluoroacetate) Example compound ( white solid) was prepared according to the procedure described in Example 1 for the preparation of compound D by purification by preparative HPLC (gradient of aqueous methanol with 0.1% TFA). Lyd. mp: 162-165 ° C.

MS (M + H) ⁺ 440.

Analysis calculated for C ₂ i H _{2 2} N ₅ OBr 0.3 H ₂ O · 1.2 TFA.

Found: C, 48.24; H, 4.12; N, 12.02; Br, 13.72; F, 11.74.

Found: C, 48.23; H, 3.91; N, 11.95; Br, 13.63; F, 11.39.

example

125

7-Bromo-2,3,4,5-tetrahydro-1- (1H-imidazol-4-ylmethyl) -4- (methylsulfonyl) -3- (phenylmethyl) -1H-1,4-benzodiazepine (hydrochloride)

A. 7-Bromo-2,3,4,5-tetrahydro-4- (methylsulfonyl) -3- (phenylmethyl) -1H-1,4-benzodiazepine, Example B, (1.0 g, 3.15 mmol), THF (20 mL), DIEA (0.6 mL, 6.3 mmol) and methanesulfonyl chloride (0.5 mL, 6.3 mmol) were stirred under argon at room temperature for 2 h. The mixture was partitioned between aqueous hydrochloric acid (100 mL, 1N) and ethyl acetate (100 mL). The aqueous phase is extracted with ethyl acetate (2 x 100 mL), the organic layers are combined, dried (MgSO 4) and concentrated in vacuo to give an oil. This oil was subjected to flash chromatography (50 g silica gel eluting with hexane: ethyl acetate (3: 1)) to give Compound A as a clear oil (330 mg, 27%).

B. 7-Bromo-2,3,4,5-tetrahydro-1- (1H-imidazol-4-ylmethyl) -4- (methylsulfonyl) -3- (phenylmethyl) -1H-1,4-benzodiazepine (hydrochloride)

To a stirred solution of compound A (330 mg, 0.84 mmol), formylimidazole (120 mg, 1.26 mmol), dichloroethane (10 mL) and acetic acid (2 mL) was added sodium triacetoxyborohydride (267 mg, 1.26 mmol) at room temperature. mmol). The solution was stirred for 1 h, diluted with ethyl acetate (20 mL) and ammonium hydroxide (2 mL, almost) and stirred for a further 18 h. The mixture was extracted with ethyl acetate (2 x 25 mL), and the combined organic extracts were washed with aqueous sodium bicarbonate (25 mL, saturated solution) and ammonium chloride (25 mL,

126 saturated aqueous solution), dried (N ₂ SO ₄ ) and concentrated in vacuo to a semi-solid. This crude material was purified by preparative HPLC (gradient of aqueous methanol with 0.1% TFA) and lyophilized. The TFA salt of Example 78 was obtained as a white solid (330 mg, 83%); melt M.p .: 118-120 ^Q C. This material was dissolved in methanol (3 mL) and 1M HCl (3 mL). The solution was evaporated and the residue triturated with methylene chloride to give Example 78 as a white solid. Lyd. 178-180 ° C. MS (M + H) ⁺ 476.

Analysis calculated for C ₂ i H ₂₃ N ₄ O ₂ SBr · 0.25 H ₂ O · 1.2 HCl.

Found: C, 48.17; H, 4.75; N, 10.70; S, 6.12; Cl, 8.12; Br, 15.26.

Found: C, 48.53; H, 4.60; N, 10.25; S, 6.95. Cl, 8.27; Br, 14.93.

4-Acetyl-2,3,4,5-tetrahydro-1- (1H-imidazol-4-ylmethyl) -7-phenyl-3 (phenylmethyl) -1H-1,4-benzodiazepine (trifluoroacetate)

A. 4-Acetyl-2,3,4,5-tetrahydro-7-phenyl-3- (phenylmethyl) -1H-1,4-benzodiazepine

A solution of Example 75 (C, 500 mg, 1.39 mmol) in toluene (20 mL) was added

Phenylboronic acid solution (340 mg, 2.8 mmol in 2 mL ethanol) was added to NaHCO ₃ (5 mL, saturated solution) under argon, tetrakistriphenylphosphine palladium (O) (42 mg, 0.07 mmol) was added and the mixture was heated to reflux. with

127 reflux under argon for 3 hours. The mixture is then poured into a saturated NaCl solution, extracted with ethyl acetate (2 x 100 mL), the organic extracts are combined, dried (MgSO ₄ ) and concentrated in vacuo to give a crude red oil which is purified by flash chromatography (50 g silica gel eluting with hexane (1: 1)). Compound A was obtained as a white solid (200 mg, 59%).

B. Example compound of 4-Acetyl-2,3,4,5-tetrahydro-1- (1H-imidazole-4-methyl) -7-phenyl-3- (phenylmethyl) -1H-1,4-benzodiazepine (trifluoroacetate) (white solid) is prepared in 79% yield from Compound A according to the procedure for Preparation of Compound D described in Example 1 by purification by preparative HPLC (gradient of aqueous methanol with 0.1% TFA). Lyd. mp: 120-123 ° C.

MS (M + H) ⁺ 437.

Analysis calculated for C ₂ 8H ₂ O 8N ₄ · 1.3 H ₂ O · 1.05 TFA.

Found: C, 62.36; H, 5.50; N, 9.66; F, 10.32.

Found: C, 62.42; H, 5.17; N, 9.61; F, 10.24.

4-Acetyl-7-bromo-3 - [(4-chlorophenyl) methyl] -2,3,4,5-tetrahydro-1- (1H-imidazol-4-ylmethyl) -1H-1,4-benzodiazepine (dihydrochloride)

A. D, L-N- (2-Amino-5-bromobenzoyl) -4-chlorophenylalanine

128

Pyridine (50 mL) was added with D, L-4-chlorophenylalanine (made from N-Boc-D, L-4-chlorophenylalanine and 4N HCl in dioxane with dimethylsulfide) and 6-Bromoisotonic acid anhydride (1.0 g, 4.15 mmol). , and the mixture is refluxed for 4 hours. The mixture was cooled, concentrated, and the residue partitioned between water (200 mL) and ethyl acetate (200 mL). The organic layer was washed with water (3 x 100 mL), saturated NaCl (50 mL), dried (MgSO ₄ ), and concentrated to give Compound A as a yellow glass (450 mg, 27%), MS (M + H). ⁺ 398.

B. 7-Bromo-3 - [(4-chlorophenyl) methyl] -2,3,4,5-tetrahydro-1H-1,4-benzodiazepine-2,5-dione

Compound A (450 mg, 1.13 mmol), EDO (737 mg, 3.85 mmol) and HOBt (519 mg, 3.85 mmol) were dissolved in DMF (10 mL) and DIEA (0.52 mL, immediately added). 2.96 mmol). The mixture was stirred for 16 h, poured into water (100 mL) and the product extracted with ethyl acetate (2 x 50 mL). The combined ethyl acetate layers were washed with water (3 x 100 mL), saturated NaCl (100 mL), dried (MgSO ₄ ), and concentrated to give Compound B as a brown glass (200 mg, 46%), MS (M + H). ) ⁺ 380.

C. 7-Bromo-3 - [(4-chlorophenyl) methyl] -2,3,4,5-tetrahydro-1 H -1,4-benzodiazepine

Compound B (200 mg, 0.53 mmol) was dissolved in THF (10 mL) and borane (1M in THF, 4 mL, 4 mmol) was added. The solution is refluxed for 3 hours, then cooled to room temperature. Methanol (5 mL) was added and the solution concentrated, 5N HCl (10 mL) was added to the concentrate and the mixture was refluxed for 4 h. The mixture was cooled to room temperature, 50% NaOH was neutralized to pH 6 and extracted with methylene chloride (3 x 50 mL). The organic layers were combined, washed with saturated NaCl (30 mL), dried (MgSO ₄ ), and concentrated to give Compound C as a slightly yellow glass (60 mg, 32%), MS (M + H) ⁺ 352.

129

D. 4-Acetyl-7-bromo-3 - [(4-chlorophenyl) methyl] -2,3,4,5-tetrahydro-1 H -1,4-benzodiazepine

Compound C (60 mg, 0.17 mmol) was dissolved in THF (5 mL), DIEA (30 μϊ, 0.17 mmol) was added followed by acetyl chloride (12 μϊ, 0.17 mmol). The solution was stirred for 30 min, concentrated, and the residue was dissolved in ethyl acetate (50 mL) and washed with water (3 x 20 mL). The organic layer is dried (MgSO ₄ ) and concentrated to give compound D, which is a slightly brownish glass.

E. 4-Acetyl-7-bromo-3 - [(4-chlorophenyl) methyl] -2,3,4,5-tetrahydro-1- (1H-imidazol-4-ylmethyl) -1H-1,4-benzodiazepine (dihydrochloride) )

Compound E (white solid) is prepared in 13% yield from Compound D according to the procedure for Compound D described in Example 1; Purification by preparative HPLC (YMC S-5 ODS-A column, 30 x 250 mm; solvent A: 0.1% TFA in 90% water and 10% methanol; solvent B: 0.1% TFA in 10% water and 90% methanol mixture; 20-100% B over 60 min, flow rate 25 mL / min) and converted to the HCl salt by adding 1N HCl to its TFA salt solution in methanol and lyophilizing.

MS (M + H) ⁺ 475.

1 H-NMR (CD a OD, 400 MHz) δ 8.85 (1H, s), 7.49-7.15 (7H, m), 6.81 (1H, m), 4.60 (2H, m), 4.49-4.35 (2H, m), 3.63 (1H, m), 2.84-2.63 (2H, m), 2.07 (2H, m), 1.94 (3H, s).

example < ^z

N

H

N

Me

130

4-Acetyl-2,3,4,5-tetrahydro-1- (1H-imidazol-4-ylmethyl) -3- (phenylmethyl) -1H-naphtho [2,3-e] -1,4-diazepine (monohydrochloride) )

A. 2,3,4,5-Tetrahydro-3- (phenylmethyl) -1H-naphtho [2,3-e] -1,4-diazepine-2,5dione

Isatoic acid anhydride 2,3-naphthyl analogue (made from 3-amino2-naphthalenecarboxylic acid, 2.3 equiv. Of triphosgene and triethylamine in acetonitrile), D, L-phenylalanine (0.77 g, 4.7 mmol) and pyridine hydrochloride (540 mg) (4.7 mmol) in pyridine (60 mL) was refluxed for 20 h. under nitrogen and then concentrated to an oil residue. Water (100 mL) was added and the solution was triturated to give a brown solid. This material was filtered off, dried in a deep vacuum to give 1.3 g (87%) of Compound A as a brown solid. MS (M + H) ⁺ 317.

B. 4-Acetyl-2,3,4,5-tetrahydro-1- (1H-imidazol-4-ylmethyl) -3- (phenylmethyl) -1H-naphtho [2,3-e] -1,4-diazepine (monohydrochloride) Example compound (off-white solid) is prepared from Compound A according to the procedures used to prepare the following compounds: Example 80 Compound C: Example 80 Compound D, with stirring for 1 hour. and purification by flash chromatography on silica gel eluting with ethyl acetate: hexanes (1: 5 to 1: 1); Example 80 for compound E.

MS (M + H) ⁺ 411.

Analysis calculated for C ₂₆ H ₂₆ N ₄ O 1.19 H ₂ O · 1.5 HCl.

Found: C, 64.44; H, 6.17; N, 11.02; Cl, 10.71.

Found: C, 64.04; H, 6.38; N, -11.40; Cl, 10.90.

example

131

N-Cyclohexyl-N '- [2,3,4,5-tetrahydro-1- (1H-imidazol-4-ylmethyl) -4- (1-naphthalenylcarbonyl) -1H-1,4-benzodiazepin-8-yl] urea (dihydrochloride) Example compound is prepared from cyclohexyl isocyanate according to the procedure described in Example 66; column chromatography eluted with CHCl 3 / CH 3 OH (19/1 then 9/1).

MS (M + H) &lt; ⁺ &gt; 523.

¹ H-NMR (270 MHz, CD ₃ OD) δ 8.83 (d, 1H, J = 19 Hz), 8.0-7.89 (m, 2.5H), 7.63-7.3 ( m, 6.5H), 7.23 (d, 0.5H, J = 7Hz), 6.8 (d, 0.5H, J = 8Hz), 6.31 (d, 0.5H, J = 7Hz), 5.83 (d, 0.5H, J = 8Hz), 4.8 (s, 1H), 4.6-3.8 (m, 4H), 3.6-3.5 (m, 1H), 3.45-3.3 (m, 2H), 3.0-2.8 (m, 1H), 1.9-1.58 (m, 5H), 1.48-1. 13 (m, 5H).

N

H

132

2,3,4,5-Tetrahydro-1- (1H-imidazol-4-ylmethyl) -4- (methylsulfonyl) -3 (phenylmethyl) -1H-naphtho [2,3-e] -1,4-diazepine (monohydrochloride) Example compound (off-white solid) is prepared from

2,3,4,5-Tetrahydro-3- (phenylmethyl) -1H-naphtho [2,3-e] -1,4-diazepine (prepared as described in Example 81) according to the procedure described in Example 78.

MS (M + H) ⁺ 447.

¹ H-NMR (CDCl 3, 400 MHz) δ 8.72 (1H, m), 7.7-7.1 (12H, m), 5.01 (1H, m), 4.43 (1H, s) , 4.41 (1H, s), 3.62 (1H, m), 3.15 (1H, m), 2.95 (1H, m), 2.72 (1H, m), 2.3 ( 3H, s).

2,2-Dimethyl-N- [2,3,4,5-tetrahydro-1- (1H-imidazol-4-ylmethyl) -4- (1-naphthalenecarbonyl) -1H-1,4-benzodiazepin-8-yl] propanamide (dihydrochloride) Example compound (white solid) is prepared from Example 26 compound and pivaloyl chloride according to the procedure described in Example 27.

MS (M + H) &lt; ⁺ &gt; 482.

¹ H-NMR (270 MHz, CD ₃ OD) δ 8.88 (d, 1H, J = 20 Hz), 8.05-7.89 (m, 2H), 7.87.4 (m, 6, 5H), 7.35 (d, 0.5H, J = 7Hz), 7.22 (d, 0.5H, J = 7Hz), 7.1 (d, 0.5H,

J = 8Hz), 6.6 (d, 0.5H, J = 8Hz), 5.9 (d, 0.5H, J = 8Hz), 4.6 (s, 1H), 4.5 (m,

2H), 4.22-3.9 (m, 2H), 3.4-3.3 (m, 2H), 3.05-2.85 (s, 1H), 1.3 (d, 9H, J = 16

Hz).

133

2,3,4,5-Tetrahydro-1- (1H-imidazol-4-ylmethyl) -4- (1-naphthalenylsulfonyl) -7-phenyl-1H-1,4-benzodiazepine (monohydrochloride)

A. 2,3,4,5-Tetrahydro-4- (1-naphthalenylsulfonyl) -7-phenyl-1H-1,4-benzodiazepine

To a solution of Example 12 Compound B (500 mg, 2.2 mmol) in dichloromethane (20 mL) was added 1-naphthylsulfonyl chloride (500 mg, 2.2 mmol) and triethylamine (0.31 mL, 2.2 mmol). The solution is stirred for 1 h, then concentrated, and the residue is partitioned between saturated aqueous sodium bicarbonate (30 mL) and ethyl acetate (40 mL). The organic layer was washed with saturated aqueous sodium bicarbonate (2 x 30 mL), water (1 x 30 mL), 1M potassium bisulfate (3 x 30 mL), dried (Na ₂ SO ₄ ), and concentrated to give 800 mg (88%). ) of compound A which is a white solid. MS (M + H) ⁺ 415.2.

B. 2,3,4,5-Tetrahydro-1- (1H-imidazol-4-ylmethyl) -4- (1-naphthalenylsulfonyl) -7-phenyl-1H-1,4-benzodiazepine (monohydrochloride) Example compound (off-white) solid) in 83% yield from Compound A according to the synthesis procedure for Compound D described in Example 1.

MS (M + H) &lt; ⁺ &gt; 415.

1 H-NMR (CD ₃ OD, 270 MHz) δ 8.83 (1H, s), 8.5 (1H, m), 8.24 (1H, d, J = 8

Hz), 8.11 (1H, J = 8 Hz), 7.94 (1H, m), 7.61-7.25 (9H, m), 7.02 (1H, d, J = 8

Hz), 4.61 (2H, s), 4.41 (2H, s), 3.52 (2H, m), 3.09 (2H, m).

Example 134

Br

4-Acetyl-7-bromo-2,3,4,5-tetrahydro-1- (1H-imidazol-4-ylmethyl) -3- (2-naphthalenylmethyl) -1H-1,4-benzodiazepine (dihydrochloride) Example Compound (white) solid) prepared from DL-2-naphthylalanine according to the procedure described in Example 80.

MS (M + H) ⁺ 475.

¹ H-NMR (CD ₃ OD, 400 MHz) δ 8.81 (1H, s), 7.84 (4H, m), 7.70 (1H, m), 7.507.25 (5H, m), δ , 87 (1H, m), 4.73-4.54 (3H, m), 4.43 (1H, m), 3.73 (1H, m), 3.23 (1H, m), 3, 05 (1H, m), 2.93 (1H, m), 2.13 (1H, m), 2.05 (3H, s).

example

Br

4-Acetyl-7-bromo-2,3,4,5-tetrahydro-1- (1H-imidazol-4-ylmethyl) -3- (1-naphthalenylmethyl) -1H-1,4-benzodiazepine (dihydrochloride)

Example 135 (white solid) is prepared from D.L-1-naphthylalanine according to the procedure described in Example 80.

MS (M + H) ⁺ 475.

¹ H-NMR (CD ₃ OD, 400 MHz) δ 8.53 (1H, s), 7.87 (1H, m), 7.74 (1H, m), 7,557.23 (8H, m), δ , 74 (1H, m), 4.57-4.43 (2H, m), 4.15 (1H, m), 3.90 (1H, m), 3.83 (1H, m), 3, 48 (2H, m), 3.12 (1H, m), 3.00 (1H, m), 2.06 (2H, m), 2.01 (3H, s).

7- (2-Chlorophenyl) -2,3,4,5-tetrahydro-1- (1H-imidazol-4-ylmethyl) -4- (1-naphthalenylcarbonyl) -1H-1,4-benzodiazepine (dihydrochloride)

A. 2-Chlorobenzeneboronic acid

A mixture of 2-bromo-chlorobenzene (5.4 mL, 46 mmol) and magnesium (chips, 1.12 g, 46 mmol) was added slowly to borane-THF (100 mL, 100 mmol). Place the flask in a water bath and sonicate overnight. Slowly add water (30 ml) to destroy the excess borane. The aqueous solution is refluxed for 2 hours. The solvent was evaporated and the residue was neutralized with aqueous HCl, the aqueous title was extracted with ether (2 x 50 mL), dried (Na ₂ SO ₄ ), and evaporated to give Compound A (6.24 g, 86%).

B. 7- (2-Chlorophenyl) -2,3,4,5-tetrahydro-1- (1H-imidazol-4-ylmethyl) -4- (1-naphthalenylcarbonyl) -1H-1,4-benzodiazepine (dihydrochloride)

Example 136 Compound (gray solid) is prepared in 55% yield from Compound A and Example 37 Compound A according to the procedure described in Example 60.

MS (M + H) &lt; ⁺ &gt; 493.

1 H-NMR (CDsOD, 300 MHz) δ 2.95 (ppm, 1H), 3.30 (m, 1H), 4.00 (ppm, 1H), 4.20 (ppm) , 1H), 4.40 (pi.d, 1H), 4.60 (m, 1H), 4.65 (m, 1H), 5.05 (s, 1H), 6.05 (d, 1H) , 7.00 (d, 1H), 7.15-8.10 (m, 13H), 8.85 (s, 1H), 8.95 (s, 1H).

2,3,4,5-Tetrahydro-1- (1H-imidazol-4-ylmethyl) -7-phenyl-1H-1,4-benzodiazepine (monohydrochloride)

2,3,4,5-Tetrahydro-4 - [(1,1-dimethylethoxy) carbonyl] -7-phenyl-1H-1,4-benzodiazepine (prepared from Example 12, Compound B according to Example 4). For synthesis A, a solution of 0.20 g) and 4-formylimidazole (0.52 g, 5.6 mmol) in CH ₂ Cl ₂ (10 mL) and acetic acid (2 mL) was stirred for 40 min. Sodium triacetoxyborohydride (0.9 g, 6 mmol) was added and stirred again for 4 h. Sodium bicarbonate (saturated, 5 ml) and ammonium hydroxide (almost 5 ml) are added and the mixture is stirred for a further 3 hours. The aqueous layer was extracted with CH ₂ Cl ₂ (3 x 50 mL). The combined organic layers were washed with 1N NaOH (2 x 10 mL) and nearly. NH ₄ OH (10 mL), dried (Na ₂ SO ₄ ) and evaporated. The remaining solid was stirred in MeOH (5 mL) and aqueous HCl in dioxane (4M, 10 mL) overnight. The solvent was evaporated and the residue triturated with CHCl ₃ to give a solid (0.35 g) which was purified by preparative HPLC (gradient of methanol / water with 0.1% TFA) to

137

HCl salt by lyophilization from 1M HCl (5 mL). Example 89 is obtained (0.12 g, 57%) which is an off-white solid.

MS (M + H) ⁺ 305.

¹ H-NMR (CD ₃ OD): 3.26 (m, 4H), 4.45 (s, 2H), 4.62 (s, 2H), 7.2-7.8 (m, 10H),

8.95 (s, 1H).

example

1-Methyl-N- [2,3,4,5-tetrahydro-1- (1H-imidazol-4-ylmethyl) -4- (1-naphthalenylcarbonyl) -1H-1,4-benzodiazepin-8-yl] -2- piperidine carboxamide (trihydrochloride) Example compound (yellowish solid) is prepared from Example 26 compound and N-methylpipecolic acid according to the procedure described in Example 62.

MS (M + H) &lt; ⁺ &gt; 523.

¹ H-NMR (270 MHz, CD ₃ OD): δ 8.9 (d, 1H, J = 22 Hz), 8.08-7.88 (m, 2.5H), 7.7-7.2 (m, 6H), 6.8 (d, 0.5H), 5.9 (m, 0.5H), 5.0 (m, 1.5H), 4.6 (s, 1H), 4.5 (m, 2H), 4.3-4.1 (m, 1H), 4.05-3.9 (m, 1H), 3.6-2.7 (m, 8H), 2.3 (t , 1H), 2,051.56 (m, 3H), 1.5-0.8 (m, 3H).

example

138

N- [2,3,4,5-Tetrahydro-1- (1H-imidazol-4-ylmethyl) -4- (1-naphthalenylcarbonyl) -1H-1,4-benzodiazepin-8-yl] -4-morpholinecarboxamide (dihydrochloride) Example 24 (yellowish solid) is prepared from Example 26 and morpholine-N-carbonyl chloride according to the procedure described in Example 27.

MS (M + H) <^+> 511.

¹ H-NMR (270 MHz, CD ₃ OD): δ 8.88 (kv, 1H), 8.1-7.88 (m, 2.5H), 7.7-7.3 (m, 6, 5H), 7.2 (t, 0.5H), 6.9 (d, 0.5H), 6.5 (d, 0.5H), 5.85 (d, 0.5H), 5.08 -4.9 (m, 2H), 4.6-4.15 (m, 4H), 3.7-3.65 (m, 3H), 3.6-3.4 (m, 4H), 3 , 4-3.28 (m, 2H), 3.15-2.8 (m, 1H).

example

N- [2,3,4,5-Tetrahydro-1- (1H-imidazol-4-ylmethyl) -4- (1-naphthalenylcarbonyl) -1H-1,4-benzodiazepin-8-yl] -3-methylbutanamide (dihydrochloride)

Example 139 Compound (yellowish solid) 67% yield is prepared from Example 26 and isobutyryl chloride according to the procedure described in Example 27 except that the reaction mixture is concentrated when the starting material is no longer visible; the residue was treated with MeOH and 1N NaOH for 30 min and after treatment the product was treated with HCl / ether.

MS (M + H) &lt; ⁺ &gt; 482.

¹ H-NMR (270 MHz, CD ₃ OD): δ 8.88 (d, 1H, J = 21 Hz), 8.08-7.9 (m, 2.5H), 7.7-7.19 (m, 6.5H), 6.81 (d, 0.5H), 5.9 (d, 0.5H), 4.9 (m, 1H), 4.6-3.9 (m, 4H) ),

3.6-3.08 (m, 2H), 3.0-2.76 (m, 4H), 2.3 (m, 1H), 2.05-1.5 (m, 3H), 1, 45-0.8 (m, 3H).

1,2,3,4-Tetrahydro-4 - [(1H-imidazol-4-yl) methyl] -1- (naphthalen-1-ylsulfonyl) quinoxaline (dihydrochloride)

A. 1,2,3,4-Tetrahydro-1- (naphthalen-1-ylsulfonyl) quinoxaline To a solution of Example 3 Compound A (270 mg, 2 mmol) in dichloromethane (8 mL) at room temperature under argon was added triethylamine (0, 42 mL, 3 mmol) and naphthalenesulfonyl chloride (500 mg, 2.2 mmol). After 18 or. the mixture was washed with saturated NaHCO ₃ followed by saturated NaCl (10 mL each), dried (MgSO ₄ ), and concentrated to a yellow solid, dichloromethane (1 mL) was added and compound A crystallized. The solution is purified by column chromatography over silica eluting with 30%

140 ethyl acetate in hexanes to give compound A. Total yield 560 mg, 87%. MS: (M + H) &lt; ⁺ &gt; = 325 ⁺ .

B. 1,2,3,4-Tetrahydro-4 - [(1H-imidazol-4-yl) methyl] -1- (naphthalen-1-ylsulfonyl) quinoxaline (dihydrochloride) Example compound (slightly yellow solid) is prepared from the compound A according to the procedure for the preparation of compound D described in Example 1. Purification by flash column chromatography on silica gel eluting with 9: 1 CHCl ₃ : MeOH afforded a solid which was converted to the HCl salt by treatment with 1M HCl in ether (95 mg, 80%).

MS (M + H + = 405).

¹ H-NMR (free base) (CDCl ₃ ): δ 8.22 (1H, d, J = 7.3 Hz), 8.15 (1H, d, J = 8 Hz), 8.02 (1H, d, J = 8Hz), 7.87 (1H, d, J = 7.3Hz), 7.49 (2H, t, Jd 8Hz), 7.39 (1H, s), 7.37 (1H , s), 7.31 (1H, t, J = 7.3 Hz), 7.26 (1H, s), 7.02 (1H, t, J = 7.3 Hz), 6.65 (1H , t, J = 7.3 Hz), 6.54 (1H, d, J = 8.0 Hz), 6.0 (1H, s), 4.0 (2H, s), 3.83 (2H) , t, J = 5.3 Hz), 2.85 (2H, t, J = 5.3 Hz).

example

N

H

1,2,3,5-Tetrahydro-1- (1H-imidazol-4-ylmethyl) -N, N, 7-triphenyl-4H-1,4-benzodiazepine-4-carboxamide (dihydrochloride) Example compound (slightly pink powder) prepared from N, N-diphenylcarbamyl chloride according to the procedure described in Example 35. Lyd.

mp:> 200 ° C.

MS (M + H) &lt; ⁺ &gt; 500.

141

Analysis calculated for C 32 H ₂₉ N ₅ O · 0.4 H ₂ O · 1.0 HCl. Found: C, 70.75; H, 5.71; N, 12.89; Cl, 6.53.

Found: C, 70.89; H, 5.53; N, 12.77; Cl, 6.65.

1,2,3,5-Tetrahydro-1- (1H-imidazol-4-ylmethyl) -3- (phenylmethyl) -4H-naphtho [2,3-e] -1,4-diazepine-4-carboxylic acid methyl ester (monohydrochloride) ) The compound of Example 1 (off-white solid) is prepared from methyl chloroformate according to the procedure described in Example 83.

MS (M + H) &lt; ⁺ &gt;

¹ H-NMR (CD 3 OD, 400 MHz): δ 8.72 (1H, m), 7.7-7.1 (12H, m), 5.01 (1H, m), 4.43 (1H, s), 4.41 (1H, s), 3.62 (1H, m), 3.15 (1H, m), 2.95 (1H, m), 2.72 (1H, m), 2 , 6 (3H, s).

example

142

2,3,4,5-Tetrahydro-1- (1H-imidazol-4-ylmethyl) -7-phenyl-4 - [(4-phenyl-1,2,3-thiadiazol-5-yl) carbonyl] -1H- 1,4-Benzodiazepine (trifluoroacetate) Example compound (white lyophilisate) 50% yield is prepared from 4-phenyl-5-carboxy-1,2,3-thiadiazole according to the procedure described in Example 34 by purification of the compound by preparative HPLC (0 , 1% TFA gradient).

MS (M + H) &lt; ⁺ &gt; 493.

Analysis calculated for C ₂₈ H ₂₄ N ₆ OS · 0.11 H ₂ O · 1.6 TFA.

Excluded; C, 55.35; H, 3.84; N, 12.41.

Found: C, 55.28; H, 3.71; N, 12.37.

2,3,4,5-Tetrahydro-1- (1H-imidazol-4-ylmethyl) -7-phenyl-4 - [(4-phenyl-1,2,3-thiadiazol-5-yl) carbonyl] -1H- 1,4-benzodiazepine (trifluoroacetate)

Example 143 (white lyophilisate) was prepared in 6% yield from 2,3-methylenedioxybenzoic acid according to the procedure described in Example 34 by purification by preparative HPLC (gradient of aqueous methanol with 0.1% TFA).

MS (M + H) ⁺ 453.

¹ H-NMR (CD ₃ OD): 3.11 (m, 1H), 3.61 (m, 1H), 3.87 (ppm, 2H), 4.61-4.64 (m, 2H). ), 5.81, 6.06 (s, 2H), 5.96 (s, 2H), 6.68-7.69 (m, 12H), 8.42 (m, 1H), 8.89 ( m, 1H).

example

8 - [[(Cyclohexylamino) carbonyl] amino] -2,3,4,5-tetrahydro-1- (1H-imidazol-4-ylmethyl) -3- (phenylmethyl) -1H-1,4-benzodiazepine-4-carboxylic acid

1,1-Dimethylethyl ester

A. 2,3,4,5-Tetrahydro-3- (phenylmethyl) -8-nitro-1H-1,4-benzodiazepine-2,5-dione

Compound A was prepared from 7-nitroisatoic acid anhydride and phenylalanine according to the procedure described in Example 1 for the preparation of Compound A, except that after refluxing for 1 day, the mixture was concentrated. Dimethylacetamide is added and the mixture is heated at 150 ° C for 4 hours, concentrated and water is added. Yellowish-green

The 144 solid was filtered off and air-dried to give Compound A (80% yield). MS (M + H) ⁺ 312.

B. 2,3,4,5-Tetrahydro-3- (phenylmethyl) -8-nitro-1H-1,4-benzodiazepine to compound A (7.5 g, 24.01 mmol) in borane solution THF (1M, 86 ml), the mixture was refluxed for 2 days, cooled to room temperature, acidified with 3N HCl and heated for 30 min. The solid was filtered off and dried to give Compound B (3.75 g, 95%) as a yellow-green solid. MS (M + H) ⁺ 254. The filtrate was basified with 5N NaOH (pH 8-9), extracted with CHCl ₃ , dried over MgSO ₄ , filtered, and concentrated to give 2,3,4,5-tetrahydro-3 (phenyl) - 8-amino-1H-1,4-benzodiazepine (1.1 g, 21%).

C. 8-Nitro-2,3,4,5-tetrahydro-3- (phenylmethyl) -1H-1,4-benzodiazepine-4-carboxylic acid 1,1-dimethylethyl ester into compound B (2.0 g, 7 mmol) and of a solution of triethylamine (0.71 g, 7 mmol) in THF (30 mL) under argon was added Boc anhydride (1.5 g, 7 mmol). After stirring for 6 h, the mixture was extracted with CHCl ₃ (3 x 70 mL). The combined extracts were washed with water (2 x 50 mL) and saturated NaCl (1 x 50 mL), dried over MgSO ₄ , filtered, and concentrated. The residue was triturated with hexane / CHCl ₃ to give Compound C as a yellow-green solid (0.89 g, 34%). MS (MH +) 382.

D. 1,1-Dimethylethyl ester of 8-nitro-2,3,4,5-tetrahydro-1- (1H-imidazol-4-ylmethyl) -3- (phenylmethyl) -1H-1,4-benzodiazepine-4-carboxylic acid

Compound D is prepared from Compound C according to the procedure described in Example 1 for the preparation of Compound D with stirring for 15 hours. MS (M + H) ⁺ 464.

E. 1,1-Dimethylethyl ester of 8-amino-2,3,4,5-tetrahydro-1- (1H-imidazol-4-ylmethyl) -3- (phenylmethyl) -1H1,4-benzodiazepine-4-carboxylic acid To a solution of compound D (1.0 g, 2.15 mmol) in AcOH / H ₂ O (16 mL, 1: 1) was added 16% aqueous TiCl ₃ (2.66 g in 15 mL H ₂ O, 17.2 mmol). After mixing

145 min, the mixture was basified with 5N NaOH, stirred for 30 min. and extracted with 10% isopropanol / CH ₂ Cl ₂ . The layers were separated, the aqueous layer was extracted with 10% isopropanol / CH ₂ Cl ₂ , the combined organic layers were dried over MgSO ₄ , filtered and concentrated to give Compound E (0.70 g, 75%). MS (M + H) ⁺ 434.

F. 8 - [[(Cyclohexylamino) carbonyl] amino] -2,3,4,5-tetrahydro-1- (1H-imidazol-4-ylmethyl) -3- (phenylmethyl) -1H-1,4-benzodiazepine-4-carboxylic acid

1,1-Dimethylethyl ester

Compound F is prepared from compound E according to the procedure described in Example 27 using cyclohexyl isocyanate. The reaction mixture was concentrated and the residue was treated with 1N NaOH and MeOH. After stirring for 30 min, the mixture was diluted with CHCl ₃ and NaHCO ₃ . The layers were separated and the aqueous layer was extracted twice with CHCl ₃ . The combined organic layers were washed with water, saturated with NaCl, dried over MgSO ₄ , filtered, and concentrated to give Example 98 as a yellowish solid. MS: [M + H] ⁺ = 559 ⁺ .

MS (M + H) ⁺ 559.

146

2,3,4,5-Tetrahydro-1- (1H-imidazol-4-ylmethyl) -8 - [[(4-methylphenyl) sulfonyl] amino] -3- (phenylmethyl) -1H-1,4-benzodiazepine-4-carboxylic acid 1 , 1-dimethylethyl ester

J 8-Amino-2,3,4,5-tetrahydro-1- (1H-imidazol-4-ylmethyl) -3- (phenylmethyl) -1H1,4-benzodiazepine-4-carboxylic acid 1,1-dimethylethyl ester (prepared according to the procedure described in Example 98 for the synthesis of compound E, 0.125 g, 0.28 mmol) and triethylamine (0.048 mL, 0.34 mmol) in CH ₂ Cl ₂ (1 mL) at 0 ° C under argon was added p-toluenesulfonyl chloride ( 0.054 g, 0.34 mmol). After stirring for 16 h, the mixture was concentrated and the residue was treated with 1N NaOH (0.6 mL) and MeOH (1 mL). After stirring for 30 min, the reaction mixture was diluted with CHCl 3 (5 mL) and NaHCO ₃ (3 mL). The layers were separated and the aqueous layer was extracted with CHCl3 (2 x 20 mL). The combined organic layers were washed with water (1x5 mL), saturated NaCl (1x5 mL), dried over MgSO ₄ , filtered, and concentrated to give Example 99 (0.15 g, 89%) as a yellowish solid.

MS (M + H) &lt; ⁺ &gt; 588.

Example 100

Br

7-Bromo-1,2,3,4-tetrahydro-1- (1H-imidazol-4-ylmethyl) -3- (phenylmethyl) -5H-1,4-benzodiazepin-5-one (dihydrochloride)

A. 7-Bromo-2,3,4,5-tetrahydro-3- (phenylmethyl) -1H-1,4-benzodiazepin-5-one

147

To a suspension of 0.5 g (1.45 mmol) of Example 75 Compound A in 5 mL of THF at room temperature and under argon is added 3 mL (3 mmol) of a 1M borane solution in THF. A clear, yellow solution is obtained. Stir overnight, then add 2 mL (2 mmol) of 1M borane in THF again and stir for a further 8 h. After hydrolysis of the excess borane by dropwise addition of methanol, the reaction mixture is evaporated to dryness and the residue is dissolved in 0.5 ml methanol and 0.5 ml almost. HCl in the mixture. The resulting solution was refluxed for 2 hours, cooled to room temperature and evaporated to dryness. The residue is isolated from methanol by addition and evaporation three times, dissolved in ethyl acetate, and the solution is washed with saturated NaCl, dried and the solvent is evaporated to give a viscous yellow oil. Purification by flash chromatography on silica gel eluting with 50% ethyl acetate in hexane afforded 205 mg (0.62 mmol, 43%) of Compound A as a white solid.

B. 7-Bromo-1,2,3,4-tetrahydro-1- (1H-imidazol-4-ylmethyl) -3- (phenylmethyl) -5H1,4-benzodiazepin-5-one (dihydrochloride)

Example 100 Compound (off-white solid) is prepared in 60% yield from Compound A according to the procedure described in Example 1 for the synthesis of Compound D by purification by preparative HPLC (aqueous methanol with 0.1% TFA gradient) and conversion to the HCl salt in HCl-MeOH.

MS (M + H) ⁺ 411.

Analysis calculated for C ₂ H ₉ N ₄ Br · 0.5 C ₂ HwO · 1.5 HCl.

Found: C, 52.53; H, 5.11; N, 11.14.

Found: C, 52.82; H, 4.7i; N, 11.52.

101-201 Examples

Copulation of each carboxylic acid with Example 33 Compound B was performed using standard HOAt / DIC-mediated copulation. The process was automated using a Hamilton 2200 fluid manipulator. Test tubes for weighing and the resulting amides

148 were cleaned using a Zymark Benchmate® robotic device. An IBM PC was used to manage the Zymark Benchmate® device operating system and to develop Benchmate® methodologies. The following examples illustrate the standard procedure for the preparation of amides:

j Place the appropriate carboxylic acid (0.10 mmol, 1 equiv.) in a 16x100 mm tube and perform the following operations on the liquid handler:

1) 0.5 ml of a 0.2M solution of 1-hydroxy-7-aza-benzotriazole (HOAt) in DMF is added;

2) 0.5 ml of a solution of Example 33 Compound B (0.2 M, 0.10 mmol, 1.0 equiv) in DMF is added;

3) 1.0 mL of a solution of diisopropylcarbodiimide (0.016 mL, 0.10 mmol, 1.0 equiv) in methylene chloride was added;

4) Mix the contents of the tube by turning for 30 seconds. 3 speeds.

After 24 or. the mixture is concentrated using a Savant Speed Vac device (about 2 mm Hg column for 72 h). The residue is purified by ion-exchange chromatography over a solid phase extraction cartridge controlled by a Benchmate® robotic apparatus using the following procedure:

1) Add 5.0 ml of methanol / methylene chloride (1.Ί) to the reaction mixture:

2) mix the contents of the tube for 60 seconds. 3 speeds;

3) A Varian solid phase extraction column (1.5 g, SCX cation exchanger) is conditioned with 10 mL of methanol / methylene chloride at 0.15 mL / sec. Speed

4) Pour the reaction mixture onto the column at 0.02 mL / sec. Speed

5) Wash the column with 2 x 7.5 mL methanol / methylene chloride (1: 1) at 0.1 mL / sec. Speed

6) Wash the column with 1 x 7.5 mL methanol at 0.1 mL / sec. Speed

7) washing the column with 0.01 M ammonia in methanol;

149

8) The column is eluted with 7.5 ml of 1M ammonia in methanol and the eluate is collected in a tared trap at 0.05 ml / sec. speed.

After adding any solution / solvent, 1.0 ml of air is added and the reaction mixture is introduced into the ion exchange column for 5 seconds before starting the column. detention. The product solution is concentrated using a Savant Speed Vac device (about 2 mm Hg column for 20 hours) to give the desired compound.

For syntheses requiring further purification, use preparative HPLC (YMC S5 ODS 50 x 100 mm, 30 ml / min, 10 min. 10-90% aqueous methanol with 0.1% TFA gradient, 220 nm control) ). Appropriate fractions were mixed and concentrated in vacuo. The residue was dissolved in methanol (5 mL) and 1N HCl (1 mL) and concentrated by Savant Speed Vac (about 2 mm Hg column for 20 h) to give the title compound. These compounds were characterized by analytical HPLC and mass spectrometry.

For example, Structure of the masses

101

102

2,3,4,5-Tetrahydro-1- (1H-imidazol-4-ylmethyl) -4- [1-oxo-3- (1-piperidinyl) propyl] -7-phenyl-1H

1,4-benzodiazepine (trihydrochloride)

2,3,4,5-Tetrahydro-1- (1H-imidazol-4-ylmethyl) -7-phenyl-4- (4-quinolinylcarbonyl) -1H-1,4-benzodiazepine (trihydrochloride) m / z 444 (M + + H) m / z 460 (M + H)

150

4 - [(5-bromo-3-pyridinyl) carbonyl]

2.3.4.5-Tetrahydro-1- (1H-imidazol-4-yl-ethyl) -7-phenyl-1H-1,4-benzodiazepine (trihydrochloride) (S) -4- [2- (dimethylamino) -1-oxo-3-phenylpropyl] -2 , 3,4,5-Tetrahydro-1- (1H-imidazol-4-ylmethyl) -7-phenyl · 1H-1,4-benzodiazepine (trihydrochloride)

2.3.4.5-Tetrahydro-4- [4-hydroxy-3- (4-morpholinylmethyl) benzoyl] -1- (1H-imidazol-4-ylmethyl) -7-phenyl-1H-1,4-benzodiazepine (trihydrochloride) (S) -2 , 3,4,5-Tetrahydro-1- (1H-imidazol-4-ylmethyl) -4 - [(1-methyl-2-pyrrolidinyl) carbonyl] -7-phenyl-1 H -1,4-benzodiazepine (trihydrochloride)

2.3.4.5-Tetrahydro-1- (1H-imidazol-4-ylmethyl) -7-phenyl-4 - [[2 (propylthio) -3-pyridinyl] carbonyl] 1H-1,4-benzodiazepine (trihydrochloride) m / z 489 (M + H) m / z 480 (M + H) m / z 524 (M + H) m / z 416 (M + H) m / z 484 (M + H)

151

111

112

108

109

110

4 - [(2-Chloro-6-methyl-4-pyridinyl) carbonyl] -2,3,4,5-tetrahydro-1- (1H-imidazol-4-ylmethyl) -7-phenyl-1H-1,4-benzodiazepine (trihydrochloride)

2,3,4,5-Tetrahydro-1- (1H-imidazol-4-ylmethyl) -7-phenyl-4 - [[2 (phenylthio) -3-pyridinyl] carbonyl] -1 H -1,4-benzodiazepine (trihydrochloride)

2,3,4,5-Tetrahydro-1- (1H-imidazol-4-ylmethyl) -4 - [[2- (4-methylphenoxy) -3-pyridinyl] carbonyl] -7-phenyl-1H-1,4-benzodiazepine ( trihydrochloride)

2.3.4.5-Tetrahydro-1- (1H-imidazol-4-ylmethyl) -4 - [(2-methoxy-3-pyridinyl) carbonyl] -7-phenyl-1H-1,4-benzodiazepine (trihydrochloride)

2.3.4.5-Tetrahydro-1- (1H-imidazol-4-ylmethyl) -7-phenyl-4 - [(5-phenyl-4-oxazole I) carbonyl] -1 H -1,4-benzodiazepine (dihydrochloride) m / z 458 (M +) H) m / z 518 (M + H) m / z 516 (M + H) m / z 440 (M + H) m / z 476 (M + H)

152

115 \

J °

4-Acetyl-2,3,4,5-tetrahydro-1- (1H-imidazol-4-ylmethyl) -7-phenyl-1H-1,4-benzodiazepine (dihydrochloride)

2.3.4.5-Tetrahydro-1- (1H-imidazol-4-ylmethyl) -7-phenyl-4 - [(tetrahydro-3-furanyl) carbonyl] -1H-1,4-benzodiazepine (dihydrochloride)

2.3.4.5-Tetrahydro-1- (1H-imidazol-4-ylmethyl) -4 - [(2-methoxyethoxy) acetyl] -7-phenyl-1 H -1,4-benzodiazepine (dihydrochloride)

2.3.4.5-Tetrahydro-1- (1H-imidazol-4-ylmethyl) -4- [4- (4-morpholinylmethyl) benzoyl] -7-phenyl-1H-1,4-benzodiazepine (trihydrochloride)

2.3.4.5-Tetrahydro-1- (1H-imidazol-4-ylmethyl) -4- [4- (methylsulfonyl) benzoyl] -7-phenyl-1H-1,4-benzodiazepine (dihydrochloride)

2,3,4,5-Tetrahydro-1- (1H-imidazol-4-ylmethyl) -4- [1-oxo-3- (phenylsulfonyl) propyl] -7-phenyl-1 H -1,4-benzodiazepine (dihydrochloride) m / z 347 (M + H) m / z 403 (M + H) m / z 421 (M + H) m / z 508 (M + H) m / z 487 (M + H) m / z 501 (M + H)

153

119

2.3.4.5-Tetrahydro-1- (1H-imidazol-4-ylmethyl) -7-phenyl-4- (3-pyridinylacetyl) -1H-1,4-benzodiazepine (trihydrochloride)

2.3.4.5-Tetrahydro-1- (1H-imidazol-4-ylmethyl) -7-phenyl-4- (2-quinoxalinylcarbonyl) -1H-1,4-benzodiazepine (tetrahydrochloride)

2.3.4.5-Tetrahydro-1- (1H-imidazol-4-ylmethyl) -4- (4-isoquinolinylcarbonyl) -7-phenyl-1 H -1,4-benzodiazepine (trihydrochloride)

4 - [(2-Chloro-3-pyridinyl) carbonyl] 2,3,4,5-tetrahydro-1- (1H-imidazol-4-ylmethyl) -7-phenyl-1H-1,4-benzodiazepine (trihydrochloride)

2,3,4,5-Tetrahydro-1- (1H-imidazol-4-ylmethyl) -7-phenyl-4- (3-pyridinylcarbonyl) -1H-1,4-benzodiazepine (trihydrochloride) m / z 424 (M + H) m / z z 461 (M + H) m / z 460 (M + H) m / z 444 (M + H) m / z 410 (M + H)

154

4 - [(2,6-Dimethoxy-3-pyridinyl) carbonyl] -2,3,4,5-tetrahydro-1- (1H-imidazol-4-ylmethyl) -7-phenyl-1H-1,4-benzodiazepine (trihydrochloride)

2,3,4,5-Tetrahydro-1- (1H-imidazol-4-ylmethyl) -7-phenyl-4- (2-pyrazinylcarbonyl) -1H-1,4-benzodiazepine (tetrahydrochloride) 4- (2-ethoxybenzoyl) -2, 3,4,5-Tetrahydro-1- (1H-imidazol-4-ylmethyl) -7-phenyl-1H-1,4-benzodiazepine (dihydrochloride)

4- [3- (dimethylamino) benzoyl] 2.3.4.5-tetrahydro-1- (1H-imidazol-4-ylmethyl) -7-phenyl-1H-1,4-benzodiazepine (trihydrochloride)

2.3.4.5-Tetrahydro-1- (1H-imidazol-4-ylmethyl) -7-phenyl-4 - [(1-phenylcyclopropyl) carbonyl] -1H-1,4-benzodiazepine (dihydrochloride) m / z 470 (M + H) m / z 411 (M + H) m / z 453 (M + H) m / z 452 (M + H) m / z 449 (M + H)

155

131

132

133

129

130

4 - [(Bicyclo [4.2.0] octa-1,3,5-trien-7-yl) carbonyl] -2,3,4,5-tetrahydro-1- (1H-imidazol-4-ylmethyl) -7-phenyl1 H -1,4-benzodiazepine (dihydrochloride)

4-Benzoyl-2,3,4,5-tetrahydro-1- (1H-imidazol-4-ylmethyl) -7-phenyl-1H-1,4-benzodiazepine (dihydrochloride)

4- (2-Chlorobenzoyl) -2,3,4,5-tetrahydro-1- (1H-imidazol-4-ylmethyl) -7-phenyl-1H-1,4-benzodiazepine (dihydrochloride)

4- (2,3-Dichlorobenzoyl) -2,3,4,5-tetrahydro-1- (1H-imidazol-4-ylmethyl) -7-phenyl-1H-1,4-benzodiazepine (dihydrochloride)

N- [2 - [[2,3,4,5-Tetrahydro-1- (1H-imidazol-4-ylmethyl) -7-phenyl-1H-1,4-benzodiazepin-4yl] carbonyl] phenyl] acetamide (dihydrochloride) m / z 435 (M + H) m / z 409 (M + H) m / z 443 (M + H) m / z 478 (M + H) m / z 466 (M + H)

156

134

135

136

137

2,3,4,5-Tetrahydro-1- (1H-imidazol-4-ylmethyl) -4- (2-phenoxybenzoyl) -7-phenyl-1H-1,4-benzodiazepine (dihydrochloride)

2,3,4,5-Tetrahydro-1- (1H-imidazol-4-ylmethyl) -4- (2-methoxybenzoyl) -7-phenyl-1H-1,4-benzodiazepine (dihydrochloride)

4- (2,3-Dimethoxybenzoyl) -2,3,4,5-tetrahydro-1- (1H-imidazol-4-ylmethyl) -7-phenyl-1H-1,4-benzodiazepine (dihydrochloride)

4- (2,4-Dimethoxybenzoyl) -2,3,4,5-tetrahydro-1- (1H-imidazol-4-ylmethyl) -7-phenyl-1H-1,4-benzodiazepine (dihydrochloride)

4- (2,5-Dimethoxybenzoyl) -2,3,4,5-tetrahydro-1- (1H-imidazol-4-ylmethyl) -7-phenyl-1H-1,4-benzodiazepine (dihydrochloride) m / z 501 (M + H) ) m / z 439 (M + H) m / z 469 (M + H) m / z 469 (M + H) m / z 469 (M + H)

138

157

141

142

139

140

4- (2,6-Dimethoxybenzoyl) -2,3,4,5-tetrahydro-1- (1H-imidazol-4-ylmethyl) -7-phenyl-1H-1,4-benzodiazepine (dihydrochloride)

4- (2,3-Dihydroxybenzoyl) -2,3,4,5-tetrahydro-1- (1H-imidazol-4-ylmethyl) -7-phenyl-1H-1,4-benzodiazepine (dihydrochloride)

4 - ([1,1'-Biphenyl] -2-ylcarbonyl) 2,3,4,5-tetrahydro-1- (1H-imidazol-4-ylmethyl) -7-phenyl-1H-1,4-benzodiazepine (dihydrochloride)

2,3,4,5-Tetrahydro-1- (1H-imidazol-4-ylmethyl) -4- (2-methylbenzoyl) -7-phenyl-1H-1,4-benzodiazepine (dihydrochloride) m / z 469 (M + H) m / z 439 (M + H) m / z 485 (M + H) m / z 423 (M + H)

158

145

146

143

144

4- (2,3-Dimethylbenzoyl) -2,3,4,5-tetrahydro-1- (1H-imidazol-4-ylmethyl) -7-phenyl-1H-1,4-benzodiazepine (dihydrochloride)

4- (3-Cyanobenzoyl) -2,3,4,5-tetrahydro-1- (1H-imidazol-4-ylmethyl) -7-phenyl-1H-1,4-benzodiazepine (dihydrochloride)

4- (3-Chlorobenzoyl) -2,3,4,5-tetrahydro-1- (1H-imidazol-4-ylmethyl) -7-phenyl-1H-1,4-benzodiazepine (dihydrochloride)

2.3.4.5-Tetrahydro-1- (1H-imidazol-4-ylmethyl) -4- (3-phenoxybenzoyl) -7-phenyl-1H-1,4-benzodiazepine (dihydrochloride)

2.3.4.5-Tetrahydro-1- (1H-imidazol-4-ylmethyl) -4- (3-methoxybenzoyl) -7-phenyl-1H-1,4-benzodiazepine (dihydrochloride) m / z 437 (M + H) m / z 434 (M + H) m / z 443 (M + H) m / z 501 (M + H) m / z 439 (M + H)

147

159

4- (3,4-Dimethoxybenzoyl) -2,3,4,5-tetrahydro-1- (1H-imidazol-4-ylmethyl) -7-phenyl-1H-1,4-benzodiazepine (dihydrochloride)

4- (3,5-Dimethoxybenzoyl) -2,3,4,5-tetrahydro-1- (1H-imidazol-4-ylmethyl) -7-phenyl-1H-1,4-benzodiazepine (dihydrochloride)

2,3,4,5-Tetrahydro-1- (1H-imidazol-4-ylmethyl) -4- (3-methylbenzoyl) -7-phenyl-1H-1,4-benzodiazepine (dihydrochloride)

4- (1,2-Dioxo-2-phenylethyl) -2,3,4,5-tetrahydro-1- (1H-imidazo-4-ylmethyl) -7-phenyl-1H-1,4-benzodiazepine (dihydrochloride)

4 - [(2-Ethoxy-1-naphthalenyl) carbonyl] -2,3,4,5-tetrahydro-1- (1H-imidazol-4-ylmethyl) -7-phenyl-1H-1,4-benzodiazepine (dihydrochloride) m / z 469 ( M + H m / z 469 (M + H) m / z 423 (M + H) m / z 437 (M + H) m / z 503 (M + H)

160

155

156

153

154

2,3,4,5-Tetrahydro-1- (1H-imidazol-4-ylmethyl) -4- (2-naphthalenylcarbonyl) -7-phenyl-1H-1,4-benzodiazepine (dihydrochloride)

4- (Fluorophenylacetyl) -2,3,4,5-tetrahydro-1- (1H-imidazol-4-ylmethyl) -7-phenyl-1H-1,4-benzodiazepine (dihydrochloride)

4- (Diphenylacetyl) -2,3,4,5-tetrahydro-1- (1H-imidazol-4-ylmethyl) -7-phenyl-1H-1,4-benzodiazepine (dihydrochloride)

2,3,4,5-Tetrahydro-4- (2-hydroxy-1-oxo-2-phenylpropyl) -1- (1H-imidazol-4-ylmethyl) -7-phenyl-1H-1,4-benzodiazepine (dihydrochloride)

2,3,4,5-Tetrahydro-1- (1H-imidazol-4-ylmethyl) -4- (1H-indol-2-ylcarbonyl) -7-phenyl-1H-1,4-benzodiazepine (dihydrochloride) m / z 459 (M + H) m / z 441 (M + H) m / z 499 (M + H) m / z 453 (M + H) m / z 448 (M + H)

157

161

m / z 448 (M + H)

2,3,4,5-Tetrahydro-1- (1H-imidazol-4-ylmethyl) -4- (1H-indol-3-ylcarbonyl) -7-phenyl-1H-1,4-benzodiazepine (dihydrochloride)

2,3,4,5-Tetrahydro-1- (1H-imidazol-4-ylmethyl) -4- (1H-indol-5-ylcarbonyl) -7-phenyl-1H-1,4-benzodiazepine (dihydrochloride)

2,3,4,5-Tetrahydro-1- (1H-imidazol-4-ylmethyl) -4 - [(1-methyl-1H-indol-2-yl) carbonyl] -7-phenyl-1H-1,4-benzodiazepine (dihydrochloride) Benzofuranylcarbonyl-2,3,4,5-tetrahydro-1- (1H-imidazol-4-ylmethyl) -7-phenyl-1H-1,4-benzodiazepine (dihydrochloride) 2,3,4,5-tetrahydro-1- (1H-imidazol-4) -ylmethyl) -7-phenyl-4- (3-pyridinylcarbonyl) -1H-1,4-benzodiazepine (N-oxide, dihydrochloride)

2,3,4,5-Tetrahydro-1- (1H-imidazol-4-ylmethyl) -7-phenyl-4- (2-pyridinecarbonyl) -1H-1,4-benzodiazepine (trihydrochloride) m / z 448 (M + H) m / z 462 (M + H) m / z 449 (M + H) m / z 426 (M + H) m / z 410 (M + H)

162

164

165

2.3.4.5-Tetrahydro-1- (1H-imidazol-4-ylmethyl) -7-phenyl-4- (2-quinolylcarbonyl) -1H-1,4-benzodiazepine (trihydrochloride)

2.3.4.5-Tetrahydro-1- (1H-imidazol-4-ylmethyl) -7-phenyl-4- (1-isoquinolinylcarbonyl) -1H-1,4-benzodiazepine (trihydrochloride)

166 m / z 460 (M + H) m / z 460 (M + H)

4- (3-Chloro-2-nitrobenzoyl) 2,3,4,5-tetrahydro-1- (1H-imidazol-4-ylmethyl) -7-phenyl-1H-1,4-benzodiazepine (dihydrochloride)

167 m / z 488 (M + H)

2,3,4,5-Tetrahydro-1- (1-imidazol-4-ylmethyl) -4- (2-nitrobenzoyl) -. 7-phenyl-1H-1,4-benzodiazepine (dihydrochloride) m / z 454 (M + H).

2,3,4,5-Tetrahydro-1- (1H-imidazol-4-ylmethyl) -4- (3-methoxy-2-nitrobenzoyl) -7-phenyl-1H-1,4-benzodiazepine (dihydrochloride) m / z 484 (M +) H)

168

163

m / z 448 (M + H)

2,3,4,5-Tetrahydro-1- (1H-imidazol-4-ylmethyl) -4- (1H-indol-4-ylcarbonyl) -7-phenyl-1H-1,4-benzodiazepine (dihydrochloride)

4 - [(2,6-Dihydroxy-3-naphthalenyl) carbonyl] -2,3,4,5-tetrahydro-1- (1H-imidazol-4-ylmethyl) -7-phenyl-1H-1,4-benzodiazepine (dihydrochloride)

4- (1H-Benzimidazol-5-ylcarbonyl) -2,3,4,5-tetrahydro-1- (1H-imidazol-4-ylmethyl) -7-phenyl-1H-1,4-benzodiazepine (trihydrochloride)

4- (1H-benzotriazol-5-ylcarbonyl) 2.3.4.5-tetrahydro-1- (1H-midazol-4-ylmethyl) -7-phenyl-1H-1,4-benzodiazepine (dihydrochloride)

2.3.4.5-Tetrahydro-1- (1H-imidazol-4-ylmethyl) -4 - [(4-methoxy-2-quinolinyl) carbonyl] -7-phenyl-1H-1,4-benzodiazepine (trihydrochloride) m / z 491 (M + H) m / z 449 (M + H) m / z 450 (M + H) m / z 490 (M + H)

164

174

175

176

177

178 \

N - [3 - [[2,3,4,5-Tetrahydro-1- (1H-imidazol-4-ylmethyl) -7-phenyl-1H-1,4-benzodiazepin-4-yl] carbonyl] phenyl] -acetamide (dihydrochloride)

2.3.4.5-Tetrahydro-1- (1H-imidazol-4-ylmethyl) -4- (2-methyl-1-oxo-2-phenylpropyl) -7-phenyl-1 H -1,4-benzodiazepine (dihydrochloride)

4- [2- (dimethylamino) benzoyl] 2.3.4.5-tetrahydro-1- (1H-midazol-4-ylmethyl) -7-phenyl-1H-1,4-benzodiazepine (trihydrochloride)

4- (3-Ethoxybenzoyl) -2,3,4,5-tetrahydro-1- (1H-imidazol-4-ylmethyl) -7-phenyl-1H-1,4-benzodiazepine (dihydrochloride)

2.3.4.5-Tetrahydro-4- (2-hydroxy [1,1'-biphenyl] -3i-carbonyl) -1- (1H-imidazol-4-ylmethyl) -7-phenyl-1H-1,4-benzodiazepine (dihydrochloride) m / z 466 (M + H) m / z 451 (M + H) m / z 452 (M + H) m / z 453 (M + H) m / z 501 (M + H)

165

179

180

2.3.4.5-Tetrahydro-4- [2 [(2-hydroxyethyl) thio] benzoyl] -1- (1H-imidazol-4-ylmethyl) -7-phenyl-1H-1,4-benzodiazepine (dihydrochloride)

2.3.4.5-Tetrahydro-1- (1H-imidazol-4-ylmethyl) -4 - [(2-methoxy-1-naphthalenyl) carbonyl] -7-phenyl-1H-1,4-benzodiazepine (dihydrochloride)

181 m / z 485 (M + H) m / z 489 (M + H)

2,3,4,5-Tetrahydro-4 - [(2-hydroxy-4-quinolinyl) carbonyl] -1- (1H-imidazol-4-ylmethyl) -7-phenyl-1H-1,4-benzodiazepine (dihydrochloride)

182 m / z 476 (M + H)

2 - [[2,3,4,5-Tetrahydro-1- (1-imidazol-4-ylmethyl) -7-phenyl-1H-1,4-benzodiazepin-4-yl] carbonyl] benzamide (dihydrochloride)

183 m / z 452 (M + H)

N - (1,1-Dimethylethyl) -2 - [[2,3,4,5-tetrahydro-1- (1H-imidazol-4-ylmethyl) -7-phenyl-1H-1,4-benzodiazepine-4-ylcarbonyl] -benzamide (dihydrochloride) m / z 508 (M + H)

166

N- (4-fluorophenyl) -N '- [3 - [[2,3,4,5-tetrahydro-1- (1H-imidazol-4-ylmethyl) -7-phenyl-1H-1,4-benzodiazepinyl] carbonyl] phenyl] urea (dihydrochloride)

2.3.4.5-Tetrahydro-1- (1H-imidazol-4-ylmethyl) -4 - [(3-methyl-4-oxo-2-phenyl-4H-benzopyran-8yl) carbonyl] -7-phenyl-1H-1,4-benzodiazepine ( dihydrochloride)

2.3.4.5-Tetrahydro-1- (1H-imidazol-4-ylmethyl) -7-phenyl-4- [3- (trifluoromethoxy) benzoyl] -1H-1,4-benzodiazepine (dihydrochloride) 4- (2-cyanobenzoyl) -2,3 , 4,5-Tetrahydro-1- (1H-imidazol-4-ylmethyl) -7-phenyl-1H-1,4-benzodiazepine (dihydrochloride)

2,3,4,5-Tetrahydro-1- (1H-imidazol-4-ylmethyl) -4- [2 - [[(4-methylphenyl) sulfonyl] amino] benzoyl] -7-phenyl-1H-1,4-benzodiazepine (dihydrochloride) ) m / z 561 (M + H) m / z 567 (M + H) m / z 493 (M + H) m / z 434 (M + H) m / z 578 (M + H)

167

2,3,4,5-Tetrahydro-1- (1H-imidazol-4-ylmethyl) -7-phenyl-4- (6-quinolinylcarbonyl) -1H-1,4-benzodiazepine (trihydrochloride)

2,3,4,5-Tetrahydro-1- (1H-imidazol-4-ylmethyl) -7-phenyl-4- (8-quinolinylcarbonyl) -1H-1,4-benzodiazepine (trihydrochloride)

4- (Benzo [b] thiophen-2-ylcarbonyl) -2,3,4,5-tetrahydro-1- (1H-imidazol-4-ylmethyl) -7-phenyl-1H-1,4-benzodiazepine (dihydrochloride)

4 - [[4- (Dimethylamino) -1-naphthalenyl] carbonyl] -2,3,4,5-tetrahydro-1- (1H-imidazol-4-ylmethyl) -7-phenyl-1H-1,4-benzodiazepine (trihydrochloride)

2,3,4,5-Tetrahydro-1- (1H-imidazol-4-ylmethyl) -7-phenyl-4- (1H-pururin-6-ylcarbonyl) -1H-1,4-benzodiazepine (trihydrochloride) m / z 460 (M +). H) m / z 460 (M + H) m / z 465 (M + H) m / z 502 (M + H) m / z 449 (M + H)

168

2,3,4,5-Tetrahydro-1- (1H-imidazol-4-ylmethyl) -4- (methoxyphenylacetyl) -7-phenyl-1 H -1,4-benzodiazepine (dihydrochloride)

2,3,4,5-Tetrahydro-1- (1H-imidazol-4-ylmethyl) -4 - [(5-methyl-1-phenyl-1H-pyrazol-4-yl) carbonyl] -7-phenyl-1H-1,4 benzodiazepine (trihydrochloride)

2.3.4.5-Tetrahydro-1- (1H-imidazol-4-ylmethyl) -4- [2- (2-methylphenyl) -1-oxopropyl] -7-phenyl-1H-1,4-benzodiazepine (dihydrochloride)

2.3.4.5-Tetrahydro-1- (1H-imidazol-4-ylmethyl) -7-phenyl-4 - [(tetrahydro-4-phenyl-2H-pyran-4yl) carbonyl] -1H-1,4-benzodiazepine (dihydrochloride)

2.3.4.5-Tetrahydro-1- (1H-imidazol-4-ylmethyl) -4- [2- (methylphenylamino) benzoyl] -7-phenyl-1H-1,4-benzodiazepine (trihydrochloride) m / z 453 (M + H) m / z z 489 (M + H) m / z 451 (M + H) m / z 493 (M + H) m / z 531 (M + H)

169

201

199

200

2,3,4,5-Tetrahydro-1- (1H-imidazol-4-ylmethyl) -7-phenyl-4- (4-quinolinylcarbonyl) -1H-1,4-benzodiazepine (N-oxide dihydrochloride)

N-Methyl-N- (2-pyridinylmethyl) -2 [[2,3,4,5-tetrahydro-1- (1H-imidazol-4-ylmethyl) -7-phenyl-1H-1,4-benzodiazepin-4-yl] carbonyl] benzamide (trihydrochloride) m / z 476 (M + H) m / z 557 (M + H)

2,3,4,5-Tetrahydro-1- (1H-imidazol-4-ylmethyl) -4- (3-isoquinolinylcarbonyl) -7-phenyl-1H-1,4-benzodiazepine (trihydrochloride) m / z 460 (M + H)

Examples 202-219 To a mixture of Example 4 Compound A (3.83 g, 15.4 mmol) and 4imidazolecarboxaldehyde (2.22 g, 23.1 mmol) in 120 mL of CH ₂ Cl ₂ and 3 mL of AcOH was added NaBH (OAc) at room temperature. ) ₃ (4.89 g, 23.1 mmol). The mixture was stirred for 1.5 h, diluted with 200 mL CH ₂ Cl ₂ and washed with 5% NaHCO ₃ . The organic phase is dried over Na ₂ SO ₄ , filtered and concentrated in vacuo. The residue was purified by flash chromatography (eluting with 5% MeOH / CH ₂ Cl ₂ with traces of NH ₄ OH) to give 2.01 g (40%) of 2,3,4,5-tetrahydro-4 - [(1,1- dimethylethoxy) carbonyl] -1- (1H-imidazol-4-ylmethyl) -1H-1,4-benzodiazepine. A further 0.42 g (8%) of product is obtained by stirring 1.5 g of high R _f material in 1: 1: 1 THF / MeOH / NH ₄ OH followed by extraction with EtOAc and purification by flash chromatography.

170

The hydroxymethyl resin (3.5 g, 6.58 mmol, 1.88 mmol / g) was swollen in 50 mL of 1,2-dichloroethane for 45 min. paraformaldehyde (0.15 g, 5.0 mmol) was added to the mixture in a 125 mL shaking flask at room temperature. Stir for 15 min. HCI (gaseous) is allowed. Paraformaldehyde (0.15 g, 5.0 mmol) was then added again to the reaction mixture and HCl (gaseous) was allowed to shake again for 4 hours. The 1,2-dichloroethane is decanted off and the resin is washed with 1,2-dichloroethane (4 x 20 mL).

This resin is suspended in 20 ml of 1,2-dichloroethane and treated with 2,3,4,5-tetrahydro-4 - [(1,1-dimethylethoxy) carbonyl] -1- (1H-imidazol-4-ylmethyl) -1H-1, 4-Benzodiazepine (2.23 g, 6.78 mmol) in 25 mL of 1,2-dichloroethane and 6 mL of DIEA. The mixture is shaken at room temperature for 12 hours. MeOH (2 mL) was added and the mixture was shaken for another 1.5 h. The solvent was removed and the resin was washed successively with 1,2-dichloroethane (2 x 20 mL), DMF (2 x 20 mL), and MeOH (2 x 20 mL). Drying in vacuo gives 4.58 g (67%) of a resin bound via imidazole 2,3,4,5-tetrahydro-4 - [(1,1-dimethylethoxy) carbonyl] -1 (1H-imidazole-4). -ylmethyl) -1H-1,4-benzodiazepine (% N = 4.39). J 150 mg (0.135 mmol, 0.90 mmol / g) of this resin are added to a 5 mL polypropylene syringe tube with 1.5 mL of 3% Et ₃ SiH CH ₂ Cl ₂ and 0.5 mL of TFA. The tube is placed in a vacuum elution chamber (24 tube capacity) and the whole apparatus is shaken in an orbital shaker for 3 hours. The solvent is removed and the resin is washed successively with 2 mL of CH ₂ Cl ₂ , 25% Et ₃ N / CH ₂ Cl ₂ , MeOH, DMF, and CH ₂ Cl ₂ . The resin is swollen with 0.5 ml of DMF solution containing 1M DIEA and 0.5M HOBT. To this mixture was added 50 mg of carboxylic acid followed by 1.5 ml of CH ₂ Cl ₂ containing 0.2M EDC. The mixture is shaken for 18 hours. The solvent was removed and the resin was washed successively with 2 mL of CH ₂ Cl ₂ , 25% Et ₃ N / CH ₂ Cl ₂ , MeOH, DMF, and CH ₂ Cl ₂ . The copying procedure is repeated. The products are separated from the resin by shaking for 18 hours with HBr / TFA / Thioanisole solution (prepared by mixing 45 mL of TFA, 1.25 mL of thioanisole and 5 mL of 30% HBr / HOAc). The solvent was removed and the resin was washed with MeOH (3x3 mL). The solvent was evaporated in vacuo and the residue was purified by HPLC (C18, 50 x 100 mm, 10% -90% MeOH with 0.1% TFA, 10 min gradient, 20 mL / min). The target compounds were characterized by analytical HPLC and mass spectrometry.

