MXPA99001110A - Novel tricyclic n-cyanoimines useful as inhibitors of farnesyl-protein transferase - Google Patents

Abstract

Novel tricyclic N-cyanoimine compounds and 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 N-cyanoimines compound to a biological system. In particular, the method inhibits the abnormal growth of cells in mammals such as a human.

Description

NEW N-CYANOIMINS TR1C1CL1CAS USEFUL AS 1NHIBIDORFS DF TRANSFERASE PROTEIN FARNESILO BACKGROUND Patent application WO 95/00497 published January 5, 1995 under the Patent Cooperation Treaty (PCT) discloses compounds that inhibit the enzyme, farnesyl protein transferase (FTase) and farnesylation of the Ras oncogenic protein. Oncogenes frequently encode the protein components of signal transduction pathways, which lead to the stimulation of cell development and mitogenesis. The expression of oncogenes in cultured cells leads to cell transformation, characterized by the ability of cells to grow on soft agar and the development of cells in the form of dense foci that lack the contact inhibition exhibited by non-transformed cells. The mutation and / or overexpression of certain oncogenes is frequently associated with human cancer. To acquire transformation potential, the precursor of the Ras' oncoprotein must be subjected to farnesylation of the cysteine residue located in a carboxyl-terminal tetrapeptide. The inhibitors of the enzyme that catalyze this modification, farnesium protein transferase, have therefore been suggested as anti-cancer agents for tumors in which Ras contributes to the transformation. The mutated oncogenic forms of Ras are frequently found in many human cancers most notably in more than 50% of pancreatic and colon carcinomas (Kohl et al, Science, Vol. 260, 1834 to 1837, 1993). In view of the current interest in farnesyl protein transferase inhibitors, a valued contribution to art would consist of compounds - Additional useful for the inhibition of farnesyl protein transferase. Said contribution is provided by this invention. SUMMARY OF THE INVENTION The inhibition of farnesyl protein transferase by tricyclic compounds according to this invention has not been previously mentioned. Therefore, this invention provides a method to inhibit farnesyl protein transferase using the tricyclic compounds of this invention, which: (i) potentially inhibit famesyl protein transferase, but not geranyl geranyl protein transferase I, in vitro: (ii) block the phenotypic change induced by a form of transforming Ras which is an acceptor farnesílo but not by a form of transforming Ras manipulated by engineering to be a geranil geranil acceptor; (iii) they block the intracellular process of Ras which is a farnesyl acceptor, but not of Ras engineered to be a geranyl geranyl acceptor; and (iv) they block the abnormal development of cells in cultures induced by Trans transformant. Several compounds of this invention have been shown to have anti-tumor activity in animal models. This invention provides a method for inhibiting the abnormal development of cells, including transformed cells, by administering an effective amount of a compound according to this invention. Abnormal cell development refers to the development of cells independently of normal regulatory mechanisms (eg, loss of contact inhibition). This includes the abnormal development of: (1) tumor cells (tumors) that express an activated Ras oncogene; (2) tumor cells in which the Ras protein is activated as a result of the oncogenic mutation in another gene; and (3) benign and malignant cells of other proliferative diseases in which aberrant Ras activation occurs.

