AU776558B2 - Tricyclic farnesyl protein transferase inhibitors - Google Patents

Description

WO 00/37459 PCT/US99/27939 -1* TRICYCLIC FARNESYL PROTEIN TRANSFERASE INHIBITORS

BACKGROUND

WO 95/10516, published April 20, 1995, W096/31478, published October 10, 1996, and copending Application Serial No.

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

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

SUMMARY OF THE INVENTION This invention provides compounds useful for the inhibition of farnesyl protein transferase (FPT). The compounds of this invention are represented by the formula: R R3 A ,B I II R 2 Y 1 R 4 a

R

5 X -R7 R8 R 32 R33 R6_ IV I 13 N N (C )n R3

R

4

R

9 RIo R"

R

1 2 or a pharmaceutically acceptable salt or solvate thererof, wherein: one of a, b, c and d represents N or and the remaining a, b, c and d groups represent CR 1 or CR 2 or WO 00/37459 PCT/US99/27939 -2each 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; 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 15 halo, -OR 16

-OCO

2

R

16 or

-OC(O)R

1 5 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

15 H and -OR 15 aryl and H, =NOR 15 or -O-(CH2)p-Owherein p is 2, 3 or 4; each R 1 and each R 2 is independently selected from H, halo,

-CF

3

-OR

15 -OCH3), -COR 15

-SR

15

-SCH

3 and

-SCH

2

C

6

H

5 -S(O)tR 16 (wherein t is 0, 1 or 2, -SOCH 3 and

-SO

2

CH

3

-N(R

1 5 2

-NO

2

-OC(O)R

15 -C0 2

R

1 5 -OC0 2

R

16

-CN,

-NR

15

COOR

16

-SR

16

C(O)OR

16

-SCH

2

CO

2

CH

3

-SR

1 6

N(R

1 7 2 (provided that R' 6 in -SR 16

N(R

1 7 2 is not -CH 2 wherein each R 17 is independently selected from H or -C(O)OR 1 6

-S(CH

2 2 NHC(0)O-t-butyl and -S(CH 2 2

NH

2 benzotriazol- 1-yloxy, or substituted tetrazol-5-ylthio alkyl substituted tetrazol-5-ylthio such as alkynyl, alkenyl or alkyl, said alkyl or alkenyl group optionally being substituted with halo, -OR 15 or -C02R15;

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, -CF3, 30/07 '04 FRI 17:50 FAX 61299255911GRFTH AC07 GRIFFITH HACK Q007 -CORI 5 alkyl or aryl, said alkyl or aryl optionally being substituted with -ORIS, -SR1 5 -S(O)tRI 6

_NR

1 5 C00RI6, -N(R 15 2

-NO

2 -COR1 5 -OCOR1 5 -0C02R1 6 -C0 2

R

15 0P0 3 RIS. or R 5 is combined with R 6 t6 represent o Ra is selected from' H, C 3 to CID alkyl (p .refermbly branched chain alkyl, and most prefer-ably 0, to7C braxiched -chain alkyl).

arl-y arylalkyl, heteroaxyl. heteroarylalkyl. cycloalkyl, cycloalkylalkyl, -substituted alkyl, substituted aryl, substituted arylalkyl, substituted heteroaryL, substituted heteroarylalkyl, -substituted cycloalkyl, substituted cycloalkylalkyl; the substutuent for -the R! substituted groups being selected 4..from: alkyl,*axyl. arylalkyi. cycloalkyl. cycoalkyrall, al. 2

-SQ

2 or -00R": 'provided that the -OR"g and'-N(R") 2 substituents are not bound to the carbon that is bound to the N of the.

moiety; each R!6 is independently selected fm:= H. alkyl, aryl.

arylalkyl, heteroaryl. or cycloalkyl; R! and R! 0 are independently selected from: H. alkyl, aryl, axylalkyl, heteroaryl. heteroazylalkyl. cycloalkyl or -CQN(R' 8 2 s..(wherein R! is' as defined above); a2nd the substitutable and R' 0 grpoups are optionally substituted with one or more 1-3) substituents selected from: alkyl methyl,- ethyl. isopropyL. and 44 -the like), cycloalkyl,. arylalkyl, or heterarylalkyl the le and/or 2.5 R'o groups can be unsubtituted or can be substituted with 1-3 of the substitutents described above, except when W 9 and/or R' is H); or R! and R'o together with the carbon atom to which they are bound, form aC 3 to t, cycloalkyl ring: RW and are'Independently selected from: H, alkyl. aryl.

arylalkyl. heteroaryl. heteroaryla~yl, cycloalkyl,

-OR'

8 or 2 wherein R' 8 is as defined above: provided that the COMS ID No: SBMI-00850317 Received by IP Australia: Time 17:13 Date 2004-07-30 WO 00/37459 PCT/US99/27939 -4-

-OR'

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

R'

2 groups are optionally substituted with one or more 1-3) substituents selected from: alkyl methyl, ethyl, isopropyl, and the like), cycloalkyl, arylalkyl, or heterarylalkyl; or R" and R' 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 is preferably N -N or -N (4.1) wherein R' 9 is selected from: H, alkyl, alkyl, aryl, arylalkyl, substituted arylalkyl wherein the substituents are selected from halo F and Cl) or CN, -C(aryl), -C(phenyl) 3 trityl) or cycloalkyl; said imidazolyl ring 2.0 or 2.1 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, 2.1, 4.0 and 4.1 are bound to the carbon atoms of said imidazole rings and said optional substituents are independently selected from: -NHC(O)R' 8

-C(R

3 2 0R 3 5

-OR

8

-SR'

8 F, Cl, Br, alkyl, aryl, arylalkyl, cycloalkyl, or -N(R' 8 2 (wherein each R' 8 is independently selected); R' 8 is as defined above; each R 3 is independently selected from H or alkyl (preferably preferably H; R 3 5 is selected from H,

-C(O)OR

2 0 or -C(O)NHR 2 0 and R 20 is as defined below (preferably R 2 0 is alkyl or cycloalkyl, most preferably cyclopentyl or cyclohexyl); Q represents an aryl ring phenyl), a cycloalkyl ring cyclopentyl or cyclohexyl) or a heteroaryl ring furanyl, pyrrolyl, thienyl, oxazolyl or thiazolyl), said Q is optionally substituted with 1 WO 00/37459 PCT/US99/27939 to 4 substituents inedependently selected from halo F or Cl), alkyl, aryl, -OR' 8

-N(R'

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

OH,

-CH

2

OC(O)OR

20 and -CH 2

OC(O)NHR

20

R'

4 is selected from: R 20 O N R20

/ISO

2 O O R 2 1 O CH 2 O R 3

S

or

R'

5 is selected from: H, alkyl, aryl or arylalkyl;

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 20 is not H when R' 4 is group 5.0 or when R 20 is other than H, then said R 20 group is optionally substituted with one or more 1-3) substituents selected from: halo, alkyl, aryl, -OC(O)R' 8 -OC(O)CH), -OR' 8 or -N(R 1 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 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 group is optionally substituted with one or more 1-3) substituents selected from: halo, alkyl, aryl, -OR' 8 or -N(R' 8 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 atom; n is 30/07 '04 FRI 17:51 FAX 61299255911GRFIHAK j00 GRIFFITH HACK la 008 -6each W 2 and R3 *for each n for each -C(R7)(Re3)- group).

are independently selected from: H. alkyl. aryt, azylalkyl, heteroaryl, heteroarylalkyl, cycloalkyl, -CON(R') 2

-OR'

6 or

-N(R

8 1 wherein R 8 is as defined above; and wherein said substitutable R7 and W 3 groups are optionally substituted with one' or more 1-3) substituents selected from alkyl methyl ethyl, isopropyl, and the like), cycloalkyl, arylalkyl, or heterarylalkyl; or Ra and W3 together with the carbon atom to which they are bound, form a C~ to C. cycloalkyl ring; and R7 selected from branched alkyl. unbranched alkyl cycloalkyl. heterocycloalkyL, or aryl phenyl); and provided thatwhen R' is selected front: group 6.0, 7.0, 7. 1 or 8.

and X is. then R! is selected from.k, C 3 to Cl 0 alkyl, substituted C 3 to

C,

0 alkyl. arylAlkyl, substituted saylalky]. heteroarylalkyl.

substituted heteroarylalkyl. cycloalkylalkyl, or substituted cycloalkylalkyl; with the further proviso- that when R!4 is selected from: group 6.0. 7.0, 7.1 or and X is N, and R! is H, then the alkyl chain between R' Iiidazole ring 2.0. 4.0 or 4.1) and the arnicl m~oiety the group) is substituted, at least one of W 9

R'

0 Re', or le is other than H, and/or R! and WO 0 and/or R' and

R!

2 are taken together to form *a cycloalkyI ring.

This invention also provides compounds of formula 1.0. as described above, wherein when W' Is group 5.0. and X Is and le is H. then the alkyl chain between R' 3 iidazole ring 2.0, 4.0 or 4.1) and the amnide moiety the. -CQO)NR' 8 group) is substituted.

at least-one of Ru'. R 2 Re. or*R7 is other than and/or R! and R' 0 'and /or and W2, are taken together to form a cyloalkyl ring.

COMS ID No: SBMI-00850317 Received by IP Australia: Time (l1:m) 17:13 Date 2004-07.30 30/07 '04 FRI 17:51 FAX 61299255911 GRIFFITH HACK 10009 6 a-.

This invention als-o provides a compound of the formula: A B b R RS e' RT R 8 e RP-- le R10 :,ot R RRI >R, 2 *or a pharmac, uticanlY acceptable salt or solvate- thererof. -whereirE *one of a. b, c and d repres ents N or N0O. and the remaining a, 5 b. c arid d* groups represent CRI or CR 2 or each of a, b, c, and d are independently selected from CRI or

CR

2 X represents N or OH when the optional bond (represented by dotted line) is* absent, and represents C When the optional bond 10 is presentthe dotted line between-carbon atoms 5.and 6 repre .sents an Optional bond, such that when* a double bond is present A and B independently represent

-R

15 halo, -OR 16 -0.C02RI 6 or *-OC(O)RI5, and *hen no double bond is Present between carbon atoms 5 and A and B each independently represent H 2

-(OR

16 2 H and halo. dihalo, alkyl and H. (alkyl) 2 -1 and COMS ID No: SBMI-00850317 Received by IP Australia: Time 17:13 Date 2004-07-30 30/07 '04 FRI 17:51 FAX 61299255911GRFIHAC j01 GRIFFITH HACK la 010 -6b- H and -OR1 5 aryl and H. =N0R 15 or -O-(CH2)p-Owherein p is 2, 3 or 4;.

each R 1 and each R 2 is independently selected from H, halo.

-OF3, -OR' 5 -C0R 15

-SR

15 -S(O)tR1 6 (wherein t is 0, 1 or 2,

-N(RI

1 2

-NO

2

-OC(O)RI

5 -C0 2

RI

5 -0C0 2

RI

6

-CN.

-NRlSCOORk16; -SR1 6 0(O)OR' 6

-SR

16 N(2RI 7 2 (provided that R 6 in -SR' 6 N(Ri' 7 2 is not -CR 2 wherein each R 17 is independently selected from H or -O(O)OR' 6 berrzotriazol- 1-yloxy, ylthio. or substituted teti-azol-5-ylthio, alkynyl, alkenyl or alkyl, said alkyl or alkenyl group o ptionally being substituted with halo,

-OR

15 or -C0 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 C 5

-C

7 fused ring to *the benzene ring (Ring III);

R

5

R

6 and R 7 each independently represents H, -CF3, -COR1 5 alkyl- or aryl. said alkyl or aryl optionally being substituted with -0R 15

-SR

15 -S(O)tR1 6

-NR

15 COOR1 6 -N(Rl 5 2

-NO

2 -0C0R 1 5 -0002R 16 -C0 2 RI 5 0P0 3

R

1 5 or R 5 is combined 'with R 6 to represent =0 ot =S; R! Is selected from: CO. to-P substitutedrlalyl heteroaryl. heteroarylalkyl. cycloalkyl, cycloalkylalkyl,sutite alkiyl, substituted -aryl, substituted arylalkyl, substituted heteroaryl, substituted heteroarylalkyl, substituted cycloalkyl, substituted cycloalkylalkyl; the substutuents for the R! substituted groups being selected from: alkyl, aryl, arylalkyl, cycloalikyl, -OR1', cycloalkyaikyl, halo. CN, -SO 2 or -COR'; provided that the -OR' 8 and -N(R'.%'substituents are not bound to the carbon that is. bound to the N of the -C(O)NR- moiety: COMS ID No: SBMI-00850317 Received by IP Australia: Time 17:13 Date 2004-07-30 30/07 '04 FRI 17:52 FAX 61299255911GRFTH AC j1 GRIFFITH HACK (21011 6ceach R s independently selected from: H, a~kyl, aryl,' arylalkyl. heteroai-yl or cycloakyL,.

R? and R' are independently selected fro=: H, alkyl, aryl.

arylalkyl, heteroaryl. heteroarylalkyl, cycloalkyl or -CONCR 18 2 is as defined above), and wherein said substitutable R! and R! groups are optionally substituted'with one or more sub stituents selected from: alkyl, cycloalcyl. arylaikyl, or heterarylalkyl; or R! and R 0 together with the carbon. atom to which they are .bound, form a C~to 0. cyrcloalkyl ring: :0R11 and R1 2 are independently selected from: H, alkyl, aryl.

arlly eeoyarylalkyl.aly cyclIoalkyl. -CNR)-O 1 or

N(R')

2 wherein R'a is a s defined above; provided that the -OR' and -N(R'Oj 2 groups are not bound to a carbon atom that is 15 adjacent to a nitrogen atom; and wherein said subst itutable W' and

R

12 groups are optionally su~bstituted with one- or more substituents selected from: alkyl, cycloalkyl, arylalkyl, or heterarylalkyl; or

R'

1 and R 2 together With the Carbon. atom to Which the are bound, form a C 3 to C, cycloalkyl ring; ~R 3 is*an inaldazolyl ring selected froxm N N or wherein R" 9 is selected from: H. alkyl, alkcyl, aryl, axylalkyl, substituted axylalkyl wherein the substituents are selected from halo or CN. -C(aryl), or cycloalkyl:.

said imidazolyl ring 2.0 optionally being subs tituted'with one or two substituents and said Imidazole ring 4.0 optionally being substituted with. 1-3 substituents and said Iiidazole ring 4.1 being optionally substituted with one suibstituent wherein said optional substituents for rings 2.0, 4.0 and 4.1 are independently selected COMS ID No: SBMI-00850317 Received by IP Australia: Time 17:13 Date 2004-07-30 30/07 '04 FRI 17:52 FAX 61299255911 GRIFFITH HACK [a 012 -6dfrom selected fro=: -NHC(O)R1 8 2 OR, -OR~a. F. Cl, Br, alkyl, aryl, arylalkyl, cycloalkyl. or wherein. R" 8 is as defled..

above, wherein each R is independiintly selected from H or ailkyl; wherein R7 is selected from or.. -C(O)NHRO. and R~is as defined below; Q represents an aryl ring, a cloalkyl ring or a heteraryl, ring, said Q is optionally substituted with I to 4 substituents independently selected from halo;- alkyl, aryL; -OR'.

(wherein each R 1 8 Is indepenidently selected), -OC(O)R!O. or (wherein each R!'is independentlyselected), -and -wherein WO is a's defined above.

R!

8 is selected from: H. alk-yL. miyl or zrylalkyl; R!6 is selected from: alkyl or aryl;- R! is selecte4 from= alkyl. alkoxy. aryl. axylkyl. cycloalkyl, heteroaryl. heteroary~alkyl, or heterocycloalkyl; 15 said*R!O gru sotionally substituted with one or -more substituents selectedfm -halo, alkyl aryL. -OC(O)R' 6

OR

1 8 or

-NW%

8 wherein each W' group is the 'same or different. and herein Wff Is as diefined above, rvdd htsi optional is not bound td a carbonatom that Is adjacent to an oxygen or nitroaen. atom= isO- *.each le. and R7 for eah n' are tndependently selected fro=: H, -aikyl, aryL azylalkyl.* heteroaryl, heteroazylalcyL cycloalkyl.

-CON(R'6), -OW' or =-N(R 8 1 Wherein lea is as defined above; and wherein said substitutable' R' and R~groups* are optionally.

suabstituted with one or more substituents selected from: aflcYL, cycloalkvl,, ayiValkyi. orheterarvlallvl; or.

*R-7 and Fe' together with the carbon atom to which they are.

bound.or a 0. to C, cycloalkyl ring, and COMS ID Na:SBMI-00850317 Received by IP Australia: Time 17:13 Date 2004-07-30 30/07 '04 FRI 17:53 FAX 61299255911 GRIFFITH HACK ZJ013 6e provided that when X is N, and Ra is H, then the alkyl chain between R,1 3 and the amide moiety is substituted.

This invention: fodrmula: also p1rovides a compound of the 0~ 0 0 0900 0 0000 0. 0 0.

.0* 0 0000 0000 0000 0** 0 00** 000 0 0 0000 0000 0 00 00 0 0 (me (Ex-ample 393).

(xmple 394) COMS ID No: SBMI-00850317 Received by IP Australia: Time 17:13 Date 2004-07-30 30/07 '04 FRI 17:53 FAX 61299255911 GRIFFITH HACK fZj014 -6f This invention also provides a compound selected from a compound of Example 26, 27, 28, 29, 30, 31, 32, 33, 34, 36, 37, 38, 39, 40, 41, 42, 43, 44, 67, 68, 69, 71, 72, 73, 74, 75, 76, 81, 98, 101, 103, 104, 105, 106, 107, 108, 110, 11.1, 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.

The compounds of this invention: potently inhibit :0.-..farnesyl protein transferase, but not geranylgeranyl protein transferase I, in COMS ID No: SBMI-00850317 Received by IP Australia: Time 17:13 Date 2004-07-30 WO 00/37459 PCT/US99/27939 -7vitro; (ii) block the phenotypic change induced by a form of transforming Ras which is a faresyl acceptor but not by a form of transforming Ras engineered to be a geranylgeranyl acceptor; (iii) block intracellular processing of Ras which is a farnesyl acceptor but not of Ras engineered to be a geranylgeranyl acceptor; and (iv) block abnormal cell growth in culture induced by transforming Ras.

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

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

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

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

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

This invention also provides a method for inhibiting or treating tumor growth by administering an effective amount of the tricyclic compounds, described herein, to a mammal a human) in need of such treatment. In particular, this invention provides a method for inhibiting or treating the growth of tumors expressing an activated Ras oncogene by the administration of an effective amount of the above described compounds. Examples of tumors which may be inhibited or treated include, but are not limited to, lung cancer WO 00/37459 PCT/US99/27939 -8lung adenocarcinoma), pancreatic cancers pancreatic carcinoma such as, for example, exocrine pancreatic carcinoma), colon cancers colorectal carcinomas, such as, for example, colon adenocarcinoma and colon adenoma), myeloid leukemias (for example, acute myelogenous leukemia thyroid follicular cancer, myelodysplastic syndrome (MDS), bladder carcinoma, epidermal carcinoma, melanoma, breast cancer and prostate cancer.

It is believed that this invention also provides a method for inhibiting or treating proliferative diseases, both benign and malignant, wherein Ras proteins are aberrantly activated as a result of oncogenic mutation in other genes--i.e., the Ras gene itself is not activated by mutation to an oncogenic form--with said inhibition or treatment being accomplished by the administration of an effective amount of the tricyclic compounds described herein, to a mammal 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 neu, src, abl, lck, and fyn), may be inhibited or treated by the tricyclic compounds described herein.

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

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

-C(O)OCH

2 CH, benzyloxycarbonyl);

CH

2 CI-represents dichloromethane; CIMS-represents chemical ionization mass spectrum; DEAD-represents diethylazodicarboxylate; DEC-represents EDCI which represents 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride; DMF-represents N,N-dimethylformamide; Et-represents ethyl; EtOAc-represents ethyl acetate; EtOH-represents ethanol; HOBT-represents 1-hydroxybenzotriazole hydrate; IPA-represents isopropanol; iPrOH-represents isopropanol; Me-represents methyl; MeOH-represents methanol; MS-represents mass spectroscopy; NMM-represents N-methylmorpholine; Ph-represents phenyl; Pr-represents propyl; TBDMS-represents tert-butyldimethylsilyl; TEA-represents triethylamine; TFA-represents trifluoroacetic acid; THF-represents tetrahydrofuran; Tr-represents trityl; WO 00/37459 PCT/US99/27939 alkyl-represents straight and branched carbon chains and contains from one to twenty carbon atoms, preferably one to six carbon atoms; acyl-represents a group wherein G represents 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 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 aryl is a phenyl ring), with all available substitutable carbon atoms of the carbocyclic group being intended as possible points of attachment, said carbocyclic group being optionally substituted 1 to 3) with one or more of halo, alkyl, hydroxy, alkoxy, phenoxy, CF 3

-C(O)N(R'

8 2

-SO

2

R'

8

-SO

2

N(R'

8 2 amino, alkylamino, dialkylamino,

-COOR

2 3 or -NO 2 wherein R 2 3 represents alkyl or aryl; and 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 1, 2 or 3) alkyl groups methyl or ethyl) and when there is more than one alkyl group each alkyl group is independently selected; cycloalkylalkyl-represents a cycloalkyl group, as defined above, substituted with an alkyl group, as defined above, such that the bond from another substituent is to the alkyl moiety; halo-represents fluoro, chloro, bromo and iodo; heteroaralkyl-represents an alkyl group, as defined above, substituted with a heteroaryl group, as defined below, such that the bond from another substituent is to the alkyl moiety; 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 aromatic character, with the aromatic heterocyclic groups preferably containing from 2 to 14 carbon atoms, 2- or 3-furyl, 2- or 3-thienyl, 4- or 5-thiazolyl, 4- or 5-imidazolyl, 4- or 2-pyrazinyl, 3- or 4-pyridazinyl, 5- or 6-[1,2,4triazinyl], 3- or 5-[1,2,4-thiadizolyl], 6- or 7benzofuranyl, 6- or 7-indolyl, 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( N N N 0 0and 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 or NR 2 4 wherein R 2 4 represents alkyl, aryl, wherein R' B is as above defined -C(O)NH 2 or acyl-(suitable heterocycloalkyl groups include 2- or 3-tetrahydrofuranyl, 2- or 3- tetrahydrothienyl, 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: 6 SI8 IIiN WO 00/37459 PTU9/73 PCT/US99/27939 12 The compounds of formula 1.0 include the 2R and 2S isomers shown below (2R is preferred): A B A, B R R7 a (1.O13) 7 R 8

R

3 2 R3

R

1 N 2S 11 I R 9 RIO R"I R 12

R

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

C(CH

3 2

-CH

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

F

H

2 C6 H 2 N H 2

C

OH

OCH

3 rN6H

C

H

2 C3".N H 2 C~N H 2 G H 2 1 I 1 1 rOCH3 CN

CONH

2

H

2 CN' H 2

C~~

I I N N I

H

2 C WO 00/37459 WO 0037459PCTIUS99/27939 13 0

NN

I(H' H 2 C

H

2

CI

2)2 1 1, and Examples of Rk 9 and R" 0 groups include H and benzyl Examples of R" and R"2 groups include: H, -CH 3

-CH

2

CH(CH

3 2

-(CH

2 3

CH

3 benzyl, ethyl, p-chlorophenyl, and -OH.

Cyclopropyl is an Example of the Rk" and R 1 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 13 moiety include: -OH3, -CH 2 OH, -CH 2 0C(O)O-cyclohexyl,

-CH

2

OC(O)O-

cyclopentyl, ethyl, isopropyl, NH 2 and -NHC(O)CF 3 Examples of R'9 include: -C(O)NH-cyclohexyl, -C(phenyl),, H, methyl or ethyl.

Examples of W20 for group 5.0 include: t-butyl, ethyl, benzyl,

-CH(CH

3 2

-CHCH(CH

3 2

-(CH

2 2

CH

3 n-butyl, n-hexyl, n-octyl, pchlorophenyl, cyclohexyl, cyclopentyl, 0113

CH

3

N-CONH-

2 7.

-C1f130

CH

3 or 1130 CH 3 Another example of R20 for group 5.0 is

OH

Examples of W20 and W'1 for 6.0 include: cyclohexyl, t-butyl, H, -OI(Cil7' ethl, iiijC 3 phenyl, benzyl, -(CH 2 2 hnl n

OH

3 Examples of RW 0 for 7.0 include: 4-pyridylNO,

-OCH

3 WO 00/37459 PCT/US99/27939 -14-

-CH(CH,)

2 -t-butyl, H, propyl, cyclohexyl and

N-CONH

2 Examples for R 36 for 7.1 include: cyclohexyl, cyclopentyl, cyclobutyl, cyclopropyl, 0 and 0 Examples for R 2 0 for 8.0 include: methyl, i-propyl and cyclohexylmethyl.

Examples of R 3 2 and Ra 3 include: H, phenyl, -OH and benzyl.

Compounds of this invention include compounds of formula 1.0 wherein when is selected from: group 6.0, 7.0, 7.1 or and X is C or CH (preferably CH), then R 8 is selected from: C 3 to C,o alkyl, substituted C 3 to C, 0 alkyl, arylalkyl, substituted arylalkyl, heteroarylalkyl, substituted heteroarylalkyl, cycloalkylalkyl, or substituted cycloalkylalkyl.

Compounds of this invention include compounds of formula wherein when R" 4 is selected from: group 6.0, 7.0, 7.1 or and X is C or CH (preferably CH), and R 8 is H, then the alkyl chain between R 1 3 imidazole ring 2.0, 4.0 or 4.1) and the amide moiety the -C(O)NR 1 group) is substituted, at least one of R 9 R'I, R 2

R

2 or R 33 is other than H, and/or R 9 and R 0 and/or R" and R 2 are taken together to form a cyloalkyl ring.

Compounds of this invention include compounds of formula 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' 3 imidazole ring 2.0, 4.0 or 4.1) and the amide moiety the -C(O)NR' 8 group) is substituted, at least one of R 9

R

0

R

2

R

3 2 or R 33 is other than H. and/or fb) R 9 and R 0 and/or R" and R2. are taken together to form a cyloalkyl ring.

WO 00/37459 PCT/US99/27939 Compounds of this invention include compounds of formula wherein when R' 4 is selected from: group 6.0, 7.0, 7.1 or and X is C or CH (preferably CH), then R 8 is selected from: arylalkyl, substituted arylalkyl, heteroarylalkyl, substituted heteroarylalkyl, cycloalkylalkyl, or substituted cycloalkylalkyl.

Compounds of this invention include compounds of formula wherein when R' 4 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 cycloalkylalkyl.

Compounds of this invention include compounds of formula wherein when R' 4 is selected from: group 6.0, 7.0, 7.1 or and X is N, then R 8 is selected from: arylalkyl, substituted arylalkyl, heteroarylalkyl, substituted heteroarylalkyl, cycloalkylalkyl, or substituted cycloalkylalkyl.

Compounds of this invention include compounds of formula wherein when R' 4 is 5.0 and X is N, then R 8 is selected from: arylalkyl, substituted arylalkyl, heteroarylalkyl, substituted heteroarylalkyl, cycloalkylalkyl, or substituted cycloalkylalkyl.

Thus, one embodiment of this invention is directed to compounds wherein R' 4 is the carbamate group 5.0 and the other substituents are as defined for formula Another embodiment of this invention is directed to compounds wherein R' 4 is the carbamate group 5.0, X is N and the other substituents are as defined for formula Another embodiment of this invention is directed to compounds wherein R' 4 is the carbamate group 5.0, X is C or CH (preferably CH) and the other substituents are as defined for formula Another embodiment of this invention is directed to compounds wherein R' 4 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 WO 00/37459 PCT/US99/27939 -16- Another embodiment of this invention is directed to compounds wherein R 1 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 formula Another embodiment of this invention is directed to compounds wherein R 14 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 formula 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 arylalkyl or substituted arylalkyl (preferably arylalkyl), and the other substituents are as defined for formula Another embodiment of this invention is directed to compounds wherein R' 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 Another embodiment of this invention is directed to compounds wherein R' 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 Another embodiment of this invention is directed to compounds wherein when R' 4 is group 5.0, and X is C or CH (preferably CH), and R 8 is H, then the alkyl chain between R' 3 imidazole ring 2.0, 4.0 or 4.1) and the amide moiety the

C(O)NR

8 group) is substituted, at least one of R 9

R",

R

2

R

32 or R is other than H, and/or R 9 and R'O, and/or R" and

R'

2 are taken together to form a cyloalkyl ring, and the other substituents are as defined for formula WO 00/37459 PCT/US99/27939 17- Another embodiment of this invention is directed to compounds wherein when R' 4 is group 5.0, and X is N, and R 8 is H, then the alkyl chain between R 1 3 imidazole ring 2.0, 4.0 or 4.1) and the amide moiety the -C(O)NR' 8 group) is substituted, at least one of R 9

R

1

R'

2

R

32 or R 3 is other than H, and/or

R

9 and R' 1 and/or R" and R12, are taken together to form a cyloalkyl ring, and the other substituents are as defined for formula Another embodiment of this invention is directed to compounds wherein R 4 is a group selected from: 6.0, 7.0, 7.1 or X is N, R 8 is arylalkyl. or substituted arylalkyl (preferably arylalkyl) and the other substituents are as defined for formula Another embodiment of this invention is directed to compounds wherein R' 4 is a group selected from: 6.0, 7.0, 7.1 or 8.0, X is N, R 8 is heteroarylalkyl or substituted heteroarylalkyl (preferably heteroarylalkyl) and the other substituents are as defined for formula Another embodiment of this invention is directed to compounds wherein R 1 4 is a group selected from: 6.0, 7.0, 7.1 or 8.0, X is N, R 8 is cycloalkylalkyl or substituted cycloalkylalkyl (preferably, cycloalkylalkyl) and the other substituents are as defined for formula Another embodiment of this invention is directed to compounds wherein R 4 is a group selected from:6.0, 7.0, 7.1 or 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 Another embodiment of this invention is directed to compounds wherein R' 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 heteroarylalkyl or substituted heteroarylalkyl (preferably, heteroarylalkyl) and the other substituents are as defined for formula WO 00/37459 PCT/US99/27939 18- Another embodiment of this invention is directed to compounds wherein R' 4 is a group selected from: 6.0, 7.0, 7.1 or 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

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 compounds, such as, for example: 3,8,10-trihalo; 3,7,8trihalo; 3,8-dihalo; 8-halo; and 10-halo substituted compounds; wherein each halo is independently selected. Preferred compounds of formula 1.0 include: 3-Br,8-C1, compounds; 3-Br,7-Br,8-Cl-substituted compounds; 3-Br,8- Cl-substituted compounds; 8-Cl-substituted compounds; and compounds. The 3,8-dihalo compounds are more preferred and the 8-halo compounds are most preferred. Thus, for example, 3-Br,8-Cl substituted compounds are more preferred and 8-C1 substituted compounds are most preferred.

Substituent a is preferably N or N'O with N being preferred.

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

R

5

R

6 and R 7 are preferably H.

X is preferably N or CH the optional bond is absent), and 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 is selected from: aryl-(C,-C)alkyl, substituted aryl-(C,-C 4 )alkyl, heteroaryl-(C,- C4)alkyl, substituted heteroaryl-(C,-C,)alkyl, cycloalkyl-(C,-C,)alkyl, or substituted cycloalkyl-(C,-C 4 )alkyl. More preferably, R 8 is selected from: aryl-CH,-, substituted aryl-CH,-, heteroaryl-CH 2 substituted heteroaryl-CH, 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 substitutable carbon atoms of the imidazole ring, the substituents are generally selected from: -N(R' 8 2

-NHC(O)R'

8 -C(R)2OR 3 5 or alkyl, -CH 3

-CH

2 OH, -CH 2 OC(O)O-cyclohexyl, -CHOC(O)Ocyclopentyl, ethyl, isopropyl, NH 2 or -NHC(O)CF 3

R'

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

is preferably a carbamate group represented by substituent 5.0 described above. Preferably, R 20 for substituent is selected from: alkyl, substituted alkyl, aryl, cycloalkyl, or cycloalkyl substituted with -OH provided that said -OH substituent is not bound to a carbon that is adjacent to an oxygen atom. More preferably R 20 for substituent 5.0 is selected from: C, to C, alkyl and Cs to C, 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 more preferred.

