MXPA99002426A - Novel tricyclic piperidinyl compounds useful as inhibitors of farnesyl-protein transferase - Google Patents

Abstract

Novel tricyclic compounds of formula (1.0) or a pharmaceutically acceptable salt or solvate thereof, wherein:one of a, b, c, and d represents N or NR9, wherein R9 is O-, -CH3 or -(CH2)nCO2H wherein n is 1 to 3, and the remaining a, b, c and d groups represent CR1 or CR2;or each of a, b, c and d is independently selected from CR1 or CR2;each R1 and each R2 is independently selected from H, halo, -CR3, -OR10, -COR10, -SR10, -S(O)tR11 (wherein t is 0, 1 or 2), -SCN, -N(R10)2, -NR10R11, -NO2, -OC(O)R10, -CO2R10, -OCO2R11, -CN, -NHC(O)R10, -NHSO2R10, -CONHR10, -CONHCH2CH2OH, -NR10COOR11, -SR11C(O)OR11, -SR11N(R75)2;n is 0 (zero), 1, 2, 3, 4, 5 or 6;T is -CO-;-SO-;-SO2-;or -CR30R31-;Z represents alkyl, aryl, aralkyl, heteroalkyl, heteroaryl, heteroarylalkyl, heterocycloalkyl, heterocycloalkylalkyl, -OR40, -SR40, -CR40R42, -NR40R42, formulae (i), (ii), (iii), (iv), (v) and (vi). Pharmaceutical compositions are disclosed which are inhibitors of the enzyme, farnesyl protein transferase. Also disclosed is a method of inhibiting Ras function and therefore inhibiting the abnormal growth of cells. The method comprises administering the novel tricyclic compound to a biological system. In particular, the method inhibits the abnormal growth of cells in a mammal such as a human.

Description

COMPOUNDS OF PIPERIDINYL TRICICLICOS NOVEDOSOS USEFUL AS INHIBITORS OF THE FARNESILPROTEINTRANSFERASA BACKGROUND OF THE INVENTION. The patent application number WO95 / 00497 published on January 5, 1995 under the Patent Cooperation Treaty (PCT) describes compounds that inhibit the enzyme, farnesylproteintransferase (Ftasa) and farnesylation of the RAS oncogene protein. Oncogenes frequently encode protein components of signal transduction pathways that stimulate cell growth and mitogenesis. The expression of oncogene in cultured cells causes cell transformation, characterized by the ability of cells to grow on soft agar and the growth of cells as dense foci that do not have the contact inhibition shown by non-transformed cells. The mutation and / or overexpression of some oncogenes is frequently related to human cancer. To obtain a transformation potential, the Ras oncoprotein precursor must undergo farnesylation of the cysteine residue located in a carboxyl terminal tetrapeptide. Inhibitors of the enzyme that catalyzes this modification, farnesylproteintransferase, have therefore been suggested as anticancer agents for tumors in which Ras contributes to the transformation.

Oncogenic, mutated forms of Ras are frequently found in many human cancers, especially in more than 50% of carcinomas of the colon and pancreas (Konhl et al., Science, Vol. 260, 1834, 1993). Taking into account the current interest for farnesylproteintransferase inhibitors, an important contribution to the technique would be additional compounds useful for the inhibition of farnesylproteintransferase. Said contribution is provided by means of this invention. COMPENDIUM OF THE INVENTION The inhibition of farnesylproteintransferase by tricyclic compounds of this invention is not reported to date. Accordingly, this invention provides a method for inhibiting farnesylproteintransferase using tricyclic compounds of this invention which: is not (i) potentially inhibits farnesylproteintransferase, but not geranylgeranylproteintransferase I in vitro; (ii) block the phenotypic change induced by a form of transforming Ras which is a farnesyl acceptor but not by a form of transforming Ras manipulated to be a geranylgeranyl acceptor; (iii) block the intracellular processing of Ras which is a farnesyl acceptor but not of Ras manipulated to be a geranylgeranyl acceptor; and (iv) they block the abnormal growth of cells in culture induced by transforming Ras. Several compounds of this invention have an antitumor activity in animal models. This invention provides a method for inhibiting the abnormal growth of cells, including transformed cells, by administering an effective amount of a compound of this invention. Abnormal cell growth refers to cell growth independent of normal regulatory mechanisms (e.g. loss of contact inhibition). This includes the abnormal growth 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 an oncogenic mutation in another gene; and (3) benign and malignant cells of other proliferative diseases where aberrant Ras activation occurs. Compounds useful in the claimed methods are represented by the formula 1. 0: Either a pharmaceutically acceptable salt or solvate thereof, wherein: one of a, b, c, and d represent N or RN9 where R9 is 0 ~, -CH3 or - (CH2) NC02H where n is from 1 to 3, and the remaining groups a, b, c, and d represent CR1 or CR2; or else each of a, b, c, and d are independently selected from CR1 or CR2; each Rl and each R2 is independently selected from H, halo, -CF3, -OR10, -COR10, -SR10, -S (0) tRll (where t is 0, how well 2), -SCH, -N (R10) 2, -NR10R11, -N02, -OC (O) R10, -C02R10, -OC02R11, -CN, -NHC (O) R10, -NHSO2R10, -CONHR10, -CONHCH2CH20H, -NR10COOR11, -SR11C (0) 0R11, -SR11N (R75) 2 wherein each R75 is independently selects between H and -C (?) ORll, benzotriazol-1-yloxy, tetrazol-5-ylthio, or substituted tetrazol-5-ylthio, alkynyl, alkenyl, or alkyl, said alkyl or alkenyl group is optionally substituted with halo , -OR1Ó or -CO2R10; 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 saturated or unsaturated C5-C7 ring fused to the benzene ring (Ring III); R5, R6, R7 and R8, each independently, represents H, -CF3, -COR10, alkyl or aryl, said alkyl or aryl is optionally substituted with -OR10, -SR10, -S (0) Trll, -NR10COOR11, -N (R10) 2, -N02, COR10, -OCOR10, -OC02R11, -COR2R10, OPO3R10, or R5 is combined with R6 to represent = 0 or = S and / or R7 is combined with R8 for represent = 0 or = S; RIO represents H, alkyl, cycloalkyl, cycloalkylalkyl, heteroaryl, aryl, aralkyl, or -NR40R42, wherein R40 and R42 independently represent H, aryl, alkyl, heteroaryl, heteroarylalkyl, heterocycloalkyl, heterocycloalkylalkyl, heteroalkyl, cycloalkyl, cycloalkylalkyl, alkenyl and alkynyl; Rll represents alkyl or aryl; The dotted line between carbon atoms 5 and 6 represents an optional triple bond, such that when a double bond is present, A and B independently represent -N02, -RIO, halo, -OR11, -0C02R11, or - OC (0) R10, and when no double bond is present between the carbon atoms 5 and 6, A and B each independently represent H2, - (ORll) 2, H and halo, dihalo, alkyl and H, ( alkyl) 2, -H, and -OC (O) R 10, H and -OR 10, oxy, aryl and H, = NOR 10 or -0- (CH 2) p-0- where p is 2, 3 or 4; N is 0 (zero), 1, 2, 3, 4, 5 or 6; T is -C0-; -S0-; S02-; or -CR30R31- where R30 and R31 independently represent H, alkyl, aryl, aralkyl, heteroalkyl, heteroaryl, heteroarylalkyl, heterocycloalkyl, or heterocycloalkylalkyl; and Z represents alkyl, aryl, heteroalkyl, heteroaryl, heteroarylalkyl, heterocycloalkyl, heterocycloalkylalkyl, -OR40, -SR40, -CR40R42, -NR40R42, where n, R40 and R42 are defined as above, -m is 2, 3, 4, 5, 6, 7 or 8; q is 0 (zero) 1 or 2; and R 14 represents H, (C 1 -C 6) alkyl, aralkyl, heteroaryl, acyl, carboxamido, carboxamidoalkyl, cyano, alkoxycarbonyl, aralkyloxycarbonyl, D- and L-amino acid covalently linked through the carboxyl, imido, imidamid, sulfamoyl, sulfonyl, dialkylphosphinyl group , N-glycosyl, Cfi 6Hp5 -C (NHCH3) = CHN? 2, provided that when T is -SO-, Z is not -NR40R42. In the compounds of formula (1), preferably a is N; b, c and d are carbon atoms; A and B each represent H2, and the optional double bond is absent. It is also preferred that R1 and R4 are H and R2 and R3 are halo selected from chlorine and bromine; or R1 is H and R2, R3 and R4 are halo selected from chlorine and bromine. It is also preferred that R2 and R3 be halo in the 3-position and the 8-position in the ring structure; or R2, R3 and R4 are in the position 3, 8 and 10 in the ring structure. It is also preferred that R2 is Br and R3 is Cl in the 3-position and the 8-position in the ring structure; or R2 is Br, R3 is Cl and R4 is Br at position 3, 8 and 10 in the ring structure. It preferred also that each of R5, R6, R7 and R8 is H. It is also preferred that the - (CH2) nTZ portion be attached in the 2, 3 or 4 position in the piperidinyl ring, more preferably in the 2 or 3 in the piperidinyl ring. It is also preferred in the compounds of the formula (1.0) that n is 0, 1 or 2; T is -CO- and Z is -NR40R42 where R40 and R42 independently represent H, aryl, alkyl, aralkyl, heteroaryl, hateroarylalkyl, heterocycloalkyl, heterocycloalkylalkyl, heteroalkyl, cycloalkyl, or cycloalkylalkyl; or else Z be where R40 is in accordance with the above defined, m is 2, 3 or 4; q is 0 (zero), 1 or 2; and R 14 represents H, (C 1 -C 6) alkyl, aralkyl, heteroaryl, acyl, carboxamido, carboxamidoalkyl, cyano, alkoxycarbonyl, aralkyloxycarbonylimido, imidamido, sulfamoyl, sulfonyl, dialkylphosphinyl, N-glycosyl or -C- (NHCH3) = CHN02. More preferably n is 0; Z is NR 40 R 42 where R 40 represents H and R 42 represents heteroarylalkyl. More preferably R40 is H and R42 is the 3-pyridylmethyl heteroaryl portion. In another embodiment, the present invention is directed toward a pharmaceutical composition for inhibiting abnormal cell growth, comprising an effective amount of a compound (1.0) in combination with a pharmaceutically acceptable carrier. In another modality, the present invention focuses on a method for inhibiting abnormal cell growth, including transformed cells, comprising administering an effective amount of compound (1.0) to a mammal (e.g., a human) that requires such treatment . Abnormal growth of cells refers to the growth of cells independently of normal regulatory mechanisms (e.g. loss of contact inhibition). This includes the abnormal growth 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 an oncogenic mutation in another gene; (3) benign and malignant cells of other proliferative diseases where aberrant activation of Ras occurs, and (4) benign or malignant cells that are activated by other mechanisms than the Ras protein. Without wishing to be limited by any theory, it is believed that these compounds can function either through the inhibition of G protein function, such as, for example, Ras p21 by blocking the protein G isoprenylation, thus becoming useful in the treatment of proliferative diseases, such as, for example, tumor growth and cancer, or else through the inhibition of ras farnesylproteintransferase, making them useful due to their antiproliferative activity against ras transformed cells. The cells to be inhibited can be tumor cells expressing an activated ras oncogene. For example, the types of cells that can be inhibited include pancreatic tumor cells, lung cancer cells, myeloid leukemia tumor cells, thyroid follicular tumor cells, myelodysplastic tumor cell, epidermal carcinoma tumor cells, carcinoma tumor cells of the bladder or colon tumor cells. Also, the inhibition of abnormal cell growth by treatment with the compound (1.0) can be by means of the inhibition of ras farnesylproteintransferase. The inhibition can be of tumor cells where the Ras protein is activated as a result of an oncogenic mutation in genes other than Ras. Alternatively, the compounds (1.0) can inhibit tumor cells activated by a protein or the Ras protein. This invention also provides a method for inhibiting tumor growth by administering an effective amount of compound (1.0) to a mammal (e.g., a human) that requires such a treatment. Particularly, this invention offers a method for inhibiting the growth of tumors expressing an activated Ras oncogene by administering an effective amount of the compounds described above. Examples of tumors that can be inhibited include, but are not limited to, lung cancer (e.g., lung adenocarcinoma) pancreatic cancers (e.g., pancreatic carcinoma such as exocrine pancreatic carcinoma) colon cancers (e.g., colorectal carcinomas as for example colon adenoma and colon adenoma), myeloid leukemias (for example acute myelogenous leukemia (AML)), follicular thyroid cancer, myelodysplastic syndrome (MDS), bladder carcinoma and epidermal carcinoma. It is believed that the invention also offers a method for inhibiting proliferative diseases, both malignant and benign, where Ras proteins are aberrantly activated as a result of an oncogenic mutation in other genes - ie, the Ras gene itself is not activated by mutation in an oncogenic form - with said inhibition accompanied by the administration of an effective amount of the carbonylpiperazinyl and piperidinyl compounds (1.0) described herein to a mammal (e.g., to a human), which requires such treatment. For example, benign proliferative disorder neurofibromatosis, or tumors where Ras is activated due to mutation or overexpression of tyrosine kinase oncogenes (eg, neu, src, abl, lck, and fyn), can be inhibited by the compounds of carbonylpiperazinyl and piperidinyl (1.0) described herein. In another embodiment, the present invention focuses on differentiating a method for inhibiting ras farnesylproteintransferase and farnesylation of the Ras oncogene protein by administering an effective amount of compounds (1.0) to mammals, especially humans. The administration of the compounds of this invention to patients to inhibit farnesylproteintransferase is useful for the treatment of the cancers described above. DETAILED DESCRIPTION OF THE INVENTION The following solvents and reagents are known herein by means of the indicated abbreviations: Tetrahydrofuran (THF); Ethanol (EtOH); Methanol (MeOH); Ethyl acetate (EtOAc); N, N-dimethylformamide (DMF); Trifluoroacetic acid (TFA); l-hydroxybenzotriazole (HOBT); 1- (3-dimethylaminopropyl) -3-ethyl carbodiimide hydrochloride (DEC); dimethisulfoxide (DMSO); 4-methylmorpholine (NMM); dimethylaminopyridine (DMAP); and dimethoxyethane (DME), t-butoxycarbonyl (BOC) acetyl (OAc). As used herein, the following terms are used as defined below unless otherwise indicated: \\ - Indicates a pure isomer; - when it is attached to a carbon atom marked with an asterisk (*), it indicates a separate isomer whose stereochemistry has not been established; ??? indicates a racemic mixture; M + represents the molecular ion of the molecule in the mass spectrum; MH + represents the molecular ion hydrogen plus the molecule in the mass spectrum; Bu represents butyl; Et represents ethyl; It represents me methyl; Ph represents phenyl; Benzotriazol-1-yloxy represents 1-met il-tetrazol-5-ylthio represents acyl is a portion of the formula -COR15, where R15 represents H, (C1-C6) alkyl, aryl, araluyl, heteroalkyl, heteroaryl, heteroarylalkyl, heterocycloalkyl, heterocycloalkylalkyl or (CH2) kNR80R81, where k is 1 or 2, and R80 and R81 can independently represent H, alkyl, cycloalkyl, cycloalkylalkyl, heteroaryl, heteroarylalkyl, aryl or aralkyl; alkyl (including the alkyl portions of alkoxy, alkylamino and dialkylamino) represents straight and branched carbon chains and contains from one to 20 carbon atoms, preferably from 1 to 6 carbon atoms (i.e., (C1-C6) alkyl); for example methyl, ethyl, propyl, isopropyl, n-butyl, t-butyl, n-pentyl, isopentyl, hexyl and the like; wherein said alkyl and said (C 1 -C 6) alkyl group may be optionally and independently substituted with 1, 2, 3 or more of the following: halo, alkyl, aryl, alkoxy, amino (-NH 2), alkylamino, cyano (-CN) ), -CF3, dialkylamino, hydroxy, oxy (= 0), phenoxy, -0CF3, heterocycloalkyl, S02NH2, -NHSO2R0, -SO2NHR10. -S02R10, -SOR10, -SR10K, -NHS02, -N02, -NCOR10 or -COORIO. Alkoxy: an alkyl portion of 1 to 20 carbon atoms covalently bonded onto an adjacent structural element through an oxygen atom, for example, methoxy, ethoxy, propoxy, butoxy, pentoxy, hexoxy and the like; wherein said alkoxy group may be optionally and independently substituted with 1, 2, 3 or more of the following: halo, alkyl, aryl, alkoxy, amino, alkylamino, cyano, -CF3, dialkylamino, hydroxy, oxy, phenoxy, -0CF3, heterocycloalkyl, -S02NH2, -NHS02R10, -S02NHR10, -S02R10, - SOR10, -SRIO, -SRIO, -NHS02, -N02, -CONRIO, -NCORIO OR -COOR10; alkoxycarbonyl represents an alkoxy moiety, in accordance with the above defined, covalently bonded to a carbonyl moiety (-CO-) through an oxygen atom, for example -C00CH3, -C00CH2, and -COOC (CH3) 3; alkenyl represents straight and branched carbon chains having at least one carbon-carbon double bond and containing from two to 12 carbon atoms, preferably from 2 to 6 carbon atoms, and more preferably from 3 to 6 carbon atoms; wherein said alkenyl group may be optionally and independently substituted by 1, 2, 3 or more of the following: halo, alkyl, aryl, alkoxy, amino, alkylamino, cyano, -CF3, dialkylamine, hydroxy, oxy, phenoxy, -OCF3, heterocycloalkyl, -S02NH2, -NHSO2R10, SO2NHR10, -S02R10, -SOR10, -SR10, -NHS02, -N02, -CONR10, -NCOR10 or -COOR10; alkynyl represents straight and branched carbon chains having at least one carbon-carbon triple bond and containing from 2 to 12 carbon atoms, preferably from 2 to 6 carbon atoms; wherein said alkynyl group may be optionally and independently substituted with one, two, three, or more of the following: halo, alkyl, aryl, alkoxy, amino, alkylamino, cyano, -CF3, dialkylamino, hydroxy, oxy, phenoxy, -OCF3 , heterocycloalkyl, -S02NH2, -NHSO2R10, SO2NHR10, -S02R10, -SOR10, -SRIO, -NHS02, -N02, -CONRIO, -NCORIO or -COOR10; amino acids refers to organic compounds having both an amino group (-NH2) and a carboxyl group (-COOH). Representative amino acids include glycine, serine, alanine, phenylalanine, tyrosine, S-methylmethionine and histidine; aryl (including the aryl portion of aralkyl) represents a carbocyclic group containing from 6 to 15 carbon atoms and having at least one aromatic ring (for example, aryl is phenyl) wherein said aryl group may optionally be fused with aryl rings , cycloalkyl, heteroaryl, or heterocycloalkyl; and wherein any of the suitable carbon and nitrogen atoms available in said aryl group and / or said fused ring (s) may be optionally and independently substituted with one, two, three or more of the following: halo , alkyl, aryl, alkoxy, amino, alkylamino, cyano, -CF3, dialkylamino, hydroxy, oxy, phenoxy, -OCF3, heterocycloalkyl, -S02NH2, -NHSO2R10, -S02NHR10, -SO2R10, -SOR10, -SR10, -NHS02, -N02, -CONR10, -NCOR10 or -COOR10; aralkyl represents an alkyl group, according to the above defined, wherein one or more hydrogen atoms of the alkyl portion have been substituted with one or more aryl groups; wherein said aralkyl group can optionally be independently is substituted with one, two, three or more of the following: halo, alkyl, aryl, alkoxy, amino, alkylamino, cyano, -CF3, dialkylamino, hydroxy, oxy, phenoxy, -OCF3, heterocycloalkyl, -S02NH2, -NHSO2R10 , - S02NHR10, -S02RH10, -SOR10, -SR10, -NHS02, -N02, -CONR10, -NOCOR10 or -COOR10; Representative aralkyl groups include benzyl and diphenylmethyl; aralkyloxy - represents an aralkyl group, according to the above defined, covalently linked with an adjacent structural element through an oxygen atom such as, for example, phenylmethyloxy and phenylethyloxy; aralkyloxycarbonyl - represents an aralkyloxy group, "Conformity with the above defined, covalently linked with a carbonyl portion (-CO-) through an oxygen atom such as, for example, -COOCH2C6H5 or -COOCH2CH2C6H5; carboxamido represents a portion of the formula -CONR40R42, including -CONH2; carboxamidoalkyl represents an alkyl group according to the above defined, wherein a hydrogen atom of the alkyl portion has been substituted with a carboxamide portion, in accordance with the above defined, through the carbonyl portion (-CO) of the carboxamide portion as for example, -CH2CONH2 or -CH2CH2CONH2; Cycloalkyl represents carbocyclic rings aturated branched or unbranched from 3 to 20 carbon atoms, preferably from 3 to 7 carbon atoms; wherein said cycloalkyl group may be optionally and independently substituted with one, two, three or more of the following: halo, alkyl, aryl, alkoxy, amino, alkylamino, cyano, -CF3, dialkylamino, hydroxy, axi, phenoxy, -OCF3, heterocycloalkyl, -S02NH2, -NHSO2R10, -SO2NHR10, -SO2R10, -SOR10, -SR10, -NHS02, -N02, -CONR10, NCOR10 or -COOR10; cycloalkylalkyl represents an alkyl group, in accordance with that defined above, wherein one or more hydrogen atoms of the alkyl portion have been substituted with one or more cycloalkyl groups; wherein said cycloalkylalkyl group may be optionally and independently substituted with one, two, three or more of the following: halo, alkyl, aryl, alkoxy, amino, alkylamino, cyano, -CF3, dialkylamino, hydroxy, oxy, phenoxy, -OCF3, heterocycloalkyl, -S02NH2, -NHS02R10, -S02NHR10, -SO2R10, -SOR10, -SR10, -NHS02, -N02, -CONR10, -NCOR10 or -COOR10; halo represents fluorine, chlorine, bromine and iodine; Heteroalkyl represents straight and branched carbon chains containing from 1 to 20 carbon atoms, preferably from 1 to 6 interrupted carbon atoms of 1 to 3 heteroatoms selected from -O-, -S- and -N-; where in any of the various substitutable and available carbon and nitrogen atoms in said heteroalkyl chain they may optionally and independently be substituted with one, two, three or more of the following: halo, alkyl (Cl-C6), aryl, cyano, hydroxy, alkoxy, oxy, phenoxy, -CF3, -0CF3, amino, alkylamino, dialkylamino , heterocycloalkyl, S02NH2, -NHS02R10, S02NHR10, -SO2R10, -SOR10, -SR10, or -NHS02, -N02, -CONR10, -NCOR10 or -COOR10; Heteroaryl represents cyclic groups having at least one heteroatom selected from O, S and N, said heteroatom interrupting a carbocyclic ring structure and having a sufficient number of delocalized pi electrons to provide an aromatic character, with aromatic heterocyclic groups that they contain from 2 to 14 carbon atoms where said heteroaryl group can optionally be fused with one or more aryl, cycloalkyl, heteroaryl or heterocycloalkyl rings; and wherein any of the substitutable and available carbon or nitrogen atoms in said heteroaryl group and / or said fused rings may optionally and independently be substituted by one, two, three or more of the following: halo, (C 1 -C 6) alkyl, aryl, cyano, hydroxy, alkoxy, oxy, phenoxy, -CF3, -OCF3, amino, alkylamino, dialkylamino, heterocycloalkyl, -S02NH2, -NHSO2R10, S02NHR10, -SO2R10, -SOR10, SR10, or -NHS02, -N02, -CONR10, -NCOR10, or -COOR10. Representative heteroaryl groups can include as per example, funaryl, imidazoyl, pyrimidinyl, triazolyl, 2-, 3- or 4-pyridyl or 2-, 3- or 4-pyridyl N-oxide, where pyridyl N-oxide may be represented as follows: heteroarylalkyl represents an alkyl group according to the above defined, wherein one or more hydrogen atoms have been rced by one or more heteroaryl groups; wherein said heteroarylalkyl group may be optionally and independently substituted with one, two, three or more of the following: halo, alkyl, aryl, alkoxy, amino, alkylamino, cyano, -CF3, dialkylamino, hydroxy, oxy, phenoxy, -OCF3, heterocycloalkyl, -S02NH2, -NHSO2R10, -SO2NHR10, -SO2R10, -SOR10, -SR10, -NHS02, -N02, -CONR10, -NCOR10, or -COOR10; as exemplified by 2-, 3-, or 4-pyridylmethyl or 2-, 3-, or 4-pyridylmethyl N-oxide; heterocycloalkyl represents a saturated carbocyclic ring, branched or unbranched, containing from 3 to 15 carbon atoms, preferably from 4 to 6 carbon atoms, said carbocyclic ring is interrupted by a three heteroatoms selected from -O-, -S-, and -N-, wherein optionally said ring may contain one or two unsaturated bonds that do not provide an aromatic character to the ring; and wherein any of the substitutable and available carbon and nitrogen atoms in the ring may optionally and independently be substituted with one, two, three or more of the following: halo, alkyl, aryl, alkoxy, amino, alkylamino, cyano, -CF3 , dialkylamino, hydroxy, oxy, phenoxy, -0CF3, heterocycloalkyl, -S02NH2, -NHS02R10, SO2NHR10, -S02R10, -SOR10, -SR10, -NHS02, -N02, -CONR10, -NCOR10, or -COOR10. Representative heterocycloalkyl groups may include morpholinyl, 2- or 3-tetrahydrofuranyl, 2- or 3-tetrahydrothienyl, 1-, 2-, 3- or 4-piperidinyl, 2-, or 3-pyrrolidinyl, 1-, 2- or 3- piperizinyl, 2- or 4-dioxanil, or where t is 0, the good 2; Heterocycloalkylalkyl represents an alkyl group, as defined above, wherein one or more hydrogen atoms have been rced by one or more heterocycloalkyl groups; wherein optionally said ring may contain one or two unsaturated bonds that do not provide an aromatic character to the ring; and wherein said heterocycloalkylalkyl group can optionally and independently be substituted by one, two, three or more of the following: halo, alkyl, aryl, alkoxy, alkylamino, cyano, -CF3, dialkylamino, hydroxy, oxy, phenoxy, -OCF3, heterocycloalkyl, -S02NH2, -NSHO2R10, -SO2NHR10, -SO2R10, -SOR10, -SR10, -NHS02, -N02, -CONR10, -NCOR10, or -COOR10; imido represents a portion of the formula NR50 R51 wherein R50 represents H, cyano, aryl, -S02NH2, -SO2NR40R42 and carboxamido and wherein R51 represents aryl and aryloxy. Representative imido groups can include, for example, imidamido represents a portion of the formula where R55 represents H, cyano, -S02NH2, -SO2NR40R42, carboxamido, hydroxy and alkoxy. Representative imidamido groups may include, for example, N j, H NS02? NEITHER N-glycosyl represents a pyranosyl or furanosyl monosaccharide. Representative N-glycosyl groups include (N-l) -tetra-0-acetyl-D-glucosyl, (N-l) -tetra-0-acetyl-D-galactosyl and (N - l) -tri-0-acetyl-D-ribosyl, as for example, D-glycosyl D-galactosyl D-ribosyl l-amino-2-nitro tentenyl represents the formula: -C (NHCH 3) = CHN02; dialkylphosphinyl represents a phosphine moiety (-PO) covalently bound to two alkyl groups. A representative dialkylphosphinyl group is -PO (CH 3) 2. Sulfonyl represents a portion of the formula -SO 2 R 60 where R60 represents amino, alkylamino and dialkylamino. Representative sulfamoyl groups may include, for example, -S02NH2, -S02NHCH3, -S02N (CH3) 2. sulfonyl represents a portion of the formula -SO2R60 where R60 represents alkyl, aryl and arylalkyl. Representative sulfonyl groups may include, for example, -S02CH3, -S02C6H5, -S02C6H4CH3, and -S02CH2C6H5. The reference to the position of the substituents R1, R2, R3, and R4 is based on the numbered structure of the ring.

