CA2117367A1 - 3-phenylureido-azepin-2-ones and benzazepin-2-ones useful as cholecystokinin antagonists - Google Patents

Abstract

The present invention relates to novel substituted hexahydroazepinones and tetrahydrobenzazepinones of formulae (I) and (II) wherein R1, Z1, Z2, Y1 and Y2 are as defined, and to novel intermediates used in the synthesis of such compounds. Such compounds are useful in the treatment and prevention of gastrointestinal disorders, pain and anxiety disorders.

Description

93/15059 C A 2 ~ ~ ~ 3 ~ 7 PC~r/US92/10720 3-PHENYLUR~IDO-AZEPIN-2-ONES AND 23Ll7367 .. CHOLECYSTOKININ ANTA60NISTS
Backaround of the Invention Tha present invention relates to novel substituted he~ahydroazepinones and tetrahydrobenzazepinones, pharmaceuticai composKions comprising such compounds 10 and the use of sueh eompounds in the treatment and prevention of central nervous system and gastrointesUnal disordars. The pharrnaeeuticaily aetive eompounds of this invenUon are selective CCK-B reCQptor antagonists.
Choleeystokinin (CCK) is a 33 arnino aeid peptide originaily discovered and characterized in 1971. (See Mutt et ~., Biochem. J., 125, 57 (1971)). It carri out its 15 biological responses by binding to Ks two receptor types: CCK-A and CCK-B. The CCK-A reeeptor is located primarily in tne gailbladder and pancreas, and mediabsCCK-induced enzyme secreUon and gallbladder contraction during a meal. The CCK-Breceptor is located in the stomach, where Tt is invoived in acid secretion, and in the brain, where it mediates pain and anxiety responses.
A number ot potent and selective non-peptide antagonists for these two receptors are known (See M.G. Bock. Drug~the Future, 16 (7)1 631440 (1991) and R.M. Freidinger, Med~ Res. ~ ev., 9, 271-290 t1989)). Merck's L~64,718 (devazepide) is a seleetive CCK-A antagonist. (See O'Neill et ai., Brain Res., 534, 287-290 (1990))~
This eompound, however, has proven not to be elintcally useful. Mer~s benzodiazepine L 365,260 Ts a sdeetive C:CK-B antagonist that was found to have an analgeste effeet on squirrei monkeys. (See O'Neill ~t al., BraiQ Res., 534, 287-290 (1990)). Clarlc~Davis' Cl988 is a selective CCK-B antagonist that was ~ound to rev~rse the pentag~n-induced anxiogenie response in rats. (Sae Sinah et al., Proe. Na~l.Acad. Scl.... ........U.S., 88, 1130-33 (1991)).
Summary of the Invention Tha Rresent Invention relates tQ compounds of the formula " CA~l 17367 1 2 ~t'',;~''.

2 - ! 2131 ~367 ~K 1 H~2 C ~t 2 1, ¦ or y2 ~H H~_ c whereln Y~ and Y' ~re indepen~enUy s~lected from the group conshting of hy~rogen, pheny~, th1enyl, pyridyl, turyl, pyrimidylj tCJ-CE~) s~raight or branched allcyl and (c~-c~?
- cycloalkyi, wherein sald phenyl, thi~n~l, py,ridyl, fulyl, and pyrimidy rnay optionatly 20 substituted With one or two substituents¦independently ~ cted from halo (~g~, chloro, fluoro, bromo or iodo), ~C,-C~) alkyl, (f~ ) alkoxy, nitro, arnino and tritluorornethyl, and wh~rein said cycloalkyl may eption~Jly b~ subslRutec with one ar two substituonts independenUy selectQd from (C,-CE~ yl; with the prov~so that one o1 Y' and y2 rnust be other ~han hydrogen; I .
W is hydrogen, meUlyl, ~thyl, c~lorine, tluotlnQ, methoxy cr trifluoromethyl;
Zl and Z~ arQ ind~pendently sale~ted ~rom the group consisting of halo, (C,-CJ
aticyt, tC,-Ca) thloalkyl, (C,-C~,) alkox~,¦ trifluorome~yl, (Cl-C~ carboal~oxy, cyano, melhylamino, diethylamlno, isoprop~arnino, t-butylamino, m~thylsut~onyiamino, acetyl~mlno, amlno and nitro;
~0 R' is ph~nyl, CO~R', SOiN~'R'~ o~ CONPI"R5, wherein saici phenyl may optton~lly be subsUtutQd with one or two substitue nts Independently selec~ed fron~ halo, ~C, C~,) allcyl. (C~ C,) alkox~, nitro, amino and t inuoromothyl, ~nd ~l~rein R~, R3 and ~ are odeponden~l1 sclcct-d ~rom hydrogrln, ~c~-c~l alkyl ond ~u-cd, s~turat~d c6rbocyrllc IDED SHE~

` ";!~ A ~ 3`6 ~ z~3L73~7 ^2a-~ystems containlng two or Ulree nngs, an~ R~ and R~ are independently seJected frorn hydro~en, benzyl, (C, C,~)alkyl and tu~ed, saturated carbocyclic ~yslems containln~
two or three rin~6;
The present in~lention ~Iso rel~tes to the pharrnaceutlcally acc~ptable acld S addi~on salts of compounds of the ~onlnulae I and 11. Th~ ~cidfl ~hich ar~ used to A~,IIEN~)ED SHE~

w093/lsos9 ~ ~ 2 1 1 7 3 6 7 PCI`/US92/10720 -3- Z~ 6 preparethe pharmaceutically acceptable acid addition salts of the aforementioned b se compounds of this invention are those which forrn non-toxic acid addition salts, i.e., salts containing pharmacologically acceptable anions, such as the hydrochloride,hydrobromide, hydroiodide, nitrate, sulfate, bisulfate, phosphate, acid phosphate, 5 acetate, lactate, citrate, acid citrate, tartrate, bitartrate, succinate, maleate, fumarate, gluconate,saccharate,benzoate,methanesulfonate,ethanesulfonate,benzenesulfonate,p-toluenesulfonate and pamoate [i.e., 1,1'-methylene-bis-(2-hydroxy~naphthoate)]salts.
The term ~aikyr, as used herein, unless otherwise indicated, includes satur~ted 10 monovalent hydrocarbon radicals having straight, branched or cyclic moieties or combinations thereof.
The term 'halo~, as used herein, unless otherwise indicated, includes chloro, lluoro, bromo and iodo.
Preferred compounds of this invenUon are compounds of the fonnula I wherein 15 either both of y1 and y2 are phenyl, or one of y1 and y2 iS cyclohexyl.
Other preferred compounds of this invention are compounds of the formula ll wherein Y' is phenyl.
Preferred compounds of the present invention include the following: .
tert-butyl 2-[~(3-(3-thlomethylphenyl)ureido)-2-oxo-5-phenyl-2,3,4,~tetrahydro-lH-(l)benzazepin-1-yl~ ethanoate;
3-((3-chlorophenyl-)ureido)-7-cyclohexyl-(N-t-butoxycarbonylmethyl)-hexahydroazepin-2-one;
3-((3-tolyl)ureido)-7-cyclohexyl-(N-t-butoxycarbonylmethyl)hexahydroazepin-2-one;
3-((3-chlorophenyl)ureido)-7-cyclohexyl-(N-1-adamantyloxycarbonylmethyl)-hexahydroazepin-2-one;
3-((3-chlorophenyl)ureido)-7-cyclohexyl-(N-2-adamantyloxycarbonylmethyl)-- hexahydroazepin-2-one;
3-((3-tolyl)ureido)-7-cyclohexyl-(N-1 -adamantyloxycarbonylmethyl)-30 hexahydroazepin-2-one;
3-((3-tolyl)ureido)-7-cyclohexyl-(N-2-adamantyloxycarbonylmethyl)-hexahydroazepin-2-one;

WO 93/15059 (~ 7 3 ~ 7 Pcr/us92/lo ~

z~7367 4-3-((3-methoxyphenyl)ureido)-7-cyclohexyl-(N-t-butoxyearbonylmethyl)-hexahydroazepin-2-one;
3-((3-methoxyphenyl)ureido)-7~yclohexyl-(N-1 -adamantyloxyearbonylmethyl)-hexahydroazepin-2 one; ~:
3-((3-methoxyphenyl)ureido)-7 eyclohexyl-(N-2-adamantyloxycarbonylmethyl)-hexahydroazepin-2-one;
3-((3-chlorophanyl)ureido)-5 ,7-diphenyl-(N-t-butoxycarbonylmethyl)-hexahydroazepin-2~ne;
- 3-((3-tolyl)ureido)-5,7-diphenyl-(N-t-butoxycarbonylmethyl)-hexahydroazepin-2-10 one;
3-((3-methoxyphenyl)ureido)-5,7-diphenyl-(N-t-butoxyearbonylmethyl)-h~xahydroazepin-2-one;
3-((3-ehlorophenyl)ureido)-5,7-diphenyl-(N-l -adamantyloxyearbonylmethyl)-hexahydroazepin-2-one;
N-teltbutyl 2-l3-(3~(3 chlorophenyl)ureido)-2-oxo~phenyl-2,3,4,5-tetrahydro-lH-(1)benzazepin-1-yll ethanoie aeld amide;
N-tert-butyl 2-13-(3-(3-tolyl)ureido)-2-oxo-5-phenyl-2,3,4,5-tetrahydro-1 H-(l)benzazepin-1-yil ethJnoie aeid amide;
N-tert-butyi 2-l3-(3-(3-methoxyphenyl)ureido)-2-oxo-5-phenyl-2,3,4,5-20 tetrahydro-1H-(l)benzazepin-l-yll ethanoie aeid amide;
N-tertbutyl 2-l~(3-(3-thiomethylphenyi)ureido~2-oxo~phenyi-2,3,4,5,-tetrahydro 1H-(1)benzazepin-1-yl] ethanoie aeid amide;
N,N-dl(2-propyl) 2-13-(3-(3-ehlorophenyl)ureido)-2-oxo-5-phenyl-2,3,4,5-tetrahydro-l H-(l )benzazepin-l-yll ethanoi¢ aeid arnide;
N,N-di(2-propyl) 2-13-(3 (3 toly)ureido)-2-oxo-5-phenyl-2,3,4,~tetrahydro-1 H-(1)benzazepin-1-yll ethanoie aeid amide;
N,N-di(2-propyl) 2-l3-(3-(3-methoxyphenyl)ureido)-2-oxo-5-phenyl-2,3,4,5-tetrahydro-lH-(l)benzazepin-l-yll ethanoie aeid amide;
N,N-di(2 propyl) 2-l3-(3-(3 thiomethylphenyl)ureldo)-2-oxo~phenyi-2,3,4,5-30 tetrahydro-1H (1)benzazepin-1-yll ethanoie aeid amide;
tert-bu~yl 2-13-(3 (3 chlorophenyl)uretdo)-2-oxo~phenyl-2,3,4,~tetrahydro-l H-(1)benzazepin-1-yll ethanoab;

~O 93/15059 C A 2 ~ ~ 7 3 6 7 PCI/US92/10720 tert-butyl 2 [3-(3-(3-tolyl)ureido)-2-oxo-5-phenyl-2,3,4,5-tetrahydro-1H-(1 )benzazepin-1 -yl] ethanoate;

N-tert-butyl 2-[3-(~(~methoxyphenyl)ureido)-2-oxo-5-phenyl-2,3,4,~tetra-5 hydro-1H-(1)benzazepin-1-yll ethanoate;
N-tert-butyl 2-[2-oxo-3-((3-tolyl)ureido)-5,7-diphenyl-hexahydroazepin-1-yl]-ethanoic acid smide;
N-tert-butyl 2-[2-oxo~((~chlorophenyl)ureido)-5,7-diphenylhexahydroaz~ ` ~
pin-1-yl] ethanoic acid amide; ` :
N-ten-butyl 2-[2-oxo~((~methoxyphenyl)ureido)-5,7-diphenylhexahydroaze-pin-1-yl] ethanoic acTd amide;
N-tert-butyl 2-[2~xo~((3-tri~luoromethylphenyl)ureido)-5,7~iphenylhexahy-droazepin-1-yll ethanoic acid amide;
N-tert-butyl 2-12-oxo~((3 rnethylthiophenyl)ureido)-5,7~iphenyl-hexahydroa-15 zepin-1-yl] ethanoic acid amide;
N-bn-butyl 2-12 oxo-3-((3-cyanophenyl)ureido)-5,7-diphenyl-hexahydroazepin-1-yl] ethanoic acid amide;
N-tert-butyl 2-l2-oxo-3-((S-dimethylaminophenyl)ureido)-S,7-diphenyl-hexahydroazepin-1-yl] ethanoic acid amide;
N-tert-butyl 2-12-oxo~((3-ethylphenyl~ureido)~,~iphenyl~exahydroazepin-1-yl] ethanoic acid amide;
N-tert-butyl 2-[2-oxo~(~tolylureido)-~phenyl-~methyl-2,3,4,~tetrahydro-1H -(1)benzazepin-l-yl] ethanoic acid arnide;
N-tert-butyl 2-[2-oxo~(3-tolylureido)-~phenyl-~methyl-2,3,4,5- tetrahydro-1H-25 (1)benzazepin-1-yl] ethanoic acid amide;
N-tert-butyl 2-[2-oxo~(~tolylureido)-5-phenyl-7-chlor~2,3,4,~t~trahydro-1 H
(l)benzazepin-1-yl] ethanoic acid amide;
N-tert butyl 2-[2-oxo~(3 tolylureido)-~(4-fluorophenyl)-2,3,4,S-tetrahydro-l H-(l)benzazepin-l-yl~ ethanoic acid ~mide;
N-brt-butyl 2-[2-oxo~(~tolylureido)~5-(4-chlorophenyl)-2,3,4,5-tetrahydro-1 H-(l)benzazepin-l-yl] ethanoic acid arnide;
N-tert-butyl 2-12-oxo~(~tolylureido)~(4methylphenyl)-2,3,4,5-tetrahydro-lH-(l~benzazepin-l-yl] ethanoic acid amide;

WO g3/15059 C A 2 1 1 7 3 6 7 PCr/US92/107,2~0 21173~ 6-- N-tert-butyl 2-[2-oxo-3-(3-tolylureido)-5-(2-fluorophenyl)-2,3,4,~tetrahydro-1 H-(1)benzazepin-1-yl) ethanoic acid amide;
N-tert-butyl 2-[2-oxo-~(3-tolylureido)-~(3-chlorophenyl)-2,3,4,~tetrahydro-1 H-(1)benzazepin-1-yll ethanoic acid amide;
N-brt~utyl 2-[2-oxo-S(~tolylureido)~(3,Wichlorophenyl~2,3,4,~tetratlydro-1 H-(1)benzazepin-1-yl] ethanoic acid amide;
N-(1 ,1-dimethyl)propyl)-2-[2-oxo-3-((~tolyl)ureido)~phenyl-2,3, 4,~tetrahydro-lH-(1)benzazepin-1-yll ethanoic acid amide;
(N-(1 -methyl)cyclohexyl)-2-l2-oxo-~((~tolyl)ureido)~phenyl-2,3,4,~tetrahydro-10 lH-(1)benzazepin-1-yl] ethanoic acid arnide;
N-tert-butyl 2-[2-oxo-3-(~tolylureido)-~eyclohexyl-2,3,4,~tetrahydr~1 H-(1~
- benzazepin-1-yl] ethanoic acid arnide;
Examples of other compounds of the present invention include.
N-tert-butyl 2-[2-oxo~((3-tolyl)ureido)-~phenyl, 7-(~pyridyl)-hexahydroazepin-1-yll ethanoic acid amide;
N-tert-butyl 2-~2-oxo-S((~tolyl)ureido)-~phenyl, 7-(2-pyndyl~-hexahydroazepin-l-yl] ethanoic acid arnide;
N-tert-butyl 2-[2-oxo~(~tolyl)ureido)-~phenyl, 7-(~pyridyl)~exahydroazepin-l-yll ethanoic acid amide;
N-tert-butyl 2-[2-oxo~((Stolyl)ureido)-~phenyl, 7-(~thienyl)-hexahydroazepin-l-yll ethanoic acid amide;
N-tert-butyl 2-12-oxo~((~tolyl)ureido)-~phenyl, 7-(2-thienyl)-hexahydroazepin-1-yll ethanoic acid amide;
N-tert~utyi 2-12~xo~((Stolyl)ureido)~;phenyl, 7-(2-pyrimidyl~hexahydroazepir~
l-yll ethanoic acid amide;
N-tert-butyl 2-~2-ox~S((~tolyl)ureido)~phenyl, 7-(4pyrimidyl)-hexahydroazepin-1-yll ethanoic acid amide;
N-tert-butyl 2-[2-oxo-3-((3-tolyl)ureido)-5-(3-fluorophenyl), 7-phenyl-hexahydroazepin-t-yl] ethanoic acid amide;
30N-tert-butyl 2-[2-oxo-3-((3-tolyl)ureido)-5-(4-chlorophenyl), 7-phenyl-hexahydroazepir~1-yll ethanoic acid amide;
N~ert-butyl 2-[2-oxo~-((3-tolyl)ureido)-5-(3-chlorophenyl), 7-phenyl-hexahydroazepin-1-yl] ethanoic acid amide;

yog3/l50s9 C ~ 2 1 1 7 3 6 7 PCl'/US92/10720 -7- ~ 36 N-tert-bu~l 2-12-oxo~((3-tolyl)ureido)-~(~trifluoromethylphenyl), 7-pherlyl-- hexahydroazepin-1-yl] ethanoie acid amide; ' .
N-tert-butyl 2-l2-oxo~((3-tolyl)ureido)-~(3-tolyl), 7-phenyl-hexahydroazepin~
yl] ethanoie acid amide; ' N-tert-butyl 2-12-oxo~((3-tolyl)ureido)-5-(4-tolyl), 7-phenyl-hexahydroazepin-1-yll ethanoie aeid amide;
N-tert-butyl 2-[2-oxo-3-((3-tolyl)ureido)-5-(4-methoxyphenyl), 7-phenyl-hexahydroazepin-l-yll ethanoie aeid amide;
N-tert-butyl 2-12-oxo-3-((~tolyl)ureido)-5-(3-methoxyphenyl), 7-phenyl-10 hexahydroazepin-1-yll ethanoie aeid amide;
N-tert-butyl 2-12-oxo~((3-tolyl)ureido)-5-(3-pyridyl), 7-phenyl-hexahydroazepin-1-yl~ ethanoie aeid amide;
N-tert-butyl 2-12-oxo~((~tolyl)ureido)-5-(3-thienyl), 7-phenyl-hexahydroazepin-1-yl] ethanoie aeid amide;
N-tert-butyl 2-12-oxo~((3-tolyl)ureido) ~(~thienyl~, 7-phenyl-hexahydroazepin-1-yll ethanoie aeid amide;
N-tert-butyl 2-12-oxo~((3-tolyl)ureido)~(2-pyridyl), 7-phenyl-hexahydroazepin-l-yl] ethanoie aeid amide; ~
N-tert~ti 2-12-oxo~((3-toyl)ureido)~eyelohexyl, 7phenyihexahydroazepin-1-20 yll ethanoic aeid amlde;
N (1,1 dimethyi)propyl) 2-12 oxo~((~to~l)ureido)-5,7-diphenyi hexahydroazepin-1-yll ethanoie aeid amide;
N (1,1-dimethyijbenzyi 2-12-oxo~((~tolyl)ureido)~,7-dipheny~ hexahydroazepin-1-yll ethanoic acid amide;
N~1 methyl)eydoh,exyl 2-[2-oxo~((~toq~l)ureido)-5,7-diphenyi-hexahydroazepin-l-yll ethanoie acid amide;
N-(1-methyi)eydoper~i 2-12-oxo~((3toiyl)ureido)-5,7-dipheny~ahydroazepin-:: o l-yll ethanoie acid amide;
N-tert-butp-[2-oxo~((3-methyiaminoph~nyl)ureido)-5,7~iiphenyl-hexahyd~:oaz-30 epin-l-yll ethanoie aeid ~nide;
N-brt-buty 2-l2-oxo~((~(N-methyi,N-acetyl)ureido)-5-eyeiohexyl, 7-phenyl-hexahydroazepin-1-yll ethanoic àcid amide;

WO 93/15059 PCI`/US92/107?~ `
z~73, i ` ~ -8-Nrltert-butyl 2-[2-oxo-~((3-(N-methyl,N-methanesulfonyl))ureido)-5-cyclohexyl, 7-phenyl-hexahydroazepin-1-yl] ethanoic acid amide;
N-tert-butyl 2-[2-oxo-3-((3-diethylaminophenyl)ureido)-5,7 cliphenyl-hexahy-droP~epin-1-yl] etharoic acid amide;
N-tert-butyl 2-[2-oxo-~((3-isopropyla~ninophenyl)ureido)-5,7-diphenyl-hexahyd-roazepin-1-yl] ethanoic acid amide;
N-tert-butyl 2-[2-oxo~((3-t-butylaminophenyl)ureido)-5,7-diphenyl-hexahydro-azepin-1-yl] ethanoic acid amide;
N-tert-butyl 2-[2-oxo-3-((~isopropylphenyl)ureido)-5,7~iphenyl-hexahydroaze-10 pin-1-yi] ethanoic acid amide;
N-tert-butyl 2-[2-oxo~((3-t-butylphenyl)ureido)-5,7~iphenyl-hexahydroazepin-1-yll ethanoic acid amide;
(N-(1 ,1 -dim~thyl)benzyl)-2-[2~xo~((3-tolyl)ureido)-5-phenyl-2,3,4,5-tetrahydro-1 H-(1 )benzazepin-1-yl] ethanoic acid amids;
(N-(1 ~nethyl)cyclopéntyl)-2-[2~xo-~((~tolyl)ureido)-~phenyl-2,3,4,~tetrahydr~
lH-(1)benzazepin-1-yl] ethanoic acid amide;
N-tert-butyl-2-12-oxo-3-((3-dimethylaminophenyl)ureido)-5-phanyl-2,3,4,5-tetrahydro-1H-(1)benzazepin-1-yl] ~th~loic acid amide;
N-tert-butyl-2-12-oxo~((3-methyiaminophenyl)ureido)~phenyi-2,3,4,~tetrahydro-1 H-(1 )benzazepin-1-yl] ethanoic acid amide;
N-tertbutyl-2-12~xo~((~(N~nethyl,N~cetyl)ureido)-~phenyl-2,3,4,~tetrahydro-1 H-(1 )benzæepin-1 -Yll ethanoic acid amide;
N-tert-buty1-2-12-oxo-3-((3-(N-methyl,N-methanesulfonyl))ureido)~phenyl-2,3,4,5-tetrahydro-lH-(1)benzazepin-1-yl] ethanoic acid amide;
N-tert-butyl-2-12-oxo-3-((3 diethylaminophenyl)ureido)~phenyl-2,3,4,~te~ahydro-1 H-(1 )benzazepin-1-yl] ethanoic acid arnide;
N-tert-butyl-2-12-oxo-3-((3-isopropylaminophenyl)ureldo)-5-phenyl-2,3,4,5-tetrahydro-1H-(1)benzazepin-1-yl] ethanoic acid amide;
N-tert-buty1-2-12-oxo-3-((3-t-butyiaminophenyi)ureido)~phenyl-2,3,4,~tetrahydro-1 H-(1 ~benzazepin-1-yl] ethanoic acid amide;
N-tert-butyl-2-12-oxo-~((3-isopropyiphenyl)ureido)~phenyl 2,3,4,~tetrahydro-1~~
(1)benzazepin-1-yl] athanoic acid amide;

CA 2 l l 7367 ``0 ~3/lS059 PCI'/US92/10720 21~3~

N-tert-butyl-2-12-oxo-3-((3-t-butylphenyl)ureido)-~phenyl-2,3,4,~tetrahydro-1 H-(l)benz~epin-1-yl] ethanoic acid amide;

N-tert-butyl 2-[2-oxo-3-(3-tolylureido)-~phenyl-8-methoxy-2,3,4,~tetrahydro 5 -1H-(1)benzazepin-1-yll ethanoic acid amide;
N-tert-butyl 2-[2-oxo-~(3-tolylureido)-5-phenyl-~ethyl-2,3,4,~tetrahydro-1 H-(1)benzazepin-1-yl] ethanoic acid arnide;
N-tert-butyl 2-[2-oxo~(3-tolylureido)-5-phenyl-~fluoro-2,3,4,5-tetrahydro-1 H
(1)benzazepin-1-yl] ethanoic acid amide;
N-tert-butyl 2-[2-oxo~(~tolylureido)-5-phenyl-~chlor~2,3,4,~tetrahydro-1H -(1)benzazepin-1-yl] ethanoic acid amide;
N-tert-butyl 2-l2~xo~(~tolylureido)-~pheny!-7-methoxy-2,3,4,~tetrahy-dro-1H-(1)benzazepin-1-yll ~thanoic acid amide;
N-tert-butyl 2-[2-oxo~(3-tolylureido)-5-phenyl-7-fluoro-2,3,4,5-tetrahydro-1H -(1)benzazepin-1-yll ethanoic acid amide;
N-tert-butyl 2-12-oxo~(~tolylureido)-5-phenyl-7-trifluoromethyl-2,3,4,5-tetra-hydro-1H-(1)berlzazepin-1-yl] ethanoic acid arnide;
N-brt butyl 2-12-oxo~(3-tolylureido)-~phenyl-~trifluorom~thyl-2,3,4,~tetra-hydro-lH-(l)benzazepin-l-yl] ethanoic acid amide;
N-tert-butyl 2-[2-oxo~(3-tolylureido)-5-(3-fluorophenyl)-2,3,4,5-tetrahydro-1 H-(1)benzazepin-1-yl] ethanoic acid amide;
N-tert-butyl 2-[2-oxo-3-(3-tolylureido)-5-(3-trifluoromethylphenyl)-2,3,4,~
tetrahydro-lH-(1)benzazepin-1-yl] ethanoic acid amide;
N-tert-butyl 2-l2-oxo-3-(3-tolylureido)-~(4-trifluoromethylphenyl)-2,3,4,~
25 tatrahydro-1 H-(l)benzazepin-l-yll ethanoic acid amide;
N-tert-butyl 2-[2-oxo-3-(3-tolylureido)-~(3-dimethylaminophenyl)-2,3,4,~tet-rahydro-1H~(1)benzazepin-1-yll ethanoic acid arnide;
N-tert-butyl 2-12-oxo~(3-tolylureido) !;(3-suHonamidophenyl~2,3,4,5-tff~ahydro-1H-(l)benzazepln-l-yl] ethanoic acid amide;
N-tert-butyl 2-l2-oxo-3-(3-tolylureido)-5-(3-(acetylamino)phenyl)-2,3,4,5-tet-rahydr~1H-(1)benzazepin-1-yl] ethanoic acid amide;
N-tert-buq~l 2-[2-oxo~(~tolylureido)~(3,4 d`~uorophenyl~2,3,4,5-tetrahydr~1 (1)benzazepin-1-yll ethanoic acid amide;

W0 93/15059 CA ~ 7 PCI`/US92/1072'`

. ~ .
Z~736~ ! -10-N-tert-butyl 2-12-oxo~(~tolylureido)-~(3,4~imethylphenyl)-2,3,4,~tetrahydro-1 H-(l)benzazepin-l-yll ethanoic acid amide;
N-tert-butyl 2-[2-oxo-3-(3-ethylphenylureido)-5-(4-chlorophenyl)-2~3,4,5-tet-. rahydro-1H-(1)benzazepin-1-yl] ethanoic acid amide;
5N-(1,1-dimethylpropyl) 2-[2-oxo-~(3-tolylureido)-~(4chlorophenyl)-2,3,4,~
t~trahydro-1 H-(1)benzazepin-1-yl] ethanoic acid amide;
N-tert-butyl 2-[2-oxo-3-(3-dimethylaminophenylureido)-~(~chlorophenyl)-2,3,-4,5-tetrahydro-1 H-(l )benzazepin-l-yll ethanoic acid amide;
N-tert-butyl 2-[2-oxo~(~dimethylaminophenylureido)-5-(~methylphenyl)-2,3,-10 4,5-tetrahydro-1 H-(l )benzazepin-1-yl] ethanoic acid amide;
N-(1 ,1-dimethylpropyl) 2-[2-oxo~(3-tolylureido)-~(4-methylphenyl)-2,3,4,-~tetrahydro-l H-(1)benzazepin-1-yl] ethanoic acid amide;
N-tert-butyl 2-[2-oxo~(3-ethylphenylureido)-~(4-chlorophenyl)~methyl-2,3,-4,5-tetrahydro-lH-(1)benzazepin-1-yl] ethanoic acid amide;
15N-(1,1-dimethylpropyl) 2-[2-oxo-3-(3-tolylureido)-~(~chlorophenyl)-8-methyl-2,3,4,~tet rahydro-lH-(1)benzazepin-1-yl] ethanoic acid amide;
N-tert-butyl 2-[2-oxo-3-(3-dimethylaminophenylureido)-~(~chlorophenyl)-~
methyl-2,3,4,5-tetrahydro-1H-(1)benzazepin-1-yl] ethanoic acid amide;
N-tert-butyl 2-l2-oxo-3-(3-dimethylaminophenylureido)-~(4-methylphenyl)~
20chloro-2,3,4,5-tetrahydro-1H-(1)benzazepin-1-yl] ethanoic acid amide;
N-(1,1-dimethylpropyl) 2-[2-oxo-~(~tolylureido)-5-(~methylphenyl)~chloro~
2,3,4,~tetrahydro-lH-(1)benzazepin-1-yl] ethanoic acid amide;
N-(1,1~iimethylpropyl) 2-[2-oxo-3-(~ethylphenylureido)-~(4-methylphenyl)~
chloro-2,3,4 ,5-tetrahydro-1 H-(1 )benzazepin-1 ~yl] ethanoic acid arnide;
25N-(1,1-dimethylpropyl) 2-12-oxo-3-(3-dimethylaminophenylureido)-5-(4-methylphenyl)-~chloro-2,3,4,5-tetrahydro-1 H-(1 )benzazepin-1 -yl] ethanoic acid amide;
N-~ dimethylpropyl) 2-[2-oxo-3-(3-dimethylaminophenylureido)-5-(4-chlorophenyl)-8 chloro-2,3,4,~tetrahydro-1H-(1)benzazepin-1-yl] ethanoic acid amide;
N-(1,1-dimethylpropyl) 2~[2-oxo-3-(3-tolylureido)-~(4-methylphenyl)-8-methyl-302,3,4,~tetrahydro-1 H-(l )benzazepin-1 -yl] ethanoic acid amlde;
N-(1,1-dimethylpropyl) 2-t2~xo-3-(3-ethylphenylureido)~(4chlorophenyl)~
methyl-2,3,4,~tetrahydro-1H-(1)benzazepin-1-yl] ethanoic acid amide;

Z~367 .- i ...
N-(1,1 dimethylpropyl) 2-[~-oxo-3-(3-din~ethylarninophenylureldo)-5 (4-chlorophenyi~ ~-m~thyl-2,3.~ tet~ahy~ro~ (1)ben~a~epin-1 yl3 ethanolc acld amide;
N,~ tert-butyl 2-13-(~(chlo¦opllenyl)ureido)-2~xo-5-phenyl-2,3,4,~
tetrahydro-l~i-(1)benzazepin-1-yl~ eth~noic acid amide;
N,N-di(tert-bl~tyl) 2-E~3-tol yl3ureido)-2~xo-5-phenyl-~,3,~,~tetrahydro-11 t^enz~zepin-1 yl] ethanoic aeid aJni~ le;
N,N-dl(tert-~utyl) ~-[~(~-(rr lethoxyphQnyl)ureldo)-2-oxo-5-phenyl-2,314,~
te1r~hydro-~H-(1)benzazepin-1-yl~ etha~oic acid arnide:
tert butyl-2 ~3-~13~hlorophenyt)~reWo~-2 oxo ~phenyl-7-(2,~imothylcycloh~
1 0 hexa11ydroazepin-1-yl]ethanoate;
tert-butyl-2-[~-t(~-tolyl)ùreido.~l 2 oxo 5-phenyl-7 (2,6-dimetllylcy~tohexyl)~
hexahydro~epin-1-yl]ethan~te;
tert-butyl-~-[3-t(3-mQthoxi~ph~nyl)ureido)-2-oxo-5-phenyl-7-~2 dimethylcyclohexyl)-hex~ydroa~epin-1¦-yl]ethano~te;
~t-adamantyl3-2-[3-((3-methox~lphenyl)ureido) 2-oxo~5-phenyl-~ycloiTe~tyl~
hexahydroazepin l-ylle~noate;
~ -adamantyl)-2 ~((3 methox~/phen~l)urelclo)-~-oxo~5-phenyl-7~cyclohexyl-hexahydroazepin 1-yilethanoate;
(1 -adamantyi)-2-[3-~3-101yl)Ureid~)-2-OXo~phenyt-7-oyClohexyl~exahydroa2epir~
20 l-yl~thanoate;
(2-adamantyl)-2-L3-~(~tclyl)ure;dol-2-ox~5-phenS~1-7~Cyclol~exyl-hexahydroze l-yl]ethanoat~; !
(1-adamantyl)-2-~3 ((3-chloropi~enyi~urei~o)-2-oxo 5-phenyl-7-cyclohexyl hexahydroazepin-1-yl]ethanoate; and ' 2~; (2~dam~ntyl)~2-[3-(~3-chtorOptenyl)urQido~2-oxo-5~phenyl~7-cyclohe hexahy~rozepin-~-yllethanoate. I

i AMENDED StlEET

CA21 1 7~67 2~36 -11a-~his In~ention also relates to compounds of the formula s ~"

. . .

