MXPA01006241A - Tricyclic farnesyl protein transferase inhibitors - Google Patents

Abstract

Disclosed are compounds of formula (1.0) wherein R13 represents an imidazole ring;R14 represents a carbamate, urea, amide or sulfonamide group;R8 represents H when the alkyl chain between the amide group and the R13 imidazole group is substituted, or R8 represents a substituent such aa arylalkyl, heteroarylalkyl or cycloalkyl;and the remaining substituents are as defined herein. Also disclosed are compounds wherein R8 is H, and the alkyl chain between the amide group and the R13 imidazole group is unsubstituted. 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, WO 96/31478 published October 10, 1996 and co-pending application No. 96/094687 filed June 15, 1998 disclose tricyclic compounds that are useful for inhibiting farnesyl protein transferase. In view of the current interest in farnesyl protein transferase inhibitors, a highly appreciated contribution in the art would be compounds useful for the inhibition of farnesyl protein transferase. Said contribution is provided through this Invention.

BRIEF DESCRIPTION OF THE INVENTION This invention provides compounds that are useful for the inhibition of farnesyl protein transferase (IFP). The compounds of this invention are represented by the formula: or a pharmaceutically acceptable salt or solvate thereof, wherein: 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; X represents N or CH when the optional link (represented by the dotted line) is absent, and represents C when the optional link is present; 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 -R15, halo, -OR16, -OC02R16, -OC (0) R15, and when there is no double bond present between carbon atoms 5 and 6, A and B independently represent H2, - (OR16) 2, H and halo, dihalo, alkyl and H, (alkyl ^, -H and -OC ( O) R15, H and -OR15, = 0, aryl and H, = NOR15 or -O- (CH2) pO- where p is 2, 3 or 4, each R1 and each R2 are independently selected from H, halo, - CF3, -OR15 (for example, -OCH3), -COR15, -SR15 (for example, -SCH3 and -SCH2C6H5), -S (O) tR16 (where t is 0, 1 or 2, for example -SOCH3 and - SO2CH3), -N (R15) 2, -N02. -OC (O) R15, -CO2R15, -OCO2R16, -CN, -NR15COOR16, -SR16C (O) OR16 (for example, SCH2CO2CH3), -SR1dN (R17) 2 (with the proviso that R16 is -SR16N (R17) 2 is not -CH2-) where each R17 is independently selected from H or -C (O) OR16 (eg, -S (CH2) 2NHC (O) Ot -butyl and -S (CH2) 2NH2), benzo triazol-1-yloxy, tetrazol-5-ylthio, or substituted tetrazol-5-ylthio (for example, tetrazol-5-ylthi substituted with alkyl such as 1-methy1-tetrazol-5-ylthio), alkynyl, alkenyl or alkyl, said alkyl or alkenyl group being optionally substituted with halo, -OR15 or -CO2R15; 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 C-5-C7 fused ring unsaturated with the benzene ring (ring III); R5, R6 and R7 each independently represent H, -CF3, -COR15, alkyl or aryl, said alkyl or aryl being optionally substituted with -OR15, -SR15, -S (O) tR16 -NR15COOR16, -N (R15) 2 , -NO2, -COR15, -OCOR15, -OCO2R16, -CO2R15, OPO3R15, or R5 is combined with R6 to represent = O or = S; R8 is selected from: H, C3 to C alkyl (preferably branched chain alkyl and more preferably C4 to C branched chain alkyl), aryl, arylalkyl, heteroaryl, heteroarylalkyl, cycloalkyl, cycloalkylalkyl, substituted alkyl, substituted aryl, substituted arylalkyl, heteroaryl substituted, substituted aryl, substituted arylalkyl, substituted heteroaryl, substituted heteroarylalkyl, substituted cycloalkyl, substituted cycloalkylalkyl, substituents for substituted groups R8 are selected from: alkyl, aryl, arylalkyl, cycloalkyl, -N (R18) 2, -OR18, cycloalkylalkyl , halo, CN, -C (O) N (R18) 2, -SO2N (R18) 2 or -CO2R18; with the proviso that the substituents -OR18 and -N (R18) 2 are not bonded to the carbon that is attached to the N of the -C (0) NR8- portion; each R18 is independently selected from: H, alkyl, aryl, arylalkyl, heteroaryl or cycloalkyl; R9 and R10 are independently selected from: H, alkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, cycloalkyl or -CON (R18) 2 (wherein R18 is as defined above); and the substitutable R9 and R10 groups are optionally substituted with one or more (eg, 1-3) substituents selected from: alkyl (e.g., methyl, ethyl, isopropyl, and the like, cycloaikyl, arylalkyl, or heteroarylalkyl (i.e. , the R9 and / or R10 groups may) be unsubstituted or can be substituted with one 1-3 of the substituents described above, except when R9 and / or R10 is H); or} R9 and R10 together with the carbon atom to which they are attached form a C3 cycloalkyl ring to Ce; R11 and R12 are independently selected from: H, alkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, cycloalkyl, -CON (R18) 2l OR18 or -N (R18) 2; where R18 is as defined above; with the proviso that the groups -OR18 and -N (R18) 2 are not bonded to a carbon atom that is adjacent to a nitrogen atom; and wherein said substitutable R11 and R12 groups are optionally substituted with one or more (e.g., 1-3) substituents selected from: alkyl (e.g., methyl, ethyl, isopropyl, and the like). Cycloalkyl, arylalkyl, or heteroarylalkyl; or R11 and R12 together with the carbon atom to which they are attached form a C3 cycloalkyl ring to Ce, R13 is an imidazolyl ring selected from: wherein R19 is selected from: (1) H, (2) alkyl, (3) alkyl, (4) aryl, (5) arylalkyl, (6) substituted arylalkyl where the substituents are selected from halo, (eg, F and Cl) or CN, (7) -C (aryl) 3 (for example, -C (phenyl) 3, ie, trityl) or (8) cycloalkyl; said imidazole ring 2.0 or 2.1 is optionally substituted with one or two substituents and said imidazole ring 4.0 are optionally substituted with 1-3 substituents and said imidazole ring 4.0 is optionally substituted with a substituent in which said optional substituents for rings 2.0, 2.1 , 4.0 and 4.1 are attached to the carbon atoms of said imidazole rings and said substituents are optionally independently selected from: -NHC (O) R18, -C (R34) 2OR35, -OR18, -SR18, F, Cl, Br, alkyl, aryl, arylalkyl, cycloalkyl, or -N (R18) 2 (wherein each R18 is independently selected); R18 is as defined above, each R34 is independently selected from H or alkyl (preferably -CH3), preferably H; R35 is selected from H, -C (O) OR20, or -C (O) NHR20, and R20 is as defined below (preferably R20 is alkyl or cycloalkyl, more preferably cyclopentyl or cyclohexyl); Q represents an aryl ring (for example, phenyl), a cycloalkyl ring (for example, cyclopentyl or cyclohexyl) or a heteroaryl ring (for example, furanllo, pyrrolyl, thienyl, oxazolyl or thiazolyl), said Q being optionally substituted with 1 to 4 substituents independently selected halo (eg, F or Cl), alkyl, aryl, -OR18, -N (R18) 2 (where each R18 is independently selected), -OC (0) R18, or -C (O) N (R18) 2 (where each R18 is independently selected), and where R18 is as defined above, (examples of the group ~ C (R34) 2OR35 include -CH2OH, -CH2OC (O) OR20 and -CH2OC (O NHR20); R14 is selected from: (5.0) (6.0) (7.0) (7.1) (8.0) R15 is selected from: H, alkyl, aryl or arylalkyl; Ri6 is selected from: alkyl or aryl; R2o is selected from: H, alkyl, alkoxy, aryl, arylalkyl, cycloalkyl, heteroaryl, heteroarylalkyl or heterocycloalkyl, with the proviso that R20 is not H when R14 is group 5.0 or 8.0; 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 (O) R18 (for example, -OC (0) CH3), OR 8 or -N (R18) 2, wherein each R18 group is the same or different and where R18 is as defined above, with the proviso that said optional substituent is not bonded to a carbon atom which is adjacent to an oxygen or nitrogen atom; R21 is selected from: H, alkyl, aryl, arylalkyl, cycloalkyl, heteroaryl, heteroarylalkyl or heterocycloalkyl; when R21 is other than H, then said group R21 is optionally substituted with one or more (for example, 1-3) substituents selected from: halo, alkyl, aryl, -OR18 or -N (R18) 2, wherein each R18 group is the same or different and where R18 is as defined above, with the proviso that said optional substituent is not bonded to a carbon atom that is adjacent to an oxygen or nitrogen atom; n is 0-5; each R32 and R33 for each n (ie, for each group - C (R32) (R33) -), are independently selected from: H, alkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, cycloalkyl, -CON (R18) 2 , -OR18 or -N (R18) 2; wherein R18 is as defined above; and wherein said substitutable R32 and R33 groups are optionally substituted with one or more (eg, 1-3) substituents selected from: alkyl (eg, methyl, ethyl, isopropyl, and the like), cycloalkyl, arylalkyl, or heteroarylalkyl; or R32 and R33 together with the carbon atom to which they are attached, form a cycloalkyl ring C3 to C &;; and R is selected from branched alkyl, unbranched alkyl, cycloalkyl, heterocycloalkyl, or aryl (e.g., phenyl); and with the proviso that: (1) when R14 is selected from: groups 6.0, 7.0, 7.1 or 8.0 and X is N, then R8 is selected from: C3 to C10 alkyl, C3 alkyl to Substituted C10, arylalkyl, substituted arylalkyl, heteroarylalkyl, substituted heteroarylalkyl, cycloalkylalkyl or substituted cycloalkylalkyl; and (2) when R14 is selected from: groups 6.0, 7.0, 7.1 or 8.0 and X is N, and R8 is H, then the alkyl chain between R3 (ie, the imidazole ring 2.0, 4.0 or 4.1) and the amide moiety (ie, the group -C (O) NR18) is substituted, ie: (a) at least one of R9, R10, R11, R12, R32, or R33 is other than H, and / or ( b) R9 and R10, and / or R11 and R12, are taken together to form a cycloalkyl ring. This invention also provides compounds of formula 1.0, as described above, wherein R14 is group 5.0, and X is N, and R8 is H, then the alkyl chain between R13 (i.e., the imidazole ring 2.0, 4.0 or 4.1) and the amide portion (ie, the group -C (O) NR18) is substituted, that is: (a) at least one of R9, R11, R12, R32, or R33 is other than H, and / or (b) R9 and R10, and / or R11 and R12, are taken together to form a cycloalkyl ring. The compounds of this invention: (i) potently inhibit farnesyl protein transferase, but not geranylgeranyl protein transferase I, in vitro: (ii) block the phenotypic change induced by a form of transforming Ras which is an acceptor of farnesyl but it is not a form of transforming Ras manipulated to be a geranylgeranyl acceptor, (iii) they block the intracellular Ras process which is a farnesyl acceptor but not of Ras manipulated to be a geranylgeranllo acceptor; (iv) block the abnormal development of cells in cultures induced by transforming Ras. The compounds of this invention inhibit famesyl protein transferase and farnesylation of the oncogenic Ras protein. 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 farnesyl protein transferase is useful for 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 a development of cells independently of normal regulatory mechanisms (e.g., 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 83) benign and malignant cells of other proliferative diseases in which an aberrant Ras activation occurs. This invention also provides a method for inhibiting or treating the development of tumors 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 that express an activated Ras oncogene by administering an effective amount of the compounds previously described. Examples of tumors that can be inhibited or treated, include but are not limited to, lung cancer (e.g., lung adenocarcinoma), pancreatic cancers (e.g., pancreatic carcinoma such as, e.g., exocrine pancreatic carcinoma), colon cancers ( for example, 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, epidermal carcinoma, breast cancer and prostate cancer. It is believed that this invention also provides a method to inhibit or treat both benign and malignant proliferative diseases, where Ras proteins are aberrantly activated as a result of oncogenic mutation in other genes - that is, the Ras gene by itself is not activated. by mutation to an oncogenic form - said inhibition or treatment being carried out by administering an effective amount of the tricyclic compounds described herein, in a mammal (eg, a human) in need of such treatment. For example, benign proliferative disorder neurofibromatosis, or tumors in which Ras is activated due to mutation or overexpression of tyrosine kinase oncogenes (eg, neu, src, abl, Ick and fyn), can be inhibited or treated by the tricyclic compounds described herein. The tricyclic compounds that are useful in the methods of this invention inhibit or treat the abnormal development of cells. Without wishing to be bound by any theory, we believe that these compounds can function through the inhibition of G protein function, such as ras P21, by blocking G protein isoprenylation, which makes them useful for the treatment of proliferative diseases such as cancer and tumor development. Without wishing to adhere to any theory, we believe that these compounds inhibit ras farnesyl protein tranferase and therefore show antiproliferative activity against ras transformed cells.

DETAILED DESCRIPTION OF THE INVENTION As used herein, the following terms are used tai as defined below unless otherwise indicated: MH + represents the molecular ion plus hydrogen of the molecule in the mass spectrum; BOC represents tert-butyloxycarbonyl; CBZ represents -C (0) OCh.2C6H5 (ie, benzyloxycarbonyl); CH2CI2 represents dichloromethane, CIMS represents chemical ionization mass spectrum; DEAD represents diethylazodicarboxylate; DEC represents EDCI representing 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; Me represents methyl, MeOH represents methanol; EM represents mass spectroscopy, NMM represents N-methylmorpholine; Ph represents phenyl; Pr represents propyl; TBDMS represents tert-butyldimethylsilyl; ASD 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; acyl represents the group G-C (O) - where 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, as defined below, so that the bond of another substituent is attached to the alkyl, aryl portion (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 available substitutable carbon atoms of the carbocyclic group intended as possible points of adhesion , said carbocyclic group being optionally substituted (eg, 1 to 3) with one or more of halo, alkyl, hydroxy, alkoxy, phenoxy, CF 3) -C (O) N (R 8) 2, -SO 2 R 18, -SO 2 N ( R18) 2, amino, alkylamino, dialkylamino, -COOR23 or -NO2, wherein R23 represents alkyl or aryl, and 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 (eg, methyl or ethyl) and when there is more than one alkyl group each group is independently selected, cycloalkylalkyl represents a cycloalkyl group, as defined above, substituted with an alkyl group, as defined below, 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, as defined above, substituted with a heteroaryl group, such as that defined below, so that the linkage 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 by interrupting said heteroatom with a carbocyclic ring structure and having a sufficient quantity of delocalized pi electrons to provide aromatic character, containing the aromatic heterocyclic groups preferably of 2 to 14 carbon atoms, for example, 2- or 3-furyl; 2- or 3-thienyl, 2-, 4- or 5-thiazolyl, 2-, 4- or 5-lmidazolyl, 2-4- or 5-pyrimidinyl, 2-pyrazinylol, 3- or 4-pyridazinyl, 3-5 - or 6- [1, 2,4-triazinyl], 3- or 5- [1, 2,4-thiadizolyl], 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 N-pyridyl oxide (optionally substituted with R3 and R4), wherein the pyridyl N-oxide may be represented as: heterocycloalkyl represents a saturated, branched or unbranched carbocyclic ring containing from 3 to 15 carbon atoms, preferably from 4 to 6 carbon atoms, whose carbocyclic ring is interrupted by 1 to 3 hetero groups selected from -O-, -S- or -NR24, wherein R24 represents alkyl, aryl, -C (0) N (R18) 2 wherein R18 is as defined above (eg, -C (0) NH2) or acyl (appropriate heterocycloalkyl groups including 2) - or 3-tetrahydrofuranyl, 2- or 3-tetrahydrodienyl, 2-, 3-or 4-piperidinyl, 2- or 3-pyrrolidinyl, 2- or 3-piperizinyl, 2- or 4-dioxanyl, mofolinyl, 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 substituents R8 include: benzyl, -CH2C (CH3) 2, CH2-cyclohexyl, -CH2-cyclopropyl, - (CH2) 2CH3, ; and Examples of groups R9 and R10 include H and benzyl. Examples of groups R 1 and R 12 include: H, -CH 3, -CH 2 CH (CH) 2, - (CH 2) s CH 3, benzyl, ethyl, p-chlorophenyl, and -OH, Cyclopropyl is an example of the group R 11 and R 12 taken together with the carbon atom to which they are attached to form a cycloalkyl ring. Examples of the optional substituents for the R13 portion include: -CH3, -CH2OH, -CH2OC (0) 0-cyclohexyl, -CH2OC (0) 0-, cyclopentyl, ethyl, isopropyl, NH2, and -NHC (O) CF3; Examples of R19 include: -C (0) NH-, -cydohexyl, -C (phenyl) 3, H, methyl or ethyl. Examples of R20 for groups 5.0 include: t-butyl, ethyl, benzyl, -CH (CH3) 2, -CH2CH (CH3) 2, - (CH2) 2CH3, n-butyl, n-hexyl, n-octyl, p chlorophenyl, cyclohexyl, cyclopentyl, Another example of R > 20 for group 5.0 is Examples of R20 and R21 for 6.0 include: cyclohexyl, t-butyl, H, -CH (CH3) 2, ethyl, - (CH2) 2CH3, phenyl, benzyl, - (CH2) 2phenyl, and -CH3. Examples of R20 for 7.0 include: 4-pyridinylNO, -OCH3, -CH (CH3) 2 > -t-butyl, H, propyl, cyclohexyl and Example for R36 for 7.1 include: clclohexyl, cyclopentyl, cyclobutyl, cyclopropyl.

Examples for R20 for 8.0 include: methyl, i-propyl and cyclohexylmethyl. Examples of R32 and R33 include: H, phenyl, -OH and benzyl.

The compounds of this invention include compounds of formula 1.0 wherein when R14 is selected from: group 6.0, 7.0, 7.1 or 8.0, and X is C or CH (preferably CH), then R8 is selected from: C3 to C10 alkyl, C3 alkyl to substituted C10, arylalkyl, substituted arylalkyl, heteroarylalkyl, substituted heteroarylalkyl, cycloalkylalkyl or substituted cycloalkylalkyl. The compounds of this invention include compounds of formula 1.0 wherein when R14 is selected from: group 6.0, 7.0, 7.1 or 8.0, and X is C or CH (preferably CH), and R8 is H, then the alkyl chain between R3 ( that is, the imidazole ring 2.0, 4.0 or 4.1) and the amide moiety (ie the group -C (0) NR18) is substituted, ie: (a) at least one of R9, R11, R12, R32 or R33 is other than H, and / or (b) R9 and R10, and / or R11 and R12, taken together form a cycloalkyl ring. The compounds of this invention include compounds of formula 1.0 where when R14 is group 5.0, and X is C or CH (preferably CH), and R8 is H, then the alkyl chain between R13 (ie, the imidazole ring 2.0, 4.0 or 4.1) and the amide moiety (ie the group -C (0) NR18) is substituted, that is: (a) at least one of R9, R11, R12, R32 or R33 is other than H, and / or (b) R9 and R10, and / or R11 and R2, taken together form a cycloalkyl ring. The compounds of this invention include compounds of formula 1.0 wherein when R 4 is selected from the group 6.0, 7.0, 7.1 or 8.0, and X is C or CH (preferably CH), then R8 is selected from: arylalkyl, substituted arylalkyl, heteroarylalkyl, substituted heteroarylalkyl, cycloalkylalkyl or substituted cycloalkylalkyl. The compounds of this invention include compounds of formula 1.0 in which when R14 is 5.0 and X is C or CH (preferably CH), then R8 is selected from: arylalkyl, substituted arylalkyl, heteroarylalkyl, substituted heteroarylalkyl, cycloalkyl-alkyl or substituted cycloalkylalkyl. The compounds of this invention include compounds of formula 1.0 wherein when R14 is selected from: group 6.0, 7.0, 7.1 or 8.0, and X is N, then R8 is selected from: arylalkyl, substituted arylalkyl, heteroarylalkyl, substituted heteroarylalkyl, cycloalkylalkyl or cycloalkylalkyl replaced. The compounds of this invention include compounds of formula 1.0 wherein when R14 is 5.0, and X is N, then R8 is selected from: arylalkyl, substituted arylalkyl, heteroarylalkyl, substituted heteroarylalkyl, cycloalkylalkyl or substituted cycloalkylalkyl. Therefore, one embodiment of this invention is directed to compounds of which R14 is the carbamate group 5.0 and the other substituents are as defined for formula 1.0. Another embodiment of this invention is directed to compounds in which R14 is the carbamate group 5.0, X is N and the other substituents are as defined for formula 1.0.

Another embodiment of this invention is directed to the compounds in which R14 is the carbamate group 5.0, X is C or CH (preferably CH) and the other substituents are as defined for formula 1.0. Another embodiment of this invention is directed to compounds in which R14 is the carbamate group 5.0, X is N, R8 is arylalkyl or substituted arylalkyl (preferably arylalkyl), and the other substituents are as defined for formula 1.0. Another embodiment of this invention is directed to compounds in which R14 is the carbamate group 5.0, X is N, R8 is heteroalkyl or substituted heteroalkyl (preferably heteroalkyl), and the other substituents are as defined for formula 1.0. Another embodiment of this invention is directed to compounds in which R 4 is the carbamate group 5.0, X is N, R 8 is cycloalkyl or substituted cycloalkyl (preferably cycloalkyl), and the other substituents are as defined for formula 1.0 . Another embodiment of this invention is directed to the compounds in which R14 is the carbamate group 5.0, X is C or CH (preferably CH), R8 is arylalkyl or substituted arylalkyl (preferably arylalkyl), and the other substituents are as defined for formula 1.0. Another embodiment of this invention is directed to compounds in which R14 is the carbamate group 5.0, X is C or CH (preferably CH), R8 is heteroarylalkyl or substituted heteroarylalkyl (preferably heteroarylalkyl), and the other substituents are as defined for formula 1.0. Another embodiment of this invention is directed to compounds in which R14 is the carbamate group 5.0, X is C or CH (preferably CH), R8 is cycloalkylalkyl or substituted cycloalkylalkyl (preferably cycloalkylalkyl), and the other substituents are as defined for formula 1.0. Another embodiment of this invention is directed to compounds in which R 4 is group 5.0, X is C or CH (preferably CH), R 8 is H, then the alkyl chain between R 13 (i.e., the imidazole ring 2.0, 4.0 or 4.1) and the amide moiety (ie the group -C (0) NR18) is substituted, that is: (a) at least one of R9, R10, R11, R12, R32 or R33 is other than H, and / or (b) R9 and R10, and / or R11 and R12, are taken together to form a cycloalkyl ring, and the other substituents are as defined for formula 1.0. Another embodiment of this invention is directed to compounds in which R14 is the group 5.0, X is N, R8 is H, then the alkyl chain (ie, the imidazole ring 2.0, 4.0 or 4.1) and the amide moiety (i.e. the group -C (0) NR18) is substituted, ie: (a) at least one of R9, R10, R11, R12, R32 or R33 is other than H, and / or (b) R9 and R10, and / or R11 and R12, taken together form a cycloalkyl ring, and the other substituents are as defined for formula 1.0. Another embodiment of this invention is directed to compounds in which R 4 is a group selected from: 6.0, 7.0, 7.1 or 8.0, X is N, arylalkyl R or substituted arylalkyl (preferably arylalkyl), and the other substituents are as have defined for formula 1.0. Another embodiment of this invention is directed to compounds in which R14 is a group selected from: 6.0, 7.0, 7.1 or 8.0, X is N, R8 is heteroarylalkyl or substituted heteroarylalkyl (preferably heteroarylalkyl), and the other substituents are as defined for formula 1.0. Another embodiment of this invention is directed to compounds in which R14 is a group selected from: 6.0, 7.0, 7.1 or 8.0, X is N, R8 cycloarylalkyl or substituted cycloarylalkyl (preferably cycloalkylalkyl), and the other substituents are as defined for formula 1.0. Another embodiment of this invention is directed to compounds in which R 4 is a group selected from: 6.0, 7.0, 7.1 or 8.0, X is C, CH (preferably CH), R 8 arylalkyl or substituted arylalkyl (preferably arylalkyl), and the other substituents are as defined for formula 1.0. Another embodiment of this invention is directed to compounds in which R14 is a group selected from: 6.0, 7.0, 7.1 or 8.0, X is C, CH (preferably CH), R8 is heteroarylalkyl or substituted heteroarylalkyl (preferably heteroarylalkyl), and the other substituents are as defined for formula 1.0. Another embodiment of this invention is directed to compounds in which R14 is a group selected from: 6.0, 7.0, 7.1 or 8.0, X is C or CH (preferably CH), R8 is cycloalkylalkyl or substituted cycloalkylalkyl (preferably cycloalkylalkyl), and other substituents are as defined for formula 1.0. R1, R2, R3 and R4 are preferably selected from H or halo, and more preferably are selected from H, Br, F or Cl, and more particularly are selected from H, Br or Cl. Representative compounds of formula 1.0 Include trihalo compounds , dihalo and monohalo substituted, such as, for example: (1) 3,8,10-triahalo; (2) 3,7,8-trihalo; (3) 3,8-dlhalo, (4) 8-halo, and (5) substituted 10-halo compounds; where each halo is independently selected. Preferred compounds of 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) 8-CI-substituted compounds, and (5) 10-CI-substituted compounds. The 3,8-dihalo compounds are most preferred and the 8-halo compounds are even more preferred. Therefore, for example, the substituted 3-Br, 8-Ci compounds are the preferred compounds and are even more preferred which 8-CI substituted. The substituent a is preferably N or N + 0", with N.sub.A and B preferably being preferably H2, ie the optional bond is absent and the C5-C-6 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.

R is preferably selected from. arylalkyl, substituted arylalkyl, heteroarylalkyl, substituted heteroarylalkyl, cycloalkylalkyl or substituted cycloalkylalkyl. More preferably, R8 is selected from. aryl- (CrC4) alkyl, aryl- (C? -C4) substituted alkyl, heteroaryl- (C? -C4) alkyl, heteroaryl- (CrC4) substituted alkyl, cycloalkyl- (C? -C4) alkyl, cycloalkyl- (CrC4 ) substituted alkyl. More preferably, R 8 is selected from: aryl-CH 2 -, substituted-aryl-CH, heteroaryl-CH 2 -, heteroaryl-CH 2 -substituted, cycloalkyl-CH 2 -, or cycloalkyl-CH 2 -substituted. More preferably still, R8 is selected from: benzyl, 3-pyridylmethyl, 4-fluoro-benzyl, or cyclopropylmethyl and even more preferably R8 is benzyl. R13 is preferably a 2.0 or 4.0 ring. When substituted on the substituted carbon atoms of the imidazole ring, the substituents are generally selected from: -N (R18) 2, -NHC (0) R18, -C (R34) 2OR35, or alkyl, for example, -CH3- , -CH2OH, -CH2OC (0) 0-cyclohexyl, -CH2OC (0) 0-cyclopentyl, ethyl, isopropyl, NH2 or -NHC (0) CF3. R19 is preferably H or alkyl, more preferably H, methyl or ethyl, and even more preferably methyl. R14 is preferably a carbamate group represented by the substituent 5.0 described above. Preferably, R20 for the substituent 5.0 is selected from: alkyl, substituted alkyl, aryl, cycloalkyl, or cycloalkyl substituted with -OH with the proviso that said -OH substituent is not bonded to a carbon atom that is adjacent to a carbon atom. oxygen. More preferably, R20 for the substituent 5.0 is selected from: Ci to C4 alkyl and C5 to C cycloalkyl. More preferably, R20 for the 5.0 substituent is selected from: t-butyl, i-propyl and cyclohexyl, with i-propyl and cyclohexyl being preferred, and cyclohexyl being still more preferable. R20 in substituent 6.0 is preferably selected from: alkyl or cycloalkyl; more preferably t-butyl, isopropyl or cyclohexyl, and even more preferably cyclohexyl. R21 is preferably selected from: H or alkyl; more preferably H, methyl or isopropyl, and even more preferably H. R20 in substituent 7.0 is preferably selected from: cycloalkyl or alkyl; more preferably t-butyl, isopropyl or cyclohexyl, and even more preferably, cyclohexyl. R36 in substituent 7.1 is preferably selected from: phenyl, cyclopropyl, cyclobutyl, cylcopentyl, cyclohexyl, and still more preferably it is selected from: cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl. R20 in substituent 8.0 is preferably selected from: alkyl or cycloalkylalkyl, more preferably methyl, isopropyl or cyclohexylmethyl; more preferably methyl or isopropyl; and still preferably methyl.

R9, R0, R11, and R12 are preferably selected from: H, Ci to C4 alkyl (e.g., methyl or isopropyl), CON (R18) 2 (e.g., - CONH2), or when R and R > 10, and / or R 11 and r R- > 12 are taken together to form a cycloalkyl ring, said ring is preferably cyclopropylo, cyclopenty or cyclohexyl. R9, R10, R11 and R12 are preferably H when R14 is the substituent carbamate 5.0 and R8 is not H. When R14 is selected from substituents 6.0, 7.0, 7.1 and 8.0, and at least one of R9, R10, R11 and R12 is other than H, then at least one of R9, R0, R11 and R12 is: (I) preferably selected from: (1) C1 to C4 alkyl, (2) -CON (R18) 2 or (3) the cycloalkyl ring formed when R9 and R10 and / or R11 and R12 are taken together with the carbon atom to which they are attached; (II) more preferably selected from: (1) methyl, (2) isopropyl, (3) -CONH2 or (4) cyclopropyl; and (III) is more preferably selected from: (1) R9 and R10 are H, and one of R11 and R12 is selected from: alkyl (preferably, methyl or isopropyl), and the other is selected from H or alkyl (preferably, methyl); (2) R9 and R10 are H, and R11 and R12 are taken together to form a cycloalkyl ring (preferably, cyclopropyl); or (3) R11 and R12 are H, and one of R9 and R10 is -CONH2, and the other is H. Preferred compounds when at least one of R9, R10, R11 and R12 is other than H, also include compounds wherein: R9 and R10 are H, and R11 and R12 are alkyl, the same or different, preferably the same, wherein said alkyl is more preferably methyl. For the compounds of the invention, n is preferably 0-4, more preferably 0-2, and even more preferably 0 or 1. Preferably, each R32 and R33 are independently selected from H, -OR18, aryl or arylalkyl (e.g. benzyl); more preferably H, -OH or phenyl; and still more preferably H. Compounds of 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 formula 1.0 also include compounds having the 2S stereochemistry and the stereochemistry C-11-R or C-11-S. The compounds of this invention include: twenty The compounds of the invention also include the compounds corresponding to 13.0-15.0, 15.1, 16.0, 16.1, 17.0-19.0, 19.1, 20.0, 20.1, 21.0-23.0, 23.1, 24.0 and 24.1-24.7, unless the compounds have the 2S stereochemistry. The compounds of the invention also include compounds corresponding to 13.0-15.0, 15.1, 16.0, 16.1, 17.0-19.0, 19.1, 20.0, 20.1, 21.0-23.0, 23.1, 24.0 and 24.1-24.7, except that ring I is phenyl instead of pyridyl. The compounds of the invention also include compounds corresponding to 13.0-15.0, 15.1, 16.0, 16.1, 17.0-19.0, 19.1, 20.0, 20.1, 21.0-23.0, 23.1, 24.0 and 24.1-24.7, except that the ring I is phenol instead of pyridyl and the compounds has the 2S stereochemistry. Preferred compounds of formula 1.0 include compounds of the formula: (ie, those in which R14 is the carbamate group 5.0) where all substituents are as defined above. A preferred compound of formula 25.0 is: with formula 27.0: being the most preferred formula (where all substituents are as defined above).

The compounds of formula 25.0 include: wherein all substituents are as defined above. Preferred compounds of formulas 28.0 and 29.0 are those in which substituents R1 and R4 are selected to produce trihalo compounds, dihalo and monohalo substituted, as described above. The compounds of formula 29.0 are the preferred compounds. More preferred are compounds of formula 29.0 in which R8 is selected from: benzyl, 4-fluorobenzyl, 3-pyridylmethyl or cyclopropylmethyl, R20 is cyclohexyl, i-propyl or t-butyl (more preferred is the cyclohexyl), R1 is Br or H, R3 is Cl, and R4 is H. More preferred are compounds of formula 29.0 in which R8 is benzyl, R20 is cyclohexyl, i-propyl or t-butyl (cyclohexyl is even more preferred), R1 is H, R3 is Cl and R4 is H or Cl. Preferred compounds of this invention include: (Example 58) (Example 78 Step B) (Example 79 Stage B Isomer A) (Example 80 Isomer A) (Example 88 Isomer A) (Example 93 Isomer d) (Example 99) (Example 100) (Example 225) (Example 226) (Example 227) (Example 228) (Example 229) (Example 232) (Example 233) (Example 234)) (Example 286B) (Example 304) (Example 308) Most preferred compounds include the compounds Example (227) (Example 228) (Example 229) (Example 232) (Example 327) More preferred compounds include the compounds of Examples 58, 199, 225, 226, 229, 232 and 326. The compounds of Examples 58, 199, 225, 229, and 326 are even more preferred. The compound of Example 225 is still more preferred. Preferably, the compound of examples 225, 229 and 326 are administered orally. This invention is also directed to the compounds of Examples 26, 30, 32, 41, 42, 43, 44, 81, 105, 106, 293 and 309. The compound of Example 309 is preferred. This invention is also directed to the compounds of examples 31, 34, 35, 36, 37, 38, 39, 40, 67, 68, 69, 70, 73, 75, 263, 282, 283, 284, 287 and 289. The compounds of examples 67 , 68, 69 and 70 are preferred.

This invention is also directed to the compounds of Examples 27, 28, 29, 71, 72, 74, 76, 98, 101, 103, 104, 107, 108, 110, 111, 255, 256, 257, 258, 259, 260, 261, 262, 264, 265, 266, 267, 268, 269, 270, 271, 272, 273, 274, 275, 276, 277, 278, 285, 286, 286A, 290, 291, 292, 294, 295, 296, 297, 299, 300, 301, 302 and 303. The compounds of the Examples 101, 103, 71, 72 stage B, 72 stage C, and 259 are preferred. This invention is also directed to the compounds of Examples 33, 279, 280 and 281. The lines drawn in the ring systems indicate that the indicated bond can be attached to any of the substitutable carbon atoms. Some compounds of the invention may exist in different isomeric forms (e.g., enantiomers, diastereoisomers, atropisomers). The invention contemplates all said isomers both those in pure form and in mixture, including racemic mixtures. The enol forms are included. Some tricyclic compounds will be acidic in nature, for example, those compounds which 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, alkyl amines, hydroxyalkylamino, N-methylglucamine and the like. Some basic tricyclic compounds 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, saililic, malic, fumaric, succinic, ascorbic, maleic, methanesulfonic and other mineral and carboxylic acids which are well known in the art. The technique. The salts are prepared by contacting the free base form with sufficient amount of the desired acid to produce a salt in the conventional manner. The free base forms can be regenerated by treating the salt with a dilute aqueous base solution such as dilute aqueous NaOH, potassium carbonate, ammonia and sodium bicarbonate. The free base forms differ from their respective salt forms somewhat in terms of 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 invention. All said basic salts and acids are 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 in solvated forms including hydrated forms, for example, the hemi-hydrate. In general, solvated forms with 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 procedures described in WO 95/10516 published on April 20, 1995, WO 96/31478 published October 10, 1996, WO 97/23478 published July 3, 1995. 1997, U.S. Patent 5,719,148 issued February 17, 1998, and the copending application N ° 09/094687 filed June 15, 1998 (see also WO 98/57960 published December 23, 1998); the descriptions of each of them are incorporated here as a reference; and therefore the procedures described below. The compounds of the invention can be prepared according to the reaction schemes described below: REACTION SCHEME 1 (n is 1) (30.0) (31.0) (32.0) In scheme 1, R11 and R12 are preferably methyl when H is attached to the amide nitrogen (ie, when R8 in formula 1.0 is H ), for example, 41.0, and preferably are H when the amide nitrogen is substituted (ie, R8 in formula 1.0 is other than H), for example, 41.1 Those skilled in the art will appreciate that other acylating agents can be used instead of cyclohexyl isocyanate to obtain compounds having different groups attached to the carbonyl group which is attached to the piperazine nitrogen. Those skilled in the art will also appreciate that other ethers can be used in place of compound 31.0 to obtain compounds having different carbon chain between the imidazole ring and the -C (0) NH- group. The 41.0 compounds can be prepared from the addition of imidazole conjugate (2-, 4-, and / or 5-substituted) with an appropriately substituted acrylate 31.0 in EtOH at reflux or only at 90 ° C. The conventional LAH reduction of ester 32.0 provides alcohol 33.0 which can be converted to phthalimide 35.0 through the Mitsunobu reaction. Removal of the phthalimido group with hydrazine EtOH at reflux provides the amine 36.0. This amine rapidly opens the piperazine anhydride 37.0 with CO 2 evolution and the subsequent reaction with the isocyanates provides the golden single stage conversion 38.0. Removal of the BOC group with 50% TFA at room temperature provides salt 39.0, which can be rapidly coupled to the tricyclic chloride 40.0 to give the desired product 41.0.

