MXPA01006153A - Farnesyl protein transferase inhibitors - Google Patents

Abstract

Disclosed are compounds of formula (1.0), wherein R8 represents a cyclic moiety to which is bound an imodazolylalkyl group;R9 represents a carbamate, urea, amide or sulfonamide group;and the remaining substituents are as defined herein. Also disclosed is a method of treating cancer and a method of inhibiting farnesyl protein transferase using the disclosed compounds.

Description

FARNESILO PROTEIN TRANSFERASE INHIBITORS BACKGROUND OF THE INVENTION WO 95/10516 published April 20, 1995, W096 / 31478, published October 10, 1996, and copending application No. 09/094687 filed June 15, 1998 disclose tricyclic compounds that are useful for inhibit farnesyl protein transferase. In view of the current interest in farnesyl protein transferase inhibitors, an appreciated contribution to the art would be constituted by compounds useful for the inhibition of farnesyl protein transferase. Said contribution is provided by this invention.

BRIEF DESCRIPTION OF THE INVENTION This invention provides compounds that are useful for the inhibition of famesyl protein transferase (FPT). The compounds of this invention are represented by the formula: A compound that has the formula or a pharmaceutically acceptable salt or solvate thereof where: one of a, b, c and d represent N or N + O, and the remaining groups a, b, c and d represent CR1 or CR2; or each of a, b, c, and d are independently selected from CR1 or CR2; each R1 and each R2 is independently selected from H, halo, -CF3, -OR10 (for example -OCH3), -COR10, -SR10 (for example, -SCH3 and -SCH2C6H5), -S (0) tR11 (where t is 0, 1 or 2, for example, -SOCH3 and -S02CH3), -N (R10) 2, -NO2, -OC (O) R10, -C02R10, -OCO2R11, -CN, -NR10COOR11, -SR1C ( O) OR11 (eg, -SCH2CO2CH3), -SR11N (R75) 2 (with the proviso that R11 in -SR11N (R75) 2 is not -CH2-) where each R75 is independently selected from H or -C (0 ) OR11 (for example -S (CH2) 2NHC (O) Ot-butyl and -S (CH2) 2NH2), benzotriazol-1-yloxy, tetrazole-5-lithium, or substituted tetrazole-5-ylthio (for example tetrazole) -thio substituted with alkyl such as 1-methyl-tetrazol-5-iitio), alkynyl, alkenyl or alkyl, said alkyl or alkenyl group being optionally substituted with halo, -OR 10 or -CO 2 R) 10.

R > 3"and or R4 are the same or different and each independently represents H, any of the substituents of R1 and R2, or R3 and R4 taken together represent a C5-C7 fused ring saturated or unsaturated with the benzene ring (Ring III); R5, R6 and R7 each independently represent H, -CF3, -COR10, alkyl or aryl, said alkyl or aryl being optionally substituted with -OR10, -SR10, -S (0) tR11, - NR10COOR11, -N (R10) 2, -N02, -COR10, -OCOR10, -OC02R11, CO2R10, OP03R10, or R5 is combined with R6 to represent = O or = S; with the proviso that for groups -OR10, -SR10, and -N (R10) 2R10 is not H; R 10 represents H, alkyl, aryl, or aralkyl (for example, benzyl); R11 represents alkyl or aryl; X represents N, CH or C, and when X is C, the optional bond (represented by the dotted line) is present with carbon atom 11, and when X is CH, the optional bond (represented by the line) is absent. of points) with carbon atom 11: the dotted line between carbon atoms 5 and 6 represents an optional bond, so that when a double bond is present, A and B independently represent -R10, halo, -OR11, -OCO2R11 or -OC (O) R10, and when no double bond is present between the carbon atoms 5 and 6, A and B each independently represent H2, - (OR11) 2, H and halo, dihalo, alkyl and H, (alkyl) 2, -H and OC (O) R 10, H and -OR 10, = O, aryl and H, = NOR 10 or -O- (CH 2) pO- where p is 2, 3 or 4; R > 8 represents a heterocyclic ring selected from: (2.0) (3.0) (2.1) (3.1) (4.1) said heterocyclic rings (2.0 to 7.0 and 2.1 to 7.1) being optionally substituted with one or more substituents independently selected from: (a) alkyl (e.g., methyl, ethyl, isopropyl and the like), (b) substituted alkyl wherein said substituents are selected from: halo, aryl, -OR15 or -N (R15) 2, heteroaryl, heterocycloalkyl, cycloalkyl, wherein each R 5 group is the same or different, with the proviso that said optional substituent is not attached to a carbon atom that is adjacent to an oxygen or nitrogen atom, and wherein R15 is selected from: H, alkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, cycloalkyl or cycloalkylalkyl; (c) hydroxyl, with the proviso that the carbon atoms adjacent to the nitrogen, sulfur or oxygen atoms of the ring are not substituted with hydroxyl; (d) alkyloxy or (e) arylalkyloxy; (i.e., each substitutable H atom in each substitutable carbon atom in said heterocyclic rings is optionally replaced with substituents selected from (a) to (e) defined above); Y represents CH2, NR16, O, S, SO, or SO2 where R16 is selected from: H, alkyl, cycloalkyl, cycloalkylalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, acyl, aroyl, carbamoyl, carboxamido, alkylsulfonyl, arylsulfonyl, arylalkysulfonyl, sulfonamido, alkylsulfonamido, arylsulfonamido and arylalkysulfonamido; n is 0 to 6 (preferably 1-3); Q represents O or N, with the proviso that Q is not adjacent to a heteroatom in the heterocycloalkyl rings of 2.1, 3.1, 4.1, 5.1, 6.1 and 7.1; R12 is selected from: (for example, R12 is 9.0); wherein R17 is selected from: (1) H, (2) alkyl, (3) aryl, (4) arylalkyl, (5) substituted arylalkyl where the substituents are selected from halo (e.g., F and Cl) or CN, ( 6) -C (aryl) 3 (e.g., -C (phenyl) 3, ie, trityl), (7) cycloalkyl, (8) substituted alkyl (as defined above in (b)), or ( 9) cycloalkylalkyl; R12A is selected from rings 8.0, 8.1 or 9.1, defined above; said ring midazolyl 8.0 and 8.1 is optionally substituted with one or two substituents, said ring imidazole 9.0 is optionally substituted with 1-3 substituents, and said pyridyl ring 9.1 is optionally substituted with 1-4 substituents, wherein said optional substituents for the rings 8.0, 8.1, 9.0 and 9.1 are attached to the carbon atoms of said rings and are independently selected from: -NHC (O) R15, -C (R18) 2OR19, -OR15, -SR15, F, Cl, Br, alkyl (for example, methyl, such as 4-methyl in 9.0), substituted alkyl (as defined above (b)), aryl, arylalkyl, cycloalkyl, or -N (R15) 2; R15 is as defined above; each R18 is independently selected from H or alkyl (preferably -CH3), preferably H; R19 is selected from H or -C (O) NHR20, and R20 is as defined above; R13 and R14 for each n are independently selected from: H, F, alkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, cycloalkyl, cycloalkylalkyl or -CON (R15) 2 (where R15 is as defined above), -OR15 or -N (R15) 2 with the proviso that the groups -OR15 and -N (R15) 2 are not bonded to a carbon atom that is adjacent to a nitrogen atom and with the proviso that there may be only one group - OH in each carbon; and the substitutable R13 and R14 groups are optionally substituted with one or more (eg, 1-3) substituents selected from: F, alkyl (eg, methyl, ethyl, isopropyl and the like), cycloalkyl, arylalkyl or heteroarylalkyl (i.e. , the R13 and / or R14 groups may be unsubstituted or may be substituted with 1-3 of the substituents described above, except when R13 and / or R14 is H); or R13 and R14, for each n, together with the carbon atom to which they are attached, form a C3 to C6 cycloalkyl ring; R9 is selected from: (12.0) (13.0) (14.0) (15.0) (16.0) R s20 is selected from: H, alkyl, aryl, arylalkyl, cycloalkyl, cycloalkylalkyl, heteroaryl, heteroarylalkyl, heterocycloalkyl, or heterocycloalkylalkyl, with the proviso that R20 is not H when R9 is group 12.0 or 16.0; when R20 is other than H, then said group R20 is optionally substituted with one or more (for example, 1-3) substituents selected from: halo, alkyl, aryl, -OC (0) R15 (for example, -OC (0) CH3), -OR15 or -N (R15) 2, where each group R15 is the same or different and where R15 is as defined above, with the proviso that said optional substituent is not attached to a carbon atom which is adjacent to an oxygen or nitrogen atom; R21 is selected from: H, alkyl, aryl, arylalkyl, cycloalkyl, cycloalkylalkyl, heteroaryl, heteroarylalkyl, heterocycloalkyl or heterocycloalkylalkyl; when R21 is other than H, then said group R21 is optionally substituted with one or more (for example, 1-3) substituents selected from: alkyl, aryl, when each group R15 is the same or different, and where R15 is as defined above; and R 322 is selected from cycloalkyl (e.g., cyclopropylmethyl, i.e. heterocycloalkyl, aryl (e.g., phenyl), substituted aryl (e.g., halo as a substituent such as F or Cl), alkyl (e.g., t-butyl), or substituted alkyl or substituted cycloalkyl (substituents include -OH, -CO2H, and -C (O) NH2). Therefore, in one embodiment of this invention R9 is 12.0. In another modality R9 is 13.0. In another modality R9 is 14.0. In another modality R9 is 15.0. In another modality R9 is 16.0. The compounds of this invention: (i) potently inhibit farnesyl protein transferase but not geraniigeranyl protein transferase I, in vitro; (ii) block the phenotypic change induced by a form of transforming Ras which is a farnesyl acceptor but not in a form of transforming Ras manipulated to be a geranylgeranyl acceptor; (iii) they block the intracellular process of Ras which is a farnesyl acceptor but not of the Ras manipulated to be a geranylgeranyl acceptor; and (iv) they block the abnormal development of cells in cultures induced by transforming Ras. The compounds of this invention inhibit farnesyl protein transferase and famesylation of the oncogenic protein Ras. Therefore, this invention further provides a method for inhibiting farnesyl protein transferase (eg, ras farnesyl protein transferase) in mammals, especially humans, by administering an effective amount of the tricyclic compounds described above. The administration of the compounds of this invention to patients, to inhibit famesyl protein transferase, is useful in the treatment of the cancers described below. This invention provides a method for inhibiting or treating the abnormal development of cells, including transformed cells, by administering an effective amount of a compound of this invention. Abnormal cell development refers to the development of cells independently of normal regulatory mechanisms (eg, loss of contact inhibition). This includes the abnormal development of: (1) tumor cells (tumors) that express an activated Ras oncogene; (2) tumor cells in which the Ras protein is activated as a result of the oncogenic mutation in another gene; and (3) benign and malignant cells of other proliferative diseases in which aberrant Ras activation occurs. This invention also provides a method for inhibiting or treating tumor development by administering an effective amount of the tricyclic compounds, described herein, to a mammal (e.g., a human) in need of such treatment. In particular, this invention provides a method for inhibiting or treating the development of tumors expressing an activated Ras oncogene by administering an effective amount of the compounds described above. Examples of tumors that can be inhibited or treated include, but are not limited to, lung cancer (e.g., adenocarcinoma of the lung), pancreatic cancers (e.g., pancreatic carcinoma, such as e.g., exocrine pancreatic carcinoma), colon cancers (e.g., colorectal carcinomas, such as, for example, colon adenocarcinoma and colon adenoma), myeloid leukemias (e.g., acute myelogenous leukemia (AML), follicular thyroid cancer, myelodysplastic syndrome (MDS), gallbladder carcinoma, carcinoma) epidermal cancer, melanoma, breast cancer and prostate cancer It is considered that this invention also provides a method for inhibiting or treating proliferative diseases, both benign and malignant, where Ras proteins are aberrantly activated as a result of oncogenic mutation in other genes ie the Ras gene itself is not activated by the mutation to an oncogenic form carrying out said inhibition or treatment by administering an effective amount of the tricyclic compounds described herein to a mammal (e.g., a human) in need of such treatment. For example, benign proliferative disorder neurofibromatosis, or tumors in which Ras is activated due to a mutation or overexpression of the tyrosine kinase oncogenes (eg, neu, src, abl, Ick and fyn), can be inhibited or treated with the tricyclic compounds described herein.

Tricyclic compounds that are useful in the methods of this invention inhibit or treat the abnormal development of cells. Without wishing to adhere to any theory it is believed that these compounds can function through the inhibition of G protein function, such as, ras p21, by blocking the isoprenylation of the G protein, which makes them useful in the treatment of proliferative diseases such as cancers and tumor development. Without wishing to adhere to any theory it is believed that these compounds inhibit famesyl ras protein transferase, and that they therefore demonstrate antiproliferative activity against ras transformed cells.

DETAILED DESCRIPTION OF THE INVENTION As used herein, the following terms are used as defined below unless otherwise indicated: MH + - represents the molecular ion in addition to the hydrogen of the molecule in the mass spectrum; BOC - represents tert-butyloxycarbonyl; BOC-ON -represents 1 - (tert-butoxycarbonyl) -2-tert-butyl-3-methyl-4-imidazolidinone nitrile; CBZ -represents -C (O) OCH2C6H5 (ie, benzyloxycarbonyl); CBZ-OSUC -represents benzyloxycarbonyl-O-succinimide; CH2Cl2 - represents dichloromethane; CIMS -represents chemical ionization mass spectrum; DEAD - represents diethylazodicarboxylate; DEC - represents EDC which represents 1- (3-dimethyl-aminopropyl) -3-ethylcarbodiimide hydrochloride; DMF -represents N, N-dimethylformamide; Et - represents ethyl; EtOAc - represents ethyl acetate; EtOH - represents ethanol; HOBT -represents 1-hydroxybenzotriazole hydrate; IPA - represents isopropanol; IPrOH - represents isopropanol; LAH -represents lithium aluminum hydride; LDA -represents lithium diisopropylamide; MCPBA -represents meta-chloroperbenzoic acid; Me -represents methyl; MeOH - represents methanol; EM - represents mass spectroscopy; NMM -represents N-methylmorpholine; Ph - represents phenyl; Pr - represents propyl; TBDMS - represents tert-butyldimethylsilyl; TEA - represents triethylamine; TFA - represents trifluoroacetic acid THF - represents tetrahydrofuran; Tr - represents trityl; alkyl - represents straight and branched carbon chains and contains from one to twenty carbon atoms, preferably one to six carbon atoms, said cycloalkyl ring being optionally substituted with one or more (eg 1, 2 or 3) alkyl groups (by example, methyl or ethyl) and when there is more than one alkyl group each alkyl group may be the same or different; acyl-represents a group G-C (O) - in which G represents alkyl, aryl, heteroaryl, cycloalkyl, heterocycloalkyl, -O-alkyl, -O-aryl, or NR25R26 where R25 and R26 are independently selected from alkyl or aryl; arylalkyl - represents an alkyl group, as defined above, substituted with an aryl group, such as defined below so that the bond of another substituent is attached to the alkyl portion; aryl (including the aryl portion of arylalkyl) -represents a carbocyclic group containing from 6 to 15 carbon atoms and having at least one aromatic ring (for example, aryl is a phenyl ring), with all substitutable carbon atoms carbocyclic group available as possible adhesion points, said carbocyclic group being optionally substituted (eg, 1 to 3) with one or more of halo, alkyl, hydroxy, alkoxy, phenoxy, CF3, -C (O) N (R18 ) 2, -SO2R18, -S02N (R18) 2, amino, alkylamino, dialkylamino, -COOR23 or -N02, wherein R23 represents alkyl or aryl; aroyl - represents -C (0) aryl where aryl is as defined above (eg, -C (O) phenyl); cycloalkyl - represents saturated carbocyclic rings of 3 to 20 carbon atoms, preferably 3 to 7 carbon atoms, said cycloalkyl ring being optionally substituted with one or more (eg, 1, 2 or 3), alkyl groups (e.g. methyl or ethyl) and when there is more than one alkyl group each alkyl group can be the same or different; cycloalkyl - represents a cycloalkyl group, as defined above, substituted with an alkyl group such as defined above, so that the bond of another substituent is attached to the alkyl portion; halo - represents fluorine, chlorine, bromine and iodine; heteroaralkyl - represents an alkyl group, such as defined above, substituted with a heteroaryl group, such as defined below, so that the bond of another substituent is attached to the alkyl portion; heteroaryl - represents cyclic groups optionally substituted with R3 and R4 having at least one heteroatom selected from O, S or N, said heteroatom interrupting a carbocyclic ring structure and having a sufficient amount of delocalized pi electrons to give them aromatic character, preferably containing aromatic heterocyclic groups from 2 to 14 carbon atoms, for example 2- or 3-furyl, 2- or 3-thienyl, 2-, 4- or 5-thiazolyl, 2-, 4- or 5-imidazolyl, 2- , 4- or 5-pyrimidinyl, 2-pyrazinyl, 3- or 4-pyridazinyl, 3-, 5- or 6- [1, 2,4-triazinyl], 3- or 5- [1,4-thiadiazolyl] ), 2-, 3-, 4-, 5-, 6- or 7-benzofuranyl, 2-, 3-, 4-, 5-, 6- or 7-indolyl, 3-, 4- or 5-pyrazolyl, 2-, 4- or 5-oxazolyl, triazolyl, 2-, 3- or 4-pyridyl or pyridyl N-oxide (optionally substituted with R3 and R4), where the pyridyl N-oxide may be represented as: heterocycloalkyl - represents a branched or unbranched saturated carbocyclic ring containing from 3 to 15 carbon atoms, preferably from 4 to 6 carbon atoms, the carbocyclic ring being interrupted by 1 to 3 hetero groups selected from -O-, -S- or -NR24, wherein R24 represents alkyl, aryl, -C (O) N (R18) 2 wherein R18 is as defined above (eg, -C (O) NH2) or acyl- (appropriate heterocycloalkyl groups which include 2- or 3-tetrahydrofuranyl, 2- or 3-tetrahydrothienyl, tetrahydropyranyl, 2-, 3- or 4-piperidinyl, 2- or 3-pyrrolidinyl, 2-or 3-piperazinyl, 2- or 4-dioxanyl, morpholinyl, etc. .).

The positions in the tricyclic ring system are: The compounds of formula 1.0 include the 2R and 2S isomers shown below (2R is preferred): Examples of the optional substituents for the R12 or R12A portion include: -CH3, -CH2OH, -CH2OC (0) 0-cyclohexyl, -CH2OC (0) 0-cyclopentyl, ethyl, isopropyl, NH2 and -NHC (O) CF3. Examples of R 17 include: -C (O) NH-cyclohexyl, -C (phenyl) 3, H, methyl or ethyl.

Examples of R20 include t-butyl, i-propyl, neopentyl, cyclohexyl, cyclopropylmethyl, Examples of R20 for group 12.0 include: t-butyl, ethyl, benzyl, -CH (CH3) 2, -CH2CH (CH3) 2- (CH2) 2CH3, n-butyl, n-hexyl, n-octyl, p -chlorophenyl, cyclohexyl, cyclopentyl, neopentyl, cyclopropylmethyl or Examples of R20 and R21 for 13.0 include: cyclohexyl, t-butyl, H, -CH (CH3) 2, ethyl, - (CH2) 2CH3, phenyl, benzyl, - (CH2) 2phenyl, and -CH3. Examples of R20 for 14.0 include: 4-pyridylNO, -OCH3, -CH (CH3) 2, -t-butyl, H, propyl, cyclohexyl and Examples for R22 for 15.0 include: t-butyl, cyclohexyl, cyclopentyl, cyclobutyl, cyclopropyl, cyclopropylmethyl, phenyl, substituted phenyl (e.g., halo, such as F or Cl), Examples for R20 for 16.0 include: methyl, phenyl, isopropyl and cyclohexylmethyl. Examples of R13 and R14 include; H, F, phenyl, -CH 3, -CH 2 CH (CH 3) 2, - (CH 2) 3 CH 3, benzyl, ethyl, p-chlorophenyl, and -OH (with the proviso that there can be only one OH in each carbon). Cyclopropyl is an example of the group R13 and R14 taken together with the carbon atom to which they are attached to form a cycloalkyl ring. R, R2, R3 and R4 are preferably selected from H and halo, and even more preferably are selected from H, Br, F and Cl. Representative compounds of formula 1.0 include trihalo, dihalo and monohalo substituted compounds, such as, for example compounds: (1) 3,8,10-trihalo; (2) 3,7,8-trihalo; (3) 3,8-dihalo; (4) 8-halo; (5) 10-halo; and (6) 3-halo, substituted (ie no substituent in ring III); where each halo is independently selected. The preferred compounds of the formula 1. 0 include: (1) 3-Br-8-CI-10-Br-substituted compounds; (2) 3-Br- 7-Br-8-CI-substituted compounds; (3) 3-Br-8-CI-substituted compounds; (4) 3- CI-8-CI-substituted compounds; (5) 3-F-8-CI-substituted compounds; (6) 8-CI-substituted compounds; (7) 10-CI-substituted compounds; (8) 3-CI-substituted compounds; (9) 3-Br-substituted compounds; and (10) 3-F-substituted compounds. The substituents are preferably N or N + O with N being preferred. A and B are preferably H2, ie, the optional bond is absent, and the C5-C6 bridge is unsubstituted.

R5, R6 and R7 are preferably H. X is preferably N or CH (ie, the optional bond is absent), and more preferably X is N. When one or more of the carbon atoms of the imidazole ring 8.0 or 9.0 are substituted. , the substituents are generally selected from: -N (R15) 2, -NHC (O) R15, -C (R18) 2OR19, or alkyl, for example, -CH3, -CH2OH, -CH2OC (0) O-cyclohexyl, -CH2OC (O) O-cyclopentyl, ethyl, isopropyl, NH2, or -NHC (0) CF3. R17 is preferably H or alkyl, more preferably H, methyl or ethyl, and more preferably methyl. R 20 in substituent 12.0 is preferably selected from: alkyl or cycloalkyl, more preferably t-butyl, isopropyl, neopentyl, cyclohexyl or cyclopropylmethyl. R 20 in substituent 13.0 is preferably selected from: alkyl or cycloalkyl; more preferably t-butyl, isopropyl or cyclohexyl, R21 is preferably selected from: H or alkyl; more preferably H, methyl or isopropyl; and more preferably H. R20 in substituent 14.0 is preferably selected from: cycloalkyl or alkyl. R22 in substituent 15.0 is preferably selected from: phenyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, t-butyl, cyclopropylmethyl, and more preferably is selected from: t-butyl, cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl. R 20 in substituent 16.0 is preferably selected from: alkyl or cycloalkylalkyl; more preferably methyl, isopropyl or cyclohexylmethyl; more preferably methyl or isopropyl; and even more preferably methyl. R13 and R14 are preferably selected from: H, F, Ci to C4 alkyl (e.g. methyl or isopropyl), -CON (R15) 2 (e.g., -CONH2), -OR15 (e.g., -OH), aryl (e.g., phenyl) or arylalkyl (e.g., benzyl); or when R13 and R14 are taken together to form a cycloalkyl ring, said ring is preferably cyclopropyl or cyclohexyl cyclopropyl. More preferably R13 and R14 are H. For the compounds of the invention, n is preferably 1-3, more preferably 1-2. For compounds in which R8 is ring 2.0 or 7.0, the substituent - (CR13R1) n -R12 may be in the 2-, 3- or 4- position relative to the ring nitrogen, provided that the substituent - (CR13R14) n-R12 is not in position 4- when Y is O, S, SO or S02. Preferably, the substituent - (CR13R14) n-R12 is in the 2- or 3- position, and more preferably in the 3- position. More preferably, the substituent - (CR13R14) n-R12 is in the 2- position when n is 2, and in the 3- position when n is 1. The compounds of the formula 1.0, wherein X is N or CH, include, with reference to the C-11 bond, the R- and S- isomers: The compounds of this invention include the C-11 R- and S- isomers having the 2S stereochemistry.

The compounds of this invention include: The compounds of the invention also include compounds corresponding to 19.0-42.0 DD, except that ring I is phenyl instead of pyridyl. The compounds of the invention also include compounds corresponding to 19.0-42.0 DD, except that ring I is phenyl instead of pyridyl, and the compounds have 2S stereochemistry. The compounds of the invention also include compounds corresponding to 19.0-42.0 DD, except that the compounds have the 2S stereochemistry. The compounds of formula 1.0 include compounds having the formula 1.0 (C): wherein R1 is H or halo (preferably Br, Cl or F), and R2 is H or halo (preferably Cl), and R9 is as defined for formula 1.0.

Preferably, R1 is halo (more preferably Br, Cl or F), and R2 is H or halo (preferably Cl). Those skilled in the art will appreciate that the compounds of formula 1.0 (C) include compounds of formulas 1.0 (D), 1. 0 (G): The lines drawn in the ring systems indicate that the indicated bond can be attached to any of the ring carbon atoms substitutable from any ring when more than one ring is present (eg ring 5.0). Some of the compounds of the invention may exist in different isomeric forms (e.g. enantiomers, diastereoisomers, atropisomers). The invention contemplates all isomers, both those in pure form and in mixture, including racemic mixtures. The enol forms are also included. Some tricyclic compounds will be acidic in nature, for example those compounds that possess a carboxylic or phenolic hydroxyl group. These compounds can form pharmaceutically acceptable salts. Examples of such salts may include sodium, potassium, calcium, aluminum, gold and silver salts. Also contemplated are salts formed with pharmaceutically acceptable amines, such as ammonia, alkylamines, hydroxyalkylamines, N-methylglucamine and the like. Some basic tricyclic compounds can also form pharmaceutically acceptable salts, for example acid addition salts. For example, pyrido nitrogen atoms can form salts with strong acids, while compounds having basic substituents, such as amino groups also form salts with weaker acids. Examples of acids suitable for the formation of salts are hydrochloric, sulfuric, phosphoric, acetic, citric, oxalic, malonic, salicylic, malic, fumaric, succinic, ascorbic, maleic, methanesulfonic and other mineral and carboxylic acids which are well known for those skilled in the art. The salts are prepared by contacting the free base form with a sufficient amount of the desired acid to produce a salt in a conventional manner. The free base forms can be regenerated by treating the salt with an appropriate diluted aqueous base solution, such as NaOH, potassium carbonate, ammonia and sodium bicarbonate. The free base forms differ from their respective salt forms in some way as regards some physical properties such as solubility in polar solvents, but on the other hand the basic salts and acids are equivalent to their respective free base forms for the purposes of the invention. All such basic salts and acids are intended to be converted into pharmaceutically acceptable salts within the scope of the invention and all basic salts and acids are considered equivalent to the free forms of the corresponding compounds for the purposes of the invention. The compounds of formula 1.0 can exist in unsolvated forms as well as solvated forms including hydrated forms, for example, hemi-hydrate. In general, solvated forms are pharmaceutically acceptable solvents such as water, ethanol and the like are equivalent to unsolvated forms for the purposes of the invention.

The compounds of the invention can be prepared according to the methods described in WO 95/10516 published April 20, 1995, WO 96/31478 published October 10, 1996, WO 97/23478 published July 3. of 1997, U.S. Patent 5,719,148 issued February 17, 1998, and copending patent application No. 09/094687 filed June 15, 1998 (see also WO98 / 57960 published December 23, 1998); the descriptions of each of them are incorporated here as a reference, and in accordance with the procedures described below. The compounds of the invention can be prepared according to the reaction schemes described below.

SCHEME 1 R = H or Br The synthesis of the carboxylic acid (scheme 1) begins with the differential protection (J. Med. Chem. (1994) 37, 3443-3451) of the piperazine dicanforsulfonic acid salt (Helv. Chim. Acta, ( 1960) 117, 888-896) which is illustrated in scheme 2. Reaction of the distant amine with CBZ.OSuc at pH 11 followed by acylation with (BOC) 2O provides the differentially protected acid. The hydrogenation on Pd-C selectively removes the CBZ group and the resulting amino acid is coupled to the desired tricyclic chloride. The compounds containing various functional groups can also be prepared by different protection strategies shown in Scheme 3, except for the compounds in which R20 is tert-butyl.

SCHEME 2 SCHEME 3 Alternatively, the amine can be coupled to the di-BOC-protected acid intermediate before incorporation of the tricyclic (scheme 4). This derivative can be prepared from the di-CSA salt (scheme 1) by treating the salt with two equivalents (BOC) under basic conditions. The coupling of the desired amine to this intermediate under conventional conditions (DEC, HOBT, NMM) provides the amide, which by TFA-mediated removal of the BOC- protecting groups can be selectively alkylated with the desired tricyclic chloride (TEA, DMF, temperature environment 48 hours). In this step, the free amine can be adhered, alkylated, or amidated under conditions obvious to those skilled in the art. When R = Br, the separation of chiral HPLC can be used to quickly resolve the C-11 diastereomers.

SCHEME 4 Finally, the anhydrous derivative can be opened with the appropriate amine (room temperature, CH 2 Cl 2) followed by acylation, alkylation, or amidation of the resulting free amine. From there, a sequence similar to that illustrated in scheme 4 (scheme 5) can be used for the synthesis of the desired derivatives.

SCHEME 5 The synthesis of the required amines is generally described in the following schemes. In each, the person skilled in the art will be able to appreciate the areas in which synthesis generalities can be applied for the synthesis of a wider variety of compounds than that specifically illustrated. The majority of the 2- and 3-substituted piperidine and pyrrolidine derivatives can be prepared by methods similar to those illustrated in Scheme 6 from the appropriate amino alcohol. Also, various midazole derivatives can be prepared using the sodium salt of the desired midazole derivative. This general scheme is not applicable when indicated, ie piperidines can not be prepared with a 2-hydroxymethyl substituent using an N-carbamoyl protecting group due to the formation of undesirable oxazolones. In these chaos NH must be protected as N-benzyl or N-allyl derivatives.

SCHEME 6 H H 2HCl The resolution of ethyl nipecotate with D- or L-tartaric acid (J. Org. Chem. (1991) 56. 1 166-1170; Gazz. Chim. Tal. (1972) 102, 189-195.) Provides the desired enantiomer which is converted to the free base by treatment with NaOH. The reduction of LAH acid followed by protection of the amine as a BOC derivative provides the alcohol. The treatment of alcohol with p-toluenesulfonyl chloride in pyridine at 0 ° C, followed by displacement with the sodium salt of the desired imidazole derivative and removal of the BOC protecting group with HCI / dioxane results in the desired amine as the hydrochloride salt. The corresponding 2- and 3-substituted piperazine derivatives are generally accessible through the anhydride (scheme 5) as shown in scheme 7. Opening the anhydride ring with EtOH followed by reduction with NaBH 4 gives the amino alcohol the which can be converted to the N-substituted derivative by reductive amination with paraformaldehyde or with another relevant aldehyde. The conversion to the desired imidazole derivative can be carried out by displacement of the mesylate or tosylate with the sodium salt of the midazole which by removal of the BOC protecting group provides the desired amine.

EXAMPLE 7 The 3-pyrrole di-methanol intermediates can be synthesized as shown in scheme 8 (J. Med. Chem. 1990, 71-77). The treatment of the amine with the enoate provides a mixture of diastereomers which is easily separated by chromatography with silica gel. The reduction of the amide with LAH and the conversion to the imidazole derivative can be carried out as previously described. The catalytic hydrogenation provides the free amine.

SCHEME 8 (i) MsCI Et3N (i) MsCI (ii) Na-Et3N I midazole (ii) Na-I midazole The 4-membered ring analogs can be synthesized as illustrated in Schemes 9 and 10. When the imidazole is directly attached to the ring, the sequence begins with the mesylation of the alcohol followed by displacement with the sodium salt of the desired imidazole derivative. The removal of the benzidril protecting group is carried out by catalytic hydrogenation.

SCHEME 9 For the 4-membered ring compounds with a methylene spacer between the imidazole and the ring, the displacement of the NaCN mesylate provides the nitrile which is readily hydrolyzed to the acid with NaOH and is esterified under Fischer esterification conditions. The desired amine can be made through previously discussed transformations.

SCHEME 10 The morpholino side chains are prepared from the epichlorohydrin as shown in scheme 1 1 (Heterocycle, 38, 1033, 1994). The ring opening of the epoxide with benzyl amine followed by alkylation of the resulting amino alcohol provides the amide. The reduction of the amide with BH3 provides the morpholine in which the midazole is incorporated by means of the previously discussed methodology. Removal of the N-benzyl protecting group provides the desired amine. Following the above procedure, but using the epichlorohydrin, the amine is obtained SCHEME 11 Compounds with a 7-membered ring in the side chain can be prepared as shown in scheme 12. Caprolactam a-bromination followed by NaCN displacement provides the nitrile. The methanolysis and subsequent reduction with LAH provides the amino alcohol which can be easily converted to the desired compound by the previously described methodology.

SCHEME 12 The 4-substituted-piperidine-3-methanol derivatives can be synthesized as illustrated in scheme 13. The protection of the carboxylic acid such as oxazoline also serves to activate the pyridine ring towards nucleophilic attack by MeLi. The rearomatization with sulfur, the hydrolysis of the oxazoline, and the esterification provide the ester which by means of cauterization and reduction provides the enoate. The addition of the conjugate with Mel provides the 4,4-dimethyl derivative. This ester can be converted to the desired compound by the previously described procedures.

SCHEME 13 Ref. J. Pharm. Sci (1992) 81, 1015; Pat. of E.U.A. (1949) 2546652.

SCHEME 14 Derivatives thiomorpholine EDC, HOBt SCHEME 15 Boc. HCl SCHEME 16 (56.0a) H H (56.0b) Those skilled in the art will appreciate that in scheme 16 the corrugated bond with H (± 52.0), OCH3 (54.0a and 54.0b), -CN (55.0a and 55.0b), -COOH (56.0a and 56.0b), -COOH ( 57.0a 57.0b, 58.0a and 58.0b) indicates that the band can be any of - O "" 'Mil The compound (±) 52.0 is stirred following procedures similar to those described in WO97 / 23478 (published July 3, 1997). The reagents used in reaction scheme 3 are: reaction step a: isatoic anhydride / methylene chloride; reaction step b: sodium nitrite / hydrochloric acid / methanol / cuprous chloride; reaction step c: (i) aqueous hydrochloric acid / methanol / reflux (i) sodium hydroxide / sodium cyanide; reaction step d: hydrochloric acid conc./reflux; and reaction step e: di-tert-butyldicarbonate / sodium hydroxide / tetrahydrofuran.

The compounds which are useful in this invention are exemplified by the following preparative examples, which should not be considered as limiting the scope of the description. Alternative mechanical routes and analogous structures within the scope of the invention will be apparent to those skilled in the art.

PREPARED EXAMPLE 1 H • 2CSA To (R) - (-) camphor sulfonic acid (2.5 kg) in distilled water (1250 ml) at 60 ° C was added a solution of the potassium salt of 2-carboxypiperazine (565 g, 3.35 mol). The mixture was left under stirring at 95 ° C until it completely dissolved. Then the solution was cooled to room temperature and allowed to stand for 48 hours. The resulting precipitate was filtered to obtain a wet solid (1444 g). The solids were then dissolved in distilled water (1200 ml) and heated in a steam bath until all the solids dissolved. The resulting solution was cooled slowly to room temperature and left to stand for 72 hours. The crystalline solids were filtered to give a white crystalline solid (362 g) [a] D = -14.9 °.

PREPARED EXAMPLE 2 The title compound of Preparative Example 1 (362 g, 0.608 mol) was dissolved in distilled water (1400 mL) and methanol (1400 mL). Added 50% NaOH to the stirred reaction mixture until the pH reached -9.5. To this solution was added di-tert-butyl dicarbonate (336 g, 1.54 moles) in portions. The pH of the reaction mixture was maintained at 9.5 with 50% NaOH (total 175 moles), and the resulting reaction mixture was stirred for 2.5 hours to obtain a white precipitate. The reaction mixture was diluted with ice / water (9000 ml) and washed with Et2O (2000 ml). The Et2O was discarded and the pH of the aqueous layer was adjusted to pH 3.0 by the portionwise addition of solid citric acid and extracted with CH2Cl2 (3 x 2000 ml). The organic layers were combined, taken up over Na 2 SO 4, filtered and evaporated to give the title compound as a white vitreous solid (201.6 g). FABMS: MH + = 331.

