AU8253598A - Novel n-substituted urea inhibitors of farnesyl-protein transferase - Google Patents

Description

WO 98/57948 PCT/US98/11507 NOVEL N-SUBSTITUTED UREA INHIBITORS OF FARNESYL-PROTEIN TRANSFERASE 5 BACKGROUND Patent application WO 95/00497 published 5 January 1995 under the Patent Cooperation Treaty (PCT) describes compounds which inhibit the enzyme, farnesyl-protein transferase (FTase) and the farnesylation of the 10 oncogene protein Ras. Oncogenes frequently encode protein components of signal transduction pathways which lead to stimulation of cell growth and mitogenesis. Oncogene expression in cultured cells leads to cellular transformation, characterized by the ability of cells to grow in soft agar and the growth of cells as dense foci lacking the contact inhibition exhibited by non 15 transformed cells. Mutation and/or overexpression of certain oncogenes is frequently associated with human cancer. 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, 20 farnesyl 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). 25 In view of the current interest in inhibitors of farnesyl protein transferase, a welcome contribution to the art would be additional compounds useful for the inhibition of farnesyl protein transferase. Such a contribution is provided by this invention. 30 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 35 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 WO 98/57948 PCT/US98/11507 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. This invention provides a method for inhibiting the abnormal growth of 5 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 10 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:

X

4 A WX3 5 X R R7 R6 ~ --R8 y1 iO N N NR 19

R

20 1 y2 v w (1.0) 15 or a pharmaceutically acceptable salt or solvate thereof, wherein: A represents N or N-oxide; X represents N, CH or C, such that when X is N or CH, there is a single bond to carbon atom 11 as represented by the solid line; or when X is C, there is a double bond to carbon atom 11, as represented by the solid and dotted lines; 20 X 1 and X2 are independently selected from bromo or chloro, and X3 and X 4 are independently selected from hydrogen, bromo or chloro provided that at least one of X3 and X 4 is hydrogen; Y1 and y2 are independently selected from hydrogen or alkyl; Z is =0 or =S; -2- WO 98/57948 PCT/US98/11507

R

5 , R 6 , R 7 and R 8 each independently represents hydrogen, -CF 3 , -COR 10 , alkyl or aryl, and further wherein R 5 may be combined with R 6 to represent =0 or =S and/or R 7 may be combined with R 8 to represent =0 or =S;

R

10 , R 19 and R 20 independently represent hydrogen, alkyl, alkoxy, aryl, aralkyl, 5 heteroaryl, heteroarylalkyl, cycloalkyl, cycloalkylalkyl, heterocycloalkyl and heterocycloalkylalkyl, with the proviso that R 19 and R 20 are not both hydrogen; v is zero, 1, 2 or 3; and w is zero or 1. 10 Preferably in compound (1.0), there is a single bond at carbon atom 11; X is CH; R 5 , R 6 , R 7 and R 8 are hydrogen; X 1 , X 2 and X 3 are bromo or chloro and X 4 is hydrogen; Z is =0; v is 1; w is 1; Y 1 and y2 are hydrogen; and R 19 and R 20 are independently selected from hydrogen, alkyl, aryl and heterocycloalkyl with the proviso that R 19 and R20 are not both hydrogen. 15 When R 19 or R20 is alkyl, optional substituents on the alkyl group may include

-OR

10 , alkoxy, -OCOR 10 , -CONR 10

R

12 or -COOR 10 , wherein R 10 and R 12 are independently selected from hydrogen, alkyl or alkoxy. When R 19 or R 2 0 is aryl, an optional substituent on the aryl group may include alkoxy. When R19 or

R

2 0 is heterocycloalkyl, an optional substituent on the heterocycloalkyl group 20 may include -COOR 10 wherein R10 is hydrogen or alkyl. Preferred title compounds include those of Examples 3, 4, 6, 7, 11, 12 and 13, disclosed hereinafter. In another embodiment, the present invention is directed toward a pharmaceutical composition for inhibiting the abnormal growth of cells 25 comprising an effective amount of compound (1.0) in combination with a pharmaceutically acceptable carrier. In another embodiment, the present invention is directed toward a method for inhibiting the abnormal growth of cells, including transformed cells, comprising administering an effective amount of compound (1.0) to a mammal 30 (e.g., a human) in need of such treatment. 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; (3) benign and 35 malignant cells of other proliferative diseases in which aberrant Ras activation occurs, and (4) benign or malignant cells that are activated by mechanisms other than the Ras protein. Without wishing to be bound by theory, it is believed -3- WO 98/57948 PCT/US98/11507 that these compounds may function either 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, or through inhibition of ras farnesyl protein transferase, thus making 5 them useful for their antiproliferative activity against ras transformed cells. The cells to be inhibited can be tumor cells expressing an activated ras oncogene. For example, the types of cells that may be inhibited include . pancreatic tumor cells, lung cancer cells, myeloid leukemia tumor cells, thyroid follicular tumor cells, myelodysplastic tumor cells, epidermal carcinoma tumor 10 cells, bladder carcinoma tumor cells, prostate tumor cells, breast tumor cells or colon tumors cells. Also, the inhibition of the abnormal growth of cells by the treatment with compound (1.0) may be by inhibiting ras farnesyl protein transferase. The inhibition may be of tumor cells wherein the Ras protein is activated as a result of oncogenic mutation in genes other than the Ras gene. 15 Alternatively, compounds (1.0) may inhibit tumor cells activated by a protein other than the Ras protein. This invention also provides a method for inhibiting tumor growth by administering an effective amount of compound (1.0) to a mammal (e.g., a human) in need of such treatment. In particular, this invention provides a 20 method for inhibiting the growth of 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), 25 colon cancers (e.g., colorectal carcinomas, such as, for example, colon adenocarcinoma and colon adenoma), myeloid leukemias (for example, acute myelogenous leukemia (AML)), thyroid follicular cancer, myelodysplastic syndrome (MDS), bladder carcinoma, prostate carcinoma and breast carcinoma and epidermal carcinoma. 30 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 35 the N-substituted urea compounds (1.0) 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 -4- WO 98/57948 PCT/US98/11507 or overexpression of tyrosine kinase oncogenes (e.g., neu, src, abl, Ick, and fyn), may be inhibited by the N-substituted urea compounds (1.0). In another embodiment, the present invention is directed toward a method for inhibiting ras farnesyl protein transferase and the farnesylation of the 5 oncogene protein Ras by administering an effective amount of compound (1.0) to mammals, especially humans. 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. 10 DETAILED DESCRIPTION OF THE INVENTION As used herein, the following terms are used as defined below unless otherwise indicated:

M

+ -represents the molecular ion of the molecule in the mass spectrum; 15 MH + -represents the molecular ion plus hydrogen of the molecule in the mass spectrum; Bu-represents butyl; Et-represents ethyl; Me-represents methyl; 20 Ph-represents phenyl; benzotriazol-1-yloxy represents N 0 1-methyl-tetrazol-5-ylthio represents N-N N%N "S. I NS

CH

3 25 alkyl-(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; for example methyl, ethyl, propyl, iso-propyl, n-butyl, t-butyl, n-pentyl, isopentyl, hexyl and the like; wherein said alkyl group may be optionally and 30 independently substituted with one, two, three or more of the following: halo, alkyl, aryl, cycloalkyl, cyano, -CF 3 , oxy (=0), aryloxy, -OR 10 , -OCF 3 , -5- WO 98/57948 PCT/US98/11507 heterocycloalkyl, heteroaryl, -NR 10

R

1 2, -NHSO 2

R

1 0, -SO 2

NH

2 , -SO 2

NHR

1 0,

-SO

2

R

10 , -SOR 1 0 o, -SR 10 , -NHSO 2 , -NO 2 , -CONR 1 0

OR

12 , -NR 12C O

R

10 , -COR 1 0 o,

-OCOR

10 , -OCO 2

R

10 or -COOR 10 , wherein R 10 io and R 12 can independently represent hydrogen, alkyl, alkoxy, aryl, aralkyl, heteroaryl, heteroarylalkyl, 5 cycloalkyl, cycloalkylalkyl, heterocycloalkyl or heterocycloalkylalkyl; alkoxy-an alkyl moiety of one to 20 carbon atoms covalently bonded to an adjacent structural element through an oxygen atom, for example, methoxy, ethoxy, propoxy, butoxy, pentoxy, hexoxy and the like; wherein said alkoxy group may be optionally and independently substituted with one, two, three or 10 more of the following: halo, alkyl, aryl, cycloalkyl, cyano, -CF 3 , oxy (=0), aryloxy, -OR 10 , -OCF 3 , heterocycloalkyl, heteroaryl, -NRo 10

R

12 , -NHSO 2 Ro 10 ,

-SO

2

NH

2 , -SO 2

NHR

10 , -SO 2 Ro 1 0 , -SOR 10 , -SR 1 0 o, -NHSO 2 , -NO 2 , -CONR 10 R 12 ,

-NR

1 2COR 10 , -COR 10 , -OCOR 1 0 , -OCO 2

R

10 or -COOR 10 , wherein R 10 and R 12 are as defined hereinabove; 15 aryl (including the aryl portion of aralkyl)-represents a carbocyclic group containing from 6 to 15 carbon atoms and having at least one aromatic ring (e.g., aryl is phenyl), wherein said aryl group optionally can be fused with aryl, cycloalkyl, heteroaryl or heterocycloalkyl rings; and wherein any of the available substitutable carbon and nitrogen atoms in said aryl group and/or 20 said fused ring(s) may be optionally and independently substituted with one, two, three or more of the following: halo, alkyl, aryl, cycloalkyl, cyano, -CF 3 , oxy (=0), aryloxy, -OR 10 , -OCF3, heterocycloalkyl, heteroaryl, -NRlOR 12 ,

-NHSO

2

R

10 , -SO 2

NH

2 , -SO 2

NHR

10 , -SO 2

R

10 , -SOR 10 , -SR 10 , -NHSO 2 , -NO 2 ,

-CONR

10

R

12 , -NR 12C O

R

10 , -COR 10 , -OCOR 10 , -OCO 2

R

10 or -COOR 10 , 25 wherein R 10 and R 12 are as defined hereinabove; aralkyl - represents an alkyl group, as defined above, wherein one or more hydrogen atoms of the alkyl moiety have been substituted with one or more aryl groups; wherein said aralkyl group may be optionally and independently substituted with one, two, three or more of the following: halo, 30 alkyl, aryl, cycloalkyl, cyano, -CF 3 , oxy (=0), aryloxy, -OR 10 , -OCF 3 , heterocycloalkyl, heteroaryl, -NR 10 oR 12 , -NHSO 2

R

10 , -SO 2

NH

2 , -SO 2

NHR

10 ,

-SO

2

R

10 , -SOR 10 , -SR 10 o, -NHSO 2 , -NO 2 , -CONR 10

R

12 , -NR 12C O R o 10 , -COR 10 ,

-OCOR

10 , -OCO 2

R

10 or -COOR 10 , wherein R 10 and R 12 are as defined hereinabove; 35 aryloxy - represents an aryl group, as defined above, wherein said aryl group is covalently bonded to an adjacent structural element through an oxygen atom, for example, phenoxy, wherein said aryl group optionally can be -6- WO 98/57948 PCT/US98/11507 fused.with aryl, cycloalkyl, heteroaryl or heterocycloalkyl rings; and wherein any of the available substitutable carbon and nitrogen atoms in said aryloxy group and/or said fused ring(s) may be optionally and independently substituted with one, two, three or more of the following: halo, alkyl, aryl, cycloalkyl, cyano, 5 -CF 3 , oxy (=0), aryloxy, -OR 10 , -OCF 3 , heterocycloalkyl, heteroaryl, -NR 10

