09/094687 filed June 15,1998 discloses tricyclic compounds useful for inhibiting farnesyl protein transferase.

In view of the current interest in inhibitors of farnesyl protein transferase, a welcome contribution to the art would be compounds useful for the inhibition of farnesyl protein transferase. Such a contribution is provided by this invention.

SUMMARY OF THE INVENTION This invention provides compounds useful for the inhibition of farnesyl protein transferase (FPT). The compounds of this invention are represented by the formula: A compound of the formula: or a pharmaceutically acceptable salt or solvate thererof, wherein: one of a, b, c and d represents N or N+O-, and the remaining a, b, c and d groups represent CR1 or CR2; or each of a, b, c, and d are independently selected from CR1 or CR2 ;

each R1 and each R2 is independently selected from H, halo, -CF3,-OR1o (e. g., -OCH3), -COR10, -SR10 (e. g.,-SCH3 and -SCHZC6H5),-S (O) tRl l (wherein t is 0,1 or 2, e. g.,-SOCH3 and -S02CH3),-N (Rlo) 2,-N02,-OC (O) RlO,-C02RIO,-OC02RII,-CN, (e.g.,-SCII2CO2CH3),-SR11N(R75)2NR10COOR11,-SR11C(O)OR11 (provided that R"in-SRllN (R75) is not-CH2-) wherein each R75 is independently selected from H or-C (O) OR11 (e. g., -S (CH2) 2NHC (O) O-t-butyl and-S (CH2) 2NH2), benzotriazol-l-yloxy, tetrazol-5-ylthio, or substituted tetrazol-5-ylthio (e. g., alkyl substituted tetrazol5-ylthio such as 1-methyl-tetrazol-5-ylthio), alkynyl, alkenyl or alkyl, said alkyl or alkenyl group optionally being substituted with halo,-ORlO or-C02R10; R3 and R4 are the same or different and each independently represents H, any of the substituents of R1 and R2, or R3 and R4 taken together represent a saturated or unsaturated Cs-Cy fused ring to the benzene ring (Ring E); R5, R6, and R7 each independently represents H,-CF3, -COR10, alkyl or aryl, said alkyl or aryl optionally being substituted with-ORl,-SR10,-S (O) tRI1,-NRlOCOOR11,-N (RIO) 2,-N02, -COR10, -OCOR10, -OCO2R11, -CO2R10, OPO3R10, or R5 is combined with R6 to represent =O or =S; provided that for the groups -OR10, -SR10, and-N (R10) 2 R'° is not H; R10 represents H, alkyl, aryl, or aralkyl (e. g., benzyl); Rl 1 represents alkyl or aryl; X represents N, CH or C, and when X is C the optional bond (represented by the dotted line) to carbon atom 11 is present, and when X is CH the optional bond (represented by the dotted line) to carbon atom 11 is absent; the dotted line between carbon atoms 5 and 6 represents an optional bond, such that when a double bond is present, A and B independently represent-R10, halo,-ORll,-OC02RH or -OC (O) R10, and when no double bond is present between carbon atoms 5 and 6, A and B each independently represent H2, - (OR1 l) 2, H(OR1 l) 2, H and halo, dihalo, alkyl and H, (alkyl) 2,-H and -OC (O) R10, H and-ORlO, =O, aryl and H, =NOR10 or-0- (CH2) p-0- wherein p is 2,3 or 4; W represents a heterocyclic ring selected from: said heterocyclic rings (2.0 to 7.0 and 2.1 to 7.1) being optionally substituted with one or more substituents independently selected from: (a) alkyl (e. g., methyl, ethyl, isopropyl, and the like),

(b) substituted alkyl wherein said substituents are selected from: halo, aryl,-OR'5 or-N (RI5) 2, heteroaryl, heterocycloalkyl, cycloalkyl, wherein each R 15 group is the same or different, provided that said optional substituent is not bound to a carbon atom that is adjacent to an oxygen or nitrogen atom, and wherein R"is selected from: H, alkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, cycloalkyl, or cycloalkylalkyl; (c) hydroxyl, with the proviso that carbon atoms adjacent to the nitrogen, sulfur or oxygen atoms of the ring are not substituted with hydroxyl; (d) alkyloxy or (e) arylalkyloxy; (i. e., each substitutable H atom on each substitutable carbon atom in said heterocyclic rings is optionally replaced with substituents selected from (a) to (e) defined above); Y represents CH2, NR'6, O, S, SO, or SO, wherein R'6 is selected from: H, alkyl, cycloalkyl, cycloalkylalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, acyl, aroyl, carbamoyl, carboxamido, alkylsulfonyl, arylsulfonyl, arylalkylsulfonyl, sulfonamido, alkylsulfonamido, arylsulfonamido and arylalkylsulfonamido; n is 0 to 6 (preferably 1-3); Q represents O or N, provided that Q is not adjacent to a heteroatom in the heterocycloalkyl rings of 1,4.1,5.1,6.1 and 7.1; Rl2 is selected from: R 17 R 17 ir N N/-'N />0 is preferably>-N N or 1115 (8.0) \ (8. 1)/' (9.0) (9.1) (e. g., R"is 9.0);

wherein R'7 is selected from: (1) H, (2) alkyl, (3) aryl, (4) arylalkyl, (5) substituted arylalkyl wherein the substituents are selected from halo (e. g., F and Cl) or CN, (6)-C (aryl) 3 (e. g., -C (phenyl) 3, i. e., trityl), (7) cycloalkyl, (8) substituted alkyl (as defined above in (b)), or (9) cycloalkylalkyl; Ruais selected from rings 8.0,8.1 or 9.1, defined above; said imidazolyl ring 8.0 and 8.1 optionally being substituted with one or two substituents, said imidazole ring 9.0 optionally being substituted with 1-3 substituents, and said pyridyl ring 9.1 optionally being substituted with 1-4 substituents, wherein said optional substituents for rings 1,9.0 and 9.1 are bound to the carbon atoms of said rings and are independently selected from: -NHC (O) R'5,-C (R'8) 20R'9,-OR'S,-SR'5, F, Cl, Br, alkyl (e. g., methyl, such as 4-methyl in 9.0), substituted alkyl (as defined above in (b)), aryl, arylalkyl, cycloalkyl, or-N (R'5) 2; R'5 is as defined above; each R'8 is independently selected from H or alkyl (preferably-CH3), preferably H; R'9 is selected from H or-C (O) NHR20, and R2° is as defined below; R'3 and R'4 for each n are independently selected from: H, F, alkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, cycloalkyl, cycloalkylalkyl or-CON (R'5) 2 (wherein R"is as defined above), providedthatthe-OR15and-N(R15)2groupsarenot-OR15or-N(R15)2 bound to a carbon atom that is adjacent to a nitrogen atom, and provided that there can be only one-OH group on each carbon; and the substitutable R'3 and R'4 groups are optionally substituted with one or more (e. g., 1-3) substituents selected from: F, alkyl (e. g., methyl, ethyl, isopropyl, and the like), cycloalkyl, arylalkyl, or heteroarylalkyl (i. e., the R'3 and/or R'4 groups can be unsubtituted or can be substituted with 1-3 of the substitutents described above, except when R'3 and/or R14 is H); or Ans and R'4, for each n, together with the carbon atom to which they are bound, form a C3 to C6 cycloalkyl ring; R9 is selected from: R20 is selected from: H, alkyl, aryl, arylalkyl, cycloalkyl, cycloalkylalkyl, heteroaryl, heteroarylalkyl, heterocycloalkyl, or heterocyloalkylalkyl, provided that R20 is not H when R9 is group 12.0 or 16.0; when R20 is other than H, then said R20 group is optionally substituted with one or more (e. g., 1-3) substituents selected from: halo, alkyl, aryl,-OC (O) RI5 (e. g., -OC (O) CH3), -OR15 or -N(R15)2, wherein each R'S group is the same or different, and wherein R15 is as defined above, provided that said optional substituent is not bound to a carbon atom that is adjacent to an oxygen or nitrogen atom; R21 is selected from: H, alkyl, aryl, arylalkyl, cycloalkyl, cycloalkylalkyl, heteroaryl, heteroarylalkyl, heterocycloalkyl or heterocycloalkylalkyl; when Wl is other than H, then said W'group is optionally substituted with one or more (e. g., 1-3) substituents selected from: alkyl, aryl, wherein each R 15 group is the same or different, and wherein R'5 is as defined above; and R22 is selected from cycloalkyl (e. g., cyclopropylmethyl, i. e., heterocycloalkyl, aryl (e. g., phenyl), substituted aryl (e. g., halo as a substituent, such as F or Cl), alkyl (e. g., t-butyl), or substituted alkyl or substitued cycloalkyl (substituents include-OH,-CO2H, and-C (O) NH2).

Thus, in one embodiment of this invention R9 is 12.0. In another embodiment R9 is 13.0. In another embodiment R9 is 14.0.

In another embodiment R9 is 15.0. In another embodiment R9 is 16.0.

The compounds of this invention: (i) potently inhibit farnesyl protein transferase, but not geranylgeranyl protein transferase I, in vitro; (ii) block the phenotypic change induced by a form of transforming Ras which is a farnesyl acceptor but not by a form of transforming Ras engineered to be a geranylgeranyl acceptor; (iii) block intracellular processing of Ras which is a farnesyl acceptor but not of Ras engineered to be a geranylgeranyl acceptor; and (iv) block abnormal cell growth in culture induced by transforming Ras.

The compounds of this invention inhibit farnesyl protein transferase and the farnesylation of the oncogene protein Ras.

Thus, this invention further provides a method of inhibiting farnesyl protein transferase, (e. g., ras farnesyl protein transferase) in mammals, especially humans, by the administration of an effective amount of the tricyclic compounds described above. The administration of the compounds of this invention to patients, to inhibit farnesyl protein transferase, is useful in the treatment of the cancers described below.

This invention provides a method for inhibiting or treating the abnormal growth of cells, including transformed cells, by administering an effective amount of a compound of this invention.

Abnormal growth of cells refers to cell growth independent of normal regulatory mechanisms (e. g., loss of contact inhibition).

This includes the abnormal growth of : (1) tumor cells (tumors) expressing an activated Ras oncogene; (2) tumor cells in which the Ras protein is activated as a result of oncogenic mutation in another gene; and (3) benign and malignant cells of other proliferative diseases in which aberrant Ras activation occurs.

This invention also provides a method for inhibiting or treating tumor growth by administering an effective amount of the tricyclic compounds, described herein, to a mammal (e. g., a human) in need of such treatment. In particular, this invention provides a

method for inhibiting or treating the growth of tumors expressing an activated Ras oncogene by the administration of an effective amount of the above described compounds. Examples of tumors which may be inhibited or treated include, but are not limited to, lung cancer (e. g., lung adenocarcinoma), pancreatic cancers (e. g., pancreatic carcinoma such as, for example, exocrine pancreatic carcinoma), colon cancers (e. g., colorectal carcinomas, such as, for example, colon adenocarcinoma and colon adenoma), myeloid leukemias (for example, acute myelogenous leukemia (AML)), thyroid follicular cancer, myelodysplastic syndrome (MDS), bladder carcinoma, epidermal carcinoma, melanoma, breast cancer and prostate cancer.

It is believed that this invention also provides a method for inhibiting or treating 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 or treatment being accomplished by the administration of an effective amount of the tricyclic compounds described herein, to a mammal (e. g., a human) in need of such treatment. For example, the benign proliferative disorder neurofibromatosis, or tumors in which Ras is activated due to mutation or overexpression of tyrosine kinase oncogenes (e. g., neu, src, abl, lck, and fyn), may be inhibited or treated by the tricyclic compounds described herein.

The tricyclic compounds useful in the methods of this invention inhibit or treat the abnormal growth of cells. Without wishing to be bound by theory, it is believed that these compounds may function through the inhibition of G-protein function, such as ras p21, by blocking G-protein isoprenylation, thus making them useful in the treatment of proliferative diseases such as tumor growth and cancer. Without wishing to be bound by theory, it is believed that these compounds inhibit ras farnesyl protein

transferase, and thus show antiproliferative activity against ras transformed cells.

DETAILED DESCRIPTION OF THE INVENTION As used herein, the following terms are used as defined below unless otherwise indicated: MH+-represents the molecular ion plus hydrogen of the molecule in the mass spectrum; BOC-represents tert-butyloxycarbonyl; BOC-ON-represents 1- (tert-butoxycarbonyl)-2-tert-butyl-3- methyl-4-imidazolidinone nitrile; CBZ-represents-C (O) OCH, CH, (i. e., benzyloxycarbonyl); CBZ-OSUC-represents benzyloxycarbonyl-O-succinimide; CHZCl-represents dichloromethane; CIMS-represents chemical ionization mass spectrum; DEAD-represents diethylazodicarboxylate; DEC-represents EDC which represents 1- (3-dimethyl- aminopropyl)-3-ethylcarbodiimide hydrochloride; DMF-represents N, N-dimethylformamide; Et-represents ethyl; EtOAc-represents ethyl acetate; EtOH-represents ethanol; HOBT-represents 1-hydroxybenzotriazole hydrate; IPA-represents isopropanol; iPrOH-represents isopropanol; LAH-represents lithium aluminum hydride; LDA-represents lithium diisopropylamide; MCPBA-represents meta-chloroperbenzoic acid; Me-represents methyl; MeOH-represents methanol; MS-represents mass spectroscopy; NMM-represents N-methylmorpholine; Ph-represents phenyl;

Pr-represents propyl; TBDMS-represents tert-butyldimethylsilyl; TEA-represents triethylamine; TFA-represents trifluoroacetic acid; THF-represents tetrahydrofuran; Tr-represents trityl; alkyl-represents straight and branched carbon chains and contains from one to twenty carbon atoms, preferably one to six carbon atoms said cycloalkyl ring being optionally substituted with one or more (e. g., 1,2 or 3) alkyl groups (e. g., methyl or ethyl) and when there is more than one alkyl group each alkyl group can be the same or different; acyl-represents a G-C (O)- group wherein G represents alkyl, aryl, heteroaryl, cycloalkyl, heterocycloalkyl,-O-alkyl,-O-aryl, or NR25R26 wherein R25 and R26 are independently selected from alkyl or aryl; arylalkyl-represents an alkyl group, as defined above, substituted with an aryl group, as defined below, such that the bond from another substituent is to the alkyl moiety; aryl- (including the aryl portion of arylalkyl)-represents a carbocyclic group containing from 6 to 15 carbon atoms and having at least one aromatic ring (e. g., aryl is a phenyl ring), with all available substitutable carbon atoms of the carbocyclic group being intended as possible points of attachment, said carbocyclic group being optionally substituted (e. g., 1 to 3) with one or more of halo, alkyl, hydroxy, alkoxy, phenoxy, CF3,-C (O) N (RI8) 2, -SO2R'8,-S02N (R'8) 2, amino, alkylamino, dialkylamino,-COOR23 or- NO2, wherein R23 represents alkyl or aryl; aroyl-represents-C (O) aryl wherein aryl is as defined above (e. g.,-C (O) phenyl); cycloalkyl-represents saturated carbocyclic rings of from 3 to 20 carbon atoms, preferably 3 to 7 carbon atoms, said cycloalkyl ring optionally substituted with one or more (e. g., 1,2 or 3) alkyl

groups (e. g., methyl or ethyl) and when there is more than one alkyl group each alkyl group can be the same or different; cycloalkylalkyl-represents a cycloalkyl group, as defined above, substituted with an alkyl group, as defined above, such that the bond from another substituent is to the alkyl moiety; halo-represents fluoro, chloro, bromo and iodo; heteroaralkyl-represents an alkyl group, as defined above, substituted with a heteroaryl group, as defined below, such that the bond from another substituent is to the alkyl moiety; heteroaryl-represents cyclic groups, optionally substituted with R3 and R4, having at least one heteroatom selected from O, S or N, said heteroatom interrupting a carbocyclic ring structure and having a sufficient number of delocalized pi electrons to provide aromatic character, with the aromatic heterocyclic groups preferably containing from 2 to 14 carbon atoms, e. g., 2-or 3-furyl, 2-or 3-thienyl, 2-, 4-or 5-thiazolyl, 2-, 4-or 5-imidazolyl, 2-, 4-or 5-pyrimidinyl, 2-pyrazinyl, 3-or 4-pyridazinyl, 3-, 5-or 6- [1, 2,4- triazinyl], 3-or 5- [1,2,4-thiadizolyl], 2-, 3-, 4-, 5-, 6-or 7- benzofuranyl, 2-, 3-, 4-, 5-, 6-or 7-indolyl, 3-, 4-or 5-pyrazolyl, 2-, 4-or 5-oxazolyl, triazolyl, 2-, 3-or 4-pyridyl or pyridyl N-oxide (optionally substituted with R3 and R4), wherein pyridyl N-oxide can be represented as: 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 hetero groups selected from-O-,-S-or-NR24, wherein R24 represents alkyl, aryl,-C (O) N (R'g) 2 wherein R'$ is as above defined (e. g.,-C (O) NH2) or acyl- (suitable heterocycloalkyl

groups include 2-or 3-tetrahydrofuranyl, 2-or 3-tetrahydrothienyl, tetrahydropyranyl, 2-, 3-or 4-piperidinyl, 2-or 3-pyrrohdinyl, 2-or 3-piperazinyl, 2-or 4-dioxanyl, morpholinyl, etc.).

The positions in the tricyclic ring system are: The compounds of formula 1.0 include the 2R and 2S isomers shown below (2R is preferred): Examples of the optional substituents for the Rl2 or Rl2A moiety include:-CH3,-CH2OH,-CH2OC (O) O-cyclohexyl, -CH2OC (O) O-cyclopentyl, ethyl, isopropyl, NH2, and-NHC (O) CF3.

Examples of R17 include :-C (O) NH-cyclohexyl,-C (phenyl) 3, H, methyl or ethyl.

Examples of R20 include t-butyl, i-propyl, neopentyl, cyclohexyl, cyclopropylmethyl,

Examples of R2° for group 12.0 include: t-butyl, ethyl, benzyl, -CH (CH3)2, -CH2CH(CH3)2, -(CH2)2CH3, n-butyl, n-hexyl, n-octyl, p- chlorophenyl, cyclohexyl, cyclopentyl, neopentyl, cyclopropylmethyl or Examples of R20 and R21 for 13.0 include: cyclohexyl, t-butyl, H,-CH (CH3)2, ethyl, -(CH2)2CH3, phenyl, benzyl,- (CH2) 2phenyl, and -CH3.

Examples of R20 for 14.0 include: 4-pyridylNO,-OCH3, -CH (CH3) 2,-t-butyl, H, propyl, cyclohexyl and Examples for R22 for 15.0 include: t-butyl, cyclohexyl, cyclopentyl, cyclobutyl, cyclopropyl, cyclopropylmethyl, phenyl, substitued phenyl (e. g., halo, such as F or Cl), Examples for R20 for 16.0 include: methyl, phenyl, isopropyl and cyclohexylmethyl.

Examples of R13 and R14 include: H, F, phenyl,-CH3, -CH2CH (CH3) 2,-(CH2) 3CH3, benzyl, ethyl, p-chlorophenyl, and-OH (provided that that there can only be one OH on each carbon).

Cyclopropyl is an Example of the Rl3 and R14 group being taken together with the carbon atom to which they are bound to form a cycloalkyl ring.

R', R2, R3, and R4 are preferably selected from H and halo, and are more preferably selected from H, Br, F and Cl. Representative

compounds of formula 1.0 include trihalo, dihalo and monohalo substituted compounds, such as, for example: (1) (2) 3,7,8-trihalo; (3) 3,8-dihalo; (4) 8-halo; (5) 10-halo; and (6) 3-halo (i. e., no substituent in Ring III) substituted compounds; wherein each halo is independently selected. Preferred compounds of formula 1.0 include: (1) 3-Br-8-Cl-10-Br-substituted compounds; (2) 3-Br-7-Br-8-Cl-substituted compounds; (3) 3-Br-8-Cl- substituted compounds; (4) 3-Cl-8-Cl-substituted compounds; (5) 3-F-8-Cl-substituted compounds; (6) 8-Cl-substituted compounds; (7) 10-Cl-substituted compounds; (8) 3-Cl-substituted compounds; (9) 3-Br-substituted compounds; and (10) 3-F-substituted compounds.

Substituent a is preferably N or N+O-with N being preferred.

A and B are preferably H2, i. e., the optional bond is absent and the C5-C6 bridge is unsubstituted.

R5, R6, and R7 are preferably H.

X is preferably N or CH (i. e., the optional bond is absent), and more preferably X is N.

When one or more of the carbon atoms of the imidazole ring 8.0 or 9.0 are substituted, the substituents are generally selected from:-N (R15)2, -NHC(O)R15, -C(R18)2OR19, or alkyl, e. g., -CH3,-CH2OH,-CH2OC (O) O-cyclohexyl,-CH2OC (O) O-cyclopentyl, ethyl, isopropyl, NHZ, or-NHC (O) CF3.

Rl7 is preferably H or alkyl, most preferably H, methyl or ethyl, and more preferably methyl.

Wo in substituent 12.0 is preferably selected from: alkyl or cycloalkyl, most preferably t-butyl, isopropyl, neopentyl, cyclohexyl or cyclopropylmethyl. leo in substituent 13.0 is preferably selected from: alkyl or cycloalkyl; most preferably t-butyl, isopropyl or cyclohexyl. R21 is preferably selected from: H or alkyl; most preferably H, methyl or isopropyl; and more preferably H.

R20 in substituent 14.0 is preferably selected from: cycloalkyl or alkyl.

R22 in substituent 15.0 is preferably selected from: phenyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, t-butyl, cyclopropyhnethyl, and most preferably selected from: t-butyl, cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl.

R20 in substituent 16.0 is preferably selected from: alkyl or cycloalkylalkyl; most preferably methyl, isopropyl or cyclohexylmethyl; more preferably methyl or isopropyl; and even more preferably methyl.

Rl3 and R14 are preferably selected from: H, F, C, to C4 alkyl (e. g., methyl or isopropyl),-CON (R"), (e. g.,-CONH,),-OR 15 (e. g., -OH), aryl (e. g., phenyl) or arylalkyl (e. g., benzyl); or when R13 and R 14 are taken together to form a cycloalkyl ring, said ring is preferably cyclopropyl cyclopentyl or cyclohexyl. Most preferably Rl3 and Rl4 are H.

For compounds of the invention, n is preferably 1-3, most preferably 1-2.

For compounds wherein W is ring 2.0 or 7.0, the - (CR'3R'4) n-R'2 substituent can be in the 2-, 3-or 4-position relative to the ring nitrogen, provided that the -(CR13R14)n-R12 substituent is not in the 4-position when Y is O, S, SO or SO2. Preferably, the- (CRR'-R'"substituent is in the 2-or 3-position, and most preferably in the 3-position. More preferably, the - (CR'3R'4) n-R'2 substituent is in the 2-position when n is 2, and in the 3-position when n is 1.

Compounds of formula 1.0, wherein X is N or CH, include, with reference to the C-11 bond, the R-and S-isomers: Compounds of this invention include the C-11 R-and S- isomers having the 2S stereochemistry.

Compounds of this invention include:

Compounds of the invention also include compounds corresponding to 19.0-42.0 DD, except that Ring I is phenyl instead ofpyridyl.

Compounds of the invention also include compounds corresonding to 19.0-42. ODD, except that Ring I is phenyl instead of Pyridyl, and the compounds have the 2S stereochemistry.

Compounds of this invention also include compounds corresponding to 19.0-42. ODD, except that the compounds have the 2S stereochemistry.

Compounds of formula 1.0 include compounds of formula 1.0 (C) wnerein R'is H or halo @preterably Br, ui or F), and R@ is H or halo (preferably Cl), and R9 is as defined for formula 1.0. Preferably, R'is halo (most preferably Br, Cl or F), and R2 is H or halo (preferably Cl).

Those skilled in the art will appreciate that compounds of formula 1.0 (C) include compounds of formulas 1. 0 (D) to 1.0 (G):

Lines drawn into the ring systems indicate that the indicated bond may be attached to any of the substitutable ring carbon atoms of any ring when more than one ring is present (e. g., ring 5.0).

Certain compounds of the invention may exist in different isomeric (e. g., enantiomers, diastereoisomers, atropisomers) forms.

The invention contemplates all such isomers both in pure form and in admixture, including racemic mixtures. Enol forms are also included.

Certain tricyclic compounds will be acidic in nature, e. g. those compounds which possess a carboxyl or phenolic hydroxyl group. These compounds may form pharmaceutically acceptable salts. Examples of such salts may include sodium, potassium, calcium, aluminum, gold and silver salts. Also contemplated are salts formed with pharmaceutically acceptable amines such as

ammonia, alkyl amines, hydroxyalkylamines, N-methylglucamine and the like.

Certain basic tricyclic compounds also form pharmaceutically acceptable salts, e. g., acid addition salts. For example, the pyrido- nitrogen atoms may form salts with strong acid, while compounds having basic substituents such as amino groups also form salts with weaker acids. Examples of suitable acids for salt formation are hydrochloric, sulfuric, phosphoric, acetic, citric, oxalic, malonic, salicylic, malic, fumaric, succinic, ascorbic, maleic, methanesulfonic and other mineral and carboxylic acids well known to those in the art. The salts are prepared by contacting the free base form with a sufficient amount of the desired acid to produce a salt in the conventional manner. The free base forms may be regenerated by treating the salt with a suitable dilute aqueous base solution such as dilute aqueous NaOH, potassium carbonate, ammonia and sodium bicarbonate. The free base forms differ from their respective salt forms somewhat in certain physical properties, such as solubility in polar solvents, but the acid and base salts are otherwise equivalent to their respective free base forms for purposes of the invention.

All such acid and base salts are intended to be pharmaceutically acceptable salts within the scope of the invention and all acid and base salts are considered equivalent to the free forms of the corresponding compounds for purposes of the invention.

The compounds of formula 1.0 can exist in unsolvated as well as solvated forms, including hydrated forms, e. g., hemi-hydrate. In general, the solvated forms, with pharmaceutically acceptable solvents such as water, ethanol and the like are equivalent to the unsolvated forms for purposes of the invention.

Compounds of the invention may be prepared according to the procedures described in WO 95/10516 published April 20, 1995, W096/31478 published October 10,1996, WO 97/23478

published July 3,1997, U. S. 5,719,148 issued February 17,1998, and copending Application Serial No. 09/094687 filed June 15, 1998 (see also W098/57960 Published December 23,1998); the disclosures of each being incorporated herein by reference thereto; and according to the procedures described below.

Compounds of the invention can be prepared according to the reaction schemes described below.

Scheme 1 Ri ci Ri ci N TEA + amine $0-8 OH 8 C..,, Rs C..., N O O O O O O The synthesis of the carboxylic acid (Scheme 1) begins with the differential protection (J. Med. Chem. (1994) 37,3443-3451) of the piperazine dicamphorsulfonic acid salt (Helv. Chun. Acta, (1960) 117,888-896) as illustrated in Scheme 2. Reaction of the distal amine with CBZ-OSuc at pH 11 followed by acylation with (BOC) O gives the differentially protected acid. Hydrogenation over Pd-C selectively removes the CBZ group and the resulting amino acid was coupled with the desired tricyclic chloride. Compounds containing various functional groups can also be prepared by the different protection strategy shown in Scheme 3, except for the compounds wherein R ! o is tert-butyl.

Scheme 2 Scheme 3 BOY i 1. BOC-ON N N HCI/dioxane ..,,,H 20'c..., oH, R-OC (O) CI N/N II I in 2CSA R O p Zo\ O Alternatively, the amine can be coupled to the di-BOC- protected acid intermediate prior to incorporation of the tricycle (Scheme 4). This derivative can be prepared from the di-CSA salt (Scheme 1) upon treatment of the salt with two equivalents (BOC) 20 under basic conditions. Coupling of the desired amine to this intermediate under standard conditions (DEC, HOBT, NMM) gives the amide, which upon TFA-mediated removal of the BOC- protecting groups can be selectively alkylated by the desired tricyclic chloride (TEA, DMF, rt, 48 hours). At this stage, the free amine can be acylated, alkylated, or amidated under conditions obvious to one skilled in the art. When R=Br, chiral HPLC separation can be employed to readily resolve the C-11 diastereomers.

Scheme 4 BOC BOC I I (N H+ + + amine > 0) 8 HF su C 0 ,, for Ri ci BOC O BOC O H Rl/1 Cl ' Cl TEA N N RI ci TEA N BOC O BOC O s H R8 Xc TEA <MC I 0 Rl=H or Br N SND", rR Ri ci - N N N Rg O

Finally, the anhydride derivative can be opened with the appropriate amine (rt, CH2Cl2), followed by acylation, alkylation, or amidation of the resulting free amine. From there, a similar sequence as illustrated in Scheme 4 (Scheme 5) may be employed for the synthesis of the desired derivatives.

Scheme 5 BOC BOC BOC N SOCI2-C°2 N 2) I- + amine-"$- C,, R2 C.. 8 9 C i DMF N r,0 (R) 2. R X N Cr (R BOC O O H H+ N R us ! !) N/f R9 IV

The synthesis of the requisite amines are described generally in the following schemes. In each, one skilled in the art can appreciate the areas where synthetic generalities can be applied for the synthesis of a wider variety of compounds than those specifically illustrated.

The majority of the 2-and 3-substituted piperidine and pyrrolidine derivatives can be prepared through similar methods as illustrated in Scheme 6 beginning with the appropriate amino alcohol. Likewise, various imidazole derivatives may be prepared by employing the sodium salt of the desired imidazole derivative. This general scheme is not applicable where indicated i. e. piperidines with a 2-hydroxymethyl substitutent cannot be prepared using an N-carbamoyl protecting group due to the formation of undesired oxazolones. In these cases the NH must be protected as the N- benzyl or N-allyl derivative.

Scheme 6 C02Et X\C02Et l. D- (-)-tartaric acid LAH OH > > 2. NaOH N N H H H BOC20 OH 1. TsCi N N (N) 2. Na-imidazole N N "< i BOC BOC N dioxane N H 2HCI Resolution of ethyl nipecotate with D-or L-tartaric acid (J.

Org. Chem. (1991) 56,1166-1170; Gazz. Chim. Ital. (1972) 102, 189-195.) gives the desired enantiomer which is converted to the free base by treatment with NaOH. Reduction of the acid with LAH followed by protection of the amine as the BOC derivative gives the alcohol. Treatment of the alcohol with p-toluenesulfonyl chloride in pyridine at 0 °C, followed by displacement with the sodium salt of the desired imidazole derivative and removal of the BOC-protecting group with Hcl/dioxane results in the desired amine as the hydrochloride salt.

The corresponding 2-and 3-substituted piperazine derivatives can generally be accessed through the anhydride (Scheme 5) as shown in Scheme 7. Ring opening of the anhydride with EtOH followed by reduction with NaBH4 gives the amino alcohol which can be converted to the N-substituted derivative by reductive amination with paraformaldehyde or another relevant aldehyde. Conversion to the desired imidazole derivative can be accomplished by displacement of the mesylate or tosylate with the sodium salt of the imidazole which upon removal of the BOC-protecting group gives the desired amine.

Scheme 7 BOC BOC BOC N NaBH4/EtOH N 1. (HCHO) X N > 1 > 1 Di 0 reflux 12h N Ti (OiPr) 4 N 1,//", OH N % O N 4 N H 2. NaBH4 Me 0 BOC 1. MsCl NEt3 N-fFA CH 2CI2 2. sodium imidazole Me Me

The 3-pyrrolidinemethanol intermediates can be synthesized as shown in Scheme 8 (J. Med. Chem. 1990,71-77). Treatment of the amine with the enoate gives a mixture of diastereomers which are readily separated by silica gel chromatography. Reduction of the amide with LAH and conversion to the imidazole derivative can be carried out as previously described. Catalytic hydrogenation gives the free amine.

Scheme 8 (i)Chromatography H3C N>OH H3CvND OH -) I- and > and (ii) LAH psi psi Et3N Et3N (ii) Na- Imidazole (ii) Na-Imidazole r\ry. H3C N N 3C N N 6 N Pd/C H Pd/C"2 i r HNr N \N \Nl N The 4-membered ring analogs can be synthesized as illustrated in Schemes 9 and 10. When the imidazole is directly attached to the ring, the sequence begins with mesylation of the alcohol followed by displacement with the sodium salt of the desired imidazole derivative. Removal of the benzhydryl protecting group is accomplished by catalytic hydrogenation.

Scheme 9 O 6) ^ MsCI/ Na-I midazole N--OH N_]-OMs CH2CI2-DMF 60C Pd 0 HN,--N zizi \/ For 4-membered ring compounds with a methylene spacer between the imidazole and the ring, displacement of the mesylate with NaCN gives the nitrile which is readily hydrolyzed to the acid with NaOH and esterified under Fischer esterification conditions.

The desired amine can be realized via transformations previously discussed.

Scheme 10 zizi (i) NaOH LAH OH (ii) MeOH/HCI U 69 ( !) MsCI \/ (i) MsCI \/N NJ (ii) Na-lmidazole HN>N (iii) Pd/C The morpholino side chains are prepared beginning with the epichlorohydrin as shown in Scheme 11 (Heterocycle, 38,1033,

1994). Ring opening of the epoxide with benzyl amine followed by alkylation of the resulting amino alcohol gives the amide.

Reduction of the amide with BH3 gives the morpholine into which the imidazole is incorporated by previously discussed methodology.

Removal of the N-benzyl protecting group gives the desired amine.

Following the above procedure, but using the epichlorohydrin gives the amine Scheme 11 H gr NAOH BH3 NaOH BHs NaOH BH3 CHC13-H20 ci tuf ¢) Na-Imidazol : 0 ip 0 L Pd/C') \ PO H2 N Compounds with a 7-membered ring in the side-chain may be prepared as shown in Scheme 12. a-Bromination of caprolactam followed by displacement with NaCN gives the nitrile. Methanolysis and subsequent reduction with LAH gives the amino alcohol which can easily be converted to the desired compound by previously described methodology.

Scheme 12 Br2/PBr3 NaCN HNC/C6H6 eBr 1 8-crown-6 HNCk O O O HCI LAH Boc20 MeOH HN) OMe HN, OH 0 0 O O 1. mol N BocN H NEt3/CH2CI2 BocN N2 2. sodium imidazole TFA N HN N2 The 4-substituted piperidine-3-methanol derivatives can be synthesized as illustrated in Scheme 13. Protection of the carboxylic acid as the oxazoline also serves to activate the pyridine ring toward nucleophilic attack by MeLi. Rearomatization with sulfur, hydrolysis of the oxazoline, and esterification gives the ester which upon quaternization and reduction gives the enoate.

Conjugate addition with MeI gives the 4,4-dimethyl derivative. This ester may be converted into the desired compound by previously described procedures.

Scheme 13 Ref. J. Pharm. ScL (1992) 81,1015; U. S. Pat. (1949) 2546652. HO--x N 1) MeLi, THF CCH3 No'-rOH 2) S, Toluene N N o Heat Heat O O 1) Con HCI, Heat CH3 2) H2SO4, MeOH Nw XOMe 2) NaBH4, MeOH H3CN OMe O O H3 CHgMg), CuC) Y Et, H3C-N <Me N 0 Scheme 14 THIOMORPHOLINE DERIVATIVES 0/0 oo Oxone \/1) LDA O\S//C02ET > f > N N N 2) EtOCOCl N N N N H Boc Boc Boc 0 O O O//\// LIBH4 SROH oms THF N N Boc Boc Na Br BocJyCr. N > N O N J N I$O rN Boc Br/ Cl 1 N C\ N N 0 N N , N, ! 5 2) (N zozo -I OO EDC,HOBt Scheme15 0 o r C 1) LDA S C02Et N quant-N 2) EtOCOCl N Boc Boc 23% Boc ! O s OH 1) Ts-CI/Pyr s ^N RIF N 2) Na Im zon 1 hr. Boc 3) HCI/diox. H. HCI 1 hr. HCI z 2) Br ci 0 g N EDC, HOBT N ."A o Bu ci 0 sr i v ci ßo s N ru con O Scheme 16

Those skilled in the art will appreciate that in Scheme 16 the wavy bond to H ( 52.0),-OCH3 (54. 0aand 54.0b),-CN (55. Oa and 55.0b),-COOH (56. Oa and 56.0b),-COOH (57.0a, 57.0b, 58. Oa and 58.0b) indicates that the band can be either # or # Compound () 52.0 is resolved following procedures similar to those disclosed in W097/23478 (published July 3,1997).

The reagents used in Reaction Scheme 3 are: Reaction Step a: Isatoic anhydride/methylene chloride; Reaction Step b: sodium nitrite/hydrochloric acid/methanol/cuprous chloride; Reaction Step c: (i) aq. hydrochloric acid/methanol/reflux (ii) sodium hydroxide/sodium cyanide; Reaction Step d: conc. hydrochloric acid/reflux.; and Reaction Step e: di-tert. butyldicarbonate/-sodium hydroxide/tetrahydrofuran.

Compounds useful in this invention are exemplified by the following preparative examples, which should not be construed to limit the scope of the disclosure. Alternative mechanistic pathways and analogous structures within the scope of the invention may be apparent to those skilled in the art.

PREPARATIVE EXAMPLE 1 To (R)- (-)-camphorsulfonic acid (2.5 kg) in distilled water (1250 mL) at 60 °C was added a solution of the potassium salt of 2-

carboxypiperazine (565 gm, 3.35 mol). The mixture was allowed to stir at 95 °C until completely dissolved. The solution was cooled to room temperature and allowed to stand 48 hrs. The resulting precipitate was filtered to obtain a damp solid (1444g). The solids were then dissolved in distilled water (1200 mL) and heated on a steam bath until all solids dissolved. The resulting solution was cooled slowly to room temperature and let stand 72 hrs. The crystalline solids were filtered to give a white crystalline solid (362 g). [c=-14. 9°.

PREPARATIVE EXAMPLE 2 The title compound from Preparative Example 1 (362 gm, 0.608 mol) was dissolved in distilled water (1400 mL) and methanol (1400 mL). 50% NaOH was added to the stirred reaction mixture until the pH reached ~9.5. To this solution was added di-tert. butyl- dicarbonate (336 gm, 1.54 mol) portionwise. The pH of the reaction mixture was maintained at 9.5 with 50% NaOH (total of 175 ml), and the reaction mixture stirred for 2.5 hours to obtain a white precipitate. The reaction mixture was diluted with ice/water (9000 mL) and washed with EtO (2000 mL). The Et,, was discarded and the pH of the aqueous layer adjusted to pH 3.0 by the portionwise addition of solid citric acid and extracted with CH2C12 (3 X 2000 mL). The organic layers were combined, dried over Na2SO4, filtered and evaporated to give the title compound as a white glassy solid (201.6g). FABMS: MH+=331.

PREPARATIVE EXAMPLE 3

To an ice cold solution DMF (49.6 ml) under a nitrogen atmosphere was added, dropwise, SOC12 (46.7 ml) over a period of 5 minutes in a 5 L round bottom flask The reaction mixture was allowed to stir for 5 minutes, warmed to room temperature, and stirred 30 minutes. The resulting solution was cooled to 0 °C and the title compound from Preparative Example 2 (201.6 gm, 0.61 mmol) in pyridine (51.7 mL) and CH3CN (1900 mL) was added via a. canule. The resulting solution was warmed to room temperature to obtain a yellowish turbid solution and stirred 18 hours. The reaction mixture was filtered and the filtrate poured into ice water (7L) and then extracted with EtOAc (4 X 2000 mL). The combined organics were dried over Na2SO4, filtered, and evaporated to dryness in vacuo to give the title product as a white solid (115.6g, 73% yield).

