TRICYCLIC AMIDE AND UREA COMPOUNDS USEFUL FOR INHIBITION OF G-PROTEIN FUNCTION AND FOR TREATMENT OF PROLIFERATIVE DISEASES

Abstract: A method of inhibiting Ras function and therefore inhibiting the abnormal growth of cells is disclosed. The method comprises the administration of a compound of formula (1.0) to a biological system. In particular, the method inhibits the abnormal growth of cells in a mammal such as a human being. Novel compounds wherein X is N, C or OH and R is (I) or (II) are disclosed.

Description: TRICYCLIC AMIDE AND UREA COMPOUNDS USEFUL FOR INHIBITION OF G-PROTEIN FUNCTION AND FOR TREATMENT OF PROLIFERATE PISF fi^ BACKGROUND International Publication Number W092/11034, published July 9, 1992, discloses a method of increasing the sensitivity of a tumor to an antineoplastic agent, which tumor is resistant to the antineoplastic agent, by the concurrent administration of the antineoplastic agent and a potentiating agent of the formula: wherein Y is hydrogen, substituted carboxyiate or substituted sulfonyl. Examples of such potentiating agents include 1 1-(4-piperidylidene)-5H- benzo[5,6]cyclohepta[1,2-b]pyridines such as Loratadine. To acquire transforming potential, the precursor of the Ras oncoprotein must undergo farnesylation of the cysteine residue located in a carboxyl-terminal tetrapeptide. Inhibitors of the enzyme that catalyzes this modification, famesyl protein transferase, have therefore been suggested as anticancer agents for tumors in which Ras contributes to transformation. Mutated, oncogenic forms of ras are frequently found in many human cancers, most notably in more than 50% of colon and pancreatic carcinomas (Kohl et al., Science, Vol. 260, 1834 to 1837, 1993). A welcome contribution to the art would be compounds useful for the inhibition of farnesyl protein transferase. Such a contribution is provided by this invention. SUMMARY OF THE INVENTION Inhibition of farnesyl protein transferase by tricyclic compounds of this invention has not been reported previously. Thus, this invention provides a method for inhibiting farnesyl protein transferase using tricyclic compounds of this invention which: (i) potently inhibit farnesyl protein transferase, but not geranylgeranyl protein transferase I, in vitro: (ii) block the phenotypic change induced by a form of transforming Ras which is a farnesyl acceptor but not by a form of transforming Ras engineered to be a geranylgeranyl acceptor; (iii) block intracellular processing of Ras which is a farnesyl acceptor but not of Ras engineered to be a geranylgeranyl acceptor; and (iv) block abnormal cell growth in culture induced by transforming Ras. Several compounds of this invention have been demonstrated to have anti-tumor 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 growth of cells 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) expressing an activated Ras oncogene; (2) tumor cells in which the Ras protein is activated as a result of oncogenic mutation in another gene; and (3) benign and malignant cells of other proliferative diseases in which aberrant Ras activation occurs. Compounds 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 NR 9 wherein R9 is O-, -CH 3 or -(CH ∑ JnCO ∑ H wherein n is 1 to 3, and the remaining a, b, c and d groups represent CR 1 or CR 2 ; or each of a, b, c, and d are independently selected from CR 1 or CR 2 ; each R 1 and each R 2 is independently selected from H, halo, -CF 3 , -OR™ (e.g., -OCH 3 ), -COR , -SR (e.g., -SCH3 and -SCH 2 C 6 H 5 ), -S(0) t R 11 (wherein t is 0, 1 or 2, e.g., -SOCH3 and -SO2CH3), -SCN, -N(R10) 2 , -NR10R , -N0 2 , -OC(0)R 10 , -C0 2 R 1 °, -OC0 2 R 11 , -CN, -NHC(0)R 10 , -NHSO2R 10 , -CONHR 10 , -CONHCH 2 CH 2 OH, -NR 10 COOR 11 , -SR 11 C(0)OR 11 (e.g., -SCH 2 C0 2 CH 3 ), -SR 11 N(R 5 ) 2 wherein each R?5 is independently selected from H and -C(0)OR 11 (e.g., -S(CH 2 ) 2 NHC(0)0-t-butyl and -S(CH 2 ) 2 NH 2 ), benzotriazol-1-yloxy, tetrazol-5-ylthio, or substituted tetrazol-5-ylthio (e.g., alkyl substituted tetrazolδ-ylthio such as 1-methyl-tetrazol-5-ylthio), alkynyl, alkenyl or alkyl, said alkyl or alkenyl group optionally being substituted with halo, -OR 10 or -CO 2 R 10 ; R 3 and R 4 are the same or different and each independently represents H, any of the substituents of R 1 and R 2 , or R 3 and R 4 taken together represent a saturated or unsaturated C5-C7 fused ring to the benzene ring (Ring III); R 5 , R 6 , R 7 and R 8 each independently represents H, -CF 3 , -COR 10 , alkyl or aryl, said alkyl or aryl optionally being substituted with -OR 10 , -SR 10 -S(0) t R 11 , -NR 1 °COOR 11 , -N(R 10 ) 2 , -N0 2 , -COR 10 , -OCOR 10 , -OC0 2 R 11 , -C0 2 R 10 , OPO3R 10 or one of R 5 , R 6 , R 7 and R 8 can be taken in combination with R 40 as defined below to represent -(CH 2 )r wherein r is 1 to 4 which can be substituted with lower alkyl, lower alkoxy, -CF 3 or aryl, or R 5 is combined with R 6 to represent =0 or =S and/or R 7 is combined with R 8 to represent =0 or =S; Rio represents H, alkyl, aryl, or aralkyl (e.g., benzyl); R 11 represents alkyl or aryl; X represents N, CH or C, which C may contain an optional double bond (represented by the dotted line) to carbon atom 11; the dotted line between carbon atoms 5 and 6 represents an optional double bond, such that when a double bond is present, A and B independently represent -N0 2 , -R 10 , halo, -OR 11 , -OC0 2 R 11 or -OC(0)R 10 , and when no double bond is present between carbon atoms 5 and 6, A and B each independently represent H 2 , -(OR 11 ) 2 , H and halo, dihalo, alkyl and H, (alkyl) 2 , -H and -OC(0)R 10 , H and -OR 10 , =0, aryl and H, =NOR 10 or -0-(CH 2 ) p -0- wherein p is 2, 3 or 4; R represents R 40 , R 42 , R 44 , or R 54 , as defined below; R40 represents H, aryl, alkyl, cycloalkyl, alkenyl, alkynyl or -D wherein -D represents wherein R 3 and R 4 are as previously defined and W is O, S or NR 10 wherein R 10 is as defined above; said R 40 cycloalkyl, alkenyl and alkynyl groups being optionally substituted with from 1-3 groups selected from halo, -CON(R 10 ) 2 , aryl, -C0 2 R 10 , -OR 12 , -SR 12 , -N(R 10 ) 2 , -N(R 10 )CO 2 R 11 , -COR 12 , -N0 2 or D, wherein -D, R 10 and R 1 are as defined above and R 12 represents R 10 , -(CH 2 ) m OR 10 or -(CH 2 ) q C0 2 R 10 wherein R 10 is as previously defined, m is 1 to 4 and q is 0 to 4; said alkenyl and alkynyl R 40 groups not containing -OH, -SH or -N(R 10 ) 2 on a carbon containing a double or triple bond respectively; or R40 represents phenyl substituted with a group selected from -S0 2 NH 2 , -NHS0 2 CH 3 , -S0 2 NHCH 3 , -S0 2 CH 3> -SOCH 3 , -SCH 3 , or -NHSO2CF3, preferably, said group is located in the para (p-) position of the phenyl ring; or R40 represents a group selected from R 42 represents wherein R 20 , R 21 and R 46 are each independently selected from the group consisting of: (1) H; (2) -(CH 2 ) q SC(0)CH 3 wherein q is 1 to 3 (e.g., -CH 2 SC(0)CH 3 ); (3) -(CH 2 ) q OS0 2 CH 3 wherein q is 1 to 3 (e.g., -CH 2 OS0 2 CH 3 ); (4) -OH; (5) -CS(CH 2 )w(substituted phenyl) wherein w is 1 to 3 and the substitutents on said substituted phenyl group are the same substitutents as described below for said substituted phenyl (e.g., -C-S-CH 2 -4- methoxyphenyl); (6) -NH 2 ; (7) -NHCBZ (wherein CBZ stands for carbonylbenzyloxy--i.e., CBZ represents -C(0)OCH 2 C 6 Hs); (8) -NHC(0)OR 22 wherein R 22 is an alkyl group having from 1 to 5 carbon atoms (e.g., R 22 is t-butyl thus forming -NHBOC wherein BOC stands for tert-butyloxycarbonyl-i.e., BOC represents -C(0)OC(CH 3 ) 3 ), or R 22 represents phenyl substituted with 1 to 3 alkyl groups (e.g., 4- methylphenyl); (9) alkyl (e.g., ethyl); (10) -(CH 2 )kPhenyl wherein k is 1 to 6, usually 1 to 4 and preferably 1 (e.g., benzyl); (11) phenyl; (12) substituted phenyl (i.e., phenyl substituted with from 1 to 3 substituents, preferably one) wherein the substituents are selected from the group consisting of: halo (e.g., Br, Cl, or I, with Br being preferred); N0 2 ; -OH; -OCH 3 ; -NH 2 ; -NHR 22 ; -N(R 22 ) 2 ; alkyl (e.g., alkyl having from 1 to 3 carbons with methyl being preferred); -0(CH 2 )tphenyl (wherein t is from 1 to 3 with 1 being preferred); and -0(CH 2 )tsubstituted phenyl (wherein t is from 1 to 3 with 1 being preferred); examples of substituted phenyls include, but are not limited to, p-bromophenyl, m-nitrophenyl, o- nitrophenyl, m-hydroxyphenyl, o-hydroxyphenyl, methoxyphenyl, p- methylphenyl, m-methylphenyl, and -OCH 2 CβH5; (13) naphthyl; (14) substituted naphthyl, wherein the substituents are as defined for substituted phenyl above; (15) bridged polycyciic hydrocarbons having from 5 to 10 carbon atoms (e.g., adamantyl and norbornyl); (16) cycloalkyl having from 5 to 7 carbon atoms (e.g., cyclopentyl, and cyclohexyl); (17) heteroaryl (e.g., pyridyl, and pyridyl N-oxide); (18) hydroxyalkyl (e.g., -(CH 2 )yOH wherein v is 1 to 3, such as, for example, -CH 2 OH); (19) substituted pyridyl or substituted pyridyl N-oxide wherein the substituents are selected from methylpyridyl, morpholinyl, imidazolyl, 1-piperidinyl, 1-(4-methylpiperazinyl), -S(0)tR 11 , or any of the substituents given above for said substituted phenyl, and said substitutents are bound to a ring carbon by replacement of the hydrogen bound to said carbon; (20) (21) (22) (23) -NHC(0)-(CH 2 )k-phenyl or -NH(0)-(CH 2 ) k -substitued phenyl, wherein said k is as defined above (i.e., 1-6, usually 1-4 and preferably 1); (24) piperidine Ring V: wherein R 50 represents H, alkyl (e.g., methyl), alkylcarbonyl (e.g., CH 3 C(0)-), alkyloxycarbonyl (e.g., -C(0)0-t-C H 9 , -C(0)OC 2 H 5 , and -C(0)OCH 3 ), haloalkyl (e.g., trifluromethyl), or -C(0)NH(R 10 ) wherein R 10 is H or alkyl; Ring V includes examples of Ring V include: (25) -NHC(0)CH 2 C 6 H 5 or -NHC(0)CH 2 -substituted-C 6 H5, for example -NHC(0)CH2-p-hydroxyphenyl, -NHC(0)CH 2 -m-hydroxyphenyl, and -NHC(0)CH 2 -o-hydroxyphenyl; (26) -NHC(0)OC 6 H 5 ; (27) (28) (29) (30) -OC(0)-heteroaryl, for example (31) -O-alkyl (e.g., -OCH 3 ); (32) -CF 3 ; (33) -CN; (34) a heterocycloalkyl group of the formula — N - O — N r-\ ) — N /-\ N- R 10 — N S(0) t \_^ ^_/ >^_ , or (35) a piperidinyl group of the formula wherein R 85 is H, alkyl, or alkyl substituted by -OH, -SCH3 or -SH (preferably -OH or -SCH3); and (36) triazolyl; or R 20 and R 21 taken together form a =0 group and the remaining R46 j S as defined above; or two of R 20 , R 21 and R 46 taken together form piperidine Ring V wherein Ring V and R 50 are as defined above; with the proviso R 46 , R 20 , and R 21 are selected such that the carbon atom to which they are bound does not contain more than one heteroatom (i.e., R 46 , R 20 , and R 21 are selected such that the carbon atom to which they are bound contains 0 or 1 heteroatom); R 44 represents wherein R 25 represents heteroaryl (e.g., pyridyl or pyridyl N-oxide), N-methyipiperidinyl or aryl (e.g., phenyl and substituted phenyl); and R 48 represents H or alkyl (e.g., methyl); R54 represents an N-oxide heterocyclic group of the formula (i), (ii), (iii) or (iv): (i) (») (iϋ) (iv) wherein R 56 , R 58 , and R 60 are the same or different and each is independently selected from H, halo, -CF 3 , -OR 10 , -C(0)R 1 ° -SR 10 , -S(0) e 11 (wherein e is 1 or 2), -N(R 10 ) 2 , -N0 2 , -C0 2 R 10 , -OC0 2 R 11 , -OCOR 10 , alkyl, aryl, alkenyl or alkynyl, which alkyl may be substituted with -OR 10 , -SR 10 or -N(R 10 ) 2 and which alkenyl may be substituted with OR 11 or SR 11 ; or R54 represents an N-oxide heterocyciic group of the formula (ia), (iia), (iiia) or (iva): (ia) (iia) (iiia) (iva) wherein Y represents N + -0" and E represents N; or R 54 represents an alkyl group substituted with one of said N-oxide heterocyciic groups (i), (ii), (iii), (iv), (ia), (iia), (iiia) or (iva); Z represents O or S such that R can be taken in combination with R 5 , R 6 , R 7 or R 8 as defined above, or R represents R 40 , R 42 , R 44 or R 54 ; with the proviso that when: (1) R 1 , R 2 , R 3 and R 4 are independently selected from H, halo, -CF 3 , -OR 10 -COR 10 , -SR 10 , -S(0) t R 11 , -N(R 10 ) 2 , -N0 2 , -OC(0)R 1 °, -C0 2 R 1 ° -OC0 2 R 11 , -CN, -NR 10 COOR 1 , -SR 1 C(O)OR 11 , -SR 11 N(R 75 ) 2 , benzotriazol-1-yloxy, tetrazol-5-ylthio, substituted tetrazol- 5-ylthio, alkynyl, alkenyl or alkyl; or R 1 and R 2 are selected from H, halo, -CF 3 , -OR 10 -COR 10 , -SR 10 , -S(0) t R 11 , -N(R 10 ) 2l -N0 2 , -OC(0)R 1 °, -C0 2 R 10 -OC0 2 R 11 , -CN, -NR 1 °COOR 11 , -SR 11 C(0)OR 11 , -SR 1 N(R 75 ) 2 , benzotriazol-1-yloxy, tetrazol-5-ylthio, substituted tetrazol- 5-ylthio, alkynyl, alkenyl or alkyl, and R 3 and R 4 taken together represent a saturated or unsaturated C5-C7 fused ring to the benzene ring (Ring III); and (2) the dotted line between carbon atoms 5 and 6 represents an optional double bond, such that when a double bond is present, A and B independently represent -R 10 , halo, -OR 1 1 , -OC0 2 R 1 or -OC(0)R 1 ° and when no double bond is present between carbon atoms 5 and 6, A and B each independently represent H 2l -(OR 11 ) 2 , H and halo, dihalo, alkyl and H, (alkyl) 2 , -H and -OC(0)R 1 °, H and -OR 10 , =0, aryl and H, =NOR 10 or -0-(CH 2 ) p -0- wherein p is 2, 3 or 4; then R is selected from: (a) R 42 wherein at least one of R 20 , R 21 or R 46 is selected from: (1) substituted pyridyl or substituted pyridyl N-oxide wherein the substituents are selected from methylpyridyl, morpholinyl, imidazolyl, 1-piperidinyl, 1-(4-methylpiperazinyl), or -S(0)tR 11 ; (2) -CN; (3) triazolyl; (4) a heterocycloalkyl group of the formula — N O — N > — N N - ] > ιo • N S(0) t or or (5) a piperidinyl group of the formula wherein R 85 is H, alkyl, or alkyl substituted by -OH, -SCH 3 or -SH (preferably -OH or -SCH3); or (b) R 44 wherein R 25 is N-methylpiperidinyl. Examples of R 20 , R 21 , and R 46 for the above formulas include: Examples of R 25 groups include: , and wherein Y represents N or NO, R 28 is selected from the group consisting of: Ci to C4 alkyl, halo, hydroxy, N0 2 , amino (-NH 2 ), -NHR 3 and -N(R 30 )2 wherein R 30 represents C1 to Cβ alkyl. This invention also provides novel compounds of Formula 1.0 having the Formula 5.0. This invention further provides novel compounds of Formula 1.0 having the Formula 5.1. Additionally, this invention provides novel compounds of Formula 1.0 having the Formula 5.2. These formulas are identified below and all substituents are as defined for Formula 1.0: This invention further provides novel compounds of Formula 1.0 having the formula: wherein a, b, c, d, R 5 , R 6 , R 7 , R 8 , A, B and Z are as defined for Formula " .0; each R 1 and each R 2 is independently selected from H, halo, -CF 3 , ■OR 10 , -COR 10 , -SR 10 , -S(0) t R 11 (wherein t is 0, 1 or 2), -SCN, -N(R 10 ) 2 , -NR 1 °R 11 , -N0 2 , -OC(0)R 10 . -C0 2 R 10 , -OC0 2 R 11 , -CN, -NHC(0)R 10 -NHS0 2 R 10 . -CONHR 10 , -CONHCH 2 CH 2 OH, -NR 10 COOR 11 . -SR 11 C(0)OR 11 , -SR 11 N(R 5 ) 2 (wherein each R 75 is independently selected from H and -C(0)OR 11 ), benzotriazol-1-yloxy, tetrazol-5-ylthio, or substituted tetrazol- 5-ylthio, alkynyl, alkenyl or alkyl, said alkyl or alkenyl group optionally being substituted with halo, -OR 10 or -CO2R 10 ; R 3 and R 4 are the same or different and each independently represents H, any of the substituents of R 1 and R 2 , or R 3 and R 4 taken together represent a saturated or unsaturated C5-C7 fused ring to the benzene ring; R 25 represents heteroaryl, N-methylpiperdinyl or aryl (preferably R 25 represents heteroaryl); and R 48 represents H or alkyl; and with the proviso that: (1) when R 25 is selected from heteroaryl or aryl then: (a) at least one of said R 1 , R 2 , R 3 and R 4 groups is selected from -SCN, -NR 10 R 11 , -NHC(0)R 10 , -NHSO2R 10 -CONHR 10 , -CONHCH 2 CH 2 OH, or (b) the double bond between carbon atoms 5 and 6 is present and at least one of A and B represents -NO2; and (2) when R 25 is N-methylpiperidinyl selected from 3-N-methyl- piperidinyl or 4-N-methylpiperidinyl then R 1 and R 2 are not H, halo, -CF3, benzotriazoMyloxy or lower alkyl when: (a) R 3 and R 4 are selected from H and halo; and (b) the double bond between carbon atoms 5 and 6 is present and A and B are selected from H, lower alkyl or lower alkoxy, or the double bond between carbon atoms 5 and 6 is absent and A and B are selected from H2, (-H and -OH) or =0; and (c) R 5 , R 6 , R 7 , and R 8 are H; and (d) Z is O. Compounds of 5.3, 5.3A and 5.3B also include compounds wherein when R 25 is N-methylpiperidinyl selected from 3-N-methyl- piperidinyl or 4-N-methylpiperidinyl then R 1 and R 2 are not H, halo, -CF 3 , benzotriazoMyloxy or lower alkyl. Compounds of 5.3, 5.3A and 5.3B further include compounds wherein when R 25 is N-methylpiperidinyl then R 1 and R 2 are not H, halo, -CF3, benzotriazoMyloxy or lower alkyl. Compounds of 5.3, 5.3A and 5.3B also include compounds wherein when R 25 is N-methylpiperidinyl then: (1) at least one of said R 1 , R 2 , R 3 and R 4 is selected from: -SCN, -NR 10 R 11 , -NHC(0)R 10 -NHSO2R 10 , -CONHR 10 , -CONHCH 2 CH 2 OH, or (2) the double bond between carbon atoms 5 and 6 is present and at least one of A and B represents -N0 2 . This invention also provides a method for inhibiting tumor growth by administering an effective amount of the tricyclic compounds, described herein, to a mammal (e.g., a human) in need of such treatment. In particular, this invention provides a method for inhibiting the growth cf tumors expressing an activated Ras oncogene by the administration of an effective amount of the above described compounds. Examples of tumors which may be inhibited include, but are not limited to, lung cancer (e.g., lung adenocarcinoma), pancreatic cancers (e.g., pancreatic carcinoma such as, for example, exocrine pancreatic carcinoma), colon cancers (e.g., colorectal carcinomas, such as, for example, colon adenocarcinoma and colon adenoma), myeloid ieukemias (for example, acute myelogenous leukemia (AML)), thyroid follicular 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, wherein Ras proteins are aberrantly activated as a result of oncogenic mutation in other genes- i.e., the Ras gene itself is not activated by mutation to an oncogenic form- with said inhibition being accomplished by the administration of an effective amount of the tricyclic compounds described herein, to a mammal (e.g., a human) in need of such treatment. For example, the benign proliferative disorder neurofibromatosis, or tumors in which Ras is activated due to mutation or overexpression of tyrosine kinase oncogenes (e.g., neu, src, abl, lck, and fyn), may be inhibited by the tricyclic compounds described herein. The compounds of this invention inhibit farnesyl protein transferase and the famesylation of the oncogene protein Ras. This invention further provides a method of inhibiting ras farnesyl protein transferase, in mammals, especially humans, by the administration of an effective amount of the tricyclic compounds described above. The administration of the compounds of this invention to patients, to inhibit farnesyl protein transferase, is useful in the treatment of the cancers described above. The tricyclic compounds useful in the methods of this invention inhibit the abnormal growth of cells. Without wishing to be bound by theory, it is believed that these compounds may function through the inhibition of G-protein function, such as ras p21, by blocking G-protein isoprenylation, thus making them useful in the treatment of proliferative diseases such as tumor growth and cancer. Without wishing to be bound by theory, it is believed that these compounds inhibit ras farnesyl protein transferase, and thus show antiproliferative activity against ras transformed cells. DETAILED DESCRIPTION OF THE INVENTION As used herein, the following terms are used as defined below unless otherwise indicated: MH + -represents the molecular ion plus hydrogen of the molecule in the mass spectrum; Bu-represents butyl; Et-represents ethyl; Me-represents methyl; Ph-represents phenyl; benzotriazoM-yloxy represents 1 -methyl-tetrazol-5-ylthio represents aikyl-(including the alkyl portions of alkoxy, alkylamino and dialkylamino)-represents straight and branched carbon chains and contains from one to twenty carbon atoms, preferably one to six carbon atoms; alkanediyl-represents a divalent, straight or branched hydrocarbon chain having from 1 to 20 carbon atoms, preferably 1 to 6 carbon atoms, the two available bonds being from the same or different carbon atoms thereof, e.g., methylene, ethylene, ethylidene, -CH2CH2CH2-, -CH2CHCH3, -CHCH2CH3, etc. cycloalkyl-represents saturated carbocyclic rings branched or unbranched of from 3 to 20 carbon atoms, preferably 3 to 7 carbon atoms; heterocycioalkyl-represents a saturated, branched or unbranched carbocylic ring containing from 3 to 15 carbon atoms, preferably from 4 to 6 carbon atoms, which carbocyclic ring is interrupted by 1 to 3 hetero groups selected from -0-, -S- or - NR 10 -(suitable heterocycloalkyl groups including 2- or 3-tetrahydrofuranyl, 2- or 3- tetrahydrothienyl, 2-, 3- or 4- piperidinyl, 2- or 3-pyrrolidinyl, 2- or 3-piperizinyl, 2- or 4-dioxanyl, etc.); alkenyl-represents straight and branched carbon chains having at least one carbon to carbon double bond and containing from 2 to 12 carbon atoms, preferably from 2 to 6 carbon atoms and most preferably from 3 to 6 carbon atoms; alkynyl-represents straight and branched carbon chains having at least one carbon to carbon triple bond and containing from 2 to 12 carbon atoms, preferably from 2 to 6 carbon atoms; aryl (including the aryl portion of aryloxy and aralkyl)-represents a carbocyclic group containing from 6 to 15 carbon atoms and having at least one aromatic ring (e.g., aryl is a phenyl ring), with all available substitutable carbon atoms of the carbocyclic group being intended as possible points of attachment, said carbocyclic group being optionally substituted (e.g., 1 to 3) with one or more of halo, alkyl, hydroxy, alkoxy, phenoxy, CF 3 , amino, alkylamino, dialkyiamino, -COOR 10 or -N0 2 ; and halo-represents fluoro, chloro, bromo and iodo; and heteroaryl-represents cyclic groups, optionally substituted with R 3 and R 4 , having at least one heteroatom selected from O, S or N, said heteroatom interrupting a carbocyclic ring structure and having a sufficient number of delocalized pi electrons to provide aromatic character, with the aromatic heterocyciic groups preferably containing from 2 to 14 carbon atoms, e.g., triazolyl, 2-, 3- or 4-pyridyl or pyridyl N-oxide (optionally substituted with R 3 and R 4 ), wherein pyridyl N-oxide can be represented as: The following solvents and reagents are referred to herein by the abbreviations indicated: tetrahydrofuran (THF); ethanol (EtOH); methanol (MeOH); acetic acid (HOAc or AcOH); ethyl acetate (EtOAc); N,N- dimethyiformamide (DMF); trifluoroacetic acid (TFA); trifluoroacetic anhydride (TFAA); 1-hydroxybenzotriazole (HOBT); m-chloroperbenzoic acid (MCPBA); triethylamine (Et3N); diethyl ether (Et2θ); ethyl chloroformate (CIC0 2 Et); and 1-(3-dimethylaminopropyl)-3-ethyl carbodiimide hydrochloride (DEC). Reference to the position of the substituents R 1 , R 2 , R 3 , and R 4 is based on the numbered ring structure: For example, R 1 can be at the C-4 position and R 2 can be at the C-2 or C-3 position. Also, for example, R 3 can be at the C-8 position and R 4 can be at the C-9 position. Representative structures of Formula 1.0 include but are not limited to: Preferably, for the compounds of Formula 1.0 (including 1.0a to 1.0d): each of a, b, c, and d are C (carbon); or one of a, b, c and d (most preferably a) represents N or NO, most preferably N, and the remaining a, b, c and d groups represent CR 1 or CR 2 ; each R 1 and each R 2 is independently selected from H, halo (e.g., Cl, Br and F), -CF 3 , -OR 10 (e.g., hydroxy and alkoxy (e.g., -OCH 3 )), alkyl (e.g., methyl and t-butyl, said alkyl group being optionally substituted with halo), benzotriazoM-yloxy, -S(0) t R 1 1 (e.g., -SCH 2 CH 3 ), -SR 1 C(0)OR (e.g., -SCH2CO2CH3), -SR 10 (e.g., R 10 represents -CH 2 C 6 H 5 ) and 1- methyl-tetrazol-5-ylthio; most preferably R 1 and R 2 are independently H, halo, -CF3, lower alkyl (e.g., C1 to C4, more preferably methyl) or benzotriazoM-yloxy; more preferably R 1 is Cl or H, and R 2 is H, Cl or Br; still more preferably R 1 is at the C-4 position, and R 2 is at the C-3 position; even more preferably R 2 is Br, Cl or I; R 3 and R 4 are the same or different and each independently represents H, halo, -CF 3 , -OR 10 , -COR 10 , -SR 10 , -S(0) t R 11 (wherein t is 0, 1 or 2), -N(R 0 ) 2 , -N0 2 , -OC(0)R 1 °, -C0 2 R 10 , -OC0 2 R 11 , -C(0)NHR 1 ° -CN, -NR 10 COOR 11 , alkynyl, alkenyl or alkyl, said alkyl or alkenyl group optionally being substituted with halo, -OR 10 or -CO2R 10 ; most preferably R 3 and R 4 independently represent H, halo, -CF3, -OR 10 or alkyl (said alkyl group being optionally substituted with halo); more preferably R 3 and R 4 independently represent H or halo (e.g., Cl, Br, or F); even more preferably R 3 is at the C-8 position and R 4 is at the C-9 positon; still more preferably R 3 is Cl at the C-8 position and R 4 is H at the C-9 position; R 5 , R 6 , R 7 and R 8 each independently represents H, -CF3 or alkyl (said alkyl optionally being substituted with -OR 10 ); most preferably R 5 , R 6 , R 7 and R 8 independently represent H and alkyl, and more preferably H; when the optional double bond between carbon atoms 5 and 6 is present, A and B independently represent H, -R 10 or -OR 10 , most preferably H, lower alkyl (C-i to C4) and alkyloxy (i.e., R 10 represents alkyl), more preferably H and -OH, and still more preferably H; and when no double bond is present between carbon atoms 5 and 6, A and B each independently represent H 2 , -(OR 10 ) 2 , alkyl and H, (alkyl) 2l - H and -OR 10 or =0, most preferably H 2 , -H and -OH, or =0, and more preferably A represents H 2 and B represents H 2 or =0; R represents R 42 or R 44 ; and Z represents O or S, and most preferably O. Compounds of Formula 5.0 include: Compounds of Formula 5.1 include: Compounds of Formula 5.2 additionally include: Compounds of Formula 5.3 include: Compounds of formula 5.3A include: For the compounds of Formulas 5.0, 5.0a-5.0h, 5.1, 5.1a-5.1h, 5.2, and 5.2a-5.2b the definitions of the substituents are as defined for Formula 1.0. For the compounds of Formulas 5.3a-5.3h, 5.3A, and 5.3Aa- 5.3Ah, the definitions of the substituents are as defined for Formulas 5.3, 5.3A and 5.3B. Preferably, for compounds of Formulas 5.0, 5.0a-5.0h, 5.1, 5.1a- 5.1h, 5.2, and 5.2a-5.2b, R 46 is selected from piperidine Ring V, heteroaryl, phenyl, substituted phenyl, substitued pyridyl or substituted pyridyl N-oxide, and R 20 and R 21 are independently selected from H or alkyl. Most preferably, R 46 is pyridyl, pyridyl N-oxide or piperidine Ring V. More preferably, R 46 is pyridyl, pyridyl N-oxide or piperidine Ring V and both R 20 and R 21 are hydrogen or both R 20 and R 21 are alkyl (still more preferably methyl). Even more preferably, R 46 is selected from 3-pyridyl, 4-pyridyl, 3- pyridyl N-oxide, 4-pyridyl N-oxide, 4-N-methylpiperidinyl, 3-N- methylpiperidinyl, 4-N-acetylpiperidinyl or 3-N-acetylpiperidinyl, and both R 20 and R 21 are hydrogen or both R 20 and R 21 are alkyl (still even more preferably methyl). Even still more preferably, R 46 is selected from 3- pyridyl, 3-pyridyl N-oxide, 4-pyridyl, and 4-pyridyl N-oxide, and both R 20 and R 21 are hydrogen or both R 20 and R 21 are methyl. For compounds of Formulas 5.0, 5.0a-5.0h, 5.1, 5.1a-5.1h, 5.2, and 5.2a-5.2b, when R 1 , R 2 , R 3 , R 4 , A and B are selected as described in the proviso at the end of the definition of Formula 1.0, then R 46 is preferably selected from: triazolyl, 1-N-methylpiperazinyl, 1- piperazinyl or a heterocycloalkyl group of the formula — N S(0) t with 1-N-methylpiperazinyl, 1-piperazinyl, or a heterocycloalkyl group of the formula -N SIO,, being more preferred. Examples of the R 42 groups include: H 3 C CH 3 H 3 JC COH 3 H 3 C CH 3 H H " Preferably for the compounds of Formulas 5.3, 5.3a-5.3h, 5.3A, 5.3Aa-5.3Ah, and 5.3B, R 25 represents phenyl, 2-pyridyl, 3-pyridyl, 4- pyridyl, or 2-, 3- or 4-pyridyl N-oxide, and most preferably 4-pyridyl or 4- pyridyl N-oxide. More prefereably, R 48 represents H or methyl and still more preferably H. Representative compounds of the invention include: Preferred compounds are the compounds of Examples: 426, 400-G, 400-C, 400-F, 400-E, 425-H, 401 , 400-B, 400, 400-L, 425-U, 413, 400-J, 417-B, 438, 411-W, 425-0, 400-D, 400-K, 410-G and 400-H. Lines drawn into the ring systems indicate that the indicated bond may be attached to any of the substitutable ring carbon atoms. Certain compounds of the invention may exist in different isomeric (e.g., enantiomers and diastereoisomers) forms. The invention contemplates all such isomers both in pure form and in admixture, including racemic mixtures. Enol forms are also included. Certain tricyclic compounds will be acidic in nature, e.g. those compounds which possess a carboxyi or phenolic hydroxyl group. These compounds may 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, hydroxyalkylamines, N-methylglucamine and the like. Certain basic tricyclic compounds also form pharmaceutically acceptable salts, e.g., acid addition salts. For example, the pyrido- nitrogen atoms may form salts with strong acid, while compounds having basic substituents such as amino groups also form salts with weaker acids. Examples of suitable acids for salt formation are hydrochloric, sulfuric, phosphoric, acetic, citric, oxalic, malonic, salicylic, malic, fumaric, succinic, ascorbic, maleic, methanesuifonic and other mineral and carboxylic acids well known to those 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 may be regenerated by treating the salt with a suitable dilute aqueous base solution such as dilute aqueous NaOH, potassium carbonate, ammonia and sodium bicarbonate. The free base forms differ from their respective salt forms somewhat in 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 purposes of the invention. All such 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 purpopses of the invention. Compounds of the invention may be made by the methods described in the examples below, and by the methods described in WO 95/10516 published April 20, 1995--see, for example, the methods for preparing compounds of Formula 400.00. On page 57 at lines 7 to 16 of WO 95/10516 a process is disclosed for introducing substituents at the C-3 position of pyridine Ring I of Formula 1.0 by nitrating a compound of Formula 415.00. The nitro group may then be reduced to the corresponding amine using the disclosed reagents or powdered Zn and either CuCI 2 or CuBr in aqueous EtOH . Compounds useful in this invention are exemplified by the following preparative examples, which should not be construed to limit the scope of the disclosure. Alternative mechanistic pathways and analogous structures within the scope of the invention may be apparent to those skilled in the art. PREPARATIVE EXAMPLE 4R 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 (9.06 mmol) of iodine. Heat the mixture at reflux for 3 hours, cool, then dilute with 50 mL of CH2CI2. Wash the organic phase with 5% NaHSθ3(aqeuous) (3 x 80 mL), then with 1 M NaOH (aqueous) (2x 80 mL), and dry over MgSθ4. Concentrate to a residue chromatograph (silica gel, 30% EtOAc/hexanes), to give 3.2 g (42% yield) of the product iodo compound. Mass Spec: MH+ = 509 The product of Step A is hydrolyzed via substantially the same procedure as described in Example 358, Step A, of WO 95/10516, to give the iodoamine product in 89% yield. PREPARATIVE EXAMPLE 49 The product of Preparative Example 47, Step C, of WO 95/10516, (2.42 g) is hydrolyzed via substantially the same procedure as described in Example 358, Step A, of WO 95/10516, to give 1.39 g (69% yield) of the bromoamine product. PREPARATIVE EXAMPLE 51 A Step Combine 82.0 g (0.26 mole) of the product of Preparative Example 1, Step G, of WO 95/10516, and 1 L of toluene, then add 20.06 g (0.53 mole) of LiAIH 4 and heat the reaction mixture at reflux overnight. Cool the mixture to room temperature and add -1 L of Et 2 0, followed by dropwise addition of saturated Na 2 S04 (aqueous) until a precipitate forms. Filter and stir the filtrate over MgSθ4 for 30 minutes, then concentrate in vacuo to give the product compound in 83% yield. Mass Spec: MH+ = 313 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 at reflux overnight. Cool to 25°C, pour into 200 mL of water and extract with EtOAc. Dry the extract over MgS04, concentrate in vacυo to a residue and chromatograph (silica gel, 50% EtOAc/hexane) to give 15 g of the product compound. Mass Spec: MH + = 385. SiaOmi-i Dissolve 3.2 g (10.51 mmol) of tetra-n-butylammonium nitrate in 25 mL of CH 2 CI 2 and add 2.2 g (10.51 mmol, 1.5 mL) of TFAA. Cool to 0°C and add the mixture (via cannula) to a solution of 3.68 g (9.56 mmol) of the product of Step B in 50 mL of CH2CI 2 at 0°C, then stir at 0°C for 3 hours. Allow the mixture to warm to 25°C while stirring overnight, then extract with saturated NaHC03 (aqueous) and dry over MgSθ 4 . Concentrate in vacuo to a residue and chromatograph (silica gel, 30% EtOAc/hexane) to give 1.2 g of the product compound. Mass Spec: MH+ = 430 Step P; Combine 2.0 g (4.7 mmol) of the Product of Step C and 150 mL of 85% EtOH (aqueous), add 2.4 g (42 mmol) of Fe filings and 0.24 g (2.1 mmol) of CaCI 2 , and heat at reflux for 16 hours. Filter the hot mixture through a bed of celite ® , wash the celite® with hot EtOH. Concentrate the filtrate in vacuo to give a 100% yield of the product compound. Mass Spec: MH+ = 400. Combine 2.0 g (5.2 mmol) of the Product of Step D and 20 mL of 48% HBr, cool the mixture to -5°C. Stir the mixture at -5°C for 15 minutes and slowly add a solution of 1.07 g (15.5 mmol) of NaN0 2 in 10 mL of water. Stir for 45 minutes, then quench with 50% NaOH (aqueous) to pH -10. Extract with EtOAc, dry the combined extracts over MgS0 and concentrate in vacuo to give the product compound. Mass Spec: MH + = 465 Step F; Hydroyze 4.0 g of the Product of Step E via substantially the same process as described for Example 358, Step A, of WO 95/10516, to give 1.39 g of the product compound. Mass Spec: MH + = 392 PREPARATIVE EXAMPLE 53 ≤ISCLA: Combine 14.95 g (39 mmol) of the Product of Preparative Example 34A, of WO 95/10516, and 150 mL of CH 2 CI 2 , then add 13.07 g (42.9 mmol) of (nBu) 4 NN03 and cool the mixture to 0°C. Slowly add (dropwise) a solution of 6.09 mL (42.9 mmol) of TFAA in 20 mL of CH2CI2 over 1.5 hours. Keep the mixture at 0°C overnight, then wash successively with saturated NaHCθ3 (aqueous), water and brine. Dry the organic solution over Na2Sθ 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 two product compounds 53(i) and 53(ii), respectively. Mass Spec(53(i)): MH + = 428.2; Mass Spec (53(H)): MH+ = 428.3 Step B; The compound 53(ii) from Step A (0.20 g) is hydrolyzed via substantially the same procedure as 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 starting compound indicated and substantially the same procedure as described in Preparative Example 53, Step B, the compounds in Table 1 are prepared: PREPARATIVE EXAMPLE 54 Combine 22.0 g (51.4 mmol) of the product 53(i) from Preparation 53, Step A, 150 mL of 85% EtOH (aqueous), 25.85 g (0.463 mole) of Fe powder and 2.42 g (21.8 mmol) of CaCl2, and heat at reflux overnight. Add 12.4 g (0.222 mole) of Fe powder and 1.2 g (10.8 mmol) of CaCI 2 and heat at reflux for 2 hours. Add another 12.4 g (0.222 mole) of Fe powder and 1.2 g (10.8 mmol) of CaCl2 and heat at reflux for 2 hours more. Filter the hot mixture through celite ® , wash the celite ® with 50 mL of hot EtOH and concentrate the filtrate in vacuo to a residue. Add 100 mL of anhydrous EtOH, concentrate to a residue and chromatograph the residue (silica gel, MeOH/CH2CI 2 gradient) to give 16.47 g of the product compound. Step B: Combine16.47 g (41.4 mmol) of the product compound from Preparative Example 54, Step A, and 150 mL of 48% HBr (aqueous) and cool to -3°C. Slowly add (dropwise) 18 mL of bromine, then slowly add (dropwise) a solution of 8.55 g (0.124 mole) of NaN0 β 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 Na 2 Sθ4. 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 Spec. (54(i)): MH+ = 461.2; Mass Spec. (54(H)): MH+ = 539 PREPARATIVE EXAMPLE 55 The title compound is known and is prepared by the procedure described in Bioorα. & Med. Chem. Lett.. 2, (No. 6) 1073-1078 (1993). PREPARATIVE EXAMPLE 5fi 'CH 3 Step A; Combine 2.04 g of the product of Preparative Example 44, of WO 95/10516 (published April 20, 1995), 1.3 mL of PBr 3 , 1.0 mL of EtβN and 20 mL of CH 2 Br2, and heat the mixture at reflux overnight. Cool the mixture, dilute with CH2CI2 and wash with 1 N NaOH (aqueous). Dry over MgSθ4 and concentrate in vacuo to give 1.22 g (53% yield) of the product compound. Mass Spec: MH + = 541 SleC B: Combine 0.3 g of the product compound from 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/CH2CI 2 ) to give 80 mg (27%) yield of the product compound. Mass Spec: MH + = 534 Step C: Combine 66 mg of the product compound from Preparative Example 56, Step B, 4 mL of anhydrous EtOH, and 5 mL of concentrated HCI stir at reflux for 60 hours. Cool the reaction mixture to about 0°C and basify by adding KOH. Extract with CH2CI2, dry the extract over MgSθ 4 , and concentrate in vacuo to give 46 mg (81% yield) of the product compound. Mass Spec: MH + = 462 PREPARAT1VE EXAMPLE 57 Ste Combine 1.19 g of the product of 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 CH2CI2, wash with saturated NaHCθ 3 (aqueous), and dry over MgS0 4 . Concentrate in vacuo to give 1.13 g (92% yield) of the product compound. Mass Spec: MH + = 493. Hydrolyze 1.13 g of the product of Step A via substantially the same procedure as described for Preparative Example 56, Step C, to give 0.61 g (63% yield) of the product compound. PREPARATIVE EXAMPLE Sfi Step A: Combine 1.07 g (3.52 mmol) of tetrabutylammonium nitrate, 4 mL of anhydrous CH2CI2 and 0.743 g (3.52 mmol) of TFAA, and add the resulting mixture to a solution of 1.22 g (3.20 mmol) of the title compound of Preparative Example 37, of WO 95/10516, in 8 mL of anhydrous CH2CI2 at room temperature. Stir at room temperature overnight, then wash with 20 mL of saturated NaHCθ3 (aqueous) and 20 mL of brine, and dry over MgSθ4. 