AU8253798A - Novel phenyl-substituted tricyclic inhibitors of farnesyl-protein transferase - Google Patents

Description

WO 98/57950 PCT/US98/11509 NOVEL PHENYL-SUBSTITUTED TRICYCLIC 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 98/57950 PCT/US98/11509 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 0 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:

R

4 R 6 R2 I Y (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;

R

1 is hydrogen, bromo, chloro, trifluoromethyl, acyl, alkyl, cycloalkyl, amino, _0 acylamino or alkoxy;

R

2 is hydrogen, halo, trifluoromethyl, alkyl, alkoxy, -OCF 3 , hydroxy, amino or acylamino;

R

3 is hydrogen, bromo, chloro, alkoxy, -OCF 3 or hydroxy; -2- WO 98/57950 PCT/US98/11509

R

4 is hydrogen, halo, trifluoromethyl, alkyl or alkoxy; provided that at least one of R 2 or R 3 or R 4 is alkyl or alkoxy and provided that at least two of R 1 , R 2 , R 3 or R 4 are substituents other than hydrogen; 5 Q is hydrogen when there is a single bond to carbon atom 11, or Q is hydrogen or hydroxy when there is a single bond to carbon 11 and X is CH, or Q is not a substituent when there is a double bond to carbon 11;

R

5 , R 6 , R 7 and R 8 independently represent hydrogen, alkyl or -CONHR 50 wherein R 50 can be any of the values represented for R, below; Z II 0 Y is -C-R or -SO 2 -R, wherein; Z is =0 or =S; and R is aryl, aralkyl, cycloalkyl, cycloalkylalkyl, heteroalkyl, heteroaryl, heteroarylalkyl, heterocycloalkyl or heterocycloalkylalkyl. 5 Preferably in compound (1.0), there is a single bond or a double bond at carbon atom 11; X is N, CH or C; R 1 is H, halo, alkyl, cycloalkyl or alkenyl; R 2 is H, halo, alkoxy, or alkyl; R 3 is H, halo, alkoxy, hydroxy or alkyl; and R 4 is H, halo or alkyl; R 5 , R 6 , R 7 and R 8 are hydrogen; Y is -SO 2

CH

3 or -COR wherein R is heteroarylalkyl, preferably pyridinyl N-oxide-methyl or heterocycloalkylalkyl, 0 preferably piperidinyl-methyl. When R 1 is other than hydrogen, preferably the halo moiety is bromo, the alkyl is methyl or ethyl, the cycloalkyl is cyclopropyl or the alkenyl is vinyl. When R 2 is other than hydrogen, preferably the alkoxy moiety is methoxy, the halo moiety is bromo or the alkyl is methyl. When R 3 is other than hydrogen, preferably the alkoxy moiety is methoxy, the halo moiety 5 is bromo or the alkyl is methyl. When R 4 is other than hydrogen, preferably the halo moiety is chloro or the alkyl is methyl. Preferred title compounds include those of Examples 1-10 and 14-37, preferably those of Examples 1, 2, 3, 6, 7, 8, 10, 16, 18, 19, 21,22, 24, 26, 27, 29, 33, 34, 35, 36 and 37, more preferably -3- WO 98/57950 PCT/US98/11509 those of Examples 3, 21, 22, 24 and 33, disclosed hereinafter. In another embodiment, the present invention is directed toward a pharmaceutical composition for inhibiting the abnormal growth of cells comprising an effective amount of compound (1.0) in combination with a 5 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 (e.g., a human) in need of such treatment. Abnormal growth of cells refers to 0 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 malignant cells of other proliferative diseases in which aberrant Ras activation 5 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 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 0 cancer, or through inhibition of ras farnesyl protein transferase, thus making 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 5 follicular tumor cells, myelodysplastic tumor cells, epidermal carcinoma tumor 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 0 activated as a result of oncogenic mutation in genes other than the Ras gene. 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 5 human) in need of such treatment. In particular, this invention provides a method for inhibiting the growth of tumors expressing an activated Ras oncogene by the administration of an effective amount of the above described -4- WO 98/57950 PCT/US98/11509 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 5 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. It is believed that this invention also provides a method for inhibiting 0 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 N-substituted urea compounds (1.0) described herein, to a mammal (e.g., a 5 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, Ick, and fyn), may be inhibited by the N-substituted urea compounds (1.0). In another embodiment, the present invention is directed toward a 0 method for inhibiting ras farnesyl protein transferase and the farnesylation of the 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. 5 DETAILED DESCRIPTION OF THE INVENTION As used herein, the following terms are used as defined below unless otherwise indicated: 0 M + -represents the molecular ion of the molecule in the mass spectrum;

MH

+ -represents the molecular ion plus hydrogen of the molecule in the mass spectrum; Bu-represents butyl; Et-represents ethyl; 5 Me-represents methyl; Ph-represents phenyl; -5- WO 98/57950 PCT/US98/11509 benzotriazol-1-yloxy represents N N 0 1-methyl-tetrazol-5-ylthio represents N-N NS N%N

"S

I

OH

3 5 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 ) independently substituted with one, two, three or more of the following: halo (i.e. trifluoromethyl), alkyl, aryl, cycloalkyl, cyano, -CF 3 , oxy (=0), aryloxy, -OR 10 (i.e. hydroxymethyl, hydroxyethyl), -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 10 , NHSO 2 , -NO 2 , -CONR 10

R

12 , -NR 12 0C R 10 , -COR 10 , -OCOR 10 , -OCO 2

R

10 or 5 COOR o 0 , wherein R 10 and R 1 2 can independently represent hydrogen, alkyl, alkoxy, aryl, aralkyl, heteroaryl, heteroarylalkyl, cycloalkyl, cycloalkylalkyl, heterocycloalkyl or heterocycloalkylalkyl; acylamino- refers to the moiety -CONR 10

R

12 wherein R 10 and R 12 are defined hereinbefore; ) 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 alkyl, aryl, cycloalkyl, cyano, -CF 3 , oxy (=0), aryloxy, -OR 10 , -OCF 3 , heterocycloalkyl, 5 heteroaryl, -NR 10

R

12 , -NHSO 2

R

10 , -SO 2

NH

2 , -SO 2

NHR

10 , -SO 2

R

10 , -SOR 10 , SRi 0 , -NHSO 2 , -NO 2 , -CONR 10

R

12 , -NR 12C O R 10 o, -COR 1 0 o, -OCOR 10 , .

OCO

2

R

10 or -COOR 1 0 , wherein R 10 and R 12 are as defined hereinabove; 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 -6- WO 98/57950 PCT/US98/11509 available substitutable carbon and nitrogen atoms in said aryl group and/or said fused ring(s) may be optionally and independently substituted with one, two, three or more of the following: halo, alkyl, aryl, cycloalkyl, cyano, -CF 3 , oxy (=0), aryloxy, -OR 10 , -OCF 3 , heterocycloalkyl, heteroaryl, -NR 10

R

12 , . 5 NHSO 2

R

1 0 , -SO 2

NH

2 , -SO 2

NHR

10 , -SO 2

R

1 0 , -SOR 1 0 , -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 , 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 0 more aryl groups; wherein said aralkyl group may be optionally and independently substituted with one, two, three or more of the following: halo, alkyl, aryl, cycloalkyl, cyano, -CF 3 , oxy (=0), aryloxy, -OR 10 , -OCF 3 , heterocycloalkyl, heteroaryl, -NRlOR 12 , -NHSO 2

R

10 , -SO 2

NH

2 , -SO 2

NHR

10 , SO 2

R

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

R

12 , -NR 12 C O R 10 , -COR 10 , 5 OCOR 10 , -OCO 2

R

10 or -COOR 10 , wherein R 10 and R 12 are as defined hereinabove; 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 .0 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, CF 3 , oxy (=0), aryloxy, -OR 10 , -OCF 3 , heterocycloalkyl, heteroaryl, -NR 10

R

12 , .5 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 1 0

R

12 , -NR 12

COR

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

R

10 or -COOR 10 , wherein

R

10 and R 12 are as defined hereinabove; cycloalkyl-represents saturated carbocyclic rings branched or unbranched of from 3 to 20 carbon atoms, preferably 3 to 7 carbon atoms; 30 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, -NR 10

R

12 , NHSO 2

R

10 , -SO 2

NH

2 , -SO 2

NHR

10 , -SO 2

R

10 , -SOR 1 0 , -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 , wherein 35 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 -7- WO 98/57950 PCT/US98/11509 or more cycloalkyl groups; wherein said cycloalkylalkyl group may be optionally and independently substituted with one, two, three or more of the following: halo, alkyl, aryl, cycloalkyl, cyano, -CF 3 , oxy (=0), aryloxy, -OR 10 , -OCF 3 , heterocycloalkyl, heteroaryl, -NR 10 oR 12 , -NHSO 2

R

i o , -SO 2

NH

2 , -SO 2

NHR

1 0o, . 5 SO 2

R

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

R

12 , -NR12COR 10 , -COR 10 , OCOR 10 , -OCO 2

R

10 or -COOR 10 , wherein R 10 and R 12 are as defined hereinabove; halo-represents fluoro, chloro, bromo and iodo; heteroalkyl-represents straight and branched carbon chains containing 0 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 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 1 0 , 5 -OCF 3 , heterocycloalkyl, heteroaryl, -NR 10

R

12 , -NHSO 2

R

10 , -SO 2

NH

2

,

SO

2

NHR

1 0 , -SO 2

R

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

R

12 , NR12COR10, -COR 10 , -OCOR10, -OCO 2

R

1 0 or -COOR 10 , wherein R 10 and R 12 are as defined hereinabove; heteroaryl-represents cyclic groups having at least one heteroatom 0 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 14 carbon atoms,wherein said heteroaryl group optionally can be fused with one or more aryl, cycloalkyl, heteroaryl or heterocycloalkyl rings; and wherein 5 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, 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 R10, -SOR 10 , . 0 SR 10 , -NHSO 2 , -NO 2 , -CONR 10

R

12 , -NR 12

COR

10 , -COR 10 , -OCORo 10 , OCO 2

R

10 or -COOR 10 , wherein R 10 and R12 are as defined hereinabove. Representative heteroaryl groups can include, for example, furanyl, imidazoyl, pyrimidinyl, triazolyl, 2-, 3- or 4-pyridyl or 2-, 3- or 4-pyridyl N-oxide wherein pyridyl N-oxide can be represented as: -8- WO 98/57950 PCT/US98/11509 or NN N 00 heteroarylalkyl - represents an alkyl group, as defined above, wherein one or more hydrogen atoms have been replaced by one or more heteroaryl groups; wherein said heteroarylalkyl group may be optionally and 5 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 1 oR 1 2 , -NHSO 2

R

1 0 , -SO 2

NH

2 , -SO 2 NHR10, .