PREPARED EXAMPLE 3 To a solution of ice-cold DMF (49.6 ml) under a nitrogen atmosphere was added dropwise SOCI2 (46.7 ml) in a period of 5 minutes, inside a round bottom flask of 5 I. The reaction mixture was left under stirring for 5 minutes, it was warmed to room temperature and stirred for 30 minutes. The resulting solution was cooled to 0 ° C and the title compound of Preparative Example 2 (201.6 g, 0.61 mmol) in pyridine (51.7 ml) and CH3CN (1900 ml) was added through a cannula. The resulting solution was warmed to room temperature to obtain a cloudy yellowish solution and stirred for 18 hours. The reaction mixture was filtered and the filtrate was poured into ice water (71) and then extracted with EtOAc (4 x 2000 ml). The combined organics were dried over Na 2 SO 4, filtered and evaporated to dryness in vacuo to give the title product as a white solid (115.6 g, 73% yield).

PREPARED EXAMPLE 4 The title compound of Preparative Example 1 (17.85 g, 30 mmol) was dissolved in distilled water (180 mL). Dioxane (180 ml) was added and the pH adjusted to ~ 11.0 with 50% NaOH. The reaction mixture was cooled to 0-5 ° C in an ice-cooled MeOH bath and a solution of benzyl chloroformate (4.28 ml, 30 mmol) in dioxane (80 ml) was added over a period of 30-45 minutes. while stirring at 0-5 ° C, and the pH was maintained at 10.5 to 11.0 with 50% NaOH. After the addition was complete, stirring was continued for 1 hour. The reaction mixture was then concentrated under reduced pressure. The residue was dissolved in distilled water (180 ml). The pH was slowly adjusted to 4.0 with 1 N HCl, and extracted with EtOAc (3 x 180 mL). The combined organics were dried over MgSO4, filtered, and evaporated to obtain the by-product consisting of N, N-di-CBZ-2-carboxy-piperazine. The pH of the aqueous layer was adjusted to about 10.5 with 50% NaOH and solid (Boc) 2 O (7.86 g, 36 mmol) was added and the mixture was stirred while maintaining the pH at -10.5 with 50% NaOH. After 1 hour, the pH stabilized. The reaction was controlled by tic (30% MeOH / NH3 / CH2CI2) and if it was not complete, more (Boc) 20 was added maintaining the pH at -10.5. When demonstrated by TLC, that the reaction is complete ', wash the reaction mixture with Et2O (2 x 180 ml) (verify that the product is not in the Et2O layer and discard the layer). The aqueous layer was cooled in an ice bath and the pH was adjusted to 2.0 with 1 N HCl (slowly) (obtain first bubbling). The aqueous layer was extracted with EtOAc (3 x 200 ml) and the combined organics were dried over MgSO4) filtered and evaporated in vacuo to obtain a white solid (9.68 g, 88% yield).

PREPARATIVE EXAMPLE 5 H The title compound of Preparative Example 4 (9.6 g, 26.3 mmol) was dissolved in absolute EtOH (100 mL) in a hydrogenation vessel. The vessel was flooded with N2 and 10% Pd / C (3.0 g, 50% by weight with water) was added. The mixture was hydrogenated at 55 psi H2 for 18 hours at which time a precipitate formed. When the reaction was complete (TLC, 30% MeOH / NH3 / CH2CI2), the reaction mixture was filtered through a pad of celite, and the pad was washed with EtOH followed by distilled H2O. The filtrate was evaporated to approximately 1/3 volume and distilled H2O (200 ml) was added. The resulting solution was extracted with EtOAc (contains pure N, N-Di-Boc-2-carboxy-piperazine, which was saved). The aqueous layer was evaporated to dryness with azeotropic removal with residual H20 with methanol (2x) to provide the pure product (3.98 g).

EXAMPLES PREPARATIVE 6 Acid 4- (3-bromo-8-chloro-6,11-dihydro-5H benzo | "5,61cycloheptal H, 2-blpiridin-11-yl) -1-R1, 1 -dimethylethoxy) carbonip-2 (R) -carboxylic piperazine The tricyclic alcohol (5.6 g, 17.33 mmol) was dissolved in CH2Cl2 (56 ml) and SOCI2 (2.46 ml) was added while stirring under dry N2 atmosphere. After 5 hours tic control (by adding an aliquot of the reaction mixture to 1 N NaOH and stirring with CH2Cl2 and CH2Cl2 layer was monitored with tic using 50% EtOAc / Hexanes as eluent). The mixture was evaporated to give a gum which was evaporated from dry toluene twice and once from CH2Cl2 to give a foamy solid. The resulting chlorotrichylic compound was dissolved in dry DMF (100 ml) and the title compound was added from preparative example 5 (3.98 g) followed by triethylamine (12.11 ml) and the mixture was stirred at room temperature under an nitrogen. After 24 hours, the reaction mixture was concentrated and the residue was dissolved in EtOAc (200 ml) and washed with brine. The brine layer was extracted with EtOAc (2x) and the combined organics were dried over MgSO4 > they were filtered, and evaporated to give a foamy solid. The solid was chromatographed on a 1 Vz x 14"column of silica gel eluting with 2 I of 0.4% 7N MeOH / NH3: CH2Cl2> 6 I of 0.5% 7N MeOH / NH3: CH2Cl2, 2 I of 0.65% 7N MeOH / NH3: CH2Cl2> 2 I of 0.8% 7N MeOH / NH3: CH2Cl2, 4 I of 1% 7N MeOH / NH3: CH2Cl2, 2 I of 3% 2N MeOH / NH3: CH2CI2, 2 I of 5% 2N MeOH NH 3: CH 2 Cl 2, 2 I of 10% 2N MeOH / NH 3: CH 2 Cl 2, 2 I of 15% 2N 7N MeOH / NH 3: CH 2 Cl 2, 4 I of 20% 2N MeOH / NH 3: CH 2 Cl 2 to obtain 4.63 g of final product.

COMPARATIVE EXAMPLE 7 Stage A Ref: Gazz. Chim. / fa / (1972) 102, 189-195; J. Org. Chem (1991) 56, 166-1170, H Ethyl nipecotate (70.16 g, 0.446 mmole) and D-tartaric acid (67 g, 1.0 eq) were dissolved in 95% hot EtOH (350 ml). The resulting solution was cooled to room temperature and filtered and the crystals were washed with 95% ice-cooled EtOH. The crystals were then recrystallized from 95% EtOH (550 ml) to give the tartrate salt (38.5 g, 56% yield). The salt (38.5 g) was dissolved in water (300 ml) and cooled to 0 ° C before neutralizing with 3M NaOH. The solution was extracted with H2CI2 (5 x 100 ml) and the combined organics were dried over Na2SO4 and concentrated under reduced pressure to give a clear oil (19.0 g, 89% yield) CIMS: MH + = 158 Stage B H H LAH (118 mL, 1.0 M in Et20, 1.0 eq) was added to a solution of the title compound of Step A (18.5 g, 0.125 mmol) in THF (250 mL) at 0 ° C for 20 minutes. The resulting solution was slowly heated to room temperature and then heated to reflux for 2 hours. The reaction was cooled to room temperature and quenched by slow addition of saturated Na 2 SO 4. The resulting suspension was dried by addition of Na2SO4 filtered through Celite and concentrated to give a colorless oil (13J g, 98% crude yield). CIMS: MH + = 116; [α] 20 D = -8.4 (5.0 mg in 2 ml MeOH).

Stage C The title compound of step B (13.6 g, 0.104 mmol) was dissolved in MeOH (100 ml) and H20 (100 ml) and di-tert-butyl dicarbonate (27.24, 1.2 eq) was added portionwise maintaining the pH a > 10.5 by the addition of 50% NaOH. The reaction mixture was stirred at room temperature for an additional 2.5 hours and then concentrated in vacuo. The residue was diluted with H20 (350 mL) and extracted with CH2Cl2, (3 x 150 mL). The combined organics were dried over Na2SO4, filtered and concentrated under reduced pressure. The crude product was purified by evaporative chromatography using 50% EtOAc in hexanes solution as eluent to give a white solid (12.13 g, 48% yield). FABMS: MH + = 216: [aj20D = -15.2 (5.0 mg in MeOH).

Stage D P-Toluenesulfonyl chloride (12.75 g, 1.2 eq) was added portionwise to the title compound of step C (12.00 g, 55.74 mmole) in pyridine (120 ml at 0 ° C). The resulting solution was stirred at 0 ° C overnight. The reaction mixture was diluted with EtOAc (300 ml) and washed with cold 1 N HCl (5 x 300 ml), saturated NaHCO 3 (2 x 150 ml), H 2 O (1 x 100 ml), brine (1 x 100 ml). ) and dried over Na2SO4 and concentrated in vacuo to give a pale yellow solid (21.0 g, 100% crude yield). FABMS: MH + = 370.

Stage E The title compound from step D (21.0 g, 55.74 mmol) in DMF (300 ml) was treated with sodium imidazole (8.37 g, 1.5 eq) and the resulting solution was heated at 60 ° C for 2 hours. The reaction mixture was cooled to room temperature and concentrated in vacuo. The residue was diluted with H20 (300 ml) and extracted with CH2Cl2 (3 x 150 ml). The combined organics were dried over Na 2 SO 4) filtered and concentrated. The crude product was purified by evaporative chromatography using a 7% solution of MeOH in CH 2 Cl 2 as eluent to obtain a pale yellow solid (7.25 g, 49% yield). FABMS: MH + 266 [a] 20 D = + 8.0 (5.0 mg in MeOH).

Stage F The title compound from step E (5.50 g, 20.73 mmol) was stirred at room temperature in 4M HCl in dioxane (50 ml) overnight. The resulting solution was concentrated and the residue was triturated with Et20 to give a yellow solid (4.90 g, 99% yield). CIMS: MH + = 166 PREPARED EXAMPLE 8 By essentially the same procedure as indicated in Preparative Example 7 except that L-aric acid was used in place of D-aric acid in step A, the title compound was prepared.

PREPARED EXAMPLE 9 A mixture of piperazine anhydride (2.56 g, 10,000 mmol, 1.0 eq) and sodium borohydride (965 mg, 25.00 mmol, 2.5 eq) in absolute ethanol (50 ml) was gently refluxed under nitrogen atmosphere for 48 hours. The reaction volume decreased to approximately 10 ml per vacuum and diluted with brine (50 ml). The mixture was extracted with ethyl acetate (8 x 25 ml). The combined organic extracts were washed with brine (50 ml), dried over Na 2 SO 4, filtered, and concentrated under vacuum at 30 ° C. The residue was chromatographed by evaporative chromatography (CH2Cl2: 10% NH4OH / MeOH = 17: 1 v / v) on silica gel to give the title compound (1.09 g, 50%) as a light yellow viscous solid. EIMS: m / z 217 ([M + H] +, 46%), 161 (B +). HR-MS (FAB): Calculated for C10H2? N2O3 ([M + Hj +): 217, 1552. Found: 217, 1549.

Stage B (Bhattacharyya, S. Tetrahedron Lett., 1994, 35, 2104.) A mixture of the title compound of step A (1.09 g, 5.04 mmol, 1.0 eq.) Paraformaldehyde (300 mg, • 10.08 mmol, 2.0 eq.), And titanium isopropoxide (1.5 ml, 5.04 mmol, 1.0 eq.) in absolute ethanol (5 ml) was stirred at 70 ° C for 30 minutes and at room temperature for an additional 30 minutes. Sodium borohydride (195 mg, 5.04 mmol, 1.0 eq.) Was added to the colorless solution. The solution was stirred at room temperature for 12 hours and then at 60 ° C for another 3 hours. The solution was cooled to 0 ° C and treated with a 2.0 M aqueous ammonia solution (25 ml., 50.00 mmoles, excess), to obtain a white-colored suspension. The suspension was filtered through a plug of Celite® 521 and the filtrate was extracted with diethyl ether (4 x 25 ml). The ether extracts were combined and washed with brine (10 ml), dried over Na 2 SO 4, filtered, and concentrated in vacuo at 30 ° C. The residue was chromatographed by evaporative chromatography (CH2Cl2: 10% NH4OH / MeOH = 9.1 v / v) on silica gel to obtain the title compound (1.10 g, 95%) as a light yellow, viscous oil. MS (El): m / z 231 ([M + Hf, 59%), 175 (B +).

HR-MS (FAB): Calculated for CnH22N2? 3 ([M + H] +): 231, 1709. Found: 231, 1716.

Stage C Methanesulfonyl chloride (296 μL, 3.80 mmol, 1.25 eq.) Was added dropwise to a stirred solution of the title compound of Step B (700 mg, 3.04 mmol), 1.0 eq.) And triethylamine (640 μL, 4.56 mmol. , 1.50 eq.) In anhydrous dichloromethane (5 ml) at 0 ° C under a nitrogen atmosphere. The resulting yellow suspension was stirred at 0 ° C for 1 hour and at room temperature for 3 more hours. The mixture was poured into brine (25 ml) and extracted with dichloromethane (5 x 10 ml). The combined organic extracts were dried over Na 2 SO 4, filtered and concentrated under vacuum at 25 ° C to provide a quantitative yield (940 mg) of crude mesylate, which was used directly in the next transformation step (vide infra) without any attempt of characterization or purification.

A mixture of the crude mesylate (940 mg, 3.5 mmol, 1.0 eq.) And sodium imidazole (608 mg, 6.08 mmol, 2.0 eq.) In anhydrous N, N-dimethylformamide (10 ml) was stirred at 60 ° C for 12 hours. under nitrogen atmosphere. The chestnut mixture was cooled to room temperature and diluted with brine (25 ml). The layers were separated and the aqueous layer was extracted with dichloromethane (4 x 25 ml). The combined organic extracts were dried over Na2SO4, filtered, and concentrated under vacuum at 50 ° C. The residue was chromatographed by evaporative chromatography (CH2CI2: 10% NH4OH / MeOH = 19: 1 v / v) on silica gel to give the title compound (432 mg, 1.54 mmol, 51%) as a thick greenish oil . MS (El): m / z 281 ([M + H] + B +) 225 (79), 157 (91). HR-MS (FAB). Calculated for C? H25N402 ([M + H] +): 281, 1978. Found: 281, 1976.

Stage D A solution of the title compound of step C (400 mg, 1.43 mmol, 1.0 eq.) In trifluoroacetic acid anhydro-dichloromethane (10 ml, 1: 1 v / v) was stirred at room temperature under nitrogen atmosphere for 12 hours . The volatiles were removed under vacuum at 40 ° C and the residue redissolved in a 2.0 M aqueous solution of NaOH (10 mL). Volatiles were again removed under vacuum but at a bath temperature of 60 ° C. The residue was chromatographed by evaporation (CH2CI2: 10% NH OH / MeOH = 6: 4 v / v) on silica gel to give the title compound (136 mg, 0J6 mmol, 53%) as a thick yellow oil . MS (El): m / z 181 ([M + H] + B +) 161 (76), HR-MS (FAB): Calculated for C 9 H 17 N ([M + H] +): 181, 1453. Found: 181, 1458 PREPARED EXAMPLE 10 Stage A N-Butoxycarbonyl-thiomorpholine Thiomorpholine (6 g, 58 mmol) was dissolved in CH2Cl2 (200 ml) under a dry nitrogen atmosphere and the reaction mixture was cooled in an ice bath. A solution of dicarbonate-di-tert-butyl (15.3 g, 70 mmol) in CH 2 Cl (50 ml) was added dropwise and the reaction mixture was stirred for 4 hours. The reaction mixture was washed with brine, followed by saturated NaHCO 3, dried over MgSO 4, filtered, and evaporated to obtain 14.37 g of the title product as a crystalline solid. p.f. = 72.9-78.9 ° C.

Stage B N-Butoxycarbonyl-thiomorpholine sulfone The title compound of step A (16 g, 78.7 mmol) was dissolved in 50% CH3OH-H20 (500 mL) at 0 ° C. An Oxone® suspension (72.6 g, 118.05 mmol) was added dropwise in portions while monitoring the pH at 10.5 with 25% NaOH. After 2 hours, the reaction mixture was filtered and the CH 3 OH was evaporated under reduced pressure. The residue was extracted with EtOAc 3 times to obtain 15.5 g, (84%) of the title product as a crystalline solid, mp = 157-159.2 ° C.

Stage C N-Butoxycarbonyl-2-ca rboxiethyl-thiomorpholinesulfone The title compound of Step B (3.0 g, 12.7 mmol) was dissolved in THF (30 mL). The reaction mixture was cooled to -78 ° C in an acetone bath and dry ice under dry nitrogen atmosphere and 8.5 ml of a 1.5 molar solution of lithium diisopropylamide in cyclohexane (LDA) was added dropwise and the solution was stirred for half an hour. Ethyl chloroformate (1.83 ml, 19.05 mmol) was added dropwise and the solution was stirred at -78 ° C for 1 hour. The temperature was allowed to rise to room temperature and the reaction mixture was stirred for an additional 2 hours. The reaction mixture was added to brine and the product was extracted 3 times with EtOAc to obtain 2.87 g of the crude product which was used in the next step without purification.

Stage D N-Butoxycarbonyl-2-hydroxymethyl-thiomorpholine sulfone The crude title compound of step C was dissolved in 30 ml of THF, cooled in a bath and stirred. A solution of 2M THF of lithium borohydride (9 mL, 18 mmol) was added dropwise and the reaction mixture was stirred for 3 hours. 1 N HCl (~ 10 mL) was added slowly and the mixture was stirred for 5 minutes. 1N NaOH (~20 mL) was added and the crude product was extracted with ethyl acetate and dried over magnesium sulfate, filtered and evaporated to obtain a crude oil. The crude oil was chromatographed on silica gel using 20% ethyl acetate / hexanes at 40% ethyl acetate / hexanes to obtain 0.88 g of the title product as a solid. p.f. = 126.9-131.9 ° C.

Stage E N-Butoxycarbonyl-2-imidazolylmethyl-thiomorpholinesulfone The title compound of step D (0.56 g, 2.14 mmol) and diisopropylethylamine (0.372 ml, 2.14 mmol) was dissolved in 5 ml of dichloromethane. Methanesulfonyl chloride (0.198 ml, 2.56 mmol) was added and the reaction mixture was stirred under a dry nitrogen atmosphere for 30 minutes. The reaction mixture was slowly added to molten imidazole (2.9 g, 20 eq.) At 120 ° C. After the dichloromethane was evaporated the reaction mixture was cooled to room temperature to obtain a tan solid. The solid was dissolved in water and the product was extracted with ethyl acetate 3 times to obtain 0.449 g of the product. p.f. = 149.7-151.3ßC, FABMS (M + 1) = 316.2.

Step F: Preparation of 2-imidazolylmethyl-thiomorpholinesulfone • 2 HCl The title compound of step E (0.44 g, 1.4 mmol) was dissolved in 5 ml of 4N HCl / dioxane and stirred for 1 hour. The mixture was evaporated to obtain 0.45 g of the title product.

PREPARED EXAMPLE 11 Stage A N-butoxycarbonyl thiomorpholine sulfoxide The N-butoxycarbonyl-thiomorpholine from preparative example 10 step A (7.07 g, 58 mmol) was dissolved in 200 ml of dichloromethane. 50-60% mCPBA (13.7 g, 80 mmol) was added in portions over a period of 15 minutes. After 2 hours at room temperature the reaction mixture was washed with saturated sodium bisulfite, followed by saturated sodium bicarbonate, and dried over magnesium sulfate, filtered and evaporated to obtain 13.08 g of a white solid. FABMS (M + 1) = 220.

Stage B • 2HCl By essentially the same procedure indicated in preparative example 10 step C-F, the title compound was prepared.

PREPARED EXAMPLE 12 2-Methylimidazole (0.27 g, 1.3 eq.) Was added to a solution of NaH (0.13 g, 1.3 eq., 60% in mineral oil) in DMF (5 ml) at room temperature and the resulting solution was stirred for 20 minutes. before adding the title compound of Preparative Example 7 stage D (0.94 g, 2.54 mmol). The reaction mixture was heated at 60 ° C for 2 hours, cooled to room temperature and concentrated. The crude product was diluted with H20 (50 mL) and extracted with CH2Cl2 (3 x 75 mL). The combined organics were dried over Na 2 SO 4, filtered and concentrated in vacuo. The product was purified by evaporative chromatography using a 7% solution of MeOH in CH 2 Cl 2 as eluent to give a white solid (0.66 g, 93% yield). CIMS: MH + = 280; [α] 20 D = + 4.9 (6.5 mg, 2.0 ml MeOH). By essentially the same procedure indicated in preparative example 7 step E, the following title compounds were synthesized in column 4 from the tosylate in column 2, using the midazole derivative in column 3, table 1: TABLE 1 TABLE 1 (continued) PREPARED EXAMPLE 17 To the title compound of Preparative Example 13 (1.0 g, 3.58 mmol, 69:31 4-Me: 5-Me) in CH 2 Cl 2 (10 mL) at 0 ° C was added TrCI (0.32 g, 1.05 eq. -Me). The resulting solution was stirred at 0 ° C for 2 hours and concentrated under reduced pressure. The crude mixture was purified by evaporative chromatography using a 50% solution of acetone in EtOAc as eluent to give the title compound as a clear oil (0.50 g, 72% yield). CIMS: MH + = 280.

PREPARED EXAMPLE 18 By essentially the same procedure indicated in preparative example 17 the title compound was prepared (0.49 g, 82% yield). By essentially the same procedure indicated in the preparative example 7 step F except that the compounds prepared in the preparative examples 12, 13, 14, 15, 16 (column 2, table 2), 16A, 16B, 16C, 16D, 17 were used , 18, 71 A (stage D), 71 A (stage F) 16E, 72A, 74A, 75A and 76, the amine hydrochlorides were prepared in column 3, table 2: TABLE 2 TABLE 2 (continued) TABLE 2 (continued) EXAMPLE 1 The title compound of Preparative Example 6 (1.0 g, 1.15 eq.) Was added to a solution of the title compound of Preparative Example 1 (2.43 g, 3.81 mmol), DEC (0.95 g, 1.3 eq) HOBT (2.57 g, 5 eq) and NMM (2.51 ml, 6.0 eq.) In DMF (50 ml). The resulting solution was stirred at room temperature for 24 hours. The reaction mixture was diluted with H20 until the precipitation ceased and suspension was filtered. The precipitate was diluted with CH2Cl2 (200 ml), washed with H20 (2 x 100 ml), dried over Na2SO4 and concentrated. The crude product was purified by evaporative chromatography using a 5% solution of (10% NH 4 OH in MeOH) in CH 2 Cl 2 as eluent to give a pale yellow solid (1.8 g, 68% yield). LCMS: MH + = 683. By essentially the same procedure indicated in Example 1 by substituting only the appropriate amine, compounds of the formula shown below can be obtained with R as listed in column 2 of Table 3.

TABLE 3 TABLE 3 (continued) EXAMPLE 10 AND EXAMPLE 11 The title compound of Example 1 was prepared in individual (R) - and (S) - isomers by preparative HPLC with a CHIRALPAK column using 15% iPrOH in hexanes solution with 0.2% DEA as eluent.

EXAMPLE 10 eleven - . 11 - (R) - isomer: retention time (analytical) = 8,845 minutes; [α] D = + 14.0 (2.72 mg in 2.0 ml MeOH); mp = 130-134 ° C; LCMS: MH + = 683.

EXAMPLE 11 11- (S) - isomer: retention time (analytical) = 15,416 minutes; [a] D =; m.p. = 122-127 ° C; LCMS: MH + = 683.

EXAMPLE 12 AND EXAMPLE 13 By essentially the same procedure indicated in Example 10 and 11 except that the title compound of Example 2 was used, the title compounds were prepared.

EXAMPLE 12 11- (R) - isomer: retention time (analytical-15% iPrOH: 0.2% DEA in hexanes) = 18.84 minutes; [a] D = p.f. = 135-138 ° C; MS: MH + = 683.

EXAMPLE 13 11- (S) - isomer: retention time (analytical-15% iPrOH: 0.2% DEA in hexanes) = 23,758 minutes; [a] D = p.f. = 127-130 ° C; MS: MH + = 683.

PREPARED EXAMPLE 24 The title compound of Example 12 (0.87 g, 1.27 mmol) in CH2Cl2 (9.0 mL) was stirred with TFA (9.0 mL) at room temperature for 1 hour. The reaction mixture was cooled to 0 C and neutralized with 50% NaOH, separated, and the aqueous layer was extracted with CH2Cl2 (3 x 200 mL). The combined organics were dried over Na 2 SO 4, filtered, and concentrated in vacuo (0.56 g, 75% crude yield).

EXAMPLE 14 The title compound of Preparative Example 24 (0.12 g, 0.21 mmol) and TEA (0.15 mL, 5.0 eq.) Were dissolved in CH2Cl2 (5.0 mL) and isopropyl chloroformate (1.05 mL, 5.0 eq.) Was added. The reaction mixture was stirred at room temperature overnight before adding H20 (15 ml) and extracted with CH2Cl2 (2 x 100 ml). The combined organics were dried over Na 2 SO, filtered, and concentrated in vacuo. The crude product was purified by evaporative chromatography using a 2.5% solution (10% NH 4 OH in MeOH) in CH 2 Cl 2 as eluent (0.096 g, 69% yield). FABMS: MH + = 669: p.f. 126-128 ° C.

EXAMPLE 15 By essentially the same procedure indicated in Example 14, replacing only cyclohexyl chloroformate, the title compound was prepared (0.053 g, 44% yield). FABMS: MH + = 709; p.f. 140-144 ° C.

EXAMPLE 16 The title compound of Preparative Example 24 (0.13 g, 0.23 mmol) was dissolved in CH2Cl2 (4.0 mL) and t-butyl socianate (0.13 mL, 5.0 eq) was added. The resulting solution was stirred at room temperature for two hours, diluted with H2O (15 ml) and extracted with CH2Cl2 (3x50 ml). The combined organics were dried over Na2SO4, filtered and concentrated in vacuo. The crude product was purified by evaporative chromatography using a gradient of 2.5% MeOH in CH 2 Cl 2, 5% MeOH in CH 2 Cl 2, and finally 10% (10% NH 4 OH in MeOH) in CH 2 Cl 2 as eluent (0.069 g, yield 44%) . LCMS: MH + = 682; mp = 148-153 ° C.

EXAMPLE 17 By essentially the same procedure indicated in Example 16, substituting only with isopropyl isocyanate, the title compound was prepared (0.09 g, 64% yield). LCMS: MH + = 668; p.f. 132-136 ° C.

PREPARATORY EXAMPLE 25 By essentially the same procedure indicated in preparative example 24 using only the title compound of Example 10, the title compound was prepared.

EXAMPLE 18 By essentially the same procedure indicated in Example 16, substituting only the title compound of Preparative Example 25, the title compound was prepared. FABMS: MH + = 682; p.f. 112-120 ° C.

EXAMPLE 19 By essentially the same procedure indicated in Example 14, substituting only the title compound of Preparative Example 25, the title compound was prepared. FABMS: MH + = 669; m.p. = 123-132 ° C; [] 20 D = 16.4 ° (4.5 mg, in 2.0 ml MeOH).

PREPARED EXAMPLE 26 • 2 HCl By essentially the same procedure indicated in preparative example 7, step C to F starting only from L-prolinol, the title compound was prepared.

PREPARED EXAMPLE 27 2 HCl By essentially the same procedure indicated in preparative example 24, starting only with D-prolinol, the title compound was prepared.

EXAMPLE PR PARATIVO 28 Piperazine anhydride (1.03 g, 1.2 eq.) Was added in portions to a solution of the title compound of Preparative Example 27 (0.75 g, 3.35 mmol) in CH2Cl2 (5.0 m) and TEA (2.33 mL, 5.0 eq.) And The resulting solution was stirred for 10 minutes at room temperature before adding CBZ-Osuc (1.00 g, 1.0 eq.). The resulting mixture was stirred at room temperature overnight and concentrated in vacuo. The crude product was purified by evaporative chromatography using 5% MeOH in a CH2Cl2 solution as eluent to obtain a white solid (0.94 g, 56% yield). LCMS: MH + = 498; [] 20D = + 61.6 ° (3.8 mg in 2.0 ml CHCl3).

EXAMPLE 20 A solution of the title compound of Preparative Example 28 (0.85 g, 1.71 mmol) was stirred at room temperature in CH2Cl2 (10 mL) and TFA (3 mL) for three hours. The reaction mixture was concentrated under reduced pressure and the compound was redissolved in CH2Cl2 (7 ml), treated with chloride. { scheme 7 4.}. (0.29 g, 1.0 eq.) And TEA (1.75 ml, 15 eq.). The resulting solution was stirred at room temperature for 96 hours. The reaction mixture was diluted with saturated NaHCO 3 (50 ml), water (50 ml) and CH 2 Cl 2 (50 ml) and separated. The aqueous layer was extracted into CH2Cl2 (2x75 ml) and the combined organics were dried over Na2SO4, filtered, and concentrated under reduced pressure. The crude product was purified by evaporative chromatography using a 6% solution (10% NH 4 OH in MeOH) in CH 2 Cl 2 as eluent to obtain a tan solid (0.29 g, 48% yield). p.f. 80-84 ° C; LCMS: MH + = 703.

PREPARED EXAMPLE 29 The title compound of Example 20 (0.24 g, 0.341 mmol) was stirred at room temperature in HBr / AcOH (2.0 mL) for 2 hours. The reaction mixture was triturated with Et20 and the remaining AcOH was removed by azeotropy with toluene to obtain the HBr salt which was neutralized with 1N NaOH and extracted into CH2Cl2 (3x50 ml). The combined organics were dried over Na 2 SO, filtered, and concentrated in vacuo to give a tan solid (0.18 g, 95% yield) which was used without further purification. LCMS: MH + = 569.

EXAMPLE 21 By essentially the same procedure indicated in Example 16, only using the title compound of Preparative Example 29, e! composed of the title (0.029 g, 50% yield). LCMS: MH + = 668; p.f. 137-139.

EXAMPLE 22 AI of the title of preparative example 29 (0.10 g, 0.175 mmol) and TEA (0.037 ml, 1.5 eq.) In CH2Cl2 (5.0 ml) was added MsCl (0.16 uL, 1.2 eq.) And the resulting solution was stirred at Room temperature during the night. The resulting solution was quenched by the addition of saturated NaHCO3 (10 mL), diluted with H20 (25 mL) and extracted with CH2Cl2 (3x25 mL). The combined organics were dried over Na2S0 > they were filtered, and concentrated in vacuo. The crude product was purified by evaporative chromatography using a 10% solution (10% NH 4 OH in MeOH) in CH 2 Cl 2 as eluent to obtain a tan solid (0.70 g, 64% yield). LCMS: MH + = 647; p.f. 135-141 ° C.

EXAMPLE 23 By essentially the same procedure indicated in Example 22 substituting only the amine hydrochloride of Preparative Example 26 and quenching with cyclohexyl isocyanate in place of CBC-OSuc, the title compound was prepared. LCMS: MH + = 669; p.f. 187 PREPARED EXAMPLE 30 Tricyclic chloride (5.04 g, 1.1 eq.) Was added to a solution of the title compound of Preparative Example 5 (4.0 g, 17.3 mmol) and TEA (12.05 mL, 5 eq.) In DMF (60 mL). The resulting solution was stirred at room temperature for 72 hours, at which time the reaction mixture was concentrated under reduced pressure. The residue was diluted with 3M NaOH and extracted with EtOAc. The aqueous layer was neutralized with 50% citric acid and extracted with EtOAc. The combined organics were dried over Na S04 > they were filtered, and concentrated in vacuo. The crude product was purified by evaporative chromatography using a 12% solution (10% NH 4 OH in MeOH) in CH 2 Cl 2 as eluent to obtain the C-11 (S) -isomer (2.13 g, 54%) as the first eluent isomer and the C -11 (R) -isomer (2.4 g, 61%) as the second eluent isomer. 11- (S) -isomer (first eluent isomer): [] 20 D = -13.4 ° (3.72 mg in 2.0 ml MeOH); LCMS: MH + = 458. 11- (R) -isomer (second eluent isomer): [] 20 D = + 84.9 ° (5.18 mg in 5.0 ml MeOH); FABMS: MH + = 458.

EXAMPLES 24-35G By essentially the same procedure indicated in Example 1, using only the title compounds of Preparative Example 30 (C-11 (S) - and (R) - individual isomers) listed in column 2 of Table 4 and substituting with the amine The compounds of the title of the formula shown below were obtained with R8 as listed in column 3 of Table 4.

TABLE 4 TABLE 4 (continued) TABLE 4 (continued) PREPARED EXAMPLE 31 Stage A 50% NaOH was added to a solution of the title compound of Preparative Example 1 (11.47 g, 19.28 mol) in dioxane: H20 (1: 1, 64 mL) until the pH was about 11.5 and BOC-ON was added. (5.22 g, 1. 1 eq.) In two portions. 50% NaOH was added to maintain the pH at approximately 11.5. When the pH stabilized, the resulting solution was stirred at room temperature overnight. The pH was adjusted to approximately 9.5 ny and the addition of 1M HCl and isopropyl chloroformate (21.21 ml, 1.0 M in toluene, 1.1 eq.) Was performed. The resulting solution was maintained at pH about 9.5 and stirred for 3 days. The reaction mixture was concentrated and extracted with Et20, the pH readjusted to 9.5 after each extraction. When the pH was stabilized at about 9.5 during 3 consecutive extractions, the aqueous layer was acidified to pH about 4.5 with 50% citric acid and at about pH 3 with 1M HCl, and extracted with EtOAc (3x100 ml). The combined organics were dried over Na 2 SO, filtered and concentrated under reduced pressure to give a white solid (5.8 g, 90% yield).

FABMS: MH + = 317. Treatment of the product with TFA provided the deprotected amine, which was used without further purification.

Stage B By essentially the same procedure indicated in preparative example by substituting only the title compound of Preparative Example 31, step A, the title compound was prepared and separated into the C-11 isomers: 11- (S) -isomer (first eluent isomer): LCMS: MH + = 444. 11- (R) -isomer (second eluent isomer): LCMS: MH + = 444.

EXAMPLES 36-411 By essentially the same procedure indicated in Example 1, substituting only the title compounds of Preparative Example 31 (individual isomers C-11 (S) and (R)), and substituting with the appropriate amine, the compounds of the formula were obtained shown below, where R8 is as indicated in column 3 of table 5.

TABLE 5 TABLE 5 (continued) TABLE 5 (continued) PREPARED EXAMPLE 32 By essentially the same procedure indicated in the preparative example 31 by replacing only cyclohexyl chloroformate the isopropyl chloroformate from step A, the title compounds (C-11 (S) - and (R) isomers) were prepared and separated into diastereomers individual Isomer 11 - (S) (first elution isomer): FABMS: MH + = 484. Isomer 11- (R) (second elution isomer): FABMS: MH + = 484.

EXAMPLES 42-47CC By essentially the same procedure indicated in Example 1, substituting only the title compounds of Preparative Example 32 (individual isomers C-11 (S) and (R)) and substituting with the appropriate amine, compounds of the formula is shown below, where R8 is as indicated in column 3 of table 6.

TABLE 6 TABLE 6 (continued) TABLE 6 (continued) TABLE 6 (continued) TABLE 6 (continued) TABLE 6 (continued) PREPARED EXAMPLE 33 By essentially the same procedure indicated in preparative example 24, using only the title compounds of example 26, the title compound was prepared. By essentially the same procedure indicated in preparative example 33, substituting only the compound of the example listed in column 2 of table 7, the title compounds of the formula shown below were prepared where R8 is as in column 4 from box 7.