- The compounds that are useful in the claimed methods are represented by Formula 1.0: or a pharmaceutically acceptable salt or solvate thereof, wherein: one of a, b, c and d represents N or NR9 where R9 is O-, -CH3 or - (CH2) nC02H where n is 1 to 3, and groups a, b, c and d remnants represent CR1 or CR2; or each of a, b, c, and d are independently selected from CR1 or from CR2; each R1 and each R2 is independently selected from H, halo, -CF3, -OR10 (for example -OCH3), -COR10, -SR10 (for example -SCH3 and -SCH2C6H5), -S (O) tR11 (where t is 0, 1 or 2 for example -SOCH3 and -S02CH3), -SCN, -N (R10) 2, -NR10R11, -NO2, -OC (O) R10, -C02R10, -CN, -NHC (0) R10, -NHS02R10, -CONHR10, -CONHCH2CH2OH, -NR10COOR11, -SR 1C (O) OR11 (eg, -SCH2C02CH3), -SR11N (R75) 2 wherein each R75 is independently selected from H and -C (O) OR11 ( for example -S (CH2) 2NHC (0) 0-t-butyl and -S (CH2) 2NH2), benzotriazol-1-yloxy, tetrazol-5-ylthio, or tetrazol-5 -thio substituted (for example tetrazole 5- alkyl-substituted ilthio such as 1-methyl-tetrazol-5-thio), alkynyl, alkenyl or alkyl, said alkyl or alkenyl group being optionally substituted with halo, -OR10 or -COzR; 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 represent H, CF3, -COR10, alkyl or aryl, said alkyl or aryl being optionally substituted with -OR10, -SR10, -S (O) tR11, -NR10COOR11, -N (R10 ) 2, -NO2, -COR10, -OCOR10, -OCO2R11, -CO2R10, OPO3R10 or one of R5, R6, R7 and R8, can be taken in combination with R40 as defined below to represent - (CH2) r -where r is 2 to 4 which can be substituted with lower alkyl, lower alkoxy, -CF3 or aryl, or R5 is combined with R6 to represent = O or = S and / or R7 is combined with R8 to represent = O or = S; R10 and R12 independently represent H, alkyl, cycloalkyl, cycloalkylalkyl, heteroaryl, aryl, aralkyl or -NR40R42 where R40 and R42 independently represent H, aryl, alkyl, aralkyl, heteroaryl, heteroarylalkyl, heterocycloalkyl, heterocycloalkylalkyl, heteroalkyl, cycloalkyl, cycloalkylalkyl, alkenyl and alkynyl; R11 represents alkyl or aryl; X represents N, CH or C, so that when X is N or CH, there is a simple bond to carbon 11 represented by the entire line; or when X is C, there is a double bond to carbon 11 represented by the whole line and dotted lines; the dotted line between carbons 5 and 6 represents an optional double bond, so that when a double bond is present, A and B independently represent -N02, - R10, halo, -OR11, -OC02R11 or -OC (0) R1 °, and when no double bond is present between carbon atoms 5 and 6, A and B independently each represent H2, - (OR11) 2, H and halo, dihalo, alkyl and H, (alkyl) 2, -H and -OC (O) R 10, H and -OR 10, oxy, aryl and H, = ÑOR 10 or -O- (CH 2) p-0 where p is 2, 3 or 4; and Z represents alkyl, aryl, aralkyl, heteroalkyl, heteroaryl, heteroarylalkyl, heterocycloalkyl ,. heterocycloalkylalkyl, -OR40, -SR40, -CR40R42 or -NR 0R42 where R40 and R42 are as defined above. Preferably in compound (1.0), there is a single bond at carbon atom 11, X is carbon, positions 3, 8 and 10 are substituted in the ring, preferably with halo; and Z is -NHR40, preferably where R40 is heteroarylalkyl, more preferably N-oxide of 3 or 4-methyl pyridyl. In another embodiment, the present invention is directed to a pharmaceutical composition for inhibiting the abnormal development of cells, comprising an effective amount of the compound (1.0) in combination with a pharmaceutically acceptable carrier. In another embodiment, the present invention is directed to a method for inhibiting the abnormal development of cells, including transformed cells, which comprises administering an effective amount of the compound (1.0) to a mammal (e.g., a human) in need of said treatment. Abnormal development of cells refers to a development of cells independent of normal regulatory mechanisms (for example loss of inhibition by contact). This includes the abnormal development of: (1) tumor cells (tumors) that express an activated Ras oncogene; (2) tumor cells in which the Ras protein is activated as a result of the oncogenic mutation in another gene; and (3) benign and malignant cells of other proliferative diseases in which aberrant Ras activation occurs, and (4) benign or malignant cells that are activated by mechanisms other than Ras protein. Without any desire to limit ourselves to theories, we believe that these compounds can work either through the inhibition of the G protein function, such as Ras p21, by blocking the protein G isoprenylation, and thus turning them useful for the treatment of proliferative diseases such as the development of tumors and cancer, or through the inhibition of ras farnesyl protein transferase, making them useful for their anti-proliferative activity against the Ras transformed cells. The cells that must be inhibited may be tumor cells expressing an activated Ras oncogene. For example, types of cells that can be inhibited include pancreatic tumor cells, lung cancer cells, myeloid leukemia tumor cells, thyroid follicular tumor cells, myelodysplastic tumor cells, epidermal carcinoma tumor cells, bladder carcinoma tumors, or colon tumor cells. Also, the inhibition of the abnormal development of cells by treatment with the compound (1.0) can be by inhibition of rasnesyl protein transferase Ras. The inhibition may be of tumor cells where the Ras protein is activated as a result of the oncogenic mutation in genes other than the Ras gene. This invention also provides a method for inhibiting tumor development by administering an effective amount of the compound (1.0) to a mammal (e.g., human being) in need of such treatment. In particular, this invention provides a method for inhibiting the development of tumors expressing an activated Ras oncogene, by administering an effective amount of the previously described compounds. Examples of tumors that can be inhibited include, but are not limited to, lung cancer (for example lung adenocarcinoma), pancreatic cancers (for example pancreatic carcinoma such as, for example, exocrine pancreatic carcinoma), colon cancers (for example colorectal carcinomas, such as for example colon adenocarcinoma and colon adenoma), myeloid leukemias (e.g., acute myelogenous leukemia (AML), follicular thyroid cancer, myelodysplastic syndrome (MDS), bladder carcinoma and epidermal carcinoma.) It is believed that this invention also provides a method for inhibiting proliferative diseases, both benign and malignant, in which Ras proteins are aberrantly activated as a result of oncogenic mutation in other genes - ie, the Ras gene itself is not activated by mutation to an oncogenic form - said inhibition being carried out by administering an effective amount of the carbonyl, piperazinyl and piperidinyl compounds (1.0) described here) up to mammal (for example what a human being) that needs such treatment. For example, benign proliferative disorder termed neurofibromatosis, or those tumors in which Ras is activated due to mutation or overexpression of tyrosine kinase oncogenes (eg neu, src, abl, Ick, and fyn), can inhibited by the piperazinyl and piperidinyl carbonyl compounds (1.0) described herein. In another embodiment, the present invention is directed to a method for inhibiting farnesyl protein transferase and farnesylation of the Ras oncogenic protein by administering an effective amount of the compound (1.0) to mammals, especially humans. The administration of the compounds of this invention to patients, to inhibit famesyl protein transferase, is useful for the treatment of the cancers described above. DETAILED DESCRIPTION OF THE INVENTION As used herein, the following terms are used in accordance with the following definitions unless otherwise indicated: M + - represents the molecular ion of the molecule in the mass spectrum; MH + represents the molecular ion plus hydrogen of the molecule in the mass spectrum; -. Bu - represents butyl; Et - represents ethyl; Me - represents methyl; Ph - represents phenyl; benzotriazol - 1 -iloxy represents 1- methyl-tetrazol-5 -thio represents N-N N N i CH. alkyl - (including the alkyl, alkoxy, alkylamino and dialkylamino) - represents straight and branched carbon chains and contains from one to twenty carbon atoms, preferably one to six carbon atoms, for example methyl, ethyl, propyl, iso propyl, n-butyl, t-butyl, n -pentyl, isopentyl, hexyl and the like; wherein said alkyl 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 (= O), phenoxy , -OCF3, heterocycloalkyl, -S02NH2, NHS02R10, -S02R10, -SOR10, -SR10, -NHS02, -N02, -CONR10 or -COOR10; alkoxy - an alkyl portion of one to 20 carbon atoms covalently attached to 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 one, "two, three or more of the following: halo, alkyl, aryl, alkoxy, amino, alkylamino, cyano, -CF3, dialkylamino, hydroxy, oxy, phenoxy, -OCF3 , heterocycloalkyl, -SO2NH2, -NHSO2R10, -SO2NHR10, -SO2R10, -SOR10, -SR10, -NHS02, -NO2, -CONR10, -NCOR10 or -COOR10; alkenyl- represents straight and branched carbon chains having at least a carbon-to-carbon double bond and containing from 2 to 12 carbon atoms, preferably from 2 to 6 carbon atoms and even more preferably from 3 to 6 carbon atoms, wherein said aikenyl 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, -S02R10, -SOR10, -SR10, -NHS02- -N02, -CONR10, -NCOR10 or -COOR10: alkynyl- represents straight and branched carbon chains having at least one triple bond of carbon to carbon and which they contain 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, -NHS02R:. -S02NHR 'c. -SOGR 0, -SOR10, -SR10, -NHS02- -N02, -CONR10, -NCOR10 or -COOR10; 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, cycloalkyl, heteroaryl or heterocycloalkyl rings: and wherein any of the available carbon and nitrogen atoms substitutable in said aryl group and / or said fused ring (s) are optionally and independently substituted with one, three more than three haloes, halo, alkyl, apho, alkoxy, amino, alkylamino, cyano, -CF3, dialkylamino, hydroxy, oxy, phenoxy, -OCF3, heterocycloalkyl, -S02NH2, -NHS02R10, -S02NHR1 °, -S02R1 °, -SOR10, -SR10, -NHSO2- -NO2, -CONR10, -NCOR10 or -COOR10; aralkyl - represents an alkyl group, as defined above, in which one or more nitrogen atoms of the alkyl portion have been substituted with one or more aryl groups; wherein said aralkyl 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, -SG2NHR1C -S02R C -SOR10. -SR1 -NHS02- -N02, -CONR10, -NCOR10 or -COOR 'Representative arayauiio groups include benzyl and diphenylmethyl cycloaiauyl-represents branched saturated branched carbocyclic rings or branched nc's of from 3 to 20 carbon atoms, preferably 3 to 7 atoms of carbon wherein cycloalkyl group can be optionally and independently suppressed with one two three or more of the following halo, alkyl alkoxy amino alkylamino cyanoCF2, dialkylamino hydroxy oxy phenoxy -OCF :. heterocycloalauic -S02NH2, -NHS02R10 -S02NHR1C -S02R10. -S O "/" -SF -KHSC - - \ 'C_ -CONR': - COF > ': G -COOR *:. cycloalkylalkyl - represents an alkyl group, as defined above, wherein one or more hydrogen atoms of the alkyl portion have been substituted with one or more cycloalkyl groups; where said group - Cycloalkylalkyl 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, -S02R10. -SOR10. -SR10, -NHSO2- -NO2. -CONR10 '-NCOR10 or -COO ^ 10 naio represents iguor, cioro, oromo and iodine; heteroalkyl - represents straight and branched carbon chains containing from one to twenty carbon atoms, preferably one to six carbon atoms interrupted by 1 to 3 heteroatoms selected from -O- -SR- and -N- where any of the atoms of available nitrogen and carbon substitutable in said heteroalkyl chain may be optionally and independently substituted with one, two, three or more of the following: halo, C, C6 alkyl, aryl, cyano hydroxy alkoxy oxy, phenoxy, CF3 OCF3, amino, alkylamino, dialkylamino, heterocycloalkyl, -S02NH2, -NHS02R10, -S02NHR1 °, -S02R10, -SOR10, -SR10, -NHS02- -N02, -CONR10, -NCOR10 or -COOR10; heteroaryl - represents cyclic groups that have at least one -? e.erG3.ornc seieccioiaac ae CS \ interrupting dicno 's neteroatomois and .B esruc.u'E ae - atí'C ca' ocicncc \ tenienac a sufficient captiaac pi electrons pi delocalised to provide aromatic character containing said aromatic neterocyclic groups aesae 2 to 14 carbon atoms where said neteroaplo group may be optionally fused with one or more cycloalauyl aplo rings. heterocarilc heterocycloalauyl and where there is one of the atomoe de caroonc c ae nifogenc substitutable disDonibles de dichc group 'eie oc'.i "\ c cicric. &amp"... fused" into this optionally and independently replaced with one, two, three or more of the following: halo, C6 alkyl, aryl, cyano hydroxy alkoxy oxy, phenoxy, CF3 -OCF3, amino, - alkylamino, dialkylamino, heterocicloaiquilo, -SO2NH2, -NHSO2R10, -SO2NHR10, -S02R10, -SOR10, -SR10, -NHS02- -N02, -CONR10, -NCOR10 or -COOR 10; halo, C, -. C6, ariio, cyano hydroxy alkoxy alkenyloxy, phenoxy, CF3 OCF3, amino, alkylamino, dialkylamino, heterocycloalkyl, -S02NH2, -NHS02R1 °, -S02NHR10, -SO2R10 '-SOR10, -SR10 or - NHS02- -N02, -CONR10, -NCOR10 or -COOR10. Representative heteroaryl groups may include, for example, furanyl, imidazolyl, pyrimidinyl, triazolyl, 2-, 3- or 4-pyridyl or 2-, 3- or 4- pyridyl N-oxide where the pyridyl N-oxide may be represented as : heteroarylalkyl - represents an alkyl group, as defined above, wherein one or more hydrogen atoms have been replaced with one or more heteroaryl groups wherein said heteroarylalkyl group may be optionally and independently substituted with one. two or more of the following alkyl halo aplo alkoxy. aminoalkylaminc cyanoCF-dialkylamino, hydroxy, oxy, phenoxy, -OCF3. heterocycloalkyl, -S02NH2. -NHS02R10, -SO2NHR1 c. -S02R 'c, -S0R1 C, -SR10. -NHS02- -N02, -CONR10, -NCOR10 or -. COOR1"as exemplified by 2-, 3- or 4- pipdilmetilo or N-oxide of 2-, 3- or 4-pipdilmetilo heterocycloalkyl -. Represents a carbocyclic ring saturated branched or non-branched chain containing 3 to 15 carbon atoms, preferably 4 to 6 carbon atoms, whose carbocyclic ring is interrupted by 1 to 3 heteroatoms selected from -O-, -S- and -N-, where optionally, said ring may contain one or two unsaturated bonds that do not impart character - - aromatic to the ring; and wherein any of the available nitrogen and carbon atoms substitutable 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. dialauylamino. hydroxy, oxy, phenoxy, -OCF3 ^ ethercycloalkyl-SO: H: -NHS02R10. -S02NHR1 ° -S02R10. -SOR10, -SR10. -NHS02, -N02, -CONR11 ', -NCORlv or -COOR10. Representative heterocycloalkyl groups can include 2 - or 3 - tetrahydrofuranyl, 2 - or 3 -tetrahidrotienilo, 1 -, 2 -, 3 - or 4 - piperidinyl, 2 - or 3 - pyrrolidinyl, 1 -, 2 - or 3-pyrrolidinyl, 1 - 2 - or 3-pipericinyl, 2 - or 4-dioxanyl, morpholinyl, wherein R1 was defined above and t is 0, 1 or 2. heterocycloalkylalkyl - represents an alkyl group, as defined above where one or more hydrogen atoms have been replaced by one or more heterocycloalkyl groups: where optionally said ring can? "Tene 'unc: cos e-.acee | r * .u sa?" AAOE aue nc t¡D3ier ca "acte?' Aromat ring cc \ aonce d > O cho DC neierocicloalquilalauuo may be optionally and independently substituted? with one, two, three or more of the following: halo, alkyl ame aicoxi aiqunamino aminc, cyano, -CF3, diaiquiiamino, hydroxy, phenoxy oxy -OCF3 heterocycloalkyl, -S02NH2, NHSO2R10.SO2NHR10 -S02R10, S0R1C -SR1 C -NHSO: -NO: -CONR10 -NCOR10 or -COOR10 The following solvents and reagents are mentioned aaui with the indicated abbreviations: tetrahydrofuran (THF); Ethanoi (EtOH); methanol (MeOH), acetic acid (HOAc or AcOH); ethyl acetate (EtOAc); N, N-dimethylformamide (DMF); trifluoroacetic acid (TFA); trifluoroacetic anhydride (TFAA); 1-hydroxybenzotriazole (HOBT); m-chloroperbenzoic acid (MCPBA); triethylamine (Et3N); diethyl ether (Et20); ethyl chloroformate (CIC02Et); and 1- (3-dimethylaminopropyl) -3-ethyl carbodiimide hydrochloride (DEC). The reference to the position of the substituents R1, R2, R3 and R4 is based on the numbered structure of the ring: Some compounds of the invention may exist in different stereoisomeric forms (e.g., enantiomers and diastereisomers). The invention contemplates all said stereoisomers in both pure form and in mixture, including racemic mixtures. For example, the carbon atom in the C-11 position can have the stereo configuration S or R. Some tricyclic compounds will be acidic in nature, for example those compounds that possess a hydroxyl carboxylic or phenolic group. These compounds can form pharmaceutically acceptable salts. Examples of such salts may include sodium, potassium, calcium, aluminum, gold and silver salts. Also contemplated are salts formed with pharmaceutically acceptable amines such as ammonia, alkyl amines, hydroxy alkyl amines, N-methyl glucamine and the like. Certain basic tricyclic compounds can also form pharmaceutically acceptable salts, for example the acid addition salts. For example, pyrido nitrogen atoms can form salts with strong acids, while compounds having basic substituents such as amino groups also form salts with weaker acids. Examples of acids suitable for the formation of salts are hydrochloric, sulfuric, phosphoric acid, - acetic, citric, oxalic, malonic salicylic, malic, fumaric, succinic, ascorbic, maleic, methanesulfonic and other mineral and carboxylic acids which are well known to those skilled in the art. The salts are prepared by contacting the free base form with a sufficient amount of the desired acid to produce a salt in the conventional manner. The free base forms can be regenerated by treating the salt with an appropriate dilute aqueous base solution such as dilute aqueous NaOH, potassium carbonate, ammonia and sodium bicarbonate. The free base forms differ from their respective salt forms in terms of certain physical properties, such as solubility in polar solvents, but the basic salts and acids are otherwise equivalent to their respective base forms. All of said acidic and basic salts are considered pharmaceutically acceptable salts within the scope of the present invention and all acidic and basic salts are considered equivalent to the free forms of the corresponding compounds for the purposes of the invention. invention The compounds of the invention can be prepared by the methods described in the following examples, and by the methods described in WO 95/10516 published April 20, 1995 - see, for example, the methods for preparing the compounds of Formula 400.00 On page 57 on lines 7 to 16 of WO 95/10516 a method for introducing a substitute is described. at the C-3 position of Ring I of pyridine of Formula 1.0 by nitration of a compound of Formula 415.00. The nitro group can then be reduced to the corresponding amine using the described reagents or Zn powder and either CuCl 2 or CuBr 2 in aqueous EtOH. The compounds of the present invention can be prepared according to the following Scheme I: 15 20 25 Scheme (1.1) (1.3) where Z1 represents alkyl, aryl, aralkyl, heteroalkyl, heteroaryl, heteroarylalkyl, heterocycloalkyl, heterocycloalkylalkyl and -CR40R42; the dotted line represents a single or double bond; and a, b, c, d, A, B, R 1, R 2, R, R, R 5, R 6, R 7, R 8, R 11, R 40 and R 2 are as defined above. With reference to Scheme I, the compounds of the formula (1.3) can be prepared by the reaction of the compounds of the formula (1.1), preferably those in which R11 is alkyl such as methyl, with alcohol (R40OH) of the formula (2.1) in the presence of an appropriate base, and an optional non-protic solvent, in amounts and under conditions that are effective to provide the compounds (1.3). Appropriate bases include organic bases such as pyridine and triethylamine; or inorganic bases of alkali and alkaline earth metals including carbonates such as sodium, lithium, potassium and cesium carbonates, hydroxides such as sodium and potassium hydroxides; hydrides such as sodium or potassium hydride; and sodium t-butoxide, preferably sodium hydride. Suitable non-protic solvents include ethers, dimethylformamide (DMF), dimethyl sulfoxide (DMSO), tetrahydrofuran (THF), dimethoxyethane (DME) and mixtures thereof, preferably DMF. Alternatively, the reaction can be carried out clearly, using an excess of the alcohol. The amounts of alcohol (2.1) can range from about 1 to about 10 moles per mole of compound (1.1). The temperatures may be between 0 ° to 100 ° C, or at reflux of the reaction mixture. The compounds of the formula (1.5) can be prepared by reacting the compounds of the formula (1.1) with thiol (R40SH) of the formula (1.1) in the presence of an appropriate base, and an optional non-protic solvent to give the compounds ( 1.5), using the reaction conditions described to prepare the compounds (1.3), above.

