AU2030700A - Tricyclic farnesyl protein transferase inhibitors - Google Patents

Description

WO 00/37459 PCT/US99/27939 -1* 5 TRICYCLIC FARNESYL PROTEIN TRANSFERASE INHIBITORS 10 BACKGROUND WO 95/10516, published April 20, 1995, WO96/31478, published October 10, 1996, and copending Application Serial No. 09/094687 filed June 15, 1998 discloses tricyclic compounds useful for inhibiting farnesyl protein transferase. 15 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. 20 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 B

R

2 1.... R3 R2 R4 Ra i(1.0) x R5 x R 7

R

8

R

3 2 R33 R6 IIV I \ / 1 N C-N ( C~~ R

R

14 0 R 9

R

1 0 R R 12 25 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 CR 1 or CR 2 ; or WO 00/37459 PCT/US99/27939 -2 each of a, b, c, and d are independently selected from CR 1 or

CR

2 ; X represents N or CH when the optional bond (represented by the dotted line) is absent, and represents C when the optional bond 5 is present; 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 -R 1 5 , halo, -OR 16 , -OCO 2

R

16 or

-OC(O)R

15 , and when no double bond is present between carbon 10 atoms 5 and 6, A and B each independently represent H 2 ,

-(OR

16

)

2 , H and halo, dihalo, alkyl and H, (alkyl) 2 , -H and

-OC(O)R

15 , H and -OR 15 , =0, aryl and H, =NOR 15 or -O-(CH2)p-O wherein p is 2, 3 or 4; each R 1 and each R 2 is independently selected from H, halo, 15 -CF 3 , -OR 15 (e.g., -OCH 3 ), -COR 15 , -SR 15 (e.g., -SCH 3 and

-SCH

2

C

6

H

5 ), -S(O)tR 1 6 (wherein t is 0, 1 or 2, e.g., -SOCH 3 and

-SO

2

CH

3 ), -N(R 15

)

2 , -NO 2 , -OC(O)R 15 , _CO 2

R

15 , -OCO 2

R

16 , -CN,

-NR

15

COOR

1 6, -SR 16

C(O)OR

16 (e.g., -SCH 2

CO

2

CH

3 ), -SR 16 N(R17 )2 (provided that R' 6 in -SR 16

N(R

17

)

2 is not -CH 2 -) wherein each R 17 is 20 independently selected from H or -C(O)OR 16 (e.g., -S(CH2)2NHC()O-t-butyl and -S(CH 2

)

2

NH

2 ), benzotriazol-1-yloxy, tetrazol-5-ylthio, or substituted tetrazol-5-ylthio (e.g., alkyl substituted tetrazol-5-ylthio such as 1-methyl-tetrazol-5-ylthio), alkynyl, alkenyl or alkyl, said alkyl or alkenyl group optionally 25 being substituted with halo, -OR 15 or -CO2R15;

R

3 and R 4 are the same or different and each independently represents H, any of the substituents of R 1 and R 2 , or R 3 and R 4 taken together represent a saturated or unsaturated C 5

-C

7 fused ring to the benzene ring (Ring III); 30 R 5 , R 6 , and R 7 each independently represents H, -CF 3

,

WO 00/37459 PCT/US99/27939 -3

-COR

1 5 , alkyl or aryl, said alkyl or aryl optionally being substituted with -OR 15 , -SR 15 , -S(O)tR 16 , -NR 15

C

O O

R

16 , -N(R 15

)

2 , -NO 2 ,

-COR

1 5 , -OCOR 15 , -OCO 2

R

16 , -CO 2

R

15 , OPO 3

R

15 , or R 5 is combined with R 6 to represent =0 or =S; 5 R 8 is selected from: H, C 3 to C 4 alkyl (preferably branched chain alkyl, and most preferably C 4 to C 7 branched chain alkyl), aryl, arylalkyl, heteroaryl, heteroarylalkyl, cycloalkyl, cycloalkylalkyl, substituted alkyl, substituted aryl, substituted arylalkyl, substituted heteroaryl, substituted heteroarylalkyl, 10 substituted cycloalkyl, substituted cycloalkylalkyl; the substutuents for the R substituted groups being selected from: alkyl, aryl, arylalkyl, cycloalkyl, -N(R 1 8

)

2 , -OR 1 8 , cycloalkyalkyl, halo, CN, -C(O)N(R' 8

)

2 , -SO 2

N(R'

8

)

2 or

-CO

2

R'

8 ; provided that the -OR' 18 and -N(R' 8

)

2 substituents are not 15 bound to the carbon that is bound to the N of the -C(O)NR- moiety; each R' 8 is independently selected from: H, alkyl, aryl, arylalkyl, heteroaryl or cycloalkyl;

R

9 and R' 0 are independently selected from: H, alkyl, aryl, 20 arylalkyl, heteroaryl, heteroarylalkyl, cycloalkyl or -CON(R') 2 (wherein R' 8 is as defined above); and the substitutable R 9 and R' 0 io groups are optionally substituted with one or more (e.g., 1-3) substituents selected from: alkyl (e.g., methyl, ethyl, isopropyl, and the like), cycloalkyl, arylalkyl, or heterarylalkyl (i.e., the R 9 and/or 25 R' 0 groups can be unsubtituted or can be substituted with 1-3 of the substitutents described above, except when R 9 and/or R"o is H); or

R

9 and Rio together with the carbon atom to which they are bound, form a C 3 to C 6 cycloalkyl ring; 30 R" and R' 2 are independently selected from: H, alkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, cycloalkyl, -CON(R' 8

)

2

-OR'

8 or

-N(R'

8

)

2 ; wherein R' 8 is as defined above; provided that the WO 00/37459 PCT/US99/27939 -4

-OR'

8 and -N(R' 8

)

2 groups are not bound to a carbon atom that is adjacent to a nitrogen atom; and wherein said substitutable R" and

RI

2 groups are optionally substituted with one or more (e.g., 1-3) substituents selected from: alkyl (e.g., methyl, ethyl, isopropyl, and 5 the like), cycloalkyl, arylalkyl, or heterarylalkyl; or R" and R 1 2 together with the carbon atom to which they are bound, form a C 3 to C 6 cycloalkyl ring; R'3 is an imidazolyl ring selected from:

R

19

R

19 r.-N ( NZz - 2.0 is preferab N -NN) or-N (2.0) (2.1) (4.0) (4.1) 10 wherein R' 9 is selected from: (1) H, (2) alkyl, (3) alkyl, (4) aryl, (5) arylalkyl, (6) substituted arylalkyl wherein the substituents are selected from halo (e.g., F and Cl) or CN, (7) -C(aryl) 3 (e.g., -C(phenyl) 3 , i.e., trityl) or (8) cycloalkyl; said imnidazolyl ring 2.0 or 2.1 optionally being substituted 15 with one or two substituents and said imidazole ring 4.0 optionally being substituted with 1-3 substituents and said imidazole ring 4.1 being optionally substituted with one substituent wherein said optional substituents for rings 2.0, 2.1, 4.0 and 4.1 are bound to the carbon atoms of said imidazole rings and said optional 20 substituents are independently selected from: -NHC(O)R'" 8 , -C(R")2OR 5 , -OR 8 , -SR' 8 , F, Cl, Br, alkyl, aryl, arylalkyl, cycloalkyl, or -N(R'") 2 (wherein each R' 8 is independently selected); R' 8 is as defined above; each R 34 is independently selected from H or alkyl (preferably -CH 3 ), preferably H; R 35 is selected from H, 25 -C(O)OR 20 , or -C(O)NHR 2 0 , and R 2 0 is as defined below (preferably R 2 0 is alkyl or cycloalkyl, most preferably cyclopentyl or cyclohexyl); Q represents an aryl ring (e.g., phenyl), a cycloalkyl ring (e.g., cyclopentyl or cyclohexyl) or a heteroaryl ring (e.g., furanyl, pyrrolyl, thienyl, oxazolyl or thiazolyl), said Q is optionally substituted with 1 WO 00/37459 PCT/US99/27939 -5 to 4 substituents inedependently selected from halo (e.g., F or Cl), alkyl, aryl, -OR' 8 , -N(R'18) 2 (wherein each R' 8 is independently selected), -OC(O)R' 1 8 , or -C(O)N(R 8

)

2 (wherein each R' 8 is independently selected), and wherein R' 8 is as defined above; 5 (examples of the -C(R 3 4) 2 0R 3 5 group include -CH 2 OH,

-CH

2 0C(O)OR 2 0 and -CH 2

OC(O)NHR

2 0 );

R'

4 is selected from: R20 O NR20 R20 I / R 6 /o2 O 0 R 2 1 O CH 2 O R 2 0 2 (5.0) , (6.0) (7.0) (7.1) or (8.0)

R'

5 is selected from: H, alkyl, aryl or arylalkyl; 10 R' 6 is selected from: alkyl or aryl;

R

2 0 is selected from: H, alkyl, alkoxy, aryl, arylalkyl, cycloalkyl, heteroaryl, heteroarylalkyl or heterocycloalkyl, provided that R 2 0 is not H when R' 4 is group 5.0 or 8.0; when R 2 0 is other than H, then said R 2 o group is optionally 15 substituted with one or more (e.g., 1-3) substituents selected from: halo, alkyl, aryl, -OC(O)R' 8 (e.g., -OC(O)CH 3 ), -OR' 8 or -N(R'8)2' wherein each R' 8 group is the same or different, and wherein R' 8 is as defined above, provided that said optional substituent is not bound to a carbon atom that is adjacent to an oxygen or nitrogen 20 atom;

R

2 ' is selected from: H, alkyl, aryl, arylalkyl, cycloalkyl, heteroaryl, heteroarylalkyl or heterocycloalkyl; when R 2 ' is other than H, then said R 2 1 group is optionally substituted with one or more (e.g., 1-3) substituents selected from: 25 halo, alkyl, aryl, -OR' 8 or -N(R' 8

)

2 , wherein each R' 8 group is the same or different, and wherein R' 1 8 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; n is 0-5; WO 00/37459 PCT/US99/27939 -6 each R 32 and R 33 for each n (i.e., for each -C(R 32

)(R

3 3 )- group), are independently selected from: H, alkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, cycloalkyl, -CON(R' 8

)

2 , -OR' 8 or

-N(R'

8

)

2 ; wherein R' 8 is as defined above; and wherein said 5 substitutable R 32 and R 33 groups are optionally substituted with one or more (e.g., 1-3) substituents selected from: alkyl (e.g., methyl, ethyl, isopropyl, and the like), cycloalkyl, arylalkyl, or heterarylalkyl; or

R

32 and R 33 together with the carbon atom to which they are 10 bound, form a C 3 to C6 cycloalkyl ring; and R is selected from branched alkyl, unbranched alkyl cycloalkyl, heterocycloalkyl, or aryl (e.g., phenyl); and provided that: (1) when RI 4 is selected from: group 6.0, 7.0, 7.1 or 8.0, 15 and X is N, then R is selected from: C3 to CIo alkyl, substituted C 3 to Co alkyl, arylalkyl, substituted arylalkyl, heteroarylalkyl, substituted heteroarylalkyl, cycloalkylalkyl, or substituted cycloalkylalkyl; and (2) when R' 4 is selected from: group 6.0, 7.0, 7.1 or 8.0, 20 and X is N, and R is H, then the alkyl chain between R 1 3 (i.e., inidazole ring 2.0, 4.0 or 4.1) and the amide moiety (i.e., the

-C(O)NR'

8 group) is substituted, i.e.,: (a) at least one of R 9 , R

I

o, R 11 ",

R'

2 , R 32 , or R 33 is other than H, and/or (b) R 9 and R'IO, and/or R'" and

R'

2, are taken together to form a cycloalkyl ring. 25 This invention also provides compounds of formula 1.0, as described above, wherein when R 14 is group 5.0, and X is N, and R is H, then the alkyl chain between R 13 (i.e., imidazole ring 2.0, 4.0 or 4.1) and the amide moiety (i.e., the -C(O)NR' 8 group) is substituted, i.e.,: (a) at least one of R 9 , RIO, R" , R12 R 32 , or R 33 is other than H, 30 and/or (b) R 9 and R i O, and/or R" and R 12 , are taken together to form a cyloalkyl ring. The compounds of this invention: (i) potently inhibit farnesyl protein transferase, but not geranylgeranyl protein transferase I, in WO 00/37459 PCT/US99/27939 -7 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 5 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 10 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 15 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 20 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 25 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 30 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 WO 00/37459 PCT/US99/27939 -8 (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 5 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 10 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 15 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 20 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 25 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 30 transformed cells.

WO 00/37459 PCT/US99/27939 -9 DETAILED DESCRIPTION OF THE INVENTION As used herein, the following tennrms are used as defined below unless otherwise indicated: MH+-represents the molecular ion plus hydrogen of the 5 molecule in the mass spectrum; BOC-represents tert-butyloxycarbonyl; CBZ-represents -C(0)OCH 2

C

6

H

5 (i.e., benzyloxycarbonyl);

CH

2 C1 2 -represents dichloromethane; CIMS-represents chemical ionization mass spectrum; 10 DEAD-represents diethylazodicarboxylate; DEC-represents EDCI which represents 1-(3-dimethyl amninopropyl)-3-ethylcarbodiimide hydrochloride; DMF-represents N,N-dimethylformamide; Et-represents ethyl; 15 EtOAc-represents ethyl acetate; EtOH-represents ethanol; HOBT-represents 1-hydroxybenzotriazole hydrate; IPA-represents isopropanol; iPrOH-represents isopropanol; 20 Me-represents methyl; MeOH-represents methanol; MS-represents mass spectroscopy; NMM-represents N-methylmorpholine; Ph-represents phenyl; 25 Pr-represents propyl; TBDMS-represents tert-butyldimethylsilyl; TEA-represents triethylamine; TFA-represents trifluoroacetic acid; THF-represents tetrahydrofuran; 30 Tr-represents trityl; WO 00/37459 PCT/US99/27939 - 10 alkyl-represents straight and branched carbon chains and contains from one to twenty carbon atoms, preferably one to six carbon atoms; acyl-represents a G-C(O)- group wherein G represents 5 alkyl, aryl, heteroaryl, cycloalkyl, heterocycloalkyl, -O-alkyl, -O-aryl, or NR 2 5

R

2 6 wherein R 2 5 and R 2 6 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 10 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 15 intended as possible points of attachment, said carbocyclic group being optionally substituted (e.g., 1 to 3) with one or more of halo, alkyl, hydroxy, alkoxy, phenoxy,

CF

3 , -C(O)N(R 8

)

2 , -SO 2 R',

-SO

2

N(R"

8

)

2 , amino, alkylamino, dialkylamino, -C00R 2 3 or -NO 2 , wherein R 2 3 represents alkyl or aryl; and 20 cycloalkyl-represents saturated carbocyclic rings of from 3 to 20 carbon atoms, preferably 3 to 7 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 is independently selected; 25 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, 30 substituted with a heteroaryl group, as defined below, such that the bond from another substituent is to the alkyl moiety; WO 00/37459 PCT/US99/27939 -11 heteroaryl-represents cyclic groups, optionally substituted with R 3 and R 4 , having at least one heteroatom selected from O, S or N, said heteroatom interrupting a carbocyclic ring structure and having a sufficient number of delocalized pi electrons to provide 5 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 10 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 R 3 and R 4 ), wherein pyridyl N-oxide can be represented as: or 0 0-i an ; and 15 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 -0-, -S- or - NR 2 4 , wherein R 2 4 represents alkyl, aryl, -C(0)N(R 1 8

)

2 wherein R' 8 is as 20 above defined (e.g., -C(0)NH 2 ) or acyl-(suitable heterocycloalkyl groups include 2- or 3-tetrahydrofuranyl, 2- or 3- tetrahydrothienyl, 2-, 3- or 4-piperidinyl, 2- or 3-pyrrolidinyl, 2- or 3-piperizinyl, 2- or 4-dioxanyl, morpholinyl, etc.). The positions in the tricyclic ring system are: 5 6 7 3 II 2 a 1 9 25 1 10o WO 00/37459 PCT/US99/27939 - 12 The compounds of formula 1.0 include the 2R and 2S isomers shown below (2R is preferred): A B R I R II R2 .-- \ R 4 bR a (1.OA) R5____ R R R 3 2

R

33 R 6 R13 %....1..,/_IN . / (C )n N2R C1 I, II 9 10 R11 R12

R

1 4 0 R R10 R R A B RI \R3 R --- I II -/) 4 R-- R4 b a (1.OB) x R5 ... .- R 7

R

8

R

3 2

R

3 3 R6_ IV / 13 N.2S .C N (C)n R R 1 4 IR 9

R

10 R1 1

R

12

R

14 0 5 Examples of R 8 substituents include: benzyl, -CH 2

C(CH)

2 ,

-CH

2 -cyclohexyl, -CH 2 -cyclopropyl, -(CH 2

)

2

CH

3 , F

H

2 C H 2 C H2C N H 2 C 1 I II OH

OCH

3 NI

H

2 C" N

H

2 C H 2 C H 2 C CN

CONH

2 O CH 3

H

2 C H 2 C H 2 C H 2 C I1I I WO 00/37459 PCT/US99/27939 - 13 0 O NI C H 2 C H 2 C

-(CH

2

)

2 , and Examples of R 9 and R'o groups include H and benzyl Examples of R" and R 12 groups include: H, -CH 3 ,

-CH

2

CH(CH)

2 , -(CH 2

)

3

CH

3 , benzyl, ethyl, p-chlorophenyl, and -OH. 5 Cyclopropyl is an Example of the R'" and R' 2 group being taken together with the carbon atom to which they are bound to form a cycloalkyl ring. Examples of the optional substituents for the R' 3 moiety include: -CH 3 , -CH 2 OH, -CH 20 C(O)O-cyclohexyl, -CH20C(O)O 10 cyclopentyl, ethyl, isopropyl, NH 2 , and -NHC(O)CF 3 . Examples of R ' 9 include: -C(O)NH-cyclohexyl, -C(phenyl) 3 , H, methyl or ethyl. Examples of R 2 0 for group 5.0 include: t-butyl, ethyl, benzyl,

-CH(CH

3

)

2 , -CH 2

CH(CH

3

)

2 , -(CH 2

)

2

CH

3 , n-butyl, n-hexyl, n-octyl, p 15 chlorophenyl, cyclohexyl, cyclopentyl,

CH

3 CH 3

N-CONH

2

SH

3 C CH 3 or H 3 C CH 3 Another example of R 2 0 for group 5.0 is OH Examples of R 2 0 and R 21 for 6.0 include: cyclohexyl, t-butyl, H, 20 -CH(CH) 2 , ethyl, -(CH 2

)

2

CH

3 , phenyl, benzyl, -(CH 2

)

2 phenyl, and CH 3 . Examples of R 2 0 for 7.0 include: 4-pyridylNO,

-OCH

3

,

WO 00/37459 PCT/US99/27939 - 14 -CH(CH3) 2 , -t-butyl, H, propyl, cyclohexyl and

N-CONH

2 Examples for R 3 6 for 7.1 include: cyclohexyl, cyclopentyl, cyclobutyl, cyclopropyl, 0 5 and 0 Examples for R 2 o for 8.0 include: methyl, i-propyl and cyclohexylmethyl. Examples of R 3 2 and R 33 include: H, phenyl, -OH and benzyl. Compounds of this invention include compounds of formula 10 1.0 wherein when R 14 is selected from: group 6.0, 7.0, 7.1 or 8.0, and X is C or CH (preferably CH), then R 8 is selected from: C 3 to CI 0 alkyl, substituted C 3 to CI 0 alkyl, arylalkyl, substituted arylalkyl, heteroarylalkyl, substituted heteroarylalkyl, cycloalkylalkyl, or substituted cycloalkylalkyl. 15 Compounds of this invention include compounds of formula 1.0 wherein when R 1 4 is selected from: group 6.0, 7.0, 7.1 or 8.0, and X is C or CH (preferably CH), and R is H, then the alkyl chain between R 13 (i.e., imidazole ring 2.0, 4.0 or 4.1) and the amide moiety (i.e., the -C(O)NR group) is substituted, i.e.,: (a) at least one 20 of R 9 , R'IO, R", R' 2 , R 3 2 , or R 33 is other than H, and/or (b) R 9 and RI, and/or R" and R' 2 , are taken together to form a cyloalkyl ring. Compounds of this invention include compounds of formula 1.0 wherein when RI 4 is group 5.0, and X is C or CH (preferably CH), and R 8 is H, then the alkyl chain between RI 3 (i.e., imidazole ring 25 2.0, 4.0 or 4.1) and the amide moiety (i.e., the -C(O)NR' 8 group) is substituted, i.e.,: (a) at least one of R 9 , RIO, R", R 2 , R 3 2 , or R 3 is other than H; and/or (b) R 9 and R'o, and/or R' 1 and R' 2 , are taken together to form a cyloalkyl ring.

WO 00/37459 PCT/US99/27939 - 15 Compounds of this invention include compounds of formula 1.0 wherein when R 14 is selected from: group 6.0, 7.0, 7.1 or 8.0, and X is C or CH (preferably CH), then R 8 is selected from: arylalkyl, substituted arylalkyl, heteroarylalkyl, substituted heteroarylalkyl, 5 cycloalkylalkyl, or substituted cycloalkylalkyl. Compounds of this invention include compounds of formula 1.0 wherein when R 14 is 5.0 and X is C or CH (preferably CH), then

R

8 is selected from: arylalkyl, substituted arylalkyl, heteroarylalkyl, substituted heteroarylalkyl, cycloalkylalkyl, or substituted 10 cycloalkylalkyl. Compounds of this invention include compounds of formula 1.0 wherein when R' 1 4 is selected from: group 6.0, 7.0, 7.1 or 8.0, and X is N, then R 8 is selected from: arylalkyl, substituted arylalkyl, heteroarylalkyl, substituted heteroarylalkyl, cycloalkylalkyl, or 15 substituted cycloalkylalkyl. Compounds of this invention include compounds of formula 1.0 wherein when R' 4 is 5.0 and X is N, then R is selected from: arylalkyl, substituted arylalkyl, heteroarylalkyl, substituted heteroarylalkyl, cycloalkylalkyl, or substituted cycloalkylalkyl. 20 Thus, one embodiment of this invention is directed to compounds wherein R 14 is the carbamate group 5.0 and the other substituents are as defined for formula 1.0. Another embodiment of this invention is directed to compounds wherein R 14 is the carbamate group 5.0, X is N and the 25 other substituents are as defined for formula 1.0. Another embodiment of this invention is directed to compounds wherein RI 4 is the carbamate group 5.0, X is C or CH (preferably CH) and the other substituents are as defined for formula 1.0. 30 Another embodiment of this invention is directed to compounds wherein R 14 is the carbamate group 5.0, X is N, R 8 is arylalkyl or substituted arylalkyl (preferably arylalkyl), and the other substituents are as defined for formula 1.0.

WO 00/37459 PCT/US99/27939 -16 Another embodiment of this invention is directed to compounds wherein R' 4 is the carbamate group 5.0, X is N, R 8 is heteroarylalkyl or substituted heteroarylalkyl (preferably heteroarylalkyl), and the other substituents are as defined for 5 formula 1.0. Another embodiment of this invention is directed to compounds wherein RI 4 is the carbamate group 5.0, X is N, R 8 is cycloalkylalkyl or substituted cycloalkylalkyl (preferably cycloalkylalkyl), and the other substituents are as defined for 10 formula 1.0. Another embodiment of this invention is directed to compounds wherein R 14 is the carbamate group 5.0, X is C or CH (preferably CH), R 8 is arylalkyl or substituted arylalkyl (preferably arylalkyl), and the other substituents are as defined for formula 1.0. 15 Another embodiment of this invention is directed to compounds wherein R 1 4 is the carbamate group 5.0, X is C or CH (preferably CH), R 8 is heteroarylalkyl or substituted heteroarylalkyl (preferably heteroarylalkyl), and the other substituents are as defined for formula 1.0. 20 Another embodiment of this invention is directed to compounds wherein RI 4 is the carbamate group 5.0, X is C or CH (preferably CH), R 8 is cycloalkylalkyl or substituted cycloalkylalkyl (preferably cycloalkylalkyl), and the other substituents are as defined for formula 1.0. 25 Another embodiment of this invention is directed to compounds wherein when R 14 is group 5.0, and X is C or CH (preferably CH), and R 8 is H, then the alkyl chain between R l " (i.e., imlidazole ring 2.0, 4.0 or 4.1) and the aide moiety (i.e., the C(O)NR 8 group) is substituted, i.e.,: (a) at least one of R 9 , R 1 0 , R", 30 R 2 , R 32 , or R is other than H, and/or (b) R 9 and R 10 , and/or R 1 ' and

RI

2 , are taken together to form a cyloalkyl ring, and the other substituents are as defined for formula 1.0.

WO 00/37459 PCT/US99/27939 - 17 Another embodiment of this invention is directed to compounds wherein when R1 4 is group 5.0, and X is N, and R 8 is H, then the alkyl chain between R' 3 (i.e., imidazole ring 2.0, 4.0 or 4.1) and the amide moiety (i.e., the -C(O)NR' 8 group) is substituted, i.e.,: 5 (a) at least one of R 9 , R' 0 , R", R' 2 , R 32 , or R 33 is other than H, and/or (b) R 9 and R 10 , and/or R" and R 12, are taken together to form a cyloalkyl ring, and the other substituents are as defined for formula 1.0. Another embodiment of this invention is directed to 10 compounds wherein R 14 is a group selected from: 6.0, 7.0, 7.1 or 8.0, X is N, R8 is arylalkyl. or substituted arylalkyl (preferably arylalkyl) and the other substituents are as defined for formula 1.0. Another embodiment of this invention is directed to compounds wherein R 14 is a group selected from: 6.0, 7.0, 7.1 or 15 8.0, X is N, R is heteroarylalkyl or substituted heteroarylalkyl (preferably heteroarylalkyl) and the other substituents are as defined for formula 1.0. Another embodiment of this invention is directed to compounds wherein R" 4 is a group selected from: 6.0, 7.0, 7.1 or 20 8.0, X is N, R8 is cycloalkylalkyl or substituted cycloalkylalkyl (preferably, cycloalkylalkyl) and the other substituents are as defined for formula 1.0. Another embodiment of this invention is directed to compounds wherein RI 4 is a group selected from:6.0, 7.0, 7.1 or 8.0, 25 X is C or CH (preferably, CH), R is arylalkyl or substituted arylalkyl (preferably arylalkyl) and the other substituents are as defined for formula 1.0. Another embodiment of this invention is directed to compounds wherein R" 4 is a group selected from: 6.0, 7.0, 7.1 or 30 8.0, X is C or CH (preferably, CH), R" is heteroarylalkyl or substituted heteroarylalkyl (preferably, heteroarylalkyl) and the other substituents are as defined for formula 1.0.

WO 00/37459 PCT/US99/27939 -18 Another embodiment of this invention is directed to compounds wherein RI 4 is a group selected from: 6.0, 7.0, 7.1 or 8.0, X is C or CH (preferably, CH), R 8 is cycloalkylalkyl or substituted cycloalkylalkyl (preferably, cycloalkylalkyl) and the 5 other substituents are as defined for formula 1.0. R', R 2 , R 3 , and R 4 are preferably selected from H or halo, and are more preferably selected from H, Br, F, or Cl, and are most preferably selected from H, Br or Cl. Representative compounds of formula 1.0 include trihalo, dihalo and monohalo substituted 10 compounds, such as, for example: (1) 3,8,10-trihalo; (2) 3,7,8 trihalo; (3) 3,8-dihalo; (4) 8-halo; and (5) 10-halo substituted compounds; wherein each halo is independently selected. Preferred compounds of formula 1.0 include: (1) 3-Br,8-C1,10-Br-substituted compounds; (2) 3-Br,7-Br,8-Cl-substituted compounds; (3) 3-Br,8 15 Cl-substituted compounds; (4) 8-Cl-substituted compounds; and (5) 10-Cl-substituted compounds. The 3,8-dihalo compounds are more preferred and the 8-halo compounds are most preferred. Thus, for example, 3-Br,8-C1 substituted compounds are more preferred and 8-C1 substituted compounds are most preferred. 20 Substituent a is preferably N or N'O with N being preferred. A and B are preferably H 2 , i.e., the optional bond is absent and the C5-C6 bridge is unsubstituted. R, R 6 , and R 7 are preferably H. X is preferably N or CH (i.e., the optional bond is absent), and 25 more preferably X is N.

R

8 is preferably selected from: arylalkyl, substituted aryl alkyl, heteroarylalkyl, substituted heteroarylalkyl, cycloalkylalkyl or substituted cycloalkylalkyl. Most preferably, R 8 is selected from: aryl-(C-C 4 )alkyl, substituted aryl-(C,-C 4 )alkyl, heteroaryl-(C, 30 C 4 )alkyl, substituted heteroaryl-(C-C 4 )alkyl, cycloalkyl-(C -C 4 )alkyl, or substituted cycloalkyl-(C-C 4 )alkyl. More preferably, R 8 is selected from: aryl-CH 2 -, substituted aryl-CH 2 -, heteroaryl-CH 2 -, substituted heteroaryl-CH 2 , cycloalkyl-CH 2 - or substituted WO 00/37459 PCT/US99/27939 - 19 cycloalkyl-CH 2 -. Even more preferably, R 8 is selected from: benzyl, 3-pyridylmethyl, 4-fluoro-benzyl or cyclopropylmethyl, and still more preferably R 8 is benzyl.

R'

3 is preferably ring 2.0 or 4.0. When substituted on the 5 substitutable carbon atoms of the imnidazole ring, the substituents are generally selected from: -N(R' 8

")

2 , -NHC(O)R' 8 , -C(R 3 4 ) 2 0R 3 5 , or alkyl, e.g., -CH 3 , -CH 2 OH, -CH 2 OC(O)O-cyclohexyl, -CH 2

,OC(O)O

cyclopentyl, ethyl, isopropyl, NH 2 , or -NHC(O)CF 3 .

R

9 is preferably H or alkyl, most preferably H, methyl or 10 ethyl, and more preferably methyl.

RI

4 is preferably a carbamate group represented by substituent 5.0 described above. Preferably, R 2 0 for substituent 5.0 is selected from: alkyl, substituted alkyl, aryl, cycloalkyl, or cycloalkyl substituted with -OH provided that said -OH substituent 15 is not bound to a carbon that is adjacent to an oxygen atom. More preferably R 2 o for substituent 5.0 is selected from: CI to C4 alkyl and C5 to C 7 cycloalkyl. Most preferably R 2 0 for substituent 5.0 is selected from: t-butyl, i-propyl and cyclohexyl, with i-propyl and cyclohexyl being more preferred, and with cyclohexyl being even 20 more preferred.

R

20 in substituent 6.0 is preferably selected from: alkyl or cycloalkyl; most preferably t-butyl, isopropyl or cyclohexyl; and more preferably cyclohexyl. R 2 ' is preferably selected from: H or alkyl; most preferably H, methyl or isopropyl; and more preferably 25 H.

R

20 in substituent 7.0 is preferably selected from: cycloalkyl or alkyl; most preferably cyclohexyl, cyclopentyl, isopropyl; and more preferably cyclohexyl.

R

36 in substituent 7.1 is preferably selected from: phenyl, 30 cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, WO 00/37459 PCT/US99/27939 - 20 0 6 or 0, and most preferably selected from: cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl.

R

20 in substituent 8.0 is preferably selected from: alkyl or 5 cycloalkylalkyl; most preferably methyl, isopropyl or cyclohexylmethyl; more preferably methyl or isopropyl; and even more preferably methyl.

R

9 , R 1 o, R"', and R 1 2 are preferably selected from: H, C 1 to C 4 alkyl (e.g., methyl or isopropyl), -CON(R1 8

)

2 (e.g., -CONH2), or when 10 R 9 and R'o, and/or R" and R 2 are taken together to form a cycloalkyl ring, said ring is preferably cyclopropyl cyclopentyl or cyclohexyl.

R

9 , Ro, R", and R 12 are preferably H when R 1 4 is the carbamate substituent 5.0 and R 8 is not H. 15 When R 4 is selected from substituents 6.0, 7.0, 7.1 and 8.0, and at least one of R 9 , R 1 0 , R", and R1 2 is other than H, then at least one of R 9 , R'

O

, R", and R' 2 is: (I) preferably selected from: (1) C 1 to C 4 alkyl, (2) -CON(R" 8

)

2 or (3) the cycloalkyl ring formed when R 9 and R'

°

, 20 and/or R" and R12, are taken together along with the carbon atom to which they are bound; (II) most preferably selected from: (1) methyl, (2) isopropyl, (3) -CONH 2 or (4) cyclopropyl; and (III) more preferably selected from: (1) R 9 and R'o being H, 25 and one of R" and R 12 being selected from: alkyl (preferably, methyl or isopropyl), and the other being selected from H or alkyl (preferably, methyl); (2) R 9 and R 1 0 being H, and R'" and R ' 1 2 being taken together to form a cycloalkyl ring (preferably, cyclopropyl); or (3) R" and R' 2 being H, and one of R 9 and R"o being -CONH 2 , and the 30 other being H.

WO 00/37459 PCT/US99/27939 -21 Preferred compounds, when at least one of R 9 , R'

O

, R", and R12 is other than H, also include compounds wherein: R 9 and RIO are H, and R" and R12 are the same or different alkyl, preferably the same, wherein said alkyl is more preferably methyl. 5 For compounds of the invention, n is preferably 0-4, more preferably 0-2, and most preferably 0 or 1. Preferably, each R32 and R 33 are independently selected from: H, -OR8, aryl or arylalkyl (e.g., benzyl); most preferably H, -OH or phenyl; and more preferably H. 10 Compounds of formula 1.0, wherein X is N or CH, include, with reference to the C-I 1 bond, the R- and S- isomers: AB

R

1

R

3 SII

R

2 - I III 4 b a (9.0) a (R) R 5 X.--R7 R 8

R

32

R

3 3

R

6 IV I 3 N C N(C)n-- R I

R

9

R

1 0

R

1 1

R

12

R

14 0R9 1 A B R R3 II R2 1 R a (10.0) (S) R5s R7 R 8

R

3 2 R33

R

6 IV R13 N C Nn R1 R 9

R

10 R" R 12

R

14 0 Compounds of formula 1.0 also include compounds having 15 the 2S stereochemistry and the C- 11 R- or C- 11 S- stereochemistry. Compounds of this invention include: WO 00/37459 PCT/US99/27939 - 22 Br / Cl Br / Cl (13.0) (14.0)

N)

B r 8Br 8 R R I I N "NC N " N

R

1 4 0 R 14 O I I 0 0 Br / Cl Br / Cl NN (15.0) (16.1) N 'I,,N R R I 1 1 R 0 R 0 WO 00/37459 PCT/US99/27939 - 23 Br--c rc NN -(19.0) (00 NN 114 14/ R 0 Br .- ci Br .- ci N(19.1) N =(20.1) N 114 1~ 1 14 0 R 0 R0 N (21. 0) (20 CN8 N ~ N"~C

R

1 0

R

1 0 N ±(23.0) N(40 NN N" N'///C, 8 1 14 1Ry1 1 4 0

R

1 0R0 WO 00/37459 PCT/US99/27939 -24 /7 Cl / Cl N (23.1) N (24.1) -I NO./I N. j

R

1 4 O RI 4 0 'N , (24.2) N (24.3) N CR C l N //C "N,0 N

R

14 0 R 14 0 N (24.4) N (24.5) (N 1R8 Cl N14 N N q .N. N / R O R 1 4 O (24.6) (24.7) N I CI N -,/...- N N -//c, -N

R

14 0 R 1 4 0 5 Compounds of the invention also include compounds corresponding to 13.0-15.0, 15.1, 16.0, 16.1, 17.0-19.0, 19.1, 20.0, 20.1, 21.0-23.0, 23.1, 24.0, and 24.1-24.7, except that the compounds have the 2S stereochemistry.

WO 00/37459 PCTIUS99/27939 - 25 Compounds of the invention also include compounds corresponding to 13.0-15.0, 15.1, 16.0, 16.1, 17.0-19.0, 19.1, 20.0, 20.1, 21.0-23.0, 23.1, 24.0, and 24.1-24.7, except that Ring I is phenyl instead of pyridyl. 5 Compounds of the invention also include compounds corresponding to 13.0-15.0, 15.1, 16.0, 16.1, 17.0-19.0, 19.1, 20.0, 20.1, 21.0-23.0, 23.1, 24.0, and 24.1-24.7, except that Ring I is phenyl instead of pyridyl and the compounds have the 2S stereochemistry. 10 Preferred compounds of formula 1.0 include compounds of the formula: A B Rc R3

R

2 ~ ~ III R2 R 4 a R (25.0) X R5.--. . --- . R 7

R

8 R32 R33 R6 IV3 / 13 1C (C) N ',i N.. N( C )nI R1 2 R20 O 0 R 9

R

10

R

1

R

1 2 (i.e., wherein RI 4 iS the carbamate group 5.0) wherein all substituents are as above defined. 15 A preferred compound of formula 25.0 is: A B R1 R 3

R

2 - I III R4 a (26.0) R5 -- R 7

R

8

R

3 2

R

3 3 R11 R6L IV I / 1 3 N t// .- N (C')n R R20 0 R 9 Ro 10 R R 12 with formula 27.0: WO 00/37459 PCT/US99/27939 - 26 A. B R.

R

3 R2 R4 b a _ (27.0) R . - 7

R

8 R R 3 2

R

33 ,6._.IV I / 13 R R13 N //C, N,; ( C )n11 R20 O0R R10 R 11 R1 being most preferred (wherein all substituents are as defined above). Compounds of formula 25.0 include: N (28.0) I \13

R

8 R N C N (C )nR

R

20 O R R1 R R1 5 00 and RI - R3 N (29.0) N R R8 R 32

R

3 3 I R 13 N - ' 4 ,N,> ( C )nR R 0

R

9

R

10 R"

R

1 2 wherein all substituents are as defined above. Preferred compounds of formulas 28.0 and 29.0 are those 10 wherein the R' to R 4 substituents are selected to produce trihalo, dihalo and monohalo substituted compounds, as described above.

WO 00/37459 PCT/US99/27939 - 27 Compounds of formula 29.0 are preferred. Most preferred are compounds of formula 29.0 wherein R 8 is selected from: benzyl, 4 fluorobenzyl, 3-pyridylmethyl or cyclopropylmethyl;

R

2 is cyclohexyl, i-propyl or t-butyl (more preferred is cyclohexyl), R' is Br 5 or H, R 3 is Cl, and R 4 is H. More preferred are compounds of formula 29.0 wherein R 8 is benzyl, R2 is cyclohexyl, i-propyl or t butyl (even more preferred cyclohexyl), R 1 is H, R 3 is Cl1, and R 4 is H or C1. Preferred compounds of this invention include: Br C1 (R-Isomer) H N (11R,2R Isomer) N -, N N N'- O 0O Me Me (Example 11) 10 H Br C1 N NH FHN (11S,2R Isomer) ' N S N Me Me (Example 16) Br Cl N H

CH

3 H O N H C CH 3 N N HaC 01o 0 'E--N (Example 58); WO 00/37459 PCT/US99/27939 - 28 Br / Cl N N cN (Example 78 Step B) O. 0 0II

H

3 C $CH 3

CH

3 Br Cl N 0 N (Example 79 Step B O N N N Isomer A) H Br ' Cl tN N C N, N N I1i (Example 80 O 0 Isomer A) I

C

2

H

5 Br /\ Cl 'N N l- N ,N (Example 88 II Isomer A) O OO Ha 3 C CH 3

CH

3 WO 00/37459 PCT/US99/27939 - 29 Br-- / Cl N C'N NN (Example 93 0 Isomer D) o -O

H

3 C CH 3

CH

3 Br /Cl \tN N NH H N :N (Example 99) N N/ O HN N 6 0 Br@ H H N H /> T , N N (Example 100) O 0 OH 0 0

H

3 C CH 3

CH

3 WO 00/37459 PCT/US99/27939 - 30 Ci oK N N CH 3 OIII N (Example 225) a oJ ,o 0 _C1 c00o N N CH 3 ON , Ot _N ,,;N (Example 226) 0 0 CH 3 Cl NJ N

N

N N CH 3 SO N N N (Example 227) 0-o 0 Cl N F N)_, CH 3 I N/N N (Example 228) 5 O' q 0 WO 00/37459 PCT/US99/27939 -31 Cl N H C o,, N N (Example 229) N C ~ /(NN N (Example 229) ao 00 ci N CH 3 NN (Example 232) N ' I r N N Z N 0 00 CI N N \ H 3 C OH 3 ( Ea H- C 3(Example 326) a N N\i~~ NN N CH 3 oN .

(Example 330) WO 00/37459 PCT/US99/27939 - 32 BCl N O. O N N CH3 (Example 327) 0N ci N

H

3 C N \CH 3 0 o N (Example 328) 0 Br / Cl N N NH (Example 243) Br ClI Me N/ N( (Example 286A) o01s o 0N WO 00/37459 PCT/US99/27939 - 33 Br Cl N O N (Example 286B) 0 N Me N O O O) (Example 304) Cl N . N Me / N / o I) (Example 306) N N N CN Me o oo (Example 307) 0 or WO 00/37459 PCT/US99/27939 - 34 Cl T M N CN N Me -o o (Example 308) Most preferred compounds include the compounds Br Cl N H

CH

3 N N Example 58

H

3 C 00 N 3a 0O 0 Cl N N

CH

3 O N N (Example 225) C' N

CH

3 5o(N , PN (xm .- / (Example 226) 0 Cy WO 00/37459 PCT/US99/27939 - 35 Cl N N'N N) CH 3 o N

N

i c (Example 227) 0 Cl (NN F N

CH

3 O (Example 228) Cl N

H

3 C N N N (Example 229) ao ~00 ci N C N

CH

3 Nf (Example 232) ON N N WO 00/37459 PCT/US99/27939 - 36 CI N N .H 3 C OH 3 CN N N (Example 326) ,N N N o o; and Cl N O (Example 327) a O .,, N CH 3 0N More preferred compounds include the compounds of Examples 58, 199, 225, 226, 229, 232 and 326. Compounds of 5 Examples 58, 199, 225, 229 and 326 are even more preferred. The compound of Example 225 is even still more preferred. Preferably the compound of Examples 225, 229 and 326 are administered orally. This invention is also directed to the compounds of Examples 10 26, 30, 32, 41, 42, 43, 44, 81, 105, 106, 293, and 309. The compound of Example 309 is preferred. This invention is also directed to the compounds of Examples 31, 34, 35, 36, 37, 38, 39, 40, 67, 68, 69, 70, 73, 75, 263, 282, 283, 284, 287, and 289. The compounds of Examples 67, 68, 69, 15 and 70 are preferred. This invention is also directed to the compounds of Examples 27, 28, 29, 71, 72, 74, 76, 98, 101, 103, 104, 107, 108, 110, 111, 255,256,257,258,259,260,261,262,264,265,266,267,268, 269,270,271,272,273,274,275,276,277,278,285,286,286A, 20 290, 291, 292, 294, 295, 296, 297, 299, 300, 301, 302, and 303.

WO 00/37459 PCT/US99/27939 - 37 Compounds of Examples 101, 103, 71, 72 Step B, 72 Step C and 259 are preferred This invention is also directed to compounds of Examples 33, 279, 280, and 281. 5 Lines drawn into the ring systems indicate that the indicated bond may be attached to any of the substitutable ring carbon atoms. Certain compounds of the invention may exist in different isomeric (e.g., enantiomers, diastereoisomers, atropisomers) forms. 10 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 15 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 20 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 25 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 30 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, WO 00/37459 PCT/US99/27939 - 38 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 5 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 10 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 15 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, WO96/31478 published October 10, 1996, WO 97/23478 published July 3, 1997, U.S. 5,719,148 issued February 17, 1998, 20 and copending Application Serial No. 09/094687 filed June 15, 1998 (see also WO98/57960 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 25 reaction schemes described below. Reaction Scheme 1 (n is 1)

R

1 1

R

12 RA AEt

NR

1 1 EtOH N N-H + CO 2 Et relu reflux -3

R

12 N (30.0) (31.0) (32.0) WO 00/37459 PCT/US99/27939 - 39 R" R 12 RA LAH R N OH 32.0 (33.0) O R11 R12 O RA Ph 3 P ' N N 33.0+ N-H DEAD N Qf NTHFO (34.0) THF (35.0)

R

1 1

R

12 RA

N

2

H

4 N NH 2 35.0 I < J EtOH N -*.J N (36.0) RB RB (36.0) + Y 1) 3A Molecular Sieves - Y (3 .)+II - II H ,Y 2)NaBH 4 N y Y ~Y N O HN N RA 11 12 (36.1) R R2 BOC BOC RA N 1) CH 2 Cl 2 N 36.0 + H 2) cyclohex 1 H k isocyanate N N N O N NO N N O N O (38.0) 0 (37.0) 1 5 H BOC BOC Y I II RA N 1)CH 2 C1 2 N 36.1 + H 2) cyc l ohex 1 PY 36.1 + K N H isocyanate (N O O N ON -I II R l "R12 N, , O 0 (38.1) 0 (37.0) I

H

WO 00/37459 PCT/US99/27939 - 40 HTFA Salt RA I RA TFA (N H r1 N 38.0 -1 \ N NR12 N O0 (39.0) I H

R

. H TFA Salt 'y SII

R

A N \, TFA Y rY 38.1 TA I \ SO N N N N> o 0 (39.1) I H A B R d R 39.0 + AB b RI R R 2 RA d TEA H CH2C12 I ab4 N lrIOX 1 4 .0) C 4 N O R (40 0 (41.0) 1 H A B

R

1 ' ** R 3 39.1 + A B 3 RI ......... Ra 4 R R TEARN R I bf ~ CH 2 Cl 2 I R2 cl 4 R R 12 (40.0) N 0 0 (41.1)

H

WO 00/37459 PCT/US99/27939 -41 In Scheme 1, R" and R1 2 are preferably methyl when H is bound to the amide nitrogen (i.e., when R 8 in formula 1.0 is H), e.g., 41.0, and are preferably H when the amide nitrogen is substituted (i.e., R 8 in formula 1.0 is other than H), e.g., 41.1. Those skilled in 5 the art will appreciate that other acylating agents can be used in place of cyclohexyl isocyanate to obtain compounds having different groups bound to the carbonyl group that is bound to the piperazine nitrogen. Those skilled in the art will also appreciate that other esters can be used in place of compound 31.0 to obtain compounds 10 having different carbon chains between the imidazole ring and the C(O)NH-group. Compounds of 41.0 can be prepared beginning with the conjugate addition of imnidazole (2-, 4-, and/or 5-substituted) to an appropriately substituted acrylate 31.0 in EtOH at reflux or neat at 15 90 0 C. Standard LAH reduction of the ester 32.0 gives the alcohol 33.0 which can be converted to the phthalimide 35.0 via the Mitsunobu reaction. Removal of the phthalimnido group with hydrazine in EtOH at reflux gives amine 36.0. This amine readily opens the piperazine anhydride 37.0 with the evolution of CO 2 and 20 subsequent reaction with isocyanates gives the one pot conversion to urea 38.0. Removal of the BOC-group with 50% TFA at room temperature gives the salt 39.0, which can be readily coupled to the tricyclic chloride 40.0 to give the desired product 41.0. In Scheme 1, and the Schemes that follow, Y represents C, N 25 or N'O - such that there can only be 0-2 Y substituents that are independently selected from N or N'O

-

. RA represents the optional substituents in the imidazole ring that are defined for inmidazole ring 4.0 above. R represents the optional substituents defined above for the aryl or heteroaryl groups for R. 30 For example, following Reaction Scheme 1, wherein R" and R 12 are methyl, and using compound 42.0 (see Preparative Example 40 in WO 95/10516 published April 20, 1995) WO 00/37459 PCT/US99/27939 - 42 Br /Cl N\ Cl (42.0) compound 43.0 Br /Cl N N o 1\ (N H N NN O

H

3 C CHN S (43.0) H can be obtained. 5 Reaction Scheme 2 (n is 0) RA

R

1 1

R

12 N RI1 RA N-Na +R12 -- CO 2 Et DMF N CO2Et (44.0) Br (45.0) N (46.0)

R

1 1

R

12

R

1 1 R12 RA OH R A OROTs 46.0 - - ( N Tc N N (47.0) (48.0) 0 O 48.0+ N-K DMF R 1 1

R

12 \ A RA (49.0) o o N (50.0) WO 00/37459 PCT/US99/27939 - 43 R 1 1

R

12 R R RA NH2

N

2

H

4 N 50.0 (51.0) RB B R" R (. +Y 1) 3A Molecular Sieves Y (51.0) + II H \ ,Y 2) NaBH 4 ' Y Y 11Y R 12 O HN R"R1 RA (51.1) N The synthesis of the intermediate amine 51.0 begins with the alkylation of the sodium salt of imidazole (or substituted imidazole) 5 44.0 with 45.0 at 900C. Standard LAH reduction of the ester 46.0 gives the alcohol 47.0. Tosylation of 47.0 and displacement of tosylate with potassium phthalimide 49.0 in DMF at 90 0 C gives the phthalimido derivative 50.0 which can be readily converted to the amine 51.0 with hydrazine in refluxing EtOH. Compounds wherein 10 R 8 WH can be prepared as described in Scheme 1. Similar to the procedure set forth in Scheme 1 for 36.0 and 36.1, 51.0 and 51.1 in Scheme 2 are reacted to form compounds of formula 1.0. In Scheme 2, R" and R' 2 are preferably methyl when H is bound to the amide nitrogen (i.e., when R 8 in formula 1.0 is H), 15 and are preferably H when the amide nitrogen is substituted (i.e., R 8 in formula 1.0 is other than H). Reaction Scheme 3 Ring IV = piperidine) Br H Cl Br Cl Br N Cl N N N H _____ H (+) H N N N H H H ((-) 52.0) ((+) 52.0) ((-) 52.0) WO 00/37459 PCT/US99/27939 - 44 Br cl Br Cl N/ NN ' H a H ((+) 52.0) N (53.0) N H O

H

2 Br Cl Br cl b N H N H (53.0) +H

H

3 CO N N OCH 3 (54.0a) o0 o (54.Ob) Br Cl Br Cl (54.0a) c N "N + H p H+ H (54.Ob) NC N N CN (55.0a) H H (55.0b) Br Br - Cl (55.0a) d N H + N 'H + (55.0b) HOOC N N COOH (56.0a) H H (56.Ob) Br cl Br ' Cl (56.0a) e N 'H N " + H H (56.Ob) + HOOC N N COOH I C 5 (57.0a) COOt-Bu (57.0b) COOt-Bu WO 00/37459 PCT/US99/27939 - 45 Br " Cl Br - C1 Br '- Cl N N H N H a-e H H + N HOOC N N COOH H50)HI I ((-)52.0) H (58.0a) COOt-Bu (58.0b) COOt-Bu Compound (±) 52.0 is resolved following procedures similar to those disclosed in WO97/23478 (published July 3, 1997). The reagents used in Reaction Scheme 3 are: Reaction Step a: 5 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 10 hydroxide/tetrahydrofuran.