TABLE 7 TABLE 7 (continued) EXAMPLE 48 By essentially the same procedure indicated in Example 16 substituting only the title compound of Preparative Example 33, the title compound was prepared. FABMS: MH + = 618; p.f. = 111-140 ° C. By essentially the same procedure indicated in example 48, substituting only the title compounds of the preparative example listed in column 2 of table 8, the title compounds of the formula shown below were obtained where R8 is as listed in column 4 of table 8. H PREPARATIVE EXAMPLE 48 (R) v (S) -r2- (1 H-lmidazole-1 -IL) Methophopholines H H Step A (R) and (S) -3-chloro-1 (benzylamino) -2-propanols (T.Mori et al., Heterocycles 38.5 1033, 1994) (R) (S) A mixture R) -epichlorohydrin (5 g, 54.03 mmol) and benzylamine (5.8 g, 54.03 mmol) in cyclohexane (50 ml) was stirred at room temperature for 16 hours. The resulting precipitates were collected to give the title compound (5.4 g, 50.09%): dH (DMSO-de) 2.28 (bs, 1H), 2.43-2.67 (m, 2H), 3.45-3.85 (m, 5H), 5.13 (bs, 1 H), 7.05-7.48 (m, 5H). In a similar manner the (S) isomer was prepared from (S) -epichlorohydrin in 67% yield.

Stage B (R) and (S) -2-chloromethyl-4-benzyl-5-oxomorpholines (R) To a mixture of the title compound from step A above (5.3 g, 26.57 mmol), NaOH (10.62 g, 265 mmol), CHCl3 (50 mL) and H20 (20 mL) was added dropwise a solution of bromoacetyl bromide. (14.98 g, 74.25 mmol) in CHCl3 (15 ml) over a period of 1 hour at 0 ° C and then at room temperature for 16 hours. The organic layer was separated and washed successively with water, with 1N HCl, and brine. The solvent was evaporated leaving the title compound ((R) isomer) (5.43g, 84.4%): FABMS (M + 1) = 240; dH (CDCl 3) 3.2-3.33 (m, 2H), 3.50 (dd, 1H), 3.51 (dd, 1H), 4.0 (m, 1H), 4.25 (d, 1H), 4.4 (d, 1H), 4.52 ( d, 1H), 4.7 (d.1H), 7.20-7.33 (m, 5H). The (S) isomer (67%) was similarly prepared. FABMS (M + 1) = 240; dH (CDCl 3) 3.2-3.33 (m, 2H), 3.50 (dd, 1H), 3.51 (dd, 1H), 4.0 (m, 1H), 4.25 (d, 1H), 4.4 (d, 1H), 4.52 ( d, 1H), 4.7 (d, 1H), 7.20-7.33 (m, 5H).

Stage C (R) -2-chloromethyl-4-benzyl-morpholines (R) To a solution of the title compound from step B was added (5.09 g, 21.23 mmol) in anhydrous THF (55 ml) to a stirred complex 1.0 M BH3-THF (109 ml) for a period of 0.5 hours at -15 ° C under nitrogen atmosphere. The mixture was stirred at room temperature for 1 hour, heated to reflux overnight and then cooled to 0 ° C. After adding concentrated HCl (75 ml) to the reaction mixture, the THF was evaporated in vacuo. The resulting aqueous solution was basified with 10% NaOH and extracted with CH2Cl2. The extract was washed successively with water and brine, and CH2C.2 was evaporated to leave a crude product, which was chromatographed on silica gel with CH2Cl2 -2% acetone to give the title compound (3.2 g, 80% ). FABMS (M + 1) = 226, dH (CDCl 3) 2.1 (dd, 1H), 2.3 (dd, 1H), 2.72 (m, 1H), 2.84 (m, 1H), 3.5-3.6 (s, 2H), 3.62-3.98 (m, 31 H), 7.2-7.4 (m, 5H).

Step D (R) -4-benzyl-2- (1H-imidazol-yl) methyl-morpholines (R) A solution of the title compound of step C (3.1 g, 13.77 mmol) in DMF (15 ml) was added to a stirred solution of NaH (1.29 g, 53.75, mmoles) and imidazole (3.67 g, 53.97 mmoles). ) in DMF (50 ml) under nitrogen atmosphere. Then, the mixture was stirred at 60 ° C for 16 hours. The DMF was evaporated in vacuo. The resulting crude product was extracted with CH2CI2 and the extract was washed successively with water and brine, and the CH2CI2 was evaporated leaving a crude product, which was chromatographed on silica gel with CH2Cl2 -5% (10% NH4OH in methanol) to give the title compound (1.65 g, 45%). FABMS (M + 1) = 258 (MH +); dH (CDC13) 1.8 (m, 1H), 2.15 (m, 1H), 2.8 (m, 2H), 3.4-3.8 (m, 7H), 6.9 (S, 1 H), 7.2 (S, 1H), 7.3 (m, 5H), 7.5 (S, 1 H).

Stage E (S) -4-benzyl-2-pH-imidazol-yl) methyl-5-oxomoríolinas (S) A solution of the title compound of Step B (2.73 g, 11.37 mmol) in DMF (15 mL) was added to a stirred solution of NaH (1.55 g, 22.79 mmol) and imidazole 0.55 g, 22.75 mol) in DMF (25 ml) under nitrogen atmosphere. The mixture was stirred at 60 ° C for 16 hours. The DMF was evaporated in vacuo. The resulting crude product was extracted with CH2CI2 and the extract was washed successively with water and brine and then the CH2Cl2 was evaporated to leave a crude product which was chromatographed on silica gel with CH2Cl2 -5% (10% NH40H in methanol) to give the title compound (0.761 g, 24.7%). FABMS (M + 1) = 272 (MH +); dH (CDC13) 3.12 (m, 2H), 3.98 -4.71 (m, 7H), 6.98 (S, 1H), 7.1 (s, 1H), 7.2-7.4 (m.5H), 7.98 (S, 1H).

Stage F (S) -4-benzyl-2- (1H-imidazol-yl) methyl-morpholines 1N LAH in ether (5.5 ml) was added to a stirred solution of the title compound (0.05 g, 2.75 mmol) from step E in anhydrous THF (25 ml) by dripping over a period of 0.5 hours and the resulting mixture was refluxed. During 4 hours. The reaction mixture was slowly decomposed with ice water and extracted with CH2Cl2. The extract was washed with water and with brine and dried (MgSO 4), filtered and evaporated to dryness to give the title compound (0.53 g, 75%). FABMS (M + 1) = 258 dH (CDC13) 1.8 (m, 1H), 2.15 (m, 1H), 2.8 (m, 2H), 3.4-3.8 (m, 7H), 6.9 (S, 1H), 7.02 (S, 1H), 7.3 (m, 5H), 7.5 (S, 1H).

Stage G (R) v (S) -r2- (1H-imidazo) -1-i [) metipmorpholines A mixture of the title compound (1.6 g) from step D and Pd (OH) 2 on carbon (0.32 g) in EtOH (20 ml) was stirred at 50 psi under hydrogen atmosphere for 24 hours. The catalyst was filtered to give the title compound (1.03 g, 99.9%). FABMS (M + 1) = 168; dH (CDCl 3) 2.4-2.5 (m, 1H), 2.8 (m, 3H), 3.5-3.9 (m, 5H), 6.9 (S, 1H), 7.02 (S, 1H), 7.45 (S, 1H). In a similar manner the (S) isomer was prepared from (0.5 g) and Pd (OH) on carbon (0.2 g) with a yield of 99%. FABMS (M + 1) = 168; dH (CDCl 3) 2.4-2.5 (m, 1H), 2.8 (m, 3H), 3.5-3.9 (m, 5H), 6.9 (S, 1H), 7.02 (S, 1H), 7.45 (S, 1H).

PREPARED EXAMPLE 49 F4- (1 H-imidazol-1-di-methylpiperidine) Stage A 1 N-tert-butoxycarbonyl-4-hydroxymethyl-piperidine To a solution of 4-hydroxymethyl-piperidine (5 g, 43.41 mmol) and triethylamine (8.78 g, 86.82 mmol) in CH 2 Cl 2 (100 mL), was added di-tert-butyl dicarbonate (18.95 g, 86.82 mmol) and it was stirred at room temperature for 16 hours. The solution was diluted with CH2Cl2 and washed with water, dried (MgSO4), filtered and evaporated to give the title compound (9.04 g, 99%). FABMS (M + 1) = 216.

Stage B 1N-tert-butoxycarbonyl-4-methanesulfonyloxymethyl-piperidine The title compound of the above step A (8.8 g, 40.87 mmol) and triethylamine (8.55 ml, 61.31 mmol) were dissolved in CH2Cl2 (100 ml) and the mixture was stirred under nitrogen at 0 ° C. Methanesulfonyl chloride (3.8 ml, 49.05 mmol) was added and the solution was stirred at room temperature for 2 hours. The solution was diluted with CH2Cl2 and washed with saturated aqueous sodium bicarbonate, water and dried (MgSO4), filtered and evaporated to dryness to give the title compound (12.8 g) FABMS (M + 1) = 294.3.

Step C 1 N-tert-butoxycarbonyl-4- (1 H-imidazol-1-yOmethyl-piperidine To a solution of the title compound from Step B (1.0 g, 3.408 mmol) in DMF (15 mL) was added to a stirred solution of NaH (0.27 g, 6.817 mmol) and imidazole (0.464 g, 6.817 mmol) in DMF. (15 ml) under nitrogen atmosphere. The mixture was stirred at 60 ° C for 16 h. DMF was evaporated under vacuum. The resulting crude product was extracted with CH2CI2 and the extract was washed successively with water and brine, and CH2Cl2 was evaporated to leave the title residue which was chromatographed on silica gel using 3% (10% conc NH4OH in methanol) - CH2Cl2 as eluent to give the title compound (0.823 g). FABMS (M + 1) = 266.2, dH (CDCI2) 0.8-1.0 (m, 2H), 1.2 (s, 9H), 1.2-1.4 (m, 1 H), 1.65 (m, 1 H), 2.4 (dt) , 2H), 3.6 (d, 2H), 4.8 (d, 2H), 6.7 (s, 1 H), 6.8 (s, 1 H), 7.2 (s, 1 H).

Stage D 4- (1 H-imidazol-1-di-methyl-piperidine) The title compound (0.187 g, 0.705 mmoles) from step C was stirred in 4N HCl in dioxane (20 ml) for 2 hours and then evaporated to dryness to give the title compound which was used to couple it with the acid tricyclic EXAMPLES PREPARATIVE 50 3 (R) v 3 (S) - (1 H-imidazol-1-yl) methyl) pyrrolidones H H (R) (S) Step A 1 N-tert-butoxycarbonyl-3 (R) 3 (S) - (1 H -imidazol-1-yl) methyl) pyrrolidines 3 (R) - (3-methanesulfonyloxymethyl) pyrrolidine (J. Med. Chem. 1990, 33, 77-77) (0.993 g, 3.56 mmol) was dissolved in anhydrous DMF (25 ml) and sodium midazole ( 0.6 g, 10 mmol). The mixture was heated at 60 ° C for two hours and then evaporated to dryness. The product was extracted with CH2Cl2 and washed with brine. The CH2Cl2 extract was evaporated to dryness to give the title compound (1.1409 g, 100%), ESMS: FABMS (M + 1) = 252; dH (CDCl2) 1.45 (s, 9H), 1.5-1.7 (m, 1 H), 1.9-2.1 (m, 1 H), 2.5-2.7 (m, 1 H), 3.0-3.2 (m, 1H), 3.3-3.6 (m, 2H), 3.9 (dd, 2H), 6.9 (s, 1H), 7.1 (s, 1H), 7.45 (s, 1 H) Similarly, the (S) isomer was separated from of 3 (S) - (3-methanesulfonyloxymethyl) pyrrolidine (0.993 g, 3.56 mmol to obtain the title compound (1.1409 g, 100%).

Stage B 3 (R) and 3CSH1 H-imidazol-1-yl) methyl) pyrroiidines The title compound (0.48 g, 1.91 mmol) of step A was stirred in 4N HCl in dioxane (10 ml) for 2 hours and then evaporated to dryness to give the title compound which was used to couple it with the acid tricyclic In a similar manner, the (S) isomer was prepared.

PREPARED EXAMPLE 51 3 (S) - (1H-4 (5) -methylimidazol-1-yl) methy1) pyrrc > lidona H (S) Step A 1 N-tert-butoxycarbonyl-3 (S) - (1 H-4 (5) -methylimidazol-1-yl) methyl) pyrrolidine 3 (S) - (3-methanesulfonyloxymethyl) pyrrolidine (1.05 g, 3.77 mmol) was dissolved in anhydrous DMF (25 ml) and sodium 4-methylimidazole (0.74 g, 10 mmol) was added. The mixture was heated at 60 ° C for 2 hours and then evaporated to dryness. The product was extracted with CH2Cl2 and washed with brine. The CH2Cl2 was evaporated to dryness to give the title compound (0.92 g, 100%), FABMS (M + 1) = 266.

Step B 3 (S) - (1 H-4 (5) -methylimidazol-1-yl) methyl) pyrrolidine The title compound (0.31 g, 1.17 mmol) of step A was stirred in 4N HCl in dioxane (10 ml) for 2 hours and then evaporated to dryness to give the title compound which was used to couple it to tricyclic acid. .

PREPARED EXAMPLE 52 3- (1H-imidazol-1-yl) methyl-pyrrolidine Stage A 1 N-diphenylmethyl azetidine-4-methylcarboxylate 1 N-diphenylmethyl azetidine-3-carboxylic acid (J. Chem. Res. 1996, 430) (5.38 g, 20.16 mmol) was refluxed with concentrated H2SO4 (2 ml) and MgSO4 (5 g) in anhydrous methanol (25 ml). ) for 16 hours. It was evaporated to dryness and the residue was extracted with ethyl acetate and the extract was washed with 10% sodium bicarbonate and water. The ethyl acetate was evaporated to give a residue which was chromatographed on silica gel using hexane-10% ethyl acetate as eluent to obtain the title compound (2.2 g, 40.64%), FABMS (M + 1) = 282; dH (CDCl 3) 3.2-3.6 (m, 5H), 3.7 (s, 3H), 4.45 (s, 1H), 7.2-7.4 (m, 10H).

Stage B 1N-diphenylmetl-3-hydroxymethyl azetidine 1 N LAH in ether (20 ml) was added to a stirred solution of the title compound (2 g, 7.11 mmol) of step A in anhydrous ether (25 ml) by dripping over a period of 0.5 hours, and the resulting mixture refluxed for 4 hours. The reaction mixture was slowly decomposed with ice water and extracted with ethyl acetate. The extract was washed with water and brine and dried (MgSO4). it was filtered and evaporated to dryness to give the title compound (1.72 g, 98%), FABMS (M + 1) = 254.

Stage C 1N-diphenylmethyl-3-methanesulfonyloxymethyl azetidine The title compound of Step B above (1.7 g, 6.72 mmol) and triethylamine (1.1 g, 10.87 mmol) were dissolved in CH2Cl2 (20 mL) and the mixture was stirred under nitrogen at 0 ° C. Methanesulfonyl chloride (1.1 g, 9.6 mmol) was added and the solution was stirred at room temperature for 2 hours. The solution was diluted with CH2Cl2 and washed with saturated aqueous sodium bicarbonate, water and dried (MgSO), filtered and evaporated to dryness to give the title compound (2.32 g, 99%) FABMS (M + 1) = 332 Stage D 1 N-Diphenylmethyl-3- (1 H-imidazol-1-iOmethyl-azetidine A solution of the title compound of Step C (2.3 g, 6.95 mmol) in DMF (15 mL) was added to a stirred solution of NaH (0.25 g, 10.42 mmol) and imidazole (0.71 g, 10.44 mmol) in DMF ( 10 ml) under nitrogen atmosphere. The mixture was stirred at 60 ° C for 16 hours. The DMF was evaporated in vacuo. The resulting crude product was extracted with CH 2 Cl 2 and the extract was washed successively in water and brine, and CH 2 Cl 2 was evaporated to give the title compound (2.1 g, 100%). FABMS (M + 1) = 304.

Step E 3- (1H-lmidazol-1-yl) methyl-pyrrolidine A mixture of the title compound (1.7 g) from step D and Pd (OH) 2 on carbon (0.2 g) in EtOH (20 ml) was stirred at 50 psi under an atmosphere of hydrogen for 24 hours. The catalyst was filtered to give the title compound (0.58 g, 66.8%). m / z = 137 (MH +).

PREPARED EXAMPLE 53 4- (1 H-imidazol-1-yl) -piperidine Stage A 1N-tert-Butoxycarbonyl-4-hydroxy-piperidine To a solution of 4-hydroxy-piperidine (2 g, 19.78 mmol) and triethylamine (4.16 mL, 29.67 mmol) in CH2Cl2 (20 mL), di-tert-butyl dicarbonate (5.18 g, 23.72 mmol) was added and stirred at room temperature for 16 hours. The solution was diluted with CH2Cl2 and washed with water, dried (MGSO4), filtered and evaporated to give the title compound (3.95 g, 99%). FABMS (M + 1) = 202.

Stage B 1N-tert-Butoxycarbonyl-4-methanesulfonyloxy-piperidine The title compound from step A above (3.5 g, 17.39 mmol) and triethylamine (4.85 ml, 34.79 mmol) were dissolved in CH2Cl2 (30 ml) and the mixture was stirred under nitrogen at 0 ° C. Methanesulfonyl chloride (1.62 mL, 20.88 mmol) was added and the solution was stirred at room temperature for 2 hours. The solution was diluted with CH2Cl2 and washed with saturated aqueous sodium bicarbonate, water and dried (MgSO), filtered and evaporated to dryness to give the title compound (4.68 g, 96.4%). ESMS: m / z = 280 (MH +).

Step C 1 N-tert-Butoxycarbonyl-4- (1 H -imidazol-1-yl) -piperidine A solution of the title compound of Step B (4.0 g, 14.32 mmol) in DMF (120 mL) was added to a stirred solution of NaH (0.52 g, 21.66 mmol) and imidazole (1.46 g, 21.47 mmol) in DMF ( 20 ml) under nitrogen atmosphere. The mixture was stirred at 60 ° C for 16 hours. The DMF was evaporated in vacuo. The resulting crude product was extracted with CH2Cl2 and the extract was washed successively with water and brine, and the CH2CI2 was evaporated to give the title residue which was chromatographed on silica gel using 3% (10% concentrated NH4OH in methanol. ) - CH 2 Cl 2 as eluent depart to give the title compound (0.94 g, 26%). FABMS (M + 1) = 252; dH (CDCl 3) 1.4 (s, 9H), 1.6-1.8 (m, 2H), 2.0 (dd, 2H), 2.8 (dt, 2H), 4.05 (m, 1H), 4.2 m, 2H), 6.9 (s) , 1 H), 7.0 (s, 1H), 7.65 (s, 1H).

Step D 4- (1 H-lmidazol-1-yl) -piperidine . 2HCI The title compound (0.21 g, 0.836 mmol) from step C was stirred in 4N HCl in dioxane (5 ml) for 2 hours and then evaporated to dryness to give the title compound which was used to couple with the tricyclic acid.

PREPARED EXAMPLE 54 3- (R) -v (SH1 H-imidazol-1-yl) -pyrrolidines H H (R) (S) Stage A 1N-Benzyl-3- (R) and (S) -metanesulfonyloxy) -pyrrolidines 1 N-benzyl-3 (R) -hydroxy-pyrrolidines (5 g, 28.21 mmol) and triethylamine (7.86 ml, 56.35 mmol) were dissolved in CH 2 Cl 2 (50 ml) and the mixture was stirred under nitrogen at 0 ° C. . Methanesulfonyl chloride (2.62 ml, 33.87 mmol) was added and the solution was stirred at room temperature for 2 hours. The solution was then diluted with CH2Cl2 and washed with saturated aqueous sodium bicarbonate, water and dried (MgSO4), filtered and evaporated to dryness to give the title compound (7.2 g, 96.4%). FABMS [M + 1] = 256: dH (CDCl 3) 2.2 (m, 1 H), 2.3 (m, 1 H), 2.52 (m, 1 H), 2J-2.85 (m, 3H), 2.95 (s, 3H), 3.65 (q, 2H), 5.16 (m, 1 H), 7.3 (s, 5H). In a similar manner, the (S) -isomer was prepared from the 1N-benzyl-3 (S) -hydroxy-pyrrolidines (5 g, 28.21 mmol) to give the title compound (7.15 g, 98%).

Stage B 1N-benzyl-3- (S) and (RH 1 H -imidazol-1-yl) -pyrrolidines (R) (S) (S) (R) A solution of the title compound of step A (2.0 g, 7.84 mmol) was added to a stirred solution of midazole (1.1 g, 16.17 mmol) in DMF (25 mL) under nitrogen atmosphere. The mixture was stirred at 60 ° C for 16 hours. The DMF was evaporated in vacuo. The resulting crude product was extracted with CH 2 Cl 2 and the extract was washed successively with water and brine, and the CH 2 Cl 2 was evaporated to leave the title residue which was chromatographed on silica gel using 3% (10% conc NH 4 OH in methanol) - CH2Cl2 as eluent to give the title compound (0.95 g, 50.56%). FABMS (M + 1) = 228. In a similar manner, the other isomer was prepared.

Stage C 3- (R) v (S 1 H-imidazol-1-yl) pyrrolidines A mixture of the title compound (0.95 g) from step B and 10% Pd on carbon (0.5 g, in EtOH (20 ml) at 50 psi under a hydrogen atmosphere for 24 hours was stirred in. The catalyst was filtered to give the title compound (0.522 g, 99.9%) which was used to couple it with the tricyclic acid In a similar manner the (R) isomer was prepared from (1.0 g) and 10% Pd on carbon (0.6 g) with a 99% yield.

PREPARATORY EXAMPLE 55 (-) 2-Methyl-3- (1 H-imidazol-4-ip-pyrrolidine This compound was prepared according to the procedure of J. Med. Chem. 1995, 1593-1599.

PREPARED EXAMPLE 56 3- (1 H-imidazol-1-yl) -azetidine Stage A 1 N-diphenylmetyl- (1 H-imidazol-1-yl) -azetidine 1 N-diphenylmethyl-3-methanesulfonyl-azetidine (J. Che. Res. 1996, 430) (10.0 g, 29.26 mmol) was added to a stirred solution of imidazole (5.96 g, 87.78 mmol) in DMF ( 10 ml) under nitrogen atmosphere. The mixture was stirred at 60 ° C for 16 hours. The DMF was evaporated in vacuo. The resulting crude product was extracted with CH2Cl2 and the extract was washed successively with water and brine, and the CH2CI2 was evaporated to leave the title residue which was chromatographed on silica gel using 4% (10% conc. NH4OH in methanol) -CH 2 Cl 2 as eluent to give the title compound (2.87 g, 33.9%). FABMS (M + 1) = 290; dH (CDCl 3) 3.3 (dd, 2H), 3.65 (dt, 2H), 4.45 (s, 1 H), 4.8 (m, 1 H), 7.1-7.5 (m, 12H), 7.8 (s, 1 H) .

Stage B 3- (1 H-imidazol-1-iQ-azetidine A mixture of the title compound (2.8 g) from step A and 10% Pd on carbon (1.1 g) in MeOH (25 ml) was stirred at 50 psi under a hydrogen atmosphere for 24 hours. The catalyst was filtered to give the title compound (1.05 g, 99.9%) which was used to couple it with the tricyclic acid.

EXAMPLE 54 4- (3-Bromo-8-chloro-6,11-dihydro-5H-benzotd.ejciclo-heptafl ^ -bjpiridinl li -l-KI. I-dimethyletoxyJcarbonylj ^ íR) -piperazinecarboxylic acid (2 g, 3.8 mmol) to a solution of the title compound of Preparative Example 50 (1.1 g, 4.7 mmol), DEC (1.8 g, 9.4 mmol.) HOBT (1.28, 9.48 mmol) and NMM (2.6 mL, 23.7 mmol) in DMF ( 100 ml). The resulting solution was stirred at room temperature for 24 hours. The reaction mixture was diluted with H20 until the precipitation ceased and the suspension was filtered. The precipitate was diluted with CH2Cl2, washed with brine, dried over Na2SO4 and concentrated. The crude product was purified by evaporative chromatography using a 5% solution (10% NH 4 OH in MeOH) in CH 2 Cl 2 as eluent to give the title compound (1.48 g, 55% yield). FABMS (M + 1) = 669 EXAMPLE 55 AND EXAMPLE 56 The title compound of example 1 was separated into individual isomers 11- (R) and 11- (S) by preparative HPLC with a CHIRALPAK AD column using a 15% solution of iPrOH in hexane with 0.2% DEA as eluent.

EXAMPLE 55 Isomer A: retention time (analytical) = 8,885 minutes; [α] D = -13.1 (3.06 mg in 2.0 ml MeOH); FABMS (M + 1) = 669.

EXAMPLE 56 Isomer B retention time (analytical) = 8,885 minutes; [α] D = + 12.1 (2.32 mg in 2.0 ml MeOH); FABMS (M + 1) = 669.

EXAMPLES 57-69 By essentially the same procedure indicated in Example 1, only by substituting the appropriate amines, can the compounds of the formula shown below be obtained, where R 8 is as defined in the following table 9: TABLE 9 TABLE 9 (continued) EXAMPLE 70 Stage A The title compound of Example 54 (0.1 g, 0.15 mmol) was stirred at room temperature in CH2Cl2 (20 mL) and TFA (1 mL) for two hours. The reaction mixture was evaporated to dryness to give the title compound which was used as in the following step B: Stage B The title compound of step A (0.186 g, 0.182 mmol) was dissolved in CH2Cl2 (20 ml) and triethylamine (0.063 g, 0.621 mmol) and t-butyl isocyanate (0.0185 g, 0.187 mmol) were added. The resulting solution was stirred at room temperature for two hours, diluted with water and extracted with CH2Cl. The CH2Cl2 extract was dried (MgSO4) and filtered and concentrated in CH2Cl2 as eluent to give the title compound (0.084 g) FABMS (M + 1) = 668.

EXAMPLES 71-73 By essentially the same procedure indicated in example 1, only that it is substituted with different isocyanates, the compounds of the formula shown below can be obtained in which R9 is as defined in the following table 10 TABLE 10 PREPARED EXAMPLE 57 2 (R / SH2- (1 H-imidazol-1 -Detillpiperidine Stage A 1N-tert-butoxycarbonyl-2- (R / S) - (2-hydroxyethyl) -piperidine 2 (R / S) - (2-hydroxyethyl) piperidine (5 g, 38.7 mmol) and sodium hydroxide (1.55 g, 67.4 mmol) were dissolved in THF-water (1: 1) (100 ml) and added di-tert-butyl dicarbonate (9.29 g, 42.6 mmol) and the mixture was stirred at 25 ° C for 120 hours. The solution was treated with BioRad 50 W-X4 (RS03H) resin (42 ml) and filtered. The resin was washed with water and with THF and the combined filtrates were evaporated to dryness. Chromatography on silica gel using 1% (10% concentrated NH 4 OH in methanol) -dichloromethane as eluent afforded the title compound (8.87 g, 95%) CIMS: m / z 230.2 (MH +): dH (CDCl 3) 1.47 ppm (9H, s, CH3); dc (CDCl 3) CH 3: 28.4, 28.4, 28.4, CH 2: 19.2, 25.6, 29.6, 32.3, -39.6, -58.3, CH: -45.9; C: 80.1, the carbonyl was not visible.

Step B 1 N-tert-butoxycarbonyl-2 (R / S) - (2-methanesulfonyloxyethyl) piperidine The title compound from step A above (2 g, 8.72 mmol) and triethylamine (7.29 ml, 52.4 mmol) were dissolved in dichloromethane (50 ml) and the mixture was stirred under argon at 0 ° C. Methanesulfonyl chloride (2.03 ml, 26.2 mmol) was added and the solution was stirred at 25 ° C for 2 hours. The solution was diluted with dichloromethane and washed with saturated aqueous sodium bicarbonate, water and dried (MgSO), filtered and evaporated to dryness. The product was chromatographed on silica gel using 2% (10% concentrated NH 4 OH in methanol) -dichloromethane as eluent to give the title compound (1.25 g, 61%): ESMS: m / z 308.1 (MH +); dc (CDCl 3) 28.5, 28.5, 28.5, 37.4 / 39.4; CH2: 19.1, 23. 8 / 25.5, 28.9 / 29.6, 33.1, 45.2; CH: 54.2; C: 79.8, -155.2.

Step C 1 N-tert-butoxycarbonyl-2 (R / S) - [2- (1 H-imidazol-1-yl) ethyl] piperidine The title compound of step B above (2.68 g, 8.72 mmol) was dissolved (crude product, before chromatography) in anhydrous DMF (30 ml) and sodium imidazole (1.18 g, 13.1 mmol) was added. The mixture was heated at 70 ° C for 2 hours and then evaporated to dryness. The product was chromatographed directly on silica gel using 1% (10% concentrated NH 4 OH in methanol) -dichloromethane as eluent to give the title compound (1.69 g, 69%): ESMS: m / z 280.1 (MH +): dH (CDCl 3) 1.48 ppm (9H, s, CH 3): dc (CDCl 3) CH 3: 28.5, 28.5, 28.5: CH 2: 19.1, 25.5, 28.9, 31.8, -39.1, 44.3; CH: 48.1, 118.9, 129.5, 137.1; C: 80.1, the carbonyl was not visible.

Stage D 2 (R / SH2- (1 H-imidazol-1-diethylpiperidine The title compound from step C above (1.6 g, 5.73 mmol) was dissolved in methanol (10 ml) and 10% concentrated H2SO4 in dioxane (v / v) (40 ml) was added and the solution was stirred at 25 ° C. ° C for 2 hours. The mixture was treated with BioRad AG1-X8 (OH ") resin until basified.The resin was filtered off and washed with methanol.The combined filtrates were evaporated to dryness and the product was chromatographed on silica gel using 5% (10%). % of concentrated NH 4 OH in methanol) -dichloromethane as eluent to give the title compound (1.02 g, 99%): CIMS: m / z 180.35 (MH +); dH (CDCl 3) 6.94 (1 H, s, lm-H2) 7.18 (1H, s, lm-H4) and 7.50 ppm (1H, s, lm-H2), dc (CDCI3) CH2: 24.6, 26.8, 33.2, 38.6, 43.8, 47.0, CH: 53.9, 118.9, 129.5, 118.8.

PREPARATIVE EXAMPLE 58 2 (R / SH3- (1 H-4-methylamidazole-1-iOpropylpiperidine H Stage A 2 (R / S) - (3-hydroxypropyl) piperidine 2- (3-Hydroxypropyl) pyridine (5 g, 36.4 mmol) was dissolved in 1N HCl (36.4 mL, 36.4 mmol) and water (63.6 mL) and platinum (IV) oxide monohydrate (1 g, 4.08 mmol) were added. ) under an argon atmosphere. The mixture was hydrogenated at 55 psi in a Parr pump at 25 ° C for 96 hours. The catalyst was removed by filtration through Celite® and washed with water. The combined filtrates were treated with BioRad AG1-X8 (OH) resin until basified. The resin was filtered off and washed with water. The combined filtrates were evaporated to dryness and the product was chromatographed on silica gel using 10% increasing to 20% (10% concentration of NH 4 OH in methanol) -dichloromethane as eluent to give the title compound (5.22 g, 100%). : CIMS: m / z 144.40 (MH +); dc (d6-DMSO) CH2: 24.0, 25.3, 28.8, 31.5, 32.8, 45.9, 60.8; CH: 56.1.

Stage B 1N-tert-butoxycarbonyl-2- (R / S) - (3-hydroxypropyl) piperidine The title compound of step A above (3 g, 20.9 mmol) was reacted with di-tert-butyl dicarbonate (5.03 g, 23 mmol) and sodium hydroxide (0.8378 g, 20.9 mmol) essentially as described in preparative example 57, stage A above, but the reaction was allowed to proceed for 166 hours. The product was chromatographed on silica gel using 3% (10% concentrated NH 4 OH in methanol) -dichloromethane as eluent to give the title compound (4.04 g, 79%): ESMS: m / z 244.0 (MH +); dH (CDCl 3) 1.45 ppm (9H, s, CH 3), dc (CDCl 3) CH 3: 28.5, 28.5, 28.5; CH2: 19.0, 25.6, 26.2, 29.2, -38.8, 62.8; CH: -50.0; C: 79.3, -155.2.

Step C 1 N-tert-butoxycarbonyl-2- (R / SH3- (4-toluenesulfonyl) propylpiperidine The title compound from step B above (2 g, 8.22 mmol) was dissolved in anhydrous pyridine (10 ml) and the solution was cooled with stirring at 0 ° C. 4-Toluenesulfonyl chloride (1.88 g, 9.86 mmol) was added and the mixture was stirred at 0 ° C for 2 hours. The mixture was evaporated to dryness and the residue was taken up in dichloromethane and washed with saturated aqueous sodium bicarbonate, water, dried (MgSO 4), filtered and evaporated to dryness. The product was chromatographed on silica gel using 0.25% methanol in dichloromethane as the eluent to give the title compound (2.53 g, 77%): ESMS: m / z 398.1 (MH +). dH (CDCI3) 1.41 (9H, s, CH3), 2.45 (3H, s, Ar-CH3), 4.06 (2H, m, CH20), 7.36 (2H, d, Ar-H3 and Ar-H5) and 7.79 ppm (2H, m, Ar-H2 and Ar-H6); dc (CDCl 3) CH 3; 19.1, 28.5, 28.5, 28.5; CH2: 21.7, 22.8, 25.7, 25.8, 28.8, 38.7, 70.6; CH: -49.6, 127.9, 127.9, 129.9, 129.9; C: 71.1, 133.2, 144.6, 155.1.

Step D 1N-tert-butoxycarbonyl-2- (R / S) -r3- (1 H-4/5-methylimidazole-1-Dpropipiperidine 4-Methylimidazole (0.5453 g, 6.64 mmoles) was dissolved in anhydrous DMF (15 ml) and 95% sodium hydride (0.1678 g, 6.64 mmoles) was added. The mixture was stirred at 25 ° C for 0.5 hour under argon atmosphere. The title compound of Preparative Example 58, Step C, (2.4 g, 6.04 mmol) in anhydrous DMF (10 mL) was added and the mixture was stirred at 25 ° C for 1 hour. The product was worked up as described in preparative example 2, step A and chromatographed on silica gel using 3% methanol in dichloromethane as the eluent to give a mixture of the title compounds (1459 g, 79%) ( 4-Me: 5-Me :: 63.37): CIMS: m / z 308.25 (MH +); 4-Me: dH (CDCl3) 1.43 (9H, s, CH3), 2.18 (3H, s, lm-4-Me), 3.87 (2H, m, CH2-lm), 6.58 (1 H, s, lm- H5) and 7.33 ppm (1 H, s, lm-H2), dc (CDCl 3) CH 3: 13.8, 28.5, 28.5, 28.5, 28.5; CH2: 19.0, 25.6, 26.4, 27.7, 28.7, 38.9, 46.5; CH: -49.4, 115.2, 136.2, C: 79.4, 138.J, 155.1 and 5-Me: dH (CDCI3) 1.43 (9H, s, CH3), 2.16 (3H, s, lm-5-Me), 3.87 (2H, m, CH2-lm), 6.74 (1 H, s, lm-H4) and 7.37 ppm (1H, s, lm-H2); dc (CDCl 3) CH 3: 9.3, 28.5, 28.5, 28.5; CH2: 19.0, 25.6, 26.5, 27.3, 28.7, 39.0, 44.4; CH: -49.4, 126.9, 136.8, C: 79.4, -138.7, 155.1.

Step E 1 N-tert-butoxycarbonyl-2- (R / SH3- (1 H-4-methylimidazol-1-iOpropylpiperidine The mixture of the compounds of step D above (1054 g) was dissolved in anhydrous CH2Cl2 (10 ml) at 0 ° C under argon atmosphere. Trityl chloride (0.3891 g, 1.1 equivalents per equivalent of the 5-methyl isomer) was added, and the mixture was stirred at 0 ° C for 2 hours. The reaction mixture was introduced directly onto a column of silica gel and the column was eluted with 50% ethyl acetate in acetone to give the pure 4-methyl isomer (0.J242 g, 69%): 4-Me: CIMS: m / z 308.30 (MH +); dH (CDCI3) 1.43 (9H, s, CH3), 2.18 (3H, s, lm-4-Me), 3.84 (2H, m, CH2 -Im), 6.58 (1H, s, lm-H5) and 7.30 ppm (1H, s, Im- H2); dc (CDCl 3) CH 3: 13.8, 28.5, 28.5, 28.5; CH2: 19.0, 25.5, 26.4, 27.7, 28.7, 38.8, 46.5; CH: -49.4, 115.2, 136.2, C: 79.3, 138.4, 155.1.

