JP2002504150A - Novel phenyl-substituted tricyclic inhibitors of farnesyl protein transferase - Google Patents

Abstract

(57) Abstract Novel phenyl-substituted tricyclic compounds of formula (1.0) and pharmaceutical compositions are disclosed. These are inhibitors of the enzyme farnesyl protein transferase. Also disclosed are methods of inhibiting Ras function, and thus inhibiting the abnormal growth of cells. The method involves administering a novel halo-N-substituted urea compound to a biological system. In particular, the method inhibits the abnormal growth of cells in a mammal, such as a human.

Description

DETAILED DESCRIPTION OF THE INVENTION                Farnesyl protein transferase New phenyl substituted tricyclic inhibitors background   Patent application WO 95/00497 (published January 5, 1995) under the Patent Cooperation Treaty (PCT) Farnesyl protein transferase (FTase) and oncogene Compounds that inhibit the farnesylation of the protein Ras are described. Oncogene Often, signaling pathways lead to stimulation of cell proliferation and mitogenesis. Encodes a protein component. Cell transformation by oncogene expression in cultured cells Is led. This means that cells have the ability to grow in soft agar, Transformed cells can grow as dense foci without the contact inhibition shown. Therefore, it is characterized. Mutation and / or overexpression of certain oncogenes Often associated with human cancer.   In order to obtain transformation ability, the precursor of Ras oncoprotein is Undergoes farnesylation of a cysteine residue located in the xyl-terminal tetrapeptide. There must be. Therefore, farnesyl protein, an enzyme that catalyzes this modification, Inhibitors of cytoplasmic transferase show potential for tumors in which Ras contributes to transformation It has been proposed as an anti-cancer drug. Mutant oncogene forms of Ras often Found in many human cancers, most notably more than 50% of the colon and pancreas (Kohl et al., Science, 260, 1834-1837, 1993).   Currently, inhibitors of farnesyl protein transferase are involved. Intent on inhibiting farnesyl protein transferase Useful additional compounds will be a welcome contribution to the art. According to the invention Thus, such a contribution is provided.Summary of the Invention   Inhibition of Farnesyl Protein Transferase by the Tricyclic Compounds of the Invention No harm has been reported to date. Therefore, the present invention uses the tricyclic compound of the present invention. And a method of inhibiting farnesyl protein transferase. This transformation The compound is capable of (i) potentiating farnesyl protein transferase in vitro But not geranylgeranyl protein transferase I (ii) a table induced by the form of the transformed Ras, a farnesyl acceptor. Blocks archetypal changes but is manipulated to become a geranylgeranyl acceptor Does not block the phenotypic changes induced by the morphology of the transformed Ras; (iii) It blocks the intracellular processing of Ras, a farnesyl acceptor, Intracellular processing of Ras engineered to geranylgeranyl acceptor Not block; and (iv) abnormal cells in culture induced by transformed Ras Block growth.   The present invention provides cells (transformed cells) by administering an effective amount of a compound of the present invention. (Including vesicles). Cell overgrowth Refers to cell growth independent of normal regulatory function (eg, lack of contact inhibition). This It involves the abnormal growth of the following cells: (1) tumors expressing activated Ras oncogene Tumor cells (tumor); (2) Ras protein is active as a result of a carcinogenic mutation in another gene Tumor cells that are transformed; and (3) benign or other proliferative disorders that result in abnormal Ras activation. And malignant cells.   Compounds useful in the method of the invention have the formula 1.0: Alternatively, it is represented by a pharmaceutically acceptable salt or solvate thereof. here:   A represents N or N-oxide;   X is relative to carbon atom 11, as represented by the solid line, when X is N or CH. Represents N, CH or C, such that a single bond is present; or, if X is C, So that there is a double bond to carbon atom 11, as represented by the line and the dotted line , N, CH or C;   R¹Is hydrogen, bromo, chloro, trifluoromethyl, acyl, alkyl, cyclo Loalkyl, amino, acylamino or alkoxy;   R^TwoIs hydrogen, halo, trifluoromethyl, alkyl, alkoxy, -OCF_Three, Hi Droxy, amino or acylamino;   R^ThreeIs hydrogen, bromo, chloro, alkoxy, -OCF_ThreeOr hydroxy;   R^FourIs hydrogen, halo, trifluoromethyl, alkyl or alkoxy;   Where R^TwoOr R^ThreeOr R^FourAt least one of which is alkyl or alkoxy And   Where R¹, R^Two, R^ThreeOr R^FourAt least two of which are substituents other than hydrogen ;   Q is hydrogen when there is a single bond to carbon atom 11, or Q is When there is a single bond to carbon 11 and X is CH, hydrogen or hydroxy Yes, or Q is not a substituent if there is a double bond to carbon 11. ;   R^Five, R⁶, R⁷And R⁸Is independently hydrogen, alkyl or -CONHR⁵⁰And here In R⁵⁰Can be any value represented below for R;   Z is = O or = S; and   R is aryl, aralkyl, cycloalkyl, cycloalkylalkyl, Teloalkyl, heteroaryl, heteroarylalkyl, heterocycloalkyl Or heterocycloalkylalkyl.   Preferably, in compound (1.0), a single bond or a double bond is present at carbon atom 11. X is N, CH or C; R¹Is H, halo, alkyl, cycloalkyl or al Kenyl; R^TwoIs H, halo, alkoxy, or alkyl; R^ThreeIs H, halo , Alkoxy, hydroxy or alkyl; and R^FourIs H, halo or a I'm Luquil; R^Five, R⁶, R⁷And R⁸Is hydrogen; Y is -SO_TwoCH_ThreeOr -COR , Where R is heteroarylalkyl, preferably pyridinyl N-oxide-methyl or Or heterocycloalkylalkyl, preferably piperidinyl-methyl. R¹ When is other than hydrogen, preferably the halo moiety is bromo and the alkyl is methyl. Or cycloalkyl is cyclopropyl, or Nyl is vinyl. R^TwoWhen is other than hydrogen, preferably the alkoxy moiety is Toxic, the halo moiety is bromo, or the alkyl is methyl. R^ThreeBut When other than hydrogen, preferably the alkoxy moiety is methoxy and the halo moiety is Bromo or alkyl is methyl. R^FourIs preferred if is other than hydrogen Alternatively, the halo moiety is chloro, or the alkyl is methyl. Preferred title Compounds are disclosed in the title compounds of Examples 1-10 and 14-37, disclosed herein below. , Preferably Examples 1, 2, 3, 6, 7, 8, 10, 16, 18, 19, 21, 22, 24, 26, 27, 29, 33, 34, 35, 36 and 37 title compounds, more preferably Examples 3, 2 Includes 1, 22, 24 and 33 title compounds.   In another embodiment, the present invention relates to a pharmaceutical composition for inhibiting the abnormal growth of cells. About things. This composition comprises an effective amount of compound (1.0) in a pharmaceutically acceptable carrier. Contains in combination with a.   In another embodiment, the invention inhibits abnormal growth of cells (including transformed cells) The method may comprise a mammal (e.g., a human) in need of such treatment. And administering an effective amount of the compound (1.0). Abnormal cell proliferation and normal regulation Refers to cell growth independent of function (eg, loss of contact inhibition). This is Vesicle overgrowth: (1) tumor cells (tumor) expressing activated Ras oncogene; (2 ) A tumor cell in which Ras protein is activated as a result of a carcinogenic mutation in another gene (3) benign and malignant cells of other proliferative disorders that result in abnormal Ras activation; and ( 4) Benign or malignant cells activated by mechanisms other than Ras protein. Bound by theory It is not intended that these compounds will function Inhibiting protein function by blocking G protein isoprenylation Make them useful for treating tumor growth and proliferative diseases such as cancer. Or inhibit ras farnesyl protein transferase, To make them useful for their antiproliferative activity against ras-transformed cells By crab It is considered possible.   The cell to be inhibited can be a tumor cell that expresses an activated ras oncogene. For example, cell types that can be inhibited include pancreatic tumor cells, lung cancer cells, myeloid Leukemia tumor cells, thyroid follicular tumor cells, myelodysplastic tumor cells, epidermal carcinoma tumor cells Cyst, bladder carcinoma tumor cells, prostate cancer cells, breast cancer cells or colon tumor cells You. In addition, inhibiting abnormal cell growth by treatment with compound (1.0) Can be done by inhibiting farnesyl protein transferase . Inhibition occurs as a result of Ras protein being a carcinogenic mutation in a gene other than the Ras gene. Inhibition of activated tumor cells. Alternatively, compound (1.0) is It can inhibit tumor cells that are activated by proteins other than proteins.   The invention also provides a method for inhibiting tumor growth. This method is Administer an effective amount of compound (1.0) to a mammal (e.g., a human) in need of such treatment. It is done by doing. In particular, the present invention relates to administering an effective amount of the compound. Thus, there is provided a method for inhibiting the growth of tumors expressing activated Ras oncogene . Examples of tumors that can be inhibited include lung cancer (e.g., lung adenocarcinoma), pancreatic cancer (e.g., exocrine Pancreatic cancer such as pancreatic cancer), colon cancer (colorectal cancer, for example, colon adenocarcinoma and colon cancer). Intestinal adenoma), myeloid leukemia (e.g., acute myeloid leukemia (AML)), follicular thyroid carcinoma, Myelodysplastic syndrome (MDS), bladder, prostate and breast and epidermal cancers But not limited to these.   