WO 00/37459 PCT/US99/27939 -46 Reaction Scheme 4 (n is 1-5) 0 32 33 B R R 0 NaH DMF R0~ ____ 32 333R" A 0 32 N~ NH 2

-NH

2 R2 R3 N C NH 0/EtOH \.. R rN R 10

RR

1 i 0 R1R 1 0 R H R;, 0 1) 3A Molecular ' R2 R33 rSieves 32 33 H2N 1 N 2) NB4N/ 112> hR 1 2 HN (C) .>7< 12

RR

10 R RK R 10

R

1 1 R RR - Y YBOC Y R2 3 3 >N N R 3 2 R HN, C~ NDEC NI 1~12 12BO0 R1 RR2 1 0

R

1 1

R

1 IV TFA - Y - Y BOG Y'Y R H - y R N 32 33 1F N0 R 2

R

3 3 ~~1 R 1 R12/(N(~ 1 N<Cfl< 1 o R 9 0 R 10

R

1

R

2 H 0 Hy 0W WO 00/37459 PCTIUS99/27939 -47 RB B1 RA y-Y l VII BOC y ly R' CN R 3 2

R

33 rN N RR 3 rN ~ N6 N1111 N R Rio R 20 J RRio R H 0 R 1 ~N 00 VII= R =C=0 TMA for R H B RP, ey TFA 11 H y ly RA N

R

3 2 \R N R2012 syTFA I H N7Y R R d N + KN N STEA c RP 2 N 'y ( Ri Rll R 12 R 01 NNJ 1 R 9 WO 00/37459 PCTIUS99/27939 - 48 RB oy TFA -k y H - y RA

R

3 N\-

R

3

\

3 >N + I I1D R 1

R'

1

R

1 Cl H 0 RTEA j~ /R R R y RA (VII N R 3 2 \ /R I R 9 Rio'

)<

12 B ci R (VIII) + R ON=C=O- R y l for R 2 0 0 H N R 32 \/RM N N2)~ Rio R 0 R12 WO 00/37459 PCT/US99/27939 - 49 R R 3 R2 1R4 y

NR

3 2

R

3 3 r0N 2CI (VIII) N N + TEA N N 0 O Rg, R .S0 2 0 20 R C(O)C1

R

2 0

CH

2 C(O)C1 + + TEA R 2 0 0C(O)C1 TEA or or R20o H or R20CH2C(O)O H

R

20 C(O)OH (R 2 0 0C(O)) 2 0R + + DEC TEA DEC LII I}, I v . N N N N N- N N, N N R2- OO R2o 0 R2 ,, 0 0 Reactants V and VI are: BOC I N BOC V =N N 0 VI = N " H O CO 2 H 0

BOC

WO 00/37459 PCT/US99/27939 - 50 Reaction Scheme 5 R"

S

Y R R 3 Y-Y cR

R

32 \ R 3 3 a\N bia l\/ N/+ HN-- (xC~ N /n/ + R 2 12%

R

R

10C .R RR OH DEC HOBT R 3 0 0 R R1 " -- R3 RB

R

2 R4 yY RA, N R32 R3 \ R R 3 7aa Y' ( ) N " ( R N R 32

R

33 (/ NN 'X R I OC ) R 1 <7 RB HO * y F a (IX TA P-R N R4R 32 y yR 33 RN (X) N - N (~-.,N / NN ";RlR Rl 1

R

1 H 0 *yTFA WO 00/37459 PCT/US99/27939 - 51 R 2 0 H R 2 0 H N R 2 0

SO

2 Cl R 2 0 N=C=0 N N N + TEA (X) + TEA N 1 0 R2%)o R202S2O RIN O "

"

0 R20CH 2 C(O)C1 R20C(O)C1 R2OC(O)C1 + TEA + TEA or or or (R200C())20 R2CH 2 C(O)OH R2C(O)OH + TEA +DEC + DEC N N N N N N N N 0 I f R O..s " .& 0 o R20 O0 R20~O O R20 Ok In Scheme 5, R 30 represents: Cc H 3 I H3 - or O o 5 Reaction Scheme 6 - n is 0

R

1 1

R

12 RA R 1 1

R

12 A H2N- C + HN / (n-Bu) 4 NS0 4 H2N N R

R

9

R

1 0 HC1 \--N NaOH R 9 i N (X I) In Scheme 6, the procedure set forth in Scheme 4 is followed, but using H2>~N ~ (XI) SR1 R12 H2 N .. R N 10 instead of RA R

R

3 2

R

3 3 / N H2N (C)n- N 1 / R9R1o R 12 R

R

9

R

10

R

1

R

WO 00/37459 PCT/US99/27939 - 52 to obtain the corresponding urea (-C(O)NHR 2 0 ), amide

(-C(O)CH

2

R

2 0 or -C(O)R 2 0 ), sulfonamide (-SO 2

R

20 ) or carbamate

(-C(O)OR

°

) products, wherein n is 0, can be prepared. Similarly, using RB Y I Y

YR

1 1 R 12 HN NK RA 5 N (obtained from XI following the procedures in Scheme 4), instead of RB -Y II 'Y RA

R

3 2

R

3 3 \/ I\ N CN HNR ( C ) n R12

R

9

R

10

R

1 1

R

12 in Scheme 4 and 5 produces the corresponding ureas, amides, sulfonamides and carbamates wherein n is 0. 10 Those skilled in the art will appreciate that in Schemes 1, 2 and 4-6, other aldehydes can be used in place of H Ij y -' Y RY H 0 to obtain the other substituents for R 8 in formula 1.0. Those skilled in the art will also appreciate that using

R

19 RA

R

3 2

R

3 3 N A N

H

2 %<I C n ) 15

R

9

R

10 R R 1 2 instead of WO 00/37459 PCT/US99/27939 - 53 RA

R

3 2

R

3 3 \/ l/ N RHR 10

R

1 1

R

1 2 in Schemes 4 and 5, and using

R

1 1 R12

R

19

H

2 N N R10 1 > R RA instead of R" R 12 RA R1O H2NRA 5 N in Scheme 6 will provide the corresponding compounds wherein the imidazole is bound to the alkyl chain by a ring carbon. Reaction Scheme 7 (R 9 and R l 0 Are Other Than H)

R

A RI R 12 pyr.-S0 3 RA R 11 R12HO pN-OH o DMSO (.. 10 N (33.0) N A R" R 12

R

9 MgX R 11

R

12

R

9 RA / CHO 0- RA NOH N N O \N J N -J In Scheme 7, the alcohol 33.0 can be oxidized under standard conditions to give the aldehyde. Addition of the corresponding Grignard of R 9 gives the alcohol which can be carried on to amine as 15 in Scheme 1 or subject to reoxidation to the ketone followed by Grignard addition of R l o. In the case where R 9

=R'

O

, the ester 32.0 (Scheme 1) can be used as the electrophile with 2 equivalents of the appropriate Grignard reagent being added.

WO 00/37459 PCT/US99/27939 -54 Reaction Scheme 8 (R 9 and R' 0 Are Other Than H, C-Linked Imidazole) R11 R12

R

11 R12 ~~~DIBAL-H -CH Tr-N CN DIBAL-H Tr -NN CHO \N N R'- RA

R

1 1

R

12

R

1 1

R

12 Tr N CHO

R

9 MgX OH \TN r- N

R

9 RA RA 5 In Scheme 8, the nitrile may be reduced with DIBAL-H to the aldehyde. Similar to the procedure in Scheme 7, the aldehyde can then be treated with the appropriate Grignard reagent to give the alcohol. There can be an additional round of oxidation and Grignard addition to give the R 9 , R' 0 disubstituted derivatives with 10 either R 9 = R 1 0 or R 9 * R'o. The resulting alcohol may be converted to the amine by the methodology shown in either Schemes 1 or 2. Compounds useful in this invention are exemplified by the following examples, which examples should not be construed as 15 limiting the scope of the disclosure. PREPARATIVE EXAMPLE 1 Me Me N NH 2 N2 Step A Me Me N

CO

2 Et 20 N Ethyl 2,2-dimethyl acrylate (50.0g, 2.0 eq.) was stirred with imidazole (13.28g, 200 mmol) at 900 C for 48 hours. The resulting WO 00/37459 PCT/US99/27939 - 55 solution was cooled, diluted with water (150 mL) and CH 2 C1 2 (150 mL) and separated. The aqueous layer was washed with CH 2 C1 2 (2 x 75 mL) and the combined organics were dried over Na 2

SO

4 and concentrated in vacuo. The crude mixture was purified by flash 5 chromatography using a 10% MeOH in CH 2 C1 2 solution as eluent to give the pure product as a clear oil (11.27g, 29% yield). CIMS: MH'= 197. Step B Me Me Me Me / N C2Et N OH 10 N N A solution of the title compound from Step A (10.Og, 50.96 mmol) was treated with LiA1H 4 (51 mL, LM solution in ether, 1.0 eq.). The reaction mixture was stirred one hour at room temperature before quenching by the dropwise addition of 15 saturated Na 2

SO

4 (-3.0 mL). The resulting slurry was dried with Na 2

SO

4 (solid), diluted with EtOAc (100 mL) and filtered through a plug of Celite. The filtrate was concentrated to give a yellow oil (6.87, 87% yield) which was used without further purification. CIMS: MH'= 155. 20 Step C Me Me Me Me 0 N e OH - ( N eN To a solution of the title compound Step B (6.85g, 44.42 mmol), phthalimide (7.19g, 1.1 eq.), and Ph 3 P (12.82g, 1.1 eq.) in 25 THF (200 mL) at 0OC was added DEAD (7.69 mL, 1.1 eq.) over 10 minutes. The resulting solution was warmed to room temperature and stirred 48 hours. The reaction mixture was concentrated under WO 00/37459 PCT/US99/27939 - 56 reduced pressure and the product isolated by crystallization from

CH

2 C1 2 /Et 2 0 to give a white solid (10.03 g, 79% yield). CIMS: MH'= 284 5 Step D Me Me 0 Me Me N 03 / N

NH

2 N N A solution of the title compound from Step C (9.50g, 33.53 mmol) and N 2

H

4 (1.25 mL, 1.2 eq.) in EtOH (100 mL) was heated at reflux 4 hours. The resulting slurry was cooled, filtered, and the 10 filtrate concentrated under reduced pressure. The crude product was purified by flash chromatography using a 15% (10% NH 4 0H in MeOH) solution in CH 2 C1 2 as eluent to give a pale yellow oil (2.80g, 53% yield). LCMS: MH'= 154 15 PREPARATIVE EXAMPLES 2-4 By essentially the same procedure as that set forth in Example 1, the amines in Column 3 of Table 1 were synthesized from the esters in Column 2. "No." represents "Preparative Example Number". 20 TABLE 1 No. ESTER AMINE Mass Spec 2 C02Et N NH2 CIMS: NMH'= 152 WO 00/37459 PCT/US99/27939 - 57 C1 N N MH = 236

CO

2 Et NHM- 2 Me Me 4 Me MH = 168 Mej- CO 2 Et NH 2 N PREPARATIVE EXAMPLE 5 BOC Me Me N NH 2 + N N ..- 0 0 O BOC N O~ Me Me H N N ON MN H 5 Piperazine anhydride (Preparative Example 44) (0.28g, 1.0 eq.) was added portionwise to a solution of the title compound from Example 1 (0.17g, 1.2 mmol) in CH 2 C2 (5.0 mL) and the resulting solution stirred 10 minutes at room temperature before adding cyclohexyl isocyanate (0.21 mL, 1.5 eq.). After stirring at room 10 temperature 15 minutes, the reaction mixture was quenched by the addition of MeOH (1 mL), concentrated in vacuo, and purified by flash chromatography using a 10% MeOH in CH 2 C1 2 solution as eluent to yield a white solid (0.46g, 85% yield). FABMS: MH'= 491.

WO 00/37459 PCT/US99/27939 - 58 PREPARATIVE EXAMPLE 6 Me Me BO BOC N

NH

2 NH N BOC a NN N N O Mee ~0 By the essentially the same procedure as that set forth in Preparative Example 5, except using = N-(benzyloxycarbonyloxy) 5 succinimide (CBZ-OSuc) instead of cyclohexyl isocyanate, the title compound was prepared (0.16g, 84% yield). PREPARATIVE EXAMPLE 6.1 By essentially the same procedure as set forth in Preparative 10 Example 6, except instead of the amine Me Me N

NH

2 N use the amine from Preparative Example 2 N .NH2 N to obtain BOC I N - HN ,N~ 15 QroO WO 00/37459 PCT/US99/27939 - 59 PREPARATIVE EXAMPLE 7 BOC N H N N tO / H Cl By essentially the same procedure as that set forth in Preparative Example 5, except using the title compound from 5 Preparative Example 3 (Table 1), the title compound was prepared. LCMS: MH'= 573. PREPARATIVE EXAMPLE 7.1 BOC I N HN N O.,N H 10 Follow the same procedure as that set forth in Preparative Example 5, except use the amine from Preparative Example 2 to obtain the title compound. PREPARATIVE EXAMPLE 7.2 BOC N NN H N N ., / N N O H 3 C CH 3 15 H WO 00/37459 PCT/US99/27939 - 60 Follow the same procedure as that set forth in Preparative Example 5, except use the amine from Preparative Example 4 to obtain the title compound. 5 PREPARATIVE EXAMPLE 7.3 BOC I N . H f\N N OO11N 3*- N N O 1 O CH 3 H Follow the same procedure as that set forth in Preparative Example 5, except use the amine from Preparative Example 10 to obtain the title compound. 10 PREPARATIVE EXAMPLE 8 Step A BOC Me Me N NH2 H N N H IH 0 Mee To the title compound from Preparative Example 1, Step D, 15 (0.82g, 5.35 mmol) in CH 2 C1 2 (10 mL) and TEA (0.75 mL, 1.0 eq) was added piperazine anhydride (1.65g, 1.2 eq.) (prepared as described in Preparative Example 44) portionwise and the resulting solution was stirred at room temperature. When the reaction was complete (TLC), the solution was concentrated in vacuo and the crude 20 product was purified by flash chromatography using a 10% (10%

NH

4 OH in MeOH) in CH 2 C1 2 then 20% (10% NH 4 OH in MeOH) in

CH

2

C

2 as eluent. CIMS: MH'= 366.

WO 00/37459 PCT/US99/27939 -61 Step B BOC H N N *y TFA H N H HN N N ., N O Me Me O MeMe 0e0 me The title compound from Step A was stirred at room temperature in a 50% solution of TFA in CH 2 C1 2 (25 mL) for 2 hours. 5 The resulting solution was concentrated under reduced pressure. Any residual TFA was removed by azeotroping with toluene to give the crude product which was used without further purification. CIMS: MH+= 266. 10 Step C H N *y TFA N H N -N NM 0 Me Me Br-/ Cl N N , HN HN, N N H 0 Me Me The title compound from Step B was dissolved in CH 2 C1 2 (30 mL) and TEA (7.62 mL, 10 eq.) was added. The reaction mixture was stirred 5 minutes before adding chloride Br / Cl N Cl 15 (42.0) WO 00/37459 PCT/US99/27939 - 62 (0.908g, 0.5 eq.). The resulting solution was stirred at room temperature for 96 hours. The reaction mixture was diluted with water (50 mL), separated and the aqueous layer extracted with

CH

2 C12 (2 x 200 mL). The combined organics were dried over 5 MgSO 4 , filtered, and concentrated under reduced pressure. The crude product was purified by flash chromatography using a 5%, 7.5%, and then 10% (10% NH 4 OH in MeOH) in CH 2 C1 2 solution as eluent (0.926 g, 30% yield). CIMS: MH'= 571. 10 Step D Br Cl N N H NN..

N (11R,2R(-)-Isomer) H . O Me Me Br /Cl tN H N (11S,2R(-)-Isomer) The title compound from Step C was separated into individual 15 diasteromers by Preparative HPLC using a ChiralPak AD column using a 20% IPA in hexanes with 0.2% diethylamine solution as eluent: Isomer A (11S,2R(-)-Isomer): retention time= 18.2 minutes; [a]20D= -31.7 (3.0 mg in 2.0 mL MeOH). 20 Isomer B (11R,2R(-)-Isomer): retention time= 30.3 minutes; [a]20D= -6.2 (2.4 mg in 2.0 mL MeOH).

WO 00/37459 PCT/US99/27939 - 63 PREPARATIVE EXAMPLE 9 < 0 N N H .., N O By essentially the same procedure as described in Preparative Example 8, except using the title compound from Preparative 5 Example 2 (Table 1), the title compound was prepared. The 11(S)- and 11(R)-isomers Br_ Cl N , HN (11 S,2R(-)-Isomer) H , N N1 NN O 0 0 Br_ Cl N (N H N% (11R,2R(-) -Isomer) 10 were separated by Preparative HPLC using a CHIRALPAK AD column using a 30% IPA in hexanes containing 0.2% diethylamine solution as eluent. 11S,2R(-)-isomer : retention time= 10.2 minutes; MH'= 569; [M ]20D= -32.7 (4.04 mg in 2.OmL MeOH).

WO 00/37459 PCT/US99/27939 -64 11R,2R(-)-isomer: retention time= 22.8 minutes; MH'=569; [oc]20D= -1.2 (3.40 mg in 2.0 mL MeOH). PREPARATIVE EXAMPLE 9.1 5 Follow the procedure set forth in Preparative Example 8, except use the amine H 2 N N -. N in Step A instead of F \N

H

2 N N-

H

3 C CH 3 10 and use the 10-C1 tricycle chloride N Cl C1 in Step C instead of the 3-Br-8-Cl-tricycle chloride (Compound 42.0) to obtain the compounds S(11S,2R-Isomer) H (N H ;,~ N N o0 and (11R,2R-Isomer) C HN 15io 5N 0 15 H o WO 00/37459 PCT/US99/27939 - 65 Obtain the 10-Cl tricycle chloride (10,11- diChloro-6,11 dihydro-5H-benzo[5,6]cyclohepta[1,2-B]pyridine) as follows: / \NaBH4 /SOCI, N N N 0 Cl OH Cl CI Cl The ketone (starting material) 5,6-dihydro- 10-Chloro- 11H 5 benzo[5,6]cyclohepta[ 1,2-c]pyridine- 11-one, can be prepared following the procedure described by Villani et al., J. Het. Chem. 8, 73-81 (1971). The product was prepared substituting the 10-Chloro for the 10H tricycle and following the procedure described in Preparative Example 169. 10 1H NMR (CDC1 38) 2.97 (m, 2H), 3.55 (m, 1H), 4.03 (m, 1H), 7.11 (s,1H), 7.13 (d, 1H), 7.22 (m, 2H), 7.31 (d, 1H), 7.53 (d, 1H), 8.49 (d, 1H). PREPARATIVE EXAMPLE 10 15 Step A N NC Me Imidazole (2.73g, 40.1 mmol) in crotonitrile (10 mL) was heated to reflux overnight. The resulting solution was concentrated in vacuo, the residue diluted with Et20 (50 mL) and washed with 20 water (2 X 100 mL) and brine (1 X 25 mL). The combined organics were dried over Na 2

SO

4 and concentrated under reduced pressure. The crude product was purified by flash chromatography using a 15% MeOH in CH 2 C1 2 solution as eluent (2.13g, 39% yield). FABMS: MH'= 136. 25 WO 00/37459 PCT/US99/27939 - 66 Step B N N O,\ \N-"' NH 2 CN N @2 Me Me A solution of the title compound from Step A (0.50 g, 0.0037 mmol) in THF (10 mL) was treated with LAH (5.5 mL, 1.0 M in 5 Et 2 0, 1.1 eq.). The reaction mixture was stirred at room temperature 3 hours and quenched by the dropwise addition of saturated Na2SO 4 . The resulting slurry was dried by the addition of solid Na 2

SO

4 and filtered through a plug of Celite. The filtrate was concentrated under reduced pressure and the crude residue 10 purified by flash chromatography using a 20% (10% NH 4 OH in MeOH) solution as eluent (0.03g, 6% yield). PREPARATIVE EXAMPLE 11 StepA Me Me Tr -NN TCN -- CN 15 N nBuLi (2.5 mL; 2.5M in hexanes; 2.1 eq.) was added to iPr 2 NH (0.87 mL, 2.1 eq.) in THF (8.0 mL) at 0OC. The resulting solution was stirred 45 minutes before adding the nitrile (1.Og, 2.97 mmol) in THF (7.0 mL). The reaction mixture was stirred at 0OC for 30 20 minutes before adding Mel (0.37 mL, 2.0 eq.). The resulting solution was warmed to room temperature and stirred one hour. The reaction was quenched by the addition of IN HCI until acidic, diluted with water (40 mL) and extracted with EtOAc (2 X 200 mL). The combined organics were dried over Na 2

SO

4 and concentrated 25 under reduced pressure. The crude product was purified by flash chromatography using a 40% EtOAc solution in hexanes as eluent (0.37 g, 33% yield). MH'= 378.

WO 00/37459 PCT/US99/27939 - 67 Step B Me Me Me Me Tr-N / x CN Tr -N NH 2 -N \ N LiA1H 4 (2.7 mL; 1.0 M solution in THF; 1.5 eq.) was added to the title compound from Step A (0.68g, 1.80 mmol) in THF (5.0 mL). 5 The resulting solution was stirred at room temperature 1.5 hours and quenched by the dropwise addition of saturated Na2SO 4 (10 mL). The solution was extracted with Et 2 0 (2 X 200 mL), the combined organics dried over MgSO 4 and concentrated under reduced pressure (0.6 g, 88% yield). 10 Step C Me Me HMe Me H Tr-N NH 2 _ __ H 2 N N following the same procedure as set forth in Preparative Example 27 Step C, the title compound was prepared. 15 PREPARATIVE EXAMPLE 12 BOC BOC I I N N OH H N N I I BOC O BOC O H O NH2 A solution of the piperazine carboxylic acid (0.29 g, 0.881 mmol) prepared as described in Preparative Example 43, L 20 histidinamide dihydrochloride (0.20 g, 1.0 eq.), DEC (0.25 g, 1.5 eq.), HOBT (0.18 g, 1.5 eq.), and NMM (0.48 mL, 1.5 eq.) in DMF (5 mL) was stirred at room temperature overnight. The reaction mixture was diluted with water (25 mL) and CH 2 C12 (50 mL), WO 00/37459 PCT/US99/27939 - 68 separated, and the aqueous layer extracted with CH 2 C12 (2 X 50 mL). The combined organics were dried over Na 2

SO

4 and concentrated under reduced pressure. The crude product was purified by flash chromatography using a 15% MeOH in CH 2 C1 2 solution as eluent 5 (0.24g, 59% yield). FABMS: MH'= 467. PREPARATIVE EXAMPLES 13-17 Following the procedures found in J. Chem. Soc. Perkin I (1979), 1341-1344, the following N-substituted histamines were 10 prepared:

CH

3

H

3 C CH 3 r

CH

3 H2N A N H 2 N NH 2 NN N N N Preparative Preparative Preparative Example 13 Example 14 Example 15

CH

3

CH

3

H

2 N N

H

2 N N N N Preparative Preparative Example 16 and Example 17 15 PREPARATIVE EXAMPLES 18-26 By essentially the same procedure as that set forth in Preparative Example 74, and using the aldehydes and amines set forth in Table 2, one can obtain the intermediate products shown in Table 2. 20 WO 00/37459 PCT/US99/27939 - 69 TABLE 2 Prep Aldehyde Amine Product Ex. 18 CHO H

H

2 H N H N> 19 CHO H2 3 H3

H

2 N___ H 3 20 H 3 C

CH

3 CH3

H

3 C CHO H2 CH 3

H

3 C

CH

3

CH

3 HNN 21 H 3 C CH 3 CH 3 H CHO 2 CH CH3

H

3 C

H

2 / H H 3 N HN 22 H 3 C H OH 3 H C CHO H 2 CH H HN

N

WO 00/37459 PCT/US99/27939 - 70 23 CHO H 3 H2 NNN H 3 CHH 24 CHO H2 H--r HH 24 H r 25 CH3

H

2 N CH3 26 CHOH

H

2 HH HN H N H K N PREPARATIVE EXAMPLE 27 Step A CH3 C H 3 NHNN (in cyclohexane). Then add dropwise over 2 hr, a solution of 790 g NC NC NC ), h__ N 5 Ph PhPh Dissolve the nitrile (1 .5 g, 4.29 mmol) in 10 mL of THE and cool to -78'C under nitrogen. Add 20 mL of a 1.5 M LDA solution (in cyclohexane). Then add dropwise over 2 hr, a solution of 790 mg (4.293 mmol) of 2-methylpropyliodide in 10 mL of THF. Allow to 10 warm to room temperature and stir overnight. Add 10 mL of water WO 00/37459 PCT/US99/27939 -71 followed by 1 N HC1 until pH of 10-11. Dilute with 100 mL of methylene chloride followed by 20 mL of sat. aqueous Na 2

SO

4 . Add MgSO 4 until solution is clear. Separate the organic layer and dry over MgSO 4 . Concentrate under vacuum and flash chromatograph 5 on silica gel using ethyl acetate-hexane (1-3) to give the product as a tan semi-solid. Step B

CH

3

CH

3

CH

3

CH

3 N H2NN NC \ NP h N Ph Ph Ph 10 Dissolve the product of Step A (0.5 g, 1.23 mmol) in 10 mL of ethanol saturated with ammonia. Add 8.8 mg (0.017 mmol) of

H

2 PtCl 6 .6H 2 0, 1 g of Raney Ni in water and hydrogenate at 54 psi on a Parr shaker over night. Filter through Celite and concentrate under vacuum. 15 Step C

CH

3

CH

3

CH

3

CH

3 H

H

2 N_ N_ H 2 N N N Ph N Ph Ph Dissolve the product of Step B (0.165 g, 0.403 mmol) in 4 mL of 2M HC1 and 2 mL of methanol. Reflux for 100 min. then 20 concentrate under vacuum. Triturate the residue with ether to give the product hydrochloride as a white solid.

WO 00/37459 PCT/US99/27939 - 72 PREPARATIVE EXAMPLES 28-29, 29.1 and 30 Following the procedure set forth in Preparative Example 27, but using the indicated alkyl or benzyl halide in place of 2-methyl propyl iodide, the substituted histamines shown were prepared. Preparative Example 28 CH 3 H~~3I H2H

H

2 N N Halide N 5 Substituted Histamine Preparative Example 29 Br H

H

2 N Halide N Substituted Histamine Preparative Example 29.1 H

H

2 N N Halide Substituted Histamine 10 Preparative Example 30 CH 3 I jH

H

2 N H Halide N Substituted Histamine WO 00/37459 PCT/US99/27939 - 73 PREPARATIVE EXAMPLE 31 O O O -'CH3O

CH

3 N N H Ethyl 4-pyridyl acetate (4.5g, 2 7.24mmoles) was placed in a 500mL Parr bottle and dissolved in anhydrous EtOH (70mL). To the 5 bottle was added 10% Palladium on charcoal (1.0Og). The bottle was put on a hydrogenator and the contents shaken under 55 psi hydrogen pressure at 25 0 C for 94h. The mixture was filtered through Celite® and washed with 4x40mL anhydrous EtOH. The filtrate was rotovapped down and the residue chromatographed on 10 silica gel using 3% (10% cone. NH40H in methanol)dichloromethane as the eluant to give the title compound (Yield: 2.944g, 63%): FABMS: m/z 172.2(MH+); 8c (CDCl 3 ) CH 3 : 14.3; CH 2 : 33.2, 33.2, 41.9, 46.5, 46.5 60.2; CH: 33.4; C: 172.7; 8H (CDC1 3 ) 1.18 (m,1 IH,H 4 ), 1.26 (t,3H,CH 3 ), 1.71(2H), 1.90(1H), 1.96(1H), 15 2.22(d,2H), 2.63(2H), 3.07(2H), 4.13(q,2H,CHCQH2-). PREPARATIVE EXAMPLE 32 o 0 O CH 3 O CH 3 N N HI O NH2 Ethyl 4-piperidinyl acetate from Preparative Example 31 20 (500mg; 2.92mmoles) was dissolved in anhydrous CH 2 C1 2 (25mL). To the stirring solution was added trimethylsilyl isocyanate (5.9mL; 4 3 .8mmoles) and the solution was stirred at 25 0 C for 17h. The WO 00/37459 PCT/US99/27939 -74 solution was worked up in CH 2 C1 2 -saturated NaHCO 3 and the product chromatographed on silica gel using 2--3%(conc. NH4OH in methanol)dichloro-methane as the eluant to give the title compound (Yield: 622mg, 99%): CIMS: m/z 215.3 (MH'); 8 c (CDC13): CH 3 : 14.2; 5 CH 2 : 31.6, 31.6, 41.0, 44.2, 44.2, 60.4; CH: 32.9; C: 158.2, 172.4; 5H (CDC1,): 1.23 (m, 1H,H 4 ), 1.27 (t,3H,CH 3 ), 1.75 (d,2H), 1.98 (m, 1H), 2.26 (d,2H), 2.85 (t,2H), 3.94 (d, 2H), 4.15 (q,2H,CHCH 2 -), 4.56 (bs,2H). 10 PREPARATIVE EXAMPLE 33 O 0 0 CH 3 OH N N 0 NH 2 O NH 2 Ethyl 1-aminocarbonyl-4-piperidinyl acetate from Preparative Example 32 (153.6mg, 0.717mmoles) was dissolved in anhydrous

CH

2 C12 (3.58mL) and EtOH (3.58mL). To the solution was added 15 LOM LiOH (1.73mL, 1.73mmoles) and the mixture was stirred at 50oC for 5.5h. The mixture was cooled quickly to 25oC and 1.0N HC1 (2.02mL, 2.02mmoles) was added and the mixture stirred for 5 minutes and then rotovapped to dryness to give the title compound which was used without further purification. 20 WO 00/37459 PCT/US99/27939 - 75 PREPARATIVE EXAMPLE 34 Br / Cl N N N H 0 Br__\ Cl N N H N (1 1R,2R(-)-Isomer) N ~,,NN H II 0 The C 1 l-racemate of the above isomers (Preparative Example 5 141) (62% pure) was subjected to preparative HPLC on a Chiralpak AD® column (50X5cm) using 75% hexane- 25% isopropyl alcohol 0.2% diethylamine as the eluant to give, in the order of elution, the 11-S(-)-isomer and the 11-R(-)-isomer. 11S,2R(-)-isomer: (Yield: 0.8756g, 55%): LCMS: m/z 543.1 10 (MH'); Sc (CDCl 3 ) CH 2 : 30.3, 30.4, 31.0, 36.3, 44.3, 44.7, 52.0, 54.5; CH: 58.7, 79.4, 118.8, 126.0, 129.6, 130.4, 132.3, 137.1, 141.3, 147.0; C: 120.0, 134.0, 135.4, 136.7, 140.9, 155.4, 172.2; 5H (CDC13) 2.02 (2H, m, 2"-CH 2 ), 3.32 (2H, m, 3"-CH 2 ), 3.98 (2H, dd, 1"

CH

2 ), 4.30 (1H, s, H, 1 ), 6.93 (1H, s, Im-H), 6.97 (1H, t, CONHCH 2 ), 15 7.06 (1H, s, Im-H 4 ), 7.11 (1H, s, Ar-H), 7.13 (2H, s, Ar-H), 7.16 (1H, s, Ar-H), 7.49 (1H, s, Ar-Ho), 7.57 (1H, d, Im-H 2 ) and 8.33 ppm (1H, s, Ar-H 2 ); [a]D20C -45.00 (MeOH, c=9.32mg/2mL). 11R,2R(-)-isomer: (Yield: 0.5979g, 38%): LCMS: m/z 543.1 (MH'); 8, (CDCl1 3 ) CH 2 : 30.2, 30.3, 31.1, 36.4, 44.1, 44.7, 52.2, 54.0; 20 CH: 58.2, 79.4, 118.8, 126.1, 129.6, 130.7, 132.3, 137.0, 141.2, 146.8; C: 119.9, 134.0, 135.2, 136.9, 140.7, 155.7, 172.1; 8H WO 00/37459 PCT/US99/27939 - 76 (CDC13) 3.34 (2H, m, 3"-CH 2 ), 3.97 (2H, dd, 1"-CH2), 4.30 (1H, s, H,,), 6.93 (1H, s, Im-H,), 7.06 (1H, s, Im-H 4 ), 7.08 (1H, s, Ar-H), 7.11 (2H, s, Ar-H), 7.14 (1H, s, Ar-H), 7.15 (1H, t, CONHCH 2 ), 7.50 (1H, s, Ar-Ho

)

, 7.58 (1H, d, Im-H 2 ) and 8.35 ppm (1H, s, Ar-H 2 ); [aD 2 3

.

5 ,c 5 12.0 ° (MeOH, c=10.19mg/2mL). PREPARATIVE EXAMPLE 35 Step A O0 OH 0 OH N N H | Boc 10 Isonipecotic acid (10g, 77.42mmoles) and sodium hydroxide (3.097g, 77.42mmoles) were dissolved in THF-water (1:1) (230mL) and di-t-butyldicarbonate (18.59mL, 85.17mmoles) was added. The solution was stirred at 25 0 C for 90h. The mixture was treated with BioRad® 50W-X4(H') ion exchange resin (86.6mL) and the resin was 15 filtered off and washed with THF and then water. The combined filtrates were evaporated to dryness to give the title compound which was used without further purification in the next step: FABMS: m/z 229.9 (MH'); 5 c (d 6 -DMSO) CH 3 : 28.0, 28.0, 28.0; CH2: 42.0-43.1(broad signal); CH: obscured; C: 78.5, 153.8, 175.6. 20 Step B 0 OH 0 N 3 N N I I Boc Boc The title compound from Step A above (2g, 8.72mmoles) was dissolved in dry DMF (40mL) and the solution was stirred at 0OC WO 00/37459 PCT/US99/27939 - 77 under an argon atmosphere. Diphenylphosphoryl azide (2.07mL, 9.59mmoles) was added over 10min followed by triethylamine (2.68mL, 9.59mmoles) and the mixture was stirred at 0 0 C for lh and then at 25oC for 19h. Evaporation to dryness followed by 5 chromatography on a silica gel column using 5% increasing to 7% methanol in dichloromethane afforded the title compound: (Yield: 1.57g, 72%): 8 c (CDC1 3 ) CH 3 : 28.5, 28.5, 28.5; CH 2 : 32.9 (broad), 42.8 (broad); CH: 47.3; C: 79.7, 154.8, 156.5. 10 PREPARATIVE EXAMPLE 36 Step A OH OH N N HL

H

2 N 0O Method 1: 4-Hydroxypiperidine (5g, 49.43mmoles) was dissolved in 15 anhydrous dichloromethane (50mL) and trimethylsilyl isocyanate (6.27g, 7.36mL, 54.38mmoles) was added. The mixture was stirred at 25oC under an argon atmosphere for 24h. Water (10mL) was added and the mixture was evaporated to dryness. The residue was chromatographed on a silica gel column using 10%(10% cone. 20 NH40H in methanol)-dichloromethane as the eluent to give the title compound: (Yield: 6.895g, 97%): CIMS: m/z 145.1 (MH'); 8 c (d 6 DMSO) CH 2 : 34.2, 34.2, 41.3, 41.3; CH: 66.1; C: 158.0; 8H (d 6 DMSO) 1.22 (2H, m, 3/5-CH 2 ), 1.68 (2H, m, 3/5-CH 2 ), 2.84 (2H, m, 2/6-CH 2 ), 3.60 (1H, m, 4-CH), 3.68 (2H, m, 2/6-CH 2 ), 4.67 (1H, d, 25 OH) and 5.87ppm (2H, s, NH 2

).

WO 00/37459 PCT/US99/27939 - 78 Method 2: 4-Hydroxypiperidine (10g, 98.86mmoles) and urea (59.4g, 988.6mmoles) were dissolved in distilled water (100mL) and the solution was heated at 100 0 C for 67h. The solution was evaporated 5 to dryness and the product was chromatographed on a silica gel column using 10%(10% conc. NH 4 OH in methanol)-dichloromethane as the eluent to give the title compound: (Yield: 8.3g, 58%). Step B 0 OH O < O N N 10 H 2 N O

H

2 N 0 The title compound from Step A above (1g, 6.94mmoles) and 4-nitrophenyl chloroformate (1.54g, 7.63mmoles) were dissolved in anhydrous pyridine (10mL) and the mixture was stirred at 25 0 C for 24h. The mixture was evaporated to dryness and the residue was 15 azeotroped with toluene. The resulting product was chromatographed on a silica gel column using 3% methanol in dichloromethane as the eluant to give the title compound: (1.35g, 63%): CIMS: m/z 310.05 (MH'); 8 c (CDC1) CH 2 : 29.9, 29.9, 40.7, 40.7; CH: 74.9, 121.7, 121.7, 125.2, 125.2; C: 145.2, 151.7, 155.3, 20 158.7; 8H (CDC13) 1.82 (2H, m, 3/5-CH 2 ), 2.01 (2H, m, 3/5-CH 2 ,), 3.06 (2H, s, NH 2 ), 3.31 (2H, m, 2/6-CH 2 ), 3.68 (2H, m, 2/6-CH 2 ), 4.98 (1H, m, 4-CH), 7.39 (2H, d, Ar-H1/6) and 8.28ppm (2H, d, Ar H3/5).

WO 00/37459 PCT/US99/27939 - 79 PREPARATIVE EXAMPLE 37 Step A Boc Boc I I N N H 0 0 The anhydride (0.5088g, 1.99mmoles) (prepared as described 5 in Preparative Example 44) and 1-(3-aminopropyl)-imidazole (0.260mL, 2.18mmoles) were dissolved in anhydrous dichloromethane (O10mL) and the mixture was stirred under argon at 25oC for 5main. The mixture was diluted with dichloromethane and extracted with saturated aqueous sodium bicarbonate. The 10 dichloromethane layer was dried (MgSO 4 ), filtered and evaporated to dryness. The resulting product was chromatographed on a silica gel column using 10% (cone, NH4OH in methanol)-dichloromethane as the eluent to give the title compound: (Yield: 0.4955g, 74%); LCMS: m/z 338.1 (MH'); 8 c (CDC1 3 ) CH 3 : 28.4, 28.4, 28.4; CH 2 : 31.1, 36.5, 15 -43.5(broad), 44.8, -46.5(broad),; CH: 58.2, ~ 119.0(broad), -129.7(broad), ~137.3(broad); C: 80.2, 154.7, 171.5; 8H (CDC1 3 ) 1.47 (9H, s, CH 3 ), 6.96 (1H, s, Im-H), 7.08 (1H, s, Im-H 4 ) and 7.52ppm (1H, s, Im-H 2 ). 20 Step B Boc I N 1"' 00 The title compound from Step A above (0.3248g, 0.96mmoles), 4-pyridylacetic acid Nl-oxide (0.1916g, 1.25mmoles), 1[3 (dimethylamino)propyll]-3-ethylcarbodimide hydrochloride (0.24g, WO 00/37459 PCT/US99/27939 - 80 1.25mmoles), 1-hydroxybenzotriazole (0.169g, 1.25mmoles) and 4 methylmorpholine (0.1376mL, 1.25mmoles) were dissolved in anhydrous DMF (1 lmL) and the mixture was stirred under argon at 25oC for 18h. The mixture was evaporated to dryness and the 5 residue was dissolved in dichloromethane and washed with saturated aqueous sodium bicarbonate. The organic layer was dried (MgSO 4 ), filtered and evaporated to dryness. The product was chromatographed on a silica gel column using 5% (10% conc.

NH

4 OH in methanol)-dichloromethane as the eluant to give the title 10 compound: (Yield: 0.4333g, 95%); LCMS: m/z 473.1 (MH); 8c (CDCl 3 ) CH3: 28.3, 28.3, 28.3; CH 2 : 30.8, 36.5, 38.7, 43.2, -43.5 (broad), -44.5 (broad); CH: 53.8, -119.2 (broad), 127.4, 127.6, -129.3 (broad), -137.5 (broad), 138.7, 138.9; C: 80.7, 134.5, 154.4, 169.6, 169.6; SH (CDC1 3 ) 1.44 (9H, s, CH 3 ), 6.97 (1H, broad s, Im-H), 15 7.09 (1H, broad s, Im-H 4 ), 7.20 (2H, m, Ar-H), 7.53 (1H, broad s, Im

H

2 ) and 8.14ppm (2H, d, Ar-H). Step C H I N CN0 1 H K \N ON O N N C'- +"INN 0 20 The title compound from Step B above (0.289g, 0.612mmoles) was dissolved in anhydrous dichloromethane (7.8mL) and trifluoroacetic acid (2.026mL, 26.3mmoles) was added. The mixture was stirred at 25oC for 1.25h under argon and then evaporated to dryness. The product.was chromatographed on a silica gel column 25 using 5% increasing to 10% (10% cone. NH40H in methanol) dichloromethane as the eluant to give the title compound: (Yield: 0.208g, 91%); LCMS: m/z 373.1 (MH ); 8 c (CDC1 3 -CD30D) CH 2 : 30.4, 36.2, 38.2, 43.9, 44.5, 46.2, 46.7; CH: 52.3, ~-119.2 (broad), 127.7, WO 00/37459 PCT/US99/27939 -81 127.7, -128.3 (broad), 137.4 (broad), 138.4, 138.5, 138.5; C: 137.3, 169.8, 170.6; 8H (CDC1 3

-CD

3 OD) 6.90 (1H, broad s, Im-H), 6.94 (1H, broad s, Im-H 4 ), 7.22 (2H, m, Ar-H), 7.47 (1H, broad s, Im-H 2 ) and 8.12ppm (2H, d, Ar-H); [IC]D26.3*+81.1 0 (c=10.43mg/2mL, methanol). 5 PREPARATIVE EXAMPLE 38 Step A Br /\ cl Br /CI N N+ To a solution of 3-bromo-8-chloro-5,6-dihydro-11H 10 benzo[5,6]cyclohepta[1,2-b]pyridin-11-one (2g) (6.2mmoles) in anhydrous dichloromethane (14ml) at 0OC and under an argon atmosphere, was added a solution of 3 -chloroperbenzoic acid (1.76g) (10.4mmoles) in anhydrous dichloromethane (35ml) dropwise over a period of 30 minutes. The mixture was allowed to 15 warm to room temperature and after 18h additional 3-chloro perbenzoic acid (0.88g) (5.2mmoles) in anhydrous dichloro-methane (25ml) was added and the mixture was stirred for a total of 42h. The mixture was diluted with dichloromethane and washed with 1N NaOH (200ml). The aqueous layer was extracted with additional 20 dichloromethane (2X200ml) and the combined organic layers were dried over magnesium sulfate, filtered and evaporated to dryness. The product was chromatographed on silica gel using 0.25%-0.5% 1% (10% cone. NH4OH in methanol)dichloromethane as the eluant to give the title compound (Yield: 1.386g, 66%): ESIMS; m/z 338.1 25 (MH+); 8c (CDC13) CH2: 30.5, 34.0; CH: 126.9, 127.6, 130.3, 132.5, 140.4; C: 121.0, 135.1, 138.3, 139.7, 141.6, 145.3, 1 8 8 .Oppm.

WO 00/37459 PCT/US99/27939 - 82 Step B Br / C1 Br / Cl tN4 N4 NN+ I \ o oo- OH The title compound of Step A (1.3422g) (3.96mmoles) was dissolved in methanol (18ml) and dichloromethane (20ml) and 5 sodium borohydride (0.219g) (5.79mmoles) was added. The mixture was stirred under argon at 0OC for lh and then allowed to warm up to 25'C over a period of lh. The mixture was diluted with dichloromethane (800ml) and washed with IN NaOH (150ml). The aqueous layer was extracted with dichloromethane (2X100ml) and 10 the combined organic layers were dried over magnesium sulfate, filtered and evaporated to dryness. The product was chromatographed on silica gel using 1% (10% conc. NH40H in methanol)dichloro-methane as the eluant to give the title compound (Yield: 1.24g, 92%): ESIMS: m/z 340.1 (MH+); 8c (CDC13) CH2: 31.2, 15 32.0; CH: 69.1, 126.8, 129.5, 131.7, 131.7, 136.7; C: 118.3, 134.7, 135.2, 139.7, 141.0, 148.9ppm. Step C Br Cl N 11 -(±+),2R N 0 OH \N N N N H O 20 The title compound from Step B (0.552g, 1.62mmoles) and triethylamine (1.19mL, 8.52mmoles) were dissolved in anhydrous dichloromethane (8.5mL) and the solution was cooled to 0OC. Methanesulfonyl chloride (0.4mL, 5.16mmoles) was added over WO 00/37459 PCT/US99/27939 - 83 30min and the mixture was stirred at 0OC for a total of 1.25h. The solution was evaporated to dryness to give the 11-mesyl derivative which was used without further purification. The latter was dissolved in anhydrous dichloromethane (40mL) and the solution 5 was stirred at 0OC. N-[3-(1H-Imidazol-1-yl)propyl]-2(R) piperazinecarboxamide (Preparative Example 136) (0.5g, 2.1 1mmoles) dissolved in anhydrous dichloromethane (20mL) and anhydrous DMF (20mL) was added at O'C and the solution was stirred and allowed to warm up to 25oC over 2h. The reaction was 10 allowed to proceed at 250C for 18h and was then diluted with dichloromethane and washed with saturated aqueous sodium bicarbonate, dried (MgSO 4 ), filtered and evaporated to dryness. The product was chromatographed on a silica gel column using 4% (10% conc. NH 4 OH in methanol)-dichloro-methane as the eluant to 15 give the title racemic compound: Yield: 0.399g, 44%); FABMS: m/z 559.3 (MH+). Step D Br__ Cl N 0 H N (11R,2R(+)-Isomer) N 1 H 0 Br Cl N + S11-S(-) H O, H N N (11S,2R(-)-Isomer) 20N N H 20 0 WO 00/37459 PCT/US99/27939 - 84 The title racemic compound from Step C above (0.395g) was subjected to preparative HPLC on a Chiralpak AD® column (50X5cm) using 65% hexane- 35% isopropyl alcohol- 0.2% diethylamine as the eluant to give in the order of elution the 11 5 R(+)-diastereoisomer of the title compound followed by the 11-S(-) diastereoisomer of the title compound. 11 R,2R(+)-diastereoisomer: (Yield: 0.1854g); FABMS: m/z 559.2 (MH); 8 c (CDC1 3 ) CH 2 : 30.1, 30.3, 31.2, 36.4, 43.9, 44.7, 51.6, 52.8; CH: 57.8, 64.3, 118.9, 126.3, 129.6, 130.6, 130.7, 133.4, 10 137.3, 138.4; C: 118.2, 133.6, 134.6, 140.1, 141.0, 148.1, 172.0; 8H (CDCl 3 ) 5.70 (1H, s, HIl), 6.95 (1H, broad s, Im-H,), 7.04 (1H, broad s, Im-H 4 ), 7.51 (1H, broad s, Im-H 2 ) and 8 .22ppm (1H, s, Ar-H 2 ); [aiD2 +41.2o (c= 11.08mg/2mL, methanol). 11S,2R(-)-diastereoisomer: (Yield: 0.18g); FABMS: m/z 559.2 15 (MH); 8c (CDC13) CH 2 : 30.1, 30.3, 31.1, 36.5, 44.4, 44.8, 51.6, 53.4; CH: 58.9, 64.4, -119.2, 126.3, 129.5, 130.6, 130.7, 133.4, -137.3, 138.5; C: 118.3, 133.7, 134.6, 139.9, 141.0, 148.1, 172.1; 6H (CDC13) 5.69 (1H, s, HI), 6.94 (1H, broad s, Im-H), 7.07 (1H, broad s, Im-H 4 ), 7.51 (1H, broad s, Im-H 2 ) and 8.26ppm (1H, s, Ar-H 2 ); 20 [a]DI 9 9° -71.0o (c=10.32mg/2mL, methanol). PREPARATIVE EXAMPLE 39 Step A O O 0 CH 3 O CH 3

I-

N N H Ethyl 4-pyridyl acetate (4.5g, 2 7.24mmoles) was placed in a 25 500mL Parr bottle and dissolved in anhydrous EtOH (70mL). 10% Palladium on charcoal (1.Og) was added and the contents shaken under 55 psi hydrogen pressure at 25 0 C for 94h. The mixture was WO 00/37459 PCT/US99/27939 - 85 filtered through Celite® and washed with 4x40mL anhydrous EtOH. The filtrate was evaporated to dryness and the residue was chromatographed on silica gel using 3% (10% cone. NH 4 OH in methanol)-dichloromethane as the eluant to give the title 5 compound: (Yield: 2.944g, 63%): FABMS: m/z 172.2 (MH'); SC (CDCl 3 ) CH 3 : 14.3; CH 2 : 33.2, 33.2, 41.9, 46.5, 46.5 60.2; CH: 33.4; C: 172.7 ; SH (CDCl 3 ) 1.18 (1H, m, H 4 ), 1.26 (3H, t,CH 3 ), 1.71(2H), 1.90(1H), 1.96(1H), 2.22(2H, d), 2.63(2H), 3.07(2H), 4.13ppm (2H, q, CH CH 2 -). 10 Step B 0 0 0

CH

3 O CH 3 N N H O NH 2 Ethyl 4-piperidinyl acetate (500mg; 2.92mmoles) from Step A above was dissolved in anhydrous dichloromethane (25mL). To the 15 stirred solution was added trimethylsilyl isocyanate (5.9mL; 43.8mmoles) and the solution was stirred at 25 0 C for 17h. The solution was diluted with dichloromethane and washed with saturated aqueous sodium bicarbonate. The dichloromethane layer was dried (MgSO 4 ), filtered and evaporated to dryness. The product 20 was chromatographed on silica gel using 2% increasing to 3%(10% cone. NH 4 OH in methanol)-dichloromethane as the eluant to give the title compound: (Yield: 622mg, 99%): CIMS: m/z 215.3 (MH'); 8, (CDC13): CH 3 : 14.2; CH 2 : 31.6, 31.6, 41.0, 44.2, 44.2, 60.4; CH: 32.9; C: 158.2, 172.4; 8H (CDC1 3 ): 1.23 (1H, m, H 4 ), 1.27 (3H, t, CH 3 ), 25 1.75 (2H, d), 1.98 (1H, m), 2.26 (2H, d), 2.85 (2H, t), 3.94 (2H, d), 4.15 (2H, q, CHCH-), 4.56 (2H, bs).