In scheme 1, and in the schemes that follow, Y represents C, N or N + 0"so that there can be only 0-2 substituents Y that are independently selected from N or N + 0". RA represents the optional substituents on the imidazole ring that are defined for the above imidazole 4.0 ring. R8 represents the optional substituents defined above for the aryl or heteroaryl groups for R8. For example, following reaction scheme 1, wherein R11 and R12 are methyl, and using compound 42.0 (see preparative example 40 in WO 95/10516 published April 20, 1995).

Compound 43.0 can be obtained REACTION SCHEME 2 (n is 0) (47.0) (48.0) (51.0) The synthesis of the intermediate amine 51.0 begins with the alkylation of sodium salt of imidazole (or substituted imldazole) 44.0 at 45.0 to 90 ° C. The conventional LAH reduction of! ester 46.0 provides alcohol 47.0. The tosylation of 47.0 and the displacement of tosylate with potassium phthalimide 49.0 in DMF at 90 ° C provides the phthalimido derivative 50.0, which can be rapidly converted to amine 51.0 with hydrazine EtOH at reflux. The compounds in which R8? H can be prepared in the manner described in scheme 1. In a manner similar to the procedure indicated in scheme 1 for 36.0 and 36.1, 51.0 and 51.1 are reacted in scheme 2 to form compounds of formula 1.0. In scheme 2, R11 and R12 are preferably methyl when H is attached to the amide nitrogen (ie, when R8 in formula 1.0 is H), and preferably are H when the amide nitrogen is substituted (i.e. R8 in formula 1.0 is different from H).

REACTION SCHEME 3 RING IV = PIPERIDINE The compounds (±) 52.0 are resolved following procedures similar to those described in WO 97/23478 (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 / chlorate chloride; reaction step c: (i) aqueous hydrochloric acid / methanol / sodium hydroxide (ii) at reflux / sodium cyanide; reaction step d: concentrated hydrochloric acid / reflux; and reaction step e: di-tert-butyldicarbonate / sodium hydroxide / tetrahydrofuran.

REACTION SCHEME 4 (n is 1-5) V TFA and TFA TEA Reagents V and VI are: REACTION SCHEME 5 DEC HOBT and TFA in scheme 5, R 30 represents: REACTION SCHEME 6- n is 0 In scheme 6, the procedure in Scheme 4 is followed but it is used instead of to obtain the corresponding products of urea (-C (O) NHR20), amide (-C (0) CH2R ° or -C (0) R20), sulfonamide (-S02R20) or carbamate (-C (O) OR20) where n is 0, they can be prepared. Similarly, using (obtained from XI following the procedures in scheme 4), instead in scheme 4 and 5 the corresponding ureas, amides, sulfonamides and carbamates are produced in which n is 0. Those skilled in the art will appreciate that in the schemes 1, 2 and 4-6 can use other aldehydes instead of to obtain the other substituents for R8 in formula 1.0. Those skilled in the art will also appreciate that using instead of in schemes 4 and 5, and using instead of in Scheme 6 the corresponding compounds will be obtained in which imidazole is attached to the alkyl chain by a ring carbon.

REACTION SCHEME 7 (Ra and R, 1? 0u ARE DIFFERENT FROM H) (33.0) In scheme 7, alcohol 33.0 can be oxidized under conventional conditions to provide the aldehyde. The addition of the corresponding Grignard reagent of R9 provides the alcohol which can be transported in the amine as in Scheme 1 or subjected to reoxidation for the ketone followed by the addition of Grignard reagent of R10. In the case where R9 = R10, ester 32.0 (Scheme 1) can be used as an electrophile, adding 2 equivalents of the appropriate Grignard reagent.

REACTION SCHEME 8 (R9 AND R10 ARE DIFFERENT FROM H. IMIDAZOL LINKED TO C) In scheme 8, nitrile can reduce DIBAL-H with aldehyde. In a manner similar to the procedure of Scheme 7, the aldehyde can be treated appropriately with the Grígnard reagent to give the alcohol. An additional round of oxidation and Grignard addition can be carried out to obtain the R9, R10 derivatives unsubstituted with any of R9 = R10 or R9 • R10. The resulting alcohol can be converted to the amine by the methodology shown in any of Schemes 1 or 2. The compounds useful in this invention are exemplified by the following examples, examples which are not to be construed as limiting the scope of the invention.

PRAMPTIVE EXAMPLE 1 Stage A Ethyl 2,2-dimethyl acrylate (50.0 g, 2.0 eq) was stirred with imidazole (13.28 g, 200 mmol) at 90 ° C for 48 hours. The resulting solution was cooled, diluted with water (150 mL) and CH2CI2 (150 mL) and separated. The aqueous layer was washed with CH 2 Cl 2 (2x 75 mL) and the combined organics were dried over Na 2 SO 4 and concentrated in vacuo. The crude mixture was purified by evaporative chromatography using a 10% solution of MeOH in CH2Cl2 as eluent to give the pure product as a clear oil (11.27 g, 29% yield). CIMS: MH + = 197.

Stage B A solution of the title compound of step A (10.0 g, 50.96 mmol) was treated with LiA1H (51 mL, 1M solution in ether, 1.0 eq.). The reaction mixture was stirred for one hour at room temperature before it was quenched by dropwise addition of saturated Na 2 SO 4 (~ 3.0 mL). The resulting suspension was dried with Na2SO4 (solid), diluted with EtOAc (100 mL) and filtered through a plug of Ceiite. The filtrate was concentrated to give a yellow oil (6.87, 87% yield) which was used without further purification. CIMS: MH + = 155.

Etapg C To a solution of the title compound of Step B (6.85 g, 44.42 mmol) phthalimide (7.19 g, 1.1 eq) and pH3P (12.82 g, 1.1 eq) in THF (200 mL) at 0 ° C was added DEAD (7.69 mL). , 1.1 eq) within 10 minutes. The resulting solution was warmed to room temperature and stirred for 48 hours. The reaction mixture was concentrated under reduced pressure and the product was isolated by crystallization from CHaC / Et ^ l to give a white solid (10.03 g, 79% yield). CIMS: MH + = 284.

Stage D A solution of the title compound from step C (9.50 g, 33.53 mmol) and N2H4 (1.25 mL, 1.2 eq.) In EtOH (100 mL) was heated at reflux for 4 hours. The resulting suspension was cooled, filtered and the filtrate was concentrated under reduced pressure. The crude product was purified by evaporative chromatography using a 15% solution (10% NH 4 OH in MeOH) in CH 2 Cl 2 as eluent to give a pale yellow oil (2.80 g, yield: 53%). LCMS: MH + = 154.

PREPARED EXAMPLES 2-4 By essentially the same procedure indicated in Example 1, the amines of column 3 of Table 1 were synthesized from the esters of column 2. "No." represents "Number of the Preparative Example".

TABLE 1 PREPARED EXAMPLE 5 H Piperazine anhydride (preparative example 44) (0.28 g, 1.0 eq.) Was added portionwise to a solution of the title compound of Example 1 (0.17 g, 1.2 mmol) in CH2Cl2 (5.0 mL) and the solution was stirred for 10 minutes at room temperature before adding the cyclohexyl-socianate (0.21 mL, 1.5 eq.) After stirring at room temperature for 15 minutes, the reaction mixture was quenched by the addition of MeOH (1 mL), concentrated to the vacuum, and purified by evaporative chromatography using a 10% solution of MeOH in CH 2 Cl 2 as eluent to give a white solid (0.46 g, 85% yield). FABMS: MH + = 491.

PREPARED EXAMPLE 6 By essentially the same procedure indicated in Preparative Example 5, except that N- (benzyloxycarbonyloxy) -succinimide (CBZ-Osuc) was used in place of cyclohexyl isocyanate, the title compound was prepared (0.16 g, yield 84%) .

PREPARED EXAMPLE 6.1 Following essentially the same procedure indicated in preparative example 6 except that in place of the amine and used the amine of preparative example 2 and was obtained PREPARED EXAMPLE 7 By essentially the same procedure as that indicated in Preparative Example 5, except that the title compound of Preparative Example 3 was used (Table 1), the title compound was prepared. LCMS: MH + -573.

PREPARED EXAMPLE 7.1 Following the same procedure as that indicated in preparative example 5, except that the amine of preparative example 2 was used to obtain the title compound.

PREPARED EXAMPLE 7.2 Following the same procedure as that indicated in preparative example 5, except that the amine of preparative example 4 is used to obtain the title compound.

PREPARATORY EXAMPLE 7.3 The same procedure is followed as that indicated in preparative example 5, except that the amine of preparative example 10 is used to obtain the title compound.

PREPARED EXAMPLE 8 Stage A To the title compound of preparative example 1, step D, (0.82 g, 5.35 mmol) in CH2Cl2 (10 mL) and TEA (0.75 mL, 1.0 eq.) Was added piperazine anhydride (1.65 g, 1.2 eq.) ( prepared as described in preparative example 44) in portions and the resulting solution was stirred at room temperature. After completion of the reaction (TLC), the solution was concentrated in vacuo and the crude product was purified by evaporative chromatography using 10% (10% NH OH in MeOH) in CH2Cl2 then 20% (10% NH4OH in MeOH) in CH2CI2 as eluent. CIMS: MH + = 366.

Stage B The title compound of step A was stirred at room temperature in a 50% solution of TFA in CH2Cl2 (25 mL) for 2 hours.

The resulting solution was concentrated under reduced pressure. Any residual TFA was extracted by azeotropy with toluene to obtain the crude product in which it was used without further purification. CIMS: MH + = 266.

Stage C H - yTFA The title compound of step B was dissolved in CH2Cl2 (30 mL) and TEA (7.62 mL, 10 eq.) Was added. The reaction mixture was stirred for 5 minutes before adding the chloride (42.0) (0.908 g, 0.5 eq.). The resulting solution was stirred at room temperature for 96 hours. The reaction mixture was diluted with water (50 mL), separated and the aqueous layer was extracted CH2CI2, (2 x 200 mL). The combined organics were dried over MgSO4, filtered, and concentrated under reduced pressure. The crude product was purified by evaporative chromatography using 5%, 7.5%, and then 10% (10% NH 4 OH in MeOH) in CH 2 Cl 2 solution as eluent (0.926 g, 30% yield). CIMS: MH + = 571.

Stage D (lsomer-11 R, 2R (-)) (lsomer-11 S, 2R (-)) The title compound of step C was prepared in individual diastereomers by preparative HPLC using a ChiralPak AD column employing 20% IPA in hexanes with 0.2% diethylamine solution as eluent: Isomer A (Isomer 11 A, 2R (-)): retention time = 18.2 minutes; [α] 20 D = 31.7 (3.0 mg in 2.0 mL MeOH). Isomer B (Isomer 11R, 2R (-)): retention time = 30.3 minutes; [a] 20 D = 6.2 (2.4 mg in 2.0 mL MeOH).

PREPARED EXAMPLE 9 Following essentially the same procedure described in Preparative Example 8, except that the title compound of Preparative Example 2 was used (Table 1), the title compound was prepared. The 11 (S) - and 11 (R) isomers (Isomer 11S, 2R (-)) (Isomer 11 R, 2R (-)) were separated by preparative HPLC using a CHRALPAK AD column using 30% IPA in hexanes containing 0.2% diethylamine solution as eluent: Isomer 11S, 2R (-): retention time = 10.2 minutes; MH + = 569; [a] 20 D = 32.7 (4.04 mg in 2.0 mL MeOH). Isomer 11 R, 2R (-): retention time = 22.8 minutes; MH + = 569; [a] 20D = 1.2 (3.40 mg in 2.0 mL MeOH).

PREPARED EXAMPLE 9.1 The procedure indicated in preparative example 8 was followed, except that the amine was used in stage A instead of and a tricyclic 10-CI chloride was used in step C instead of the tricyclic 3-Br-8-CI chloride (Compound 42.0) to obtain the compounds The tricyclic 10-CI chloride (10,11-dichloro-6,11-dihydro-5H-benzo [5,6] cyclohepta [1,2-B] pyridine) is obtained in the following manner: The ketone (starting material) 5,6-dihydro-10-chloro-11H-benzo [5,6] cyclohepta [1,2-c] pyridine-11-one can be prepared following the procedure described by Villani et al. al., J. Het. Chem. 8, 73-81 (1971). The product was prepared by replacing the tricyclic compound 10H with 10-chloro following the procedure described in the preparative example 169. 1 H NMR (CDCl 3 d) 2.97 (m, 2 H), 3.55 (m, 1 H), 4.03 (m, 1 H), 7.11 (s, 1 H), 7.13 (d, 1 H), 7.22 (m, 2 H), 7.31 (d, 1 H), 7.53 (d, 1H), 8.49 (d, 1H).

PREPARED EXAMPLE 10 Stage A Imidazole (2.73 g, 40.1 mmol) in crotonitrile (10 mL) was heated at reflux overnight. The resulting solution was concentrated in vacuo, the residue was diluted with Et2O (50 mL) and washed with water (2 x 100 mL) and brine (1 x 25 mL). The combined organics were dried over Na 2 SO 4 and concentrated under reduced pressure. The product was purified by evaporative chromatography using 15% MeOH in a CH2Cl2 solution as eluent (2.13 g, 39% yield). FABMS: MH + = 136.

Stage B A solution of the title compound from step A (0.50 g, 0.0037 mmol) in THF (10 mL) was treated with LAH (5.5 mL, 1.0 M in Et20, 1.1 eq.). The reaction mixture was stirred at room temperature for 3 hours and quenched by dropwise addition of saturated Na 2 S 4. The resulting suspension was dried by the addition of solid Na 2 SO 4 and filtered through a plug of Celite. The filtrate was concentrated under reduced pressure and the crude residue was purified by evaporative chromatography using a 20% solution (10% NH 4 OH in MeOH) as eluent (0.03 g, 6% yield).

PREPARED EXAMPLE 11 Stage A NBuLi (2.5 mL, 2.5 M in hexanes, 2.1 eq.) Was added to iPr2NH (0.87 mL, 2.1 eq.) In THF (8.0 mL) at 0 ° C. The resulting solution was stirred for 45 minutes before adding the nitrile (1.0 g, 2.97 mmol) in THF (7.0 mL). The reaction mixture was stirred at 0 ° C for 30 minutes before Mel (0.37 mL, 2.0 eq.) Was added. The resulting solution was warmed to room temperature and stirred for 1 hour. The reaction was quenched by the addition of 1N HCl until acidic and diluted with water (40 mL) and extracted with EtOAc (2 x 200 mL). The combined organics were dried over Na2SO4 and concentrated under reduced pressure. The crude product was purified by evaporative chromatography using a solution of 40% EtOAc in hexanes as eluent (0.37 g, 33% yield). MH + = 3.78.

Stage B LiA1H4 (2.7 mL, 1.0 M solution in THF, 1.5 eq.) Was added to the title compound of Step A (0.68 g, 1.80 mmol) in THF (5.0 mL). The resulting solution was stirred at room temperature for 1.5 hours and quenched by dropwise addition of saturated Na 2 SO 4 (10 mL). The solution was extracted with Et2? (2 x 200 mL), the combined organics were dried over MgSO 4 and concentrated under reduced pressure (0.6 g, 88% yield).

Stage C Following the same procedure indicated in preparative example 27 step C, the title compound was prepared.

PREPARED EXAMPLE 12 a p-perazine carboxylic acid solution (0.29 g, 0.881 mmol) prepared as described in preparative example 43, L-histidinamide dihydrochloride (0.20 g, 1.0 eq.), DEC (0.25 g, 1.5 eq.), HOBT (0.18 g, 1.5 eq.), And NMM (0.48 mL, 1.5 eq.) In DMF (5 mL) was stirred at room temperature overnight. The reaction mixture was diluted with water (25 mL) and CH2Cl2 (50 mL), separated and the aqueous layer was extracted CH2CI2 (2 x 50 mL). The combined organics were dried over Na 2 SO 4 and concentrated under reduced pressure. The crude product was purified by evaporative chromatography using a 15% solution of MeOH in CH 2 Cl 2 as eluent (0.24 g, 59% yield). FABMS: MH + = 467.

PREPARATION EXAMPLES 13-17 Following the procedures of J. Chem. Soc. Perkin I (1979), 1341-1344, the following N-substituted histamines were prepared: Example Example Preparative Example 13, Preparative 14, Preparative 15, Example Preparation Example 16, Preparation 17, PREPARED EXAMPLES 18-26 Following essentially the same procedure indicated in preparative example 74, and using the aldehydes and amines indicated in Table 2 can obtain the intermediary products shown in table 2.

TABLE 2 PREPARED EXAMPLE 27 Stage A The nitrile (1.5 g, 4.29 mmol) is dissolved in 10 mL of THF and cooled to -78 ° C under nitrogen. 20 mL of a 1.5 M LDA solution (in cyclohexane) are added. Then a solution of 790 mg (4,293 mmoles) of 2-methylpropyl iodide in 10 mL of THF is added dropwise in 2 hours. Allow to warm to room temperature and stir overnight. 10 mL of water are added followed by 1N HCl until the pH is 10-11. It is diluted with 100 mL of methyl chloride followed by 20 mL of saturated Na2S? 4. MgSO is added until the solution is clear. The organic layer is separated and dried over MgSO 4. Concentrate in vacuo and chromatograph by evaporative chromatography on silica gel using ethyl acetate-hexane (1-3) to give the product as a semi-solid.

Stage B Dissolve the product of step A (0.5 g, 1.23 mmol) in 10 mL of ethanol saturated with ammonia. 8.8 mg (0.017 mmoles) of H2PtCl6 6H2O, 1 g of Raney nickel in water are added and hydrogenated at 3.80 kg / cm2 on a Parr shaker overnight. It is filtered through Celite and concentrated in vacuo.

Stage C The product of step B (0.165 g, 0.403 mmol) is dissolved in 4 mL of 2M HCl and 2 mL of methanol. It is refluxed for 100 minutes and then concentrated in vacuo. The residue is triturated with ether to give the hydrochloride as a white solid.

PREPARED EXAMPLES 28-29. 29.1 and 30 Following the procedure indicated in preparative example 27, but using the indicated alkyl or benzyl halide in place of 2-methylpropyl iodide, the substituted histamines shown were prepared.

PREPARED EXAMPLE 28 Halide Substituted Histamine EXAMPLE PREPARATIVE 29 Substituted Histamine PREPARED EXAMPLE 29.1 Halide Substituted Histamine PREPARED EXAMPLE 30 Halide Substituted Histamine PREPARED EXAMPLE 31 Ethyl 4-pyridyl acetate (4.5 g, 27.24 mmol) was placed in a Parr 500 mL bottle and dissolved in anhydrous EtOH (70 mL). 10% palladium on charcoal (1.0 g) was added to the bottle. The bottle was placed in a hydrogenator and the contents were stirred under 3.86 kg / cm2 of hydrogen pressure at 25 ° C for 94 hours. The mixture was filtered through Celite® and washed with 4x40 mL of anhydrous EtOH. The filtrate was rotoevaporated and the residue was chromatographed on silica gel using 3% (10% concentrated NH 4 OH in methanol) dichloromethane as eluent to give the title compound (Yield: 2,944 g, 63%): FABMS: m / z 172.2 (MH +); dc (CDCl 3) CH 3: 14.3; CH2: 33.2, 33.2, 41.9, 46.5, 46.5 60.2; CH: 33.4; C; 172.7; dH (CDCl 3) 1.18 (m, 1 H, H 4), 1.26 (t, 3 H, CH 3), 1.71 (2 H), 1.90 (1 H), 1.96 (1 H), 2.22 (d, 2 H), 2.63 (2 H), 3.07 (2H), 4.13 (q, 2H) CH3CHr).

PREPARED EXAMPLE 32 4-piperidinyl ethyl acetate was dissolved from the preparative example 31 (500 g, 2.92 mmol) in anhydrous CH 2 Cl 2 (25 mL). To the stirred solution was added trimethylsilyl socianate (5.9 mL, 43.8 mmol) and the solution was stirred at 25 ° C for 17 hours. The solution was worked in NHCO3 saturated with CH2Cl2 and the product was chromatographed on silica gel using 2- > 3% (conc. In NH 4 OH methanol) dichloromethane as eluent to give the title compound (yield: 622 mg, 99%): CIMS m / z 215.3 (MH +); dc (CDCl 3): CH 3: 14.2; CH2: 31.6, 31.6, 41.0, 44.2, 44.2, 60.4; CH: 32.9; C: 158.2, 172.4; dH (CDCl 3): 1.23 (m, 1 H, H 4), 1.27 (t, 3 H, CH 3), 1.75 (d, 2 H), 1.98 (m, 1 H), 2.26 (d, 2 H), 2.85 (t, 2 H) ), 3.94 (d, 2H), 4.15 (q, 2H, CHsC ± h-), 4.56 (bs, 2H).

PREPARED EXAMPLE 33 Ethyl 1-aminocarbonyl-4-piperidinyl acetate from Preparative Example 32 (153.6 mg, 0.717 mmol) was dissolved in anhydrous CH2Cl2 (3.58 mL) and EtOH (3.58 mL). 1.0 M LiOH (1.73 mL, 1.73 mmol) was added to the solution and the mixture was stirred at 50 ° C for 5.5 hours. The mixture was rapidly cooled to 25 ° C and HCl 1, N (2.02 mL, 2.02 mmol) was added and the mixture was stirred for 5 minutes and then rotoevaporated to dryness to provide the title compound which was used. without additional purification.

PREPARED EXAMPLE 34 (Isomer 11 S, 2R (-)) (Isomer 11 R, 2R (-)) The Cu racemate of the previous Isomers (preparative example 141) (62% pure) was subjected to preparative HPLC on a Chiralpak AD® column (50X5 cm) using 75% hexane-25% isopropyl alcohol-0.2% diethylamine as eluent to give in order of elution, Isomer 11 -S (-) and the 11-R (-) isomer. Isomer 11S, 2R (-): Yield: 0.8756 g, 55%): LCMS: m / z 543.1 (MH +); dc (CDCl 3) CH 2: 30.3, 30.4, 31.0, 36.3, 44.3, 44.7, 52.0, 54.5; CH: 58.7, 79.4, 118.8, 126.0, 129.6, 130.4, 132.3, 137.1, 141.3, 147.0; C: 120.0, 134.0, 135.4, 136.7, 140.9, 155.4, 172.2; dH (CDCl3) 2.02 (2H, m, 2"-CH2), 3.32 (2H, m, 3" -CH2), 3.98 (2H, dd, 1"-CH2), 4.30 (1H, s, H11), 6.93 (1H, s, Im-Hs), 6.97 (1H, t, CONHCH2), 7.06 (1H, s, Im-H4), 7.11 (1H, s Ar-H), 7.13 (2H, s, Ar-H) , 7.16 (1H, s, Ar-H), 7.49 (1H, s, Ar-Hio), 7.57 (1H, d, lm-H2) and 8.33 ppm (1H, s, Ar-H2): [a] D20 ° c -45.0 ° (MeOH, c = 9.32 mg / 2 mL), Isomer 11R, 2R (-): Yield: 0.5979 g, 38%): LCMS: m / z 543.1 (MH +), dc (CDCl3) CH2: 30.2, 30.3, 31.1, 36.4, 44.1, 44.7, 52.2, 54.0, CH: 58.2, 79.4, 118.8, 126.1, 129.6, 130.7, 132.3, 137.0, 141.2, 146.8, C: 119.9, 134.0, 135.2, 136.9, 140.7, 155.7, 172.1; dH (CDCl3) 3.34 (2H, m, 3"-CH2), 3.97 (2H, dd, 1" -CH2), 4.30 (1H, s, Hn), 6.93 (1H, s, Im-Hs ), 7.06 (1H, s, im-H4), 7.08 (1H, s, Ar-H), 7.11 (2H, s, Ar-H), 7.14 (1H, s, Ar-H), 7.15 (1H, t, CONHCH2), 7.50 (1H, s, Ar-H? 0), 7.58 (1H, d, lm-H2) and 8.35 ppm (1H, s, Ar-H2); [a] D23-5 ° c- 12.0 ° (MeOH, c = 10.19 mg / 2 mL).

PREPARATORY EXAMPLE 35 Stage A Isonipecotic acid (10 g, 77.42 mmoles) and sodium hydroxide (3.097 g, 77.42 mmoles) were dissolved in THF-water (1: 1) (230 mL) and di-t-butyl dicarbonate (18.59 mL, 85.17 mmoles). The solution was stirred at 25 ° C for 90 hours. The mixture was treated with BioRad® 50W-X4 ion exchange resin (H +) (86.6 mL) and the resin was filtered off and washed with THF and then with water. The combined filtrates were evaporated to dryness to provide the title compound which was used without further purification in the next step: FABS: m / z 229.9 (MH +); dc (d6-DMSO) CH3: 28.0, 28.0, 28.0; CH2: 42.0-43.1 (broad signal); CH: obscured: C: 78.5, 153.8, 175.6.

Stage B The title compound of step A above (2 g, 8.72 mmol) was dissolved in dry DMF (40 mL) and the solution was stirred at 0 ° C under argon atmosphere. Diphenylphosphoryl azide (2.07 mL, 9.59 mmol) was added in 10 minutes followed by triethylamine (2.68 mL, 9.59 mmol) and the mixture was stirred at 0 ° C for 1 hour and then at 25 ° C for 19 hours. Evaporation to dryness followed by chromatography on a column of silica gel using 5% increasing to 7% methanol in dichloromethane gave the title compound: (Yield: 1.57 g, 72%): dc (CDCl 3) CH 3: 28.5, 28.5, 28.5; CH2: 32.9 (width), 42.8 (width); CH: 47.3; C: 79.7, 154.8, 156.5.

PREPARED EXAMPLE 36 Stage A Method 1 4-Hydroxypiperidine (5 g, 49.43 mmol) was dissolved in dichloromethaneanhydride (50 mL) and trimethylsilyl isocyanate (6.27 g, 7.36 mL, 54.38 mmol) was added. The mixture was stirred at 25 ° C under argon atmosphere for 24 hours. Water (10 ml) was added and the mixture was evaporated to dryness. The residue was chromatographed on a column of silica gel using 10% (10% concentrated NH 4 OH in methanol) -dichloromethane as eluent to give the title compound: (Yield: 6.895 g, 97%): CIMS: m / z 145.1 (MH +); dc (d6-DMSO) CH2: 34.2, 34.2, 41.3, 41.3; CH: 66.1; C: 158.0; dH (d6-DMSO) 1.22 (2H, m, 3/5-CH2), 1.68 (2H, m, 35-CH2), 2.84 (2H, m, 2/6-CH2), 3.60 (1H, m, 4 -CH), 3.68 (2H, m), 2/6-CH2), 4.67 (1 H, d, OH) and 5.87 ppm (2H, s, NH2).

Method 2 4-Hydroxypiperidine (10 g, 98.86 mmol) and urea (59.4 g, 988.6 mmol) were dissolved in distilled water (100 mL) and the solution was heated at 100 ° C for 67 hours. The solution was evaporated to dryness and the product was chromatographed on a column of silica gel using 10% (10% concentrated NH 4 OH in methanol) -dicoromethane as eluent to give the title compound (yield: 8.3 g, 58%).

Stage B The title compound from step A above (1 g, 6.94 mmol) and 4-nitrophenyl chloroformate (1.54 g, 7.63 mmol) were dissolved in anhydrous pyridine (10 mL) and the mixture was stirred at 25 ° C for 24 hours. . The mixture was evaporated to dryness and the residue was azeotroped with toluene. The resulting product was chromatographed on a column of silica gel using 3% methanol in dichloromethane as eluent to give the title compound: (1.35 g, 63%): CIMS: m / z 310.05 (MH +); dc (CDCl 3) CH 2: 29.9, 29.9, 40.7, 40.7; CH: 74.9, 121.7, 121.7, 125.2, 125.2: C: 145.2, 151.7, 155.3, 158.7; dH (CDCl3) 1.82 (2H, m, 3/5-CH2), 2.01 (2H, m, 3/5-CH2), 3.06 (2H, s, NH2), 3.31 (2H, m, 2/6-CH2 ), 3.68 (2H, m, 2/6-CH2), 4.98 (1 H, m, 4-CH), 7.39 (2H, d, Ar-H1 / 6) and 8.28 ppm (2H, d, Ar-H3) /5).

PREPARED EXAMPLE 37 Stage A The anhydride (0.5088 g, 1.99 mmol) (prepared as described in preparative example 44) and 1- (3-aminopropyl) imidazole (0.260 mL, 2.18 mmol) were dissolved in anhydrous dichloromethane (10 mL) and the mixture was stirred under argon at 25 ° C for 5 minutes. The mixture was diluted with dichloromethane and extracted with saturated aqueous sodium bicarbonate. The dichloromethane layer was dried (MgSO 4), filtered and evaporated to dryness. The resulting product was chromatographed on a column of silica gel using 10% (concentrated NHOH in methanol) -dichloromethane as eluent to give the title compound: (Yield: 0.4955 g, 74%); LCMS: m / z 338.1 (MH +); dc (CDCl 3) CH 3: 28.4, 28.4; CH2: 31.1, 36.5, -43.5 (width), 44.8, -46.5 (width); CH: 58.2, -119.0 (width), -129.7 (width), -137.3 (width); C: 80.2, 154.7, 171.5; dH (CDCl3) 1.47 (9H, s, CH3), 6.96 (1H, s, lm-H5), 7.08 (1H, s, lm-H4) and 7.52 ppm (1H, s, lm-H2).

Stage B The title compound of step A above (0.3248 g, 0.96 mmole), N1-oxide of 4-pyridylacetic acid (0.191 g, 1.25 mmole), 1 [3- (d.methylamino) propyl] -3-ethylcarbodiimide hydrochloride (0.24 g, 1.25 mmol) 1-hydroxybenzotriazole (0.169 g, 1.25 mmol) and 4-methylmorphoiin (0.1376 mL, 1.25 mmol) were dissolved in anhydrous DMF (11 mL) and the mixture was stirred under argon at 25 ° C for 18 h. hours. The mixture was evaporated to dryness and the residue was dissolved in dichloromethane and washed with saturated aqueous sodium bicarbonate. The organic layer was dried (MgSO4) filtered and evaporated to dryness. The product was chromatographed on a column of silica gel using 5% (10% concentrated NH 4 OH in methanol) -dichloromethane as eluent to give the title compound: (yield: 0.4333 g, 95%); LCMS: m / z 473.1 (MH +); dc (CDCl 3) CH 3: 28.3, 28.3, 28.3; CH2: . 8, 36.5, 38.7, 43.2, -43.5 (width), -44.5 (width); CH: 53.8, -119.2 (width), 127.4, 127.6, -129.3 (width), -137.5 (width), 138.7, 138.9; C: 80.7, 134.5, 154.4, 169.6, 169.6; dH (CDCl3) 1.44 (9H, s, CH3), 6.97 (1H, width s, lm-H5), 7.09 (1H, width s, lm-H4), 7.20 (2H, m, Ar-H), 7.53 ( 1H, width s, lm-H2) and 8.14 ppm (2H, d, Ar-H).

Stage C The title compound of step B (0.289 g, 0.612 mmol) was dissolved in anhydrous dichloromethane (7.8 mL) and trifluoroacetic acid (2.026 mL, 26.3 mmol) was added. The mixture was stirred at 25 ° C for 1.25 hours under argon and then evaporated to dryness. The product was chromatographed on a column of silica gel using 5% increasing to 10% (10% concentrated NH 4 OH in methanol) -dichloromethane as eluent to give the title compound: (yield: 0.208 g, 91%); LCMS: m / z 373.1 (MH +); dc (CDCl3-CD3OD) CH2: 30.4, 36.2, 38.2, 43.9, 44.5, 46.2, 46.7; CH: 52.3, -119.2 (width), 127.7, 127.7, -128.3 (width), 137.4 (width), 138.4, 138.5, 138.5; C: 137.3, 169.8, 170.6; dH (CDCI3-CD3OD) 6.90 (1 H, width s, lm-H5), 6.94 (1H, width s, Im-H4), 7.22 (2H, m, Ar-H), 7.47 (1H, width s, lm -H2) and 8.12 ppm (2H, d, Ar-H); [a] D26 3 ° + 81.1 ° (c = 10.43 mg / 2 mL, methanol).

PREPARED EXAMPLE 38 Stage A To a solution of 3-bromo-8-chloro-5,6-dihydro-11H-benzo [5,6] cyclohepta [1,2-b] pyridin-11-one (2 g) (6.2 mmol) in anhydrous dichloromethane (14 ml) at 0 ° C and under argon atmosphere was added a solution of 3-chloroperbenzoic acid (1.76 g) (10.4 mmoles) in anhydrous dichloromethane (35 ml) by dripping over a period of 30 minutes. The mixture was allowed to warm to room temperature and after 18 hours additional 3-chloroperbenzoic acid (0.88 g) (5.2 mmol) in anhydrous dichloromethane (25 ml) was added and the mixture was stirred for a total of 42 hours. The mixture was diluted with dichloromethane and washed with 1N NaOH (200 ml). The aqueous layer was extracted with additional dichloromethane (2 × 200 ml) and the combined organic layers were dried over magnesium sulfate, filtered and evaporated to dryness. The product was chromatographed on silica gel using 0.25% -0.5% -1% (10% concentrated NH 4 OH in methanol) dichloromethane as eluent to give the title compound (Yield: 1386 g, 66%): ESIMS; m / z 338.1 (MH +); dc (CDCl 3) CH 2: 30.5, 34.0; CH: 126.9. 127.6, 130.3, 132.5, 140.4; C: 121.0, 135.1, 138.3, 139.7, 141.6, 145.3, 188.0 ppm.

Stage B The title compound from step A (1.3422 g) (3.96 mmol) was dissolved in methanol (18 ml) and dichloromethane (20 ml) and sodium borohydride (0.219 g) (5.79 mmol) were added. The mixture was stirred under argon at 0 ° C for 1 hour and then allowed to warm to 25 ° C over a period of 1 hour. The mixture was diluted with dichloromethane (800 ml) and washed with 1 N NaOH (150 ml). The aqueous layer was extracted with dichloromethane (2 × 200 ml) and the combined organic layers were dried over magnesium sulfate, filtered and evaporated to dryness. The product was chromatographed on silica gel using 1% (10% concentrated NH 4 OH in methanol) dichloromethane as eluent to give the title compound (Yield: 1.24 g, 92%): ESIMS; m / z 340.1 (MH +); dc (CDCl 3) CH 2: 31.2, 32.0; CH: 69.1. 126.8, 129.5, 131.7, 131.7, 136.7; C: 118.3, 134.7, 135.2, 139.7, 141.0, 148.9 ppm.

Stage C The title compound of Step B (0.552 g, 1.62 mmol) and triethylamine (1.19 mL, 8.52 mmol) were dissolved in anhydrous dichloromethane (8.5 mL) and the solution was cooled to 0 ° C. Methanesulfonyl chloride (0.4 mL, . 16 mmoles) in 30 minutes and the mixture was stirred at 0 ° C for a total of 1.25 hours. The solution was evaporated to dryness to give the 11-methyl derivative which was used without further purification. The latter was dissolved in anhydrous dichloromethane (40 mL) and the solution was stirred at 0 ° C. N- [3- (1H-imidazol-1-yl) propyl] -2 (R) -piperazinecarboxamide (preparative example 136) was added (0.5 g, 2.11 mmol) in anhydrous dichloromethane (20 mL) and anhydrous DMF (20 mL) was added and the solution was stirred and allowed to warm to 25 ° C for 2 hours. The reaction was allowed to proceed at 25 ° C for 18 hours and then diluted with dichloromethane and washed with saturated aqueous sodium bicarbonate, dried (MgSO 4), filtered and evaporated to dryness. The product was chromatographed on a column of silica gel using 4% (10% concentrated NH4OH in methane) as dichloromethane to give the racemic compound of the title: Yield: 0.399 g, 44%); FABMS: m / z 559.3 (MH +).