Certain compounds of the invention can exist in different stereoisomeric forms (e.g., isomers such as enantiomers and diastereoisomers). The invention contemplates all of these stereoisomers, both in pure form and in mixture, including racemic mixtures. For example, the carbon atom at position C-11 may be in the stereo configuration S or R. Likewise the carbon atom at positions C-2, C-3, C-5 and C-6 of the piperidinyl moiety attached to C-ll can also be in the stereo configuration S or R.

Certain tricyclic compounds will be acidic in nature, such as, for example, compounds possessing a carboxyl or phenolic hydroxyl group. These compounds can form pharmaceutically acceptable salts. Examples of these salts may include sodium, potassium, calcium, aluminum, gold and silver salts. Also contemplated are salts formed with pharmaceutically acceptable amines such as, for example, ammonia, alkylamines, hydroxyalkylamines, N-methylglucamine and the like. Certain basic tricyclic compounds also form pharmaceutically acceptable salts, such as, 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 suitable acids for the formation of salts are hydrochloric, sulfuric, phosphoric, acetic, citric, oxalic, malonic, salicylic, malic, fumaric, succinic, ascorbic, maleic, methanesulfonic and other carbocyclic and mineral acids well known to the Expert people in the field. The salts are prepared by contacting the free base forms with a sufficient amount of the desired acid to produce a salt in a conventional manner. The free base forms can be regenerated by treating the salt with a base solution narrow divided suitable as for example NaOH, diluted aqueous, potassium carbonate, ammonia and sodium bicarbonate. The free base forms differ from their respective salt forms in terms of certain physical properties, such as solubility in polar solvents, but the acid and base salts are otherwise equivalent to their respective free base forms for the purposes of the invention. All of these acid and base salts are intended to be pharmaceutically acceptable salts within the scope of the invention and all acid and base salts are considered equivalent to the free forms of the corresponding compounds for the purposes of the invention. Compounds of the present invention invention can be prepared in accordance with the following scheme I: Scheme I where L mixture represents a labile group such as halo, preferably chlorine or a labile group such as o-tosyl and o-mesyl; the dotted line represents a double bond or a single link; a, b, c, d, A, B, Rl, R2, R3, R4, R5, R6, R7, R8, n, T and Z are in accordance with the above defined. As reference to Scheme I, compounds of the formula (5.0) can be prepared by reacting the compounds of the formula (3.0) with the halogenation agent or a sulfonylating agent in the presence of a suitable base and an optional aprotic solvent, in amounts and under effective conditions to provide the compounds (5.0). Suitable bases include organic bases such as, for example, pyridine and triethylamine; or inorganic bases of alkaline earth metals and alkali metals including carbonates treated as sodium, lithium, potassium, and cesium carbonates, hydroxides such as sodium, lithium and potassium hydroxides; and hydrides such as, for example, sodium or potassium hydride; and sodium t-butoxide, preferably sodium hydride. Suitable aprotic solvents include ethers, DMF, DMSO, THF, DME and mixtures thereof, preferably DMF. Preferably, the halogenating agent is a chlorinating agent, such as for example thionyl fluoride. The sulforination agent can be methanesulfonyl chloride or toluenesulfonyl chloride. The amounts of the halogenating agent or the sulfonylating agent can be in the range of one to about 10 moles per mole of compound (3.0). The temperatures can be located from 0 ° C to 50 ° C, or else at reflux temperature of the reaction mixture. The desired tricyclic piperidinyl compounds of the formula (1.0) can be prepared by reacting the compounds of the formula (5.0) with a substituted piperidinyl compound of the formula (7.0) in the presence of a suitable base and an optional aprotic solvent , as for example those described above, to provide the compounds (1.0). The amounts of the substituted piperidinyl compound of the formula (7.0) in relation to the compound (5.0) can be located within a range of about one to about 10 moles per mole of compound (5.0). The temperatures can be within an ambient temperature range of approximately 80 ° C. The tricyclic piperidinyl compounds of the formula (1.0) can be isolated from the reaction mixture using conventional procedures, such as, for example, extraction of the water-based reaction mixture with organic solvents, evaporation of the organic solvents, followed by chromotography on silica gel, or other suitable chromotographic means. Selected compounds of formula (1.0) can be prepared in accordance with Scheme 2. SCHEME 2 1 (8.0) (1.1) (8.5) where the mixture L represents a leaving group, preferably chlorine; the dotted line represents a single link or a double link; and a, b, c, d, A, B, Rl, R2, R3, R4, R5, R6, R7, R8, R8, Rll, R40, R42 and n are in accordance with the above defined. With reference to Scheme 2, compounds of the formula (8.0) can be prepared by reacting the compounds of the formula (5.0) with piperidinylcarboxylic acid ester of the formula (7.5) in the presence of a base and an aprotic solvent optionally, in amounts and under effective conditions to provide the compounds (8.0). Suitable bases and suitable aprotic solvents are described above. The amounts of piperidinyl compounds (7.5) can be located within a range of about one to about 10 moles per mole of compound (5.0). The Temperatures can be located within a range from room temperature to approximately 80 ° C. The compound (8.0) can be isolated in accordance with that described above. Carboxylic acid compounds of the formula (8.5) can be prepared by the hydrolyzation of carboxylic acid ester (8.0) with an excess amount of base acid. Suitable acids include inorganic acids, organic acids, or a mixture of them. Inorganic acids include hydrogen chloride, hydrogen bromide, sulfuric acid, nitric acid, phosphoric acid, perchloric acid and the like. Organic acids include acetic, citric, formic, maleic, tartaric, methanesulfonic and arylsulfonic acids. Suitable bases, such as sodium hydroxide or lithium hydroxide, preferably in an aqueous alcohol, have been described above. The temperature can be located within a range of about 0 ° C to about 100 ° C. The desired amide compounds of the formula (1.1) can be prepared by reacting the compounds of the formula (8.5) with the appropriate amide of the formula (9.0) in the presence of a coupling agent such as DÉC / HOBT, a base such as NMM and a suitable aprotic solvent effective to provide an amide compound (1.1). Suitable bases and suitable aprotic solvents are described above. The amounts of amine (9.0) can be located within a range of approximately from one to about 10 moles per mole of carboxylic acid (8.5). The temperatures can be located within the same range from 0 ° C to 100 ° C. The compound can be isolated (1.1) in accordance with what is described above. Compounds of the present invention and initial preparation materials thereof are exemplified in the following examples, which should not be considered as limiting the scope of the invention. EXAMPLE 1. l- (8-Chloro-6,11-dihydro-5H-benzo (5,6) cyclohepta (1, 2-b) pyridin-1-yl) -N (4-pyridinyl) -4-piperidinecarboxamide 8,11-Dichloro-6,11-dihydro-5H-benzo (5,6) cyclohepta (1,2-b) pyridine (prepared as described in Preparation Example 7, Step B in IN0291K) (0.088g; 1 equivalent) in anhydrous toluene (0.819 ml) to anhydrous DMSO (1.5 ml). 4-Piperidinyl-N- (4-pyridinyl) carboximide (0.0684 g: 1 equivalent) (prepared in accordance with that described in Preparation Example 1, Step C below) and the mixture are added. it is stirred at 25 ° C for 22 hours. The mixture is diluted with dichloromethane and washed with water. The dichloromethane layer is dried over magnesium sulfate, filtered and evaporated to dryness. The product is subjected to chromatography on a silica gel column (15X2.5 cm) using from 1% to 8% (10% concentrated ammonium hydroxide in methanol) -dichloromethane as the eluent to provide the title compound (0.0272). g, 19% yield), is CIMS: m / z 433 (MH +).