WO 00/37459 PCT/US99/27939 - 86 Step C 0 CH 3 OH N N 0 NH 2 O NH 2 Ethyl 1-aminocarbonyl-4-piperidinyl acetate (153.6mg, 5 0.717mmoles) from Step B above was dissolved in anhydrous dichloromethane (3.58mL) and ethanol (3.58mL). To the solution was added 1. OM LiOH (1.73mL, 1.73mmoles) and the mixture was stirred at 50 0 C for 5.5h. The mixture was cooled quickly to 25 0 C and 1 .ON HC1 (2.02mL, 2.02mmoles) was added and the mixture 10 stirred for 5 minutes and then evaporated to dryness to give the title compound, which was used without further purification. PREPARATIVE EXAMPLE 40 Step A 0 O CH 3 Y NKCH3 0H 2 N N CH NN 15H2N N O H/" N / 15 ao0 The title compound from Preparative Example 37, Step A above (0.45g, 1.33mmoles), 1[3-(dimethylamino)propyl]-3 ethylcarbodimide hydrochloride (0.332g, 1.73mmoles), 1 hydroxybenzotriazole (0.234g, 1.73mmoles) and 4-methyl 20 morpholine (0.382mL, 3.46mmoles) were dissolved in anhydrous DMF (7mL). The title compound from Preparative Example 33, Step C above (0.3228g, 1.73mmoles) dissolved in anhydrous DMF (8mL) WO 00/37459 PCT/US99/27939 - 87 was added and the mixture was stirred at 25oC for 22h. The solution was evaporated to dryness and the residue was taken up in dichloromethane and washed with saturated aqueous sodium bicarbonate, dried (MgSOJ4), filtered and evaporated to dryness. The 5 residue was chromatographed on a silica gel column using 5% (10% cone. NH 4 OH in methanol)-dichloromethane as the eluant to give the title compound: (Yield: 0.3553g, 53%). Step B H N H KN

H

2 N N 10 0 The title compound from Step A above (0.45g, 0.9mmoles) was dissolved in methanol (5.625mL). A 10% (v/v) solution of cone.

H

2

SO

4 in dioxane (13.5mL) was added and the mixture was stirred at 25 0 C for 2h. Anhydrous methanol (200mL) was added followed 15 by BioRad® AG1 -X8 (OH) resin until the solution was neutral to pH paper. The resin was filtered off and washed with methanol and the combined filtrates were evaporated to dryness. The residue was chromatographed on a silica gel column using 5% increasing to 6.5% (10% cone. NH40H in methanol)dichloro-methane as the 20 eluant to give the title compound: (Yield: 0.317g, 96%); FABMS: m/z 406.2 (MH'); 8 c (CDC1 3 -~5% CD 3 OD) CH 2 : 30.8, 31.9, 31.9, 36.2/36.3/36.6, 39.1/39.3/39.5, 44.1/44.2, 44.4, 44.4, 44.8, 44.8; CH: 51.2/56.3, 119.0, 128.8, 137.0; C: 158.7, 171.0/171.1, 171.9/172.6; 8H (CDC13- 2.86% CD 3 OD) 4.84 (1H, d, H 2 ), 6.96 (1H, 25 broad s, Im-H 5 ), 7.04 (1H, broad s, Im-H 4 ) and 7.53ppm (1H, broad s, Im-H 2

).

WO 00/37459 PCT/US99/27939 - 88 PREPARATIVE EXAMPLE 40A Step A Br Cl Br Cl N N N N (52.i) co2ET (52.ii) H A solution of 52.i (J. Med. Chem. 4890-4902 (1988))(205 g) in 5 conc. HC1 (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). 10 Step B Br N Cl Br - Cl N N (52.ii) H (() 52.0) H A LM 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 0-5oC and stirred for 15 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/CH 2

C

2 affords the title compound (±) 52.0 (104 g): HRMS (FAB) calcd for C, 19 H21 N27 9 BrC1 393.0556, found 20 393.0554.

WO 00/37459 PCT/US99/27939 - 89 Step C The racemate (+) 52.0 (96 g) is resolved by HPLC on a 8x30 cm CHIRALPAK AD column at 25 0 C with the UVdetector set at 290 nm. Elution with 0.05% diethylamine-methanol affords: Peak 1 (-) 5 52.0 (40 g): [a]2 -28.4o (c 0.3, MeOH); Further elution with the same solvent affords: Peak 2 (+) 52.0 (42 g): [a]" +27.50 (c 0.3, MeOH). PREPARATIVE EXAMPLE 41 10 Step A Br Cl N "' __ __N_ _, H "/H ((+)52.0) N N H (53.0) o

H

2 N 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 15 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 20 afford the title compound 53.0 as an amorphous solid (3.68 g). MS(FAB): m/z 510 (MH)*.

WO 00/37459 PCT/US99/27939 - 90 Step B Br-_ c Br C N N" (53.0) _ H +

H

3 CO N N OCH3 (54.0a) 0 0 (54.Ob) 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 5 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 (4xl00ml). 10 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 54.0a and 54.Ob as an off-white amorphous solid (2.97 g). 'H NMR (CDC1 3 , 300 MHz) d 3.30 (s, 3H); MS (FAB) 15 m/e 525 (MH)*. Steps C-E Br CC (54.0Oa) C-E N N / + + H H (54.0Ob) HOOC N N COOH (57.0a) I (57.Ob) (57.a)COOt-Bu COOt-Bu A solution of 54.Oa and 54.0b (17 g) in methanol (150 ml) and 20 2N hydrochloric acid (170 ml) and conc. HC1 (60 ml) is heated under WO 00/37459 PCT/US99/27939 - 91 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 5 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 (120oC) 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 10 addition of a solution of (BOC) 2 0 (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 15 is purified by flash chromatography to afford the mixture of 57.0a and 57.0b as light tan solid that appears as a single tic spot (16 g). 'H NMR (CDC1 3 , 300 MHz) d 1.40 (s, 9H); MS (FAB) m/z 535 (MH)Y. The single tic spot is a mixture of four isomers which are separated after derivatization into the compounds of Examples 77 to 20 79 and 87 to 97 below. Following the above procedure (Steps A-E), except using Compound (-)-52.0 (17 g), a mixture of 58.0a and 58.Ob is obtained as a light solid that appears as a single tic spot (17 g). MS(ES) m/z 535 (MH*). 25 PREPARATIVE EXAMPLE 42 H N .,, *2Camphorsulfonic acid H OH To 2.5 kg of (R)-(-)-camphorsulfonic acid stirring at 600C in 1250 ml of distilled water was added a soution of the potassium salt WO 00/37459 PCT/US99/27939 - 92 of 2-carboxyl-piperazine (565 gin, 3.35 mol). The mixture was allowed to stir at 951C until completely dissolved. The solution was allowed to stand at ambient temperature for 48 hrs. The resulting precipitate was filtered to obtain 1444 gm of damp solid. The solids 5 were then dissolved in 1200 ml of distilled water and heated on a steam bath until all solids dissolved. The hot solution was then set aside to cool slowly for 72 hrs. The crystalline solids were filtered to give 362 gm of the pure 2-R-enantiomeric product as a white crystalline solid. [c]D=- 14.90. 10 PREPARATIVE EXAMPLE 43 Boc N Boc OH 2-R-carboxyl-piperazine-di-(R)-(-)-camphorsulfonic acid (Preparative Example 42) (362 gm, 0.608 mol) was dissolved in 1.4 L 15 of distilled water and 1.4 L of methanol. 75 ml of 50% NaOH was dripped in to the stirred reaction mixture to obtain a ~pH 9.5 solution. To this solution was added di-tert-butyl-dicarbonate (336 gm, 1.54 mol) as a solid. The pH dropped to ~7.0. The pH of the reaction mixture was maintained at 9.5 with 50% NaOH (total of 20 175 ml), and the reaction mixture stirred for 2.5 hours to obtain a white precipitate. The reaction mixture was diluted to 9 L with ice/water followed by washing with 2 L of ether. The ether was discarded and the pH of the aqueous layer adjusted to pH 3.0 by the portionwise addition of solid citric acid. The acidified aqueous 25 layer was then extracted with dichloro-methane 3X with 2L. The organic layers were combined, dried over sodium sulfate, filtered and evaporated to obtain 201.6 gm of title compound as a white glassy solid. FABMS (M+1)=331.

WO 00/37459 PCT/US99/27939 - 93 PREPARATIVE EXAMPLE 44 Boc N "wO To an ice cold solution N,N-dimethylformamide (49.6 ml) was added, dropwise, thionylchloride (46.7 ml) over a period of 5 5 minutes in a 5 L round bottom flask under a nitrogen atmosphere. The reaction mixture was allowed to stir for 5 min. and the ice bath removed and the reaction mixture allowed to stir at ambient temperature for 30 min. The reaction mixture was cooled again in an ice bath and a solution of of N,N-di-tert-butoxycarbonyl-2-R 10 carboxyl-piperazine (Preparative Example 43) (201.6 gm, 0.61 mmol) in 51.7 ml of pyridine and 1.9 L of acetonitrile was cannulated into the reaction mixture. The reaction mixture was allowed to warm to ambient temperature to obtain a yellowish turbid solution. After stirring at ambient temperature for 18 hours, 15 the reaction mixture was filtered and the filtrate poured into ice water (7L) and then extracted with 4X 2 L of ethyl acetate, dried over sodium sulfate, filtered and evaporated to dryness under vacuo to obtain 115.6 gm (73%) of the title product as a white solid.

WO 00/37459 PCT/US99/27939 - 94 PREPARATIVE EXAMPLE 45 CN Boc N H N 0

HN

6 0 1N-p-Cyanobenzyl histamine (0.34, 1.5 mmol) (prepared as described in Preparative Example 163) was added to a solution of 5 the Boc-anhydride (Preparative Example 44) (0.38 gm, 1.5 mmol) in 10 ml of dichloromethane and stirred under a nitrogen. After 1 hr, 0.15 gm more of the Boc-anhydride was added and the reaction monitored for completion by normal phase tlc using 10% methanol/dichloromethane as the eluent. After the reaction went to 10 completion (- 1 hour), 0.25 ml (2 mmol) of cyclohexyl isocyanate was added to the reaction mixture and stirred for 1 hour. The reaction mixture was poured into brine and extracted with dichloromethane (3X). The dichloromethane layers were combined, dried over MgSO 4 , filtered and evaporated to dryness. The residue was 15 chromatographed on a flash column of silica gel using 5% methanol/dichloromethane to obtain 0.714 gm of pure title compound as a solid. FABMS (M+1)=564.

WO 00/37459 PCT/US99/27939 - 95 PREPARATIVE EXAMPLE 46 0 N O HO N N-(2,3-Epoxypropyl)phthalimide (2.3 gm, 11.3 mmol) was dissolved in N,N-dimethylformamide and imidazole (1.53 gm, 1.5 5 eq.) was added and the reaction mixture stirred at 90 oC for 5 hours. Brine was added and the product extracted with ethylacetate to obtain the title product (0.67 gm). PREPARATIVE EXAMPLE 47

H

2 N HO N 10 4 1-Phthalamido-2-hydroxy-3-1-H-imidazole-propane (from Preparative Example 46) (0.6 gm) was dissolved in ethanol and 5 ml of hydrazine hydrate added. The reaction mixture was refluxed for 3 hours. The reaction mixture was cooled to ambient temperature 15 and the resulting precipitate filtered. The filtrate was evaporated to dryness to obtain the title product which was used without further purification.

WO 00/37459 PCT/US99/27939 - 96 PREPARATIVE EXAMPLE 48 Boc N HO H N N "/ 0 HN 0 1-Amino-2-hydroxy-3-1-H-imidazole-propane (from Preparative Example 47) (2.2 mmol) was added to a solution of the 5 Boc-anhydride (Preparative Example 44) (0.57gm, 2.2 mmol) in 10 ml of dichloromethane and stirred under nitrogen. After 1 hr, 0.15 gm more of the Boc-anhydride was added and the reaction monitored for completion by normal phase tlc using 10% methanol/dichloromethane as the eluent. After the reaction went to 10 completion (- 1 hour), 0.85 ml (6.6 mmol) of cyclohexyl-isocyanate was added to the reaction mixture and stirred for 1 hour. The reaction mixture was poured into brine and extracted with dichloromethane (3X). The dichloromethane layers were combined, dried over MgSO 4 , filtered and evaporated to dryness. The residue 15 was chromatographed on a flash column of silica gel using 5% methanol/dichloromethane to obtain 0.487 gm of pure title compound as a solid.

WO 00/37459 PCT/US99/27939 - 97 PREPARATIVE EXAMPLE 49

H

2 /C C> N N", OH I O Boc 2-Carboxy-piperazine-dicamphorsulfonic acid salt (Preparative Example 42) (17.85 gm, 30 mmole) was dissolved in 5 180 ml of distilled water. Dioxane (180 mL) was added and the pH adjusted to 11.0 with 50% NaOH. The reaction mixture was cooled to 0-5OC in an ice-MeOH bath and a solution of benzyl chloroformate (4.28 mL, 30 mmol) in 80 mL of dioxane was added over a period of 30-45 minutes while stirring at 0-5oC and keeping 10 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 evaporated to dryness (to get rid of the dioxane for extraction). The residue was dissolved in 180 mL of dist. water and the pH adjusted slowly to 4.0 with IN HC1. The aqueous solution was 15 washed with 3X180 mL of ethyl acetate (The ethyl acetate was dried over MgSO 4 , filtered, and evaporated to obtain N,N-di-CBZ-2 carboxy-piperazine and saved). The pH of the aqueous layer, which contains the desired product, was adjusted to 10.5 to 11.0 with 50% NaOH and solid di-tert-butyl-dicarbonate (7.86 gm, 36 mmol) 20 was added and the mixture was stirred while keeping the pH at 10.5 to 11.0 with 50% NaOH. After 1 hr. the pH stabilized. When reaction was complete, the reaction mixture was washed with 2X180 mL of Et20. The aqueous layer was cooled in an ice bath and adjusted pH to 2.0 with IN HC1 (slowly). Extract the product 25 with 3X200 mL of ethyl acetate. Dry over MgSO 4 , filter and evaporate to obtain 9.68 ginm (88%) of pure product as a white solid.

WO 00/37459 PCT/US99/27939 - 98 PREPARATIVE EXAMPLE 50 H N N '/ OH I T 0 Boc 4-N-CBZ- 1N-Boc-2-carboxy-piperazine (Preparative Example 49) (9.6 gm, 26.3 mmol) was dissolved in 100 mL of absolute 5 ethanol in a hydrogenation vessel. The vessel was flushed with nitrogen and 3 gm of 10% Pd/C (50% by weight with water) was added. The mixture was hydrogenated at 55 psi of H 2 for 18 hours. After 18 hrs, the reaction mixture had a precipitate. The tic was checked (30% MeOH/NH 3

/CH

2

C

2 ). The reaction mixture was 10 filtered on a pad of Celite, and the pad washed with EtOH followed by distilled water. The filtrate was evaporated to ~ 1/3 the volume (to get rid of the EtOH) and 200 mL of distilled water was added. The aqueous layer was extracted with ethyl acetate three times (the ethyl acetate layer contained pure N,N-Di-Boc-2-carboxy-piperazine 15 which was saved). The water layer was evporated to dryness and evaporated from methanol two times to obtain 3.98 (17.37gm, mmol) of pure product. PREPARATIVE EXAMPLE 51 Br / Cl N N N 9,N OH Ha C O~ H3Cy33 0 20

H

3 C 0 o The tricyclic alcohol (Preparative Example 40 in WO 95/10516) WO 00/37459 PCT/US99/27939 - 99 Br Cl N OH (5.6 gm, 17.33 mmol) was dissolved in 56 ml of dichloromethane and 2.46 ml of thionyl chloride was added while stirring under a dry nitrogen atmosphere. After 5 hrs. the tic was checked (by adding 5 an aliquot of the reaction mixture to IN NaOH and shaking with dichloromethane and checking the dichloromethane layer by tic using 50% EtOAc/Hexanes as the eluent). The mixture was evaporated to give a gum which was evaporated from dry toluene twice and once from dichloro-methane to give the 11-chloro 10 derivative as a foamy solid which was used without further purification. The resulting 11-chloro-tricyclic compound was dissolved in 100 ml of dry DMF, IN-Boc-2-carboxy-piperazine (Preparative Example 50) (3.98 gm) was added followed by 12.11 ml of triethylamine and the mixture stirred at ambient temperature 15 under a nitrogen atmosphere. After 24 hours the DMF was evaporated and the residue dissolved in 200 ml of ethyl acetate and washed with brine. The brine layer was washed with ethyl acetate two more times and the ethyl acetate layers combined, dried over magnesium sulfate, filtered, and evaporated to give a foamy solid. 20 The solid was chromatographed on a 1 1/2" X 14" column of silica gel eluting with 2L of 0.4% 7N MeOH/NH:CH 2 C12, 6L of 0.5% 7N MeOH/-NH 3

:CH

2 C12, 2L of 0.65% 7N MeOH/NH 3

:CH

2 C2, 2L of 0.8% 7N MeOH/NH:CH 2 C12, 4L of 1% 7N MeOH/NH:CH 2 C1 2 , 2L of 3% 2N MeOH/NH:CH 2 C12, 2L of 5% 2N MeOH/NH:CH 2 C1 2 , 2L of 10% 2N 25 MeOH/NH 3

:CH

2

C

2 , 2L of 15% 2N MeOH/NH 3

:CH

2

CI

2 , 4L of 20% 2N MeOH/NH 3

:CH

2 C1 2 to obtain 4.63 gm of final product.

WO 00/37459 PCT/US99/27939 - 100 PREPARATIVE EXAMPLE 52 Br CI N N N H OH

H

3 C

CH

3

CH

3 The title compound from Preparative Example 51 (1 gm, 1.86 mmol) was dissolved in 50 ml of DMF and 1-amino-3-propanol 5 (0.214ml, 1.5 eq.), DEC (0.71 gm, 2 eq.), HOBT (0.5 gm, 2 eq.), and N-methyl-morpholine (1.02 ml, 5 eq.) was added and the reaction mixture stirred for 18 hours. The reaction mixture was added to brine and the product extracted with ethyl acetate 3 times to obtain a crude oil, after the solvent was evaporated under reduced 10 pressure, which was purified by chromatography on a silica gel column 20%-50% ethyl acetate/hexanes as the eluent. The product containing fractions were pooled to obtain 0.67 gm (60%) of pure title compound. 15 PREPARATIVE EXAMPLE 53 O N N

NH

2 0 2-Aminoimidazole (8 g, 60 mmol) was dissolved in 200 ml of DMF and cooled in an ice bath. Sodium hydride 60% oil dispersion (2.4 g, 60 mmol) was added portionwise and the reaction mixture 20 stirred for 1 hour. N-(3-Bromopropyl)-phthalimide (16g, 74 mmol) was added and the reaction mixture stirred for 1/2 hour at 0OC, 1 hour at ambient temperature, and then 1 hour at 85 0 C. The WO 00/37459 PCT/US99/27939 - 101 reaction mixture was then cooled to ambient temperature and added to brine and extracted with ethyl acetate to obtain the crude product which was purified by column chromatography using 2% methanol/methylene chloride to obtain 4.88 gm of title compound. 5 PREPARATIVE EXAMPLE 54 N

H

2 N N 2HCI NH 2 0.5 gm of 1-phthalimidopropyl-2-aminoinmidazole (from Preparative Example 53) was refluxed in 20 ml of 6N HC1 for 6 10 hours. The mixture was washed with ethyl acetate and the aqueous layer evaporated to dryness to obtain 0.45 g of the title product. PREPARATIVE EXAMPLE 55 Boc N H N BN NH2 o 0 15 1-Aminopropyl-2-aminoimidazole (Preparative Example 54) ( 0.25 gm) and N,N-di-butoxycarbonyl-2-R-carboxyl-piperazine (from Preparative Example 43) (0.32 gm) was dissolved in 10 ml of DMF. DEC (0.2 gin.), 1-hydroxybenzotriazole (0.135 gin), and N-methyl morpholine (0.54 ml) was added and the reaction mixture stirred for 20 5 hours. The reaction was poured into brine and extracted with dichloromethane to obtain 0.43 gm of the title product after chromatography on silica gel using 2% methanol/-dichloromethane up to 10 %. FABMS M+I= 453.3.

WO 00/37459 PCT/US99/27939 - 102 PREPARATIVE EXAMPLE 56 Boc N N H N Boc O 0 CBZ 1-Aminopropyl-2-aminoimidazolyl-N1,N4-di-tert.butyl-1,2(R) piperazinedicarboxamide (Preparative Example 55) (0.38gm) was 5 dissolved in 20 mL of dichloromethane and 0.24 ml of triethylamine. Benzyloxycarbonyl-N-hydroxysuccinimide (0.22 gm) was added and the reaction mixture stirred for 18 hours at ambient temperature. The reaction mixture was washed with brine and chromatographed on a silica gel column using ethyl acetate as the 10 eluent to obtain 0.39 gm of title product. FABMS M+1=587.3. PREPARATIVE EXAMPLE 57 H (N H N H I 2 TFA HN CBZ 1-benzyloxycarbonylaminopropyl-2-amniinoimidazolyl-N 1 ,N4 15 di-tert.butyl-1,2(R)-piperazinedicarboxamide (Preparative Example 56) (0.4 gm) was dissolved in 3 ml of dichloromethane and 1 ml of trifluoroacetic acid was added and the reaction mixture stirred for 3 hours at ambient temperature. The reaction mixture was then evaporated to dryness to obtain the pure title product. 20 WO 00/37459 PCT/US99/27939 - 103 PREPARATIVE EXAMPLE 58 Br N/ C1 N NH N N HN 0 CBZ 1-benzyloxycarbonylaminopropyl-2-aminoimidazolyl- 1,2(R) 5 piperazinedicarboxamide (Preparative Example 57) was dissolved in 50 ml of DMF and 0.46 ml of triethylamine. 3-Bromo-8,11 dichloro-6,11-dihydro-5H-benzo[5,6]cyclohepta[1,2-blpyridine (171 mg) was added and the reaction mixture stirred for 24 hours. The reaction mixture was added to brine and extracted with 10 dichloromethane to obtain 82 mg of pure title product after silica gel chromatography using methanol/dichloro-methane as the eluent. FABMS (M+1) = 694. PREPARATIVE EXAMPLE 59 N Boc-NH N OH 15 H 3 C 1-tert-Butoxycarbonylaminopropyl-imidazole (0.991 gm, 4.4 mmol) was dissolved in 25 mol of dry THF and cooled to -78 0 C. A 2.5M solution of n-butyllithium (3.88 ml, 9.68 mmol) in cyclohexanes was added dropwise and the reaaction stirred for 1/2 20 hour. Acetaldehyde (0.49 ml, 8.8 mmol) was added and the reaction stirred for 1/2 hour. The reaction mixture was allowed to warm to ambient temperature. The reaction was diluted with ethyl acetate and washed with brine. The ethyl acetate layer was WO 00/37459 PCT/US99/27939 - 104 evaporated to obtain a gum which was chromatographed on silica gel to obtain 0.54 gm of title product. (MH' = 170). PREPARATIVE EXAMPLE 60 N

H

2 N *- N / H OH 5

H

3 C 1-tert-Butoxycarbonylaminopropyl-2-hydroxyethyl-imidazole (Preparative Example 59) (0.51gm) was dissolved in trifluoroacetic acid and stirred for 3-4 hours. The mixture was evaporated to dryness to obtain the pure TFA salt of the title compound. 10 PREPARATIVE EXAMPLE 61 /NH N

H

2 N OH 1-N-Trityl-4-iodoimidazole (1.91 gm) was dissolved in 20 ml of dichloromethane and 1.46 ml of ethyl magnesiumbromide was 15 added while stirring. After 15 min. N-Boc-phenylalanine aldehyde (0.5 gm) was added and the reaction mixture was stirred for 18 hours. The reaction mixture was washed with saturated ammonium chloride, dried over magnesium sulfate, and chromatographed on silica gel to obtain 0.8 gm of the intermediate 20 blocked product. FABMS (M+1)= 561. This was then treated with 4M HC1/dioxane for 18 hours. The mixture was evaporated to dryness and dissolved in distilled water and washed with ethyl acetate. The aqueous layer was evaporated to obtain pure title product. (MH' = 218).

WO 00/37459 PCT/US99/27939 - 105 PREPARATIVE EXAMPLE 62 Step A Me ON,, N ~Me_ _ N-. . Br + H MNN O 0

M

e 0 N- N N O 5 A mixture of N-(3-bromopropyl)phthalimide (12.3 g, 46 mmol), 4-methylimidazole (3.78 g, 46 mmol), sodium hydride (60% in mineral oil, 1.84 g, 46 mmol) and anhydrous DMF (50 mL) was stirred at 25-70'C under N 2 overnight. The mixture was concentrated in vacuo to give a residue which was diluted with 10 dichloromethane, filtered, concentrated in vacuo and purified by flash column chromatography (silica gel) using 1% MeOH-CH 2 Cl 2 saturated with aqueous ammonium hydroxide to give the title compound as an oil (8.04 g, 65%, MH + = 270). 15 Step B Me Me H2N O 0 Me M 0 To a solution of the title compound from Step A (8.02 g, 29.8 mmol) dissolved in absolute EtOH (150 mL) was added hydrazine mono hydrate (15 mL) and the mixture was stirred at reflux for 12 h WO 00/37459 PCT/US99/27939 - 106 under N 2 . The mixture was diluted with dichloromethane, filtered and concentrated in vacuo. The residue was purified by flash column chromatography (silica gel) using 5% MeOH-CH 2 Cl 2 saturated with aqueous ammonium hydroxide to give the title 5 compound as an oil (2.95 g, 71%, MH + = 140). PREPARATIVE EXAMPLES 63-67 Following the procedure set forth in Preparative Example 62, but using the substituted imidazole in Table 3 below instead of 4 10 methylimidazole in Step A, the amines (Product) listed in Table 3 were prepared. TABLE 3 Prep. Imidazole Product MH ' Yield Ex. (%) 63 Me Me HN N

H

2 N N N Me Me Me 154 70

H

2 N N N N Me 64 H 3 C CH3 H N N

H

2 N - N N HC 154 60

H

2 N \ N,, N WO 00/37459 PCT/US99/27939 - 107 65 H N N H 2 N-- ,. N N CH3 CH 3 154 68 66 .NN H2N N ,N H N 140 46 Me Me 66.1 H 88 NN H MH 266.1657 PREPARATIVE EXAMPLE 67 If the procedure set forth in Preparative Example 62 were 5 followed, except the imidazole

H

3 C

CH

3 H -1N N would be used instead of 4-methylimidazole in Step A, the amine HC >

CH

3

H

2 N N N would be obtained. 10 PREPARATIVE EXAMPLE 67.1 If the procedure set forth in Preparative Example 62 were followed, except the imidazole M Me H,N \10 N WO 00/37459 PCT/US99/27939 -108 would be used instead of 4-methylimidazole in Step A, the amine Me Me H2N N would be obtained. 5 PREPARATIVE EXAMPLE 68 Me Me

H

2 N NT N HCI Me H2N c + HN N Me C1 Me Me H2N - N N Me A mixture of 2-chloroethylamine hydrochloride (7.66 g, 66 mmol), 2,4-dimethylimidazole (5.88 g, 61 mmol), tetrabutyl ammonium sulfate (0.83 g, 2.5 mmol), solid NaOH (8.81 g, 220 10 mmol) and anhydrous acetonitrile (80 mL) was stirred at reflux for 48 h under N2. The mixture was filtered, concentrated in vacuo and purified by flash column chromatography (silica gel) using 2% MeOH-CH2C12 saturated with aqueous ammonium hydroxide to give the title compound as an oil (10.7 g, 100%, MH + = 140). 15 PREPARATIVE EXAMPLES 69-73 Following the procedure set forth in Preparative Example 68, but using the substituted imnidazole or triazole in Table 4 below instead of 2,4-dimethylimidazole, the amines (Product) listed in 20 Table 4 were prepared.

WO 00/37459 PCT/US99/27939 - 109 TABLE 4 Prep. Imidazole Product MH' Yield Ex. (%) 69 Me Me H, Nl N H2N I N 126 75 Me

H

2 N -\ N.N 70 HN ,N HN N ,N H H 2 N N 112 65 71 HNT H2N NN 176 55 Me Me 72

H"NT

N

H

2 N N,,N 126 53 Me Me 73 (A) N, N H2N N.N N (A): (A): H N N 163 60 Q (B) (B): (B):

H

2 N N 163 40 PREPARATIVE EXAMPLE 74 0 H + H2N == N N 5 H-N A mixture of 1-(3-aminopropyl)imidazole (37.1 g, 297 mmol), benzaldehyde (30 g, 283 mmol), 3A molecular sieves (50 g), sodium acetate (24.1 g, 283 mmol) and anhydrous methanol (700 mL) was stirred at room temperature under N2 overnight. The mixture was WO 00/37459 PCT/US99/27939 -110 cooled to 0OC and sodium borohydride (10.9 g, 288 mmol) was added portionwise over 1 hour. The mixture was stirred at room temperature for 3 hours. The mixture was filtered through celite, washed with methanol, and concentrated in vacuo to give a residue 5 which was diluted with dichloro-methane and washed with 10% aqueous sodium hydroxide. The organic phases were washed with brine, dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo to give the title compound as a pale yellow oil (56.3 g, 92%, MH + = 216). 10 PREPARATIVE EXAMPLES 75-95 Following the procedure set forth in Preparative Example 74, but using the aldehyde and imidazolylalkyl amine (Imidazole) in Table 5, the amines (Product) in Table 5 were obtained. 15 TABLE 5 Prep Aldehyde Imidazole Product % Ex. Yield (MH-) 75 F O H2NNN F 46 H / (234) .-N H N NN 76 0 H 2 N N= F 91 F Y (234) H -N N /-N 77 0 H2 N N 74 HQ (217) H -N H N r-N WO 00/37459 PCT/US99/27939 - 111 78 H H2N NN 92 \ _ (2 17) H N 79 HO 0 H 2 N OH 9 \1 NN 9 \ (232) H 80 MeO 0 H 2 N OMe C H H2r4 97 6 (246) H-N F91 HN N 81 OH H2 N OMe 81 (246) -NN N MeO 82 NC O0 H2N\ PN= CN68 HN N N N H-) (241) H83 H 2 N 87 (266) I-N H NN 0 H2N. N 84 O H H 84 QH (222) H-N N ,,N 85 0 Me (A) (A): 45 ~~~H2 N A:4 Me Me (230)

HH

2 HNMe NN H2JN (B): 21 SB) (230) H- N WO 00/37459 PCT/US99/27939 -112 86 0 M e N M 62 9 N,,N e (239) H IN Me\Me H2N N -N H N... N.N 87 OH. H2N N' 80 'H= (202) HN N', HN 88 0 H2N N 88 HN~~~J~463 H (244) Me H- N , Me 89 O H 2 N Me 86 Cy-H 2 .. \ N N /-o e8 SHN , (244) Me H- N N Me H2N 9 Me H2N- N Me Me HN - NN T Me 90 0 Me -,F 83 9O NN , N e/M e (248) H-N Me 20 H2N ( N NN N __ &JH HN A K-' A (244) \ ...... N,, N H-x .N N HNN MeN H2N Me ____________

HN

WO 00/37459 PCT/US99/27939 - 113 93 0 Me 44 9 3 OHH 2 H 2 N (216) Me H2N -- N ZMe HN Ni LN N HN N Me N 94 O H2N e N 95 H \-N N 95 H 2 NH N- 68 Me 9 5 OH H 2N N , 6 8 H ~N \,- f- NN PREPARATIVE EXAMPLE 95.1 Step A 0 Me 0 Me NY N 5 N.N 0 N N,,N To a CH 2 C (500 mL) solution of the title compound from Preparative Example 62 Step A (65.7 g) cooled to 0oC was added trityl chloride (27.2 g). The resulting mixture was warmed to and stirred at room temperature for 1.5 hr, then concentrated in vacuo 10 without heating. Purification by flash column chromatography (silica, 1:1 Acetone-EtOAc) afforded the pure 4-methyl isomer (35.02 g, MH' = 270).

WO 00/37459 PCT/US99/27939 -114 Step B /" Me Me N MeH 2 N N N O N N NN N Following essentially the same procedure as that described in 5 Preparative Example 62 Step B except using the pure 4 methylimidazole product from Preparative Example 95.1 Step A (35.02 g), the title compound was afforded (16.12 g, MH = 140). Step C H2N ~ Me M H2H NNN N 10 HN Following essentially the same procedure as that described in Preparative Example 74 except using the pure 4 methylimidazolepropylamine product from Preparative Example 95.1 Step B above (16.12 g) instead of 1-(3-aminopropyl)imidazole, 15 the title compound was afforded (18.03 g, MH = 230). PREPARATIVE EXAMPLE 97 CN

CONH

2 H-N N N -H N NN A mixture of the title compound from Preparative Example 82 20 (0.50 g, 2.1 mmol), absolute EtOH (50 mL), 30% hydrogen peroxide (aq) (0.45 mL, 4.4 mmol) and IM NaOH (aq) (4.4 mL, 4.4 mmol) was stirred at 50 0 C for 12 h. The mixture was concentrated in vacuo and purified by flash column chromatography (silica gel) using 10% WO 00/37459 PCT/US99/27939 - 115 MeOH-CH2C12 saturated with aqueous ammonium hydroxide to give the title compound as an oil (0.33 g, 61%, MH + = 259). PREPARATIVE EXAMPLE 98 CI + H2 - 0 NeHNf-N 5 H N,,N To a cooled (0OC) solution of 1-(3-aminopropyl)imidazole (Aldrich, 1.9 mL, 16 mmol) and triethylamine (5.6 mL, 40 mmol) dissolved in anhydrous CH2C12 (20 mL) was added phenylacetyl chloride (2.12 mL, 16 mmol). The mixture was warmed to and 10 stirred at room temperature overnight. The mixture was washed with IN aqueous NaOH, dried over anhydrous MgSO4 and filtered. The solution was concentrated in vacuo and purified by flash column chromatography (silica gel) using 2% MeOH-98% CH2C12 saturated with aqueous ammonium hydroxide to give the title 15 compound as an oil (1.8 g, 45%, MH + = 244). PREPARATIVE EXAMPLE 99 0 H-N .- N N N i , , N To a refluxing solution of the title compound from Preparative 20 Example 98 (0.51 g, 2.1 mmol) dissolved in anhydrous THF (5 mL) was added borane dimethylsulfide complex (6.3 mL, 2M in THF, 13 mmol). After 1 hr, the mixture was cooled to room temperature and stirred overnight. Hydrochloric acid (IN) was added dropwise until the reaction mixture was determined to be acidic (pH paper). The 25 mixture was basified with IN aqueous NaOH, extracted with WO 00/37459 PCT/US99/27939 -116 CH2C12, dried over anhydrous MgSO4 and filtered. The solution was concentrated in vacuo and purified by flash column chromatography (silica gel) using 2% MeOH-98% CH2C12 saturated with aqueous ammonium hydroxide to give the title compound as 5 an oil (0.25 g, 52%, MH + = 230). PREPARATIVE EXAMPLE 100 Me 0 H2N Me NN H N,, N MeO

H

2 N M O 0 Me -N H

N,,

N To a cooled (0OC) solution of the title compound from 10 Preparative Example 62 Step B (0.7 g, 5 mmol) and triethylamine (1.7 mL, 12.5 mmol) dissolved in anhydrous CH2C12 (10 mL) was added phenylacetyl chloride (0.67 mL, 5 mmol). The mixture was warmed to and stirred at room temperature overnight. The mixture was washed with IM HC1 (aq) and the aqueous phase was basified 15 with IN aqueous NaOH. This phase was extracted with CH2C12 and dried over anhydrous MgSO4 and filtered. The solution was concentrated in vacuo to give the title compound as an oil (0.72 g, 56%, MH

+

= 258).

WO 00/37459 PCT/US99/27939 - 117 PREPARATIVE EXAMPLE 101 O Me Me N rN H \.- N N ~HN N Me Me N N"'-N H \ N To a refluxing solution of the title compound from Preparative Example 100 (0.66 g, 2.5 mmol) dissolved in anhydrous THF (15 5 mL) was added borane-THF complex (5 mL, IM in THF, 5 mmol). The mixture was refluxed for 12 h, then cooled to room temperature and concentrated in vacuo. The residue was diluted with 1M HC1 and washed with CH 2 C1 2 then the aqueous phase was basified with 50% aqueous NaOH and extracted with CH 2 C1 2 and dried over 10 anhydrous MgSO 4 and filtered. The solution was concentrated in vacuo and purified by preparative plate chromatography (silica gel) using 3% MeOH-CH 2 C1 2 saturated with aqueous ammonium hydroxide to give the title compound as an oil (0.21 g, 35%, MH + = 244) which was purified by preparative chiral chromatography 15 (Chiralpack AD, 5 cm X 50 cm column, flow rate 80 mL/min, 5-8% IPA-Hexane +0.2% diethylamine). PREPARATIVE EXAMPLE 101.1 If the procedure of Preparative Example 100 were followed, 20 but the compound N N Cl WO 00/37459 PCT/US99/27939 -118 was to be reacted with the title compound from Preparative Example 62 Step B, then the Product N

CH

3 H N N N would be obtained. 5 PREPARATIVE EXAMPLE 101.2 If the procedure of Preparative Example 101 were followed, but the Product from Preparative Example 101.1 was to be used, then the Product N N CH 3 10 HN N N would be obtained=. PREPARATIVE EXAMPLE 102 Step A O CF 3

H

2 N /1 HN 15 -NN To a cooled (0OC) solution of 1-(3-aminopropyl)imidazole (10 g, 80 mmol) and triethylamine (17.1 mL, 120 mmol) dissolved in anhydrous CH 2 C1 2 (50 mL) was added trifluoroacetic anhydride (12.4 mL, 88 mmol). The mixture was warmed to and stirred at 20 room temperature overnight. The mixture was washed with water, dried over anhydrous MgSO 4 , filtered and concentrated in vacuo to give the title compound as an oil (15.7 g, 88%, MH

+

= 222).

WO 00/37459 PCT/US99/27939 - 119 Step B O CF 3 OY CF 3 H-N N-M 'H N N N Me N

N

F N To the title compound from Step A (0.24 g, 1.1 mmol) dissolved in anhydrous DMF (10 mL) was added solid sodium 5 hydride (85 mg, 2.1 mmol, 60% dispersion in mineral oil). When gas evolution ceased, methyl iodide (0.1 mL, 1.1 mmol) was added and the mixture was stirred at 70 0 C for 40 min. The resulting mixture was cooled to room temperature, concentrated in vacuo, diluted with CH 2 C1 2 and washed with water. The solution was dried 10 over anhydrous MgSO 4 , filtered and concentrated in vacuo to give an oil (0.28 g). Purification by preparative plate chromatography (silica gel) using 2% MeOH-98% CH 2 C1 2 saturated with aqueous ammonium hydroxide gave the title compound as a yellow oil (78 mg, 30%, MH + = 236). 15 Step C O CF 3 N- H Me-N N MeN /---I M e "- N ,, N M e ' A mixture of the title compound from Step B (74 mg, 0.3 mmol) and 20% KOH in H 2 0 (0.6 mL) was stirred at room 20 temperature for 15 min. The resulting mixture was concentrated in vacuo and purified by flash column chromatography (silica gel) using 10% MeOH-90% CH 2 C1 2 saturated with aqueous ammonium hydroxide to gave the title compound as an oil (65 mg, 100%, MH + = 140). 25 WO 00/37459 PCT/US99/27939 - 120 PREPARATIVE EXAMPLE 103

OCF

3 Et I H'N /=\-- H-N rFl SNNN NN Following a similar procedure as that used for the preparation of the title compounds from Preparative Example 102 Steps B-C, 5 but using ethyl iodide instead of methyl iodide, the ethyl amine was obtained as an oil (893 mg, 43%, MH + = 154). PREPARATIVE EXAMPLE 104 O. CF 3 Pr NI H--N '-IH.N/ Pr=propyl 10 Following a similar procedure as that used for the preparation of the title compounds from Preparative Example 102 Steps B-C, but using propyl iodide instead of methyl iodide, the propyl amine was obtained as an oil (649 mg, 29%, MH + = 168). 15 PREPARATIVE EXAMPLE 105 (Alternative Procedure to Preparative Example 74 O CF 3 H,N ---N HN- N N Following a similar procedure as that used for the preparation of the title compounds from Preparative Example 102 Steps B-C, 20 but using benzyl bromide instead of methyl iodide), the benzyl amine was obtained as an oil (1.64 g, 56%, MH

+

= 216).

WO 00/37459 PCT/US99/27939 - 121 PREPARATIVE EXAMPLE 106 Me 00 H Me f_ NIN MeCN + HN N N3, N N N II O_ N: N 0O HO A mixture of the title compound from Preparative Example 74 (1.34 g, 6.2 mmol), the title compound from Preparative Example 44 5 (1.6 g, 6.2 mmol), triethyl amine (1.3 mL, 9.3 mmol) and anhydrous

CH

2 C1 2 (10 mL) was stirred at room temperature for 48 hrs. Trifluoroacetic acid (10 mL) was added and the resulting mixture was stirred for an additional 1.5 hrs. Aqueous NaOH (IN) was added dropwise to neutralize the reaction mixture and the resulting 10 mixture was extracted with CH 2 C1 2 . The organic phase was dried over anhydrous MgSO 4 , filtered and concentrated in vacuo to give a residue which was purified by flash column chromatography (silica gel) using 1% MeOH-99% CH 2 Cl 2 saturated with aqueous ammonium hydroxide to give the title compound as an oil (520 mg, 15 26%, MH + = 328). PREPARATIVE EXAMPLE 107 Me 00 F H (- F Me N - N C. + H-N C 'I/-N O---NN H 0 0-0 Using the procedure described for Preparative Example 106, 20 but using the title compound from Preparative Example 76, the title compound was prepared: 0.16 g, 10%, MH

+

= 346).

WO 00/37459 PCT/US99/27939 -122 PREPARATIVE EXAMPLE 108 H F FlC F N N N N 7 IrN N=1 O HO N4N HO N4N Using the procedure described for Preparative Example 110 (below), but using the title compound from Preparative Example 107 5 (146 mg, 0.55 mmol), and the 8-Cl-tricyclic chloride (see Preparative Example 7 in WO 95/10516) CC (N Cl (159 mg, 0.46 mmol), the title compounds were prepared and separated by preparative plate chromatography (silica gel) using 2% 10 MeOH-CH 2 C1 2 saturated with aqueous ammonium hydroxide: diastereomer A (45, 17.1%, MH + = 573); diastereomer B (43 mg, 16.3%, MH + = 573). PREPARATIVE EXAMPLE 109 Br C1 Br Cl Br 1 (NJ fG N } ,g5N Me N 71-N . r- 1N 0 (S Me-). tNN N NJ , N 15 Me 0 oH H N N To a solution of the title compound from Example 113 (below) (4.90, 6.7 mmol) dissolved in anhydrous CH 2 C1 2 (25 mL) was added TFA (15 mL). The solution was stirred at room temperature under

N

2 for 2 hrs, then concentrated in vacuo, diluted with CH 2 Cl 2 , 20 washed with a saturated aqueous solution of NaHCO 3 and dried over anhydrous MgSO 4 . The mixture was filtered, concentrated in vacuo and purified by flash column chromatography (silica gel) WO 00/37459 PCT/US99/27939 - 123 using 2% MeOH-98% CH 2 C1 2 saturated with aqueous ammonium hydroxide to give the title compound as a mixture of diastereomers (3.66 g, quantitative). The diastereomers were separated by preparative chiral chromatography (Chiralpack AD, 5 cm X 50 cm 5 column, flow rate 80 mL/min., 99.8% MeOH +0.2% diethylamine) to give 1.62g of the 11S,2R diastereomer A and 1.97 g of the 11R,2R diastereomer B. Physical chemical data 11S,2R diastereomer A: mp = 109.3oC;

MH

+ = 633; [c] 2 0 D= -66.2o (3.93 mg/2 mL MeOH). 10 Physical chemical data 11R,2R diastereomer B: mp = 64.5oC;

MH

+ = 633; [(]20D= -41.80 (4.69 mg/2 mL MeOH). PREPARATIVE EXAMPLE 110 (Alternative procedure to Preparative Example 109) Br(or CI Br CI H N N 15 N N~N HO HO N N N 15 A 000 A mixture of the title compound from Preparative Example 106 (510 mg, 1.6 mmol), the tricyclic chloride (Compound No. 42.0) (534 mg, 1.6 mmol), triethylamine (1.1 mL, 7.8 mmol) and CH 2 C012 (10 mL) was stirred at room temperature overnight. The reaction 20 mixture was concentrated in vacuo and purified by flash column chromatography (silica gel) using 2% MeOH-98% CH 2 C1 2 saturated with aqueous ammonium hydroxide to give the title compound as a light yellow solid (420 mg, 42%, MH + = 633). The diastereomers were separated by preparative chiral chromatography (Chiralpack 25 AD, 5 cm X 50 cm column, flow rate 80 mL/min., 99.8% MeOH +0.2% diethylamine) to give 182 mg of diastereomer A and 126 mg of diastereomer

B.

WO 00/37459 PCT/US99/27939 -124 PREPARATIVE EXAMPLE 111 \1 C1 H N N _ rD + N (I%~I ..N ~ ~ ~ .N NA A- HC H 6- A mixture of the title compound from Preparative Example 106 (1.93 g, 5.9 mmol), the 8-Cl-tricyclic chloride (see Preparative 5 Example 7 in WO95/10516) (1.56 g, 5.9 mmol), triethylamine (4.1 mL, 29.5 mmol) and CH 2 C1 2 (10 mL) was stirred at room temperature for 48 h. The reaction mixture was concentrated in vacuo and purified by flash column chromatography (silica gel) using 2% MeOH-98% CH 2 Cl 2 saturated with aqueous ammonium 10 hydroxide to give the title compound as a light yellow solid (1.56 g, 49%, MH + = 555 ). The diastereomers were separated by preparative chiral chromatography (Chiralpack AD, 5 cm X 50 cm column, flow rate 80 mL/min., 30% IPA +70% Hexane +0.2% diethylamine) to give 0.72 g of the 11S,2R diastereomer A and 0.57 15 g of the 11R,2R diastereomer B. PREPARATIVE EXAMPLE 111.1 Follow the procedure of Preparative Example 111, but use the 10-Cl-tricycle chloride N 20 Cl cl to obtain WO 00/37459 PCT/US99/27939 - 125 N C Nd H 0 PREPARATIVE EXAMPLE 112 N0 N Me CO2H- Me Q N4 OH 0 N O O 5 To the carboxylic acid from Preparative Example 43 (2 g, 6 mmol) were added HOBT (0.82 g, 6.1 mmol), DEC (1.2 g, 6.0 mmol), the title compound from Preparative Example 85 (1.39 g, 6.1 mmol, isolated by preparative chiral chromatography (Chiralpack AD, 5 cm X 50 cm column, flow rate 80 mL/min., 8% IPA +92% Hexane 10 +0.2% diethylanine), NMM (1.7 mL, 15.5 mmol) and anhydrous DMF (60 mL). The mixture was stirred at room temperature under

N

2 overnight. The mixture was concentrated in vacuo, diluted with

CH

2 Cl 2 and washed with NaOH (aq). The organic phase was dried over anhydrous Na 2

SO

4 , filtered and concentrated in vacuo. The 15 residue was purified by flash column chromatography (silica gel) using 2-15% MeOH-CH 2 Cl 2 saturated with aqueous ammonium hydroxide to give the title compound (1.8 g, 55%, MH

+

= 542).

WO 00/37459 PCT/US99/27939 - 126 PREPARATIVE EXAMPLE 113 Br \ C fIN.-. Nw...N" N Br Cl N - N N 0 N N o NN H 0 Using the procedure described for Preparative Example 109, but using the title compound from Example 126 below, the title 5 compounds were prepared and separated: 11S,2R(-)- diastereomer A: 25.4% yield,MH + = 619; [a] 2 0 D= -46.70 (1.86 mg/2 mL MeOH); 11R,2R(-)- diastereomer B: 21.1% yield, MH + = 619; [C]20D= -23.00 (2.6 mg/2 mL MeOH). 10 PREPARATIVE EXAMPLE 114 QC l N '/ Me OON N HIO NO":y N N Me H Ne HO-~ N\ Cl N __Me To a solution of the title compound from Preparative Example 112 (1.8, 3.33 mmol) dissolved in anhydrous CH 2 C1 2 (5 mL) was added TFA (5 mL). The solution was stirred at room temperature WO 00/37459 PCT/US99/27939 - 127 under N 2 overnight, concentrated in vacuo and diluted with DMF (10 mL). To this was added the 8-Cl-tricyclic chloride (562 mg, 1.1 mmol) and triethylamine (10 mL) and allowed to stir at room temperature for 48 h. The reaction mixture was concentrated in 5 vacuo, diluted with CH 2 C1 2 , washed with a saturated aqueous solution of NaHCO 3 and dried over anhydrous MgSO 4 . After filtration and concentration in vacuo, the residue was purified by flash column chromatography (silica gel) using 3-10% MeOH-98%

CH

2 C12 saturated with aqueous ammonium hydroxide to give the 10 title compounds (11 S,2R diastereomer A, 152 mg, 27%, MH + = 569; and 11R,2R diastereomer B, 316 mg, 56%, MH + = 569). PREPARATIVE EXAMPLE 115 ~N N ---- NN N y /CO2H N1-N N N 2~ ~ \\ ,N..., N OAO NO 0 0 0 15 To the title compound from Preparative Example 43 (2.64 g, 8.0 mmol) were added HOBT (1.26 g, 9.3 mmol), DEC (1.79 g, 9.3 mmol), the title compound from Preparative Example 78 (1.44 g, 6.7 mmol), NMM (1.5 mL, 13.6 mmol) and anhydrous DMF (10 mL). The mixture was stirred at room temperature under N 2 overnight. 20 The mixture was concentrated in vacuo, diluted with CH 2 C1 2 and washed with NaOH (aq). The organic phase was dried over anhydrous Na 2

SO

4 , filtered and concentrated in vacuo. The residue was purified by flash column chromatography (silica gel) using 1% MeOH-CH 2 C1 2 saturated with aqueous ammonium hydroxide to give 25 the title compound (0.94 g, 27%, MH

+

= 529).