The compounds of formula (1.7) can be prepared by reacting the compounds of the formula (2.0) with N-cyanoimidate of formula (2.7) in the presence of an optional non-protic solvent to give the compounds (1.7), using the conditions of reaction described to prepare the compounds (1.3) above. The compounds of the present invention can be prepared according to the following scheme II: Scheme II C = ^ NR40R 2 (1.9) NHR40R42 (2.6) - where a, b, c, d, A, B, R1, R2, R3, R4, R5, R6, R7, R8, R11, R40 and R42 are as defined above; and the dotted line represents a single or double link. With reference to Scheme I !, the compounds of the formula (1.1) can be prepared by reacting the compounds of the formula (2.0) with N-cyanodithioiminocarbonate (NCN = C- (SR11) 2 of formula (2.9) in the presence of an appropriate protic or non-protic solvent, in amounts and under conditions which are effective to give the compounds (1.1). Suitable protic solvents include C,. ^ alkanols, such as methanol, ethanol, propanol, hexanol, octanol, decanol and the like. Suitable non-protic solvents have been described above The amounts of N-cyanodithioiminocarbonate (2.9) can range from about 1 to about 10 moles per mole of compound (2.0) .The temperatures can range from 0 ° to 100 ° C. or to reflux of the reaction mixture The compounds of formula (1.9) can be prepared by reacting the compounds of formula (1.1) with amine (NHR40R42) of formula (2.6) with an optional base. and / or an optional protic or aprotic solvent such as those described in Jo above. In a first process, the compound (1.1) is reacted with amine (2.6) clearly, at temperatures between about 50 ° C to 80 ° C. In a second procedure, the compound (1.1) is reacted with approximately equimolar amounts of amine (2.6) in the presence of a base such as sodium hydride and an aprotic solvent such as DMSO or DMF. In a third procedure the compound (1.1) is reacted with an excess of amine (2.6) in a protic solvent such as ethanol. In a fourth procedure, the compound (1.1) is reacted with amine (2.6) clearly, using catalytic amounts of base, such as sodium hydride. In a fifth process, the compound (1.1) is reacted with - - more than two equivalents of amine (2.6) in an aprotic solvent such as DMF at a temperature of about 75 ° C. Except where indicated, temperatures may range from 0 ° to 100 ° C, or reflux of the mixture of reaction and the amounts of amine (2.6) can be comprised between 1 to about 10 moles per mole of compound (1, 1). The compounds of formula (2.4) can be prepared by reaction of the compounds of formula (2.0) with isothiocyanate (R 0NCS) of formula (2.2) in the presence of an appropriate non-protic solvent in amounts and under conditions which are effective to give the compounds (2.4). Suitable non-protic solvents have been described above. The amounts of isothiocyanate (2.2) may be comprised between about 1 to about 10 moles per mole of compound (2.0). Temperatures can vary from 0 ° to 100 ° C, or to reflux of the reaction mixture. The compounds of formula (1.8) can be prepared by reacting the compounds of formula (2.4) with lead cyanamine (PbNCN) in the presence of an appropriate non-protic solvent in amounts and under conditions which are effective to give the compounds (2.4) . Suitable non-protic solvents have been described above, preferably DMF. The amounts of lead cyanamine can be from about 1 to about 10 moles per mole of compound (2.4). The temperatures can range from 0 ° to 100 ° C at reflux of the reaction mixture. The compound of formula 1.0 can be isolated from the reaction mixture using conventional procedures, such as, for example, extraction of the reaction mixture from water with organic solvents, evaporation of the organic solvents, followed by chromatography on a silica or other appropriate chromatographic medium.

- The compounds of the present invention and the preparation starting materials thereof are exemplified by the following examples, which are not to be considered as limiting the scope of the description.