R

12 ,

-NHSO

2

R

1 0 o, -SO 2

NH

2 , -SO 2

NHR

1 0, -SO 2

R

10 o, -SOR 10 , -SR 1 0, -NHSO 2 , -NO 2 ,

-CONR

10 R 12 , -NR 12C O

R

10 , -COR 10 , -OCOR 10 , -OCO 2

R

10 or -COOR 10 , wherein R 1 0 and R 12 are as defined hereinabove; cycloalkyl-represents saturated carbocyclic rings branched or 10 unbranched of from 3 to 20 carbon atoms, preferably 3 to 7 carbon atoms; wherein said cycloalkyl group may be optionally and independently substituted with one, two, three or more of the following: halo, alkyl, aryl, cycloalkyl, cyano,

-CF

3 , oxy (=0), aryloxy, -OR 10 , -OCF 3 , heterocycloalkyl, heteroaryl, -NR10R 12 ,

-NHSO

2

R

1 0 , -SO 2

NH

2 , -SO 2

NHR

10 , -SO 2

R

10 , -SOR 10 , -SR 10 , -NHSO 2 , -NO 2 , 15 -CONR 1 0

R

1 2 , -NR 1 2COR 10 , -COR 10 , -OCOR 10 , -OCO 2

R

10 or -COOR 10 , wherein R 10 and R 12 are as defined hereinabove; cycloalkylalkyl - represents an alkyl group, as defined above, wherein one or more hydrogen atoms of the alkyl moiety have been substituted with one or more cycloalkyl groups; wherein said cycloalkylalkyl group may be optionally 20 and independently substituted with one, two, three or more of the following: halo, alkyl, aryl, cycloalkyl, cyano, -CF 3 , oxy (=0), aryloxy, -OR 10 , -OCF 3 , heterocycloalkyl, heteroaryl, -NR 10

R

12 , -NHSO 2

R

10 , -SO 2

NH

2 , -SO 2

NHR

1 0 ,

-SO

2

R

10 , -SOR 10 , -SR 1 0 o, -NHSO 2 , -NO 2 , -CONR10R 12 , -NR 12C O

R

1 0, -COR 1 0 o,

-OCOR

1 o, -OCO 2

R

10 or -COOR 10 , wherein R 10 and R 12 are as defined 25 hereinabove; halo-represents fluoro, chloro, bromo and iodo; heteroalkyl-represents straight and branched carbon chains containing from one to twenty carbon atoms, preferably one to six carbon atoms interrupted by 1 to 3 heteroatoms selected from -0-, -S- and -N-; wherein any of the 30 available substitutable carbon and nitrogen atoms in said heteroalkyl chain may be optionally and independently substituted with one, two, three or more of the following: halo, alkyl, aryl, cycloalkyl, cyano, -CF 3 , oxy (=0), aryloxy, -OR 10 ,

-OCF

3 , heterocycloalkyl, heteroaryl, -NR 10

R

1 2, -NHSO 2

R

1 0, -SO 2

NH

2 ,

-SO

2

NHR

1 0, -SO 2

R

10 , -SOR 10 , -SR 10 , -NHSO 2 , -NO 2 , -CONR 10

R

12 , 35 -NR 1 2COR 10 , -COR 10 , -OCOR 10 , -OCO 2

R

10 or -COOR 10 , wherein R 10 and R 12 are as defined hereinabove; -7- WO 98/57948 PCT/US98/11507 heteroaryl-represents cyclic groups having at least one heteroatom selected from O, S and N, said heteroatom(s) interrupting a carbocyclic ring structure and having a sufficient number of delocalized pi electrons to provide aromatic character, with the aromatic heterocyclic groups containing from 2 to 5 14 carbon atoms,wherein said heteroaryl group optionally can be fused with one or more aryl, cycloalkyl, heteroaryl or heterocycloalkyl rings; and wherein any of the available substitutable carbon or nitrogen atoms in said heteroaryl group and/or said fused ring(s) may be optionally and independently substituted with one, two, three or more of the following: halo, alkyl, aryl, 10 cycloalkyl, cyano, -CF 3 , oxy (=0), aryloxy, -OR 10 , -OCF 3 , heterocycloalkyl, heteroaryl, -NR 10

R

12 , -NHSO 2

R

10 , -SO 2

NH

2 , -SO 2

NHR

10 , -SO 2

R

10 , -SOR 10 ,

-SR

1 0o, -NHSO 2 , -NO 2 , -CONR 10

R

12 , -NR 12

COR

10 , -COR 10 , -OCOR 1 0 o,

-OCO

2

R

10 or -COOR 10 , wherein R 10 and R 12 are as defined hereinabove. Representative heteroaryl groups can include, for example, furanyl, 15 imidazoyl, pyrimidinyl, triazolyl, 2-, 3- or 4-pyridyl or 2-, 3- or 4-pyridyl N-oxide wherein pyridyl N-oxide can be represented as: or N N N I I O 00 heteroarylalkyl - represents an alkyl group, as defined above, wherein one or more hydrogen atoms have been replaced by one or more heteroaryl 20 groups; wherein said heteroarylalkyl group may be optionally and independently substituted with one, two, three or more of the following: halo, alkyl, aryl, cycloalkyl, cyano, -CF 3 , oxy (=0), aryloxy, -OR 10 , -OCF 3 , heterocycloalkyl, heteroaryl, -NR 10

R

12 , -NHSO 2

R

10 , -SO 2

NH

2 , -SO 2 NHR10,

-SO

2

R

1 0 , -SOR 10 , -SR 10 , -NHSO 2 , -NO 2 , -CONR 10

R

12 , -NR 12 C O

R

10 , -COR 1 0 o, 25 -OCOR 1 o, -OCO 2

R

10 or -COOR 10 , wherein R 10 and R 12 are as defined hereinabove; heterocycloalkyl-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 heteroatoms 30 selected from -0-, -S- and -N- , wherein optionally, said ring may contain one or two unsaturated bonds which do not impart aromatic character to the ring; and wherein any of the available substitutable carbon and nitrogen atoms in the ring may be optionally and independently substituted with one, two, three or more of -8- WO 98/57948 PCT/US98/11507 the following: halo, alkyl, aryl, cycloalkyl, cyano, -CF 3 , oxy (=0), aryloxy, -OR 1 0 ,

-OCF

3 , heterocycloalkyl, heteroaryl, -NR 10

R

12 , -NHSO 2

R

10 , -SO 2

NH

2 ,

-SO

2

NHR

10 , -SO 2

R

10 , -SOR 10 , -SR 1 0 , -NHSO 2 , -NO 2 , -CONR 10 R 12 ,

-NR

1 2COR 10 , -COR 10 , -OCOR 10 , -OCO 2

R

10 or -COOR 10 , wherein R10 and R 12 5 are as defined hereinabove. Representative heterocycloalkyl groups can include 2- or 3-tetrahydrofuranyl, 2- or 3- tetrahydrothienyl, 1-, 2-, 3- or 4 piperidinyl, 2- or 3-pyrrolidinyl, 1-, 2- or 3-piperizinyl, 2- or 4-dioxanyl,

N-R

10 -N S(O\ morpholinyl, or wherein R 1 0 is defined hereinbefore and t is 0, 1 or 2. 10 heterocycloalkalkyl- represents an alkyl group, as defined above, wherein one or more hydrogen atoms have been replaced by one or more heterocycloalkyl groups; wherein optionally, said ring may contain one or two unsaturated bonds which do not impart aromatic character to the ring; and wherein said heterocycloalkylalkyl group may be optionally and independently 15 substituted with one, two, three or more of the following: halo, alkyl, aryl, cycloalkyl, cyano, -CF 3 , oxy (=0), aryloxy, -OR 10 , -OCF 3 , heterocycloalkyl, heteroaryl, -NR 10

R

12 , -NHSO 2

R

1 O, -SO 2

NH

2 , -SO 2 NHR10o, -SO 2

R

1 0 , -SOR 10 ,

-SR

10 o, -NHSO 2 , -NO 2 , -CONR 1 0

R

12 , -NR 12C O

R

10 , -COR 10 o, -OCOR 1 0 o,

-OCO

2

R

10 or -COOR 10 , wherein R 10 and R 12 are as defined hereinabove. 20 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 dimethylformamide (DMF); trifluoroacetic acid (TFA); trifluoroacetic anhydride (TFAA); 1-hydroxybenzotriazole (HOBT); m-chloroperbenzoic acid (MCPBA); 25 triethylamine (Et 3 N); diethyl ether (Et 2 0); ethyl chloroformate (CICO 2 Et); and 1 (3-dimethylaminopropyl)-3-ethyl carbodiimide hydrochloride (DEC). Reference to the position of the substituents X 1 , X2 and X 3 is based on the numbered ring structure: -9- WO 98/57948 PCT/US98/11507

X

4 Xi56 x2 -7 3 8 II' X 3 X3

R

6

-

R8 1 'N NR 19

R

20 Y2 v w (1.0) Certain compounds of the invention may exist in different stereoisomeric forms (e.g., enantiomers, diastereoisomers and atropisomers) . The invention contemplates all such stereoisomers both in pure form and in mixture, including 5 racemic mixtures. For example, the carbon atom at the C-11 position can be in the S or R stereoconfiguration. Certain tricyclic compounds will be acidic in nature, e.g. those compounds which possess a carboxyl or phenolic hydroxyl group. These compounds may form pharmaceutically acceptable salts. Examples of such 10 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 15 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, methanesulfonic 20 and other mineral and carboxylic acids well known to those skilled in the art. The salts are prepared by contacting the free base form with a sufficient amount of the desired acid to produce a salt in the conventional manner. The free base forms may be regenerated by treating the salt with a suitable dilute aqueous base solution such as dilute aqueous NaOH, potassium carbonate, ammonia 25 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. -10- WO 98/57948 PCT/US98/11507 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. 5 Compounds of the present invention can be prepared according to the following Schemes I, II or III wherein A, X, X 1 , X2, X 3 , X 4 , y1, y2, Z, R 5 , R 6 , R 7 and R 8 , R19, R 20 , v, w, the solid and dotted lines are as defined hereinbefore. Scheme I x 4

X

4 Xl X 2 X1 X2 A A 02 3 HNRI9R20 3 R5__ X R7 (2.6) R5 X R 7 IJR 8 81 0 R6..-----1R6-- .-- R 8 yl1O N (/" N

'

k u CI N " "N A NR19R2° Z@ b

I

y2 ZY w 72 10 1(2.0) (1.0) Referring to the Scheme I, compounds of formula (1.0) can be prepared by reacting the compounds of formula (2.0) with amine (NHR1 9

R

20 ) of formula (2.6) with an optional base and/or optional aprotic solvent such as THF, dioxane, acetonitrile, CH 2

CI

2 or DMF. In a first procedure, compound (2.0) is 15 reacted with amine (2.6) neat, at temperatures ranging from about 00 to 800C. In a second procedure, compound (2.0) is reacted with about equimolar amounts of amine (2.6) in the presence of a base such as sodium hydride and an aprotic solvent such as CH 2

CI

2 or THF. In a third procedure, compound (2.0) is reacted with amine (2.6) neat, using catalytic amounts of base, such as 20 sodium hydride. In a fourth procedure, compound (2.0) is reacted with greater than two equivalents of amine (2.6) in an aprotic solvent at a temperature of about 750C. Except as noted otherwise, temperatures can range from 00 to 1000C, or reflux of the reaction mixture and amounts of amine (2.6) can range from 1 to about 10 moles per mole of compound (2.0). 25 -11 - WO 98/57948 PCT/US98/11507 Scheme II

X

4

X

4 X1/

X

2 X1 X 2 A A X3 CICONR 1 9

R

20 3 R5 X R 7 (2.9) RS XR 7 R R RsylO R6"-__-_.