171

For example,

202

Structure

2,3,4,5-Tetrahydro-1- (1H-imidazol-4-ylmethyl) -4 - [(2-naphthalenylthio) acetyl] -1H-1,4-benzodiazepine (trifluoroacetate, 1: 2)

Mass spectrum m / z 429 (M + H)

203

4- (3- (3,4-dimethoxyphenyl) -1-oxopropyl] -2,3,4,5-tetrahydro-1 · (1 H -imidazol-4-ylmethyl) -1 H -1,4-benzodiazepine (trifluoroacetate, 1 : 2) m / z 421 (M + H)

204

205

4 ([1,1'-Biphenyl] -4-ylacetyl) -2,3,4,5-tetrahydro-1- (1H-imidazol-4-ylmethyl) -1H-1,4-benzodiazepine (trifluoroacetate, 1: 2)

2,3,4,5-Tetrahydro-1- (1H-imidazol-4-ylmethyl) -4- (2-naphthalenylacetyl) -1H-1,4-benzodiazepine (trifluoroacetate, 1: 2) m / z 423 (M + H) m / z z 397 (M + H)

172

206

4 - ([1,1'-Biphenyl] -2-ylcarbonyl) -2,3,4,5-tetrahydro-1- (1H-imidazol-4-ylmethyl) -1H-1,4-benzodiazepine (trifluoroacetate, 1) : 2)

207

208

209

2,3,4,5-Tetrahydro-1- (1H-imidazol-4-ylmethyl) -4 - [(2-phenyl-4-quinolinyl) carbonyl] -1H-1,4-benzodiazepine (trifluoroacetate, 1: 3).

2,3,4,5-Tetrahydro-1- (1H-imidazol-4-ylmethyl) -4- (3-pyridinylacetyl) -1H-1,4-benzodiazepine (trifluoroacetate, 1: 3)

4- (9H-fluoren-9-ylacetyl) -2,3,4,5-tetrahydro-1- (1H-imidazol-4-ylmethyl) -1H-1,4-benzodiazepine (trifluoroacetate, 1: 2)

Ghiral (S) -4- [2- (Dimethylamino) -1-oxo-3-phenylpropyl] -2,3,4,5-tetrahydro-1- (1H-imidazol-4-ylmethyl) -1H-1,4-benzodiazepine ( trifluoroacetate, 1: 3) m / z 409 (M + H) m / z 460 (M + H) m / z 384 (M + H) m / z 435 (M + H) m / z 404 (M + H) )

210

173

211

212

213

(S) -2,3,4,5-Tetrahydro-1- (1H-imidazol-4-ylmethyl) -4 - [(2-oxo-4-phenyl-3-oxazolidinyl) acetyl] -1H1,4-benzodiazepine (trifluoroacetate, 1) : 2) 4- (9-acridinylcarbonyl) -2,3,4,5-tetrahydro-1- (1H-imidazol-4-ylmethyl) -1H-1,4-benzodiazepine (trifluoroacetate, 1: 3) m / z 432 ( M + H m / z 434 (M + H)

M

2,3,4,5-Tetrahydro-1- (1H-imidazol-4-ylmethyl) -4- (3-phenoxybenzoyl) -1H-1,4-benzodiazepine (trifluoroacetate, 1: 2) m / z 425 (M + H)

2,3,4,5-Tetrahydro-1- (1H-imidazol-4-ylmethyl) -4 - [[4 '(trifluoromethyl) [1,1'-biphenyl] -2-yl] carbonyl] -1H-1, 4-benzodiazepine (trifluoroacetate, 1: 2) m / z 477 (M + H)

174

215

216

217

218

2,3,4,5-Tetrahydro-1- (1H-imidazol-4-ylmethyl) -4- (4-phenoxybenzoyl) -1H-1,4-benzodiazepine (trifluoroacetate, 1: 2) m / z 425 (M + H)

2.3.4.5- Tetrahydro-1- (1-imidazol-4-ylmethyl) -4- (2-naphthalenylcarbonyl) -1H-1,4-benzodiazepine (trifluoroacetate, 1: 2)

2.3.4.5- Tetrahydro-1- (1H-imidazol-4-ylmethyl) -4- (1-oxo-4-phenylbutyl) -1H-1,4-benzodiazepine (trifluoroacetate, 1: 2)

2.3.4.5-Tetrahydro-1- (1H-imidazol-4-ylethylethyl) -4 - [(2-phenoxyphenyl) acetyl] -1H-1,4-benzodiazepine (trifluoroacetate, 1: 2)

2.3.4.5-Tetrahydro-1- (1H-imidazol-4-ylmethyl) -4- [2 - [(4-methylphenyl) sulfinyl] benzoyl] -1 H -1,4-benzodiazepine (trifluoroacetate, 1: 2) m / z 383 (M +) H) m / z 375 (M + H) m / z 439 (M + H) m / z 471 (M + H)

219

175

220

2,3,4,5-Tetrahydro-1- (1H-imidazol-4-ylmethyl) -4- [2 [(phenylmethyl) amino] benzoyl] -1H

1,4-benzodiazepine (trifluoroacetate, 1: 3) m / z 438 (M + H)

1,2,3,5-Tetrahydro-1- (1H-imidazol-4-yl-methyl) -N, N-diphenyl-4H-1,4-benzodiazepine-4-carboxamide (hydrochloride)

Example 221 (yellowish solid) is prepared from N, N-diphenylcarbamyl chloride according to the procedure described in Example 9.

MS (M + H) &lt; ⁺ &gt;

Analysis calculated for C 26 H ₂₅ N ₅ O · 2.2 H ₂ O · 2.2 HCl

Found: C, 57.47; H, 5.87; N, 12.89; Cl, 14.35

Found: C, 57.25; H, 5.78; N, 13.25; Cl, 14.73.

176

1,2,3,5-Tetrahydro-1- (1H-imidazol-4-yl-methyl) -α, 7-diphenyl-4H-1,4-benzodiazepine-4-acetic acid methyl ester (hydrochloride) in a stirred mixture of Example 12 To a suspension of B (220 mg, 1.0 mmol) in MeOH in solid K2CO3 was added methyl bromophenyl acetate (0.18 mL, 1.1 mmol) at room temperature under argon. The mixture was stirred for 18 hours, the solvent was evaporated, and the residue was purified by flash column chromatography (3: 2, hexanes and ethyl acetate). 1,2,3,5-Tetrahydro-a, 7-diphenyl-4H-1,4-benzodiazepine-4-acetic acid methyl ester is obtained which is an oil (220 mg, 63%). This material was subjected to the procedure for the preparation of Example D Compound D to afford Example 222 as a yellow solid.

MS (M + H) ⁺ 453

Analysis calculated for C ₂₈ H ₂ 8 N ₄ O ₂ · 0.2 H ₂ O · 2.5 HCl

Found: C, 61.44; H, 5.69; N, 10.24; Cl, 16.19.

Found; C, 61.33; H, 5.88; N, 9.94; Cl, 16.00.

4-Acetyl-2,3,4,5-tetrahydro-1- (1H-imidazol-4-ylmethyl) -3- (phenylmethyl) -1H-1,4-benzodiazepine (hydrochloride)

Example 223 (tan solid) is prepared from isatoic acid anhydride and D, L-phenylalanine O-methyl ester hydrochloride according to the procedure described in Example 71, except that acetyl chloride (0.25 eq) is used instead of naphthoyl chloride.

177

MS (M + H) ⁺ 453

Analysis calculated for C 22 H ₂₄ N ₄ O · 1.5 H ₂ O · 1.2 HCl Calculated: C, 61.74; H, 6.26; N, 13.26; Cl, 9.49.

Found: C, 61.80; H, 6.62; N, 13.10; Cl, 9.12.

Example 224

(R) -7-Bromo-2,3,4,5-tetrahydro-1- (1H-imidazol-4-ylmethyl) -4- (methylsulfonyl) -3 (phenylmethyl) -1H-1,4-benzodiazepine ( hydrochloride)

A. (R) -7-Bromo-2,3,4,5-tetrahydro-3- (phenylmethyl) -1H-1,4-benzodiazepine-2,5-dione

A stirred solution of bromoacetic anhydride (150 g, 0.62 mol) and diphenylalanine methyl ester hydrochloride (127.3 g, 0.59 mol) in 4-dimethylaminopyridine (2 g) was heated to reflux with pyridine (1500 ml). refrigerated under argon for 3 days. The pyridine is evaporated in vacuo and the residue is dissolved in methylene chloride (3 L). The solution was washed with 10% HCl and saturated NaCl. The organic solution was dried and concentrated in vacuo to a small volume. Separation and drying of the resulting solid afforded 152 g (71%) of A. Lyd. mp: 242-243 ° C.

B. (R) -7-Bromo-2,3,4,5-tetrahydro-3- (phenylmethyl) -1H-1,4-benzodiazepine

178

A stirred solution of Compound A (30 g, 87 mmol) in anhydrous THF (870 mL) was treated with boranotetrahydrofuran complex (440 mL of 1M solution, 440 mmol) under argon. The solution is slowly brought to the boil and refluxed for 18 hours. The mixture was cooled to 0 ° C and methanol (150 mL) was added to destroy the excess BH ₃ . The resulting solution was concentrated in vacuo, the residue was dissolved in methanol (250 mL) and 7N HCl solution (50 mL) was added. This mixture is heated in a steam bath for 2 hours. The resulting solid is separated, suspended in water (400 mL), the aqueous suspension is basified to pH 11 with 5N NaOH solution and extracted with ethyl acetate (2 x 300 mL). The organic extracts were combined, dried, concentrated in vacuo and recrystallized from methanol / water (9: 1) to give 25 g of compound B as a white solid (91%). Lyd. m.p. 135-138 ° C.

C. (R) -7-Bromo-2,3,4,5-tetrahydro-4- (methylsulfonyl) -3- (phenylmethyl) -1H-1,4-benzodiazepine

To a stirred solution of compound B (1.5 g, 4.73 mmol), pyridine (3 mL) and DIEA (1.6 mL, 9.46 mmol) at 0 ° C under argon was added methanesulfonyl chloride (0.55 mL, 7 mL). , 11 mmol). The resulting mixture was stirred at 0 ° C for 2 h. and 1N NaOH solution (30 mL) was added. This mixture was stirred for 2 h, the organic layer was separated, washed with 1N HCl (2 x 100 mL), dried and concentrated in vacuo to give 1.7 g of compound C as a yellow solid (91%).

D. (R) -7-Bromo-2,3,4,5-tetrahydro-1- (1H-imidazol-4-ylmethyl) -4- (methylsulfonyl) -3- (phenylmethyl) -1H-1,4- Benzodiazepine (hydrochloride) was added 4-formylimidazole (6.6 g, 68.5 mmol) to a stirred solution of Compound C (18 g, 45.6 mmol) in acetic acid (50 mL) and dichloroethane (200 mL) at room temperature. The mixture was stirred at room temperature for 30 min. To the resulting solution was added sodium triacetoxyborohydride (14.5 g, 68.5 mmol). The mixture was stirred at room temperature for 18 h, diluted with ethyl acetate (500 mL), cooled to 0 ° C and basified to pH 9

179 in concentrated NH ₄ OH solution. This mixture is stirred for 2 hours. and partitioned between ethyl acetate and saturated NaHCO ₃ solution. The organic layer was separated, washed with saturated NH ₄ Cl solution, dried over Na ₂ SO ₄ and concentrated in vacuo. The residue was recrystallized from methanol to give a white solid (14 g, 65%). This solid was dissolved in ethyl acetate and added with 1N HCl in ether (60 mL). The solvent was evaporated in vacuo and the solid dried in a heated oven in vacuo to afford Example 224 as a white solid. Lyd. mp: 180-185 ° C.

MS (M + H) ⁺ 476.

[?] ²⁰ : + 58 ° (c = 0.4, MeOH).

(R) -2,3,4,5-Tetrahydro-1- (1H-imidazol-4-ylmethyl) -4- (methylsulfonyl) -3 (phenylmethyl) -1H-1,4-benzodiazepine-7-carbonitrile ( monohydrochloride)

A. (R) -2,3,4,5'Tetrahydro-4- (methylsulfonyl) -3- (phenylmethyl) -1H-1,4-benzodiazepine-7-carbonitrile

A stirred solution of Example 224 Compound C (6.9 g, 17.5 mmol) and copper cyanide (4.0 g, 44 mmol) in N-methylpyrrolidinone (90 mL) was heated at 200 ° C for 5 h. Cool the mixture to room temperature and add 10% aqueous ethylenediamine (800 mL). The resulting suspension was stirred at room temperature for 2 hours. and extracted with ethyl acetate (3 x 150 mL). The combined organic extracts were washed with 5% NH ₄ OH (2 x 100 mL), brine, dried over MgSO _4, and concentrated. The residue is purified

180 by flash chromatography (ethyl acetate, hexanes; 1: 1) to give Foam Compound A (4.5 g, 75%).

B. (R) -2,3,4,5-Tetrahydro-1- (1H-imidazol-4-ylmethyl) -4- (methylsulfonyl) -3 (phenylmethyl) -1H-1,4-benzodiazepine-7- carbonitrile (monohydrochloride)

To a stirred solution of compound A (4.7 g, 13.8 mmol) in acetic acid (30 mL) and dichloroethane (120 mL) was added 4-formylimidazole (2.1 g, 22 mmol) at room temperature. The mixture was stirred at room temperature for 30 min. To the resulting solution was added sodium triacetoxyborohydride (4.4 g, 22 mmol). The mixture was stirred at room temperature for 2 hours, 4-formylimidazole (1.3 g, 13.5 mmol) was added and the mixture was stirred for 30 min. and sodium triacetoxyborohydride (3.0 g, 14 mmol) was added. This cycle is repeated twice until all starting material has reacted. The workup and product are isolated according to the procedure for the preparation of compound D described in Example 224. Example 225 is obtained as a white solid (4.1 g, 65%). Lyd. mp: 165 ° C.

MS (M + H) &lt; ⁺ &gt; 422.

[α] _D ²⁰ : + 218 ° (c = 0.23, MeOH).

Analysis calculated for C 22 H ₂₃ N ₅ O ₂ S · 1.7H ₂ O · 1 HCl.

Found: C, 54.08; H, 5.65; N, 14.33; Cl, 7.26.

Found: C, 54.04; H, 5.38; N, 14.33; Cl, 7.27.

Example 226

181

V

Me (R) -4-Acetyl-2,3,4,5-tetrahydro-1- (1H-imidazol-4-ylmethyl) -7-phenyl-3- (phenylmethyl) -1H-1,4-benzodiazepine (monohydrochloride) )

A. 2-Amino-5-phenylbenzoic acid To a mixture of water (300 mL) and THF (300 mL) was added 2-amino-5-bromobenzoic acid (30.0 g, 139 mmol), benzeneboronic acid (18.6 g, 153 mmol), and K2CO3 (48.0 g, 348 mmol). For degassing the solution through the mixture for 1 hour. heavy current is allowed to flow through argon, and within 1 hour. a solution of palladium (II) acetate (2.52 g, 11.2 mmol) in degassed THF (50 mL) was added dropwise. This mixture was stirred at room temperature for 16 h with Ar. The mixture is concentrated, filtered through a pad of celite and lyophilized to remove water. The lyophilisate was triturated with a mixture of 90% dichloromethane and 10% methanol (500 mL). The filtrate was concentrated and recrystallized from ethyl acetate / hexane to give compound A as a brown solid (25 g, 84%). MS (M + H) &lt; ⁺ &gt; 214.

B. 6-Phenyl-3,1-oxazine-2,4 (1H) -dione

To a solution of Compound A (25.0 g, 0.177 mol) and triphosgene (25.0 g, 0.084 mol) in acetonitrile (250 mL) at 0 ° C under N ₂ for 1 h. A solution of triethylamine (3.0 g, 4.1 mL, 0.029 mol) in acetonitrile (50 mL) was added dropwise. The mixture is stirred at room temperature for 16 hours and the solid is filtered off.

The material on the filter is washed with dichloromethane and dried in vacuo,

182 gives compound B, which is an off-white solid (17.8 g, 63%). MS (M + H) ⁺ 241.

C. (R) -2,3,4,5-Tetrahydro-7-phenyl-3- (phenylmethyl) -1H-1,4-benzodiazepine-2,5-dione

Compound B (9.40 g, 0.0392 mol), D-Phe (6.5 g, 0.0392 mol) and pyridine-HCl (22.6 g, 0.196 mol) were dissolved in pyridine (100 mL). The solution was heated to reflux for 4 hours, cooled and concentrated. The residue was partitioned between water (200 mL) and ethyl acetate (200 mL). The organic layer was washed with water (3 x 100 mL), brine (50 mL), dried (MgSO ₄ ), and concentrated to give Compound C as a yellowish glass (6.0 g, 45%). MS (M + H) &lt; ⁺ &gt; 343.

D. (R) -2,3,4,5-Tetrahydro-7-phenyl-3- (phenylmethyl) -1H-1,4-benzodiazepine

Compound C (6.0 g, 0.017 mol) was dissolved in THF (100 mL) and borane (1M in THF, 50 mL, 50 mmol) was added. The solution is heated to reflux for 4 hours. and cooled to room temperature. Methanol (50 mL) was added to decompose the remaining borane, and the solution was concentrated and 1N HCl (100 mL) was added to the residue, and the mixture was refluxed for 4 hours. The mixture was cooled to room temperature, acidified to pH 2 with 1N HCl (110 mL) and extracted with dichloromethane (3 x 200 mL). The organic layers were combined, washed with brine (300 mL), dried (N ₂ SO ₄ ) and concentrated to give Compound D as a yellowish glass (5.5 g, 99%). MS (M + H) ⁺ 315.

E. (R) -4-Acetyl-2,3,4,5-tetrahydro-7-phenyl-3- (phenylmethyl) -1H-1,4-benzodiazepine

Compound D (5.0 g, 0.016 mol) was dissolved in dichloromethane (300 mL) and DIEA (2.06 g, 2.8 mL, 0.016 mol) was added immediately. A solution of acetic anhydride (1.46 g, 1.35 mL, 0.0143 mol) in dichloromethane (20 mL) was added dropwise over 30 min. The solution is stirred for 30 min, washed with saturated sodium bicarbonate (3 x 100 mL), water (3 x 100 mL), saturated NaCl solution (100 mL),

183 was dried (Na ₂ SO ₄ ) to give compound E, which is a brownish glassy material (5.0 g, 88%).

F. (R) -4-Acetyl-2,3,4,5-tetrahydro-1- (1H-imidazol-4-ylmethyl) -7-phenyl-3- (phenylmethyl) -1H-1,4-benzodiazepine ( monohydrochloride)

Compound E (5.0 g, 14.0 mmol) and 4-formylimidazole (4.45 g, 46.3 mmol) were dissolved in 1,2-DCE (100 mL) and acetic acid (50 mL). Sodium triacetoxyborohydride (4.45 g, 21.0 mmol) was added immediately and the mixture was stirred at room temperature for 1 h. Saturated NaHCO ₃ (50 mL) was added followed by ammonium hydroxide (50 mL). The mixture was stirred for 2 h, concentrated and the residue partitioned between water (100 mL) and ethyl acetate (200 mL). The organic layer was washed with water (100 mL), brine (100 mL), dried (Na ₂ SO ₄ ), concentrated, and chromatographed (silica gel, 5.1 x 15 cm, 95% dichloromethane, 5% methanol) to give 226 samples. the free base of the compound which is a brown solid (4.9 g). This brown material was further purified by preparative HPLC (YMC S-15 ODS column, 50 x 500 mm; solvent A: 0.1% TFA in 90% water / 10% methanol; solvent B: 0.1% TFA in 10% water and 90% methanol in the mixture; 20-100% B in 60 min; flow rate 25 mL / min). The fractions containing the desired product are mixed, concentrated and lyophilized. The lyophilisate was dissolved in acetonitrile (50 mL) and 1N HCl (50 mL). This mixture is concentrated and lyophilized. Repeat this procedure to afford Example 226 as a yellow solid (2.3 g, 35%).

MS (M + H) ⁺ 437.

¹ H-NMR (CD ₃ OD, 400 MHz) δ (md) 8.95 (1H, m), 7.68-7.30 (13H, m), 7.04 (1H, m), δ 21-5.10 (1H, m), 4.78-4.63 (2H, m), 4.63-4.48 (1H, m), 4.38 (1H, m), 3.81-. 3.76 (1H, m), 3.28-3.15 (1H, m), 2.98-2.93 (1H, m), 2.88-2.80 (1H, m), 2, 09 (2H, s), 1.62 (1H, s).

Example 227

184

7-Bromo-4 - [[2- (dimethylamino) ethyl] sulfonyl] -2,3,4,5-tetrahydro-1- (1H-imidazol-4-ylmethyl) -3- (phenylmethyl) -4H-1,4- benzodiazepine (trifluoroacetate, 1: 2)

A. 7-Bromo-4- [ethenylsulfonyl] -2,3,4,5-tetrahydro-3- (phenylmethyl) -4H-1,4-benzodiazepine

A mixture of compound J from Example J 224 (250 mg, 0.79 mmol) and THF (20 mL) was successively added with 2-chloro-ethanesulfonyl chloride (0.1 mL, 0.95 mmol) and DIEA (0.18 mL, 1.98 mmol). ). The solution was stirred under argon at room temperature for 18 h, partitioned between aqueous hydrochloric acid (100 mL, 1N) and ethyl acetate (100 mL) and extracted with ethyl acetate (2 x 100 mL). The organic layers were combined, dried (MgSO ₄ ), and concentrated in vacuo to give a crude oil which was purified by flash chromatography (silica gel, hexane: ethyl acetate 3: 1). Compound A is obtained which is a clear oil (85 mg, 26%).

B. 7-Bromo-4 - [[2- (dimethylamino) ethyl] sulfonyl] -2,3,4,5-tetrahydro-3- (phenylmethyl) -4 H -1,4-benzodiazepine, Compound A (85 mg, 0 , 21 mmol) in THF (5 mL) was added dimethylamine (2 mL, 2M in THF) solution. The solution is heated in a hermetically sealed pressure bottle at 60 ° C for 48 hours, cooled to room temperature and concentrated in vacuo to give crude oil compound B.

185

C. 7-Bromo-4 - [[2- (dimethylamino) ethyl] sulfonyl] -2,3,4,5-tetrahydro-1- (1H-imidazol-4-ylmethyl) -3- (phenylmethyl) -4H-1, 4-benzodiazepine (trifluoroacetate, 1: 2)

A stirred solution of Compound B (90 mg, crude, assumed to contain 0.21 mmol), 4-formylimidazole (30 mg, 0.32 mmol), dichloroethane (4 mL), and acetic acid (2 mL) was added at room temperature. sodium triacetoxyborohydride (67 mg, 0.32 mmol) was added. The solution was stirred for 48 h, diluted with ethyl acetate (20 mL) and ammonium hydroxide (5 mL, almost) and stirred for a further 18 h. The mixture was extracted with ethyl acetate (2 x 25 mL), the combined organic extracts washed with aqueous sodium bicarbonate (25 mL, saturated solution) followed by ammonium chloride (25 mL, saturated aqueous solution), dried (Na ₂ SO ₄ ) and concentrated in vacuo to semi-solids. This crude material was purified by preparative HPLC (gradient from water to methanol containing 0.1% trifluoroacetic acid, C-18 column) to give, after lyophilization, the title compound 227 as a white solid (50 mg, 44% yield). compound A). Lyd. mp: 118-120 ° C.

Analysis calculated for C ₂₄ H ₃ O ₅ OSBr · 1.0 H ₂ O · 2.0 TFA.

Found: C, 43.20; H, 4.40; N, 9.00; S, 4.12; Br, 10.26.

Found: C, 43.85; H, 4.00; N, 8.35; S, 4.39; Br, 9.43.

2,3,4,5-Tetrahydro-1- (1H-imidazol-4-ylmethyl) -7-phenyl-4 - [(1,2,3,4-tetrahydro-1-quinolinyl) carbonyl] -1H-1, 4-Benzodiazepine (monohydrochloride)

186

Example 228 is prepared from N-chlorocarbonyl-1,2,3,4-tetrahydroquinoline according to the procedure described in Example 35 except that the acylation product is chromatographed (silica gel, 8: 2 chloroform: ethyl acetate).

MS (M + H) ⁺ 464.

Analysis calculated for C 29 H ₂₉ N ₅ O · 1.0 H ₂ O 1.1 HCl · 0.25 ether. Found: C, 66.70; H, 6.46; N, 12.96; Cl, 7.22.

Found: C, 66.88; H, 6.36; N, 12.62; Cl, 7.30.

Example 229

H

Me

N-Ethyl-1,2,3,5-tetrahydro-1- (1H-imidazol-4-ylmethyl) -N, 7-diphenyl-4H-1,4-benzodiazepine-4-carboxamide (monohydrochloride)

Example 229 is prepared from N-chlorocarbonyl-N-ethylaniline in accordance with the procedure described in Example 35. The HCl salt is prepared by dissolving the product in methanol, adding 4N HCl in dioxane, evaporating, redissolving in methanol and precipitating with ether.

MS (M + H) &lt; ⁺ &gt; 452.

Analysis calculated for C ₂₈ H ₂ 9 N ₅ O · 0.4 H ₂ O · 1.2 HCl 0.25 ether. Excluded; C, 66.85; H, 6.48; N, 13.44; Cl, 8.16.

Found: C, 66.78; H, 6.38; N, 13.49; Cl, 8.05.

Example 230

187

4 - [(2,3-Dihydro-1H-indol-1-yl) carbonyl] -2,3,4,5-tetrahydro-1- (1H-imidazol-4-ylmethyl) -7-phenyl-1H-1, 4-Benzodiazepine (monohydrochloride)

Example 230 is prepared from N-chlorocarbonylindoline according to the procedure described in Example 229. Lyd. mp 156-166 ° C.

MS (M + H) &lt; ⁺ &gt; 450.

Analysis calculated for C ₂₈ H ₂₇ N ₅ O · 0.5 H ₂ O 1.5 HCl.

Found: C, 65.52; H, 5.79; N, 13.65; Cl, 10.36.

Found: C, 65.40; H, 5.74; N, 13.47; Cl, 10.49.

2,3,4,5-Tetrahydro-1- (1H-imidazol-4-ylmethyl) -4- (methylsulfonyl) -3- (phenylmethyl) -7- (4-pyridinyl) -1H- 1,4-benzodiazepine (trihydrochloride)

188

A. 2,3,4,5-Tetrahydro-1- (trifluoroacetyl) -4- (methylsulfonyl) -3- (phenylmethyl) -7bromo-1H-1,4-benzodiazepine {Example 78 Compound A (0.3 mmol) ) and triethylamine (2.75 mmol, 384 μΙ) in CH ₂ Cl ₂ (4 mL) was added trifluoroacetic anhydride (1.2 mmol, 165 μΙ), and the homogeneous solution was kept at room temperature for 5 hours. The reaction mixture was concentrated and purified by flash chromatography (40% EtOAc / hexane). Compound A was isolated as a fluffy white solid (100 mg, 68%). MS (M + NH ₄ ) 508.

B. 2,3,4,5-Tetrahydro-1- (trifluoroacetyl) -4- (methylsulfonyl) -3- (phenylmethyl) -7- (4-pyridinyl) -1H-1,4-benzodiazepine

A solution of Compound A (0.15 mmol), 4-stanylpyridine (0.3 mmol, 110 mg) and 15 mol% Pd (PPh ₃ ) ₄ (26 mg) was degassed in 3 mL of THF and refluxed under argon. After 48 or. an additional 20 mol% of catalyst is added to fully react the starting material. The reaction mixture was concentrated and purified by flash chromatography (EtOAc). Compound B (46 mg, 63%) was isolated as a yellow oil. MS (M + H) &lt; ⁺ &gt; 490.

C. 2,3,4,5-Tetrahydro-1- (1H-imidazol-4-ylmethyl) -4- (methylsulfonyl) -3- (phenylmethyl) -7- (4-pyridinyl) -1H-1,4-benzodiazepine (trihydrochloride)

To a solution of Compound B (40 mg, 0.082 mmol) in 3 mL of MeOH was added NaOH (5 drops of 2N NaOH solution), and the mixture was kept at room temperature for 20 min. and concentrated. The residue was partitioned between 2N NaOH (5 mL) and 10% isopropanol in CH ₂ Cl ₂ (5 mL), extracted with 10% isopropanol in CH ₂ Cl ₂ (3x5 mL), dried over Na ₂ SO ₄ and concentrated. This material was dissolved in 1 mL of 1: 1 AcOH: dichloroethane, treated with 4-formylimidazole (0.66 mmol, 63 mg) and NaBH (OAc) ₃ (0.66 mmol, 140 mg); the mixture is heated at 50 ° C for 2 hours. and concentrated. The residue was partitioned between 2N NaOH-saturated NaCl-saturated NH ₄ OH (10:10: 0.3, 23 mL total) and 10% isopropanol-CH ₂ Cl ₂ (5 mL), and the aqueous phase was extracted with 10% isopropanol-CH ₂ Cl _2. (2x5 mL).

189

The combined organic phases are concentrated and the residue is purified by preparative HPLC (YMC S5 ODS 20 x 100 mm, gradient elution 15 to 75% buffer B over 60 min. Buffer A = MeOH: H ₂ O: TFA (10: 90: 0.1) buffer B = MeOH: H ₂ O: TFA (90: 10: 0.1); flow rate 25 mL / min). The TFA salt was converted to the HCl salt using 1N HCl to give Example 231 as a yellow solid (6.0 mg, 13%).

MS (M + H) &lt; ⁺ &gt; 474.

¹ H-NMR (CD ₃ OD) δ 8.9 (s, 1H), 8.7 (m, 2H), 8.3 (m, 2H), 7.8 (m, 2H), 7.5 ( s, 1H), 7.3 (m, 4H), 7.0 (d, J = 9Hz, 1H), 4.8 (d, J = 8Hz, 2H), 4.65 (t, J = 14 Hz, 2H), 4.45 (ss, 1H), 3.7 (dd, J = 7, 14 Hz, 1H), 3.4 (dd, J = 7.5 Hz, 1H),

2.96 (dd, J = 14, 7Hz, 1H), 2.8 (dd, J = 14, 7Hz, 1H), 2.3 (s, 3H).

(R) -4 - [[2- (Dimethylamino) ethyl] sulfonyl] -2,3,4,5-tetrahydro-1- (1H-imidazol-4-yl-ethyl) -7-phenyl-3- ( phenylmethyl I) -1H-1,4-benzodiazepine (trifluoroacetate, 1: 1)

A. (R) -7-Bromo-2,3,4,5-tetrahydro-3- (phenylmethyl) -1H-1,4-benzodiazepine

Compound A is prepared from Example 224 Compound A according to the procedure for the synthesis of Compound B described in Example 75.

190

B. (R) -7-Phenyl-2,3,4,5-tetrahydro-3- (phenylmethyl) -1H-1,4-benzodiazepine Compound A (500 mg, 1.58 mmol) in toluene (20 mL) and aqueous sodium bicarbonate (10 mL, saturated solution) was added a solution of phenylboronic acid (385 mg in 5 mL of absolute ethanol) under argon. Tetrakis (triphenylphosphine) palladium (O) (91 mg) is added and the solution is refluxed (~ 80 ° C). After 18 or. the mixture was cooled to room temperature and partitioned between aqueous sodium hydroxide (100 mL, 3N) and ethyl acetate (100 mL). The mixture was extracted with ethyl acetate (2 x 200 mL), the organic layers were combined, dried (MgSO ₄ ) and concentrated in vacuo to an oil which was purified by flash chromatography (60 g silica gel, 10: 0.5: 0.05 ethyl acetate: methanol: ammonium hydroxide). ). Compound B (350 mg, 70%) is obtained which is a waxy solid.

C. (R) -4-Ethenylsulfonyl-2,3,4,5-tetrahydro-7-phenyl-3- (phenylmethyl) -1H-1,4-benzodiazepine in Compound B (45 mg, 0.14 mmol) in methylene chloride (5 mL) and aqueous sodium hydroxide (1 mL, 1M solution) were added 2-chloroethanesulfonyl chloride (0.8 mL, 0.07 mmol). What 6 or. additional portions of 2-chloro-ethanesulfonyl chloride (0.1 mL, 0.2 mL, 0.2 mL) were added, the mixture was stirred for 18 h, poured into saturated NaCl solution and extracted with ethyl acetate (3 x 100 mL). The organic layers were combined, dried (MgSO ₄ ), and concentrated in vacuo to an oil which was purified by preparative HPLC (ODS column, gradient of aqueous methanol containing trifluoroacetic acid). The appropriate samples containing the product were combined and concentrated in vacuo to give Compound C (10 mg, 17%) as a clear oil.

D. (R) -4 - [[2- (Dimethylamino) ethyl] sulfonyl] -2,3,4,5-tetrahydro-7-phenyl-3 (phenylmethyl) -1H-1,4-benzodiazepine

191

To a solution of Compound C (20 mg, 0.025 mmol) in tetrahydrofuran (2 mL) was added dimethylamine solution (1 mL, 2M THF). This solution is heated in a sealed pressure bottle at 60 ° C for 18 hours, cooled to room temperature and concentrated in vacuo to an oil.

E. (R) -4 - [[2- (Dimethylamino) ethyl] sulfonyl] -2,3,4,5-tetrahydro-1- (1H-imidazol-4-ylmethyl) -7-phenyl-3- (phenylmethyl) - 1H-1,4-benzodiazepine (trifluoroacetate, 1: 1)

A solution of compound D (20 mg, crude, assumed to contain 0.05 mmol) and 4-formylimidazole (10 mg, 0.1 mmol) in dichloroethane (4 mL) and acetic acid (2 mL) was stirred at room temperature for 30 min. . Sodium triacetoxyborohydride (22 mg, 0.1 mmol) was added and the solution was stirred for 48 h, diluted with ethyl acetate (20 mL) and ammonium hydroxide (5 mL, almost) and stirred for a further 30 min. The mixture was extracted with ethyl acetate (2 x 25 mL), the combined organic extracts washed with aqueous sodium bicarbonate (25 mL, saturated solution) followed by ammonium chloride (25 mL, saturated aqueous solution), dried (Na ₂ SO ₄ ) and concentrated in vacuo to semi-solids. This crude material was purified by preparative HPLC (gradient of aqueous methanol containing 0.1% trifluoroacetic acid, C-18 column) to give, after lyophilization, the compound of Example 232 as a white solid (10 mg, 37% yield). compound C). Lyd. mp: 115-120 ° C.

MS (M + H) &lt; ⁺ &gt; 530.

1 H-NMR (200 MHz, CD ₃ OD) δ 8.8 (d, 1H), 7.7-7.4 (m, 12H), 7.1 (d, 1H), 4.9 (s, 6H) ), 3.4-3.1 (m, 8H), 3.8-3.2 (m, 8H), 2.7 (s, 6H).

Example 233

192 ° γθ

[2,3,4,5-Tetrahydro-1- (1H-imidazol-4-ylmethyl) -4- (1-naphthalenylcarbonyl) -1H1,4-benzodiazepin-8-yl] carbamic acid cyclohexyl ester (dihydrochloride)

Cyclohexanol (0.14 mL, 0.137 g, 1.38 mmol) and phosgene (0.14 mL, 2M in THF) were stirred at 4 ° C for 2 h. To this cold solution was added triethylamine (0.19 mL, 0.14 g, 1.38 mmol) and Example 26 (0.050 g, 0.12 mmol), after stirring for 16 h. At 4 ° C, the mixture was diluted with chloroform and NaHCO ₃ solution and the layers separated. The aqueous layer was extracted with CHCl ₃ (2 x 30 mL), the combined organic layers were washed with brine (1 x 30 mL), dried over MgSO ₄ , filtered, and concentrated. The residue was treated with MeOH and 1N NaOH for 30 min. The crude product was purified by preparative HPLC (gradient of aqueous methanol containing 0.1% trifluoroacetic acid, C-18 column) and lyophilized. The residue was treated with HCl / ether to give Example 233 (0.030 g, 46%) as a yellowish solid.

MS (M + H) &lt; ⁺ &gt; 524.

¹ H-NMR (270 MHz, CD ₃ OD) δ 8.0-6.9 (m, 11H), 6.81 (d, 0.5H, J = 8 Hz), 5.85 (d, 0, 5H, J = 9Hz), 5.85 (m, 1H), 4.4-4.0 (m, 3H), 3.9-3.7 (m, 0.5H), 3.4-3 , 1 (m, 1.5H), 2.88 (m, 1H), 2.0-1.2 (m, 12H).

Example 234

193

(R) -7-Bromo-2,3,4,5-tetrahydro-1- (1-methyl-1H-imidazol-5-yl) methyl) -4- (methylsulfonyl) -3- (phenylmethyl) -1H- 1,4-Benzodiazepine (hydrochloride)

A. (R) -7-Bromo-2,3,4,5-tetrahydro-1 - [(((1,1-dimethoxyethoxy) carbonyl) -1Himidazol-4-yl) methyl] -4- (methylsulfonyl) - 3- (phenylmethyl) -1H-1,4-benzodiazepine

To a solution of 260 mg (0.55 mmol) of Example 224 in 10 mL of methylene chloride was added 131 mg (0.60 mmol) of BOC anhydride and 3 mg (0.025 mmol) of DMAP. The clear colorless solution was stirred at room temperature under argon for 3 hours. Another 40 mg of BOC anhydride was added and stirred overnight. The crude mixture was applied to a 30 cm ³ silica gel column and eluted with 25% ethyl acetate in hexane; 290 mg (0.55 mmol, 100%) of compound A is obtained which is a white foam.

B. (R) -7-Bromo-2,3,4,5-tetrahydro-1- (1-methyl-1H-imidazol-5-yl) methyl) -4 (methylsulfonyl) -3- (phenylmethyl) -1H -1,4-benzodiazepine (hydrochloride)

A solution of 275 mg (0.48 mmol) of Compound A and 0.091 mL (0.52 mmol) of DIEA in 5 mL of methylene chloride is added dropwise to 0.059 mL (0.52 mmol) of methyl triflate at -78 ° C under argon. The mixture was allowed to warm to room temperature over 3 hours. A further 0.091 mL (0.52 mmol) of DIEA and 0.059 mL (0.52 mmol) of methyl triflate are added. Stir at room temperature overnight. What 1 or. three additional portions of 0.091 mL (0.52 mmol) of diisopropylethylamine and 0.059 mL (0.52 mmol) of methyl triflate were added. The crude reaction mixture was applied to a 50 cm ³ silica gel column. Elute with CHCKMeOH (98: 2) and

194 gives 134 mg of the free base of compound 234 as a white foam. To a solution of this material in 2 ml of ethyl acetate is added 0.26 ml of 1N HCl / ether. Filtration of the resulting solid gave Example 234 (102 mg, 38%) as a white solid.

MS (M + H) ⁺ 489, 491.

Analysis calculated for C22H24N4O2Cl 0.25 EtOAc · 1.25 HCl.

Found: C, 49.59; H, 5.11; N, 10.06.

Found: C, 49.97; H, 5.15; N, 9.90.

(R) -7-Cyano-2,3,4,5-tetrahydro-1 - [(1-methyl-1H-imidazol-5-yl) methyl] -4 (methylsulfonyl) -3- (phenylmethyl) -1H -1,4-Benzodiazepine (monohydrochloride) 200 mg (0.38 mmol) of (R) -7-cyano-2,3,4,5-tetrahydro-1 - [(((1,1-dimethylethoxy) carbonyl) -1 H-Imidazol-4-yl) methyl] -4- (methylsulfonyl) -3- (phenylmethyl) -1H-1,4-benzodiazepine (prepared from the compound of Example 224 according to the procedure for the synthesis of Compound A described in Example 225) in 2 mL of methylene chloride - At 78 ° C, 59 μΙ (0.48 mmol) of methyl triflate was added dropwise under argon. The reaction mixture was allowed to warm to room temperature (a white precipitate formed during this time). After stirring at room temperature for 3 hours, 140 μΙ (0.8 mmol) of DIEA was added and stirred at room temperature overnight. The crude mixture was purified by flash chromatography over a 30 cm ³ silica gel column.

195

Elution with 2% MeOH-CHCl ₃ gave 122 mg (0.28 mmol, 74%) of a clear colorless oil which crystallized on standing. This material was converted to the hydrochloride salt by adding 0.28 mL of 1M HCl in ether to a solution of the free base in methylene chloride (2 mL). A white precipitate is formed which, after filtration, gives 90 mg of the compound of Example 235 as a white powder.

MS (M + H) ⁺ 436.

Example 236 (R) -2,3,4,5-Tetrahydro-1- (1H-imidazol-4-ylmethyl) -4- (methylsulfonyl) -7-phenyl-3 (phenylmethyl) -1H-pyrido [3.2 -e] -1,4-diazepine (monohydrochloride). BMS-214693

A. 2-Hydroxy-5-nitro-6-methylpyridine in 2: 1 mixture of 2-amino-5'-nitro-6-methylpyridine and 2-amino-3-nitro-6-methylpyridine (2.5 g, 16.3) mmol) in 15 mL of water at 0 ° C was added concentrated sulfuric acid (5 mL) followed by 90 min. a solution of NaNO ₂ (2.25 g, 32.6 mmol) in 5 mL of water was added dropwise. After the solution has reached room temperature, it is stirred for 5 hours, cooled to 0 ° C and filtered. The solid was washed with water (2x) and dried in vacuo to give 1.84 g of a> 4: 1 mixture of Compound A and 2-hydroxy-3-nitro-6-methylpyridine (73%) as a tan solid. .

196

B. 2-Chloro-5-nitro-6-methylpyridine

A mixture of compound A, 2-hydroxy-3-nitro-6-methylpyridine (0.93 g, 6.05 mmol) and phosphorus pentachloride (48.9 g, 235 mmol) in toluene (10 mL) was heated at 92 ° C for 16 h. . and cooled to 0 ° C. Ice is added and the mixture is stirred and distributed. The aqueous layer is washed with toluene, the combined organic phases are dried (magnesium sulfate), filtered and evaporated to give 1.03 g of a 6: 1 mixture (100%) of Compound B and 2-chloro-3-nitro-6-methylpyridine (100%). crystalline material.

C. 2-Phenyl-5-nitro-6-methylpyridine

A mixture of compound B and 2-chloro-3-nitro-6-methylpyridine (0.42 g, 2.40 mmol) in THF (10 mL) was degassed with nitrogen. Tetrakistriphenylphosphine palladium (28 mg, 0.024 mmol) is added and the mixture is stirred for 30 min. Phenylboronic acid (0.44 g, 3.6 mmol) and 2M Na ₂ CO ₃ (1.8 mL) were added and the mixture heated at 75 ° C for 17 h. and stirred at room temperature for 48 hours. Methylene chloride is added and the mixture is filtered through celite and partitioned. The mixture was washed with saturated aqueous NaHCO ₃ , dried (magnesium sulfate), filtered and evaporated to give 0.77 g of a brown solid. Flash chromatography (silica gel, 10% ethyl acetate / hexanes) affords 0.37 g of compound C (72%) as a white solid and 0.05 g of 2-phenyl-3-nitro-6-methylpyridine (10%) is oil.

D. 2-Phenyl-5-amino-6-methylpyridine into a suspension of Compound C (3.0 g, 14 mmol) in concentrated HCl (30 mL) over 45 min. tin chloride dihydrate (9.91 g, 44 mmol) was added. Within 2 or. the solution was allowed to warm to room temperature, warmed to 78 ° C for 15 min, cooled to 0 ° C, neutralized with 4M NaOH and extracted with methylene chloride (3x). The combined organic phases were dried (magnesium sulfate), filtered and evaporated to give 2.62 g of compound D (100%) as a yellow oil which crystallized on standing.

E. 2-Phenyl-5- (phenylsulfonylamino) -6-methylpyridine

197

A mixture of 2-phenyl-5-amino-6-methylpyridine (2.29 g, 12.4 mmol) and benzenesulfonyl chloride (1.65 mL, 12.9 mmol) was heated at 88 ° C for 15 h. The mixture was cooled and the resulting glass material was dissolved in a mixture of methylene chloride and 10% NaOH. The mixture is partitioned, the organic phase is washed with 10% NaOH, the combined aqueous phases are acidified with concentrated HCl and extracted with methylene chloride (2x). The combined organic phases were dried (magnesium sulfate), filtered and evaporated to give 3.40 g of compound D (85%) as a yellowish crystalline solid.

F. 2-Phenyl-5- (phenylsulfonylamino) -6-methylpyridine-N-oxide {A suspension of E (3.0 g, 9.24 mmol) in acetic acid (28 mL) was added with 30% aqueous hydrogen peroxide (9.25) ml). The mixture was heated at 72 ° C for 4 h. and at 62 ° C for 22 hours. An additional 3 ml of H ₂ O _{2 was added} and the mixture heated at 54 ° C for 20 hours. and pouring on ice. The mixture is left overnight, 200 ml of water are added, the resulting solid is filtered off, washed with water and ether and dried in vacuo to give 1.43 g (46%) of the compound F, which is a yellow solid, containing impurity E. The washing water and ether were extracted with methylene chloride to give 1.0 g of a mixture of compound E and compound F (approximately 4: 1).

MS (M + H) ⁺ 341.1.

G. 2-Phenyl-5- (phenylsulfonylamino) -6-acetoxymethylpyridine

A solution of crude compound F (0.50 g, <1.47 mmol) and acetic anhydride (2.5 mL) in acetic acid (5 mL) was heated at 90 ° C for 4 h, cooled and poured into ice. After standing overnight, the mixture was extracted twice with methylene chloride, the combined organic extracts dried (MgSO ₄ ), filtered and evaporated to give compound G (0.60 g,> 100%) as a yellow foam.

H. 2-Phenyl-5- (phenylsulfonylamino) -6-hydroxymethylpyridine

198

A mixture of Compound G (0.60 g, <1.47 mmol) and 2M NaOH (2 mL) was heated at 50 ° C for 2.25 h. and cooled to 0 ° C. Methylene chloride is added followed by concentrated aqueous HCl until the solid is dissolved. Solid Na ₂ HPO ₄ is added until the aqueous phase reaches pH 7 and the mixture is partitioned. The aqueous phase is extracted with methylene chloride, the combined organic extracts are dried (MgSO ₄ ), filtered and evaporated. The residue was purified by silica gel flash chromatography eluting with 50% ethyl acetate / hexanes to give 0.09 g of compound F and 0.24 g of resin compound H (48% based on crude compound F).

I. 2-Phenyl-5- (phenylsulfonylamino) -pyridine-6-carboxaldehyde

To a solution of crude compound H (0.70 g, 2.06 mmol) in THF (10 mL) was added MnO ₂ (0.36 g, 4.11 mmol). The mixture was stirred at room temperature and MnO ₂ was added again after 1 h, 0.36 g; 2 or 0.36 g; 3 or 0.36 g; 7.5 or 0.72 g; 22.5 or 0.72 g; 32 or 0.72 g. After stirring for 32.5 hours, the mixture is filtered through celite, the filter cake is washed three times with celite to give 0.55 g of compound I (79%) as an orange solid. MS (M + H) ⁺ 339.0.

J. D- [N- (2-Phenyl-5- (phenylsulfonylamino) -6- (pyridinylmethyl) -phenylalanine] methyl ester

Compound I (0.55 g, 1.62 mmol), D-phenylalanine methyl ester hydrochloride (1.05 g, 4.88 mmol), NaOAc (0.40 g, 4.88 mmol) and 10% Pd / C The suspension (50 mg) in a mixture of 4 ml of methanol and 2 ml of acetic acid was hydrogenated by bubbling hydrogen from the cylinder for 18 hours and filtered through celite. The filter cake is washed twice with methanol and the filtrate is evaporated. The residue is partitioned between pH 7 phosphate buffer and methylene chloride. The aqueous phase was extracted with methylene chloride, the combined organic extracts dried (MgSO ₄ ), filtered and evaporated to give compound J (1.21 g,> 100%).

199

K. (R) -2,3,4,5-Tetrahydro-7-phenyl-3- (phenylmethyl) -1H-pyrido [3,2-e] -1,4-diazepin-2-one

A mixture of compound J (1.21 g, <1.62 mmol) and polyphosphoric acid (16 g) was heated at 100 ° C for 5 h. Ice and methylene chloride are added and the mixture is cooled, basified with 4N NaOH and the layers separated. The aqueous phase is washed twice with methylene chloride, and the combined organic extracts are dried (MgSO ₄ ), filtered and evaporated. The residue was purified by flash chromatography on silica gel eluting with 75% ethyl acetate / hexanes to give 0.31 g (58% based on compound).

I) Compound K which is an off-white solid. MS (M + H) ⁺ 330.0.

L. (R) -2,3,4,5-Tetrahydro-4- (methylsulfonyl) -7-phenyl-3- (phenylmethyl) -1H-pyrido [3,2-e] -1,4-diazepin-2-one

To a solution of compound J (117 mg, 0.36 mmol) and TEA (0.06 mL, 0.43 mmol) in methylene chloride (3 mL) at 0 ° C was added methanesulfonyl chloride (0.033 mL, 0.43 mmol). The solution was stirred at 0 ° C for 30 min. and at room temperature for 90 min. TEA (0.06 mL) and methanesulfonyl chloride (0.032 mL) were added again and the solution was stirred for 1 h. and partitioned between aqueous NaHCO ₃ and methylene chloride containing a small amount of isopropanol (<10%). The aqueous layer was washed with methylene chloride, the combined organic extracts dried (MgSO ₄ ), filtered and evaporated to give 145 mg of compound L as a solid (100%).

MS (M + H) ⁺ 408.1.

M. (R) -2,3,4,5-Tetrahydro-4- (methylsulfonyl) -7-phenyl-3- (phenylmethyl) -1H-pyrido [3,2-e] -1,4-diazepine

To a solution of compound L (53 mg, 0.13 mmol) in THF (2 mL) at 0 ° C was added 1M borane in THF (0.39 mL). The solution was allowed to warm to room temperature overnight, methanol was added and the mixture was evaporated. Dissolve the residue in a small amount of 10% HCl and methanol, heat until the solution becomes clear, and evaporate the methanol. Methylene chloride is added followed by solid K2CO3 until the aqueous layer reaches pH 11.

200

The mixture is partitioned, the aqueous layer is washed with methylene chloride, the combined organic extracts are dried (MgSO ₄ ), filtered and evaporated. The residue was purified by preparative thin layer chromatography on silica gel eluting with 50% ethyl acetate / hexanes. The principal R _f band is cut and extracted with methylene chloride containing a few drops of methanol; Yield: 25 mg of compound M (49%).

N. (R) -2,3,4,5-Tetrahydro-1- (1H-imidazol-4-ylmethyl) -4- (methylsulfonyl) -7-phenyl-3- (phenylmethyl) -1H-pyrido [3,2- e] -1,4-diazepine (monohydrochloride).

of compound M (24 mg, 0.06 mmol) and imidazole-4-carboxaldehyde (17 mg,

A solution of 18 mmol) in dichloroethane (1 mL) and acetic acid (0.5 mL) was added sodium triacetoxyborohydride (32 mg, 0.15 mmol). The solution is stirred for 1 hour and aldehyde (16 mg) and hydride (16 mg) are added again. The solution was stirred for 45 min and hydride (16 mg) was added again. NH ₄ OH (0.5 mL) was added followed by ethyl acetate and aqueous NaHCO ₃ . The mixture is partitioned, the aqueous layer is washed with ethyl acetate, the combined organic extracts are washed with saturated NaHCO ₃ and saturated NaCl, dried (MgSO ₄ ), filtered and evaporated to give the free base of compound N (25 mg, 89%) as a white foam. This material is dissolved in methylene chloride, the solution is filtered through glass wool and evaporated. The residue was dissolved in methanol, added with 0.5 mL of 1M HCl in ether, and the mixture was evaporated. Evaporate the residue from methanol, dissolve in 2 ml of methanol and filter through a glass of cotton wool. The filtrate was evaporated and the residue was dissolved in 0.5 ml of methanol. Ether (10 mL) was added and the resulting precipitate was filtered off, washed with ether and dried to give Example 236 (24 mg) as a yellow solid.

MS (M + H) ⁺ 474.3.

1 H-NMR (CD ₃ OD) δ 2.18 (3H, s); 2.76-2.92 (2 H, m); 3.65 (1H, dd, J = 4.4,

15.2 Hz); 3.98 (1H, dd, J = 10.6, 15.2 Hz); 4.75 (1H, m); 5.18 (1H, d, J = 18.8

Hz); 7.26-7.40 (5 H, m); 7.58-7.61 (4 H, m); 7.76-7.90 (4 H, m).

201

4- [2- (4-Chlorophenyl) -1,2-dioxoethyl] -2,3,4,5-tetrahydro-1- (1H-imidazol-4-ylmethyl) -7-phenyl-1H-1,4-benzodiazepine ( hydrochloride).

To a solution of 2- (4-chlorophenyl) -2-oxoacetic acid (0.017 g, 0.092 mmol) in HOAt (0.013 g, 0.092 mmol) in DMF (0.5 mL) was added. DMF (0.2M, 0.46 mL, 0.092 mmol) and DIC (0.2M, 0.014 mL, 0.092 mmol) in Example 33 were added to the mixture, and the mixture was stirred at room temperature for 16 h. The mixture is purified by ion-exchange chromatography over a solid phase extraction cartridge using the following procedure:

1) Varian solid phase extraction column (1.5 g, SCX cation exchanger) is conditioned with 10 mL MeOH / CH ₂ Cl ₂ ;

2) the mixture is injected onto the column using a 10 ml syringe to maintain a constant system pressure;

3) washing the column with 3 x 7.5 mL MeOH / CH ₂ Cl ₂ (1: 1);

4) washing the column with 1 x 7.5 mL of 0.01 N ammonia in MeOH;

5) Elute the column with 7.5 mL of 1.0 N ammonia in MeOH and collect the eluate in a tared trap.

The product solution is concentrated using a Savant Speed Vac device (about 2 mm Hg column for 20 hours). The residue was dissolved in CH ₃ CN (2 mt), 1N Hci (0.10 mL), and water (1 mL), and lyophilized to give Example 237 (0.042 g, 86%) as a byte lyophilisate.

202

MS: (M + H) ⁺ 471.

Analysis calculated for C 27 H ₂₃ N ₄ O ₂ Cl · 0.15 CH ₃ CN · 1.0 HCl 0.84 H ₂ O. Calculated: C, 61.40; H, 4.93; N, 10.88.

Found: C, 61.41; H, 5.02; N, 11.28.

4- (1,2-Dioxopropyl) -1,2-dioxopropyl] -2,3,4,5-tetrahydro-1- (1H-imidazol-4-ylmethyl) -7-phenyl-1H-1,4-benzodiazepine ( hydrochloride).

Example 238 is prepared from pyruvic acid according to the procedure described in Example 237.

MS: (M + H) &lt; ⁺ &gt; 375.

Analysis calculated for C22H22N4O2 · 1.0 HCl · 0.67 H ₂ O.

Found: C, 62.47; H, 5.80; N, 13.25.

Found: C, 62.46; H, 5.59; N, 13.28.

Example 239

203

2,3,4,5-Tetrahydro-1- (1H-imidazol-4-ylmethyl) -4- [2- (4-nitrophenyl) -1,2-dioxoethyl] -7-phenyl-1H-1,4-benzodiazepine (hydrochloride) ).

Example 239 is prepared from 4-nitrophenylpyruvic acid according to the procedure described in Example 237.

MS: (M + H) &lt; ⁺ &gt; 482.

Analysis calculated for C27H23N5O4 1.0 HCl · 0.38 H ₂ O.

Found: C, 61.79; H, 4.76; N, 13.34.

Found: C, 61.80; H, 4.72; N, 13.54.

2,3,4,5-Tetrahydro-1- (1H-imidazol-4-ylmethyl) -4- [2- (4-methoxyphenyl) -1,2-dioxoethyl] -7-phenyl-1H-1,4-benzodiazepine ( hydrochloride).

204

Example 240 is prepared from 4-methoxyphenylpyruvic acid according to the procedure described in Example 237.

MS: (M + H) ⁺ 467.

Analysis calculated for C28H26N4O3 · 1.0 HCl · 0.79 H ₂ O.

Found: C, 65.02; H, 5.57; N, 10.83.

Found; C, 65.01; H, 5.66; N, 10.75.

2,3,4,5-Tetrahydro-1- (1H-imidazol-4-ylmethyl) -7-phenyl-4- (3,3,3-trifluoro-1,2-dioxopropyl) -1H-1,4-benzodiazepine ( trifluoroacetate, 1: 2)

Example 241 is prepared from trifluoropyruvic acid according to the procedure described in Example 237 using methylene chloride as a cosolvent. Purification by reverse phase preparative HPLC (aqueous methanol, 0.1% TFA).

MS: (M + H) &lt; ⁺ &gt; 429.

Analysis calculated for C ₂₂ Hi ₉ N ₄ O ₂ F ₃ 1.5 TFA · 0.81 H ₂ O.

Found: C, 48.90; H, 3.63; N, 9.12.

Found: C, 48.90; H, 3.58; N, 9.13.

Example 242

205

(R) -7-Chloro-2,3,4,5-tetrahydro-1 - [(1H-imidazol-4-yl) methyl] -4- (methylsulfonyl) -3- (phenylmethyl) -1 H -pyrido [3,2-e] -1,4-diazepine (hydrochloride)

A. 2-Chloro-5- (phenylsulfonylamino) -6-methylpyridine

Compound A is prepared from Compound B of Example 236 according to the procedures for preparation of Compound D and Example 236 described in Example 236.

B. 2-Chloro-5- (phenylsulfonylamino) -6-methylpyridine-N-oxide To a suspension of compound A (3.0 g, 10.6 mmol) in TFA (12.5 mL) was added 30% aqueous hydrogen peroxide (2, 2 ml). The mixture was refluxed for 80 min. Another 2.5 mL of H2O2 was added and the mixture was refluxed for 95 min. An additional 2.5 ml of H ₂ O _{2 is added} and the mixture is refluxed for 1 hour. and pouring 'j ice cream. The mixture was left overnight, then filtered. The solid is washed with water, dissolved in 10% isopropanol in methylene chloride, and dried to give 2.44 g of compound B, which contains impurities of compound A. A further 0.33 g of crude compound B is precipitated from the aqueous filtrate. Total yield 2.77 g (88%).

(M + H) ⁺ 298.9.

C. 2-Chloro-5- (phenylsulfonylamino) -6-hydroxymethylpyridine

Compound C (in the form of a resin) is prepared from compound B according to the procedures for the preparation of compounds G and H described in Example 236. (M + H) ⁺ 299.0.

206

D. 2-Chloro-5- (phenylsulfonylamino) -pyridine-6-carboxaldehyde To a solution of crude C (2.45 g, 8.20 mmol) in THF (20 mL) was added MnO ₂ (1.43 g, 16.4). mmol). The mixture was stirred at room temperature and MnO ₂ was added again after 1 h. - 2.86 g: 28 or. - 2.86 g. After stirring for 21 h, the mixture was directly purified by flash chromatography (25% ethyl acetate / hexanes) to give 0.82 g of crude compound.

D.

E. D- [N- (2-Chloro-5- (phenylsulfonylamino) -6-pyridinylmethyl) -phenylalanine] methyl ester and the dehydrogenated compound D (0.81 g, 2.73 mmol), D-phenylalanine methyl ester hydrochloride ( 0.88 g, 4.10 mmol) and NaOAc (0.67 g, 8.20 mmol) in aliquots of a mixture of 15 mL of methylene chloride and 3 mL of acetic acid over 90 min. sodium triacetoxyborohydride (0.87 g, 4.10 mmol) was added. The mixture was stirred for 90 min. and is distributed between pH 7 phosphate buffer and methylene chloride. The aqueous phase is extracted with methylene chloride, the combined organic extracts are dried (MgSO ₄ ), filtered and evaporated to give E (1.62 g,> 100%) as an orange gum.

F. (R) -2,3,4,5-Tetrahydro-1- (1H-imidazol-4-ylmethyl) -4- (methylsulfonyl) -7-chloro-3- (phenylmethyl) -1H-pyrido [3,2- e] -1,4-diazepine (monohydrochloride)

Example 242 is prepared from Compound E according to the procedures described for the following compounds: Example 236 Compound K, Example 236 Compound L, Example 236 Compound M, Example 236 Compound N. The HCl salt is precipitated from isopropanol in ether to give Example 242 in the form of highly hygroscopic foam. compound.

MS (M + H) ⁺ 432.1.

¹³ C-NMR (CDCl 3, free base) δ 7.96, 39.60, 47.97, 48.34, 55.73, 59.27, 118.66, 122.59, 124.89, 126.91 , 128.64, 129.16, 135.59, 137.15, 138.88, 139.63, 144.10, 144.54, 182.64 md

Example 243

207

6,7,8,9-Tetrahydro-5- (1H-imidazol-4-ylmethyl) -8- (1-naphthalenylcarbonyl) -2-phenyl-5H-pyrimido [5,4-e] [1,4] diazepine ( monohydrochloride)

A. 2-Phenyl-5-bromo-4-pyrimidine carboxylic acid

To a solution of mucobromic acid (16 g, 62 mmol) in 800 mL of water was added benzamidine hydrochloride hydrate (26 g, 166 mmol) and triton B (100 mL, 40% in water). The solution is stirred for 23 hours, filtered off with a small amount of dark solid and acidified with concentrated HCl. The resinous precipitate was filtered off and recrystallized from 4: 1 ethanol / water to give 5.87 g (34%) of Compound A as a brown crystalline solid. Concentration of the subcrystallization solution yields another 1.72 g (44% overall yield).

B. 2-Phenyl-5- (2-aminoethylamino) -4-pyrimidinecarboxylic acid

A mixture of 3.0 g (10.8 mmol) of Compound A and 300 mg of copper sulphate in 15 ml of water and 15 ml of ethylenediamine was heated at 100 ° C for 3 hours. The dark solution is evaporated to dryness and the semi-solid residue is diluted with water to give a very rich precipitate which is filtered off, rinsed well with water and dried overnight in air to give 2.45 g of Compound B which is a tan solid. The filtrate is evaporated to dryness and the residue is diluted with water. A further 0.6 g of compound B is obtained at room temperature. These materials are mixed and dried overnight 60

At 208 ° C in vacuo, 2.85 g (about 100%) of Compound B is obtained as a yellowish solid.

C. 6,7,8,9-Tetrahydro-2-phenyl-5H-pyrimido [5,4-e] [1,4] -diazepin-9-one

To a suspension of 2.8 g (10.8 mmol) of Compound B in 100 ml of pyridine is added

3.1 g (16.3 mmol) of EDC and 2.2 g (16.3 mmol) of HOBT were added and the suspension was stirred at room temperature under argon for 36 h. The resulting cloudy solution is evaporated to dryness, the semisolid residue is diluted with 10% isopropanol in water and washed with brine (2x). A clear yellow precipitate is formed in the aqueous layer during washing. Filtration of this material gives 1.9 g of crude compound C. This material is suspended in methanol and heated in a steam bath. The remaining insoluble matter is filtered off and the material is again extracted with hot methanol on the filter. The combined filtrates were evaporated to dryness to give 1.53 g (59%) of Compound C as a yellowish powder.

D. 6,7,8,9-Tetrahydro-2-phenyl-5H-pyrimido [5,4-e] [1,4] -diazepine

To a stirred solution of 100 mg (0.42 mmol) of Compound C in 2 mL of gluten was added 85 mg (2.1 mmol) of lithium aluminum hydride, and the reaction mixture was refluxed for 18 hours. 0.5 mL of pyridine, 80 mg of LAH was added to the reaction mixture, and heating was continued for 85 hours at 85 ° C. The mixture was quenched by addition of 5 mL of ethyl acetate followed by 0.5 mL of almost. NH ₄ OH. The resulting suspension is filtered and the filter cake is rinsed well with ethyl acetate. The filtrate is evaporated to dryness and the product obtained is used without further purification. This material can also be purified by flash chromatography on silica gel eluting with 10% methanol in ethyl acetate to give pure compound D, which is an orange solid crystalline.

E. 6,7,8,9-Tetrahydro-8- (1-naphthalenylcarbonyl) -2-phenyl-5H-pyrimido [5,4e] [1,4] -diazepine

209

To a solution of 80 mg of crude compound D (0.35 mmol) in 3 mL of methylene chloride and 3 mL of 1N sodium hydroxide is added 60 μΙ (0.4 mmol) of 1-naphthoyl chloride. The reaction mixture was stirred at 0 ° C for 1 h. The organic layer was separated, washed with saturated ammonium chloride, dried (MgSO ₄ ) and evaporated. The residue was purified by silica gel flash chromatography. Elute with ethyl acetate-hexane (3: 1) to give 40 mg (25% based on Compound C) of the foam compound

E,

F. 6,7,8,9-Tetrahydro-5- (1H-imidazol-4-ylmethyl) -8- (1-naphthalenylcarbonyl) -2-phenyl-5H-pyrimido- [5,4-e] [1,4] diazepine (monohydrochloride)

To a solution of 23 mg (0.062 mmol) of compound E in 1 mL of methylene chloride and 0.2 mL of acetic acid is added 10 mg (1 mmol) of 4-formylimidazole. The reaction mixture was stirred for 15 min and 21 mg (1 mmol) of sodium triacetoxyborohydride was added. After 1, 2, 3 is 4 or. 10 mg of imidazole and 21 mg of hydride were added under stirring. Stirring continued overnight. The reaction mixture was diluted with methanol and the crude mixture was purified by preparative HPLC over a YMC ODS-A S 10 column using a gradient elution of 0-100% solvent B (A: 10% MeOH-H ₂ O + 0.1% TFA, B: 10 % H ₂ O-MeOH + 0.1% TFA). The appropriate fractions are mixed and evaporated. The residue is converted to the hydrochloride salt by dilution with methanolic HCl and evaporation of the solvent. 31 mg of a yellow solid are obtained. This material is dissolved in a minimum amount of methanol and precipitated by the dropwise addition of ether. 12 mg (39%) of the pure compound of Example 243 is obtained as a yellow powder.

MS (M + H) ⁺ 461.

¹ H-NMR (CD 3 OD): δ 3.69 (2H, pl.s), 3.90 (2H, m), 4.20 (1H, m), 4.45 (1H, m),

4.70 (1H, m), 4.82 (1H, m), 5.49 (1H, m), 7.32-8.30 (11H, m), 8.43 (1H, s),

8.60 (1H, s), 8.95 (1H, m), 9.11 (1H, s).

Example 244

210

(R) -7-Bromo-2,3,4,5-tetrahydro-1- (1H-imidazol-4-ylacetyl) -4- (methylsulfonyl) 3- (phenylmethyl) -1H-1,4-benzodiazepine (monohydrochloride) )

A. (R) -7-Bromo-2,3,4,5-tetrahydro-4- (1,1-dimethylethoxycarbonyl) -3 (phenylmethyl) -1H-1,4-benzodiazepine, 250 mg (0.79) A solution of compound B of Example 244 in 5 mL of methylene chloride at room temperature under argon was added 192 mg (0.88 mmol) of BOC anhydride dissolved in 1 mL of methylene chloride. After 1 or. another 100 mg of BOC anhydride was added and stirred for another 0.5 h. The crude reaction mixture was purified by flash chromatography over a 50 cm ³ silica gel column. Elution with 20% EtOAc in hexane afforded 319 mg (96%) of Compound A as a white solid.

B. (R) -7-Bromo-2,3,4,5-tetrahydro-1- (1-triphenylmethylimidazol-4-ylacetyl) 4- (1,1-dimethylethoxycarbonyl) -3- (phenylmethyl) -1H -1,4-Benzodiazepine To a suspension of 2.2 g (6 mmol) of 1-triphenymethyl-4-imidazolylacetic acid in 50 mL of THF at room temperature and under argon was added 836 μΙ (6 mmol) of triethylamine. The resulting cloudy solution was cooled to -30 ° C and 839 μΙ (6.6 mmol) of i-butyl chloroformate was added dropwise. After stirring for another 0.5 hours. At -30 ° C, a solution of 500 mg (1.2 mmol) of Compound A in 10 ml of THF is added dropwise. The reaction mixture was allowed to warm to room temperature over three hours and stirred overnight. The resulting black reaction mixture was diluted with ethyl acetate and washed with saturated NaCl solution (2x), dried (MgSO ₄ ) and evaporated to give a black foam which

211 was purified by flash chromatography on silica gel. Elution with 25% ethyl acetate in hexane afforded 376 mg (40%) of Compound B as a gray foamy solid, as well as 294 mg of Compound A.

C. (R) -7-Bromo-2,3,4,5-tetrahydro-1- (1-triphenylmethyl-imidazol-4-yl-acetyl) -3- (phenylmethyl) -1H-1,4-benzodiazepine (hydrochloride)

A solution of 370 mg (0.48 mmol) of Compound B in 2 mL of 1M HCl in acetic acid was stirred at room temperature for 0.5 h. The reaction mixture was evaporated to dryness at low temperature and diluted with ethyl acetate. Filtration of the resulting solid afforded 280 mg (83%) of Compound C.