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 Spec (58(i)): MH + =426. m.p. (58(i)) 97.5° - 99.2°C. SlficB: Reduce the product 58(i) from Step A via essentially the same procedure as described in Preparative Example 47, Step B, of WO 95/10516, to give the product compound. Mass Spec: MH + = 396 Step C; React the product from Step B with HBr and bromine via essentially the same procedure as described in Preparative Example 47, Step C, of WO 95/10516, to give the product compound. Mass Spec: MH+ = 459 tep D: Hydrolyze 0.83 g of the product from Step C via essentially the same procedure as described in Preparative Example 56, Step C, to give 0.56 g of the product compound. Mass Spec: MH + = 387 PREPARATIVE EXAMPLE 59 Ste Combine 7.3 g (26.4 mmol) of the starting ketone (see J. Med. Chem.. 4238 (1992)) and 230 mL of THF and cool to 0°C. Add a solution of 32.2 mmol) of N-methyl-piperidine-4-magnesium bromide in 26 mL of THF and stir at 0°-5°C for 4 hours. Add 400 mL of EtOAc, wash with saturated NH4CI (aqueous), and dry over MgS04- Concentrate in vacuo to a residue, add -200 mL of CH2CI2 and stir for 0.5 hours. Filter to collect the resulting solid and concentrate the filtrate to a volume of -100 mL and let sit at 5 °C for 18 hours. Filter and combine the solids to obtain a total of 7 g (19.4 mmol) of the product compound. m.p.=153.7°-158 °C; Mass Spec: (Cl) MH + = 376 SiecLfi; Combine 5 g of the product from Step A and 30 mL of TFA at ambient temperature and stir for 1 hour. Concentrate in vacuo to a residue, dissolve the residue in CH 2 CI and wash with a saturated NaHCθ3 (aqueous). Concentrate in vacuo to give 4.64 g of the product compound. m.p.= 136.7°-138°C; Mass Spec: (FAB) MH + = 358.1 Combine 0.6 g (1.75 mmol) of the product of Step B and 25 mL of toluene, add 0.73 mL (5.27 mmol) of Et 3 N and 1.34 mL (14 mmol) of CIC0 2 Et, and heat to 80°C for 2 hours. Add 0.7 mL more of CIC0 2 Et, heat for 1 more hour, then cool to 25 °C and concentrate in vacuo to a residue. Dissolve the residue in EtOAc and wash with 1 N NaOH (aqueous) followed by brine. Dry over MgSθ4, concentrate in vacuo to a residue and chromatograph (silica gel, 10% EtOAc/hexanes) to give 0.55 g of the product compound. Mass Spec: (FAB) MH+ = 416.2 Step D: Dissolve 5 g (12.5 mmol) of the product of Step C in 30% HBr in HOAc and heat at 40°C for 24 hours, then cautiously add the mixture to cold 25 % NaOH (aqueous). Extract with CH 2 CI 2 (3 X 100 mL), concentrate the extracts to a residue and chromatograph (silica gel, 5% to 30 % MeOH/CH 2 CI 2 ) to give 2.18 g of the product compound. m.p.= 159.5°-160.8°C; Mass Spec: (FAB) MH+ = 344.1 PREPARATIVE EXAMPLE 60 ≤l££ A Combine 16.25 g (40.83 mmol) of the product of Preparative Example 47, Step B, of WO 95/10516, and a slurry of 7.14 g (61.11 mmol) of NOBF 4 in 100 mL of CH 2 CI 2 and stir the mixture for 3 hours. Add 100 mL of o-dichlorobenzene and heat for 5 hours, distilling the CH 2 CI 2 from the mixture. Concentrate in vacuo to a residue, add 200 mL of CH2CI 2 and wash with water (2 X 200 mL). Dry over MgSθ4, concentrate in vacuo to a residue, and chromatograph (silica gel, 20% EtOAc/hexane) to give 4.1 g of product compound 60(i) and 4.01 g of Product compound 60(ii). Mass Spec (60 (i)): MH + = 418. Mass Spec (60 (ii)): MH + = 401 Step B; Hydrolyze 3.4 g of the product 60 (ii) from Step A via essentially the same process as described for Example 358, Step A, of WO 95/10516, to give 3.01 g of product compound. Mass Spec: MH + = 329 Using compound 60(i) from Preparative Example 60, Step A, and following substantially the same procedure as described in Preparative Example 60, Step B, the compound: (Preparative Example 60A) was prepared. Mass Spec: MH + = 346. PREPARATIVE EXAMPLE B1 Step A: Combine 10 g (60.5 mmol) of ethyl 4-pyridylacetate and 120 mL of dry CH2CI2 at -20°C, add 10.45 g (60.5 mmol) of MCPBA and stir at -20°C for 1 hour and then at 25°C for 67 hours. Add an additional 3.48 g (20.2 mmoles) of MCPBA and stir at 25°C for 24 hours. Dilute with CH2CI2 and wash with saturated NaHCθ3 (aqueous) and then water. Dry over MgSθ4, concentrate in vacuo to a residue, and chromatograph (silica gel, 2%- 5.5% (10% NH4OH in MeOH)/CH2Cl2) to give 8.12 g of the product compound. Mass Spec: MH+ = 182.15 Combine 3.5 g (19.3 mmol) of the product of Step A, 17.5 mL of EtOH and 96.6 mL of 10% NaOH (aqueous) and heat the mixture at 67°C for 2 hours. Add 2 N HCI (aqueous) to adjust to pH = 2.37 and concentrate in vacuo to a residue. Add 200 mL of dry EtOH, filter through celite® and wash the filter cake with dry EtOH (2X50 ml). Concentrate the combined filtrates in vacuo to give2.43 g of the title compound. Using the product of Preparative Example 26, of WO 95/10516, and substantially the same procedure as described for Preparative Example 61 , Steps A and B, the following compound was prepared: PREPARATIVE EXAMPLE 62 σ NHCOOCH 3 Combine 10 g (65.7 mmol) of 3-methoxycarbonylaminopyridine and 150 mL of CH2CI2, cool to 0°C and slowly add (dropwise) a solution of 13.61 g (78.84 mmol) of MCPBA in 120 mL of CH2CI2 at 0°C over a period of 1 hour. Stir the mixture at 25°C for 5 days, then wash with saturated NaHCOβ (aqueous), then water and dry over MgSθ4. Concentrate in vacuo to a residue and chromatograph (silica gel, 2%-5% (10% NH4OH in MeOH)/CH2Cl2) to give the product compound. Mass Spec: MH+ = 169 PREPARATIVEEXAMPLE63 Combi 5 g (36.0 mmol) of isonicotinic acid 1 - -oxide and 1 0 mL of anhydrous DMF, add 5.5 mL (39.6 mmol) of Et3N and stir at 0°C for 0.5 hours. Slowly add (dropwise) 8.5 mL (39.6 mmol) of diphenylphosphoryl azide at 0°C over 10 minutes, stir at 0°C for 1 hour and then at 25°C for 24 hours (as generally described in Pavia, θt al., Journal of Medicinal Chemistry. 33. 854-861 (1990). Concentrate in vacuo to a residue and chromatograph (silica gel, 0.5%-1% MeOH/CH 2 CI 2 ) to give 5.9 g of the product compound. Using nicotinic acid 1 -N-oxide and substantially the same procedure as described for Preparative Example 63 the following compound was prepared: PREPARATIVE EXAMPLE 64 Step A: Hydrogenate 25 g (144 mmol) of 3-pyridylacetic acid hydrochloride or 144 hours using the procedure described in Preparative Example 15, of WO 95/10516, to give 20 g of the product compound. Mass Spec: MH+ - 144. React 12 g (83.8 mmol) of the product of Step B for 148 hours using the procedure described in Preparative Example 13, Step B, of WO 95/10516, to give 17.5 g of the product compound. Mass Spec: MH + = 244.25 PREPARATIVE EXA PLE 65 Combine 25 g (164.4 mmol) of methyl 3-pyridyicarbamate and 163.3 mL of 1 N HCI (aqueous), stir until all of the solid dissolves, then hydrogenate over 10% Pd/C at 25°C at 55 psi for 220 hours. Filter, wash the solids with water and treat the combined filtrates with 150 mL of BioRad AG1X8 ion exchange resin (OH * ). Filter, wash the resin with water and concentrate the filtrate to a volume of 100 mL Add 16.43 mL (197.3 mmol) of 37% formalin and hydrogenate over 10% Pd/C at 25 β C at 55 psi for 89 hours. Filter, wash the solids with water and concentrate in vacuo to give 24.3 g of the title compound. Mass Spec: MH+ = 173.2 PREPARATIVE EXAMPLE 66 Cool 50.0 g (20.5 mmol) of 8-chioro-5,6-dihydro-11H- benzo[5,6Jcyclohepta[1,2-b]pyridin-11-one to 0°C, slowly add 75 mL (93.69 mmol) of sulfur monochloride over 20 minutes, then slowly add 25 mL (48.59 mmol) of Br 2 over 15. Heat at 95 °C for 20 hour, add 12.5 mL (24.3 mmol) of Br 2 and heat for a another 24 hours. Cool the mixture, and slowly add to a mixture of CH 2 CI 2 and 1 N NaOH (aqueous) at 0°C. Wash 0363 - 52 the organic phase with water, dry over MgS0 4 and concentrate in vacuo to a residue. Chromatograph the residue (silica gel, 500 mL CH2CI2 then 0.2%-5% (10% NH4OH in MeOH)/CH2Cl2), then chromatograph again (silica gel, 3%-8.5% EtOAc hexane) to give 8.66 g of the product compound. Mass Spec: MH+ = 322 PREPARATIVE EXAMPLE 67 Dissolve 0.16 g (0.46 mmol) of 4-(8-methyl-5,6-dihydro-11H- benzo[5,6]cyclohepta[1 ,2-b]pyridin-11-ylidine)-1-ethoxycarbonyl- piperidine, in 2 mL EtOH and add 4 mL of 12 N HCI. Heat the solution for 3 hours at 85°C, then cool to 25°C. Adjust to pH = 10 with 50% NaOH (aqueous) and extract several times with 50 mL of EtOAc. Combine the organic layers, dry them over MgSθ4, and concentrate in vacuo to give the product compound. PREPARATIVE EXAMPLE 68 Step A: Disolve 2 g (5.22 mmol) of the title compound of Preparative Example 1F, of WO 95/10516, in 2.6 mL of dry N-methylpyrrolidinone. Add 0.87 g (9.4 mmol) of CuCN and 0.139 g (0.93 mmol) of sodium iodide. Heat the mixture at 200°C under nitrogen for 20 hours, cool to 25°C and repeatedly grind and mix with five 50 mL portions of CH2CI2 and 7 M NH4OH (aqueous). Wash the organic layer with 7 M NH4OH until the organic layer is no longer blue or green. Dry the combined organic layers over MgS04 and concentrate in vacuo to a residue. Chromatograph (silica gel 70% EtOAc/hexane), then recrystallize from EtOAc/hexane to give the product compound, m.p. = 152.4°-153.5°C; Mass Spec: MH + = 374 SiSQmmml Dissolve 4.08 g (10.93 mmol) of the product of Step A in 12 M HCI and heat at 85°C for 18 hours. Concentrate in vacuo to a residue. Dissolve the residue in 175 mL of MeOH, saturate with HCI gas, and heat at reflux for 18 hours. Concentrate in vacuo to give the product compound as its HCI salt. Mass Spec: MH + = 335 PREPARATIVE EXAMPLE 69 Combine 75 g (0.196 mole) of the Product of Example 1 , Step F, of WO 95/10516, and 300 mL of CH 2 CI 2 at 0°C, and slowly add (dropwise) a solution of 72 g (0.236 mole) of tetrabutylammonium nitrate and 35 mL (0.247 mole) of TFAA in 500 mL of CH 2 CI 2 . Stir at 25°C overnight, slowly add (dropwise) 1 L of saturated NaHC0 3 (aqueous). Separate the layers, wash the organic phase with brine and dry over MgSθ4- Concentrate in vacuo to a residue, chromatograph twice (1 kg silica gel, gradient of EtOAc/CH 2 CI 2 ) to give 8.63 g of product compound 69(i), and 34 g of product compound (ii). Recrystallize compound 69(i) from CH 2 CI 2 /hexane to give the purified product compound 69(i). m.p.