1 t R8 ,Y1 R6 ..

8 y10 Ny ./ NH NNR19R 2 0 S(3.0) Z w (1.0) Referring to Scheme II, compounds of formula (1.0) can be prepared by reacting the compounds of formula (3.0) with carbonyl chloride of formula (2.9) with an optional base and/or optional aprotic solvent. In a first procedure, 5 compound (3.0) is reacted with carbonyl chloride (2.9) neat, at temperatures ranging from about 0oC to 800C. In a second procedure, compound (3.0) is reacted with about equimolar amounts of carbonyl chloride (2.9) in the presence of a base such as sodium hydride and an aprotic solvent. In a third procedure, compound (3.0) is reacted with carbonyl chloride (2.9) neat, using 10 catalytic amounts of base, such as sodium hydride. In a fourth procedure, compound (3.0) is reacted with greater than two equivalents of carbonyl chloride (2.9) in an aprotic solvent at a temperature of about 750C. Except as noted otherwise, temperatures can range from 0OC to 1000C, or reflux of the reaction mixture and amounts of carbonyl chloride (2.9) can range from 1 to 15 about 10 moles per mole of compound (3.0).

X

4 Scheme III X X2 XI/ x 2 A RI9NCO A X3 (3.6) x 3 RS X R 7 Y5 . X R O

R

8 y

R

6 7N,,"4'N R6 .. 7R/,I I 6. R R6N2(3.0) N " NH - R 19 y2 y2 (3.0) v • (1.0) Referring to the Scheme III, compounds of formula (1.0) wherein R 20 is hydrogen (i.e. compound (1.0) is a mono-substituted urea) can be prepared by reacting the compounds of formula (3.0) with isocyanate R 19

N

C O of formula 20 (3.6) with an optional base and/or optional aprotic solvent such as those -12- WO 98/57948 PCT/US98/11507 described hereinbefore. In a first procedure, compound (3.0) is reacted with isocyanate (3.6) neat at temperatures ranging from about 00 to 800 C. In a second procedure, compound (3.0) is reacted with about equimolar amounts of isocyanate (3.6) in the presence of a base such as triethylamine and an aprotic 5 solvent such as CH 2

CI

2 or THF. In a third procedure, compound (3.0) is reacted with about equimolar amounts of isocyanate (3.6) in the presence of a base such as sodium hydride and an aprotic solvent such as DMF or THF. In a fourth procedure, compound (3.0) is reacted with greater than two equivalents of isocyanate (3.6) in an aprotic solvent such as DMF at a temperature of about 10 750C. In a fifth procedure, compound (3.0) is reacted with excess isocyanate (3.6) using catalytic amounts of a base such as sodium hydride and an aprotic solvent such as DMF or THF. Except as noted otherwise, temperatures can range from 00 to 1000C, or reflux of the reaction mixture and amounts of isocyanate (3.6) can range from 1 to about 10 moles per mole of compound 15 (3.0). Compounds of fomula (1.0) can be isolated from the reaction mixture using conventional procedures, such as, for example, extraction of the reaction mixture from water with organic solvents, evaporation of the organic solvents, followed by chromatography on silica gel or other suitable chromatographic 20 media. Alternatively, compounds (1.0) can be dissolved in a water-miscible solvent, such as methanol, the methanol solution is added to water to precipitate the compound, and the precipitate is isolated by filtration or centrifugation. 25 (+)-Isomers of compounds of formula (5.0, 6.0 and 10.9) wherein X is CH can be prepared with high enantioselectivity by using a process comprising enzyme catalyzed transesterification. Preferably, a racemic compound of formula (5.0, 6.0 and 10.9) , wherein X is C, the double bond is present and X3 is not H, is reacted with an enzyme such as Toyobo LIP-300 and an acylating 30 agent such as trifluoroethly isobutyrate; the resultant (+)-amide is then hydrolyzed, for example by refluxing with an acid such as H 2

SO

4 , to obtain the corresponding optically enriched (+)-isomer wherein X is CH and R 3 is not H. Alternatively, a racemic compound of formula (5.0, 6.0 and 10.9), wherein X is C, the double bond is present and R 3 is not H, is first reduced to the 35 corresponding racemic compound of formula (5.0, 6.0 and 10.9) wherein X is CH and then treated with the enzyme (Toyobo LIP-300) and acylating agent as -13- WO 98/57948 PCT/US98/11507 described above to obtain the (+)-amide, which is hydrolyzed to obtain the optically enriched (+)-isomer. Compounds of the present invention and preparative starting materials therof, are exemplified by the following examples, which should not be 5 construed as limiting the scope of the disclosure. 10 Example 1. (+)-4-[2-[4-[(3,10-Dibromo -8-chloro-6,11-dihydro-5H benzo[5,6]cyclohepta[1,2-b]pyridin-11 (R)-yl)-1 -piperidinyl]-2-oxoethyl]-N-(2 methoxyphenyl)-1l-piperidinecarboxamide Br Cl N Br 0 N N Nk 3l

OCH

3 The title compound of Preparative Example 5 (90 mg, 0.15 mmol) was 15 dissolved in 1.5 mL of anhydrous CH 2 CI01 2 and 0.02 mL (0.2 mmol) 2 methoxyphenyl isocyanate was added. After 1 h the reaction was diluted with saturated NaHCO 3 solution (aqueous) and extracted with CH 2 0C1 2 . The combined organic extracts were washed with brine and water, dried (MgSO 4 ), filtered and the solvent evaporated. The residue was purified by preparative 20 TLC using 5% (NH 3 saturated MeOH)/CH 2

CI

2 as eluent to afford 62 mg (52%) of the title compound as an off white solid (mp 135.2 - 137.0 OC). Example 2. (+)-4-[2-[4-[(3,10-dibromo -8-chloro-6,11-dihydro-5H benzo[5,6]cyclohepta[1,2-b]pyridin- 1 (R)-yl)-1-piperidinyl]-2-oxoethyl]-N 25 phenyl-1-piperidinecarboxamide - 14- WO 98/57948 PCT/US98/11507 Br - \Cl N Br 0 N N NH 0 Following the procedure described in Example 1 using 90 mg (0.15 mmol) of the title compound of Preparative Example 5 and 0.02 mL (0.2 mmol) of phenyl isocyanate 58 mg (54%) of the title compound was obtained as an off white 5 solid (mp 154.7 - 157.2 C00). Example 3. (+)-4-[2-[4-[(3,10-Dibromo -8-chloro-6,11 -dihydro-5H 10 benzo[5,6]cyclohepta[1,2-b]pyridin- 1 (R)-yl)-1-piperidinyl]-2-oxoethyl]-N methyl-1 -piperidinecarboxamide Br Cl N Br 0 'J

CH

3 N N H Following the procedure described in Example 1 using 90 mg (0.15 mmol) of the title compound of Preparative Example 5 and 0.01 mL (0.2 mmol) of methyl 15 isocyanate and stirring the mixture overnight 53 mg (54%) of the title compound was obtained as a white solid (mp 108.5 - 110.3 C00). Example 4. (+)-Ethyl [[[4-[2-[4-[(3,10-dibromo -8-chloro-6,11 -dihydro-5H benzo[5,6]cyclohepta[1,2-b]pyridin-11 (R)-yl)-1-piperidinyl]-2-oxoethyl]-1 20 piperidinyl]carbonyl]amino]acetate -15- WO 98/57948 PCT/US98/11507 Br 1 C1 N Br O O N NHCH 2 COOCH 2

CH

3 Following the procedure described in Example 1 using 90 mg (0.1.5 mmol) of the title compound of Preparative Example 5 and 0.02 mL (0.2 mmol) of ethyl isocyanatoacetate and stirring the mixture 2 h gave a material that was purified 5 by flash chromatography (silica, 2%-4% (NH 3 saturated MeOH)/CH 2

CI

2 as eluent). The title compound was obtained as a white solid (45 mg, 40%, mp 126.4 - 128.2 oqC). 10 Example 5. (+)-Methyl alpha(S)-[[[4-[2-[4-[(3,10-dibromo -8-chloro-6,11 -dihydro-5H benzo[5,6]cyclohepta[1,2-b]pyridin- 1 (R)-yl)-1 -piperidinyl]-2-oxoethyl]-1 15 piperidinyl]carbonyl]amino]-beta-methylbutanoate Br Cl N Br H 3 C CH3 0 Br

OCH

2

CH

3 N N N SH H O Following the procedure described in Example 1 using 90 mg (0.15 mmol) of the title compound of Preparative Example 5 and 49 mg (0.31 mmol) of (S)-(-) 2-isocyanato-3-methylbutyric acid methyl ester and stirring the mixture 3 h 102 20 mg (90%) of the title compound was obtained as a white solid without purification (mp 98.1 - 100.0 OC). Example 6. (+)-Ethyl 4-[[[4-[2-[4-[(3,10-dibromo -8-chloro-6,11-dihydro-5H benzo[5,6]cyclohepta[1,2-b]pyridin- 1 (R)-yl)-1-piperidinyl]-2-oxoethyl]-1 25 piperidinyl]carbonyl]amino]-1 -piperidinecarboxylate -16- WO 98/57948 PCT/US98/11507 Br - \ C N Br NJNH N

COOCH

2

CH

3 Ethyl 4-aminopiperidine carboxylate (1.00 mL, 5.83 mmol) was dissolved in anhydrous THF (5 mL) and the mixture was cooled to 00 C. A 1.93 M solution of phosgene in toluene (4.50 mL 8.69 mmol) was added followed by triethylamine 5 (3.30 mL, 23.7 mmol). The resulting slurry was stirred at 00 C 3 h then at room temperature overnight. The mixture was diluted with ether (20 mL), filtered and the filter cake washed with ether. The combined filtrate was evaporated to give a yellow oil 149 mg of which was dissolved in 1 mL anhydrous CH 2 C1 2 and added to a solution of the title compound of Preparative Example 5 in 2 mL of 10 anhydrous CH 2

CI

2 . After 3 h the mixture was diluted with saturated NaHCO 3 and extracted with CH 2 CI2. The combined organic extracts were washed with brine, water, dried (MgSO 4 ), filtered and evaporated. The residue was purified by flash chromatography (silica, 2.5% - 5% (NH 3 saturated MeOH)/CH 2

CI

2 as eluent) to give the title compound (50 mg, 50%) as a white solid (mp 139.7 15 142.0 OC). Example 7. (+)-4-[2-[4-[(3,10-Dibromo -8-chloro-6,11 -dihydro-5H benzo[5,6]cyclohepta[1,2-b]pyridin- 1 (R)-yl)-1 -piperidinyl]-2-oxoethyl]-N,N bis(2-hydroxyethyl)-1l-piperidinecarboxamide Br C1 N Br 0 N N N OH 20 0 OH The title compound of Preparative Example 5 (200 mg, 0.34 mmol) was dissolved in anhydrous CH 2

CI

2 (2 mL) and 0.23 mL triethylamine (1.7 mmol). This solution was added to a 1.93 M solution of phosgene in toluene (0.88 mL, -17- WO 98/57948 PCT/US98/11507 1.7 mmol) at 00 C and the resulting mixture was stirred at 00 C for 1 hour. The mixture was evaporated and the residue stored under vacuum (10 mm Hg) overnight. This was dissolved in anhydrous CH 2

CI

2 (2 mL) and triethylamine (0.23 mL, 1.7 mmol) was added. To this was added a mixture of 0.04 mL 5 diethanolamine hydrochloride (0.37 mmol) and triethylamine (0.1 mL, 0.74 mmol) in anhydrous CH 2