D. (R) -7-Bromo-2,3,4,5-tetrahydro-1- (1-triphenylmethylimidazol-4-ylacetyl) 4- (methylsulfonyl) -3- (phenylmethyl) -1H-1 , 4-Benzodiazepine To a solution of 280 mg (0.4 mmol) of Compound C in 3 mL of methylene chloride was added 167 μΙ (1.2 mmol) of triethylamine at room temperature under argon followed by 46 μΙ (0.6 mmol) of methanesulfonyl chloride. After stirring for 0.5 h, another 167 μΙ of triethylamine and 46 μΙ of methanesulfonyl chloride were added and stirred for another 0.5 h. The crude solution is chromatographed on a 50 cm ³ silica gel flash column. Elution with 50% ethyl acetate in hexane afforded 165 mg (55%) of Compound D as a white foamy solid.

E. (R) -7-Bromo-2,3,4,5-tetrahydro-1- (1H-imidazol-4-ylacetyl) -4 (methylsulfonyl) -3- (phenylmethyl) -1H-1,4 Benzodiazepine (monohydrochloride) To a solution of 80 mg (0.11 mmol) of Compound D in 2 mL of methylene chloride was added 0.5 mL of triethylsilane and 1 mL of TFA, and the mixture was stirred at room temperature under argon for 3 h. The reaction mixture is evaporated to dryness to give a white solid which is diluted with ether and stirred for 0.5 h. The solvent is removed and the remaining insoluble materials are washed twice with ether. The remaining solid was dissolved in ethyl acetate

212 and washed with saturated NaHCO _3, saturated NaCl, dried (MgSO ₄₎ and evaporation of the solvent yields 45 mg of a white foam solid. This material is dissolved in a minimal amount of methylene chloride and added dropwise to 90 μΙ of 1M HCl in ether. The reaction mixture was diluted with ether and the resulting suspension was left overnight in the refrigerator, the solid was filtered off under a nitrogen atmosphere to give 36 mg (62%) of Example 244 as a white powder.

MS: (M + H) ⁺ 503.

Analysis calculated for C _{2 2} H _{2 3} N ₄ O ₃ S · 1.5 HCl.

Found: C, 47.35; H, 4.42; N, 10.04.

Found: C, 47.55; H, 4.41; N, 9.92.

O O

Me (R) -7-Bromo-2,3,4,5-tetrahydro-1- (2-1H-imidazol-4-yl-ethyl) -4- (methylsulfonyl) -3 (phenylmethyl) -1 H-1,4-Benzodiazepine (Monohydrochloride) To a solution of 804 mg (0.107 mmol) of the free base 244 'in 0.5 mL of THF at room temperature under argon was added 1 mL of 1M borane solution in THF. The clear, colorless solution is refluxed for 2 hours, added with 0.5 ml. HCl is heated for 2 more hours. At 65 ° C. The reaction mixture was diluted with water and washed twice with ethyl acetate. The combined organic layers are washed once with saturated NaCl, dried and evaporated to give a clear oil which is purified by flash chromatography over 30 cm ^{3 of} silica gel.

213 column. Eluted with CHCl _3: MeOH: NH ₄ OH (95: 5: 0.5) to give 112 mg of oil. This material is diluted in 0.5 ml almost. HCl was again heated at 80 ° C for 2 h. After cooling to room temperature, the reaction mixture was diluted with water and extracted twice with ethyl acetate. The combined organic layers were dried (MgSO ₄₎ and solvent evaporated to afford 30 mg of residue. Trituration with ether gives a white solid which is dissolved in 0.2 ml of methanol and precipitated with ether. Filtration of the resulting solid gave 12 mg (21%) of the 245 sample, which was a white powder.

MS (M + H) ⁺ (high resolution): calculated: 489.0957; found: 489,096. ¹³ C NMR (67.8 MHz, CD ₃ OD): 24.7, 39.2, 40.3, 47.3, 53.3, 58.1, 60.8, 113.3, 118.1, 118.8, 128.3, 130.1, 130.8, 131.0, 132.4, 134.0, 135.3, 139.8, 149.9

m.d.

Example 246

8 - [(Cyclohexylcarbonyl) amino] -1,2,3,5-tetrahydro-1- (1H-imidazol-4-ylmethyl) -3- (phenylmethyl) -4H-1,4-benzodiazepine-4-carboxylic acid methyl ester (dihydrochloride) )

A. 8-Amino-2,3,4,5-tetrahydro-1- (1H-imidazol-4-ylmethyl) -3- (phenylmethyl) -1H-1,4-benzodiazepine-4-carboxylic acid 1,1-dimethylethyl ester

Compound A (white solid) is prepared from Example 98 Compound D according to the procedure described in Example 26. The crude free base is used. MS (M + H) <^+> = 434.

214

B. 8- (Cyclohexylcarbonylamino) -2,3,4,5-tetrahydro-1- (1H-imidazol-4-ylmethyl) -3- (phenylmethyl) -1H-1,4-benzodiazepine-4-carboxylic acid

1,1-Dimethylethyl ester

Compound B (a white foamy solid) is prepared from Compound A according to the procedure described in Example 27. The crude free base is used. MS (M + H) <^+> = 544.

C. N- [2,3,4,5-Tetrahydro-1- (1H-imidazol-4-ylmethyl) -3- (phenylmethyl) -1H1,4-benzodiazepin-8-yl] cyclohexanamide

Compound C (brownish solid) is prepared from compound B by treatment with Hcl / dioxane in methanol at room temperature. MS (M + H) <^+> = 444.

D. 8 - [(Cyclohexylcarbonyl) amino] -1,2,3,5-tetrahydro-1- (1H-imidazol-4-ylmethyl) -3- (phenylmethyl) -4H-1,4-benzodiazepine-4-carboxylic acid methyl ester (dihydrochloride)

To a stirred solution of Compound C (0.05 g, 0.09 mmol) in CH ₂ Cl ₂ at room temperature under argon was added methyl chloroformate (0.05 g, 0.09 mmol). After stirring for 3 days, the mixture was partitioned between CHCl ₃ (5 mL) and NaHCO ₃ (2 mL). The aqueous layer was extracted with CHCl ₃ (2 x 10 mL). The combined organic layers were washed with NaHCO ₃ and saturated NaCl, dried over MgSO 4, filtered, and concentrated. The residue was purified by preparative HPLC using a gradient of 50-100% aqueous methanol in 0.1% TFA, and the HCl salt was made in 1M HCl / ether.

MS (M + H) <^+> = 502.

¹ H NMR (CD ₃ OD): δ 8.8 (s, 1H), 7.45-7.1 (m, 7.5H), 7.05 (m, 1H), 6.8 (m , 0.5H), 4.67-4.35 (m, 4H), 4.58 (s, 3H), 3.4-3.0 (m, 3H), 2.9 (m, 1H), 2.7 (m, 1H), 2.3 (m, 1H), 1.9-1.2 (m, 10H).

Example 247

215 yrs

H

N

HN

N- [2,3,4,5-Tetrahydro-1- (1H-imidazol-4-ylmethyl) -4- (1-naphthalenylcarbonyl) -1H-1,4-benzodiazepin-8-yl] -1-piperidinecarboxamide ( dihydrochloride) To a solution of Example 26 (0.050 g, 0.125 mmol) and triethylamine (0.038 mL, 0.275 mmol) in dry methylene chloride (1 mL) was added carbonyldiimidazole (0.045 g, 0.137 mmol) at room temperature. After stirring for 2 hours, piperidine (0.013 mL, 0.13 mmol) was added. After stirring for 15 h, the reaction mixture was diluted with NaHCO ₃ and CHCl ₃ . The organic layer was washed with NaHCO _3, water and saturated aqueous NaCl (1 x 3 ml), dried over MgSO filtered and concentrated _4l. The product was purified by reverse phase HPLC using a gradient of 40-90% aqueous methanol in 0.1% TFA and the HCl salt was made in 1M HCl / ether; Example 247 (0.006 g, 10%) is obtained.

MS (M + H) ⁺ 509.

¹ H-NMR (CD ₃ OD): δ 8.5 (d, 1H, J = 19Hz), 8.06-7.9 (m, 2H), 7.69-7.3 (m, 7H),

7.2 (d, 0.5H, J = 7Hz), 6.9 (d, 0.5H, J = 7Hz), 6.5 (d, 0.5H, J = 7Hz), 5.89 (t , 0.5H),

4.6-3.88 (m, 4.5H), 3.6-3.3 (m, 6H), 3.18-2.85 (m, 1.5H), 1.65-1.55 (m, 6H).

Example 248

216

(R) -7-Cyano-1,2,3,5-tetrahydro-1- (1H-imidazol-4-ylmethyl) -3- (phenylmethyl) -4H1,4-benzodiazepine-4-carboxylic acid ethyl ester (hydrochloride)

A. (R) -7-Bromo-2,3,4,5-tetrahydro-3- (phenylmethyl) -1H-1,4-benzodiazepine-2,5-dione to a stirred 5-bromoisatoic acid anhydride (150 g, 563). of anhydrous pyridine (1.5 L) under argon was added Dphenylalanine methyl ester hydrochloride (127 g, 590 mmol) and 4-dimethylaminopyridine (2 g). The resulting solution was refluxed for 3 days and cooled to room temperature. The solvent is evaporated. The residue is dissolved in CH ₂ Cl ₂ (3 L) and the solution is washed with 10% HCl and saturated NaCl, dried over anhydrous Na ₂ SO ₄ , and evaporated to give a foam which is suspended in Et ₂ O (1.0 L). The mixture was stirred and CH ₂ Cl ₂ (100 mL) was added to cleave the emulsion. After freezing in an ice bath for 3 hours, the solid is filtered off, washed with Et ₂ O and a small amount of CH ₂ Cl ₂ and dried under deep vacuum to give 152 g (78.4%) of Compound A.

¹³ C-NMR (DMSO-d ₆ ): 33.31, 53.69, 115.94, 123.31, 126.43, 128.22, 129.39, 132.63, 134.97, 136.19 , 137.76, 166.45, 171.11 md

B. (R) -7-Bromo-2,3,4,5-tetrahydro-3- (phenylmethyl) -1H-1,4-benzodiazepine

A solution of Compound A (100 g, 290 mmol) in anhydrous THF (1.5 L) under argon was stirred and cooled (0 °, ice bath).

217 tetrahydrofuran complex (1.0 M tirol, 1450 mL, 1450 mmol). The resulting solution is gently boiled under reflux overnight. This solution is cooled to 0 ° and slowly added to MeOH until it stops foaming. The solvent is evaporated to dryness. The residue was diluted with MeOH (900 mL), 25% aqueous HCl (180 mL) was added and the mixture was gently refluxed under argon for 2 h. The resulting solution was cooled to 0 ° in an ice bath, slowly added with Et ₂ O (300 mL) and stirred for 1 h. The solid is filtered off. The filtrate is evaporated, the residue is mixed with the solid, washed with Et ₂ O (500 mL) and acetone (500 mL) and suspended in a mixture of CH ₂ Cl ₂ (2 L) and water (1 L). The pH of the 3N NaOH suspension is adjusted to 11. The layer is separated from CH ₂ Cl ₂ . The aqueous layer is saturated with NaCl and extracted with CH ₂ Cl ₂ . The combined CH ₂ Cl ₂ extracts were washed with saturated NaCl, dried over anhydrous Na ₂ SO _4, and evaporated to give 89 g (97% yield) of Compound B as a tan solid.

¹³ C-NMR (CDCl ₃ ): 40.55, 52.19, 54.22, 61.74, 112.52, 120.25, 126.50, 128.60, 129.30, 130.13, 132 , 09, 133.96, 138.52, 148.13 md

C. (R) -2,3,4,5-Tetrahydro-3- (phenylmethyl) -1H-1,4-benzodiazepine-7-carbonitrile in a stirred suspension of compound B (60 g, 190 mmol) in anhydrous 1-methyl-2-pyrrolidinone ( Copper (I) cyanide (51 g, 569 mmol) was added under nitrogen (600 mL). The mixture is heated to 200 ° for 3.5 hours. With vigorous stirring, this mixture was slowly added to a 15% solution of ethylenediamine in water (1.5 L). After stirring for 1.0 h, the suspension was extracted with EtOAc (3 x 750 mL). The EtOAc extracts were combined, washed with 10% NH ₄ OH (2 x 750 mL) and saturated NaCl, dried over anhydrous Na ₂ SO ₄ , and evaporated to give a black gum. This material was passed through a pad of silica (E. Merck 230400 mesh, 1.2 kg) eluting with EtOAc to give 40 g (80%) of Compound C, which is a tan solid.

¹³ C-NMR (CD 3 OD): 40.84, 49.23, 51.62, 51.71, 62.56, 101.42, 119.14, 120.99,

127.56, 129.66, 130.38, 132.71, 134.86, 139.82, 165.29 ppm.

218

D. (R) -7-Cyano-1,2,3,5-tetrahydro-1- (1H-imidazol-4-ylmethyl) -3 (phenylmethyl) -4H-1,4-benzodiazepine

Compound D is prepared from Compound C according to the reaction sequence used to obtain the following compounds: Compound C of Example 98 is reacted without triethylamine and purified by flash chromatography on silica eluting with 4: hexanes: ethyl acetate; Example 1 for compound D; in 4M HCl in 1: 1 dioxane: ethyl acetate, MS (M + H) ⁺ 344.

E. (R) -7-Cyano-1,2,3,5-tetrahydro-1- (1H-imidazol-4-ylmethyl) -3- (phenylmethyl) -4H-1,4-benzodiazepine-4-carboxylic acid ethyl ester. (hydrochloride)

To a solution of compound J (0.10 g, 0.22 mmol) and DIPEA (0.16 mL, 0.9 mmol) in dry methylene chloride (1 mL) at 0 ° C was added ethyl chloroformate (0.023 mL, 0.24) under argon. mmol). After stirring for 2.5 days, the reaction mixture was partitioned between NaHCO ₃ (5 mL) and CHCl ₃ (20 mL). The aqueous layer was extracted with CHCl ₃ (2 x 10 mL). The combined organic layers were washed with NaHCO ₃ , water and saturated NaCl, dried over MgSO ₄ , filtered and concentrated. The product was purified by flash column chromatography eluting with EtOAc (200 mL) and 19/1 CHCl3 / CH3OH (200 mL), treated with 1N NaOH to remove the imidazole acyl group, and treated with HCl / ether; Example 248 is obtained (0.047 g, 52%). MS (M + H) <^+> = 416.

¹ H-NMR (CD 3 OD): δ 8.9 (d, 1H, J = 16 Hz), 7.48-7.12 (m, 8H), 6.9 (m, 1H), 5.0-4 , 4 (m, 5H), 4.8-3.7 (m, 3H), 3.4-3.2 (m, 2H), 2.89-2.7 (m, 2H), 1.03 (m, 3H).

Example 249

219

N- [2,3,4,5-Tetrahydro-1- (1H-imidazol-4-ylmethyl) -4- (methylsulfonyl) -3 (phenylmethyl) -1H-1,4-benzodiazepin-8-yl ] cyclohexanecarboxamide (dihydrochloride): To a heterogeneous mixture of Example 246 Compound C (0.030 g, 0.054 mmol), DMF (0.2 mL) and triethylamine (0.2 mL) in dry methylene chloride (0.3 mL) was added methanesulfonyl chloride at room temperature under argon. (0.024 mL, 0.38 mmol). After stirring for 2.5 days, another equivalent of methanesulfonyl chloride is added. After stirring for 3 h, the mixture was diluted with NaHCO ₃ and CHCl ₃ , the layers were separated, and the aqueous layer was extracted with chloroform (2 x 20 mL). The combined organic layers were washed with water (5 mL) and saturated NaCl (5 mL), dried over MgSO ₄ , filtered, and concentrated. The residue was purified by flash column chromatography on silica gel eluting with CHCl ₃ and 9/1 CHCl ₃ / CH ₃ OH (200 mL each) to give Example 249 (5 mg, 17%).

MS (M + H) <^+> = 522.

¹ H-NMR (CD ₃ OD): δ 8.88 (s, 1H), 7.5 (m, 2H), 7.3 (m, 5H), 7.05 (d, 1H, J = 8 Hz), 6.8 (d, 1H, J = 8Hz), 4.8-4.2 (m, 5H), 3.6 (m, 1H), 3.2 (m, 1H), 3, 0 (m, 1H), 2.7 (m, 1H), 2.3 (m, 3H), 1.6-1.9 (m, 5H), 1.1-1.5 (m, 4H) 0.9 (m, 2H).

Example 250

220

(R) -7-Cyano-4 - [[2- (dimethylamino) ethyl] sulfonyl] -2,3,4,5-tetrahydro-1- (1H-imidazol-4-ylmethyl) -3- (phenylmethyl) -4H- 1,4-Benzodiazepine (dihydrochloride)

A. (R) -7-Cyano-4- (ethenylsulfonyl) -2,3,4,5-tetrahydro-1- (1H-imidazol-4-ylmethyl) -3- (phenylmethyl) -4H-1,4-benzodiazepine

To a solution of Example D 248 Compound D (1.0 g, 3.79 mmol) and DIPEA (2.6 mL, 15.2 mmol) in dichloromethane (16 mL) at 0 ° C under argon was added 2-chloro-ethanesulfonyl chloride (1.85 g). , 11.4 mmol). After stirring for 16 h, the reaction mixture was diluted with chloroform and aqueous NaHCO ₃ . The layers were separated and the aqueous again extracted twice with chloroform. The combined organic extracts were washed twice with saturated NaHCO ₃ and NaCl, dried over MgSO _4, filtered and concentrated. The product was purified by flash column chromatography on silica gel eluting with 75%, followed by 50% h exanes / ethyl acetate to afford Compound A (0.31 g, 23%). MS: (M + H) &lt; ⁺ &gt; = 434.

B. (R) -7-Cyano-4 - [[2- (dimethylamino) ethyl] sulfonyl] -2,3,4,5-tetrahydro-1- (1H-imidazol-4-ylmethyl) -3- (phenylmethyl) - 4H-1,4-benzodiazepine (dihydrochloride)

Compound A (0.59 g, 1.36 mmol) in 2M dimethylamine in THF (15 mL, 30 mmol) was heated in a sealed tube at 60 ° C for 16 h.

The reaction mixture is concentrated and the residue is purified by preparative

By HPLC (30-90% aqueous methanol with 0.1% TFA gradient).

221

The purified TFA salt was converted to the HCl salt using HCl / ether and lyophilized to afford Example 250 (11 mg, 1.7%).

MS: (M + H) &lt; ⁺ &gt; = 479.

¹ H-NMR (CD 3 OD): δ 8.9 (s, 1H), 7.5-7.2 (m, 8H), 6.9 (m, 1H), 4.8-4.4 (m, 5H),

3.95 (m, 1H), 3.4-3.1 (m, 5H), 3.0-2.7 (m, 8H).

Example 251

(R) -7-Cyano-2,3,4,5-tetrahydro-1- (1H-imidazol-4-ylmethyl) -4 - [[2- (4-morpholinyl) ethyl] sulfonyl] -3- (phenylmethyl) -4H-1,4-benzodiazepine (dihydrochloride)

Example 251 is prepared from Example 250 Compound A and morpholine according to the procedure described in Example 250 (61%).

MS: (M + H) &lt; ⁺ &gt; = 521.

¹ H-NMR (CD 3 OD): δ 8.9 (s, 1H), 7.75-7.2 (m, 8H), 6.95 (m, 1H), 5.0-4.4 (m, 3H), 4.1-3.7 (m, 7H), 3.5-3.1 (m, 6H), 3.0 (m, 3H), 2.85 (m, 1H), 2.55 (m, 1H).

222

N- [2,3,4,5-Tetrahydro-1- (1H-imidazol-4-ylmethyl) -4- (2-methoxy-3-methylbenzoyl) -1H-1,4-benzodiazepin-8-yl] cyclohexanecarboxamide (dihydrochloride) ) To a solution of Example 246 Compound C (46 mg, 0.1 mmol) in DMF (1 mL) at room temperature under argon was added successively 2-methoxy-3-methylbenzoic acid (20 mg, 0.12 mmol), DIPEA (0.09 mL, 0.5 mmol), HOAt (16 mg, 0.12 mmol) and EDC (23 mg, 0.12 mmol). After 18 or. NaOH (1N, 1 mL) and MeOH (2 mL) were added. After 25 minutes the volatiles were evaporated in vacuo and the residue partitioned between chloroform (15 mL) and NaHCO ₃ (10 mL). The organic layer was separated, dried and concentrated in vacuo. The residue was purified by chromatography on silica gel eluting with 5% MeOH in chloroform to give a white solid (42 mg, 83%) which was dissolved in MeOH (1 mL) and added to HCl in ether (1N, 2 mL). Concentration in vacuo gave Example 252 as a yellow solid (50 mg).

MS (M + H) <^+> = 502.3.

8 - [(Cyclohexylcarbonyl) amino] -2,3,4,5-tetrahydro-1- (1H-imidazol-4-ylmethyl) -N-phenyl-1H-1,4-benzodiazepine-4-carboxamide (dihydrochloride)

A solution of compound C (46 mg, 0.1 mmol) in Example J 246 in DMF (1 mL) at room temperature under argon was added sequentially.

223 Phenylisocyanate (13 μΙ, 0.12 mmol) and DIPEA (0.09 mL, 0.5 mmol). After 18 or. NaOH (1N, 1 mL) and MeOH (2 mL) were added. After 25 minutes the volatiles were removed in vacuo and the residue partitioned between chloroform (15 mL) and water (10 mL). A precipitate of the desired product is filtered off. The organic layer was separated and concentrated in vacuo. The residue is mixed with the filtered solid, dissolved in MeOHTTHF and purified by reverse phase HPLC eluting with 50% to 90% aqueous MeOH containing 0.1% TFA. The appropriate fractions are collected and concentrated. The residue is taken up in 1N HCl and concentrated. After three such treatments, the residue is dissolved in water and lyophilized to give Example 253 as a yellow solid (30 mg, 55%).

MS (M + H) <^+> = 473.3.

N- [2,3,4,5-Tetrahydro-1- (1H-imidazol-4-ylmethyl) -4 - [(2-methylphenyl) sulfonyl] 1H-1,4-benzodiazepin-8-yl] cyclohexanamide (dihydrochloride)

Example 254 (yellow solid) was prepared from Example 246, C and 2-methylbenzenesulfonyl chloride according to the procedure described in Example 253, except that the cleaved and evaporated reaction mixture was directly purified by preparative HPLC (29%).

MS (M + H) &lt; ⁺ &gt; = 508.2.

Example 255

224

N- [2,3,4,5-Tetrahydro-1- (1H-imidazol-4-ylmethyl) -4 - [(2-methoxyphenyl) carbonyl] -1H-1,4-benzodiazepin-8-yl] cyclohexanamide (dihydrochloride)

Example 255 Compound (yellowish solid) is prepared from Example 246 Compound C and 2-methoxybenzoic acid according to the procedure described in Example 252.

MS (M + H) + = 488.3 ^4.

Example 256

(R) -7-Cyano-1,2,3,5-tetrahydro-1- (1H-imidazol-4-ylmethyl) -3- (phenylmethyl) -4H1,4-benzodiazepine-4-sulfonic acid ethyl ester (hydrochloride)

A. (R) -7-Cyano-1,2,3,5-tetrahydro-3- (phenylmethyl) -4H-1,4-benzodiazepine-4sulfonic acid ethyl ester in Example 248 Compound C (0.3 g, 1, 13 mmol) and DIPEA (0.78 mL, 4.55 mmol) in dichloromethane (8 mL) at 0 ° C under argon

Ethyl chlorosulfonate (0.49 g, 3.41 mmol) was added in 225. After stirring for 16 hours. when returned to room temperature, the mixture was diluted with chloroform and NaHCO _third The layers are separated and the aqueous layer is extracted with chloroform. The combined organic extracts were washed with NaHCO ₃ , water, 1N HCl and twice saturated NaCl, dried over MgSO ₄ , filtered and concentrated to give Compound A (0.54 g, 13%). MS (MH +) = 370.

B. (R) -7-Cyano-1,2,3,5-tetrahydro-1- (1H-imidazol-4-ylmethyl) -3- (phenylmethyl) -4H-1,4-benzodiazepine-4-sulfonic acid ethyl ester. (hydrochloride)

Example 256 is prepared from Compound A according to the procedure described in Example 1 for the preparation of Compound D using dichloroethane and 3A molecular mesh. Purification by preparative HPLC followed by conversion to HCl salt and lyophilization afforded Example 256.

MS (M + H) <^+> = 535.

¹ H-NMR (400 MHz, CD ₃ OD): δ 8.9 (s, 1H), 7.5-7.2 (m, 8H), 6.9 (d, 1H, J = 8 Hz), 5-4.4 (m, 4H), 4.3 (m, 1H), 4-3.2 (m, 4H), 3.0 (m, 1H), 2.8 (m, 1H), 1 , 05 (t, 3H).

Example 257

Br

(3R) -7-Bromo-1- [cyano (1H-imidazol-4-yl) methyl] -2,3,4,5-tetrahydro-4- (methylsulfonyl) -3- (phenylmethyl) -1H-1, 4-Benzodiazepine (monohydrochloride)

226 | To a stirred solution of Example 224 Compound C (390 mg, 1.0 mmol) in acetonitrile: methanol: acetic acid (3 mL, 1: 1: 1) was added 4-formylimidazole (100 mg, 1.04 mmol) followed by sodium cyanide ( 55 mg, 1.12 mmol). The mixture was stirred at room temperature for 2 days, partitioned between saturated potassium carbonate (2 mL) and partitioned between ethyl acetate and 1N NH ₄ OH. The organic layer was separated, washed with brine, dried, and concentrated to give a solid (400 mg, 80%). A portion of this material is converted to its HCl salt by dissolving in methanol with 1N HCl in ether and evaporating the solvent to give Example 257. TLC: R _f = 0.50 (ethyl acetate, two spots).

MS (M + H) &lt; ⁺ &gt; 500.

(3R) -1- [2-Amino-1- (1H-imidazol-4-yl) ethyl] -2,3,4,5-tetrahydro-4- (methylsulfonyl) -3- (phenylmethyl) -1H-1, 4-Benzodiazepine (dihydrochloride) To a stirred suspension of lithium aluminum hydride (95 mg, 2.5 mmol) in ether under argon at room temperature was added a solution of Example 257 free base (250 mg, 0.5 mmol) in anhydrous THF. The mixture was stirred at room temperature for 8 hours, diluted with THF, followed by ethyl acetate and ammonium hydroxide. The suspension is stirred at room temperature for 18 hours. and filtered off. The filtrate was concentrated in vacuo and the residue was purified by silica gel chromatography (ethyl acetate / methanol / NH ₄ OH, 10: 1: 0.1); yielding a semi-solid (80 mg, 38%). Part of this material is converted to its HCl salt as described in Example 257.

227

MS (M + H) &lt; ⁺ &gt;

Example 259

Me ₂ N

(3R) -1- [2- (Dimethylamino) -1- (1H-imidazol-4-yl) ethyl] -2,3,4,5-tetrahydro-4- (methylsulfonyl) -3- (phenylmethyl) -1 H-1,4-Benzodiazepine (dihydrochloride) was added to a stirred solution of 258 free base 20 mg) in methanol (1 mL) and acetic acid (0.5 mL) with sodium acetate (100 mg) and 30 μΙ formaldehyde (37% aqueous solution) was added. ) followed by NaCNBH ₃ (15 mg). The mixture is stirred for 15 min, formaldehyde (30 μΙ) and NaCNBH ₃ are added again, the mixture is stirred for 30 min, diluted with ethyl acetate and quenched with 3 mL of NH ₄ OH. The organic layer was separated, washed with 1N NH ₄ OH solution and saturated NaCl, dried and concentrated. The residue is converted to its HCl salt as described in Example 257 (23 mg).

MS (M + H) ⁺ 454.

Example 260

Br

H ₂ N

228 (3R) -1- [2-Amino-1- (1H-imidazol-4-yl) ethyl] -7-bromo-2,3,4,5-tetrahydro-4- (methylsulfonyl) -3- (phenylmethyl) -1 H -1,4-Benzodiazepine (dihydrochloride) To a stirred solution of the free base (20 mg) of Example 258 in chloroform (1.5 mL) was added tetrabutylammonium perbromide. The mixture was stirred at room temperature for 10 min. and quenched with aqueous NaS ₂ O ₃ . The organic layer was separated and washed with chloroform. The combined organic layers were dried over MgSO ₄ and concentrated in vacuo. The residue was purified by column chromatography (ethyl acetate / methanol / NH ₄ OH; 10: 1: 0 1) to give a white solid (17 mg) which was converted to its hydrochloride salt as described in Example 257.

MS (M + H) ⁺ 504.

Example 261

(3R) -1- [2- (Dimethylamino) -1- (1H-imidazol-4-yl) ethyl] -7-bromo-2,3,4,5-tetrahydro-4- (methylsulfonyl) -3- (phenylmethyl) -1H-1,4-benzodiazepine (dihydrochloride)

Example 261 is prepared from Example 260 according to

259.

MS (M + H) <^+> 532.

Example 262

229

7-Cyano-1,3,4,5-tetrahydro-1- (1-methyl-1H-imidazol-5-ylmethyl) -3- (phenylmethyl) 4- (phenylsulfonyl) -2H-1,4-benzodiazepine-2 -one (monohydrochloride)

A. (R) -N- (2-Amino-5-bromo-phenylmethyl) -N- (methanesulfonyl) phenylalanine methyl ester

A stirred R (-N) -N- (2-aminophenylmethyl) -N- (methanesulfonyl) -phenylalanine methyl ester prepared from D-phenylalanine methyl ester hydrochloride by reductive amination with 2-nitrobenzyl aldehyde followed by reaction with methanesulfonyl chloride in pyridine chloride in ethyl acetate (7.0 g, 16.5 mmol) in chloroform (75 mL) at room temperature was added portionwise tetrabutylammonium perbromide (7.1 g, 14.8 mmol). The mixture was stirred at room temperature for 30 min. {Saturated NaHCO ₃ solution is added followed by addition of solid Na ₂ S ₂ O ₃ . The mixture was stirred for 1 h, concentrated in vacuo and the residue partitioned between water and 50% ethyl acetate / hexanes. The organic layer was separated, washed with water, saturated NaCl, dried and concentrated in vacuo. The residue was purified by flash column chromatography to give compound A (4) as an oil (5 g, 54%). MS (M + H) ⁺ 503. [α] ²⁰ : + 29.6 ° (CHCl3), c = 0.25).

B. 7-Cyano-1,3,4,5-tetrahydro-3- (phenylmethyl) -4- (phenylsulfonyl) -2H-1,4-benzodiazepin-2-one

A solution of Compound A (2.05 g, 4.07 mmol) in N-methylpyrrolidinone (10 mL) was added at 195 ° C for 4 h with the addition of CuCN (1.1 g, 12.3 mmol). The mixture was cooled to room temperature and partitioned between NH ₄ OH

230 solution and methylene chloride. The organic layer is separated and the aqueous layer is extracted with methylene chloride. The combined organic layers were washed with saturated NaCl, dried and concentrated. Recrystallization of the residue from methanol gives compound B, which is a brown solid (1.1 g, 65%). MS (M + H) &lt; ⁺ &gt; mp: 222-223 ° C.

C. 7-Cyano-1,3,4,5-tetrahydro-1- (1-triphenylmethyl-1H-imidazol-4-ylmethyl) -3- (phenylmethyl) -4- (phenylsulfonyl) -2H-1,4-benzodiazepine -2-one to a stirred solution of compound B (310 mg, 0.74 mmol), N-tritylimidazole-4-methanol (510 mg, 1.5 mmol) and triphenylphosphine (450 mg, 1.72 mmol) in toluene and dichloroethane ( 20 mL / 3 mL) was added diethyl azodicarboxylate (300 μΙ, 1.9 mmol) at 60 ° C under argon. The mixture is stirred at 60 ° C for 1 hour. and partitioned between ethyl acetate and water. The organic layer was washed with water and saturated NaCl, dried, concentrated in vacuo and purified by flash column chromatography (ethyl acetate / hexanes, 2: 3) to give O-compound (450 mg, 82%) as an oil. MS (M + H) ⁺ 740.

D. 7-Cyano-1,3,4,5-tetrahydro-1- (1-methyl-1H-imidazol-5-ylmethyl) -3- (phenylmethyl) -4- (phenylsulfonyl) -2H-1,4-benzodiazepine -2-one (monohydrochloride)

To a stirred solution of Compound C (210 mg, 0.28 mmol) in THF at room temperature under argon was added trifluoromethylsulfonate (35 μΐ, 0.31 mmol). The mixture was stirred at room temperature for 10 min. Acetic acid (0.5 mL) and triethylsilane (0.25 mL) were added. The mixture was heated at 60 ° C for 30 min. and partitioned between 1N NaOH and ethyl acetate. The organic layer was separated and washed with saturated NaCl, dried and concentrated in vacuo. The residue was purified by flash column chromatography to give the free base of Compound D as an oil (100 mg, 71%). This base is dissolved in methanol and added with 1N HCl in ether. Evaporation of the solvent afforded Example 262 as a solid.

231

MS (M + H) &lt; ⁺ &gt; 512. m.p. mp: 160 ° C.

Example 263

7-Cyano-1,3,4,5-tetrahydro-1- (1H-imidazol-4-ylmethyl) -3- (phenylmethyl) -4- (phenylsulfonyl) -2H-1,4-benzodiazepin-2-one (monohydrochloride) )

To a stirred solution of Example 262 Compound C (200 mg, 0.27 mmol) in CHCl ₃ at room temperature under argon was added trifluoroacetic acid (1 mL) followed by triethylsilane (0.5 mL). The mixture was stirred at room temperature for 2 hours. and partitioned between 1N NH ₄ OH and ethyl acetate. The organic layer was separated, washed with saturated NaCl, dried and concentrated in vacuo. The residue was purified by flash column chromatography (ethyl acetate, methanol: 95: 5) to give the free base of Example 263 as an oil (110 mg, 82%). This base is dissolved in methanol and added with 1N HCl in ether. Evaporation of the solvent afforded Example 263 as a solid.

MS (M + H) &lt; ⁺ &gt; 498.

Lyd. mp: 195 ° C.

Example 264

232

7-Bromo-2,3,4,5-tetrahydro-1- (1H-imidazol-4-ylmethyl) -4- (methylsulfonyl) -3- (2-phenylethyl) -1H-1,4-benzodiazepine (dihydrochloride)

A. 7-Bromo-2,3,4,5-tetrahydro-3- (2-phenylethyl) -1H-1,4-benzodiazepine

Compound A is prepared from D.L-homoPhe and 6-bromoacetic acid anhydride according to the reaction sequence described to give the following compounds of Example 80, except that DMF is substituted for pyridine and heated at 50 ° C for 24 hours; Example 80 for compound B; Example 80 for compound C.

B. 7-Bromo-2,3,4,5-tetrahydro-4- (methylsulfonyl) -3- (2-phenylethyl) -1H-1,4-benzodiazepine

Compound A (100 mg, 0.30 mmol) was dissolved in THF (5 mL), DIEA (211 μΙ, 1.21 mmol) was added followed by methanesulfonyl chloride (94 μΙ, 1.21 mmol). The solution was stirred for 30 min, concentrated, dissolved in ethyl acetate (50 mL) and washed with water (3 x 20 mL). The organic layer is dried (Na ₂ SO ₄ ) to give compound B as a brown glass upon concentration.

C. 7-Bromo-2,3,4,5-tetrahydro-1- (1H-imidazol-4-ylmethyl) -4- (methylsulfonyl) -3- (2-phenylethyl) -1H-1,4-benzodiazepine ( dihydrochloride)

Compound C and 4-formylimidazole were dissolved in 1,2-DCE (5 mL) and acetic acid (0.5 mL) and sodium triacetoxyborohydride was added. The mixture was stirred at ° C for 2 h. and saturated NaHCO ₃ (5 mL) was added. The mixture was concentrated and the residue partitioned between water (20 mL) and ethyl acetate

233 (20 mL). The organic layer was washed with water (10 mL), saturated NaCl (10 mL), dried (MgSO ₄ ), concentrated, and purified by preparative HPLC (aqueous methanol gradient, 0.1% TFA). Appropriate fractions are mixed, concentrated, and lyophilized. The lyophilisate was dissolved in methanol (0.5 mL) and 1N HCl (5 mL). The mixture is concentrated and lyophilized. Repeat this procedure to give Example 264 as a white solid (15 mg, 19%).

MS (M + H) &lt; ⁺ &gt; 490.

Example 265

7-Bromo-3 - [(3-chlorophenyl) methyl] -2,3,4,5-tetrahydro-1- (1H-imidazol-4-ylmethyl) 4- (methylsulfonyl) -1H-1,4 benzodiazepine (dihydrochloride)

A. 2- (2- (1,1-Dimethyl-ethoxycarbonylamino) -3- (3-chlorophenyl) propylamino] -5-bromobenzoic acid

N-Boc-3-chlorophenylalaninal (800 mg, 2.8 mmol) and 2-amino-5-bromobenzoic acid (660 mg, 3.06 mmol) were dissolved in MeOH (10 mL). Molecular grids (3A, 7.0 g) and glacial acetic acid (0.2 mL) were added and the mixture was stirred for 30 min. Within 30 minutes sodium cyanoborohydride (200 mg, 2.99 mmol) was added portionwise. The mixture was stirred for 16 h, cooled to 0 ° C, and saturated NaHCO ₃ (30 mL) was added slowly. The mixture was stirred for 30 min, concentrated and extracted with ethyl acetate (100 mL). The ethyl acetate layer was washed with water (100 mL), saturated NaCl (100 mL), dried (MgSO ₄ ) and

234 concentrated. Preparative HPLC (aqueous methanol gradient, 0.1% TFA) afforded Compound A as a clear oil (100 mg, 7%).

MS (M + H) ⁺ 481.

B. 2- [2-Amino-3- (3-chlorophenyl) propylamino] -5-bromobenzoic acid

Compound A (100 mg, 0.21 mmol) was stirred in dimethyl sulfide (0.1 mL) and 4N HCl in dioxane (10 mL) for 40 min. The mixture was concentrated, dissolved in methylene chloride (20 mL) and concentrated. The latter procedure is repeated three times to give compound B in the form of a clear glass.

C. 7-Bromo-3 - [(3-chlorophenyl) methyl] -2,3,4,5-tetrahydro-1- (1H-imidazol-4-ylmethyl) -4- (methylsulfonyl) -1H-1,4-benzodiazepine (dihydrochloride)

Compound C (white solid) is prepared from Compound B according to the reaction sequence used to prepare the following compounds: Example 80, Compound B; Example 80 for compound C; 264 for compound B; 264 for the compound of Example

C. MS (M + H) ⁺ 510.

Example 266

(R) -7-Bromo- (3-cyclohexylmethyl) -2,3,4,5-tetrahydro-1- (1H-imidazol-4-ylmethyl) -4- (methylsulfonyl) -1H-1,4-benzodiazepine (dihydrochloride)

Example 266 (white solid) is prepared from D-NBoc-cyclohexylalaninal according to the procedure described in Example 265.

235

MS (M + H) ⁺ 510.

Example 267

7-Bromo-3 - [(2-chlorophenyl) methyl] -2,3,4,5-tetrahydro-1- (1H-imidazol-4-ylmethyl) 4- (methylsulfonyl) -1H-1,4-benzodiazepine (dihydrochloride)

Example 267 (white solid) is prepared from D.L-NBoc-2-chlorophenylalaninal according to the procedure described in Example 265.

MS (M + H) ⁺ 510.

Example 268

(S) -7-Bromo- (3-cyclohexylmethyl) -2,3,4,5-tetrahydro-1- (1H-imidazol-4-ylmethyl) -4- (methylsulfonyl) -1H-1,4-benzodiazepine (dihydrochloride) )

Example 268 (white solid) is prepared from L-NBoc-cyclohexylalaninal according to the procedure described in Example 265.

236

Example 269

MS (M + H) &lt; ⁺ &gt; 482.

7-Bromo-2,3,4,5-tetrahydro-1- (1H-imidazol-4-ylmethyl) -3 - [(4-methoxyphenyl) methyl] -4- (methylsulfonyl) -1H-1,4-benzodiazepine (dihydrochloride) )

Example 269 (white solid) is prepared from D, L-NBoc-4-methoxyphenylalaninal according to the procedure described in Example 265.

MS (M + H) ⁺ 506.

270 Example

4-Acetyl-7-bromo-3 - [(2-chlorophenyl) methyl] -2,3,4,5-tetrahydro-1- (1H-imidazol-4-ylmethyl) -1H-1,4-benzodiazepine (dihydrochloride)

237

Example 270 (white solid) is prepared from 7brom-3 - [(2-chlorophenyl) methyl] -2,3,4,5-tetrahydro-1 H -1,4-benzodiazepine according to the procedures for the preparation of compounds D and E described in the example. .

MS (M + H) ⁺ 475.

Example 271

Br

4-Acetyl-7-bromo-3 - [(3-chlorophenyl) methyl] -2,3,4,5-tetrahydro-1- (1H-imidazol-4-ylmethyl) -1H-1,4-benzodiazepine (dihydrochloride)

Example 271 (white solid) is prepared from 7bromo-3 - [(3-chlorophenyl) methyl] -2,3,4,5-tetrahydro-1H-1,4-benzodiazepine according to the procedure described in Example 270.

MS (M + H) ⁺ 475.

Example 272

Br

HO

238

7-Bromo-2,3,4,5-tetrahydro-1- (1H-imidazol-4-ylmethyl) -3 - [(4-hydroxyphenyl) methyl] -4- (methylsulfonyl) -1H-1,4-benzodiazepine ( dihydrochloride)

A solution of Example 269 (30 mg, 0.059 mmol) in dichloromethane (5 mL) was added

To the mixture of 1,2-dichloroethane (5 mL) was added a solution of BBr ₃ (1M in dichloromethane, 0.5 mL). The mixture was stirred for 16 h and 5% ammonium hydroxide (10 mL) was added. The mixture was stirred for an additional 1 h, concentrated, and the residue was purified by preparative HPLC (gradient of aqueous methanol with 0.1% TFA). Appropriate fractions are mixed, concentrated, and lyophilized. This lyophilisate was dissolved in methanol (0.5 mL) and 1N HCl (5 mL). This mixture is concentrated and lyophilized. Repeat this procedure to give Example 272 as a white solid (20 mg, 60%).

MS (M + H) &lt; ⁺ &gt; 490.

(R) -2,3,4,5-Tetrahydro-1- (1H-imidazol-4-ylmethyl) -4- (methylsulfonyl) -7-phenyl-3- (3-pyridinylmethyl) -1H-1,4-benzodiazepine (dihydrochloride)

Example 273 (yellowish solid) is prepared from Dpyridylalanine and Example 226 by Compound B according to the reaction sequence used

239 for the following compounds: 226 for compound C; Example 226 for compound D;

264 for compound B; 264 for compound C.

MS (M + H) &lt; ⁺ &gt; 474.

Example 274

2,3,4,5-Tetrahydro-8- (hydroxymethyl) -1- (1H-imidazol-4-ylmethyl) -4- (1-naphthalenecarbonyl) -1H-1,4-benzodiazepine (dihydrochloride)

A. 8- [2,3,4,5-Tetrahydro-1H-1,4-benzodiazepine-2,5-dionyl] carboxylic acid

A mixture of 7-carboxysatoic anhydride (made from triphosgene and 4-carboxy-2-aminobenzoic acid, 20 g, 0.09 mol) and ethylglycine hydrochloride (13.5 g, 0.097 mol) in anhydrous pyridine (200 ml) was heated under reflux for 30 hours. , then cooled to room temperature. The pyridine was evaporated and the residue was washed with water followed by EtOAc. The solid was dried under reduced pressure to give Compound A (17.5 g, 88%) as a white solid.

B. 2,3,4,5-Tetrahydro-8- (hydroxymethyl) -1H-1,4-benzodiazepine To a suspension of compound A (10 g, 45 mmol) in ethylene glycol dimethyl ether (10 mL) was added borane (1.0). M THF, 1 L). The suspension was stirred at room temperature for 1 h, refluxed for 8 h, cooled to 0 °, and quenched with 6N HCl (20 mL). Evaporate the solvent, dissolve the residue in water (30 ml), neutralize with saturated Na ₂ CO ₃ and evaporate. The residue was evaporated from methanol and purified by flash columns

240 chromatography (10% MeOH, 1% NH ₄ OH CH ₂ Cl 2) afforded Compound B as a white solid. MS (M + H) &lt; ⁺ &gt; 179.

C. 2,3,4,5-Tetrahydro-8- (hydroxymethyl) -1- (1H-imidazol-4-ylmethyl) -4- (1-naphthalenylcarbonyl) -1H-1,4-benzodiazepine (dihydrochloride)

Example 274 (off-white solid) is prepared from Compound B according to the procedure described in Example 41 for the preparation of Compound F using chromatography in 5% MeOH / 0.5% NH ₄ OH / methylene chloride and following the procedure for the preparation of Compound D in Example 1. HCl salt purification by preparative HPLC.

MS (M + H) 413.

Example 275

2,3,4,5-Tetrahydro-1- (1H-imidazol-4-ylmethyl) -4- (1-naphthalenylcarbonyl) -8 (phenoxymethyl) -1H-1,4-benzodiazepine (dihydrochloride)

A solution of Example 274 (0.38 g, 0.9 mmol) and Boc ₂ O (1.2 g, 5.4 mmol) in CH ₂ Cl ₂ (10 mL) was stirred for 48 h then evaporated. The residue was purified by flash chromatography (4% MeOH in CH ₂ Cl ₂ ) to give the blocked imidazole analog as a white solid (0.190 g, 40%). A mixture of part of this material (42 mg, 0.08 mmol), Ph ₃ P (28 mg, 0.1 mmol), phenol (30 mg, 0.3 mmol) and diethyl azodicarboxylate (0.05 mL, 0.3 mmol) THF (7 mL) was stirred under N _{2 for} 48 h. 1N HCl (5 mL) was added. The mixture is stirred for 1 hour. and is suppressed. The residue is exposed to 6M

241

HCl extracted with CH ₂ Cl ₂ ( ₂ x 10 mL) and evaporation of the aqueous layer to give a solid which was purified by preparative HPLC (gradient of aqueous methanol with 0.1% TFA); it is converted to the HCl salt by lyophilization from 1M HCl (5 mL) to give Example 275 as a white solid (10 mg, 24%).

MS (M + H) &lt; ⁺ &gt; 489.

Example 276

NH

N-Cyclohexyl-2,3,4,5-tetrahydro-1- (1H-imidazol-4-ylmethyl) -4- (1-naphthalenylcarbonyl) -1H-1,4-benzodiazepine-8-carboxamide (dihydrochloride)

A. 2,3,4,5-Tetrahydro-8- (hydroxymethyl) -1H-1,4-bis (1-naphthalenylcarbonyl) -benzodiazepine

A solution of Example 274 Compound B (24 g, 29 mmol) in pyridine (150 mL) was added naphthalenecarboxylic acid anhydride (18 g, 110 mmol), and the resulting solution was stirred for 10 h and poured into ice water. The precipitate formed is filtered off, the solid is washed with water and chromatographed on flash chromatography (3% MeOH in CH ₂ Cl ₂ ); trinaaptoate is obtained as a yellow solid (8.4 g, 45%). A portion of this material (5.63 g, 87 mmol) in MeOH (60 mL) was stirred with 1M NaOMe in MeOH (40 mL) for 10 h and the solvent was evaporated. The residue was dissolved in CH ₂ Cl ₂ (150 mL), washed with H ₂ O (50 mL) and 1N HCl (50 mL), dried over Na ₂ SO ₄ and evaporated. After purifying the shortcut

Chromatography (242) (5% MeOH CH ₂ Cl ₂ ) afforded Compound A as a white solid (3.8 g, 89%). MS (M + H) &lt; ⁺ &gt; 486.

B. 2,3,4,5-Tetrahydro-1- (1-naphthalenylcarbonyl) -4- (1-naphthalenylcarbonyl) -1H-1,4-benzodiazepine-8-carboxylic acid

To a solution of compound A (2.7 g, 5.6 mmol) in acetone (50 mL) at 0 ° C was slowly added Jones reagent (5% CrO _{3 in} 10% H ₂ SO ₄ water, 15 mL). The solution is stirred for 1 hour. at room temperature. Excess CrO ₃ is destroyed by the addition of iPrOH. The aqueous solution was extracted with CH ₂ Cl ₂ (3 x 100 mL). The combined organic phases are dried over Na ₂ SO ₄ and evaporated to give a solid which is purified by flash chromatography (5% MeOH in CH ₂ Cl ₂ ); to give Compound B as a solid (2.30 g, 82.7%). MS (M + H) ⁺ 499.

C. 2,3,4,5-Tetrahydro-4- (1-naphthalenylcarbonyl) -1H-1,4-benzodiazepine-8-carboxylic acid

A mixture of Compound B (1.02 g, 2 mmol) in MeOH (40 mL) and KOH (7.75 g, 138 mmol) in H ₂ O (10 mL) was heated at reflux for 40 h. The MeOH is evaporated and the aqueous layer is almost neutralized. HCl. The resulting precipitate is filtered off and washed with H ₂ O. Drying of the solid gives compound C, which is a white solid (0.635 g, 90%). MS (M + H) &lt; ⁺ &gt; 347.

D. N-Cyclohexyl-2,3,4,5-tetrahydro-4- (1-naphthalenylcarbonyl) -1H-1,4-benzodiazepine-8-carboxamide to EDC (0.12 g, 0.62 mmol), HOBT (0 , A solution of 13 g, 0.9 mmol) and compound C (20 mg, 0.06 mmol) in DMF (5 mL) was added to cyclohexylamine (0.32 g, 3.2 mmol) and diisopropylethylamine (1 mL, 5.7 mmol) ) solution in DMF (1 mL). This solution is stirred for 24 hours. and is suppressed. The residue was dissolved in EtOAc (20 mL) and the solution was washed with saturated NaHCO ₃ , 1N HCl (5 mL), dried, Na ₂ SO ₄ and evaporated to give Compound D as a yellowish solid (40 mg).

243

E. N-Cyclohexyl-2,3,4,5-tetrahydro-1- (1H-imidazol-4-ylmethyl) -4- (1-naphthalenylcarbonyl) -1H-1,4-benzodiazepine-8-carboxamide (dihydrochloride)

Compound E is prepared from Compound D according to the procedure described in Example 1 for the preparation of Compound D: The compound is purified by preparative HPLC prior to its HCl salt.

MS (M + H) ⁺ 508.

Example 277

N- (Cyclohexylmethyl) -2,3,4,5-tetrahydro-1- (1H-imidazol-4-ylmethyl) -4- (1-naphthalenylcarbonyl) -1H-1,4-benzodiazepine-8-carboxamide (dihydrochloride)

Example 2JT (off-white solid) is prepared from Example 276 Compound C and cyclohexylamine according to the procedures described in Example 276 for preparing compounds D and E.

MS (M + H) &lt; ⁺ &gt; 522.

Example 278

244

2,3,4,5-Tetrahydro-1- (1H-imidazol-4-ylmethyl) -4- (1-naphthalenylcarbonyl) -N- (phenylmethyl) -1H-1,4-benzodiazepine-8-carboxamide (dihydrochloride)

Example 278 (off-white solid) is prepared from Example 276 Compound C and benzylamine according to the procedures for preparation of compounds D and E described in Example 276.

MS (M + H) ⁺ 517.

Example 279

Me

N

H

Me

(R) -4-Acetyl-7- [2 - [(dimethylamino) methyl] phenyl] -2,3,4,5-tetrahydro-1- (1H-imidazol-4-ylmethyl) -3- (phenylmethyl) -1H -1,4-benzodiazepine (dihydrochloride)

245

A. 2 - [(R) -2,3,4,5-Tetrahydro-3- (phenylmethyl) -1H-1,4-benzodiazepine-2,5-dione-7-yl] -benzaldehyde

Compound A (a yellow solid) is prepared from the compound A of Example 224 and 4-formylbenzene boronic acid according to the procedure for the synthesis of Compound A described in Example 12 using THF as solvent, boiling under reflux for 10 hours, and extraction. MS (M + H) ⁺ 371.

B. (R) -7- [2- (Dimethylaminomethyl) -phenyl] -2,3,4,5-tetrahydro-3- (phenylmethyl) -1H-1,4-benzodiazepine-2,5-dione

A solution of compound A and dimethylamine (1.0 M in THF, 10 mL) in 1:10 AcOH: CH ₂ Cl ₂ (20 mL) was stirred for 1 h. NaBH (OAc) ₃ (2.0 g) was added. Stir for another 14 or. The solvent was evaporated and the residue was treated with 1N NaOH (10 mL). The aqueous layer was extracted with 10% iPrOH CH ₂ Cl ₂ . The organic phase is dried and evaporated to give a yellow solid which is purified by flash chromatography (10% MeOH, 1% Et ₃ N CH ₂ Cl ₂ ). Compound B was obtained as a white solid (1.13 g, 98%). MS (M + H) &lt; ⁺ &gt; 400.

C. (R) -7- [2- (Dimethylaminomethyl) -phenyl] -2,3,4,5-tetrahydro-3- (phenylmethyl) -1H-1,4-benzodiazepine

A solution of Compound B (1.13 g) in dry THF at 0 ° C was treated with LAH (1.0 M in THF, 15 mL). The solution was refluxed for 10 h, cooled to 0 ° C, H ₂ O (5 mL) was added followed by THF (10 mL) and 20% NaOH (5 mL). The THF solution is drained off and the solid is washed with THF. The combined THF solutions were evaporated and the residue was dissolved in CH ₂ Cl ₂ (20 mL). Evaporation of the solution gave Compound C as a yellowish solid (0.7 g, 67%). MS (M + H) ⁺ 372.

D. (R) -4-Acetyl-7- [2 - [(dimethylamino) methyl] phenyl] -2,3,4,5-tetrahydro-3 (phenylmethyl) -1H-1,4-benzodiazepine

To a solution of 246 compounds of Compound C (0.155 g, 0.41 mmol) and DIEA (0.4 mL, 2.7 mmol) in CH 2 Cl 2 (10 mL) was added acetyl chloride (0.03 mL, 1.1 equiv) in CH 2 Cl 2 (0 , 3 ml). The mixture was stirred for 20 min. and is suppressed. The residue was dissolved in EtOAc and the solution was washed with saturated NaHCO ₃ , dried over Na ₂ SO ₄ , and evaporated to give the oil as a compound D (0.14 g, 84%).

E. (R) -4-Acetyl-7- [2 - [(dimethylamino) methyl] phenyl] -2,3,4,5-tetrahydro-1- (1H-imidazol-4-ylmethyl) -3- (phenylmethyl) -1H-1,4-benzodiazepine (dihydrochloride)

Compound E is prepared from compound D according to the procedure for preparing compound E described in Example 276.

MS (M + H) &lt; ⁺ &gt; 492.

(R) -4-Acetyl-7-cyano-2,3,4,5-tetrahydro-1- (1H-imidazol-4-ylmethyl) -3 (phenylmethyl) -1H-1,4-benzodiazepine (monohydrochloride)

A. (R) -7-Cyano-2,3,4,5-tetrahydro-3- (phenylmethyl) -4 - [(1,1-dimethylethoxy) carbonyl] -1H-1,4-benzodiazepine

Compound A (white solid) is prepared from Example C of Example 248 according to the procedure described in Example 4 for the preparation of Compound A by stirring in THF for 10 hours.

247

B. (R) -7-Cyano-2,3,4,5-tetrahydro-1- (1H-imidazol-4-ylmethyl) -3- (phenylmethyl) -4 - [(1,1-dimethylethoxy) carbonyl] - 1H-1,4-benzodiazepine

Compound B is prepared from Compound A according to the procedure for the preparation of Compound D described in Example 1.

C. (R) -7-Cyano-2,3,4,5-tetrahydro-1- (1H-imidazol-4-ylmethyl) -3- (phenylmethyl) -1H-1,4-benzodiazepine

Compound C is prepared from Compound B in 4M HCl in 4: 1 ethyl acetate: dioxane. MS (M + H) ⁺ 244.

D. (R) -4-Acetyl-7-cyano-2,3,4,5-tetrahydro-1- (1H-imidazol-4-ylmethyl) -3 (phenylmethyl) -1H-1,4-benzodiazepine (monohydrochloride) )

Compound D is prepared from compound C by treatment with DIEA, EDC, HOBT and acetic acid in DMF for 14 hours. Purification by preparative HPLC (gradient of aqueous methanol with 0.1% TFA) and its HCl salt by lyophilization from 1M HCl afforded Example 280 as a solid.

MS (MH) ⁺ 386.

Example 281

CN

(R) -7-Cyano-2,3,4,5-tetrahydro-1- (1H-imidazol-4-ylmethyl) -4- (1-oxobutyl) -3 (phenylmethyl) -1H-1,4-benzodiazepine (monohydrochloride

248

Example 281 (solid) is prepared from Example C compound C and butyric acid according to the procedure described in Example 280 for the preparation of compound D.

MS (MH) ⁺ 414.

Example 282

CN

(R) -7-Cyano-2,3,4,5-tetrahydro-1- (1H-imidazol-4-ylmethyl) -4- (2-methyl-1-oxopropyl) -3- (phenylmethyl) -1H-1, 4-Benzodiazepine (monohydrochloride)

Example 282 (solid) is prepared from Example C compound C and isobutyric acid according to the procedure described in Example 280 for the preparation of compound D.

MS (MH) ⁺ 414.

Example 283

.0

N = \

O

249 (R) -7-Cyano-2,3,4,5-tetrahydro-1- (1H-imidazol-4-ylmethyl) -3- (phenylmethyl) -4- (2-pyridinylacetyl) -1H-1,4-benzodiazepine (dihydrochloride)

Example 283 (off-white solid) is prepared from Example C compound C and 2-pyridylacetic acid according to the procedure described in Example 280 for the preparation of compound D.

MS (MH) ⁺ 464.

Example 284

CN

(R) -7-Cyano-2,3,4,5-tetrahydro-1- (1H-imidazol-4-ylmethyl) -3- (phenylmethyl) -4- (2-thienesulfonyl) -1H-1,4-benzodiazepine ( monohydrochloride)

A. (R) -7-Cyano-2,3,4,5-tetrahydro-3- (phenylmethyl) -4- (2-thienylsulfonyl) -1H1,4-benzodiazepine, m.p. 0.142 mol) and DIEA (38 mL, 0.23 mol) in CH ₂ Cl ₂ (500 mL) at room temperature were added 2-thiophenesulfonyl chloride (34.56 g, 0.19 mol) in CH ₂ Cl ₂ (200 mL). The solution was stirred for 48 h. and is suppressed. The residue was partitioned between CH ₂ Cl ₂ (500 mL) and saturated NaHCO ₃ (2 x 500 mL). The organic layer is dried (Na ₂ SO ₄ ) and evaporated. The remaining yellow oil was purified by flash chromatography (20% followed by 50% ethyl acetate / hexanes) to give Compound A as a yellow solid (55 g, 95%).

250

B. (R) -7-Cyano-2,3,4,5-tetrahydro-1- (1H-imidazol-4-ylmethyl) -3- (phenylmethyl) -4- (2-thienylsulfonyl) -1H-1,4 benzodiazepine (monohydrochloride)

A mixture of Compound A (55 g,> 0.134 mol) and 4-formylimidazole (51 g, 0.53 mol) in AcOH / CH ₂ Cl ₂ (140 mL / 600 mL) was stirred for 50 min. At 55 ° C _{under an} atmosphere of N ₂ . Within 15 or. NaBH (OAc) ₃ (total: 72 g, 0.34 mol) (1.5-2 hours approximately 6 g each) was added until HPLC analysis showed no compound A was added. MeOH (250 mL) was added, and evaporated solvent The residue was stirred with H ₂ O (100 mL) followed by 4% NaOH (800 mL) for 30 min. The aqueous solution was extracted with ethyl acetate (2 x 800 mL). The combined organic layers were washed with 5% NaOH (800 mL) and dried over Na ₂ SO ₄ . Evaporation of the solvent afforded an oil (85 g) which was purified by flash chromatography (silica gel, 5% MeOH in EtOAc) to give 70 g of a wet solid, which was added to a solution of this solid in EtOAc (600 mL), 1.0 M in ether, 400 mL, 0.4 mol). The resulting suspension was stirred for 20 min. and is stripped. The residue was washed with EtOAc (2 x 500 mL) and ether (2 x 100 mL) and dried under deep vacuum to give Compound B (63 g, 83%) as an off-white solid.

MS (M + H) &lt; ⁺ &gt; 490.

¹ H-NMR (CD ₃ OD, 300 MHz) δ 2.90 (m, 2H), 3.15 (m, 2H), 3.90 (m, 1H), 4.35.1 (m, 4H) , 6.40 (d, 7Hz, 1H), 7.0-7.6 (m, 11H), 8.90 (s, 1H).

285-295 Examples

Examples 285-295 are prepared from Example 248 Compound C (Examples 285, 286, 291, 292, 293, 294, 295), Example 224 Compound B (Examples 287, 288) or Example 232 Compound B (Examples 289, 290) compounds) and the corresponding sulfonyl chloride according to the procedure described in Example 284.

Example Mass spectrum

251

285 (R) -7-Cyano-2,3,4,5-tetrahydro-1- (1H-imidazol-4-ylmethyl) -4 - [(1- _N .

methylethyl) sulfonyl] -3 (phenylmethyl) -1H-1,4-n benzodiazepine (monohydrochloride) BMS-214665

CN

450 (M + H) m / z

286 (R) -7-Cyano-2,3,4,5-tetrahydro-1- (1H-imidazol-4-ylmethyl) -3- (phenylmethyl) -4- _{N -} [(trifluoromethyl) sulfonyl] -1H-A 1,4 benzodiazepine \ (monohydrochloride) ^H

BMS-214666

m / z 476 (M + H)

287 (R) -7-Bromo-2,3,4,5-tetrahydro-1- (1H-imidazol-4-ylmethyl) -3- (phenylmethyl) -4- (propylsulfonyl) -1H-1,4-benzodiazepine (monohydrochloride)

BMS-215354

Br

m / z

501 (M + H)

288 (R) -7-Bromo-2,3,4,5-tetrahydro-1- (1H-imidazol-4-ylmethyl) -3- (phenylmethyl) -4- (phenylsulfonyl) -1H-1,4-benzodiazepine (monohydrochloride)

BMS-215355

m / z 539 (M + H) (R) -2,3,4,5-Tetrahydro-1- (1H-imidazol-4-ylmethyl) -7-phenyl-3- (phenylmethyl) -4- (phenylsulfonyl) -1 H-1,4-benzodiazepine n (monohydrochloride) BMS-215356 m / z 535 (M + H)

289

252

Ph

290 (R) -2,3,4,5-Tetrahydro-1- (1H-imidazol-4-ylmethyl) -7-phenyl-3- (phenylmethyl) -4 (propylsulfonyl) -1H-1,4-benzodiazepine (monohydrochloride)

BMS-215357

N ' _N

H

291 (R) -7-Cyano-4 - [(4-fluorophenyl) sulfonyl] -2,3,4,5-tetrahydro-1- (1H-imidazolen-4-ylmethyl) -3- (phenylmethyl) -1H1,4- benzodiazepine (monohydrochloride) BMS-218319

CN

m / z

501 (M + H) m / z 502 (M + H)

292 (R) -7-Cyano-4 - [(3-cyanophenyl) sulfonyl] 2,3,4,5-tetrahydro-1- (1H-imidazol-4-ylmethyl) -3 (phenylmethyl) -1H-1,4-benzodiazepine (monohydrochloride) )

BMS-218320

m / z 509 (M + H)

293 (R) -7-Cyano-2,3,4,5-tetrahydro-1- (1H-imidazol-4-ylmethyl) -4 - [(1-methyl-1H-imidazol-4-yl) sulfonyl] -3 (phenylmethyl) - l H-1,4-benzodiazepine (dihydrochloride) BMS-218322

CN m / z 488 (M + H)

294 (R) -4 - [(3-Bromophenyl) sulfonyl] -7 cyano-2,3,4,5-tetrahydro-1- (1H-imidazol-4-ylmethyl) -3- (phenylmethyl) -1H-1,4-benzodiazepine (monohydrochloride) )

BMS-218735

m / z 563 (M + H)

253

295 (R) -N- [5 - [[7-Cyano-2,3,4,5-tetrahydro-1- (1H-imidazol-4-ylmethyl) -3 (phenylmethyl) -1H-1,4-benzodiazepin-4-yl] sulfonyl ] -4-Methyl-2-thiazolyl] -acetamide (dihydrochloride)

BMS-218736

m / z 562 (M + H)

4-Acetyl-2,3,4,5-tetrahydro-1- (1H-imidazol-4-ylmethyl) -3- (phenylmethyl) -7- (4-pyridinyl) -1H-1,4-benzodiazepine (trihydrochloride) )

A. 4-Acetyl-2,3,4,5-tetrahydro-1-trifluoroacetyl-3- (phenylmethyl) -7-bromo-1H-1,4-benzodiazepine

To a solution of Example 75 compound B (0.32 mmol, 100 mg) and NEt ₃ (220 μΙ, 1.58 mmol) in 5 mL of CH ₂ Cl _{2 at} 0 ° G was added acetyl chloride (35 μΙ, 0.47 mmol). After 5 minutes trifluoroacetic anhydride (0.63 mmol, 90 μΙ) was added, the reaction mixture was stirred for a further 10 min, concentrated, and purified by flash chromatography (50%).

EtOAc / hexanes) to give Compound A as a white solid (140 mg, 98% for two steps). MS (M + H) 455.

254

B. 4-Acetyl-2,3,4,5-tetrahydro-1-trifluoroacetyl-3- (thienylmethyl) -7- (4-pyridinyl) -1H-1,4-benzodiazepine

A mixture of compound A (0.27 mmol, 124 mg), 4-tributyltanylpyridine (0.54 mmol, 200 mg) and 15 mol% Pd (PPh ₃ ) ₄ (47 mg) was degassed in 3 mL of toluene and refluxed under argon. . After 16 or. concentrate the reaction mixture and purify by flash chromatography (10% EtOAc / hexanes); yielding Compound B as a yellow oil (60 mg, 49%). MS (M + H) 454.

C. A solution of 4-Acetyl-2,3,4,5-tetrahydro-3- (phenylmethyl) -7- (4-pyridinyl) -1H-1,4-benzodiazepine in Compound B (60 mg, 0.13 mmol) in 3 mL MeOH was added NaOH (5 drops of 2N aqueous NaOH), the mixture was kept at room temperature for 30 min, concentrated and partitioned between 2N NaOH (5 mL) and 10% isopropanol-CH ₂ Cl ₂ (5 mL). The aqueous layer was extracted 3 times with 10% isopropanol-CH ₂ Cl ₂ , the combined organic layers were dried over Na ₂ SO ₄ and concentrated to give compound C.

D. 4-Acetyl-2,3,4,5-tetrahydro-1- (1H-imidazol-4-ylmethyl) -3- (phenylmethyl) -7 (4-pyridinyl) -1H-1,4-benzodiazepine ( trihydrochloride)

To a mixture of compound J and 2 mL of 1: 1 AcOH: CICH ₂ CH ₂ Cl was added 4formylimidazole (0.39 mmol, 38 mL) and NaBH (OAc) ₃ (0.39 mmol, 83 mg). The mixture was heated at 50 ° C for 4 h, concentrated and partitioned between 2N NaOH and 10% isopropanol-CH ₂ Cl ₂ (5 mL). The aqueous layer was extracted 3 times with 10% isopropanol-CH ₂ Cl ₂ , the combined organic layers were dried over Na ₂ SO ₄ , concentrated and purified by preparative HPLC (gradient of aqueous methanol to 0.1% TFA). The TFA salt was converted to the HCl salt using 1N HCl to give Example 296 as a yellowish solid (32 mg, 49% based on Compound B).

MS (M + H) 438.

255

2,3,4,5-Tetrahydro-1- (1H-imidazol-4-ylmethyl) -4- (2-phenyl-1,2-dioxoethyl) -7- (4-pyridinyl) -1H-1 , 4-benzodiazepine (trihydrochloride)

Example 297 (yellow solid) is prepared from 7bromo-1,4-benzodiazepine (see Example 11) and benzoyl-formic acid according to the reaction sequence used to obtain the following compounds: Example 252, 10: 1 mixture of methylene chloride and DMF, and chromatography. using 50% EtOAc / hexanes; treated with trifluoroacetic anhydride and treated as described in Preparation Example 296 for Compound A: Example 296 for Compounds B, C, and D.

MS (M + H) 438.

Example 298

2,3,4,5-Tetrahydro-1- (1H-imidazol-4-ylmethyl) -7- (4-pyridinyl) -4- [2- (trifluoromethoxy) benzoyl] -1H-1,4-benzodiazepine (trihydrochloride) )

256

Example 298 (yellow solid) is prepared from 2- (trifluoromethoxy) benzoic acid according to the procedure described in Example 297.

MS (M + H) 494.