EXAMPLE 2. l- (3-Bromo-8-chloro-6,11-dihydro-5H-benzo (5,6) cyclohepta (1,2-b) pyridin-11-yl) -N- (4-pyridinyl) -4- piperidinecarboxamide Add l- (3-bromo-8-chloro-6,11-dihydro-5H-benzo (5,6) cyclohepta (1,2- b) pyridin-1-yl) -4-piperidinecarboxylate (0.25g) ( 1 equivalent) (prepared in accordance with that described in Preparative Example 2 below) dissolved in anhydrous DMF (9 ml) to a solution of 4-aminopyridine (0.0761 g) (1.5 equivalents), DEC (0.155 g) (1.5 equivalents) ), HOBT (0.1093 g) (1.5 equivalent) and N-methylmorpholine (0.0889 ml) (1.5 equivalents) in anhydrous DMF (4 ml) and the mixture is stirred at a temperature of 25 ° C for 42 hours. The solution is evaporated to dryness and the residue is taken up in dichloromethane and washed with 1.0 N sodium hydroxide. The dichloromethane layer is dried in sulphate, filtered and evaporated to dryness. The product is subjected to chromatography on a column of silica gel (60X2.5 cm) using from 1.5% to 3% (10% concentrated ammonium hydroxide in methanol) - dichloromethane as eluent to provide the title compound (0.0308 g; 12%), CIMS: m / z 511 (MH + ). Inhibition of FPT = 0% to 0.39 μM dc (CDC13) Tricyclic CH2: 30.4, 29.9 CH: 146.9,141.3,132.2,126.1,130.5, 79 \ 4 C: 119.8, 140.7, 134.0, 136.1, 136.7, 156.5 Piperidine CH2: 29.0, 51.2, 51.5, 30.4 CH: 44.5 C: 174.6 N-piperidine substituent CH: 150.5, 113.8, 113.8, 150.5 C: 145.9 EXAMPLE 3. l- (3-Bromo-8-chloro-6, ll -dihydro-5H) benzo (5, 6) cyclohepta (1, 2-b) pyridin-11-yl) -N- (4-pyridinylmethyl) -4-piperidinecarboxamide 1- (3-Bromo-8-chloro-6,11-dihydro-5H-benzo (5,6) cyclohepta (1, 2-b) pyridin-ll-yl) -4-piperidicarboxylate (0.25g; equivalent) (prepared in accordance with that described in Preparation Example 2 below) dissolved in anhydrous DMF (9 ml) to a solution of 4-aminomethylpyridine (0.0821 ml, 1.5 equivalents), DEC (0.155 g, 1.5 equivalents), HOBT (0.1093 g; 1.5 equivalents) and N-methylmorpholine (0.0889 ml; 1.5 equivalents) in anhydrous DMF (4 ml) and the mixture is stirred at 25 ° C for 19 hours. The solution is evaporated to dryness and the residue is taken up in dichloromethane and washed with 1.0 N sodium hydroxide. The dichloromethane layer is dried over magnesium sulfate, filtered and evaporated to dryness. The product is chromatographed on a silica gel column (30X2.5 cm) using 2% to 3% (10% concentrated ammonium hydroxide in methanol) -dichloromethane as the eluent to provide the title compound (0.2128). g; yield: 75%), FABMS: m / z 524.9 (MH +). Inhibition of FPT = 21% at 1.1 μM dc CDC13) Tricyclic CH2: 30.4, 30.3 CH: 146.9, 141.2, 132.2, 126.1, 130.5, 79.4 C: 119.9, 140.7, 134.0, 136.1, 136.7, 156.5 Piperidine CH2: 29.0, 51.4, 51.6, 29.2 CH: 43.3 C: 175.3 N-substituent of piperidine CH2: 42.1 CH: 122.3, 149.9, 149.9, 122.3 C: 147.7 EXAMPLE 4. l- (3-Bromo-8-chloro- 6, 11-dihydro-5H) benzo (5,6) cyclohepta (1, 2-b) pyridin-ll-yl) -N- (3-pyridinylmethyl) -4-piperidinecarboxamide L- (3-Bromo-8-chloro-6,11-dihydro-5H) -benzo (5,6) cyclohepta (1,2-b) pyridin-11-yl) -N- (4-piperidinecarboxylate ( 0.25 g, 1 equivalent) (prepared in accordance with that described in preparation example 2 below) dissolved in anhydrous DMF (9 ml) to a solution of 3-aminomethylpyridine (0.0823 ml, 1.5 equivalent), DEC (0.155 g, 1.5 equivalents), HOBT (0.1093g, 1.5 equivalents) and N-methylmorpholine (0.0889ml, 1.5 equivalents) in anhydrous DMF (4 ml) and the mixture it is stirred at 25 ° C for 18 hours. The solution is evaporated to dryness and the residue is taken up in dichloromethane and washed with 1.0 N sodium hydroxide. The dichloromethane layer is dried over magnesium sulphate, filtered and evaporated to dryness. The product is subjected to chromatography on a silica gel column (60X2.5 cm) using 2% (10% concentrated ammonium hydroxide in methanol) -dichloromethane as eluent to provide the title compound (0.246g, 87%). , FABMS: m / z 525 (MH +). IC50 of FPT = 1.3 μM dc (CDC13) Tricyclic CH2: 30.4, 30.3 CH: 146.9, 141.3, 132.2, 126.1, 130.6, 79.4 C: 119.9, 140.7, 134.0, 136.2, 136.7, 156.6 Piperidine CH2: 29.2, 51.4, 51.7 , 29.2 CH: 43.4 C: 175.2 N-substituent of piperidine CH2: 40.9 CH: 149.1, 135.7, 123.7, 148.8 C: 134.2 EXAMPLE 5. l- (3-Bromo-8-chloro-6,11-dihydro-5H) benzo (5,6) cyclohepta (1,2-b) pyridin-11-yl) -N- (2 - pyridinylmethyl) -4-piperidinecarboxamide L- (3-Bromo-8-chloro-6,11-dihydro-5H) -benzo (5,6) cyclohepta (1, 2-b) pyridin-ll-yl) -4-piperidinecarboxylate (0.25 g; 1 equivalent) (prepared in accordance with that described in Preparation Example 2 below) dissolved in anhydrous DMF (9ml) to a solution of 2-aminomethylpyridine (0.0834ml, 1.5 equivalent) DEC (0.155g, 1.5 equivalents), HOBT (0.1093g; 1.5 equivalent) and N-methylmorpholine (0.0889 ml; 1.5 equivalent) in anhydrous DMF (4 ml) and the mixture is stirred at a temperature of 25 ° C for 18 hours. The solution is evaporated to dryness and the residue is taken up in dichloromethane and washed with hydroxide.

Sodium 1.0 N. The dichloromethane layer is dried over magnesium sulphate, filtered and evaporated to dryness. The product is subjected to chromatography on a silica gel column (60X2.5 cm) using 0.85% (10% concentrated ammonium hydroxide in methanol) -dichloromethane as eluent to provide the title compound (0.2475g; yield: 87 %), FABMS; m / Z 525 (MH +). IC50 of FPT = 1.8 μM dc (CDC13) Tricyclic CH2: 30.4, 30.3 CH: 146.9, 141.2, 132.3, 126.1, 130.6, 79.5 C: 119.9, 140.7, 133.9, 136.3, 136.7, 156.7 Piperidine CH2: 29.1, 51.5, 51.7 , 29.1 CH: 43.4 C: 175.1 N-substituent of piperidine CH2: 44.2 CH: 122.4, 137.1, 122.2, 148.9 C: 156.2 EXAMPLE 6. l- (3-Bromo-8-chloro-6, 11-dihydro-5H) -benzo (5, 6) cyclohepta (1, 2-b) pyridin-11-yl) -N- (2-pyridinylethyl) -4-piperidinecarboxamide L- (3-Bromo-8-chloro-6,11-dihydro-5H) -benzo (5,6) cyclohepta (1, 2-b) pyridin-ll-yl) -4-piperidinecarboxylate (0.4g; 1 equivalent) (prepared in accordance with that described in Preparation Example 2 below) dissolved in anhydrous DMF (14 mL) to a solution of 2-aminoethylpyridine (0.134 mL, 1.3 equivalent) DEC (0.215 g, 1.3 equivalent), HOBT (0.1515g; 1.3 equivalents) and N-methylmorpholine (0.123 ml; 2.6 equivalent) in anhydrous DMF (6 ml) and the mixture is stirred at a temperature of 25 ° C for 67 hours. The solution is evaporated to dryness and the residue is taken up in dichloromethane and washed with 1.0 N sodium hydroxide. The dichloromethane layer is dried over magnesium sulphate, filtered and evaporated to dryness. The product is subjected to chromatography on a silica gel column (69X2.5 cm) using 1% increasing to 2% (10% concentrated ammonium hydroxide in methanol) -dichloromethane as eluent to provide the title compound (0.4003 g).; yield: 86%), FABMS: m / z 539.2 (MH +). Inhibition of FPT = 9% μM dc (CDC13) Tricyclic CH2: 30.4, 30.3 CH: 146.9, 141.2, 132.3, 126.1, 130.6, 79.5 C: 119.9, 140.7, 133.9, 136.4, 136.7, 156.8 Piperidine CH2: 29.1, 29.1, 51.5, 51.7 CH: 43.5 C: 174.9 N-substituent of piperidine CH2: 38.6, 36.7 CH: 123.6, 136.9, 121.7, 149.0 C: 159.7 EXAMPLE 7. l- (3-Bromo-8- chloro-6, ll-dihydro-5H-benzo (5,6) cyclohepta (1,2-b) pyridin-11-y1) -N- (4-N-carboxamidepiperidinyl)) -4-piperidinecarboxamide Step A:? - (3-Bromo-8-chloro-6,11-dihydro-5H-benzo (5,6) cyclohepta (1-2) b) pyridin-ll-yl) -N- (4- (N-benzylpiperidinyl)) -4-piperidinecarboxamide L- (3-Bromo-8-chloro-6,11-dihydro-5H-benzo (5,6) cyclohepta (1, 2-b) pyridin-1-yl) -4-piperidinecarboxylate (0.8g; equivalent) (prepared in accordance with that described in preparation example 2 below) dissolved in anhydrous DMF (29 ml) to a solution of lN-benzyl-4-aminopiperidine (0.4573 ml) (1.3 equivalent), DEC (0.43) g; 1.3 equivalent), HOBT (0.303g, 1.3 equivalent) and N-methylmorpholine (0.494 ml, 2.6 equivalent in anhydrous DMS (12.8 ml) and the mixture is stirred at a temperature of 25 ° C for 18 hours. evaporated to dryness and the residue taken up in dichloromethane and washed with 1.0 N sodium hydroxide. of dichloromethane is dried over magnesium sulfate, filtered and evaporated to dryness. The product is subjected to chromatography on a column of silica gel (60X2.5 cm) using 2% (10% concentrated ammonium hydroxide in methanol) -dichloromethane as eluent to provide the title compound (0.8143 g, 78% yield ), FABMS: m / z 607.1 (MH +). dc (CDC13) Tricyclic CH2: 30.4, 30.3 CH: 146.9, 141.2, 132.2, 126.1, 130.6, 79.5 C: 119.8, 140.7, 133.9, 136.3, 136.7, 156.8 Piperidine CH2: 29.2, 51.4, 51.7, 29.2 CH: 43.6 C : 174.3 N-substituent of piperidine CH2: 52.3, 52.3, 32.3, 32.3, 63.0 CH: 46.3, 128.3, 128.3, 129.2, 129.2, 127.2 C: 138.1 Step B: l- (3-Bromo-8-chloro-6, II-dihydro-5H-benzo (5, 6) cyclohepta (1, 2-b) pyridin-11-yl) -N- (4-piperidinyl)) -4-iperidinecarboxamide Dissolve l- (3-Bromo-8-chloro-6,11-dihydro-5H-benzo (5,6) cyclohepta (1,2-b) pyridin-11-yl) - N- (4- (N- benzylpiperidinyl) -4-piperidinecarboxamide (0.51 g, 1 equivalent) (prepared in accordance with that described in step A above) in anhydrous dichloromethane (3 ml) and the solution is cooled to 0 ° C. A-chloroethoxycarbonyl (0.09027) is added. ml, one equivalent) in 5 minutes and allow the solution to warm at 25 ° C for 1 hour.The dichloromethane is removed in vacuo and anhydrous methanol (14 ml) is added.The solution is heated under reflux for 1 hour. The solution is evaporated to dryness and the residue is taken up in dichloromethane and washed with 1.0 N sodium hydroxide. The dichloromethane layer is dried over magnesium sulphate, filtered and evaporated to dryness. chromatography on a column of silica gel (60X2.5 cm) using 2.5% (10% concentrated ammonium hydrochloride in methanol) - dichloromethane as the eluent to provide 1- (3-Bromo-8-chloro-6, 11- dihydro-5H-benzo (5, 6) cyclohepta (1, 2-b) pyridin-11-yl) -N- (4- (N-benzylpiperidinyl)) -4-piperidinecarboxamide (0.1921 g, 38% yield) react and the title compound (0.199g, 46%), FABMS: m / z 517.5 (MH +). Inhibition of FPT = 8.65% to 0.39μM dc (CDC13 + CD30D) Tricyclic CH2: 146.6, 141.4, 132.2, 126.1, 130.5, 79.2 CH: 30.3, 30.2 C: 119.8, 140.6, 133.9, 136.1, 136.9, 156.7 Piperidine CH2: 119.8, 140.6, 133.9, 136.1, 136.9, 156.7 CH: 119.8, 140.6, 133.9, 136.1, 136.9, 156.7 C: 175.0 N-piperidine substituent CH2: 119.8, 140.6, 133.9, 136.1, 136.9, 156.7 CH: 46.0 Step C : 1- (3-Bromo-8-chloro-6,11-dihydro-5H-benzo (5,6) cyclohepta (1, 2-b) pyridin-ll-yl) -N- (4- (N-carboxamidepiperidinyl) ) -4- piperidinecarboxamide Dissolve l- (3-Bromo-8-chloro-6,11-dihydro-5H-benzo (5,6) cyclohepta (1,2-b) pyridin-ll-yl) - N- (4-piperidinyl) - 4-piperidinecarboxamide (0.119lg); 1 equivalent) (prepared in accordance with that described in step B above) in anhydrous dichloromethane (3.3 ml). 80,467 ml trimethylsilyl isolate is added; 15 equivalents) and the mixture is stirred under an argon atmosphere at a temperature of 22 ° C for 22 hours. Additional trimethylsilyl isocyanate (0.156 ml, 5 equivalent) is added and the mixture is stirred for a total of 27 hours. The solution is diluted with dichloromethane and washed with saturated aqueous sodium bicarbonate. The dichloromethane layer is dried over magnesium sulfate, filtered and evaporated to dryness. The product is subjected to chromatography on a column of silica gel (15X2.5 cm) using 4% (10% concentrated ammonium hydroxide in methanol) -dichloromethane as eluent to provide the title compound (0.0678 g; %), FABMS: m / z 560 (MH +). Inhibition of FPT = 15% at 0.36μM dc (CDC13) Tricyclic CH2: 30.4, 30.3 CH: 146.8, 141.2, 132.2, 126.1, 130.6, 79.4 C: 119.8, 140.7, 133.9, 136.2, 136.7, 156.7 Piperidine CH2: 29.1, 51.4, 51.7, 29.1 CH: 43.5 C : 174.7 N-substituent of piperidine CH2: 43.3, 43.3, 31.9, 31.9 CH: 46.3 C: 46.3 EXAMPLE 8. l- (3-Bromo-8-chloro-6,11-dihydro-5H-benzo (5, 6) cyclohepta (1, 2-b) pyridin-ll-yl) -N- (4-N-carboxamidepiperidinyl) methyl-4-piperidinecarboxamide Method 1, Step A: 1- (3-Bromo-8-chloro-6,11-dihydro-5H-benzi- (5,6) cyclohepta (1,2-b) pyridin-ll-yl) -N- ( 4- (N-benzylpiperidinyl) methyl) -4-piperidinecarboxamide L- (3-Bromo-8-chloro-6,11-dihydro-5H-benzo (5,6) cyclohepta (1, 2-b) pyridin-1-yl) -4-piperidinecarboxa ida (0.8g; 1 equivalent) (prepared in accordance with that described in Preparation Example 2 below) dissolved in anhydrous DMF 829 ml) to a solution of lN-benzyl-4-aminoethylpiperidine (0.4581 g, 1.3 equivalent) (prepared in accordance with described in preparation example 4, step B below), DEC (0.43g) (1.3 equivalent) HOBT (0.303 g, 1.3 equivalent) and N-methylmorpholine (0.493 ml, 2.6 equivalents) in anhydrous DMF (12.8 ml) and The mixture is stirred at a temperature of 25 ° C for 24 hours. The solution is evaporated to dryness and the residue which has been taken up in dichloromethane and washed with l.ON sodium hydroxide. The dichloromethane layer is dried over magnesium sulfate, filtered and evaporated to dryness. The product is subjected to chromatography on a silica gel column (60X2.5 cm) using 2% (10% concentrated ammonium hydroxide in methanol) -dichloromethane as eluent to provide the title compound (0.7475g; %), FABMS: m / z 621.6 (MH +). dc (CDC13) Tricyclic CH2: 30.4, 30.3 CH: 146.9, 141.2, 132.2, 126.1, 130.6, 79.5 C: 119.8, 140.7, 133.9, 136.3, 136.7, 156.8 Piperidine CH2: 29.1, 51.5, 51.8, 29.3 CH: 43.7 C: 175.1 N-substituent of piperidine CH2: 53.3, 29.9, 29.9.53.3, 63.4, 44.9 CH: 36.0, 128.2, 129.2, 127.0, 129.2, 128.2 C: 138.3 Step B: 1- (3-Bromo) -8-chloro-6, 11-dihydro-5H-benzo- (5, 6) cyclohepta (1,2-b) pyridin-ll-yl) -N- (4-piperidinyl) -4-piperidinecarboxamide Dissolve l- (3-Bromo-8-chloro-6,11-dihydro-5H-benzo (5,6) cyclohepta (1,2-b) pyridin-ll-yl) - N- (4- (N- benzylpiperidinylmethyl)) -4-piperidinecarboxamide in (0.568g, 1 equivalent) (prepared in accordance with that described in step A above) in anhydrous dichloromethane (5.9 ml) and the solution is cooled to a temperature of 0 ° C. A-chloroethoxycarbonyl chloride (0.487ml, 5 equivalents) is added in 30 minutes and the solution allowed to warm to 25 ° C for 2.5 hours. The dichloromethane is removed in vacuo and anhydrous methanol (14.2 ml) is added. The solution is heated under reflux for 1.25 hours. The solution is evaporated to dryness and the residue is taken up in dichloromethane and washed with 1.0 N sodium hydroxide. The dichloromethane layer is dried over magnesium sulphate, filtered and evaporated to dryness. The product is subjected to chromatography on a column of silica gel (30X2.5 cm) using 2% (10% concentrated ammonium hydroxide in methanol) - 2% dichloromethane as eluent to provide l- (3-Bromo-8 6-chloro-6, 11-dihydro-5H-benzo (5,6) cyclohepta (1, 2-b) pyridin-1-yl) -N- (4- (N-benzylpiperidinylmethyl)) -4-piperidinecarboxamide unreacted ( 0.1487 g, 23% yield) and the title compound (0.1932 g, 34% yield), FABMS: m / z 531.0 (MH +). The title compound is identical to the compound prepared in procedure 2, step B below. Inhibition of FPT = 12% at 0.38 μM 5c (CDC13) Tricyclic CH2: 30.4, 30.3 CH: 146.9, 141.2, 132.2, 126.1, 130.6, 79.5 C: 119.8, 140.7, 133.9, 136.3, 136.7, 156.7 Piperidine CH2: 29.3, 51.5, 51.7, 29.3 CH: 43.7 C: 175.2 N-substituent of piperidine CH2: 30.9, 30, .9, 46.2, 46.2, 45.2 CH: 36.5 Step C: l- (3-Bromo-8- chloro-6, ll-dihydro-5H-benzo- (5,6) cyclohepta (1,2-b) pyridin-ll-yl) -N- (4 - (N-carboxamidopiperidinyl) methyl) 4-piperidinecarboxamide Dissolve l- (3-Bromo-8-chloro-6,11-dihydro-5H-benzo (5,6) cyclohepta (1, 2-b) pyridin-ll-yl) - N- (4- piperidinylmethyl) -4-piperidinecarboxamide (0.005g, 1 equivalent) (prepared according to that described in step B above) in anhydrous dichloromethane (0.161ml). Trimethylsilyl isolate (0.0038 ml, 3 equivalent) is added and the mixture is stirred at a temperature of 25 ° C under an argon atmosphere for 16 hours. The mixture is diluted with dichloromethane and washed with saturated aqueous sodium bicarbonate. The dichloromethane layer is dried over magnesium sulfate, filtered and evaporated to dryness to give the title compound which is identical in thin bed chromatography (TLC) to the preparation in procedure 2, step C, below. Method 2, Step A: 1- (3-Bromo-8-chloro-6,11-dihydro-5H-benzo- (5,6) cyclohepta (1, 2-b) pyridin-ll-yl) -N- ( 4- (N-tert-butoxycarbonylpiperidine) methyl) -4-piperidinecarboxamide BOC L- (3-Bromo-8-chloro-6,11-dihydro-5H-benzo (5,6) cyclohepta (1,2-b) pyridin-1-yl) -4-piperidinecarboxylate (0.5g, 1) is added. equivalent) (prepared in accordance with that described in Preparation Example 2 below) dissolved in anhydrous DMF to a solution of 1-N-tet-butoxycarbonyl-4-aminomethylpiperidine (0.1778 g, 1 equivalent) prepared in accordance with that described in preparation example 3, step C below), DEC (0.2067g, 1.3 equivalents), HOBT (0.1457g, 1.3 equivalents9 and N-methylmorpholine (0.1185 ml, 1.3 equivalent) in anhydrous DMF (8 ml) and the mixture It is stirred at a temperature of 25 ° C for 19 hours, then the solution is evaporated to dryness and the residue is taken up in dichloromethane and washed with 1.0 N sodium hydroxide. The dichloromethane layer is dried in magnesium sulfate, filtered and evaporated to dryness. dryness.The product is chromatographed on a column on silica gel (60X2.5cm) using 0.65% (ammonium hydroxide concentrated to 10% in methanol) -dichloromethane as eluent to provide the title compound (0.4805g; 71% yield), FABNS: m / z 631 (MH +). dc (CDC13) Tricyclic CH2: 30.4, 30.3 CH: 146.9, 141.2, 132.2, 126.1, 130.6, 79.5 C: 119.8, 140.7, 133.9, 136.3, 136.7, 156.7 Piperidine CH2: 29.3, 51.7, 51.4, 29.3 CH: 43.6 C: 175.2 N-substituent of piperidine CH3: 43.6 CH2: 43.6, 43.6, 29.3, 29.3, 44.7 CH: 36.4 C: 79.5, 154.8 Step B: 1- (3-Bromo-8-chloro-6, ll-dihydro-5H-benzo- (5,6) hepta (1,2- b) pyridin-ll-yl) -N- (4-piperidinimethyl) -4-piperidinecarboxamide Dissolve l- (3-Bromo-8-chloro-6,11-dihydro-5H-benzo (5,6) cyclohepta (1,2-b) pyridin-ll-yl) -N- (4- (N- tert-butoxycarbonylpiperidine) methyl) -4-piperidine carboxamide (0.3936g; 1 equivalent) in anhydrous dichloromethane (30 ml).