PREPARATIVE EXAMPLE 4 The title compound from Preparative Example 1 (17.85 gm, 30 mmol) was dissolved in distilled water (180 mL). Dioxane (180 mL) was added and the pH adjusted to-11.0 with 50% NaOH. The reaction mixture was cooled to 0-5°C in an ice-MeOH bath and a solution of benzylchloroformate (4.28 mL, 30 mmol) in dioxane (80 mL) was added over a period of 30-45 minutes while stirring at 0- 5°C and keeping the pH at 10.5 to 11.0 with 50% NaOH. After the

addition was complete, stirring was continued for 1 hr. The reaction mixture was then concentrated under reduced pressure.

The residue was dissolved in distilled water (180 mL), the pH adjusted slowly to 4.0 with IN HCl, and extracted with EtOAc (3 X 180 mL). The combined organics were dried over MgSO4, filtered, and evaporated to obtain the N, N-di-CBZ-2-carboxy-piperazine byproduct. The pH of the aqueous layer was adjusted to-10.5 with 50% NaOH and solid (Boc) O (7.86 gm, 36 mmol) was added and the mixture was stirred while keeping the pH at # 10. 5 with 50% NaOH. After 1 hr. the pH stablized. The reaction was checked by tlc (30% MeOH/NH3/CH2Cl2) and if not complete, more (Boc) 20 was added keeping the pH at ~10.5. When reaction was shown to be complete by TLC, the reaction mixture was washed with Et2O (2 X 180 mL) (check that the product is not in the Et2O layer and dispose of the Et20 layer). The aqueous layer was cooled in an ice bath and pH to adjusted to 2.0 with IN HC1 (slowly) (get bubbling initially). The aqueous layer was extracted with EtOAc (3 X 200 mL) and the combined organics dried over MgSO4, filtered and evaporated in vacuo to obtain a white solid (9.68 g, 88% yield).

PREPARATIVE EXAMPLE 5 The title compound from Prepartive Example 4 (9.6 gm, 26.3 mmol) was dissolved in absoluteEtOH (100 mL) in a hydrogenation vessel. The vessel was flushed with N2 and 10% Pd/C (3.0g, 50% by weight with water) was added. The mixture was hydrogenated at 55 psi of H2 for 18 hours during which time a precipitate formed.

When the reaction was complete (TLC, 30%-MeOH/NH3/CH2Cl2), the reaction mixture was filtered through a pad of celite, and the pad washed with EtOH followed by distilled H20. The filtrate was

evaporated to # 1/3 the volume and distilled H20 (200 mL) was added. The resulting solution was extracted with EtOAc (contains pure N, N-Di-Boc-2-carboxy-piperazine which was saved). The water layer was evaporated to dryness with azeotropic removal of residual H2O with methanol (2X) to give pure product (3.98g).

PREPARATIVE EXAMPLE 6 4- (3-bromo-8-chloro-6, 11-dihydro-5H benzo [5,6] cyclohepta [1,2- b] pyridin-11-yl)-1- [(1, 1-dimethylethoxy) carbonyl]-2[(1, 1-dimethylethoxy) carbonyl]-2 (R)- piperazinecarboxylic acid The tricyclic alcohol (5.6 gm, 17.33 mmol) was dissolved in CH2C12 (56 mL) and SOC12 (2.46 mL) was added while stirring under a dry N2 atmosphere.

After 5 hrs. the tlc was checked (by adding an aliquot of the reaction mixture to 1N NaOH and shaking with CH2C12 and checking the CH2C12 layer by tlc using 50% EtOAc/Hexanes as the eluent).

The mixture was evaporated to give a gum which was evporated from dry toluene twice and once from CH2Cl2 to give a foamy solid.

The resulting chloro-tricyclic compound was dissolved in dry DMF (100 mL) and the title compound from Preparative Example 5 (3.98 gm) was added followed by triethylamine (12.11 mL) and the mixture stirred at ambient temperature under a nitrogen atmosphere. After 24 hours, the reaction mixture was concentrated and the residue dissolved in EtOAc (200 mL) and

washed with brine. The brine layer was extracted with EtOAc (2X) and the combined organics were dried over MgS04, filtered, and evaporated to give a foamy solid. The solid was chromatographed on a 1 1/2"X 14"column of silica gel eluting with 2L of 0.4% 7N MeOH/NH3: CH, CL, 6L of 0.5% 7N MeOH/NH3 : CH2C4,2L of 0.65% 7N MeOH/NH3: CH2Cl2, 2L of 0.. 8% 7N MeOH/NH3; CH2Cl2, 4L of 1% 7N MeOH/NH3: CH2Cl2, 2L of 3% 2N MeOH/NH3;CH2Cl2, 2L of 5% 2N MeOH/NH3: CH2Cl2, 2L of 10% 2N MeOH/NH3: CH2Cl2, 2L of 15% 2N MeOH/NH3 : CH 2C4,4L of 20% 2N MeOH/NH3 : CH2Cl2 to obtain 4.63 gm of final product.

PREPARATIVE EXAMPLE 7 Step A Ref : Gazz. Chim. Ital. (1972) 102,189-195; J. Org. Chem. (1991) 56, 1166-1170.

Ethyl nipecotate (70.16g, 0.446 mmol) and D-tartaric acid (67g, 1.0 eq) were dissolved in hot 95% EtOH (350 mL). The resulting solution was cooled to room temperature and filtered and the crystals washed with ice-cold 95% EtOH. The crystals were then recrystallized from 95% EtOH (550 mL) to give the tartrate salt (38.5g, 56% yield). The salt (38.5g) was dissolved in water (300 mL) and cooled to 0 °C before neutralizing with 3M NaOH. The solution was extracted with CH2Cl2 (5 X 100 mL) and the combined organics dried over Na2SO4 and concentrated under reduced pressure to give a clear oil (l9. Og, 89% yield). CIMS: MH+= 158.

Step B

LAH (118 mL, 1.0 M in Et2O, 1.0 eq.) was added to a solution of the title compound from Step A (18.5g, 0.125 mmol) in THF (250 mL) at 0 °C over 20 minutes. The resulting solution was warmed slowly to room temperature and then heated at reflux 2 hours. The reaction was cooled to room temperature and quenched by the slow addition of saturated Na2SO4. The resulting slurry was dried by the addition of Na2SO4, filtered through Celite and concentrated to give a colorless oil (13.7g, 98% crude yield). CIMS: MH+=116; [α] 2°D=- 8.4° (5.0 mg in 2 mL MeOH).

Step C The title compound from Step B (13.6g, 0.104 mmol) was dissolved in MeOH (100 mL) and H20 (100 mL) and di-tert-butyl dicarbonate (27.24,1.2 eq.) was added portionwise keeping the pH >10.5 by the addition of 50% NaOH. The reaction mixture was stirred at room temperature an additional 2.5 hours and concentrated in vacuo. The residue was diluted with H20 (350 mL) and extracted with CH2C12 (3 X 150 mL). The combined organics were dried over Na2SO4, filtered, and concentrated under reduced pressure. The crude product was purified by flash chromatography using a 50% EtOAc in hexanes solution as eluent to give a white solid (12.13g, 48% yield). FABMS: MH+= 216; [a] 20D= +15.2 (5.0 mg in MeOH).

Step D

p-Toluenesulfonyl chloride (12.75g, 1.2 eq.) was added portionwise to the title compound from Step C (12.00g, 55.74 mmol) in pyridine (120 mL) at 0 °C. The resulting solution was stirred 0 °C overnight. Thereaction mixture was diluted with EtOAc (300 mL) and washed with cold IN HCl (5 X 300 mL), saturated NaHCO3 (2 X 150 mL), H20 (1 X 100 mL), brine (1 X 100 mL), and dried over Na, S04 and concentrated in vacuo to give a pale yellow solid (21.0g, 100% crude yield). FABMS: MH+= 370.

Step E The title compound from Step D (21.0g, 55.74 mmol) in DMF (300 mL) was treated with sodium imidazole (8.37g, 1.5 eq.) and the resulting solution heated at 60 °C for 2 hours. The reaction mixture was cooled to room temperature and concentrated in vacuo. The residue was diluted with H20 (300 mL) and extracted with CH2C12 (3 X 150 mL). The combined organics were dried over Na2SO4, filtered, and concentrated. The crude product was purified by flash chromatography using a 7% MeOH in CH2C12 solution as eluent to give a pale yellow solid (7.25g, 49% yield). FABMS: MH+= 266; [a] 20D = +8.0 (5.0 mg in MeOH).

Step F

The title compound from Step E (5.50g, 20.73 mmol) stirred at room temperature in 4M HCl in dioxane (50 mL) overnight. The resutlig solution was concentrated and the residue triturated with Et, 0 to give a yellow solid (4.90g, 99% yield). CIMS: MH+= 166.

PREPARATIVE EXAMPLE 8

By essentially the same procedure set forth in Preparative Example 7 except using L-tartaric acid instead of D-tartaric acid in Step A, the title compound was prepared.

PREPARATIVE EXAMPLE 9 Step A

A mixture of the piperazine anhydride (2. 56 g, 10. 00 mmol, 1.0 eq.) and sodium borohydride (965 mg, 25.00 mmol, 2.5 eq.) in absolute ethanol (50 ml) was gently refluxed under a nitrogen atmosphere for 48h. The reaction volume was decreased to approximately 10 ml under house vacuum and diluted with brine (50 ml). The mixture was extracted with ethyl acetate (8 x 25 ml).

The combined organic extracts were washed with brine (50 rnl), dried over Na2SO4, filtered, and concentrated under house vacuum at 30 °C. The residue was flash chromatographed (CH2C12: 10% NH4OH/MeOH = 17: 1 v/v) over silica gel to give the title compound (1.09 g, 50%) as a light-yellow, viscous oil. EIMS: m/z 217 ([M+H]+, 46%), 161 (B+). HR-MS (FAB): Calculated for CloH2lN203 (1M+H] +) : 217. 1552. Found: 217.1549.

Step B (Bhattacharyya, S. Tetrahedron Lett. 1994,35,2401.)

A mixture of the title compound from Step A (1.09 g, 5.04 mmol, 1.0 eq.), paraformaldehyde (300 mg, 10.08 mmol, 2.0 eq.), and titanium isopropoxide (1.5 ml, 5.04 mmol, 1.0 eq.) in absolute ethanol (5 ml) was stirred at 70 °C for 30 minutes and at room temperature for another 30 minutes. Sodium borohydride (195 mg, 5.04 mmol, 1.0 eq.) was added to the colorless solution. The solution was stirred at room temperature for 12h and at 60 °C for another 3h. The solution was cooled to 0 °C and treated with a 2.0 M aqueous ammonia solution (25 ml, 50.00 mmol, excess) to give a snow-white suspension. The suspension was filtered through a Celite# 521 plug and the filtrate was extracted with diethyl ether (4 x 25 ml). The ethereal extracts were combined and washed with brine (10 ml), dried over Na2SO4, filtered, and concentrated under house vacuum at 30 °C. The residue was flash chromatographed (CH2C12 : 10% NH4OH/MeOH = 9: 1 v/v) over silica gel to give the title compound (1.10 g, 95%) as a light-yellow, viscous oil. MS (EI) : m/z 231 ([M+H]+, 59%), 175 (B+). HR-MS (FAB): Calculated for C"H22N203 ([M+H] +) : 231.1709. Found: 231.1716.

Step C Methanesulfonyl chloride (296, ut, 3.80 mmol, 1.25 eq.) was added dropwise to a stirred solution of the title compound from Step

B (700 mg, 3.04 mmol, 1.0 eq.) and triethylamine (640 µl, 4.56 mmol, 1.50 eq.) in anhydrous dichloromethane (5 ml) at 0 °C under a nitrogen atmosphere. The resulting yellow suspension was stirred at 0 °C for lh and at room temperature for another 3h. The mixture was poured onto brine (25 ml) and extracted with dichloromethane (5 x 10 ml). The combined organic extracts were dried over Na2SO4, filtered, and concentrated under house vacuum at 25 °C to give a quantitative yield (940 mg) of crude mesylate, which was used directly in the next transformation (vide infra) without any attempts at characterization or purification.

A mixture of crude mesylate (940 mg, 3.05 mmol, 1.0 eq.) and sodium imidazole (608 mg, 6.08 mmol, 2.0 eq.) in anhydrous N, N-<BR> dimethylformamide (10 ml) was stirred at 60 °C for 12h under a nitrogen atmosphere. The brownish mixture was cooled to room temperature and diluted with brine (25 ml). The layers were separated and the aqueous layer was extracted with dichloromethane (4 x 25 ml). The combined organic extracts were dried over Na2SO4, filtered, and concentrated under house vacuum at 50 °C. The residue was flash chromatographed (CH2C12: 10% NHOH/MeOH =19: 1 v/v) over silica gel to give the title compound (432 mg, 1.54 mmol, 51%) as a thick, greenish oil. MS (EI): m/z 281 ([M+h]+, B+), 225 (79), 157 (91). HR-MS (FAB): Calculated for ,, N, O, ( [M+H]') : 281.1978. Found : 281.1976.

Step D A solution of the title compound from Step C (400 mg, 1.43 mmol, 1.0 eq.) in anhydrous trifluoroacetic acid-dichloromethane (10 ml, 1: 1 v/v) was stirred at room temperature under a nitrogen atmosphere for 12h. The volatiles were removed under house

vacuum at 40 °C and the residue was redissolved in 2.0 M aqueous NaOH solution (10 ml). The volatiles were again removed under house vacuum, but at a bath temperature of 60 °C. The residue was flash chromatographed (CH2C12: 10% NH4OH/MeOH = 6: 4 v/v) over silica gel to give the title compound (136 mg, 0.76 mmol, 53%) as a thick, yellow oil. MS (EI): m/z 181 ([M+H] +, B+), 161 (76). HR- MS (FAB): Calculated for C9H17 N, ( [M+H] +) : 181.1453. Found: 181.1458.

PREPARATIVE EXAMPLE 10 Step A N-Butoxycarbonyl-thiomorpholine Thiomorpholine (6 gm, 58 mmol) was dissolved in CH2C12 (200 mL) under a dry nitrogen atmosphere and the reaction mixture cooled in an ice bath. A solution of di-tert. butyl-dicarbonate (15.3 gm, 70 mmol) in CH2Cl2 (50 mL) was added dropwise and the reaction mixture stirred for 4 hours. The reaction mixture was washed with brine, followed by saturated NaHCO3, dried over MgSO4, filtered, and evaporated to obtain 14.37 gm of title product as a crystalline solid. mp= 72.9-78.9 °C.

Step B N-Butoxycarbonyl-thiomorpholinesulfone The title compound from Step A (16 gm, 78.7 mmol) was dissolved in 50% CH3OH-H20 (500 mL) at 0°C. A slurry of Oxone° (

72.6 gm, 118.05 mmol) was added portionwise while monitoring the pH at 10.5 with 25 % NaOH. After 2 hours, the reaction mixture was filtered and the CH30H was evaporated under reduced pressure. The residue was extracted with EtOAc 3 times to obtain 15.5 gm (84%) of title product as a crystalline solid. mp= 157-159.2 °C.

Step C N-Butoxycarbonyl-2-carboxyethyl-thiomorpholinesulfone The title compound from Step B (3.0 gm, 12.7 mmol) was dissolved in THF (30 mL). The reaction mixture was cooled to -78°C in a dryice acetone bath under a dry nitrogen atmosphere and 8.5 ml of a 1.5 Molar solution of lithium diisopropylamide in cyclohexane (LDA) was added dropwise and the solution stirred for 1/2 hour. Ethylchloroformate (1.83 mL, 19.05 mmol) was added dropwise and the solution stirred at-78 °C for 1 hour. The temperature was allowed to rise to ambient and the reaction mixture stirred an additional 2 hours. The reaction mixture was added to brine and the product extracted three times with EtOAc to obtain 2.87 gm of crude product which was used in the next step without purification.

Step D<BR> <BR> N-Butoxycarbonyl-2-hydroxymethyl-thiomorpholinesulfone The crude tile compound from Step C was dissolved in 30 ml of THF, cooled in an ice bath, and stirred. A 2M THF solution of Lithium borohydride (9 mL, 18 mmol) was added dropwise and the reaction mixture stirred for 3 hours. IN HCl (~ 10 mL) was added slowly and the mixture stirred for 5 min. IN NaOH (~20 mL) was added and the crude product extracted with ethylacetate, dried over magnesium sulfate, filtered, and evaporated to obtain a crude oil.

The crude oil was chromatographed on silica gel using 20% ethyl acetate/hexanes to 40% ethylacetate/hexanes to obtain 0.88 gm of title product as a solid. mp= 126.9-131.9 °C.

Step E N-Butoxycarbonyl-2-imidazolylmethyl-thiomorpholinesulfone The title compound from Step D (0.56gm, 2.14 mmol) and diisopropylethylamine (0.372 ml, 2.14 mmol) was dissolved in 5 mL of dichloromethane. Methanesulfonyl chloride (0.198 ml, 2.56 mmol) was added and the reaction mixture stirred under a dry nitrogen atmosphere for 30 min. The reaction mixture was added slowly to melted imidazole (2.9 gm, 20 eq.) at 120 °C. After the dichloromethane evaporated the reaction mixture was cooled to ambient to obtain a brown solid. The solid was dissolved in water and the product extracted with ethylacetate three times to obtain

0.449 gm of title product. mp= 149.7-151.3 °C, FABMS (M+1) =316.2.

Step F Preparation of 2-imidazolylmethyl-thiomorpholinesulfone The title compound from Step E (0.44 gm, 1.4 mmol) was dissolved in 5 ml of 4NHCl/dioxane and stirred for 1 hr. The mixture was evaporated to obtain 0.45 gm of title product.

PREPARATIVE EXAMPLE 11 Step A N-Butoxycarbonyl-thiomorpholinesulfoxide N-Butoxycarbonyl-thiomorpholine from Preparative Example 10 Step A (7.07 gm, 58 mmol) was dissolved in 200 ml of dichloromethane. 50-60% mCPBA (13.7 gm, 80 mmol) was added portionwise over a period of 15 min. After 2 hours at ambient temperature the reaction mixture was washed with sat. sodium bisulfite, followed by sat. sodium bicarbonate, and the dried over magnesium sulfate, filtered, and evaporated to obtain 13.08 gm of a white solid. FABMS (M+1) =220.

Step B

By essentially the same procedures set forth in Preparative Example 10 Step C-F, the title compound was prepared.

PREPARATIVE EXAMPLE 12 2-Methylimidazole (0.27g, 1.3 eq.) was added to a solution of NaH (0.13g, 1.3 eq., 60% in mineral oil) in DMF (5 mL) at room temperature and the resulitng solution stirred 20 minutes before adding the title compound from Preparative Example 7 Step D (0.94g, 2.54 mmol). The reaction mixture was heated to 60 °C for 2 hours, cooled to room temperature and concentrated. The crude product was diluted with H2O (50 mL) and extracted with CH2C12 (3 X 75 mL). The combined organics were dried over Na2SO4, filtered and concentrated in vacuo. The product was purified by flash chromatography using a 7% MeOH in CH, C4 solution as eluent to give a white solid (0.66g, 93% yield). CIMS: MH+= 280; [a] 2°D +4.9 (6.5 mg in 2.0 mL MeOH).

By essentially the same procedure set forth in Preparative Example 7 Step E, the following title compounds in Column 4 were synthesized beginning with the tosylate in column 2, using the imidazole derivative in Column 3, Table 1: TABLE1 Prep Column 2 Column 3 Column 4 Ex. 13 'OTs N 3 BOY BOY Bouc BOC 14 OTsN N RU HAN/, BOC CH3 BOC BOC BOC LCMS: MH+= 280 15 3-, \ H3 OT s H3 N ^/C H3 N N N N BOC Boy BOC BOC SOTS HAN N N \N BOC CHs NJ sr sr BOC 16 (A) 0. , CH3 O, O OMs H HNN NI,/N cl3 BOC BOC 16 (B) %"° eN BOC OMs HN '. N BOCBOC N BOC BOC TABLE 1-continued Prep Column 2 Column 3 Column 4 Ex. 16 (C) OTs H3 CH3 CH3 BOC CH3) HN,N H3C N CH3 BOC \ J CH3 ZON BOC 16(D)'OTs H CH3 i N H3C,/, N CH3 Bouc BOC CH3 ZON BOC 16 (E) mOTs HOSCH3 Ht HBr' /N BOC N CH3 BOY BOC BOC PREPARATIVE EXAMPLE 17

To the title compound from Preparative Example 13 (1. Og, 3.58 mmol, 69: 31 4-Me: 5-Me) in CH2Cl2 (10 mL) at 0 °C was added TrCl (0.32g, 1.05 eq. based on 5-Me). The resulting solution was stirred at 0 °C for 2 hours and concentrated under reduced pressure. The crude mixture was purifed by flash chromatography using a 50 % acetone in EtOAc solution as eluent to give the title compound as a clear oil (0.50g, 72% yield). CIMS: MH+= 280.

PREPARATIVE EXAMPLE 18 By essentially the same procedure set forth in Preparative Example 17, the title compound was prepared (0.49g, 82% yield).

By essentially the same procedure set forth in Preparative Example 7 Step F except using the compounds prepared in Preparative Examples 12,13,14,15,16 (Column 2, Table 2), 16A, 16B, 16C, 16D, 17,18,71A. (step D), 71A (step F) 16E, 72A, 74A, 75A and 76, the amine hydrochlorides in Column 3, Table 2 were prepared: TABLE 2 Prep N-Boc Amine Amine Ex. _ _ _QH ; CCH ; C2hui HC N NJHC N BOC CIMS: MH+= 180 20 C H3-CH3 IN N ON BOC 2HCI CIMS: MH+= 180

TABLE 2-continued Prep N-Boc Amine Amine Ex. 21 CH, _CH3 BOC BOC H . 2HCI 22 N N N NU BOC 2HC1 23 rCH3, CH3 IN ut N z BOC 2HCI H H 23(A) H H Z N CON BOC H 2HC1 k L, L, C 23 (B) N N (>tN N (NN N N k k, BOC H 2HCI H H 23 (C) H H N z N OU BOC H 2HCI 23 (D) NJ NJ NJ NJ BOC H 2HCI TABLE 2-continued Prep N-Boc Amine Ex. 23 (E) N J N'CH s N N CH3 BOC H 2HCI 23 (F)0 r\f NH3CA N aH3CA N BOC H 2HCI 23 (H) 0t"° O\,/O N Nq N N L-- N BOC CH3 H 2HCI 3 23 (I) %"° CH3 Ou,"o XCH3 0\ 0 N v tXN@NN z BOC H 2HCI 23 (J) CH3 CH3 N aNX HIC N CH3 C/ BOCH TABLE 2-continued Prep N-Boc Amine Amine Ex. 23 (K) CHs CH3 0"'0"' N NJ 2OC1 BOC H 23 (L) HO H N N il "N"N 2HC) BOCK EXAMPLE 1 The title compound from Preparative Example 6 (1. Og, 1.15 eq.) was added to a solution of the title compound from Preparative Example 1 (2.43g, 3.81 mmol), DEC (0. 95g, 1.3 eq.), HOBT (2.57g, 5 eq.) and NMM (2.51 mL, 6.0 eq.) in DMF (50 mL). The resulting solution was stirred at room temperature 24 hours. The reaction mixture was diluted with H2O until precipitation ceased and the slurry filtered. The precipitate was diluted with CH2C12 (200 mL), washed with H20 (2 X 100 mL), dried over Na2SO4 and concentrated.

The crude product was purified by flash chromatography using a 5% (10% NH40H in MeOH) solution in CH2C12 as eluent to give a pale yellow solid (1.8g, 68% yield). LCMS: MH+= 683.

By essentially the same procedure set forth in Example 1 only substituting the appropriate amine, one can obtain compounds of the formula shown below with R as listed in Column 2 of Table 3.

TABLE 3 Ex. R8= MP (°C) CMPD 2 ----LCMS: MH+= 683 zizi 11- (R, S) 3 \ t 126-131 LCMS: MH+= 697 W CH ; C H3. 11- (R, S)

TABLE 3-continued Ex. R$= MP (°C) CMPD 4 128-133 LCMS: MH+= 697 N . N J, _,, N/ CH3 ; 11- (R, S) 4.1CHg 114-121 LCMS: MH+= 697 J N . e 4.2 CH3 131-135 LCMS: MH+= 697 , xN<NoN 5 N-Me 123-134 FABMS: MH+= r 698 11- (R, S) 6----FABMS: MH+= N,,//N 701 7----FABMS: MH+=717 8 179-182 FABMS: MH+=733 . N NjN NkN t, N 175-183 FABMS: MH+=669 L. N N : 11- (R, S) EXAMPLE 10 and EXAMPLE 11 The title compound from Example 1 was separated into individual (R)-and (S)-isomers by Preparative HPLC with a CHIRALPAK AD column using a 15% iPrOH in hexanes solution with 0.2% DEA as eluent.

EXAMPLE 10 11- (R)-isomer: retention time (analytical) =8.845 minutes;<BR> [a] D= +14.0 (2.72 mg in 2.0 mL MeOH); mp=130-134 °C; LCMS: MH+= 683.

EXAMPLE 11 11- (S)-isomer: retention time (analytical) =15.416 minutes;<BR> [(X] D=; mp=122-127 °C ; LCMS: MH+= 683.

EXAMPLE 12 and EXAMPLE 13 By essentially the same procedure set forth in Example 10 and 11 except using the title compound from Example 2, the title compounds were prepared.

EXAMPLE 12 11- (R)-isomer: retention time (analytical-15% iPrOH: 0.2%<BR> DEA in hexanes) = 18.84 minutes; [a] D= ; mp=135-138 °C ; MS: MH+=683.

EXAMPLE 13 11- (S)-isomer: retention time (analytical-15% iPrOH: 0.2%<BR> DEA in hexanes) = 23.758 minutes; [OC] D=; mp=127-130 °C ; MS: MH+=683.

PREPARATIVE EXAMPLE 24 The title compound from Example 12 (0.87g, 1.27 mmol) in CH2Cl2 (9.0 mL) was stirred with TFA (9. 0 mL) at room temperature 1 hour. The reaction mixture was cooled to 0 °C and neutralized

with 50% NaOH, separated, and the aqueous layer extracted with CH2C12 (3 X 200 mL). The combined organics were dried over Na2SO4, filtered, and concentrated in vacuo (0.56g, 75% crude yield).

EXAMPLE 14 The title compound from Preparative Example 24 (0.12g, 0.21 mmol) and TEA (0.15 mL, 5.0 eq.) were dissolved in CH2C12 (5.0 mL) and isopropyl chloroformate (1.05 mL, 5.0 eq.) was added.

The reaction mixture was stirred at room temperature overnight before adding H2O (15.0 mL) and extracting with CH2Cl2 (2 X 100 mL). The combined organics were dried over Na2SO4, filtered, and concentrated in vacuo. The crude product was purified by flash chromatography using a 2.5% (10% NH40H in MeOH) solution in CH2C12 as eluent (0.096g, 69% yield). FABMS: MH+= 669; mp= 126- 128 °C.

EXAMPLE 15 By essentially the same procedure set forth in Example 14 only substituting cyclohexyl chloroformate, the title compound was prepared (0.053g, 44% yield). FABMS: MH+=709 ; mp= 140-144 °C.

EXAMPLE 16 The title compound from Preparative Example 24 (0.13g, 0.23 mmol) was dissolved in CHCL ; (4. 0 mL) and t-butylisocyanate (0.13 mL, 5.0 eq.) was added. The resulting solution was stirred at room temperature 2 hours, diuted with H2O (15 mL) and extracted with CH2Cl2 (3 X 50 mL). The combined organics were dried over Na2S04, filtered, and concentrated in vacuo. The crude product was purified by flash chromatography using gradient of 2.5% MeOH in CH2C12,5% MeOH in CH. CL, and finally a 10% (10% NH40H in MeOH) in CH2Cl2 as eluent (0.069g, 44% yield). LCMS: MH+= 682; mp=148-153°C.

EXAMPLE 17 By essentially the same procedure set forth in Example 16 only substituting the isopropylisocyanate, the title compound was prepared (0.09g, 64% yield). LCMS: MH+= 668; mp= 132-136 °C.

PREPARATIVE EXAMPLE 25 By essentially the same procedure set forth in Preparative Example 24 only using the title compound from Example 10, the title compound was prepared.

EXAMPLE 18 By essentially the same procedure set forth in Example 16 only substituting the title compound from Preparative Example 25, the title compound was prepared. FABMS: MH+=682; mp=112-120 °C.

EXAMPLE 19 By essentially the same procedure set forth in Example 14 only substituting the title compound from Preparative Example 25,

the title compound was prepared. FABMS: MH+=669; mp= 123-132 °C; [OC] 20D= +16. 4° (4.5 mg in 2.0 mL MeOH) PREPARATIVE EXAMPLE 26 By essentially the same procedure set forth in Preparative Example 7Steps C to F only beginning with L-prolinol, the title compound was prepared.

PREPARATIVE EXAMPLE 27 By essentially the same procedure set forth in Preparative Example 24, only beginning with D-prolinol, the title compound was prepared.

PREPARATIVE EXAMPLE 28 Piperazine anhydride (1.03g, 1.2 eq.) was added portionwise to a solution of the title compound from Preparative Example 27 (0. 75g, 3.35 mmol) in CHOC4 (5.0 mL) and TEA (2.33 mL, 5.0 eq.) and the resulting solution was stirred 10 minutes at room

temperature before adding CBZ-OSuc (l. OOg, l. Oeq.) The resulting mixture was stirred at room temperature overnight, and concentrated in vacuo. The crude product was purified by flash chromatography using a5% MeOH in CH2C12 solution as eluent to yield a white solid (0.94g, 56% yield). LCMS: MH+= 498; [ 2OD= +61.6° (3.8mgin2. 0mLCHCl3).

EXAMPLE 20 A solution of the title compound from Preparative Example 28 (0.85g, 1.71 mmol) was stirred at room temperature in CH2C12 (10 mL) and TFA (3 mL) three hours. The reaction mixture was concentrated under reduced pressure and the compound was redissolved in CH2Cl2 (7 mL), treated with chloride {Scheme7 4} (0.29g, 1.0 eq.) and TEA (1.75 mL, 15 eq.). The resulting solution was stirred at room temperature 96 hours. The reaction mixture was diluted with saturated NaHCO3 (50 mL), water (50 mL), and CH2C12 (50 mL) and separated. The aqueous layer was extracted with CH2Cl2 (2 X 75 mL) and the combined organics dried over Na2SO4, filtered, and concentrated under reduced pressure. The crude product was purified by flash chromatography using a 6% (10% NH40H in MeOH) solution in CH2Cl2 as eluent to yield a tan solid (0.29g, 48% yield). mp 80-84 °C; LCMS: MH+= 703.

PREPARATIVE EXAMPLE 29 The title compound from Example 20 (0.24g, 0.341 mmol) was stirred at room temperature in HBr/AcOH (2.0 mL) 2 hours.

The reaction mixture was triturated with Et20 and any remaining AcOH removed by azeotroping with toluene to give the HBr salt which was neutralized with IN NaOH and extracted into CH2C12 (3 X 50 mL). The combined organics were dried over Na2SO4, filtered, and concentrated in vacuo to give a tan solid (0.18g, 95% yield) which was used without further purification. LCMS: MH+= 569.

EXAMPLE 21 By essentially the same procedure set forth in Example 16, only using the title compound from Preparative Example 29, the title compound was prepared (0.029g, 50% yield). LCMS: MH+= 668; mp=137-139 °C.

EXAMPLE 22 To the title compound from Preparative Example 29 (0.10g, 0.175 mmol) and TEA (0.037 mL, 1.5 eq.) in CH2C12 (5.0 mL) was added MsCl (0.16 uL, 1.2 eq.) and the resulting solution was stirred at room temperature overnight. The resulting solution was quenched by the addition of saturated NaHCO3 (10 mL), diluted with H20 (25 mL) and extracted with CH2Cl2 (3 X 25 mL). The combined organics were dried over Na2SO4, filtered, and concentrated in uacuo. The crude product was purified by flash chromatography using a 10% (10% NH40H in MeOH) solution in CH 2C4 as eluent to yield a tan solid (0.70g, 64% yield). LCMS: MH+= 647; mp= 135-141 °C.

EXAMPLE 23 By essentially the same procedure set forth in Example 22 only substituting the amine hydrochloride from Preparative Example 26 and quenching with cyclohexyl isocyanate in place of CBC-OSuc, the title compound was prepared. LCMS: MH+= 669; mp=187.

PREPARATIVE EXAMPLE 30 Tricyclic chloride (5.04g, 1.1 eq.) was added to a solution of the title compound from Preparative Example 5 (4.0g, 17.3 mmol) and TEA (12.05 mL, 5 eq.) in DMF (60 mL). The resulting solution was stirred at room temperature 72 hours at which time the reaction mixture was concentrated under reduced pressure. The residue was diluted with 3M NaOH and extracted with EtOAc. The aqueous layer was neutralized with 50% citric acid and extracted with EtOAc. The combine organics were dried over Na2SO4, filtered, and concentrated in vacuo. The crude product was purified by flash chromatography using a 12% (10% NH, OH in MeOH) solution in CH2C12 as eluent to give the C-11 (S)-isomer (2.13g, 54%) as the first eluting isomer and the C-l 1 (R)-isomer (2.4g, 61%) as the second eluting isomer.

11- (S)-isomer (first eluting isomer): [a] 2OD=-13. 4° (3.72 mg in 2.0 mL MeOH); LCMS: MH+= 458.

11- (R)-isomer (second eluting isomer): [α] 2°D=+84. 9° (5.18 mg in 5.0 mL MeOH); FABMS: MH+= 458.

EXAMPLES 24-35G By essentially the same procedure set forth in Example 1 only using the title compounds from Preparative Example 30 (individual C-11 (S)-and (R)-isomers) as listed in column 2 of Table 4 and substituting the appropriate amine, the title compounds of the formula shown below with W as listed in column 3 of Table 4 are obtained.

TABLE 4 EX. C-11 RS= MP CMPD isomer (OC) 24 S n 1S\ 115-LCMS: w NN9'-",/N bN 126 MH'= 60$

TABLE 4-continued EX. C-11 R8= MP CMPD isomer (°C) 25 R 124-LCMS: NC)-, N,// 26 s 120-LCMS: CH3 CHg 27 R 110-LCMS: . N N (N 119 MH+= 619 CH3 28 S C H3 11 5-LCMS: 132 MH+= 619 N 29 R CH3 109-LCMS: 124 MH+= 619 N. N 30 S ^ 105-LCMS: CH3 TABLE 4-continued EX. C-11 R8= MP CMPD isomer (°C) 31 R 121-LCMS: , NNSN>t 142 MH+= 619 CH3 32 S CH3 80-85 LCMS: MH+= 619 rN<NvN 33 R CH3 117-LCMS: 120 MH+= 619 N N 34 S ^----LCMS: N N MH'=634 cl3 CHs 35 R----LCMS: N N MH+=634 Cl3 "CHs 35 (A) S \ 110-MS: 112 MH+=633 RNJ."NsN TABLE 4-continued EX. C-11 RS= MP CMPD isomer (°C) 35 (B) R \ 89-92 MS: MH+=633 . 35 (C) S \ 104-MS: 106 MH'=633 No,.N9X N@N 35 (D) R \ 79-81 MS: mu+=633 , N<N@N 35 (E) R ip---FABMS: MH+=670 N . N CH3 35 (F) S 115-LCMS: 120 MH'=606 /CH3 zon 35 (G) S 97--LCMS: NR N2" » N 122 MH+=605 H PREPARATIVE EXAMPLE 31 Step A 50% NaOH was added to a solution of the title compound from Preparative Example 1 (11.47g, 19.28 mmol) in dioxane: H2O (1: 1,64 mL) until the pH was-11.5 and BOC-ON (5.22g, 1. 1 eq.) was added in two portions. 50% NaOH was added to keep the pH at -11.5. When the pH stabilized the resulting solution was stirred at room temperature overnight. The pH was adjusted to-9.5 ny the addition of 1M HC1 and isopropyl chloroformate (21.21 mL, 1.0 M in toluene, 1.1 eq.) was added. The resulting solution was kept at pH #9. 5 and stirred 3 days. The reaction mixture was concentrated and extracted with Et20, readjusting the pH to 9.5 following each extraction. When the pH stabilized at-9.5 for 3 consecutive extractions the aqueous layer was acidified to pH #4. 5 with 50% citric acid and to pH-3 with 1M HC1 and extracted with EtOAc (3 x 100 mL). The combined organics were dried over Na2S04, filtered, and concentrated under reduced pressure to give a white solid (5.8g, 90% yield). FABMS: MH+= 317. Treatment of the product with TFA yielded the deprotected amine which was used without further purification.

Step B By essentially the same procedure set forth in Preparative Example 30 only substituting the compound from Preparative Example 31 Step A, the title compound was prepared and separated into C-11 isomers: 11- (S)-isomer (first eluting isomer): LCMS: MH+= 444.

11- (R)-isomer (second eluting isomer): LCMS: MH+=444.

EXAMPLES 36-411 By essentially the same procedure set forth in Example 1 only substituting the title compounds from Preparative Example 31 (individual C-l 1 (S)-and (R)-isomers) and substituting the

appropriate amine, the compounds of the formula shown below with W as listed in column 3 of Table 5 are obtained.

TABLE 5 EX. C-11 R= MP CMPD isomer (°C) 36 S CH3 123-LCMS: 132 132 MH'=605 , NJ", NN<N 37 R CH3 95-LCMS: 111 MH+=605 RN\J"N<N 38 s 92-FABMS: NNJ-", N4N 101 MH+=605CH3 CHg CH3 39 R n 1S\ 111-FABMS: w NNJ-",/NXN 125 MH+=605 J-.., CH3 TABLE 5-continued EX. C-11 R$= MP CMPD isomer (°C) 40 s 107-FABMS: w . N N CH3 41 R 95-FABMS: . N N CH3 C H3 41 (A) S CH3 117-LCMS: 120 l 120 MH+=605 r N4 N@N 41 (B) R CH3 101-LCMS: 120 MH+=605 J-N 41 (C) S 104-LCMS: ,IN 108 MH'=604 Isomer 1,2 41 (D) S 98-LCMS: . N N 100 MH+=604 Isomer 1 TABLE 5-continued EX. C-11 R$= MP CMPD isomer (°C) 41 (E) S/ 100-LCMS: I I 103 MH+=604 Isomer 2 41 (F) s CH3 90-LCMS: 105 MH+=618 N Isomer 1,2 41 (G) s""CH3 90-LCMS: 105 MH+=618 oc Isomer 1 41 (H) s CH3 95-LCMS: Na 105 MH+=618 1 Isomer 2 41 (I) S nez 95-LCMS: I I N N< N 104 MH+=602 . Isomer 1,2 PREPARATIVE EXAMPLE 32

By essentially the same procedure set forth in Preparative Example 31 only substituting cyclohexyl chloroformate for isopropyl chloroformate in Step A, the title compounds (C-11 (S)-and (R)- isomers) were prepared and separated into individual diastereomers: ll- (S)-isomer (first eluting isomer): FABMS: MH+=484. ll- (R)-isomer (second eluting isomer): FABMS: MH+=484.

EXAMPLES 42-47CC By essentially the same procedure set forth in Example 1 only substituting the title compounds from Preparative Example 32 (individual C-11 (S)-and (R)-isomers) and substituting the appropriate amine, the compounds of the formula shown below with W as listed in Column 3 of Table 6 can be obtained.