CI

2 (1 mL) and the mixture stirred 2 hours, diluted with 1 M NaOH and extracted with CH 2

CI

2 . The combined extracts were washed with brine, dried (MgSO 4 ) and evaporated. The residue was purified by flash chromatography (2.5%, 5%, 10% (NH 3 saturated MeOH)/CH 2

CI

2 as eluent)) to 10 give the product (79 mg, 32%) as a white solid (mp 105.3 - 107.40 C). Example 8. (+)-Methyl 2(S)-[[[4-[2-[4-[(3,10-dibromo-8-chloro-6,11-dihydro-5H benzo[5,6]cyclohepta[1,2-b]pyridin- 11 (R)-yl)-1 -piperidinyl]-2-oxoethyl]-1 piperidinyl]carbonyl]amino]-3-(1,1 -dimethylethoxy)propanoate Br . Cl \ I

H

3 C CH 3 N

H

3 C0 Br 0 1O OCH3 150 Following the procedure described in Example 1 using 450 mg (0.76 mmol) of the title compound of Preparative Example 5 and 369 mg (0.1.54 mmol) of methyl (S)-2-isocyanato-3-(1,1-dimethylethoxy)propanoate (J. S. Nowick et. al J. Org. Chem. 1992, 57, 7364) and stirring the mixture 3 h gave 459 mg (76%) 20 of the title compound as a white solid after flash chromatography (silica, 5%

(NH

3 saturated MeOH)/CH 2

CI

2 as eluent) mp 98.4 - 100.50C. Example 9. (+)-Methyl 2(S)-[[[4-[2-[4-[(3,10-dibromo -8-chloro-6, 11-dihydro-5H benzo[5,6]cyclohepta[1,2-b]pyridin- 1 (R)-yl)-1 -piperidinyl]-2-oxoethyl]-1 piperidinyl]carbonyl]amino]-3-hydroxypropanoate Br N C1 N OH Br O N N 'KNH 0 25 oOCH3 25-18 -18- WO 98/57948 PCT/US98/11507 The title compound of Example 8 (330 mg, 0.41 mmol) was dissolved in anhydrous MeOH (2.5 mL) and 6 mL of 10% H2SO4/dioxane (v/v) was added. The mixture was stirred overnight then 0.2 mL conc. H 2

SO

4 was added. After 4 h 1 M NaOH was added, water was added and the mixture extracted with 5 CH 2

CI

2 . The combined extracts were washed (brine), dried (MgSO 4 ), filtered and evaporated to give the title compound as a white solid (291.1 mg, 96%, mp 122.4-1250 C). -19- WO 98/57948 PCT/US98/11507 Example 10. (+)-N-2[2-Amino-l1(S)-(hydroxymethyl)-2-oxoethyl]-4-[2-[4-[(3,10 dibromo -8-chloro-6,11-dihydro-5H-benzo[5,6]cyclohepta[1,2-b]pyridin- 11(R) yl)-1 -piperidinyl]-2-oxoethyl]-1 -piperidinecarboxamide Br \ C1 N OH Br 0 N~K SNH

NH

2 50 Similar to the procedure in Hogberg, T. et. al J. Org. Chem. 1987, 52, 2033, in a sealable vessel the title compound of Example 9 (99 mg, 0.13 mmol) was dissolved in 9 M NH 4 OH/MeOH and 0.64 mg (0.013 mmol) NaCN was added. The sealed reaction vessel was heated at 500 C (bath temperature) for 5 h, 10 cooled to room temperature and stood overnight. The mixture was evaporated, the residue dissolved in CH 2 CI01 2 and washed with H 2 0. The aqueous wash was extracted with CH 2

CI

2 , the combined extracts were dried (MgSO 4 ), filtered and evaporated to give the title compound as a white solid (30.4 mg, 32%, mp 150.5 -153.30 C) 15 Example 11. (+)-4-[2-[4-[(3,10-Dibromo -8-chloro-6,11-dihydro-5H benzo[5,6]cyclohepta[1,2-b]pyridin- 1 (R)-yl)-1-piperidinyl]-2-oxoethyl]-N-(2 hydroxyethyl)-1l-piperidinecarboxamide Br 1 \ C1 N Br O N N pNH OH Following the procedure described in Example 7 using 200 mg (0.34 mmol) of 20 the title compound of Preparative Example 5, 0.88 mL of 1.93 M phosgene in toluene (1.7 mmol), two 0.23 mL portions of triethylamine (1.7 mmol each) and 0.04 mL (0.66 mmol) of ethanolamine the title compound was obtained after precipitation from water as a brown solid (138.1 mg, 56%, mp 142.3 -145.90 C). - 20 - WO 98/57948 PCT/US98/11507 Example 12. (+)-[[[4-[2-[4-[(3,10-Dibromo -8-chloro-6,11 -dihydro-5H benzo[5,6]cyclohepta[1,2-b]pyridin- 1 (R)-yl)-1 -piperdinyl]-2-oxoethyl]-1 piperdinyl]carbonyl]amino]acetic acid Br C1 N Br O N N OH 5 o O The title compound of Example 4 was dissolved in 6 M HCI and the mixture stirred 72 h. The reaction was diluted with H 2 0 and brine and extracted with

CH

2 0CI 2 . The combined organic extracts were dried (MgSO 4 ), filtered and evaporated and the residue purified by flash chromatography (C18 reverse 10 phase silica (Aldrich), gradient elution, 1 L 50% MeOH/0.1% HOAc reservoir A, 1 L 90% MeOH/0.1% HOAc reservoir B) to give the title compound as a white solid (162.2 mg, 31%, mp 123.4 -125.80 C). Example 13. (+)-N-(2-Amino-2-oxoethyl)-4-[2-[4-[(3,10-dibromo -8-chloro-6,11 15 dihydro-5H-benzo[5,6]cyclohepta[1,2-b]pyridin- 1 (R)-yl)-1 -piperidinyl]-2 oxoethyl]-1l-piperidinecarboxamide Br C1 N Br 0 O NH

-

NH 2 0 & 0 The title compound of Example 12 (60 mg, 0.086 mmol) was dissolved in DMF and NH 4 CI (7 mg, 0.13 mmol), N-methylmorpholine (0.015 mL, 0.13 mmol), 1 20 (3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (25 mg, 0.13 mmol) and 1-hydroxybenzotriazole hydrate (17 mg, 0.13 mmol) were added. After 3.5 h an additional 21 mg of NH 4 CI (0.39 mmol) was added and the mixture stirred overnight. Water was added to give the title compound as a white solid (33.4 mg, 55%, mp 144.8 - 149.80 C). 25 -21 - WO 98/57948 PCT/US98/11507 EXAMPLE 14. 4-[2-[4-(3-Bromo-8-chloro-6,11-dihydro-5H-benzo[5,6] cyclohepta[1,2-b]pyridin- 11-yl)-1-piperazinyl]-2-oxoethyl]-N-methyl-1 piperidinecarboxamide Br 1 \CI Br 1 \C H N N NH O N CH 3 o 0J 5 1-(3-Bromo-8-chloro-6,11-dihydro-5H-benzo[5,6]cyclohepta[1,2-b]pyridin-1 1 yl)-4-[(4-piperidinyl)acetyl]piperazine (Preparative Example 10) (500mg, 0.9mmoles) was dissolved in anhydrous dichloromethane (5mi) and methyl isocyanate (220.3mg, 3.6mmoles) was added. The mixture was stirred under argon at 250C for 47h. Additional methyl isocyanate (110.15mg, 1.8mmoles) 10 was added and the reaction was stirred for a total of 144h. The solution was heated at 740C for 5h and the stirred at 250C for an additional 24h. The solution was chromatographed on silica gel using 2% (10% conc. NH 4 OH in methanol)dichloromethane as the eluant to give 438.9mg of the title compound (Yield: 79%). 15 EXAMPLE 15. 4-[2-[4-(3-Bromo-8-chloro-6,11-dihydro-5H benzo[5,6]cyclohepta[1,2-b]pyridin- 11-yl)-1-piperazinyl]-2-oxoethyl]-N-propyl-1 20 piperidinecarboxamide Br C Br Cl N ) N NJ ,

-

CH N N N 1-(3-Bromo-8-chloro-6,11 -dihydro-5H-benzo[5,6]cyclohepta[1,2-b]pyridin- 1 yl)-4-[(4-piperidinyl)acetyl]piperazine (Preparative Example 10) (490mg, 0.8mmoles) was dissolved in anhydrous dichloromethane (5 ml) and n-propyl 25 isocyanate (322.1mg, 3.2mmoles) was added. The mixture was stirred under argon at 250C for 44h. The solution was chromatographed on silica gel using 2% (10% concentrated NH 4 OH in methanol)dichloromethane as the eluant to give 544.8mg of the title compound (Yield: 95%). 30 -22 - WO 98/57948 PCT/US98/11507 EXAMPLE 16. 4-[2-[4-(3-Bromo-8-chloro-6,11-dihydro-5H benzo[5,6]cyclohepta[1,2-b]pyridin-11-yl)-1 -piperazinyl]-2-oxoethyl]-N-(1,1 dimethylethyl)-1l-piperidinecarboxamide Br \CI Br CI N N CO NH C) N NC(CH) 3 5 1-(3-Bromo-8-chloro-6,11-dihydro-5H-benzo[5,6]cyclohepta[1,2-b]pyridin-11-yl)-4 [(4-piperidinyl)acetyl]piperazine (Preparative Example 10) (500mg, 0.8mmoles) was dissolved in anhydrous dichloromethane (5 ml) and tert -butyl isocyanate (383.8mg, 3.2mmoles) was added. The mixture was stirred under argon at 250C for 47h. Additional tert -butyl isocyanate (191.4 mg, 1.6 mmoles) was added and 10 the reaction was stirred for a total of 144h. The solution was heated at 740C for 5h and the stirred at 250C for an additional 24h. The solution was chromatographed on silica gel using 2% (10% conc. NH 4 OH in methanol) dichloromethane as the eluant to give 421.8mg of the title compound (Yield: 71%). 15 PREPARATION OF STARTING MATERIALS Starting materials useful in preparing the compounds of the present invention are exemplified by the following preparative examples, which should not be construed to limit the scope of the disclosure. The tricylic compounds used as starting materials, such as compound (11.0), inorganic and organic bases, and 20 alcohols can be prepared using known methods in the art, such as taught in See J. K. Wong et al., Bioorganic & Medicinal Chemistry Letters, Vol. 3, No. 6, pp. 1073-1078, (1993); U.S. Patents 5,089,496; 5,151,423; 4,454,143; 4,355,036; PCT /US94/11390 (WO95/10514); PCT/US94/11391 (WO 95/10515); PCT/US94/11392 (WO95/10516); Stanley R. Sander and Wolf 25 Karo, Organic Functional Group Preparations, 2nd Edition, Academic Press, Inc., San Diego, California, Vol. 1-3, (1983), and in J. March, Advanced Organic Chemistry, Reactions & Mechanisms, and Structure, 3rd Edition, John Wiley & Sons, New York, 1346 pp. (1985). Alternative mechanistic pathways and analogous structures within the scope of the invention may be apparent to those 30 skilled in the art. Starting materials used to prepare the compounds of the present invention are depicted in Scheme IV: - 23 - WO 98/57948 PCT/US98/11507 Scheme IV X X2 X X1