R

2 0 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

H.

R

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

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

R

2 0 in substituent 8.0 is preferably selected from: alkyl or cycloalkylalkyl; most preferably methyl, isopropyl or cyclohexylmethyl; more preferably methyl or isopropyl; and even more preferably methyl.

R

9

R'

0 and R 2 are preferably selected from: H, C, to C 4 alkyl methyl or isopropyl), -CON(R' 8 -CONH2), or when

R

9 and R1 0 and/or R" and R' 2 are taken together to form a cycloalkyl ring, said ring is preferably cyclopropyl cyclopentyl or cyclohexyl.

R

9

R

10 and R 1 2 are preferably H when R' 4 is the carbamate substituent 5.0 and R 8 is not H.

When R 14 is selected from substituents 6.0, 7.0, 7.1 and and at least one of R 9

R'

O

and R' 2 is other than H, then at least one of R 9 R'O, and R 2 is: preferably selected from: C, to C 4 alkyl,

-CON(R'

8 2 or the cycloalkyl ring formed when R 9 and R' 0 and/or R" and R' 2 are taken together along with the carbon atom to which they are bound; (II) most preferably selected from: methyl, (2) isopropyl, -CONH, or cyclopropyl; and (III) more preferably selected from: R 9 and R'O being H, and one of R" and R' 2 being selected from: alkyl (preferably, methyl or isopropyl), and the other being selected from H or alkyl (preferably, methyl); R 9 and R o being H, and R" and R 2 being taken together to form a cycloalkyl ring (preferably, cyclopropyl); or R" and R' 2 being H, and one of R 9 and R 0 being -CONH,, and the other being H.

WO 00/37459 PCT/US99/2793 9 -21 Preferred compounds, when at least one of R 9 and R 12 is other than H, also include compounds wherein: R 9 and R are H, and R" and R1 2 are the same or different alkyl, preferably the same, wherein said alkyl is more preferably methyl.

For compounds of the invention, n is preferably 0-4, more preferably 0-2, and most preferably 0 or 1.

Preferably, each R 32 and R 33 are independently selected from: H, -OR' 8 aryl or arylalkyl benzyl); most preferably H, -OH or phenyl; and more preferably H.

Compounds of formula 1.0, wherein X is N or CH, include, with reference to the C- 11 bond, the R- and S- isomers: A. B

R

2

R

3

L

R2 Ra 4 a

R

5 R7 R 8

R

32 R33 R6._I IV R 13 A B

R

1 R3 c' II R2-- I- 4 bz- \V I (10.0) a X

R

6 IV11 S R 9> R R 1 0

R

1 1

R

12

R

1 4 0 R

R

Compounds of formula 1.0 also include compounds having the 2S stereochemistry and the C-1 1 R- or C-l 1 S- stereochemistry.

Compounds of this invention include: WO 00/37459 PCTIUS99/27939 22 (13.0) Br R 0 WO 00/37459 WO 0037459PCTIUS99/27939 -23- C c Br N I4I

K'N

(19.1) 8

R

8 R 14 0 R 14 0 N(0 N

R

1 1 4 11 11 R 0 R 0 C CN

NN

R

1 0

R

1 0 WO 00/37459 WO 0037459PCT[US99/27939 24 N (23.1) N ±(24.1) R 8 8

R

1 0 R 1 0 N2.2 (24.3)

SN

0 C N "C 1 14 1 1 (24-N (24.5) R' 0 R 1 0 N2.6 (24.7) (II R8

C'

R

1 0 R 1 0 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 PCT/US99/27939 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.

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.

Preferred compounds of formula 1.0 include compounds of the formula: A B RI I3 R2 I III bII I R2 R4 a 1 (25.0) R R 8

R

3 2 R33 R6 IV I 13 SN C N

C

R

R 2 O

R

9 10 R

R

1 2 wherein R' 4 is the carbamate group 5.0) wherein all substituents are as above defined.

A preferred compound of formula 25.0 is: A. ,B (26.0) .R33 with formula 27.0: WO 00/37459 PCT/US99/27939 -26- (27.0)

.R

3 3 being most preferred (wherein all substituents are as defined above).

Compounds of formula 25.0 include: and (29.0) K CN (C )n R 3 l

R

9 RI R 1

R

1 2 \0 0 wherein all substituents are as defined above.

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

WO 00/37459 PCTIUS99/7939 -27- Compounds of formula 29.0 are preferred. Most preferred are compounds of formula 29.0 wherein R 8 is selected from: benzyl, 4fluorobenzyl, 3-pyridylmethyl or cyclopropylmethyl; R 20 is cyclohexyl, i-propyl or t-butyl (more preferred is cyclohexyl), R' is Br or H, R 3 is Cl, and R 4 is H. More preferred are compounds of formula 29.0 wherein R 8 is benzyl, R 20 is cyclohexyl, i-propyl or tbutyl (even more preferred cyclohexyl), R' is H, R 3 is Cl, and R 4 is H or Cl.

Preferred compounds of this invention include:

N

H

(R-Isomer) fI N (11R,2R Isomer) Me (Example 11) 1 N (11S,2R Isomer) Mi (Example 16) (Example 58).

i WO 00/37459 PTU9/73 PCT[tJS99/27939 28

N

(Example 78 Step B) a f\(Example 79 Step B \k~NIsomer

A)

NN NN (Example Isomer A) (Example 88 Isomer A) WO 00/37459 WO 0037459PCT[US99/279 3 9 29 I I 0 (Example 93 Isomer D) N(Example9)

H

N (Example 100)

CH

3

CH

3 WO 00/37459 WO 0037459PCT[US99/27939 30

NN

[H3 (Example 225) (Example 226) 13 (Example 227) (Example 228)

CH-

NN

WO 00/37459 WO 0037459PCTIUS99/27939 31 (Example 229)

CH

3 f( (Example 232) (Example 326) <CH3

NN

(Example 330) WO 00/37459 WO 0037459PCTIUS99/27939 32 (Example 327)

H

3 (Example 328) (Example 243) (Example 286A) Me WO 00/37459 PTU9/73 PCT/US99/27939 33 (Example 286B) le (Example 304) (Example 306) (Example 307) Me

-N

'N

;or WO 00/37459 WO 0037459PCTIUS99/27939 34 F- Me (Example 308) Most preferred compounds include the compounds N

H

N

CH

3 ~N I~, 4 K CH 3 N N KJL II\ ~',Example 58 0,o 0

N

C1

CN-

N

CH

3 N NZZN (Example 225)

CH

3

CH

3 (Example 226) WO 00/37459 WO 0037459PCT/US99/27939 35

CH

(Example 227)

CH

3

-N

(Example 228)

H

3

C

N

(Example 229) (Example 232) WO 00/37459 PCT/US99/27939 36- NS H" CH3 N U3N N (Exam p l e 326

CI

S-

N

N N Examples 58, 199, 225, 226, 229, 232 and 326. Compounds of 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 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, 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, 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.

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 enantiomers, diastereoisomers, atropisomers) forms.

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

Certain tricyclic compounds will be acidic in nature, e.g.

those compounds which possess a carboxyl or phenolic hydroxyl group. These compounds may form pharmaceutically acceptable salts. Examples of such salts may include sodium, potassium, calcium, aluminum, gold and silver salts. Also contemplated are salts formed with pharmaceutically acceptable amines such as ammonia, alkyl amines, hydroxyalkylamines, N-methylglucamine and the like.

Certain basic tricyclic compounds also form pharmaceutically acceptable salts, acid addition salts. For example, the pyridonitrogen atoms may form salts with strong acid, while compounds having basic substituents such as amino groups also form salts with weaker acids. Examples of suitable acids for salt formation are hydrochloric, sulfuric, phosphoric, acetic, citric, oxalic, malonic, salicylic, malic, fumaric, succinic, ascorbic, maleic, methanesulfonic and other mineral and carboxylic acids well known to those in the art. The salts are prepared by contacting the free base form with a sufficient amount of the desired acid to produce a salt in the conventional manner. The free base forms may be regenerated by treating the salt with a suitable dilute aqueous base solution such as dilute aqueous NaOH, potassium carbonate, 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 of the invention.

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

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

Compounds of the invention may be prepared according to the procedures described in WO 95/10516 published April 1995, WO96/31478 published October 10, 1996, WO 97/23478 published July 3, 1997, U.S. 5,719,148 issued February 17, 1998, and copending Application Serial No. 09/094687 filed June 1998 (see also W098/57960 published December 23, 1998); the disclosures of each being incorporated herein by reference thereto; and according to the procedures described below.

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

Reaction Scheme 1 (n is 1)

R

1 1

R

12 RA RA R X .CO 2 Et N+ R\ EtOH N H CO2Et

S

1 reflux (300)(31.0) (32.0) WO 00/37459 WO 0037459PCTIUS99/27939 39

R

11

R

12

RA

320LAH >N

OF

(33.0) 0

R'

33.0+1 N-H P3

DEAD

(34.0) 0

H

R'1 R 12 R

A

N

2

H

4 N Ni-I.

35 0 (36.0)

RB

(36.0) 1 H 0 1) 3A Molecular Sieves 2) NaBH 4

N

HIN

11 12 (36.1 R R

BOC

N 1) CH1 2

CI

2 360 K 2) cyclohex-7i 36.0 H isocyanate N 0 O (37.0)

BOC

N 1)CH 2

CI

2 K Ti 2) cyclohex51i 36.1 I IOH isoevanate

BOG

~RA

(38.1) WO 00/37459 PTU9173 PCTIUS99/27939 40

TEA

38.0 HTEA Salt I

RA

N

HN

N

a N -'0

H

(;Ju.u) 38.1

A

I I RA 39.0 (40.0) (0.0)(41.0) WO 00/37459 PCT/US99/27939 -41 In Scheme 1, R" and R 2 are preferably methyl when H is bound to the amide nitrogen when R 8 in formula 1.0 is e.g., 41.0, and are preferably H when the amide nitrogen is substituted

R

8 in formula 1.0 is other than 41.1. Those skilled in 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 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 imidazole and/or 5-substituted) to an appropriately substituted acrylate 31.0 in EtOH at reflux or neat at 90°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 phthalimido 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 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 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 imidazole ring above. RB represents the optional substituents defined above for the aryl or heteroaryl groups for R 8 For example, following Reaction Scheme 1, wherein R" and

R

2 are methyl, and using compound 42.0 (see Preparative Example in WO 95/10516 published April 20, 1995) WO 00/37459 WO 0037459PCT/US99/27939 42 (42.0) compound 43.0

N

can be obtained.

Reaction Scheme 2 fn is 0) R\DMF

RA,

K,,NNa R12 >~C0 2 Et 90 0

C

(44.0)

R'

1

R

1 2 LRA OH TSIR- 46 .0 __jTEA (47.0) (46.0) (48.0) 48.0 -K

DMF

N-

(50.0) WO 00/37459 PCT/US99/27939 -43-

R"

1

R

12 RA NH 2

N

2

H

4 N 50.0

N

(51.0)

R

B

RP

S Y 1) 3A Molecular Sieves Y (51.0)

II

H Y 2) NaBH 4

Y

S R R 12 O HN 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) 44.0 with 45.0 at 90°C. 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°C gives the phthalimido derivative 50.0 which can be readily converted to the amine 51.0 with hydrazine in refluxing EtOH. Compounds wherein

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 when R 8 in formula 1.0 is H), and are preferably H when the amide nitrogen is substituted R 8 in formula 1.0 is other than H).

Reaction Scheme 3 Ring IV piperidine) Br Cl Br Cl Br C N H N

N

H_ H H N N N H H H 52.0) 52.0) 52.0) WO 00/37459 PTUS92 3 PCT/US99/27939 44 a 52.0) (53.0) 0HNO b (53.0) (54.0a) (54.0b) (55.0a) (55.0b) (56.0a) (56.0b) NC N (55.0a) H Br c d N H HOOC

N

(56.0a)

H

Br Cl e -NI HOOC

N

(57.0a) COOt-Bu Br-C CI N

H

N CN H (55.0b) Br Cl N

H

N COOH H (56.0b) Br-' Cl

N

N COOH (57.0b) COOt-Bu WO 00/37459 PCTIS99/27939 Br Cl Br C l Br Cl N N N H a-e H H N HOOC N N COOH

I

H (58.0a) COOt-Bu (58.0b) COOt-Bu Compound 52.0 is resolved following procedures similar to those disclosed in W097/23478 (published July 3, 1997).

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

WO 00/37459 WO 0037459PCTIUS99/27939 46 Reaction Scheme 4 (n is 'Br

RA

R12 FIN Z H2-NH2RA.

N H-H R 3 2 R 33 RH2 2 0/EtOH HN N R

B

I RB H R -y A 1) 3A Molecular y R Sieves R 32 K/R 3 3K 2) NaBH 4 C. RioR 1

R

1 1 R 1 -y BOC I A R32 33.

N R fX DEC N.

RA

R

32 R 33 r- (C hR 1

R

9

R

10

R

BOC

H BOC RA <N4 1 SR 12 ey TFA WO 00/37459 PTU9/73 PCTIUS99/27939 -47- VII BOC R

A

K

R 0*11

N

VI for R 200H

R"

K

*y TA

H

R!

tTEA

RA

n 1// RI' R 1 2 WO 00/37459 WO 0037459PCT/US99/27939 48 R

B

ey TFA I I H Y R CN

R

3 2 R3 \N

CN

H 0" R9 R 1

R{TEA

(VIII CN~ 32 I R 9

R

C

(VIII) 2NCO R2 for R 2 0 0 HelN RFO'll N It-, 0 WO 00/37459 WO 0037459PCTIUS99/27939 49

R

2 0 S0 2

CI

TEA

N H 0 R 20

CH

2 C(O)C1

TEA

or R2 CH 2

C(O)OH

DEC

R 20

C(O)CI

TEA

or R 20

C(O)OH

DEC

R 20 0C(O)CI or (R 20 0C(O)) 2 0

TEA

150 2 R20 o

N

R 2K 0 1 0 Reactants V and VI are:

BOC

N

0

BOC

I C0 2

H

BOG

WO 00/37459 WO 0037459PCT[US99127939 50 Reaction Scheme R

B

DEC HOET (IX) TA

R

11 R1 2 H 0 y TEA WO 00/37459 PCTIUS99/27939 -51

OH

R

2 0 S0 2 C1

TEA

R20 O H

R

2 0 N C=

TEA

/r 0 S 0 N I;ZFON, (N y

R

2 0 -S0 2 R 20CH 2

C(O)CI

TEA

or 2 C(0)OH

DEC

N

N Ni 0 R 2C(0)CI

TEA

or R20C(O)OH

DEC

R

2 0 0C(0)CI or (R 20OC(O)) 2 0

+TEA

N

R20 A~ i' In Scheme 5, R 30 represents:

CH

3 or Q0a, Reaction Scheme 6 n is 0 R" R 12

H

2 N-9 C

R

9

R

10

*HCI

HN

I

(n-Bu) 4 NS0 4 NaOH PaI) In Scheme 6, the procedure set forth in Scheme 4 is followed, but using H2N R(XI)

N

instead of

RA

R

3 2

R

3 3 -flk H2N R 11 ,9 -10 R' WO 00/37459 PCT/US99/27939 -52to obtain the corresponding urea (-C(O)NHR 20 amide

(-C(O)CH

2

R

20 or -C(O)R 2 0 sulfonamide (-S0 2

R

2 or carbamate

(-C(O)OR

2 0 products, wherein n is 0, can be prepared. Similarly, using

RB

Y

y

R

1 1 R12

N

(obtained from XI following the procedures in Scheme instead of R B

RA

R32 R 3 3 r-\

IN

HNR IC)In--

N

R

9 RiO

R

1 1

R

12 in Scheme 4 and 5 produces the corresponding ureas, amides, sulfonamides and carbamates wherein n is 0.

Those skilled in the art will appreciate that in Schemes 1, 2 and 4-6, other aldehydes can be used in place of

RB

H Y

Y

0 to obtain the other substituents for R 8 in formula Those skilled in the art will also appreciate that using R9

A

R

3 2

R

3 3 N R

SN

H

2 N C n

R

9

R

10

R

instead of WO 00/37459 PCT/US99/27939 -53-

R

A

RR

R

3 2

R

3 3 nN H2N 1 C

N

R

R

10

R

1 1

R

12 in Schemes 4 and 5, and using

R

1 1 R12

R

19

H

2 N N

-N

RA

instead of R" R' 2

R

9 R0 N

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 Are Other Than H) 11 12 R 1 1 R 12 RA OH pyr.-S0 3 RA N CHO

N

S

O H

DMSO

N (33.0)

N

R

11

R

12 R9Mg R 11

R

12

R

9 N--CHO N OH NJ N 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 in Scheme 1 or subject to reoxidation to the ketone followed by Grignard addition of R' 0 In the case where R 9 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 Are Other Than H, C-Linked Imidazole)

R

1 1 R2

R

1

R

12 TrCN DIBAL-H TrCHO Tr- CN Tr_ CHO \AN

:N

R

11

R

12 R 11

R

12 Tr-N CHO R 9 MgX w-Tr-N OH \=VN \A-N R9

R

A

RA

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 either R 9 or R 9

R'

0 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 PREPARATIVE EXAMPLE 1 Me Me N NH

N

Step A Me Me XN Y COEt

N

9 Ethyl 2,2-dimethyl acrylate (50.0g, 2.0 eq.) was stirred with imidazole (13.28g, 200 mmol) at 90° C for 48 hours. The resulting WO 00/37459 PCT/US99/27939 solution was cooled, diluted with water (150 mL) and CH 2 C1, (150 mL) and separated. The aqueous layer was washed with CH 2 C1 2 (2 x mL) and the combined organics were dried over Na 2 SO, and concentrated in vacuo. The crude mixture was purified by flash chromatography using a 10% MeOH in CH 2

CL

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 XN CO2Et N OH N N A solution of the title compound from Step A (10.Og, 50.96 mmol) was treated with LiAlH 4 (51 mL, IM solution in ether, The reaction mixture was stirred one hour at room temperature before quenching by the dropwise addition of saturated Na2SO, mL). The resulting slurry was dried with NaSO, (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.

Step C Me Me Me Me NOH N To a solution of the title compound Step B (6.85g, 44.42 mmol), phthalimide (7.19g, 1.1 and Ph 3 P (12.82g, 1.1 eq.) in THF (200 mL) at 0°C was added DEAD (7.69 mL. 1.1 eq.) over 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 56reduced pressure and the product isolated by crystallization from

CH

2 Cl/Et2O to give a white solid (10.03 g, 79% yield). CIMS: MH'= 284 Step D Me Me Me Me N ^N 0

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 filtrate concentrated under reduced pressure. The crude product was purified by flash chromatography using a 15% (10% NH 4 OH in MeOH) solution in CH 2 CL, as eluent to give a pale yellow oil (2.80g, 53% yield). LCMS: MH'= 154 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. represents "Preparative Example Number".

TABLE 1 WO 00/37459 PCT/US99/27939 -57- Me Me

N

N

PREPARATIVE EXAMPLE

BOC

H2

N

N O yr- 0

SBOC

N

H

N

N 0 N M 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

CI

2 (5.0 mL) and the resulting solution stirred 10 minutes at room temperature before adding cyclohexyl isocyanate (0.21 mL, 1.5 After stirring at room 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 C, 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 BOC

BOC

N >NH 2 N H N BOC N N 0N Me Me N 0 By the essentially the same procedure as that set forth in Preparative Example 5, except using N-(benzyloxycarbonyloxy)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 Example 6, except instead of the amine Me Me NyN NH 2

N

use the amine from Preparative Example 2 N NH2

N

to obtain

BOC

I

N

H N WO 00/37459 PCT/US99/27939 -59- PREPARATIVE EXAMPLE 7 a Cl By essentially the same procedure as that set forth in Preparative Example 5, except using the title compound from Preparative Example 3 (Table the title compound was prepared.

LCMS: MH'= 573.

PREPARATIVE EXAMPLE 7.1

BOC

I

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

_H N

CH

3 WO 00/37459 PCT/US99/27939 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.

PREPARATIVE EXAMPLE 7.3

BOC

I

N

H p^\N N 0 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.

PREPARATIVE EXAMPLE 8 Step A

BOC

Me Me I N 1IZJ N j

N

H IN 0 Mee To the title compound from Preparative Example 1, Step D, (0.82g, 5.35 mmol) in CH 2 C,1 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 product was purified by flash chromatography using a 10%

NH

4 OH in MeOH) in CH 2 C14 then 20% (10% NH 4 OH in MeOH) in

CH

2 C1 as eluent. CIMS: MH= 366.

WO 00/37459 PCT/US99/27939 -61 Step B

BOC

H

N N *y TFA H IH I 0 Me Me 0 Me Me The title compound from Step A was stirred at room temperature in a 50% solution of TFA in CH 2 C, (25 mL) for 2 hours.

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.

Step C

H

S y TFA

N

HH I 0 Me Me B r Cl

N

N

SH

N

H N

N

0 Me Me The title compound from Step B was dissolved in CH 2

CL

I mL) and TEA (7.62 mL, 10 eq.) was added. The reaction mixture was stirred 5 minutes before adding chloride Cl (42.0) WO 00/37459 PCTIUS99/7939 -62- (0.908g, 0.5 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 C1, (2 x 200 mL). The combined organics were dried over MgSO,, filtered, and concentrated under reduced pressure. The crude product was purified by flash chromatography using a and then 10% (10% NH4OH in MeOH) in CH 2

C

2 solution as eluent (0.926 g, 30% yield). CIMS: MH'= 571.

Step D

N

H N (11R,2R(-)-Isomer) O Me Me Br Cl tN

N

N H N (11S,2R(-)-Isomer) C N N N4 O MeMe The title compound from Step C was separated into individual 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; aj -31.7 (3.0 mg in 2.0 mL MeOH).

Isomer B (11R,2R(-)-Isomer): retention time= 30.3 minutes; [al 20 D= -6.2 (2.4 mg in 2.0 mL MeOH).

WO 00/37459 PCT/US99/27939 63 PREPARATIVE EXAMPLE 9 By essentially the same procedure as described in Preparative Example 8, except using the title compound from Preparative Example 2 (Table the title compound was prepared.

The 11(S)- and 11(R)-isomers SN N (11S,2R(-)-Isomer) (11R,2R(-)-Isomer) 0 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; [oc] 2 0 -32.7 (4.04 mg in 2.0mL MeOH).

WO 00/37459 PTU9/73 PCT[US99/27939 64 11 R,2R(-)-isomer: retention timne= 22.8 minutes; MH*=569;

[C

2 0 D= 1.2 (3.40 mg in 2.0 mL MeOH).

PREPARATIVE EXAMPLE 9.1 Follow the procedure set forth in Preparative Example 8, except use the amine H 2 N N.

in Step A instead of H2N

H

3 C CH 3 and use the 10-Cl tricycle chloride

N

CI

C

in Step C instead of the 3-Br-8-Cl-tricycle chloride (Compound 42.0) to obtain the compounds N (11 S, 2R-Isomer) H 0and N (ILIR,2R-Isomer) rN NCI

H

H I WO 00/37459 PCT/US99/27939 Obtain the 10-C1 tricycle chloride (10, 11- diChloro-6,11dihydro-5H-benzo[5,6]cyclohepta[1, 2 -Bjpyridine) as follows: /i NaBH4 H 4SOC12 N N

N

0 CI OH C CI CI The ketone (starting material) 5,6-dihydro-10-Chloro- 1Hbenzo[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 for the 10H tricycle and following the procedure described in Preparative Example 169.

1H NMR (CDC13 2.97 2H), 3.55 1H), 4.03 1H), 7.11 7.13 1H), 7.22 2H), 7.31 1H), 7.53 1H), 8.49 1H).

PREPARATIVE EXAMPLE Step A

N

N "CN 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 Et.O (50 mL) and washed with water (2 X 100 mL) and brine (1 X 25 mL). The combined organics were dried over Na2SO, and concentrated under reduced pressure.

The crude product was purified by flash chromatography using a MeOH in CH 2 CI, solution as eluent (2.13g, 39% yield). FABMS: MH'= 136.

WO 00/37459 PCT/US99/27939 -66- Step B N N N CNN NH2 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 Et 2 0, 1.1 The reaction mixture was stirred at room temperature 3 hours and quenched by the dropwise addition of saturated Na 2 SO,. The resulting slurry was dried by the addition of solid NaSO, and filtered through a plug of Celite. The filtrate was concentrated under reduced pressure and the crude residue purified by flash chromatography using a 20% (10% NH 4 OH in MeOH) solution as eluent (0.03g, 6% yield).

PREPARATIVE EXAMPLE 11 Step A Me Me Tr-N Tr--N

CN

N

nBuLi (2.5 mL; 2.5M in hexanes; 2.1 eq.) was added to iPrNH (0.87 mL, 2.1 eq.) in THF (8.0 mL) at 0°C. The resulting solution was stirred 45 minutes before adding the nitrile (1.0g, 2.97 mmol) in THF (7.0 mL). The reaction mixture was stirred at 0°C for minutes before adding Mel (0.37 mL, 2.0 The resulting solution was warmed to room temperature and stirred one hour.

The reaction was quenched by the addition of 1N HC1 until acidic, diluted with water (40 mL) and extracted with EtOAc (2 X 200 mL).

The combined organics were dried over Na 2 SO, and concentrated under reduced pressure. The crude product was purified by flash .chromatogaphy 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 CN

NH

2 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).

The resulting solution was stirred at room temperature 1.5 hours and quenched by the dropwise addition of saturated Na 2 SO, mL). The solution was extracted with EtO (2 X 200 mL), the combined organics dried over MgSO. and concentrated under reduced pressure (0.6 g, 88% yield).

Step C Me Me

H

N H Me /Me I Tr- N NH

H

2 N N following the same procedure as set forth in Preparative Example 27 Step C, the title compound was prepared.

PREPARATIVE EXAMPLE 12 BOC

BOC

I

I

BOC O BOC O H 0- NH2 A solution of the piperazine carboxylic acid (0.29 g, 0.881 mmol) prepared as described in Preparative Example 43, Lhistidinamide dihydrochloride (0.20 g, 1.0 DEC (0.25 g, HOBT (0.18 g, 1.5 and NMM (0.48 mL, 1.5 eq.) in DMF mL) was stirred at room temperature overnight. The reaction mixture was diluted with water (25 mL) and CH 2 C1 2 (50 mL), WO 00/37459 PCT/US99/27939 -68separated, 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, solution as eluent (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 prepared: S CH 3 H2N, A .N

N

Preparative Example 13

CH

3

H

2

N

N

Preparative Example 14

H

3 C CH 3

H

2 N N

-N

Preparative Example

CH

3

CH

3

H

2 N N

N

Preparative Example 16 Preparative Example 17 and 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.

WO 00/37459 WO 0037459PCT/US99/27939 69 TABLE 2 F N H2N $H3 F N H2 F H HN N WO 00/37459 WO 0037459PCTIUS99/27939 70 23 CHO TH

N

H H3

NN

HH

NN

H kK_)N

N

>-CHO

IH

H2NN

CH

3 N

HNN

N

>-CHO

HH

N Ph N

N

Ph- Ph P Disole henPRiEPA(1.5E, 4.29 PL 2m 7 n 0mf H n coto A7C ne irgn d 0m (incycohxan).The ad dop~~eovr 2hr a oltio o (4.93 mol of2-mthyproyliclie i 10mL f H.Alwt warmstolo tepertre and g stir moverntd 10 mL of ater WO 00/37459 PCT/US99/27939 -71 followed by IN HC1 until pH of 10-11. Dilute with 100 mL of methylene chloride followed by 20 mL of sat. aqueous Na 2 SO,. Add MgSO, until solution is clear. Separate the organic layer and dry over MgSO,. Concentrate under vacuum and flash chromatograph on silica gel using ethyl acetate-hexane to give the product as a tan semi-solid.

Step B

CH

3

CH

3 C H 3

CH

3 NN H2NN N Ph Ph Phph 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 HPtCle.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.

Step C

CH

3

CH

3

CH

3

H

H

2 N 3

H

2

N.JC

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 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 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

2

N.

Halide Substituted Histamine Preparative Example 29 Halide

H

2

N.

Substituted Histamine Preparative Example 29.1

H

H

2 N N

SN

Substituted Histamine C al Cl Halide Preparative Example Halide

H

2

N

H

.N

Substituted Histamine WO 00/37459 WO 0037459PCT[US99/27939 73 PREPARATIVE EXAMPLE 31 0 0 0 "'CH 3

H

N

N

H

Ethyl 4-pyridyl acetate (4.5g, 27.24mimoles) was placed in a 500m.b Parr bottle and dissolved in anhydrous EtOH (70mb). To the bottle was added 10% Palladium on charcoal (1 The bottle was put on a hydrogenator and the contents shaken under 55 psi hydrogen pressure at 25'C for 94h. The mixture was filtered through Celite" and washed with 4x4Omb anhydrous EtOH. The filtrate was rotovapped down and the residue chromatographed on silica gel using 3% (10% conc. NH 4 0H in methanol)dichloromethane as the eluant to give the title compound (Yield: 2.944g, 63%): FABMS: m/z l72.2(MH*); 8c (CDCI,) CH,: 14.3; CH 2 33.2, 33.2, 41.9, 46.5, 46.5 60.2; CH: 33.4; C: 172.7 8 (CDC 3 1.18 (m,1H,HJ,, 1.26 (t,3H,CH)I, 1.71(2H) 1.90(LH), 1.96(1H), 2.22(d,2H), 2.63(2H), 3.07(2H), 4.13(q,2H,CH,,fl 2 PREPARATIVE EXAMPLE 32 0 0 0 CH 3 0" CH 3 N

N

0 NH 2 Ethyl 4-piperidinyl acetate from Preparative Example 31 (500mgri; 2.92mmunoles)x ws dissolved in& rnhyrou THC 2 (2m To the stirring solution was added trimethylsilyl isocyanate (5.9mb; 4 3.8mmLuoles) and the solution was stirred at 25 0 C for 17h. The WO 00/37459 WOOO/7459PCT/U599/27939 74 solution was worked up in CH.Cl 2 -saturated NaHCO, and the product chromatographed on silica gel using 2--)3%(conc. NH4O in methanol) dichloro-methane as the eluant to give the title compound (Yield: 622mg, CIMS: m/z 215.3 (MHi); 8c (CDCI 3 CH,: 14.2; CH 2 31.6, 31.6, 41.0, 44.2, 44.2, 60.4; CH: 32.9; C: 158.2, 172.4; 8,H (CDCI.,: 1.23 lH,H J, 1.27 1.75 1.98 (m,1IH), 2.26 2.85 3.94 2H), 4.15 (q,2H,CHCi 2 4.56 (bs,2H).

PREPARATIVE EXAMPLE 33 0 0 0 C 3

OH

N N 0 1 NH 2 O-N Ethyl 1 -axninocarbonyl-4-piperidinyl acetate from Preparative Example 32 (153.6mg, O.7l7mmnoles) was dissolved in anhydrous

CH

2

CL

2 (3.58mL) and EtOH (3.58mL). To the solution was added 1.OM LiGH (1.73mL, 1.73mmoles) and the mixture was stirred at for 5.5h. The mixture was cooled quickly to 25*C and L.ON HCl (2.O2mL, 2.O2mmoles) was added and the mixture stirred for minutes and then rotovapped to dryness to give the title compound which was used without further purification.

WO 00/37459 PTU9/73 PCT/US99/27939 75 PREPARATIVE EXAMPLE 34 Br C I N

Z

(NH F~N(11 -Isomer) N rN N.%

H

0 Br \NC1 CNH f (11 R,2R(-)-lsomer) N

N

H

The C, 1 -racemate of the above isomers (Preparative Example 141) (62% pure) was subjected to preparative HPLC on a Chiralpak ADO columnn (5OX5cm) using 75% hexane- 25% isopropyl alcohol- 0.2% diethylarnine as the eluant to give, in the order of elution, the 1 1-S(-)-isomer and the 1 1-R(-)-isomer.