Step F 2- (R / SH3- (1 H-4-methyl-m -dazol-1 -npropylpiperidine The title compound of step E above (0.4456 g, 1.5 mmol) was deprotected as described in preparative example 57, step D and the product was chromatographed on silica gel using 20% (10% concentrated NH4OH in methanol ) -dichloromethane as eluent to give the title compound (0.2627 g, 87%): CIMS: m / z 208.25 (MH +): dH (CDCl3) 2.14 (3H, s, lm-4-Me), 3.79 (2H, m, CHrlm), 6.52 (1 H, s, lm-H2), 6.52 (1 H, s, lm-H5) and 7.24 ppm (1 H, s, lm-H2), dc (CDCi3) CH3: 13. J; CH2: 24.J, 26.6, 2J.5, 32.9, 34.3, 47.0, 47.1; CH: 56.3, 115.2, 136.1, C: 138.4.

PREPARED EXAMPLE 59 Stage A 4 (R / S) - (3-hydroxypropylpiperidine H 4- (3-Hydroxypropyl) pyridine (5 g, 36.4 mmol) was dissolved in 1 N HCl (36.4 mL, 36.4 mmol) and water (63.6 mL) and platinum (IV) monohydrate (1 g) were added., 4.08 mmole) under an argon atmosphere. The mixture was hydrogenated at 55 psi in a Parr pump at 25 ° C for 66 hours. The catalyst was removed by filtration through Celite® and washed with water. The combined filtrates were treated with BioRad AG1-X8 (OH) resin until basicity. The resin was filtered off and washed with water. The combined filtrates were evaporated to dryness and the product was chromatographed on silica gel using 7% (10% concentrated NH 4 OH in methanol) -dichloromethane as eluent to give the title compound (4.91 g, 94%): CIMS: m / z 144.40 (MH +); dc (d6-DMSO) CH2: 29.4, 31.6, 32.8, 45.1, 45.1, 60.8; CH: 34.8.

Stage B N-tert-butoxycarbonyl-4- (R S) - (3-hydroxypropyl) piperidine The title compound from step A above (3 g, 20.9 mmol) was reacted with di-tert-butyl dicarbonate (5.03 g, 23 mmol) and sodium hydroxide (0.8378 g, 20.9 mol) essentially as described in preparative example 57, stage A above, but the reaction was allowed to proceed for 166 hours. The product was chromatographed on silica gel using 3% (10% concentrated NH 4 OH in methanol) -dichloromethane as eluent to give the title compound (3.33 g, 65%): ESMS: m / z 244.2 (MH +); dH (CDCl 3) 1.47 ppm (9H, s, CH 3), dc (CDCl 3) CH 3: 28.5, 28.5; 28.5; CH2: 29.9, 29.9, 32.2, 32.6, 44.1, 44.1; CH: 35.9; C: 79.3, -154.8.

Step C 1N-tert-butoxycarbonii-4 (R / SH3- (4-toluenesulfonyloxy) propyl1piperidine The title compound of Step B above (2 g, 8.22 mmol) was dissolved in anhydrous pyridine (10 mL) and the solution was cooled with stirring at 0 ° C. 4-Toluenesulfonyl chloride (1.88 g, 9.86 mmol) was added and the mixture was stirred at 0 ° C for 2 hours. The mixture was evaporated to dryness and the residue was taken up in dichloromethane and washed with saturated aqueous sodium bicarbonate, water, dried (MgSO4), filtered and evaporated to dryness. The product was chromatographed on silica gel using 0.5% methanol in dichloromethane as the eluent to give the title compound (2.86 g, 88%): ESMS: m / z 398.1 (MH +). dH (CDCI3) 1.44 (9H, s, CH3), 2.46 (3H, s, Ar-CH3), 4.01 (2H, m, CH20), 7.35 (2H, d, Ar-H3 and Ar-H5) and 7.79 ppm (2H, d, Ar-H2 and H6); dc (CDCl 3) CH 3; 21.7, 28.6, 28.6, 28.6; CH2: 26.1, 32.0, 32.0, 32.1, 43.9, 43.9, 70.7; CH: 35.5, 127.9, 127.9, 129.9, 129.9; C: 79.3, 133.1, 144.8, 154.9.

Stage D 1 N-tert-butoxycarbonyl-4-r3- (1 H-4/5-methylimidazol-1-Dpropylpiperidine 4-Methylimidazole (0.5453 g, 6.64 mmol) was dissolved in anhydrous DMF (15 mL) and 95% sodium hydride (0.1678 g, 6.64 mmol) was added to the stirred solution at 25 ° C under an argon atmosphere. The solution was stirred at 25 ° C for 0.5 hours. The title compound of Preparative Example 59, Step C, (2.4 g, 6.04 mmol) in anhydrous DMF (10 mL) was added and the mixture was stirred at 25 ° C for 1 hour. The product was worked up as described in preparative example 2, step A and chromatographed on silica gel using 3% methanol in dichloromethane as the eluent to give the title mixture of the compounds (1584 g, 85%) ( 4-Me: 5-Me :: 58: 42): CIMS: m / z 308.25 (MH +); 4-Me: dH (CDCl3) 1.44 (9H, s, CH3), 2.21 (3H, s, lm-4-Me), 3.82 (2H, m, CH2-lm), 6.59 (1 H, s, lm- H5) and 7.33 ppm (1 H, s, lm-H2), dc (CDCl 3) CH 3: 13.8, 28.5, 28.5, 28.5; CH2: 28.3, 32.1, 33.4, 33.4, 44.0, 47.1, 47.1, CH: 35.8, 115.2, 136.2, C: 79.4, 138.5, 154.9 and 5-Me: dH (CDCI3) 1.44 (9H, s, CH3), 2.19 (3H, s, lm-5-Me), 3.82 (2H, m, CH2-lm), 6.77 (1 H, s, lm-H4) and 7.39 ppm (1 H, s, lm-H2), dc ( CDCl 3) CH 3: 9.3, 28.5, 28.5, 28.5; CH2: 28.1, 32.1, 33.4, 33.4, 44.0, 44.0, 44.9; CH: 35.8, 127.0, 136.2, C: 79.3, 133.7, 154.9.

Step E 1 N-tert-butoxycarbonyl-4-r3- (1 H-4-methylimidazol-1-yl) propyl] piperidine The mixture of the compounds from step D above (1.51 g) was dissolved in anhydrous CH 2 Cl 2 (10 ml) at 0 ° C under an argon atmosphere. Trityl chloride (1.15 g, 2 equivalents per equivalent of the 5-methyl isomer) was added, and the mixture was stirred at 0 ° C for 2 hours. The reaction mixture was introduced directly onto a column of silica gel and the column was eluted with 50% ethyl acetate in acetone to give the pure 4-methyl isomer (0.635 g, 65%): 4-Me: CIMS: m / z 308.30 (MH +); dH (CDCl3) 1.44 (9H, s, CH3), 2.22 (3H, s, lm-4-Me), 3.83 (2H, m, CH2-lm), 6.60 (1 H, s, lm-H5) and 7.33 ppm (1 H, s, Im-H2); dc (CDCl 3) CH 3: 13.8, 28.5, 28.5, 28.5; CH2: 28.2, 32.0, 33.4, 33.4, 43.9, 47.1, 47.1; CH: 35.J, 115.2, 136.2, C: J9.3, 138.5, 154.8.

Stage F 4-F3-I1 H-4-methylimidazole-1-Opropylpiperidine The title compound was deprotected as described in preparative example 57, step D to give after chromatography on silica gel using 20% (10% concentrated NHOH in methanol) -dichloromethane as eluent to give the title compound (0.3581 g, 89%): CIMS: m / z 208.25 (MH +): dH (CDCl3) 2.12 (3H, s, lm-4-Me), 3.74 (2H, m, CH2-lm), 6.51 (1H, s, lm-H5) and 7.25 ppm (1 H, s, lm-H2); dc (CDCl 3) CH 3: 13.6, CH 2: 28.1, 33.3, 33.3, 33.9, 46.5, 46.5, 47.1; CH: 35.8, 115.1, 136.0, C: 138.2.

PREPARATIVE EXAMPLE 60 3 (R / SH (1 H-imidazol-1-diMethyl H, 2,3,4-tetrahydroquinoline Stage A 3 (? R / SHh-hydroxymethyl) -1, 2.3.4-tetrahydroquinoline 3-Hydroxymethylquinoline (0.45 g, 2.83 mmol) (prepared as described in: BR Brown, D. L1, Hammick and BH Thewiis, J. Chem. Soc. 1951, 1145-1149) was dissolved in methanol (100 ml). and it was placed in a Parr bomb. Platinum (IV) oxide monohydrate (0.225 g, 0.918 mmol) was added and the mixture was hydrogenated at 50 psi at 25 ° C for 6 hours. The catalyst was removed by decantation and washed with methanol. The methanol was evaporated to dryness and the product was chromatographed on silica gel using 3% (10% concentrated NH 4 OH in methanol) -dichloromethane as eluent to give the title compound (0.3843 g, 83%): CIMS: m / z 164.35 (MH +); dH (CDCl3) 6.50 (1 H, d, Ar-H8), 6.64 (1H, t, Ar-H6), 6.98 (1 H, d, Ar-H5) and 6.99 ppm (1 H, m, Ar-H7 ); dc (CDCl 3) CH 2: 29.5, 44.0, 65.2; CH: 34.9, 114.2, 117.4, 126.9, 129.8; C: 120.2, 144.5.

Step B 1 N-tert-butoxycarbonyl-2 (R / S) - (hydroxypropyl) -1.2.3.4-tetrahydroquinoline The title compound from step A above (2.578 g, 15.79 mmol) was dissolved in THF (51.5 ml) and sodium hydroxide (0.634 g, 15.79 mmol) in water (51.5 ml) was added. Di-tert-butyl dicarbonate (6.888 g, 31.58 mmol) was added and the mixture was stirred at 25 ° C for 187 hours. Additional di-tert-butyl dicarbonate (0.6888 g, 3.16 mmol) was added and the reaction was allowed to proceed for a total of 301 hours. The product was worked up and purified as described in preparative example 1, step A to provide the title compound (3.794 g, 91%): FABMS: m / z 264.1 (MH +); dH (CDCl3) 1.50 (9H, s, CH3), 7.03 (1 H, m Ar-H), 7.19-7.10 (2H, m, Ar-H) and 7.58 ppm (1H, d, Ar-H); dc (CDCl 3) CH 3: 28.3, 28.3, 28.3; CH2: 29.5, 45.1, 63.6; CH: 36.1, 124.0, 124.6, 125.6, 129.2; C: 81.5, 128.2, -138.8, -154.7.

Step C 1 N-tert-butoxycarbonyl-3 (R / SH (4-tosyloxy metin-1.2.3.4-tetrahydroquinoline The racemic compound of the title of step B above (0.322 g, 1.22 mmol) was dissolved in anhydrous pyridine (2 ml) and the solution was cooled to 0 ° C. 4-Toluenesulfonyl chloride (0.28 g, 1464 mmol) was added and the reaction was stirred at 0 ° C for 5 hours. The mixture was then heated at 40 ° C for 13 hours and worked up as described in preparative example 2, step C to give the title compound (0.481 g) which was used directly in the next step E. The pure individual enantiomers of step C above can be treated in a similar manner to give the 3 (R) and 3 (S) enantiomers of the title compound.

Stage D 1 N-tert-butoxycarbonyl-3 (R / S) -lY1 H-imidazol-1-yl) metip-1, 2,3,4-tetrahydroquinoline The racemic product of the title of step D above was dissolved in anhydrous DMF (5 ml) and sodium imidazole (0.1652 g, 1.83 mmol) was added. The mixture was heated at 65 ° C under argon for 4 hours. The solution was evaporated to dryness and the residue was taken up in dichloromethane, washed with water, dried (MgSO), filtered and evaporated to dryness. Chromatography on silica gel using 2.5% (10% concentrated NH 4 OH in methanol) -dichloromethane gives the title compound (0.3284 g, 86%): ESMS: m / z 314.1 (MH +); dH (CDCl3) 1.51 (9H, s, CH3), 6.97 (1 H, s, lm-H5), 7.01 (1 H, t, Ar-H6), 7.06 (1 H, t, Ar-H7), 7.12 (1 H, s, lm-H4), 7.17 (1 H, t, Ar-H5), 7.51 (1 H, s, lm-H2) and 7.68 ppm (1 H, d, Ar-H8); dc (CDCl 3) CH 3: 28.4, 28.4, 28.4; CH2: 31.0, 46.7, 49.5; CH: 35.9, 119.1, 123.8 / 123.9, 126.4, 126.9, 129.0, 129.8, 137.5; C: 81.5, 137.5, 138.2, 153.7. The pure individual enantiomers of step D above can be treated in a similar manner to provide the 3 (R) and 3 (S) enantiomers of the title compound.

Step E 3 (R / S) -r (1 H-imidazol-1-yl) met.p-1.2.3.4-tetrahydroquinoline The racemic compound of the title of the above step E (0.3208 g, 1024 mmol) was dissolved in anhydrous methanol (5.42 ml) and 10% concentrated H2SO / dioxane (v / v) (13.95 ml) was added and the mixture was mixed. stirred at 25 ° C for 1 hour. The product was worked up as described in preparative example 1, step D above. Chromatography on silica gel using 2.5% (10% concentrated NH OH in methane!) - dichloromethane as eluent afforded the title compound (0.19 g, 90%): CIMS: m / z 214.2 (MH +); dH (CDCl 3) 3.97 (2H, m, Im-CÜ), 6.51 (1 H, d, Ar-Hβ), 6.65 (1 H, t, Ar-H 6), 6.95 (1 H, s, lm-H 5) , 6.96 (1 H, t, Ar-H7), 7.01 (1 H, t, Ar-H5), 7.09 (1 H, s, lm-H4) and 7.50 ppm (1 H, s, lm-H2); dc (CDCl 3) CH 2: 30.2, 43.5, 49.0; CH2: 33.7, 114.2, 117.7, 119.3, 127.3, 129.5, 130.0, 137.7; C: 118.4, 143.9.

Step F 3 (R) -f (1 H-imidazol-1-yl) methyl] -1, 2,3,4-tetrahydroquinoline and 3 (S) -r (1 H-imidazol-1-yl) metin-1 , 2.3.4-tetrahydroquinoline H 3R 3S The racemic title compound (0.6545 g) from step E above was separated by preparative HPLC on a Chiralpak® AD column (50 X 5 cm) using hexane-iso-propanol-diethylamine :: 80: 20: 0.2 as eluent to give a less polar (-) - enantiomer (0.3244 g): CIMS: m / z 214.15 (MH +); dH (CDCl3) 3.97 (2H, m, lm-CH2), 6.52 (1 H, d, Ar-H8), 6.68 (1 H, t, Ar-H6), 6.96 (1 H, s, lm-H5) , 6.96 (1 H, t, Ar-H7), 7.02 (1 H, t, Ar-H5), 7.10 (1 H, s, lm-H4) and 7.49 ppm (1 H, s, lm-H2); dc (CDCl 3) CH 2: 30.2, 43.5, 49.0; CH: 33.7, 114.2, 117.7, 119.3, 127.3, 129.6, 130.0, 137.7; C: 118.5, 143.9; [a] D20 ° C -57.3 ° (c = 10.43 mg / 2 ml, methanol) and one (+) - more polar enantiomer (0.3286 g): CIMS: m / z 214.15 (MH +); dH (CDCl 3) 3.97 (2H, m, lm-CH 2), 6.52 (1 H, d, Ar-Hβ), 6.67 (1 H, t, Ar-H 6), 6.96 (1 H, s, lm-H 5) , 6.96 (1 H, t, Ar-H7), 7.01 (1 H, t, Ar-H5), 7. 1 (1 H, s, lm-H4) and 7.50 ppm (1 H, s, lm-H2 ); dc (CDCl 3) CH 2: 30.2, 43.5, 49.0; CH2: 33.7, 114.2, 117.7, 119.3, 127.3, 129.6, 130.1, 137.7; C: 118.5, 143.9; [a] D20 ° C -56.8 ° (c = 10J0 mg / 2 ml, methanol) which. corresponds to the title compounds.

PREPARATIVE EXAMPLE 61 3-IY1 H-4-methylimidazoM-iDmetill-l, 2,3,4-tetrahydroquinoline Step A 1 N-tert-butoxycarbonyl-3-y (1 H-4-methylimidazol-1-yl) methan-1, 2,3,4-tetrahydroquinoline 4-Methyimidazole (0.9504 g, 11.6 mmol) was dissolved in anhydrous DMF (52 mL) and 95% sodium hydride (0.2924 g, 11.6 mmol) was added in portions to the stirred solution at 25 ° C under an argon atmosphere. . The mixture was stirred for 1 hour. The racemic compound of the title of Preparative Example 60, Step C (4.394 g, 10.5 mmol) in anhydrous DMF (25 mL) was added and the mixture was stirred at 25 ° C for 1 hour and then at 55-60 ° C for 7 hours. hours. The mixture was evaporated to dryness and the residue was chromatographed on silica gel using 0.5% -2% -4% -6% -10% (10% concentrated NHOH in methanol) -dichloromethane as eluent to give the racemic compound of the title (1.93 g, 56%) (4-Me: 5-Me :: 1.46: 1.0): CIMS: m / z 328.25 (MH +); dH (CDCl3) 1.51 (9H, s, CH2), 2.20 / 2.24 (3H, s, 5-Me / 4-Me), 3.81 / 3.88 (2H, m, 5-Me-lm-CH2 / 4-Me- lm-CH2), 6.65 / 6.83 (1 H, s, 4-Me-lm-H5 / 5-Me-lm-H4), 6.99-7.07 (2H, m, Ar-H7 and Ar-H8), 7.17 / 7.20 (1 H, d, Ar-H6), 7.36 / 7.43 (1 H, s, 4-Me-lm-H2 / 5-Me-! M-H2) and 7.67 / 7.71 ppm (1 H, d, Ar -H9); dc (CDCl 3) 4-Me: CH 3: 13.8, 28.4, 28.4, 28.4; CH2: 31.0, 46.8, 49.4, CH: 35.8, 115.6, 123.8, 123.9, 126.3, 129.1, 139.7; C: 81.4, 127.0, 138.2, 153.7; and 5-Me: CH 3: 9.4, 28.4, 28.4, 28.4; CH2: 31.0, 46.9, 47.1; CH: 35.3, 123.9, 123.9, 126.4, 126.9, 129.1, 137.3; C: 81.5, 127.3, 138.9, 153.7.

Step B 3-R 1 H-4-methylimidazol-1-yl) methyl-1, 2,3,4-tetrahydroquinoline The title compound of step A above was deprotected essentially as described in preparative example 57, step D above and chromatographed on silica gel to give the title compound.

PREPARATIVE EXAMPLE 62 6-r (1H-imidazol-1-yl) metip-1,2,3,4-tetrahydroquinoline Route 1 Step A 6- (methanesulfonyloxymethyl) quinoline 6-hydroxymethylquinoline (0.4325 g, 2.72 mmol) (prepared by the method of: CE Kaslow and WR Clark, J. Org.Chem, 1953, 18, 55-58) and triethylamine (1.5147 ml, 10.87 mmol) were dissolved in anhydrous dichloromethane (16 ml) and the mixture was cooled to 0 ° C. Methanesulfonyl chloride (0.421 ml, 5.43 mmol) was added and the mixture was stirred under argon atmosphere at 0 ° C for 1 hour. Additional triethiamine (0.758 ml, 5.435 mmol) and methanesulfonyl chloride (0.211 ml, 2.72 mmol) were added and the reaction was allowed to proceed for an additional 1 hour at 0 ° C. The mixture was evaporated to dryness to give the title compound which was used without further purification for the next step.

Stage B 6-r (1 H-imidazol-1-iDmethipquinoline SW??? The title product from step A above was dissolved in anhydrous DMF (10 ml) and sodium imidazole (0.367 g, 4.08 moles) was added. The mixture was heated to 70 ° C under argon atmosphere for 2 hours and then evaporated to dryness. The product was chromatographed on silica gel to give the title compound (0.1559 g, 27%) FABMS: m / z 210.0 (MH +); dH (CDCl 3) 5.34 (1 H, s, CH 2), 6.97 (1 H, s, Im-Hs), 7.15 (1 H, s, lm-H 4), 7.44 (1 H, dd, Ar-H 3), 7.52 (2H, m, Ar-H5 and Ar-H7), 7.64 (1 H, s, lm-H2), 8.12 (2H, d, Ar-H4 and Ar-H8) and 8.95 ppm (1 H, d, Ar -H2); dc (CDCl 3) CH 2: 50.6; CH: 119.4, 121.8, 125.9, 128.4, 130.1, 130.5, 136.0, 137.6, 151.0; C: 128.2, 134.6, 147.9.

Step C 6-α (1 H-imidazol-1-yl) methyl-1, 2,3,4-tetrahydroauinoline The title compound from step B above (0.045 g, 0.215 mmol) and methanol (11 ml) were placed in a Parr pump and platinum (IV) oxide monohydrate (0.05 g, 0.204 mmol) was added. The mixture was hydrogenated at 50 psi at 25 ° C for 2 hours. The catalyst was removed by decantation and washed with methanol. The methanol was evaporated to dryness and the product was chromatographed on silica gel using 3% (10% concentrated NH 4 OH in methanol) -dichloromethane as eluent to give the title compound (0.0325 g, 71%): CIMS: m / z 214.15 (MH +); dH (CDCl 3) 1.92 (2 H, t, 3-CH 2), 2.61 (2 H, m, 4-CH 2), 3.30 (2 H, m, 2-CH 2), 4.93 (2 H, s, CH 2), 6.42 (1 H , d, Ar-H8), 6.77 (1 H, s, Ar-Hs), 6.79 (1 H, d, Ar-H7) 6.90 (1 H, bs, lm-H5) 7.07 (1 H, bs, Im -H4) and 7.52 ppm (1 H, bs, lm-H2); dc (CDCl 3) CH 2: 21.9, 27.0, 41.9, 50.8; CH: 114.2, 119.2 (b), 126.4, 128.7, 129.1, 137.2 (b); C: 121.6, 123.8, 144.8.

Route 2 Stage A 6-hydroxymethyl-1, 2,3,4-tetrahydroquinoline 6-hydroxymethylquinoline (1 g, 6.28 mmol) (prepared by the method of: CE Kaslow and WR Clark, J. Org. Chem, 1953, 18, 55-58) and methanol (200 ml) were placed in a Parr pump and Platinum (IV) oxide monohydrate (0.5 g, 2.04 mmol) was added. The mixture was hydrogenated at 50 psi at 25 ° C for 2 hours. The catalyst was removed by filtration and washed with methanol. The combined filtrates were evaporated to dryness and the product was chromatographed on silica gel using 1.5% (10% concentrated NH OH in methanol) -dichloromethane as eluent to give the title compound (0.7044 g, 68%): CIMS: m / z 164.35 (MH +); dH (CDCl 3) 1.93 (2H, m, 3-CH 2) and 2.76 (2H, t, 4-CH 2), 3.30 (2H, m, 2-CH 2), 4.50 (2H, s, CH 2 OH), 6.45 (1 H , d, Ar-H8), 6.96 ppm (2H, m, Ar-H5 and Ar-H7); d0 (CDCl3) CH2: 22.1, 27.0, 42.0, 65.6; CH: 114.2, 126.4, 129.2; C: 121.5, 129.4, 144.5.

Stage B 1N-tert-butoxycarbonyl-6-hydroxymethyl-1, 2,3,4-tetrahydroquinoline The title compound from step A above (0.684 g, 4.19 mmol) was dissolved in THF (25 ml) and sodium hydroxide (0.21 g, 5.25 mmol) in water (10 ml) was added. Di-tert-butyl dicarbonate (1.26 g, 5.76 mmol) was added and the mixture was stirred at 25 ° C for 92 hours Additional di-tert-butyl dicarbonate (0.628 g, 2.88 mmol) was added and the reaction was continued for a total of 116 hours The reaction was worked up as described in preparative example 1, step A above and the product was chromatographed on silica gel using 0.5% (10% concentrated NH 4 OH in methanol) -dichloromethane as eluent for give the title compound (0.7978 g, 72%): ESMS: m / z 264.1 (MH +), dH (CDCl3) 1.52 (9H, s, CH3), 1.91 (2H, M, 3-CH2), 2.76 (2H , t, 4-CH2), 3J0 (2H, m, 2-CH2), 4.60 (2H, s, CH2-OH), 7.09 (1 H, s, Ar-H5), 7.12 (1 H, d, Ar -H7) and 7.64 ppm (1 H, d, Ar-H8), dc (CDCl3) CH3: 28.4, 28.4, 28.4, CH2: 23.5, 27.6, 44J, 65.1, CH: 124.3, 124.7, 127.4, 124.7; : 80.9, 130.1, 135.6, -138.4, -154.2.

Step C 1 N-tert-butoxycarbonyl-6- (4-tosyloxymethyl) -1,2,3,4-tetrahydroquinoline The title compound of step B above can be reacted with 4-toluenesulfonyl chloride and pyridine under essentially the same conditions described in preparative example 58, step C and chromatographed on silica gel to give the title compound.

Step D 1 N-tert-butoxycarbonyl-6-y (1 H-imidazol-1-yl) metip-1, 2,3,4-tetrahydroquinoline The title compound of step C above can be reacted with sodium midazole in anhydrous DMF under essentially the same conditions described in preparative example 62, lane 1, step B and chromatographed on silica gel to give the title compound. Alternatively: The title compound of route 2, step B above (0.5166 g, 1.96 mmol) was dissolved in anhydrous THF (5.5 ml) and N, N'-carbonyl-diimidazoi (0.668 g, 4.12 mmol) and the mixture were added. it was heated under reflux at 75 ° C for 4.5 hours. The solution was evaporated to dryness and chromatographed on silica gel using 2% (10% concentrated NH OH in methanol) -dichloromethane as eluent to give the title compound (0.0612 g, 10%): CIMS: m / z 314.25 (MH +); dH (CDCl3) 1.51 (9H, s, CH3), 1.92 (2H, m, 3-CH2), 2.72 (2H, d, 4-CH2), 3.69 (2H, d, 2-CH2), 5.04 (2H, s, CH2-lm), 6.85 (1H, s, Im-Hs), 6.91 (1 H, s, Ar-H6) 6.97 (1 H, d, Ar-H8) 7.08 (1 H, s, lm-H4 ), 7.59 (1 H, s, lm-H2) and 7.67 ppm (1 H, d, Ar-H9); dc (CDCl 3) CH 3: 28.4, 28.4, 28.4, CH 2: 23.4, 27.6, 44.8, 50.5; CH: 119.4, 124.5, 125.0, 127.6, 129.4, 137.3; C: 81.1, 130.5, 130.5, 138.J, 153.9.

Step E 6-1Y1 H-imidazol-1-yl) methan-1, 2,3,4-tetrahydroquinoline The title compound of step D above can be deprotected essentially as described in preparative example 57, step D and chromatographed on silica gel to give the title compound.

PREPARATIVE EXAMPLE 63 4 (R / S) -I? 1 H-4/5-methylimidazol-1-di methyl, 2,3,4-tetrahydroquinoline Route l Stage A 4-Hydroxymethylisoquinoline 4-lsoquinolinecarboxaldehyde (6.15 g, 39.13 mmol) (prepared by the method of: JB Wommack, TG Barbee, Jr., DJ Thoennes, MA McDonald and DE Pearson, J. Heterocyciic Chem., 1969, 6, 243-245) dissolved in anhydrous dichloromethane (369 ml) and the solution was cooled to 0 ° C. A borane-dimethylsulfide complex (1 M in THF) (5.23 ml, 5.09 mmol) (described in: E. Mincione, J. Org. Chem., 1978, 43, 1829-1830) was added and the mixture stirred at 0 ° C for 1.5 hours. An additional borane-dimethylsulfide complex (1 M in THF) (10455 mL, 1.35 mmol) was added and the reaction was stirred for an additional 2 hours at 0 ° C. Methanol (93.3 ml) was added and the solution was evaporated to dryness and chromatographed on silica gel using 2-3% (10% concentrated NH OH in methanoi) -dichloromethane as eluent to give unreacted 4-isoquinolinecarboxaldehyde (-23). %), 4- (1,2-dihydroisoquinoline) -carboxaldehyde (identical to that described in preparative example 63, lane 3, step A (-27%) and the title compound (1.94 g, 31%). prepare the title compound by catalytic hydrogenation of 4-ioquinolinecarboxaldehyde using 10% Pd-AI203 as catalyst (described in: J. Vassant, G. Smets, JP Declercq G. Germain and M. Van Meerssche, J. Org. Chem. 1980, 45, 1557-1565).

Stage B 4-r (4-toluenesulfonyloxy) methylisoquinoline To a stirred solution of the title compound from step A above (1.94 g, 12.2 mmol) in anhydrous pyridine (14 ml) at 0 ° C was added 4-toluenesulfonyl chloride (2.784 g, 14.6 mmol) and the mixture was stirred. stirred at 0 ° C for 2.5 hours. The solution was evaporated to dryness and the product was azeotroped with toluene and then taken up in dichloromethane and washed with saturated aqueous sodium bicarbonate, filtered and evaporated to give the title compound which was used without purification for the next stage.

Stage C 4-IY1 H-4/5-methylaldazol-1-p-P-methylisoquinoline 4-Methylimidazole (1.099 g, 13.38 mmol) was dissolved in anhydrous DMF (33.5 mL) and 95% sodium hydride (0.338 g, 13.42 mmol) was added in portions to the stirred solution at 25 ° C. The title compound of step B above was dissolved in anhydrous DMF (14 ml) and added dropwise to the stirred solution at 25 ° C for 20 minutes. The mixture was stirred at 25 ° C for 17 hours and evaporated to dryness. The residue was taken up in dichloromethane and washed with water, dried (MgSO 4), filtered and evaporated to dryness. The product was chromatographed on silica gel using 2.5% methanol in dichloromethane as eluent to give a mixture of the title compounds (0.5085 g, 19%) (4-Me: 5-Me :: 1.2: 1): dH ( CDCI3) 2.18 / 2.22 (3H, s, 4-Me / 5-Me), 5.46 (2H, s, CH2-lm), 6.63 / 6.89 (1 H, s, 4-Me: lm-Hs / 5-Me : lm-H4), 7.43 / 7.55 (1 H, s, 5-Me: lm-H2 / 4-Me: lm-H2) 7.63-7.86 (3H, d, yt, Ar-H6.7.8), 8.02 / 8.38 (1 H, s, 5-Me: Ar-H3 / 4-Me: Ar-H3) 8.05 (0.5H, d, 5-Me: Ar-H3) and 9.26 / 9.28 ppm (1H, s, 5- Me: Ar-H? / 4-Me: Ar-Hi) dc (CDCl 3) 4-Me: CH 3: 13.6; CH2: 46.5, CH: 115.J, 121.8, 127.8, 128.7, 131.6, 136.3, 143.3, 154.1; C: 124.7, 128.5, 133.8, 138.7; and 5-Me: CH 3: 9.5; CH2: 44.4: CH: 121.6, 127.4, 127.8, 128.7, 131.5, 137.2, 142.0, 153.7; C: 124.8, 128.2, 133.4, 138.7.

Step D 4-K1 H-4-methylimidazol-1-yl) metiopinoquinoline and 4-y (1 H-5-methylimidazol-1-di-methyl-isoquinoline) The regio-isomer titer mixture from step C above (0.45 g) was subjected to chiral HPLC on a Chiralpak® HPLC column using hexane-iso-propanol: diethylamine :: 85: 15: 09.2 to give the 4- isomer first methyl (0.0406 g): FABMS: m / z 224.0 (MH +); dH (CDCl3) 2.18 (3H, s, 4-CH3), 5.46 (2H, s, CHa-lm), 6.62 (1 H, s, lm-H5), 7.54 (1H, s, Im-H2), 7.67 (1 H, t, Ar-H8), 7.76 (1 H, t, A1 - H7), 7.84 (1 H, d, Ar-H6), 8.04 (1 H, d, Ar-H9), 8.39 (1 H, s, Ar-H3) and 9.27 ppm (1 H , s, Ar-Hi); dc (CDCl 3) CH 3: 13.6; CH2: 46.5; CH: 115.7, 121.8, 127.8, 128.J, 131.6, 136.3, 143.3, 154.1; C: 124.7, 128.7, 133.8, 138.8; and then the 5-methyl isomer (0.0361 g): FABMS: m / z 224.1 (MH +); dH (CDCl3) 2.20 (3H, s, 5-CH3), 5.45 (2H, s, CHz-lm), 6.86 (1 H, s, lm-H4), 7.41 (1 H, s, lm-H2), 7.68 (1 H, t, Ar-H8), 7.98 (1 H, t, A1-H7), 7.84 (1 H, d, Ar-H6), 8.02 (1 H, s, Ar-H3), 8.05 (1 H, d, Ar-H9) and 9.22 ppm (1H, s Ar-Hi); dc (CDCl 3) CH 3: 9.4; CH2: 44.3; CH: 121.5, 126.9, 127.9, 128.8, 131.7, 137.0, 141.7, 153.6; C: 124.9, 128.2, 133.4; 138.7 and a superimposed fraction (0.28 g).

Stage E 4í (1 H-4/5-Methylimidazol-1-iDmeti.1-1, 2.3.4-tetrahydroisoquinoline The title compound of step C above (0.346 g, 1.55 mmol) was dissolved in anhydrous methanol (80 ml) and platinum (IV) oxide monohydrate (0.11 g) was added. The mixture was hydrogenated at 25 ° C at 50 psi in a Parr pump for 2 hours. The catalyst was removed by filtration and washed with methanol and the methanol filtrates were evaporated to dryness. The residue was chromatographed on silica gel using 3% (10% concentrated NH OH in methanol) -dichloromethane as eluent to give the title 4-methyl compound (0.0299 g, 95): ESMS: m / z 228.0; dH (CDCl 3) 2.24 (3 H, s, lm-4-CH 3), 2.81 (1 H, bs, NH), 2.93 (2 H, m, 3-CH 2), 3.03 (1 H, m, 4-CH), 4.04 (2H, s, 1-CH2), 4.08, 4.27 (2H, dd, CH2-lm), 6.68 (1 H, lm-H2), 7.01-7.09 (2H, m, Ar-H), 7.18 (2H, m, Ar-H) and 7.36 ppm (1 H, s, lm-H5); dc (CDCl 3) CH 3: 13.8; CH2: 45.0, 48.4, 51.1; CH: 39.6, 115.6, 126.5, 126.8, 126.9, 129.1, 136.9; C: 134.5, 135.7, 138.6 and the title compound 5-methyl (0.0641 g, 18%): CH3: 9.3; CH2: 44.9, 48.8, 50.5; CH: 39.4, 126.5, 126.9, 126.9, 129.0, 136.7; C: 127.0, 134.4, 145.7, 138.5.

Route 2 Stage A 4-Hydroxymethylisoquinoline 4-Isoquinolinecarboxaldehyde (1 mmol) (prepared by the method of JB Wommack, TG Barbee, Jr., DJ Thoennes, McDonald MA and DE Pearson, J. Heterocyclic Chem., 1969, 6, 243-245 in anhydrous THF was dissolved. 50 ml) and treated with borane-methyl sulfide (0.3 mmoles) (as described in: E. Mincione, J. Org. Chem., 1978, 43, 1829-1830) at 0 ° C for 0.5- 1 hour and worked up in the usual way to obtain the title compound Alternatively the title compound can be prepared by catalytic hydrogenation of 4-ioquinolinecarboxaldehyde using 10% Pd-AI2 3 3 as catalyst (described in: J. Vassant, G. Smets, JP Declercq, G. Germain and M. Van Meerssche, J. Org. Chem., 1980, 45, 1557-1565).