X

2 A A NO 2 A NH 2 R ---.... R AR 5 7 5 .... R 7R R - R 7 B R 5 -- R

R

6

-

7 R ~- 8 B~ 6 R5" 8R A R 6..-_R R NjR8 R6 N,,- R8 R N Il ,N1 / (11.0) (10.0) (9.0) 0 OR' 5 0 OR 5 0 OR1 5 C

X

1 X 2 X1 X 2 Xk X2 RA -A .A NH 2 x3 x3X RX-3---- -. D R 5 ;RR R 7 1 RI .g-R8 z 5 - R 7 62 - 8 R- R 8

R

6 ---- R-R 8 - N N G N (7.0) N (8.0) H (6.0 O OR 15 0 OR 5 F X 1 X 2 y 0 X / A X 2 X X \ X'//~T S/N ' OR1 5 X A 0 --!-y2 A o" w (5.5) x

R

5 - X R 7 G R5 X.. R 7 R --- R 8 R 6 R8 y O SR6 --- N /N OR15 H (5.0) Scheme IVa (6.7) --2-y2 X=CH from (6.0) 0 (4.0) X=N from (6.7) H Scheme M XI X2 X/ X A A X3 I X3 Scheme I R 5 .. R R5 X. R 7 R6 , R 8 y1 R6 R8 yl N NC1 N N NH z-, y2 y2 Scheme II w (2.0) (3.0) /J Sulfurating agent -24- WO 98/57948 PCT/US98/11507 Scheme IVa X1 / X 2 5 N 7 X X2 R-R A R5 X R 7 H (6.9) Cl X3 --- (6.7)

R

6 " -R 8 Q N H (5.0, X =N) P 2 X2 X X2 XZ \X N2 X1 0.. 'A 2 A OH x3 0 (6.5) M (6.31) (6.3) XKXIN XlY X2 A AA O NH 2 O NO 2 O (6.2) (6.1) (5.9) wherein for Schemes IV and IVa, X, X 1 , X 2 , X3, yl, y2, Z, R 5 , R 6 , R 7 and R 8 , R 19 , R 20 , v, w, the solid and dotted 5 lines are as defined hereinbefore; and R 15 can represent any of the values for

R

10 as defined hereinbefore; and T is OH, -OCOR 10 , halo such as chloro or

-OR

10 .l In Step A (Scheme IV), compounds of formula (10.0) can be prepared by reacting the compounds of formula (11.0) with a nitrating agent and/or optional 10 protic or aprotic solvent such as those described hereinbefore. In a first procedure, compound (11.0) is reacted with about an equimolar amount of a nitrate salt, such as potassium nitrate, and acid, such as sulfuric acid at temperatures ranging from about -200 to +50 C. In a second procedure, compound (11.0) is reacted with about an equimolar amount of nitric acid and 15 acid, such as sulfuric acid at temperatures ranging from about -200 to +50 C. In a third procedure, compound (11.0) is treated with a mixture comprised of about two equivalents of trifluoromethanesulfonic acid and about one equivalent nitric acid in a solvent such as trifluoromethanesulfonic acid. In a fourth procedure, compound (11.0) is treated with a mixture comprised of about one equivalent of 20 fuming nitric acid and about ten equivalents of trifluoromethanesulfonic - 25 - WO 98/57948 PCT/US98/11507 anhydride in a solvent such as nitromethane. In a fifth procedure, compound (11.0) is treated with a nitronium salt, such as nitronium tetrafluoroborate, in a solvent, such as sulfolane. In a sixth procedure, compound (11.0) is reacted with fuming nitric acid at temperatures ranging from about -200 to +500 C. 5 In Step B(Scheme IV), compounds of formula (9.0) can be prepared by reacting compounds of the formula (10.0) with a reducing agent. In a first procedure, compound (10.0) can be reacted with about ten equivalents of a metal, such as iron, in a solvent, such as ethanol, in the presence of a salt, such as calcium chloride, at temperatures ranging from about 00 to +800 C. In a 10 second procedure, compound (10.0) can be reacted with about ten equivalents of a metal, such as zinc, in a solvent, such as ethanol, in the presence of an acid, such as acetic acid at temperatures ranging from about 00 to +800 C. In a third procedure, compound (10.0) can be reacted with about five equivalents of stannous chloride hydrate in a solvent, such as ethyl acetate. In a fourth 15 procedure, compound (10.0) can be reacted with about ten equivalents of a metal, such as tin, in a solvent, such as ethanol, in the presence of an acid, such as hydrochloric acid. In Step C(Scheme IV), compounds of formula (8.0) can be prepared by reacting compounds of the formula (9.0) with a halogenating agent. In a first 20 procedure, compound (9.0) can be reacted with an excess of an elemental halogen, such as bromine, in a suitable solvent, such as acetic acid at temperatures ranging from about 00 to +800 C. In a second procedure, compound (9.0) can be reacted with an excess of a mineral acid, such as hydrogen bromide, in a suitable solvent, such as dimethyl sulfoxide at 25 temperatures ranging from about 200 C to about 1350C. In a third procedure, compound (9.0) can be reacted with a salt, such as pyridinium bromide perbromide, in a solvent, such as THF, at temperatures from about 00 to +400 C. In a fourth procedure, compound (9.0) can be reacted with a halogen, such as chlorine, in the presence of a Lewis acid, such as iron(Ill) chloride, in a suitable 30 solvent, such as dichloromethane. In Step D(Scheme IV), compounds of formula (7.0) can be prepared by reacting compounds of the formula (8.0) with an oxidizing agent followed by a reducing agent, or by reacting compounds of the formula (8.0) with an oxidizing agent in the presence of a hydrogen atom source. In a first procedure, 35 compound (8.0) can be reacted with a diazotizing agent, such as t-butyl nitrite, in a solvent and hydrogen atom source, such as DMF at temperatures from about 00 to +1000 C. In a second procedure, compound (8.0) can be reacted - 26 - WO 98/57948 PCT/US98/11507 with a diazotizing agent, such as sodium nitrite, and an acid, such as hydrochloric acid, and a reducing agent, such as hypophosphorous acid at temperatures from about -150 to +500 C. In a third procedure, compound (8.0) can be reacted with a diazotizing agent, such as sodium nitrite, and an acid, 5 such as aqueous sulfuric acid, followed by treatment with a metal, such as copper. In a fourth procedure, compound (8.0) can be reacted with a diazotizing agent, such as sodium nitrite, and an acid, such as fluoboric acid, followed by treatment with a reducing agent, such as sodium borohydride. In Step E(Scheme IV), compounds of formula (6.0) can be prepared by 10 reacting compounds of the formula (7.0) under hydrolysis conditions. In a first procedure, compound (7.0) can be reacted with an acid, such as hydrochloric acid, at temperatures from about 200 to +900 C. In a second procedure, compound (7.0) can be reacted with a base, such as aqueous sodium hydroxide, in a suitable solvent, such as ethanol, at temperatures from about 15 200 to +900 C. In a third procedure, compound (7.0) can be reacted with a nucleophile, such as hydrazine hydrate, in a solvent, such as ethanol, with an optional base, such as sodium hydroxide, at temperatures from about 200 to +900 C. In a fourth procedure, compound (7.0) can be reacted with a silyl chloride, such as trimethylsilyl chloride, in a solvent, such as THF or CH 2 0CI 2 at 20 temperatures ranging from about 0oC to reflux. In a fifth procedure, compound (7.0) can be reacted with an acid, such as trifluoroacetic acid, in an aprotic solvent, such as CH2CI 2 . In Step F(Scheme IV), compounds of formula (5.0) wherein X = CH can be prepared by reacting compounds of the formula (6.0) under reducing 25 conditions. Compound (6.0) can be reacted with an alkyl-metal hydride, such as diisobutyl aluminum hydride, in a solvent, such as toluene, at temperatures from about 00 to +900 C. In Step G(Scheme IV), compounds of formula (4.0) can be prepared by reacting compounds of the formula (5.0) with a carboxylic acid under 30 dehydrating conditions. In a first example, compound (5.0) or (6.0) can be reacted with carboxylic acid (5.5 wherein T = -OH) in the presence of a carbodiimide, such as DEC, with an optional base, such as 1 methylmorpholine, with an optional catalyst, such as HOBT, in a solvent such as DMF. In a second example, compound (5.0) or (6.0) can be reacted with an 35 carboxylic anhydride in a protic or aprotic solvent such as THF. In a third example, compound (5.0) or (6.0) can be reacted with a carboxylic acid chloride (5.5 wherein T=CI) in an aprotic solvent such as THF or CH 2

CI

2 . In a fourth -27- WO 98/57948 PCT/US98/11507 example, compound (5.0) or (6.0) can be reacted with an carboxylic acid ester (5.5 wherein T= -ORlO), such as a pentafluorophenyl ester, in an aprotic solvent such as THF or CH 2

CI

2 . In Step H(Scheme IV), compounds of formula (3.0) can be prepared by 5 reacting compounds of the formula (4.0) under hydrolysis conditions. In a first procedure, compound (4.0) can be reacted with an acid, such as hydrochloric acid, at temperatures from about 200 to +900 C. In a second procedure, compound (4.0) can be reacted with a base, such as aqueous sodium hydroxide, in a suitable solvent, such as ethanol, at temperatures from about 10 200 to +900 C. In a third procedure, compound (4.0) can be reacted with a nucleophile, such as hydrazine hydrate, in a solvent, such as ethanol, with an optional base, such as sodium hydroxide, at temperatures from about 200 to +900 C. In a fourth procedure, compound (4.0) can be reacted with a silyl chloride, such as trimethylsilyl chloride, in a solvent, such as THF or CH 2 C1 2 . In 15 a fifth procedure, compound (4.0) can be reacted with an acid, such as trifluoroacetic acid, in an aprotic solvent, such as CH 2 0CI 2 . In Step I(Scheme IV), compounds of formula (2.0) can be prepared by reacting compounds of the formula (3.0) and (3.1) with an excess amount of phosgene or a compound capable of releasing phosgene, in the presence of an 20 optional base, such as Et 3 N, either neat, or in an optional aprotic solvent. In Step J,.the sulfur-containing compounds of formula (3.0) wherein Z = S, can be prepared by the amide (3.0) can be reacted with a sulfurating agent such as Lawesson's Reagent in a suitable aprotic solvent such as toluene at about 1000C to give the thioamide (3.1). Alternative sulfurating reagents 25 include bis-(1,5-cyclooctanediarylboryl)sulfide in hexane at -780C; or phosphorous pentasulfide (P 2

S

5 , also of the formula P 4 Slo) in toluene at reflux temperatures, or in THF using ultrasound at 400C; or bis-(9 Borabicyclo[3.3.1]nonane)sulfide ((9-BBN) 2 S) in heptane at reflux temperatures. 30 In Step K(Scheme IVa), compounds of formula (6.1) can be prepared by reacting the compound of formula (5.9) with a nitrating agent and/or optional protic or aprotic solvent according to the procedures described in Step A (Scheme IV). In Step L (Scheme IVa), compounds of formula (6.2) can be prepared by 35 reacting the compound of formula (6.1) with a reducing agent according to the procedures described in Step B (Scheme IV). -28 - WO 98/57948 PCT/US98/11507 In Step M (Scheme IVa), compounds of formula (6.31) can be prepared by reacting the compound of formula (6.2) with a halogenating agent according to the procedures described in Step C (Scheme IV). In Step N (Scheme IVa), compounds of formula (6.3) can be prepared by 5 reacting the compound of formula (6.31) with an oxidizing agent followed by a reducing agent, or by reacting compounds of the formula (6.31) with an oxidizing agent in the presence of a hydrogen atom source according to the procedures described in Step D (Scheme IV). In Step O(Scheme IVa), compounds of formula (6.5) can be prepared by 10 reacting compounds of formula (6.3) with sodium borohydride (NaBH 4 ) in a solvent such as ethanol/toluene under reflux conditions for 10 minutes or at 250C for two hours or more. In Step P (Scheme IVa), compounds of formula (6.7) can be prepared by reacting compounds of formula (6.5) with SOC 2 in a solvent such as CH 2