The present invention also provides methods for inhibiting proliferative diseases (both benign and malignant). It is considered to be served. Here, Ras protein binds to carcinogenic mutations in other genes. Abnormally activated as a result (i.e., the Ras gene itself is a carcinogenic form due to mutation) It is not activated to the state). This inhibition is achieved by the N-substituted ureas described herein. Administering an effective amount of Compound (1.0) to a mammal (e.g., a human) in need of such treatment Is achieved by doing For example, neurofibromatosis, a benign proliferative disorder, Or Ras is mutated or tyrosine kinase oncogene (e.g., neu, src, abl , Lck and fyn) are activated by overexpression of N-substituted urea compounds (1. 0).   In another embodiment, the present invention provides that an effective amount of compound (1.0) is administered to a mammal, especially a human. To By administering ras farnesyl protein transferase and The present invention relates to a method for inhibiting farnesylation of the oncogene protein Ras. The present invention Inhibits Farnesyl Protein Transferase by Administering Compounds to Patients Is useful in treating the above-mentioned cancers.Detailed description of the invention   As used herein, the following terms are defined below unless otherwise indicated. Used as:   M⁺Represents the molecular ion of the molecule in the mass spectrum;   MH⁺Represents the molecular ion of the molecule plus hydrogen in the mass spectrum;   Bu- represents butyl;   Et- represents ethyl;   Me- represents methyl;   Ph- represents phenyl;   Benzotriazol-1-yloxy is                                 Represents;   1-methyl-tetrazol-5-ylthio is                                Represents;   Alkyl- (alkyl moiety of alkoxy, alkylamino and dialkylamino -Represents straight and branched carbon chains, from 1 to 20 carbon atoms, It preferably contains 1 to 6 carbon atoms; for example, methyl, ethyl, propyl, Isopropyl, n-butyl, t-butyl, n-pentyl, isopentyl, hexyl, etc. Wherein the alkyl group is optionally and independently 1, 2, 3, or So It may be substituted with more than one of the following groups: halo (ie trifluoromethyl), alkyl , Aryl, cycloalkyl, cyano, -CF_Three, Oxy (= O), aryloxy, -OR^Ten(Ie hydroxymethyl, hydroxyethyl), -OCF_Three, Heterocyclo Alkyl, heteroaryl, -NR^TenR¹², -NHSO_TwoR^Ten, -SO_TwoNH_Two, -SO_TwoNHR^Ten, -SO_TwoR^Ten , -SOR^Ten, -SR^Ten, -NHSO_Two, -NO_Two, -CONR^TenR¹², -NR¹²COR^Ten, -COR^Ten, -OCOR^Ten , -OCO_TwoR^TenOr -COOR^Ten, Where R^TenAnd R¹²Is independently hydrogen, alkyl , Alkoxy, aryl, aralkyl, heteroaryl, heteroarylalkyl , Cycloalkyl, cycloalkylalkyl, heterocycloalkyl or May represent telocycloalkylalkyl;   Acylamino has the moiety -CONR^TenR¹²Where R^TenAnd R¹²Is in this specification As defined above;   1-20 carbons covalently linked to adjacent structural elements via an alkoxy-oxygen atom The alkyl portion of the atom (eg, methoxy, ethoxy, propoxy, butoxy, Wherein the alkoxy group is an alkyl, aryl, etc. , Cycloalkyl, cyano, -CF_Three, Oxy (= O), aryloxy, -OR^Ten, -OC F_Three, Heterocycloalkyl, heteroaryl, -NR^TenR¹², -NHSO_TwoR^Ten, -SO_TwoNH_Two, -SO_TwoNHR^Ten, -SO_TwoR^Ten, -SOR^Ten, -SR^Ten, -NHSO_Two, -NO_Two, -CONR^TenR¹², -NR¹²COR^Ten , -COR^Ten, -OCOR^Ten, -OCO_TwoR^TenOr -COOR^TenOptionally and independently substituted with Where R^TenAnd R¹²Is as defined herein above;   Aryl (including the aryl portion of aralkyl)-is a compound having 6 to 15 carbon atoms And represents a carbocyclic group having at least one aromatic ring (e.g., aryl Is aryl, wherein the aryl group is optionally aryl, cycloal A fused, heteroaryl or heterocycloalkyl ring; and An aryl group and / or any available substitutable carbon atom in the fused ring And the nitrogen atom is optionally and independently below one, two, three or more May be substituted with halo, alkyl, aryl, cycloalkyl, cyano, -CF_Three, Oxy (= O), aryloxy, -OR^Ten, -OCF_Three, Heterocycloalkyl, f Teloaryl, -NR^TenR¹², -NHSO_TwoR^Ten, -SO_TwoNH_Two, -SO_TwoNHR^Ten, -SO_TwoR^Ten, -SOR^Ten, -SR^Ten, -NHSO_Two, -NO_Two, -CONR^TenR¹², -NR¹²COR^Ten, -COR^Ten, -OCOR^Ten, -OCO_TwoR^TenMa Or -COOR^Ten, Where R ^Ten And R¹²Is as defined herein above;   Aralkyl- is an alkyl group as defined above, wherein the alkyl moiety Represents one or more hydrogen atoms of which are substituted with one or more aryl groups; The aralkyl group may optionally and independently comprise one, two, three or more of the following: May be substituted with: halo, alkyl, aryl, cycloalkyl, cyano, -C F_Three, Oxy (= O), aryloxy, -OR^Ten, -0CF_Three, Heterocycloalkyl, hete Lower aryl, -NR^TenR¹², -NHSO_TwoR^Ten, -SO_TwoNH_Two, -SO_TwoNHR^Ten, -SO_TwoR^Ten, -SOR^Ten, -S R^Ten, -NHSO_Two, -NO_Two, -CONR^TenR¹², -NR¹²COR^Ten, -COR^Ten, -OCOR^Ten, -OCO_TwoR^TenAlso Is -COOR^Ten, Where R^TenAnd R¹²Is as defined herein above;   Aryloxy- represents an aryl group as defined above, wherein aryl is A covalent bond to an adjacent structural element via an oxygen atom (eg, phenoxy ), Wherein the aryl group is an aryl, cycloalkyl, heteroaryl, A aryl or heterocycloalkyl ring; and wherein the aryl A substitutable available carbon atom in the above-mentioned fused ring and / or And the nitrogen atom is optionally and independently below one, two, three or more May be substituted with halo, alkyl, aryl, cycloalkyl, cyano, -CF_Three, Oxy (= O), aryloxy, -OR^Ten, -OCF_Three, Heterocycloalkyl, f Teloaryl, -NR^TenR¹², -NHSO_TwoR^Ten, -SO_TwoNH_Two, -SO_TwoNHR^Ten, -SO_TwoR^Ten, -SOR^Ten, -SR^Ten, -NHSO_Two, -NO_Two, -CONR^TenR¹², -NR¹²COR^Ten, -COR^Ten, -OCOR^Ten, -OCO_TwoR^TenMa Or -COOR^Ten, Where R^TenAnd R¹²Is as defined herein above;   Cycloalkyl- is a branched or unbranched saturated carbocyclic ring containing from 3 to 20 carbon atoms. Represents an atom, preferably 3 to 7 carbon atoms; The alkyl groups are optionally and independently one, two, three or more of the following groups: Can be substituted with: halo, alkyl, aryl, cycloalkyl, cyano, -CF_Three, Oxy (= O), aryloxy, -OR^Ten, -OCF_Three, Heterocycloalkyl, heteroa Reel, -NR^TenR¹², -NHSO_TwoR^Ten, -SO_TwoNH_Two, -SO_TwoNHR^Ten, -SO_TwoR^Ten, -SOR^Ten, -SR^Ten , -NHSO_Two, -NO_Two, -CONR^TenR¹², -NR¹²COR^Ten, -COR^Ten, -OCOR^Ten, -OCO_TwoR^TenOr- COOR^Ten, Where R^TenAnd R¹²Is as defined herein above;   Cycloalkylalkyl- is an alkyl group as defined above, A One or more hydrogen atoms in the alkyl moiety are replaced by one or more cycloalkyl groups Wherein the cycloalkylalkyl groups are optionally and independently one Can be substituted with two, three or more of the following groups: halo, alkyl, ant , Cycloalkyl, cyano, -CF_Three, Oxy (= O), aryloxy, -OR^Ten,- OCF_Three, Heterocycloalkyl, heteroaryl, -NR^TenR¹², -NHSO_TwoR^Ten, -SO_TwoNH_Two , -SO_TwoNHR^Ten, -SO_TwoR^Ten, -SOR^Ten, -SR^Ten, -NHSO_Two, -NO_Two, -CONR^TenR¹², -NR¹²COR^{1 0} , -COR^Ten, -OCOR^Ten, -OCO_TwoR¹²Or -COOR^Ten, Where R^TenAnd R¹²Is the specification As defined above in the text;   Halo- represents fluoro, chloro, bromo and iodo;   Heteroalkyl- is a straight and branched carbon chain having 1-20 carbon atoms, preferably Preferably one containing from 1 to 6 carbon atoms and selected from -O-, -S- and -N- Represents three heteroatoms inserted between them; Any available and replaceable carbon and nitrogen atoms in the And may be substituted with one, two, three or more of the following groups: halo, a Alkyl, aryl, cycloalkyl, cyano, -CF_Three, Oxy (= O), aryloxy Si, -OR^Ten, -OCF_Three, Heterocycloalkyl, heteroaryl, -NR^TenR¹², -NHSO_Two R^Ten, -SO_TwoNH_Two, -SO_TwoNHR^Ten, -SO_TwoR^Ten, -SOR^Ten, -SR^Ten, -NHSO_Two, -NO_Two, -CONR^TenR^{1 Two} , -NR¹²COR^Ten, -COR^Ten, -OCOR^Ten, -OCO_TwoR^TenOr -COOR^Ten, Where R^TenAnd R^{1 Two} Is as defined herein above;   Heteroaryl is at least one heteroatom selected from O, S and N Wherein the heteroatom is inserted between carbocyclic ring structures, and Have a sufficient number of delocalized pi electrons to provide aromatic properties A bicyclic group contains 2 to 14 carbon atoms. Here, the heteroaryl group is Optionally one or more aryl, cycloalkyl, heteroaryl or heterocyclo An alkyl ring; and wherein the heteroaryl group and / or Any available substitutable carbon or nitrogen atom in the fused ring is optionally Independently can be substituted with one, two, three or more of the following groups: halo , Alkyl, aryl, cycloalkyl, cyano, -CF_Three, Oxy (= O), aryl Oxy, -OR^Ten, -OCF_Three, Heterocycloalkyl, heteroaryl, -NR^TenR¹², -N HSO_TwoR^Ten, -SO _Two NH_Two, -SO_TwoNHR^Ten, -SO_TwoR^Ten, -SOR^Ten, -SR^Ten, -NHSO_Two, -NO_Two, -CONR^TenR¹², -NR¹² COR^Ten, -COR^Ten, -OCOR^Ten, -OCO_TwoR^TenOr -COOR^Ten, Where R^TenAnd R¹²The book As defined above in the specification.   Representative heteroaryl groups include, for example, furanyl, imidazoyl, pyrimidini , Triazolyl, 2-, 3- or 4-pyridyl or 2-, 3- or 4-pyridyl N- Oxides, wherein the pyridyl N-oxide is: Can be represented as   Heteroarylalkyl- is an alkyl group as defined above, wherein 1 Represents one or more hydrogen atoms replaced with one or more heteroaryl groups; Here, the above-mentioned heteroarylalkyl group is arbitrarily and independently 1, 2, 3, Or more substituted with the following groups: halo, alkyl, aryl, cyclo Alkyl, cyano, -CF_Three, Oxy (= O), aryloxy, -OR^Ten, -OCF_Three, Hetero Cycloalkyl, heteroaryl, -NR^TenR¹², -NHSO_TwoR^Ten, -SO_TwoNH_Two, -SO_TwoNHR^Ten , -SO_TwoR^Ten, -SOR^Ten, -SR^Ten, -NHSO_Two, -NO_Two, -CONR^TenR¹², -NR¹²COR^Ten, -COR^Ten, -OCOR^Ten, -OCO_TwoR^TenOr -COOR^Ten, Where R^TenAnd R¹²Is defined above in this specification. As defined;   Heterocycloalkyl- is a saturated branched or unbranched carbocyclic ring having 3 It contains 15 carbon atoms, preferably 4 to 6 carbon atoms, and this carbocyclic ring has -O With 1 to 3 heteroatoms selected from-, -S- and -N- Represents optionally one or two unsaturated bonds which do not impart aromatic character to the ring And wherein any available carbon atom available in the ring and nitrogen The elementary atoms are optionally and independently of one, two, three or more of the following groups: May be substituted: halo, alkyl, aryl, cycloalkyl, cyano, -CF_Three, Oh Xy (= O), aryloxy, -OR^Ten, -OCF_Three, Heterocycloalkyl, heteroant , -NR^TenR¹², -NHSO_TwoR^Ten, -SO_TwoNH_Two, -SO_TwoNHR^Ten, -SO_TwoR^Ten, -SOR^Ten, -SR^Ten,- NHSO_Two, -NO_Two, -C ONR^TenR¹², -NR¹²COR^Ten, -COR^Ten, -OCOR^Ten, -OCO_TwoR^TenOr -COOR^Ten, Where R^Ten And R¹²Is as defined herein above. Representative heterocycloa Alkyl groups are 2- or 3-tetrahydrofuranyl, 2- or 3-tetrahydrothienyl 1, 2-, 3- or 4-piperidinyl, 2- or 3-pyrrolidinyl, 1-, 2- or 3-piperidinyl, 2- or 4-dioxanyl, morpholinyl, Where R^TenIs defined herein above and t is 0, 1 or 2 It is.   