SO

2

R

10 , -SOR10, -SR 1 o, -NHSO 2 , -NO 2 , -CONRiOR 12 , -NR 12C O

R

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

R

1 0 or -COOR 10 , wherein R 10 and R 12 are as defined D 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 selected from -0-, -S- and -N- , wherein optionally, said ring may contain one or 5 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 the following: halo, alkyl, aryl, cycloalkyl, cyano, -CF 3 , oxy (=0), aryloxy, -OR1 0 , -OCF 3 , heterocycloalkyl, heteroaryl, -NR 10

R

12 , -NHSO 2

R

i o , . 3 SO 2

NH

2 , -SO 2

NHR

10 , -SO 2

R

10 , -SOR 10 , -SR 10 , -NHSO 2 , -NO 2 , -CONR 1 oR 12 ,

-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. 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 S(O-\ 5 morpholinyl, or wherein R o 10 is defined hereinbefore and t is 0, 1 or 2. 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 D unsaturated bonds which do not impart aromatic character to the ring; and wherein said heterocycloalkylalkyl group may be optionally and independently -9- WO 98/57950 PCT/US98/11509 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

10 , -SO 2

R

10 , -SOR o 0 , SR 10 , -NHSO 2 , -NO 2 , -CONR 1 oR 12 , -NR1 2

COR

10 , -COR 1 0 o, -OCOR 1 0 o, . 5 OCO 2

R

10 or -COOR 10 , wherein R 10 and R 12 are as defined hereinabove. 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 0 (TFAA); 1-hydroxybenzotriazole (HOBT); m-chloroperbenzoic acid (MCPBA); triethylamine (Et 3 N); diethyl ether (Et 2 0); ethyl chloroformate (CICO 2 Et); lithium di-isopropylamide (LDA) and 1-(3-dimethylaminopropyl)-3-ethyl carbodiimide hydrochloride (EDCl or DEC). Reference to the position of the substituents R 1 , R 2 , R 3 and R 4 is based 5 on the numbered ring structure:

R

4 R / .. kR2 N I Y (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 .0 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 ?5 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. -10- WO 98/57950 PCT/US98/11509 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 5 salt formation are hydrochloric, sulfuric, phosphoric, acetic, citric, oxalic, malonic, salicylic, malic, fumaric, succinic, ascorbic, maleic, methanesulfonic 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 0 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 5 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. !0 Compounds of the present invention can be prepared according to the following Schemes I, II or Ill wherein Scheme I

R

4

R

4 R4 RI RR2 RI R 2 RIR R2 N N N RR 3 O Q

R

3 R5.. X R 7 R5 X R R 5 -_ X R 7 R R R 6 -- R R6 N-- R8 I I HY Y (11, 11.3, 13d, 13.3d, 19, 19.3, 20, 20.3) 1.0a 1.0b A, R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , Y, the solid and dotted lines are as defined ?5 hereinbefore. -11 - WO 98/57950 PCT/US98/11509 Z II In Scheme I, compound 1.0 wherein Y

=

-C-R and Z=O wherein R is defined hereinbefore, can be prepared by acylating compound (11, 11.3), (19, 19.3) or (20, 20.3) with a carboxylic acid of the formula RCOOH (30.0) wherein R is defined hereinbefore, in an aprotic solvent, at temperatures ranging from 5 about 00 to 200C, using about 1 to 2 moles of carboxylic acid (30.0) per mole of compound (11, 11.3), (19, 19.3) or (20, 20.3). Alternatively, compound 1.0 wherein Y = SO 2 R, can be prepared by reacting compound (11, 11.3), (19, 19.3) or (20, 20.3) with a sulfonyl chloride of the formula RSO 2 CI (20.7) wherein R is as defined before, in a solvent such a ) pyridine and a base such as 4-dimethylaminopyridine or triethylamine, using 1 to 3 moles of sulfonyl chloride (20.7) per mole of compound (11, 11.3), (19, 19.3) or (20, 20.3). The amount of base can range from catalytic to about 1.5 moles per mole of compound (11, 11.3), (19, 19.3) or (20, 20.3). The compounds of formula (1.0) wherein A is N-O (i.e. the N-oxide), can be 5 prepared by treating compound (1.0) wherein A is N with metachloroperbenzoic acid (MCPBA) in an aprotic solvent such as methylene chloride at temperatures ranging from about 00 to 250C, using 1 to 2 equivalents of MCPBA per mole of compound (1.0). The sulfur-containing compounds of formula (1.0) wherein Z = S, can be ) treating compounds (1.0) wherein Z=O with a sulfurating agent such as Lawesson's Reagent in a suitable aprotic solvent such as toluene at about 100C to give the thioamide (1.0). Alternative sulfurating reagents include bis (1,5-cyclooctanediarylboryl)sulfide in hexane at -78oC; or phosphorous pentasulfide (P 2

S

5 , also of the formula P 4

S

10 ) in toluene at reflux 5 temperatures, or in THF using ultrasound at 40oC; or bis-(9 Borabicyclo[3.3.1]nonane)sulfide ((9-BBN) 2 S) in heptane at reflux temperatures. Compounds of formula (1.0) can be isolated from the reaction mixture using conventional procedures, such as, for example, extraction of the reaction D mixture from water with organic solvents, evaporation of the organic solvents, followed by chromatography on silica gel or other suitable chromatographic 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 5 centrifugation. -12- WO 98/57950 PCT/US98/11509 Compounds of formula 1.0, 1.0a and 1.0b in Scheme I, wherein X is CH or N may be racemates. These racemates can be resolved into their (+) and (-) enantiomers by HPLC procedures on Chiralpak columns (Daicel Chemical 5 Ind.). Alternatively, (+)-Isomers of compounds of formula (19, 19.3, 20, 20.3) wherein X is CH can be prepared with high enantioselectivity by using a process comprising enzyme catalyzed transesterification. Preferably, a racemic compound of formula (19, 19.3, 20, 20.3) , wherein X is C, the double bond is present and X 3 is not H, is reacted with an enzyme such as Toyobo LIP-300 D and an acylating 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 5 the corresponding racemic compound of formula (19, 19.3, 20, 20.3) wherein X is CH and then treated with the enzyme (Toyobo LIP-300) and acylating agent as described above to obtain the (+)-amide, which is hydrolyzed to obtain the optically enriched (+)-isomer. Compounds of the present invention and preparative starting materials 0 thereof, are exemplified by the following examples, which should not be construed as limiting the scope of the disclosure. Example 1. 1-(3-Bromo-6,11-dihydro-8,10-dimethoxy-5H benzo[5,6]cyclohepta[1,2-b]pyridin- 11-yl)-4-(4-pyridinylacetyl)piperazine N4-oxide Br \ OCH 3 N (N) OCH3 N "N 5 0 Example 1, Step 1. -13- WO 98/57950 PCT/US98/11509

H

3 CO CH,/

OCH

3 Br_ Br O 1.BuLi/ i-Pr 2 NH Br O N0 -- C\ o A NH Cl N B SH3CH 2. aOCH3 NH

H

3 C H 3 CO H3C- C H 3

H

3 C To a solution of diisopropylamine (2.28 ml) in THF (10 ml) at -780C under a nitrogen atmosphere, 2.5 M Butyl lithium in hexanes (6.5 ml) is added dropwise. After stirring the mixture for 10 mins, a solution of compound A (2.0 g) in THF 5 (10 ml) is added. The resulting purple reaction mixture is stirred for 10 mins before adding a solution of 3,5-dimethoxy benzyl chloride (2.07 g) in THF (10 ml). The reaction mixture is stirred at -780C for 15 mins, lhr at 0oC and then at room temp for 1hr. The pale burgundy color reaction is diluted with ice/water and extracted with dichloromethane. The crude product obtained on 0 evaporation of the organic extract is evaporated and flash chromatographed on silica gel (200ml). Elution with 10% ethylacetate-hexane affords the title compound B as an oil (2.3 g, 75% yield): MS m/e 421, 423(MH),. Example 1, Step 2.

H

3 CO

H

3 CO

OCH

3

OCH

3 Br -\-~ r 0 POC13 Br N B 85% N CN C NHt-Bu 5 Phosphorous oxychloride (12 ml) is added dropwise to a solution of B (2.3g) in toluene (20ml). The mixture is heated in an oil bath (1150C). After one hour a droplet of DMF is added, the solution is heated for an additional 4 hrs and is then cooled to room temp before evaporation under reduced pressure. The residual oil is dissolved in ethylacetate (50 ml) and ice/water (20ml) and stirred 0 while adding 10% sodium hydroxide until the aqueous phase is basic. The basic solution is extracted with ethylacetate, the organic extracts are combined, washed with brine, dried and evaporated. The crude product is dissolved in ethylacetate and filtered through a silica gel plug. The colorless filtrate is -14- WO 98/57950 PCT/US98/11509 concentrated under reduced pressure and diluted slowly with hexane to afford the title compound C as a crystalline solid (1.62g, 85%): m.p. 106-107OC; MS m/e 347, 349 (MH). 5 Example 1, Step 3.