CI

2 at 15 a temperature of about 250C for about 4 hours or more. In Step Q (Scheme IVa), compounds of formula (5.0) wherein X = N, can be prepared by reacting compounds (6.7) with an excess amount of the piperazine compound of formula (6.9) in a solvent such as THF at 250C or reflux for one hour or more. 20 Additional starting materials which can be used to prepare the compounds of the present invention are depicted in Scheme V. -29 - WO 98/57948 PCT/US98/11507 Scheme V X X2 X 1 X4 2 X X4 2 SX / ~ \X2 X\ X 2 A

NO

2 NO A

R

5 7 A NO2 A NH 2 RA R R6RS AA .R 5 - ... R 7 BB RS --... ,...R 7 N R6 - R R6 R 8 o OR' 5 .1 N S(10.0) O OR 15 (10.3) 0 OR15 (10.5) A X 1 X 2 X 4

SX

4 X X R, R7 X1 /x2 R 5 .....

7

A\X

2 R6. - -- R8 A N V-- .. A D R 5 .N R R7 O O R 15 5 7 D R6--

R

8 R ---.. ,..R N (11.0) R 6 - R 8 N O OR15 (10.7) H (10.9) EE

X

4 X1I\ X2 O A 0 (10.8) In Step A (Scheme V), compounds of fomula (10.0) can be prepared from compound of formula (11.0) using the procedures described in Scheme IV, Step A. In Step AA(Scheme V), compounds of formula (10.3) can be prepared by 5 reacting compound of formula (10.0) with 1,3-dibromo-5,5-dimethylhydantoin in an acid, such as trifluoromethane sulfonic acid or sulfuric acid for about 24 h or more at 250C. In Step BB (Scheme V), compounds of the formula (10.5) can be prepared by treating the compounds of formula (10.3) with a reducing agent, 10 using the procedures taught in Scheme IV, Step B. In Step CC (Scheme V), compounds of formula (10.7) can be prepared by reacting compounds of formula (10.5) with sodium nitrite (NaNO 2 ) in concentrated aqueous HCI at temperatures ranging from about -10oC to 0oC for - 30 - WO 98/57948 PCT/US98/11507 about 2 h or more, then treating the reaction mixture with phosphorous acid

(H

3

PO

2 ) at 0OC for 4 h or more. In Step DD(Scheme V), compounds of formula (10.9) can be prepared by reacting compounds of formula (10.7) with concentrated aqueous HCI at about 5 850C for about 18 h or more. Compound (10.9) can be reacted using the same procedures described in Scheme IV for treating compound (5.0) and (6.0) and subsequent intermediates therefrom, in order to obtain the desired compounds of formula (1.0). In Step EE (Scheme V), compounds of formula (10.8) can be prepared 10 by reacting compound of formula (10.7) with NalO 4 and RuO 2 in acetonitrile and water for about 18 to 24 h or more at 250C. Compound (10.8) can be reacted using the same procedures described in Scheme IVa for treating compound (6.3) and subsequent intermediates therefrom, such as compound (5.0) or (6.0), in order to obtain the desired compounds of formula (1.0). 15 Referring to the Schemes IV, IVa and V, except as noted otherwise, temperatures can range from 00 to 1000C, or reflux of the reaction mixture and amounts of the reagents (e.g. compound 5.5) can range from 1 to about 10 moles per mole of reactant (e.g. compound 5.0 or 6.0). The following preparative examples are intended to exemplify selected 20 starting materials for preparing compounds of the present invention. Preparative Example 1 Br / \ CI Br N ts H Step A: Br- CI B r: NC No2 25 0 OCH 2

CH

3 0 OCH 2

CH

3 -31 - WO 98/57948 PCT/US98/11507 Combine 15 g (38.5 mmol) of 4-(8-chloro-3-bromo-5,6-dihydro-1 1 H benzo[5,6]cyclohepta[1,2-b]pyridin-11-ylidene)-1 -piperidine-1 -carboxylic acid ethyl ester (as taught in Preparative Example 47 of PCT/US 94/11392) and 150 mL of concentrated H 2

SO

4 at -5oC, then add 3.89 g (38.5 mmol) of KNO 3 and 5 stir for 4 hours. Pour the mixture into 3 L of ice and basify with 50% NaOH (aqueous). Extract with CH 2

CI

2 , dry over MgSO 4 , then filter and concentrate in vacuo to a residue. Recrystallize the residue from acetone to give 6.69 g of the product. Step B: Br \ CI Br CI NO2 NH2 10 0 j OCH2CH3 0 OCH 2

CH

3 Combine 6.69 g (13.1 mmol) of the product of Step A and 100 mL of 85% EtOH/water, then add 0.66 g (5.9 mmol) of CaCl2 and 6.56 g (117.9 mmol) of Fe and heat the mixture at reflux overnight. Filter the hot reaction mixture through Celite® and rinse the filter cake with hot EtOH. Concentrate the filtrate in vacuo 15 to give 7.72 g of the product. Step C: Br N CI Br Cl

NH

2 NH2 Br N N 0 OCH2CHs 0 OCH 2

CH

3 Combine 7.70 g of the product of Step B and 35 mL of HOAc, then add 45 mL of a solution of Br 2 in HOAc and stir the mixture at room temperature overnight. 20 Add 300 mL of 1 N NaOH (aqueous), then 75 mL of 50% NaOH (aqueous) and extract with EtOAc. Dry the extract over MgSO 4 and concentrate in vacuo to a residue. Chromatograph the residue (silica gel, 20%-30% EtOAc/hexane) to give 3.47 g of the product (along with another 1.28 g of partially purified product). 25 Step D: - 32 - WO 98/57948 PCT/US98/11507 Br "\ CI Br \ Cl N j NH 2 Br Br N N 0 BOCH 2

CH

3 0 OCH 2

CH

3 Combine 0.557 g (5.4 mmol) of t-butylnitrite and 3 mL of DMF, and heat the mixture at to 60o-70oC. Slowly add (dropwise) a mixture of 2.00 g (3.6 mmol) of the product of Step C and 4 mL of DMF, then cool the mixture to room 5 temperature. Add another 0.64 mL of t-butylnitrite at 400C and reheat the mixture to 600-70oC for 0.5 hrs. Cool to room temperature and pour the mixture into 150 mL of water. Extract with CH 2

CI

2 , dry the extract over MgSO 4 and concentrate in vacuo to a residue. Chromatograph the residue (silica gel, 10% 20% EtOAc/hexane) to give 0.74 g of the product. 10 Step E: Br_ N- Cl Br N CI Br Br N N 0'

OCH

2

CH

3 H Combine 0.70 g (1.4 mmol) of the product of Step D and 8 mL of concentrated HCI (aqueous) and heat the mixture at reflux overnight. Add 30 mL of 1 N NaOH (aqueous), then 5 mL of 50% NaOH (aqueous) and extract 15 with CH 2 1CI 2 . Dry the extract over MgSO 4 and concentrate in vacuo to give 0.59 g of the title compound. Preparative Example 2 Br \ CI Br CI N N Br Br N N H - 33 - WO 98/57948 PCT/US98/11507 [racemic as well as (+)- and (-)-isomers] Prepare a solution of 8.1 g of the title compound from Preparative Example 7 in toluene and add 17.3 mL of a 1M solution of DIBAL (diisobutyl aluminum hydride) in toluene. Heat the mixture at reflux and slowly add (dropwise) 5 another 21 mL of 1 M DIBAL/toluene solution over a period of 40 min. Cool the reaction mixture to about 00C and add 700 mL of 1 M HCI (aqueous). Separate and discard the organic phase. Wash the aqueous phase with CH 2

CI

2 , discard the extract, then basify the aqueous phase by adding 50% NaOH (aqueous). Extract with CH 2

CI

2 , dry the extract over MgSO 4 and concentrate in vacuo to 10 give 7.30 g of the title compound, which is a racemic mixture of enantiomers. Preparative Example 3 - Separation of Enantiomers: Br H \ CI Br CI \B/ B Br N N H Br CI N Br H The racemic title compound of Preparative Example 1 is separated by 15 preparative chiral chromatography (Chiralpack AD, 5 cm X 50 cm column, using 20% iPrOH/hexane + 0.2% diethylamine), to give the (+)-isomer and the (-)-isomer of the title compound. Altenatively, the enantiomers can also be separated by crystallization with an amino acid such as N-acetylphenylalanine. 20 Preparative Example 4 (+)-l,1 -Dimethylethyl 4-[2-[4-(3,10-dibromo-8-chloro-6,11-dihydro-5H benzo[5,6]cyclohepta[1,2-b]pyridin- 1 (R)-yl)-1-piperidinyl]-2-oxoethyl]-1 piperdinecarboxylate - 34 - WO 98/57948 PCT/US98/11507 Br H \ CI Br 1;z C I N N Br Br 0 CH 3 0CH3 N N 0 CH 3 SCH 72379 Combine 2.56 g (5.44 mmol) of the (+)-isomer of Preparative Example 3 with 1.71 g (7.03 mmol) of N-BOC-4-piperidylacetic acid, 1.01 g (7.47 mmol) 1 hydroxybenzotriazole hydrate and 1.40 mL (12.7.mmol) N-methylmorpholine in 5 15 mL of anhydrous DMF and add 1.29 g (6.73 mmol) of 1-(3 dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride and stir at room temperature for 5 h. The mixture was diluted with 15 mL water and 15 mL saturated NaHCO 3 solution (aqueous) and extracted with ethyl acetate. The organic extracts were washed with saturated NaHCO 3 solution, brine and dried 10 (MgSO 4 ) to give the product. Preparative Example 5 (+)-4-(8-Chloro-3,10-dibromo-6,11-dihydro-5H-benzo[5,6]cyclohepta-[1,2 b]pyridin- 11-yl)-1-(4-piperidinylacetyl)piperidine Br CI Br \ CI N N Br 0 CH 3 Br 0 0 Cs0 NH 15 SCH 72379 SCH 69132 The title compound of Preparative Example 4 (4.10 g, 5.44 mmol) was suspended in 10% H 2 SO4/dioxane (v/v) and small potions of methanol were added till a clear solution resulted. After 2 h at room temperature 10% NaOH solution (aqueous) was added untill the mixture became cloudy and this was 20 diluted with ethyl acetate. The aqueous layer was adjusted to pH 8-9 with 10% NaOH solution, the layers were separated and the aqueous mixture extracted with ethyl acetate. The combined organic mixture was washed with brine, dried (MgSO 4 ) and evaporated to give the product (2.77 g, 85%). - 35 - WO 98/57948 PCT/US98/11507 Preparative Example 6 Br aCl N Br N H 5 [racemic as well as (+)- and (-)-enantiomer] Step A:

NO

2 Br N Br N \- O N 0 Br a N/ N o

NO

2 Combine 40.0 g (0.124 mole) of the starting ketone (as taught in Preparative Example 20 of PCT/US 94/11392)and 200 mL of H 2