Stage D (Isomer 11 R, 2R (+)) (Isomer 11 S, 2R (-)) The racemic compound of the title of step C above (0.395 g) was subjected to preparative HPLC on a Chiralpak AD® column (50X5 cm) using 65% hexane-35% isopropyl alcohol-0.2% diethylamine as eluent to provide the order of elution of the diastereomer 11-R (+) of the title compound followed by the diastereomer 11 -S (-) of the title compound. Diastereoisomer 11R, 2R (+): (Yield: 0.1854 g); FABMS: m / z 559.2 (MH +); (CDCl 3) CH 2: 30.1, 30.3, 31.2, 36.4, 43.9, 44.7, 51.6, 52.8; CH: 57.8, 64.3, 118.9, 125.3, 129.6, 130.6, 130.7, 133.4, 137.3, 138.4; C: 118.2, 133.6, 134.6, 140.1, 141.0, 148.1, 172.0; dH (CDCl3) 5.70 (1H, s, H11), 6.95 (1H, width s, lm-H5), 7.04 (1H, width s, Im- H4), 7.51 (1H, width s, lm-H2) and 8.22 ppm (1H, s, Ar-H2; [a] D20 ° + 41.2 ° (c = 11.08 mg / 2 mL, methanol). Diastereoisomer 11S, 2R (-): (Yield: 0.18 g); FABMS: m / z 559.2 (MH +); (CDCl 3) CH 2: 30.1, 30.3, 31.1, 36.5, 44.4, 44.8, 51.6, 53.4; CH: 58.9, 64.4, -119.2, 126.3, 129.5, 130.6, 130.7, 133. 4, 138.5; C: 118.3, 133.7, 134.6, 139.9, 141.0, 148.1, 172.1; dH (CDCI3) . 69 (1 H, s, Hn), 6.94 (1 H, width s, lm-H5), 7.07 (1H, width s, lm-H4), 7.51 (1H, width s, lm-H2) and 8.26 ppm (1 H, s, Ar-H2); [a] D19 9 ° -71.0 ° (c = 10.32 mg / 2 mL, methanol).

PREPARED EXAMPLE 39 Stage A H 4-Pyridyl-ethyl acetate (4.5 g, 27.24 mmol) was placed in a Parr 500 mL bottle and dissolved in anhydrous EtOH (70 mL). 10% palladium on carbon (1.0 g) was added and the contents were stirred under a pressure of 3.86 kg / cm2 at 25 ° C for 94 hours. The mixture was filtered through Celite® and washed with 4X40 mL of anhydrous EtOH. The filtrate was evaporated to dryness and the residue was chromatographed on silica gel using 3% (10% concentrated NH 4 OH in methanol) -dichloromethane as eluent to give the title compound: (Yield: 2,944 g, 63%); FABMS: m / z 172.2 (MH +); dC (CDCl 3) CH 3: 14.3, CH 2: 33.2, 33.2, 41.9, 46.5, 46.5, 60.2; CH: 33.4; C: 172.7; dH (CDCl 3) 1.18 (1 H, m, H 4), 1.26 (3 H, t, CH 3), 1.71 (2 H), 1.90 (1 H), 1.96 (1 H), 2.22 (2 H, d), 2.63 (2 H), 3.07 (2H), 4.13 ppm (2H, q, CHsCH? -).

Stage B Ethyl 4-piperidinyl acetate (500 mg, 2.92 mmol) from step A above was dissolved in anhydrous dichloromethane (25 mL). To the stirred solution was added trimethylsium isocyaninate (5.9 mL, 43.8 mmol) and the solution was stirred at 25 ° C for 17 hours. The solution was diluted with dichloromethane and washed with saturated aqueous sodium bicarbonate. The dichloromethane layer was dried (MgSO 4), filtered and evaporated to dryness. The product was chromatographed on silica gel using 2% increasing to 3% (10% of concentrated NA4HH in methanol) -dichloromethane as eluent to give the title compound (Yield: 622 mg, 99%); CIMS: m / z 215.3 (MH +); dc (CDCl 3) CH 3: 14.2; CH2: 31.6, 31.6, 41.0, 44.2, 44.2, 60.4; CH: 32.9; C: 158.2, 172.4; dH (CDCl 3): 1.23 (1H, m, H4), 1.27 (3H, t, CH3), 1.75 (2H, d), 198 (1H, m), 2.26 (2H, d), 2.85 (2H, t ), 3.94 (2H, d), 4.15 (2H, q, CH3CH2-), 4.56 (2H, bs).

Stage C Ethyl 1-aminocarbonyl-4-pyridinyl acetate (153 mg, 0.717 mmol) was dissolved from step B in anhydrous dichloromethane (3.58 mL). To the solution was added 1.0N LiOH (1.73 mL, 1.73 mmol) and the mixture was stirred at 50 ° C for 5.5 hours. The mixture was rapidly cooled to 25 ° C and 1.0 N HCl (2.02 mL, 2.02 mmol) was added and the mixture was stirred for 5 minutes and then evaporated to dryness to provide the title compound which was used without further purification. .

PREPARATORY EXAMPLE 40 Stage A The title compound of Preparative Example 37, Step A above (0.45 g, 1.33 mmol), 1 [3- (dimethylamino) propyl] -3-etiicarbodimide hydrochloride (0.332 g, 1.73 mmol), 1-hydroxybenzotriazole (0.234 g, 1.73 mmole) and 4-methyl-morpholine (0.382 mL, 3.46 mmole) were dissolved in anhydrous DMF (7 mL). The title compound of preparative example 33 was added, stage C above (0.3228 g, 1.73 mmol) dissolved in anhydrous DMF (8 mL) and the mixture was stirred at 25 ° C for 22 hours. The solution was evaporated to dryness and the residue was taken up in dichloromethane and washed with saturated aqueous sodium bicarbonate, dried (MgSO 4), and evaporated to dryness. The residue was chromatographed on a column of silica gel using 5% (10% concentrated NH OH in methanol) -dichloromethane as eluent to give the title compound (Yield 0.3553 g, 53%).

Stage B The title compound from step A above (0.45 g, 0.9 mmol) was dissolved in methanol (5.625 mL). A 10% (v / v) solution of concentrated H2SO4 in dioxane (13.5 mL) was added and the mixture was stirred at 25 ° C for 2 hours. Anhydrous methanol (200 mL) was added followed by the BioRad® AG1-X8 (OH) resin until the solution was neutralized to paper pH. The resin was filtered off and washed with methanol and the combined filtrates were evaporated to dryness. The residue was chromatographed on a column of silica gel using 5% increasing to 6.5% (10% concentrated NH 4 OH in methanol) dichloromethane as eluent to give the title compound: (Yield 0.317 g, 96%); FABMS: m / z 406.2 (MH +); dC (CDCl3-5% CD3OD) CH2: 30.8, 31.9, 31.9, 36.2 / 36.3 / 36.6, 39.1 / 39.3 / 39.5, 44.1 / 44.2, 44.4, 44.4, 44.8, 44.8, CH: 51.2 / 56.3, 119.0, 128.8, 137.0; C: 158.7, 171.0 / 171.1, 171.9 / 172.6; dH (CDCIs-2.86% CD3OD) 4.84 (1H, d, H2), 6.98 (1H, width s, lm-H5), 7.04 (1 H, width s, I1? .- H4) and 7.53 ppm (1 H, width s, lm-H2). 40A PREPARED EXAMPLE Stage A A solution of 52.I (J. Med. Chem. 4890-4902 (1998)) (205 g) in concentrated HCl (1 L) and water (100 mL) was refluxed for 18 hours, and then poured on ice (3 kg. ). 50% aqueous NaOH pH 12 was added followed by extraction with EtOAc (3x4 L), and the extracts were washed with brine, dried and evaporated to provide 52.ii (166 g).

Stage B A 1 M solution of DIBAL in toluene (908 mL) was added dropwise over 2 hours to a solution of 52% (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 L). The aqueous extract was basified to pH 10 with 50% NaOH and extracted with EtOAc (3x2 L). 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 C19H2iN279BrCI 393.0556, found 393.0554.

Step C The racemate (+) was resolved by HPLC on a CHIRALPAK AD 8x30 cm column at 25 ° C with a UV detector set at 290 nm. Elution with 0.05% diethylamino-methanol provided: Peak 1 (-) 52.0 (40 g): [< X] D20-28.4O (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 41 Stage A To a solution of (+) - 52.0 (2.3 g) in dimethylformamide (30 ml) was reacted with anhydrous isatol (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 (3x100 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 the title compound 53.0 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 solution of hydrochloric acid was added dropwise in 10 minutes. 4M / 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 (4x100 ml). The combined extract was evaporated under reduced pressure and the crude reaction product was chromatographed by evaporation on silica gel (400 ml). Elution with 25% ethyl acetate-hexane afforded after evaporation the title compound 54.0 a and 54.0 b 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 54.0 a and 54.0 b (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 (30 ml) was added at pH >; 8 followed by drip addition to a solution of (BOC) 2? (9 g) in THF (50 ml) with vigorous stirring for 24 hours. The solution was concentrated at low volume, stirred with hexane (2x120 ml) and 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 the mixture of 57.0 a and 57.0 b as a light tan solid which appeared as a single tic stain (16 g). 1 H NMR (CDCl 3, 300 MHz) d 1.40 (s, 9H); MS (FAB) m / z 535 (MH +). The unique tic spot is a mixture of four isomers that were separated after derivatization into the compounds of Examples 77 to 79 and 87 to 97 below. Following the above procedure (steps AE) except that the compound (-) - 52.0 (17 g) was used, a mixture of 58.0 a and 58.0 b was obtained as a clear solid which appeared as a single tic stain (17 g) . MS (ES) m / z 535 (MH +).

PREPARATIVE EXAMPLE 42 H 2-camphorsulfonic acid To 2.5 kg of (R) - (-) - camphorsulfonic acid stirred at 60 ° C in 1250 ml of distilled water was added a solution of the potassium salt of 2-carboxy-piperazine (565 g, 3.35 moles). The mixture was left under stirring at 95 ° C until it completely dissolved. The solution was allowed to stand at room temperature for 48 hours. The resulting precipitate was filtered to obtain 1444 g of a wet solid. The solids were then dissolved in 1200 ml of distilled water and heated in a steam bath until all the solids dissolved. The quenching solution was then separated to cool slowly for 72 hours. The crystalline solids were filtered to give 362 g of pure 2-R-enantiomeric product as a white crystalline solid [a] D = 14.9 °.

PREPARED EXAMPLE 43 Boc Boc OH 2-R-carboxyl-piperazine-di- (R) - (-) - camphor sulfonic acid (preparative example 42) (362 g, 0.608 mol) was dissolved in 1.4 L of distilled water and 1.4 L of methanol. 75 ml of 50% NaOH were introduced dropwise into the stirred reaction mixture to obtain a solution of -pH 9.5. To this solution was added di-tert-butyl dicarbonate (336 g, 1.54 moles) as a solid. The pH dropped to -7.0. The pH of the reaction mixture was maintained at 9.5 with 50% NaOH (total of 175 ml), and the reaction mixture was stirred for 2.5 hours to obtain a white precipitate. The reaction mixture was diluted to 9 L with ice / water followed by washing with two liters of ether. The ether was discarded and the pH of the aqueous layer was adjusted to pH 3.0 by the addition in portions of solid citric acid. The acidified aqueous layer was then extracted with 3X dichloromethane with 2L. The organic layers were combined, dried over sodium sulfate and filtered, and evaporated to obtain 201.6 g of the title compound as a white glassy solid. FABMS (M + 1) = 331.

PREPARED EXAMPLE 44 Boc A solution of ice-cold N, N, -dimethylformamide (49.6 ml) was added, dropwise, thionyl chloride (46.7 ml) over a period of 5 minutes in a 5 L round bottom flask under nitrogen atmosphere. The reaction mixture was left under stirring for 5 minutes and then the ice bath was removed and the reaction mixture was allowed to stir at room temperature for 30 minutes. The reaction mixture was again cooled in an ice bath and a solution of N, N-di-tert-butoxycarbonyl-2-R-carboxyl-plperazine (Preparative Example 43) (201.6 g, 0.61 mmol) in 51.7 was added. ml of pyridine and 1.9 L of acetonitrile in the reaction mixture was cannulated. The reaction mixture was allowed to warm to room temperature to obtain a cloudy yellowish solution. After stirring at room temperature for 18 hours, the reaction mixture was filtered and the filtrate was poured into ice water (7 L) and then extracted with 4x2 L ethyl acetate, dried over sodium sulfate, filtered and evaporated to dryness in vacuo to obtain 115.6 g (73%) of the title product as a white solid.

PREPARED EXAMPLE 45 1 Np-Cyanobenzyl histamine (0.34, 1.5 mmol) (prepared as described in Preparative Example 163) was added to a solution of Boc anhydride (Preparative Example 44) (0.38 g, 1.5 mmol) in 10 mL of dichloromethane and it was stirred under a nitrogen atmosphere. After 1 hour 0.15 g more of the Boc anhydride was added and the reaction was monitored until complete by normal phase tic using 10% methanol / dichloromethane as eluent. After completion of the reaction (-1 hour), 0.25 ml (2 mmoles) of cyclohexyl isocyanate was added to the reaction mixture and stirred for 1 hour. The reaction mixture was poured into brine and extracted with dichloromethane (3 x). The dichloromethane layers were combined, dried over MgSO4, filtered and evaporated to dryness. The residue was chromatographed on an evaporative column of silica gel using 5% methanol / dichloromethane to obtain 0.714 g of the pure title compound as a solid. FABMS (M + 1) = 564.

PREPARED EXAMPLE 46 N- (2,3-epoxypropyl) phthalamide (2.3 g, 11.3 mmol) was dissolved in N, N-dimethylformamide and imidazole (1.53 g, 1.5 eq.) Was added and the reaction mixture was stirred at 90 ° C for 5 hours. Brine was added and the product was extracted with ethyl acetate to obtain the title product (0.67 g).

PREPARED EXAMPLE 47 1-phthalamido-2-hydroxy-3-1-H-imidazole-propane (from preparative example 46) (0.6 g) was dissolved in ethanol and 5 ml of hydrazine hydrate was added. The reaction mixture was refluxed for 3 hours. The reaction mixture was cooled to room temperature and the resulting precipitate was filtered.

The filtrate was evaporated to dryness to obtain the title product, which was used without further purification.

PREPARED EXAMPLE 48 1-Amino-2-hydroxy-3-1-H-imidazole-propane (from Preparative Example 47) (2.2 mmol) was added to a solution of Boc anhydride (Preparative Example 44) (0.57 g, 2.2 mmol) in 10 ml. of dichloromethane and stirred under nitrogen. After 1 hour, 0.15 g more of the Boc anhydride was added and the reaction was monitored to its complement by normal phase tic using 10% methanol / dichloromethane as eluent. After completion of the reaction (-1 hour), 0.85 ml (6.6 mmoles) of cyclohexyl isocyanate was added to the reaction mixture, and stirred for 1 hour. The reaction mixture was poured into brine and extracted with dichloromethane (3x). The dichloromethane layers were combined, dried over gS? 4, filtered and evaporated to dryness. The residue was chromatographed on an evaporative column of silica gel using 5% methanol / dichloromethane to obtain 0.487 g of the pure title compound as a solid.

PREPARED EXAMPLE 49 The salt of 2-carboxy-piperacna-dicamforsulfonic acid (preparative example 42) (17.85 g, 30 mmol) was dissolved in 180 ml of distilled water. 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-MeOH bath and a solution of benzyl chloroformate (4.28 mL, 30 mmol) in 80 mL of dioxane was added over a period of 30-45 minutes while stirred at 0-5 ° C and maintained the pH at 10.5 to 11.0 with 50% NaOH. After completing the addition, stirring is continued for 1 hour. The reaction mixture was then evaporated to dryness (to liberate it from dioxane for extraction). The residue was dissolved in 180 ml of distilled water and the pH was slowly adjusted to 4.0 with 1N HCl. The aqueous solution was washed with 3x180 ml of ethyl acetate. (The ethyl acetate was dried over MgSO4, filtered and evaporated to obtain N, N-dl-CBZ-2-carboxy-piperazine and stored). The pH of the aqueous layer containing the desired product was adjusted to 10.5 to 11.0 with 50% NaOH and solid di-tert-butyl-dicarbonate (7.86 g, 36 mmol) was added and the mixture was stirred while maintaining the pH at 10.5 to 11.0 with 50% NaOH. After 1 hour the pH was stabilized. When the reaction was completed, the reaction mixture was washed with 2x180 ml of Et20. The aqueous layer was cooled in an ice bath and the pH was adjusted to 2.0 with 1N HCl (slowly). The product was extracted with 3x200 m! of ethyl acetate. It was dried over MgSO4, filtered and evaporated to obtain 9.68 g (88%) of the pure product as a white solid.

PREPARATIVE EXAMPLE 50 H 4-N-CBZ-1N-Boc-2-carboxy-piperazine (Preparative Example 49) (9.6 g 26.3 mmol) was dissolved in 100 mL of absolute ethanol in a hydrogenation vessel. The vessel was flooded with nitrogen and 3 g of 10% Pd / C (50% by weight with water) were added. The mixture was hydrogenated at 3.86 kg / cm2 of H2 for 18 hours. After 18 hours the reaction mixture precipitated. The tic was controlled (30% MeOH / NH3 / CH2CI2). The reaction mixture was filtered on a pad of Celite and the pad was washed with EtOH followed by distilled water. The filtrate was evaporated to -1/3 volume (to liberate it from EtOH) and 200 ml of distilled water was added. The aqueous layer was extracted with ethyl acetate three times (the ethyl acetate layer contained pure N, N-Di-Boc-2-carboxy-piperazine which was stored). The aqueous layer was evaporated to dryness and evaporated from methanol twice to obtain 3.98 g (17.37 mmol) of the pure product.

PREPARED EXAMPLE 51 The tricyclic alcohol (preparative example 40 in WO 95/10516) (5.6 g, 17.33 mmol) was dissolved in 56 ml of dichloromethane and 2.46 ml of thionyl chloride was added while stirring under a dry nitrogen atmosphere. After 5 hours the tic was controlled (by adding an aliquot of the reaction mixture to 1N NaOH and stirring with dichloromethane and controlling the dichloromethane layer with tic using 50% EtOAc / hexanes as eluent). The mixture was evaporated to a gum, which was evaporated from dry toluene twice and once from dichloromethane to give the 11-chloro derivative as a foamy solid which was used without further purification. The resulting 11-chloro-tricyclic compound was dissolved in 100 ml of dry DMF, 1N-Boc-2-carboxy-piperazine (preparative example 50) (3.98 g) was added followed by 12.11 ml of triethylamine and the mixture was stirred at room temperature. environment under nitrogen atmosphere. After 24 hours the DMF was evaporated and the residue was dissolved in 200 ml of ethyl acetate and washed with brine. The brine layer was washed with ethyl acetate twice more, and the ethyl acetate layers were combined. They were dried over magnesium sulfate, filtered and evaporated to give a foamy solid. The solid was chromatographed on a 3.81 X 35.56 cm column of silica gel eluting with 2 L of 0.4% 7N MeOH / NH3: CH2Cl2, 6L of 0.5% 7N MeOH / -NH3: CH2Cl2, 2L of 0.65% 7N MeOH / NH3 : CH2Cl2 (2L of 0.8% 7N MeOH / NH3: CH2Cl2, 4L of 1% 7N MeOH / NH3: CH2Cl2, 2L of 3% 2N MeOH / NH3: CH2Cl2, 2L of 5% 2N MeOH / NH3: CH2Cl2, 2L of 10 % 2N MeOH / NH 3: CH 2 Cl 2, 2L of 15% 2N MeOH / NH 3: CH 2 Cl 2, 4L of 20% 2N MeOH / NH 3: CH 2 Cl 2 to obtain 4.63 g of final product.

PREPARED EXAMPLE 52 The title compound of Preparative Example 51 (1 g, 1.86 mmol) was dissolved in 50 mL of DMF and 1-amino-3-propanol (0.214 mL, 1.5 eq.), DEC (0.71 g, 2 eq.) Was added. , HOBT (0.5 g, 2 eq.) And N-methy-morpholine (1.02 ml, 5 eq.) And the reaction mixture was stirred for 18 hours. The reaction mixture was added to brine and the product was extracted with ethyl acetate 3 times to obtain a crude oil, after evaporating the solvent under reduced pressure, which was purified by chromatography on a column of silica gel with 20% - 50% ethyl acetate / hexanes as eluent. The product containing the fractions was pooled to obtain 0.67 g (60%) of the pure title compound.

PREPARED EXAMPLE 53 2-Aminoimidazole (8 g, 60 mmol) was dissolved in 200 ml of DMF and cooled in an ice bath. Sodium hydride (60% dispersion in oil) (2.4 g, 60 mmol) was added in portions and the reaction mixture was stirred for 1 hour. N- (3-Bromopropyl) -phthalimide (16 g, 74 mmol) was added and the reaction mixture was stirred for V2 hour at 0 ° C and 1 hour at room temperature and added 1 hour at 85 ° C. The reaction mixture was then cooled to room temperature and added to brine and extracted with ethyl acetate to obtain the crude product which was purified by column chromatography using 2% methanol / methylene chloride to obtain 4.88 g of the title compound. Title.

PREPARED EXAMPLE 54 0. 5 g of 1-phthalimidopropyl-2-aminoimidazo (from preparative example 53) was refluxed in 20 ml of 6N HCl for 6 hours. The mixture was washed with ethyl acetate and the aqueous layer was evaporated to dryness to obtain 0.45 g of the title product.

PREPARATORY EXAMPLE 55 1-aminopropyl-2-aminoimidazole (preparative example 54) (0.25 g) and N, N-di-butoxycarbonyl-2-R-carboxyl-piperazine (from preparative example 43) (0.32 g) were dissolved in 10 g. ml of DMF. DEC (0.2 g), 1-hydroxybenzotriazole (0.135 g), and N-methyl-morpholino (0.54 m) were added and the reaction mixture was stirred for 5 hours. The reaction was poured into brine and extracted with dichloromethane to obtain 0.43 g of the title product after chromatography on silica gel using 2% methanol / dichloromethane up to 10%. FABMS M + 1 = 453.3.

PREPARATIVE EXAMPLE 56 Boc 1-Aminopropyl-2-aminonoldazole-N1, N4-di-tert-butyl-1,2- (R) -piperazinedicarboxamide (preparative example 55) (0.38 g) was dissolved in 20 ml of dichloromethane and 0.24 ml of triethylamine. Benzyloxycarbonyl-N-hydroxysuccinimide (0.22 g) was added and the reaction mixture was stirred for 18 hours at room temperature. The reaction mixture was washed with brine and chromatographed on a column of silica gel using ethyl acetate as eluent to obtain 0.39 g of the title product. FABMS M + 1 = 587.3.

PREPARED EXAMPLE 57 H 1-Benzyloxycarbonylaminopropyl-2-aminoimidazoyl-N1, N4-di-tert-butyl-1, 2- (R) -piperandicarboxamide (preparative example 56) was dissolved (0.4 g) in 3 ml of dichloromethane and 1 ml of trifluoroacetic acid was added and the reaction mixture was stirred for 3 hours at room temperature. The mixture was then evaporated to dryness to obtain the pure title product.

PREPARED EXAMPLE 58 1-Benzyloxycarbonylaminopropyl-2-aminoimldazolyl-1,2 (R) -piperazinedicarboxamide (preparative example 57) was dissolved in 50 ml of DMF and 0.46 ml of triethylamine. 3-Bromo-8,11-dichloro-6,11-dihydro-5H-benzo [5,6] cyclohepta [1,2-b] pyridine (171 mg) was added and the reaction mixture was stirred for 24 hours. hours. The reaction mixture was added to brine and extracted with dichloromethane to obtain 82 mg of the title product after chromatography with silica gel using methanol / dichloromethane as eluent. FABMS (M + 1) = 694.

PREPARED EXAMPLE 59 1-tert-Butoxycarbonylaminopropyl-imidazole (0.991 g, 4.4 mmol) was dissolved in 25 moles of dry THF and cooled to -78 ° C. A 2.5 M solution of n-butyllithium (3.88 mL, 9.68 mmol) in cyclohexanes was added dropwise and the reaction was stirred for V2 hour. Acetaldehyde (0.49 mL, 8.8 mmol) was added and the reaction was stirred for V2 hour. The reaction mixture was heated to room temperature. The reaction was diluted with ethyl acetate and washed with brine. The ethyl acetate layer was evaporated to obtain a gum which was chromatographed on silica gel to obtain 0.54 g of the title product. (MH + = 170).

PREPARED EXAMPLE 60 1-tert-Butoxycarbonylaminopropyl-2-hydroxyethyl-imidazole (Preparative Example 59) (0.51 g) was dissolved in trifluoroacetic acid and stirred for 3-4 hours. The mixture was evaporated to dryness to obtain the pure TFA sai of the title compound.

PREPARED EXAMPLE 61 1-N-Trityl-4-iodo-midazole (1.91 g) was dissolved in 20 ml of dichloromethane and 1.46 ml of ethylmagnesium bromide was added with stirring. After 15 minutes N-boc-phenylalanine aldehyde (0.5 g) was added and the reaction mixture was stirred for 18 hours. The reaction mixture was washed with saturated ammonium chloride, dried over magnesium sulfate, and chromatographed on silica gel to obtain 0.8 g of the intermediate blocked product. FABMS (m + 1) = 561. This was then treated with 4M HCl / dloxane for 18 hours. The mixture was evaporated to dryness and dissolved in distilled water and washed with ethyl acetate. The aqueous layer was evaporated to obtain the pure title product. (MH + = 218).

PREPARED EXAMPLE 62 Stage A A mixture of N- (3-bromopropyl) phthalimide (12.3 g, 46 mmol), 4-methylimidazole (3.78 g, 46 mmol), sodium hydride (60% in mineral oil, 1.84 g, 46 mmol) and anhydrous DMF (50 ml) were stirred at 25-70 ° C under N2 overnight. The mixture was concentrated in vacuo to give a residue which was diluted with dichloromethane, filtered, concentrated in vacuo and purified by evaporative column chromatography (silica gel) using 1% MeOH-CH2Cl2 saturated with aqueous ammonium hydroxide for give the title compound as an oil (8.04 g, 65%, MH '= 270).

To a solution of the title compound from Step A (8.02 g, 29.8 mmol) dissolved in absolute EtOH (150 mL) was added hydrazine monohydrate (15 mL) and the mixture was stirred under reflux for 12 hours under N2. The mixture was diluted with dichloromethane, filtered and concentrated in vacuo. The residue was purified by evaporative column chromatography (silica gel) using 50% MeOH-CH2Cl2 saturated with aqueous ammonium hydroxide to give the title compound as an oil (2.95 g, 71%, MH + = 140).

PREPARED EXAMPLES 63-67 Following the procedure indicated in preparative example 62, but using the substituted imidazole in Table 3 below in place of 4-methylimidazole from step A, the amines (product) listed in Table 3 were prepared.

TABLE 3 PREPARED EXAMPLE 67 If the procedure indicated in the preparative example is followed 62 except that imidazole is used instead of 4-methylimidazole in step A, the amine is obtained PREPARED EXAMPLE 67.1 If the procedure indicated in preparative example 62 is followed, except that imidazole is used instead of 4-methylimidazole in step A, the amine is obtained H2N. . PREPARED EXAMPLE 68 A mixture of 2-cyclohexylamine hydrochloride (7.66 g, 66 mmol), 2,4-dimethyl imidazole (5.88 g, 61 mmol), tetrabutyl ammonium sulfate (0.83 g, 2.5 mmol), solid NaOH (8.81 g, 220 mmol) and anhydrous acetonitrile (80 ml) was stirred at reflux for 48 hours under N2. The mixture was filtered, concentrated in vacuo and purified by evaporative chromatography (silica gel) using 2% MeOH-C ^ C saturated with aqueous ammonium hydroxide to give the title compound as an oil (10.7 g, 100%, MH + = 140).

PREPARED EXAMPLES 69-73 Following the procedure indicated in Preparative Example 68, but using the substituted imidazole or triazole of Table 4 below in place of 2,4-dimethylimidazole, the amines (product) of Table 4 were prepared.

TABLE 4 PREPARED EXAMPLE 74 A mixture of 1- (3-aminopropyl) imidazole (37.1 g, 297 mmol), benzaldehyde (30 g, 283 mmol), 3 A molecular sieves (50 g), sodium acetate (24.1 g, 283 mmol) and anhydrous methanol (700 ml) were stirred at room temperature under N2 atmosphere overnight. The mixture was cooled to 0 ° C and sodium borohydride (10.9 g, 288 mmol) was added in portions in one hour. The mixture was stirred at room temperature for 3 hours. The mixture was then filtered through celite, washed with methanol, and concentrated in vacuo to give a residue which was diluted with dichloromethane and washed with 10% aqueous sodium hydroxide. The organic phases were washed with brine, dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo to give the title compound as a pale yellow oil (56.3 g, 92%, MH + = 216).

PREPARED EXAMPLES 75-95 Following the procedure indicated in the preparative example 74, but using the aldehyde and the imidazolylalkylamine (midazole) in Table 5 the amines (product) of Table 5 were obtained.

TABLE 5 PREPARED EXAMPLE 95.1 Stage A To a solution of CH2Cl2 (500 ml) of the title compound of preparative example 92, step A (65.7 g) cooled to 0 ° C was added trityl chloride (27.2 g). The resulting reaction mixture was heated and stirred at room temperature for 1.5 hours, and then concentrated in vacuo without heating. Purification by column in evaporative chromatography (silica, 1: 1 acetone-EtOAc) provided the pure 4-methyl isomer (35.02 g, MH + = 270).

Stage B Following essentially the same procedure as that described in Preparative Example 62, Step B, except that the pure 4-methylimidazole product of Preparative Example 95.1 Step A (35.02 g) was used, the title compound was obtained (16.12 g, MH + = 140).

Stage O Following essentially the same procedure as that described in preparative example 74, except that the 4-methylimidazole propylamine product of Preparative Example 95.1, step B above (16.12 g) was used in place of 1- (3-aminopropyl) imidazole, the title compound (18.03 g, MH + = 230).

PREPARED EXAMPLE 97 A mixture of the title compound of Preparative Example 82 (0.50 g, 2.1 mmol), Absolute EtOH (50 mL), 30% Hydrogen Peroxide (aqueous), (0.45 mL, 4.4 mmol) and 1M NaOH (aqueous) (4.4 ml, 4.4 mmol) were stirred at 50 ° C for 12 hours. The mixture was concentrated in vacuo and purified by evaporative chromatography (silica gel) using 10% MeOH-CH 2 Cl 2 saturated with aqueous ammonium hydroxide to give the title compound as an oil (0.33 g, 61%, MH + = 259).

PREPARED EXAMPLE 98 To a cooled solution (0 ° C) of 1- (3-aminopropyl) imidazole (Aldrich, 1.9 ml, 16 mmol) and triethylamine (5.6 ml, 40 mmol) dissolved in anhydrous CH2Cl2 (20 ml) was added phenylacetyl chloride (2.12 ml, 16 mmol). The mixture was heated and stirred at room temperature overnight. The mixture was washed with 1 N aqueous NaOH, dried over anhydrous MgSO 4 and filtered. The solution was concentrated in vacuo and purified by evaporative column chromatography (silica gel) using 2% MeOH-98% CH 2 Cl 2 saturated with aqueous ammonium hydroxide to give the title compound as an oil (1.8 g, %, MH + = 244).

PREPARED EXAMPLE 99 To a refluxing solution of the title compound of Preparative Example 98 (0.51 g, 2.1 mmol) dissolved in anhydrous THF (5 mL) was added a complex of borane dimethyl sulfide (6.3 mL, 2M in THF, 13 mmol). After 1 hour the mixture was cooled to room temperature and stirred overnight. Hydrochloric acid (1N) was added dropwise until the reaction mixture was determined to be acidic (pH paper). The mixture was basified with 1N aqueous NaOH, extracted with CH2Cl2, dried over anhydrous MgSO4 and filtered. The solution was concentrated in vacuo and purified by evaporative column chromatography (silica gel) using 2% MeOH-98% CH2Cl2 saturated with aqueous ammonium hydroxide to give the title compound as an oil (0.25 g, 52%). %, MH + = 230).

PREPARATORY EXAMPLE 100 To a cooled solution (0 ° C) of the title compound of Preparative Example 62 step B (0.7 g, 5 mmol) and triethylamine (1.7 ml, 12.5 mmol) dissolved in anhydrous CH 2 Cl 2 (10 ml) was added phenylacetyl chloride ( 0.67 ml, 5 mmol). The mixture was heated and stirred at room temperature overnight. The mixture was washed with 1 M HCl (aqueous) and the aqueous phase was basified with 1N aqueous NaOH. This phase was extracted with CH CI2 and dried over anhydrous MgSO4 and filtered. The solution was concentrated in vacuo to give the title compound as an oil (0.72 g, 56%, MH + = 258).

PREPARED EXAMPLE 101 To a refluxing solution of the title compound of Preparative Example 100 (0.66 g, 2.5 mmol) dissolved in anhydrous THF (15 mL) was added a borane-THF complex (5 mL, 1 M in THF, 5 mmol). The mixture was refluxed for 12 hours and then cooled to room temperature and concentrated in vacuo. The residue was diluted with 1M HCl and washed with CH 2 Cl 2 and then the aqueous base was basified with 50% aqueous NaOH and extracted with CH 2 Cl 2 and then dried over anhydrous MgSO 4 and filtered. The solution was concentrated in vacuo and purified by preparative plate chromatography (silica gel) using 3% MeOH-CH2Cl2 saturated with aqueous ammonium hydroxide to give the title compound as an oil (0.21 g, 35%, MH + = 244) which was purified by preparative chiral chromatography (Chiralpack AD column, 5 cm X 50 cm, flow rate 80 ml / min, 5-8% IPA-Hexane + 0.2% diethylamine).

PREPARED EXAMPLE 101.1 If the procedure of preparative example 100 is followed but the compound is reacted with the title compound of preparative example 62 step B then the product is obtained PREPARED EXAMPLE 101.2 If the procedure of preparative example 101 is followed but the product of preparative example 101.1 is used, then the product is obtained PREPARED EXAMPLE 102 Stage A To a cold (0 ° C) solution of 1- (3-aminopropyl) lmidazole (10 g, 80 mmol), and triethylamine (17.1 ml, 120 mmol) dissolved in anhydrous CH 2 Cl (50 ml) was added trifluoroacetic anhydride ( 12.4 mL, 88 mmol) The mixture was heated and stirred at room temperature overnight, then the mixture was washed with water, dried over anhydrous MgSO4, filtered, and concentrated in vacuo to give the title compound in vacuo. shape of an oil (15.7 g, 88%, MH + = 222).

Stage B To the title compound of step A (0.24 g, 1.1 mmol) dissolved in anhydrous DMF (10 ml) was added solid sodium hydride (85 mg., 2.1 mmol, 60% dispersion in mineral oil). When the evolution of gas ceased, methyl iodide (0.1 ml, 1.1 mmol) was added and the mixture was stirred at 70 ° C for 40 minutes. The resulting mixture was cooled to room temperature, concentrated in vacuo, diluted with CH2Cl2 and washed with water. The solution was dried over anhydrous MgSO 4, filtered and concentrated in vacuo to give an oil (0.28 g). Purification by preparative layer chromatography (silica gel) using 2% MeOH-98% CH2Cl2 saturated with aqueous ammonium hydroxide gave the title compound as a yellow oil (78 mg, 30%, MH + = 236 ).

Stage C A mixture of the title compound from step B (74 mg, 0.3 mmol) and 20% KOH in H20 (0.6 ml) was stirred at room temperature for 15 minutes. The resulting mixture was concentrated in vacuo and purified by evaporative column chromatography (silica gel) using 10% MeOH-90% CH2Cl2 saturated with aqueous ammonium hydroxide to give the title compound as an oil (65 mg, 100%, MH + = 140).