Trifluoroacetic acid (6.039 ml, 127 equivalent) is added to the stirred solution at a temperature of 0 ° C under argon. The mixture is stirred at 0 ° C for 1.5 hours and then allowed to warm at 25 ° C for 1 hour. The mixture is diluted with dichloromethane and washed with 1.0 N sodium hydroxide. The dichloromethane layer is dried over magnesium sulfate, filtered and evaporated to dryness. The product is subjected to chromatography on a column of silica gel (60X2.5 cm) using 7% increasing to 10% (10% concentrated ammonium hydroxide in methanol) -dichloromethane as eluent to provide the title compound (0.2023 g; 61% yield), FABMS; m / z 531.1 (MH +). dc (CDC13) Tricyclic CH2: 30.4, 30.3 CH: 146.9, 141.2, 132.2, 126.1, 130.6, 79.5 C: 119.8, 140.7, 133.9, 136.3, 136.7, 156.7 Piperidine CH2: 119.8, 140.7, 133.9, 136.3, 136.7, 156.7 CH: 119.8, 140.7, 133.9, 136.3, 136.7, 156.7 C: 175.1 N-substituent of piperidine CH2: 119.8, 140.7, 133.9, 136. 3, 136. 7, 156. 7 CH: 119.8, 140.7, 133. 9, 136. 3, 136.7, 156.7 Step C: 1- (3-Bromo-8-chloro-6,11-dihydro-5H-benzo- (5,6) cyclohepta 1,2-b) pyridin-1-yl ) -N- (4 - (N-carboxamidopiperidinyl) methyl) - 4-piperidinecarboxamide Dissolve l- (3-Bromo-8-chloro-6,11-dihydro-5H-benzo (5,6) cyclohepta (1,2-b) pyridin-ll-yl) -N- (4-piperidinylmethyl) - 4-piperidinecarboxamide (0.140 g, 1 equivalent) (prepared accordto that described in step D above) in anhydrous dichloromethane (4.5 ml). Trimethylsilyl isocyanate (0.534 ml) (15 equivalent) is added and the mixture is stirred at 25 ° C under an argon atmosphere for 18 hours. The mixture is diluted with dichloromethane and washed with saturated aqueous sodium bicarbonate. The dichloromethane layer is dried over magnesium sulphate, filtered and evaporated to dryness. "The product is subjected to chromatography on a silica gel column (30X2.5 cm) us4% (10% concentrated ammonium hydroxide in methanol) -dichloromethane as eluent to provide the title compound (0.1084 g, 72% yield), FABMS; m / z 573.9 (MH +). Inhibition of FPT = 41% at 1.04 μM. dc (CDC13) Tricyclic CH2: 30.4, 30.3 CH: 146.8, 141.2, 132.2, 126.1, 130.6, 79.5 C: 119.8, 140.7, 133.9, 136.3, 136.7, 156.7 Piperidine CH2: 29.3, 51.4, 51.7, 29.3 CH: 29.3, 51.4, 51.7, 29.3 C: 175.4 N-substituent of piperidine CH2: 29.6, 29.6, 44.6, 44.6, 44.1 CH: 36.1 C: 158.1 EXAMPLE 9. 1- (1- (3-Bromo-8-chloro-6, ll -dihydro-5H-benzo (5,6) cyclohepta (1,2-b) pyridin-ll-yl) -4-piperidinylcarbonyl) -4- ((1-aminomethanamido) methyl) piperidine Step A: 1- (1- (3-Bromo-8-chloro-6,11-dihydro-5H-benzo (5,6) cyclohepta (1, 2-b) pyridin-ll-yl) 4-piperidinylcarbonyl) - 4-N-tert-butoxycarbonylamine) methyl) piperidine L- (3-Bromo-8-chloro-6,11-dihydro-5H-benzo (5,6) cyclohepta (1,2-b) pyridin-1-yl) -4-piperidinecarboxylate (0.3195g; equivalent) (prepared in accordance with that described in Preparation Example 2 below) dissolved in anhydrous DMF (11.5 mL) to a solution of 4- ((N-tert-butoxycarbonylamine) -methylpiperidine (0.1904 g, 1.3 equivalents) ( prepared in accordance with that described in preparation example 5, step C, a continued), DEC (0.1703g, 1.3 equivalent), HOBT (0.1201g, 1.3 equivalent) and N-methylmorpholine (0.195 ml, 2.6 equivalent) in anhydrous DMF and the mixture is stirred at a temperature of 25 ° C for 19 hours. The solution is evaporated to dryness and the residue is taken up in dichloromethane and washed with 1.0 N sodium hydroxide. The dichloromethane layer is dried over magnesium sulfate, filtered and evaporated to dryness. The product is chromatographed on a column of silica gel (60X2.5 cm) us0.8% "(10% concentrated ammonium hydroxide in methanol) dichloromethane as eluent to provide the title compound (0.3701g, yield: 86%) , FABMS: m / z 631.3 (MH +). dc (CDC13) Tricyclic CH2: 30.7, 30.4 CH: 146.8, 141.2, 132.2, 126.0, 130.6, 79.6 C: 119.7, 140.7, 133.8, 136.4, 136.7, 156.9 Piperidine CH2: 51.6, 29.1, 28.9, 51.9 CH: 38.8 C : 173.4 N-substituent of piperidine CH3: 28.4 CH2: 45.3 / 45.9, 28.9 / 29.1, 29.5 / 30.2, 45.3 / 45.9, 41.7 CH: 37.0 C: 79.4, 156.1 Step B: 1- (1- (3-Bromo-8-chloro-6,11-dihydro-5H-benzo (5,6) cyclohepta (1,2-b) pyridin-ll-yl) -4- (piperidinyl ) -4- aminomet i lpiper idina Dissolve l- (1- (3-Bromo-8-chloro-6,11-dihydro-5H-benzo (5,6) cyclohepta (1,2-b) pyridin-ll-yl) -4-piperidinylcarbonyl) - 4- ((N-tert-butoxycarbonylamino) (0.35 g) (1 equivalent) in methanol (3.1 ml) A 10% (volume / volume) solution of concentrated sulfuric acid in dioxane (7.568 ml) is added and the mixture The mixture is stirred at 0 ° C for 1.5 hours and then allowed to warm to 25 ° C for 1 hour. dichloromethane and washed with 1.0 N sodium hydroxide. The dichloromethane layer is dried over magnesium sulfate, filtered and evaporated to dryness. The product is subjected to chromatography on a silica gel column (30X2.5 cm) us4% (10% concentrated ammonium hydroxide in methanol) -dichloromethane as eluent to provide the title compound (0.226g).; 77% yield), FABMS: m / z 531.4 (MH +). Inhibition of FPT = 16% at 0.38 μM dc (CDC13) Tricyclic CH2: 30.4, 30.2 CH: 146.8, 141.2, 132.2, 126.0, 130.6, 79.6 C: 119.8, 140.7, 133.8, 136.4, 136.7, 156.9 Piperidine CH2: 51.6, 29.1, 28.9, 51.9 CH: 38.8 C: 173.4 N-substituent of piperidine CH2: 42.0, 29.7 / 30.9, 29.0 / 29.2, 42.0, 45.5 CH: 38.8 Step C: 1- (1- (3-Bromo-8-chloro -6, 11-dihydro-5H-benzo (5, 6) cyclohepta (1, 2-b) pyridin-ll-yl) -4-piperidinylcarbonyl) -4- ((1-aminomethanamido) methyl) piperidine Dissolve l- (1- (3-Bromo-8-chloro-6,11-dihydro-5H-benzo (5,6) cyclohepta (1, 2-b) pyridin-1-yl) -4-piperidinylcarbonyl) - 4- ((N-tert-butoxycarbonylamino) methyl) piperidine (0.185 g) (1 equivalent) (prepared according to that described in example 9, step B above) in anhydrous dichloromethane (5 ml). Trimethylsilyl isolate (0.706 ml) is added (15 equivalents) and the mixture is stirred at a temperature of 25 ° C under an argon atmosphere for 22 hours. Additional trimethylsilyl isocyanate (0.235 ml) is added (5 equivalents) and the stirring is continued for a total of 26.75 hours. The mixture is diluted with dichloromethane and washed with saturated aqueous sodium bicarbonate. The dichloromethane layer is dried over magnesium sulfate, filtered and evaporated to dryness. The product is subjected to chromatography on a column of silica gel (30 X 2.5 cm) using 3.5% (10% concentrated ammonium hydroxide in methanol) -dichloromethane to provide the title compound (0.1502 g, 75% yield), FABMS: m / z 574.2 (MH +). IC50 of FPT = 0.66μM dc (CDC13) Tricyclic CH2: 30.4, 30.2 CH: 146.8, 141.2, 132.2, 126.0, 130.6, 79.6 C: 119.8, 140.7, 133.9, 136.2, 136.7, 156.7 Piperidine CH2: 51.5, 29.0, 28.9 , 51.8 CH: 38.8 C: 173.6 N-substituent of Piperidine CH2: 41.9, 41.9, 30.7, 29.6, 45.4 CH: 36.9 C: 159.2 EXAMPLE 10. l- (8-chloro-3-bromo-5,6-dihydro- llH-benzo (5,6) -cyclohepta (1,2-b) pyridin-ll-yl) piperidine-3- (N-3-pyridylmethylamine) carboxamide Method 1, Step A. l- (ethyl 3-bromo-8-chloro-6,1-dihydro-5H-benzo (5,6) cyclohepta (1,2) pyridin-1-yl) -3-piperidinecarboxylate Dissolve 3-Bromo-8,11-dichloro-6,11-dihydro- + 5H-benzo (5,6) cyclohepta (1,2-b) pyridine (lg, 2.5 mmol) in 10 ml of N, N- dimethylformamide (DMF). Ethyl nipecotate 80.6 ml, 3.7 mmol) and N-methylmorpholine (0.69 ml, 6.2 mmol) are added and the reaction mixture is stirred at room temperature for 18 hours. The reaction mixture is poured into water and extracted with dichloromethane twice. The combined extracts are dried in magnesium sulfate and the mixture filtered and evaporated to obtain an oil. The oil is chromatographed on silica gel using 10% ethyl acetate / hexane as eluent to obtain 0.55 gm of the title compound. FABMS (MH +) = 464.

Step B. l- (3-bromo-8-chloro-6,11-dihydro-5H-benzo (5,6) cyclohepta (1,2) pyridin-ll-yl) -3-piperidinecarboxylate L- (3-Bromo-8-chloro-6,1-dihydro-5H-benzo (5,6) cyclohepta (1,2-b) pyridin-1-yl) -3-piperidinecarboxylic acid ethyl ester (1.9 gm) is refluxed. ) in 25 ml of 6N hydrochloric acid for 8 hours. The HCl and water t are evaporated to obtain the compound, in the form of a solid. Step C. 1- (3-Bromo-8-chloro-6,11-dihydro-5H-benzo (5,6) cyclohepta (1,2-b) pyridin-1-yl) -N- (3-pyridinylmethyl) -3 -piperidinecarboxamide The compound of example 10, step B is dissolved in 12 ml of DMF and l- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (DEC) (0.37 g, 1.9 mmol), 1- hydroxybenzotriazole (HOBT) (0.36 g) NMM (0.5 mL) and (0.216 g, 2.0 mmol) of 3-aminomethylpyridine are added to the reaction mixture and stirred at room temperature. After 17 hours, the reaction mixture is poured into water and extracted with dichloromethane twice. The combined extracts are dried over magnesium sulfate and the mixture is filtered and evaporated to obtain an oil. The oil is chromatographed on silica gel using 5% methanol / dichloromethane as eluent to obtain 0.44 gm of the title compound. FABS (MH +) = 603 IC50 of FPT = 0.21μM Step D separation of isomers The compound of example 10, procedure 1, step C is separated into its four optical isomers by HPLC chromatography with an Chiralpak® AD (0.46cmX25cm) analytical chiral column (amylose tris (3,5-dimethylphenyl carbamate) coated on a lOμM silica gel substrate (trademark of Chiral Technologies, Exton, Pennsylvania), using as solvent elution, 20% isopropanol / hexane / .02% diethylamine at 1 ml / minute, the four compounds are eluted at 10.27 (isomer A), 11.43 (isomer B), 11.57 (isomer C) and 18.37 (isomer D) minutes.

Isomer A isomer B FABMS (MH +) = 526.8 FABMS (MH +) = 526.8 Inhibition of FPT = 6.1% to 1.14 μM IC50 of FPT = 0.194 μM Isomer C isomer D FABMS (MH +) = 526.8 FABMS (MH +) = 526. 8 IC50 of FPT = 0. 179 μM IC50 of FPT = 0.187 μM Procedure 2, Step A.

To a solution of N- (tert-butoxycarbonyl) nipecotic acid (0.50 g, 2.41 mmol) in dichloromethane (10 mL) is added 3- (to inomethyl) pyridine (0.27 mL, 2.65 mmol), monohydrate 1-hydroxybenzotriazole (HOBT) and 1,3-dicyclohexylcarbodiimide (0.547 g, 2.65 mmol). The mixture is stirred at room temperature for 16 hours and then filtered. The solution is purified by flash chromatography (SI02, 2% methanol in CH2C12) to give 0.67 g of the product. Step B Treat a solution of the product of Example 10, procedure 2, step A (0.04 g, 0.125 mmol) in CH2C12 (3 mL) is treated with trifluoroacetic acid (TFA) (0.5 mL) for 1 hour. The mixture is then evaporated to dryness in vacuo and subjected to the treatment with methanol (3X5ml portions). Step C.