SO

4 and cool to 0oC. 10 Slowly add 13.78 g (0.136 mole) of KNO 3 over a period of 1.5 hrs., then warm to room temperature and stir overnight. Work up the reaction using substantially the same procedure as described for Preparative Example 4, Step A. Chromatograph (silica gel, 20%, 30%, 40%, 50% EtOAc/hexane, then 100% EtOAc) to give 28 g of the 9-nitro product, along with a smaller quantity of the 7 15 nitro product and 19 g of a mixture of the 7-nitro and 9-nitro compounds. MH + (9-nitro) = 367. Step B: Br \ O Br- \ Cl N N O NO 2 O NH 2 - 36 - WO 98/57948 PCT/US98/11507 React 28 g (76.2 mmol) of the 9-nitro product of Step A, 400 mL of 85% EtOH/water, 3.8 g (34.3 mmol) of CaCI 2 and 38.28 g (0.685 mole) of Fe at 500C. Heat the mixture at reflux overnight, filter through Celite® and wash the filter cake with 2 X 200 mL of hot EtOH. Combine the filtrate and washes, and 5 concentrate in vacuo to a residue. Extract the residue with 600 mL of CH 2

CI

2 , wash with 300 mL of water and dry over MgSO 4 . Filter and concentrate in vacuo to a residue, then chromatograph (silica gel, 30% EtOAc/CH 2 CI01 2 ) to give 24 g of the product. Step C: Br C Br 2 N N

ONH

2 O NH 2 10 0 NH2 Br Combine 13 g (38.5 mmol) of the product of Step B, 140 mL of HOAc and slowly add a solution of 2.95 mL (57.8 mmol) of Br 2 in 10 mL of HOAc over a period of 20 min. Stir the reaction mixture at room temperature, then concentrate in vacuo to a residue. Add CH 2

CI

2 and water, then adjust to pH = 8-9 with 50% 15 NaOH (aqueous). Wash the organic phase with water, then brine and dry over Na 2

SO

4 . Concentrate in vacuo to give 11.3 g of the product. Step D: Br C Br N N O Br 2 O Br 20 Cool 100 mL of concentrated HCI (aqueous) to 0oC, then add 5.61 g (81.4 mmol) of NaNO 2 and stir for 10 min. Slowly add (in portions) 11.3 g (27.1 mmol) of the product of Step C and stir the mixture at 0 0 -3 0 C for 2.25 hrs. Slowly add (dropwise) 180 mL of 50% H 3

PO

2 (aqueous) and allow the mixture to stand at 00C overnight. Slowly add (dropwise) 150 mL of 50% NaOH over 30 25 min., to adjust to pH = 9, then extract with CH 2

CI

2 . Wash the extract with water, then brine and dry over Na 2

SO

4 . Concentrate in vacuo to a residue and chromatograph (silica gel, 2% EtOAc/ CH 2

CI

2 ) to give 8.6 g of the product. 30 - 37- WO 98/57948 PCT/US98/11507 Step E: Br C Br CI N N O Br OH Br Combine 8.6 g (21.4 mmol) of the product of Step D and 300 mL of MeOH and 5 cool to Oo-2oC. Add 1.21 g (32.1 mmol) of NaBH 4 and stir the mixture at -OoC for 1 hr. Add another 0.121 g (3.21 mmol) of NaBH 4 , stir for 2 hr. at 0C, then let stand overnight at 000C. Concentrate in vacuo to a residue then partition the residue between CH 2

CI

2 and water. Separate the organic phase and concentrate in vacuo (500C) to give 8.2 g of the product. 10 Step F: Br CI Br ""\ \ CI _ N/ Br aC N Br H Br N H Combine 8.2 g (20.3 mmol) of the product of Step E and 160 mL of CH 2

CI

2 , cool to 0oC, then slowly add (dropwise) 14.8 mL (203 mmol) of SOCI 2 over a 30 min. 15 period. Warm the mixture to room temperature and stir for 4.5 hrs., then concentrate in vacuo to a residue, add CH 2

CI

2 and wash with 1 N NaOH (aqueous) then brine and dry over Na 2

SO

4 . Concentrate in vacuo to a residue, then add dry THF and 8.7 g (101 mmol) of piperazine and stir at room temperature overnight. Concentrate in vacuo to a residue, add CH 2

CI

2 , and 20 wash with 0.25 N NaOH (aqueous), water, then brine. Dry over Na 2

SO

4 and concentrate in vacuo to give 9.46 g of the crude product. Chromatograph (silica gel, 5% MeOH/CH 2

CI

2 + NH 3 ) to give 3.59 g of the title compound, as a racemate. 25 - 38 - WO 98/57948 PCT/US98/11507 Step G - Separation of Enantiomers: Br Ha H N SN Br Br R-(+) / N N H N Br H N Br (N

S-

H 5 The racemic title compound from Step F (5.7 g) is chromatographed by preparative chiral chromatography (Chiralpack AD, 5 cm X 50 cm column, flow rate 100 mL/min) using 30% iPrOH/hexane + 0.2% diethylamine, to give 2.88 g of the R-(+)-enantiomer and 2.77 g of the S-(-)-enantiomer of the title compound. 10 Preparative Example 7 Br Br -\ C N N H 15 - 39 - WO 98/57948 PCT/US98/11507 Step A: Br a'* Br ' N N 5 OCH 2CH 3 O OCH 2

CH

3 Combine 25.86 g (55.9 mmol) of 4-(8-chloro-3-bromo-5,6-dihydro-1 1 H benzo[5,6]cyclohepta[1,2-b]pyridin-1 1 -ylidene)-1l-piperidine-1 -carboxylic acid ethyl ester and 250 mL of concentrated H 2

SO

4 at -5oC, then add 4.8 g (56.4 mmol) of NaNO 3 and stir for 2 hours. Pour the mixture into 600 g of ice and 10 basify with concentrated NH 4 OH (aqueous). Filter the mixture, wash with 300 mL of water, then extract with 500 mL of CH 2

CI

2 . Wash the extract with 200 mL of water, dry over MgSO 4 , then filter and concentrate in vacuo to a residue. Chromatograph the residue (silica gel, 10% EtOAc/ CH 2

CI

2 ) to give 24.4 g (86% yield) of the product. m.p. = 165-1670C. 15 Step B: Br Br " -C Br "N \ CI N N NN NO2

NO

2 N N O)- OCH 2CH 3 O)- OCH 2CH 3 Combine 20 g (40.5 mmol) of the product of Step A and 200 mL of concentrated

H

2

SO

4 at 200C, then cool the mixture to 0oC. Add 7.12 g (24.89 mmol) of 1,3 20 dibromo-5,5-dimethyl-hydantoin to the mixture and stir for 3 hours at 200C. Cool to 0 0 C, add an additional 1.0 g (3.5 mmol) of the dibromohydantoin and stir at 200C for 2 hours. Pour the mixture into 400 g of ice, basify with concentrated NH 4 OH (aqueous) at 0 0 C, and collect the resulting solid by -40- WO 98/57948 PCT/US98/11507 filtration. Wash the solid with 300 mL of water, slurry in 200 mL of acetone and filter to provide 19.79 g (85.6% yield) of the product. Step C: Br Br Br "N \ CO Br "N aC N N N NO2

NH

2 N N 5 O- OCH 2CH 3 O OCH 2CH 3 Combine 25 g (447 mmol) of Fe filings, 10 g (90 mmol) of CaCl 2 and a suspension of 20 g (34.19 mmol) of the product of Step B in 700 mL of 90:10 EtOH/water at 500C. Heat the mixture at reflux overnight, filter through Celite® and wash the filter cake with 2 X 200 mL of hot EtOH. Combine the filtrate and 10 washes, and concentrate in vacuo to a residue. Extract the residue with 600 mL of CH 2 C01 2 , wash with 300 mL of water and dry over MgSO 4 . Filter and concentrate in vacuo to a residue, then chromatograph (silica gel, 30% EtOAc/CH 2

CI

2 ) to give 11.4 g (60% yield) of the product. 15 Step D: Br Br Br a C Br\ Cl N

NH

2 : "NI " NN 2 O OCH 2CH 3 O-- OCH 2CH 3 Slowly add (in portions) 20 g (35.9 mmol) of the product of Step C to a solution of 8 g (116 mmol) of NaNO 2 in 120 mL of concentrated HCI (aqueous) at -10C. Stir the resulting mixture at 00C for 2 hours, then slowly add (dropwise) 150 mL 20 (1.44 mole) of 50% H 3

PO

2 at 0oC over a 1 hour period. Stir at 0oC for 3 hours, then pour into 600 g of ice and basify with concentrated NH 4 OH (aqueous). Extract with 2 X 300 mL of CH 2

CI

2 , dry the extracts over MgSO 4 , then filter and -41- WO 98/57948 PCT/US98/11507 concentrate in vacuo to a residue. Chromatograph the residue (silica gel, 25% EtOAc/ hexanes) to give 13.67 g (70% yield) of the product. Step E: Br Br N I

..

N N 5 O OCH 2CH 3 Combine 6.8 g (12.59 mmol) of the product of Step D and 100 mL of concentrated HCI (aqueous) and stir at 850C overnight. Cool the mixture, pour it into 300 g of ice and basify with concentrated NH 4 OH (aqueous). Extract with 2 x 300 mL of CH 2

CI

2 , then dry the extracts over MgSO 4 . Filter, concentrate in 10 vacuo to a residue, then chromatograph (silica gel, 10% MeOH/EtOAc + 2%

NH

4 OH (aqueous)) to give 5.4 g (92% yield) of the title compound. Preparative Example 8 Br Br QCl N N N H 15 [racemic as well as (+)- and (-)-enantiomers] Step A: Br Br Brr Br " Br"N \CI N 0 N 0 - OCH 2CH 3 -42

-

WO 98/57948 PCT/US98/11507 Combine 16.6 g (0.03 mole) of the product of Preparative Example 7, Step D, with a 3:1 solution of CH 3 CN and water (212.65 mL CH 3 CN and 70.8 mL of water) and stir the resulting slurry overnight at room temperature. Add 32.833 g (0.153 mole) of NalO 4 and then 0.31 g (2.30 mmol) of RuO 2 and stir at room 5 temperature (the addition of RuO 2 is accompanied by an exothermic reaction and the temperature climbs from 200 to 300C). Stir the mixture for 1.3 hrs. (temperature returned to 250C after about 30 min.), then filter to remove the solids and wash the solids with CH 2

CI

2 . Concentrate the filtrate in vacuo to a residue and dissolve the residue in CH 2

CI

2 . Filter to remove insoluble solids 10 and wash the solids with CH 2

CI

2 . Wash the filtrate with water, concentrate to a volume of about 200 mL and wash with bleach, then with water. Extract with 6 N HCI (aqueous). Cool the aqueous extract to 0oC and slowly add 50% NaOH (aqueous) to adjust to pH = 4 while keeping the temperature <300C. Extract twice with CH 2

CI

2 , dry over MgSO 4 and concentrate in vacuo to a residue. 15 Slurry the residue in 20 mL of EtOH and cool to 0oC. Collect the resulting solids by filtration and dry the solids in vacuo to give 7.95 g of the product. Step B: Br Br Br \ CI Br \ Cl N N 0 OH 20 Combine 21.58 g (53.75 mmol) of the product of Step A and 500 mL of an anhydrous 1:1 mixture of EtOH and toluene, add 1.43 g (37.8 mmol) of NaBH 4 and heat the mixture at reflux for 10 min. Cool the mixture to 0oC, add 100 mL of water, then adjust to pH= 4-5 with 1 M HCI (aqueous) while keeping the temperature <1000C. Add 250 mL of EtOAc and separate the layers. Wash the 25 organic layer with brine (3 X 50 mL) then dry over Na 2

SO

4 . Concentrate in vacuo to a residue (24.01 g) and chromatograph the residue (silica gel, 30 % hexane/CH 2