N~ S~EE~

wo g3/l50s9 C A ~ 7 PCI/US92/1072~

. ~
2~i`736`7 -12-wherein R7 is hydrogen or one of the radicals set forth in the definition of R' above, RB
is bromine, amino or azido and yl is defined as above. These compounds are useful as intermediates in the synthesis of compounds of the formula ll.
The present invention also relates to a pharmaceutical composition for treating or preventing a condition selected from the group consisting of pain, gastrointestinal disorders such as ulcer and colitis, and central nervous system disorders such as anxiety and panic disorder in a mammal, including a human, comprising an amount of a compound of the formula I or ll, or a pharmaceutically acceptable salt thereof, 10 effective in treating or preventing such condition, and a pharmaceutically acceptable carrier.
The present invention also relates to a method of treating or preventing a condition selected from the group consisting of pain, gastrointestinal disorders such as ulcer and colitis, and central nervous system disorders such as anxiety and panic 15 disorder in a mammal, including a human, comprising administering to said mammal an amount of a compound of the forrnula I or ll, or a pharmaceutically acceptable salt thereof, effective in treating or preventing such condition.
The present invention also relates to a phamaceutical composmon for antagonizing the effects of cholecystokinin in a mammal, including a human, 20 comprising a cholecystokinin antagonizing amount of a compound of the formula I or Il, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.
The present invention also relates to a method of antagonking the effects of cholecystokinin in a mammal, including a human, comprising administering to said25 mammal a cholecystokinin antagonizing amount of a compound of the formula I or ll, or a pharmaceutically acceptable sait thereof.
The present invention also relates to a pharmaceutical composition fortroating or preventing a chohcystoklnin mediated disorder In a mammai, including a human,comprising a cholecystokinin antagonizing amount of a compound ot the formula I or 30 Il, or a phannaceutically acceptable salt thereof, and a pharmaceuticaily acceptable carrier.
The present invention also relates to a method of treaUng or prevenUng a - cholecystokinin medicated disorder in a mammal, including a human, comprising -`V93/15059 ` C A2`I l 7 3 6~ P~/US92/10720 -13- 211~7~67 ` Y ~
administering to said mammal a cholecystokinin antagonizing amount of a compoundof the fonnula I or ll, or a pharrnaceutically aceeptable sait thereof.
The present invention ~so relates to a pharrnaceutical composition for treating or prevenUng a condition selected from the group consisting of pain, ~astrointestinal 5 disorders such as ulcer and eolitis, and eentral nervous system disorders sueh as anxiety and panic disorder in a marnmal, including a human, eomprising an amount of a compound of the formula I or ll, or a pharmaeeutically aceeptable salt thereof, effective in antagoneing the effeet of eholeeystokinin at its receptor site, and a pharmaceutioally acceptable carrhr.
The present invention also relates to a method of treatin~ or prevenUng a condition seleeted from the group eonsisUng of pain, gastrointestinal disorders sueh as uleer and eolitis, and central nervous system disorders such as ar~iety and panic disorder in a mammal, including a human, oomprising administering to said mammalan amount of a eompound of the formula I or ll, or a pharmaeeutieally aeeeptable sal~
15 thereof, effeetive in antagonizing the effeet of eholeeystokinin at its reeeptor site.
The eompounds of the formulae I and ll hava chiral eenters and therefore exist in dfflerent enanUomerie and diastereomie forms. This invention relates to all optieai isomers and all stereoisomers of eompounds of the formulae I and ll, and mixtures thereof.
Formula I and formula 11 above inelude eompounds identieai to those depicted but for the fact that one or more hydrogen or carbon atoms ue replaced by isotopes thereof. Such eompounds are useful as researeh and diagnostie tools in metabolism pharmaeokinetie studies and in binding assays.
Detailed Deseription of the Invention The compounds of the formulae I and ll may be prepared as described in the following reaetion sehemes and diseussion. Unless otherwise Tndicated, R', R2, R3, R~, R5, R~, yl, ~2, Zl and Z2 in the reaction schemes and diseussion that follow are defineJ
as above.

WO93/lSOSg CA21 l 7367 PCI`/US92/107r- ~
... . . .
-14- ~:
2117367 Scheme 1 y~ y~ I y2 5 [~Y2 ~Y ' \OH
I I I lV V
I

(~N, --~9r (~9 r CH2 ICH2 H .
- Rl Rl Yl I I Vl I Yl I

C~ ~N H~

Rl Rl IX IA
(RI~C02R2, C~H~, CoNR~R5 or So2NR3R~) O 93/15059 C 1~ 2 1 1 7 3 67 PCI'/US92/10720 -1~ 21 ~7367 Scheme 2 ~H H~

I A
( R1 - C02R2, R2= H ) ~,H H~

ID

( Rl - CO~H ~
' I :

5~, R

( R C 0 N R R

CA~1 1 7367 2~36 ~chem~ 3 6 ~ ' X 1~1 10 ~,~

x t5 :`

C H, '''' I
(R~C02R2 . C~H5, COiNR~R~ o r 502NR3R6) I ' ~
i A~ N~E~ S~EE~

3/15059 C A 2 1 1 7 3 6 7 PCI`/US92/10720 2~7~.7 The preparation ot compounds of the formula I wherein Rl is CO2R2, C~H5, CONR~R5 or SO2NR3R~ (hereinafter referred to as compounds of th~ formula IA) is illustrated in scheme 1.
Referring to scheme 1, a compound of the formula lll is reacted with 5 hydroxylamine hydrochloride in methanol in the presence of sodium bicarbonate or triethybmine, to form a compound of the formula IV. This re~ction is generally carried out at a temperature from about room temperature to about the rellux bmperature of the reaction mixture. The compound of formula IV so formed is then converted to a compound of the formula V by reacting it with tosyl chloride in pyridine at about 0C
10 for about 24 hours.
Aitematively, compounds of the formula lll may be converted directly into the corresponding compounds having formula V in a one step procedure. According to this procedure, a compound of the forrnula lll is reacted with NH2OSO3H
(hydroxylamine ~ sulfonic acid) in formic acid at about the reflux temperature of the 15 reacUon mixture. This one step procedure is prefened over the two step procedure described above ~or all compounds of the formula IV except those wherein Y' is phenyl and adjacent to the oxo group.
BrominaUon of the compound of fonmulaV yieids the conesponding compound hsving fonmula Vl. The bromination is typically ~:arried out by first adding a compound 20 of the fonmula V to a mixture of phosphorus pentachloride anq pyridine in methylene chloride at about 0C. Then, phenytlrimethyiammonium bromide tribromide is addedto the reaction mixture, also at a temperature ot about 0C. Aiternativeiy, the second step, which involves the addition of the brominating agent, may be replaced by aprocedure In which bromine i$ added at a temperature of about 0C and allowed to25 react for a period of about 0.5 hours to about 5 hours, preferably about 2 hours, resuHing in dibrominaffon of the saturated nitrogen containing seven membered ring One of the bromine atoms is then seiectively removed by treatment with hydrogen gas in the presence of pailadium which has been poisoned with quinollne.
The brominated compound of forrnula Vl is then alkyiated at the ring nitrogen 30 by reaction with a compound of the formula XCH2R', whereln X Is bromine when R' is phenyl and X Is iodine for ail other Rl, in tetrahydrofuran (THF) in the pr~sence of sodium hydride. This reaction, which yieids the corresponding compound of formula WO 93/15059 ~ 7 PCI`/US92/10721~

Vll, is usually condueted at a temperature ~om about room temperature to about 150C. It is preferably conducted at the reflux temperature of the reac~ion mixture.
The compound of formula Vll formed in the above step is then reacted with an alkali metal azide to produce a compound of the formula Vlll. The preferred reactant 5 is sodium azide. Generally, this reaction is carried out in a reaction inert solvent sueh as dimethyiformamide (DMi~ or dimethylsultoxide (DMSO), preferably DMF, at a temperature trom about 60C to about 100C, preferably about 80C.
Reduction of the azide ot formula Vlll yields the eorresponding arnine ot tormula IX. The reduetion is typieally accompllshed using hydrogen gas at a pressure ot trom 10 about 1 to about 3 atmospheres in the presenee ot palladium on earbon (PdlC).Suitable reaetion inert solvents include halogenated hydroearbons and (Cl-CO) alkanols.
Ethanol is the preferred solvent. The reaction temperature may range *om about 1 5C
to about 70C, with about room bmperature being preferred.
Alternatively, the reduetion may be aecomplished using a trialkyl or triaryl 15 phosphine. Examples of appropriate reactants are triphenylphosphine ~nd tributylphosphine. This reaction is generally conducted in a reaction inert solvent suah as THF or another ethereai water miscible solvsnt in the presence ot water, at atemperature from about room temperature to about 1 00C. Preferably, it is eonducted in THF at about room temperature.
The eompound of formula IX so formed is then eonverted into the eorresponding eompound having fonmula IA by reacting it with an isoeyanate of the hrmula C"H~Z'Z2NCO. Appropriate reaction inert solvents for this reaction indude hydrocarbons such as hexane, benzene and toluene~ halogenated hydrocarbons such as methylene chloride and 1,2-dichloroethane, ethereal so3vents such as ethyl ether, 25 THF and glyme, and pyridine. The preferred sohrent is 1, 2-dichloroethane or methylene chloride. Tertiary organic amines may be useful as cataiysts. The reaction tempera~ture may range from about 0C to about 150C. The refiux temperature Is preferred.
The isocyanate of the 1Ormula C,,H4Z'Z2NCO used in the foregoing reaction can 30 be formed by procedures well known to those skilled in the art. One such method involves mixing a benzoic acid derivative with diphenylphos~horylazide, or an anaiagous reagent, in the presence of an organic base such as a triaikylamine, preferably triethylamine or diisopropylethylamins. This reaction is usuaily conductec ; ~093/15059 C A 2 l ~ 7 3;67 P~/US92/10720 ~ $~3$7 in an ethereal, hydrocarbon or chlorinated hydrocarbon solvent, preferably tetrahydrofuran or benzene, at a temperature from about room temperature to about 100C, preferably at the reflux temperature of the solvent, for a period from about 20 minutes to about 24 hours, preferably about 1 hour.
Scheme 2 illustrates the synthesis of compounds of the formula I wherdn P~' is CO2H (hereinafter referred to as compounds of the formula IB) from compounds of the formula IA wherein R' is CO2R2. It also illustrates a method of preparing compounds of the formula IA wherain R is an amida (i.s., R' is CONR~R5) from the corresponding acids of tormula IB. ~
Referring to scheme 2, hydrolysis of a compound of the formula IA wherein R' is CO2R2 yields the corresponding acid of formula IB. The hydrolysis is typically carried out using trifluoroacetic acid in a reaction inen solvent as hexane, an ethereal solvent (e.g., ethyi ether or THF) or a haiogenated hydrocarbon solvent (e.g., methylenechloride or 1, 2 dichloroethane), at a temperature from about - 78C to about 50C.
it is preferably carried out using trifiuoroacetic acid in a haiogenated hydrocarbon cosoivent at about 0C.
The acid of formula IB may be converted into the corresponding amlde ot formula IA, wherein R' is CONR~R5, by reaeting the acid with an amine ot the formula NHR~R5 in the presence of a dehydrating agent. The dehydraUng agent is preferably 20 a carbodilmide. Other dehydraffng agents that may be used are 1,1~-earbonyldilmidazole and isobutylehloroformate/N-methylmorpholine. This reaetion is generally eondueted in a reaeUon inert soivent selected from hydroearbons sueh as benzene, toluene and hexane, halogenated hydroearbons such as methylene chlorideand 1,2 dichloroethane, ethereal solvents such as ethyl ether, THF and glyrne, and 2S pyridine, preferably THF, at a temperature from about 0C to about 120C, preferably at about room temperature.
Scheme 3 illustrates the preparaUon of compounds of the formula ll wherein R' is CO2R2, C~H5, CONR~R5 or SO2NR3R (herelnafter referred to as compounds of theformula IIA).
Referring to scheme 3, a compound of the formula X is conve~ted into the corresponding eompound of formulaXII bythefollowing two step procedure. First, the eompound of fonnula X is conve~ted into an oxime by the method deseribed above and illustrated in seheme 1 for forming eompounds of the formula IV from compounds of wo 93/15059 ~ A 2 1 1 7 3 ~ 7 PCr/USg2/l072l - ?

z~G~ -2~

the formula lll. Then, rearrangement of the oxime to form the lactam having tormula Xl is accomplished by reacting the oxime with polyphosphoric acid. This reaction may be carried out at temperatures ranging trom about room tsmperature to about 200C.
Preterably, the reaction mixture is heated to about 160C.
The resuting compound of formula Xl is then brominated to form a compound of the formula Xll by first reacffng It with phosphorous pentachloride and pyridlne, and then adding bromine. Tne reaction with phosphorus pentachloride and pyridine is conducted as described above for the first step in the brominaUon of compounds of the formula V. The reaction with bromine, which results in monobrominaffon, is carried out at a temperature from about -78C about 0C, preferably at about -40C.
Aliq~lation of the compound of formula Xll yields the corresponding compound of formula Xlll. The aikylaUon is carried out by reacUng the compound of formu!a Xll with a compound of the tormula XCH2Rl, wherein X is bromine when R1 Ts phenyl and X is iodine for all other R', in THF/DMSO In the presence of lithium dialkylamWe. It k 15 preferable to add the DMSO cosoivent after adding the lithium dialkyiamide. The reaction temperature may range from about -78C to about 0C during addition of the base, and is preferably about -78C. The reaction is slowly wumed to a temperature from about -20C to about 50C when the DMSO is added. Preferabiy, the reaction is warmed to about room temperature during addition of DMSO. -;
The conversion of compounds of the formula Xlll formed by the foregoing procedure into the corresponding compounds of the formula IIA by the reaction sequence Xlll--XIV--XV _ IIA depicted in scheme 3 in canied out by the method described above for the anaiogous reaction steps Vll--Vlll _ IX--IA deplcted in scheme 1 .
Compounds of the formula ll wherein Rl is CO2H may be prepared, and compounds of the formula ll wherein R' is CONR~R5 may be prepared, aiternativeiy, by the procedure depicted in scheme 2 and described above forming the analogous compounds of formula 1.
The starting materials used in the procedures of schemes 1 and 9 are either 90 commercblly available, known in the art or readily obtainable form known compounds by methods that will be apparent to those skilled in the art.
The preparation ot other compounds ot the formulae I and ll not specifically described in the foregoing experunentai section can be accomplished using ; O 93/15059 C A 2 1 1 ~ 3 6 7 PCl`/US92/10720 2~3~7 combinations of the reactions described above that will be apparent to those skilled In the art.
In each of the reaetions discussed or illustrated in schemes 1 to 3 above, pressure is not cntical unless othelwise indicated. Pressures from about 0.5 5 atmospheres to about 5 atmospheres are generally acceptable, and ambient pressure, i.e. about 1 atmosphere~ is pr~ferred as a matter of convenience.
The eompounds of the forrnulae I and ll (the ~etive compounds of this invention)which are basic in nature are eapable of forming a wide varie1y of dfflerent salts with various inorganie and organie aeids. Although such salts must be pharmaceutieally 10 acceptable for administraUon to animals, it is often desirable in practice to initially isolate a compound of the formula I ~r ll from the rea~tion mixlure as a pharmaceutically unacceptable satt and then simply convert the latter back to the free base eompound by treatment wiUl an alkaline reagent and su~sequenUy convert the latter free base to a pharmaeeutically aeeeptable aeid addiUon salt. The acid addition 15 saits of the aetive base compounds of this invention ue readily prepared by treaUng the base eompound with a substantially equivalent amount of the chosen mineral or organic aeid in an aqueous solvent medium or in a suitable organic solvent, sueh as methanol or ethanol. Upon euaful evaporation of the solvent, the desired solid salt is readily obtained.
The aetive compounds of this Invention and their pharmaeeutically acceptable saits are useful as selective CCK-B receptor antagonists, i.e., they possess the abtlity to antagonize the effects of CCK at its B receptor site in mammais, and therefore they are able to function as therapeuUe agents in the treatment of the aforemenUoned disorders and dis~ases in an afflicted mammai.
The active compounds ot this invention and their phannaceutically acceptable saits càn be administered via either the oral, parenteral or topical routes. In general, these compounds are most desirably administered in dosages ranging from about 6.0 mg up to about 15C0 mg per day, although variations will necessarily occur depending upon the weight and condition of the subject belng treated and tne 30 particular route of administraUon ehosen. However, a dosage level that is in the range of about 0.07 mg to about 21 mg pèr kg of body weight per day is most desirably employed. Variations may nevertheless occur depending upon the species of animalbeing treated and its individual response to said medicarnent, as well as on the type ~ .~ 7 ~
WO93/15059 C A 2 1 1 7 3 6 7 PCr/US92/107?~ `

21~7367 -22-of pharmaceutical formulation chosen and the time period and interval at whieh such administration is carried out. In some instances, dos~ge levels below the lower limit of the aforesaid range may be more than adequate, while in other eases sUII larger doses may be employed without causing any harmful side effect, provided that such 5 larger doses are first divided into several small doses for administration throughout the day.
The aetive compounds of the invention may be administered alone or in combination with pharmaeeutically acceptable carners or diluents by either of thethree routes previously indieated, and sueh administraUon may be earried out in single or 10 multiple dosas. More partieularly, the novel therapeuUe agents of this invention ean be administered in a wide variety of dfflerent dosage forms, i.e., they may be eombined with various pharmaeeutieally aeeeptable inert earriers in the form ot tablets, eapsules, Iozenges, troehes, hard eandies, powders, sprays, ereams, salves, suppositories,jellies, gels, pastes, lotions, ointments, aqueous suspensions, injeetable solutions, 15 elixirs, syrups, and the like. Sueh earriers include solid diluents or fillers, sterile aqueous media and various non-toxic organic solvents, ete. Moreover, oral pharmaeeutieai eomposmons ean be suitably sweetened and/or flavored. In general,the therapeutieally-effeetive eom,~ounds of this invention are present in sueh dosage terms at eoneentration levels ranging from about 5.0% to about 70% by weight.
For oral administration, tablets containing various exeipients sueh as mieroerystalline eellulose, sodium eitrate, ealeium earbonate, diealeium phosphate and glyeine may be employed along with various disintegrants sueh as stareh (snd preferably eom, potato or tapioea stareh), alginie aeid and eertain eomplex silieates, togetherwith granulaUon binders like polyvinylpyrrolidone, suerose, gelatin snd aeaeia.
2S Additionally, lubrieating agents sueh as magnesium sbarate, sodium laury~ sulfate and tale are oflen very usetul for tabletting purposes. Solid eompositions of a similar type may also ~e employed as tillers in gelatin eapsules; preferred materhls in thls eonneetion slso inelude laetose or milk sugar as well as high moleoular weight polyethylene glyeols. When aqueous suspensions andlor elb(irs sre desired tor oral 30 administraffon, the aetive ingredier~t may be combined with various sweetening or flavoring agents, eoloring matter or dyes, and, it so deslred, emulsitying snd/or suspending agents as well, together with sueh diluents as water, ethanol, propylene glyeol, glyeerin and various like comblnations thereof.

"1 93/1~;059 PCI'/US92/10720 2~367 For parenteral administration, solutions of an active compound of thè present invention in either sesame or peanut oil or in aqueous propylens glycol may be employed. The aqueous solutions should be suitably buftered (preferably pH greater than 8) it necessary and the liquid diluent first rendered isotonic. These aqueous S solutions are suitable for intravenous inJection pUrpOS9S. The oily solutions ~re suitable for intraarticular, intramuscular and subcutaneous injection purposeæ. The preparation of all these solutions under sterile conditions is readily accomplished by standard pharmaceutical techniques well known to those skilled in the art.
Additionaily, it is also possible to administer the active compounds of the 10 present invention topically when treating inflammatory conditions ot the skin and thls may preferably be done by way of crearnsl jellies, gels, pastes, ointrnents and the like, in accordance with standard pharmaceuticai practice.
The activity of the compounds ot the present invention as CCK-B antagonists may be determined by an assay that measures their ability to inhibit the binding of 125-15 1-BH-CCK-8 to the CCK-B receptor in a guinea pig cortical membrane preparation. This procedure is carried out as follows. The cortex is dissected from one male Hartley Guinea pig and homogenized (15 strokes) with a t~flon homogenker in 20 volumes (w.h.) of the assay buffer, which consists of 50 mM Tris ti.e., trimethamine, which is 2-arnino-2-hydroxymethyl-1 ,3-propanediol) hydrochloric acid having pH 7.4 and 5 mM of 20 manganese chloride at 4C. The homcgenate is centrifuged at 4C for 30 minutes at 100,000 x G. The pell~t is resuspended in the same buffer and spun as described above. The finai pellet is diluted to a concentration of 20 mglml with the assay buffer for use in the binding assay. The tissue is kept on Tce at all times.
An incubation mixture is prepared, which consists of 50uL of the Ussue 25 preparation, prepared as described above, lOOul 12~1-BH-CCK-8 (to give a concentration of 50 pM in the final assay), 20uL of a blank or the compound being tested, and 30uL of Tris with 4% DMS0. Ail drugs and dilutlons are made using 4%C)MS0 in the assay buffer yielding a final assay DMS0 concentration of 1%.
The reaction is initiated with tha addition of tissue to a 96 well plate containing 30 12~1-BH-CCK-8 and the appro? iate blank or compound being tested. Non-specific binding is estimated using 1uM sulphated CCK~. The reaction is terminated by spinning the plates in a H1OOOB rotorfitted on a Sorvall RT6000 refrigerated centrifuge at 4~C. The supernatant is discarded, and the pellets washed with 200uL of assay WO93~15059 ` CA21 ~ 7~7 PCI~/US92/1072 2il!~367 ` -24-- buffer, and the plate is spun as above. The supematant is decanted again, and the pellet is harvested onto Betaplate filters (which have ~een soaked in 0.2%
polyethyleneimine for a minimum of 2 hours) using a Skatron cell harvester at setting 222 using Tris HCI pH 7.4 as the wash buffer. The fiitermats are counted on a 5 Betaplate counter for 45 seeonds per sample.
Data are expressed as IC50 values (the concentration which inhibits 50% of the specffic binding of 125-l-BH-CCK-8). The data is analyzed using non-linear regression analysis.
The present invenffon is illustrated by the following examples. It will be 10 understood, however, that the invention is not limited to the specific detaTls of these examples.

N-tert-Butvl 2-r3-~3-(3-tolYl)ureido~-2-oxo-5-Dhenvl-2.3.4.5-tetrahvdro-1 H- ~-(1)benzazeDin-l-SM ethanoie acid amide s A. 3-Bromo-5-Dhenyl-2.3.4.5-tetrahvdro-1 H-(l )benzazeDin~2-one To a 125 ml round-bottomed flask eontaining PCls (1.041 9, 5 mmoles) dissolved in 50 ml methylene ehloride under nitrogen in an icelacetone bath was added 5-phenyl-2,3,4,5-tetrahydro-1H-(1)benzazepin-2-one (1.187 9, 5 mmoles). A slighttemperature rise was noted, and then pyridine (0.42 ml, 5.25 mmoles) in 5 ml 20 methylene chloride was added rapidly dropwise. The mixture was stirred for 15minutes. and then cooled to -45C. Bromine (0.258 ml, 5 mmoles) in 7 ml methylene ehloride was then added dropwise over 30 minutes. with rapid stirring. The bath was removed after 15 minutes. and the mixture was allowed to eome to room temperature.
Thin layer chromatography (TLC) (silica gel, 23:2, methylene chloride:ethyl aeetate) 25 showed no starting material, only a non-polar interrnediate (iminochloride). The remainder of the reaetion was diluted with an equal volume of tetrahydrofuran and 200 ml water added. This mixture was stirred for 40 minutes, then separated. The aqueous layer was rè-extracted with methylene ehloride and the eombined organie fractions washed with water, dried with brine and sodium suifate, tiltered, and evaporated30 yielding 1.56 9 (98.7%) of erude produet~
The diastereomerie bromides (R,=0.57, and 0.48) may be separated by ehromatography or erystallized from ether and hexane; howe~/er, the mixture was used directly in the next step (B).

~yo 93/15059 C A 2 1 1 7 3 6 7 PCI`/US92/1072û
Z1~3~
-2~

The solid obtained by crystallization was predominately the more polar i~omer while tha mother liquor contained more of the less polar isomer as well as traces of the iminochloride and starting material. Recrystallization of the more polar diastereomer from chloroform gave large crystals, mp 191-192C:
lH-NMR (~, CDCI3): 2.92 (m, 1H), 3.14 (m, 1H), 4.49 (m, 1H), 4.63 (m, lH), 6.77 (d, lH), 7.09 (m, 3H), 7.æ (m, 6H), 7.85 (bs, lH).
MS (%): 315/317 (parent for Br'~/Br8', 20118), 236 (78), 208 (100)r 194 (36), 180 (73), 130 (47), 115 (39), 91 (79).
B. t-Butvl_2 r~brom~xo-~henvl-2.3.4.5-tetrahYdr~l~(lLereazee~:
1 0 yllethanoate To a 125 ml thre~neck round bottomed flask equipped with septum and N2 inlet were added ~bromo-~phenyl-2,3,4,~tetrahydro-lH-(1)benzazepin-2~ne (3.216 g, 10.17 mmoles) and 50 ml dry t~3trahydro~uran (THF) under nitrogen. The reaction was cooled in a dry ice bath, and lithium bis-trim~thylsilyl amids (11.2 ml of 1 M in THF) was 15 added slowly. The mixture was stirred for S minutes. T-butyl iodoac~tate (2.708 g, 11.19 mrnoles) was then added. Tha bath was removed and 25 ml of dimethylsulfo~dde (DMS0) was added at -20C. Aner one hour at room temperature, an acid-~ied aliquot showed only a tr~ce of starting material by TLC (24:1, CH2CI2:EtOAe). The reacUon mixture was poured into ice water and ethyl acetate containing 25 ml of N HCI, stirred 20 ~or 5 minutes. and separated. The ethyl ac~tate ~xtraction was repeated and the combined extracts washed three !imes with water, dried with brine and sodium sulfate, and filtered and evaporated, yielding 4.9 9 (>100%, still containing ~aces of solvent) crude product.
Similarly, the lactam was alkylated with N^tert-butyl iodoa~tamide to yield N-t-Butyl 2-~3-bromo-2~xo-~phenyl-2,3,~,5,-tetrahycir~lH-(l)benza_epin-l-yl]-ethanoic acid arnide.
C. N-tert-Butvl 2-~3-azido-2-oxo-5-Phenvl-2.3.4.5-tetrahvdro-1 H-(l)benza_epin-l-yll ethanoic acid amide To a 250 ml round-bottomed flask equipped with N2 inlet were sdded N-tert-butyl - 30 2-[3-bromo-2~xo~phenyl-2,3,4,~tetrshydro-lH~(l)ben_a_epin-t-yll ethanoic acid amide, (8.317 9, 19.37 mmoles), 90 ml dimethylformsmide (DMF), and sodium A71de (5.25 9, 80 mmoles, under nitrogen), snd the m xture was heated at 75C ~or 20 hours with stirring. The reaction mixture was then cooled and distributed between water snd ~21 1:73~
WO 93/15059 ~ PCr/US92/10~2~
Z~,~,736q -; ,~ 2~

ethyl aeetate, separated, and the aqueous phase was again extraeted. The combined extraets were washed with water three times, with biearbonate solution once, and then dried with brine and sodium suHate and fittered and evaporated, leaving ~ gummy residue, 8.58 9 (100%), eontaining some solvent.
1H-NMR (~, CDCI3): 1.48 (s, 9H), 2.88 (m, 2H), 4.52 (AB quartet, J~"=17, Ay=138, 2H), 4.57 (m, 1H), 5.06 (m, lH), 6.73 (d, lH), 7.26 (m, 8H).