WO 00/37459 PCT/US99/27939 - 128 PREPARATIVE EXAMPLE 116 0 0H YN N _ NI O O N N OA OO N N N N N The title compound from Preparative Example 115 (0.73 g, 1.38 mmol) and anhydrous CH 2 Cl 2 (5 mL) was stirred at room 5 temperature for 48 hrs. Trifluoroacetic acid (2 mL) was added and the resulting mixture was stirred for an additional 1.5 hrs. Aqueous NaOH (IN) was added dropwise to neutralize the reaction mixture and the resulting mixture was extracted with CH 2 C1 2 . The organic phase was dried over anhydrous MgSO 4 , filtered and 10 concentrated in vacuo to give a residue which was purified by flash column chromatography (silica gel) using 5-15% MeOH-CH 2 C12 saturated with aqueous ammonium hydroxide to give the title compound as an oil (346 mg, 76%, MH + = 329). 15 PREPARATIVE EXAMPLE 117 Br CI N -N N H 0 Br C1 N N F H NN, N O Using the procedure described for Preparative Example 110, but using the title compound from Preparative Example 116 (343 mg, 1 mmol) and the tricyclic chloride (Compound No. 42.0) (718 WO 00/37459 PCT/US99/27939 - 129 mg, 2 mmol), the title compounds were prepared and separated: 11S,2R diastereomer A: 135 mg, 29%, MH + = 634; 11R,2R diastereomer B: 126 mg, 27%, MH + = 634. 5 PREPARATIVE EXAMPLE 118 OOO

°

O N +_ ro-P N N H -N N CO 2 H HN+ N ON ON NJ O0-"0 0 To the carboxylic acid from Preparative Example 43 (7.26 g, 22 mmol) were added HOBt (3.92 g, 29 mmol), DEC (5.49 g, 29 mmol), the title compound from Preparative Example 74 (4.73 g, 22 10 mmol), NMM (4.84 mL, 44 mmol) and anhydrous DMF (35 mL). The mixture was stirred at room temperature under N 2 overnight. The mixture was concentrated in vacuo, diluted with CH 2 Cl 2 and washed with NaOH (aq). The organic phase was dried over anhydrous Na 2

SO

4 , filtered and concentrated in vacuo. The residue 15 was purified by flash column chromatography (silica gel) using 1% MeOH-CH 2 C1 2 saturated with aqueous ammonium hydroxide to give the title compound (1.71 g, 15%, MH + = 528). PREPARATIVE EXAMPLE 119 N N'N )N1"/ N . .IN P- CN )-I/ N ' N ic *-,N,,1 N \-, N OKO OO K0 0 O OO O, OO .OH 20 The title compound from Preparative Example 118 (1.4 g, 2.7 mmol) and paraformaldehyde (solid, 2.8 g) were heated at 130 0 C in WO 00/37459 PCT/US99/27939 - 130 a sealed tube for 12 h. The mixture was diluted with CH 2 C1 2 and filtered. The organic phase was concentrated in vacuo and purified by flash column chromatography (silica gel) using 1% MeOH

CH

2 C1 2 saturated with aqueous ammonium hydroxide to give the 5 title compound (0.89 g, 59%, MH + = 558). PREPARATIVE EXAMPLE 120 0 0H 0 OH if0IOH The title compound from Preparative Example 119 (0.88 g, 10 1.6 mmol), anhydrous

CH

2 C1 2 (10 mL) and trifluoroacetic acid (10 mL) were stirred at room temperature for 1.5 hrs. Aqueous NaOH (IN) was added dropwise to neutralize the reaction mixture followed by concentration in vacuo and purification by flash column chromatography (silica gel) using 5-12% MeOH-CH 2 C1 2 saturated 15 with aqueous ammonium hydroxide to give the title compound as an oil (503 mg, 88%, MH

+

= 358).

WO 00/37459 PCT/US99/27939 - 131 PREPARATIVE EXAMPLE 121 cl (H O.,-*** ^\,...-- N,, N CN H O Io- N fr The title compound from Preparative Example 120 (498 mg, 1.4 mmol) was dissolved in anhydrous CH2C12 (10 mL). To this was 5 added the 8-C1-tricyclic chloride (370 mg, 1.4 mmol) and triethylamine (0.6 mL) and allowed to stir at room temperature for 24 h. The reaction mixture was concentrated in vacuo and diluted with CH2C12, purified by flash column chromatography (silica gel) NN using 3% MeOH-CH2Cl2 saturated with aqueous ammonium CN LOH 10 hydroxide to ge t the title compound frompounds as a mixturample 120of diastereomers(498 mg, 1.4 mmol) was dissolved in anhydrous CH 2 Cl 2 (10 mL). To this was 5 added the 8-Cl-tricyclec chloride (370 mg, 1.4 mmol) and triethylanine (0.6 mL) and allowed to stir at room temperature for 24 h. The reaction mixture was concentrated in vacuo and diluted with CH 2 Cl 2 , purified by flash column chromatography (silica gel) using 3% MeOH-CH 2 Cl 2 saturated with aqueous ammonium 10 hydroxide to give the title compounds as a mixture of diastereomers (38% yield) which were separated by preparative chiral chromatography (Chiralpack AD, 5 cm X 50 cm column, flow rate 80 mL/min, 30% IPA-Hexane +0.2% diethylamine). (diastereomer A: 178 mg, MH + = 585; and diastereomer B: 130 mg, MH + = 585). 15 PREPARATIVE EXAMPLE 122 NH-N ~N ) C02H O ON WO 00/37459 PCT/US99/27939 - 132 To the carboxylic acid from Preparative Example 43 (8.11 g, 25 mmol) were added HOBT (4.39 g, 33 mmol), DEC (6.33 g, 33 mmol), the title compound from Preparative Example 88 (5.97 g, 25 mmol), NMM (5.5 mL, 50 mmol) and anhydrous DMF (40 mL). The 5 mixture was stirred at room temperature under N 2 for 48 h. The mixture was concentrated in vacuo, diluted with CH 2 C1 2 and washed with NaOH (aq). The organic phase was dried over anhydrous Na 2

SO

4 , filtered and concentrated in vacuo. The residue was purified by flash column chromatography (silica gel) using 1% 10 MeOH-CH 2 C1 2 saturated with aqueous ammonium hydroxide to give the title compound (5.24 g, 38%, MH + = 556). PREPARATIVE EXAMPLE 123 N OO NHN 0 N ~~ / I N 15 The title compound from Preparative Example 122 (5.23 g, 9.4 mmol), anhydrous CH 2 C1 2 (10 mL) and trifluoroacetic acid (10 mL) were stirred overnight. Aqueous NaOH (iN) was added dropwise to neutralize the reaction mixture, concentrated in vacuo, and purified by flash column chromatography (silica gel) using 5-9% 20 MeOH-CH 2 C1 2 saturated with aqueous ammonium hydroxide to give the title compound as an oil (2.69 mg, 81%, MH

+

= 356).

WO 00/37459 PCT/US99/27939 - 133 PREPARATIVE EXAMPLE 124 H C1 H~ PI(N N N\N H ~ HI - N, . + \C1 N H O '-N- N The title compound from Preparative Example 123 (2.67, 7.5 mmol) was dissolved in anhydrous CH 2 C1 2 (40 mL). To this was 5 added the 8-Cl-tricyclic chloride (1.98 g, 7.5 mmol) and triethylamine (3.14 mL) and allowed to stir at room temperature for 12 h. The reaction mixture was concentrated in vacuo, diluted with

CH

2 C1 2 , washed with a saturated aqueous solution of NaHCO 3 and dried over anhydrous MgSO 4 . After filtration and concentration in 10 vacuo, the residue was purified by flash column chromatography (silica gel) using 1-2% MeOH-CH 2 C1 2 saturated with aqueous ammonium hydroxide to give the title compounds in 43% yield (diastereomer A, 1.2 g, MH + = 583; and diastereomer B, 681 mg,

MH

+ = 583). 15 WO 00/37459 PCT/US99/27939 - 134 PREPARATIVE EXAMPLE 125 N N N f NN HO HH 0 A mixture of the title compound from Preparative Example 106 (200 mg, 0.61 mmol), chlorobenzosuberane (140 mg, 0.61 5 mmol), triethylamine (0.43 mL, 3.1 mmol) and CH 2 C1 2 (10 mL) was stirred at room temperature overnight. The reaction mixture was concentrated in vacuo and purified by preparative plate chromatography (silica gel) using 2% MeOH-CH 2 C1 2 saturated with aqueous ammonium hydroxide to give the title compound as a light 10 yellow solid (63 mg, 20%, MH + = 520). PREPARATIVE EXAMPLE 126 C1 C1 N

CH

3 N

ICI

I H O If the procedure of Preparative Example 114 is followed, 15 except the 3,8-dichloro tricyclic compound Cl Z Cl C1 is used instead of the 8-Cl-tricycle chloride, the title compound would be obtained.

WO 00/37459 PCT/US99/27939 - 135 PREPARATIVE EXAMPLE 127 Step A >rY H O O I ), 2CSA (N) N CO 2 H COH H O 0 To the piperazine carboxylic acid dicamphorsulfonic acid salt 5 (Preparative Example 42) (14.63 g, 24.6 mmol) dissolved in water (80 mL) and dioxane (80 mL) was added 50% NaOH (aq) until pH 11. BOC-ON (6.65 g, 27.04 mmol) was added while stirring at room temperature for 6.5 hrs and while maintaining the pH at 11 with 50% NaOH. The pH was lowered to 9.5 using 10% HCI (aq) and 10 cyclohexyl chloroformate (4.0 g, 24.6 mnimol) was added dropwise while maintaining the pH at 9.5 with a slow addition of 50% NaOH (aq) with stirring at 25 0 C for an additional 12 h. The mixture was extracted with Et 2 0 and the aqueous phase was acidified to pH 3 with 6M HC1 (aq). This aqueous phase was extracted with EtOAc 15 and the organic phase was dried over anhydrous MgSO 4 , filtered and concentrated in vacuo, and purified by flash chromatography (silica gel) using 25-50% EtOAc-hexane to give the title compound (6.65 g, 76%, MH

+

= 357).

WO 00/37459 PCT/US99/27939 - 136 Step B O H N N N '/C02H

/CO

2 H O 0 0O O O The title compound from Step A (6.65 g, 18.7 mmol) and trifluoroacetic acid (20 mL) dissolved in anhydrous CH 2 Cl 2 (50 mL) 5 were stirred at room temperature for 1 hr. The organic phase was concentrated in vacuo to give a residue. Step C H CN Cl NN CO2H ->N + N O N )'/CO 2 H N 2 OO O 2 O 6 10 The title compound from Step B was dissolved in anhydrous

CH

2 C1 2 (50 mL) and DMF (50 mL). To this was added the 8-C1 tricyclic chloride (8.42 g, 31.8 mmol) and triethylamine (3 mL) and allowed to stir at room temperature for 48 h. The reaction mixture was concentrated in vacuo, diluted with EtOAc, washed with 3N 15 NaOH and the organic phase was neutralized with 50% citric acid and dried over anhydrous Na 2

SO

4 . After filtration and concentration in vacuo, the residue was purified by flash column WO 00/37459 PCT/US99/27939 - 137 chromatography (silica gel) using 2-5% MeOH-CH 2 Cl 2 to give the title compounds (11S,2R diastereomer A, 2.43 g, 27%, MH + = 485; and 11R,2R diastereomer B, 2.5 g, 30%, MH + = 484). 5 PREPARATIVE EXAMPLE 128 O O + H -N AoTo N CO H N zN To the title compound from Preparative Example 43 (1.83 g, 5.6 mmol) were added HOBT (0.88 g, 6.5 mmol), DEC (1.24 g, 6.5 mmol), the title compound from Preparative Example 95 (1 g, 4.6 10 mmol), NMM (1.0 mL, 9.25 mmol) and anhydrous DMF (10 mL). The mixture was stirred at room temperature under N 2 overnight. The mixture was concentrated in vacuo, diluted with CH 2 C1 2 and washed with NaOH (aq). The organic phase was dried over anhydrous Na 2

SO

4 , filtered and concentrated in vacuo. The residue 15 was purified by flash column chromatography (silica gel) using 10% MeOH-CH 2 Cl 2 saturated with aqueous ammonium hydroxide to give the title compound (0.70 g, 24%, MH + = 529). PREPARATIVE EXAMPLE 129 NN N v'- N. 4

H

0 00t 20 0 o The title compound from Preparative Example 128 (0.70 g, 1.3 mmol), anhydrous CH 2 Cl 2 (10 mL) and trifluoroacetic acid (10 WO 00/37459 PCT/US99/27939 - 138 mL) were stirred at room temperature for 12 h, then concentrated in vacuo. Aqueous NaOH (IN) was added dropwise to neutralize the reaction mixture and the resulting mixture was extracted with

CH

2 C1 2 . The organic phase was dried over anhydrous Na 2

SO

4 , 5 filtered and concentrated in vacuo to give a residue which was purified by flash column chromatography (silica gel) using 10% MeOH-CH 2 C1 2 saturated with aqueous ammonium hydroxide to give the title compound as a brown oil (232 mg, 53%, MH + = 329). 10 PREPARATIVE EXAMPLE 130 Br Cl IH N N NN ' N rN H O The title compound from Preparative Example 129 (0.20 g, 0.61 mmol) was dissolved in anhydrous DMF (5 mL). To this was added the tricyclic chloride (Compound No. 42.0) (0.2 g, 0.58 mmol) 15 and triethylamnine (0.43 mL, 3.0 mmol) and allowed to stir at room temperature for 12 h. The reaction mixture was poured into brine and extracted with EtOAc. The organic extract was dried over anhydrous Na 2

SO

4 , filtered and concentrated in vacuo. Purification by flash column chromatography (silica gel) using 10% MeOH 20 CH 2 Cl 2 saturated with aqueous ammonium hydroxide afforded the title compound (100 mg, 27%, MH

+

= 634).

WO 00/37459 PCT/US99/27939 - 139 PREPARATIVE EXAMPLE 131 Step A Br/\ C MeBr C1 N + H-N N \Me r Me -4 N N Me N OH 0 N, N 0N O 0 To the title compound from Preparative Example 51 (1.4 g, 5 70% purity, 1.8 mmol) and CH 2 C1 2 (10 mL) cooled to oC were added triethylamine (0.5 mL, 3.6 mmol) and isobutyl chloro-formate (0.25 mL, 1.9 mmol). After stirring the mixture at 0OC for 3 h, the title compound from Preparative Example 95.1 (0.4 g, 1.7 mmol, isolated by preparative chiral chromatography (Chiralpack AD, 5 cm X 50 10 cm column, flow rate 80 mL/min, 8% IPA +92% Hexane +0.2% diethylamine) was added and the mixture was stirred at room temperature under N 2 overnight. The mixture was washed with IM NaOH(aq) and the organic phase was dried over anhydrous Na 2

SO

4 , filtered and concentrated in vacuo. The residue was purified by 15 flash column chromatography (silica gel) using 2-5% MeOH-CH 2 C12 saturated with aqueous ammonium hydroxide to give the title compound as a mixture of diastereomers (0.45 g, 34%, MH

+

= 747).

WO 00/37459 PCT/US99/27939 - 140 Step B Br Cl B r \C M ON- N ____ H 0 NN L Me ." N + N o .. N B r /c 0H0 0 N CN NMe To a solution of the title compound from Step A (0.45, 0.60 mmol) dissolved in anhydrous CH 2 Cl 2 (5 mL) was added TFA (5 mL). 5 The solution was stirred at room temperature under N 2 overnight, then concentrated in vacuo, diluted with CH 2 C1 2 , washed with IN NaOH (aq) and dried over anhydrous Na 2

SO

4 . The mixture was filtered, concentrated in vacuo and purified by flash column chromatography (silica gel) using 2-5% MeOH-CH 2 Cl 2 saturated 10 with aqueous ammonium hydroxide to give the title compound as a mixture of diastereomers. The diastereomers were separated by preparative chiral chromatography (Chiralpack AD, 5 cm X 50 cm column, flow rate 80 mL/min., 60% IPA + 40% hexane +0.2% diethylamine) to give 0.11 g of diastereomer A and 0.23 g of 15 diastereomer B. Physical chemical data for the 11 S, 2 R(-)-diastereomer A: MH + = 647; [a120D= -45.40 (2.91 mg/2 mL MeOH). Physical chemical data for the 11 R, 2 R(-)-diastereomer B: MH + = 647; [a120D= -23.50 (2.21 mg/2 mL MeOH). 20 WO 00/37459 PCT/US99/27939 - 141 PREPARATIVE EXAMPLE 132 HNN H S Tr Step A 0 HOO Tr Tr 0 5 To a stirred solution of 1-(triphenylmethyl-1H-inmidazol-4-yl) 3 -hydroxypropane (WO 9629315) (5.04g, 13.68 mmoles), phthalimide (2g, 13.6 mmoles) and triphenyl phosphine (3.57g, 13.6 mmoles) in THF (100 mL) at 0OC was added diethyl azodicarboxylate (2.14 mL, 13.6 mmoles) dropwise. The reaction mixture stirred for 10 lh at 0OC and then at room temperature for 16h. Filtered to give the title compound (4.6g, 100%), CIMS: m/z (MH') = 498 ; 8, (CDC13 ) 1.72 (bs, 1H), 1.9 (mn, 1H), 2.05 (m, 1H), 2.6 (mn, 1H), 3.75 (mn, 2H), 6.6- 7.8 (m, 21H). 15 Step B 0 N

\NH

2 N Tr Tr O 0 The title compound from Step A (2g, 4.02 mmoles) and hydrazinehydrate (3.89 mL, 80.39 mmoles) were heated under reflux in ethanol (80 mL) for 16h. The solids were filtered off and 20 the filtrate was evaporated to give the title compound ( 1.35g, 91%), CIMS: m/z (MH ) 368; S, (CDC13 ) 1.8-1.85 (mn, 2H), 2.6-2.62 (inm, 2H), 2.8-2.83 (m, 2H), 7 .1(s, 1H), 7.3 (s, 1H).

WO 00/37459 PCT/US99/27939 - 142 Step C Ph H2N N H N 2 NTr HNN Tr Ph = phenyl To a stirred solution of the title compound from Step B (1.5g, 4.08 mmoles) and benzaldehyde (0.433g, 4.08 mmoles) was added 5 sodium cyanoborohydride (0.256g, 4.08 mmoles). The pH of the solution was adjusted to -4.25 with acetic acid. The reaction mixture was then stirred for 2h. The pH was then adjusted to 11.5 with 50% NaOH and extracted with ethyl acetate. The ethyl acetate extract was washed with water and brine and dried (MgSO 4 ) 10 Evaporated to give a crude residue which was chromatographed on silica gel using 4% (10% conc NH40H in methanol)-CH 2 C1 2 as the eluant to give the title compound (1.04 g, 78%), CIMS: m/z (MH') = 458; 8H (CDC13 ) 1.8-1.82 (m, 2H), 2.58-2.64 (m, 4H), 3.6 (s, 2H), 6.5 (s, 1H), 7.15-7.4 (m, 6H). 15 PREPARATIVE EXAMPLE 133

CH

3 Ph. . I HN N Step A O

CH

3 Q N I2 N TrN O 0 20 The title compound from Preparative Example 132 Step A (2g, 4.1 mmoles) in CH 2 C1 2 (20 mL) was treated with methyl iodide (0.75 mL 12.05 mmoles) and stirred for 16h. Evaporated to dryness to a gummy residue which was then refluxed with 6N HCI (25 mL) for 16h. Evaporation to dryness gave a semisolid which was WO 00/37459 PCT/US99/27939 - 143 neutralized with aqueous NaHCO 3 and evaporation to dryness again gave semi-white solids. Stirred with CH 2 C 2 (100 mL)and MeOH (50 mL) and filtered off the solids. The filtrate was evaporated to give the title compound (0.3g), CIMS: m/z (MH ) 140; 5H (CDC13 ) 1.8 (m, 5 2H), 2.6-2.8 (m, 4H), 3.6 (s, 3H), 6.68 (s, 1H), 7.4 (s, 1H). Step B

CH

3

CH

3 Ph I -2N HN N% N

H

2 The title compound from Step A (1.97g 14.14 mmoles), 10 benzaldehyde (1.65g 1 5.55mmoles), sodium acetate (1. 1g, 13.42 mmoles) and 3A molecular sieves (2g) in methanol were stirred for 18h. To this sodium borohydride (0.519g 13.72 mmoles) was added and stirred for 4h. The solids were filtered off and the filtrate was evaporated to a residue which was chromatographed to give the title 15 compound (0.59g 18.5%) CIMS: m/z (MH') 230; 6H (CDCl,)1.8 (q, 2H), 2.6 (t, 2H), 2.65 (t, 2H), 3.25 (s, 3H), 3.8 (s, 2H), 7.2-7.4 (m, 7H). PREPARATIVE EXAMPLE 134

NH

2 N OH 20 Step A

N

3 ON N N OH 1-(2-Phenyl-2,3-epoxypropyl)-1H-imidazole (GB 2 099818 A) (2.15g, 10.85 mmoles) and sodium azide (1.41g, 21.71 mmoles) WO 00/37459 PCT/US99/27939 -144 were heated in DMF (20 mL) at 600C for 16h. Evaporated to dryness and extracted with CH 2

C

2 , washed with brine and dried (MgSO 4 ). Evaporated to give the title compound (0.932g, 36%), CIMS: m/z (MH ) = 244; 5H (CDC13) 3.7 (q, 2H0, 4.5 (dd, 2H), 6.6 (s, 5 1H), 6.95 (s, 1H), 7.3-7.45 (m, 5H), 8.2 (s, 1H). Step B

N

3 NH 2 N /N \N OH OHN ION 10O The title compound from Step A ( 0.8g, 3.31 mmoles) in 10 ethanol (15 mL) was hydrogenated over 10% Pd on carbon (0.2g) at 50 psi overnight. The catalyst was filtered off and evaporated to give the title compound (0.71g 98%). CIMS: m/z (MH') = 218. PREPARATIVE EXAMPLE 135 Br , Cl Br Cl Br N Cl H Br H Br + H Br (+) N HOOC N N % COOH H COOt-Bu COOt-Bu 15 (A) (B) By following Steps a to e of Preparative Example 41 starting with the (+) isomer, a mixture of the title compounds A and B is obtained as a light tan solid that appears as a single tlc spot: 'NMR (CDC1 3 , 300 MHz) 8 1.42 (s, 9H), 4.85 (m, 2H), 7.12 (s, 1H), 7.50 (s, 20 1H), 7.55 (s, 1H), 8.48 (m, 1H); HRMS (FAB) calcd for C 25

H

28

N

2 0 4 BrCl 1 'Br 615.0084, found 615.0092.

WO 00/37459 PCT/US99/27939 - 145 PREPARATIVE EXAMPLE 136 BOC H N N H H N t1N N, N N "t/ N N N H O H 0 Following the procedure set forth in Preparative Example 123, but using the title compound from Preparative Example 37 Step A. 5 the title compound was obtained (quantitative yield; MH' = 338). PREPARATIVE EXAMPLES 137-138 Following the procedure described for Preparative Example 106, the piperazines listed in Table 5A below were prepared using 10 the corresponding amines. TABLE 5A Prep. Amine Product yield MH* Ex. o% H2H H 2 N -, r Me H 47 238 137 N N N' N H Me H2N N N N He 138 e Y ., NHYe 10Me H-0 100 238

H

2 N-\,NN ___~~~ Me\__ J ~~/ _ _ _ _H_ H o: WO 00/37459 PCT/US99/27939 -146 PREPARATIVE EXAMPLES 139-141 Similarly, using the procedure described for Preparative Example 110 and the piperazines listed in the Table 5B below, the corresponding tricyclic amines were prepared. 5 TABLE 5B Prep. Piperazine Product yield MH' Ex. Q)H -- N N.Br Cl 139 n N N 73 543 Me N MN f' -N/'-r He Me Hd Br cl Me N Be 1? *. ' Jr-N,,N (N). Me 140 H )( H 34 543 ) H H 14N" -N N B C4I H N~ 0 I N H 141 0 N (N 31 543

H

0 _,N WO 00/37459 PCT/US99/27939 - 147 PREPARATIVE EXAMPLE 142 Br CI Br \ C

NIN

1 H, f- N... N*N, (AO+A+B O N Me N Me HH N -N N N N H NN H N N, 00 (A+B) (A+B) Br CI Br Cl -A-N H eNzN H' N N e1-NN (A+B) D-" O (A+B) The title compound from Example 289 (0.39 g, 0.51 mmol), anhydrous CH2C12 (3 mL) and trifluoroacetic acid (3 mL) were 5 stirred at room temperature for 2 h, then concentrated in vacuo. Aqueous NaOH (IN) was added dropwise to neutralize the reaction mixture and the resulting mixture was extracted with CH2C12. The organic phase was dried over anhydrous MgSO4, filtered and concentrated in vacuo to give a residue which was purified by flash 10 column chromatography (silica gel) using 5% MeOH-CH2C12 saturated with aqueous ammonium hydroxide to give the title compound as an off-white solid (52 mg, 15%, mp = 150oC, MH + = 768). 15 PREPARATIVE EXAMPLE 143 N H2 H2N N o N HO N Me WO 00/37459 PCT/US99/27939 - 148 A solution of the title compound from Preparative Example 71 (0.9 g, 5.14 mmol) and the anhydride from Preparative Example 44 (1.38 g, 1.05 eq) dissolved in anhydrous dichloromethane (10 ml) was stirred at room temperature overnight. Additional anhydride 5 (0.105 g) was added and after 1 hr cyclohexyl isocyanate (0.98 mL, 7.71 mmol) was added to the reaction mixture which was stirred for an additional 1.5 hrs. Concentration in vacuo and purification by flash column chromatography (silica gel) using 1-3% MeOH-CH2C12 saturated with ammonium hydroxide as eluent afforded the title 10 compound as a white solid (1.82 g, 69%, mp = 126.9-128.9 oC, MH+ = 513). PREPARATIVE EXAMPLES 144-149 Following essentially the same procedure as that described for 15 Preparative Example 143, the BOC-protected piperazines listed in Table SC below were prepared using the corresponding amines. TABLE 5C Prep. Amine Product yield MH+ Ex. (%) 145 2N NN 100 500 _________ _______N N,,_ __ _ __ WO 00/37459 PCT/US99/27939 - 149 H

CF

3 N 3

H

2 N ' . ?'R 146 ,HJ 57 517 0, NOr \--- CF 3 IN tMe BOC 2 O0 BOC 149 "! r OH 58 465 149A H2NM H BOC N N NBOC N N "N MeN H 149B H2H HNMeH N OO N H PREPARATIVE EXAMPLE 150 BOC I N N N N Cz

N

0 H 5 If one were to follow essentially the same procedure as that described for Preparative Example 143, but using the amine WO 00/37459 PCT/US99/27939 - 150 H

H

2 N v /- CH 3 N instead of the amine from Preparative Example 71, the title compound would be obtained. 5 PREPARATIVE EXAMPLE 151 0 Me N)",-- H OO N

H

2 N O NN N O O1\0 N Me Me Me O

H

2 N- N

M

e. Me O OO N : N Me A solution of the title compound from Preparative Example 68 (2.12 g, 15.2 mmol), triethylamine (30.4 mmol) and the anhydride from Preparative Example 44 (3.89 g, 15.2 mmol) dissolved in 10 anhydrous dichloromethane (30 ml) was stirred at room temperature for 30 min. Benzyloxycarbonylsuccinimide (4.17 g, 16.7 mmol) was added and the resulting mixture was stirred at room temperature overnight. Concentration in vacuo and purification by flash column chromatography (silica gel) using 2% 15 MeOH-CH2C1 2 saturated with ammonium hydroxide as eluent afforded the title compounds (2.57 g, 35%). The regioisomers were separated by HPLC (Chiracel AD column) using 5% isopropanol 95% hexane-0.2% diethylamine to give the 2,4-dimethyl isomer (mp = 64.2 0 C, MH + = 486) and the 2,5-dimethyl isomer (mp = 71.5 oC, 20 MH

+

= 486).

WO 00/37459 PCT/US99/27939 - 151 PREPARATIVE EXAMPLE 152 Br C1 Br/\ C1 N 'N N (A) N (A) Me N N Me 0 NY HO N Me HBr Me A solution of the title compound from Example 293 5 diastereomer A (0.386 g, 0.56 mmol), glacial acetic acid (3 mL) and 33% HBr in acetic acid (1 mL) was stirred at room for 2 hr. Diethyl ether was added and the precipitate filtered and dried under vacuo to afford the title compound (0.48 g, 100%, MH + = 557. 10 PREPARATIVE EXAMPLE 153 B \k CI Br7 CI N (B) < (B) O(N) a Me H Me 0 0o . " 0 Me HBr M A solution of the title compound from Example 293 diastereomer B (0.372 g), glacial acetic acid (3 mL) and 33% HBr in acetic acid (1 mL) was stirred at room for 2 hr. Diethyl ether was 15 added and the precipitate filtered and dried in vacuo to afford the title compound (0.433 g, 100%, MH

+

= 557.

WO 00/37459 PCT/US99/27939 - 152 PREPARATIVE EXAMPLE 154 Step A HO (N + H N) N N ) O Me H N Me A mixture of the title compound from Preparative Example 66 5 (1.0 g, 7.2 mmol), the anhydride from Preparative Example 44 (2.2 g, 8.6 mmol), triethyl amine (1.5 mL, 10.8 mmol) and anhydrous CH2C12 (10 mL) was stirred at room temperature for 12 hrs. The mixture was concentrated in vacuo, diluted with CH2C12 and washed with a saturated aqueous solution of NaHCO3. The organic 10 phase was dried over anhydrous Na2SO 4 , filtered and concentrated in vacuo. Step B BOC Br \ CI HN N HO 0 NN Q H Me HO N Me 15 Trifluoroacetic acid (10 mniL) was added to the title compound from Step A above (1.0 g, 7.2 mmol) dissolved in CH2C12 (10 mL) and the resulting mixture was stirred for 5 hrs at 25oC. The mixture was concentrated in vacuo, diluted with CH2C12 (50 mL) and combined with the tricyclic chloride (compound # 42.0) (2.7 g, 7.9 20 mmol) and triethylamine (5-10 mL) and stirred at room temperature overnight. The mixture was concentrated in vacuo, diluted with CH2C12 and washed with a saturated aqueous solution of NaHCO3. The organic phase was dried over anhydrous Na2SO 4 , filtered, concentrated in vacuo and purified by flash column chromatography WO 00/37459 PCT/US99/27939 - 153 (silica gel) using 5% MeOH-CH2C12 saturated with aqueous ammonium hydroxide to give the title compound as a mixture of diastereomers (1.9 g, 47%, MH + = 557). 5 PREPARATIVE EXAMPLE 155 Step A 0 N40 N__N OEt + NH N 0 ~ 2 HC1.H 2

N

N H N-Carbethoxyphthalimide (62.8 g, 0.275 mol, 1.1 eq.) was added portionwise over a period of 30 minutes to a stirred solution 10 of histamine dihydrochloride (46.7 g, 0.250 mol, 1.0 eq.) and sodium carbonate (54.3 g, 0.513 mol, 2.05 eq.) in distilled water (1250 ml) at room temperature. The resulting snow-white suspension was stirred vigorously at room temperature for 90 minutes. The solid was filtered off and thoroughly washed with ice 15 cold distilled water (4 x 50 ml). The solid was collected and dried under vacuum over P 2 0 5 at 600C for 12h to give the title compound (59.2 g, 0.245 mol, 98%, MH + = 242). Step B o o \0 ---- NH 0N O 20 A solution of chloromethyl pivalate (18.5 ml, 0.125 mol, 1.2 eq.) in anhydrous N,N-dimethylformamide (DMF, 100 ml) was added dropwise over a period of one hour to a stirred mixture of Step A above (25.0 g, 0.104 mol, 1.0 eq.) and potassium carbonate (17.2 g, WO 00/37459 PCT/US99/27939 -154 0.125 mol, 1.2 eq.) in anhydrous DMF (500 ml) at 90 0 C under a nitrogen atmosphere. The mixture was stirred at 90 0 C for 12h. The volatiles were removed under vacuum at 50 0 C. The residue was taken up in brine (100 ml) and extracted with ethyl acetate (4 x 25 5 ml). The combined organic extracts were dried over Na 2

SO

4 , filtered, and concentrated under vacuum at 30oC. The residual off-white solid was flash-chromatographed (hexanes : acetone = 6: 4 v/v) over silica gel to give the title compound (20 g, 0.056 mol, 54%,

MH

+ = 356). 10 Step C

O

O CI Cl N O N NO \-o LO-o A solution of the title compound from Step B above (5 g, 14.1 mmol) and 4-chlorobenzylchloride (2.5 g, 15.5 mmol) was stirred in 15 anhydrous acetonitrile (60 ml) at reflux under a nitrogen atmosphere for 48 h. The mixture was concentrated in vacuo and recrystallized from ethyl acetate-hexane to give the title compound as a solid (3.2 g, 47%, MH+ = 480), and the filtrate which was concentrated to give additional product (3.6 g, 53%). 20 Step D o Cl l o Cl NO N A 7 N solution of ammonia in methanol (10 ml, 0.07 mol) was added slowly to a stirred solution of the title compound from Step C 25 above (3.2 g, 6.6 mmol) diluted with MeOH (10 mL) at WO 00/37459 PCT/US99/27939 - 155 -20 0 C. The resulting mixture was warmed to room temperature and stirred for another 12 h, then concentrated in vacuo and purified by flash column chromatography (silica gel) using 3% MeOH-CH2Cl2 saturated with ammonium hydroxide as eluent to afford the title 5 compound as a sticky solid (1.2 g, 51%, MH + = 366). Step E O Cl H- Cl N H 2 N r0 N N N N A solution of the title compound from Step D above (1.21 g, 10 3.3 mmol) and hydrazine monohydrate (1.7 ml, 0.033 mol, 10 eq.) in absolute ethanol (20 ml) was stirred at 50 oC under a nitrogen atmosphere for 20 min. The resulting suspension was diluted with ethanol and dichloromethane and filtered. The filtrate was concentrated in vacuo to afford the title compound as a yellow oily 15 solid (0.7 g, 91%, MH + = 236). Step F oO%

H

2 N ( , C1 H2C /H N Cl N HO N A solution of the title compound from Step E above (0.695 g, 20 2.94 mmol) and the anhydride from Preparative Example 44 (0.75 g, 2.94 mmol) dissolved in anhydrous dichloromethane (10 ml) was stirred at room temperature overnight. Additional anhydride (0.1 g) was added and after 1 hr the reaction mixture was diluted with CH2C12 and extracted with IM HC1 (aq). The aqueous phase was 25 basified with IN NaOH (aq), extracted with CH2Cl2 and the organic WO 00/37459 PCT/US99/27939 - 156 phase dried over anhydrous MgSO4. After filtration, the organic phase was concentrated in vacuo to afford a white foam (0.744 g, 57%, MH + = 448). 5 PREPARATIVE EXAMPLES 156-157 Following the procedure described for Preparative Example 155 Steps C-F, the piperazines listed in Table 5D below were prepared using the corresponding arylalkyl halides. 10 TABLE 5D Prep. Halide Product MH' Ex. 156 H 428 Br Br 0 CN 157 HCN 441 N PREPARATIVE EXAMPLE 158 STEP A BOC

H

2 N 0H 15 N N - HNNN NN To 3 -(1H-imidazol-1-yl)propylamine (20 mL, 167.6 mmol) dissolved in water (200 mL) and MeOH (200 mL) was added 50% NaOH (aq) until pH 9.5. Di-tert-butyldicarbonate (41 g, 187.9 mmol) was added while stirring at room temperature for 4 hrs and 20 while maintaining the pH at 9.5 with 50% NaOH. The mixture was WO 00/37459 PCT/US99/27939 - 157 concentrated in vacuo to remove most MeOH, then extracted with CH2C12. The organic phase was dried over anhydrous MgSO4, filtered and concentrated in vacuo to give the title compound (23.7 g, 63%, MH + =226). 5 Step B BOC BOC HN __HN___.N HNF OH To a solution of the title compound from Step A above (0.50 g, 2.22 mmol) dissolved in anhydrous THF (15 ml) and stirred at -78oC 10 was added n-butyllithium (2.8 mL, 1.75M in hexane) and the resulting mixture was warmed to and stirred at -20 0 C for 1.5 h. The reaction mixture was recooled to -780C and anhydrous DMF (0.35 mL, 4.52 mmol) was added. After warming to and stirring at 25oC for 2 h, MeOH (2 mL) and NaBH4 (171 mg, 4.5 mmol) were 15 added and the resulting mixture was stirred for 1 h at 25oC. The mixture was concentrated in vacuo, diluted with dichloromethane, washed with water, and the organic phase was dried over anhydrous Na2SO4, filtered, and concentrated in vacuo. Purification by flash column chromatography (silica gel) using 5-10% MeOH 20 CH2C12 saturated with ammonium hydroxide as eluent afforded the title compound (0.32 g, 56%, MH

+

= 256).

WO 00/37459 PCT/US99/27939 - 158 Step C BOC HN _N ,N

H

2 N /= HCI OH OH To the title compound from Step B above (0.31 g, 1.2 mmol) was added 4M HC1 in dioxane (5 mL) and the mixture was stirred at 5 25 0 C for 12 h. Concentration in vacuo afforded a residue which was used directly in Step D. Step D Br CI/ S H 2 N HCI N + N N N O OH '/ N N O O H O NK- OH H 10 A mixture of the title compound from Step C above, triethylamine (4 mL) and the anhydride from Preparative Example 44 (0.55 g, 2.15 mmol) dissolved in anhydrous DMF (10 ml) was stirred at room temperature overnight. The mixture was concentrated in vacuo and diluted with anhydrous CH2C12 (5 mL), 15 DMF (5 mL) and trifluoroacetic acid (10 mL). The resulting mixture was stirred for 12 hrs at room temperature, then concentrated in vacuo and diluted with anhydrous CH2Cl2 (5 mL) and DMF (5 mL). The tricyclic chloride (compound # 42.0) (0.75 g, 2.17 mmol) and triethylamine (3 mL) were added and the mixture was stirred at 20 25 0 C for 48 h. The mixture was concentrated in vacuo, diluted with CH2C12 and washed with a saturated aqueous solution of NaHCO3. The organic phase was dried over anhydrous Na2SO4, filtered, concentrated in vacuo and purified by flash column chromatography (silica gel) using 5-10% MeOH-CH2C12 saturated with aqueous WO 00/37459 PCT/US99/27939 - 159 ammonium hydroxide to give the title compound as a mixture of diastereomers (0.376 g, 33%, MH + = 573). PREPARATIVE EXAMPLES 159-160 5 Following the procedure described for Preparative Example 158 Step D, the piperazines listed in Table 5E below were prepared using the corresponding amines or amine hydrochlorides. TABLE 5E 10 Prep. Amine Product 1. yield Ex. (%) 2. MH' HC1 BA{ -(- CI 1.37 HN N 2.559 159 H2N 2N OH rN OH B 1.25 OTBDMS N OH 2.573 160 H2N NN N HvN PREPARATIVE EXAMPLE 161 Step A OH OTBDMS H-N N H-NN 15 A mixture of 4-hydroxymethylimidazole (2 g, 14.9 mmol), triethylamine (5 mL) and TBDMS-C1 (2.5 g, 16.6 mmol) dissolved in anhydrous CH2C12 (20 ml) was stirred at room temperature overnight. The mixture was filtered, diluted with anhydrous Et20 and refiltered. The filtrate was concentrated in vacuo, diluted with 20 CH2C12 and washed with a saturated aqueous solution of NaHCO3.

WO 00/37459 PCT/US99/27939 -160 The organic phase was dried over anhydrous Na2SO4, filtered and concentrated in vacuo to give the title compound (2.22 g, 71%, MH + = 213). 5 Step B OTBDMS NOTBDMS OTBDMS H-N NC N.N + NC ' N..N A solution of the title compound from Step A above (2.22 g, 10.5 mmol) dissolved in acrylonitrile (10 ml) was stirred at reflux for 48 h. Concentration in vacuo afforded the title compound (2.09 g, 10 75%, MH + = 266). Step C W OTBDMS HN OTBDMS NC N--.

N

H

2 N NN + ol + OTBDMS OTBDMS 11::; H2N NCH NC'^\.N--;N 2 N. A mixture of the title compound from Step B above (2.08 g, 15 7.85 mmol), Raney nickel (230 mg), MeOH (20 mL) and NH 4 OH (7.5 mL) was stirred in a Parr hydrogenator at room temperature for 48 h. The mixture was filtered through celite, concentrated in vacuo, diluted with CH2C12 and washed with a saturated aqueous solution of NaHCO3. The organic phase was dried over anhydrous Na2SO4, 20 filtered, concentrated in vacuo and purified by flash column chromatography (silica gel) using 5% MeOH-CH2C1 2 saturated with aqueous ammonium hydroxide to give the title compounds [(4 substituted isomer, 465 mg, 22%, MH + = 270) and (5-substituted isomer, 220 mg, 10%, MH

+

= 270)].

WO 00/37459 PCT/US99/27939 - 161 PREPARATIVE EXAMPLE 162

H

2 N N Following the procedure described for Preparative Example 155 Steps C-E, except using 4-fluorobenzyl bromide instead of 4 5 chlorobenzyl chloride in Preparative Example 155 Step C, the title compound was prepared (52%, MH + = 220). PREPARATIVE EXAMPLE 163 CN

H

2 N N N 10 Following the procedure described for Preparative Example 155 Steps C-E, except using 4-cyanobenzyl bromide instead of 4 chlorobenzyl chloride in Preparative Example 155 Step C, the title compound was prepared (63%, MH + = 227). 15 PREPARATIVE EXAMPLE 164 C1 H Cl N N N ' -. , OH N Cl OK O ~~ OKO., O Tricyclic chloride (5.04g, 1.1 eq.) was added to a solution of the title compound from Preparative Example 50 (4.0g, 17.3 mmol) and TEA (12.05 mL, 5 eq.) in DMF (60 mL). The resulting solution 20 was stirred at room temperature 72 hours at which time the WO 00/37459 PCT/US99/27939 - 162 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 Na 2

SO

4 , filtered, 5 and concentrated in vacuo. The crude product was purified by flash chromatography using a 12% (10% NH40H in MeOH) solution in

CH

2 C12 as eluent to give the C-11 (S)-isomer (2.13g, 54%) as the first eluting isomer and the C-11 (R)-isomer (2.4g, 61%) as the second eluting isomer. N N 11 S,2R(+)-Isomer C. OH N ",I °" 10 O 11 I(S),2(R) (+)-isomer (first eluting isomer): [u1 2 0 D= +84.9 (5.18mg in 5.0 mL MeOH); LCMS: MH'= 458. \KC N 11 R,2R Isomer O OH N I 1 (R),2(R)-isomer (second eluting isomer): FABMS: MH'= 458. 15 PREPARATIVE EXAMPLE 165 Me HN N

N

WO 00/37459 PCT/US99/27939 - 163 Following the procedure described for Preparative Example 25, except using the title compound from Preparative Example 13 instead of N-1-methyl histamine, the title compound was prepared (33%, MH + = 195). 5 PREPARATIVE EXAMPLE 166 Br/\ Cl Diastereomer A ) Me N " H KN N Similarly, using the procedure described for Preparative Example 142, except using the title compound from Example 305 10 diastereomer A instead of the title compound from Example 289, the title compound was prepared (80%, MH + = 599). PREPARATIVE EXAMPLE 167 Br"/ ClOM N Diastereomer B Me H 0 N 15 Following the procedure described for Preparative Example 142, except using the title compound from Example 305 diastereomer B instead of the title compound from Example 289, the title compound was prepared (100%, MH

+

= 599).

WO 00/37459 PCT/US99/27939 - 164 PREPARATIVE EXAMPLE 168 Step A Br Cl Br Cl N N N Cl \ N H MeO OMe MeO MeOMe The title compound from Preparative Example 40A Step A 5 (compound 52.ii) (5 g, 12.8 mmol) was dissolved in 2.7 ml of 2,4 dimethoxybenzaldehyde by heating to 120 0 C. Formic acid (1.3mL) was dripped into the reaction mixture while the reaction mixture stirred at 120 'C for 45 min. The resulting solid mixture was dissolved in dichloromethane and dried over magnesium sulfate, 10 filtered and evaporated to dryness to obtain a solid which was chromatographed on silica gel to obtain 5.17 g of title product. FABMS (M+1)= 463.4 Step B Br C1 Br Ci 1) Hg(OAc) 2 /85 0 C ~N 2) KCN/ 0 0 C >r.t. N CN N N C 57% 15 Meo OMe Meo OMe The title compound from Step A (1 gm, 1.8 mmol) was dissolved in 45 ml of 5% acetic acid/water and stirred at 85 0 C. Mercuric acetate ( 2.3 gm) was added and the reaction mixture stirred for 5 hours. After cooling in an ice bath, potassium cyanide 20 ( 1.25 gm) was added and the reaction mixture stirred vigorously for WO 00/37459 PCT/US99/27939 - 165 18 hours. iN Sodium hydroxide (excess) was added and the product extracted with ethyl acetate three times. After chromatography on silica gel using ethylacetate as the eluent,0.747 gm of title product was obtained. 5 Step C Br C1 N Br C1 N N CN TFA/anisole H + 47% N CN Br Cl N MeO OMe N NH 2 HI 0 major The title product from Step B (0.2 gin) was dissolved in 6 ml of trifluoroacetic acid and 0.5 ml of anisole and stirred for 1 hour at 10 60'C to obtain the title carboxamide product (72 mg) after silica gel chromatography using 2% methanol/dichloro-methane as the eluent. FABMS (M+I)= 432. Step D Br C1 Br Cl NI N I N N H 2

CH

3 OH HCH N H O HzC'O 0O 15 H3C WO 00/37459 PCT/US99/27939 - 166 The major product (carboxamide) from Step C (0.19 gin) was dissolved in 10 ml of 6N hydrochloric acid and refluxed for 24 hours. The 6 N HC1 was removed under vacuum and the residue dissolved in water (5 ml). Di-tert-butyldicarbonate ( 0.13 gin) was 5 added and the pH of the reaction mixture brought to 9.0 with 1 N sodium hydroxide. After stirring 2 hours at ambient temperature, the reaction mixture was added to citric acid and extracted with dichloromethane to obtain the crude product which was chromatographed on silica gel to obtain 93 mg of title product. 10 FABMS (M+1)= 533. Step E Br Cl Br Cl N N H fN

CH

3 N OH CH N N N H3C'o O H3C- o 0

H

3 C H 3 C The title compound from Step D (70 mg, 0.13 mmol) 15 was dissolved in 2 ml of DMF and DEC (37 mg, 0.19 mmol.), HOBT (26 mg, 0.19 mmol), and N-methyl-morpholine (42 uL, 0.4 mmol) were added and the reaction mixture stirred at ambient temperature for 7 hours. After addition to water and extraction with dichloromethane, the crude product was chromatographed on 20 a silica gel column to obtain 86 mg of title product. FABMS (M+1) = 640.

WO 00/37459 PCT/US99/27939 - 167 PREPARATIVE EXAMPLE 169 11-Chloro-6,11-dihydro-5H-benzo[5,6]cyclohepta[1,2-B]pyridine. / \4NaBH/ \ SOC12/ N N N 0 OH Cl The ketone (starting material) 5,6-dihydro- 11H 5 benzo[5,6]cyclohepta[ 1,2-c]pyridine- 11-one, may be prepared by following the methods described in U.S. 3,419,565. Sodium borohydride (2g, 53.3mmol) was added to a solution of the ketone (3g, 14.35mmol) in methanol (50ml) at 0oC, then stirred for 2 hours at room temperature. The reaction was quenched 10 by addition of ice (10g) and 2N HC1 (10ml, basified with 2N NaOH (13ml)and extracted with MeC1, (2x50ml). The organic layer was separated,dried over MgSO 4 , filtered and solvent evaporated yielding the alcohol (3g, 100%). 1H NMR (DMSO, 8) 3.0-3.4(m,4H) 6.101(brs,2H) 7.0 15 7.3(m,4H) 7.5(m,2H) 8.314(d,1H). Thionyl chloride (3ml, 41.12mmol) was added to a solution of the alcohol (2.5g, 11.84 mmol) in MeCl 2 (50ml) at room temperature,then stirred for 1 hour. The solvent was evaporated, water 50 (ml) and 5% NaOH (10ml) were added. The mixture was 20 extracted with MeCl 2 (100ml), organic layer was dried over MgSO 4 , filtered, and solvent evaporated yielding a tan solid, which was triturated with ether, and filtrate concentrated yielding a white solid. (1.5g). 1H NMR (CDC1 3 , 8) 2.9-3.0 (m, 2H), 3.6 (mn, 1H), 3.9 (m, 1H), 25 6.3 (s, 1H), 7.2 (m,3H). 7.3 (d, 1H), 7.4 (d, 1H), 7.5(d, 1H), 8.42 (d, 1H). The filtered solid was dried yielding (0.9g) of additional material. Total yield (2.4g, 87%).