TABLE 6 EX. C-11 R8= MP CMPD isomer (°C) 42 S CH3 99-FABMS : 113 MH=645 No N/1 43 R CH3 108-FABMS: 118 MH+=645 .NJ'''.Nw% N 44 R nN 112-FABMS : C H3 45 R 108-FABMS : CH3 46 s 91-FABMS: , N<NXN 94 MH+=645 CH3 47 R ? 1 100-FABMS: N 106 MH+=645 CH3 TABLE 6-continued EX. C-11 R8= MP CMPD isomer (°C) 47 (A) S CH3 122-FABMS: 127 MH+=645 , N4N@N 47 (B) R CH3 133-FABMS: 9 HN 139 MH+=645 N N N P 47 (K) R \ 74-MS: 76 MH+=659 N N--//N 47 (D) S \ 66-MS: 68 MH'=659 8 N9X N@N N 47 (E) R \ 85-MS: 89 MH+=659 e mq.. NJ.,,,,/N,'/ 47 (F) S \ 48-MS: 52 MH+=659 N non TABLE 6-continued EX. C-11 R$= MP CMPD isomer (°C) 47 (G) S H3 CH3 98-LCMS: 130 MH+=659 , N N,//N -1 47 (H) S H3C CH3 106-LCMS: 125 MH+=659 Nid non s 47 (I) S N 113-LCMS 113-LCMS 8, No/J"> N) 115 MH+=631 H 47 (J) S e r 106-LCMS: 'N 132 MH'=631 H 47 (K) S N 101-LCMS: 123 MH+=645 N, CH3 47 (L) S---FABMS: 0 MH'=696 N \ N H3C TABLE 6-continued EX. C-11 R$= MP CMPD isomer (°C) 47 (M) R---FABMS: MH+=696 N N N H3C 47 (N) S FABMS : ZOZO f MH+=696 , N, N J'-"'N N N H3C HsC 47 (0) R/P---FABMS: N NC MH+=696 f N ì1 N N H3C 47 (P) S H3G=N FABMS: , N MH+-674 CH3 47 (Q) R H3Cf N---FABMS: , _ MH+=674 CH3' CHg TABLE 6-continued EX. C-1 1 R8= MP CMPD isomer (°C) 47 (R) S Hs N---FABMS: MH+-674 N N N/CH3 CH3 47 (S) S 1 FABMS: MH+=646 ? N HIC HIC H3C 47 S---FABMS: N MH'=646 < N) H3C H3C HgC 47 (U) S e f 1 117-FABMS: 120 MH+=644 Isomer 1 47M s 105-FABMS: iI Na 0, Cl N 108 MH+=644 Isomer 2 TABLE 6-continued EX. C-11 R8= MP CMPD isomer (°C) 47 (W) S/ (CH3 94-LCMS: 113 MH+=658 i (Isomer 1,2) 47 (X) s CH3 94-FABMS: 113 113 MH+=658 Isomer 1 47 (Y) s CH3 100-LCMS: Na 118 MH+=658 L Isomer 2 47 (Z) S/ 100-LCMS: 108 MH+=658 CHg Isomer 1,2 47 (AA) S 100-LCMS: 115 MH+=658 CH3 Isomer 1 47 (BB) S 108-LCMS: 120 MH+=658 CH3 Isomer 2 _ TABLE 6-continued EX. C-11 R8= MP CMPD isomer (°C) 47 (CC) S CHs 108-FABMS: -\ 113 MH+=659 NN Rp N Isomer 1,2 PREPARATIVE EXAMPLE 33 By essentially the same procedure set forth in Preparative Example 24, only using the title compounds from Example 26, the title compound was prepared.

By essentially the same procedure set forth in Preparative Example 33 only substituting the compound from the example listed in column 2 of Table 7, the title compounds of the formula shown below with R8 as in column 4 of Table 7 were prepared:

TABLE 7 Prep. Ex. Ex. C-11 R8= Isomer 34 27 R . N J. _,, N CHs 35 28 S H3 36 29 R CH3 36 (A) 30 S ,/N CHs MP=99-112°C LCMS: MH+=618 36 (B) 31 R . NIV N CH3 CHg MP=110-123°C LCMS: MH+=618 36 (C) 32 S CH3 e 14rN MP=96-106°C LCMS: MH+=618 TABLE 7-continued Prep. Ex. Ex. C-11 W= Isomer 36 (D) 33 R CH3 N . MP=150-152°C LCMS:MH+=618 EXAMPLE 48

By essentially the same procedure set forth in Example 16 only substituting the title compound from Preparative Example 33, the title compound was prepared. FABMS: MH+=618; mp= 111-140 °C.

By essentially the same procedure set forth in Example 48 only substituting the title compounds from the Preparative Example listed in column 2 of Table 8, the title compounds of the formula shown below with R8 listed as in column 4 of Table 8 are obtained.

TABLE 8 Ex. Prep. C-11 MP (OC) CMPD Ex. isomer 49 34 R 102-125 FABMS : w . N J. _,,, N 618 CH3 618 50 35 S H3 123-135 FABMS: N 618 51 36 R CH3 112-130 FABMS: MH+= N 618 51A 36A S 99-112 LCMS: MH+= N zon CH3 51B 36B R 110-123 LCMS: CH3 618 cl3 CHs 51 C 36C S CH3 96-106 LCMS : MH+= R N9>g N@N 618 TABLE 8-continued Ex. Prep. C-11 R8= MP (°C) CMPD Ex. isomer 51D 36D R CH3 150-152 LCMS: mu+=61 , X Nt N4N MH+-61 .

PREPARATIVE EXAMPLE 48 (R) AND (S)-[2-(lH-IMIDAZOL--1-YL) METHYL] MORPHOLINES Step A (R) AND (S)-3-CHLORO-1 (BENZYLAMINO)-2-PROPANOLS (T. Mori et al Heterocycles 38,5 1033,1994)

A mixture of (R)-epichlorohydrin (5g, 54.03 mmoles) and benzylamine (5.8g, 54.03 mmoles) in cyclohexane (50 mL) was stirred at room temperature for 16 h. The resulting precipitates

were collected to give the title compound (5.4g, 50. 09%): aH (DMSO- ,) 2.28 (bs, 1H), (m, 2H), 3.45-3.85 (m, 5H), 5.13 (bs, 1H), 7.05-7.48 (m, 5H).

In a similar manner (S) isomer was prepared from (S)- epichlorohydrin in 67% yield.

Step B (R) AND (S)-2-CHLOROMETHYL-4-BENZYL-5-OXOMORPHOLINES To a mixture of the title compound from step A above (5.3g, 26.57 mmoles), NaOH (10.62g, 265 mmoles) CHCl3 (50mL) and H, O (20mL) was added dropwise a solution of bromoacetyl bromide (14.98g, 74.25 mmoles) in CHC13 (15mL) over a period of lh at 0°C and then at room temperature for 16h. The organic layer was separated and washed successively with water, 1NHC1, and brine.

The solvent evaporated to leave the title compound ( (R) isomer) (5.43g, 84.4%): FABMS (M+1) =240; 8H (CDC13) 3.2-3.33 (m, 2H).

3.50 (dd, 1H), 3.51 (dd, 1H), 4.0 (m, lH), 4.25 (d, 1H), 4.4 (d, 1H), 4.52 (d, 1H), 4.7 (d. 1H), 7.20-7. 33 (m, 5H), In a similar manner (S) isomer was prepared (67 %). FABMS (M+1) = 240; 8H (CDC13) 3.2-3.33 (m, 2H). 3.50 (dd, 1H), 3.51 (dd, 1H), 4.0 (m, lH), 4.25 (d, 1H), 4.4 (d, 1H), 4.52 (d, 1H), 4.7 (d. 1H), 7.20-7.33 (m, 5H).

StepC (R)-2-CHLOROMETHYL-4-BENZYL-MORPHOLINES

A solution of the title compound from Step B (5.09g, 21.23 mmoles) in anhydrous THF (55 mL) was added to a stirred l. OM BH3-THF complex (109 mL) over a period of 0.5h at-15° C under nitrogen atmosphere. The mixture was stirred at room temperature for 1h, heated to reflux overnight and then cooled to 0° C. After concentrated HC1 (75mL) was added to the reaction mixture, THF was evaporated in vacuo. The resulting aqueous solution was basified with 10% NaOH and extracted with CH2Cl2. The extract was successively washed with water and brine, and the CH2C12 was evaporated to leave a crude product, which was chromatographed on silica gel with CH2Cl2-2% acetone to give the title compound (3.2 g, 80%). FABMS (M+1) = 226,8H (CDC1,) 2.1 (dd, lH). 2.3 (dd, 1H), 2.72 (m, 1H), 2.84 (m, lH), 3.5-3.6 (s, 2H), (m, 31H), 7.2- 7.4 (m, 5H).

Step D (R)-4-BENZYL-2- (1 H-IMIDAZOL-YL) METHYL-MORPHOLINES

A solution of the title compound from Step C (3. 1g, 13.77 mmoles) in DMF (15 mL) was added to a stirred solution of NaH (1.29g 53.75 mmoles) and imidazole (3.67g, 53.97 mmoles) in DMF (50mL) under nitrogen atmosphere. The mixture was stirred at 60° C for 16h. DMF was evaporated in vacuo. The resulting crude product was extracted with CH2C12 and the extract was successively washed with water and brine, and the CH2C12 was evaporated to leave a crude product, which was chromatographed on silica gel with CH2C12-5 % (10% NH40H in methanol) to give the title compound (1.65 g, 45%). FABMS (M+1) = 258 (MH+); 8H (CDC13) 1.8 (m, lH), 2.15 (m, 1H), 2.8 (m, 2H), 3.4-3.8 (m, 7H), 6.9 (S, 1H), 7.02 (S, 1H), 7.3 (m. 5H), 7.5 (S, 1H).

Step E (S)-4-BENZYL-2- (lH-IMIDAZOL-YL) METHYL-5-OXOMORPHOLINES A solution of the title compound from Step B (2.73g, 11.37 mmoles) in DMF (15 mL) was added to a stirred solution of NaH (1.55g 22.79 mmoles) and imidazole 0.55g, 22.75 mmoles) in DMF (25 mL) under nitrogen atmosphere. The mixture was stirred at 60°

C for 16h. DMF was evaporated in vacuo. The resulting crude product was extracted with CH2C12 and the extract was successively washed with water and brine, and the CH2Cl2 was evaporated to leave a crude product, which was chromatographed on silica gel with CH, C12-5 % (10% NH40H in methanol) to give the title compound (0.761 g, 24.7%). FABMS (M+1) = 272 (MH+); aH (CDC13 3.12 (m, 2H), 3.98-4.71 (m, 7H), 6.98 (S, 1H), 7.1 (S, 1H), 7.2- 7.4 (m. 5H), 7.98 (S, 1H).

Step F (S)-4-BENZYL-2-(1 H-IMIDAZOL-YL) METHYL-MORPHOLINES 1 N LAH in ether (5.5 mL) was added to a stirred solution of the title compound (0.75g, 2.75 mmole) from step E in anhydrous THF (25 mL) dropwise over a period of 0.5h and the resuting mixture was refluxed for 4h. The reaction mixture was slowly decomposed with ice-water and extracted with CH2Cl2. The extract was washed with with water and brine and dried (MgSO4), filtered and evaporated to dryness to give the title compound (0.53g, 75%). <BR> <BR> <P>FABMS (M+1) = 258 8H (CDC13) 1.8 (m, 1H), 2.15 (m, 1H), 2.8 (m, 2H), 3.4-3.8 (m, 7H), 6.9 (S, 1H), 7.02 (S, 1H), 7.3 (m. 5H), 7.5 (S, 1H).

Step G (R) AND (S)-12-(lH-IMIDAZOL--1-YL) METHYL] MORPHOLINES

A mixture of the title compound (1.6g) from Step D and Pd (OH)2 on carbon (0.32g) in EtOH (20 mL) was stirred at 50 psi under an atmosphere of hydrogen for 24h. The catalyst was filtered to give the title compound (1.03g, 99.9%). FABMS (M+1) = 168; 8H (CDCl3) (m, 1H), 2.8 (m, 3H), 3.5-3.9 (m, 5H), 6.9 (S, 1 H), 7.02 (S, 1H), 7.45 (S, 1H).

In a similar manner (S) isomer was prepared from (0.5g) and Pd (OH)2 on carbon (0.2g) in 99% yield. FABMS (M+1) = 168; aH @ (CDCl3) (m, 1H), 2.8 (m, 3H), 3.5-3.9 (m, 5H), 6.9 (S, 1H), 7.02 (S, 1H), 7.45 (S, 1H).

PREPARATIVE EXAMPLE 49 [4- ( H-IMIDAZOL--1-YL) METHYL] PIPERIDINE Step A <BR> <BR> lN-tert-BUTOXYCARBONYL-4-HYDROXYMETHYL-PIPERIDINE

To a solution of 4-hydroxymethyl-piperidine (5g, 43.41 mmoles) and triethylamine (8.78g, 86. 82 mmoles) in CHOC4 (lOOmL), di-tert-butyldicarbonate (18.95g, 86.82 mmoles) was added and stirred at room temperature for 16h. The solution was diluted with CH2Cl2 and washed with water, dried (MgSO4) filtered and evaporated to give the title compound (9.04g, 99%). FABMS (M+1)= 216.

Step B 1 N-tert-BUTOXYCARBONYL-4-METHANESULFONYLOXYMETHYL- PIPERIDINE The title compound from Step A above (8.8g, 40.87 mmoles) and triethylamine (8.55 mL, 61.31 mmoles) were dissolved in CH,, C4 (100 mL) and the mixture was stirred under nitrogen at 0°C.

Methanesulfonylchloride (3.8 mL mL, 49.05 mmoles) was added and the solution was stirred at room temperature for 2h. The solution was diluted with CH2Cl2 and washed with saturated aqueous sodium bicarbonate, water and dried (MgS04), filtered and evaporated to dryness to give the title compound (12.8g) FABMS (M+1) = 294.3.

Step C<BR> lN-tert-BUTOXYCARBONYL-4-(1 H-IMIDAZOL-1-YL)(1 H-IMIDAZOL-1-YL) METHYL- PIPERIDINE

A solution of the title compound from Step B (1. Og, 3.408 mmoles) in DMF (15 mL) was added to a stirred solution of NaH (0.27g, 6.817 mmoles) and imidazole (0.464g, 6.817 mmoles) in DMF (15 mL) under nitrogen atmosphere. The mixture was stirred at 60° C for 16h. DMF was evaporated in vacuo. The resulting crude product was extracted with CH2Cl2 and the extract was successively washed with water and brine, and the CH2C12 was evaporated to leave the title residue which was chromatographed on silica gel using 3% (10% conc NH40H in methanol)-CH2C12 as eluant to give the title compound (0.823 g). FABMS (M+1) = 266.2,8H (CDCl3) 0.8-1.0 (m, 2H), 1.2 (s, 9H), (m, 1H), 1.65 (m, 1H), 2.4 (dt, 2H), 3.6 (d, 2H), 4.8 (d, 2H), 6.7 (s, 1H), 6.8 (s, 1H), 7.2 (s, 1H).

Step D 4- (1 H-IMIDAZOL-1-YL) METHYL-PIPERIDINE The title compound (0.187g, 0.705 mmoles) from Step C was stirred in 4N HC1 in dioxane (20 mL) for 2h and then evaporated to dryness to give the title compound which was used to couple with the tricyclic acid.

PREPARATIVE EXAMPLE 50 3 (R) AND 3 (S)-(lH-IMIDAZOL--l-YL) METHYL] PYRROLIDINES

(R) (S) Step A lN-tert-BUTOXYCARBONYL-3 (R) AND 3 (S)-(1H-IMIDAZOL-I-YL) METHYL) PYRROLIDINES 3 (R)- (3-Methanesulfonyloxymethyl) pyrrolidine (J. Med. Chem.

1990,33,77-77) (0. 993g, 3.56 mmoles) was dissolved in anhydrous DMF (25 mL) and sodium imidazole (0.6g, 10 mmoles) was added. The mixture was heated at 60° C for 2h and then evaporated to dryness. The product was extracted with CH,, C4 and washed with brine. CH2Cl2 extract was evaporated to dryness to give the titled compound (1.1409g, 100%), ESMS: FABMS (M+1) = 252; aH (CDCl3) 1.45 (s, 9H), 1.5-1.7 (m, 1H), 1.9-2.1 (m, 1H), 2.5-2.7 (m, 1H), 3.0-3.2 (m, 1H), (m, 2H), 3.9 (dd, 2H), 6.9 (s, 1H), 7.1 (s, 1H), 7.45 (s, 1H) In a similar manner, (S) isomer was prepared from 3 (S)- (3- Methanesulfonyloxymethyl) pyrrolidine (0.993g, 3.56 mmoles to give the title compound (1.1409g, 100%).

Step B 3 (R) AND 3 (S)-(lH-IMIDAZOL--1-YL) METHYL1PYRROLIDINES

The title compound (0.48g, 1.91 mmoles) from Step A was stirred in 4N HCl in dioxane (10 mL) for 2h and then evaporated to dryness to give the title compound which was used to couple with the tricylic acid.

In a similar manner (S) isomer was prepared.

PREPARATIVE EXAMPLE 51 3 (S)- (1H-4 (5)-METHYLIMIDAZOL--1-YL) METHYL] PYRROLIDINE Step A 1N-tert-BUTOXYCARBONYL- 3 (S)- (1H-4 (5)-METHYLIMIDAZOL-I- YL) METHYL) PYRROLIDINE 3 (S)- (3-Methanesulfonyloxymethyl) pyrrolidine (1.05g, 3.77 mmoles) was dissolved in anhydrous DMF (25 mL) and sodium 4-

methylimidazole (0.74g, 10 mmoles) was added. The mixture was heated at 60° C for 2h and then evaporated to dryness. The product was extracted with CH2C12 and washed with brine.

CH 2C4was evaporated to dryness to give the titled compound (0.92g, 100%), FABMS (M+1) = 266.

Step B 3 (S)- (1H-4 (5)-METHYLIMIDAZOL-1-YL) METHYL] PYRROLIDINE The title compound (0.31g, 1.17 mmoles) from Step A was stirred in 4N HC1 in dioxane (10 mL) for 2h and then evaporated to dryness to give the title compound which was used to couple with the tricylic acid.

PREPARATIVE EXAMPLE 52 3-(1 H-IMIDAZOL-1-YL) METHYL-PYRROLIDINE Step A 1 N-DIPHENYLMETHYL-AZETIDINE-4-METHYLCARBOXYLATE

lN-Diphenylmethyl-azetidine-3-carboxylic acid (J. Chem.

Res. 1996,430) (5.38g, 20.16 mmoles) was refluxed with conc, H2SO4 (2mL) and MgSO4 (5g) in anhydrous methanol (25 mL) for 16h. Evaporated to dryness and the residue was extracted with

ethylacetate and washed the extract with 10% sodiumbicarbonate and water. Ethylacetate was evaporated to give a residue which was chromatographed on silica gel using hexane-10% ethylacetate as the eluant afforded the title compound (2.2g, 40.64%), FABMS (M+1) = 282; 8H (CDC13) (m, 5H), 3.7 (s, 3H), 4.45 (s, 1H), 7.2-7.4 (m, 10H).

Step B 1 N-DIPHENYLMETHYL-3-HYDROXYMETHYL-AZETIDINE

1 N LAH in ether (20 mL) was added to a stirred solution of the title compound (2g, 7.11 mmole) from Step A in anhydrous ether (25 mL) dropwise over a period of 0.5h and the resuting mixture was refluxed for 4h. The reaction mixture was slowly decomposed with ice-water and extracted with ethylacetate. The extract was washed with with water and brine and dried (MgSO4), filtered and evaporated to dryness to give title compound (1.72g, 98%). FABMS (M+1) = 254.

Step C 1N-DIPHENYLMETHYL-3-METHANESULFONYLOXYMETHYL- AZETIDINE

The title compound from Step B above (1.7g, 6.72 mmoles) and triethylamine (l. lg, 10.87 mmoles) were dissolved in CH2C12 (20 mL) and the mixture was stirred under nitrogen at 0°C.

Methanesulfonylchloride (1. 1g, 9.6 mmoles) was added and the solution was stirred at room temperature for 2h. The solution was diluted with CH2CI2 and washed with saturated aqueous sodium bicarbonate, water and dried (MgSO4), filtered and evaporated to dryness to give the title compound (2.32g, 99%). FABMS (M+1) = 332.

Step D 1 N-DIPHENYLMETHYL-3- (1 H-IMIDAZOL-lYL) METHYL-AZETIDINE

A solution of the title compound from Step C (2.3g, 6.95 mmoles) in DMF (15 mL) was added to a stirred solution of NaH (0.25g, 10.42 mmoles) and imidazole (0.71g, 10.44 mmoles) in DMF (10 mL) under nitrogen atmosphere. The mixture was stirred at 60° C for 16h. DMF was evaporated in vacuo. The resulting crude product was extracted with CH2C12 and the extract was successively washed with water and brine, and the CH2Cl2 was evaporated to leave the title compound (2.1 g, 100%). FABMS (M+1) = 304 Step E 3-(1H-IMIDAZOL-1-YL)METHYL-PYRROLIDINE A mixture of the title compound (1.7g) from Step D and Pd (OH) 2 on carbon (0.2g) in EtOH (20 mL) was stirred at 50 psi under an atmosphere of hydrogen for 24h. The catalyst was filtered to give the title compound (0.508g, 66.8%). m/z =137 (MH+) PREPARATIVE EXAMPLE 53 4- (1 H-IMIDAZOL-1-YL)-PIPERIDINE

Step A lN-tert-BUTOXYCARBONYL-4-HYDROXY-PIPERIDINE

To a solution of 4-hydroxy-piperidine (2g, 19.78 mmoles) and triethylamine (4.16 mL, 29.67 mmoles) in CH, C4 (20mL), di-tert- butyldicarbonate (5.18g, 23.72 mmoles) was added and stirred at room temperature for 16h. The solution was diluted with CH2Cl2 and washed with water, dried (MgSO4) filtered and evaporated to give the title compound (3.95g, 99%). FABMS (M+1) = 202.

Step B 1 N-tert-BUTOXYCARBONYL-4-METHANESULFONYLOXY- PIPERIDINE

The title compound from Step A above (3.5g, 17.39 mmoles) and triethylamine (4.85mL, 34.79 mmoles) were dissolved in CH2Cl2 (30 mL) and the mixture was stirred under nitrogen at 0°C.

Methanesulfonylchloride (1.62 mL, 20.88 mmoles) was added and the solution was stirred at room temperature for 2h. The solution was diluted with CH2C12 and washed with saturated aqueous sodium bicarbonate, water and dried (MgSO4), filtered and evaporated to dryness to give the title compound (4.68g, 96.4 %).

ESMS: m/z= 280 (MH+) Step C<BR> <BR> 1N-tert-BUTOXYCARBONYL-4- (lH-IMIDAZOL-1-YL)-PIPERIDINE

A solution of the title compound from Step B (4.0g, 14.32 mmoles) in DMF (120 mL) was added to a stirred solution of NaH (0.52g, 21.66 mmoles) and imidazole (1.46g, 21.47 mmoles) in DMF (20 mL) under nitrogen atmosphere. The mixture was stirred at 60° C for 16h. DMF was evaporated in vacuo. The resulting crude product was extracted with CH2C12 and the extract was successively washed with water and brine, and the CH2C12 was evaporated to leave the title residue which was chromatographed on silica gel using 3% (10% conc NH40H in methanol)-CH2C12 as eluant to give the title compound (0.94 g, 26%). FABMS (M+1) = 252; 8H (CDCl3) 1.4 (s, 9H), 1.6-1.8 (m, 2H), 2.0 (dd, 2H), 2.8 (dt, 2H), 4.05 (m, 1H), 4.2 m, 2H), 6.9 (s, 1H), 7.0 (s, 1H), 7.65 (s, 1H).

Step D 4-(1H-IMIDAZOL-1-YL)-PIPERIDINE The title compound (0. 21g, 0.836 mmoles) from Step C was stirred in 4N HCl in dioxane (5 mL) for 2h and then evaporated to dryness to give the title compound which was used to couple with the tricylic acid.

PREPARATIVE EXAMPLE 54 3- (R) AND (S)-(lH-IMIDAZOL-1-YL)-PYRROLIDINES

(R) (S) Step A 1N-BENZYL-3- (R) AND (S)-METHANESULFONYLOXY)- PYRROLIDINES 1N-Benzyl-3 (R)-hydroxy-pyrrolidines (5g, 28.21 mmoles) and triethylamine (7. 86 mL, 56. 35 mmoles) were dissolved in CH2C12 (50 mL) and the mixture was stirred under nitrogen at 0°C.

Methanesulfonylchloride (2.62 mL, 33.87 mmoles) was added and the solution was stirred at room temperature for 2h. The solution was diluted with CH2Cl2 and washed with saturated aqueous sodium bicarbonate, water and dried (MgS04), filtered and evaporated to dryness to give the title compound (7.2g, 96.4 %). <BR> <BR> <BR> <P>FABMS (M+1) = 256; 8H (CDC13) 2.2 (m, 1H), 2.3 (m, 1H), 2.52 (m, 1H), 2.7-2.85 (m, 3H), 2.95 (s, 3H), 3.65 (q, 2H), 5.16 (m, 1H), 7.3 (s, 5H).

In a similar way (S) isomer was prepared from 1N-Benzyl- 3 (S)-hydroxy-pyrrolidines (5g, 28.21 mmoles) to give the title compound (7.15g, 98%) Step B 1N-BENZYL-3- (S) AND (R)-(lH-IMIDAZOL-1-YL)-PYRROLIDINES

(S) (R) A solution of the title compound from Step A (2.0g, 7.84 mmoles) was added to a stirred solution imidazole (l. lg, 16.17 mmoles) in DMF (25 mL) under nitrogen atmosphere. The mixture was stirred at 60° C for 16h. DMF was evaporated in vacuo.. The resulting crude product was extracted with CH2Cl2 and the extract was successively washed with water and brine, and the CH2C12 was evaporated to leave the title residue which was chromatographed on silica gel using 3% (10% conc NH40H in methanol)- CH2Cl2 as eluant to give the title compound (0.95 g, 50.56%). FABMS (M+1) = 228.

In a similar fashion the other isomer was prepared.

Step C 3- (R) AND (S)-(lH-IMIDAZOL-1-YL)-PYRROLIDINES

A mixture of the title compound (0.95 g) from Step B and 10% Pd on carbon (0.5 g) in EtOH (20 mL) was stirred at 50 psi under an atmosphere of hydrogen for 24h. The catalyst was filtered to give the title compound (0.522 g, 99.9%) which was used to couple with the tricylic acid.

In a similar manner (R) isomer was prepared from (1.0 g) and 10% Pd on carbon on carbon (0.6 g) in 99% yield.

PREPARATIVE EXAMPLE 55 (-) 2-METHYL-3- (1H-IMIDAZOL-4-YL)-PYRROLIDINE

This compound was prepared according to the procedure in J. Med. Chem. 1995,1593-1599.

PREPARATIVE EXAMPLE 56 3-(1H-IMIDAZOL-1-YL)-AZETIDINE Step A 1 N-DIPHENYLMETHYL- (1 H-IMIDAZOL-1-YL)-AZETIDINE

Che.1N-Diphenylmethyl-3-methanesulfonyloxy-azetidine(J.

Res. 1996,430) (10. Og, 29.26 mmoles) was added to a stirred solution imidazole (5.96g, 87.78 mmoles) in DMF (100 mL) under nitrogen atmosphere. The mixture was stirred at 60° C for 16h.

DMF was evaporated in vacuo. The resulting crude product was extracted with CH2CI2 and the extract was successively washed with water and brine, and the CH2Cl2 was evaporated to leave the title residue which was chromatographed on silica gel using 4 % (10% conc NH40H in methanol)-CH2C12 as eluent to give the title compound (2.87 g, 33.9 %). FABMS (M+1) = 290; 8H (CDC13) 3.3 (dd, 2H), 3.65 (dt, 2H), 4.45 (s, 1H), 4.8 (m, 1H), 7.1-7.5 (m, 12H), 7.8 (s, 1H).

Step B 3- (1H-IMIDAZOL- 1-YL)-AZETIDINE A mixture of the title compound (2.8g) from Step A and 10% Pd on carbon (1. Ig) in MeOH (25 mL) was stirred at 50 psi under an atmosphere of hydrogen for 24h. The catalyst was filtered to give the title compound (1.05 g, 99.9%) which was used to couple with the tricylic acid.

EXAMPLE 54

4-(3-bromo-8-chloro-6,11-dihydro-5H-benzo[5,6]cyclo- hepta [1,2-b] pyridin-11-yl)-1-[(1, 1-dimethylethoxy) carbonyl]-2 (R)- piperazinecarboxylic acid (2g, 3.8 mmoles.) was added to a solution of the title compound from Preprative Example 50 (1. lg, 4.7 mmol), DEC (1.8g, 9.4 mmoles.), HOBT 48 mmoles.) and NMM (2.6 mL, 23.7 mmoles.) in DMF (100 mL). The resulting solution was stirred at room temperature 24 hours. The reaction mixture was diluted with H20 until precipitation ceased and the slurry filtered.

The precipitate was diluted with CH 2C4 washed with brine, dried over Na2SO4 and concentrated. The crude product was purified by flash chromatography using a 5% (10% NH40H in MeOH) solution in CH2Cl2 as eluent to give the title compound (1.48g, 55 % yield). FABMS (M+1) = 669.

EXAMPLE 55 and EXAMPLE 56 The title compound from Example 1 was separated into individual 11- (R)- and 11- (S)- isomers by Preparative HPLC with a CHIRALPAK AD column using a 15% iPrOH in hexane solution with 0.2% DEA as eluant.

EXAMPLE 55 Isomer A: retention time (analytical) = 8.885 minutes; [α]D : -13.1 (3.06 mg in 2.0 mL MeOH); FABMS (M+1) = 669.

EXAMPLE 56

Isomer B: retention time (analytical) = 8.885 minutes; [a] D = + 12.1 (2.32 mg in 2.0 mL MeOH); FABMS (M+1) = 669.

EXAMPLE 57-69 By essentially the same procedure set forth in Example 1 only substituting the appropriate amines, one can obtain compounds of the formula shown below wherein W is defined in Table 9 below.

TABLE 9 Ex. R$ CMPD FABMS (M+1) = 669 57 11- (R, S) TABLE 9-continued Ex. RUS CMPD RFABMS (M+1) = N,,,IN 58 11-(R,(R, S) FABMS (M+ 1) _ N 655 r 59 11-(R,(R, S) \ FABMS (M+1) = r 60 N ç N 669 H H H 11- (R, S) FABMS (M+ 1) _ \N\/\oN641641 61 11- (R, S) FABMS (M+1) = 62 683 , N 62 11-(R,(R, S) FABMS (M+1) = 63 63 63 11-(R,(R, S) TABLE 9-continued Ex. R8 CMPD FABMS (M+1) = N,//N 685 64 11- (R, S) v\ FABMS (M+1) = 669 65 65 11- (R, S) FABMS (M+ 1) _ 66 ll-S 66 11-S <\ FABMS (M+1) = N669 67 11-R Hs FABMS (M+1) = 683 68'' 11- (R, S) FABMS (M+1) = oN N 655 655 i 69 11- (R, S) EXAMPLE 70 Step A

The title compound from Example 54 (0. 1g, 0.15 mmoles) was stirred at room temperature in CH2C12 (20 mL) and TFA (1 mL) for 2h. The reaction mixture was evaporated to dryness to give the title compound which was used as such in Step B below.

Step B The title compound from Step A (0.186g, 0.182 mmoles) dissilved in CH2C12 (20 mL) and triethyl amine (0.063 g, 0.621 mmoles) and t-butylisocyanate (0.0185g, 0.187 mmoles) was added. The resulting solution was stirred at room temperature for 2 h, diluted with water and extracted with CH2C12. CH2Cl2extract was dried (MgS04) and filtered and concentrated in CH2Cl2as eluant to give the title compound (0.084g) FABMS (M+1) = 668.

EXAMPLES 71-73 By essentially the same procedure set forth in Example 1 only substituting with different isocyanates, one can obtain compounds of the formula shown below wherein R9 is as defined in Table 10 below.

TABLE 10

R9 CMPD . FABMS (M+1) = 668 ONT Ex. 71 H 11- (R, S) OlNzO FABMS (M+1) = 696 O N-/ Ex. 72 H 11- (R, S) HA FABMS (M+1) 710 b H Ex. 73 H3 11- (R, S) PREPARATIVE EXAMPLE 57 2(R/S)-[2-(1H-IMIDAZOL-1-YL)ETHYL]PIPERIDINE Step A 1 N-tert-BUTOXYCARBONYL-2 (R/S)- (2-HYDROXYETHYL)- PIPERIDINE

2 (R/S)- (2-Hydroxyethyl) piperidine (5g, 38.7mmoles) and sodium hydroxide (1.55g, 67.4mmoles) were dissolved in THF-water (1: 1) (100mL) and di-tert-butyldicarbonate (9.29g, 42.6mmoles) was added and the mixture was stirred at 25°C for 120h. The solution was treated with BioRad 50W-X4 (RSO3H) resin (42mL) and filtered.

The resin was washed with water and THF and the combined filtrates were evaporated to dryness. Chromatography on silica gel using 1% (10% conc. NH40H in methanol)-dichloromethane as the eluant afforded the title compound (8.87g, 95%): CIMS: m/z 230.2 (MH+); 8H (CDCl3) 1.47ppm (9H, s, CH3); bc (CDC13) CH3: 4, 28.4; CH2: C: 80.1, carbonyl not visible.

Step B l N-tert-BUTOXYCARBONYL-2 (R/S)-(2- METHANESULFONYLOXYETHYL) PIPERIDINE The title compound from Step A above (2g, 8.72mmoles) and triethylamine 52.4mmoles) were dissolved in dichloromethane (50mL) and the mixture was stirred under argon at 0°C. Methanesulfonyl chloride (2.03mL; 26.2mmoles) was added and the solution was stirred at 25°C for 2h. The solution was diluted with dichloromethane and washed with saturated aqueous sodium bicarbonate, water and dried (MgS04), filtered and evaporated to dryness. The product was chromatographed on silica

gel using 2% (10% conc. NH40H in methanol)-dichloromethane as the eluant to give the title compound (1.25g, 61%): ESMS: m/z 308.1 (MH+); bc (CDC13) 5,37.4/39.3; CH2: 19. 1, 23.8/25.5,28.9/29.6,33.1,45.2; CH: 54.2; C: 79.8,-155.2.

Step C 1N-tert-BUTOXYCARBONYL-2(R/S)-[2-(1H-IMIDAZOL-1- YL) ETHYL] PIPERIDINE

The title compound from Step B above (2.68g, 8.72mmoles) (crude product, prior to chromatography) was dissolved in anhydrous DMF (30mL) and sodium imidazole (1.18g, 13.1 mmoles) was added. The mixture was heated at 70°C for 2h and then evaporated to dryness. The product was directly chromatographed on silica gel using 1% (10% conc. NH40H in methanol)- dichloromethane as the eluant to give the title compound (1.69g, 69%): ESMS: m/z 280.1 (MH+); dH (CDCl3) 1.48ppm (9H, s, CH3); dc (CDC13) CH3: 28.5,28.5,28.5; CH2,: 5,28.9,31.8,-39.1, 44.3; CH: 1; C: 80.1, carbonyl not visible.

Step D 2 (R/S)- [2-(1 H-IMIDAZOL-1-YL) ETHYL] PIPERIDINE

The title compound from Step C above (1.6g, 5.73mmoles) was dissolved in methanol (lOmL) and 10% conc. H2SO4 in dioxane (v/v) (40mL) was added and the solution was stirred at 25°C for 2h.

The mixture was treated with BioRad AG 1-X8 (OH-) resin until basic. The resin was filtered off and washed with methanol. The combined filtrates were evaporated to dryness and the product was

chromatographed on silica gel using 5% (10% conc. NH40H in methanol)-dichloromethane as the eluant to give the title compound (1.02g, 99%): CIMS: m/z 180. 35 (MH+); aH (CDC13) 6.94 (1H, s, Im- H5), 7.18 (1H, s, Im-H4) and 7.50ppm (1H, s, Im-H2); bc (CDC13) CH2: 0; CH: 5,118.8.

PREPARATIVE EXAMPLE 58 2 (R/S)- [3- (1 H-4-METHYLIMIDAZOL-1-YL) PROPYL] PIPERIDINE

Step A 2 (R/S)- (3-HYDROXYPROPYL) PIPERIDINE

2- (3-Hydroxypropyl) pyridine (5g, 36.4mmoles) was dissolved in IN HC1 (36.4mL, 36.4mmoles) and water (63.6mL) and platinum (IV) oxide monohydrate (lg, 4.08mmoles) was added under an argon atmosphere. The mixture was hydrogenated at 55psi in a Parr bomb at 25°C for 96h. The catalyst was filtered off through Celite" and washed with water. The combined filtrates were treated with BioRad AG1-X8 (OH) resin until basic. The resin was filtered off and washed with water. The combined filtrates were evaporated to dryness and the product was chromatographed on silica gel using 10% increasing to 20% (10% conc. NH40H in methanol)- dichloromethane as the eluant to give the title compound (5.22g, 100%): CIMS: m/z 144.40 (MH+); 8c (d6-DMSO) CH2: 24.0,25.3, 28.8,31.5,32.8,45.9,60.8; CH: 56.1.

Step B<BR> <BR> 1 N-tert-BUTOXYCARBONYL-2 (R/S)- (3-HYDROXYPROPYL) PIPERIDINE

The title compound from Step A above (3g, 20.9mmoles) was reacted with di-tert-butyldicarbonate (5.03g, 23mmoles) and sodium hydroxide (0.8378g, 20.9mmoles) essentially as described in Preparative Example 57, Step A above, but allowing the reaction to proceed for 166h. The product was chromatographed on silica gel using 3% (10% conc. NH40H in methanol)-dichloromethane as the eluant to give the title compound (4.04g, 79%): ESMS: m/z 244.0 (MH+); 8H (CDC13) 1.45ppm (9H, s, CH3); 8c (CDC13) CH3: 28.5,28.5, 28.5; CH2: 2,-38.8,62.8; C: 79.3, -155.2.<BR> <BR> <P>Step C 1N-tert-BUTOXYCARBONYL-2(R/S)-[3-(4- TOLUENESULFONYLOXY) PROPYL] PIPERIDINE The title compound from Step B above (2g, 8.22mmoles) was dissolved in anhydrous pyridine (lOmL) and the solution was cooled with stirring to 0°C. 4-Toluenesulfonyl chloride (1.88g, 9.86mmoles) was added and the mixture was stirred at 0°C for 2h. The mixture was evaporated to dryness and the residue was taken up in dichloromethane and washed with saturated aqueous sodium bicarbonate, water, dried (MgSO4), filtered and evaporated to dryness. The product was chromatographed on silica gel using 0.25% methanol in dichloromethane as the eluant to give the title compound (2.53g, 77%): ESMS: m/z 398.1 (MH+).

bH (CDC13) 1.41 (9H, s, CH3), 2.45 (3H, s, Ar-CH3), 4.06 (2H, m, CH2O), 7.36 (2H, d, Ar-H3 and Ar-H5) and 7.79ppm (2H, m, Ar-H2 and Ar-H6) ; #c(CDCl3) CH3 : 5; CH2 : 21.7,22.8, 25.7,25.8,28.8,38.7,70.6; CH : #49.6, 127.9,127.9,129.9,129.9; C: 1.