D. N-tert-Butvl 2-l3-amino-2-oxo-5-phenvl-2.3.4.5-tetrahvdro-1 H-~l )benzazeoin-l -yll ~thanoie aeid amide The erude produet from the previous displaeement reaetion, N-tert-butyl 2-13-azido-2-oxo-5-phenyl-2,3,4,5-tetrahydro-lH-(l)benzazepin-l-yl] ethanoic aeid amide, (8.5B 9,19.37 mmoles), was dissolved in 75 mi methanol under nitrogen. The eatalyst, 6 9 of 5% Pd/C, 50% wh~, was added and the mixture was hydrogenated at 55 psi H215 for 5 hours. The mixture was flltered through Celite~ and the eatalyst washed three ~mes with methanol and the filtrate evaporated. TLC (24:1, methylene ehloride:
methanol, silica gel), showed less polar material and the product at R,=0.25. The erude produet taken up in ethyl ac~tab and extracted with acid. The acidie extract was baek washed with ethyl acetab and then the aqueous fraction was taken wlth fresh20 ethyl acetate and the pH adJusted to 10Ø The organie fraction was then dried ~Ath brine and sodium suitate, filtered and eoncentrated, yielding 1.832 9 (25.8%) of the crystaOine amine (mp 189-192C, one diastereomer~. The mother liquor yielded 1.545 9 (21.8%) of a toam upon stripping the solvent, which contained near~y a 1 :1 mixture ot the diastereomers.
'H-NMR (~, CDCI3): 1.30 (s, 9H), 2.2 (bs, 2H), 3.06 (AB quartet, J~"=15, /~V=276,2H), 2.67 (m, lH),2.84 (m, lH),3.57 (m, lH), 4.18 (m, lH),6~01 (bs, lH), 7.2 (m, 9H).
E. N-tert-Butvl 2-~3-(3-(~tolyl)ureido)-2-oxo-5-phenvl-2.3.4.5-tetrahvdro-lH-~l)benzazepin-l-yil ethanoic acid amide To a 25 ml round-bottomed tlask equipped with N2 inlet were ~dded N tert-butyl 2-l3amir~2~xo~phenyl-2,3,4,$teO~hydro-1H-(l)b~azepin~ e~andc acid am~
(0.50 9, 1.368 mmoies) and 10 ml methylene chloride under nitrogen, and the reaction eooled in an ice bath. A soluUon of m-tolyl isocyanate (0.194 ml, 1.5 mmol) in 5 ml f~O93/15059 CA21 1~367 PCI/US92/10720 -27- 2~-7367 m~thylene chloride was then added dropwis~. A solid formed immediately. SUrring was continued for 15 minutes and then the ice bath removed, allowing the reacUon to come to room temperature for severai hours. The solid was filtered and washed with methylene chloride/hexane (1:1), yielding 600 mg (87.9%) of product, mp 263 266C.
S NMR (ô, DMSO-do): 1.23 (s, 9H), 2.21 (s, 3H), 2.54 (m, 1H), 2.9 (m, lH), 3.34 (AB quutet, JA"=16, ~v=255, 2H), 3.4 (HOD peak), 4.34 (m, 2H), 6.8 (m, 2H), 7.3 (m, 11 H), 8.78 (s, l H).
The Utle compounds of Examples 2 through 10 were prepared using procedure analogous to that of Ex~mple 1.

tert-Butvl 2-r3-(3-(4chloroDhenvi)ureido)-2-oxo-5-phenvl-2.3.4.~tetrahydro-lH-(1)benzazepin-1-yl~ ethanoate Prepued in 30% yield after chromatography and crystalleaUon, M .P.148-150 C.
tH-NMR (~, CDCI3): 1.37 (s, 9H), 2.~3.1 (m, 2H), 3.30 (AB quartet, J~B=17, ~v=188, 2H), 4.27 (m, lH), 4.76 (m, 1H), 6.8 (broad s, 1H), 7.~7.5 (m, 14H).
MS (%): 520 (18, parent), 366 (35J, S37 (43), 267 (70), 206 (85), 153 p6), 127 (100), 91 ~53).
HRMS caic'd for C28H3,N3O"CI: 520.2003. Found: 520.1983.

N-tert-Butyl 2-r3-(~(3-chloroDhenvl)ureido)-2-oxo-5-~henvl-2.3.4.5-tetrahvdro-1H-(l)benzazeDin-1-vll ethanoic acid amide Pr~pared in 90% yield, mp 264 266C.
'H-NMR (~, DMS~d"): 1.21 (s, 9H), 2.56 (m,1 H),2.9 (m, lH), 3.35 (AB quartot, J~"=17, ~v=255, 2H), 4.37 (m, 2H), 6.7-7.6 (m, 14H), 9.08 (s, lH).
MS (%): 518 (1, parent), æ2 (40), 194 (60), 91 p0), 58 (100).
HRMS calc'd tor C29H3,N,,03CI: 518.2097. Found: 518.2100.

N-tert-Butvl 2-~3-(3-(2-tolvl)ureido)-?-oxo-5 Dhenvl-2.S.4.6-tetrahydro-lH-(l)benzazeDin-1-vll ethanoic ~cid amide Prepared in 85% yield, mp 231~233C.
'H-NMR (~, CDCI3): 1.28 (s, 9H), 2.24 (s, 8H), 2.65 (m, 1H), 3.09 (AB quarbt JA,=17j ~v=291, 2H), 3.11 (m, lH), 4.æ (m, lH), 4.62 (m, lH), 6.01 (broad s, lH), 6.41 (broad s, lH), 6.~7~5 (m, 13H).

WO 93/15059 C IJ 2 1 1 7 3 6 7 PCI`/US92/107~- .

zl~ 7~67 -28-.
MS (%): 498 (0.5, parent), 322 (5), 249 (8),133 (80), 105 (100), 78 (80).
HRMS calc'd for C30H34N403: 498.2630. Found: 498.25475.
E)(AMPLE 5 N-tert-Butvl 2-~3-(3-(~methoxvohenvl)ureido!-2-oxo-~Phenvl-2.3.4.~tetrahyd-ro-1 H-~1)benzazepin-1-vll ethanoic acid amide Prepared in 81% yield, mp 254257C.

7 H-NMR (~, DMSO-do): 1.21 (s,9H),2.56 (m,1 H),2.9 (m,1 H), 3.33 (AB quartet, JA,~=16, ~v=259, 2H), 4.35 (m, 2H), 6.47.6 (m, 14H), 8.865 (broad s, lH).
MS (%): 514 (0.1, parent), 322 (6), 149 (100), 106 (40).
HRMS calc'd tor C30H3"N"O~: 514.2553. Found: 514.26134.

N-tert-Butvl 2-~3-(3-(4-chloro~henvi)ureido!-2~xo-~Phenvl-2.3.4.5-tetrahvdr~
1 H-(l !benzazepin-l ~11 ethanoic acid arnide Prepared in 88% yield, mp 247-249C.
lH-NMP~ (~, CDCI3): 1.31 (s, 9H), 2.92 (m,1 H), 3.10 (m,1 H), ~.æ (AB quartet, JAB=16, ~v=260, 2H), 4.29 (m, lH), 4.60 (m, lH), 5.74 ~broad s, lH), 6.43 (broa~ s, lH), 7.0-7.5 (m, 13H).
MS (%): 518 (1, p~rent), 322 (40), 261 (70), 153 ~100).
HRMS calc'd tor C29H3l N~03CI: 518.2070. Found: 518.21007.

N-tert-Butvl 2-~3-(3-(4-tolyl)ureTdo)-2-oxo-5-~henvl-?.3.4.~tetrahydro-1 H-~l)benzazepin-l-vll ethanoic add amide Prepared in 95% yield, mp 235-238QC.
'H-NMR (~, CDCI3): 1.29 (s, 9H), 2.27 (s, 3H), 2.72 (m, lH), 3.12 (m, lH), 3.2 (AB quartet, JA~=16, av= 283, 2H), 4.24 (m, l H),4.60 (m,1 H),5.88 (broad s,1 H~, 6.
7.4 (m, 14H).
MS ~): 498 (1, parent), 322 (30), 249 (15), 221 (20), 194 (20), 133 (100).
HRMS calc'd tor C30H3~N"03: 498.2646. Found: 498.26153.

N-tert-Butvl 2-~(~trifluoromethvlDhQnvl~ureid~2-oxo~henyî 2.3.4.5-t~trahydro~
1 H-(l )benzazepln-1-v!l ethanoic acid amide Prepared in 67% yield, mp t3~139~C.

.` -Y093/15059 CA21 173~7 PCI/US92/10720 -29- 2~736~

'H-NMR (~, CDCI3): 1.30 (s, 9H), 3.t (m, 2H), 3.31 (AB quartet, JA8-16, ~v=
270, 2H),4.32 (m,1 H), 4.62 (m, ~ H), 5.77 (broad s,1 H), 6.6 (broad s,1 H), 7.~7.9 (m, 13H).
MS (%): 552 (0.2, parent), 416 (1), 322 (5), 254 (20), 91 (100).
HRMS calc'd for C30H3lN4O3F3: 552.2341. Found: 552.2288.

~tert-Butyl 2-~3-(~thiomethylDhenvl)ured~2-oxo~;Dhenvl 2.314.~tebahvdro-111-(l)benzazeDin-l-vll ethanoic acid amide Prepared in 78% yield.
lH-NMR (~, CDCI3): 1.22 (s, 9Hj, 2.35 (s, 3H), 2.58 (m, lH), 2.97 (m, lH), 3.21 (AB quartet, JA"=16, ~v=288, 2H), 4.18 (m, lH), 4.40 (m, lH), 6.~7.4 (m,13H), 7.75 !broad s, lH), 8.67 (broad s, lH).
MS (%): 530 (0.7, parent), 322 (18), 261 (21), 165 (100), 132 (32).
HRMS calc'dfor C30H3~N,03S: 530.2352. Found: 530.2332.
i3CAMPLE 10 tert-Butvl 2-~S~3-l3-tolvl)ureido~-2-oxo-5-Dhenyl-2.3.4~5-tetrahvdro-1 H-~1)benzazepin-1-vll ethanoate Prepared in 76% yield, mp 195C.
1H-NMR (~, CDCI3): 1.4 (s, 9H), 2.29 (s, 3H), 2.72 (m, lH), 3.19 (m, lH), 3.28 (AB quartet, J~=16,-av=230, 2H), 4.22 (m, lH),4.7 (m, lH), 6.37 (broad s, lH), 6.78-7.5 (m, 14H).
MS (%): 500 (18, parent+l),484 (4),444 (20),426 (4), 337 (42), 311 (100),266 (20), 240 (30),194 (34).
E)(AMPi E 11 3-(~-.Tolvlureido)-7-Dhenyl-~N-LN-2-adamantvl)carboxamidomethyl)-hexahvdro azeDin-2-one A. 7-Phenvl-hexahvdroazeDin-2-one To a 250 ml reund-bottomed flask equippeci wlth N2 inlet were added 7.33 9 (38.8 mmol) 2-phenylcyclohexanone oxime (Chem. Ber., 55, 3664 (1922)) and 25 ml pyridine. The solution was cooled to 0C, and 9.61 g (50.4 mmol) p-toluenesuffonyi chloride was added. The re~:~.on was ailowed to stir ovemight as the ice meited, and WO 93/15059 C A 2 1 1 7 3 6 7 PCI`/US92/107V'-: `
2~7367 3~

then poured into water. Excess chloride was skimmed off the sur~ace, and the reaction mixture was stirred at pH 4 for 3 hours. The precipitate was filtered, washed with water, and dried to a solid, 4.65 9 (55%), mp 135-137C (J. Am. Chem. Soc., 82, 4671 (1960) gives mp 13~141C).
B. ~romo-7-Dhenvl-hexahvdroazepin-2-one To a 250 ml round-bottomed tlask equipped with N2 inlet were added 5.12 9 (24.6 mmol) phosphorus pentachloride and 45 ml methylene chloride. To the stirring mixture cooled to 0C was added dropwise over 20 minutes, a solution of 4.65 9 (24.6 mmol) 7-phenyl-hexahydroazepin-2-one and 3.98 ml (49.2 mmol) pyridine in 40 ml methylene chloride. To the stirring mixture at 0C was then added 9.25 g (24.6 mmol) phenyitrimethylammonium bromide tribromide. The reaction was then allowed to warm to room temperature and stirred for 3 hours. It was then evaporated, taken up in- tetrahydrofuran, quenched with water, evaporated, and partitioned b~tween water and methylene chloride. The organic layer was washed with water and saturated a~iueous 15 sodium bisulfite, dried over sodium suifate, and evaporated. The residue was chromatographed on silicagel with ethyl acetate/hexane as eluentto afford the product as an oil, 4.0 9 (61%).
lH-NMR (~, CDCI3): 1.~2.4 (m, 6H), 4.35 and 4.63 (muitiplets, 1H), 4.74.9 (m, lH), 5.73 and 5.81 (broad singlets, lH, NO, 7.2-.74 (m, 5H).
IR (cm. l,CHCI3): 1670 (C=0).
MS (%): 267 (6,parent), 188 (39), 160 pO), 106 (100), 91 (43), 55 (59).
C. 3-Bromo-7-phenyl-(N-t-butoxvcarbonvlmethvl)-hexahvdroazepin-2-one To a 100 ml thre~necked round-bottomed flask equipped with N2 inlet were added 0.30 9 (6.07 mmol) sodium hydride, which was washed with hexane and 25 suspended in 3 ml dry tetrahydrofuran. To the stirring mixture was added a solution of 1.55 9 (5.78 mmol) ~bromo-7-phenyl-hexahydroazepin-2-one and 1.42 g (6.07 mmol) t-butyl iodoacetate dropwise over 20 minutes. The reaction was stlrreci for 3 hours at room temperature, quenched with saturated aqueous ammonlum chloride, and taken up in ethyl acetate. The organic layer was washed with water and brine, driec~ over 30 sodium sulfate, and evaporated. The residue was chromatographed on silica gei using ethyl acetate/hexane as eluent to afford the product as an oil, 1.65 9 t75%).

`'O 93/150S9 ` C A 2 1 1 7 3 6 7 PC~/US92/10720 z~7~;7 'H-NMR (o~, CDCI3): 1.40 and 1.42 (singlets, 9H, two diastereomers), 1.~2.4 (m, 6H), 3.~3.9 (m, 2H), 4.56 and 4.95 (multiplets, 1H), 4.71 and 5.16 (multiplets, lH), 7.2-7.4 (m, 5H).
D. ~Azido-7-Phenyl-(N-butoxvcarbonylmethyll-hexahydroaze~in-2-one To a 100 ml round-bottomed flask equipped with N2 inlet were added 1.65 g (4.32 mmol) ~bromo-7-phenyl-(N-t-butoxycarbonylm0thyl)-h~xahydroazepin-2~ne, 4 ml dimethyHormamide, 0.34 9 (5.18 mmol) sodium azide, and a drop of water. The mixture was heated at 80C for 36 hours, and then pour~d into water and extracted into ethyl acetate. The organic layer was washed with water and brine, dried over 10 sodium sulfate and evaporated. The residue was chr~matographed on silica gel with ethyl acetate/hexane as eluent to afford the produ~t as an oil, 1.0 9 (679~).
tH-NMR (~, CDCI3): 1.34 (s, 9H), 1.7-2.4 (m, 6H) (only one diastereomer could be accurately identified), 3.62 (AB quart~t, J,u,=17, ~r=193, 2H), 4.38 (m, lH), 4.77 (m, lH), 7.2-7.4 (m, 5H).
IR (cm. l, KBr): 2106 (N3) and 1739 and ~661 (C=0).
E. 3-Amino-7-Dhenyl-(N-t-butox~carbonvlmethvl)-hexahvdroazeDin-2~ne The azide from step D above (6. 1.0 9, 2.91 mmol~ was treated under 45 Ibrm2 hydrogen in the presence of 200 mg 10% palladium-on-carbon in 30 ml ethanol for 4.6 hours. The reaction was filtered through Celite~ and evaporat~d to leave an oil, which 20 was used directly in the following step.
lH-NMR (~, CDCI3): 1.~2.4 (m, 6H), 3.63 (only one diastereomer could be accurately identffled) (AB quart~t, J,~= 17, ~ y= 156, 2H), 4.02 (~n, 1 H), 4.91 ~m, 1 H), 7.2-7.4 (m, 5H).
IR (cm. ', neat): 1741 and 1649 (C=0).
F. ~Tolvlureido2~ehen~1-(N-t~u~oxycarbon~methvi)he3tahydroazepi~2-one To a 100 ml round-bottomed flask equippeci with N2 inlet were added 1.28 g (4.02 mmol) ~nino-7-phenyl-(N-t-butoxycarbonylmethyl)-hexahydroazepin-2-one, 5 ml 1, 2-dichlorethane and 0.57 ml (4.43 mmol) 3-tolylisocyanate. The reaction was 30 stirred for 3 hours at room temperature and chromatographed on silica gel, uslng ethyi acatat~/hexane as eluent, to afford the product as an oil. The oil was crystallized from isopropyl ether to give a solid, mp 194 196C.

WO 93/15059 ~ A ~ q i 7 3;6 ~ Pcr/usg2/lo72r "'~ ' 2~1736~ -32-lH-NMR (~, CDCI3~: 1.25 (s, 9H), 1.~2.3 (m, 6H), 2.17 and 2.20 (singlets, 3H, diastereomers), 3.56 (AB quartet, JAB-17, ~ 236, 2H), 5.01 ~d, J=11, lH), 5.08 (m, lH), 6.71 (d, J=7, lH), 6.~7.3 (m, 9H), 7.87 (s, lH).
iP~ (cm. l, KBr): 1743 and 1650 (C:=O).
MS (%): 451 ~14, parent), 159 (45),117 (64), 107 (100), 91 (46), 57 (41), 56 (48).
Anal. calc'd for C2~H33N304: C, 69.16; H, 7.57; N, 9.31. Found: C, 69.10; H, 7.75; N, 9.08.
G. ~(~Tolvlureido)-7-Dhenvl-!N-c~rboxymethyl)~exahvdroazepin-2-one To a 100 ml round-bottomed flask equipped with N2 inletwere added 1.5 9 (3.32 10 mmol) 3-(~tolylureido~7phenyl(N-t~utoxycarbonylmethyl~hexahydroazepi~2-one and 25 ml methylene chloride. The solution was cooled to 0C and 5 ml trifluoroacetic acid was added. Tha reaction was then stirrad at 0C for 1.2 hours. The reaction was poured into water, extracted into methylen~ chloride, and th~ organic layer was washed wffl water and brine, dried over sodium sulfate, and evaporated. The residue wascrystallized from isopropyl ether to afford a solid, mp 121-130~C, 1.1 9 (84%).
lH-NMR ~, CDCI3): 1.~2.2 (m, 6H), 2.22 and 2.24 (singlets, 3H (one for esch diastereomer)), 3.55 and 3.61 (AB quartet-1, JAB=18, ~y=138 and AB quartet-2, JA"=18, ~y=348, 2H), 3.4-3.8 (m, lH), 4.0 ~.1 (m, lH), 6.6 and 6.78 (m, 2H), 7.07-7.4 (m, 9H).
IR (cm. ', KBr): 1740 and 1640 (C=O).
MS (%): 395 (9, parent), 159 (63), 133 (100), 98 (78).
HRMS calc'd for C22H25N3O": 395.1769. Found: 395.1853.
H. 3-(3-Tolvlureido~-7-Phenyl-tN-(N-2-adamantyl)carboxamidomethyl)-hexahydroazepin-2-one To a 100 ml round-bottomed fiask equipped with N2 inlet were added 330 mg (0.835mmol)~(~tolyiureido)-7-phenyl-(N~arboxymethyl)-hexahydroazepin-2-one,5ml 1,2-dichloroethane, 0.2S 9 (1.7 mmol) 2-arninoadamantane, and 0.24 g (1.25 mmol)ethyl(dimethylaminopropyl)carbodiimide. The reaction was stirrQd 3 days at room temperature and chromatographed on silica 9QI using methanol/methylene chloride as eluent to atford an oil which was crystailized from isopropyl ether to give a solid,20 mg (4.5%), mp 14~153C.
'H-NMR (~, CDCI3): 1.42.2 (m, 22H), 2.20 and 2.23 (singlets, 3H, for each diastereomer), 3.6 (AB quartet, JAB=14. ~V=121 (for one sst, other set obscured),2H), C ~ 2 1 1 7 3 6 7 PCl'/US92/10720 21~367 3.9 (m, lH), 4.54.8 (m, lH), 5.04 and 5.12 multiplets, lH), 6.08 and 6.42 (d, J=8, lH), 6.7 and 7.~7.4 (m, 9H), 7.65 and 7.77 ~m, 1 H).
IR (cm.1, KBr): 1650 (C=0).
MS (%): 528 (6, parent), 193 (100), 171 ~65).
HRMS caic'dtorC32H~ON"03: 528.3tO0. Found: 528.3051.
Anai. caic'd for C32H~oN~O3-0.5H20: C, 71.48; H, 7.69; N, 10.42. Found: C, 71.61; H, 7.34; N, 10.27.
Thc titie compounds of E~camples 12-21 were prepared using a procedure anaiogous to that of Examph 11.

.

3-(3-Tolylureido)-7-benzyl-!N-t-butoxvcarbonylmethyi)-hexahvdroazeoin-2~ne Prepared in 79% yield, M.P. 7~86C.
'H-NMR (~, CDC13): 1.3-2.1 (series of multiplets, 6H), 1.44 (s, 9H), 2.29 (s, 3H), 2.7~.2 (m, 2H), 4.05 (AB, ~=17, ~v=66, 2H), 4.2 ~.3 (m, 1H)I 5.0S (m, lH), 6.8 7.5 (m, 11H).
l3C-NMR (~, CDCI3): 21.5, 28.0, 30.4, 32.2, 39.7, 45.2, 52.3, 58.4, 81.9, 117.1,120.8, 127.0, 128.8, 128.9,137.1, 155,168.7,175, (not all aromati~ carbons assigned In this scan).
MS (%): 465 (9, parent), 374 (17),185 (66),170 (61),107 ~100),91 (64), 83 (43), 57 (58)-HRMS calc'dfor C20H40N3O4: 465.2593. Found: 46S.26576.

3-((3-Chlorophenyl)ureido)-7-cyclohexvl-(N-t-butoxycarbo~lmethyl~- -hexahydroazepin-2-one - Prepared in 87% yield, mp 75-84C.
'H-NMR (~, CDCI3): 1.3-2.1 (series of muitiplets, 6H), 1.44 (s, 9H), 2.7~.2 (m, 2H), 4.06 (AB, J~,~=17"~v=62, 2H), 4.24.3 (m, lH), 5.0S (m, lH), 6~9-7.6 (m, 11H).
MS (%): 485 (1, parcnt), 394 (22), 338 (23), 303 ~34), 185 (100), 170 (76), 127 (90), 91 p3), 57 (74), 56 (80). -HRMS calc'dforC20H37N304F3: 485.20929. Found: 485.20705.

WO 93/150~9 C A 2 1 1 7 3 6 7 Pcr/usg2/~o72 z~736~

3-~(3-Chloror~henyl)ureido)-7-Phenyl-(N-t-butoxvcarbonvlmethvl).-hexahydroazepir~2~ne_1more polar diastereomer) Prepared in 55% yield, mp 201-203C.
lH-NMR (~, CDCI3): 1.38 (s, 9H), 1.6-2.4 (series of muitiplets, 6H), 4.05 (AB, JAB=17, ~v=357, 2H), 4.~4.7 (m, 2H), 6.6-7.8 (m, 11H).
IR (cm. ', KBr): 1719, 1680, 1625 (C=O).
MS (%): 471 (14, parent), 415 (47), 345 (52), 289 (100), 127 (51), 83 (45), 55 (39).
Anai. caic'd for C25H30N304CI: C, 63.62; H, 6.41; N, 8.90. Found: C, 63.74; H, 6.49; N, 8.62.

E)(AMPLE 15 3-(3-To~eido)-7-pheny!-~N-t-butoxvcarbonylmethvl)-hexahyd!oazepin-2-one 15 (more i?olar diastereomer) Prepared in 44% yield, mp 181-183C.
'H-NMR (~, CDCI3): 1.38 (s, 9H),1.~2.4 (series of muitiplcts, 6H), 2.74 (s, 3H),4.01 (AB, JAB,=17, ~v=381. 2H), 4.5-4.6 (m, 1H), 4.62 (t, J=7,1H), 6.57 (m,1H), 6.76 (m, 1H), 7.0-7.5 (m, 9H).
IR (cm. ', KBr): 1721, 1680, 1636` (C=0).
Anal. calc'd for C2oH33N30,~-0.25H20 C 68.47, H 7.40, N 9.21. Found: C 68.71, H. 7.47, N 9.22.

3-((3-Methoxypheny,l~ureido)-7-phenyl-(N-t-butoxycarbonylmethy!)-hexahYdroaze,~in-2-one (more polar diastereomer) Prepared in 44% yield, mp 16~170C.
'H-Ni~lR (~, CDCI3)~ 8 ts, 9H),1.6-2.4 (series of muitiplets,6H), 3.71 (s, 3H), 4.02 (AB, JAB=17, ~v=375, 2H), 4.~4.7 (m, 2H), 6.47 (m, 1H), 6.50 (m, lH), 6.81 (m, lH), 7.0-7.6 (m, 8H).
IR (cm.-l, KBr): 1727, 1628 (C=O).
Anal. calc'd for C20H33N3O5: C, 66.79; H, 7.11; N, 8.99. Found: C, 66.59; H, 7.12; N, 8.9æ

v~o 93/1505~ C A 2 1 1 7 3 6 ~ PCJ/US92/10720 ., . ,'.. .
3-((3-Methoxyphenvl)ureido)-7-phen~l-(N-t-butoxvcarbonylmethvl~-h~xahvdroazepin-2-one ~y~
Prepared in 39% yield, mp 180 90C.
lH-NMR (~, CDCI3): 1.27 (S, 9H),1.~2.4 (series of multiplets, 6H),3.69 (s, 3H), 5 3.57 (AB, JAB=17, ~v=226, 2H), 5.01 (m,1H), 5.08 (m,1H), 6.45 (m, lH), 6.8 (m, 2H), 7.~7.6 (m, 8H).
IR (cm. l, KBr): 1741, 1640, 1605 (C=O).
MS (%): 467 (11, parRnt), 159 (32), 123 (100), 117 (25).
Anal. c~c'd for C2"H33N3Os-0.5H2O: C, 65.53; H, 7.19; N, 8.82. Found: C, tO 65.44; H, 6.952; N, 8.84.

3-((3-Chloro~henvl)ureido)-7-phenyl-(N-t-butoxvcarbonvlmethvl)-hexahvdroazepin-2~ne (less polar diastereomer~
Prepared in 19% yield, as a foam.
H-NMR (~, CDCI3): 1.26 (s, 9H), 1.~2.4 (series of multipl~ts, 6H~, 3.51 (AB, ~IAB=17, ~V=195~ 2H), 5.00 (m, 1H), 5.08 5m, 1H), 6.8-7.4 (m, 9H), 7.98 (broad s, 1H), 20 8.13 (broad s, 1H).
'3GNMR (~, CDCI3): 27.1, 27.8, 31.1, 31.8, 46.8, 52.7, 60.5, 61.9, 81.7,117.2, 117.3.,117.4, 119.4, 122.5, 122.8, 128.7, 129.1, 129.79, 129.82,134.4,134.5,138.1, 140.1,140.5,15S.0, 155.2, 168.5, 175.2.
IR (cm. l, KBr): 174t, 1629, 1598 (C=O~.
MS (%): 471 (3, parent), 345 (20), 129 (35), 127 (100), 117 (22), 83 (41).
HRMS calc'd for C2SH30N30~CI: 471.19411. Found: 471.19455.

~(3-Tolvlureido)-7-phenyl-[N-2-adamantyl)carbonylmethvl)-hexahydroozepin~
one Prepared in 42% yield, mp 120-130C.
'H-NMR (o', CDCI3): 1.4-2.4 (series of multiplets, 20H), 2.23 (S,3H),3.71 (AB, JA~3=17~ ~v=213, 2H),4.75 (m, lH), 5.04 (m, lH),5.1 (m, lH), 6.75 (m,2H),7.0-7.6 (m, 9H).

WO93/15059 C A 2 1 1 73 6 7 pcr/usg2/lo72r z,~736'7 -3~

IR (cm.-l, KBr): 1750, 1650 (C=0).
MS (%): 529 (8, parent), 159 ~46), 135 t49), 133 (47), 117 (31), 107 (100), 85 (39), 83 (39).
Anal. calc'd for C32H39N304-0.5H20: C, 71.35; H, 7.48; N, 7.80. Found: C, 71.72; H, 7.33; N, 7.80.

~(3-Tolvlureido)-7-phenyl-(N-(1 -adamantvl!carbonylmethyl~-hexahydroazepin-2-one Prepared in 3% yield, as a foam.
lH-NMR (~, CDCI3): 1.42.4 (series of multiplets, 20H), 2.26 (s, 3H), 3.57 (AB, JAB=17, ~ve250, 2H), 5.02 (rn, lH), 5.1 (m, lH), 6.7-6.8 (m, 2H), 7.1-7.4 (m, 9H).
IR (cm.-1, KBr): 1745, 1650 (C=O).

MS (%): 529 (14, parent), 378 (60), 159 (78), 135 (100), 107 (60).
HRMS calc'd for C32H39N304: 629.29403. Found: 529.2902.
E)(AMPLE 21 3-~3-Tolylureido)-7-Phenvl-(N~ adamantvl?carboxamidomethyl)-hexahydroazep n -one Prepared in 28% yield, mp 145-1 S4C.
'H-NMR (~, CDCI3): 1.42.4 (series ot multiplets, 20H), 2.245 (s, 3H), 3.50 (AB, JAB=16, ~v=174, 2H), 5.03 (m, 1H), 5.1 (m, lH~, 5.26 (s, lH), 6.7~.8 (m, 2H), 7.1-7.7 (m, 9H).
IR (cm. t, KBr): 1645 (very broad) (C=O).
MS (%): 528 (<1, parent), 203 (36),133 (100),132 (30),117 (44),107 (61),104 (31).
Anal. calc'd ~or C32H40N4O3-0.5H20: C, 71.48; H, 7.69; N, 10.42. Found: C, 71.37; H, 7.80; N, 10.29.