Heterocycloalkylalkyl- is defined as above. An alkyl group as defined above, wherein one or more hydrogen atoms is one or more heterocycloalkyl Represents a group that is substituted with a kill group; this ring optionally has no aromatic character to the ring May contain one or two unsaturated bonds; wherein the heterocycloalkyl The kill groups are optionally and independently substituted by one, two, three or more of the following groups: Can be substituted: halo, alkyl, aryl, cycloalkyl, cyano, -CF_Three, Oki Si (= O), aryloxy, -OR^Ten, -OCF_Three, Heterocycloalkyl, heteroaryl , -NR^TenR¹², -NHSO_TwoR^Ten, -SO_TwoNH_Two, -SO_TwoNHR^Ten, -SO_TwoR^Ten, -SOR^Ten, -SR^Ten, -NH SO_Two, -NO_Two, -CONR^TenR¹², -NR¹²COR^Ten, -COR^Ten, -OCOR^Ten, -OCO_TwoR^TenOr -COOR^{1 0} , Where R^TenAnd R¹²Is as defined herein above.   The following solvents and reagents are referred to herein by the abbreviations shown below. : Tetrahydrofuran (THF); ethanol (EtOH); methanol (MeOH); acetic acid ( HOAc or AcOH); ethyl acetate (EtOAc); N, N-dimethylformamide (DMF); Fluoroacetic acid (TFA); trifluoroacetic anhydride (TFAA); 1-hydroxybenzotria Sol (HOBT); m-chloroperbenzoic acid (MCPBA); triethylamine (Et_ThreeN); Ruether (Et_TwoO); Ethyl chloroformate (ClCO_TwoEt); lithium diisopropylamide (LDA) and 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydroc Lorido (EDCl or DEC).   Substituent R¹, R^Two, R^ThreeAnd R^FourReferences to positions are based on the numbered ring structures below. Zu K:   Certain compounds of the present invention may have different stereoisomers (e.g., enantiomers, diastereomers). Stereoisomers and atropisomers). The present invention All pure forms and mixtures of stereoisomers (including racemic mixtures) Intend. For example, the carbon atom at position C-11 can be in the S or R configuration.   Certain tricyclic compounds, such as carboxyl groups or phenolic hydroxy Compounds having a hydroxyl group are acidic in nature. These compounds are pharmaceutically acceptable Salt may be formed. Examples of such salts are sodium, potassium, calcium , Aluminum, gold and silver salts may be included. Also pharmaceutically acceptable Amines, such as ammonia, alkylamines, hydroxyalkylamines, Salts formed with N-methylglucamine and the like are also contemplated.   Certain basic tricyclic compounds also form pharmaceutically acceptable salts, such as acid addition salts. To achieve. For example, a pyrido nitrogen atom can form a salt with a strong acid, while an amino group Compounds having a basic substituent such as are also capable of forming salts with weak acids. Suitable for salt formation Examples of such acids are hydrochloric, sulfuric, phosphoric, acetic, citric, oxalic, malonic, and Lylic acid, malic acid, fumaric acid, succinic acid, ascorbic acid, maleic acid, meta Sulfonic acids and other inorganic and carboxylic acids well known to those skilled in the art. Salt is The free base form is contacted with a sufficient amount of the desired acid to produce the salt in the conventional manner. And is prepared by The free base form can be prepared by converting the salt to a suitable dilute aqueous base solution, e.g., Na Treat with a dilute aqueous solution of OH, potassium carbonate, ammonia, and sodium bicarbonate. Can be regenerated. The free base form has certain physical properties, such as polar Some differences in solubility in the medium from their corresponding salt forms, A salt is otherwise equivalent to its corresponding free base form for the purposes of the present invention. You.   All such acid and base salts are pharmaceutically acceptable within the scope of the present invention. Salts and salts of acids and bases are all intended for the purposes of the present invention. And is considered equivalent to the free form of the corresponding compound.   Compounds of the invention can be prepared according to Scheme I, II or III below:                                 Scheme IWhere A, R¹, R^Two, R^Three, R^Four, R^Five, R⁶, R⁷, R⁸, Y, solid and dotted lines are at the top of this specification. As defined above.   In Scheme I, compound 1.0 (where p12 has the formula Z = O, wherein R is as defined herein above) is a compound (11, 11.3), ( 19, 19.3) or (20, 20.3) in an aprotic solvent at a temperature ranging from about 0 ° C to 20 ° C. About 1 to 2 per mole of the compound (11, 11.3), (19, 19.3) or (20, 20.3). Using a molar carboxylic acid (30.0), the formula RCOOH (30.0), where R is as defined herein above (As defined)).   Alternatively, compound 1.0 can be used with Y = SO_TwoR) is the compound (11, 11.3), (19, 19.3) or (20, 20.3) with a solvent (e.g., pyridine) and a base (e.g., 4-dimethylamino) Compound (11, 11.3), (19, 19.3) or (20 20.3) Using 1 to 3 moles of sulfonyl chloride (20.7) per mole, formula RSO_Two C l (20.7) (where R is as defined above) with the sulfonyl chloride Can be prepared by The amount of the base is the compound (11, 11.3), (19, 19.3) or (20, 20.3) The amount may range from a catalytic amount to about 1.5 mol per 1 mol.   Compound (1.0) (where A is N-O (ie, N-oxide)) is compound (1.0) (this Wherein A is N) in an aprotic solvent (e.g., methylene chloride) at about 0 ° C to 25 ° C. At a temperature in the range of ° C, 1 to 2 equivalents of MCPBA per mole of compound (1.0) It can be prepared by treating with tachloroperbenzoic acid (MCPBA).   The sulfur-containing compound of formula (1.0) (where Z = S) converts compound (1.0) (where Z = O) to a suitable In an aprotic solvent (e.g., toluene) at about 100 ° C., a sulfurizing reagent (e.g., Lawe sson's reagent) to give the thioamide (1.0). Another sulfurizing reagent is Bis- (1,5-cyclooctanediarylboryl) sulfide in xane at -78 ° C; Or pentasulfide using ultrasonic waves at 40 ° C in toluene, reflux temperature or THF Phosphorus (P_TwoS_Five, Formula P_FourS_TenBis- (9-bora) in heptane at reflux temperature Bicyclo [3.3.1] nonane) sulfide ((9-BBN)_TwoS).   The compound of formula (1.0) can be prepared by a conventional method (for example, reaction mixture from water using an organic solvent). Extraction, evaporation of organic solvents, followed by silica gel or other suitable The reaction mixture using chromatography Can be isolated from Alternatively, compound (1.0) is a water-miscible solvent (e.g., methanol ), The methanol solution is added to water, the compound precipitates, and The precipitate is isolated by filtration or centrifugation.   Compounds of Formula 1.0, 1.0a and 1.0b in Scheme I, where X is CH or N , May be racemic. These racemates were prepared using a Chiralpak column (Daicel Chemica l Ind.) to separate them into their (+) and (-) enantiomers. Can be Alternatively, the (+)-isomer of a compound of formula (19, 19.3, 20, 20.3), wherein X is C H) is enantiomerically enriched using a process involving an enzyme-catalyzed transesterification reaction. It can be prepared with selectivity. Preferably, a racemic compound of the formula (19, 19.3, 20, 20.3) ( Where X is C, there is a double bond, and X^ThreeIs not H) is an enzyme (for example, For example, Toyobo LIP-300) and acylating agent (for example, trifluoroethylisobuty Rate); and the resulting (+)-amide is, for example, an acid (eg, , H_TwoSO_Four) And the corresponding optically enriched (+)-isomer ( Where X is CH, and R^ThreeIs not H). Alternatively, the formula (5.0, 6.0 And 10.9), wherein X is C, a double bond is present, and R^ThreeIs Is not the first, the corresponding racemic compound of formula (19, 19.3, 20, 20.3) (where X is CH) and then the above enzyme (Toyobo LIP-300) and acyl Treatment with an agent yields (+)-amide, which is hydrolyzed to optically enrich The (+)-isomer is obtained.   The compounds of the present invention and their preparation starting materials are illustrated by the following examples. They should not be construed as limiting the scope of the present disclosure. Example 1. 1- (3-Bromo-6,11-dihydro-8,10-dimethoxy-5H-benzo [5,6] cyclo Hepta [1,2-b] pyridin-11-yl) -4- (4-pyridinylacetyl) piperazine N4-O Oxide Example 1, Step 1. To a solution of diisopropylamine (2.28 ml) in THF (10 ml) at -78 ° C under a nitrogen atmosphere 2.5 M butyllithium in hexane (6.5 ml) is added dropwise. After stirring the mixture for 10 minutes A solution of compound A (2.0 g) in THF (10 ml) is added. The resulting purple reaction mixture is Stir for 10 minutes, then 3,5-dimethoxybenzyl chloride (2.07 g) in THF (10 ml) Add the solution. The reaction mixture is allowed to stand at -78 ° C for 15 minutes, at 0 ° C for 1 hour, Stir for 1 hour. Dilute the pale magenta reaction with ice / water and add Extract with The crude product obtained by evaporation of the organic extract is And flash chromatography on silica gel (200 ml). I can. The title compound B was eluted with 10% ethyl acetate-hexane to give an oil (2.3 g, yield 75%): Ms m / e 421, 423 (MH). Example 1, Step 2. Phosphorus oxychloride (12 ml) is added dropwise to a solution of B (2.3 g) in toluene (20 ml). mixture Heat the thing in an oil bath (115 ° C.). After 1 hour, add 1 drop of DMF and allow the solution to run for another 4 hours Heat for a while and then cool to room temperature, then evaporate under reduced pressure. Residue oy Dissolved in ethyl acetate (50 ml) and ice / water (20 ml) and the aqueous phase becomes basic Stir with addition of 10% sodium hydroxide until stirring. Extract the basic solution with ethyl acetate Drain, combine the organic extracts, wash with brine, dry and evaporate You. The crude product is dissolved in ethyl acetate and filtered through a silica gel plug You. The colorless filtrate