WO 00/37459 PCT/US99/27939 - 168 PREPARATIVE EXAMPLE 170 H N

CH

3 N C N+, N, N N N /r CIl H 0 N Cl

CH

3 N *l '/ NN I ~II H 0 Acetonitrile (5ml) was added to a mixture of the O10-Chloro 5 tricycle (0.5g, 1.90mmol) (Preparative Example 9.1) and the substituted piperazine (0.78g, 1.90mmol).Triethylamine (lml, 7.18mmol) was added,and the mixture stirred overnight at room temperature.Water (50ml) and 5% NaOH were added and the mixture was extracted with MeC12 (2xl00ml). The organic layer was 10 separated,dried over MgSO 4 and solvent was evaporated yielding desired product (0.7g, 57%) as a mixture of 2 diastereomers, which were separated by column chromatography on silica gel, eluting with 5% v/vMeOH/MeCl 2 containing 2% NH 4 OH. Isomer A (the less polar isomer) eluted first. 15 TABLE 5F Isomer Mass [a] (Fabs, MH) A, B 569.1

-----

A 569.2786 -55.90 c= 0.1085 B 569.2816 -27.4c = 0.1085 WO 00/37459 PCT/US99/2793 9 - 169 PREPARATIVE EXAMPLE 171

NH

2 H N3 >1OH STEP A H3 Cl + HN H3 5 A mixture of 2-chloroacetophenone (25g, 0.16 moles) and 4 methyl imidazole (66. 1g, 0.8 moles) was heated at 100 oC for 2h. Cooled and the crude product chromatographed on a silica gel column eluting with CH 2 C1 2 / 3% CH30H saturated with aqueous ammonium hydroxide to give mixture of 4- and 5- methyl 1H 10 imidazolyl acetophenone (23g, 73%), MS, MH + = 201). STEP B O CH 3 O CH 3 Trityl chloride (7.28g, 0.26 moles) was added to the product 15 from Step A in CH 2

C

2 (200 mL) and stirred overnight at room temperature. The mixture was chromatographed on a silica gel column eluting with ethyl acetate / acetone (3:1) to give 4-methyl 1H-imidazolyl acetophenone (15.5 g), FabMS: MH'= 201. 20 STEP C

CH

z NaH/DMSO C H3 /N+ (C-S-1 I N + To a mixture of NaH (0.998 g, 24.97 mmoles, and trimethyl sulfoxonium iodide (5.49g, 24.97 mmoles) in DMSO (50 mL) the WO 00/37459 PCT/US99/27939 - 170 product (5g) from Step B was added and stirred for 1.5h. Extracted the product with ethyl acetate and washed with brine, dried and solvent evaporated to give 1 -( 2 -phenyl-2,3-epoxypropyl)-l1H-4 methyl imidazole ( 3.44 g, 64 %) , FABMS : MH = 215) 5 STEP D

N

3 CH,

OH

3 NaN3/ DMF OlN ; N /N N OH The product from Step C (3.45g, 16.11 mmoles) and sodium azide (2.093g, 32.21 mmoles) were heated in DMF (100 mL) at 60 0 10 C for 12h. Evaporated to dryness and extracted with CH 2 C14, washed with brine and dried (MgSO 4 ). Evaporated to give the title compound (3.83g, 93%). FABMS: MH' = 258 STEP E

N

3

NH

2

CH

3 OH 3 15 OH -OH The title compound from Step D in ethanol ( 80 mL) was hydrogenated over 10% Pd on carbon (1.2 g) at 50 psi overnight. The catalyst was filtered off and evaporated to give the title compound (2.83g, as yellow viscous oil). 20 PREPARATIVE EXAMPLES 172-188 Following the procedure set forth in Preparative Example 74 but using the aldehyde and imidazoalkyl amine (Imidazole) in Table 5G, the amines (Product) in Table 5G were obtained. 25 WO 00/37459 PCT/US99/27939 - 171 TABLE 5G Prep Aldehyde Imidazole Product Ex. HO OH 0 172 H H/Me Me H H %/oYield = 60 MH = 246 N-0 0 173 H e/ ONN, / H N N %Yield = 22 MH = 247 C,H H H H 174 H ,OH Ne "H .,M 0 H -,NN %Yield = 27 MH'= 214 0 175 c H e Cl e ci H N N %Yield = 59 MH = 299 CI 0 o 176 C' H H<e H e H N Cl~H ~ N \,N %Yield = 76 MH = 264 WO 00/37459 PCT/US99/27939 - 172 Cl 0 177 I H =Me Me C H\ H N O/oYield = 77 MH = 264 C 178 /H Me N N H IN\,N 0 CI HA\\N~ ~ %Yield = 79 MH = 264 HO HO 0 H .Me e 179 H H ==Me N O H , N H N l/N OH Me %Yield = 45 MH= 291 Me Me 180 H H \ N H NN NN %Yield = 71 MH*= 244 1 8 1 H, , .. -. 181 H N N H N N %/oYield = 25 MH*= 258 O o Me 182 H HlN Me N HN N I o %Yield = 89 MH= 247 WO 00/37459 PCTIUS99/27939 -173 0 ~H2 N 183 H\-eHN, C Me %/Yield = 13 _____ ____ ____ MH'= 180 N8 H H N H %Yield = 27 _______ ___ ___MH= 232 HO JH,

H

3

H

2 N N 185

CH

3 H 11N " CH 3 %/Yield = 50 MH'= 195 HO H

H

2 N N 186 NH N

H

3 %Yield = 12 ____ MH'= 180 187 0meq\MI NT N Me\~M H NTN Me %/Yield = 84 _____ ____ ____ MH+= 258 WO 00/37459 PCT/US99/27939 - 174 H2 1 88 H K' \/\~JN~,N NH %Yield = 88 _MH+= 266 PREPARATIVE EXAMPLES 190-197 Using the procedure described for Preparative Example 109, 5 but using the title compounds from the Examples listed in the Table 5H, the Product amines were prepared. TABLE 5H Prep. BOC Product 1.Yield Ex. compound (%) from Ex. 2. MH' No. Br /l CI N 190 343N 1 1.661 N N Me 2.87 N N O N ,N HT Me Isomer A Br CI N 191 344 N1.661 N Me 2.80 N N N HO Me Isomer B WO 00/37459 PCT/US99/27939 - 175 Br CI N 192 345 I 1.72 N Me Me 2. 661 N N NN H Isomer A Br CI N 193 346 N 1.71 Me \ Me 2. 661 N N H Isomer B Br/\ CI N 194 347 N 1.93 KN Me 2. 661 H 0 NN Isomer A Br CI N 195 348 N 1.92 .. Me 2. 661 H 0 N N Isomer B WO 00/37459 PCT/US99/27939 - 176 Br/ CI 196 349 1.85 N 2.647 N '/N HO N N Me Isomer A 197 350 N C 1.87 1.o.,Y 2.647 Me Isomer B PREPARATIVE EXAMPLE 199 Step A CI 0 N Cl Me C1 Me HC NM e HA -~.N N A.N / 5 H The title compound from Preparative Example 175 (0.9 g), benzyl alcohol (0.68 mL), solid potassium hydroxide (0.66 g), 18 crown-6-ether (80 mg) and anhydrous toluene (20 mL) were stirred at reflux. Purification by preparative plate chromatography (silica, 10 4% MeOH-CH 2 C1 2 , NH 4 OH saturated) afforded the benzyl ether (0.73 g, 68%, MH' = 371).

WO 00/37459 PCT/US99/27939 - 177 "OH OH CH Me e The title compound from Step A above (0.72 g), methanol (60 mL) and 10%palladium on carbon (300 mg) were stirred under 50 5 psi hydrogen atmosphere for 3 days. Filtration through celite afforded a solution which was treated with TEA (3 equiv) and

CH

2 C1 2 . Filtration and purification by preparative plate chromatography (silica, 5% MeOH-CH 2 C12, NH 4 OH saturated) afforded the title compound (0.20 g, 42%, MH' = 247). 10 WO 00/37459 PCT/US99/27939 - 178 PREPARATIVE EXAMPLE 200 Preparation of the tricyclic N-oxide moiety \CI MCPBA / CUCCl NQ o o I 2 NaBt- / MeOH CI SOC /toluene cl 4 3 H*T FA N N .OH /NEt 3

/CH

2 Cb OWOO 5 \ CI \CI eN Chromatography N N X OH O }yOH 6 6a + CI N O L.-. 0 6b A solution of 3 -peroxybenzoic acid (25 g, 102.59 mmol, 5 2.5 eq.) in anhydrous dichloromethane (250 mL) was added WO 00/37459 PCT/US99/27939 - 179 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 1 (10 g, 41.04 mmol, 1.0 eq.) in anhydrous dichloromethane (100 mL) at 0 oC under a nitrogen atmosphere. The solution was slowly (3h) 5 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 Na 2

SO

4 , filtered, and concentrated under house vacuum at 30 oC to give 2 as a canary-yellow solid. The title compound 2 was used directly 10 without further attempts at purification. Yield: 10 g 38.51 mmol - 94% [M + HI+: 260 HRMS (FAB+): Calculated for C 14 HuiC1NO 2 ([M + H]+): 260.0475 15 Observed: 260.0478 2-3 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 oC 20 under a nitrogen atmosphere. The resulting suspension was stirred at 0 oC for one hour and at room temperature for another hour. The volatiles were removed under house vacuum at 30 oC 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). 25 The combined organic extracts were washed with brine (100 mL), dried over Na 2

SO

4 , filtered, and concentrated under house vacuum at 30 oC 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% 30 [M + H]J': 262 HRMS (FAB+): Calculated for C 1 4HI 3 C1NO 2 ([M + H]): 262.0635 WO 00/37459 PCT/US99/27939 - 180 Observed: 262.0636 F 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 5 g, 34.39 mmol, 1.0 eq.) and anhydrous toluene (150 mL) at 0 0C 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 10 with ice-cold, saturated aqueous NaHCO 3 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 Na 2

SO

4 , filtered, and concentrated under house vacuum at 30 0C to give 4 as a cream-colored solid in essentially quantitative yield. Due to its 15 high reactivity, compound 4 was used directly without any attempts at purification or characterization (other than 1 H NMR). Yield: 9.55 g - 34.09 mmol = 99% -6 Triethylamine (18 mL, 126.65 mmol, 5.0 eq.) was added 20 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 0C. A solution of 4 (8.52 g, 30.39 mmol, 1.2 eq.) in anhydrous 25 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 0C. The residue was taken up in 50% m/v aqueous citric acid solution (100 mL) and extracted with ethyl 30 acetate (5 x 100 mL). The organic extracts were combined and dried over Na 2

SO

4 , filtered, and concentrated under house vacuum at 30 C. The residual cream-colored solid was flash-chromatographed WO 00/37459 PCT/US99/27939 -181 (CH 2

CI

2 :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% 5 Off-white foam; M.p.: 78-83 oC [M + H]I: 500 HRMS (FAB+): Calculated for C 2 6 H3 1 C1N 3 0, 5 ([M + HI+): 500.1953 Observed: 500.1952 10 For 6b: Yield: 3.00 g =6.00 mmol = 24% Off-white solid; M.p.: 94-99 oC [M + H]+: 500 HRMS (FAB+): 15 Calculated for C 26

H

3 azC1N 3 0, ([M + H]*): 500.1953 Observed: 500.1952 PREPARATIVE EXAMPLE 201 Step A 20 0 CI Following the procedure outlined in US 5,151,423, except substituting the 8-chloro tricycle with the 8-H analog described in US 3,419,565, the 8-hydrido tricyclic chloride is obtained. 25 Step B H N Q+~ S "'Co 2 H + N a ~ CI

)"CO

2 H a00 WO 00/37459 PCT/US99/27939 - 182 Following the procedure described for Preparative Example 127 Step C, except using the 8-hydrido tricyclic chloride from Preparative Example 201 Step A instead of the 8-chloro tricyclic chloride, the title compounds were isolated. 5 The isomers were separated by column chromatography (silica) using 3% MeOH/CH 2

C

2 . Isomer A: C(11)-(S): 38%, MH'=450. Isomer B: C(11)-(R): 31%, MH'=450. 10 PREPARATIVE EXAMPLE 202 Step A Following the procedure set forth in Preparative Example 127 Step C, but substituting the tricyclic chloride H CI 15 for the 8-C1 tricyclic chloride, one obtains the following acid: H N o , OH 0 Solid, 51% yield, mp=120.5-125.1 C. PREPARATIVE EXAMPLE 202A /\ CI H 2 N N N 20 0 0 By essentially the same procedure set forth in Njoroge et. al. (J. Med. Chem. (1997),40, 4290) for the preparation of 3- WO 00/37459 PCT/US99/27939 - 183 aminoloratadine only substituting the 3-H ketone (J. Het. Chem (1971) 8, 73) for loratadine, the title compound was prepared. PREPARATIVE EXAMPLE 203

H

2 N Cl F-/ CI N) N 5 O 0 The title compound from Preparative Example 202A (1.62g, 6.26 mmol) was added portionwise to NO'BF4 (0.81g, 1.1 eq.) in toluene (10 mL) at 0 oC. The resulting slurry was stirred at 0 oC for 2.5 hours before warming to room temperature. The reaction 10 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 NaHCO 3 (1 X 25 mL), and water (1 X 15 mL), dried over Na 2

SO

4 , filtered, and concentrated under reduced pressure. The crude product was 15 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 204 F- CI tN 20 Cl By essentially the same procedure set forth in Preparative Example 201 Step A, the title compound was prepared from the ketone of Preparative Example 203 and used without further purification (0.66g, 100% crude yield). 25 WO 00/37459 PCT/US99/27939 - 184 PREPARATIVE EXAMPLE 205

H

2 N N 0

*NH

4

HCO

2- (2.44g, 10eq.) was added to a solution of the title compound from Preparative Example 202A (2.OOg, 7.74 mmol) and 5 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 H 2 0 (100 mL) and extracted with

CH

2 Cl 2 (3 x 75 mL). The combined organics were dried over Na 2

SO

4 , 10 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 206 ClI N\ 15 0 The title compound from Preparative Example 205 (1.22g, 5.44mmol) was added portionwise to CuCl 2 (0.88g, 1.2eq) and tBuONO (0.98mL, 1.5eq) in CH 3 CN (25mL) at 0 oC. The resulting solution was warmed to RT and stirred for 72 hours. The reaction 20 mixture was quenched by the addition of IM HC1 (10mL), neutralized with 15% NH 4 0H and extracted with EtOAc (3 x 100mL). The combined organics were washed with 15% NH40H (1 x 50mL), IM HC1 (1 x 50mL) and saturated NaHCO 3 , dried over Na 2

SO

4 , filtered and concentrated. The crude product was purified 25 by flash chromatography using a 50:50 EtOAc:hexanes mixture as eluent to give a pale yellow solid (0.81g, 61% yield): CIMS: MH+=244.

WO 00/37459 PCT/US99/27939 - 185 PREPARATIVE EXAMPLE 207 Cl N CI By essentially the same procedure set forth in Preparative Example 201 Step A, the title compound was prepared from the 5 ketone of Preparative Example 206 and used without further purification. PREPARATIVE EXAMPLE 208 Br / N 0 10 By essentially the same procedure set forth in Preparative Example 206, only substituting CuBr 2 for CuC1 2 the title compound was prepared (1.33g, 60% yield):FABMS: MH'= 244. PREPARATIVE EXAMPLE 209 Br/ N 15 Cl By essentially the same procedure set forth in Preparative Example 201 Step A, the title compound was prepared from the ketone of Preparative Example 208 and used without further purification. 20 PREPARATIVE EXAMPLE 210 N 0 WO 00/37459 PCT/US99/27939 - 186 By essentially the same procedure set forth in Preparative Example 203 only substituting the title compound from Preparative Example 205, the title compound can be prepared. 5 PREPARATIVE EXAMPLE 211 N\ CI By essentially the same procedure set forth in Preparative Example 201 Step A, except starting with the ketone of Preparative Example 210, the title compound can be prepared. 10 PREPARATIVE EXAMPLE 212 Cl / N N I OH By essentially the same procedure set forth in Preparative 15 Example 127 Step C, only substituting the 3-C1, 8-H tricyclic chloride prepared in Preparative Example 207 for the 3-H, 8-C1 tricyclic chloride the title compound (C-11(S)- and (R)-isomers) was prepared. FABMS: MH'= 484.

WO 00/37459 PCT/US99/27939 - 187 EXAMPLE 1 BOC I N "N N N H N H Br Cl N CN H e Me N 0 N H A solution of the title compound from Preparative Example 5 (0.44g, 0.897 mmol) was stirred at room temperature in CH 2

C

2 (10 5 mL) and TFA (4 mL) until starting material was consumed (TLC). The reaction mixture was concentrated under reduced pressure to remove any excess TFA and the compound was redissolved in

CH

2 C12 (5 mL), treated with chloride (42.0) Br Cl N Cl (42.0) 10 (0.37g, 1.2 eq.) and TEA (2.5 mL, 10 eq.) and stirred at room temperature for 84 hours. The reaction mixture was diluted with saturated NaHCO, (25 mL), water (25 mL), and CH 2 C1 2 (25 mL) and separated. The aqueous layer was extracted with CH 2

C

2 and the combined organics dried over Na 2

SO

4 and concentrated under 15 reduced pressure. The crude product was purified by flash chromatography using a 5% (10% NH40H in MeOH) solution in WO 00/37459 PCT/US99/27939 - 188 CH 2

C

2 as eluent to yield a tan solid (0.45g, 71% yield). mp 142 1440C; FABMS: MH'= 696. EXAMPLE 2 Br Cl N (N N (11S,2R(+)-Isomer) O OMe M N ON N 5 H Br Cl N N f N..] H /---N (1 1R,2R(+)-Isomer) N00 t Me Me H The title compound from Example 1 was separated into the 11(S) (+)- and 11(R) (+)- diastereomers by preparative HPLC using a CHIRALPAK AD column using a 12% i-PrOH in hexanes solution 10 with 0.2% diethylamine as eluent: 11S,2R(+)-Isomer: retention time= 29.21 minutes; [a]235D +19.1 (3.35 mg in 2.0 mL CHCl 3 ); mp= 147-1490C; LCMS: MH = 696. 11R,2R(+)-Isomer: retention time= 39.8 minutes; [a] 2 4 D= 15 +73.0 (3.07 mg in 2.0 mL CHC1 3 ; mp= 128-1310C; LCMS: MH = 696.

WO 00/37459 PCT/US99/27939 - 189 EXAMPLE 3 Br /1 N N H C N O Me Me By essentially the same procedure as that set forth in Example 1, except using the title compound from Preparative 5 Example 6, the title compound was prepared (0.085g, 45% yield). mp 103-106'C; LCMS: MH'= 705. EXAMPLE 4 Br /' Cl N0 NN N

O

O

O 10 By essentially the same procedure as that set forth in Example 3, except using the title compound from Preparative Example 6.1, the title compound was prepared. mp = 111-115'C; MH' = 703 WO 00/37459 PCT/US99/27939 - 190 EXAMPLE 5 Br / Cl N N H Hfl N N OI H Cl By essentially the same procedure as that set forth in Example 1, except using the title compound from Preparative 5 Example 7, the title compound was prepared. mp 138-140 0 C; LCMS: MH 4 = 778. EXAMPLE 6 Br / Cl N N (N NN (1 1R,2R Isomer) N ,N N,1 O MeMe O O 10 A solution of the title compound from Preparative Example 8 (0.10 g, 0.17 mmol) (11S,2R(-)-isomer) in DMF (1.0 mL) was treated with 4-pyridylacetic acid N-oxide (0.039 g, 1.5 eq.), NMM (0.03 mL, 1.5 eq), DEC (0.049 g, 1.5 eq.), and HOBT (0.034 g, 1.5 eq.) and the resulting solution stirred at room temperature overnight. The 0 N 0 10 A solution of the title compound from Preparative Example 8 (0. 10 g, 0. 17 minol) (11 S, 2R(-) -isomer) in DMF (1. 0 mL) was treated with 4-pyridylacetic acid N-oxide (0.039 g, 1.5 eq.), NMM (0.03 mL, 1.5 eq), DEC (0.049 g, 1.5 eq.), and HOBT (0.034 g, 1.5 eq.) and the resulting solution stirred at room temperature overnight. The WO 00/37459 PCT/US99/27939 -191 reaction mixture was quenched by the addition of saturated NaHCO 3 (10 mL) and extracted with CH 2 C1 2 (4 X 50 mL). The combined organics were dried over MgSO 4 , filtered, and concentrated in vacuo. The crude residue was purified by 5 Preparative TLC using a 15% (10% NH40H in MeOH) solution in

CH

2 C12 as eluent to yield the 11S,2R isomer(0.044g, 39% yield). mp= 115-117'C; LCMS: MH'= 706. By essentially the same procedure, except using the racemate or 11R,2R isomer from Preparative Example 8, one can obtain the 10 corresponding racemate or 11R,2R isomer product. EXAMPLES 7-9 By essentially the same procedure as that set forth in Example 6, the compounds of the formula Br C1 N N H f N 1 1 i 15 R 14 0 MeMe wherein R 14 is as defined in Table 6 below, were obtained. TABLE 6 EX. R4= MP (C) Mass Spec 7 N "O O 148-150 LCMS: 0 MH'=706 11 R,2R isomer 20 WO 00/37459 PCT/US99/27939 - 192 8 O Nk NH 2 123-127 LCMS: O MH'=739 0 11S,2R isomer 9 0 N NH 2 150-153 LCMS: oj V MH'=739 11R,2R isomer EXAMPLE 10 Br Cl N N (11S,2R Isomer) N OO N- &0 M Me H 5 A solution of the title compound from Preparative Example 8 (11S,2R-isomer) (0.080 g, 0.14 mmol) in CH 2 C12 (2.0 mL) was treated with t-BuNCO (0.080 mL, 5.0 eq). The resulting solution was stirred at room temperature overnight and concentrated under reduced pressure. The crude product was purified by preparative 10 TLC using a 10% (10% NH40H in MeOH) solution in CH 2 C1 2 as eluent to give the title compound (0.045g, 48% yield). mp=139 142oC; LCMS: MH'= 670.

WO 00/37459 PCT/US99/27939 - 193 EXAMPLE 11 Br Cl N NN (11R,2R Isomer) O M e H The title compound was prepared by essentially the same procedure as that set forth in Example 10, but substituting the 5 11R,2R-isomer from Preparative Example 8. mp= 157-159 0 C; LCMS: MH'= 670. EXAMPLES 12-14 By essentially the same procedure as that set forth in 10 Example 10, except the title compounds from Preparative Example 9 are used, the compounds of the formula Br /\ cl N N H 'N NN 1 14 R 0 wherein R 14 is as defined in Table 7 below, were obtained.

WO 00/37459 PCT/US99/27939 - 194 TABLE 7 EX. R= MP (oC) Mass Spec 12 O -N 136-139 LCMS: H MH = 668 11S,2R isomer 13 0 N 106-110 LCMS: H MH = 668 11R,2R isomer 14 0 N 133-139 LCMS: H MH = 654 11R/S,2R isomers EXAMPLE 15 Br /Cl N\ CN H .H N ,-Is 0 Me Me Me II Fo 5 o To a solution of the title compound (11-racemate) from Preparative Example 8 (0.072g, 0.12 mmol) and TEA (0.010 mL, 1.1 eq.) in CH 2 C1 2 (4 mL) was added MeSO 2 C1 (0.01 mL, 1.1 eq.) and the resulting solution was stirred at room temperature overnight. The 10 reaction mixture was quenched by the addition of saturated NaHCO 3 (5 mL), separated and extracted with CH 2 C12 (2 X 50 mL).

WO 00/37459 PCT/US99/27939 - 195 The combined organics were dried over Na 2 SO, and concentrated in vacuo. The crude residue was purified by preparative TLC using a 10% (10% NH 4 OH in MeOH) solution in CH 2 C1 2 as eluent (44 mg, 63% yield). mp= 107-110C; LCMS: MH = 649. 5 By essentially the same procedure, the 11R,2R or 11S,2R isomers can be obtained by using the 11R,2R or 11S,2R isomer, respectively, title compounds from Preparative Example 8. EXAMPLES 16-18 10 By essentially the same procedure as that set forth in Example 15, compounds of the formula: Br Cl N N HN

R

14 0 Me Me wherein R 1 4 is as defined in Table 8, were obtained. 15 TABLE 8 EX. R= MP (oC) Mass Spec 16 O O 109-111 LCMS: 11S,2R isomer MH'=657 WO 00/37459 PCT/US99/27939 - 196 17 O O 107-108 LCMS: 11R,2R isomer MH'=657 18 0 N 139-142 LCMS: MH+=642 11R/S,2R isomers EXAMPLE 19 Br FN N N , NMe H 5 By essentially the same procedure as that set forth in Example 1, except using the title compound from Preparative Example 7.3, the title compound was obtained. mp= 133-138oC; LCMS: MH+= 682. 10 EXAMPLE 20 Br Cl Br/ Cl N N N1 To OH , N N > ,, 0 0'k-0f0 WO 00/37459 PCT/US99/27939 - 197 The title compound from Preparative Example 4 (0.211 g, 1.4 eq.) found in Table 1 was added to a solution of acid from Preparative Example 51 (0.487 g, 0.90 mmol), DEC (0.201 g, 1.2 eq.), HOBT (0.73 g, 6.0 eq.), and NMM (0.60 mL, 6.0 eq.) in DMF 5 (6.0 mL). The resulting solution was stirred at room temperature 3 days. The crude product was precipitated from the reaction mixture by the addition of water and filtered. The residue was purified by flash chromatography using a gradient of 0.5% to 3% by 0.5% increments (10% NH 4 OH in MeOH) solution in CH 2 Ck as eluent to 10 give the title compound (0.411 g, 67% yield). mp= 178-179oC; MH'= 685. EXAMPLE 21 Br Cl N N H Me Me H N O N N H 15 The title compound was prepared by essentially the same procedure as that set forth in Example 110, but substituting the title compound from Preparative Example 11 Step C. mp= 150 154'C; MH'= 682.

WO 00/37459 PCT/US99/27939 - 198 EXAMPLE 22 Br C1 tN N H H 0 N N , N N H The title compound was prepared by essentially the same procedure as that set forth in Example 110, but substituting for the 5 title compound from Preparative Example 102 Step C the amine prepared by the method described in Preparative Example 11 Steps A-C only substituting dichloroethane for methyl iodide in Preparative Example 11 Step A. mp= 156-158 0 C; MH*= 680. 10 EXAMPLE 24 Step A Br / C1 N N H H H 0 ' O

NH

2 The title compound from Preparative Example 12 (0.23 g, 0.49 mmol) in CH 2 C1 2 (5.0 mL) and TFA (3.0 mL) was stirred at room 15 temperature 2 hours and concentrated in vacuo. The residue was dissolved in CH 2 C1 2 (5.0 mL) and treated with TEA (0.45 mL, 20 eq.) and chloride WO 00/37459 PCT/US99/279 3 9 - 199 Br / ~ Cl N C1 (42.0) (0.056 g, 0.33 eq.) and stirred at room temperature 48 hours. The reaction mixture was diluted with saturated NaHCO 3 (5.0 mL), water (15 mL), and extracted with CH 2 C1 2 (2 X 50 mL). The combined 5 organics were dried over Na2SO 4 and concentrated under reduced pressure. The crude product was purified by flash chromatography using a 15% (10% NH 4 0H in MeOH) solution in CH 2 C12 as eluent (0.063g, 67% yield). mp= 157oC(dec.); FABMS: MH'= 572. 10 Step B B r Cl N N HH N O 0 NH2 H N- N O H The title compound from Step A (0.058 g, 0.101 mmol) in CH 2 C12 (3 mL) was treated with excess cyclohexyl isocyanate and stirred at room temperature for one hour. The reaction mixture was 15 concentrated in vacuo and purified by flash chromatography using an 8% MeOH in CH 2 C12 solution as eluent to give the title compound (0.062g, 75% yield). mp= 164-167oC;FABMS: MH'= 822.

WO 00/37459 PCT/US99/27939 - 200 EXAMPLE 25 Br C1 tN N N N O 0 NH 2 N H The title compound from Example 24 (0.045 g, 0.0547 mmol) was stirred in concentrated NH 4 OH (3.0 mL) and MeOH (3.0 mL) 5 overnight. The resulting solution was concentrated in vacuo and the residue purified by flash chromatography using a 15% MeOH in

CH

2 C12 solution as eluent to give the title compound (0.022 g, 58% yield). mp= 164-169 0 C; FABMS: MH = 697. 10 EXAMPLE 26 Br/ C N N 0N 0 NNN 0H H3,O0

COO

WO 00/37459 PCT/US99/27939 - 201 Step A BOC BOC I I (N

CH

3 _ _H I N NN 0 -0 H Dissolve 2.99 g (15.09 mmol) of the 3-methylhistamine hydrochloride in 100 mL of methylene chloride followed by 3.21 g 5 (31.70 mmole) of triethylamine. Stir under nitrogen for 30 min then add, in small portions, 4.83 g (18.87 mmol) of anhydride from Preparative Example 44 and stir under nitrogen for 30 min. Add 4.14 g (16.60 mmol) of benzyl chloroformate and stir over night. Dilute with 100 mL of methylene chloride and wash with aqueous 10 NaHCO 3 solution. Dry the organic layer over MgSO 4 and concentrate in vacuo. Flash chromatograph on 650 g of silica gel using 97% CH 2 C12 (NH 4 OH) - 3% methanol to give the product as a white solid, mp = 51.8-63.2 0 C. 15 Step B H I N (N CH 3 H I NN Dissolve 4.9 g of the product from Step A in 30 mL of methylene chloride and add 13 mL of trffluoroacetic acid. Stir overnight under nitrogen then concentrate in vacuo. The residue 20 was triturated with ether then dried in vacuo giving the product as a clear oil.

WO 00/37459 PCT/US99/27939 - 202 Step C Br Cl N H CN

OH

3 H NN 0 N Dissolve 10.01 g (11.04 mmol) of the product of Step B in 50 mL of DMF containing 5.6 g (55.19 mmol) of triethylamine. Add 5 dropwise a solution of the chloride Br -- Cl N Cl (42.0) in 70 mL of DMF and stir under nitrogen overnight. Concentrate under vacuo and dissolve the residue in 50 mL of methylene chloride. Wash with aqueous NaHCO 3 solution, dry the organic 10 layer over MgSO 4 and concentrate in vacuo. Flash chromatograph the residue on 640 g of silica gel using 97% CH 2 C1 2

(NH

4 OH) - 3% methanol to give the product as a tan solid, mp = 111.8-114.5oC, MH+ = 677 (FAB).

WO 00/37459 PCT/US99/27939 - 203 EXAMPLE 27 Step A Br /Cl N H I N N N H 0H3 Dissolve 4.61 g (6.8 mmol) of the product of Example 26, Step 5 C, in 6 mL of acetic acid 9 mL of a 5.7 M (33%) solution of HBr in acetic. After 3 hr the reaction was complete by silica gel tic (95%

CH

2 Cl 2

(NH

4 OH) - 5% methanol). Add 25 mL of diethyl ether and filter the resulting precipitate under nitrogen giving 5.8 g of a tan solid. Chromatograph on a Chiralpack AD, 5 cm x 50 cm column 10 (Chiral Technologies) using 25% 2-propanol/-hexane + 0.2% diethylamine, and a flow rate of 80 mL/min to give the two diastereomers. Diastereomer A: Mp = 122.2-130.2 0 C, MH = 543 (FAB). Diastereomer B: Mp = 122.1-130.2oC, MH' = 543 (FAB). 15 Step B Br Cl N H

NCH

3 H I F N ,N N N N 00N H Dissolve 0.07 g (0.129 mmol) of Diastereomer A of Step A in 2 mL of methylene chloride followed by 0.021 g (0.155 mmol) of 4 20 fluorophenylisocyanate and stir over night under nitrogen. Dilute WO 00/37459 PCT/US99/27939 -204 with 20 mL of methylene chloride and wash with aqueous NaHCO 3 solution, dry the organic layer over MgSO 4 and concentrate under vacuo. Chromatograph the residue by preparative silica gel TLC using 95% CH 2

C

2

(NH

4 OH) - 5% methanol to give 0.0179 g of the 5 product as a white solid. Diastereomer A: Mp = 143.1-145.2 0 C, MH' = 680 (FAB). In a similar manner react 0.07 g (0.129 mmol) of Diastereomer B from Step A with 4-fluorophenylisocyanate to obtain 0.018 g of the Diastereomer B product as a white solid. 10 Diastereomer B: Mp = 140.1-149.4oC, MH' = 680 (FAB). EXAMPLE 28 Br Cl N H N HzCN N

CH

3 H I CH N "ir/ N

H

3 CK t

H

3 C N 0 H Following the procedure of Example 27, react 0.07 g (0.129 15 mmol) of Diastereomer A from Example 27, Step A, with tert butylisocyanate to obtain 0.065 g of the Diastereomer A product as a white solid. Mp = 125.1-133.5 0 C, MH = 642 (FAB). Following the above procedure, but using Diastereomer B from Example 27, Step A, obtain 0.052 g of the Diastereomer B 20 product as a white solid. Mp = 128.1-135.2 0 C, MH' = 642 (FAB).

WO 00/37459 PCT/US99/27939 - 205 EXAMPLE 29 Br C1 tN

HCH

3 H I HN N

CH

3 N trN

H

3 C N N H Following the procedure of Example 27, react 0.10 g (0.184 mmol) of Diastereomer A from Example 27, Step A, with iso 5 propylisocyanate to obtain 0.041 g of the Diastereomer A product as a white solid. Mp = 128.1-133.3oC, MH = 628 (FAB). Following the above procedure, but using Diastereomer B from Example 27, Step A, obtain 0.040 g of the Diastereomer B product as a white solid. Mp = 128.1-133.4oC, MH' = 628 (FAB). 10 EXAMPLE 30 Br /NC1 N H I

H

3 C0 0 N Dissolve 0.116 g (0.202 mmol) of Diastereomer A of Example 27, Step A, in 2 mL of methylene chloride followed by 0.02 g (0.202 15 mmol) of triethyl amine and 0.24 mL (0.24 mmol) of a 1.OM solution of isopropyl chloroformate in toluene and stir overnight under nitrogen. Dilute with 20 mL of methylene chloride and wash with aqueous NaHCO 3 solution, dry the organic layer over MgSO 4 and concentrate under vacuo. Chromatograph the residue by WO 00/37459 PCT/US99/27939 - 206 preparative silica gel TLC using 95% CH 2 C12 (NH 4 OH) - 5% methanol to give 0.044 g of the Diastereomer A product as a white solid. Following the above procedure, but using Diastereomer B from Example 27, Step A, obtain 0.038 g of the Diastereomer B 5 product as a white solid. Diastereomer A: Mp = 120.5-125.5oC, MH = 629 (FAB). Diastereomer B: Mp = 120.3-126.1oC, MH' = 629 (FAB). 10 EXAMPLE 31 Br Cl N H N CHH N H N O\j Following the procedure of Example 30, react 0.07 g (0.128 mmol) of Diastereomer A from Example 27, Step A, with 0.021 g (0.142 mmol) of 4-morpholinecarbonyl chloride and 0.035 g (0.256 15 mmol) triethylamine to obtain 0.024 g of the Diastereomer A product as a white solid. Following the above procedure, but using Diastereomer B from Example 27, Step A, obtain 0.019 g of the Diastereomer B product as a white solid. 20 Diastereomer A: Mp = 137.9-138.9 0 C, MH' = 656 (FAB). Diastereomer B: Mp = 136.4-138.6oC, MH = 656 (FAB).

WO 00/37459 PCT/US99/27939 - 207 EXAMPLE 32 Br /Cl NCHH N H CH N

H

3 C

H

3 N

H

3 C O 0 Dissolve 0.07 g (0.129 mmol) of Diastereomer A of Example 27, Step A, in 0.5 mL of methylene chloride followed by 0.033 g 5 (0.152 mmol) di-tert-butyldicarbonate and stir overnight under nitrogen. Dilute with 20 mL of methylene chloride and wash with aqueous NaHCO 3 solution, dry the organic layer over MgSO 4 and concentrate under vacuo. Chromatograph the residue by preparative silica gel TLC using 95% CH 2 C1 2

(NH

4 OH) - 5% methanol 10 to give 0.024 g of the Diastereomer A product as a white solid. Following the above procedure, but using Diastereomer B from Example 27, Step A, obtain 0.026 g of the Diastereomer B product as a white solid. Diastereomer A: Mp = 127.1-128.4oC, MH' = 643 (FAB). 15 Diastereomer B: Mp = 134.9-137.5oC, MH' = 643 (FAB).

WO 00/37459 PCT/US99/27939 - 208 EXAMPLE 33 Br /Cl NCH N

.SO

2 O N

H

3 C Following the procedure of Example 30, react 0.05 g (0.092 mmol) of Diastereomer A from Example 27, Step A, with 1. 1g (0.10 5 mmol) of methanesulfonyl chloride and 0.019 g (0.183 mmol) triethylamine in 1.5 mL of methylene chloride to obtain 0.011 g of the Diastereomer A product as a white solid. Following the above procedure, but using Diastereomer B from Example 27, Step A, obtain 0.032 g of the Diastereomer B 10 product as a white solid. Diastereomer A: Mp = 138.1-144.6 0 C, MH' = 621 (FAB). Diastereomer B: Mp = 139-145.1oC, MH = 621 (FAB). EXAMPLE 34 Br / \e1 tN

HOH

3 H I ) I., N,,,Io' N 00 N 15 F Dissolve 0.07 g (0.129 mmol) of Diastereomer A of Example 27, Step A, in 1.0 mL of DMF followed by 0.023 g (0.167 mmol) 4 fluorobenzoic acid, 0.032 g (0.167 mmol) DEC, 0.0225 g (0.167 WO 00/37459 PCT/US99/27939 - 209 mmol) HOBT and 0.018 mL (0.167 mmol) N-methylmorpholine and stir overnight under nitrogen. Concentrate in vacuo and dissolve the residue in 20 mL of methylene chloride. Wash with aqueous 1N NaOH, dry the organic layer over MgSO 4 and concentrate in vacuo. 5 Flash chromatograph on silica gel using 93% CH 2 C1 2

(NH

4 OH) - 7% methanol to give 0.060 g of the Diastereomer A product as a white solid. Following the above procedure, but using Diastereomer B from Example 27, Step A, obtain the Diastereomer B product as a 10 white solid. Diastereomer A: Mp = 141.5-145.8oC, MH' = 665 (FAB). Diastereomer B: Mp = 144.9-148.7oC, MH' = 665 (FAB). EXAMPLE 35 Br Cl N H (N

CH

3 F H N F N Nj N 15 o Following the procedure of Example 34, use 4-fluoro phenylacetic acid instead of 4-fluorobenzoic acid to obtain the Diastereomer A product as a white solid. Mp = 132.8-140.1 0 C, MH' = 679 (FAB). 20 Following the above procedure obtain the Diastereomer B product as a white solid. Mp = 132.5-139.70C, MH = 679 (FAB).

WO 00/37459 PCT/US99/27939 - 210 EXAMPLE 36 Br / Cl N H 0 Following the procedure of Example 34, use 4-pyridylacetic acid N-oxide instead of 4-fluorobenzoic acid to obtain the 5 Diastereomer A product as a white solid, and the Diastereomer B product as a white solid. Diastereomer A: Mp = 168.5-172.4oC, MH' = 678 (FAB).. Diastereomer B: Mp = 168.9-172.3oC, MH' = 678 (FAB). 10 EXAMPLE 37 Br Cl N H 0 NGI H 3 H N NH NO N N 0 0 Following the procedure of Example 34, use N-t-butoxy carbony-4-piperidinacetic acid instead of 4-fluorobenzoic acid to obtain the Diastereomer A product as a white solid, and the 15 Diastereomer B product as a white solid. Diastereomer A: Mp = 135.1-142.1oC, MH' = 768 (FAB). . Diastereomer B: Mp = 141.7 143.2 0 C, MH' = 768 (FAB).

WO 00/37459 PCT/US99/27939 -211 EXAMPLE 38 Br Cl N H N CH 3 H N HN O N ciao 0 Dissolve 0.23 g (0.31 mmol) of the Diastereomer A product of Example 37 in 3 mL of methylene chloride and 3 mL of 5 trifluoroacetic acid and stir under nitrogen for 3.5 hr. Concentrate under vacuo and dissolve the residue in 20 mL methylene chloride and wash with 1.0 N aqueous NaOH. Concentrate the organic layer in vacuo and chromatograph the residue by preparative silica gel TLC using 80% CH 2 C12 (NH 4 OH) - 20% methanol to give 0.113 g of 10 the Diastereomer A product as a white solid. Following the above procedure, but using the Diastereomer B product of Example 37, StepA, obtain the Diastereomer B product as a white solid. Diastereomer A: Mp = 136.1-139.5 0 C, MH' = 668 (FAB). 15 Diastereomer B: MH = 6668 (FAB).). EXAMPLE 39 Br C N H N CH 3 0 I OH N

H

2 N 'N N ~iiN 0 0 WO 00/37459 PCT/US99/27939 - 212 Dissolve 0.073 g (0.11 mmol) of the Diastereomer A product from Example 38 in 3 mL methylene chloride containing 0.013 g (0.121 mmol) of trimethylsilyl isocyanate and stir under nitrogen overnight. Dilute with 5 mL methylene chloride and wash with 10 5 mL sat aqueous NaHCO 3 . Dry the organic layer over MgSO 4 and concentrate in vacuo. Chromatograph the residue by preparative silica gel TLC using 90% CH 2 Cl 2

(NH

4 OH) - 10% methanol to give 0.032 g of the Diastereomer A product as a white solid. Following the above procedure, but using the Diastereomer B 10 product of Example 38, obtain the Diastereomer B product as a white solid. Diastereomer A: Mp = 148.2-151.3oC, MH' = 711 (FAB). Diastereomer B: Mp = 148.1-150.4oC, MH+ = 711 (FAB).). 15 EXAMPLE 40 Br / \ C1 N H H C CH3 N 3 NN N H3C>K i

H

3 C O 0 Dissolve the carboxylic acid from Preparative Example 51 (0.32 g, 0.596 mmol), the product from Preparative Example 13 (0.108 g, 0.775 mmol), DEC (0.149 g, 0.775 mmol), HOBT (0.105 g, 20 0.775 mmol) and 0.13 mL of N-methylmorpholine in 5 mL of DMF and stir overnight. Concentrate in vacuo and dissolve the residue in 20 mL of methylene chloride. Wash with satd. NaHCO 3 solution, dry over MgSO, and flash chromatograph on silica gel using 97%

CH

2 C1 2

(NH

4 OH) - 3% methanol to give 0.2 g of the product as a 25 white solid. Separate the diastereomers by preparative chiral WO 00/37459 PCT/US99/27939 - 213 chromatography (Chiralpack AD, 5 cm x 50 cm column, flow rate 100 mL/min., 15% 2-propanol/hexane + 0.2% diethylamine). Diastereomer A: Mp = 54-58oC, MH' = 657 (FAB). Diastereomer A: Mp = 64-58oC, MH' = 657 (FAB). 5 EXAMPLE 41 Br / C1 H

CH

3

CH

3 NN N

H

3 C H3 30 OO

H

3 C Following the procedure of Example 40, use the product from 10 Preparative Example 14 instead of Preparative Example 13 to obtain the product as a white solid. Mp = 116-123 0 C, MH' = 671 (FAB). EXAMPLE 42 Br / Cl N H N H3C CH 3 H 3 3 0H H "' N N

H

3 C 15 Following the procedure of Example 40, use the product from Preparative Example 15 instead of Preparative Example 13 to obtain the product as a white solid. Diastereomer A: Mp = 115-120 0 C, MH' = 671 (FAB). Diastereomer A: Mp = 98-101 OC, MH' = 671 (FAB).

WO 00/37459 PCT/US99/27939 -214 EXAMPLE 43 Br \ Cl N CH3 N N H CH3 N N

H

3 C 3 HC 0 )f O N 5 Following the procedure of Example 40, use the product from Preparative Example 16 instead of Preparative Example 13 to obtain the product as a white solid. Mp = 120-122oC, MH' = 685 (FAB). EXAMPLE 44 Br C1 N H N CH 3 N 10 HaC O O Following the procedure of Example 40, use the product from Preparative Example 17 instead of Preparative Example 13 to obtain the product as a white solid. Mp = 101-103'C, MH' = 733 (FAB).

WO 00/37459 PCT/US99/27939 - 215 EXAMPLES 45-59 Following the procedure of Example 40, use the amines from Preparative Examples 18-26 instead of Preparative Example 13 to obtain the compounds Br /Cl N CH N* R 2 7 H 3 C C 3 N 5 H C 0 0 O wherein R 2 7 is defined in Table 9. TABLE 9 Ex. Prep. Product Melting Mass Ex. R= Point Spec (amine) (oC) MH+ 45 18 128-133 719 H I N Isomer A 46 18 129-132 719 H NN Isomer B WO 00/37459 PCT/US99/27939 - 216 47 19 106-112 733 1

CH

3 N Isomer A 48 19 105-111 733

CH

3 I N Isomer B 49 20 CH CH 3 115-117 713 3 CH3

CH

3 C H 3 N Isomer A 50 20 CH3 CH 108-110 713 CH

H

3

CH

3 N Isomer B 51 21

CH

3 86-89 699

CH

3

CH

3 N N N Isomer A WO 00/37459 PCT/US99/27939 - 217 52 21

CH

3 58-86 699

CH

3 CH 3 N Isomer B 53 22

CH

3 106-111 685 C H 3 H N Isomer A 54 22

CH

3 110-114 685

C

H

3 H N Isomer B 55 23 98-111 739

CH

3 7N N) N Isomer A 56 23 99-111 739

CH

3 NN Isomer B WO 00/37459 PCT/US99/27939 - 218 57 24 136-144 725 H 7N N/)CN N 58 25 101-103 697

CH

3 N 59 26 128-133 683 H N EXAMVIPLE 60 Br CI N HI N O N 0 0 N H 5 StepA Dissolve the product of Example 47 (0.148 g, 0.202 mmol) in 0.78 mL of methylene chloride and add 0.45 mL of trifluoroacetic acid and stir under nitrogen for 2 hr. Concentrate under vacuum. Dissolve the residue in 20 mL of methylene chloride and wash with 10 aqueous NaHCO 3 , dry the organic layer over MgSO 4 , and concentrate under vacuum to give the amine as a white solid.

WO 00/37459 PCT/US99/27939 - 219 Step B Dissolve the product of Step A (0.05 g, 0.078 mmol) in 2 mL of methylene chloride and add 0.015 g, 0.118 mmol of cyclohexyl isocyanate. Stir overnight then concentrate under vacuum. Flash 5 chromatograph the residue on silica gel using 99% CH 2 C12 (NH 4 OH) 1% methanol giving the Isomer A product as a white solid. Mp = 138-142 0 C, MH' = 758 (FAB). Follow the above procedure, but use the product of Example 48 instead of Example 47 in Step A, to obtain the Isomer B product 10 as a white solid. Mp = 130-139oC, MH' = 758 (FAB). EXAMPLE 61 Br \ Cl N /~ H (N CH3 3C' N O-,N N

H

3 C>N O O N H Step A 15 Using the product of Example 47, follow the procedure of Example 60, but use t-butyl isocyanate instead of cyclohexyl isocyanate in Step B, to obtain the Isomer A product as a white solid. Mp = 127-1320C, MH' = 732 (FAB). 20 Step B Follow the procedure of Example 60, but use the product of Example 48 instead of Example 47 in Step A and t-butyl isocyanate instead of cyclohexyl isocyanate in Step B to obtain the Isomer B product as a white solid. Mp = 127-130 0 C, MH' = 732 (FAB).

WO 00/37459 PCT/US99/27939 - 220 EXAMPLE 62 Cl N H N

CH

3 H N 0 NA

H

3 C 3 H3C O O Step A

H

3 C

H

3 C

H

3 C O O OY yO

H

3 C

H

3 C N

CH

3

CH

3 H CH3N 0CH 'IN'I _ \ N

H

3 C 3N

CH

3 UK0 H3 N>

H

3 C O O H 3 C 0 O 5 Dissolve the acid from Preparative Example 43 (0.37 g, 1.12 mmol), the product from Preparative Example 19 (0.29 g, 1.35 mmol), DEC (0.289 g, 1.46 mmol), HOBT (0.197 g, 1.46 mmol), N methylmorpholine (0.25 mL, 2.24 mmol) in 20 mL of DMF and stir under nitrogen over night. Concentrate under vacuum. Dissolve 10 the residue in 50 mL of methylene chloride, wash with sat. NaHCO 3 soln., dry the organic layer over MgSO 4 and concentrate under vacuum. Flash chromatograph the residue on silica gel using 100%

CH

2 C12 (NH 4 0H) giving a white solid.

WO 00/37459 PCT/US99/27939 - 221 Step B

H

3 C

H

3 C O H

H

3 N N N H3C C3 N/rH I 0 'N- 0 N

H

3 C O Dissolve the product of Step A (0.59 g, 1.048 mmol) in 3 mL of methylene chloride and add 2.5 mL of trifluoroacetic acid. Stir 5 overnight and concentrate under vacuum. Step C H N

CH

3 C c1 , N NN H N H N CH3 0I N Cl H .,r NN 0N NON Cl Dissolve the product of Step B (0.5 g, 1.048 mmol), the 8-C1 10 tricyclic chloride (0.359 g, 1.048 mmol) and triethyl amine (2.19 mL, 15.72 mmol) in 5 mL of methylene chloride and stir overnight. Concentrate under vacuum and flash chromatograph the residue on silica gel using 95% CH 2 C1 2

(NH

4 OH) - 5% methanol giving the product as a white solid. 15 WO 00/37459 PCT/US99/27939 - 222 Step D Cl N N CH 3 H3C K 3 N 0 N

H

3 C 0 0 Dissolve the product of Step C (0.27 g, 0.486 mmol) in 2 mL of methylene and add di-tert-butyldicarbonate ( 0.125 g, 0.57 mmol) 5 and stir for 2 hr. Concentrate under vacuum and separate the diastereomers by preparative chiral chromatography (Chiralpack AD, 5 cm x 50 cm column, flow rate 100 mL/min., 5% 2 propanol/hexane + 0.2% diethylamine) giving the products as white solids. 10 Diastereomer A: Mp = 93.1-99.8'C, MH' = 655 (FAB). Diastereomer B: Mp = 93.1-99.8oC, MH = 655 (FAB). EXAMPLE 63 BrB C Br C1 N H CH H

CH

3 N H N

CH

3 N 1- H H HCH 3 3 H CH 3 N OH H 3 0 0 N 15

H

3 C O O O 0 Following the procedure of Example 40, use the product from Preparative Example 27 instead of Preparative Example 13 to obtain the products as white solids. Isomer mix 1: Mp = 148-151 0 C, MH' = 687 (FAB).

WO 00/37459 PCT/US99/27939 - 223 Isomer mix 2: Mp = 110-114oC, MH' = 687 (FAB). EXAMPLE 64 Br C1 Br\ C CH N CHN HOH "H 3Cg H 0 0C 5

H

3 C O0 1O Following the procedure of Example 40, use the product from Preparative Example 28 instead of Preparative Example 13 to obtain the product as a white solid: Mp = 131-138oC decomp., MH = 687 (FAB). 10 EXAMPLE 65 Br C B r C lN H H N H ___ N N C CNH OH.CN N N CH3N CH3 *,,OH H3C O N

H

3 C 1 0 o Following the procedure of Example 40, use the product from Preparative Example 29 instead of Preparative Example 13 to obtain 15 the products as white solids. Isomer mix 1: Mp = 148-157oC, MH' = 721 (FAB). Isomer mix 2: Mp = 120-126 0 C, MH' = 721 (FAB).

WO 00/37459 PCT/US99/27939 -224 EXAMPLE 66 Br zCl Br C1 N

CH

3 N H (N CH3 N H H

CH

3 NN CH, "/ 0 ,OH H 3 C OO N

H

3 C or o3 Following the procedure of Example 40, use the product from Preparative Example 30 instead of Preparative Example 13 to obtain 5 the products as white solids. Isomer mix 1: Mp = 146-154oC, MH = 657 (FAB). Isomer mix 2: Mp = 122-127oC, MH' = 657 (FAB). 10 EXAMPLE 67 Br Cl N ON NNN 0 The 11R,2R(-)-diastereoisomer from Preparative Example 34 (0.25g, 0.46mmoles), 4-pyridylacetic acid Nl-oxide (0.0915g, 0.598mmoles) (see Preparative Example 61 of US 5,719,148 issued 15 February 17, 1998), DEC (0.1146g, 0.598mmoles), HOBt (0.0807g, 0.598mmoles) and 4-methyl-morpholine (0.0657mL, 0.598mmoles) were dissolved in anhydrous DMF (9mL) and the mixture was stirred under argon at 25 0 C for 96h. The reaction was worked up as described in Preparative Example 40, Step A above, and WO 00/37459 PCT/US99/27939 - 225 chromatographed on a silica gel column using 5% (10% cone.