H

3 CO / OCH 3 Br

OCH

3 Br - 5 eq.AICl 3 O \ -C DCE/r.t./1 hr N N' CN NH OCH 3 C 70% D Aluminum Chloride (1.0 g) is added in small lots during 10 minutes to a well stirred solution of C (1.16 g) in dichloroethane (100 ml). The pale yellow solution is stirred at room temperature for 1 hr and is then worked up by the 3 addition of ice/water and 10% sodium hydroxide to pH 10. The mixture is extracted several times with dichloromethane, and the crude product obtained on evaporation of the combined extracts is flash chromatographed on silica gel (100ml). Elution with 10% methanol-2% ammonium hydroxide-ethylacetate affords the intermediate imine D (0.89g). 5 Example 1, Step 3a. Br OCH3 H Br C

OCH

3 N 2N HCI \B NH OCH3 N 1000/1.5 hr. 0 OCH 3 D 90% E Product D of Step 3 is dissolved in 2N hydrochloric acid. The solution is heated in an oil bath (1200C) for 1.5hrs, cooled, made basic with 10% sodium D hydroxide and extracted with dichloromethane (4 x 50 ml portions). The crude product is obtained by concentration of the combined extract filtered through a silica gel plug; evaporation of the filtrate affords the title ketone E as an amorphous solid (0.81g, 91%). MS m/e 348, 350 (MH) . 5 Example 1, Step 4. -15- WO 98/57950 PCT/US98/11509 Br - CH

BOCH

3 BH4 OCH O OCH 3 98% OH OCH 3 E F Sodium borohydride (0.09g) is added in portions, with stirring, to a solution of ketone E (0.8 g) in methanol (20 ml) at 0OC. The reaction is then stirred at room temperature for one hour, acidified with acetic acid-water and most of the 5 solvent is removed by evaporation under reduced pressure. The residual mixture is made basic with 10% sodium hydroxide to pH 10 followed by extraction with ethylacetate (4x50ml). The combined extract is filtered through a plug of silica gel and the filtrate is evaporated to afford product F as a resin puff (0.79g). MS m/e 350, 352 (MH). 0 Example 1, Steps 5 and 6. Br OCH 3 1 3 z Br OCH 3 2. Piperazine N F OH OCH 3 70%

OCH

3 N G H Phosphorous oxychloride (2.0ml) is added dropwise to a solution of product F (0.45 g) in dichloromethane (5 ml) under nitrogen. The reaction mixture is 5 stirred at room temperature for one hour and is then evaporated under reduced pressure at 450C. The dark residual gum is azeotroped with toluene (2 xl0 ml) and is then dissolved in acetonitrile (15 ml) containing piperazine (0.5 g). The reaction mixture is stirred at room temperature for 2 hrs and is worked up by evaporating under reduced pressure and diluting with water followed by 0 addition of 10% sodium hydroxide(5 ml). The product is extracted with dichloromethane (5 x 20 ml) and flash chromatographed on silica gel. Elution with 10% methanol-2% ammonium hydroxide-dichloromethane affords product G as a tan puff (0.22g). MS m/e 418, 420 (MH). 5 Example 1, Step 7. -16- WO 98/57950 PCT/US98/11509 Br - OCH 3 Br -. -~ OCH 3 / \I B O I ArCOOH coupling -NOH N~. 00H 3 N OCH3 95% H G H H 0 racemate A solution of product G (0.2 g), 1-hydroxybenzotriazole (0.13 g) and 4-pyridyl acetic acid N-oxide (0.15 g) in dimethylformamide (3.0 ml) is cooled in ice and treated with N-(3-dimethyl aminopropyl)-N'-ethylcarbodiimide hydrochloride 5 (0.18 g) followed by N-methyl morpholine (0.3 ml). The mixture is allowed to warm to room temperature overnight and is then evaporated under reduced pressure. The residual gum is stirred with 10% sodium carbonate and extracted with dichloroethane. The crude product obtained by evaporation of the extract is flash chromatographed on silica gel (30 ml). Elution with 5% methanol-2% 0 ammonium hydroxide-dichloromethane affords product H as a pale tan foam (0.25 g). MS m/e 553, 555 (MH). Example 2. 4-(6,11-dihydro-10-methoxy-3,8-dimethyl-5H benzo[5,6]cyclohepta[1,2-b]pyridin-11-yl)-1l-(4-pyridinylacetyl)piperidine N1 5 oxide

CH

3 CH3 N OCH3 N NO Example 2, Step 1.

H

3 CO

H

3 CH 1.BuLi / i-Pr 2 NH

CH

3 SBr CC

H

3

CH

3 C 2. CH /-- 0 NHt-Bu \ N A

H

3 CO NHt-Bu -17- WO 98/57950 PCT/US98/11509 Using similar reaction conditions as described in Step 1, Example 1, reagent A (5-methyl-t-butyl amide) is first treated with di-isopropylamine and butyl lithium, then reacted with benzylbromide 2 to give compound B. Example 2, Step 2.

H

3 CO

H

3 CO / CH 3 / H H3 OH3 POC13 CH3

H

3 CI C/85% H 3 NHt-Bu C N CN 5 B Using similar reaction conditions as described in Step 2, Example 1, the crude product B is reacted with phosphorous oxychloride to afford compound C: m.p. 188-190 oC, MS: m/e 301 (MH). Example 2, Step 3. HCC / CH 3 C

H

3 \ CI

H

3 - - CH 3 / CN I. CF 3

SO

3 H N N CO OCH 3 0 C 2. HO D Nitrile compound C (1.65g) is added with stirring to cold (0oC) triflic acid (30 ml). The solution is stored overnight at room temperature, diluted with ice/water (50 ml) and heated in an oil bath (120 oC) for 4 hrs. The reaction mixture is then cooled, neutrallized with 50% sodium hydroxide and the crude product is 5 extracted with dichloromethane (6 x 50 ml) and flash chromatographed on silica gel (300 ml). Elution with 1:1 ethylacetate-hexane followed by crystallization from ethylacetate-hexane affords compound D (1.54g): MS m/e 302 (MH). Example 2, Step 4. CI

H

3 CH 3

H

3 0

CH

3 C O OCH 3 O OCH 3 N D EN F CH 3 E 1

CH

3 -18- WO 98/57950 PCT/US98/11509 A solution of E (0.8M, 13.2 ml) in THF is added with stirring under nitrogen to a cold (ice bath) solution of D (1.6g) in THF ( 30ml). The reaction is stirred for 30 min and is then diluted with ice/water followed by extraction with dichlorometrhane (3 x 50 ml). The crude product obtained by evaporation of the 5 extract is flash chromatographed on silica gel (100 ml). The column is first eluted with 10% methanol-dichloromethane to remove impurities; elution with 10% methanol-3% ammonium hydroxidel-dichloromethane affords compound F as an amorphous solid (1.6g): MS m/e 401 (MH). Example 2, Step 5. CI CI

H

3 C CH 3

H

3 ' CH 3 \/ \I~ N O OCH 3 CICOOEt HO OCH 3 0 F CH 3 G COOEt A solution of ethylchloroformate (1.5ml) in toluene (20 ml) is added dropwise during 10 min. with stirring to a solution of compound F (1.5 g) and triethylamine (0.9 ml) in toluene (30 ml) heated in an oil bath at 850 C. The reaction is heated for an additional 45 min and is then cooled and stirred with 5 ice-water, followed by washing with 10% sodium carbonate. The crude product is isolated by extraction with ethylacetate and is flash chromatographed on silica gel to afford compound G. MS m/e 459 (MH). Example 2, Step 6. CI

H

3

-

C

H

3

H

3 C CH 3 .O OCH 3

H

2 /Pd , HO OCH 3 N N G COOEt H COOEt 0 A solution of compound G (1.2g) in ethanol (40ml) and 10% palladium-carbon is hydrogenated in a Parr flask at 50 psi for 6 hrs. The catalyst is removed by filtration and the filtrate is evaporated. The residue is dissolved in ethylacetate and the solution is washed with 10% sodium carbonate. The organic layer is evaporated to afford compound H. 5 Example 2, Step 7. -19- WO 98/57950 PCT/US98/11509

H

3 C CH 3

H

3 C CH3 -O OCH 3 PPA N OCH 3 H COOEt COOEt A paste obtained by combining compound H (0.58g) with polyphosphoric acid (PPA) (1.5ml) is heated in an oil bath at 100 oC for 30 min. The dark brown liquid is cooled and stirred with ice-water (10 ml), the resulting solution is made 5 basic with 50% sodium hydroxide and then extracted with dichloromethane (5 x 30 ml). The extract is filtered through a plug of silica gel which is then eluted with 10% methanol-dichloromethane. The combined filtrates are evaporated and chromatographed on silica gel (50ml). Elution with 5%methanol-dichloromethane affords compound I as a tan solid. 0 MS m/e 407 (MH). Example 2, Step 8.

H

3

-

C

H

3

H

3 C' -CH 3 -N OCH3 4NHCI H N |OCH 3 I I COOEt H A solution of compound I (0.5g) in 4 N hydrochloric acid (20ml) is heated in an oil bath (1300C) for 14 hrs. The reaction is cooled and made basic with 50% 5 sodium hydroxide to pH 8 and extracted with dichloromethane. The extract is dried over sodium sulfate and evaporated to dryness to afford compound J. Example 2, Step 9.

H

3

CH

3

H

3 ' - CH 3 N O e

H

3 DIBAL H O C

H

3 H K H Diisobutylaluminum hydride (DIBAL H) (1 M solution in toluene, 4.8ml) is added ?0 dropwise with stirring to a solution of compound J (0.45 g) in dry toluene (10 ml) at 150C. The reaction mixture is stirred at room temperature for 2 hrs and is then quenched by addition of water (10 ml) and 10% sodium hydroxide. The mixture is extracted with dichloromethane and the crude product is - 20 - WO 98/57950 PCT/US98/11509 chromatographed on silica gel (30ml). Elution with 10% methanol-2% ammonium hydroxide-dichloromethane affords compound J: MS m/e 337 (MH). Example 2, Step 10. ~H3 'CH3

H

3

CH

3

H

3

H

3 N OCH 3 ArCOOH coupling OCH 3 N N N H KOO 5 J racemate A solution of product J (0.2 g), 1-hydroxybenzotriazole (0.13 g) and 4-pyridyl acetic acid N-oxide (0.15 g) in dimethylformamide (3.0 ml) is cooled in ice and treated with N-(3-dimethyl aminopropyl)-N'-ethylcarbodiimide hydrochloride (0.18 g) followed by N-methyl morpholine (0.3 ml). The mixture is allowed to 3 warm to room temperature overnight and is then evaporated under reduced pressure. The residual gum is stirred with 10% sodium carbonate and extracted with dichloromethane. The crude product obtained by evaporation of the extract is flash chromatographed on silica gel (30 ml). Elution with 5% methanol-2% ammonium hydroxide-dichloromethane affords product K as a 5 pale tan foam. MS 471 (CI) 472. Example 3. (+,-)-4-(3-Bromo-10-methoxy-8-methyl-6,11-dihydro-5H benzo[5,6]cyclohepta[1,2-b]pyridin-11-yl)-1l-(4-pyridinylacetyl)piperidine N1 oxide Br - -

CH

3 N

OCH

3 0 'N racemate H Example 3, Steps 1 & 2. -21 - WO 98/57950 PCT/US98/11509

H

3 CO Br\ Bo 1.BuLi / i-Pr 2 NH / CH3 N Br B NHt-Bu r B 2. CH 3 O A B

H

3 CO NHt-Bu

H

3 CO HCO / C H 3 /CH Br PO Br PC1 N B 85% N'CN C NHt-Bu 5 Following the procedures as described in Example 1, Steps 1 and 2, except that reactant 2 is substituted for reactant 2 of Example 1, gives intermediate compounds B and C. Example 3, Step 3.