11 S, 2R(--isomer: (Yield: 0.8756g, LCMS: m/z 543.1 8c (CDC 3 CH,: 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; 51

(CDC

3 2.02 (2H, m, 3.32 (2H, m, 3"-CH 2 3.98 (2H, dd, 1"-

CH

2 4.30 (lH, s, H, 1 6.93 (LH, s, Im-H 5 6.97 (LH, t, CONHCH 2 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-HJd, 7.57 (lH. d, Im-H 2 and 8.33 ppm. (1H, s, Ar-H 2 [aD 2 o-c -45.00 (MeOH, c=9.32mg/2mL).

11 R, 2R(--isomer: (Yield: 0.5979g, LCMS: m/z 543.1 (Mi-l; 6c (CDC) CH- 2 30.2, 30.3, 31.1, 36.4, 44.1, 44.7, 52.2, 54.0; 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; 811 WO 00/37459 WO 0037459PCTIUS99/27939 76

(ODCI

3 3.34 (2H, m, 3"-CH 2 3.97 (2H, dd, Il"-CH 2 4.30 (I1H, s, 6.93 (1 H, s, 7.06 (1H, s, Im-H 4 7.08 (1 H, s, Ar-H), 7. 11 (2H, s, Ar-H), 7.14 (1H, s, Ar-H), 7.15 (1H, t, CONHCH 2 7.50 (1 H, s, Ar-H 1 0 7.58 (1H, d, Im-H 2 and 8.35 ppm (1H, s, Ar-H 2 [aJD3'C 12.00 (MeGH, c= 10.l19mg/2mL).

PREPARATIVE EXAMPLE Step A 0 OH 0 OH N

N

H

I

Boc Isonipecotic acid (10g, 77.42mmoles) and sodium hydroxide (3.097g, 77.42mxnoles) were dissolved in THF-water 1) (230mL) and di-t-butyldicarbonate (18.59mL, 85. l7mmoles) was added. The solution was stirred at 250C for 90h. The mixture was treated with BioRado 50W-X4(H*) ion exchange resin (86.6mL) and the resin was 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 8, (d, 6 -DMSO) OH 3 28.0, 28.0, 28.0; OH 2 42.0-43. 1(broad signal); OH: obscured; C: 78.5, 153.8, 175.6.

Step B O OH 0 N

NN

I

I

Boc B o The title compound from Step A above (2g, 8.72mmoles) was dissolved in dry DMF (4OmL) and the solution was stirreda at 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°C for lh and then at 25°C for 19h. Evaporation to dryness followed by chromatography on a silica gel column using 5% increasing to 7% methanol in dichloromethane afforded the title compound: (Yield: 1.57g, 8c (CDC 3

CH

3 28.5, 28.5, 28.5; CH,: 32.9 (broad), 42.8 (broad); CH: 47.3; C: 79.7, 154.8, 156.5.

PREPARATIVE EXAMPLE 36 Step A OH

OH

N N

H

H

2 N 0 Method 1: 4-Hydroxypiperidine (5g, 49.43mmoles) was dissolved in anhydrous dichloromethane (50mL) and trimethylsilyl isocyanate (6.27g, 7.36mL, 54.38mmoles) was added. The mixture was stirred at 25°C 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.

NH40H in methanol)-dichloromethane as the eluent to give the title compound: (Yield: 6.895g, CIMS: m/z 145.1 8c (ds- DMSO) CH 2 34.2, 34.2, 41.3, 41.3; CH: 66.1; C: 158.0; 6 H (d 6 DMSO) 1.22 (2H, m, 1.68 (2H, m, 2.84 (2H, m, 3.60 (1H, m, 4-CH), 3.68 (2H, m, 4.67 (1H, d, 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°C for 67h. The solution was evaporated to dryness and the product was chromatographed on a silica gel column using 10%(10% cone. NH 4 OH in methanol)-dichloromethane as the eluent to give the title compound: (Yield: 8.3g, 58%).

Step B 0 NO 2 OH O O< 0 N N

H

2 N O

H

2 N 0 The title compound from Step A above (Ig, 6.94mmoles) and 4-nitrophenyl chloroformate (1.54g, 7.63mmoles) were dissolved in anhydrous pyridine (10mL) and the mixture was stirred at 25°C for 24h. The mixture was evaporated to dryness and the residue was 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, CIMS: m/z 310.05 5c (CDC1 3 CH,: 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, 158.7; 86 (CDC13) 1.82 (2H, m, 2.01 (2H, m, 3.06 (2H, s, 3.31 (2H, m, 3.68 (2H, m, 2/6-CH 4.98 (1H, m, 4-CH), 7.39 (2H, d, Ar-H1/6) and 8.28ppm (2H, d, Ar- WO 00/37459 WO 0037459PCT[US99/27939 79 PREPARATIVE EXAMPLE 37 StepA Boc Boc N N (Ni K)

H

>N H The anhydride (0.5088g, 1.99mmoles) (prepared as described in Preparative Example 44) and 1 -(3-ammnopropyl)-imiidazole (0.26OmL, 2. l8mmoles) were dissolved in anhydrous dichioromethane (1 OmL) and the mixture was stirred under argon at for 5min. The mixture was diluted with dichloromethane and extracted with saturated aqueous sodium bicarbonate. The dichloromethane layer was dried (MgSO 4 filtered and evaporated to dryness. The resulting product was chromatographed on a silica gel column using 10% (cone, NHO in methanol) -dichloromethane as the eluent to give the title compound: (Yield: 0.4955g, LCMS: m/z 338.1 8c (CDC 3 28.4, 28.4, 28.4; CH 2 31.1, 36.5, ~43.5(broad), 44.8, -46.5(broad),; CH: 58.2, -119.0(broad), '-129.7(broad), -1-37.3(broad); C: 80.2, 154.7, 171.5; 51j (CDC1 3 1.47 O9H, s, CH 3 6.96 (1H. s, 7.08 (LH, s, Im-H 4 and 7.52ppm (1H, s, Im-H 2 Step B Boc

N

00 The title compound fromn S3tep A above (032"48a, 0 QOR,,nLIs 4-pyr-idylacetic acid Ni-oxNide 19 16g, 1.25mmoles), 113- (diniAethiylam-rinoc))propyll -3'-ethLjyicarbodirnide hydrochloride 24g, WO 00/37459 PCT/US99/7939 1.25mmoles), 1-hydroxybenzotriazole (0.169g, 1.25mmoles) and 4methylmorpholine (0.1376mL, 1.25mmoles) were dissolved in anhydrous DMF (1 mL) and the mixture was stirred under argon at for 18h. The mixture was evaporated to dryness and the 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% cone.

NH

4 OH in methanol)-dichloromethane as the eluant to give the title compound: (Yield: 0.4333g, LCMS: m/z 473.1 8c (CDCl 3 CH,: 28.3, 28.3, 28.3; CH,: 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; 85 (CDC1 3 1.44 (9H, s, 6.97 (1H, broad s, Im-H,), 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

No, 0 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 25 0 C for 1.25h under argon and then evaporated to dryness. The product was chromatographed on a silica gel column using 5% increasing to 10% (10% cone. NH 4 OH in methanol)dichloromethane as the eluant to give the title compound: (Yield: 0.208g, LCMS: m/z 373.1 6c (CDCl 3

-CD

3 OD) CH,: 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; (CDCl 3

-CD

3 OD) 6.90 (1H, broad s, Im-H), 6.94 (1H, broad s, 7.22 (2H, m, Ar-H), 7.47 (1H, broad s, Im-H 2 and 8.12ppm (2H, d, Ar-H); [a]D 2 6 3 '+81.10 (c=10.43mg/2mL, methanol).

PREPARATIVE EXAMPLE 38 Step A B r

C

1 Br C C 1 N

N-

0 O- o To a solution of 3 -bromo-8-chloro-5,6-dihydro-11Hbenzo[5,6]cyclohepta[ 1,2-bjpyridin- 11-one (2g) (6.2mmoles) in anhydrous dichloromethane (14ml) at 0°C and under an argon atmosphere, was added a solution of 3-chloroperbenzoic acid (1.76g) (10.4mmoles) in anhydrous dichloromethane dropwise over a period of 30 minutes. The mixture was allowed to warm to room temperature and after 18h additional 3-chloroperbenzoic acid (0.88g) (5.2mmoles) in anhydrous dichloro-methane 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 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. NH40H in methanol)dichloromethane as the eluant to give the title compound (Yield:1.386g, ESIMS; m/z 338.1 8c (CDCI3) 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, 188.0ppm.

WO 00/37459 PCT/US99/27939 82- Step B Br /C Br C N+ N I I O OH 0 0 The title compound of Step A (1.3422g) (3.96mmoles) was dissolved in methanol (18ml) and dichloromethane (20ml) and sodium borohydride (0.219g) (5.79mmoles) was added. The mixture was stirred under argon at O'C for lh and then allowed to warm up to 25 0 C over a period of lh. The mixture was diluted with dichloromethane (800ml) and washed with 1N NaOH (150ml). The aqueous layer was extracted with dichloromethane (2X100ml) and the combined organic layers were dried over magnesium sulfate, filtered and evaporated to dryness. The product was chromatographed on silica gel using 1% (10% cone. NH40H in methanol)dichloro-methane as the eluant to give the title compound (Yield: 1.24g, ESIMS: m/z 340.1 6 c (CDCl3) CH2: 31.2, 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

OC H

N

H

N

0 The title compound from Step B (0.552g, 1.62mmoles) and Lriethyl-amnine (1.19 mL R.52pm o1es) were dissov-ed in -hadrous c is I nhx.,d n! dichloromethane (8.5mL) and the solution was cooled to OOC.

Ivethanesulfonyl chloride (0.4mL, 5.16mmoles) was added over WO 00/37459 PCTIUS99/27939 83 and the mixture was stirred at 0°C 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 was stirred at 0°C. N-[3-(1H-Imidazol-l-yl)propyl]-2(R)piperazinecarboxamide (Preparative Example 136) 2.1 Immoles) dissolved in anhydrous dichloromethane (20mL) and anhydrous DMF (20mL) was added at 0°C and the solution was stirred and allowed to warm up to 25 0 C over 2h. The reaction was allowed to proceed at 25 0 C 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% cone. NH 4 OH in methanol)-dichloro-methane as the eluant to give the title racemic compound: Yield: 0.399g, FABMS: m/z 559.3 (MH).

Step D H N (11R,2R(+)-Isomer) NN N Br C1 N H N (11S,2R(--Isomer) H II 0 WO 00/37459 PTU9/73 PCTIUS99/27939 -84- The title racemnic compound from Step C above (0.395g) was subjected to preparative HPLC on a Chiralpak ADO column using 65% hexane- 35% isopropyl alcohol- 0.2% diethylanune as the eluant to give in the order of elution the I11- -diastereoisomer of the title compound followed by the I11 diastereoisomer of the title compound.

11 R,2R(+)-diastereojsomer: (Yield: 0. 1854g); FABMS: m/z 559.2 8. (CDCI,) 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, 137.3, 138.4; C: 118.2, 133.6, 134.6, 140.1, 141.0, 148.1, 172.0; 511 (CDC 3 5.70 (1H, s, 6.95 (1 H, broad s, lm-H)j, 7.04 (1H, broad s, Im-H 4 7.51 (1H, broad s, Im-H 2 and 8 .22ppm (lH, s, Ar-H 2 20 +41.20 1 1.08mg/2m-L, methanol).

I1lS, 2 R(-)-diastereoisomer: (Yield: 0. 18g); FABMS: m/z 559.2 8, (CDC 3

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; 51f

(CDC

3 5.69 (1H, s, 6.94 (1H, broad s, Im-H 5 7.07 (1H, broad s, Im-H 4 7.51 (1H, broad s, Im-H 2 and 8.26ppm (1H, s, Ar-H 2 [a1D' 99 71.0' 10.32mg/2rnL, methanol).

PREPARATI-VE EXAMPLE 39 StepA 0 0

CH

3 0 1 CH 3 N

N

H

Ethyl 4-pyridyl acetate (4.5g, 27.24mmuoles) was placed in a SO0m.L Parr bottle and dissolved in anhydrous EtOH (7OmL). Palladium on charcoal (1-0g) was added and the contents shaken under 55 psi hydrogen pressure at 2500 for 94h. The mixture was WO 00/37459 WO 0037459PCT/US99/27939 85 filtered through Celiteo and washed with 4x4OmL an-hydrous EtOH.

The filtrate was evaporated to dryness and the residue was chromatographed on silica gel using 3% (10% cone. NH 4 0H in methanol) -dichloromethane as the eluant to give the title compound: (Yield: 2.944g, FABMS: m/z 172.2 8C

(CDC

3 CH,: 14.3; CH 2 33.2, 33.2, 41.9, 46.5, 46.5 60.2; CH: 33.4; C: 172.7 5H (CDCl 3 1. 18 (1H, m, H 4 1.26 t,CH 3 1. 71(2H), 1.90(1H), 1.96(1H), 2.22(2H, 2.63(2H), 3.07(2H), 4.l3ppm (2H, q, CH CH 2 Step B 0 0 0- CH 3 0 CH 3 N

N

N2 Ethyl 4-piperidinyl acetate (500mg; 2.92mmoles) from Step A above was dissolved in anhydrous dichloromethane (25mL). To the stirred solution was added trimethylsilyl isocyanate (5.9mb; 43.8mmoles) and the solution was stirred at 25'C for 17h. The solution was diluted with dichioromethane and washed with saturated aqueous sodium bicarbonate. The dichioromethane layer was dried (MgSOJ., filtered and evaporated to dryness. The product was chromatographed on silica gel using 2% increasing to 3%(10% cone. NH 4 0H in methanol) -dichloromethane as the eluant to give the title compound: (Yield: 622mg, CIMS: m/z 215.3 8, (CDC1I: 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 (CDCLJ: 1.23 (1H, m, H 4 1.27 (3H, t, CH 3 1.75 (2H, 1.98 (1H, in), 2.26 (2H, 2.85 (2H, 3.94 (2H, d), 4.15 (2H, q, CH CHA, 4.56 (2H. bs).

WO 00/37459 WO 0037459PCT[US99/27939 86 StepC 0 0 ICH 3 OH N

N

0 -5kNH 2 0OJ< NH 2 Ethyl I1-aminocarbonyl-4-piperidinyl acetate (153.6mg, 0.71 7mmoles) from Step B above was dissolved in anhydrous dichioromethane (3.58mL) and ethanol (3.58mL). To the solution was added 1.OM LiGH (1.73mL, 1.73mmoles) and the mixture was stirred at 5000 for 5.5h. The mixture was cooled quickly to 2500 and L.ON HCl (2.O2mL, 2.O2mmoles) was added and the mixture stirred for 5 minutes and then evaporated to dryness to give the title compound, which was used without further purification.

PREPARATI'VE EXAMPLE StepA 0 0 OH 3 Y [<OH 3 0CHN l CH H2 N .I r-/ (DO0 The title compound from Preparative Example 37, Step A above (0.45g, 1 .33mmoles), 1 [3-(dimnethylamino)propyll-3ethylcarbodimride hydrochloride (0.332g, 1.73mmoles), 1hydroxybenzotriazole (0.234g, 1 .73mmoles) and 4-methylmrp-ho inIc (0.3S2mL, 3.46mno1ec :Trj c%-r DMF (7mL). The title compound from Preparative Example 33, Step C above (0.3228g, 1. 7 3mxnoles) dissolved in anhydrous DMF (8mb) WO 00/37459 PCT/US99/27939 -87was added and the mixture was stirred at 25°C for 22h. The solution was evaporated to dryness and the residue was taken up in dichloromethane and washed with saturated aqueous sodium bicarbonate, dried (MgSO 4 filtered and evaporated to dryness. The residue was chromatographed on a silica gel column using 5% cone. NH 4 OH in methanol)-dichloromethane as the eluant to give the title compound: (Yield: 0.3553g, 53%).

Step B

H

N

C H KN 2 O

N

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

H,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 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 (10% cone. NH4OH in methanol)dichloro-methane as the eluant to give the title compound: (Yield: 0.317g, FABMS: m/z 406.2 8c (CDC1 3 CD3OD) CIH: 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; 6H (CDC 3 2.86% CD 3 OD) 4.84 (1H, d, H2), 6.96 (1H, broad s, Im-H), 7.04 (1H, broad s, Im-H 4 and 7.53ppm (1H, broad s, Im-H).

WO 00/37459 PCT/US99/27939 -88- PREPARATIVE EXAMPLE Step A Br Cl Br CJ N

NI

N

N

(52.i) CO 2 ET (52.ii) H A solution of 52.i Med. Chem. 4890-4902 (1988))(205 g) in cone. HCI (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 the extracts are washed with brine, dried and evaporated to afford 52.ii (166 g).

Step B Br C Br Cl

NH

N

N

(52.ii) H 52.0) H A 1M solution of DIBAL in toluene (908 mL) is added dropwise during 2h to a solution of 52.ii (166 g) in toluene (4 L) at rt. followed by stirring for 18 h. The mixture is cooled to 0-5°C and stirred for lh and extracted with IN HC1 (2 The aqueous extract is basified to pH 10 with 50% NaOH and extracted with EtOAc 3x2 The extracts are evaporated and chromatographed on silica-gel (1 Kg).

Elution with 10% MeOH/CH 2

CI

2 affords the title compound 52.0 (104 HRMS (FAB) calcd for C 1 ,H21,N 2 BrC1 393.0556, found 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°C with the UVdetector set at 290 nm. Elution with 0.05% diethylamine-methanol affords: Peak 1 52.0 (40 -28.4° (c 0.3, MeOH); Further elution with the same solvent affords: Peak 2 52.0 (42 [a] +27.5° (c 0.3, MeOH).

PREPARATIVE EXAMPLE 41 Step A Br C

C

N c l N H H N

N

(53.0) o

H

2

N

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

MS(FAB): m/z 510 WO 00/37459 PCT/US99/27939 Step B Br Br NC

C

(53.0)

H

3 CO N N OCH3 (54.0a) o 0 (54.0b) A solution of 53.0 (3.1 g) and sodium nitrite (0.8 g) in methanol (500 ml) is stirred at r.t. under nitrogen with cuprous chloride (0.15 g) while adding dropwise over 10 minutes a 4M hydrochloric acid/dioxane solution (3.9 ml). The reaction mixture is stirred for 24hrs followed by the addition of 10% sodium carbonate to pH 8, concentrated under reduced pressure, diluted with water (200 ml) and extracted with dichloromethane (4x100ml).

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 54.0b as an off-white amorphous solid (2.97 'H NMR (CDCI,, 300 MHz) d 3.30 3H); MS (FAB) m/e 525 (MH).

Steps C-E Br<\ C Br-

C

(54.0a) C-E N N '9 H H (54.0b) HOOC N N COOH (57.0a) I (57.0b) COOt-Bu COOt-Bu COOt-Bu A solution of 54.0a and 54.0b (17 g) in methanol (150 ml) and 2N hydrochloric acid (170 ml) and cone. HCI (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 The reaction is stirred for 2 h, diluted with dichloromethane (300 ml) and filtered. The filtrate is evaporated and the residue is dissolved in cone HC1 (150 ml) and the mixture is heated in an oil bath (120 0 C) for 4h and is then evaporated under reduced pressure. The residue is dissolved in THF (100 ml) and NaOH (30 ml) is added to pH>8 followed by the dropwise 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 is purified by flash chromatography to afford the mixture of 57.0a and 57.0b as light tan solid that appears as a single tlc spot (16 g).

'H NMR (CDCl 3 300 MHz) d 1.40 9H); MS (FAB) m/z 535 (MH).

The single tlc spot is a mixture of four isomers which are separated after derivatization into the compounds of Examples 77 to 79 and 87 to 97 below.

Following the above procedure (Steps except using Compound (17 a mixture of 58.0a and 58.0b is obtained as a light solid that appears as a single tic spot (17 MS(ES) m/z 535 PREPARATIVE EXAMPLE 42

H

N

N *2Camphorsulfonic acid

OH

To 2.5 kg of (R)-(-)-camphorsulfonic acid stirring at 60°C 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 gm, 3.35 mol). The mixture was allowed to stir at 95 0 C 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 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. 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 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 solution. To this solution was added di-tert-butyl-dicarbonate (336 gm, 1.54 mol) as a solid. The pH dropped to The pH of the reaction mixture was maintained at 9.5 with 50% NaOH (total of 175 ml), and the reaction mixture stirred for 2.5 hours to obtain a white precipitate. The reaction mixture was diluted 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 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

0 0 To an ice cold solution N,N-dimethylformamide (49.6 ml) was added, dropwise, thionylchloride (46.7 ml) over a period of 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-Rcarboxyl-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, 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 of the title product as a white solid.

WO 00/37459 PCT/US99/27939 -94- PREPARATIVE EXAMPLE

CN

Boc NH N 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 methanol/dichloromethane as the eluent. After the reaction went to completion hour), 0.25 m i (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 The dichloromethane layers were combined, dried over MgSO, filtered and evaporated to dryness. The residue was chromatographed on a flash column of silica gel using methanol/dichloromethane to obtain 0.714 gm of pure title compound as a solid. FABMS (M+1)=564.

WO 00/37459 PCT/US99/27939 PREPARATIVE EXAMPLE 46 0

N

O HO N o \N N-(2,3-Epoxypropyl)phthalimide (2.3 gm, 11.3 mmol) was dissolved in N,N-dimethylformamide and imidazole (1.53 gm, eq.) was added and the reaction mixture stirred at 90 oC for 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 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 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 H O (N N

HN-

1-Amino-2-hydroxy-3-1 -H-imidazole-propane (from Preparative Example 47) (2.2 mmol) was added to a solution of the Boc-anhydride (Preparative Example 44) (0.57gm, 2.2 mmol) in 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 tic using methanol/dichloromethane as the eluent. After the reaction went to completion 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 The dichloromethane layers were combined, dried over MgSO 4 filtered and evaporated to dryness. The residue was chromatographed on a flash column of silica gel using methanol/dichloromethane to obtain 0.487 gm of pure title compound as a solid.

WO 00/37459 PCT/US99/27939 -97- PREPARATIVE EXAMPLE 49 I O Boc 2-Carboxy-piperazine-dicamphorsulfonic acid salt (Preparative Example 42) (17.85 gm, 30 mmole) was dissolved in 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 0-5'C in an ice-MeOH bath and a solution of benzylchloroformate (4.28 mL, 30 mmol) in 80 mL of dioxane was added over a period of 30-45 minutes while stirring at 0-5°C and keeping the pH at 10.5 to 11.0 with 50% NaOH. After the addition was complete, stirring was continued for 1 hr. The reaction mixture was then 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 washed with 3X180 mL of ethyl acetate (The ethyl acetate was dried over MgSO filtered, and evaporated to obtain N,N-di-CBZ-2carboxy-piperazine and saved). The pH of the aqueous layer, which contains the desired product, was adjusted to 10.5 to 11.0 with NaOH and solid di-tert-butyl-dicarbonate (7.86 gm, 36 mmol) 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 EtO. The aqueous layer was cooled in an ice bath and adjusted pH to 2.0 with IN HCI (slowly). Extract the product with 3X200 mL of ethyl acetate. Dry over MgSO, filter and evaporate to obtain 9.68 gm of pure product as a white solid.

WO 00/37459 PCTIUS997939 -98- PREPARATIVE EXAMPLE

H

N

N

OH

I T 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 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, for 18 hours.

After 18 hrs, the reaction mixture had a precipitate. The tli was checked (30% MeOH/NH,/CHC1 2 The reaction mixture was 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 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 1

CI

N

H3 N

OH

CH3

H

3 C 0 0 The tricyclic alcohol (Preparative Example 40 in WO 95/10516) WO 00/37459 PCT/US99/27939 -99- Br c 0 1

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 an aliquot of the reaction mixture to 1N 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 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, 1N-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 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.

The solid was chromatographed on a 1 1/2" X 14" column of silica gel eluting with 2L of 0.4% 7N MeOH/NH 3

:CH

2 C1, 6L of 0.5% 7N MeOH/-NH 3

:CH

2 C1 2 2L of 0.65% 7N MeOH/NH 3

:CH

2 C2, 2L of 0.8% 7N MeOH/NH 3

:CH

2

C

2 4L of 1% 7N MeOH/NH 3

:CH

2 C1, 2L of 3% 2N MeOH/NH 3

:CHCL

2 2L of 5% 2N MeOH/NH 3

:CH

2

C

2 2L of 10% 2N MeOH/NH 3

:CHC

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

:CH

2

C

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

:CH

2 CL to obtain 4.63 gm of final product.

WO 00/37459 PCT/US99/27939 -100- PREPARATIVE EXAMPLE 52 Br

CI

N

N

NC, N

OH

O O\ 0

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 (0.214ml, 1.5 DEC (0.71 gm, 2 HOBT (0.5 gm, 2 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 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 of pure title compound.

PREPARATIVE EXAMPLE 53 0

N

IN

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 stirred for 1 hour. N-(3-Bromopropyl)-phthalimide (16g, 74 mmol) was added and the reaction mixture stirred for 1/2 hour at 0°C, 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.

PREPARATIVE EXAMPLE 54

N

H

2 N N 2HCI NH 2 gm of 1-phthalimidopropyl-2-aminoimidazole (from Preparative Example 53) was refluxed in 20 ml of 6N HC1 for 6 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 Boc N H

N

Boc N NH2 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 1-hydroxybenzotriazole (0.135 gm), and N-methylmorpholine (0.54 ml) was added and the reaction mixture stirred for 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 H

N

N N

N

Boc

HN

0 CBZ 1-Aminopropyl-2-aminoimidazolyl-N 1,N4-di-tert.butyl-1,2(R)piperazinedicarboxamide (Preparative Example 55) (0.38gm) was 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 eluent to obtain 0.39 gm of title product. FABMS M+1=587.3.

PREPARATIVE EXAMPLE 57

H

<N H N N N. N N H 2TFA HN 0 CBZ 1 -benzyloxycarbonylaminopropyl-2-aminoimidazolyl-N 1,N4di-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.

WO 00/37459 PCT/US99/7939 103- PREPARATIVE EXAMPLE 58 Br C1

N

N H

N

N N

N

N HN

CBZ

1 -benzyloxycarbonylaminopropyl-2-aminoimidazolyl- 1,2(R)piperazinedicarboxamide (Preparative Example 57) was dissolved in ml of DMF and 0.46 ml of triethylamine. 3-Bromo-8,11dichloro-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 dichloromethane to obtain 82 mg of pure title product after silica gel chromatography using methanol/dichloro-methane as the eluent.

FABMS 694.

PREPARATIVE EXAMPLE 59 Boc-NH -N

-OH

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 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 laver was WO 00/37459 PCT/US99/27939 104evaporated to obtain a gum which was chromatographed on silica gel to obtain 0.54 gm of title product. (MH 170).

PREPARATIVE EXAMPLE HzN N/

-OH

H

3

C

3 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.

PREPARATIVE EXAMPLE 61 /7NH

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 added while stirring. After 15 min. N-Boc-phenylalanine aldehyde 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 blocked product. FABMS 561. This was then treated with 4M HCl/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 WO 0037459PCT/US99/27939 105 PREPARATIVE EXAMPLE 62 Step A 0 I Br 0 Me Me 0 HNeN0 Me 0 A mixture of N-(3-bromopropyl)phthalim-ide (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 dichioromethane, filtered, concentrated in vacuo and purified by flash column chromatography (silica gel) using 1% MeOH-CH 2

CI

2 saturated with aqueous ammonium hydroxNide to give the title compound as an oil (8.04 g, 65%, MH+ 270).

Step B Me rN

N

0 Me> /Me

H

2 N N To a solution of the title coirpoound from Step A (8.02 g. 29.8 mniol) dissolved in absolute EtOH (150 mL) was added hydrazineinono hydrate (15 rnL) and the mixture was stirred at reflux for 12 hI- WO 00/37459 PCT/US99/27939 106under 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

CI

2 saturated with aqueous ammonium hydroxide to give the title 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 4methylimidazole in Step A, the amines (Product) listed in Table 3 were prepared.

TABLE 3 Prep. Imidazole Product MH' Yield Ex. 63 Me Me H.N N HzNN N N Me Me Me 154 Me 64 H 3 C CH3 SN N

H

2 N %N N

H

H3 154

H

2 N. N WO 00/37459 PCT/US99/27939 -107- HN N H2N'

PN,

CH

3

CH

3 154 61 66 H"N

H

2 N N N 140 41 Me Me 66.1 H 8( MH' 266.1657 PREPARATIVE EXAMPLE 67 If the procedure set forth in Preparative Example 62 were followed, except the imidazole

H

3 C

CH

3 HN

N

would be used instead of 4-methylimidazole in Step A, the amine

H

3 C CH3

H

2 N N, N would be obtained.

PREPARATIVE EXAMPLE 67.1 If the procedure set forth in Preparative Example 62 were followed, except the imidazole M Me H 1N1

N

WO 00/37459 PCT/US99/27939 108would be used instead of 4-methylimidazole in Step A, the amine Me Me H2N

N

would be obtained.

PREPARATIVE EXAMPLE 68 Me Me

H

2 N N#N

N

HCI Me

H

2 N ,C HN N Me Me

H

2 N 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 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).

PREPARATIVE EXAMPLES 69-73 Following the procedure set forth in Preparative Example 68, but using the substituted imidazole or triazole in Table 4 below instead of 2,4-dimethylimidazole, the amines (Product) listed in Table 4 were prepared.

WO 00/37459 PCT/US99/27939 109- TABLE 4 Prep. Imidazole Product MH' Yield Ex. 69 Me Me HN, N

H

2 N- N N 126 Me

H

2 N N- N: N ,NN H2N N H 112 71 N N HN

H

2 N N. N 176 Me Me 72

H'N

N H 126 53 73 Me 73

(A)

/N N- N

H

2 N N H N N 163 N

(B)

HN n 2 __163 PREPARATIVE EXAMPLE 74 oH -H2N N N N N H N,4, N^ A mixture of 1-(3-aminopropyl)imidazole (37.1 g, 297 mmol), benzaldehyde (30 g, 283 mmol), 3A molecular sieves (50 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 -110cooled to 0°C 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 which was diluted with dichloro-methane and washed with 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).

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.

TABLE Prep Aldehyde Imidazole Product Ex. Yield

(MH+)

7 5 F H2N N N 46 SH (234)

N

76 0 H 2N 9 91 H N11fNN F-^H N (234) 77 oN r 7 H NN 74 H (217) H- r

N

WO 00/37459 PCTIUS99/27939 ill WO 00/37459 WO 0037459PCTIUS99/27939 112 860 Me rN 62

H

2 N\r Nu Me (239) Me Hf N

H

2 N N 87 0 H2N~N~H~N AH 'N(f~J(202)

HN.N'

88 0 H 2 N~ 6 H Me (244) Mee 89 0 HM NMe 86

H

2 N (244) MMe N T N Me N- N 0 Me rme

T

Me 0 Me F83

H

2 N f- FQ N HN 1 Me (248) Me H-Ns, N,.,N H2N

H-

91 0 Me Me

I~~HH

2 N A HN (244) <Me -C ____IH2N 14H-__ WO 00/37459 PCT/US99/27939 -113- I r CrH Me

H

2 N~ H2N 10 Me

'"N

f Me HN

=N

r N 44 (216) HN N Me

H'=N

94 OH H2N95 N -N N H T (230) MeMe N H 2 N N- 68 HN N H N

N

PREPARATIVE EXAMPLE 95.1 Step A \0 Me 0 M N N 0 N N o NN To a CH 2 C1l (500 mL) solution of the title compound from Preparative Example 62 Step A (65.7 g) cooled to o0C was added trityl chloride (27.2 The resulting mixture was warmed to and stirred at room temperature for 1.5 hr, then concentrated in vacuo 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 SMe Me M H H2N O N NrN N N Following essentially the same procedure as that described in Preparative Example 62 Step B except using the pure 4methylimidazole product from Preparative Example 95.1 Step A (35.02 the title compound was afforded (16.12 g, MH 140).

Step C

H

2 N e Me N N H N N N Following essentially the same procedure as that described in Preparative Example 74 except using the pure 4methylimidazolepropylamine product from Preparative Example 95.1 Step B above (16.12 g) instead of 1-(3-aminopropyl)imidazole, the title compound was afforded (18.03 g, MH' 230).