Example 1. 4- (3-Bromo-8-chloro-5,6-dihydro-11 H -benzo [5.6] cyclohepta [1,2-b] pyridin-1-lidene) -B-cyano-1- methyl piperidinecarboximidethioate.

Dissolve 4- (3-bromo-8-chloro-5,6-dihydro-1 1 H -benzo [5.6] cyclohepta [1,2- b] pyridin-1-ylidene) -1-piperidine (40 g., 0.1 mol) in 600 ml of absolute ethanol. Add dimethyl N-cyanodithioiminocarbonate (16.5 g, 0.11 mol) and reflux under a dry nitrogen atmosphere for two hours. Evaporate to dryness to obtain a brown foamy solid. Chromatograph on silica gel using 25% to 50% ethyl acetate / hexanes as eluent to obtain 50.8 g of the title compound. FABMS M + 1 = 489.

Example 2. 4 - [[[4- (4- (3-bromo-8-chloro-5,6-dihydro-11 H-benzo [5,6] cyclohepta [1,2-b] pyridin-1-1- ethyl) -1-piperidinyl] (cyanoimino) methyl] amino] -1-piperidinecarboxylate - Dissolve 4- (3-bromo-8-chloro-5,6-dihydro-11 H -benzo [5.6] cyclohepta [1,2- b] pyridin-11-ylidene) -B-cyano-1-piperidinecarboximidothioate methyl ( 0.1 g, 0.20 mmol) in 1 ml of ethyl r-amine-1-piperidinecarboxylate. Stir at 100 ° C for 18 hours. Allow to cool to room temperature. Add the mixture to water and filter the resulting solids. Dissolve the solid in methylene chloride and chromatograph on silica gel using 5% methanol / methylene chloride as eluent to obtain 0.15 g. (34%) of the title product. FABMS M + 1 = 613.

EXAMPLE 3 N I-oxide 4 - [[4- (3-bromo-8-chloro-5,6-dihydro-11 H -benzo [5,6] cyclohepta [1,2-b] pyridin-11-ylidene] ) -1-piperidinyl] (4-pyridinylamino) methylene] cyanamide.

Dissolve 4- (3-bromo-8-chloro-5,6-dihydro-1 1 H -benzo [5.6] cyclohepta [1,2-b] pyridin-1-ylidene) -B-cyano-1-piperidinecarboximidothioate methy (0.3 g, 0.60 mmol) and 4-aminopyridyl N-oxide (0.07 g, 060 mmol) in 5 ml of dimethyl sulfoxide under a dry nitrogen atmosphere at room temperature. Add sodium hydride as a 60% dispersion of oil (24 mg, 0.6 mmol) in portions while stirring. After stirring for 2 hours, add the reaction mixture to the brine and extract with 20 ml of methylene chloride three times. Combine the extracts, dry over magnesium sulfate, filter and evaporate until an oil is obtained. Chromatograph the oil on a column of silica gel using 2% to 10% methanol in methylene chloride to obtain 0.15 g (47%) of the title compound as a solid. FABMS M + 1 = 549.1 Example 4. [[4- (3-bromo-8-chloro-5,6-dihydro-11 H -benzo [5,6] cyclohepta [1,2- b] pyridin-11-ylidene) -1-piperidinyl] [cyclopropylamino] methylen] cyanamide (4-pyridinylamino) methylene] cyanamide.

Dissolve 4- (3-bromo-8-cioro-5,6-dihydro-11 H -benzo [5.6] cyclohepta [1,2-b] pyridin-11-yldene) -Bc-1-piperidinecarboxy Methyl midothioate (0.15 g, 0.31 mmol) in 3 ml of absolute ethanol. Add cyclopropylamine (0.3 mL, 4.30 mmol) and stir at room temperature. After 24 hours, add the reaction mixture to brine and extract with 20 ml of methylene chloride three times. Combine the extracts, dry over magnesium sulfate, filter and evaporate to an oil. Chromatograph the oil on a column of silica gel using 2% to 10% methanol in methylene chloride to obtain 0.133 g (86%) of the title compound as a solid. FABMS M + 1 = 498.

Example 5. [[4- (3-Bromo-8-chloro-5,6-dihydro-11 H -benzo [5.6] cyclohepta [1,2- b] pyridin-11-ylidene) -1-piperidinyl [[( 4-methoxyphenyl) methi] amino] methylene] cyanamide.

Dissolve 4- (3-bromo-8-chloro-5,6-dihydro-11 H -benzo [5.6] cyclohepta [1,2- b] pyridin-11-ylidene) -B-cyano-1-piperidinecarboximidothioate (0, 5 g, 1.02 mmol) in 5 ml of DMF. Add 4-methoxybenzylamine (0.4 mL, 2.9 mmol) and stir at 75 ° C for 24 hours. Add to brine and extract with ethyl acetate three times. Dry the extract over magnesium sulfate, filter, and evaporate to dryness.

Chromatograph on silica gel using 5% methanol / methylene chloride as eluent to obtain 0.4 g, (68%) of the title compound. FABMS M + 1 = 578. Example 6. [[4- (3-bromo-8-chloro-5,6-dihydro-11 H -benzo [5.6] cyclohepta [1,2- b] pyridin-11-ylidjeno) -1-piperidinyl] [( 4-fluorophenyl) amino] methylene] cyanamide.

Dissolve 4- (3-bromo-8-chloro-5,6-dihydro-11 H -benzo [5.6] cyclohepta [, 2-b] pyridin-1-ylidene) -B-cyano-1-piperidinecarboximidothioate (0.25) g, 0.51 mmol) in 2.5 ml - of 4-fIuoranaline. While stirring under a nitrogen atmosphere, add approximately 10 mg of sodium hydride and stir at 10 ° C for 1 hr. Allow to cool to room temperature. Add to brine and extract with ethyl acetate three times. Dry the extract over magnesium sulfate, filter, and evaporate to dryness and chromatograph on silica gel using 5% methanol / methylene chloride as eluent to obtain 0.1555 g (55%) of the title compound. FABMS M + 1 = 552.

Example 7. [[(4H-1, 3-benzodioxin-6-yl) amino] [4- (3-bromo-8-chloro-5,6-dihydro-1 H-benzo [5.6] cyclohepta [1, 2-b] pyridin-11-ylidene) -1-piperidinylmethylene] cyanamide.

Dissolve 4- (3-bromo-8-chloro-5,6-dihydro-1 1 H -benzo [5.6] cyclohepta [1,2- b] pyridin-11-phenylidene) -N- (4H-1, 3- benzodioxin-6-yl) -1-piperidinecarbothioamide (0.1 g, 0.198 mmol) in dry N, N-dimethylformamide (DMF). Add lead cyanamide (98 mg, 0.39 mmol) and benzyltriethylammonium chloride (5 mg) and stir at 90 ° C for 2 days). Add lead cyanamide (98 mg, 0.39 mmol) and benzyltriethylammonium chloride (5 mg) again and stir for 24 hrs. Add to brine and extract with ethyl acetate three times. Dry the extract over magnesium sulfate, filter and evaporate to dryness. Chromatograph on silica gel using 5% methanol / methylene chloride as eluent to obtain 39 mg (38%) of the title compound. FABMS M + 1 = 701.

- Example 8. [[4- (3,10-Dibromo-8-chloro-5,6-dihydro-11 H -benzo [5.6] cyclohepta [, 2-b] pyridin-1-ylidene) -1-piper dinyl] (3-pyridinyl) methylene] cyanamide.

Dissolve 4- (3,10-dibromo-8-chloro-5,6-dihydro-11 H-benzo [5.6] cyclohepta [1,2-b] pyridin-1-yldene) -1-piper Dina (0.2 g, 0.43 mmol) in 2 ml of DMF. Add isopropyl-N-cyano-3-pyridylimidate [ref: Chem. Pharm. Bull. 42 (12) 2475 (1994)] (0.16 g, 90.86 mmol) and stir at 75 ° C for 24 hours. Add to brine and extract with ethyl acetate three times. Dry the extract over magnesium sulfate, filter, and evaporate to dryness. Chromatograph on silica gel using 5% methanol / methylene chloride as eluent to obtain 0.16 g. of the title compound. FABMS M + 1 = 599.

Example 9. N 1-N-cyano-4- (3,10-dibromo-8-chloro-6,11-dihydro-5 H -benzo [5,6] cyclohepta [1,2-b] pyridin-1-oxide L) -n'-pyridinylmethyl) -1-piperidinecarboximidamide - Dissolve 4- (3-bromo-8-chloro-5,6-dihydro-11 H -benzo [5.6] cyclohepta [1,2-b] pyridin-11-ylidene) -B-cyano-1-1-piperidinecarboximidothioate ( 1.0 g, 1.76 mmol) and methyl 3-amomethylpyridyl-N-oxide (0.65 g, 5.8 mmol) in 10 ml of N, N-dimethylformamide under a dry nitrogen atmosphere at 135 ° C. C while shake After stirring for 2 hours, the reaction mixture is added to the brine and extracted with 20 ml of methylene chloride three times. The extracts are combined, dried over magnesium sulfate, filtered and evaporated to an oil. The oil is chromatographed on a column of silica gel using 2% to 10% methanol in methylene chloride to obtain 0.23 g of the compound of the title in the form of a solid. FABMS M + 1 = 563. • fifteen twenty - - Using the procedures described above and substituting the appropriate reagents, the compounds described in the following table were prepared.