NH

4 OH in methanol)-dichloromethane as the eluant to give the title compound: (Yield: 0.2434g, 78%); FABMS: m/z 678.0 (MH'); 8 c (CDC13) 30.1, 30.3, 30.9, 36.5, 38.5, 44.1, 44.3, 50.7, 52.5; CH: 5 53.4, 78.3, -119.1, 126.2, 127.3, 127.3, -129.1, 130.6, 132.3, ~-137.1, 138.6, 138.6, 141.1, 146.9; C: 120.1, 134.2, 134.6, 134.8, 137.1, 140.8, 155.1, 169.2, 169.8; 8H (CDC13) 4.31 (1H, s, H,,), 4.97 (1H, broad s, CHCO), 6.74 (1H, broad s, Im-H), 6.91 (1H, broad s, Im-H 4 ), 7.02 (1H, broad s, Ar-H), 7.07-7.17 (5H, m, CONHCH and 10 Ar-H), 7.38 (1H, broad s, Im-H 2 ), 7.56 (1H, s, Ar-H), 8.08, (1H, d, Ar H), 8.10 (1H, d, Ar-H) and 8.35ppm (1H, s, Ar-H 2 ); [aD22 +44.4o (c= 10.64mg/2mL, methanol). 15 EXAMPLE 68 Br Cl N - NH F '.N N N N The 11S,2R(-)-diastereoisomer from Preparative Example 34 (0.3g, O.552mmoles), 4-pyridylacetic acid N1-oxide (0.110 g, 0.718mmoles) (US 5,719,148, Feb. 17, 1998), DEC (0.1375g, 20 0.718mmoles), HOBt (0.0969g, 0.718mmoles) and 4 methylmorpholine (0.0788mL, 0.718mmoles) were dissolved in anhydrous DMF (9mL) and the mixture was stirred under argon at 25oC for 19h. The reaction was worked up as described in Preparative Example 40, Step A above, and chromatographed on a 25 silica gel column using 6% (10% cone. NH 4 OH in methanol) dichloromethane as the eluant to give the title compound: (Yield: WO 00/37459 PCT/US99/27939 - 226 0.2847g, 80%); FABMS: m/z 678.0 (MH'); 5 c (CDC13) 30.1, 30.6, 30.8, 36.5, 38.5, 44.0, 44.4, 51.1, 52.7; CH: 53.4, 78.5, -119.0, 126.2/126.3, 127.2/127.3, 127.2/127.3, -129.2, 130.3, 132.4/132.6, -137.1, 138.7, 138.7, 141.2/141.5, 147.0/147.2; C: 5 120.1, 134.2/134.4, 134.3, 134.9, 136.9, 141.5, 154.4/154.7, 168.8/169.2, 169.0/169.9; 8H (CDCl 3 ) 4.30 (1H, s, H,,), 4.96 (1H, broad s, CHCO), 6.64 (1H, broad s, CONHCH 2 ), 6.89-7.02 (3H, broad overlap, Im-H 5 , Im-H 4 and Ar-H), 7.10-7.18 (4H, m, Ar-H), 7.33 (1H, broad s, Im-H 2 ), 7.59 (1H, s, Ar-H), 8.08, (1H, d, Ar-H), 10 8.10 (1H, d, Ar-H) and 8.37ppm (1H, s, Ar-H 2 ); [a]D 23 4 +6.90 (c= 10.48mg/2mL, methanol). EXAMPLE 69 Br Cl N N , N

H

2 N KN N 0 15 0 The 11R,2R(-)-diastereoisomer from Preparative Example 34 (0.3g, 0.552mmoles), 1-aminocarbonyl-4-piperidinylacetic acid (0.1335g, 0.718mmoles) (Preparative Example 33), DEC (0.1375g, 0.718mmoles), HOBt (0.0969g, 0.718mmoles) and 4 20 methylmorpholine (0.157mL, 1.436mmoles) were dissolved in anhydrous DMF (7mL) and the mixture was stirred under argon at 25oC for 68h. The reaction was worked up as described in Preparative Example 40, Step A above, and chromatographed on a silica gel column using 6% (10% cone. NH 4 OH in methanol) 25 dichloromethane as the eluant to give the title compound: (Yield: 0.3547g, 90%); LCMS: m/z 711.2 (MH+); 6 c (CDCl 3 ): 30.3, 30,4, 31.2, WO 00/37459 PCT/US99/2793 9 - 227 32.0, 32.0, 36.6/37.2, 39.3/39.6, 43.9, 44.4, 44.4, 44.4, 51.0, 51.8; CH: 32.9, 53.0, 78.7, 118.9, 126.2, 129.7, 130.5/130.7, 132.3, 137.3, 141.3, 147.0; C: 120.3, 134.3, 135.1, 137.3, 141.1, 155.1, 157.9, 170.0, 171.9; 8, (CDCl 3 ) 4.30 (1H, s, H,,), 4.89 (2H, s, 5 NCONH 2 ), 4.98 (1H, s, CHCO), 6.92 (1H, broad s, Im-H,), 6.99 (1H, broad s, Im-H 4 ), 7.07-7.14 (3H, m, Ar-H), 7.41 (1H, broad s, Im-H 2 ), 7.57 (1H, s, Ar-H), 7.59 (1H, broad s, CONHCH 2 ) and 8.35ppm (1H, s, Ar-H 2 ); [a]D 20 0 + 35 .5 o (c=9.40mg/2mL, methanol). 10 EXAMPLE 70 Br Cl N N /k/ , N N H 2 N K N O 0 0 Following the procedure of Example 69, except using the 11S,2R(-)-diastereoisomer from Preparative Example 34 instead of 15 the 11R,2R(-)-diastereoisomer, and stirring under argon for 96h instead of 68h, the title compound was obtained: (Yield: 0.3241g, 83%); LCMS: m/z 711.2 (MH'); 5 c

(CDCL

3 ): 30.2, 30,6, 31.1, 32.0, 32.0, 36.5/36.8, 39.6/39.7, 43.8, 44.4, 44.4, 44.4, 51.3, 51.6; CH: 32.9, 53.0, 78.8, 119.0, 126.3/126.4, 129.4, 130.4/130.6, 20 132.5/132.6, 137.1, 141.5, 147.1; C: 120.2, 134.3, 135.0, 137.1, 141.5, 155.1, 158.1, 170.3, 172.4; 8H (CDC13) 4.29 (1H, s, H 1 ,), 4.55 (2H, s, NCONH 2 ), 4.98 (1H, s, CHCO), 6.23 (1H, t, CONHCH 2 ), 6.92 (1H, broad s, Im-H), 7.03 (1H, broad s, Im-H 4 ), 7.10-7.17 (3H, m, Ar-H), 7.43 (1H, broad s, Im-H 2 ), 7.59 (1H, s, Ar-H) and 8.37ppm 25 (1H, s, Ar-H 2 ); [a]D 23.1" +1.0o (c=10.OOmg/2mL, methanol).

WO 00/37459 PCT/US99/27939 - 228 EXAMPLE 71 Br /Cl N N H N O N'N N N

~

o H Pyridine-4-acylazide Nl-oxide (J. Med. Chem., 1998, 41, 877 893) (0.346g, 2.30mmoles) was dissolved in dry toluene (30mL) and 5 the solution was heated under reflux in an argon atmosphere at 110C for lh. The solution was cooled to room temperature and the

C

1 ,-Racemic title compound from Preparative Example 141 (0.250g, 0.46mmoles) was added. The mixture was stirred at 25oC for 22h. The solution was evaporated to dryness and the residue was 10 chromatographed on a silica gel column using 4% (10% cone.

NH

4 0H in methanol)-dichloro-methane as the eluant to give the title compound: (Yield: 0.1265g, 32%); LCMS: m/z 679.2 (MH'); 5 c (CDC1 3 ) CH 2 : 30.3, 30.6, 31.0/31.1, 36.7/36.8, 42.6, 44.6, 51.0/51.3, 52.4/52.6; CH: 55.1/55.2, 78.8, 115.8, 115.8, 119.2, 15 126.3, 129.1, 130.5/130.6, 132.7, 137.2, 138.6, 138.6, 141.4, 147.0/147.2; C: 120.2, 134.2, 134.3, 134.9, 136.9, 141.3, 155.0, 155.2, 170.4; 8H (CDC1 3 ) 4.34 (1H, s, H,,), 4.67 (1H, s, CHCO), 6.89 (1H, d, Im-H), 6.99 (1H, d, Im-H 4 ), 7.10-7.15 (3H, m, Ar-H), 7.46 (2H, d, Ar-H), 7.59 (1H, s, Im-H 2 ), 7.90 (2H, d, Ar-H), 8.39 (1H, s, 20 Ar-H 2 ) and 9.77ppm (1H, broad s, NCONHI).

WO 00/37459 PCT/US99/27939 - 229 EXAMPLE 72 Br / C N H2H Step A N O0 H 5 1 -N-t-Butoxycarbonylpiperidine- 3-acylazide (Preparative Example 35, Step B above) (1.177g, 4.3mmoles), was dissolved in Br Cl N N HC N N H No H 5 1-N-t-Butoxycarbonylpiperidine-3-acylazide (Preparative Example 35, Step B above) (1. 177g, 4.63mmoles), was dissolved in dry toluene (150mL) and the solution was heated under reflux in an argon atmosphere at 110'C for 1h. The solution was cooled to room temperature and added in three portions (1.47mmoles at Oh; 10 2.21mmoles at 69h and 0.95mmoles at 93h) to a solution of the C 1

,

Racemic title compound from Preparative Example 141 (0.4g, O.735mmoles) in anhydrous dichloromethane (26mL). The mixture was stirred at 25oC for 117h. The solution was evaporated to dryness and the residue was chromatographed on a silica gel 15 column using 4% (10% conc. NH40H in methanol)-dichloromethane as the eluant to give the title compound: (Yield: 0.1265g, 32%); LCMS: m/z 679.2 (MH'); 5 c (CDC13) CH.,: 28.5, 28.5, 28.5; CH 2 : 30.5, 30.6, 31.2/31.3, 32.5, 32.5, 36.6, 41.8, 42.7, 42.7, 44.6, 50.9/51.1, 51.9/52.2; CH: 48.2, 54.9/55.0, 78.9/79.0, -119.0, 126.4/126.5, WO 00/37459 PCT/US99/27939 - 230 -129.6, 130.5/130.6, 132.8, -137.1, 141.3/141.4, 147.1/147.3; C: 79.6, 120.3, 134.5, 134.7, 136.9, 141.1, 154.7, 154.8, 157.6, 171.0; 6H(CDC13) 1.46 (9H, s, CH 3 ), 4.33 (1H, s, H,,), 4.41 (1H, broad s, CHCO), 5.18 (1H, d, NCONHJJ), 6.55 (1H, broad m, CONHCH 2 ), 6.92 5 (1H, broad s, Im-H,), 7.08 (1H, broad s, Im-H 4 ), 7.10-7.15 (3H, m, Ar-H), 7.50 (1H, broad s, Im-H2), 7.59 (1H, d, Ar-H) and 8.40ppm (1H, s, Ar-H 2 ). Step B Br Cl H N N (NH z:\N H N 'N / N N 10 H The title compound from Step A above (0.2361g, 0.307mmoles) was dissolved in methanol (1.61mL) and a 10% (v/v) solution of cone. H2SO4 in dioxane (4.18mL) was added. The mixture was stirred under argon at 25 0 C for lh. The mixture was 15 passed over a bed of BioRad® AG l -X8 (OH) resin and the resin was washed with methanol. The combined eluates were evaporated to dryness and the residue was chromatographed on a silica gel column using 20% (10% cone. NH40H in methanol) dichloromethane as the eluant to give the title compound: (Yield: 20 0.1984g, 97%); LCMS: m/z 669.2 (MH'); 8 c (CDC13) CH 2 : 30.3, 30.5, 30.9, 31.6, 31.6, 36.3/36.4, 42.3, 42.3, 42.3, 44.3, 50.8/51.2, 52.1/52.4; CH: 47.2/47.3, 54.8, 78.9, 119.1, 126.3, 129.0, 130.5/130.6, 132.7, 137.5, 141.3, 147.0/147.1; C: 120.1, 134.2/134.3, 134.9, 136.9, 141.2, 155.2, 157.7/157.8, 171.2; 8 H 25 (CDC1 3 ) 4.29 (1H, s, H,,), 4.61 (1H, broad s, CHCO), 5.72 (1H, broad m, NCONH)i, 6.85 (1H, m, CONHCH 2 ), 6.92 (1H, broad s, Im-H5)

,

WO 00/37459 PCT/US99/27939 - 231 6.99 (1H, broad s, Im-H 4 ), 7.10-7.15 (3H, m, Ar-H), 7.57 (1H, s, Ar H), 7.66 (1H, broad s, Im-H 2 ) and 8.37ppm (1H, s, Ar-H 2 ). Step C Br ' Cl N

H

2 N 'N N 5N 0 0O 5 H The title compound from Step B above (0.195g, 0.291mmoles) was dissolved in anhydrous dichloromethane (10mL) and trimethylsilyl isocyanate (0.394mL, 2.91mmoles) was added. The mixture was stirred under argon at 25 0 C for 20h. Additional 10 trimethylsilyl isocyanate (0.188mL, O.873mmoles) was added and the mixture was stirred for a total of 23h. The mixture was diluted with dichloromethane (900mL) and washed with saturated aqueous sodium bicarbonate, dried (MgSO 4 ), filtered and evaporated to dryness. The product was chromatographed on a silica gel column 15 using 4% (10% conc. NH40H in methanol)-dichloromethane as the eluant to give the title compound: (Yield: 0.1325g, 64%); LCMS: m/z 712.2 (MH'), Sc (CDC13) CH 2 : 30.3/30.4, 30.6, 31.0/31.1, 32.4, 32.4, 36.5, 42.0, 43.4, 43.4, 44.4, 50.9/51.2, 52.4/52.6; CH: 48.1, 54.9/55.0, 78.9, 119.0, 126.3/126.4, 129.4, 130.5/130.6, 132.7, 20 137.3, 141.3/141.4, 147.1/147.2; C: 120.2, 134.2/134.3, 135.1, 136.9, 141.2, 155.1, 157.8/157.9, 158.1, 171.4/171.5; 8H: (CDC13) 4.31 (1H, s, H,,), 4.53 (1H, broad s, CHCO), 4.75 (2H, broad s, NCONH2), 5.73 (1H, d, NCONH), 6.65 (1H, t, CONHCH 2 ), 6.92 (1H, broad s, Im-H,), 7.04 (1H, broad s, Im-H 4 ), 7.10-7.15 (3H, m, Ar-H), 25 7.46 (1H, s, Ar-H), 7.58 (1H, broad s, Im-H 2 ) and 8

.

3 8 ppm (1H, s, Ar-H 2

).

WO 00/37459 PCT/US99/27939 - 232 EXAMPLE 73 Br, C N. 0-H N ONN i, NN o O The 11R,2R(+)-diastereoisomer from Preparative Example 38, 5 Step D above (0.1647g, 0.294mmoles), 4-pyridylacetic acid N 1-oxide (0.0586g, 0.382mmoles), DEC (0.0733g, 0.382mmoles), HOBt (0.0517g, 0.382mmoles) and 4-methyl-morpholine (0.042mL, 0.382mmoles) were dissolved in anhydrous DMF (5mL) and the mixture was stirred under argon at 25oC for 25h. The reaction was 10 worked up as described in Preparative Example 40, Step A above, and chromatographed on a silica gel column using 2% increasing to 6% (10% conc. NH 4 OH in methanol)-dichloromethane as the eluant to give the title compound: (Yield: 0.1048g, 51%); SIMS: m/z 694.5 (MH'); 8 c (CDCl) 30.0, 30.4, 31.0, 36.7, 38.5, 44.1, 44.5, 50.5, 51.3; 15 CH: 53.6, 63.6, 119.1, 126.4, 127.4, 127.4, ~-129.1, 130.7, 130.8, 133.4, ~137.2, 138.4/138.6, 138.7, 138.7; C: 118.5, 133.3, 134.6, 134.9, 140.4, 141.4, 147.4, 169.2, 169.9; 8H(CDC13) 4.98 (1H, broad s, CHCO), 5.70 (1H, s, H,,), 6.92/6.97 (1H, broad s, Im-H), 7.01 (1H, broad s, Im-H 4 ), 7.08-7.18 (5H, m, Ar-H), 7.43/7.51 (1H, broad 20 s, Im-H 2 ), 7.79 (1H, t, CONHCH 2 ), 8.05 (1H, d, Ar-H), 8.09 (2H, d, Ar-H), 8.26/8.31lppm (1H, s, Ar-H 2 ); [aD 2 +82.80 (c=9.1 1mg/2mL, methanol).

WO 00/37459 PCT/US99/27939 - 233 EXAMPLE 74 Br Cl NI + 0 +N H N NN N 0 N N I . 0 0 l o The 11S,2R(-)-diastereoisomer from Preparative Example 38, Step D above (0.1576g, 0.281mmoles), 4-pyridylacetic acid N1-oxide 5 (0.0560g, 0.366mmoles), DEC (0.0702g, 0.366mmoles), HOBt (0.0495g, 0.366mmoles) and 4-methyl-morpholine (0.040mL, 0.366mmoles) were dissolved in anhydrous DMF (5mL) and the mixture was stirred under argon at 25oC for 26h. The reaction was worked up as described in Preparative Example 40, Step A above, 10 and chromatographed on a silica gel column using 2% increasing to 6% (10% cone. NH 4 OH in methanol)-dichloromethane as the eluant to give the title compound: (Yield: 0.1017g, 50%); SIMS: m/z 694.5 (MH'); 8 c (CDC13) 29.7, 30.5, 30.8, 36.5, 38.4, 44.2, 44.3, 50.1, 52.3; CH: 53.4, 63.6, ~ 119.0, 126.4, 127.4, 127.4, -129.1, 130.3, 130.9, 15 133.3, -137.3, 138.3/138.7, 138.7, 138.7; C: 118.4, 133.3, 134.6, 134.8, 140.1, 141.6, 147.4, 169.2, 169.9; 8H(CDC1 3 ) 4.97 (1H, broad s, CHCO), 5.71 (1H, s, H 11 ), 6,58 (1H, t, CONHCH 2 ), 6.88 (1H, broad s, Im-H 5 ), 6.98/7.03 (1H, broad s, Im-H 4 ), 7.09-7.21 (5H, m, Ar-H), 7.34/7.41 (1H, broad s, Im-H2), 8.09 (1H, d, Ar-H), 8.10 (2H, d, Ar 20 H), 8.27/8.28ppm (1H, s, Ar-H 2 ); [alD 20 0* -12.70 (c=10.08mg/2mL, methanol).

WO 00/37459 PCT/US99/27939 -234 EXAMPLE 75 0 H Br ClN N+N

H

2 N N N IN (DaO 0 3-Bromo-8,11-dichloro-6,11-dihydro-5H-benzo[5,5]cyclo hepta[1,2-b]pyridine Ni-oxide (Preparative Example, 38 Step C) 5 (0.2656g, 0.74mmoles) in anhydrous dichloromethane (3.8mL) was added to 1-[2-[N-[3-(1H-imidazol-1-yl)propyl]-2(R) piperazinecarboxamide]-2-oxoethyl-1-piperidinecarboxamide (Preparative Example 40, Step B above) (0.3g, 0.74mmoles) and triethylamine (1.031 6mL, 7.40mmoles) in anhydrous 10 dichloromethane (6mL) and the mixture was stirred at 250C under argon for 19h. The solution was directly chromatographed on a silica gel column using 3.5% (10% cone. NH40H in methanol) dichloromethane as the eluant to give the title compound: (Yield: 0.3727g, 69%); LCMS: m/z 727.2 (MH'); Sc (CDC 3 ) CH 2 : 29.9/30.1, 15 30.4/30.5, 31.1/31.2, 32.0, 32.0, 36.5/36.6, 39.6, 44.0/44.4, 44.0/44.4, 44.4, 44.4, 50.5/50.7/51.1, 52.1; CH: 32.9, 53.0/53.1, 63.8, -119.2, 126.4/126.5, ~129.4, 130.5/130.7, 130.9, 133.4, -137.2, 138.4; C: 118.5, 133.3/133.4, 134.8/134.9, 140.2/140.5, 141.4/141.6, 147.6/147.8, 158.1, 169.3/170.2, 171.4/172.0; SH 20 (CDC1) 4.60 (1H, s, NCONH 2 ), 4.98 (1H, broad s, CHCO), 5.69 (1H, s, HI 1 ), 6.29/6.53 (1H, t, CONHCH 2 , S(-) and R(+) isomers at C,, respectively), 6.92 (1H, broad s, Im-H,), 7.05 (1H, broad s, Im-H 4 ), 7.14 (2H, m, Ar-H), 7.18 (1H, m Ar-H), 7.20 (1H, m, Ar-H), 7.56 (1H, broad s, Im-H 2 ) and 8.27ppm (1H, s, Ar-H 2 ). 25 WO 00/37459 PCT/US99/27939 - 235 EXAMPLE 76 Br Cl N K(N. H ( lS,2R(-) -Isomer) N "_ O 0 H Br C N (11R,2R(+)-Isomer)

°

O N 0 H Method 1: 5 3-Bromo-8,1 1-dichloro-6,1 1-dihydro-5H-benzo[5,51cyclo hepta[1,2-blpyridine Ni -oxide (Preparative Example 38, Step C) (0.2818g, 0.785mmoles) in anhydrous dichloromethane (4mL) was added to Ni -cyclohexyl-N2-[3- (1 H-imidazol- 1 -yl)propyll-1,2(R) piperazinedicarboxamide (below) (0.2844g, 0.785mmoles) and 10 triethylamine (1.094mL, 7.85mmoles) in anhydrous dichloromethane (4.5mL) and the mixture was stirred at 25°C under argon for 67h. The solution was directly chromatographed on a silica gel column using 3% (10% cone. NH 4 OH in methanol) dichloromethane as the eluant to give the racemic mixture of the 15 title compounds: (Yield: 0.4664g, 87%). The mixture was subjected to preparative HPLC on a Chiralpak AD® column (5OX5cm) using 65% hexane- 35% isopropyl alcohol- 0.2% diethylamine as the eluant to give in the order of elution the 1 S, 2 R(-)-diastereoisomer and the 1 1R,2R(+)-diastereoisomer.

WO 00/37459 PCT/US99/27939 - 236 11S,2R(-)-diastereoisomer: (Yield: 0155.5g); LCMS: m/z 684.2 (MH'); 8 c (CDC13) 25.0, 25.1, 25.6, 30.1, 30.5, 31.1, 33.7, 33.7, 36.4, 42.4, 44.5, 50.2, 51.5; CH: 49.9, 54.8, 64.1, 119.1, 126.5, 129.3, 130.5, 130.8, 133.5, 137.2, 138.4; C: 118.4, 133.1, 134.9, 140.2, 5. 141.4, 147.8, 157.6, 171.2; 8, (CDC13) 4.53 (1H, broad s, CHCO), 4.91 (1H, d, NCONHjj), 5.68 (1H, s, H,,), 6.62 (1H, t, CONHCH 2 ), 6.94 (1H, broad s, Im-H), 7.08 (1H, broad s, Im-H 4 ), 7.15 (1H, m, Ar-H), 7.17 (1H, s, Ar-H), 7.21 (1H, s, Ar-H), 7.23 (1H, m, Ar-H), 7.55 (1H, broad s, Im-H 2 ) and 8.27ppm (1H, s, Ar-H 2 ); [aD 2 0 0' -33.10 10 (c=8.76mg/2mL, methanol). 11R,2R(+)-diastereoisomer: (Yield: 0.1890g); LCMS: m/z 684.2 (MH'); S c (CDC13) 25.1, 25.1, 25.6, 30.3, 30.7, 31.1, 33.7, 33.7, 36.5, 42.3, 44.7, 50.2, 50.7; CH: 50.0, 55.0, 64.2, 119.1, 126.3, 128.8, 130.6, 130.9, 133.5, 137.2, 138.5; C: 118.5, 133.1, 15 134.7, 140.4, 141.4, 147.5, 157.5, 171.1; 8,H (CDC1 3 ) 4.52 (1H, broad s, CHCO), 4.95 (1H, d, NCONH), 5.69 (1H, s, H, I ) , 6.97 (1H, t,

CONHCH

2 ), 6.97 (1H, broad s, Im-H), 7.10 (1H, broad s, Im-H4 , 7.13 (1H, m, Ar-H), 7.18 (2H, s, Ar-H), 7.21 (1H, m, Ar-H), 7.69 (1H, broad s, Im-H 2 ) and 8.27ppm (1H, s, Ar-H 2 ); [a2 +49.90 20 (c=10.23mg/2mL, methanol). The starting reactant Ni1-cyclohexyl-N2- [3- (1H-imniidazol- 1 yl)propyl]-1,2(R)-piperazinedicarboxamide is obtained following the procedure of Preparative Example 5, except that N

NH

2

N

25 is used instead of Me Me

NNH

2 The resulting BOC protected compound is deprotected with TFA following the procedure in Preparative Example 8, Step B.

WO 00/37459 PCT/US99/27939 - 237 Method 2: The 11S,2R(-)-diastereoisomer (Preparative Example 38, Step D above) (1mg, 0.001l79mmoles) was dissolved in anhydrous dichloromethane (0.05mL) and cyclohexylisocyanate (0.0023mL, 5 0.0179mmoles) was added. The mixture was stirred at 25oC for 0.5h under argon. The solution was evaporated to dryness to give the title compound which was identical on chiral HPLC to the 11S,2R(-) diastereoisomer prepared in Method 1 above. 10 EXAMPLE 77 Br C+ Br Cl + EDCI, HOBT, N . NMM reagent 1 DMF N COOH reagent 2 N c. N N N 0

H

3 C CH 3 H3CCHs

CH

3 CH 3 Reagent 2 = N IVN NH The imrnidazole from Preparative Example 74 (Reagent 2), (250mg, 1.16mmol), was added to a solution of the BOC-acid 15 (Reagent 1, see Preparative Example 41), (0.45g,0.842mmol) , EDCI (200mg, 1.O43mmol), HOBT (130mg, 0.962mmol),and N-methyl morpholine (0.2ml, 1.81mmol) in DMF (anhydrous, 2ml) at room temperature (20 0 C). The resultant solution was stirred overnight at 20 0 C. The solvent was evaporated, water (70ml) and EtOAC (120 20 ml) were added. The organic layer was separated, and washed with 10% Na 2 CO, solution (50ml), then dried over MgSO 4 , filtered and evaporated solvent yielding an oil, which chromatographed on silica gel eluting with 100% EtOAC yielding the product as a white solid (300mg). Mixture of 4 isomers A,B,C,D.

WO 00/37459 PCT/US99/27939 - 238 Mass Spec: High Resolution(ES) Estimated(MH ) 732.2316 Observed 732.2332 EXAMPLE 78 5 Step A Br Cl Br Cl N N N C, N N.;; N N C NN N N I I I I I O oO H 0

H

3 C+ CH 3

CH

3 A solution of the title compound from Example 77, (Isomers A, B, C and D), (150mg,0.205mmol) in 50% trifluoro-acetic acid

CH

2 C12 was stirred at 20oC for 3 hours. The solvent was evaporated, 10 water (25ml) and 10% NaOH (4ml) were added, then extracted with

CH

2 C12 (2x100ml). The organic layer was separated, dried over MgSO 4 , and solvent evaporated yielding a solid which was purified by chromatography on silica gel eluting with 3% MeOH- CH 2 C1 2 containing 2% NH 4 OH yielding the product as a white solid (70mg, 15 54% yield). The product was obtained as a mixture of 2 Isomers (C and D). (Product 1) Mass Spec FABS (MH) 632. Further elution yielded a white solid (25mg,20% yield). This product was a mixture of 2 Isomers (A and B) (Product 2) Mass Spec 20 FABS (MH') 632. Product 2 was separated into single isomers on a Chiralcell AD column eluting with 40% IPA-Hexanes yielding Isomer A as a white solid FABS (MH') 632. Further elution yielded Isomer B as a white solid, FABS (MH) 632. 25 Product 1 was derivatised and separated into constituent Isomers C and D as shown in Step B below.

WO 00/37459 PCT/US99/27939 - 239 Step B Br Cl Br Cl N N I II I . II N 'CN N N C-N N~c H 0 0

H

3 C

'CH

3

CH

3 A solution of di-tert-butyldicarbonate (65mg,0.29mmol) in 5 CH 2 Cl 2 (2ml) was added to a solution of Product 1 (Step A, Isomers C and D) (150mg, 0.237mmol) in CH 2 C12 (10ml), at 0oC, then stirred at 20oC for 10 minutes. The reaction was cooled to 0OC, water (5ml), 10% NaOH (2ml) and CH 2 C1 2 (10ml) were added. The organic layer was separated, dried over MgSO 4 , filtered and solvent 10 evaporated yielding an oil, which was chromatographed on silica gel, eluting with 3% v/v MeOH: CH 2 C2 yielding the product as a white solid (150mg) as a mixture of 2 isomers, which were separated on Chiralcell AD column, eluting with 30% IPA-Hexanes/ 0.2% Diethylamine yielding Isomer C 60mg. Mass Spec (FABS, MH') 15 Calculated (C 38

H

44 N 5 0O 3 BrCl:734.2296) Measured: 734.2304. Further elution yielded Isomer D 70mg. Mass Spec (FABS, MH') CALC MH (734.2296) Measured: (734.2305).

WO 00/37459 PCT/US99/27939 -240 EXAMPLE 79 Step A Br CI Br C1 N C N N N N C, N N N I II I II O 00 H O

H

3 C+ CH 3

CH

3 Following the procedure of Example 78 Step A, the BOC 5 group of the Isomer C product of Step B was removed to produce the Isomer C title product as a white solid (Mass Spec, MH') FABS (632). Step B Br C1 Br C1

N

N I NN C' NN O _1 N O H 0 0>N~ 10 H Cyclohexyl isocyanate (0.025ml,0.19mmol) was added to a solution of Isomer A (Example 78, Step A) (25mg, 0.039mmol), in

CH

2 C1 2 (3ml) at 0oC, then stirred at 20 0 C for 30 minutes. Methylene chloride (20ml) and water (20ml) were added. The organic layer was 15 separated, dried over MgSO 4 , filtered and solvent was evaporated yielding a residue, which chromatographed on silica gel, eluting with 2% v/v MeOH: CH 2 C12, yielding the product (Isomer A) as a white solid (25mg). High resolution Mass Spec (ES) Calculated:

C

4 oH 47 ,02N 6 C1Br (757.2632)(Br=79) Measured: 757.2643.

WO 00/37459 PCT/US99/27939 -241 Following the above procedure, but substituting an equivalent quantity of Isomer B (Example 78, Step A) for Isomer A, the title product (Isomer B) was obtained. Mass Spec (FABS, HRMS) Calculated 759.2612 (Br=81) Measured 759.2626 5 Following the above procedure, but substituting an equivalent quantity of Isomer C (Example 79, Step A) for Isomer A, the title product Isomer C was obtained. Mass Spec (ES, MH') 757 (Br =79) Following the above procedure, except using the mixture of Isomers C and D (Product 1 from Example 78 Step A), yields the C 10 and D isomer mixture of the title compound Mass Spec (ES,MH*) 757 EXAMPLE 80 Br C1 Br C1

N

H O __IO ONO I

C

2

H

5 15 Ethyl chloroformate (0. 1ml, 1.04mmol) was added to a solution of the Isomer A (Example 78, Step A) ( 20mg, 0.03nmmol) in

CH

2 C1 2 (2ml) at 20 0 C. Triethylamine (0. 1ml, 0.7mmol) was added, and the solution was stirred for 30 minutes at 20 0 C. The solvent was evaporated, and the residue chromatographed on silica gel, 20 eluting with 3% v/v MeOH: CH 2 C1 2 containing 2% NH 4 OH, yielding the Isomer A product as a white solid (20mg). Mass Spec (ES, MH') 704. Following the above procedure, but substituting an equivalent quantity of the Isomer B (Example 78, Step A) for Isomer A, the 25 Isomer B product was obtained. Mass Spec (ES, MH') 704: HRMS (ES) Calculated (704.2003) (Br= 79) Measured (704.2012).

WO 00/37459 PCT/US99/27939 -242 EXAMPLES 81-85 Follow the procedure of Examples 127 and 80, but use the title compounds from Preparative Examples 9.1 or 111.1 with the appropriate isocyanate or chloroformate to obtain compounds of the 5 formula: N

(N

Cl

R

8 'N pC -N N I II

R

14 O wherein R 8 and R1 4 are defined in Table 10 below are obtained. TABLE 10 10 Ex. R 8

R

1 4 Isomer MS 81 H A Fabs (Product of Prep. 0 0 and (MH) Ex. 9.1 and di-t- H 3 C ' CH 3 B 565 butyldicarbonate) CH 3 (RS) (R, S) 82 A ES (Product of Prep. o and (MH) Ex. 111.1 and di-t- H 3 C @CH 3 B 655 butyldicarbonate) CH 3

(R,S)

WO 00/37459 PCT/US99/27939 -243 83 J, A ES (Product of Prep. 0 O (R(+)) (MH) Ex. 111.1 and di-t- H 3

C--CH

3 655 HzC CH3655 butyldicarbonate)

CH

3 [a]2 =+2.5o 84 J B ES (Product of Prep. OO (S(-)) (MH) Ex. 111.1 and di-t- HC.-CH 3 HgC CH3655 butyldicarbonate)

CH

3 [a]0=-34.90 85 / A ES (Product of Prep. AN and (MH) Ex. 111.1 and H B 680 cyclohexyl (RS) isocyanate) The compounds of Examples 83 and 84 were separated on Chiralcell AD column. 5 EXAMPLE 86 Br Cl Br /Cl S- 1 IS Isomer 11R Isomer H N H N NO NO H H Following the procedures of Examples 77-79, but substituting an equivalent quantity of 1-(3-aminopropyl)imnidazole for the N 10 benzyl substituted imidazole from Preparative Example 74 in Example 77, the title compounds are obtained. 11S-Isomer: Mass Spec: Fabs (MH') 667(Br=79) HRMS Cale (MH) C 33

H

41

N

6 0 2 C1(81)Br 669.2142 Measured 669.2151 WO 00/37459 PCT/US99/27939 -244 11R-Isomer: FABS (MH) 667. EXAMPLE 86A Br C1 N HO H H O 3C 5 Use the imidazole from Preparative Example 1 Step D and follow the procedure of Example 77 and Example 79 Step A to obtain the compound Br Cl

H

3 H N N CH

Z-

H

3 C NVj which is then reacted with cyclohexyl isocyanate according to the 10 procedure set forth in Example 79 Step B. Mass Spec: Fabs (MH) 695 (Br=79) 669.2142. EXAMPLES 87-97 Following the procedures set forth in Examples 77-80, but 15 using the 11(R)-isomer, compounds of the formula: WO 00/37459 PCT/US99/2793 9 - 245 Br Cl N CN

R

1 4 0 are obtained. R1 4 is defined in Table 11. TABLE 11 5 Ex. R 4 Isomer Mass Spec Observed (Estimated) 87 A, B, C, D 732.2343 o 0 (732.2316) H3C -CH 3

CH

3 88 [ A 732.2332 o 0 (732.2316)

H

3

C

4

CH

3

CH

3 89 o B 734.2305 o0 o (743.2296) C CH

CH

3 90 A 757.2641 N (757.2632) H 91 < B 759.2618 ' N -O (759.2612)

H

WO 00/37459 PCT/US99/27939 -246 92 C 734.2296 o o (732.2296)

H

3

CCH

3

CH

3 93 [ D 734.2297 o 0 (734.2296)

H

3 C bCH 3

CH

3 94 C, D 734.2318 O 0 (734.2296) H3C CH 3

CH

3 95 C 759.2611 N 'O (759.2612) H 96 < D 759.2618 N (759.2612) H 97 C, D 759.2626 NZO (759.2612) H EXAMPLE 98 Br / Cl CN N N N 0 HN 0 WO 00/37459 PCT/US99/27939 - 247 The product of Preparative Example 45 (0.6 gm) was dissolved in 6 ml of dichloromethane and 6 ml of trifluoroacetic acid was added and the reaction mixture stirred for 2 hours. After 2 hours the reaction mixture was evaporated to an oil. The oil was dissolved 5 in N,N,-dimethylformamide and triethyl amine (0.445 mL, 3 eq.) was added and 3-bromo-8, 11-dichloro-6, 11-dihydro-5H benzo[5,6lcyclohepta[1,2-b]pyridine (0.39 gm, 113 mmol.) was added and the reaction mixture stirred for 24 hours. The reaction mixture was added to brine and the product extracted with 10 ethylacetate 3 times to obtain a crude oil after the solvent was evaporated under reduced pressure, which was purified by chromatography on a silica gel column using 2% up to 4% methanol/dichloromethane as the eluent. The product containing fractions were pooled to obtain 0.34 gm of pure title compound. 15 The compound was separated into its pure enantiomeric forms by HPLC on a Chiral Technologies AD column using 20% isopropanol/hexanes. Isomer 1: mp= 148.3-157.5oC; Isomer 2: mp= 148.3-157.5oC 20 EXAMPLE 99 Br / 1 O HO 0 HN 0 The title compound from Preparative Example 48 (0.487 gm) was dissolved in dichloromethane (3 ml) and trifluoroacetic acid (3 WO 00/37459 PCT/US99/27939 - 248 ml) and the reaction mixture stirred for 2 hours. The reaction mixture was evaporated to dryness and dissolved in 10 mL of N,N dimethyl-formamide. Triethylamine (1.42 mL, 10 eq.) was added and 3-bromo-8, 11-dichloro-6, 11-dihydro-5H-benzo 5 [5,6]cyclohepta[1,2-b]pyridine (Compound No. 42.0) (0.45 gm, 1.2 eq.) was added and the reaction mixture stirred for 24 hours. The reaction mixture was added to brine and the product extracted with ethylacetate 3 times to obtain a crude oil after the solvent was evaporated under reduced pressure, which was purified by 10 chromatography on a silica gel column using 2% up to 4% methanol/dichloromethane as the eluent. The product containing fractions were pooled to obtain 0.26 gm of pure title compound as a mixture of isomers. Isomers were separated by HPLC on a Chiral Technologies AD column using 20-30% isopropanol/hexanes. 15 Isomer 1: mp= 192.7-194.3 oC; Isomer 2: mp= 189.2-190.7 0 C EXAMPLE 100 Br / Cl N H N N H N N NN 0 OH 00

H

3 C CH 3

CH

3 The title compound from Preparative Example 52 (0.3 gm, 0.5 20 mmol) was stirred in a mixture of 10 ml of dichloromethane and 15 gL of water and Dess-Martin Periodinane (0.32 gm, 1.5 eq.) was added and the reaction mixture stirred at ambient temperature. After 24 hours the reaction mixture was washed with 20% Na 2

S

2 0 3 solution followed by sodium bicarbonate solution and evaporated to 25 dryness under vacuum. This compound was dissolved in WO 00/37459 PCT/US99/27939 -249 dichloromethane and a premixed solution of 4-iodo-1-trityl imidazole (89 mg) and ethylmagnesiumbromide (3M soln in ether, 66 AL, added to the reaction mixture and stirred at ambient temperature for 4 hours. The reaction mixture was poured into 5 saturated ammonium chloride solution and the product extracted with dichloromethane to obtain the crude product which was purified by preparative tic to obtain 52 mg of title product after deprotection with TFA and introduction of the Boc group with

(BOC)

2 0. 10 EXAMPLES 101-102 Following procedures similar to those described in Examples 98-100, the following compounds are obtained: Br C 1 N N ON H \O Example 101 H \ INN N a ~N- 0 Example 10 1 H H 15 and Br Cl N NN N'H NH Oj\O 0 HO

H

3 C CH 3

CH

3 Example 102 WO 00/37459 PCT/US99/27939 - 250 EXAMPLE 103 Br/ C N N r N

H

3 C CH N N / NH 2

H

3 C>K"Nk 0 H The title compound from Preparative Example 58 was 5 dissolved in 1 ml of dichloromethane and 68 microliters of tert butylisocyanate was added and the reaction mixture stirred. The reaction mixture was evaporated to obtain the crude product which was stirred with 33% HBr/HOAc to obtain 20 mg of the title product after addition to ether, collection of the product as a tan solid, and 10 preparative thin layer chromatography. FABMS M+ 1= 659.

WO 00/37459 PCT/US99/27939 -251 EXAMPLE 104 Br \ Cl N N H N

CH

3 N HN

H

3 C N O N O H

H

3 C The title compound from Example 103 (50 mg) was dissolved in 5 ml of dichloromethane and 0.5 ml of acetic anhydride was 5 added. The reaction mixture was evaporated to dryness after 18 hours and chromatographed by preparative tic to obtain 39 mg of pure title product. FABMS MH'= 699. EXAMPLE 105 Br /\ Cl tN N H N H3C H 3 N O NH 2 10 H3C O 0 O The title compound was prepared following essentially the same procedure as set forth in Preparative Example 52, but substituting 1-(3-aminopropyl)-2-aminoimidazole for 1-amino-3 propanol to obtain the title product in 65% yield. FABMS MH'= 15 660.

WO 00/37459 PCT/US99/27939 - 252 EXAMPLE 106 Br / Cl tN\ N H N if, N N N

CH

3 NH HC O 0O F3C. O The title compound was prepared following the procedure set forth in Example 104, but using the title compound from 5 Preparative Example 105 in place of the title compound from Example 103 and trifluoroacetic anhydride in place of acetic anhydride to obtain the pure title product. FABMS MH*=756. EXAMPLE 107 Br / 1 N N H N o H

CH

3 NH H3C Or H3C>< N 0 0 F 3 C / O 10 H Follow the precedure set forth in Example 104, but substitute trifluoracetic anhydride for acetic anhydride to obtain the pure title product. FABMS MH*= 755.

WO 00/37459 PCT/US99/27939 - 253 EXAMPLE 108 Br /Cl N N H N CH3 N OH H3C N O H 3 C

H

3 C N O H The title product was prepared following the procedure set forth in Example 110, but substituting the title compound from 5 Preparative Example 60 for that from Preparative Example 102 Step C and tert-butyl isocyanate for cyclohexyl isocyanate to obtain the pure title product. FABMS MH' = 688. EXAMPLE 109 Br C1 NH N N H N

CH

3 N OH

H

3 C OL ~

H

3 C O O 10 The title product was obtained following the procedure set forth in Preparative Example 52, but substituting 2-S-benzyl-3-R,S hydroxy-histamine for 1-amino-3-propanol. FABMS (MH')= 737.

WO 00/37459 PCT/US99/27939 - 254 EXAMPLE 110 Br \ C1 N Me N H-N

CH

3 NNN N N H A mixture of the title compound from Preparative Example 102 Step C (0.28 g, 2 mmol), the title compound from Preparative 5 Example 44 (0.5 g, 2 mmol) and anhydrous CH 2 Cl 2 (5 mL) was stirred at room temperature for 15 min. Cyclohexyl-isocyanate (0.51 mL, 4 mmol) was added and the reaction mixture allowed to stir at room temperature for an additional 48 hrs. After concentrating the reaction mixture in vacuo, the residue was 10 diluted with CH 2 C1 2 (10 mL) and trifluoroacetic acid (10 mL) and stirred at room temperature overnight. The resulting mixture was concentrated in vacuo, diluted with anhydrous DMF (5 mL) and to it were added N-methylmorpholine (2.2 mL, 20 mmol) and the tricyclic chloride (compound No. 42.0) (0.83 g, 2 mmol). The reaction 15 mixture was stirred at room temperature overnight, concentrated in vacuo and purified by flash column chromatography (silica gel) using 5% MeOH-95% CH 2 C1 2 saturated with aqueous ammonium hydroxide to give the title compound as a mixture of diastereomers (tan solid, 95 mg, 7%, MH + = 682, mp = 118.4°C). 20 WO 00/37459 PCT/US99/27939 - 255 EXAMPLE 111 Et Br c H-N NN N' CH 2

CH

3 N N N N #""\N H Following a similar procedure as that used for the preparation of the title compound from Example 110, but using the title 5 compound from Preparative Example 103, the title compound was obtained as a mixture of diastereomers (brown, sticky solid, 28.7 mg, 2%, MH + = 696, mp = 79.3oC). EXAMPLE 112 Br/\ C Pr N II H- '

-

,,N CH2CH2CH 3 10 H Following a similar procedure as that used for the preparation of the title compound from Example 110, but using the title compound from Preparative Example 104, the title compound was obtained as a mixture of diastereomers (tan solid, 18.5 mg, 1%, 15 MH

+

= 710, mp = 63.8-67.4oC).

WO 00/37459 PCT/US99/27939 - 256 EXAMPLE 113 Br /\C1 Br /\C1 N 'N N + N N)/OH HNN N N / N / O OO O 0O N %4 N 0 0l To the title compound from Preparative Example 51 (10.04 g, 19 mmol) were added HOBT (3.34 g, 25 mmol), DEC (4.79 g, 25 5 mmol), the title compound from Preparative Example 74 (4.32 g, 20 mmol), NMM (5.5 mL, 50 mmol) and anhydrous DMF (20 mL). The mixture was stirred at room temperature under N 2 overnight. The mixture was concentrated in vacuo, diluted with CH 2 Cl 2 and washed with a saturated aqueous solution of NaHCO 3 . The organic 10 phase was dried over anhydrous MgSO 4 , filtered and concentrated in vacuo. The residue was purified by flash column chromatography (silica gel) using 2% MeOH-98% CH 2 Cl 2 saturated with aqueous ammonium hydroxide to give the title compound as a mixture of diastereomers (4.92 g, 36%, MH + = 733). 15 EXAMPLE 114 If the procedure set forth in Example 113 is followed, but the N-substituted imidazolylalkyl amine below is used the indicated compound would be obtained. Br \ C1 F FN 2nN HN N NN

H

3 C 20 Amine A Compound A WO 00/37459 PCT/US99/27939 - 257 Br C\Cl N N) CH

SCH

3 CH N N HN N

H

3 C , Amine B Compound B Br \ C1 N N

CH

3 N CHH N N N N H 3 tI) A HN N N

H

3 C Amine C Compound C Br \cI N

C

H

3 NH N N HCON3 CH3 H ;o , 0 N

H

3 C Amine D Compound D 5 EXAMPLES 115-126 Following the procedure set forth in Example 113, but using the N-substituted imidazolylalkyl amine (Imidazole) in Table 12 and the carboxylic acid from Preparative Example 51, the Products in Table 12 were obtained. 10 WO 00/37459 PCT/US99/27939 - 258 TABLE 12 Ex. Amine Product 1. %Yield 2. MH 3. mp (OC) 115 F Br C1 1.19 2.751 H- N N F -N~NN 3. 105.4 O N,4,N 1 1 6N Br s2 0 116 N Br c 1 \ 1 1.27 H -. 2.734 .N N N 3. semi N solid Or__ , NN 0 117 N Br C1 1.35 N _N 2.734 H- N /I 3. semi N N solid 0 118 OH Br c 1.52 H-N r= N\ / 3. 65-70 .ONNI1 NN N3o 0 119 OMe Br/ \C1 Oe 1.18 O~e 2.763 I-' N \I3.65-70 HIN\ -, , N,,,, N -I _ _ _ _ _ _ _0 0_ _ _ WO 00/37459 PCT/US99/27939 - 259 120 OMe Br/ \ C 1 1.48 2.763 H N% N N 0 OMe 3.125

N

NN N\ 130 N /N N O - O 121 CN Br X\C1 1.20 16 CN 2.758 H-N - _1 N 3. semi \- N.N

.

solid N "/ -N =1 O N N 0O 122 ONH2 Br ci 1.19 CONH 2 2.776 H N 3. semi HN NNisolid O f- N zN N 0 /O"O 123 Br /1 1.15

-

/ 2.783 N N \ 3.85-90 H -- -N O~ NN 0 , 124 Br ci 1.12 2. 739 HN - NN N N 3. semi N " solid N0N WO 00/37459 PCT/US99/27939 - 260 125 / \ Br c1 1.35 f-N 2.747 aN N 3. (A): 86 NN O N N (B) 84.7 126 Br c 1.15 fN2. 719 HN N N 3. (A ( N 206.7 o oo (B) 0 0J 121.2 N 130.4 EXAMPLE 127 Br 1/

C

1 Br C I N N HNONN N N /NNN H O0 5 To a solution of the title compound from Preparative Example 109 (11R,2R diastereomer B, 1.7 g, 2.7 mmol) dissolved in anhydrous CH 2 C1 2 (10 mL) was added cyclohexylisocyanate (0.38 mL, 2.9 mmol) and the resulting solution was stirred at room temperature under N 2 for 1.5 hrs. The solution was concentrated in 10 vacuo and purified by flash column chromatography (silica gel) using 2% MeOH-98% CH 2 C1 2 saturated with aqueous ammonium hydroxide to give the title compound as a light yellow solid (1.98 g, 84%, MH

+

= 758).