= 186°-187°C; Mass Spec: (FAB) 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 glacial HOAc, and heat at reflux for 1.5 hours. Cool the mixture, wash with saturated NaHCθ 3 (aqueous), then with brine, dry over MgS04, and concentrate in vacuo to a residue. Chromatograph (silica gel, 5%-15% EtOAc CH2Cl2) to give 0.34 g of the product compound. Mass Spec: (FAB) MH + = 448 PREPARATIVE EXAMPLE 70 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 H 2 Sθ4 in 45 mL of water and stir the mixture. Slowly add (dropwise) a solution of 2.55 g (40 mmol) of NaN0 2 in 75 mL of water and stir at 0°-5°C for 0.5 hours. Add a boiling solution of 35.1 g CUSO 4 in 135 mL of water and heat at 100°C for 15 min. Cool the mixture, extract with CH 2 CI 2 (2 X 200 mL), wash the extracts with brine, dry over MgS0 4 , and concentrate in vacuo to a residue. Chromatograph (silica gel, 1.5%- 10% MeOH/ CH 2 CI 2 ) to give 11.36 g of the product compound. Combine 11.36 g (28.5 mmol) of the Product of Step A and 12.4 g (34.7 mmol) of N-phenyltriflimide in 120 mL of dry CH 2 CI 2 at 0°C, add 4.6 mL (33 mmol) of Et3N and stir at 25°C overnight. Concentrate in vacuo to a residue and chromatograph (silica gel, 2%-5% EtOAc/ CH 2 CI 2 ) to give 10.95 g of the product compound. Recrystallize from hot MeOH. m.p. = 154.5°-156°C; Mass Spec: (FAB) MH + = 531 £t£G-£l Combine 12.2 g (23 mmol) of the Product of Step B and 85 mL of 1- methyl-2-pyrroiidinone at 25°C, then add 2.84 g LiCI, 0.212 g of tris- furylphosphine and 0.585 g of dipalladiumtribenzylideneacetone and stir for 15 min. Slowly add (dropwise) 7.5 mL (25.77 mmol) of tributylvinyltin 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 MgSC . Concentrate in vacuo to a residue and chromatograph (silica gel, 15%-40% EtOAc/hexane) to give 8.58 g of the product compound. Mass Spec: (FAB) MH + = 409 Using 2-(tributylstannyl)thiophene and the compound of Preparative Example 70, Step B, and following substantially the same procedure as described for Preparative Example 70, Step C, the compound: (Preparative Example 70-A) was prepared, m.p. 155°-157°C, Mass Spec: MH + = 465. Step D: Hydrolyze 1.18 g (2.89 mmol) of the product of Step C via substantially the same procedure as described in Example 358, Step A, of WO 95/10516 ,to give 0.95 g of the product compound. Mass Spec: (FAB) MH + = 337 PREPARATIVE EXAMPLE 71 F,C Step A Combine 1.01 g (19.9 mmol) of the Product of Preparative Example 48, Step A, 30 mL of DMF, 1.33 g (6.96 mmol) of methyl 2,2-difluoro-2- (fluorosulfonyl)-acetate and 0.75 g (3.97 g) of Cul. Heat the mixture &\ 60°-80°C for 3 hours, then concentrate to a residue. Dilute the residue with water, extract with CH 2 CI 2 , and concentrate in vacuo to a residue. Chromatograph (silica gel, 30% EtOAc/hexane, then 10% MeOH/CH 2 CI 2 + NH4OH) to give 0.15 g of the product compound. Mass Spec: MH+ = 451.1 Step B: Hydrolyze the product of Step A using essentially the same procedure as described in Preparative Example 1, Step G, of WO 95/10516, to give the product compound. Mass Spec: MH + = 379 PREPARATIVE EXAMPLE 7? Dissolve 20 g (50 mmol) of the Product of Preparative Example 1 , Step F, of WO 95/10516, in 400 mL of concentrated H 2 Sθ4, cool to -5°C and add 5.1 g (50 mmol) of KNO3 in small portions. Stir for 3 hours, cool the mixture and slowly basify with 50% NaOH (aqueous). Extract with CH 2 CI 2 (3 X 500 mL), dry the combined extracts over MgS04, and concentrate in vacuo to a residue. Chromatograph (silica gel, 50% EtOAc/hexane) to give 16.33 g of the product compound (72i) and 2.6 g of the product compound (72ii). Mass Spec. (72(i) and (72(ii)): MH + = 428 Hydrolyze 5.46 g (12.76 mmol) of the Product of (72i) from Step A, via substantially the same procdure as described for Example 358, Step A, of WO 95/10516, to give 4.34 g of the product compound. Mass Spec: MH + = 356 PREPARATIVE EXAMPI F 73 Step A; Combine 1.6 g of the Product (54i) of Preparative Example 54, Step B, 12 mL of CH2CI2, and 1.16 g of tetrabutylammonium nitrate, cool to 0°C and slowly add (dropwise) a solution of 0.8 g of TFAA in 2 mL of CH2CI 2 . Stir for 6 hours at 0°C, let the mixture stand at 0°C overnight, then wash successively with saturated NaHC03 (aqueous), water and brine, and dry over Na 2 Sθ 4 . Concentrate in vacuo to a residue, then chromatograph (silica gel, 30% EtOAc/hexane) to give 0.38 g of the product compound. Hydrolyze 0.38 g of the Product of Step A via substantially the same procedure as described for Example 358, Step A, of WO 95/10516, to give 0.235 g of the product compound. EXAMPLE 4QQ The product of Preparative Example 48, Step B, is reacted with 4- pyridyi acetic acid via essentially the same procedure as described in Example 180, of WO 95/10516, to give the product compound (5.210). Mass Spec: MH+ = 556 Using the appropriate carboxylic acid and the starting compound indicated, the compounds in Table 2 were prepared via substantially the same procedure as described for Example 400: Preparative Mass Spec: Example 53C MH+ = 508.0 Example 400-G (5.204) Preparative Mass Spec: Example 49 MH + = 530.2 xample 400-H (5.220) Preparative Mass Spec: Example 51 A MH + = 532.3 Example 400-J (5.212) Preparative Mass Spec: Example 49 MH + = 530.2 Example 400-K (5.218) EXAMPLE 401 The product of Preparative Example 48, Step B, is reacted with 4- pyridyl acetic acid N-oxide via essentially the same procedure as described in Example 227 to give the product compound (5.209). Mass Spec: MH+ = 572 EXAMPLE 402 The product of Example 358. Step B, of WO 95/10516, is reduced via essentially the same procedure as described in Step B of Preparative Example 47, of WO 95/10516, to give the product compound. mp=133.2- 133.4 °C MH+ 445 Using the compound of Example 411-B, and following substantially the same procedure as described for Example 402, the compound: (Example 402-A) was prepared. Mass Spec: MH + = 445.2 EXAMPLE 403 Combine 0.3 g (0.67 mmol) of the product of Example 402, 5 mL of pyridine and 0.1 g (1.01 mmol) of acetic anhydride and stir the mixture at room temperature for 2 days. Add another 100 μL of acetic anhydride, warm to 60°C and stir for 6h. Neutralize the reaction mixture then basify with 1 N NaOH (aqueous) to pH =10. Extract with CH2CI2, dry the extract over MgSθ4 and concentrate to a residue. Purify the residue by HPLC eluting 8% MeOH/CH 2 CI 2 + concentrated NH 4 OH (aqueous) to give 0.22 g of the product compound. Mass Spec: MH+ = 487 EXAMPLE 404 The product of Example 402 is reacted with methanesulfonyl chloride via substantially the same procedure as described for Example 403 to give the 0.32 g of the product compound. Mass Spec: MH+ = 523 EXAMPLE 405 Combine 1.5 g (3.37 mmol) of the product of Example 402 and 10 mL of AcOH, then add 3.37 mL of a solution of bromine in AcOH and stir the mixture at room temperature overnight. Basify the mixture with 1 N NaOH (aqueous) to basic pH, then extract with EtOAc. Concentrate the extract to a residue and chromatograph (silica gel, 90% EtOAc/hexane, then 5% Et3N/EtOAc) to give the product compound. Mass Spec: MH + = 525. EXAMPLE 406 Combine 0.5 g (1.12 mmol) of the product of Example 402 and 10 mL of acetone, add 230 μL of cone HCI (aqueous) and 4 mL of water, and cool to -10°C. Add a solution of 0.085 g NaNθ2 in 4 mL of water, stir for 15 min., then add the reaction mixture to a solution of CuCN [freshly prepared by adding 0.336 g (1.34 mmol) of CuSθ4 in 2 mL of water to H2O a solution of 0.365 g (5.6 mmol) of KCN in 2 mL of H2O]. Heat the mixture to 60°-70°C, then at 70°-80°C to remove acetone. Cool the mixture and dilute with H2O, then exhaustively extracted with CH2CI2. Concentrate the extracts to a residue then purify by HPLC using 3 % methanolic ammonia in CH2CI2 to give 0.25 g (50% yield) of the product compound. Mass Spec: MH+ = 455. EXAMPLE 407 Combine 0.55 g (1.25 mmol) of the product of Example 402 and 50 mL of dilute H2SO4 at room temperature. Cool the mixture to -10°C, add a solution of 0.092 g of NaNθ2 in 5 mL of water was added and stir for 15 min. Slowly add a solution of 0.46 g (4.7 mmol) of KSCN and 0.3 g (2.49 mmol) of CuSCN in 15 mL of water over a period of 0.5 hours. Stir for 0.5 hour then heat at reflux for 15 min. Cool the mixture and adjust the pH to -7, then extract with CH2CI2. Concentrate the extracts to a residue and chromatograph (silica gel, 3% MeOH CH2Cl2 + NH4OH) to give the product compound. Mass Spec: MH + = 487 EXAMPLE 410 Using the appropriate carboxylic acid and the starting compound indicated, the compounds in Table 3 were prepared via substantially the same procedure as described in Example 180 of of WO 95/10516: TABLE 3 EXAMPLE 411 The product of Preparative Example 49 was reacted with 2-methyl- 2-(4-pyridyl)propanoic acid via substantially the same procedure as described for Example 180, of WO 95/10516, to give the product compound. Mass Spec: MH + = 538 Using the appropriate carboxylic acid (or carboxylate salt, e.g. lithium carboxylate) and the starting compound indicated, the compounds in Table 4 were prepared via substantially the same procedure as described for Example 410: EXAMPLE 412 Combine 50 mg (0.11 mmol) of the compound of Example 400-N, and 1.5 mL of SOCi 2 and stir a room temperature overnight. Concentrate in vacuo to a residue, add 2.0 mL of DMF to the residue, then add 20 mg (0.2 mmol) of 1,2,4-triazole sodium salt and heat to 100°C overnight. Cool the mixture, concentrate in vacuo to remove most of the solvent, wash with water (3 times), then dry the resiude over Na 2 S0 4 . Concentrate in vacuo to a residue and chromatograph (silica gel, 75% (10%NH 4 θH in MeOH) in CH 2 CI 2 ) to give 26 mg of the product compound. Mass Spec: MH+ = 498 Using the appropriate starting compound and substantially the same procedure as described for Example 412, but substituting the amine nucleophile indicated in place of the 1 ,2,4-triazole sodium salt, the compounds in Table 5 were prepared: EXAMPLE 413 Combine 0.32 g of the product from Preparative Example 46, of WO 95/10516 and 2 mL of anhydrous CH2CI2 and add 6 mL of a mixture of 4.17 g of N-methyl-4-piperidylacetic acid. 1.03 mL of methanesulfonyl chloride, 6.83 mL of Et3N and 50 mL of CH2CI 2 . Stir at 25°C overnight, then add 1 N NaOH (aqueous) and shake well. Separate the layers, dry the organic phase over MgS04, and concentrate to a residue. Chromatograph the residue (silica gel, 3% MeOH/CH 2 CI 2 + NH 4 OH) to give 0.19 g (45% yield) of the product compound. m.p.= 105°C (dec); Mass Spec: MH + = 564. EXAMPLE 414 H Combine 84 mg of the product from Preparative Example 46, of WO 95/10516, 5 mL of pyridine and 0.04 mL of phenylisocyanate and stir at 25°C for 48 hours. Concentrate in vacuo to a residue, dilute with CH 2 CI 2 and wash with saturated NaHCθ 3 (aqueous). Dry over MgSθ4, concentrate to a residue and chromatograph (silica gel, 50-70% hexane/EtOAc) to give 14 mg (13% yield) of the product compound, m.p. = 125.6°C (dec); Mass Spec: MH + = 544 Using the starting compound indicated, the compounds in Table 6 were prepared via substantially the same procedure as described for Example 414: EXAMPLE 415 Combine 0.64 g of the product from Example 411-C and 16 mL of glacial HOAc, and add 15 mL of a 0.54 M solution of bromine in HOAc at 25°C under N 2 . After 10 minutes, pour the mixture into water, filter to collect the resulting solid, and wash with water. Dry the solid under vacuum, then chromatograph (silica gel, 6-15% MeOH/CH 2 CI 2 ) to give 0.26 grams (35% yield) of the product compound, m.p. = 150.0 °C (dec), Mass Spec: MH+ = 526 EXAMPLE 416 Combine 0.33 g of the product from Preparative Example 57, 2 mL of anhydrous CH 2 CI 2 , and 10 mL of a mixture of 7.20 g of 4-pyridylacetic acid hydrochloride, 1.61 mL of methanesulfonylchloride, 27 mL of E 3N and 60 mL of CH2CI 2 , and stir at 25 °C for 48 hours. Dilute the mixture with CH 2 CI 2 , wash with saturated NaHCθ3 (aqueous), then with brine. Dry over MgSθ4, concentrate to a residue and chromatograph (silica gel, 5% MeOH/CH 2 CI 2 + NH 4 OH) to give 0.23 g (55% yield) of the product compound, m.p. = 142 °C (dec); Mass Spec: MH + = 540 EXAMPLE 417 React the product from Preparative Example 35, of WO 95/10516, with 4-pyridylacetic acid via substantially the same procedure as described for Example 266, of WO 95/10516, to give the product compound. Mass Spec: MH + = 458 Using the appropriate carboxyi ic acid and the starting compound indicated, the compounds in Table 7 were prepared via substantially the same procedure as described for Example 417: EXAMPLE 418 Following the procedure of Example 283, of WO 95/10516, except using 4-pyridylacetic acid N-oxide gave the product compound. Mass Spec: MH + = 460 EXAMPLE 41Q Dissolve 4.01 g (8.42 mmol) of the compound of Example 410-L in EtOAc and add 14.25 g (63.1 mmol) of finely powdered SnCI 2 dihydrate and stir the mixture for 5 hours. Add 150 mL of saturated NaF (aqueous) and stir for 15 min, then separate the layers and dry the organic phase over MgSθ4. Filtration and concentrate in vacuo to a residue, then chromatograph (silica gel, 95% CH 2 CI 2 /MeOH + NH 4 OH) to give 2.95 g of the product compound. Mass Spec: MH + = 461 EXAMPLE 420 Combine 0.50 g (1.08 mmol) of the compound of Example 419 and 10 mL of anhydrous CH 2 CI 2 , and add 0.11 mL (1.62 mmol) of CH 3 COCI. Add 0.34 mL (4.32 mmol) of pyridine and stir at room temperature for 2.5 hours. Dilute the mixture with saturated NaHC0 3 (aqueous), extract with CH 2 CI 2 , wash the extracts with brine and dry over MgS0 - Concentrate in vacuo to a residue and chromatograph (silica gel, 10% MeOH/CH 2 CI 2 + NH 4 OH) to give 0.271 g of the product compound. Mass Spec: MH + = 503 EXAMPLE 421 Combine 0.65 g (1.41 mmol) of the product compound of Example 419, 20 mL of CH 2 CI 2 , 0.22 mL (3.52 mmol) of methyl iodide, 4.4 mL of 10% NaOH (aqueous) and 68 mg (0.21 mmol) of tetra-π-butyl-ammonium bromide. Stir the mixture for 5 hours, then separate the layers and dry the organic phase over MgSθ 4 . Concentrate in vacuo to a residue and chromatograph (silica gel, 5% MeOH/CH 2 CI 2 + NH 4 OH) to give 169 mg of the product compound. Mass Spec: MH+ = 475 EXAMPLE 422 Combine 0.1 g (0.21 mmol) of the product compound of Example 411-L and 10 mL of CH 2 CI 2 , add 0.11 g (0.66 mmol) of MCPBA and stir at ambient temperature for 1 hour. Wash with saturated NaHCθ 3 (aqueous), dry over MgS04, and concentrate in vacuo to give 0.14 gm of the product compound. m.p.