Step D 1 N-tert-BUTOXYCARBONYL-2 (R/S)- [3- (1 H-4/5-METHYLIMIDAZOL- 1-YL)PROPYL] PIPERIDINE 4-Methylimidazole (0.5453g, 6.64mmoles) was dissolved in anhydrous DMF (15mL) and 95% sodium hydride (0.1678g, 6,64mmoles) was added. The mixture was stirred at 25°C for 0.5h. under argon. The title compound from Preparative Example 58, Step C, (2.4g, 6.04mmoles) in anhydrous DMF (lOmL) was added and the mixture was stirred at 25°C for 1h. The product was worked up as described in Preparative Example 2, Step A and chromatographed on silica gel using 3% methanol in dichloromethane as the eluant to give a mixture of the title compounds (1.459g, 79%) (4-Me: 5-Me:: 63: 37): CIMS; m/z 308.25 (MH+); 4-Me: 8H (CDCl3) 1.43 (9H, s, CH3) 2.18 (3H, s, Im-4-Me), 3.87 (2H, m, CH2-Im), 6.58 (1H, s, Im-H5) and 7.33ppm (1H, s, Im-H2); #c(CDCl3) CH3 : 5,28.5,28.5; CH2: 6,26.4,27.7, 28.7,38.9,46.5; 2; C: 79.4,138.7,155.1 and 5-Me: 8H (CDCl3) 1.43 (9H, s, CH3), 2.16 (3H, s, Im-5-Me), 3.87 (2H, m, CH2-Im), 6.74 (1H, s, Im-H4) and 7.37ppm (1H, s, Im-H2); #c(CDCl3) CH3 : 5,28.5; CH2: 6,26.5,27.3, 0,44.4; CH : #49. 4,126.9,136.8; C: 79. 4, #138.7, 155.1.

Step E 1 N-tert-BUTOXYCARBONYL-2 (R/S)- [3- (1 H-4-METHYLIMIDAZOL-1- YL) PROPYL] PIPERIDINE

The mixture of compounds from Step D above (1.054g) was dissolved in anhydrous CH2Cl2 (lOmL) at 0°C under argon. Trityl chloride (0. 3891g, 1.1 equivalents per equivalent of the 5-methyl isomer) was added and the mixture was stirred at 0°C for 2h. The reaction mixture was introduced directly onto a silica gel column and the column was eluted with 50% ethyl acetate in acetone to give the pure 4-methyl isomer (0.7242g, 69%): 4-Me: CIMS: m/z 308.30 <BR> <BR> <BR> (MH+); 5, (CDCl3) 1.43 (9H, s, CH3), 2.18 (3H, s, Im-4-Me), 3.84 (2H, m, CH2-Im), 6.58 (1H, s, Im-H5) and 7.30ppm (1H, s, Im-H2): #c(CDCl3) CH3 : 5; CH2: 5,26.4,27.7, 28.7,38.8,46.5; 115.2,136.2; C: 79.3,138.4,155.1.

Step F 2- (R/S)- [3- (1 H-4-METHYLIMIDAZOL-1-YL) PROPYL] PIPERIDINE The title compound from Step E above (0.4456g, 1.5mmoles) was deprotected as described in Preparative Example 57, Step D and the product was chromatographed on silica gel using 20% (10% conc. NH40H in methanol)-dichloromethane as the eluant to give the title compound (0.2627g, 87%): CIMS: m/z 208.25 (MH+); aH (CDCl3 2.14 (3H, s, Im-4-Me), 3.79 (2H, m, CH2-Im), 6.52 (1H, s, Im-H5) and 7.24ppm (1H, s, Im-H,); bC (CDC13) CH3: 13.7; CH2 : 24.7, 0,47.1; CH: 2,136.1; C: 138.4.

PREPARATIVE EXAMPLE 59

Step A 4 (R/S)- (3-HYDROXYPROPYL) PIPERIDINE 4- (3-Hydroxypropyl) pyridine (5g, 36.4mmoles) was dissolved in 1N HC1 (36.4mL, 36.4mmoles) and water (63.6mL) and platinum (IV) oxide monohydrate (lg, 4.08mmoles) was added under an argon atmosphere. The mixture was hydrogenated at 55psi in a Parr bomb at 25°C for 66h. The catalyst was filtered off through Cette' and washed with water. The combined filtrates were treated with BioRad AG1-X8 (OH-) resin until basic. The resin was filtered off and washed with water. The combined filtrates were evaporated to dryness and the product was chromatographed on silica gel using 7% (10% conc. NH40H in methanol)-dichloromethane as the eluant to give the title compound (4.91g, 94%): CIMS: m/z 144.40 (MH+); bc (d6-DMSO) CH2: 6,32.8,45.1,45.1,60.8; CH: 34.8.

Step B N-tert-BUTOXYCARBONYL-4 (R/S)- (3-HYDROXYPROPYL) PIPERIDINE

The title compound from Step A above (3g, 20.9mmoles) was reacted with di-tert-butyldicarbonate (5. 03g, 23mmoles) and sodium hydroxide (0.8378g, 20.9mmoles) essentially as described in Preparative Example 57, Step A above, but allowing the reaction to proceed for 166h. The product was chromatographed on silica gel using 3% (10% conc. NH40H in methanol)-dichloromethane as the eluant to give the title compound (3.33g, 65%): ESMS: m/z 244.2 (MH+); aH (CDC13) 1.47ppm (9H, s, CH3) ; bc (CDCl3) CH,: 5, 28.5; CH2 : 9,32.2,32.6,44.1,44.1; CH: 35.9; C: 79.3, 154.8.<BR> <BR> <P>Step C<BR> 1 N-tert-BUTOXYCARBONYL-4 (R/S)- [3- (4-<BR> TOLUENESULFONYLOXY) PROPYL] PIPERIDINE The title compound from Step B above (2g, 8.22mmoles) was dissolved in anhydrous pyridine (lOmL) and the solution was cooled with stirring to 0°C. 4-Toluenesulfonyl chloride (1.88g, 9.86mmoles) was added and the mixture was stirred at 0°C for 2h. The mixture was evaporated to dryness and the residue was taken up in dichloromethane and washed with saturated aqueous sodium bicarbonate, water, dried (MgSO4), filtered and evaporated to dryness. The product was chromatographed on silica gel using

0.5% methanol in dichloromethane as the eluant to give the title compound (2.86g, 88%): ESMS: m/z 398.1 (MH+).

8H (CDCl3) 1.44 (9H, s, CH3), 2.46 (3H, s, Ar-CH3), 4.01 (2H, m, CH2O), 7.35 (2H, d, Ar-H3 and H5) and 7.79ppm (2H, d, Ar-H2 and H6); #c(CDCl3) CH3 : 6; CH2: 26.1,32.0,32.0, 7; CH: 9,129.9; C: 79.3,133.1,144.8,154.9.

Step D 1 N-tert-BUTOXYCARBONYL-4- [3- (lH-4/5-METHYLIMIDAZOL 1- YL)PROPYL] PIPERIDINE 4-Methylimidazole (0.5453g, 6.64mmoles) was dissolved in anhydrous DMF (15mL) and 95% sodium hydride (0.1678g, 6.64mmoles) was added to the stirred solution at 25°C under argon.

The solution was stirred at 25°C for 0.5h. The title compound from Preparative Example 59, Step C, (2.4g, 6.04mmoles) in anhydrous DMF (lOmL) was added and the mixture was stirred at 25°C for lh.

The product was worked up as described in Preparative Example 2, Step A and chromatographed on silica gel using 3% methanol in dichloromethane as the eluant to give the title mixture of compounds (1.584g, 85%) (4-Me: 5-Me:: 58: 42): CIMS: m/z 308.25 (MH+); 4-Me: aH (CDCl3) 1.44 (9H, s, CH3), 2.21 (3H, s, Im-4-Me), 3.82 (2H, m, CH2-Im), 6.59 (1H, s, Im-Hg) and 7.33ppm (1H, s, Im-H2); #c(CDCl3) CH3 : 5; CH2: 28.3,32.1,33.4,33.4, 44.0,47.1,47.1; CH: 2,136.2; C: 79.3,138.5,154.9 and <BR> <BR> <BR> <BR> <BR> 5-Me: 8H (CDC13) 1.44 (9H, s, CH3), 2.19 (3H, s, Im-5-Me), 3.82 (2H, m, CH2-Im), 6.77 (1H, s, Im-H4) and 7.39ppm 1H, s, Im-H2); bC (CDCl3) CH3: 5,28.5; CH2: 1,33.4,33.4, 9; CH: 0,136.2; C: 7,154.9.

Step E 1N-tert-BUTOXYCARBONYL-4-[3-(1H-4-METHYLIMIDAZOL-1- YL) PROPYL] PIPERIDINE

The mixture of compounds from Step D above (1.51g) was dissolved in anhydrous CH,, C4 (lOmL) at 0°C under argon. Trityl chloride (1.15g, 2 equivalents per equivalent of the 5-methyl isomer) was added and the mixture was stirred at 0°C for 2h. The reaction mixture was introduced directly onto a silica gel column and the column was eluted with 50% ethyl acetate in acetone to give the pure 4-methyl isomer (0.635g, 65%): 4-Me: CIMS: m/z 308.30 (MH+); 8H (CDCl3) 1.44 (9H, s, CH3), 2.22 (3H, s, Im-4-Me), 3.83 (2H, m, CH2-Im), 6.60 (1H, s, Im-H5) and 7.33ppm (1H, s, Im-H2); #c(CDCl3) CH3 : 13.8,28.5,28.5,28.5; CH2: 4, 43.9,47.1,47.1; CH: 2; C: 8.

Step F 4- [3- (1 H-4-METHYLIMIDAZOL-1-YL) PROPYL] PIPERIDINE

The title compound was deprotected as described in Preparative Example 57, Step D to give after chromatography on silica gel using 20% (10% conc. NH40H in methanol)- dichloromethane as the eluant, the title compound (0.3581g, 89%): CIMS: m/z 208.25 (MH+); aH (CDCl3) 2.12 (3H, s, Im-4-Me), 3.74 (2H, m, (CH2-Im), 6.51 (1H, s, Im-H5) and 7.25ppm (1H, s, Im-H2); bc (CDCl3) CH3: 13.6; CH2: 5,46.5,47.1; CH: 0; C: 138.2.

PREPARATIVE EXAMPLE 60 3 (R/S)-[(lH-IMIDAZOL-1-YL) METHYL]-1,2,3,4- TETRAHYDROQUINOLINE Step A 3 (R/S)-(HYDROXYMETHYL)-1, 2,3,4-TETRAHYDRO-QUINOLINE 3-Hydroxymethylquinoline (0.45g, 2.83mmoles) (prepared as described in: B. R. Brown, D. Ll. Hammick and B. H. Thewlis, J.

Chem. Soc., 1951,1145-1149.) was dissolved in methanol (lOOmL) and placed in a Parr bomb. Platinum (IV) oxide monohydrate (0.225g. 0.918mmoles) was added and the mixture was hydrogenated at 50psi at 25°C for 6h. The catalyst was removed by decantation and washed with methanol. The methanol was

evaporated to dryness and the product was chromatographed on silica gel using 3% (10% conc. NH40H in methanol)- dichloromethane as the eluant to give the title compound (0.3843g, <BR> <BR> <BR> <BR> 83%): CIMS: m/z 164.35 (MH+) ; aH (CDC13) 6.50 (1H, d, Ar-H8), 6.64 (1H, t, Ar-H6), 6.98 (1H, d, Ar-H5) and 6.99ppm (1H, m, Ar-H7); bc (CDC13) CH2: 29.5,44.0,65.2; CH: 8; C: 120.2,144.5.

Step B 1 N-tert-BUTOXYCARBONYL-3 (R/S)- (HYDROXYMETHYL)-1,2,3,4- TETRAHYDROQUINOLINE The title compound from Step A above (2.578g, 15.79mmoles) was dissolved in THF (51.5mL) and sodium hydroxide (0.634g, 15.79mmoles) in water (51.5mL) was added. Di-tert- butyldicarbonate (6. 888g, 31.58mmoles) was added and the mixture was stirred at 25°C for 187h. Additional di-tert-butyl dicarbonate (0.6888g, 3.16mmoles) was added and the reaction was allowed to proceed for a total of 301h. The product was worked up and purified as described in Preparative Example 1, Step A to give the title compound (3.794g, 91%): FABMS; m/z 264.1 (MH+) ; 8H (CDCl3) 1.50 (9H, s, CH3), 7.03 (1H, m, Ar-H), 7.19-7.10 (2H, m, Ar- H) and 7.58ppm (1H, d, Ar-H); 8c (CDC13) CH3: 3,28.3; CH2: 1,63.6; CH: 6,129.2; C: 81.5, 128.2, #154.7.138.8, Step C 1 N-tert-BUTOXYCARBONYL-3 (R/S)- [ (4-TOSYLOXY) METHYL]- 1,2,3,4-TETRAHYDROQUINOLINE

The title racemic compound from Step B above (0.322g, 1.22mmoles) was dissolved in anhydrous pyridine (2mL) and the solution was cooled to 0°C. 4-Toluenesulfonyl chloride (0.28g, 1.464mmoles) was added and the reaction was stirred at 0°C for 5h.

The mixture was then heated at 40°C for 13h and worked up as described in Preparative Example 2, Step C to give the title compound (0.481g) which was used directly in Step E below.

The individual pure enantiomers from Step C above may be similarly treated to give the 3 (R) and 3 (S) enantiomers of the title compound.

Step D 1 N-tert-BUTOXYCARBONYL-3 (R/S)- [ (lH-IMIDAZOL-l-YL) METHYL]- 1,2,3,4-TETRAHYDROQUINOLINE The title racemic product from Step D above was dissolved in anhydrous DMF (5mL) and sodium imidazole (0.1652g, 1.83mmoles) was added. The mixture was heated at 65°C under argon for 4h. The solution was evaporated to dryness and the residue was taken up in dichloromethane, washed with water, dried (MgSO4), filtered and evaporated to dryness. Chromatography on silica gel using 2.5% (10% conc. NH40H in methanol)- dichloromethane afforded the title compound (0.3284g, 86%): ESMS: m/z 314.1 (MH+); 8H (CDCl3) 1.51 (9H, s, CH3), 6.97 (1H, s, Im-H5), 7.01 (1H, t, Ar-H6), 7.06 (1H, t, Ar-H,), 7.12 (1H, s, Im-H4),

7.17 (1H, t, Ar-H5), 7.51 (1H, s, Im-H2) and 7.68ppm (1H, d, Ar-Hg); #c(CDCl3) CH3 : 4; CH3 : 31.0,46.7,49.5; CH: 35.9, 8/123.9,126.4,126.9,129.0,129.8,137.5; C: 81.5, 2,153.7.

The individual pure enantiomers from Step D above may be similarly treated to give the 3 (R) and 3 (S) enantiomers of the title compound.

Step E 3 (R/S)-[(1H-IMIDAZOL-1-YL)METHYL-1, 2,3,4- TETRAHYDROQUINOLINE The title racemic compound from Step E above (0.3208g, 1.024mmoles) was dissolved in anhydrous methanol (5.42mL) and 10% conc. HZSO4/dioxane (v/v) (13.95mL) was added and the mixture was stirred at 25°C for 1h. The product was worked up as described in Preparative Example 1, Step D above. Chromatography on silica gel using 2.5% (10% conc. NH40H in methanol)- dichloromethane as the eluant gave the title compound (0.19g, 90%): CIMS: m/z 214.2 (MH; 8, (CDC13) 3.97 (2H, m, Im-CH2), 6.51 (1H, d, Ar-H8), 6.65 (1H, t, Ar-H6), 6.95 (1H, s, Im-H5), 6.96 (1H, t, Ar-H,), 7.01 (1H, t, Ar-H5), 7.09 (1H, s, Im-H4) and 7.50ppm (1 H, s, Im-H2); bc (CDC13) CH2: 30.2,43.5,49.0; CH: 33.7,114.2,117.7, 0,137.7; C: 9.

StepF 3 (R)-[(1H-IMIDAZOL-1-YL)METHYL]-1. 2,3,4- TETRAHYDROQUINOLINE and 3 (S)-[(1H-IMIDAZOL-1-YL)METHYL]-1, 2,3,4-TETRAHYDROQUINOLINE The racemic title compound (0.6545g) from Step E above was separated by preparative HPLC on a Chiralpak AD column (50X5cm) using hexane-iso-propanol-diethylamine:: 80: 20: 0.2 as the eluant to give a less polar (-)-enantiomer CIMS: m/z 214.15 (MH+) ; 8H (CDCl3) 3.97 (2H, m, Im-CH2), 6.52 (1H, d, Ar-H8), 6.68 (1H, t, Ar-H6), 6.96 (1H, s, Im-H5), 6.96 (1H, t, Ar-H,), 7.02 (1H, t, Ar-H5), 7.10 (1H, s, Im-H4) and 7.49ppm (1H, s, Im-H2); bc (CDCl3) CH2: 5,49.0; CH: 3,129.6, 130.0,137.7; C: 118.5,143.9; [α]D 20°C -57.3° (c=10.43mg/2mL, methanol) and a more polar (+)-enantiomer CIMS: m/z 214.15 (MH+); #H (CDCl3) 3.97 (2H, m, Im-CH,), 6.52 (1H, d, Ar-H8), 6.67 (1H, t, Ar-H8), 6.96 (1H, s, Im-H5), 6.96 (1H, t, Ar-H,), 7.01 (1H, t, Ar-H5), 7.11 (1H, s, Im-H4) and 7.50ppm (1H, s, Im-H2); bc (CDCl3) CH2: 30.2,43.5,49.0; CH: 6, 130.1,137.7; C: 118.5,143.9; [α]D20°C +56.8° (c=10.70mg/2mL, methanol), corresponding to the title compounds.

PREPARATIVE EXAMPLE 61 3-[[(1H-4-METHYLIMIDAZOL-1-YL)METHYL]-1,2,3,4- TETRAHYDROQUINOLINE Step A 1N-tert-BUTOXYCARBONYL-3-[(1H-4-METHYLMIDAZOL-1- YL)METHYL]-1,2,3,4-TETRAHYDROQUINOLINE

4-Methylimidazole (0.9504g, 11. 6mmoles) was dissolved in anhydrous DMF (52mL) and 95% sodium hydride (0.2924g, 11.6mmoles) was added in portions to the stirred solution at 25°C under argon. The mixture was stirred for lh. The title racemic compound from Preparative Example 60, Step C (4.394g, 10.5mmoles) in anhydrous DMF (25mL) was added and the mixture was stirred at 25°C for lh and then at 55-60°C for 7h. The mixture was evaporated to dryness and the residue was chromatographed on silica gel using 0.5%-2%-4%--6%-10% (10% conc. NH40H in methanol)-dichloromethane as the eluant to give the racemic title compound (1.93g, 56%) (4-Me: 5-Me:: 1.46: 1.0): CIMS: m/z 328.25 (MH+); 8H (CDCl3) 1.51 (9H, s, CH3), 2.20/2.24 (3H, s, 5-Me/4-Me), 3.81/3.88 (2H, m, 5-Me-Im-CH,/4-Me-Im-CHZ), 6.65/6.83 (1H, s, 4- Me-Im-H5/5-Me-Im-H4), 6.99-7.07 (2H, m, Ar-H, and Ar-H8), 7.17/7.20 (1H, d, Ar-H6), 7.36/7.43 (1H, s, 4-Me-Im-H,/5-Me-Im-HZ) and 7.67/7.71ppm (1H, d, Ar-Hg); bc (CDC13) 4-Me: CH3: 13.8,28.4, 4; CH2: 31.0,46.8,49.4; CH: 6,123.8,123.9, 1,136.7; C: 0,138.2,153.7; and 5-Me: CH3: 9.4,28.4,28.4,28.4; CH2: 31.0,46.9,47.1; CH: 9,123.9, 126.4,126.9,129.1,137.3; C: 7.

Step B 3- [ (1H-4-METHYLIMIDAZOL-1-YL) METHYL]-1, 2.3,4-<BR> TETRAHYDROQUINOLINE

The title compound from Step A above was deprotected essentially as described in Preparative Example 57, Step D above and chromatographed on silica gel to give the title compound.

PREPARATIVE EXAMPLE 62 6- [(lH-IMIDAZOL-1-YL) METHYL]-1,[(lH-IMIDAZOL-1-YL) METHYL]-1, 2,3,4-TETRAHYDROQUINOLINE

ROUTE1 Step A 6- (METHANESULFONYLOXYMETHYL) QUINOLINE

6-Hydroxymethylquinoline (0.4325g, 2.72mmoles) (prepared by the method of : C. E. Kaslow and W. R. Clark, J. Org. Chem., 1953,18,55-58.) and triethylamine (1.5147mL, 10.87mmoles) were dissolved in anhydrous dichloromethane (16mL) and the mixture was cooled to 0°C. Methanesulfonyl chloride (0.421mL, 5.43mmoles) was added and the mixture was stirred under argon at 0°C for lh. Additional triethylamine (0.758mL, 5.435mmoles) and methanesulfonyl chloride (0.211mL, 2.72mmoles) were added and the reaction was allowed to proceed for a further lh at 0°C. The mixture was evaporated to dryness to give the title compound which was used without further purification in the next step.

Step B 6-[(1 H-IMIDAZOL-1-YL) METHYL] QUINOLINE The title product from Step A above was dissolved in anhydrous DMF (lOmL) and sodium imidazole (0.367g, 4.08mmoles) was added. The mixture was heated at 70°C under

argon for 2h and then evaporated to dryness. The product was chromatographed on silica gel to give the title compound (0.1559g, 27%): FABMS: m/z 210.0 (MH+); 8, (CDCl3) 5.34 (1H, s, CH2), 6.97 (1H, s, Im-H5), 7.15 (1H, s, Im-H4), 7.44 (1H, dd, Ar-H3), 7.52 (2H, m, Ar-H5 and Ar-H,), 7.64 (1H, s, Im-H2), 8.12 (2H, d, Ar-H4 and Ar- H8) and 8.95ppm (1H, d, Ar-H2); bc (CDCl3) CH2: 50.6; CH: 119.4, 121.8,125.9,128. 4, C: 128.2, 134.6,147.9.

Step C<BR> <BR> <BR> <BR> <BR> 6-[(1H-IMIDAZOL-1-YL)METHYL-1,2,3,4-TETRAHYDRO#UINOLINE The title compound from Step B above (0.045g, 0.215mmoles) and methanol (1 lmL) were placed in a Parr bomb and platinum (IV) oxide monohydrate (0.05g, 0.204mmoles) was added. The mixture was hydrogenated at 50psi at 25°C for 2h. The catalyst was removed by decantation and washed with methanol. The methanol was evaporated to dryness and the product was chromatographed on silica gel using 3% (10% conc. NH40H in methanol)- dichloromethane as the eluant to give the title compound (0.0325g, @71%) : CIMS: m/z 214.15 (MH+); AH (CDCl3) 1.92 (2H, t, 3-CH2), 2.61 (2H, m, 4-CH2), 3.30 (2H, m, 2-CHZ), 4.93 (2H, s, CH2), 6.42 (1H, d, Ar-H3), 6.77 (1H, s, Ar-H5), 6.79 (1H, d, Ar-H7), 6.90 (1H, bs, Im-H5), 7.07 (1H, bs, Im-H4) and 7.52ppm (1H, bs, Im-H2); bc (CDC13) CH2 : 21.9,27.0,41.9,50.8; CH: 114.2,119.2 (b), 126.4,128.7,129.1, 137.2 (b); C: 8,144.8.

ROUTE 2 Step A 6-HYDROXYMETHYL-1,2,3,4-TETRAHYDROQUINOLINE

6-Hydroxymethylquinoline (lg, 6.28mmoles) (prepared by the method of : C. E. Kaslow and W. R. Clark, J. Org. Chem., 1953,18, 55-58.) and methanol (200mL) were placed in a Parr bomb and platinum (IV) oxide monohydrate (0.5g, 2.04mmoles) was added.

The mixture was hydrogenated at 50psi at 25°C for 2h. The catalyst was filtered off and washed with methanol. The combined filtrates were evaporated to dryness and the product was chromatographed on silica gel using 1.5% (10% conc. NH40H in methanol)- dichloromethane as the eluant to give the title compound (0.7044g, <BR> <BR> <BR> 68%): CIMS: m/z 164.35 (MH+); AH (CDC13) 1.93 (2H, m, 3-CH2) and 2.76 (2H, t, 4-CH2), 3.30 (2H, m, 2-CH,), 4.50 (2H, s, CH, OH), 6.45 (1H, d, Ar-H8), 6.96ppm (2H, m, Ar-H5 and Ar-H,); bc (CDC13) CH2 : 22.1,27.0,42.0,65.6; CH: 114.2,126.4,129.2; C: 4, 144.5.

Step B lN-tert-BUTOXYCARBONYL-6-HYDROXYMETHYL-1,2,3,4- TETRAHYDROQUINOLINE The title compound from Step A above (0.684g, 4.19mmoles) was dissolved in THF (25mL) and sodium hydroxide 0. 21g, 5.25mmoles) in water (lOmL) was added. Di-tert-butyldicarbonate (1.26g, 5.76mmoles was added and the mixture was stirred at 25°C for 92h. Additional di-tert-butyldicarbonate (0.628g, 2.88mmoles) was added and the reaction was continued for a total of 116h. The reaction was worked up as described in Preparative Example 1 Step

A above and the product was chromatographed on silica gel using 0.5% (10% conc. NH40H in methanol)-dichloromethane as the eluant to give the title compound (0.7978g, 72%): ESMS: m/z 264.1 (MH+); AH (CDC13) 1.52 (9H, s, CH3), 1.91 (2H, m, 3-CH2) 2.76 (2H, t, 4-CH2), 3.70 (2H, m, 2-CH2), 4.60 (2H, s, CH2OH), 7.09 (1H, s, Ar- H5), 7.12 (1H, d, Ar-H,) and 7.64ppm (1H, d, Ar-H8); bc (CDCl3) CH3: 4; CH2: 7,65.1; CH: 124.3,124.7, 127.4; C: 80.9,130.1,135.6,-138. 4,-154.2.

Step C lN-tert-BUTOXYCARBONYL-6- (4-TOSYLOXYMETHYL)-1,2,3,4- TETRAHYDROQUINOLINE

The title compound from Step B above may be reacted with 4- toluenesulfonyl chloride and pyridine under essentially the same conditions as described in Preparative Example 58, Step C and chromatographed on silica gel to give the title compound.

Step D<BR> lN-tert-BUTOXYCARBONYL-6- [ (1 H-IMIDAZOL-1-YL) METHYL]-<BR> 1,2,3, 4-TETRAHYDRO#UINOLINE

The title compound from Step C above may be reacted with sodium imidazole in anhydrous DMF under essentially the same conditions as described in Preparative Example 62, Route 1, Step B and chromatographed on silica gel to give the title compound.

Alternatively:

The title compound from Route 2, Step B above (0.5166g, 1.96mmoles) was dissolved in anhydrous THF (5.5mL) and N, N'- carbonyldiimidazole (0.668g, 4.12mmoles) was added and the mixture was heated under reflux at 75°C for 4.5h. The solution was evaporated to dryness and chromatographed on silica gel using 2% (10% conc. NH40H in methanol)-dichloromethane as the eluant to give the title compound (0.0612g, 10%): CIMS: m/z 314.25 (MH+); AH (CDCl3) 1.51 (9H, s, CH3), 1.92 (2H, m, 3-CH2), 2.72 (2H, d, 4-CH2), 3.69 (2H, d, 2-CH2), 5.04 (2H, s, CH,-Im), 6.85 (1H, s, Im-H5), 6.91 (1H, s, Ar-H6), 6.97 (1H, d, Ar-H8), 7.08 (1H, s, Im-H4), 7.59 (1H, s, Im-H2) and 7.67ppm (1H, d, Ar-H9) ; bc (CDC13) CH3: 28.4,28.4,28.4; CH2: 5; CH: 6,129.4, 137.3; C: 5,138.7,153.9.

Step E 6- [(lH-IMIDAZOL-1-YL) METHYL]-1, 2,[(lH-IMIDAZOL-1-YL) METHYL]-1, 2, 3,4-TETRAHYDROQUINOLINE UINOLINE The title compound from Step D above may be deprotected essentially as described in Preparative Example 57, Step D and chromatographed on silica gel to give the title compound.

PREPARATIVE EXAMPLE 63 4 (R/S)-[(lH-4/5METHYLIMIDAZOL-1-YL) METHYL]-1,2,3,4- TETRAHYDROISOQUINOLINE ROUTE 1 Step A 4-HYDROXYMETHYLISOQUINOLINE

4-Isoquinolinecarboxaldehyde (6.15g, 39.13mmoles) (prepared by the method of : J. B. Wommack, T. G. Barbee, Jr., D. J.

Thoennes, M. A. McDonald and D. E. Pearson, J. Heterocyclic Chem., 1969,6,243-245.) was dissolved in anhydrous dichloromethane (369mL) and the solution was cooled to 0°C.

Borane-dimethyl sulfide complex (1M in THF) (5.23mL, 5.09mmoles) (as described in: E. Mincione, J. Org. Chem., 1978,43,1829-1830) was added and the mixture was stirred at 0°C for a 1.5h. Additional borane-dimethylsulfide complex (1M in THF) (10.455mL, 1.35mmoles) was added and the reaction was stirred for an additional 2h at 0°C. Methanol (93.3mL) was added and the solution was evaporated to dryness and chromatographed on silica gel using 2-3% (10% conc. NH40H in methanol)-dichloromethane as the eluant to give unreacted 4-Isoquinolinecarboxaldehyde (-23%),.

4 (1,2-dihydroisoquinoline) carboxaldehyde (identical to that described in Preparative Example 63, Route 3, Step A (-27%) and the title compound (1.94g, 31%).

Alternatively the title compound may be prepared by catalytic hydrogenation of 4-isoquinolinecarboxaldehyde using 10% Pd-AI203 as the catalyst (as described in: J. Vassant, G, Smets, J. P.

Declercq, G. Germain and M. Van Meerssche, J. Org. Chem., 1980, 45,1557-1565).

Step B 4- [ (4-TOLUENESULFONYLOXY) METHYL] ISOQUINOLINE

To a stirred solution of the title compound from Step A above (1.94g, 12.2mmoles) in anhydrous pyridine (14mL) at 0°C was added 4-toluenesulfonyl chloride (2.784g, 14. 6mmoles) and the mixture was stirred at 0°C for 2.5h. The solution was evaporated to dryness and the product was azeotroped with toluene and then taken up in dichloromethane and washed with saturated aqueous sodium bicarbonate, filtered and evaporated to give the title compound which was used without purification in the next step.

Step C 4- [(1 H-4/5-METHYLIMIDAZOL-1-YL) METHYL] ISOQUINOLINE 4-Methylimidazole (1.099g, 13.38mmoles) was dissolved in anhydrous DMF (33.5mL) and 95% sodium hydride (0.338g, 13.42mmoles) was added in portions to the stirred solution at 25°C.

The title compound from Step B above was dissolved in anhydrous DMF (14mL) and added dropwise to the stirred solution at 25°C over 20min. The mixture was stirred at 25°C for 17h and evaporated to dryness. The residue was taken up in dichloromethane and washed with water, dried (MgSO4), filtered and evaporated to dryness. The product was chromatograped on silica gel using 2.5% methanol in dichloromethane as the eluant to give a mixture of the title compounds (0.5085g, 19%) (4-Me: 5-Me:: 1.2: 1): AH (CDC13) 2.18/2.22 (3H, s, 4-Me/5-Me), 5.46 (2H, s, CH,-Im), 6.63/6.89 (1H, s, 4-Me: Im-H5/5-Me: Im-H4), 7.43/7. 55 (1H, s, 5-

Me: Im-H2/4-Me: Im-H2), 7.63-7.86 (3H, d and t, Ar-H6,7,8), 8, 02/8.38 (1H, s, 5-Me: Ar-H3/4-Me: Ar-H3), 8.05 (0.5H, d, 5-Me: Ar-H3) and 9.26/9.28ppm (1H, s, 5-Me: Ar-H,/4-Me: Ar-H,), bc (CDCl3) 4-Me: CH3: 13.6; CH2: 46.5; CH: 8,127.8,128.7,131.6,136.3, 143.3,154.1; C: 7; and 5-Me: CH3: 9.5; CH2: 44.4; CH: 121.6,127.4,127.8,128.7,131.5,137.2,142.0, 153.7; C: 124.8,128.2,133.4,138.7.

Step D 4- [ ( H-4-METHYLIMIDAZOL-1-YL) METHYL] ISOQUINOLINE and 4- [ ( H-5-METHYLIMIDAZOL-1-YL) METHYL] ISOQUINOLINE The title mixture of regio-isomers from Step C above (0.45g) was subjected to chiral HPLC on a Chiralpak# HPLC column using hexane: iso-propanol: diethylamine:: 85: 15: 09.2 to give first the 4- methyl isomer FABMS: m/z 224.0 (MH+) ; #H (CDC13) 2.18 (3H, s, 4-CH3), 5.46 (2H, s, CH2-Im), 6.62 (1H, s, Im-H5), 7.54 (1H, s, Im-H2), 7.67 (1H, t, Ar-H8), 7.76 (1H, t, Ar-H,), 7.84 (1H, d, Ar-H6), 8.04 (1H, d, Ar-H9), 8.39 (1H, s, Ar-H3) and 9.27ppm (1H, s, Ar-H,); bc (CDClw3) CH3: 13.6; CH,: 46.5; CH: 7, 131.6,136.3,143.3,154.1; C: 7,133.8,138.8; and then the 5-methyl isomer (0. 0361g) : FABMS: m/z 224.1 (MH+); #1 @ (CDCl3) 2.20 (3H, s, 5-CH3), 5.45 (2H, s, CH2-Im), 6.86 (1H, s, Im-H4), 7.41 Im-H2),7.68(1H,t,Ar-H8),7.98(1H,t,Ar-H7),7.84(1H,d,(1H,s, Ar-H6), 8.02 (1H, s, Ar-H3), 8.05 (1H, d, Ar-H9) and 9.22ppm (1H, s, Ar-H1) ; bc (CDC13) CH3: 9.4; CH2: 44.3; CH: 121.5,126.9,127.9, 0,141.7,153.6; C: 7 and an overlap fraction (0.28g).

Step E 4 [(1H-4/5-METHYLIMIDAZOL-1-YL) METHYL]-1,2,3,4- TETRAHYDROISOQUINOLINE

The title compound from Step C above (0. 346g, 1.55mmoles) was dissolved in anhydrous methanol (80mL) and platinum(IV) oxide. monohydrate (0. 11g) was added. The mixture was hydrogenated at 25°C at 50psi in a Parr bomb for 2h. The catalyst was filtered off and washed with methanol and the methanol filtrates were evaporated to dryness. The residue was chromatographed on silica gel using 3% (10% conc. NH40H in methanol)-dichloromethane as the eluant to give the title 4-methyl compound (0.0299g, 9%): ESMS: m/z 228.0; 8H (CDC13) 2.24 (3H, s, Im-4-CH3), 2.81 (1H, bs, NH), 2.93 (2H, m, 3-CH2), 3.03 (1H, m, 4- CH), 4.04 (2H, s, 1-CH2), 4.08,4.27 (2H, dd, CH2-Im), 6.68 (1H, Im- H2), 7.01-7.09 (2H, m, Ar-H), 7.18 (2H, m, Ar-H) and 7.36ppm (1H, s, Im-H5); bc (CDCl3) CH3: 13.8; CH2: 1; CH: 39.6, 8,126.9,129.1,136.9; C: 134.5,135.7,138.6, and the title 5-methyl compound (0.0641g, 18%): CH3: 9.3; CH2: 44.9,48.8,50.5; CH: 9,129.0,136.7; C: 127.0,134.4,135.7,138.5.

ROUTE 2 Step A 4-HYDROXYMETHYLISOQUINOLINE 4-Isoquinolinecarboxaldehyde (lmmole) (prepared by the method of : J. B. Wommack, T. G. Barbee, Jr., D. J. Thoennes, M. A.

McDonald and D. E. Pearson, J. Heterocyclic Chem., 1969,6,243- 245.) is dissolved in anhydrous THF (50mL) and treated with borane-methyl sulfide (0.3mmoles) (as described in: E. Mincione, J.

Org. Chem., 1978,43,1829-1830) at 0°C for 0.5-lh and worked up in the usual way to give the title compound.

Alternatively the title compound may be prepared by catalytic hydrogenation of 4-isoquinolinecarboxaldehyde using 10% Pd-AI203 as the catalyst (as described in: J. Vassant, G, Smets, J. P.

Declercq, G. Germain and M. Van Meerssche, J. Org. Chem., 1980, 45,1557-1565).

Step B 4- [ (4-TOLUENESULFONYLOXY) METHYL] ISOQUINOLINE

The title compound from Step A above is dissolved in anhydrous pyridine and cooled to 0°C with stirring. 4- Toluenesulfonyl chloride is added and the reaction is carried out as described in Preparative Example 60, Step D to give the title compound which may be used without further purification.

Step C 4-HYDROXYMETHYL-1,2-DIHYDROISOQUINOLINE

The title compound from Step A above may be selectively reduced with freshly prepared zinc borohydride (as described in: D.

C. Sakar, A. R. Das and B. C. Ranu, J. Org. Chem., 1990,55,5799- 5801.) to give title allylic alcohol.

Step D<BR> <BR> N-tert-BLJTOXYCARBONYL-4-HYDROXYMETHYL-1,2-<BR> <BR> DIHYDROISOQUINOLINE

The title compound from Step B above is reacted with zinc borohydride as described in Step C above to give the title compound.

Alternatively: The title compound from Step C above is reacted with di-tert- buylydicarbonate and sodium hydroxide as described in Preparative Example 57, Step A to give the title compound.

Step E 4 (R/S)-[(1 H-4/5-METHYLIMIDAZOL-1-YL) METHYL]-1,2- DIHYDROISOQUINOLINE The title compound from Step C above may be reacted with N, N'-carbonyldiimidazole using the procedure described in Preparative Example 22, part two of Step D, to give the title compounds.

Step F 4 (R/S)-[(lH-4/5-METHYLIMIDAZOL-1-YL) METHYL]-1,2,3,4- TETRAHYDROISOQUINOLINE

The title compounds of Step E above is reduced with platinum (IV) oxide as described in Route 1, Step D above to give the title compounds.

Step G 4 [4- (TOLUENESULFONYLOXY) METHYL]-1,2- DIHYDROISOQUINOLINE

The title compound from Step D above is reacted with 4- toluenesulfonyl chloride in pyridine as described in Preparative Example 4, Step D to give the title compound.

Step H 2N-tert-BUTOXYCARBONYL-4 (R/S)- [ (lH-4/5-METHYLIMIDAZOL-l- YL)METHYL]-1,2-DIHYDROISOQUINOLINE

The title compounds from Step G above was reacted with sodium 4-methylimidazole as described in Route 1, Step C above to give the title compounds.

The regio-isomers may be separated by chiral HPLC on a Chiralpak# column, or by treatment with trityl chloride as described above.

Step I 2N-tert-BUTOXYCARBONYL-4 (R/S)-[(1 H-4/5-METHYLIMIDAZOL-1- YL)METHYL]-1,2,3,4-TETRAHYDROISOQUINOLINE

The title compounds from Step H above were reduced with platinum (IV) oxide as described in Route 1 Step D above to give the title compounds.

Step J 4 (R/S)- [ ( H-4/5-METHYLIMIDAZOL-1-YL) METHYL]-1, 2,3,4- TETRAHYDROISOQUINOLINE The title compounds from Step H above were deprotected as described in Preparative Example 57, Step D, to give the title compounds.