is concentrated under reduced pressure and slowly diluted with hexane to give the title Compound C is obtained as a crystalline solid (1.62 g, 85%): mp 106-107 ° C .; Ms m / e 347, 34 9 (MH). Example 1, Step 3. Aluminum chloride (1.0 g) was stirred well with C (1.16 g) in dichloroethane (100 ml). To the solution over a period of 10 minutes. Stir the pale yellow solution at room temperature for 1 hour, then Work up by adding ice / water and 10% sodium hydroxide to pH 10. The mixture is extracted several times with dichloromethane and the combined extracts are evaporated. The crude product obtained by the chromatography is flash chromatographed on silica gel (100 ml). Put a fee. Elution with 10% methanol-2% ammonium hydroxide-ethyl acetate To give the intermediate imine D (0.89 g). Example 1, Step 3a. Dissolve the product D from step 3 in 2N hydrochloric acid. Heat the solution in an oil bath (120 ° C) for 1.5 hours Cool, basify with 10% sodium hydroxide, and add dichloromethane (4 × 50 m l part). The crude product was filtered through a silica gel plug and the combined extracts were filtered. Obtained by concentrating the effluent; evaporating the filtrate to give the title ketone E in amorphous form. Obtained as a crystalline solid (0.81 g, 91%). Ms m / e 348, 350 (MH)⁺. Example 1, step 4. A solution of sodium borohydride (0.09 g) in ketone E (0.8 g) in methanol (20 ml) At 0 ° C. while stirring in small portions. The reaction was then stirred at room temperature for 1 hour. , Acidify with acetic acid-water and evaporate most of the solvent under reduced pressure Remove. The residue mixture is basified with 10% sodium hydroxide to pH 10, followed by Extract with ethyl acetate (4 × 50 ml). Pass the combined extracts through a plug of silica gel And the filtrate was evaporated to give the product F as a resin puff (0.79 g). You. MS m / e 350, 352 (MH). Example 1, steps 5 and 6. Phosphorus oxychloride (2.0 ml) was added under nitrogen to product F (0.45) in dichloromethane (5 ml). Add dropwise to the solution of g). The reaction mixture was stirred at room temperature for 1 hour and then at 45 ° C. under reduced pressure To evaporate. The dark residue gum is azeotroped with toluene (2 × 10 ml) and then pipetted. Dissolve in acetonitrile (15 ml) containing azine (0.5 g). Reaction mixture at room temperature Stir for 2 hours and evaporate under reduced pressure, dilute with water, followed by 10% hydroxylation Work up by adding sodium (5 ml). The product was treated with dichloromethane (5 × 20 ml) and flash chromatographed on silica gel . The product was eluted with 10% methanol-2% ammonium hydroxide-dichloromethane G Obtained as a tan puff (0.22 g). Ms m / e 418, 420 (MH). Example 1, Step 7. Product G (0.2 g) in dimethylformamide (3.0 ml), 1-hydroxybenzotriazo (0.13 g) and 4-pyridylacetic acid N-oxide (0.15 g) were cooled in ice, And N- (3-dimethylaminopropyl) -N'-ethylcarbodiimide hydrochloride (0.18 g) Followed by treatment with N-methylmorpholine (0.3 ml). Warm the mixture to room temperature overnight And then evaporated under reduced pressure. Stir the residual gum with 10% sodium carbonate Stir and extract with dichloroethane. Obtained by evaporation of the extract The crude product obtained is subjected to flash chromatography on silica gel (30 ml). . The product was eluted with 5% methanol-2% ammonium hydroxide-dichloromethane. H is obtained as a light 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] cyclo Hepta [1,2-b] pyridin-11-yl) -1- (4-pyridinylacetyl) piperidine N1-oxo SidExample 2, Step 1.   Using the same reaction conditions as described in Step 1 of Example 1, reagent A (5-methyl-t- Butylamide) is first treated with diisopropylamine and butyllithium. And then with benzyl bromide 2 to give compound B. Example 2, step 2.   Using the same reaction conditions as described in Step 2 of Example 1, the crude product B Reaction with phosphorous oxychloride to give compound C: mp 188 190190 ° C., MS: m / e 301 (MH). Example 2, step 3.  The nitrile compound C (1.65 g) was added to cold (0 ° C) triflic acid (triflic acid) while stirring.  acid) (30 ml). Store solution at room temperature overnight, dilute with ice / water (50 ml), And heat in an oil bath (120 ° C.) for 4 hours. The reaction mixture was then cooled and 50% water Neutralize with sodium oxide and extract the crude product with dichloromethane (6 × 50 ml) And flash chromatographed on silica gel (300 ml). 1: 1 acetic acid Elution with ethyl-hexane followed by crystallization from ethyl acetate-hexane Compound D (1.54 g) is obtained: MS m / e 302 (MH). Example 2, step 4.   E (0.8 M, 13.2 ml) in THF was stirred under nitrogen while D (1.6 g) in THF was cooled. (Ice bath) Add to the solution (30 ml). Stir reaction for 30 minutes then dilute with ice / water And then extract with dichloromethane (3 × 50 ml). Evaporation of extract The crude product obtained by flash chromatography on silica gel (100 ml) Hang on. Clean the column by first eluting with 10% methanol-dichloromethane. Removed; 10% methanol-3% ammonium hydroxide )-Elution with dichloromethane afforded compound F (1.6 g) as an amorphous solid : MS m / e 401 (MH). Example 2, step 5.  A solution of ethyl chloroformate (1.5 ml) in toluene (20 ml) was added while stirring. Drops of compound F (1.5 g) and triethylamine (0.9 ml) were added dropwise for 10 minutes. Solution (30 ml) and heat at 85 ° C. in an oil bath. Heat reaction for an additional 45 minutes And then cooled and stirred with ice water, then washed with 10% sodium carbonate Cleanse. The crude product is isolated by extraction with ethyl acetate and silica gel To give compound G. MS m / e 459 (MH). Example 2, step 6.   A solution of compound G (1.2 g) in ethanol (40 ml) and 10% palladium-carbon Is hydrogenated in a Parr flask at 50 psi for 6 hours. The catalyst is removed by filtration And the filtrate is evaporated down. The residue is dissolved in ethyl acetate and the solution is Wash with 5% sodium carbonate. The organic layer is evaporated to give compound H. Example 2, step 7.   Compound H (0.58 g) was obtained by combining with polyphosphoric acid (PPA) (1.5 ml). The paste obtained is heated in an oil bath at 100 ° C. for 30 minutes. Cool the dark brown liquid, Then, the mixture is stirred with ice water (10 ml), and the resulting solution is salted with 50% sodium hydroxide. Basify and then extract with dichloromethane (5 × 30 ml). Extract silica gel And then elute with 10% methanol-dichloromethane. The combined filtrate was evaporated and chromatographed on silica gel (50 ml). Multiply. Elution with 5% methanol-dichloromethane gave compound I yellow Obtained as a brown solid. MS m / e 407 (MH). Example 2, step 8.   A solution of compound I (0.5 g) in 4N hydrochloric acid (20 ml) was added in an oil bath (130 ° C.) for 14 hours. heat. The reaction was cooled and basified to pH 8 with 50% sodium hydroxide, Then extract with dichloromethane. Dry the extract over sodium sulfate, and Evaporate to dryness to give compound J. Example 2, step 9.   Diisobutylaluminum hydride (DIBAL H) (4.8 ml of a 1 M solution in toluene) A solution of compound J (0.45 g) in dry toluene (10 ml) was stirred at 15 ° C. And add it drop by drop. The reaction mixture was stirred at room temperature for 2 hours, then water (10 ml) and And quenched by the addition of 10% sodium hydroxide. Dichlorometa mixture And the crude product is chromatographed on silica gel (30 ml). Elution with 10% methanol-2% ammonium hydroxide-dichloromethane To give compound J: MS m / e 337 (MH). Example 2, step 10.   Product J (0.2 g), 1-hydroxybenzotriazole (0.13 g) and 4-pyri Cool a solution of N-oxide of disilacetic acid (0.15 g) in dimethylformamide (3.0 ml) in ice And N- (3-dimethylaminopropyl) -N'-ethylcarbodiimide hydrochloride (0. 18 g) and then treated with N-methylmorpholine (0.3 ml). Mixture overnight to room temperature Warm and then evaporate under reduced pressure. Residual gum with 10% sodium carbonate Stir together and extract with dichloromethane. For evaporation of extracts The crude product thus obtained was subjected to flash chromatography on silica gel (30 ml). Multiply. Dissolution using 5% methanol-2% ammonium hydroxide-dichloromethane The product K is obtained by light tan foam. MS 471 (CI) 472. Embodiment 3 FIG. (+,-)-4- (3-bromo-10-methoxy-8-methyl-6,11-dihydro-5H-benzo [5,6] cyclohepta [1,2-b] pyridin-11-yl) -1- (4-pyridinylacetyl) piperi Zin N1-oxide Example 3, steps 1 and 2.  Except for replacing reactant 2 with reactant 2 of example 1, steps 1 and 2 of example 1 The intermediate compounds B and C are obtained according to the procedures described in paragraphs 2 and 3. Example 3, step 3.   A 0.5 M solution of 1-methyl-4-piperidylmagnesium chloride in THF (28 ml) was To a solution of compound C (4.8 g) in THF (60 ml) is added dropwise under argon. The dark reactant was heated at 55 ° C. for 15 minutes, cooled in an ice bath, quenched with water, and And extract with ethyl acetate (4 × 50 ml). Dry the combined extracts over sodium sulfate Dry and evaporate under reduced pressure. The resulting intermediate was combined with 4N HCl (40 ml) and And methanol (20 ml) and the solution is heated on a steam bath for 1 hour, Cool in a bath and basify with 10% NaOH, then extract with ethyl acetate. Lottery Evaporate the eluate and flash chromatograph on silica gel . Elution with 10% ethyl acetate-hexane gives compound D (2.7 g): MS m / e 431 (MH). Example 3, step 4.   Triflic acid (55 ml) is added to compound D (2.9 g) with stirring and dark Store the syrup solution at 4 ° C. overnight. Later by pouring the reaction mixture onto ice Work up, basify with 50% NaOH, then extract with dichloromethane (3 × 50 ml) . The extract was evaporated under reduced pressure and the crude product was flashed on silica gel Chromatograph. Elution with 5% methanol-dichloromethane To give compound E (1.37 g); MS m / e 413 (MH). Example 3, step 5.   Following the procedure described in Step 5 of Example 2 yields intermediate compound F. Example 3, steps 6 and 7.  