CI

2 ) to give the product. Impure fractions were purified by rechromatography. A total of 18.57 g of the product is obtained. 30 -43- WO 98/57948 PCT/US98/11507 Step C: Br Br Br Br N N 5 H Combine 18.57 g (46.02 mmol) of the product of Step B and 500 mL of CHCI 3 , then add 6.70 mL (91.2 mmol) of SOCI 2 , and stir the mixture at room temperature for 4 hrs. Add a solution of 35.6 g (0.413 mole) of piperazine in 800 mL of THF over a period of 5 min. and stir the mixture for 1 hr. at room 10 temperature. Heat the mixture at reflux overnight, then cool to room temperature and dilute the mixture with 1 L of CH 2

CI

2 . Wash with water (5 X 200 mL), and extract the aqueous wash with CHCI 3 (3 X 100 mL). Combine all of the organic solutions, wash with brine (3 X 200 mL) and dry over MgSO 4 . Concentrate in vacuo to a residue and chromatograph (silica gel, gradient of 15 5%, 7.5%, 10% MeOH/CH 2

CI

2 + NH 4 OH) to give 18.49 g of the title compound as a racemic mixture. Step D - Separation of Enantiomers: -44 - WO 98/57948 PCT/US98/11507 Br Br Ha Br \ N Br \ a N N / (+)-enantiomer N N HB Br N H Br H H N/ (-)-enantiomer N H The racemic title compound of Step C is separated by preparative chiral chromatography (Chiralpack AD, 5 cm X 50 cm column, flow rate 100 mL/min., 20% iPrOH/hexane + 0.2% diethylamine), to give 9.14 g of the (+)-enantiomer 5 and 9.30 g of the (-)-enantiomer. Preparative Example 9 Br Br -- ' a N N H [racemic as well as (+)- and (-)-enantiomer] 10 Step A: Br Br Br "'a Br -' \ Ca N N N N H H -45 - WO 98/57948 PCT/US98/11507 Combine 13 g (33.3 mmol) of the title compound from Preparative Example 7, and 300 mL of toluene at 200C, then add 32.5 mL (32.5 mmol) of a 1 M solution of DIBAL in toluene. Heat the mixture at reflux for 1 hr., cool to 200C, add another 32.5 mL of 1 M DIBAL solution and heat at reflux for 1 hr. Cool the 5 mixture to 20 0 C and pour it into a mixture of 400 g of ice, 500 mL of EtOAc and 300 mL of 10% NaOH (aqueous). Extract the aqueous layer with CH 2

CI

2 (3 x 200 mL), dry the organic layers over MgSO 4 , then concentrate in vacuo to a residue. Chromatograph (silica gel, 12% MeOH/CH 2

CI

2 + 4% NH 4 OH) to give 10.4 g of the title compound as a racemate. 10 15 20 Step B - Separation of Enantiomers: Br Br H C N Br N Br Br" \ O Br " H N N H H The racemic title compound of Step A is separated by preparative chiral chromatography (Chiralpack AD, 5 cm X 50 cm column, using 5% iPrOH/hexane + 0.2% diethylamine), to give the (+)-enantiomer and the (-) 25 enantiomer of the title compound. Preparative Example 10. 1-(3-Bromo-8-chloro-6,1 1 -dihydro-5H benzo[5,6]cyclohepta[1,2-b]pyridin-1 1 -yl)-4-[(4-piperidinyl)acetyl]piperazine -46 - WO 98/57948 PCT/US98/11507 Br CI N Q NH 0 O Step A: 1,1-Dimethylethyl 4-[[[4-(3-bromo-8-chloro-6,11-dihydro-5H benzo[5,6]cyclohepta[1,2-b]pyridin-11-YL)-1-piperazinyl]carbonyl]methyl]-1 piperidinecarboxylate 5 Br C Br \ C N N CN) NNO CH3 N CH 3 3-Bromo-8-chloro-6,1 1-dihydro-11 -(1-piperazinyl)-5H benzo[5,6]cyclohepta[1,2-b]pyridine (3g, 7.6mmoles), 1-N-tert butoxycarbonylpiperidinyl-4-acetic acid (2.42g, 9.9mmoles), 1-(3 10 dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (1.9g, 9.9mmoles), 1 hydroxybenzotriazole (1.34g, 9.9mmoles) and 4-methylmorpholine (1.092mL, 9.9mmoles) were dissolved in anhydrous DMF (lOOmL) and the mixture was stirred at 250C under argon for 24h. The solution was evaporated to dryness and the residue was taken up in dichloromethane and washed with saturated 15 aqueous sodium bicarbonate, water and then dried over MgSO 4 . The mixture was filtered and evaporated to dryness. Chromatography on silica gel using 2% (10% conc. NH 4 0H in methanol)dichloromethane as the eluant afforded the title compound (Yield: 4.72g; 100%). 20 Step B: 1-(3-bromo-8-chloro-6,11-dihydro-5H-benzo[5,6]cyclohepta[1,2 b]pyridin- 11-yl)-4-[(4-piperidinyl)acetyl]piperazine -47- WO 98/57948 PCT/US98/11507 Br Cl Br Cl N 0 CH 3 ( N N NH O N" % CH3 0 0 The title compound from Step A above (4.61g) (7.5mmoles) was dissolved in methanol (40mL) and a 10% (v/v) conc. H 2

SO

4 in dioxane solution (100mL) was added. The mixture was stirred at 250C for 2h and then basified with conc. 5 aqueous NaOH. The mixture was extracted with dichloromethane and the latter was washed with water, dried over MgSO 4 , filtered and evaporated to dryness. The product was chromatographed on silica gel using 10% (10% conc. NH 4 OH in methanol)dichloromethane as the eluant to give the title compound (Yield: 2.86g; 74%) -48 - WO 98/57948 PCT/US98/11507 ASSAYS 1. In vitro enzyme assays: FPT IC50 (inhibition of farnesyl protein transferase, in vitro enzyme assay) are determined by the methods disclosed in 5 WO/10515 or WO 95/10516. 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 (IC50o <10 iM) inhibitors of Ras-CVLS farnesylation by partially purified rat brain FPT. 10 2. Cell-based assay. COS IC50 values refer to the COS cells activity inhibition of Ras processing, are determined by the methods disclosed in WO/10515 or WO 95/10516. Example FPT IC50 (iM) COS Cell IC 5 0 (tM) 1 0.0051 0.0500 2 0.0054 0.0330 3 0.0019 0.0085 4 0.0020 0.0220 5 0.0050 0.1500 6 0.0017 0.0200 7 0.0038 0.0180 8 0.0087 0.1200 9 0.0033 0.1100 10 0.0046 0.3000 11 0.0031 0.0180 12 0.0008 0.3600 13 0.0009 0.0250 14 0.0500 0.7500 15 0.1000 1.5000 16 0.1080 15 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. 20 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. -49 - WO 98/57948 PCT/US98/11507 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 5 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 10 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 15 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 20 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 25 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. 30 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 35 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. - 50 - WO 98/57948 PCT/US98/11507 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 5 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 10 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. -51 - WO 98/57948 PCT/US98/11507 Pharmaceutical Dosage Form Examples EXAMPLE A-Tablets No. Ingredients mg/tablet mg/tablet 1. Active compound 100 500 2. Lactose USP 122 113 3. Corn Starch, Food Grade, 30 40 as a 10% paste in Purified Water 4. Corn Starch, Food Grade 45 40 5. Magnesium Stearate 3 7 Total 300 700 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 5 (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. No. Inge EXAMPLE B-Capsules No. Ingredient mg/capsule mg/capsule 1. Active compound 100 500 2. Lactose USP 106 123 3. Corn Starch, Food Grade 40 70 4. Magnesium Stearate NF 7 7 Total 253 700 10 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 15 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. - 52 -

Claims (15)

1. A compound of the formula: X 4 X1' X3 X R- R R 6 -R 8 1 i'N NR 19 R20 <.y2 v w (1.0) or a pharmaceutically acceptable salt or solvate thereof, wherein: 5 A represents N or N-oxide; X represents N, CH or C, such that when X is N or CH, there is a single bond to carbon atom 11 as represented by the solid line; or when X is C, there is a double bond to carbon atom 11, as represented by the solid and dotted lines; X 1 and X2 are independently selected from bromo or chloro, and X 3 and X 4 are 10 independently selected from hydrogen, bromo or chloro provided that at least one of X 3 and X 4 is hydrogen; Y1 and y2 are independently selected from hydrogen or alkyl; Z is =0 or =S; R 5 , R 6 , R 7 and R 8 each independently represents hydrogen, -CF 3 , -COR 10 , 15 alkyl or aryl, and further wherein R 5 may be combined with R 6 to represent =0 or =S and/or R 7 may be combined with R 8 to represent =0 or =S; R 10 o, R 19 and R 20 independently represent hydrogen, alkyl, alkoxy, aryl, aralkyl, heteroaryl, heteroarylalkyl, cycloalkyl, cycloalkylalkyl, heterocycloalkyl and heterocycloalkylalkyl, with the proviso that R 19 and R20 are not both 20 hydrogen; v is zero, 1, 2 or 3; and w is zero or 1. - 53 - WO 98/57948 PCT/US98/11507

2. The compound of claim 1 wherein there is a single bond at carbon atom 11, X is CH, Z is =0 and R 5 , R 6 , R 7 and R 8 are hydrogen.

3. The compound of claim 2 wherein X 1 is bromo, X2 is chloro, X 3 is bromo 5 and X 4 is hydrogen.

4. The compound of claim 3 wherein Z is =0; v is 1, w is 1, and Y1 and y2 are hydrogen. 10

5. The compound of claim 4 wherein R 19 and R 20 are independently selected from hydrogen, alkyl, aryl and heterocycloalkyl with the proviso that R 19 and R 20 are not both hydrogen.

6. The compound of claim 4 wherein the alkyl group is substituted with 15 -OR 10 , alkoxy, -OCOR 10 , -CONR 10 R 12 or -COOR 10 , wherein R 10 and R 12 are independently selected from hydrogen, alkyl or alkoxy; the aryl group is substituted with alkoxy; and the heterocycloalkyl group is substituted with -COOR 10 wherein R 10 is hydrogen or alkyl. 20

7. The compound of claim 1 wherein there is a single bond at carbon atom 11, X is CH, Z is =0, R 5 , R 6 , R 7 and R 8 are hydrogen, X 1 is bromo, X2 is chloro, X 3 is bromo and X 4 is hydrogen, v is 1, w is 1, and y1 and y2 are hydrogen, R 19 and R 20 are independently selected from hydrogen, alkyl, aryl and heterocycloalkyl, wherein the alkyl group is substituted with -OR 10 , alkoxy, 25 -OCOR 1 0 , -CONRiOR 12 or -COOR 1 0 , wherein R 10 and R 12 are independently selected from hydrogen, alkyl or alkoxy; the aryl group is substituted with alkoxy; the heterocycloalkyl group is substituted with -COOR 10 wherein R 10 is hydrogen or alkyl, with the proviso that R 19 and R 20 are not both hydrogen. 30

8. The compound of claim 1 selected from any of the title compounds of Examples 1-16.

9. The compound of claim 1 selected from any of the title compounds of Examples 3, 4, 6, 7,11, 12 and 13. 35 - 54- WO 98/57948 PCT/US98/11507

10. A pharmaceutical composition for inhibiting the abnormal growth of cells comprising an effective amount of compound of claim 1 in combination with a pharmaceutically acceptable carrier. 5

11. A method for inhibiting the abnormal growth of cells comprising administering an effective amount of a compound of claim 1.

12. The method of Claim 11 wherein the the cells inhibited are tumor cells expressing an activated ras oncogene. 10

13. The method of Claim 11 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 prostate tumor cells, breast tumor cells or colon tumors 15 cells.

14. The method of Claim 11 wherein the inhibition of the abnormal growth of cells occurs by the inhibition of ras farnesyl protein transferase. 20

15. The method of Claim 11 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. - 55 -