PREPARATIVE EXAMPLE 97 CN

CONH

2 H-N N H H N N A mixture of the title compound from Preparative Example 82 (0.50 g, 2.1 mmol), absolute EtOH (50 mL), 30% hydrogen peroxide (aq) (0.45 mL, 4.4 mmol) and 1M NaOH (aq) (4.4 mL, 4.4 mmol) was stirred at 50 C for 12 h. The mixture was concentrated in vacuo and purified by flash column chromatography (silica gel) using WO 00/37459 PCT/US99/27939 -115- MeOH-CH2Cl2 saturated with aqueous ammonium hydroxide to give the title compound as an oil (0.33 g, 61%, MH+ 259).

PREPARATIVE EXAMPLE 98 C +N N N+ HN N N To a cooled 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 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 compound as an oil (1.8 g, 45%, MH 244).

PREPARATIVE EXAMPLE 99 0 1 -N =1 N H '--NVN H N To a refluxing solution of the title compound from Preparative 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 (1N) was added dropwise until the reaction mixture was determined to be acidic (pH paper). The 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 an oil (0.25 g, 52%, MH+ 230).

PREPARATIVE EXAMPLE 100 Me

O

H

2

N

CI Me_ H"

NN

To a cooled solution of the title compound from 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 1M HC1 (aq) and the aqueous phase was basified with IN aqueous NaOH. This phase was extracted with CH2C12 and dried over anhydrous MgS04 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 B Me -N H-N i H N

^-N

S Me Me Me N H =N H~ -N ,NN H

NN

To a refluxing solution of the title compound from Preparative Example 100 (0.66 g, 2.5 mmol) dissolved in anhydrous THF mL) was added borane-THF complex (5 mL, 1M 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 aqueous NaOH and extracted with CH 2 C12 and dried over 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 (Chiralpack AD, 5 cm X 50 cm column, flow rate 80 mL/min, 5-8% IPA-Hexane diethylamine).

PREPARATIVE EXAMPLE 101.1 If the procedure of Preparative Example 100 were followed, but the compound N

N

C

WO 00/37459 PCTIUS99/7939 118was to be reacted with the title compound from Preparative Example 62 Step B, then the Product

N

N CH 3 H N N/ would be obtained.

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

H N C H 3 rN would be obtained=.

PREPARATIVE EXAMPLE 102 Step A O

CF

3 H2N NY N

N

N, N To a cooled solution of 1-(3-aminopropyl)imidazole (10 g, mmol) and triethylamine (17.1 mL, 120 mmol) dissolved in anhydrous CH 2 C12 (50 mL) was added trifluoroacetic anhydride (12.4 mL, 88 mmol). The mixture was warmed to and stirred at 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

SCF

3 F3 N N H N N Me' N N N To the title compound from Step A (0.24 g, 1.1 mmol) dissolved in anhydrous DMF (10 mL) was added solid sodium 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 over anhydrous MgSO 4 filtered and concentrated in vacuo to give an oil (0.28 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).

Step C O CF 3 I H MeNN Me /=1 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 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).

WO 00/37459 PCT/US99/27939 120- PREPARATIVE EXAMPLE 103 O CF 3 Et N N ,N N N\ Following a similar procedure as that used for the preparation of the title compounds from Preparative Example 102 Steps B-C, but using ethyl iodide instead of methyl iodide, the ethyl amine was obtained as an oil (893 mg, 43%, MH+ 154).

PREPARATIVE EXAMPLE 104

OCF

3

H-'N

\-N-NN

I

NfN Pr=propyl 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).

PREPARATIVE EXAMPLE 105 (Alternative Procedure to Preparative Example 74 0 CF 3 -N H\ HN F-= N N

N

Following a similar procedure as that used for the preparation of the title compounds from Preparative Example 102 Steps B-C, 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 r N H -N C I NM N N

N

OO H O A mixture of the title compound from Preparative Example 74 (1.34 g, 6.2 mmol), the title compound from Preparative Example 44 (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 mixture was extracted with CH 2 C12. 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 C1 2 saturated with aqueous ammonium hydroxide to give the title compound as an oil (520 mg, 26%, MH 328).

PREPARATIVE EXAMPLE 107 Me 0 0O H Me Me N N 0N H 0 Using the procedure described for Preparative Example 106, 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 Cl

C

N- N NN 1=1 H0 0 0 N4N Using the procedure described for Preparative Example 110 (below), but using the title compound from Preparative Example 107 (146 mg, 0.55 mmol), and the 8-Cl-tricyclic chloride (see Preparative Example 7 in WO 95/10516) Cl (159 mg, 0.46 mmol), the title compounds were prepared and separated by preparative plate chromatography (silica gel) using 2% 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 Cl Br Cl Br ,C rT r

N

Me N-NN Me O N N N Me 00 H H N H 0 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 C12, washed with a saturated aqueous solution of NaH.r-,^ a- dricd 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 column, flow rate 80 mL/min., 99.8% MeOH 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 109.3°C; MH+ 633; [(a 20 D= -66.20 (3.93 mg/2 mL MeOH).

Physical chemical data 11R,2R diastereomer B: mp 64.5°C; MH 633; [a]2 0 D= -41.8° (4.69 mg/2 mL MeOH).

PREPARATIVE EXAMPLE 110 (Alternative procedure to Preparative Example 109) HBr cI Br CI S+

N

N' N r- N v N_ ^N N N N H N 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 C12 mL) was stirred at room temperature overnight. The reaction mixture was concentrated in vacuo and purified by flash column chromatography (silica gel) using 2% MeOH-98% CH 2 C12 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 AD, 5 cm X 50 cm column, flow rate 80 mL/min., 99.8% MeOH diethylamine) to give 182 mg of diastereomer A and 126 mg of diastereomer B.

WO 00/37459 PCT[US99/27939 124- PREPARATIVE EXAMPLE 111 N N N fH 0

H

A mixture of the title compound from Preparative Example 106 (1.93 g, 5.9 mmol), the 8-Cl-tricyclic chloride (see Preparative Example 7 in W095/10516) (1.56 g, 5.9 mmol), triethylamine (4.1 mL, 29.5 mmol) and CH 2 C12 (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 C12 saturated with aqueous ammonium 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 g of the 11R,2R diastereomer B.

PREPARATIVE EXAMPLE 111.1 Follow the procedure of Preparative Example 111, but use the chloride

N

C1 C1 to obtain WO 00/37459 PCT/US99/27939 125 N C1

N

H O PREPARATIVE EXAMPLE 112 N Me N Me

'CO

2 H -N OO H NN' N ON 0 0 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 diethylamine), 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 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 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 C1

N

H0 \-N BrV C1 -N fN'

N--

N

;IX P 0' Using the procedure described for Preparative Example 109, but using the title compound from Example 126 below, the title compounds were prepared and separated: 11S,2R(-)- diastereomer A: 25.4% yield,MH+ 619; [a)20D= -46.70 (1.86 mg/2 mL MeOH); 11R,2R(-)- diastereomer B: 21.1% yield, MH+ 619; [aX] 20 D= -23.00 (2.6 mg/2 mL MeOH).

PREPARATIVE EXAMPLE 114 r~Me H NrN H 0 N ,N >YO r= >rN Me <1N N N1N N C1 O L NN Me To a solution of the title compound from Preparative Example 112 3.33 mmol) dissolved in anhydrous CH 2 Cl 2 (5 mL) was added TFA (5 mL). The solution was stirred at room temperature WO 00/37459 PCT/US99/27939 127under N 2 overnight, concentrated in vacuo and diluted with DMF 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 vacuo, diluted with CH 2 C12, 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 C2 saturated with aqueous ammonium hydroxide to give the title compounds (11S,2R diastereomer A, 152 mg, 27%, MH+ 569; and 11R,2R diastereomer B, 316 mg, 56%, MH 569).

PREPARATIVE EXAMPLE 115 N

N

H-N NeC N CO2H NN To the title compound from Preparative Example 43 (2.64 g, 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.

The mixture was concentrated in vacuo, diluted with CH 2 C12 and washed with NaOH 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 Cl 2 saturated with aqueous ammonium hydroxide to give the title compound (0.94 g, 27%, MH 529).

WO 00/37459 PCT/US99/27939 128- PREPARATIVE EXAMPLE 116 N

(N

OO HN N O N N The title compound from Preparative Example 115 (0.73 g, 1.38 mmol) and anhydrous CH 2 C1 2 (5 mL) was stirred at room 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 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).

PREPARATIVE EXAMPLE 117 Br

CI

IN H N N-- 0 H N N Ho Br C t- IN N N r

N

0 Using the procedure described for Preparative Example 110, but using the title compound from Preparative Example 116 (343 mg, 1 nnmol) and the tricyclic chloride (Compound No. 42.0) (718 WO 00/37459 PCT/US99/27939 129mg, 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.

PREPARATIVE EXAMPLE 118 00 O 0 0 N CO 2 H HN NN N N.

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 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 C12 and washed with NaOH The organic phase was dried over anhydrous Na 2 S0 4 filtered and concentrated in vacuo. The residue was purified by flash column chromatography (silica gel) using 1% MeOH-CH 2

CI

2 saturated with aqueous ammonium hydroxide to give the title compound (1.71 g, 15%, MH+ 528).

PREPARATIVE EXAMPLE 119 00 0OH OO

OO

The title compound from Preparative Example 118 (1.4 g, 2.7 mmol) and paraformaldehyde (solid, 2.8 g) were heated at 1300C 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 title compound (0.89 g, 59%, MH+ 558).

PREPARATIVE EXAMPLE 120 0 0H N O N N 0 0 0 -"OH H 0 -O The title compound from Preparative Example 119 (0.88 g, 1.6 mmol), anhydrous CH 2 C1 2 (10 mL) and trifluoroacetic acid 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 Cl 2 saturated 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 c 0 1 H N N OH O N O /N N /=1 H 0 L\ N N NC1

-OH

The title compound from Preparative Example 120 (498 mg, 1.4 mmol) was dissolved in anhydrous CH 2 C12 (10 mL). To this was added the 8-Cl-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 CH 2 C1 2 purified by flash column chromatography (silica gel) using 3% MeOH-CH 2 Cl 2 saturated with aqueous ammonium 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 mL/min, 30% IPA-Hexane diethylamine). (diastereomer A: 178 mg, MH+ 585; and diastereomer B: 130 mg, MH+ 585).

PREPARATIVE EXAMPLE 122 N H-N r -0 COH -N N O O O O WO 00/37459 PCT/US99/27939 132 To the carboxylic acid from Preparative Example 43 (8.11 g, 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, mmol), NMM (5.5 mL, 50 mmol) and anhydrous DMF (40 mL). The mixture was stirred at room temperature under N 2 for 48 h. The mixture was concentrated in vacuo, diluted with CH 2 Cl 2 and washed with NaOH 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

CI

2 saturated with aqueous ammonium hydroxide to give the title compound (5.24 g, 38%, MH+ 556).

PREPARATIVE EXAMPLE 123 N N CN -N Soo io N The title compound from Preparative Example 122 (5.23 g, 9.4 mmol), anhydrous CH 2 C12 (10 mL) and trifluoroacetic acid mL) were stirred overnight. Aqueous NaOH (1N) was added dropwise to neutralize the reaction mixture, concentrated in vacuo, and purified by flash column chromatography (silica gel) using 5-9% MeOH-CH 2 C12 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 Cl ^N

HO

The title compound from Preparative Example 123 (2.67, mmol) was dissolved in anhydrous CH 2 Cl 2 (40 mL). To this was 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 vacuo, the residue was purified by flash column chromatography (silica gel) using 1-2% MeOH-CH 2 C12 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).

WO 00/37459 PCTIUS997939 134- PREPARATIVE EXAMPLE 125

-HO

HO

A mixture of the title compound from Preparative Example 106 (200 mg, 0.61 mmol), chlorobenzosuberane (140 mg, 0.61 mmol), triethylamine (0.43 mL, 3.1 mmol) and CH 2 C12 (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 C12 saturated with aqueous ammonium hydroxide to give the title compound as a light yellow solid (63 mg, 20%, MH+ 520).

PREPARATIVE EXAMPLE 126 N r C H 3 H O If the procedure of Preparative Example 114 is followed, except the 3,8-dichloro tricyclic compound Cl CI Cl is used instead of the 8-Cl-tricycle chloride, the title compound rwould be obtained.

WO 00/37459 PCT/US99/27939 135- PREPARATIVE EXAMPLE 127 Step A

N

k N 2CSA N CO N CO2H /CO2H H O0 To the piperazine carboxylic acid dicamphorsulfonic acid salt (Preparative Example 42) (14.63 g, 24.6 mmol) dissolved in water 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 NaOH. The pH was lowered to 9.5 using 10% HC1 (aq) and cyclohexyl chloroformate (4.0 g, 24.6 mmol) 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 Et20 and the aqueous phase was acidified to pH 3 with 6M HCI This aqueous phase was extracted with EtOAc 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 N CO2H CO2H 6 6 The title compound from Step A (6.65 g, 18.7 mmol) and trifluoroacetic acid (20 mL) dissolved in anhydrous CH 2 C12 (50 mL) were stirred at room temperature for 1 hr. The organic phase was concentrated in vacuo to give a residue.

Step C H 0 1

C

1

CO

2 H p- N N SN

CCO

2

H

O

N

6 6 The title compound from Step B was dissolved in anhydrous

CH

2 C12 (50 mL) and DMF (50 mL). To this was added the 8-C1tricyclic 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 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).

PREPARATIVE EXAMPLE 128 mmol), NMM 1.0 mL, 9.25 mmol) and anhydrous DMF (10 mL).

r H-N

N

N

N.N%

4 N N rZ 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, mmol), the title compound from Preparative Example 95 (1 g, 4.6 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 C12 and washed with NaOH 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 MeOH-CH 2

C

2 saturated with aqueous ammonium hydroxide to give the title compound (0.70 g, 24%, MH+ 529).

PREPARATIVE EXAMPLE 129 OOf

H

o o The title compound from Preparative Example 128 (0.70 g, 1.3 mmol), anhydrous CH 2 Cl 2 (10 mL) and trifluoroacetic acid WO 00/37459 PCTIUS99/27939 138mL) were stirred at room temperature for 12 h, then concentrated in vacuo. Aqueous NaOH (1N) was added dropwise to neutralize the reaction mixture and the resulting mixture was extracted with

CH

2 Cl 2 The organic phase was dried over anhydrous Na 2

SO

4 filtered and concentrated in vacuo to give a residue which was purified by flash column chromatography (silica gel) using MeOH-CH 2 C2 saturated with aqueous ammonium hydroxide to give the title compound as a brown oil (232 mg, 53%, MH+ 329).

PREPARATIVE EXAMPLE 130 B r C H N

H

HO

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) and triethylamine (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-

CH

2 C12 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 Br 0 1 N H -N M e ON OH O O N N 0 o To the title compound from Preparative Example 51 (1.4 g, 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 0°C 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 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 1M NaOH(aq) and 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 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

C

Br,/ Cl Me H 0 Me O O O N N Br

C

N

N Me N N N To a solution of the title compound from Step A (0.45, 0.60 mmol) dissolved in anhydrous CH 2 C1 2 (5 mL) was added TFA (5 mL).

The solution was stirred at room temperature under N 2 overnight, then concentrated in vacuo, diluted with CH 2 C12, washed with 1N 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 C1 2 saturated 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 diastereomer

B.

Physical chemical data for the 1 1S, 2 R(-)-diastereomer A: MH+ 647; [a] 2 0 D= -45.40 (2.91 mg/2 mL MeOH).

Physical chemical data for the 1 1R, 2 R(-)-diastereomer B: MH+ 647; [a] 2 0 D= -23.50 (2.21 mg/2 mL MeOH).

WO 00/37459 WO 0037459PCTIUS99/27939 141 PREPRTE EXAMPLE 132

H

Tr Step A 0 HO Tr ~Tr 0 To a stirred solution of l-(triphenylmethyl-H-idazol4yl).

3 -hydroxypropane (WO 9629315) (5.04g, 13.68 mmoles), phthalinide (2g, 13.6 mmoles) and triphenyl phosphine (3.57g, 13.6 mimoles) in THF (100 mL) at 0 0 C was added diethyl azodicarboxylate (2.14 mL, 13.6 mmoles) dropwise. The reaction mixture stirred for 1 h at 0 0 C and then at room temperature for 1 6h. Filtered to give the title compound (4.6g, 100%), CIMS: m/z 498 8, (CDCl 3 )1.72 (bs, 1H), 1.9 (in, 1H), 2.05 (in, 1H), 2.6 (in, 1H), 3.75 (in, 2H), 6.6- 7.8 (in, 2 1H).

Step B 0 I N N~ 2 Tr Tr 0 The title compound from Step A (2g, 4.02 mmoles) and hydrazinehydrate (3.89 inL, 80.39 mmoles) were heated under reflux in ethanol (80 mL) for 16h. The solids were filtered off and the filtrate was evaporated to give the title compound 1.35g, 9 CIMS: in/z 368; 8, (CDC1 3 1.8-1.85 (in, 2H), 2.6-2.62 (mn.

2H), 2.8-2.83 (mn, 2H), 7 1( s, 1 7.3 1 H).

WO 00/37459 PCTIUS99/27939 -142- Step C Ph H N

N

2 N HNJ TrN Tr Ph phenyl To a stirred solution of the title compound from Step B 4.08 mmoles) and benzaldehyde (0.433g, 4.08 mmoles) was added 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 Evaporated to give a crude residue which was chromatographed on silica gel using 4% (10% cone NH 4 OH in methanol)-CH 2 C1 2 as the eluant to give the title compound (1.04 g, CIMS: m/z 458; 8, (CDC13) 1.8-1.82 2H), 2.58-2.64 4H), 3.6 2H), 1H), 7.15-7.4 6H).

PREPARATIVE EXAMPLE 133

CH

3 Ph 3 HN1

N

Step A 0

CH

3 0 The title compound from Preparative Example 132 Step A (2g, 4.1 mmoles) in CHI- 2 C (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 WO 0037459PCT/US99/27939 143 neutralized with aqueous NaHCO 3 and evaporation to dryness again gave semi-white solids. Stirred with CH 2 Cl, (100 mL)and MeGH mL) and filtered off the solids. The filtrate was evaporated to give the title compound CIMS: m/z 140; 8H (CDCI 3 1.8 (in, 2H), 2.6-2.8 (in, 4H), 3.6 3H), 6.68 11H), 7.4 IH).

Step B

CH

3 PhCH 3

H

2 N \N The title compound from Step A (1.97g 14.14 mmoles), benzaldehyde 65g 15.5 5mmoles), sodium acetate (1.1 g, 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 chroinatographed to give the title compound (0.59g 18.5%) CIMS: in/z 230; (CDCI 3 )1.8 (q, 2H), 2.6 2H), 2.65 2H), 3.25 3H), 3.8 2H), 7.2-7.4 (in.

7H).

PREPARATIVE EXAMPLE 134

NH

2

IH

StepA

N

3 \zN IOH \-N l-( 2 -Phenyl-23-epoxypropyl).H..xnidazole (GB 2 099818 A) (2.15g. 10.85 noles) and sodium azide (1.41 g; 21.71 m1.,noles) WO 00/37459 PCT/US99/27939 144were heated in DMF (20 mL) at 60 0 C for 16h. Evaporated to dryness and extracted with CH 2 Cl 2 washed with brine and dried (MgSO 4 Evaporated to give the title compound (0.932g, 36%), CIMS: m/z (MH) 244; (CDC1 3 3.7 2HO, 4.5 (dd, 2H), 6.6 (s, 1H), 6.95 1H), 7.3-7.45 5H), 8.2 1H).

Step B

N

3 NH2 _N N OH OH The title compound from Step A 0.8g, 3.31 mmoles) in ethanol (15 mL) was hydrogenated over 10% Pd on carbon (0.2g) at psi overnight. The catalyst was filtered off and evaporated to give the title compound (0.71g CIMS: m/z 218.

PREPARATIVE EXAMPLE 135 Br CI Br C 1 Br 'C NN

N\'

H Br H Br H Br N HOOC N N COOH H COOt-Bu COOt-Bu

(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 tic spot: 'NMR

(CDC

3 300 MHz) 5 1.42 9H), 4.85 2H), 7.12 1H), 7.50 (s, 1H), 7.55 1H), 8.48 1H); HRMS (FAB) calcd for C 2 H,,N204 BrCl'Br 615.0084, found 615.0092.

WO 00/37459 PCT/US99/27939 145- PREPARATIVE EXAMPLE 136

BOC

I

HN N 0N

N

H O

H

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.

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 the corresponding amines.

TABLE Prep.

Ex.

Amine Product yield

MH

I

I

137 Me H2N-\NN Me H2N

N.N

_Me H2N-\^N

N

Me HN e

N

H 0 238 138 100 N H

M

238 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.

TABLE

V

C' H Mq-- WO 00/37459 PCT/US99/27939 147 PREPARATIVE EXAMPLE 142 Br Cl Br C1 0 N Me N Me o H H H -N 0 (A+B) Br Cl Br Cl 0 Me M e ?Nr

H

e H O NN N N, N II' U

(A+B)

The title compound from Example 289 (0.39 g, 0.51 mmol), anhydrous CH2C12 (3 mL) and trifluoroacetic acid (3 mL) were 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 CH2Cl2. The organic phase was dried over anhydrous MgSO4, filtered and concentrated in vacuo to give a residue which was purified by flash 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 150°C, MH+ 768).

PREPARATIVE EXAMPLE 143 NMe

N

H2o-, K> N Me O L 0 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 (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-CH2Cl2 saturated with ammonium hydroxide as eluent afforded the title 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 Preparative Example 143, the BOC-protected piperazines listed in Table 5C below were prepared using the corresponding amines.

TABLE Prep. Amine Product yield MH' Ex. o H2N~ N N 144 100 500 N N 145 NN 100 500 WO 00/37459 PCT/US99/27939 -149- H2N CF 3 146 H 2 N -H 57 517 CF3 Me BOC

H

2 N r= HN N Me N H 147 H e, 100 477 F4I 0

BOC

OH me,

N

BOC

N OH 149 j oI U OH 58 465 149A H2Me

BOC

H2

N

N N P Mek Mer 0

N

H

149B H2O

CH

H~r N N -N

WOO

NH

PREPARATIVE EXAMPLE 150

BOC

H

A/ H o;CH3 0 N

H

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 N

N

instead of the amine from Preparative Example 71, the title compound would be obtained.

PREPARATIVE EXAMPLE 151 o 4

NM

SMe Me +Me

P-

N

Me (2.12 g, 15.2 mmol), triethylamine (30.4 mmol) and the anhydride a Me A\08OY-- 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 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% MeOH-CH2C12 saturated with ammonium hydroxide as eluent afforded the title compounds (2.57 g, The regioisomers were separated by HPLC (Chiracel AD column) using 5% isopropanolhexane-0.2% diethylamine to give the 2,4-diniehyl isomer (mp 64.2°C, MH+ 486) and the 2,5-dimethyl isomer (mp 71.5 oC, MH+ 486).

WO 00/37459 PCTIUS99/27939 151 PREPARATIVE EXAMPLE 152 (N

H

N D N Me ,0 N"*

HO

Me HBr Me A solution of the title compound from Example 293 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.

PREPARATIVE EXAMPLE 153 Me HBr Md A solution of the title compound from Example 293 diastereomer B (0.372 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 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 OO

BOC

N HN H I NN H o]r° 0 Nr,^ O Me HO Me A mixture of the title compound from Preparative Example 66 (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 CH2Cl2 (10 mL) was stirred at room temperature for 12 hrs. The mixture was concentrated in vacuo, diluted with CH2Cl2 and washed with a saturated aqueous solution of NaHCO3. The organic phase was dried over anhydrous Na2SO 4 filtered and concentrated in vacuo.

Step B Br l c BOC Br\ \i C

H

N

N

N

H

H

o k N r NN ,N Me

HO

Me Trifluoroacetic acid (10 mL) 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 25 0 C. 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 mmol) and triethylamine (5-10 mL) and stirred at room temperature overnight. The mixture was concentrated in vacuo, diluted with CH2Cl2 and washed with a saturated aqueous solution of NaHCO3.

The organic phase was dried over anhydrous Na2S0 4 filtered, concentrated in vacuo and purified by flash column- chromatography WO 00/37459 PCTIUS99/27939 153 (silica gel) using 5% MeOH-CH2Cl2 saturated with aqueous ammonium hydroxide to give the title compound as a mixture of diastereomers (1.9 g, 47%, MH+ 557).

PREPARATIVE EXAMPLE 155 Step A 0 0 N- 0 N N-

O

Et NH

N

2 HCIlH2N N-Carbethoxyphthalimide (62.8 g, 0.275 mol, 1.1 eq.) was added portionwise over a period of 30 minutes to a stirred solution 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 minutes. The solid was filtered off and thoroughly washed with icecold distilled water (4 x 50 ml). The solid was collected and dried under vacuum over P 2 0, at 60 0 C for 12h to give the title compound (59.2 g, 0.245 mol, 98%, MH+ 242).

Step B N0 0% 0 NH ON O O 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 ml). The combined organic extracts were dried over Na 2 SO., filtered, and concentrated under vacuum at 30 0 C. 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).

Step C 0 0 C1 Cl 0 0 o -o, N 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 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%).

Step D o N N 0 0 0 fl NO N A 7 N solution of arniora in methanol (10 nil, 0.07 mol) was added slowly to a stirred solution of the title compound from Step C above (3.2 g, 6.6 mmol) diluted with MeOH (10 mL) at WO 00/37459 PCT/US99/27939 155- 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 compound as a sticky solid (1.2 g, 51%, MH+ 366).

Step E 17. C1 C1 N H 2

N

N N A solution of the title compound from Step D above (1.21 g, 3.3 mmol) and hydrazine monohydrate (1.7 ml, 0.033 mol, 10 eq.) in absolute ethanol (20 ml) was stirred at 50 °C 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 solid (0.7 g, 91%, MH+ 236).

Step F

H

2 N Cl N H 0 O

N

A solution of the title compound from Step E above (0.695 g, 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 1M HC1 The aqueous phase was basified with IN NaOH extracted with CH2CI2 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).

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.

TABLE PREPARATIVE EXAMPLE 158 STEP A

H

2 N =1

BOC

N

NN N\N To 3 -(1H-imidazol-l-yl)propylamine (20 mL, 167.6 mmol) dissolved in water (200 mL) and MeOH (200 mL) was added 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 while maintaining the pH at 9.5 with 50% NaOH. The mixture was WO 00/37459 PCT/TJS99/27939 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).

Step B BOC

BOC

HN 1 _9 N, N N- ,N

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 -78°C 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 -78 0 C and anhydrous DMF (0.35 mL, 4.52 mmol) was added. After warming to and stirring at 0 C for 2 h, MeOH (2 mL) and NaBH4 (171 mg, 4.5 mmol) were added and the resulting mixture was stirred for 1 h at 25 0 C. 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- 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

NN 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 25 0 C for 12 h. Concentration in vacuo afforded a residue which was used directly in Step D.

Step D Br/ Ci B r

CI

oNH 2 N HCI

N

N NN N N O OH N N OH0 N 0 H

OH

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), 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 CH2C12 (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 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 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 PREPARATIVE EXAMPLE 161 Step A

H-N-&N

,H

-OTBMS

H-N-f, 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 and refiltered. The filtrate was concentrated in vacuo, diluted with CH2C12 and washed with a saturated aqueous solution of NaHCO3.

WO 00/37459 PCT/US99/27939 160- The organic phase was dried over anhydrous Na2S04, filtered and concentrated in vacuo to give the title compound (2.22 g, 71%, MH+ 213).

Step B

OTBDMS

W OTBDMS

OTBDMS

H-NJ-

N NC -NN 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, 75%, MH+ 266).

Step C OTBDMS

OTBDMS

NC NN

H

2 N N..N P OTBDMS

OTBDMS

NC N 2

N..N

A mixture of the title compound from Step B above (2.08 g, 7.85 mmol), Raney nickel (230 mg), MeOH (20 mL) and NH 4 OH 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 Na2S04, filtered, concentrated in vacuo and purified by flash column chromatography (silica gel) using 5% MeOH-CH2C12 saturated with aqueous ammonium hydroxide to give the title compounds substituted isomer, 465 mg, 22%, MH+ 270) and 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 4chlorobenzyl chloride in Preparative Example 155 Step C, the title compound was prepared MH+ 220).

PREPARATIVE EXAMPLE 163 H 2

N-

N

N

N

Following the procedure described for Preparative Example 155 Steps C-E, except using 4-cyanobenzyl bromide instead of 4chlorobenzyl chloride in Preparative Example 155 Step C, the title compound was prepared MH+ 227).

PREPARATIVE EXAMPLE 164 ClCl C--C (N N) N N OH -O Cl N O Tricyclic chloride (5.04g, 1.1 eq.) was added to a solution of the title compoundn from Preparative Example 50 (4.0g, 17.3 mmol) and TEA (12.05 mL, 5 eq.) in DMF (60 mL). The resulting solution was stirred at room temperature 72 hours at which time the WO 00/37459 PCTIUS99/7939 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,, filtered, and concentrated in vacuo. The crude product was purified by flash chromatography using a 12% (10% NH 4 OH in MeOH) solution in

CH

2 CL, 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.

C I

N

N 11S,2R(+)-Isomer

OH

11(S),2(R)(+)-isomer (first eluting isomer): [a]2 0 D= +84.9 (5.18mg in 5.0 mL MeOH); LCMS: MH'= 458.

,CI

N

N 11R,2R Isomer L

O

H

O O

H

11(R),2(R)-isomer (second eluting isomer): FABMS: MH*= 458.

PREPARATIVE EXAMPLE 165 Me HN I

N

WO 00/37459 PCT/US99/27939 163- Following the procedure described for Preparative Example except using the title compound from Preparative Example 13 instead of N-1-methyl histamine, the title compound was prepared MH+ 195).

PREPARATIVE EXAMPLE 166 Br/\ Ci

N

N

Diastereomer A Me

NN

Similarly, using the procedure described for Preparative Example 142, except using the title compound from Example 305 diastereomer A instead of the title compound from Example 289, the title compound was prepared MH 599).

PREPARATIVE EXAMPLE 167 Br/\ \C

N

N

Diastereomer B Me

N"

N

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 MeOOMe The title compound from Preparative Example 40A Step A (compound 52.ii) (5 g, 12.8 mmol) was dissolved in 2.7 ml of 2,4dimethoxybenzaldehyde 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, filtered and evaporated to dryness to obtain a solid which was chromatographed on silica gel to obtain 5.17 g of title product.

FABMS 463.4 Step B Br C 1 B'r c 1 N l 1) Hg(OAc) 2 /85 0

C

2) KCN/ O0C >r.t.

N N CN 57% 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 1.25 gm) was added and the reaction mixture stirred vigorously for WO 00/37459 PCT/US99/27939 165- 18 hours. 1N 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.

Step C TFA/anisole 47% OMe major The title product from Step B (0.2 gm) was dissolved in 6 ml of trifluoroacetic acid and 0.5 ml of anisole and stirred for 1 hour at 60°C to obtain the title carboxamide product (72 mg) after silica gel chromatography using 2% methanol/dichloro-methane as the eluent. FABMS 432.

Step D WO 00/37459 PCT/US99/27939 166- The major product (carboxamide) from Step C (0.19 gm) 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 gm) was 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.

FABMS 533.

Step E Br c Br Cl H /=N

CH

3 N CH 3

N

H

3 zC O 0 H 3 C O O H 3 C H 3 Ck The title compound from Step D (70 mg, 0.13 mmol) 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 a silica gel column to obtain 86 mg of title product. FABMS 640.

WO 00/37459 PCTIUS99/27939 167 PREPARATIVE EXAMPLE 169 11-Chloro-6,11 -dihydro-5H-benzo[5,6]cyclohepta[1,2-B]pyridine.

NaBH4 SOC 2 N N N 0 OH CI The ketone (starting material) 5,6-dihydro-11Hbenzo[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 0°C, then stirred for 2 hours at room temperature. The reaction was quenched by addition of ice (10g) and 2N HC1 (10ml, basified with 2N NaOH (13ml)and extracted with MeC, (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) 7.3(m,4H) 7.5(m,2H) 8.314(d,lH).