Example 299

(R) -2,3,4,5-Tetrahydro-1 - [(1-methyl-1H-imidazol-5-yl) methyl] -4- (methylsulfonyl) 7-phenyl-3- (phenylmethyl) -1H -1,4-benzodiazepine

A. (R) -2,3,4,5-Tetrahydro-4- (methylsulfonyl) -7-phenyl-3- (phenylmethyl) -1H-1,4-benzodiazepine

A solution of compound D (0.50 g, 1.3 mmol) and DIEA (0.78 mL, 4.5 mmol) in Example J 226 in methylene chloride (20 mL) was added dropwise at -78 ° C to methanesulfonyl chloride (0.12 mL, 1 mL). , 6 mmol). The mixture was allowed to warm to room temperature and stirred for 16 h, quenched with 10% NaHCO ₃ (100 mL) and extracted with ethyl acetate (3 x 150 mL). The combined organic layers were dried (Na ₂ SO ₄ ), filtered and concentrated in vacuo. The residue was purified by flash chromatography (5/2 hexane / ethyl acetate) to give Compound A (0.52 g, 100%) as a yellow solid.

257

B. 1- [1,1-Dimethylethoxycarbonyl] -4-imidazolecarboxaldehyde

To a suspension of 4-formylimidazole (20.0 g, 208 mmol) and DIEA (36.2 mL, 208 mmol) in 400 mL of methylene chloride was added ditretbutyl dicarbonate (55.4 g, 254 mmol) at room temperature. The mixture was heated at 40 ° C (clear solution upon heating) and stirred for 16 h, cooled to room temperature, quenched with sat. NaHCO ₃ (200 mL) and extracted with CH ₂ Cl ₂ (3 x 400 mL). The combined organic extracts were dried (Na ₂ SO ₄ ), filtered and concentrated in vacuo. The residue was purified by flash chromatography (5-50% ethyl acetate / hexane) to give Compound B (35.2 g, 87%) as a white solid. MS: (M + NH ₄ + CH ₃ CN) ⁺ 256.

C. 1-Methyl-5-imidazolecarboxyldehyde To a solution of Compound B (35.1 g, 179 mmol) in CH ₂ Cl ₂ (740 mL) at -78 ° C was slowly added methyl triflate (22.3 mL, 197 mmol). The mixture was allowed to warm slowly to room temperature and stirred for 16 h. The resulting white precipitate was partitioned between saturated potassium carbonate solution (112 g / 100 ml H ₂ O) at room temperature. This biphasic solution was stirred at room temperature for 30 min. The phases were separated, and the aqueous layer was extracted with 9/1 CH2Cl2 (4 x 300 mL). The combined organic extracts were dried (Na ₂ SO ₄ ), filtered and concentrated in vacuo. Purification of the residue by flash chromatography (19/1 CHCl ₃ / MeOH) gave Compound C (17.4 g, 88%) as a white solid. MS (M + H) &lt; ⁺ &gt;

D. (R) -2,3,4,5-Tetrahydro-1 - [(1-methyl-1H-imidazol-5-yl) methyl] -4 (methylethyl) -7-f Enil-3- (Phenylmethyl) -1H-1,4-benzodiazepine in a solution of compound A (0.23 g, 0.59 mmol) with 3A molecular mesh

1/1 DCE: Compound C (0.065 g, 0.59 mmol) was added in acetic acid (4 mL) and the mixture was stirred at 70 ° C for 1 h. Sodium triacetoxyborohydride (0.13 g, 0.59 mmol) was added and the mixture was stirred at 70 ° C for 30 min. The latter procedure is repeated two more times.

258

The mixture was cooled to room temperature, diluted with methylene chloride (10 mL), filtered and the filtrate concentrated in vacuo. The residue was diluted with 25% NH ₄ OH (100 mL) and stirred at room temperature for 10 min. The solution was extracted with CH ₂ Cl ₂ (3 x 100 mL), the combined organic extracts dried (Na ₂ SO ₄ ), filtered and concentrated in vacuo. The residue was purified by preparative HPLC (10-90% aqueous MeOH with 0.1% TFA), the appropriate fractions were mixed and concentrated in vacuo. The residue was dissolved and evaporated four times from CH ₃ OH (5 mL) and 1N HCl (3 mL). This residue was dissolved in CH ₃ CN (3 mL) and water (3 mL) and lyophilized to give Example 299 (0.26 g, 80%) as a white solid. Lyd. mp: 106-114 ° C.

MS (M + H) ⁺ 487.

[α] ^D = + 91 ° (c = 0.35, CH ₃ OH).

Elemental analysis calculated for C ₂₈ H ₃₀ N ₄ O ₂ S · HCl · 0.9 H ₂ O Calculated: C, 57.88; H, 5.17; N, 9.06; Cl, 4.59; S, 5.18.

Found: C, 57.88; H, 5.49; N, 9.14; Cl, 4.64; S, 5.31.

(R) -7-Cyano-2,3,4,5-tetrahydro-1- (1H-imidazol-4-ylmethyl) -4- (phenylacetyl) -3 (phenylmethyl) -1H-1,4-benzodiazepine (monohydrochloride) refluxing (R) -7-cyano-2,3,4,5-tetrahydro-4- (phenylacetyl) -3- (phenylmethyl) -1H-1,4-benzodiazepine (prepared from Compound 248 of Example 248). , using EDC / HOAt copolymer with phenylacetic acid, 0.100

A solution of 259 g, 0.26 mmol) and 4-formylimidazole (0.025 g, 0.26 mmol) in AcOH (0.3 mL) and dichloroethane (0.5 mL) with 3A molecular mesh was added barium triacetoxyborohydride (0.055 g, 0, 26 mmol). The mixture was stirred for 16 hours, followed by daily addition of aldehyde and sodium triacetoxyborohydride (3 x 1 eq.) For 3 days. The mixture was diluted with CHCl 3 (10 mL), NH ₄ OH (5 mL) and NaHCO ₃ (5 mL) and stirred for 30 min. The layers were separated and the aqueous layer was extracted with CHCl ₃ (2 x 20 mL). The combined organic extracts were washed with NaHCO ₃ , water and saturated NaCl, dried over MgSO ₄ , filtered and concentrated. The product was purified by preparative HPLC (20-90% aqueous methanol with 0.1% TFA gradient) to give the HCl salt of Example 300 as a yellowish solid (4 mg, 3%).

MS (M + H) &lt; ⁺ &gt; = 462 ⁺ .

Example 301

4- (2-Benzothiazolyl) -2,3,4,5-tetrahydro-1- (1H-imidazole-4-methyl) -7-phenyl-1 H -1,4-benzodiazepine (trihydrochloride)

A. 4- (2-Benzothiazolyl) -2,3,4,5-tetrahydro-7-phenyl-1H-1,4-benzodiazepine, Example B 12 (0.34 mmol, 100 mg) and triethylamine (1.36) of a solution of mmol, 190 μΙ) in DMF (1.0 mL) was added chlorobenzothiazole (0.41 mmol, μΙ) and the reaction mixture was stored at 60 ° C. After 1 or. again 2-chlorobenzothiazole (60 μΙ) was added. After 2 or. the reaction is stopped at 2N

260

NaOH (10 mL), extracted with CH ₂ Cl ₂ (2 x 10 mL), dried over Na ₂ SO ₄ , and concentrated to give Compound A.

B. 4- (2-Benzothiazolyl) -2,3,4,5-tetrahydro-1- (1H-imidazol-4-ylmethyl) -7-phenyl-1H-1,4-benzodiazepine (trihydrochloride)

To a solution of Compound A in 1: 1 AcOH / (CH ₂ Cl ₂ ) ₂ (2 mL) was added 4-formylimidazole (0.68 mmol, 65 mg). The mixture was stirred for 1 h, quenched with 5 mL of saturated NaHCO ₃ , diluted with 2N NaOH (50 mL) and extracted with 10% IPA / CH ₂ Cl ₂ (2 x 25 mL). The combined organic extracts were dried over Na ₂ SO ₄ , evaporated, and the residue purified by flash chromatography (94 mg, 50% over two steps). After lyophilization from 1N HCl, Example 301 is obtained which is a gray solid.

MS (M + H) ⁺ 438.

2,3,4,5-Tetrahydro-1- (1H-imidazol-4-ylmethyl) -3- (phenylmethyl) -7- (3-pyridinyl) -4 (trifluoromethyl) -1H- 1,4-benzodiazepine (trihydrochloride)

A. 2,3,4,5-Tetrahydro-3- (phenylmethyl) -7-bromo-1,4-bis (trifluoroacetyl) -1H1,4-benzodiazepine

A solution of Example 75 compound B (1.61 mmol, 510 mg) and triethylamine (9.66 mmol, 1.35 mL) in CH ₂ Cl ₂ (10 mL) was added at room temperature.

261 (CF ₃ CO) ₂ O (7.25 mmol, 1.0 mL). After 30 minutes the reaction mixture was concentrated and purified by flash chromatography to give Compound A as a white solid (770 mg, 94%).

MS (MH) ⁺ 507.

B. 2,3,4,5-Tetrahydro-1- (1H-imidazol-4-ylmethyl) -3- (phenylmethyl) -7- (3-pyridinyl) -4- (trifluoroacetyl) -1H- 1,4-benzodiazepine (trihydrochloride)

Example 302 (yellow solid) is prepared from Compound A according to the reaction sequence used to prepare the following compounds: Example 296 Compound B using 3-tributylstanylpyridine; Example 296 for compound C; 296 for compound D.

MS (M + H) &lt; ⁺ &gt; 492.

2,3,4,5-Tetrahydro-1- (1H-imidazol-4-ylmethyl) -4- (methylsulfonyl) -3- (phenylmethyl) -7- (3-pyridine) -1 H-1,4-benzodiazepine (trihydrochloride)

A. 2,3,4,5-Tetrahydro-3- (phenylmethyl) -7- (3-pyridinyl) -1H-1,4-benzodiazepine

J 2,3,4,5-Tetrahydro-3- (phenylmethyl) -7- (3-pyridinyl) -1,4-bis (trifluoroacetyl) -1H1,4-benzodiazepine (prepared according to compound B described in Example 302). Synthesis procedure: 100 mg, 0.2 mmol) of MeOH (4 mL) was added as a solid

262

KOH (150 mg). The solution was stirred at 50 ° C for 3 h, concentrated, diluted with 2N NaOH (15 mL) and extracted with 10% IPA / CH ₂ Cl ₂ (3 x 5 mL) to give 60 mg of Compound A.

B. 2,3,4,5-Tetrahydro-1- (1H-imidazol-4-ylmethyl) -4- (methylsulfonyl) -3- (phenylmethyl) -7- (3-pyridinyl) -1H-1,4-benzodiazepine (trihydrochloride) To a mixture of Compound A (0.086 mmol, 27 mg) and DIEA (0.86 mmol, 150 μΙ) in CH 2 Cl 2 (1.0 mL) was added methanesulfonyl chloride (0.39 mmol, 30 μΙ). The mixture was stirred for 1 h, concentrated, diluted with 2N NaOH (10 mL) and extracted with 10% IPA / CH ₂ Cl ₂ (2x5 mL). The solution was dried over Na ₂ SO ₄ and concentrated. The residue was dissolved in 1: 1 AcOH: (CH ₂ Cl) ₂ (2 mL). 4-Formylimidazole (0.69 mmol, 66.3 mg) and NaBH (OAc) ₃ (0.69 mmol, 146 mg) were added and the mixture was heated at 50 ° C for 16 h, concentrated and diluted with 2N NaOH (20 mL). / saturated NH ₄ OH (5 mL) and extracted with 10% IPA / CH ₂ Cl ₂ (2x5 mL). The combined organic extracts are concentrated and the residue is purified by preparative HPLC (gradient of aqueous methanol with 0.1% TFA). The required fractions are mixed, evaporated and the TFA salt is converted to the HCl salt using 1N HCl. Example 303 is obtained (5 mg, yield 3 steps: 9%).

MS (M + H) &lt; ⁺ &gt; 474.

Example 304

Br

NH

Me

7-Bromo-3 - [(1,1-dimethylethoxy) methyl] -1,2,3,4-tetrahydro-1- (1H-imidazol-4-ylmethyl) -5H-1,4-benzodiazepin-5-one

263

A. 2 - [(2- (Fluorenylmethoxycarbonylamino) -3- (1,1-dimethylethoxy) propyl) amino] -5-bromobenzoic acid

D, L-Fmoc- (O-tBu) -serinal (prepared by reduction of D, L-FmocSer (tBu) -N (Me) OMe in LAH; 18 g, 49 mmol), bromoanthranilic acid (19 g, 88 mmol) and glacial a solution of acetic acid (2 mL) in dry methanol (5 mL) and THF (40 mL) was stirred for 10 min and then over 1 h. NaBH ₃ CN (5.5 g, 88 mmol) was added. Stir for another 1 or. The precipitate is filtered off, washed with water and dried under deep vacuum to give 25 g (89.4%) of Compound A as a white solid. (M + H) ⁺ 569.

B. 7-Bromo-3 - [(1,1-dimethylethoxy) methyl] -1,2,3,4-tetrahydro-5H-1,4-benzodiazepin-5-one

To a solution of compound A (17 g, 29 mmol) in THF (150 mL) was added diethylamine (30 mL, 290 mmol). The solution is stirred for 2 hours. and concentrated. The resulting residue was dissolved in ethyl ether (100 mL) and 1N aqueous hydrochloric acid (400 mL). The resulting heavy white precipitate was filtered off, washed with hexanes / ethyl ether and dried in a deep vacuum. Part of the resulting white solid (8.2 g, 24 mmol) with EDC (4.5 g, 24 mmol), HOBt (3.2 g, 24 mmol) and DIEA (12.4 mL, 71 mmol) in DMF (80 ml) was stirred for 16 hours and the mixture was poured into a mixture of 10% aqueous LiCl solution (200 ml) and ethyl acetate (90 ml). The layers are separated. The organic layer was washed with 4 x 40 mL 10% aqueous LiCl, 4 χ 1N aqueous hydrochloric acid, 2 x 50 mL saturated NaCl, and 1 x 50 mL water. The solution is dried (Na ₂ SO ₄ ), filtered, and concentrated to give 7.2 g (83% over both steps) of Compound B as a white solid. (M + H) ⁺ 329.

C. 7-Bromo-3 - [(1,1-dimethylethoxy) methyl] -1,2,3,4-tetrahydro-1- (1H-imidazol-4-ylmethyl) -5H-1,4-benzodiazepin-5-one

264

Example 304 Compound (white solid) is prepared in 40% yield from Compound B according to the procedure for Compound D described in Example 224. (M + H) ⁺ 409.

Example 305

7-Bromo-2,3,4,5-tetrahydro-1- (1H-imidazol-4-ylmethyl) -4- (methylsulfonyl) -3 (phenoxymethyl) -1H-1,4-benzodiazepine (dihydrochloride)

A. 7-Bromo-3 - [(1,1-dimethylethoxy) methyl] -1,2,3,4-tetrahydro-5H-1,4-benzodiazepine

Example 304 Compound B (0.5 g, 1.5 mmol) was mixed with 10 mL of THF and 1M LAH in THF (4 mL, 4 mmol). The solution is refluxed for 16 hours. Diethyl ether (40 mL) and 1N NaOH (40 mL) were added followed by saturated NaCl and the layers separated. The organic layer was washed with 1N aqueous NaOH, dried (Na ₂ SO ₄ ), filtered and concentrated to afford 413 mg (88%) of Compound A as a glass solid. MS (M + H) ⁺ 314.

B. 7-Bromo-3 - [(1,1-dimethylethoxy) methyl] -4-methanesulfonyl-1,2,3,4-tetrahydro-5 H -1,4-benzodiazepine

Compound B (white solid) is prepared in 71% yield from Compound A according to the procedure for Compound C described in Example 224. MS (M + H-tBu) ⁺ 337.

265

C. 7-Bromo-3- (hydroxymethyl) -4-methanesulfonyl-1,2,3,4-tetrahydro-5H-1,4-benzodiazepine

A solution of Compound B (1.1 g, 2.8 mmol) in THF (8 mL) and methylene chloride (8 mL) was stirred for 3 h. and concentrated. Trituration of the residue with ethyl ether and drying in vacuo afforded 700 mg (74%) of Compound C as a white solid. MS (M + H) ⁺ 337.

D. 7-Bromo-2,3,4,5-tetrahydro-4- (methylsulfonyl) -3- (phenoxymethyl) -1H-1,4-benzodiazepine

To a solution of compound C (50 mg, 0.15 mmol) in methylene chloride (10 mL) was added 2,6-di-tert-butyl-4-methylpyridine (62 mg, 0.30 mmol). The solution is cooled to -40 ° C under N ₂ . Triflic acid anhydride (0.85 mL, 0.30 mmol) was added and the solution was stirred under N _{2 at} -40 ° C for 1 h. In a separate flask, phenol (100 mg, 1.1 mmol) was added to a solution of sodium hydride (44 mg, 1.1 mmol, 60% dispersion in mineral oil, before washing with hexanes) in THF (2.5 mL). This solution is stirred for 20 min at room temperature under N ₂ and rapidly added to the triflate solution. After stirring for 20 min, the solution was diluted with methylene chloride (40 mL) and washed with a saturated aqueous sodium bicarbonate solution. The organic layer was dried (Na ₂ SO ₄ ), filtered and concentrated to give a solid. This material was purified by flash column chromatography on silica gel eluting with 1: 1 ethyl acetate: hexanes to give 30 mg (49%) of Compound D as an off-white solid. MS (M + H) ⁺ 411.

E. 7-Bromo-2,3,4,5-tetrahydro-1- (1H-imidazol-4-ylmethyl) -4- (methylsulfonyl) -3- (phenoxymethyl) -1H-1,4-benzodiazepine (dihydrochloride)

Example 305 Compound (white solid) is prepared in 27% yield from Compound D according to the procedure for Compound D described in Example 224.

MS (M + H) &lt; ⁺ &gt; 491.

266

Example 306

7-Bromo-2,3,4,5-tetrahydro-3- (hydroxymethyl) -1- (1H-imidazol-4-ylmethyl) -4- (methylsulfonyl) -1H-1,4-benzodiazepine (monohydrochloride)

Example 306 (off-white solid) is prepared in 12% yield from Example 305 Compound C according to the procedure described in Example 224 for the preparation of Compound D.

MS (M + H) &lt; ⁺ &gt; 417.

Example 307

7-Bromo-3 - [(1,1-dimethylethoxy) methyl] -2,3,4,5-tetrahydro-1- (1H-imidazol-4-ylmethyl) -4- (methylsulfonyl) -1H-1,4- benzodiazepine

Example 307 Compound (off-white solid) is prepared in 23% yield from Example 305 Compound B according to the procedure for Compound D described in Example 224.

MS (M + H) ⁺ 472.

267

Example 308

[7-Bromo-2,3,4,5-tetrahydro-1- (1H-imidazol-4-ylmethyl) -3- (phenylmethyl) -1H-1,4-benzodiazepin-8-yl] carbamic acid 2-methylpropyl ester ( trihydrochloride)

A. 2,3,4,5-Tetrahydro-3- (phenylmethyl) -4 - [(1,1-dimethylethoxy) carbonyl] -8-amino-1H-1,4-benzodiazepine

2,3,4,5-Tetrahydro-3- (phenylmethyl) -8-amino-1H-1,4-benzodiazepine (described in Example 98, compound B, 1.0 g, 3.5 mmol) and Boc anhydride (O, A solution of 77 g, 3.5 mmol) in THF (15 mL) was stirred at room temperature under argon. After 16 or. the mixture is concentrated. The residue was triturated with hexane and CHCl _3l to give yellow greenish gray solid. The filtrate was concentrated and the residue was erased with hexane and CHCl _3, also obtained a yellow-green-gray solid. The following solids were combined and purified by silica gel flash chromatography (20% followed by 30% EtOAc in hexane) to give Compound A (0.542 g, 40%). MS (M + H) &lt; ⁺ &gt; 345.

B. [2,3,4,5-Tetrahydro-3- (phenylmethyl) -4 - [(1,1-dimethylethoxy) carbonyl] -1H1,4-benzodiazepin-8-yl] carbamic acid 2-methylpropyl ester

A solution of 268 compound A (115 mg, 0.3 mol) in dichloromethane (2 mL) under argon was added dropwise to DIPEA (0.1 mL, 0.6 mmol) and isobutyl chloroformate, After 20 min. water (2 mL) and saturated NaHCO3 are added and the mixture is extracted with chloroform (15 mL). The organic layer was dried (MgSO ₄ ) and concentrated in vacuo to give a solid which was purified by flash chromatography on silica gel eluting with 20% EtOAc in hexanes to give Compound B (125 mg, 92%) as a solid. MS (M + H) &lt; ⁺ &gt; = 454 ⁺ .

C. [7-Bromo-2,3,4,5-tetrahydro-3- (phenylmethyl) -4 - [(1,1-dimethylethoxy) carbonyl] -1H-1,4-benzodiazepin-8-yl] carbamic acid 2-Methylpropyl ester

To a solution of Compound B (100 mg, 0.22 mmol) in chloroform (2 mL) was added over 5 min. a solution of tetrabutylammonium tribromide (106 mg, 0.22 mmol) in chloroform (1 mL) was added dropwise. After 10 minutes. the mixture was washed with sodium bisulfate solution (5 mL), dried (MgSO ₄ ), and concentrated. Purification by silica gel column chromatography eluting with 20% EtOAc in hexanes afforded compound C (110 mg, 94%) as a solid. MS (M + H) <^+> = 532 ⁺ .

D. [7-Bromo-2,3,4,5-tetrahydro-1- (1H-imidazol-4-ylmethyl) -3- (phenylmethyl) 4 - [(1,1-dimethylethoxy) carbonyl] -1H- 1,4-Benzodiazepin-8-yl] -carbamic acid 2-methylpropyl ester into a solution of compound C (100 mg, 0.19 mmol) and 4-formylimidazole (36 mg, 0.3 mmol) in dichloromethane (2 'mL) and acetic acid acid (0.6 mL) was added to the mixture with 3A molecular grids and the mixture was stirred for 15 min. Sodium triacetoxyborohydride (105 mg, 0.5 mmol) was added and the mixture was stirred overnight (18 h). Another portion of the aldehyde and borohydride reagent (36 mg and 105 mg, respectively) is added. After 4 or. the mixture is filtered through celite and washed with chloroform. The filtrate was concentrated and treated with chloroform and NH ₄ OH (10 mL each). After stirring vigorously for 30 minutes, the organic layer is covered

269 was separated, dried (MgSO ₄ ), and concentrated in vacuo to give Compound D (110 mg, 86%). MS (M + H) &lt; ⁺ &gt; = 612 ⁺ .

E. [7-Bromo-2,3,4,5-tetrahydro-1- (1H-imidazol-4-ylmethyl) -3- (phenylmethyl) -1H-1,4-benzodiazepin-8-yl] carbamic acid 2-. methylpropyl ester (trihydrochloride)

To a solution of compound D (105 mg, 0.17 mmol) in chloroform (1 mL) was added HCl in dioxane (3 mL, 4M solution). After 4 or. the mixture is concentrated. Chloroform (5 mL) was added and concentration of the mixture in vacuo gave Example 308 as an off-white powder (110 mg, 100%).

MS (M + H) <^+> = 512.

[4-Acetyl-7-bromo-2,3,4,5-tetrahydro-1- (1H-imidazol-4-ylmethyl) -3- (phenylmethyl) -1H-1,4-benzodiazepin-8-yl] carbamic acid 2-Methylpropyl ester To a solution of Example 308 (18 mg, 0.03 mmol) in DMF (0.2 mL) was added pyridine (0.3 mL), acetic anhydride (0.2 mL), and DMAP (10 mg), and the mixture is stirred for 20 hours. Acetic anhydride (0.1 ml) was added and the mixture was stirred for 4 hours. This mixture is partitioned between chloroform and water (10 mL each). The organic layer is separated and washed with CuSO ₄ (2 x 10 mL),

270 dried (K2CO3) and concentrated. Purification by RP HPLC chromatography on a C-18 column eluting with 40-90% aqueous methanol containing 0.1% TFA afforded a solid which was treated with 1N aqueous HCl (2 x 10 mL) and then concentrated. The solid was dissolved in water to give, after lyophilization, Example 309 as a yellowish solid (13 mg, 70%).

MS (M + H) &lt; ⁺ &gt; = 554.

N- [4-Acetyl-2,3,4,5-tetrahydro-1- (1H-imidazol-4-ylmethyl) -3- (phenylmethyl) -1H1,4-benzodiazepin-8-yl] cyclohexanecarboxamide (dihydrochloride)

Example 310 Compound (yellowish solid) is prepared in 50% yield from Example 246 Compound C according to the procedure described in Example 309.

MS (M + H) &lt; ⁺ &gt; = 486.

Example 311

271

[7-Bromo-2,3,4,5-tetrahydro-1- (1H-imidazol-4-ylmethyl) -4- (methylsulfonyl) -3 (phenylmethyl) -1H-1,4-benzodiazepin-8-yl] 2-Methylpropyl ester of carbamic acid To a solution of the compound of Example 308 (31 mg, 0.05 mmol) in DMF (0.2 mL) at room temperature was added TEA (0.2 mL), dichloromethane (0.2 mL) and methanesulfonyl chloride (0.024 mL) (0.3 mmol), the mixture was stirred for 18 h. and partitioned between chloroform and saturated NaHCO ₃ (10 mL each). The organic layer was separated, dried (K ₂ CO ₃ ) and concentrated. Purification by RP HPLC chromatography on a C-18 column eluting with 40-90% aqueous methanol containing 0.1% TFA afforded a solid which was treated with 1N aqueous HCl (2 x 10 mL) and then concentrated. The solid was dissolved in water to give, after lyophilization, the compound of Example 311 as a yellowish solid (13 mg, 70%).

MS (M + H) <^+> = 590.

Example 312

272

CN

(R) -2,3,4,5-Tetrahydro-1- (1H-imidazol-4-ylmethyl) -4- (phenylsulfonyl) -3 (phenylmethyl) -1H-1,4-benzodiazepine-7-carbonitrile (monohydrochloride) )

A. (R) -2,3,4,5-Tetrahydro-4- (phenylsulfonyl) -3- (phenylmethyl) -1H-1,4-benzodiazepine-7-carbonitrile

A stirred solution of Example 248 Compound C (45 g, 171.54 mmol) in DIEA (50 mL, 287 mmol) in anhydrous CH ₂ Cl ₂ (1 L) under argon was added dropwise to a solution of benzenesulfonyl chloride (30 mL). ml, 235 ml) solution in anhydrous CH ₂ Cl ₂ (50 ml). After the addition is complete, the mixture is warmed to room temperature and stirred for 4 h. The solution was diluted with CH ₂ Cl ₂ (500 mL), washed with water (2 x 250 mL), 10% KHSO ₄ (750 mL), saturated NaHCO ₃ and saturated NaCl, dried and evaporated. The residue was recrystallized from EtOAc-hexane to give 65 g (94%) of Compound A as a solid. MS (MH) &lt; 402 &gt;.

¹³ C-NMR (CDCl ₃ ) 40.22, 46.00, 47.23, 61.36, 116.34, 119.55, 120.99, 126.99, 127.11, 128.10, 129, 76, 129.40, .131.97, 132.09, 134.03, 136.77, 139.53, 150.77 md

B. (R) -2,3,4,5-Tetrahydro-1- (1H-imidazol-4-ylmethyl) -4- (phenylsulfonyl) -3 (phenylmethyl) -1H-1,4-benzodiazepine-7-carbonitrile (monohydrochloride)

To a stirred mixture of compound A (64.3 g, 159 mmol) and 4-formylimidazole (15.3 g,

159 mmol) HOAC (glacial, 150 mL) and 1,2-dichloroethane (720 mL) were added sodium triacetoxyborohydride (33.8 g, 159 mmol) under argon. The mixture is heated at 60 ° C for 6 hours. Again, 4273 formylimidazole (15.3 g) and sodium triacetoxyborohydride (33.8 g) were added. This was added three times until HPLC indicated that 7% of unreacted compound A remained. The resulting solution was cooled to room temperature. MeOH (250 mL) was added slowly, and the mixture was stirred for 30 min. and is suppressed. The residue is aceotropically distilled with toluene (2 x 500 ml). The resinous residue was diluted with saturated NaHCO ₃ solution and stirred. Solid NaHCO ₃ is added until foaming ceases. The suspension is extracted with EtOAc (3 x 1 L), the combined EtOAc extracts are washed with saturated NaHCO ₃ solution and saturated NaCl solution, dried over anhydrous MgSO ₄ , and evaporated to give a foamy residue. This residue was flash chromatographed on a silica gel column (E. Merck 230-400 mesh, 1.6 kg) eluting with EtOAc-MeOH (95: 5) to give the free base of Example 312. This base was dissolved in EtOAc (1.0 L), treated with 1.0 N HCl in Et ₂ O (250 mL), and stirred for 30 min. and filtered off. The solid was washed with EtOAc (500 mL) and Et ₂ O (500 mL) and dried under deep vacuum at 50 ° C overnight to give 58 g (70%) of Example 312 as a solid.

MS (M + H) <^+> = 484.

Analysis calculated for C ₂₇ H ₂₅ N ₅ O ₂ S · 0.7H ₂ O · 1 HCl · 0.05 EtOAc-0.03 ether

Found: C, 60.85; H, 5.25: N, 12.99; Cl, 6.57: S, 5.94.

Found: C, 60.85; H, 5.19; N, 13.05; Cl, 6.60; S, 5.95.

Example 313

274

7-Bromo-1,2,3,5-tetrahydro-1- (1H-imidazol-4-ylmethyl) -3- (phenylmethyl) -4H-1,4-benzodiazepine-4-acetamide

A. 7-Bromo-1,2,3,5-tetrahydro-3- (phenylmethyl) -4H-1,4-benzodiazepine-4-acetamide Example B (250 mg, 0.74 mmol), DIEA (0.067 mL, 0 , 74 mmol) and 2-chloroacetamide (69 mg, 0.74 mmol) in THF (10 mL) were stirred under argon at room temperature for 8 h. The mixture was partitioned between saturated NaCl solution (50 mL) and ethyl acetate (50 mL), the aqueous layer was extracted with ethyl acetate (2 x 50 mL), the combined organic layers dried (MgSO ₄ ) and concentrated to give Compound A as a clear oil (260 mg). , 94%).

B. 7-Bromo-1,2,3,5-tetrahydro-1- (1H-imidazol-4-ylmethyl) -3- (phenylmethyl) -4H-1,4-benzodiazepine-4-acetamide

Example 313 (white solid) is obtained in 38% yield from Compound A according to the procedure described in Example 1 for the preparation of Compound D with stirring for 18 hours. and purification by preparative HPLC.

MS (M + H) <^+> = 454.

Analysis calculated for C ₂₂ H ₂₄ N ₅ OBr · 0.3 H ₂ O · 1.5 TFA

Found: C, 45.81; H, 3.95; N, 10.35; Br, 11.81; F, 16.01,

Found: C, 45.43; H, 3.80; N, 9.96; Br, 11.50; F, 15.74.

Example 314 • Br

Me

275

7-Bromo-4 - [(dimethylamino) acetyl] -2,3,4,5-tetrahydro-1- (1H-imidazol-4-ylmethyl) -3- (phenylmethyl) -1H-1, 4-Benzodiazepine

A. 7-Bromo-4- (bromoacetyl) -2,3,4,5-tetrahydro-3- (phenylmethyl) -1H-1,4-benzodiazepine

Compound A (clear oil) is prepared from Example B Compound B and bromoacetyl bromide according to the procedure described in Example 313 for the preparation of Compound A by flash chromatography (silica gel, 3: 1 hexanes: ethyl acetate).

B. 7-Bromo-4 - [(dimethylamino) acetyl] -2,3,4,5-tetrahydro-3- (phenylmethyl) -1H-1,4-benzodiazepine, Compound A (126 mg, 0.29 mmol) to a solution of THF (2 mL) was added dimethylamine (2 mL, 1M THF). The solution is stirred at room temperature in a sealed pressure-maintaining tube for 7 hours, poured into water and extracted with ethyl acetate. The solution was dried (MgSO ₄ ) and concentrated to give Compound B as an oil (110 mg, 94%).

C. 7-Bromo-4 - [(dimethylamino) acetyl] -2,3,4,5-tetrahydro-1- (1H-imidazol-4-ylmethyl) -3- (phenylmethyl) -1H-1,4-benzodiazepine

Compound C (white solid) is obtained in 65% yield from compound B according to the procedure for preparation of compound B described in Example 313.

MS (M + H) &lt; ⁺ &gt; = 483.

Analysis calculated for C ₂₄ H ₂₈ N ₅ OBr · 1.2 H ₂ O · 2.1 TFA.

Found: C, 45.56; H, 4.41; N, 9.42; Br, 10.75; F, 16.10.

Found: C, 45.75; H, 4.02; N, 9.19; Br, 11.14; F, 16.08.

Example 315

276

(R) -7-Bromo-4- (1,2-dioxopropyl) -2,3,4,5-tetrahydro-1- (1H-imidazol-4-ylmethyl) -3- (phenylmethyl) - 1H-1,4-benzodiazepine (trifluoroacetate)

Example 315 (white solid) is obtained in a total 25% yield from Example 224, compound B, by coupling pyruvic acid in DMF with EDC / HOBt as a reaction medium by flash chromatography (silica gel, 4: 1 hexanes: ethyl acetate) followed by Example 313 describes the synthesis of compound B.

MS (M + H) &lt; ⁺ &gt; = 468.

Analysis calculated for C ₂ 3 H _{2 3} N ₄ O ₂ Br · 0.8 H ₂ O · 0.95 TFA.

Found: C, 50.68; H, 4.36; N, 9.49; Br, 13.54; F, 9.18.

Found: C, 50.37; H, 4.04; N, 9.23; Br, 14.07; F, 9.55.

(R) -7-Bromo-4- (cyclopropylcarbonyl) -2,3,4,5-tetrahydro-1- (1H-imidazole-411-methyl) -3- (phenylmethyl) -1H-1,4-benzodiazepine (trifluoroacetate) )

277

Example 316 (white solid) is prepared in a total 6% yield from Example 224B and cyclopropanecarboxylic acid using the two-step procedure described in Example 315 without purifying the intermediate.

MS (M + H) &lt; ⁺ &gt; = 466.

Analysis was subtracted from Ο ₂₄ Η 25Η ₄ ΟΒγ · 1.0 Η ₂ Ο · 0.8 TFA.

Found: C, 52.59; H, 4.68; N, 9.43; Br, 13.46; F, 9.60.

Found: C, 52.62; H, 4.37; N, 9.46; Br, 12.23; F, 9.46.

Example 317 CN

Me (R) -7-Cyano-2,3,4,5-tetrahydro-1- (1H-imidazol-4-ylmethyl) -3- (phenylmethyl) -4 (propylsulfonyl) -1H-1,4-benzodiazepine ( monohydrochloride)

A. (R) -7-Cyano-2,3,4,5-tetrahydro-3- (phenylmethyl) -4- (propylsulfonyl) -1H1,4-benzodiazepine

A solution of compound C (6.0 g, 23 mmol) in Example 248 and DIEA (12 mL, 68 mmol) in methylene chloride (120 mL) was added dropwise at -78 ° C to n-propylsulfonyl chloride (3.4 mL, 34 mmol). The mixture was allowed to warm to room temperature and stirred for 16 h, quenched with 10% NaHCO ₃ (50 mL) and extracted with methylene chloride (3 x 75 mL). The combined organic layers were dried (Na ₂ SO ₄ ), filtered and concentrated in vacuo. Remain

278 was purified by flash chromatography (2/1 hexane / ethyl acetate) to give Compound A (7.1 g, 85%) as a yellow solid.

MS (M + H) ⁺ 370.

Analysis calculated for C20H23N3O2S -0.19 H ₂ O.

Found: C, 64.42; H, 6.32; N, 11.27.

Found: C, 64.43; H, 6.25; N, 11.09.

B. (R) -7-Cyano-2,3,4,5-tetrahydro-1- (1H-imidazol-4-ylmethyl) -3- (phenylmethyl) -4- (propylsulfonyl) -1H-1,4-benzodiazepine (monohydrochloride) 4-formylimidazole (3.1 g, 33 mmol) was added to a solution of compound A (6.0 g, 16 mmol) in 3A molecular weight mesh in 1/1 CH ₂ Cl ₂ : acetic acid (80 mL), and the mixture was stirred at 70 ° C for 1 h. Sodium triacetoxyborohydride (6.9 g, 33 mmol) was added and the mixture was stirred at 70 ° C for 30 min. 4-Formylimidazole (3.1 g, 33 mmol, 2.0 equiv.) was added again and stirred at 70 ° C for a further 1 h. Sodium triacetoxyborohydride (6.9 g, 33 mmol, 2.0 equiv.) Was added and the mixture was stirred at 70 ° C for 30 min. The addition of formylimidazole and hydride is repeated eight times. The mixture was cooled to room temperature, diluted with methylene chloride (200 mL), filtered, and the filtrate concentrated in vacuo. The residue was diluted with 25% NH ₄ OH (200 mL). The solution was stirred at room temperature for 10 min, extracted with CH ₂ Cl ₂ (2 x 200 mL), the combined organic extracts dried (MgSO ₄ ), filtered and concentrated. The residue was purified by preparative HPLC (gradient of aqueous MeOH with 0.1% TFA), the desired fractions selected and concentrated in vacuo. The residue was dissolved in CH ₃ OH (20 mL) and 1N HCl (40 mL) and concentrated in vacuo. This procedure is repeated 3 times. The residue was dissolved in CH ₃ CN (20 mL) and 1N HCl (20 mL) and lyophilized to give Example 317 (6.8 g, 74%) as a white solid. Lyd. 140-151 ° C.

MS (M + H) &lt; ⁺ &gt; 450.

Analysis calculated for C ₂ 4 H ₂₇ N ₅ O ₂ S -1.1 HCl-0.59 H ₂ O.

279

Found: C, 57.62; H, 5.90; N, 14.00; Cl, 7.79: S, 6.41. Found: C, 57.61; H, 5.70; N, 13.97; Cl, 7.62; S, 6.44.

[α] _D = + 201 ° (c = 1.41, CH ₃ OH).

7-Bromo-2,3,4,5-tetrahydro-1,4-bis (1H-imidazol-4-ylmethyl) -3- (phenylmethyl) -1H1,4-benzodiazepine (dihydrochloride)

Example 318 (white solid) 55% yield of Example 75 Compound B according to the procedure described in Example 1 for the preparation of Compound D using 3 equivalents of formylimidazole and stirring for 2 hours. MS (M + H) <^+> = 477.

Example 319

Br

^ Me

Me

280

7-Bromo-1,2,3,5-tetrahydro-1- (1H-imidazol-4-ylmethyl) -N, N-dimethyl-3- (phenylmethyl) -4H-1,4-benzodiazepine-4-sulfonamide (monohydrochloride) )

A. 7-Bromo-1,2,3,5-tetrahydro-N, N-dimethyl-3- (phenylmethyl) -4H-1,4-benzodiazepine-4-sulfonamide

A stirred solution of Example 75 Compound B (100 mg, 0.32 mmol), N, N-dimethylsulfamoyl chloride (50 mg, 0.35 mmol), and DIPEA (61 μΙ, 0.35 mmol) in acetonitrile under catalytic amount of DMAP was heated to reflux. 18 or. The mixture was partitioned between ethyl acetate and 1N HCl solution. The organic layer was separated, dried (MgSO ₄ ), and concentrated. The residue was purified by flash chromatography (1: 2, hexanes: ethyl acetate) to give Compound A as an oil.

B. 7-Bromo-1,2,3,5-tetrahydro-1- (1H-imidazol-4-ylmethyl) -N, N-dimethyl-3- (phenylmethyl) -4H-1,4-benzodiazepine-4-sulfonamide (monohydrochloride)

Example 319 Compound (Solid) 92% yield is prepared from Compound A according to the procedure for Compound D described in Example 224.

MS (M + H) ⁺ 504.

Analysis calculated for C _{2 2} H 26 N ₅ O ₂ SBr · 1.0 HCl · 0.5 ether.

Found: C, 49.88; H, 5.58; N, 12.12; Br, 13.82; S, 5.55.

Found: C, 49.90; H, 5.42; N, 12.13; Br, 13.22; S, 6.44.

320 Example

281

2,3,4,5-Tetrahydro-1- (1H-imidazol-4-ylmethyl) -4- (methylsulfonyl) -3 (phenylmethyl) -1H-1,4-benzodiazepine-7-carbonitrile (monohydrochloride)

Example 320 Compound (yellow solid) is prepared from Example 75 Compound B according to the reaction sequence described for the following compounds: Example 224 Compound C, Example 225 Compound A, and Example 225 Compound B.

MS (M + H) &lt; ⁺ &gt; 422.

Analysis calculated for C 22 H 23 N 5 O 2 S · 1.0 HCl · 0.2 CH ₃ OH.

Found: C, 57.42; H, 5.38; N, 15.08; Cl, 7.63; S, 6.90.

Found: C, 57.12; H, 5.58; N, 11.94; Cl, 7.77; S, 4.95.

Example 321

CN

Me (R) -7-Cyano-1,2,3,5-tetrahydro-1- (1H-imidazol-4-ylmethyl) -N, N-dimethyl-3 (phenylmethyl) -4H-1,4-benzodiazepine -4-Carboxamide (monohydrochloride)

Example 321 (yellow solid) was prepared from Example 248 by Compound C according to the reaction sequence used to prepare Example 319, Compound A using dimethylcarbamoyl chloride and stirring at 60 ° C for 2 hours. and chromatography using a 1: 1 mixture of hexanes and ethyl acetate; For the compound of Example 225, B. Lyd. mp 147-150 ° C.

MS (M + H) <^+> = 415.

282

Analysis calculated for C ₂₄ H ₂₆ N ₆ O · 0.74 H ₂ O · 1.0 HCl. Found: C, 62.09; H, 6.18; N, 18.10; Cl, 7.61.

Found: C, 62.09; H, 6.04; N, 17.86; Cl, 7.91.

[α] _D ²⁰ : + 244 ° (c = 0.24, MeOH).

N, N-Diethyl-2,3,4,5-tetrahydro-1- (1H-imidazol-4-ylmethyl) -4- (methylsulfonyl) -3 (phenylmethyl) -1H-1,4-benzodiazepine-7-carboxamide (monohydrochloride)

A. 2,3,4,5-Tetrahydro-4- (methylsulfonyl) -3- (phenylmethyl) -1H-1,4-benzodiazepine-7-carboxylic acid

A solution of Example 225 Compound A (200 mg, 0.59 mmol) in ethanol was added to reflux for 5 hours with the addition of 10N NaOH (4 mL, 40 mmol). The mixture was cooled to room temperature, concentrated and poured aqueous HCl to pH 3. This mixture was concentrated. The residue was partitioned between 1N HCl and ethyl acetate. The organic layer was separated, dried over MgSO _4, and concentrated. The residue was triturated with methanol to give Compound A as a solid (156 mg, 73%).

B. N, N-Diethyl-2,3,4,5-tetrahydro-4- (methylsulfonyl) -3- (phenylmethyl) -1H-1,4-benzodiazepine-7-carboxamide

To a solution of compound A (50 mg, 0.14 mmol) in DMF was added diethylamine (50 μΙ) followed by catalytic amounts of HOBT and DMAP, followed by EDC (30 mg). Mixture

283 was stirred at room temperature for 2 days and partitioned between ethyl acetate and

1N HCl solution. The organic layer was separated, washed with saturated NaHCO ₃ solution, dried over MgSO _4, and concentrated to an oil compound B.

C. N, N-Diethyl-2,3,4,5-tetrahydro-1- (1H-imidazol-4-ylmethyl) -4- (methylsulfonyl) -3- (phenylmethyl) -1H-1,4-benzodiazepine-7 -carboxamide (monohydrochloride)

Compound C is prepared from Compound B according to the procedure for the preparation of Compound B described in Example 225.

MS (M + H) <^+> = 496.

2,3,4,5-Tetrahydro-1- (1H-imidazol-4-ylmethyl) -7-phenyl-4- (1-phenyl-1H-tetrazol-5-yl) -1H-1,4-benzodiazepine (monohydrochloride)

A. Solution of 2,3,4,5-Tetrahydro-7-phenyl-4- (1-phenyl-1H-tetrazol-5-yl) -1H-1,4-benzodiazepine, Compound B (100 mg, 0.45 mmol) DMF (2 mL) was treated with 5-chloro-1-phenyltetrazole (100 mg, 0.55 mmol) with potassium carbonate (60 mg). The mixture was stirred at 60 ° C for 18 hours. and partitioned between ethyl acetate and saturated NH ₄ Cl solution. The organic layer was washed with saturated NaHCO ₃ solution, dried (MgSO ₄ ), and concentrated.

284

Purification of the residue by column chromatography afforded Compound A as a white solid (75 mg, 45%). Lyd. mp: 150-151 ° C.

B. 2,3,4,5-Tetrahydro-1- (1H-imidazol-4-ylmethyl) -7-phenyl-4- (1-phenyl-1H-tetrazol-5-yl) -1H-1,4-benzodiazepine ( monohydrochloride)

Compound B (yellow solid) is prepared from Compound A according to the procedure described in Example 1 for the preparation of Compound D. Lyd. mp: 158 ° C.

Analysis calculated for C ₂₆ H ₂₄ N ₈ · 0.5 CH ₃ OH · 2.5 HCl.

Found: C, 57.28; H, 5.17; N, 20.16.

Found: C, 57.62: H, 5.12; N, 19.93.

Example 324

CN (R) -7-Cyano-2,3,4,5-tetrahydro-1- (1H-imidazol-4-ylmethyl) -3- (phenylmethyl) -4- (2-pyrazinylcarbonyl) -4H-1,4-benzodiazepine (monohydrochloride)

Example 324 (yellow solid) is prepared from Example 248, Compound C, and pyrazinecarboxylic acid according to the reaction sequence used to prepare Example 322, Compound B, after stirring for 18 hours and purifying by flash chromatography (3: 2, ethyl acetate: hexanes); 225 for compound B,

MS (M + H) <^+> = 450.

Analysis calculated for C ₂₆ H ₂₃ N ₇ O · 1.2 H ₂ O · 1.0 HCl · 1.2 toluene. Found: C, 66.09; H, 5.78; N, 16.35; Cl, 5.91.

Found: C, 65.83; H, 5.45; N, 16.11; Cl, 5.96.

285

Example 325

(R) -4- [7-Bromo-2,3,4,5-tetrahydro-1- (1H-imidazol-4-ylmethyl) -3- (phenylmethyl) -4H-1,4-benzodiazepin-4-yl] -4-Oxobutanoic acid methyl ester (monohydrochloride)

A. (R) -4- [7-Bromo-2,3,4,5-tetrahydro-3- (phenylmethyl) -4H-1,4-benzodiazepin-4-yl] -4-oxobutanoic acid methyl ester

A stirred solution of Compound B (100 mg, 0.31 mmol) in Example 224 was treated with succinic anhydride (40 mg, 0.40 mmol) in ethyl acetate. The mixture was stirred at room temperature for 18 hours. and distributed in 1N HCl solution. The organic layer was dried (MgSO ₄ ) and concentrated to give compound A.

B. (R) -4- [7-Bromo-2,3,4,5-tetrahydro-1- (1H-imidazol-4-ylmethyl) -3 (phenylmethyl) -4H-1,4-benzodiazepine-4- il] -4-Oxobutanoic acid methyl ester (monohydrochloride)

Compound B (a yellow solid) is prepared from Compound A according to the procedure for the preparation of Compound B described in Example 225.

MS (M + H) <^+> = 511.

Example 326

286

(R) -7-Cyano-2,3,4,5-tetrahydro-1- (1H-imidazol-4-ylmethyl) -4- (4-morpholinylcarbonyl) -3- (phenylmethyl) -1H-1,4-benzodiazepine (monohydrochloride)

Example 326 (yellow solid) is prepared from Example 248, compound C, and morpholinocarbamoyl chloride according to the procedure described in Example 321.

MS (M + H) <^+> = 457.

Analysis calculated for C26H28N6O2 · 0.8 H ₂ O · 1.2 HCl · 0.2 ether. Found: C, 60.79: H, 6.24; N, 15.87; Cl, 8.03.

Found: C, 60.85; H, 6.02; N, 15.56; Cl, 8.06.

Example 327

(R) -7-Cyano-2,3,4,5-tetrahydro-1- (1H-imidazol-4-ylmethyl) -3- (phenylmethyl) -4- [2- (1-pyrrolidinone) ) ethyl] sulfonyl] -1H-1,4-benzodiazepine (dihydrochloride)

287

Example 327 Compound (yellowish solid) is prepared in 46% yield from Example 250 Compound A and pyrrolidine according to the procedure for Preparation Compound B described in Example 250.

MS (M + H) <^+> = 505.

(S) -2,3,4,5-Tetrahydro-1- (1H-imidazol-4-ylmethyl) -4- (methylsulfonyl) -7-phenyl-3- (3-pyridinylmethyl) -1H-1,4-benzodiazepine (dihydrochloride)

Example 328 (off-white solid) is prepared from L- (3-pyridyl) alanine and Example 226 Compound B according to the sequence used to prepare the following compounds: Example 226 Compound C; Example 226 for compound D; 264 for compound B; 264 for compound C.

MS (M + H) &lt; ⁺ &gt; 474.

Example 329

288

(R) -2,3,4,5-Tetrahydro-1- (1H-imidazol-4-ylmethyl) -7-phenyl-3- (3-pyridinylmethyl) 4- (2-thienylsulfonyl) -1H-1, 4-Benzodiazepine (dihydrochloride)

Example 329 (off-white solid) is prepared from (R) -2,3,4,5-tetrahydro-7-phenyl-3- (3-pyridinylmethyl) -1H-1,4-benzodiazepine (273). and the 2-thiophensulfonyl chloride according to the reaction sequence used to prepare the following compounds: Example 224, Compound C; Example 224 for compound D.

MS (M + H) &lt; ⁺ &gt; 542.

Example 330

(R) -2,3,4,5-Tetrahydro-1- (1H-imidazol-4-ylmethyl) -7-phenyl-4- (propylsulfonyl) -3- (3-pyridinylmethyl) -1H-1,4- benzodiazepine (monohydrochloride)

289

A. (R) -2,3,4,5-Tetrahydro-7-phenyl-4- (propylsulfonyl) -3- (3-pyridinylmethyl) -1H-1,4-benzodiazepine

To a stirred (R) -2,3,4,5-tetrahydro-7-phenyl-3- (3-pyridinylmethyl) -1H-1,4-benzodiazepine (prepared as described in Example 273; 200 mg, 0, A solution of 63 mmol) and DIEA (0.33 mL, 1.9 mmol) at -60 ° C under argon was added propanesulfonyl chloride (0.11 mL, 0.94 mmol). The mixture was kept at 4 ° C for two days, quenched with aqueous saturated NaHCO ₃ solution (10 mL) and extracted with CH 2 Cl 2 (3 x 10 mL). The combined extracts were dried (Na2S ₄₎ and evaporated under reduced pressure to obtain a compound A as a yellow solid. MS (M + H) &lt; ⁺ &gt; 422.

B. (R) -2,3,4,5-Tetrahydro-1- (1H-imidazol-4-ylmethyl) -7-phenyl-4- (propylsulfonyl) -3- (3-pyridinyl) ethyl I) -1H-1,4-benzodiazepine (monohydrochloride)

Compound B (yellow solid) is prepared in 45% yield from Compound A according to the procedure for the preparation of Compound D described in Example 224 by preparative HPLC (gradient of aqueous methanol with 0.1% TFA). The HCl salt is prepared by adding 1N HCl in ether to a solution of the TFA salt in ethyl acetate and evaporating. MS: (M + H) &lt; ⁺ &gt; 502.

Example 331

(R) -7-Bromo-2,3,4,5-tetrahydro-1- (1H-imidazol-4-ylmethyl) -4- (methylsulfonyl) -3 (2-pyridinylmethyl) -1H-1,4-benzodiazepine (monohydrochloride)

290

Example 331 (yellow solid) is prepared from D (2-pyridyl) alanine and Example 226 Compound B according to the reaction sequence used to prepare the following compounds: Example 226 Compound C; Example 226, Compound D, refluxed for 48 hours; Example 264, Compound B, purified by preparative HPLC using aqueous methanol with 0.1% TFA; 264 for compound C.

MS (M + H) &lt; ⁺ &gt; 478.

Example 332

2,3,4,5-Tetrahydro-1- (1H-imidazol-4-ylmethyl) -4- (methylsulfonyl) -3- (phenylmethyl) -7- (2-pyrimidinyl) -1H-1,4-benzodiazepine (dihydrochloride) )

Example 332 (yellow solid) is prepared from Example 231, Compound A and 2-stanylpyrimidine according to the procedures for preparation of Compounds B and C described in Example 231.

MS (M + H) ⁺ 475.

Example 333

292

Example 334 (white solid) is prepared in 26% yield from Example 226 Compound D by treatment with trifluoroacetic anhydride and DIEA in methylene chloride followed by the procedure described in Example 264 for the preparation of Compound C by preparative HPLC (aqueous methanol 0.1%). TFA gradient). The HCl salt is obtained by lyophilization twice from 1N HCl.

MS (M + H) &lt; ⁺ &gt; 491.

(R) -2,3,4,5-Tetrahydro-1- (1H-imidazol-4-ylmethyl) -4- (methylsulfonyl) -3 (phenylmethyl) -7- (4-pyridinyl) -1H-1,4 benzodiazepine (dihydrochloride)

A. (R) -2,3,4,5-Tetrahydro-3- (phenylmethyl) -7- (4-pyridinyl) -1H-1,4-benzodiazepine-2,5-dione

Example 224 A mixture of compound A (55.6 mmol, 19.2 g), 4-stanylpyridine (111 mmol, 40.9 g) and Pd (PPh ₃ ) ₄ (8.24 mmol, 9.6 g) in toluene (2000) ml) degassed and heated at 110 ° C for 16 hours. The reaction mixture was concentrated, diluted 1: 1 with ether and hexanes and filtered. The solid is washed with 500 mL of a 1: 1 mixture of ether and hexanes to give 16.7 g of compound A. The combined filtrate is concentrated to give 5.8 g of compound A (80% overall yield). MS (M + H) ⁺ 344.

291

Br

Λ

N

(R) -7-Bromo-2,3,4,5-tetrahydro-1- (1H-imidazol-4-ylmethyl) -3- (phenylmethyl) -4 - [(trifluoromethyl) sulfone] -1 H -1,4-benzodiazepine (monohydrochloride)

Example 333 (off-white solid) is prepared in 44% yield from Example 224 Compound B according to the procedure described in Example 224 for the preparation of Compound C (using trifluoromethanesulfonyl chloride in place of methanesulfonyl chloride) and Example 224.

MS (M + H) &lt; ⁺ &gt; 528.

Example 334

CF.

(R) -2,3,4,5-Tetrahydro-1- (1H-imidazol-4-ylmethyl) -7-phenyl-3- (phenylmethyl) -4 (trifluoroacetyl) -1H-1,4-benzodiazepine ( monohydrochloride)

293

B. (R) -2,3,4,5-Tetrahydro-3- (phenylmethyl) -7- (4-pyridinyl) -1H-1,4-benzodiazepine

A suspension of Compound A (16.7 g, 32 mmol) in THF (250 mL) was treated with BH _{3 in} THF (1.0 M THF). The mixture was refluxed for 12 h and quenched by slow addition of 6N HCl (500 mL). The THF was evaporated under reduced pressure and the remaining solution was basified by slow addition of concentrated NaOH. The aqueous phase was extracted with 10% IPA-CH ₂ Cl ₂ (3 x 300 mL), dried over Na ₂ SO _4, and concentrated to give 9.0 g (90% yield) of Compound B. MS (M + H) ⁺ 316.

C. (R) -2,3,4,5-Tetrahydro-4- (methylsulfonyl) -3- (phenylmethyl) -7- (4-pyridinyl) -1H-1,4-benzodiazepine, Compound B (28.5) mmol, 9.0 g) in CH ₂ Cl ₂ (200 mL) was added TEA (142.5 mmol, 20 mL) and methanesulfonyl chloride (37.5 mmol, 2.9 mL). The mixture was stirred at room temperature for 1 h, poured into 2N NaOH (500 mL) and extracted with 10% IPA-CH ₂ Cl ₂ (3 x 250 mL). The combined organic layers were dried over Na ₂ SO ₄ , concentrated, and aceotropically distilled off with toluene to give Compound C.

D. (R) -2,3,4,5-Tetrahydro-1- (1H-imidazol-4-ylmethyl) -4- (methylsulfonyl) -3 (phenylmethyl) -7- (4-pyridinyl) -1H-1 , 4-benzodiazepine (dihydrochloride)

The crude compound C was dissolved in 300 mL of 1: 1 AcOH: CH ₂ Cl ₂ with NaBH (OAc) ₃ (123 mmol, 26 g) and 4-formylimidazole (123 mmol, 11.8 g) and the mixture was heated at 55 ° C. 3 or. The reaction mixture was concentrated, diluted with 2N NaOH (500 mL) and extracted with 10% IPA-CH ₂ Cl ₂ (3 x 250 mL). The combined organic layers were evaporated and the residue purified by preparative HPLC (gradient of aqueous methanol to 0.1% TFA). The TFA salt was converted to the HCl salt using 1N HCl (2 x 150 mL) to give Compound D as a yellow solid (2.9 g, 18% based on Compound B). MS (M + H) &lt; ⁺ &gt; 491.

336-343 examples

294

Examples 336-343 are prepared from the corresponding sulfonyl chloride and Example 335 Compound B according to Example 335 Synthesis of Compounds C and D (Examples 336-338) or Example 248 Compound C according to Example 317 Synthesis Method (0 ° C to 0 ° C). room temperature) and the procedure for the synthesis of compound D described in Example 335 (Examples 339-343).

For example,

336 (R) -2,3,4,5-Tetrahydro-1- (1H-imidazol-4-ylmethyl) -3- (phenylmethyl) -7- (4-pyridinyl) -4- (2-thienesulfonyl) - 1H-1,4-benzodiazepine (dihydrochloride) BMS-218962

337 (R) -2,3,4,5-Tetrahydro-1- (1H-imidazol-4-ylmethyl) -3- (phenylmethyl) -4- (phenylsulfonyl) 7- (4-pyridinyl) -1H-1, 4-Benzodiazepine (dihydrochloride) BMS-218963

Mass spectrum m / z 542 (M + H) m / z 536 (M + H)

295

338 (R) -2,3,4,5-Tetrahydro-1 '(1H-imidazol-4-ylmethyl) -3 (phenylmethyl) -4 (propylsulfonyl) -7- (4-pyridinyl) -1H-1,4-benzodiazepine (dihydrochloride) BMS-219395

339 (R) -7-Cyano-2,3,4,5-tetrahydro-1- (1H-imidazol-4-ylmethyl) -3- (phenylmethyl) -4 - [(3,5-dimethylisoxazol-4-yl) sulfonyl] -1 H-1,4-benzodiazepine (dihydrochloride) BMS-220904

340 (R) -7-Cyano-4 - [(4-cyanophenyl) sulfonyl] -2,3,4,5-tetrahydro-1- (1H-imidazol-4-ylmethyl) -3- (phenylmethyl) -1H1,4-benzodiazepine (dihydrochloride) ) BMS-221604

341 (R) -7-Cyano-2,3,4,5-tetrahydro-1- (1H-imidazol-4-ylmethyl) -3- (phenylmethyl) -4- [2,2,2-trifluoroethyl) sulfonyl] 1H-1 , 4-benzodiazepine (dihydrochloride)

BMS-221764

m / z 539 (M + H) m / z 509 (M + H) m / z 502 (M + H)

296

342 (R) - [(5-Bromo-2-thienyl) sulfonyl] -7-cyano-2,3,4,5-tetrahydro-1- (1H-imidazol-4-ylmethyl) -3- (phenylmethyl) -1H-1,4-benzodiazepine ( dihydrochloride) BMS-221766

343 (R) -7-Cyano-2,3,4,5-tetrahydro-1- (1H-imidazol-4-ylmethyl) -4 - [(4-methoxyphenyl) sulfonyl] -3 (phenylmethyl) -1H-1,4-benzodiazepine (dihydrochloride) ) BMS-221970

344 Example

m / z

569 (M + H) m / z 514 (M + H)

N - [[7-Bromo-2,3,4,5-tetrahydro-1- (1H-imidazol-4-ylmethyl) -4- (methylsulfonyl) 1H-1,4-benzodiazepin-3-yl] methyl] benzamide (dihydrochloride)

A. N - [[7-Bromo-2,3,4,5-tetrahydro-4- (methylsulfonyl) -1H-1,4-benzodiazepin-3-yl] methyl] benzamide

297

To a solution of Example 305 Compound C (50 mg, 0.15 mmol) in methylene chloride (10 mL) was added 2,6-di-butyl-butyl-4-methylpyridine (62 mg, 0.30 mmol). The solution is cooled to -40 ° C under N ₂ . Triflic acid anhydride (0.85 mL, 0.30 mmol) was added and the solution was stirred for 1 h. In N ₂ atmosphere at -40 ° C. Gaseous NH _{3 is} bubbled through the tube for 10 minutes. Bubbles are bubbled with NH _{3 at} -40 ° C. The solution is slowly warmed to room temperature with continuous NH ₃ . Add ethyl ether (30 mL) and saturated aqueous sodium bicarbonate solution (30 mL) and separate the layers. The organic layer was washed with 1N aqueous HCl. The aqueous layer was basified with 5N aqueous NaOH and the product was extracted with methylene chloride (30 mL). The organic layer was dried (Na ₂ SO ₄ ) and concentrated to 5 mL. Benzoic acid (26 mg, 0.21 mmol) and EDC (40 mg, 0.21 mmol) were added and the solution was stirred for 16 h. and concentrated. The residue was chromatographed (flash chromatography on silica gel, 1: 5-1: 1 ethyl acetate: hexane) to give 15 mg (16% for two steps) of Compound A as a white solid. MS (M + H) ⁺ 439.

B. N - [[7-Bromo-2,3,4,5-tetrahydro-1- (1H-imidazol-4-ylmethyl) -4 (methylsulfonyl) -1H-1,4-benzodiazepin-3-yl] methyl] benzamide (dihydrochloride)

Compound B (white solid) is prepared in 16% yield using the procedure described in Example 224 for the preparation of compound D.

MS (M + H) &lt; ⁺ &gt; 518.

. ·· Example 345

298

(R) -7 "Cyano-1,2,3,5-tetrahydro-1- (1 H -imidazol-4-ylmethyl) -N, N-dimethyl-3 (phenylmethyl) -4 H -1,4-benzodiazepine-4 -sulfonamide (hydrochloride)

A. (R) -7-Cyano-1,2,3,5-tetrahydro-N, N-dimethyl-3- (phenylmethyl) -4H-1,4-benzodiazepine-4-sulfonamide, m.p. dimethylsulfamoyl chloride (0.12 mL, 0.16 g, 1.13 mmol) was added to a solution of gIE, 0.75 mmol) and DIEA (0.19 mL, 1.13 mmol) in acetonitrile (3 mL) at 0 ° C under argon. . After stirring for 16 hours. at room temperature, the reaction mixture was diluted with chloroform (20 mL) and NaHCO ₃ (5 mL). The layers were separated and the aqueous layer was extracted with chloroform (2 x 20 mL). The combined organic extracts were washed with NaHCO ₃ (2 x 5 mL), water (1 x 10 mL) and saturated NaCl (2 x 10 mL), dried over MgSO ₄ , filtered, and concentrated. The residue was purified by flash column chromatography on silica gel eluting with 30% EtOAc in hexane to give Compound A as a yellow oil (0.14 g, 51%). MS (M + H) &lt; ⁺ &gt; = 371 ⁺ .

B. (R) -7-Cyano-1,2,3,5-tetrahydro-1- (1H-imidazol-4-ylmethyl) -N, N-dimethyl-3- (phenylmethyl) -4H-1,4-benzodiazepine 4-sulfonamide (hydrochloride)

A solution of Compound A (0.068 g, 0.18 mmol), 4-formylimidazole (0.017 g, 0.18 mmol) and AcOH (0.5 mL) in dichloroethane (0.5 mL) and 3A molecules was heated under reflux for 1 hour. . Sodium triacetoxyborohydride (0.038 g, 0.18 mmol) was added. Daily (for a total of 6 days) aldehyde and

299 sodium triacetoxyborohydride (1 eq each). After stirring for 6 days, the mixture was diluted with CHCl 3 (10 mL), NH ₄ OH (5 mL) and NaHCO ₃ (5 mL) and stirred for 30 min. The layers were separated and the aqueous layer was extracted with CHCl 3 (3 x 30 mL). The combined organic extracts were dried over MgSO ₄ , filtered, and concentrated. The product was purified by preparative HPLC (gradient from aqueous methanol to 0.1% TFA) to give Compound B as a yellow solid (40 mg, 50%).

MS (M + H) <^+> = 451.

346 Example

(R) -7-Cyano-1,2,3,5-tetrahydro-N, N-dimethyl-1 - [(1-methyl-1H-imidazol-5-yl) methyl] -3- (phenylmethyl) -4H-1 , 4-benzodiazepine-4-sulfonamide (hydrochloride)

A solution of Example 345 Compound A (0.068 g, 0.18 mmol), 1-methyl-5-formylimidazole (0.041 g, 0.36 mmol), AcOH (0.2 mL) in dichloroethane (0.5 mL) was heated to 2 with molecular mesh. or. Sodium triacetoxyborohydride (0.076 g, 0.36 mmol) was added. After 1.5, 3 is 4.5 or. aldehyde and sodium triacetoxyborohydride (2 eq. each) are added again. After stirring for 2 days, the mixture was diluted with CHCl 3 (10 mL), NH ₄ OH (5 mL) and NaHCO 3 (5 mL) and stirred for 30 min. The layers were separated and the aqueous layer was extracted with CHCl 3 (3 x 30 mL). The combined organic extracts were washed with NaHCCb and saturated aqueous NaCl (2 x 5 mL), dried over MgSO _4, filtered and concentrated. The product was purified by reverse phase preparative HPLC (gradient of aqueous methanol with 0.1% TFA) and

300

The HCl salt gives Example 246 as a yellowish solid (32 mg, 38%).

MS (M + H) ⁺ 465.

347 Example

(R) -7-Chloro-2,3,4,5-tetrahydro-1 - [(1-methyl-1H-imidazol-5-yl) methyl] -4 (methylsulfonyl) -3- (phenylmethyl) -1H -1,4-benzodiazepine (monohydrochloride)

A. (R) -7-Chloro-2,3,4,5-tetrahydro-3- (phenylmethyl) -1H-1,4-benzodiazepine-2,5-dione

A mixture of chloro-anhydride anhydride (25 g, 0.126 mol), D-Phe methyl ester (27.2 g, 0.126 mol) and DMAP (0.4 g) in pyridine (275 ml) was refluxed for 5 days. The mixture was concentrated and dissolved in CH2Cl2. This solution was washed with 10% HCl (3 x 100 mL), dried over MgSO ₄ , filtered and concentrated to a pink solid (39 g) which was recrystallized 3 times from ether / CH ₂ Cl ₂ to give compound A (15.0 g, 40 mL). %). MS (M + H) &lt; ⁺ &gt; = 301 ⁺ .

B. (R) -7-Chloro-2,3,4,5-tetrahydro-3- (phenylmethyl) -1H-1,4-benzodiazepine: Compound A (20 g, 66.5 mmol) in THF (200 mL) was added with borane. THF (1M, 300 mL). The mixture was refluxed for 1 day, cooled in an ice bath, slowly stirred with MeOH (115 mL) and concentrated.

301

The residue was diluted with MeOH (200 mL), added with 40 mL of 25% HCl, refluxed for 2 hours, and concentrated to dryness to give an off-white solid which was triturated several times with ether and suspended in water. NaOH (1N to pH 11) is added to the suspension, the resulting solid is filtered off, washed with ether and dried in vacuo to give 7.9 g of compound B, which is a yellowish solid. Concentration of the filtrate yields another 10.5 g of compound B, which is a yellowish solid (100%). MS (M + H) <^+> = 273.

C. (R) -7-Chloro-2,3,4,5-tetrahydro-4- (methylsulfonyl) -3- (phenylmethyl) -1H1,4-benzodiazepine in a solution of compound B (10 g, 36.6 mmol) CH ₂ Cl ₂ (130 mL) at 0 ° C was added dropwise a solution of methanesulfonyl chloride (3.68 mL, 47.6 mmol) in CH ₂ Cl ₂ (20 mL) under argon. After stirring at room temperature for 16 h, the reaction mixture was diluted with water (20 mL). The layers were separated and the aqueous layer was extracted with CH ₂ Cl ₂ (2 x 40 mL). The combined organic layers were washed with water (1 x 30 mL), KHSO ₄ (2 x 30 mL), water (1 x 30 mL), NaHCO ₃ (2 x 30 mL), brine (1 x 30 mL), dried over MgSO 4 ₄ , the oil is filtered off and concentrated to a yellow-brown oil. This oil was crystallized from EtOAc / hexanes, triturated with hexane to give a yellow solid, compound C (10.6 g, 82%). MS: (M + H) &lt; ⁺ &gt; = 351.

D. (R) -7-Chloro-2,3,4,5-tetrahydro-1 - [(1-methyl-1H-imidazol-5-yl) methyl] -4 (methylsulfonyl) -3- (phenylmethyl) - 1H-1,4-benzodiazepine (monohydrochloride) in a solution of compound C (4.0 g, 11.4 mmol), 1-methyl-5-formylimidazole (2.6 g, 22.8 mmol) and AcOH (22 mL) CH ₂ Cl ₂ (22 mL) was added sodium triacetoxyborohydride (4.83 g, 22.8 mmol). After stirring for 2 days, the mixture was diluted with CH ₂ Cl ₂ (30 mL), NH ₄ OH (30 mL) and NaHCO ₃ (30 mL) and stirred for 30 min. The layers were separated and the aqueous layer was extracted with CH ₂ Cl ₂ (3 x 50 mL). The combined organic extracts are washed

302

NaHCO ₃ , water, saturated NaCl solution (3 x 30 mL), dried over MgSO ₄ , filtered and concentrated to give 6.0 g of a foamy solid. This product was purified by flash column chromatography eluting with 7/3 EtOAc / hexane (1 L) and 19/1 CHCl ₃ / MeOH (2 L); a white foam is obtained which is treated with 1N HCl in ether (2 x 25 mL). The solid is triturated with ether to give compound D, which is a yellowish solid (3.44 g, 63%).