The residue from Example 10, Procedure 2, step b above, is then dissolved in CH 3 CN (1 mL) and a solution of 3-bromo-8,11-dichloro-6,11-dihydro-5H-benzo (5, 6) Cyclohepta (1,2-b) pyridine (0.07 g, 0.2 mmol) in CH 2 CN, followed by 1, 2, 2, 6, 6-pentamethylpiperidine (0.2 ml, 1.1 mmol). The solution is heated to a temperature of 45 ° C for 16 hours and then evaporated to dryness under vacuum. The residue is purified by flash chromatography (Si02, 3% methanol in CH2C12) to give 0.04 g of the title compound. ÍH NMR (300 Mhz) CDC13; d = 1.45-1.75 (, 2H); 1.8-1.92 (m, 1H9; 2.02-2.15 (m, ÍH); 2.16-2.30 (m, ÍH); 2.38-2.52 (m, 2H); 2.58-2.72 (m, 2H); 3.16-3.3 (m, ÍH), 3.46-3.70 (, 2H), 3.70-3.82 (m, ÍH), 4.32 (br, s, 2H), 4.39 (d, ÍH), 4.45-4.52 (m, ÍH), 6.93 (br, s , 0.5 H); 7.06-7.17 (m, 3H); 7.22-7.28 (m, ÍH); 7.35 (br, s, 0.5H); 7.45-7.52 (m, ÍH); 7.53 (d, 0.5H); 8. 49 (br, s, ÍH); 1.58 (m, ÍH). EXAMPLE 11. l- (3-bromo-8-chloro-6,11-dihydro-5H-benzo (5,6) cyclohepta (1,2-b) pyridin-ll-yl) -N- (3-pyridinyl) -3- piperidinecarboxamide Dissolve l- (3-bromo-8-chloro-6,11-dihydro-5H-benzo (5,6) cyclohepta (1,2-b) pyridin-ll-yl) -3-piperidinecarbocylate (0.12 gm, 0.27 mmol) of Example 10, Method 1, Step B, in 4 mL of DMF. Add l- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (DEC), (79 mg, 0.41 mmol), 1-hydroxybenzotriazole (HOBT) (55 mg, 0.41 mmol), N-methylmorpholine (NMM) (0.29 ml) , 2.7 mmol) and 3-aminopyridine (0.05 gm) and the mixture of the reaction products is stirred for 18 hours. The reaction mixture is poured into water and extracted with ethyl acetate 3 times. The combined extracts are dried in sulfate magnesium, filtered and chromatographed on silica gel to obtain 42 mg of the title compound. FABMS (MH +) = 512.8 IC50 of FTP = 0.065μM. EXAMPLE 12. Amide Al isomer of l- (3-bromo-8-chloro-6,11-dihydro-5H-benzo (5,6) cyclohepta (1, 2-b) pyridin-ll-yl) -N- (4-pyridinylmethyl) -2S-piperidinecarboxamide Step Al. L-pipecolinic acid ethyl ether hydrochloride L-pipecolinic acid (0.9g, 6.97 mmol) is dissolved in 40 mL of absolute EtOh. It is treated with HCl gas in bubbles for about one minute. The reaction is refluxed for 20 minutes, cooled and the solvents removed by rotary evaporation to provide 1.34 g of the title compound, a wax that is used without purification national Step 2. D-pipecolinic acid ethyl ester hydrochloride It is used in essentially the same conditions as described in Example 12, Step Al, but replacing the L-pipecolinic acid with D-pipecolinic acid, and thus the title compound is obtained. Step B. 3-Bromo-8, 11-dihydro-5H-benzo (5,6) cyclohepta (1, 2-b-pyridine (1.10 g, 3.00 mmol) and L-pipecolinic acid ethyl ester hydrochloride of Example 12 are dissolved., step Al (1.34g, 6.98 mmol), triethylamine (2.91 μL, 21 mmol) in dry CH2C12 (20 mL) and the mixture is stirred at 25 ° C under a nitrogen atmosphere for 72 hours.The reaction mixture is washed with saturated NaHC03 H20, brine and then filtered through NaS04 and evaporated to dryness The product is subjected to chromatography on a silica gel column using 1% ethyl acetate-dichloromethane as eluent to separate the two separable diastereomeric isomers (ester of Al isomer and isomer ester Bl), the less polar is known as the ester of Al isomer and the more polar is known as ester of isomer Bl. FABMS MH + = 464. Step C.

Al isomer of Al isomer The ester of Al isomer of example 12, step B (0.26g, 0.6 mmol) is dissolved in 6 ml of ethanol and 1.4 ml of 1M LiOH (1.4 mmol) is added. The reaction mixture is heated in an oil bath at a temperature of 80 ° C for 10 hours, cooled and 1.5 mL of IN HCl are added to adjust the pH to about 4.5. The solvents are then removed by evaporation and the resulting crude acid is used in the next reaction without further purification. Step D.

Al isomer acid Al isomer of Al isomer Al isomer acid of example 12, step C (of 0.26 g, 0.6 mmol of isomer A ester) is dissolved in 3 ml of DMF and NMM (184 μL, 1.6 mmol), - (aminomethyl) pyridine (74μL, 0.078g, 0.73mmol), HOBT (0.098g, 0.72mmol), DEC (0.139g, 0.72mmol) are then added. The reaction mixture is stirred at room temperature for 16 hours. DMF is removed by rotary evaporation and the resulting crude mixture is partitioned between EtOAc-NaHCO3. The organic phase is washed with , brine, and filter through Na2SO4 to provide a crude product which is purified by flash chromatography eluting with a 3% solvent system (10% NH40H-CH30H) -CH2C12 to obtain the title compound, a white FAB solid -MS MH + = 527 Inhibition of FPT = 18% at 1.1 μM EXAMPLE 13. l- (3-bromo-8-chloro-6,11-dihydro-5H-benzo (5,6) cyclohepta (l, 2-b) pyridin-ll-yl) -N- (4-pyridinylmethyl) -2S-piperidinecarboxamide-isomer Bl Amide of Bl isomer Employing the method of Example 12, steps C and D except that the ester of isomer Bl of Example 12, step B is employed instead of the ester of Al isomer, the title compound is obtained. MH + = 527 Inhibition of FPT = 21% at l.lμM Example 14. Employing the method of examples 12 and 13 except that acid ethyl ester hydrochloride is used D-pipecolinic instead of L-pipecolinic acid ethyl ester hydrochloride, the following two diasteriomers are obtained: Amide isomer A2 amide of isomer B2 MH + = 527 MH + = 527 Inhibition of FPT = 0% at l.lμM inhibition of FPT = 13% at l.lμM Example 15. Using the method of examples 12-14, except that in Example 12, step D, 3- (aminomethyl) pyridine is used in place of 4- (aminomethyl) pyridine, the following four diastereoisols being prepared.

Amide of isomer Cl amide of DI isomer MH + = 527 MH + = 527 Melting point (p.f.) = 198.5-198 ° C p.f. = 180.9- 181.5 ° C IC50 of FPT = 0.3μM IC50 of FPT = 0.16 μM Amide of C2 isomer amide of D2 isomer MH + = 527. MH + = 527 Melting point (mp) = 168.2-168.4 ° C pf = 205.5- .5-206.4 ° C Inhibition of FPT = 11% at 0.38μM inhibition of FPT = 0% at 0.38μM Example 16. l- (3 , 10-dibromo-8-chloro-6, 11-dihydro-5H-benzo (5,6) cyclohepta (1,2-b) pyridin-ll-yl) -N- (3-piperidinylmethyl) -3-piperidinecarboxamide Using the method of Example 10, procedure 1, eXcept that the compound 3, 10-dibromo-8,11-diorioro-6,11-dihicro-5H-benzo (5,6) cyclohepta (1,2-b) pyridine is substituted by 3-bromo-8, ll-dichloro-6,11-dihydro-5H-benzo (5,6) cyclohepta (1,2- b) pyridine, the title compound is obtained. FABMS MH + = 605.7 IC50 of FPT = 0.027 μM Example 17 l- (3,10-dibromo-8-chloro-6,11-dihydro-5H-benzo (5,6) cyclohepta (1,2-b) piperidin-11 -yl) -N- (3-pyridinylmethyl) -3-piperidinecarboxamide Employing the method of example 10, procedure 1, except that the compound 3,10-dibromo-8,11-dichloro-6,11-dichloro-6,11 -dihydro-5H-benzo (5,6) cyclohepta (1, 2-b) pyridine is substituted by 3-bromo-8,11-dichloro-6,11-dihydro-5H-benzo (5,6) cyclohepta ( l, 2-b) pyridine and ethyl nipecotate optically pure is used, the title compound is obtained. Optically pure ethyl norpecotate can be prepared from L-tartaric acid in accordance with (Recl.Trav Chi Chi P. 899, 1951). The separation of the two resulting isomers by HPLC chromatography is carried out on an Chiral Technlogies AD (0.46cmX25 cm) analytical chiral column using 10% isopropanol / hexane / 0.02% diethylamine at 1 ml / minute. The two compounds are eluted at 14.85 (isomer A) and 24.7 (isomer B) minutes. isomer A isomer B MH + = 605.7 MH + = 605.7 IC5 from FPT < 0.0099 μM inhibition of FPT = 3.4% at 0, lμM Example 18. l- (3-bromo-6,11-dihydro-5H-benzo (5,6) cyclohepta (1, 2-b) pyridin-ll-yl) -N- (3-pyridinylmethyl) -3-piperidineacetamide Using the method of example 10, procedure 1, except that 3-Ethylpiperidinacetate is replaced by ethylpipecotate, the title compound is obtained, FABMS (MH +) = 541.0 Inhibition of FPT = 9% at 1.1 μM Example 19, 1- (3-bromo-8-chloro-6,11-dihydro-5H-benzo (5,6) cyclohepta (1, 2-b) pyridin-ll-yl) -N- (3-pyridinyl) -3-piperidinacetamide Using the method of Example 10. Process 1, except that '3-ethylpiperidinacetate is replaced by ethylnipropeptide, and of Example 11, except that the nicotinic acid is substituted by 3-pyridylacetic acid, the title compound is obtained. FABMX (MH +) = 526.9 Inhibition of FPT = 15% at 1.1 μM Example 20. l- (3-bromo-8-chloro-6,11-dihydro-5H-benzo (5,6) cyclohepta (1, 2-b) pyridin-ll-yl) -4-piperidinecarboxylate (1 equivalent) (prepared in accordance with that described in Preparation Example 2) reacts with lN-methyl-4- (aminomethyl) -piperidine (1.3 equivalents) (prepared by reductive formation of 4-ethoxycarbonylaminomethylpyridine, followed by hydrolysis of the protecting group under standard conditions ) under conditions similar to the conditions described in Preparation Example 2 below, to provide the title compound. Example 21 l- (3-bromo-8-chloro-6,11-dihydro-5H-benzo (5,6) cyclohepta (1, 2-b) pyridin-ll-yl) -N- (4-piperidinylmethyl) -4- piperidinecarboxamide (1 equivalent) (prepared according as described in example 8, procedures 1 or 2, step B above) is reacted with 2-bromoacetamide (1.1 equivalent) and sodium carbonate in anhydrous DMF at a temperature of 25 ° C for provide the title compound. Example 22 l- (3-bromo-8-chloro-6,11-dihydro-5H-benzo (5,6) cyclohepta (1, 2-b) pyridin-ll-yl) -N- (4-piperidinylmethyl) -4- piperidinecarboxamide (i equivalent) prepared according to that described in example 8, procedures 1 or 2, step D above) is reacted with an excess of acetic anhydride in methanol at a temperature of 25 ° C for 24 hours to provide the title compound . Example 23 1- (3-bromo-8-chloro-6,11-dihydro-5H-benzo (5,6) cyclohepta (1,2- b) pyridin-ll-yl) -N- (4-piperidinylmethyl) -4- piperidinecarboxamide (1 equivalent) (prepared according to example 8, procedures 1 or 2, step B above) is reacted with chloroacetyl chloride (ll equivalent) and triethylamine (2 equivalent) in dichloromethane to give the intermediate chloroacetate. The latter reacts with an excess of dimethylamine in the presence of sodium carbonate in DMF at a temperature of 25 ° C to provide the title compound. Example 24 1- (3-bromo-8-chloro-6,11-dihydro-5H-benzo (5,6) cyclohepta (1,2-b) pyridin-ll-yl) -N- (4-piperidinylmethyl) -4- piperidinecarboxamide (1 equivalent) (prepared according to that described in Example 8, procedures 1 or 2, step B above) reacts with ethyl chloroformate (1.1 equivalent) in anhydrous dichloromethane at a temperature of 25 ° C for 24 hours to provide the title compound. Example 25 NHBOC 1- (3-bromo-8-chloro-6,11-dihydro-5H-benzo (5,6) cyclohepta (1,2-b) pyridin-ll-yl) -N- (4-piperidinylmethyl) -4- piperidinecarboxamide (1 equivalent) (prepared in accordance with that described in example 8, procedure 1 or 2, step B above) reacts with N- (tert-butoxycarbonyl) glycine (1.3 equivalent), DEC. HCl (1.3 equivalent), HOBT (1.3 equivalent) and N-methylmorpholine (1.3 equivalent) in anhydrous DMF at a temperature of 25 ° C for 24 hours to provide the intermediate N-BOC. The latter is dissolved in methanol and reacted with 10% concentrated sulfuric acid in dioxane at a temperature of 25 ° C for 2 hours to provide, after pacification and chromatography on silica gel, the title compound. Example 26 1- (3-bromo-8-chloro-6,11-dihydro-5H-benzo (5,6) cyclohepta (1,2- b) pyridin-ll-yl) -N- (4-piperidinylmethyl) -4- piperidinecarboxamide (1 equivalent) (prepared according to that described in example 8, procedures 1 or 2, step b above) in dichloromethane reacts with phenyl cyanate (2 equivalent) and disopropylethylamine at a temperature of 25 ° C for 15 minutes to provide the title compound. '4 Example 27 1- (3-bromo-8-chloro-6,11-dihydro-5H-benzo (5,6) cyclohepta (1,2-b) pyridin-ll-yl) -N- (4-piperidinylmethyl) -4- piperidinecarboxamide (1 equivalent) (prepared according to that described in example 8, procedure 1 or 2, step B above and diphenylcyancarbonimidate (1.2 equivalent) are dissolved in 2-propanol and the mixture is heated to a temperature of 80 ° C during 24 hours to provide the title compound Example 28 l- (3-bromo-8-chloro-6,11-dihydro-5H-benzo (5,6) cyclohepta (1, 2-b) pyridin-ll-yl) -N- (4-piperidinylmethyl) -4- piperidinecarboxamide (1 equivalent) (prepared according to that described in example 8, procedures 1 or 2, step B above) and diphenylsulfamoylcarbonimidate (1.2 equivalent) prepared in accordance with that described in: M Haake and B. Schu melfeder, Synthesis, 753-758 (1991) are dissolved in 2-propanol and the mixture is heated at a temperature of 80 ° C for 24 hours to provide the composed of the title. Example 29 The phenoxyimidate (1 equivalent) (prepared in accordance with that described in example 26 above) is dissolved in anhydrous THF. A dispersion of 60% sodium hydride in oil (4 equivalent) is added and the mixture is stirred at a temperature of 25 ° C for 2 hours. The mixture is diluted with dichloromethane and washed with sodium hydroxide IN. Chromatography on silica gel provides the title compound. Example 30 The phenoxyimidate (1 equivalent) (prepared according to that described in example 26 above) is dissolved in concentrated ammonium hydroxide and ammonium chloride (1 equivalent) is added. The mixture is heated in a sealed tube to a temperature of 90 ° C to provide the title compound. Example 31 The N-cyanophenoxyimidate (1 equivalent) (prepared according to that described in example 27 above) is dissolved in concentrated ammonium hydroxide and the mixture is stirred at a temperature of 25 ° C for 24 hours to provide the title compound. Example 32 > Dissolve N-sulfamoylphenoxyimidate (1 equivalent) (prepared according to that described in example 28 above) in concentrated ammonium hydroxide and the mixture is stirred at a temperature of 25 ° C for 24 hours to provide the title compound. Example 33 The phenoimidate (1 equivalent) (prepared according to that described in example 26 above) is dissolved in methanol. An aqueous solution of methoxylamine (1 equivalent) (prepared by dissolving methoxylamine hydrochloride (1 equivalent) in 50% (weight / volume) of sodium hydroxide (1 equivalent) is added and the mixture is stirred at a temperature of 25 ° C to give the title compound Example 34 Using the method of Example 14 except that 3, 10-dibromo-8,11-dichloro-6,11-dihydro-5H-benzo (5,6) cyclohepta (1) 2-b) pyridine is substituted by 3-bromo-8,11-dichloro-6,11-dihydro-5H-benzo (5,6) cyclohepta (1,2-b) pyridine, the following two compounds are obtained: Amide of C3 isomer Amide of D3 isomer MH + = 605 MH + = 605 IC50 of FPT-0.3 μM IC50 of FPT = 0.0.0042 μM Example 35 % 1- (3-bromo-8-chloro-6,11-dihydro-5H-benzo (5,6) cyclohepta (1,2- b) pyridin-ll-yl) -N- (4-piperidinyl ethyl) is added ) -4-piperidinecarboxamide (1 equivalent) (prepared according to that described in Example 8, procedures 1 or 2, step B above) and sulfonamide (10 equivalents) to water and the mixture is stirred under reflux at a temperature of 100 ° C for 43 hours to provide the compound of the title. Example 36 Scheme 78193 1- (3-bromo-8-chloro-6,1-l-dihydro-5H-benzo (5,6) cyclohepta (1,2-b) pyridin-ll-yl) -N- (4-piperidinylmethyl) -4 - piperidinecarboxamide (1 equivalent) (prepared according to that described in example 8, procedures 1 or 2 step B above) in dichloromethane reacts with dimethylsulfamoyl chloride (1.1 equivalent) in the presence of triethylamine (2 equivalents) at a temperature comprised between 0 ° C and 25 ° C to provide the title compound. Example 37 1- (3-Bromo-8-chloro-6,11-dihydro-5H-benzo (5,6) cyclohepta (1,2- b) pyridin-11-yl) -N- (4-piperidinylmethyl) -4- piperidinecarboxamide (1 equivalent) (prepared according to that described in example 8 as procedures 1 or 2, step B above) in dichloromethane reacts with chloride of methanesulfonyl (1.1 equivalents) in the presence of triethylamine (2 equivalents) at a temperature of 25 ° C to provide the title compound. EXAMPLE 38 1- (3-Bromo-8-chloro-6,11-dihydro-5H-benzo (5,6) cyclohepta (1,2-b) pyridin-1-yl) -N- (4-piperidinylmethyl) -4- piperidinecarboxamide (1 equivalent) (prepared according to that described in example 8, procedures 1 or 2, step B above) DMF reacts with dimethylfosphinic chloride (1.1 equivalents) and sodium carbonate at a temperature of 25 ° C to provide the compound of the title.

EXAMPLE 39 l- (3-Bromo-8-chloro-6,11-dihydro-5H-benzo (5,6) cyclohepta (1, 2-b) pyridin-11-yl) -N- (4-piperidinylmethyl) -4- piperidinecarboxamide (1 equivalent) (prepared from according to that described in example 8, procedures 1 or 2, step B above) DMF reacts with tetra-O-acetyl-D-glucopyranosyl bromide (1.1 equivalents) in the presence of sodium carbonate to provide the title compound. EXAMPLE 40 1- (3-Bromo-8-chloro-6,11-dihydro-5H-benzo (5,6) cyclohepta (1,2-b) pyridin-11-yl) -N- (4-piperidinylmethyl) -4- piperidinecarboxamide (1 equivalent) (prepared according to that described in example 8, procedures 1 or 2, step B above) DMF reacts with 2-chloropyridine (1.1 equivalents) in the presence of sodium carbonate to provide the title compound.

EXAMPLE 41 The benzanilide is converted to the chloroimidate (according to that described in: AC Honz and EC Wagner, Org. Syn. Coll. Vol. 4,383-386 (1963) (1.1 equivalents) and this reacts with l- (3-Bromo- 8-chloro-6, 11-dihydro-5H-benzo (5,6) cyclohepta (1, 2-b) pyridin-11-yl) -N- (4-piperidinylmethyl) -4-piperidinecarboxamide (1 equivalent) (prepared according to example 8, procedures 1 or 2, step B above) in pyridine at reflux temperature to provide the title compound.