4-Phenyl-~ n~thyl-1,2.3.4-tetrahydronaphth-1-one Prepared in analogy with a procedure in ~IACS, 69, 74 (1947) as shown in Scheme 4:
A. ~Carboethoxv-(4phenvl. 4~3-methvlphenvl))-but~enoic acid ; ''Og3/15059 CA2~ 17367 PCI`/US92~10720 2~7367 37 ~ r~
~ ~...,. ~, To a 250 mL round-bottomed flask equipped with condenser and N2 inlet were added 100 mL t-butanol, 12.57 9 t112 mmol) potassium t-butoxide, 20 9 (102 mmol)3-methylbenzophenone, and 21.31 g (122 mmol) diethyl succinate. The reaction wasrefluxed for 14 hours, c0016d, and acidified with HCI, then partitioned b~tween water 5 and ether. The organic layer was washed with 1 N a~ueous sodium hydroxide solution, which was then acidified and extractad into ether. The organic layer was dried and - concentrated to an orange oil which was used directly.
B. (~Phenvl. 4-(~methvlDhenyl~)-but~en.oic acid The above oil was heated to reflux in a solution of 60 mL acetic acid, 60 mL 48%10 hydrobromi¢ acid, and 50 mL additional ac~tic acid for solubility for 14 hours. The brown oil that separated on cooling was isolated, dissolved in ~thyl acetate, washed ~nth water, then with 2% aqueous sodium hydroxide solution. Thc basic aqueous phas~ was acidiffed, extracted into ethyî acetate, dried, and concentrated. The product was a mixtur~ of olefin isomers by NMP.:
lH-NMR (~, CDCI3): 2.27 and 2.29 (s, 3H), 3.t9 (rn, 2H), 6.18 (t, J=7, lH), 6.
7.4 (m, 9H)-C. (4-Phenyl, 4-(3-methylphenyl~)-butanoic acid The abova oil (25.7 g) was hydrogenated at 30 p.s.i. hydrogen in ethyl acetate with 1.25 9 10% palladium-on-carbon for 2 hours. Filtration through Celite and 20 concentration, followed by chromatography on silica gel using methanol/m~thylene chloride as eluant afforded an oil which was crystallized trom heptane, 4.70 g (18%), M.P. 9~100C.
lH-NMR (o~, CDCI3): 2.35 (s, 3H),2.2-2.3 (m, 4H), 3.95 (t, J=7, lH), 7.0-7.4 (m, 9H).
l3C-NM~ (~, CDCI3): 21.6, 30.3, 32.6, 50.4, 124.8, t26.5, 127.3, 127.9, 128.5, 128.6, 138.2, 143.9, 144.2, 180.3.
IR (cm. l, KBr): 1720 (C=O).
MS (%): 254 (parent, 23), 182 (100),165 (23), 32 (36), 28 (100).
Anal. calc'd for Cl,Hl9O2: C 80.28, H 7.13. Found: C 80.54, H 7.05.
D. 4Phenvl~methyl-1.2,3,4-tetrahydronaphth-1-one:
To a 250 mL round-bottomed flask equipped with condenser and N2 inlet war~
added 8.2 g (32.3 mmol) (4-phenyl,4(3-methylphenyl))-butanoic acid, 54 mL toluene, and 4.6 g (38.64 mmol) thionyl chloride. The reaction was refluxed ~or 1 hour, cooled, WO 93!15059 -C A 2 1 1 7 ~ 6 7 PCl`/US92/10~21`

.;.....
.. ~
z~ 36'^~ -38-and concentrated. The oil was dissolved in 15 mL carbon disulfide, and added dropwise to a slurry of 29.98 9 (225 mmol) aluminum chloride in 50 mL carbon disulfide which had been cooled to 0C. The reaction was allowed to stand 16 hours, pouredonto ice, and partitioned between water and ethyl acetate. The organic phase was5 washed with water, aqueous sodium bicarbonate solution, and water, then dried and evaporated. The oil was chromatographed on silica gel using hexanelethyl acetate as eluant to afford an oil, 4.03 9 ~53%).
'H-NMR (~, CDC13): 2.28 (s, 3H), 2.2-2.7 (m,4H), 4.24 (m, lH), 6.8-7.4 (m, 7H), 8.02 (d, J=7, lH).
'3C-NMR'(~, CDCI3): 21.8, 31.9, 36.4, 36.5, 45.2, 126.8, 128.1, 128.5, 128.6, 129.9, 130.6, 143.8, 144.5, 146.2, 197.8.
IR (cm.~ <Br): 1680 (C=0).
MS (%): 236 (parent, 96), 208 (92), 194 (42), 166 (43).
E. 4Phenyl~methyl 1.2.9.~tetrahvdronaphth-1~ne oxime To a 125 mL round-bottomed flask equipped with condenser and N2 inlet were added 4.3 g (18.29 mmol) 4-phenyl~methyl-1,2,3,4-tetrahydronaphth-1-one, 46 mL
methanol, 2.95 9 (29.26 mmol) triethylamine, and 2.02 9 (29.26 mmol) hydroxylamine hydrochloride. The reaction was sUrred at room temperature for 3 days, evaporated, partitioned between ethyl acetate and water, and the aqueous layer extracted with tresh 20 ethyl acetate. The eombined organic layer was dried over sodium suHate and evaporated to an oil, 4.57 9 (100%).
'H-NMR (d, CDCI3): 2.1-2.3 (m,2H), 2.28 (s, 3H),2.8-3.0 (m, 2H),4.17 (m,1 H), 6.8-7.4 (m, 7H), 7.95 (d, J=7, 1H).
l3C-NMR (d, CDCI3): 21.1, 21.4, 29.6, 45.0, 126.5, 128.0, 128.1, 128.5, 129.2, 129.9, 139.7, 141.4, 144.0,155.3. "''-~' IR (cm.~ (Br): 1610 (C=N).
MS ~%): 251 (parent, 94), 234 (æ), 156 (17), 91 (17).
HRMS: Ca~e'd. tor Cl,Hl,NO: 251.1310. Found: 251.130æ.
F. 5-phenyl-7-methyl-2.3.4.5-tetrahYdro-1 H-~1)benzazepin-2 one To a 250 mL round-bottomed tbsk equipped with N~ inlet were added 4.5 9 (18.3 mmol) 4~henyl~methyl-1,2,3,4-tetrahydronaphth-1~ne oxime and 59.45 9 polyphosphoric aeid. The mixture was heated in a 130C oil bath ~or 25 minutes, then - pourr~d onto iee and stirred until homogeneous. The mixture was ex~eted with ethy~

A 2 ~ 1 7 3 6 ~ PCI`/US92/10720 ~7367 acetate, and the organic layer washed with water and brine, dried over sodium suHate, and evaporated. The residue was chromatographed on silica gcl using hexane/ethylacetate as eluant to afford an oil, 2.20 9 (49%), which could be crystailized from methylene chlorid~ and isopropyl ~ther to aflord a solid, mp 15~173C.
1H-NMR (~, CDCI3): 2.16 (s, 3H), 2.4-2.6 (m, 4H),4.40 (m, 1H), 6.6 and 7.~7.4 (m, 8H), 9.15 (bs, lH).
t3C-NMR (~, CDCI3): 21.1, 32.9, 33.9, 45.0, 121.9, t27.0,127.9,128.6, 129.0, 129.1, 135.0, 135.2, 136.5, 141.2, 175.8.
IR (cm.-l, KBr): 1680 (C=O).
MS (%): 252 (parent+1, 100), 196 (10), 147 (10),135 (14), 119 (13), 103 (12).
Anai. calc'd for C17H,7NO: C 81.24, H 6.82, N 5.57. Found: C 81.04, H 6.6g, N 5.47.
The remainder of U~e synthesis was c~rried out as descnbed in Example 1:
G. 3-Bromo-~pbenyJ-7-methyl-2.3.4.5-tetrahvdro-1 H-(1)benzaze Din-2~ne M.P. 20~211 C, 62% yield.
lH-NMR (~, CDCI3): 2.13 (s, 3H), 2.83 (m, lH), 3.09 (m, lH), 4.42 (m,1H),4.62 (m, 1H), 6.6 and 7.~7.4 (m, 8H), 8.99 (bs, lH).
'3C-NMR (~, CDCI3): 21.1, 45.0, 46.1, 47.3, 122.5, 127.4, 128.3, 128.6, 128.8, 128.9, 133.5, 133.6, 135.8, 136.4, 139.3, 169.3.
IR (cm.-l, KBr): 1678 (C=0).
- MS (%): 330/332 (parent, Br'3/Br31, 100/98), 251 (26), 137 (32), 119 (32), 85 - (27).
Anal. caic'd for C"H,ONOBr: C 61.83, H 4.88, N 4.24. Found: C 61.79, H 4.57, N 4.09.
H. N-t-Butvl 2-~3-bromo-2~xo-5-phenyl-7-methv!-2,3.4.5.-tetrahydro-l H-(1)benzazepin-1-yllethanoic aci~ amide M.P. 12~133C, 93% yi~ld.
'H NMR (~, CDCI3): 1.33 (s, 9H), 2.14 (s, 3H), 2.83 (m,1H), 3.01 (m, lH), 4.3-4.5 (m, 2H), 4.59 (m, lH), 4.66 (m, lH), 6.14 (bs, lH), 6.48 (bs, lH), 7.~7.4 (m, 8H).
l3C-NMR (~, CDCI3): 21.2,28.7,43.9,45.7,47.3,51.5,54.8,123.0,127.3, t28.3, 128.7, 128.8, 128.9, 129.û, 137.4, 137.5, 138.4, 139.1, 167.1,168.2.
IR (cm. ', KBr): 1662 (C=O).

wo 93/l50sg C A 2 1 1 7 3 6 7 Pcr/usg2/lo72r ... ..
2117~67 4~

MS (%): 443/445 (parent, Br79/Br~',90/92),370/372 (Br7~/Br~l,100/98),290 (50), 262 (45), 134 (65).
Anal. calc'd for C23H27N202Br-1/3H20: C 61.47, H 6.21, N 6.23. Found: C
61.20, H 6.12, N 5.96.
I. N-tert-Butyl 2-[3-azido-2-oxo-5-phenyl-7-methyl-2.3.4 ~tetrahydro-1H-(1) benzazeein-1-ylLethanoic acid amide Foam, mixture of diasbreomers, 81% yield.
1H-NMR (~, CDCI3): 1.27,1.32 (s's, 9H), 2.12, 2.37 (s's, 3H), 2.78 (m,1H),2.95 (m,1H),2.98 (ABq, JA~-15, ~v-279, part of 2H), 3.82, 3.96,4.06, and 4.64 (muitiplets, 2H), 4.35 (s, rest of 2H), 6.17 (bs, lH), 6.45 (bs, lH), 7.~7.4 (m, 8H).
l3C-NMR (~, CDCI3): 21.0, 21.2, 28.6, 28.7, 35.5, 39.8, 41.9, 43.7, 51.3, 51.5, 54.6, 58.3, 59.0, 60.4, 123.0, 125.6, 126.1, 126.5, 127.3, 127.33, 127.4, 128.2, 128.3, 128.4, 128.5, 128.6, t28.65, 128.7, 128.8, 128.9, 129.58, 129.64, 130.9, 137.2, 137.6, 137.7, 138.5, 139.4, 141.1, 167.i, 167.9, 169.9, 170.4.
IR (cm. ', KBr): 2098 (N3), 1660 (C=O).
MS (%): 406 (parent~1, 74), 380 (43), 347 (41), 333 9100~, 249 (45), 234 (62), 222 (77), 220 (74), 208 (79), 144 (51), 132 (41), 105 (47), 91 (90).
HRMS calc'd for C23H2~NSO2: 405.2165. Found: 405.2t622.
J. N-tQrt-Butyl 2-r3-~mino-2-oxo-5-phenvl-7-methv!-2.3.4.5-tetrahydro-1 H-20 l1) benzazeDin-1-vl! ethanoic acid amide M.P. 100-110C, m~nure of diastereomers, 2996 yield.
H-NMR (~, CDCI3): 1.24, 1.31 (s's, 9H), 2.11, 2.35 (s's, 3H), 2.62 (bs, 2H), 2.
. 2.8 (m, 2H), 3.2-3.4 (m, 2H), 4.04.5 (m, 4H), 6.09 (bs, lH), 6.4 (bs, lH), 7.0-7.4 (m, 8H)-IR (cm. l, KBr): 1660 (C=O).
MS (%): 379 (parent, 2), 336 (17), 235 916), 202 (22), æ (35), 28 (100).
HRMS calc'd. for C23H2"N302: 379.2260. Found: 379.22848.
Anal. calc'd for C23H29N3O2-213H20: C 70.56, H 7.81, N 10.73. Found: C
70.64, H 7.47, N 10.04 ~-0.69~.
K N-tert-Butvl 2-[~3-(3-tolvl)ureidol-2-oxo~phenyl-7~nQthyl-?.3.4.5-tetra-hydro-1H-(~)benzazeoin~ 11 ethanoic acid amide Prepared as a mixture of diastereomers, one of which precipitated from the reaction mixture (more polar); the other was purified by chromatography (less polàr).

`"O 93/150~9 ` C A 2 1 1 7 3 6 7 PCI/US92/10720 21~7~67 More polar isomer, M.P. 28~283C,45.5% yield.
lH-NMR (~, CDCI3): 1.30 (s, 9H), 2.11 ~s, 3H), 2.22 (s, 3H), 2.8 3.2 (m, 2H), 3.90 (m, 1H), 4-34 (AB~. JAB=16. /~V=59, 2H), 4.62 (m, lH), 6.4-6.8 (multiplets, 3H), 7.~7.4 (m, 12H).
IR(cm.l, KBr): 1640 broad (C=O).
FAB MS(%): 513(paJent+1,7~,380(98),307(53),165(51),119(100).
HRMS calc'd for C3,1t3~N403: 512.27541. Found: 512.27528.
Anal. calc'd for C3,H3GN403~2/3H~O: C 70.97, H 7.17, N 10.68. Found: C
70.80, H 6.71 (~.46~, N 10.39.
Less po,ar isomer, M.P. 13~135C, 42% yield.
lH-NMR (d, CDCI3): 1.26 (s, 9H~, 2.21 (s, 3H), 2.38 ~s, 3H)3 2.77 (m, 1H), 3.01 (m, 1H), 3.22 (ABq, JA,~=16, ~v=287, 2H), 4.15 (m, lH), 4.60 (m, 1H), 5.89 (bs, lH), 6.~7.3 (m, 13H), 7.67 (bs, 1H).
- t3~NMR (d, CDCI3): 21.0, 21.4, 28.6, 37.1, 44.4, 50~2, 51.6, 53.6, 116.7, 123.4, 123.5, 126.3, 126.4, 128.3, 128.6, 129.4, 131.39, 131.43, 137.7, 137.9, 138.5, 138.6, 139.1,141.9, 155.4,167.6, 173Ø
IR (cm.-t, KBr): 1640 broad (t:=O).
FAB MS (%): 513 (parent+1, 78), 440 (98), 380 (46), 305 (44), 251 (77), 234 (g3~, 222 (67), 220 (45), 208 (100), 144 (44), 107 (54).
HRMS calc'd. for C3,H3BN403: 512.27541. Found: 512.28240.
Anal. calc'd for C31H35N~03-1/2H20: C 71.58, H 7.15, N 10.74. Found: C
71.5~, H 7.10, N 10.33 (-0~41).

N-tert-Butvl 2-r3-(3-l~chlorophenyl!ureido)-2-ox~5-phenyl-7-mQthyl-2.3.4.
25 tetrahvdr~1 H-(1 )benzazepin-1-vll ethanoic acid amide Prepared as a mixture o~ diastereomers from thetitle compound of Example æJ, one of which precipitatecl from the reaction mixture (more polar); the other w~ pur~fled by chromatography tless polar).
More polar isomer, M.P. 282-285C, 38% yield.
'H-NMR (~, CDCI3): 1.28 (s, 9H), 2.tO (s, 3H), 2.~3.2 (m, 2H), 3.90 (m, lH), 4.32 (ABql ~=16, Av=52, 2H), 4.57 (m, lH), 6.42 (bs, 1H), 6.6-7.4 (m, 14H).
IR (cm.-1, KBr): 1640 broad (C=O).

9 (~ A 2 I 1 7 3 6 7 P~/US92/1072~
.. . . ..

FAB MS (%): 533/535 (parent+1, Cl35/CI3~, 9/4), 380 (52), 307/309 (29/11),155 (70), 135 (46~, 119 (100), 103 (68).
Anal. calc'd for C30H33N4O3CI-1/2H2O: C 66.47, H 6.32, N 10.34. Found: C
66.17, H 6.25, N 10.04.
Less polar isomer, M.P. 15~165C, 46% yield.
lH-NMR (~, CDCI3): 1.28 (s, 9H), 2.39 (s, 3H), 2.~3.0 (m, 2H), 3.28 (AB,t, JA~t--16, ~v=281, 2H), 4.11 (m, lH), 4.38 (m, lH), 5.83 (bs,1H), 6.~7.2 (m,12H), 7.57 (bs, 1 H), 7.98 (bs, 1 H).
13C-NMR (~, CDCI3): 21.0,28.7,3B.8,44.4,50.4, S1.8,53.2,116.9,122.1,126.3, 126.5,128.3,129.5,131.5,134.3,137.7,137.8,137.9,138.4,140.7,141.9,155.1,167.4, 173.3.
IR (cm.1, KBr): 1640 broad (C=0).
FAE~ MS (%): 533/535 (parent+1, Cl35/CI3', 37/15), 460/462 (81131), 380 (33), 307 (61), 251 (61), 234 (100), 222 (62), 208 ~99), 91 (51).
Anal. calc'd for C30H33N403CI: C 67.598, H 6.24, N 10.51. Found: C 67.50, H
6.18, N 10.14.

N-ter~-Bulvl 2-~3~ ~methoxvPhenyl)ureido~-2-oxo-~Phenvl-7-methyl-2.3.4.5-tetrahydro-lH-(l)benzazepin-l-yll ethanoic acid amide Prepared as a mixture of diastereomers from the tile compound of Example æJ, one of which precipitated from the reaction mixture (more polar); the other was purified by chromatography (less polar).
More polar isomer, M.P. 28~286C, 47% yield.
l H-NMR (~, CDCI3): 1.31 (s,9H),2.11 (s,3H),2.~3.2 (m,2H),3.7 (singlets,3H), 3.50 (m, lH~, 4.29 (ABq. JAB=15, ~v=138, 2H), 4.46 (m, lH), 6.4-7.4 (multiplets, t5H).
IR (cm. ', KBr): 1640 broad (C=0).
FAB MS (%): 529 (parent+1, 7), 380 (100), 307 (92), 251 (47), 208 (42).
Anal. calc'd for C3lH30N404-112H20: C 69.25, H 6.94, N 10.42. Found: C
6~.22, H 6.59, N 10.24.
Less polar isomer, M.P. 12~125C, yield 37%.
tH-NMR ~, CDCI3): 1.25 (s, 9H~, 2.38 (s, 3H), 2.79 (m, lH), 3.03 (m,1H), 3.25 (ABq, JAB=16, ~vn=260, 2H), 3.68 (s, 3H), 4.17 (m, lH), 4.62 (m, lH), 5.84 (bs, lH), 6.~7.3 (m, 13H), 7.80 (bs, 1H).

``~ 93/15059 C ~ 2 1 1 7 3 6 7 PCI/US92/10720 2~367 l3C-NMR (~, CDCI3): 21.0, 28.6,37.2, 44.3, 50.1, 51.6, 53.6, 55.1,104.7,108.8, 111.5,124.5,126.3,126A,128.3,129.3,129.4,137.7,138.0,138.5,140.6,141.9,155.2, 160.1, 167.5, 172.9.
IR (cm.-', KBr): 1640 broad (C=O).
FAB MS (%): 529 (par~nt+1, 83), 456 (100), 380 (44), 307 (J0), 251 (52), 234 (67), 208 (65).
Anal. ealc'd for C3,H3~,N"O"-1/3H2O: C 68.87, H 6.96, N 10.36. Found: C
68.94, H 6.67, N 10.00.

N-tert~Butvl 2-~3-(3-(3-tolvl)ureido)-2-oxo-5-(3-ehlorophenvl)-2.3.4.5-tetrahvdro-1H-(1)benzazepin-l-vl1 ethanoie aeid unide A. 4-Phenyl~ehloro-1.2.3.4tetrahydronaDhth-1-one Prepared in analogy with Example 22 above by treatment of (4phenyl,4(3-ehlorophenyl))-butanoie aeid (prepared in analogy with 4phenyl, 4(~methylphenyl)-15 butanoie aeid as deseribed abov~ in Exarnple 22), with thionyl ehloride in toluene -followed by eyelk~tion with aluminum ehloride in earbon disuHide to affo~d the desired 4(3-chlorophenyl)-1,2,3,4-te!rahydron~phth-1 -one and the isomeric produet 4phenyl~
ehloro-1,2,3,4tetrahydron4Dhth1-one as an inseparabl~ mixture in 53% yield, whieh was eonverted to the oximes and s~parated.
B. 4(~Chlorophenyl)-1.2.3.4tetrahydronaDhth-1~ne oxime M.P. 129-131 C, 28% yield.
'H-NMR (~, CDCI3): 1.56 (bs, lH), 2.0-2.3 (m, 2H), 2.7-2.9 (m, 2H), 4.18 (m, 1H), 6.8-7.4 and 8.0 (m, 8H).
'3C-NMR (~, CDCI3): 21.2, 29.3, 44.8,124.2,126.7,127.2,128.6,129.3,129.8, 130.7, 134.5, ~40.7, 146.0, 154.9.
IR (cm.-', KBr): 1598 (C=N).
MS (~): 271/273 (p~rent, Cl35/CI3', 100/35), 254 (42), 217 (24), 190 (29).
Anal. ealc'd for C,oHI~NOCi: C 70.72, H 5.19, N 5.15. Found: C 70.70, H 5.01, N 5.22.
C. 4-Phonvl~chloro-1.2.3.4tP~~~ahvdronaDhth-1 oneoximQ
Oil, 27% yhld.
'H-NMR (~, CDCI3): 2.0-2.3 (m,2H),2.77 (t, J=7,2H),4.07 (m, lH),6.8-7.3 and 7.86 (m, 8H).

WO93/15059 ` (~ A ~ 1 1 7 ~ 67 PCl`/US92/1072~
~ f ~
z~7367 (3-Chlorophenyl) compounds:
D. 5-(3-Chlorophenyl!-2.3.4~tetrahydro-1 H~ benzazepin-2-one Prepared as in Exarnple 22, M.P. 174-176C, yield 51%.
Anal. calc'd for C,oH,4NOCI: C 70.72, H 5.19, N 5.15. Found: C 70.90, H 4.90, N5.02. --E. ~Bromo-5-(3-chlorophenyl)-2.3.4.~tetrahvdro-1 H-!1)benzazepin-2~ne M.P. 15~15~C, 51% yield.
Anal. calc'd for C"~H,3NOBrCI: C 54.81, H 3.74, N 3.99. Found: C 55.48 (+0.67), H 3.46, N 3.87.
F. N-t-Butyl 2-~3-bromo-2-oxo-~(~chlorophenvl)-2.3.4.5.-tetrahvdro~
(l!benzazepin-l-yllethanoic acid amide M.P. 148-152C (from cyclohexane), 57% yield.
Anal. calc'd for C22H2"N2O2BrCI-1/2 cyclohexane: C 59.36, H 5.98, N 5.54.
Found: C 59.26, H 6.16, N 5.54.
G. N-tert-Butyl 2-,~azido-2-oxo-~(3-chlorophenyl)-2.3.4.~tetrahydro~
(l)benzazepin-t-yll ethanoic acid amide M.P. 132-135C, 72.5% yield.
Anal. calc'd for C22H2~N502CI: C 62.04, H 5.68, N 16.44. Found: C 62.12, H
5.S6, N 16.51.
H. N-tert-Butvl 2-r3-amino-2-oxo-5-(3-chloroPhenvl)-2,3.4.5-tetrahydro-1 H-(1)benzazePin-1 yll ethanoic acid amide The reduction was carried out with 1 equivalent of triphenylphosphine ~nd water in tetrahydrofuran ovemight at room temperature to give a foam in 9596 yield.
HRMS calc'd for C22H2,N302CI: 400.1786. Found: 400.17876.
I. N-tert-Butyl 2-~3-~3-(~tolvl~ureido)-2-oxo-5~ chlorophenyl)-2.3.4.5 tetrahvdro-1H-(1)benzazeDin-l-vl~ ethanoic acid amide Prepared *om a single diastereomer of the amino compound, which gave 8 diastereomer corresponding to the less polar isomer in Example 22K, M.P.251-253C, 85% yield.
'H-NMR (~, CDCI3, TFA): 1.33 (s, 9H), 2.33 (s, 3H), 2.79 (m, lH), 2.96 (m, lH), 3.33 (ABq, JA"=16, ~v=150, 2H), 4.22 (m, lH), 4.58 (m, lH), 6.7-7.5 (m, 15H).

93~1~059 CA2~ ~ ~367 PCI`/US92/107~".
~7367 l3C-NMR (~, CDCI3, TFA): 20.7, 28.0, 36.3, 43.4, 50.5,53.4, 53.5,121.4,124.2, 124.8,125.1,125.9, t27.2,128.6,129.5,129.8,130.0,131.0,134.1,134.~,137.2,139.2, 140.6, ~42.7, 158.2, 169.1, 173.6.
IR (om.-1, KBr): 1640 broad (C=O).
6 FAB MS (%): 533/535 (parent, Cl35/CI3', 32113), 155 (46), 119 (1û0), 103 (45).
Anal. calc'd for C30H33N"03CI 113H20: C 66.84, H 6.29, N 10.39. Found: C
66.90, H 6.25, N 10.32.

N-tert-Butyl 2-~(3-(~chloro~henyl)ureido~-2-ox~(~chlorophenYI~-2.3.4.5-10 tetrahyd-ro-1H~ benzazepin-1-vl1 ethanoic acid amide Prepared ~rom a single diastareomer of the amino compound, which gave a diastereomer corresponding to the less polar isomer in Example 22K, M.P.24~243C, 84% yield.
lH-NMR (~, CDCI3, TFA): 1.~ (s, 9H), 2.79 (m, 1H), 3.02 (m, lH), 3.34 (AB~"
JAB-16- ~v=143, 2H), 4.25 (m, lH), 4.59 (m, lH), 6.7-7.5 (m, 15H).
t3C-NMR (~, CDCI3, TFA): 27.8, 36.6, 43.3,44.0, 50.3,53.4, S3.5,121.2,123.4, 124.2,124.7,126.0,126.8,127.2,129.5,129.9,130.0,130.7,131.1,134.8,135.S,136.4, 137.2, 139.2, 142.7, 157.3, 169.1, 173.9.
IR (cm. ', KBr): 1640 broad (C-0).
FAB MS (%): 553/554/555/556/557 (parent+1, Cl35/CI37,14/6/12/3/2), 309 (16), 155 (60), 135 (30), 119 (100), 103 (42).
Anal. oalc'dtor C29H30N~O3CI2-1/3H2O: C 62.26, H 5.52, N 10.01. Found: C
62.32, H 5.38, N 9.77.

N-tert-Butyl 2-~3-(3-(3-methoxvphenYl)ureido!-2-oxo~(3 chlorophenyl)-2.3.4.5-tetrahydr~1H~ benzazepin-1-yl1 ethanoic acid amide Prepared from a single diastereomer of the amino compound, which gave a diastereomer corresponding to the less polar isomer in i:xample 22K, M.P.22~227C, 80% yield.
'H-NMR (~, CDCI3, TFA): 1.32 (s, 9H), 2.77 (m, lH), 2.97 (m, 1H), 3.31 (AB~"
~=16, ~v=157, 2H), 3.83 (s, 3H), 4.21 (m, lH), 4.55 (m, lH), 6.7-7.5 (m, 15H).

CA2~ ~ 7367 ~0 93/15059 pcr/uss2/1o72~
2~73~,7 l3C-NMR (~, CDCI3, TFA): 27.9,36.4,43.4,50.4,53.4,55.5,109.9, 112.7,116.4, 124.2,124.8,126.0,127.2,129.4,129.9,130.0,130.7,131.1,134.8,136.1,137.2,139.3, 142.7,157.7,169.1,173.8.
IR (cm. l, I<Br): 1640 broad (C=O).
FAB MS (%): 5491551 (parent, Cl35/CI37,45117),476 (23),400 (22), æ7 (25),155 (50), 135 (æ), 119 (100), 103 (47).
Anal. cal~d for C30H33N"04CI: C 65.63, H 6.06, N lQ.20. Found: C 65.73, H
6.03, N 9.89.
E)(AMPi~ 28 N-tert-Bytvl 2-r3-(3-(3-ethylphenylLureido)-2-oxo-5-~3-chlorophenvl)-2.3.4.5-tetrahydr~1 H~ benzazepin-1-yl~ othanoic acid amide Prepared from a single diastereomer of the arnino compound, which gave a diastereomer conesponding to the less polar isomer in Example 22K, M.P.223-228C, 77% yield.
lH-NMR (~, CDCI3, TFA): 1.21 (t, J=7,3H),1.32 (s, 9H),2.63 (q, J=7,2H~,2.77 (m, lH),2.98 (m,1H),3.31 (AB~, JAB=16, AV=174~ 2H),4.23 (m,1H),4.58 (m,1H), 6~7-7.5 (m, lSH).
l3~NMR (~, CDCI3, TFA): 14.9, 27.9, 28.5, 36.4, 43.4, 5~.4, 53.3, 53.4,121.4, 123.7,124.2,124.8,126.0,127.1,127.2,129.4,129.9,130.0,131.0,134.5,134.8,137.2, 20 139.4, 142.7, 146.8, 158.1,169.0, 173.7.
IR (cm. l, KBr): 1640 broad (C=0).
- FAB MS (%): 547/549 (parent, Cl351CI37,92/35),474 (60),400 (55),327 (72),119 (1 00).
Anal. calc'd for C31H35N~03CI: C 68.06, H 6.45, N 10.24. Found: C 67.98, H
25 6.35, N 10.05.

A. ~phenyl-7-chlQro-2,3A~,~etrahvdro-1H-(1)benzazepin~_ Prepared from thetTtle compound of Example 25C as Tn Ex~rnple 25C, M.P.184-186C, 5896 yield.
Anai. calc'd for CloHl~NOCI: C 70.72, H 5.19, N 5.15. Found: C 71.00, H 4.86, N 5.07.
B. ~Bromo-5-phenyl-7-chloro-2.3.4.~tetrahydro-1 H-(1)benzazepin-2-one - M.P. 22~223C, 56% yTeld.