MS (M + H) ⁺ 445.

348 Example

(R) -7-Chloro-2,3,4,5-tetrahydro-1- (1H-imidazol-4-ylmethyl) -4- (methylsulfonyl) -3 (phenylmethyl) -1H-1 , 4-benzodiazepine (monohydrochloride)

Example 348 (yellowish solid) Prepared in 70% yield from Example 247 Compound C according to the procedure described in Example 247 for the preparation of Compound D using 4-formylimidazole and refluxing for 1 hour. and stirring at room temperature for 16 hours.

MS (M + H) &lt; ⁺ &gt; = 431.

349 Example

303

(R) -7-Chloro-2,3,4,5-tetrahydro-1 - [(1-methyl-1H-imidazol-5-yl) methyl] -4- (phenylsulfonyl) -3- ( Phenylmethyl I) -1H-1,4-benzodiazepine (monohydrochloride)

Example 249 (yellowish solid) is prepared from Example 247 by Compound B according to the reaction sequence used to prepare Example 247, Compound C using benzenesulfonyl chloride, with stirring at room temperature for 3 hours. and chromatography over silica gel eluting with 7/3 hexanes / EtOAc (57%); Example 247 Compound D was stirred at room temperature for 12 hours and stirred for 2 days with the addition of another equivalent of hydride and aldehyde and purified by reverse phase HPLC (gradient of aqueous methanol to 0.1% TFA; 52%).

MS (M + H) <^+> = 507.

Example 350

304 (R) -7-Cyano-2,3,4,5-tetrahydro-1- (1H-imidazol-4-ylmethyl) -3- (pyridin-3-ylmethyl) -4- (methylsulfone I) -1 H -1,4-benzodiazepine (tetrahydrochloride)

A. (R) -7-Bromo-2,3,4,5-tetrahydro-3- (pyridin-3-ylmethyl) -1H-1,4-benzodiazepine

J (R) -7-Bromo-2,3,4,5-tetrahydro-3- (pyridine-3-methyl) -1H-1,4-benzodiazepine-2,5-dione (prepared from 5 bromoacetic anhydride and D-3-pyridylalanine methyl ester hydrochloride according to the procedure for the synthesis of Example 226 Compound C: 11.2 g, 32.4 mmol) in THF (50 mL) at 0 ° C dropwise borane-THF (1M, 168 mL, 0.168 mmol ). When it ceases, the mixture is refluxed for 4 hours, cooled to 0 ° C and an additional 1M borane-TFH equivalent (32.4 mL, 32.4 mmol) is added. The mixture was refluxed for 2 h, cooled to 0 ° C, quenched with 6N HCl (125 mL), and then refluxed for 1 h. The reaction mixture was cooled to room temperature and concentrated in vacuo. The solid is dissolved in water (100 mL) and the solution is extracted with Et ₂ O (3 x 100 mL). The aqueous layer is cooled to 0 ° C and sodium hydroxide (50%) is added until the solution becomes alkaline. This alkaline solution is extracted with 9/1 CH ₂ Cl ₂ / iPrOH (3 x 200 mL). The combined organic extracts were dried (MgSO ₄ ), filtered, and concentrated in vacuo to give Compound A (8.0 g, 80%). MS (M + H) ⁺ 318.320.

B. (R) -7-Cyano-2,3,4,5-tetrahydro-3- (pyridin-3-ylmethyl) -1H-1,4-benzodiazepine

To a solution of Compound A (8.3 g, 26 mmol) in NMP (41.5 mL) which was purged with nitrogen was added copper cyanide (2.6 g, 29 mmol) at room temperature. The mixture is heated to 195 ° C for 3 hours, cooled to room temperature and quenched. NH ₄ OH (100 mL). water is added and the mixture is extracted with 9/1 CH2Cl2 (3 x 200 mL). The combined organic extracts are concentrated in vacuo. The residue was dissolved in 6N HCl (200 mL) and the solution was extracted with ethyl acetate (4 x 200 mL). Aqueous

The solution of 305 was cooled to 0 ° C, basified with concentrated ammonium hydroxide and extracted with 9/1 C 1 Cl 2 / iPrOH (3 x 200 mL). The combined organic extracts were dried (Na ₂ SO ₄ ), filtered and concentrated in vacuo. The residue was purified by flash chromatography (gradient gradient, ethyl acetate, 19/1 CFKCl2 / iPrOH, 4/1/1 0.2 CH2Cl2 / MeOH / triethylamine). Concentration of the appropriate fractions in vacuo afforded compound B (4.1 g, 60%) as a brown solid. MS (M + H) ⁺ 265.

C. (R) -7-Cyano-2,3,4,5-tetrahydro-3- (pyridin-3-ylmethyl) -4- (methylsulfonyl) -1H-1,4-benzodiazepine, Compound B (0.070 g). A solution of 0.27 mmol) and DIEA (0.14 mL, 0.80 mmol) in methylene chloride (2 mL) was added dropwise at -78 ° C to methyl sulfonyl chloride (0.031 mL, 0.39 mmol). The mixture was allowed to warm slowly to room temperature and stirred at room temperature for 16 hours. The mixture was quenched with 10% NaHCO ₃ (10 mL) and the solution was extracted with methylene chloride (3 x 10 mL). The combined organic layers were dried (Na ₂ SO ₄ ), filtered and concentrated in vacuo. Purification of the residue by flash chromatography (19/1 methylene chloride / iPrOH) gave Compound C (0.064 g, 85%) as a solid. MS (M + H) &lt; ⁺ &gt; 343.

D. (R) -7-Cyano-2,3,4,5-tetrahydro-1- (1H-imidazol-4-ylmethyl) -3- (pyridin-3-ylmethyl) -4- (methylsulfonyl) -1H-1, 4-Benzodiazepine (tetrahydrochloride)

To a solution of Compound C (0.055 g, 0.16 mmol) in 1/1 DCE / acetic acid (2 mL) with 3A molecular mesh was added 4-formylimidazole (0.062 g, 0.64 mmol) and the mixture was stirred at 70 ° C. 1 or. Sodium triacetoxyborohydride (0.034 g, 0.32 mmol) was added and the mixture was stirred at 70 ° C for 30 min. 4-Formylimidazole (0.032 g, 0.32 mmol) was added and the mixture was stirred at 70 ° C for 1 h. Sodium triacetoxyborohydride (0.34 g, 0.32 mmol) was added and the mixture was stirred at 70 ° C for 30 min. The latter two stages are repeated six times. The mixture was cooled to room temperature and diluted with methylene

306 chloride (30 mL) was filtered off and the filtrate was concentrated in vacuo. The residue was diluted with 25% NH ₄ OH (50 mL) and the solution was extracted with CH ₂ Cl ₂ (2 x 200 mL). The combined organic extracts were dried (Na ₂ SO ₄ ), filtered and concentrated in vacuo. The residue was purified by preparative HPLC (gradient of aqueous methanol with 0.1% TFA) and the appropriate fractions concentrated in vacuo. The residue was evaporated from CH ₃ OH (1 mL) and 1N HCl (1 mL) 4 times. This residue was dissolved in CH ₃ CN (1 mL) and 1N HCl (1 mL) and lyophilized to give Compound D (0.040 g, 50%) as a solid. Lyd. temp .: decomposes above 180 ° C.

MS: (M + H) &lt; ⁺ &gt;

[α] _D = + 89 ° (c = 0.39, CH ₃ OH).

Analysis calculated for C ₂ i H ₂₂ N ₆ O ₂ S · 1.4 H ₂ O · 4 HCl.

Found: C, 42.44; H, 4.90; N, 14.14.

Found: C, 42.44; H, 4.66; N, 14.01.

Example 351

(R) -7-Bromo-2,3,4,5-tetrahydro-1- (1H-imidazol-2-ylmethyl) -4- (methylsulfonyl) -3 (phenylmethyl) -1H-1,4-benzodiazepine (dihydrochloride) )

The product (off-white solid) is obtained in 54% yield

Example 224 Compound C and 2-formylimidazole according to the procedure described in Example 1 for the preparation of compound D.

MS (M + H) <^+> = 476.

307

Example 352

Br

N, Me (R) -7-Bromo-2,3,4,5-tetrahydro-1- (1H-imidazol-4-ylmethyl) -4 - [(1-methyl-1 Himidazol-4-yl) sulfonyl] - 3- (Phenylmethyl) -1H-1,4-benzodiazepine (trihydrochloride)

Example 352 (off-white solid) is prepared in 54% yield from Example 224 Compound B and 1-methylimidazole-4-sulfonyl chloride according to the procedure for Preparation 224 Compounds C and D.

MS (M + H) <^+> = 542.

Example 353

Cl < ^z

N

C h

O (R) -7-Chloro-2,3,4,5-tetrahydro-1- (1-methylimidazol-5-ylmethyl) -4 - [(2-morpholin-4-yl-ethyl) sulfonyl] -3 - (phenylmethyl) -1H-1,4-benzodiazepine (dihydrochloride)

308

A. (R) -7-Chloro-2,3,4,5-tetrahydro-4- (ethenylsulfonyl) -3- (phenylmethyl) -1H1,4-benzodiazepine, 4.4 g (16.1 mmol) of Example 347 To a solution of compound B in 75 mL of methylene chloride is added dropwise about -1.5 mL of a 2-chlorosulfonyl chloride solution in 15 mL of methylene chloride at -78 ° C under argon. Then 5 mL of DIPEA was added rapidly followed by the remaining sulfonyl chloride solution and another 2.4 mL of DIPEA (7.4 mL total, 40.3 mmol). The resulting yellowish solution was stirred at -78 ° C for 0.5 h, allowed to warm to room temperature and evaporated to half volume. This solution of crude compound A is used in the next step.

B. (R) -7-Chloro-2,3,4,5-tetrahydro-4 - [(2-morpholin-4-yl-ethyl) sulfonyl] -3 (phenylmethyl) -1H-1,4-benzodiazepine Morpholine (15 mL) was added dropwise to Compound A solution and stirred at room temperature overnight. The reaction mixture was washed with water and saturated NaCl solution, dried (MgSO ₄ ), and evaporated to give an orange oil which was purified by flash chromatography on silica gel (5% ethyl acetate in hexane); 3.9 g (54%) of compound B is obtained which is a white foamy solid.

C. (R) -7-Chloro-2,3,4,5-tetrahydro-1- (1-methylimidazol-5-ylmethyl) -4 - [(2-morpholin-4-yl-ethyl) sulfonyl] -3 - (phenylmethyl) -1H-1,4-benzodiazepine (dihydrochloride) in a solution of 3.9 g (8.7 mmol) of compound B in 40 ml of methylene chloride and 4 ml of acetic acid at room temperature; 3.8 g (34 mmol) of 1-methyl-5-imidazolecarboxaldehyde are added under argon. After stirring for 0.5 h, 1.9 g (9 mmol) of sodium triacetoxyborohydride are added and the solution is heated to 40 ° C. Additional portions of 1.9 g of hydride are added after 1 and 2.5 hours. After 4 or. another 1.0 g of aldehyde and 1.9 g of hydride were added and stirred overnight at room temperature. The reaction mixture is evaporated to dryness and the residue is diluted with ethyl acetate and saturated NaHCO ₃ . Solid NaHCO _{3 is} added again in portions until the aqueous layer becomes alkaline. The organic layer

309 is separated and the aqueous layer is extracted twice more with ethyl acetate. The combined organic fractions were washed with saturated NaCl, dried (MgSO ₄ ), and evaporated to give a viscous oil which was purified by flash chromatography on silica gel (10% methanol in chloroform) followed by preparative HPLC (0.1% aqueous methanol). TFA gradient) to give 3.2 g of free base as a white foamy solid. An excess of 1M HCl in ether was added to a solution of the free amine in ethyl acetate, and the resulting white precipitate was filtered off to give 3.2 g (63%) of Compound C as a white powder.

MS: (M + H) &lt; ⁺ &gt; 544.

Analysis calculated for C 27 H ₃₄ N ₅ O ₃ SCI · 2 HCl · H ₂ O.

Found: C, 51.07; H, 6.03; N, 11.03.

Found: C, 50.76; H, 5.94; N, 11.13.

Example 354

Cl

HN

(R) -7-Chloro-2,3,4,5-tetrahydro-1- (1H-imidazol-4-ylmethyl) -4 - [(2-morpholin-4-yl-ethyl) sulfonyl] -3- (phenylmethyl) -1H-1,4-benzodiazepine (dihydrochloride)

Example 353 Compound B (0.10 g, 0.22 mmol), 4-formylimidazole (0.042 g, 0.32 mmol), molecular mesh 3A, and AcOH (0.3 mL) were refluxed in dichloroethane (0.3 mL). ) under argon atmosphere for 2 hours. Sodium triacetoxyborohydride (0.07 g, 0.32 mmol) was added and the mixture was refluxed for 1 h, stirred at room temperature for 16 h. and diluted with CHCl ₃ , NH ₄ OH and NaHCO ₃ (5 mL each). Separated

310 layers, and the aqueous layer was extracted with CHCl3 (2 x 20 mL). The combined organic extracts were washed with water and saturated aqueous NaCl (2 x 5 mL), dried over MgSO filtered and concentrated to _4l. The residue was purified by preparative HPLC (gradient of aqueous MeOH with 0.1% TFA). The appropriate fractions were concentrated and the residue was evaporated from MeOH (1 mL) and 1N HCl (1 mL) 3 times. This residue was dissolved in water to give, after lyophilization, the compound of Example 354 (0.034 g, 29%) as a solid.

MS (M-H) - = 529.

Example 355

(R) -7-Chloro-2,3,4,5-tetrahydro-4 - [(dimethylamino) sulfonyl] -1 - [(1-methyl-1H-imidazol-5-yl) methyl] -3- (phenylmethyl) - 1H-1,4-benzodiazepine (monohydrochloride)

A. (R) -7-Chloro-2,3,4,5-tetrahydro-4 - [(dimethylamino) sulfonyl] -3 (phenylmethyl) -1H-1,4-benzodiazepine, Example 347, B (0.1) g, 0.36 mmol) and DIEA (0.095 mL, 0.54 mmol) in CH ₃ CN (2 mL) at 0 ° C under argon was added dropwise dimethylsulfamoyl chloride (0.058 mL, 0.54 mmol). 16 hours. warm slowly to room temperature and dilute with NaHCCb (3 mL) and CHCl3 (10 mL). The layers were separated and the aqueous layer was extracted with CHCl 3 (2 x 30 mL). The combined organic layers were washed with NaHCCb (1 x 10 mL), water (1 x 10 mL) and saturated aqueous NaCl (1 x 10 mL), dried over MgSO _4, filtered and concentrated to give an orange oil,

311 which was purified by flash column chromatography over silica gel (30% EtOAc / hexane); Compound A is obtained which is a clear oil (0.44 g, 32%). MS (M + H) ⁺ 380.

B. (R) -7-Chloro-2,3,4,5-tetrahydro-4 - [(dimethylamino) sulfonyl] -1 - [(1-methyl-1H-imidazol-5-yl) methyl] -3- ( phenylmethyl) -1H-1,4-benzodiazepine (monohydrochloride)

Compound B (white solid) is prepared in 52% yield from Compound A according to the procedure described in Example 353 for the preparation of Compound C by boiling under reflux for 4 hours. and purification by preparative HPLC only.

MS (M + H) &lt; ⁺ &gt; 474.

Example 356

CH ₃ (R) -7-Chloro-2,3,4,5-tetrahydro-1- (1-methylimidazol-5-ylmethyl) -4 - [(4-methylpiperidin-4-yl-ethyl) sulfonyl] -3- (phenylmethyl) -1H-1,4-benzodiazepine (dihydrochloride)

Example 356 Compound (yellowish solid) was prepared in 28% yield from Example 353 Compound A and 1-methylpiperazine according to the procedure for Example 353 in Compound B using 20% acetone in hexane followed by 10% methanol in CHCl ₃ and Example 353. the procedure for the preparation of compound C by purification only by preparative HPLC.

MS: (M + H) &lt; ⁺ &gt; = 557.

Example 357

312

(R) -7-Bromo-2,3,4,5-tetrahydro-1- (1-methylimidazol-5-ylmethyl) -4 - [(4-methylpiperidin-4-yl-ethyl) sulfonyl] -3 - (phenylmethyl) -1H-1,4-benzodiazepine (dihydrochloride)

Example 357 Compound (white solid) is prepared in 23% yield from Example 224 Compound B and 1-methylpiperazine according to the reaction sequence used to prepare the following compounds: Example 353 Compound A; Example 353, Compound B, chromatography using 9/1 CHCl ₃ / MeOH; Example 353 for compound C purification by preparative HPLC only.

MS: (M + H) <^+> = 601.

Example 358

(R) -7-Cyano-1,2,3,5-tetrahydro-1- (1H-imidazol-4-ylmethyl) -3- (phenylmethyl) -4H1,4-benzodiazepine-4-carboxylic acid isopropyl ester (hydrochloride)

Example 358 Compound (yellowish solid) is prepared in 42% yield from Example 248 Compound C according to the reaction sequence used

313 to afford the following compounds: Example 248 Compound E using isopropyl chloroformate in toluene and 40% hexane in EtOAc to give the free base: Example 354.

MS: (M + H) &lt; ⁺ &gt; = 430.

Example 359

(R) -7-Bromo-2,3,4,5-tetrahydro-4 - [[2- (1H-imidazol-1-yl) ethyl] sulfonyl] -1- (1H-imidazol-4-ylmethyl) -3- (phenylmethyl) -1H-1,4-benzodiazepine (dihydrochloride)

Example 359 Compound (yellowish solid) is prepared in 21% yield from Example 224 Compound B according to the reaction sequence used to prepare Example 353 Compound A: Example 353 Compound B using sodium imidazolate in 2: 1 THF.IPA solvent and chromatography using 10% EtOAc in CHCl ₃ followed by EtOAc; Example 353 Compound C with daily addition of aldehyde and hydride for 8 days without purification.

MS: (M + H) &lt; ⁺ &gt; = 557.

360 example

314

(R) -7-Cyano-2,3,4,5-tetrahydro-1- (1H-imidazol-4-ylmethyl) -4- (propylsulfonyl) 3- (3-pyridinylmethyl) -1H-1,4-benzodiazepine (hydrochloride)

Example 360 Compound (white solid) is prepared in 15% yield from propanesulfonyl chloride and Example 350 Compound B according to the procedure for Preparation C and D described in Example 350.

MS: (M + H) ⁺ 451.

Analysis calculated for C23H26N6O2S · 2.6 HCl 2.02 H ₂ O.

Found: C, 47.50; H, 5.65; N, 14.45.

Found: C, 47.50; H, 5.51; N, 14.10.

Example 361

7-Bromo-2,3,4,5-tetrahydro-1- (1H-imidazol-4-ylmethyl) -3- (phenylmethyl) -1H-1,4-benzodiazepin-5-one (hydrochloride)

A. 7-Bromo-2,3,4,5-tetrahydro-3- (phenylmethyl) -1H-1,4-benzodiazepin-5-one

To a suspension of 0.5 g (1.45 mmol) of Example 75 Compound A in 75 mL of THF at room temperature under argon is added 3 mL (3 mmol) of 1M

315 borane THF. Stir overnight, then add another 2 mL (2 mmol) of 1M borane in THF and stir for a further 8 h. After hydrolysis of the excess borane by dropwise addition of methanol, the reaction mixture is evaporated to dryness and the residue is dissolved in 0.5 ml methanol and 0.5 ml almost. HCl. The resulting solution was refluxed for 2 hours, cooled to room temperature and evaporated to dryness. The residue is evaporated from methanol three more times. The crude product is dissolved in ethyl acetate and the solution is washed with saturated NaCl solution, dried, and evaporated to give a viscous yellow oil which is purified by flash chromatography on silica gel (50% ethyl acetate in hexane) to give 205 mg (43%) of white solid. material.

B. 7-Bromo-2,3,4,5-tetrahydro-1- (1H-imidazol-4-ylmethyl) -3- (phenylmethyl) -1H-1,4-benzodiazepin-5-one (hydrochloride); To a suspension of mg (0.62 mmol) of Compound A in 10 mL of methylene chloride and 1 mL of acetic acid was added 120 mg (1.25 mmol) of 4-formylimidazole. The solution is stirred for 1 hour, 197 mg (0.93 mmol) of sodium triacetoxyborohydride are added and stirred overnight. Again 60 mg of 4-formylimidazole and 100 mg of sodium triacetoxyborohydride are added and stirring is continued for 4 hours. The reaction mixture is evaporated to dryness. The residue is diluted with methylene chloride and the solution is washed with a saturated solution of NaHCO ₃ and a saturated NaCl solution, dried (MgSO ₄ ), and evaporated to give a yellow foamy solid residue which is purified by preparative HPLC (aqueous methanol with 0.1% TFA gradient). Concentration of the appropriate fractions affords a clear oil residue which is converted to the HCl salt by treatment with HCl-MeOH; 187 mg (60%) of compound B is obtained which is an off-white solid.

MS: (M + H) ⁺ 411.

Analysis calculated for C ₂₀ Hi ₉ N ₄ OBr · 1.5 HCl · 0.5 C ₂ HwO.

Found: C, 52.53; H, 5.11; N, 11.14.

Found: C, 52.82; H, 4.71; N, 11.52.

Example 362

316

(R) -7-Bromo-2,3,4,5-tetrahydro-1- (1H-imidazol-1-ylacetyl) -4- (methylsulfonyl) 3- (phenylmethyl) -1H-1,4-benzodiazepine (trifluoroacetate) )

A. (R) -7-Bromo-2,3,4,5-tetrahydro-1- (chloroacetyl) -4- (methylsulfonyl) -3 (phenylmethyl) -1H-1,4-benzodiazepine

To a mixture of Example J 224 Compound C (2.0 g, 5.06 mmol) and DIEA (4.4 mL, 25 mmol) in dichloromethane (100 mL) was added chloroacetyl chloride (2.0 mL, 25.3 mmol) in an ice bath. . The mixture was stirred for 30 min, poured into aqueous sodium hydroxide (200 mL, 1N) and extracted with dichloromethane (2 x 100 mL). The organic layers were combined, washed with brine (200 mL) and water (200 mL), dried (MgSO ₄ ) and concentrated to an oil which was purified by flash chromatography (60 g silica gel, 3: 1 hexane: ethyl acetate) to give the title compound. A (760 mg, 1.62 mmol, 33%) which is a colorless oil.

B. (R) -7-Bromo-2,3,4,5-tetrahydro-1- (1H-imidazol-1-ylacetyl) -4- (methylsulfonyl) -3- (phenylmethyl) -1H-1,4- benzodiazepine (trifluoroacetate)

A mixture of Compound A (300 mg, 0.64 mmol), potassium carbonate (177 mg, 1.28 mmol) and imidazole (87 mg, 1.28 mmol) was stirred for 48 h. The mixture was poured into aqueous hydrochloric acid (200 mL, 1N) and ethyl acetate (200 mL), the layers were separated, and the aqueous layer was basified to pH 11 with solid sodium hydroxide. The alkaline aqueous solution was extracted with ethyl acetate (200 ml) and the organic extracts were combined, dried (Na2S _4), and concentrated to a semi-solid which was purified by preparative HPLC (aqueous methanol with 0.1% trifluoroacetic acid

317 gradient, C-18 column). After lyophilization, compound B is obtained which is a white solid (100 mg, 32%).

MS: (M + H) ⁺ 504.

Example 363

1,2,4,5-Tetrahydro-1- (1H-imidazol-4-ylmethyl) -2- (2-phenylethyl) -3H-1,4-benzodiazepin-3-one

A. 1,2,4,5-Tetrahydro-2- (2-phenylethyl) -3H-1,4-benzodiazepin-3-one

A stirred solution of N-Boc- (2-amino) benzylamine (1.0 g, 4.5 mmol) and ethyl 2-oxo-4-phenylbutyrate (1.0 mL, 5.3 mmol) in dichloroethane (20 mL) and acetic acid was added. of NaOH (OAc) _{3 was} added immediately at room temperature under argon. The mixture was stirred for 18 h, TFA (4 mL) was added and the mixture was heated at 60 ° C under argon for 2 h. The solvent was evaporated and the residue was dissolved in methanol (15 ml). The solution is cooled to 0 ° C and 10N NaOH is added to pH 11. The solution is stirred at room temperature for 18 hours. The solvent was evaporated and the residue partitioned between ethyl acetate and saturated NaHCO ₃ solution. The organic layer was separated, dried over MgSO _4, and concentrated in vacuo. Recrystallization of the residue from MeOH gives compound A (480 mg, 40%) as a white solid. Lyd. mp 147-148 ° C.

B. 1,2,4,5-Tetrahydro-1- (1H-imidazol-4-ylmethyl) -2- (2-phenylethyl) -3H-1,4-benzodiazepin-3-one

318

Compound B (white solid) is prepared from Compound A according to the procedure described in Example 1 for the preparation of Compound D.

MS: (M + H) &lt; ⁺ &gt; 347.

2,3,4,5-Tetrahydro-1- (1H-imidazol-4-ylmethyl) -4- (methylsulfonyl) -2- (2-phenylethyl) -1H-1,4-benzodiazepine (monohydrochloride)

A. 2,3,4,5-T tetrahydro-1- (1H-imidazol-4-ylmethyl) -2- (2-phenylethyl) -1H-1,4-benzodiazepine

To a stirred suspension of lithium aluminum hydride (160 mg) at room temperature under argon was added a solution of the free base (150 mg) of the compound of Example 363 in glime. The mixture was stirred at room temperature for 18 h, quenched with ethyl acetate (20 mL), followed by ammonium hydroxide (0.5 mL), stirred for 2 h. and filtered off. Concentration of the filtrate in vacuo afforded compound A as an oil.

B. 2,3,4,5-Tetrahydro-1- (1H-imidazol-4-ylmethyl) -4- (methylsulfonyl) -2- (2-phenylethyl) -1H-1,4-benzodiazepine (monohydrochloride), mixed with compound A (50 mg) in methylene chloride (5 mL) containing solid K ₂ CO _{3 was} added 100 μΙ of methanesulfonyl chloride at room temperature. The solution was stirred for 10 min, diluted with 10 mL of methanol followed by 1 mL of 10N NaOH solution, stirred for 2 h. and concentrated. The residue is partitioned between ethyl acetate and saturated NH ₄ Cl

319 of the solution. The organic layer was separated, dried over MgSO _4, and concentrated in vacuo. The residue is purified by column chromatography (ethyl acetate / methanol / NH ₄ OH; 10: 1: 0.1) to give an oil which is converted to its HCl salt as described in Example 1 for the preparation of compound D.

MS: (M + H) 411.

T \

Me (R) -2,3,4,5-Tetrahydro-1- (1H-imidazol-4-ylmethyl) -4- (methylsulfonyl) -7-phenyl-3 (4-pyridinylmethyl) -1H -1,4-benzodiazepine (dihydrochloride)

Example 365 Compound (yellowish solid) is prepared in 99% yield from Example 226 Compound B and D- (4-pyridyl) alanine according to the reaction sequence. used to prepare the following compounds: Compound C of Example 226; Example 226 for compound D; 264 for compound B; 264 for the compound of Example

D.

MS (M + H) &lt; ⁺ &gt; 474.

Example 366

320

(R) -2,3,4,5-Tetrahydro-1- (1H-imidazol-2-ylmethyl) -4- (phenylsulfonyl) -3 (phenylmethyl) -1H-1,4-benzodiazepine-7-carbonitrile (hydrochloride) )

Example 366 (yellow solid) is prepared in 95% yield from Example 312, Compound A and 2-formylimidazole according to the procedure described in Example 1 for the preparation of Compound D.

MS (M + H) &lt; ⁺ &gt; = 484.1.

Analysis calculated for C 27 H ₂₅ N ₅ O ₂ S · 0.6 H ₂ O · 1.1 HCl.

Found: C, 60.67; H, 5.15; N, 13.10; S, 5.99; Cl, 7.29.

Found: C, 60.34; H, 5.16: N, 12.81; S, 5.74. Cl, 7.46.

Example 367

(R) -7-Cyano-1,2,3,5-tetrahydro-1- (1H-imidazol-4-ylmethyl) -N, N-dimethyl-3- (3-pyridinylmethyl) -4H-1,4-benzodiazepine; 4-Carboxamide (dihydrochloride)

Example 367 Compound (solid) is prepared in 2% yield from Ν, Ν-dimethylcarbamoyl chloride and Example 350 Compound B as described

321 reaction sequences used to obtain these compounds; Example 350 for compound C, extracted with 10% isopropanol in methylene chloride; Example 350 for compound D, extracted with 10% isopropanol in methylene chloride, and lyophilized from 1N HCl / methanol.

HRMS: (M + H) ⁺ Calcd: 416.2198; found: 416.2211.

Example 368 CN

(R) -7-Cyano-1,2,3,5-tetrahydro-1- (1H-imidazol-4-ylmethyl) -N, N-dimethyl-3- (3-pyridinylmethyl) -4H-1,4-benzodiazepine; 4-sulfonamide (dihydrochloride)

Example 368 (solid) is prepared in 1% yield from Ν, Ν-dimethylsulfamoyl chloride and Example 350 Compound B according to the procedure described in Example 367.

HRMS: (M + H) ⁺ Calcd .: 452.1868; found: 452.1860.

Example 369

4 - [(4-Horophenyl) sulfonyl] -2,3,4,5-tetrahydro-1 - [(1-methyl-1H-imidazol-5-yl) -3 (phenylmethyl) -1H-thieno [2,3-e] -1,4-diazepine (monohydrochloride)

322

A. 2,3,4,5-Tetrahydro-3- (phenylmethyl) -1H-thieno [2,3-e] -1,4-diazepine-2,5dione

D, LN- (2-Cyano-1-oxoethyl) phenylalanine methyl ester (5.0 g, 20 mmol), dithiandiol (1.6 g, 10.5 mmol), piperidine (2.0 mL, 20.2) and a solution of TEA (2.8 mL, 20.2 mmol) in ethanol (30 mL) was refluxed for 3 h. and is suppressed. The residue is evaporated from toluene three times. The dry residue is dissolved in pyridine and pyridine chloride (2.0 g) is added. This solution was heated at 130 ° C under argon for 3 days and evaporated. The residue was dissolved in methylene chloride and the solution was washed with 1N HCl (2 x 100 mL). The organic layer was dried and concentrated in vacuo. The residue was triturated with ether to give Compound A as a brown solid (2.0 g, 40%). Lyd. mp: 268-270 ° C.

B. 2,3,4,5-Tetrahydro-3- (phenylmethyl) -1H-thieno [2,3-e] -1,4-diazepine in a stirred suspension of lithium aluminum hydride (400 mg) at room temperature under argon of Compound A (500 mg, 2.05 mmol) was added portionwise. The resulting suspension was refluxed for 3 days, cooled to 0 ° C, and the excess LAH was decomposed by slow addition of ethyl acetate. NH ₄ OH solution (1 mL) was added, the resulting suspension was filtered and the filter cake washed with ethyl acetate. The filtrate is concentrated in vacuo. The residue is triturated with ether to give the compound

B, which is a brown solid (220 mg). Lyd. m.p. 139-141 ° C.

MS: (M + H) &lt; ⁺ &gt; 245.

C. 4 - [(4-Fluorophenyl) sulfonyl] -2,3,4,5-tetrahydro-3- (phenylmethyl) -1H-thieno [2,3-e] -1,4-diazepine

To a stirred solution of Compound B (150 mg, 0.6 mmol) in methylene chloride with saturated NaHCO 3 solution was added 4-fluorobenzenesulfonyl chloride (300 mg, 1.55 mmol). The mixture was stirred at room temperature for 18 hours. and diluted with methanol. 10N NaOH is added and the mixture is stirred for 2 hours. Concentrated NH ₄ OH is added and the mixture is stirred for 18 hours. and concentrated

323 in a vacuum. The residue is partitioned between ethyl acetate and saturated NaHCCb. The organic layer was separated, dried over MgSO _4, and concentrated in vacuo.

Chromatographic purification of the residue (1: 4, ethyl acetate and hexanes) affords compound C which is an oil (120 mg, 50%).

D. 4 - [(4-Fluorophenyl) sulfonyl] -2,3,4,5-tetrahydro-1 - [(1-methyl-1H-imidazol-5-yl) -3- (phenylmethyl) -1H-thieno [2, 3-e] -1,4-diazepine (monohydrochloride)

Compound D (solid) is prepared in 48% yield from Compound C and 1-methyl-5-formylimidazole according to the procedure for Compound D described in Example 224.

MS (M + H) &lt; ⁺ &gt; 497.

Example 370

(R) -2,3,4,5-Tetrahydro-1- (1- (4-cyanophenylmethyl) -imidazol-5-ylmethyl) -4- (methylsulfonyl) -3- (phenylmethyl) -1H-1,4-benzodiazepine -7-carbonitrile (hydrochloride)

A. (R) -2,3,4,5-Tetrahydro-1- (1- (triphenylmethyl) -imidazol-4-ylmethyl) -4- (methylsulfonyl) -3- (phenylmethyl) -1H-1,4-benzodiazepine -7-Carbonitrile To a solution of 1.2 g (2.85 mmol) of the free base of Example 225 in 20 mL of acetonitrile at room temperature under argon was added 1.2 mL (8.55 mmol) of TEA followed by 1.2 g (4 , 3 mmol) triphenylmethyl chloride. Stir overnight. The resulting cloudy solution is evaporated to dryness and the residue is purified by flash chromatography over 100 cm ^{3 of} silica gel.

324 column (50% ethyl acetate in hexane). 1.2 g (64%) of viscous white foam A are obtained.

B. (R) -2,3,4,5-Tetrahydro-1- (1- (4-cyanophenylmethyl) -imidazol-5-ylmethyl) -4- (methylsulfonyl) -3- (phenylmethyl) -1H-1,4 benzodiazepine-7-carbonitrile (hydrochloride)

A solution of 200 mg (0.3 mmol) of Compound A and 59 mg (0.3 mmol) of 4-cyanobenzyl bromide in 0.5 mL of DMF was heated at 100 ° C under argon for 10 h. The reaction mixture was diluted with methylene chloride and 0.1 mL of triethylsilane was added followed by 0.5 mL of TFA. The mixture is stirred for 1 hour and evaporation gives a yellow viscous oil which is mixed with a material obtained in a similar reaction; Flash chromatography on silica gel (2% methanol in chloroform) gives 76 mg of a viscous yellow-brown foam. A second flash chromatography (1% methanol in chloroform followed by 3% methanol in chloroform) yields 53 mg of free base of Compound B as a white solid foam. To a solution of 50 mg of the free base in ethyl acetate is added 90 μΙ of 1M HCl in ether. The resulting white precipitate was filtered off and dried to give 43 mg (0.07 mmol) of Compound B as a white solid.

Analysis calculated for C ₂ H _{2 8} N ₅ O ₂ S · HCl · H ₂ O.

Found: C, 60.96; H, 5.29; N, 14.22.

Found: C, 61.11; H, 5.10; N, 14.07.

MS (M + H) <^+> = 537.

Example 371

325

(R) -2,3,4,5-Tetrahydro-1- (1- (4-cyanophenylmethyl) imidazol-4-ylmethyl) -4- (methylsulfonyl) -3- (phenylmethyl) -1H-1,4- benzodiazepine-7-carbonitrile (hydrochloride)

A. (R) -2,3,4,5-Tetrahydro-1- (1 - ((1,1-dimethyl) ethoxycarbonyl) imidazol-4-ylmethyl) -4- (methylsulfonyl) -3- (phenylmethyl) -1H -1,4-benzodiazepine-7-carbonitrile

To a solution of 250 mg (0.53 mmol) of the free base of Example 225 and 0.6 mg (0.005 mmol) of DMAP in 2 mL of methylene chloride was added a solution of 144 mg (0.66 mmol) of BOC anhydride in 2 mL of methylene chloride at room temperature. Stir in 1 or. The crude reaction mixture was purified by flash chromatography on a 50 cm ³ silica gel column (45% ethyl acetate in hexane) to afford 307 mg (about 100%) of solid A as a white foam.

B. (R) -2,3,4,5-Tetrahydro-1- (1- (4-cyanophenylmethyl) -imidazol-4-ylmethyl) -4 (methylsulfonyl) -3- (phenylmethyl) -1H-1,4 Benzodiazepine-7-carbonitrile (hydrochloride) A solution of mg (0.115 mmol) of compound A and 23 mg (0.115 mmol) of 4-cyanobenzyl bromide in 1 mL of DMF was heated at 100 ° C under argon for 10 h. and then evaporated. The residue was diluted with methylene chloride and saturated NaHCO ₃ and stirred for 0.5 h. The organic layer was separated, dried (MgSO ₄ ) and evaporated to give a clear colorless glassy residue. This impure product is purified

326 was subjected to flash chromatography on a 25 cm ³ silica gel column (1% methanol in chloroform followed by 3% methanol in chloroform) to give 6 mg of a free base of solid white foam Compound B in 100 µl of 1M HCl in a minimum amount of ethyl acetate. . The resulting white precipitate was filtered off and dried to give 4.5 mg (7%) of Compound B as a white solid.

MS: (M + H) &lt; ⁺ &gt; 537.

Example 372

NC

HN (R) -4-Benzoyl-7-cyano-2,3,4,5-tetrahydro-1- (1H-imidazol-4-ylmethyl) -3- (phenylmethyl) -1H-1,4-benzodiazepine (monohydrochloride) )

A. (R) -4-Benzoyl-7-cyano-2,3,4,5-tetrahydro-3- (phenylmethyl) -1H-1,4-benzodiazepine, Example 248, Compound C and DIEA (0.32 mL, 1, A solution of 99 mmol) in dichloromethane (3 mL) at 0 ° C under argon was added benzoyl chloride (2.2 mL, 1.9 mmol). The solution is slowly warmed to room temperature. After 15 is 30 or. 0.5 equivalents of benzoyl chloride and DIEA are added. After stirring for 2 days, the mixture was diluted with chloroform (20 mL) and NaHCO ₃ (5 mL). The layers were separated and the aqueous layer was extracted with chloroform (2 x 15 mL). The combined organic extracts were washed with NaHCO ₃ (2 x 5 mL), water (1 x 10 mL), and saturated NaCl solution (2 x 10 mL), dried over MgSO ₄ , filtered and concentrated. The residue was purified by flash column chromatography eluting with 20% and 30% EtOAc in hexane to give Compound A as a yellow oil (0.21 g, 77%).

327

MS (M + H) ⁺ 368.

B. (R) -4-Benzoyl-7-cyano-2,3,4,5-tetrahydro-1- (1H-imidazol-4-ylmethyl) -3- (phenylmethyl) -1H-1,4 benzodiazepine (monohydrochloride)

A mixture of compound A (0.1 g, 0.27 mmol), 4-formylimidazole (0.039 g, 0.40 mmol) and AcOH (0.3 mL) in toluene (1.0 mL) and 3 A molecular mesh was refluxed refrigerator for 15 hours. Sodium triacetoxyborohydride (0.086 g, 0.4 mmol) is added and the mixture is refluxed for 8 hours, cooled to room temperature and stirred for 15 hours. Another equivalent of aldehyde is added, the solution is stirred for 30 min, another equivalent of hydride is added and the solution is stirred for 16 hours. Again, one equivalent of aldehyde and hydride was added as above, the mixture was stirred for 4 h, diluted with CHCl ₃ (10 mL), NH ₄ OH (5 mL) and NaHCO ₃ (5 mL) and stirred for 10 min. The layers were separated and the aqueous layer was extracted with CHCl ₃ (3 x 30 mL). The combined organic extracts were washed with NaHCO ₃ , water, and brine ( ₂ x ₁₀ mL), dried over MgSO ₄ , filtered, and concentrated. The product was purified by preparative HPLC (gradient of aqueous MeOH with 0.1% TFA). The appropriate fractions are concentrated in vacuo. The residue was evaporated from methanol (1 mL) and 1N HCl (1 mL) three times. This residue was dissolved in water to give, after lyophilization, Compound B as a yellowish solid (36 mg, 30%).

MS (M + H) <^+> = 448.

Example 373

CN

O

II

328 (R) -7-Cyano-2,3,4,5-tetrahydro-1 - [(1-methyl-1H-imidazol-5-yl) methyl] -3- (pyridyl) -3-methyl ) -4- (Methylsulfonyl) -1H-1,4-benzodiazepine (dihydrochloride)

Example 373 Compound (solid) is prepared in 13% yield from Example 350 Compound B according to the procedures described in Example 350 for the preparation of Compound C and Example 350 using 1-methyl-5-formylimidazole.

MS: (M + H) ⁺ 437

Analysis calculated for C ₂₂ H ₂₄ N _s O ₂ S · 2 HCl · 2.1 H ₂ O.

Found: C, 48.28; H, 5.56; N, 15.36.

Found: C, 48.28; H, 5.42; N, 15.45.

Example 374 CN

Me (R) -7-Cyano-2,3,4,5-tetrahydro-1 - [(1-methyl-1H-imidazol-5-yl) methyl] -3- (pyridin-3-ylmethyl) -4- ( propylsulfonyl) -1H-1,4-benzodiazepine (trihydrochloride)

Example 374 (solid) is prepared in 11% yield from propanesulfonyl chloride according to the procedure described in Example 373.

MS: (M + H) ⁺ 465.

Analysis calculated for C24H28N6O2S · HCl 3 - 0.26 H ₂ O.

Found: C, 49.82; H, 5.49; N, 14.52.

Found: C, 49.81; H, 5.37; N, 14.58.

329

Example 375

(R) -7-Cyano-2,3,4,5-tetrahydro-1 - [(1H-imidazol-4-yl) methyl] -3- (pyridin-3-ylmethyl) -4- (phenylsulfonyl) -1H-1 , 4-benzodiazepine (dihydrochloride)

Example 375 Compound (solid) is prepared in 2% yield from Example 350 Compound B according to the procedure described in Example 350 for the preparation of Compound C using benzenesulfonyl chloride and Example 350 for the preparation of Compound D.

MS: (M + H) &lt; ⁺ &gt; 485.

2,3,4,5-Tetrahydro-1- (1H-imidazol-4-ylmethyl) -4- (methylsulfonyl) -7-phenyl-3 (phenylmethyl) -1H-1,4-benzodiazepine

A. 2,3,4,5-Tetrahydro-7-phenyl-3- (phenylmethyl) -1H-1,4-benzodiazepine

A solution of phenylbutyric acid (153 mg in 5 ml absolute ethanol) was added to a mixture of 330 to 75 compound B (200 mg, 0.63 mmol) in toluene (20 ml) and aqueous sodium bicarbonate (10 ml, saturated solution) under argon. Tetrakis (triphenyphosphine) palladium (O) (36 mg) is added, the solution is refluxed (~ 80 ° C) for 18 hours, cooled to room temperature and partitioned between aqueous sodium hydroxide (100 mL, 3N) and ethyl acetate (100 mL). . The mixture is extracted with ethyl acetate (2 x 200 mL), the organic layers are combined, dried (MgSO ₄ ) and concentrated in vacuo to a crude oil which is purified by flash chromatography (silica gel, 10: 0.5: 0.05 ethyl acetate: methanol: ammonium hydroxide). . Compound A (90 mg, 45%) is obtained, which is a waxy solid.

B. 2,3,4,5-Tetrahydro-1- (1H-imidazol-4-ylmethyl) -4- (methylsulfonyl) -7-phenyl-3 '(phenylmethyl) -1H-1,4-benzodiazepine

Compound B (white solid) is prepared in 40% yield from Compound A according to the reaction sequence described for the following compounds: Example 78 Compound A with stirring for 18 hours. and by non-chromatography; Example 78 for compound B.

MS: (M + H) ⁺ 473.

The analysis was based on Ο ₂₇ Η ₂₈ Ν ₄ Ο ₂ · 0.5 H ₂ O · 0.8 TFA.

Found: C, 59.97; H, 5.24; N, 9.78; S, 5.60; F, 7.96.

Found: C, 59.94; H, 4.87; N, 8.21; S, 4.48. F, 7.86.

Example 377

331

1,2,3,5-Tetrahydro-1- (1H-imidazol-4-ylmethyl) -N- (1-naphthalenyl) -7-phenyl-4H-1,4-benzodiazepine-4-carboxamide (monohydrochloride)

A. 1,2,3,5-Tetrahydro-N- (1-naphthalenyl) -7-phenyl-4H-1,4-benzodiazepine-4-carboxamide

To a solution of 1-naphthylisocyanate (116 mg, 0.66 mmol) in 3 mL of dry CH ₂ Cl _{2 under} argon was added Example 12 Compound B (148 mg, 0.66 mmol) and stir for 16 h. and concentrating to give crude compound A (267 mg).

B. 1,2,3,5-Tetrahydro-1- (1H-imidazol-4-ylmethyl) -N- (1-naphthalenyl) -7-phenyl-4H-1,4-benzodiazepine-4-carboxamide (monohydrochloride)

Compound B (mild pink solid) is prepared in 46% yield from Compound A according to the procedure described in Example 1 for the preparation of Compound D. Lyd. mp 170-177 ° C (dec.).

MS: (M + H) 474.

Analysis calculated for C 30 H ₂₇ N ₅ O · 1.2 HCl · 0.6 H ₂ O · 0.25 Et ₂ O Calculated: C, 68.11; H, 5.88; N, 12.81; Cl, 7.78.

Found: C, 68.02; H, 5.92; N, 12.61; Cl, 7.75.

Example 378

332

(S) -7-Bromo-2,3,4,5-tetrahydro-1- (1H-imidazol-4-ylmethyl) -4- (methylsulfonyl) -3 (phenylmethyl) -1H-1,4-benzodiazepine ( hydrochloride) of the free base (100 mg, 0.31 mmol) of the sample compound in isopropanol (5 mL) was purified using chiral phase preparative HPLC (chiralpak AD column, Chiral Technologies Ine. (50mm x 500mm), 25:75): 0.1 isopropanol: hexane: triethylamine, flow rate 55 ml / min) to give isomer A at 36 min. retention time (18 mg, 13%, free base of Example 378), and isomer B at 54 min. for detention time. The hydrochloride is prepared according to the procedure for the preparation of compound D as described in Example 224.

MS: (M + H) ⁺ 476.

Analysis calculated for C ₂ i H _{2 3} N ₄ O ₂ SBr · 1.2 H ₂ O · 0.7 HCl.

Found: C, 47.43; H, 4.85; N, 10.54; S, 6.03; Br, 15.03; Cl, 8.00.

Found: C, 47.71; H, 4.66; N, 9.71; S, 5.59; Br, 12.54; Cl, 8.14.

Example 379

333

N- [2,3,4,5-Tetrahydro-1- (1H-imidazol-4-ylmethyl) -4- (2,3-dimethylbenzoyl) -1H1,4-benzodiazepin-8-yl] cyclohexanecarboxamide (dihydrochloride)

A. 8-Nitro-2,3,4,5-tetrahydro-4-Fmoc-1H-1,4-benzodiazepine

To a solution of compound D dihydrochloride (15.0 g, 56.4 mmol) and DIEA (19.6 mL, 113 mmol) in dichloromethane (100 mL) at -10 ° C was added FmocOSu (19.0 g, 56.4) mmol). The mixture was stirred at 0 ° C for 2 h, digested with 10% NaHCO 3 (100 mL) and extracted with CH ₂ Cl ₂ (2 x 100 mL). The combined organic extracts were washed with 1N HCl (2 x 100 mL). The organic fraction was washed with 10% NaHCO ₃ (2 x 100 mL), dried (MgSO ₄ ), filtered and concentrated in vacuo. The residue was triturated with ether and dried in vacuo to give Compound A as a white solid (15.6 g, 67%). MS: (M + H) &lt; ⁺ &gt; 416.

B. 8-Nitro-2,3,4,5-tetrahydro-1- (1H-imidazol-4-ylmethyl) -4-Fmoc-1H-1,4-benzodiazepine

To a solution of compound A (15.5 g, 37.3 mmol) in 1/1 CH ₂ Cl ₂ / AcOH (200 mL) with 4A molecular mesh (6 gm) was added 4-formylimidazole (7.16 g, 74.6 mmol). . The mixture was stirred at room temperature for 2 hours. Installed in 15 minutes sodium triacetoxyborohydride (11.9 g, 56 mmol) was added and the resulting solution was stirred for 3 h. 4-Formylimidazole (1.10 g, 11.5 mmol) was added and the mixture was stirred for 1 h. Installed in 15 minutes sodium triacetoxyborohydride (2.39 g, 11.3 mmol) was added and the resulting solution was stirred for 16 h. The mixture was filtered and the filtrate concentrated in vacuo. The residue is dissolved

334

CH 2 Cl 2 (100 mL) and decomposed with 10% NaHCO ₃ (200 mL). The organic fraction was separated and the aqueous layer was extracted with CH ₂ Cl ₂ (2 x 100 mL). The combined organic fractions were dried (MgSO ₄ ), filtered and concentrated in vacuo. The residue is purified by silica gel chromatography (eluting with CH ₂ Cl ₂ , discarding all fractions, and expelling the product from the column 9/1 CHCl ₃ / MeOH). Compound B (17.6 g, 95%) is obtained as a glassy solid. (M + H) ⁺ 496.

C. N- [2,3,4,5-Tetrahydro-1- (1H-imidazol-4-ylmethyl) -4- (2,3-dimethylbenzoyl) -1H-1,4-benzodiazepin-8-yl] cyclohexanecarboxamide (dihydrochloride) )

A solution of Compound B (12.0 g, 24.2 mmol) in DCE (70 mL) was charged into a 2-chlorotriethylchloride polystyrene resin (13.9 g, 24.2 mmol, 1.74 mmol / g) in a glass shaker flask, Advanced Chem Tech) which was swelled with DCE (50 mL) at room temperature. DIEA (4.19 ml,

24.2 mmol) and the mixture is shaken at room temperature for 72 hours. The resin was filtered off and washed with DCE (4 x 50 mL). The resin was washed with MeOH (4 x 50 mL), filtered, and dried in vacuo to give Compound B as an orange granule, bound to the resin via the imidazole group (23.1 g, 89%; load 0.90 mmol / g by nitrogen assay). This dose (23.1 g, 23.1 mmol) was swelled in DMF (50 mL) for 15 min. Piperidine (50 mL) is added, the mixture is foamed for 5 h, filtered, rinsed with DMF (50 mL) and filtered. DMF (50 mL) was added and the mixture was shaken for 15 min. Add piperidine (50 mL) and shake for 5 h. The resin was filtered off, washed and filtered through successive DMF (3 x 50 mL), CH ₂ Cl ₂ (3 x 50 mL), and MeOH (3 x 80 mL) solutions for 15 minutes to equilibrate the resin. . Drying of the resin in vacuo afforded an orange granular deblocked bond to the resin (18.2 g 80%, load 1.17 mmol / g, according to nitrogen analysis). The resin is packed into 25 ml Varian Bont Elut Reservoir tubes connected to a 20 mM Varian frit and a stopcock with a polypropylene tip. The tube is connected to Vac Elut SPS24 on the Innova 2000 Platform Shaker. The resin is swollen with CH ₂ CI ₂

335 (2 mi) 15 min. To the resin was added a solution of 2,3-dimethylbenzoic acid in 0.77 M DMF (1.25 mL). to this resin mixture was added 0.92 M HOAT solution in DMF (1.04 mL) and 0.46 M DIC in CH ₂ Cl ₂ (2.08 mL). The platform shaker solid-state reaction is stirred at @ 285 RPM for 16 h. The mixture in the tube is filtered and the resin is washed and filtered by successive addition of DMF (3 x 5 mL), CH ₂ Cl ₂ (3 x 5 mL) and MeOH (3 x 5 mL) with the resin maintained for 15 min to equilibrate. . The resin was swelled again with CH ₂ Cl ₂ (2 mL) for 15 min. 0.77 M solution of 2,3-dimethylbenzoic acid in DMF (1.25 ml) was added to the resin. to this resin mixture was added 0.92 M HOAT solution in DMF (1.04 mL) and 0.46 M DIC in CH ₂ Cl ₂ (2.08 mL). The platform shaker solid-state reaction is stirred at @ 285 RPM for 16 h. The mixture in the tube was filtered and the resin was washed and filtered by successive addition of DMF (3x5 mL), CH ₂ Cl ₂ (3x5 mL), and MeOH (4x5 mL), with the resin held for 15 min to equilibrate. This sequence of operations yields N4-acylated resin-bound material for use in the subsequent step. This resin was swelled with 1/1 DMF / CH ₂ Cl ₂ (2 mL) for 15 min. To the resin mixture was added a solution of 0.23 M SnCl _{2 -} 2H ₂ O (0.222 g, 0.97 mmol) and a solution of TEA (0.672 mL, 4.83 mmol) in CH ₂ Cl ₂ (4 mL). The resin mixture is shaken for 16 hours. The mixture in the tube is filtered off, and the resin is washed and filtered by successive addition of DMF (3 x 5 mL), CH ₂ Cl ₂ (3 x 5 mL) and MeOH (3 x 5 mL), maintaining the resin for 15 min to equilibrate. . This resin is swelled with 1/1 DMF / CH ₂ Cl ₂ (2 mL) for 15 min and the entire procedure of this step is repeated twice. This sequence of operations yields an 8-amino-containing resin-bound material for use in the subsequent step. This resin was swelled in CH ₂ Cl ₂ (2 mL) for 15 min. To the resin was added 0.77 M solution of cyclohexylcarboxylic acid in DMF (1.25 mL). 0.92 M HOAT solution in DMF (1.04 mL) and 0.46 M DIC in CH ₂ Cl ₂ (2.08 mL) are added. The platform shaker solid-state reaction is stirred at @ 285 RPM for 16 h. The mixture in the tube is filtered off and the resin is washed and filtered by successive addition of DMF (3x5 mL), CH ₂ Cl ₂ (3x5 mL) and MeOH (3x5 mL), each resin being maintained for 15 min to equilibrate. This resin was swelled again with CH ₂ Cl ₂ (2 mL) for 15 min. To the resin was added 0.77 M solution of cyclohexylcarboxylic acid in DMF (1.25 mL).

336

0.92 M HOAT solution in DMF (1.04 mL) and 0.46 M DIC in CH ₂ Cl ₂ (2.08 mL) are added. The platform shaker solid-state reaction is stirred at @ 285 RPM for 16 h. The mixture in the tube is filtered off and the resin is washed and filtered by successive addition of DMF (3x5 mL), CH ₂ Cl ₂ (3x5 mL) and MeOH (3x5 mL), each resin being maintained for 15 min to equilibrate. This sequence of operations yields an 8-acylated resin-bound material for use in the subsequent step. The resin was swelled with CH ₂ Cl ₂ (4 mL) for 15 min. Triethylsilane (0.51 mL, 3.2 mmol, 10 equiv) is added. The resin mixture is treated with TFA (4 mL) and the reaction mixture is shaken for 1 h. The filtrate is collected by vacuum filtration. The resin was swelled again with CH ₂ Cl ₂ (4 mL) for 15 min. Triethylsilane (0.51 mL, 3.2 mmol, 10 equiv) is added. The resin mixture is treated with TFA (4 mL) and the reaction mixture is shaken for 1 h. The filtrate is collected by vacuum filtration. The residue was purified by preparative HPLC (gradient of aqueous methanol with 0.1% TFA), the required fractions were collected and concentrated in vacuo. The residue was dissolved in CH ₃ CN (2 mL), treated with 1N HCl (1 mL), and concentrated in vacuo four times. This residue was dissolved in CH ₃ CN (2 mL), treated with 1N HCl (1 mL), and lyophilized to give Example 379 (0.0075 g, 4% overall yield) as a glassy solid.

MS (M + H) &lt; ⁺ &gt; 486.

Me

Example 380 NC

337 (R) -7-Cyano-N- [2- (dimethylamino) ethyl] -2,3,4,5-tetrahydro-1- (1H-imidazol-4-ylmethyl) -N-methyl-3- (phenylmethyl) - 1H-1,4-Benzodiazepine-4-carboxamide (Trifluoroacetate, 1: 2)

A. (R) -7-Cyano-2,3,4,5-tetrahydro-4- (4-nitrophenyloxycarbonyl) -3 (phenylmethyl) -1H-1,4-benzodiazepine

To a solution of compound C (200 mg, 0.76 mmol) in Example 248 in THF (20 mL) under argon was added 4-nitrophenyl chloroformate (0.88 mL, 0.76 mmol). The solution was stirred for 8 h, poured into aqueous hydrochloric acid (150 mL, 1N), extracted with ethyl acetate (2 x 150 mL), dried (MgSO ₄ ), and concentrated to an oil which was purified by flash chromatography (50 g silica gel, 2: 1 hexane: ethyl acetate) to give Compound A (230 mg, 70%) as a clear oil.

B. (R) -7-Cyano-N- [2- (dimethylamino) ethyl] -2,3,4,5-tetrahydro-N-methyl-3 (phenylmethyl) -1H-1,4- benzodiazepine-4-carboxamide

A solution of Compound A (110 mg, 0.26 mmol) in Ν, Ν, Ν'-trimethylethylenediamine (2 mL) was heated in an airtight pressure tube at 110 ° C for 18 h. After cooling to room temperature, the solution was poured into aqueous sodium hydroxide (100 mL, 1N), extracted with ethyl acetate (2 x 150 mL), dried (MgSO ₄ ), and concentrated in vacuo to give crude paste compound B (> 100% yield).

C. (R) -7-Cyano-N- [2- (dimethylamino) ethyl] -2,3,4,5-tetrahydro-1- (1H-imidazol-4-ylmethyl) -N-methyl-3- (phenylmethyl) -1H-1,4-benzodiazepine-4-carboxamide (trifluoroacetate, 1: 2)

A solution of compound B (140 mg, 0.35 mmol) and 4-formylimidazole (68 mg, 0.7 mmol) in dichloroethane (2 mL) and acetic acid (2 mL) was stirred at room temperature for 30 min and sodium triacetoxyborohydride (150 mL) was added. mg, 0.7 mmol). The solution is heated to 60 ° C, stirred for 18 hours, and additional portions of 4-formylimidazole and sodium triacetoxyborohydride (0.2 mmol, 4 portions over 8 hours) are added; the mixture was diluted with ethyl acetate (20 mL) and

338 ammonium hydroxide (5 mL, almost) and stirred for a further 30 min. This mixture was extracted with ethyl acetate (2 x 25 mL), the combined organic extracts washed with aqueous sodium bicarbonate (25 mL, saturated solution), followed by ammonium chloride (25 mL, saturated aqueous solution), dried (Na ₂ SO ₄ ) and concentrated in vacuo. to semi-solids. This crude material was purified by preparative HPLC (gradient from aqueous methanol to 0.1% TFA, C-18 column) to give, after lyophilization, Compound C as a white solid (80 mg, 48%).

MS: (M + H) ⁺ 471.

Analysis calculated for C ₂₇ H ₃₃ N ₇ O · 1.1 H ₂ O · 2.1 TFA.

Found: C, 51.27: H, 5.14; N, 13.42; F, 16.38.

Found: C, 51.60; H, 4.93; N, 13.47; F, 16.28.

Example 381

7-Bromo-2,3,4,5-tetrahydro-1- (1H-imidazol-4-ylmethyl) -4- (methylsulfonyl) -2-oxo-3- (phenylmethyl) -1H-1,4-benzodiazepine (trifluoroacetate)

A. N - ((2-Nitrophenyl) methyl) phenylalanine methyl ester To a solution of 2-nitrobenzaldehyde (5 g, 33 mmol) in acetic acid (150 mL) was added D, L-phenylalanine O-methyl ester (8.54 g, 40 mL). mmol) followed by sodium acetate (3.5 g, 43 mmol). Sodium triacetoxyborohydride (9.09 g, 43 mmol) was added slowly, and the mixture was heated at 80 ° C for 4 h, cooled to room temperature, concentrated in vacuo to a paste (<20 mL) and dissolved in ethyl acetate (100 mL). The solution is neutralized with saturated sodium

339 carbonate and extracted with ethyl acetate (3 x 200 mL). The combined organic layers were dried (MgSO ₄ ) and concentrated to give Compound A as a brown oil (11.25 g,> 100%).

B. N - ((2-Nitrophenyl) methyl) -N- (methanesilophonyl) -phenylalanine methyl ester into a solution of compound A (1.12 g, 3.5 mmol) in pyridine (10 mL) in an ice bath under argon slowly methanesulfonyl chloride (1.08 mL, 14.0 mmol) was added. The solution was warmed to room temperature, poured into aqueous hydrochloric acid (250 mL, 1N), extracted with ethyl acetate (2 x 200 mL), and the combined organic layers were dried (MgSO ₄ ) and concentrated. Purification of the resulting oil by flash chromatography (4: 1 hexane: ethyl acetate) gave compound B (660 mg, 48%) as a clear oil.

C. N - ((2-Aminophenyl) methyl) -N- (methanesulfonyl) -phenylalanine methyl ester

A mixture of Compound B (660 mg, 1.68 mmol), tin (II) chloride (1.52 g, 6.7 mmol), and ethyl acetate (75 mL) was stirred at room temperature for 18 h, then quenched with aqueous and then solid potassium carbonate (5 mL, followed by 5 g). The mixture was filtered, the filtrate extracted, the organic phase dried (MgSO ₄ ), concentrated in vacuo and purified by flash chromatography (3: 1 hexane: ethyl acetate). The compound C (315 mg, 52%) is obtained which is a clear oil.

D. N - ((2-Amino-5-bromophenyl) methyl) -N- (methanesulfonyl) -phenylalanine methyl ester

Compound D (white solid) is prepared in 60% yield from Compound C according to the procedure for Compound A described in Example 262, except that the compound is purified by recrystallization from methanol.

E. N - [[2- (Imidazol-4-yl) methyl) -amino) -phenyl] -methyl] -N- (methanesulfonyl) phenylalanine methyl ester

340

Compound E (semi-solid) is prepared in 100% yield from Compound D according to the procedure described in Example 1 for the preparation of Compound D, with stirring for 4 hours, and the crude free base is further used.

F. N - [[2- (Imidazol-4-yl) methyl) -amino) -phenyl] -methyl] -N- (methanesulfonyl) phenylalanine

A solution of E (200 mg, 0.38 mmol) and LiOH (80 mg, 2 mmol) in THF (6 mL), methanol (1 mL), and water (1 mL) was stirred at room temperature for 1 h and concentrated in vacuo to 2 mL. and poured into aqueous hydrochloric acid (20 mL). The mixture was extracted with ethyl acetate (2 x 50 mL), the combined organic layers dried (MgSO ₄ ) and concentrated to give compound F (150 mg, 78%) as a clear oil.

G. 7-Bromo-2,3,4,5-tetrahydro-1- (1H-imidazol-4-ylmethyl) -4- (methylsulfonyl) -2-oxo-3- (phenylmethyl) -1H-1,4- benzodiazepine (trifluoroacetate)

A mixture of compound F (150 mg, 0.29 mmol), DMF (3 mL), DIEA (0.66 mL, 0.725 mmol) and BOP (193 mg, 0.43 mmol) was stirred at room temperature for 3 h. The mixture was partitioned between sodium carbonate (100 mL, saturated solution) and ethyl acetate (100 mL), the aqueous phase was extracted with ethyl acetate (2 x 50 mL), and the combined organic layers were dried (MgSO ₄ ) and concentrated. The residue was purified by preparative HPLC (gradient of aqueous methanol with 0.1% trifluoroacetic acid, C-18 column) to give, after lyophilization, Compound G as a white solid (65 mg, 46%).

MS: (M + H) &lt; ⁺ &gt; 490.

Analysis calculated for C2iH ₂ IN ₄ O ₃ -1.1 SBR H ₂ O · 1.0 TFA.

Found: C, 44.33; H, 3.91; N, 8.99; S, 5.14; Br, 12.82.

Found: C, 44.29; H, 3.59; N, 8.74; S, 5.05; Br, 12.78.

Example 382

341

(R) -7-Cyano-4- (2-furanylcarbonyl) -2,3,4,5-tetrahydro-1- (1H-imidazol-4-ylmethyl) -3- (phenylmethyl) -1H-1,4-benzodiazepine ( trifluoroacetate, 1: 1)

A. (R) -7-Cyano-4- (2-furanylcarbonyl) -2,3,4,5-tetrahydro-3- (phenylmethyl) -1H-1,4-benzodiazepine

Compound A (oil) is prepared in 100% yield from Compound C of Example 248 and furan-2-carboxylic acid according to the procedure described in Example 381 for the preparation of Compound G, with stirring for 18 hours, without treatment with citric acid.

B. (R) -7-Cyano-4- (2-furanylcarbonyl) -2,3,4,5-tetrahydro-1- (1H-imidazol-4-ylmethyl) -3- (phenylmethyl) -1H-1,4- benzodiazepine (trifluoroacetate, 1: 1)

Compound B (white solid) is prepared in 7% yield from Compound A according to the procedure described in Example 380 for the preparation of Compound C.

MS: (M + H) &lt; ⁺ &gt; 438.

Analysis calculated for C26H23N5O2 · 2.0 H ₂ O · 1.0 TFA.

Found: C, 57.24; H, 4.80; N, 11.92.

Found: C, 57.22; H, 4.26; N, 11.74.

Example 383

342

(R) -7-Cyano-2,3,4,5-tetrahydro-1- (1H-imidazol-4-ylmethyl) -4 - [(4-nitrophenyl) with If on] -3- (Phenyl) I Methyl) -1H-1,4-benzodiazepine (trifluoroacetate)

Example 383 (white solid) is prepared in 3% yield from 4-nitrobenzenesulfonyl chloride and Example 248 Compound C according to the reaction sequence used to prepare the following compounds: Example 350 Compound C except that the reaction is carried out at room temperature and is not purified; 380 for compound C.

MS: (M + H) &lt; ⁺ &gt; 529.

Example 384

343 (R) -7-Cyano-2,3,4,5-tetrahydro-1- (1H-imidazol-4-ylmethyl) -4 - [[4- (4-methyl-1-piperazinyl) phenyl] sulfonyl] - 3- (Phenylmethyl) -1H-1,4-benzodiazepine (trifluoroacetate)

A. (R) -7-Cyano-2,3,4,5-tetrahydro-4 - [[(4-methyl-1-piperazinyl) phenyl] sulfonyl] -3- (phenylmethyl) -1H-1,4-benzodiazepine) (R) -7-Cyano-2,3,4,5-tetrahydro-4 - [(4-fluorophenyl) sulfonyl] -3- (phenylmethyl) -1H1,4-benzodiazepine (200 mg, 0.48 mmol, as described in Example 291) and DMF (2 mL) was added to the mixture with N-methylpiperazine (2 mL). The solution was heated at 110 ° C and stirred for 6 h, poured into aqueous hydrochloric acid (150 mL, 1M) and extracted with ethyl acetate (2 x 100 mL). The organic layers were combined, dried (MgSO ₄ ), concentrated, and recrystallized from dichloromethane to give Compound A (50 mg, 21%) as a gray solid.

B. (R) -7-Cyano-2,3,4,5-tetrahydro-1- (1H-imidazol-4-ylmethyl) -4 - [[(4-methyl-1-piperazinyl) phenyl] sulfonyl] -3- (phenylmethyl) -1H-1,4-benzodiazepine (trifluoroacetate)

Compound B (white solid) is prepared in 65% yield from Compound A according to the procedure described in Example 380 for the preparation of Compound C with stirring at room temperature.

MS: (M + H) ⁺ 581.

Analysis calculated for C32H35N7O3S · 2.0 H ₂ O · 2.0 TFA.

Found: C, 51.12; H, 4.89; N, 11.59; S, 3.79.

Found: C, 50.83; H, 4.68; N, 11.43; S, 4.47.

Example 385

344

CN

Me

A k,

Me

N ^ 1 v

(R) -7-Cyano-2,3,4,5-tetrahydro-1- (1H-imidazol-4-ylmethyl) -4 - [[(4-dimethylamino) phenyl] sulfonyl] -3- (phenylmethyl) -1H -1,4-benzodiazepine (trifluoroacetate)

A. (R) -7-Cyano-2,3,4,5-tetrahydro-4 - [[(4-dimethylamino) phenyl] sulfonyl] -3 (phenylmethyl) -1H-1,4-benzodiazepine (R) - 7-Cyano-2,3,4,5-tetrahydro-4 - [(4-fluorophenyl) sulfonyl] -3 (phenylmethyl) -1H-1,4-benzodiazepine (200 mg, 0.48 mmol, prepared as (Example 291)) The solution was stirred in dimethylamine (2 mL, 2M THF) in a sealed pressure tube at 60 ° C for 24 h. Dimethylamine (4 mL, 2M THF) was added again and the solution stirred for a further 6 h. The reaction mixture was concentrated in vacuo to a paste residue and recrystallized from methanol to give Compound A (50 mg, 25%) as a gray solid.

B. (R) -7-Cyano-2,3,4,5-tetrahydro-1- (1H-imidazol-4-ylmethyl) -4 - [[4- (4-dimethylamino) phenyl] sulfonyl] -3- (phenylmethyl) ) -1H-1,4-benzodiazepine (trifluoroacetate)

Compound B (byte solid) is prepared in 43% yield from Compound A according to the procedure for Compound C described in Example 380.