PREPARED EXAMPLE 103 Following a procedure similar to that used for the preparation of the title compounds from preparative example 102, steps BC, but using ethyl iodide instead of methyl iodide, ethylamine was obtained in the form of an oil (893 mg , 43%, MH + = 154).

PREPARED EXAMPLE 104 Following a procedure similar to that used for the preparation of the title compound from preparative example 102, steps BC, but using propyl iodide instead of methyl iodide, the appropriate propllamine was obtained in the form of an oil (649 mg , 29%, MH + = 168).

PREPARED EXAMPLE 105 Alternative procedure for the preparative example 74 Following a procedure similar to that used for the preparation of the title compounds from preparative example 102, steps BC but using benzyl bromide instead of methyl iodide, benzylamine was obtained in the form of an oil (1.64 g, 56%, MH + = 216).

PREPARED EXAMPLE 106 A mixture of the title compound of Preparative Example 74 (1.34 g, 6.2 mmol), the title compound of Preparative Example 44 (1.6 g, 6.2 mmol), triethylamine (1.3 mL, 9.3 mmol) and anhydrous CH 2 Cl 2 (10 mL) were stirred at room temperature for 48 hours. Trifluoroacetic acid (10 ml) was added and the resulting mixture was stirred for an additional 1.5 hours. Aqueous NaOH (1N) was added dropwise to neutralize the reaction mixture and the resulting mixture was extracted with CH2Cl2. The organic phase was dried over anhydrous MgSO4, filtered and concentrated in vacuo to give a residue, which was purified by evaporative column chromatography (silica gel) using 1% MeOH-99% CH2Cl2 saturated with aqueous ammonium hydroxide for obtain the title compound as an oil (520 mg, 26%, MH + 328).

PREPARED EXAMPLE 107 Using the procedure described for preparative example 106, but using the title compound of Preparative Example 76, the title compound was prepared (0.16 g, 10%, MH + = 346).

PREPARED EXAMPLE 108 Using the procedure described for preparative example 110, (following), but using the title compound of Preparative Example 107 (146 mg, 0.55 mmol), and 8-CI-tricyclic chloride (see Preparative Example 7, in WO 95 / 10516). (159 mg, 0.46 mmol), the title compounds were prepared and separated by preparative plate chromatography (silica gel) using 2% MeOH-CH2Cl2 saturated with aqueous ammonium hydroxide: diastereomer A (45 mg, 17.1% MH + = 573); dlaestereomer B (43 mg, 16.3%, MH + = 573).

PREPARED EXAMPLE 109 To a solution of the title compound of Example 113 (below) (4.90, 6.7 mmol) dissolved in anhydrous CH 2 Cl 2 (25 mL) was added TFA (15 mL). The solution was stirred at room temperature under N2 for 2 hours, then concentrated in vacuo, diluted with CH2Cl2, washed with a saturated aqueous solution of NaHCO3 and dried over anhydrous MgSO4. The mixture was filtered, concentrated in vacuo and purified by evaporative column chromatography (silica gel) using 2% MeOH-98% CH2Cl2 saturated with aqueous ammonium hydroxide to give the title compound as a mixture of deaereomers (3.66 g, quantitative). The diastereomers were separated by preparative chiral chromatography (Chiralpack AD, 5 cm x 50 cm column, flow rate 80 ml / min., 99.8% MeOH + 0.2% diethylamine) to give 1.62 g of the 11S.2R diastereomer A and 1.97 g of the 11 R, 2R diastereomer B. Physicochemical data of diastereomer A 11 S, 2R: pf 109.3 ° C; MH + = 633; [α] 0D = -66.2 ° (3.93 mg / 2 ml MeOH). Physical chemical data of the diastereomer B 11R, 2R: p.f. 64.5 ° C; MH + = 633; [α] 20 D = -41.8 ° (4.69 mg / 2 ml MeOH).

PREPARATIVE EXAMPLE 110 (Alternative procedure for preparative example 109) A mixture of the title compound of Preparative Example 106 (510 mg, 1.6 mmol), tricyclic chloride (Compound No. 42.0) (534 mg, 1.6 mmol), triethylamine (1.1 mL, 7.8 mmol) and CH2Cl2 (10 mL) was stirred at room temperature overnight. The reaction mixture was concentrated in vacuo and purified by column evaporative chromatography (silica gel) using 2% MeOH-98% CH2Cl2 saturated with aqueous ammonium hydroxide to give the title compound as a yellow solid. clear (420 mg, 42%, MH + = 633). The diastereomers were separated by preparative chiral chromatography (Chlralpack Ad column, 5 cm x 50 cm, flow rate 80 ml / min., 99.8% MeOH + 0.2% diethylamine) to give 182 mg of diastereomer A and 126 mg of diastereomer B.

PREPARED EXAMPLE 111 A mixture of the title compound of Preparative Example 106 (1.93 g, 5.9 mmol), 8-Ci-tricyclic chloride (see Preparative Example 7 in WO 95/10516) (1.56 g, 5.9 mmol), triethylamine (4.1 mL, 29.5 mmoies) and CH2CO2 (10 ml) was stirred at room temperature for 48 hours. The reaction mixture was concentrated in vacuo and purified by evaporative column chromatography (silica gel) using 2% MeOH-98% CH2Cl2 saturated with aqueous ammonium hydroxide to give the title compound as a yellow solid. clear (1.56 g, 49%, MH + = 555). The diastereomers were separated by preparative chiral chromatography (Chiralpack AD column, 5 cm x 50 cm, flow rate 80 ml / min, 30% IPA + 70% Hexane + 0.2% diethylamine) to give 0.72 g of diastereomer A 11S.2R, and 0.57 g of the diastereomer B 11R, 2R.

PREPARED EXAMPLE 111.1 The procedure of Preparative Example 111 was followed, but the 10-CI-tricyclic chloride was used to get PREPARED EXAMPLE 112 HOBT (0.82 g, 6.1 mmol), DEC (1.2 g, 6.0 mmol), the title compound of Preparative Example 85 (1.39 g, 6.1 mmol, was added to the carboxylic acid of Preparative Example 43). isolated by preparative chiral chromatography (Chiralpack AD column, 5 cm x 50 cm, flow rate 80 ml / min., 8% IPA + 92% hexane + 0.2% diethylamine), NMM (1.7 ml, 15.5 mmol) and DMF Anhydrous (60 ml) The mixture was stirred at room temperature under N2 overnight The mixture was concentrated in vacuo, diluted with CH2Cl2 and washed with NaOH (aqueous) The organic phase was dried over anhydrous Na2SO4, filtered and concentrated in vacuo The residue was purified by evaporative column chromatography (silica gel) using 2-15% MeOH-CH2Cl2 saturated with aqueous ammonium hydroxide to give the title compound (1.8 g, 55%, MH + = 542).

PREPARED EXAMPLE 113 Using the procedure described for Preparative Example 109, but using the title compound of Example 126 below, the title compounds were prepared and separated: diastereomer A 11S, 2R (-): yield 25.4, MH + = 619; [α] 20 D = -46.7 ° (1.86 mg / 2 ml MeOH); diastereomer B 11R.2R (-): yield 21.2%, MH + = 619; [α] 20 D = -23.0 ° (2.6 mg / 2 ml MeOH).

PREPARED EXAMPLE 114 To a solution of the title compound of Preparative Example 112 (1.8, 3.33 mmol) dissolved in anhydrous CH 2 Cl 2 (5 mL) was added TFA (5 mL). The solution was stirred at room temperature under N2 overnight, concentrated in vacuo and diluted with DMF (10 mL). To this was added 8-Cl-tricyclic chloride (562 mg, 1.1 mmol) and triethylamine (10 ml) and left under stirring at room temperature for 48 hours. The reaction mixture was concentrated in vacuo, diluted with CH 2 Cl 2, washed with a solution with a saturated aqueous solution of NaHCO 3 and dried over MgSO 4, anhydrous. After filtration and concentration in vacuo the residue was purified by evaporative column chromatography (silica gel) using 3-10% CH 2 Cl 2 saturated with aqueous ammonium hydroxide to obtain the title compounds (diastereomer A, 11S.2R, 152 mg , 27%, MH + = 569, and diastereomer B 11R.2R, 316 mg, 56%, MH + = 569).

PREPARED EXAMPLE 115 To the title compound of Preparative Example 43 (2.64 g, 8.0 mmol) was added HOBT (1.26 g, 9.3 mmol), DEC (1.79 g, 9.3 mmol), the title compound of Preparative Example 78 (1.44 g, 6.7 mmol). NMM (1.5 ml, 13.6 mmol) and anhydrous DMF (10 ml). The mixture was stirred at room temperature under N2 overnight. The mixture was concentrated in vacuo, diluted with CH2Cl2 and washed with NaOH (aqueous). The organic phase was dried over anhydrous Na 2 SO 4, filtered and concentrated in vacuo. The residue was purified by evaporative column chromatography (silica gel) using 1% MeOH-CH2Cl2 saturated with aqueous ammonium hydroxide to give the title compound (0.94 g, 27%, MH + = 529).

PREPARED EXAMPLE 116 The title compound of Preparative Example 115 (0.73 g, 1.38 mmol) and anhydrous CH 2 Cl 2 (5 mL) were stirred at room temperature for 48 hours. Trifluoroacetic acid (2 ml) was added and the resulting mixture was stirred for an additional 1.5 hours. NaOH (1N) was added dropwise to neutralize the reaction mixture, and the resulting mixture was extracted with CH2Cl2. The organic phase was dried over anhydrous MgSO 4, filtered and concentrated in vacuo to give a residue, which was purified by evaporative column chromatography (silica gel), using 5-15% MeOH-CH 2 Cl 2 saturated with hydroxide. of aqueous ammonium to give the title compound as an oil (346 mg, 76%, MH + = 329).

PREPARED EXAMPLE 117 Using the procedure described by preparative example 110, but using the title compound of Preparative Example 116 (343 mg, 1 mmol) and the tricyclic chloride (Compound No. 42.0) (718 mg, 2 mmol), the titre and separated: diastereomer A 11S, 2R: 135 mg, 29%, MH + = 634; diastereomer B 11R.2R: 126 mg, 27%, MH + = 634.

PREPARED EXAMPLE 118 To the carboxylic acid of Preparative Example 43 (7.26 g, 22 mmol) was added HOBt (3.92 g, 29 mmol), DEC (5.49 g, 29 mmol), the title compound of Preparative Example 74 (4.73 g, 22 mmol) NMM (4.84 ml, 44 mmol) and anhydrous DMF (35 ml). The mixture was stirred at room temperature under N2 overnight. The mixture was concentrated in vacuo, diluted with CH2Cl2 and washed with NaOH (aqueous). The organic phase was dried over Na 2 SO, filtered and concentrated in vacuo. The residue was purified by evaporative column chromatography (silica gel) using 1% MeOH-CH 2 Cl 2 saturated with aqueous ammonium hydroxide to give the title compound (1.71 g, 15%, MH + = 528).

PREPARED EXAMPLE 119 The title compound of Preparative Example 118 (1.4 g, 2.7 mmol) and paraformaldehyde (solid, 2.8 g) were heated at 130 ° in a sealed tube for 12 hours. The mixture was diluted with CH2Cl2 and filtered. The organic phase was concentrated in vacuo and purified by evaporative column chromatography (silica gel) using 1% MeOH-CH2Cl2 saturated with aqueous aminium hydroxide to give the title compound (0.89 g, 59%, MH + = 558). .

PREPARED EXAMPLE 120 The title compound of Preparative Example 119 (0.88 g, 1.6 mmol), anhydrous CH 2 Cl 2 (10 mL) and trifluoroacetic acid (10 mL) were stirred at room temperature for 1.5 hours. Aqueous NaOH (1N) was added dropwise to neutralize the reaction mixture followed by concentration in vacuo and purification by evaporative column chromatography (silica gel) using 5-12% MeOH-CH 2 Cl 2 saturated with aqueous ammonium hydroxide to give the compound of the title in the form of an oil (503 mg, 88%, MH + = 358).

PREPARED EXAMPLE 121 The title compound of Preparative Example 120 (498 mg, 1.4 mmol) was dissolved in anhydrous CH 2 Cl 2 (10 mL). To this was added the 8-CI-tricyclic chloride (370 mg, 1.4 mmol) and triethylamine (0.6 ml) and it was left under stirring at room temperature for 24 hours. The reaction mixture was concentrated in vacuo and diluted with CH2Cl2, purified by evaporative column chromatography (silica gel) using 3% MeOH-CH2CI2 saturated with aqueous ammonium hydroxide to give the title compounds as a mixture. of diastereomers (38% yield) which were separated by preparative chiral chromatography (Chiralpack AD column, 5 cm x 50 cm, flow rate 80 ml / min, 30% IPA-Hexane + 0.2% diethylamine). (diastereomer A: 178 mg, MH + = 585, and diastereomer B: 130 mg, MH + = 585).

PREPARED EXAMPLE 122 HOBT (4.39 g, 33 mmol), DEC (6.33 g, 33 mmol), the title compound of Preparative Example 88 (5.97 g, 25 mmol) was added to the carboxylic acid of Preparative Example 43 (8.11 g, 25 mmol). NMM (5.5 ml, 50 mmol) and anhydrous DMF (40 ml). The mixture was stirred at room temperature under N2 for 48 hours. The mixture was concentrated in vacuo, diluted with CH2Cl2 and washed with NaOH (aqueous). The organic phase was dried over anhydrous Na 2 SO 4, filtered and concentrated in vacuo. The residue was purified by evaporative column chromatography (silica gel), using 15 MeOH-CH 2 Cl 2 saturated with aqueous ammonium hydroxide to give the title compound (5.24 g, 38%, MH + = 556).

PREPARED EXAMPLE 123 The title compound of Preparative Example 122 (5.23 g, 9.4 mmol) anhydrous CH 2 Cl 2 (10 mL) and trifluoroacetic acid (10 mL) were stirred overnight. Aqueous NaOH (1N) was added dropwise to neutralize the reaction mixture, concentrated in vacuo and purified by evaporative column chromatography (silica gel) using 5-9% MeOH-CH 2 Cl 2 saturated with aqueous ammonium hydroxide to obtain the title compound in the form of an oil (2.69 mg, 81%, MH + = 356).

PREPARED EXAMPLE 124 The title compound of Preparative Example 123 (2.67, 7.5 mmol) was dissolved in anhydrous CH 2 Cl 2 (40 mL). To this was added 8-CI-tricyclic chloride (1.98 g, 7.5 mmol) and triethylamine (3.14 ml) and left under stirring at room temperature for 12 hours. The reaction mixture was concentrated in vacuo, diluted with CH 2 Cl 2, washed with a saturated aqueous solution of NaHCO 3 and dried over anhydrous MgSO 4. After filtration and concentration in vacuo the residue was purified by evaporative column chromatography (silica gel) using 1-2% MeOH-CH2Cl2 saturated with aqueous ammonium hydroxide to give the title compounds in 43% yield (diaesstereomer A, 1.2 g, MH + = 583, and diastereomer B, 681 mg, MH + = 583).

PREPARATORY EXAMPLE 125 A mixture of the title compound of Preparative Example 106 (200 mg, 0.61 mmol), chlorobenzosuberane (140 mg, 0.61 mmol), triethylamine (0.43 mL, 3.1 mmol) and CH2Cl2 was stirred at room temperature overnight. The reaction mixture was concentrated in vacuo and purified by preparative plate chromatography (silica gel) using 2% MeOH-CH2Cl2 saturated with aqueous ammonium hydroxide to give the title compound as a light yellow solid ( 63 mg, 20%, MH + = 520).

PREPARED EXAMPLE 126 If the procedure of Preparative Example 114 is followed except that the 3-trichloro tricyclic compound is used in place of the 8-CI-tricyclic chloride, the title compound would be obtained.

PREPARED EXAMPLE 127 Stage A To the salt of dialcanephosphonic acid of piperazine carboxylic acid (Preparative Example 42) (14.63 g, 24.6 mmol) dissolved in water (80 ml) and dioxane (80 ml) was added 50% NaOH (aqueous) to pH 11. added BOC-ON (6.65 g, 27.04 mmol) while stirring at room temperature for 6.5 hours and while maintaining the pH at 11 with 50% NaOH. The pH was decreased to 9.5 using 10% HCl (aqueous) and cyclohexyl chloroformate (4.0 g, 24.6 mmol) which was added dropwise while maintaining the pH at 9.5 with a slow addition of 50% NaOH (aqueous) with stirring at 25 ° C for additional 12 hours. The mixture was extracted with Et2? and the aqueous phase was acidified to pH 3 with 6M HCl (aqueous). This aqueous phase was extracted with EtOAc and the organic phase was dried over anhydrous gS04, filtered and concentrated in vacuo and purified by evaporative chromatography (silica gel) using 25-50% EtOAc-hexane to give the title compound ( 6.65 g, 76% MH + = 357).

Stage B The title compound of step A (6.65 g, 18.7 mmol) and trifluoroacetic acid (20 ml) dissolved in anhydrous CH2Cl2 (50 ml) was dissolved at room temperature for 1 hour. The organic phase was concentrated in vacuo to give a residue.

Stage Q The title compound of step B was dissolved in anhydrous CH2Cl2 (50 ml) and DMF (50 ml). To this was added the 8-CI-tricyclic chloride (8.42 g, 31.8 mmol) and triethylamine (3 ml) and it was left under stirring at room temperature for 48 hours. The reaction mixture was concentrated in vacuo, diluted with EtOAc, washed with 3N NaOH and the organic phase was neutralized with 50% citric acid and dried over anhydrous Na2S? 4. After filtration and concentration in vacuo, the residue was purified by evaporative column chromatography (silica gel) using 2-5% MeOH-CH2Cl2 to give the title compounds (diastereomer A of 11S.2R 2.43 g, 27%, MH + = 485, and diastereomer B 11 R.2R, 2.5 g, 30%, MH + = 484).

PREPARED EXAMPLE 128 To the title compound of Preparative Example 43 (1.83 g, 5.6 mmol) was added HOBT (0.88 g, 6.5 mmol), DEC (1.24 g, 6.5 mmol), the title compound of Preparative Example 95 (1 g, 4.6 mmol). NMM (1.0 ml, 9.25 mmol) and anhydrous DMF (10 ml). The mixture was stirred at room temperature under N2 overnight. The mixture was concentrated in vacuo, diluted with CH2Cl2 and washed with NaOH (aqueous). The organic phase was dried over anhydrous Na2SO, filtered and concentrated in vacuo. The residue was purified by evaporative column chromatography (silica gel) using 10% MeOH-CH 2 Cl 2 saturated with aqueous ammonium hydroxide to give the title compound (0.70 g, 24%, MH + = 529).

PREPARED EXAMPLE 129 The title compound of Preparative Example 128 (0.70 g, 1.3 mmol), anhydrous CH 2 Cl 2 (10 mL), and trifluoroacetic acid (10 mL) were stirred at room temperature for 12 hours and then concentrated in vacuo. Aqueous NaOH (1N) was added dropwise to neutralize the reaction mixture, and the resulting mixture was extracted with CH2Cl2. The organic phase was dried over Na 2 SO 4, filtered and concentrated in vacuo to give a residue which was purified by evaporative column chromatography (silica gel) using 10% MeOH-CH 2 Cl 2 saturated with aqueous ammonium hydroxide to give the title compound in the form of a brown oil (232 mg, 53%, MH + = 329).

EXAMPLE PREPARATION 130 The title compound of Preparative Example 129 (0.20 g, 0.61 mmol) was dissolved in anhydrous DMF (5 mL). To this was added tricyclic chloride (compound No. 42.0) (0.2 g, 0.58 mmole) and triethylamine (0.43 ml, 3.0 mmole) and left under stirring at room temperature for 12 hours. The reaction mixture was poured into water and extracted with EtOAc. The organic extracts were dried over Na 2 SO, filtered and concentrated in vacuo. Purification by evaporative column chromatography (silica gel) using 10% MeOH-CH 2 Cl 2 saturated with aqueous ammonium hydroxide afforded the title compound (100 mg, 27%, MH + = 634).

PREPARED EXAMPLE 131 Stage A To the title compound of Preparative Example 51 (1.4 g, 70% purity, 1.8 mmol) and CH 2 Cl 2 (10 mL) cooled to 0 ° C was added triethylamine (0.5 mL, 3.6 mmol) and isobutyl chloroformate (0.25 mL, 1.9 mmol). After stirring the mixture at 0 ° C for 3 hours, the title compound of Preparative Example 95.1 (0.4 g, 1.7 mmol), isolated by preparative chiral chromatography (Chiralpack AD, 5 cm x 50 cm, flow rate 80 ml / min, 8% IPA + 92% Hexane + 0.2% diethylamine) was added and the mixture was stirred at room temperature under N overnight. The mixture was washed with NaOH (M) (aqueous) and the organic phase was dried over Na2SO, filtered and concentrated in vacuo. The residue was purified by evaporative column chromatography (silica gel) using 2-5% MeOH-CH 2 Cl 2 saturated with aqueous ammonium hydroxide to give the title compound as a mixture of diastereomers (0.45 g, 34%, MH + = 747).

Stage B To a solution of the title compound of Step A (0.45, 0.60 mmol) dissolved in anhydrous CH2Cl2 (5 mL) was added TFA (5 mL). The solution was stirred at room temperature under N2 overnight, then it was concentrated in vacuo, diluted with CH2Cl2, washed with 1 N NaOH (aqueous) and dried over anhydrous Na2SO4. The mixture was filtered, concentrated in vacuo and purified by column evaporative chromatography (silica gel) using 2-5% MeOH-CH 2 Cl 2 saturated with aqueous ammonium hydroxide to give the title compound as a mixture of diastereomers . The diastereomers were separated by preparative chiral chromatography (Chiralpack AD column; 5 cm x 50 cm, flow rate 80 ml / min., 60% IPA + 40% hexane + 0.2% diethylamine to obtain 0.11 g of diastereomer A and 0.23 g of diastereomer B. Physicochemical data for diastereomer A 11S, 2R (-): MH + = 647; [α] 20 D = -45.4 ° (2.91 mg / 2 ml MeOH). Physicochemical data for the diastereomer B 11 R, 2R (-): MH + = 647; [α] 20 D = -23.5 ° (2.21 mg / 2 ml MeOH).

PREPARED EXAMPLE 132 Stage A To a stirred solution of 1- (triphenylmethyl-1H-lmidazol-4-yl) -3-hydroxypropane (WO 9629315) (5.04 g, 13.68 mmol), phthalimide (2 g, 13.6 mmol) and triphenyl phosphine (3.57 g, 13.6 g) mmoles) in THF (100 ml) at 0 ° C was added diethyl azodicarboxylate (2.14 ml, 13.6 mmol) per drop. The reaction mixture was stirred for 1 hour at 0 ° C and then at room temperature for 16 hours. It was filtered to obtain the title compound (4.6 g, 100%). CIMS: m / z (MH +) = 498; dH (CDCl 3) 1.72 (bs, 1H), 1.9 (m, 1H), 2.05 (m, 1H), 2.6 (m, 1H), 3.75 (m, 2H), 6.6-7.8 (m, 21 H).

Stage B The title compound of Step A (2 g, 4.02 mmol) and the hydrazine hydrate (3.89 mL, 80.39 mmol) were heated under reflux in ethanol (80 mL) for 16 hours. The solids were removed by filtration and the filtrate was evaporated to give the title compound (1.35 g, 91%). CIMS: m / z (MH +) 368; dH (CDCl 3) 1.8-1.85 (m, 2H), 2.6-2.62 (m, 2H), 2.8-2.83 (m, 2H), 7.1 (s, 1 H), 7.3 (s, 1 H).

Step C Ph = phenyl A to a stirred solution of the title compound of Step B (1.5 g, 4.08 mmol) and benzaldehyde (0.433 g, 4.08 mmol) were added with sodium cyanoborohydride (0.256 g, 4.08 mmol). The pH of the solution was adjusted to -4.25 with acetic acid. The reaction mixture was then stirred for 2 hours. The pH was then adjusted to 1.5 with 50% NaOH and extracted with ethyl acetate. The ethyl acetate extract was washed with water and brine and dried (MgSO 4). Evaporated to give a crude residue which was chromatographed on silica gel using 4% (10% concentrated NH 4 OH in methanol) -CH 2 Cl 2 as eluent to give the title compound (1.04 g, 78%). CIMS: m / z (MH +) = PREPARED EXAMPLE 133 The title compound of Preparative Example 132 Step A (2 g, 4.1 mmol) in CH 2 Cl 2 (20 mL) was treated with methyl iodide, (0.75 mL, 12.05 mmol) and stirred for 16 h. It was evaporated to dryness to give a gummy residue which was then refluxed with 6N HCl (25 ml) for 16 hours. Evaporation to dryness gave a semi-solid which was neutralized with aqueous NaHCO3 and evaporation to dryness again gave semi-white solids. It was stirred with CH2Cl2 (100 mL) and MeOH (50 mL) and the solids were removed by filtration. The filtrate was evaporated to give the title compound (0.3 g). CIMS: m / z (MH +) 140; dH (CDCl 3) 1.8 (m, 2H), 2.6-2.8 (m, 4H), 3.6 (s, 3H), 6.68 (s, 1H), 7.4 (s, 1H).

Stage B The title compound of step A (1.97 g 14.14 mmol), benzaldehyde (1.65 g, 15.55 mmol), sodium acetate (1.1 g, 13.42 mmol) and molecular sieves 3 Angstroms (2 g) in methanol were stirred for 18 hours. To this was added sodium borohydride (0.519 g, 13.72 mmol) and stirred for 4 hours. The solids were removed by filtration and the filtrate was evaporated to a residue which was chromatographed to give the title compound (0.59 g, 18.5%). CIMS: m / z (MH +) 230; dH (CDCl 3) 1.8 (q.2H), 2.6 (t, 2H), 2.65 (t, 2H), 3.8 (s, 2H), 7.2-7.4 (m, 7H).

PREPARED EXAMPLE 134 1- (phenyl-2,3-epoxypropyl) -1 H-imidazole (GB 2 099818 A) (2.15 g, . 85 mmol) and sodium azide (1.41 g, 21.71 mmol) were heated in DMF (20 ml) at 60 ° C for 16 hours. It was evaporated to dryness and extracted to dryness with CH2Cl2, washed with brine and dried (MgSO4). Evaporated to give the title compound (0.932 g, 36%). CIMS: m / z (MH +) = 244; dH (CDCl3) 3.7 (q, 2H0. 4.5 (dd, 2H), 6.6 (s, 1H), 6.95 (s, 1H), 7.3-7.45 (m, 5H), 8.2 (s, 1H).

Stage B The title compound of step A (0.8 g, 3.31 mmol) in ethanol (15 ml) was hydrogenated over 10% Pd on carbon (0.2 g) at 3.5 kg / cm2 overnight. The catalyst was removed by filtration and evaporated to give the title compound (0.71 g 98%). CIMS: m / z (MH +) = 218.

PREPARATORY EXAMPLE 135 (A) (B) Following steps a to e of preparative example 41 from the (+) isomer, a mixture of the title compounds A and B was obtained as a light tan solid which appears as a single tick spot: 1RMN (CDCI3, 300 MHz) d 1.42 (s, 9H), 4.85 (m, 2H), 7.12 (s, 1H), 7.50 (s, 1H), 7.55 (s, 1 H), 8.48 ( m, 1H); HRMS (FAB) cale. p / C25H28N204 BrC 1r 81'Br 615.0084, H: 615,0092.

PREPARED EXAMPLE 136 Following the procedure indicated in preparative example 123, but using the title compound of preparative example 37 step A, the title compound was obtained (quantitative yield: MH + = 338).

PREPARATION EXAMPLES 137-138 Following the procedure described for preparative example 106, the piperazines listed in the following table 5A were prepared using the corresponding amines.

TABLE 5A PREPARED EXAMPLES 139-141 In a similar manner using the procedures described for preparative example 110 and the piperazines listed in the following Table 5B, the corresponding tricyclic amines were prepared TABLE 5B PREPARED EXAMPLE 142 (A + B) (A + B) (A + B) (A + B) The title compound of Example 289 (0.39 g, 0.51 mmol), anhydrous CH 2 Cl 2 (3 mL) and trifluoroacetic acid (3 mL) were stirred. at room temperature for two hours and then concentrated in vacuo. Aqueous NaOH (1N) was added dropwise to neutralize the reaction mixture and then the resulting mixture was extracted with CH2Cl2. The organic phase was dried over anhydrous MgSO 3, filtered and concentrated in vacuo to give a residue which was purified by evaporative column chromatography (silica gel) using 5% MeOH-CH 2 Cl 2 saturated with aqueous ammonium hydroxide to give the title compound. title in the form of a whitish solid (52 mg, 15%, mp = 150 ° C, MH + = 768).

PREPARED EXAMPLE 143 A solution of the title compound of Preparative Example 71 (0.9 g, 5.14 mmol) and the anhydride from Preparative Example 44 (1.38 g, 1.05 eq.) Were dissolved in anhydrous dichloromethane (10 mL) and stirred at room temperature overnight. Additional anhydride (0.105 g) was added and after 1 hour cyclohexyl isocyanate (0.98 ml, 7.71 mmole) was added to the reaction mixture which was stirred for an additional 1.5 hours. Concentration in vacuo and purification by evaporative column chromatography (silica gel) using 1-3% MeOH-CH 2 Cl 2 saturated with ammonium hydroxide as eluent afforded the title compound as a white solid (1.82 g, 69% , mp = 126.9-128.9 ° C. MH + = 513) PREPARED EXAMPLES 144-149 Following essentially the same procedure as described in preparative example 143, the BOC-protease piperazines listed in the following Table 5C were prepared using the corresponding amines.

TABLE 5C PREPARATORY EXAMPLE 150 If essentially the same procedure as described for preparative example 143 is followed, but the amine is used instead of the amine of preparative example 71, the title compound is obtained.

PREPARATORY EXAMPLE 151 A solution of the title compound of Preparative Example 68 (2.12 g, 15.2 mmol), triethylamine (30.4 mole) and the anhydride of Preparative Example 44 (3.89 g, 15.2 mmol) dissolved in anhydrous dichloromethane (30 mL) was stirred at room temperature for 30 minutes. Benzyloxycarbonyl succinimide (4.17 g, 16.7 mmol) was added and the resulting mixture was stirred at room temperature overnight. Concentration in vacuo and purification by evaporative column chromatography (silica gel) using 2% MeOH-CH2Cl2 saturated with ammonium hydroxide as eluent afforded the title compounds (2.57 g, 35%). The regioisomers were separated by HPLC (Chiracel AD column) using 5% isopropanol-95% hexane-0.2% diethylamine to give the 2,4-dimethyl isomer (mp = 64.2 ° C, MH + = 486) and isomer 2 , 5-dimethyl (mp = 71.5 ° C, MH + = 486).

PREPARED EXAMPLE 152 A solution of the title compound of Example 293 diastereomer A (0.386 g, 0.56 mmol), glacial acetic acid (3 mL) 33% HBr in acetic acid (1 mL) was stirred at room temperature for 2 hours. Diethyl ether was added and the precipitate was filtered and dried under vacuum to provide the title compound (0.48 g, 100%, MH + = 557).

PREPARATORY EXAMPLE 153 A solution of the title compound of example 293 diastereomer B (0.372 g), glacial acetic acid (3 ml) 33% HBr in acetic acid (1 ml) was stirred at room temperature for 2 hours. Diethyl ether was added and the precipitate was filtered and dried under vacuum to provide the title compound (0.433 g, 100%, MH + = 557).

PREPARED EXAMPLE 154 Stage A A mixture of the title compound of Preparative Example 66 (1.0 g, 7.2 mmol), the anhydride of Preparative Example 44 (2.2 g, 8.6 mmol), triethyl amine (1.5 mL, 10.8 mmol) and anhydrous CH 2 Cl 2 (10 mL) was stirred at room temperature for 12 hours. The mixture was concentrated in vacuo, diluted with CH2Cl2 and washed with a saturated aqueous solution of NaHCO3. The organic phase was dried over anhydrous Na 2 SO 4, filtered and concentrated in vacuo.

Stage B Trifluoroacetic acid (10 ml) was added to the title compound of step A above (1.0 g, 7.2 mmol) dissolved in CH2Cl2 (10 ml) and the resulting mixture was stirred for 5 hours at 25 ° C. The mixture was concentrated in vacuo, diluted with CH2Cl2 (50 ml) and combined with tricyclic chloride (compound # 42.0) (2.7 g, 7.9 mmol) and triethylamine (5-10 ml) and stirred at room temperature night. The mixture was concentrated in vacuo, diluted with CH2Cl2 and washed with a saturated solution of NaHCO3. The organic phase was dried over anhydrous Na 2 SO 4, filtered, concentrated in vacuo and purified by evaporative column chromatography (silica gel) using 5% MeOH-CH 2 Cl 2 saturated with aqueous ammonium hydroxide to give the title compound in the form of a mixture of diastereomers (1.9 g, 47%, MH + = 557).

PREPARED EXAMPLE 155 Stage A N-Carbetoxyphthalimide (62.8 g, 0.275 moles, 1.1 eq.) Was added in portions over a period of 30 minutes to a stirred solution of histamine dihydrochloride (46.7 g, 0.250 moles, 1.0 eq.) And sodium carbonate (54.3 g. , 0.513 moles, 2.05 eq.) In distilled water (1250 ml) at room temperature. The resulting white-colored solution was stirred vigorously at room temperature for 90 minutes. The solid was separated by filtration and carefully washed with ice distilled water (4 x 50 ml). The solid was collected and dried under vacuum over P2O5 at 60 ° C for 12 hours to obtain the compound (59.2 g, 0.245 mol, 98%, MH + = 242).

Stage B A solution of chloromethyl pivalate (18.5 ml, 0.125 moles, 1.2 eq.) In anhydrous N, N-dimethylformamide (DMF, 100 ml) was added dropwise over a period of 1 hour to a stirred mixture from step A above ( 25.0 g, 0.104 moles, 1.0 eq.) And potassium carbonate (17.2 g, 0.125 moles, 1.2 eq.) In anhydrous DMF (500 ml) at 90 ° C under nitrogen atmosphere. The mixture was stirred at 90 ° C for 12 hours. Volatiles were removed in vacuo at 50 ° C. The residue was taken up in brine (100 ml) and extracted with ethyl acetate (4 x 25 ml). The combined organic extracts were dried over Na 2 SO 4, filtered, and concentrated in vacuo at 30 ° C. The residual whitish solid was chromatographed by evaporative column (hexanes: acetone = 6: 4 v / v) on silica gel to obtain the title compound (20 g, 0.056 mol, 54%, MH + = 356).

Stage C A solution of the title compound from Step B above (5 g, 14.1 mmol) and 4-chlorobenzyl chloride (2.5 g, 15.5 mmol) was stirred in anhydrous acetonitrile (60 mL) at reflux temperature under nitrogen atmosphere for 48 hours. hours. The mixture was concentrated in vacuo and recrystallized from ethyl acetate-hexane to give the title compound as a solid (3.2 g, 47%, MH + = 480), and the filtrate that was concentrated gave the additional product (3.6 g, 53%).

Stage D A 7 N solution of ammonia in methanol (10 mL, 0.07 mole) was added slowly to a stirred solution of the title compound from Step C above (3.2 g, 6.6 mmol) diluted with MeOH (10 mL) at -20 ° C. . The resulting mixture was warmed to room temperature and stirred for a further 12 hours and then concentrated in vacuo and purified by evaporative column chromatography (silica gel) using 3% MeOH-CH 2 Cl 2 saturated with ammonium hydroxide as eluent to provide the title compound in the form of a sticky solid (1.2 g, 51%, MH + = 366).