H

3 CO MgCI Br 0 OCH 3 N N 1. I Br CH 3

H

3 C N N C 2. H + N D 0

CH

3 A 0.5M solution of 1-methyl-4-piperidyl magnesium chloride in THF (28 ml) is added dropwise to a solution of compound C (4.8 g) in THF (60 ml) under argon. The dark color reaction is heated at 550C for 15 min., cooled in an ice bath, quenched with water and extracted with ethylacetate (4 x 50 ml). The 5 combined extract is dried over sodium sulfate and evaporated under reduced pressure. The resulting intermediate is dissolved in 4N HCI (40 ml) and methanol (20 ml) and the solution is heated on a steam bath for 1 hour, cooled in an ice bath and made basic with 10% NaOH followed by extraction with ethylacetate. The extract is evaporated and flash chromatographed on silica 0 gel. Elution with 10% ethylacetate-hexane affords compound D (2.7g): MS m/e 431 (MH). -22- WO 98/57950 PCT/US98/11509 Example 3, Step 4. Br -- % OH Br '

CH

3 \ 0 \ N N

H

3 C CF 3

SO

3 H

OCH

3 D NE

CH

3 CH 3 Triflic acid (55 ml) is added with stirring to compound D (2.9 g) and the dark 5 syrupy solution is stored overnight at 40C. The reaction mixture is worked up by pouring on ice, making basic with 50% NaOH, followed by extraction with dichloromethane (3 x 50ml). The extract is evaporated under reduced pressure and the crude product is flash chromatographed on silica gel. Elution with 5% methanol-dichloromethane affords compound E (1.37g); MS m/e 413 (MH). 0 Example 3, Step 5. Br -'

CH

3 Br -'

CH

3

OCH

3 CICOOEt N OCH 3 E CH 3 F COOEt Following the procedure as described in Example 2, Step 5 gives intermediate compound F. 5 Example 3, Steps 6 & 7. Br

CH

3 Br -

H

3 N|IN

OCH

3 3NHCI

OCH

3 F COOEt G Br oCH 3 Br '

CH

3 N DIBAL H N

OCH

3

.OCH

3 G H H Following the procedures as described in Example 2, Steps 8 and 9, gives intermediate compounds G and H. Compound H is resolved into its (+) and (-) - 23 - WO 98/57950 PCT/US98/11509 enatiomers by dissolving 0.580 g in i-propanol/hexane (0.2%dea) containing EtOH with heating on a steambath. The solution is applied to a preparative HPLC chiralpac AD, 5 by 50cm column (Daicel Chemical Ind.), and eluted with i-propanol/hexane (0.2%DEA) with a flow rate at 20 ml/min and collecting 5 500ml fractions. After the first peak is eluted the solvent is changed to 25/75 i-propanol/hexane (0.2%DEA) at a flow rate of 40 ml/min. The (+) enantiomer (0265 g) is obtained in fraction 2. Optical rotation =+2.69 at concentration of (5.2 mg/2ml EtOH) at 20.5 OC. The (-) enantiomer (0.2280 g) is obtained from fractions 7 to 8. Both the (+) and (-) enantiomers are determined pure by 0 analytical HPLC on a chiralpak AD 0.46 cm by 25 cm column. Example 3, Step 8. Br "'

CH

3 Br

CH

3 N I ArCOOH N N O Coupling N

OCH

3

OCH

3 H H I W0 0 "N racemate Following the procedures as described in Example 1, Step 7, gives the desired 5 title compound I, a racemate. Example 4. (+,-)-4-(6,11-dihydro-10-methoxy-8-methyl-5H benzo[5,6]cyclohepta[1,2-b]pyridin-11-yl)-1l-(4-pyridinylacetyl)piperidine N-1 oxide *

CH

3 N

OCH

3 NN "I 0 0 racemate H -24- WO 98/57950 PCT/US98/11509

H

3 CO 1 .BuLi / i-Pr 2 NH O Br C CI N 2. CH 3 , O NHt-Bu \ N N

H

3 CO NHt-Bu H3CO A B HH 3 3CO CH3 SCl POC 3 CH3 \ 0 CI N 85% N NHt-Bu 8 N CN B C

H

3 CO / CH 3 Cl CI CH, ON, 1. CF 3

SO

3 H N CN O OCH 3 C 2. HO D CI o

C

H 3 ' O O C H 3 O OCH3 D EF CH 3 NE CH3 Cl Cl CH3 CH3 C3 CICOOEt HO .OCH3 qiO OCF O 3 5 F cH3 G COOEt Cl

CH

3

CH

3 O 00CH 3

H

2

O

/Pd HO OCH 3 I G COOEt H COOEt -25 - WO 98/57950 PCT/US98/11509

C

H

3

CH

3 O OCH 3 PPA N OCH 3 H COOEt COOEt

CH

3 CH3 ./ S3N HCI N I

OCH

3 OCH 3 I COOEt H CH3

CH

3 N DIBAL H N

OCH

3 OCH 3 J H K H CH3 PD H / ArCOOH coupling N N ,_OCH_

OCH

3 OCH 3 Q 0 N K H L 0 racemate 5 Following the procedures as described in Example 2, Steps 1-9, except that reactant 2 is substituted for reactant 2 in Example 2, gives intermediate compounds A-K, and the desired title compound L, a racemate. 0 Example 5. (+,-)-4-(7-Chloro-5,6-dihydro-8-methyl-10-methoxy-11 H benzo[5,6]cyclohepta[1,2-b]pyridin- 11-ylidene)-1-(4-pyridinylacetyl)piperidine Nl-oxide -26- WO 98/57950 PCT/US98/11509 CI

CH

3 N

OCH

3 00 O N O By substituting 3-methyl-2-chloro-5-methoxybenzylchloride for reagent 2 and 3 methyl-2-t-butyl carboxamidopyridine for compound A in Example 3, Step 1, and by following Example 3, Steps 1-8 but omitting Example 3, Step 7 with 5 DIBALH, the title compound is obtained. Example 6. (+,-)-4-(3-Bromo-10-hydroxy-8-methyl--5,6-dihydro-11H benzo[5,6]cyclohepta[1,2-b]pyridin- 11-ylidene)-1-(4-pyridinylacetyl)piperidine Nl-oxide Br

CH

3 NI OH N N 0 0 By starting with 5-bromo-3-methyl-2-t-butyl carboxamido pyridine and by following Example 3, Step 1-6 gives compound A, below. Br CH 3 Br CH 3

CF

3

SO

3 H, AI/ N N

OCH

3 OH H A H B Compound A (500mg,1.34mmol) is stirred in triflic acid (3 ml) at 800C, for 2 5 hours, then cooled to room temperature. The reaction mixture is diluted with ice (20 g), basified with 10% sodium carbonate, then extracted with CH2CI2 (2 x 60ml). The organic layer is separated, dried over MgSO4, filtered, and evaporated solvent, to yield an oil, which chromatographs on silica gel eluting with 7%(v/v) methanol-methylene chloride containing 2% ammonium 0 hydroxide, yielding Compound B, as a white solid. Using the procedure of - 27 - WO 98/57950 PCT/US98/11509 Example 1, Step 7, substituting an equivalent amount of Compound B for Compound G, gives the title compound. FABS 519 MH. Example 7. 4-(5,6-dihydro-10-methoxy-3,8-dimethyl-11H 5 benzo[5,6]cyclohepta[1,2-b]pyridin- 11-ylidene)-1-(4-pyridinylacetyl)piperidine N1 -oxide

H

3 C

CH

3 N

OCH

3 O N WN' By substituting 3-methyl-5-methoxybenzylchloride for reagent 2 and 3,5 dimethyl-2-t-butyl carboxamidopyridine for compound A in Example 1, Step 1, 0 and by following Example 1, Steps 1-7, the title compound is obtained. Example 8. (+,-)-4-(3-bromo-1 0-methoxy-8-methyl-5,6-dihydro-1 1 H benzo[5,6]cyclohepta[1,2-b]pyridin-1 1-ylidene)-1-(4-pyridinylacetyl)piperidine N1-oxide Br -

CH

3 NI

OCH

3 O N ~N 5 0 By starting with intermediate G of Example 3, Step 6 and by following Example 1, Steps 1-7, the title compound is obtained. Example 9. (+,-)-4-(3-Bromo-10-hydroxy-8-methyl--5,6-dihydro-11 H 0 benzo[5,6]cyclohepta[1,2-b]pyridin- 11-yl)-1 -(4-pyridinylacetyl)piperidine Nl-oxide Br

COH

3 N OH 0 oo -28 - WO 98/57950 PCT/US98/11509 By following the procedure of Example 6, except that the procedure of Example 2, Step 9 is carried out prior to the procedure of Example 1, Step 7, to give the title compound. Example 10. (+,-)-1l-(3-Bromo-10-methoxy-8-methyl-6,11-dihydro-5H benzo[5,6]cyclohepta[1,2-b]pyridin- 11-yl)-4-(4-pyridinylacetyl)piperazine N4-oxide Br-

CH

3 N )CH3 By substituting 3-methyl-5-methoxybenzylchloride for reagent 2 in Example 1, Step 1, and by following Example 1, Steps 1-7, the title compound is obtained. ) Example 14. (+,-)-1-(3-Bromo-7-methyl-6,11-dihydro-5H benzo[5,6]cyclohepta[1,2-b]pyridin- 11-yl)-4-(4-pyridinylacetyl)piperazine N4-oxide