EXAMPLE 42 Copper (I) chloride (1 equivalent) is dissolved in anhydrous acetonitrile. To this solution, a solution of l- (3-Bromo-8-chloro-6,11-dihydro-5H-benzo (5,6) cyclohepta (1,2-b) pyridin-11-yl) -N- ( 4-piperidinylmethyl) -4-piperidinecarboxamide (1 equivalent) (prepared in accordance with that described in example 8, procedures 1 or 2, step B above), 1-methylthio-l-methylamino-2-nitroethene (1 equivalent) (prepared in accordance with that described in Canadian Patent No. 1,178,289 (1984)) and triethylamine in anhydrous acetenitrile is added drop or drop for 10 minutes with stirring. The solid is removed by filtration. The volume is reduced and dichloromethane is added. The mixture is washed with aqueous sodium bicarbonate and the Dichloromethane is dried over magnesium sulfate, filtered and evaporated to dryness. The residue is purified on silica gel to provide the title compound. EXAMPLE 43. 1- (3-Bromo-8-chloro-6,11-dihydro-5H-benzo (5,6) cyclohepta (1, 2-b) pyridin-11-yl) -N- (3-pyridylmethyl) -4-piperidinacetamide.

Dissolve 3-Bromo-8,11-dichloro-6,11-dihydro-5H-benzo (5,6) cyclohepta (1, 2-b) pyridine (0.317g, 0924mmol) anhydrous THF (4.6ml). N- (3-pyridylmethyl) -4-piperidinaceta ida (prepared in accordance with that described in preparation example 7, step B) (0.2803g, 1.2mmol) and triethylamine (0.386ml, 2.77mmol) in anhydrous dichloromethane are added. (5ml) are added and the mixture is stirred at a temperature of ° C for 18 hours. The solution is diluted with dichloromethane and washed with IN NaOH, dried over magnesium sulfate, filtered and evaporated to dryness. The product is subjected to chromatography on silica gel using 4% (10% concentrated ammonium hydroxide in methanol) dichloromethane as eluent to provide the title compound (0.219g, 44%), SIMS: m / z539 (MH +), FPT INH 43% 0.22μM.

EXAMPLE 44 1- (3-Bromo-8-chloro-6,11-dihydro-5H-benzo (5,6) cyclohepta (1,2-bpyridin-1-yl) -N- (3-pyridylmethyl) -4- piperidinepropanamide Dissolve 3-Bromo-8, ll-dichloro-6, 11. Dihydro-5H-benxo (5,6) cyclohepta (1,2-b) pyridine (0.317 g, 0.924 mmol) THF (5 ml). N- (3-pyridylmethyl) -4-piperidinepropanamide (prepared in accordance with that described in Preparation Example 8, Step C) (0.2972g, 1.2mmol) and triethylamine (0.386ml, 2.77mmol) in anhydrous dichloromethane (20ml) they are added and the mixture is stirred at a temperature of 25 ° C for 20 hours. The solution is diluted with dichloromethane and washed with IN NaOH, dried over magnesium sulfate, filtered and evaporated to dryness. The product is subjected to chromatography on silica gel using 2.5% (10% concentrated ammonium hydroxide in methanol) -dichloromethane as eluent to provide the title compound (0.3022g, 59%), ESIMS: m / Z 553.2 (MH + ), FPT INH 39% 0.35μM < EXAMPLE 45. 1- (8-chloro-3, 10-dibromo-6,11-dihydro-5H-benzo (5,6) cyclohepta (1,2-b) pyridin-11-yl) -N- (3- pyridylmethyl) -4-piper idinacetamine 3, 10-Dibromo-8, ll-dichloro-6,11-dihydro-5H-benzo (5,6) cyclohepta (1,2-b) pyridine (prepared in accordance with that described in Preparation Example 6, Step F) (0.2426g, 0.575mmol) is dissolved in anhydrous THF (2.86ml). N- (3-pyridylmethyl) -4-piperidineacetamide (prepared in accordance with that described in preparative example 7, step B) (0.175g, 0.748mmol) and triethylamine (0.24ml, 1.725mmol) THF in anhydrous (5ml) and the mixture is stirred at a temperature of 25 ° C for 138 hours. The solution is evaporated to dryness and the residue dissolved in dichloromethane and washed with NaOH IN, dried over magnesium sulfate, filtered and evaporated to dryness. The product is subjected to chromatography on silica gel using 5% (10% concentrated ammonium hydroxide in methanol) -dichloromethane as eluent to provide the title compound (0.021g, 6%), ESIMS: m / z 617.2 (MH + ), FPT IC50 = 0.042μM.

EXAMPLE 46. 4-Carboxamido-l- (1- (chloro-3, 10-dibromo-6,11-dihydro-5H-benzo (5,6) cyclohepta (1, 2-b) pyridin-1-yl) - 4-piperidinacetil) piperidine L- (8-Chloro-3, 10-dibromo-6,11-dihydro-5H-benzo (5,6) cyclohepta (1,2-b) pyridin-11-yl) -4-piperidinacetic acid (0.5287) is dissolved g, lmmole) (prepared in accordance with that described in preparation example 10, step B), isonipecotamide (0.1666g, 1.3mmol), DEC.HCl (0.2492g, 1.3mmol), HOBT (1757g, 1.3mmol) and NMM (01315g, 1.3mmol) in anhydrous DMF (lOml) and the mixture is stirred at a temperature of 25 ° C under an argon atmosphere for 24 hours. The solution is evaporated to dryness and the residue dissolved in dichloromethane, washed with IN NaOH, dried over magnesium sulfate, filtered and evaporated to dryness. The product is subjected to chromatography on silica gel using 0.65% (10% concentrated ammonium hydroxide in methanol) -dichloromethane as the eluent to provide the title compound. EXAMPLE 47. 3-Carboxamide-1- (1- (8-chloro-3,10-dibromo-6,11-dihydro-5H-benzo (5,6) cyclohepta (1, 2-b) pyridin-1-yl) ) -4-piperidihacetyl) piperidine L- (8-Chloro-3, 10-dibromo-6,11-dihydro-5H-benzo (5,6) cyclohepta (1,2-b) pyridin-11-yl) -4-piperidinacetic acid (0.5287) is dissolved g, Immole) (prepared in accordance with that described in the example of proportion 10, step B) and nipecotamide (0.1666g, 1.3mmol), DEC. HCl (02492g, 1.3mmol), HOBT (0.1757g, 1.3mmol) and NMM (0.1315g), 1.3 mmol) in anhydrous DNF (lOml) and the mixture is stirred at a temperature of 25 ° C under an argon atmosphere for 24 hours. The solution is evaporated to dryness and the residue dissolved in dichloromethane, washed with IN NaOH, dried over magnesium sulfate, filtered and evaporated to dryness. The product is subjected to chromatography on silica gel using 0.75% (10% concentrated ammonium hydroxide in methanol) -dichloromethane as eluent to provide the title compound. EXAMPLE 48. 4- (1- (8-Chloro-3, 10-dibromo-6,11-dihydro-5H-benzo (5,6) cyclohepta (1, 2-b) pyridin-11-yl) -4- piperidinacetil) -1-piperazinecarboxamide . STEP A. 4- (1- (8-Chloro-3, 10-dibromo-6,11-dihydro-5H-benzo (5,6) cyclohepta (1, 2-b) pyridin-1-yl) -4- piperidinacetil) -lN-tert-butoxycarbonylpiperazine 1- (8-Chloro-3, 10-dibromo-6,11-dihydro-5H-benzo (5,6) cyclohepta (1,2-b) pyridin-11-yl) -4-piperidinacetic acid (05287g) is dissolved , lmmole) (prepared in accordance with that described in Preparation Example 10, Step B) and 1-N-tert-butoxycarbonylpiperazine (0.1667g, 1.3mmol), DEC.HCl (0.2492g, 1.3mmol), HOBT (0.1757 g, 1.3 mmol) and NMM (0.1315 g, 1.3 mmol) in anhydrous DNF (lOml) and the mixture is stirred at a temperature of 25 ° C under an argon atmosphere for 24 hours. The solution is evaporated to dryness and the residue dissolved in dichloromethane, washed with IN NaOH, dried over magnesium sulfate, filtered and evaporated to dryness. The product is subjected to chromatography on silica gel using 0.75% (10% concentrated ammonium hydroxide in methanol) -dichloromethane as eluent to provide the title compound. STEP B. l- (8-Chloro-3,10-dibromo-6,11-dihydro-5H-benzo (5,6) cyclohepta (1, 2-b) pyridin-1-yl) -4-piperidinacetyl) piperazine 4- (1- (8-Chloro-3, 10-dibromo-6,11-dihydro-5H-benzo (5,6) cyclohepta (1,2-b) pyridin-11-yl) -4-piperidinacetyl) - 1-N-tert-butoxycarbonylpiperazine (prepared according to that described in step A above) becomes. l- (1- (8-Chloro-3, 10-dibromo-6,11-dihydro-5H-benzo (5,6) cyclohepta (1,2-b) pyridin-11-yl) -4-piperidinacetyl) piperazine is essentially by the same procedure as that described in example 8, procedure 2, step B. STEP C. 4- (1- (8-Chloro-3,10-dibromo-6,11-dihydro-5H-benzo (5 , 6) cyclohepta (1, 2-b) pyridin-11-yl) -4-piperidinacetyl) -1-piperazinecarboxamide 1- (1- (8-Chloro-3,1-dibromo-6,11-dihydro-5H-benzo (5,6) cyclohepta (1,2-b) pyridin-11-yl) -4-piperidinacetyl) piperazine (prepared according to that described in step B above) is converted to 4- (1- (8-chloro-3, 10-dibromo-6,11-dihydro-5H-benzo (5,6) cyclohepta (l , 2- b) pyridin-1-yl) -4-piperidinacetyl) -l-piperazinecarboxamide essentially by means of the same procedure as that described in example 8, method 2, step C above. EXAMPLE 49. N-Cyclopropyl-1- (3,10-dibromo-8-chloro-6,11-dihydro-5H-benzo (5,6) cyclohepta (1,2-b) pyridin-11-yl) -3 - piperidincarboxamide Following the method of example 10, as procedure 1, except (a) compound 3, 10-dibromo-8, 10-dichloro-6,11-dihydro-5H-benzo (5,6) cyclohepta (1,2-b) pyridine is substituted by 3-bromo-8, 10-dichloro-6,11-dihydro-5H-benzo (5,6) cyclohepta (1,2b) pyridine in step A, and (b) cyclopropylamine is substituted by 3-aminomethylpyridine in the Step C, the title compound is obtained. FABMS (MH +) = 554. FPT IC50 = 0.58μM. EXAMPLE 50. 1- (3, 10-Dibromo-8-chloro-6,11-dihydro-5H-benzo (5,6) cyclohepta (1, 2-b) pyridin-1-yl) -N-methyl-3-piperidinecarboxamide Following the method of Example 10, Procedure 1, except that (a) compound 3, 10-dibromo-8,10-dichloro-6,11-dihydro-5H-benzo (5,6) cyclohepta (1,2-b) ) pyridine is substituted by 3-bromo-8, 10-dichloro-6,11-dihydro-5H-benzo (5,6) cyclohepta (1,2-b) pyridine in Step A, and (b) methylamine is is replaced by 3-aminomethylpyridine in Step C, the title compound is obtained. FABMS (MH +) = 528. IC 50 of FPT = 0.96 μM. Example 51. Nitrogen NI of l- (3,10-dibromo-8-chloro-6,11-dihydro-5H-benzo (5,6) cyclohepta (1, 2-b) pyridin-1-yl) -N- (3-pyridinylmethyl) -3-piperidinecarboxamide (Isomer B) Following the method of Example 10, Procedure 1, except that (a) compound 3, 10-dibromo-8, 10-dichloro-6,11-dihydro-5H-benzo (5,6) cyclohepta (1,2-b) ) pyridine is substituted by 3-bromo-8, 10-dichloro-6,11-dihydro-5H-benzo (5,6) cyclohepta (1,2-b) pyridine in Step A, and (b) 3- Aminoethyl pyridine-N-oxide is substituted by 3-aminomethylpyridine in Step C, the title compound is obtained. FABMS (MH +) = 619 .. IC 50 of FPT = 0.1 μM. Example 52. l- (3,10-dibromo-8-chloro-6,11-dihydro-5H-benzo (5,6) cyclohepta (1,2-b) pyridin-11-yl) -N- (2- (3-pyridinyl) ethyl) -3-piperidinecarboxamide Following the method of Example 10, Procedure 1, except that (a) compound 3, 10-dibromo-8, 10-dichloro-6,11-dihydro-5H-benzo (5,6) cyclohepta (1,2-b) ) pyridine is substituted by 3-bromo-8, 10-dichloro-6,11-dihydro-5H-benzo (5,6) cyclohepta (1, 2-b) pyridine in Step A, and (b) 3- Aminoethylpyridine is substituted by 3-aminomethylpyridine in Step C, the title compound is obtained. FABMS (MH +) = 617. IC 50 of FPT = 0.081 μM. Example 53. 1- (3, 10-dibromo-8-chloro-6,11-dihydro-5H-benzo (5,6) cyclohepta (1,2-b) pyridin-11-yl) -N- ((1 - ((dimethylamino) -4-piperidinyl) methyl) -3-piperidinecarboxamide Following the method of Example 10, Procedure 1, except that (a) compound 3, 10-dibromo-8, 10-dichloro-6,11-dihydro-5H-benzo (5,6) x3 Iclohepta (l, 2-b) ) pyridine is substituted by 3-bromo-8, 10-dichloro-6,11-dihydro-5H-benzo (5,6) cyclohepta (1, 2-b) pyridine in Step A, and (b) dimethylaminoacetyl-4-piperidinylmethyl-3-amine is substituted by 3-aminomethylpyridine in Step C, the title compound is obtained. FABMS (MH +) = 694. IC 50 of FPT = 0.11 μM. Example 54. l- (3, 10-dibromo-8-chloro-6,11-dihydro-5H-benzo (5,6) cyclohepta (1,2-b) pyridin-11-yl) -N- (3- (2-oxo-l-pyrrolinyl) propyl) -3-piperidinecarboxamide Following the method of Example 10, Procedure 1, except that (a) the compound 3,10-dibromo-8,10-dichloro-6,11-dihydro-5H-benzo (5,6) cyclohepta (1,2-b) ) pyridine is substituted by 3-bromo-8,10-dichloro-6,11-dihydro-5H-benzo (5,6) cyclohepta (1, 2-b) pyridine in Step A, and (b) 3- aminopropylpyrrolidonamine is substituted by 3-aminomethylpyridine in Step C, the title compound is obtained. FABMS (MH +) = 637. IC 50 of FPT = 0.1 μM. PREPARATION OF INITIAL MATERIALS Starting materials for the preparation of the compounds of the present invention are exemplified by the following preparation examples which should not be considered as limiting the scope of the presentation. The tricyclic compounds (3.0) and substituted piperidinyl compounds (7.0) employed as starting materials are known in the art and / or can be prepared using known methods such as those taught in U.S. Patent Nos. 5,089,496; 5,151,423; 4,454,143; 4,355,036; PCT / US94 / 11390 (WO95 / 10514); PCT / US94 / 11391 (WO 95/10515); PCT / US94 / 11392 (W095 / 10516); Stanley R. Sandler and Wolf Karo, Organic Functional Group Preparations, (Preparations of Organic Functional Groups), 2nd. Edition, Academic Press, Inc., San Diego, California, Volume 1-3 (1983); in J. March, Advanced Organic Chemistry, Reactions & Mechanisms, and Structure, (Advanced Organic Chemistry, Reactions and Mechanisms, and Structure), 3rd. Edition, John Wiley & Sons, New York, page 1346 et seq. (1985); in G.R. Newkome (Ed.), Pyridine and its Derivatives (Pyridine and its Derivatives), John Wiley and Sons Inc., New York, NY. , Volumes 1-5, (1984); A.J. Boulton and A. McKillop (Eds.), Comprehensive Heterocyclic Chemistry, Volume 2, part 2A, Six Membered Rings With One Nitrogen Atom (Pergamon Press, Six Members Rings with a Nitrogen Atom), Elmsford, New York, (1960-1985); and Chia-Lin J. Wang and Mark A. Wuonola, Recent Progress in the Synthesis and Reactions of Substituted Piperidines (Recent Advances in the Synthesis and Reactions of Substituted Piperidines). A Review, Organic Preparations and Procedures International Vol. 24, page 585, (1992). The initial materials may also be prepared in accordance with that indicated in copending US Patent Application Serial No. 08 / 410,187, filed March 24, 1995, in copending US Patent Application Serial No. 08 / 577,951, filed on December 22, 1995, and copending US Patent Application Serial No. 08 / 615,760, filed on March 13, 1996; the presentations are incorporated here by reference. Alternative mechanical paths and analogous structures within the scope of the present invention may be apparent to those skilled in the art. For example, piperidinyl compounds of the formula (7.0) can be prepared, where T = -CO- or -CR30R31- by initially preparing a pyridine compound substituted with the required portion 2-, 3-, or 4 - (CH2) nCR30R31Z or - (CH2) nCOZ, together with any optional portion -R5, -R6, -R7 and / or -R8, in accordance with that described in the aforementioned references. The pyridine compounds substituted in 2-, 3-, or 4- can subsequently be reduced using procedures conventional reduction agents such as, for example, catalytic hydrogenation, to provide the desired piperidinyl compound (7.0). One skilled in the art will note that in cases where the portions R5, -R6, -R7, -R8 and / or Z also contain reducible groups, it may be useful to employ alternative methods. The sulfonylpiperidinyl compounds of the formula (7.0), where T = -S02-, can be prepared by reacting the 2-, 3- or 4-hydroxy-N-blocked piperidine with a suitable chlorinating agent such as, for example, chloride of thionyl to obtain the piperidine 2-, 3- or 4-chloro-N-blocked, using N-blocking groups such as benzyloxycarbonyl or tert-butoxycarbonyl. The 2-, 3-, or 4-chloro-N-blocked piperidine can then be reacted with sodium disulfite to obtain the sodium salt of N-blocked piperidine of 2-, 3- or 4-sulfonic acid. This salt then reacts with an appropriate chlorinating agent such as, for example, phosphorus pentachloride or phosphorus oxychloride to obtain the 2-, 3- or 4-sulfonylchloride blocked with N-piperidine. This sulfonyl chloride then reacts with the corresponding agent containing the desired Z group (ie, amines, alkylating agents and the like) to obtain the sulfonylpiperidine (7.0).