Stage E A solution of the title compound from step D above (1.21 g, 3.3 mmol) and hydrazine monohydrate (1.7 ml, 0.033 mol, 10 eq.) In absolute ethanol (20 ml) was stirred at 50 ° C under nitrogen atmosphere during 20 minutes. The resulting suspension was diluted with ethanol and dichloromethane and filtered. The filtrate was concentrated in vacuo to provide the title compound as a yellowish solid oil (0.7 g, 91%, MH + = 236). ta to F A solution of the title compound of step E above (0.695 g, 2.94 mmol) and the anhydride of Preparative Example 44 (0.75 g, 2.94 mmol) dissolved in anhydrous dichloromethane (10 mL) was stirred at room temperature overnight. Additional anhydride (0.1 g) was added and after 1 hour the reaction mixture was diluted with CH2Cl2 and extracted with 1M HCl (aqueous). The aqueous phase was basified with 1 N NaOH (aqueous), extracted with CH 2 Cl 2 and the organic phase was dried over anhydrous MgSO 4. After filtration, the organic phase was concentrated in vacuo to give a white foam (0.744 g, 57%, MH + = 448).

PREPARED EXAMPLES 156-157 Following the procedure described for the preparative example 155 steps C-F, the piperazines listed in the following Table 5D were prepared using the corresponding arylalkyl halides.

TABLE 5D PREPARED EXAMPLE 158 Stage A To 3- (1 H-imidazol-1-yl) propylamine (20 ml, 167.6 mmol) dissolved in water (200 ml) and MeOH (200 ml) was added 50% NaOH (aqueous) to pH 9.5. Di-tert-butyl dicarbonate (41 g, 187.9 mmol) was added while stirring at room temperature for 4 hours and while maintaining the pH at 9.5 with 50% NaOH. The mixture was concentrated in vacuo to remove most of the MeOH, and then extracted with CH2Cl. The organic phase was dried over anhydrous MgSO 4, filtered and concentrated in vacuo to give the title compound (23.7 g, 63%, MH + = 226).

Stage B To a solution of the title compound of step A above (0.50 g, 2.22 mmol) dissolved in anhydrous THF (15 mL) and stirred at -78 ° C was added n-butyllithium (2.8 mL, 1.75M in hexane) and the resulting mixture was heated and stirred at -20 ° C. for 1.5 hours. The reaction mixture was again cooled to -78 ° C and anhydrous DMF (0.35 mL, 4.52 mmol) was added.

After heating and stirring at 25 ° C for 2 hours, MeOH (2 ml) and NaBH 4 (171 mg, 4.5 mmol) were added and the resulting mixture was stirred for 1 hour at 25 ° C. The mixture was concentrated in vacuo, diluted with dichloromethane, washed with water and the organic phase was dried over anhydrous Na2SO4, filtered and concentrated in vacuo. Purification by evaporative column chromatography (silica gel) using 5-10% MeOH-C ^ C saturated with ammonium hydroxide as eluent afforded the title compound (0.32 g, 56%, MH + = 256).

Stage C To the title compound of step B above (0.31 g, 1.2 mmol) was added 4M HCl in dioxane (5 ml) and the mixture was stirred at 25 ° C for 12 hours. Concentration in vacuo provided a residue which was used directly in stage D.

Stage D A mixture of the title compound of step C above, triethylamine (4 ml) and the anhydride of preparative example 44 (0.55 g, 2.15 mmoles) dissolved in anhydrous DMF (10 ml) was stirred at room temperature overnight. The mixture was concentrated in vacuo and diluted with anhydrous CH2Cl2 (5 mL), DMF (5 mL) and trifluoroacetic acid (10 mL). The resulting mixture was stirred for 12 hours at room temperature, and then concentrated in vacuo and diluted with anhydrous CH2Cl2 (5 mL) and DMF (5 mL). Tricyclic chloride (compound No. 42.0) (0.75 g, 2.17 mmol) and triethylamine (3 ml) were added and the mixture was stirred at 25 ° C for 48 hours. The mixture was concentrated in vacuo, diluted with CH 2 Cl 2 and washed with a saturated aqueous solution of NaHC 3. The organic phase was dried over anhydrous Na2SO4, filtered, concentrated in vacuo and purified by evaporative column chromatography (silica gel) using 5-10% MeOH-CH2Cl2 saturated with aqueous ammonium hydroxide to give the title compound in form of a mixture of dlassestereomers (0.376 g, 33%, MH + = 573).

PREPARATIVE EXAMPLES 159-160 Following the procedure described for preparative example 158 step D, the piperazines listed in the following Table 5E were prepared using the corresponding amines or amine hydrochlorides.

TABLE 5E PREPARED EXAMPLE 161 Stage A TBDMS A mixture of 4-hydroxymethylimidazole (2 g, 14.9 mmol), triethylamine (5 ml) and TBDMS-Cl (2.5 g, 16.6 mmol) dissolved in anhydrous CH2Cl2 (20 ml) was stirred at room temperature overnight. The mixture was filtered, diluted with anhydrous Et20 and filtered again. The filtrate was concentrated in vacuo, diluted with CH2Cl2 and washed with a saturated aqueous solution of NaHCO3. The organic phase was dried over anhydrous Na 2 SO 4, filtered and concentrated in vacuo to give the title compound (2.22 g, 71%, MH + = 213).

Stage B A solution of the title compound from step A above (2.22 g, 10.5 mmol) dissolved in acrylonitrile (10 ml) was stirred at reflux for 48 hours. Concentration in vacuo afforded the title compound (2.09 g, 75%, MH + = 266).

Stage C + A mixture of the title compound from step B above (2.08 g, 7.85 mmol), Raney nickel (230 mg), MeOH (20 ml) and NH 4 OH (7.5 ml) was stirred in a Parr hydrogenator at room temperature for 48 hours. The mixture was filtered through Celite, concentrated in vacuo, diluted with CH2Cl2 and washed with a saturated aqueous solution of NaHCO3. The organic phase was dried over anhydrous Na 2 SO 4, filtered, concentrated in vacuo and purified by evaporative column chromatography (silica gel) using 5% MeOH-CH 2 Cl 2 saturated with aqueous ammonium hydroxide to give the title compounds [( 4-substituted isomer, 465 mg, 22%, MH + = 270) and (5-substituted isomer, 220 mg, 10%, MH + = 270)].

PREPARED EXAMPLE 162 Following the procedure described for the preparative example 155 CE steps, except that 4-fluorobenzyl bromide was used in place of 4-chlorobenzyl chloride in the preparative example 155 step C, the title compound was prepared (52%, MH + = 220 ).

PREPARED EXAMPLE 163 Following the procedure described in the preparative example 155 CE steps, except that 4-cyanobenzyl bromide was used in place of 4-chlorobenzyl chloride in the preparative example 144 step C, the title compound was prepared (63%, MH + = 227 ).

PREPARED EXAMPLE 164 Tricyclic chloride (5.04 g, 1.1 equivalents) was added to a solution of the title compound of Preparative Example 50 (4.0 g, 17.3 mmol) and TEA (12.05 mL, aqueous) 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 2 SO, 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 give the C-11 (S) isomer (2.13 g, 54%) as the first eluent isomer and the C-isomer -11 (R) (2.4 g, 61%) as the second eluent isomer.

(Isomer 11 S, 2R (+)) Isomer 11 (S), 2 (R) (+) (first eluent isomer): [a] 20 D = +84.9 (5.18 mg in 5.0 ml of MeOH); LCMS: MH + = 458.

Isomer 11 R, 2R Isomer 11 (R) 2 (R) (second eluent isomer): FABMS: MH = 458.

PREPARED EXAMPLE 165 Following the procedure described for preparative example 25 except that the title compound of Preparative Example 13 was used in place of N-methyl histamine, the title compound was prepared (33%, MH + = 195).

PREPARED EXAMPLE 166 Similarly, using the procedure described for preparative example 142, except that the title compound of example 305 diastereomer A was used in place of the title compound of example 289, the title compound was prepared (80%, MH + = 599 ).

PREPARED EXAMPLE 167 Following the procedure described for preparative example 142, except that the title compound of example 305 diastereomer B was used in place of the title compound of example 289, the title compound was prepared (100%, MH + = 599).

PREPARED EXAMPLE 168 Stage A The title compound of preparative example 40A step A (compound 52i) (5 g, 12.8 mmol) was dissolved in 2.7 ml of 2,4-dimethoxybenzaldehyde by heating to 120 ° C. Formic acid (1.3 ml) was allowed to drip into the reaction mixture while stirring the reaction mixture at 120 ° C for 45 minutes. The resulting solid mixture was dissolved in dichloromethane and dried over magnesium sulfate, filtered and evaporated to dryness to obtain a solid which was subjected to chromatography on silica gel to obtain 5.17 g of the title product FABMS (M + 1) = 463.4.

Stage B The title compound of step A (1 g, 1.8 mmol) was dissolved in 45 ml of 5% acetic acid / water and stirred at 85 ° C. Mercuric acetate (2.3 g) was added and the reaction mixture was stirred for 5 hours. After cooling in an ice bath, potassium cyanide (1.25 g) was added and the reaction mixture was stirred vigorously for 18 hours. 1 N sodium hydroxide (excess) was added and the product was extracted with ethyl acetate three times. After chromatography on silica gel using ethyl acetate as eluent, 0.747 g of the title product was obtained.

Stage C The title product of step B (0.2 g) was dissolved in 6 ml of trifiuoracic acid and 0.5 ml of anisole and stirred for 1 hour at 60 ° C to obtain the title carboxamide product (72 mg) after chromatography with silica gel using 2% methanol / dichloromethane as eluent, FABMS (M + 1) = 432.

Stage D The main product (carboxamide) from step C (0.19 g) was dissolved in 10 ml of 6N hydrochloric acid and refluxed for 24 hours. It was extracted into 6N HCl in vacuo and the residue was dissolved in water (5 ml). Di-tert-butyl dicarbonate (0.13 g) was added and the pH of the reaction mixture was brought to 9.0 with 1N sodium hydroxide. After stirring for 2 hours at room temperature, the reaction mixture was added to citric acid and extracted with dichloromethane to obtain the crude product which was chromatographed on silica gel to obtain 93 mg of the title product FABMS (M + 1). = 533.

Stage E The title compound of step D (70 mg, 0.13 mmol) was dissolved in 2 ml of DMF and DEC (37 mg, 0.19 mmol), HOBT (25 mg, 0.19 mmol), and N-methylmorpholine (24 μL) were added. , 0.4 mmoles) and the reaction mixture was stirred at room temperature for 7 hours. After addition to water and extraction with dichloromethane, the crude product was chromatographed on a column of silica gel to obtain 86 mg of the title product. FABMS (M + 1) = 640.

PREPARATIVE EXAMPLE 169 11-Chloro-6.11-dihydro-5H-benzo [5.6] cycloheptaf1.2-B] pyridine The ketone (starting material) 5,6-dihydro-11H-benzo [5,6] cyclohepta [1,2-c] pyridine-11-one can be prepared following the methods described in US Patent No. 3,419,565.

Sodium borohydride (2 g, 53.3 mmol) was added to a solution of the ketone (3 g, 14.35 mmol) in methanol (50 mL) at 0 ° C, and then stirred for 2 hours at room temperature. The reaction was quenched by the addition of ice (10 g) and 2N HCl (10 ml, basified with 2N NaOH (13 ml) and extracted with MeCI2 (2 x 50 ml)). The organic layer was separated, dried over MgSO4, filtered and the solvent was evaporated to obtain the alcohol (3 g, 100%). 1 H NMR (DMSO, d) 3.0-3.4 (m, 4H), 6.10 (brs, 2H), 7.0-7.3 (m, 4H), 7.5 (m, 2H), 8.314 (d, 1H). Thionyl chloride (3 mL, 41.12 mmol) was added to a solution of the alcohol (2.5 g, 11.84 mmol) in MeCl2 (50 mL) at room temperature and then stirred for 1 hour. The solvent was evaporated, and water (50 ml) and 5% NaOH (10 ml) were added. The mixture was extracted with MeCI2 (100 ml), the organic layer was dried over MgSO4, filtered, and the solvent was evaporated obtaining a tan solid, which was triturated with ether, and the filtrate was concentrated and a solid was obtained white (1.5 g). H NMR (CDCl 3, 6) 2.9-3.0 (m, 2H), 3.6 (m, 1H), 3.9 (m, 1 H), 6.3 (s, 1H), 7.2 (m, 3H), 7.3 (d, 1H) ), 7.4 (d, 1H), 7.5 (d, 1H), 8.42 (d, 1H). The filtered solid was dried obtaining (0.9 g) of an additional material. Total yield (2.4 g, 87%).

PREPARED EXAMPLE 170 Acetonitrile (5 ml) was added to a mixture of 10-chloro-tricyclo (0.5 g, 1.90 mmol) (preparative example 9.1) and substituted piperazine (0.78 g, 1.90 mmol). Triethylamine (1 ml, 7.18 mmol) was added and the mixture was stirred overnight at room temperature. Water (50 ml) and 5% NaOH were added and the mixture was extracted with eC (2 x 100 ml). The organic layer was separated, dried over MgSO4 and the solvent was evaporated to obtain the desired product (0.7 g, 57%) as a mixture of 2 dlassestereomers, which were separated by column chromatography on silica gel eluting with silica gel. % v / v MeOH / MeCl2 containing 2% NH4OH. Isomer A (the less polar isomer) was eluted first.

TABLE 5 F PREPARED EXAMPLE 171 Stage A A mixture of 2-chloroacetophenone (25 g, 0.16 mol) and 4-methyl imidazole (66.1 g, 0.8 mol) was heated at 100 ° C for 12 hours. It was cooled and the crude product was chromatographed on a column of silica gel eluting with CH 2 Cl / 3% CH 3 OH saturated with aqueous ammonium hydroxide to provide a mixture of 4- and 5-methyl-1H-imidazolyl acetophenone (23 g, 73%). , MS, MH + = 201).

Stage B Trityl chloride (7.28 g, 0.26 mole) was added to the product from Step A in CH2Cl2 (200 ml) and stirred overnight at room temperature. The mixture was chromatographed on a column of silica gel using ethyl acetate / acetone (3: 1) to give 4-methyl-1 H-imidazoyl acetophenone (15.5 g), FABMS; MH + = 201.

Stage C To a mixture of NaH (0.998 g, 24.97 mmol), and trimethyl sulfoxonium iodide (5.49 g, 24.97 mmol) in DMSO (50 ml), the product (5 g) from stage B was added and stirred for 1.5 hours. . The product was extracted with ethyl acetate and washed with brine, dried and the solvent was evaporated to give 1- (2-phenyl-2,3-epoxypropyl) -1H-4-methyl imidazole (3.44 g. 64%), FABMS: MH + = 215).

Stage D The product from step C (3.45 g, 16.11 mmol) and sodium azide (2.093 g, 32.21 mmol) were heated in DMF (100 ml) at 60 ° C for 12 hours. It was evaporated to dryness and extracted with CH2Cl2, washed with brine and dried (MgSO4). Evaporated to give the title compound (3.83 g, 93%). FABMS: MH + = 258.

Stage E The title compound of step D in ethanol (80 ml) was hydrogenated over 10% Pd on carbon (1.2 g) at 3.51 kg / cm2 overnight. The catalyst was filtered off and evaporated to give the title compound (2.83 g, as a yellow viscous oil).

PREPARATIVE EXAMPLES 172-188 Following the procedure indicated in Preparative Example 74 but using the aldehyde and the imidazoalkyl amine (Imidazole) of Table 5G, the amines (product) were obtained in Table 5G.

TABLE 5G PREPARED EXAMPLES 190-197 Using the procedure described for Preparative Example 109, but using the title compounds of the examples listed in Table 5H, the amines constituting the Product were prepared.

TABLE 5H PREPARED EXAMPLE 199 Stage A The title compound of preparative example 175 (0.9 g.), Benzyl alcohol (0.68 ml), potassium hydroxide (0.66 g), 18-crown-6-ether (80 mg) and anhydrous toluene (20 ml) were stirred at Reflux. Purification by preparative plate chromatography (silica, 4% MeOH-CH2Cl2, saturated NH4OH) provided the benzyl ether (0.73 g, 68%, MH + = 371).

Stage_B The title compound from Step A above (0.72 g.), Methanol (60 m!) And 10% palladium on carbon (300 mg) were stirred under a hydrogen atmosphere of 3.51 kg / cm.sup.2 for 3 days. Filtration through Celite provided a solution that was treated with TEA (3 equivalents) and CH2CI2. Filtration was purified by preparative plate chromatography (silica, 5% MeOH-CH 2 Cl 2, saturated with NH 4 OH), afforded the title compound (0.20 g, 42%, MH + = 247).

PREPARATIVE EXAMPLE 200 Preparation of the tricyclic N-oxide moiety 1- > 2 A solution of 3-peroxybenzoic acid (25 g, 102.59 mmoles, 2.5 equivalents) in anhydrous dichloromethane (250 ml) was added dropwise over a period of 1 hour to a stirred solution of 8-chloro-4-aza-10,11-dihydro-5H-dibenzo [a, d ] cyclohepten-5-one 1 (10 g, 41.04 mmoles, 1.0 equivalents) in anhydrous dichloromethane (100 ml) at 0 ° C under nitrogen atmosphere. The solution was slowly heated (3 hours) to room temperature and stirred for 12 hours. The solution was extracted with a 1 M aqueous sodium hydroxide solution (5 x 100 ml), washed with brine (2 x 100 ml), dried over Na 2 SO 4, and concentrated in vacuo at 30 ° C to give 2 in vacuo. shape of a solid yellow canary. The title 2 compound was used directly without further attempts at purification. Yield: 10 g D 38.51 mmoles = 94% [M + H] +: 260 HRMS (FAB +): Calculated for C? 4HnCINO2 ([M + H] +): 260.0475 Found: 260.0478 2- »3 Borohydride added in portions Sodium (2.21 g, 57.76 mmol, 1.5 equivalents) is a period of 15 minutes at a solution of 2 (10 g, 38.51 mmol, 1.0 equivalents) in anhydrous methanol (500 mL) at 0 ° C under nitrogen atmosphere. The resulting suspension was stirred at 0 ° C for 1 hour and at room temperature for an additional hour. The volatiles were removed under vacuum at 30 ° C and the residue was taken up in a 1 M aqueous solution of NaOH (250 ml). The aqueous solution was extracted with dichloromethane (5 x 100 mL). The combined extracts were washed with brine (100 ml), dried over Na 2 SO 4, filtered, and concentrated in vacuo at 30 ° C to provide 3 as a milky green solid. Compound 3 was used directly without any purification attempt. Yield: 9 g D 34.39 mmoles = 89% [M * H] +: 262 HRMS (FAB +): Calculated for C14Hi3CINO ([M + H] +): 262.0635 Observed: 262.0636 3- 4 Thionyl chloride (5 ml) was added , 68.78 mmoles, 2.0 equivalents) by dripping in a period of 10 minutes to a stirred suspension of 3 (9 g, 34.39 mmoles, 1.0 equivalents) and anhydrous toluene (150 ml) at 0 ° C under nitrogen atmosphere. The cream suspension was heated slowly (3 hours) at room temperature and stirred for a further 12 hours. The volatiles were removed under vacuum at 30 ° C. The residue was taken up in dichloromethane (250 ml) and washed with ice, with a saturated aqueous solution of NaHC 3 (5 x 100 ml) until the aqueous washes were moderately basic at pH 9. The organic layer was washed with brine (100 ml), dried over Na 2 SO 4, filtered, and concentrated under vacuum at 30 ° C to give 4 as a cream-colored solid with essentially quantitative performance.

Due to its high reactivity compound 4 was used directly without any purification or characterization attempt (other than 1 HNRM). Yield: 9.55 g, Q 34.09 mmoles = 99% 4-6 Triethylamine (18 ml, 126.65 mmoles, 5.0 equivalents) was added dropwise to a stirred solution of 5 (previously described in the art); 9.38 g, 25.33 mmoles, 1.0 equivalents) in anhydrous dichloromethane (50 ml) at room temperature under nitrogen atmosphere. The solution was stirred at room temperature for 30 minutes and cooled to 0 ° C. A solution of 4 (8.52 g, 30.39 mmoles, 1.2 equivalents) 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 of aqueous citric acid solution (100 ml) and extracted with ethyl acetate (5 x 100 ml). The organic extracts were combined and dried over S02S? 4, filtered, and concentrated in vacuo at 30 ° C. The residual cream-colored solid was chromatographed on an evaporative column (CH2Cl2: MeOH = 19: 1 v / v) to give the diastereomerically pure isomers 6a and 6b to C-11 of the tricyclic compound.

For 6a: Yield: 5.75 g D 11.50 mmoles D 45% White foam: p.f. 78-83 ° C [M + H] +: 500 HRMS (FAB +): Calculated for C26H31CIN3O5 ([M + H]): 500.1953 Observed: 500.1952 For 6b Yield: 3.00 g D 6.00 mmol D 24% Whitening Foam: m.p. 94-99 ° C [M + H] +: 500 HRMS (FAB +): Calculated for tfM + HJ): 500.1953 Obervado: 500.1952 PREPARED EXAMPLE 201 Stage A Following the procedure indicated in the patent No. 5,151, 423, except that the 8-H analog was replaced by the tricyclic 8-chloro described in US Pat. No. 3,419,565, the tricyclic 8-hydrido chloride was obtained.

Stage B Following the procedure described for preparative example 127 step C, except that tricyclic 8-hydrido chloride of Preparative Example 201 was used in step A instead of 8-chloro tricyclic chloride, the title compounds were isolated. The isomers were separated by column chromatography (silica) using 3% MeOH / CH2Cl2. Isomer A: C (11) - (S): 38%, MH + = 450. Isomer B: C (11) - (R): 31%, MH + = 450.

PREPARED EXAMPLE 202 Stage A Following the procedure indicated in the preparatory example 127 stage C, replacing the tricyclic chloride by the tricyclic chloride 8-CI, the following acid is obtained: Yield 51% of a solid, m.p. = 120.5 -125.1 ° C.

PREPARED EXAMPLE 202A Following essentially the same procedure indicated in Njoroge et al (J. Med. Chem. (1997), 40, 4290) for the preparation of 3-aminoloratadine substituting only loratadine for 3H ketone (J. Het Chem. (1971) 8 , 73), the title compound was prepared.

PREPARED EXAMPLE 203 The title compound of Preparative Example 202A (1.62 g, 6.26 mmol) was added in portions to NO + BF4"(0.81 g, 1.1 equivalents) in toluene (10 mL) at 0 ° 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 (3 x 50 ml) The combined organics were washed with 1 N HCl (2 x 25 mL) with saturated NaHCO3 (1 x 25 mL), and water (1 x 15 mL), dried over Na2S4, filtered, and concentrated under reduced pressure. by evaporative chromatography using 70: 30 hexanes: EtOAc mixture as eluent to give a yellow solid (0.68 g, 42% yield) LCMS: MH + = 262.

PREPARED EXAMPLE 204 Following essentially the same procedure indicated in Preparative Example 201 Step A, the title compound was prepared from the ketone of Preparative Example 203 and used without further purification (0.66 g, 100% crude yield).

PREPARED EXAMPLE 205 + NH4HC? 2_ (2.44 g, 10 equivalents) was added to a solution of the title compound of Preparative Example 202A (2.00 g, 7.74 mmol) and 5% Pd / C (0.50 g) in EtOH (100 mL) and the solution The resulting mixture 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 H2O (100 ml) and extracted with CH2CI (3 x 75 ml). The combined organics were dried over a2S? 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 206 The title compound of Preparative Example 205 (1.22 g, 5.44 mmol) was added in portions to CuC (0.88 g, 1.2 equivalents) and tBuONO (0.98 mL, 1.5 equivalents) in CH3CN (25 mL) at 0 ° C. The resulting solution was warmed to room temperature and stirred for 72 hours. The reaction mixture was quenched by the addition of 1 M HCl (10 mL), neutralized with 15% NH4OH and extracted with EtOAc (3 x 100 mL). The combined organics were washed with 15% NHOH (1 x 50 ml), 1M HCl (1 x 50 ml) and saturated NaHCO3, dried over Na2SO4, filtered and concentrated. The crude product was purified by evaporative chromatography using a mixture of 50:50 EtOAc: hexanes as eluent to give a pale yellow solid (0.81 g, 61% yield): CIMS: MH + = 244.

PREPARED EXAMPLE 207 Following essentially the same procedure indicated in preparative example 201 step A, the title compound was prepared from the ketone of preparative example 206 and used without further purification.

PREPARED EXAMPLE 208 Following essentially the same procedure Indicated in Preparative Example 206, substituting only CuBr2 for CuC, the title compound was prepared (1.33 g, 60% yield): FABMS: MH + = 244.

PREPARED EXAMPLE 209 Following essentially the same procedure indicated in preparative example 201 step A, the title compound was prepared from the ketone of preparative example 208 and used without further purification.

PREPARED EXAMPLE 210 Following essentially the same procedure indicated in preparative example 203 substituting only the title compound of Preparative Example 205, the title compound can be prepared.

PREPARED EXAMPLE 211 Following essentially the same procedure indicated in preparative example 201 step A, except starting from the ketone of preparative example 210, the title compound can be prepared.

PREPARED EXAMPLE 212 Following essentially the same procedure indicated in preparative example 127 step C, substituting only tricyclic 3H 8-CI chloride for the 3-CI, tricyclic 8H chloride prepared in preparative example 207, the title compound (isomer C-11) is prepared (S) - and (R). FABMS: MH + = 484.

EXAMPLE 1 A solution of the title compound of Preparative Example 5 (0.44 g, 0.897 mmol) was stirred at room temperature in CH2Cl2 (10 mL) and TFA (4 mL) until the starting material (TLC) was taken up. The reaction mixture was concentrated under reduced pressure to remove any excess TFA and the compound was redissolved in CH2Cl2 (5 ml), and treated with chloride (42.0) (0.37 g, 1.2 equivalents) and TEA (2.5 ml, 10 equivalents) and stirred at room temperature for 84 hours. The reaction mixture was diluted with saturated NaHCO 3 (25 ml), water (25 ml), and CH 2 Cl 2 (25 ml), and separated. The aqueous layer was extracted with CH2Cl2 and the combined organics were dried over Na2S4 and concentrated under reduced pressure. 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 a tan solid (0.45 g, 71% yield), m.p. 142-144 ° C; FABMS: MH + = 696.

EXAMPLE 2 (Isomer 11 S, 2R (+)) (Isomer 11 R, 2R (+)) The title compound of example 1 was separated into the diastereomers 11 (S) (+) - and 11 (R) (+) - by preparative HPLC using a CHIRALPAK AD column using a 12% solution of i-PrOH in hexanes with 0.2% diethylamine as eluent. Isomer 11S, 2R (+): retention time = 29.91 minutes: [a] 23.5 D = +19.1 (3.35 mg, in 2.0 ml CHCl3); p.f. 147-149 ° C; LCMS: MH + = 696. Isomer 11 R, 2R (+): retention time = 39.8 minutes; [α] 24 1D = + 73.0 (3.07 mg, 2.0 ml CHCl3); p.f. 128-131 ° C; LCMS: MH + = 696.

EXAMPLE 3 Following essentially the same procedure as that indicated in Example 1, except that the title compound of Preparative Example 6 was used, the title compound was prepared (0.085 g, 45% yield). p.f. 103-106 ° C; LCMS: MH + = 705.

EXAMPLE 4 Following essentially the same procedure indicated in Example 3, except that the title compound of Preparative Example 6.1 was used, the title compound was prepared, mp. 111-115 ° C: MH + = 703.

EXAMPLE 5 Following essentially the same procedure indicated in Example 1, except that the title compound of the preparative example was used 7, the title compound was prepared, m.p. 138-140 ° C; LCMS: MH + = 778.

EXAMPLE 6 (Isomer 11R.2R) A solution of the title compound of Preparative Example 8 (0.10 g, 0.17 mmol) (11S, 2R (-) -) isomer in DMF (10 mL) was treated with 4-pyridylacetic acid N-oxide (0.039 g, 1.5 equivalents ), NMM (0.03 ml, 1.5 equivalents), DEC (0.049 g, 1.5 equivalents) and HOBT (0.034 g, 1.5 equivalents) and the resulting solution was stirred at room temperature overnight. The reaction mixture was quenched by addition of saturated NaHC 3 (10 mL) and extracted with CH 2 Cl 2 (4 x 50 mL). The combined organics were dried over MgSO4, filtered, and concentrated in vacuo. The crude residue was purified by preparative TLC using a 15% solution (10% NH4OH in MeOH) in CH2Cl2 as eluent to provide the 11S.2R isomer (0.044 g, 39% yield). p. F. = 115-117 ° C; LCMS: MH + = 706. Following essentially the same procedure except that the racemate or 11R.2R isomer of Preparative Example 8 was used, it can obtain the corresponding racemate or the 11R.2R isomer product.

EXAMPLES 7-9 Following essentially the same procedure as that indicated in Example 6, the compounds of the formula were prepared where R14 is as defined in Table 6 below TABLE 6 EXAMPLE 10 (Isomer 11 S, 2R) A solution of the title compound of Preparative Example 8 (11S.2R isomer) (0.080 g, 0.14 mmol) in CH 2 Cl 2 (2.0 mL) was treated with t-BuNCO (0.080 mL, 5.0 equivalents). The resulting solution was stirred at room temperature overnight and concentrated under reduced pressure. The crude product was purified by preparative TLC using a 10% solution (10% NH 4 OH in MeOH) in CH 2 Cl 2 as eluent to give the title compound (0.045 g, 48% yield), m.p. = 139-142 ° C; LCMS: MH + = 670.

EXAMPLE 11 (Isomer 11 R, 2R) The title compound was prepared essentially by the same procedure indicated in Example 10, but substituting the 11R.2R isomer of Preparative Example 8, p.f. = 157-159 ° C; LCMS: MH + = 670.

EXAMPLES 12-14 Following essentially the same procedure indicated in Example 10, except that the title compounds of Preparative Example 9 were used, the compounds of the formula were obtained in which R > 14 is as defined in Table 7, below. TABLE 7 EXAMPLE 15 To a solution of the title compound (11 -racemate) of Preparative Example 8 (0.072 g, 0.12 mmol) and TEA (0.010 mL, 1.1 equivalents) in CH 2 Cl 2 (4 mL) was added MeSO 2 Cl (0.01 mL, 1.1 equivalents) and The resulting solution was stirred at room temperature overnight. The reaction mixture was quenched by the addition of saturated NaHC 3 (5 mL), separated and extracted with CH 2 Cl 2 (2 x 50 mL). The combined organics were dried Na2SO4 and concentrated in vacuo. The crude residue was purified by preparative TLC using a 10% solution of (10% NH OH in MeOH) in CH2Cl2 as eluent (44 mg, 63% yield). p.f. = 107-110 ° C; LCMS: MH + = 649. Following essentially the same procedure, the 11R, 2R or 11S, 2R isomers can be obtained by using the isomer 11R.2R or 11S.2R, respectively, the title compounds for the preparative example 8.

EXAMPLES 16-18 Following essentially the same procedure as that indicated in Example 15, the compounds of the formula were obtained: where R14 is as defined in table 8.

TABLE 8 EXAMPLE 19 Following essentially the same procedure as that indicated in Example 1, except that the title compound of Preparative Example 7.3 was used, the title compound, m.p. = 133-138 ° C; LCMS: MH + = 682.

EXAMPLE 20 The title compound of Preparative Example 4 (0.211 g, 1.4 equivalents) found in Table 1 was added to an acid solution of Preparative Example 51 (0.487 g, 0.90 mmol), DEC (0.201 g, 1.2 equivalents), HOBT (0.73 g, 6.0 equivalents) and NMM (0.60 mL, 6.0 equivalents) in DMF (6.0 mL). The resulting solution was stirred at room temperature for 3 days. The crude product was precipitated from the reaction mixture by addition of water and filtered. The residue was purified by evaporative chromatography using a gradient of a 0.5% solution > to 3% in 0.5% increments (10% NH 4 OH in MeOH) in CH 2 Cl 2 solution as eluent to obtain the title compound (0.411 g, 67% yield). p.f. = 178-179 ° C; MH + = 685.

EXAMPLE 21 The title compound was prepared essentially following the same procedure indicated in Example 110, but substituting the title compound of Preparative Example 11 Step O p.f. = 150-154 ° C; MH + = 682.

EXAMPLE 22 The title compound was prepared by following essentially the same procedure indicated in Example 110, but replacing the title compound of Preparative Example 102 with the amine prepared by the method described in the preparative example 11 AC steps by replacing only the methyl by dichloroethane in preparative example 11 stage A. pf = 156-158 ° C; MH + = 680.

EXAMPLE 24 Stage A The title compound of Preparative Example 12 (0.23 g, 0.49 mmol) in CH 2 Cl 2 (5.0 mL) in TFA (3.0 mL) was stirred at room temperature for 2 hours and concentrated in vacuo. The residue was dissolved in CH2Cl2 (5.0 ml) and treated with TEA (0.45 ml, 20 equivalents) and chloride (0.056 g, 0.33 equivalents) and stirred at room temperature for 48 hours. The reaction mixture was diluted with saturated NaHCO3 (5.0 mL), water (15 mL), and extracted with CH2Cl2 (2 x 50 mL). The combined organics were dried over Na 2 SO 4 and concentrated under reduced pressure. The crude product was purified by evaporative chromatography using a 15% solution (10% NH 4 OH in MeOH) in CH 2 Cl 2 as eluent (0.063 g, 67% yield), m.p. = 157 ° C (dec.): FABMS: MH + = 572.

Stage B The title compound of Step A (0.058 g, 0.101 mmol) in CH2Cl2 (3 mL) was treated with an excess of cyclohexyl isocyanate and stirred at room temperature for one hour. The reaction mixture was concentrated in vacuo and purified by evaporative chromatography using an 8% solution of MeOH in CH 2 Cl 2 as a solvent to give the title compound (0.062 g, 75% yield). p.f. = 164-167 ° C; FABMS: MH + = 822.

The title compound of Example 24 (0.045 g, 0.0547 mmol) in concentrated NH OH (3.0 mL) and MeOH (3.0 mL) was stirred overnight. The resulting solution was concentrated in vacuo and the residue was purified by evaporative chromatography using a 15% solution of MeOH in CH 2 Cl 2 as eluent to give the title compound (0.022 g, 58% yield). p.f. = 164-169 ° C; FABMS; MH + = 697.

EXAMPLE 26 Stage A 2.99 g (15.09 mmol) of 3-methyl-histamine hydrochloride were dissolved in 100 ml of methylene chloride followed by 3.21 g (31.70 mmol) of triethylamine. It was stirred under a nitrogen atmosphere for 30 minutes and then 4.83 g (18.87 mmol) of anhydride from Preparative Example 44 was added in small portions and stirred under nitrogen for 30 minutes. 4.14 g (16.60 mmol) of benzyl chloroformate were added and stirred overnight. It was diluted with 100 ml of methylene chloride and washed with aqueous NaHC 3 solution. The organic layer was dried over MgSO 4 and concentrated in vacuo. Evaporative chromatography on 650 g of silica gel using 97% CH2Cl2 (NH4 · H) -3% methanol gave the product as a white solid, m.p. 51.8-63.2 ° C: Stage B 4.9 g of the product of step A were dissolved in 30 ml of methylene chloride and 13 ml of trifluoroacetic acid were added. It was stirred overnight under a nitrogen atmosphere and then concentrated in vacuo. The residue was triturated with ether and then dried in vacuo to obtain the product as a clear oil.

Stage C .01 g (11.04 mmoles) of the product of step B were dissolved in 50 ml of DMF containing 5.6 g (55.19 mmoles) of triethylamine. A chloride solution was added dropwise in 70 ml of DMF and stirred under nitrogen overnight. It was concentrated in vacuo and the residue was dissolved in 50 ml of methylene chloride. It was washed with aqueous NaHC 3 solution, the organic layer was dried over MgSO 4 and concentrated in vacuo. Evaporative chromatography of the residue on 640 g of silica gel using 97% CH2Cl2 (NH4OH) -3% methanol gives the product as a tan solid, m.p. = 111.8-114.5 ° C. MH + = 677 (FAB).