CH

3 Br N '00 5 By substituting 2-methylbenzylchloride for reagent 2 in Example 1, Step 1, and by following Example 1, Steps 1-7 (except for Steps 3 and 3a), and by substituting the procedure of Example 2, Step 3 in place of Example 1, Step 3 and 3a, gives the title compound. ) Example 15. (+,-)-1-(3-Bromo-7,10-dimethyl-6,11-dihydro-5H benzo[5,6]cyclohepta[1,2-bjpyridin- 11-yl)-4-(4-pyridinylacetyl)piperazine N4-oxide -29- WO 98/57950 PCT/US98/11509

CH

3 Br N CH3 0 By substituting 2,5-dimethylbenzyl chloride for reagent 2 in Example 1, Step 1, and by following Example 1, Steps 1-7 (except for Steps 3 and 3a), and by substituting the procedure of Example 2, Step 3 in place of Example 1, Step 3 5 and 3a, gives the title compound. Example 16. (+,-)-1-(3-Bromo-8-methyl-6,11-dihydro-5H benzo[5,6]cyclohepta[1,2-b]pyridin- 11-yl)-4-(4-pyridinylacetyl)piperazine N4-oxide Br - CH 3 N O-r CN N 10 By substituting 3-methylbenzylchloride for reagent 2 in Example 1, Step 1, and by following Example 1, Steps 1-7 (except for Steps 3 and 3a), and by substituting the procedure of Example 2, Step 3 in place of Example 1, Step 3 and 3a, gives the title compound. 15 Example 17. (+,-)-1l-(3-Bromo-6,11-dihydro-8-methoxy-5H benzo[5,6]cyclohepta[1,2-b]pyridin- 11-yl)-4-(4-pyridinylacetyl)piperazine N4-oxide Br--

OCH

3 N C) o 0 N 20 By substituting 3-methoxybenzylchloride for reagent 2 in Example 1, Step 1, and by following Example 1, Steps 1-7 (except for Steps 3 and 3a), and by substituting the procedure of Example 2, Step 3 in place of Example 1, Step 3 and 3a, gives the title compound. -30 - WO 98/57950 PCT/US98/11509 Example 18. (+,-)-1l-(3-Bromo-6,11-dihydro-8,10-dimethyl-5H benzo[5,6]cyclohepta[1,2-b]pyridin- 11-yl)-4-(4-pyridinylacetyl)piperazine N4-oxide Br - CH 3 N N )CH 3 50 By substituting 3,5-dimethylbenzylbromide for reagent 2 in Example 1, Step 1, and by following Example 1, Steps 1-7 (except for Steps 3 and 3a), and by substituting the procedure of Example 2, Step 3 in place of Example 1, Step 3 and 3a, gives the title compound. D Example 19. (-)-1-(3-Bromo-10-methoxy-8-methyl-6,11-dihydro-5H benzo[5,6]cyclohepta[1,2-b]pyridin-11-yl)-4-(4-pyridinylacetyl)piperazine N4-oxide, (-) enantiomer Br ~CH 3 N

SOCH

3 0 (-) enantiomer 5 The racemic title compound of Example 10 (67 mg) is dissolved into 50/50 i-propanol/hexane containing 0.2% diethylamine and the solution is injected into a preparative high performance liquid chromatography column, chiralpak AD 5 by 50cm column (Daicel Chemical Ind.). Elution with ethanol (EtOH)/Hexane (containing 0.2% diethylamine or DEA) at 20 ml/min for two 0 hours, then changing the eluting phase to 7% EtOH/Hexane (0.2%DEA) and increasing the flow rate to 40 ml/min (500 ml fractions are collected) gives: -31 - WO 98/57950 PCT/US98/11509 fractions 10-12, 30.9 mg of title compound of Example 19: [a(]D 23 -18.8 0 (c. 0.32, ethanol), mp=1 11-1160C. Example 20. (+)-1l-(3-Bromo-10-methoxy-8-methyl-6,11-dihydro-5H 5 benzo[5,6]cyclohepta[1,2-b]pyridin- 11-yl)-4-(4-pyridinylacetyl)piperazine N4-oxide, (+) enantiomer Br CH 3 OCH3 0 O (+) enantiomer Following the preparative high performance liquid chromatography procedure described in Example 19, the title compound is obtained: fractions 14-16, the 0 title compound of Example 20: []D 2 3 +19.60(c. 0.28, ethanol), mp=110-117 0 C. Example 21. (+,-)-1l-(3,10-Dibromo-6,1 1 -dihydro-8-methyl-5H benzo[5,6]cyclohepta[1,2-b]pyridin- 11-yl)-4-(4-pyridinylacetyl)piperazine N4-oxide Br

CH

3 Br 0 5 racemate By substituting 3-methyl-5-bromobenzyl bromide for reagent 2 in Example 1, Step 1, and by following Example 1, Steps 1-7 (except for Steps 3 and 3a), and -32 - WO 98/57950 PCT/US98/11509 by substituting the procedure of Example 2, Step 3 in place of Example 1, Step 3 and 3a, gives the title compound. Example 22. (+,-)-1l-(3,8-Dibromo-6,11-dihydro-10-methyl-5H 5 benzo[5,6]cyclohepta[1,2-b]pyridin- 11-yl)-4-(4-pyridinylacetyl)piperazine N4-oxide Br Br CH3 O 0 By substituting 3-bromo-5-methyl-benzyl bromide for reagent 2 in Example 1, Step 1, and by following Example 1, Steps 1-7 (except for Steps 3 and 3a), and 0 by substituting the procedure of Example 2, Step 3 with heating to 600C for 4 hours with triflic acid, in place of Example 1, Step 3 and 3a, gives the title compound. Example 23. (+,-)-4-[6,11 -dihydro-3-(1-hydroxy-1 -methylethyl)-1 O-methoxy-8 5 methyl-5H-benzo[5,6]cyclohepta[1,2-b]pyridin- 11-yl]-1-(4 pyridinylacetyl)piperidine N1-oxide O H CH3

CH

3 H3C \/ N OCH3 Step 1: - 33 - WO 98/57950 PCT/US98/11509 B 'CH OH I CH 3 Step 1 N I A BOC B BOC A nitrogen blanketed solution of the compound A of Example 27, Step 1 (0.4g) in tetrahydrofuran (8 ml) is cooled to -780C and then treated with 2.5M solution of butyl lithium in hexanes (0.4 ml). After stirring for 5 minutes, acetone (0.4 ml) 5 is added and after 5 minutes the reaction mixture is evaporated under reduced pressure to yield an oil that is flash chromatographed on silica gel (50 ml). Elution with 3% methanol-dichloromethane affords B as white powder (0.13 g). MS(CI) 479. 0 Step 2: O0 CH3 OCH3 N OC3Step 2 N OH B BOC C H Product B from Step 1 is converted to intermediate C by following the procedures described in Steps 3 and 4, Example 27. Tan powder, MS(CI)381. 5 Step 3: HH - H 3 QOCH3 C H C3D O O racemate Product C from Step 2 is converted to the title compound D by following the procedure described in Example 1, Step 7. White powder, MS(Cl) 516. 0 Example 24. (+)-4-(3-Bromo-10-methoxy-8-methyl-6,11-dihydro-5H benzo[5,6]cyclohepta[1,2-b]pyridin- 11-yl)-4-(4-pyridinylacetyl)piperidine Nl-oxide, (+) enantiomer -34 - WO 98/57950 PCT/US98/11509 Br

CH

3 N

OCH

3 0 O (+) enantiomer By substituting 3-methyl-5-methoxy-benzylbromide for reagent 2 in Example 3, Step 1, and by following Example 3, Steps 1-8 and using the resolved (+) enantiomer H of Step 7, the title compound is obtained. Optical rotation: 5 +31.90 at concentration of 5.7 mg/2 ml ethanol at 220C (sodium D line). Example 25. (-)-4-(3-Bromo-1 0-methoxy-8-methyl-6, 11 -dihydro-5H benzo[5,6]cyclohepta[1,2-b]pyridin-1 1 -yl)-4-(4-pyridinylacetyl)piperidine Nl-oxide, (-) enantiomer Br

CH

3 N

OCH

3 0 O 0 0 (-) enantiomer By substituting 3-methyl-5-methoxy-benzylbromide for reagent 2 in Example 3, Step 1, and by following Example 3, Steps 1-8 and using the resolved (-) enantiomer H of Step 7, the title compound is obtained. Optical rotation: -31.60 at concentration of 6.2 mg/2 ml ethanol at 22.40C (sodium D line). 5 -35- WO 98/57950 PCT/US98/11509 Example 26. (+,-)-1l-(3-Bromo-8-methoxy-10-methyl-6,11-dihydro-5H benzo[5,6]cyclohepta[1,2-b]pyridin- 11-yl)-4-(4-pyridinylacetyl)piperzazine N4-oxide Br OCH 3 Ni Q OH 3 o 0 5 By substituting 3-methoxy-5-methyl-benzylbromide for reagent 2 in Example 1, Step 1, and by following Example 1, Steps 1-7 (except for Steps 3 and 3a), and by substituting the procedure of Example 2, Step 3 in place of Example 1, Step 3 and 3a, gives the title compound. 10 Example 27. 4-(3-Ethenyl-6, 11-dihydro-10-methoxy-8-methyl-5H benzo[5,6]cyclohepta[1,2-b]pyridin- 11-yl)-1-(4-pyridinylacetyl)piperidine N1 -Oxide

H

2 C CH 3 N

OCH

3 0 O Step 1. 1,1-Dimethylethyl-4-(3-bromo-5,6-dihydro-10-methoxy-8-methyl-11H 15 benzo[5,6]cyclohepta[1,2-b]pyridin-1 1 -ylidene)-1 -piperidinecarboxylate - 36 - WO 98/57950 PCT/US98/11509 Br .V CH 3 Br C CH 3 I I