Sulfoxypiperidine where T = -SO- (provided that Z is not -NR40R42) can be prepared by reaction of the 2-, 3-, or 4-hydroxy-N-blocked piperidine with a suitable chlorinating agent such as, for example, chloride of thionyl to obtain the 2-, 3-, or 4-chloro-N-blocked piperidine, using N-blocking groups such as benzyloxycarbonyl or tert-butoxycarbonyl. The 2-, 3-, or 4-chloro-N-blocked piperidine can then be reacted with the corresponding substituted sulfide (i.e., aryl sulfide, alkyl sulfides and the like) to obtain the 2-, 3-, or 4- Sulfur-N-blocked piperidine. This compound can then be reacted with an oxidation agent such as meta-chloroperbenzoic acid to obtain the desired sulfoxypiperidine (7.0). EXAMPLE OF PREPARATION 1. 4-Piperidinyl-N- (4-pyridinyl) carboxamide Step A: l-N- (tert-Butoxycarbonyl-4-piperidinecarboxylic acid or l-N- (tert-butoxycarbonyl) isonipecotic acid Isonipecotic acid (5g, 1 equivalent) is dissolved in water (50 ml) and a solution of di-tert-butyldicarbonate is added (8.62g, 1.02 equivalents) in THF (70 ml) with stirring. The mixture is stirred at a temperature of 80 ° C for 2 hours and then evaporated to dryness. The residue is partitioned between dichloromethane and brine and the dichloromethane layer is dried over magnesium sulfate, filtered and evaporated to dryness. The product is subjected to chromatography on a silica gel column (30 X 5 cm) using 15% (concentrated ammonium hydroxide in methanol) -dichloromethane as eluent to provide the title compound (4.3l09g, 49% yield) , CIMS: m / z 230 (MH +). Step B: 1-N- (tert-Butoxycarbonyl) -4-piperidinyl-N- (4-pyridinyl) carboxamide L-N- (tert-Butoxycarbonyl) 4-piperidinecarboxylic acid (1,218, 1 equivalent) is dissolved (prepared from in accordance with that described in Step A above), DEC (1.0184g, 1 equivalent), HOBT (0.7179g, 1 equivalent) and N-methylmorpholine (0.5841 ml, 1 equivalent) in anhydrous DMF (30 ml) and the mixture is stirred under an argon atmosphere at a temperature of 25 ° C for 19 hours. The solution is evaporated to dryness. The residue is taken up in dichloromethane and washed with water. The dichloromethane layer is dried over magnesium sulfate, filtered and evaporated to dryness. The product is subjected to chromatography on a column of silica gel (60 X 2.5 cm), using 5% (10% concentrated ammonium hydroxide in methanol) -dichloromethane as eluent to provide the title compound (0.8142 g; 50%), CIMS: m / z 306 (MH +). Step C: 4-piperidinyl-N- (4-pyridinyl) carboxamide 1-N- (tert-Butoxycarbonyl) -4-piperidinyl-N- (4-pyridyl) carboxamide (1: 1 equivalent) is dissolved in concentrated 10% (volume / volume) sulfuric acid in dioxane (24.36 ml) and the The mixture is stirred at a temperature of 25 ° C for 0.5 hours. The mixture is poured into water (150 ml) and neutralized with an ion exchange resin Amberlite IRA401S (OH) (300 ml). The resin is eluted with water (1500 ml) and the eluent evaporated to provide the title compound (0.4258 g, 63% yield), CIMS: m / z 206 (MH +). PREPARATION EXAMPLE 2 1- (3-bromo-8-chloro-6,11-dihydro-5H-benzo (5,6) cyclohepta (1, 2-b) pyridin-11-yl) 4-piperidinecarboxylate Method 1, Step A: 1- (3-bromo-8-chloro-6,11-dihydro-5H-benzo (5,6) cyclohepta (1, 2-b) pyridin-1-yl) -4-piperidinecarboxylate ethyl 3-Bromo-8,11-dichloro-6,11-dihydro-5H-benzo (5,6) cyclohepta (1, 2-b) pyridine (lg; 1 equivalent) and ethyl isonipecotate (2.3735 ml) are dissolved ( 5 equivalents) in dry THF (20 ml) and the mixture is stirred at a temperature of 25 ° C under an argon atmosphere for 19 hours. The solution is evaporated to dryness and the residue is taken up in dichloromethane and washed with 1N sodium hydroxide. The dichloromethane layer is dried over magnesium sulfate, filtered and evaporated to dryness. The product is subjected to chromatography on a column of silica gel (30X5 cm) using 0.75% (10% concentrated ammonium hydroxide in methanol) -dichloromethane as eluent to provide the title compound (1.5134g, 100% yield) , CIMS: m / z 463.15 (MH +). Step B: l- (3-bromo-8-chloro-6,11-dihydro-5H-benzo (5,6) cyclohepta (1, 2-b) pyridin-11-yl) -4-piperidinecarboxylate Dissolve l- (3-bromo-8-chloro-6,11-dihydro-5H-benzo (5,6) cyclohepta (1, 2-b) pyridin-1-yl) -4-piperidinecarboxylic acid ethyl ester (0.250g 1 equivalent) (prepared according to that described in step A above), in ethanol (3 ml) and dichloromethane (3 ml) and add l.OM lithium hydroxide in water (1.3044 ml, 2.42 equivalents). The mixture is stirred at a temperature of 50 ° C for 5 hours. 1.0 N hydrochloric acid (1.5169 ml) (2.81 equivalents) is added and the solution is evaporated to dryness after stirring for 5 minutes to provide the title compound which is employed without further purification. Method 2: 1- (3-bromo-8-chloro-6,11-dihydro-5H-benzo (5,6) cyclohepta (1,2-b) pyridin-11-IL) -4-piperidinecarboxylate 3-Bromo-8,11-dichloro-6,11-dihydro-5H-benzoyl (5,6) cyclohepta (1,2-b) pyridine (prepared in accordance with that described in the example of Preparation 40, Step 1) is dissolved. B in IN0291K) (0.5g, 1 equivalent), isonipecotic acid (0.3978g, 2 equivalents) and 4-N-methylmorpholine (0.847 ml, 5 equivalents) in anhydrous DMF (9.6ml) and the mixture is heated to a temperature of 80 ° C for 16.5 hours. The solution is evaporated to dryness and the product is subjected to chromatography on a column of silica gel (60X2.5 cm) using 10% ethyl acetate in hexane, followed by 1% (10% concentrated ammonium hydroxide in methanol. ) -dichloromethane as eluent to provide the title compound (0.2426g, 36% yield), CIMS: mz 435.1 (MH +). EXAMPLE OF PREPARATION 3 4- (aminomethyl) -1-N- (tert-butoxycarbonyl) piperidine Ref: J.D. Prugh, L.A. Birchenough and M.S. Egbertson, Synthetic Communications, (Synthetic Communications), 22 (16), 2357-2360 (1992). Step A: 4- (Benzylidinaminomethyl) piperidine Dissolve 4-aminomethylpiperidine (11.4 g) (1 equivalent) in anhydrous toluene (125 ml) and add benzaldehyde (10.6 g) (1 equivalent). The mixture is heated to a temperature of 120 ° C under reflux for 4 hours, using a Dean-Stark trap to remove the water. The crude solution of the title compound is used directly in Step B below. Step B: l-N- (tert-Butoxycarbonyl) -4- (benzylidinaminomethyl) piperidine 4- (Benzylidenaminomethyl) piperidine in toluene (from Step A above) is treated with di-tert-butyldicarbonate (24g) (1.1 equivalents) in portions in 0.5 hours. The mixture is stirred at a temperature of 25 ° C for 69 hours. The solution is evaporated to dryness to provide the title compound which is used directly in Step C below. Step C: 4- (aminomethyl) -l-N- (tert-butoxycarbonyl) piperidine LN- (tert-butoxycarbonyl) -4- (benzylidenaminomethyl) piperidine (prepared according to that described in Step B above) is dissolved in l.ON aqueous potassium hydrogen sulfate (220 ml) and the mixture is stirred at 25 °. C for 4 hours. The solution is extracted with ether (3 × 200 ml) and the ether is discarded. The aqueous layer is adjusted to a pH of 12.5 using 50% aqueous sodium hydroxide and the solution is then saturated with solid sodium chloride and extracted with dichloromethane. The dichloromethane layer is dried over magnesium sulfate, filtered and evaporated to dryness. The product is subjected to chromatography on a column of silica gel (60 X 5 cm) using 1% increment to 7% (10% concentrated ammonium hydroxide in methanol) -dichloromethane as eluent to provide the title (9.82g; yield: 46%), one oil, CIMS: m / z 215 (MH +). EXAMPLE OF PREPARATION 4: l-N-benzyl-4- (aminomethyl) piperidine Step A: l-N-benzyl-4-piperidinecarboxamide 4-piperidinecarboxamide (5 g, 1 equivalent) and triethylamine (16.3 ml) (3 equivalents) are dissolved in anhydrous dichloromethane (30 ml) and anhydrous DMF (80 ml). A solution of benzyl bromide (4.55 ml) (0.98 equivalents) in anhydrous dichloromethane (10 ml) is added dropwise over 10 minutes and the mixture is stirred at a temperature of 25 ° C for 22 hours. The mixture is filtered and the filtrate is evaporated to dryness. The product is subjected to chromatography on a column of silica gel (60X5cm) using dichloromethane (1 liter) and then 5% (10% concentrated ammonium hydroxide in methanol) -dichloromethane as eluent to provide the title compound (6.15g, 72% yield ), CIMS: m / z 219.05 (MH +). Step B: l-N-Benzyl-4- (aminomethyl) piperidine L-N-benzyl-4-piperidinecarboxamide (1: 1 equivalent) (prepared according to that described in Step A above) is dissolved in anhydrous THF (25 ml). Lithium aluminum hydride (0.2173g) (1.25 equivalents) in anhydrous THF (5.726ml) is added dropwise in 0.5 hour and the mixture is heated under reflux in a nitrogen atmosphere for 20 hours. The mixture is cooled and diluted with dichloromethane (750ml) and washed with 1N sodium hydroxide. The dichloromethane layer is dried over magnesium sulfate, filtered and evaporated to dryness. The product is subjected to chromatography on a column of silica gel (60X2.5 cm) and plearing 2% (10% concentrated ammonium hydroxide in methanol) -dichloromethane as eluent to provide the title compound (0.5237g: 56% yield), FABMS: m / z 205.4 (MH +). PREPARATION EXAMPLE 5 Step A: 4- (N-benzyloxycarbonylaminomethyl) piperidine 4-aminomethylpiperidine (1: 1 equivalent) and DMAP (0.054 g, 0.05 equivalent) are dissolved in anhydrous dichloromethane (40 ml). N-Benzyloxycarbonylimidazole (1.7709 g, 1 equivalent) is added (prepared according to that described in: SK Sharma, MJ Miller and SM Payne, J. Med. Chem., 32, 357-367 (1989)) and the mixture is stirred at a temperature of 25 ° C for 23 hours. The solution is diluted with dichloromethane and washed with l.ON sodium hydroxide. The dichloromethane layer is dried over magnesium sulfate, filtered and evaporated to dryness. The product is subjected to chromatography on a column of silica gel (60X2.5 cm) using 3% increasing to 7% (10% concentrated ammonium hydroxide in methanol) -dichloromethane as eluent to provide the title compound (1.07 l9g; yield 49%), FABMS: m / z 249.3 (MH +).

Step B: l-N- (benzyloxycarbonyl) -4- (N- (tert-butoxycarbonyl) aminomethyl) piperidine 4- (N-benzyloxycarbonylaminomethyl) piperidine (0.6814 g, 1 equivalent) (prepared as described in Step A above) is dissolved in anhydrous toluene (5 ml) and di-tert-butyldicarbonate (0.599 g).; 1 equivalent) in anhydrous toluene (5 ml) is added dropwise. The mixture is stirred at 0 ° C for 2 hours and then at a temperature of 25 ° C for 20 hours. The solution is evaporated to dryness and the residue is taken up in dichloromethane and washed with l.ON sodium hydroxide. The dichloromethane layer is dried over magnesium sulfate, filtered and evaporated to dryness. The product is subjected to chromatography on a silica gel column (60X2.5 cm) using 0.5% (10% concentrated ammonium hydroxide in methanol) -dichloromethane as eluent to provide the title compound (0.9314g; %), FABMS: m / z 349.3 (MH +). Step C: 4- (tert-butoxycarbonylamino) methyl) piperidine LN- (benzyloxycarbonyl) -4- ((tert-butoxycarbonylamino) methyl) -piperidine (0.4 g) (1 equivalent) (prepared according to that described in Step B above) is dissolved in methanol (I6 ml) and added to the mixture. % Pd-C (0.0638g). The mixture is hydrogenated at 30 psi at a temperature of 25 ° C for 17 hours. The catalyst is removed by filtration through Celite which is washed with methanol. The combined filtrates are evaporated to dryness. The residue is taken up in dichloromethane and washed with l.ON sodium hydroxide. The dichloromethane layer is dried over magnesium sulfate, filtered and evaporated to dryness. The product is chromatographed on a column of silica gel (45X2.5cm) using 2% increment to 7% (10% concentrated ammonium hydroxide in methanol) -dichloromethane as eluent to provide the title compound (0.2001g; 81%), FABMS: m / z 215.4 (MH +). EXAMPLE OF PREPARATION 6 Step A Combine 40.0 g (0.124 mol) of the initial ketone and 200 mL of H2SO4 and cool to 0 ° C. Slowly add 13.78 g (0.136 mol) of KN03 over a period of 1.5 hours, then warm to room temperature and stir overnight. Treat the reaction using substantially the same procedure as that described for Preparation Example 4, Step A. Chromatograph (silica gel, 20%, 30%, 40%, 50% EtOAc / hexane, and then 100% EtOAc to provide 28 g of the 9-nitro product, together with a minor amount of 7-nitro product and 19 g of a mixture of the 7-nitro and 9-nitro compounds. 28 g (76.2 mmol) of the 9-nitro product from Step A, 400 mL of 85% EtOH / water, 3.8 g (34.3 mmol) of CaC12 and 38.28 g (0.685 mol) of Fe are reacted using substantially the same procedure as the one described in Preparation Example 4, Step C, to provide the 24 g of the product Step C Combine 13 g (38.5 mmol) of the product from Step B, 140 mL of HOAc and slowly add a solution of 2.95 mL (57.8 mmol) of Br2 in 10 mL of HOAc in a period of 20 minutes. Shake the reaction mixture at room temperature, then concentrate in vacuo until a residue is obtained. Add CH2C12 and water, then adjust to a pH of 8-9 with 50% NaOH (aqueous). Wash the organic phase with water, then with brine, and dry in Na 2 SO 4. Concentrate in vacuum to provide 11.3 g of product. Step D Cool 100 ml of concentrated HCl (aqueous) at 0 ° C, then add 5.61 g (81.4 mmol) of NaN02 and stir for 10 minutes. Slowly add (in portions) 11.3 g (27.1 mmol) of the product from Step C and stir the mixture at 0 ° -3 ° C for 2.25 hours. Slowly add (dropwise) 180 mL of 50% H3P02 (aqueous) and allow the mixture to stand at 0 ° C overnight. Slowly add (dropwise) 150 mL of 50% NaOH in 30 minutes, to adjust the pH to 9, then extract with CH2C12. Wash the extract with water, then with brine and dry in Na 2 SO 4. Concentrate in vacuo to a residue and chromatograph (silica gel, 2% EtOAc / CH2Cl2) to provide 8.6 g of the product. Step E Combine 8.6 g (21.4 mmol) of the product from Step D and 300 mL of MeOH and cool to 0 ° -2 ° C. Add 1.21 g (32.1 mmol) of NaBH4 and stir the mixture at about 0 ° C for 1 hour. Add an additional 0.121 g (3.21 mmol) of NaBH4, stir for 2 hours at 0 ° C, and then let stand overnight at 0 ° C. Concentrate in vacuum until a residue is obtained, then divide the residue between CH2C12 and water. Separate the organic phase and Concentrate in vacuum (50 ° C) to provide 8.2 g of the product. Step F.3, 10-dibromo-8, ll-dichloro-6,11-dihydro-5H-benzo (5,6) cyclohepta (1,2-b) pyridine Combine 8.2 g (20.3 mmol) of the product from Step E and 160 mL of CH2C12, cool to 0 ° C, then slowly add (dropwise) 14.8 mL (203 mmol) of S0C12 in a period of 30 minutes. Heat the mixture to room temperature and stir for 4.5 hours, then concentrate in vacuo to provide the title compound. EXAMPLE OF PREPARATION 7. N- (3-pyridylmethyl) -4-piperidineacetamide Step A. 1-tert-Butoxycarbonyl-N- (3-pyridylmethyl) -4-piperidineacetamide L-Tert-butoxycarbonyl-4-piperidineacetic acid (5g, 20.55 mmol) (prepared according to that described in Preparation Example 17, Step A in IN0291K), 3-aminomethylpyridine (2.72g, 26.7 mmol), DEC is dissolved. HCl (5.12 g, 26.7 mmol), HOBT (3.61 g, 26.7 mmol) and NMM (2.94 mL, 26.7 mmol) in anhydrous DMF (100 ml) and the mixture is stirred under an argon atmosphere at a temperature of 25 ° C. for 22 hours. The solution is evaporated to dryness and the residue is dissolved in dichloromethane, washed with IN NaOH, dried over magnesium sulfate, filtered and evaporated to dryness. The residue is subjected to chromatography on silica gel using 2% (10% concentrated ammonium hydroxide in methanol) -dichloromethane as eluent to provide the title compound (6.05g, 77%) ESIMS: m / z 334.1 (MH +) . Step B. N- (3-pyridylmethyl) -4-piperidineacetamide L-tert-butoxycarbonyl-N- (3-pyridimethyl) -4-piperidinaceta ida (5.59g, 16.76 mmol) was dissolved in methanol (100 ml) and 10% concentrated sulfuric acid in dioxane (volume / volume) was added ( 250 ml). The mixture is stirred at 25 ° C for 2 hours and neutralized with a Bio Rad AG-1X8 (OH ~) resin. The resin is washed with methanol and the eluate is evaporated to dryness. The residue is subjected to chromatography on silica gel using 5% -20% -30% (10% concentrated ammonium hydroxide in methanol) -dichloromethane as eluent to provide 3.64 g (93% yield) of the title compound: ESIMS: m / z 234.1 (MH +). EXAMPLE OF PREPARATION 8. N- (3-pyridylmethyl) -4-piperidinepropanamide Step A. 4-piperidinpropionic acid * c, 3- (4-pyridyl) acrylic acid (2 g, 13.4 mmol) is dissolved in water (70 ml) and concentrated hydrochloric acid (lml). 10% Pd-C (1.5 spatulas) is added and the mixture is hydrogenated at a temperature of 25 ° C to 55 psi for 72 hours. The mixture is filtered through Celite (MR) and then passed on a resin bed Bio Rad AG 1-X8 (OH ~). The resin is washed with water and the combined eluates are evaporated to dryness to provide the title compound which is used in Step B without further purification. Step B. l-Tert-butoxycarbonyl-4-piperidinpropionic acid 4-piperidinpropionic acid (13.4 mmol) (prepared according to that described in Step A above), di-tert-butyldicarbonate (3.22 g, 14.75 mmol) and sodium hydroxide (0.5364 g, 13.4 mmol) in THF are dissolved. water (1: 1) (40ml) and the mixture is stirred at 25 ° C for 18 hours. The mixture is passed in Bio Rad 50WX4 (H +) resin (15ml bed) and the resin is washed in THF-water. The combined eluates are evaporated to dryness and then subjected to azeotropy with THF to provide the title compound (2.72g, 79%), FABMS: m / z 258.1 (MH +).