~7-Anal. caidd for Cl~H13NOClBr: C 54.81, H 3.74, N 3.99. Found: C 61.79, H
4.57, N 4.09.
C. N-t-Butyl 2-l~bromo-2-oxo-5-~henyl-7~hloro-2,3.4.5.-tetrahvdro-1 H-~1)benzazepin-1-yll ethanoic acid amide M.P. 12~130C (from cyclohexane), 64% yield.
Anal. caic'd for C22H2~N202ClBrl/3 cyclohexane: C 58.61, H 5.74, N 5.70.
Found: C 58.72, H 5.50, N 5.58.
D. N-tert-Butvl 2-13-azido-2-oxo-5-phenvl-7-chloro-2.3.4.5-tetrahydro-1 H-~1) benzazeDin-l-yllethanoic acid amide M.P. 167-170C, 38% yieid.
Anal. calc'd for C22H2~N5O2CI-1/3H20: C 61.18, H 5.76, N 16.21. Found: C
61.28, H 5.56, N 15.91.
E. N-tert-Butyl 2-r3 amino-2-oxo-5-Dhenvl-7~hloro-2.3.4.5-tetrahydro-1H-~1) benzazeDin-1-vll ethanoic acid amide Foam, 65% yield.
HRMS calc'd tor C22H27N3O2CI: 400.1786. Found: 400.17952.
F. N-tert-Butyl 2-l3-(3-(3-tolyl)ureldo)-2-oxo-5-Dhenvl-7-chloro-2.3.4.
tetrahvdro-1H-(1~benzazepin-1-vl1 ethanoie acid amide Prepared from a single diastereomer of the amino compound, which gave a diastereomer corresponding to th~ less polar ~somer in Example 22K, M.P.1~160C,829~ yield.
lH-NMR (~S, CC)CI3): 1.24 (s, 9H), 2.æ (s, 3H), 2.78 (m, lH), 3.03 (m,1H), 3.18 (AB", JAB=16, ~v=279,2H),4.18 (m,1H),4.57 (m,1H),5.76 (bs,1H), 6.7-7.4 (m,14H).
13C-NMR (~, CDCI3): 21.5,28.5,36.9,44.2,50.1,51.7,53.5,116.9,120.7,123.8, 126.2,126.7,128.5,128.7,129.0,130.5,133.1,138.8,139.7,140.1,141.0,155.3,167.2, 172.6.
IR (cm. l, KBr): 1640 broad (C=O).
FAB MS (%): 533/535 (parent, C135/CP7, 100/39), 460 (74), 400 (56), æ7 (72), 119 (68), 107 (72), 91 (67).
An~ Wd ~or C30H33N~03CI l/3H20: C 66.84, H 6.29, N 10.39. Found: C
66.87, H 6.19, N 10.13.

WO 93/15059 C A 2 1 ~ 7 :~ 6 7 PCI`/US92/1072~- "
21~7~67 ~8-N-tert-Butyl 2-r~(3-(3-chlorophenvl)ureido)-2-oxo-5-phenyl-7~hloro-2.3,4.5-tetrahydro-1H-l1~benzazepin-1-yl1 ethanoic acid amide Prepared from a single diastereomer of the amino compound, which gave a diastereomer corresponding to the less polar isomer in Example 22K, M.P.234236C, 5 83% yield.
'H-NMR (~, CDCI3): 1.27 (s, 9H), 2.8-3.0 (m, 2H), 3.24 (AB4, J~,~=16, ~v=274, 2H), 4.21 (m, lH), 4.55 (m, lH), 5.76 (bs, lH), 6.8-7.5 (m, 13H), 7.92 (bs, lH).l3C-NMR (~, CDCI3): 28.7,36.6,44.3,50.3,52.0,53.1,53.5,117.0,119.1,122.4, 125.8,126.2,126.9,128.5,129.0,129.6,130.7,133.2,134.3,139.6,140.0,140.5,140.9, 155.0, 167.0, 173Ø
IR (crn;', KBr): 1640 broad (C=O).
FAB MS (%): 5531554/555155615571558 (parent, C135/C137, 75/32/54/19/10), 400 (100), 327 (82), 254 (83), æs (73).
Anal. caic'd for C29H30N"03CI21/3H20: C 62.26, H 5.52, N 10.01. Found: C
62.49, H 5.40, N 9.70.

N-tert-Butyl 2-r3-(3-(3-tolvllureidol-2-oxo-~(4-fluoroDhenvl!-2.3.4.5-tetrahvdro- -~
1~(1)benzazepin-1-yll ethanoic acid amide A. 4-~4-Fluorophenyl)-1.2.3.~tetrahvdronaphth-1 one oxime Prepared as in Example æ above from the known 4(~fluorophenyl)-1,2,3,4-tetrahydronaphth-1-one (see Koptyug, V.A. and Andreeva, T.P., ~h. Or~anich. Khim., 7, 239~2403 (1971)) as shown in Scheme 5 tn 93% yield, M.P.154-158C (from ethylacebte/hexane) .
'H-NMR (~, CDCI3): 2.0-2.3 (m,2H),2.84 (m,2H),4.13 (m,1H),6.~7.3 (m,7H), 7.97 (m, 1H), 9.36 (bs, 1 H).
13~NMR (~, CDCI3): 21.3, 29.5,44.3, 115.2,115.5, 124.1,127.1, 129.2,129.6, 129.8, 129.9, 130.7, 139.4, 141.4, 1S5.1, 163.2. `
IR (cm.1, KBr): 1602 (C=N).
MS (9~): 255 (parent, 100), 238 (42), 183 (23).
HRMS calc'd for CloHl~NOF: 255.10595. Found: 255.10679.
B. 5 (4-Fiuorophenyll-2~3.4~5-tetrahvdro-1 H-(1)benz~zepin-2~ne Pr;epared f~om the tltle compound of Exarnple 31A as in Example 22F in 48"h yield, M.P. 209 212C (from 2-propanol).

- ~'?VO 93/15059 C i~ 2 1 ~ 7 3 6 7 PCr/US92/10720 2~L~7~6~

'H-NMR (~, CDCI3): 2.42.6 (m,4H), 4.2 (m, lH), 6.75 and 7.0-7.3 (m, 8H), 8.41 (bs, lH).
l3C-NMP~ (~, CDC:13): 32.7, 33.9,44.3,115.3,115.6,122.0,125.7, 127.4,128.5, 130.2, 130.4, 136.6, 136.7, 137.3, 160.2, 160.4, 175.2.
IR (cm. ~, KBr): 1680 (C=O).
MS (%): 255 (parent, 83), 213 (29), 200 (100), 198 (55~, 183 (22).
Anal. oalc'd tor C,~,H,~NOF: C 75.28, H 5.53, N 5.49. Found: C 75.20, H 5.50, N ~.35.
The remainder of the synthesTs wa~ carried out as described in Ex~mple 1:
C. Bromo-5-(~fluorophenyl)-2.3.4,5-tetrahydro-1 H-(1)benzazepin-2-one M.P. 170-180C (from methylene chloride/h~xane), 58% yield, mixture of diaster~omers.
lH-NMR (~, CDCI3): 2.8-3.2 (m, 2H), ~.50 (m,1 H),4.65 (m,1 H),6.7-7.4 (rn,8H), 8.97 and 9.23 (slnglets, 1H).
'3C-NMR (~, CDCI3): 43.8, 44.1, 44.3, 45.1, 46.2, 46.9, 115.4, 115.6, 115.7, 115.9,122.7,126.6,127.9,128.1,128.2,129.1,129.6,129.7,129.8,130.3,130.5,134.8, 135.0, 135.8, 136.2, 136.6, 160.4, 163.7, 169.3, 170.2.
IR (cm. l, KBr): 1690 (C-O).
MS (%): 333/335 (parent, Br'~/Br3l, 46/60~, 254 (100),226 (100), 200 (60), 198 (77), 109 (60).
HRMS calc'd for Cl~Hl3NOFBr: 333.01466. Found: 333.01409.
D. N-t-Buty~ 2-13-brom~2-oxo-5-(4-fiuorophQnyl?-2.S .4.5.-tetrattvdro-1 H-~l)benzazepin-1 yll ethanoic acid amid~
M.P. 215-220C (from cycloh~xane), 59% yiald.
lH-NMR (~, CDCI3): 1.3~ (s, 9H), 2.8-3.0 (m, 2H), 4.2-4.6 (m, 3H),4.77 (m,1 H), 6.04 (bs, 1 H), 6.6 and 7.0-7.4 ~m, 8H).
'3C~NMR (o, CDCI,): 28.7, 43.1, 45.8, 47.0, 51.6, 54.6, 115A, ~16.7, 123.2, 127.5,127.8,128.1,130.3,130.4,130.5,134.9,135.0,137.7,140.9,163.6,166.9,167.9.
IR (cm. l, KBr): 1660 (C=O).
FAB MS (%): 447/M9 (parent, Br7~/Br8', 21123), 374/376 (100/94), 346/348 (48l4~), 266 (93), 238 (44).
Anal. calc'd for C22H24N202BrF: C 59.07, H 5.41, N 6.26. Found: C 59.05, H
5.15, N6.20.

WO93/15059 (~ ~ 2 1 1 7 3 6 7 PCI`/US92/1072~

2~L~l7367 -5~

E. N-tert-Butv! 2~ ido-2-oxo-~(~fluoro~hen~ 2.3.4.5-t~trahvdro-1 H-(1?benzæepin-1-yl1 ethanoic acid amide M.P. 7~85C, mixture of diastereomers, 92% yield.
1 H-NMR (~, CDCI3): 1.28, 1.32 (s's, 9H), 2.4-2.g (m, 2H and part of a 2H signal), 5 3.6, 3.77, 3.91, 4.12, 4.32, and 4.69 ~muKiplets for 2H and the remaining 2H signal), 6.0 (broad singlets, 1 H), 6.6 and 6.~7.4 (m, 8H).
t3C-NMR (~, CDCI3): 28.6, 35.9, 39.9, 41.1, 43.2,51.6,53.6,54.5,58.2,58.9, 115.1,115.4,115.7,123.2,125.9,127.3,127.5,127.6,127.7,127.8,127.9,128.0,129.3, 129.5,130.2,130.3,130.4,135.1,137.5,138.0,140.2,141.0,166.9,167.6,169.8,170.2.
IR (cm. l, KBr): 2100 (N3), 1670 (C=O). :
MS (%): 410 (parent+1, 55),384 (35),311 (19),155 (50), 119 (100), 103 (40).
HRMS calc'd for C22H2"N502F: 409.1914. Found: 409.1903.
F. N-tert-Butyl ?-~amin~2~Xo-~(~fiuorophenvl)~3.4 t~trahydr~1 (1)benzazePin-1-yl1 ethanoic aci_mide The mix~ure of diastereomers was separated into an ethyl acetate insoluble, M.P.2~295C,32% yield, isomer A and an isopropyl ether insoluble, mp 215-225C,32~K
yield, isomer B.
Isomer A:
lH-NMR (~, CDCI3): 1.26 (S,9H),2.48 (m, 1H), 2.7 (broad s, 2H), 3.03 (m, 1H), 20 3.90 (m, 1H), 4.17 (AB~, JAB=16, Dn=20, 2H), 4.87 (m, 1H), 6.6 and 7.0-7.4 (m, 8H).
IR (cm. l, KBr): 1680 (C=O).
MS (%): 384 (parent+1, 100), 311 (44),25S (19),119 (20).
Isomer B:
1 H-NMR (~, CDCI3): 1.26 (S,9H),2.5 (m, 1 H),3.0L3.4 (m, 2H),2.61 (m, 1 H), 4.1-25 4.3 (m, 2H),6.12 (broad s, 1H),6.8-7.4 (m, 8H),8.78 (broad s, 2H).
13C~NMR (d, CDCI3): 22.8,28.8, 43.2,50.3, 51.8,53.3, 115.1, 115.4,125.2, 128.1,128.2, J29.4,130.7,136.6,137.8,140.1,159.7,162.9,167.5,168.7.
IR (cm. ', KBr): 1680 (C=O).
MS (%): 383 (parent, 10), 340 (94),267 (65),261 ~9),255 (62),239 (81), 224 30 (65),212 (100),188 (86), 57 (80).
An~. c~c'd ~or C22H20N3O2F H2CO3: C 62.01, H 6.33, N 9.43. Found: C 62.00, H 6.61, N 9.37.

CA21 ~ 7367 O93/1~059 Pcr/uss~/lo72o 21 ~36~

G. N-tert-ButvI 2-~(3-i~tolvl)ureido)-2~xo-5-~4fluoroPhenyl)-2.3.4 5-tetrahydro-lH-(1)benzazepin-1-vll ethanoic acid amide Prepared from each of ~ne above isomers:
From isomer B, M.P. 302-307C, 69% yield.
1H-NMR (~, CDCI3, TFA): 1.34 (s, 9H), 2.34 (s, 3H), 2.85 (m, lH), 3.03 (m, lH), 3.34 (ABq, J.~=16, ~v=147, 2H), 4.27 (m, lH), 4.62 (m, lH), 6.8-7.6 (m, 15H).
13C: NMR (~, CDCI3, TFA): 20.4, 27.5, 36.6,42.9, 50.6, 53.4,53.6,115.2,115.5, 121.5,124.7,125.3,127.3,127.4,128.9,129.5, t29.8,131.0,133.7,136.1,137.6,139.1, 140.8, 160.0, 169.2, 173.5.
IR (cm. ', KBr): 1650 broad (C=O).
FAB MS (%): 516 (parent,1", 340 (100), 267 (70), 239 (58), 212 (46).
Anai. cal~d for C30H33N"03F 113H20: C 68.95, H 6.49, N 10.72. Found: C
68.89, H 6.31, N 10.69.
From isomer A, M.P. 310-315C, 55% yield.
'H-NMR (~, CDCI3, TFA): 1.3S (s, 9H), 2.32 (s, 3H), 2.93 (m, 2H), 4.44.7 (m, 4H), 6.8 and 7.0-7.5 (m, 15H).
'3C-NMR (~, CDCI3, TFA): 20.5, 27.7, 40.9, 41.2, 51.5,53.5, 53.8,115.5,115.8, 121.7,122.6,125.4,128.1,128.9, t29.8,129.9,130.1,130.2,133.6,133.7,133.8,137.4, 138.3, 140.8, 158.3, 160.6, 163.9, 169.0, 173.8.
IR (cm. ', KBr): 1650 broad (C=O).
FAB MS (%): 517 tparQnt+1, 2), 309 (15), 185 (20), tS5 (58), 135 (45), 119 (100), 103 (57).
Anai. caic'd tor C30H33N~03F-H2CO3: C 65.81, H 6.34, N 10.07~ Found: C
65.63, H 6.07, N 10.36.

N-tert-ButvI 2-~3-(3-(3-chloroDhenyl)ureido)-2-oxo-~(4-fluoropheny1)-2.3.4.5-tetrahyd-ro-JH-~1)benzazepln-1-yil ethanoic acid amIde Prep~re~i trom each ot the above isomers in ExampIe 31 F:
From isomer B, M.P. 271-273C, 78% yield.
lH-NMR (~, CDCI3,TFA): 1.35 (s, 9H), 2.84 (m, 1H), 3.05 (m, lH), 3.35 (AB~, JAB=16, ~v=139, 2H), 4.30 (m, lH), 4.64 ~m, lH), 6.~7.6 (m, 15H).

WO93/15059 C A 2 1 1 7 3 6 7 Pcr/usg2/1o72n ~

~36~
Z '3C-NMF~ (~, CDCI3,TFA): 27.5,36.8,43.0,50.5, 53.4,53.8,115.3,115.5,121.5, 123.7, 124.7, 127.1, t27.3, 127.4, 129.5, 129.8, 130.7, 131.0, 135.5, 136.0, 137.7, 139.1, 157.5, 160.0, 163.3, 169.3, 173.9.
IR (cm. l, KBr): 1650 broad (C=O).
FAB MS (%): 536 (parent,5.5), 340 (76),267 (65), 239 (100), 212 (76~,127 (71).
Anal. caic'dfor C2~H30N4O3FCI-1/3H2O: C 64.14, H 5.69, N 10.32. Found: C
64.31, H 5.70, N 9.92.
From isomer A, M.P. 324 328C, 28% yield.
lH-NMR (~, CD3SOCD3): 1.20 (s, 9H),2.03 ~m, lH), 2.75 (m, lH),4.18 (m,1H), 4.46 (ABq, JA,~=16, ~v-146), 2H), 5.16 (m, 1H), 8.~7.7 and 9.17 (m, l~H).
IR (cm. l, KBr): 1650 broad (C=O).
FAB MS (%): 537 (parent,10),309 (12),233 (25),155 (71),135 (68),119 (100), 103 (~3)-HRMS oaic'd for C29H30N"O3FCI: 537.2062. Found: 537.2056.
1~ Anal. caic'd for C29H30N"03FCi-2H2CO3: C 56.32, H 5.18, N 8.48. Found: C
56.87 (+0.55), H 4.98, N 8.86. ~-EXAMPi F 33 hi-tert-Butyl 2-~ L3-methoxyphenyl)ureido~-2-ox~5-(~fluorophenyl)-2.3~4,~
tetrahydro-lH~ benzazepin-1-ylLethanoic acid amide Preparad trom each of the above isomers in Example 31 F:
From isomer B, M.P. 27~284C, 60% yield.
'H-NMR (~, CDCI3, TFA): 1.33 (s, 9H), 2.82 (m, lH), 3.01 (m, lH), 3.34 (AB~"
JA8=16, ~v=150, 2H), 3.87 (s, 3H), 4.26 (m, 1~), 4.61 (m, lH), 6.~7.5 (m, 15H).
'3C-NMR (~, CDCI3, TFA): 27.6, 36.6,43.0, 50.5, 53.3, 53.7, 55.6,115.2,115.5, 25 124.7,127.3,127.4,129.4,129.8,130.7,131.0,136.1,137.7,139.1,157.8,160.0,163.2, 169.2, 173.7.
IR (Gm.-', KBr): 1650 broad (C=O).
MS (%): 532 (parent,10), 340 (100), 267 (91), 239 (92), 212 (84).
Anal. calc'd for C30H33N40~F-113H20: C 66.90, H 6.30, N 10.40. Found: C
30 67.09, H 6.08, N 10.27.
From isomer A, M.P. 317-320C, 21% yield.

`~!VO93/15059 C A2l l 73~ PCI`/US92/10720 3 ~17367 lH-NMR (~, CD3SOCD3): 1.20 (s, 9H), 2.16 (m, lH), 2.91 (m, lH), 3.66 (s, 3H), 4.22 (m, lH), 4.47 (ABq, JA,I=16, ~v=t46, 2H), 5.10 (m, lH), 6.~6.8,7.~7.5,7.73, and 8.91 (m, 15H).
IR (cm.-l, KBr): 1650 broad (C=O).
MS (%): 532 (parent, 5), 340 (68), 267 (77), 239 (86), 212 (66), 188 (44), 149 (100), 123 (72).
HRMS calc'd tor C30H34N404F: 533.2556. Found: 533.2518.
Anal. caic'd for C30H33N"O~F-2H2CO3: C 57.14, H 5.54, N 8.33. Found: C
57.47, H 5.25, N 8.89 (+0.56).

N tert-Butvl 2-13 (3-(~tolyl)ureido)-2-oxo-5-(2-fluoroDhenvl)-2.3.4.5-tetrahydro-1 H-(1)benzazePin-1-v11 ethanoic acid amide A. 4(2-FluoroPhenyl)-1.2.3.4-tetrahvdronaphth-1~ne oxime Prepared as in Example 31 above from the known 4-(2-fluorophenyl)-1,2,3,4 t~trahydronaphth-1-one (see Koptyug, V.A. and Andreeva, T.P., Zh. Organich. Khim., 7, 2398-2403 (1971)) in 90% yield, M.P. 118-122C (from ethyl acetate/hexane).
Anal. caic'd for C10H"NOF: C 75.28, H 5.53, N 5.49. Found: C 74.84, H 5.25, N 5.71.
B. 5 (2-FluoroDhenyl~-2.3.4.~tetrahvdro-1 H-(1 ~benzazeDin-2-one Prepared from the title compound of Example 34A as in Example 31 above in 43% yield, M.P. 21~213C (from 2-propanol).
Anai. caic'd for C,oHl"NOF: C 75.28j H 5.53, N 5.49. Found: C 75.30, H 5.53, N 5.41.
The remainder of the synthesis was carried out as described in Example 1:
C., . 3~Bromo-~12-fluoroDhenY1~-,..3.4.~tetrahYdr~ benzazeDin-2-one M.P. 208-214C (from methylen~ chloride/hexane), 48% yield, mixture of diastereomers.
Anai. calc'd for C,oH,3NOFBr: C 57.51, H 3.92, N 4.19. Found: C 57.60, H
3.66, N 4.35.
D. N-t-Butyl 2-l3-brom~2-oxo-~(2-fluorophenyl)-2.3,4 5 -~trahydro~
(1)benza2eoin-1-vl1 ethanoic acid amide C~2~ ~ 7367 WO 93il~05~ ` PCI'/US92/1072~

21~7~Ç7 54 M.P. 85-90C (from isopropyl ether/hexane), 100% yield.
HRMS calc'd hr C22H24BrFN202: 446.0999. Found: 446.10136.
E. N-tert-Butvl 2-r3-azido-2-oxo-~(2-fluoroPhenyl)-2.3.4.~tetrahydro-1 H-11)benzazepin-1-vl1 ethanoic acid amide Mixture of diastereomers, 80% yield.
HRMS calc'd for C22H24NsO2F: 409.1914. Found: 409.19362.
F. N-tert-Butyl 2-~3-a~mino-2-oxo-5-(2-fluoroDhenyl)-2.3.4.5-tetrahvqro-1 H-~1)benz~epin-1-vll ethanoic acid amide From the mixture of diastereomers, one isomer was isolated by crystailkation from ethyl acetate, M.P. 190 195C, in 22% yield.
Anal. calc'd for C22H2~N3O2F: C 68.91, H 6.83~ N 10.95. Found: C: 68.93, H
6.81, N 10.90.
G. N-tert-ButYI 2-r3-(3-(3-tolvl)ureido)-2-oxo-~(2-nuorophenyQ2.3.4.
tetrahydro-1H-(1!benzazepin-1-yl~ ethanoic acid amide One isomer was obtained from ths title compound of ex~nple 34F, M.P. 285-300C, 79% ~eld.
lH-NMR (~, CDCI3,TFA): 1.35 (s, 9H), 2.34 (s, 3H), 2.71 (m,1H), 3.02 (m, 1H), 3.44 (AB", JA~=17, ~v=230, 2H), 4.48 (m, 1H), 4.62 (m, 1H), 6.~7.6 (m, 15H).
13C-NMR (d, CDCI3): 20.5,27.6,37.0,39.5,50.8,53.6,53.7,116.1,116.4,121.4, 123.7,124.0,125.1,126.2,127.9,128.7,129.1,129.2,129.3,129.5,129.8,131.7,136.1, 138.8, 140.7, 169.2, t73.7.
IR (cm. l, KBr): 1650 broad (C=O).
FAB MS (%): 517 (parent+1, 56), 311 (55), 255 (47), 212 (42), tl9 (100).
Anai. calc'd for C30H33N~O3F: C 70.33, H 6.44, N 10.85. Found: C 70.30, H
6.28, N 10.85.

N-tert-ButYl 2-~3-(3-(~chlorophenvl!ureido)-2-oxo-5-~2-fluoropheny!l-2.3.4.5-tetra-hvdro-1H-(1!benzazepin-1-vl~ ethanoic acid amide One isomer was obtained, M.P. 270-283C, 82% yield.
lH-NMR (~, CDCI3, TFA): 1.36 (s, 9H), 2.72 (m, lH), 3.04 (m, 1H), 3.55 (AB~"
JAB=17, ~v=219, 2H), 4.50 (m, lH), 4.64 (m, lH), 6.8-7.6 (m,15H).

JO 93/15059 C A 2 1 1 7 3 6 7 PCI`/US92i10720 -5~

'3C-NMR (~, CDCI3,TFA): 27.6, 37.2, 39.6, 50.7,53.6,53.8,116.2,116.5,121.2, 123.4,123.8,124.0,126.3,126.3,126.8,128.0,129.1,129.2,129.3,129.5,130.6,131.7, 135.5, 136.2, 138.9, 157.4, t69.3, 174.1.
IR (cm.1, KBr): 1650 broad (C=O~.
FAB MS (%): 537 (parent+1, 14~, 311 (17), 238 (16), 195 (17), 165 (55), 110 (1 00).
Anal. calc'd for C29H30N403FCI: C: 64.86, H 5.63, N 10.43. Found: C 64.90, H
5.38, N 10.20.

N-tert-Butvl 2-r~(~(3-methoxvDhenyl)ureido)-2~x~(2-fluorophenvl)-2.3.4.
tetrahvdr~1H-(1~benzazepin-1-vl1 ethanoic acid am~de One isomer was obtained from the title compound of Exarnple 34F, mp 265-280C, 83% yield.
1H-NMR (~, CDCI3, TFA). 1.35 ~s, 9H), 2.74 (m, lH), 3.92 (m, lH~, 3.61 (AB", JAB-16, ~v=229, 2H), 3.87 (s, 3H), 4.52 (m, lH), 4.64 (m, lH), 6.8-7.5 (m, 15H).l3C-NMR (~, CDCI3): 27.6,37.0,39.5,50.7,53.5,53.8,55.6,116.4,1 æ.7,123.7, 124.0,126.~ 7.9,129.1,129.2,129.3,129.5,130.7,131.7,138.8,157.7,169.3,174Ø
IR (cm.1, KBr): 1650 broad (C-O).
MS (%): 533 (parent+1,15), 311 (18), 195 (60), 155 (59), 135 (64), 110 (100), 103 (85).
Anal. calc'd for C30H33N404F-114~120: C 67.09, H 6.29, N 10.43. Found: C
- 67.12, H 6.02, N 10.42.

N-tert-Butvl 2-r3~ ~tolvl~ureidol-2-oxo-~(4chloroDhenYI~-2.3.4.~t~trahydr~
1H-~1)benzazeDin-1-yl1 ~thanoic acid arnide A. 4~4~Chlorophenvl!-1.2.3.4-tetrahvdronaphth-1~ne oxime Prep~ared as in Example 31 above from the known 4-(4chlorophenyl)-1,2,3,~
tetrahydronaphth-1~one (see Koptyug, V.A. and Andreeva, T.P., a~. Organich. Khim., 7, 2398-2403 (1971)) In 79% yield, M.P. 15~154DC (from ethyl acetate/he3~ane).
Anal. calc'd for C,~,Ht4NOCI: C 70.72, H 5.19, N 5.15~ Found: C 70.70, H 5.37, N 5.08.
B. 5-~Chlorophenvl~-2.3.4.5-t~trahydr~1 H-(1)benzazePin-2-one W093/15059 C A ~ 3`~ 7 PCI`/US92/1072~", .. .- .
z~ 56-Prepared from the title compound of Exarnple 37A as in Example 31 above in 31% yield, M.P. 20~212C (from ethyl acetate/hexane).
Anal. caic'd for C10Hl4NOCI: C 70.72, H 5.191 N 5.15. Found: C 71.01, H 5.10, N 5.22.
The remainder of the synthesis was carried out as described in Example 1:
C. 3-Bromo-5-(4-chloroPhenvl~-2.3.4.~tetrahvdro-1 H-(1)benzazer)in-2~ne M.P. 194 198C (from methylene chloride/hexane), 20% yield, mixture of diastereomers.
Anal. caic'd for Cl~H,3NOClBr-H20: C S2.13, H 4.10, N 3.80. Found: C 52.24, H 4.10 (+0.66), N 3.81.
D. N-t-Butvl 2-l~bromo-2-oxo-~t4-chloroPhenvl)-2,3.4.5.-tetrahvdr~1 H-.(1)benzazepiQ-1-vl1ethanoic acid amide .

M.P. 12~130C (from cyclohexane), 75% yield.
Anai. caic'dforC22H2~N202BrCI-2t3H20: C 55.54, H 5.37, N 5.89. Found: C
1S 55.45, H 4.82 (-0.55), N 5.93.
E. N-tert-Butvl 2-r3-azido-2-oxo-~4-chlorophenvl)-2.3~4.5-tetrahydro-1 I l-(1!benzazePin-1-vl1 ethanoic acid amide M.P. 15~168C, mixture of diastereomers, 75~6 yield.
Anal. calc'd for C22H24N5O2CI-l/3H20: C 61.18, H 5.76, N 16.21. Found: C
20 61.03, H 5.59, N 15.8!.
- F. N-tert-Butyl 2 L~amino-2-oxo-~4-chloroPhenyl)-2.3.4.5-tetrahvdro-1H-(1)benzazepin-1-yll ethanoic scid amide The mixture of diasbreomers was separated into an ethyl acetate insoluble,13%
yield, isom~r A and an ethyl acetate soluble foarn, 8296 yield, isomer B.
25 Isomer B: -HRMS caic'd for C22H20N3O2CI: 399.1708. Found: 399.16959.
G. N-tert-Butyl 2-~3-(3- (3 tolyl)ureido~-2 oxo-5-(~chloroohenvi)-2.3.4.
tetrahvdro-1H-(1)benzazeDin-1-vl1 ethanoic acid amide One isorner was obtained trom isomer B above, M.P~ 303-310C, 88% yield.
lH-NMR (~, CDCI3): 1.33 (s, 9H), 2.33 (s, 3H), 2.89 (m,1H), 3.00 (m,1H), 3.35 (AB~" JA~=16, ~v=159, 2H), 4.23 (m, lH), 4.59 (m, 1H), 6.8-7.6 (m, 15H).

C~l~211:736:~
; y,o 93/1~059 PCI`/US92/107~0 -57- ;~67. ~ ~

'3C-NMR (~, CDCI3): 20.5, 27.7, 36.6, 43.1, 50.5, 53.S, 121.4, 124.7, 125.2, 129.1,128.7,129.0,129.4,129.8,129.9,131.0,133.1,137.3,139.0,139.2,140.7,158.1, 169.0, 173.5.
IR (cm.-', KBr): 1650 broad (C=O).
FAB MS (%): 356 (56), 261 (67), 188 (70), 133 (100), 57 (77), 28 (96).
Anal. calc'd for C30H33N~03CI: C 67.60, H 6.24, N 10.51. Found: C 67.68, H
6.19, N 10.41.