NOCH

3 (130H0 H Boc Add di-tert-butyldicarbonate (2.0 g,9.16 mmol) in methylene chloride (5 ml) to a solution of the intermediate compound G of Example 3, Step 6 (1.0 g, 2.51 mmol) in methylene chloride (15 ml) at 200C, then stir 1hour at room 5 temperature. The solvent is evaporated, and the residual oil is chromatographed on silica gel eluting with 15% (v/v) ethyl acetate-hexanes yielding the product as a white solid (1.1 g, 92%yield). MS (CI) 499, MH. 10 Step 2. 1,1-Dimethylethyl-4-(3-ethenyl-5,6-dihydro-10-methoxy-8-methyl-1 1 H benzo[5,6]cyclohepta[1,2-b]pyridin- 11-ylidene)-1-piperidinecarboxylate. Br

CH

3 H 2 C CH3 I / Vinyl Tributyltin, N /Pd(dba) 3 ,/Tri-2-furoylphosphine N

OCH

3

OCH

3 Toluene,1000C OC I Boc Boc Add tributylvinyltin (3ml,10.26mmol) to a solution of the title compound of Step 1 15 (950 mg, 1.90 mmol), lithium chloride (1.0 g, 23.6 mmol), tris(dibenzylideneacetone)dipalladium (180 mg), and tri-2-furoyl phosphine (90 mg, 0.38 mmol) in toluene (6 ml) at room temperature, then stir at 100C overnight. The reaction is cooled, extracted with ethyl acetate (100 ml), washed with water (50 ml), dried over magnesium sulfate, filtered and the solvent 20 evaporated, yielding an oil, which chromatographs on silica gel eluting with 40%(v/v) ethylacetate-hexanes yielding the product as a white solid (800 mg, 95% yield). MS (CI) 447,MH. Step 3. 4-(3-Ethenyl-5,6-dihydro-10-methoxy-8-methyl-11H 25 benzo[5,6]cyclohepta[1,2-b]pyridin- 11-ylidene)-1-piperidine -37- WO 98/57950 PCT/US98/11509

CH

3 CH3 H2C TA H2C 11 I iTFA N __ _ _ N

OCH

3

CH

2

CI

2 OCH 3 Boc H A 20% solution of trifluoroacetic acid in methylene chloride (10 ml) is added to the title compound of Step 2 (400mg,0.89mmol) at room temperature, then stirred for 1/2 hour at 200C. Water(20ml), methylene chloride (20ml), and 1N 5 NaOH (3 ml) are added, and the organic layer is separated, dried over MgSO4, filtered, and the solvent evaporated, yielding a solid (305 mg, 98% yield) MS(CI) 347,MH. Step 4. 3-Ethenyl-6,1 1 -Dihydro-10-Methoxy-8-Methyl-11-(4-Piperidinyl)-5H 10 Benzo[5,6]Cyclohepta[1,2-b]Pyridine

H

2 C C H 3 Dibal H 2 OC

,CH

3 I HH OCH A 1 M solution of DIBAL in toluene (3 ml,3 mmol) is added dropwise to a solution of the title compound of Step 3 (310 mg, 0.89 mmol) in toluene(2 ml) at 200C, then stirred 45 minutes. Water (15 ml), EtOAc (30 ml) and 1N NaOH (5 15 ml) are added. The organic layer is separated, dried over MgSO4, filtered, and the solvent evaporated to yield an oil, which chromatographs on silica gel eluting with 10% methanol-methylene chloride containing 2% NH4OH, yielding the product as a white solid. (200mg,65% yield), MS (FABS) 349,MH. 20 Step 5. 4-(3-Ethenyl-6,11-dihydro-10-methoxy-8-methyl-5H benzo[5,6]cyclohepta[1,2-b]pyridin-11-yl)-1 -(4-pyridinylacetyl)piperidine N1-Oxide. -38 - WO 98/57950 PCT/US98/11509

H

2 C CH 3

H

2 C CH 3 N O- - \N N

OCH

3 COOH OCH 3 HOBT,EDCI,NMM,DMF H 0 0 O EDCI (50 mg,0.26 mmol),1-hydroxybenzotriazole, monohydrate (40 mg, 0.29 mmol) and 4-methyl morpholine (0.5 ml, 4.5 mmol) are added to a solution of the title compound of Step 4 (50 mg, 0.14 mmol) and 4-pyridyl-N-oxide acetic 5 acid (50 mg, 0.326 mmol) in dimethylformamide (anhydrous,2 ml) at 0OC , then stirred at room temperature overnight. The solvent is evaporated, and the residue extracted with methylene chloride (60 ml), and water (25 ml). The organic layer is separated, washed with saturated sodium carbonate (2 x15ml), dried over MgSO4, filtered and the solvent evaporated to yield an oil which 10 chromatographs on silica gel eluting with 10% MeOH-MeCl2 containing 2% NH4OH yielding the product as a white solid (55 mg,79% yield), MS (FABS) 484, MH. Example 28. 4-(3-Ethenyl-6,11-dihydro-10-methoxy-8-methyl-5H 15 benzo[5,6]cyclohepta[1,2-b]pyridin-11 -yl)-1 -(methylsulfonyl)piperidine H2

CH

3 H2C, 3 N CH 3

SO

2 CI / N __ _ _N

OCH

3 Pyridine, DMAP OCH 3 I H SO 2

CH

3 Methanesulfonyl chloride (0.5 ml, 6.46 mmol) is added to a solution of the title compound of Example 27, Step 4 (30 mg, 0.086 mmol) in anhydrous pyridine (2 ml) at 00C, then 4-dimethylaminopyridine (10 mg, 0.08 mmol) is added, and the 20 solution stirred overnight at 200C. The solvent is evaporated, water (30 ml) and CH2CI2 (60 ml) are added. The organic layer is separated, dried over MgSO4, filtered, and solvent evaporated to yield an oil, which chromatographs on silica - 39 - WO 98/57950 PCT/US98/11509 gel eluting with 70% v/v EtOAC-hexanes yielding the product as a white solid (30 mg, 69% yield), MS(CI) 427, MH. Example 29. 4-(3-Ethyl-6,11-dihydro-10-methoxy-8-methyl-5H 5 benzo[5,6]cyclohepta[1,2-b]pyridin- 11-yl)-1-(4-pyridinylacetyl)piperidine, N1-Oxide

H

3 C j -CH 3 N

OCH

3 N 0 Step 1. 3-Ethyl-6,11-dihydro-10-methoxy-8-methyl-11 -(4-piperidinyl)-5H 0 benzo[5,6]cyclohepta[1 ,2-b]pyridine

CH

3 CH 3 H2C3 H3C 10% Pd/C, MeOH N N

OCH

3 HCOONH 4 , A

OCH

3 H H Ammonium formate (200 mg, 2.08 mmol) and 10% Pd/C(20mg) are added to a solution of the title compound of Example 27, Step 4 (90 mg, 0.258mmol) in methanol (5 ml) at 200C, then refluxed for 4 hours. Methanol (20 ml) is added, 5 and the reaction is filtered through a celite pad, then washed with methanol (10 ml) and CH2CI2 (3 x 20ml). The filtrate and wash are combined, concentrated, and the residue extracted with CH2CI2 (50 ml) and water (25 ml). The organic layer is separated, dried over MgSO4, filtered and solvent removed yielding a white solid (75mg, 84% yield). 20 Step 2. 4-(3-Ethyl-6,1 1 -dihydro-10-methoxy-8-methyl-5H benzo[5,6]cyclohepta[1,2-b]pyridin- 11-yl)-1-(4-pyridinylacetyl)piperidine, N1-Oxide -40- WO 98/57950 PCT/US98/11509

H

3

H

3 C

CH

3 H° -N Noo N- COOH

OCH

3

OCH

3 EDCI,HOBT,NMM,DMF 0 I H I 0 EDCl (75 mg, 0.39 mmol), HOBT (70mg, 0.51 mmol) and NMM (0.5 ml, 4.5 mmol) are added to a solution of the title compound of Step 1 (75 mg, 0.214 mmol) and 4-pyridyl N-oxide acetic acid (75 mg, 0.48 mmol) in DMF(anhydrous, 5 3 ml) at 00C, then stirred at room temperature overnight. The solvent is evaporated, and the residue extracted with CH2Cl2 (60 ml) and water (25 ml), the organic layer separated, washed with 10% Na2CO3 (2 x 20ml), dried over MgSO4, filtered, and the solvent evaporated to yield an oil, which chromatographs on silica gel eluting with 7% v/v MeOH:methylene chloride 10 (MeCl2) containing 2% NH4OH yielding product as white solid (75mg,76% yield), MS (FABS) 486(MH). Example 30. (+,-)-4-(3-Bromo-6,11-dihydro-8,10-dimethyl-5H benzo[5,6]cyclohepta[1,2-b]pyridin- 11-yl)-1-(4-piperidinylacetyl)piperazine Br - CH 3 N 0C H3 NH 15 0 By substituting 3,5-dimethylbenzylbromide for reagent 2 and by substituting the corresponding 5-bromo-t-butyl amide for reagent A in Example 1, Step 1, and by following Example 1, Steps 1-6 (except for Steps 3, 3a and 7), and by substituting the procedure of Example 2, Step 3 with heating to 600C using triflic 20 acid, in place of Example 1, Step 3 and 3a, gives the 8,10-dimethyl analog of Example 1, Step 6, compound G. By following the procedure of Example 1, Step 7, substituting 4-pyridyl acetic acid N-oxide with an equivalent amount of -41 - WO 98/57950 PCT/US98/11509 N-BOC-4-piperidyl acetic acid, then removing the BOC group with trifluoroacetic acid, the title compound is obtained. Example 31. (+,-)-4-(3-Bromo-6,11-dihydro-8,10-dimethyl-5H 5 benzo[5,6]cyclohepta[1,2-b]pyridin- 11-yl)-1-(4-piperidinylacetyl-N carboxamido) piperazine Br-