Stage B 4-f (4-Toluenesulfonioxy) metifsoquinolitan The title compound of step A above was dissolved in anhydrous pyridine and cooled to 0 ° C with stirring. 4-Toluenesulfonyl chloride was added and the reaction was carried out as described in preparative example 60, step D to give the title compound which was used without further purification.

Stage C 4-Hydroxymethyl-1,2-dihydroisoquinoline The title compound of step A above can be selectively reduced with freshly prepared zinc borohydride (as described in: D. O Sakar, AR Das and BC Ranu, J. Org. Chem., 1990, 55, 5799-5801 ) to give the allylic alcohol of the title.

Stage D N-tert-Butoxycarbonyl-4-hydroxymethyl-1,2-dihydroisoquinoline The title compound of step B above was reacted with zinc borohydride as described in step C above to give the title compound. Alternatively: The title compound of step C above was reacted with di-tert-butyl dicarbonate and with sodium hydroxide as described in preparative example 57, step A to provide the title compound.

Step E 4- (R S) -r (1 H-4/5-Methylamide-1-inmetim-1,2-dihydroisoquinoline) The title compound of step C above can be reacted with N, N'-carbonyldiimidazole using the procedure described in preparative example 22, part two of step D, to give the title compounds.

Step F 4 (R / SH (1 H-4/5-Methylimidazol-1-yl) methyl-1, 2,3,4-tetrahydroisoquinoline The title compounds of step E above were reduced with platinum (IV) oxide as described in route 1, step D above to give the title compounds.

Stage G 4-r4- (Toluenesulfonylloxy) metin-1,2-dihydroisoquinoline The title compound of step D above was reacted with 4-toluenesulfonyl chloride in pyridine as described in preparative example 4, step D to give the title compound.

Step H 2N-tert-Butoxycarbonyl-4 (R / S) -r (1 H-4/5-methylimidazol-1-inmetim-1,2-dihydroisoquinoline) The title compounds of step G above were reacted with sodium 4-methylimidazole as described in route 1, step C above to give the title compounds. The regio-isomers can be separated by chiral HPLC on a Chiralpak® column, or by treatment with trityl chloride as described above.

Step 2N-tert-Butoxycarbonyl-4- (R / S) -r (l H-4/5-Methylimidazol-1-yl) metin-1, 2,3,4-tetrahydroisoquinoline The title compounds of step H above were reduced with platinum (IV) oxide as described in route 1, step D above to give the title compounds.

Stage J 4 (R / S) -1Y1 H-4/5-Methylimidazol-1-di-methyl-l, 2,3,4-tetrahydroisoquinoline The title compounds of the above step H were deprotected as described in preparative example 57, step D, to give the title compounds.

EXAMPLE 74 1 -1 -Pimethylethyl-4- (3-bromo-8-chloro-6,11-dihydro-5H-benzor5.61cycloheptap, 2-b1pyridin-11 -IL) -2 (R) -lT2-r2- ( 1 H-imidazol-1 - DetilU-piperidinipcarbonill-1-piperazinecarboxylate Route 1 1, 1 -Dimethylethyl-4- (3-bromo-8-chloro-6,11-dihydro-5H-benzo [5,6] cyclohepta [1,2-b] pyridin-11-yl) -2 (R) -carboxy-1-piperazinecarboxylate (0.250 g, 0.466 mmol) (prepared as described in Preparative Example 6), 2- [2- (1 H-imidazol-1-yl) ethyl] piperidine (0.1085 g, 0.6054) mmoles) (prepared as described in preparative example 1), 1- (3-dimethylamino-propyl) -3-ethylcarbodiimide hydrochloride (0.116 g, 0.6054 mmol), 1-hydroxybenzotriazole (0.0818 g) , 0.6054 mmoles) and 4-methylmorpholine (0.0665 ml, 0.6054 mmoles) were dissolved in anhydrous DMF (10 ml) and the mixture was stirred under argon atmosphere at 25 ° C for 18 hours. The solution was evaporated to dryness and the residue was washed with water, dried (MgSO 4), filtered and evaporated to dryness. The residue was chromatographed on silica gel using 1% (10% concentrated NH OH in methanol) -dichloromethane as eluent to give the title compound (0.0617 g, 19%): ESMS: m / z 697.2 (MH +); dH (CDCl3) 6.97 (1 H, broad s, lm-H5), 7.04 (1 H, broad s, lm-H4), 7.09-7.20 (broad m, Ar-H), 7.56 (2H, broad s, Ar -H and lm-H2) and 8.38 ppm (1H, broad s, Ar-H2); dc (CDCl 3) CH 3: 28.4, 28.4, 28.4; CH2: 18.9 / 19.1, 25.2 / 25.3 / 25.8, 30.4, 30.5, 31.4 / 31.6, 36.6, 40.2, 42.9, 43.4 / 43J, 50.3, 52J / 53.0; CH: 45.8 / 46.4, 50.1 / 51. J / 52.2, 78.3 / 78.4 / ~ 79.3, -119.0, 126.3, -129.8, 130.7 / 130.8, 132.5 / 132.6, -137.1, 141.4 / 141.5, 146.9; C: 80.4, 120.0 134.3, 134.8, 137.5, 141.0, 155.9, 156.8, 157.2.

Route 2 Step A 4-r 3 -Bromo-8-chloro-6,11-dihydro-5H-benzoyl 5,61 cycloheptap. 2 -birpyridin-11-yl) -2 (RH 2 -I 2 - (1 H -imidazole-1-O-ethyl-1-piperidinylcarbonin-1) -piperazine 3-Bromo-8,11-dicioro-6,11-dihydro-5H-benzo [5,6] cyclohepta [1,2-b] pyridine (prepared as described in preparative example 40 (US Pat. 5.J19.148) with the title compound of Preparative Example 1, Step B, and triethylamine in a mixture of anhydrous THF and dichloromethane at 25 ° C to give the title compound.

Stage B 1.1-Dimethylethyl 4- (3-bromo-8-chloro-6.11-dihydro-5H-benzor5,61cycloheptaH2-b1pyridin-11-yl) -2 (R) -IT2-r2-r (1H-imidazole -1-yl) etpi-piperidinyljcarbonin-1-Piperazinecarboxylate The title compound of Example 74 was reacted, step A with di-tert-butyl dicarbonate and with sodium hydroxide in THF water (1: 1) at 25 ° C as described in preparative example 57, step A and the product was chromatographed on silica gel to give the title compound.

EXAMPLES 75-86 11 (R), 2 (R) 11 (R), 2 (R) 11 (S), 2 (R) 11 (S), 2 (R) Where Using essentially the same procedure described in example 74 above, acids 11 (R), 2 (R) and 11 (S), 2 (R) can be reacted from preparative example 30, with the product of the preparative example 58, step E to give the desired compounds of examples 75-80; or with the product of preparative example 59, step E to give the desired compounds of examples 81-86, respectively (table 11).

TABLE 11 TABLE 11 (continued) EXAMPLES 87-110 Where; R8 = ^ '^^ -? By reacting the anhydride of Preparative Example 3 shown in the above scheme, with the product of Preparative Example 60, Step E, or F, the intermediary of Examples 87-98 can be obtained; or with the product of preparative example 61, step B, the intermediary of examples 99-102 can be obtained; or with the product of preparative example 62, step C, the intermediary of examples 103-106 can be obtained; or with the intermediary of preparative example 63, step D of route 1, or steps F or J of route 2, the intermediary of examples 107-110 can be obtained. By reacting the intermediates thus obtained with 8,11-dichloro-6,11-dihydro-5H-benzo [5,6] cyclohepta [1,2-b] pyridine (prepared as described in U.S. Patent 5,807,853 , September 15, 1998) can be obtained, after reaction with di-tert-butyl dicarbonate and with sodium hydroxide or with iso-propyl chloroformate and triethiamine, or with cyclohexyl chloroformate and triethylamine as described herein, the title compounds of Examples 87-110 (Table 12).

TABLE 12 TABLE 12 (continued) TABLE 12 (continued) TABLE 12 (continued) PREPARED EXAMPLE 64 Stage A A solution of 52.i (J. Med. Chem. 4890-4902 (1988) (205 g) in concentrated HCl (1 I) and water (100 ml) was refluxed for 18 hours and then poured onto ice (3 kg. 50% aqueous NaOH was added to pH 12 followed by extraction with EtOAc (3x4 I) and the extracts were washed with brine, dried and evaporated to provide 52.ii (166 g).

Stage B A 1M solution of DIBAL in toluene (908 ml) was added dropwise over 2 hours to a solution of 52. ii (166 g) in toluene (4 L) at room temperature followed by stirring for 18 hours. The mixture was cooled to 0-5 ° C and stirred for 1 hour and extracted with 1 N HCl (2 I). The aqueous extract was basified to pH 10 with 50% NaOH and extracted with EtOAc (3x2 I). The extracts were evaporated and chromatographed on silica gel (1 kg). Elution with 10% MeOH / CH2Cl2 provides the title compound (±) 52.0 (104 g): HRMS (FAB) calculated for C19H2? N279BrCI 393.0556, found 393.0554.

Step C The presytrate (+) 52.0 (96 g) was resolved by HPLC on a CHIRALPAK AD 8 × 30 cm column at 25 ° C with a UV detector set at 290 nm. Elution with 0.05% diethylamine-methanol gave: peak 1 (-) 52.0 (40 g): [a] D20-28.4 ° (c 0.3, MeOH). Additional elution with the same solvent provided: peak 2 (+) 52.0 (42 g): [a] D20 + 27.5 ° (c 0.3, MeOH).

PREPARED EXAMPLE 65 Stage A A solution of (+) - 52.0 (2.3 g) in dimethylformamide (30 ml) was reacted with isatoic anhydride (1.25 g) in the presence of DMAP (0.1 g) at room temperature for 3 hours and then evaporated under reduced pressure and the residual dimethylformamide was subjected to azeotropy with toluene. The residue was dissolved in ethyl acetate (50 ml) and the solution was extracted with 10% sodium carbonate (3 x 100 ml). The organic layer was filtered through silica gel (100 ml) followed by elution with ethyl acetate. The filtrate was evaporated under reduced pressure to provide 53.0 of the title compound as an amorphous solid (3.68 g). MS (FAB): m / z 510 (MH) +.

Stage B A solution of 53.0 (3.1 g) and sodium nitrite (0.8 g) in methanol (500 ml) was stirred at room temperature under nitrogen with cuprous chloride (0.15 g) while a 4M solution of acid was added dropwise over 10 minutes. hydrochloric / dioxane (3.9 ml). The reaction mixture was stirred for 24 hours followed by addition of 10% sodium carbonate at pH 8, concentrated under reduced pressure, diluted with water (200 ml) and extracted with dichloromethane (4 x 100 ml). The combined extract was evaporated under reduced pressure and the crude reaction product was chromatographed by evaporative chromatography on silica gel (400 ml). Elution with 25% ethyl acetate-hexane provided after evaporation 54.0a and 54.0b of the title compound as an off-white amorphous solid (2.97 g). 1 H NMR (CDCl 3, 300 MHz) d 3.30 (s, 3H); MS (FAB) m / e 525 (MH) +.

Stages C-E A solution of 54.0a and 54.0b (17 g) in methanol (150 ml) and 2N hydrochloric acid (170 ml) and concentrated HCl (60 ml) was heated under reflux for 17 hours, followed by evaporation under reduced pressure. The resulting amorphous solid was dissolved in methanol (160 ml) and sodium cyanide (15 g) was added with stirring until the reaction was basified (pH 8). The reaction was stirred for 2 hours, diluted with dichloromethane (300 ml) and filtered. The filtrate was evaporated and the residue was dissolved in concentrated HCl (150 ml) and the mixture was heated in an oil bath (120 ° C) for 4 hours and then evaporated under reduced pressure. The residue was dissolved in THF (100 ml) and 10% NaOH (300 ml) was added at pH > 8 followed by dropwise addition of a solution of (BOC) 20 (9 g) in THF (50 ml) with vigorous stirring for 24 hours. The solution was concentrated to a small volume, stirred with hexane (2 x 120 ml) and with ice water followed by acidification of the aqueous layer with citric acid and extraction with EtOAc. The crude product obtained by evaporation of the extract was purified by evaporative chromatography to give a mixture of 57.0a and 57.0b as a light tan solid which appears as a single spot by tic (16). 1 H NMR (CDCls, 300 MHz) d 1.40 (s, 9H); MS (FAB) m / z 535 (MH) +. The unique tic stain is a mixture of four isomers. Following the above procedure (step AE), except that the compound (-) - 52.0 (17 g) was used, a mixture of 58.0a and 58.0b was obtained as a clear solid that appears as a single tic stain (17 g) ). MS (ES) m / z 535 (MH +).

EXAMPLE 118 Midazoi (reagent 2), (220 mg, 0.92 mmol) was added to a solution of Boc-acid (reagent 1), (0.45 g, 0.842 mmol), EDCI (200 mg, 1.043 mmol), HOBT (130 mg, 0.962 mmole) and N-methyl morpholine (0.2 ml, 1.81 mmole) in DMF (anhydrous, 3 ml) at room temperature (20 ° C). The resulting solution was stirred overnight at 20 ° C. The solvent was evaporated, water (70 ml) and EtOAc (120 ml) were added. The organic layer was separated and washed with a 10% solution of Na2CO3 (50 ml) and then dried over MgSO4, filtered and the solvent evaporated obtaining an oil which was chromatographed on silica gel and eluted with 5%. of MeOH: MeCI2, the product being obtained as a white solid (425 mg, 74%). Mixture of 4 isomers A, B, C, D. Espect. mass (ES, MH, 682) of high resolution estimated between (MH) 684.2139 (Br = 81) observed 684.2120.

EXAMPLE 119 Stage A A solution of the tricyclic isomers (A, B, C, D) of Example 118 (150 mg, 0.205 mmol) in 4N HCl-dioxane (3 mL) and MeOH (3 mL) was stirred at 20 ° C for 3 hours. The solvent was evaporated, water (25 ml) and 10% NaOH (4 ml) were added and then extracted with MeCI2 (2 x 100 ml). The organic layer was separated, dried over MgSO 4, and the solvent was evaporated obtaining a solid which was purified by chromatography on silica gel eluting with 3% MeOH-MeCl 2 containing 2% NH 4 OH which gave the product in form of a white solid (70 mg, 54% yield). Mixture of 2 isomers (C, D) (product 1). Espect. of mass ES (MH) 582. The additional elution gives a white solid (25 mg, yield 20%). Mixture of 2 isomers. (A, B) (product 2). Espect. of dough ES (MH) 582.

Stage B A solution of Boc dicarbonate (100 mg, 0.45 mmol) in THF (2 ml) was added to a solution of the tricyclic (170 mg, 0.29 mmol) - (isomer (C, D) product 1, stage A in THF: H20 (VV 1: 1) (10 ml) and 10% NaOH (2 ml) at 20 ° C. After stirring at this temperature for 60 minutes, water (5 ml) and MeCI2 (10 ml) were added. The organic phase was separated, dried over MgSO4, filtered and the solvent was evaporated obtaining an oil, which was chromatographed on silica gel, eluting with 3% v / v MeOH: MeCI2 to provide the product as a white solid ( 170 mg) as a mixture of 2 isomers, C isomers, D. Mass spec (ES, MH) 682. Following the above procedure, but substituting product 1 for product 2 of stage A (isomers A / B) , product 2 was obtained in the form of a mixture of 2 isomers (A / B) Mass Spec (ES.HM) 682.

EXAMPLE 120 The compounds were obtained with the stereochemistry (R) to Cu using the procedures of Examples 118 and 119, but substituting reagent 1, Example 118 with the corresponding tricyclic isomer (R).

EXAMPLES 121-126 By replacing reagent 2, example 118, with the corresponding 2-methyl imidazole analog, the following structures were obtained: where R9 is defined in the following table 14: TABLE 14 TABLE 14 (continued) EXAMPLES 127-132 Following the procedures of Examples 118 and 119, the isomers identified in the following Table 15 were obtained.

TABLE 15 PREPARED EXAMPLE 66 A solution of 6-methylnicotinic acid (9.97 g, 72.7 mmol), water (100 ml) and ammonium hydroxide was hydrogenated (40 psi) in a Parr low pressure hydrogenation apparatus with 5% Rh-Al20 catalyst (3.22 g). ) for 72 hours. The mixture was filtered and the filtrate was concentrated in vacuo to give the title compound as a white solid (10.58 g, 100%, MH + = 144).

A mixture of the title compound of step A (10.40 g, 72. 72 mmol), ethyl alcohol (190 proof, 50 ml) and HCl (4 ml) was stirred under reflux for 4 hours. The reaction mixture was cooled to room temperature and poured into water. Basification of the mixture to pH = 10 with 10% aqueous NaOH, extraction of the aqueous layer with EtOAc and drying of the organic phase over anhydrous Na 2 SO 4 gave the title compound after filtration and concentration in vacuo (1.85 g, 15%, MH + = 172).

Following the procedure indicated in preparative example 7 stage B but using the title compound of preparative example 66 step B In place of the title compound of Preparative Example 7 step A, the product was isolated as a mixture of diastereomers and used directly in step D (MH + = 130).

Following the procedure indicated in preparative example 7 stage C but using the title compound of preparative example 66 step C instead of the title compound of preparative example 7 step B, the product was isolated as a mixture of diastereomers (1.7 g , 70%, MH + = 230).

Stage E Following the procedure indicated in preparative example 7 stage D but using the title compound of preparative example 66 step D instead of the title compound of preparative example 7 step C, the product was isolated as a mixture of diastereomers and used directly in stage F (MH + = 384).

Stage F Following the procedure indicated in preparative example 7 stage E but using the title compound of preparative example 66 step E instead of the title compound of preparative example 7 step D, the product was isolated as a mixture of diastereomers 5: 1 (328 mg, 16%, MH + = 280).

Stage G Following the procedure indicated in preparative example 7 stage F, except that the title compound of preparative example 66 was used in step F instead of the title compound of preparative example 7 step E, amine hydrochloride (290 mg, 100 mg) was obtained. %): MH + = 180.

PREPARED EXAMPLE 67 Step A If the procedures set forth in the preparative example 66 steps A-E were followed, except that 5-hydroxynicotinic acid was used in place of 6-methylnicotinic acid in step A, alcohol would be obtained Stage B If the product of step A was treated with PCC according to conventional procedures established in the literature, then the ketone could be obtained If the procedures set forth in the preparative example 7 EF steps were followed, except that the title compound of Preparative Example 67 was used in place of the title compound of Preparative Example 7 step D in step E, the hydrochloride of amine.

Step D If the product of Preparative Example 67 were treated with an excess of NaBH 4 according to conventional procedures such as those established in the literature, then alcohol would be obtained.

PREPARED EXAMPLE 68 Stage A Following the procedure indicated in preparative example 7 stage C, except that the title compound of preparative example 7, step A is used instead of the title compound of preparative example 7, step B, the ester can be obtained (62 g, 96 %): MH + = 258.

Stage B The product from preparative example 68, step A was treated with LDA in anhydrous THF and the resulting anion was alkylated with methyl iodide to give the title product (3.53 g, 82%): MH + = 272.

Stage O The title compound of Preparative Example 68, Step B was treated with TFA in CH 2 Cl 2 to give the amine as the TFA salt (1.63 g, 84%): MH + = 172.

Stage D Following the procedures established in the preparative example 7 steps BE, except that the title compound of preparative example 68, step C is used in place of the title compound of preparative example 7, step A, in step B, the product is obtained! midazole (0.445 g, 100%): MH + = 280.

Stage E Following the procedure set forth in the preparative example 68 step C, except that the title compound of preparative example 68, step D, is used, the amine is obtained in the form of its TFA salt. The mixture was basified with 1N NaOH and CH2Cl2 was extracted to give the product (14.6 g, 96%): MH + = 194.

PREPARED EXAMPLE 69 Following the procedures set forth in the preparative example 68 steps A-D, except that benzyl bromide is used in preparative example 68 step B instead of methyl iodide, the amine hydrochloride can be obtained.

EXAMPLE 133 If the established procedure were followed to prepare the compounds of Table 4 using the title compound of Preparative Example 66, Step G, the 11 (S) or 11 (R) isomers of the carboxylic acid of Preparative Example 30, DEC, HOBt would be obtained. and NMM, which is the product of the title.

EXAMPLE 134 If the established procedure were followed to prepare the compounds of Table 4 using the title compound of Preparative Example 67 step D, the 11 (S) or 11 (R) isomers of the carboxylic acid of Preparative Example 30, DEC, HOBt and NMM, which are the products of the title.

EXAMPLE 135 If the indicated procedure were followed to prepare the compounds of Table 4 using the title compound of Preparative Example 68, Step D, the 11 (S) or 11 (R) isomers of the carboxylic acid of Preparative Example 30, DEC would be obtained. , HOBt and NMM, which are the products of the title.

EXAMPLE 136 If the procedure for preparing the compounds of Table 4 were followed using the title compound of Preparative Example 69, the 11 (S) or 11 (R) isomers of the carboxylic acid of Preparative Example 30, DEC, HOBt and NMM, would be obtained. they are the products of the title.

EXAMPLE 137 If the established procedure for preparing the compounds of Table 4 were followed using the title compound of Preparative Example 70 step B, the 11 (S) or 11 (R) isomers of the carboxylic acid of Preparative Example 30, DEC, HOBt and NMM, which are the products of the title.

PREPARATIVE EXAMPLE 71 2 (R) - [(2- [2- (1H-imidazol-1-yl) ethyl] -1-piperidinyl] carbonylpiperazine H Step A Bis- (1. 1-dimethylethyl) 2 (R - [f 2 - [2- (1 H -imidazol-1-yl) ethyl] -1-piperidinyl] carbonyl] -1,4-piperazineadicarboxylate 1,4-Di-N-tert-butoxycarbonylpiperazine-2 (R) -carboxylate (prepared as descriin preparative example 2) (0.6946 g, 2.1 mmol), 2 (R / S) - [2- (1 H -imidazol-1-yl) ethyl] piperidine (0.49 g, 2.73 mmol) (prepared as descriin preparative example 57, step D) (IN0972), 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride ( 0.524 g, 2.73 mmol), 1-hydroxybenzotriazole (0.3693 g, 2.73 mmol) and 4-methylmorpholine (0.2765 g, 0.3005 ml, 2.73 mmol) were dissolved in anhydrous DMF (3 ml) and the mixture was stirred under argon at 25 ° C. C for 122 hours. The mixture was evaporated to dryness and chromatographed on silica gel using 2-3% (10% concentrated ammonium hydroxide in methanol) -dichloromethane as eluent to give the title compound (0.3127 g, 30%): CIMS: m / z 492.4 (MH +); dH (CDCl3) 1.47 (18H, s, CH3), 7.01 (1H, s, Im-Hs), 7.05 (1H, s, lm-H4) and 7.63 ppm (1H, s, lm-H2); dc (CDCl 3) CH 3: 28.2, 28.2, 28.2, 28.4, 28.4, 28.4; CH2: 19.1, 25.9, 26.2, 31.9, 40.8 / 41.3, 41.7, 43.0, 44.0; CH: 46.0, -52.1, 128.4, 137.2; C: -80.4, 80.6, -154.3, -154.3 and -169.8.

Step B 2 (R) - [[2- [2- (1H-imidazol-1-yl) ethyl] -1-piperidinyl] carbonyl] piperazine The title compound from step A above was deprotected as descriin Example 57, step D and chromatographed on silica gel to give the title compound.

EXAMPLE 138 1.1 -Dimethylethyl 4- (3-bromo-8-chloro-6.11-dihydro-5H-benzo [5.6] cyclohepta [1,2-b] pyridin-11 (S) -yl) -2 (R) - [ [2-f2- (1H-imidazol-1-yl) ethyl] -1-piperidinyl] carbonyl] -1-piperazinecarboxylate 1, 1-Dimethylethyl 4- (3-bromo-8-chloro-6,11-dihydro-5H-benzo [5,6] cyclohepta [1,2- b] pyridin-11 (S) -yl) -2 ( R) -carboxy-1-piperazinecarboxylate sodium (prepared as descriin Preparative Example 6 (sodium salt)) (0.1 g, 0.179 mmol), 2- [2- (1 H-imidazol-1-yl) ethyl] piperidine (prepared as descriin preparative example 57, step D) (0.0417 g, 0.233 mmole), 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (0.0446 g, 0.233 mmole), 1-hydroxybenzo -triazole (0.03174 g, 0.233 mmole) and 4-methylmorpholine (0.0512 ml, 0.466 mmole) were dissolved in anhydrous DMF (4 ml) and the mixture was stirred under argon at 25 ° C for 42 hours. The solution was evaporated to dryness and the residue was taken up in dichloromethane and washed with 1 N NaOH, dried (MgSO 4), filtered and evaporated to dryness. The residue was chromatographed on silica gel using 2.5% -4.5% -7.5% (10% concentrated NH4OH in methanol) -dichloromethane as eluent to give the title compound (0.0172 g, 14%): HRFABMS: m / z 697.2285 (MH +) (calculated m / z 697.2269); dH (CDCls) 1.38 / 1.41 (9H, s, CH3), 4.31 (1 H, s, Hn), 4.68 (1H, bs, H2), 7.03-7.20 (5H, br, Ar-H and lm-H4 and lm-H5), 7.57 (1H, s, IM-H2), 7.83 / 8.19 (s, Ar-H) and 8.38 ppm (1 H, s, Ar-H2): dc (CDCI3) CH3: 28.4, 28.4, 28.4; CH2: 19.1, 24.8 / 24.9, 28.3, 30.3, 30.5, 21.4, 40.3, 42.9 / 43.2, 44.1 / 44.6, 45.6, 50.2 / 50.5; CH: 44.1 / 44.6, 52.4, 78.4, 119.2, 126.2, 127.9, 130.8 / 130.9, 132.6, 136J, 141.6, 146.9 / 147.2; C: 80.4, 119.8 / 120.2, 134.4, 135.9, 137.0, 141.5, 155.0, 156.7 / 157.1, 170.3 / 170.9.

EXAMPLE 139 1.1 -Dimethyl 4- (8-chloro-6.11-dihydro-5H-benzo [5.6] cyclohepta [1,2-b] pyridin-11 (S) -yl) -2 (R) - [[2-f2 - (1 H-imidazoi-1-yl) ethyl-1-pperidylcarbonyl] - 1-piperazinecarboxylate 1, 1-Dimethylethi 4- (8-chloro-6,11-dihydro-5H-benzo [5,6] cyclohepta [1,2-b] plridin-11 (S) -yl) -2 (R) -carboxi Sodium 1-piperazinecarboxylate (prepared as described in Preparative Example 6 (sodium salt)) (0.5239 g, 1.09 mmol), 2- [2- (1 H-imidazol-1-yl) ethyljpiperidine (prepared as as described in preparative example 57, step D) (0.2544 g, 1.42 mmol), 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (0.272 g, 1.42 mmol), 1-hydroxybenzo-triazole (0.1918 g, 1.42 mmole) and 4-methylmorpholine (0.156 ml, 1.42 mmole) were dissolved in anhydrous DMF (23.5 ml) and the mixture was stirred under argon at 25 ° C for 286 hours. The solution was evaporated to dryness and the residue was taken up in dichloromethane and washed with 1 N NaOH, dried (MgSO 4), filtered and evaporated to dryness. The residue was chromatographed on silica gel using 2.5% (10% concentrated NH 4 OH in methanol) -dichloromethane as eluent to give the title compound (0.2298 g, 32%): HRFABMS: m / z 619.3169 (MH +) (Cale, m / z 691.3163).

EXAMPLE 140 4- (8-Chloro-6.11-dihydro-5H-benzof5.6] cycloheptaf1.2-b] pyridin-11 (S) -yl) -2 (R) - [[2- [2- (1H- imidazol-1-yl) ethyl] -1-piperidinyl] carbonyl] -1-piperazine The title compound of Example 2 (0.225 g, 0.363 mmol) was dissolved in methanol (2 mL). A 10% (v / v) solution of concentrated H2SO4 in dioxane (v / v) (4.92 ml) was added and the mixture was stirred at 25 ° C for 30 hours. The mixture was diluted with methanol (300 ml) and then treated with BioRad AG1-X8 resin until basified. The resin was filtered off and washed with methanol. The combined filtrates were evaporated to dryness and the residue was chromatographed on silica gel using 4% (10% concentrated NH 4 OH in methanol) -dichloromethane as eluent to give the title compound (0.1692 g, 90%): HRFABMS: m / z 519.2655 (MH +) (calculated m / z 519.26390), oH (CDCI3) 4.43 (1 H, s, H11), 6.89, 6.93, 7.00, 7.10, 7.13, 7.19, 7.21, 7.43, 7.45, 7.50, 7.58, 8.03 , 8.30 and 8.33 ppm (8H, Ar-H and Im-H); dc (CDCl 3) CH 2: 19.0 / 19.1, 25.0 / 25.7 / 26.1, 28.3 / 29.0, 30.7 / 30.8, 30.9 / 31.0, 31.5 / 31.9, 40.0 / 40.7, 43.5, 44.1 / 44.2 / 44.4, 49.3, 51.5 / 52.3; CH: 45.J / 46.1, 54.4 / 55.8, 79.5 / 79.7, 118.3 / 118.9, 123.1, 126.1 / 126.2, 129.1 / 129.5 / 129.7, 130.4 / 130.5, 132.7 / 132.8, 137.0 / 137.5, 138.9, 146.3; C: 134.0, 134.9, 135.5, 141.3, 157.1 and 169.8 / 170.5.

EXAMPLE 141 CyclohexH-4- (8-chloro-6.11-dihydro-5H-benzo [5, 6] cyclohepta [1,2-b] pyridin-11 (S) -yl) -2 (R) - [f2- [2- (RS) - (1 H-imidazole-1H) ethyl] -1-piperidinyl] carbonyl] -1-piperazinecarboxylate The title compound of Example 3 (0.165 g, 0.318 mmol) and triethylamine (0.1329 mL, 0.954 mmol) were dissolved in anhydrous dichloromethane (5 mL). Cyclohexyl chloroformate (0.0517 g, 0.318 mmol) was dissolved in anhydrous dichloromethane (3.18 ml) and the mixture was stirred at 25 ° C for 18 hours. Additional cyclohexyl chloroformate (0.0129 g, 0.0795 mmol) was added and stirring continued for a total of 43 hours. Methanol (10 ml) was added, and the mixture was evaporated to dryness. The residue was chromatographed on silica gel using 2% (10% concentrated NH 4 OH in methano) -dichloromethane as eluent to give the title compound (0.153 9, 75%): HRFABMS: m / z 645.3323 (MH +) (calculated MH + for C36H46N6O3CI: m / z 645.3320).

EXAMPLE 142 Cyclohexyl 4- (8-chloro-6.11-dihydro-5H-benzof5.6] cyclohepta [1,2-b] pyridin-11 (S) - »l) -2 (R) -rC2-f2- (S ) -1 H-imidazol-1-yl) ethyl] -1-piperidinyl IcarbonirM-piperazinecarboxylate (-) - Cyclohexyl 4- (8-chloro-6.11-dihydro-5H-benzo [5.6] cycloheptap .2- blpiridin-1 (S) -yl) -2 (R) - [[2- [2- (R ) -1 H-imidazol-1-yl) ethyl] -1-piperidgyl] carbonylj-1-piperazinecarboxylate Isomer 2 The diastereomeric mixture was separated from the compounds of Example 4 (0.154 g) using chiral HPLC on a Chiralpak AD® analytical column using hexane: iso-propanol: diethylamine :: 85: 15: 0.2 as eluent to provide first isomer 1 (0.0376 g): HRFABMS: m / z 645.3305 (MH +) (calculated MH + for C36H4ßN6? 3CI: m / z 645.3320); dH (CDCl 3) 4.30 (1 H, s, Hn), 6.69, 7.00, 7.08, 7.11, 7.16, 7.18, 7.42, 7.J0, 8.32 ppm (9H, s and m, Ar-H and Im-H); dc (CDCl 3) CH 2: 18.9, 23.6, 23.6, 24.8 / 25.1, 25.5, 28.0 / 28.2, 30.7 / 30.8, 30.9, 31.4, 31.8, 31.8, 42.7, 43.9 / 44.2, 50.9, 52.7; CH: 49.9 / 50.5, 52.3, 73.6, 79.3 / 79.9, 119.1 / 119.3, 123.3, 126.0, 128.7, 132.8, 137.1, 139.0 / 139.3, 146.3 / 146.9; C: 134.0, 135.1, 136.4, 141.8 / 142.0, 156.1, 157.0 and 170.1; [a] D20 ° c 0 ° (c = 6.89 mg / 2 ml, MeOH) and then isomer 2 (0.0867 g): HRFABMS: m / z 645.3305 (MH +) (calculated MH + for C36H46N6O3CI: m / z 645.3320); dH (CDCl 3) 4.34 (1H, s, Hn), 6.93, 6.99, 7.06, 7.12, 7.17, 7.21, 7.43, 7.70 and 8.33 ppm (9H, s and m, Ar-H and Im-H); dc (CDCl 3) CH 2: 19.1, 23.5, 23.5, 24.7 / 24.8, 25.5, 28.9, 30.6 / 30.8, 31.5, 31.7, 31.7, 36.J, 40.4, 42.8, 44.1, 50.5, 52.5; CH: 45.9, 52.3, 73.7, 79.2 / 79.4, 119.4, 123.4, 126.0, 128.1, 130.7, 132.7, 137.1, 139.4, 146.3 / 146.9; C: 134.1, 135.1, 136.6, 142.0, 156.1, 157.0 and 170.2; [a] D20 ° C -44.1 ° (c = 10.05 mg / 2 ml, MeOH). An overlay was also obtained which consisted of a mixture of isomer 1 and isomer 2 (0.0196 g).

PREPARATIVE EXAMPLE 72 2 (R / S) -2- (1 H -methylimidazol-1 -yl) etii] piperidine Step A 1 N-tert-butoxycarbonyl-2- (R / S) - [2- (1 H-4/5-methylimidazol-1-yl) ethyl] piperidine 4-Methylimidazole (6.46 g, 78.64 mmol) was dissolved in anhydrous DMF (300 ml) and 95% sodium hydride (1987 g, 86.5 mmol) in portions over 0.25 hours to the stirred solution at 25 ° C under argon. The mixture was stirred at 1.5 hours. A solution of 1-tert-butoxycarbonyl-2 (R / S) - (2-methanesulfoniioxyethyl) -piperidine (21.97 g, 71.49 mmol) (prepared as described in preparative example 57, step B) in DMF was added. anhydrous (70 ml) and the mixture was heated under reflux at 65 ° C for 2.25 hours. The mixture was evaporated to dryness and the residue was taken up in dichloromethane and washed with water, dried (MgSO 4), filtered and evaporated to dryness. The product was chromatographed on silica gel using 1% (10% concentrated NH 4 OH in methanol) -dichloromethane to give a mixture of the title compounds (12.06 g, 58%) (4-Me: 5-Me :: 63: 37): CIMS: m / z 294.25 (MH +); 4-Me: dH (CDCI3) 1.43 (9H, s, CH3), 2.20 (3H, s, lm-4-CH3), 6.63 (1H, s, lm-H5) and 7.35 ppm (1H, s, lm- H2); dc (CDCls) CH3: 13.6, 28.4, 28.4, 28.4; CH2: 19.0, 25.4, 28.7, 31.6, 38.8, 44.1; CH: 48.0, 115.2, 136.1; C: 79.J, 138.3, 155.0 and 5-Me: dH (CDCI3) 1.43 (9H, s, CH3), 2.19, 2.19 (3H, s, lm-5-Me), 6.75 (1H, s, lm- H4) and 7.41 ppm (1H, s, Im-H2); dc (CDCl 3) CH 3: 9.2, 28.4, 28.4, 28.4; CH2: 19.0, 25.4, 28.7, 31.4, 38.8, 42.0; CH: 48.0, 126.9, 136.5; C: 79.7, 138.3, 155.0.