EXAMPLE 27 Stage A 4.61 g (6.8 mmol) of the product from Example 26, Step C, were dissolved in 6 ml of acetic acid 9 ml of a 5.7 M solution (33%) of HBr in acetic acid. After 3 hours, the reaction was completed by TLC with silica gel (95% CH2Cl2 (NH OH) -5% methanol). 25 ml of diethyl ether were added and the precipitate was filtered under nitrogen to obtain 5.8 g of a tan solid. Chromatography on a Chlralpack AD column, 5 cm x 50 cm (Chiral Technologies) using 25% 2-propanol / -hexane + 0.2% diethylamine, and a flow rate of 80 ml / minute provided the two diastereomers. Diastereomer A p.f. = 122.2-130.2 ° C, MH + = 543 (FAB). Diastereomer B p.f. = 122.1-130.2 ° C, MH + = 543 (FAB). 0.07 g (0.129 mmoles) of diastereomer A from step A were dissolved in 2 ml of methylene chloride followed by 0.021 g (0.155 mmoles) of 4-fluorophenyl socianate and stirred overnight under nitrogen. It was diluted with 20 ml of methylene chloride and washed with an aqueous solution of NaHCO 3, the organic layer was dried over MgSO 4 and concentrated in vacuo. The residue was chromatographed by TLC with preparative silica gel using 95% CH2Cl2 (NH4OH) -5% methanol to obtain 0.0179 g of the product as a white solid. Diastereomer A: p.f. = 143.1-145.2 ° C, MH + = 680 (FAB). In a similar manner, 0.07 g (0.129 mmol) of diastereomer B from step A are reacted with 4-fluorophenium isocyanate to obtain 0.18 g of the diastereomer B product as a white solid: Diastereomer B: m.p. = 140.1-149.4 ° C, MH + = 680 (FAB).

EXAMPLE 28 Following the procedure of example 27, 0.07 g (0.129 mmoles) of diastereomer A of example 27, step A, is reacted with tert-butyl socianate to obtain 0.065 g of dlastereomer A product as a white solid, m.p. = 125.1-133.5 ° C, MH + = 642 (FAB). Following the above procedure but using the diastereomer B of example 27, step A, 0.052 g of the diastereomer B product is obtained in the form of a white solid, m.p. = 128.1-135 ° C, MH + = 642 (FAB).

EXAMPLE 29 Following the procedure of example 27, it is reacted 0. 10 g (0.184 mmoles) of diastereomer A of example 27, step A, with Isopropyl socianate to obtain 0.041 g of the diastereomer A product as a white solid, m.p. = 128.1-133.3 ° C, MH + = 628 (FAB). Following the procedure above, but using diastereomer B of example 27, step A, 0.040 g of the diastereomer product are obtained B in the form of a white solid, m.p. = 128.1-133.4 ° C, MH + = 628 (FAB).

EXAMPLE 30 0.116 g (0.202 mmol) of diastereomer A from example 27, step A, are dissolved in 2 ml of methylene chloride followed by 0.02 g (0.202 mmoles) of triethylamine and 0.24 ml (0.24 mmoles) of a 1.0 M solution of chloroformate. isopropyl in toluene and stirred overnight under nitrogen. It was diluted with 20 ml of methylene chloride and washed with an aqueous solution of NaHC 3.The organic layer was dried over MgSO 4 and concentrated in vacuo. The residue was chromatographed by TLC with preparative silica gel using 95% CH2Cl2 (NH OH) -5% methanol to give 0.044 g of the diastereomer A product as a white solid. Following the above procedure but using the diastereomer B of example 27, step A, 0.038 g of the diastereomer B product was obtained in the form of a white solid. Diastereomer A: p.f. = 120.5-125-5 ° C MH + = 629 (FAB). diastereomer B: p.f. = 120.3-126-1 ° C MH + = 629 (FAB).

Following the procedure of example 30, 0.07 g (0.128 mmol) of diastereomer A of example 27, step A, was reacted with 0.021 g (0.142 mmol) of 4-morpholinecarbonyl chloride and 0.035 g (0.256 mmol) of triethylamine to obtain 0.024 g of the diastereomer A product in the form of a white solid. Following the above procedure, but using the dlastereomer B of example 27, step A, 0.019 g of the diastereomer B product is obtained in the form of a white solid. Diastereomer A: p.f. = 137.9-138.9 ° C MH + = 656 (FAB). Diastereomer B: p.f. = 136.4-138.6 ° C MH + = 656 (FAB).

EXAMPLE 32 0.07 g (0.129 mmoles) of diastereomer A of example 27, step A in 0.5 ml of methylene chloride are dissolved followed by 0.033 g (0.152 mmoles) of di-tert-butyl dicarbonate and stirred overnight under nitrogen. It is diluted with 20 ml of methylene chloride and washed with an aqueous solution of NaHCO 3, the organic layer is dried over MgSO 4 and concentrated in vacuo. The residue is chromatographed by preparative TLC with silica gel using 95% CH2Cl2 (NH OH) -5% methanol to obtain 0.024 g of the diastereomer A product as a white solid.

Following the above procedure, but using the diastereomer B of example 27, step A, 0.026 grams of the diastereomer B product is obtained in the form of a white solid. Diastereomer A: p.f. = 127.1-128.4 ° C, MH + = 643 (FAB). Diastereomer B: p.f. = 134.9-137.5 ° C, MH + = 643 (FAB).

EXAMPLE 33 Following the procedure of example 30, 0.05 grams (0.092 mmoles) of diastereomer A of example 27, step A, is reacted with 1.1 gram (0.10 mmoles) of methanesulfonyl chloride and 0.019 grams (0.0183 mmoles) of triethylamine in 1.5 ml of methylene chloride to obtain 0.011 grams of the product of diastereomer A as a white solid. Following the above procedure, but using the diastereomer B of example 27, step A, 0.032 grams of the diastereomer B product was obtained as a white solid. Diastereomer A: p.f. = 138.1-144.6 ° C, MH + = 621 (FAB). Diastereomer B: p.f. = 139-145.1 ° C, MH + = 621 (FAB).

EXAMPLE 34 0.07 grams (0.129 mmoles) of diastereomer A of example 27, step A, are dissolved in 1.0 ml of DMF followed by 0.023 grams (0.167 mmoles) of 4-fluorobenzoic acid, 0.032 grams (0.167 mmoles) DEC, 0.0225 grams (0.167 mmoles) ) HOBT and 0.018 ml (0.167 mmoles) N-methylmorpholine and stir overnight under nitrogen. Concentrate in vacuo and dissolve the residue in 20 ml of methylene chloride. Wash with 1 N aqueous NaOH, dry the organic layer over MgSO 4 and concentrate in vacuo. Evaporative chromatography on silica gel using 93% CH2Cl2 (NH OH) -7% methanol gives 0.060 grams of the diastereomer A product as a white solid. Following the above procedure, but using the diastereomer B of example 27, step A, the product of diastereomer B is obtained in the form of a white solid. Dlastereomer A: p.f. = 138.1-144.6 ° C, MH + = 621 (FAB). Diastereomer B: p.f. = 139-145.1 ° C, MH + = 621 (FAB).

EXAMPLE 35 Following the procedure of Example 34, 4-trifluorocacetic acid was used in place of 4-fluorobenzonic acid to obtain the diastereomer A product as a white solid. p.f. = 132.8-140.1 ° C, MH + = 679 (FAB). Following the above procedure, the product of diastereomer B is obtained in the form of a white solid, m.p. = 132.5-139.7 ° C, MH + = 679 (FAB).

EXAMPLE 36 Following the procedure of Example 34, 4-pyridylacetic acid N-oxide is used in place of fluorobenzonic acid to obtain the diastereomer product A as a white solid, and the diastereomer product B as a white solid. Diastereomer A: p.f. = 168.5-172.4 ° C, MH + = 678 (FAB). Diastereomer B: p.f. = 168.9-172.3 ° C, MH + = 678 (FAB).

EXAMPLE 37 Following the procedure of Example 34, Nt-butoxycarbonyl-4-piperidineacetic acid was used in place of 4-fluorobenzoic acid to obtain the product of diastereomer A as a white solid and the product of diastereomer B as a solid White. Dlastereomer A: p.f. = 135.1-142.1 ° C, MH + = 768 (FAB). Diastereomer B: p.f. = 141.7-143.2 ° C, MH + = 768 (FAB).

EXAMPLE 38 0.23 grams (0.31 mmol) of the diastereomer product A of example 37 are dissolved in 3 ml of methylene chloride and 3 ml of trifluoroacetic acid and stirred under nitrogen for 3.5 hours. Concentrate in vacuo and dissolve the residue in 20 ml of methylene chloride and wash with 1.0 N aqueous NaOH. The organic layer is concentrated in vacuo and the residue is chromatographed by preparative TLC silica gel using 80% CH2Cl2 (NH4). H) -20% methanol to give 0.113 grams of the dlastereomer A product as a white solid. Following the above procedure, but using the diastereomer product A of example 37, step A, the product of diastereomer B is obtained in the form of a white solid.

Diastereomer A: p.f. = 136.1-139.5 ° C, MH + = 668 (FAB). Diastereomer B: MH + = 6668 (FAB).

EXAMPLE 39 0.073 grams (0.11 mmol) of the diastereomer product A of example 38 is dissolved in 3 ml of methylene chloride containing 0.013 grams (0.121 mmol) of trimethylsilyl socianate and stirred under nitrogen overnight. Dilute with 5 ml of methylene chloride and wash with 10 ml of saturated aqueous NaHCO 3. The organic layer is dried over MgSO 4 and concentrated in vacuo. The residue is chromatographed by TLC with preparative silica gel using 90% CH2Cl2 (NH4OH) -10% methanol to obtain 0.032 grams of the diastereomer B product as a white solid. Following the above procedure, but using the diastereomer product B of Example 38, the product of diastereomer B is obtained in the form of a white solid. Diastereomer A: p.f. = 148.2-151.3 ° C, MH + = 711 (FAB). Diastereomer B: p.f. = 148.1-150.4 ° C, MH + = 711 (FAB).

EXAMPLE 40 The carboxylic acid of Preparative Example 51 (0.32 grams, 0.596 mmol), the product of Preparative Example 13 (0.108 grams, 0.775 mmol), DEC (0.149 grams, 0.775 mmol), HOBT (0.105 grams, 0.775 mmol) and 0.13 are dissolved. ml of N-methylmorpholine in 5 ml of DMF and stir overnight. Concentrate in vacuo and dissolve the residue in 20 ml of methylene chloride. Wash with a saturated solution of NaHC 3, dry over MgSO 4, and chromatograph on an evaporative column on silica gel using 97% CH 2 Cl 2 (NH OH) -3% methanol to obtain 0.2 grams of the product in the form of a white solid, the dlastereomers are separated by preparative chiral chromatography (Chiralpack AD column, 5 cm x 50 cm, flow rate 100 ml / min., 15% 2-propanol / hexane + 0.2% diethylamine). Diastereomer A: p.f. = 148.2-151.3 ° C, MH + = 711 (FAB). Diastereomer B: p.f. = 148.1-150.4 ° C, MH + = 711 (FAB).

EXAMPLE 41 Following the procedure of example 40, the product of preparative example 14 is used instead of preparative example 13 to obtain the product as a white solid. mp = 116-123 ° C, MH + = 671 (FAB).

EXAMPLE 42 Following the procedure of example 40, the product of preparative example 15 is used instead of preparative example 13 to obtain the product as a white solid. Diastereomer A: p.f. = 115-120 ° C, MH + = 671 (FAB). Diastereomer B: p.f. = 98.1-101 ßC, MH + = 671 (FAB).

EXAMPLE 43 Following the procedure of example 40, the product of preparative example 16 is used instead of preparative example 13 to obtain the product as a white solid. Mp = 120-122 ° C, MH + = 685 (FAB).

EXAMPLE 44 Following the procedure of example 40, the product of preparative example 17 is used instead of preparative example 13 to obtain the product as a white solid. Mp = 101-133 ° C, MH + = 733 (FAB).

EXAMPLES 45-59 Following the procedure of example 40, the amines of the preparative examples 18-26 are used instead of the preparative example 13 to obtain the compounds R27 is as defined in Table 9 TABLE 9 EXAMPLE 60 Step A The product of example 47 (0.148 g, 0.202 mmol) is dissolved in 0.78 ml of methylene chloride and 0.45 ml of trifluoroacetic acid is added and stirred under nitrogen for 2 hours. It concentrates in a vacuum. The residue was dissolved in 20 ml of methylene chloride and washed with aqueous NaHCO 3, the organic layer was dried over MgSO 4, and concentrated in vacuo to give the amine as a white solid.

Step B: Dissolve the product of step A (0.05 g, 0.078 mmol) in 2 ml of methylene chloride and add 0.015 g, 0.118 mmol, of cyclohexyl isocyanate. It is stirred overnight and then concentrated in vacuo. The residue is chromatographed on silica gel using 99% CH2Cl2 (NH4OH) 1% methanol to obtain the product of isomer A as a white solid.

Mp = 138-142 ° C, MH + = 758 (FAB). The above procedure is followed, but the product of example 48 is used instead of example 47 in stage A, to obtain the product of isomer B in the form of a white solid. Mp = 130-139 ° C, MH + = 758 (FAB).

EXAMPLE 61 Step A Using the product of Example 47, following the procedure of Example 60, but using t-butyl isocyanate in place of cyclohexyl isocyanate in Step B, the product of isomer A is obtained as a white solid. Mp = 127-132 ° C, MH + = 732 (FAB).

Step B Following the procedure of Example 60, but using the product of Example 48 instead of Example 47 in the t-butyl isocyanate step in place of cyclohexyl isocyanate in Step B, the product of Isomer B in the form of a white solid. Mp = 127-130 ° C, MH + = 732 (FAB).

EXAMPLE 62 Stage A The acid of preparative example 43 (0.37 g, 1.12 mmol), the product of preparative example 19 (0.29 g, 1.35 mmol), DEC (0.289 g, 1.46 mmol), HOBt (0.197 g, 1.46 mmol), N- is dissolved. Methylmorphoiin (0.25 ml, 2.24 mmoles) in 20 ml of DMF and stir under nitrogen overnight. It concentrates in a vacuum. The residue is dissolved in 50 ml of methyl chloride, washed with a saturated solution of NaHCO 3, the organic layer is dried over MgSO 4, and concentrated in vacuo. Evaporate chromatography of the residue on silica gel using 100% CH2Cl2 (NH OH) which gives a white solid.

Stage B The product of step A (0.59 g, 1048 mmol) is dissolved in 3 ml of methylene chloride and 2.5 ml of trifluoroacetic acid are added. It is stirred overnight and concentrated in vacuo.

The product from step B (0.5 g, 1048 mmol), tricyclic 8-CI chloride (0.359 g, 1048 mmol) and triethylamine (2.19 ml, 15.72 mmol) in 5 ml methylene chloride are dissolved and stirred overnight . Concentrate in vacuo and evaporate the chromatography of the residue on silica gel using 95% CH2Cl2 (NH4 · H) -5% methanol to provide the product as a white solid.

Stage D The product from step C (0.27g, 0.486 mmol) is dissolved in 2 ml of methylene and di-tert-butyl dicarbonate (0.125 g, 0.57 mmol) is added and stirred for 2 hours. Concentration in vacuo separates the diastereomers by preparative chiral chromatography (Chiralpack AD column, 5 cm x 50 cm, flow rate 100 ml / min, 5% 2-propanol-hexane + 0.2% diethylamine) obtaining the products in the form of white solids. Diastereomer A: Pf = 93.1-99.8 ° C, MH + = 655 (FAB). Diastereomer B: Pf = 93.1-99.8 ° C, MH + = 655 (FAB).

EXAMPLE 63 Following the procedure of example 40, the product of preparative example 27 is used instead of preparative example 13 to obtain the products in the form of white solids. Isomeric mixture 1: Pf = 148-151 ° C, MH + = 687 (FAB). Isomeric mixture 2: Pf = 110-114 ° C, MH + = 687 (FAB).

EXAMPLE 64 Following the procedure of Example 40, the product of Preparative Example 28 is used instead of Preparative Example 13 to obtain the product as a white solid: Mp = 131-138 °, MH + = 687 (FAB).

EXAMPLE 65 Following the procedure of example 40, the product of preparative example 29 is used instead of preparative example 13 to obtain the products in the form of white solids.

Isomeric mixture 1: Pf = 148-157 ° C, MH + = 721 (FAB). Isomeric mixture 2: Mp = 120-126 ° C, MH + = 721 (FAB).

EXAMPLE 66 Following the procedure of example 40, the product of preparative example 30 was used instead of preparative example 13 to obtain the products in the form of white solids. Isomeric mixture 1: Pf = 146-154 ° C, MH + = 657 (FAB). Isomeric mixture 2: Mp = 122-127 ° C, MH + = 657 (FAB).

EXAMPLE 67 The diastereoisomer 11 R, 2R (-) of preparative example 34 (0.25 g 0.46 mmol), N1-oxide of 4-pyridylacetic acid (0.0915 g, 0.598 mmol) (see preparative example 61 of U.S. patent 5,719,148 granted on 17 February 1998), DEC (0.1146 g 0.598 moles), HOBt (0.0807 g, 0.598 mmol) and 4-methyl-morpholine (0.0657 ml, 0.598 mmol) were dissolved in anhydrous DMF (9 ml) and the mixture was stirred under argon at 25 ° C for 96 hours, the reaction was worked up as described in preparative example 40, step A above, and chromatographed on a column of silica gel using 5% (10% concentrated NH 4 OH in methanol) -dicoromethane as eluent to give the title compound: (Yield: 0.2434 g, 78%); FABMS: m / z 678.0 (MH +); dc (CDCl 3) 30.1, 30.3, 30.9, 36.5, 38.5, 44.1, 44.3, 50.7, 52.5; CH: 53.4, 78.3, -119.1, 126.2, 127.3, 127.3, -129.1, 130.6, 132.3, -137.1, 138.6, 141.1, 146.9; C: 120.1, 134.2, 134.6, 134.8, 137.1, 140.8, 155.1, 169.2, 169.8; dH (CDCIs) 4.31 (1H, s, H11), 4.97 (1H, width s, CUCO), 6.74 (1H, width s, im-H5), 6.91 (1 H, width s, lm-H4), 7.02 ( 1 H, width s, Ar-H), 7.07-7.17 (5H, m, CONHCH2 and Ar-H), 7.38 (1H, s, lm-H2), 7.56 (1H, s, Ar-H), 8.08 (1 H, d, Ar-H), 8.10 (1 H, d, Ar-H), and 8.35 ppm (1 H, s, Ar-H2); [a] D23-2 ° + 44.4 ° (c = 10.64 mg / 2 ml, methanol).

EXAMPLE 68 The diastereomer 11S, 2R (-) of preparative example 34 (0.3 g, 0.552 mmol), N1-oxide of 4-pyridylacetic acid (0.110 g, 0.718 mmol) (U.S. patent 5,719,148, February 17, 1998), DEC (0.1375g, 0.718mmol), HOBt (0.0969g, 0.718mmol) and 4-methylmorpholine (0.0788ml, 0.718mmol) were dissolved in anhydrous DMF (9ml) and the mixture was stirred under argon at 25 ° C for 19 hours . The reaction was worked up as described in Preparative Example 40, Step A above, and chromatographed on a column of silica gel using 6% (10% concentrated NH 4 OH in methanol) -dicoromethane as eluent to obtain the title compound : (Yield: 0.2847 g, 80%); FABMS: m / z 678.0 (MH +); dc (CDCl 3) 30.1, 30.6, 30.8, 36.5, 38.5, 44.0, 44.4, 51.1, 52.7; CH: 53.4, 78.3, -119.0, 126.2 / 126.3, 127.2 / 127.3, 127.2 / 127.3, -129.2, 130.3, 132.4 / 132.6, -137.1, 138.7, 138.7, 141.2 / 141.5, 147.0 / 147.2; C: 120.1, 134.2 / 134.4, 134.3, 134.9, 136.9, 141.5, 154.4 / 154.7, 168.8 / 169.2, 169.0 / 169.9; dH (CDCl 3) 4.30 (1H, s, H ??), 4.96 (1 H, width s, CHCO), 6.64 (1H, width s, CONHCH2), 6.89-7.02 (3H, wide overlap, lm-H5, lm -H4 and Ar-H), 7.10-7.18 (4H, m, Ar-H), 7.33 (1H, width s, lm-H2), 7.59 (1H, s, Ar-H), 8.08 (1H, d , Ar-H), 8.08 (1H, d, Ar-H), 8.10 (1H, d, Ar-H) and 8.37 ppm (1H, s, Ar-H2); [a] D23'4 ° + 6.90 (c = 10.48 mg / 2 ml, methanol).

EXAMPLE 69 The 11r, 2R (-) diastereoisomer of preparative example 34 (0.3 g, 0.552 mmol), 1-aminocarbonyl-4-piperidinyl acetic acid (0.1335 g, 0.718 mmol) (preparative example 33), DEC (0.1375 g, 0.718 mmole), HOBt (0.0969 g, 0.718 mmole) and 4-methylmorpholine (0.157 ml, 1436 mmole) were dissolved in anhydrous DMF (7 ml) and the mixture was stirred under argon at 25 ° C for 68 hours. The reaction was worked up as described in Preparative Example 40, Step A above, and chromatographed on a column of silica gel using 6% (10% concentrated NH OH in methanol) -dichloromethane as eluent to obtain the title compound. title: (Yield: 0.3547 g, 90%); LCMS: m / z 711.2 (MH +); dc (CDCI3) 30.3, 30.4, 31.2, 32.0, 36.6 / 37.2, 39.3 / 39.6, 43.9, 44.4, 44.4, 44.4, 51.0, 51.8; CH: 32.9, 53.0, 78.7, 118.9, 126.2, 129.7, 130.5 / 130.7, 132.3, 137.3, 141.3, 147.0; C.120.3, 134.3, 135.1, 137.3, 141.1, 155.1, 157.9, 170.0, 171.9; dH (CDCl 3) 4.30 (1 H, s, Hn), 4.89 (2H, s, NCONJ ±), 4.98 (1H, s, CHCO), 6.92 (1 H, broad s, lm-H5), 6.99 ( 1H, width s, im-H4), 7.07-7.14 (3H, m, Ar-H), 7.41 (1H, width s, lm-H2), 7.57 (1 H, s, Ar-H), 7.59 (1 H, width s, CONHCH2) and 8.35 ppm (1H, s, Ar-H2); [a] D2a0 ° + 35.5o (c = 9.40 mg / 2 ml, methanol).

EXAMPLE 70 Following the procedure of Example 69, except that the 11S, 2R (-) diastereomer of Preparative Example 34 was used in place of the diastereomer 11R, 2R (-) and stirring under argon for 96 hours instead of 68 hours the compound of Title: (Yield: 0.3241 g, 83%); LCMS: m / z 711.2 (MH +); dc (CDCI3) 30.2, 30.6, 31.1, 32.0, 32.0, 36.5 / 36.8, 39.6 / 39.7, 43.8, 44.4, 44.4, 44.4, 51.3, 51.6; CH: 32.9, 53.0, 78.8, 119.0, 126.3 / 126.4, 129.4, 130.4 / 130.6, 132.5 / 132.6, 137.1, 141.5. 147.1; C: 120.2 134.3, 135.0, 137.1, 141.5, 155.1, 158.1, 170.3, 172.4; dH (CDCl 3) 4.29 (1H, s, H11), 4.55 (2H, s, NCONH2), 4.98 (1H, s, CHCO), 6.23 (1H, t, CONHCH2), 6.92 (1H, broad s, lm-H5 ), 7.03 (1H, width s, lm-H4), 7.10-7.17 (3H, m, Ar-H), 7.43 (1H, s, Ar-H), 7.59 (1H, s, Ar-H), and 8.37 ppm (1H, s, Ar-H2); [a] D23 r + 1.0 ° (c = 10.00 mg / 2 ml, methanol).

EXAMPLE 71 N1-pyridine-4-acylazide oxide (J. Med. Chem. 1998, 41, 877-893 (0.346 g, 2.30 mmol) was dissolved in dry toluene (30 ml) and the solution was heated under reflux under an atmosphere of Argon at 110 ° C for 1 hour The solution was cooled to room temperature and the racemic title compound Cu from Preparative Example 141 (0.250 g 0.46 mmol) was added.The mixture was stirred at 25 ° C for 2 hours. evaporated to dryness and the residue was chromatographed on a column of silica gel using 4% (10% concentrated NH 4 OH in methanol) -dichloromethane as eluent to obtain the title compound: (Yield: 0.1265 g, 32%); : m / z 679.2 (MH +); dc (CDCI3) 30.3, 30.6, 31.0 / 31.1, 36.7 / 36.8, 42.6, 44.6, 51.0 / 51.3, 52.4 / 52.6, CH: 55.1 / 55.2, 78.8, 115.8, 115.8, 119.2 , 126.3, 129.1, 130. 5 / 130.6, 132.7, 137.2, 138.6, 138.6, 141.4, 147.0 / 147.2; C: 120.2, 134.2, 134.3, 134.9, 136.9, 141.3, 155.0, 155.2, 170.4; dH (CDCl3) 4.34 (1 H, s, H11), 4.67 (1H, s, CHCO), 6.89 (1H, d, Im-Hs), 6.99 (1H, d, lm-H4), 7.10-7.15 (3H , m, Ar-H), 7.46 (2H, d, Ar-H), 7.59 (1 H, s, im-H2), 7.90 (2H, d, Ar-H), 8.39 (1H, s, Ar- H2) and 9.77 ppm (1H, width s, NCONH) EXAMPLE 72 Stage A 1-Nt-Butoxycarbonylpiperidine-3-acylazide (preparative example 35, step B above) (1177 g 4.63 mmol) was dissolved in dry toluene (150 ml) and the solution was heated under reflux under an argon atmosphere at 110 ° C for 1 hour. The solution was cooled to room temperature and added in three portions (1.47 mmole at 0 h, 2.21 mmole at 69 h and 0.95 mmole at 93 h) to a solution of the racemic title compound Cu from preparative example 141 (0.4 g, 0.735 mmole). ) in anhydrous dichloromethane (26 ml). The mixture was stirred at 25 ° C for 17 hours. The solution was evaporated to dryness and the residue was chromatographed on a column of silica gel using 4% (10% concentrated NH 4 OH in methanol) -dichloromethane as eluent to obtain the title compound: (Yield: 0.1265 g, 32%); LCMS: m / z 679.2 (MH +); dc (CDC) CH3; 28.5, 28.5, 28.5; CH2: 30.5, 30.6, 31.2 / 31.3, 32.5, 32.5, 36.6, 41.8, 42.7, 42.7, 44. 6, 50.9 / 51.1, 51.9 / 52.2; CH: 48.2, 54.9 / 55.0, 78.9 79.0, -119.0, 126.4 / 126.5, -129.6, 130.5 / 130.6, 132.8, -137.1, 141.3 / 141.4, 147.1 / 147.3; C: 79.6, 120.3, 134.5, 134.7, 136.9, 141.1, 154.7, 154.8, 157.6, 171.0; dH (CDCb) 1-46 (9H, s, CH3), 4.33 (1H, s Hn), 4.41 (1 H, broad s, CHCO), 5.18 (1 H, d, NCONH), 6.55 (1 H, broad m, CONjHCH2), 6.92 (1 H, width s, lm-H5), 7.08 (1H, width s, lm-H4), 7.10-7.15 (3H, m, Ar-H), 7.50 (1 H, broad s , lm-H2), 7.59 (1 H, d, Ar-H) and 8.40 ppm (1 H, s, Ar-H2).

Stage B The title compound from step A above (0.2361 g, 0.307 mmol) was dissolved in methanol (1.61 ml) and a 10% (v / v) solution of concentrated N2SO4 in dioxane (4.18 ml) was added. The mixture was stirred under argon at 25 ° C for 1 hour. The mixture was passed through a bed of Bio Rad® AG1-X8 (OH ") resin and the resin was washed with methanol.The combined eluates were evaporated to dryness and the residue was chromatographed on a column of silica gel using 20% (10% concentrated NH 4 OH in methanol) -dichloromethane as eluent to give the title compound: (Yield: 0.1984 g, 97%); LCMS: m / z 669.2 (MH +); dc (CDCl 3) 30.3, 30.5, 30.9, 31.6, 31.6, 36.3 / 36.4, 42.3, 42.3, 42.3, 44.3, 50.8 / 51.2, 52.1 / 52.4, CH: 47.2 / 47.3, 54.8, 78.9, 119.1, 126.3, 129.0, 130.5 / 130.6, 132.7, 137.5, 141.3, 147.0 / 147.1; C: 120.1, 134.2 / 134.3, 134.9, 136.9, 141.2, 155.2, 157.7 / 157.8, 171.2, dH (CDCb) 4.29 (1 H, s, H11), 4.61 (1H, width s, CHCO ), 5.72 (1H, width m, NCONH), 6.85 (1 H, m, CONHCH2), 6.92 (1 H, width s, lm-H5), 6.99 (1H, width s, lm-H4), 7.10-7.15 (3H, m-Ar-H), 7.57 (1 H, s, Ar-H) 7.66 (1 H, s s, lm-H2) and 8.37 ppm (1H, s, Ar-H2).

Stage C The title compound from step B above (0.195 g, 0.291 mmol) was dissolved in anhydrous dichloromethane (10 ml) and trimethylsilyl socianate (0.394 ml) was added., 2.91 mmole). The mixture was stirred under argon at 25 ° C for 20 hours. Additional trimethylsilyl socianate (0.188 ml, 0.873 mmol) was added and the mixture was stirred for a total of 23 hours. The mixture was diluted with dichloromethane (900 ml) and washed with saturated aqueous sodium bicarbonate, dried (MgSO 4), filtered and evaporated to dryness. The product was chromatographed on a column of silica gel using 4% (10% concentrated NH4OH in methanoi) -dichloromethane as eluent to give the title compound: (Yield: 0.1325 g, 64%); LCMS: m / z 712.2 (MH +); dc (CDCI3) 30.3 / 30.4, 30.6, 31.0 / 31.1, 32.4, 32.4, 36.5, 42.0, 43.4, 43A 44.4, 50 = 9/51 -.2, 52.4 / 52.6; CH: 48.1, 54.9 / 55.0, 78.9, 119.0, 126.3 / 126.4, 129.4, 130.5 / 130.6, 132.7, 137.3, 141.3 / 141.4, 147.1 / 147.2; C: 120.2, 134.2 / 134.3, 135.1, 136.9, 141.2, 155.1, 157.8 / 157.9, 158.1, 171.4 / 171.5; d (CDCl3) 4.31 (1 H, s, H11), 4.53 (1H, width s, CHCO), 4.75 (2H, width s, NCONtb), 5.73 (1H, d, NCONH), 6.65 (1H, t, CONHCH2 ) 6.92 (1 H, width s, Im H5), 7.04 (1 H, width s, lm-H4), 7.10-7.15 (3H, m, Ar-H), 7.46 (1H, s, Ar-H), 7.58 (1H, width s, lm-H2) and 8.38 ppm (1H, s, Ar-H2) EXAMPLE 73 The diastereomer 11R, 2R (+) of preparative example 38, step D above (0.1647 g, 0.294 mmole), N1-4-pyridinylacetic acid oxide (0.0586 g, 0.382 mmole), DEC (0.0733 g, 0.382 mmole), HOBt (0.0517 g, 0.382 mmol) and 4-methylmorpholine (0.042 ml, 0.382 mmol) were dissolved in DMF ahnidra (5 ml) and the mixture was stirred under argon at 25 ° C for 25 hours. The reaction was worked up as described in preparative example 40, step A above, and chromatographed on a column of silica gel using 2% increasing to 6% (10% concentrated NH 4 OH in methanol) -dichloromethane as eluent to obtain the title compound: (Yield: 0.1048 g, 51%); SIMS: m / z 694.5 (MH +); dc (CDCl 3) 30.0, 30.4, 31.0, 36.7, 38.5, 44.1, 44.5, 50.5, 51.3; CH: 53.6, 63.6, 119.1, 126.4, 127.4, 127.4, -129.1, 130.7, 130.8, 133.4, -137.2, 138.4 / 138.6, 138.7, 138.7; C: 118.5, 133.3, 134.6, 134.9, 140.4, 141.4, 147.4, 169.2, 169.9; dH (CDCl 3) 4.98 (1H, width s, CHCO), 5.70 (1H, s, Hn), 6.92 6.97 (1H, width s, lm-H5), 7.01 (1H, width s, lm-H4), 7.08- 7.18 (5H, m, Ar-H), 7.43 / 7.51 (1H, width s, lm-H2), 7.79 (1H, t, CONHCH2), 8.05 (1H, d, Ar-H) 8.09 (2H, d, Ar-H), 8.26 / 8.31 ppm (1H, s, Ar-H2) [a] D20'0 ° + 82.8 ° (c = 9.11 mg / 2 ml, methanol).

EXAMPLE 74 The diastereomer 11S, 2R (-) of preparative example 38, step D above (0.1576 g, 0.281 mmol), N1-oxide of 4-pyridylacetic acid (0.0560 g, 0.366 mmole), DEC (0.0702 g, 0.366 mmole), HOBt (0.0495 g, 0.366 mmole) and 4-methylmorpholine (0.040 ml, 0.366 mmole) were dissolved in DMF ahnldra (5 ml) and the mixture was stirred under argon at 25 ° C for 26 hours. The reaction was worked up as described in preparative example 40, step A above, and chromatographed on a column of silica gel using 2% increasing to 6% (10% concentrated NH 4 OH in methanol) -dichloromethane as eluent to give the title compound: (Yield: 0.1017 g, 50%); SIMS: m / z 694.5 (MH +); dc (CDCl 3) 29.7, 30.5, 30.8, 36.5, 38.4, 44.2, 44.3, 50.1, 52.3; CH: 53.4, 63.6, -119.0, 126.4, 127.4, 127.4, -129.1, 130.3, 130.9, 133.3, -137.3, 138.3 / 138.7, 138.7, 138.7; C: 118.4, 133.3, 134.6, 134.8, 140.1, 141.6, 147.4, 169.2, 169.9; dH (CDCl 3) 4.97 (1 H, broad s, CHCO), 5.71 (1H, s, Hn), 6.58 (1H, t, CONHCH2) 6.88 (1 H, broad s, m-H5), 6.98 / 7.03 ( 1H, width s, lm-H4), 7.09-7.21 (5H, m, Ar-H), 7.34 / 7.41 (1H, width s, lm-H2), 8.09 (1 H, d, Ar-H), 8.10 (2H, d, Ar-H), 8.27 / 8.28 ppm (1H, s, Ar-H2); [aJD20-0 ° -12.7 ° (c = 10.08 mg / 2 ml, methanol).

N1-oxido of 3-bromo-8,11-dichloro-6,11-dihydro-5H-benzo [5,5] cyclohept [1,2-b] pyridine (preparative example 38, step C) ( 0.2656 g, 0.74 mmole) in anhydrous dichloromethane (3.8 ml) was added to 1 - [2- [N- [3- [1 H-imidazol-1-yl] propyl] -2 (R) -piperazinecarboxamide] - 2-oxoethyl-1-piperidinecarboxamide (preparative example 40, step B above) (0.3 g, 0.74 mmole) and triethylamine (1.0316 ml, 7.40 mmole) in anhydrous dichloromethane (6 ml) and the mixture was stirred at 25 ° C under argon for 19 hours. The solution was chromatographed directly on a column of silica gel using 3.5% (10% concentrated HN OH in methanol) -dichloromethane as eluent to give the title compound: (Yield: 0.3727 g, 69%); LCMS: m / z 727.2 (MH +); dc (CDCI3) 29.9 / 30.1, 30.4 / 30.5, 31.1 / 31.2, 32.0, 32.0, 36.5 / 36.6, 39.6, 44.0 / 44.4, 44.0 / 44.4, 44.4, 44.4, 50.5 / 50.7 / 51.1, 52.1; CH: 32.9, 53.0 / 53.1, 63.8, -119.2, 126.4 / 126.5, -129.4, 130.5 / 130.7, 130.9, 133.4, -137.2, 138.4; C: 118.5, 133.3 / 133.4, 134.8 / 134.9, 140.2 / 140.5, 141.4 / 141.6, 147.6 / 147.8, 158.1, 169.3 / 170.2, 171.4 / 172.0; dH (CDCl3) 4.60 (1 H, s, NCONH2) 4.98 (1H, broad s, CHCO), 5.69 (1 H, s, H11), 6.29 / 6.53 (1H, t, CONHCH2, S (-) and R isomers (+) to Cu, respectiv) 6.92 (1 H, width s, lm-H5), 7.05 (1H, width s, lm-H), 7.14 (2H, m, Ar-H), 7.18 (1 H, m , Ar-H), 7.20 (1 H, m, Ar-H), 7.56 81 H, width s, lm-H2) and 8.27 ppm (1 H, s, Ar-H2).