=100°-104°C Using the compound of Example 423 and following substantially the same procedure as described for Example 422 the compound: was prepared. Mass Spec: (FAB) MH+ = 480.2 EXAMPLE 423 H Combine 0.4 g (1.22 mmol) of the product compound of Preparative Example 59 and 0.2 g (1.2 mmol) of 4-aminopyridylethylcarbamate and heat to 180°C under a dry N 2 atmosphere for 2 hours. Cool the mixture and crystallize the product by adding EtOAc to give 0.49 g of the product compound. m.p.= 206.4°-207°C; Mass Spec: (FAB) MH + =464.0 Using the appropriate ethylcarbamate and the starting compound indicated, the compounds in Table 8 were prepared via substantially the same procedure as described for Example 423: H N Combine 1 g of the product of Example 402 and 20 mL of MeOH, cool to -0°C, and adjust to pH ■ 3 by adding 1 N HCI (aqueous). Add 1.25 mL of CH 3 CHO and 1.41 g of NaCNBH 3 , and stir the mixture for 1 hour. Concentrate in vacuo to a residue, extract with 100 mL of CH 2 CI 2 and wash the extract with 100 mL of 10% NaHCOs, then with 100 mL of water. Dry over MgS04, concentrate in vacuo to a residue and chromatograph (silica gel, 1.5% (10% NH4OH in MeOH)/CH 2 CI ) to give 0.158 g of the product compound of Example 424 and 0.198 g of the product compound Example 424-A. Mass Spec (424): MH + = 474. Mass Spec ( 424-A): MH + = 502. EXAMPLE 425 React the products of Preparative Example 7, Step C, of WO 95/10516, and Preparative Example 26, of WO 95/10516, via substantially the same procedure as described for Example 75, of WO 95/10516, to give the title compound. Mass Spec: MH + = 461.35 Using the appropriate carboxylic acid and the starting compound indicated, the compounds in Table 9 were prepared via substantially the same procedure as described for Example 425: 0363 -96- EXAMPLE 426 React the product of Preparative Example 40, of WO 95/10516, and 3-pyridylacetic acid via substantially the same procedure as described for Example 351, of WO 95/10516, to give the title compound. Mass Spec: MH+ = 511 Using the appropriate carboxyiic acid and the compound of Preparative Example 41 of WO 95/10516, and following substantially the same procedure as described for Example 426, the compound: (Example 426-A) was prepared. Mass Spec: MH + = 483.2 EXAMPLE 427 H Combine 0.288 g (1.76 mmol) of the product of Preparative Example 63 and 25 mL of anhydrous toluene, heated at (110°C) for 0.5 hours, then cool to 25°C. Add a solution of 0.1 g (0.293 mmol) of the product of Preparative Example 7, Step C, of WO 95/10516, in 1.5 mL of anhydrous toluene, and stir at 25°C under an argon atmosphere for 112 hours. Concentrate in vacuo to a residue and chromatograph (silica gel, 3%-4% (10% NH OH in MeOH)/CH 2 CI 2 ) to give 0.065 g of the title compound. Mass Spec: MH+ = 450.3 Using the appropriate azide and the starting compound indicated, the compounds in Table 10 were prepared via substantially the same procedure as described for Example 427: EXAMPLE 428 Combine 14.73 g (27.3 mmol) of the compound from Example 193, of WO 95/10516, and 125 mL of anhydrous MeOH, and add (in portions) 300 mL of a 10% solution of concentrated H2SO 4 in dioxane. Stir the mixture at 25°C for 2 hours, then pour into water and adjust to pH =13 with 50% NaOH (aqueous). Extract with CH2CI2, wash the extract with water and dry over MgSθ4- Concentrate in vacuo to a residue and chromatograph (silica gel, 10% (10% NH4OH in MeOH)/CH2Cl2) to give 8.9 g of the title compound. Mass Spec: MH + = 539 Using the compound of Example 425-T, and following substantially the same procedure as described for Example 428, the compound: (Example 428-A) was prepared. Mass Spec: MH + = 439.45 EXAMPLE 429 Combine 0.5 g (1.14 mmol) of the compound of Example 428 and 10 mL of 0.6 N HCI in CH2CI2, stir for 10 minutes and concentrate n vacuo to a residue. Add 20 mL of anhydrous MeOH, then add 0.2006 g (4.56 mmol) of CH 3 CHO, 0.0859 g ( 1.36 mmol) NaCNBH 3 and 0.5 g of 3A molecular sieves, and heat at 40°C for 115 hours. Filter the mixture, wash the sieves with MeOH and concentrate the combined filtrates in vacuo to a residue. Dissolve the residue in CH 2 CI 2 and wash with saturated NaHCU 3 (aqueous), then water and dry over MgSO Concentrate in vacuo to a residue and chromatograph (silica gel, 8% (10% NH4OH in MeOH)/CH 2 CI 2 ) to give the title compound. Mass Spec: MH + = 467.3 EXAMPLE 430 Combine 0.5 g (1.14 mmol) of the compound of Example 428 and 5 mL of anhydrous THF, add 0.1076 g (1.14 mmol) CIC0 2 CH 3 , and stir at 25°C for 1 hour. Concentrate in vacuo to a residue, add CH 2 CI 2 and wash with saturated NaHCθ 3 (aqueous), then water. Dry the organic phase over MgS04, concentrate in vacuo to a residue and chromatograph (silica gel, 1.5% (10% NH OH in MeOH)/CH 2 CI 2 ) to give 0.4213 g of the title compound. Mass Spec: MH + = 497.35 Using the compound of Example 428-A, and following substantially the same procedure as described for Example 430, the compound: (Example 430-A) was prepared. Mass Spec: MH + = 497.35 EXAMPLE 431 Combine 0.5 g (1.14 mmol) of the compound of Example 428 and 5 mL of anhydrous CH 2 CI 2 , add 0.2624 g (2.28 mmol) of trimethylsilylisocyanate and stir under argon at 25°C for 22 hours. Add 0.1312 g (1.14 mmol) of trimethylsilylisocyanate and stir for 8 hours, then dilute with CH 2 CI 2 and wash with saturated NaHCθ3 (aqueous), then water. Dry over MgSθ4, concentrate in vacuo to a residue and chromatograph (silica gel, 5% (10% NH4OH in MeOH)/CH2Cl2) to give 0.3878 g of the title compound. Mass Spec: MH+ = 482.2 Using the isocyanate (or isothiocyanate) and starting compound indicated, the compounds in Table 11 were prepared via substantially the same procedure as described for Example 431: EXAMPLE 432 Combine 0.5 g (1.6 mmol) of the compound of Preparative Example 7, of WO 95/10516, and 1.098 g (6.4 mmol) of the compound from Preparative Example 65 and heat in a sealed vessel at 160°C for 17 hours. Cool the mixture, add CH 2 CI 2 , wash with water and dry the organic phase over MgSθ4. Concentrate in vacuo to a residue and chromatograph (silica gel, 1.5% (10% NH 4 OH in MeOH)/CH 2 CI ) to give 0.0364 g of the title compound. Mass Spec: MH + = 454.25 EXAMPLE 433 Ste React 0.5 g (1.59 mmol) of the compound of Example 428 and 0.3232 g (2.39 mmol) of N-(tert-butoxycarbonyl)-L-alanine (0.3232 grams) (2.39 mmoles) via essentially the same conditions as described in Example 425 to give the product compound. Sisc_B: Combine the product of Step A, 5 mL of MeOH and 10 mL of 10% concentrated H 2 Sθ 4 in dioxane and stir at 25°C for 2 hours. Neutralize with Biorad AG1X8 (OH-) ion exchange resin, filter, wash the resin witl" 1 :1 MeOH/water and concentrate the filtrate to a residue. Chromatograph the residue (silica gel, 8% (10% NH 4 OH in MeOH)/CH 2 CI 2 ) to give the title compound. Mass Spec: MH + = 510.35 Using the appropriate BOC-amino acid and the starting compound indicated, the compounds in table 12 were prepared via substantially the same procedure as described for Example 433: EXAMPLE 434 React the product of Preparative Example 67 with 4-pyridylacetic acid via essentially the same procedure as described for Example 411 to give the title compound. Mass Spec: MH+ = 410 Using the appropriate carboxylic acid and the compound of Preparative Example 68, and following substantially the same procedure as described for Example 434, the compound: (Example 434-A) was prepared, m.p. = 68.6°-70.3°C, Mass Spec: MH + =454. EXAMPLE 435 Dissolve 3.04 g (6.7 mmol) of the compound of Example 434-A in 100 mL of MeOH. Add 100 mL of a 12% KOH (aqueous) and stir for one hour at 25°C. Remove the MeOH under vacuum, neutralize to pH 7 with 12 N HCI and concentrate in vacuo to a residue. Dry under vacuum and triturate with 10 mL of EtOH, then filter, concentrate the filtrate in vacuo to give the title compound, m.p. = 238°-240° C; Mass Spec: MH+ = 440 EXAMPLE 436 Dissolve 0.5 g (1.14 mmol) of the product of Example 435 in 25 mL of DMF, add 0.122 g (1.14 mmol) of benzylamine, 0.33 g (1.7 mmol) of DEC, 0.15 g (1.1 mmol) of HOBT, and 0.23 g (2.27 mmol) of N-methyl- morpholine, and stir at 25°C, under nitrogen for 18 hours. Concentrate in vacuo to a residue, add 20 mL of water and extract with 50 mL of EtOAc. Dry the organic layer over MgSθ4 and concentrate in vacuo to a residue. Chromatograph (silica gel, 98% CH 2 CI 2 /MeOH + NH 4 OH) to give the product compound. m.p.=118°-120°C; Mass Spec: MH + =529 Using the appropriate amine and the starting compound indicated, the compounds in Table 13 were prepared via substantially the same procedure as described for Example 436: EXAMPLE 437 Dissolve 0.18 g (0.41 mmol) of the product of Example 435 in 2 mL of toluene, add 0.12 g (0.43 mmol) of diphenylphosphoryl azide, 0.041 g (0.41 mmol) of Et3N, and 0.092 g (0.44 mmol) of benzyl alcohol and heat at reflux under nitrogen for 18 hours. Concentrate in vacuo to a residue and chromatograph (silica gel 95% CH 2 CI 2 /MeOH) to obtain the title compound, m.p. = 132.8°-133.7°C; MH + = 545 EXAMPLE 438 0363 111 React the product of Preparative Example 70 with 4-pyridylacetic acid via essentially the same procedure as described for Example 411 to give the title compound. Mass Spec: (FAB) MH + = 456 Using the appropriate carboxylic acid and the starting compound indicated, the compounds of Table 14 were prepared via substantially the same procedure as described for Example 438: TABLE 14 EXAMPLE 439 Combine 1.7 g (5 mmol) of the product of Preparative Example 70, Step D, and 10 mL of anhydrous pyridine at 0°C under N 2 atmosphere, then slowly add (dropwise) 1 mL (7 mmol) of TFAA and stir at 25°C overnight, Dilute with 100 ml of cold water, extract with CH 2 CI 2 (2 x 75 mL), wash the extracts successfully with 10% CUSO4 (aqueous) and brine, then dry over MgSθ4. Concentrate in vacuo to a residue and chromatograph (silica gel 30%40% EtOAc hexane) to give 1.75 g of the title compound. Mass Spec: (FAB) MH + = 433 EXAMPLE 440 Combine 0.07 g (0.154 mmol) of the product of Example 438, 7 mL of EtOH and 12 mg of Ptθ2, and hydrogenate at 25°C and atmospheric pressure for 1 hour. Filter, wash with EtOH and concentrate in vacuo to give 0.066 g of the title compound. Mass Spec: (FAB) MH + = 458 Using the compound of Example 438-B, and following substantially the same procedure as described for Example 440, the compound: (Example 440-A) was prepared. Mass Spec: (FAB) MH + = 474 Combine 0.07 g of the compound of Example 410-R, 2 mL of THF, 0.5 mL of water, 10 drops of glacial HOAc, and 0.1 g of powdered Zn, and stir the mixture for 0.5 hours at 25°C. Purify the mixture by preparative thin layer chromatography (Prep TLC), (silica gel, 10% (10% NH 4 OH in MeOH)/CH 2 CI 2 ), to give a total of 68 mg of the crude product. Purify again by Prep TLC), (silica gel, 13% (10% NH4OH in MeOH)/CH 2 CI 2 ), to give 33 mg of the product compound. Mass Spec: MH + = 555 The compounds in Table 15 were prepared using the product of Preparative Example 40, of WO 95/10516, and following substantially the same procedures as described for Examples 183 and 193 of WO 95/10516, and Examples 428, 431 , 433-A disclosed above, as appropriate: TABLE 15 3 114 Analytical data for Example 505 are: H-1 NMR: 5H (D 2 0) 7.35 (1H, aromatic), 7.44 (1H, aromatic), 7.49 (1H, aromatic), 7.93 (1H, aromatic) and 8.58 (1H, aromatic). Analytical data for Example 506 are: δc (CDCI3) (a) Tricyclic: (i) CH 2 : 30.0, 30.0; (ii) CH: 146.5, 140.7, 132.0, 125.7, 130.0, 78.6; and (iii) C: 119.4, 140.3, 133.6, 135.0, 136.3, 155.4; (b) Piperazine: (i) CH 2 : 43.4, 43.4, 50.8, 50.8; and (c) Piperazine N-substituent: (i) CH 3 : 46.1; (ii) CH 2 : 28.3, 21.4, 55.4; (iii) CH: 45.5; and (iv) C: 156.4. EXAMPLE 507 React the compound of Example 501 with an excess of acetic anhydride in MeOH via standard procedures to form the product compound in 91% yield. Mass Spec: MH + = 559 EXAMPLE 508 React the compound of Preparative Example 49 with 4-(2- bromopyridyl)acetic acid via the substantially the same procedure as described for Example 410 to give the product compound, m.p. = 134°- 136.1°C; Mass Spec: MH + = 588 ASSAYS FPT IC5 0 (inhibition of farnesyl protein transferase, in vitro enzyme assay), GGPT IC5 0 (inhibition of geranylgeranyl protein transferase, in vitro enzyme assay), COS Cell IC5 0 (Cell-Based Assay) and Cell Mat Assay were determined by the methods disclosed in WO 95/10516. Results of these assays are given in Tables 16-19. TABLE 16 - FPT INHIBITION RESULTS: 1. Enzvmoloαv: The data demonstrate that the compounds of the invention are inhibitors of Ras-CVLS farnesylation by partially purified rat brain farnesyl protein transferase (FPT). The data also show that there are compounds of the invention which can be considered as potent (IC50 <10 μM) inhibitors of Ras-CVLS farnesylation by partially purified rat brain FPT. The data also demonstrate that compounds of the invention are poorer inhibitors of geranylgeranyl protein transferase (GGPT) assayed using Ras-CVLL as isoprenoid acceptor. Generally, the compounds of the invention are inactive or weakly active as geranylgeranyl transferase inhibitors at 20 μg/mL. This selectivity is important for the therapeutic potential of the compounds used in the methods of this invention, and increases the potential that the compounds will have selective growth inhibitory properties against R as-transformed cells. 