- - - PREPARATION OF STARTING MATERIALS The starting materials that are useful for preparing the compounds of the present invention are exemplified by the following preparative examples, which should not be considered as limiting the scope of the description. Starting materials using the tricyclic compounds, such as compound (2.0), inorganic and organic bases, N-cyanoimidates and alcohols can be prepared using methods known in the art, such as those described in U.S. Patent Nos. 5,089,496; 5,151,423; 4,454,143; 4. 355,036; PCT / usa94 / 11290 (WO95 / 10514); PCT / US94 / 11391 (WO 95/10515); PCT / US94 / 1 1392 (WO95 / 10516); Stanley R Sandler and Wolf Karo, Organic Functional Group Preparations, 2nd Edition, Academic Press, Inc., San Diego, California, Vol. 1 -3, (1983), and in J. March, Advanced Organ. Chemistry, Reactions & Mechanisms, and Structure, 3rd Edition, John Wiley & Sons, New York, 1346 pp (1985). Alternative mechanistic pathways and analogous structures within the scope of the invention will be apparent to those skilled in the art.

PREPARATION FEMALE 7 Stage A: Combine 15 g (38.5 mmol) of 4- (8-chloro-3-bromo-5,6-dihydrol-1H-benzo [5,6] cyclohepta [1,2-b] pyridin-11-ylidene ethyl ester) ) -1-piperidine-1-carboxylic acid and 150 ml of concentrated H2SO4 at -5 ° C, and then add 3.89 g (38.5 mmol) of KN03 and stir for 4 hours. Pour the mixture into 3 liters of ice and basify with 50% NaOH (aqueous). Extract with CH2CI2, dry over MgSO4, then filter and concentrate in vacuo to a residue. Recrystallize the residue from acetone to give 6.69 g of the product.

Combine 6.69 g (13.1 mmol) of the product from Step A and 100 ml of 85% EtOH / water, then add 0.66 g (5.9 mmol) of CaCl2 and 6.56 g (117, 9 mmol) of Fe and heating the reflux mixture overnight. Filter the hot reaction mixture through Celite ® and rinse the filter cake with hot EtOH. Stage C Combine 7.70 g of the product from step B and 35 ml of HOAc, then add 45 ml of a Br2 solution in HOAc and stir the mixture at room temperature overnight, Add 300 ml of 1 N NaOH (aqueous), then 75 ml of 50% L NaOH (aqueous) and extract with EtOAC. Dry the extract over MgSO and concentrate in vacuo to a residue. Chromatograph the residue (silica gel, 20% -30% ETOAc / hexane) to give 3.47 g of the product (together with another 1.28 g of the partially purified product).

Ftapa D: Combine 0,557 g (5,4 mmol) of t-butyl nitrite and 3 ml of DMF, and heat the mixture to 60 ° - 70 ° C. Slowly add (drip) a mixture of 2,00 gd (3,6 g) mmol) of the product of Step C and 4 ml of DMF ,. then cool the mixture at room temperature. Add another 0.64 ml of t-butyl nitrite at 40 ° C and reheat the mixture in 150 ml of water. Extract with CH2Cl2, dry the extract over MgSO4 and concentrate in vacuo to a residue. Chromatograph the residue (silica gel, 10% -20% EtOAc / hexane) to give 0.74 g of the product. Stage E " Combine 0.70 g (1.4 mmol) of the product of Step D and 8 ml of concentrated HCl (aqueous) and heat the mixture to reflux overnight. Add I30 ml of 1 N NaOH (aqueous), then 5 ml of 50% NaOH (aqueous) and extract with CH2Cl2. Dry the extract over MgSO4 and concentrate in vacuo to give 0.59 g of the title compound. PREPARED EXAMPLE 8 [Racemic isomers as well as (+) and (-)] Stage A: Prepare a solution of 8.1 g of the title compound from Preparative Example 7 in toluene and add 17.3 ml of a 1 M solution of DIBAL in toluene. Heat the mixture to reflux and slowly add (drip) another 21 ml of a 1 M DIBAL solution / toluene in a period of 40 min. Cool the reaction mixture to about 0 ° C and add 700 ml of 1 M HCl (aqueous). Separate and discard the organic phase. Wash the aqueous phase with CH2Cl2, discard the extract, then basify the aqueous phase by adding 50% NaOH (aqueous). Extract with CH2CI2, dry the extract over MgSO4 and concentrate in vacuo to give 7.30 g. of the title compound, which is a racemic mixture of enaniomers. Stage B - Separation of Enantiomers: The racemic compound of the title of Step A is separated by chiral preparative chromatography (Chiralpack AD, 5 cm X 50 cm column, using 20% iPrOH / hexane + 0.2% diethylamine), to give the isomer (+ ) and the (-) isomer of the title compound EXAMPLE PREPARATION 48 Step A: Combine 6 g (15, 11 mmol) of the title compound of Preparative Example 47B of WO 95/10516, and benzene, and add 2.3 g (0.06 mmol) of iodine. Heat the mixture at reflux for 4 hours, cool, then dilute with 50 ml of CH 2 Cl 2. Wash the organic phase with 5% NaOH 3 (aqueous) (3 x 80 ml), then with 1M NaOH (2 x 80 ml), and dry over MgSO 4. Concentrate to a residue, chromatograph (silica gel, 30% ETOAc / hexanes), to give 3.2 g (42% yield) of the compound of the iodine product. Mass Spectrum: MH + = 509. Stage B: The product from Step A was hydrolyzed by substantially the same procedure described in Example 358, Step A, of WO 95/10526, to obtain the iodoamine product in 89% yield. PREPARED EXAMPLE 49 The product from Preparative Example 47, Step c, of WO 97/10526, (2.42 g) was hydrolyzed by substantially the same procedure described in Example 358, Step A, of WO 95/10516, to give 1.39 g (69% yield) of the bromoamine product. PREPARED EXAMPLE 51A Etap Combine 82.0 g (0.26 mmol) of the title compound of Preparative Example 1, Step G, of WO 95/10516, and 1 liter of toluene, and then add 20.06 g (0.53 mol) of LiAiH4 and heating the reaction mixture to reflux overnight. Cool the mixture to room temperature and add ~ 1 liter of Et20, followed by dropwise addition of saturated Na2SO4 (aqueous until a precipitate forms.) Filter and stir the filtrate over MgSO for 30 minutes, then concentrate in vacuo to give the compound of the product with a yield of 83% Mass Spectrum: MH + = 313. Stage B: Combine 24.32 g (74.9 mmol) of the product from Step A, 500 ml of toluene, 83 ml of Et3N and 65.9 ml of ethyl chloroformate and heat the mixture to reflux overnight. Cool to 25 ° C, pour into 200 ml of water and extract with EtOAc. Dry the extract over MgSO4, concentrate in vacuo to a residue and chromatograph (silica gel, 50%, EtOAc / hexane) to give 15 g of the product compound. Mass Spectrum: MH + = 385. Stage C: Dissolve 3.2 g (10.15) mmol) of tetra-n-butylammonium nitrate in 25 ml of CH2CI2 and add 2.2 g) (10.51 ml) of TFA. Cool to 0 ° C and add the mixture (through a cannula) to a solution of 3.68 g (9.56 mmol) of the product of Step B in 50 ml of CH2Cl2 at 0 ° C then stir at 0 ° C. C for 3 hours. Allow the mixture to warm to 25 ° C while stirring overnight, then extract with saturated NaHCO 3 (aqueous) and dry over MgSO 4. Concentrate in vacuo to a residue and chromatograph (silica gel, 30% EtOAc / hexane) to give 1.2 g of the product compound. Mass Spectrum: MH + = 430. Stage D: Combine 2.0 g (4.7 mmol) of the product from Step C and 150 ml of 85% EtOH (aqueous), add 2.4 g (42 mmol) of Fe and 0.24 g (2, 1 mmol) of CaCl2, and heating at reflux for 16 hours. Filter the hot mixture through a pad of celite ® and wash the celite ® with hot EtOH. Concentrate the filtrate in vacuo to give a 100% yield of the product compound. Mass Spectrum: MH + = 400. Stage E: Combine 2.0 g (5.2 mmol) of the product from Step D, and 20 ml of 48% HBr, cool the mixture at -5 ° C. Stir the mixture at -5 ° C for 15 minutes and add slowly a solution of 1.07 g (15.5 mmol) of NaN02 in 10 ml of water. Stir for 45 minutes, then quench with 50% NaOH (aqueous pH-10. Extract with EtOAc, dry the combined extracts over MgSO4, and concentrate in vacuo to give the product compound.) Mass Spectrum: MH + = 465. Stage F: Hydrolyze 4.0 g of the Product from Step E by substantially the same procedure described for Example 358, Step A of WO 95/10516, to obtain 1.39 g of the product compound. Mass Spectrum: MH + = 392. EXAMPLE PREPARATION 53 Combine 14.95 g (39 mmol) of the Product of Preparative Example 34A, WO 95/10516, and 150 mL of CH2Cl2, then add 13.07 g (42.9 mmol) of (nSu) 4NN03 and cool the mixture to 0 ° C. Add slowly (dropwise) a solution of 6.09 ml (42.9 mmol) of TFAA in 20 ml of CH2Cl2 within 1.5 hours. Maintain the mixture at 0 ° C overnight and then wash successively with saturated NaHC03 (aqueous), water and brine. Dry the organic solution over Na 2 SO 4, concentrate in vacuo to a residue and chromatograph the residue (silica gel, EtOAc / hexane gradient) to give 4.32 g and 1.90 g of the compounds of the two products 53 (i) and 53 (¡), respectively. Mass Spectrum (53 (i)): MH + = 428.2; Mass Spectrum (53 (¡)): MH + = 428.3 Compound 53 (ii) from Step A (0.20 g) was hydrolyzed by substantially the same procedure described for Example 358, Step A, of WO 95/10516 (published April 20, 1995), to give 0 , 16 g of the product compound. Using the indicated starting compound and substantially the same procedure described in Preparative Example 53, Step B, the compounds of Table 1 were prepared: TABLE - PREPARED EXAMPLE 54 Combine 22.0 g (51.4 mmol) of the product 53 (i) of Preparation 53, Step A, 150 mL of 85% EtOH (aqueous), 25.85 g (0.463 mol) of Fe powder and , 42 g (21.8 mmol) of CaCl2, and heat at reflux overnight. Add 12.4 g (0.222 mol) of Fe powder and 1.2 g (10.8 mmol) of CaCl2 and heat at reflux for 2 hours. Add 12.4 g more (0.222 mol) of Fe powder and 1.2 g (10.8 mmol) of CaCl2 and heat at reflux for a further 2 hours. Filter the hot mixture through celite ®, wash the celite ® with 50 ml of hot EtOH and concentrate the filtrate in vacuo until a residue is obtained. Add 100 ml of anhydrous EtOH, concentrate to a residue and chromatograph the residue (silica gel, gradient of MeOH / CH2Cl2) to obtain 16.47 g of the product compound.