EXAMPLE 74 1,1-DIMETHYLETHYL-4- (3-BROMO-8-CHLORO-6, 11-DIHYDRO- 5H-BENZO [5,6] CYCLOHEPTA [1,2-b] PYRIDIN-11-YL)-2 (R)- [[2-[2-(1H- IMIDAZOL-1-YL) ETHYL]-1-PIPERIDINYL] CARBONYL]-1- PIPERAZINECARBOXYLATE Route 1

1,1-Dimethylethyl-4-(3-bromo-8-chloro-6,11-dihydro-5H- benzo [5,6] cyclohepta [1, 2-b] pyridin-11-yl)-2 (R)-carboxy-1- piperazinecarboxylate (0.250g, 0.466mmoles) (prepared as described in Preparative Example 6), 2-[2-(1H-imidazol-1- yl) ethyl] piperidine (0.1085g, 0.6054mmoles) (prepared as described in Preparative Example 1), 1-(3-dimethylamino-propyl)-3- ethylcarbodiimide hydrochloride (0.116g, 0.6054mmoles), 1- hydroxybenzotriazole (0.0818g, 0.6054mmoles) and 4- methylmorpholine (0.0665mL, 0.6054mmoles) were dissolved in anhydrous DMF (lOmL) and the mixture was stirred under argon at 25°C for 18h. The solution was evaporated to dryness and the residue was washed with water, dried (MgSO4), filtered and evaporated to dryness. The residue was chromatographed silica gel using 1% (10% conc. NH40H in methanol)-dichloromethane as the eluant to give the title compound (0.0617g, 19%): ESMS: m/z 697.2 (MH+) ; BH (CDCl3) 6.97 (1H, broad s, Im-H5), 7.04 (1H, broad s, Im- H4), 7.09-7.20 (broad m, Ar-H), 7.56 (2H, broad s, Ar-H and Im-H,) and 8.38ppm (1H, broad s, Ar-H,); bc (CDCl3) CH3: 28.4,28.4,28.4; CH2: 6,40.2, CH: 45.8/46.4,50.1/51.7/52.2, 130.7/130. 8, 4/141.5,146.9; C: 80.4,120.0,134.3, 2.

Route 2 Step A.

4- (3-BROMO-8-CHLORO-6, 11-DIHYDRO-5H- BENZO [5,6] CYCLOHEPTA [1,2-b] PYRIDIN-11-YL)-2 (R)-[[2- [2-(1H- IMIDAZOL-1-YL) ETHYL]-1-PIPERIDINYL] CARBONYL] 1-PIPERAZINE

3-Bromo-8,11-dichloro-6, 11-dihydro-5H- benzo [5,6] cyclohepta [1,2-b] pyridine (prepared as described in Preparative Example 40 (U. S. 5,719,148) was reacted with the title compound from Peparative Example 1, Step B, and triethylamine, in a mixture of anhydrous THF and dichloromethane at 25°C to give the title compound.

Step B 1,1-DIMETHYLETHYL 4- (3-BROMO-8-CHLORO-6, 11-DIHYDRO-5H- BENZO [5,6] CYCLOHEPTA [1,2-b] PYRIDIN-11-YL)-2 (R)- [ [2- [2- [ (lH- IMIDAZOL-1-YL) ETHYL]-1-PIPERIDINYL] CARBONYL]-1- PIPERAZINECARBOXYLATE The title compound from Example 74, Step A was reacted with di-tert-butyldicarbonate and sodium hydroxide in THF-water (1: 1) at 25°C as described in Preparative Example 57, Step A, and the product was chromatographed on silica gel, to give the title compound.

EXAMPLES 75-86 Using essentially the same procedure as described in Example 74 above the 11 (R), 2 (R) and 11 (S), 2 (R) acids from Preparative Example 30, may be reacted with the product from Preparative Example 58, Step E to give the targets of Examples 75- 80; or with the product from Preparative Example 59, Step E to give the targets of Examples 81-86, respectively (Table 11).

TABLE 11 Ex Product R9 R8 75 Hs, N"" r H 3C,. O NI--CH3 N 11 (R), 2 (R) 2 (R/S)

TABLE 11-continued Ex Product Rs Rg 76 H3 C-H3 , m H3C0 NCH3 N 11 (S), 2 (R) 2 (R/S) 77 qu3 H 3C O'O NCHg N 11 (R), 2 (R) 2 (R/S) 78 CH3 H 3C''O N NCHs 11 (S), 2 (R) 2 (R/S) 79 NCH3 N 11 (R), 2 (R) 2 (R/S) 80 i S_ O N 11 (S), 2 (R) 2 (R/S) SlHCP-Lf\ H3C'O NCH3 11 (R), 2 (R) g N v 4 (R/S) TABLE 11-continued Ex Product R9 R8 82 H H3 i 3 H C'O'7 3 v 11 (S), 2 (R) N i 4 (R/S) 83 ho HCO)N-CHs 3 11 (R), 2 (R) v N 4 (R/S) 84 H3 J__ HsC''O 11 (S), 2 (R) 7 N 4 (R/S) 85: Izo """,. NCHs O 11 (R), 2 (R) S N i 4 (R/S) 86 PT I N/-. CH3 11 (S), 2 (R) t N 4 (R/S) EXAMPLE 87-110

By reacting the anhydride from Preparative Example 3 as shown in the scheme above, with the product of Preparative Example 60, Steps E, or F, one may obtain the intermediate of Examples 87-98; or with the product of Preparative Example 61, Step B, one may obtain the intermediate of Examples 99-102; or with the product of Preparative Example 62, Step C, one may obtain the intermediate of Examples 103-106; or with the intermediate of Preparative Example 63, Step D of Route 1, or Steps F or J of Route 2 one may obtain the intermediate of Examples 107-110. By reacting the intermediates so obtained with 8,11-dichloro-6, 11- dihydro-5H-benzo [5,6] cyclohepta [1,2-b] pyridine (prepared as described in US 5,807,853, Sept. 15,1998) one may obtain, after reaction with either di-tert-butyldicarbonate and sodium hydroxide, or with iso-propyl chloroformate and triethylamine, or with cyclohexyl chloroformate and triethylamine as described herein, the title compounds of Examples 87-110 (Table 12).

TABLE 12 Ex Product R9 R i I H 3C O N 11 (R), 2 (R) 3 (R/S) _ 88 88H3 N N 11 (S), 2 (R)' 3(R/S) 89 L : _N 7-b N 11 (R), 2 (R) ~ 3 (R/S) 90 a0R wO N'\ 11 (S), 2 (R) 3 (R/S) 91 4. v N\2 v N 11 (R), 2 (R) 3H3 3 (R) 92 , 3C N N 11 (S), 2 (R) 3 (R) 93 93 H3 H C O-'O 11 (R), 2 (R) 3 (R) _. 94 "" H rn 11 1 (S), 2 (R) H3Ca 3 (R) TABLE 12-continued Ex Product R9 R8 95 H C'O/ ,., \ ZON 3 N HsCOO N 11 (R), 2 (R)"^" 3 (S) 96 CQ"TY M N 11 (S), 2 (R) ~ 3(S) 97 N UN COR, 11 (R), 2 (R) 3 (S) 98 i, ,",",, \ (, N 11 (S), 2 (R) 3 (S) 98 O>+ X tN H 3C O N 11 (R) 2 (R) oyl- 3 (R/S) 100 XH3 WJ <CH Ton 11 (S), 2 (R) CH3 3 (R/S) 101 N in 11 (R), 2 (R) CH3 3 (R/S) 102 ao IN ., r",. CH3 " cw 11 (S), 2 (R) VrIl CH3 3 (R/S) TABLE 12-continued Ex Product R9 R8 103 H C''O _ N I_ II N 11 (R), 2 (R) _ 104 H3 l , z 0---0 N zon 11 (S), 2 (R) nô. * 11 (R), 2 (R) 106 N. N j j t\j 11 (S), 2 (R) 1073C''O _ 107 H3 yN 11 (R), 2 (R) >1 kL'N 4 (R/S) 108 CH3 HsCO N-CHs 11 (S), 2 (R) >1 w nez 4 (R/S) 109 N N CH3 ,""". Nw% CH3 O 11 (R), 2 (R) i w 4 (R/S) TABLE 12-continued Ex Product R9 R8 110 1 e-CH3 N in 11 (S), 2 (R) I nu 4 (R/S)

PREPARATIVE EXAMPLE 64 Step A A solution of 52. i (J. Med. Chem. 4890-4902 (1988)) (205 g) in conc. HCl (1 L) and water (100 mL) is refluxed for 18h, then poured into ice (3 Kg). Aq. 50% NaOH is added to pH 12 followed by extraction with EtOAc (3x4 L), the extracts are washed with brine, dried and evaporated to afford 52. ii (166 g).

Step B A 1M solution of DIBAL in toluene (908 mL) is added dropwise during 2h to a solution of 52. ii (166 g) in toluene (4 L) at rt. followed by stirring for 18 h. The mixture is cooled to 0-5°C and stirred for

lh and extracted with IN HC1 (2 L). The aqueous extract is basified to pH 10 with 50% NaOH and extracted with EtOAc (3x2 L). The extracts are evaporated and chromatographed on silica-gel (1 Kg).

Elution with 10% MeOH/CH2Cl2 affords the title compound (t) 52.0 (104 g): HRMS (FAB) calcd for ClgH2, N279BrCl 393.0556, found 393.0554.

Step C The racemate (i) 52.0 (96 g) is resolved by HPLC on a 8x30 cm CHIRALPAK AD column at 25°C with the LTVdetector set at 290 <BR> <BR> <BR> nm. Elution with 0.05% diethylamine-methanol affords: Peak 1 (-)<BR> <BR> <BR> 52.0 (40 g): [(Z] 20-28. 4° (c 0.3, MeOH); Further elution with the<BR> <BR> <BR> same solvent affords: Peak 2 (+) 52.0 (42 g): [a] 20 +27. 5° (c 0.3,<BR> <BR> <BR> MeOH).

PREPARATIVE EXAMPLE 65 Step A A solution of (+)-52.0 (2.3 g) in dimethylformamide (30 ml) is reacted with isatoic anhydride (1.25 g) in the presence of DMAP (0.1 g) at r. t. for 3hrs and is then evaporated under reduced pressure and residual dimethylformamide is azeotroped with toluene. The residue is dissolved in ethylacetate (50 ml) and the solution is extracted with 10% sodium carbonate (3x100 ml). The organic layer is filtered through silica-gel (100ml) followed by elution with ethylacetate. The filtrate is evaporated under reduced pressure to afford the title compound 53.0 as an amorphous solid (3.68 g).

MS (FAB): m/z 510 (MH) +.

Step B

A solution of 53.0 (3.1 g) and sodium nitrite (0.8 g) in methanol (500 ml) is stirred at r. t. under nitrogen with cuprous chloride (0.15 g) while adding dropwise over 10 minutes a 4M hydrochloric acid/dioxane solution (3.9 ml). The reaction mixture is stirred for 24hrs followed by the addition of 10% sodium carbonate to pH 8, concentrated under reduced pressure, diluted with water (200 ml) and extracted with dichloromethane (4xlOOml).

The combined extract is evaporated under reduced pressure and the crude reaction product is flash chromatographed on silica-gel (400 ml). Elution with 25% ethylacetate-hexane affords after evaporation the title compound 54. Oa and 54. Ob as an off-white amorphous solid (2.97 g).'H NMR (CDC13,300 MHz) d 3.30 (s, 3H); MS (FAB) m/e 525 (MH) +.

Steps C-E

A solution of 54. Oa and 54. Ob (17 g) in methanol (150 ml) and 2N hydrochloric acid (170 ml) and conc. HC1 (60 ml) is heated under reflux for 17 hrs, followed by evaporation under reduced pressure.

The resulting amorphous solid is dissolved in methanol (160 ml) and sodium cyanide (15 g) is added with stirring until the reaction is basic (pH 8). The reaction is stirred for 2 h, diluted with dichloromethane (300 ml) and filtered. The filtrate is evaporated and the residue is dissolved in conc HC1 (150 ml) and the mixture is heated in an oil bath (120°C) for 4h and is then evaporated under reduced pressure. The residue is dissolved in THF (100 ml) and 10% NaOH (30 ml) is added to pH>8 followed by the dropwise addition of a solution of (BOC) O (9 g) in THF (50 ml) with vigorous stirring for 24 h. The solution is concentrated to a low volume, stirred with hexane (2x120 ml) and ice-water followed by acidification of the aqueous layer with citric acid and extraction with EtOAc. The crude product obtained by evaporating the extract is purified by flash chromatography to afford the mixture of 57. Oa and 57. Ob as light tan solid that appears as a single tlc spot (16 g).

'H NMR (CDC13,300 MHz) d 1.40 (s, 9H); MS (FAB) m/z 535 (MH) +.

The single tlc spot is a mixture of four isomers.

Following the above procedure (Steps A-E), except using Compound (-)-52.0 (17 g), a mixture of 58. Oa and 58. Ob is obtained as a light solid that appears as a single tlc spot (17 g). MS (ES) m/z 535 (MH+).

EXAMPLE 118 B/ CI CI ber,, + EDCI, HOBT, NMM I DU F Nu DMF) 0- z reagent 1 COOH V Reagent2 Oi N

The imidazole (reagent 2), (220mg, 0.92mmol) was added to a solution of the Boc-acid (reagent 1), (0.45g, 0.842mmol), EDCI (200mg, 1.043mmol), HOBT (130mg, 0.962mmol), and N-methyl morpholine (0.2ml, 1.81mmol) in DMF (anhydrous, 3ml) at room temperature (20°C). The resultant solution was stirred overnight at 20°C. The solvent was evaporated, water (70ml) and EtOAC (120 ml) were added. The organic layer was separated, and washed with 10% Na2CO3 solution (50ml), then dried over MgSO4, filtered and evaporated solvent yielding an oil, which chromatographed on silica gel eluting with 5% MeOH: MeCl2 yielding the product as a white solid (425mg, 74%). Mixture of 4 isomers A, B, C, D.

Mass Spec (ES, MH, 682) High Resolution Mass Spec Estimated (MH) 684.2139 (Br =81) Observed 684.2120 EXAMPLE 119 Step A Br/ CI Br/I CL / 4NHCI-dioxane z s 14l I/ Non N N A solution of the tricycle Isomers (A, B, C, D) from Example 118 (150mg, 0.205mmol) in 4N Hcl-dioxane (3ml) and MeOH (3ml) was stirred at 20°C for 3 hours. The solvent was evaporated, water (25ml)

and 10% NaOH (4ml) were added, then extracted with MeCl2 (2x100ml). The organic layer was separated, dried over MgSO4, and solvent evaporated yielding a solid which was purified by chromatography on silica gel eluting with 3% MeOH-MeCl2 containing 2% NH40H yielding the product as a white solid (70mg, 54% yield). Mixture of 2 Isomers (C, D) (PRODUCT 1) Mass Spec ES (MH) 582.

Further elution yielded a white solid (25mg, 20% yield).

Mixture of 2 isomers. (A, B) (PRODUCT 2) Mass Spec ES (MH) 582.

Step B A solution of Boc dicarbonate (100mg, 0.45mmol) in THF (2ml) was added to a solution of the tricycle (170mg, 0.29mmol)- (Isomers (C, D) Product 1 Step A in THF: H20 (V/V 1: 1) (lOml), and 10% NaOH (2ml) at 20°C. Then stirred at this temperature for 60 minutes.

Water (5ml), and Mecs2 (lOml) were added. The organic layer was separated, dried over MgSO4, filtered and solvent evaporated yielding an oil, which chromatographed on silica gel, eluting with 3% v/v MeOH: MeCl yielding the product as a white solid (170mg) as a mixture of 2 isomers. Isomers C, D. Mass Spec (ES, MH) 682.

Following the above procedure but, substituting Product 2 from Step A (isomers A/B) for Product 1, the title Product 2 was obtained as a mixture of 2 isomers (A/B). Mass Spec (ES. MH) 682 EXAMPLE 120

Compounds with (R) stereochemistry at C"were obtained using the procedures of Examples 118 and 119, but substituting reagent 1, Example 118 with the corresponding (R) tricyclic isomer.

EXAMPLES 121-126 By substituting reagent 2, Example 118, with the corresponding 2-methyl imidazole analog, the following structures were obtained

wherein R9 is defined in Table 14 below.

TABLE 14 Ex. R9 Isomer C-11 Isomer 121 CHs. A, B, C, D S HsC) t H\ H3C O MS ES (MH) =696 TABLE 14-continued Ex. R9 Isomer C-11 Isomer 122 H C CHs A, B, C, D R 3 /\ H3C O MS ES (MH) =696 123 H c CHs C, D S 3 HgC 0o MS ES (MH) =696 124 H c CH3 A, B S 3 H3C O MS ES (MH) =696 125 CH3 C, D R 3 H3c 0 H3C/O O MS ES (MH) =696 126 H c CHs A, B 3 HgC 0o 3 MS ES (MH) =696 EXAMPLES 127-132

Following the procedures of Examples 118 and 119 the isomers identified in Table 15 below are obtained.

TABLE 15 Ex. C-11 Isomer Isomer mass spectra observed (estimate) 127 R A, B, C, D 684.2123 (684.2139) 128 R A, B 684.2163 (684.2139) 129 R C, D 684.2163 (684.2139) 130 S A, B, C, D 684.2149 684.2139 131 S A, B, 684.2139 (684.2139)

PREPARATIVE EXAMPLE 66 Step A A solution of 6-methylnicotinic acid (9.97 g, 72.7 mmol), water (100 mL) and ammonium hydroxide was hydrogenated (40 psi) in a Parr low-pressure hydrogenation apparatus with 5% Rh- Ale03 (3.22g) catalyst over 72 hours. The mixture was filtered and <BR> <BR> the filtrate was concentrated in uacuo to give the title compound as a white solid (10.58g, 100%, MH+ = 144).

Step B

A mixture of the title compound from Step A (10.40 g, 72.72 mmol), ethyl alcohol (190 proof, 50 ml) and HCl (4ml) was stirred at reflux for 4 hours. The reaction mixture was cooled to room temperature and poured into water. Basification of the mixture to pH=10 with 10% aqueous NaOH, extraction of the aqueous layer with EtOAc and drying of the organic phase over anhydrous Na2SO4 gave the title compound after filtration and concentration in vacuo (1.85 g, 15%, MH+ =172).

Step C Following the procedure set forth in Preparative Example 7 Step B but using the title compound from Preparative Example 66 Step B instead of the title compound from Preparative Example 7 Step A, the product was isolated as a mixture of diastereomers and used directly in Step D (MH+ = 130).

Step D Following the procedure set forth in Preparative Example 7 Step C but using the title compound from Preparative Example 66

Step C instead of the title compound from Preparative Example 7 Step B, the product was isolated as a mixture of diastereomers (1.7 g, 70%, MH+ = 230).

Step E Following the procedure set forth in Preparative Example 7 Step D but using the title compound from Preparative Example 66 Step D instead of the title compound from Preparative Example 7 Step C, the product was isolated as a mixture of diastereomers and used directly in Step F (MH+ = 384).

Step F Following the procedure set forth in Preparative Example 7 Step E but using the title compound from Preparative Example 66 Step E instead of the title compound from Preparative Example 7 Step D, the product was isolated as a 5: 1 mixture of diastereomers (328 mg, 16 %, MH+ = 280).

Step G Following the procedure set forth in Preparative Example 7, Step F, except using the title compound from Preparative Example

66, Step F instead of the title compound from Preparative Example 7, Step E, the amine hydrochloride was obtained (290 mg, 100%): MH+= 180.

PREPARATIVE EXAMPLE 67 Step A If the procedures set forth in Preparative Example 66 Steps A- E were followed, except using 5-hydroxynicotinic acid instead of 6- methylnicotinic acid in Step A, the alcohol would be obtained.

Step B If the product from Step A were treated with PCC according to standard procedures set forth in the literature, then the ketone would be obtained.

Step C If the procedures set forth in Preparative Example 7 Steps E- F were followed, except using the title compound from Preparative Example 67 Step B instead of the title compound from Preparative Example 7 Step D in Step E, the amine hydrochloride

would be obtained.

Step D If the product from Preparative Example 67 Step C were treated with excess NaBH4 according to standard procedures set forth in the literature, then the alcohol would be obtained.

PREPARATIVE EXAMPLE 68 Step A Following the procedure set forth in Preparative Example 7 Step C, except using the title compound from Preparative Example 7, Step A instead of the title compound from Preparative Example 7, Step B the ester was obtained (62 g, 96%): Mu+ =258.

Step B The product from Preparative Example 68, Step A was treated with LDA in anhydrous THF and the resulting anion was alkylated with methyl iodide to afford the title product (3.53 g, 82%): Mut =272.

Step C The title compound from Preparative Example 68, Step B was treated with TFA in CH 2C4 to afford the amine as a TFA salt (1.63 g, 84%): MH+ = 172.

Following the procedures set forth in Preparative Example 7, Steps B-E, except using the title compound from Preparative Example 68, Step C instead of the title compound from Preparative Example 7, Step A in Step B, the imidazole product was obtained (0.445g, 100%): MH+= 280.

Step E Following the procedure set forth in Preparative Example 68 Step C, except using the title compound from Preparative Example 68 Step D, the amine was obtained as its TFA salt. The mixture was basified with 1N NaOH and extracted with CH2Cl2 to afford the product (14.6 g, 96%): MH+= 194.

PREPARATIVE EXAMPLE 69 Following the procedures set forth in Preparative Example 68 Steps A-D, except using benzyl bromide in Preparative Example 68 Step B instead of methyl iodide, the amine hydrochloride

would be obtained.

EXAMPLE 133

If the procedure set forth for preparing the compounds in Table 4 were followed using the title compound from Preparative Example 66 Step G, the 11 (S) or 11 (R) isomers of the carboxylic acid from Preparative Example 30, DEC, HOBt and NMM, the title products would be obtained.

EXAMPLE 134

If the procedure set forth for preparing the compounds in Table 4 were followed using the title compound from Preparative Example 67 Step D, the 11 (S) or 11 (R) isomers of the carboxylic acid from Preparative Example 30, DEC, HOBt and NMM, the title products would be obtained.

EXAMPLE 135

If the procedure set forth for preparing the compounds in Table 4 were followed using the title compound from Preparative Example 68 Step D, the 11 (S) or 11 (R) isomers of the carboxylic acid from Preparative Example 30, DEC, HOBt and NMM, the title products would be obtained.

EXAMPLE 136

If the procedure set forth for preparing the compounds in Table 4 were followed using the title compound from Preparative Example 69, the 11 (S) or 11 (R) isomers of the carboxylic acid from Preparative Example 30, DEC, HOBt and NMM, the title products would be obtained.

EXAMPLE 137

If the procedure set forth for preparing the compounds in Table 4 were followed using the title compound from Preparative Example 70 Step B, the 11 (S) or 11 (R) isomers of the carboxylic acid from Preparative Example 30, DEC, HOBt and NMM, the title products would be obtained.

PREPARATIVE EXAMPLE 71 2 (R)-[[2-[2-(lH-IMIDAZOL-1-YL) ETHYL]-1- PIPERIDINYL] CARBONYL] PIPERAZINE

Step A BIS-(1,1-DIMETHYLETHYL) 2(R)-[[2-[2-(1H-IMIDAZOL-1-YL)ETHYL]- 1-PIPERIDINYL] CARBONYL]-1, 4-PIPERAZINEDICARBOXYLATE 1,4-Di-N-tert-butoxycarbonylpiperazine-2 (R)-carboxylate (prepared as described in Preparative Example 2) (0.6946g, 2.1mmoles), 2 (R/S)-[2-(lH-imidazol-1-yl) ethyl] piperidine (0.49g, 2.73mmoles) (prepared as described in Preparative Example 57, Step D) (IN0972), 1- (3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (0.524g, 2.73mmoles), 1-hydroxybenzotriazole (0. 3693g, 2.73mmoles) and 4-methylmorpholine (0.2765g, 0.3005mL, 2.73mmoles) were dissolved in anhydrous DMF (3mL) and the mixture was stirred under argon at 25°C for 122h. The mixture was evaporated to dryness and chromatographed on silica gel using 2-3% (10% conc. ammonium hydroxide in methanol)- dichloromethane as the eluant to give the title compound (0.3127g, <BR> <BR> <BR> 30%): CIMS: m/z 492.4 (MH+); AH @ (CDCl3) 1.47 (18H, s, CH3), 7.01 (1H, s, Im-H5), 7.05 (1H, s, Im-H4) and 7.63ppm (1H, (CDCl3) s, Im-H2); bc 0, CH3: 4; CH2: 19.1,25.9, 26.2,31.9,40.8/41.3,41.7,43.0,44.0; CH: 46. 52.1, 128.4, 137.2; and # 169. 8.

Step B 2 (R)-[[2-[2-(lH-IMIDAZOL-1-YL) ETHYL]-1- PIPERIDINYL] CARBONYL] PIPERAZINE

The title compound from Step A above was deprotected as described in Preparative Example 57, Step D and chromatographed on silica gel to give the title compound.

EXAMPLE 138 1,1-DIMETHYLETHYL 4-(3-BROMO-8-CHLORO-6, 11-DIHYDRO-5H- BENZO [5,6] CYCLOHEPTA [1,2-b] PYRIDIN-11 (S)-YL)-2 (R)-[[2-[2-(1H- IMIDAZOL-1-YL)ETHYL]-1-PIPERIDINYL]CARBONYL]-1- PIPERAZINECARBOXYLATE Sodium 1,1-dimethylethyl 4- (3-bromo-8-chloro-6, 11-dihydro- 5H-benzo [5,6] cyclohepta [1, 2-b] pyridin-11 (S)-yl)-2 (R)-carboxy-1- piperazinecarboxylate (prepared as described in Preparative Example 6 (sodium salt)) (0. lg, 0.179mmoles), 2- [2- (lH-imidazol-1- yl) ethyl] piperidine (prepared as described in Preparative Example 57, Step D) (0.0417g, 0.233mmoles), 1- (3-dimethylaminopropyl)-3- ethylcarbodiimide hydrochloride (0.0446g, 0.233mmoles), 1- hydroxybenzotriazole (0.0314g, 0.233mmoles) and 4- methylmorpholine (0.0512mL, 0.466mmoles) were dissolved in anhydrous DMF (4mL) and the mixture was stirred under argon at 25°C for 42h. The solution was evaporated to dryness and the residue was taken up in dichloromethane and washed with 1N NaOH, dried (MgSO4), filtered and evaporated to dryness. The residue was chromatographed on silica gel using 2.5%-4.5%-7.5%

(10% conc. NH40H in methanol)-dichloromethane as the eluant to give the title compound (0.0172g, 14%): HRFABMS: m/z 697.2285 (MH+) (Calcd. m/z 697.2269); AH (CDC13) (9H, s, CH3), 4.31 (1H, s, H"), 4.68 (1H, bs, H2), 7.03-7.20 (5H, bm, Ar-H and Im-H4 and Im-H), 7.57 (1H, s, Im-H,), 7.83/8.19 (s, Ar-H) and 8.38ppm (1H, s, Ar-H,); bc (CDCl3) CH3: 28.4,28.4,28.4; CH2 : 19.1, 5,31.4,40.3,42. 9/43.2,44.1/44.6,45.6, 50.2/50.5; CH: 2,127.9, C: 80.4, 155.0,156.7/157.1, 170.3/170.9.

EXAMPLE 139 1,1-DIMETHYLETHYL 4- (8-CHLORO-6,11-DIHYDRO-5H- BENZO [5,6] CYCLOHEPTA [1,2-b] PYRIDIN-11 (S)-YL)-2 (R)- [ [2- [2- (1H- IMIDAZOL-1-YL) ETHYL]-1-PIPERIDINYL] CARBONYL]-1- PIPERAZINECARBOXYLATE Sodium 1,1-dimethylethyl 4- (8-cWoro-6, 1 1-dihydro-5H- benzo [5,6] cyclohepta [1, 2-b] pyridin-11 (S)-yl)-2 (R)-carboxy-1- piperazinecarboxylate (prepared as described in Preparative Example 6 (sodium salt)) (0.5239g, 1.09mmoles), 2-[2-(lH-imidazol- 1-yl) ethyl] piperidine (prepared as described in Preparative Example 57, Step D) (0.2544g, 1.42mmoles), 1- (3-dimethylaminopropyl)-3- ethylcarbodiimide hydrochloride (0.272g, 1.42mmoles), 1- hydroxybenzotriazole (0.1918g, 1.42mmoles) and 4- methylmorpholine (0.156mL, 1.42mmoles) were dissolved in anhydrous DMF (23.5mL) and the mixture was stirred under argon at 25°C for 286h. The solution was evaporated to dryness and the residue was taken up in dichloromethane and washed with IN

NaOH, dried (MgS04), filtered and evaporated to dryness. The residue was chromatographed on silica gel using 2.5% (10% conc.

NH40H in methanol)-dichloromethane as the eluant to give the title compound (0.2298g, 32%): HRFABMS: m/z 619.3169 (MH+) (Calcd. m/z 691.3163).

EXAMPLE 140 4- (8-CHLORO-6, 11-DIHYDRO-5H-BENZO [5,6] CYCLOHEPTA [1,2- b] PYRIDIN-11 (S)-YL)-2 (R)-[[2-[2-(1H-IMIDAZOL-1-YL)ETHYL]-1- PIPERIDINYL CARBONYL]-1-PIPERAZINE The title compound from Example 2 (0.225g, 0.363mmoles) was dissolved in methanol (2mL). A 10% (v/v) solution of conc.

H2SO4 in dioxane (v/v) (4.92mL) was added and the mixture was stirred at 25°C for 30h. The mixture was diluted with methanol (300mL) and then treated with BioRad AG 1-X8 (OH-) resin until it was basic. The resin was filtered off and washed with methanol. The combined filtrates were evaporated to dryness and the residue was chromatographed on silica gel using 4% (10% conc. NH40H in methanol)-dichloromethane as the eluant to give the title compound (0.1692g, 90%): HRFABMS: m/z 519.2655 (MH+) (Calcd. m/z <BR> <BR> <BR> <BR> <BR> 519.26390), 8H (CDC13) 4.43 (1H, s, H"), 93,7.00,7.10,7.13, 03,8.30 and 8.33ppm (8H, Ar- H and Im-H); #c(CDCl3) CH2 : 3/29.0, 9/31.0,31.5/31.9,40.0/40.7,43.5,44.1/44.2/44.4, 49.3,51.5/52.3; CH: 5/79.7, 1/129.5/129.7, 137. 0/137. 5,138.9,146.3; C: 134.0, 1 and 169.8/170.5.

EXAMPLE 141 CYCLOHEXYL 4- (8-CHLORO-6, 11-DIHYDRO-5H- BENZO [5,6] CYCLOHEPTA [1,2-b] PYRIDIN-11 (S)-YL)-2 (R)-[[2-[2 (R/S)- (1 H-IMIDAZOL-1-YL) ETHYL-1-PIPERIDINYL] CARBONYL]-1- PIPERAZINECARBOXYLATE The title compound from Example 3 (0.165g, 0.318mmoles) and triethylamine (0.1329mL, 0.954mmoles) were dissolved in anhydrous dichloromethane (5mL). Cyclohexylchloroformate (0.0517g, 0.318mmoles) dissolved in anhydrous dichloromethane (3.18mL) was added and the mixture was stirred at 25°C for 18h.

Additional cyclohexylchloroformate (0.0129g, 0.0795mmoles) was added and the stirring was continued for a total of 43h. Methanol (lOmL) was added and the mixture was evaporated to dryness. The residue was chromatographed on silica gel using 2% (10% conc.

NH40H in methanol)-dichloromethane as the eluant to give the title compound (0.153g, 75%): HRFABMS: m/z 645.3323 (MH+) (Calcd.

MH+ for C36H46N603C1 : m/z 645.3320).

EXAMPLE 142 CYCLOHEXYL 4- (8-CHLORO-6, 11-DIHYDRO-5H- BENZO [5,6] CYCLOHEPTA [1, 2-b] PYRIDIN-11 (S)-YL)-2 (R)-[[2-12 (S)- (lH-IMIDAZOL-1-YL) ETHYL-1-PIPERIDINYL] CARBONYL]-1- PIPERAZINECARBOXYLATE Isomer 1 and (-)-CYCLOHEXYL 4- (8-CHLORO-6, 11-DIHYDRO-5H- BENZO [5,6] CYCLOHEPTA [1,2-b] PYRIDIN-11 (S)-YL)-2 (R)-[[2-[2(R)-(1 H- IMIDAZOL-1-YL) ETHYL-1-PIPERIDINYL] CARBONYL]-1- PIPERAZINECARBOXYLATE

Isomer 2 The diastereoisomeric mixture of compounds from Example 4 (0.154g) was separated using chiral HPLC on a Chiralpak AD analytical column using hexane: iso-propanol: diethylamine:: 85: 15: 0.2 as the eluant to give firstly isomer 1 (0. 0376g): HRFABMS: m/z 645.3305 (MH+) (Calcd. MH+ for C36H46N603C1 : m/z 645.3320); 8H (CDCl3) 4.30 (1H, s, H11), 00, 7.08,7.11,7.16,7.18,7.42,7.70,8.32ppm (9H, s and m, Ar-H and Im-H); #c(CDCl3) CH2 : 6,23.6,24.8/25.1,25.5,28.0/28.2, 9,31.4,31.8,31.8,42.7,43.9/44.2,50.9,52.7; CH: 0, 128.7,132.8,137.1,139.0/139.3,146.3/146.9; C: 134.0,135.1, 1,157.0 and 170.1; [a] (c=6.89mg/2mL, MeOH) and then isomer 2 HRFABMS:

m/z 645. 3305 (MH+) (Calcd. MH'for for C36H46N603C1 m/z 645-3320); aH (CDC13) 4.34 (1H, s, Hl,), 43, 7.70 and 8.33ppm (9H, s and m, Ar-H and Im-H); bc (CDCl3) CH2: 5,28.9,30.6/30.8,31.5,31.7,31.7, 36.7,40.4,42.8,44.1,50.5,52.5; CH: 2/79.4, 1,130.7,132.7,137.1,139.4, 146.3/146.9; C: 1,157.0 and 170.2; M-44. 1° (c=10. 05mg/2mL, MeOH). An overlap cut consisting of a mixture of isomer 1 and isomer 2 was also obtained (0.0196g).

PREPARATIVE EXAMPLE 72 2 (R/S)- [2- (1 H-4-METHYLIMIDAZOL-1-YL) ETHYL] PIPERIDINE

Step A <BR> 1 N-tert-BUTOXYCARBONYL-2 (R/S)-[2-(1 H-4/5-METHYLIMIDAZOL- 1-YL) ETHYL] PIPERIDINE

4-Methylimidazole (6. 46g, 78.64mmoles) was dissolved in anhydrous DMF (300mL) and 95% sodium hydride (1.987g, 86.5mmoles) was added in portions over 0.25h to the stirred solution at 25°C under argon. The mixture was stirred for 1.5h. A solution of l-tert-butoxycarbonyl-2 (R/S)- (2- methanesulfonyloxyethyl) piperidine (21.97g, 71.49mmoles) (prepared as described in Preparative Example 57, Step B) in anhydrous DMF (70mL) was added and the mixture was heated under reflux at 65°C for 2.25h. The mixture was evaporated to dryness and the residue was taken up in dichloromethane and washed with water, dried (MgS04), filtered and evaporated to

dryness. The product was chromatographed on silica gel using 1% (10% conc. NH40H in methanol)-dichloromethane to give a mixture of the title compounds (12. 06g, 58%) (4-Me: 5-Me:: 63: 37): CIMS: m/z 294.25 (MH+); 4-Me: 8H (CDC13) 1.43 (9H, s, CH3), 2.20 (3H, s, Im-4-CH3), 6.63 (1H, s, Im-Hg) and 7.35ppm (1H, s, Im-H2); âc (CDCl3) CH3: 4,28.4; CH2: 7,31.6,38.8,44.1; CH: 2,136.1; C: 79.7,138.3,155.0 and 5-Me: AH (CDCl3) 1.43 (9H, s, CH3), 2.19 (3H, s, Im-5-Me), 6.75 (1H, s, Im-H4) and 7.41ppm (1H, s, Im-H2); #c(CDCl3) CH3 : 4; CH2 : 19.0,25.4,28.7,31.4,38.8,42.0; CH: 5; C: 79.7, 0.

Step B <BR> <BR> <BR> 1 N-tert-BUTOXYCARBONYL-2 (R/S)-12- (1 H-4-METHYLIMIDAZOL-1- YL)ETHYL] PIPERIDINE The mixture of compounds from Step A above (1.77g) was dissolved in anhydrous CH2Cl2 (18.6mL) at 0°C under argon. Trityl chloride (1.2445g, 2 equivalents per equivalent of the 5-methyl isomer) was added and the mixture was stirred at 0°C for 2h. The reaction mixture was introduced directly onto a silica gel column and the column was eluted with 50% ethyl acetate in acetone to give the pure 4-methyl isomer (0.6267g, 56%): 4-Me: aH (CDC13) 1.44 (9H, s, CH3), 2.20 (3H, s, Im-4-CH3), 6.64 (1H, s, Im-H5) and 7.36ppm (1H, s, Im-H2); #c(CDCl3) CH3 : 5,28.5; CH2: 19.1,

25.5,28.9,31.7,39.0,44.2; CH: 1,136.2; C: 79.8,138.4, 155.1.

Step C 2 (R/S)-12-(1 H-4-METHYLIMIDAZOL-1-YL) ETHYL] PIPERIDINE The pure 4-methyl isomer (0.7518g, 2., 56mmoles) was deprotected as described in Preparative Example 57, Step D, to give after purification, the title compound (0.4366g, 88%): FABMS: m/z 194.2 (MH+); 8H (CDCl3) 1.76 (2H, m, CH2), 2.19 (3H, s, Im-4-CH3), 3.94 (2H, m, CH2-Im), 6.60 (1H, s, Im-H5) and 7.33ppm (1H, s, Im- H2); #c(CDCl3) CH3 : 13.7; CH2: 6,46.8; CH: 2; C: 138.4.

EXAMPLE 143 CYCLOHEXYL 4- (8-CHLORO-6, 11-DIHYDRO-5H- BENZO [5,6] CYCLOHEPTA [1, 2-b] PYRIDIN-11 (S)-YL)-2 (R)- [ [2- [2 (R/S)- (4-METHYL-1H-IMIDAZOL-1-YL) ETHYL-1- PIPERIDINYL] CARBONYL]-1-PIPERAZINECARBOXYLATE Cyclohexyl 4- (8-chloro-6, 11-dihydro-5H- benzo [5,6] cyclohepta [1, 2-b] pyridin-11 (S)-yl)-2 (R)-carboxy-1- piperazinecarboxylate (0.275g, 0.568mmoles) (prepared as described in Preparative Example 32), 2- [2 (R/S)- (4-methyl-lH- imidazol-1-yl) ethyl] piperidine (0.1428g, 0.7386mmoles) (prepared as described in Preparative Example 2, Step C), 1- (3- dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (0.1416g, 0.7386mmoles), 1-hydroxybenzotriazole (0.0998g, 0.7386mmoles) and 4-methylmorpholine (0.0812mL, 0.7386mmoles) were dissolved in anhydrous DMF (12.2mL) and the mixture was stirred at 25°C for 212h under argon. The solution was evaporated to dryness and

taken up in dichloromethane and washed with IN NaOH. The aqueous layer was extracted 3X with dichloromethane (200mL) and the combined organic layers were dried (MgSO4), filtered and evaporated. The product was chromatographed on silica gel using 2% (10% conc. NH4OH in methanol)-dichloromethane as the eluant to give the title compound (0.149g, 40%): FABMS: m/z 659.62 (MH+).