Following the procedures described in Steps 8 and 9 of Example 2, intermediate compounds G and H obtain. Heat i-propanol / hexane (0.2% dea) containing EtOH on a steam bath. However, by dissolving Compound H (0.580 g) in this, the (+) and (-) Split into enantiomers. The solution was subjected to preparative HPLC chiralpac AD, a 5 × 50 cm column ( Daicel Chemical Ind.) And i-propanol / hex at a flow rate of 20 ml / min. Elute with sun (0.2% DEA) and collect 500 ml fractions. After eluting the first peak, Change solvent to 25 / 75i-propanol / hexane (0.2% DEA) at a flow rate of 40 ml / min. You. The (+) enantiomer (0.265 g) is obtained in fraction 2. At 20.5 ° C (5.2mg / 2ml E Optical rotation at a concentration of (tOH) = +2.69. The (-) enantiomer (0.2280 g) was added to fractions 7 to Obtain from 8. Both the (+) and (-) enantiomers were chiralpac AD 0.46 cm The purity is determined by analytical HPLC on a × 25 cm column. Example 3, step 8.   Following the procedure described in Step 7 of Example 1 provided the desired racemic form of title compound I You. Embodiment 4 FIG. (+,-)-4- (6,11-dihydro-10-methoxy-8-methyl-5H-benzo [5,6] cyclo Lobepta [1,2-b] pyridin-11-yl) -1- (4-pyridinylacetyl) piperidine N-1 Oxide   Except for replacing reactant 2 with reactant 2 of example 2, steps 1 to 2 of example 2 According to the procedure described in 9 above, the intermediate compound AK and the desired title compound L Get semi-form. Embodiment 5 FIG. (+,-)-4- (7-Chloro-5,6-dihydro-8-methyl-10-methoxy-11H-benzo [5,6] cyclohepta [1,2-b] pyridine-11-ylidene) -1- (4-pyridinylacetyl) pi Peridine N1-oxide   Replacing 3-methyl-2-chloro-5-methoxybenzyl chloride with reagent 2 and 3- Methyl-2-t-butylcarboxamide pyridine was replaced with compound A from step 1 of Example 3. By substituting as well as steps 1 to 8 of example 3 but step 7 of example 3. Is omitted with DIBALH to give the title compound. Embodiment 6 FIG. (+,-)-4- (3-bromo-10-hydroxy-8-methyl-5,6-dihydro-11H-ben Zo [5,6] cyclohepta [1,2-b] pyridine-11-ylidene) -1- (4-pyridinylacetyl) Piperidine N1-oxide   Starting with 5-bromo-3-methyl-2-t-butylcarboxamide pyridine And according to steps 1 to 6 of Example 3, the following compound A is obtained.   Compound A (500 mg, 1.34 mmol) is stirred in triflic acid (3 ml) at 80 ° C. for 2 hours And then cooled to room temperature. Dilute the reaction mixture with ice (20 g) and add 10% Basify with thorium, then CH_TwoCl_Two(2 × 60 ml). Separate the organic layer , MgSO_FourDried over, filtered and the solvent was evaporated to give an oil which was Elution with 7% (v / v) methanol-methylene chloride containing 2% ammonium hydroxide Chromatography on silica gel gives compound B as a white solid. Example 1 By substituting an equivalent amount of Compound B with Compound G using the procedure of Step 7 of To give the title compound. FABS 519 MH. Example 7. 4- (5,6-Dihydro-10-methoxy-3,8-dimethyl-11H-benzo [5,6] cyclo Hepta [1,2-b] pyridine-11-ylidene) -1- (4-pyridinylacetyl) piperidine N1- Oxide   Replacing 3-methyl-5-methoxybenzyl chloride with reagent 2 and 3,5-dimethyl Substitute the compound 2-A-t-butylcarboxamide pyridine with compound A from step 1 of Example 1. And according to steps 1 to 7 of Example 1 to give the title compound. Embodiment 8 FIG. (+,-)-4- (3-Bromo-10-methoxy-8-methyl-5,6-dihydro-11H-benzo [5,6] cyclohepta [1,2-b] pyridine-11-ylidene) -1- (4-pyridinylacetyl) pi Peridine N1-oxide   By starting with intermediate G of step 6 of example 3 and step 1 of example 1 The title compound is obtained according to ７7. Embodiment 9 FIG. (+,-)-4- (3-bromo-10-hydroxy-8-methyl-5,6-dihydro-11H-ben Zo [5,6] cyclohepta [1,2-b] pyridin-11-yl) -1- (4-pyridinylacetyl) pipe Lysine N1-oxide   Except that the procedure of Step 9 of Example 2 is performed before the procedure of Step 7 of Example 1, According to the procedure of Example 6, the title compound is obtained. Embodiment 10 FIG. (+,-)-1- (3-bromo-10-methoxy-8-methyl-6,11-dihydro-5H-benzo [5,6] cyclohepta [1,2-b] pyridin-11-yl) -4- (4-pyridinylacetyl) pipera Gin N4-oxide   Replace 3-methyl-5-methoxybenzyl chloride with reagent 2 from step 1 of Example 1. And according to steps 1 to 7 of Example 1 to give the title compound. Example 14 FIG. (+,-)-1- (3-Bromo-7-methyl-6,11-dihydro-5H-benzo [5,6] cyclo Hepta [1,2-b] pyridin-11-yl) -4- (4-pyridinylacetyl) piperazine N4-oxo Sid   By substituting 2-methylbenzyl chloride with reagent 2 from step 1 of Example 1, And according to steps 1 to 7 of Example 1 (excluding steps 3 and 3a), and Substituting the procedure of Step 3 of Example 2 for Steps 3 and 3a of Example 1 Thus, the title compound is obtained. Example 15 FIG. (+,-)-1- (3-Bromo-7,10-dimethyl-6,11-dihydro-5H-benzo [5,6 [ Chlohepta [1,2-b] pyridin-11-yl) -4- (4-pyridinylacetyl) piperazine N4- Oxide   Replacing 2,5-dimethylbenzyl chloride with reagent 2 from step 1 of Example 1 Thus, and according to steps 1 to 7 of Example 1 (excluding steps 3 and 3a), In addition, the procedure of Step 3 of Example 2 can be substituted for Steps 3 and 3a of Example 1. Affords the title compound. Example 16 FIG. (+,-)-1- (3-bromo-8-methyl-6,11-dihydro-5H-benzo [5,6] cyclo Hepta [1,2-b] pyridin-11-yl) -4- (4-pyridinylacetyl) piperazine N4-oxo Sid   By substituting 3-methylbenzyl chloride with reagent 2 from step 1 of Example 1, And according to steps 1 to 7 of Example 1 (excluding steps 3 and 3a), and Substituting the procedure of Step 3 of Example 2 for Steps 3 and 3a of Example 1 Thus, the title compound is obtained. Example 17 FIG. (+,-)-1- (3-bromo-6,11-dihydro-8-methoxy-5H-benzo [5,6] cyclo Rohepta [1,2-b] pyridin-11-yl) -4- (4-pyridinylacetyl) piperazine N4-O Oxide   By substituting 3-methoxybenzyl chloride with reagent 2 from step 1 of Example 1 And according to steps 1 to 7 of Example 1 (excluding steps 3 and 3a) Substituting the procedure of Step 3 of Example 2 for Steps 3 and 3a of Example 1 Gives the title compound. Example 18 FIG. (+,-)-1- (3-bromo-6,11-dihydro-8,10-dimethyl-5H-benzo [5,6] cy Chlohepta [1,2-b] pyridin-11-yl) -4- (4-pyridinylacetyl) piperazine N4- Oxide   Replacing 3,5-dimethylbenzyl bromide with reagent 2 from step 1 of Example 1 Thus, and according to steps 1 to 7 of Example 1 (excluding steps 3 and 3a), In addition, the procedure of Step 3 of Example 2 can be substituted for Steps 3 and 3a of Example 1. Affords the title compound. Example 19 FIG. (-)-1- (3-bromo-10-methoxy-8-methyl-6,11-dihydro-5H-benzo [5 , 6] Cyclohepta [1,2-b] pyridin-11-yl) -4- (4-pyridinylacetyl) piperazi N4-oxide, (-) enantiomer   The racemic title compound of Example 10 (67 mg) was prepared in 50 / 50i- Dissolve in propanol / hexanes and separate the solution by preparative high performance liquid chromatography. Column, chiralpak AD 5 × 50cm column (Daicel Chemical Ind.) . 2 using ethanol (EtOH) / hexane (containing 0.2% diethylamine or DEA) Elution at 0 ml / min for 2 hours, then eluted layer with 7% EtOH / hexane (0.2% DEA) And increase the flow rate to 40 ml / min (collect 500 ml fractions) to obtain fractions 10-12 To give 30.9 mg of the title compound of Example 19: [α]_D ^{twenty three}-18.8 ° (c. 0.32, ethanol M) = 111-116 ° C. Embodiment 20 FIG. (+)-1- (3-bromo-10-methoxy-8-methyl-6,11-dihydro-5H-benzo [ 5,6] Cyclohepta [1,2-b] pyridin-11-yl) -4- (4-pyridinylacetyl) pipera Gin N4-oxide, (+) enantiomer   The title compound was prepared according to the preparative high performance liquid chromatography procedure described in Example 19. To give: Fractions 14-16, title compound of Example 20: [α]_D ^{twenty three}+ 19.6 ° (c. 0.28, eta ), Melting point = 110-117 ° C. Example 21. (+,-)-1- (3,10-dibromo-6,11-dihydro-8-methyl-5H-benzo [5,6] cy Chlohepta [1,2-b] pyridin-11-yl) -4- (4-pyridinylacetyl) piperazine N4- Oxide   Replace 3-methyl-5-bromobenzyl bromide with reagent 2 from step 1 of example 1 And according to steps 1 to 7 of Example 1 (excluding steps 3 and 3a) , And the procedure of Step 3 of Example 2 is used instead of Steps 3 and 3a of Example 1. To give the title compound. Example 22. (+,-)-1- (3,8-dibromo-6,11-dihydro-10-methyl-5H-benzo [5,6] cy Chlohepta [1,2-b] pyridin-11-yl) -4- (4-pyridinylacetyl) piperazine N4- Oxide   Replace 3-bromo-5-methyl-benzyl bromide with reagent 2 from step 1 of Example 1 And according to steps 1 to 7 of Example 1 (excluding steps 3 and 3a) , And the procedure of Step 3 of Example 2 was repeated in place of Steps 3 and 3a of Example 1. By substituting by heating at 60 ° C. for 4 hours with furic acid, the title Obtain the compound. Embodiment 23 FIG. (+,-)-4- [6,11-dihydro-3- (1-hydroxy-1-methylethyl) -10-metho Xy-8-methyl-5H-benzo [5,6] cyclohepta [1,2-b] pyridin-11-yl] -1- (4-pi (Lidinylacetyl) piperidine N1-oxide Step 1:  Nitrogen of compound A (0.4 g) from step 1 of Example 27 in tetrahydrofuran (8 ml) The blanketed solution was cooled to -78 ° C and then hexane (0.4 ml Treat with a 2.5M solution of butyllithium in a). After stirring for 5 minutes, acetone (0. 4 ml) and after 5 minutes the reaction mixture is evaporated under reduced pressure to remove the oil. This is flash chromatographed on silica gel (50 ml). 3% meta Elution with knol-dichloromethane gives B as a white powder (0.13 g). MS (CI) 479. Step 2:   Purifying the product B from Step 1 according to the procedure described in Steps 3 and 4 of Example 27 To intermediate C. Yellow-brown powder, MS (CI) 381. Step 3:   The product C from Step 2 was prepared by following the procedure described in Step 1 of Example 1. To the title compound D. White powder, MS (CI) 516. 