- - Stage B: Combine 16.47 g (41.4 mmol) of the product compound of Preparative Example 54, Step A, and 150 mL of 48% HBr (aqueous) and cool to -3 ° C. Add slowly (drip) 18 mL of bromine, then add slowly (dropwise) a solution of 8.55 g (0.124 mol) of NaN02ß in 85 ml of water. Stir for 45 minutes at -3 ° to 0 ° C, then adjust to pH = 10 by adding 50% NaOH (aqueous). Extract with EtOAc, wash the extracts with brine and dry the extracts over Na2SO4. Concentrate to a residue and chromatograph (silica gel, EtOAc / hexane gradient) to give 10.6 g and 3.28 g of the two product compounds 54 (i) and 54 (ii), respectively. Mass Spectrum (54 (i): MH + = 461, 2; Mass Spectrum (54 (i)): MH + = 539 PREPARATORY EXAMPLE 55 The title compound is known and is prepared by the procedure described in Biora. & Med. Chem. Lett .. 3. (No. 6) 1073 - 1078 (1993). PREPARED EXAMPLE 56 Combine 2.04 g of the product of Preparative Example 44, from WO 95/10516 (published April 20, 1995), 1.3 ml of PBr3, 1.0 ml of Et3N and 20 ml of CH2Br2, and heat the mixture reflux overnight. Cool the mixture, dilute with CH 2 Cl 2 and wash with 1 N NaOH (aqueous). Dry over MgSO4 and concentrate in vacuo to obtain 1.22 g (53% yield) of the product compound. Mass Spectrum: MH + = 541 Stage B: Combine 0.3 g of the product of the compound of Preparative Example 56, Step A, and 8 ml of n-butylamine and stir at 120 ° C in a sealed tube for 48 hours. Concentrate in vacuo to a residue and purify by preparative plate chromatography (silica gel, 1.5-2.5% MeOH / CH 2 Cl 2) to give 80 mg (27%) yield of the product compound. Mass Spectrum: MH + = 534.

Stage C: • Combine 66 mg of the product of the compound of Preparative Example 56, Step B, 4 ml of anhydrous EtOH, and 15 ml of concentrated HCl, and stir at reflux for 60 hours. Cool the reaction mixture to about 0 ° C basify by adding KOH. Extract with CH2Cl2, dry the extract over MgSO4, and concentrate in vacuo to give 46 mg (yield 81%) of the product compound. Mass Spectrum: MH + = 462. PREPARATORY EXAMPLE 57 Stage A: Combine 1.19 g of the product from Preparative Example 44 of WO 95/10516, 10 ml of anhydrous DMF, 0.2 g of NaH (60% in mineral oil) and 0.19 ml of methyl iodide, and stir at room temperature. overnight. Concentrate in vacuo to a residue, dilute the residue with CH 2 Cl 2, wash with NaHCO 3 (aqueous), and dry over MgSO 4. Concentrate in vacuo to give 1.13 g (92% yield) of the product compound. Mass Spectrum: MH + = 493. Stage B Hydrolyze 1.13 g of the product from Step A by substantially the same procedure described for Preparative Example 56, Step C, to obtain 0.61 g (63% yield) of the product compound.

PRFPARATIVE EXAMPLE 58 Combine 1. 07 g (3.52 mmol) of tetrabutylammonium nitrate, 4 ml of CH 2 Cl 2 and 0,743 g (3.52 mmol) of TFAA, and add the resulting mixture to a solution of 1.22 g (3.20 g. mmol) of the title compound of Preparative Example 37, WO 95/10516, in 8 ml of anhydrous CH 2 Cl 2 at room temperature. Stir at room temperature overnight and then wash with 20 ml of NaHCO 3 Saturated (aqueous) and 20 ml of brine, and dried over MgSO4. Concentrate in vacuo and chromatograph the resulting residue (silica gel, EtOAc / hexane) to give 0.216 g of the product compound 58 (i) and 0.27 g of the product compound 58 (ii). Mass Spectrum (58 (¡)): MH + = 426. p. F. (58 (¡)) 97.5 ° - 99.2 ° C. Stage B: Reduce the product 58 (i) from Step A by essentially the same procedure described in Preparative Example 47, Step B, of WO 95/10516, to give the product compound. Mass Spectrum: MH + = 396 Stage C: React the product of Step B with HBr and bromine by essentially the same procedure described in Preparative Example 47, Step C of WO 95/10516, to give the product compound. Mass Spectrum: MH + = 459 - Stage D: Hydrolyze 0.83 g of the product from Step C by essentially the same procedure described in Preparative Example 56, Step C, to give 0.56 g of the product compound. Mass Spectrum: MH + = 387. PREPARATORY EXAMPLE 60 Stage A: Combine 16.25 g (40.83 mmol) of the product of Preparative Example 47, Step B, from WO 95/10516, and a suspension of 7.14 g (61.1 1 mmol) of NOBF4 in 100 mL of CH2CI and stir the mixture for 3 hours. Add 100 ml of o-dichlorobenzene and heat for 5 hours, distill the CH2CI2 from the mixture. Concentrate in vacuo to a residue, add 200 ml of CH2CI2 and wash with water (2 x 200 ml). Dry over MgSO4, concentrate in vacuo to a residue, and chromatograph (silica gel 20% EtOAc / hexane) to give 4.1 g of the product compound 60 (i) and 4.01 g of the Product 60 compound ( ii). Mass Spectrum: (60 (i)): MH + = 418. Mass Spectrum: (60 (ii)): MH + = 401.

Stage B- Hydrolyze 3.4 g of the product 60 (i) from Step A by essentially the same procedure described for Example 358, Step A, of WO 95/10516, to obtain 3.01 g of the product compound. Mass Spectrum: MH + = 329. Using compound 60 (i) of Preparative Example 60, Step A and following substantially the same procedure described in Preparative Example 69, Step B, the compound was prepared (Preparative Example 60A) Mass Spectrum: MH + = 346. PREPARATORY EXAMPLE 66 Cool 50.0 g (20.5 mmol) of 8-chloro-5,6-dihydro-11 H-benzo [5.6] cyclohepta [1,2-b] pyridin-1-one at 0 ° C, and add slowly 75 ml (93.69 mmol) of sulfur monochloride for 20 minutes, and then slowly add 25 ml (48.59 mmol) of Br2 for 15 h. Heat at 95 ° C for 20 hours, add 12.5 ml (24.3 mmol) of Br2 and heat for an additional 24 hours. Cool the mixture, and slowly add a mixture of CH 2 Cl 2 and 1 N aqueous NaOH at 0 ° C. Wash the organic phase with water, dry over MgSO 4 and concentrate in vacuo to a residue. Chromatograph the residue (silica gel, 500 ml of CH 2 Cl 2, and then 0.2% -5% (10% of NH 4 OH in MeOH) / CH 2 Cl 2). then chromatograph again (silica gel, 3% l EtOAc / hexane) to give 8.66 g of the product compound. Mass Spectrum: MH + = 322. PREPARED EXAMPLE 67 Dissolve 0.16 g (0.46 mmol) of 4- (8-methyl-5,6-dihydro-1 1 H -benzo [5.6] cyclohepta [1,2-b] pyridin-1-lidine ) -1-ethoxycarbonyl-p-peridine, in 2 ml of ETOH and add 4 ml of 12 N HCl. Heat the solution for 3 hours at 85 ° C, then cool to 25 ° C. Adjust to pH = 10 with 50% NaOH () was added and extracted several times with 50 ml of EtOAc. Combine the organic layers, dry over MgSO4, and concentrate in vacuo to obtain the product compound.