EXAMPLE 144 (-)-CYCLOHEXYL 4- (8-CHLORO-6, 11-DIHYDRO-5H- BENZO [5,6] CYCLOHEPTA [ 1,2-b] PYRIDIN-11 (S)-YL)-2 (R)- [ [2- [2 (S)- (4- <BR> <BR> <BR> METHYL-1 H-IMIDAZOL-1-YL) ETHYL-1-PIPERIDINYL] CARBONYL]- 1-PIPERAZINECARBOXYLATE

Isomer 1 and (-)-CYCLOHEXYL 4- (8-CHLORO-6, 11-DIHYDRO-5H- BENZO [5,6] CYCLOHEPTA11,2-b] PYRIDIN-11 (S)-YL)-2 (R)- [ [2- [2 (R)- (4- METHYL-1H-IMIDAZOL-1-YL)ETHYL-1-PIPERIDINYL]CARBONYL]- 1-PIPERAZINECARBOXYLATE

Isomer 2 The diastereoisomeric mixture of compounds from Example 6 (0.145g) was separated using chiral HPLC on a Chiralpak AD* analytical column using hexane: iso-propanol: diethylamine:: 70: 30: 0.2 as the eluant to give firstly isomer 1

(0. 0475G) : FABMS: m/z 659.4 (MH+); aH (CDCl3) 1.66 (2H, m, CH2), 2.23 (3H, s, Im-4-CH3), 3.71 (2H, m, CH,-Im), 4.32 (1H, s, H11), 6.58, 60 and 8.34ppm (9H, s and m, Ar-H and Im-H); bc (CDC13) CH3: CH2: 18.9,23.5,23.5, 8,31.8,36.7,42.4/42.6, 43.8/44.1,50.5/50.8,52.8; CH: 3,73.6,79.3/80.0, 8,136.0, 146.3; C: 137.8, 0,170.1; [CC] D20°C -4.3° (c=8.07mg/2mL, MeOH), and then isomer 2 HRFABMS: m/z 659.3492 (MH+) (Calcd. MH+ for C37H48N6O3Cl: m/z 659.3476); 8H (CDCl3) 1.64 (2H, m, CH2), 2.22 (3H, s, Im-4-CH3), 3.72 (2H, m, CH2-Im), 4.35 (1H, s, Hl,), 43,7.57 and 8.35ppm (9H, s and m, Ar-H and Im-H); bc [CDCl3] CH3: CH2: 19. 1, 7/28.9,30.6,30.8,31.5,31.7,31.7,40.3, 42.1/42.8,44.1/44.2,50.5/50.7,52.6/52.7; CH: 46.0/46.2,52.5, 4,126.0,130.7,132.7, 139.4,146.3; C: 137.2, 142.0,156.1,157.1,170.3; [a] 20C-44. 7° (c=9. Omg/2mL, MeOH).

PREPARATIVE EXAMPLE 73 2 (R/S)- [3- (1H-IMIDAZOL-1-YL) PROPYL] PIPERIDINE btep A 1N-tert-BUTOXYCARBONYL-2(R/S)-[3-(1H-IMIDAZOL-I- YL)PROPYL] PIPERIDINE The title compound from Preparative Example 58, Step C, (1.29g, 4.3mmoles) was dissolved in anhydrous DMF (15mL).

Sodium imidazole (0.3215g, 4.7mmoles) was added and the mixture

was stirred at 25°C under argon for 3h. The solution was evaporated to dryness and the residue was chromatographed on silica gel using 2% (10% conc. NH4OH in methanol)- dichloromethane as the eluant to give the title compound (0. 6813g, 72%): CIMS: m/z 294.25 (MH+); 8H (CDCl3) 1.43 (9H, s, CH3), 3.97 (2H, m, CH2-Im), 6, 90 (1H, s, Im-H5), 7.04 (1H, s, Im-H4) and 7.45ppm (1H, s, Im-H2); #c(CDCl3) CH2 : 4,28.4; CH2: 18.9, 7,28.6,38.8,46.5; 118.6,129.4,137.1; C: 79.3,155.0.

Step B 2 (R/S)- [3- (1 H-IMIDAZOL-I-YL) PROPYL] PIPERIDINE The title compound from Step A above (0.6075g, 2. lmmoles) was deprotected as described in Preparative Example 57, Step D, and chromatographed on silica gel using 10% (10% conc. NH40H in methanol)-dichloromethane as the eluant to give the title compound (0. 3805g, 95%): CIMS: m/z 194.20 (MH+); #H (CDC1,) 3.89 (2H, m, CH2-Im), 6.84 (1H, s, Im-H5), 6.99 (1H, s, Im-H4) and 7.41ppm (1H, s, Im-H2); #c(CDCl3) CH2 : 1,34.4,47.2,47.2; CH: 56.4,118.8,129.6,137.1.

EXAMPLE 145 1,1-DIMETHYLETHYL 4- (3-BROMO-8-CHLORO-6, 11-DIHYDRO-5H- BENZO [5,6] CYCLOHEPTA [1,2-b] PYRIDIN-11-YL)-2 (R)-[[2-13- (1 H- IMIDAZOL-1-YL) PROPYL]-1-PIPERIDINYL] CARBONYL]-1- PIPERAZINECARBOXYLATE Isomers 1,2,3 and 4.

1,1-dimethylethyl 4- (3-bromo-8-chloro-6, 11-dihydro-5H- benzo [5,6] cyclohepta [1, 2-b] pyridin-11-yl)-2 (R)-carboxy-1- piperazinecarboxylate (0.7225g, 1.3mmoles) (prepared as described in Preparative Example 6), the title compound from Preparative Example 8, Step B (0.3382g, 1.7mmoles), 1- (3- dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (0.3354g, 1.7mmoles), l-hydroxybenzotriazole (0.2364g, 1.7mmoles) and 4- methylmorpholine (0.192mL, 1.7mmoles) were dissolved in anhydrous DMF (3mL) and the mixture was stirred under argon at 25°C for 319h. The solution was evaporated to dryness and the residue was taken up in dichloromethane and washed with saturated aqueous sodium bicarbonate, water, dried (MgSO4), filtered and evaporated to dryness. The residue was chromatographed on silica gel using 3% (10% conc. NH40H in methanol)-dichloromethane as the eluant to give the partially purified title compounds. The appropriate fractions were rechromatographed using 1.5% (10% conc. NH40H-methanol)- dichloromethane as the eluant to give title compound as a mixture of 4 diastereoisomers (0.3718g, 39%): FABMS: m/z 711.4 (MH+); AH <BR> <BR> <BR> (CDC13) 1.39 (9H, s, CH3), 13,7.17,7.56,7.67 (Ar-H), 6.97 (1H, s, Im-H5), 7.04 (1H, s, Im-H4), 7.58 (1H, s, Im-H,) and

8.38ppm (1H, m, Ar-H,); bC (CDCl3) CH3: 3/28.4, 28.3/28.4; CH2: 1, 42.7/43.0,46.5/46.7,50.1/50.3/50.7,52.7/52.9; CH: 46.9, 2/126.3,128.6,130.8/130.9,132.6, C: 80. 2, #120,1. 6, 140.8,140.8,# 156.8,#170.3.# A portion of the diastereomeric mixture (0.28g) was subjected to chiral HPLC on a Chiralpak# AD column using hexane: iso- propanol: diethylamine:: 85: 15: 0.2 as the eluant to give only a partial separation. Isomer 1 (0.0604g) was obtained pure while isomers 3 and 4 (0.0376g) were obtained as a 97% pure mixture.

The remaining overlap cuts could not be separated.

Isomer 1: HRFABMS: m/z 711.2429 (MH+) (Calcd. MH+ for C35H45N603BrCl: m/z 711.2425); #H (CDCl3) 1.41 (9H, s, CH3), 4.29 (1H, s, H11), 20 (Ar-H), 6.98 (1H, s, Im-H5), 7.08 (1H, s, Im-H4), 7.58 (1H, s, Im-H2), 7.63 (1H, s, Ar-H4) and 8.38ppm (1H, s, Ar-H,); #c(CDCl3) CH3 : 3; CH2: 7,25.4, 1,46.6,50.6/50.7,52.6; CH: 2,128.3,130.9,132.6, C: 79.7/80.2,120.2,133.6,134.2, 7,170.2; [a]-22. 2° (c=6.74mg/2mL, MeOH).

Isomers 3 and 4: FABMS: m/z 711.3 (MH+); 8H (CDCl3) 1.39, 1.42 (9H, s, CH3), 4.27,4.29 (1H, s, H"), 6.85,6.91,7. 05, 7.12- 43 (Ar-H), 6.98 (1H, s, Im-H5), 7.08 (1H, s, Im-H4), 7.56 (1H, s, Im-H2), 71 (1H, s, Ar-H4) and 8.38ppm (1H, s, Ar-H2); #c(CDCl3) CH3 : 3/28.4; CH,: 18.8,25.2, 6,50.5,52.7/53.3; CH: 5/78.6,119.2,126.2,128.6, 6,137.0,141.5,146.9; C: 1,120.0, 6,156.6, 0/170.2.

PREPARATIVE EXAMPLE 74 4- [3- (1 H-IMIDAZOL-1-YL) PROPYL] PIPERIDINE

Step A lN-tert-BUTOXYCARBONYL-4- [3- (lH-IMIDAZOL-l-<BR> <BR> YL) PROPYLIPIPERIDINE

The title compound from Preparative Example 59, Step C (1.39g, 3.5mmoles) was dissolved in anhydrous DMF (lOmL) and sodium imidazole (0.3464g, 3.85mmoles) was added and the mixture was stirred at 25°C for 3h under argon. The solution was evaporated to dryness and the residue was chromatographed on silica gel using 2% (10% conc. NH40H in methanol)- dichloromethane as the eluant to give the title compound (0.7637g, 74%): FABMS: m/z 294.20 (MH+); #H (CDCl3) 1.39 (9H, s, CH3), 3.88 (2H, m, CH2-Im), 6.85 (1H, s, Im-H5), 7.00 (1H, s, Im-H4) and 7.40ppm (1H, s, Im-H2) ; bC (CDCl3) CH3: 28.5,28.5,28.5; CH2: 28.3, 32.0,33.3,33.3,44.0,44.0,47.2,118.7,129.5,137.1; CH: 35.7; C: 79.3,154.8.

Step B 4- [3-(1 H-IMIDAZOL-1-YL) PROPYL] PIPERIDINE

The title compound from Preparative Example 4, Step A above was deprotected as described in Preparative Example 57, Step D, to

give after chromatography on silica gel using 20% (10% conc.

NH40H in methanol)-dichloromethane as the eluant, the title compound (0.4346g, 95%): CIMS: m/z 194.20 (MH+); AH (CDCl3) 3.89 (2H, m, CH2-Im), 6.88 (1H, s, Im-H5), 7.02 (1H, s, Im-H4) and 7.42ppm (1H, s, Im-H2); bC (CDCl3) CH2: 7, 46.7,47.4; CH: 36.0,118.8,129.6,137.2.

PREPARATIVE EXAMPLE 75 2(R)-[[4-[3-(1H-IMIDAZOL-1-YL)PROPYL]-1- PIPERIDINAL] CARBONYL] PIPERAZINE Step A 1,4-BIS-1,1-DIMETHYLETHYL 2 (R)-[[4-[3-(1H-IMIDAZOL-I- YL) PROPYL]-1-PIPERIDINYL] CARBONYL] PIPERAZINE-1,4-BIS- CARBOXYLATE 1,4-Di-N-tert-butoxycarbonylpiperazine-2 (R)-carboxylate (0.521g, 1. 6mmoles) (prepared as described in Preparative Example 2), 1- (3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (0. 393g, 2. 1mmoles), 1-hydroxybenzotriazole (0.0.277g, 2. 1mmoles) and 4-methylmorpholine (0.225mL, 2. 1mmoles) were dissolved in anhydrous DMF (3mL) and the mixture was stirred under argon at 25°C for 150h. The solution was evaporated to dryness and the residue was taken up in dichloromethane and washed with saturated aqueous sodium bicarbonate, water, dried (MgSO4), filtered and evaporated to dryness. The residue was chromatographed on silica gel using 3% (10% conc. NH40H in methanol)-dichloromethane as the eluant to give the title compound (0. 693g, 87%): CIMS: m/z 506.35 (MH+); BH @ (CDCl3) 1.42 (18H, s, CH3), 3.91 (2H, m, CH2-Im.), 6.88 (1H, s, Im-H5), 7.03 (1H, s, Im-H4)

and 7.43ppm (1H, s, Im-H2); bc (CDC13) CH3: 4,28.4,28.4, 28.4,28.4; CH2: 8,33.1,33.1,41.2/41.6,43.8,43.8,45.6, 47. 1, #51. 0; CH: 35.8,52,9,118.7,129.6,137.1; C: 80.1,80.4, 168.1,168.1 168.1.

Step B 2(R)-[[4-[3-(1H-IMIDAZOl-1-YL)PROPYL]-1- PIPERIDINYL] CARBONYL] PIPERAZINE The title compound from Preparative Example 5, Step A above (0.6344g, 1.26mmoles) was deprotected as described in Preparative Example 57, Step D, and the product was chromatographed on silica gel using 10% (10% conc. NH40H in methanol)- dichloromethane as the eluant to give the title compound (0.3076g, 80%): CIMS: m/z 306.30 (MH+); AH (CDCl3) 3.87 (2H, m, CH2-Im), 6.82 (1H, s, Im-H5), 6.99 (1H, s, Im-H4) and 7.38ppm (1H, s, Im-H2); bc (CDCl3) CH2: 0/42.2, 45.2/45.5,46.9/47.0,46.9/47.0,46.9; CH: 7, 129.4,137.0; C: 169.7.

EXAMPLE 146 4- (3-BROMO-8-CHLORO-6, 11-DIHYDRO-5H- BENZO[5, 6] CYCLOHEPTA [1,2- b]PYRIDIN-11-YL)-2(R)-[[4-[3-(1H-IMIDAZOL-1-YL)PROPYL]-1- PIPERIDINYL] CARBONYL] PIPERAZINECARBOXYLATE 3-Bromo-8,11-dichloro-6, 11-dihydro [5,6] cycloheptall, 2- pyridine (0.2043g, 0.596mmoles) (prepared as described in Preparative Example 40 (U. S. 5,719,148)), the titled compound from Preparative Example 5, Step B (0.2729g, 0.894mmoles) and triethylamine (0.249mL, 1.79mmoles) were dissolved in anhydrous THF (8mL) and anhydrous dichloromethane (20mL) and the mixture was stirred at 25°C for 72h under argon. The solution was evaporated to dryness and the residue was chromatographed on silica gel using 3% then 5% and the 10% (10% conc. NH40H in methanol)-dichloromethane as the eluant to give first the dimer (Sch 377314) (0.0681g, 12%): SIMS: m/z 916.2 (MH+); AH (CDC13) 3.99 (4H, m, CH2-Im), 54,7.69,8.28,8.31 and 8.34ppm (13H, s and m, Ar-H and Im-H); #c(CDCl3) CH2 : 28. 3/28.5,30.3/30.4,30.5,31. 3/31.5, 33.1,33.1.41.0/41.1, 9/54.1/54.2; CH: 35.7, 9/126. 0/126.2,128.6/128.7,130.7, 141.5, 146.7/146. 9; C: 119.0,130.0,

8,170.0 and the then monomer (Sch 377318) (0.2291g, 63%): CIMS: m/z 611.20 (MH+); 8H (CDC13) 3.93 (2H, m, CH2-Im), 12,7.14,7.47, 7.49,7.57,7.59,8.33,8.35and 8.38ppm (8H, s and m, Ar-H and Im-H); 8JCDC1J CH,: 1/33.3, 4/44.9,44.4/44 9,45.3/45.7,47.2, 52.2/52.7,55.0; CH: 8,126.2/126.3,129.6, 1,141.3,146.9/147.1; C: 120.1, 169.0/170.0.

EXAMPLE 147 1,1-DIMETHYLETHYL 4- (3-BROMO-8-CHLORO-6, 11-DIHYDRO-5H- BENZO [5,6] CYCLOHEPTA [1,2- b] PYRIDIN-11-YL)-2 (R)- [ [4- [3- (1 H-IMIDAZOL-1-YL) PROPYL]-1- PIPERIDINYL] CARBONYL] PIPERAZINECARBOXYLATE The title compound from Example 9 (0.1768g, 0.29mmoles) was reacted with di-tert-butyldicarbonate (0.0694g, 0.319mmoles) and sodium hydroxide (0.0116g, 0.29mmoles) inTHF-water (1: 1) (5mL) and purified as described in Preparative Example 57, to give <BR> <BR> the title compound (0.1294g, 63%): FABMS: m/z 711.1 (MH+); AH @ (CDCl3) (9H, s, CH3), 3.98 (2H, m, CH2-Im), 6.93,7.03, 32 and 8.38ppm (8H, s and m, Ar-H and Im-H); 8c (CDC13) CH3: 28.4,28.4,28.4; CH2: 2,30.7, 4,44.6,44.6,47.4, 50. 4, #50. 9; CH: 3,130.2,130.8, 7/141.5,147.2; C: 9,133.4,134.0, 2,168.8.

PREPARATIVE EXAMPLE 71A Step A

lo the title compound trom Preparative Example 8, Step B (1.63g, 7.57 mmol) in DMSO (5.0 mL) was added iPrNEt (6.59 mL, <BR> <BR> <BR> 5.0 eq.) followed by pyre SO3 (7.23g, 3.0 eq.) in DMSO (10 mL). The resulting solution was stirred 1 hour, diluted with EtOAc and washed with IN HC1, H2O, and sat. NaHCO3. The organics were dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was used without purification (1.26g, 76% yield): LCMS: MH+=214.

StepB NaHMDS (14.7 mL, 1M in THF, 1.5 eq.) was added to a solution of CH3OCH2P+Ph3Cl- (5. 06g, 1.5 eq.) in THF (25 mL) at 0 °C.

The resulting solution was stirred 15 minutes before adding via canulae to a solution of the title compound from Preparative Example 71A, Step A (2. lg, 9.80 mmol) in THF (25 mL) at-78 °C.

The reaction mixture was stirred 1 hour at-78 °C, warmed to 0 °C and stirred 1 hour. The resulting solution was diluted with Et2O, washed with H2O, and dried over Na2SO4. The organics were dried over Na2SO4, filtered and concentrated. The crude product was purified by flash chromatography using a 65: 35 hexanes EtOAc solution as eluent (1.51g, 64% yield).

Step C

The title compound from Preparative Example 71A, Step B (0.70g, 2.90 mmol) was stirred in 40% HC1 (6.6 mL) at room temperature overnight at which time additional 40% HC1 (3.0 mL) was added and the reaction mixture stirred an additional 4 hours.

The resulting solution was neutralized with Na2CO3 (aq.) and extracted with Et2O. The combined organics were dried over Na2SO4, filtered, and concentrated in uacuo. The residue was purified by flash chromatography using a 65: 35 hexanes: EtOAc solution as eluent (0.30g, 46% yield + SM): LCMS: MH+=228.

Step D The title compound from Prepartive Example 71A, Step C (0. 90g, 1.02 eq.) was stirred with TosMIC (0.77g, 3.88 mmol) and NaCN (0.0194g, O. leq.) in EtOH (7.0 mL) for 30 minutes. The reaction mixture was transferred to a sealed tube, diluted with 7M NH3 in MeOH (13.0 mL) and heated to 90 °C for 22 hours. The resulting solution was cooled, concentrated under reduced pressure, diluted with IN NaOH and extracted with CH2C12. The combined organics were dried over Na2So4, filtered, and concentrated. The crude product was purified by flash chromatography using a 5% (10% NH40H in MeOH) solution in CH2C12 as eluent (0.53g, 51% yield): LCMS: MH+=266.

Step E

The title compound from Preparative Example 71A, Step D (0.34g, 1.28 mmol) in CH2C12 was treated with TrCl (0.38g, 1.05 eq.) and TEA (0.27 mL, 1.5 eq.). The resulting solution was stirred 2 hours at room temperature, diluted with saturated NaHCO3, and extracted with CH2C12. The combined organics were dried over NaS04, filtered, and concentrated in vacuo. The crude product was purified by flash chromatography using a 3% (10% NH40H in MeOH) solution in CH. Cl, as eluent (0.43g, 66%): LCMS: MH+=508.

Step F The title compound from Prepartive Example 71A, Step E (0.43g, 0.846mmol) in Et2O was treated with MeI (0.79 mL, 15 eq.) and stirred overnight and filtered. The resulting solid washed with Et2O, dissolved in MeOH and heated at reflux overnight. The reaction mixture was concentrated in vacuo and purified by flash chromatography using a 5% (10% NH40H in MeOH) solution in CH2Cl2 as eluent (0.14g, 79% yield): LCMS: MH+=280.

PREPARATIVE EXAMPLE 72A

By essentially the same procedure set forth in Preparative Example 71A, the title compound was prepared.

PREPARATIVE EXAMPLE 73A Step A

A solution ofe-caprolactam (6.86 g, 60 mmol, 1.0 eq.) in anhydrous THF (50 mL) was added dropwise over a period of 50 minutes to a stirred suspension of sodium hydride (1.59 g, 1.05 eq.) in anhydrous THF (20 mL) at 0 °C under a nitrogen atmosphere.

The snow-white mixture was stirred at room temperature for 2h, whereupon a solution of benzyl bromide (7.65 mL, 1.05 eq.) in anhydrous THF (20 mL) was added dropwise over a period of 30 minutes. The mixture was stirred at room temperature for 2h and filtered through CELITE 521 to remove sodium bromide. The volatiles were evaporated under house vacuum at 30 °C to give the title compound as a dark-yellow oil which was used without further purification (10.60 g, 87% yield). FABMS: MH+=204.

Step B

A 2.45 M solution of n-butyllithium in hexanes (18.1 mL, 44.3 mmol, 1.44 eq.) was added dropwise over a period of 30 minutes to a stirred solution of diisopropylamine (5.2 mL, 36.9 mmol, 1.2 eq.) in anhydrous THF (100 mL) at 0 °C under a nitrogen atmosphere.

The yellow solution was stirred at 0 °C for another 30 minutes and was then cooled to-78 °C. A solution of the title compound from Preparative Example 73A, Step A (6.25 g, l. Oeq.) in anhydrous THF (50 mL) was subsequently added dropwise over a period of 25 minutes and the solution was stirred at-78 °C for another 3h.

Neat benzyl chloromethyl ether (7.0 mL, 1.3 eq.) was added dropwise over a period of 10 minutes. The dirty-brown solution was slowly (3h) warmed to room temperature and stirred for another 12h. The volatiles were removed under house vacuum at 30 °C.

The residual deep-yellow oil was partitioned between distilled water (100 mL) and diethyl ether (100 mL). The layers were separated and the aqueous phase was extracted with diethyl ether (5 x 50 mL).

The organic layer of earlier and the ethereal extracts were combined and washed with brine (50 mL), dried over Na2SO4, filtered, and concentrated under house vacuum at 30 °C. The oily residue was flash-chromatographed (hexanes: acetone = 8: 2 v/v) over silica gel to give the title compound as a lime-green oil (6.77g, 68% yield).

[M+H+]: 324; HRMS (FAB+): Calculated for C2, H26 NO, ( [M + H] +) : 324.1961; Observed: 324.1964.

Step C A 1 M solution of lithium aluminum hydride in diethyl ether (23 mL, 1.1 eq.) was added dropwise over a period of 25 minutes to a stirred solution of the title compound from Preparative Example 73A, Step B (6.77 g, 20.9 mmol) in anhydrous THF (100 mL) at-20 °C under a nitrogen atmosphere. The yellow solution was slowly (3h) warmed to room temperature and stirred for another 12h. The solution was cooled to 0 °C and carefully treated with a saturated,

aqueous NASO, solution (10 mL) to give a snow-white slurry. The mixture was filtered and the precipitate was carefully washed with diethyl ether (3 x 50 mL) and absolute alcohol (3 x 50 mL). The filtrate was concentrated under house vacuum at 30 °C, redissolved in acetone (100 mL) and dried over Na2SO4, filtered, and again concentrated under house vacuum at 30 °C. The oily residue was flash-chromatographed (hexanes: acetone = 9: 1 v/v) over silica gel to give the title compound as a lime-green oil (5.08 g, 78% yield): [M + H] + : 310; HRMS (FAB+): Calculated for C2, NO ( [M + H] +) : 310.2173; Observed: 310.2171.

Step D A mixture of the title cmpound from Preparative Example 73A, Step C (5.08 g, 16.4 mmol) 20 wt. % Pd (OH)2 ("Pearlman's catalyst,"2.54 g, 50 wt. % reagent), and absolute alcohol (100 mL) was hydrogenated at 4.5 atmosphere pressure and room temperature for 8h. The mixture was filtered through CELITE 521 and the filtrate was concentrated under house vacuum at 30 °C.

The residual oil was flash-chromatographed (CH2C12: 10% NH40H- MeOH=9: 1 v/v) over silica gel to give the title compound as a yellow oil (2.86 g, 79% yield): [M + H] + : 220; HRMS (FAB+): Calculated for CJNO ( [M + H] +) : 220.1698; Observed: 220.1701.

Step E

Potassium metal (2.60 g, 5.0 eq.) was added portionwise to a stirred solution of the title compound fro Preparaive Example 73A, Step D (2.86 g, 13.0 mmol) and t-butanol (1.5 mL, 1.2 eq.) in a mixture of liquefied ammonia (125 mL) and anhydrous THF (125 mL) at-60 °C under a nitrogen atmosphere. The dark-blue mixture was slowly (12h) warmed to room temperature and the volatiles were removed under house vacuum at 30 °C. The residue was taken up in distilled water (50 mL) and extracted with diethyl ether (5 x 50 mL). The ethereal extracts were discarded and the aqueous layer was concentrated under house vacuum at 50 °C to give the title compound (1.70 g, 100% crude yield): [M + H] + : 130; HRMS (FAB+): Calculated for C7HI6NO ([M + H] +) : 130.1232; Observed: 130.1231.

Step F By essentially the same procedure set forth in Preparative Example 7, Step C through Step F only substituting the title compound from Preparative Example 73A, Step F, the title compound was prepared.

PREPARATIVE EXAMPLE 74A Step A

Di-isopropyl azodicarboxylate (0.54 mL, 1.5eq.) was added to N-t-butoxycarbonylpiperidin-3-ol 83 mmol), 3- hydroxypyridine (0.26g, 1.5eq.), and PPh3 (0.72g, 1.5 eq.) in THF (5.0 mL). The resulting solution was stirred at room temperature overnight, concentrated in vacuo, and purified by flash chromatography using a 30% hexanes in EtOAc solution as eluent (0.14g, 27% yield): LCMS: MH+=279.

Step B

By essentially the same procedure set forth in Preparative Example 8, the title compound was prepared.

PREPARATIVE EXAMPLES 74B AND 74C The title compound from Preparative Example 74A was separated into individual C-3 isomers by Preparative HPLC using a CHIRALPAK AD column using a20% iPrOH in hexanes with 0.2% DEA as eluent.

PREPARATIVE EXAMPLE 74A First eluting isomer: LCMS: MH+=279.

PREPARATIVE EXAMPLE 74B

Second eluting isomer: LCMS: MH+=279.

PREPARATIVE EXAMPLE 74C

By essentially the same procedure set forth in Preparative Example 8 only substituting the title compound from Preparative Example 74A, the title compound was prepared.

By essentially the same procedure as set forth in Preparative Example 74A, the title compounds in Column 4 of Table 16 were prepared using the 3-hydroxypyridine derivative in Column 2 of Table 16.

TABLE 16 Prep. Column 2 Column 3 Column 4 Ex. _ oil N N CH3 N N CH3 N CH3 -2HC) 76 H \ NJH C NJ J H3C N 3 N H3C N BOC H BOC H . 2HCI

PREPARATIVE EXAMPLE 77 Step A

By essentially the same procedure set forth in Preparative Example 73A, Step A, the title compound was prepared: LCMS: MH+=190.

Step B

To a solution of the title compound from Preparative Example 77, Step A (3.68g, 2.4eq.) in THF (50 mL) was added LiHMDS (19.4 mL, 2.4 eq., 1M solution in THF) at-78 °C. The resulting solution was stirred at-78 °C for 2.5 hours before adding 3- bromomethylpyridine hydrobromide (1.39g, 8.09 mmol). The reaction mixture was warmed slowly to room temperature and stirred overnight. The resulting solution was diluted with saturated NH4Cl (20 mL), extracted with CH2C12 (3 X 75 mL), dried over Na2SO4, filtered and concentrated to give a yellow oil (0.63g, 28% yield): LCMS: MH+=281.

Step C

To a solution of the title compound from Preparative Example 77, Step B (0.65g, 2.31 mmol) in THF (3.0 mL) was added LAH (2. 54 mL, 1M in Et2O) and the resulting solution stirred at room temperature overnight. The reaction mixture was quenched by the addition of saturated Na2SO4, filtered through Celite and concentrated under reduced pressure. The product was purified by flash chromatography using a 20% hexanes in EtOAc solution as eluent a give a yellow oil (0.42g, 68% yield): LCMS: MH+=267.

Step D

The title compound from Preparative Example 77, Step C (0.40g, 1.50 mmol) in dichloroethane (3 mL) was treated with 1- chloroethylchloroformate (0.37 mL, 2.3 eq.). The resulting solution was stirred 3 hours, concentrated under reduced pressure, diluted with MeOH, and heated at reflux for 3 hours. The recation mixture was cooled, concentrated under educed pressure, and purified by flash chromatography using a 10% (10% NH40H in MeOH) in CH2C12 solution as eluent (0.20g, 63% yield): LCMS: MH+=177.

PREPARATIVE EXAMPLE 78 STEP A To a solution of (S)-l-benzyl-2-pyrrolidinemethanol (15.5 g, 81.03 mmoles) and TEA (16.38 g, 161.93 mmoles) in CH, C4 (200 mL). MsCl (11.13 g, 97.16 mmoles) was added at 10 °C and stirred at room temperature overnight. Washed with H20 and evaporated to dryness to give mesylate (15.6 g) which without further purification, was mixed with NaCN (5.64 g, 115 mmoles) and heated at 80° C in DMF (100 mL) overnight. The reaction mixture was evaporated to dryness and extracted with EtOAc, washed with H2O, and dried (MgS04). The solvent evaporated to give (S)-l-benzyl-2- cyanomethyl-pyrrolidine (11.5 g): (MS, MH+=201.

STEP B

The title compound from Preparative Example 78, Step A (13.0 g) was refluxed in concentrated HCl (100 mL) overnight and evaporated to dryness. The semisolid residue was stirred in MeOH (100 mL), MgSO4 (5 g) and concentrated H, SO, (2 mL) at 80 °C overnight. The reaction mixture was evaporated to dryness to give (S)-1-benzyl-methy-2-pyrrolidineacetate (11.5 g): MS, MH+ = 234.

STEP C The title compound from Preparative Example 78, Step B (13 g, 55. 76 mmoles) was dissolved in THF (100 mL) and cooled to 10 °C (ice water bath). 1M LAH in ether (111.52 mL, 111.46 mmoles) was added slowly and the resulting mixture was refluxed for 2h.

The reaction mixture was cooled to room temperature and decomposed with the addition of ice. The residue was extracted with EtOAc and washed with brine and H2O. The organics were dried and evaporated to a residue which was flash chromatographed on a silica gel column in CH2C12/5% CH30H to give (S)-benzyl-hydroxyethyl-pyrrolidine (7.8 g): MS, MH+ = 206.

STEP D

The title compound from Preparative Example 78, Step C (7.7 g) was dissolved in EtOH (80 mL) and hydrogenated over Pd (OH) 2 (2.5 g) at room temperature at 50 psi overnight. The catalyst was filtered and solvent was removed to give (S)-2-hydroxyethyl- pyrrolidine (4.4 g): MS, Mu+ = 116.

STEP E

The title compound from Preparative Example 78, Step D (2.4 g, 20.85 mmoles) was dissolved in CH2C12 (250 mL) and cooled to 10 °C. TsCl (11.92 g, 62. 52 mmloes) followed by TEA (10.54 g, 104.2 mmoles) were added and stirred at room temperature overnight. The reaction mixture was diluted with CH2C12 and washed with brine and H20. The organics were dried and solvent evaporated to give (S)-tosyl-2-O-tosylethyl-pyrrolidine (3.96 g): MS, MH+ = 332.

STEP F

The title compound from Preparative Example 78, Step E (3.96 g, 9.2 mmoles) was dissolved in DMF (15 mL) and cooled to 10 °C. NaH (0.74 g, 60%, 18.43 mmoles) was added slowly and stirred at room temperature until a clear solution was obtained. 4-Methyl- imidazole (1.51 g, 18.43 mmoles) was then added and heated at 80°

C overnight. The resulting solution was evaporated to dryness and the residue was extracted with CH2C12 and washed with brine and H2O. The comboned organics were dried and solvent evaporated to give a crude product which was flash chromatographed on a silica get column in CH2Cl2/ 5% (CH3OH-10%NH4OH) to give a mixture (S)-tosyl-2- (4-methyl-1 H-imidazol)-ethyl-1-pyrrolidine (2.98 g, MS, MH+= 334) and (S)-tosyl-2- (5-methyl-lH-imidazol)-ethyl-l- pyrrolidine (2.98 g): MS, MH+ = 334.

STEP G

The title compound from 78, Step F (2.9 g) and trityl chloride (1.5 g) were stirred in CH2C12 (35 mL) at 10 °C overnight. The reaction mixture was flash chromatographed on a silica gel column in acetone/ethyl acetate (1: 1) to give (S)-tosyl-2- (4-methyl-lH- imidazol)-ethyl-l-pyrrolidine (0.827 g): (MS, MH+= 334).

STEP H

The title compound from Preparative Example 78, Step G (0.82 g) was dissolved in dry THF (2 mL) and liquid ammonia (150 mL). Sodium pieces were added until the blue colour remained and the resulting solution was stirred for 1/2 hr. EtOH was added dropwise until the blue coloured disappeared. The resulting solution was evaporated to dryness to give sticky white solid which was chromatographed on a flash silica gel column in CHCK/20% (CH30H-10% NH40H) to give the title compound (S)-2- (4-methyl-lH- imidazol)-ethyl-l-pyrrolidine, (0. 375 g): MS, MH+= 180.

PREPARATIVE EXAMPLE 79

By essentially the same procedure as that set forth in Preparative Example 78, (R)-2- (4-methyl-lH-imidazol)-ethyl-l- pyrrolidine was prepared from (R)-1-benzyl-2-pyrrolidinemethanol.

PREPARATIVE EXAMPLE 80 Step A The title compound from Preparative Example 68, Step C was treated with D- (-)-Tartaric acid and recrystallized from acetone- water to afford a piperidine salt enriched in the 3- (S) isomer which was neutralized with hydroxide to afford the title compound (11.1 g, 18%): MH'=172.

Step B Following the procedures set forth in Preparative Example 7, Steps B-E, except using the title compound from Preparative Example 80, Step A instead of the title compound from Preparative Example 7, Step A in Step B, and using 4-methylimidazole and NaH instead of sodium imidazole in Step E, the regioisomeric imidazole products were obtained (1. 1 g, 84%): Mu+ =294.

Step C

Following the procedure set forth in Preparative Example 17, except using the title compound from Preparative Example 80, Step B instead of the title compound from Preparative Example 13, the 4-methylimidazole product was obtained (0.501 g, 68%): Mu+ =294.

Step D Following the procedure set forth in Preparative Example 68 Step C, except using the title compound from Preparative Example 80 Step C, the amine was obtained as its TFA salt (0.72 g, 100%): MH+= 194.

PREPARATIVE EXAMPLE 81 Following essentially the same procedures set forth in Preparative Example 80, Steps A-D, except using L- (+)-Tartaric acid instead of D- (-)-Tartaric acid in Step A, the amine enriched in the 3- (R) isomer was obtained as its TFA salt (0.157 g, 100%): MH+= 194.

PREPARATIVE EXAMPLE 82 Step A

Following essentially the same procedure set forth in Preparative Example 80, Steps A, except using the benzylpiperidine prepared as described in J. Med. Chem. 41,2439 (1998) instead of the title compound from Preparative Example 68, Step C, the amine enriched in the 3- (S) enantiomer was obtained (6.81 g, 25%): MH'= 248.

Step B

Following the procedures set forth in Preparative Example 80, Steps B-D, except using the title compound from Preparative Example 82, Step A instead of the title compound from Preparative Example 80, Step A in Step B, the 4-methylimidazole product was obtained as its TFA salt which was neutralized with NaOH (aq.) to give the amine product (0.163 g, 86%): MH+ = 270.

PREPARATIVE EXAMPLE 83 Step A

The epoxide (J. Med. Chem. 30 (1), 1987, pps. 222-225) was treated with 4-methylimidazole and NaH in anhydrous DMF to obtain the resulting mixture of regioisomeric imidazole products (7.77 g, 100%): MH+=302.

Step B

The product from Preparative Example 83, Step A was treated with H2, Pd (OH) 2/C and EtOH in a Parr hydrogenator to afford the amine as a mixture of imidazole regioisomers which were used directly in Step C.

Step C

Following the procedure set forth in Preparative Example 7, Step C except using the title compound from Preparative Example

83, Step B instead of the title compound from Preparative Example 7, Step B the BOC derivatives of the regioisomeric methylimidazole products were obtained (5.4 g, 87%): MH+= 296.

Step D Following the procedure set forth in Preparative Example 17, except using the title compound from Preparative Example 83, Step C instead of the title compound from Preparative Example 13, the 4-methylimidazole products were obtained as an enantiomeric mixture (1.03 g, 43%): MH+= 296.

Step E Following the procedure set forth in Preparative Example 68, Step C except using the title compound from Preparative Example 83, Step D the amine was obtained as its TFA salt (6.3 g, 100%): MH+= 197.

PREPARATIVE EXAMPLE 84 Step A N-Butoxyearbonyl-[(ltriazolyl-imidazol-5-yl) hydroxymethyl]-4- thiomorpholinyl] carbonyl]-1-piperazinecarboxylate s, s-dioxide

N-Butoxycarbonyl-thiomorpholine (3.19 gm, 13.5 mmol) was dissolved in 70 ml of THF and cooled to-78 °C under a nitrogen atmosphere. 1.2 equivalents of LDA was added to the reaction mixture and stirred for 20 minutes. 1-N-trityl-imidazole-4- carboxaldehyde (4.62 gm, 13.6 mmol) was dissolved in in 70 ml of THF and added to the reaction mixture. After 4 hours the reaction mixture was poured into sat. NH4C1 solution and extracted with EtOAc three times. The extracts were combined, dried over MgSO4 and the solvent evaporated under reduced pressure. The crude mixture was chromatographed on a silica gel column using 1% MeOH/CH2Cl2 to obtain 3.21 gm of title product.

Step B N-Butoxycarbonyl- [ (1 triazolyl-imid azol-5-yl) methylene]-4- thiomorpholinyl] carbonyl]-1-piperazinecarboxylate s, s-dioxide N-Butoxyearbonyl-[(ltriazolyl-imidazol-5-yl) hydroxymethyl]-4- thiomorpholinyl] carbonyl]-l-piperazinecarboxylate s, s-dioxide (2.4 gm) was dissolved in CH2C12 (48 mL). TEA (1.32 ml) and MsCl (0.4 ml) was added and the reaction mixture stirred under dry nitrogen.

After 24 hours the reaction mixture was added to brine and the product extracted with CH2C12 to obtain 1.56 gm of title product.

Step C N-Butoxycarbonyl-[(1H-imidazol-5-yl)methyl]-4- thiomorpholinyl] carbonyl]-1-piperazinecarboxylate s, s-dioxide

N-Butoxycarbonyl-[(l triazolyl-imidazol-5-yl) methylene]-4- thiomorpholinyl] carbonyl]-1-piperazinecarboxylate s, s-dioxide (0.68 gm) was dissolved in EtOH. 10% Pd/C (0.1g) was added and the mixture hydrogenated under balloon H2 conditions for 24 hours.

The catalyst was filtered and the filtrate evaporated to obtain 0.3g of a mixture which was then treated with IN HCl/Et2O to obtain the HC1 salt.

PREPARATIVE EXAMPLE 85 Step A

4-Hydroxymethyl-5-methylimidazole hydrochloride (4 g, 30 mmol) was dissolved in DMF. TBDMSC1 (6. 1 g, 45 mmol) and imidazole (5.1 g, 75 mmol) were added and the reaction mixture stirred at ambient temperature for 24 hours. The reaction mixture was poured into water and extracted with EtOAc to obtain 7 gms of title product.

Step B

4-tert. butyldimethylsilyloxymethyl-5-methyl-imidazole (9 gm, 40 mmol) was dissolved in 100 ml of CH, C1. TEA (6 ml) and TrCl (11 gm, 40 mmol) were added and the reaction mixture stirred for six hours. The reaction mixture was added to brine, extracted with EtOAc, and purified on a silica gel column to obtain 7.97 gm of title product as a white solid.