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) piperidi N1-oxide, (+) enantiomer   Replace 3-methyl-5-methoxy-benzyl bromide with reagent 2 from step 1 of Example 3. And according to steps 1 to 8 of example 3 and the splitting of step 7 The title compound is obtained by using the (+) enantiomer H. 5.7 at 22 ° C Optical rotation at a concentration of mg / 2 ml ethanol: + 31.9 ° (sodium D line). Example 25. (-)-4- (3-Bromo-10-methoxy-8-methyl-6,11-dihydro-5H-benzo [5 , 6] Cyclohepta [1,2-b] pyridin-11-yl) -4- (4-pyridinylacetyl) piperidi N1-oxide, (-) enantiomer   Replace 3-methyl-5-methoxy-benzyl bromide with reagent 2 from step 1 of Example 3. And according to steps 1 to 8 of example 3 and the splitting of step 7 The title compound is obtained by using the (-) enantiomer H. At 22.4 ° C Optical rotation at a concentration of 6.2 mg / 2 ml ethanol: -31.6 ° (sodium D line). Example 26. (+,-)-1- (3-bromo-8-methoxy-10-methyl-6,11-dihydro-5H-benzo [5,6] cyclohepta [1,2-b] pyridin-11-yl) -4- (4-pyridinylacetyl) pipera Gin N4-oxide   Replace 3-methoxy-5-methyl-benzyl bromide with reagent 2 from step 1 of Example 1 And according to steps 1 to 7 of Example 1 (excluding steps 3 and 3a) And the procedure of Step 3 of Example 2 is substituted for Steps 3 and 3a of Example 1. To give the title compound. 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 Step 1. 1,1-dimethylethyl-4- (3-bromo-5,6-dihydro-10-methoxy-8-methyl -11H-benzo [5,6] cyclohepta [1,2-b] pyridine-11-ylidene) -1-piperidine Ruboxylate   Di-tert-butyl dicarbonate (2.0 g, 9.16 mmol) in methylene chloride (5 ml) Was synthesized with Intermediate Compound G of Step 3 of Example 3 (1.0 g, 2.51 g) in methylene chloride (15 ml). mmol) at 20 ° C. and then stirred at room temperature for 1 hour. Evaporate the solvent And elute the residual oil with silica eluting with 15% (v / v) ethyl acetate-hexane. Chromatograph the gel to obtain the product as a white solid (1.1 g, 92% yield) ). MS (CI) 499, MH. Step 2. 1,1-dimethylethyl-4- (3-ethenyl-5,6-dihydro-10-methoxy-8-methyl 11H-benzo [5,6] cyclohepta [1,2-b] pyridine-11-ylidene) -1-piperidine Carboxylate.   Tributylvinyltin (3 ml, 10.26 mmol) was added from step 1 in toluene (6 ml). Title compound (950 mg, 1.90 mmol), lithium chloride (1.0 g, 23.6 mmol), tris Benzylideneacetone) dipalladium (180mg) and tri-2-furoylfo Add to the solution of sphine (90 mg, 0.38 mmol) at room temperature, then stir at 100 ° C. overnight. Mix. The reaction was cooled, extracted with ethyl acetate (100ml), washed with water (50ml) , Dried over magnesium sulfate, filtered and the solvent was evaporated to give an oil. Which was chromatographed on silica gel eluting with 40% (v / v) ethyl acetate-hexane. Graph to give 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-benzo [5,6] Cyclohepta [1,2-b] pyridine-11-ylidene) -1-piperidine   A 20% solution of trifluoroacetic acid in methylene chloride (10 ml) was added to the title compound of Step 2. (400 mg, 0.89 mmol) at room temperature and then stirred at 20 ° C. for 1/2 hour. Add water (20 ml), methylene chloride (20 ml), and 1N NaOH (3 ml), and add Layers separated and MgSO_FourDried over, filtered and the solvent was evaporated to a solid (305 mg, 98% yield). MS (CI) 347, MH. Step 4. 3-Ethenyl-6,11-dihydro-10-methoxy-8-methyl-11- (4-piperidinyl ) -5H-Benzo [5,6] cyclohepta [1,2-b] pyridine   A 1 M solution of DIBAL in toluene (3 ml, 3 mmol) was added to the title of step 3 in toluene (2 ml) A solution of the compound (310 mg, 0.89 mmol) is added dropwise at 20 ° C. and then stirred for 45 minutes. Mix. Add water (15 ml), EtOAc (30 ml), and 1N NaOH (5 ml). Organic The layers were separated and MgSO_FourDried over, filtered and the solvent was evaporated to an oil Which is converted to 2% NH_FourSilica gel eluted with 10% methanol-methylene chloride containing OH The product is obtained as a white solid. (200mg, 65% yield ), MS (FABS) 349, MH. 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.   EDCl (50 mg, 0.26 mmol), 1-hydroxybenzotriazole monohydrate (40 mg, 0.2 9 mmol) and 4-methylmorpholine (0.5 ml, 4.5 mmol) Compound (50 mg, 0.14 mmol) and 4-pyridyl in anhydrous (anhydrous, 2 ml) To a solution of n-oxide-acetic acid (50 mg, 0.326 mmol) at 0 ° C. And stir overnight. The solvent was evaporated and the residue was methylene chloride (60 ml) And water (25 ml). Separate the organic layer and wash with saturated sodium carbonate (2 × 15 ml), MgSO_FourDried over, filtered and the solvent was evaporated, Oil was obtained, which was 2% NH_Four10% MeOH-MeCl containing OH_TwoOf silica gel eluted with Chromatography gives 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-benzo [5,6 ] Cyclohepta [1,2-b] pyridin-11-yl) -1- (methylsulfonyl) piperidine   Methanesulfonyl chloride (0.5 ml, 6.46 mmol) was added in anhydrous pyridine (2 ml). To a solution of the title compound of Step 4 of Example 27 (30 mg, 0.086 mmol) at 0 ° C. Then, 4-dimethylaminopyridine (10 mg, 0.08 mmol) is added and the solution is Stir at 20 ° C. overnight. Evaporate the solvent, water (30 ml) and CH_TwoCl_Two(60ml ) Is added. The organic layer was separated and MgSO_FourDried over, filtered and the solvent removed. Vaporate to give an oil which is silica eluted with 70% v / v EtOAC-hexane Chromatography of the gel gives 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-benzo [5,6] Cyclohepta [1,2-b] pyridin-11-yl) -1- (4-pyridinylacetyl) piperidine , N₁-Oxide Step 1. 3-Ethyl-6,11-dihydro-10-methoxy-8-methyl-11- (4-piperidinyl)- 5H-benzo [5,6] cyclohepta [1,2-b] pyridine   Ammonium formate (200 mg, 2.08 mmol) and 10% Pd / C (20 mg) To a solution of the title compound of Step 4 of Example 27 (90 mg, 0.258 mmol) in toluene (5 ml) was added 20 C. and then reflux for 4 hours. Add methanol (20 ml) and add The reaction was filtered through a cehte pad and then methanol (10 ml). ) And CH_TwoCl_Two(3 × 20 ml). Combine the filtrate and washings, concentrate, And the residue CH_TwoCl_Two(50 ml) and water (25 ml). Separate the organic layer, Mg SO_FourDry over, filter and remove the solvent to give a white solid (75 mg, yield Rate 84%). Step 2. 4- (3-ethyl-6,11-dihydro-10-methoxy-8-methyl-5H-benzo [5,6] cy Clohepta [1,2-b] pyridin-11-yl) -1- (4-pyridinylacetyl) piperidine, N₁-Oxide   EDCl (75 mg, 0.39 mmol), HOBT (70 mg, 0.51 mmol), and NMM (0.5 ml, 4.5 m mol) with the title compound of Step 1 (75 mg, 0.214 mmol) in DMF (anhydrous, 3 ml) And 4-pyridyl N-oxideacetic acid (75 mg, 0.48 mmol) at 0 ° C. And then stirred at room temperature overnight. Evaporate the solvent and remove the residue in CH_TwoCl_Two( 60 ml) and water (25 ml), the organic layer is separated and 10% Na_TwoCO_Three(2x20ml) Wash and MgSO_FourDry over, filter and evaporate the solvent to give an oil , With 2% NH_Four7% v / v MeOH containing OH: methylene chloride (MeCl_Two) Chromatograph on Ricagel to obtain the product as a white solid. (75 mg, yield 76%), MS (FABS) 486 (MH). Example 30. (+,-)-4- (3-Bromo-6,11-dihydro-8,10-dimethyl-5H-benzo [5,6] cy Chlohepta [1,2-b] pyridin-11-yl) -1- (4-piperidinylacetyl) piperazine   By substituting 3,5-dimethylbenzyl bromide with reagent 2, and By substituting 5-bromo-t-butylamide with reagent A of step 1 of Example 1. And steps 1 to 6 of Example 1 (excluding steps 3, 3a and 7). In addition, instead of steps 3 and 3a of Example 1, use triflic acid to heat up to 60 ° C. Example 1 was obtained by substituting the procedure of step 3 of Example 2 with heating. To give the 8,10-dimethyl analog, compound G from step 6. Procedure of Step 7 of Example 1 Substitute 4-pyridylacetic acid N-oxide with an equivalent amount of N-BOC-4-piperidylacetic acid according to Then the BOC group is removed with trifluoroacetic acid to give the title compound . Example 31. (+,-)-4- (3-Bromo-6,11-dihydro-8,10-dimethyl-5H-benzo [5,6] cy Chlohepta [1,2-b] pyridin-11-yl) -1- (4-piperidinylacetyl-N-carboxy (Samide) piperazine   Starting with the title compound of Example 30 and 3 equivalents of trimethylsilane in methylene chloride Treated with lysyl isocyanate at 25 ° C, then with excess sodium bicarbonate To remove the silyl group to give the title compound. Embodiment 32 FIG. (+,-)-4- (3-Cyclopropyl-6,11-dihydro-10-methoxy-5H-benzo [ 5,6] Cyclohepta [1,2-b] pyridin-11-yl) -1- (4-pyridinylacetyl) piperi gin Step 1:  Diazomethane containing ether formed from diazaid (15g) Until the TLC sample indicates the completion of the reaction, Example 27 (Step 2) in benzene (1 ml). These compounds A (0.11 g) and palladium acetate (7 mg) were added to a solution with stirring. Add dropwise. Evaporation under reduced pressure gives the compound as a white powder Get B. MS (CI) 461. Step 2:   The product B from Step 1 was prepared according to the procedure described in Steps 3 and 4 of Example 27, Convert to intermediate C. Yellow-brown powder, MS (CI) 362. Step 3:   The product C from Step 2 was purified according to the procedure described in Step 7 of Example 1 to give the title compound. Convert to object D. White powder, MS (CI) 498. 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   Replace 5-bromo-t-butylamide with reagent A, and add 3-methyl-5-bromobenzyl By substituting rubromide with reagent 2 of Example 2, step 1, About In Step 3, the reaction with triflic acid is performed at 60 ° C. for 4 hours, and Step 6 is omitted. Except for omitting, the title compound was converted to the racemate according to steps 1 to 10 of Example 2. Get it. MS (FABS) m / e 584 (MH). The racemate is purified by preparative HPLC chiralpak AD column (D aicel Chemical Industries,) and 30% isopropanol-hexane (0. Split into enantiomers by eluting with 2% DEA). Desired (+) ena The enantiomer elutes last. MS (FABS) m / e 584 (MH), optical rotation at 20 ° C. = + 51. 