Step B 1-N-tert-butoxycarbonyl ^ -rR / SV ^ -d H-methylimidazol-1-yl) ethyl] piperidine The mixture of compounds from step A above (1.77 g) was dissolved in anhydrous CH 2 Cl 2 (18.6 ml) at 0 ° C under argon atmosphere. Trityl chloride (1.2445 g, 2 equivalents per equivalent of the 5-methyl isomer) was added and the mixture was stirred at 0CC for 2 hours. The reaction mixture was introduced directly onto a column of silica gel and the column was eluted with 50% ethyl acetate in acetone to give the pure 4-methyl isomer (0.6267 g, 56%): 4-Me: dH ( CDCl3) 1.44, (9H, s, CH3), 2.20 (3H, s, lm-4-CH3), 6.64 (1 H, s, lm-H5) and 7.36 ppm (1H, s, lm-H2); dc (CDCl 3) CH 3: 13.7, 28.5, 28.5, 28.5; CH2: 19.1, 25.5, 28.9, 31.7, 39.0, 44.2: CH: 48.1, 115.1, 136.2; C: 79.8, 138.4, 155.1.

Step Q 2 (R / S) - [2- (1 H -4-Methylimidazol-1-yl) ethyl] piperidine The pure 4-methyl isomer (0.7518 g, 2.56 mmole) was deprotected as described in the example Preparation 57, step D, to give, after purification, the title compound (0.4366 g, 88%): FABMS: m / z 194.2 (MH +): dH (CDCl 3) 1.76 (2H, m, CH 2), 2.19 (3H, s, lm-4-CHs), 3.94 (2H, m, CH2-lm), 6.60 (1H, s, lm-H5) and 7.33 ppm (1 H, s, lm-H2); dc (CDCl 3) CH 3: 13.7; CH2: 24.5, 26.6, 32.9, 38.4, 43.6, 46.8; CH: 53.9, 115.2, 136.2; C: 138.4.

EXAMPLE 143 Cyclohexyl 4- (8-chloro-6.11-dihydro-5H-benzo [5.6] cyclohepta [1,2-b] pyridin-11 (S) -ii) -2 (R) -rr2- [2- (R / S) - (4-methyl-1H-imidazol-1-ii) ethyl] -1- piperidinyl] carbonyl] -1-piperazinecarboxylate 4- (8-Chloro-6,11-dihydro-5H-benzo [5,6] cyclohepta [1,2- b] pyridine-11 (S) -iI) -2 (R) -carboxy-1-piperazinecarboxylate cyclohexyl (0.275 g, 0.568 mmol) (prepared as rt as described in Preparative Example 32), 2- [2 (R / S) - (4-methyl-1 H-imidazol-1-yl) ethyl] piperidine ( 0.1428 g, 0.7386 mmole) (prepared as described in preparative example 2, step C), 1- (3-dimethylamino-propyl) -3-ethylcarbodiimide hydrochloride (10.1416 g, 0.7386 mmole), 1-hydroxybenzotriazole (0.0998 g, 0.7386 mmole) and 4-methylmorpholine (0.0812 ml, 0.7386 mmoles) were dissolved in anhydrous DMF (12.2 ml) and the mixture was stirred at 25 ° C for 212 hours under argon atmosphere. The solution was evaporated to dryness and taken up in dichloromethane and washed with 1N NaOH. The aqueous layer was extracted 3 times with dichloromethane (200 ml) and the combined organic layers were dried (MgSO 4), filtered and evaporated. The product was chromatographed on silica gel using 2% (10% concentrated NH 4 OH in methanol) -dichloromethane as eluent to give the title compound (0.149 g, 40%): FABMS: m / z 659.62 (MH +).

EXAMPLE 144 (-) - Cyclohexyl 4- (8-chloro-6.11-dihydro-5H-benzo [5.6] cycloheptan [1,2- b] pyridin-11 (S) -yl) -2 (R) - [[2- [ 2- (S) -4-methyl-1 H-imidazol-1-yl) ethyl-1-piperidinyl carbonyl] -1-piperazinecarboxylate Isomer 1 (-) - Cyclohexyl 4- (8-chloro-6.11-dihydro-5H-benzor5.6] cycloheptaf1.2- b] pyridin-11 (S) -yl) -2 (R) - [[2- (2- (R) - (4-metll-1 H-imidazol-1-yl) ethyl] -1-piperidSnyl] carbonyl] -1-piperazinecarboxylate Isomer 2 The diastereoisomeric mixture of the compounds of Example 6 (0.145 g) was separated using chiral HPLC on an analytical column Chiralpak AD using hexane: iso-propane !: diethylamine :: 70: 30: 0.2 as eluent to first provide the isomer 1 (0.0475 g): FABMS: m / z 659.4 (MH +); dH (CDCl3) 1.66 (2H, m, CH2), 2.23 (3H, s, lm-4-CH3), 3.71 (2H, m, CH2-lm), 4.32 (1H, s, Hn), 6.58, 6.72, 6.75, 7.10, 7.14, 7.20, 7.41, 7.60 and 8.34 ppm (9H, sym, Ar-H and Im-H); dc (CDCl 3) CH 3: 13.4 / 13.7; CH2: 18.9, 23.5, 23.5, 24.2 / 25.1, 25.5, 28.1, 30.J, 30.8, 31.4, 31.8, 31.8, 36.7, 42.4 / 42.6, 43.8 / 44.1, 50.5 / 50.8, 52.8; CH: 49.8, 52.3, 73.6, 79.3 / 80.0, 115.5 / 115.8, 123.3, 126.0, 130.6 / 130.8, 132.8, 136.0, 139.2 / 139.3, 146.3; C: 134.0, 135.0 / 135.1, 136.2 / 136.5, 137.8, 141.8 / 142.0, 156.1, 157.0, 170.1, [a] D20 ° C -4.3 ° (c = 8.07 mg / 2 ml, MeOH), and then the 2-isomer (0.852 g): HRFABMS: m / z 659.3492 (MH +) (calculated MH + for C37H48N6O3C !: m / z 659.3476); dH (CDCl3) 1 -64 (2H, m, CH2), 2.22 (3H, s, lm-4-CH3), 3.72 (2H, m, CH2-lm), 4.35 (1H, s, Hn), 6.61, 6.67, 7.12, 7.17, 7.22, 7. 43, 7.57 and 8.35 ppm (9H, s and m-Ar-H and Im-H); dc (CDCl 3) CH 3: 13.3 / 13.5; CH2: 19.1, 23.5, 23.5, 24J, 25.5, 28.7 / 28.9, 30.6, 30.8, 31.5, 31 J, 31.7, 40.3, 42.1 / 42.8, 44.1 / 44.2, 50.5 / 50.7, 52.6 / 52.7; CH: 46.0 / 46.2, 52.5, 73.7, 79.3 / 79.4, 115.6 / 115.8, 123.4, 126.0, 130.7, 132.7, 136.0 / 136.2, 139.4, 146.3; C: 134.1, 135.1, 136.2 / 136.6, 137.2, 142.0, 156.1, 157.1, 170.3; [a] D20 ° C -44.7 ° (c = 9.0 mg / 2 ml, MeOH).

PREPARATIVE EXAMPLE 73 2 (R / S) ~ [3- (1 H-imidazol-1-yl) propyl] piperidine Step A 1N-tert-butoxycarbonyl-2- (R / S) - [3- (1 H-imidazol-1-yl) propyl] piperidine The title compound of Preparative Example 58, Step C, (1.29 g, 4.3 mmol) was dissolved in anhydrous DMF (15 mL). Sodium imidazole (0.3215 g, 4.7 mmol) was added and the mixture was stirred at 25 ° C under argon atmosphere for 3 hours. The solution was evaporated to dryness and the residue was chromatographed on silica gel using 2% (10% concentrated NH 4 OH in methanol) -dichloromethane as eluent to give the title compound (0.6813 g, 72%): CIMS: m / z 294.25 (MH +); dH (CDCl3) 1.43 (9H, s, CH3), 3.97 (2H, m, CH2-lm), 6.90 (1 H, s, lm-H5), 7.04 (1H, s, lm-H4) and 7.45 ppm ( 1H, s, lm-H2); dc (CDCl 3) CH 2: 28.4, 28.4, 28.4; CH2: 18.9, 25.4, 26.3, 27.7, 28.6, 38.8, 46.5; CH: -49.0, 118.6, 129.4, 137.1; C: 79.3, 155.0.

Stage B 2 (R / S) - [3- (1 H-imidazol-1 -Dpropiljpiperidine The title compound from step A above (0.6075 g, 2.1 mmol) was deprotected as described in preparative example 57, step D, and chromatographed on silica gel using 10% (10% concentrated NH 4 OH in methanol) - dichloromethane as eluent to give the title compound (0.3805 g, 95%): CIMS: m / z 194.20 (MH +); dH (CDCl3) 3.89 (2H, m, CH2-lm), 6.84 (1 H, s, Im-Hs), 6.99 (1H, s, Im-H) and 7.41 ppm (1 H, s, lm-H2); dc (CDCl 3) CH 2: 24.9, 26.7, 27.2, 33.1, 34.4, 47.2, 47.2; CH: 56.4, 118.8, 129.6, 137.1.

EXAMPLE 145 1.1 -Dimethyl 4- (3-bromo-8-chloro-6.11-dihydro-5H-benzo [5.6] cyclohepta [1,2-b] pyridin-11-yl) -2 (R) - [[2- [3 -1 H-imidazol-1-yl) propyl] -1-piperidinyl] carbon.] - 1 • piperazinecarboxylate Isomer 1, 2, 3 and 4. 1,1-Dimethylethyl 4- (3-bromo-8-chloro-6,11-dihydro-5H-benzo [5,6] cyclohepta [1,2-b] pyridine was dissolved. -11-yl) -1 (R) -carboxy-1-piperazinecarboxylate (0.7225 g, 1.3 mmol) (prepared as described in Preparative Example 6), the title compound of Preparative Example 8, Step B (0.3382 g) , 1.7 mmoles), 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (0.3354 g, 1.7 mmol), 1-hydroxybenzotriazole (0.2364 g, 1.7 mmol) and 4-methylmorpholine (0.192 mL, 1.7 mmol) in anhydrous DMF (3 mL) and the mixture was stirred under argon at 25 ° C for 319 hours. The solution was evaporated to dryness and the residue was taken up in dichloromethane and washed with saturated aqueous sodium bicarbonate, water, dried (MgSO 4), filtered and evaporated to dryness. The residue was chromatographed on silica gel using 3% (10% concentrated NH 4 OH in methanol) -dichloromethane as eluent to provide the partially purified title compounds.

The appropriate fractions were chromatographed using 1.5% (10% concentrated NH 4 OH in methanol) -dichloromethane as eluent to give the title compound as a mixture of 4 diastereomers (0.3718 g, 39%): FABMS: m / z 711.4 ( MH +); dH (CDCI3) 1.39 (9H, s, CH3), 6.91, 7. 08, 7.13, 7.17, 7.7.56, 7.67 (Ar-H), 6.97 (1H, s, lm-H5), 7.04 (1H, s, lm-H4), 7.58 (1 H, s, lm-H2) and 8.38 ppm (1 H, m, Ar-H2); dc (CDCl 3) CH 3: 28.3 / 28.4, 28.3 / 28.4, 28.3 / 28.4; CH2: 18.9, 24.9 / 25.0 / 25.5, 26.8, 30.2, 30.5, 36.2, 40.1, 42.7 / 43.0, 46.5 / 46.7, 50.1 / 50.3 / 50.7, 52.7 / 52.9; CH: 46.9, 51.6 / 52.0, 78.5, 119.0, 126.2 / 126.3, 128.6, 130.8 / 130.9, 132.6, 137.0, 141.5, 146.9 / 147.2; C: 80.2, -120.1, 134.3, 134.9, 137.6, 140.8, -155.1 / 156.1, -156.8, -170.3. A portion of the diastereomeric mixture (0.28 g) was subjected to chiral HPLC on a Chiralpak® AD column using hexane: isopropanol: diethylamine :: 86: 15: 0.2 as eluent to provide only partial separation. Isomer 1 (0.0604 g) was obtained while isomers 3 and 4 (0.0376 g) were obtained in the form of a 97% pure mixture. The remaining overlapping cuts could not be separated. Isomer 1 HRFABMS: m / z 711.2429 (MH +) (Caled.

C35H45N6O3B1-CI: m / z 711.2425); dH (CDCl 3) 1.41 (9H, s, CH 3). 4.29 (1 H, s, H11), 6.92, 7.14, 7.18, 7.20 (Ar-H), 6.98 (1H, s, Im, H5), 7.08 (1H, s, lm-H4), 7.58 (1H, s , lm-H2), 7.63 (1H, s, Ar-H4) and 8.38 ppm (1 H, s, Ar-H2); dc (CDCl 3) CH 3: 28.3, 28.3, 28.3; CH2: 18.9, 24.7, 25.4, 26.7, 28.8, 30.3, 30.5, 40.2, 43.1, 46.6, 50.6 / 50.7, 52.6; CH 46.9 / 47.1, 52.1, 78.5 / 78.6, 119.1, 126.3, 128.3, 130.9, 132.6, 136.9, 141.5, 146.9 / 147.2; C: 79.7 / 80.2, 120.2, 133.6, 134.2, 136.9, 136.9, 155.1, 156.7, 170.2; [α] D20 ° C -22.2 ° (c = 6.74 mg / 2 ml, MeOH). Isomers 3 and 4: FABMS: m / z 711.3 (MH +); dH (CDCI3) 1.39, 1.42 (9H, s CH3), 4.27, 4.29 (1 H, s Hn), 6.85, 6.91, 7.05, 7.12-7.18, 7.43 (Ar-H), 6.98 (1 H, s, Im -Hs), 7.08 (1H, s lm-H4), 7.56 (1 H, s, lm-H2), 7.60, 7.71 (1H, s, Ar-H4) and 8.38 ppm (1 H, s, Ar-H2) ); dc (CDCl 3) CH 3: 28.3 / 28.4, 28.3 / 28.4, 28.3 / 28.4; CH2: 18.8, 25.2, 25.3, 26.8, 28.6, 30.2, 30.4 / 30.5, 36.4, 42.8, 46.6, 50.5, 52.7 / 53.3; CH: 46.9 / 47.2, 51.6 / 52.2, 78.5 / 78.6, 119.2, 126.2, 128.6, 103.7 / 130.8, 132.6, 137. 0, 141.5, 146.9; C: 80.1, 80.1, 120.0, 134.4, 134.8, 137.5 / 137.6, 141.0, 156. 1, 156.6, 156.6, 170.0 / 170.2, 170.0 / 170.2 PREPARATIVE EXAMPLE 74 4-f3- (1H-imidazol-1-y.) Propyl] piperidine Step A 1N-tert-butoxycarbonyl-4- [3- (1 H-imidazol-1-yl) propyl] piperidine The title compound of Preparative Example 59, Step C, (1.39 g, 3.5 mmol) was dissolved in anhydrous DMF (10 mL) and sodium imidazole (0.3464 g, 3.85 mmol) was added and the mixture was stirred at 25 ° C. ° C for 3 hours under argon. The solution was evaporated to dryness and the residue was chromatographed on silica gel using 2% (10% concentrated NH4OH in methanoi) -dichloromethane as eluent to give the title compound (0.7637 g, 74%): FABMS: m / z 294.20 (MH +); dH (CDCl3) 1.39 (9H, s, CH3), 3.88 (2H, m, CHz-Im), 6.85 (1H, s, lm-H5), 7.00 (1H, s, lm-H4) and 7.40 ppm (1H , s, Im-Hz); dc (CDCl 3) CH 3: 28.5, 28.5, 28.5; CH2: 28.3, 32.0, 33.3, 33.3, 44.0, 44.0, 47.2, 118.7, 129.5 137.1; CH: 35.7; C: 79.3, 154.8.

Step B 4- [3- (1H-imidazol-1-yl) propyl] piperidine The title compound of preparative example 4, step A above, was deprotected as described in preparative example 57, step D, to provide after chromatography on silica gel using 20% (10% concentrated NH OH in methanol) Dichloromethane as eluent, the title compound (0.4346 g, 95%): CIMS: m / z 194.20 (MH +): dH (CDCl 3) 3.89 (2H, m, CH 2 -lm), 6.88 (1 H, s, Im-Hs), 7.02 (1 H, s, lm-H4) and 7.42 ppm (1 H, s, lm-H2); dc (CDCl 3) CH 2: 28.3, 33.5, 33.5, 34.1, 46.7, 46.J, 4J.4; CH: 36.0, 118.8 129.6 137.2.

PREPARATIVE EXAMPLE 75 2 (R) - [[4- [3- (1 H-imidazol-1 -yl) propyl] -1-piperidinal] carbonyl] piperazine H Step A 1.4-bis-1,1-dimethylethyl 2 (RH443- (1H-imidazol-1-yl) propyl] -1-piperidinyl] carbonyl] piperazine-1,4-bis-carboxylate 1, 4, Di-N-tert-butoxycarbonylpiperazine-2 (R) -carboxylate (0.521 g, 1.6 mmol) (prepared as described in preparative example 2), 1- (3-dimethylaminoprop) hydrochloride were dissolved. ) -3-ethylcarbodiimide (0.393 g, 2.1 mmol), 1-hydroxybenzotriazole (0.0.277 g, 2.1 mmol) and 4-methylmorpholine (0.225 mL, 2.1 mmol), in anhydrous DMF (3 mL) and the mixture was stirred under Argon at 25 ° C for 150 hours. The solution was evaporated to dryness and the residue was taken up in dichloromethane and washed with saturated aqueous sodium bicarbonate, water, dried (MgSO 4), filtered and evaporated to dryness. The residue was chromatographed on silica gel using 3% (10% concentrated NH 4 OH in methanol) -dichloromethane as eluent to give the title compound. (0.693 g, 87%): CIMS: m / z 506.35 (MH +); dH (CDCI3) 1.42 (18 H, s, CH3), 3.91 (2H, m, CH2-lm), 6.88 (1H, s, lm-H5), 7.03 (1 H, s, im-H4) and 7.43 ppm (1 H, s, IM-H2); dc (CDCls) CH3: 28.4, 28.4, 28.4, 28.4, 28.4, 28.4; CH2: 28.4, 31.8, 33.1, 33.1, 41.2 / 41.6, 43.8, 43.8, 45.6, 47.1, -51.0; CH: 35.8, 52.9, 118.7, 129.6, 137.1; C: 80.1, 80.4, 168.1, 168.1, 168.1.

Step B 2 (R -r [4-r 3 - (1 H -midazol-1-yl) propyl-1-piperidinyljcarboni Piperazine The title compound of Preparative Example 5, Step A above (0.6344g, 1.26 mmol) was deprotected as described in Preparative Example 57, Step D, and the product was chromatographed on silica gel using 10% (concentrated NH 4 OH) ai 10% in methanol) -dichloromethane as eluent to give the title compound (0.3076 g, 80%): CIMS: m / z 306.30 (MH +); dH (CDCl 3) 3.87 (2H, m, CH 2 -lm), 6.82 (1H, s, Im H5), 6.99 (1H, s, lm-H4) and 7.38 ppm (1H, s, Im H2); dc (CDCl 3) CH 2: 28.1, 31.7, 32.6 / 32.9, 33.0 / 33.1, 42.0 / 42.2, 45.2 / 45.5, 46.9 / 47.0, 46.9 / 47.0, 46.9; CH: 35J / 35.8, 55.6, 118.7, 129.4, 137.0; C: 169.J.

EXAMPLE 146 4- (3-bromo-8-chloro-6.11-dihydro-5H-benzo [5.6] cyclohepta [1,2-b] pyridin-11 • il) -2 (R) - [[4- [3- (1H -imidazol-1-yl) propyl-1-piperidinyl] carbonyl] piperazine carboxylate 3-Bromo-8,11-dichloro-6,11-dihydro [5,6] cycloheptal [1,2-b] pyridine (0.2043 g, 0.596 mmol) (prepared as described in preparative example 40 ( U.S. Patent 5,719,148)), the title compound of Preparative Example 5, Step B (0.2729 g, 0.894 mmol) and triethylamine (0249 mL, 1.79 mmol) were dissolved in anhydrous THF (8 mL) and anhydrous dichloromethane (20 mL) and The mixture was stirred at 25 ° C for 72 hours under argon. The solution was evaporated to dryness and the residue was chromatographed on silica gel using 3% and then 5% and 10% (10% concentrated NH 4 OH in methanol) - dichloromethane as eluent to give first the dimer (Sch 377314) (0, 0681 g, 12%): SIMS: m / z 916.2 (MH +) 3.99 (4H, m, CH2-lm), 6.95, 7.08, 7.10, 7.12, 7.26, 7.54, 7.69, 8.28, 8.31 and 8.34 ppm (13H, sym, Ar-H and Im-H); dc (CDCls) CH2: 28.3 / 28.5, 30.3 / 30.4, 30.5, 31.3 / 31.5, 33.1, 33.1, 41.0 / 41.1, 41.0 / 41.1, 45.0, 47.5, 51.2 / 51.3 / 52.0, 53.9 / 54.1 / 54.2; CH: 35.7, 78.8 / 79.0, 119.7 / 119.9, 125.9 / 126.0 / 126.2, 128.6 / 128.7, 130.7, 133.8 / 134.1, 136.9 / 137.6, 141.5, 146.7 / 146.9; C: 119.0, 130.0, 132.5 / 133.2, 134.6, 141.1 / 141.3, 156.2, 156.8, 170.0 and monomer (Sch 377318) (0.2291 g, 63%): CIMS: m / z 611.20 (MH +); dH (CDCls) 3.93 (2H, m, CH2-lm), 6.90, 6.92, 7.07, 7.12, 7.14, 7.47, 7.49, 7.57, 7.59, 8.33, 8.35 and 8.38 ppm (8H, sym, Ar-H and Im- H); dc (CDCI3): 28.3, 30.6, 30.6, 31.6 / 31.7 / 31.9, 33.1 / 33.3, 33.1 / 33.3, 41.6 / 42.2, 44.4 / 44.9, 44.4 / 44.9, 45.3 / 45.7, 47.2, 52.2 / 52.7, 55.0; CH: 35.6, 55.4, 78.8, 118.8, 126.2 / 126.3, 129.6, 130.3 / 130.6, 133.0 / 133.2, 137.1, 141.3, 146.9 / 147.1; C.120.1, 134.1, 135.0, 137.2, 141, 1, 154.4 / 155.9, 169.0 / 170.0.

EXAMPLE 147 1.1 -dimethylethyl-4- (3-bromo-8-chloro-6.11-dihydro-5H-benzof5.61cycloheptari, 2-b1-pyridin-11-yl) 2 (R) - [[4- [3- (1H-imidazole -1 - l) propyl] -1-piperidinyl] carbonii] piperazinecarboxylate The title compound of Example 9 (0.1768 g, 0.29 mmol) was reacted with di-tert-butyl dicarbonate (0.0694 g, 0.319 mmol) and sodium hydroxide (0.116 g, 0.29 mmol) in THF-water (1: 1) (5 ml) and purified as described in preparative example 57, to give the title compound (0.1294 g, 63%): FABMS: m / z 711.1 (MH +); dH (CDCI3) 1.38 / 1.40 (9H, s, CH3), 3.98 (2H, m, CH2-lm), 6.93, 7.03, 7.09, 7.18, 7.54, 7.58, 7.63, 8.32 and 8.38 ppm (8H, s and m, Ar-H and Im-H); dc (CDCl 3) CH 3: 28.4, 28.4, 28.4; CH2: 28.3, 30.2, 30.7, 31.3 / 31.8, 33.2, 33.2, 42.2 / 42.6, 44.4 / 45.4, 44.6, 44.6, 47.4, -50.4, -50.9; CH: 35.8, 78.6 / 78.8, 118.9, 126.3, 130.2, 130.8, 132.7, 137.0, 140.7 / 141.5, 147.2; C: 80.0, 119.9, 133.4, 134.0, 137.5, 141.4, 56.2, 156.2, 168.8.

PREPARED EXAMPLE 71A Stage A To the title compound of Preparative Example 8, Step B (1.63 g, 7.57 mmol) in DMSO (5.0 mL) was added iPr2NEt (6.59 mL, 5.0 eq.) Followed by pyr »S? 3 (7.23 g, 3.0 eq. ) in DMSO (10 ml). The resulting solution was stirred for 1 hour, diluted with EtOAc and washed with 1 N HCl, H20 and saturated NaHCO 3. The organics were dried over Na 2 SO 4, filtered and concentrated under reduced pressure. The residue was used without purification (1.26 g, 76% yield): LCMS: MH + = 214.

Stage B NaHMDS (1.47 ml, 1 M in THF, 1.5 eq.) Was added to a solution of CH OCH2P + Ph3Cr (5.06 g, 1.5 eq.) In THF (25 ml) at 0 ° C. The resulting solution was stirred for 15 minutes before being added through a cannula to a solution of the title compound of Preparative Example 71A, Step A (2.1 g, 9.80 mmol) in THF (25 mL) at -78 ° C. The reaction mixture was stirred 1 hour at -78 ° C, warmed to 0 ° C and stirred for 1 hour. The resulting solution was diluted with Et20, washed with H20, and dried over Na2SO4. The organics were dried over Na 2 SO 4, filtered and concentrated. The crude product was purified by evaporative chromatography using a 65:35 hexane EtOAc solution (1.51 g, 64% yield) as eluent.

Stage C The title compound of Preparative Example 71 A, Step B (OX g, 2.90 mmol) in 40% HCl (6.6 mL) was stirred at room temperature overnight at which time additional 40% HCl (3.0 mL) was added. , and the reaction mixture was stirred an additional 4 hours. The resulting solution was neutralized with Na 2 S 3 (aqueous), and extracted with Et 20. The combined organics were dried over Na 2 SO 4, filtered and concentrated in vacuo. The residue was purified by evaporative chromatography using a solution of 65:35 hexanes: EtOAc as eluent (0.30 g, yield 46% + SM): LCMS: MH + = 228 Step D: The title compound of Preparative Example 71 A, Step C (0.90 g, 1.02 eq) was stirred with TosMIC (OJJ g, 3.88 mmol) and NaCN (0.0194 g, 0.1 eq.) In EtOH (7.0 ml) for 30 minutes. The reaction mixture was transferred to a sealed tube, diluted with 7M NH3 in MeOH (13.0 ml) and heated at 90 ° C for 22 hours. The resulting solution was cooled, concentrated under reduced pressure, diluted with 1 N NaOH, and extracted with CH2Cl2. The combined organics were dried over Na2SO2, filtered, and concentrated. The crude product was purified by evaporative chromatography using a 5% solution (10% NH 4 OH in MeOH) in CH 2 Cl 2 as eluent (0.53 g, 51% yield): LCMS: MH + = 266.

Stage E The title compound for preparative example 71 A, step D, (0.34 g, 1.28 mmol) in CH2CI2 was treated with TrCI (0.38 g, 1.05 eq.) And TEA (0.27 ml, 1.5 eq.). The resulting solution was stirred for two hours at room temperature, diluted with saturated NaHCO 3, and extracted with CH 2 Cl 2. The combined organics were dried over Na 2 SO 4, filtered, and concentrated in vacuo. The crude product was purified by evaporative chromatography using a 3% solution (10% NH 4 OH in MeOH) in CH 2 Cl 2 as eluent (0.43 g, 66%). LCMS: MH + = 508.

Stage F The title compound of Preparative Example 7A, Step E (0.43 g, 0.846 mmol) in Et20 was treated with Mel (0J9 mL, 15 eq.) And stirred overnight and filtered. The resulting solid was washed with Et20, dissolved in MeOH and heated to reflux overnight. The reaction mixture was concentrated in vacuo and purified by evaporative chromatography using a 5% solution. (10% NH 4 OH in MeOH) in CH 2 Cl 2 as eluent (0.14 g, 79% yield): LCMS: MH + = 280.

PREPARED EXAMPLE 72A By essentially the same procedure indicated in Preparative Example 71 A, the title compound was prepared.

PREPARATIVE EXAMPLE 73A Stage A A solution of e-caprolactam (6.86 g, 60 mmol, 1.0 eq.) In anhydrous THF (50 ml) was added dropwise over a period of 50 minutes to a stirred suspension of sodium hydride (1.59 g, 1.05 eq.) in anhydrous THF (20 ml) at 0 ° C under nitrogen atmosphere. The white-colored mixture was stirred at room temperature for 2 hours, after which a solution of benzyl bromide (7.65 ml, 1.05 eq) in anhydrous THF (20 ml) was added dropwise over a period of 30 minutes. The mixture was stirred at room temperature for 2 hours and then filtered through CELITE 521 to remove the sodium bromide. The volatiles were evaporated under vacuum at 30 ° C to provide the title compound as a dark yellow oil which was used without further purification (10.60 g, 87% yield). FABMS: MH + = 204.

Stage B A solution of 2.45 M n-butyllithium in hexanes (18.1 ml, 44.3 mmoles, 1.44 eq.) Was added dropwise over a period of 30 minutes to a stirred solution of diisopropylamine (5.2 ml, 36.9 mmoles, 1.2 eq) in THF anhydrous (100 ml) at 0 ° C under nitrogen atmosphere. The yellow solution was stirred at 0 ° C for an additional 30 minutes and then cooled to -78 ° C. Subsequently, a solution of the title compound of Preparative Example 73A, Step A (6.25 g, 1.0 eq) in anhydrous THF (50 mL) was added dropwise over a period of 25 minutes and the solution was stirred at -78 ° C for 3 minutes. more hours Chloromethylbenzyl ether alone (7.0 ml, 1.3 eq.) Was added dropwise in a period of 10 minutes. The dark brown solution was heated slowly (3 hours) at room temperature, stirred for a further 12 hours. The volatiles were extracted under vacuum at 30 ° C. The residual dark yellow oil was divided between distilled water (100 ml) and diethyl ether (100 ml). The layers were separated and the aqueous phase was extracted with diethyl ether (5 x 50 ml). The organic layer of the first extracts and the ethereals were combined and washed with brine (50 ml), dried over Na 2 SO 4, filtered, and concentrated in vacuo at 30 ° C. The oily residue was chromatographed by evaporative chromatography (hexanes: acetone = 8: 2 v / v) on silica gel to give the title compound as a milky green oil (6.77% g, 68% yield). [M + H +]: 324; HRMS (FAB +): Calculated for C21H26N02 ([M + H] +): 324.1961; Observed: 3324, 1964.

Stage C A 1M solution of lithium aluminum hydride in diethyl ether (23 ml, 1.1 eq.) Was added dropwise over a period of 25 minutes to a stirred solution of the title compound of preparative example 73a, step B (6J7 g, 20.9 mmoles) in anhydrous THF (100 ml) at -20 ° C under nitrogen atmosphere. The yellow solution was slowly heated (3 hours) to room temperature and stirred for 12 hours. The solution was cooled to 0 ° C and carefully treated with a saturated aqueous Na 2 S 4 solution (10 ml) to give a white, flush suspension. The mixture was filtered and the precipitate was carefully washed with diethyl ether (3 x 50 ml) and absolute alcohol (3 x 50 ml). The filtrate was concentrated under vacuum at 30 ° C, redissolved in acetone (100 ml) and dried over Na 2 SO 4, filtered and concentrated again under vacuum at 30 ° C. The oily residue was chromatographed by evaporative chromatography (hexanes: acetone = 9: 1 v / v) on silica gel to give the title compound as a milky green oil (5.08 g, 78% yield): [M + H ] +: 310; HRMS (FAB +): Calculated for C2? H28NO ([M-H] +): 310.2173; Observed: 310.2171.

Stage D A mixture of the title compound for preparative example 73A, step C (5.08 g, 16.4 mmoles) 20 wt% of Pd (OH) 2 ("Pearlman's catalyst," 2.54 g, 50 wt% reagent), and alcohol Absolute (100 ml) was hydrogenated under a pressure of 4.5 atmospheres and at room temperature for 8 hours. The mixture was filtered through CELITE 521 and the filtrate was concentrated under vacuum at 30 ° C. The residual oil was chromatographed by evaporative chromatography (CH2Cl2: 10% NH4? H-MeOH = 9: 1 v / v) on silica gel to give the title compound as a yellow oil (2.86 g, yield 79). %): [M + H] +: 220; HRMS (FAB +): Calculated for C? 4H22NO ([M + H] +): 220.1698; Observed 220.1701.

Stage E Potassium metal (2.60 g, 5.0 eq.) Was added portionwise to a stirred solution of the title compound for preparative example 73A, step D (2.86 g, 13.0 mmol) and t-butanol (1.5 ml, 1.2 eq.) in a mixture of liquefied ammonia (125 ml) and anhydrous THF (125 ml) at -60 ° C under nitrogen atmosphere. The dark blue mixture was slowly heated (12 hours) to room temperature and the volatiles were removed under vacuum at 30 ° C. The residue was taken up in distilled water (50 ml) and extracted with diethyl ether (5 x 50 ml). The ether extracts were discarded and the aqueous layer was concentrated in vacuo at 50 ° C to give the title compound (1.70 g, 100% crude yield): [M + H] +: 130; HRMS (FAB +): Calculated for C7H16NO ([M + H] +): 130.1232; Observed; 130.1231.

Stage F By essentially the same procedure as indicated in preparative example 7, step C, up to step F, replacing only the title compound of preparative example 73A, step F, the title compound was prepared.

PREPARED EXAMPLE 74A Stage A Di-isopropyl azodicarboxylate (0.54 ml, 1.5 eq.) Was added to Nt-butoxycarbonylpiperidin-3-ol (0.37, 1.83 mmoles), 3-hydroxypyridine (0.26 g, 1.5 eq.) And PPh3 (0.72 g, 1.5 eq. ) in THF (5.0 ml). The resulting solution was stirred at room temperature overnight, concentrated in vacuo and purified by evaporative chromatography using 30% hexanes in an EtOAc solution as eluent (0.14 g, 27% yield): LCMS: MH + = 279.

Stage B H By essentially the same procedure indicated in Preparative Example 8, the title compound was prepared.

PREPARED EXAMPLES 78B AND 74C The title compound of Preparative Example 74A was separated into the individual C-3 isomers by preparative HPLC using a CHIRALPAK AD column using 20% PrOH in hexanes with 0.2% DEA as eluent.

PREPARED EXAMPLE 74A First eluent isomer: LCMS: MH + = 279.

PREPARED EXAMPLE 74B Second eluent isomer: LCMS: MH + = 279.

PREPARED EXAMPLE 74C 2HCl Essentially by the same procedure indicated in preparative example 8 substituting only the title compound of preparative example 74A, the title compound was prepared. By essentially the same procedure indicated in Preparative Example 74A, the title compounds were prepared in column 4 of Table 16 using the 3-hydroxypyridine derivative in column 2 of Table 16.

TABLE 16 PREPARATORY EXAMPLE 77 Stage A Essentially by the same procedure indicated in preparative example 73A, step A, the title compound was prepared: LCMS: MH + = 190.

Stage B To a solution of the title compound of Preparative Example 77, Step A (3.68 g, 2.4 eq.) In THF (50 mL) was added LiHMDS (19.4 mL, 2.4 eq., 1 M solution in THF) at -78 ° C. . The resulting solution was stirred at -78 ° C for 2.5 hours in which 3-bromomethyipyridine hydrobromide (1.39 g, 8.09 mmol) was added. The reaction mixture was slowly warmed to room temperature and stirred overnight. The resulting solution was diluted with saturated NH 4 Cl (20 mL), extracted with CH 2 Cl 2 (3x 75 mL), dried over Na 2 SO 4, filtered and concentrated to give a yellow oil (0.63 g, 28% yield): LCMS : MH + = 281.

Stage C To a solution of the title compound of Preparative Example 77, Step B (0.65 g, 2.31 mmol) in THF (3.0 mL) was added LAH (2.54 mL, 1M in Et20) and the resulting solution was stirred at room temperature during the night. The reaction mixture was quenched by the addition of saturated Na 2 SO 4, filtered through Celite and concentrated under reduced pressure. The product was purified by evaporative chromatography using 20% hexanes in an EtOAc solution as eluent to give a yellow oil (0.42 g, 68% yield): LCMS: MH + = 267.