WO 00/37459 PCT/US99/27939 - 261 EXAMPLES 128-148 Following the procedure set forth for Example 127, but using the isocyanates and the compounds of the preparative examples given in Table 13 below, the Products given in Table 13 were 5 obtained. TABLE 13 Ex. Isocyanate Product 1.Yield (%) and 2. MH' Prep. Ex. 3. mp (oC) Compound 128 J Br 0' C1 1.87 NCO N N 2.760 Prep. Ex. 109 o ,NN 3. 125.2 Diastereomer A N H 222421 129 Nco B r C 1.61 NCO N 2.732 N N /=1 Prep. Ex. 109 N ' 3. 126.6 Diastereomer A N 0 I H 130 Br c, 1.100 NCO N 2. 732 Prep. Ex. 109 A rN ' 3. 112.3 Diastereomer B N 0

H

WO 00/37459 PCT/US99/27939 - 262 131 NCO Br cl 1.95 NCO N 2.718 Prep. Ex. 109 . - N 3. 109.8 Diastereomer A N 0 I H 132 Br \ C 1.63 NCO N 2.718 N 'dr-, r-N Prep. Ex. 109 No N 3. 118.1 Diastereomer B N o I H 133 ~Nco Br f7 c1 1.95 2.704 Prep. Ex. 109 " N /,N -N---I Diastereomer A NN N 3.93.5 NO I H 134 NCO Br/ j C1 1.86 N (N 2. 718 Prep. Ex. 109 N ,7' Diastereomer B oo :NN 3.98.9 I H WO 00/37459 PCT/US99/2793 9 - 263 135 Br cl 1.56 NCO N N2. 752 oN N4N 3.81.4 Prep. Ex. 109 , 3.81.4 NO0 Diastereomer A H H 136 NCO B C1 1.17 NCO Br N 2.766 N -X pN Prep. Ex. 109 N-N o, Diastereomer A H 137 NcoBr cl 1.80 NCON / 2.780 N 0- N,- N .6. Prep. Ex. 109 N 3.68.4 Diastereomer A H 138 NBr ( c<7l 1.68 NCO -: 2.772 r Me Prep. Ex. 131 o 4N NO0 Diastereomer A I

H

WO 00/37459 PCT/US99/27939 - 264 139 NCO Br cl 1.53 NCON N Iie 2.772 ) Me Prep. Ex. 131 oN oN" . N O Diastereomer B H 140 NCO Br C1 1.83 ( 2.744 Prep. Ex.113 3. 143.8 Diastereomer A H N HN 141 Nco Br \ C 1.96 NCO fN N 2.744 Prep. Ex.113 2 N o 3. 135.4 Diastereomer B H H N 142 Br B Cl 1.77 NCO fN N CN , 1 2.733 Prep. Ex.117 " N N-N 3.120.8 Diastereomer B

H

WO 00/37459 PCT/US99/27939 - 265 143 c Br cl 1.64 NCO N _N N ), 4 2.733 Prep. Ex.117 N \ _ N_,N 3. 116.8 Diastereomer A N 0 H 144 NICO C 1. 100 NCCO N 2. 680 Prep. Ex.111 Oo N,,N Diastereomer B H 145 N( cl 1. 79 NCO N 2.654 P rep. Ex.111 r i3 r o .I,, N 3.61.3 Diastereomer A o 69.3 146 o-

C

l 1.97 NCO N,, NF-0 2. 654 Prep. Ex.111 >H-N,"N 3. 97.0 Diastereomer B o 47H 0 147 NCO 1.91 N'.-N I=1 Prep. Ex.125 0 \"',, N., N H O WO 00/37459 PCT/US99/27939 - 266 148 Br \ Cl 1.68 NCO -N( 2.735 >K N "4- N Prep. Ex.130 N H EXAMPLE 149 -fN N (N)._ N Br l Br C el H O NN N- N 5 To a solution of the title compound from Preparative Example 109 (11S,2R diastereomer A, 50 mg, 0.08 mmol) dissolved in anhydrous CH 2 C1 2 (1 mL) was added benzoyl chloride (0.02 mL, 0.16 mmol) and triethylamine (0.03 mL, 0.2 mmol) and the resulting mixture was stirred at room temperature under N 2 10 overnight. The solution was diluted with dichloromethane, washed with IN aqueous NaOH and dried over anhydrous MgSO 4 . Filtration and concentration in vacuo provided a residue which was purified by preparative plate chromatography (silica gel) using 5% MeOH-95% CH 2 C1 2 saturated with aqueous ammonium hydroxide 15 to give the title compound as an off-white solid (54.4 mg, 93%, MH + = 737). SCH EXAMPLES 150-217 Similarly, using the procedure described for Example 149, the 20 title compound (diastereomer A or B) from the Preparative Example given in Table 14 was treated with the corresponding acid chloride, WO 00/37459 PCT/US99/2793 9 - 267 chloroformate, carbamyl chloride, dicarbonate, anhydride or sulfonyl chloride given in Table 14 below (Electrophile column) to give the N-substituted arylalkyl or heteroarylalkyl Products listed in Table 14. 5 TABLE 14 Ex. Electrophile Product 1. Yield and (%) Prep. Ex. 2. MH' Compound 3. mp (oC) 150 c Br 1.54 H C , N C1 2.675 3.79.7 N Prep Ex. 109 -N Diastereomer A oNN O 151 Br/ \C1 1.75 2.675

H

3 C O N 3.69.3 N Prep Ex. 109 -N N/ Diastereomer B 'o - N N 1 52 O Br C1 1.72 2.717 3.86.4 N Prep Ex. 109 r Diastereomer A O n-C 4 9 n'C4H9" 0 WO 00/37459 PCT/US99/27939 - 268 153 cl Br 1.172 2.731 0- - 3.85.4 O N Prep Ex. 109 N Diastereomer A 0 0 154 1.8 1O54 cl Br cl 1.85 B 2.743 3.100 101 Prep Ex. 109 o Diastereomer A 1 5 5 0 1 B r l 1 .8 8 o 2.729 S3.101 N , /104 Prep Ex. 109 o S Diastereomer A 0 156 MeO o Br l 1.61 o N "- 2. 705 3. 102.7 N Prep Ex. 109 N

"

3 Diastereomer A N - -N MeO N

O

WO 00/37459 PCT/US99/27939 - 269 157 Me" to Br c1 1.92

N

0 N.- 2.704 I 3. 114.7 Me N N /N / Prep Ex. 109 Me. o 0 N--N Diastereomer A 0 Me 158 Me Br/ Cl 1. 100 N N0 - 2.704 M N f , 3.110.4 Me N Prep Ex. 109 Me, N0 o Diastereomer B N 0 1 Me 159 o Br cl 1.97 i ' o2 N 2.733 N 3. 103.5 Prep Ex. 109 C== Diastereomer A o ooN,,N 0 160 0Br 1.83 o o 2.733 2N 2 3.94.5 Prep Ex. 109 N N Diastereomer B o N,, N oo WO 00/37459 PCTIUS99/27939 - 270 161 C 1B81 Br Cl " 0 N 2.719 3. 95.5 Prep Ex. 109 - / Diastereomer A N 0 0 162 cl Br c1 1.87 0 0 2.733 rE 03.84.5 N Prep Ex. 109 N Diastereomer A o ,, N , NN O 0 163 cl Br ,1.89 " 0 Br , el 1 8 N0 N 2.705 3.93.7 N Prep Ex. 109 0 Diastereomer A N 0 1 6 4 c 1 ./ . 164 0 Brc l 1.89 0or. -"--0 2.719 3.79.8 N Prep Ex. 109I Diastereomer A N

O~O

WO 00/37459 PCT/US99/27939 - 271 165 clO Br C1 1.87 n-C 4

H

9 1---' 0N \ 2.733 - 3.70.5 Prep Ex. 109 Diastereomer A N N n-C 4

H

9 0 166 cl Br cI 1.83 n-C 6

H

13 -O O N0 2.761 3.60.2 N Prep Ex. 109 Q Diastereomer A n-C 6 HO,, f O__ 167 cl B, / Br C 1.86 N 2.789 3. 63.1 Prep Ex. 109 , Diastereomer A o- NN n-C 8

H

1 7 O O 168 C l Br . C1 1.50 oS 0f 2.753 O -3.91.1 Prep Ex. 109 ( , Diastereomer A oa 0 N,,, N ao 0 169 Cl - C 1 Br ci 1.91 o -4 _ 2.787 N 3.87.3 Prep Ex. 109 cl Ni- N Diastereomer A -oo 0 WO 00/37459 PCT/US99/279 3 9 - 272 170 Br cl 1.83 a o 2.759 3.78.7 Prep Ex. 109 Diastereomer A N, 00 171 Br, cl 1.96 K> cl -N- 2.815 N 3.96.4 N N o Prep Ex. 109 0 0 Diastereomer A 172 Br cl 1.88 2.815 o o3.95.8 N Prep Ex. 109 1 N,,o, N Diastereomer A 0 173 MeSO 2 C Br Cl 1.68 2.711 Prep Ex. 109 3.113.6 N Diastereomer A, O NNN 7:"o Me" \\ 0 WO 00/37459 PCT/US99/27939 - 273 174 MeSO 2 C1 Br cI 1.83 N 2.711 Prep Ex. 109 N 3. 114.6 Diastereomer B (/ O/ NqN =o Me" 0 175 n-PrSO 2 CI Br -- cI 1.50 2.739 Prep Ex. 109 3.86.5 N Diastereomer A r No NX..-N 0 N.. ,N 0 176 n-PrSO 2 C1 Br \ C 1.15 2.739 N Prep Ex. 109 3.93.8 N i Diastereomer B ( N O N,,,N o 0 177 n-BuSO 2 C1 r C 1 1.40 2.753 Prep Ex. 109 3.87.9 N Diastereomer A 0 NqN 0 / !o

°

WO 00/37459 PCT/US99/27939 -274 178 i-PrSO 2 C1 Br / Cl 1.21 2.739 N Prep ex. 109 [- . 3.93.2 Diastereomer A , 0 N,, N 4JN o s=o 0 179 PhCH 2

SO

2 C rl. 50 2. 787 Prep Ex. 109 -3.110.4 N Diastereomer A /' O NN 0 180 cl Br cl 1.92 2.715 3. 105.5 \N Prep Ex. 109 o Diastereomer A 0 181 0 Br cl 1.98 2.701 3. 106.8 'N N N- Prep Ex. 109 o Diastereomer A 0 WO 00/37459 PCT/US99/27939 - 275 182 c Br Cl 1.90 fN' 2.787 3.78.8 0 l Cl ,," O C o NN.,N O 0 Prep Ex. 109 Diastereomer B 183 C Br/ C 1.57 o 2.719 ,/ 3. 95.2 Prep Ex. 109 N ), /_ DiastereomerB o 0 OO 184 01 184 C Br/ \ c 1 1.95 O o' 2. 733 N 3. 84.9 N Prep Ex. 109 II:IN N F, Diastereomer B o o 0 185 C1 1.53 0 0 2.641 3. 89.6 N Prep Ex. 111 3 8 9 6 Diastereomer A o 0 0 WO 00/37459 PCT/US99/27939 - 276 186 cl / C 1.- 68 0 N 2.681 3. 101.1 Prep Ex. 111 N 3.0 Diastereomer A o "N O O 187 cl / Cl 1.77 oo N 2.641 P x3.68 Prep Ex. 111 C,ZN -- o /== Diastereomer B o N 0 0 188 Cl C1 1.61 N

-

2 . 6 8 1 N 3.87.9 Prep Ex. 111 rN N Diastereomer B 0 189 C1 Br /Cl 1.85 N -2.745 (N 3. 94.2 Prep Ex. 109 == Diastereomer B o o 0 190 c/ cl 1. 72 N -2.667 SN 3.97.2 Prep Ex. 111 = Diastereomer B o 0 0 WO 00/37459 PCT/US99/27939 - 277 191 Br cl 1.52 2.717 N 3.91.8 N N Prep Ex. 109 o N,, N Diastereomer B o 192 c . c1 1.81 No -2.667 O/ 3.85.8 Prep Ex. 111 N = Diastereomer A N N N a O 193 Br /C 1.76 2 0 _ 2.719 3. 206.7 Prep Ex. 113 N 194 Br / cl 1.85 k o o - 2.719 2 N 3. 121.2 Prep Ex. 113 130.4 Diastereomer B o

N

WO 00/37459 PCT/US99/27939 - 278 195 Cl Brc .6 / 1 BrC1 1.69 SN o2.733 N ,3.96.1 Prep Ex. 131 hJ,,N Me 120.3 Diastereomer A o o 1 196 cl Br C1 1.77 o ON 2.733 N 3. 105.1 Prep Ex. 131 Me 114.2 Diastereomer B 1r N.N 197 a Co Br/ c1 1.56 2. 775 N Me 3. 100.4 "N' I N 1-No Me108.8 PrepEx. 131 ,08. N Diastereomer B 0 0 198 c ioc 1.69 O' o 2. 695 NMe 3.82.5 Me Prep Ex. 114 Q ,o 0 N Diastereomer B 0 0 199 c 1 c ° c1 1.60 2.695 N 3. 83.4 O/Me Prep Ex. 114 0" N 0 NM Diastereomer A o o WO 00/37459 PCT/US99/27939 - 279 2000 200 o Cl 1.61 N - 2.655 . 3.83.2 Prep Ex. 114 " - Me Diastereomer A N COO 201 Cl 1.64 2' O N 2.655 Prep Ex. 114 N Me 3.81.2 SDiastereomer B N 'o,,,NN 2 0 2 c l6 202 1.72 2. 681 0 3.98.2 CIN\ Me Prep Ex. 114 N NN Diastereomer A o N 203 clo cl 1.76 2. 681 N. 3. 94.5 /--0 Me Prep Ex. 114 N,' ~0 Diastereomer B 0 0 204 oo 204, Cl o1.62 0 0 2.659 F 3.97.8 Prep Ex. 108 NDiastereomer A N . Diastereomer A o oo

N

WO 00/37459 PCT/US99/27939 - 280 205 Cl cl 1.83 o 2.56.7 - F 3. 659 N Prep Ex. 108 ( N /.6F I N//r, N f Diastereomer B N, o 0 206 Br cl 1.64 0 N 2.734 2= 2- "I 3. 114.9 N Prep Ex. 117 /N Diastereomer A 0N 207 Br> cl 1.36 o ' 2.734 2 N3.124.2 Prep Ex. 117 NN N Diastereomer B o 2.711 OO 3. 95.1 Prep Ex. 121 o 000 N Diastereomer A 0 0 OH WO 00/37459 PCT/US99/27939 - 281 208 c cl --- A O, o oN Sr°0 x Prep Ex. 121 N N Diastereomer A 0 0 O-0 F=o 209 cl cl 1.39 N rN 2.711 e 3.101.8 Prep Ex. 121 NIN Diastereomer B o o OHr 209 c O cl 1 .49 A AI 0 N Prep Ex. 121 O NN.r Diastereomer B 0 o O 210 cl <-N: 2.697 3. 64.3 Prep Ex. 121 K oAN Diastereomer A 0 oOH WO 00/37459 PCT/US99/27939 - 282 210 Co A C~ N 0) f-a Prep Ex. 121 oo N Diastereomer A o o O ,r=o -o 0. 0 OO 210 cl \/ Cl - B ~ ~ 2 80 o clN Prep Ex. 121 0'/ N Diastereomer B 0 0 0 0-)-o 21 1 c0(>j -1 19 '~N ~'2. 709 SN 3.83.2 Prep Ex. 124 c,, \,-,- N A\0 NmrB Diastereomer A 0 0 212 c0 cl 1.94 0- \o2.709 N 3. 83.6 Prep Ex. 124 7 N N Diastereomer B 0 0 WO 00/37459 PCT/US99/27939 - 283 213 ci ~ Y -116 S1.68 2131 2.695 OO N 3.88.2 Prep Ex. 124 Nr N N Diastereomer A 0 0 214 MeSO 2 C] /1.81 2. 598 Prep Ex. 125 3. 81 ON N Me \\ O 215 MeSO 2 CI 1.69 01 1. 69 2.633 Prep Ex. 111 3.69 Diastereomrner A N /= O N f4N Me' \ 0 216 MeSO 2 C1 c 1.71 N - 2. 633 rep rEEx. 111 3.106 Diastereomer B ij/ _ O N N S=0 Me" \ O0 WO 00/37459 PCT/US99/27939 - 284 217 Br \1 c 1.73 O O N 2.736 2 Prep Ex. 130 m,'. N N EXAMPLE 218 If the procedure described in Example 149 were followed, the 5 title compound from Preparative Example 109 (diastereomer A) could be reacted with Cl 0 O to give the compound Br CI N O NN 0 0 lOO 10 EXAMPLE 219 If the procedure described in Example 149 were followed, the title compound from Preparative Example 109 (diastereomer A) could be reacted with Cl 15 0 to give the compound WO 00/37459 PCT/US99/27939 - 285 Br Cl ON N N -0 0 EXAMPLE 220 If the procedure set forth in Preparative Example 51 were 5 followed, but substituting the 3,8-dichloro tricyclic alcohol Cl / / Cl OH for the 3-Br-8-C1 tricyclic alcohol, the following compound could be prepared: Cl Cl N C N~"/OH CH3 N

H

3 C 0 HCC30 O O 10 Then, if the procedure of Example 113 were followed to react the above compound with the title compound from Preparative Example 95.1 the following compound could be obtained WO 00/37459 PCT/US99/27939 - 286 iCl Cl N

CH

3

CH

3 "1 N H3C Q

H

3 0 Then, if the procedure of Preparative Example 109 were followed using the above compound the following compound could be obtained: Cl Cl / N CH 3 N N NN 5 H O Then if the procedure of Example 149 were followed using the above compound and O the following compound could be obtained CI Cl Cl /l N CH 3 K -// NN>I/-,,N,, 10 o EXAMPLE 220A If the procedure of Example 220 were followed, but the title compound from Preparative Example 90 were used instead of the WO 00/37459 PCT/US99/27939 - 287 title compound from Preparative Example 95.1 in the procedural step of Example 113, the following compound could be obtained c//Cl Cl F N

ICH

3 O N N N N 5 EXAMPLE 221 Br CI Br CI O "A-N N :;/'.............. .. H 0 x-k 0~ 0 To a solution of the title compound from Preparative Example 109 (11S,2Rdiastereomer A, 75 mg, 0.12 mmol) dissolved in anhydrous DMF (1 mL) was added HOBT (32 mg, 0.24 mmol), DEC 10 (45.4 mg, 0.24 mmol) and isovaleric acid (0.026 mL, 0.24 mmol) and the resulting solution was stirred at room temperature under

N

2 overnight. The solution was concentrated in vacuo, diluted with dichloromethane, washed with 1N aqueous NaOH and dried over anhydrous MgSO 4 . Filtration and concentration in vacuo provided 15 a residue which was purified by preparative plate chromatography (silica gel) using 5% MeOH-95% CH 2 C1 2 saturated with aqueous ammonium hydroxide to give the title compound as an off-white solid (81.5 mg, 96%, MH

+

= 717).

WO 00/37459 PCT/US99/27939 - 288 EXAMPLES 222-224 Following the procedure described for Example 221, the title compound (diastereomer A or B) from Preparative Example 109 was treated with the carboxylic acid given in Table 15 to give the N 5 benzyl Product listed in Table 15. TABLE 15 Ex. Carboxylic Acid Product 1. Yield and (%) Diastereomer of 2. MH Prep. Ex. 109 3. mp(OC) 222 OH Br C l 1.74 O:i 2.757 O 3.94.7 Diastereomer A ON 0 223 Br.~ c 1.85 N 2.757 O N 3. 104.2 Diastereomer B - .__0 N 0 224 H 2 N 0 Br C1 1.59 N 2.801 =N 3. 129.3 00 OH H 2 N NJ O N O 0O Diastereomer A WO 00/37459 PCT/US99/27939 - 289 EXAMPLE 225 C1 + N N H-N Nj CH 3 N CO 2 H f 6 6 To the title compound from Preparative Example 127 Step C (11S,2R diastereomer A) (1.73 g, 3.57 mmol) were added HOBt 5 (0.689 g, 5.1 mmol), DEC (0.98 g, 5.1 mmol), the title compound from Preparative Example 95.1 (0.9 g, 3.9 mmol), NMM (0.87 mL, 7.9 mmol) and anhydrous DMF (20 mL). The mixture was stirred at room temperature under N 2 overnight. The mixture was concentrated in vacuo, diluted with CH 2 C1 2 and washed with a 10 saturated aqueous solution of NaHCO 3 . The organic phase was dried over anhydrous MgSO 4 , filtered and concentrated in vacuo. The residue was purified by flash column chromatography (silica gel) using 2% MeOH-98% CH 2 C1 2 saturated with aqueous ammonium hydroxide to give the title compound (1.7 g, 69%, MH + = 15 695). EXAMPLES 226-232 Following the procedure described for Example 225, the Products listed in Table 16 below were prepared using the 20 carboxylic acid from Preparative Example 127 Step C (diastereomer A) and the appropriate N-substituted imidazolylalkyl amine purified by preparative chiral chromatography (Chiralpack AD, 5 cm X 50 cm column, flow rate 80 mL/min, 5-13% IPA-Hexane +0.2% diethylamine).

WO 00/37459 PCT/US99/27939 - 290 TABLE 16 Ex. Amine of Product 1. Yield (%) Prep Ex. 2. MH 4 No. 3. mp (oC) 226 89 c1 1.40 2. 709 227 86 1 6 2. 696 Me3. 93.7 N N 228 90 1.39 N F2.713 ~~ Me 3.74.6 Me N N

O

0 0 NN 6 WO 00/37459 PCT/US99/27939 - 291 229 91 cl 1.44 2.708 N 3.85.6 N 6 230 93 1 i0 1 -l 1.29 2.681 N 3.82.2 NMe 231 94 1.71

-

2.695 3.79.7 O ON N N 0 o0 Me 232 101 \cl/ \ 1.62 2.709 SMe 3.85.6 O 0ONO Oo 0 6 WO 00/37459 PCT/US99/27939 - 292 EXAMPLES 234B If the procedure of Example 225 were followed, but the amine from Preparative Example 101.2 was to be used, then the following compound would be obtained N

N

CN) ( Example 234B 5 a o--1 oo EXAMPLE 235 Br C l Br C h _N CN Ph sOH Nd;NP BoB 0 Boc 0 Ph Ph The title compound from Preparative Example 51 (0.184g, 10 0.35 mmoles.) was added to a solution of the title compound from Preprative Example 132 Step C (0.2g, 0.437 mmol), DEC (0.168g, 0.87 mmoles.), HOBT (0.118g, 0.87 mmoles.) and NMM (0.22 g, 2.19 mmoles.) in DMF (10 mL). The resulting solution was stirred at room temperature 24 hours. The reaction mixture was diluted 15 with H20 until precipitation ceased and the slurry filtered. The precipitate was diluted with CH 2 C12 ,washed with brine,dried over Na 2

SO

4 and concentrated. The crude product was purified by chromatography using a 5% (10%NH40H in MeOH) solution in

CH

2 C12 as eluent to give the title compound (0.18g, 42 % yield). 20 WO 00/37459 PCT/US99/27939 - 293 EXAMPLES 236-238 Following essentially the same procedure as set forth in Example 235, except using the amine given in Table 18, compounds of the formula Br Cl N N CH3 N 5

H

3 C 0 are obtained, wherein Z is as defined in Table 18. TABLE 18 Ex. Amine Z 236 Ph Nz Ph HN - \ N Ph -- N N Ph Y Ph \N Ph Ph Ph FAB: MH = 975 237

CH

3 CH 3 Ph I Ph I N N HN N FAB: MH = 747 WO 00/37459 PCT/US99/27939 -294 238 H

H

2 \N /N N\N OH OH FAB: MH' = 735 EXAMPLE 239 Br Cl N Ph \INH N -A NH CH3 H3 O O O0 H3C 5 Step A Br CI Br Cl N N N Ph N Ph ",NN,-N N N N "/N \N. Tr H r NH S0 0 .F O O TFA Boo The title compound from Example 235 (0.5g, 0.517 mmoles) in CH 2

CI

2 (50 mL) was stirred with TFA (6 mL) at room temperature overnight. The reaction mixture was evaporated to give the title 10 compound as a TFA salt (0.743g) which was used for following reactions.

WO 00/37459 PCT/US99/27939 - 295 Step B Br Cl Br \ Cl N Ph N- N Ph CN J"" N- r N' -N \NH H NH N H 0 CH3/ o .TFA H 3 C O, 0

H

3 To a stirred solution of the title compound from Step A (0.102g, 0.0936 mmoles), triethyl amine (0.0798g, 0.798 mmoles) in 5 CH 2 C1 2 , di-tert-butyldicarbonate (0.0515g, 0.236 mmoles) was added and stirred overnight. Evaporated to a residue which was stirred in 2N ammonia solution in methanol (2 mL) overnight and evaporated to dryness. The residue was chromatographed on silica gel using 5% (10% conc NH 4 OH in methanol) to give the title compound 10 (0.043g). EXAMPLES 240-243 Following essentially the same procedure as that set forth in Example 239 Step B, except using the chloroformate given in Table 15 19 below, compounds of the formula: Br CI N Ph N 0H R14 were obtained, wherein R 14 is as defined in Table 19.

WO 00/37459 PCT/US99/27939 - 296 TABLE 19 Ex. Chloroformate

RI

4 240 H 3 0C Cl H 3 0 H3H 3 O- J

H

3 C O O H 3 C O O (R, S) FAB: MH' = 733 241 H 3 C cI H3C

H

3 C 0"'0 H 3 C 0 (R, S) FAB: MH' = 719 242 c1

H

3 CO

H

3 C O

CH

3 CH 3 (R, S) FAB: MH = 733 243 Cl

A

0 , (R, S) FAB: MH = 759 WO 00/37459 PCT/US99/27939 - 297 EXAMPLE 244 Br Cl Br CI N N N Ph N Ph N1 7r~i r HNH H 3 N 0 TFA

H

3 C

H

3 C \- N O H To a solution of the title compound from Step A of Example 239 (0.126g, 0.126 mmoles), triethylamine (0.071g, 0.726 mmoles) 5 in CH 2 C12 (5 mL), t-butylisocyanate (0.018g, 0.189 mmoles) was added. The resulting solution was stirred at room temperature overnight. Evaporated to dryness and the residue was then stirred with 2N ammonia solution in methanol (3 mL) overnight. Evaporated to dryness and the product was chromatographed on 10 silica gel using 5% (10% conc. NH 4 0H in methanol)-CH 2

C

2 as the eluant to give the title compound. (0.046g) CIMS: m/z (MH ) 732. Examples 245-254 Following the procedures set forth in Examples 77-79 and 86, 15 but using the diastereomeric mixture A and B from Preparative Example 135 and the appropriate amido-imidazole, the following compounds were prepared: Br Cl Br Cl HBr N HBr H H N N N] N/' NKN O O COOt-Bu N (Example 245) H (Example 246) 20 WO 00/37459 PCT/US99/27939 - 298 (Example 247) (Example 248) Br Cl Br Cl N 'H/ r N H Br H HBr N H No N/ N) O O o (Example 249) (Example 24850) Br Cl BrN Cl N NH BrN NN H Br COOt-Bu Mixture CONI-It-Bu Mixture 5 (Example 251) (Example 252) BrH ClB '/ CH rN NN H HBr N N Mixture o 0

CONH

2 ycHexyl COOt-Bu (Example 24953) (Example 254) Br Cl Br Cl N ~ rPh N /HrPh N N N, Q I10 0 COO t-Bu Mixture CONH t-Bu Mixture 5(Example 25 1) (Example 252) Br Cl Br Cl N H rPh N ~HB Ph NN

N~~

7 Mixture I 0J 0 CONHcycflexyl COO t-Bu (Example 253) (Example 254) WO 00/37459 PCT/US99/27939 - 299 EXAMPLES 255-278 Following the procedure described for Example 127, the title compound (diastereomer A or B or A+B) from the Preparative Example indicated in Table 20 below was treated with the 5 corresponding isocyanate to give the urea products listed in Table 20. TABLE 20 Ex. Isocyanate Product 1.Yield and (%) Prep. Ex. 2. MH 4 3. mp (oC) NCO Br Cl 255 CH 1.49 ci I

N

.

N 2.695 139 O Me 3. 159.1 diastereomer A (A) NCO Br C1 256 N H - 1.65 139 N N 2.642 139 Me 3. 141.5 diastereomer B (B) H (B) NCO Br C 1 257 N H 1.82 rNrN N 2.668 139 N Me 3. 147.5 N 0 diastereomer A I (A)

H

WO 00/37459 PCT/US99/27939 - 300 Br 'rc1 NCO Br Cl 258 IIN H i 1.90 NN ~ ' N N 2.668 zr II/ 139 N O Me 3. 148.2 N 0 diastereomer B I (B) H NCO Br f Cl 259 N Me 1.7 H 1.7 N H-N N

,

,N 2.668 140 140 3. 141.5 diastereomer 14(A+B). H -146.6 A+B Br/

C

l N Me, /H (A+B) H C NCO Br C1 Cr'CNC0 260 N Me H 1.17 < N N

N

N 2.696 140 o3. 136.1 diastereomer H 0 (A+B) H A+B Br N9 Cl N H Me,. 010 I (A+B)

H

WO 00/37459 PCT/US99/27939 - 301 Ck NCO Br C1 NCO fN' 261 N H ,Me 1.15 Cl N / N NN 2.696 140 0 3. 140.8 diastereomer H (A+B) H A+B Br \ Cl IN Me Cl_ , ,, ]/ H _N N VlN_-NfN

N

0 H (A+B) H F NCO Br 01 262 N Me I1JH 1. 12 NN 2.680 140 0 3. 130.3 diastereomer I (A+B) H A+B Br cl N Me F Al '/Z N/tIHNN: N

N

0 I (A+B)

H

WO 00/37459 PCT/US99/27939 - 302 Br C1 TMS-NCO B Ne 263 H (Me 1 2 5

H

2 N2N ,H 1.25 HN N -N N 7--,N 2. 711 142 , 3. 165.5 (A+B) Br Cl N Me

H

2 N NH 0 0 (A+B) O NCO Br 1 Cl N 264 1.34 N (A) S H 2.682 N152 '-N Me 3.131.6 H Me NCO Br C N 265 1.71 N (B) 1N H 2.682 153 \N N Me 3. 120.6 H Me NCO Br/ \ C1 N 266 1.65 [N) H(A) H 2.656 N152 M N/Me 3. 143.6 N 0 H Me WO 00/37459 PCT/US99/27939 - 303 NCO Br/\

C

l N 267 1.64 S H (B) 2.656 153 N 15 NMe 3. 142.9 N o H Me >NCO Br Cl 268 N (A) 1.83 154 N N fN 3. 142.8 diastereomer A 0312 N 0 Me H NCO Br Cl 269 (B) 1.89 154 /H 2.656 diastereomer B 0, NO NN 3.146.8 N 'O Me NCO B ' CI 270 (A+B) 1.43 H NfNe 2.682 154 N,, N 3. 14N4.6 diastereomer N 0 Me

A+B

WO 00/37459 PCT/US99/27939 -304 NCO Br Cl 1.52 271 2. 672 158 N" H N 3. 122.5 N'i N

"

N

O O - 143.6 diastereomer > OH o A+B H NCO Br Cl 272 1.21 N ) H N 2.769 158 N ,--N 3.141.0 diastereomer o-Nk 0 0 A+B H 0 N'H NCO Br cl 273 H 1.61 9 ,2.658 N '/4N 2.6T 159 OH 3. 151.7 diastereomer N o A+B H NCO BrN C 274 N H 1.48 1'Nr N INC N 2.683 159 O OH 3. 133.1 diastereomer H

A+B

WO 00/37459 PCT/US99/27939 - 305 Br -c NCO Br 1 275 N H 1.46 ",N 7 N N N 2. 809 diastereomer N o H Yo A+B N'H NCO Br Cl N 276 N OH 1.52 vi 1N 2.672 160 N NN N 3. 130.8 diastereomer A+B H N 277 \ 1.38 H 2. 771 160 N I 4 3. 144.6 diastereomer A+B H [ NCO Br C1 278 1.75 N N S S N 2.698 158 O) OH\- 3. 141.2 diastereomer (D\ 0 OH

A+B

WO 00/37459 PCT/US99/27939 - 306 EXAMPLES 279-286 Following the procedure described for Example 149, the title compound (diastereomer A or B or A+B) from the Preparative Example indicated in Table 21 below was treated with the 5 corresponding acid chloride, chloroformate, carbamyl chloride, dicarbonate, anhydride or sulfonyl chloride to give the products listed in the Table 21. TABLE 21 10 Ex. Electrophile Product 1.Yield and (%) Prep. Exam. 2. MH* 3. mp (oC) Br C1 279 PhCH 2

SO

2 C1 H 1. 66 /N --N N 2.697 o Me 3. 148.5 139 (A) 0 diastereomer A Br~ \Cl 280 CH 3

SO

2 C1 MBre 1.10 ( N) Me 1 1 H 2.621 N 3. 134.8 140 MeSO 2 0 (A+B) diastereomer A+B Br \ C N Me (N) H Me N /N N N MeSO 2 0

(A+B)

WO 00/37459 PCT/US99/27939 - 307 Br , cI 281 CH 3

CH

2

SO

2 CI N Me 1. 11 H 2.635 N N 3.124.8 140 CH 3

CH

2

SO

2 0 (A+B) diastereomer A+B Br N \C1 N Me C)H N / N "" NeN

N

CH

3

CH

2

SO

2 0 (A+B) Br c l fN 282 CH3CH 2 COCI N H =(Me 1.17 N //1N7N

'-

N 2. 599 o o 3. 93.2 140 (A+B) diastereomer A + B Br cl N Me N NV ,N

S(A+B)

WO 00/37459 PCT/US99/27939 - 308 Brc1 283 CH 3

CH

2

CH

2 COCl N H Me 1.17 N 1N N 2.613 3. 85.7 140 (A+B) diastereomer A + B Br cl N Me\ ),H N N "-N,,N (A+B) C O Br jC1 N 284 l 1 H Me .11 I N /r NN 2. 695 140 03. (A+B)128.4 diastereomer (A+B) A+B Br Cl N Me CN H, N ,N 0 0 0 (A+B) c, Br/ \C1 285 (A) 1.55 N H H 2.628 154 N ' ,< NNN 3. 108.9 diastereomer A

\

N- Me

I

WO 00/37459 PCT/US99/27939 - 309 C1 Brc I 286 O I (B) 1.23 1.23 N -N,\_A?2.628 154 0 Me 3. 109.3 154 / diastereomer B Br ci 2860 0N S1. 70 286A (A) N 1.70 A Me 2.725 166 3.88-96 166 N r Br 2860 0 286 (B) N 1.60 B K Me 2.725 167 3.89-96 16OO N EXAMPLES 287-289 Following the procedure described for Example 221, the title 5 compound (diastereomer A or B or A+B) from the Preparative Example indicated in Table 22 below was treated with the corresponding carboxylic acid to give the products listed in Table 22.

WO 00/37459 PCT/US99/27939 - 310 TABLE 22 Ex. Carboxylic Acid Product 1.Yield and (%) Prep. Ex. 2. MH* 3. mp (o C) o O Br eC 287 I 0 Nfll 287 H 1.71 o'N N %N NN 2.678 139 0 Me 3. 139.5 diastereomer A 0 (A) H2Br C1 288 o N 1.39 , H 3--9

H

2 NK N N N N 2.711 139 o0 Me 3. 136.1 diastereomer A (A) 0 Of-N +Z,, OBr Q c l 289 o0 N Me H 1. 21 N N,/ N, N 2. 768 140 (A+B) 3. 115.5 140 0(A+B) diastereomer A+B Br fGCI N NH Me ONN /X N' - N r N 0(A+B) CL" 0

(A+B)

WO 00/37459 PCT/US99/27939 -311 EXAMPLE 290 O Z0 0 Br / 0 H N N / 1r Ne N H 2 =\ c~N'Jk. N] Me H 0N Me A solution of the title compound from Preparative Example 143 (0.59 g, 1.15 mmol) dissolved in anhydrous dichloromethane 5 (10 ml) and trifluoroacetic acid (2 ml) was stirred at room temperature for 3 hrs. The resulting solution was concentrated in vacuo, then the residue was combined with anhydrous dichloromethane (10 ml), the tricyclic chloride (compound No. 42.0) (0.474 g, 1.38 mmol) and triethylamine (1.61 mnL, 11.5 mmol) and 10 allowed to stir at 25-40oC for 12 h. The reaction mixture was concentrated in vacuo and purified by flash column and preparative plate chromatography (silica gel) using 1-4% MeOH-CH2C12 saturated with aqueous ammonium hydroxide to afford the title compounds (457 mg, 55%, MH + = 718). 15 EXAMPLES 291-297 Following the procedure described for Preparative Example 290 and the BOC-protected piperazines listed in Table 23 below, the 20 tricyclic compounds in Table 23 were prepared as diastereomeric mixtures. The diastereomers that were separated, were separated by preparative chiral chromatography (Chiralpack AD, 5 cm X 50 cm column, flow rate 80 mL/min., 7-12% IPA-Hexane +0.2% diethylamine) to give diastereomer A and diastereomer B. 25 WO 00/37459 PCT/US99/27939 - 312 TABLE 23 Ex. BOC-Piperazine Product 0B r Br Cl N N 2 9 1 N ' H

N

0 N 1. Yield: 44% 2. MH = 705 3. mp = 132-1350C Br/\ ci 1. Yield: 14% 2. MH*= 705 3. mp = 127-1320C oBr /\ C1 H fN 293 N o Pe H HMNe/O N " N Me O O \ N Me For (A): For (B): 1. Yield: 38%1. Yield: 36% 2. MH= 691 2. MH = 691 3. mp = 107.50C 3. mp = 82.2C WO 00/37459 PCT/US99/27939 - 313 Br \ 1 C1 294 04 HFN N H H ON NCz 0/ ~ ~ N / CF 3 AO H 1. Yield: 36% 2. MH*= 722 3. mp = 173.80C BOC N Me Br/ \ C1 295 H (A+B) R Br 'l (C+D) rN' H Me BOC .. .o -N..s N N H N For (A): For (B): 1. Yield: 30% 1. Yield: 25% H N (C+D) 2. MH = 682 2. MHW= 682 N H Me N"N\- N NN ~0 For (A): For(13): 1. Yield: 30% 1. Yield: 25% 2. MH = 682 2. MH'= 682 For (C): For (D): 1. Yield: 10% 1. Yield: 13% 2. MH

+

= 682 2. MH = 682 WO 00/37459 PCT/US99/27939 -314 N Br / \ Cl 296 H_ OH (Nj] H ' 1-N \_, N v lN N OH 0 H 1. Yield: 75% 2. MH = 698 Boc3. mp = 141.20C BOC I N Br/ C 297 O H HN ~Nj~H SN OH iN 0 N H 1. Yield: 13% 2. MH = 670 3. mp = 182.1-219.4oC EXAMPLE 299 Step A H NC _ N N N1 5 N H To a solution of the title compound from Preparative Example 155 Step F (0.30 g, 0.67 mmol) dissolved in anhydrous dichloromethane (3 ml) was added cyclohexylisocyanate (0.09 mL, 0.7 mmol) and the resulting solution was stirred at room 10 temperature for 30 min, then concentrated in vacuo. The resulting residue was diluted with dichloromethane (3 ml) trifluoroacetic acid (3 ml). The solution was stirred at room temperature overnight, WO 00/37459 PCT/US99/27939 - 315 then concentrated in vacuo, diluted with dichloromethane and washed with IN NaOH (aq). The organic phase was dried over anhydrous MgSO4, filtered, and concentrated in vacuo to afford a yellow foam (0.319 g, 100%, MH + = 473). 5 Step B H Br ,\ CI I N H NCI N rJ NH )-/ N Y N 0 H A\I H N O 1 N H To a solution of the title compound from Step A above (0.212 g, 0.45 mmol) dissolved in anhydrous dichloromethane (10 nml) was 10 added the tricyclic chloride (compound # 42.0) (0.154 g, 0.45 mmol) and triethylamine (0.32 mL, 2.25 mmol) and allowed to stir at 25 0 C for 48 h. The reaction mixture was concentrated in vacuo and purified by preparative plate chromatography (silica gel) using 5% MeOH-CH2Cl 2 saturated with aqueous ammonium hydroxide to 15 afford the title compounds (125 mg, 35%, mp = 114.8 0 C, MH + = 778). EXAMPLE 300 Following the procedure described for Example 299 Steps A 20 B, the product listed in Table 24 below was prepared using the corresponding piperazine from the indicated Preparative Example.

WO 00/37459 PCT/US99/27939 -316 TABLE 24 Ex. Prep. Product 1.Yield (%) Ex. 2. MH* 3. mp (0C) "Br\ Cl 300 156 1.38 H 2. 758 N 3. 117.3 N 0 N H EXAMPLE 302 5 StepA H N'O I N oy o 1> / H A mixture of the title compound from Preparative Example 162 (400 mg, 1.86 mmol), the anhydride from Preparative Example 44 (561 mg, 2.19 mmol) and anhydrous CH2C12 (10 mL) was stirred 10 at 25oC for 3 hrs before tert-butylisocyanate (0.26 mL, 2.19 mmol) was added. After 12 h, the mixture was concentrated in vacuo, diluted with CH2C12 and washed with water. The organic phase was dried over anhydrous Na 2

SO

4 , filtered and concentrated. The resulting foam was diluted with anhydrous CH2C12 (10 mL) and 15 trifluoroacetic acid (10 ml) and stirred for 3 h. Concentration in vacuo, redilution with CH2Cl2 and washing with IN NaOH (0.5 M, aq) provided an organic solution which was dried over anhydrous WO 00/37459 PCT/US99/27939 - 317 Na 2

SO

4 , filtered, concentrated and used without further purification (181 mg, 27%, MH + = 431.5). Step B H Br/ , c1 N H F N H ) F 5 H To a solution of the title compound from Step A (170 mg, 0.39 mmol) dissolved in anhydrous dichloromethane (10 ml) was added the tricyclic chloride (compound No. 42.0) (175 mg, 0.51 mmol) and triethylamine (71 pL, 0.51 mmol) and allowed to stir at 25 0 C for 48 10 h. The reaction mixture was concentrated in vacuo and purified by preparative plate chromatography (silica gel) using 5% MeOH CH2C12 saturated with aqueous ammonium hydroxide to afford the title compounds (oil, 24 mg, 8%, MH + = 736). 15 EXAMPLE 303 B / CI N N H O1 CH If the procedure set forth in Example 302 were followed using in Step A WO 00/37459 PCT/US99/27939 - 318 Ii

H

2 N N H, .N CH3 N instead of the title compound from Preparative Example 162, the title compound would be obtained. 5 EXAMPLE 304 Br / CI N N Me N Following the procedure described for Example 58, except using the title compound from Preparative Example 165 instead of the title compound from Preparative Example 25, the title 10 compound was prepared (51%, MH

+

=711, mp = 103.7-107.5).

WO 00/37459 PCT/US99/27939 - 319 EXAMPLE 305 Br/ C1 N N Me O 0 N N Br Cl Br CI N N SMe Me N N />q 1 /> O 0O N O OO N The title compound from Example 58 was separated into its two diastereomers by HPLC (Chiracel AD column) using 10% 5 isopropanol-90% hexane-0.2% diethylamine to give the 11(R),2(R) and 11(S),2(R) isomers. Diastereomer A: MH+ = 697; mp = 103-108 0 C. Diastereomer B : MH+ = 697; mp = 101-107 0 C. 10 EXAMPLE 306 C I N Me O >/ r N NN Following the procedure described for Example 58, except using the 11(S),2(R) diastereomer from Preparative Example 164 instead of the title compound from Preparative Example 51, the title 15 compound was prepared (59%, MH

+

= 619, mp = 100-114 0

C).

WO 00/37459 PCT/US99/27939 - 320 EXAMPLE 307 /CI , /-Me N N N Following the procedure described for Example 306, except 5 using the title compound from Preparative Example 165 instead of the title compound from Preparative Example 25, the title compound was prepared (73%, MH + = 633, mp = 89.1-96.5 0 C). EXAMPLE 308 CI N N N *1 N 10 N 10 O 0 0 "N Following the procedure described for Example 58, except using the 1 1(R),2(R) diastereomer from Preparative Example 164 Step C instead of the title compound from Preparative Example 51, and using the title compound from Preparative Example 165 15 instead of the title compound from Preparative Example 25, the title compound was prepared (65%, MH

+

= 633, mp = 89.1-96.5).

WO 00/37459 PCT/US99/27939 - 321 EXAMPLE 309 Br/ CI N N 0 rN H 2/.NO , H -N

H

2 N N NN ,J(/",N The racemic product from Preparative Example 141 (0.2g, 5 0.368mmoles), 4-( 4 -nitrophenyloxycarbonyl)piperidine- 1 carboxamide (0.1706g, O.552mmoles) (Preparative Example 36, Step B) and isopropanol (10mL) were heated under reflux and under argon at 87oC for 24h. The solution was evaporated to dryness and the residue was taken up in dichloromethane and washed with 10 satd. aqueous NaHCO 3 , water, dried (MgSO 4 ), filtered and evaporated to dryness. The residue was chromatographed on a silica gel column using 3%-6%-10% (10% cone. NH 4 OH in methanol)-dichloromethane as the eluant to give the title compound (0.057g, 22%): FABMS; m/z 712.9 (MH'); 8 c (CDC13) CH 2 : 30.3, 30.5, 15 30.6, 30.6, 31.1, 36.7, 41.3, 41.3, 42.2, 44.5, 50.7/51.1, 52.3; CH: 55.4, 71.0, 78.8, -118.9, 126.3, 129.4, 130.5, 132.5, 137.0, 141.4, 147.1; C: 120.2, 134.3, 135.0, 137.0, 141.3, 155.2, 155.2, 158.0, 170.2; 8H (CDC13) 4.31/4.32 (1H, s, H,,), 4.56 (2H, broad s,

NCONH

2 ), 6.93 (1H, broad s, Im-H 5 ), 7.07 (1H, broad s, Im-H 4 ), 7.10 20 7.16 (3H, m, Ar-H), 7.48 (1H, m, Ar-H), 7.60 (1H, broad s, Im-H 2 ) and 8.30ppm (1H, s, Ar-H 2 ). EXAMPLES 310-342 Following the procedure described for Example 225, the 25 Products listed in Table 25 were prepared using the carboxylic acid (diastereomer A or B) from Preparative Example 127 Step C and the appropriate N-substituted imidazolylalkyl amine.

WO 00/37459 PCT/US99/27939 - 322 TABLE 25 Ex. Amine of Prep. Product 1.Yield Ex. No. (%) Carboxylic acid 2. MH' diastereomer A 3. mp or B (OC) CI

N

310 94 1.71 N S2.695 diastereomer A N 'N 3.79.7 O OO N N Me CI N 311 93 1.29 N N 2.681 diastereomer A N N 3.82.2 aO OO N Me 312 89 Cl 1.43 N 2.709 diastereomer B CO Me 3.88.4 N N O O N N ______ _____Me CI 313 94 C 1.47 N 2.695 N diastereomer B (3.86.3 O O N N Me WO 00/37459 PCT/US99/27939 - 323 CI 314 101 1.52 2. 709 diastereomer B N . Me 3.89.1 O OO N Nd ,\CI N. c 315 179 HO N 1.14 Me 2.756 diastereomer A , NO N OH M Me 3. semi diastereomer A - OHMe 2. N N 3 0 , N '... N soli 0

N

0 122.2 c I 317 173 ,O 1.27 I' 2.712 diastereomer A N Me .62.9 N\

"

% 88 .2 O OO

NN

WO 00/37459 PCT/US99/27939 -324 CI OH 318 174 1.19 N \\,.-OH 2. 679 diastereomer A ., \ H 3.78.3 S -N N Me j \o %N Cl N 319 199 StepB - IN 120 OH Me 2.712 diastereomer A "N' -- 3. N O /NN 135.7 cl 320 91 N 1.32 2.709 diastereomer B N N 3.94.6 \ N,, N~ N CI N 321 95.1 - 1.4 N s Me 2. 695 diastereomer A . N 3. 76.7 O O N N CI @c, N 322 176 1.37 N II" CI Me 2. 729 diastereomerA , N "'N 3.78 O KAIL N / N 83 v "O " WO 00/37459 PCT/US99/27939 - 325 c l 323 177 1.50 NI Me 2.729 diastereomerA " rN 3.96 0\0N N 101 CI 324 178 1.45 N") ( , .

Me2.9 diastereomer A - N e 2. 87 O 0 N N 92 c1 325 85 (B) 1.55 Nd 2. 695 diastereomer A () 'PMe 3.88 OON__ 93 Cl N 326 180 > 1.5 d AP )Me Me 2.709 diastereomer A N 3.87.7 O 0 N, N cI 327 183 1.63 1. 63 N 2. 645 diastereomer A 2.645 o ,L0Me 103.6

N

WO 00/37459 PCT/US99/27939 - 326 Cl N. 328 181 1.40 2. 723 diastereomer A N N 3.86.5 O N,, ~N 95.2 CI QN N 329 184 N I 1.16 diastereomer A Me 2. 697 diastereomer A N 3.95 OA0 N N 100 Cl N17 330 182 1.7 N -. N~ a 0 Me 2.712 diastereomerA N~ 3. semi O 0 N N solid 331 165 1.52 2. 660 Diastereomer "3 90.7-0 AN N 3907 A lii N101.7 332 c CNCI 165 N H 1.69 N 2.660 Diastereomer N 3.91.6 B O oN 91.6 B Nr 102.8 0_ 0N/N WO 00/37459 PCT/US99/27939 - 327 Cl 1.29 2.660 333 185 N H 2.6 333 185 H 3.75.9 N N 82.8 Diastereomer N , N82.8 N N N A O 0OO>/ N 186 -Cl 1.90 \ 2.646 334 Diastereomer N 3. 83 A 89.7 N H N 133 CI 335 N 335 1 63. diastereomer A N 2. 696 Me. N N cI 336 133 1.59 N 2.696 diastereomer B Me. NN 0 CI N= 337 171 OH 1.15 H __ /CH3 2. 698 diastereomer A N . N S 0 OH N ___ 00 OH WO 00/37459 PCT/US99/27939 - 328 CI N 338 171 N 1.36

(

N ) H CH 3 2.698 diastereomer B N O NN O -OH CI

N

339 171 N 1.26 diastereomer A N (1) O N O 0'O OH Cl

N

340 171 N 1.42 1 H , CH 3 2.698 diastereomer A N or, (2N) N 0 0 OH CI 341 171 N 1.57 N N 1 ) CH3 2.698 diastereomer B O ON O N N 0Ao OH CI N\ 342 171 N 1.21 H H 3 2.698 diastereomer B O H N(2) N _____ __ _ _ _ _ OH EXAMPLES 343-361 Following the procedure described for Example 40, the 5 Products listed in Table 26 were prepared using either the mixture or the pure isomers of the carboxylic acids (diastereomer A and/or WO 00/37459 PCT/US99/27939 - 329 B) from Preparative Example 51 and the appropriate N-substituted imidazolylalkyl amine instead of the amine from Preparative Example 13. The resulting Products were separated by HPLC (Chiracel, AD column, 85/15 Hexane/IPA). 5 TABLE 26 Ex Amine of Product 1.Yield Prep. Ex. No. (%) 2. MH* 3. mp (oC) Br / \ C1 For (A): N 3 4 3 8 9 M e 2 1 and Me 2.761 344 N 3.99.3 O 0O N N Me For (B): Isomer A (Ex. 343) 1.30 And 2.761 Isomer B (Ex. 344) 3. 92.3 Br / \ C1I For (A): N 345 177 1.16 and N "2.761 IMe Me 346 0 Me Me== M 3.92.4 O OO r N ", N N:4 N For (B): Isomer A (Ex. 345) 1.17 And 2.761 Isomer B (Ex. 346) 3.96.5 WO 00/37459 PCT/US99/27939 - 330 Br/ \ CI / For (A): N 347 101 N 1.25 and , Me 2.761 348j NO O N For (B): Isomer A (Ex. 347) 1.30 And 2.761 Isomer B (Ex. 348) Br / CI For (A): 94 N 349 94 and N 1.24 350 N., 2.747 N N 0 For (B): Me 1.26 Isomer A (Ex. 349) 2. 747 And Isomer B (Ex. 350) Br cci 1.55 2. 713 351 185 H 3. I 102.9 diastereomer o 'NN 107.5 A 0-kO 0N Br c 1.67 187 2.724 352 3.diastereomer N N Me Me __ __ _ _Me B1 N(/ \N =N WO 00/37459 PCT/US99/27939 - 331 Br-C / \c 1.66 187 N 2.724 353 N= 353 3. diastereomer Me Me A 'N N 0 Me Br l 1.18 188 R 2.783 N 354 3.98 diastereomer N 108 B NRIIII/r N N N BOCO 0 Br c 1.28 188 r 2.783 355 3.98 diastereomer N ) 105 A / N BOC 0 Br c l 356 171 N 1.54 N 2. 751 diastereomer N NCH 2.H A 0'eN OO

OH

WO 00/37459 PCT/US99/27939 - 332 171 Br Cl 171 357 diastereomer N 1. 55 B H H 3 2.751 ONN OO OH 171 Br CI 171N 358 diastereomer N 1. 17 A

-

H

N 1) CH3 2.751 >KO N~N OH 171 Br CI 171 Nr 359 diastereomer 1. 12 A N1I CH 1.OH2

N)

H (CH3 2.751 O NN OO0 OH Br CI 360disteeoeAMPES1.2-62 171 BC Following the procedure described for Example 225, except 5 using the (11IS, 2R(+))-carboxylic acid from Preparative Example 164 360 instead of that frreom Preparative Example 127 Step C, and. using the62 substituted amine from the indicated Preparative Example in Table B 111 /i H OH 3 2.751 N

~

4 N (1) o' 0 OH Br C1 171 ~ 361 diastereomer N N1. 25 B (} H ~ C,.H 3 2.751 EXAMPLES 362-366 Following the procedure described for Example 225, except 5 using the ( 1iS, 2R(+))-carboxylic acid from Preparative Example 164 instead of that from Preparative Example 127 Step C, and using the substituted amine, from the indicated Preparative Example in Table WO 00/37459 PCT/US99/27939 - 333 27 instead of that from Preparative Example 95.1, the product listed in Table 27 was prepared. TABLE 27 5 Ex. Amine of Product 1.Yield Prep. Ex. No. (%) 2. MH' 3. mp (CC) Ocl 1.69 362 183 NN2.619 3.98.8 O O NN Me -CI - Cl 1.44 363 89 I2.683 N ) Me 3.91.7 O1 OO 0 ,N N Me -CI CI 1.42 364 95.1 2.609 N P Me 3. 83.5 O O N NN WO 00/37459 PCT/US99/27939 - 334 C1 C 1.57 N 634 365 185 H 2.634 I 3.92.1 N N O O.- 102.7 C1 366 186 N 1.71 N2 620 O./,N 3. N 130.2 o 0 140.2 EXAMPLES 367-374 Following the procedure described for Example 225, the 5 Products listed in Table 28 were prepared using the Carboxylic acid (diastereomer A or B) from Preparative Example listed in Table 28 below instead of the carboxylic acid from Preparative Example 127 Step C, and the appropriate imidazolylalkyl amine (Amine).