Step C Tr\ _ß 1. TBAFN- B. ho

1-trityl-4-tert. butyldimethylsilyloxymethyl-5-methyl-imidazole (7.92 gm, 17 mmol) was dissolved in dry THF and 17ml of 1M TBAF in THF was added. The reaction mixture was stirred at room temperature for 3 hours. 100 ml of H2O was added and the precipitate was filtered and dried under vacuum to obtain 5.33 gm of title product. <BR> <BR> <P>Step D<BR> N-Butoxycarbonyl-[ (lH-4-methyl-imidazol-5-yl) methylenej-4- thiomorpholinyl] carbonyl]-1-piperazinecarboxylate s, s-dioxide

By essentially the same procedure set forth in Preparative Example 84, Step 1 through Step C, the title product was prepared.

PREPARATIVE EXAMPLE 85A

By essentially the same procedure set forth in Njoroge et. al.

(J. Med. Chem. (1997), 40,4290) for the preparation of 3- aminoloratadine only substituting the 3-H ketone (J. Het. Chem (1971) 8,73) for loratadine, the title compound was prepared.

PREPARATIVE EXAMPLE 86

The title compound from Preparative Example 85A (l. Og, 3.87 mmol) was added portionwise to t-butyl nitrite (0.69 mL, 1.5 eq.) and Cuti2 (0.62g, 1.2 eq.) in CH3CN (20 mL) at 0 °C. The resulting solution was warmed slowly to room temperature and stirred 72 hours. The reaction mixture was quenched with IN HC1 (10 mL), neutralized with 15% NH40H and extracted with EtOAc (3X50 mL).

The combined organics were dried over Na2SO4, filtered, and concentrated under reduced pressure. The crude product was purified by flash chromatography using a 50: 50 EtOAc: hexanes mixture as eluent to give a pale yellow solid (0.72g, 67% yield).

FABMS: MH+=278.

PREPARATIVE EXAMPLE 87

The title compound from Preparative Example 85A (0. 72g, 2.59 mmol) was dissolved in THF (10 mL) and treated with NaBH4

(0.13g, 1.3 eq.). The resulting solution was stirred at room temperature 1 hour. The reacton mixture was quenched by the addition of IN NaOH and the resulting solution extracted with EtOAc (3 X 50 mL). The combined organics were dried over Na2SO4, filtered, and concentrated under reduced pressure to give a tan solid which was used without further purification (0.71g, 97% crude yield). The crude product was dissolved in toluene (15 mL), cooled to 0 °C, and treated with SOC12 (0.32 mL, 1.75 eq.). The resulting solution was stirred at 0 °C for 1 hour and room temperature for 2 additional hours. The reaction mixture was diluted with CH2C12 (30 mL) and washed with IN NaOH (20 mL) and the organic layer dried over Na2SO4, filtered, concentrated, and used without further purification (0.76g, 100 crude yield).

PREPARATIVE EXAMPLE 88 The title compound from Preparative Example 85A (1.62g, 6.26 mmol) was added portionwise to NO+BF4- (0.81g, 1.1 eq.) in toluene (10 mL) at 0 °C. The resulting slurry was stirred at 0 °C for 2.5 hours before warming to room temperature. The reaction mixture was heated at reflux for 2 hours, cooled, neutralized with IN NaOH and extracted with EtOAc (3 X 50 mL). The combined organics were washed with IN HC1 (2 X 25 ml), saturated NaHCO3 (1 X 25 mL), and water (1 X 15 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure. The crude product was purified by flash chromatography using a 70: 30 hexanes: EtOAc mix as eluent to yield a yellow solid (0.68g, 42% yield). LCMS: MH+=262.

PREPARATIVE EXAMPLE 89

By essentially the same procedure set forth in Preparative Example 87, the title compound was prepared and used without further purification (0.66g, 100% crude yield).

PREPARATIVE EXAMPLE 90

+NH4HCO2- (2.44g, 10eq.) was added to a solution of the title compound from Preparative Example 73A (2.00g, 7.74 mmol) and 5% Pd/C (0.50g) in EtOH (100 mL) and the resulting solution was heated to reflux 2 hours. The reaction mixture was cooled, filtered through a plug of Celite and concentrated under reduced pressure.

The residue was diluted with H20 (100 mL) and extracted with CH2C12 (3 x 75 mL). The combined organics were dried over Na2SO4, filtered, and concentrated in vacuo to give a yellow solid (1.22g, 70% yield) which was used without further purification: FABMS: MH+= 225.

PREPARATIVE EXAMPLE 91

By essentially the same procedure set forth in Preparative Example 86, the title compound was prepared (0.81g, 61% yield): FABMS: MH+= 244.

PREPARATIVE EXAMPLE 92

By essentially the same procedure set forth in Preparative Example 87, the title compound was prepared and used without further purification.

PREPARATIVE EXAMPLE 92A By essentially the same procedure set forth in Preparative Example 86, only substituting CuBr2 for Cucul the title compound was prepared (1.33g, 60% yield): FABMS: MH+= 244.

PREPARATIVE EXAMPLE 93 By essentially the same procedure set forth in Preparative Example 87, the title compound was prepared and used without further purification.

PREPARATIVE EXAMPLE 94 By essentially the same procedure set forth in Preparative Example 88 only substituting the title compound from Preparative Example 90, the title compound was prepared. FABMS: MH+=228.

PREPARATIVE EXAMPLE 95

By essentially the same procedure set forth in Preparative Example 87, the title compound was prepared.

PREPARATIVE EXAMPLE 96

A solution of 3-peroxybenzoic acid (25 g, 2.5 eq.) in anhydrous dichloromethane (250 mL) was added dropwise over a period of one hour to a stirred solution of 8-chloro-4-aza-10,11- dihydro-5H-dibenzo [a, d] cyclohepten-5-one (10 g, 41.04 mmol) in anhydrous CI-LClg (100 mL) at 0 °C under a nitrogen atmosphere.

The solution was slowly (3h) warmed to room temperature and stirred for another 12h. The solution was extracted with 1 M NaOH (5 x 100 mL), washed with brine (2 x 100 mL), dried over Na2SO4, filtered, and concentrated under house vacuum at 30 °C to give a canary-yellow solid which was used without purification (10 g, 94% yield): IM + H] + : 260; HRMS (FAB+): Calculated for Cl4H, lClNO2 ([M + H] +) : 260.0475 Observed: 260.0478.

PREPARATIVE EXAMPLE 97

By essentially the same procedure set forth in Preparative Example 87, the title compound was prepared (9.55g, 99% yield).

PREPARATIVE EXAMPLE 98

The title compound was prepared according to the methods described in U. S. Patent No. 3,419,565.

PREPARATIVE EXAMPLE 99 By essentially the same procedure set forth in Preparative Example 87, the title compound was prepared (2.4g, 87% yield).

PREPARATIVE EXAMPLE 100 MeI (1.75 mL, 3.0 eq.) added to a solution of CS2CO3 (9. 12g, 3.0 eq.) and the title compound from Preparative Example 4 (3.40g, 9.33 mmol) in DMF (10 mL). The resulting solution was stirred at room temperature 4 hours. The reaction mixture was concentrated under reduced pressure, diluted with H20 (50 mL) and extracted with CH2C12 (3 X 50 mL). The combined organics were dried over Na2SO4, filtered, and concentrated in vacuo. The crude product was purified using a 50: 50 EtOAc: hexanes mix as eluent (1.4g, 40% yield). FABMS: MH+=379.

Preparative Example 101

A solution of the title compound from Preparative Example 100 (1.40g, 3.70 mmol) and 5% Pd/C (0.50g) in MeOH (20 mL) and 1N HC1 (5 mL) was stirred under 1 atm of H2 overnight. The reaction mixture was filtered through a plug of Celite and concentrated in vacuo to give a white solid (1.02g, 98% yield) which was used without purification. FABMS: MH+=245.

PREPARATIVE EXAMPLE 102 A solution of the title compound from Preparative Example 101 (l. Olg, 3.78 mmol) and TEA (2.63 mL, 5 eq.) in DMF (10 mL) were stirred at room temperature for 30 minutes before adding the title compound from Preparative Example 87 (1.68g, 1.5eq.). The resulting solution was stirred at room temperature overnight and concentrated under reduced pressure. The residue wasdiluted with saturated NaHCO3 (25 mL) and extrated with CH2C12 (3 X 50 mL).

The combined orgaincs were dried over Na2SO4, filtered, and concentrated and the crude product purified by flash chromatography using a 3% EtOAc in CH 2C4 solution as eluent to give an off-white solid (1. lg, 39% yield): LCMS: MH+=506.

The individual C-11 (R)-and (S)-isomers were separated by Preparative HPLC using a CHIRALPAK AD column using a 15% iPrOH in hexanes with 0.2% DEA solution as eluent.

11- (R)-isomer (first eluting isomer): FABMS: MH+= 506; [(X] D= +70° (5.0 mg in 2.0 mL MeOH).

11- (S)-isomer (second eluting isomer): FABMS: MH+=506; [a] D=<BR> ° (28 mg in 2.0 mL MeOH).

PREPARATIVE EXAMPLE 103 A solution of the title compound (C-11 (R)-isomer) from Preparative Example 102 (0.465g, 0.918 mmol) and 1N NaOH (2.76 mL, 3.0 eq.) in MeOH (15 mL) was heated at reflux 2 hours. The reaction mixture was cooled, concentrated, diluted with EtOAc (25 mL) and washed with brine (10 mL). The organics were dried over Na2SO4, filtered, and concentrated under reduced pressure to give a white solid (0.45g, 96% yield): FABMS: MH+= 492; [α]= +57.4° (5.0 mg in 2. 0 mL MeOH).

PREPARATIVE EXAMPLE 104

By essentially the same procedure set forth in Preparative Example 103, the title compound (C-11 (S)-isomer) was prepared (0.45g, 96% yield): FABMS: MH+= 492; [a] D= +13.7° (5.0 mg in 2.0<BR> mL MeOH).

PREPARATIVE EXAMPLE 105

By essentially the same procedure set forth in Prepartive Example 102, the title compound (C-ll (R)-and (S)-isomers) was prepared only the C-11 (R)-and (S)-isomers were separated by flash chromatography using a 3% EtOAc in CH2Cl2 solution as eluent.

PREPARATIVE EXAMPLE 106

By essentially the same procedure set forth in Preparative Example 103, the title compounds (individual C-11 (R)- and (S)-isomers) were prepared.

PREPARATIVE EXAMPLE 107

By essentially the same procedure set forth in Preparative Example 102 only substituting the title compound from Preparative Example 89, the title smpound was prepared (C-11 (R)-and (S)- isomers) (0.71g, 57% yield): FABMS: MH+=490.

PREPARATIVE EXAMPLE 108

By essentially the same procedure set forth in Preparative Example 103, only using the title compounds (C-11 (R)-and (S)- isomers) from Preparative Example 107, the title compound were prepared. The individual C-11 (R)-and (S)-isomers were separated by flash chromatography using a 12% (10% NH40H in MeOH) solution in CH2C12 as eluent: C-11 (S)-isomer (first eluting isomer): FABMS: MH+= 476.

C-11 (R)-isomer (second eluting isomer): FABMS: MH+= 476.

PREPARATIVE EXAMPLE 109

By essentially the same procedure set forth in Preparative Example 102, only substituting the 3-C1,8-H title compound from Preparative Example 92 for the 3-Cl, 8-Cl title compound from Preparative Example 101, the title compound (individual C-11 (R)- and C-ll (S)-isomers) was prepared. LCMS: MH+-479.

PREPARATIVE EXAMPLE 110

By essentially the same procedure set forth in Preparative Example 103, the title compound (individual C-11 (R)-and C-11 (S)- isomers) was prepared. LCMS MH+=458.

PREPARATIVE EXAMPLE 111

By essentially the same procedure set forth in Preparative Example 102, only substituting the 3-Br, 8-H title compound from Preparative Example 93 for the 3-Cl, 8-C1 title compound from Preparative Example 101, the title compound (individual C-11 (R)- and C-11 (S)-isomers) was prepared.

PREPARATIVE EXAMPLE 112

By essentially the same procedure set forth in Preparative Example 103, the title compound (individual C-11 (R)-and C-11 (S)- isomers) was prepared.

PREPARATIVE EXAMPLE 113

By essentially the same procedure set forth in Preparative Example 102, only substituting the 3-F, 8-H title compound from Preparative Example 95 for the 3-Cl, 8-C1 title compound from Preparative Example 101, the title compound (individual C-11 (R)- and C-11 (S)-isomers) can be prepared.

PREPARATIVE EXAMPLE 114

By essentially the same procedure set forth in Preparative Example 103, the title compound (individual C-ll (R)-and C-11 (S)- isomers) can be prepared.

EXAMPLES 138A-168 By essentially the same procedure set forth in Example 1 only substituting the title compounds from Preparative Example 106 (individual (R)-and (S)-isomers) and substituting the appropriate amine, the compunds of the formula shown below with W listed in column 3 of Table 17 were obtained.

TABLE 17 Ex. C-11 MP (°C) CMPD isomer 138A S CH3 131-FABMS: 135 MH+=697 , N<NxN 139A R CH3 120-FABMS: 126 MH+=697 N 140A S CH3 114-FABMS: 121 MH+=697 , N9"oN@N 141A R CH3 122-FABMS: 126 MH+=697 _---_ _ 142A R \ 125-MS: MH+= 127 712 R N\S'"/NN 143A S 109-MS : MH+= 112 712 .'N''/Nw% TABLE 17-continued Ex. C-11 R$= MP (°C) CMPD isomerisomer 144A R 68-71 MS : MH'= 712 . N N 145A S 97-100 MS : MH+= 712 Na,, N, N 146A S IP FABMS: MH+=749 zon ft H3C 147A R/2 FABMS: 0 MH'=749 N /\ N H3C TABLE 17-continued Ex. C-11 R8= MP (°C) CMPD isomer 148 s//0---FABMS: MH+=749 , N-., I N H3C 149 R//0---FABMS: MH+=749 N N H3C 150 R/2 FABMS: MH+=749 N 0 H3C 151 S 1l FABMS: MH+=749 N N CH3 ZUT TABLE 17-continued Ex. C-11 R8 MP (°C) CMPD isomer 152 S---FABMS: MH'=749 N H3C N 153 s//0---FABMS: MH+=749 .-.,, I H3C N 154 S---FABMS: 0 MH+=749 N H3C N 155 S FABMS- mu+=735 8t Ns/) N HO 156 s------ ro N , N j ; H3C\ NH (Isomer 1) TABLE 17-continued Ex. C-11 MP (OC) CMPD isomer 157 N j ; -O 3 cl H3C N HAN (Isomer 2) 158 R H3 <---FABMS : MH+=727 N-"/"-N 3 CHg 159 S H3C)-----FABMS: MH+=727 Chu CH3 160 R, S H----FABMS: /MH+=729 CHg 161 1 H---FABMS: /MH+=729 CHs 162 2 H---FABMS: N mu'=729 CHg CH3 TABLE 17-continued Ex. C-11 R8= MP (°C) CMPD isomer 163 S---FABMS: X, N MH+=699 H3C f HsC 164 S In FABMS: N tX MH+=699 . nez N N H3C 165 S CH3---FABMS: N MH+=685 N N 166 R H3---FABMS: MH'=685 N rua/" . N N 167 S HO---FABMS: t j MH+=685 J'' , N c TABLE 17-continued Ex. C-11 R8= MP (°C) CMPD isomer 168 R H3---FABMS: MH'=685 J, r \, N . \, N PREPARATIVE EXAMPLE 115

By essentially the same procedure set forth in Preparative Example 24 only using the title compound from Example 73A, the title compound was prepared: FABMS: MH+= 599.

By essentially the same procedure set forth in Preparative Example 115 only substituting the title compounds from the example listed in column 2, the title compounds of formula shown below with R8 as listed in column 4 of Table 18 can be obtained.

TABLE 18 Prep Ex. C-11 R8= Ex. isomer 116 139A R CH3 Nw/ NN . 117 140A s %"13 Ru non 118 141A R CH3 NJ-.N

EXAMPLES 169-182 By essentially the same procedure set forth in Example 14, only substituting the title compounds from the Preparative Example listed in column 2 of Table 19, the compounds of the formula shown below with R9 as listed in Column 4 of Table 19, were obtained (where data is provided) or can be obtained (where no data is provided) by using the appropriate electrophile.

TABLE 19 Ex. Prep. C-I1 R9= MP CMPD Ex. isomer (°C) 169 116 R 123-LCMS: MH+= 0@02\ 127 683 170 115 S 117-FABMS: 123 MH'=683 171 116 R 78-83 LCMS: mu+=723 O O 172 115 S, 129-FABMS: 135 MH'=723 Ouzo 173 116 R 129-LCMS: O 132 MH+=711 174 115 S-121-LCMS : 0A09< 125 MH+=711 175 116 R 108-LCMS: O 113 MH+=694 176 115 S-101-LCMS: O 111 MH+=694 177 116 R l l 148-LCMS: OX 151 MH'=696 H TABLE 19-continued Ex. Prep. C-11 R9= MP CMPD Ex. isomer (°C) 178 115 S ~ ~ 149-FABMS. OA Nt 154 MH+=696 H 179 116 R 129-LCMS: 133 MH'=681 180 115 S 119-FABMS: 123 MH'=681 181 116 R,------ O N ON H 182 115 S,------ V\A^l H

EXAMPLES 183-196 By essentially the same procedure set forth in Example 14, only substituting the title compounds from the Preparative Example listed in column 2 of Table 20, the compounds of the formula shown below, with R9 as listed in Column 4 of Table 20 were obtained (where data is provided) or can be obtained (where data is not provided) by using the appropriate electrophile.

TABLE 20 Ex. Prep. C-11 R9= MP CMPD Ex. isomer (°C) 183 118 R'g 115-FABMS: 0 02\ 118 MH+=683 184 117 S'| 109-LCMS: 130 MH'=683 185 118 R 82-FABMS: 0 o<J 85 MH+=723 O 186 117 S 101-LCMS: 116 MH'=723 O 187 118 R 122-LCMS: 126 MH'=711 188 117 S l 128-FABMS: O O 131 MH+=711 189 118 R l 111-LCMS: O@OX 116 MH+=695 TABLE 20-continued Ex. Prep. C-11 R9= MP CMPD Ex. isomer (°C) 190 117 s 90-LCMS: 94 mu'=695 v 191 118 R l l 149-FABMS: 152 MH+=696 O N H 192 117 S'1, 110-LCMS: 0@N\ 135 MH+=696 H 193 118 R 129-LCMS: 133 133 MH+=681 194 117 S 132-LCMS: 143 MH'=681 195 118 R------ O N H H 196 117 S (+NvO H H EXAMPLE 197

A solution of the title compound from Preparative Example 115 (0. lOg, 0.17 mmol) in CH, C4 (5.0 mL) was treated with p- fluorophenylacetic acid (0.034g, 1.3 eq.), NMM (0.11 mL, 6.0 eq.), HOBt (0.029g, 1.3 eq.), and DEC (0.042g, 1.3 eq.) and the resulting solution was stirred at room temperature overnight. The reaction mixture was concentrated in vacuo and the crude product purified by flash chromatography using a 5% (10% NH40H in MeOH) solution in CH2C12 as eluent (0.066g, 53% yield): mp = 105-110 °C; LCMS: MH+= 733.

EXAMPLES 198-200 By essentially the same procedure set forth in Example 197, only using the title compounds from the Preparative Example listed in column 2 of Table 21, the title compounds of the formula shown below, with R8 as listed in column 4 of Table 21, were obtained.

TABLE 21 Ex. Prep. C-11 R8= MP CMPD Ex. isomer (°C) 198 116 R &H3 134-LCMS: 136 MH+=733 !/\) . 199 117 S CH3 88-92 LCMS: MH+=733 N 200 118 R CH3 129-LCMS: < 3I MH=733 '' N

EXAMPLES 201-204 By essentially the same procedure set forth in Example 197, only substituting cyclopropylmethylacetic acid in place of p-fluoro- phenylacetic acid, and using the title compounds from the Preparative Example listed in column 2 of Table 22, the title compounds of the formula shown below, with W as listed in column 4 of Table 22, were obtained (Examples 201 and 203) or can be obtained (Examples 202 and 204).

TABLE 22 Ex. Prep. C-11 R$= MP CMPD Ex. isomer (°C) 201 115 S CH3 135-LCMS: 137 MH'=679 N 202 27 R CHs ___ ___ N N__,// 203 28 S CH3 135-LCMS: 139 MH'=679 N 204 29 R CHs------ RNJ"/NsN

PREPARATIVE EXAMPLES 119-134 By essentially the same procedure set forth in Preparative Example 115, only substituting the title compounds from the example listed in column 2 of Table 23, the title compounds of the formula shown below, with R8 as listed in column 4 of Table 23 were obtained.

TABLE 23 Prep Ex. Ex. C-11 isomer R8= 119 145A S . N N ___ 120 144A R \ _.- . N NN 121 143A S \ N . 122 142A R \ - non 123 150 R0 -O zon zizi N H3C 124 149 S rs=o . N., ., N _ H3C TABLE 23-continued Prep Ex. Ex. C-11 isomer R8= 125 146A s ip 0 NN > N N HIC 126 156 S C'po -O r N H3C N HN (Isomer 1) 127 157 S -O 3 C H3C N HN-/i (Isomer 2) 128 159 s H3 NCH . N J..,, N/ C3 129 163 S ruz N N-1 ion II N H3C TABLE 23-continued Prep Ex. Ex. C-11 isomer R$= 130 164 S N ? N H3C N HbC 131 165 S 4, 3N N N nH 132 166 R CH3 N N-IJ / 133 167 S 4, N3 N N 134 168 R CH3 N N-/i N

EXAMPLES 205-214 By essentially the same procedure set forth in Example 14, only substituting the title compounds from the Preparative Example listed in column 2 of Table 24, the compounds of the formula shown below, with R8 as listed in column 4 of Table 24, were obtained.

TABLE 24 Ex. Prep. C-11 Mi MP CMPD Ex. isomer (°C) 205 122 R \ 68-MS: 70 MH+=736 rN9"oN@N 206 121 S \ N non 207 120 R \ 80-MS: 83 MH+=736 _- . N N 208 119 S 99-MS: 101 MH+=736 R N,//N TABLE 24-continued Ex. Prep. C-11 R8= MP CMPD Ex. isomer (°C) 209 123 R---FABMS: MH+=775 N I N N HsC 0---FABMS: PO MH+=775 N \ N H3C 211 126 S IP FABMS: MH+=775 . N f) N N HsC 212 126 S 1/FABMS: mu+=775 ktN CN H3CXN (Isomer 1) TABLE 24-continued Ex. Prep. C-11 R8= MP CMPD Ex. isomer (°C) 213 127 S l/FABMS: MH'=775 0 H3C\ N HNj HN- (Isomer 2) 214 128 S H3N---FABMS: . NJ,/N>tCH3 MH+=753 roi CH3

EXAMPLE 215 By essentially the same procedure set forth in Example 14, only substituting the title compound from Preparative Example 129, and using the appropriate electrophile, the compound of formula

was obtained (C-11 S isomer). FABMS: MH+=725.

EXAMPLE 216 By essentially the same procedure set forth in Example 14, only substituting the title compound from the Preparative Example 130, and using the appropriate electrophile, the compound of formula

can be obtained (C-11 S isomer). FABMS: MH+=725.

EXAMPLES 217-221 By essentially the same procedure set forth in Example 14, only substituting the title compounds from the Preparative Example listed in column 2 OF Table 25, the compounds of the formula shown below, with R9 as listed in column 4 of Table 25, were obtained by using the appropriate electrophile.

TABLE 25 Ex. Prep. C-11 le= MP CMPD Ex. isomer (°C) 217 131 S (---FABMS : mu+=711 O 218 132 R I---FABMS : mu+=711 O TABLE 25-continued Ex. Prep. C-ll R'= MP CMPD Ex. isomer (°C) 219 131 FABMS: O@OA MH+=671 220 131 S--FABMS: OA OX MH+=699 I I 221 131 S, g FABMS: O N MH+=684 H

EXAMPLES 222-226 By essentially the same procedure set forth in Example 14, only substituting the title compounds from the Preparative Example listed in column 2 of Table 26, the compounds of the formula shown below, with R9 as listed in column 4 of Table 26, were obtained by using the appropriate electrophile.

TABLE 26 Ex. Prep. C-11 Rg= MP CMPD Ex. isomer (°C) 222 133 FABMS: mu+=711 O O 223 134 R---FABMS: MH+=711 O O 224 133 S---FABMS: MH'=671 225 133 S---HRFABMS: MH'=699 I 226 133 S FABMS: O N MH+=684 H

EXAMPLES 227-230 By essentially the same procedure set forth in Example 1, only substituting the title compounds from Preparative Example 87 and Preparative Example 101, and substituting the appropriate amine, the compounds of the formula shown below with R8 listed in column 3 of Table 27 were obtained.

TABLE 27 Ex. C-11 R8= MP (°C) CMPD isomer 227 S CH3 100-116 LCMS: MH'=653 jj N,/ . 228 R CH3 115-128 LCMS: MH+=653 N NxJ> N@N 229 S CH3 102-113 LCMS: MH+=653 zon 230 R CH3 121-127 LCMS: MH'=653 PREPARATIVE EXAMPLE 135

By essentially the same procedure set forth in Preparative Example 24, only using the title compound from Example 227, the title compound was prepared: LCMS: MH+=553.

By essentially the same procedure, only substituting the title compounds from the example listed in column 2 of Table 28, the title compounds of the formula shown below, with W as listed in column 3 of 28, were obtained.

TABLE 28 Prep Ex. Ex. C-11 isomer R3= 136 228 R CH3 r--N . 137 229 S CH3 NJ-N 138 230 R CH3 zon . 1111 N--//

Examples 231-242 By essentially the same procedure set forth in Example 14, only substituting the title compounds from the Preparative Example listed in column 2 of Table 29, the compounds of the formula shown below, with R9 as listed in column 4 of Table 29 were obtained (where data is provided) or can be obtained (were no data is provided) by using the appropriate electrophile.

TABLE 29 Ex. Prep. C-11 Rg= MP CMPD Ex. isomer (°C) 231 136 R 106-LCMS: O O 115 MH+=639 232 135 S 92-LCMS: 0@02\ 101 MH+=639 233 136 R 107-LCMS: 117 MH'=667 234 135 S 106-LCMS: 117 MH'=667 ( 235 136 R-- O O 236 135 S-- 0 TABLE 29-continued Ex. Prep. C-11 R9= MP CMPD Ex. isomer (°C) 237 136 R------ ON H 238 135 S 107-LCMS: O N 113 MH+=652 H 239 136 R 107-LCMS: pi 114 MH+=637 240 135 S 100-LCMS: 112 MH'=637 I 241 136 R------ zon ON H 242 135 s------ O N ON H

EXAMPLES 243-254 By essentially the same procedure set forth in Example 14, only substituting the title compounds from the Preparative Example listed in column 2 of Table 30, the compounds of the formula shown below, with R9 as listed in column 4 of Table 30, were obtained (where data is provided) or can be obtained (where no data is provided) by using the appropriate electrophile.

TABLE 30 Ex. Prep. C-ll R'= MP CMPD Ex. isomer (°C) 243 138 R 103-LCMS: 0@02\ 114 MH+=639 244 137 S 96-LCMS: 106 MH'=639 245 138 R 104-LCMS: 108-MH'=667 246 137 S 100-LCMS: 107 MH'=667 247 138 R 0 248 137 S-- ouzo TABLE 30-continued Ex. Prep. C-11 R9= MP CMPD Ex. isomer (°C) 249 138 R l l ZON H 250 137 S- ! H H 251 138 R 104-LCMS: 119 119 MH+=637 252 137 S 100-LCMS: 106 MH+=637 253 138 R------ O N ONJ H 254 137 S ^ o0 v 0- N H PREPARATIVE EXAMPLE 139

By essentially the same procedure set forth in Preparative Example 32 only substituting the 3-C1,8-C1 tricyclic chloride prepared in Preparative Example 87 for the 3-H, 8-C1 tricyclic chloride in Step B, the title compound was prepared. FABMS: MH+=518.

PREPARATIVE EXAMPLES 140 and 141 By essentially the same procedure set forth in Example 1, only substituting the appropriate amine, the compounds of the formula shown below, with W as listed in column 3 of Table 31, were obtained.

TABLE 31 Prep. C-11 R8= MP (°C) CMPD Ex. isomer 140 R, S CHs---FABMS: , Nt IN4N MH+=679 N-N 141 R, S CH3---LCMS: mu+= 679 RNC",/NtN N J'r,/N, % EXAMPLE 254A

By essentially the same procedure set forth in Example 1 only substituting the title compound from Preparative Example 139 and the amine from Preparative Example 74B, the title compound was prepared. mp=105-113; LCMS: MH+=678.

EXAMPLE 255-258 The title compounds from Preparative Examples 140 and 141 were separated into individual C-11 (S)-and (R)-diastereomers by Preparative HPLC with a CHIRALPAK AD column using a 20% iPrOH in hexanes solution with 0. 2% DEA as eluent to give the compounds of the formula shown below with R8 as listed in Column 3 of Table 32.

TABLE 32 Ex. C-11 R8= MP CMPD isomer (°C) 255 S CH3 116-FABMS: 126 MH+=679 NN M, =+21.1 (3.62 mg in 2.0 mL MeOH) 256 R C'3 122-FABMS: 128 MH+=679 [a] D=-20.7 (5.0 mgin 2.0 mL MeOH) 257 S &H3 115-LCMS: MH+= 128 679 halo=+20.1 (5.0 mg in 2.0 mL MeOH) 258 R CHs 115-LCMS: 128 MH'=679 , =-13.3 (5.0 mg in 2.0 mL MeOH)

EXAMPLES 259-262 By essentially the same procedure set forth in Example 1, only substituting the title compounds from Preparative Example 89 and Preparative Example 101 and substituting the appropriate amine, the compounds of the formula shown below, with R8 listed in column 3 of Table 33 were obtained.

TABLE 33

Ex. C-11 R$= MP (°C) CMPD l isomer l 259 S/CH3 126-135 LCMS: MH+=637 , N9> N a 260 R CH3 110-116 FABMS: MH+=637 N N 261 S CH3 115-118 LCMS: MH+=637 xNJ"zNSN 262 R CH3 122-126 FABMS: Mu+=637 tNJ"zNwN PREPARATIVE EXAMPLE 142

By essentially the same procedure set forth in Preparative Example 24, only using the title compound from Example 259, the title compound can be prepared.

By essentially the same procedure, only substituting the title compounds from the example listed in column 2 of Table 34, the title compounds of the formula shown below, with R8 as listed in column 3 of Table 34, can be prepared.

TABLE 34 Prep Ex. Ex. C-11 isomer R8= 143 260 R CHs r--N Nw/ NN 144 261 S CHs xNJ"zNa TABLE 34-continued Prep Ex. Ex. C-11 isomer R8= 145 262 R CH3 NJ..N

EXAMPLES 263-274 By essentially the same procedure set forth in Example 14, only substituting the title compounds from the Preparative Example listed in column 2 of Table 35, the compounds of the formula shown below, with R9 as listed in column 4 of Table 35, were obtained (where data is provided) or can be obtained (where no data is provided) by using the appropriate electrophile.

TABLE 35 Ex. Prep. C-11 R9= MP CMPD Ex. isomer (°C) 263 143 r 92-95 LCMS: MH+=623 264 142 S 103-LCMS: 0 106 MH+=623 265 143 R l 74-81 LCMS: O O MH+=651 TABLE 35-continued Ex. Prep. C-11 R9= MP CMPD Ex. isomer (°C) 266 142 S--90-95 LCMS: mu'=651 267 143 R 100-LCMS: 104 MH'=635 268 142 S--83-87 LCMS: ° °+V MH+=635 v 269 143 R- ! 0 N H 270 142 S--tu O N H H 271 143 R 105-LCMS: 107 MH'=621 272 142 S 75-77 LCMS: MH+=621 273 143 R-------- ON H 274 142 s-------- C3 N < H

EXAMPLES 275-286 By essentially the same procedure set forth in Example 14, only substituting the title compounds from the Preparative Example listed in column 2 of Table 36, the compounds of the formula shown below, with R9 as listed in column 4 of Table 36, can be obtained by using the appropriate electrophile.

TABLE 36 Ex. Prep. C-11 R9= Ex. isomer 275 145 R oily 276 144 S oral 00 277 145 R O O 278 144 S ouzo 279 145 R "\7 280 144 S ouzo 281 145 R H H 282 144 S 0 N'-k H TABLE 36-continued Ex. Prep. C-ll R'= Ex. isomer 283 145 R oY : 284 144 S O' 285 145 R, O N H 286 144 R, O N H H

PREPARATIVE EXAMPLE 146 AND 147

By essentially the same procedure set forth in Preparative Example 36, only substituting the 3-F, 8-Cl tricyclic chloride prepared in Preparative Example 89 for the 3-H, 8-Cl tricyclic chloride in Step B, the title compounds (C-1 1 (S)-and (R)-isomers) were prepared and separated into individual diasteromers by flash chromatography using a 12% (10% NH40H in MeOH) solution in CH2C12:

PREPARATIVE EXAMPLE 146 11- (S)-isomer (first eluting isomer): FABMS: MH+=502 ; [a] D= +7.7° (5.0 mg in 2 mL MeOH).

PREPARATIVE EXAMPLE 147 11- (R)-isomer (second eluting isomer): FABMS: MH+=502 ; 1 (X] D= +74.6 (5.0 mg in 2 mL MeOH.

EXAMPLES 287-290 By essentially the same procedure set forth in Example 1, only substituting the title compounds from Preparative Example 132 (individual (S)-and (R)-isomers) and substituting the appropriate amine, the compunds of the formula shown below, with W as listed in Column 3 of Table 37 were obtained.

TABLE 37 Ex. C-11 R8= MP CMPD isomer (°C) 287 S CH3 116-FABMS: 123 MH+=663 , =-34.4 (5.0 mg in 2.0 mL MeOH) 288 R CH3 128-FABMS: 134 MH+=663 [a] D=+38.6 (5.0 mg in 2.0 mL MeOH) TABLE 37-continued Ex. C-11 Rg= MP CMPD isomer (°C) 289 S CH3 120-FABMS: 126 MH'=663 halo=-29.4 (5.0 mg in 2.0 mL MeOH) 290 R CH3 121-FABMS: 125 MH+=663 foclD=+34. 2 (5.0mgin2.0 mL MeOH)

EXAMPLES 291-294 By essentially the same procedure set forth in Example 1, only substituting the title compounds from Preparative Example 110 and substituting the appropriate amine, the compounds of the formula shown below, with W listed in column 3 of Table 38 were prepared.

TABLE 38 Ex. C-11 R$= MP CMPD isomer (°C) 291 S CHs 99-107 LCMS: MH'=619 N N 292 R CH3 95-105 LCMS: 9 HN MH+=619 , N >g N a 293 S CH3 110-123 LCMS: MH+=619 R N",/N > 294 R CH3 102-118 LCMS: MH+=619 N N 294 S 93-107 LCMS: A N O 294 R n nI 102-113 LCMS: B MH'=618

PREPARATIVE EXAMPLE 148-151 By essentially the same procedure set forth in Preparative Example 107, only substituting the title compounds from the example listed in column 2 of Table 39, the title compounds of formula shown below, with R8 as listed in column 4 of Table 39, were prepared.

TABLE 39

Prep Ex. C-11 CMPD Ex. isomer 148 291 S CH3 LCMS: Mu+-519 N 6z 149 292 R CH3 LCMS : MH+=519 , rN4N@N 150 293 S CH3 LCMS: MH+=519 151 294 R CHs LCMS: N MH+=519 EXAMPLES 295-306 By essentially the same procedure set forth in Example 14, only substituting the title compounds from the Preparative Example listed in column 2 of Table 40, the compounds of the formula shown below, with R9 as listed in column 4 of Table 40, were obtained (where data is provided) or can be obtained (where no data is provided) by using the appropriate electrophile.

TABLE 40 Ex. Prep C-11 R9= MP CMPD isomer Ex.---=-- 295 149 R 00 296 l48 _ O@OX _ ____ 297 149 R-94-119 LCMS: MH'=633 298 148 S-110-LCMS: 125 MH+--633 299 149 R 95-104 LCMS : mu'=617 300 148 S l 95-101 LCMS: 0 MH'=617 TABLE 40-continued Ex. Prep C-11 R9= MP CMPD . isomer (°C) Ex. _ _ 301 149 R 107-LCMS: 0-- 119 MH+=618 H 302 148 110-LCMS: 0-- N 121 MH'=618 H 303 149 R 96-119 LCMS: MH'=603 304 148 S t/ 0 305 149 R 0------ ON ON H 306 148 s------ 0-- N'C ON H

EXAMPLES 307-318 By essentially the same procedure set forth in Example 14, only substituting the title compounds from the Preparative Example listed in column 2 of Table 41, the compounds of the formula shown below, with R9 as listed in column 4 of Table 41, can be obtained by using the appropriate electrophile.

TABLE 41 Ex. Prep. C-1 1 R9= Ex. isomer 307 151 R oill 308 150 S 00 309 151 R.. w.- O O 310 150 S- O O 311 151 R o°7 312 150 S 0° 313 151 R N H 314 150 S. ZON H 315 151 R c TABLE 41-continued Ex. Prep. C-11 R9= Ex. isomer 316 150 S os 0 317 151 R O@NzO O N ON 318 150 S, O N H H PREPARATIVE EXAMPLE 152

By essentially the same procedure set forth in Preparative Example 36, only substituting the 3-Cl, 8-H tricyclic chloride prepared in Preparative Example 92 for the 3-H, 8-C1 tricyclic chloride in Step B, the title compounds (C-l l (S)-and (R)-isomers) was prepared. FABMS: MH+= 484.

PREPARATIVE EXAMPLES 153 and 154 By essentially the same procedure set forth in Example 1, only substituting the title compounds from Preparative Example 152 and substituting the appropriate amine, the compounds of the formula shown below, with R8 as listed in column 3 of Table 42, were obtained.

TABLE 42

Prep. C-11 W= CMPD Ex. isomer 1õ5 R, S ~ u M S153 R, S CHs FABMS: MH+=645 RN\J"/N aN 154 R, S CHs FABMS : MH+=645 .

EXAMPLES 319-322 The title compounds from Preparative Examples 153 and 154 were separated into individual C-11 (S)-and (R)-diastereomers by Preparative HPLC with a CHIRALPAK AD column using a 25% iPrOH in hexanes solution with 0.2% DEA as eluent to give the compounds of the formula shown below with R8 as listed in column 3 of Table 43.

TABLE 43 Ex. C-11 R$= MP CMPD isomer (°C) 319 S &H3 114-FABMS: /) 14 118 MH+=645 N--// . 320 R CH3 115-FABMS: 120 MH+=645 N » N k Nw/ NN 321 S CHs 112-FABMS: 121 MH+=645 322 R CH3 117 FABMS: 125 q 125 MH+=645 ,N2",/Ng

EXAMPLES 323-326 By essentially the same procedure set forth in Example 1, only substituting the title compounds from Preparative Example 112 and substituting the appropriate amine, the compounds of the formula shown below, with R8 listed in column 3 of Table 44, can be obtained.

TABLE 44 Ex. C-11 R8= MP CMPD isomer (°C) 323 S C 3 109-124 LCMS: r--N MH'=663 NkN 324 R CH3 102-119 LCMS: MH+=663 NN 325 S CHs ___ ___ 326 R CH3------

PREPARATIVE EXAMPLE 155-158 By essentially the same procedure set forth in Preparative Example 115, only substituting the title compounds from the example listed in column 2 of Table 45, the title compounds of the formula shown below, with W as listed in column 4 of Table 45, can be prepared.