Stage D The title compound of preparative example 77Step C (0.40 g, 1.50 mmol) in dichloroethane (3 ml) was treated with 1-chloroethyl chloroformate (0.37 ml, 2.3 eq.). The resulting solution was stirred for 3 hours, concentrated under reduced pressure, diluted with MeOH, and heated to reflux for 3 hours. The reaction mixture was cooled, concentrated under reduced pressure, and purified by evaporative chromatography using a 10% solution of (10% NH 4 OH in MeOH) in CH 2 Cl 2 as eluent (0.20 g 63% yield): LCMS: MH + = 177 .

PREPARED EXAMPLE 78 Stage A To a solution of (S) -1-benzyl-2-pyrrolidinemethanol (15.5 g, 81.03 mmol) and TEA (16.38 g, 161.93 mmol) in CH2Cl2 (200 mL) was added MsCI (11.13 g, 97.16 mmol) at 10 °. C and was stirred at room temperature overnight. It was washed with H20 and evaporated to dryness to give mesylate (15.6 g) which was mixed without further purification with NaCN (5.64 g, 115 mmol) and heated at 80 ° C in DMF (100 ml) overnight. The reaction mixture was evaporated to dryness and extracted with EtOAc, washed with H2O, and dried (MgSO4). The solvent was evaporated to give (S) -1-benzyl-2-cyanomethyl-pyrrolidine (11.5 g): (MS, MH + = 201.

Stage B P The title compound of Preparative Example 78, Step A, (13.0 g) was refluxed in concentrated HCl (100 mL) overnight, and evaporated to dryness. The semisolid residue was stirred in MeOH (100 ml), MgSO 4 (5 g), and concentrated H 2 S 4 (2 ml) at 80 ° C overnight. The reaction mixture was evaporated to dryness to give (S) -1-benzyl-methyl-2-pyrrolidinacetate acetate (11.5 g): MS, MH + = 234.

Stage C The title compound of Preparative Example 78, Step B (13 g, 55.76 mmol) was dissolved in THF (100 mL) and cooled to 10 ° C (ice bath). 1M LAH in ether (111.52 ml, 111.46 mmole) was slowly added and the resulting mixture refluxed for 2 hours. The reaction mixture was cooled to room temperature and decomposed with the addition of ice. The residue was extracted with EtOAc and washed with brine and H20. The organics were dried and evaporated to a residue which was chromatographed by evaporative chromatography on a silica gel column in CH2Cl2 / 5%.

CH 3 OH to give (S) -benzyl-hydroxyethyl-pyrrolidine (7.8 g): MS, MH + = 206.

Stage D P The title compound of Preparative Example 78, Step C (7.7 g) in EtOH (80 mL) was dissolved and hydrogenated over Pd (OH) 2 (2.5 g) at room temperature at 50 psi overnight. The catalyst was filtered and the solvent was extracted to give (S) -2-hydroxyethyl-pyrrolidine (4.4 g): MS, MH + = 116.

Stage E The title compound of Preparative Example 78, Step D (2.4 g, 20.85 mmoies) was dissolved in CH2Cl2 (250 mL) and cooled to 10 ° C. TsCl (11.92 g, 62.52 mmol) was added followed by TEA (10.54 g, 104.2 mmol) and stirred at room temperature overnight. The reaction mixture was diluted with CH2Cl2 and washed with brine and H20. The organics were dried and the solvent was evaporated to give (S) -tosii-2-0-tosylethyl-pyrrolidine (3.96 g): MS, MH + = 332 Step F The title compound of preparative example 78, step E (3.96 g, 9.2 mmol) was dissolved in DMF (15 ml) and cooled to 10 ° C. NaH (0.J4 g, 60%, 18.43 mmol) was added slowly and stirred at room temperature until a clear solution was obtained. Then 4-methyl-imidazole (1.51 g, 18.43 mmol) was added and heated at 80 ° C overnight. The resulting solution was evaporated to dryness and the residue was extracted with CH2Cl2 and washed with brine and H2O. The combined organics were dried and the solvent was evaporated to give a crude product which was chromatographed by evaporative chromatography on a column of silica gel in CH2Cl2 / 5% (CH3OH-10% NH4OH) to give a mixture of (S) -tosyl -2- (4-methyl-1 H-imidazole) -ethyl-1-pyrrolidine (2.98 g, MS, MH + = 334) and (S) -tosyl-2- (5-methyl-1H-imidazole) -eitl- 1-pyrrolidine (2.98 g): MS. MH + = 334.

Stage G The title compound of 78, step F (2.9 g) and trityl chloride (1.5 g) were stirred in CH2Cl2 (35 ml) at 10 ° C overnight. The reaction mixture was chromatographed by evaporative chromatography on a column of silica gel in acetone / ethyl acetate (1: 1) to give (S) -tosyl-2- (4-methyl-1H-imidazole) -ethyl-1 -pyrrolidine (0.827 g): (MS, MH + = 334).

Stage H The title compound of preparative example 78, step G (0.82 g) was dissolved in dry THF (2 ml) and liquid ammonia (150 ml). Pieces of sodium were added until the blue color remained and the resulting solution was stirred for half an hour. EtOH was added by dripping until the blue color disappeared. The resulting solution was evaporated to dryness to provide a white sticky solid which was chromatographed on an evaporative column with silica gel in CH2Cl2 / 20% (CH3OH-10% NH4OH) to give the title compound (S) -2- ( 4-methyl-1 H-imidazole) -ethyl-1-pyrroiidine, (0.375 g): MS. MH + = 180.

PREPARED EXAMPLE 79 By essentially the same procedure indicated in Preparative Example 78, (R) -2- (4-methyl-1H-imidazole) -ethyl-1-pyrrolidine was prepared from (R) -1-benzyl-2-pyrrolidinemethanol.

EXAMPLE PREPARATION 80 Stage A The title compound of Preparative Example 68, Step C, was treated with D - (-) - tartaric acid and recrystallized from acetone-water to provide a piperidine salt enriched in 3- (S) isomer which was neutralized with hydroxide to provide the title compound (11.1 g, 18%): MH + = 172.

Stage B Following the procedures indicated in preparative example 7, step BE, except that the title compound of preparative example 80, step A, was used in place of the title compound of preparative example 7, step A, in step B, and using 4-methylimidazole and NaH in place of sodium imidazole in step E, the regioisomeric imidazole products (1.1 g, 84%) were obtained: MH + = 294.

Stage C Following the procedure indicated in Preparative Example 17, except that the title compound of Preparative Example 80, Step B was used in place of the title compound of Preparative Example 13, the product 4-methylimidazole (0.501 g, 68%) was obtained. : MH + = 294.

Stage D Following the procedure indicated in the preparative example 68, step C, except that the title compound of Preparative Example 80, Step C was used, the amine was obtained in the form of its TFA salt (0.72 g, 100%): MH + = 194.

PREPARED EXAMPLE 81 Following essentially the same procedures indicated in preparative example 80, steps AD, except that L - (+) - tartaric acid was used in place of D - (-) - tartaric acid in step A, the amine enriched in isomer was obtained 3- (R) in the form of its TFA salt (0.157 g, 100%): MH + = 194.

PREPARED EXAMPLE 82 Stage A Following essentially the same procedure indicated in preparative example 80, steps A, except that benzylpiperidine prepared as described in J. Med. Chem. 41, 2439 (1998) was used in place of the title compound of preparative example 68, Step C, the amine enriched in enantiomer 3- (S) (6.81 g, 25%) was obtained: MH + = 248.

Stage B Following the procedures indicated in preparative example 80, steps BD, except that the title compound of preparative example 82, step A was used, instead of the title compound of preparative example 80, step A, in step B, was obtained the 4-methylimidazole product in the form of its TFA salt which was neutralized with NaOH (aqueous) to give the amine product (0.163 g, 86%): MH + = 270.

PREPARED EXAMPLE 83 Stage A The epoxide (J. Med. Chem. 30 (1), 1987, pp. 222-225) was treated with 4-methylimidazole and NaH in anhydrous DMF to obtain the resulting mixture of regioisomeric imidazole products (7.77 g, 100%). : MH + = 302.

Stage B The product from preparative example 83, step A with H2, Pd (OH) 2 / C and EtOH, was treated in a Parr hydrogenator to provide the amine as a mixture of imidazole regioisomers which were used directly for stage C.

Stage C Following the procedure indicated in preparative example 7, step C, except that the title compound of preparative example 83 was used, step B instead of the title compound of preparative example 7, step B, the BOC derivatives of the products were obtained. Regimisomers of methylimidazole (5.4 g, 87%): MH + = 296.

Stage D Following the procedure indicated in Preparative Example 17, except that the title compound of Preparative Example 83, Step C was used in place of the title compound of Preparative Example 13, the 4-methylimidazole products were obtained in the form of an enantiomeric mixture. (1.03 g, 43%): MH + = 296.

Stage E Following the procedure indicated in Preparative Example 68, Step C, except that the title compound of Preparative Example 83, Step D was used, the amine was obtained in the form of its TFA salt (6.3 g, 100%): MH + = 197 PREPARATORY EXAMPLE 84 Stage A S.s-dioxide dg N-butoxycarbonyl - [(1-triazolyl-imidazol-5-yl) hydroxymethyl-1-4-thiomorpholinyl] carbonyl] -1-piperazinecarboxylate N-Butoxycarbonyl-thiomorfoiin (3.19 g, 13.5 mmol) was dissolved in 70 mL of THF and cooled to -78 ° C under nitrogen atmosphere. 1.2 equivalents of LDA were added to the reaction mixture and stirred for 20 minutes. 1-N-Trityl-imidazole-4-carboxaldehyde (4.62 g, 13.6 mmol) was dissolved in 70 ml of THF and added to the reaction mixture. After 4 hours the reaction mixture was poured into a saturated solution of NH 4 Cl and extracted with EtOAc three times. The extracts were combined, dried over MgSO4 and the solvent was evaporated under reduced pressure. The crude mixture was chromatographed on a column of silica gel using 1% MeOH / CH2Cl2 to obtain 3.21 g of the title product.

Step B: N-Butoxycarbonyl - [(1-triazolyl-imidazol-5-yl) methylene] -4-thiomorpholinyl] carbonyl] -1-piperazinecarboxylate S-N-butoxycarbonyl [(1-triazolyl-imidazol-5-yl) hydroxymethyl] -4-thiomorpholinyl] carbonyl] -1-piperazinecarboxylate (2.4 g) was dissolved in CH2Cl2 (48 ml). TEA (1.32 ml) and MsCl (0.4 ml) were added and the reaction mixture was stirred under dry nitrogen. After 24 hours, the reaction mixture was added to brine and the product was extracted with CH2Cl2 to obtain 1.56 g of the title product.

Step C S.s-dioxide N-butoxycarbonyl - [(1 H -imidazol-5-yl) methyl] -4-thiomorpholinyl] carbonyl] -1-piperazinecarboxylate S-N-butoxycarbonyl - [(1-triazolyl-ylazol-5-yl) methylene] -4-thomorpholinyl] carbonyl] -1-piperazinecarboxylate (0.68 g) was dissolved in EtOH. 10% Pd / C (0.1 g) was added and the mixture was hydrogenated under a balloon with H2 conditions for 24 hours. The catalyst was filtered and the filtrate was evaporated to obtain 0.3 g of a mixture which was then treated with 1N HCl / Et20 to obtain the HCl salt.

PREPARATORY EXAMPLE 85 Stage A 4-Hydroxymethyl-5-methylimidazole hydrochloride (4 g, 30 mmol) was dissolved in DMF. TBDMSC1 (6.1 g, 45 mmol) and imidazole (5.1 g, 75 mmol) was added and the reaction mixture was stirred at room temperature for 24 hours. The reaction mixture was poured into water and extracted with EtOAc to obtain 7 g of the title product.

Stage B It was dissolved in 10 ml of CH2Cl2, 4-tert.butyldimethylsilyoxymethyl-5-methyl-imidazole (9 g, 40 mmol). TEA (6 mL) and TrCI (11 g, 40 mmol) were added and the reaction mixture was stirred for 6 hours. The reaction mixture was added to the brine, extracted with EtOAc and purified on a column of silica gel to obtain 7.97 g of the title product as a white solid.

Stage C 1-Trityl-4-tert.butylmethylsilyloxymethyl-5-methyl-imidazole (7.92 g, 17 mmol) was dissolved in dry THF and 17 mL of 1 M TBAF in THF was added. The reaction mixture was stirred at room temperature for 3 hours. 10 ml of H20 were added and the precipitate was filtered and dried under vacuum to obtain 5.33 g of the title product.

Step D: N-Butoxycarbonyl - [(1 H-4-methy-imidazol-5-yl) methylene] -4-thiomorpholinyl] carbonyl] -1-piperazinecarboxylate.

By essentially the same procedure indicated in preparative example 84, step 1 to step C, the title compound was prepared.

PREPARATIVE EXAMPLE 85A By essentially the same procedure established in Njoroge et. Al. (J. Med. Chem. (1997), 40, 4290) for the preparation of 3-aminoloratadine substituting only 3-H ketone (J. Het. Chem. (1971) 8, 73) with loratadine, was prepared the title compound.

PREPARED EXAMPLE 86 The title compound of preparative example 85A (1.0 g, 3.87 mmol) was added in portions to t-butyl nitrite (0.69 ml, 1.5 eq.) And CuCI2 (0.62 g, 1.2 eq.) In CH3CN (200 ml) at 0 ° C. The resulting solution was heated slowly to room temperature and stirred for 72 hours. The reaction mixture was quenched with 1N HCl (10 mL), neutralized with 15% NH4OH and extracted with EtOAc (3 x 50 mL). The combined organics were dried over Na 2 SO 4, filtered and concentrated under reduced pressure. The crude product was purified by evaporative chromatography using a mixture of 50:50 EtOAc: hexanes as eluent to give a pale yellow solid (0.72 g, 67% yield). FABMS: MH + = 278.

PREPARATORY EXAMPLE 87 The compound of preparative title 85A (0.72 g, 2.59 mmoies) was dissolved in THF (10 ml) and treated with NaBH 4 (0.13 g, 1.3 eq.). The resulting solution was stirred at room temperature for 1 hour. The reaction mixture was quenched by the addition of 1 N NaOH and the resulting solution was extracted with EtOAc (3 x 50 mL). The combined organics were dried over Na 2 SO 4, filtered and concentrated under reduced pressure to give a tan solid which was used without further purification (0J1 g, 97% crude yield). The crude product was dissolved in toluene (15 ml), cooled to 0 ° C and treated with SOCI2 (0.32 ml, 1.75 eq.). The resulting solution was stirred at 0 ° C for 1 hour and at room temperature for a further 2 hours. The reaction mixture was diluted with CH2Cl2 (30 ml) and washed with 1 N NaOH (20 ml) and the organic layer was dried over NaS? 4, filtered, concentrated and used without further purification (0.76 g, yield). 100 crude).

PREPARED EXAMPLE 88 The title compound of Preparative Example 85A (1.62 g, 6.26 mmol) was added in portions to NO + BF4"(0.81 g, 1.1 eq.) In toluene (10 mL) at 0 [deg.] C. The resulting suspension was stirred at 0 ° C for 2.5 hours before heating to room temperature The reaction mixture was heated to reflux for 2 hours, cooled, neutralized with 1N NaOH and extracted with EtOAc (3x50 ml) The combined organics were washed with 1N HCl (2x25 ml), saturated NaHC 3 (1x25 ml), and water (1x15 ml), dried over Na 2 SO 4, filtered and concentrated under reduced pressure The crude product was purified by evaporative chromatography using a mixture of 70:30 hexanes.?tOAc as eluent to provide a yellow solid (0.68 g, 42% yield) LCMS: MH + = 262.

PREPARED EXAMPLE 89 By essentially the same procedure indicated in Preparative Example 87, the title compound was prepared and used without further purification (0.66 g, 100% yield of the crude product).

PREPARED EXAMPLE 90 + NH 4 HCO 2"(2.44 g, 10 eq.) Was added to a solution of the title compound of Preparative Example 73 A (2.00 g, 7.74 mmol) and 5% Pd / C (0.50 g) in EtOH (100 mL) and The resulting solution was refluxed for 2 hours, the reaction mixture was cooled, filtered through a plug of Celite, and concentrated under reduced pressure.The residue was diluted with H20 (100 ml) and extracted with CH2Cl2. (3x75 ml) The combined organics were dried over Na 2 S 4, filtered and concentrated in vacuo to give a yellow solid (1.22 g, 70% yield), which was used without further purification: FABMS: MH + = 225 .

PREPARED EXAMPLE 91 By essentially the same procedure indicated in preparative example 86, the title compound was prepared (0.81 g, 61% yield): FABMS: MH + = 244.

PREPARED EXAMPLE 92 By essentially the same procedure indicated in Preparative Example 87, the title compound was prepared and used without further purification.

PREPARATIVE EXAMPLE 92A By essentially the same procedure indicated in Preparative Example 86, substituting only CuBr2 for CuCl 2, the title compound was prepared (1.33 g, 60% yield): FABMS: MH + = 244.

PREPARED EXAMPLE 93 By essentially the same procedure indicated in Preparative Example 87, the title compound was prepared and used without further purification.

PREPARED EXAMPLE 94 By essentially the same procedure indicated in Preparative Example 88 by substituting only the title compound of Preparative Example 90, the title compound FABMS: MH + = 228 was prepared.

PREPARED EXAMPLE 95 By essentially the same procedure indicated in preparative example 87, the title compound was prepared.

PREPARED EXAMPLE 96 A solution of 3-peroxybenzoic acid (25 g, 2.5 eq.) In anhydrous dichloromethane (250 ml) over a period of one hour was added dropwise to a stirred solution of 8-chloro-4-aza-10., 11-dihydro-5H-dibenzo [a, d] cyclohepten-5-one (10 g, 41.04 mmoles) in anhydrous CH 2 Cl 2 (100 ml) at 0 ° C under nitrogen atmosphere. The solution was heated slowly (3 h) at room temperature and stirred for a further 12 hours. The solution was extracted with 1 M NaOH (5x100 ml), washed with brine (2x100 ml), dried over Na 2 SO 4, filtered and concentrated in vacuo at 30 ° C to give a yellow-colored solid which was used without purification (10 g, 94% yield): [M + H] +: 260; HRMS (FAB +): Calculated for C14H11CIN02 ([M + Hf): 260.0475 Found 260.0478.

PREPARED EXAMPLE 97 By essentially the same procedure indicated in Preparative Example 87, the title compound was prepared (9.55 g, 99% yield).

PREPARED EXAMPLE 98 The title compound was prepared according to the methods described in U.S. Patent No. 3,419,565.

PREPARED EXAMPLE 99 By essentially the same procedure indicated in preparative example 87, the title compound was prepared (2.4 g, 87% yield).

PREPARATORY EXAMPLE 100 Mel (1.75 mL, 3.0 eq.) Was added to a solution of Cs2CO3 (9.12 g, 3.0 eq.), And the title compound of Preparative Example 4 (3.40 g, 9.33 mmol) in DMF (10 mL). The remaining solution was stirred at room temperature for 4 hours. The reaction mixture was concentrated under reduced pressure, diluted with H20 (50 ml) and extracted with CH2Cl2 (3x50 ml). The combined organics were dried over Na 2 SO 4, filtered, and concentrated in vacuo. The crude product was purified using a mixture of 50:50 EtOAc: hexanes as eluent (1.4 g, 40% yield). FABMS: MH + = 379.

PREPARED EXAMPLE 101 A solution of the title compound of Preparative Example 100 (1.4 g, 3.70 mmol) and 5% Pd / C (0.50 g) in MeOH (20 mL) and 1N HCl (5 mL) was stirred under an atmosphere of H2 during the night. The reaction mixture was filtered through a plug of Celite and concentrated in vacuo to give a white solid (1.02 g, 98% yield) which was used without further purification. FABMS: MH + = 245.

PREPARED EXAMPLE 102 A solution of the title compound of Preparative Example 101 (1.01 g, 3.78 mmol) and TEA (2.63 mL, 5 eq.) In DMF (10 mL) was stirred at room temperature for 30 minutes before adding the title compound of the example Preparatory 87 (1.68 g, 1.5 eq.). The resulting solution was stirred at room temperature overnight and concentrated under reduced pressure. The residue was diluted with saturated NaHCO 3 (25 ml) and extracted with CH 2 Cl 2 (3x50 ml). The combined organics were dried over Na 2 S 4, filtered and concentrated and the crude product was purified by evaporative chromatography using a 3% solution of EtOAc in CH 2 Cl 2 as eluent to give an off white solid (1.1 g, 39% yield): LCMS : MH "" = 506. The individual isomers C-11 (R) - and (S) - were separated by preparative HPLC using a CHIRALPAK AD column employing 15% iPrOH in hexanes with a 0.2% solution of DEA as eluent. Isomer 11 - (R) - (isomer of first elution): FABMS: MH + = 506 [a] D = + 70 ° C (5.0 mg in 2.0 ml MeOH). Isomer 11 - (S) - (isomer of second elution). FABMS: MH + = 506 [a] D = ° (28 mg, in 2.0 ml MeOH).

PREPARED EXAMPLE 103 A solution of the title compound (Isomer C-11 (R)) of Preparative Example 102 (0.465 g, 0.918 mmol) and 1 N NaOH (2.76 mL, 3.0 eq.) In MeOH (15 mL) was heated to reflux for 2 hours. hours. The reaction mixture was cooled, concentrated, diluted with EtOAc (25 mL) and washed with brine (10 mL). The organics were dried over Na 2 SO 4, filtered, and concentrated under reduced pressure to give a white solid (0.45 g, 96% yield): FABMS: MH + = 492; [α] D = + 57.4 ° (5.0 mg in 2.0 ml MeOH).

PREPARED EXAMPLE 104 By essentially the same procedure indicated in Preparative Example 103, the title compound (isomer C-11 (S)) (0.45 g, 96% yield) was prepared: FABMS: MH + = 492: [aJD = + 13.7 ° ( 5.0 mg in 2.0 ml MeOH).

PREPARATORY EXAMPLE 105 By essentially the same procedure indicated in preparative example 102, the title compound (isomer C-11 (R) and (S)) was prepared, only the C-11 (R) - and (S) isomers were separated by chromatography evaporation using a 3% solution of EtOAc in CH2Cl2 as eluent.

PREPARED EXAMPLE 106 Essentially by the same procedure indicated in preparative example 103, the title compounds were prepared (individual isomers C-11 (R) - and (S) -).

PREPARED EXAMPLE 107 Essentially by the same procedure indicated in preparative example 102 substituting only the title compound of Preparative Example 89, the title compound (C-11 (R) -y (S) -) isomers (0.71 g, 57% of yield): FABMS: MH + = 490.

PREPARED EXAMPLE 108 Essentially by the same procedure indicated in preparative example 103, using only the title compounds (C-11 (R) - and (S) -) isomers of Preparative Example 107, the title compound was prepared. The individual C-11 (R) - and (S) - isomers were separated by evaporative chromatography using a 12% solution (10% NH 4 OH in MeOH) in CH 2 Cl 2 as eluent. Isomer C-11 (S) - (isomer of first elution): FABMS: MH + = 476. Isomer C-11 (R) - (isomer of second elution): FABMS: MH + = 476.

PREPARED EXAMPLE 109 Essentially by the same procedure indicated in preparative example 102, substituting only the title compound 3-CI, 8-H of preparative example 92 with the title compounds 3-CI, 8-CI of preparative example 101, the compound was prepared of the title (individual isomers C-11 (R) - and C-11 (S) -). LCMS: MH + = 479.

PREPARED EXAMPLE 1 0 Following essentially the same procedure indicated in preparative example 103, the title compounds were prepared (individual isomers C-11 (R) - and C-11 (S) -). LCMS MH + = 458.

PREPARED EXAMPLE 111 Following essentially the same procedure indicated in preparative example 102, substituting only the title compound 3-Br, 8-H of preparative example 93 with the title compound 3-Cl, 8-CI of preparative example 101, the compound of title (individual isomers C-11 (R) - and C-11 (S) -).

PREPARED EXAMPLE 112 Following essentially the same procedure indicated in preparative example 103, the title compound was prepared (individual isomers C-1 1 (R) - and C-11 (S) -).

PREPARED EXAMPLE 113 Following essentially the same procedure indicated in preparative example 102, substituting only the title compound 3-F, 8-H of preparative example 95 with the title compound 3-Cl, 8-CI of preparative example 101, the compound can be prepared of the title (individual isomers C-11 (R) - and C-11 (S) -).

PREPARED EXAMPLE 114 Following essentially the same procedure indicated in preparative example 103, the title compounds can be prepared (individual isomers C-11 (R) - and C-11 (S) -).

EXAMPLES 138A-168 Following essentially the same procedure indicated in example 1, substituting only the title compounds of preparative example 106 (individual isomers (R) - and (S) -) and substituting the appropriate amine, compounds of the formula shows below with R8 listed in column 3 of table 17.

TABLE 17 TABLE 17 (continued) TABLE 17 (continued) TABLE 17 (continued) TABLE 17 (continued) TABLE 17 (continued) PREPARED EXAMPLE 115 Following essentially the same procedure indicated in preparative example 24 using only the title compound of example 73A, the title compound was prepared: FABMS: MH + = 599. Following essentially the same procedure indicated in preparative example 115 by substituting only the title compounds of the example numbered in column 2, the title compounds of the formula shown below with R8 can be obtained as listed in column 4 of the table 18 TABLE 18 EXAMPLES 169-182 Following essentially the same procedure indicated in example 14, substituting only the title compounds of the preparative example listed in column 2 of table 19, the compounds of the formula shown below were obtained where R9 is as indicated in column 4 of table 19, (when the data are provided) or can be obtained (when the data are provided) using the appropriate electrophile.

TABLE 19 TABLE 19 (continued) EXAMPLES 183-196 Following essentially the same procedure indicated in example 14, substituting only the title compounds of the preparative example listed in column 2 of table 20, the compounds of the formula shown below were obtained, where R9 is as indicated in column 4 of table 20, (when the data are provided) or can be obtained (when data is not provided) using the appropriate electrophile.

TABLE 20 TABLE 20 (continued) EXAMPLE 197 A solution of the title compound of Preparative Example 115 (0.10 g, 0.17 mmol) in CH2Cl2 (5.0 mL) was treated with p-fluorophenylacetic acid (0.034 g, 1.3 eq.), NMM (0.11 mL, 6.0 eq.) HOBt ( 0.29 g, 1.3 eq.), And DEC (0.042 g, 1.3 eq.) And the resulting solution was stirred at room temperature overnight. The reaction mixture was concentrated in vacuo and the crude product was purified by evaporative chromatography using a 5% solution (10% NH 4 OH in MeOH) in CH 2 Cl 2 as eluent (0.066 g, 53% yield): mp = 105-110 ° C; LCMS: MH + = 733.

EXAMPLES 198-200 Following essentially the same procedure indicated in Example 197, using only the title compounds of the preparative example listed in column 2 of Table 21, the title compounds of the formula shown below were obtained, R8 is as indicated in column 4 of table 21. TABLE 21 EXAMPLES 201-204 Essentially by the same procedure indicated in Example 197, by substituting only p-fluoro-phenylacetic acid, for cyclopropylmethylacetic acid, and using the title compounds of the preparative example listed in column 2 of Table 22, the title compounds of the formula shown below, where R8 is as listed in column 4 of table 22, were obtained (examples 201 and 203) or can be obtained (examples 202 and 204).

TABLE 22 PREPARED EXAMPLES 119-134 Following essentially the same procedure indicated in Example 115, substituting only the title compounds of the preparative example listed in column 2 of Table 23, the title compounds of the formula shown below were obtained, where R 8 is as defined. indicates in column 4 of table 23.

TABLE 23 TABLE 23 (continued) TABLE 23 (continued) EXAMPLES 205-214 Following essentially the same procedure indicated in example 14, substituting only the compounds of the title of the preparative example listed in column 2 of table 24, the compounds were obtained by the formula shown below, where R8 is as indicated in column 4 of table 24.

TABLE 24 TABLE 24 (continued) EXAMPLE 215 Essentially by the same procedure indicated in Example 14, substituting only the title compound of Preparative Example 129, and using the appropriate electrophile, the compound of the formula was obtained (isomer C-11 S). FABMS: MH + = 725 EXAMPLE 216 Following essentially the same procedure indicated in Example 14, substituting only the title compound of Preparative Example 130, and using the appropriate electrophile, the compound of the formula was obtained (isomer C-11 S). FABMS: MH + = 725 EXAMPLES 217-221 Essentially by the same procedure indicated in Example 14, substituting only the compounds of the title of the preparative example listed in column 2 of Table 25, the compounds of the formula shown below were obtained, where R9 is as indicated in column 4 of table 25, using the appropriate electrophile.

TABLE 25 EXAMPLES 222-226 Following essentially the same procedure indicated in example 14, substituting only the compounds of the title of the preparative example listed in column 2 of table 26, the compounds of the formula shown below were obtained, where R9 is as indicated in column 4 of table 26, using the appropriate electrophile.

TABLE 26 EXAMPLES 227-230 Following essentially the same procedure indicated in Example 1, substituting only the title compounds of Preparative Example 87 and Preparative Example 101, and substituting the appropriate amine, compounds of the formula shown below were obtained where R8 is as it is indicated in column 3 of table 27.

TABLE 27 PREPARATORY EXAMPLE 135 Following essentially the same procedure as indicated in preparative example 24, using only the title compound of example 227, the title compound LCMS was prepared: MH + = 653 Following essentially the same procedure, substituting only the title compounds of the enumerated example in column 2 of table 28, the title compounds of the formula shown below were obtained, where R8 is as listed in column 3 of 28.

TABLE 28 EXAMPLES 231-242 Following essentially the same procedure indicated in example 14, substituting only the compounds of the title of the preparative example listed in column 2 of table 28, the compounds of the formula shown below were obtained, where R9 is as listed in column 4 of table 29 (when data are provided) or can be obtained (when data is not provided) using the appropriate electrophile.

TABLE 29 TABLE 29 (continued) EXAMPLES 243-254 Following essentially the same procedure indicated in Example 14, substituting only the title compounds of the preparative example listed in column 2 of Table 30, the compounds of the formula shown below were obtained, where R9 is as listed in column 4 of table 30 (when data are provided) or can be obtained (when data is not provided) using the appropriate electrophile.

CUAD &O 30 TABLE 30 (continued) PREPARED EXAMPLE 139 Using essentially the same procedure indicated in the preparative example 32, substituting only the tricyclic chloride 3-H, 8-CI of step B by the tricyclic chloride 3-Cl, 8-CI prepared in the preparative example 87, the compound was prepared of the title. FABMS: MH + = 518.

EXAMPLES PREPARATION 140 AND 141 Following essentially the same procedure indicated in Example 1, substituting only the appropriate amine, the compounds of the formula shown below were obtained, where R8 is as listed in the column of Table 31.

TABLE 31 EXAMPLE 254A Following essentially the same procedure indicated in Example 1, substituting only the title compound of Preparative Example 139 and the amine of Preparative Example 74B, the title compound was prepared, mp = 105-113; LCMS: MH + = 678 EXAMPLE 255-258 The title compounds of the preparative examples 140 and 141 were separated into the individual diastereomers C-11 (S) and (R) by preparative HPLC with a CHIRALPAK AD column using a 20% solution of iPrOH in hexanes with 0.2% of DEA as eluent to provide the compounds of the formula shown below, wherein R8 is as listed in column 3 of Table 32.

TABLE 32 EXAMPLES 259-262 Following essentially the same procedure indicated in Example 1, substituting only the title compounds of Preparative Example 89 and Preparative Example 101 and substituting the appropriate amine, the compounds of the formula shown below were obtained, where R8 is as it is indicated in column 3 of table 33.

TABLE 33 PREPARED EXAMPLE 142 Following essentially the same procedure as indicated in preparative example 24, using only the title compound of example 259, the title compound can be prepared. Following essentially the same procedure, substituting only the title compounds of the example listed in column 2 of Table 34, the title compounds of the formula shown below can be prepared, where R8 is as indicated in column 3 of 3. 4.

TABLE 34 EXAMPLES 263-274 Following essentially the same procedure indicated in example 14, substituting only the compounds of the title of the preparative example indicated in column 2 of table 35, the compounds of the formula shown below were obtained, where R9 is as listed in column 4 of table 35, (when data are provided) or can be obtained (when data is not provided) using the appropriate electrophile.

TABLE 35 TABLE 35 (continued) EXAMPLES 275-286 Following essentially the same procedure indicated in example 14, substituting only the title compounds of the preparative example listed in column 2 of table 36, compounds of the formula shown below can be obtained, where R9 is as indicated in column 4 of table 36 using the appropriate electrophile.

TABLE 36 TABLE 36 (continued) PREPARED EXAMPLE 146 AND 147 Following essentially the same procedure indicated in the preparative example 36, substituting only the tricyclic 3-H, 8-CI chloride of step B for the tricyclic 3-F, 8-CI chloride prepared in the preparative example 89, the compounds were prepared of the title (C-11 (S) - and (R) isomers) and separated into individual diastereomers by evaporative chromatography using a 12% ai solution (10% NH 4 OH in MeOH) in CH 2 Cl 2.

PREPARED EXAMPLE 146 Isomer 11 - (S) (first elution isomer): FABMS: MH + = 502; [a] D = + 7.7 ° (5.0 mg in 2 ml of MeOH).

PREPARED EXAMPLE 147 Isomer 11 - (R) (second elution isomer): FABMS: MH + = 502; [α] D = + 74.6 ° (5.0 mg in 2 ml of MeOH).

EXAMPLES 287-290 Following essentially the same procedure indicated in Example 1, substituting only the title compounds of Preparative Example 132, (individual isomers (S) - and (R)) and substituting the appropriate amine, compounds of the formula shown below, where R8 is as indicated in column 3 of table 37.

TABLE 37 EXAMPLES 291-294 Following essentially the same procedure indicated in Example 1, substituting only the title compounds of Preparative Example 110 and substituting the appropriate amine, the compounds of the formula shown below were prepared, where R8 is as indicated in the column 3 of table 38.

TABLE 38 PREPARED EXAMPLES 148-151 Following essentially the same procedure indicated in preparative example 107, substituting only the title compounds from the example listed in column 2 of table 39, the title compounds of the formula shown below were prepared, where R8 is as it is indicated in column 4 of table 39.

TABLE 39 EXAMPLES 295-306 Following essentially the same procedure as indicated in Example 14, substituting only the title compounds of the preparative example listed in column 2 of Table 40, the compounds of the formula shown below were obtained, where R9 is as indicates in column 4 of table 40 (when data are provided) or can be obtained (when data is not provided) using the appropriate electrophile.

TABLE 40 TABLE 40 (continued) EXAMPLES 307-318 Following essentially the same procedure indicated in example 14, substituting only the title compounds of the preparative example listed in column 2 of table 41, the compounds of the formula shown below can be obtained, where R9 is as indicated in column 4 of table 41, using the appropriate electrophile.

TABLE 41 TABLE 41 (continued) PREPARED EXAMPLE 152 Following essentially the same procedure as indicated in preparative example 36, substituting only the tricyclic 3-H, 8-CI chloride of step B for the tricyclic 3-Cl, 8-H chloride prepared in preparative example 92, were prepared the title compounds (isomers C-11 (S) - and (R)).

FABMS: MH + = 484.

EXAMPLES PREPARATION 153 AND 154 Following essentially the same procedure indicated in Example 1, substituting only the title compounds of Preparative Example 152 and substituting the appropriate amine, the compounds of the formula shown below were obtained, where R8 is as indicated in the column 3 of table 42.

TABLE 42 EXAMPLES 319-322 The title compounds of the preparative examples 153 and 154 were separated into the individual diastereomers C-11 (S) - and (R) by preparative HPLC with a CHIRALPAK AD column using 25% iPrOH in a solution of hexanes with 0.2% DEA as eluent to obtain the compounds of the formula shown below, where R8 is as indicated in column 3 of table 43.

TABLE 43 EXAMPLES 323-326 Following essentially the same procedure indicated in example 1, substituting only the title compounds of preparative example 112 and substituting the appropriate amine, compounds of the formula shown below can be obtained, where R8 is as indicated in the column 3 of table 44.

TABLE 44 PREPARED EXAMPLES 155-158 Following essentially the same procedure indicated in preparative example 115, substituting only the title compounds of the example listed in column 2 of Table 45, the title compounds of the formula shown below can be prepared, where R8 is as indicates in column 4 of table 45.