Analysis calculated for C 29 H ₃₀ N ₆ O ₂ S · 1.3 H ₂ O · 0.9 TFA.

Found: C, 56.68; H, 5.17; N, 12.88; S, 4.91; F, 7.80.

Found: C, 56.36; H, 5.07; N, 12.51; S, 5.39; F, 7.78.

345

Example 386

(R) -7-Bromo-4 - [[2- (dimethylamino) ethyl] sulfonyl] -2,3,4,5-tetrahydro-1- (1H-imidazol-4-ylmethyl) -3- (phenylmethyl) -4H- 1,4-Benzodiazepine (dihydrochloride)

A. (R) -7-Bromo-4- [ethenylsulfonyl] -2,3,4,5-tetrahydro-3- (phenylmethyl) -4H1,4-benzodiazepine | A solution of Example 224 Compound B (10 g, 31.5 mmol) in dichloromethane (120 mL) at 0 ° C was added dropwise to a solution of 2-chloro-ethanesulfonyl chloride (3.2 mL, 30 mmol) in dichloromethane (10 mL). DIEA (5.2 mL, 30 mmol) was added dropwise. After 15 minutes 2-chloro-ethanesulfonyl chloride (1.5 mL, 15 mmol) was added followed by DIEA (10.4 mL, 60 mmol). The mixture was allowed to warm to room temperature and then poured into water (80 ml). The organic layer was separated, washed with 1N HCl and saturated aqueous NaHCO ₃ (80 mL each), dried (MgSO ₄ ), and concentrated in vacuo to give yellowish foam compound A (15.2 g). MS: (M + H) &lt; ⁺ &gt; = 406 ⁺ .

B. Compound (R) -7-Bromo-4 - [[2- (dimethylamino) ethyl] sulfonyl] -2,3,4,5-tetrahydro-3 (phenylmethyl) -4H-1,4-benzodiazepine A (7 g) and add a solution of dimethylamine

THF (2M, 20 mL). Stopper the flask, stir for 18 hours, concentrate and purify by silica gel column chromatography,

346 eluted with 20% acetone in chloroform afforded Compound B (48% based on Example 224 Compound B).

C. (R) -7-Bromo-4 - [[2- (dimethylamino) ethyl] sulfonyl] -2,3,4,5-tetrahydro-1- (1H-imidazol-4-ylmethyl) -3- (phenylmethyl) -4H-1,4'-benzodiazepine (dihydrochloride)

To a solution of Compound B (5.3 g, 11.7 mmol) in dichloromethane (100 mL) was added acetic acid (15 mL) and 4-formylimidazole (1.15 g, 12 mmol). After 10 minutes. sodium triacetoxyborohydride (2.54 g, 12 mmol) was added. After 3 or. 4-formylimidazole (0.5 g, 5.8 mmol) and borohydride (1.2 g, 5.5 mmol) were added. After 5 or. the mixture is concentrated. To the residue was added aqueous ammonia (100 mL) and chloroform (100 mL) and the mixture was stirred vigorously for 0.5 h. The two layers were separated and the organic layer was washed again with aqueous ammonia (100 mL). The combined aqueous layers were extracted with chloroform (100 mL), the two organic extracts were combined, dried (K ₂ CO ₃ ) and concentrated. Purification of the residue by flash column chromatography on silica gel (5% and 10% MeOH in chloroform gradient) gave a solid which was dissolved in dichloromethane (50 mL) and bubbled with HCl gas. Concentration in vacuo gave a solid which was dissolved in water to give compound C (5.2 g, 73%) after lyophilization.

MS: (M + H) &lt; ⁺ &gt; 532.

Analysis calculated for C ₂₄ H ₃₀ BrN ₅ O ₂ S · 2 HCl.

Found: C, 47.61; H, 5.33; N, 11.57.

Found: C, 47.36; H, 5.45; N, 11.34.

Example 387

347

(R) -7-Cyano-2,3,4,5-tetrahydro-1- (1H-imidazol-4-ylmethyl) -3- (phenylmethyl) -4- (3-pyridinyl) -1H -1,4-benzodiazepine (trihydrochloride)

Example 387 (yellow solid) is prepared in 15% yield from Example 248, C and 3-pyridinesulfonyl chloride according to the procedure described in Example 284.

MS: (M + H) &lt; ⁺ &gt; 485.

2,3,4,5-Tetrahydro-1- (1H-imidazol-4-ylmethyl) -4- (methylsulfonyl) -3- (phenylmethyl) -1H-1,4-benzodiazepine (dihydrochloride) and the free compound of Example 224. base (0.104 g, 0.19 mmol)

BuLi (1.0 M in THF, 5 mmol) was added in THF (10 mL) at -78 ° C. After 5 minutes H ₂ O / THF (1: 1, 10 mL) was added. The solution is saturated with NaCl.

The aqueous layer was extracted with CH2Cl2. Mixed organic phases

348 dried Na ₂ SO ₄ . Evaporation of the solvent affords a solid which is purified by reverse phase preparative HPLC (gradient from aqueous methanol with 0.1% TFA) to the HCl salt to give 25 mg (30%) of Example 388 as a yellow solid.

MS: (M + H) &lt; ⁺ &gt; 397.

Example 389

(R) -7-Bromo-2,3,4,5-tetrahydro-1 - [(1-methyl-1H-imidazol-4-yl) methyl] -4- (methylsulfonyl) -3- (phenylmethyl) -1H- 1,4-Benzodiazepine (dihydrochloride) To a solution of the free base of the compound of Example 224 (0.23 g, 0.19 mmol) in DMF / THF (1: 1.10 mL) at -10 ° C was added NaH (60% in mineral oil, 1 g). After 20 minutes Mel (0.7 mL) was added. The mixture was stirred at -5 ° C for 1 h, quenched with MeOH (5 mL) and diluted with CH ₂ Cl ₂ (20 mL). The organic phase was washed with 2.5% NaOH. The organic phase is dried over Na ₂ SO ₄ . Evaporation of the solvent gives a solid which is purified by reverse phase preparative HPLC (gradient of aqueous methanol with 0.1% TFA) followed by preparative TLC (8% MeOH, 2% iPr ₂ NH CH ₂ Cl ₂ ) to give a solid. 10 mg (10%) of the compound of Example 389 which is a white solid.

MS: (M + H) &lt; ⁺ &gt; 491.

Example 390

349

Ph

A

N \

_z Me

Me (R) -4 - [(3- (Dimethylamino) propyl] sulfonyl] -2,3,4,5-tetrahydro-1- (1H-imidazol-4-ylmethyl) -7-phenyl-3- (phenylmethyl) -1 H-1,4-benzodiazepine (dihydrochloride)

A. (R) -4- [13-Chloropropyl] sulfonyl] -2,3,4,5-tetrahydro-7-phenyl-3 (phenylmethyl) -1H-1,4-benzodiazepine

A solution of compound D (4.7 g, 15 mmol) and DIEA (7 mL, 40 mmol) in Example J 226 in CK ₂ Cl ₂ (40 mL) at 0 ° C was slowly added a solution of 3-chloropropanesulfonyl chloride (2 mL, 16 mmol) in CH ₂ Cl _{2. 2} (5 mL). After 2 or. the solvent is evaporated. The residue was dissolved in CH ₂ Cl ₂ (20 mL), washed with 1N NaOH (2 x 50 mL), dried, and evaporated to give the title compound as an oil (5.5 g).

B. (R) -4 - [[3-Chloropropyl] sulfonyl] -2,3,4,5-tetrahydro-1- (1H-imidazol-4-ylmethyl) -7-phenyl-3- (phenylmethyl) -1H-1 , 4-Benzodiazepine

A solution of compound A (5.5 g) and 4-formylimidazole (3 g, 30 mmol) in AcOH / CH ₂ Cl ₂ (1: 5, 300 mL) was stirred for 1 h. NaBH (OAc) ₃ (9 g, 42 mmol) (3 g every 4 ') was added and the solution was stirred for 12 h. The solvent was evaporated and the residue was treated with 3% NaOH (50 mL). The solid was filtered off, washed with water (5 x 100 mL) and dried to give Compound B (7.5 g).

C. (R) -4 - [[3- (Dimethylamino) propyl] sulfonyl] -2,3,4,5-tetrahydro-1- (1H-imidazol-4-ylmethyl) -7-phenyl-3- (phenylmethyl) ) -1H-1,4-benzodiazepine (dihydrochloride)

350

A solution of compound B (7 g) and dimethylamine (2.0 M in THF, 75 mL, 150 mmol) in DMF (150 mL) was heated (in a sealed tube) at 80 ° C for 30 h. DMF is evaporated. The residue was passed through a short silica gel column (5% MeOH, 0.5% NH ₄ OH CH ₂ Cl 2). Evaporation of the eluent and purification of the residue by reverse phase preparative HPLC (gradient of aqueous methanol with 0.1% TFA) to the HCl salt afforded Compound C, which was an off-white solid (5.0 g, 60% based on 226). Example D).

MS: (M + H) &lt; ⁺ &gt; 544.

¹ H-NMR (CD 3 OD, 300 MHz) δ: 1.80 (m, 2H), 2.8 (m, 2H), 3.0 (m, 4H), 3.20 (m, 2H), 3, 60 (m, 2H), 4.30 (m, 1H), 4.6 (m, 2H), 6.8 (d, 7Hz, 1H), 7.1-7.6 (m, 13H, 8 , 92 (s, 1H).

Example 391

(R) -7-Cyano-2,3,4,5-tetrahydro-1- (1H-imidazol-4-ylmethyl) -3- (phenylmethyl) -1H1,4-benzodiazepine (trihydrochloride)

The compound of Example 391 is the compound of Example 280.

MS (M + H + 244).

Example 392

351

CN

Me

4-Butyl-2,3,4,5-tetrahydro-1- (1H-imidazol-4-ylmethyl) -3- (phenylmethyl) -1H-1,4-benzodiazepine (trihydrochloride)

A solution of Example 391 (0.23 g, 0.7 mmol) and butter aldehyde (1 g, 14 mmol) in 1: 4 AcOH / CH ₂ Cl ₂ (25 mL) was stirred at room temperature for 1 h. NaBH (OAc) ₃ (3.0 g, 14 mmol) was added and stirred for 14 h. The reaction is stopped almost. NH ₄ OH, and the mixture was diluted with 10% iPrOH in CH ₂ Cl ₂ (50 mL). The organic phase is washed with 1N NaOH (2 x 20 mL), dried over Na ₂ SO ₄ and evaporated to give a yellow solid (0.4 g) which is purified by reverse phase preparative HPLC (gradient of aqueous methanol with 0.1% TFA). Conversion of the HCl salt to lyophilization with 1N HCl gave Example 392 as a yellow solid (45 mg, 12%).

MS (M + H) &lt; ⁺ &gt; 400.

Example 393

352 (R) -7-Bromo-2,3,4,5-tetrahydro-1- (1H-imidazol-4-ylmethyl) -4 - [[2- (4-morpholinyl) ethyl] sulfonyl] -3- (phenylmethyl) -1H-1,4-benzodiazepine (dihydrochloride)

A. (R) -7-Bromo-2,3,4,5-tetrahydro-4 - [[2- (4-morpholinyl) ethyl] sulfonyl] -3 (phenylmethyl) -1H-1,4-benzodiazepine

A solution of compound A of Example J 386 (0.23 g, 0.34 mmol, 61% purity) in THF (1.5 mL) was added at room temperature with morpholine (0.2 mL). The mixture was stirred for 16 h, diluted with ethyl acetate (15 mL), washed with water and brine (15 mL each), dried and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel eluting with 20% acetone in chloroform to give Compound A as a white solid (130 mg, 77%).

B. (R) -7-Bromo-2,3,4,5-tetrahydro-1- (1H-imidazol-4-ylmethyl) -4 - [[2- (4-morpholinyl) ethyl] sulfonyl] -3- (phenylmethyl) ) -1H-1,4-benzodiazepine (dihydrochloride)

A mixture of compound A (0.060 g, 0.12 mmol), 4-formylimidazole (0.011 g, 0.12 mmol), 3A molecular weight grids, and AcOH (0.2 mL) in dichloroethane (0.3 mL) was stirred at room temperature under argon. After 2 or. sodium triacetoxyborohydride (0.025 g, 0.12 mmol) was added. After stirring for 16 h, the mixture was diluted with CHCl ₃ (10 mL), NH ₄ OH (5 mL) and NaHCO ₃ (5 mL) and stirred for 30 min. The layers were separated and the aqueous layer was extracted with CHCl 3 (2 x 20 mL). The combined organic extracts were washed with NaHCCb, water, and saturated aqueous NaCl (3 x 10 mL), dried over MgSO _4, filtered and concentrated. The residue was purified by reverse phase preparative HPLC (gradient of aqueous methanol with 0.1% TFA). The appropriate fractions are concentrated in vacuo. The residue was evaporated from MeOH (1 mL) and 1N HCl (1 mL) 3 times. This residue was dissolved in water and lyophilized to give Compound B as a yellow solid (0.019 g, 28%).

MS (M + H) ⁺ 574.

353

Example 394

(R) -7-Bromo-2,3,4,5-tetrahydro-1 - [(1-methyl-1H-imidazol-5-yl) methyl] -4 - [[2- (4-morpholinyl) ethyl] sulfonyl] -3- (phenylmethyl) -1H-1,4-benzodiazepine (dihydrochloride)

Example 394 Compound (yellowish solid) was prepared in 23% yield from Example 393 Compound A and N-methyl-5-formylimidazole according to the procedure described in Example 393 for the preparation of Compound B by stirring and refluxing for 7 hours. before adding the hydride, cooling to room temperature, adding the hydride and stirring for 16 hours with the addition of the hydride.

MS (M + H) ⁺ 588,

(R) -7-Cyano-2,3,4,5-tetrahydro-1- (1H-imidazol-4-ylmethyl) -4- (4-morpholinylsulfonyl) -3- (phenylmethyl) -1H-1,4-benzodiazepine (monohydrochloride)

354

A. (R) -7-Cyano-2,3,4,5-tetrahydro-4- (4-morpholinylsulfonyl) -3- (phenylmethyl) -1H-1,4-benzodiazepine

A solution of Compound C (263 mg, 1 mmol) in Example 248 in acetonitrile (2 mL) at room temperature under argon was added morpholine sulfamoyl chloride (371 mg, 2 mmol) and DIEA (0.35 mL, 2 mmol). The resulting brown mixture was stirred for 65 h, concentrated, and the residue partitioned between 1N HCl and chloroform (10 mL each). The organic layer was separated, washed with saturated NaHCO ₃ , dried (MgSO ₄ ), and concentrated. The residue was purified by flash column chromatography on silica gel eluting with a gradient gradient of 40% and 50% EtOAc in hexanes to afford Compound A (95 mg, 71%) as a yellowish solid.

MS (M + H) <^+> = 413.

B. (R) -7-Cyano-2,3,4,5-tetrahydro-1- (1H-imidazol-4-ylmethyl) -4- (4-morolinylsulfonyl) -3- (phenylmethyl) -1H-1,4 benzodiazepine (monohydrochloride)

To a solution of Compound A (206 mg, 0.5 mmol) in 1,2-dichloroethane (2 mL) at room temperature under argon was added 4-formylimidazole (380 mg, 4 mmol), HOAc (0.5 mL), and 3A molar mesh. The mixture was warmed to 50 ° C and sodium triacetoxyborohydride (330 mg, 1.5 mmol) was added. After 18 or. additional hydride (212 mg, 1 mmol) was added. 5 more hours. the mixture was cooled to room temperature, filtered through celite and carefully treated with 30% NH ₄ OH (10 mL) and chloroform (10 mL). The mixture was stirred vigorously for 1 h., The organic layer was separated and washed with 15% ammonia solution (15 ml), dried (K2CO _3), and concentrated. The resulting brown oil was purified by chromatography on a silica gel column eluting with 5% MeOH in chloroform to give Compound B free base (150 mg, 61%) as a white solid. 26 mg of this material is treated with 1N HCl in ether and concentrated under vacuum to give Compound B (28 mg).

MS (M + H) <^+> = 493; (MH) '= 491.

355

Example 396

(R) -7-Cyano-2,3,4,5-tetrahydro-1 - [(1-methyl-1H-imidazol-5-yl) methyl] -4 - [(4-morpholinyl) sulfonyl] -3- (phenylmethyl) ) -1H-1,4-benzodiazepine (monohydrochloride)

A. (R) -7-Cyano-2,3,4,5-tetrahydro-1 - [(1-triphenylmethyl-1H-imidazol-4-yl) methyl] -4 - [(4-morpholinyl) sulfonyl] -3- (phenylmethyl) -1H-1,4-benzodiazepine To a solution of the free base of Example 395 (120 mg, 0.24 mmol) in acetonitrile (2 mL) at room temperature under argon was added triphenylmethyl chloride (83 mg, 0.3 mmol) and DIEA ( 0.053 mL, 0.3 mmol). The mixture was refluxed for 4 hours, cooled to room temperature, and concentrated. The residue was dissolved in chloroform (15 mL) and the solution was washed with water and saturated NaHCO ₃ (15 mL each). The organic layer was dried (MgSO ₄ ) and concentrated. The residue was washed with warm hexanes (2 x 5 mL) to give Compound A (178 mg, 100%) as a yellowish solid.

B. (R) -7-Cyano-2,3,4,5-tetrahydro-1 - [(1-methyl-1H-imidazol-5-yl) methyl] -4 - [(4-morpholinyl) sulfonyl] -3 - (phenylmethyl) -1H-1,4-benzodiazepine (monohydrochloride)

To a solution of Compound A (170 mg, 0.23 mmol) in dichloromethane (2 mL) at -78 ° C under argon was added methyl triflate (0.027 mL, 0.24 mmol). After 1 or. replace the cooling bath with an ice bath (0 ° C). After 2 or. 50% aqueous acetic acid (2 ml) is added and the mixture is refluxed

356 under reflux for 40 min. Chloroform and saturated NaHCO3 (10 mL each) are added and the mixture is stirred gently until gas evolution is reduced. Carefully add solid K ₂ CO ₃ until the aqueous layer has a pH of 11. The organic layer is separated, dried (K ₂ CO ₃ ) and concentrated in vacuo. The solid residue was washed with warm hexanes and ether (2 x 10 mL each). The solid was dissolved in EtOAc (5 mL) and added with 1N HCl in ether (2 mL). The precipitate was filtered off and washed with EtOAc (3x5 mL). Drying this solid in vacuo at 40 ° C gave compound B as a yellowish solid (110 mg, 84%).

MS: (M + H) &lt; ⁺ &gt; = 507.

Analysis calculated for C ₂₆ H ₃₀ N ₆ O ₃ S · 1.7 HCl.

Found: C, 54.75; H, 5.61; N, 14.73.

Found: C, 55.15; H, 5.68; N, 14.29.

Example 397

CN (R) -7-Cyano-2,3,4,5-tetrahydro-1- (1H-imidazol-4-ylmethyl) -4 - [(4aminophenyl) sulfonyl] -3- (phenylmethyl) -1H-1, 4-Benzodiazepine (hydrochloride)

To a stirred solution of the free base (5 mg) of the compound of Example 383 in ethyl acetate was added SnCl ₂ . The solution was stirred at room temperature for 18 hours. Adds ΝΗ ₄ ΟΗ followed by MgSO ₄ . The suspension is filtered off and the filtrate is concentrated in vacuo. The residue was dissolved in methanol and 1N was added

357

HCl in ether. Evaporation of the solvent afforded 2.0 mg (40%) of Example 397 as a yellow solid.

Example 398

2,3,4,5-Tetrahydro-1- (1H-imidazo-4-methylmethyl) -4 - [(4-pyridylthio) acetyl] -7-phenyl-1H-1,4-benzodiazepine (dihydrochloride)

Example 398 is prepared from Example 33 by Compound B according to the procedures described in Examples 101-201.

MS (M + H) ⁺ 456.

N

N- (4-Chlorophenyl) -N'-cyano-1,2,3,5-tetrahydro-1- (1H-imidazol-4-ylmethyl) -7-phenyl-4H-1,4-benzodiazepine-4-imidamine (monohydrochloride) )

358

A. N '(4-Chlorophenyl) -N'-cyano-1,2,3,5-tetrahydro-7-phenyl-4H-1,4-benzodiazepine-4-imidamine in Example 12 Compound B (110 mg, 0, To a solution of 5 mmol) in DMF was added N- (4-chlorophenyl) -N'-cyanocarbamide (130 mg, 0.62 mmol) followed by EDC (120 mg, 0.61 mmol). The solution was stirred at room temperature for 18 hours. and partitioned between ethyl acetate and saturated NH ₄ Cl solution. The organic layer was separated, washed with saturated NaHCO ₃ solution and saturated NaCl solution, dried and concentrated. Recrystallization of the residue from MeOH gives Compound A as a solid (150 mg, 75%). MS: 402 (M + H) @ +.

B. N- (4-Chlorophenyl) -N'-cyano-1,2,3,5-tetrahydro-1- (1H-imidazol-4-ylmethyl) -7-phenyl-4H-1,4-benzodiazepine-4-imidamine (monohydrochloride)

Compound B (solid) is prepared in 78% yield from Compound A according to the procedure for Compound D described in Example 1.

MS: 482 (M + H) @ +.

Analysis calculated for C ₂₇ H ₂₃ N 7 Cl · 2.2 HCl · 2 H ₂ O

Found: C, 54.30; H, 4.93; N, 16.42; Cl, 18.99.

Found: C, 54.57; H, 4.90; N, 16.76; Cl, 18.90.

Example 400

4-Acetyl-7-bromo-1,2,4,5,1'-hexahydro-1- (1H-imidazol-4-ylmethyl) spiro [3H-1,4-benzodiazepine-3,2 '- [2H] indene] (dihydrochloride)

359

A. N - [(2-Amino-5-bromophenyl) carbonyl] -2-amino-2-indanoic acid

A solution of 2-amino-2-indanecarboxylic acid (680 mg, 4.15 mmol), bromoacetic anhydride (1.0 g, 4.15 mmol) and pyridine-HCl (2.0 g, 1.72 mmol) in pyridine (30 ml) is refluxed for 4 hours, cooled and concentrated. The residue was partitioned between water (200 mL) and ethyl acetate (200 mL). The organic layer was washed with water (3 x 100 mL), brine (50 mL), dried (MgSO ₄ ), and concentrated to give a yellowish glassy compound A (350 mg, 22%). MS (M + H) &lt; ⁺ &gt; 375.

B. 7-Bromo-1,2,4,5,1 ', 3'-hexahydro-spiro [3H-1,4-benzodiazepine-2,5dione-3,2' - [2H] indene]

A solution of compound A (350 mg, 0.93 mmol), EDC (203 mg, 1.02 mmol), DIEA (0.35 mL, 2.00 mmol) and HOBt (135 mg, 1.00 mmol) in DMF (10 ml) is stirred for 16 hours, then added to water (100 ml). The mixture was extracted with ethyl acetate (2 x 50 mL). The combined ethyl acetate layers were washed with water (3 x 100 mL), brine (100 mL), dried (MgSO ₄ ), and concentrated to give a brown glass compound B (150 mg, 45%). MS (M + H) &lt; ⁺ &gt; 358.

C. 7-Bromo-1,2,4,5,1 ', 3'-hexahydro-spiro [3H-1,4-benzodiazepine-3,2' [2H] indene]

To a solution of compound B (150 mg, 0.42 mmol) in THF (10 mL) was added borane (1M THF, 3 mL, 3 mmol). The solution is refluxed for 3 hours. and cooled to room temperature. Methanol (5 mL) was added and the solution concentrated. 5N HCl (10 mL) was added, the mixture was refluxed for 4 h, cooled to room temperature, neutralized to pH 6 with 50% NaOH and extracted with methylene chloride (3 x 50 mL). The combined organic layers were washed with saturated NaCl solution (30 mL), dried (MgSO ₄ ), and concentrated to give yellowish glass compound C (70 mg, 50%). MS (M + H) ⁺ 330.

360

D. 4-Acetyl-7-bromo-1,2,4,5,1 ', 3'-hexahydro-spiro [3H-1,4-benzodiazepine-3,2' - [2H] indene]

Compound C (70 mg, 0.21 mmol) was dissolved in THF (5 mL) and DIEA (37 μΙ, 0.21 mmol) was added followed by acetyl chloride (15 μΙ, 0.21 mmol). The solution was stirred for 30 min, concentrated, and the residue was dissolved in ethyl acetate (50 mL) and washed with water (3 x 20 mL). The organic layer was dried (MgSO ₄ ) and concentrated to give brownish compound D.

E. 4-Acetyl-7-bromo-1,2,4,5,1'-hexahydro-1- (1H-imidazol-4-ylmethyl) spiro [3H-1,4-benzodiazepine-3,2 '- [ 2H] indene] (dihydrochloride)

Compound D and 4-formylimidazole were dissolved in 1,2-DCE (5 mL) and acetic acid (0.5 mL) was added followed by sodium triacetoxyborohydride. The mixture was stirred at 50 ° C for 2 h and saturated NaHCO ₃ (5 mL) was added. The mixture was concentrated and the residue partitioned between water (20 mL) and ethyl acetate (20 mL). The organic layer was washed with water (10 mL), brine (10 mL), dried (MgSO ₄ ), concentrated, and the residue was purified by reverse phase preparative HPLC (gradient of aqueous methanol with 0.1% TFA). The fractions containing the desired product are mixed by concentration and lyophilized. The lyophilisate was dissolved in methanol (0.5 mL) and 1N HCl (5 mL). This mixture is concentrated and lyophilized. Repeating this procedure gives compound E, which is a white solid (12 mg, 13%).

MS: (M + H) ⁺ 451.

Example 401

361

7-Bromo-4- [3- (dimethylamino) -1-oxopropyl] -2,3,4,5-tetrahydro-1- (1H-imidazol-4-ylmethyl) -3- (phenylmethyl) -1H-1,4 benzodiazepine (trifluoroacetate, 1: 1)

Example 401 (white solid) is prepared in a total 6% yield from Example 224 by Compound B according to the following reaction sequence: EDC / HOBt-mediated copolymerization of acrylic acid in DMF by flash chromatography; the reaction used to yield Example 232, Compound D; reaction used to obtain Example 224, Compound D.

MS: (M + H) ⁺ 466.

Example 402

(R) -2,3,4,5-Tetrahydro-1- (1-methyl-1H-imidazol-5-ylmethyl) -4- (phenylsulfonyl) -3 (phenylmethyl) -1H-1,4-benzodiazepine 7-carbonitrile (monohydrochloride)

362 (R) -7-Cyano-2,3,4,5-tetrahydro-1 - [(((1,1-dimethylethoxy) carbonyl) -1Himidazol-4-yl) methyl] -4- (phenylsulfonyl) - Solution of 3- (phenylmethyl) -1H-1,4-benzodiazepine (0.23 g, 0.4 mmol, prepared from Example 312 according to the procedure for the preparation of Compound A in Example 234) CH ₂ Cl ₂ (3 mL) -78 At 30 ° C for 30 min. Pour into a cooled solution of methyl triflate (2 mL, 17.6 mmol) in CH ₂ Cl ₂ (10 mL). Solutions within 4 or. slowly warm to 0 ° C. PBS buffer (10 mL) was added and stirred for 20 min. The organic phase is separated. The aqueous layer was extracted with CH ₂ Cl ₂ (2 x 10 mL). The combined organic layers were dried over Na ₂ SO ₄ and evaporated to an oil, which was purified by reverse phase preparative HPLC (gradient from aqueous methanol to 0.1% TFA) and converted to the HCl salt to give Example 402 as a yellow solid (60 mg). , 28%).

MS (M + H) &lt; ⁺ &gt; 498.

2,3,4,5-Tetrahydro-1 - [(1-methyl-1H-imidazol-5-yl) methyl] -4- (methylsulfonyl) -7-phenyl-3- (pyridin-3-ylmethyl) -1H -1,4-benzodiazepine (hydrochloride, 1: 1.5, and trifluoroacetate, 1: 0.75, salt) to 2,3,4,5-tetrahydro-4- (methylsulfonyl) -7-phenyl - 3- (Pyridin-3-ylmethyl) -1H-1,4-benzodiazepine (0.11 g, 0.27 mmol, prepared as described in 328).

In Example 363) with 3 A molecular mesh (50 mg), a solution of 1/1 DCE in acetic acid (1.8 mL) was added 1-methyl-5-formylimidazole (0.060 g, 0.54 mmol) and the mixture was stirred at 70 ° C. At C for 1 h, sodium triacetoxyborohydride (0.057 g, 0.27 mmol) was added and the mixture was stirred at 70 for 30 min. To the mixture was added 1-methyl-5-formylimidazole (0.060 g, 0.54 mmol), and the mixture was stirred at 70 ° C for 1 h. Sodium triacetoxyborohydride (0.057 g, 0.27 mmol) was added and the mixture was stirred at 70 ° C for 30 min. The latter procedure is repeated. The mixture was cooled to room temperature, diluted with methylene chloride (10 mL), filtered, and the filtrate concentrated in vacuo. The residue was diluted with 1N NaOH (10 mL) and stirred at room temperature for 10 min. The solution was extracted with CH 2 Cl 2 (3 x 50 mL), the combined organic extracts dried (Na ₂ SO ₄ ), filtered and concentrated in vacuo. The residue is purified by preparative HPLC (gradient of aqueous MeOH with 0.1% TFA), the appropriate fractions selected and concentrated in vacuo. The residue was evaporated from CH ₃ CN (5 mL) and 1N HCl (1 mL) 3 times. This residue was dissolved in CH ₃ CN (1 mL) and ΊN HCl (2 mL) and lyophilized to give Example 403 (0.025 g, 19%) as a white solid.

MS: (M + H) &lt; ⁺ &gt; 488.

Analysis calculated for C ₂₇ H ₂₉ N ₅ O ₂ S 1.5 HCl · 2.02 H ₂ O · 0.75 TFA. Found: C, 51.54; H, 5.36; N, 10.54.

Found: C, 51.27; H, 5.72; N, 10.95.

Example 404

364

4- [4- (Fluorophenyl) sulfonyl] -2,3,4,5-tetrahydro-1- (1H-imidazol-4-ylmethyl) -2- (2-phenylethyl) -1H-1,4-benzodiazepine (monohydrochloride)

Example 404 Compound (Solid) 41% yield is prepared from Example 364 Compound A and 4-Fluorobenzenesulfonyl chloride according to the procedure described in Example 364 for the preparation of Compound B.

MS: (M + H) &lt; ⁺ &gt; 491.

Example 405

Br

7-Bromo-2,3,4,5-tetrahydro-1- (1H-imidazol-4-ylmethyl) -4- (methylsulfonyl) -2- (2-phenylethyl) -1H-1,4-benzodiazepine (monohydrochloride)

A. 2,3,4,5-Tetrahydro-2- (2-phenylethyl) -1H-1,4-benzodiazepine is added to a stirred solution of Example 363 Compound A (140 mg, 0.52 mmol) in anhydrous THF at room temperature. (110 mg). The resulting suspension was stirred at room temperature for 18 hours, quenched by addition of ethyl acetate, followed by 0.5 ml. NH ₄ OH solution and filter. Concentration of the filtrate in vacuo afforded Compound A as an oil (110 mg, 84%).

B. 2,3,4,5-Tetrahydro-4- (methylsulfonyl) -2- (2-phenylethyl) -1H-1,4-benzodiazepine

365

Compound B (oil) is prepared in 61% yield from Compound A according to the procedure for Compound C described in Example 224.

C. 7-Bromo-2,3,4,5-tetrahydro-4- (methylsulfonyl) -2- (2-phenylethyl) -1H-1,4-benzodiazepine in a stirred solution of Compound C (80 mg, 0.24 mmol) CHCl ₃ was immediately added with tetrabutylammonium perbromide (120 mg, 0.24 mmol). The mixture was stirred at room temperature for 30 min. and evaporating the solvent. The residue is partitioned between water and 50% ethyl acetate in hexanes. The organic layer was separated, washed with water, saturated NH ₄ Cl solution, dried, and concentrated to give O-compound (100 mg, 100%) as an oil.

D. 7-Bromo-2,3,4,5-tetrahydro-1- (1H-imidazol-4-ylmethyl) -4- (methylphenyl) -2- (2-phenyl) -1H -1,4-benzodiazepine (monohydrochloride)

Compound D (solid) is prepared in 92% yield from Compound C according to the procedure for the preparation of Compound D described in Example 224.

MS: (M + H) &lt; ⁺ &gt; 489.

Example 406

(R) -7-Cyano-2,3,4,5-tetrahydro-1- (1-methyl-1H-imidazol-5-ylmethyl) -4 - [[2- (1-morpholinyl) ethyl] sulfonyl] -3- (phenylmethyl) -1H-1,4-benzodiazepine (dihydrochloride)

366

A. (R) -7-Cyano-2,3,4,5-tetrahydro-4- [ethenylsulfonyl] -3- (phenylmethyl) -1H1,4-benzodiazepine, Example 248 Example C (1.0 g, 3, 79 mmol) and DIEA (2.6 mL, 15.16 mmol) in dichloromethane (16 mL) at 0 ° C under argon are added 2-chloro-ethanesulfonyl chloride. After stirring for 16 h, the reaction mixture was diluted with chloroform (20 mL) and NaHCO ₃ (5 mL). The layers were separated and the aqueous layer was extracted with chloroform (2 x 50 mL). The combined organic extracts were washed with NaHCO ₃ (2 x 20 mL) and brine (2 x 50 mL), dried over MgSO ₄ , filtered, and concentrated to give Compound A (1.55 g, 116.5%).

B. (R) -7-Cyano-2,3,4,5-tetrahydro-1- (1-methyl-1H-imidazol-5-ylmethyl) -4 - [[2- (1-morpholinyl) ethyl] sulfonyl] -3- (phenylmethyl) -1H-1,4-benzodiazepine (dihydrochloride)

Compound B (yellowish solid) is prepared in a total 12% yield from the reaction sequence used to prepare Example 353 Compound B using 1: 1 ethyl acetate in chromatography; hexanes; Example 353 Compound C was reacted at room temperature with stirring for 2 days and purified by reverse phase preparative HPLC (gradient of aqueous methanol with 0.1% TFA).

MS: (M + H) &lt; ⁺ &gt; 535.

Example 407

(R) -7-Bromo-2,3,4,5-tetrahydro-1- (1H-imidazol-4-ylmethyl) -4- (methylsulfonyl) -3 (4-bromophenylmethyl) -1H-1,4-benzodiazepine (hydrochloride)

367

Example 407 is prepared from D-4-bromophenylalanine according to the procedure described in Example 224; the crude product was purified by reverse phase preparative HPLC (gradient of aqueous methanol with 0.1% TFA). The fractions containing the desired product are mixed, neutralized with a saturated aqueous solution of Na ₂ CO ₃ and extracted with CH ₂ Cl ₂ . The combined extracts are dried (Na ₂ SO ₄ ) and evaporated under reduced pressure. The residue was dissolved in ethyl acetate (10 mL) and added with 1N HCl in ether (10 mL). Evaporation of the solvent in vacuo gave Example 407 as a yellow solid.

MS (M + H) ⁺ 555.

Example 408

Br '3 (R) -7-Bromo-2,3,4,5-tetrahydro-1- (1H-imidazol-4-ylmethyl) -4- (methylsulfonyl) -3 (thiazol-4-ylmethyl) -1 H-1,4-benzodiazepine (hydrochloride)

Example 408 (yellow solid) is prepared from D (thiazol-4-yl) alanine methyl ester according to the procedure described in Example 407.

MS (M + H) &lt; ⁺ &gt; 484.

Example 409

368

Br

A

Me (R) -7-Bromo-2,3,4,5-tetrahydro-1- (1H-imidazol-4-ylmethyl) -4- (propylsulfonyl) -3- (thiazol-4-ylmethyl) -1H-1, 4-Benzodiazepine (hydrochloride)

The compound of Example 409 is prepared according to the procedure described in Example 408, except that propanesulfonyl chloride is used in place of methanesulfonyl chloride.

MS (M + H) ⁺ 510.

Example 410

Br

Me

Br (R) -7-Bromo-2,3,4,5-tetrahydro-1- (1H-imidazol-4-ylmethyl) -4- (propylsulfonyl) 3- (4-bromophenylmethyl) -1H-1,4 benzodiazepine (hydrochloride)

The compound of Example 410 is prepared according to the procedure described in Example 407, except that propanesulfonyl chloride is used in place of methanesulfonyl chloride.

MS (M + H) ⁺ 583.

Example 411

369

Br

A

N

N-SO ₂ Me (R) -7-Bromo-2,3,4,5-tetrahydro-1- (1H-imidazol-4-ylmethyl) -3- (pyridin-3-ylmethyl) -4- (methylsulfonyl) -1 H-1,4-benzodiazepine (trihydrochloride)

Example 411 (yellowish solid) was prepared in 16% yield from Example 350 Compound A according to the reaction sequence used to prepare Example 350 Compound C, coupled at 0 ° C, and chromatography using ethyl acetate; 350 for compound D, heated at 60 ° C.

MS: (M + H) ⁺ 476.

Analysis calculated for C ₂₀ H ₂₂ N ₅ BrO ₂ S · 3.00 HCl · 0.17 H ₂ O.

Found: C, 40.80; H, 4.34; N, 11.89.

Found: C, 40.79; H, 4.36; N, 11.79.

Example 412

Br

N — S0 _o Me

370 (R) -7-Bromo-2,3,4,5-tetrahydro-1- (1H-1-methylimidazol-5-ylmethyl) -3- (pyridin3-ylmethyl) -4- (methyl isulf oni I) -1H-1,4-benzodiazepine (dihydrochloride)

Example 412 (yellowish solid) is prepared in a 31% yield from (R) -7-bromo-2,3,4,5-tetrahydro-3- (pyridin-3-ylmethyl) -4 (methylsulfonyl) -1H-1 , 4-benzodiazepine (prepared as described in Example 411) and 1-methyl-5-formylimidazole according to the procedure described in Example 350 for the preparation of compound D by heating at 60 ° C.

MS; (M + H) ⁺ 490.

Analysis calculated for C ₂ i H ₂₄ N ₅ BrO ₂ S · 2.25 HCl 1.38 H ₂ O.

Excluded; C, 42.23; H, 4.90; N, 11.72.

Found: C, 42.23; H, 4.90; N, 11.66.

Example 413

1,2,3,4-Tetrahydro-7-bromo-4 - [(1H-imidazol-4-yl) methyl] -2-phenylmethyl-1- (phenylmethyloxycarbonyl) quinoxaline (hydrochloride)

A. N- (2-Nitrophenyl) -phenylalanine To a suspension of DL-phenylalanine (490 mg, 3 mmol) in water at room temperature was added sodium bicarbonate (0.84 g, 10 mmol) and 2-fluoronitrobenzene (0.63 mL, 6 mmol). . The mixture is heated to 80 ° C. After 16 or. ethanol (95%, 3 mL) was added. After 6 or. the mixture was partially concentrated to remove ethanol and the resulting solution was washed with ethyl acetate and chloroform (10 mL each). The aqueous layer is acidified to

371 pH 1 and extracted with chloroform (2 x 10 mL). The chloroform extracts were combined, dried (MgSO ₄ ), and concentrated in vacuo to give Compound A as a solid (0.81 g, 94%). MS (M +) ⁺ 287.

B. N- (2-Nitrophenyl) phenylalanine methyl ester

To a solution of Compound A (780 mg, 2.7 mmol) in MeOH (15 mL) was added HCl in dioxane (3 mL, 4M) at room temperature. After 18 or. the mixture is concentrated. The residue is dissolved in chloroform (15 ml) and the solution is taken up in saturated NaHCO ₃ (10 ml) and saturated NaCl solution (15 ml). The organic layer was dried (MgSO ₄ ) and concentrated in vacuo. Yellow oil chromatography (silica gel, flash chromatography, 20%

EtOAc / hexanes) to give Compound B (740 mg, 91%) as a yellow solid. MS (M + H) ⁺ 301.

C. 1,2,3,4-Tetrahydro-3-oxo-2-phenylmethyl-quinoxaline To a solution of compound B (720 mg, 2.34 mmol) in ethyl acetate (5 mL) at room temperature was added 20% Pd (OH) 2 /. C (40 mg). The flask is filled with hydrogen gas from the cylinder. After 5 or. the mixture was filtered through celite and the filtrate concentrated in vacuo. Colorless solid chromatography (silica gel, flash chromatography, 30%

EtOAc / hexanes) to give Compound C (550 mg, 98%) as a solid. MS (M + H) &lt; ⁺ &gt; 239.

D. 1,2,3,4-Tetrahydro-3-oxo-2-phenylmethyl-1- (phenylmethyloxycarbonyl) quinoxaline To a solution of compound C (525 mg, 2.2 mmol) in dichloromethane (6 mL) at 0 ° C was added DIEA (0.52 mL, 3 mmol) and benzyl chloroformate. The mixture was allowed to warm to room temperature over 3 hours. DMAP (10 mg) and pyridine (1 mL) were added and the mixture was stirred overnight (16 h). The mixture was concentrated in vacuo and the residue partitioned between ethyl acetate (20 mL) and 1N HCl (15 mL). The organic layer was separated, washed with 1N HCl (15 mL), dried (MgSO ₄ ) and concentrated in vacuo. Remain

372 Chromatography (silica gel, flash chromatography, 10%

EtOAc / chloroform) to give Compound D as a solid (440 mg, 54%). MS (M + H) ⁺ 373.1.

E. 1,2,3,4-Tetrahydro-2-phenylmethyl-1- (phenylmethyloxycarbonyl) quinoxaline

A mixture of Compound D (380 mg, 1.02 mmol) and borane in THF (1M, 3 mL) was stirred at room temperature under argon. After 24 or. MeOH (10 mL) was added carefully followed by 1N HCl (1M in ether, 5 mL). After 1 or. the mixture is concentrated in vacuo. Repeating the above procedure again gives a white solid which is then treated with chloroform and 10% ammonium hydroxide (20 mL each) and stirred vigorously. After 1 or. the organic layer was separated, dried (MgSO ₄ ), and concentrated in vacuo to give Compound E as a solid (366 mg, 100%).

MS (M + H) ⁺ 359.1.

F. 1,2,3,4-Tetrahydro-7-bromo-2-phenylmethyl-1- (phenylmethyloxycarbonyl) quinoxaline to a stirred solution of Compound E (340 mg, 0.95 mmol) in chloroform (3 mL) at room temperature over 2 min. . a solution of tetrabutylammonium tribromide (457 mg, 0.95 mmol) in chloroform (2 mL) was added. After 10 minutes. aqueous sodium bisulfite solution (10 ml) is added and the mixture is extracted with chloroform (10 ml). The organic layer was separated, dried (MgSO ₄ ), and concentrated in vacuo. The residue was chromatographed (silica gel, flash chromatography, 15%: EtOAc / hexanes) to give compound F (355 mg, 86%) as a thick oil. MS (M + H) ⁺ 437, 439.

G. 1,2,3,4-Tetrahydro-7-bromo-4 - [(1H-imidazol-4-yl) methyl] -2-phenylmethyl-1- (phenylmethyloxycarbonyl) quinoxaline (hydrochloride)

To a solution of compound F (345 mg, 0.79 mmol) in dichloromethane (3 mL) at room temperature was added 4-formylimidazole (0.3 g, 3.1 mmol), acetic acid (1 mL), 3A molecular weight grids, and sodium triacetoxyborohydride ( 212 mg, 1

373 mmol). After 5 or. sodium borohydride (212 mg, 1 mmol) was added. After 15 or. the mixture was filtered and the filtrate concentrated in vacuo. The residue was dissolved in chloroform (15 ml), aqueous ammonia (15 ml) was added and vigorously stirred. After 1 or. the organic layer was separated, dried (MgSO ₄ ) and concentrated in vacuo. Chromatography (silica gel, flash chromatography, 10% i-PrOH in chloroform) gives the free base (280 mg, 69%). To this solid was added 1N HCl in ether (2 mL), the mixture was dried in vacuo to give compound G (28 mg).

MS (M + H) <^+> = 517, 519.

Example 414

CN

CN (R) -7-Cyano-2,3,4,5-tetrahydro-1- (1H-imidazol-4-ylmethyl) -4- (phenylsulfonyl) -3 (4-cyanophenylmethyl) -1H-1,4- benzodiazepine (hydrochloride)

Example 414 (solid) is prepared in 12% yield from (R) -7-bromo-2,3,4,5-tetrahydro-3- (4-bromophenylmethyl) -1H-1,4-benzodiazepine (prepared as as described in Example 407) according to the reaction sequence used to prepare the following compounds: Compound C of Example 248; Example 224 for compound C using benzenesulfonyl chloride; Example 224 for compound D by reverse phase HPLC purification (gradient of aqueous methanol with 0.1% TFA).

MS (M + H) ⁺ 509.

374 ¹³ C-NMR (CD ₃ OD, 100 MHz) 39.60, 47.69, 50.29, 55.65, 60.46, 102.42, 111.55, 116.13, 118.47, 119 , 87, 125.00, 128.22, 129.73, 132.14, 133.34, 133.48, 133.62, 135.32, 136.22, 141.24, 144.60, 152.53 md

(R) -7-Cyano-4 - [(N-methyl-N-phenylmethyl) aminosulfonyl] -2,3,4,5-tetrahydro-1 [(1H-imidazol-4-yl) methyl] -3- (phenylmethyl) -1H-1,4-benzodiazepine (monohydrochloride)

Example 415 (fluffy solid) was prepared in 8% yield from N-methyl-N-phenylmethylsulfamoyl chloride and Example 248 Compound C according to the reaction sequence used for the preparation of Example 355 Compound A at 0 ° C to room temperature. temperature and chromatography using 20% ethyl acetate in hexanes; 353 of Example 353 under reflux and addition of 3A molecular mesh. MS: (M + H) &lt; ⁺ &gt; = 527.

Example 416

375

(R) -7-Cyano-4- [N- (tetrahydroisoquinolinyl) sulfonyl] -2,3,4,5-tetrahydro-1 [(1H-imidazol-4-yl) methyl] -3- (phenylmethyl) -1H -1,4-benzodiazepine (monohydrochloride)

Example 416 (white solid) is prepared in 11% yield from tetrahydroisoquinolinylsulfamoyl chloride and Example 248 Compound C according to the procedure described in Example 415,

MS: (M + H) &lt; ⁺ &gt; = 539.

Example 417

(R) * 7-Cyano-2,3,4,5-tetrahydro-1- (1H-imidazol-4-ylmethyl) -4- (phenylsulfonyl) -3 (2-thienylmethyl) -1H -1,4-benzodiazepine (hydrochloride)

Example 417 (yellow solid) is prepared from 2 (thienyl) alanine and bromoacetic anhydride according to the procedure described in Example 407 using benzenesulfonyl chloride in place of methanesulfonyl chloride.

376

MS: (M + H) &lt; ⁺ &gt; 490.

cis-2,3,4,5-Tetrahydro-1,5-bis (1H-imidazol-4-ylmethyl) -3- (phenylmethyl) -1H-1,5-benzodiazepine-2-carboxylic acid ethyl ester (trifluoroacetate, 1: 2) )

A. 2-Oxo-3-phenylmethyl · but-3-enecarboxylic acid ethyl ester

Ethyl 2-oxo-4-phenylbutyrate (31.8 mmol, 6.0 mL), Ν, Ν, Ν ', Ν-tetramethyldiaminomethane (6.6 mL, 54 mmol) and acetic anhydride (10 mL, 106 mmol) DMF (100 mL) was stirred at room temperature for 16 h. and is suppressed. The residue was chromatographed (flash chromatography, silica gel, 20% EtOAc in hexanes) to give Compound A as a clear oil (6.46 g, 93%). MS (M + NH ₄ ) ⁺ 236.

B. 2,3-Dihydro-3- (phenylmethyl) -1H-1,5-benzodiazepine-2-carboxylic acid ethyl ester

A mixture of compound A (6.46 g, 29.6 mmol), phenylenediamine (3.5 g, 32.6 mmol) and hydroquinone (300 mg, 2.72 mmol) in toluene (250 mL) was refluxed in a Dean-Stark reflux condenser. 's conditions 6 hours. Concentrate the mixture and purify the residue by flash chromatography (20% EtOAc in hexanes) to give Compound B as a viscous yellow oil (3.3 g, 36%). MS (M + H) ⁺ 309.

377

C, cis-2,3,4,5-Tetrahydro-1,5-bis (1H-imidazol-4-ylmethyl) -3- (phenylmethyl) -1H-1,5-benzodiazepine-2-carboxylic acid ethyl ester (trifluoroacetate,

1: 2)

Compound B (165 mg, 0.76 mmol) was dissolved in 2 mL AcOH and 2 mL CH ₂ Cl ₂ and treated with 4-formylimidazole (183 mg, 1.9 mmol) and NaBH (OAc) ₃ (645 mg, 3.0 mmol) ). The mixture was stirred at room temperature for 16 h, concentrated and the residue partitioned between saturated NaHCO ₃ (50 mL) and 10% isopropanol in CH ₂ Cl ₂ . The organic phase is washed with saturated NaHCO ₃ (50 mL), dried over Na ₂ SO ₄ , dissolved in MeOH (2 mL), and purified by reverse phase preparative HPLC (a gradient of aqueous methanol with 0.1% TFA) to give a yellow oil (120 mg, 23%). %) which, when lyophilized from water, yields compound C, which is an off-white, fluffy solid. MS (M + H) ⁺ 471.

(R) -7-Cyano-4 - [(N-piperidinyl) sulfonyl] -2,3,4,5-tetrahydro-1 - [(1H-imidazol4-yl) methyl] -3- (phenylmethyl) -1H- 1,4-benzodiazepine (monohydrochloride)

Example 419 (fluffy white solid) is prepared in 26% yield from N-piperidinylsulfamoyl chloride and Example 248 Compound C according to the procedure described in Example 415 using 5% methanol in chloroform for chromatography on the final product.

MS (M + H) <^+> = 491.

Example 420

378

(R) -7-Cyano-2,3,4,5-tetrahydro-1- (1H-1-methylimidazol-5-ylmethyl) -3- (phenylmethyl) -4- (2-thienylsulfonyl) -1H- 1,4-Benzodiazepine (hydrochloride)

A mixture of Example 284 Compound A (150 mg, 0.366 mmol), 1-methyl-5-formylimidazole (121 mg, 1.10 mmol) and 200 mg of 3A molecular mesh was heated in 2 mL of 3: 1 DCE / AcOH at 60 ° C. After 1 or., 4 or., 7 or. is 10 or. aliquots of sodium triacetoxyborohydride (116 mg, 0.549 mmol) were added. After 3 or., 6 or. is 9 or. aliquots of aldehyde (91 mg, 0.946 mmol) were added. After 9am. acetic acid (1 mi) was also added. After the final hydride portion was added, the mixture was stirred at 60 ° C for 2 h, diluted with 5 mL of methanol, filtered and concentrated in vacuo. The residue was diluted with 100 ml EtOAc and washed with 1N NaOH (3 x 50 mL) and saturated aqueous NaCl, dried over Na2S organic layer _4, filtered and concentrated in vacuo. The residue was purified by reverse phase preparative HPLC (gradient of aqueous methanol with 0.1% TFA) and the appropriate fractions were concentrated. The residue was dissolved in 1M HCl (3x5 mL) and concentrated in vacuo. This residue was dissolved in a minimum amount of acetonitrile, diluted with water, and freeze-dried to give 60 mg (29%) of Example 420 as a white solid.

(M + H) ⁺ 504.

Analysis calculated for C26H25N5O2S2 · 1.50 HCl · 0.66 H ₂ O.

Found: C, 54.77; H, 4.92; N, 12.28.

Found: C, 54.77; H, 4.92; N, 12.25.

379

Example 421

CN

(R) -7-Cyano-2,3,4,5-tetrahydro-1- (1H-imidazol-4-ylmethyl) -3- (pyridin-3-ylmethyl) -4 - [[2- (dimethylamino) ethyl] sulfonyl ] -1H-1,4-benzodiazepine (trihydrochloride)

A. (R) -7-Cyano-2,3,4,5-tetrahydro-3- (pyridin-3-ylmethyl) -4 - [[2- (dimethylamino) ethyl] sulfonyl] -1H-1,4-benzodiazepine To a solution of 350 in Example 350 Compound B (1.0 g, 3.8 mmol) and DIE (0.66 mL, 3.8 mmol) at -78 ° C was added 2-chloro-ethanesulfonyl chloride (0.79 mL, 7.6 mmol) ). The mixture was stirred at -78 ° C for 15 min. DIEA (0.66 mL, 3.8 mmol) was added and the mixture was stirred at -78 ° C for 1 h. DIEA (2.6 mL, 15.2 mmol) was again added to the reaction mixture at -78 ° C. The mixture was allowed to warm to room temperature and stirred for 16 hours. The solution is concentrated in vacuo. The residue was dissolved in 3/1 THF / CH 2 Cl 2 (4 mL). The mixture is saturated with dimethylamine, configured using a dry ice-cooled trap at room temperature. The mixture was stirred at room temperature for 2 hours. The resulting solution was diluted with 10% NaHCO ₃ (100 mL) and the solution was extracted with 9/1 CH ₂ Cl ₂ / iPrOH (3 x 150 mL). The combined organic extracts were dried (Na ₂ SO ₄ ), filtered and concentrated in vacuo to give Compound A (1.5 g, 100%).

MS: (M + H) &lt; ⁺ &gt; 400.

380

B. (R) -7-Cyano-2,3,4,5-tetrahydro-1- (1H-imidazol-4-ylmethyl) -3- (pyridin-3-ylmethyl) -4 - [[2- (dimethylamino) ethyl] sulfonyl] -1H-1,4-benzodiazepine (trihydrochloride)

A solution of Compound J (0.30 g, 0.75 mmol) in 1/1 DCE / acetic acid (5 mL) with 3A molecular mesh was added with 4-formylimidazole (0.14 g, 1.5 mmol) and the mixture was stirred At 70 ° C for 0.5 h. Sodium triacetoxyborohydride (0.32 g, 1.5 mmol) was added and the mixture was stirred at 70 ° C for 15 min. 4-Formylimidazole (0.14 g, 1.5 mmol) was added and the mixture was stirred at 70 ° C for 0.5 h. Sodium triacetoxyborohydride (0.32 g, 1.5 mmol) was added and the mixture was stirred at 70 ° C for 15 min. The latter two operations are repeated four times. The mixture was cooled to room temperature, diluted with methylene chloride (30 mL), filtered and the filtrate concentrated in vacuo. The residue is diluted with 25% NH ₄ OH (50 mL) and the solution is extracted with 9/1 CH ₂ Cl ₂ / iPrOH (4 x 50 mL). The combined organic extracts were dried (Na ₂ SO ₄ ), filtered and concentrated in vacuo. The residue was purified by reverse phase preparative HPLC (gradient of aqueous MeOH with 0.1% TFA), the desired fractions were collected and concentrated in vacuo. The residue was evaporated from 1/1 CH ₃ OH / 1N HCl (2 mL) 5 times. This residue was dissolved in CH ₃ CN (2 mL) and 1N HCl (4 mL) and lyophilized to give Compound B (0.071 g, 16%) as a solid.

MS: (M + H) ⁺ 480.

Analysis calculated for C ₂₄ H ₂₉ N ₇ O ₂ S · 3.3 HCl 0.74 H ₂ O.

Calculated: C, 47.01; H, 5.55; N. 15.99; S, 5.23; Cl, 19.08.

Found: C, 47.00; H, 5.43; N, 15.53; S, 5.00; Cl, 18.98.

Example 422

381

CN

(R) -7-Cyano-2,3,4,5-tetrahydro-1- (1H-1-methylimidazol-5-ylmethyl) -3- (phenylmethyl) -4- (propylsulfonyl) -1H-1, 4-Benzodiazepine (hydrochloride)

A solution of 320 mg (0.87 mmol) of Example 317 Compound A in 5 mL of dichloroethane and 500 mL of glacial acetic acid was treated with 478 mg (4.34 mmol) of 1-methylimidazole-5-carboxaldehyde and 3 A molecular mesh. The mixture is heated to 60 ° C and stirred for 5 hours. and treated with 763 mg (3.60 mmol) of sodium triacetoxyborohydride. The mixture was allowed to cool to room temperature and stirred for 18 hours. and filtered off. The filtrate is concentrated in vacuo. The residue is partitioned between 150 ml of 1N sodium hydroxide and 150 ml of ethyl acetate. The organic layer was washed with saturated NaCl solution, dried (Na ₂ SO ₄ ), filtered and concentrated in vacuo. The brown oil was purified by reverse phase preparative HPLC (gradient of aqueous methanol with 0.1% TFA). The resulting white foam was evaporated 3 times from a solution of aqueous chloride in methanol. The white foam is dissolved in water to give, after lyophilization, the compound 422 (59 mg, 15%) as a white lyophilisate.

MS: (M + H) &lt; ⁺ &gt; = 464 ⁺ .

Example 423

382

N- (Cyano) -N'-methyl-1,2,3,5-tetrahydro-1- (1H-imidazol-4-ylmethyl) -7-phenyl-4 H -1,4-benzodiazepine-4-imidate (hydrochloride)

A. N- (Cyano) -O-phenyl-1,2,3,5-tetrahydro-7-phenyl-4H-1,4-benzodiazepin-4-imidate

A solution of 500 mg (1.58 mmol) of Compound B of Example 224 in 20 mL of DMF under argon was treated with 390 mg (1.64 mmol) of diphenylcyanocarbonimide followed by 275 μΙ (1.58 mmol) of DIEA and 97 mg (0.79 mmol). DMAP. The mixture was stirred at room temperature for 15 minutes and at 80 ° C for 3.5 hours. and again at room temperature for 80 hours. The mixture was then partitioned between 250 mL of ethyl acetate and 250 mL of 1N sodium hydroxide. The aqueous layer was extracted 3 times with 100 mL of ethyl acetate. The combined organic layers were washed with brine, dried (Na ₂ SO ₄ ), filtered, and concentrated in vacuo. The oily residue is purified by flash chromatography (silica gel, 40% ethyl acetate in hexane) to give 456 mg (63%) of Compound A as a white solid.

B. N- (Cyano) -N'-methyl-1,2,3,5-tetrahydro-7-phenyl-4H-1,4-benzodiazepine-4-imidate

A solution of 180 mg (0.39 mmol) of Compound A in 1 mL of DMF was treated with 242 μΙ (1.94 mmol) of a 33% solution of methylamine in ethanol. The mixture was stirred at room temperature for 1 hour. and concentrated. The residue is dissolved in 100 ml of ethyl acetate, washed with saturated NaCl solution, dried (Na ₂ SO ₄ ), and

Concentration in vacuo yielded 125 mg (87%) of Compound B as a white solid. MS (M + H) <^+> = 400.

C. N- (Cyano) -N'-Methyl-1,2,3,5-tetrahydro-1- (1H-imidazol-4-ylmethyl) -7-phenyl-4H-1,4-benzodiazepine-4-imidate ( hydrochloride)

A solution of 115 mg (0.29 mmol) of Compound B in 2.5 mL of dichloroethane and 2.5 mL of glacial acetic acid was treated with 69 mg (0.71 mmol) of 4-imidazolecarboxaldehyde with 3A molecular mesh and stirred at room temperature for 18 h. This mixture was treated with 122 mg (0.58 mmol) of sodium triacetoxyborohydride which was added immediately and stirred at room temperature for 30 min. and filtered off. The filtrate is partitioned between 100 ml of ethyl acetate and 100 ml of 1N sodium hydroxide. The organic layer was washed with saturated NaCl solution, dried (Na ₂ SO ₄ ) and concentrated in vacuo. The oily residue is purified by reverse phase preparative HPLC (gradient of aqueous methanol with 0.1% TFA). The yellow foamy residue is evaporated 3 times from a solution of hydrogen chloride in methanol. The foamy residue is dissolved in water and lyophilized to give 30 mg (22%) of Compound C, which is a yellow lyophilisate.

MS: (M + H) &lt; ⁺ &gt; = 430.

424-430 examples

Examples 424-430 are prepared from Example 248 Compound C and the corresponding sulfonyl chloride according to the reaction sequence used to prepare Example 299 Compound A, Example 317 Compound B. Satisfactory data are obtained for Examples 424-430 Compounds C, H, and N.

Fig.