- - PREPARATIVE EXAMPLE 68 Stage A: Dissolve 2 g (5.22 mmol) of the title compound of Preparative Example 1 H of WO 95/10516, in 2.6 ml of N-methylpyrrolidinone. Add 0.87 g (9.4 mmol) of CuCN and 0.139 g (0.93 mmol) of sodium iodide. Heat the mixture to 200 ° C under nitrogen for 20 hours, cool to 25 ° C and repeatedly triturate and mix with five 50 ml portions of CH 2 Cl 2 and 7 M NH 4 OH (aqueous). Wash the organic layer with 7 M NH 4 OH until the organic layer is no longer blue or green. Dry the combined organic layers over MgSO4 and concentrate in vacuo to a residue. Chromatograph (70% EtOAc / hexane silica gel), then recrystallize from EtOAc / hexane to obtain the product compound, e.g. F. = 152.4 ° - 153.5 ° C; Mass Spectrum: MH + = 374.

Stage B: Dissolve 4.08 g (10.93 mmol) of the product from Step A in 12 M HCl and heat at 85 ° C for 8 hours. Concentrate in vacuo to a residue. Dissolve the residue in 175 ml of MeOH, saturate with HCl gas, and heat at reflux for 18 hours. Concentrate in vacuo to give the product compound in the form of its HCl salt. Mass Spectrum: MH + = 335. EXAMPLE PREPARATION 69 - Combine 75 g (0.169 mol) of the Product of Example 1, Step F, of WO 95/10516, and 300 ml of CH2CI2 at 0 ° C, and slowly add (dropwise) a solution of 72 g (0.236 mol) of tetrabutylammonium nitrate and 35 ml (0.247 mol) of TFAA in 500 ml of CH2Cl2. Stir at 25 ° C overnight, slowly add (dropwise) 1 liter of saturated NaHCO 3 (aqueous). Separate the layers, wash the organic phase with brine and dry over MgSO4. Concentrate in vacuo to a residue, chromatograph twice (1 kg of silica gel, gradient of EtOAc / CH 2 Cl 2) to obtain 8.63 g of the product compound 69 (i) of CH 2 Cl 2 / hexane to obtain the compound of the purified product. (i), p. F. = 186 ° - .187 ° C; Mass Spectrum: 8FAB9 MH + = 401. PREPARATIVE EXAMPLE 69A Combine 0.4 g (1 mmol) of the Product of Example 47, Step B, of WO 95/10516 (published April 20, 1995), and 0.2 ml (1.2 mmoles) of 2,5-diethoxytetrahydrofuran in 3 ml of HOAc, glacial, and heat at reflux for 1.5 hours. Cool the mixture, wash with saturated NaHC03 (aqueous), then with brine, dry over MgSO4, and concentrate in vacuo to a residue.

Chromatograph (silica gel, 5% EtOAc / CH 2 C, 2) to give 0.34 g of the product compound. Mass Spectrum: (FAB) MH + = 448. F.IFMPI OR PREPARATIVE 70 Stage A: Combine 13.8 g (34.7 mmol) of the Product of Example 47, Step B, of WO 95/10516, and 90 ml of water at 0 ° C, add a solution of 6.9 ml of concentrated H2SO4 in 45 ml. of water and stir the mixture. Slowly add (dropwise) a solution of 2.55 g (40 mmol) of NaN02 in 75 ml of water and stir at 0 ° - 5 ° C for 0.5 hour. Add a boiling solution of 35.1 g of CuS04 in 135 ml of water and heat at 100 ° C for 15 min. Cool the mixture, extract with CH2Cl2 (2 X 200 ml), wash the extracts with brine, dry over MgSO4, and concentrate in vacuo to a residue. Chromatograph (silica gel, 1.5% -10% MeOH / CH2Cl2) to give 11.36 g of the product compound. Stage B: Combine 1 1, 36 g (28.5 mmol) of the product from Step A and 12.4 g (34.7 mmol) of N-phenyltriflimide in 120 ml of dry CH2Cl2 at 0 ° C, add 4.6 ml ( 33 mmol) of Et 3 N and stir at 25 ° C overnight. Concentrate in vacuo to a residue and chromatograph (silica gel, 2% -5% ETOAc / CH2Cl2) to give 10.95 g of the product compound. Recrystallize from hot MeOH, p. F. = 154.5 ° - 156 ° C; Mass Spectrum: (FAB) MH + = 531. Stage C: Combine 12.2 g (23 mmol) of the product from Step B and 85 ml of 1-methyl-2-pyrrolidinone at 25 ° C, then add 2.84 g of LiCl, 0.212 g of tris furylphosphine and 0.585 g of dipaladiotribenzylidene ketone. and stir for 15 minutes. Add slowly (drip) 7.5 ml (25, 77 mmol) of tributyl vinyl tin and stir at 25 ° C for 2.5 hours. Dilute with 500 ml of water at 0 ° C and extract with 6700 ml of EtOAc. Filter the organic phase through celite ®, wash the celite with EtOAc, then wash the filtrate twice with 30% NaF (aqueous). Filter the organic solution, wash with brine and dry over MgSO4. Concentrate in vacuo to a residue and chromatograph (silica gel, 15% -40% EtOAc / hexane) to give 8.58 g of the product compound. Mass Spectrum: 8FAB9 MH + = 409. Using 2- (tributylstannane) thiophene and the compound of Preparative Example 70, Step B, and following substantially the same procedure described for Preparative Example 70, Step C, was prepared The compound: (Preparatory Example 70-A) p.f. = 155 ° ~ 157 ° C, Mass Spectrum: MH + = 465. Stage D: Hydrolyze 1.18 g (2.89 mmol) of the product of step C by substantially the same procedure described in Example 358, Step A of WO 95/10516, to obtain 0.95 g of the product compound. Mass Spectrum: (FAB) MH + = 337. PRFPARATIVE EXAMPLE 71 Stage A: Combine 1.01 g (19.9 mmol) of the product from Preparative Example 48, Step A, 30 mL of DMF, 1.33 g (6.96 mmol) of 2,2-difluoro-2- (fluorowolyl) -acetate. of methyl and 0..75 g (3.97 g) of Cul. Heat the mixture at 60 ° - 80 ° C for 3 hours, then concentrate to a residue. Dilute the residue with water, extract with CH2C12, and concentrate in vacuo to obtain a residue. Chromatograph (silica gel, 30% EtOAc / hexane, then 10% MeOH / CH 2 Cl 2 + NH 4 OH) to obtain 0.15 g of the product compound. Mass Spectrum: MH + = 451, 1. Stage B: Hydrolyze the product from Step A using essentially the same procedure described in Preparative Example 1, Step G, of WO 95/10516, to obtain the product compound. Mass Spectrum: MH + = 379. EXAMPLE PREPARATION 72 - Dissolve 20 g (50 mmol) of the Product of Preparative Example 1, Step F, of WO 95/10516, in 400 ml of concentrated H2SO4, cool to -5 ° C and add 5.1 g (50 mmo!) Of KN03 in little portions. Stir for 3 hours, cool the mixture and basify slowly with 50% NaOH (aqueous). Extract with CH2Cl2 (3 X 500 mL), dry the combined extracts over MgSO4, and concentrate in vacuo to the residue. Chromatograph (silica gel, 50% EtOAc / hexane) to give 16m, 33 g of the product compound (72%) and 2.6 g of the product compound (72%). Mass Spectrum (72 (¡) and (72 (ii)): MH + = 428. Stage B: Hydrate 5.46 g (12.76 mmol) of the Product from (72i) of Step A, by substantially the same procedure described for Example 358, Step IA, of WO 95/10516, to give 4.34 g of the compound of the product. Mass Spectrum: MH + = 356. EXAMPLE PREPARATION 73 Stage A: Combine 1, 6 g of Product (54¡) of Preparative Example 54, Step B, 12 ml of CH2Cl2, and 1.16 g of tetrabutylammonium nitrate, cool to 0 ° C and add slowly (dropwise) to a solution of 0.8 g of TFAA in 2 ml of CH2Cl2. Stir for 6 hours at 0 ° C, allow the mixture to stand at 0 ° C overnight, then wash successively with saturated NaHCO 3 (aqueous), water and brine, and dry over Na 2 SO 4. Concentrate in vacuo to a residue, then chromatograph (silica gel, 30% EtOAc / hexane) to give 0.38 g of the product compound. Stage B: Hydrolyze 0.38 g of the Product from Step A by substantially the same procedure described for Example 358, Step A, of WO 95/10516, to obtain 0.235 g of the product compound. Example Preparatiyo 75. Dissolve 4- (3-bromo-8-chloro-5,6-dihydro-11 H -benzo [5.6] cyclohepta [1,2-b] pyridin-11-ylidene) -N- (4H-1, 3-benzodioxin-6-yl) -1- piperidinecarbothioamide.