Step C. N- (3-pyridylmethyl) -l-tert-butoxycarbonyl-4-piperidinepropanamide L-tert-butoxycarbonyl-4-piperidinpropionic acid (2 g, 7.77 mmol), 3- (aminomethyl) pyridine (1029 ml, 10.1 mmol), DEC. HCl (1.937g, 10.1 mmol), HOBT (1365g, 10.1 mmol) and NMM (1111 mL, 10.1 mmol) in anhydrous DMF (25 mL) and the mixture is stirred under an argon atmosphere at a temperature of 25 ° C during 20 hours. The solution is evaporated to dryness and the residue is taken up in dichloromethane, washed with 0.3 N NaOH, dried over magnesium sulfate, filtered and evaporated to dryness. The residue is subjected to silica gel chromatography using 1.5% -2.5% (10% concentrated ammonium hydroxide in methanol) -dichloromethane as eluent to provide the title compound (2.555g, 95%), ESIMS: m / z 348.1 (MH +). Step D. N- (3-pyridylmethyl) -4-piperidinepropanamide Dissolve N- (3-pyridylmethyl) -l-tert-butoxycarbonyl-4-piperidinepropanamide (2222g, 6.4 mmol) in methanol (38.15ml) and 10% concentrated H2SO4 in dioxane (volume / volume) (95.38ml). add and the mixture is stirred under an argon atmosphere at a temperature of 25 ° C for 1.5 hours. The volume is halved and the mixture is basified to a pH of 12 with 50% aqueous NaOH and extracted with dichloromethane. The latter is dried in magnesium sulfate, filtered and evaporated to dryness. The residue is chromatographed on silica gel using 10% (10% concentrated ammonium hydroxide in methanol) -dichloromethane as eluent to provide the title compound (0.9586g, 61%), CIMS: EXAMPLE OF PREPARATION 9. Ethyl 4-piperidinacetate Step A. Ethyl l-tert-butoxycarboni-1-4-piperidinacetate L-tert-butoxycarbonyl-4-piperdinacetic acid (lg, 4.1 mmol) (prepared in accordance with that described in Preparation Example 17, Step C in IN0291K), ethanol (200 proof) (0.284g, 0.362ml, 6.2 mmole), DEC.HCl (1.18 g, 6.2 mmole), HOBT (0.8331 g, 6.2 mmole) and NMM (0.624 g, 0.678 ml, 6.2 mmole). In anhydrous DMF (30 ml) and the mixture is stirred at a temperature of 25 ° C under an argon atmosphere for 24 hours. The solution is evaporated to dryness and the residue dissolved in dichloromethane, washed with saturated aqueous NaHCO3, water, dried over magnesium sulfate, filtered and evaporated to dryness. The residue is subjected to chromatography on silica gel using 0.5% (10% concentrated ammonium hydroxide in methanol) -dichloromethane as the eluent to provide the title compound (0.682g, 61%), ESIMS: m / Z 272.0 ( MH +).

Step B. Ethyl 4-piperidinacetate Dissolve ethyl l-tert-butoxycarbonyl-4-piperidineacetate (0.6 g, 2.2 mmol) in ethanol (30 ml) and 10% concentrated H2SO4 in dioxane (volume / volume) (30 ml) is added and the mixture is stirred at a temperature of 25 ° C for 2 hours. The mixture is passed on a bed of Bio Rad AG1-X8 resin (OH ") and the resin is then eluted with ethanol.The combined eluates are evaporated to dryness and the residue is chromatographed on silica gel using 1% (hydroxide) of 10% concentrated ammonium in ethanol) -dichloromethane as eluent to provide the title compound EXAMPLE OF PREPARATION 10 L- (8-chloro-3,10-dibromo-6,11-dihydro-5H-benzo (5, 6) cyclohepta (1, 2-b) pyridin-1-yl) -4-piperidine acetic Step A. 1- (8-Chloro-3, 10-dibromo-6,11-dihydro-5H-benzo (5,6) cyclohepta (1, 2-b) pyridin-1-yl) -4-ethylpiperidineacetate 3,10-Dibromo-8,11-dichloro-6,11-dihydro-5H-benzo (5,6) cyclohepta (1, 2-b) pyridine (prepared in accordance with that described in Preparation Example 6) is dissolved. , Step F) (0.486g, 1.15mmol) in anhydrous THF (5ml). Ethyl 4-piperidinacetate (prepared according to that described in Preparation Example 9, Step B) (0.6241g, 2.3 mmol) and triethylamine (0.321ml, 2.3 mmol) in anhydrous THF (5ml) are added and the The mixture is stirred at a temperature of 25 ° C for 24 hours. The solution is evaporated to dryness and the residue dissolved in dichloromethane and washed with NaOH. IN, dried (MgSO4), filtered and evaporated to dryness. The product is subjected to chromatography on silica gel using 5% (hydroxide of % concentrated ammonium in methanol) -dichloromethane as eluent to provide the title compound. Step B. Acid 1- (8-chloro-3, 10-dibromo-6,11-dihydro-5H-benzo (5,6) cyclohepta (1,2-b) pyridin-11-yl) -4-piperidineacetic acid Dissolve l- (8-chloro-3, 10-dibromo-6,11-dihydro-5H-benzo (5,6) cyclohepta (1,2-b) pyridin-11-yl) -4-ethylpiperidinacetate ( 0.3g, 0.5mmol) (prepared according to that described in Step A above) in ethanol (4ml) and dichloromethane (4ml) and 1M lithium hydroxide in water (1.21mmol) is added. The mixture is stirred at 50 ° C for 5 hours. 1 N Hydrochloric acid (1.21 mmol) is added and the solution is evaporated to dryness to provide the title compound which is employed without further purification. TESTS 1. Enzyme assays in vitro: IC50 were determined from FPT (inhibition of farnesylproteintransferase, in an in vitro enzymatic assay) by the methods presented in WO / 10515 or WO 95/10516. The data shows that the compounds of the invention are inhibitors of Ras-CVLS farnesylation by partially purified rat brain farnesylproteintransferase (FPT). The data also shows that there are compounds of the invention that can be considered as potent inhibitors (IC50 <10 μM) of Ras-CVLS farnesylation by FPT of partially purified rat brain. Under the test protocols used, there are certain compounds within the scope of the present invention that do not show activity. It is believed that these compounds would present an activity under a different test protocol. 2. Cell-based assay. The Cos IC 50 values refer to the inhibition of the Ras processing COS cells activity, they are determined by the methods presented in WO / 10515 or WO 95/10516. For the preparation of pharmaceutical compositions from the compounds described in this invention, the pharmaceutically acceptable, inert carriers can be either solid or liquid form. Solid form preparations include powders, tablets, dispersible granules, capsules, and suppositories. The powders and tablets may consist of about 5 to about 70% active ingredient. Suitable solid carriers are known in the art, such as for example magnesium carbonate, magnesium stearate, talc, sugar, lactose.

Tablets, powders, capsules can be employed as solid dosage forms suitable for oral administration. To prepare suppositories, a wax with a low melting point, such as a mixture of fatty acid glycerides or cocoa butter, is first melted and then the active ingredient is dispersed homogeneously, for example by stirring. The melted homogeneous mixture is then emptied into molds of suitable size, allowed to cool and solidified in this way. Liquid form preparations include solutions, suspensions and emulsions. As an example, water or water-propylene glycol solutions for parenteral injection may be mentioned. 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 an inert compressed gas. Also included are solid form preparations whose purpose is to be converted, shortly before use, into liquid form preparations for either oral or parenteral administration. Such liquid forms include solutions, suspensions and emulsions.

The compounds of the present invention can also be administered transdermally. The transdermal compositions may take the form of creams, lotions, aerosols and / or emulsions and may be included in a matrix or reserve type transdermal patch conventional in the art for this purpose. Preferably, the compound is administered orally. Preferably, the pharmaceutical preparation is in unit dosage form. In this form, the preparation is subdivided into unit doses containing appropriate quantities of the active component, for example, the effective amount to achieve the desired purpose. The amount of active compound in a unit dose of preparation can be varied or adjusted from about 0.1 mg to 1000 mg, more preferably from about 1 mg to 300 mg, depending on the particular application. The actual dosage used may vary according to the requirements of the patient and the severity of the condition to be treated. The determination of an appropriate dosage for a particular situation is within the scope of the art. Generally, treatment is initiated with lower dosages that are less than the optimum dose of the compound. Then, the dosage is increased by small increments until the optimum effect is reached under the circumstances. For convenience, the daily dosage Total can be divided and administered in portions during the day, if desired. The amount and frequency of administration of the compounds of the present invention and the pharmaceutically acceptable salts thereof are regulated in accordance with the physician's criteria considering factors such as the age, condition and size of the patient as well as the severity of the symptoms that They are being treated. A typical recommended dosage regimen is oral administration of 10 mg to 2000 mg / day, preferably 10 to 1000 mg / day, in two to four divided doses to block tumor growth. The compounds are non-toxic when administered within this dosage range. Following are examples of pharmaceutical dosage forms containing a compound of the invention. The scope of the invention in terms of its pharmaceutical composition aspect is not limited by the examples offered. Examples of pharmaceutical dosage forms EXAMPLE A - Tablets Manufacturing method Mix items Number 1 and 2 in a suitable mixer for 10-15 minutes. Form the mixture into granules with the No. 3 element. Grind the wet granules through a coarse sieve (eg, 1/4", 0.63 cm) if necessary, dry the wet granules, sieve the dry granules, if necessary. and mix it with element No. 4, and mix for 10-15 minutes Add element No. 5 and mix for 1-3 minutes Compress the mixture to an appropriate size and weight on a tabletting machine EXAMPLE B - Cá sulas

Claims (20)

1. Manufacturing method Mix items Number 1, 2 and 3 in a suitable mixer for 10-15 minutes. Add item No. 4 and mix for 1-3 minutes. Fill the mixture in a suitable two-piece hard gelatin capsule in a machine to form suitable capsules. While the present invention has been described in relation to the specific embodiments raised above, many alternatives, modifications and variations thereto will be apparent to those with certain skill in the art. All these alternatives, modifications and variations fall within the spirit and scope of the present invention. CLAIMS 1. A compound of the formula: Either a pharmaceutically acceptable salt or solvate thereof, wherein: one of a, b, c, and d represent N or RN9 where R9 is 0", -CH3 or - (CH2) NC02H where n is from 1 to 3, and the remaining groups a, b, c, and d represent CR1 or CR2, or each of a, b, c, and d are independently selected from CR1 or CR2, each R1 and R2 is independently selected from H, halo , -CF3, -OR10, -COR10, -SR10, -S (0) tRll (where t is 0, how well 2), -SCH, -N (R10) 2, -NR10R11, -N02, -OC (O R10, -CO2R10, -0C02R11, -CN, -NHC (0) R10, -NHSO2R10, -CONHR10, -C0NHCH2CH20H, -NR10COOR11, -SR11C (0) 0R11, -SR11N (R75) 2 wherein each R75 is independently selected between H and -C (0) 0R11, benzotriazol-1-yloxy, tetrazol-5-ylthio, or substituted tetrazole-5-ylthio, alkynyl, alkenyl, or alkyl, said alkyl or alkenyl group is optionally substituted with halo, - OR10 or -CO2R10; R3 and R4 are the same or different and each independently represents H, any of the substituents Rl and R2, or R3 and R4, taken together, represent a saturated or unsaturated C5-C7 ring fused to the benzene ring (Ring III); R5, R6, R7 and R8, each independently, represents H, -CF3, -COR10, alkyl or aryl, said alkyl or aryl is optionally substituted with -OR10, -SR10, -S (0) Trll, -NRlOCOORll, -N (R10) 2, -N02, CORIO, -OCOR10, -OC02R11, -COR2R10, OPO3R10, or R5 is combined with R6 to represent = 0 or = S and / or R7 is combined with R8 for represent = 0 or = S; RIO represents H, alkyl, cycloalkyl, cycloalkylalkyl, heteroaryl, aryl, aralkyl, or -NR 40 R 42, where R 40 and R 42 independently represent H, aryl, alkyl, heteroaryl, heteroarylalkyl, heterocycloalkyl, heterocycloalkylalkyl, heteroalkyl, cycloalkyl, cycloalkylalkyl, alkenyl and alkynyl; Rll represents alkyl or aryl; the dotted line between carbon atoms 5 and 6 represents an optional triple bond, such that when a double bond is present, A and B independently represent -N02, -RIO, halo, -OR11, -0C02R11, or - OC (O) R10, and when no double bond is present between the carbon atoms 5 and 6, A and B each independently represent H2, - (ORll) 2, H and halo, dihalo, alkyl and H, ( alkyl) 2, -H, and -OC (O) R 10, H and -OR 10, oxy, aryl and H, = NOR 10 or -0- (CH 2) p-0- where p is 2, 3 or 4; N is 0 (zero), 1, 2, 3, 4, 5 or 6; T is -C0-; -S0-; S02-; or -CR30R31- where R30 and R31 independently represent H, alkyl, aryl, aralkyl, heteroalkyl, heteroaryl, heteroarylalkyl, heterocycloalkyl, or heterocycloalkylalkyl; and Z represents alkyl, aryl, heteroalkyl, heteroaryl, heteroarylalkyl, heterocycloalkyl, heterocycloalkylalkyl, -OR40, -SR40, -CR40R42, -NR40R42, H where n, R40 and R42 are defined as before, m is 2, 3, 4, 5, 6, 7 or 8; q is 0 (zero) 1 or 2; and R 14 represents H, (C 1 -C 6) alkyl, aralkyl, heteroaryl, acyl, carboxamido, carboxamidoalkyl, cyano, alkoxycarbonyl, aralkyloxycarbonyl, D- and L-amino acid covalently linked through the carboxyl, imido, imidamid, sulfamoyl, sulfonyl, dialkylphosphinyl group , N-glycosyl, Cfi 6Hp5 -C (NHCH3) = CHNO, provided that when T is -SO-, Z is not -NR40R42.
2. 2. The compound of claim 1 wherein a is N; b, c and d are carbon; A and B each represent H2 and the optional double bond is absent.
3. 3. The compound of claim 2 wherein R1 and R4 are H and R2 and R3 are halo selected from chlorine and bromine; or R1 is H and R2, R3 and R4 are halo selected from chlorine and bromine.
4. 4. The compound of claim 3 wherein R2 and R3 are halo in the 3-position and in the 8-position in the ring structure; or R2, R3 and R4 are in the position 3, 8 and 10 in the ring structure.
5. 5. The compound of claim 4 wherein R2 is Br and R3 is Cl in the 3-position and in the 8-position in the structure of ring; or R2 is Br, R3 is Cl and R4 is Br in the position 3, 8 and 10 in the ring structure.
6. 6. The compound of claim 5 wherein each of R5, R6, R7 and R8 is H.
7. The compound of claim 6 wherein the -CH2) n-T-Z portion is attached in the 2, 3 or 4 position in the piperidinyl ring.
8. 8. The compound of claim 7 wherein the -CH2) n-T-Z portion is attached in the 2 or 3 position in the piperidinyl ring.
9. 9. The compound of claim 8 wherein n is zero, 1 or 2; T is -CO- and Z is -NR40R42 where R40 and R42 independently represent H, aryl, alkyl, aralkyl, heteroaryl, heteroarylalkyl, heterocycloalkyl, heterocycloalkylalkyl, heteroalkyl, cycloalkyl or cycloalkylalkyl; or else Z is where R40 is defined in accordance with the above, M is 2, 3 or 4; Q is 0 (zero), 1 or 2; and R14 represents H, (Cl-C6) alkyl, aralkyl, heteroaryl, acyl, carboxamido, carboxamidoalkyl, cyano, alkoxycarbonyl, aralkyloxycarbonyl, imido, imidamido, sulfamoyl, sulfonyl, dialkylphosphinyl, N-glycosyl or -C (NHCH3) = CHN02 .
10. 10. The compound of claim 9 wherein n is zero; Z is -NR40R42 where R40 represents H and R42 represents heteroaryl.
11. 11. The compound of claim 10 wherein R40 is H and R42 is 3-pyridylmethyl.
12. 12. The compound of claim 9 selected from any of the title compounds of examples 1-54.
13. 13. The compound of claim 12 selected from and D3 isomer amide or a pharmaceutically acceptable salt thereof.
14. 14. The compound of claim 13 which is
15. 15. A pharmaceutical composition for inhibiting abnormal cell growth comprising an effective amount of the compound of claim 1 in combination with a pharmaceutically acceptable carrier.
16. 16. A method for inhibiting abnormal cell growth comprising administering an effective amount of a compound of claim 1.
17. 17. The method of claim 16 wherein the inhibited cells are tumor cells expressing an activated ras oncogene.
18. 18. The method of claim 16 wherein the inhibited cells are pancreatic tumor cells, lung cancer cells, myeloid leukemia tumor cells, thyroid follicular tumor cells, myelodysplastic tumor cells, carcinoma tumor cells epidermal, bladder carcinoma tumor cells or colon tumor cells. The method of claim 16 wherein the inhibition of abnormal cell growth occurs by the inhibition of ras farnesylproteintransferase. The method of claim 16 wherein the inhibition is from tumor cells where the Ras protein is activated as a result of the oncogenic mutation in genes other than the Ras gene.