N-tert-ButyL 2.-~ ~chloro~henvl!ureido)-2~xo-5-(~chloroPhenxlL2.3.4.5-10 tetra-hydro-1 H-(1 ~benzazepin-1-yl1 ethanQic acid amide One isomerwas obtained from isomer B in Example 37F, M.P. 304 307C,36%
yield.
lH-NMR (~, CDCI3, TFA): 1.32 (s, 9H), 2.87 (m, lH), 3.oe (m, lH), 3.41 (AB~"
JAB=16. AV=1S1. 2H), 4.23 (m, lH), 4.58 (m, 1H), 6.8-7.6 (m, 15H).
'3C-NMR (~, CDCI3, TFA): 27.8, 43.1, 50.4, 53.5, 124.7, 127.2, 128.7, 129.0, 129.4, 129.9, 130.7, remaining carbons not visible in this scan.
IR (cm.-', KBr): 1650 broad (C=O).
FAB MS (%): 356 (48), 261 (43), 188 (44), t53 (100), 125 (45), 90 (52), 57 (63),28 (47).
Anai. calcd ~or C29H30N4O3CI2-1/2H2O: C 61.92, H 5.55, N 9.96. Found: C
61.95, H 5.31, N 9.90.

EXAMPi~ 39 N-tert-Butyl 2-13-(3-~3-methoxyphenyl)ureido)-2-oxo-~(~chloroDheny!)-2 tetrahydro-1H-(1)benzazepin-1-y!Lethanoic acid amide One isomer was obtain~d from isomer B in Example 37FI M.P.303-307C,65%
yi~ld.
1H-NMR (~, CDCI3,TFA): 1.32 (s, 9H), 2.85 (m, 1H), 3.00 (m, lH), 3.35 (AB~, JAB=16, Av=161, 2H), 3.85 (s, 3H), 4.20 (m, 1H), 4.55 (m, lH), 6.8-7.5 (m, 15H).l3C-NMR (~, CDCI3~: 27.7,36.6,41.3,43.1,50.5,53.4,55.6,122.7,124.7,127.1, 128.7,129.0,12 ~,129.9,13~.7,131.0,133~1,137.4,139.0,139.2,169.1,173.9,174.1.

~,~ ?,~ ,, CA 21 1 736 7 Wo g3/1~59 pcl/vss2/lo72r~ -....,... . ~,. .
21~7367 -58-IR (cm.-', KBr): 1650 broad (C=O).
MS (~6): 548 (parent-1,2), 356 (32), 283 (37), 255 (34), 28 (100).
Anal. calcd for C30H33N404CI-l/3H20: C: 64.92, H 6.14, N 10.04. Found: C
65.19, H 5.93, N 9.99.
E)CAMPLE 40 N-tert-B~yl 2-L~(3-(~Q!yl)ureido)-2-oxo-~4-methvlphen~-2.3.4.~tetrahvdro-l H-~l)ben~azepin~ yl1 ethanoic ac d amide A. ~Methylphenyl)-1 .2.3.4-tetrahydronaPhth-1-one oxime Prepared as in Example 31 above 1rom the title compound of Exarnple 40A from the known 4(~methylphenyl)-1,2,3,~tetrahydronaphth-1~ne (see K~ptyug, V.A. and Andreeva, T.P., Zh. Organich. Khim., 7, 239~24û3 (1971)) in 94% yield, M.P. 97-101 C
(from ethyl acetate/hexane).
Anal. calc'd for Cl7H"NO: C 81.24, H 6.82, N 5.57. Found: C B1.03, H 6.63, N 5.57.
B. ~(~Methvlphenvl)-2.3.4.~tetrahvdro-1 H-(1 ~benzazePin-2~ne Prepared from the title compound of Example 40A as in ~xample 31 above in 41% yield, M.P. 178-181 C (frorn ethyl acatate/hexane).
Anal. calc'd for C"H"NO: C 81.24, H 6.82, N 5.57. Found: C 80.80 (~.44), 116.63, N 5.51.
The remainder of the synthesis was carried out as described in Example 1:
C. Bromo-~(4-methylDhenvl~-2.3.4.5-tetrahydro-1 H-(1 !benzazepin-2~one - M.P. 168-176C, 68% yield! mixture of diastereom~rs.
D. N-t-Butyl 2-~3-bromo-2-oxo-~(4methylphenyl)-2.S.4,5.-tetrahydro-1 H-(1?benzaze~in-1-vl1ethanoic acid amide M.P. 12~138C (~rom hexane), 56% yield.
Anai. calc'd for C23H27N202Br: C 62.31, H 6.14, N 6.32. Found: C 62.49, H
6.21, N 6.2~.
E. N-tert-Butyl 2-~3-azido-2-oxo-~4-methylphenvl)-2.3,4,5-tetrahydro-~
(1)benzazepin-1-yll ethanoic acld amide M.P. 5~65C, mixture of diastereomers, 75% yield.
al. caic'd for C23H2,N502-113H20: C 67.13, H 6.7~, N 17.02. Found: C
67.09, H 6.67, N 16.81.

`"O93/15059 .C ~..2 1 1 .73~ PCI/US92/10720 sg 211736~

F. N-tert-Butvl 2-~3-amino-2-oxo-~(4-methvlphenvl)-2l3~tetrahYdro-1H-~1)benzazeDin-1-vl1 ethanoic acid amide The mixture of diastereomers was separ~ted into an ethyl acetate insoluble, mp 292-295C, 5.4% yield, isomer A and an isopropyl ether insoluble, M.P. 150-170C, 5 12% yield, Isomer B.
Isomer A:
HRMS calc'dfor C23H2gN302 379.2253. Found: 379.22664 l~omer B:
HRMS calcldfor C23H2gN302 379.2~53. Found: 379.22455.
~;. N-tert-Butvl 2-13 (~l~toJyl)ureido~-2~xo-~4methv!~henvl~:2.3.4 5-tetrahvdro-l H-~1 ?benzaze~in-l -yll ethanoic acid amide - Prepared from each of the above isomers of E~ample 40F:
From isomer B, M.P. 23~238C, 29% yield. ~ `-'H-NMR (~, CDCI3): 1.27 (s, 9H), 2.21 (s, 3H), 2.80 (m, lH), 3.00 (m, lH), S.21 (ABq, ~JAB=16, ~v=296, 2H), 4.22 (m, lH), 4.58 (m, 1H), 6.07 (bs, 1H), 6.30 tbs, 1H), 6.~7.4 (m, 12H), 7.64 (bs, lH).
l3C-NMR (~, CDCI3): 21.4,28.5,37.1,44.3,50.1,51.6,53.7, t16.6,123.2,123.5, 127.1,127.7,128.6,128.8,128.9,129.0,137.9,138.2,138.7,139.0,141.1,155.4,167.9, 173Ø
IR (cm. ', KBr): 1650 broad (C=O).
FAB MS (%): 513 (par~nt+1, 82), 440 (92)1 234 9100), 208 (96), 119 (85).
HRMS calc'd for C3,H3~,N~03: 512.27514. Found: 512.27474.
From isomer A, M.P. 298-305C, 68% yield.
lH-NMR (o~, CD3SOCD3): 1.22 ts, 9H), 2.03 (m, 1H), 2.21 (s, 3H), 2.31 (s, 3H), 2.82 (m, lH), 4.45 (ABq, JA~=16, ~ =135, 2H), 4.24 (m, lH), 4.99 (m, lH), 6.~7.3 (m, 13H), 7.66 (bs, lH), 8.67 (bs, lH~.
'3C-NMR (~, CD3SOCD3): 21.2,28.5,41.2,49.6,5û.3, 51.1,114.7,118.1, læ.o, 123.0,125.9,126.4,126.5,127.0,127.6,128.4,128.5,129.4,137.6,137.8,139.0,140.1, 140.5, 154.4, 167.0, 171.1.
IR (cm. l, KBr): 1650 broad (C=O).
FAB MS (9~): 513 ~parent+1, 10), 380 (100), 307 (56), 155 (46), 119 (98).
Anal. calc'd for C3,H3~,N4O3 514H2O: C 69.57, H 7.25, N 10.47. Found: C 69.55, H 7.05, N 10.42.

WO 93/15059 C i4 2 1 ~ 7 3 6 7 PCI`~US92/ 1 0721~

6~
2~17367 N-tert-Butyl 2-l3~ 3-chlorophenvl)ureido)-2-oxo-~(4methvlDhenvl)-2.3.4.
tetrahvdro-1 H-(1)benzazepin-1-yll ethanoic acid amide Prepared from each of the abova isomers în txarnple 40F:
From isomer B, M.P. 235-238C, 65% yield.
H-NMR (~, CDCI3): 1.30 (s, 9H), 2.21 (s, 3H), 3.0 (m, 2H), 3.36 (ABq, J~B=16, ~v=291, 2H),4.30 (m,1 H), 4.64 (m,1 H), 6.7-7.5 (m,13H),7.57 (bs,1 H),8.06 (bs,1 H).
'3C-NMR (~, CDCI3) 21.5,28.7,36.8,44.5,50.5,51.9,53.2,116.9,119.0,122.1, 123.4,124.2,126.1,127.1,127.2,127.3,127.8,128.1,128.2,129.0,129.6,130.9,137.9, 138.3, 140.7, 141.1, 141.6, 15B.2, 167.4, 173.3.
IR (cm. l, KBr): 1B50 broad (C=O).
FAB MS (%): 533 (par~nt+1, 35), 460 (67), 262 (37), 234 (100), 208 (85), 105 (36).
Anal. caic'd for C30H33N403CI: C 67.60, H 6.24, N 10.51. Found: C 67.50, H
6.59, N 10.34.
From isomer A, M.P. 25~263C, 68% yield.
1H-NMR ~, CD3SOCD33: 1.21 (s, 9H), 2.03 (m, lH), 2.31 (s, 3H), 2.75 (m, lH), 4.20 (m, lH), 4.44 (ABq, JAE,=16, AV=116)~ 2H), 4.96 (m, lH), 6.~7.3 (h~, 13H), 7.59 (bs, lH), 8.17 (bs, lH).
'3C-NMR (~, CD3SOCD3): 21.2, 28.4, 106.9,115.5, 115.6, 120.7, 122.g, 125.8, 126.4, 127.0, 127.1, 128.3, 129.4, 129.9, 133.3, 137.5, 139.2, 140.3, 140.4, remaining carbons not visible in this scan.
IR (cm.-l, KBr): 1650 broad (C-O).
FAB MS (%): 533 (parent+1, 12), 335 (15), 234 920), 169 (67), 155 ~33), 135 940), 119 ~100), 103 (57~.
HRMS calc'd for C29H30N403FCI: 5S2.2319. Found: 532.2312.
iO(AMPLE 42 N-tert-Butyl 2-~3-(3-(3-methoxvphenyl)ureido)-2-oxo-~(~meth~lphQnyl)-2.3.4~S-tetrahvdro-1 H-(1 !benzazepin-1 -yll ethanoic acld amide Prepared from isomer B from Example 40F, M.P. 233 236C, 60% yield.
'H-NMR (~, CDCI3,TFA): t.27 (s, 9H), 2.20 (s, 3H), 2.85 (m, lH), 3.10 (m, lH), 3.28 (ABq, JA9=16, ~v=294, 2H), 3.68 (s, 3H), 4.24 ~m, 111), 4.65 (m, lH), 6.~7.5 (m, 14H), 7.82 (bs, lH).

.

vo 93/l5nsg ~ A 2 1 1 7 3 6 ;~ PCI`/US92/10720 -61- 21~7367 l3C-NMR (~, CDCI3): 21.5, 28.6, 37.3, 44.4, 50.2, 51.7,53.6, 55.1,104.9,108.8, 111.6,123.3,124.7,126.1,127.1,127.2,127.7,127.8,128.2,128.9,129.0,129.4,130.8, 137.9, 138.3, 140.6, 141.2, 155.2, 160.2, 167.5, 173Ø
IR 'cm.-l, KBr): 1650 broad (C=O~.
FAB MS (%): 529 (parent+1,5Q), 456 (B8), 307 (50), 262 (50), 234 9100), 208 (92). . .
Anal. calc'd ~or C3l H3BN4O4: C 70.43, H 6.86, N 10.60. Found: C 70.23, H 7.22, N 10.36.
i-:XAMPi~ 43 N-te~-Butyl 2-~(~(3-ethvl~hen~ ureido~2~x~(~m~thylphenyl~.3.4.5-tetrahvd-ro-1H-~1)benzazepin-1-vl1 ethanoic acid amide Prepared from isomer B from Example 40F, M.P. 21~214C, 5!;% yield 1H-NMR (~, CDCI3): 114 (t, J--7, 3H), 1.26 (s, 9H), 2.20 (s, 3H), 2.52 (q, J=7, 2H), 2.85 (m, lH), 3.07 (m, lH), 3.31 (A~ql JAB=16, ~v-293, 2H), 4.23 (m, lH), 4.64 (m, lH), 5.90 (bs, lH), 6.54 (bs, 1H), 6.8-7.4 (m, 12H), 7.76 (bs, lH).
l3C-NMR (~, CDCI3): 16.0, 20.9, 21.5, 28.6, 37.2, ~4.4, 50.3, 51.6, 53.6, 117.0,11g.4,122.3,123.3,124.6,126.2,127.2,127.7,128.2,128.7,129.0,130.8,137.9,138.3, 139.2, 141.2, 141.8, 145.2, 155.4, 167.6, 173Ø
IR (cm.-l, ICE~r): 1650 broad (C=O).
FAB MS ~%): 527 (parent+1, 40), 454 (47), 380 (45), 307 (60), 262 (53), 234 (100), 208 (60).
Ana~. calc'd tor C32H3~N403: C 72.98, H 7.27, N 10.64. Found: C 72.97, H 7.74 (+0.47~, N 10.39.
HRMS calc'd for C32H38N403: 526.2877. Found: 526.28695.

N-tert-Butvl 2~ ~(~tolyi)ureido~2-oxo~(3,4~iichlorophenyi)-2.3.4.~tetrahydro-1H-(l)benza2epin-l-yll ethanolc acid amidQ
A. 4-(3.4-Dichlorophenvl~-1.2.3.4-tetrahydronaphth-1-one o~ime Prepareci as in i-xample 31A above from the known 4-(3,4-dichlorophenyl)-30 1,2,3,~tetrahydronaphth-1~ne (se~ Quallich, G.J., ~Illiams, M.T., FrTedmann, R.C. J.
Org. Chem., 55, 49714973 (1991)) in 70% yield, M.P. 159-162C (from methylene chloride/cyclohexane).

WO93/15059 ~ )i 3,~;67 P~r/usg2/lo 2~17367 ~2-Anal. calc'd tor Cl~Hl3NOCI2: C 62.76, H 4.28, N 4.57. Found: C 62.41, H 4.04, N 4.44.
B. ~(3!~Dichlorophenyl~-2,3,4,~tetrahydro-1 H-(l )benzazepin2-one Prepared ~rom the title compound of Example 44A as in Exampîe 31 B above in 89% yield, IJI.P. 191-194C.
Anal. calc'd for C,oH,3NOCI2: C 62.76, H 4.28, N 4.57. Found: C 62.56, H 4.14, N4.59.
The remainder ot the synthesis was carried out as described in Example 1:
C. ~Bromo-5-(3.4dichlorophenvl~2.3.4.~tetrahvdro 1H-(1)benzazeDi~2~ne M.P. 1B3 188C (from ethyl ac~tate/hexane), 73% yield, mixture of diastereomers.
HRMS calc'd for C,~Hl2NOBrCI2: 382.9477. Found: 382.9480.
D. N-t-Butvl 2-!~bromo-2~xo-~(3,4dich!oropbenvl~-2.3.4.5.-tetrahvdro-1 H-(1 )benzazer in-1-vllethanoic acid amide M.P. 8~95, 92% yield.
HRMS c~c'd for C22H23N202BrCI2: 496.0315. Found: 496.03341.
E. N-tert-Butyl 2-r~azido-2~x~(3.Wichlorophenvl)-2,3~4.~tetrahydro-1 H-l1)benzazeDin-1-yll ethanoic a d amide M.P. 7~99C, mixture of diastereomers, 91% yield.
HRMS c~lc'd for C22H23Ns02CI2: 459.1225. Found: 459.12421.
F. N-tert-But~ 2-i3 arnino-2-oxo~(3.~dichlorophenvl~2!3,4.5-t~ahvdro 1 (l)benzazepin-l-yll ethanoic acid amide Prepared by reduction with triphenylphosphine in aqueous tetrahydro~ran ~s a mixture of diastereomers, which was separated into an isopropyl ether insoluble, M.i'.
18~190C, 31% yield, isomer A and a chloroform insoluble, M.P. 14~150C, 1.5%
yield, isomer B.
Isomer A:
Anal. calc'd for C22H25N3O2CI2: C 60.83, H 5.80, N 9.67. Found: C 6C.91, H
5.71, N 9.46.
G. N-tert-B~ ly3-(3-tolyl)ureido)-~-oxo-5-(3.4~ichlo~k~l3 tetrahvdro-1H-(1)benzazer~in-1-vll ethanoic acid amTde Prepared ~rom each of the above isomers from Example 44F:
From isomer B, M;P. 299-301 C, 58% yield.

.~ ., .. . ~ .. - ; i , . ... ,u ~ . . . . . ..

` ~VO 93~15059 C A 2 ~ l 7 3 ~ ~ PCI`/US92/10720 21~7367 ~63~

lH-N M R (~, C D3S O C D3): 1.23 (s,9H),2.21 (s,3H),2.92 (m, l H),3.4 (m,1 H), 3.42 (ABq, JA~=16, ~v= 229,2 H),4.35 (m,1 H),4.El3(m,1 H),6.6-7.6 (m,14 H),8.75 (bs, 13C-N M R (~, C D CI3): 21.2,28.5,42.8,48.7,50.3,51.9,60.3,72.3,114.8,118.2, 122.0,124.4,126.9,127.2,128.4,128.5,128.6,129.1,130.2,130.8,136.6,137.8,14UD.l, 141.7,144.0,154.1,166.8,170.3.
IR (c m.1, KBr): 1650 broad (C = O).
FAB MS (%): 566/568 (parent, Cl35CI37, 4/2), 39ND(25),289/291 (42l40),261 (50), 188 (60), 133 (100), 57 (65).
H R M S cE~c'd for C3~H32N403CI2: 566.1~45. Found: 566.1861.
From isomer A, M.P. 331-334~C, 90% yield.
'H-NMR (~, CD3SOCD3): 1.20 (s, 9H), 2.10 (m, 1H), 2.20 (s, 3H),2.82 (m,2H), 4.12 (m,1 H),4.46 (A Bq, JAB= 16, ~v-1~0,2 H),5.C~4 (m,1 H),6.5-6.7 aund 7.SL7.8 (m, 14 H),8.68 (bs, 1H).
IR (cm.-', KBr): 1650 broad (C=O).
FA B M S (%): 567 (parent,1),309 (6),233 (t7),157 (lCKD),135 (23),119 (58), 103 (28).
Anal. calc'd for C30H32N~O3CI2: G 6~3.49, H 5.6~, N 9.87. Found: C 6~3.82, H
5.60, N 9.60.
E~G~M PLE 45 N-te~-ButvI 2-~3-l3~(3-chIoroDhenyI)ureidol2-oxo-5r~3.4-dichIoroDhenvI)-2.3.-4,~tetrahvdr~1H-(1)benzaze~in-1-YI1 ~thanoic acid amide Prepared from isomer A in Eicample 44F, M.P.329L332 C,86 % ~i~Id.
lH-N M R (~, C D3S O C D3): 1.20 (s,9H),2.08 (m,l H~,2.80 (m,1 H),4.20 (m, l H),26 4.47 (ABq. JA~=16~ ~v=147),2 H),5.10 (m,1 H),6.5-7.8 (m,14 H),8.9#9 (bs, l H).
l3C-N M R (~, C D3S O C D3): 28.9,49.9,60.8,51.4,56.1,6~D.7,72.7, E~;.2,116.4, 117.4,121.3,12S.7,127.18,122.22,128.0,129.6,130.1,130.7,131.18, 131.æ, 133.6, 138.5,140.7,142.1,142.3,154.6,167.5,171.3.
IR (cm. l, KBr): 1650 broad (C=O).
FA B M S (%): 385 (35),233 (18),155 (56),135 (35),119 (100),1CX3 (44).
Anal. calc'd for C29H~gN403CI3 C 59.24, H 4.97, N 9.S3. Found: C 59.S2, H
4.9r2, N 9.23.

WO 93/1 5059 (~ A ~ I l 7 ~ 6 ~ PCrlUS92/ 1 0720~

~7367 ~:

N-tert-Buty 2-~(~(~metho~phenyl)ureido)-2~xo-~(3 4dichlorophenvl!-2.3.4.
tetrahydro-lH-(l)benzazepin-l-yq ~thanoic acid amide Prepared from isomer A in Example 44F, M.P. 32~327C, 92% yield.
'H-NMR (~, CD3SOCD3): 1.20 (s, 9H), 2.08 (m, 1H), 2.83 (m, lH), 3.67 (s, 3H), 4.22 (m, lH),4.47 (ABq, JA~=16~ ~V=149, 2H),5.14 (m, lH), 6.47.7 (m,14H), 8.77 (bs, lH).
'3C-NMR (~, CD3SOCD3): 28.9, 49.8, 50.8, 51.4, 55.3, 60.7, 72.7,103.7,107.~, 110.3,123.6,123.7,127.1,127.2,128.0,129.6,129.9,130.0,131,1,131.2,131.7,138.6, 140.8, 141.8, 142.4, 154.7, 160.1, 167.5, 171.4.
IR (un.-t, KBr): 1650 broad (C:=O).
MS (%): 583 (parent,1), 456 921), 293 925), 279 (27), 233 939),157 ~100),156 (94), 154 (53), 135 (60), 119 (100), 103 (90).
Anal. calc'd for C30H32N~O~CI2: C 61.75, H 5.53, N 9.60. Found: C 61.81, H
5.35, N 9.37.

N-tert-Butvl 2-~(~(3-tolyl)ureido1-2~xo-~phenyl-8-methvl-2.3.4.5-tetrahvdro-1 H-(1)benzazeDin-l-vll ethanoic acid amide A. 8-Methyl-1-naPhthol Prepued from the known (J. Chem. Soc., C, (1966) 523) ~hydrox~nnethyl-1-naphthol by hydrogenolysis using 0.1 equiv. of 20% palladium hydroxide on carbon(Pearlmann's catalyst) in ethanol at 45 psi hydrogen for 4 hours in quanfflaUve yield, M.P. 5~59C.
B. 4-Phenvl-7-methvl-1.2.3.4-tQtrahvdrona~hth-l-one~ henvl-~methv!-1.2.3.~tetrahydronaphth-1 ~ne Prepared from ~methy~1-naphthol using the procedure described above in Example 31 from Koptyug, V.A. and Andreeva, T~P., Zh. Organich. Khim.,7,239~2403(1971) The products were separated by chromatography on silica gel using hexane/eU~yl acetate as eluant and crystallized separately from methanol. X-ray 30 analysis of single crystals of both compounds, grown in methanol, established the structures of the tNo isomers.
7-Methyl isomer, M.P. 72-74C.

-~093/1~059 CA21 17367 PCl`/US92/10720 :
. .
-6~ 211'736'7 1 H-NMR (~, CDCI3): 2.2-2.8 (m, 4H), 2.36 (s, 3H), 4.25 (m, 1 H), 6.~7.4 ani (m, 8H).
73C-NMR (~, CDC.3): 21 .0, 32.0, 36.8, 45.0, 1 26.7,1 26.9,1 27.2, 1 28.4,1 28.6, 129.5,1 32.6,1 34.6,143.5, 143.9, 1 98.4.
IR (cm.-1, KBr): 1681 (C=O).
MS (%): 236 (puent, 100),194 (70),165 (50~.
Anal. calc'dforCl7HlOO: C86.40, ~f ~.82. Found: C 86.39, H 6.76.
~Methyl tsomer, M.P. 60 63C.
lH-NMR (~, CDCI3): 2.2-2.7 (m, 4H~, 2.68 (s, 3H), 4.28 (m, 1 H), 6.~7.~ (m, 8H).l3~NMR (~, CDCI3): 23.4, 31.2, 38.1, 46.1~ 126.6, 126.8, 127.8, I28.6, 131.0, ~31.6, 132.4, 141.2, 144.1, 147.3, 200Ø
IR (cm.-l, KBr): 1680 (C=O).
MS (%): 236 (parent, 100), 208 (85`~, 165 (50).
Anal. caic'd fo~ Cl,Hl"O: C 86.40, ~i 6.82. Found: C 86.77, H 6.66.
Preparation of 5~Dhenvl-~methvl-2.3.4.~tetrahydro-lH-(1)benzazePin-2~ne:

C. 4phenvl-7-methyl-1 .2.3.4-tetrahvdronaphth-1-one oxime Prepared trom 4phenyl-7-methyl-1,2,3,~tetrat ydroaphth-1-one.
M.P. 143-146C, yield 72%.
Anai. calc'dtorCl7Hl,NO: C 81.24, H 6.82, N 5.57. Found: C81.11, H7.02, N 5.51.
D. ~Phenvl~methvl-2.3.4,~tetrahvdro-1 H-(1 )benzazepin-2-one M.P. 230-234C, yield 28.5%.
Anal. calc'd for Cl7Ht7NO: C 81.24, H 6.82, N 5.57. Found: C 81.25, H 6.89, 26 N 5.54.
The remainder of the synthesis was carned out as described in Example 1:
E. ~Bromo-5-Dhenvl~methvl-2.3.4.5~tetrahvdr~1 H-~1 )benz~ze~in-2~ne M.P. 228-232C, 46% yield.
Anal. calc'd for Cl7H,~NOBr-1/4H2O: C 61.00, H 4.97, N 4.18. Found: C 61.07, H 5.01, N 4.38.
F. N-t-Butvl 2-~bromo-2~xo-~Phenvl-8-methvl-2.3.4.5.-tetrahydro~
(1)benzaze~in-1-vllethanoic aciJ amide M.P. 227-230 i% yield.

WO 93/15059 C J~ 2 3 1 7 ~ PCI'~US92tlO72Q

2~
HRMS calc'd for C23H27N202Br: 442.1249. Found: 442.12321.
G. N-tert-Bu~l 2-~azido-2-oxo-~ph~ methyl-2,3.4 ~tetrahvdro-1 H-(1)_zaze~-vll ethanoic acid amide M.P. 112-115C, 56% yield as a single diasteromer.
Anai. calc'dtor C23H27NsO2: C 68.13, H 6.71, N 17.27. Found: C 68.40, H 6.82, N 17.12.
H. N-tert-Butvl 2-~amino-2~xo-5-phenvl-~methvl-2.3.4.~tetrahvdro-1H-~1)benzazeoin-1-yll ethanoic acid amide:
Prepared as a single diastersomer corresponding to isomer B of Example 44F.
M.P. i7~180C, 75% yield.
HRMS calc'dfor C23H29N3O2: 379.2253. Found: 379.2267.
1. N-tert-Butyl 2-r3-(3-(3-tolvl~ureido)-2-oxo-~phenYI-8-methyl-2.3~4.
tetrahydro-l H-(1)benzazepin-1-yll ethanoic acid arnide M.P. 232-238C, 72% yield.
'H-NMR (~, CDCI3): 1.26 (s, 9H), 2.21 (s, 3H), 2.30 (s, 3H~, 2.64 (m,1H), 2.92 (m, 1H), 3.12 (ABq, JAB=16, ~v=283, 2H), 4.15 (m, 1H), 4.50 (m, 1H), 6.10 (bs, 1H), 6.2-7.2 (m,14H).
'3C-NMR (~, CDCI3): 21.0, .1.4, 28.5,36.8, 43.8,49.9, 51.5, 53.6,116.3,120.0, 123.4,125.2,126.2,126.3,128.2,128.3,128.6,130.5,135.1,138.6,139.0,140.8,141.9, 155.4, 168.0, 173Ø
IR (cm. ', KBr): 1640 broad (C=O).
FAB MS (%): 512 (parent, 77), 440 (100), 307 (72), 208 (68).
Anal.calc'dforC3,H3"N403: C72.63,H7.08,N10.93. Found: C72.29,H6.85, N 10.78.

N-tert-Butvl 2~3-(3-(3-chlorophenyl)ureido)-2-oxo-~phenyl~methyl-2.3.4.5-tetrahydro-1 H-~.1)benzazepin-1 yll 0thanoic acid amide Prepared from Exarnple 47H, M.P. 155-165C, 68% yield.
'H-NMR (~, CDCI3): 1.29 (s, 9H), 2.33 (s, 3H), 2.~3.0 (m, 2H), 3.32 (AB", JAea16, ~=285, 2H),4.20 (m,1H),4.56 (m, lH), 6.~7.3 (m,13H), 7.56 (bs,1H), 8.00 (bs, 1H).