Mass spectrum

384

CN

424 (R) -7-Cyano-4 - [(2-nitrophenyl) sulfonyl] -2,3,4,5-tetrahydro-1- (1H-imidazol-4-ylmethyl) -3 (phenylmethyl) -1H- 1,4-benzodiazepine (hydrochloride)

425 (R) -7-Cyano-4 - [(4-methylphenyl) sulfonyl] -2,3,4,5-tetrahydro-1- (1H-imidazol-4-ylmethyl) -3 (phenylmethyl) -1H- 1,4-benzodiazepine (hydrochloride)

426 (R) -7-Cyano-4- (butylsulfonyl) 2,3,4,5-tetrahydro-1- (1H-imidazol-4-ylmethyl) -3 (phenylmethyl) -1H-1,4-benzodiazepine (hydrochloride)

427 (R) -7-Cyano-4 - [(2-trifluoromethylphenyl) sulfonyl] 2,3,4,5-tetrahydro-1- (1H-imidazol-4-ylmethyl) -3 (phenylmethyl) -1H-1,4-benzodiazepine ( hydrochloride)

428 (R) -7-Cyano-4 - [(2-trifluoromethoxyphenyl) sulfonyl] -2,3,4,5-tetrahydro-1- (1H-imidazol-4-ylmethyl) -3- (phenylmethyl) -1H- 1,4-benzodiazepine (hydrochloride)

m / z

498 (M + H) m / z

464 (M + H) m / z 552 (M + H) m / z 529 (M + H) m / z

568 (M + H)

385

429 (R) -7-Cyano-4 - [(2-methoxycarbonylphenyl) sulfonyl] -2,3,4,5-tetrahydro-1- (1H-imidazol-4-ylmethyl) -3- (phenylmethyl) -1H- 1,4-benzodiazepine (hydrochloride)

430 (R) -7-Cyano-4 - [(2-methylsulfonylphenyl) sulfonyl] -2,3,4,5-tetrahydro-1- (1H-imidazol-4-ylmethyl) -3- (phenylmethyl) -1H -1,4-benzodiazepine (hydrochloride)

Example 431

Using the methods described herein and other methods known to those skilled in the art, the following compounds were prepared:

(R) -7-Cyano-2,3,4,5-tetrahydro-1- (1H-imidazol-4-ylmethyl) -3- m / z 562 (phenylmethyl) -4 - (((4-methylsulfonyl) phenyl) sulfonyl) -1H-1,4- (M + H) benzodiazepine (R) -7-cyano-2,3,4,5-tetrahydro-1- (1H-imidazol-4-ylmethyl) -3 - m / z 552 (phenylmethyl) -4 - (((4-trifluoromethyl) phenyl) sulfonyl) -1H-1,4- (M + H) benzodiazepine (R) -7-cyano-2,3,4,5 -tetrahydro-1- (1H-imidazol-4-ylmethyl) -3- m / z 480 (phenylmethyl) -4 - ((3-methoxypropyl) sulfonyl) -1H-1,4-benzodiazepine (M + H) ( R) -7-Cyano-2,3,4,5-tetrahydro-1- (1H-imidazol-4-ylmethyl) -3-m / z 544 (phenylmethyl) -4 - ((3,4-dimethoxyphenyl) sulfonyl) -1H-1,4- (M + H) benzodiazepine (R) -7-cyano-2,3,4,5-tetrahydro-1- (1H-imidazol-4-ylmethyl) -3-m / z 502 ((4-fluorophenyl) methyl) -4- (phenylsulfonyl) -1H-1,4-benzodiazepine (M + H) (R) -7-cyano-4 - [(N-cyclopropylmethyl-N-propyl) -aminosulfonyl] -1 - [(1H-m / z 519 imidazol-4-yl) methyl] -3- (phenylmethyl) -1H-1,4-benzodiazepine (M + H)

386 (R) -7-Cyano-4 - [(N, N- (dibutylamino)) sulfonyl] -1 - [(1H-imidazole-4-m / z 535 yl) methyl] -3- (phenylmethyl) - 1H-1,4-Benzodiazepine (M + H) (R) -7-Chloro-4- (methanesulfonyl) -2,3,4,5-tetrahydro-1- (1H-imidazole-4-m / z) 432 ylmethyl) -3- (phenylmethyl) -1H-pyrido [3,4-e] -1,4-diazepine (M + H)

1,2,3,4-Tetrahydro-7-bromo-4 - [(1H-imidazol-4-yl) methyl] -2-phenylmethyl-1- m / z 460 (methylsulfonyl) quinoxaline (M + H) ( R) -7-Cyano-2,3,4,5-tetrahydro-1- (1H-imidazol-4-ylmethyl) -3-m / z 424 (phenylmethyl) -4 - ((imidazol-4-yl) methylsulfonyl) -1H-1,4-benzodiazepine (M + H)

The following compounds may be prepared according to the procedures described above:

(R) -7-Cyano-2,3,4,5-tetrahydro-1- (1H-imidazol-4-ylmethyl) -3 - ((2-thienyl) methyl) -4 (propylsulfonyl) -1H- 1,4-Benzodiazepine (R) -7-cyano-2,3,4,5-tetrahydro-1- (1H-imidazol-4-ylmethyl) -3 - ((2-thienyl) methyl) -4 - (( 2-thienyl) sulfonyl) -1H-1,4-benzodiazepine (R) -7-cyano-2,3,4,5-tetrahydro-1- (1H-imidazol-4-ylmethyl) -3- (phenylmethyl) -4 - ((3-methylpropyl) sulfonyl) -1H-1,4-benzodiazepine (R) -7-cyano-2,3,4,5-tetrahydro-1- (1H-imidazol-4-ylmethyl) -3- ( phenylmethyl) -4 - (((3-methylthioxo) propyl) sulfonyl) -1H-1,4-benzodiazepine (R) -7-cyano-2,3,4,5-tetrahydro-1- (1H-imidazole-4- ylmethyl) -3- (phenylmethyl) -4 - (((3-methylsulfonyl) propyl) sulfonyl) -1H-1,4-benzodiazepine (R) -7-cyano-2,3,4,5-tetrahydro-1- ( 1H-imidazol-4-ylmethyl) -3- (phenylmethyl) -4 - ((2-methylpropyl) sulfonyl) -1H-1,4-benzodiazepine (R) -7-cyano-2,3,4,5-tetrahydro- 1- (1H-imidazol-4-ylmethyl) -3- (phenylmethyl) -4- (cyclopentylsulfonyl) -1H-1,4-benzodiazepine (R) -7-cyano-2,3,4,5- tetrahydro-1- (1H-imidazol-4-ylmethyl) -3- (phenylmethyl) -4 - ((4,4,4-trifluorobutyl) sulfonyl) -1H-1,4-benz odiazepine (R) -7-cyano-2,3,4,5-tetrahydro-1- (1H-imidazol-4-ylmethyl) -3- (phenylmethyl) -4 ((phenylmethyl) sulfonyl) -1H-1, 4-Benzodiazepine (R) -7-cyano-2,3,4,5-tetrahydro-1- (1H-imidazol-4-ylmethyl) -3- (phenylmethyl) -4 - [[2- (5 (N- benzoyl) aminomethyl) thienyl] sulfonyl) -1H-1,4-benzodiazepine

387 (R) -7-Cyano-2,3,4,5-tetrahydro-1- (1H-imidazol-4-ylmethyl) -3- (phenylmethyl) -4 - [[2- (1 (3-chloro) 5-methyl-pyridin-2-yl) pyrrolyl] sulfonyl] -1H-1,4-benzodiazepine (R) -7-cyano-2,3,4,5-tetrahydro-1- (1H-imidazole-4 -ylmethyl) -3- (phenylmethyl) -4 - ((4-carboxyphenyl) sulfone) -1H-1,4-benzodiazepine (R) -7-cyano-2,3,4,5-tetrahydro-1- ( 1H-imidazol-4-ylmethyl) -3- (phenylmethyl) -4 - [((3-methyl-1,2,4-oxadiazol-5-yl) phenyl) sulfonyl] -1H-1,4-benzodiazepine (R) -7-cyano-2,3,4,5-tetrahydro-1- (1H-imidazol-4-ylmethyl) -3- (phenylmethyl) -4 - ((2,5d imethoxyphenyl) sulfonyl) -1H- 1,4-Benzodiazepine (R) -7-cyano-4 - [(N-tetrahydroquinolinyl) sulfonyl] -1 - [(1H-imidazol-4-yl) methyl] -3 (phenylmethyl) -1H-1 , 4-Benzodiazepine (R) -7-cyano-4 - [(N, N-bis- [1- (2-methylpropyl) amino] sulfonyl] -1 - [(1H-imidazol-4yl) methyl] -3- (phenylmethyl) -1H-1,4-benzodiazepine (R) -7-cyano-4 - [(N-methyl-N-phenyl) aminosulfonyl] -1 - [(1H-imidazol-4-yl) methyl] - 3- (phenylmethyl) -1H-1,4-benzodiazepine (R) -7-cyano-2,3,4,5-tetrahydro-1- (1H-imidazol-4-ylmethyl) -3- (2- (2) , 6-dimethylphenyl) e ethyl) -4- (methylsulfonyl) -1H-1,4-benzodiazepine (R) -7-cyano-2,3,4,5-tetrahydro-1- (1- (N-phthalimidoethyl) imidazole-5- ylmethyl) -3- (phenylmethyl) -4- (methylsulfonyl) -1H-1,4-benzodiazepine (R) -7-cyano-2,3,4,5-tetrahydro-1 - [(2- (N, N -dimethylamino) ethyl) -imidazol-5-ylmethyl] 3- (phenylmethyl) -4- (methylsulfonyl) -1H-1,4-benzodiazepine (R) -7-cyano-2,3,4,5-tetrahydro- 1 - [(2- (N, N-aminoethyl) imidazol-5-ylmethyl] -3- (phenylmethyl) -4- (methylsulfonyl) -1H-1,4-benzodiazepine (R) -7-bromo-4 - (methanesulfonyl) -2,3,4,5-tetrahydro-1 - [(1H-imidazol-4-ylmethyl) -3 (phenylmethyl) -1H-thieno [2,3-e] -1,4-diazepine (R) -7-Bromo-4- (methanesulfonyl) -2,3,4,5-tetrahydro-1 - [(1H-imidazol-4-ylmethyl) -3 (phenylmethyl) -1H-thieno [3.2 -e] -1,4-diazepine (R) -4- (methanesulfonyl) -2,3,4,5-tetrahydro-1 - [(1H-imidazol-4-ylmethyl) -3- (phenylmethyl) 1H- 8-Oxo-pyrimidino [4,5-e] -1,4-diazepine (R) -7-cyano-2,3,4,5-tetrahydro-1- (1H-imidazol-4-ylmethyl) -3- (((4- (2-methoxyethoxy) phenyl) methyl) -4- (phenylsulfonyl) -1H-1,4-benzodiazepine (R) -7-cyano-2,3,4,5-tetrahydro-1- (1H) -imidazol-4-yl ethyl) -3 - ((4- (2- (dimethylamino) ethoxy) phenyl) methyl) -4- (phenylsulfonyl) -1H-1,4-benzodiazepine

388 (R) -7-Cyano-2,3,4,5-tetrahydro-1- (1H-imidazol-4-ylsulfonyl) -3- (phenylmethyl) -4 (methylsulfonyl) -1H-1,4- benzodiazepine (R) -7-cyano-2,3,4,5-tetrahydro-1- (1H-imidazol-4-ylsulfonyl) -3- (phenylmethyl) -4- (pyropisulfonyl) -1H-1, 4-Benzodiazepine (R) -7-cyano-2,3,4,5-tetrahydro-1- (1H-imidazol-4-ylsulfonyl) -3- (phenylmethyl) -4 (phenylsulfonyl) -1H-1, 4-Benzodiazepine (R) -7-cyano-2,3,4,5-tetrahydro-1- (1H-innidazol-4-ylsulfonyl) -3- (phenylmethyl) -4- (2-thienylsulfonyl) -1H-1, 4-Benzodiazepine

7-Cyano-2,3,4,5-tetrahydro-1- (1H-imidazol-4-ylmethyl) -3- (R) - [(R) -1-phenylethyl] -4 (methylsulfonyl) -1 H-1,4-benzodiazepine

7-Cyano-2,3,4,5-tetrahydro-1- (1H-imidazol-4-ylmethyl) -3- (R) - [(R) -1-phenylethyl] -4 (propylsulfonyl) -1 H-1,4-benzodiazepine

7-Cyano-2,3,4,5-tetrahydro-1- (1H-imidazol-4-ylmethyl) -3- (R) - [(R) -1-phenyl ethyl] -4 (phenylsulfonyl) -1 H -1,4-benzodiazepine

7-Cyano-2,3,4,5-tetrahydro-1- (1H-imidazol-4-ylmethyl) -3- (R) - [(R) -1-phenylethyl] -4 - ((2-thienyl) sulfonyl) -1H-1,4-benzodiazepine

7-Cyano-2,3,4,5-tetrahydro-1- (1H-imidazol-4-ylmethyl) -3- (S) - [(R) -1-phenylethyl] -4 (methylsulfonyl) -1H -1,4-benzodiazepine

7-Cyano-2,3,4,5-tetrahydro-1- (1H-imidazol-4-ylmethyl) -3- (S) - [(R) -1-phenylethyl] -4 (propylsulfonyl) -1H- 1,4-Benzodiazepine

7-Cyano-2,3,4,5-tetrahydro-1- (1H-imidazol-4-ylmethyl) -3- (S) - [(R) -1-phenyl ethyl] -4 (phenylsulfonyl) -1 H -1,4-benzodiazepine

7-Cyano-2,3,4,5-tetrahydro-1- (1H-imidazol-4-ylmethyl) -3- (S) - [(R) -1-phenyl ethyl] -4 - ((2-thienyl) ) sulfonyl) -1H-1,4-benzodiazepine

7-Cyano-2,3,4,5-tetrahydro-1- (1H-imidazol-4-ylmethyl) -3- (R) - [(S) -1-phenylethyl] -4 (methylsulfonyl) -1H -1,4-benzodiazepine

7-Cyano-2,3,4,5-tetrahydro-1- (1H-imidazol-4-ylmethyl) -3- (R) - [(S) -1-phenylethyl] -4 (propylsulfonyl) - 1H-1,4-benzodiazepine

7-Cyano-2,3,4,5-tetrahydro-1- (1H-imidazol-4-ylmethyl) -3- (R) - [(S) -1-phenyl ethyl] -4 (phenylsulfonyl) -1 H -1,4-benzodiazepine

7-Cyano-2,3,4,5-tetrahydro-1- (1H-imidazol-4-ylmethyl) -3- (R) - [(S) -1-phenylethyl] -4 - ((2-thienyl) ) sulfonyl) -1H-1,4-benzodiazepine

389

7-Cyano-2,3,4,5-tetrahydro-1- (1H-imidazol-4-ylmethyl) -3- (S) - [(S) -1-phenylethyl] -4 (methylsulfonyl) -1H- 1,4-Benzodiazepine

7-Cyano-2,3,4,5-tetrahydro-1- (1H-imidazol-4-ylmethyl) -3- (S) - [(S) -1-phenyl] -4- (propylsulfonyl) -1 H -1,4-benzodiazepine

7-Cyano-2,3,4,5-tetrahydro-1- (1H-imidazol-4-ylmethyl) -3- (S) - [(S) -1-phenylethyl] -4 (phenylsulfonyl) -1H- 1,4-Benzodiazepine

7-Cyano-2,3,4,5-tetrahydro-1- (1H-imidazol-4-ylmethyl) -3- (S) - [(S) -1-phenyl ethyl] -4 - ((2-thienyl) ) sulfonyl) -1H-1,4-benzodiazepine

7-Cyano-2,3,4,5-tetrahydro-1- (1H-imidazol-4-ylmethyl) -3- (R) - [(R) -phenylcyclopropyl) 4- (methylsulfonyl) -1H- 1,4-Benzodiazepine

7-Cyano-2,3,4,5-tetrahydro-1- (1H-imidazol-4-ylmethyl) -3- (R) - [(R) -phenylcyclopropyl) 4- (propylsulfonyl) -1H-1 , 4-Benzodiazepine

7-cyano-2,3,4,5-tetrahydro-1- (1H-imidazol-4-ylmethyl) -3- (R) - [(R) -phenylcyclopropyl) 4- (phenylsulfonyl) -1H-1, 4-Benzodiazepine

7-Cyano-2,3,4,5-tetrahydro-1- (1H-imidazol-4-ylmethyl) -3- (R) - [(R) -phenylcyclopropyl) 4 - ((2-thienyl) sulfonyl) - 1H-1,4-benzodiazepine

7-cyano-2,3,4,5-tetrahydro-1- (1H-imidazol-4-ylmethyl) -3- (R) - [(S) -phenylcyclopropyl) 4- (methylsulfonyl) -1H-1, 4-Benzodiazepine

7-cyano-2,3,4,5-tetrahydro-1- (1H-imidazol-4-ylmethyl) -3- (R) - [(S) -phenylcyclopropyl) 4- (propylsulfonyl) -1H-1, 4-Benzodiazepine

7-cyano-2,3,4,5-tetrahydro-1- (1H-imidazol-4-ylmethyl) -3- (R) - [(S) -phenylcyclopropyl) 4- (phenylsulfonyl) -1H-1, 4-Benzodiazepine

7-Cyano-2,3,4,5-tetrahydro-1- (1H-imidazol-4-ylmethyl) -3- (R) - [(S) -phenylcyclopropyl) 4 - ((2-thienyl) sulfonyl) - 1H-1,4-benzodiazepine

7-cyano-2,3,4,5-tetrahydro-1- (1H-imidazol-4-ylmethyl) -3- (S) - [(R) -phenylcyclopropyl) 4- (methylsulfonyl) -1H-1, 4-Benzodiazepine

7-cyano-2,3,4,5-tetrahydro-1- (1H-imidazol-4-ylmethyl) -3- (S) - [(R) -phenylcyclopropyl) 4- (propylsulfonyl) -1H-1, 4-Benzodiazepine

7-Cyano-2,3,4,5-tetrahydro-1- (1H-imidazol-4-ylmethyl) -3- (S) - [(R) -phenylcyclopropyl] 4- (phenylsulfonyl) -1H-1 , 4-Benzodiazepine

7-Cyano-2,3,4,5-tetrahydro-1- (1H-imidazol-4-ylmethyl) -3- (S) - [(R) -phenylcyclopropyl) 4 - ((2-thienyl) sulfonyl) - 1H-1,4-benzodiazepine

390

7-cyano-2,3,4,5-tetrahydro-1- (1H-imidazol-4-ylmethyl) -3- (S) - [(S) -phenylcyclopropyl) 4- (methylsulfonyl) -1H-1, 4-Benzodiazepine

7-cyano-2,3,4,5-tetrahydro-1- (1H-imidazol-4-ylmethyl) -3- (S) - [(S) -phenylcyclopropyl) 4- (propylsulfonyl) -1H-1, 4-Benzodiazepine

7-cyano-2,3,4,5-tetrahydro-1- (1H-imidazol-4-ylmethyl) -3- (S) - [(S) -phenylcyclopropyl) 4- (phenylsulfonyl) -1H-1, 4-Benzodiazepine

7-Cyano-2,3,4,5-tetrahydro-1- (1H-imidazol-4-ylmethyl) -3- (S) - [(S) -phenylcyclopropyl) 4 - ((2-thienyl) sulfonyl) - 1H-1,4-Benzodiazepine (R) -7-cyano-2,3,4,5-tetrahydro-1- (1H-imidazol-4-ylmethyl) -3- (phenylmethyl) -4 - [(2- (5-pyridin-2-yl) thienyl) sulfonyl j) -1H-1,4-benzodiazepine (R) -7-cyano-2,3,4,5-tetrahydro-1- (1H-imidazol-4-ylmethyl) ) -3- (phenylmethyl) -4 - [(2- (5 (1,2-isoxazol-3-yl)) thienyl) sulfonyl]) - 1H-1,4-benzodiazepine (R) -7-cyano 2,3,4,5-Tetrahydro-1- (3- (1H-imidazol-2-yl) -propyl) -3- (phenylmethyl) -4-phenylsulfonyl) -1H-1,4-benzodiazepine (R) -7 -cyano-2,3,4,5-tetrahydro-1- (3- (1H-imidazol-2-yl) -propyl) -3- (phenylmethyl) -4-methylsulfonyl) -1H-1,4-benzodiazepine (R ) -7-Cyano-2,3,4,5-tetrahydro-1- (3- (1H-imidazol-2-yl) -propyl) -3- (phenylmethyl) -4β-sulfonyl) -1H- 1,4-Benzodiazepine (R) -7-cyano-2,3,4,5-tetrahydro-1- (3- (1H-imidazol-2-yl) -propyl) -3- (phenylmethyl) -4- ((2-thienyl) sulfonyl) -1H-1,4-benzodiazepine (R) -7-cyano-2,3,4,5-tetrahydro-1- (2- (1H-imidazol-2-yl) ethylsulfonyl) -3- (phenylmethyl) 4-phenylsulfonyl) -1H -1,4-Benzodiazepine (R) -7-cyano-2,3,4,5-tetrahydro-1- (2- (1H-imidazol-2-yl) ethylsulfonyl) -3- (phenylmethyl) 4- methylsulfonyl) -1H-1,4-benzodiazepine (R) -7-cyano-2,3,4,5-tetrahydro-1- (2 - (; 1H-imidazol-2-yl) ethylsulfonyl) -3- (phenylmethyl) 4-propylsulfonyl) -1H-1,4-benzodiazepine (R) -7-cyano-2,3,4,5-tetrahydro-1- (2- (1H-imidazol-2-yl) ethylsulfonyl) ) -3- (Phenylmethyl) 4 - ((2-thienyl) sulfonyl) -1H-1,4-benzodiazepine (R) -7-cyano-2,3,4,5-tetrahydro-1- (1H-imidazole) -4-ylmethyl) -3- (phenylmethyl) -4 - ((1-oxoethyl) amino) -1H-1,4-benzodiazepine (R) -7-cyano-2,3,4,5-tetrahydro-1- ( 1H-imidazol-4-ylmethyl) -3- (phenylmethyl) -4- (methanesulfonylamino) -1H-1,4-benzodiazepine

391 (R) -7-Cyano-2,3A-5-tetrahydro-1- (1H-imidazol-4-ylmethyl) -3- (phenylmethyl) -4- (phenylsulfonylamino) -1H-1,4-benzodiazepine.

Claims (17)