TABLE 45 Prep Ex. Ex. C-1 1 isomer R8= 155 323 S CH3 N-,//N 156 324 R CH3 ZON N, 157 325 S CHs NiN 158 326 R CHs

EXAMPLES 327-338 By essentially the same procedure set forth in Example 14, only substituting the title compounds from the Preparative Example listed in column 2 of Table 46, the compounds of the formula shown below, with R9 as listed in column 4 of Table 46, were obtained (where data is provided) or can be obtained (where no data is provided) by using the appropriate electrophile.

TABLE 46 Ex. Prep. C-11 R9= MP CMPD Ex. isomer (°C) 327 156 R l l 00 328 155 S l l 00 329 156 R 112-LCMS: 118 MH'=677 330 155 s 98-LCMS: 122 MH'=677 331 156 R 93-LCMS: 103 MH'=661 332 155 LCMS: 108 MH'=661 333 156 R 84-LCMS: 0 N < 108 MH+=662 H 334 155 S--L. 91-LCMS: OAN 118 MH+=662 H 335 156 R 103-LCMS: 113 mu'=647 TABLE 46-continued Ex. Prep. C-11 R9= MP CMPD Ex. isomer (°C) 336 155 S 115-LCMS: OC 124 MH+=647 337 156 R (-------- O N I H H 338 155 S,-------- 0-- N'0 H H

EXAMPLES 339-350 By essentially the same procedure set forth in Example 14, only substituting the title compounds from the Preparative Example listed in column 2 of Table 47, the compounds of the formula shown below with R9 as listed in column 4 of Table 47, can be obtained by using the appropriate electrophile.

TABLE 47 Ex. Prep. C-11 R9= Ex. isomer 339 158 R O O TABLE 47-continued Ex. Prep. C-11 R9= Ex. isomer 340 157 S ouzo 341 158 R O O 342 157 S oKol ouzo 343 158 R ouzo 344 157 S 145158 1e O °z\V° 345 158 R N H 346 157 S O N H 347 158 R _ 348 157 S in 349 158 R zon H H 350 157 S, C3/N H PREPARATIVE EXAMPLE 159

By essentially the same procedure set forth in Preparative Example 36, only substituting the 3-Br, 8-H tricyclic chloride prepared in Preparative Example 93 for the 3-H, 8-C1 tricyclic chloride in Step B, the title compounds (C-11 (S)-and (R)-isomers) were prepared. FABMS: MH+=528.

PREPARATIVE EXAMPLES 160 and 161 By essentially the same procedure set forth in Preparative Example 126, only substituting the title compounds from Preparative Example 144 and substituting the appropriate amine, the compounds of the formula shown below, with W as listed in column 3 of Table 48, were obtained.

TABLE 48 Prep. C-11 R'= CMPD Ex. isomer 160 R, S &H3 FABMS: MH+=689 ''M . 161 R, S CH3 FABMS: MH+=689 N N'r N

EXAMPLES 351-354 The title compounds from Preparative Examples 160 and 161 were separated into individual C-11 (S)-and (R)-diastereomers by Preparative HPLC with a CHIRALPAK AD column using a iPrOH in hexanes solution with 0.2% DEA as eluent to give the compounds of the formula shown below with W as listed in column 3 of Table 49.

TABLE 49 Ex. C-11 RS= MP CMPD isomer (°C) 351 S CH3 120-FABMS: 124 MH+=689 N NN TABLE 49-continued Ex. C-11 R8= MP CMPD isomer (°C) 352 R CH3 122-FABMS: 125 MH+=689 R N9X N@N 353 S CHs 121-FABMS: 127 MH+=689 Ny/N pN . 354 R CH3 124-FABMS: 128 (N 128 MH+=689 N N

EXAMPLES 355-358 By essentially the same procedure set forth in Example 1 only substituting the title compounds from Preparative Example 114 and substituting the appropriate amine, the compounds of the formula shown below, with W listed in column 3 of Table 50, can be obtained.

TABLE 50 Ex. C-11 R8= isomer 355 S CHs Nw/ NN 356 R CH3 356 R CH3 Nw/ NN --1 357 S CHs . 358 R CHs 'D N Nt)", N aN

PREPARATIVE EXAMPLE 162-165 By essentially the same procedure set forth in Preparative Example 115, only substituting the title compounds from the example listed in column 2 of Table 51, the title compounds of the formula shown below, with W as listed in column 4 of Table 51, can be prepared.

TABLE 51 Prep Ex. Ex. C-11 isomer R8= 162 355 S S N ,- 163 356 R CH3 163 356 R CH3 Nw/ NN 164 357 S CHs 'D N 165 358 R CHs NJ-.N

EXAMPLES 359-370 By essentially the same procedure set forth in Example 14, only substituting the title compounds from the Preparative Example listed in column 2 of Table 52, the compounds of the formula shown below, with R9 as listed in column 4 of Table 52, can be obtained by using the appropriate electrophile.

TABLE 52 Ex. Prep. C-11 R9= Ex. isomer 359 163 R."%.". 00 360 162 s ouzo 361 163 R."%.... ouzo 362 162 ouzo 363 163 R. ooV 364 162 S...'"". °°7 365 163 R-- ! N H 366 162 S O' N H 367 163 R 0 368 162 S 0 91i7 sa _ of <369 163 R <v ON H TABLE 52-continued Ex. Prep. C-11 R9= Ex. isomer 370 162 S O N I.--H H

EXAMPLES 371-382 By essentially the same procedure set forth in Example 14, only substituting the title compounds from the Preparative Example listed in column 2 of Table 53, the compounds of the formula shown below, with R9 as listed in Column 4 of Table 53, can be obtained by using the appropriate electrophile.

TABLE 53 Ex. Prep. C-11 R9= Ex. isomer 371 165 R 00 372 164 S 0-- TABLE 53-continued Ex. Prep. C-11 R9= Ex. isomer 373 165 R O O 374 164 S ouzo 375 165 R oy 376 164 S zozo 377 165 R ZON H 378 164 S ON H 379 165 R if 380 164 S.. 0 381 165 R NJ H H 382 164 S, NJ H H PREPARATIVE EXAMPLE 166

By essentially the same procedure set forth in Example 1 only substituting the title compound from Preparative Example 32 Step A and the title amine from Preparative Example 21, the title compound was prepared. FABMS: MH+=518.

PREPARATIVE EXAMPLE 166A By essentially the same procedure set forth in Example 1 only substituting the title compound from Preparative Example 32 Step A and the title amine from Preparative Example 20, the title compound ca be prepared.

PREPARATIVE EXAMPLES 167 and 168 By essentially the same procedure set forth in Preparative Example 32, only substituting the title compounds from Preparative Example 166 and 166A and the 3-F, 8-H tricyclic chloride from Preparative Example 95, the compound of the formula shown below with W as listed in Column 3 of Table 54 was prepared (Prep.

Example 167) or can be prepared (Prep. Example 168).

TABLE 54

Prep. C-11 R8= CMPD Ex. isomer 167 R, S CH3 FABMS: MH'=629 Nw/NN zon 168 R, S CHs ___ NJ-.,N EXAMPLES 383-386 The title compounds from Preparative Examples 167 and 168 were (Preparative Examples 167) and can be (Preparative Example 168) separated into individual C-11 (S)-and (R)-diastereomers by Preparative HPLC with a CHIRALPAK AD column using an iPrOH in hexanes solution with 0.2% DEA as eluent to give the compounds of the formula shown below with R8 as listed in Column 3 of Table 55.

TABLE 55 Ex. C-11 MP (OC) CMPD isomer 383 S CH3 121-126 FABMS: MH+=629 No,,. N 384 R CHs 104-111 FABMS: MH+=629 , rN4NXN fun N N 386 R CH3 ___ ___ NN PREPARATIVE EXAMPLE 168A Preparation of the moietyN-oxide vCI MCPBA/CH2C12 vCI + o 0 o 1 2 2 | NaBH4/MeOH SOCI2/toluene \ CI ci OH ou 4 3 H TFA NEt3 CH OH 2CI2 C J. OH NEt3/CH2C12 N 5 5 ci ci N Chromatography N N OH OH o 00 00 6 6a (11-S Isomer) ci CI 00"" OH a ND Ir°H L o 0 0 6b (11-R isomer)

A solution of 3-peroxybenzoic acid (25 g, 102.59 mmol, 2.5 eq.) in anhydrous dichloromethane (250 mL) was added dropwise over a period of one hour to a stirred solution of 8-chloro- 4-aza-10,11-dihydro-5H-dibenzola, dlcyclohepten-5-one 1 (10 g, 41.04 mmol, 1.0 eq.) in anhydrous dichloromethane (100 mL) at 0 °C under a nitrogen atmosphere. The solution was slowly (3h) warmed to room temperature and stirred for another 12h. The solution was extracted with 1 M aqueous sodium hydroxide solution (5 x 100 mL), washed with brine (2 x 100 mL), dried over Na2SO4, filtered, and concentrated under house vacuum at 30 °C to give 2 as a canary-yellow solid. The title compound 2 was used directly without further attempts at purification.

Yield: 10 g = 38.51 mmol-94% [M + H] +: 260 HRMS (FAB+): Calculated for Cl4HllClNO2 ([M + Hj+): 260.0475 Observed: 260.0478 Sodium borohydride (2.21 g, 57.76 mmol, 1.5 eq.) was added portionwise over a period of 15 minutes to a solution of 2 (10 g, 38.51 mmol, 1.0 eq.) in anhydrous methanol (500 mL) at 0 °C under a nitrogen atmosphere. The resulting suspension was stirred at 0 °C for one hour and at room temperature for another hour.

The volatiles were removed under house vacuum at 30 °C and the residue was taken up in 1 M aqueous NaOH solution (250 mL). The aqueous solution was extracted with dichloromethane (5 x 100 mL).

The combined organic extracts were washed with brine (100 mL), dried over Na2SO4, filtered, and concentrated under house vacuum at 30 °C to give 3 as a lime-green solid. Compound 3 was used directly without any attempts at purification.

Yield: 9 g--34.39 mmol 89% [M + H] + : 262 HRMS(FAB+):

Calculated for Cl4Hl3ClNO2 ([M + H] +) : 262.0635 Observed: 262.0636 Thionyl chloride (5 mL, 68.78 mmol, 2.0 eq.) was added dropwise over a period of 10 minutes to a stirred suspension of 3 (9 g, 34. 39 mmol, 1.0 eq.) and anhydrous toluene (150 mL) at 0 °C under a nitrogen atmosphere. The cream-colored suspension was slowly (3h) warmed to room temperature and stirred for another 12h. The volatiles were removed under house vacuum at 30 °C.

The residue was taken up in dichloromethane (250 mL) and washed with ice-cold, saturated aqueous NaHCO3 solution (5 x 100 mL) until the aqueous washings were moderately basic at pH 9. The organic layer was washed with brine (100 mL), dried over Na2SO4, filtered, and concentrated under house vacuum at 30 °C to give 4 as a cream-colored solid in essentially quantitative yield. Due to its high reactivity, compound 4 was used directly without any attempts at purification or characterization (other than'H NMR).

Yield: 9.55 g-34.09 mmol--_ 99% Triethylamine (18 mL, 126.65 mmol, 5.0 eq.) was added dropwise to a stirred solution of 5 (previously described in the art; 9.38 g, 25.33 mmol, 1.0 eq.) in anhydrous dichloromethane (50 mL) at room temperature under a nitrogen atmosphere. The solution was stirred at room temperature for 30 minutes and was cooled to 0 °C. A solution of 4 (8.52 g, 30.39 mmol, 1.2 eq.) in anhydrous dichloromethane (50 mL) was added dropwise over a period of 25 minutes. The mixture was slowly (3h) warmed to room temperature and stirred for another 12h. The volatiles were removed under house vacuum at 30 °C. The residue was taken up in 50% m/v aqueous citric acid solution (100 mL) and extracted with ethyl acetate (5 x 100 mL). The organic extracts were combined and dried over Na2SO4, filtered, and concentrated under house vacuum at 30 °C. The residual cream-colored solid was flash-chromatographed

(CH2Cl2:MeOH = 19: 1 v/v) to give the diastereomerically pure isomers 6a and 6b at C-11 of the tricycle.

For 6a: Yield: 5.75 g = 11.50 mmol = 45% Off-white foam; M. p.: 78-83 °C [M + H] +: 500 HRMS (FAB+): Calculated for C26 H3lClN 30, ( [M + H] +): 500.1953 Observed: 500.1952 For 6b: Yield: 3.00 g = 6.00 mmol = 24% Off-white solid; M. p.: 94-99 °C [M + H] + : 500 HRMS (FAB+): Calculated for C26H31 ClN3O5 ([M + H] +): 500.1953 Observed: 500.1952 EXAMPLE 387 By essentially the same procedure set forth in Example 47A, only substituting the title compound from Preparative Example 168A, the title compound was prepared: mp = 85-90 °C; [M+H] + : 661.

EXAMPLE 388

By essentially the same procedure set forth in Example 42 (see Table 6), only substituting the title compound from Preparative Example 168A, the title compound was prepared: mp = 108-113 °C; [M+H] + : 661.

PREPARATIVE EXAMPLE 169

By essentially the same procedure set forth in Example 1, only substituting the title compound from Preparative Example 2 and susbtituting the appropriate amine, the title compound was prepared.

PREPARATIVE EXAMPLE 170 By essentially the same procedure set forth in Preparative Example 147, the title compound was prepared.

PREPARATIVE EXAMPLE 171

By essentially the same procedure set forth in Preparative Example 8, the title compound was prepared and used without further purification.

PREPARATIVE EXAMPLE 172 By essentially the same procedure set forth in Preparative Example 8, the title compound was prepared and used without further purification.

PREPARATIVE EXAMPLE 173 By essentially the same procedure set forth in Preparative Example 6, only substituting the title compounds from Preparative Example 171 and Preparative Example 99, the title compound was obtained: FABMS: MH+=519.

By essentially the same procedure set forth in Example 14, only substituting the title compounds from the Preparative Example listed in column 2 of Table 56, the compounds of the formula shown below, with R9 as listed in column 4 of Table 56, were obtained by using the appropriate acylating agent.

TABLE 56 Ex. Prep. C-11 R9 CMPD Ex. isomer 389 173 R FABMS: MH+=644 O N H 390 173 S FABMS: mu+=644 O N H 391 173 A FABMS: mu+=645 O 230 173 B FABMS: mu'=645 O 393 173 R'1, FABMS: MH'=619 TABLE 56-continued Ex. Prep. C-11 R9= CMPD Ex. isomer 394 173 S FABMS: O O MH+=619 PREPARATIVE EXAMPLE 174

By essentially the same procedure set forth in Preparative Example 6, only substituting the title compounds from Preparative Example 172 and Preparative Example 99 the title compound was obtained: FABMS: MH+=519.

EXAMPLES 395-397 By essentially the same procedure set forth in Example 14, only substituting the title compounds from the Preparative Example listed in column 2 of Table 57, the compounds of the formula shown below, with le as listed in column 4 of Table 57, was obtained by using the appropriate acylating agent.

TABLE 57 Ex. Prep. C-11 R= CMPD Ex. isomer 395 174 R, S l l FABMS: O O MH+=619 396 174 A FABMS : 0-- MH'=619 397 174 B--tFABMS: O OA MH+=619 EXAMPLE 398

The title compound from Example 165 (0.076 g) was balloon hydrogenated over 10% Pd/C (0.025 g) in EtOH (15 mL) overnight at room temperature. The catalyst and the solvent removed to give the title compound: MS MH+= 606.

EXAMPLES 399-402 By essentially the same procedures set forth in Preparative Example 24 and Example 14, only using the title compound from Example 398, the title compounds of the formula shown below, with R9 listed in column 3 of Table 58, were obtained.

TABLE 58

Ex. C-11 R9= CMPD isomer 399 S FABMS: mu+=632 O O 400 FABMS: 0@02\ MH+=592 401 FABMS: 0-- MH+=620 402 s I FABMS: OANt MH+=605 H EXAMPLES 403-406 By essentially the same procedure set forth in Example 399, compounds of the formula shown below, with R9 listed in column 4 of Table 59, were obtained.

TABLE 59

Ex. C-11 R9= CMPD isomer 403 S, FABMS: mu+=632 O 404 S FABMS: 0@ 02\ MH+=592 405 S FABMS: 0 09< MH+=620 I 406 HRFABMS: O N MH+=605 H EXAMPLES 407-408 By essentially the same procedure set forth in Example 1, only substituting the appropriate amine, the compounds of the formula shown below, with R8 as listed in column 3 of Table 60 were obtained.

TABLE 60

Ex. C-11 R8= CMPD isomer 407 1 CH3 FABMS : MH+=699 N 2 NJ'r,, N 408 CH3 FABMS: MH+=699 /,,, N/ EXAMPLES 409 and 410 The title compound from Example 47 (CC) was separated into individual diasteromers using a CHIRALPAK AD column using a 15% iPrOH in hexanes with 0.2% DEA as eluent to give the title compounds of formula shown below wherein R8 is as defined in column 3 of Table 60A.

TABLE 60A Ex. C-11 R8= CMPD isomer 409 S CHs FABMS: -\ MH+=659 zon Isomer 1 410 S CHs FABMS: LI MH+=659 N\. N Isomer 2

PREPARATIVE EXAMPLE 175 By essentially the same procedure put forth in Preparative Example 115 only substituting the title compound from Example 32, the title compound was prepared.

EXAMPLE 411

By essentially the same procedure set forth in Example 14, only substituting the title compound from Preparative Example 175 and neopentyl chloroformate, the title compound was prepared: mp=103-115 °C; LCMS: MH+=633.] EXAMPLES 412 and 413 The title compounds of the formula shown below with R9 as listed in column 3 of the Table 61 were prepared by essentially the same procedure as set forth in Example 1, only substituting the title compound from Preparative Example 175 and the appropriate carboxylic acid.

TABLE 61

Ex. C-11 R9-MP (°C) CMPD isomer 412 S NA | 175 FABMS: (dec.) MH+=654 I 413 S O 150-FABMS: H2NA N) 152 MH+=687 LO

PREPARATIVE EXAMPLE 175A By essentially the same procedure set forth in Preparative Example 31, Step A only substituting CBz-NOS for isopropyl chloroformate, the title compound was prepared.

PREPARATIVE EXAMPLES 175B and 175C By essentially the same procedure set forth in Preparative Example 31, Step B only substituting the title compound from Preparative Example 175A, the title compounds (individual C-11 (S)-and (R)-isomers) were prepared.

Example 175B: C-11 (S)-isomer, Yield=13%, MH+=492.

Example 175C: C-11 (R)-isomer, Yield=13%, MH+=492.

PREPARATIVE EXAMPLES 175D and 175E

By essentially the sames procedure set forth in Preparative Example 31, Step B only substituting the title compounds from Preparative Example 97 and Preparative Example 175A, the title compounds (individual C-11 (S)-and (R)-isomers) were prepared.

Example 175D: C-11 (S)-isomer, Yield= 12%, MH+=508.

Example 175E: C-11 (R)-isomer, Yield=15%, MH+=508.

EXAMPLE 414 The title compound was prepared by essentially the same procedure as set forth in Example 387, only substituting the dibenzosuberyl chloride for the tricyclic chloride: mp=98-112 °C; FABMS: MH+=610.] EXAMPLES 415-425 Following essentially the same procedure set forth in Example 1, only substituting the Carboxylic acid (ll- (S) or 11- (R) isomer) from the Preparative Example listed in Table 62 and the appropriately substituted piperidine (Amine), the pure isomeric products were prepared and separated by Preparative HPLC (AD column) using IPA-hexanes.

TABLE 62 Ex. Prep. Ex. Product 1. Amine 2. Acid 415 1. 68 Step E ci N 2. 32 (N ii (S) N isomer Me N r"Y 0 N 1. Yield (%): 82 2. MH+: 645 3. mp (°C): 116.2 416 1. 80 Stop D ZON 2. 32 N 1 vs, isomer zozo a Me Me 1. Yield (%): 50.8 2. MH+: 659 3. mp (°C): 112.5-116.3 417 1.81 cri 2. 32 N il (S) N isomer c iq Me mye O N 1. Yield (%) : 51. 4 2. MH+: 659 3. mp (°C): 85.1-115 _ _ TABLE 62-continued Ex. Prep. Ex. Product 1. Amine 2. Acid 418 1.82 Step B ci N Me e Me 2. 32 N N zozo isomer OO O 1. Yield (%): 63 2. MH': 735 3. mp (°C): 135.9 419 1.83 Isomer A Step z 2. 32 N 2.32 N v e N 11 (S) isomer N-bu OH 0 O O 1. Yield (%): 35.7 2. MH+: 661 3. mp (°C): 117.6-124.8 Isomer B ci N .,. N) N "Ir OH 1. Yield (%): 35.7 2. MH+: 661 3. mp (°C): 95.7-107.2 TABLE 62-continued Ex. Prep. Ex. Product 1. Amine 2. Acid 420 1. 83 Isomer A Step E cl ii (S) 0 N O N 11 (S) isomer. OH 168A N O O 1. Yield (%) : 36 2. MH+: 677 3. mp (°C): 172.4 Isomer B ci wN v i 0 N XCI Q tX NaNS OH \N 0I _O N 1. Yield (%): 36 2. MH+: 677 3. mp (°C): 152.9 Table 62-CONTINUED Ex. Prep. Ex. Product 1. Amine 2. Acid _. 421 1.83 Isomer A Step E CI I I (R) z iN Me 11 (R) isoler, N OH O O N 1. Yield (%): 50 2. MH+: 677 3. mp (°C): 152.6 Isomer B ci CN O N IOI OH N Mye O O N 1. Yield (%): 50 2. MH+: 677 3. mp (°C): 145.4 Table 62-continued Ex. Prep. Ex. Product 1. Amine 2. Acid 422 1.83 Isomer A StepE Step E 2.175B ci 11(S)N' isomer (N) 1 (OH N_ J OH\N \ p/\ Me 0 / 1. Yield (%): 32.7 2. MH+: 669 3. mp (°C): 142.2-150.9 Isomer B ci N J..., N N N OU 1. Yield (%) : 32.7 2. MH+: 669 3. mp (°C): 133.2-148.1 TABLE 62-continued Ex. Prep. Ex. Product 1. Amine 2. Acid 423 1.83 Isomer A Step E c 2.175C N N 11 (R) isomer IOI O \N Me 1. Yield (%): 27 2. MH+: 669 3. mp (°C): 117.7 Isomer B ci zon N J.,, N N oh OH Me 1. Yield (%): 32 2. MH+: 669 3. mp (°C): 140.1 TABLE 62-continued Ex. Prep. Ex. Product 1.Amine 2. Acid 424 1. 66 StepG J7 V Zon 2. 32 N M N N/ isomer O'-O 1. Yield (%): 54.5 2. MH+: 645 3. mp (°C): 127.3 TABLE 62-continued Ex. Prep. Ex. Product 1. Amine 2. Acid 425 1.83 Isomer A StepE Step E 2.175D ci ii (S) N isomer tN) N\N N OH I v, \ OH \ Me O O 1. Yield (%): 35 2. MH+: 685 3. mp (°C): 140-142 Isomer B ci N\ . N t 3", N\ 0--lu 0 0 e zoo 1. Yield (%) : 19 2. MH+: 685 3. mp (°C): 133-135

PREPARATIVE EXAMPLES 176-179 Stirring the benzyloxycarbonyl (CBZ) compounds listed in Column 2 of Table 63 and Palladium on carbon catalyst in EtOH under 1 atmosphere of hydrogen gas afforded the Product amines.

TABLE 63 Prep. CBZ Product Ex. compound from Example No. 176 422/\\ Isomer A ci N (N N OH N N 0 IMe OH \ Me N 1. Yield (%): 95 2. MH+: 535 Isomer A 177 422 cri /1 I ci Isomer B <~ N (N N OH N OU N N Me N 1. Yield (%): 82 2. MH+: 535 Isomer B TABLE 63-continued Prep. CBZ Product Ex. compound from Example No. 178 423 ci isoler A Isomer A Zon N OS N Isomer A N N Isomer A cri /1 ci 423 N Isomer B 1.,,, N NOI N OH Me N Isomer B EXAMPLES 426-434

T_CI <_CI u N Electrophile N N, H RO ° IV R' O \ N _ Me By essentially the same procedure as set forth in Example 14, only substituting the piperazine amines (isomer A or B) listed in column 2 of Table 64 for the title compound from Preparative

Example 24, and using as the Electrophile either an isocyanate to give the urea products, or a carboxylic acid, HOBt, DEC and DMF to give the amide products listed in Table 64.

TABLE 64 Ex. Prep. Ex. Product No. of Amine Electrophile 426 1. 176 ci 2. N N +N=C=0 Ir OH H, in 0 0 N Me N O 1. Yield (%) : 100 2. MH+: 634 3. mp (°C): 240.2-253.7 Isomer A 427 1.177 ci 2. N zon Zon Ho Or H N, OI \ v OH Me N O 1. Yield (%): 100 Isomer B 2. MH+: 634 3. m (°C): 148.7-164.2 TABLE 64-continued Ex. Prep. Ex. Product No. of Amine Electrophile 428 1. 176 ci 2. N C=O N J..., N N OH N H 0 Me N O 1. Yield (%) : 75 2. MH+: 620 3. mp (°C): 165.5-178.2 Isomer A 429 1.176 < ce 2. N OH V'OU ..., OH Me O N OH 1. Yield (%): 21.4 2. MH+: 619 3. mp (°C): 148.7-168.3 Isomer A TABLE 64-continued Ex. Prep. Ex. Product No. of Amine Electrophile 430 1.177 ci 2. N C02H (N "-or 1 0 Me 0 N OH N OH 1. Yield (%): 10 2. MH+: 619 3. mp (°C): 169.2-190.9 Isomer B 431 1. 176 ci If OH N /CO2H II N OH N 0 (11--e Me 0 N OH 1. Yield (%): 29 2. MH+: 621 3. mp (°C): 146.5-153.6 Isomer A TABLE 64-continued Ex. Prep. Ex. Product No. of Amine Electrophile 432 1.177 ci cj" 2. N Na /CH Y zou oh OH OH 1. Yield (%): 31 2. MH+: 621 3. mp (°C): 138.3-161.3 Isomer B 433 1.176 ci CI N +° N Me C02H \ OH OH Me OH 1. Yield (%): 36 2. MH+: 649 3. mp (°C): 123.4-133.9 Isomer A TABLE 64-continued Ex. Prep. Ex. Product No. of Amine Electrophile 434 1.177 ci 2. N N C02H fOHOH N OH 1. Yield (%): 35 2. MH+: 649 3. mp (°C): 119.3-135.7 Isomer B 435 1. 178 ci 2. 2. N OH N I N NII \ \N t O N r 1. Yield (%): 63 2. MH+: 634 3. mp (°C): 159.2 Isomer A 436 1.179 < ci 2. N --t-N=C=O N OH N H, 0 , N 0 N ---k- 1. Yield (%): 69 2. MH+: 634 3. mp (°C): 175 Isomer B 437 1. 178 ci 2. N zon N OH N /, J,... N OHMe N O 1. Yield (%): 77 2. MH+: 620 3. mp (°C): 167.2 Isomer A EXAMPLES 438-457 i N Electrophile C. _ N ... C,,. OHOH'ir OH 4-- 0 Me

If the procedure described for Example 426 were followed using the piperazine amines (isomer A or B) listed in column 2 of Table 65 and, as the Electrophile, either an isocyanate, or a carboxylic acid and HOBt, DEC and DMF, then the urea or amide products, respectively, listed in Table 65 would be obtained.

TABLE 65 Ex. Prep. Ex. No. Product of Amine Electrophile 438 1. 179 ci =c=c, jazz IN OH N /N-O N H, me . N 0 N N O Isomer B 439 1. 177 ci 2. N 2. ON zon YY OH N H, 0 N-Me \ Isomer B TABLE 65-CONTINUED Ex. Prep. Ex. No. Product of Amine Electrophile 440 1.178 ci /1 ci zon CH OH OH 0 Me O OFF OH N OH Isomer A 441 1.179 cri /! ci 2. N C02H (N OH 0 OH Me Me OU OH Isomer B 442 1. 178 con 2. N \, C02H N C OH OH OU OU Isomer A Table 65-CONTINUED Ex. Prep. Ex. No. Product of Amine Electrophile 443 1. 179 ci con /CO2H OH 1 J..,. N C02H N OH N 0 N-, Me OH Isomer B 444 1. 178 2. : N N C02H +0 N Me OH OHMe ZON OH Isomer A 445 1. 179 cl 2. N N C02H oH J... N 0 N N OH XN Me N OH Isomer B Table 65-continued Ex. Prep. Ex. No. Product of Amine Electrophile 446 1. 178 ci CN 2. N N 0-Y C02H N N 6 Isomer A N Isomer A 447 1.179 2. N N OY N OH 0 H OH I OH H Me Zozo 6 Isomer B TABLE 65-continued Ex. Prep. Ex. No. Product of Amine Electrophile 448 1.176 ci / 2. N C2H OY C02H N N N OH H 0 OH Me 0 N N 6 Isomer A 449 1.177 cri / N N CH N ou H O Me 2. N\ 6 Isomer B 450 1.176 cri / 2. N v N OU OH OH N I HN Me 1'_ O N OH Isomer A TABLE 65-continued Ex. Prep. Ex. No. Product of Amine Electrophile 451 1.177 ci 1--y t (N 2. Zon N CZH OH OH N OH N mye OH Isomer B 452 1.178 ci CO2H tN)"Nn , N C02H OH 4 OH Me Me OU Oh OH Isomer A 453 1.179 ci /1 ci 2. N C02H 1 OH 0 0 OH N-Me Me zon OH Isomer B TABLE 65-continued Ex. Prep. Ex. No. Product of Amine Electrophile 454 1.176 ci 2. N 2. OH N OH N- N OH OH N'I HN Me _O N OH Isomer A 455 1.177 ci 2. N 2. N C02H OH OH Me 0 0 N OH Isomer B 456 1.178 ci 2. N C02H (N) 0 C02H 1 J. _. N OU 0 N OH Isomer A Isomer A TABLE 65-continued Ex. Prep. Ex. No. Product of Amine Electrophile 457 1.179 ci 2./N\ vA N oH N'' N Y OH Me OH Isomer B Isomer B

EXAMPLES 458-463 Using a similar procedure as that described for Example 14, only using the piperazine amine from Preparative Example 175 instead of the title compound from Preparative Example 24, and using as the Electrophile either a chloroformate to give a carbamate or an anhydride, or a carboxylic acid, HOBt, DEC and DMF to give the amide products listed in Table 66.

Table 66 Ex. Electrophile Product 1. Yield (%) 2. MU* 3. m °C ci 458 Me 1. 54. 1 1. 5 2. 603 2. 603 N N, N OH oh cri OU \N/Me 459 Me 1. 67. 8 3. 86. 7 0 ou OH Me 462 N 1. 100 O 1 (Sbo cg 4623. 86.2 HO 0 TABLE 66-continued Ex. Electrophile Product 1. Yield (%) 2. MH+ 3. m °C -ci M e 463 1.100 O N 2.661 -A 0 0 0 3. 65. 1 0 HO 0 ci Mye 463A 9 c N 1.85 O 2.647 O p 3. 52. 1

PREPARATIVE EXAMPLE 180 Following essentially the same procedure as that used in Example 466 Step A, except using tetrahydro-4H-pyran-4-ol, the title compound was prepared (3. 1g, 78%, MH+=165).

EXAMPLE 464

The title compound from Preparative Example 462 (0.205 g), 0.5M ammonia in dioxane (2 mL), DEC (0.175 g), HOBt (0.123 g) and anhydrous DMF (5 mL) were stirred at room temperature overnight. Purification by preparative plate chromatography (silica, 5% MeOH-CH2Cl2, NH40H såturated) afforded the title compound (0.136 g, 66%, MH+ = 646).

EXAMPLE 465

The title compound from Preparative Example 463 (0.228 g), 0.5M ammonia in dioxane (2 mL), DEC (0.175 g), HOBt (0.123 g) and anhydrous DMF (5 mL) were stirred at room temperature overnight. Purification by preparative plate chromatography (silica, 5% MeOH-CH2Cl2, NH40H saturated) afforded the title compound (0.139 g, 61%, MH+ = 660).

EXAMPLE 466 Step A

cis cis cis The commercially available cis-acetoxycyclohexanol (0.25 g) was treated with phosgene (2 mL). Concentration in vacuo afforded the chloroformate (0.307 g, 88%).

Step B Combining the chloroformate (0.052 g) from Step A with the piperazine amine (0.103 g) from Preparative Example 175 and

following a similar procedure as that described in Example 14, the title compound was obtained (0.07 g, 50%, MH+ = 703).

EXAMPLE 467

Treatment of the product from Example 466 (0.06 g) with potassium carbonate (0.2 g) in MeOH (2 mL) afforded the title compound (0.056 g, 100%, MH+ = 661).

EXAMPLE 468

Step A trans trans The commercially available trans-acetoxycyclohexanol (0.05 g) was treated with phosgene (0.5 mL). Concentration in vacuo afforded the chloroformate (0.062 g, 89%).

Step B -ci cri = 0 MYE ci O C J, N N/N N/,., N trans °

Combining the chloroformate (0.062g) from Step A with the piperazine amine (0.103 g) from Preparative Example 175 and following a similar procedure as that described in Example 14, the title compound was obtained (0.058 g, 42%, MH+ = 703).

EXAMPLE 469

Treatment of the product from Example 466 (0. 05 g) with potassium carbonate (0.2 g) in MeOH (2 mL) afforded the title compound (0.047 g, 100%, MH+ = 661).

EXAMPLE 470

Step A If the commercially available cyclohexanol were treated with phosgene then the chloroformate would be obtained.

Step B

If the chloroformate from Step A were combined with the piperazine amine shown above according to the procedure described for Example 461 then the ketal would be obtained.

Step C

If the product of Step B were treated with aqueous acid the ketone would be obtained.

Step D If the product of Step C were treated with MeMgBr or MeLi then the title product would be obtained.

EXAMPLE 471 Step A

If the commercially available ketone were treated with methyl magnesium bromide, then the desired alcohol would be obtained.

Step B

If the product of Step A above were treated with acetic anhydride, then the desired acetate would be obtained.

Step C

If the product of Step B were treated with formic acid, then the desired ketone would be obtained.

ASSAYS FPT IC5o (inhibition of farnesyl protein transferase, in vitro enzyme assay) was determined following the assay procedures described in WO 95/10516, published April 20,1995. GGPT ICso (inhibition of geranylgeranyl protein transferase, in vitro enzyme assay), Cell Mat Assay, COS Cell ICso (Cell-Based Assay), and anti- tumor activity (in vivo anti-tumor studies) could be determined by the assay procedures described in WO 95/10516. The disclosure of WO 95/10516 is incorporated herein by reference thereto.

Additional assays can be carried out by following essentially the same procedure as described above, but with substitution of alternative indicator tumor cell lines in place of the T24-BAG cells.

The assays can be conducted using either DLD-1-BAG human colon carcinoma cells expressing an activated K-ras gene or SW620-BAG human colon carcinoma cells expressing an activated K-ras gene.

Using other tumor cell lines known in the art, the activity of the compounds of this invention against other types of cancer cells could be demonstrated.

SoftAgar Assay: Anchorage-independent growth is a characteristic of tumorigenic cell lines. Human tumor cells can be suspended in growth medium containing 0.3% agarose and an indicated concentration of a farnesyl transferase inhibitor. The solution can be overlayed onto growth medium solidified with 0.6% agarose containing the same concentration of farnesyl transferase inhibitor as the top layer. After the top layer is solidified, plates can be incubated for 10-16 days at 37°C under 5% C02 to allow colony outgrowth. After incubation, the colonies can be stained by overlaying the agar with a solution of MTT (3- [4,5-dimethyl-thiazol- 2-yl]-2,5-diphenyltetrazolium bromide, Thiazolyl blue) (1 mg/mL in PBS). Colonies can be counted and the IC5o's can be determined.

Compounds of this invention had an FPT ICgo within the range of <0.04nM to 20nM, and a Soft Agar ICSO within the range of <0.5nM to >500nM.

Compounds of Examples 1-4,4.1,4.2,5,7,8,10-19,24-51, and 74,138,142,144,145 had an FPT IC. Owithin the range of <0.04nM to 2.7nM. Compounds of Examples 1-4,4.1,4.2,5,7,10- 19,24-51, and had a Soft Agar ICSO within the range of <0.5nM to 30nM.

Compounds of Examples 35 (A), 35 (C), 35 (D), 35 (E), 35 (F), 41 (A), 41 (B), 41 (C), 47 (A), 47 (B), 47 (D), 47 (G), 47 (H), 47 (I), 47 (K), 47 (L), 47 (M), 47 (N), 47 (0), 47 (P), 47 (R), 47 (S), 47 (T), 47 (U), 47 (CC), 51 (A) to 51 (D), 138 A to 147A, 148 to 163,169 to 180,183 to 201,207 to 216,227 to 234,238 to to 262,287 to 294,297 to 303,316 to 324,351 to

354,383,384,387,388,391,392,394 to 397,407,408,409,410, to 417,419,422 and 424 had an FPT ICg, within the range of <0.04 to 2.7 nM, and a Soft Agar ICgo within the range of <0.05 to 30 nM.

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 95 percent active ingredient.

Suitable solid carriers are known in the art, e. g. magnesium carbonate, magnesium stearate, talc, sugar or lactose. Tablets, powders, cachets and capsules can be used as solid dosage forms suitable for oral administration. Examples of pharmaceutically acceptable carriers and methods of manufacture for various compositions may be found in A. Gennaro (ed.), Remington's Pharmaceutical Sciences, 18th Edition, (1990), Mack Publishing Co., Easton, Pennsylvania.

Liquid form preparations include solutions, suspensions and emulsions. As an example may be mentioned water or water- propylene glycol solutions for parenteral injection or addition of sweeteners and opacifiers for oral solutions, suspensions and emulsions. Liquid form preparations may also include solutions for intranasal administration.

Aerosol preparations suitable for inhalation may include solutions and solids in powder form, which may be in combination with a pharmaceutically acceptable carrier, such as an inert compressed gas, e. g. nitrogen.

Also included are solid form preparations which are intended to be converted, shortly before use, to liquid form preparations for either oral or parenteral administration. Such liquid forms include solutions, suspensions and emulsions.

The compounds of the invention may also be deliverable transdermally. The transdermal compositions can take the form of creams, lotions, aerosols and/or emulsions and can be included in a transdermal patch of the matrix or reservoir type as are conventional in the art for this purpose.

Preferably, the pharmaceutical preparation is in a unit dosage form. In such form, the preparation is subdivided into suitably sized unit doses containing appropriate quantities of the active component, e. g., an effective amount to achieve the desired purpose.

The quantity of active compound in a unit dose of preparation may be varied or adjusted from about 0.01 mg to about 1000 mg, preferably from about 0.01 mg to about 750 mg, more preferably from about 0.01 mg to about 500mg, and most preferably from about 0.01 mg to about 250mg, according to the particular application.

The actual dosage employed may be varied depending upon the requirements of the patient and the severity of the condition being treated. Determination of the proper dosage regimen for a particular situation is within the skill of the art. For convenience, the total daily dosage may be divided and administered in portions during the day as required.

The amount and frequency of administration of the compounds of the invention and/or the pharmaceutically acceptable salts thereof will be regulated according to the judgment of the attending clinician considering such factors as age, condition and size of the patient as well as severity of the symptoms being treated. A typical recommended daily dosage regimen for oral administration can range from about 0.04 mg/day to about 4000 mg/day, in two to four divided doses.

While the present invention has been described in conjunction with the specific embodiments set forth above, many alternatives, modifications and variations thereof will be apparent to those of ordinary skill in the art. AH such alternatives, modifications and variations are intended to fall within the spirit and scope of the present invention.