YVO 93/15059 C A 2 1 1 7 3 6 7 PCI`/US92/10720 -67- 21i7~

l3C-NMR (~, CDCI3): 21.1, 28.7, 36.8,44.0, 50.5, 51.9, 53.1, 60.4,116.9,118.9, 122.0,124.8,126.3,126.4,126.5,128.3,128.4,129.5,130.7,134.2,135.0,139.1,140.7, 140.8, 142.0, 155.2, 167.4, 173.4.
IR ~cm.-', KBr): 1640 broad (C=O).
FAB MS (%): ~33/535 (parent+1, Cl35/CI3',69/26~,460 (100),307 (52),234 (60), 208 (70).
Anal. calc'd for C30H33N"O3CI: C 67.60, H 6.24, N 10.51. Found: C 67.27, H
6.06, N 10.23.
E)(AMPLE 49 Phenvl-~methvl-2.3.4.5-tetrahydro-1 H-(1)benzazeDin-2-one Prepared as in i-xample 31 from ~phenyl-8-methyl-t,2,3,4tetrahydronaphth-1-one.
A. 4PhenYl~methYI-1.2.3.~tetrahydronaphth-1-oneoxime M.P. 1~136C, 73% yield.
Anai. caic'd for C,7H,~NO: C 81.24, H 6.82, N 5.57 Found: C 81.19, H 6.61, N 5.51.
B. 5-Dhenvl-~methyl-2.3.4.5-tetrahvdro-1 H-(1)benz~zepin-2-one M.P. 15~157C, 81% yield.
Anai. calc'd tor Cl,H,7NO: C 81.24, H 6.82, N 5.57. Found: C 81.09, H 6.52, N 5.45.
The remainder of the synthesis was carried out as describad in txample 1.
C. ~Bromo-~phenYI-~methYI-2.3.4.5-tetrahydro-1 H-(1 ~benzaze~pin-2-one As a mixture of diastereomers, one of which had M.P. 240 243C, 44% yield.
Anai. caic'd tor C,7H,~,NOBr: C 61.83, H 4.38, N 4.24. Found: C 61.79, H 4.57, N 4.09.
The remaining materiai, 26% yield, was obtainec as a mixture of diastereomers, and was co~nbined with the above diastereomer in the next step.
D N-t-ButYI 2 l3-bromo-2-oxo-~henvl-~methvl-2.3.4.5.-tetrahydro-1i~
(1)benzazepin-1-\lllethanoic acid amide The diastereomers were separated by chromatography on silica gel using hexana/cthyl acetate as eluant, then aystailized from methylene chloride/hexane:Isomer A, M.P. 199-202C, 15% yield WO 93/150~9 C A 2 1 1 7 3 6 7 PCr/US92/1072Q .
z~173~ r~ . ~t: -68-Anal. calc'd for C23H27N202Br: C 62.311 H 6.14, N 6.32. Found: C 62.60, H
5.87, N6.12.
Isomer B, M.P. 227-230C, 63% yield.
Anal- calc'd ~or C23H27N2O2Br: C 62.31, H 6.14, N 6.32. Found: C 62.83 5 (+0.52), H 6.48, N 6.22.
E. N-tert-But~-r3-azido-2-oxo-~phenyl-~m~thyl-2.3.4.~tetrahydro-1 H-(1 ~-benzazepin-1-vl1 cthanoic acid amide Obtained as a mixture of diastereomers, which were separated by chromatography on silica gel using hsxane/ethyl ac~tate as eluant.
Isomer A, oil, 18% yield.
HRMS calc'd for C23H2,NS02: 405.2159. Found: 405.21724.
Isomer B, M.P. 16~164C, 76% yield.
Anal. calc'd for C23H2,N502: C 68.13, H 6.71, N 17.27. Found: C 68.09, H 6.71, N 17.08.
F. N-tert-Butyl 2-~amin~2~xo-~henyl-~methyl-2.3.4!5-tetrahvdr~l H-(l benzazeDin-1-yl1 ~thanoic acid amide Each isomer from Exarnple 49E was hydrog~nated separately.
Isomer A, oll.
HRMS calc'dfor C23H27NsO2 380.2331. Found: 380.23462.
20 Isomer B, oil, 13% yield.
HRMS calc'dfor C23H2,N5O2: 380.233t. Found: 380.23276.
G. N-tert-Butvl 2-~3-(3-~3-tolvl)ureido)-2-oxo-5-phenyl-9-methyl-2.3.4.
tetrahydro-1H-(1)benza2eDin-1-yl1 eth~u~oic acid amid~
Prepared from isomer A above, M.P. 221-223C, 84% yield.
'H-NMR (~, CDCI3): 1.21 (s, 9H), 2.24 (s, 3H), 2.28 (s, 3H), 2.74 (AB~, JAE~--16, ~v=135,2H),2.82 (m, lH),2.95 (m, lH),4.14 (m,1H), 4.51 (m, lH),6.54 (bs, lH), 6.8 7.3 (m, 13H), 7J8 (bs, lH).
13C-NMR (~, CDCI3): 18.8, 21.5, 28.5, 35.8, 44.6, 50.0, 51.2, 53.5, 55.2, 116.9,120.6,123.7,126.3,126.7,128.4,128.7,128.8,131.6,135.8,138.8,139.1,139.3,139.9, 30 141.3, 155.4, 168.0, 174.7.
IR (cm.-l, KBr): 1640 broad (C=O).
FAB MS (%): 513 (parent~1, 27), 440 (100~, 251 (37), 234 (65), 208 (50).

VO 93/1~059 C 1~ 2 1 1 7 3 6 7 PCI`/US92/10720 -69- 21173~7 Anal. Calc'd for C3,H3~,N403: C 72.63, H 7.08, N 10.93. Found: t:: 72.89, H
7.02, N 10.90.

N-tert-Butvl 2-~(3-(3-methox~phenvl)ureido)-2-oxo-~phenyl-~methyl 2.3 4 5-5 tetrahvdro-1H-(1)benzazepin-1-yl1 ethanoic acid amide Prepared from isomer A in Example 49F, M.P. 162-167C, 81% yield.
1H-NMR (~, CDCI3): 1.20 (s, 9H~,2.27 (s,3H),2.72 (ABq, JA~=16, ~v=141,2H), 2.75 (m, lH), 2.92 (m, lH), 3.71 (s, 3H), 4.20 (m,1H), 4.48 tm, lH), 6.~7.8 (m, 15H~.
13C-NMR (~, CDCI3): 18.8,28.5, 36.0, 44.5, 50.0,51.2,53.4, 55.2,105.3,109.2, lQ 112.0,126.3,126.7,128.4,128.5,128.7,129.7,131.6,135.8,139.3,139.8,140.3,141.2, 155.2, 160.3, 168.1, 174.6.
IR (cm. l, KBr): 1640 broad (C=O).
FAB MS (%): 529 (parent+1, 35), 456 (100), 307 (44), 234 (62), 208 t54).
Anal. calc'd tor C3lH3~,N~04-3/4H20: C 68.68, H 6.97, N 10.33. Found: C
68.74, H 6.89, N 10.09.
AMPLE 5t N-tert-Butvl 2-~(~chloroohenvl)urQido)-2~xo-~chenvl-~methyl-2,3.4.
tetrahvdro-1H-(1)benzazepin-1-vll ethanoic acid amide:
Prepared from isomer A in Example 4gF, M.P. 26~262C, 77% yield.
lH-NMR (~, CDCI3): 1.20 (s, 9H), 2.30 (s, 3H), 2.80 (AB~" JA8=16, ~va98, 2H), 2.~3.0 (m, 2H), 4.26 (m, lH), 4.48 (m, lH), 6.17 (bs, 111), 6.~7.3 (m, 12H), 7.56 (bs, 1 H), 7.96 (m, 1H).
l3C-NMR (~, CDCI3): 18.9,28.5,35.6,44.7,50.2,51.5,54.4,117.1,119.2,122.4, 126.4,126.7,128.4,128.5,128.8,129.7,131.7,134.4,135.6,139.3,139.8,140.6,141.3, 155.1, 167.4, 174.7.
IR (cm. l, KBr): 1640 broad (C=0).
FAB MS (9~): 5331535 (parent, Cl3s/CI37,23/8),460 (100),408 (68),234 (85),208 (75).
Anal. calc'd for C31H30N403CI: C 67.60, H 6.24, N 10.~1. Found: C 67.59, H
6.25, N 10.1B.

N-tert-Butvl 2-~3-(3-(3-ethvlph~nyl~ureido~-2-oxo-~Phenyl~methyl~2~3.4 tetrahvdro-1 H-(1 ~benzazePin-1-yl1 ethanoic acid amide ~! ~d2 1 1 7367 1, ~70_ Z~

Preparsd from lson~er A in Ex~npl~ 4~F. M.P. 222-2~4C, 8~% yield.
~H-NhlR ~, CDCI,): 1.J7 ~t, Jl--7, 3H), 1.20 (s, 9H), 2.28 ts, 3H), 2.65 ~q, J_7, 2H), ~.7~ (ABq, J,~B=16, ~v=138, 2Hj, 2.76 (m, lH), 2.~ n, lH), 4.20 (m, lH), 4.60 (m, 1H), 6.60 (bs, lH), ~.~7.3 lm, 1+H).
'3C-tJM~ ~, C~a3~: 15~6, 181~, 28.5, 28.g, 36.~, 44.S, 50.0, B1.2, 56.4,117.4, 119.8,1æ.8~ t26.3, 126.7,128.4, 128.~, 128.7, 128.9, 1S1.6, 13~.8,1~8.8,139.3,139.9, 141.2,146.4,156.3, lS8.1, 174.6 cm. ~, K8r): 1640 broad (C~cO~.
FAE~ MS (%): 627 ~ nt~t, ~371. 454 ItoO), 347 ~ ), 234 ~54), 208 (47).
An~l. calc'd for C3~H3"N~0~: C p2.98, H 7.27, N 11).64. Found C 72.77, H 7.24, N 10.27.
E~ lPLE ~3 N Methyl.N-tert-butyl2~3-(3-~3~lto1yl)ureido)-2-oiYo~henyll-2.34.5-~etrahydr~
1H ~i~ben~2epin-1-yQ e~oic aa~ i ~mid~
Propared fronn N~thyl, ~ l-tert~uq~l 2-[~amln~2~xo~(ph~nyl)^2,3,4,6~
tetrahydro-1H-(1)bellza~ep1n-1-yl] ~th ~noic a~d amide ~s h Exampl~ 1, M.P. 140-1 50~C, 83% yleld.
'H-NMR (~, CDCI3): 1.30 (S, 9~), 2,1g ~8, 3H), 2.31 (~, 3~1), 2.88 (m, 111), 3.t8 ~m, 1 H), 3.~2 (A~q, J~"=16; ~v=297, ~H3, 4.~a ~m~ lH), 4.68 (rn, lH), 6.6~7.4 (m, 14~), 7.72 ~bs, lH).
'3C~NI~IIR (~, CDCI~); 21.5, 28.~, 30.5, ~8,1, 44.~, 49.8, 63.0, S7.4, 1 t6.9, 120.7, 123.0, 124.9,125.0,1~6.6,127.5, ~2~.~,128.3,128.~, 128.7,130.4,13~.3,138.g, 139.6, 141.4,142.7,154.9, 168.9, 172.3.
1~ tcm- '. KBr); 16~0 broad (Cl_0).
FA~ MS ~%): 513 (parent~ 0), 426 ~ , 29~ ~42), 2~û (46),194 ~60).
Anal. c~Jc'd for C3,1 l~ot~l~0 ,: C ~,2.63, H 7.08, N 10.93. Found~ 72.~3, H 7.16, N 10.84.
E~lPLE 54 N-Methyl ~tert~12-~ ~hlo~Q~h~ny~ Qldo~xo-5-~.4h~nyl~2~ 4~6 t~trah\~q~Q~lH~ zepin~ yl1 et~oic aç~sLarnld~
Prepared trom N-rnethyl, Nltert-butyl 2 ~3-arn;no~2-oxo~ enyl) ~,3,4,~
tetrahydro 1H-~1)benzazepin-t-yl] ethar~olc acid ~mlde as In Ex~npl~ 1, M.P. 1SS^
162C, 97% yield.

, o-~S~

C ~ 2 1 ~ 7 3 6 7 2117367 ~ H-~IMR ~o~, CDCI9): 1.32 ~8, 9hl), 2.50 (~, 3H), 2.84 (m, 1H), 3.02 (m, lH), 3.40 ~B~" J~ =288), 2H),4.26 (nn, 1H), ~4.62 (m, 111), t3.~7.~m, '1411), 7.~6 (bs, l H)- I
'J~NMR (~, CDCI3~: 2~.2, ~0.7,~38.0,44.6,49.6, 53.1, ~7.5,117.4,118.~,121.5, 6 124.7, t26.2, 12~.6, 127.5, 128.2,128.8;1~9.3,130.5,13~.8, 138.7,141.1,141.3,1~.~, 1~.6, 167.0, 172.8.
Ifl ~cm. ', I~E~r)~ 0 bro~d (C~0).
~AB ~IS t%): 633 tparent+1, 1~), 446 (80), 2~3 (S4), ~37 ~52), 220 (98), 1~?4 ~100). , tO ~nal. calc'd for C30H3aN40;~CI: C! 67.60, H ~24, ~110.51. ~ound: C 67.7~, It 8.2~, N 1~).40.

N ben~yl. N-tsrt-buty~ (3-f~tolyl)ureido~2~xo-5-hVdrO-1~ t1)b~n~ ~~ hl ~mig~
PrePar~d frOm N-b~nZY~, N-t~ ~rtb4~YI 2-~ nO ~2~0XO~PhenYI~2~4~6-tetrahYdlrO-1H ~1)benZa~ePjn~ q ethan ~jC ~ld atn;dO aS ;~ Example 1, M.P. 22 230C, 63;5~6 Yleld. I
' H-NMR ~, CDCI3~ H),I2,1~ ~5, 3H), ;~ m, ~ H), 3. 1 0 ~m, 1 H), 3. 18 " JA~I=16, ~VC2~3, 2H), 4.0~.3 ~ , 4.75 ~m, l~t), 6.~7.6 ~m. l~H), ~.7~ (b~, 20 tll).
'3C-NM~ (0~, C~C13): 2i.S, 28.6, 3~.9, 44.4, 47.7, 49.5, ~9.2, ~.3, 1~6.8, t20.4, 1Z.9, t2~.5, 12~.9,126.0,126.S, t27.0, 1~7.t, 127.6..127.9, l2a.0, 12~.3, 128.7, 128.8, 128.9, t~0.2, 138.2,139.2,13g.4, 141.5~42.3,165~0, t68.3, 172.~.
IR (cnn, ', K8r~: 1650 broad ~C=Q).
~5 F~B MS ~%): ~8g ~arent~t, 10)~ 426 (54~, 29~ (41). 220 (40~, 91 ~100).
Anal. ca o'd for C ~7H~oN.~OI C 76,~18, H 6.85, N 8.52. Found: C 7&.09, 11 6.88,N9.~).
0C~PI ~66 N-~nzy, N~ butYI ik.~9 t~.t3~ torq~her~yl)~rQdo) ~XQ~er~YI~-2.
30 tetra~ycfr~1H L1)4~n~1 vI1 ~anQi ~ açld ~mW~?
Prepared from ~ben~yl, N te butyt 2~ amino-2~xo^5~(ph~nyI)-2,3,4,~
~etrahy~ro-111-~t)benza~epin-1 yl~ ~th~noi-I~ ~dd ~rnide a~ In Ex~nple 1, M.P. 2 243C, 68% yiold.

t~;~ S~

'~NO93/15059 ~ 2 1 l 7367 PCI/US92/10720 1 2~7367~

1H-NMR (~, CDCI3): 1.32 (s, 9H), 2.98 (m, 2H), 3.22 (ABq, JA~=16~ ~-,r=204), 2H),4.27 ~ABq, ~IAB=17, ~v=61), 2H),4.31 (m, lH), 5.2fi (m,1H), ~.8-7.6 (m,14H),7.79 (bs, 1 H).
'3C-NMR t~, CDCI3): 28.6,37.7,44.4,47.7,49.4,53.5,58.5,117.1,121.5,125.5, 125.7,126~1,126.2,126.3,127.0,127.6,127.7,127.9,128.7,128.8,128.9,129.2,130.2, 133.8, 138.1, 139.2, 140.9, 141.4, 142.2, 154.8, 168.1, 173.5.
IR (cm.-l, KBr): 1650 broad (C=O).
FAB MS ~%): 609 (parent+1,8),446 (56~,293 (37), æo (57),194 (44),91 (100).
Anai. caicld for C30H37N~O3CI: C 70.98, H 6.12, N 9.20. Found: C 70.68, H
6.30, N 8.95.

N-Benzvl. tert-butyl 2-~3-(3-~3-methoxvphenyl)ureido)-2 ox~(~henvl)-2.3.4.
tetrahydr~1 H~ benzazeDin-1-vl1 ethanoic acid amide Prepared from N-benzyi, N-tert-butyl 2-l3-amin~oxo~(phenyi~2,3,4,5-tetrahydro-1H-(1)benzazepin-1-yl] ethanoic acid amide as in Example 1, M.P. 2 2 226C, 62% yield.
'H-NMR (~, CDCI3): 1.33 (s,9H),2.90 (m,1H), 3.09 (m, lH), 3.17 (AB~" J~"=16, ~v=236, 2H), 3.65 (s, 3H), 4.1-4.3 (m, 3H), 4.77 (m, lH), 6.47.4 (m, 14H), 7.55 (bs, lH).
l3C-NMR ~, CDCI3): 28.5,37.9, 44.4,47.7, 49.4,53.3,55.1, 58.3,104.2,109.0, 111.6,125.5,125.8,126.2,126.9,127.0,127.6,127.7,127.9,128.0, t28.6128.8,129.1, - 130.2, 138.3, 139.2, 140.8, 141.4, 142.3, 154.8, 159.9, 168.2, 172.8.
IR ~cm. ', KBr): 1650 broad (C=0).
MS (%): 605 (parent+1, 10, 442 (72), 293 ~55), 220 (59), 194 (56), 91 (100).
Anai. caic'd for C37H"oN"O"-1.5H2O: C 70.34, H 6.86, N 8.87. Found: C 70.40, H 6.48, N 8.65.

N-tert-Amvl 2-~3-(3-~3-tolYl)ureido)-2-oxo-5-(phenvl~-2.3.4.5-tetrahydro~1 H-(1)benzazepin-1-yl1 Qthanol¢ acid amide Pr~pareci from N-tert-amyi 2-[3~mino-2-oxo-~(phenyi)-2,3,4,5-tetrahydro-1 (1)benzazepin-1-yl] ethanoic acid arnide ~s in Example 1, M.P.22~229C, 7096 yield.

~O93/15059 CA21 17367 PCI/US92/10720 -73~

IH-NMR (~, CDCI3): 0.73 (t, J=7, 3H), 1.21 (s, 9H), 1.63 (q, J=7, 2H), 2.23 (s, 3H), 2.88 (m, 1H), 3.04 (m, lH), 3.26 (AB~I, J~"=16, av=282, 2H), 4.11 (m, lH), 4.60 (m, 1H), 5.80 (bs,1H), 6.5-7.4 (m, 13H), 7.70 (bs, 1H).
- '3C-NMR (~, CDCI3): 8.3, 21.4, 26.2, 32.8, 37.1, 44.4, 50.2, 53.6, 54.4; 116.7, 120.4,120.5,123.5,124.8,126.3,126.5,127.7,128.3,128.6,129.0,130.8,1~8.3,138.7, 139.1, 141.2, 141.8, 155.4, 167.5, 173Ø
IR (cm.1, KBr): 1650 broad (C=O).
FAB MS (%): 513 (parent+1, 65), 426 (50), 119 (100), 103 (48).
Anal. calc'd for C3,H3~,N~O3: C 72.63, H 7.08, N 10.93. Found: C 72.57, H 6.78, N 10.67.

N-tert-Amvl 2-i3-~3-~3~hloroDhenyl)ureido)-2-oxo-5-fDhenvl)-2.3.4.5-tetrahvdro-lH-(l)benzazeDin-l-vll ~thanoic acid amide Prepared from N-tert-arnyl 2-l3-amino-2-oxo~(phenyl)-2,3,4,5-1etrahydro-1H-(1)benzazepin-1-yi] othanoic acid amide as in Exarnple 1, M.P. 2l9-~22oc~ 73% yield.
'H-NMR (~, CDCI3): 0.74 (t, J=7, 3H),1.23 (s, 9H), 1.64 (q, J=7, 2H), 2.94 (m, lH), 3.01 (m, lH), 3.32 (AB~" JA"=1fi, ~v=274, 2H), 4.15 (m, 1H), 4.59 (m, 1H), 5.73 (bs, 1H), 6.5-7.4 (m, 12H), 7.S7 (bs, ~H), 7.97 (bs, 1H).
'3C-NMR (~, CDCI3): 8.4, 26.2, 32.9, 36.9, 44.5, 50.4, 53.2, 54.7, 117.0, 118.9,119.0,122.1,124.3,124.4,126.3,126.4,126.6,127.8,128.3,129.1,129.5,130.9,134.3, 138.2, 140.7, 141.1, 141.8, 155.1, 167.2, 173.2.
1R (crn. ', i(Br): 1650 broad (C=O).
FAB MS (%): 533/535 (parent+1, Cl35/CI3~ 34/13), 446 p5), 293 (~0), 220 (86), 194 (100).
Anai. calc'd for C30H33N"03CI: C 67.60, H 6.24, N 10.26. Found: C 67.25, H
6.06, N 10.27.
E)tAMPLL ~0 Trans-1-(t Butvlacetamido)~(3-tolvlureido)-5.7-dlDhenvlhexahvdroaze~Din-2-one A. 2.4-Diphenvicyclohexanone Prepared in anaiogy with a method in Hussey, A.S. and Herr, R.R., J. Org.
Chem.,24,843, (1959). To a 500 mL round-bottomed flask equipped with N2 inlet were added 37 g (0.212 mol) of 4phenylcyclohexanone and 80 mL carbon tetrachloride. To the stirring solution was added dropwise over 30 minutes a soluUon of 20.5 mL (0.255 WO 93/150S9 , '( A ~ 3 :6 ~ PCI'/US92/1072f''"

z~.~7367 -74-mol) sulfuryl chloride in 10 mL carbon tetrachloride. The reaction was stirred 14 hours at room temperature and poured into saturated aqueous sodium bicarbonate solution.
The organic layer was separated, washed again with saturated aqueous sodium bicarbonate solution, dried over sodium sulfate, and evaporated to a yellow oil, 34.8 9 5 (78%) which was used direetly in the next step.
lH-NMR (~, CDCI3): (mixture of diastereomers) 1.9-3.6 (series of multiplets, 7H), 4.7 and 5.3 (multiplets, 1H), 7~2-7.4 (m, 5H).
IR (em. 1, KBr): 1735 (C=O).
MS (%): 208/210 (parent, Cl35/CI3', 36/12), 145 (49), 117 (88), 115 (83), 104 10 (100),101 (88), 91 (82), 55 (67).
The oil was dissolved h 400 mL benzene and added dropwise over 40 minutes to 83 mL (250 mmol) of 8 3.0 M solution of phenylmagnesium bromide in ether, cooling so the temperature did not rise above 10C. The reaetion was then allowed to warm and heated to reflux for 14 hours. It was then eooled, quenched with aqueous 15 ammonium ehloride solution, then washed with water and brine, dried over sodium sulfate, and evaporated. The yield was 53.9 9 (approximately theoretical), and the crude oil was used direetly in the next step.
lH-NMR (~, CDCla): (mtxture of diastereomers~ 1.9 3.3 (series of multiplets, 7H), 3.9 (m, lH), 7.1-7.6 (m, lOH).
B. 2.4Diphenyicyelohexanone oxime The above oil was dissolved in 200 mL methanol, and asolution ot 18.6 9 (0.267 mol) hydroxylamine hydroehloride and 37.2 mL`(0.267 mol) triethylamine in 100 mLmethanol added. The solution was deeanted off the oily precipitate which separated and stirred at room temperature for 1.5 hours. The white precipitate was filtered and dried to-give 13.6 g (31%) of a white solid, mp 214215C.
C. 5.7 diDhanylhexahvdroazepln-2-one To a 250 mL round-bottomed tlask equipped with N2 inlet were added 8.52 9 (32.15 mmol) 2,Wiphenyleyelohexanone oxime and 110 mL pyridine. Once the solid had dissolved, the solution was cooled to 0C, and 12.3 9 (64.3 mmol) p-30 toluenesulfonyl chloride was added. The reaction was allowed to stirhr 16 hours while the iee bath melted and the reaetion warmed to room temperature. it was then poured into 300 mL 3N HCI, extraeted into ethyl acetate, and the organie layer washed with additionai HCI and brine, dried over sodium suHate, and evaporated. The residue was JO 93/15059 C A 2 1 1 ~ 3 6 7 PCr/US92/10720 21~73~
-7.~ '~ t t;' chrom~togr~phed on s~lica gel using meth~nol/methylene chloride as eluant to afford 2.4 ~ (28%) ot an oil which w~s ayst~lked from isopropanol to give mp t71-173.5C.
'H-NMR (~, CDCIJ): 2.0 (m, lH), 2.1 (m, 3H), 2.75 ~m, 2H), 2.95 (m, 1H), 4.60 (~n, 1H), 5.78 (bs, NH, lH), 7.1-7.5 (m, 10H).
"C NMR (~, CDCI,): 30.3, 36.3, 45.3, 48.6, 58.1, 126.3, 126.6, 128.4, 128.7, : .
129.2, 142.1, 146.1, 176.5.
IR (cm. ', KBr): 1662 (C~0).
MS (%): 265 (parent, 82), 266 (85), 160 (47), 106 (100), 104 (87).
An~l. o~lc'd br C",H,9N0: C 81.48, H 7.21, N 5.27. Found C 81 .æ, H 7.41, N
5.28.
D. 3-~romo-5.7-diDhonvlhox~hvdroazeDin.-2-ono To a 250 mL round-bottomed ~lask oquipped with ~ddition funnel and N2 inlet wo added 1.51 9 (727 mmol) phosphorus penhchloride and 25 mL dry methybne ohhride. Tho mbdure was cooled with stirring ~o 0C, and a solu~on ot 1.93 9 (727 16 mmol) 5,7 diphenylhe3tahydroazepin-2 one and 1.18 mL (14.5 mmol) pyridine in 50 mL
m thybne ohloride w~s added dropwise over 20 mhutes. The r~cffon was ~rred 5 mlnutes at 0C, then Q82 mL (16.0 mmol) bromine In 5 mL methylene c!hloride was added dropwise over 5 mhutes. Th- reacUon was stirr d 5 mhutes at 0C, then 1.8 hours at room temper~ture. The reaction was evaporated, taken up in 40 mL ot 1 ~20 t~hydro1uran:water, and stirred for 1 2 hours. The reaction was then pour d into wder and ex~cted into ethyl ~cetate. The organic byer w~ woshed ~dth aqu~ous sodium bisuffite solution and brine, dried over sodium sulhb, and vaporated to an oil.
`~ The dl was taken up in 20 mL methylene chlorlde and 20 mL ethanol, and hydrogended under 42 psi hydrogen in the presence of 0.30 9 109~ pailadium-on-25 carbon and 3 drops of quinoline tor 1 hour. Tlc showed mostiy desired monobromo product at R, = 0.4, with a litUe dibromo precursor at Rl = 0.7 and sbrting hcbrn at R, = 0.15, in 1~1~thyl acetate/hexane. The reaction was fllt~d through Cellt wlth ethanol cnd methylene chloride, evaporated, ~nd chromatographed on dlica gel using 2/1-hexane/ethyl acetate as eluant to afford 2.06 g (82%) of a foam M.P. 70-78C.
`H-NMR (~, CDCI3): (mixture of dlastereomers) 1.9-2.7 (m, 4H), 3.12 and 3.52 - (multipbts, 1H), 4.52 and 4.76 (multiplets, lH), 5.01 (m, lH), 5.79 and 5.89 (broad dnglets, lH, ~, 7.1-7.4 (m, 10H).

WOg~/15059 ~A~117~ PCl`/US92/1072~;
V

Z1~7367 7~
13C-NMR (~, CDCI3): 42.4, 44.0, 48.0, 50.5, 57.6, 126.3, t26.6, 126.9, 127.1, 128.7, 128.9, 129.3, 129.4, 169.6.
IR (cm. ', KBr): 1667 (C=OJ.
- MS (%): 343/345 (11/10, parent for Br7~'~'), 236 (32), 117 (32), 106 (100), 91 (39), 55 (31)-Anal. calc'd for Ct8Hl8NOBr: C 62.80, H 5.27, N 4.07. Found: C 62.86, H 5.26, - N3.98.
E. 1-(t-Butvlacetamido?~bromo-5.7~iPhenvlhexahvdroazepin-2-one To a 100mL3-necked round-bottomed~ask equipped wHh additiontunnel and 10 N2 inlst were ~dded o.æ g (6.59 mmol) sodium hydride, which was then washed with hexane, and 4 mLdry tetrahydrofuran. To the stirring suspension was added a solution of 2.06 g (5.99 mmol) ~bromo-5,7-diphenylhexahydroazepin-2-one and 1.59 9 (6.59 mmol) t-butyi iodoacetamide. The reaction was stirred d room bmperatura for 60 hours, quenched with ammonium chloride solution, then poureci into water, extracted 15 tunee into ethyl aeetate, washed witn brine, dried over sodium suHab, and evaporated.
The residue was chromatographed on silica gel using 2/1-hexane/ethyi aeehte as elu~nt to nfford 1.585 9 (58%) of an oil, iR, = 0.4 (1/1-hexane ethyi a~etate).
'H-NMR (~, CDCI3): (mixture of diastereomers) 1.22 and 1.25 (singlets,9H, ratio 35165),2.0-2.7 (m,4H),3.08 and 3.21 (muitiplets,1 H),3.~3.9 (m,2H),5.01 and 5.45.7 20 (m, 2H), 7.1-7.4 (m, 10H).
'3C-NMR (~, CDCI3): 14.2, 26.9,2B.7,40.6, 43.9, 51.1, 60.3,61.7,126.8,127.0, 128.2, 128.4, 128.7, 128.9, 139.5, 144.6, 167.5, 170Ø
IR (cm. I, KBr): 1675 and 1632 (C=0).
MS (%): 377 (parent-Br, 39), 304 (42), 219 (21), 144 (25), 118 (31), 117 (33), 25 115 (42),104 (21), 91 (100), 57 (50), 55 (34).
F. 1-lt-Bubriaeetamido)~azido-5.7-diphenv!hexahYdroazepin-2-one To * 100 mL round-bottomed flask equipped with N2 inlet were added 1.58 9 (3.46mmol)1-(t-butylaeetamido)~bromo-5,7-diphenylhexahydroazepin-2 one,SmLdry dimethyiformarnide, and 0.27 g (4.15 mmol) sodium azide. The reaetion was heated30 at 80C for 3.5 days, eooled, poured into water, snd extraeteci into ethyi acetate. The organie layer was washed with water and brine, dried over sodium sulfate, ancl evaporated. The residue was chromatographed on silica gel using 40% ethyl acetate ','093/15059 CA21 17367 PCI'/US92/10720 77 2lfqa67 in hexane as eluant to afford 1.09 g (75%) of an oil, which was found to be an 8/3 mixture of diastareomers, R,=0.~0.5 in 1/1-ethyl acetate/h~xane.
'H-NMR (~, CDCl3): 1.21 and 1.~1 (singlets, 9H), 2.17 and 2.58 (multiplets, 4H),3.05 and 3.32 (multiplets, 1H), 3.57 (AB~" J~B = 16, ~v=213 for one Isomer of the 2 5 proton signal CH7CONHt-butyl), 4.~5.0 (multiplets, 2H), 5.68 and 6.17 (singlets, lH, NO, 7.~7.3 (m, 10H).
IR (cm.-l, KBr): 2105 (N3), 1647 ~CsO).
MS (%): 377 (parent-N3, <1), 31g (parent-(CONHt-butyl), 4~, 235 (21), 146 (43), 115 (47), 104 p3), 103 (40), 91 (100), 84 (32~, 57 (46).
G. 1-It-Butvlac~tarnldo)~amino-5.7~ henYlhexahvdro~zepin-2-one A soluUon of 1.09 g (2.60 mmol) 1-~t-butylacetamido~azido-5,7-diphenylhexahydroazepin-2-one in 30 mL ethanoi and 15 mL methylene ehloride was hydrogenated at 42 psi in the presence of 0.40 g 10% palladium~r~carbon for 36 hours. The reaction showed R,=0.30/0.15 iodoplatinate positive, in 30% m~thanol in 15 ethyl acetate. lt was filtered through Celite with ethanol and m~thylene chloride, evaporated, anJ chromatographed on silica gel using ~0% methanol in ethyl acetate as eluart to afford S00 mg t29%) of the less polar diastereomer as an oil and 420 mg (41%) of the more polar diastereomer as an oil.
L~ss Dolar diastereomer:
tH-NMR (~, CDCI3): 1.25 (singlet, 9H), 2.18, 2.~0 ~md 3.23 (munipl~ts~ 7H), 4.52and 4.90 (multiplets, 2H), 6.5 (broad singlet, lH, NO, 7.~7.4 (m, 10H).
'3C-NMR (~, CDCI3): 28.8, 37.7, 40.5, 51.3, 51.7, 52.7, 60.3, 64, 125.6, 126.5, 126.8, 127.8, 128.7, 129.1, 140.7, 145.4, 167.9, 171.
IR (cm.-', KBr): 1655 (C=O).
More Polar diastereomer:
lH-NMR (~, CDCl3): 1.20 (singlet, 9H), 1.~2.5 (multiplets, 4H), 3.10 (m, lH), 3.56 (AB~" JAB = 16, ~v=213, 2H), 4.12 (d, J=16, lH), 4.99 (d, J=10, lH), 5.68 (broad singlet, lH, NO, 7.1-7.4 (m, 10H).
'3G-NMR (~, CDCl3): 28.6, 39.4, 41.8,46.6,48.3, 50.8,53.2,60.7,126.7,126.8, 128.5, 128.6, 128.8, 129.5, 138.4, 145.5, 168.0, 177.4.
IR (cm.-1, KBr): 1645 and 1670 (shoulder) (C=O).
MS (%): 3~3 (parent, 1.4), 265 (17), 193 (24), 132 (100), 91 (27).