CH

3 N CN- CH 3 O O H NH 2 Starting with the title compound of Example 30, and treating with 3 equivalents of trimethylsilylisocyanate in methylene chloride at 250C, then removing the silyl 10 group with excess sodium bicarbonate, the title compound is obtained. Example 32. (+,-)-4-(3-cyclopropyl-6,11-dihydro-10-methoxy-5H benzo[5,6]cyclohepta[1,2-b]pyridin-1 1 -yl)-1-(4-pyridinylacetyl)piperidine Z-' CH3 N OCH3 O N, 15 Step 1: OCH3 OCH3 A BOC BOC B BOC Ethereal diazomethane generated from Diazald (15 g) is added dropwise with stirring to a solution of compound A (0.11 g) from Example 27 (Step 2), and palladium acetate (7 mg) in benzene (1 ml) until a TLC sample showed 20 completion of the reaction. Evaporation under reduced pressure affords compound B as a white powder. MS(CI) 461. -42 - WO 98/57950 PCT/US98/11509 Step 2. CH3 CH3 N OHStep 2 N OH ()OCHs . OCHs II B BOC C H Product B from Step 1 is converted to intermediate C by following the procedures described in Steps 3 and 4, Example 27. Tan powder, MS(CI) 362 5 Step 3:

CH

3 CH3 \ / Step 3 N N, OCH 0 C H C3DOO racemate The product C from Step 2 is converted to the title compound D by following the procedure described in Example 1, Step 7. White powder, MS(CI) 498. 10 Example 33. (+) 4-(3-Bromo-6,11-dihydro-10-bromo-8-methyl-5H benzo[5,6]cyclohepta[1,2-b]pyridin- 11-yl)-1-(4-pyridinylacetyl)piperidine N1-Oxide Br H3 'Br O--NCO 15 By substituting 5-bromo-t-butyl amide for reagent A and 3-methyl-5 bromobenzyl bromide for reagent 2 in Example 2, Step 1 and by following Example 2, Steps 1-10 - except in step 3, the reaction with triflic acid is carried out at 600C for 4 hours, and by omitting step 6, the title compound is obtained as a racemate. MS(FABS) m/e 584(MH). The racemate is resolved into its -43- WO 98/57950 PCT/US98/11509 enantiomers using a preparative HPLC chiralpak AD column (Daicel Chemical Industries, ) and eluting with 30% isopropanol-hexanes (0.2% DEA). The desired (+) enantiomer elutes last. MS (FABS)mle 584(MH) Rotation = +51.70@200C, c = 0.211. 5 Example 34. (-) 4-(3-Bromo-6,11-dihydro-10-bromo-8-methyl-5H benzo[5,6]cyclohepta[1,2-b]pyridin-1 1 -yl)-1-(4-pyridinylacetyl)piperidine N1-Oxide 10 Essentially the same procedure is followed as in Example 33 except that the (-) enantiomer is also collected MS (FABS)mle 584(MH) Rotation = - 47.50@200C, c = 0.2125. Example 35. (+) 4-(3-Bromo-6, 11-dihydro-1 1 -hydroxy-10-bromo-8-methyl-5H 15 benzo[5,6]cyclohepta[1,2-b]pyridin-1 1 -yl)-1 -(4-pyridinylacetyl)piperidine N1-Oxide Br H3 N OH Br By following the procedures used to prepare title compound of Example 33,- steps 6,7 and 9, from example 2 are omitted 20 the title compound is obtained, as a racemate (+,-). FABS MS m/e 599.9(MH). The racemate is resolved using the same procedure as Example 33. The (+)enantiomer elutes first MS (FABS)m/e 599.9(MH), Rotation = +10.40@200C, c =0.1155. 25 Example 36. (-) 4-(3-Bromo-6,11 -dihydro-1 1 -hydroxy-10-bromo-8-methyl-5H benzo[5,6]cyclohepta[1,2-b]pyridin- 11-yl)-1-(4-pyridinylacetyl)piperidine N1-Oxide -44 - WO 98/57950 PCT/US98/11509 Essentially the same procedure is followed as in Example 35, except that the (-) enantiomer elutes second MS (FABS)m/e 599.9(MH) Rotation = -7.30@200C, c = 0.1375. 5 Example 37. -(3-Bromo-5,6-dihydro--10-bromo-8-methyl-11H benzo[5,6]cyclohepta[1,2-b]pyridin- 11 -ylidene)-1 -(4-pyridinylacetyl)piperidine N1-Oxide Br H3 N I Br 0- - N O 10 By following procedures used to prepare the title compound of Example 33 steps 6, and 9- from example 2 are omitted, the title compound is obtained. MS (FABS)m/e 582(MH). PREPARATION OF STARTING MATERIALS 15 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 pyridyl and phenyl compounds used as starting materials, such as compounds (1, 1.3, 3, 3.5), inorganic and organic bases, and alcohols can be prepared using known 20 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 Karo, Organic Functional Group Preparations, 2nd Edition, 25 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 skilled in the art. -45 - WO 98/57950 PCT/US98/1 1509 Scheme HI Br CI ci 2 H Cl R 2 R CHR b N CN PO1 3 N N3 __ _ N 0 B R R CR NHt-Bu A NHtBu + CLDA 5 C ICF 3

SO

3 H RC R MgC] C ci

R

2 R5 - '>R7 R C N R2 \jR 6 - ±R8 K 1

R

2 --s- NC IK N "I N 3 N HO RH3 12 75N

R

5 - -H 1 0 87.

R

6 < N R 8 13a E EENaBH 4

CH

3 I I C RR2OH 9H N " SOCI 2

R

5 -::: :>-R 7 HO0 R3 CI R6-L +R8 R) R R RN 12a

NR

8 N, N 13b Rx3 N~ Rj COOEt Cl Go Rk R7. 10 ~ ~ R6 8 ' G H 2 /Pd NR RI R H Naq HO0R. HO R 3 HCI R 5 - .7

R

5 R R N~ R 8 R' N R 8 H H 13d N COt 13c R HIPPA DiBAIH R j

IN'R

8 K

RIR

2 R R 2 1 2 N R3 H N

R

3

R

5 - p 7 5 - R 7 ______________ \1 \R R 6 \RCO 1.0

RNR

8 RN R8K COOEt 15 H - 46- WO 98/57950 PCT/US98/11509 Scheme I Br R4 R4 R 4 R CH 3

R

2 R R 2 R R2 1.~ ~ ~~ 3.0J-- - NC N I N POC1 3 I N 0 LDA NHtBu R+ 3 B R 1 NHt-Bu A 53 C 1.3R 4 R R 2 R M6 C R R R2 RR R H R3 CH3 12 O 83 7.53 R5R-5;e--' , 8R7 7.5 1\1 R I -4-L-C HON N R3 DNH R _HO R3 CH 3 12 0 3 R- -R 8.3 7.53 R6 R' 133a E

CH

3 R R4 F C1COOEt I RR R4 OH 93 RI 1,R 2 H FF SOCl2 R NIHC Cl 103 RR N R RR .II"/ , R H I FF HO R 3 R6. R8 R R 2 PP R7 R 2

R

6 /" R2 H 12a / H' R N R 4 13.3b 13.3d COOEt R3

R

4

R

4 10.3 R6 K RRR 20 .

S

R H R2 N K R RRC O PPA R 5 - RR 7 R R

R

6 \1 R1.0 N R 8 NR NNR K \.19.3 N~ R3H~N

R

5 - ~ ~ ~ ~ ~ DB1 R5- -R7 R ___________ CO

R

6 ~ \ I R~ ~ >- 1. NNR3 H N R3 COOEt 15.3 H wherein for Schemes 11 and Ill,

R

1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 and R 8 , the solid and dotted lines are as defined hereinbefore. 5 In Schemes II and Ill, respectively, for Step A, compound 5 and 5.3 is prepared by alkylating compound 1 and 1.3 with an electrophile compound 3 and 3.3 employing a base such as lithium di-isopropylamide (LDA) in an aprotic -47- WO 98/57950 PCT/US98/11509 solvent such as THF, toluene, benzene, ether and the like, at temperatures ranging from about -780 to 200C, using about 1 to 1.5 moles of electrophile compound 3 per mole of compound 1 and 1.3. In Step B, compound 7 and 7.3 is prepared by treating compound 5 and 5 5.3 with a dehydrating agent such as phosphorus oxychloride (POCI 3 ) or thionyl chloride in an aprotic solvent, at temperatures ranging from about 800 to 1200C, using about 3 to 10 moles of dehydrating agent per mole of compound 5 and 5.3. In Step C, compound 7.5 and 7.53 is prepared by treating compound 7 0 and 7.3 with a Lewis acid such as triflic acid (CF 3

SO

3 H) or aluminum chloride

(AICI

3 ). The reaction can be practised neat (i.e. no additional solvents). Optionally, when AIC 3 is used, a solvent such as dichloroethane can be employed. The reaction can be conducted at temperatures ranging from about 200 to about 1750C, using about 3 to 10 moles of the Lewis acid per mole of 5 compound 7 and 7.3. In Step D, compound 8 and 8.3 is prepared by treating compound 7.5 and 7.53 with a dilute acid such as aqueous hydrochloric or aqueous sulfuric acid, at temperatures ranging from about 200C to reflux of the reaction mixture, using about 20 to 100 volumes of the aqueous acid per mole of compound 7.5 and ?0 7.53. In Step E, compound 13a and 13.3a is prepared by treating compound 8 and 8.3 with a Grignard reagent 12 derived from N-methyl-4-chloropiperidine in an aprotic solvent, at temperatures ranging from about 00 to 500C, using about 1 to 1.5 moles of Grignard reagent 12 per mole of compound 8 and 8.3. ?5 In Step F, compound 13b and 13.3b is prepared by treating compound 13a and 13.3a with ethylchloroformate in an aprotic solvent, at temperatures ranging from about 600 to 900C, using 5 to 10 moles of ethylchloroformate per mole of compound 13a and 13.3a. In Step G, compound 13c is prepared by subjecting compound 13b to 30 catalytic hydrogenation at pressures ranging from atmospheric (ambient) to 50 pounds per square inch (psi) using hydrogen (H 2 ) and 10% palladium (Pd)/Carbon (C) as a catalyst. Alternatively, compound 13c can be prepared by treating compound 13b with a hydrogen source such as ammonium formate, using 10% Pd/C as a catalyst at atmospheric pressure, at temperatures ranging 35 from 500 to 700C, optionally using a protic solvent such as methanol or ethanol. In Step H, compound 15 and 15.3 is prepared by treating compound 13c and 13.3c with an acid such as polyphosphoric acid (PPA). The reaction can -48- WO 98/57950 PCT/US98/11509 be practised neat. The reaction can be conducted at temperatures ranging from about 600 to 1000C, using about 5 to 10 volumes of polyphosphoric acid per mole of compound 13c and 13.3c. Alternatively, in Step H, compound 13d and 13.3d can be prepared by treating compound 13c and 13.3b with aqueous 5 hydrochloric acid (Hcl) or aqueous sulfuric acid (H 2