Dissolve 4- (3-bromo-8-chloro-5,6-dihydro-1 1 H -benzo [5.6] cyclohepta [1, 2-b] pyridin-11-yldene) -1-pperidine (0.5 g, 1.61 mmol) in 5 ml of dry tetrahydrofuran. Add isothiocyanate of 4H-1,3-benzodioxin-6-yl) (0.34 g, 1.77 mmol) and stir at room temperature for 24 hours. Evaporate the reaction mixture to an oil and chromatograph on silica gel using 1% to 5% methanol / methylene chloride as eluent to obtain 0.893 g of the title compound. FABMS M + 1 = 694. TESTS Q In vitro enzyme assays: The Cl50 of FPT (famesyl protein transferase inhibition, in vitro enzyme assay) was determined by the methods described in WO / 10515 or WO 95/10516. The data demonstrate that the compounds of the invention are Ras-CVLS farnesylation inhibitors by the purified rat brain farnesyl protein transferase (FPT). The data also show that there are compounds of the invention that can be considered potent inhibitors (Cl50 <10 μM) of Ras-CVLS farnesylation by FPT of partially purified rat brain. 2. Cell-based assay. The IC59 values of COS refer to the inhibition of the COS cell activity of the Ras process, were determined by the methods described in WO / 10515 or WO 95/10516. For the preparation of the pharmaceutical compositions of the compounds described by this invention, the inert, pharmaceutically acceptable carriers can be solid or liquid. Solid form preparations include powders, tablets, dispersible granules, capsules, seals and suppositories. The powders and tablets may be comprised of from about 5 to about 70 percent active ingredient. Suitable solid carriers are known in the art, for example magnesium carbonate, magnesium stearate, talc, sugar, lactose. Tablets, powders, seals and capsules can be used as solid dosage forms suitable for oral administration. To prepare suppositories, a low-melting wax such as a mixture of fatty acid glycerides or cocoa butter is first melted, and the active ingredient is homogeneously dispersed therein eg by stirring. The molten homogeneous mixture is then poured into molds of a convenient size that are allowed to cool and therefore solidify. Liquid form preparations include solutions, suspensions and emulsions. As an example, water or water and propylene glycol solutions for parenteral injection may be mentioned. The liquid form preparations may also include solutions for intranasal administration. Aerosol preparations suitable for inhalation may include solutions and solids in the form of powders, which may be combined with a pharmaceutically acceptable carrier, such as inert compressed gas. Also included are preparations in solid form which are intended to be converted, shortly before use, to liquid form preparations for oral or parenteral administration. Such liquid forms include solutions, suspensions and emulsions. The compounds of the invention can also be administered transdermally. The transdermal compositions may be in the form of creams, lotions, aerosols and / or emulsions and may be included in a transdermal patch of the matrix or reservoir type as is conventional in the art for that purpose. Preferably the compound is administered orally. Preferably, the pharmaceutical preparation is in unit dosage form. In such form, the preparation is subdivided into unit doses containing appropriate quantities of the active component, for example an effective amount to achieve the desired purpose. The amount of active compound in a unit dose of preparation may vary or be adjusted from about 0.1 mg to 1000 mg, more preferably from about 1 mg to 300 mg, according to the particular application. The actual dosage used may vary depending on the requirements of the patient and the severity of the disease being treated. The determination of the appropriate dosage for a particular situation is within the experience in the subject. In general, the treatment is initiated with small doses that are lower than the optimum dose of the compound. Next, the dose is increased in small increments until the optimum effect is reached under the circumstances. For reasons of convenience, the total daily dosage may be divided and administered in portions during the day, if desired. The amount and frequency of administration of the compounds of the invention and pharmaceutically acceptable salts thereof will be regulated according to the criterion of the attending physician considering factors such as the age, condition and weight of the patient as well as the severity of the symptoms that are treated. A typical recommended dosage regimen is a real administration of from 10 mg to 2000 mg / day preferably from 10 to 1000 mg / day, in two to four divided doses to block the development of tumors. The compounds are non-toxic when administered within this dosage range. The following are examples of pharmaceutical dosage forms containing a compound of the invention. The scope of the invention in this aspect of the pharmaceutical composition is not limited by the examples provided. Examples of Pharmaceutical Dosage Forms EXAMPLE A - Tablets - Manufacturing Method Mix items Nos. 1 and 2 in an appropriate mixer for 10 - 15 minutes. Granulate the mixture with item No. 3. Crush the wet granules through a coarse screen (eg 1/4", 0.63 cm) if necessary Dry the wet granules Sift the dried granules if necessary and Mix them with item No. 4 and mix for 10 - 15 minutes Add item No. 5 and mix for 1 - 3 minutes Compress the mixture to the appropriate size and weigh it in a machine suitable for tablets EXAMPLE B - Capsules Manufacturing Method Mix items Nos. 1, 2 and 3 in an appropriate mixer for 10 - 15 minutes. Add item No. 4 and mix for 1 - 3 minutes. Fill the mixture with appropriate two-piece hard gelatin capsules in an appropriate encapsulating machine. Although the present invention has been described in conjunction with the specific embodiments indicated above, many alternatives, modifications and variations thereof will be apparent to those skilled in the art. All said alternatives, modifications and variations are intended to be within the spirit and scope of the present invention.

Claims (13)

1. A compound of formula: Or a pharmaceutically acceptable salt or solvate thereof, wherein: one of a, b, c and d represents N or NR9 where R9 is O-, -CH3o - (CH2) nC02H where n is 1 to 3, and groups a, b, c and d remnants represent CR '' or CR2; or ~ each of a, b, c, and d are independently selected from CR1 or 20 of CR2; each R and each R2 is independently selected from H, halo, - CF3, -OR10 (for example -OCH3), - COR10, -SR10 (for example -SCH3 and - SCH2C6H5), -S (0) tR11 (where t is 0, 1 or 2 for example -SOCH3 and -S02CH3), -SCN, -N (R10) 2, -NR10R11, -N02, -OC (0) R1 °, -C02R10, .0CO2RH. -CN, -NHC (0) R10, - NHS02R10, -CONHR10, -CONHCH2CH2OH, -NR10COOR11, -SR11C (0) OR11 (by Each example., -SCH2C02CH3), -SR11N (R75) 2 wherein each R75 is independently selected from H and -C (0) OR11 (for example -S (CH2) 2NHC (0) 0- t -butyl and -S ( CH2) 2NH2), benzotriazol-1-yloxy, tetrazol-5-ylthio, or tetrazole-5 -Iti or substituted (for example tetrazol-5-ylthio-substituted alkyl such as 1-methyl-tetrazole-5-thio), alkynyl , alkenyl- or alkyl, said alkyl or alkenyl group being optionally substituted with halo, -OR1 or -C02R; 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 Rd each independently represent H, CF3, -COR10, alkyl or aryl, said alkyl or aryl being optionally substituted with -OR10, -SR10, -S (0) tR11, -NR10COOR11, -N (R10 ) 2, -N02, - COR10, -OCOR10, -OC02R11, -C02R1 °, OP03R10 or one of R5, R6, R7 and R8, can be taken in combination with R40 as defined below to represent - (CH2) r - where r is 2 to 4 which may be substituted with lower alkyl, lower alkoxy, -CF3 or aryl, or R5 is combined with R6 to represent = O or = S and / or R is combined with R8 to represent = O or = S; R10 and R12 independently represent H, alkyl, cycloalkyl, cycloalkylalkyl, heteroaryl, aryio, aralkyl or -NR40R42 where R40 and R42 independently represent H, aryl, alkyl, aralkyl, heteroaryl, heteroarylalkyl, heterocycloalkyl, heterocycloalkylalkyl, heteroalkyl, cycloalkyl, cycloalkylalkyl, alkenyl and alkynyl; R11 represents alkyl or aryl; X represents N, CH or C, so that when X is N or CH, there is a simple bond to carbon 1 1 represented by the whole line; or when X is C, there is a double bond to carbon 1 1 represented by the whole line and the dotted lines; the dotted line between carbons 5 and 6 represents an optional double bond, so that when a double bond is present, A and B independently represent -N02, - R 0, halo, -OR11, -OC02R11 or -OC (0 ) R10, and when no double bond is present between the carbon atoms 5 and 6, A and B independently each represent H2, - (OR11) 2, H and halo, dihalo, alkyl and H, (alkyl) 2, -H and -OC (0) R1 °, H and -OR10, oxy, aryl and H, = ÑOR10 or -0- (CH2) p-0 5 where p is 2, 3 or 4; and Z represents alkyl, aryl, aralkyl, heteroalkyl, heteroaryl, heteroarylalkyl, heterocycloalkyl ,. heterocycloalkylalkyl, -OR40, -SR40, -CR 0R42 or -NR40R42 where R40 and R42 are as defined above. Preferably in compound (1.0), there is a single bond at carbon atom 11, X is carbon, positions 3, 8 and 10 are substituted in the ring, preferably with halo; and Z is -NHR40, preferably where R40 is heteroarylalkyl, more preferably N-oxide of 3 or 4-methyl pyridyl.

2. The compound of claim 1, wherein a is N, and R1 is H; R2, R3 and R4 are halo; X is CH; and R5, R6, R7 and R8 are hydrogen.

3. The compound of claim 2 wherein Z is -NR 0R42.

4. The compound of claim 3 wherein R40 is H and R42. it is heteroarylalkyl.

5. The compound of claim 4 wherein R42 is 2- N-oxide, 3- or 4-20 pyridylmethyl.

6. The compound of claim 1 selected from any of Examples 1-83. The compound of claim 1 selected from Example 9. 8. A pharmaceutical composition for inhibiting the abnormal development of cells comprising an effective amount of the compound of claim 1 in combination with a pharmaceutically acceptable carrier. 9. A method for inhibiting abnormal cell development comprising administering an effective amount of a compound of claim 1. The method of claim 9 wherein the inhibited cells are tumor cells expressing an activated ras oncogene. The method of Claim 9 wherein the inhibited cells are pancreatic tumor cells, lung cancer cells, myeloid leukemia tumor cells, thyroid follicular tumor cells, myelodysplastic tumor cells, epidermal carcinoma tumor cells, tumor cells of bladder carcinoma or colon tumor cells, 12. The method of claim 9 wherein the inhibition of abnormal cell development occurs by the inhibition of ras farnesyl protein transferase. 13. The method of claim 9 wherein the inhibition is of tumor cells in the Ras protein is activated as a result of the oncogenic mutation in genes other than the Ras gene.