EXAMPLE 76 (Isomer 11S, 2R (-)) (Isomer 11R, 2R (+)) Method 1: N-3-bromo-8,11-dicylamido-6,11-dihydro-5H-benzo [5,5] cyclohepta [1,2-b] pyridine oxide (Preparative Example 38, Step C) (0.2818 g, 0.785 mmol) in anhydrous dichloromethane (4 mL) was added to N1-cyclohexyl-N2 [3- (1 H-imidazol-1-yl) propyl] -1, 2 (R) -piperazindylcarboxamide (following) (0.2844 g, 0.785 mmol) and triethylamine (1.094 mL, 7.85 mmol) in anhydrous dichloromethane (4.5 mL) and the mixture was stirred at 25 ° C under argon for 67 hours. The solution was chromatographed directly on a column of silica gel using 3% (10% concentrated NH 4 OH in methanol) -dichloromethane as eluent to give the racemic mixture of the title compounds: (Yield: 0.4664 g, 87%). The mixture was subjected to preparative HPLC on a Chiralpak AD® column (50X5 cm) using 65% hexane-35% isopropyl alcohol-0.2% diethylamine as eluent to provide in the order of elution the diastereomer 11S, 2R ( -) and the diastereomer 11 R, 2R (+). Diastereoisomer 11S, 2R (-): (Yield 0155.5 g); LCMS: m / z 684.2 684.2 (MH +); dc (CDCI3) 25.1, 25.1, 25.6, 30.3, 30.7, 31.1, 33.7, 33.7, 36.5, 42. 3, 44.7, 50.2, 50.7; CH: 50.0, 55.0, 64.2, 119.1, 126.3, 128.8, 130.6, 130.9, 133.5, 137.2, 138.5; C: 118.5, 133.1, 134.7, 140.4, 141.4, 147.5, 157.5, 171.1 dH (CDCl3) 4.52 (1 H, broad, s, CHCO), 4.95 (1H, d, NCONH). . 69 (1H, s, H11), 6.97 (1 H, t, CONHCH2), 6.97 (1H, width s, lm-H5), 7.10 (1H, width s, lm-H4), 7.13 (1H, m, Ar -H), 7.18 (2H, s, Ar-H), 7.21 (1 H, m Ar-H), 7.69 (1H, s, lm-H2) and 8.27 ppm (1H, s, Ar-H2); [α] D20'0 ° + 49.9 ° (c = 10.23 mg / 2 ml, methanol). Diastereoisomer 11R, 2R (+): (Yield: 0.1890 g); LCMS: m / z (MH +); dc (CDCI3) 25.0, 25.1, 25.6, 30.1, 30.5, 31.1, 33.7, 33.7, 36.4, 42. 4, 44.5, 50.2, 51.5; CH: 49.9, 54.8, 64.1, 119.1, 126.5, 129.3, 130.5, 130.8, 133.5, 137.2, 138.4; C: 118.4, 133.1, 134.9, 140.2, 141.4, 147.8, 157.6, 171.2 dH (CDCl3) 4.53 (1 H, broad, s, CHCO), 4.91 (1H, d, NCONH). 5.68 (1 H, s, H11), 6.62 (1 H, t, CONHCH2), 6.94 (1H, width s, lm-H5), 7.08 (1H, width s, lm-H4), 7.15 (1H, m, Ar-H), 7.17 (1 H, s, Ar-H), 7.21 (1 H, s Ar-H), 7.23 (1 H, m, Ar-H) 7.55 (1 H, width s, lm-H2) and 8.27 ppm (1H, s, Ar-H2); [a] D200 ° -33.1 ° (c = 8.76 mg / 2 ml, methanol). The starting reagent N1-cyclohexyl-N2- [3- (1H-ylamdazol-1-yl) propyl] -1, 2 (R) -plperazindcarboxamide was obtained following the procedure of Preparative Example 5, except that it was used instead of The resulting protected BOC compound was deprotected with TFA following the procedure of preparative example 8, step B.

Method 2: The 11S, 2R (-) diastereomer of Preparative Example 38, Step D above (1 mg, 0.00179 mmol) was dissolved in anhydrous dichloromethane (0.05 mL) and cyclohexyl isocyanate (0.0023 mL, 0.0179 mmol) was added. The mixture was stirred at 25 ° C for 0.5 hours under argon. The solution was evaporated to dryness to give the title compound which was identical on chiral HPLC to the diastereomer 11S, 2R (-) prepared in the method 1 above EXAMPLE 77 Reagent 2 = Nss .N-, Imidazole from preparative example 74 (reagent 2) (250 mg, 1.16 mmol) was added to a solution of BOC-acid (reagent 1, see preparative example 41), (0.45 g, 0.842 mmoles), EDCI (200 mg, 1043 mmol), HOBT (130 mg, 0.962 mmol) and N-methyl-morpholine (0.2 mL, 1.81 mmol) in DMF (anhydrous, 2 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 10% Na2CO3 solution (50 ml), then dried over MgSO4, the solvent was filtered off and an oil was obtained which was chromatographed on silica gel eluting with 100% EtOAC which provided the product in the form of a white solid (300 mg). Mixture of 4 Isomers A, B, C and D. Mass espectography: Estimated alpha resolution (ES) (MH +) 732.2316, observed 732.2332.

EXAMPLE 78 Stage A A solution of the title compound of Example 77 (isomers A, B, C and D) (150 mg, 0.205 mmole) in 50% trifluoroacetic acid-CH2Cl2 was stirred at 20 ° C for 3 hours. The solvent was evaporated, water and 10% NaOH (4 ml) were added, then extracted with CH2Cl2 (2x100 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-CH 2 Cl 2 containing 2% NH 4 OH which gave the product in form of a white solid (70 mg, 54% yield). The product was obtained in the form of a mixture of 2 isomers (C and D) (product 1), mass spectrum FABS (MH) 632. The additional solution gave a white solid (25 mg, yield 20%). This product consisted of a mixture of two isomers (A and B) (product 2), mass spectrum FABS (MH + 632.

Product 2 was separated into simple isomers on a Chilracell AD column with 40% IPA-hexanes that provided isomer a as a white FABS (MH +) 632. Additional elution provided isomer B as a white FABS solid ( MH +) 632. The product 1 was derived and separated into the constituent isomers C and D as shown in the next step B.

Stage B A solution of di-tert-butyl dicarbonate (65 mg, 0.29 mmol) in CH2Cl2 (2 mL) was added to a solution of product 1 (step a, isomers c and D) (150 mg, 0.237 mmol) in CH2Cl2 (10 mL). ml), at 0 ° C, then stirred at 20 ° C for 10 minutes, the reaction was cooled to 0 ° C, water (5 ml), 10% NaOH (2 ml) and CH 2 Cl 2 (10 ml) were added. . The organic layer was separated, dried over MgSO 4, filtered and the solvent was evaporated obtaining an oil, which was chromatographed on silica gel eluting with 3% v / v MeOH: CH 2 Cl 2 obtaining the product in the form of a white solid (150 mg) as a mixture of two isomers, which were separated on a Chiracell AD column, eluting with 30% IPA-hexanes / 0.2% diethylamine which provided 60 mg of the C isomer. FABS mass spectrum (MH +) calculated (C38H44N5O3B.-CI: 734.2296), measured: 734.2304. Additional elution afforded 70 mg of isomer D. Mass spectrum FABS (MH +) calculated MH (734.2296), measured: 734.2305.

EXAMPLE 79 Stage A Following the procedure of Example 78 step A, the BOC group was extracted from the product of isomer C of step B to produce the title product, isomer C, as a white solid (mass spectrum FABS (MH +) (632) .

Stage B Cyclohexyisocyanate (0.025 ml, 0.19 mmol) was added to a solution of isomer A (example 78, step A) (25 mg, 0.039 mmol) in CH2Cl2 (3 ml) at 0 ° C and then stirred at 20 ° C. for 30 minutes. Methylene chloride (20 ml) and water (20 ml) were added. The organic layer was separated, dried over MgSO 4, filtered and the solvent was evaporated obtaining a residue which was chromatographed on silica gel eluting with 2% v / v MeOH: CH 2 Cl 2, providing the product (isomer A) as a white solid (25 mg). High resolution mass spectroscopy (ES) calculated C4oH47N6? 2BrCI: (757.2632) (Br = 79), measured 757.2643. Following the above procedure but substituting isomer a for an equivalent amount of isomer B (example 78, step A), the title compound (isomer B) was obtained. Mass spectrum (FABS, HRMS) calculated (759.2612) (Br = 81), measured: 759.2626. Following the previous procedure but substituting the isomer For an equivalent amount of C-isomer (example 79, step A) the title compound (isomer C) was obtained. Mass spectrum (ES, MH +) 757 (Br = 79).

Following the above procedure but replacing isomer A with an equivalent amount of isomer C and D (product 1 of example 78, step A), the mixture of C and D isomers of the title compound was obtained. Mass spectrum (ES, MH +) 757.

EXAMPLE 80 Ethyl chloroformate (0.1 ml, 1.04 mmol) was added to a solution of isomer A (example 78, stage A) (20 mg, 0.03 mmol) in CH2CI2 (2 ml) at 20 ° C. Trilethylamine (0.1 ml, 0.7 mmol) was added and the solution was stirred for 30 minutes at 20 ° C. The solvent was evaporated and the residue was chromatographed on silica gel eluting with 3% v / v MeOH: CH 2 Cl 2 containing 2% NH 4 OH to obtain the product of isomer A as a white solid (20 mg). Mass spectrum (ES, MH +) 704. Following the above procedure but replacing isomer A with an equivalent amount of isomer B (example 78, step A) was obtained the compound of isomer B.

Mass spectrum (ES, MH +) 704 HRMS (ES) calculated (704.2003) (Br = 79), measured: 704.2012.

EXAMPLES 81-85 Following the procedure of Examples 127 and 80 but using the title compounds of Preparative Examples 9.1 or 111.1 with the appropriate isocyanate or chloroformate, the compounds of the formula were obtained wherein R > 8 y. , RD14 are as defined in Table 10 below.

TABLE 10 The compounds of examples 83 and 84 were prepared on a Chiracell AD column.

EXAMPLE 86 Following the procedure of Examples 77-79 but substituting an equivalent amount of substituted N-benzyl imidazole of Preparative Example 74 in Example 77 for an equivalent amount of 1- (3-aminopropyl) imidazole, the title compounds were obtained. 11S isomer: mass spectrography: Fabs (MH +) 667 (Br = 79) calculated HRMS (MH) C33H4iN602CI (81) Br 669.2142, measured: 669.2151. Isomer 11 R: FABS (MH +) 667.

EXAMPLE 86A The imidazole from preparative example 1, step D and following the procedure of example 77 and example 79, step A were used to obtain the compound which was reacted with cyclohexyl isocyanate according to the procedure indicated in example 79, step B. Mass spectrum: Fabs (MH) 695 (Br = 79) 669.2142.

EXAMPLES 87-97 Following the procedures indicated in Examples 77-80 but using isomer 11 (R) the compounds of the formula were obtained: R > 14 is as defined in table 11, TABLE 11 EXAMPLE 98 The product of preparative example 45 (0.6 g) was dissolved in 6 ml of dichloromethane and 6 ml of trifluoroacetic acid was added and the reaction mixture was stirred for 2 hours. After 2 hours the reaction mixture was evaporated to an oil. The oil dissolved in N, N-dimethylformamide and triethylamine (0.445 ml, 3 equivalents) and 3-bromo-8,11-dichloro-6,11-dlhydro-5H-benzo [5,6] cyclohepta [1,2-b] were added. pyridine (0.39 g, 113 mmol) and the reaction mixture was stirred for 24 hours. The reaction mixture was added to the brine and the product was extracted with ethyl acetate 3 times to obtain a crude oil after evaporating the solvent under reduced pressure, which was purified by chromatography on a silica gel column using 2% until 4% methanol / dichloromethane as eluent. The product containing the fractions was pooled to obtain 0.34 g of the pure title compound. The compound was separated into its pure enantiomers by HPLC on a column of Chiral Technologies AD using % isopropanol / hexanes.

Isomer 1: p.f. = 148.3-157.5 ° C; isomer 2: p.f. = 148.3-157.5 ° C.

The title compound of Preparative Example 48 (0.487 g) was dissolved in 3 mL of dichloromethane and 3 mL of trifluoroacetic acid and the reaction mixture was stirred for 2 hours. The reaction mixture was evaporated to dryness and dissolved in 10 ml of N, N-dimethylformamide. Triethylamine (1.42 ml, 10 equivalents) was added and 3-bromo-8,11-dichloro-6,11-dihydro-5H-benzo [5,6] cyclohepta [1,2-b] pyridine (compound N) was added. 42.0) (0.45 g, 1.2 equivalents) and the reaction mixture was stirred for 24 hours. The reaction mixture was added to the brine and the product was extracted with ethyl acetate 3 times to obtain a crude oil after evaporating the solvent under reduced pressure, which was purified by chromatography on a silica gel column using 2% until 4% methanol / dichloromethane as eluent. The product containing the fractions was pooled to obtain 0.26 g of the pure title compound as a mixture of isomers. The isomers were prepared by HPLC on a column of Chiral Technologies AD using 20-30% isopropanol / hexanes. Isomer 1: p.f. = 192.7-194.3 ° C. Isomer 2: p.f. = 189.2-190.7 ° C.

EXAMPLE 100 The title compound of Preparative Example 52 (0.3 g, 0.5 mmol) was stirred in a mixture of 10 mL of dichloromethane and 15 μL of water and Dess-Martin Periodinano (0.32 g) was added., 1.5 equivalents) and the reaction mixture was stirred at room temperature. After 24 hours the reaction mixture was washed with 20% of a Na 2 S 2+ solution followed by a solution of sodium bicarbonate and evaporated to dryness in vacuo. This compound was dissolved in dichloromethane and with a premixed solution of 4-iodo-1-trityl imidazole (89 mg) and ethylmagnesium bromide (3M solution in ether, 66 μl, added to the reaction mixture and stirred at room temperature for 4 hours The reaction mixture was poured into a saturated solution of ammonium chloride and the product was extracted with dichloromethane to obtain the crude product which was purified by preparative tic to obtain 52 mg of the title product after deprotection with TFA and the introduction of the Boc group with (BOC) 2 ?.

EXAMPLES 101-102 Following procedures similar to those described in examples 98-100, the following compounds were obtained.

Example 101 EXAMPLE 103 The title compound of Preparative Example 58 was dissolved in 1 ml of dichloromethane and 68 microliters of tert-butyl socianate was added and the reaction mixture was stirred. The reaction mixture was evaporated to obtain the crude product which was stirred with 33% HBr / HOAc to obtain 20 mg of the title compound after addition to the ether, the product being collected in the form of a tan solid and preparative thin layer chromatography FABMS M + 1 = 659.

EXAMPLE 104 The title compound of example 105 (50 mg) was dissolved in 5 ml of dichloromethane and 0.5 microliter of acetic anhydride was added thereto. The reaction mixture was evaporated to dryness after 18 hours and chromatographed by preparative tic to obtain 39 mg of the pure title product. FABMS MH + = 699.

The title compound was prepared by following essentially the same procedure indicated in Preparative Example 52, but substituting 1-amino-3-propanol for 1- (3-aminopropyl) -2-aminoimidazole to obtain the title product in a yield of 65% FABMS MH + = 690.

EXAMPLE 106 The title compound was prepared following the procedure indicated in Example 104, but using the title compound of Preparative Example 105 in place of the title compound of Example 103 and trifluoroacetic anhydride in place of acetic anhydride to obtain the pure title product. FABMS MH + = 756.

EXAMPLE 107 Following the procedure of Example 104, but substituting the acetic anhydride for trifluoroacetic anhydride to obtain the pure product of the title FABMS MH + = 755.

EXAMPLE 108 The title product was prepared following the procedure indicated in example 110, but substituting the product of preparative example 102 step C for the title compound of preparative example 60 and cyclohexyl isocyanate for tert-butyl isocyanate to obtain the pure product of Title. FABMS MH + = 688.

EXAMPLE 109 The title product was obtained following the procedure indicated in preparative example 52, but substituting 1-amino-3-propanol for 2-S-benzyl-3-R, S-hydroxy-histamine.

FABMS MH + = 737.

EXAMPLE 110 A mixture of the title compound of Preparative Example 102, Step C (0.28 g, 2 mmol), the title compound of Preparative Example 44 (0.5 g, 2 mmol) and anhydrous CH 2 Cl 2 (5 mL) were stirred at room temperature for 15 minutes. minutes Cyclohexyl isocyanate (0.51 ml, 4 mmol) was added and the reaction mixture was allowed to stir at room temperature for an additional 48 hours. After concentrating the reaction mixture in vacuo, the residue was diluted with CH2Cl2 (10 ml) and trifluoroacetic acid (10 ml) and stirred at room temperature overnight. The resulting mixture was concentrated in vacuo, diluted with anhydrous DMF (5 ml) and then 1-methylmorpholine (2.2 ml, 20 mmol) and tricyclic chloride (compound No. 42.0) (0.83 g, 2 mmol) were added. The reaction mixture was stirred at room temperature overnight concentrated in vacuo and purified by evaporative column chromatography (silica gel) using 50% MeOH-95% CH2Cl2 saturated with aqueous ammonium hydroxide to give the title compound in the form of a mixture of diastereomers (tan solid, 95 mg, 7%, MH1 * 682, mp = 118.4 ° C).

EXAMPLE 111 Following a procedure similar to that used for the preparation of the title compound of Example 110 but using the title compound of Preparative Example 103, the title compound was obtained as a mixture of diastereomers (viscous solid, brown, 28.7 mg, 2%, MH + = 696, mp = 79.3 ° C).

EXAMPLE 112 Following a procedure similar to that used for the preparation of the title compound of Example 110 but using the title compound of Preparative Example 104, the title compound was obtained as a mixture of diastereomers (tan solid, 18.5 mg, 1%, MH + = 710, m.p. = 63.8-67.4 ° C).

EXAMPLE 113 To the title compound of Preparative Example 51 (10.04 g, 19 mmol) were added HOBT (3.34 g, 25 mmol), DEC (4.79 g, 25 mmol), the title compound of Preparative Example 74 (4.32 g, 20 mmol). NMM (5.5 ml, 50 mmol) and anhydrous DMF (20 ml). The mixture was stirred at room temperature under N2 overnight. The mixture was concentrated in vacuo, diluted with CH 2 Cl 2 and washed with a saturated aqueous solution of NaHC 3. The organic phase was dried over anhydrous MgSO 4, filtered and concentrated in vacuo. The residue was purified by column evaporative chromatography (silica gel) using 2% MeOH-98% CH 2 Cl 2 saturated with aqueous ammonium hydroxide to obtain the title compound as a mixture of diastereomers (4.92 g, 36%, MH + = 733).

EXAMPLE 114 If the procedure of Example 113 is followed but N-substituted-midazolylalkyl amine is used as shown below, the indicated compound would be obtained.

Amine A Compound A Amine B Compound B Amine C Compound C H Amine D Compound D EXAMPLES 115-126 Following the procedure indicated in Example 113 but N-substituted imidazolylalkyl amine (imidazole) is used in Table 12 and the carboxylic acid of Preparative Example 51 the products of Table 12 were obtained.

TABLE 12 EXAMPLE 127 To a solution of the title compound of Preparative Example 109 (D-diastereomer 11R, 2R, 1.7 g, 2.7 mmol) dissolved in anhydrous CH 2 Cl 2 (10 mL) was added cyclohexyl isocyanate (0.38 mL, 2.9 mmol) and the resulting solution was stirred at room temperature under N2 for 1.5 hours. The solution was concentrated in vacuo and purified by evaporative column chromatography (silica gel) using 2% MeOH-98% CH 2 Cl 2 saturated with aqueous ammonium hydroxide to give the title compound as a light yellow solid. (1.98 g, 84%, MH + = 758).

EXAMPLES 128-148 Following the procedure indicated in Example 127 but using the isocyanates and the compounds of the preparative examples given in Table 13 below, the products of Table 13 were obtained.

TABLE 13 EXAMPLE 149 To a solution of the title compound of Preparative Example 109 (diastereomer A 11S, 2R, 50 mg, 0.08 mmol) dissolved in anhydrous CH 2 Cl 2 (1 mL) was added benzoyl chloride (0.02 mL, 0.16 mmol) and triethylamine (0.043 mL). , 0.2 mmol) and the resulting solution was stirred at room temperature under N2 overnight. The solution was diluted with dichloromethane, washed with aqueous 1 N NaOH and dried over anhydrous MgSO 4. Filtration and concentration in vacuo afforded a residue which was purified by preparative plate chromatography (silica gel) using 5% MeOH-95% CH 2 Cl 2 saturated with aqueous ammonium hydroxide to give the title compound as a white solid. whitish color (54.4 mg, 93%, MH + = 737). SHC EXAMPLE1 150-217 In a similar manner using the procedure described for Example 149, the title compound (diastereomer A or B) of the preparative example given in Table 14 was treated with the corresponding acid chloride, chloroformate, carbamyl chloride, dicarbonate, anhydride or sulfonyl chloride which is given in Table 14 below (electrophilic column) to provide the N-substituted arylalkyl or heteroarylalkyl products listed in Table 14.

TABLE 14 34ß EXAMPLE 218 If the procedure described in example 149 is followed, the title compound of Preparative Example 109 (diastereomer A) can be reacted with to get the compound EXAMPLE 219 If the procedure described in example 149 is followed, the title compound of Preparative Example 109 (diastereomer A) can be reacted with to get the compound EXAMPLE 220 If the procedure described in Example 51 is followed, but the tricyclic 3-Br-8-CI alcohol is replaced by the alcohol 3,8-tricyclic dichloro to prepare the following compound Then if the procedure of Example 113 is followed to react the above compound with the title compound of Preparative Example 95.1, the following compound can be obtained Then, if the procedure of Preparative Example 109 is followed using the above compound, the following compound can be obtained: Then if the procedure of example 149 is followed using the above compound and the following compound can be obtained EXAMPLE 220A If the procedure of Example 220 is followed but the title compound of Preparative Example 90 is used in place of the title compound of Preparative Example 95.1 in the process step of Example 113, the following compound can be obtained EXAMPLE 221 To a solution of the title compound of Preparative Example 109 (diastereomer A 11S.2R, 75 mg, 0.12 mmol) dissolved in anhydrous DMF (1 mL) was added HOBT (32 mg, 0.24 mmol), DEC (45.4 mg 0.24 mmol). ) and isovaleric acid (0.026 ml, 0.24 mmol) and the resulting solution is stirred at low N2 temperature overnight. The solution was concentrated in vacuo, diluted with dichloromethane, washed with 1 N aqueous NaOH and dried over anhydrous MgSO 4. Filtration and concentration in vacuo afforded a residue which was purified by preparative plate chromatography (silica gel) using 5% MeOH-95% CH 2 Cl 2 saturated with aqueous ammonium hydroxide to give the title compound as an off-white solid. (81.5 mg, 96%, MH + = 717).

EXAMPLES 222-224 If the procedure described for Example 221 is followed, the title compound (diastereomer A or B) of Preparative Example 109 was treated with the carboxylic acid given in Table 15 to obtain the N-benzyl product listed in Table 15.

TABLE 15 EXAMPLE 225 To the title compound of Preparative Example 127 step C (diastereomer A 11S.2R) (1.73 g, 3.57 mmol) was added HOBT (0.689 g, 5.1 mmol), DEC (0.98 g, 5.1 mmol), the title compound of preparative example 95.1 (0.9 g, 3.9 mmol) NMM (0.87 mL, 7.9 mmol) and anhydrous DMF (20 mL). The mixture is stirred at room temperature under N2 overnight. The mixture was concentrated in vacuo, diluted with dichloromethane and washed with a saturated aqueous solution of NaHCO3. The phrase was dried over anhydrous MgSO. It was filtered and concentrated in vacuo. The residue was purified by evaporative column chromatography (silica gel) using 2% MeOH-98% CH 2 Cl saturated with aqueous ammonium hydroxide to give the title compound (1.7 g, 69%, MH + = 695).

EXAMPLES 226-232 Following the procedure described to give example 225, the carbons were prepared the products listed in Table 16 using the carboxylic acid given in Preparative Example 127 step C (diastereomer A) and the appropriate, purified N-substituted imidazolylalkyl amine by preparative chiral chromatography (Chiralpack AD column, 5cm X 50 cm, flow rate 80 ml / min, 5-13% IPA-hexane + 0.2% diethylamine).

TABLE 16 EXAMPLE 234B If the procedure of example 225 is followed but the anima of preparative example 101.2 is used, the following compound is obtained Example 234B EXAMPLE 235 The title compound of Preparative Example 51 (0.184 g, 0.35 mmol) was added to a solution of the title compound of Preparative Example 132, Step C (0.2 g, 0.437 mmol), DEC (0.168 g, 0.87 mmol), HOBT ( 0.118 g, 0.87 mmol) and NMM (0.22 g, 2.19 mmol) in DMF (10 mL). The resulting solution is stirred at room temperature for 24 hours. The reaction mixture was diluted with water until the precipitation ceased and the suspension was filtered. The precipitate was diluted with dichloromethane, washed with brine, dried over Na 2 SO and concentrated. The crude product was purified by chromatography using a 5% solution of (10% NH 4 OH in MeOH) in CH 2 Cl 2 as eluent to give the title compound (0.18 g, 42% yield).

EXAMPLES 236-238 Following essentially the same procedure indicated in Example 235, except that the anima given in Table 18 was used, the compounds of the formula were obtained where Z is as defined in table 18.

TABLE 18 EXAMPLE 239 Stage A The title compound of Example 235 (0.5 g, 0.517 mmol) in CH2Cl2 850 ML9 was stirred with TFA (6 mL) at room temperature overnight. The reaction mixture was evaporated to give the title compound as a TFA salt (0.743 g) which was used to give the title compound as a TFA salt (0.743 g) which was used for the following reactions .

Stage B To a stirred solution of the title compound from step A (0.102 g, 0.0936 mmol), triethylamine (0.0798 g, 0.798 mmol) in CH2Cl2 was added di-tert-butyl dicarbonate (0.0515 g, 0.236 mmol) and stirred overnight. It was evaporated to a residue which was stirred in a solution of 2N ammonia in methanol (2 ml) overnight and evaporated to dryness. The residue was chromatographed on silica gel using 5% (10% concentrated NH 4 OH in methanol) to give the title compound (0.043 g).

EXAMPLES 240-243 Following the procedure the same procedure indicating in the example 239 step B, except that the chloroformate was used as indicated in the following table 19, the compounds of the formula were obtained: where R14 is as defined in table 19.

TABLE 19 EXAMPLE 244 To a solution of the title compound from Step A of Example 239 (0.126 g, 0.126 mmol), triethylamine (0.71 g, 0.726 mmol) in CH2Cl2 (5 mL), t-butyl isocyanate (0.018 g, 0.726 g) was added. mmoles). The resulting solution was stirred at room temperature overnight. It was evaporated to dryness and the residue was then stirred with a solution of 2N ammonia in methanol (3 ml) overnight. It was evaporated to dryness and the product was chromatographed on silica gel using 5% (10% conc. NH 4 OH in methanol) -CH 2 Cl 2 as eluent to give the title compound (0.046 g) CIMS: M / Z (MH +) 732.

EXAMPLES 245-254 Following the procedures indicated in examples 77-79 and 86, but using the dlastereomeric mixture A and B of preparative example 135 and the appropriate amidomidazole, the following compounds were prepared: (Example 248) (Example 247) (Example 250) (Example 249) (Example 252) (Example 251) EXAMPLES 255-278 Following the procedure described for Example 127, the title compound (diastereomer A or B or A + B) of the Preparative Example indicated in Table 20 below was treated with the corresponding isocyanate to obtain the urea products in Table 20.

TABLE 20 EXAMPLES 279-286 Following the procedure described for Example 149, the title compound (diastereomer A or B or A + B) of the preparative example indicated in Table 21 below was treated with the corresponding acid chloride, chloroformate, carbamyl chloride, dicarbonate, anhydride or sulfonyl chloride to obtain the products listed in Table 21.

TABLE 21 EXAMPLES 287-289 Following the procedure described for Example 221, the title compound (diastereomer A or B or A + B) of the preparative example indicated in Table 22 below was treated with the corresponding acid chloride, carboxylate to obtain the products listed in Table 22. .

TABLE 22 EXAMPLE 290 A solution of the title compound of Preparative Example 143 (0.59 g, 1115 mmol) dissolved in anhydrous dichloromethane (10 mL) and trifluoroacetic acid (2 mL) was stirred at room temperature for 3 hours. The solution was concentrated in vacuo and then the residue was combined with anhydrous dichloromethane (10 ml), tricyclic chloride (compound No. 42.0) (0.474 g, 1.38 mmole) and triethylamine (1.61 ml, 11.5 mmole) and left under stirring. at 25-40 ° C for 12 hours. The reaction mixture was concentrated in vacuo and purified by evaporative column and preparative plate chromatography (silica gel) using 1-4% MeOH-CH.2Cl2 saturated with aqueous amino hydroxide to provide the title compounds (457 mg , 55%, MH + = 718).

EXAMPLES 291-297 Following the procedure described for preparative example 290 and the BOC-protected piperazines listed in Table 23 below, the tricyclic compounds of Table 23 were prepared as diastereomeric mixtures. The separated diastereomers were separated by preparative chiral chromatography (Chiralpack AD Column, 5 cm X 50 cm, flow rate 80 mL / min, 7-12% IPA-Hexane + 0.2% diethylamine) to obtain diastereomer A and diastereomer B.

TABLE 23 EXAMPLE 299 Stage A To a solution of the title compound of Preparative Example 5 (0.30 g, 0.67 mmol) dissolved in anhydrous dichloromethane (3 mL) was added cyclohexyl-socianate (0.09 mL, 0.7 mmol) and the resulting solution was stirred at room temperature. environment for 30 minutes and then concentrated in vacuo. The resulting residue was diluted with dichloromethane (3 ml) trifluoroacetic acid (3 ml). The solution was stirred at room temperature overnight and then concentrated in vacuo, diluted with dichloromethane and washed with 1 N NaOH. The organic phase was dried over MgSO4, filtered, and concentrated in vacuo to give a foam of yellow color (0.319 g, 100%, MH + = 473).

Stage B To a solution of the title compound from step A above (0.212 g, 1.45 mmol) dissolved in anhydrous dichloromethane (10 ml) was added tricyclic chloride (compound No. 42.0) (0.154 g, 0.45 mmol) and triethylamine (0.32 mL). , 2.25 mmol) and left under stirring at 25 ° C for 48 hours. The reaction mixture was concentrated in vacuo and purified by preparative plate chromatography (silica gel) using 5% MeOH-CH 2 Cl 2 saturated with aqueous ammonium hydroxide to provide the title compounds (125 mg, 35%, mp = 114.8. ° C, MH + = 778).

EXAMPLE 300 Following the procedure described for Example 299 Steps A-B, the product listed in Table 24 below was prepared using the corresponding piperazine of the indicated preparative example.

TABLE 24 EXAMPLE 302 Stage A To a mixture of the title compound of Preparative Example 162 (400 mg, 1.86 mmol), the anhydride of Preparative Example 44 (561 mg, 2.19 mmol) and anhydrous CH 2 Cl 2 (10 mL) was stirred at 25 ° C for 3 hours before add tert-butyl socianate (0.26 mL, 2.16 mmol). After 12 hours, the mixture was concentrated in vacuo, diluted with CH2Cl2 and washed with water. The organic phase was dried over anhydrous Na2SO, filtered and concentrated. The resulting foam was diluted with anhydrous CH 2 Cl 2 (10 mL) and trifluoroacetic acid (10 mL) and stirred for 3 hours. Concentration in vacuo, redilution with CH2CI2 and washing with 1N NaOH (0.5 aqueous) provided an organic solution which was dried over anhydrous Na2SO, filtered, concentrated and used without further purification (181 mg, 27%, MH + = 431.5 ).

Stage B To a solution of the title compound of step A (170 mg, 0.39 mmol) dissolved in anhydrous dichloromethane (10 ml) was added to the tricyclic chloride (compound No. 42.0) (175 mg, 0.51 mmol) and triethylamine (71 μL). , 0.51 mmole) and allowed to stir at 25 ° C for 48 hours. The reaction mixture was concentrated in vacuo and purified by preparative plate chromatography (silica gel) using 5% MeOH-CH 2 Cl 2 saturated with aqueous ammonium hydroxide to provide the title compounds (oil, 24 mg, 8% NH + = 736).

EXAMPLE 303 If the procedure indicated in example 302 is followed using in step A instead of the title compound of Preparative Example 162, the title compound will be obtained.

EXAMPLE 304 Following the procedure described for Example 58, except that the title compound of Preparative Example 165 is used in place of the title compound of Preparative Example 25, the title compound is prepared (51% MH + = 711, mp = 103.7-107.5 ).

EXAMPLE 305 The title compound of example 58 was separated into its two diastereomers by HPLC (Chiracel AD column) using 10% isoproparol-90% hexane-0.2% diethylamine to obtain the 11 (R), 2 (R) and 11 isomers. (S), 2 (R). Diastereomer A: MH + = 697; p.f. = 103-108 ° C. Diastereomer B: MH + = 697; p.f. = 101-107 ° C.

EXAMPLE 306 Following the procedure described for Example 58, except that the diastereomer 1 (S), 2 (R) of Preparative Example 164 was used in place of the title compound of Preparative Example 51, the title compound was prepared (59%, MH + = 619, mp = 100-114 ° C).

EXAMPLE 307 Following the procedure described for example 306, except that the title compound of Preparative Example 25 was used, the title compound was prepared (73%, MH + = 633, mp = 89.1-96.5 ° C).

Following the procedure described for example 58, except that diastereomer 11 (R), 2 (R) of preparative example 164 was used in step C instead of the title compound of preparative example 51, and using the title compound of the preparative example In place of the title compound of Preparative Example 25, the title compound was prepared (65%, MH + = 633, mp = 89.1-96.5).

EXAMPLE 309 The racemic product of preparative example 141 (0.2 g, 0.368 mmol), 4- (4-nitrophenyloxycarbonyl) piperidine-1-carboxamide (0.1706 g, 0.552 mmol) (preparative example 36, step B) and isopropanol (10 mL) were heated at reflux and under argon at 87 ° C for 24 hours. The solution was evaporated to dryness and the residue was taken up in dichloromethane and washed with saturated aqueous NaHCO3, water, dried (MgSO4), filtered and evaporated to dryness. The residue was chromatographed on a column of silica gel using 3% -6% -10% (10% concentrated NH 4 OH in methanol) -dichloromethane as eluent to give the title compound (0.057% g, 22%): FABMS; m / z 712.9 (MH +): dc (CDCl 3) CH 2: 30.3, 30.5, 30.6, 31.1, 36.7, 41.3, 42.2, 44.5, 50.7 / 51.1, 52.3; CH: 55.4, 71.0, 78.8, ~ 118.9, 126.3, 129.4, 130.5, 137.0, 141.4, 147.1; C: 120.2, 134.3, 135.0, 137.0, 141.3, 155.2, 158.0, 170.2; dH (CDCI3) 4.31 / 4.32 (1 H, s, Hn), 4.56 (2H, width s, NCONH2), 6.93 / 1H, width s, lm-H5), 7.07 (1H, width s, lm-H), 7.10-7.16 (3H, m, Ar-H), 7.48 (1H, m, Ar-H), 7.60 (1H, s, l-H2) and 8.30 ppm (1H, s, Ar-H2).

EXAMPLES 310-342 Following the procedure described for Example 225, the products listed in Table 25 were prepared using the carboxylic acid (diastereomer A or B) of Preparative Example 127 step C and the appropriate N-substituted imidazolylalkyl amine.

EXAMPLES 343-361 Following the procedure described for Example 40, the products listed in Table 26 were prepared using either the mixture or the pure isomers of the carboxylic acids (diastereomer A and / or B) of Preparative Example 51 and the N-substituted imidazolylalkyl amine was added in place of the amine of Preparative Example 13. The resulting products were separated by HPLC (Chiracel, AD, 85/15 Hexane / IPA column) TABLE 26 EXAMPLES 362-366 Following the procedure described for example 225, except that the (11 (S), 2 (R) (+)) carboxylic acid of Preparative Example 164 was used in place of preparative example 127 step C, and using the substituted amine of the example For the preparation indicated in Table 27 instead of Preparative Example 95.1, the product listed in Table 27 was prepared.