Thionyl chloride (3ml, 41.12mmol) was added to a solution of the alcohol (2.5g, 11.84 mmol) in MeCl(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 extracted with MeC12 (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. 1H NMR (CDC,, 6) 2.9-3.0 2H), 3.6 1H), 3.9 1H), 6.3 1H), 7.2 7.3 1H), 7.4 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 PTU9/73 PCT/US99/27939 168 PREPARATIVE EXAMPLE 170

CH

3 H 0 Acetonitrile (5m1.L) was added to a mixture of the 1 0-Chioro tricycle 1. .9mmol) (Preparative Example 9. 1) and the substituted piperazine (0.78g, 1 .9Ommol).Triethylarnine (1ml, 7. l8mmol) was added,and the mixture stirred overnight at room temperature.Water (50m1) and 5% NaOH were added and the mixture was extracted with MeCl, (2x 1 O0ml). The organic layer was separated,dried over MgSO, 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, containing 2% NHOH. Isomer A (the less polar isomer) eluted first.

TABLE Isomer Mass [f (Fabs, MH) A, B 569.1 A 569.2786 -55-90c 1085 B 1569.2816 1-27.4c=O0.1085 WO 00/37459 PTU9173 PCT/US99/27939 169 PREPARATIVE EXAMPLE 171

NH

2

OH

3

N

OH

STEP A H3

H

'I

N.-

HN~NI

A mixture of 2-chioroacetophenone (25g, 0. 16 moles) arnd 4methyl imidazole (66. 1g, 0.8 moles) was heated at 100 00 for 2h.

Cooled and the crude product chromatographed on a silica gel column eluting with CHCL 2 3% CH30H saturated with aqueous ammonium hydroxide to give mixture of 4- and 5- methyl 1 Himidazolyl acetophenone (23g, 73%) MS, MH =20 1).

STEP B 0OH 3 O H 3

N

Trityl chloride (7.28g, 0.26 moles) was added to the product from Step A in CH 2 C1 2 (200 mL) and stirred overnight at room temperature. The mixture was chromatographed on a silica gel column eluting with ethyl acetate acetone 1) to give 4-methyl- 1H-inuiidazolyl acetophenone (15.5 FabMS: MH*= 201.

STEP Q

,<CH

3 aIDS

H

N+ (I-$Cb-S-i To a mixture of NaR (0.998 g, 24.97 mmoles, and trimethyl sulfoxonium iodide (5.49g, 24.97 minoles), in DM!50 (150 tLfil WO 00/37459 PCT/US99/27939 170product (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)-1H-4methyl imidazole 3.44 g, 64 FABMS MH' 215) STEP D

N

3 CH3 NaN3/ DMF CH3

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 C for 12h. Evaporated to dryness and extracted with CHCl, washed with brine and dried (MgSO 4 Evaporated to give the title compound (3.83g, FABMS: MH' 258 STEP E

N

3 NH,

CH

3

CH

3 15 H

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).

PREPARATIVE EXAMPLES 172-188 Following the procedure set forth in Preparative Example 74 but using the aldehyde and imidazoalkyl amine (Imidazole) in Table the amines (Product) in Table 5G were obtained.

WO 00/37459 WO 0037459PCTIUS99/27939 171 TABLE ~<e 0

H

m<e

WI

0 yr<e HoNlor< e

H

%/Yield 59

H

%/Yield 76 PCT1US99/27939 WO 00/37459 172 0 C /Me ~Me y =Me H

N

C I--lH I Me Me H"\IN

NN

y ~Me %/Yield 89 WO 00/37459 PCT/US99/27939 173 WO 00/37459 PTU9173 PCT/US99/27939 174 H2 N 188 H N,1c: %/Yield 88 MH= 266 PREPARATIVE EXAMPLES 190-197 Using the procedure described for Preparative Example 109, but using the title compounds from the Examples listed in the Table the Product amines were prepared.

TABLE WO 00/37459 PCTIUS99/27939 175 WO 00/37459 PCT/US99/27939 176- Br N/ 4CI 196 349 1.85 N 2.647

NN

H

Me Isomer A 197 350 N 1. 87 J. 2.647 Me Isomer B PREPARATIVE EXAMPLE 199 Step A

CI

0

N

CI MeMe N rC/l /Me H

N

H 'H The title compound from Preparative Example 175 (0.9 g), benzyl alcohol (0.68 mL), solid potassium hydroxide (0.66 18crown-6-ether (80 mg) and anhydrous toluene (20 mL) were stirred at reflux. Purification by preparative plate chromatography (silica, 4% MeOH-CH 2 C4, NH 4 OH saturated) afforded the benzyl ether (0.73 g, 68%, MH' 371).

WO 00/37459 PCT/US99/27939 -177- Step B

OH

H N N r(

H

M

H

The title compound from Step A above (0.72 methanol mL) and 10%palladium on carbon (300 mg) were stirred under psi hydrogen atmosphere for 3 days. Filtration through celite afforded a solution which was treated with TEA (3 equiv) and

CH

2 C1.. Filtration and purification by preparative plate chromatography (silica, 5% MeOH-CH 2

CL

2

NH

4 OH saturated) afforded the title compound (0.20 g, 42%, MH' 247).

WO 00/37459 PCTIUS99/27939 -178- PREPARATIVE EXAMPLE 200 Preparation of the tricyclic N-oxide moiety CI MCPBA/ CIJYC cC 0 c p 1 2 NaBj MeOH CI -SOCk/toluene cP C

OH

4 3 H*T FA

IC

N Chromatographyl N OH NP 3 C

OH

6 6a CI

\CI

)"OL OH7OH "r~l.

Ab Lj-2j A solution of 3 -peroxybenzoic acid (25 g, 102.59 mrol, 2.5 eq.) in anhydrous dichloromethane (250 mL) was added WO 00/37459 PCT/US99/27939 179dropwise 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 °C under a nitrogen atmosphere. The solution was slowly (3h) warmed to room temperature and stirred for another 12h. The solution was extracted with 1 M aqueous sodium hydroxide solution 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 without further attempts at purification.

Yield: 10 g 38.51 mmol 94% [M 260 HRMS (FAB+): Calculated for C1 4 HiiClNO 2 260.0475 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 g, 38.51 mmol, 1.0 eq.) in anhydrous methanol (500 mL) at 0 °C under a nitrogen atmosphere. The resulting suspension was stirred at 0 "C for one hour and at room temperature for another hour.

The volatiles were removed under house vacuum at 30 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).

The combined organic extracts were washed with brine (100 mL), dried over Na 2

SO

4 filtered, and concentrated under house vacuum at 30 "C to give 3 as a lime-green solid. Compound 3 was used directly without any attempts at purification.

Yield: 9 g 34.39 mmol 89% [M HJ': 262 HRMS (FAB+): Calculated for CH,,CINO, (IM 262.0635 WO 00/37459 PCT/US99/27939 180- Observed: 262.0636 4 Thionyl chloride (5 mL, 68.78 mmol, 2.0 eq.) was added dropwise over a period of 10 minutes to a stirred suspension of 3 (9 g, 34.39 mmol, 1.0 eq.) and anhydrous toluene (150 mL) at 0 °C under a nitrogen atmosphere. The cream-colored suspension was slowly (3h) warmed to room temperature and stirred for another 12h. The volatiles were removed under house vacuum at 30 °C.

The residue was taken up in dichloromethane (250 mL) and washed with ice-cold, saturated aqueous 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 °C to give 4 as a cream-colored solid in essentially quantitative yield. Due to its high reactivity, compound 4 was used directly without any attempts at purification or characterization (other than 'H NMR).

Yield: 9.55 g 34.09 mmol 99% 6 Triethylamine (18 mL, 126.65 mmol, 5.0 eq.) was added dropwise to a stirred solution of 5 (previously described in the art; 9.38 g, 25.33 mmol, 1.0 eq.) in anhydrous dichloromethane (50 mL) at room temperature under a nitrogen atmosphere. The solution was stirred at room temperature for 30 minutes and was cooled to 0 A solution of 4 (8.52 g, 30.39 mmol, 1.2 eq.) in anhydrous dichloromethane (50 mL) was added dropwise over a period of minutes. The mixture was slowly (3h) warmed to room temperature and stirred for another 12h. The volatiles were removed under house vacuum at 30 The residue was taken up in 50% m/v aqueous citric acid solution (100 mL) and extracted with ethyl acetate (5 x 100 mL). The organic extracts were combined and dried over Na 2 SO, filtered, and concentrated under house vacuum at The residual cream-colored solid was flash-chromatographed WO 00/37459 PCT/US99/27939 181

(CH,

2

C

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 Off-white foam; 78-83 °C [M HfI: 500 HRMS (FAB+): Calculated for C 2

H

3 1

,CIN

3 0, 500.1953 Observed: 500.1952 For 6b: Yield: 3.00 g 6.00 mmol 24% Off-white solid; 94-99 °C [M H] 500 HRMS (FAB+): Calculated for C 26

H

3 1

,CIN

3 0 500.1953 Observed: 500.1952 PREPARATIVE EXAMPLE 201 Step A 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.

StepB CIl 'C02H oO 1O WO 00/37459 PCTIUS99/27939 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.

The isomers were separated by column chromatography (silica) using 3% MeOH/CHC 2 Isomer A: 38%, MH'=450.

Isomer B: 31%, MH'=450.

PREPARATIVE EXAMPLE 202 Step A Following the procedure set forth in Preparative Example 127 Step C, but substituting the tricyclic chloride for the 8-C1 tricyclic chloride, one obtains the following acid: Solid, 51% yield, mp=120.5-125.1 0

C.

PREPARATIVE EXAMPLE 202A 0 O By essentially the same procedure set forth in Njoroge et. al.

Med. Chem. (1997),40, 4290) for the preparation of 3- WO 00/37459 PCT/US99/27939 183aminoloratadine only substituting the 3-H ketone Het. Chem (1971) 8, 73) for loratadine, the title compound was prepared.

PREPARATIVE EXAMPLE 203 N N 0 0 The title compound from Preparative Example 202A (1.62g, 6.26 mmol) was added portionwise to NOBF4 (0.81g, 1.1 eq.) in toluene (10 mL) at 0 The resulting slurry was stirred at 0 oC for hours before warming to room temperature. The reaction mixture was heated at reflux for 2 hours, cooled, neutralized with 1N NaOH and extracted with EtOAc (3 X 50 mL). The combined organics were washed with 1N HC1 (2 X 25 ml), saturated NaHCO 3 (1 X 25 mL), and water (1 X 15 mL), dried over Na2SO 4 filtered, and concentrated under reduced pressure. The crude product was purified by flash chromatography using a 70 30 hexanes EtOAc mix as eluent to yield a yellow solid (0.68g, 42% yield). LCMS: MH'=262.

PREPARATIVE EXAMPLE 204 F CI

N

CI

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).

WO 00/37459 PCT/US99/27939 184 PREPARATIVE EXAMPLE 205

H

2

N

N

0 'NHHCO, (2.44g, 10eq.) was added to a solution of the title compound from Preparative Example 202A (2.00g, 7.74 mmol) and 5% Pd/C (0.50g) in EtOH (100 mL) and the resulting solution was heated to reflux 2 hours. The reaction mixture was cooled, filtered through a plug of Celite and concentrated under reduced pressure.

The residue was diluted with H20 (100 mL) and extracted with

CH

2 Cl2 (3 x 75 mL). The combined organics were dried over NaSO 4 filtered, and concentrated in vacuo to give a yellow solid (1.22g, yield) which was used without further purification: FABMS: MH'= 225.

PREPARATIVE EXAMPLE 206 0 The title compound from Preparative Example 205 (1.22g, 5.44mmol) was added portionwise to CuCl, (0.88g, 1.2eq) and tBuONO (0.98mL, 1.5eq) in CH 3 CN (25mL) at 0 The resulting solution was warmed to RT and stirred for 72 hours. The reaction mixture was quenched by the addition of 1M HCI neutralized with 15% NH40H and extracted with EtOAc (3 x 100mL). The combined organics were washed with 15% NH 4 OH (1 x 1M HCI (1 x 50mL) and saturated NaHCO 3 dried over NaSO,, filtered and concentrated. The crude product was purified 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 C C

N

CI

By essentially the same procedure set forth in Preparative Example 201 Step A, the title compound was prepared from the ketone of Preparative Example 206 and used without further purification.

PREPARATIVE EXAMPLE 208 Br-,

N

0 By essentially the same procedure set forth in Preparative Example 206, only substituting CuBr, for CuCI, the title compound was prepared (1.33g, 60% yield):FABMS: MH'= 244.

PREPARATIVE EXAMPLE 209 Br

N

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.

PREPARATIVE EXAMPLE 210 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.

PREPARATIVE EXAMPLE 211 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.

PREPARATIVE EXAMPLE 212

OH

By essentially the same procedure set forth in Preparative 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 and (R)-isomers) was prepared. FABMS: MH'= 484.

WO 00/37459 PCT/US99/27939 -187- EXAMPLE 1

BOC

NN

C H N N

M

aN 0

H

N

H N A solution of the title compound from Preparative Example (0.44g, 0.897 mmol) was stirred at room temperature in CH 2

CL

2 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 C1, (5 mL), treated with chloride (42.0) Br Cl

N

Cl (42.0) (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 CHC1l (25 mL) and separated. The aqueous layer was extracted with CH 2 CL1 and the combined organics dried over NaSO 4 and concentrated under reduced pressure. The crude product was purified by flash chromatography using a 5% (10% NH 4 OH in MeOH) solution in WO 00/37459 PTU9173 PCT[US99/27939 188 CH 2 Cl as eluent to yield a tan solid (0.45g, 7 1% yield). mp 142- 144 0 C; FABMS: MH*= 696.

EXAMPLE 2 (1 I S,2R(+)-Isomer) f N(1 LR,2R(+)-Isomer)

H

The title compound from Example 1 was separated into the 11 and I11 diastereomers by preparative HPLC using a CHIRALPAK AD column using a 12% i-PrOH in hexanes solution with 0.2% diethylammne as eluent: 11 -Isomer: retention time= 29.21 minutes; Ioc]" 5

D=

19.1 (3.35 mg in 2.0 ml CHC 3 MP= 147- 149*C; LCMS: MH*= 696.

1 IR,2R(+)-Isomer: retention time= 39.8 minutes; [aC(JD= +73.0 (3.07 mg in 2.0 mL CHC4-; mp= 128-131 0 LCMS: MH*= 696.

WO 00/37459 PCT/US99/27939 189- EXAMPLE 3 r:

\N

N

0 Me Me By essentially the same procedure as that set forth in Example 1, except using the title compound from Preparative Example 6, the title compound was prepared (0.085g, 45% yield).

mp 103-106 0 C; LCMS: MH'= 705.

EXAMPLE 4 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 0

C;

MH' 703 WO 00/37459 PCT/S99/27939 190- EXAMPLE a Cl By essentially the same procedure as that set forth in Example 1, except using the title compound from Preparative Example 7, the title compound was prepared. mp 138-140 0

C;

LCMS: MH'= 778.

EXAMPLE 6 (11R,2R Isomer) 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-pyridyiacetic acid N-oxide (0.039 g, 1.5 NMM (0.03 mL, eq), DEC (0.049 g, 1.5 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 C12 (4 X 50 mL). The combined organics were dried over MgSO 4 filtered, and concentrated in vacuo. The crude residue was purified by Preparative TLC using a 15% (10% NH 4 OH in MeOH) solution in

CH

2 C1, as eluent to yield the 11S,2R isomer(0.044g, 39% yield). mp= 115-1170C; LCMS: MH'= 706.

By essentially the same procedure, except using the racemate or 11R,2R isomer from Preparative Example 8, one can obtain the 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

R

14 0 Me Me wherein R' 4 is as defined in Table 6 below, were obtained.

TABLE 6 EX. R 4= MP Mass Spec 7 N 148-150 LCMS: MH'=706 11R,2R isomer i WO 00/37459 PTU9/73 PCT[US99/27939 -192 8 0 Nk<NH2 123-127

LCMS:

0jl~ MH*=739 1 1S,2R isomer

N~NH

2 150-153 LCMS: 0 MH*=739 1 1R,2R isomer EXAMPLE

N

NN (1 1S,2R Isomer) N" OMe Me

H

A solution of the title compound from Preparative Example 8 (1 IlS,2R-isomer) (0.080 g, 0. 14 mmol) in CH 2

CL

2 (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 TLC using a 10% (10% NH40H in MeOH) solution in CH 2 CI, as eluent to give the title compound (0.045g, 48% yield). mp=139- 142 0 C; LCMS: MH*= 670.

WO 00/37459 PCTIUS997939 193 EXAMPLE 11 Br Cl

N

N

H N (11R,2R Isomer) N N O Me Me

H

The title compound was prepared by essentially the same procedure as that set forth in Example 10, but substituting the 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 Example 10, except the title compounds from Preparative Example 9 are used, the compounds of the formula wherein R" is as defined in Table 7 below, were obtained.

WO 00/37459 WO 0037459PCTIUS99/27939 194 TABLE 7 EX. R= MP (OC) Mass Spec 12 136-139

LCMS:

H MH*= 668 1 1S,2R isomer 13 0 k106-110

LOMS:

H 668 11 R,2R isomer 14 N 133-139

LCMS:

H MH'= 654 11 R/S,2R isomers EXAMPLE "'iIs 0 Me Me 0 To a solution of the title compound (11I -racemate) from Preparative Example 8 (0.072g, 0. 12 mmol) and TEA (0.0 10 mL, 1.1 eq.) in GH 2

CI

2 (4 mL) was added MeSO 2 C1 01 mL, 1. 1 eq.) and the nes&iuarg soluuun was Strred at room temperature overnight. The reaction mixture was quenched by the addition of saturated NaHCO,, (5 mL), separated and extracted with CH 2 C1 2 (2 X 50 mL).

WO 00/37459 PCT/US99/27939 195- The combined organics were dried over Na 2

SO

4 and concentrated in vacuo. The crude residue was purified by preparative TLC using a (10% NH 4 OH in MeOH) solution in CH 2 C, as eluent (44 mg, 63% yield). mp= 107-110oC; LCMS: MH'= 649.

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 By essentially the same procedure as that set forth in Example 15, compounds of the formula: Br Cl

N

NH N

R

1 4 0 Me Me wherein R 1 4 is as defined in Table 8, were obtained.

TABLE 8 WO 00/37459 WO 0037459PCTIUS99/27939 196 17 18 1 I R2Risomer

N

11 R/S,2R isomers 107-108 107- 18LCMS: MH*=657 139- 142LCS MI-C=642 EXAMPLE 19 F.N~4 N 0 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= 133-138'C; LCMS: MH*= 682.

EXAMPLE

N

WO 00/37459 PCTIUS99/7939 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 HOBT (0.73 g, 6.0 and NMM (0.60 mL, 6.0 eq.) in DMF (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 increments (10% NH 4 OH in MeOH) solution in CHC1, as eluent to give the title compound (0.411 g, 67% yield). mp= 178-179 0 C; MH*= 685.

EXAMPLE 21 Br Cl

N

N

H Me Me H N O 0

N

H

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 The title compound was prepared by essentially the same procedure as that set forth in Example 110, but substituting for the 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.

EXAMPLE 24 Step A O' -NH 2 The title compound from Preparative Example 12 (0.23 g, 0.49 mmol) in CH 2 CL1 (5.0 mL) and TFA (3.0 mL) was stirred at room temperature 2 hours and concentrated in vacuo. The residue was dissolved in CH 2 C12 (5.0 mL) and treated with TEA (0.45 mL, 20 eq.) and chloride WO 00/37459 PCT/US99/27939 -199- Br Cl Cl (42.0) (0.056 g, 0.33 eq.) and stirred at room temperature 48 hours. The reaction mixture was diluted with saturated NaHCO, (5.0 mL), water mL), and extracted with CH 2 C1 2 (2 X 50 mL). The combined organics were dried over Na 2 SO, and concentrated under reduced pressure. The crude product was purified by flash chromatography using a 15% (10% NH 4 OH in MeOH) solution in CH 2 C1~ as eluent (0.063g, 67% yield). mp= 157 0 C(dec.); FABMS: MH'= 572.

Step B B r

C

1 t N

N

HH

N N N 0 O NH 2 H

N

O H The title compound from Step A (0.058 g, 0.101 mmol) in CH,C1I (3 mL) was treated with excess cyclohexyl isocyanate and stirred at room temperature for one hour. The reaction mixture was concentrated in vacuo and purified by flash chromatography using an 8% MeOH in CH 2

CL

2 solution as eluent to give the title compound (0.062g, 75% yield). mp= 164-167 0 C;FABMS: MH*= 822.

WO 00/37459 PCT/US99/27939 -200- EXAMPLE 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) overnight. The resulting solution was concentrated in vacuo and the residue purified by flash chromatography using a 15% MeOH in

CH

2 C1 2 solution as eluent to give the title compound (0.022 g, 58% yield). mp= 164-169 0 C; FABMS: MH'= 697.

EXAMPLE 26 WO 00/37459 PCT/US99/27939 -201 Step A BOC BOC N N N N

N

O

0 Dissolve 2.99 g (15.09 mmol) of the 3-methylhistamine hydrochloride in 100 mL of methylene chloride followed by 3.21 g (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 NaHCO, solution. Dry the organic layer over MgSO and concentrate in vacuo. Flash chromatograph on 650 g of silica gel using 97% CH 2 C1 2

(NH

4 OH) 3% methanol to give the product as a white solid, mp 51.8-63.2 0

C.

Step B

H

I

CH

3

N

Dissolve 4.9 g of the product from Step A in 30 mL of methylene chloride and add 13 mL of trifluoroacetic acid. Stir overnight under nitrogen then concentrate in vacuo. The residue 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 CI N

H

Dissolve 10.01 g (11.04 mmol) of the product of Step B in mL of DMF containing 5.6 g (55.19 mmol) of triethylamine. Add dropwise a solution of the chloride Br

^C\

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, solution, dry the organic layer over MgSO 4 and concentrate in vacuo. Flash chromatograph the residue on 640 g of silica gel using 97% CHC1, (NH 4 OH) 3% methanol to give the product as a tan solid, mp 111.8-114.5 0

C,

MH' 677 (FAB).

WO 00/37459 PCTIUS9917939 -203- EXAMPLE 27 Step A Br 5 Cl

N

CH3 H 0 N Dissolve 4.61 g (6.8 mmol) of the product of Example 26, Step C, in 6 mL of acetic acid 9 mL of a 5.7 M solution of HBr in acetic. After 3 hr the reaction was complete by silica gel tic

CH

2 Cl1 (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 (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 122.1-130.2 0 C, MH' 543 (FAB).

Step B Br 0/Cl

N

CH

3

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 4fluorophenylisocyanate and stir over night under nitrogen. Dilute WO 00/37459 PCT/US99/27939 -204with 20 mL of methylene chloride and wash with aqueous NaHCO 3 solution, dry the organic layer over MgSO, and concentrate under vacuo. Chromatograph the residue by preparative silica gel TLC using 95% CHCl1 (NH 4 OH) 5% methanol to give 0.0179 g of the 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.

Diastereomer B: Mp 140.1-149.4°C, MH' 680 (FAB).

EXAMPLE 28 Br /Cl N

H

N

CH

3 H3C N

H

Following the procedure of Example 27, react 0.07 g (0.129 mmol) of Diastereomer A from Example 27, Step A, with tertbutylisocyanate 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 product as a white solid. Mp 128.1-135.2 0 C, MH' 642 (FAB).

WO 00/37459 PCTIUS99/7939 205- EXAMPLE 29 Br Cl

N

CH

3 H I HNN

N

H

3 C N

H

Following the procedure of Example 27, react 0.10 g (0.184 mmol) of Diastereomer A from Example 27, Step A, with isopropylisocyanate to obtain 0.041 g of the Diastereomer A product as a white solid. Mp 128.1-133.3°C, 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 128.1-133.4°C, MH' 628 (FAB).

EXAMPLE B r

C

1

NH

H

CH

3

N

CH3

N

H

3 C O 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 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, and concentrate under vacuo. Chromatograph the residue by WO 00/37459 PCT/US99/27939 -206preparative silica gel TLC using 95% CH 2 C1 2 (NH,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 product as a white solid.

Diastereomer A: Mp 120.5-125.5°C, MH' 629 (FAB).

Diastereomer B: Mp 120.3-126.1°C, MH* 629 (FAB).

EXAMPLE 31 Br Cl tN\ N

H

N

H 1

N

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 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.

Diastereomer A: Mp 137.9-138.9 0 C, MH' 656 (FAB).

Diastereomer B: Mp 136.4-138.6 0 C, MH' 656 (FAB).

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

N

C

3 H3

H

3 C O O 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 (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, and concentrate under vacuo. Chromatograph the residue by preparative silica gel TLC using 95% CHCI, (NH 4 OH) 5% methanol 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 127.1-128.4 0 C, MH' 643 (FAB).

Diastereomer B: Mp 134.9-137.5 0 C, MH' 643 (FAB).

WO 00/37459 PCT/US99/27939 -208- EXAMPLE 33 I0 I

,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. lg (0.10 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 product as a white solid.

Diastereomer A: Mp 138.1-144.6°C, MH' 621 (FAB).

Diastereomer B: Mp 139-145.1°C, MH' 621 (FAB).

EXAMPLE 34 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) 4fluorobenzoic acid, 0.032 g (0.167 mmol) DEC, 0.0225 g (0.167 WO 00/37459 PCTIUS99/7939 -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.

Flash chromatograph on silica gel using 93% CHC12 (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 white solid.

Diastereomer A: Mp 141.5-145.8 0 C, MH' 665 (FAB).

Diastereomer B: Mp 144.9-148.7 0 C, MH' 665 (FAB).

EXAMPLE Br C 1 N

H

KN CH 3 0 Following the procedure of Example 34, use 4-fluorophenylacetic 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).

Following the above procedure obtain the Diastereomer B product as a white solid. Mp 132.5-139.7 0 C, MH' 679 (FAB).

WO 00/37459 WO 0037459PCT/US99/27939 210 EXAMPLE 36 (N

CH

3

N(N

0

N

Following the procedure of Example 34, use 4-pyridylacetic acid N-oxide instead of 4-fluorobenzoic acid to obtain the Diastereomer A product as a white solid, and the Diastereomer

B

product as a white solid. Diastereomer A: Mp 168.5-172.4'C, MW* 678 (FAB). Diastereomer B: Mp 168.9-172.3'C, MH 678 (FAB).

EXAMPLE 37 Br 7\ C1 N

H

0(N N) CH3

NNN

00 Following the procedure of Example 34, use N-t--butoxycarbony-4-piperidmnacetic acid instead of 4-fluorobenzoic acid to obtain the Diastereomner A product as a white solid, and the Diastereomer B product as a white solid. Diastereomer A: Mp= 135.1-142. 1 C, MH" 768 (FAB). DiastereomerEB: Mp 141.7- 143.2*C, MH* 768 (FAB).

WO 00/37459 PCT/US99/27939 -211- EXAMPLE 38 Br N CI N CH 3 H N H N C )J 1

N\

0o 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 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 C1, (NH 4 OH) 20% methanol to give 0.113 g of 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°C, MH' 668 (FAB).

Diastereomer B: MH' 6668 EXAMPLE 39 Br Cl N NH 3 K) H N H1 '*VJ i I I I 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 mL sat aqueous NaHCO 3 Dry the organic layer over MgSO, and concentrate in vacuo. Chromatograph the residue by preparative silica gel TLC using 90% CH 2

C

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 product of Example 38, obtain the Diastereomer B product as a white solid.

Diastereomer A: Mp 148.2-151.3°C, MH' 711 (FAB).

Diastereomer B: Mp 148.1-150.4 0 C, MH' 711 EXAMPLE Br ci N

H

H CH3 CH3N 3 N N N

H

3 C 3 I N

H

3 CO O 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, 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 mL of methylene chloride. Wash with satd. NaHCO 3 solution, dry over MgSO, and flash chromatograph on silica gel using 97% CHC1, (NH 4 OH) 3% methanol to give 0.2 g of the product as a white solid. Separate the diastereomers by preparative chiral WO 00/37459 PCT/US99/27939 -213chromatography (Chiralpack AD, 5 cm x 50 cm column, flow rate 100 mL/min., 15% 2-propanol/hexane 0.2% diethylamine).

Diastereomer A: Mp 54-58 0 C, MH' 657 (FAB).

Diastereomer A: Mp 64-58 0 C, MH' 657 (FAB).

EXAMPLE 41 Br C 1 H

CH

3 N

H

H

3

C

Following the procedure of Example 40, use the product from Preparative Example 14 instead of Preparative Example 13 to obtain the product as a white solid. Mp 116-123°C, MH* 671 (FAB).

EXAMPLE 42 Br 'N C N H H3

CH

CH N HC O O

H

3

C

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°C, MH' 671 (FAB).

Diastereomer A: Mp 98-101 C, MH' 671 (FAB).

WO 00/37459 PCT/US99/27939 -214- EXAMPLE 43 CH3 'N H3CH3

H

3 C0 0

N

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 120-122 0 C, MH' 685 (FAB).

EXAMPLE 44

H

3 C 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 0 C, MH' 733 (FAB).

WO 00/37459 WO 0037459PCT/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

H

3 0 wherein R 2 is defined in Table 9.

R2 TABLE 9 Ex. Prep. Product Melting Mass Ex.

R

2 -Point Spec (amine) (OC) MH+ 18 128-133 719

H

N

N

Isomer A 46 18 129-132 719

N

Isomer B WO 00/37459 WO 0037459PCTIUS99/27939 -216-

CH

3

N

Isomer A 105-111 Isomer B 115-117 Isomer A

OH

3 CH 3 _CH 3 CH 3

N

Isomer B

OH

3

OH

3 OH 3

N

Isomer A WO 00/37459 PCTIUS99/27939 217 WO 00/37459 PCT/US99/27939 -218- 57 24 136-144 725

H

II

N

58 25 101-103 697

CH

3

N

59 26 128-133 683

H

N

EXAMPLE a-

CH

3 N N Step A 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 aqueous NaHCO, dry the organic layer over MgSO,, 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 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 as a white solid. Mp 130-139 0 C, MH' 758 (FAB).

EXAMPLE 61 Br 7

C

1 N

N

H N N H3C>K N

N

H

Step A 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 127-132 0 C, MH' 732 (FAB).

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 127-130c, MH' 732 (ma WO 00/37459 PCT/US99/27939 -220- EXAMPLE 62 Step A 1 1 3

CHOH

3 N O H C H 3

H

3 C O O H 3 C O O 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), Nmethylmorpholine (0.25 mL, 2.24 mmol) in 20 mL of DMF and stir under nitrogen over night. Concentrate under vacuum. Dissolve the residue in 50 mL of methylene chloride, wash with sat. NaHCO, soln., dry the organic layer over MgSO 4 and concentrate under vacuum. Flash chromatograph the residue on silica gel using 100%

CH

2 C1 2

(NH

4 OH) giving a white solid.

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

H

3

C

H

3

C

H3C 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 overnight and concentrate under vacuum.

Step C Cl Dissolve the product of Step B (0.5 g, 1.048 mmol), the 8-C1tricyclic 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.

WO 00/37459 WO 0037459PCT/US99/27939 222 StepR D

CI

N

H N H3C )JHj NN

H

3 C OJ" 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) 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 m-L/min., 5% 2propanol/hexane 0.2% diethylamine) giving the products as white solids.

Diastereomer A: Mp 93.1-99.8'C, MW* 655 (FAB).

Diastereomer B: Mp 93. 1-99.8'C, MW* 655 (FAB).

EXAMPLE 63

HH

NH

H

3 N H- H )111N N OH H 3 0> \H N 3 C OH 3

NH

3 C O0N Following the procedure of Example 40, use the product from Preparative Example 27 insztead of Prepaatv Ea.mpL..je 13 to obtain the products as white solids.

Isomer mix 1: Mp 148-15 1 C, MH' 687 (FAB).

WO 00/37459 PCT/US99/27939 -223- Isomer mix 2: Mp 110-114°C, MH' 687 (FAB).

EXAMPLE 64

,CH

3 v H H HCH3 NH OH HC O

N

H

3 C O O H3C

N

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 131-138 0 C decomp., MH* 687

(FAB).

EXAMPLE H3C: L II H 3 C/ *0 0

H

3 C- O

O

Following the procedure of Example 40, use the product from Preparative Example 29 instead of Preparative Example 13 to obtain the products as white solids.

Isomer mix 1: Mp 148-157 0 C, MH' 721 (FAB).

Isomer mix 2: Mp 120-126 0 C, MH 721 (FAB).