SO

4 ) such as 2 N to concentrated hydrochloric acid at temperatures ranging from about 800 to 100C, using 5 to 10 volumes of the aqueous acid per mole of compound 13c and 13.3b. In Step I, compound 19 and 19.3 is prepared by treating compound 15 and 0 15.3 with an aqueous acid such as 3 N to concentrated hydrochloric acid (HCI), at temperatures ranging from about 800 to 1000C, using 5 to 10 volumes of the aqueous acid per mole of compound 15 and 15.3. In Step J, compound 20 and 20.3 is prepared by treating compound 19 and 19.3 with a reducing agent such as diisobutyl aluminum hydride (DBAHAI) 5 in an aprotic solvent, at temperatures ranging from about 00 to 200C, using 1 to 4 moles of reducing agent per moles of compound 19 and 19.3. In Step EE, alcohol compound 9 and 9.3 is prepared by reducing compound 8 and 8.3 with a reducing agent such as as sodium borohydride (NaBH 4 ) in a protic solvent such as methanol, ethanol and acetic acid, at 20 temperatures ranging from 00 to 200C, using one to three moles of the reducing agent per mole of compound 8 and 8.3. In Step FF, compound 10 and 10.3 is prepared by treating alcohol compound 9 and 9.3 with a chlorinating agent such as thionyl chloride or phosphorous oxychloride (POCl 3 ) in an aprotic solvent such as 1,2 25 dichoroethane or methylene chloride, at temperatures ranging from 00 to 250C, using one to two moles of the chlorinating agent per mole of compound 9 and 9.3 In Step GG, compound 11 and 11.3 is prepared by reacting compound 10 and 10.3 with a piperazine compound 12 and 12.3 in a solvent such as 30 acetonitrile, toluene or methylene chloride at temperatures ranging from 00 to 600C, using one to 10 moles of piperazine compound 12 and 12.3 per mole of compound 10 and 10.3. In Step K, the desired compound of formula 1.0 can prepared from compounds (11, 11.3), (13d, 13.3d), (19, 19.3) or (20, 20.3) as described in 35 Scheme I described hereinbefore. -49- WO 98/57950 PCT/US98/11509 Scheme IV Br R4 R4 R 4 R B R .POCl3 R RR2 S1 R2C nl7 CJ N 0 .N R3 POC1 3 R3I NLDA 3.5 NHtBu B 7.3 NHt-Bu 53 1.3 NH-Bu A MgCI L R ----- R R R8 N CH3 12 R4 RR R4 R2 RI R2I R 2 N R3S NR R3 NH R NR O R 3 CF3SO3H .7 HC R5 R

R

5 7

R

5 -.. -- R 7 aq HC R6 R R R. -6L R 6 LLR8-R R6 R6 R 8 M N N R 8 N N M , I CH 3 25

CH

3 27

CH

3 26

CH

3 25 O0 CICOOEt

R

4

R

4

R

4 RI ..... R 2 RI R 2 RI R 2 SR R 3 DIBALH R

R

5

R

7

R

5 - -R 7

R

5 -- (1.0) RNR8 28 R 6 NR8 R6 NI R "N R 8 129 1 30 COOEt H 29 H 30 wherein for Scheme IV,

R

1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 and R 8 , the solid and dotted lines are as defined hereinbefore. 5 In Scheme IV, in Steps A and B, compounds 5.3 and 7.3 are prepared as described in Scheme III, hereinbefore. In Step L, compound 25 is prepared by reacting compound 7.3 with a Grignard reagent 12 derived from N-methyl-4-chloropiperidine in an aprotic 10 solvent, at temperatures ranging from about 0 to 500C, using about 1 to 1.5 moles of Grignard reagent 12 per mole of compound 7.3. In Step M, compound 26 is prepared by treating compound 25 with a dilute acid such as aqueous hydrochloric or aqueous sulfuric acid, at temperatures -50 - WO 98/57950 PCT/US98/11509 ranging from about 200C to reflux of the reaction mixture, using about 20 to 100 volumes of the aqueous acid per mole of compound 25. In Step N, compound 27 is prepared by treating compound 25 with a Lewis acid such as triflic acid or aluminum chloride (AICl 3 ). The reaction can 5 be practised neat (i.e. no additional solvents). When triflic acid is used, the reaction can be conducted at temperatures ranging from 00 to 700C, using 5 to 100 moles of triflic acid per mole of compound 25. Optionally, when AICI 3 is used, a solvent such as dichloroethane can be employed. The reaction can be conducted at temperatures ranging from about 200 to about 1750C, using about 10 3 to 10 moles of the Lewis acid per mole of compound 25. In Step O, compound 28 is prepared by treating compound 27 with ethylchloroformate in an aprotic solvent, at temperatures ranging from about 600 to 900C, using 5 to 10 moles of ethylchloroformate per mole of compound 27. 15 In Step P, compound 29 is prepared by treating compound 28 with an aqueous acid such as 3 N to concentrated hydrochloric acid (HCI), at temperatures ranging from about 800 to 100C, using 5 to 10 volumes of the aqueous acid per mole of compound 28. In Step Q, compound 30 is prepared by treating compound 29 with a 20 reducing agent such as diisobutyl aluminum hydride (DIBALH) in an aprotic solvent, at temperatures ranging from about 00 to 200C, using 1 to 4 moles of reducing agent per moles of compound 29. In Step K, compound 30 is converted to desired compound (1.0) as described in Scheme I, described hereinbefore. -51 - WO 98/57950 PCT/US98/11509 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 (IC50 <10 gM) inhibitors of Ras-CVLS farnesylation by partially purified rat brain FPT. 0 2. Cell-based assay. COS IC 50 values refer to the COS cells activity inhibition of Ras processing, are determined by the methods disclosed in WO/10515 or WO 95/10516. Exampl FPT IC 50 Exampl FPT IC 5 0 e (M) e (M) 1 0.0670 21 0.0048 2 0.0340 22 0.0099 3 0.0032 23 >0.200 4 0.1400 24 0.0036 5 >0.2 25 0.2200 6 0.0450 26 0.058 7 0.0600 27 0.0590 8 0.0300 28 0.1320 9 0.1200 29 0.0740 10 0.0160 30 14 0.1100 31 0.2000 15 0.1300 32 >0.200 16 0.0640 33 0.0012 17 0.2900 34 >0.016 18 0.0430 35 0.0108 19 0.0042 36 0.0054 20 >0.180 37 0.0054 5 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. - 52 - WO 98/57950 PCT/US98/11509 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. -53 - WO 98/57950 PCT/US98/11509 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 0 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. - 54 - WO 98/57950 PCT/US98/11509 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 1 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. 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 0 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 5 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. - 55 -

Claims (17)

1. A compound of the formula: R 4 RI R 2 I N Y (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; R 1 is hydrogen, bromo, chloro, trifluoromethyl, acyl, alkyl, cycloalkyl, amino, D acylamino or alkoxy; R 2 is hydrogen, halo, trifluoromethyl, alkyl, alkoxy, -OCF 3 , hydroxy, amino or acylamino; R 3 is hydrogen, bromo, chloro, alkoxy, -OCF 3 or hydroxy; R 4 is hydrogen, halo, trifluoromethyl, alkyl or alkoxy; 5 provided that at least one of R 2 or R 3 or R 4 is alkyl or alkoxy and provided that at least two of R 1 , R 2 , R 3 or R 4 are substituents other than hydrogen; R 5 , R 6 , R 7 and R 8 independently represent hydrogen, alkyl or -CONHR 5 0 wherein R 5 0 can be any of the values represented for R, below; 0 - 56 - WO 98/57950 PCT/US98/11509 Q is hydrogen when there is a single bond to carbon atom 11, or Q is hydrogen or hydroxy when there is a single bond to carbon 11 and X is CH, or Q is not a substituent when there is a double bond to carbon 11; Z Y is -C-R or -SO 2 -R, wherein; 5 Z is=O or=S; and R is aryl, aralkyl, cycloalkyl, cycloalkylalkyl, heteroalkyl, heteroaryl, heteroarylalkyl, heterocycloalkyl or heterocycloalkylalkyl.

2. The compound of claim 1 wherein R 1 is H, halo, alkyl, cycloalkyl or alkenyl; 0 R 2 is H, halo, alkoxy, or alkyl; R 3 is H, halo, alkoxy, hydroxy or alkyl; and R 4 is H, halo or alkyl; and R 5 , R 6 , R 7 and R 8 are hydrogen.

3. The compound of claim 2 wherein Y is -SO2CH 3 . 5

4. The compound of claim 2 wherein Y is -COR wherein R is heteroarylalkyl, or heterocycloalkylalkyl.

5. The compound of claim 2 wherein R 1 is bromo, methyl, ethyl, cyclopropyl or vinyl. 0

6. The compound of claim 2 wherein R 2 is methoxy, bromo or methyl.

7. The compound of claim 2 wherein R 3 is methoxy, bromo or methyl. 25

8. The compound of claim 2 wherein R 4 is chloro or methyl.

9. The compound of claim 1 selected from any of the title compounds of Examples 1-10 and 14-37. 30

10. The compound of claim 1 selected from any of the title compounds of Examples 1, 2, 3, 6, 7, 8, 10, 16, 18, 19, 21, 22, 24, 26, 27, 29, 33, 34, 34, 36 and 37. - 57- WO 98/57950 PCT/US98/11509

11. The compound of claim 1 selected from any of the title compounds of Examples 3, 21, 22, 24 and 33.

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

13. A method for inhibiting the abnormal growth of cells comprising administering an effective amount of a compound of claim 1. 0

14. The method of Claim 13 wherein the the cells inhibited are tumor cells expressing an activated ras oncogene.

15. The method of Claim 13 wherein the cells inhibited are pancreatic tumor 5 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 cells. 0

16. The method of Claim 13 wherein the inhibition of the abnormal growth of cells occurs by the inhibition of ras farnesyl protein transferase.

17. The method of Claim 13 wherein the inhibition is of tumor cells wherein the Ras protein is activated as a result of oncogenic mutation in genes other than 5 the Ras gene. -58-