TABLE 27 EXAMPLES 367-374 Following the procedure described for Example 225, the products listed in Table 28 were prepared using the carboxylic acid (diastereomer A or B) of the preparative example listed in Table 28 below in place of the carboxylic acid of Preparative Example 127 step C and ia suitable imidazolylalkyl amine (amine). TABLE 28 EXAMPLES 375-382 Following essentially the same procedure described for Example 149, the title compound (diastereomer A or B) of the preparative example given in Table 29 was treated with cyclohexyl chloroformate to give the products listed in Table 29.

TABLE 29 EXAMPLES 383-392 Following essentially the same procedure described for Example 149, the title compound (diastereomer A or B) of Preparative Example 170 was treated with the appropriate acylating agent (ie cyclohexyl chloroformate, or Boc dicarbonate, or cyclohexyl isocyanate, or tert-butyl isocyanate or isobutyl chloroformate) to obtain the products of the formula: where R1 is as defined in column 2 of Table 30.

TABLE 30 EXAMPLE 393 Stage A If the acetocyclohexanol commercially obtainable with phosgene were treated, the chloroformlate would be obtained.

Stage B If the chloroformate from step A were combined with the piperazine amine shown above according to the procedure described for Example 149, the acetate would be obtained.

Step C If the product of Step B were treated with potassium carbonate MeOH, the title compound would be obtained.

EXAMPLE 394 Stage A If the cyclohexanol commercially obtainable with phosgene is treated, chloroformitate would be obtained.

Stage B If the chloroformate from step A is combined with the piperazine shown above according to the procedure described for Example 149, the ketal would be obtained.

Stage C If it is stage B with aqueous acid, the ketone would be obtained.

Stage D If the product of stage c were treated with MeMgBr or MeLi, the product of the title would be obtained.

EXAMPLE 395 Following essentially the same procedure indicated in Example 225 (coupling), replacing only the preparative example acid 127 step C, by the title compound of the preparative example 212 would yield the title compound P.f. 91-107 ° C, LCMS MH * = 695.

EXAMPLE 397 Step A If the 3-bromotrichic chloride of Preparative Example 209 was used in place of the chloride of Preparative Example 127 step C then the carboxylic acid would be obtained Step B If the carboxylic acid of step a were used essentially by the same procedure as that used for example 225 then the title compound would be prepared. The separation of isomers could be carried out using chiral HPLC (column AD) using IPA-Hexane as eluent.

EXAMPLE 398 Step A If the 3-flouortricyl chloride of Preparative Example 211 was used instead of the chloride of Preparative Example 127 step C then the carboxylic acid would be obtained "Calm acid from stage A essentially Then the computer is prepared. Chiral HPLC (AUJ column u could be performed using HPLC co or eluent. 0 Step B If the carboxylic acid of step A were used essentially by the same procedure as that used for example 225 then the title compound would be prepared. The separation of isomers could be carried out using chiral HPLC (column AD) using IPA-Hexane as eluent.

ESSAYS The IC50 FPT (famesyl protein transferase inhibition, in vitro enzymatic assay) and the COS cell IC50 (Cell-based Assays) were determined following the assay procedures described in WO 95/10516, published on April 20 from 1995. The IC50 GGPPT (gerangenranyl protein transferase inhibition, in vitro enzyme assay), Cel Cell Assay, and anti-tumor activity (anti-tumor 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. Assays can be carried out using any of human colon carcinoma cell DLD-1-BAG expressing an activated K-ras gene or with SW620-BAG human colon carcinoma cells expressing an activated K-ras gene. By 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 assay The independent development of adhesion is a characteristic of tumorigenic cell lines. Human tumor cells can be suspended in a culture medium containing 0.3% agarose and an indicated concentration of a farnesyl transferase inhibitor. The solution can be deposited on a culture medium solidified with 0.6% agarose containing the same concentration of the famesyl transferase inhibitor as the upper layer. After solidification of the upper layer plates can be incubated for 10-16 days at 37 ° C under 5% CO2 to allow the development of the colony. After the incubation, the colonies can be stained by covering the agar with a solution of MTT (3- [4,5-dimethyl-tlazol-2-yl] -2,5-diphenyltetrazolium bromide, thiazolyl blue) (1 mg / mL in PBS) ). The colonies can be counted and the IC 50 can be determined. The compounds of examples 1-19, 21-25, 67-71, 72 stage B, 72 stage C, 73-77, 78 stage B (isomer C), stage 78 (isomer D), stage 79 (isomer) A, B and C), 80 (isomers A and B), 81-86, 86A, 87, 88, 93-104, 106, 108, 110-113, 115-211, 214-217, 221-228, 236 -238, 236-238, 241-244, 255-286, 286A, 286B, 287-297, 299 stage B, 300, 302 stage B, 305 and 309 had a Cl50 FPT within the range of <0.05nM to 20% @ 170nM. The compounds of examples 1, 2, 6-13, 16-17, 19, 78 stage B (isomer D), 80 (isomer A), 67-71, 72 stage B., 72 stage C, 73, 76, 81-86, 87, 88, 93, 95-101, 103, 106, 108, 110, 111, 113, 115-118, 121, 122, 124, 125 (isomer A), 127-134, 137, 142, 144-146, 148, 189-192, 195-196, 198-208, 210-211, 216-217, 221, 222, 225, 237, 238, 242-245, 247-263, 265, 268-286, 286A, 286B, 288-289, 292, 295-296, 299 stage B, 300, 302 stage B, 305, 309, 310-342, 343-373 and 375-382 had an I50 of FPT within the range of < 0.04nM to 6.7nM. The compounds of examples 11, 19, 78 stage B (isomers C and D), 79 stage B (isomer A), 80 (isomer A), 88 (isomer A), 93 (isomer D), 99, 100, 225 , 243, 367 and 368 had an IC50 of FPT within the range of < 0.04nM to 2.7nM. The compound of Example 225 had an IC50 of FPT of 0.04nM. The compounds of examples 1, 2, 8, 25, 86, 100 had a Cos cell IC50 within the range of < 10-920nM. The compounds of Examples 98, 101, 103, 104, 106, 108, 258, 259, 261, and 262 had a Cos cell Cl50 within the range of < 5nM to 500nM. The compounds of examples 245-250 had an IC50 of Cos cell within the range of 100% @ 0.01 to 0.87μm. The compounds of Examples 100, 101, 103 and 259 had a Cos cell IC50 within the range of < 5nM to 35nM. The compounds of examples 1, 2, 3, 7, 8, 10-16, 21, 25, 67-69, 70, 81, 82, 86 (isomer 11 R, 2R), 88-95, 97, 110, 111-113, 115-119, 121-176, 178-184, 186-200, 202-204, 206-211, 214-217, 221,225, 256, 258, 259, 261, 262, 268-271, 273- 274, 276, 278, 280-286, 289, 292, 295-296, 299n stage B, 305, 309-346, 351-373 and 375-382 had a soft agar IC50 within the range of < 5nM to 500nM. The compounds of Examples 116, 117, 160, 170, 184, 186-188, 196-200, 202-204, 206-208, 217, 225, 205 (isomer 11s, 2R), 316, 321, 322, 324 , 325, 335, 339, 365, 364, 372, 373, 375, and 382 had a Cl50 of soft agar within the range of 2 to 10nM. The compounds of examples 11, 16, 79 stage B (isomer A), 80 (isomer A), 88 (isomer A), 93 (isomer D), and 225 had an IC50 of soft agar within a range of 2 to 300nM The compound of Example 225 had an IC50 of soft agar within the range of 2nM. To prepare the pharmaceutical compositions of the compounds described in this invention, the inert pharmaceutically acceptable carriers can be solid or liquid. Solid form preparations include powders, tablets, dispersible granules, capsules, cachets and suppositories. The powders and tablets may be comprised of 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. Tablets, 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), Marck Publishing Co., Easton, Pennsylvania. Liquid form preparations include solutions, suspensions and emulsions. As an example may be mentioned water or propylene glycol solutions in water 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 in combination with a pharmaceutically acceptable carrier, such as 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. These liquid forms include solutions, suspensions and emulsions. The compounds of the invention can also be delivered transdermally. The transdermal compositions may have the forms of cream, lotions, aerosols and / or emulsions and may be included in a transdermal patch of the matrix or reservoir type which are conventional in the art for this purpose. Preferably the pharmaceutical preparation is in unit dosage form. In such form the preparation is subdivided into a unit dose of the appropriate size containing the appropriate quantities of the active component, for example, an effective amount to achieve the desired purpose. The amount of the active compound in a unit dose of preparation may be varied or adjusted to from about 0.01 mg to about 1000 mg, preferably from about 0.01 mg to about 750 mg, more preferably from about 0.01 mg to about 500 mg, and further preferably from about 0.01 mg to about 250 mg, according to the particular application. The actual dose used may vary depending on the patient's requirements and the severity of the condition being treated. The determination of the 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 of administration frequency of the compounds of the invention and / or the pharmaceutically acceptable salts thereof will be regulated in accordance with the opinion of the attending physician considering factors such as the age, condition, and weight of the patient as well as also the severity of the symptoms that are being treated. A typical recommended daily dosage regimen for total administration may be from 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 alternative modifications and variations may be made that will be apparent to those skilled in the art. All such alternatives, modifications, and variations are within the spirit and scope of the present invention.

Claims (2)

1. NOVELTY OF THE INVENTION CLAIMS 1. - A compound of the formula; or a pharmaceutically acceptable salt or solvate thereof, wherein; where one of a, b, c and d represents N or NO ", 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; X represents N or CH where the optional bond (represented by the dotted line) is absent, and represents C when present in the optional bond, the dotted line between the carbon atoms 5 and 6 represents an optional bond, so that when present a double bond A and B independently represent -R15, halo, -OR16, -OC02R16 or -OC (0) R15, and when no double bond is present between the carbon atoms 5 and 6, A and B each represent independently H2, - (OR 6) 2, H and halo, dihalo, alkyl and H, (alkyl ^, -H and -OC (0) R15, H and -OR15, = 0, Aryan and H, = NOR15 or -0 - (CH2) p-0- where p is 2.3 or 4, each R1 and each R2 is independently selected from H, halo, -CF3, -OH15, -COR15, -SR15, -S (0) tR16 (where t is 0, 1 or 2, m -NR (R15) 2, -N02, -OC (0) R15, -C02R15, -OC02R16, -CN, -NR15COOR16, -SSR16C (0) OR16, -SR 6N (R17) 2 (with the proviso that R16 in -SR16N (R17) 2 is not -CH2-), wherein each R17 is independently selected from H or -C (0) OR16, benzotriazol-1-yloxy, tetrazol-5-ylthio, or substituted tetrazole-5-ylthio, alkynyl, alkenyl or alkyl, said alkyl or alkenyl group being optionally substituted with halo, -OR15 or -CO2R15; R3 and R4 are the same or different and each represents independently 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 represents each independently H, -CF3 -COR15, alkyl or aryl, said alkyl or aryl being optionally substituted with -OR15, -SR15, -S (0) tR16, -NR15COOR16, -N (R15) 2, -N02, -COR15, -OCOR15, OCO2R16, -C02R15, OPO3R15, or R5 is combined with R6 to represent = O or = S; R8 is selected from H, C3 to C alkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, cycloalkyl, cycloalkyl-alkyl, substituted alkyl, substituted aryl, substituted aralkyl, substituted heteroaryl, substituted heteroarylalkyl, substituted cycloalkyl, substituted cycloalkyl-alkyl; the substituents for the substituted groups R8 are selected from: alkyl, aryl, arylalkyl, chloroalkyl, -NR (R18) 2, -OR18, cycloalkylalkyl, halo, CN, -CO (0) N (R18) 2, -SO2N (R18 ) 2 or -CO2R18, with the proviso that the substituents -OR18 and -N (R18) 2 are not bonded to the carbon atom that is bonded to the N of the -C (0) NR8- portion; each R18 is independently selected from: H, alkyl, aryl, arylalkyl, heteroaryl or cycloalkyl; R9 and R10 are independently selected from: H, alkyl, aryl arylalkyl, heteroaryl, heteroarylalkyl, cycloalkyl or -CON (R18) 2 (wherein R18 is as defined above); and the groups R9 and R10 are substitutable are optionally substituted with one or more substituents selected from; alkyl, cycloalkyl, arylalkyl, or heteroarylalkyl; or R9 and R10 together with the carbon atom to which they are attached form a cycloalkyl ring C3 to Ce; R11 and R12 are independently selected from; H, alkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, cycloalkyl, -CON (R18) 2 -OR18 O -N (R18) 2 -OR18 O-N (R18) 2; wherein R18 is as defined above; with the proviso that the groups -OR18 and N (R18) 2 are not bonded to the carbon atom that is adjacent to the nitrogen atom; and where said groups R .11 and R > 12 replaceable are optionally substituted with one or more substituents selected from: alkyl, cycloalkyl, arylalkyl, or heteroarylalkyl; or R11 and R12 together with the carbon atom to which they are attached form a C3 cycloalkyl ring to Ce; R13 is an imidazolyl ring selected from: where R19 is selectable from; (1) H, (2) alkyl, (3) alkyl, (4) aryl, (5) arylalkyl, (6) substituted arylalkyl where the substituents are selected from halo or CN, (7) -C (aryl) 3 or (8) cycloalkyl; said imidazolyl ring 2.0 is optionally substituted with one or two substituents, and said imidazole ring 4.0 is optionally substituted with 1-3 substituents and said ring midazole 4.1 is optionally substituted with a substituent wherein said optional substituents for rings 2.0, 4.0 and 4.1 are independently selected from: -NHC (O) R18, -C (R34) 2OR35, OR18, -SR18, F, Cl, Br, alkyl, aryl, arylalkyl, cycloalkyl or -N (R18) 2 (wherein each R18 is independently selected); wherein R18 is as defined above; wherein each R34 is independently selected from H or alkyl; wherein R35 is selected from H, -C (O) OR20, or -C (0) NHR20, and R20 is as defined below. Q represents an aryl ring, a cycloalkyl ring or a heteroaryl ring, said Q being optionally substituted with 1 to 4 substituents independently selected from halo, alkyl, aryl, -OR18, or -N (R18) 2 (wherein each R18 is independently selected ), -OC (0) R18, or C (O) N (R18) 2 (where each R18 is independently selected), and where R18 is as defined above; R14 is selected from; (5.0), ((66..00)), (7.0), (7.1) or (8.0) R15 is selected from H, alkyl, aryl or arylalkyl; R1d is selected from; alkyl or aryl; R20 is selected from; H, alkyl, alkoxy, aryl or arylalkyl, cycloalkyl, heteroaryl, heteroarylalkyl or heterocycloalkyl, with the proviso that R20 is not H when R14 is group 5.0 and 8.0; 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) R18, -OR18 or -N (R18) 2, where each R18 is the same or different, and wherein R18 is as defined above, with the proviso that said optional substituent is not bonded to a carbon atom that is adjacent to an oxygen or nitrogen atom; R21 is selected from: H, alkyl, aryl, arylalkyl, cycloalkyl, heteroaryl, heteroarylalkyl or heterocycloaicyl; when R21 is other than H, then said group R21 is optionally substituted with one or more substituents selected from: halo, alky, aryl -OR18 O -N (R18) 2 wherein each R18 is the same or different, and wherein R18 is such as is defined above, with the proviso that said optional substituent is not attached to a carbon atom that is adjacent to an oxygen or nitrogen atom; n is 0-5; each R32 and R33 for each n are independently selected from: H, alkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, cycloalkyl, -CON (R18) 2 -OR18 or = N (R18) 2, wherein R18 is as defined higher; and wherein said substitutable R32 and R33 groups are optionally substituted with one or more substituents selected from: alkyl, cycloalkyl, arylalkyl, or heteroarylalkyl; or R32 and R33 together with the carbon atom to which they are attached form a cycloalkyl ring C3 to C &;; and R36 is selected from branched alkyl, unbranched alkyl, cycloalkyl, heterocycloalkyl or aryl; and with the proviso that: (1) when R 4 is selected from: groups 6.0, 7.0, 7.1 or 8.0, and X is N, then R8 is selected from: C3 alkyl to C-io, C3 alkyl substituted, arylalkyl, substituted arylalkyl, heteroarylalkyl, substituted heteroarylalkyl, cycloalkylalkyl, or substituted cycloalkylalkyl; Y (2) when R14 is selected from: groups 6.0, 7.0, 7.1 and 8.0, and X is N, and R8 is H, then the alkyl chain between R13 and the amine portion is substituted.
2. 2. The compound of claim 1 having the structure: 3. - The compound of claim 1 wherein: R1 to R4 is independently selected from H, Br, 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; n is 0 or 1; R13 is a group 2.0 or 4.0. 4. The compound of claim 1 wherein: (a) R8 is selected from: arylalkyl, substituted arylalkyl, cycloalkylalkyl, substituted cycloalkylalkyl, heteroarylalkyl or substituted heteroarylalkyl; (b) R9 and R10 are independently selected from: H, alkyl, -C (O) N (R18) 2, or arylalkyl; (c) R11 and R12 are independently selected from: H, alkyl, substituted aryl, -OR18, or R11 and R12 taken together with the carbon atom to which they are attached form a cycloalkyl ring; (d) R32 and R33 are independently selected from: H, -OR18, arylalkyl or aryl; (e) R19 is selected from; -C (0) N (R18) 2, alkyl, arylalkio, or -C (aryl) 3; and (f) said optional R13 substituents are selected from: -N (R18) 2, -NHC (0) R18, -C (R34) 2OR35, alkyl, substituted cycloalkyl with the proviso that the -OH substituent is not attached to the carbon atom that is adjacent to an oxygen atom. 5. The compound according to claim 1, wherein R14 is: a) 5.0 and R20 are selected from: alkyl, aralkyl, heterocycloalkyl, aryl, aryl substituted with halo, cycloalkyl, or cycloalkyl substituted with alkyl; b) 6.0 where R20 and R21 are independently selected from: H, cycloalkyl, alkyl, aryl, or arylalkyl; c) 7.0 wherein R20 is selected from: heteroaryl, cycloalkyl, heterocycloalkyl, alkoxy, heterocycloalkyl substituted with -C (O) N (R18) 2; d) 7.1 where R36 is selected from: cycloalkyl or heterocycloalkyl; or e) 8.0 where R20 is selected from: alkyl or cycloalkyl. 6. The compound of claim 1, wherein: a) R1 to R4 is independently selected from H, Br or Cl; b) R5 to R7 is H; c) a is N and the remaining substituents b, c and d are carbon; d) A and B are H2; e) n is 0 or 1; f) R13 is a 2.0 or 4.0 group and said optional R13 substituents are selected from: -N (R18) 2, -NHC (0) R18, -CYR ^ OR3, or alkyl; g) R8 is selected from: arylalkyl, substituted arylalkyl, cycloalkylalkyl, substituted cycloalkylalkyl, heteroarylalkyl, or substituted heteroarylalkyl; (a) and R10 are independently selected from: H, alkyl, -C (O) N (R18) 2, or arylalkyl; h) R11 and R12 are independently selected from: H, alkyl, substituted aryl, -OR18, or R1 and R12 taken together with the carbon atom to which they are attached form a cycloalkyl ring; i) R11 and R12 are independently selected from H, alkyl, substituted aryl, -OR18, or R11 and R12 taken together with the carbon atom to which they are attached form a cycloalkyl ring; j) X is CH or N; k) R19 is selected from: -C (O) N (R18) 2, alkyl, arylalkyl, or -C (arid) 3; I) R20 for 5.0 is selected from: (1) alkyl, (2) arylalkyl, (3) heterocycloalkyl, (4) aryl, (5) aryl substituted with halo, (6) cycloalkyl, (7) cycloalkyl substituted with alkyl, u (8) cycloalkyl substituted with -OC (0) R18 or -OH with the proviso that said -OH substituent is not bonded to a carbon atom that is adjacent to an oxygen atom; m) R20 and R21 for 6.0 are independently selected from: H, cycloalkyl, alkyl, aryl, or arylalkyl; n) R20 for 7.0 is selected from: heteroaryl, cycloalkyl, alkoxy, heterocycloalkyl substituted with -C (0) N (R18) 2; o) R36 for 7.1 is selected from heterocycloalkyl or cycloalkyl; p) R20 for 8.0 is selected from: alkyl or cycloalkyl; and q) R32 and R33 are independently selected from: H, -OR18, arylalkyl or aryl. 7. The compound of claim 6, wherein: a) R is selected from arylalkyl, cycloalkylalkyl, or heteroarylalkyl; b) R9 and R10 are independently selected from: H or benzyl; c) R11 and R12 are independently selected from: H, -CH3, -CH2CH (CH3) 2, - (CH2) 3, benzyl, ethyl, p-chlorophenyl, -OH, or R11 and R12 taken together with the carbon atom to which they are attached form a cyclopropyl ring; d) R32 and R33 are independently selected from: H, phenyl, -OH or benzyl; e) R19 is selected from: -C (0) NH-cyclohexyl, -C (phenyl) 3, H, methyl or ethyl; f) said optional R13 substituents are selected from: -CH3, -CH2OH, -CH2OC (0) 0-cyclohexyl, -CH2OC (0) 0-cyclopentyl, ethyl, isopropyl, NH2, or -NHC (0) CF3; g) R20 for groups 5.0 is selected from: t-butyl, ethyl, benzyl, -CH (CH3) 2, -CH2CH (CH3) 2, - (CH2) 2CH3, n-butyl, n-hexyl, n-octyl , p-chlorophenyl, cyclohexyl, cyclopentyl, h) R20 and R21 for 6.0 are independently selected from cyclohexyl, t-butyl, H, -CH (CH3) 2, ethyl, - (CH2) 2CH3, phenyl, benzyl, - (CH2) 2phenyl, or -CH3; i) R20 for 7.0 is selected from: 4-pyridylNO, -OCH3, -CH (CH3) 2, -t-butyl, H, propyl, cyclohexyl or j) R36 for 7.1 is selected from: cyclohexyl, cyclopentyl, cyclobutyl, cyclopropyl, k) R20 for 8.0 is selected from: methyl, i-propyl or cyclohexylmethyl. 8. The compound of claim 7, wherein R8 is selected from benzyl, -CH2C (CH3) 2, -CH2-cyclohexyio, -CH2-cyclopropyl, - 9. - The compound of claim 8 wherein: a) R8 is selected from: benzyl or -CH2-cyclopropyl; b) R20 for 5.0 is cyclohexyl; c) R20 for 6.0 is selected from: t-butyl, i-propyl, or cyclohexyl; and R21 is selected from: H CH3 or i-propyl; d) R20 for 7.0 is selected from: cyclohexyl, cyclopentyl, or i-propyl; e) R36 for 7.1 is selected from: cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl; and d) R20 for 8.0 is methyl. 10. The compound of claim 9, wherein said compound is and 2R isomer. 11. The compound of claim 1, wherein R8 is H and the alkyl chain between the amide substituent -C (0) NR8 and R13 is substituted. 12. The compound of claim 1 wherein when R14 is the group 5.0 and X is N, and R8 is H, then (a) the alkyl chain between R13 and the amide portion is substituted and / or (b) R9 and R10 and / or R11 and R2 are taken together to form a cycloalkyl ring. 13. A compound that has the formula: or a pharmaceutically acceptable salt or solvate thereof, wherein one of a, b, c and d represents 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; X represents N or CH when the optional link (represented by the dotted line) is absent, and represents C when the optional link is present; the dotted line between carbon atoms 5 and 6 represent a double bond, so that when a double bond is present A and B independently represent -R15, halo, -OR16, -OCO2R16 or -OC (O) R15, and when there is no double bond present between the carbon atoms 5 and 6, A and B each independently represent H2, - (OR16) 2, H and halo, dihalo, alkyl and H, (alkyl ^, -H and -OC (O) R15, H and -OR15, = O, aryl and H, = ÑOR15 or -0- (CH2) p-0- where p is 2, 3 or 4, each R1 and each R2 are independently selected from H, halo, -CF3, -OR15, -SR15, -S (0) tR16 (where t is 0, 1 or 2, -N (R15) 2, -NO2, -OC (0) R15, -C02R15, -OCO2R16, -CN, -NR15COOR16, -SR16C (O) OR16, -SR16N (R17) 2 (with the proviso that R6 in -SR16N (R17) 2 is not -CH2) where each R17 is independently selected from H or -C (0) OR16, benzotriazoi-1-yloxy, tetrazole-5-lithium, or tetrazole-5-lithium, alkynyl, alkenyl or alkyl, said alkyl or alkenyl group being optionally substituted with halo, -OR15 or -C02R15; R3 and R4 are the same or different, and each independently represents H, any of the substituents R1 and R2, or R3 and R4 taken together represent a saturated or unsaturated Cs-C ring fused to the benzene ring (Ring III); R5, R6 and R7 each independently represent H, -CF3, -COR15, alkyl or aryl, said alkyl or aryl are optionally substituted with -OR15, -SR15, -S (O) tr16, -NR15COOR16, -N (R15) 2, -N02 > -COR15, -OCOR15, -OC02R16, -C02R15, OPO3R15, or R5 is combined with R6 to represent = 0 or = S; R8 is selected from: H, C3, C4 alkyl, aryl, arylalkio, heteroaryl, heteroarylalkyl, cycloalkyl, cycloalkylalkyl, substituted alkyl, substituted aryl, substituted arylalkyl, substituted heteroaryl, substituted heteroarylalkyl, substituted cycloalkyl, substituted cycloalkylalkyl; the substituents for the substituted groups R8 are selected from: alkyl, aryl, arylalkyl, cycloalkyl, -N (R182, -OR18, cycloalkylalkyl, halo, CN, -C (0) N (R18) 2, -S02N (R18) 2 , or -C02R18, with the proviso that the substituents -OR18 and -N (R18) 2 are not bonded to the carbon atom that is attached to the N of the -C (0) NR8 portion, each R18 are independently selected from: H, alkyl, aryl, arylalkyl, heteroaryl or cycloalkyl; R9 and R10 are independently selected from: H, alkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, cycloalkyl or -C0N (R18) 2 (wherein R18 is as defined above) and wherein said substituted R9 and R10 subgroups are optionally substituted with one or more substituents selected from: alkyl, cycloalkyl, arylalkyl or heteroarylalkyl, or R9 and R10 together with the carbon to which they are attached form a C3 cycloalkyl ring to Ce, R "11 and R" 12 are independently selected from H, alkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, cycloalkyl, -CON (R18) 2-OR18 or -N (R18) 2; wherein R13 is as defined above, with the proviso that the groups -OR18 and -N (R18) 2 are not bonded to a carbon atom that is adjacent to a hydrogen atom; and wherein said substitutable R11 and R12 groups are optionally substituted with one or more substituents selected from; alkyl, cycloalkyl, arylalkyl, or heteroarylalkyl; or R11 and R12 together with the carbon atom to which they are joined form a cycloalkyl ring C3 to Ce; R > 13 is an imidazolyl ring selected from: wherein R19 is selected from: (1) H, (2) alkyl, (3) alkyl, (4) aryl, (5) arylalkyl, (6) substituted arylalkyl where the substituents are selected from halo or CN, (7) -C (aryl) 3 or (8) cycloalkyl; said imidazolyl ring 2.0 is optionally substituted with one or two substituents and said imidazole ring 4.0 is optionally substituted with 1-3 substituents and said imidazole ring 4.1 is optionally substituted with a substituent wherein said optional substituents for rings 2.0, 4.0 and 4.1 are independently selected from: -NHC (O) R18, -C (R34) 2OR35, -OR18, -SR18, F, Cl, Br, alkyl, aryl, arylalkyl, cycloalkyl, or -N (R18) 2) wherein R18 is such as is defined above, wherein each R34 is independently selected from H or alkyl; wherein R35 is selected from H, -C (O) OR20, OC (O) NHR20, and R20 is as defined above; Q represents an aryl ring, a cycloalkyl ring or a heteroaryl ring, said Q being optionally substituted with 1 to 4 substituents independently selected from halo, alkyl, aryl, -OR18, -N (R18) 2 (wherein each R18 is independently selected) , -OC (0) R18, or -C (0) N (R18) 2 (wherein each R18 is independently selected), and wherein R18 is as defined above; R15 is selected from: H, alkyl, aryl or arylalkyl; R16 is selected from: alkyl or aryl; R 20 is selected from: alkyl, alkoxy, aryl, arylalkyl, cycloalkyl, heteroaryl, heteroarylalkyl or heterocycloalkyl; said R20 group is optionally substituted with one or more substituents selected from: halo, alkyl, aryl, -OC (O) R18, -OR18 or -N (R18) 2, where each R18 group is the same or different and where R18 is such as defined above with the proviso that said optional substituent is not bonded to a carbon atom that is adjacent to an oxygen or nitrogen atom, N is 0-5; each R32 and R33 for each n are independently selected from: H, alkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, cycloalkyl, -CON (R18) 2 -OR18 or = N (R18) 2; wherein R18 is as defined above; and wherein said substitutable R32 and R33 groups are optionally substituted with one or more substituents selected from: alkyl, cycloalkyl, arylalkyl, or heteroarylalkyl; or R32 and R33 together with the carbon atom to which they are attached form a C3 cycloalkyl ring to Ce and with the proviso that when X is N, and R8 is H then the alkyl chain between R13 and the amide portion is substituted. 14. - The compound of claim 13 having the structure: OR 15. The compound 25.OB of claim 14 wherein R8 is H and the alkyl chain between the amide substituent -C (O) NR8 and R13 is substituted. 16. The compound 25.OB of claim 14 wherein: a) R1 to R4 is independently selected from H, Br or Cl; b) R5 to R7 is H; c) (1) a, b, c and d are carbon and R 20 is selected from alkyl, alkoxy, aryl, arylalkyl, cycloalkyl, heteroaryl, heteroarylalkyl or heterocycloalkyl; said R20 group is optionally substituted with one or more substituents selected from: halo, alkyl, aryl, -OC (0) R18, -OR18 or -N (R18) 2, wherein each R18 group is the same or different and where R18 is such as defined above, with the proviso that said optional substituent is not attached to a carbon atom that is adjacent to an oxygen or nitrogen atom; or (2) a is N and the remaining substituents b, c and d are carbon and R 20 is selected from: alkyl, arylalkyl, heterocyclealkyl, aryl, halo substituted aryl, cycloalkyl, cycloalkyl substituted with alkyl or cycloalkyl substituted with -OH with the condition that said -OH substituent is not attached to a carbon atom adjacent to an oxygen atom; d) A and B are H2; e) n is O or 1; f) R3 is a group 2.0 or 4.0; g) R8 is selected from: arylalkyl, substituted arylalkyl, cycloalkyl, substituted cycloalkyl, heteroarylalkyl, substituted heteroarylalkyl, and h) X is CH or N; i) R9 and R10 are independently selected from H, alkyl, -C (0) N (R18) 2 or arylalkyl; j) R11 and R12 are independently selected from: H, alkyl, substituted aryl, -OR18, or R11 and R12 taken together with the carbon atom which are attached form a cycloalkyl ring: k) R32 and R33 are independently selected: H , -OR18, arylalkyl, or aryl; I) R19 is selected from: -C (0) N (R18) 2, alkyl, arylalkyl, or -C (aryl) 3 and m) said optional R13 substituents are selected from: -N (R18) 2, -NHC (0 ) R18, -C (R34) 20R35, or alkyl. 17. The compound of claim 16 wherein a is N and the remaining substituents b, c and d are carbon and a) R8 is selected from arylalkyl, cycloalkyl-alkyl, or heteroarylalkyl; b) R9 and R10 are independently selected from: H or benzyl; c) R11 and R12 are independently selected from: H, -CH3, -CH2CH (CH3) 2, - (CH2) 3CH3, benzyl, ethyl, p-chlorophenyl, -OH, or R11 and R12 taken together with the carbon atom to which they are attached form a cyclopropyl ring; d) R32 and R33 are independently selected from: H, phenyl, -OH or benzyl; e) R19 is selected from: -C (O) NH-cyclohexyl, -C (phenyl) 3, H, methyl or ethyl; f) said optional R3 substituents are selected from: -CH3, -CH OH, -CH2OC (0) 0-cyclohexyl, -CH2OC (0) 0-cyclopentyl, ethyl, isopropyl, NH2, or -NHC (0) CF3; and g) R20 is selected from: t-butyl, ethyl, benzyl, -CH (CH3) 2, - CH2CH (CH3) 2, - (CH2) 2CH3, n-butyl, n-hexyl, n-octyl, p-chlorophenyl , cyclohexyl, cyclopentyl, 18. The compound of claim 17 wherein R9, R10, R11, R2, R32, and R33 are H. 19. The compound of claim 17 wherein R8 is selected from: benzyl, -CH2C (CH3) 2, -CH2 -cyclohexyl, -CH2-cyclopropyl, - (CH2) 2CH3. 20. The compound of claim 19 wherein: a) R8 is selected from: benzyl or -CH2-cyclopropyl; and b) R20 is cyclohexyl. 21. The compound of claim 20 which consists of (1) a compound 3-Br-8-CI-, and a compound 8-CI or a compound 10-CI; or (2) a 3-Br 8-CI compound, a 8-CI compound, or a 10-CI compound where R 9, R 10, R 11, R 12, R 32 and R 33 are H. 22. - The compound of claim 1 which is selected from: (Isomer 11 R, 2R) (Example 11) (Isomer 11S 2R) (Example 16) (Example 58) (Example 78 Step B) (Example 79 Isomer A) (Example 80 Isomer A) (Example 88 Isomer A) (Example 93 Isomer D) (Example 99) (Example 100) (Example 225) (Example 226) (Example 227) (Example 228) (Example 229) (Example 232) (Example 326) (Example 330) (Example 327) (Example 328) (Example 243) (Example 286A) (Example 286B) (Example 304) 15 (Example 306) (Example 307); or (Example 308) 23. - The compound of claim 1 selected from: Example 58 (Example 225) (Example 226) (Example 227) (Example 228) (Example 229) (Example 232) (Example 326) (Example 330) (Example 327) 24. - A compound of the formula: (Example 225) 25.- A compound of the formula: (Example 393) fifteen (Example 394) 26. The compound of claim 1 selected from a compound of example 1-22, 25, 45-66, 77, 78 stage B, 79, 80, 82-85, 86, 86A, 87-97, 99, 100, 102 , 112-208, 208A, 209, 209A, 210, 210A, 210B, 211-220, 220A, 221-232, 234B, 234C, 234E, 235-254, 286A, 286B, 304-308, 310-342, 343 -366, 367-373 or 375-382. 27.- A compound selected from a compound of example 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 4, 42, 43, 44, 67 , 68, 69, 70, 71, 72, 73, 74, 75, 76, 81, 98, 101, 103, 104, 105, 106, 107, 108, 110, 111, 255, 256, 257, 258, 259 , 260, 261, 262, 263, 264, 265, 266, 267, 268, 269, 270, 271, 272, 273, 274, 275, 276, 277, 278, 279, 280, 281, 282, 283, 284 , 285, 286, 287, 289, 290, 291, 292, 293, 294, 295, 296, 297, 299, 300, 301, 302, 303 or 309. 28.- The use of a compound of any of the claims 1-27 for the manufacture of a medicament for treating tumor cells. 29. The use of claim 28 wherein the treated tumor cells are pancreatic tumor cells, lung cancer cells, myeloid leukemia tumor cells, follicular thyroid tumor cells, myelodysplastic tumor cells, epidermal carcinoma tumor cells. , vesicle carcinoma tumor cells, colon tumor cells, melanomas, breast tumor cells and prostate tumor cells. 30. The use of a compound of any of claims 1-27 for the manufacture of a medicament for treating tumor cells, wherein the Ras protein is activated as a result of the oncogenic mutation in genes other than the Ras gene. 31. A pharmaceutical composition for inhibiting farnesyl protein transferase comprising an effective amount of a compound of any of claims 1-27 in combination with a pharmaceutically acceptable carrier. 32. A use of a compound of any of claims 1-27 for the manufacture of a medicament for inhibiting famesyl protein transferase.