DEFINITION OF INVENTION 1,2,3,4-Tetrahydro-7-bromo-4 - [(1H-imidazol-4-yl) methyl] -2-phenylmethyl-1- (methylsulfonyl) quinoxaline; (R) -7-Cyano-2,3,4,5-tetrahydro-1- (1H-imidazol-4-ylmethyl) -3- (phenylmethyl) -4 ((imidazol-4-yl) methylsulfonyl) -1H -1,4-benzodiazepine; (R) -7-Cyano-2,3,4,5-tetrahydro-1- (1H-imidazol-4-ylmethyl) -3 - ((2-thienyl) methyl) -4 (propylsulfonyl) -1H-1 , 4-benzodiazepine; (R) -7-Cyano-2,3,4,5-tetrahydro-1- (1H-imidazol-4-ylmethyl) -3 - ((2-thienyl) methyl) -4 - ((2-thienyl) sulfonyl) -1 H -1,4-benzodiazepine; (R) -7-Cyano-2,3,4,5-tetrahydro-1- (1H-imidazol-4-ylmethyl) -3- (phenylmethyl) -4 - ((3-methylthiopropyl) sulfonyl) -1 H-1,4-benzodiazepine; (R) -7-Cyano-2,3,4,5-tetrahydro-1- (1H-imidazol-4-ylmethyl) -3- (phenylmethyl) -4 - (((3-methylthioxo) propyl) sulfone I) -1 H -1,4-benzodiazepine; (R) -7-Cyano-2,3,4,5-tetrahydro-1- (1H-imidazol-4-ylmethyl) -3- (phenylmethyl) -4 - (((3-methylsulfonyl) propyl) sulfonyl) - 1H-1,4-benzodiazepine; (R) -7-Cyano-2,3,4,5-tetrahydro-1- (1H-imidazol-4-ylmethyl) -3- (phenylmethyl) -4 - ((2-methylpropyl) sulfonyl) -1 H-1,4-benzodiazepine; (R) -7-Cyano-2,3,4,5-tetrahydro-1- (1H-imidazol-4-ylmethyl) -3- (phenylmethyl) -4- (cyclopentenesulfonyl) -1H-1,4 benzodiazepine; (R) -7-Cyano-2,3,4,5-tetrahydro-1- (1H-imidazol-4-ylmethyl) -3- (phenylmethyl) -4 - ((4,4,4-trifluorobutyl) -su (phenyl) ) -1H-1,4-benzodiazepine; (R) -7-cyano-2,3,4,5-tetrahydro-1- (1H-imidazol-4-ylmethyl) -3- (phenylmethyl) -4 (( phenylmethyl) sulfonyl) -1H-1,4-benzodiazepine; (R) -7-Cyano-2,3,4,5-tetrahydro-1- (1H-imidazol-4-ylmethyl) -3- (phenylmethyl) -4 - [[2- (5 (N-benzoyl) - aminomethyl) -thienyl] sulfonyl] -1H-1,4-benzodiazepine; (R) -7-Cyano-2,3,4,5-tetrahydro-1- (1H-imidazol-4-ylmethyl) -3- (phenylmethyl) -4 - [[2- (1 (3-chloro-5) -methyl-pyridin-2-yl) -pyrrolyl] sulfonyl] -1H-1,4-benzodiazepine; (R) -7-Cyano-2,3,4,5-tetrahydro-1- (1H-imidazol-4-ylmethyl) -3- (phenylmethyl) -4 - ((4-carboxyphenyl) sulfonyl) -1H-1 , 4-benzodiazepine; (R) -7-Cyano-2,3,4,5-tetrahydro-1- (1H-imidazol-4-ylmethyl) -3- (phenylmethyl) -4 - [((3-methyl-1,2,4-oxadiazole) 5-yl) -phenyl) sulfonyl] -1H-1,4-benzodiazepine; (R) -7-Cyano-2,3,4,5-tetrahydro-1- (1H-imidazol-4-ylmethyl) -3- (phenylmethyl) -4 - ((2,5-dimethoxyphenyl) sulfonyl) -1H -1,4-benzodiazepine; (R) -7-Cyano-4 - [(N-tetrahydroquinolinyl) sulfonyl] -1 - [(1H-imidazol-4-yl) methyl] -3 (phenylmethyl) -1H-1,4-benzodiazepine; (R) -7-Cyano-4 - [(N, N-bis- [1- (2-methylpropyl) amino] sulfonyl] -1 - [(1H-imidazol-4-yl) methyl] -3- (phenylmethyl) -1 H -1,4-benzodiazepine; (R) -7-Cyano-4 - [(N-methyl-N-phenyl) aminosulfonyl] -1 - [(1H-imidazol-4-yl) methyl] -3 (phenylmethyl) -1H-1,4- benzodiazepine; (R) -7-Cyano-2,3,4,5-tetrahydro-1- (1H-imidazol-4-ylmethyl) -3- (2- (2,6-dimethylphenyl) ethyl) -4- (m ethylsulfonyl) -1H-1,4-benzodiazepine; (R) -7-Cyano-2,3,4,5-tetrahydro-1- (1- (N-phthalimidoethyl) imidazol-5-ylmethyl) -3 (phenylmethyl) -4- (methylsulfonyl) -1H- 1,4-benzodiazepine; (R) -7-Cyano-2,3,4,5-tetrahydro-1 - [(2- (N, N-dimethylamino) ethyl) imidazol-5-ylmethyl] 3- (phenylmethyl) -4- ( methylsulfonyl) -1H-1,4-benzodiazepine; (R) -7-Cyano-2,3,4,5-tetrahydro-1 - [(2-aminoethyl) imidazol-5-ylmethyl] -3- (phenylmethyl) 4- (methylsulfonyl) -1H-1 , 4-benzodiazepine; (R) -7-Bromo-4- (methanesulfonyl) -2,3,4,5-tetrahydro-1 - [(1H-imidazol-4-ylmethyl) -3 (phenylmethyl) -1H-thieno [2,3] -e] -1,4-diazepine; (R) -7-Bromo-4- (methanesulfonyl) -2,3,4,5-tetrahydro-1 - [(1H-imidazol-4-ylmethyl) -3 (phenylmethyl) -1H-thieno [3.2 -e] -1,4-diazepine; (R) -4- (Methanesulfonyl) -2,3,4,5-tetrahydro-1 - [(1H-imidazol-4-ylmethyl) -3- (phenylmethyl) -1H-8-oxo-pyrimidino [4,5 -e] -1,4-diazepine; (R) -7-Cyano-2,3,4,5-tetrahydro-1- (1H-imidazol-4-ylmethyl) -3 - ((4- (2- (methoxyethoxy) phenyl) methyl) -4- ( phenylsulfonyl) -1H-1,4-benzodiazepine; (R) -7-cyano-2,3,4,5-tetrahydro-1- (1H-imidazol-4-ylmethyl) -3 - ((4- (2 - (dimethylamino) ethoxy) phenyl) methyl) -4- (phenylsulfonyl) -1H-1,4-benzodiazepine; (R) -7-cyano-2,3,4,5-tetrahydro-1- (1H- imidazol-4-ylsulfonyl) -3- (phenylmethyl) -4 (methylsulfonyl) -1H-1,4-benzodiazepine; (R) -7-Cyano-2,3,4,5-tetrahydro-1- (1H-imidazol-4-ylsulfonyl) -3- (phenylmethyl) -4 (propylsulfonyl) -1H-1,4 benzodiazepine; (R) -7-Cyano-2,3,4,5-tetrahydro-1- (1H-imidazol-4-ylsulfonyl) -3- (phenylmethyl) -4 (phenylsulfonyl) -1H-1,4-benzodiazepine; (R) -7-Cyano-2,3,4,5-tetrahydro-1- (1H-imidazol-4-ylsulfonyl) -3- (phenylmethyl) -4- (2-thienisulfonyl) -1H-1,4-benzodiazepine ; 1.2 _L 3,4-Tetrahydro-7-bromo-4 - [(1H-imidazol-4-yl) methyl] -2-phenylmethyl-1- (phenylmethyloxycarbonyl) quinoxaline (hydrochloride); (R) -7-Cyano-2,3,4,5-tetrahydro-1- (1H-imidazol-4-ylmethyl) -4- (phenylsulfonyl) -3- (4cyanophenylmethyl) -1H-1,4 benzodiazepine (hydrochloride); (R) -7-Cyano-4 - [(N-methyl-N-phenylmethyl) aminosulfonyl] -1 - [(1H-imidazol-4-yl) methyl] 3- (phenylmethyl) -1H-1,4- benzodiazepine (monohydrochloride); (R) -7-Cyano-4- [N- (tetrahydroisoquinolinyl) sulfonyl] -1 - [(1H-imidazol-4-yl) methyl] -3 (phenylmethyl) -1H-1,4-benzodiazepine (monohydrochloride); (R) -7-Cyano-2,3,4,5-tetrahydro-1- (1H-imidazol-4-ylmethyl) -4- (phenylsulfonyl) -3- (2-thienylmethyl) -1H-1,4-benzodiazepine (hydrochloride); cis-2,3,4,5-Tetrahydro-1,5-bis (1H-imidazol-4-ylmethyl) -3- (phenylmethyl) -1H-1,5-benzodiazepine-2-carboxylic acid ethyl ester (trifluoroacetate, 1 : 2); (R) -7-Cyano-4 - [(N-piperidinyl) sulfonyl] -1 - [(1H-imidazol-4-yl) methyl] -3- (phenylmethyl) -1H-1,4-benzodiazepine (monohydrochloride) ; (R) -7-Cyano-2,3,4,5-tetrahydro-1- (1H-1-methylimidazol-5-ylmethyl) -3- (phenylmethyl) -4 (2-thienylsulfonyl) -1H- 1,4-benzodiazepine (hydrochloride); (R) -7-Cyano-2,3,4,5-tetrahydro-1- (1H-imidazol-4-ylmethyl) -3- (pyridin-3-ylmethyl) -4 - [[2- (dimethylamino) ethyl] ] sulfonyl] -1H-1,4-benzodiazepine (trihydrochloride); (R) -7-Cyano-2,3,4,5-tetrahydro-1- (1H-1-methylimidazol-5-ylmethyl) -3- (phenylmethyl) -4 (propylsulfonyl) -1H -1,4-benzodiazepine (hydrochloride); N- (Cyano) -N'-methyl-1,2,3,5-tetrahydro-1- (1H-imidazol-4-ylmethyl) -7-phenyl-4H-1,4-benzodiazepine-4-imidamide (hydrochloride) ; (R) -7-Cyano-4 - [(2-nitrophenyl) sulfonyl] -2,3,4,5-tetrahydro-1- (1H-imidazol-4-ylmethyl) -3- (phenylmethyl) -1H-1 , 4-benzodiazepine (hydrochloride); (R) -7-Cyano-4 - [(4-methylphenyl) sulfonyl] -2,3,4,5-tetrahydro-1- (1H-imidazol-4-ylmethyl) -3- (phenylmethyl) -1H- 1,4-benzodiazepine (hydrochloride); (R) -7-Cyano-4- (butylsulfonyl) -2,3,4,5-tetrahydro-1- (1H-imidazol-4-ylmethyl) -3 (phenylmethyl) -1H-1,4-benzodiazepine (hydrochloride); (R) -7-Cyano-4 - [(2-trifluoromethylphenyl) sulfonyl] -2,3,4,5-tetrahydro-1- (1H-imidazol-4-ylmethyl) -3- (phenylmethyl) -1H-1, 4-benzodiazepine (hydrochloride); (R) -7-Cyano-4 - [(2-trifluoromethoxyphenyl) sulfonyl] -2,3,4,5-tetrahydro-1- (1H-imidazol-4-ylmethyl) -3- (phenylmethyl) -1H-1, 4-benzodiazepine (hydrochloride); (R) -7-Cyano-4 - [(2-methoxycarbonylphenyl) sulfonyl] -2,3,4,5-tetrahydro-1- (1H-imidazol-4-ylmethyl) -3- (phenylmethyl) -1H- 1,4-benzodiazepine (hydrochloride); (R) -7-Cyano-4 - [(2-methylsulfonylphenyl) sulfonyl] -2,3,4,5-tetrahydro-1- (1H-imidazol-4-ylmethyl) -3- (phenylmethyl) -1H- 1,4-benzodiazepine (hydrochloride); (R) -7-Cyano-2,3,4,5-tetrahydro-1- (1H-imidazol-4-ylmethyl) -3- (phenylmethyl) -4 - (((4-methylsulfonyl) phenyl) sulfonyl) - 1H-1,4-benzodiazepine; (R) -7-Cyano-2,3,4,5-tetrahydro-1- (1H-imidazol-4-ylmethyl) -3- (phenylmethyl) -4 - (((4-trifluoromethyl) phenyl) sulfonyl) - 1H-1,4-benzodiazepine; (R) -7-Cyano-2,3,4,5-tetrahydro-1- (1H-imidazol-4-ylmethyl) -3- (phenylmethyl) -4 - ((3methoxypropyl) sulfonyl) -1H-1 , 4-benzodiazepine; (R) -7-Cyano-2,3,4,5-tetrahydro-1- (1H-imidazol-4-ylmethyl) -3- (phenylmethyl) -4 - ((3,4-dimethoxyphenyl) sulfonyl) -1H -1,4-benzodiazepine; (R) -7-Cyano-2,3,4,5-tetrahydro-1- (1H-imidazol-4-ylmethyl) -3 - ((4-fluorophenyl) methyl) -4 (phenylsulfonyl) -1H-1 , 4-benzodiazepine; (R) -7-Cyano-4 - [(N-cyclopropylmethyl-N-propyl) -aminosulfonyl] -1 - [(1H-imidazol-4ii) methyl] -3- (phenylmethyl) -1H-1,4- benzodiazepine; (R) -7-Cyano-4 - [(N, N- (dibutylamino)) sulfonyl] -1 - [(1H-imidazol-4-yl) methyl] -3 (phenylmethyl) -1H-1,4 benzodiazepine; (R) -7-Chloro-4- (methanesulfonyl) -2,3,4,5-tetrahydro-1- (1H-imidazol-4-ylmethyl) -3 (phenylmethyl) -1H-pyrido [3,4- e] -1,4-diazepine; 1.2.3.5-Tetrahydro-1- (1H-imidazol-4-ylmethyl) -N- (1-naphthalenyl) -7-phenyl-4H-1,4-benzodiazepine-4-carboxamide (monohydrochloride); (S) -7-Bromo-2,3,4,5-tetrahydro-1- (1H-imidazol-4-ylmethyl) -4- (methylsulfonyl) -3 (phenylmethyl) -1H-1,4-benzodiazepine (hydrochloride) ); N- [2,3,4,5-Tetrahydro-1- (1H-imidazol-4-ylmethyl) -4- (2,3-dimethylbenzoyl) -1H-1,4-benzodiazepin-8-yl] cyclohexanecarboxamide (dihydrochloride) ); (R) -7-Cyano-N- [2- (dimethylamino) ethyl] -2,3,4,5-tetrahydro-1- (1H-imidazol-4-ylmethyl) -N-methyl-3- (phenylmethyl) -1 H-1,4-benzodiazepine-4-carboxamide (trifluoroacetate, 1: 2); 1,2,4,5-Tetrahydro-1- (1H-imidazol-4-ylmethyl) -2- (2-phenylethyl) -3H-1,4-benzodiazepin-3-one; 1.2.3.5-Tetrahydro-1- (1H-imidazol-4-yl-methyl) -α, 7-diphenyl-4H-1,4-benzodiazepine-4-acetic acid methyl ester (hydrochloride); 1.2.3.5-Tetrahydro-1- (1H-imidazol-4-ylmethyl) -N, N-diphenyl-4H-1,4-benzodiazepine-4-carboxamide (hydrochloride); 1.2.3.5-Tetrahydro-1- (1H-imidazol-4-ylmethyl) -3- (phenylmethyl) -4H-naphtho [2,3-e] -1,4-diazepine-4-carboxylic acid methyl ester (monohydrochloride); 1.2.3.5-Tetrahydro-1- (1H-imidazol-4-ylmethyl) -N, N, 7-triphenyl-4H-1,4-benzodiazepine-4-carboxamide (dihydrochloride); 1.2.3.4-Tetrahydro-4 - [(1H-imidazol-4-yl) methyl] -1- (naphthalen-1-ylsulfonyl) quinoxaline (dihydrochloride); 1-Methyl-N- [2,3,4,5-tetrahydro-1- (1H-imidazol-4-ylmethyl) -4- (1-naphthalenylcarbonyl) -1H-1,4-benzodiazepin-8-yl] -2-piperidinecarboxamide (trihydrochloride); N - [2,3,4,5-Tetrahydro-1- (1H-imidazol-4-ylmethyl) -4- (1-naphthalenylcarbonyl) -1H-1,4-benzodiazepin-8-yl] - 4-morpholinecarboxamide (dihydrochloride); N- [2,3,4,5-Tetrahydro-1- (1H-imidazol-4-ylmethyl) -4- (1-naphthalenylcarbonyl) -1H-1,4-benzodiazepin-8-yl] -3-methylbutanamide (dihydrochloride) ; 1-Methyl-N- [2,3,4,5-tetrahydro-1- (1H-imidazol-4-ylmethyl) -4- (1-naphthalenylcarbonyl) -1H-1,4-benzodiazepin-8-yl] -1H-pyrrole-2-carboxamide (trihydrochloride); N- [2,3,4,5-Tetrahydro-1- (1H-imidazol-4-ylmethyl) -4- (1-naphthalenylcarbonyl) -1H-1,4-benzodiazepin-8-yl] -3-furancarboxamide (dihydrochloride) ; 1 - [[2- (2-Aminoethyl) -1H-imidazol-4-yl] methyl] -2,3,4,5-tetrahydro-4- (1-naphthalenylcarbonyl) -7-phenyl-1H-1,4 benzodiazepine (trihydrochloride); 1 - [[2- (2-Aminomethyl) -1H-imidazol-4-yl] methyl] -2,3,4,5-tetrahydro-4- (1-naphthalenylcarbonyl) -7-phenyl-1 H -1,4-benzodiazepine (trihydrochloride); 1.2.3.5-Tetrahydro-1- (1H-imidazol-4-ylmethyl) -N-methyl-N, 7-diphenyl-4H-1,4-benzodiazepine-4-carboxamide (dihydrochloride); 1 - [[1- (2-Aminomethyl) -1H-imidazol-5-yl) methyl] -2,3,4,5-tetrahydro-4- (1-naphthalenylcarbonyl) -7-phenyl-1H-1,4 benzodiazepine (trihydrochloride); 1 - [[2-aminomethyl) -1H-imidazol-4-yl) methyl] -2,3,4,5-tetrahydro-4- (1-naphthalenylcarbonyl) -1H-1,4-benzodiazepine (trihydrochloride); N- [2,3,4,5-Tetrahydro-1- (1H-imidazol-4-ylmethyl) -4- (1-naphthalenylcarbonyl) -1H-1,4-benzodiazepin-8-yl] acetamide (dihydrochloride); 1 - [[2- (2-aminoethyl) -1H-imidazol-4-yl) methyl] -2,3,4,5-tetrahydro-4- (1-naphthalenylcarbonyl) -1H-1,4-benzodiazepine (trihydrochloride) ; 1- [3-amino-3- (1H-imidazol-2-yl) propyl] -2,3,4,5-tetrahydro-4- (1-naphthalenylcarbonyl) -1H-1,4-benzodiazepine (trihydrochloride); 1.2.3.4-Tetrahydro-4 - [(3H-imidazol-4-yl) methyl] -1- (naphthalen-1-ylcarbonyl) quinoxaline (dihydrochloride); ¹ '15 only if Y is O, NR ¹⁰ , CHR ⁹ , ^{R 14 R 1 S} in formulas III and IV, or When m is zero, V and W cannot both be oxygen, or 1. A compound having the formula: R ⁴ , R ⁵ R ⁶ , R ⁷ R ¹ , R ² , R ³ and their enantiomers, diastereomers and pharmaceutically acceptable salts, their prodrugs and solvates which inhibit farnesyl protein transferase, an enzyme involved in the expression of ras oncogene, in which: m, n, r, s and t are 0 or 1; p is 0, 1 or 2; V, W and X are selected from the group consisting of oxygen, hydrogen, R ¹ , R ² or R ³ ; Z and Y are selected from the group consisting of CHR ⁹ , SO 2, SO 3, CO, CO 2, O, NR ¹⁰ , SO ² NR ¹¹ , CONR ¹² , N ' II - c.CN _X CN N II - C-NI R ¹³ O II N - ΟΙ R ¹⁴ N-SO ₂ R ¹⁵ o II C - N - N R 16 _R 17 - SO ₂ - N - N I and ¹⁸ R ¹⁹ O. .NR ²⁰ R ²¹ NNR ²² N '/ g —S—' S 'or Z may not be present; _R 6 R ⁷ _r 9 _r 10 1 p12 _r 13 p14 _R 15 _R 16 _R 17 _R 18 _R 19 p20 _r 21 r22 _R 24 _R 25 R ²⁶ R ²⁷ , R ²⁸ , R ²⁹ , R ³⁰ , R ³¹ , R ³² , R ³³ , R ³⁴ , R ³⁵ , R ³⁶ , R ³⁷ and R ³⁸ are selected from the group consisting of alkyl, aryl or aryl with alternately; R ⁴ , R ⁵ are selected from the group consisting of hydrogen, halogen, nitro, cyano and UR ²³ ; U is selected from the group consisting of sulfur, oxygen, NR ²⁴ , CO, SO, SO 2, CO2, NR ²⁵ CO2, NR ²⁶ CONR ²⁷ , NR ²⁸ SO 2i NR ²⁹ SO 2 NR ³⁰ , SO ² NR ³ ', NR ³² CO, CONR ³³ , PO2R ³⁴ and PO ₃ R ³⁵ or U are absent; R ¹ , R ² and R ³ are selected from the group consisting of hydrogen, alkyl, alkoxycarbonyl, substituted alkyl, alkenyl, alkenyl substituted, alkynyl, alkynyl substituted, aralkyl, cycloalkyl, aryl, aryl substituted, heterocyclic, heterocyclic substituted with cyano, carboxy, carbamyl (e.g., CONH ₂ ) or carbamyl substituted with CONH-alkyl, CONHaryl, CONH-aralkyl, or substituted with two nitrogen atoms selected from alkyl, aryl or aralkyl; R ⁸ and R ²³ are selected from the group consisting of hydrogen, alkyl, substituted alkyl, alkenyl, alkenyl substituted, alkynyl, alkynyl substituted, aralkyl, cycloalkyl, aryl, aryl substituted, heterocyclic, heterocyclic substituted; any two of R ¹ , R ² and R ³ may be joined together to form a cycloalkyl group; R, S and T are selected from the group consisting of CH ₂ , CO and CH (CH ₂ ) _P Q wherein Q is NR ³⁶ R ³⁷ , OR ³⁸ or CN; and A, B, C and D are carbon, oxygen, sulfur or nitrogen; provided that 2.3.4.5-Tetrahydro-1 - [(1-methyl-1H-imidazol-5-yl) methyl] -4- (methylsulfonyl) -7-phenyl-3 (pyridin-3-yl- methyl) -1H-1,4-benzodiazepine (hydrochloride, 1: 1.5, and trifluoroacetate, 1: 0.75 salt); 2.3.4.5-Tetrahydro-1- (1H-imidazol-4-ylmethyl) -4 - [(4-pyridylthio) acetyl] -7-phenyl-1H-1,4-benzodiazepine (dihydrochloride); N- (4-chlorophenyl) -N'-cyano-1,2,3,5-tetrahydro-1- (1H-imidazol-4-ylmethyl) -7-phenyl-4H-1,4-benzodiazepine-4-imidamide (monohydrochloride) ; 2,3,4,5-Tetrahydro-1- (1H-imidazol-4-ylmethyl) -4- (methylsulfonyl) -3- (phenylmethyl) -1H1,4-benzodiazepine (dihydrochloride); (R) -7-Bromo-2,3,4,5-tetrahydro-1 - [(1-methyl-1H-imidazol-4-yl) methyl] -4- (methylsulfonyl) -3- (phenylmethyl) -1H- 1,4-benzodiazepine (dihydrochloride); (R) -4 - [[3- (Dimethylamino) propyl] sulfonyl] -2,3,4,5-tetrahydro-1- (1H-imidazol-4-ylmethyl) -7-phenyl-3- (phenylmethyl) -1H -1,4-benzodiazepine (dihydrochloride); (R) -7-Cyano-2,3,4,5-tetrahydro-1- (1H-imidazol-4-ylmethyl) -3- (phenylmethyl) -1H-1,4-benzodiazepine (trihydrochloride); 2.3.4.5-Tetrahydro-1- (1H-imidazol-4-ylmethyl) -4- (methylsulfonyl) -7-phenyl-3- (phenylmethyl) -1H-1,4-benzodiazepine; 2.3.4.5-Tetrahydro-1- (1H-imidazol-4-ylmethyl) -4- (methylsulfonyl) -2- (2-phenylethyl) -1H1,4-benzodiazepine (monohydrochloride); (R) -2,3,4,5-Tetrahydro-1- (1H-imidazol-4-ylmethyl) -4- (methylsulfonyl) -7-phenyl-3- (4-pyridinylmethyl) -1H-1,4-benzodiazepine ( dihydrochloride); (R) -2,3,4,5-Tetrahydro-1- (1H-imidazol-2-ylmethyl) -4- (phenylsulfonyl) -3- (phenylmethyl) -1H-1,4-benzodiazepine-7-carbonitrile (hydrochloride): (R) -7-Cyano-1,2,3,5-tetrahydro-1- (1H-imidazol-4-ylmethyl) -N, N-dimethyl-3- (3-pyridinylmethyl) -4H-1,4-benzodiazepine -4-Carboxamide (dihydrochloride): (R) -7-Cyano-1,2,3,5-tetrahydro-1- (1H-imidazol-4-ylmethyl) -N, N-dimethyl-3- (3-pyridinylmethyl) - 4H-1,4-benzodiazepine-4-sulfonamide (dihydrochloride); 4 - [(4-fluorophenyl) sulfonyl] -2,3,4,5-tetrahydro-1 - [(1-methyl-1H-imidazol-5-yl) -3 (phenylmethyl) -1H-thieno [2, 3-e] -1,4-diazepine (monohydrochloride); (R) -2,3,4,5-Tetrahydro-1- (1- (4-cyanophenylmethyl) -imidazol-5-ylmethyl) -4- (methylsulfonyl) -3- (phenylmethyl) -1H-1,4-benzodiazepine -7-carbonitrile (hydrochloride); (R) -2,3,4,5-Tetrahydro-1- (1- (4-cyanophenylmethyl) -imidazol-4-ylmethyl) -4- (methylsulfonyl) -3- (phenylmethyl) -1H-1,4-benzodiazepine -7-carbonitrile (hydrochloride); (R) -4-Benzoyl-7-cyano-2,3,4,5-tetrahydro-1- (1H-imidazol-4-ylmethyl) -3- (phenylmethyl) -1H-1,4-benzodiazepine (monohydrochloride) ; (R) -7-Cyano-2,3,4,5-tetrahydro-1 - [(1-methyl-1 H -imidazol-5-yl) methyl] -3- (pyridin-3-ylmethyl) - 4- (methylsulfonyl) -1H-1,4-benzodiazepine (dihydrochloride); (R) -7-Cyano-2,3,4,5-tetrahydro-1 - [(1-methyl-1H-imidazol-5-yl) methyl] -3- (pyridin-3-ylmethyl) -4- (propylsulfonyl) ) -1 H -1,4-benzodiazepine (trihydrochloride); (R) -7-Cyano-2,3,4,5-tetrahydro-1 - [(1H-imidazol-4-yl) methyl] -3- (pyridin-3-ylmethyl) -4 (phenylsulfonyl) -1H- 1,4-benzodiazepine (dihydrochloride); 2.3.4.5-Tetrahydro-1- (1H-imidazol-4-ylmethyl) -4- (methylsulfonyl) -3- (phenylmethyl) -7- (2-pyridinyl) -1H-1,4-benzodiazepine (dihydrochloride); (R) -7-Bromo-2,3,4,5-tetrahydro-1- (1H-imidazol-4-ylmethyl) -3- (phenylmethyl) -4 - [(trifluoromethyl) sulfonyl] -1H-1,4 benzodiazepine (monohydrochloride); (R) -2,3,4,5-Tetrahydro-1- (1H-imidazol-4-ylmethyl) -7-phenyl-3- (phenylmethyl) -4 (trifluoroacetyl) -1H-1,4-benzodiazepine ( monohydrochloride); (R) -2,3,4,5-Tetrahydro-1- (1H-imidazol-4-ylmethyl) -4- (methylsulfonyl) -3- (phenylmethyl) -7 (4-pyridinyl) -1H-1, 4-benzodiazepine (dihydrochloride); (R) -2,3,4,5-Tetrahydro-1- (1H-imidazol-4-ylmethyl) -3- (phenylmethyl) -7- (4-pyridinyl) -4- (2-thienylsulfonyl) -1H-1 , 4-benzodiazepine (dihydrochloride); (R) -2,3,4,5-Tetrahydro-1- (1H-imidazol-4-ylmethyl) -3- (phenylmethyl) -4- (phenylsulfonyl) -7 (4-pyridinyl) -1H-1, 4-benzodiazepine (dihydrochloride); (R) -2,3,4,5-Tetrahydro-1- (1H-imidazol-4-ylmethyl) -3- (phenylmethyl) -4- (propylsulfonyl) 7- (4-pyridinyl) -1H-1, 4-benzodiazepine (dihydrochloride); (R) -7-Cyano-2,3,4,5-tetrahydro-1- (1H-imidazol-4-ylmethyl) -3- (phenylmethyl) -4 - [(3,5-dimethylisoxazol-4-yl) sulfonyl] -1H-1,4-benzodiazepine (dihydrochloride); (R) -7-Cyano-4 - [(4-cyanophenyl) sulfonyl] -2,3,4,5-tetrahydro-1- (1H-imidazol-4-ylmethyl) -3- (phenylmethyl) -1H-1, 4-benzodiazepine (dihydrochloride); (R) -7-Cyano-2,3,4,5-tetrahydro-1- (1H-imidazol-4-ylmethyl) -3- (phenylmethyl) -4 - [(2,2,2-trifluoroethyl) sulfonyl] -1 H-1,4-benzodiazepine (dihydrochloride); (R) - [(5-Bromo-2-thienyl) sulfonyl] -7-cyano-2,3,4,5-tetrahydro-1- (1H-imidazol-4-ylmethyl) -3- (phenylmethyl) -1H- 1,4-benzodiazepine (dihydrochloride); (R) -7-Cyano-2,3,4,5-tetrahydro-1- (1H-imidazol-4-ylmethyl) -4 - [(4-methoxyphenyl) sulfonyl] -3- (phenylmethyl) -1H-1,4 benzodiazepine (dihydrochloride); N - [[7-Bromo-2,3,4,5-tetrahydro-1- (1H-imidazol-4-ylmethyl) -4- (methylsulfonyl) -1H-1,4-benzodiazepin-3-yl] methyl] benzamide (dihydrochloride); (R) -7-Cyano-1,2,3,5-tetrahydro-1- (1H-imidazol-4-ylmethyl) -N, N-dimethyl-3 (phenylmethyl) -4H-1,4-benzodiazepine; 4-sulfonamide (hydrochloride); (R) -7-Cyano-1,2,3,5-tetrahydro-N, N-dimethyl-1 - [(1-methyl-1H-imidazol-5-yl) methyl] -3 (phenylmethyl) -4H -1,4-benzodiazepine-4-sulfonamide (hydrochloride); (R) -7-Chloro-2,3,4,5-tetrahydro-1 - [(1-methyl-1H-imidazol-5-yl) methyl] -4 (methylsulfonyl) -3- (phenylmethyl) -1 H-1,4-benzodiazepine (monohydrochloride); (R) -7-Chloro-2,3,4,5-tetrahydro-1- (1H-imidazol-4-ylmethyl) -4- (methylsulfonyl) -3 (phenylmethyl) -1H-1,4-benzodiazepine (monohydrochloride) ); (R) -7-Chloro-2,3,4,5-tetrahydro-1 - [(1-methyl-1H-imidazol-5-yl) methyl] -4- (phenylsulfonyl) -3- (phenylmethyl) -1 H-1,4-benzodiazepine (monohydrochloride); (R) -7-Cyano-2,3,4,5-tetrahydro-1- (1H-imidazol-4-ylmethyl) -3- (pyridin-3-ylmethyl) -4 (methylsulfonyl) -1H-1,4 benzodiazepine (tetrahydrochloride); (R) -7-Bromo-2,3,4,5-tetrahydro-1- (1H-imidazol-2-ylmethyl) -4- (methylsulfonyl) -3 (phenylmethyl) -1H-1,4-benzodiazepine ( dihydrochloride); (R) -7-Bromo-2,3,4,5-tetrahydro-1- (1H-imidazol-4-ylmethyl) -4 - [(1-methyl-1H-imidazol4-yl) sulfonyl] -3- (phenylmethyl) -1H-1,4-benzodiazepine (trihydrochloride); (R) -7-Chloro-2,3,4,5-tetrahydro-1- (1-methylimidazol-5-ylmethyl) -4 - [(2-morpholin-4-ylethyl) sulfonyl] -3- ( phenylmethyl) -1H-1,4-benzodiazepine (dihydrochloride); (R) -7-Chloro-2,3,4,5-tetrahydro-1- (1H-imidazol-4-ylmethyl) -4 - [(2-morpholin-4-ylethyl) sulfonyl] -3- (phenylmethyl) -1 H -1,4-benzodiazepine (dihydrochloride); (R) -7-Chloro-4 - [(dimethylamino) sulfonyl] -1 - [(1-methyl-1H-imidazol-5-yl) methyl] -3 (phenylmethyl) -1H-1,4-benzodiazepine (monohydrochloride); (R) -7-Chloro-2,3,4,5-tetrahydro-1- (1-methylimidazol-5-ylmethyl) -4 - [(4-methylpiperidin-4-yl-ethyl) sulfonyl] -3 - (phenylmethyl) -1H-1,4-benzodiazepine (dihydrochloride); (R) -7-Bromo-2,3,4,5-tetrahydro-1- (1-methylimidazol-5-ylmethyl) -4 - [(4-methylpiperidin-4-yl-ethyl) sulfonyl] -3 - (phenylmethyl) -1H-1,4-benzodiazepine (dihydrochloride); (R) -7-Cyano-1,2,3,5-tetrahydro-1- (1H-imidazol-4-ylmethyl) -3- (phenylmethyl) -4H-1,4-benzodiazepine-4-carboxylic acid isopropyl ester (hydrochloride) ; (R) -7-Bromo-2,3,4,5-tetrahydro-4 - [[2-1H-imidazol-1-yl) ethyl] sulfonyl] -1- (1H-imidazol-4-ylmethyl) -3- ( phenylmethyl) -1H-1,4-benzodiazepine (dihydrochloride); (R) -7-Cyano-2,3,4,5-tetrahydro-1- (1H-imidazol-4-ylmethyl) -4- (propylsulfonyl) -3- (3- (pyridinylmethyl) -1H-1,4 benzodiazepine (hydrochloride); 2.3.4.5-Tetrahydro-1- (1H-imidazol-4-ylmethyl) -7-phenyl-4- (1-phenyl-1H-tetrazol-5-yl) -1H-1,4-benzodiazepine (monohydrochloride); (R) -7-Cyano-2,3,4,5-tetrahydro-1- (1H-imidazol-4-ylmethyl) -3- (phenylmethyl) -4- (2-pyrazinylcarbonyl) -4H-1,4-benzodiazepine ( monohydrochloride); (R) -4- [7-Bromo-2,3,4,5-tetrahydro-1- (1H-imidazol-4-ylmethyl) -3- (phenylmethyl) -4H-1,4-benzodiazepin-4-yl] -4-oxobutanecarboxylic acid methyl ester (monohydrochloride); (R) -7-Cyano-2,3,4,5-tetrahydro-1- (1H-imidazol-4-ylmethyl) -4- (4-morpholinylcarbonyl) -3- (phenylmethyl) -1H-1,4- benzodiazepine (monohydrochloride); (R) -7-Cyano-2,3,4,5-tetrahydro-1- (1H-imidazol-4-ylmethyl) -3- (phenylmethyl) -4 - [[2- (1-pyrrolidinyl) ethylsulfonyl] -1H -1,4-benzodiazepine (dihydrochloride); (S) -2,3,4,5-Tetrahydro-1- (1H-imidazol-4-ylmethyl) -4- (methylsulfonyl) -7-phenyl-3- (3-pyridinylmethyl) -1H-1,4-benzodiazepine (dihydrochloride); (R) -2,3,4,5-Tetrahydro-1- (1H-imidazol-4-ylmethyl) -7-phenyl-3- (3-pyridinylmethyl) -4- (2-thienylsulfonyl) -1H-1, 4-benzodiazepine (dihydrochloride); (R) -2,3,4,5-Tetrahydro-1- (1H-imidazol-4-ylmethyl) -7-phenyl-4- (propylsulfonyl) -3- (3-pyridinylmethyl) -1H-1,4-benzodiazepine (monohydrochloride); (R) -7-Bromo-2,3,4,5-tetrahydro-1- (1H-imidazol-4-ylmethyl) -4- (methylsulfonyl) -3- (2-pyridinylmethyl) -1H-1,4-benzodiazepine (monohydrochloride); 2.3.4.5-Tetrahydro-1- (1H-imidazol-4-ylmethyl) -4- (methylsulfonyl) -3- (phenylmethyl) -1H1,4-benzodiazepine-4-carbonitrile (monohydrochloride); (R) -7-Cyano-1,2,3,5-tetrahydro-1- (1H-imidazol-4-ylmethyl) -N, N-dimethyl-3 (phenylmethyl) -4H-1,4-benzodiazepine-4 -carboxamide (monohydrochloride); N, N-Diethyl-2,3,4,5-tetrahydro-1- (1H-imidazol-4-ylmethyl) -4- (methylsulfonyl) -3 (phenylmethyl) -1H-1,4-benzodiazepine-4- carboxamide (monohydrochloride); 2.3.4.5-Tetrahydro-1- (1H-imidazol-4-ylmethyl) -4- (methylsulfonyl) -3- (phenylmethyl) -7- (3pyridinyl) -1H-1,4-benzodiazepine (trihydrochloride); 2.3.4.5-Tetrahydro-1- (1H-imidazol-4-ylmethyl) -3- (phenylmethyl) -7- (3-pyridinyl) -4 (trifluoroacetyl) -1H-1,4-benzodiazepine (trihydrochloride); 2,3,4,5-Tetrahydro-1- (1H-imidazol-4-ylmethyl) -7- (4-pyridinyl) -4- [2- (trifluoromethoxy) benzoyl] -1H-1,4-behzodiazepine (trihydrochloride) ); (R) -2,3,4,5-Tetrahydro-1 - [(1-methyl-1H-imidazol-5-yl) methyl] -4- (methylsulfonyl) -7-phenyl-3- (phenylmethyl) -1H -1,4-benzodiazepine; (R) -7-Cyano-2,3,4,5-tetrahydro-1- (1H-imidazol-4-ylmethyl) -4- (phenylacetyl) -3 (phenylmethyl) -1H-1,4- benzodiazepine (monohydrochloride); 2,3,4 _{5-tetrahydro-1-} (1H-imidazol-4-ylmethyl) -4- (2-phenyl-1,2-dioxoethyl) -7- (4- pyridinyl) -1H-1,4-benzodiazepine (trihydrochloride); 2.3.4.5-Tetrahydro-1- (1H-imidazol-4-ylmethyl) -4- (1-naphthalenylcarbonyl) -N- (phenylmethyl) -1H-1,4-benzodiazepine-8-carboxamide (dihydrochloride); (R) -4-Acetyl-7- [2 - [(dimethylamino) methyl] phenyl] -2,3,4,5-tetrahydro-1- (1H-imidazol-4-ylmethyl) -3- (phenylmethyl) -1H -1,4-benzodiazepine (dihydrochloride); (R) -4-Acetyl-7-cyano-2,3,4,5-tetrahydro-1- (1H-imidazol-4-ylmethyl) -3- (phenylmethyl) -1H-1,4-benzodiazepine (monohydrochloride) ; (R) -7-Cyano-2,3,4,5-tetrahydro-1- (1H-imidazol-4-ylmethyl) -4- (1-oxobutyl) -3 (phenylmethyl) -1H-1,4- benzodiazepine (monohydrochloride); (R) -7-Cyano-2,3,4,5-tetrahydro-1- (1H-imidazol-4-ylmethyl) -4- (2-methyl-1-oxopropyl) -3- (phenylmethyl) -1H-1, 4-benzodiazepine (monohydrochloride); (R) -7-Cyano-2,3,4,5-tetrahydro-1- (1H-imidazol-4-ylmethyl) -3- (phenylmethyl) -4- (2-pyridinylacetyl) -1H-1,4-benzodiazepine (dihydrochloride); (R) -7-Cyano-2,3,4,5-tetrahydro-1- (1H-imidazol-4-ylmethyl) -3- (phenylmethyl) -4- (2-thienylsulfonyl) -1H-1,4-benzodiazepine (monohydrochloride); (R) -7-Cyano-2,3,4,5-tetrahydro-1- (1H-imidazol-4-ylmethyl) -4 - [(1-methylethyl) sulfonyl] 3- (phenylmethyl) -1H- 1,4-benzodiazepine (monohydrochloride); (R) -7-Cyano-2,3,4,5-tetrahydro-1- (1H-imidazol-4-ylmethyl) -3- (phenylmethyl) -4 - [(trifluoromethyl) sulfonyl] -1H-1,4 benzodiazepine (monohydrochloride); (R) -7-Bromo-2,3,4,5-tetrahydro-1- (1H-imidazol-4-ylmethyl) -3- (phenylmethyl) -4 (propylsulfonyl) -1H-1,4-benzodiazepine (monohydrochloride) ); (R) -7-Bromo-2,3,4,5-tetrahydro-1- (1H-imidazol-4-ylmethyl) -3- (phenylmethyl) -4- (phenylsulfonyl) -1H-1,4-benzodiazepine ( monohydrochloride); (R) -2,3,4,5-Tetrahydro-1- (1H-imidazol-4-ylmethyl) -7-phenyl-3- (phenylmethyl) -4 (phenylsulfonyl) -1H-1,4-benzodiazepine ( monohydrochloride); (R) -2,3,4,5-Tetrahydro-1- (1H-imidazol-4-ylmethyl) -7-phenyl-3- (phenylmethyl) -4 (propylsulfonyl) -1H-1,4- benzodiazepine (monohydrochloride); (R) -7-Cyano-4 - [(4-fluorophenyl) sulfonyl] -2,3,4,5-tetrahydro-1- (1H-imidazol-4-ylmethyl) -3- (phenylmethyl) -1H-1 , 4-benzodiazepine (monohydrochloride); (R) -7-cyano-4 - [(3-cyanophenyl) sulfonyl] -2,3,4,5-tetrahydro-1- (1H-imidazol-4-ylmethyl) -3- (phenylmethyl) -1H-1, 4-benzodiazepine (monohydrochloride); (R) -7-Cyano-2,3,4,5-tetrahydro-1- (1H-imidazol-4-ylmethyl) -4 - [(1-methyl-1H-imidazol-2-yl) sulfonyl] -3- ( phenylmethyl) -1H-1,4-benzodiazepine (dihydrochloride); (R) -4 - [(3-Bromophenyl) sulfonyl] -7-cyano-2,3,4,5-tetrahydro-1- (1H-imidazol-4-ylmethyl) -3- (phenylmethyl) -1H-1, 4-benzodiazepine (monohydrochloride); (R) -N- [5 - [[7-Cyano-2,3,4,5-tetrahydro-1- (1H-imidazol-4-yl-ethyl) -3- (phenylmethyl) -1H-1,4- benzodiazepin-4-yl] sulfonyl] -4-methyl-2-thiazolyl] acetamide (dihydrochloride); 2.3.4.5-Tetrahydro-1- (1H-imidazol-4-ylmethyl) -4- (1- (naphthalenylcarbonyl) -8 (phenoxymethyl) -1H-1,4-benzodiazepine (dihydrochloride); N-Cyclohexyl I-2,3,4,5-Tetrahydro-1- (1H-midazol-4-ylmethyl) -4- (1- (naphthalenylcarbonyl) -1H-1,4-benzodiazepine-8-carboxamide (dihydrochloride) N- (cyclohexylmethyl) -2,3,4,5-tetrahydro-1- (1H-imidazol-4-ylmethyl) -4- (1- (naphthalenylcarbonyl) -1H-1,4-benzodiazepine-8-carboxamide (dihydrochloride); 2.3.4.5-Tetrahydro-8- (hydroxymethyl) -1- (1H-imidazol-4-ylmethyl) -4- (1- (naphthalenylcarbonyl) -1H-1,4-benzodiazepine (dihydrochloride); 2,3,4,5-Tetrahydro-1- (1H-imidazol-4-ylmethyl) -7-phenyl-4- (3,3,3-trifluoro-1,2-dioxopropyl) -1H-1,4- benzodiazepine (trifluoroacetate, 1: 2); (R) -7-Chloro-2,3,4,5-tetrahydro-1 - [(1H-imidazol-4-yl) methyl] -4- (methylsulfonyl) -3 (phenylmethyl) -1H-pyrido [3 2-e] -1,4-diazepine (hydrochloride); 6,7,8,9-Tetrahydro-5- (1H-imidazol-4-ylmethyl) -8- (1-naphthalenylcarbonyl) -2-phenyl-5H-pyrimido [5,4-e] [1,4 ] diazepine (monohydrochloride); (R) -7-Bromo-2,3,4,5-tetrahydro-1- (1H-imidazol-4-ylacetyl) -4- (methylsulfonyl) -3 (phenylmethyl) -1H-1,4-benzodiazepine (monohydrochloride) ); (R) -7-Bromo-2,3,4,5-tetrahydro-1- (2-1H-imidazol-4-yl-ethyl) -4- (methylsulfonyl) -3 (phenylmethyl) -1H-1,4- benzodiazepine (monohydrochloride); 8 - [(Cyclohexylcarbonyl) amino] -1,2,3,5-tetrahydro-1- (1H-imidazol-4-ylmethyl) -3 (phenylmethyl) -4H-1,4-benzodiazepine-4-carboxylic acid methyl ester (dihydrochloride); N- [2,3,4,5-Tetrahydro-1- (1H-imidazol-4-ylmethyl) -4- (1-naphthalenylcarbonyl) -1H-1,4-benzodiazepin-8-yl] -1-piperidinecarboxamide (dihydrochloride); (R) -7-Cyano-1,2,3,5-tetrahydro-1- (1H-imidazol-4-ylmethyl) -3- (phenylmethyl) -4H-1,4-benzodiazepine-4-carboxylic acid ethyl ester (hydrochloride) ); N- [2,3,4,5-Tetrahydro-1- (1H-imidazol-4-ylmethyl) -4- (methylsulfonyl) -3- (phenylmethyl) 1H-1,4-benzodiazepin-8-yl] cyclohexanecarboxamide (dihydrochloride): (R) -7-cyano-4 - [[2- (dimethylamino) ethyl] sulfonyl] -2,3,4,5-tetrahydro-1- (1H-imidazol-4-ylmethyl) -3- ( phenylmethyl) -4 H -1,4-benzodiazepine (dihydrochloride); (R) -7-Cyano-2,3,4,5-tetrahydro-1- (1H-imidazol-4-ylmethyl) -4 - [[2- (4-morpholinyl) ethyl] sulfonyl] -3- (phenylmethyl) - 4H-1,4-benzodiazepine (dihydrochloride); N- [2,3,4,5-Tetrahydro-1- (1H-imidazol-4-ylmethyl) -4- (2-methoxy-3-methylbenzoyl) -1H1,4-benzodiazepin-8-yl] cyclohexanecarboxamide (dihydrochloride); 8 - [(Cyclohexylcarbonyl) amino] -2,3,4,5-tetrahydro-1- (1H-imidazol-4-ylmethyl) -N-phenyl-1H-1,4-benzodiazepine-4-carboxamide (dihydrochloride) ); N- [2,3,4,5-Tetrahydro-1- (1H-imidazol-4-ylmethyl) -4 - [(2-methylphenyl) sulfonyl] -1H-1,4-benzodiazepin-8-yl] cyclohexanamide (dihydrochloride) ); N- [2,3,4,5-Tetrahydro-1- (1H-imidazol-4-ylmethyl) -4 - [(2-methoxyphenyl) carbonyl] -1H1,4-benzodiazepin-8-yl] cyclohexanamide ( dihydrochloride); (R) -7-Cyano-1,2,3,5-tetrahydro-1- (1H-imidazol-4-ylmethyl) -3- (phenylmethyl) -4H-1,4-benzodiazepine-4-sulfonic acid ethyl ester (hydrochloride); (3R) -7brom-1- [cyano (1H-imidazol-4-yl) methyl] -2.3 _I 4,5-tetrahydro-4- (methylsulfonyl) -3- (phenyl m ethyl) -1 H-1, 4-benzodiazepine (monohydrochloride); (3R) -1- [2-Amino-1- (1H-imidazol-4-yl) ethyl] -2,3,4,5-tetrahydro-4- (methylsulfonyl) -3 (phenylmethyl) -1H- 1,4-benzodiazepine (dihydrochloride); (3R) -1- [2- (Dimethylamino) -1- (1H-imidazol-4-yl) ethyl] -2,3,4,5-tetrahydro-4- (methylsulfonyl) -3- (phenylmethyl) - 1H-1,4-benzodiazepine (dihydrochloride); (3R) -1- [2-Amino-1- (1H-imidazol-4-yl) ethyl] -7-bromo-2,3,4,5-tetrahydro-4- (methylsulfonyl) -3- (phenylmethyl) - 1H-1,4-benzodiazepine (dihydrochloride); (3R) -1- [2- (Dimethylamino) -1- (1H-imidazol-4-yl) ethyl] -7-bromo-2,3,4,5-tetrahydro-4- (methylsulfonyl) -3- (phenylmethyl) ) -1 H -1,4-benzodiazepine (dihydrochloride); 7-Cyano-1,3,4,5-tetrahydro-1- (1-methyl-1H-imidazol-5-ylmethyl) -3- (phenylmethyl) -4- (phenylsulfonyl) -2H-1,4-benzodiazepine-2 -one (monohydrochloride); 2,3,4,5-Tetrahydro-1- (1H-imidazol-4-ylmethyl) -4- [2- (4-methoxyphenyl) -1,2-dioxoethyl] -7-phenyl-1H-1,4-benzodiazepine (hydrochloride); 2,3,4,5-Tetrahydro-1- (1H-imidazol-4-ylmethyl) -4- [2- (4-nitrophenyl) -1,2-dioxoethyl] -7-phenyl-1H-1,4- benzodiazepine (hydrochloride); 2,3,4,5-Tetrahydro-1- (1H-imidazol-4-ylmethyl) -4- (methylsulfonyl) -3- (phenylmethyl) -7- (4-pyridinyl) -1H-1,4-benzodiazepine (trihydrochloride) ); (R) -4 - [[2- (Dimethylamino) ethyl] sulfonyl] -2,3,4,5-tetrahydro-1- (1H-imidazol-4-ylmethyl) -7-phenyl-3- (phenylmethyl) -1H- 1,4-benzodiazepine (trifluoroacetate, 1: 1); [2,3,4,5-Tetrahydro-1- (1H-imidazol-4-ylmethyl) -4- (naphthalenylcarbonyl) -1H-1,4-benzodiazepin-8-yl] carbamic acid cyclohexyl ester (dihydrochloride); (R) -7-Bromo-2,3,4,5-tetrahydro-1- (1-methyl-1H-imidazol-5-yl) methyl) -4 (methylsulfonyl) -3- (phenylmethyl) -1 H-1,4-benzodiazepine (hydrochloride); (R) -7-Cyano-2,3,4,5-tetrahydro-1 - [(1-methyl-1H-imidazol-5-yl) methyl] -4 (methylsulfonyl) -3- (phenylmethyl) -1 H-1,4-benzodiazepine (hydrochloride); (R) -2,3,4,5-Tetrahydro-1- (1H-imidazol-4-ylmethyl) -4- (methylsulfonyl) -7-phenyl-3- (phenylmethyl) -1H-pyrido [3,2-e ] -1,4-diazepine (monohydrochloride); 4- [2- (4-chlorophenyl) -1,2-dioxoethyl] -2,3,4,5-tetrahydro-1- (1H-imidazol-4-ylmethyl) -7-phenyl-1H-1,4-benzodiazepine (hydrochloride); 2,3,4,5-Tetrahydro-1- (1H-imidazol-4-ylmethyl) -7-phenyl-4 - [(1,2,3,4-tetrahydro-1quinolinyl) carbonyl] -1H-1 , 4-benzodiazepine (monohydrochloride); N-ethyl-1,2,3,5-tetrahydro-1- (1H-imidazol-4-ylmethyl) -N, 7-diphenyl-4H-1,4-benzodiazepine-4-carboxamide (monohydrochloride); 4 - [(2,3-dihydro-1H-indol-1-yl) carbonyl] -2,3,4,5-tetrahydro-1- (1H-imidazol-4-ylmethyl) -7-phenyl-1H-1,4 benzodiazepine (monohydrochloride); 2.3.4.5-Tetrahydro-1- (1H-imidazol-4-yl) -4- [2 - [(phenylmethyl) amino] benzoyl] -1H1,4-benzodiazepine (trifluoroacetate, 1: 3); 2.3.4.5-Tetrahydro-1- (1H-imidazol-4-yl) -4- [2 - [(4-methylphenyl) sulfinyl] benzoyl] 1H-1,4-benzodiazepine (trifluoroacetate, 1: 2); 2.3.4.5-Tetrahydro-1- (1H-imidazol-4-ylmethyl) -4 - [(2-phenoxyphenyl) acetyl] -1H-1,4-benzodiazepine (trifluoroacetate, 1: 2); 2.3.4.5-Tetrahydro-1- (1H-imidazol-4-yl) -4- (1-oxo-4-phenylbutyl) -1H-1,4-benzodiazepine (trifluoroacetate, 1: 2); 2.3.4.5-Tetrahydro-1- (1H-imidazol-4-ylmethyl) -4- (2-naphthalenylcarbonyl) -1H-1,4-benzodiazepine (trifluoroacetate, 1: 2); 2.3.4.5-Tetrahydro-1- (1H-imidazol-4-ylmethyl) -4- (4-phenoxybenzoyl) -1H-1,4-benzodiazepine (trifluoroacetate, 1: 2); 2.3.4.5-Tetrahydro-1- (1H-imidazol-4-ylmethyl) -4 - [[4 '- (trifluoromethyl) [1,1'-biphenyl] -2yl] carbonyl] -1H-1,4-benzodiazepine (trifluoroacetate, 1: 2); 2.3.4.5-Tetrahydro-1- (1H-imidazol-4-ylmethyl) -4- (3-phenoxybenzoyl) -1H-1,4-benzodiazepine (trifluoroacetate, 1: 2); 2.3.4.5-Tetrahydro-1- (1H-imidazol-4-ylmethyl) -4- (3-pyridinylacetyl) -1H-1,4-benzodiazepine (trifluoroacetate, 1: 3); 2.3.4.5-Tetrahydro-1- (1H-imidazol-4-ylmethyl) -4 - [(2-phenyl-4-quinolinyl) carbonyl] -1 H -1,4-benzodiazepine (trifluoroacetate, 1: 3); 2,3,4,5-Tetrahydro-1- (1H-imidazol-4-ylmethyl) -4- (2-naphthalenylacetyl) -1H-1,4-benzodiazepine (trifluoroacetate, 1: 2); 2.3.4.5-Tetrahydro-1- (1H-imidazol-4-ylmethyl) -4 - [(2-naphthalenethio) acetyl] -1H-1,4-benzodiazepine (trifluoroacetate, 1: 2); 2.3.4.5-Tetrahydro-1- (1H-imidazol-4-ylmethyl) -4- (3-isoquinolinylcarbonyl) -7-phenyl-1H-1,4-benzodiazepine (trihydrochloride); 2.3.4.5-Tetrahydro-1- (1H-imidazol-4-ylmethyl) -7-phenyl-4- (4-quinolinylcarbonyl) -1 H -1,4-benzodiazepine, N-oxide (dihydrochloride); N-Methyl-N- (2-pyridinylmethyl) -2 - [[2,3,4,5-tetrahydro-1- (1H-imidazol-4-ylmethyl) -7-phenyl-1H-1,4-benzodiazepine] 4-yl] carbonyl] benzamide (trihydrochloride); 2.3.4.5-Tetrahydro-1- (1H-imidazol-4-ylmethyl) -4- [2- (methylphenylamino) benzoyl] -7-phenyl-1H-1,4-benzodiazepine (trihydrochloride); 2.3.4.5-Tetrahydro-1- (1H-imidazol-4-ylmethyl) -7-phenyl-4 - [(tetrahydro-4-phenyl-2H-pyran-4-yl) carbonyl] -1H-1,4-benzodiazepine ( dihydrochloride); 2.3.4.5-Tetrahydro-1- (1H-imidazol-4-ylmethyl) -4- [2- (2-methylphenyl) -1-oxopropyl] -7-phenyl-1H-1,4-benzodiazepine ( dihydrochloride); 2.3.4.5-Tetrahydro-1- (1H-imidazol-4-ylmethyl) -4 - [(5-methyl-1-phenyl-1H-pyrazol-4yl) carbonyl] -7-phenyl-1H-1,4- benzodiazepine (trihydrochloride); 2.3.4.5-Tetrahydro-1- (1H-imidazol-4-ylmethyl) -4- (methoxyphenylacetyl) -7-phenyl-1H-1,4-benzodiazepine (dihydrochloride); 2.3.4.5-Tetrahydro-1- (1H-imidazol-4-yl-ethyl) -7-phenyl-4- (1H-purin-6-ylcarbonyl) -1H1,4-benzodiazepine (trihydrochloride); 2,3,4,5-Tetrahydro-1- (1H-imidazol-4-yl-ethyl) -7-phenyl-4- (8-quinolinylcarbonyl) -1 H -1,4-benzodiazepine (trihydrochloride); 2.3.4.5-Tetrahydro-1- (1H-imidazol-4-ylmethyl) -7-phenyl-4- (6-quinolinylcarbonyl) -1H1,4-benzodiazepine (trihydrochloride); 2.3.4.5-Tetrahydro-1- (1H-imidazol-4-ylmethyl) -4- [2 - [[(4-methylphenyl) sulfonyl] amino] benzoyl] -7-phenyl-1H-1,4-benzodiazepine ( dihydrochloride); 2,3,4,5-Tetrahydro-1- (1H-imidazol-4-ylmethyl) -7-phenyl-4- [3-trifluoromethoxy) benzoyl] 1H-1,4-benzodiazepine (dihydrochloride); 2.3.4.5-Tetrahydro-1- (1H-imidazol-4-ylmethyl) -4 - [(3-methyl-4-oxo-2-phenyl-4H-benzopyran-8-yl) carbonyl] -7-phenyl-1H -1,4-benzodiazepine (dihydrochloride); 2.3.4.5-Tetrahydro-4 - [(2-hydroxy-4-quinolinyl) carbonyl] -1- (1H-imidazol-4-ylmethyl) -7-phenyl-1H-1,4-benzodiazepine (dihydrochloride); 2 - [[2,3,4,5-Tetrahydro-1- (1H-imidazol-4-ylmethyl) -7-phenyl-1H-1,4-benzodiazepin-4yl] carbonyl] benzamide (dihydrochloride); N- (1,1-dimethylethyl) -2 - [[2,3,4,5-tetrahydro-1- (1H-imidazol-4-ylmethyl) -7-phenyl-1H-1,4-benzodiazepine-4] yl] carbonyl] benzamide (dihydrochloride); N- (4-fluorophenyl) -N '- [3 - [[2,3,4,5-tetrahydro-1- (1H-imidazol-4-ylmethyl) -7-phenyl-1H-1,4-benzodiazepine]. 4-yl] carbonyl] phenyl] urea (dihydrochloride); 2.3.4.5-Tetrahydro-1- (1H-imidazol-4-ylmethyl) -4 - [(2-methoxy-1-naphthalenyl) carbonyl] 7-phenyl-1H-1,4-benzodiazepine (dihydrochloride); 2.3.4.5-Tetrahydro-4- [2 - [(2-hydroxyethyl) thio] benzoyl] -1- (1H-imidazol-4-ylmethyl) -7-phenyl-1H-1,4-benzodiazepine (dihydrochloride); 2.3.4.5-Tetrahydro-4- (2-hydroxy [1,1'-biphenyl] -3-ylcarbonyl) -1- (1H-imidazol-4-ylmethyl) -7-phenyl-1H-1,4-benzodiazepine ( dihydrochloride); 2.3.4.5-Tetrahydro-1- (1H-imidazol-4-ylmethyl) -4- (2-methyl-1-oxo-2-phenylpropyl) -7-phenyl-1H-1,4-benzodiazepine (dihydrochloride); 2.3.4.5-Tetrahydro-1- (1H-imidazol-4-ylmethyl) -4 - [(4-methoxy-2-quinolinyl) carbonyl] -7-phenyl-1H-1,4-benzodiazepine (trihydrochloride); N- [3 - [[2,3,4,5-Tetrahydro-1- (1H-imidazol-4-ylmethyl) -7-phenyl-1H-1,4-benzodiazepin-4-yl] carbonyl] phenyl] - acetamide (dihydrochloride); 2.3.4.5-Tetrahydro-1- (1H-imidazol-4-ylmethyl) -4- (1H-indol-4-ylcarbonyl) -7-phenyl-1H-1,4-benzodiazepine (dihydrochloride); 2.3.4.5-Tetrahydro-1- (1H-imidazol-4-ylmethyl) -4- (3-methoxy-2-nitrobenzoyl) -7-phenyl-1H-1,4-benzodiazepine (dihydrochloride); 2.3.4.5-Tetrahydro-1- (1H-imidazol-4-ylmethyl) -4- (2-nitrobenzoyl) -7-phenyl-1H-1,4-benzodiazepine (dihydrochloride); 2.3.4.5-Tetrahydro-1- (1H-imidazol-4-ylmethyl) -7-phenyl-4- (1-isoquinolinylcarbonyl) -1H-1,4-benzodiazepine (trihydrochloride); 2.3.4.5-Tetrahydro-1- (1H-imidazol-4-ylmethyl) -7-phenyl-4- (2-quinolinylcarbonyl) -1H1,4-benzodiazepine (trihydrochloride); 2.3.4.5-Tetrahydro-1- (1H-imidazol-4-ylmethyl) -7-phenyl-4- (2-pyridinylcarbonyl) -1H-1,4-benzodiazepine (trihydrochloride); 2.3.4.5-Tetrahydro-1- (1H-imidazol-4-ylmethyl) -7-phenyl-4- (3-pyridinylcarbonyl) -1H-1,4-benzodiazepine N-oxide (dihydrochloride); 2.3.4.5-Tetrahydro-1- (1H-imidazol-4-ylmethyl) -4 - [(1-methyl-1H-indol-2-yl) carbonyl] -7-phenyl-1H-1,4-benzodiazepine (dihydrochloride) ; 2.3.4.5-Tetrahydro-1- (1H-imidazol-4-ylmethyl) -4- (1H-indol-5-ylcarbonyl) -7-phenyl-1H-1,4-benzodiazepine (dihydrochloride); 2.3.4.5-Tetrahydro-1- (1H-imidazol-4-ylmethyl) -4- (1H-indol-3-ylcarbonyl) -7-phenyl-1H-1,4-benzodiazepine (dihydrochloride); 2.3.4.5-Tetrahydro-1- (1H-imidazol-4-ylmethyl) -4- (1H-indol-2-ylcarbonyl) -7-phenyl-1H-1,4-benzodiazepine (dihydrochloride); 2.3.4.5-Tetrahydro-4- (2-hydroxy-1-oxo-2-phenylpropyl) -1- (1H-imidazol-4-ylmethyl) 7-phenyl-1H-1,4-benzodiazepine (dihydrochloride); 2.3.4.5-Tetrahydro-1- (1H-imidazol-4-ylmethyl) -4- (2-naphthalenylcarbonyl) -7-phenyl-1H-1,4-benzodiazepine (dihydrochloride); 2.3.4.5-Tetrahydro-1- (1H-imidazol-4-ylmethyl) -4- (3-methylbenzoyl) -7-phenyl-1H-1,4-benzodiazepine (dihydrochloride); 2.3.4.5-Tetrahydro-1- (1H-imidazol-4-ylmethyl) -4- (3-methoxybenzoyl) -7-phenyl-1H-1,4-benzodiazepine (dihydrochloride), · 2.3.4.5-Tetrahydro-1- (1H-imidazol-4-ylmethyl) -4- (3-phenoxybenzoyl) -7-phenyl-1H-1,4-benzodiazepine (dihydrochloride); 2.3.4.5-Tetrahydro-1- (1H-imidazol-4-ylmethyl) -4- (2-methylbenzoyl) -7-phenyl-1H-1,4-benzodiazepine (dihydrochloride); 2.3.4.5-Tetrahydro-1- (1H-imidazol-4-ylmethyl) -4- (2-methoxybenzoyl) -7-phenyl-1H-1,4-benzodiazepine (dihydrochloride); 2.3.4.5-Tetrahydro-1- (1H-imidazol-4-ylmethyl) -4- (2-phenoxybenzoyl) -7-phenyl-1H-1,4-benzodiazepine (dihydrochloride); 2.3.4.5-Tetrahydro-1- (1H-imidazol-4-ylmethyl) -7-phenyl-4 - [(1-phenylcyclopropyl) carbonyl] -1H-1,4-benzodiazepine (dihydrochloride); 2.3.4.5-Tetrahydro-1- (1H-imidazol-4-ylmethyl) -7-phenyl-4- (2-pyrazinylcarbonyl) -1H-1,4-benzodiazepine (tetrahydrochloride); 2.3.4.5-Tetrahydro-1- (1H-imidazol-4-ylmethyl) -7-phenyl-4- (3-pyridinylcarbonyl) -1H-1,4-benzodiazepine (trihydrochloride); 2.3.4.5-Tetrahydro-1- (1H-imidazol-4-ylmethyl) -4- (4-isoquinolinylcarbonyl) -7-phenyl-1H-1,4-benzodiazepine (trihydrochloride); 2.3.4.5-Tetrahydro-1- (1H-imidazol-4-ylmethyl) -7-phenyl-4- (2-quinoxalinylcarbonyl) -1H-1,4-benzodiazepine (tetrahydrochloride); 2.3.4.5-Tetrahydro-1- (1H-imidazol-4-ylmethyl) -7-phenyl-4- (3-pyridinylacetyl) -1H-1,4-benzodiazepine (trihydrochloride); 2.3.4.5-Tetrahydro-1- (1H-imidazol-4-ylmethyl) -4- [1-oxo-3- (phenylsulfonyl) propyl] -7-phenyl-1H-1,4-benzodiazepine (dihydrochloride); 2.3.4.5-Tetrahydro-1- (1H-imidazol-4-ylmethyl) -4- [4- (methylsulfonyl) benzoyl] -7-phenyl-1H-1,4-benzodiazepine (dihydrochloride); 2.3.4.5-Tetrahydro-1- (1H-imidazol-4-ylmethyl) -4- [4- (4-morpholinylmethyl) benzoyl] -7-phenyl-1H-1,4-benzodiazepine (trihydrochloride); 2.3.4.5-Tetrahydro-1- (1H-imidazol-4-ylmethyl) -4 - [(2-methoxyethoxy) acetyl] -7-phenyl-1H-1,4-benzodiazepine (dihydrochloride); 2.3.4.5-Tetrahydro-1- (1H-imidazol-4-ylmethyl) -7-phenyl-4 - [(tetrahydro-3-furanyl) carbonyl] -1H-1,4-benzodiazepine (dihydrochloride); 2.3.4.5- Tetrahydro-1- (1 - [(3-hydroxy-3-hydroxy-4-hydroxy-4-oxazolyl) carbonyl] -1 H -1,4-benzodiazepine (dihydrochloride); 2.3.4.5-Tetrahydro-1- (1H-imidazol-4-ylmethyl) -4 - [(2-methoxy-3-pyridinyl) carbonyl] -7-phenyl-1H-1,4-benzodiazepine (trihydrochloride); 2.3.4.5-Tetrahydro-1- (1H-imidazol-4-ylmethyl) -4 - [[2- (4-methylphenoxy) -3-pyridinyl] carbonyl] -7-phenyl-1H-1,4-benzodiazepine (trihydrochloride) ; 2.3.4.5-Tetrahydro-1- (1H-imidazol-4-ylmethyl) -7-phenyl-4 - [(2-phenylthio) -3-pyridinyl] carbonyl] -1H-1,4-benzodiazepine (trihydrochloride); 2.3.4.5-Tetrahydro-1- (1H-imidazol-4-ylmethyl) -7-phenyl-4 - [[2-propylthio) -3-pyridinyl] carbonyl] -1H-1,4-benzodiazepine (trihydrochloride); 4 - [(2-Chloro-6-methyl-4-pyridinyl) carbonyl] -2,3,4,5-tetrahydro-1- (1H-imidazol-4-ylmethyl) -7-phenyl-1H-1,4- benzodiazepine (trihydrochloride); 2.3.4.5-Tetrahydro-4- [4-hydroxy-3- (4-morpholinylmethyl) benzoyl] -1- (1H-imidazol-4-ylmethyl) -7-phenyl-1H-1,4-benzodiazepine (trihydrochloride); (S) -2,3,4,5-Tetrahydro-1- (1H-imidazol-4-ylmethyl) -4 - [(1-methyl-2-pyrrolidine) carbonyl] 7-phenyl-1H-1,4 benzodiazepine (trihydrochloride); 2.3.4.5-Tetrahydro-1- (1H-imidazol-4-ylmethyl) -7-phenyl-4- (4-quinolinylcarbonyl) -1H1,4-benzodiazepine (trihydrochloride); 2,3,4,5-Tetrahydro-1- (1H-imidazol-4-ylmethyl) -4- [1-oxo-3- (1-piperidinyl) propyl] -7-phenyl-1H-1,4-benzodiazepine (trihydrochloride); 2.3.4.5-Tetrahydro-1- (1H-imidazol-4-ylmethyl) -8 - [[(4-methylphenyl) sulfonyl] amino] -3 (phenylmethyl) -1H-1,4-benzodiazepine-4-carboxylic acid 1,1-dimethylethyl ester; 7-bromo-1,2,3,4-tetrahydro-1- (1H-imidazol-4-yl-ethyl) -3- (phenylmethyl) -5H-1,4-benzodiazepin-5-one (dihydrochloride); 2.3.4.5-Tetrahydro-1- (1H-imidazol-4-ylmethyl) -7-phenyl-4 - [(4-phenyl-1,2,3-thiadiazol-5-yl) carbonyl] -1H-1,4 benzodiazepine (trifluoroacetate); 8 - [[(Cyclohexylamino) carbonyl] amino] -2,3,4,5-tetrahydro-1- (1H-imidazol-4-ylmethyl) -3- (phenylmethyl) -1H-1,4-benzodiazepine-4-carboxylic acid 1 , 1-dimethylethyl ester; 2.3.4.5-Tetrahydro-1- (1H-imidazol-4-ylmethyl) -7-phenyl-1H-1,4-benzodiazepine (monohydrochloride); 2.3.4.5-Tetrahydro-1- (1H-imidazol-4-ylmethyl) -4- (1-naphthalenylsulfonyl) -7-phenyl-1H-1,4-benzodiazepine (monohydrochloride); 2,2-Dimethyl-N- [2,3,4,5-tetrahydro-1- (1H-imidazol-4-ylmethyl) -4- (1-naphthalenylcarbonyl) -1H-1,4-benzodiazepin-8-yl ] propanamide (dihydrochloride); 2.3.4.5-Tetrahydro-1- (1H-imidazol-4-ylmethyl) -4- (methylsulfonyl) -3- (phenylmethyl) -1H-naphtho [2,3-e] -1,4-diazepine (monohydrochloride); 2.3.4.5-Tetrahydro-4- (1H-imidazol-4-ylmethyl) -1- (1-naphthalenylcarbonyl) -3 (phenylmethyl) -1H-1,4-benzodiazepine (1.5 hydrochloride); 2.3.4.5-Tetrahydro-4- (1H-imidazol-4-ylmethyl) -3- [2- (methylthio) ethyl] -4- (1-naphthalenylcarbonyl) -1H-1,4-benzodiazepine (trifluoroacetate); (S) -2,3,4,5-Tetrahydro-1- (1H-imidazol-4-ylmethyl) -4- (1-naphthalenylcarbonyl) -3 (phenylmethyl) -1H-1,4-benzodiazepine (trifluoroacetate); 2.3.4.5-Tetrahydro-3- (2-hydroxyethyl) -1- (1H-imidazol-4-ylmethyl) -4- (1-naphthalenecarbonyl) -1H-1,4-benzodiazepine (trifluoroacetate); 2.3.4.5-Tetrahydro-1- (1H-imidazol-4-ylmethyl) -4- (1-naphthalenylcarbonyl) -3 (phenylmethyl) -1H-1,4-benzodiazepine (hydrochloride); 2.3.4.5-Tetrahydro-1- (1H-imidazol-4-ylmethyl) -4- (1-naphthalenylcarbonyl) -7-phenyl-1H-pyrido [2,3-e] -1,4-diazepine (trihydrochloride); (R) -2,3,4,5-Tetrahydro-1- (1H-imidazol-4-ylmethyl) -3- [2- (methylthio) ethyl] -4- (naphthalenylcarbonyl) -1H-1,4- benzodiazepine (hydrochloride); 2.3.4.5-Tetrahydro-1- (1H-imidazol-4-ylmethyl) -9-methoxy-4- (1-naphthalenylcarbonyl) -1H-1,4-diazepine (dihydrochloride); 2.3.4.5-Tetrahydro-1- (1H-imidazol-4-ylmethyl) -4- (1-naphthalenylcarbonyl) -7- (3-pyridinyl) -1H-1,4-benzodiazepine (trihydrochloride); 2.3.4.5-Tetrahydro-1- (1H-imidazol-4-ylmethyl) -4- (1-naphthalenylcarbonyl) -8- [N, Nbis (phenylmethyl) amino] -1H-1,4-benzodiazepine (trihydrochloride) ); N- [2,3,4,5-Tetrahydro-1- (1H-imidazol-4-yl-methyl) -4- (1-naphthalenylcarbonyl) -1H-1,4-benzodiazepin-8-yl] phenylsulfonamide (dihydrochloride); N-phenyl-2,3,4,5-tetrahydro-1- (1H-imidazol-4-ylmethyl) -4- (1-naphthalenylcarbonyl) -1H1,4-benzodiazepine-7-carboxamide (dihydrochloride); N- [2,3,4,5-Tetrahydro-1- (1H-midazol-4-ylmethyl) -4- (1-naphthalenylcarbonyl) -1H-1,4-benzodiazepin-8-yl] -3-methylbenzamide ( dihydrochloride); N- [2,3,4,5-Tetrahydro-1- (1H-imidazol-4-ylmethyl) -4- (1-naphthalenylcarbonyl) -1H-1,4-benzodiazepin-8-yl] -4-methylbenzamide (dihydrochloride) ; 2.3.4.5-Tetrahydro-1- (1H-imidazol-5-ylmethyl) -4- (1-naphthalenylcarbonyl) -7-cyclohexyl-1H-1,4-benzodiazepine (2.5 hydrochloride); 2.3.4.5-Tetrahydro-1- (1H-imidazol-4-ylmethyl) -4- (1-naphthalenecarbonyl) -1H-1,4-benzodiazepine-7-carboxylic acid (dihydrochloride); 2.3.4.5-Tetrahydro-1- (1H-imidazol-4-ylmethyl) -7-methoxy-4- (1-naphthalenylcarbonyl) -1H-1,4-benzodiazepine (dihydrochloride); 2.3.4.5-Tetrahydro-1- (1H-imidazol-4-ylmethyl) -4- (1-naphthalenylcarbonyl) -7-phenyl-1 H -1,4-benzodiazepine (trifluoroacetate); 2.3.4.5-Tetrahydro-1,4-bis (1H-imidazol-4-ylmethyl) -7-phenyl-1H-1,4-benzodiazepine (dihydrochloride); 2.3.4.5-Tetrahydro-4- (1H-imidazol-4-ylmethyl) -1- (1-naphthalenylcarbonyl) -7-phenyl-1H-1,4-benzodiazepine (hydrochloride); 2.3.4.5-Tetrahydro-1- [3- (1H-imidazol-2-yl) propyl] -4- (1-naphthalenylcarbonyl) -7-phenyl-1H-1,4-benzodiazepine (dihydrochloride); 2.3.4.5-Tetrahydro-1- (1H-imidazol-4-ylmethyl) -4- (1-naphthalenecarbonyl) -7- (4-pyridinyl) -1H-1,4-benzodiazepine (trihydrochloride); 2.3.4.5-Tetrahydro-1- (1H-imidazol-4-ylmethyl) -4- (1-naphthalenylcarbonyl) -7- (2-thienyl) -1H-1,4-benzodiazepine (dihydrochloride); 2.3.4.5-Tetrahydro-1- (1H-imidazol-4-ylmethyl) -4- (1-naphthalenylcarbonyl) -7-pyridin-2-yl-1H-1,4-benzodiazepine (trihydrochloride); 2.3.4.5-Tetrahydro-1- (1H-imidazol-4-ylmethyl) -4- (1-naphthalenylcarbonyl) -7- (1-piperidinylsulfonyl) -1H-1,4-benzodiazepine (monohydrochloride); 2.3.4.5-Tetrahydro-1- (1H-imidazol-4-ylmethyl) -7-phenyl-4- [2- (trifluoromethoxy) benzoyl] -1H-1,4-benzodiazepine; 2.3.4.5-Tetrahydro-1- (1H-imidazol-4-ylmethyl) -7-phenyl-1H-1,4-benzodiazepine-4-carboxylic acid (phenylmethyl ester); 2.3.4.5-Tetrahydro-1- [2- (1H-imidazol-4-yl) ethyl] -4- (1-naphthalenylcarbonyl) -7-phenyl-1 H -1,4-benzodiazepine (dihydrochloride); 2.3.4.5-Tetrahydro-1- [2- (1H-imidazol-4-yl) ethyl] -4- (1-naphthalenylcarbonyl) -1H-1,4-benzodiazepine (dihydrochloride); 2.3.4.5-Tetrahydro-1- (1H-imidazol-4-ylmethyl) -4- (1-naphthalenylcarbonyl) -8-amino-1 H -1,4-benzodiazepine (dihydrochloride); N- [2,3,4,5-Tetrahydro-1- (1H-imidazol-4-ylmethyl) -4- (1-naphthalenylcarbonyl) -1H-1,4-benzodiazepin-8-yl] benzamide (dihydrochloride); N- [2,3,4,5-Tetrahydro-1- (1H-imidazol-4-ylmethyl) -4- (1-naphthalenylcarbonyl) -1H-1,4-benzodiazepin-8-yl] cyclohexanamide (dihydrochloride); 2.3.4.5-Tetrahydro-1- (1H-imidazol-4-ylmethyl) -4- (1-naphthalenylcarbonyl) -8-nitro-1 H -1,4-benzodiazepine (dihydrochloride); 2.3.4.5-Tetrahydro-1- (1H-imidazol-4-ylmethyl) -4- (1-naphthalenylcarbonyl) -1H-naphtho [2,3-e] -1,4-diazepine (dihydrochloride); 2.3.4.5-Tetrahydro-1- (1H-imidazol-4-ylmethyl) -4- (1-naphthalenylcarbonyl) -1H-pyrido [2,3-e] -1,4-diazepine (trihydrochloride); 2.3.4.5-Tetrahydro-1- (1H-imidazol-4-ylmethyl) -9-methyl-1- (1-naphthalenylcarbonyl) -1H1,4-benzodiazepine (dihydrochloride); 2.3.4.5-Tetrahydro-1- (1H-imidazol-4-ylmethyl) -9-methyl-4- (1-naphthalenylcarbonyl) -1H1,4-benzodiazepine (dihydrochloride); 2.3.4.5-Tetrahydro-1- (1H-imidazol-4-ylmethyl) -3-methyl-4- (1-naphthalenylcarbonyl) -1H1,4-benzodiazepine (hydrochloride); (S) -2,3,4,5-Tetrahydro-1- (1H-imidazol-4-ylmethyl) -3- [2- (methylthio) ethyl] -4- (1-naphthalenylmethyl) -1H-1,4 benzodiazepine (hydrochloride); 2.3.4.5-Tetrahydro-1- [3- (1H-imidazol-2-yl) propyl] -4- (1-naphthalenylcarbonyl) -1H-1,4-benzodiazepine (dihydrochloride); 2.3.4.5-Tetrahydro-1- (1H-imidazol-2-ylmethyl) -4- (1-naphthalenylcarbonyl) -1H-1,4-benzodiazepine (dihydrochloride); 2.3.4.5-Tetrahydro-1- (1H-imidazol-4-ylmethyl) -4- (1-naphthalenylcarbonyl) -7-phenyl-1 H -1,4-benzodiazepine (hydrochloride): 2- [2,3,4,5-Tetrahydro-1- (1H-imidazol-4-yl-methyl) -1H-1,4-benzodiazepin-4-ylsulfonyl] -benzoic acid methyl ester (hydrochloride); 7-bromo-2,3,4,5-tetrahydro-1- (1H-imidazol-4-ylmethyl) -4- (1-naphthalenylcarbonyl) -1H1,4-benzodiazepine (hydrochloride); 2.3.4.5-Tetrahydro-1- (1H-imidazol-4-ylmethyl) -N-methyl-N-phenyl-4H-1,4-benzodiazepine-4-carboxamide (hydrochloride); 2.3.4.5-Tetrahydro- (1H-imidazol-4-yl-methyl) -4- (1-naphthalenylsulfonyl) -1H-1,4-benzodiazepine (hydrochloride): (S) -2,3,4,5-Tetrahydro-1- (1H-imidazol-4-ylmethyl) -3- [2- (methylthio) ethyl] -4- (1-naphthalenylcarbonyl) -1H-1,4 benzodiazepine (hydrochloride); 2.3.4.5-Tetrahydro-4- (1-naphthalenylcarbonyl) -1 - [[1- (phenylmethyl) -1H-imidazol-5yl] methyl] -1H-1,4-benzodiazepine (hydrochloride); 2.3.4.5-Tetrahydro-1- (1H-imidazol-4-ylmethyl) -2-methyl-4- (1-naphthalenylcarbonyl) -1H1,4-benzodiazepine (hydrochloride); 2.3.4.5-Tetrahydro-4- (1H-methylimidazol-4-yl) -1- (1-naphthalenylcarbonyl) -1H-1,4-benzodiazepine (dihydrochloride); 2,3,4,5-Tetrahydro-1- (1H-imidazol-4-ylmethyl) -4- (1-naphthalenylcarbonyl) -1H-1,4-benzodiazepine (hydrochloride); 2. A compound according to claim 1 wherein it is selected from the group consisting of; or R ⁶ , R ⁷ R ⁶ , R ⁷ 2) W and X together can be oxygen only when Z is absent or Z is O, NR ¹⁰ , CHR ⁹ , O - N - C - '- N - SO ₂ - II R ¹⁴ R ¹⁵ In formulas I, II and V, and X may together be oxygen O - N - C - - N - S0 ₇ -. 3-Chloro-N- [2,3,4,5-tetrahydro-1- (1H-imidazol-4-ylmethyl) -4- (1-naphthalenylcarbonyl) -1 H -1,4-benzodiazepin-8-yl ] -4-benzamide (dihydrochloride); 7-Bromo-2,3,4,5-tetrahydro-1 - [[2 - [(dimethylamino) methyl] -1H-imidazol-4-yl] methyl] 4- (1-naphthalenylcarbonyl) -1H-1 , 4-benzodiazepine (dihydrochloride); 7- (4-chlorophenyl) -2,3,4,5-tetrahydro-1- (1H-imidazol-4-ylmethyl) -4- (1-naphthalenylcarbonyl) -1H-1,4-benzodiazepine (dihydrochloride); (3-aminophenyl) -2,3,4,5-tetrahydro-1- (1H-imidazol-4-ylmethyl) -4- (1-naphthalenylcarbonyl) -1H-1,4-benzodiazepine (trihydrochloride); 3. A compound according to claim 2 wherein m is zero and ABCD is a carbocyclic ring. 3) R ²³ may be hydrogen unless U is SO, SO 2, NR ²⁵ CO2 or NR ²⁸ SO ₂ ; or 4- [4- (fluorophenyl) sulfonyl] -2,3,4,5-tetrahydro-1- (1H-imidazol-4-ylmethyl) -2- (2-phenylethyl) -1H-1,4-benzodiazepine (monohydrochloride) 7-bromo-2,3,4,5-tetrahydro-1- (1H-imidazol-4-ylmethyl) -4- (methylsulfonyl) -2- (2-phenylethyl) -1H-1,4-benzodiazepine ( monohydrochloride); (R) -7-Cyano-2,3,4,5-tetrahydro-1- (1-methyl-1H-imidazol-5-ylmethyl) -4 - [[2- (1-morpholinyl) ethyl] sulfonyl] -3- (phenylmethyl) -1H-1,4-benzodiazepine (dihydrochloride); (R) -7-Bromo-2,3,4,5-tetrahydro-1- (1H-imidazol-4-ylmethyl) -4- (methylsulfonyl) -3- (4-bromophenylmethyl) -1H-1,4-benzodiazepine (hydrochloride); (R) -7-Bromo-2,3,4,5-tetrahydro-1- (1H-imidazol-4-ylmethyl) -4- (methylsulfonyl) -3 (thiazol-4-ylmethyl) -1H- 1,4-Benzodiazepine (hydrochloride): (R) -7-Bromo-2,3A5-tetrahydro-1- (1H-imidazol-4-ylmethyl) -4- (propylsulfonyl) -3 (thiazol-4-ylmethyl) -1H-1,4- benzodiazepine (hydrochloride); (R) -7-Bromo-2,3,4,5-tetrahydro-1- (1H-imidazol-4-ylmethyl) -4- (propylsulfonyl) -3- (4-bromophenylmethyl) -1H-1,4-benzodiazepine (hydrochloride); (R) -7-Bromo-2,3,4,5-tetrahydro-1- (1H-imidazol-4-ylmethyl) -3- (pyridin-3-ylmethyl) -4 (methylsulfonyl) -1H-1, 4-benzodiazepine (trihydrochloride); (R) -7-Bromo-2,3,4,5-tetrahydro-1- (1H-1-methylimidazol-5-ylmethyl) -3- (pyridin-3-ylmethyl) -4- (methylsulfonyl) -1 H -1,4-benzodiazepine (dihydrochloride); 4-Acetyl-7-bromo-1,2,4,5,1 ', 3'-hexahydro-1- (1H-imidazol-4-ylmethyl) spiro [3H-1,4-benzodiazepine-3,2' - [2H ] indeno] (dihydrochloride); 4-Butyl-2,3,4,5-tetrahydro-1- (1H-imidazol-4-ylmethyl) -3- (phenylmethyl) -1H-1,4-benzodiazepine (trihydrochloride); (R) -7-Bromo-2,3,4,5-tetrahydro-1- (1H-imidazol-4-ylmethyl) -4 - [[2- (4-morpholinyl) ethyl] sulfonyl] -3- (phenylmethyl) - 1H-1,4-benzodiazepine (dihydrochloride); (R) -7-Bromo-2,3,4,5-tetrahydro-1 - [(1-methyl-1H-imidazol-5-yl) methyl] -4 - [[2- (4-morpholinyl) ethyl] sulfonyl ] -3- (phenylmethyl) -1H-1,4-benzodiazepine (dihydrochloride); (R) -7-Cyano-1- (1H-imidazol-4-ylmethyl) -4- (4-morpholinylsulfonyl) -3- (phenylmethyl) -1H1,4-benzodiazepine (monohydrochloride); (R) -7-Cyano-1 - [(1-methyl-1 H -imidazol-5-yl) methyl] -4 - [(4-morpholinyl) sulfonyl] -3 (phenylmethyl) -1H-1, 4-benzodiazepine (monohydrochloride); (R) -7-Cyano-2,3,4,5-tetrahydro-1- (1H-imidazol-4-ylmethyl) -4 - [(4aminophenyl) sulfonyl] -3- (phenylmethyl) -1H-1, 4-benzodiazepine (hydrochloride); 4- (2-Benzothiazolyl) -2,3,4,5-tetrahydro-1- (1H-imidazol-4-ylmethyl) -7-phenyl-1H-1,4-benzodiazepine (trihydrochloride); 4-Acetyl-2,3,4,5-tetrahydro-1- (1H-imidazol-4-ylmethyl) -3- (phenylmethyl) -7- (4-pyridinyl) -1H-1,4-benzodiazepine ( trihydrochloride); 4-Acetyl-7-bromo-3 - [(2-chlorophenyl) methyl] -2,3,4,5-tetrahydro-1- (1H-imidazol-4-ylmethyl) -1H-1,4-benzodiazepine (dihydrochloride) ; 4-Acetyl-7-bromo-3 - [(3-chlorophenyl) methyl] -2,3,4 _l 5-tetrahydro-1- (1H-imidazol-4-ylmethyl) -1H-1,4-benzodiazepine (dihydrochloride) ; 4- (1,2-dioxopropyl) -2,3,4,5-tetrahydro-1- (1H-imidazol-4-ylmethyl) -7-phenyl-1H-1,4-benzodiazepine (hydrochloride); 4-Acetif-2,3,4,5-tetrahydro-1- (1H-imidazol-4-ylmethyl) -3- (phenylmethyl) -1H-1,4-benzodiazepine (hydrochloride); (R) -7-Bromo-2,3,4,5-tetrahydro-1- (1H-imidazol-4-ylmethyl) -4- (methylsulfonyl) -3 (phenylmethyl) -1H-1,4-benzodiazepine ( hydrochloride); (R) -2,3,4,5-Tetrahydro-1- (1H-imidazol-4-ylmethyl) -4- (methylsulfonyl) -3- (phenylmethyl) -1H-1,4-benzodiazepine-7-carbonitrile ( monohydrochloride); (R) -4-Acetyl-2,3,4,5-tetrahydro-1- (1H-imidazol-4-ylmethyl) -7-phenyl-3- (phenylmethyl) -1H1,4-benzodiazepine (monohydrochloride) ); 4- (9H-fluoren-9-ylacetyl) -2,3,4,5-tetrahydro-1- (1H-imidazol-4-ylmethyl) -1H-1,4-benzodiazepine (trifluoroacetate, 1: 2); (S) -4- [2- (Dimethylamino) -1-oxo-3-phenylpropyl] -2,3,4,5-tetrahydro-1- (1H-imidazol-4-ylmethyl) -1H-1,4-benzodiazepine (trifluoroacetate, 1: 3); (S) -2,3,4,5-Tetrahydro-1- (1H-imidazol-4-yl) -4 - [(2-oxo-4-phenyl-3-oxazolidinyl) acetyl] -1H-1 , 4-benzodiazepine (trifluoroacetate, 1: 2); 4- (9-acridinylcarbonyl) -2,3,4,5-tetrahydro-1- (1H-imidazol-4-ylmethyl) -1H-1,4-benzodiazepine (trifluoroacetate, 1: 3); 4 - ([1,1'-Biphenyl] -2-ylcarbonyl) -2,3,4,5-tetrahydro-1- (1H-imidazol-4-ylmethyl) -1H-1,4-benzodiazepine (trifluoroacetate, 1: 2); 4- [3- (3,4- (dimethoxyphenyl) -1-oxopropyl] -2,3,4,5-tetrahydro-1- (1H-imidazol-4-ylmethyl) -1H-1,4-benzodiazepine (trifluoroacetate, 1: 2); 4 - ([1,1'-Biphenyl] -4-ylacetyl) -2,3,4,5-tetrahydro-1- (1H-imidazol-4-ylmethyl) -1H-1,4-benzodiazepine (trifluoroacetate, 1: 2); 4 - [[4 '(dimethylamino) -1-naphthalenyl] carbonyl] -2,3,4 _l 5-tetrahydro-1' (1H-imidazol-4-ylmethyl) -7-phenyl-1H-1,4-benzodiazepine ( trihydrochloride); 4- (benzo [b] thiophen-2-ylcarbonyl) -2,3,4,5-tetrahydro-1- (1H-imidazol-4-ylmethyl) -7-phenyl-1H-1,4-benzodiazepine (dihydrochloride); 4- (2-cyanobenzoyl) -2,3,4,5-tetrahydro-1- (1H-imidazol-4-yl (methyl) -7-phenyl-1H-1,4-benzodiazepine (dihydrochloride); 4- (3-ethoxybenzoyl) -2,3,4,5-tetrahydro-1- (1H-imidazol-4-ylmethyl) -7-phenyl-1H-1,4-benzodiazepine (dihydrochloride); 4- [2- (dimethylamino) benzoyl] -2,3,4,5-tetrahydro-1- (1H-imidazol-4-ylmethyl) -7-phenyl-1H-1,4-benzodiazepine (trihydrochloride); 4- (1H-benzotriazol-5-ylcarbonyl) -2,3,4,5-tetrahydro-1- (1H-imidazol-4-ylmethyl) -7-phenyl-1H-1,4-benzodiazepine (dihydrochloride); 4 - [(2,6-Dihydroxy-3-naphthalenyl) carbonyl] -2,3,4,5-tetrahydro-1- (1H-imidazol-4-ylmethyl) -7-phenyl-1H-1,4-benzodiazepine ( dihydrochloride); 4- (1H-benzimidazol-5-ylcarbonyl) -2,3,4,5-tetrahydro-1- (1H-imidazol-4-ylmethyl) -7-phenyl-1H-1,4-benzodiazepine (trihydrochloride); 4- (3-chloro-2-nitrobenzoyl) -2,3,4,5-tetrahydro-1- (1H-imidazol-4-ylmethyl) -7-phenyl-1H-1,4-benzodiazepine (dihydrochloride); 4- (2-Benzofuranylcarbonyl) -2,3,4,5-tetrahydro-1- (1H-imidazol-4-ylmethyl) -7-phenyl-1H-1,4-benzodiazepine (dihydrochloride); 4- (diphenylacetyl) -2,3,4,5-tetrahydro-1- (1H-imidazol-4-ylmethyl) -7-phenyl-1H-1,4-benzodiazepine (dihydrochloride); 4- (fluorophenylacetyl) -2,3,4,5-tetrahydro-1- (1H-imidazol-4-ylmethyl) -7-phenyl-1H-1,4-benzodiazepine (dihydrochloride); 4 - [(2-Ethoxy-1-naphthalene I) carbonyl] -2,3,4,5-tetrahydro-1- (1H-imidazol-4-ylmethyl) -7-phenyl-1H-1,4-benzodiazepine (dihydrochloride); 4- (1,2-Dioxo-2-phenyl) -2,3,4,5-tetrahydro-1- (1H-imidazol-4-ylmethyl) -7-phenyl-1H benzodiazepine (dihydrochloride); 4- (3,5-dimethoxybenzoyl) -2,3,4,5-tetrahydro-1- (1H-imidazol-4-ylmethyl) -7-phenyl-1 H -1,4-benzodiazepine (dihydrochloride); 4- (3,4-dimethoxybenzoyl) -2,3,4,5-tetrahydro-1- (1H-imidazol-4-ylmethyl) -7-phenyl-1 H -1,4-benzodiazepine (dihydrochloride); 4- (3-chlorobenzoyl) -2,3,4,5-tetrahydro-1- (1H-imidazol-4-ylmethyl) -7-phenyl-1H-1,4-benzodiazepine (dihydrochloride); 4- (3-cyanobenzoyl) -2,3,4,5-tetrahydro-1- (1H-imidazol-4-ylmethyl) -7-phenyl-1H-1,4-benzodiazepine (dihydrochloride); 4- (2,3-dimethylbenzoyl) -2,3,4,5-tetrahydro-1- (1H-imidazol-4-ylmethyl) -7-phenyl-1 H -1,4-benzodiazepine (dihydrochloride); 4 - ([1,1'-Biphenyl] -2-ylcarbonyl) -2,3,4,5-tetrahydro-1- (1H-imidazol-4-ylmethyl) -7-phenyl-1H-1,4-benzodiazepine (dihydrochloride) ); 4- (2,3-dihydroxybenzoyl) -2,3,4,5-tetrahydro-1- (1H-imidazol-4-ylmethyl) -7-phenyl-1 H -1,4-benzodiazepine (dihydrochloride); 4- (2,6-dimethoxybenzoyl) -2,3,4,5-tetrahydro-1- (1H-imidazol-4-ylmethyl) -7-phenyl-1 H -1,4-benzodiazepine (dihydrochloride); 4- (2,5-Dimethoxybenzoyl) -2,3,4,5-tetrahydro-1- (1H-imidazol-4-ylmethyl) -7-phenyl-1 H -1,4-benzodiazepine (dihydrochloride); 4- (2,4-Dimethoxybenzoyl) -2,3,4,5-tetrahydro-1- (1H-imidazol-4-ylmethyl) -7-phenyl-1H-1,4-benzodiazepine (dihydrochloride); 4- (2,3-dimethoxybenzoyl) -2,3,4,5-tetrahydro-1- (1H-imidazol-4-ylmethyl) -7-phenyl-1 H -1,4-benzodiazepine (dihydrochloride); 4- (2,3-dichlorobenzoyl) -2,3,4,5-tetrahydro-1- (1H-imidazol-4-ylmethyl) -7-phenyl-1 H -1,4-benzodiazepine (dihydrochloride); N- [2 - [[2,3,4,5-Tetrahydro-1- (1H-imidazol-4-ylmethyl) -7-phenyl-1H-1,4-benzodiazepin-4-yl] carbonyl] phenyl ] acetamide (dihydrochloride); 4- (2-chlorobenzoyl) -2,3,4,5-tetrahydro-1- (1H-imidazol-4-ylmethyl) -7-phenyl-1H-1,4-benzodiazepine (dihydrochloride); 4-Benzoyl-2,3,4,5-tetrahydro-1- (1H-imidazol-4-ylmethyl) -7-phenyl-1H-1,4-benzodiazepine (dihydrochloride); 4 - [(Bicyclo [4.2.0] octa-1,3,5-trien-7-yl) carbonyl] -2,3,4,5-tetrahydro-1- (1H-imidazol-4-ylmethyl) -7-phenyl -1 H -1,4-benzodiazepine (dihydrochloride); 4- [3- (dimethylamino) benzoyl] -2,3,4,5-tetrahydro-1- (1H-imidazol-4-ylmethyl) -7-phenyl-1H-1,4-benzodiazepine (trihydrochloride); 4- (2-ethoxybenzoyl) -2,3,4,5-tetrahydro-1- (1H-imidazol-4-ylmethyl) -7-phenyl-1H-1,4-benzodiazepine (dihydrochloride); 4 - [(2,6-Dimethoxy-3-pyridinyl) carbonyl] -2,3,4,5-tetrahydro-1- (1H-imidazol-4-ylmethyl) -7-phenyl-1H-1,4-benzodiazepine (trihydrochloride); 4 - [(2-Chloro-3-pyridinyl) carbonyl] -2,3,4,5-tetrahydro-1- (1H-imidazol-4-ylmethyl) -7-phenyl-1H-1,4-benzodiazepine (trihydrochloride) ; 4-acetyl-2,3,4,5-tetrahydro-1- (1H-imidazol-4-ylmethyl) -7-phenyl-1H-1,4-benzodiazepine (dihydrochloride); 4 - [(5-Bromo-3-pyridinyl) carbonyl] -2,3,4,5-tetrahydro-1- (1H-imidazol-4-ylmethyl) -7-phenyl-1H-1,4-benzodiazepine (trihydrochloride) ; (S) -4- [2- (Dimethylamino) -1-oxo-3-phenylpropyl] -2,3,4,5-tetrahydro-1- (1H-imidazol-4-ylmethyl) -7-phenyl-1H-1 , 4-benzodiazepine (trihydrochloride); 4-acetyl-7-bromo-2,3,4,5-tetrahydro-1- (1H-imidazol-4-ylmethyl) -3- (1-naphthalenylmethyl) -1H-1,4-benzodiazepine (dihydrochloride); 4-acetyl-7-bromo-2,3,4,5-tetrahydro-1- (1H-imidazol-4-ylmethyl) -3- (2-naphthalenylmethyl) -1H-1,4-benzodiazepine (dihydrochloride); 4-Acetyl-2,3,4,5-tetrahydro-1- (1H-imidazol-4-ylmethyl) -3- (phenylmethyl) -1H-naphtho [2,3e] -1,4-diazepine ( monohydrochloride); N-Cyclohexyl-N '- [2,3,4,5-tetrahydro-1- (1H-imidazol-4-ylmethyl) -4- (1-naphthalenylcarbonyl) -1H-1,4-benzodiazepin-8-yl] urea (dihydrochloride); 4-Acetyl-7-bromo-3 - [(4-chlorophenyl) methyl] -2,3,4,5-tetrahydro-1- (1H-imidazol-4-ylmethyl) -1H-1,4-benzodiazepine (dihydrochloride) ); 4-Acetyl-7-bromo-2,3,4,5-tetrahydro-1- (1H-imidazol-4-ylmethyl) -3- (phenylmethyl) -1H1,4-benzodiazepine (hydrochloride); 4. A compound according to claim 3 wherein the carbocyclic ring is a benzo ring. 4) R ⁸ may be hydrogen unless Z is SO _{2 l} CO ₂ or Oh, NR ²⁰ R ²¹ NNR ²² \\ // F y / - N — SO ₇ — —S—. —S— I Z J I R ¹⁵ 5. A compound of claim 1 having the formula: R ^{3 4 5} , R ⁷ wherein m is zero and ABCD is a carbocyclic ring. 6. A compound according to claim 5, wherein the carbocyclic ring is a benzo ring. 7-Cyano-2,3,4,5-tetrahydro-1- (1H-imidazol-4-ylmethyl) -3- (S) - [(S) -phenylcyclopropyl) 4 - ((2-thienyl) sulfonyl) - 1H-1,4-benzodiazepine; (R) -7-Cyano-2,3,4,5-tetrahydro-1- (1H-imidazol-4-ylmethyl) -3- (phenylmethyl) -4 - [(2- (5 (pyridin-2-yl) )) - thienyl) sulfonyl]) - 1 H -1,4-benzodiazepine; (R) -7-Cyano-2,3,4,5-tetrahydro-1- (1H-imidazol-4-ylmethyl) -3- (phenylmethyl) -4 - [(2- (5 (1,2-isoxazole) -3-yl) -thienium I) -sulfonyl] -1H-1,4-benzodiazepine; (R) -7-Cyano-2,3,4,5-tetrahydro-1- (3- (1H-imidazol-2-yl) -propyl) -3- (phenylmethyl) -4- (phenylsulfonyl) -1H- 1,4-benzodiazepine; (R) -7-Cyano-2,3,4,5-tetrahydro-1- (3- (1H-imidazol-2-yl) -propyl) -3- (phenylmethyl) -4 (methylsulfonyl) -1H -1,4-benzodiazepine; (R) -7-Cyano-2,3,4,5-tetrahydro-1- (3- (1H-imidazol-2-yl) -propyl) -3- (phenylmethyl) -4 (propylsulfonyl) -1H- 1,4-benzodiazepine; (R) -7-Cyano-2,3,4,5-tetrahydro-1- (3- (1H-imidazol-2-yl) propyl) -3- (phenylmethyl) -4 - ((2-thienyl) sulfonyl) ) -1 H -1,4-benzodiazepine; (R) -7-Cyano-2,3,4,5-tetrahydro-1- (2- (1H-imidazol-2-yl) ethylsulfonyl) -3- (phenylmethyl) 4- (phenylsulfonyl) -1H- 1,4-benzodiazepine; (R) -7-Cyano-2,3,4,5-tetrahydro-1- (2- (1H-imidazol-2-yl) ethylsulfonyl) -3- (phenylmethyl) 4- (methylsulfonyl) -1H -1,4-benzodiazepine; (R) -7-Cyano-2,3,4,5-tetrahydro-1- (2- (1H-imidazol-2-yl) ethylsulfonyl) -3- (phenylmethyl) 4- (propylsulfonate) -1 H -1,4-benzodiazepine; (R) -7-Cyano-2,3,4,5-tetrahydro-1- (2- (1H-imidazol-2-yl) ethylsulfonyl) -3- (phenylmethyl) 4 - ((2-thienyl) - sulfonyl) -1H-1,4-benzodiazepine; (R) -7-Cyano-2,3,4,5-tetrahydro-1- (1H-imidazol-4-ylmethyl) -3- (phenylmethyl) -4 - ((1-oxoethyl) amino) -1H -1,4-benzodiazepine; (R) -7-Cyano-2,3,4,5-tetrahydro-1- (1H-imidazol-4-ylmethyl) -3- (phenylmethyl) -4- (methanesulfonylamino) -1H-1,4-benzodiazepine; (R) -7-Cyano-2,3,4,5-tetrahydro-1- (1H-imidazol-4-ylmethyl) -3- (phenylmethyl) -4- (phenylsulfonylamino) -1H-1,4-benzodiazepine. 7-Cyano-2,3,4,5-tetrahydro-1- (1H-imidazol-4-ylmethyl) -3- (S) - [(S) -phenylcyclopropyl) 4- (phenylsulfonyl) -1H-1 , 4-benzodiazepine; 7-cyano-2,3,4,5-tetrahydro-1- (1H-imidazol-4-ylmethyl) -3- (S) - [(S) -phenylcyclopropyl) 4- (propylsulfonyl) -1H-1, 4-benzodiazepine; 7-cyano-2,3,4,5-tetrahydro-1- (1H-imidazol-4-ylmethyl) -3- (S) - [(S) -phenylcyclopropyl) 4- (methylsulfonyl) -1H-1, 4-benzodiazepine; 7-Cyano-2,3,4,5-tetrahydro-1- (1H-imidazol-4-ylmethyl) -3- (S) - [(R) -phenylcyclopropyl] 4 - ((2-thienyl) sulfonyl) ) -1 H -1,4-benzodiazepine; 7-cyano-2,3,4,5-tetrahydro-1- (1H-imidazol-4-ylmethyl) -3- (S) - [(R) -phenylcyclopropyl] 4- (phenylsulfonyl) -1H-1, 4-benzodiazepine; 7-Cyano-2,3,4,5-tetrahydro-1- (1H-imidazol-4-ylmethyl) -3- (S) - [(R) -phenylcyclopropyl) 4- (propylsulfonyl) -1H-1 , 4-benzodiazepine; 7-cyano-2,3,4,5-tetrahydro-1- (1H-imidazol-4-ylmethyl) -3- (S) - [(R) -phenylcyclopropyl) 4- (methylsulfonyl) -1H-1, 4-benzodiazepine; 7-Cyano-2,3,4,5-tetrahydro-1- (1H-imidazol-4-ylmethyl) -3- (R) - ((S) -phenylcyclopropyl) 4 - ((2-thienyl) (phenyl) -1H-1,4-benzodiazepine; 7-Cyano-2,3,4,5-tetrahydro-1- (1H-imidazol-4-ylmethyl) -3- (R) - [(S) -phenylcyclopropyl) 4- (phenylsulfonyl) -1H-1 , 4-benzodiazepine; 7-Cyano-2,3,4,5-tetrahydro-1- (1H-imidazol-4-ylmethyl) -3- (R) - [(S) -phenylcyclopropyl) 4- (propylsulfonyl) -1H-1,4- benzodiazepine; 7-Cyano-2,3,4,5-tetrahydro-1- (1H-imidazol-4-ylmethyl) -3- (R) - [(S) -phenylcyclopropyl) 4- (methylsulfonyl) -1H-1 , 4-benzodiazepine; 7-Cyano-2,3,4,5-tetrahydro-1- (1H-imidazol-4-ylmethyl) -3- (R) - [(R) -phenylcyclopropyl) 4 - ((2-thienyl) sulfonyl) -1 H -1,4-benzodiazepine; 7-cyano-2,3,4,5-tetrahydro-1- (1H-imidazol-4-ylmethyl) -3- (R) - [(R) -phenylcyclopropyl) 4- (phenylsulfonyl) -1H-1, 4-benzodiazepine; 7-Cyano-2,3,4,5-tetrahydro-1- (1H-imidazol-4-ylmethyl) -3- (R) - [(R) -phenylcyclopropyl) 4- (propylsulfonyl) -1H- 1,4-benzodiazepine; 7-cyano-2,3,4,5-tetrahydro-1- (1H-imidazol-4-ylmethyl) -3- (R) - [(R) -phenylcyclopropyl) 4- (methylsulfonyl) -1H-1, 4-benzodiazepine; 7-Cyano-2,3,4,5-tetrahydro-1- (1H-imidazol-4-ylmethyl) -3- (S) - [(S) -1-phenyl] -4 - (( 2-thienyl) sulfonyl) -1H-1,4-benzodiazepine; 7-Cyano-2,3,4,5-tetrahydro-1- (1H-imidazol-4-ylmethyl) -3- (S) - [(S) -1-phenylethyl] -4 (phenylsulfonyl) -1H -1,4-benzodiazepine; 7-Cyano-2,3,4,5-tetrahydro-1- (1H-imidazol-4-ylmethyl) -3- (S) - [(S) -1-phenylethyl] -4 (propylsulfonyl) -1H- 1,4-benzodiazepine; 7-Cyano-2,3,4,5-tetrahydro-1- (1H-imidazol-4-ylmethyl) -3- (S) - [(S) -1-phenyl] -4- (methylsulfonyl) -1 H -1,4-benzodiazepine; 7-Cyano-2,3,4,5-tetrahydro-1- (1H-imidazol-4-ylmethyl) -3- (R) - [(S) -1-phenylethyl] -4 - ((2-thienyl) sulfonyl) ) -1 H -1,4-benzodiazepine; 7-Cyano-2,3,4,5-tetrahydro-1- (1H-imidazol-4-ylmethyl) -3- (R) - [(S) -1-phenyl] -4- (phenylsulfonyl) -1 H -1,4-benzodiazepine; 7-Cyano-2,3,4,5-tetrahydro-1- (1H-imidazol-4-ylmethyl) -3- (R) - [(S) -1-phenyl] -4- (propylsulfone) I) -1 H -1,4-benzodiazepine; 7-Cyano-2,3,4,5-tetrahydro-1- (1H-midazol-4-ylmethyl) -3- (R) - [(S) -1-phenylethyl] -4 (methylsulfonyl) -1H- 1,4-benzodiazepine; 7-Cyano-2,3,4,5-tetrahydro-1- (1H-imidazol-4-ylmethyl) -3- (S) - [(R) -1-phenylethyl] -4 - ((2-thienyl) sulfonyl) ) -1 H -1,4-benzodiazepine; 7-Cyano-2,3,4,5-tetrahydro-1- (1H-imidazol-4-ylmethyl) -3- (S) - [(R) -1-phenylethyl] -4 (phenylsulfonyl) -1H- 1,4-benzodiazepine; 7-Cyano-2,3,4,5-tetrahydro-1- (1H-imidazol-4-ylmethyl) -3- (S) - [(R) -1-phenylethyl] -4 (propylsulfonyl) -1H- 1,4-benzodiazepine; 7-Cyano-2,3,4,5-tetrahydro-1- (1H-imidazol-4-ylmethyl) -3- (S) - [(R) -1-phenylethyl] -4 (methylsulfonyl) -1H -1,4-benzodiazepine; 7-Cyano-2,3,4,5-tetrahydro-1- (1H-imidazol-4-ylmethyl) -3- (R) - [(R) -1-phenylethyl] -4 - ((2-thienyl) sulfonyl) ) -1 H -1,4-benzodiazepine; 7-Cyano-2,3,4,5-tetrahydro-1- (1H-imidazol-4-ylmethyl) -3- (R) - [(R) -1-phenylethyl] -4 (phenylsulfonyl) -1H- 1,4-benzodiazepine; 7-Cyano-2,3,4,5-tetrahydro-1- (1H-imidazol-4-ylmethyl) -3- (R) - [(R) -1-phenyl] -4- (propylsulfonyl) -1 H -1,4-benzodiazepine; 7-Cyano-2,3,4,5-tetrahydro-1- (1H-imidazol-4-ylmethyl) -3- (R) - [(R) -1-phenylethyl] -4 (methylsulfonyl) -1H- 1,4-benzodiazepine; 7-Bromo-4- [3- (dimethylamino) -1-oxopropyl] -2,3,4,5-tetrahydro-1- (1H-imidazol-4-ylmethyl) -3- (phenylmethyl) -1H-1, 4-benzodiazepine (trifluoroacetate, 1: 1); (R) -2,3,4,5-Tetrahydro-1- (1-methyl-1H-imidazol-5-ylmethyl) -4- (phenylsulfonyl) -3 (phenylmethyl) -1H-1,4-benzodiazepine-7 -carbonitrile (monohydrochloride); 7-Bromo-2,3,4,5-tetrahydro-1- (1H-imidazol-4-ylmethyl) -4- (methylsulfonyl) -2-oxo-3 (phenylmethyl) -1H-1,4-benzodiazepine (trifluoroacetate) ); (R) -7-Cyano-4- (2-furanylcarbonyl) -2,3,4,5-tetrahydro-1- (1H-imidazol-4-ylmethyl) -3 (phenylmethyl) -1H-1,4-benzodiazepine (trifluoroacetate, 1: 1); (R) -7-Cyano-2,3,4,5-tetrahydro-1- (1H-imidazol-4-ylmethyl) -4 - [(4-nitrophenyl) sulfonyl] 3- (phenylmethyl) -1H-1 , 4-benzodiazepine (trifluoroacetate); (R) -7-Cyano-2,3,4,5-tetrahydro-1- (1H-imidazol-4-ylmethyl) -4 - [[4- (4-methyl-1-piperazinyl) phenyl] sulfonyl] -3- (phenylmethyl) -1H-1,4-benzodiazepine (trifluoroacetate); (R) -7-Cyano-2,3,4,5-tetrahydro-1- (1H-imidazol-4-ylmethyl) -4 - [[(4-dimethylamino) phenyl] sulfonyl] -3- (phenylmethyl) -1H -1,4-benzodiazepine (trifluoroacetate): (R) -7-Bromo-4 - [[2- (dimethylamino) ethyl] sulfonyl] -2,3,4,5-tetrahydro-1- (1H-imidazol-4-ylmethyl) -3- (phenylmethyl) -4H- 1,4-benzodiazepine (dihydrochloride); (R) -7-Cyano-2,3,4,5-tetrahydro-1- (1H-imidazol-4-ylmethyl) -3- (phenylmethyl) -4- (3-pyridinylsulfonyl) -1H-1,4-benzodiazepine (trihydrochloride); 7-bromo-2,3,4,5-tetrahydro-1- (1H-imidazol-4-ylmethyl) -3- (phenylmethyl) -1H-1,4-benzodiazepin-5-one (hydrochloride); (R) -7-Bromo-2,3,4,5-tetrahydro-1- (1H-imidazol-1-ylacetyl) -4- (methylsulfonyl) -3 (phenylmethyl) -1H-1,4-benzodiazepine ( trifluoroacetate); 7-Bromo-1,2,3,5-tetrahydro-1- (1H-imidazol-4-ylmethyl) -N, N-dimethyl-3- (phenylmethyl) -4H-1,4-benzodiazepine-4-sulfonamide (monohydrochloride) ); 7-bromo-2,3,4,5-tetrahydro-1,4-bis (1H-imidazol-4-ylmethyl) -3- (phenylmethyl) -1H-1,4-benzodiazepine (dihydrochloride); 7-bromo-4 - [(dimethylamino) acetyl] -2,3,4,5-tetrahydro-1- (1H-imidazol-4-ylmethyl) -3- (phenylmethyl) -1H-1,4-benzodiazepine; (R) -7-Bromo-4- (1,2-dioxopropyl) -2,3,4,5-tetrahydro-1- (1H-imidazol-4-ylmethyl) -3 (phenylmethyl) -1H-1 , 4-benzodiazepine (trifluoroacetate); (R) -7-Bromo-4- (cyclopropylcarbonyl) -2,3,4,5-tetrahydro-1- (1H-imidazol-4-ylmethyl) -3- (phenylmethyl) -1H-1,4-benzodiazepine ( trifluoroacetate); (R) -7-Cyano-2,3,4,5-tetrahydro-1- (1H-imidazol-4-ylmethyl) -3- (phenylmethyl) -4 (propylsulfonyl) -1H-1,4-benzodiazepine ( monohydrochloride); 7-Bromo-1,2,3,5-tetrahydro-1- (1H-imidazol-4-ylmethyl) -3- (phenylmethyl) -4H-1,4-benzodiazepine-4-acetamide; [7-Bromo-2,3,4,5-tetrahydro-1- (1H-imidazol-4-ylmethyl) -3- (phenylmethyl) -1H-1,4-benzodiazepin-8-yl] carbamic acid 2-methylpropyl an ester (trihydrochloride); [4-Acetyl-7-bromo-2,3,4,5-tetrahydro-1- (1H-imidazol-4-ylmethyl) -3- (phenylmethyl) -1H1,4-benzodiazepin-8-yl] carbamic acid 2-methylpropyl ester; N- [4-Acetyl-2,3,4,5-tetrahydro-1- (1H-imidazol-4-ylmethyl) -3- (phenylmethyl) -1H-1,4-benzodiazepin-8-yl] cyclohexanecarboxamide (dihydrochloride); [7-Bromo-2,3,4,5-tetrahydro-1- (1H-imidazol-4-ylmethyl) -4- (methylsulfonyl) -3 (phenylmethyl) -1H-1,4-benzodiazepin-8-yl. ] 2-methylpropyl ester of carbamic acid; (R) -2,3,4,5-Tetrahydro-1- (1H-imidazol-4-ylmethyl) -4- (phenylsulfonyl) -3- (phenylmethyl) 1H-1,4-benzodiazepine-7-carbonitrile (monohydrochloride) ); 7-bromo-3 - [(1,1-dimethylethoxy) methyl] -1,2,3,4-tetrahydro-1- (1H-imidazol-4-ylmethyl) 4- (methylsulfonyl) -1H-1, 4-benzodiazepine; 7-bromo-2,3,4,5-tetrahydro-3- (hydroxymethyl) -1- (1H-imidazol-4-ylmethyl) -4- (methylsulfonyl) -1H-1,4-benzodiazepine (monohydrochloride); 7-bromo-2,3,4,5-tetrahydro-1- (1H-imidazol-4-ylmethyl) -4- (methylsulfonyl) -3 (phenoxymethyl) -1H-1,4-benzodiazepine (dihydrochloride); 7-Bromo-3 - [(1,1-dimethylethoxy) methyl] -1,2,3,4-tetrahydro-1- (1H-imidazol-4-ylmethyl) -5H-1,4-benzodiazepin-5-one ; 7-Bromo-2,3,4,5-tetrahydro-1- (1H-imidazol-4-ylmethyl) -3 - [(4- (hydroxyphenyl) methyl] -4 (methylsulfonyl) -1H-1,4- benzodiazepine (dihydrochloride); (R) -2,3,4,5-Tetrahydro-1- (1H-imidazol-4-ylmethyl) -4- (methylsulfonyl) -7-phenyl-3- (3-pyridinylmethyl) -1H- 1,4-benzodiazepine (dihydrochloride); 7-Bromo-3 - [(3-chlorophenyl) methyl] -2,3,4,5-tetrahydro-1- (1H-imidazol-4-ylmethyl) -4- (methylsulfonyl) -1H-1,4-benzodiazepine ( dihydrochloride); (R) -7-Bromo-3- (cyclohexylmethyl) -2,3,4,5-tetrahydro-1- (1H-imidazol-4-ylmethyl) -4 (methylsulfonyl) -1H-1,4-benzodiazepine (dihydrochloride) ; 7-Bromo-3 - [(2-chlorophenyl) methyl] -2,3,4,5-tetrahydro-1- (1H-imidazol-4-ylmethyl) -4 (methylsulfonyl) -1H-1,4-benzodiazepine (dihydrochloride); (S) -7-bromo-3- (cyclohexylmethyl) -2,3,4,5-tetrahydro-1- (1H-imidazol-4-ylmethyl) -4- (methylsulfonyl) -1H-1,4-benzodiazepine (dihydrochloride); 7-Bromo-2,3,4,5-tetrahydro-1- (1H-imidazol-4-ylmethyl) -3 - [(4-methoxyphenyl) methyl] -4- (methylsulfonyl) -1H-1,4-benzodiazepine ( dihydrochloride); 7-Cyano-1,3,4,5-tetrahydro-1- (1H-imidazol-4-ylmethyl) -3- (phenylmethyl) -4- (phenylsulfonyl) -2H-1,4-benzodiazepin-2-one (monohydrochloride); 7-Bromo-2,3,4,5-tetrahydro-1- (1H-imidazol-4-ylmethyl) -4- (methylsulfonyl) -3- (2-phenylethyl) -1H-1,4-benzodiazepine (dihydrochloride) ; 7-Bromo-4 - [[2- (dimethylamino) ethyl] sulfonyl] -2,3,4,5-tetrahydro-1- (1H-imidazol-4-ylmethyl) -3- (phenylmethyl) -4H-1,4- benzodiazepine (trifluoroacetate, 1: 2); 7- (2-chlorophenyl) -2,3,4,5-tetrahydro-1- (1H-imidazol-4-ylmethyl) -4- (1-naphthalenecarbonyl) -1H-1,4-benzodiazepine (dihydrochloride); 7-bromo-2,3,4,5-tetrahydro-1- (1H-imidazol-4-ylmethyl) -4- (methylsulfonyl) -3- (phenylmethyl) -1H-1,4-benzodiazepine (hydrochloride); 4-acetyl-2,3,4,5-tetrahydro-1- (1H-imidazol-4-yl) -7-phenyl-3- (phenylmethyl) -1H1,4-benzodiazepine (trifluoroacetate); 7-bromo-1,2,3,5-tetrahydro-1- (1H-imidazol-4-ylmethyl) -3- (phenylmethyl) -4H-1,4-benzodiazepine-4-carboxamide (trifluoroacetate); 7- (3-chlorophenyl) -2,3,4,5-tetrahydro-1- (1H-imidazol-4-ylmethyl) -4- (1-naphthalenylcarbonyl) -1H-1,4-benzodiazepine (dihydrochloride); -methyl-N- [2,3,4,5-tetrahydro-1- (1H-imidazol-4-ylmethyl) -4- (1-naphthalenylcarbonyl) -1H-1,4-benzodiazepin-8-yl] benzamide (dihydrochloride) N-phenyl-N '- [2,3,4,5-tetrahydro-1- (1H-imidazol-4-ylmethyl) -4- (1-naphthalenylcarbonyl) 1H-1,4-benzodiazepine-8 -yl] urea (dihydrochloride); 7-butyl-2,3,4,5-tetrahydro-1- (1H-imidazol-4-ylmethyl) -4- (1-naphthalenylcarbonyl) -1H1,4-benzodiazepine (dihydrochloride); 7-bromo-2,3,4,5-tetrahydro-4- (1H-imidazol-4-ylmethyl) -1- (1-naphthalenylcarbonyl) -1H1,4-benzodiazepine (dihydrochloride); 7- (2-furanyl) -2,3,4,5-tetrahydro-1- (1H-imidazol-4-ylmethyl) -4- (1-naphthalenylcarbonyl) -1H-1,4-benzodiazepine (dihydrochloride); 7-Bromo-2,3,4,5-tetrahydro-1- [2- (1H-imidazol-4-yl) ethyl] -4- (1-naphthalenecarbonyl) -1H-1,4-benzodiazepine (dihydrochloride); 7. A compound according to claim 1 wherein it is selected from the group consisting of: The compound of claim 1 for use in inhibiting farnesyl protein transferase. 8-chloro-2,3,4,5-tetrahydro-4- (1H-imidazol-4-ylmethyl) -1- (1-naphthalenylcarbonyl) -1H1,4-benzodiazepine (dihydrochloride); 8-Chloro-2,3,4,5-tetrahydro-1- (1H-imidazol-4-ylmethyl) -4- (1-naphthalenylcarbonyl) -1H1,4-benzodiazepine (hydrochloride): The compound of claim 1 for use in inhibiting prenyltransferases. The compound of claim 1 for use in inhibiting tumors. The compound of claim 1 for use in the treatment of diseases associated with Ras-mediated signaling pathways. The compound of claim 1 for use in the treatment of diseases associated with post-translational modification of farnesyl protein transferase. A compound according to claim 1 for use in the treatment of diseases associated with post-translationally modified geranylgeranyltransferase. 14. A compound having the formula: wherein R 1 is selected from Cl, Br, phenyl, pyridyl or cyano, and R ₂ is selected from aralkyl substituted or heterocycloalkyl substituted. 15. A compound having the formula: wherein R 1 is selected from Cl, Br, phenyl, pyridyl or cyano and R ₂ is selected from aralkyl substituted or heterocycloalkyl substituted. 16. A compound having the formula: wherein R 1 is selected from Cl, Br, phenyl, pyridyl or cyano and R ₂ is selected from aralkyl substituted or heterocycloalkyl substituted; R ₃ is selected from alkyl, substituted, aryl or substituted heterocycle; Z 1 is selected from CO, SO ₂ , CO ₂ , CONHR ₅ , SO ₃ , SO ₂ NR ₅ , C (NCN) NR ₅ ; R ₅ is selected from hydrogen, lower alkyl, substituted alkyl, aryl or aryl substituted. 17. A compound having the formula: P rot wherein R 1 is selected from Cl, Br, phenyl, pyridyl or cyano; R ₂ is selected from aralkyl substituted or heterocycloalkyl substituted; R ₃ is selected from alkyl, substituted, aryl or substituted heterocycle; Z 1 is selected from CO, SO ₂ , CO ₂ , CONHR ₅ , SO ₃ , SO ₂ NR ₅ or C (NCN) NR ₅ ; Prot is selected from triphenylmethyl or Boc; R ₅ is selected from hydrogen, lower alkyl, substituted alkyl, aryl or aryl substituted.