7 °, c = 0.111. Example 34. (-) 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   Follow essentially the same procedure as in Example 33, except also collecting the (-) enantiomer . MS (FABS) m / e 584 (MH), optical rotation at 20 ° C = -47.5 °, c = 0.2125. Example 35. (+) 4- (3-bromo-6,11-dihydro-11-hydroxy-10-bromo-8-methyl- 5H-benzo [5,6] cyclohepta [1,2-b] pyridin-11-yl) -1- (4-pyridinylacetyl L) piperidine N₁-Oxide  Following the procedure used to prepare the title compound of Example 33, Omitting steps 6, 7, and 9 above, the title compound is converted as a racemate (+,-) obtain. FABS MS m / e 599.9 (MH). The racemate was separated using the same procedure as in Example 33. Crack. The (+) enantiomer elutes first. MS (FABS) m / e 599.9 (MH) at 20 ° C Optical rotation = + 10.4 °, c = 0.1155. Example 36. (-) 4- (3-bromo-6,11-dihydro-11-hydroxy-10-bromo-8-methyl- 5H-benzo [5,6] cyclohepta [1,2-b] pyridin-11-yl) -1- (4-pyridinylacetyl L) piperidine N₁-Oxide   Essentially the same as Example 35 except that the (-) enantiomer elutes second Follow the steps. MS (FABS) m / e 599.9 (MH), optical rotation at 20 ° C = -7.3 °, c = 0.1375. Example 37. -(3-Bromo-5,6-dihydro-10-bromo-8-methyl-11H-benzo [5,6] cyclo Rohepta [1,2-b] pyridine-11-ylidene) -1- (4-pyridinylacetyl) piperidine N₁-Oxide   Following the procedure used to prepare the title compound of Example 33, Omit steps 6 and 9 to give the title compound. MS (FABS) m / e 582 (MH).Preparation of starting materials   Starting materials useful for preparing compounds of the present invention are described by the following preparative examples. And should not be construed as limiting the scope of the disclosure. Starting materials and Pyridyl and phenyl compounds (for example, compounds (1, 1.3, 3 , 3.5)), inorganic and organic bases, and alcohols are known in the art. Can be prepared using the method of See J.K. Wong et al., Bioorganic & Medici nal Chemistry Letters, Volume 3, No. 6, pages 1073-1078, (1993); U.S. Pat. No. 5,089,4. No. 96; 5,151,423; 4,454,143; 4,355,036; PCT / US94 / 11390 (WO95 / 10514); PCT / US94 / 11391 (WO95 / 10515); PCT / US94 / 11392 (WO95 / 10516); Stanley R .; Sandler and Wolf Karo, Organic Functional Grou p Preparations, 2nd edition, Academic Press, Inc., San Diego, Cahfornia, Vol. 1-3, (1983), and J. March, Advanced Organic Chemistry, Reactions & Mechanism s, and Structure, Third Edition, John Wiley & Sons, New York, p. 1346 (1985). It is. Alternative mechanistic pathways and similar structures within the scope of the invention will be apparent to those skilled in the art. Can be                                Scheme II                              Scheme IIIHere, for Schemes II and III, R¹, R^Two, R^Three, R^Four, R^Five, R⁶, R⁷, And R⁸ , Solid and dotted lines are as defined above.   In schemes II and III, for step A, compound 5 and And 5.3 at about -78 ° C to 20 ° C in THF, toluene, benzene, ether Lithium diisopropylamide (LDA) in aprotic solvents such as Using such a base, about 1 to 1.5 moles of electrophile per mole of compounds 1 and 1.3 Compounds 1 and 1.3 were converted to alkyl groups with electrophilic compounds 3 and 3.3 using neutral compound 3. And prepared by filtration.   In step B, compounds 7 and 7.3 are converted to non-protocol at a temperature in the range of about 80 ° C to 120 ° C. Phosphorus oxychloride (POCl_Three) Or a dehydrating agent such as thionyl chloride, Using about 3 to 10 moles of dehydrating agent per mole of Compounds 5 and 5.3, Compound 5 And 5.3 by processing.   In Step C, compounds 7.5 and 7.53 are converted to triflic acid (CF_ThreeSO_ThreeH) or Al chloride Minium (AlCl_ThreeBy treating compounds 7 and 7.3 with a Lewis acid such as To be prepared. The reaction can be performed neat (ie, without added solvent). You. If necessary, AlCl_ThreeWhen using a solvent such as dichloroethane obtain. The reaction uses about 3 to 10 moles of Lewis acid per mole of compounds 7 and 7.3 And at a temperature in the range of about 20 ° C to about 175 ° C.   In Step D, compounds 8 and 8.3 are combined with about 20 per mole of compounds 7.5 and 7.53. Temperatures ranging from about 20 ° C to the reflux of the reaction mixture using ~ 100 volumes of aqueous acid solution Treat compounds 7.5 and 7.53 with a dilute acid such as aqueous hydrochloric acid or aqueous sulfuric acid. Prepared by   In Step E, Compounds 13a and 13.3a are combined with about 8 moles of Compounds 8 and 8.3 Using 1-1.5 moles of Grignard reagent 12, at a temperature ranging from about 0 ° C to 50 ° C, Grignard reagent 1 derived from N-methyl-4-chloropiperidine in an aprotic solvent Prepared by treating compounds 8 and 8.3 with 2.   In Step F, Compounds 13b and 13.3b are combined with Compounds 13a and 13.3a per mole Using 5-10 moles of ethyl chloroformate at temperatures ranging from about 60 ° C to 90 ° C Treats compounds 13a and 13.3a with ethyl chloroformate in aprotic solvent Prepared by   In step G, compound 13c is converted to hydrogen (H_Two) And 10% palladium (Pd) / From atmospheric pressure (ambient) to 50 pounds per square inch (psi) using carbon (C) Prepared by subjecting compound 13b to catalytic hydrogenation at a pressure in the range Alternatively, compound 13c can be prepared at 50 ° C. to 70 ° C. at atmospheric pressure using 10% Pd / C as a catalyst. Protons such as methanol or ethanol as needed at temperatures in the range of Compound 13b using an aprotic solvent and a hydrogen source such as ammonium formate It can be prepared by processing.   In Step H, Compounds 15 and 15.3 are converted to Compound 1 with an acid such as polyphosphoric acid (PPA). Prepared by processing 3c and 13.3c. Run the reaction neat I can do it. The reaction is carried out with about 5 to 10 volumes of polyphosphorin per mole of compounds 13c and 13.3c. The reaction can be carried out using an acid at a temperature in the range of about 60C to 100C. Alternatively, in step H , 13d and 13.3d in 5-10 volumes per mole of compounds 13c and 13.3b Using an aqueous acid solution, at a temperature in the range of about 80 ° C to 100 ° C, hydrochloric acid such as 2N to concentrated hydrochloric acid Aqueous solution (Hcl) or sulfuric acid aqueous solution (H_TwoSO_Four) Treats compounds 13c and 13.3b Can be prepared by   In Step I, Compounds 19 and 19.3 are combined with 5 to 15 moles of Compounds 15 and 15.3. Using 10 volumes of aqueous acid, at a temperature in the range of about 80 ° C to 100 ° C, 3N to concentrated hydrochloric acid (HCl Prepared by treating compounds 15 and 15.3 with an aqueous acid such as   In Step J, Compounds 20 and 20.3 are added at a rate of 1 to 1 per mole of Compounds 19 and 19.3. Using 4 moles of reducing agent, at a temperature in the range of about 0 ° C. to 20 ° C., in an aprotic solvent With a reducing agent such as diisobutylaluminum hydride (DBAHAI) And 19.3 by treatment.   In step EE, alcohol compounds 9 and 9.3 are converted to 1 mole equivalent of compounds 8 and 8.3. At a temperature ranging from 0 ° C. to 20 ° C. using 1 to 3 mol of a reducing agent, Sodium borohydride in a protic solvent such as ethanol and acetic acid (NaBH_FourPrepared by reducing compounds 8 and 8.3 with a reducing agent such as .   In Step FF, Compounds 10 and 10.3 were added at a rate of 1 to 1 per mole of Compounds 9 and 9.3. Using 2-mol chlorinating agent, at a temperature ranging from 0 ° C. to 25 ° C., 1,2-dichloroethane Or thionyl chloride or oxychloride in an aprotic solvent such as methylene chloride. Phosphorus chloride (POCl_ThreeTreatment of alcohol compounds 9 and 9.3 with a chlorinating agent such as To be prepared.   In Step GG, Compounds 11 and 11.3 are added in an amount of 1 to 1 per mole of Compounds 10 and 10.3. Using 10 moles of piperazine compounds 12 and 12.3 at temperatures ranging from 0 ° C to 60 ° C Piperazine in a solvent such as water, acetonitrile, toluene, or methylene chloride. Prepared by reacting compounds 12 and 12.3 with compounds 10 and 10.3. You.   In step K, the desired compound of formula 1.0 is prepared as described in Scheme I above. Can be prepared from compounds (11,11.3), (13d, 13.3d), (19,19.3), or (20,20.3).                                Scheme IV Here, for scheme IV, R¹, R^Two, R^Three, R^Four, R^Five, R⁶, R⁷, And R⁸ , Solid and dotted lines are as defined herein above.   In Scheme IV, in steps A and B, compounds 5.3 and 7.3 Prepared as described in section III.   In Step L, Compound 25 is prepared by adding about 1 to 1.5 moles of Grignard per mole of Compound 7.3. Using reagent reagent 12 at a temperature in the range of about 0 ° C. to 50 ° C. in an aprotic solvent, Reaction of Grignard reagent 12 derived from N-methyl-4-chloropiperidine with compound 7.3 Prepared by the reaction.   In Step M, Compound 26 is prepared by adding about 20 to 100 volumes of an aqueous acid solution per mole of Compound 25 Using aqueous hydrochloric acid or sulfuric acid at a temperature ranging from about 20 ° C. to the reflux of the reaction mixture. Prepared by treating compound 25 with a dilute acid, such as an aqueous solution.   In step N, compound 27 is converted to triflic acid or aluminum chloride (AlCl_Three) Prepared by treating compound 25 with such Lewis acid. The reaction, (Ie, without additional solvent). When using triflic acid, The reaction was carried out at 0-70 ° C. using 5-100 mol of triflic acid per mole of compound 25. Temperature. If necessary, AlCl_ThreeWhen using dichloroethane A solvent such as a solvent may be used. The reaction is carried out with about 3 to 10 mol of Lew per mole of compound 25. The reaction may be performed at a temperature in the range of about 20C to about 175C using an is acid.   In step O, compound 28 is converted to 5-10 moles of ethylchloroform per mole of compound 27 Using formate, at a temperature in the range of about 60 ° C to 90 ° C, the air in aprotic solvent Prepared by treating compound 27 with tyl chloroformate.   In step P, compound 29 is used with 5 to 10 volumes of an aqueous acid solution per mole of compound 28. Using an aqueous acid solution such as 3N to concentrated hydrochloric acid (HCl) at a temperature in the range of about 80 ° C to 100 ° C. Prepared by treating compound 28.   In step Q, compound 30 is used using 1 mole of compound 29 or 1-4 moles of a reducing agent. Diisobutyl aluminum in an aprotic solvent at a temperature in the range of about 0 ° C to 20 ° C. By treating compound 29 with a reducing agent such as sodium hydride (DIBALH). To make.   