WO 00/37459 PCTIS99/27939 224- EXAMPLE 66 Br C Br CC N

H

N H N CH3 N H H O, H3C CH3

N

CH

3 'O H S O 0 N

H

3 C O O H3C O

O

HaC o o 0

O

Following the procedure of Example 40, use the product from Preparative Example 30 instead of Preparative Example 13 to obtain the products as white solids.

Isomer mix 1: Mp 146-154°C, MH* 657 (FAB).

Isomer mix 2: Mp 122-127 0 C, MH' 657 (FAB).

EXAMPLE 67 B r I Cl

N

-1 H N The 1 1R,2R(-)-diastereoisomer from Preparative Example 34 (0.25g, 0.46mmoles), 4-pyridylacetic acid N1-oxide (0.0915g, 0.598mmoles) (see Preparative Example 61 of US 5,719,148 issued 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 PTU9/73 PCTIUS99/27939 225 chromatographed on a silica gel column using 5% (10% conc.

NH

4 0H in methanol) -dichloromethane as the eluant to give the title compound: (Yield: 0.2434g, FABMS: m/z 678.0 (CDCl 3 30.1, 30.3, 30.9, 36.5, 38.5, 44.1, 44.3, 50.7, 52.5; CH: 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; 8 H (CDCl 3 4.31 (LH, s, H, 1 4.97 (LH, broad s, CHCO), 6.74 O1H, broad s, Im-H 5 6.91 broad s, lm-H 4 7.02 (1 H, broad s, Ar-H), 7.07-7.17 (5H, m, CONHCH, and Ar-H), 7.38 broad s, Imn-HJ), 7.56 (1H, s, Ar-H), 8.08, (1H, d, Ar- 8. 10 (1 H. d, Ar-H) and 8.35ppm (I1H, s, Ar-H 2 [a]D +44.40 10. 64mg/2mL, methanol).

EXAMPLE 68 Br Cl N N

H

01+ Q /1

HNF,

N-

0 The 1 LS,2R(-)-diastereoisomer from Preparative Example 34 (0.3g, 0.S52mmoles), 4-pyridylacetic acid Ni1-oxide 1 0.7l8mmoles) (US 5,719,148 Feb. 17, 1998), DEC 1375g, 0.718mmoles), HO~t (0.0969g, 0.7l8mmoles) and 4methylmorpholine (0.0788miL, 0.7 l8mmoles) were dissolved in anhydrous DMF (9mL) and the mnixture was stirred under argon at for 19h. The reaction was worked up as described in Preparative Example 40, Step A above, and chromatographed on a silica gel column using 6% (10% conc. NHOH in methanol)dichiorome thane as the eluant to give the title compound: (Ytield: WO 00/37459 PTU9/73 PCTIUS99/27939 226 0.2847g, FABMS: m/z 678.0 8c: (CDC 3 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: 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; 8, (CDC 3 4.30 (LH, s, H 11 4.96 (1H, broad s, CHCO), 6.64 (LH, broad s, CONHCH 2 6.89-7.02 (3H, broad overlap, lm-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), 8.10 (1H, d, Ar-H) and 8.37ppm (1H, s, Ar-H 2 +6.90 10.48mg/2mL, methanol).

EXAMPLE 69

H

2 N <N CNIJ O 0 The 1 1R,2R(-)-diastereoisomer from Preparative Example 34 3g, 0. S52mm-oles), 1 -aminocarbonyl-4-piperidinylacetic acid 1335g, 0.7l8mmoles) (Preparative Example 33), DEC 1375g, 0.7l8mmoles), HO~t (0.0969g, 0.7l8mimoles) and 4methylmorpholine 157mb, 1 .436nunoles) were dissolved in anhydrous DMF (7mL) and the mixture was stirred under argon at 0 C for 68h. The reaction was worked up as described in Preparative Example 40, Step A above, and chromatographed on a silica gelI c o~u I:--in11Rinr-:, 6% f' 10%/ c. NH H inmethanol)dichioromethane as the eluant to give the title compound: (Yield: 0.3547g, LCMvS: m/z 711.2 8c (CDC 3 30.3, 30,4, 31.2, WO 00137459 PCTIUS99/279 3 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 s, 4.89 (2H, s, NCONH 2 4.98 (1H, s, CHCO), 6.92 (1H, broad s, Im-H 5 6.99 (1H, broad s, Im-H 4 7.07-7. 14 (3H, m, Ar-H), 7.41 (1H, broad s, Im-H,), 7.57 (LH, s, Ar-H), 7.59 (LH, broad s, CONHCH 2 and 8.35ppm. (IH, s, Ar-H 2 200 35.5' 40mg! 2mL, methanol).

EXAMPLE Br C1

N

0 C0 0 Following the procedure of Example 69, except using the 1 1S,2R(-)-diastereoisomer from Preparative Example 34 instead of the 1 lR,2R(-)-diastereoisomer, and stining under argon for 96h instead of 68h, the title compound was obtained: (Yield: 0.3241g, LCMS: m/z 711.2 5, (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, 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; 8. (CDC 3 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 5 7.03 (1H, broad s, Im-H 4 7.10-7.17 (3H, m, AArH), 7.430 broad S, lM-H 2 .9(H ,A-)ad83pr (1H, s, Ar-H 2 [a]ID 23i-l.O0 (c=10.00mg/21mL, methanol).

WO 00/37459 PCT/US99/27939 -228- EXAMPLE 71 Br Cl

N

O+ a N N N,1

H

Pyridine-4-acylazide N1-oxide Med. Chem., 1998, 41, 877- 893) (0.346g, 2.30mmoles) was dissolved in dry toluene (30mL) and the solution was heated under reflux in an argon atmosphere at 110 0 C for Ih. The solution was cooled to room temperature and the C,-Racemic title compound from Preparative Example 141 (0.250g, 0.46mmoles) was added. The mixture was stirred at 25°C for 22h.

The solution was evaporated to dryness and the residue was chromatographed on a silica gel column using 4% (10% cone.

NH

4 OH in methanol)-dichloro-methane as the eluant to give the title compound: (Yield: 0.1265g, LCMS: m/z 679.2 6 c (CDCI,) CH,: 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, 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, 4.67 (1H, s, CHCO), 6.89 (1H, d, 6.99 (1H, d, 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, Ar-H,) and 9.77ppm (1H, broad s, NCONH).

WO 00/37459 PCTfUS997939 -229- EXAMPLE 72 Br

C

l

N

N

H

N

H CN N N Y^O 0

H

Step A Br ClI

N

CH

3 0

H

H

3 C o N N Ir N

N

H

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 lh. The solution was cooled to room temperature and added in three portions (1.47mmoles at Oh; 2.21mmoles at 69h and O.95mmoles at 93h) to a solution of the Racemic title compound from Preparative Example 141 (0.4g, 0.735mmoles) in anhydrous dichloromethane (26mL). The mixture was stirred at 25 0 C for 117h. The solution was evaporated to dryness and the residue was chromatographed on a silica gel column using 4% (10% cone. NHO4H in methanol)-dichloromethane as the eluant to give the title compound: (Yield: 0.1265g, 32%); LCMS: m/z 679.2 ,c (CDCL) CH 3 28.5, 28.5, 28.5; CH-: 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; 8H(CDC1 3 1.46 (9H, s, 4.33 (1H, s, 4.41 (1H, broad s, CHCO), 5.18 (1H, d, NCONH), 6.55 (1H, broad m, CONHCH 2 6.92 (1H, broad s, 7.08 (1H, broad s, Im-H4), 7.10-7.15 (3H, m, Ar-H), 7.50 (1H, broad s, Im-H 2 7.59 (1H, d, Ar-H) and 8.40ppm (1H, s, Ar-H 2 Step B B r /X C1 HN

N

HN N N N

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. H2SO, in dioxane (4.18mL) was added. The mixture was stirred under argon at 25 0 C for Ih. The mixture was passed over a bed of BioRad® AG 1-X8 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. NH 4 OH in methanol)dichloromethane as the eluant to give the title compound: (Yield: 0.1984g, LCMS: m/z 669.2 8 c (CDCs) 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, (CDC1) 4.29 (1H, s, 4.61 (1H, broad s, CHCO), 5.72 (1H, broad m, NCONH), 6.85 (1H, m, CONHCH,), 6.92 (1H, broad s, Im-H.J, 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- 7.66 (1H, broad s, Im-H,) and 8.37ppm (1H, s, Ar-H 2 Step C B r I c

N

O H

N

H2N NN N N

H

The title compound from Step B above (0.195g, 0.

2 91mmoles) was dissolved in anhydrous dichloromethane (10mL) and trimethylsilyl isocyanate (0.394mL, 2.91mmoles) was added. The mixture was stirred under argon at 250C for 20h. Additional trimethylsilyl isocyanate (0.188mL, 0.873mmoles) 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,), filtered and evaporated to dryness. The product was chromatographed on a silica gel column using 4% (10% conc. NH 4 OH in methanol)-dichloromethane as the eluant to give the title compound: (Yield: 0.1325g, LCMS: m/z 712.2 8 c (CDCI,) CH,: 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, 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;

(CDC

3 4.31 (1H, s, 4.53 (1H, broad s, CHCO), 4.75 (2H, broad s, NCONH,), 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), 7.10-7.15 (3H, m, Ar-H), 7.46 (1H, s, Ar-H), 7.58 (1H, broad s, Im-H 2 and 8 .38ppm (1H, s, Ar-H,).

WO 00/37459 PTU9/73 PCT/US99/27939 232 EXAMPLE 73 0 4, N 0 The 11 R,2R(+)-diastereoisomer from Preparative Example 38, Step D above 1647g, 0.294mmoles), 4-pyridylacetic acid N I-oxide (0.0586g, 0.382mmoles), DEC (0.0733g, 0.382mrnoles), HOBt (0.05 17g, 0.382mmoles) and 4-methyl-morpholine (0.042m-L, 0.382mmoles) were dissolved in anhydrous DMF (5mL) and the mixture was stirred under argon at 25'C for 25h. The reaction was 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, 5 1 SIMS: m/z 694.5 8c (CDCl 3 30.0, 30.4, 31.0, 36.7, 38.5, 44.1, 44.5, 50.5, 51.3; 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; 86H(CDCl 3 4.98 (1H, broad s, CHCO), 5.70 (1H, s, H 11 6.92/6.97 (1H, broad s, lm-H 5 7.01 (lH, broad s, Im-Hj, 7.08-7.18 (5H, m, Ar-H), 7.43/7.51 (1H, broad s, Im-H 2 7.79 (1H, t, CONHCH 2 8.05 (1 H, d, Ar-H), 8.09 (2H, d, Ar-H), 8.26/8.3lppm (1H, s, Ar-H 2 [a]D 0 +82.80 (c=9.1 lmg/2mL, methanol).

WO 00/37459 PTU9/73 PCT/US99/27939 233 EXAMPLE 74 Br- C I

N+H

NN 11 0 The 1 1S,2R(-)-diastereoisomer from Preparative Example 38, Step D above 1576g, 0. 28 1immoles), 4-pyridylacetic acid N I-oxide (0.0560g, 0.366mmoles), DEC (0.0702g, 0.366rnmoles), HOBt (0.0495g, 0.366mrnoles) and 4-methyl-morpholine (0.040mL, 0.366mmoles) were dissolved in anhydrous DMF (5m L) and the mixture was stirred under argon at 250C for 26h. The reaction was worked up as described in Preparative Example 40, Step A above, and chromatographed on a silica gel colunm using 2% increasing to 6% (10% conc. NH 4 0H in methanol) -dichloromethane as the eluant to give the title compound: (Yield: 0.10 17g, SIMS: m/z 694.5 (CDCI.) 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, 133.3, -137.3, 138.3/138.7, 138.7, 138.7; 0: 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, 1 6,58 (1H, t, CONHCH 2 6.88 (1H, broad s, Im-H 5 6.98/7.03 (1H, broad s, Im-H4), 7.09-7.2 1 (5H, m, Ar-H), 7.34/7.41 (LH, broad s, Lm-H2), 8.09 (LH1, d, Ar-H), 8.10 (2H, d, Ar- 8.27/8.28ppm (1H, s, Ar-H 2 Ia D 20 *1 -12.7- (c=10.O8mg/2mL, methanol).

WO 00/37459 PTU9/73 PCTIUS99/27939 234 EXAMPLE 0

H

H

2 N NN 0 0 3-Bromo-8, 11 -dichloro-6, 11 l-dthydro-5H-benzo[5,5cyclohepta[1,2-blpyridine N I-oxide (Preparative Example, 38 Step C) (0.2656g, 0.74nrnoles) in anhydrous dichioromethane (3.8m-L) was added to 1 -12-[N-[3-(l1H-im-idazol- 1-yl)propylJ-2(R)piperazinecarboxam-idel -2-oxoethyl- 1 -piperidinecarboxamide (Preparative Example 40, Step B above) (0.3g, 0.74mmoles) and triethylan-Ane (1.03 l6mL, 7.40mmoles) in anhydrous dichioromethane (6mL) and the mixture was stirred at 25'C under argon for 1 9h. The solution was directly chromatographed on a silica gel column using 3.5% (10% conc. NHHin methanol)dichioromethane as the eluant to give the title compound: (Yield: 0.3727g, LCMS: m/z 727.2 (CDC 3 CH,: 29.9/30. 1, 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; 8H

(CDC

3 4.60 (1H, s, NCONH 2 4.98 (1H, broad s. CHCO), 5.69 (1H, s, H, 1 6.29/6.53 (1H, t, CONHCH 2 and isomers at C,, respectively), 6.92 (1H, broad s, lm-H 5 7.05 (LH, broad s, Im-H J1 7.14 (2H, m, Air-H), 7.18 (1H, m.Ar-H), 7.20 (1H, m, Ar-H), 7.56 (1H, broad s, JmT-H,.) and 8.27Tppm (1H. s, WO 00/37459 WO 0037459PCT/US99/27939 235 EXAMPLE 76 Br, C1

N

C(N~ NH (1 -Isomer)

HH

N(11 R, -Isomer) N 0

H

Method 1: 3-Bromo-8, 1 -dichloro-6, 11 -dihydro-5H-benzo[5,5]cyclohepta[ 1,2-blpyridine Ni -oxide (Preparative Example 38, Step C) (0.28 18g, 0.785mmoles) in anhydrous dichloromethane (4mb) was added to NI -cyclohexyl-N2- 13- (1H-imridazol- 1-yl)propyll- 1,2(R)piperazinedicarboxamide (below) (0.2844g, 0.785mmoles) and triethylammne (1.094mb, 7.85mmoles) in anhydrous dichioromethane (4.5mb) 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% conc. NH 4 OH in methanol)dichioromethane as the eluant to give the racemic mixture of the title compounds: (Yield: 0.4664g, The mixture was subjected to preparative HPLC on a Chiralpak ADO column (5OX5cm) using hexane- 35% isopropyl alcohol- 0.2% diethyiam e"as the11 eluant to give in the order of elution the 1 1S, 2 R(-)-diastereoisomer and the I IR,2R(-i--diastereoisome.

WO 00/37459 WO 0037459PCTIUS99/27939 236 11 -diastereoisomer: (Yield: 0 155.5g); LCMIS: m/z 684.2 8c (ODC1 3 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; OH: 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, 141.4, 147.8, 157.6, 171.2; (CD01 3 4.53 broad s, CHOO), 4.91 (1H, d, NCONI, 5.68 (1H, s, 6.62 (11H, t, CONHCH 2 6.94 (1H, broad s, Im-H- 5 7.08 (1 H, broad s, lm-H 4 7.15 (1 H, m, Ar-H), 7.17 (1H, s, Ar-H), 7.21 s, Ar-H), 7.23 (11H, m, Ar-H), 7.55 (LH-, broad s, Im-H- 2 and 8.27ppm (1H, s, Ar-H 2 [aID 2 0 0 -33.1- (c=8.76mg/2mL, methanol).

11 R,2R(+)-diastereoisomer: (Yield: 0. 1890g); LOMS: m/z 684.2 8c (ODCI,) 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, 134.7, 140.4, 141.4, 147.5, 157.5, 17 1. 1; (CDC1 3 4.52 (1H, broad s, CHCO), 4.95 d, NCONjIf, 5.69 (1H, s, 6.97 (1H, t, CONHCH,), 6.97 RLH, broad s, Im-H 5 7. 10 (1 H, broad s, Im-H- 4 7.13 (1H, m, Ar-H), 7.18 (2H, s, Ar-H), 7.21 m, Ar-H), 7.69 (1H, broad s, Im-H,) and 8.27ppm s, Ar-H 2 oO+49.90 (c=1.23mg/2miL, methanol).

The starting reactant N I -cyclohexyl-N2-[3- (1 H-iniidazol- 1 yl)propylj- 1,2(R)-piperazinedicarboxanude is obtained following the procedure of Preparative Example 5, except that N _H 2 is used instead of Me Me The resulting BOO protected compound is deprotected with TFA following the procedure in Preparative Example 8. Step B.

WO 00/37459 PCT/US99/7939 -237- Method 2: The 1 1S,2R(-)-diastereoisomer (Preparative Example 38, Step D above) (Img, 0.00179mmoles) was dissolved in anhydrous dichloromethane (0.05mL) and cyclohexylisocyanate (0.0023mL, 0.0179mmoles) was added. The mixture was stirred at 25 0 C for 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.

EXAMPLE 77 Br C1 Br C EDCI, HOBT, N

NMM

DMF

reagent 1 DMF N COOH reagent 2 N C-N N

H

3

CCH

3 H 3 C CH 3

CH

3 CH3 Reagent 2 NVN,-- NH The imidazole from Preparative Example 74 (Reagent 2), (250mg, 1.16mmol), was added to a solution of the BOC-acid (Reagent 1, see Preparative Example 41), (0.45g,0.842mmol) EDCI (200mg, 1.043mmol), HOBT (130mg, 0.962mmol),and N-methyl morpholine (0.2ml, 1.81mmol) in DMF (anhydrous, 2ml) at room temperature (20 0 The resultant solution was stirred overnight at 0 C. The solvent was evaporated, water (70ml) and EtOAC (120 ml) were added. The organic layer was separated, and washed with Na 2

CO

3 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 PCTIUS99/7939 -238- Mass Spec: High Resolution(ES) Estimated(MH*) 732.2316 Observed 732.2332 EXAMPLE 78 Step A Br Cl Br Cl N N II I II N C N N N N CN N N O o0

H

H

3 C k CH3

CH

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

CH

2 C1 2 was stirred at 20°C for 3 hours. The solvent was evaporated, water (25ml) and 10% NaOH (4ml) were added, then extracted with

CH

2

C

2 (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- CHCL, containing 2% NH 4 OH yielding the product as a white solid 54% yield).

The product was obtained as a mixture of 2 Isomers (C and (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 FABS 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 632.

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 C 1 Br 1

C

1 N

N

N CN NN N N C, N N N I II I II H 0 0O0° Ha 3

CCH

3

CH

3 A solution of di-tert-butyldicarbonate (65mg,0.29mmol) in

CH

2 C, (2ml) was added to a solution of Product 1 (Step A, Isomers C and D) (150mg, 0.237mmol) in CH 2 C2 (10ml), at 0°C, then stirred at 20 0 C for 10 minutes. The reaction was cooled to 0°C, water 10% NaOH (2ml) and CH 2 C1 2 (10ml) were added. The organic layer was separated, dried over MgSO 4 filtered and solvent evaporated yielding an oil, which was chromatographed on silica gel, eluting with 3% v/v MeOH: CH 2 C 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') Calculated (CH,N 5

O

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 H N "N NN CN N N II I II 0 0 H 0 H3C' tCH3 CH3 Following the procedure of Example 78 Step A, the BOC 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

C

1 Br C1 H ONN K) NI N i If J' I IQ ON Vc N 0

H

Cyclohexyl isocyanate (0.025m,0.19mmol) was added to a solution of Isomer A (Example 78, Step A) (25mg, 0.039mmol), in

CH

2 C 2 (3ml) at 0°C, then stirred at 20 0 C for 30 minutes. Methylene chloride (20ml) and water (20ml) were added. The organic layer was 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 C4, yielding the product (Isomer A) as a white solid (25mg). High resolution Mass Spec (ES) Calculated:

C,

4

H

4

,O

2

N

6 CIBr (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 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 yields the C and D isomer mixture of the title compound Mass Spec (ES,MH*) 757 EXAMPLE N N N N C N N H O I II

C

2

H

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

CH

2 C, (2ml) at 20 0 C. Triethylamine (0.lml, 0.7mmol) was added, and the solution was stirred for 30 minutes at 20°C. The solvent was evaporated, and the residue chromatographed on silica gel, eluting with 3% v/v MeOH: CH 2

C

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 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 formula:

N

S R8

R

1 4

O

wherein R 8 and R 1 4 are defined in Table 10 below are obtained.

TABLE .0 Ex. R" R" Isomer MS 81 (Product of Prep.

Ex. 9.1 and di-tbutyldicarbonate) 0

H

3 C VCH 3

CH

3

A

and

B

(R,S)

Fabs

(MH)

565 82 (Product of Prep.

Ex. 111.1 and di-tbutyldicarbonate) A ES 0 0 and (MH) H3C CH 3 B 655

CH

3

(R,S)

WO 00/37459 PCT/US99/27939 -243 83 (Product of Prep.

Ex. 111.1 and di-tbutyldicarbonate) 84 (Product of Prep.

Ex. 111.1 and di-tbutyldicarbonate) (Product of Prep.

Ex. 111.1 and cyclohexyl isocyanate) J A

ES

0 o

(MH)

H3C CH 3 655 CH3 0 OJO B

ES

0 (MH) H3C CH 3 655 [a]CH34 P H

A

and

B

(R,S)

ES

(MH)

680 The compounds of Examples 83 and 84 were separated on Chiralcell AD column.

EXAMPLE 86 Br C1 Br N\ C1 N 1IS Isomer N11R Isomer H

HN

N O N O H H Following the procedures of Examples 77-79, but substituting an equivalent quantity of l-(3-aminopropyl)imidazole for the Nbenzyl substituted imidazole from Preparative Example 74 in Example 77, the title compounds are obtained.

11S-Isomer: Mass Spec: Fabs 667(Br=79) HRMS Calc (MH) C 33

H

4

,N

6 0 2 C1(8 )Br 669.2142 Measured 669.2151 WO 00/37459 PCTIUS9927939 -244- 11R-Isomer: FABS 667.

EXAMPLE 86A 0

H

3 C N\^j N O H N 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

C

which is then reacted with cyclohexyl isocyanate according to the 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 using the 11(R)-isomer, compounds of the formula: PCTIUS99/27939 WO 00/37459 PTU9/73 245 KN #N NX 14 1

R

1 0 are obtained. R 1 4 is defined in Table 11.

TABLE I11 Ex. R 4Isomer Mass Spec Observed (Estimated) 87 1A, B, C, D 732.2343 0 0 (732.2316)

H

3 C+ CH 3 3 88 [A 732.2332 0 0 (732.2316) 3

C,'+-CH

3

CH

3 89 1B 734.2305 0 0 (743.2296) 3CCH 3 A 757.2641 N -J O(757.2632)

H

91 B 759.2618 N o (759.2612)

H

WO 00/37459 WO 0037459PCT/US99/27939 -246- 92 C 734.2296 0 J~o(732.2296)

GH

3 93J D 734.2297 0 0 (734.2296) H3GH 3 3 94I C, D 734.2318 0 0 (734.2296) H CCH 3

CH

3 1C 759.2611 K>N'O (759.2612)

H

96 1D 759.2618 K>N O (759.2612)

H

97 C, D 759.2626 N 'N"O (759.2612)

H

EXAMPLE 98 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 in N,N,-dimethylformamide and triethyl amine (0.445 mL, 3 eq.) was added and 3-bromo-8,11-dichloro-6,11-dihydro-5Hbenzo[5,6]cyclohepta[ ,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 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.

The compound was separated into its pure enantiomeric forms by HPLC on a Chiral Technologies AD column using isopropanol/hexanes. Isomer 1: mp= 148.3-157.5°C; Isomer 2: mp= 148.3-157.5°C EXAMPLE 99 Br

C

I

N

HO

HN-

The title compound from Preparative Example 48 (0.487 gm) was dissolved in dichloromethane (3 ml) and trilluoroaceic acid (3 WO 00/37459 PCT/US99/27939 -248ml) and the reaction mixture stirred for 2 hours. The reaction mixture was evaporated to dryness and dissolved in 10 mL of N,Ndimethyl-formamide. Triethylamine (1.42 mL, 10 eq.) was added and 3-bromo-8, 11-dichloro-6, 11 [5,6]cyclohepta[l,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 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.

Isomer 1: mp= 192.7-194.3 oC; Isomer 2: mp= 189.2-190.7 0

C

EXAMPLE 100 Br C 1 N

H

N N

OH

0 OH 0 ^0

H

3 C CH 3

CH

3 The title compound from Preparative Example 52 (0.3 gm, mmol) was stirred in a mixture of 10 ml of dichloromethane and /LL 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% NaSO, solution followed by sodium bicarbonate solution and evaporated to dryness under vacuum. This compound was dissolved in WO 00/37459 PCT/US99/27939 249 dichloromethane and a premixed solution of 4-iodo-1-tritylimidazole (89 mg) and ethylmagnesiumbromide (3M soln in ether, 66 IL, added to the reaction mixture and stirred at ambient temperature for 4 hours. The reaction mixture was poured into 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.

EXAMPLES 101-102 Following procedures similar to those described in Examples 98-100, the following compounds are obtained: Br/ Cl O CH N Example 101

H

and

H

3 C-1-CH 3

CH

3 Example 102 WO 00/37459 PCT/US99/27939 -250 EXAMPLE 103 H N

N

NH

2

CH

3

H

3 C H 3

H

3 C K N The title compound from Preparative Example 58 was dissolved in 1 ml of dichloromethane and 68 microliters of tertbutylisocyanate 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 preparative thin layer chromatography. FABMS M+1= 659.

WO 00/37459 PCT/US99/27939 -251 EXAMPLE 104 Br C l

N

CH

NN

HN

H3C N O O =0 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 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 N C1 N H N N N

CH

3 N

NH

2 H3C "O 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-3propanol to obtain the title product in 65% yield. FABMS MH'= 660.

WO 00/37459 PCT/US99/7939 -252- EXAMPLE 106 B r

C

1

N

N H

N

CH3 i N H3C ON 0

H

3 C >O 0 F3 The title compound was prepared following the procedure set forth in Example 104, but using the title compound from 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 N Cl

N

(N H

N

CH3 N

N

HCC O 0 HC N O O H 3 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 N HN CH3 §N

OH

H3 0 H 3

C

H

3 C N O The title product was prepared following the procedure set forth in Example 110, but substituting the title compound from 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 CH _N OH HBrC C The title product was obtained following the procedure set forth in Preparative Example 52, but substituting 2-S-benzyl-3-R,Shydroxy-histamine for 1-amino-3-propanol. FABMS 737.

WO 00/37459 PCT/US99/27939 -254 EXAMPLE 110 Br CC 1 Me H-N

CH

3

,N

INN

H

A mixture of the title compound from Preparative Example 102 Step C (0.28 g, 2 mmol), the title compound from Preparative Example 44 (0.5 g, 2 mmol) and anhydrous CH 2 C12 (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 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 mixture was stirred at room temperature overnight, concentrated in vacuo and purified by flash column chromatography (silica gel) using 5% MeOH-95% CH 2 C12 saturated with aqueous ammonium hydroxide to give the title compound as a mixture of diastereomers (tan solid, 95 mg, MH+ 682, mp 118.4°C).

WO 00/37459 PCT/US99/27939 -255- EXAMPLE 111 Br Et H-N

N

N N N NN CH 2

CH

3 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 compound from Preparative Example 103, the title compound was obtained as a mixture of diastereomers (brown, sticky solid, 28.7 mg, MH+ 696, mp 79.3°C).

EXAMPLE 112 Br/

C

l PrN H-N

N

N N, N

CH

2

CH

2

CH

3 N N

CH

N O N Hi 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%, MH+ 710, mp 63.8-67.4°C).

WO 00/37459 PCT/US99/27939 -256- EXAMPLE 113 Br /\CI Br /C 0 1 Nr N N \OH -N N N 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, mmol), the title compound from Preparative Example 74 (4.32 g, 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 C1 2 and washed with a 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 as a mixture of diastereomers (4.92 g, 36%, MH+ 733).

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 \c 0 1 F jb CHr"N Amine

A

Compound A WO 00/37459 WO 0037459PCTIUS99/27939 257 P~~CH3 Amine B Compound

B

N

Amne CCompound

C

I~ CH3

H

Amine D

CH

3

H

3

C'

H

3

C,

Compound

D

EXAMPLES 115-126 Following the procedure set forth in Example 113, but using the N-substituted imidazolylalkyl amine (Imridazole) in Table 12 and the carboxylic acid from Preparative Example 51, the Products in Table 12 were obtained.

WO 00/37459 WO 0037459PCTIUS99/27939 258 TABLE 12 IF1

N--NN

HNN

Br/

\CI

0

N

1.-6 f---1

N

Br k 1 \C

OH

N

1.52 2. 749 3. oil PCT[US99/27939 WO 00/37459 259 ~~OMe H-N r1=1 1. 48 2. 763 3. 125- 130 N H jN Br/ \C1

CN

AK -0

N,

0 1. 2. 758 3. semisolid 1. 19 2. 776 3. semisolid H-N r-_7

NI

H-

Br/\ y ,C1

NN

1.15 2. 783 3. 85-90 /_0

N~

1. 12 2. 739 3. semisolid WO 00/37459 PCT/US99/27939 -260- 125 126 H-N N N Br C1

N

0N rr oo 747 86 84.7

HN

Br C1

NN

O 0N1 0 1. 2. 719 3. 206.7

(B)

121.2- 130.4 EXAMPLE 127

N

N~N~N

1=\ .N N H u 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 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 obtained.

TABLE 13 Ex. Isocyanate Product 1.Yield and 2. MH' Prep. Ex. 3. mp (oC) Compound 128 NO Br l 1.87 NC 2.760 Prep. Ex. 109 o N 3. 125.2 Diastereomer A N O

H

222421 129 Br 7 C 1.61

NCO

N r 2.732 Prep. Ex. 109 N, o N 3. 126.6 Diastereomer A o

H

130 >jo Br i 1.100 NCO

N

N. 2.732 Prep. Ex. 109 0 N N 3. 112.3 Diastereomer B N o

H

WO 00/37459 PCT/US99/27939 262 131 S 'NCO Prep. Ex. 109 Diastereomer A N l

NNN

N o

I

H

1.95 2.718 3. 109.8 132 NO Br 1 1.63

NCO

(NN 2.718 N N'4-N Prep. Ex. 109 o N 3.118.1 Diastereomer B N o

I

H

133 NCO Br r/Cl 1.95 N 2.704 Prep. Ex. 109 L ).N Diastereomer A N 0 3. 93.5

H

134 N'^Nco Br'%^rY C1 1.86 N -2.718 Prep. Ex. 109 N 2.718 Diastereomer B 0 A 0 N 3. 98.9

S

0

H

PCTIUS99/27939 WO 00/37459 -263 135 NCoBr %\Cl 1.56 N ro 2. 752 N, N 3. 81.4 Prep. Ex. 109 (a 0 2.75 N 0 Diastereomer A

H

136 N NCO Br[N C1 1.17 N 2.766 Prep. Ex. 109 N 0 Diastereomer AH 137 Br.. 1 1.80 NCO N N 2. 780 Prep. Ex. 109 N 36 Diastereomer A H 138 Br. CC 1 1.68

NCO

N 2. 772 Izz C-0Me

N\

Prep. Ex. 131 0 N O Diastereomer AI

H

WO 00/37459 PTU9/73 PCT[US99/27939 264 Oa NCO Prep. Ex. 131 Diastereomer B OkNCO ro Prep. Ex.1 13 Diastereomer A

N

Prep. Ex. 113 Diastereomer B

>(NCO

Prep. Ex.117 Diastereomer B WO 00/37459 PCT/US99/27939 -265-

NCO

Prep. Ex.117 Diastereomer A

NN

0 2 N, N

N

Hl N N 0r N

H

Prep. Exll Diastereomer

B

N~r N N~ 0

H

Prep. Ex. 111 Diastereomer

A

2. 654 3.61.3- 69.3

NCO

Prep. Ex. 111 Diastereomer

B

1.91 2. 645 Prep. Ex.125 WO 00/37459 PCT/US99/27939 -266- 148 N Br c l 1.68

NCO

1

N^\

.N 2. 2 735 Prep. Ex.130 o N,

H

EXAMPLE 149 BrY C1 Br C1 So 0 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 Cl 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 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 CH2C1 2 saturated with aqueous ammonium hydroxide to give the title compound as an off-white solid (54.4 mg, 93%, MH 737). SCH EXAMPLES 150-217 Similarly, using the -pro ure describ ed for Exampie 149, the 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/US99/27939 -267chloroformate, 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.