2. Cell-Based: COS Cell Assay Western blot analysis of the Ras protein expressed in Ras-transfected COS cells following treatment with the tricyclic farnesyl protein transferase inhibitors of this invention indicated that they inhibit Ras-CVLS processing, causing accumulation of unprocessed Ras These results provide evidence for specific inhibition of farnesyl protein transferase, but not geranylgeranyl transferase I, by compounds of this invention in intact cells and indicate their potential to block cellular transformation by activated Ras oncogenes. 3. Cell-Based: Cell Mat Assay Tricyclic farnesyl protein transferase inhibitors of this invention also inhibited the growth of Ras-transformed tumor cells in the Mat assay without displaying cytotoxic activity against the normal monolayer. In Vivo Anti-Tumor Studies: Tumor cells (5 X 10 5 to 8 X 10 6 ) of DLD-1 (human colon carcinoma cells, ATCC # CCL 221), and PT-24 (mouse fibroblast cell line transfected with human H-ras), are innoculated subcutaneously into the flank of 5-6 week old athymic nu/nu female mice. Tumor bearing animals are selected and randomized when the tumors are established. Animals are treated with vehicle only or with a compound of the present invention in vehicle four times a day (QID) for 7 days per week for 4 weeks. The percent inhibition of tumor growth relative to vehicle controls is determined by tumor measurements. The results are reported in Table 20. IN VIVO ANTI-TUMOR STUDIES For preparing pharmaceutical compositions from the compounds described by this invention, inert, pharmaceutically acceptable carriers can be either solid or liquid. Solid form preparations include powders, tablets, dispersible granules, capsules, cachets and suppositories. The powders and tablets may be comprised of from about 5 to about 70 percent active ingredient. Suitable solid carriers are known in the art, e.g. magnesium carbonate, magnesium stearate, talc, sugar, lactose. Tablets, powders, cachets and capsules can be used as solid dosage forms suitable for oral administration. For preparing suppositories, a low melting wax such as a mixture of fatty acid glycerides or cocoa butter is first melted, and the active ingredient is dispersed homogeneously therein as by stirring. The molten homogeneous mixture is then poured into convenient sized molds, allowed to cool and thereby solidify. Liquid form preparations include solutions, suspensions and emulsions. As an example may be mentioned water or water-propylene glycol solutions for parenteral injection. 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 which are intended to be converted, shortly before use, to liquid form preparations for either oral or parenteral administration. Such liquid forms include solutions, suspensions and emulsions. The compounds of the invention may also be deliverable transdermally. The transdermal compositions can take the form of creams, lotions, aerosols and/or emulsions and can be included in a transdermal patch of the matrix or reservoir type as are conventional in the art for this 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, e.g., an effective amount to achieve the desired purpose. The quantity of active compound in a unit dose of preparation may be varied or 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 employed may be varied depending upon the requirements of the patient and the severity of the condition being treated. Determination of the proper dosage for a particular situation is within the skill of the art. Generally, treatment is initiated with smaller dosages which are less than the optimum dose of the compound. Thereafter, the dosage is increased by small increments until the optimum effect under the circumstances is reached. For 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 the pharmaceutically acceptable salts thereof will be regulated according to the judgment of the attending clinician considering such factors as age, condition and size of the patient as well as severity of the symptoms being treated. A typical recommended dosage regimen is oral administration of from 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. The following are examples of pharmaceutical dosage forms which contain a compound of the invention. The scope of the invention in its pharmaceutical composition aspect is not to be limited by the examples provided. Pharmaceutical Dosage Form Examples EXAMPLE A Tablets Method of Manufacture Mix Item Nos. 1 and 2 in a suitable mixer for 10-15 minutes. Granulate the mixture with Item No. 3. Mill the damp granules through a coarse screen (e.g., 1/4", 0.63 cm) if necessary. Dry the damp granules. Screen the dried granules if necessary and mix with Item No. 4 and mix for 10-15 minutes. Add Item No. 5 and mix for 1-3 minutes. Compress the mixture to appropriate size and weigh on a suitable tablet machine. EXAMPLE B Capsules Method of Manufacture Mix Item Nos. 1, 2 and 3 in a suitable blender for 10-15 minutes. Add Item No. 4 and mix for 1-3 minutes. Fill the mixture into suitable two- piece hard gelatin capsules on a suitable encapsulating machine. While the present invention has been described in conjunction with the specific embodiments set forth above, many alternatives, modifications and variations thereof will be apparent to those of ordinary skill in the art. All such alternatives, modifications and variations are intended to fall within the spirit and scope of the present invention.

Claims: WHAT IS CLAIMED IS: 1. A method for inhibiting the abnormal growth of cells comprising administering an effective amount of a compound of Formula 1.0: or a pharmaceutically acceptable salt or solvate thereof, wherein: one of a, b, c and d represents N or NR 9 wherein R 9 is O", -CH3 or -(CH2)nC02H wherein n is 1 to 3, and the remaining a, b, c and d groups represent CR 1 or CR 2 ; or each of a, b, c, and d are independently selected from CR 1 or CR 2 ; each R 1 and each R 2 is independently selected from H, halo, -CF 3 , -OR 10 , -COR 10 , -SR 10 , -S(0)tR 11 (wherein t is 0, 1 or 2), -SCN, -N(R 10 ) 2 , -NR 10 R 11 , -N0 2 , -OC(0)R 1 °, -C0 2 R 1 °, -OC0 2 R 11 , -CN. -NHC(0)R 1 °, -NHSO2R 10 , -CONHR 10 , -CONHCH 2 CH 2 OH, -NR °COOR 11 , -SR 1 C(0)OR 11 , -SR 11 N(R 75 )2 (wherein each R 75 is independently selected from H and -C(0)OR 11 ), benzotriazol-1-yloxy, tetrazol-5-ylthio, or substituted tetrazol- 5-ylthio, alkynyl, alkenyl or alkyl, said alkyl or alkenyl group optionally being substituted with halo, -OR 10 or -C0 2 R 10 ; R 3 and R 4 are the same or different and each independently represents H, any of the substituents of R 1 and R 2 , or R 3 and R 4 taken together represent a saturated or unsaturated C5-C7 fused ring to the benzene ring; R 5 , R 6 , R 7 and R 8 each independently represents H, -CF3, -COR 10 , alkyl or aryl, said alkyl or aryl optionally being substituted with -OR 10 , -SR 10 , -S(0)tR 11 , -NR 10 COOR 11 , -N(R 10 ) 2 , -N0 2 , -COR 10 , -OCOR 10 -OCO2R 11 . -CO2R 10 , OPO3R 10 or one of R 5 , R β , R 7 and R 8 can be taken in combination with R 40 as defined below to represent -(CH 2 )r wherein r is 1 to 4 which can be substituted with lower alkyl, lower alkoxy, -CF 3 or aryl, or R 5 is combined with R 6 to represent =0 or =S and/or R 7 is combined with R θ to represent =0 or =S; R 10 represents H, alkyl, aryl, or aralkyl; R 11 represents alkyl or aryl; X represents N, CH or C, which C may contain an optional double bond, represented by the dotted line, to carbon atom 11 ; the dotted line between carbon atoms 5 and 6 represents an optional double bond, such that when a double bond is present, A and B independently represent -NO2, -R 10 , halo, -OR 11 , -OCO2R 11 or -OC(0)R 10 , and when no double bond is present between carbon atoms 5 and 6, A and B each independently represent H2, -(OR 11 )2, H and halo, dihalo, alkyl and H, (alkyl) 2 , -H and -OC(0)R 1 °, H and -OR 10 , =0, aryl and H, =NOR 10 or -0-(CH 2 ) p -0- wherein p is 2, 3 or 4; R represents R 40 , R 42 , R 44 , or R 54 , as defined below; R4 0 represents H, aryl, alkyl, cycloalkyl, alkenyl, alkynyl or -D wherein -D represents wherein R 3 and R 4 are as previously defined and W is O, S or NR 10 wherein R 10 is as defined above; said R 40 cycloalkyl, alkenyl and alkynyl groups being optionally substituted with from 1-3 groups selected from halo, -CON(R 10 ) 2 , aryl, -C0 2 R 10 , -OR 12 , -SR 12 , -N(R 10 ) 2 , -N(R 10 )CO 2 R 11 , -COR 12 , -NO2 or D, wherein -D, R 10 and R 11 are as defined above and R 12 represents R 10 , -(CH 2 ) m OR 10 or -(CH 2 ) q Cθ2R 10 wherein R 10 is as previously defined, m is 1 to 4 and q is 0 to 4; said alkenyl and alkynyl R 40 groups not containing -OH, -SH or -N(R 10 ) 2 on a carbon containing a double or triple bond respectively; or R40 represents phenyl substituted with a group selected from -SO2NH2, -NHSO2CH3, -SO2NHCH3, -SO2CH3, -SOCH3, -SCH 3 , or -NHSO2CF3, preferably, said group is located in the para position of the phenyl ring; or R 40 represents a group selected from R 42 represents wherein R 20 , R 2 and R 46 are each independently selected from the group consisting of: (1) H; (2) -(CH 2 )qSC(0)CH 3 wherein q is 1 to 3; (3) -(CH2)qOSθ2CH3 wherein q is 1 to 3; (4) -OH; (5) -CS(CH2)w(substituted phenyl) wherein w is 1 to 3 and the substitutents on said substituted phenyl group are the same substitutents as described below for said substituted phenyl; (6) -NH 2 ; (7) -NHCBZ; (8) -NHC(0)OR 22 wherein R 22 is an alkyl group having from 1 to 5 carbon atoms, or R 22 represents phenyl substituted with 1 to 3 alkyl groups; (9) alkyl; (10) -(CH 2 )kphenyl wherein k is 1 to 6; (11) phenyl; (12) substituted phenyl wherein the substituents are selected from the group consisting of: halo, N0 2 , -OH, -OCH 3 , -NH 2 , -NHR 22 , -N(R 22 ) 2 , alkyl, -0(CH 2 )tphβnyl (wherein t is from 1 to 3), and -0(CH 2 )tsubstituted phenyl (wherein t is from 1 to 3); (13) naphthyl; (14) substituted naphthyl, wherein the substituents are as defined for substituted phenyl above; (15) bridged polycyclic hydrocarbons having from 5 to 10 carbon atoms; (16) cycloalkyl having from 5 to 7 carbon atoms; (17) heteroaryl; (18) hydroxyalkyl; (19) substituted pyridyl or substituted pyridyl N-oxide wherein the substituents are selected from methylpyridyl, morpholinyl, imidazolyl, 1 -piperidinyl, 1-(4-methylpiperazinyl), -S(0)tR 11 , or any of the substituents given above for said substituted phenyl, and said substitutents are bound to a ring carbon by replacement of the hydrogen bound to said carbon; (23) -NHC(0)-(CH2)k-phenyl or -NH(0)-(CH 2 )k-substitued phenyl, wherein said k is as defined above; (24) piperidine Ring V: wherein R 50 represents H, alkyl, alkylcarbonyl, alkyloxycarbonyl, haloalkyl, or -C(0)NH(R 10 ) wherein R 10 is H or alkyl; (25) -NHC(0)CH 2 C6H 5 or -NHC(0)CH2-substituted-C 6 H 5 ; (26) -NHC(0)OC 6 H 5 ; (27) (28) (29) (30) -OC(0)-heteroaryl, for example (31) -O-alkyl (e.g., -OCH 3 ); and (32) -CF 3 ; (33) -CN; (34) a heterocycloalkyl group of the formula — N O — N ) — N N --TRj lO ■N / s(oι t ^/ or (35) a piperidinyl group of the formula wherein R 85 is H, alkyl, or alkyl substituted by -OH, -SCH 