TABLE 45 EXAMPLES 327-338 Following essentially the same procedure as indicated in example 14, substituting only the compounds of the title of the preparative example listed in column 2 of table 46, the compounds of the formula shown below were obtained, where R9 is as indicated in column 4 of table 46, (when data are provided) or can be obtained (when data is not provided) by using the appropriate electrophile.

TABLE 46 TABLE 46 (continued) EXAMPLES 339-350 Following essentially the same procedure indicated in example 14, substituting only the compounds of the title of the preparative example listed in column 2 of table 47, compounds of the formula shown below can be obtained, where R9 is as indicated in column 4 of table 47, using the appropriate electrophile.

TABLE 47 TABLE 47 (continued) COMPARATIVE EXAMPLE 159 Following the same procedure indicated in the preparative example 36, substituting only the tricyclic chloride 3-H, 8-CI of step B by the tricyclic chloride 3-Br, 8-H prepared in the preparative example 93, the compounds of title (isomers C-11 (S) - and (R)). FABMS: MH + = 528.

EXAMPLES PREPARATION 160 AND 161 Following essentially the same procedure indicated in preparative example 126, substituting only the title compounds of preparative example 144 and substituting the appropriate amine, the compounds of the formula shown below were obtained, where R8 is as indicated in column 3 of table 48.

TABLE 48 EXAMPLES 351-354 The title compounds of the preparative examples 160 and 161 were separated into individual diastereomers C-11 (S) - and (R) by preparative HPLC with a CHIRALPAK AD column using a solution of iPrOH in hexanes with 0.2% DEA as eluent for obtain the compounds of the formula shown below, where R8 is tai as indicated in column 3 of table 49.

TABLE 49 EXAMPLES 355-358 Following essentially the same procedure indicated in example 1, substituting only the title compounds of preparative example 114 and substituting the appropriate amine, compounds of the formula shown below can be obtained, where R8 is indicated in column 3 of the table fifty.

TABLE 50 PREPARED EXAMPLE 162-165 Following essentially the same procedure indicated in preparative example 115, substituting only the compounds of the title of the example indicated in column 2 of table 51, the title compounds of the formula shown below can be prepared, where R8 is as indicates in column 4 of table 51.

TABLE 51 EXAMPLES 359-370 Following essentially the same procedure indicated in example 14, substituting only the title compounds of the preparative example indicated in column 2 of table 52, the compounds of the formula shown below can be obtained, where R9 is as indicated in column 4 of table 52, using the appropriate electrophile.

TABLE 52 TABLE 52 (continued) EXAMPLES 371-382 Following essentially the same procedure indicated in example 14, substituting only the title compounds of the preparative example listed in column 2 of table 53, compounds of the formula shown below can be obtained, where R9 is as indicated in column 4 of table 53, using the appropriate electrophile.

TABLE 53 TABLE 53 (continued) PREPARED EXAMPLE 166 Following essentially the same procedure indicated in Example 1, substituting only the title compounds of Preparative Example 32 Step A and the title amine of Preparative Example 21, the title compound was prepared. FABMS: MH + = 518.

PREPARATIVE EXAMPLE 166A Following essentially the same procedure indicated in Example 1, substituting only the title compound of Preparative Example 32 Step A and the title amine of Preparative Example 20, the title compound can be prepared.

PREPARATIVE EXAMPLES 167 and 168 Following essentially the same procedure indicated in example 1, substituting only the title compounds of preparative example 166 and 166A and the tricyclic chloride 3-F, 8-H of preparative example 95, the compound of the formula shown then, where R8 is as indicated in column 3 of table 54 (preparative example 167) or can be prepared (preparative example 168).

TABLE 54 EXAMPLES 383-386 The title compounds of the preparative examples 167 and 168 were separated (preparative example 167) and can be separated (preparative example 168) into individual diastereomers C-11 (S) - and (R) by preparative HPLC on a CHIRALPAK AD column using a solution of iPrOH in hexanes with 0.2% DEA as eluent to give the compounds of the formula shown below, where R8 is as indicated in column 3 of Table 55.

TABLE 55 PREPARATIVE EXAMPLE 168A Preparation of the tricyclic portion N-oxide NaBH4 / MeOH (Isomer 11-S) (Isomer 11-R) 1? A solution of 3-peroxybenzoic acid (25 g, 102.59 mmol, 2.5 eq.) In anhydrous dichloromethane (250 ml) was added dropwise over a period of one hour to a stirred solution of 8-c! Oro-4-aza-10,11-dihydro-H-dibenzo- [a] , d] cyclohepten-5-one 1 (10 g, 41.04 mmol, 1.0 eq.) in anhydrous dichloromethane (100 ml) at 0 ° C under nitrogen atmosphere. The solution was slowly warmed to room temperature (3 hours) and stirred for a further 12 hours. The solution was extracted with a 1M aqueous sodium hydroxide solution (5 x 100 ml), washed with brine (2 x 100 ml), dried over Na2SO, filtered and concentrated under vacuum at 30 ° C to give 2 in the form of a solid yellow canary. The title 2 compound was used directly without any additional purification attempts. Yield: 10 g = 38.51 mmoles = 94% [M + H] +: 260 HRMS (FAB +): Calculated for C14HnCINO ([M + H] +): 260.04% Observed: 260.0478 2 3 l Sodium borohydride (2.21 g, 57.76 mmoles, 1.5 eq.) Was added in portions over a period of 15 minutes to a solution of 2 (10 g, 38.51 mmol, 1 g., 0 eq.) In anhydrous methanol (500 ml) at 0 ° C under nitrogen atmosphere. The resulting suspension was stirred at 0 ° C for 1 hour and then at room temperature for an additional 1 hour. The volatiles were removed under vacuum at 30 ° C and the residue was taken up in an aqueous solution of 1 M NaOH (250 ml). The aqueous solution was extracted with dichloromethane (5 x 100 ml). The combined organic extracts were washed with brine (100 ml). They were dried over Na 2 S 4, filtered, and concentrated under vacuum at 30 ° C to give 3 as a milky green solid. Compound 3 was used directly without any purification attempts. Performance: 9 g & amp;; 34.39 mmoles = 89% [M + Hf 262 HRMS (FAB +): Calculated for C14H13CIN02 (¡M + H] +): 262.0635 Observed: 262.0636 3? 4 Thionyl chloride (5 ml, 68.78 mmol, 2.0 eq.) Was added dropwise over a period of 10 minutes to a stirred suspension of 3 (9 g, 34.39 mmoles 1.0 eq. ) and anhydrous toluene (150 ml) at 0 ° C under nitrogen atmosphere. The cream colored suspension was heated slowly (3 h) at room temperature and stirred for a further 12 hours. Volatiles were removed under vacuum at 30 ° C. The residue was taken up in dichloromethane (250 ml) and washed with a solution of saturated aqueous NaHCOs cooled with ice (5 x 100 ml) until the aqueous washings were moderately basic at pH 9. The organic layer was washed with brine (100 g. ml), dried over Na 2 SO 4, filtered and concentrated in vacuo at 30 ° C to give 4 as a cream solid in essentially quantitative yield. Due to its high reactivity, compound 4 was used directly without any purification or characterization attempt (other than 1 H NMR). Yield: 9.55 g = 34.09 mmoles = 99% 6 I Triethylamine (18 ml, 126.65 mmol, 5.0 eq.) Was added dropwise to a stirred solution of 5 (previously described in the art: 9.38 g, 25.33 mmol, 1.0 eq. ) in anhydrous dichloromethane (50 ml) at room temperature under nitrogen atmosphere. The solution was stirred at temperature for 30 minutes, and then cooled to 0 ° C. A solution of 4 (8.52 g 30.39 mmole, 1.2 eq.) In anhydrous dichloromethane (50 ml) was added dropwise over a period of 25 minutes. The mixture was heated slowly (3 hours) at room temperature and stirred for a further 12 hours. The volatiles were extracted under vacuum at 30 ° C. The residue was taken up in 50% m / v aqueous citric acid solution (100 ml) and extracted with ethyl acetate (5 x 100 ml). The organic extracts were combined and dried over Na 2 SO 4, filtered and concentrated in vacuo at 30 ° C. The creamy residual solid was chromatographed by evaporative chromatography (CH2Cl2MeOH = 19: 1 v / v) to give the diastereomerically pure isomers 6a and 6b to C-11 of the tricyclic.

For 6a: Performance. 5J5 g = 11, 50 mmoles = 50% Whitening foam; p.f. 78-83 ° C [M + H] +: 500 HRMS (FAB +): Calculated for C26H3 CIN3? 5 ([M + H] +): 500.1953 Found: 500.1952 For 6b: Performance. 3.00 g = 6.00 mmoles == 24% Whitish solid; p.f. 94-99 ° C [M + H] +: 500 HRMS (FAB +): Calculated for C26H3iCIN3? 5 ([M + H] +): 500.1953 Found: 500.1952 EXAMPLE 387 Following essentially the same procedure indicated in Example 1, substituting only the title compound of Preparative Example 168A, the title compound was prepared: mp. = 85-90 ° C; [M + H] +: 661.

EXAMPLE 388 Following essentially the same procedure indicated in Example 42 (see Table 6), substituting only the title compound of Preparative Example 168A, the title compound was prepared: m.p. = 108-113 ° C; [M + H] +: 661.

EXAMPLE 169 Following essentially the same procedure indicated in Example 1, substituting only the title compound of Preparative Example 2 and substituting the appropriate amine, the title compound was prepared.

EXAMPLE 170 Following essentially the same procedure indicated in Preparative Example 147, the title compound was prepared.

EXAMPLE 171 x HCl Following essentially the same procedure indicated in preparative example 8, the title compound was prepared, and used without further purification.

PREPARED EXAMPLE 172 x HCl Following essentially the same procedure indicated in preparative example 8, the title compound was prepared, and used without further purification.

PREPARED EXAMPLE 173 Following essentially the same procedure indicated in preparative example 6, replacing only the title compounds of Preparative Example 171 and Preparative Example 99, the title compound was obtained: FABMS: MH + = 519 Following essentially the same procedure indicated in the preparative example 14, substituting only the compounds of the title of the preparative example in column 2 of Table 56, the compounds of the formula shown below were obtained where R9 is as indicated in column 4 of Table 56, using the appropriate agent .

TABLE 56 PREPARED EXAMPLE 174 Following essentially the same procedure indicated in Preparative Example 6, substituting only the title compounds of Preparative Example 172 and Preparative Example 99, the title compound was obtained: FABMS: MH + = 519.

EXAMPLES 395-397 Following essentially the same procedure indicated in example 14, substituting only the compounds of the title of the preparative example listed in column 2 of table 57, the compounds of the formula shown below were obtained where R9 is as listed in column 4 of table 57, using the appropriate acylating agent.

TABLE 57 EXAMPLE 398 The title compound of Example 165 (0.076 g) was hydrogenated with balloon over 10% Pd / C (0.025 g) in EtOH (15 mL) overnight at room temperature. The catalyst and the solvent were removed to give the title compound: MS MH + = 606.

EXAMPLES 399-402 Following essentially the same procedures indicated in preparative example 24 and example 14, using only the title compound of example 398, the title compounds of the formula shown below were obtained, where R9 is as indicated in column 3 on page 58.

TABLE 58 EXAMPLES 403-406 Following essentially the same procedure indicated in Example 399, the compounds of the formula shown below were obtained, where R9 is as listed in column 4 of the table 59.

TABLE 59 EXAMPLES 407-408 Following essentially the same procedure indicated in Example 1, substituting only the appropriate amine, the compounds of the formula shown below were obtained, where R8 is as indicated in column 3 of Table 60.

TABLE 60 EXAMPLE 409 AND 410 The title compound of example 47 (CC) was separated into individual diastereomers using a CHIRALPAK AD column employing 15% iPrOH in hexanes with 0.2% DEA as eluent to obtain the title compounds of the formula shown below where R8 it is as defined in column 3 of table 60A.

TABLE 60A PREPARED EXAMPLE 175 Following essentially the same procedure as is indicated in preparative example 115 by substituting only the title compound of example 32, the title compound was prepared.

EXAMPLE 411 Following essentially the same procedure indicated in Example 14, substituting only the title compound of Preparative Example 175 and neopentyl chloroformate, the title compound was prepared: mp = 103-115 ° C; LCMS: MH + = 633.

EXAMPLES 412 AND 413 The compounds of the title of the formula shown below where R9 is as listed in column 3 of table 61 were prepared essentially by the same procedure indicated in example 1, substituting only the title compound of the preparative example. 175 and the appropriate carboxylic acid.

TABLE 61 PREPARED EXAMPLE 175A Following essentially the same procedure indicated in preparative example 31, step A substituting only isopropyl chloroformate for CBz-NOS, the title compound was prepared.

PREPARED EXAMPLES 175B AND 175C Following essentially the same procedure indicated in preparative example 31, step B by substituting only the title compound of preparative example 175A, the title compounds were prepared (individual isomers C-11 (S) - and (R). Example 175B: isomer C-11 (S), Yield 3%, MH + = 492. Example 175C: C-11 isomer (R), Yield 3%, MH + = 492.

PREPARED EXAMPLES 175D and 175E Following essentially the same procedure indicated in preparative example 31, step B substituting only the title compounds of preparative example 97 and preparative example 175A, the title compounds were prepared (individual isomers C-11 (S) and (R). Example 175D: Isomer C-11 (S), Yield ^ 2%, MH + = 508. Example 175E: Isomer C-11 (R), Yield ^ 5%, MH + = 508.

EXAMPLE 414 The title compound was prepared essentially by the same procedure set forth in Example 387, substituting only the tricyclic chloride with dibenzosuberyl chloride: mp = 98-112 ° C; FABMS: MH + = 610.

EXAMPLES 415-425 Following essentially the same procedure indicated in Example 1, substituting only the carboxylic acid (isomer 11 - (S) or 11- (R) of the preparative example listed in Table 62 and the appropriately substituted piperidine (amine), the products were prepared pure isomers and separated by preparative HPLC (AD column) using IPA-hexanes.

TABLE 62 TABLE 62 (continued) TABLE 62 (continued) TABLE 62 (continued) TABLE 62 (continued) TABLE 62 (continued) TABLE 62 (continued) PREPARED EXAMPLE 176-179 By stirring the benzyloxycarbonyl compounds (CBZ) listed in column 2 of Table 63 and the palladium on carbon catalyst in EtOH under an atmosphere of hydrogen gas, the product of amines was obtained.

TABLE 63 TABLE 63 (continued) EXAMPLES 426-434 Following essentially the same procedure indicated in example 14, replacing only the piperazine amines (isomer A or B) listed in column 2 of table 64 for the title compound of preparative example 24 and using as an electrophile or an isocyanate to give the products of urea, or a carboxylic acid, HOBt, DEC and DMF to give the amide products listed in Table 64.

TABLE 64 TABLE 64 (continued) TABLE 64 (continued) TABLE 64 (continued) TABLE 64 (continued) EXAMPLES 438-457 If the procedure described for Example 426 is described using the piperazine amines (isomer A or B) listed in column 2 of Table 65, and, electrophile, an isocyanate, or a carboxylic acid and HOBt, DEC and DMF, then they would obtain the urea or amide products, respectively listed in Table 65.

TABLE 65 TABLE 65 (continued) TABLE 65 (continued) TABLE 65 (continued) TABLE 65 (continued) TABLE 65 (continued) TABLE 65 (continued) EXAMPLES 458-463 Using a procedure similar to that described for Example 14 using only the piperazine amine of Preparative Example 175 in place of the title compound of Preparative Example 24 and using an electrophile to obtain a carbonate or anhydride, or a carboxylic acid, HOBt , DEC and DMF to obtain the amide products listed in Table 66.

TABLE 66 TABLE 66 (continued) PREPARED EXAMPLE 180 Following essentially the same procedure as that used in example 466, step A, except that tetrahydro-4H-pyran-4-ol was used, the title compound was prepared (3.1 g, 78%, M + = 165).

EXAMPLE 464 The title compound of Preparative Example 462 (0.205 g), 0.5M ammonia in dioxane (2 ml), DEC (0.175 g), HOBt (0.123 g) and anhydrous DMF (5 ml) were stirred at room temperature overnight. Purification by preparative plate chromatography (silica, 5% MeOH-CH 2 Cl 2, saturated NH 4 OH) provided the title compound (1136 g, 66%, MH + = 646).

EXAMPLE 465 The title compound of preparative example 463 (0.228 g), 0.5M ammonia in dioxane (2 ml), DEC (0.175 g), HOBt (0.123 g) and anhydrous DMF (5 ml) were stirred at room temperature overnight. Purification by preparative plate chromatography (silica, 5% MeOH-CH 2 Cl 2, saturated NH 4 OH) provided the title compound (0.139 g, 61%, MH + = 660).

EXAMPLE 466 Step cis cis The commercially available c / s-acetoxycyclohexanol (0.25 g) (0.25 g) was treated with phosgene (2 ml). Concentration in vacuo provided the chloroformate (0.307 g, 88%).

Stage B By combining the chlorine (0.052 g) of step A with the piperazine amine (0.103 g) of preparative example 175 and following a procedure similar to that described in example 14, the title compound was obtained (0.07 g, 50%, MH + = 703).

EXAMPLE 467 Treatment of the product of Example 466 (0.06 g) with potassium carbonate (0.2 g) in MeOH (2 mL) afforded the title compound (0.056 g, 100%, MH + = 661).

EXAMPLE 468 Stage A trans trans The commercially available fraos-acetoxycohexanol (0.05 g) was treated with phosgene (0.5 ml). Concentration in vacuo provided the chloroformate (0.062 g, 89%).

Stage B By combining the chloroformate (0.062 g) from step A with the piperazine amine (0.103 g) of preparative example 175 and following a procedure similar to that described in example 14, the title compound was obtained (0.058 g, 42%, MH + = 703).

EXAMPLE 469 The treatment product of Example 466 (0.05 g) with potassium carbonate (0.2 g) in MeOH (2 mL) afforded the title compound (0.047 g, 100%, MH + = 661).

EXAMPLE 470 Stage A If the cyclohexanol commercially obtainable with phosgene is treated, the chloroformate can be obtained.

Stage B If the chloroformate from step A is combined with the piperazine amine shown above according to the procedure described for Example 461, ketal can be obtained.

Stage C the ketone.

Stage D If the product of stage C is treated with MeMgBr or MeLi then the product of the title is obtained.

EXAMPLE 471 Stage A The ketone commercially obtainable with methyl magnesium bromide is treated, then the desired alcohol is obtained.

Stage B If the product from step A above is treated with acetic anhydride, then the desired acetate is obtained.

Stage C If the product of Step B is treated with formic acid then the desired ketone is obtained.

ESSAYS The Cl50 of FPT (farnesyl protein transferase inhibition, in vitro enzymatic assay) was determined following the assay procedures described in WO 95/10516, published on April 20, 1995. The IC5o of GGPT (fa transferase inhibition) of the geranylgeranyl protein, in vitro enzyme assay), Cell Mat assay, COS cell (cell-based) CI5o, and antitumor activity (anti-tumoral studies in vivo) could be determined by the assay procedures described in WO 95/10516. The description of WO 95/10516 is incorporated herein by reference. Additional assays can be carried out by following essentially the same procedure described above but with substitution of the alternative indicator tumor cell lines in place of the T24-BAG cells.

The assays can be carried out using any of the human colon carcinoma cells DLD-1-BAG that express an activated K-ras gene or with human colon carcinoma cells SW620-BAG that express an activated K-ras gene. Using other tumor cell lines known in the art, the activity of the compounds of this invention against other types of cancer cells can be demonstrated.

Soft Agar Test The independent development of adhesion is a characteristic of tumorigenic cell lines. Human tumor cells can be suspended in culture medium containing 0.3% agarose and with an indicated concentration of a femesyl transferase inhibitor. The solution may be superimposed on a culture medium solidified with 0.6% agarose containing the same concentration of the famesyl transferase inhibitor as the top layer. Once the upper layer has solidified, the plates can be incubated for 10-6 days at 37 ° C under 5% C02 to allow the development of the colony. After incubation, the colonies can be stained with an overlayer of agar with an MTT solution (3- [4,5-dimethyl-thiazol-2-yl] -2,5-diphenyltetrazolium bromide, thiazolyl blue) (1 mg / ml in PBS). The colonies can be counted and the IC5 can be determined. The compounds of this invention had an IC50 FPT within the scale of < 0.04nM at 20nM, and an IC50 of soft agar within the scale of < 0.5nN a > 500nM.

The compounds of Examples 1-4, 4.1, 4.2, 5, 7, 8, 10-19, 24-51, and 74, 138, 142, 144, 145 had a Cl50 of FPT within the scale of < 00.4nM to 2JnM. The compounds of examples 1-4, 4.1, 4.2, 5, 7, 10-19, 24-51, and 74, 138, 142, 144, 145 had a soft agar IC5o within the scale of < 0.5nM to 30nM. The compounds of examples 35 (A), 35 (C), 35 (D), 35 (E), 35 (F), 41 (A), 41 (B), 41 (C), 47 (A), 47 (B), 47 (D), 47 (G), 47 (H), 47 (L), 47 (K), 47 (L), 47 (M), 47 (N), 47 (0), 47 (P), 47 (R), 47 (S), 47 (T), 47 (U), 47 (CC), 51 (A) to 51 (D), 138 A to 147A, 148 to 158, 160 , 161, 163, 169 to 180, 183 to 188, 191, 192, 197, 201, 207 to 216, 227 to 234, 238 to 240, 245, 255 to 262, 287 to 294, 297 to 303, 316 to 324 , 351 to 354, 383, 384, 387, 388, 391, 392, 394 to 397, 407, 408, 409, 410, 411, 412, 414, 415 to 417, 419, 422 and 424 had a Cl50 of FPT within of the scale of < 0.04 to 0.7 nM, and a soft agar IC50 within the scale of < 0.05 to 30 nM. To prepare the pharmaceutical compositions of the compounds described by this invention, the inert pharmaceutically acceptable carriers can be solid or liquid. Solid form preparations include powders, lozenges, dispensable granules, capsules, cachets and suppositories. The powders and lozenges can be constituted by from about 5 to about 95 percent active ingredient. Suitable solid carriers are known in the art, for example magnesium carbonate, magnesium stearate, talc, sugar or lactose. Pills, powders, cachets and capsules can be used as solid dosage forms suitable for oral administration. Examples of pharmaceutically acceptable carriers and manufacturing methods for various compositions can be found in A. Gennaro (ed.) Remington's Pharmaceutical Sciences, 18th Edition, (1990), Mack Publishing Co., Easton, Pennsylvania. Liquid form preparations include solutions, suspensions and emulsions. As an example may be mentioned water or water or propylene glycol solutions for parenteral injection or addition of sweeteners and opacifiers for oral solutions, suspensions and emulsions. The liquid form preparations may also include solutions for intranasal administration. Aerosol preparations suitable for inhalation may include solutions and solids in powder form which may be combined with such a pharmaceutically acceptable carrier with an inert compressed gas, for example nitrogen. Also included are solid form preparations which are intended to be converted, shortly before use, to liquid form preparations for oral or parenteral administration. Said liquid forms include solutions, suspensions and emulsions. The compounds of the invention can also be administrable transdermally. The transdermal compositions may take the form of creams, lotions, aerosols and / or emulsions and may be included in a transdermal patch of matrix or reservoir types that are conventional in the art for this purpose. Preferably, the pharmaceutical preparation is in a unit dosage form. In such form, the preparation is subdivided into unit doses of an appropriate size containing the appropriate quantities of active component, for example an effective amount to achieve the desired purpose. The amount of active compound in a unit dose of preparation may vary or be adjusted to from about 0.01 mg to about 1000 mg, preferably from 0.01 to 750 mg and more preferably from about 0.01 mg to about 500 mg, and even more preferably from about 0.01 mg to approximately 250 mg, according to the particular application. The actual dose used may vary depending on the requirements of the patient and the severity of the condition being treated. The determination of an appropriate dosage regimen for a particular situation is within the skill in the art. For reasons of convenience, the total daily dose may be divided and administered in portions during the day as required. The amount and frequency of administration of the compounds of the invention and / or their pharmaceutically acceptable salts will be regulated according to the opinion of the attending physician considering factors such as agephysical condition and weight of the patient, as well as the severity of the symptoms that are being treated. A typical daily dosage regimen recommended for oral administration may be comprised between about 0.04 mg / day to about 4000 mg / day in two to four divided doses, Although the present invention has been described in conjunction with the specific embodiments indicated above, many Alternatives, modifications and variations of it will be apparent to those who have experience in the technique. All such alternatives, modifications and variations fall within the spirit and scope of the present invention.

Claims (27)

NOVELTY OF THE INVENTION CLAIMS

1. - A compound of formula: or a pharmaceutically acceptable salt or solvate thereof where; one of a, b, c and d represent N or N + 0", and the remaining groups a, b, c, and d represent CR1 or CR2, or each of a, b, c and d are independently selected from CR1 or CR2; and each R2 is independently selected from H, halo, -CF3, -OR10, -COR10, -SR10, -S (0) tR11 (where t is 0, 1 or 2), -N (R10) 2 -N02, - OC (0) R1 °, -C02R10, -OC02R11, -CN, -NR10COOR11, -SR11C (0) OR11, -SR11N (R75) 2 (with the proviso that R11 in -SR11N (R75) 2 is not -CH2 -) wherein each R75 is independently selected from H or -C (0) OR11, benzotriazol-1-yloxy, tetrazole-5-ylthio, or substituted tetrazoi-5-ylthio, alkynyl, alkenyl or alkyl, said alkyl or alkenyl group being optionally substituted with halo, -OR10 or -C02R10, R3 and R4 are the same or different and each independently represents H, any of the substituents of R1 and R2, or R3 and R4 taken together represent a fused annulus C5-C7 saturated or not saturated with the benzene ring (ring III); R5, R6 and R7 each independently represent H, -CF3, -COR10, alkyl or aryl, said alkyl or aryl are optionally substituted with -OR10, -SR10, -S (0) tR11, -NR10COOR11, -N (R10) 2, -N02, -COR10 , -OCOR10. -OC02R11, -C02R10, OPO3R10, or R5 is combined with R6 to represent = 0 or = S; with the proviso that for groups -OR10, -SR10 'and -N (R10) 2 R10 is not H; R10 represents H, alkyl, aryl, or aralkyl; R11 represents alkyl or aryl; X represents N, CH or C, and when X is C, the optional bond (represented by the dotted line) is present with carbon atom 11, and when X is CH, the optional bond (represented by the line) is absent. of points) with the carbon atom 11; the dotted line between carbon atoms 5 and 6 represents an optional bond, so that when a double bond is present, A and B independently represent -R10, halo, -OR11, -OC02R11 or -OC (0) R1 °, and when no double bond is present between carbon atoms 5 and 6, A and B each independently represent H2, - (OR11) 2, H and halo, dihalo, alkyl and H, (alkyl) 2, -H and -OC (0) R1 °, H and -OR10, = 0, aryl and H, = NOR10 or -0- (CH2) p-0- where p is 2, 3 or 4; R8 represents a heterocyclic ring selected from; (2.0) (3.0) (2.1) (3-1) (4.1) said heterocyclic rings (2.0 to 7.0 and 2.1 to 7.1) being optionally substituted with one or more substituents independently selected from; (a) alkyl, (b) substituted alkyl wherein said substituents are selected from; halo, aryl, -OR15 or -N (R15) 2, heteroaryl, heterocycloalkyl, cycloalkyl, wherein each R15 group is the same or different, with the proviso that said optional substituent is not attached to a carbon atom that is adjacent to a oxygen atom or nitrogen, and wherein R15 is selected from: H, alkyl, aryl, airlalkyl, heteroaryl, heteroarylalkyl, cycloalkyl, or cycloalkylalkyl; (c) hydroxyl, with the proviso that the carbon atoms adjacent to the nitrogen, sulfur or oxygen atoms of the ring are not substituted with hydroxyl; (d) alkyloxy or (e) arylalkyloxy; Y represents CH2, NR16, O, S, SO, or S02 where R16 is selected from: H, alkyl, cycloalkyl, cycloalkylalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, acyl, aroyl, carbamoyl, carboxamido, alkylsulfonyl, arylsulfonyl, arylalkysulfonyl, sulfonamido, alkylsulfonamido, arylsulfonamido and arylalkysulfonamido; n is 0 to 6; Q represents O or N, with the proviso that Q is not adjacent to a heteroatom in the heterocycloalkyl rings of 2.1, 3.1, 4.1, 5.1, 6.1 and 7.1; R12 is selected from; (8.0) (9.0) (9.1) wherein R17 is selected from: (1) H, (2) alkyl, (3) aryl, (4) arylalkyl, (5) substituted arylalkyl where the substituents are selected from halo or CN, (6) -C (aryl) 3, (7) cycloalkyl, (8) substituted alkyl (as defined above in (b)), or (9) cycloalkylalkyl; R12A is selected from rings 8.0, or 9.1, defined above; said imidazolyl ring 8.0 is optionally substituted with one or two substituents, said imidazole ring 9.0 is optionally substituted with 1-3 substituents, and said pyridyl ring 9.1 is optionally substituted with 1-4 substituents, wherein said optional substituents for rings 8.0, 9.0 and 9.1 are attached to the carbon atoms of said rings and are independently selected from -NHC (0) R15, -C (R18) 2OR19, -OR15, -SR15, F, Cl, Br, alkyl, substituted alkyl (as defined above in (b)), aryl, arylalkyl, cycloalkyl or -N (R15) 2; R15 is as defined above; each R18 is independently selected from H or alkyl, R19 is selected from H or -C (0) NHR2 °, and R20 is as defined below; R13 and R14 for each n are independently selected from, H, F, alkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, cycloalkyl, cycloalkylalkyl or -CON (R15) 2 (where R15 is as defined above), -OR15 or -N (R15) 2 with the proviso that the groups -OR15 and -N (R15) 2 are not bonded to a carbon atom that is adjacent to a nitrogen atom and with the proviso that there may be only one group -OH in each carbon; and that the substitutable R13 and R14 groups are optionally substituted with one or more substituents selected from; F, alkyl, cycloalkyl, arylalkyl, or heteroarylalkyl, or R 13 and R 14, for each n, together with the carbon atom to which they are attached, form a C 3 to C 3 cycloalkyl ring, R 9 is selected from: (12.0) (13.0) (14.0), (15.0) 0 (16.0); R > Is selected from, H, alkyl, aryl, arylalkyl, cycloalkyl, cycloalkylalkyl, heteroaryl, heteroarylalkyl, heterocycloalkyl, or heterocycloalkylalkyl, with the proviso that R20 is not H when R9 is group 12.0 or 16.0; when R20 is other than H, then said group R20 is optionally substituted with one or more substituents selected from; halo, alkyl, aryl, -OC (0) R15, -OR15 or -N (R15) 2, wherein each R15 group is the same or different and where R15 is as defined above, with the proviso that said optional substituent it is not attached to a carbon atom that is adjacent to an oxygen or nitrogen atom; R21 is selected from; H, alkyl, aryl, arylalkyl, cycloalkyl, cycloalkylalkyl, heteroaryl, heteroarylalkyl, heterocycloalkyl or heterocycloalkylalkyo; R21 is other than H, then said R21 group is optionally substituted with one or more substituents selected from: alkyl, aryl, where each R15 group is the same or different, and where R15 is as defined above; and R22 is selected from cycloalkyl, heterocycloalkyl, aryl, substituted aryl, alkyl, substituted alkyl or substituted cycloalkyl.

2. - The compound according to claim 1 having the structure

3. - The compound according to claim 1, wherein R1 to R4 is independently selected from H, Br, F or Cl; R5 to R7 is H; a is N and the remaining substituents b, c and d are carbon, or a, b, c, and d are carbon; A and B are H2; and n is 1 to 3.

4. The compound according to claim 1, wherein R8 is ring 2.0 and the substituent - (CR13R14) n-R12 is in position 2 or 3.

5.- The compound according to claim 1, wherein R8 is ring 2.0 and the substituent - (CR13R14) n-R12 is in position 2 or 3, and Y is CH2.

6. The compound according to claim 1, wherein R 13 and R14 are H.

7. - The compound according to claim 1, wherein Y is selected from S, SO, or S02.

8. The compound according to claim 1, wherein Y is O.

9. The compound according to claim 1 wherein Y is NR16.

10. The compound according to claim 1, wherein R9 is selected from 12.0, 13.0 or 15.0.

11. The compound according to claim 1, wherein R1 and R4 is independently selected from H, Br, F or Cl; R5 to R7 is H, a is N and the remaining substituents b, c and d are carbon; A and B are H2; and n is 1 to 3; R8 is ring 2.0 and the substituent - (CR13R14) n-R12 is in position 2 or 3, and Y is CH2.

12. The compound according to claim 11, having the structure;

13. - The compound according to claim 12, wherein R 3 and R 4 are H.

14. - The compound according to claim 13, wherein R12 is 9.0.

15. The compound according to claim 12, wherein R9 is selected from 12.0, 13.0 or 15.0.

16. The compound according to claim 12, wherein R20 is selected from t-butyl, i-propyl, neopentyl, cyclohexyl, cyclopropylmethyl,

17. The compound according to claim 13, wherein R9 is selected from 12.0 or 13.0 and wherein R21 for 13.0 is H.

18. The compound according to claim 1, selected from a compound of examples; 1-4, 4.1, 4.2, 10-19, 24-51, 74, 138, 142, 144, 145, 35 (A), 35 (C), 35 (D), 35 (E), 5 (F) , 41 (A), 41 (B), 41 (C), 47 (A), 47 (B), 47 (D), 47 (G), 47 (H), 47 (L), 47 (K) , 47 (L), 47 (M), 47 (N), 47 (0), 47 (P), 47 (R), 47 (S), 47 (T), 47 (U), 47 (CC) , 51 (A) to 51 (D), 138A to 147A, 148 to 158, 160, 161, 163, 169 to 180, 183 to 188, 191, 192, 197, 201, 207 to 216, 227, to 234, 238 to 240, 245, 255 to 262, 287 to 294, 297 to 303, 316 to 324, 351 to 354, 383, 384, 387, 388, 391, 392, 394 to 397, 407, 408, 409, 410, 411, 412, 414, 415 to 417, 419, 422, 424, 463A or 466-469.

19. The compound according to claim 1, selected from a compound of examples 35 (C), 41 (A), 47 (S), 47 (T), 140A, 144 isomer 1, 144 isomer 2, 163, 164, 183, 185, 215, 238, 258, 259, 287, 291, 292, 298, 300, 320, 251, 353, 411 or 416 ..

20. The compound according to claim 1, selected from a compound of examples 47 (A) or 140A.

21. The use of a compound as claimed in claim 1, for the manufacture of a medicament for treating tumor cells.

22. The use as claimed in claim 21, wherein the tumor cells are pancreatic tumor cells, lung cancer cells, myeloid leukemia tumor cells, follicular thyroid tumor cells, myelodysplastic tumor cells, tumor cells of epidermal carcinoma , tumoral carcinoma tumor cells, colon tumor cells, melanoma, breast tumor cells, prostate tumor cells.

23. The use of a compound as claimed in claim 1, for the manufacture of a medicament for treating tumor cells where the Ras protein is activated as a result of the oncogenic mutation in genes other than the Ras gene.

24. The use of a compound as claimed in claim 1, for the manufacture of a medicament for inhibiting famesyl protein transferase.

25. A pharmaceutical composition for inhibiting farnesyl protein transferase comprising an effective amount of a compound of claim 1, in combination with a pharmaceutically acceptable carrier.

26. A use of a compound as claimed in claims 1 to 20 for the manufacture of a medicament for the treatment of pancreatic tumor cells, lung cancer cells, myeloid leukemia tumor cells, thyroid follicular tumor cells , myelodysplastic tumor cells, tumor cells of epidermal carcinoma, tumoral cells of vesicle carcinoma, colon tumor cells, melanoma, breast tumor cells and prostate tumor cells.

27. A use of a compound as claimed in claims 1 to 20 for the manufacture of a medicament for inhibiting famesyl protein transferase.