TABLE 14 Ex. Electrophile Product 1. Yield and Prep. Ex. 2. MH' Compound 3. mp

(OC)

150 CO Br CI 1.54 2.675 H3C

N

3. 79.7

N

Prep Ex. 109 N 2 Diastereomer A oN N 0 151 C Br CI 1.75 2.675 H3C O f-N N 3. 69.3 Prep Ex. 109 N 3.69.3 N N Diastereomer B o N N 0 152 Co Br 1 1.72 2.717 3. 86.4 Prep Ex. 109 Diastereomer A 7I n-C4H9 0 WO 00/37459 PTU9173 PCTIUS99/27939 268 cl 0 Prep Ex. 109 Diastereomer A

N

0 0 Prep Ex. 109 Diastereomer A

.N

Prep Ex. 109 Diastereomer A Prep Ex. 109 Diastereomner A /=k WO 00/37459 PCT/US99/27939 -269- 157 1

C'

Me* N Me Prep Ex. 109 Diastereomer

A

I

Br c Me. 0

N

Me Me 1.92 2. 704 3. 114.7 1 I 158 1

C'

Me .t Me Br\ \ci

N'

N

0 Me 0 Me 1.100 2. 704 3. 110.4 Prep Ex. 109 Diastereomer B 159 0 l Br2 cl1.97 2 N 2.733 Prep Ex. 109 N 3. 103.5 Diastereomer A -j, 0 N N N 160 0 Br r\ ci 1.83 SN2.733 2N 3. 94.5 Prep Ex. 109 Diastereomer B 0 WO 00/37459 PCT/US99/27939 -270- 161 cy Prep Ex. 109 Diastereomer A N, N 1. 2. 719 3. 95.5 162 Cl Prep Ex. 109 Diastereomer A ci /a0- 1.87 2. 733 3. 84.5 *1~ 163 cl Prep Ex. 109 Diastereomer A

NN

0 0 0 1.89 2. 705 3. 93.7 164 Br CI 1.89 0 O N Yi 2.719 3. 79.8 Prep Ex. 109

N

Diastereomer A 0 0 WO 00/37459 PTU9/73 PCT[US99/27939 271 Prep Ex. 109 Diastereomer A Prep Ex. 109 Diastereomer A Prep Ex. 109 Diastereomer A Prep Ex. 109 Diastereomer A 00 Prep Ex. 109 Diastereomer A WO 00/37459 PCT/US99/7939 -272 170 cl Br/k ci 1.83 S1o 0N 2.759 Prep Ex. 109 c 3.78.7 Diastereomer A 0 N N 171 Br Cl 1.96 cl 2.815 LK j N. 3.96.4 N N=\ b od o Prep Ex. 109 0 Diastereorer A 172 B\1.88 Br Cl 2.815 0 3.95.8 Prep Ex. 109 O Diastereomer A 0 0 173 MeSO 2 C Br C 1 1.68 2.711 Prep Ex. 109 3.113.6 Diastereomer A (NJ AJI Me-' 0 WO 00/37459 PCTIUS99/27939 -273- 174 MeSO 2

CI

Prep Ex. 109 Diastereomer B

N

\NN, N 1. 83 2.711 3. 114.6 T 4-, 175 n-PrSO 2

CI

Prep Ex. 109 Diastereomer A Br 7l

N

0N /k 0 1.50 2. 739 3. 86.5 I i 1 176 n-PrSO 2

CI

Prep Ex. 109 Diastereomer B 1.15 2. 739 3. 93.8 N J 0 0 T t J 177 n-BuSO 2

CI

Prep Ex. 109 Diastereomer A Br c

N

I(

0 1.40 2. 753 3. 87.9

L

WO 00/37459 PCTIUS99/7939 -274- 178 i-PrSO 2 C1 Prep Ex. 109 Diastereomer A Br/\ ,\C1

N

NV

Br 0 1.21 2. 739 3. 93.2 4. *1* 179 PhCH 2

SO

2

CI

Prep Ex. 109 Diastereomer A Br cl N b rP 6 j 1.50 2. 787 3. 110.4 180

C'

0-1\ 0 Prep Ex. 109 Diastereomer A Br v Cl ol 0 1.92 2. 715 3. 105.5 t 181 1

C'

0 Prep Ex. 109 Diastereomer A Br ci 1.98 2. 701 3. 106.8 WO 00/37459 PCT[US99/27939 275 WO 00/37459 WO 0037459PCT/US99/27939 276 Prep Ex. 111 Diastereomer

A

N~

Prep Ex. 111 Diastereomer B Prep Ex. 111 Diastereomer B /-0 1= Prep Ex. 109 Diastereomer

B

Prep Ex. 111 Diastereomer B WO 00/37459 PCT/US99/27939 277 WO 00/37459 PCT/US99/27939 -278- 195 Br C 1.69 2.733 N 3. 96.1- Prep Ex. 131 Me 120.*3 Diastereomer A No OON N N o 0 196 cl Br X ci 1.77 O0 o N 2.733 3. 105.1- Prep Ex. 131 Me 114.2 Diastereomer BN N 197 Cl Br 1.56 2. 775 N 3. 100.4me Prep Ex. 131 <N 108.8 Diastereomer B 0 o 198 Cl 1.69 2. 695 0 N 3. 82.5 Me Prep Ex. 114 0 ,y N Diastereomer B 0 o 199 cl cl 1.60 2. 695 N' 3. 83.4 Me Prep Ex. 114 N N f=< Diastereomer A o 0 WO 00137459 PCT/US99/27939 -279- 200 201 202 203 204 c' Prep Ex. 114 Me Diastereomer A N N 0 0

C'

Prep Ex. 114 Diastereomer B a Cl 00- o Prep Ex. 114 Diastereomer A Prep Ex. 114 Diastereomer B Cl 1 \cl -Se

'N

Me 00 NN D~.rhN 1.61 2. 655 3. 83.2 1. 64 2. 655 3. 81.2 1. 72 2. 681 3. 98.2 1. 76 2. 681 3. 94.5 1.62 2. 659 3. 97.8 Me

N

f-F Prep Ex. 108

N

DiastereomerA o I fl0 WO 00/37459 WO 0037459PCT/US99/27939 280 Prep Ex. 108

CN

Diastereomner B

OA

(A 0 4 Br 2 Prep Ex. 117 Diastereomner A Prep Ex. 117 r Diastereomner B c i

C

o,-koN

F

N 0 0 I 0

N

N

0 NeN 0 Prep Ex. 121 Diastereomner A WO 00/37459 WO 0037459PCTIUS99/27939 281 a cl Prep Ex. 121 Diastereomner A Q- 0 [a Cl Prep Ex. 121 Diastereomner B a Cl Prep Ex. 121 Diastereomner B 0)= O- 0 Cl Prep Ex. 121 Diastereomner A WO 00/37459 PCTIUS99/27939 -282- 210

A

Prep Ex. 121 Diastereomer A C1

N

(N)

(IN fNN~ 0 2 r t J 210

B

Prep Ex. 121 Diastereomer B

N

coN 0 0 0 )r 0 211 Cl 1.93 SN> 2.709 N 3.83.2 Prep Ex. 124 N N Diastereomer A LN 212 cl 1.94 2.709 N 3. 83.6 Prep Ex. 124 7 N Diastereomer B 0 o I_ _I _I WO 00/37459 PCT/US99/27939 -283r 213 a cl~ Prep Ex. 124 Diastereomer A 214 MeSO 2

C

Prep Ex. 125 215 1 MeSOCI

N

N

N

iJ 0,

N

CN./ N s= 0 Me' 0

(N

Me'\\ 0 \1 c

Q

N W 14 z N s=O Me" -0O 1.68 2. 695 3. 88.2 1. 81 2. 598 3.81 1.69 2. 633 3. 69 1.71 2. 633 3. 106 Prep Ex. 111 Diastereomer A 216 MeSO 2 C1 Prep Ex. 111 Diastereomer B 1 PCT/US99/27939 WO 00/37459 -284- 217 r cl 1.73 N 2. 736 Prep Ex. 130 N N N N EXAMPLE 218 If the procedure described in Example 149 were followed, the title compound from Preparative Example 109 (diastereomer A) could be reacted with Cl 0

O

to give the compound Br f- \Cl O C 1 0N^N EXAMPLE 219 If the procedure described in Example 149 were followed, the title compound from Preparative Example 109 (diastereomer A) could be reacted with to give the compound WO 00/37459 PCT/US99/27939 -285- Br -Cl

N

0 0 EXAMPLE 220 If the procedure set forth in Preparative Example 51 were followed, but substituting the 3,8-dichloro tricyclic alcohol CI

CI

OH

for the 3-Br-8-Cl tricyclic alcohol, the following compound could be prepared: Cl C1 H C ,3 ,/OH CH 3 N

H

3 C 0 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 PCTIUS99/27939 -286- CH3 11

H

3 C O Then, if the procedure of Preparative Example 109 were followed using the above compound the following compound could be obtained: Cl N CH3 H 0 Then if the procedure of Example 149 were followed using the above compound and

CO

oxyo the following compound could be obtained Cl Cl N

C

H

3 O 0 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 CI C F N

CH

3 O N N N

N

EXAMPLE 221 Br y \Cl Br/N C1 I N Ni N

N

H 0 NN N N N 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 (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 MgS0 4 Filtration and concentration in vacuo provided a residue which was purified by preparative plate chromatography (silica gel) using 5% MeOH-95% CH 2

CI

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 WO 0037459PCT/US99/27939 288 EXAMPLES 222-224 Following the procedure described for Example 22 1, the title compound (diastereomer A or B) from Preparative Example 109 was treated with the carboxylic acid given in Table 15 to give the Nbenzyl Product listed in Table TABLE Ex. Carboxylic Acid Product 1. Yield and

N%

Diastereomer of 2. MH+ Prep. Ex. 109 1_ 13. mp(*C)I 222

OH

U-"Z 0 Diastereomner A Br

C

0 74 757 94.7 223

OH

01,, 0 Diastereomner B 13. 104.2 2241I

H

2 Ny0

N

OH

0 Diastereomner A CI11. 59 2. 801 3. 129.3

H

2

N

WO 00/37459 PCT/US99/27939 289 EXAMPLE 225 1 CH3 N H-N /CH3 co NNN N NI N N o0 0 2 o0 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 (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 Cl 2 and washed with a 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 Cl 2 saturated with aqueous ammonium hydroxide to give the title compound (1.7 g, 69%, MH 695).

EXAMPLES 226-232 Following the procedure described for Example 225, the Products listed in Table 16 below were prepared using the 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 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* No. 3. mp (OC) 226 89 (1 1.40 2.709 Me J3. 92.4

N

N N O'o Me 227 86 \1 C 1. 43 2. 696 S3. Me3.7 228 90 cl 1.39 N 2.713 FMe 3 .74.6 N Me 6 WO 00/37459 WO 0037459PCTIUS99/27939 291 1. 44 2. 708 3. 85.6 1. 29 2. 681 3. 82.2 Ne- Me 00

NN

6 Me 1.71 2. 695 3. 79.7 1. 62 2. 709 3. 85.6 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 Cl N NCH

N-

(N C3 Example 234B O (o o EXAMPLE 235 Br C Br Cl 1 N N Ph Nr OH .v N Ph Boc 0 Ph Ph The title compound from Preparative Example 51 (0.184g, 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 with H 2 0 until precipitation ceased and the slurry filtered. The precipitate was diluted with CHC1 ,washed with brine,dried over NaSO, and concentrated. The crude product was purified by chromatography using a 5% (10%NHO4H in MeOH) solution in

CH

2

C

2 as eluent to give the title compound (0.18g, 42 yield).

WO 00/37459 PCTIUS99/27939 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 are obtained, wherein Z is as defined in Table 18.

TABLE 18 Amine

Z

Ph Ph Ph Ph N N Ph Ph Ph FAB: MH' 975

CH

3

CH

3 Ph Ph I

HNN

FAB: MH' 747 WO 00/37459 WO 0037459PCTIUS99/27939 294 238 H2N P~nH

H

2 N N OH OH FAB: MH-V= 735 EXAMPLE 239

CH

3

H

3 C .>j

H

3 C Step A

-_CI

Ph

NH

TFA

The title compound from Example 235 (0.5g, 0.5 17 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 compound as a TFA salt (0.743g) which was used for following reactions.

WO 00/37459 PCT/US99/27939 -295- Step B Br- C\ Br ,\sCI N Ph N N Ph N NH NH H NHCH3 N

N

H

0 .TFA H3OC. oO

H

3

C

To a stirred solution of the title compound from Step A (0.102g, 0.0936 mmoles), triethyl amine (0.0798g, 0.798 mmoles) in

CH

2 Cl 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 (10% cone NH 4 OH in methanol) to give the title compound (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 19 below, compounds of the formula: Br N CI N. Ph N NH

R

1 4 were obtained, wherein R' 4 is as defined in Table 19.

WO 00/37459 PCTUS99/7939 -296- TABLE 19 Ex. Chioroformate R 1 240 H 3 C\ c H 3 0 H3C

H

3

C

H

3 C 0 0 H 3 C 0 0

S)

FAB: MH* 733 241 H 3 C ci H 3

C

H

3 0 0> 0 H 3 C o--kO

S)

FAB: MW* 719 242 HH

CH

3 CH 3

S)

FAB: MH' 733 243

S)

FAB: MW* 759 WO 00/37459 PCT/US99/27939 -297- EXAMPLE 244 Br

C

1 Br

CI

N

N

N Ph N Ph Srl CN N N NH* H3N N

NNH

H 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) in CHC1, (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 silica gel using 5% (10% cone. NH 4 OH in methanol)-CHCL 2 as the eluant to give the title compound. (0.046g) CIMS: m/z 732.

Examples 245-254 Following the procedures set forth in Examples 77-79 and 86, but using the diastereomeric mixture A and B from Preparative Example 135 and the appropriate amido-imidazole, the following compounds were prepared: Br Ci Br Ci Hj1 B H Br N H Br H

H

N ON 0,

N

COOt-Bu N 0 (Example 245)

H

(Example 246) WO 00/37459 WO 0037459PCT/US99/27939 298

K

0 'l H -N (Example 247) (Example 248)

NN

NN

S0 2

CH

3 (Example 249)

HN

-121N (Example 250) uuut-bsU Mixture CONHt-Bu (Example 2 51) (Example 252) Mixture Ph CONH cyd-lexyl 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 corresponding isocyanate to give the urea products listed in Table TABLE WO 00/37459 PCT/US99/27939 -300- 258 QC

NCO

139 diastereomer

B

Br 9C H F== 1.90 2. 668 3. 148.2

T

-t I

I

259 aNCO 140 diastereomer

A+B

Br fND-c N Me

N,

0 1 (A+B)

H

Br1;)' N H Me,=, 0,o0

(A+B)

H

1.7 2. 668 3. 141.5 -146.6 I i

I

260 Cr(IINCO 140 diastereomer

A+B

Br f-N 17 696 136.1 0 (A+B) Br ,9 -c

HXN

0 Me,.

(A+B)

i WO 00/37459 PTU9173 PCTfUS99/27939 301 ~1 261 Cl' NCO 140 diastereomer A+ B

I

Br fN? Cl C, l 1. 2. 696 3. 140.8

(A+B)

Br fN? Cl clrN Me N, Cl N1ZII:K N 'N-N I

(A+B)

262 140 diastereomer A+ B Br. I cI Me H 1. 12 2. 680 3. 130.3

(A+B)

Br f-1j cl N M

N

0

I(A+B)

L I WO 00/37459 PTU9/73 PCTIUS99/27939 302 263

TMS-NCO

142 Br Y7~~C1 0N Me 0(A+B) 1. 2.711 3. 165.5 Br fgC1

H

2

J

Me\,

(A+B)

264 OaNCO 152 1. 34 2. 682 3. 131.6 265 aNCO 153 1.71 2. 682 3. 120.6 NCO Br /N Cl 266 fN ()1.65 (A 2.656 152 NAN a :0 NY 1,iMe WO 00/37459 PTU9/73 PCTfUS99/27939 -303- NCO Br Cl 267 1.64 2. 656 3. 142.9 153 >NCO Br\ Cl 268 txN 1.83 154F." 2.656 diastereomer A 3.14.

N 0 Me >NCO Br 7

\C

269 N(B) 1.89 154 N N2. 656 154 ,N 3. 146.8 diastereomer B 0" Ij N o Me O-INCO NrOc 270 NN(A+B) 1.43 N 2.682 154 -k 0 3. 144.6 diastereomer N 0 Me A+B I I WO 00/37459 PTU9/73 PCTIUS99/27939 304

NCO

271 158 diastereomer A B 1. 52 2. 672 3. 122.5 143.6 272

NCO

158 diastereomer A+ B \C1

N

\oo

~N-H

1.21 2. 769 3. 141.0 NCOBr%

C

273 NH1.61 159 111 N Nr2.658 diastereomer N 6OH 3.57 A +B

H

Br c C-INCO Ng 274 ~N 1.48 llN",l N2.683 0OH 3. 133.1 diastereomer

H

A+B

WO 00/37459 WO 0037459PCTIUS99/27939 -305cI-NCO 159 diastereomer A+ B c

NH

NCO

160 diastereomer

A+B

NCO

160 diastereomer A+ B cI-NCO 158 diastereomer

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 corresponding acid chloride, chloroformate, carbamyl chloride, dicarbonate, anhydride or sulfonyl chloride to give the products listed in the Table 21.

TABLE 21 0 Ex. Electrophile Product 1.Yield and Prep. Exam. 2. MH' 3. mp Br f C1 279 PhCH 2

SO

2 CIH 1. 66 N, N N 2.697 SO Me 3. 148.5 139

(A)

diastereomer A Br -Ng

-C

280 CH 3

SO

2 C N e 1. S H 2.621 N "-NN N 3. 134.8 140 MeSO 2 0 (A+B) diastereomer A+B Br f c I

C

>N Me Nr N N N MeSO 2 0 WO 00/37459 PTU9/73 PCTIUS99/27939 307

CH

3

CH

2

SO

2

CI

Me 140 diastereomer A +B

(A+B)

Br/ f 1 \o-C1

NN

CH

3

CH

2

SO

2 0

(A+B)

CH

3

CH

2

COCI

140 diastereomer A+ B

(A+B)

Br f~acl N ~Me N /irN"'l-N,,N WO 00/37459 PTU9/73 PCT[US99/27939 308 283 1 CH 3

CH

2

CH

9

COCJ

140 diastereomer A+ B Br CI N Me

(A+B)

Br c N H Me,=

NN

(A+B)

1. 17 2.613 3. 85.7 4. .4 284 0 140 diastereomer A +B Br 'C1 1.11 2. 695 3. 128.4

(A+B)

Br fq Cl N Me 0(A+B) 285 154 diastereomner A

(A)

N

1. 2. 628 3. 108.9 WO 00/37459 PCT/US99/27939 309 C1 286 N B (B) 2 8 6 1.23 'I 4-,2.628 154 0 Me 3. 109.3 diastereomer B 0 1 0 Br ci 286 0 A8 N 1.70 A Me 2.725 166 X 3.88-96 01 f Br \ci 286 0 N N 1. B Me 2.725 167 N 3.89-96 EXAMPLES 287-289 Following the procedure described for Example 221, the title 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 PTU9/73 PCT[US99/27939 310- TABLE 22 Product and Prep. Ex.

OuH 139 diastereomer

A

139 diastereomer A 140 diastereomer

A+B

Br fmjD7 C1 0 N Me 001"(A+B) Br vYI 7?iCi N, >H Me.

N

F j

(A+B)

WO 00/37459 PCT/US99/27939 -311- EXAMPLE 290 o or 0 r ci N N MeQH O N Me A solution of the title compound from Preparative Example 143 (0.59 g, 1.15 mmol) dissolved in anhydrous dichloromethane (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 mL, 11.5 mmol) and allowed to stir at 25-40 0 C 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).

EXAMPLES 291-297 Following the procedure described for Preparative Example 290 and the BOC-protected piperazines listed in Table 23 below, the 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 cm column, flow rate 80 mL/min., 7-12% IPA-Hexane +0.2% diethylamine) to give diastereomer A and diastereomer B.

WO 00/37459 PCT/US99/27939 -312- TABLE 23 Ex. BOC-Piperazine Product 0 Br/C1 291 CN Hf

N

0 0 N 1. Yield: 44% 2. MH* 705 3. mp 132-1350C Br ci 292 N N NI S0 0N=N

H

1. Yield: 14% 2. MH* 705 3. mp 127-1320C Br/ -Cl H N 293 H0

A

0 Me Me For(A): For(B): 1. Yield: 38% 1. Yield: 36% f2. MH =691 2. 5H=691 3. mp 107.50C 3. mp =82.200 WO 00/37459 PTU9/73 PCT[US99/27939 313 r, CF3 0

N

1. Yield: 36% 2. MH'= 722 3. mp 173.8 0

C

(C+D)

Ok H Me -N N N For 1. Yield: 30% 2. MH~= 682 For 1. Yield: 10% 2. MH'= 682 For (B3): 1. Yield: 2. MH* 682 For 1. Yield: 13% 2. MH'= 682 WO 00/37459 PCT/US99/27939 -314- 7oc N j 0, OH 0

I

Br7\

CI

N

296 0

OH

H

1. Yield: 2. MH 698 3. mp 141.20C Br Cl

BOC

II;'

N

oNo 297 H j

N

N

1. Yield: 13% 2. MH' 670 3. mp 182.1-219.4oC EXAMPLE 299 Step A

OOY

rNN N H C

N

N

H rCl 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 temperature for 30 min, then concentrated in vacuo, The n.-Irfig 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 -315then concentrated in vacuo, diluted with dichloromethane and washed with IN NaOH The organic phase was dried over anhydrous MgS04, filtered, and concentrated in vacuo to afford a yellow foam (0.319 g, 100%, MH+ 473).

Step B H Br C1

I

N N

C

N) N rN 0 N '11rN r N 0 N ~f7~ H NO

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 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 for 48 h. The reaction mixture was concentrated in vacuo and purified by preparative plate chromatography (silica gel) using MeOH-CH2Cl 2 saturated with aqueous ammonium hydroxide to afford the title compounds (125 mg, 35%, mp 114.8°C, MH+ 778).

EXAMPLE 300 Following the procedure described for Example 299 Steps A- 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

N

H 2.758 N 3. 117.3

H

EXAMPLE 302 Step A H2N N O

N

O N

H

I

N rH r

FI

O N N I N

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 at 25 0 C 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 NaSO 4 filtered and concentrated. The resulting foam was diluted with anhydrous CH2Cl2 (10 mL) and trifluoroacetic acid (10 ml) and stirred for 3 h. Concentration in vacuo, redilution with CH2C12 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 fN9 (N )'Xy r N 2 N\ N F r_, 0 o I N N

N

I N H

IL.N''\

N

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 /iL, 0.51 mmol) and allowed to stir at 25°C for 48 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, MH+ 736).

EXAMPLE 303 C1

N

0 0 0 N N H If the procedure set forth in Example 302 were followed using in Step A WO 00/37459 PCT/US99/27939 -318- CH3

H

2 N N CH3

-N

instead of the title compound from Preparative Example 162, the title compound would be obtained.

EXAMPLE 304 Br /VCI

N

N Me N Nr o

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 compound was prepared MH+ =711, mp 103.7-107.5).

WO 00/37459 PTU9173 PCT/US99/27939 319 EXAMPLE 305 Br/ C1

N

(N Me

N

0N N Br C1 Br c I N N Me 0Me The title compound from Example 58 was separated into its two diastereomers by HPLC (Chiracel AD column) using isopropanol-90% hexane-0.2% diethylamine to give the 1 1(R),2(R) and 1 I1(S), 2(R) isomers.

Diastereomer A: MH+ 697; mp 103- 108'C.

Diastereomer B MH+ 697; mp 10 1- 107*C.

EXAMPLE 306 C I

N

(N r"Z Me Following the procedure described for Example 58, except using the 1 1(S)L2(R) diastereomer from Preparative Example 164 instead of the title compound from Preparative Example 5 1, the title compound was prepared MH+ -619, mp 100-1 1L4 0

C).

WO 00/37459 PCT/US99/27939 -320- EXAMPLE 307

/\CI

C

N

N

N

O M e Following the procedure described for Example 306, except using the title compound from Preparative Example 165 instead of the title compound from Preparative Example 25, the title compound was prepared MH+ 633, mp 89.1-96.5 0

C).

EXAMPLE 308 rIC

N

N

Following the procedure described for Example 58, except using the 11(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 instead of the title compound from Preparative Example 25, the title compound was prepared MH+ 633, mp 89.1-96.5).

WO 00/37459 PCT/US99/27939 321 EXAMPLE 309 Br X

C

N

0 2N H N The racemic product from Preparative Example 141 (0.2g, 0.368mmoles), 4-( 4 -nitrophenyloxycarbonyl)piperidine- 1carboxamide (0.1706g, 0.552mmoles) (Preparative Example 36, Step B) and isopropanol (10mL) were heated under reflux and under argon at 87 0 C for 24h. The solution was evaporated to dryness and the residue was taken up in dichloromethane and washed with satd. aqueous NaHCO 3 water, dried (MgSO), filtered and evaporated to dryness. The residue was chromatographed on a silica gel column using (10% cone. NH 4 OH in methanol)-dichloromethane as the eluant to give the title compound (0.057g, FABMS; m/z 712.9 c (CDCl,) CH 2 30.3, 30.5, 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; 8, (CDCl,) 4.31/4.32 (1H, s, 4.56 (2H, broad s,

NCONI-H

2 6.93 (1H, broad s, Im-H), 7.07 (1H, broad s, Im-H 4 7.10- 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 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 PCTIUS99/7939 -322- TABLE Ex. Amine of Prep. Product 1.Yield Ex. No. Carboxylic acid 2. MH* diastereomer A 3. mp or B

-CI

310 94 1.71 SP 2.695 diastereomer A c N =N 3.79.7 Ja o V

N

Me

CI

N:

311 93 1.29 (N 2.681 diastereomer A N N3. 82.2 N00 LMe

CI~

312 89 CN 1.43 N 2.709 diastereomer B IMe 3.88.4 N -N 0o \NTNN

CI

313 94 N 1.47 2.695 diastereomer B IN N, 3. 86.3 Me WO 00/37459 WO 0037459PCT/US99/27939 323 101 diastereomer B 179 diastereomer A 172 diastereomer A 173 diastereomer A WO 00/37459 PTU9/73 PCT/US99/27939 324 174 diastereomer A 199 Step B diastereomer A 91 diastereomer B 95.1 diastereomer A 176 diastereomer A WO 00/37459 WO 0037459PCT[US99/27939 325 177 diastereomer A 178 diastereomer A

(B)

diastereomer A 180 diastereomer A 183 diastereomer A WO 00/37459 WO 0037459PCT/US99/27939 326 181 diastereomer A 184 diastereomer

A

182 diastereomer A 165 Diastereomer

A

165 Diastereomer

B

WO 00/37459 WO 0037459PCTIUS99/27939 327 -CI 1.29 333 85 NE H2.660 33 A8 3.75.9- Diastereomer NN/, 8.

N> llCN

K

0

I

0

A>

N

186 1.90 2. 646 3. 83- 89.7 334 Diastereomer

A

4- 335 133 diastereomer A 1 63.

2. 696 336 133N diastereomer B 1. 59 2. 696 4 337 1.15 2. 698 diastereomer A WO 00/37459 PCT/US99/27939 328 EXAMPLES 343-361 Following the procedure described for Example 40, the 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 WO 0037459PCT/US99/27939 329 B) from Preparative Example 51 and the appropriate N-substituted im-idazolylalkyl amine instead of the amine from Preparative Example 13. The resulting Products were separated by HPLC (Chiracel, AD column, 85/15 Hexane/IPA).

TABLE 26 Ex Amine, of Product i .Yieid Prep. Ex. No.

N%

2. MH* 3. mp Br /\C1 For

N

343 89 N I1.27 and ,Me 2.761 344 N Nr 3. 99.3 Me For Isomer A (Ex. 343) 1. And 2.761 _____Isomer B (Ex. 344) 3. 92.3 Br For

N

345 177 I1.16 and N 2. 761 346 )N -NM r=M 3.92.4 o0 For(13): Isomer A (Ex. 345) 1. 17 And 2. 761 B (Ex. 346) 3. 96.5 WO 00/37459 WO 0037459PCTIUS99/27939 330 I I 347 and 348i Me For 1. 2. 761 For 1.30 2. 761 Isomer A (Ex. 347) And Isomer B (Ex. 348) I -t 349 and 350 Me For 1. 24 2. 747 For 1. 26 2. 747 Isomer A (Ex. 349) And 4 1 Isomer B (Ex. 350) I I 4 351 185 diastereomer

A

1. 2. 713 3.

102.9- 107.5 i. v 352 187 diastereomer

B

cl~ 1.6 1.

WO 00/37459 WO 0037459PCTIUS99/27939 331 187 diastereomer

A

188 diastereomer

B

188 diastereomer

A

171 diastereomer

A

NlN WO 00/37459 WO 0037459PCTIUS99/27939 332 EXAMPLES 362-366 Following the procedure described for Example 225, except using the (P IS. 2RW+)-carboxylic acd fr pparative 1-Examnpie 164 instead of that from Preparative Example 127 Step C, and using the substituted amine from tLhe 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 WO 00/37459 PCT[US997939 -334- C 1.57

N

92.1- O 'K 102.7 0 N 366 186 N H 1.71 2620 SN 130.2-

S

0 140.2 EXAMPLES 367-374 Following the procedure described for Example 225, the 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 WO 0037459PCTIUS99/27939 -335- TABLE 28 Ex. 1. Prep. Ex. Product 1 .Yield No. of

N%

Carboxylic 2. MH+ acid 3. mp 2. Prep. Ex.

(OC)

No. of Amine

CI

CN

367 1.200 I 1.46 diastereomer P~j Me 2.7 11 A -N N 39- 2. 95.1 Isomer A

CI

368 1.200 1113 diastereomer N rk Me 2.711 B il f 3.65- 0 0 95.1 ___Isomer B \C I

N

369 1.200 1J 1.61 diastereomner Or9-F Me 2. 727 A N O 3. 128.5 2. 172 A_ WO 00/37459 WO 0037459PCT/US99/27939 336 1 F V 370 1.200 diastereomer

B

2. 169 Me N N 1. 66 2. 727 3. 133.9 1* 371 1.200 diastereomer

B

2. 199 Step

B

1.16 2. 728 3. 135.7 Isomer B 4- 372 1. 201 Step

B

diastereomner

A

2. 95.1 I Me

-N

1. 2. 661 3. oil Isomer A 4- 373 1. 201 Step

B

diastereomer

B

1.49 2. 661 3. oil 2. 95.1 Isonner B U WO 00/37459 WO 0037459PCT/US99/27939 -337- EXAMPLES 375-382 Similarly, using the procedure described for Example 149, the title compound (diastereomer A or B) from the Preparative Example given in Table 29 was treated with cyclohexyl chioroformate to give the products listed in the Table 29.

TABLE 29 0 Ex. Prep. Ex. Product 1 .Yield No.