In step K, compound 30 is converted to the desired compound as described in Scheme I above. Is converted to an object (1.0).Assay   1.In vitro enzyme assay: FPT IC₅₀(Farnesyl protein transfer Inhibitor, in vitro enzyme assay) as described in WO95 / 10515 or WO95 / 10516. Determined by the method described. This data indicates that the compound of the invention was partially purified. Ras-CVLS protein by rat brain farnesyl protein transferase (FPT) Indicates an inhibitor of renesylation. This data is also partially purified Of Ras-CVLS farnesylation by isolated rat brain FPT (IC₅₀<10 μM) Indicates that there are compounds of the invention that can be considered bitter.   2.Cell-based assays: COS IC₅₀Values indicate inhibition of COS cell activity during Ras processing. Harm and is determined by the methods disclosed in WO / 10515 or WO95 / 10516.   In order to prepare pharmaceutical compositions from the compounds described in this invention, an inert drug A chemically acceptable carrier can be either solid or liquid. Solid form Formulations include powders, tablets, dispersible granules, capsules, cachets and suppositories. It is. Powders and tablets may contain from about 5% to about 70% active ingredient. Suitable solid Carriers are known in the art and include, for example, magnesium carbonate, G Nesium, talc, sugar and lactose. Tablets, powders, cachets and capsules It can be used as a solid dosage form suitable for buccal administration.   For preparing suppositories, a mixture of fatty acid glycerides or cocoa butter is recommended. Such a low melting wax is first melted, and stirred to evenly disperse the active ingredient therein. Sprinkle. The molten homogeneous mixture is then poured into convenient sized molds and allowed to cool. To solidify.   Liquid form preparations include solutions, suspensions and emulsions. As an example And water or water-propylene glycol solutions for parenteral injection.   Liquid form preparations may also include solutions for nasal administration.   Aerosol preparations suitable for inhalation may include solutions and solids in powder form. May be combined with a pharmaceutically acceptable carrier such as an inert compressed gas.   It is also intended to be converted to a liquid form immediately before use, orally or Also included are solid form preparations for either parenteral administration. Such a liquid form States include solutions, suspensions, and emulsions.   The compounds of the present invention may also be delivered transdermally. Transdermal composition, cream, raw Solutions, aerosols and / or emulsions, and can be used for this purpose. Included in conventional matrix or reservoir type transdermal patches Can be   Preferably, the compounds are administered orally.   Preferably, the pharmaceutical preparation is in a unit dosage form. In such a form, The agent is administered in a unit dose containing an appropriate amount of the active ingredient (e.g., an effective amount to achieve the desired purpose). It is further divided.   The amount of active ingredient in the unit dose of the preparation may range from about 0.1 mg to 1000 m, depending on the individual application. g, more preferably from about 1 mg to 300 mg.   The actual dosage used will depend on the needs of the patient and the severity of the condition being treated. Can be changed. Determination of the proper dosage for a particular situation is within the skill of the art. You. Generally, treatment is initiated with relatively small dosages that are less than the optimum dose of the compound. Is done. Thereafter, the dosage may be increased by small amounts until the optimum effect under the circumstances is reached. increase. For convenience, if desired, the daily dosage can be divided into portions and administered during the day. Can give.   The amount and frequency of administration of the compounds of the present invention and pharmaceutically acceptable salts thereof will vary. The clinician should be able to determine the age, condition and size of the patient and the severity of the condition being treated. It is adjusted according to the judgment made in consideration of such factors. Typical recommended medication The method is preferably 10 mg to 2000 mg / day orally to block tumor growth. The dose is 10 mg to 1000 mg / day in 2 to 4 divided doses. The compound is in this dosage range Non-toxic when administered intravenously.   The following are examples of pharmaceutical dosage forms containing a compound of the present invention. The scope of the present invention Aspects related to the pharmaceutical composition are not limited to these provided examples. .                            Examples of pharmaceutical dosage forms Example A-Tablet Production method   Mix ingredients 1 and 2 in a suitable mixer for 10-15 minutes. Mix the mixture with ingredient 3 Into granules. If necessary, wet the granules with a coarse screen (eg 1/4 inch , 0.63 cm). Dry the wet granules. Dry condyle if necessary Sieve the granules and mix with ingredient 4 and mix for 10-15 minutes. Ingredient 5 Add and mix for 1-3 minutes. Use a suitable tablet press to reduce the mixture to the appropriate size. Compress and weigh.                            Example B-Capsule Production method   Mix ingredients 1, 2 and 3 in a suitable blender for 10-15 minutes. Add ingredient 4, Then mix for 1-3 minutes. In a suitable capsule maker, mix the mixture into 2 pieces of Fill into chin capsule.   Although the invention has been described in conjunction with the specific embodiments described above, many alternatives, modifications, and variations are possible. Variations and changes will be apparent to those skilled in the art. All such alternatives, modifications and variations Further modifications are intended to fall within the spirit and scope of the present invention.

──────────────────────────────────────────────────続 き Continued on the front page (51) Int.Cl. ⁷ Identification symbol FI Theme court ゛ (Reference) C07D 401/12 C07D 401/12 (81) Designated country EP (AT, BE, CH, CY, DE, DK, ES, FI, FR, GB, GR, IE, IT, LU, MC, NL, PT, SE), OA (BF, BJ, CF, CG, CI, CM, GA, GN, ML, MR, NE, SN, TD, TG), AP (GH, GM, KE, LS, MW, SD, SZ, UG, ZW), EA (AM, AZ, BY, KG, KZ, MD, RU, TJ, TM), AL, AM, AU, AZ, BA, BB, BG, BR, BY, CA, CN, CZ, EE, GE, GW, HU, ID, IL, IS, JP, KG, KR, Z, LC, LK, LR, LT, LV, MD, MG, MK, MN, MX, NO, NZ, PL, RO, RU, SG, SI, SK, SL, TJ, TM, TR, TT, UA , UZ, VN, YU (72) Inventor Wayne Stain, Jay United States of America New Jersey 07043, Upper Montclair, Bellevue Avenue 191, Apartment A6 (72) Inventor Walin, Ronald El. United States of America New Jersey 07921, Bedminister, Heatherwood Lane 42 (72) Inventor Rosenblum, Stuart Bee. United States 07052, West Orange, Steven Terrace 16

Claims (1)

[Claims] 1. A compound of the formula: Or a pharmaceutically acceptable salt or solvate thereof, wherein: A represents N or N-oxide: X represents a carbon atom 11 as represented by the solid line when X is N or CH. Represents N, CH or C such that there is a single bond to; or, if X is C, a double bond to carbon atom 11 as represented by the solid and dotted lines. , N, CH or C; R ¹ is hydrogen, bromo, chloro, trifluoromethyl, acyl, alkyl, cycloalkyl, amino, acylamino or alkoxy; R ² is hydrogen, halo, trifluoromethyl, R ³ is hydrogen, bromo, chloro, alkoxy, —OCF ₃ or hydroxy; R ⁴ is hydrogen, halo, trifluoromethyl, alkyl, or alkyl, alkoxy, —OCF ₃ , hydroxy, amino or acylamino; Or at least one of R ² or R ³ or R ⁴ , wherein at least one of R ¹ , R ² , R ³ or R ⁴ is alkyl or alkoxy; R ⁵ , R ⁶ , R ⁷ and R ⁸ independently represent hydrogen, alkyl or —CONHR ₅₀ , wherein R ⁵⁰ is any group represented below for R Q is hydrogen when there is a single bond to carbon atom 11, or Q is when there is a single bond to carbon 11 and X is CH; Is hydrogen or hydroxy, or Q is not a substituent when there is a double bond to carbon 11; Z is = O or = S; and R is aryl, aralkyl, cycloalkyl, cycloalkylalkyl, heteroalkyl, heteroaryl, heteroarylalkyl, heterocycloalkyl or heterocycloalkylalkyl. 2. 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; and R ⁵ , R ⁶ , R ⁷ and R ⁸ are hydrogen. 3. Y is -SO ₂ CH _3, The compound according to claim 2. 4. 3. The compound according to claim 2, wherein Y is -COR, wherein R is heteroarylalkyl or heterocycloalkylalkyl. 5. R ¹ is bromo, methyl, ethyl, cyclopropyl or vinyl, A compound according to claim 2. 6. ^3. The compound according to claim 2, wherein R2 is methoxy, bromo or methyl. 7. ^3. The compound according to claim 2, wherein R3 is methoxy, bromo or methyl. 8. R ⁴ is chloro or methyl, A compound according to claim 2. 9. The compound of claim 1, wherein the compound is selected from any of the title compounds of Examples 1-10 and 14-37. 10. 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 The compound according to claim 1, which is selected. 11. The compound of claim 1, wherein the compound is selected from any of the title compounds of Examples 3, 21, 22, 24 and 33. 12. A pharmaceutical composition for inhibiting abnormal growth of cells, comprising an effective amount of a compound of claim 1 in combination with a pharmaceutically acceptable carrier. 13. A method of inhibiting the abnormal growth of cells, comprising administering an effective amount of the compound of claim 1. 14． 14. The method of claim 13, wherein the cells to be inhibited are tumor cells that express an activated ras oncogene. 15. The inhibited cells are pancreatic tumor cells, lung cancer cells, myeloid leukemia tumor cells, thyroid follicular tumor cells, myelodysplastic tumor cells, epidermal carcinoma tumor cells, bladder carcinoma tumor cells, or prostate tumor cells, breast tumor cells or 14. The method according to claim 13, which is a colon tumor cell. 16. 14. The method of claim 13, wherein the inhibition of the abnormal growth of the cells occurs by inhibiting ras farnesyl protein transferase. 17． 14. The method of claim 13, wherein the inhibition is inhibition of a tumor cell, wherein the Ras protein is activated as a result of an oncogenic mutation in a gene other than the Ras gene.