3 or -SH; and (36) triazolyl; or R 20 and R 21 taken together form a =0 group and the remaining R46 j S as defined above; or two of R 20 , R 21 and R 46 taken together form piperidine Ring V wherein R 50 is as defined above; with the proviso that R 46 , R 20 and R 21 are selected such that the carbon atom to which they are bound does not contain more than one heteroatom; R 44 represents wherein R 25 represents heteroaryl, N-methylpiperdinyl or aryl; and R 48 represents H or alkyl; R54 represents an N-oxide heterocyciic group of the formula (i), (ii), (iii) or (iv): (0 (ϋ) (iϋ) (iv) wherein R 56 , R 58 , and R 60 are the same or different and each is independently selected from H, halo, -CF 3 , -OR 10 , -C(0)R 10 , -SR 10 , -S(0) e R 11 (wherein e is 1 or 2), -N(R 10 ) 2 , -N0 2 , -C0 2 R 10 , -0C0 2 R 11 , -OCOR 10 , alkyl, aryl, alkenyl or alkynyl, which alkyl may be substituted with -OR 10 , -SR 10 or -N(R 10 ) 2 and which alkenyl may be substituted with OR 11 or SR 11 ; or R54 represents an N-oxide heterocyciic group of the formula (ia), (iia), (iiia) or (iva): (ia) (iia) (iiia) (iva) wherein Y represents N+-0- and E represents N; or R54 represents an alkyl group substituted with one of said N-oxide heterocyciic groups (i). (ii), (iii), (iv), (ia), (iia), (iiia) or (iva); and Z represents O or S such that R can be taken in combination with R 5 , R 6 , R 7 or R 8 as defined above, or R represents R 40 , R 42 , R 44 or R 54 ; with the proviso that when: (1 ) R 1 , R 2 , R 3 and R 4 are independently selected from H, halo, -CF 3 , -OR 10 , -COR 10 , -SR 10 , -S(0) t R 11 , -N(R 10 ) 2 , -N0 2 , -OC(0)R 1 °, -CO2R 10 , -OCO2R 11 , -CN, -NR 10 COOR 11 , -SR 1 C(0)OR 11 , -SR 11 N(R 75 )2, benzotriazol-1-yioxy, tetrazol-5-ylthio, substituted tetrazol- 5-ylthio, alkynyl, alkenyl or alkyl; or R 1 and R 2 are selected from H, halo, -CF 3 , -OR 10 . -COR 10 , -SR 10 . -S(0)tR 11 . -N(R 10 ) 2 , -N0 2 . -OC(0)R 10 , -CO2R 10 , -OCO2R 11 , -CN. -NR 10 COOR 11 , -SR 11 C(0)OR 11 , -SR 11 N(R 75 )2, benzotriazol-1-yloxy, tetrazol-5-ylthio, substituted tetrazol- 5-ylthio, alkynyl, alkenyl or alkyl. and R 3 and R 4 taken together represent a saturated or unsaturated C5-C7 fused ring to the benzene ring (Ring III); and (2) the dotted line between carbon atoms 5 and 6 represents an optional double bond, such that when a double bond is present, A and B independently represent -R 10 , halo, -OR 11 , -OCO2R 11 or -OC(0)R 10 , and when no double bond is present between carbon atoms 5 and 6, A and B each independently represent H 2 , -(OR 11 ) 2 , H and halo, dihalo, alkyl and H, (alkyl) 2 , -H and -OC(0)R 1 °, H and -OR 10 , =0, aryl and H, =NOR 10 or -0-(CH 2 ) p -0- wherein p is 2, 3 or 4; then R is selected from: (a) R 42 wherein at least one of R 20 , R 21 or R 46 is selected from: (1) substituted pyridyl or substituted pyridyl N-oxide wherein the substituents are selected from methylpyridyl, morpholinyl, imidazolyl, 1 -piperidinyl, 1-(4-methylpiperazinyl), or -S(0)tR 11 ; (2) -CN; (3) triazolyl; (4) a heterocycloalkyl group of the formula (5) a piperidinyl group of the formula wherein R 85 is H, alkyl, or alkyl substituted by -OH, -SCH 3 or -SH; or (b) R 44 wherein R 25 is N-methylpiperidinyl. 2. The method of Claim 1 wherein a is N and b, c, and d are carbon; R 1 and R 2 are the same or different and each is independently selected from H, halo, -CF 3 , lower alkyl, or benzotriazol-1-yloxy, and R 1 is at the C-4 position and R 2 is at the C-3 position; R 3 and R 4 are the same or different and each is independently selected from H or halo, and R 3 is at the C-8 position and R 4 is at the C-9 position; when the double bond between carbon atoms 5 and 6 is present, A and B independently represent H, tower alkyl or alkyloxy; and when the double bond between carbon atoms 5 and 6 is absent, A and B independently represent H 2 , (-H and -OH) or =0; R 5 , R 8 , R 7 , and R 8 are H; Z is O; and R represents R 42 and the R 46 is selected from: (1) -CN; triazolyl; (2) a heterocycloalkyl group of the formula piperidinyl group of the formula wherein R 85 is H, alkyl, or a yl substituted by -OH or -SCH 3 ; or (4) substituted pyridyl or substituted pyridyl N-oxide wherein the substituents are selected from methylpyridyl, morpholinyl, imidazolyl, 1 -piperidinyl, 1- (4-methylpiperazinyl), or -S(0)tR 11 . 3. The method of Claim 2 wherein R 20 and R 21 are each independently selected from H and alkyl; R 3 is Cl; R 4 is H; R 1 and R 2 are individually selected from H, benzotriazol-1-yloxy, C-i to C 4 alkyl or halo; and R 46 represents triazolyl, a heterocycloalkyl of the formula a piperidinyl group of the formula 4. The method of Claim 3 wherein both R 20 and R 21 are H, or both R 20 and R 21 are methyl; R 1 and R 2 are individually selected from H, Br, Cl, methyl or benzotriazol-1-yloxy; and R 46 represents triazolyl, 1-N- methylpiperazinyl, 1-piperazinyl, a heterocycloalkyl of the formula a piperidinyl group of the formula 5. The method of Claim 1 wherein a is N and b, c, and d are carbon; R 1 and R 2 are the same or different and each is independently selected from H, halo, -CF3, lower alkyl, or benzotriazol-1-yloxy, and R 1 is at the C-4 position and R 2 is at the C-3 position; R 3 and R 4 are the same or different and each is independently selected from H or halo, and R 3 is at the C-8 position and R 4 is at the C-9 position; when the double bond between carbon atoms 5 and 6 is present, A and B independently represent H, lower alkyl or alkyloxy; and when the double bond between carbon atoms 5 and 6 is absent, A and B independently represent H 2 , (-H and -OH) or =0; R 5 , R 6 , R 7 , and R 8 are H; Z is O; and R represents R 44 and the R 25 represents, 3-N-methylpiperidinyl or 4-N-methylpiperidinyl. 6. The method of Claim 5 wherein R 3 is Cl; R 4 is H; R 48 represents are H or methyl; and R 1 and R 2 are individually selected from H, benzotriazol-1-yloxy, methyl, Br or Cl. 7. The method of Claim 1 wherein the the cells inhibited are tumor cells expressing an activated ras oncogene. 8. The method of Claim 7 wherein the cells inhibited are pancreatic tumor cells, lung cancer cells, myeloid leukemia tumor cells, thyroid follicular tumor cells, myelodysplastic tumor cells, epidermal carcinoma tumor cells, bladder carcinoma tumor cells or colon tumors cells. 9. The method of Claim 1 wherein the inhibition of the abnormal growth of cells occurs by the inhibition of farnesyl protein transferase. 10. The method of Claim 1 wherein the inhibition is of tumor cells wherein the Ras protein is activated as a result of oncogenic mutation in genes other than the Ras gene. 11. The method of Claim 1 wherein the compound is selected from the compounds of Examples: 426, 400-G, 400-C, 400-F, 400-E, 425- H. 401. 400-B, 400, 400-L, 425-U, 413, 400-J. 417-B, 438, 411-W, 425-0, 400-D, 400-K, 410-G or 400-H. 12. A compound selected from a compound of the formula: or a pharmaceutically acceptable salt or solvate thereof, wherein all the substituents are as defined in Claim 1. 13. The compound of Claim 12 wherein a is N and b, c, and d are carbon; R and R 2 are the same or different and each is independentiy selected from H, halo, -CF3, lower alkyl, or benzotriazol-1- yloxy, and R 1 is at the C-4 position and R 2 is at the C-3 position; R 3 and R 4 are the same or different and each is independently selected from H or halo, and R 3 is at the C-8 position and R 4 is at the C-9 position; when the double bond between carbon atoms 5 and 6 is present, A and B independently represent H, lower alkyl or alkyloxy; and when the double bond between carbon atoms 5 and 6 is absent, A and B independently represent H 2 , (-H and -OH) or =0; R 5 , R 6 . R 7 , and R 8 are H; Z is O; and R4 6 J S selected from triazolyl, 1-N-methylpiperazinyl, 1-piperazinyl or a heterocycloalkyl of the formula — N S(0) t 14. The compound of Claim 13 wherein R 20 and R 21 are each independently selected from H and alkyl; R 3 is Cl; R 4 is H; R 1 and R 2 are individually selected from H, benzotriazol-1-yloxy, C-i to C 4 alkyl or halo; and R 46 represents 1-N-methylpiperazinyl, 1-piperazinyl or a heterocycloalkyl of the formula /—\ — N SCO), 15. The compound of Claim 14 wherein both R 20 and R 21 are H, or both R 20 and R 21 are methyl; and R and R 2 are individually selected from H, Br, Cl, methyl or benzotriazol-1-yloxy. 16. A compound selected from a compound of the formula: or a pharmaceutically acceptable salt thereof, wherein a, b, c, d, R 5 , R 6 , R 7 , R 8 , A, B and Z are as defined in Claim 1; each R 1 and each R 2 is independently selected from H, halo, -CF3, -OR 10 , -COR 10 , -SR 10 , -S(0)tR 11 (wherein t is 0, 1 or 2), -SCN, -N(R 10 ) 2 , -NR 1 °R 11 , -N0 2 , -OC(0)R 10 , -C0 2 R 10 , -OCO2R 11 , -CN, -NHC(0)R 10 , -NHSO2R 10 , -CONHR 10 , -CONHCH 2 CH 2 OH, -NR 10 COOR 11 , -SR 11 C(0)OR 11 , -SR 11 N(R 75 ) 2 (wherein each R 75 is independently selected from H and -C(0)OR 11 ), benzotriazol-1-yloxy, tetrazol-5-ylthio, or substituted tetrazol- 5-ytthio, alkynyl, alkenyl or alkyl, said alkyl or alkenyl group optionally being substituted with halo. -OR 10 or -C0 2 R 10 ; R 3 and R 4 are the same or different and each independently represents H, any of the substituents of R 1 and R 2 , or R 3 and R 4 taken together represent a saturated or unsaturated C5-C7 fused ring to the benzene ring; R25 represents heteroaryl, N-methylpiperidinyl or aryl; and R48 represents H or alkyl; and with the proviso that: (1) when R 25 is selected from heteroaryl or aryl then: (a) at least one of said R 1 , R 2 , R 3 and R 4 groups is selected from -SCN, -NR 0 R 1 1 , -NHC(0)R 10 , -NHSO2R 10 , -CONHR 10 , -CONHCH 2 CH 2 OH, or (b) the double bond between carbon atoms 5 and 6 is present and at least one of A and B represents -N0 2 ; and (2) when R 25 is N-methylpiperidinyl selected from 3-N-methyl¬ piperidinyl or 4-N-methylpiperidinyl then R 1 and R 2 are not H, halo, -CF3, benzotriazoMyloxy or lower alkyl when: (a) R 3 and R 4 are selected from H and halo; and (b) the double bond between carbon atoms 5 and 6 is present and A and B are selected from H, lower alkyl or lower alkoxy, or the double bond between carbon atoms 5 and 6 is absent and A and B are selected from H , (-H and -OH) or =0; and (c) R 5 , R 6 , R 7 , and R 8 are H; and (d) Z is O. 17. A compound selected from a compound having the structure number: 5.200, 5.201, 5.202, 5.203, 5.204, 5.205, 5.206, 5.207, 5.208, 5.209, 5.210, 5.211 , 5.212, 5.213, 5.214, 5.215, 5.216, 5.217, 5.218, 5.219, 5.220. 18. A compound selected from the compounds of Examples: 400-A, 400-M, 400-N, 400-P, 400-Q, 402, 402-A, 403, 404, 405, 406, 407, 410-H, 410-J, 410-L, 410-M, 410-Q, 410-R. 410-S, 410-T, 410-U, 410-V, 410-W, 410-X, 411 , 411-A, 411-B, 411-C, 411-D, 411-E, 411-F, 411-G, 411-H, 411-J. 411-K, 411-L. 411-M. 411-N, 411-0, 411-P. 411-Q, 411-R. 411-S. 411-T. 411-U, 411-V, 411-X, 411-Z, 411-AA, 411-BB, 411-CC. 411-DD. 411-EE, 411-FF, 411-GG, 412, 412-A, 412-B, 412-C, 412-D, 412-E, 412-F, 412G. 412-H, 414. 414-A, 414-B, 415. 416, 417, 417-A. 418. 419, 420, 421, 422,422-A, 423, 423-A, 423-B, 424, 424-A, 425. 425- A. 425-B. 425-C. 425-D, 425-E, 425-F. 425-G. 425-J. 425-K, 425-L, 425- M, 425-N, 425-P, 425-Q, 425-R, 425-S, 425-T, 425-V, 426-A, 427, 427-A, 427-B. 427-C, 428, 428-A. 429, 430, 430-A, 431, 431 -A, 431 -B, 431 -C, 431 -D. 431 -E. 431 -F, 431-G, 432, 433, 433-A, 433-B, 433-C, 434, 434-A, 435, 436, 436-A, 436-B, 436-C, 436-D, 437, 438-A, 438-B, 439, 440, 440- A, 441, 500, 501, 502, 503, 504, 505, 506, 507 or 508. 19. A pharmaceutical composition for inhibiting the abnormal growth of cells comprising an effective amount of a compound of any of Claims 12, 16 or 18 in combination with a pharmaceutically acceptable carrier. 20. The use of a compound of any of Claims 12, 16 or 18 for the manufacture of a medicament for use in inhibiting the abnormal growth of cells. 21. The use of a compound of any of Claims 12, 16 or 18 for inhibiting the abnormal growth of cells.

Inventors: BISHOP W ROBERT, DOLL RONALD J, MALLAMS ALAN K, NJOROGE F GEORGE, PETRIN JOANNE M, PIWINSKI JOHN J, REMISZEWSKI STACY W, TAVERAS ARTHUR G, WOLIN RONALD L, BISHOP, W., ROBERT, DOLL, RONALD, J., MALLAMS, ALAN, K., NJOROGE, F., GEORGE, PETRIN, JOANNE, M., PIWINSKI, JOHN, J., REMISZEWSKI, STACY, W., TAVERAS, ARTHUR, G., WOLIN, RONALD, L.
Applicants: SCHERING CORP, SCHERING CORPORATION
Application year: 1996
Main classification: C07D401
IPC codes: A61K31, A61P35, C07D221, C07D401, C07D405, C07D409, C07D417, C07D521