N%

2. MH+ 3. mp Br

CI

N

375 190 N Me 1.76 C} r) M 2.787 Me _____Isomer

A

Br

CI

376 191 N MeU 1.67 Me2.787 N N 3. 92.3 __Isom er BM WO 00/37459 PCT/US99/27939 338 WO 00/37459 PTU9/73 PCT/US99/27939 339 Br C1 382 197 N 1.73 2. 773 Me __IsomerB I EXAMPLES 383-392 Following essentially the same procedure described for Example 149, the title compound (diastereomer A or B) from Preparative Example 170 was treated with the appropriate acylating agent (iLe cyclohexylchloroformate, or Boc dicarbonate, or cyclohexylisocyanate, or tert-butyl isocyanate or isobutyl chioroformate) to give the products of the formula: N HC1

CH

3 N C 0 wherein R' is as defined in column 2 of Table TABLE Ex. R1Isomer Mass [a]D

HRMS

MH)

383 A 695.3473 -29.20 c =0.107 WO 00/37459 PCTIUS99/7939 -340- 384 B 695.3473 +19.50 c 0. 1295 385 -COOC(CH 3 3 A 669.3366 -42.5) c 0.89 386 -COOC(CH4..). B 669.3322 387 A 694.3629 -51.00 _c 0.2575 0 388 B 694.3642 389 H A 668.3480 -41.00 c =0.19

N

390 H B 668.3488

N

391 0 A 669.3322 -56.30 0 c 0.3005 392o x B 669.3330 EXAMPLE 393 (O pMe HOQ ao N

N,

Step A 6. OH

N-

0

N--~NC!

I0 WO 00/37459 PCTIUS99/27939 -341 If the commercially available acetoxycyclohexanol were treated with phosgene the chloroformate would be obtained.

Step B o 0 o N X N 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.

Step C If the product of Step B were treated with potassium carbonate in MeOH the title compound would be obtained.

WO 00/37459 PTU9173 PCT[US99/27939 342 .111 Me N N Step A OH0 If the commercially available cyclohexanol were treated with phosgene the chioroformate would be obtained.

Step B 0 0 C

I

00 Me IL thle chio0rofoLrmnatle hro Sti ep 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 If the product of Step B were treated with aqueous acid the ketone would be obtained.

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

EXAMPLE 395 o

O

By essentially the same procedure set forth in Example 225 (coupling), only substituting the title compound from Preparative Er x ple 212 for the acid from Preparative Exmpile 127 Step C, the title compound was obtained. Mp 91-107 LCMS MH*=695.

WO 00/37459 PCT/US99/27939 -344- EXAMPLE 397 Br and N I Me

-N

^NN

Step A 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 would be obtained.

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.

WO 00/37459 PCT[US99/27939 -345 EXAMPLE 398 Me -N N Step A 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

would be obtained.

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.

WO 00/37459 PCT/US99/27939 -346- EXAMPLE 399 O '0 0 N N Step A If the 3-fluoro-8-chlorotricyclic chloride from Preparative Example 204 were used instead of the chloride in Preparative Example 127 Step C then the carboxylic acid would be obtained.

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.

ASSAYS

FPT IC 5 0 (inhibition of farnesyl protein transferase, in vitro enzyme assay) and COS Cell IC 5 0 (Cell-Based Assay) were determined following the assay procedures described in WO 95/10516, published April 20, 1995. G-GPT IC 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 incorrted hrein by reference thereto.

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

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

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

Soft Agar Assay: Anchorage-independent growth is a characteristic of tumorigenic cell lines. Human tumor cells can be suspended in growth medium containing 0.3% agarose and an indicated concentration of a farnesyl transferase inhibitor. The solution can be overlayed onto growth medium solidified with 0.6% agarose containing the same concentration of farnesyl transferase inhibitor as the top layer. After the top layer is solidified, plates can be incubated for 10-16 days at 37 0 C 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 PBS). Colonies can be counted and the ICso'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 78 Step B (Isomer 79 Step B (Isomers A, B, and 80 Isomers A and 81-86, 86A, 87, 88, 93-104, 106, 108, 110-113, 115-211, 214-217, 221-228, 236- 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, 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 80 (Isomer 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 (IsomerA), 127-134, 137, 142, 144-146, 148, 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 FPT ICs within the range of <0.04nM to 6.7nM.

The compounds of Examples 11, 16, 78 Step B (Isomers C and 79 Step B (Isomer 80 (Isomer 88 (Isomer 93 (Isomer 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 had an FPT IC5 of 0.36nM.

The compounds of Examples 1, 2, 8, 25, 86, 100, had a Cos Cell ICo 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 ICo within the range of <5 to >500nM. The compounds of Examples 245-250 had a Cos Cell ICo within the range of 100%@0.01 to 0.087 ItM. The compounds of Examples 100, 101, 103 and 259 had a Cos Cell IC 5 0 within the range of <5nM to 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- 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 ICo 5 within the range of <5 to >500nM.

The compounds of Examples 116, 117, 160, 170, 184, 186- 188, 196-200, 202-204, 206-208, 217, 225, 305 (11s,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 WO 00/37459 PCT/US99/27939 -349 The compounds of Examples 11, 16, 79 Step B (Isomer A) 00 (T Ar ome (Isomer (omer A (Isomer, and 225 had a Soft Agar IC,, within the range of 2 to 300nM. The compound of Example 225 had a Soft Agar IC, of 2nM.

For preparing pharmaceutical compositions from the compounds described by this invention, inert, pharmaceutically acceptable carriers can be either solid or liquid. Solid form preparations include powders, tablets, dispersible granules, capsules, cachets and suppositories. The powders and tablets may be comprised of from about 5 to about 95 percent active ingredient.

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

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

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

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

WO 00/37459 PCT/US99/27939 -350 The compounds of the invention may also be deliverable transdermally. The transdermal compositions can take the for m of creams, lotions, aerosols and/or emulsions and can be included in a transdermal patch of the matrix or reservoir type as are conventional in the art for this purpose.

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

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

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

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

While the present invention has been described in conjunction with the specific embodiments set forth above, many 30/07 '04 FRI 17:53 FAX 61299255911 GRIFFITH HACK 1015 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.

In the claims which follow and in the preceding description of the invention, except where the context requires otherwise due to express language or necessary implication, the word "comprise" or variations such as "comprises" or "comprising" is used in an inclusive sense, i.e. to specify the presence of the stated features but not to preclude the presence or addition or further features in various embodiments of the invention.

*oo It is to be understood that a reference herein to a prior art publication does not constitute an admission that the publication forms a part of the common general .o knowledge in the art in Australia, or any other country.

S *oo° COMS ID No: SBMI-00850317 Received by IP Australia: Time 17:13 Date 2004-07-30

Claims (4)

1. A compound of the formula: A, B R1 )R3 XII R 2 III R6 I 3 CN (1.0C) R I R 9 RO 1 R R 12 or a pharmaceutically acceptable salt or solvate thererof, wherein: one of a, b, c and d represents N or 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 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 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 1 6 2 H and halo, dihalo, alkyl and H, (alkyl)2, -H and -OC(O)R 15 H and -OR 15 aryl and H, =NOR 1 5 or -O-(CH2)p-O- wherein p is 2, 3 or 4; each RI and each R 2 is independently selected from H, halo, -CF 3 -OR 15 -COR 15 -SR 1 5 -S(O)tR 16 (wherein t is 0, 1 or 2, -N(R 15 2 -NO 2 -OC(O)R 15 CR 15 -OC0 2 R 1 6 -CN, -NR 15 COOR 1 6 -SR 1 6 C(O)OR 16 -SR 1 6 N(R 17 2 (provided that R' in -SR 1 6 N(R 1 7 2 is not -CH 2 wherein each R 17 is independently 30/07 '04 FRI 17:53 FAX 61299255911GRFIH AC 06 GRIFFITH HACK (jh 016 353 selected from H- or -C(O)OR' 6 benZotriazol-1.yloxy, yithio. or substituted tetrazol-5-ylthio. alkcynyl, alkenyl or alkyl, said alkyl or alkenyl' group -optionally being* substituted with halo, -OR 15 Or -CO 2 RI 5 R 3 and R 4 are the same or different and each independently represents H, any of the substituents of RI 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 MI); R 5 R 6 and R 7 each independently represents H, *-CF3. -COR 15 alkyl or aryl. said alkyl or aryl optionally being substituted with -OR 15 -SR 15 -S(O)tR1 6 -NRISOOR16. -N(Rl 5 2 -NO 2 -COR1 5 -OCOR' 5 -000 2 RI 6 _002R 15 OPO 3 R15, or RS is combined with R 6 to represent =0 or =S; R 8 is selected from: H, C 3 to CIO alkyl', aryl, aryl..yl *:15 heteroaryl, heteroarylalkyL cycloalkyl, cycloalkylalkyl, substituted alkyl, substituted aryl, substituted aryla lkyl, substituted heteroaryl, substituted heteroarylalkyl, substituted cycloalkyl. substituted .cycloalklalkyl;. the substutuents for the R 8 substituted groups being selected from= alkorl, aryL. arykakyl. cycloalkyl, 4N(R') 2 -O)R 8 cycoalkyalkyl, halo. CN, -SO 2 N(R' pr -00 2 R! 8 provided that the -OR 8 and -N(R' 8 substituents are not bound to the carbon that is bound to the N. of the moiety: each W' is independe!ntly selected frocm: H. alkyL, aryl, aryialkyl. heteroaryl or cycloalksyl; R! and are independently se lected from: H, alkyl, aryl, arylaikyl. heteroaxyl, heteroarylalkyl, cycloalkyl or -CON(R 8 3 2 (wherein is as de-fined above); and the substitutable R 9 and R' 0 groups are optionally substituted with one or more sub stituents selected from: alkyl, cycloalkyL aryialkyl, or heterarytalkyl; or R! and R' 0 together with the carbon atom to which they are bound, form* a 03 to 0, cycloalkyl ring: COMS ID No: SBMI-00850317 Received by IP Australia: Time 17:13 Date 2004-07-30 WO 00/37459 PCT/US99/27939 -354- R" and R' 2 are independently selected from: H, alkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, cycloalkyl, -CON(R' 8 2 -OR 1 8 or -N(R' 8 2 wherein R' 8 is as defined above; provided that the -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 R 1 2 groups are optionally substituted with one or more substituents selected from: alkyl, 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: R19 S or N (4.1) wherein R 19 is selected from: H, alkyl, alkyl, aryl, arylalkyl, substituted arylalkyl wherein the substituents are selected from halo or CN, -C(aryl) 3 or cycloalkyl; 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 from -NHC(O)R' 8 -C(R) 2 OR 3 -OR' 8 F, Cl, Br, alkyl, aryl, arylalkyl, cycloalkyl, or -N(R' 8 (wherein each R' 8 is independently selected); wherein R' 8 is as defined above; wherein each R 3 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 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 8 is II.nIATR'8I I- independently selected), -OC(0)R' 8 or 8 2 wherein each R is independently selected), and wherein R' 8 is as defined above; R' 4 is selected from: WO 00/37459 PCT/US99/27939 355 l A R 2 0 i SR20 O "N R2 0 0 O R 2 1 O CH 2 O R 3 6 20 2 or R' 5 is selected from: H, alkyl, aryl or arylalkyl; R' 6 is selected from: alkyl or aryl; R 20 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 when R 2 0 is other than H, then said R 2 0 group is optionally substituted with one or more substituents selected from: halo, alkyl, aryl, -OR' 8 or -N(R' 8 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 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 group is optionally substituted with one or more substituents selected from: halo, alkyl, aryl, -OR' 8 or -N(R' 8 wherein each R' 1 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 atom; n is each R 32 and R 33 for each n are independently selected from: H, alkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, cycloalkyl, -CON(R' 8 2 -OR' 8 or 8 wherein R' 8 is as defined above; and wherein said substitutable R 32 and R 33 groups are optionally substituted with one or more substituents selected from: alkyl, cycloalkyl, arylalkyl, or heterarylalkyl; or R 32 and R 3 together with the carbon atom to which they are bound, form a C 3 to C, cycloalkyl ring; and 30/07.'04 FRI 17:54 FAX 61299255911GRFTHAC J01 GRIFFITH HACK (0017 356 WoR is selected fr6m branchedakl unb"ranct-.eCd alkyl. cycloallkyl. -heterocycloalkyL. or aryl; and provided that: when Fe' is selected h764; group 6. 0 7.0. 7. 1 or and Xis N, then R! is selected from: H, C 3 to CIO alkyl, substituted'C 3 to 01, alklzL axyLn*ky. substituted aryLafWLyl heteroarylikyl. substituted heteroarylalkyl, cycloalkylankyL or substituted cycloalkylalkyl; with the further proviso that when R 1 4 is selected from: group 6.0, 7.0;V 7.1 or 10 and X Is and WI is. H, then the a~kyl cb~atn between RS and the amide moiety is substituted. .fl*

2.- The coxmpound of Claim 1 having the sfructurje: A, B .15 or

3. The compound of CLaim I wherein: R! to R 4 is independently selected from H, Br or Cl; R to R" is H; is N and the COMS ID No: SBMI-00850317 Received by IP Australia: Time 17:13 Date 2004-07-30 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' 3 is group 2.0 or 4. The compound of claim 1 wherein: R 8 is selected from: arylalkyl, substituted arylalkyl, cycloalkylalkyl, substituted cycloalkylalkyl, heteroarylalkyl or substituted heteroarylalkyl R 9 and are independently selected from: H, alkyl, -C(O)N(R' 8 or arylalkyl; R" and R' 2 are independently selected from: H, 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; R 32 and R 3 3 are independently selected from: H, -OR' 8 arylalkyl or aryl; R' 9 is selected from: 2 alkyl, arylalkyl, or -C(aryl) 3 and said optional R' 3 substitutents are selected from: -N(R' 8 2 -NHC(O)R' 8 -C(R 3 2 0R 3 5 alkyl, or cycloalkyl substituted with -OH provided that the -OH substitutent is not bound to a carbon that is adjacent to an oxygen atom. The compound of claim 1 wherein R' 4 is: 5.0 and R 2 0 is selected from: alkyl, arylalkyl, heterocycloalkyl, aryl, aryl substituted with halo, cycloalkyl, or cycloalkyl substituted with alkyl; 6.0 wherein R 2 0 and R 2 are independently selected from: H, cycloalkyl, alkyl, aryl, or arylalkyl; 7.0 wherein R 2 0 is selected from: heteroaryl, cycloalkyl, heterocycloalkyl, alkoxy, heterocycloalkyl substituted with -C(O)N(R' 8 7.1 wherein R 3 is selected from: cycloalkyl or heterocycloalkyl; or WO 00/37459 PCT/US99/27939 358 8.0 wherein R 20 is selected from: alkyl or cycloalkyl. 6. The compound of Claim 1 wherein: R' to R 4 is independently selected from H, Br or C1; R 5 to R 7 is H; a is N and the remaining b, c and d substituents are carbon; A and B are H,; n is O or 1; R' 3 is group 2.0 or 4.0, and said optional R' 3 substitutents are selected from: -N(R 1 8 -NHC(O)R' 8 -C(Re) 2 OR 3 or alkyl; R 8 is selected from: arylalkyl, substituted arylalkyl, cycloalkylalkyl, substituted cycloalkylalkyl, heteroarylalkyl, or substituted heteroarylalkyl; R 9 and R' 0 are independently selected from: H, alkyl, C(O)N(R') 2 or arylalkyl; R" and R 2 are independently selected from: H, alkyl, substituted aryl, -OR' 8 or R" and R12 taken together with the carbon atom to which they are bound form a cycloalkyl ring; R" and R 2 are independently selected from: H, 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; X is CH or N; R' 9 is selected from: -C(O)N(R 1 8 alkyl, arylalkyl, or -C(aryl) 3 R 20 for 5.0 is selected from: alkyl, arylalkyl, heterocycloalkyl, aryl, aryl substituted with halo, (6) cycloalkyl, cycloalkyl substituted with alkyl, or cycloalkyl substituted with -OC(O)R 18 or -OH provided said -OH substitutent is not bound to a carbon atom that is adjacent to an oxygen atom; WO 00/37459 WO 0037459PCT[US99/27939 359 (in) R 20 and R 2 for 6.0 are independently selected from: H, cycloalkyl, alkyl, aryl, or arylalkvl: R 2 for 7.0 is selected from: heteroaryl, cycloalkyl, alkoxy, heterocycloalkyl substituted with -C(O)N(R' 8 2 R 36 for 7.1 is selected from heterocycloalkyl or cycloalkyl; R 20 for 8.0 is selected from: alkyl or cycloalkyl; and R 3 2 and W 3 3 are independently selected from: H, -OR 8 arylalkyl or aryl. 7. The compound of Claim 6 wherein: W 8 is selected from arylalkyl, cycloalkylalkyl, or heteroarylalkyl; Re and R" 0 are independently selected from: H or benzyl; R" and R 12 are independently selected from: H, -CH 3 -CH 2 CH(CH 3 2 -(CH 2 3 CH 3 benzyl, ethyl, p-chlorophenyl, -OH, or R" and R 1 2 taken together with the carbon atom to which they are bound form a cyclopropyl. ring; W 32 and W 33 are independently selected from: H, phenyl, -OH or benzyl; R' 9 is selected from: -C(O)NH-cyclohexyl, -C(phenyl) 3 H, methyl. or ethyl; said optional R 1 3 substitutents are selected from: -CH 3 -CH 2 OH, -CH 2 O0C(O)O-cyclohexyl, -CH 2 OC()O-cyclopentyl, ethyl, isopropyl, NH 2 or -NHC(O)CF 3 WO' for group 5.0 is selected from: t-butyl, ethyl, benzyl, -CH(CH 3 2 -CH- 2 CH(CH 3 2 -(CH 2 2 CH,, n-butyl, n-hexyl, n- octyl, p-chor-ophenyl, cyciohexyi, cyciopentyl, WO 00/37459 PTU9/73 PCTIUS99/27939 360 CH 3 CH 3 NCN2 H 3 C CH 3 H 3 C CR 3 or OH R 20 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,; Wi R 20 for 7.0 is selected from: 4-pyridyNO, -OCH 3 -CH(CH 3 2 -t-butyl, H, propyl, cyclohexyl or C N -CONH 2 U) R 6 for 7.1 is selected from: cyclohexyl, cyclopentyl, cyclobutyl, cyclopropyl, 6 0 ;and R 20 for 8.0 is selected from: methyl, i-propyl or cyclohexylmethyl. 8. The compound of Claim 7 wherein R 8 is selected from: benzyl, -CH 2 C(CH 3 2 -CH 2 -cyclohexyl, -CH,-cyclopropyl, WO 00/37459 WO 0037459PCT/US99127939 361 F H 2 C H 2 C .NH 2 C N H 2 OH OCH 3 NN-~ N- II I I H2C J::rCH 3 I- 2 CN CONH 2 H 2 C6 H 2 C6 I I H 2 C 7 -(CH2)2H 2 C 0 N ,or cyclol, 9. The compound of Claim 8 wherein: W 8 is selected from: benzyl or -CH 2 -cyclopropyl; W 20 for 5.0 is cyclohexyl; R 20 for 6.0 is selected from: t-butyl, i-propyl, or iexyl; and W 2 is selected from: H, -CH 3 or i-propyl; R 20 for 7.0 is selected from: cyclohexyl, ~entyl, or i-propyl; Wr 3 for 7. 1 is selected from: cyclopropyl, iutyl, cyclopentyl, or cyclohexyl; and R 2 for 8.0 is methyl. cycloy cyclob 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 amide substituent -C(O)NR 8 and R' 3 is substituted. 12. The compound of Claim 1 wherein when R 1 4 is group and X is N, and R 8 is H, then the alkyl chain between R' 3 and the amide moiety is substituted and/or R 9 and R' 1 and/or R" and R' 2 are taken together to form a cyloalkyl ring. 13. A compound of the formula: A. B R bd R3 R2 III 4 R2 1 R4 a R 5 X R7 R 8 R 3 2 R 3 3 R6- IV I 13 C C 2 SI 13 R 20 O R 9 R 10 R" R 2 0 0 or a pharmaceutically acceptable salt or solvate thererof, wherein: one of a, b, c and d represents N or NO 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 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 independently represent -R 15 halo, -OR 16 -OC0 2 R 16 or -OC(O)R 15 and when no double bond is present between cr-hrn 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 30/07 '04 FRI 17:54 FAX 61299255911 GRIFFITH HACK 018 363 -OC(O)R' 5 H and -OR' 5 aryl arid H, =N0R 15 or -O-(CHilp-O- wherein p is 2, 3 or 4; each RI and each R 2 Is independently selected from H, halo,- -CF 3 -OR 15 -CaR1 5 -SR 15 -S(O)tRI 6 (wherein t is 0, 1 or 2, -N(R1 5 2 -NO 2 -OC(O)R1lS. -CO 2 R1 5 -OCQ2RI 6 -CN. -NR 15 000R 1 6, -SR' 6 C(O)0R 1 6 -SR 16 N(RI 7 2 (provided that R' 6 in -SR16N(R 1 7 2 is not wherein each R 1 7 is independently selected from H or -C(OR 16 ,'benzotriazo- 1-yoxy, ylthio. or substituted tetrazol-5-ylthio. alkynyl, alkenyl or ailkyl, 10 said alkyl or alkenyl group optionally being substituted with halo, -OR 15 or -C0 2 R 15 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 05-C 7 fused ring to the benzene rng (Ring 111]; R 5 R 6 and R 7 each independently represents H, -CF 3 -CaR1 5 alkyl or aryl, said alkyl or aryl optionally being substituted with -OR' 5 -SR' 5 -S(O)tR' 6 -NRlSCOOR16. -N(R 1 5 2 -N02. :-C0RIS. -OCOR'. 5 -OCO2RI 6 -C0 2 RI 5 OPO3RI 5 or R 5 is combined with k 6 to represent =0 or =S; Ris selected. from: C3 to alkyl, aryl. aylalkyI, heteroaryl, heteroarylalkyl, cycloalkyl. cycloalkylalkyl, substituted alkyl. substituted aryl. substituted arylalkyl. substituted heteroaryl, substituted heteroaiylalcyl, substituted cyclakyl, substituted cycloalkylalkyl; the substutuents for the Ra substituted groups being selected from: alkyl,* aryl, arylalkyl. cydloalkyl. -N(R'B) 2 -OR' 8 cycloalkyalkyl. halo. CN, -SON(R 18 or -00 2 R'a; provided that the -ORsg and substituents are* not bound to the carbon that Is. bound to the N of the -C(O)NRe- moiety; COMS ID No: SBMI-00850317 Received by 1P Australia: Time 17:13 Date 2004-07-30 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 (wherein R' 8 is as defined above); and wherein said substitutable R 9 and groups are optionally substituted with one or more substituents selected from: alkyl, cycloalkyl, arylalkyl, or heterarylalkyl; or R 9 and R' 1 together with the carbon atom to which they are bound, form a C 3 to C, cycloalkyl ring; R" and R' 2 are independently selected from: H, alkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, cycloalkyl, -CON(R' 8 -OR' 8 or -N(R" 8 2 wherein R 1 8 is as defined above; provided that the -OR 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 R' 2 groups are optionally substituted with one or more substituents selected from: alkyl, 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 1 9 NN N N -N N or (4.1) wherein R 19 is selected from: H, alkyl, alkyl, aryl, arylalkyl, substituted arylalkyl wherein the substituents are selected from halo or CN, -C(aryl), or cycloalkyl; 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 PCTIUS99/27939 -365 from selected from: -NHC(O)R' 8 -C(R) 2 0R 3 5 -OR' 8 -SR 18 F, Cl, Br, alkyl, aryl, arylalkyl, cycloalkyl, or -N(R' 8 2 wherein is as defined above; wherein each R 3 4 is independently selected from H or alkyl; wherein R 35 is selected from H, -C(O)OR 20 or -C(O)NHR 20 and R 20 is 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' 8 -N(R 1 8 2 (wherein each R' 8 is independently selected), -OC(O)R' 8 or C(O)N(R' 8 2 (wherein each R' 8 is independently selected), and wherein R' 8 is as defined above; R' 5 is selected from: H, alkyl, aryl or arylalkyl; R' 6 is selected from: alkyl or aryl; R 2 0 is 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' 8 -OR 1 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 atom; n is each R 3 2 and R" for each n are independently selected from: H, alkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, cycloalkyl, -CON(R' 8 -OR' 8 or 8 2 wherein R' 8 is as defined above; and wherein said substitutable R 3 2 and R 33 groups are optionally substituted with one or more substituents selected from: alkyl, cycloalkyl, arylalkyl, or heterarylalkyl; or R 3 2 and R 33 together with the carbon atom to which they are bound, form a C 3 to C 6 cycloalkyl ring; and provided that when X is N, and R 8 is H, then the alkyl chain between R' 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 R3 Cr R2 4 RK~ cR a X R7 R 8 R 32 R 3 3 R6 IV 13 N C N C (R OR9 R or A B R R 3 II R 2 4' b a a x N R- 7 R 8 R 3 2 R 3 3 6- IV 1 0R R2 FO O 15. The compound 25.OB of Claim 14 wherein R 8 is H and the alkyl chain between the amide substituent -C(O)NRW and R' 3 is substituted. 16. The compound 25.OB of Claim 14 wherein: R' to R 4 is independently selected from H, Br or Cl; R 5 to R7 is H; (c) a, b, c, and d are carbon, and R 20 is selected from: alkyl, alkoxy, aryl, arylalkyl, cycloalkyl, heteroaryl, heteroarylalkyl or heterocycloalkyl; said R 20 group is optionally substituted with one or more substituents selected from: halo, alkyl, aryl, -OC(O)R' 8 -OR' 8 or -N(R' 8 wherein each group is the WO 00/37459 PCTUS99/27939 -367- same or different, and wherein R' 8 is as defined above, provided that said optional substituent is Lot bound to a carbon atom Itt is adjacent to an oxygen or nitrogen atom; or a is N and the remaining b, c and d substituents are carbon, and R 20 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; A and B are H 2 n is O or 1; R' 3 is group 2.0 or R 8 is selected from: arylalkyl, substituted arylalkyl, cycloalkylalkyl, substituted cycloalkylalkyl, heteroarylalkyl or substituted heteroarylalkyl; and X is CH or N; R 9 and R' 0 are independently selected from: H, alkyl, -C(O)N(R' 8 2 or arylalkyl; R" and R' 2 are independently selected from: H, 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; R 32 and R 33 are independently selected from: H, -OR' 8 arylalkyl or aryl; R 1 9 is selected from: 2 alkyl, arylalky, or -C(aryl) 3 and said optional R' 3 substitutents are selected from: -N(R' 8 -NHC(O)R 8 -C(R) 2 OR 3 5 or alkyl. 17. The compound of Claim 16 wherein a is N and the remaining b, c, and d substituents are carbon and: R 8 is selected from arylalkyl, cycloalkylalkyl, or heteroarylalkyl; WO 00/37459 WO 0037459PCT/US99/27939 368 R' and R" 0 are independently selected from: H or benzyl; R" and R' 2 are independently selected from: H, -CH 3 -CH 2 CH(CH 3 2 -(CH 2 ),CH 3 benzyl, ethyl, p-chlorophenyl, -OH, or R" and R 1 2 taken together with the carbon atom to wh-ich they are bound form a cyclopropyl. ring; R 32 and R 33 are independently selected from: H, phenyl, -OH or benzyl; R' 9 is selected from: -C(O)NH-cyclohexyl, -C(phenyl),, H, methyl or ethyl; said optional R' substitutents are selected from: -CH 3 -CH 2 -CH 2 OC(0)0-cyclohexyl, -CH 2 OC(O)O-cyclopentyl, ethyl, isopropyl, NH 2 or -NHC(O)CF 3 and R 2 0 is selected from: t-butyl, ethyl, benzyl, CH(H 3 -H 2 C(CH) 2 n-butyl, n-hexyl, n-octyl, p- chlorophenyl, cyclohexyl, cyclopentyl, CH 3 CH 3 N -CONH 2 -Ct H 3 C CH 3 H 3 C CH 3 or OH WO 00137459 WO 0037459PCTJUS99/27939 369 18. The compound of Claim 17 wherein RW, R' 0 R" 1 R' 2 R 32 and R 33 are H. 19. The compound of Claim 17 wherein R 8 is selected from: benzyl, -CH 2 C(CH 3 2 -CH 2 -cyclohexyl, -CH cyclopropyl, -(CH 2 2 CH 3 F H 2 C I H 2 C 0 NNF 12C H 2 C N H 2 Gc OH OCH 3 H 2 C 2 C6 H 2 C 1 1 H~cjc~rOCH 3 I 2 CN H 2 C6 CONI1 2 H 2 C6 H 2 C 'I -(CH 2 2 N N H 2 C 0 N H 2 CO The compound of Claim 19 wherein: RW is selected from: benzyl or -CH 2 cyclopropyl; and W 20 is cyclohexyl. 2 1. The compound of Claim 20 which is a 3-Br-8-CI- compound, an 8-Cl-compound, or a 10-Cl-compound; or a 3-Br- WO 00/37459 C/J9293 PCr[US99/27939 370 8-Cl-compound, an 8-Cl-compound, or a 10-Cl-compound wherein 09 pl DI I 11 1 T-)32 3j33 T 22. The compound of Claim 1 selected from: 1 N (1 I1R,2R Isomer) (Example 11) (1 1S,2R Isomer) (Example 16) (Example 58); WO 00/37459 PTU9173 PCT/US99/27939 371 (Example 78 Step B) rf= N N (Example 79 Isomer A) N c 0 10, I (Example Isomer A) (Example 88 Isomer A) H 3 C WO 00/37459 PTU9/73 PCTIUS99/27939 372 0 (Example 93 Isomer D) CH 3 N(Example 99) H 7/> N (Example 100) CH 3 WO 00/37459 WO 0037459PCT/US99/27939 -373- cI NI (Example 225) OH 3 a (Example 226) 13 (Example 227) (Example 228) WO 00/37459 WO 0037459PCT[US99/27939 374 (Example 229) (Example 232) (Example 326) OH 3 N N (Example 330) WO 00/37459 PTU9173 PCT/US99/27939 375 (Example 327) H 3 (Example 328) (Example 243) (Example 286A) Me /N N WO 00/37459 WO 0037459PCT[US99/27939 376 Me (Example 286B) (Example 304) Me N N Me (Example 306) fMe N> (Example 307) 'N ;or WO 00/37459 WO 0037459PCTIUS99/27939 377 I ,f-Me N (Example 308) 23 The compound of Claim 1 selected from: 7/ X C I H N N CH 3 CH 3 N 4 L Example 58 CH 3 N N (Example 225) CH 3 WO 00/37459 WO 0037459PCTIUS99/27939 -378- cl (Example 227) 13 (Example 228) (Example 229) (Example 232) WO 00/37459 WO 0037459PCT/US99/27939 379 (Example 326) (Example 330) ;or (Example 327) N~ CH 3 24. A compound of the formula: CH3 (Example 225) WO 00/37459 PCT/US99/27939 380 A compound of the formula: Me (Example 393) (Example 394) 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, 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, 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. 30/07 '04 FRI 17:55 FAX 61299255911 GRIFFITH HACK 019 381 28. A method of treating tumor cells comprising administering an effective amount of a compound of any one of Claims 1-27. 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 tumor cells. 30. A method of treating tumor cells wherein the Ras protein is activated as a result of oncogenic ooo. 15 mutation in genes other than the Ras gene, comprising administering an effective amount of a compound of any one of Claims 1-27. 31. A method of inhibiting farnesyl protein transferase 20 comprising the administration of an effective amount of a compound of any one of Claims 1-27. 32. A pharmaceutical composition for inhibiting farnesyl protein transferase comprising an effective amount of a compound of any one of Claims 1-27 in combination with a pharmaceutically acceptable carrier. 33. A use of a compound of any one of Claims 1-27 for the manufacture of a medicament for inhibiting farnesyl protein transferase. 34. A use of a compound of any one of Claims 1-27 for the manufacture a medicament for treating pancreatic COMS ID No: SBMI-00850317 Received by IP Australia: Time 17:13 Date 2004-07-30 30/07 '04 FRI 17:55 FAX 61299255911 GRIFFITH HACK 1020 382 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 tumor cells, melanoma, breast tumor cells and prostate tumor cells. A use of a compound of any one of Claims 1-27 for inhibiting farnesyl protein transferase. 36. A use of a compound of any one of Claims 1-27 for o treating 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 tumor cells. o** 37. A compound of claim 1 substantially as hereinbefore 20 described with reference to any one of the Examples. 38. A method of treating tumor cells comprising administering an effective amount of a compound of claim 37. 39. A method of inhibiting farnesyl protein transferase comprising administering an effective amount of a compound of claim 37. DATED this 3 0 t h day of July 2004 SCHERING CORPORATION By their Patent Attorneys GRIFFITH HACK COMS ID No: SBMI-00850317 Received by IP Australia: Time 17:13 Date 2004-07-30