WO 00/37459 PCT/US99/27939 - 335 TABLE 28 Ex. 1. Prep. Ex. Product 1.Yield No. of (%) Carboxylic 2. MH' acid 3. mp 2. Prep. Ex. (oC) No. of Amine /CI Nq 1.4 367 1.200 1.46 O N diastereomer ) Me 2.711 A 0N 90 390 C LO 0 095 2.95.1 Isomer A CI (N 368 1.200 1.30 diastereomer O( N Me 2.711 B N N3.65 0 0 70 2.95.1 Isomer B \CI (N 369 1.200 1.61 diastereomer (N [ Me 2.727 A 0 0"-N OH 3. 128.5 0 ~NN 2. 172 Isomer A WO 00/37459 PCT/US99/27939 - 336 CI N 370 1.200 0 N1.66 diastereomer Me 2.727 B N OH 3. 133.9 2. 169 Isomer B 371 1.200 0 N 1. 16 diastereomer OH Me 2. 728 B NN 3. 135.7 2. 199 Step B Isomer B N 372 1. 201 Step N 1.35 B Me 2.661 diastereomrer NO NO 3. oil A L 1 o IN , N 3 .oil 2.95.1 Isomer A 373 1.201 Step N 1.49 B Me 2.661 diastereomer N rN 3. oil B 0 N N 2.95.1 Isomer B WO 00/37459 PCT/US99/27939 - 337 374 1.202 H CH 3 N CH3 1.41 . N NNN 2.660 2. 95.1 0 N 8'

N

N

' ' " N3.80.1 _O O 88.5 EXAMPLES 375-382 Similarly, using the procedure described for Example 149, the 5 title compound (diastereomer A or B) from the Preparative Example given in Table 29 was treated with cyclohexyl chloroformate to give the products listed in the Table 29. TABLE 29 10 Ex. Prep. Ex. Product 1.Yield No. (%) 2. MH + 3. mp (oC) Br CI 375 190 N 1.76 J [N '/N Me 2.787 SO O N N 3.94.7 Me Isomer A Br CI N 376 191 N 1.67 N

-

N Me 2.787 O - N NN 3.92.3 Me Isomer B WO 00/37459 PCT/US99/27939 - 338 Br ci N 377 192 N 1.87 Me M e 2.787 NNIN 0 go N N3. 90.8 Isomer A Br cI 378 193 N 1.85 Me Me 2.787 N0 -NNN 3.84.2 Isomer B Br cl N 379 194 N 1.72 U 1Me 2.787 0 N 3.89.7 Isomer A Br Cl 380 195 1.62 5

'

Me 2.787 O fr NN 3.89.7 -~0 Isomer B Br/\ cI N / .7 381 196 1.74 2.773 O- N %~N N\ N 3. 83.9 0NN 0 0T Me Isomer A WO 00/37459 PCT/US99/27939 - 339 Br CI N/ 382 197 N 1.73 2.773 N " N 0 3. 89.8 O OO N N Me Isomer B EXAMPLES 383-392 Following essentially the same procedure described for 5 Example 149, the title compound (diastereomer A or B) from Preparative Example 170 was treated with the appropriate acylating agent (i.e cyclohexylchloroformate, or Boc dicarbonate, or cyclohexylisocyanate, or tert-butyl isocyanate or isobutyl chloroformate) to give the products of the formula: N H N Cl CH 3 10 R O wherein R' is as defined in column 2 of Table 30. TABLE 30 Ex. R, Isomer Mass [a] 2 HRMS S(FABS, MH) 383 A 695.3473 -29.20 _oc = 0.107

O

WO 00/37459 PCT/US99/27939 -340 384 B 695.3473 +19.50 c = 0.1295 0 385 -COOC(CH 3

)

3 A 669.3366 -42.50 c = 0.89 386 -COOC(CH,), B 669.3322 --- 387 H A 694.3629 -51.00 Nc = 0.2575 388 H B 694.3642 --- )fN 0 389 H A 668.3480 -41.00 c =0.19 N O 390 H B 668.3488 --- N O 391 --- o A 669.3322 -56.30 o c = 0.3005 392 - / B 669.3330 --- EXAMPLE 393 .ol N Me HOOO N6r 5 Step A OH 0 WO 00/37459 PCT/US99/27939 -341 If the commercially available acetoxycyclohexanol were treated with phosgene the chloroformate would be obtained. Step B O ONNM e 0 N~N N N N ____ fliMe I N.,, N o 0 5 0 If the chloroformate from Step A were combined with the piperazine amine shown above according to the procedure described for Example 149 then the acetate would be obtained. 10 Step C If the product of Step B were treated with potassium carbonate in MeOH the title compound would be obtained.

WO 00/37459 PCT/US99/27939 -342 EXAMPLE 394 CN Me MeO N N Step A OH 0 5 If the commercially available cyclohexanol were treated with phosgene the chloroformate would be obtained. Step B N I N 0 ( <PMe 0 O N N Me 10 If the chloroformate from Step A were combined with the piperazine amine shown above according to the procedure described for Example 149 then the ketal would be obtained.

WO 00/37459 PCT/US99/27939 - 343 Step C CI N N CO Me 0 0O 7r N N c C1 N Me 0 0 If the product of Step B were treated with aqueous acid the 5 ketone would be obtained. Step D If the product of Step C were treated with MeMgBr or MeLi the title product would be obtained. 10 EXAMPLE 395

CH

3 NZ),,N 2N~t By essentially the same procedure set forth in Example 225 (coupling), only substituting the title compound from Preparative 15 Example 212 for the acid from Preparative Example 127 Step C, the title compound was obtained. Mp 91-107 oC, LCMS MH-=695.

WO 00/37459 PCT/US99/27939 -344 EXAMPLE 397 Br Br N and N N N M e C N >M e 0 0 Step A 5 If the 3-bromotricyclic chloride from Preparative Example 209 were used instead of the chloride in Preparative Example 127 Step C then the carboxylic acid Br/ N N 0-O OH would be obtained. 10 Step B If the carboxylic acid from Step A was used in essentially the same procedure as that used for Example 225 then the title compound would be prepared. Separation of isomers could be 15 made using chiral HPLC (AD column) using IPA-Hexane as eluent.

WO 00/37459 PCT/US99/27939 - 345 EXAMPLE 398 N _ and N N N Me Me N No N 7)No NN Step A 5 If the 3-fluorotricyclic chloride from Preparative Example 211 were used instead of the chloride in Preparative Example 127 Step C then the carboxylic acid F/ N N OH would be obtained. 10 Step B If the carboxylic acid from Step A was used in essentially the same procedure as that used for Example 225 then the title compound would be prepared. Separation of isomers could be 15 made using chiral HPLC (AD column) using IPA-Hexane as eluent.

WO 00/37459 PCT/US99/27939 - 346 EXAMPLE 399 F Cl F CI N and -N ' Me Me N<~rN N N .7-NNN 'o- 7) 1 - ' \ Step A If the 3-fluoro-8-chlorotricyclic chloride from Preparative 5 Example 204 were used instead of the chloride in Preparative Example 127 Step C then the carboxylic acid F \N CI N OH would be obtained. 10 Step B If the carboxylic acid from Step A was used in essentially the same procedure as that used for Example 225 then the title compound would be prepared. Separation of isomers could be made using chiral HPLC (AD column) using IPA-Hexane as eluent. 15 ASSAYS FPT IC 50 (inhibition of farnesyl protein transferase, in vitro enzyme assay) and COS Cell IC 50 (Cell-Based Assay) were determined following the assay procedures described in WO 20 95/10516, published April 20, 1995. GGPT IC 50 (inhibition of geranylgeranyl protein transferase, in vitro enzyme assay), Cell Mat Assay, and anti-tumor activity (in vivo anti-tumor studies) could be WO 00/37459 PCT/US99/27939 - 347 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 5 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. 10 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. Soft Agar Assay: Anchorage-independent growth is a characteristic of 15 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 20 as the top layer. After the top layer is solidified, plates can be incubated for 10-16 days at 37oC under 5% CO 2 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 -yll-2,5-diphenyltetrazolium bromide, Thiazolyl blue) (1 mg/mL in 25 PBS). Colonies can be counted and the IC5 0 's can be determined. The compounds of Examples 1-19, 21-25, 67-71, 72 Step B, 72 Step C, 73-77, 78 Step B (Isomer C), 78 Step B (Isomer D), 79 Step B (Isomers A, B, and C), 80 Isomers A and B), 81-86, 86A, 87, 88, 93-104, 106, 108, 110-113, 115-211, 214-217, 221-228, 236 30 238, 236-238, 241-244, 255-286, 286A, 286B, 287-297, 299 Step B, 300, 302 Step B, 305 and 309 had an FPT IC 5 0 within the range of <0.05nM to 20%@170nM.

WO 00/37459 PCT/US99/27939 -348 The compounds of Examples 1, 2, 6-13, 15-17, 19, 78 Step B (Isomer D), 80 (Isomer A), 67-71, 72 Step B, 72 Step C, 73, 76, 81 86, 87, 88, 93, 95-101, 103, 106, 108, 110, 111, 113, 115-118, 121, 122, 124, 125 (Isomer A), 127-134, 137, 142, 144-146, 148, 5 151-153, 155-157, 161-162, 164, 166, 168, 173-175, 177, 180-187, 189-192, 195-196, 198-208, 210-211, 216-217, 221, 222, 225, 237, 238, 242-245, 247-263, 265, 268-286, 286A, 286B, 288-289, 292, 295-296, 299 Step B, 300, 302 StepB, 305, 309, 310-342, 343-373 and 375-382 had an FIPT IC 5 o within the range of <0.04nM to 10 6.7nM. The compounds of Examples 11, 16, 78 Step B (Isomers C and D), 79 Step B (Isomer A), 80 (Isomer A), 88 (Isomer A), 93 (Isomer D), 99, 100, 225, 243, 367 and 368 had an FPT ICo within the range of <0.04nM to 2.7nM. The compound of Example 225 15 had an FPT IC 5 0 of 0.36nM. The compounds of Examples 1, 2, 8, 25, 86, 100, had a Cos Cell ICo 50 within the range of <10-920nM. The compounds of Examples 98, 101, 103, 104, 106, 108, 258, 259, 261, and 262 had a Cos Cell IC 5 0 within the range of <5 to >500nM. The compounds 20 of Examples 245-250 had a Cos Cell IC 5 o within the range of 100%@0.01 to 0.087 AM. The compounds of Examples 100, 101, 103 and 259 had a Cos Cell IC 5 0 o within the range of <5nM to 35nM. The compounds of Examples 1, 2, 3, 7, 8, 10-16, 21, 25, 67 69, 70, 81, 82 86 (11R,2R Isomer), 88-95, 97, 110, 111-113, 115 25 119, 121-176, 178-184, 186-200, 202-204, 206-211, 214-217, 221 225, 256, 258, 259, 261, 262, 268-271, 273-274, 276, 278, 280 286, 289, 292, 295-296, 299 Step B, 305, 309-346, 351-373 and 375-382 had a Soft Agar IC 0 within the range of <5 to >500nM. The compounds of Examples 116, 117, 160, 170, 184, 186 30 188, 196-200, 202-204, 206-208, 217, 225, 305 (1 ls,2R isomer), 316, 321,322, 324, 325, 335, 339, 365, 364, 372, 373, 375, and 382 had a Soft Agar ICo within the range of 2 to 10nM.

WO 00/37459 PCT/US99/27939 -349 The compounds of Examples 11, 16, 79 Step B (Isomer A), 80 (Isomer A), 88 (Isomer A), 93 (Isomer D), and 225 had a Soft Agar IC50o within the range of 2 to 300nM. The compound of Example 225 had a Soft Agar ICo of 2nM. 5 For preparing pharmaceutical compositions from the compounds described by this invention, inert, pharmaceutically acceptable carriers can be either solid or liquid. Solid form preparations include powders, tablets, dispersible granules, capsules, cachets and suppositories. The powders and tablets may 10 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 15 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 20 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. 25 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 30 to be converted, shortly before use, to liquid form preparations for either oral or parenteral administration. Such liquid forms include solutions, suspensions and emulsions.

WO 00/37459 PCT/US99/27939 - 350 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 5 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 10 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 15 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 20 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 25 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 30 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 WO 00/37459 PCT/US99/27939 - 351 alternatives, modifications and variations thereof will be apparent to those of ordinary skill in the art. All such alternatives, modifications and variations are intended to fall within the spirit and scope of the present invention.

Claims (16)

1. A compound of the formula: A, B RI R3 R2 R4 a (1.0) R5 x ~.-R7 R 8 R 3 2 R 3 3 R 6 , IV | \ / 13 \N C,--N (C ) R S IR 9 R 10 R 1 1 R 12 R 14 0 5 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 CR 1 or CR 2 ; or each of a, b, c, and d are independently selected from CR 1 or CR 2 ; 10 X represents N or CH when the optional bond (represented by the dotted line) is absent, and represents C when the optional bond is present; the dotted line between carbon atoms 5 and 6 represents an optional bond, such that when a double bond is present, A and B 15 independently represent -R 15 , halo, -OR 16 , -OCO 2 R 1 6 or -OC(O)R 15 , and when no double bond is present between carbon atoms 5 and 6, A and B each independently represent H 2 , -(OR 16 ) 2 , H and halo, dihalo, alkyl and H, (alkyl)2, -H and -OC(O)R 1 5 , H and -OR 15 , =0, aryl and H, =NOR 15 or -O-(CH2)p-O 20 wherein p is 2, 3 or 4; each R 1 and each R 2 is independently selected from H, halo, -CF3, -OR 15 , -COR 1 5 , -SR 15 , -S(O)tR 16 (wherein t is 0, 1 or 2, -N(R 15 ) 2 , -NO 2 , -OC(O)R 15 , -C0 2 R 15 , -0C0 2 R 16 , -CN, -NR 1 5 COOR 16 , -SR 16 C(O)OR 16 , -SR 16 N(R 17 ) 2 (provided that R" in 25 -SR 16 N(R 1 7 ) 2 is not -CH 2 -) wherein each R 17 is independently WO 00/37459 PCT/US99/27939 - 353 selected from H or -C(O)OR 16 , benzotriazol- 1-yloxy, tetrazol-5 ylthio, or substituted tetrazol-5-ylthio, alkynyl, alkenyl or alkyl, said alkyl or alkenyl group optionally being substituted with halo, -OR 15 or -CO 2 R 1 5 ; 5 R 3 and R 4 are the same or different and each independently represents H, any of the substituents of R 1 and R 2 , or R 3 and R 4 taken together represent a saturated or unsaturated C 5 -C 7 fused ring to the benzene ring (Ring III); R 5 , R 6 , and R 7 each independently represents H, -CF 3 , 10 -COR 15 , alkyl or aryl, said alkyl or aryl optionally being substituted with -OR 15 , -SR 1 5 , -S(O)tR 16 , -NR 15 COOR 16 , -N(R 15 ) 2 , -NO 2 , -COR1 5 , -OCOR 15 , -OCO 2 R 16 , -C0 2 R 15 , OP0 3 R 15 , or R 5 is combined with R 6 to represent =0 or =S; R is selected from: H, C 3 to C 4 alkyl, aryl, arylalkyl, 15 heteroaryl, heteroarylalkyl, cycloalkyl, cycloalkylalkyl, substituted alkyl, substituted aryl, substituted arylalkyl, substituted heteroaryl, substituted heteroarylalkyl, substituted cycloalkyl, substituted cycloalkylalkyl; the substutuents for the R substituted groups being selected 20 from: alkyl, aryl, arylalkyl, cycloalkyl, -N(R' 1 8 ) 2 , -OR' 8 , cycloalkyalkyl, halo, CN, -C(O)N(R' 8 ) 2 , -SO 2 N(R' 8 ) 2 or -CO 2 R' 8 ; provided that the -OR' 8 and -N(R' 8 ) 2 substituents are not bound to the carbon that is bound to the N of the -C(O)NR 8 - moiety; each R' 8 is independently selected from: H, alkyl, aryl, 25 arylalkyl, heteroaryl or cycloalkyl; R 9 and R' 0 are independently selected from: H, alkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, cycloalkyl or -CON(R' 8 ) 2 (wherein R 1 8 is as defined above); and the substitutable R 9 and R1 0 groups are optionally substituted with one or more substituents 30 selected from: alkyl, cycloalkyl, arylalkyl, or heterarylalkyl; or R 9 and R'o together with the carbon atom to which they are bound, form a C 3 to C 6 cycloalkyl ring; WO 00/37459 PCT/US99/27939 -354 R" and R I2 are independently selected from: H, alkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, cycloalkyl, -CON(R' 8 ) 2 -OR 8 or -N(R' 8 ) 2 ; wherein R'" is as defined above; provided that the -OR 8 and -N(Rl 8 ) 2 groups are not bound to a carbon atom that is 5 adjacent to a nitrogen atom; and wherein said substitutable R" and R 1 2 groups are optionally substituted with one or more substituents selected from: alkyl, cycloalkyl, arylalkyl, or heterarylalkyl; or R" 11 and R' 2 together with the carbon atom to which they are bound, form a C 3 to C 6 cycloalkyl ring; 10 R' 3 is an imidazolyl ring selected from: R 1 9 I t N N or _N (2.0) (4.0) (4.1) 9 wherein R I9 is selected from: (1) H, (2) alkyl, (3) alkyl, (4) aryl, (5) arylalkyl, (6) substituted arylalkyl wherein the substituents are selected from halo or CN, (7) -C(aryl) 3 or (8) cycloalkyl; 15 said imidazolyl ring 2.0 optionally being substituted with one or two substituents, and said imnidazole ring 4.0 optionally being substituted with 1-3 substituents, and said imidazole ring 4.1 being optionally substituted with one substituent wherein said optional substituents for rings 2.0, 4.0 and 4.1 are independently selected 20 from: -NHC(O)R' 8 , -C(R) 2 OR 3 5 , -OR', -SR' 8 , F, Cl, Br, alkyl, aryl, arylalkyl, cycloalkyl, or -N(R' 8 ) 2 (wherein each R' 8 is independently selected); wherein R'" is as defined above; wherein each R 4 is independently selected from H or alkyl; wherein R 35 is selected from H, -C(O)OR 2 0 , or -C(O)NHR 2 0 , and R 2 0 is as defined below; Q 25 represents an aryl ring, a cycloalkyl ring or a heteroaryl ring, said Q is optionally substituted with 1 to 4 substituents inedependently selected from halo, alkyl, aryl, -OR' 8 , -N(R' 8 ) 2 (wherein each R'" is independently selected), -OC(O)R" 8 , or -C(O)N(Ri's) 2 (wherein each R' 8 is independently selected), and wherein R Is is as defined above; 30 R 14 is selected from: WO 00/37459 PCT/US99/27939 - 355 R20 NR20 R 20 O O R 2 1 CH 2 R36 2 0 /SO 2 (5.0) , (6.0) , (7.0) , (7.1) or (8.0) R' * 5 is selected from: H, alkyl, aryl or arylalkyl; R 1 6 is selected from: alkyl or aryl; R 20 is selected from: H, alkyl, alkoxy, aryl, arylalkyl, 5 cycloalkyl, heteroaryl, heteroarylalkyl or heterocycloalkyl, provided that R 2 0 is not H when R 14 is group 5.0 or 8.0; when R 20 is other than H, then said R 2 group is optionally substituted with one or more substituents selected from: halo, alkyl, aryl, -OC(O)R' 8 , -OR 8 or -N(Rs) 2 , wherein each R 8 group is the 10 same or different, and wherein R' 8 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; R 2 ' is selected from: H, alkyl, aryl, arylalkyl, cycloalkyl, heteroaryl, heteroarylalkyl or heterocycloalkyl; 15 when R 2 ' is other than H, then said R 2 1 group is optionally substituted with one or more substituents selected from: halo, alkyl, aryl, -OR 8 or -N(R' 8 ) 2 , wherein each R 8 group is the same or different, and wherein R' 8 is as defined above, provided that said optional substituent is not bound to a carbon atom that is adjacent 20 to an oxygen or nitrogen atom; n is 0-5; each R 3 2 and R 33 for each n are independently selected from: H, alkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, cycloalkyl, -CON(R' 8 ) 2 -OR' 8 or =-N(R 8 ) 2 ; wherein R 18 is as defined above; and 25 wherein said substitutable R 3 2 and R 3 3 groups are optionally substituted with one or more substituents selected from: alkyl, cycloalkyl, arylalkyl, or heterarylalkyl; or R 32 and R together with the carbon atom to which they are bound, form a C 3 to C 6 cycloalkyl ring; and WO 00/37459 PCT/US99/27939 - 356 R 3 6 is selected from branched alkyl, unbranched alkyl, cycloalkyl, heterocycloalkyl, or aryl; and provided that: (1) when RI 4 is selected from: group 6.0, 7.0, 7.1 or 8.0, 5 and X is N, then R 8 is selected from: C 3 to Co alkyl, substituted C 3 to C, 0 alkyl, arylalkyl, substituted arylalkyl, heteroarylalkyl, substituted heteroarylalkyl, cycloalkylalkyl, or substituted cycloalkylalkyl; and (2) when R' 4 is selected from: group 6.0, 7.0, 7.1 or 8.0, 10 and X is N, and R 8 is H, then the alkyl chain between R' 3 and the amide moiety is substituted.

2. The compound of Claim 1 having the structure: A B R 1 R3 C,d II R2-- I I R 4 a . (1.OA) R 5 ..- R R 8 R32 R33 R6 IV I \ / R R13 N 2R CN ( CC)> R IR R 9 R 10 R 1 1 R 12 R 1 4 0 15 or A B II -7-R R2. R4 a (1.0B) R5 -- x§ R 7 R 8 R 32 R 33 R 6 IV RI13\ (Cn N 2S CN ( C)n R 14 R 9 R 10 R 11 R 12

3. The compound of Claim 1 wherein: R' to R 4 is independently selected from H, Br or Cl; R 5 to R is H; a is N and the WO 00/37459 PCT/US99/27939 - 357 remaining b, c and d substituents are carbon, or a, b, c, and d are carbon; A and B are H 2 ; n is 0 or 1; and R' 13 is group 2.0 or 4.0.

4. The compound of claim 1 wherein: 5 (a) R 8 is selected from: arylalkyl, substituted arylalkyl, cycloalkylalkyl, substituted cycloalkylalkyl, heteroarylalkyl or substituted heteroarylalkyl (b) R 9 and R 1 0 are independently selected from: H, alkyl, -C(O)N(R 8 ) 2 , or arylalkyl; 10 (c) R" and R 12 are independently selected from: H, alkyl, substituted aryl, -OR 8 , or R" and R 12 taken together with the carbon atom to which they are bound form a cycloalkyl ring; (d) R 3 2 and R 3 3 are independently selected from: H, -OR' 8 , arylalkyl or aryl; 15 (e) R 1 9 is selected from: -C(O)N(R' 1 8 ) 2 , alkyl, arylalkyl, or -C(aryl) 3 ; and (f) said optional R' 3 substitutents are selected from: -N(R' 8 ) 2 , -NHC(O)R '8 , -C(R 34 ) 2 0R 35 , alkyl, or cycloalkyl substituted with -OH provided that the -OH substitutent is not bound to a 20 carbon that is adjacent to an oxygen atom.

5. The compound of claim 1 wherein R 14 is: (a) 5.0 and R 2 0 is selected from: alkyl, arylalkyl, heterocycloalkyl, aryl, aryl substituted with halo, cycloalkyl, or 25 cycloalkyl substituted with alkyl; (b) 6.0 wherein R 2 0 and R 2 ' are independently selected from: H, cycloalkyl, alkyl, aryl, or arylalkyl; (c) 7.0 wherein R 2 0 is selected from: heteroaryl, cycloalkyl, heterocycloalkyl, alkoxy, heterocycloalkyl substituted 30 with -C(O)N(R 1 8 ) 2 ; (d) 7.1 wherein R 3 6 is selected from: cycloalkyl or heterocycloalkyl; or WO 00/37459 PCT/US99/27939 - 358 (e) 8.0 wherein R 2 0 is selected from: alkyl or cycloalkyl.

6. The compound of Claim 1 wherein: 5 (a) R' to R 4 is independently selected from H, Br or Cl; (b) R to R 7 is H; (c) a is N and the remaining b, c and d substituents are carbon; 10 (d) A and B are H 2 ; (e) nis Oor 1; (f) R' 13 is group 2.0 or 4.0, and said optional R 13 substitutents are selected from: -N(R 8 ) 2 , -NHC(O)R' 8 , -C(R 3 4 ) 2 0R 35 , or alkyl; 15 (g) R 8 is selected from: arylalkyl, substituted arylalkyl, cycloalkylalkyl, substituted cycloalkylalkyl, heteroarylalkyl, or substituted heteroarylalkyl; (a) R 9 and R'o are independently selected from: H, alkyl, C(O)N(R' 8 ) 2 , or arylalkyl; 20 (h) R" and R' 2 are independently selected from: H, alkyl, substituted aryl, -OR' 8 , or R" and RI 2 taken together with the carbon atom to which they are bound form a cycloalkyl ring; (i) R" 11 and R 12 are independently selected from: H, alkyl, substituted aryl, -OR' 8 , or R" and R 2 taken together with the 25 carbon atom to which they are bound form a cycloalkyl ring; (j) X is CH or N; (k) RI 9 is selected from: -C(O)N(R') 2 , alkyl, arylalkyl, or -C(aryl) 3 ; (1) R 2 o for 5.0 is selected from: (1) alkyl, (2) arylalkyl, 30 (3) heterocycloalkyl, (4) aryl, (5) aryl substituted with halo, (6) cycloalkyl, (7) cycloalkyl substituted with alkyl, or (8) cycloalkyl substituted with -OC(O)R' 8 or -OH provided said -OH substitutent is not bound to a carbon atom that is adjacent to an oxygen atom; WO 00/37459 PCT/US99/27939 - 359 (m) R 2 0 and R 2 ' for 6.0 are independently selected from: H, cycloalkyl, alkyl, aryl, or arylalkyl; (n) R 20 for 7.0 is selected from: heteroaryl, cycloalkyl, alkoxy, heterocycloalkyl substituted with 5 -C(O)N(R' 8 ) 2 ; (o) R 3 6 for 7.1 is selected from heterocycloalkyl or cycloalkyl; (p) R 2 for 8.0 is selected from: alkyl or cycloalkyl; and 10 (q) R 3 2 and R 33 are independently selected from: H, -OR' 18 , arylalkyl or aryl.

7. The compound of Claim 6 wherein: (a) R is selected from arylalkyl, cycloalkylalkyl, or 15 heteroarylalkyl; (b) R 9 and Rio are independently selected from: H or benzyl; (c) R" and R12 are independently selected from: H, -CH 3 , -CH 2 CH(CH) 2 , -(CH 2 ) 3 CH 3 , benzyl, ethyl, p-chlorophenyl, 20 -OH, or R" and RI 2 taken together with the carbon atom to which they are bound form a cyclopropyl ring; (d) R 3 2 and R 3 are independently selected from: H, phenyl, -OH or benzyl; (e) R' 9 is selected from: -C(O)NH-cyclohexyl, 25 -C(phenyl) 3 , H, methyl or ethyl; (f) said optional R' 3 substitutents are selected from: -CH., -CH 2 OH, -CH 2 OC(0)O-cyclohexyl, -CH 2 0C(0)O-cyclopentyl, ethyl, isopropyl, NH 2 , or -NHC(O)CF; (g) R20 for group 5.0 is selected from: t-butyl, ethyl, 30 benzyl, -CH(CH 3 ) 2 , -CH 2 CH(CH) 2 , -(CH 2 ) 2 CH 3 , n-butyl, n-hexyl, n octyl, p-chlorophenyl, cyclohexyl, cyclopentyl, WO 00/37459 PCT/US99/27939 - 360 CH 3 CH 3 N-CONH 2 A H 3 C CH 3 H 3 C CH 3 or OH (h) R 2 0 and R 2 ' for 6.0 are independently selected from: cyclohexyl, t-butyl, H, -CH(CH 3 ) 2 , ethyl, -(CH 2 ) 2 CH 3 , phenyl, benzyl, (CH 2 ) 2 phenyl, or -CH 3 ; 5 (i) R 2 0 for 7.0 is selected from: 4-pyridyNO, -OCH 3 , -CH(CH 3 ) 2 , -t-butyl, H, propyl, cyclohexyl or -- N-CONH 2 j) R 36 for 7.1 is selected from: cyclohexyl, cyclopentyl, cyclobutyl, cyclopropyl, 0 10 or 0 ;and (k) R 2 0 for 8.0 is selected from: methyl, i-propyl or cyclohexylmethyl.

8. The compound of Claim 7 wherein R 8 is selected from: 15 benzyl, -CH 2 C(CH) 2 , -CH 2 -cyclohexyl, -CH 2 -cyclopropyl, -(CH 2 ) 2 CH , WO 00/37459 PCT/US99/27939 - 361 F NN F H 2 C H 2 C H 2 C N H 2 C I j I OH OCH 3 N- I H 2 CL H 2 C H 2 C H 2 C CN CONH 2 OCH 3 H 2 C H 2 C H 2 C H 2 C C I II 0 NN H 2 C H 2 C -(CH2)2 , or 5

9. The compound of Claim 8 wherein: (a) R 8 is selected from: benzyl or -CH 2 -cyclopropyl; (b) R 2 for 5.0 is cyclohexyl; (c) R 2 0 for 6.0 is selected from: t-butyl, i-propyl, or 10 cyclohexyl; and R 2 ' is selected from: H, -CH 3 or i-propyl; (d) R 2 o for 7.0 is selected from: cyclohexyl, cyclopentyl, or i-propyl; (e) R 3 6 for 7.1 is selected from: cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl; and 15 (d) R 2 o for 8.0 is methyl.

10. The compound of Claim 9 wherein said compound is the 2R isomer. WO 00/37459 PCT/US99/27939 - 362 11. The compound of Claim 1 wherein R 8 is H and the alkyl chain between the aide substituent -C(O)NR and RI 3 is substituted. 5 12. The compound of Claim 1 wherein when R" 4 is group 5.0, and X is N, and R is H, then (a) the alkyl chain between R1 3 and the amide moiety is substituted and/or (b) R 9 and R1 0 , and/or R"' and R' 2 , are taken together to form a cyloalkyl ring. 10 13. A compound of the formula: A, B R1 3 'd R R2 I R4 a (25.OA) R5 X .. R7 R 8 R 3 2 R 3 3 R6 I V W I / 13 N N ( )n R

20.N , 91 0 10 R1IX R12 RO R RIoR R 0 0 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 CR 1 or CR 2 ; or 15 each of a, b, c, and d are independently selected from CR 1 or CR 2 ; X represents N or CH when the optional bond (represented by the dotted line) is absent, and represents C when the optional bond is present; 20 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 -R 1 5 , halo, -OR 16 , -OC0 2 R 16 or -OC(O)R 15 , and when no double bond is present between carbon atoms 5 and 6, A and B each independently represent H 2 , 25 -(OR 16 ) 2 , H and halo, dihalo, alkyl and H, (alkyl) 2 , -H and WO 00/37459 PCT/US99/27939 - 363 -OC(O)R 15 , H and -OR 15 , =0, aryl and H, =NOR 15 or -O-(CH2)p-O wherein p is 2, 3 or 4; each R 1 and each R 2 is independently selected from H, halo, -CF 3 , -OR 15 , -COR 15 , -SR 15 , -S(O)tR 16 (wherein t is 0, 1 or 2, 5 -N(R 15 ) 2 , -NO 2 , -OC(O)R 15 , -CO 2 R 1 5 , -OC0 2 R 16 , -CN, -NR 15 COOR 1 6 , -SR 16 C(O)OR 16 , -SR 16 N(R 1 7 ) 2 (provided that R 1 6 in -SR 16 N(R 17 ) 2 is not -CH 2 -) wherein each R 17 is independently selected from H or -C(O)OR 16 , benzotriazol-1-yloxy, tetrazol-5 ylthio, or substituted tetrazol-5-ylthio, alkynyl, alkenyl or alkyl, 10 said alkyl or alkenyl group optionally being substituted with halo, -OR 15 or -CO 2 R 1 5 ; R 3 and R 4 are the same or different and each independently represents H, any of the substituents of R 1 and R 2 , or R 3 and R 4 taken together represent a saturated or unsaturated C5-C 7 fused 15 ring to the benzene ring (Ring III); R 5 , R6, and R 7 each independently represents H, -CF 3 , -COR 15 , alkyl or aryl, said alkyl or aryl optionally being substituted with -OR 1 5, _SR 15 , -S(O)tR 16 , -NR 1 5 C O O R 16 , -N(R 15 ) 2 , -NO 2 , -COR 1 5 , -OCOR 1 5 , -0CO 2 R 16 , -CO 2 R 15 , OP0 3 R 15 , or R 5 is 20 combined with R 6 to represent =0 or =S; R8 is selected from: H, C 3 to C 4 alkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, cycloalkyl, cycloalkylalkyl, substituted alkyl, substituted aryl, substituted arylalkyl, substituted heteroaryl, substituted heteroarylalkyl, substituted cycloalkyl, substituted 25 cycloalkylalkyl; the substutuents for the R substituted groups being selected from: alkyl, aryl, arylalkyl, cycloalkyl, -N(R 18 ) 2 , -OR 1 8 , cycloalkyalkyl, halo, CN, -C(O)N(R' 8 ) 2 , -SO 2 N(R 8 ) 2 or -CO2R"8; provided that the -OR 8 and -N(R' 1 8 ) 2 substituents are not bound to the carbon that is bound 30 to the N of the -C(O)NR 8 - moiety; WO 00/37459 PCT/US99/27939 -364 each R' 8 is independently selected from: H, alkyl, aryl, arylalkyl, heteroaryl or cycloalkyl; R 9 and R' 0 are independently selected from: H, alkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, cycloalkyl or -CON(R' 8 ) 2 5 (wherein R' 8 is as defined above); and wherein said substitutable R 9 and R'o groups are optionally substituted with one or more substituents selected from: alkyl, cycloalkyl, arylalkyl, or heterarylalkyl; or R 9 and R"o together with the carbon atom to which they are 10 bound, form a C 3 to C 6 cycloalkyl ring; R" and R12 are independently selected from: H, alkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, cycloalkyl, -CON(R 8 ) 2 -OR' 8 or -N(R' 8 ) 2 ; wherein R' 8 is as defined above; provided that the -OR' 8 and -N(R'18) 2 groups are not bound to a carbon atom that is 15 adjacent to a nitrogen atom; and wherein said substitutable R" and R' 2 groups are optionally substituted with one or more substituents selected from: alkyl, cycloalkyl, arylalkyl, or heterarylalkyl; or R" and RI 2 together with the carbon atom to which they are bound, form a C 3 to C 6 cycloalkyl ring; 20 R' 3 is an imidazolyl ring selected from: R 1 9 N 1/> -N/> NNN (2.0) (4.0) or (4. 1) wherein R' 9 is selected from: (1) H, (2) alkyl, (3) alkyl, (4) aryl, (5) arylalkyl, (6) substituted arylalkyl wherein the substituents are selected from halo or CN, (7) -C(aryl) 3 or (8) cycloalkyl; 25 said imidazolyl ring 2.0 optionally being substituted with one or two substituents and said imidazole ring 4.0 optionally being substituted with 1-3 substituents and said imidazole ring 4.1 being optionally substituted with one substituent wherein said optional substituents for rings 2.0, 4.0 and 4.1 are independently selected WO 00/37459 PCT/US99/27939 - 365 from selected from: -NHC(O)R " ', -C(R 34 ) 2 OR 3 5 , -OR' 8 , -SR' 8 , F, Cl, Br, alkyl, aryl, arylalkyl, cycloalkyl, or -N(R") 2 ; wherein R' 8 is as defined above; wherein each R 34 is independently selected from H or alkyl; wherein R 35 is selected from H, -C(O)OR 2 0 , or -C(O)NHR 20 , and R20 is 5 as defined below; Q represents an aryl ring, a cycloalkyl ring or a heteroaryl ring, said Q is optionally substituted with 1 to 4 substituents independently selected from halo, alkyl, aryl, -OR'", -N(R' 8 ") 2 (wherein each R'" is independently selected), -OC(O)R' 8 , or C(O)N(R 8 ) 2 (wherein each R' 8 is independently selected), and 10 wherein R' is as defined above; R'" is selected from: H, alkyl, aryl or arylalkyl; R' 16 is selected from: alkyl or aryl; R20 is selected from: alkyl, alkoxy, aryl, arylalkyl, cycloalkyl, heteroaryl, heteroarylalkyl or heterocycloalkyl; 15 said R20 group is optionally substituted with one or more substituents selected from: halo, alkyl, aryl, -OC(O)R' 8 , -OR' or -N(Rs 8 ) 2 , wherein each R"' group is the same or different, and wherein R18 is as defined above, provided that said optional substituent is not bound to a carbon atom that is adjacent to an 20 oxygen or nitrogen atom; n is 0-5; each R 32 and R 33 for each n are independently selected from: H, alkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, cycloalkyl, -CON(R') 2 -OR' 8 or =-N(R'") 2 ; wherein R' 8 is as defined above; and 25 wherein said substitutable R 32 and R groups are optionally substituted with one or more substituents selected from: alkyl, cycloalkyl, arylalkyl, or heterarylalkyl; or R 32 and R 33 together with the carbon atom to which they are bound, form a C 3 to C 6 cycloalkyl ring; and 30 provided that when X is N, and R is H, then the alkyl chain between Rl 3 and the amide moiety is substituted. 14. The compound of Claim 13 having the structure: WO 00/37459 PCT/US99/27939 - 366 A, B R 1 d R 3 R2 R 4 a (25.OB) R5 .- R 7 R 8 R 3 2 R 3 3 R6 IV I \ / 13 N.'/// ,N (C)~ ' R N "q N )n R H / 10 R1 i R 1 2 Ro R9 R or R\ 3 bB R cR 2 -" II a (25.OC) R R 7 R R 3 2 R 3 3 R 6 1V I \ / R 1 3 I ~~ _-N. ( C )fi ' R I R 9 R 1 0 R 1 R 12 0o 0 5 15. The compound 25.OB of Claim 14 wherein R 8 is H and the alkyl chain between the amide substituent -C(O)NR 8 and R 13 is substituted. 16. The compound 25.OB of Claim 14 wherein: 10 (a) R' to R 4 is independently selected from H, Br or Cl; (b) R 5 to R is H; (c) (1) a, b, c, and d are carbon, and R 2 0 is 15 selected from: alkyl, alkoxy, aryl, arylalkyl, cycloalkyl, heteroaryl, heteroarylalkyl or heterocycloalkyl; said R 2 0 group is optionally substituted with one or more substituents selected from: halo, alkyl, aryl, -OC(O)R i 8 , -OR"' or -N(R 8 ) 2 , wherein each R" 8 group is the WO 00/37459 PCT/US99/27939 - 367 same or different, and wherein R' 8 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; or (2) a is N and the remaining b, c and d 5 substituents are carbon, and R 2 0 is selected from: alkyl, arylalkyl, heterocycloalkyl, aryl, aryl substituted with halo, cycloalkyl, cycloalkyl substituted with alkyl, or cycloalkyl substituted with -OH provided that said -OH substituent is not bound to a carbon adjacent to an oxygen atom; 10 (d) A and B are H 2 ; (e) n is 0 or 1; (f) R' 3 is group 2.0 or 4.0; (g) R 8 is selected from: arylalkyl, substituted arylalkyl, cycloalkylalkyl, substituted cycloalkylalkyl, 15 heteroarylalkyl or substituted heteroarylalkyl; and (h) X is CH or N; (i) R 9 and R"o are independently selected from: H, alkyl, -C(O)N(R' 8 ) 2 , or arylalkyl; (j) R" and RI 2 are independently selected from: H, 20 alkyl, substituted aryl, -OR' 8 , or R" and R 2 taken together with the carbon atom to which they are bound form a cycloalkyl ring; (k) R 2 and R 33 are independently selected from: H, -OR " 8 , arylalkyl or aryl; (1) R' 9 is selected from: -C(O)N(R 8 ) 2 , alkyl, arylalkyl, 25 or -C(aryl),; and (m) said optional R'" substitutents are selected from: -N(R'18) 2 , -NHC(O)R' 8 8 , -C(R1)20R 5 , or alkyl. 17. The compound of Claim 16 wherein a is N and the 30 remaining b, c, and d substituents are carbon and: (a) R 8 is selected from arylalkyl, cycloalkylalkyl, or heteroarylalkyl; WO 00/37459 PCT/US99/27939 - 368 (b) R 9 and R'o are independently selected from: H or benzyl; (c) R" and R12 are independently selected from: H, -CH 3 , -CH 2 CH(CH) 2 , -(CH 2 ) 3 CH 3 , benzyl, ethyl, p-chlorophenyl, 5 -OH, or R" and RI 2 taken together with the carbon atom to which they are bound form a cyclopropyl ring; (d) R 2 and R 33 are independently selected from: H, phenyl, -OH or benzyl; (e) R 9 is selected from: -C(O)NH-cyclohexyl, 10 -C(phenyl) 3 , H, methyl or ethyl; (f) said optional R13 substitutents are selected from: -CH 3 , -CH 2 OH, -CH 2 OC(O)O-cyclohexyl, -CH 2 OC(O)O-cyclopentyl, ethyl, isopropyl, NH 2 , or -NHC(O)CF 3 ; and (g) R20 is selected from: t-butyl, ethyl, benzyl, 15 -CH(CH) 2 , -CH 2 CH(CH) 2 , -(CH 2 ) 2 CH 3 , n-butyl, n-hexyl, n-octyl, p chlorophenyl, cyclohexyl, cyclopentyl, CH 3 CH 3 N-CONH2 H 3 C CH 3 H 3 C CH 3 or OH WO 00/37459 PCT/US99/27939 - 369 18. The compound of Claim 17 wherein R 9 , R l o, R", R 1 2 , R 32 , and R 33 are H. 19. The compound of Claim 17 wherein R is selected from: 5 benzyl, -CH 2 C(CH 3 ) 2 , -CH 2 -cyclohexyl, -CH 2 -cyclopropyl, -(CH 2 ) 2 CH 3 , F N N F H 2 C H 2 C H 2 C N H 2 1 I , I I OH OCH 3 H 2 C N H 2 C 7 H 2 C H 2 C II , I , I CN CONH 2 SOCH 3 - ' 1 H 2 C OC: H 2 C H 2 C H 2 C ) 0 ID C'O H 2 C H 2 10 -(CH2)2, , or 20. The compound of Claim 19 wherein: (a) R is selected from: benzyl or -CH 2 -cyclopropyl; and 15 (b) R 2 0 is cyclohexyl.

21. The compound of Claim 20 which is (1) a 3-Br-8-C1 compound, an 8-Cl-compound, or a 10-Cl-compound; or (2) a 3-Br- WO 00/37459 PCT/US99/27939 - 370 8-Cl-compound, an 8-Cl-compound, or a 10-Cl-compound wherein R 9 , R1 0 , R", R 2 , R 32 , and R 3 3 are H.

22. The compound of Claim 1 selected from: Br--/ Cl N (H N (11R,2R Isomer) N , N N~, o Me Me (Example 11) 5 H Br- C1 N H N (11S,2R Isomer) O I Me (Example 16) 00 Br /C1 N H N N C H 3 CH N N N H 3 C 3 H3C O 1-O O N (Example 58) . WO 00/37459 PCT/US99/27939 - 371 Br Cl N (N' N (Example 78 Step B) O~O H 3 C V CH 3 CH 3 Br Cl N [\ (Example 79 N c Isomer A) N 0 H Br Cl NL N C, N . %N N a IN I N(Example 80 0 0 0 Isomer A) I C 2 H 5 Br /Cl N'-NiN (Example 88 I Isomer A) H 3 C CH 3 CH 3 WO 00/37459 PCT/US99/27939 - 372 Br C N0 N NN N c(Example 93 So Isomer D) H 3 C CH 3 CH 3 N N H N (Example 99) N O HNH Br /\ Cl NN H /H N H N (Example 100) O 0/O H 3 C CH 3 CH 3 WO 00/37459 PCT/US99/27939 - 373 N N C -z NCH 3 O rq N N (Example 225) Cl N N CH 3 ON - N (Example 226) 00 CH 3 Cl N F N CH 3 5 ost, N N N (Example 227) 0 Cl (N)_ CH3 Ir ~(Example 28 WO 00/37459 PCT/US99/27939 - 374 / / Cl N - H 3 C (N),NN N (Example 229) 0 ci N N CH 3 (N (Example 232) O CI CN N H 3 C CH 3 No N (Example 326) 0 CI O I~cI N N N NCH 3 oH. (Example 330) 0 WO 00/37459 PCT/US99/27939 - 375 ci N O O, N N CH 3 (Example 327) 0 \- N H 3 C CH 3 C) 1 N" l(Example 328) Br / Cl t1, N N N NH (Example 243) Br Cl N Me N N (Example 286A) o o WO 00/37459 PCT/US99/27939 - 376 Br Cl N Me NN N N O Ir M (Example 286B) 0 0 Br Cl N NN Cl N Me Nm~ N N O 0 0 (Example 306) NN CN (N) N Me O Oi (Example 307) , 0 N or WO 00/37459 PCT/US99/27939 - 377 N N N-Me N " N Nf O .O (Example 308) 23 The compound of Claim 1 selected from: Br / 0 N H H 3 C ZO C Example 58 Cl -N 5N) ,,o N N (Example 225) 5 0 Cl N - CH 3 N N ,N (Example 226) 0 OH WO 00/37459 PCT/US99/27939 - 378 Cl \' N N -CH3 O 7'sN (Example 227) O N r N CH 3 K N"N N (Example 228) Cl N - H 3 C 5 o; N , NN (Example 229) Cl N N CH 3 (Example 232) :O i 1fr N N N 0 0C WO 00/37459 PCT/US99/27939 - 379 Ci N _ N H 3 C OH 3 N N (Example 326) N N0 IH 3 N"(N)'. (Example 330) "; or N N N H 3 (Example 327) 0N 5 24. A compound of the formula: / " Ci N N . CH 3 N' N>I (Example 225) 0-J,0 WO 00/37459 PCT/US99/27939 - 380 25. A compound of the formula: Cl Me (Example 393) HO N 0 o 0 or HMe (Example 394) Me 0- 0 N,",, N 5

26. The compound of Claim 1 selected from a compound of Example 1-22, 25, 45-66, 77, 78 Step B, 79, 80, 82-85, 86, 86A,

87-97, 99, 100, 102, 112-208, 208A, 209, 209A, 210, 210A, 210B,

211-220, 220A, 221-232, 234B, 234C, 234E, 235-254, 286A, 286B, 10 304-308, 310-342, 343-366, 367-373 or 375-382. 27. A compound selected from a compound of Example 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 81, 98, 101, 103, 104, 15 105, 106, 107, 108, 110, 111, 255, 256, 257, 258, 259, 260, 261, 262, 263, 264, 265, 266, 267, 268, 269, 270, 271,272, 273, 274, 275, 276, 277, 278, 279, 280, 281,282, 283, 284, 285, 286, 287, 289, 290, 291, 292, 293, 294, 295, 296, 297 299, 300, 301, 302, 303 or 309. 20 WO 00/37459 PCT/US99/27939 - 381 28. A method of treating tumor cells comprising administering an effective amount of a compound of any of Claims 1-27. 5 29. The method of Claim 28 wherein the tumor cells treated are pancreatic tumor cells, lung cancer cells, myeloid leukemia tumor cells, thyroid follicular tumor cells, myelodysplastic tumor cells, epidermal carcinoma tumor cells, bladder carcinoma tumor cells, colon tumors cells, melanoma, breast tumor cells and prostate 10 tumor cells. 30. A method of treating tumor cells wherein the Ras protein is activated as a result of oncogenic mutation in genes other than the Ras gene, comprising administering an effective amount of 15 a compound of any of Claims 1-27. 31. A method of inhibiting farnesyl protein transferase comprising the administration of an effective amount of a compound of any of Claims 1-27. 20 32. A pharmaceutical composition for inhibiting farnesyl protein transferase comprising an effective amount of a compound of any of Claims 1-27 in combination with a pharmaceutically acceptable carrier. 25 33. A use of a compound of any of Claims 1-27 for the manufacture of a medicament for inhibiting farnesyl protein transferase. 30 34. A use of a compound of any of Claims 1-27 for the manufacture a medicament for treating pancreatic tumor cells, lung cancer cells, myeloid leukemia tumor cells, thyroid follicular tumor cells, myelodysplastic tumor cells, epidermal carcinoma tumor cells, WO 00/37459 PCT/US99/27939 - 382 bladder carcinoma tumor cells, colon tumors cells, melanoma, breast tumor cells and prostate tumor cells. 35. A use of a compound of any of Claims 1-27 for 5 inhibiting farnesyl protein transferase. 36. A use of a compound of any of Claims 1-27 for treating pancreatic tumor cells, lung cancer cells, myeloid leukemia tumor cells, thyroid follicular tumor cells, myelodysplastic tumor cells, 10 epidermal carcinoma tumor cells, bladder carcinoma tumor cells, colon tumors cells, melanoma, breast tumor cells and prostate tumor cells.