WO 93/15059 C A ~ I i 7 3 6 7 P~/US92/10721~ ` `
li~67 -78-H. tran~1-(t-Butylacetamido)~(3-tolylureido)-5.7-diphenylhexahvdroazeDin-2-one To a 35 mL round-bottomed nask equipped with N2 inlet were added 150 mg (0.~2 mmol) 1-(t-butyiacetamido)~amino-5,7-diphenylhexahydroazQpin-2-one (less polar diastereomer), 4 mL 1,2-dichloroethane, and 49 mL (0.~? mmol) 3-5 tolylisocyanate. The reaction was stirred at room bmperature for 2.7 hours, dUuted with 10 volumes of diisopropyl ether, stirred 30 mTnutes, ffitered, washed with diisopropyl ether, and dried to a whtte solid, M.P. 245-246C, 109 mg (54%).
lH-NMR (~, CDC13) 1.26 (singlet,9H),1.7-2.6 (muniplets,5H),2.23 (s,3H),3.64 (m, 1H), 3.80 (AB~" J~"=16, ~v=399, 2H), 4.14 and 4.64.8 (muitiplets, 2H), 6.57 (d, 10 J=9, 1H), 6.70 (d, Jz7, 1H), 7.0-7.6 (m, 10H), 8.33 (broad singlet, 1H).
IR (cm. l, K~r): 1673 and 1640 (C=0).
MS (%): 526 (parent, c1), 235 (73), 234 (82), 193 (36), 132 (100), 57 (æ), 43 (46), 41 (æ).
An~l. caic'd for C32H3~N"0,-1.75 H20: C 68.86, H 7.49, N 10.04. Found: C
15 68.90, H 7.25, N 9.B6.

trans-1 -(t-Butylacetamido~-3-(3-methoxyDhenylureido)-5.7-~: diphenylhexahydroaze,Din-2 one Prepared trom the le~s polar amine diastereomer in Example 60G in 49% yield, 20 mp 242-244C.
-NMR (~5, CDC13) 1.26 (singlet, 9H), 1.7-2.6 (multiplets, SH), 3.64 (m, 1H), 3.69 (s, 3H), 3.81 (AB", J~B = 16, ~v=401, 2H), 4.14 and 4.6-4.8 (multiplek, 2H), 6.6-6.9 (multiplets, 2H), 7.0-7.6 (m, 10H), 8.34 (broad dnglet, lH).
IR (cm:', KBr): 1673 and 1640 (C=0).
MS (%): 542 (parent, 0.9), 348 (16),305 (68),235 (58),234 (65),149 (100),1æ
(89), 123 (33), 91 (39), 57 (39), 44 (47).
Anal. calc'd hr C,;,H,"N~0,~-1.S H~0: C 67.47, H 7.2S, N 9.83. Found: C 67.52, H 7.17, N 9.60.

cis-1-(t-Bulylacetamido)~(3-tolylureido)-S.7-diphenvlhexahydroazepin-2-one Prepared from the more polar amine diastercomer in Example 60G in 68% yield, M.P. 2S3-253.5C.

~ `~WOg3/~ 9 C~ 2 1 1 7367 PCr/USg2/10720 -7~ a.~6q 1H-NMR (~, CDCI3): 1.15 (singl~t,9H),1.9~2.7 (multiplets,4H),2.22 (s,3H),3.27 (m, lH), 3.50 (AB~" ~J~8 = 16, ~v=224, 2H), 5.09 (dd, J=1,5, 1H), 5.29 (d, J=10, lH), 6.69 (d, ~I=7, lH), 6.83 (d, J=6, lH), 7.~7.6 (m,11H).
IR (cm.-', KBr): 1660 (broad, C=O).
MS (%): 526 (parent, 0.8), æo (æ), 319 (38),235 (44),234 (44),133 (100),1æ
(91), 57 (41), 44 (36), 41 (38), 39 (33).
Anal. calc'd tor C32H3~,N"03: C 72.98, H 7.27, N 10.64. Found: C 72.94, H 7.31, N 10.45.

1~t-But~llaoetamido)~3_~thoxvphenvlureido1-5.7-diDhenYlhexahvdroazeDln-2-Prepared from the more polar amine diastereomer in Example 60G in 43% yield, mp 166-173C.
'H-NMR (~, CDCI3): 1.15 (singlet, 9H), 1.9-2.7 (multiplets, 4H), 3.25 (m, lH), 3.52 (AB~" J~,l = 16, ~v=225, 2H), 3.69 (s, 3H), 5.09 (m, lH), 5.29 (d, Jz10, lH), 6.45 (d, J=8, lH), 6.84 (broad s, lH), 7.0-7.6 (m, 11H).
. IR (cm:', KBr): 1645 (broad, C=O). ~-MS (%): 542 (parent, <1), 265 (15), 235 (37), 234 (340), 193 (18), 149 (100), ~`
123 915), 91 (41), 78 (18), 57 (16).
Anal. cal~dforC32H3BN~0": C 70.83, H 7.06, N lO.æ. Found: C 70.66, H 6.80, - 20 N10.æ.

Butviacetamido)~(3-chloro~henyhlreido) 5.7 diphenvlhexahydroazepin-2 Prepared from the more polar amine diastereomer in E~ample 60G h 36% yield, M.P. 78-185C.
'H-NMR (ô, CDCI3): 1.15 (slnglet, 9H), 1.9-2.7 (multiplets, 4H), 3.27 (m, 1H), 3.51 (AB", JA~ = 16, ~v=226,2H), 5.09 (dd, J=1,5, lH), 5.29 (d, J=10, lH),6.9 7.6 (m, 12H), 7.68~(s, 1H).
IR (cm. ', KBr): 1665 and 1642 (and shoulder at 1682) (C=O).
MS (%): 646/648 (parent, CPUs7, c1), 265 (14), 193 (21), 1631165 (100/34, C13~/37), 115 (21), 91 (28), 90 (25), 68 (29).
Anal. caWd for C3,H35N~03CI: C 68.06, H 6.45, N 10.24. Found: C 67.73 H
6.13, N 10.07.
HRMS calc'd for C31H35N~03CI35: 546.23895. Found: 546.23581.

WO gJ/15051 ~ C ~ Pcr/~lss2/1o72 ~`~3~ 8~
E)(AMPLE 65 l-(t-Bulylacetamido)~3-ethvlphenylureido)-5,7-diphenylhexahydroazepin-2-one Prepared trom the more polar amine diastereomer of Example 60G in 46% yield, M.P. 233-234C.
S tH-NMR (~, CD3SOCD3): 1.14 (t, J=7, 3H),1.1S (single1, 9H), 1.8-2.1 (m, 3H), 2A9 (m,2H),2.5-2.7 (m,1H), 3.23 (m,1H), 3.51 (AB~" JA, ~ 16, ~v=æS,2H),5.07 (m, 1H), 5.28 (d, J=10, lH), 6.72 (d, J=8, 1H), 6.82 (d, J~5, 1H), 7.0-7.6 (m, 14H), 8.94 (bs, 1H).
l3C-NMR (~, CD3SOCD3): 15.6, æ.8, 28.6, 45.0, 47.0, 49.9, 51.5, 59.4, 120.6, 10 126.8, 128.5, 129.4, 139.2, 140.5, 144.2, 146.3, 154.1, 167.3, 173.3.
.
IR (cm. l, KBr): 1660 (brG~d, C=O).
MS (%): 540 (parent, 2), æ35 (21), 147 (32), 132 (100), 121 (48), 91 (31).
Anal. calc'd for C33H~oN~03-1/2H20: C 72.10, H 7.52, N 10.19. Found: C
72.15, H 7.16, N 9.74 (~.45).

1 -(t-Butylacetamido~-3-(3-trifluoromethylphenvlureido)-5.7-~phenylhexahvdroaze~in-2-one Prepared from the more polar amine diastereomer ot Example 60G in 36% yield, M.P. 263-264C.
'H-NMR (~, CD3SOCD3): 1.15 (singlet, 9H),1.8-2.1 (m, 3H), 2.58 (m,1H), 3.23 - (m, 1H), 3.51 (ABq, JA~I = 16, Av=æ7, 2H~, 5.10 (dd, J=1,5, 1H), 5.30 (d, J=10, lH), 6.95 (d, J=5, 1H), 7.02 (s, 1H), 7.1-7.5 (m, 13H), 8.00 (bs, lH), 9.41 (bs, lH)., '3C-NMP~ (~, CD3SOCD3): 28.5,44.9,47.0,50.0,51.6,59.4,126.3,126.8,128.1, 128.4, 128.5, 129.4, 129.8, 139.2, 141.3, 146.2, 154.0, 167.2, 173.1.
IR (cm. l, KBr): 1660 (bro~d, C=O).
MS (%): 580 (parent, 5), 262 (50), 193 (62), 187 (65), 132 9100), 91 (87), 57 (99) - Anal. calc'd tor C32H35N~03F3-1/2H20: C 65.18, H 6.15, N 9.50. Fou~d: C
62.25, H 5.93, N 9.18.

Butylacetamido)~(3 m~thylthiophenvlureido)-5.7JiphenylhexahydroazeDin-2-one a~l~367,, Prepared from the more poIar amine diastereomer of Example 60G of 49% yield, M.P. 17~176C.
lH-NMR (~, CD3SOCD3): 1.15 (singlet, 9H),1.9-2.1 (m, 3H), 2.41 (s, 3H), 2.62 (m,1H), 3.27 (m, lH), 3.52 (AB", ~=16, av=226, 2H), 5.11 (dd, J=l,~, lH), 5.30 (d, 5 J=10, lH), 6.77 (d, J=5, 1H), 6.85 (d, J=5, 1H), 7.0-7.6 (m, 14H), 9.06 (bs, lH).
13C: NMR (~, CD3SOCD3): 14.6, 28.5,44.9, 47.0,49.9, 51.5, 59.4,114.0,114.4, 118.5,126.3,126.8,126.9,128.5,128.6,129.2,129.4,138.5,139.2,141.1,146.2,154.0, 167.3, 173.2.
IR (cm. l, KBr): 1660 (broad, C=O).
FAB MS (%): 559 (parent+l, 10), 394 (12), 233 913), 193 914), 155 (97), 135 924), 119 (100), 103 (38).
Anal. calc'd for C32H38N~03S: C 68.79, H 6.85, N 10.03. Found: C 68.91, H
6.948, N 9.96.

1-(t-ButyIacetamido~-3-(3-carboxamidoDhenvIureido)-5.7-diphenylhexahvdroazeDin-2-one Prepared from the more poIar amine diastereomer of Example 60G in 18% yield, M.P. 155-165C.
lH-NMR (~, CDCI3): 1.145 (singIet, 9H), 2.00 (m, 1H), 2.2-2.5 (m, 3H), 3.æ (m~
20 lH), 3.66 (AB~" J~" = 16, av=73, 2H),5.25 (bs,2H), 5.28 (m, lH), 5.76 (m, lH),7.1-7.4 (m, 13H), 7.67 (d, J=7, lH), 7.80 (s, lH), 8.18 (bs, lH), 9.09 (bs, lH).
l3C-NMR (~, CDCI,): 28.6, 38.0,39.2, 45.7,47.91 51.4, 56.7, 61.0,112.7,118A, 126.6,126.8,127.0,128.1,128.2,128.3,128.5, t28.6,128.7,128.8,129.0,129.4,129.5, 129.6, 129.7, 137.8, 139.3, 145.0, 167.0,174.8, 179.9.
IR (cm. l, KBr): 1660 (broad, C=O).
FAB MS (%): 555 (parent, 62), 481 (15),424 (23),193 (56),155 (23),119 (100), 103 (38).
An~l. calc'd for C,2H37N~0~-113H20: C 68.43, H 6.76, N 12.47. Feund: C
68.47, H 6.47, N 12.44.

.l-ft-Butylacet~rn.do)~4-tolylureido)-5.7-diPhenvlhexahvdroazeDir~2-one Prepared from the more polar amine diastereomer in Ex~mple 60G in 25% yield, M.P. 156-165C.

-~YO 93/15059 C A 2 ~ 6 Y PCI`/US92/10720 . ~

-~2- 2~ 7:

lH-NMR (~, CD3SOCD3): 1.15 (singlet, 9H), 1.9-2.1 (m, 3H), 2.20 (s, 3H), 2.61 (m, 1H), 3.27 (m, lH), 3.51 (AB~ AB = 16, av=225~ 2H), 5.08 (m, lH), 5.29 (d, J=10, lH), 6.78 (d, J=5, lH), 7.0 and 7.2-7.4 (m, 15H), 8.87 (bs, lH).
13C-NMR (~, CD3SOCD3): 20.3, 28.5, 45.0, 47.0, 49.9, 51.5, 59.4,117.6,126.3, 5 126.8,128.5,128.7,129.1,129.2,129.3,129.4,129.5,129.7,138.0,139.3,14fi.3,154.2, 167.3, 173.4.
IR (cm. ', KBr): 1660 (broad, C=Q).
FAB MS (%): 527 ~parent+1, 30), 454 (6), 313 (12), 235 910), 157 t100)-Anal. calcd tor C32H3~N403~2/3H20: C 71.35, H 7.36, N 10.40. Found: C10 71.20, H 7.26, N 10.23.
i3CAMPLE 70 Resolution of 1-(N-t-butvlacetamido)-3-(3-tolvlureido)-5.7-di~henvl-hexahvdroazeDin-2~ne ' Carried out in analogy with a procedure developed by Bock, M.G., et al., J. Ora.15 Chem., 52, 3232~239 (1987) using L-phenylalanine as the resolving agent:
A. 1-(N-t-Butylacetamido~-3-(2-1t-butoxvcarbonylamino)-3-Phenvl~ropionamldo)-5~7-diphenylhexahvdroazepin-2-one To a 100 mL round-bo~tomed flask equipped with N2 inl~t were added 650 mg (1.65 mmol) of the more polar isomer of1-(t-butylacetamido)~arnino-5,7-20 diphenylhexahydroazepin-2 -one, 439 mg (1.65 mmol) t-BOC-L-phenyla-ianine, 253 mg (1.65 mmol) N-hydroxybenzotriazole, 13 mL dry methylene chloride, 317 mg (1.65 mmol) ethyl(dimethylarninopropyl)carbodiimide, and 0.415 mL (2.98 mmol) triethylamine. The reaction was stirred at room temperature for 14 hr, poured into wa~ar, and extracted inio ethyl ao~tab. The organi¢ layer was washed with 1N Ht~25 water, saturated aqueous sodium bicarbonate solution, and brine, dried over sodium suffate, and evaporated. TLC showed one spot of Rt=0.30 in 1/1~thyl acetate/hexane for the product, which was a foam, 950 mg (90%), oDs 5.77 (c=0.8, CH2CI2).
lH-NMR (~, CDCI3): 1.20 (singlet, 9H), 1.28 (s, 9H), 1.g~2.2 (m, 3H), 2.43 and 2.57 (multlpl~ts tor the two diastereomers,1 H),2.~3.0 (m,3H),3.53 and 3.54 (two AB"
30 pattems for Qach diastereomer, JAE~ = 15 and 15,1~v=198 and 195,2H),4.18 and 4.æ
(multipl~ts for the two diastereomers, lH), 5.~5.2 (m, 2H), 5.48 and 5.66 (broad- singlets for each diastereomer,1 H), 7.~7.4 (m, 17H).

;WO93/15059 CA2~ ~ 7~6~ PCI/U~;92/107~1).

2117367 ; -83-l3C-NMR (~, CDCI3): (pairs of peaks were observed because ot the two diastereorners) 28.2 and 28.6, 38.6 and 39.0, 45.8 and 45.9, 48.0 and 48.2, 50.9 and 51.0, 51.4 and 51.5, 55.2 and 55.8, 60:S, 61.1 and 61.2, 126.7, 126.8, 126.9, 128.6, 128.8, 128.9, 129.3, 129.5, 129.6, ~29.7, 129.8, 130.0, 138.0, 138.2, 145.0, 145.2, 167.3 5 and 167.4, 170.2 and 170.5, 171.0 and 171.05, 173.0 and 173.1.
IR (cm.-1, I<Br): 1723, 1667, and 1635 (C=0).
MS ~%): 640 (parent, 0.35), 452 (27), 376 (32~, 264 (26), 193 (46), 120 (100), 91 (92).
B. 1~t-ButylacetamidoL~(2-amino~phenylproDionamido)-5 7~ipheny!-10 hexahydroazeDin-2-one To a 126 mL round-bottomed flask equipped with N2 inlet were added 960 mg (1.49 mmol) 1-(N-t-butylacetamido)-3-(2-(t-butoxycarbonyiamino)-3-phcnylpropionamido)-5,7~iphenyl-hexahydroa~epin-2-one (mixture ot diastereomers)and 40 mL ethyl acetate. The solution was cooled to 0C, saturated wiU~ HCI gas, and 15 stirred at 0C for 20 minutes, then at room tempèrature for 40 minutes. Th~ reaction was poured into aqueous sodium bicarbonate solution, diluted with ethyl acetate, and the organic layer washed with additional aqueous sodium bicarbonate solution andbrine, dried over sodium sulfate, and evaporateci. The diastereomeric products were separated by chromatography on silica gel using ethyl acetate/methanol as eluant to 20 afford each diastereomer as an oil.
L~ss polar diastereomer (R,=0.4 in 10% methanol in ethyl acetate): OD='28.2 (c=1.5, CH2CI2), 50% yield.
'H-NMR (~, CDCI3): 1.24 (singlet, 9H),1.8-2.6 (series of rr~.ltiplets,4H), 3.1 (m, 3H), 3.58 (ABq, JAB = 16, ~v=202, 2H), 3.59 (m, 1 H), 4.18 and 4.32 ~multiplets for the 25 two diaster~omers, lH), 5.12 (d, J=10, lH), 5.17 (m, lH), 5.49 (bs, lH), 7.~7.4 (m, 15H), 8.49 (d, .I=7, 1H).
13C-NMR (~, CC)CI3): 28.7, 39.2, 41.1, 46.0, 48.1, 51.0, 66.5, 60.3, 61.2, 126.7, 126.8,127.0,128.4,128.6,128.9,129.0,129.3,129.5,137.8,138.1,145.2,167.5,173.5.
IR (cm. ', KBr): 1665 ~nd 1635 (C=O).
MS (%): 540 (parant, 3), 449 (32), 376 (41), 264 (35), 193 ~38), 120 (100), 91 , (43)- ' More oolar diastereomer (R,=0.2 in 10% meU~anol in ~thyl acetate): aD=~2.2 (c=1.5, CH2CI2), 50% yield.

C~ 2 i 1 7367 ,~0 93/1~059 PCI`/US92/10720 `
2~736:7.
-84 `

1H-NMR ~, CDCI3): 1.23 (singlet, 9H),1.~2.6 (series of mu~iplets,4H),3.1 (m, 3H), 3.55 (m,1H), 3.58 (ABq. JAB = 16, ~v=220, 2H~, 4.~8 and 4.32 (multiplets for the two diastereomers, 1H), 5.10 (d, J=10, lH), 6.17 (m, 1H), 5.49 (bs, lH), 7.0-7.4 (m, 15H), 8.30 (d, J=7, lH).
l3C-NMR (o', CDCI3): 28.7, 39.2, 41.2, 46.0, 48.1, 51.0, 56.9, 60.3, 61.2, 126.7, 126.8,127.0,128.4,128.6,128.9,129.0,129.3,129.5,138.1,138.2,145.1,167.5,173.5 IR (cm.-l, KBr): 1655 and 1635 (C=O).
MS (%): 540 (parent, 2), 449 (37), 376 ~53), 264 (35), 193 (35), 120 (100), 91 (42).
C. I-)-1-(N-t-bu~ylacetamido)~amino-5.7-diPhenvlhexahvdroazeDin-2-one To a 100 mL round-bottomed nask equipped with N2 inlet and condensor were added 0.40 g (0.745 mmol) 1-(N-t-butylacetamido)-3-(2-amino~phenyipropionamido)-5,7- diphenyl-hexahydroazepin-2-one (more polar isomer from above), 8 mL 1,2-dichloroethane, and 0.093 mL (0.782 mmol) phenylisothiocyanate. The raaction was15 r fluxed for 1 hr, cooled, and evaporated. The residue was taken up in 10 mL
trifluoroacetic acid and heated at 70-80C for 2 hr. The re~ction was cooled, ~nd the product precipitated as a salt with ether and hexane. The precipitate was co71ected, dissolved in ethyl acetate, washed with aqueous sodium bicarbonate sclution and brine, dried over sodium sulfate, and evaporated. The oil solidified from chloroform to 20 give mp 204-205C, 0.30 9 (100%), aD=-3.72 (c=0.5, TFA). 1H-NMR and '3C-NMR
spectra match those of the racemate.
D. (+~1~(N-t-butvlacetamido)-~amino-5.7-d!phenyl-hexahydroazepin-2-one Prepared as above from 1-(N-t-butylacetamido)-3-(2 amino-3 phenylpropionamido)-5,7- diphenylhexahydroazepin-2-one (less polar isomer) as an oil 25 in 92% yield, OD=~3.21 (c=0.8, ~thyl scetate). The 1H NMR spectrum matches that of the racemate.
E. . (-)-1 (N-t-butylacetamido)~l3-tol~lurQido)-5~7di~henylhexahvdroazepin-2-one To a 35 mL round-bottomed fiask equipped with N2 inlet and condenser were 30 added 293 mg (0.745 mmol) (-)-1-(N-t-butylacetamido)-3-amino-5,7-diphenylhexahydroazepin-2-one, 10 mL ethyl acetate, and 0.096 mL (0.745 mmol) m-tolylisocyanate. The reaction was refiuxed for 2.5 hr, cooled, and evaporated. Th~
residue was chromatographed on silica gel using hexane/ethyl acetate as eluant to ~O 93/15059 (~ A 2 1 1 7 3 6 7 PCI'/US92/10720 -85~

afford an oil which was crystallized ~rom methylene chloriderlsopropyl eth~r to a give mp 14~150~C, 71 mg (18%), aD=-18.6 (c-1, CH2CI2). The R, value on TLC and 'H-NMR spectrum match those of the racemate.
Anal. calc'd hr C32H38N4O3-l/2H2O: C 71.75, H 7.34, N 10.46. Found: C
5 71.66, H 6.75 (~.59), N 10.29.
~ . .(+~ N-t-butvlacetamido~(~tolvlureido)-5~7-diphenyl~ex~hvdroazepln 2-one Prepared as above from (+)-1-(N-t-butylacetamido)~arnin~5,7~iphenyl-hexahydroazepin-2~ne ~s an oil in 30% yield, which was aysbJlized from methylenechloride/isopropy~ ether to a give mp 14~150C, in 15% yield, OD= 1-18.2 (C=1, 10 CH2CI2). Ths R, vaîue on TLC and 1H-NMR and l3C-NMR spectra match those of the racemate.
An~. c~cd for C32H38N~O3-1/2H2O: C 71.75, H 7.34j N 10.46. Found: C
71.65, H 6.89 (~.45), N 10.49.

1 5 (1-t-ButoxvcarbonvlmethYI!-~(~tolvlureido~-7-~yclohexvlhexahydroazeDin-2-one Prepar~d from ~1~t-butoxycarbonylmethyl)-3-amino-7-cycloh~xyl-hexahydroazepin-2~ne as in Example 11 in 31% yield, M.P. 10~110C.
tH-NMR (~, CDCI3): 0.8~1.0 (m,2H),1.1-1.3 (m, 4H),1.37 (S,9H),1.~1.9 (m, 10H), 2.08 ~m, 1H), 2.25 (s, 3H),3.42 (t, J=7,1H),3-88 (ABq, JA~=17~ ~V=180,2H),5.01 (m, 1H), 6.65 and 7.1-7.4 ~m, 6H (includes broad singlets for 2 NH signals)).
'3C-NMR (~, CDCI3): 21.5,25.7, 25.9, 26.0, 26.2,27.2, 28.0, 30.1, 31.7,32.2, 39.4,45.6,51.5,63.4,81.8,123.6,128.7,138.7,139.1,155.2,168.4.
IR (cm. l, KBr): 1730 (C2R) and 1640 (CONR).
MS (%): 457 (2, parent), 295 ~23),185 (23),107 (100).
HRMS c~c'd~or C20H40N3O4: 458.2984. Found: 458.3057.

(1-t-Butoxvcarbonylmethvl)-3-((3-trifluoromQthvlphenvl~ureido)-7-cvclohexylhexahydroazepin-2-onQ
Prepared from (1-t-butoxycarbonylmethyl)-3-amino-7-cyclohexyl-hexahydro ~epin-2~ne as in Example 11 in 36% yield, M.P. 114117C.
lH-NMR (~, CDCI3): 0.~1.0 (m, 2H), 1.1-1.3 (m, 4H), 1.34 (s, 9H), 1.~1.9 (m, 10H), 2.0 (m, 111), 3.48 (~, J=7, lH), 3.90 ~AB", JA,~=17, ~v=160, 2H), 5.04 (m, lH), 6.
8.0 (series of multiplets, 6H).

WO 93/1~059 '.t~ 2 1 ll 7 3 6 7 PC~/US92/1072 Z11~73~: - -8~

13C-NMR (~, CDCI3): 25.7, 25.8,26.0,26.1, 27.1, 27.9, 30.1,31.56,31.63, 39.5, 45.7,51.3,63.5, 82.0,129.1,140.2,154.8,168.3,175.9 (not all aromatic carbons could be assigned).
IR (cm. l, KBr): 1730 (CO2R) and 1638 (CONR).
MS (%): 511 (<1, parent), 295 (82), 196 (28), 185 (98), 161 (100), 57 (97).
HRMS calc'd for C2~,H37N30"F3: 5t2.2732. Found: 512.2751.

.(1-t-Butox~carbonvlme~vl~(3-tolv!ure do)-5~7-diphenvlhexahYdro~ze~ 2-one Prepared from (1-t-butoxycarbonylmethyl)-3-amino-5,7-diphenyl-hexahydroazepin-2-one as in Exarnple 60 as a ~oam in 6.3% yield.
lH-NMR (~, CDCI3): 1.2-1.4 (m, 2H), 1.29 (s, 9H), 2.~2.2 and 2.~2.6 (m, 2H), 2.25 (s,3H~,3.21 (m,1 H),3.60 (ABq, JAB-18, ~v=160 (2H), 5.15 (m,1 H), 5.22 (m,1 H), 6.8 and 7.~7.4 (m, 16H).
IR (cm.-l, KBr): 1723 (CO2R) and 1638 (CONR).
MS (%): 527 (15, parent), 235 (30), 133 (100) HRMS calc'd for C32H37N30~: 527.2822. Found: 527.27~2.

11-t Butoxyc~rbonylmethvl)~(~tolylureido3~hen~1-7~enzvlhexahvdroazepTn-2-one A. 2-Benzyl4-~enylcyclohexanone Prepared in analogy with a procedure developed by Stork, G. and Dowd, S. J.
Am. Chem. Soc., 85, 2178 (1963). To a 250 mL round-bottomed flask equipped wiUl N2 inlet, Dean~Stark trap, and cond~nser were added 8.71 g (50 mmol~ 4 phenylcyclohexanone,5.72 mL (50 mmol) cyclohexylamine, and 100 mL benzene. The soluUon was refluxed until water removal was complete (12 hours). Twenty mL of this solution, upon cooling, was added to 10.0 mL of a 1.0 M solution of ethyl magnesium bromide in tetrahydrofuran, and the reaction heated to 6~70C for 30 minutes. The solution was cooled, and 1.43 mL (12 mmol) benzyl bromide added, producing an immediate color change. The reaction was refluxed 3.S hours, cooled, and evaporated.
The residue was taken up in 40 mL 1 N HCI, sUrred at room temperature 18 hours, and extracted into ethyi acetate, which was washed w~h water and brine, dfied over sodium sul~ate, and evaporated. The crude yellow oil was used without further purffication, 3.2 g (100%).

V093/15059 C A 2 1 1 7 3 6 7 PCl`/US92/10720 21~367 -87- t ","~S,~

1H-NMR (d, CDCI3): 1.62 (m, lH), 1.95 (m, 1H), 2.20 (m, 2H), 2.41 (dd, J=8.5, 14, 1H), 2.55 (m, 2H), 2.77 (m, 1H), 3.01 (m, 1H), 3.34 (dd, J=4, 14, 1H), 7.~7.4 (m, 1 OH).
IR (cm.-l, KBr): 1715 (C=O).
MS (%): 264 (parent, 38), 235 (10), 159 (16), 146 (28),145 (26),131 (31),104 (35), 91 (100).
B. Phenvl-7-benzvlhexahvdroazeDin-2-one To a 250 mL round-bottomed flask equipped wiUl condenser and N2 inlet were added 2.64 9 (10 mmol) of 2-benzyl~phenylcyclohexanone, 1.70 g (15 mmol) 10 hydroxylamine-O-suifonic acid, and 50 mL formic acid. The reaction was refluxed 5.5 hours, cooled, and poured into 3N NaOH. The mixture was extrac~ed into ethyl acetate, washed with brine, dried, and evaporated. Th~ residue was chromatographed on silica gel using methanollmethylene chloride, collecting the product spot at R,=0.30 as an oil, 1.8 9 (64%).
'H-NMR (d, CDCI3): 1.~2.0 (m, 4H), 2.57 (m, 1H), 2.7-2.9 (m, 4H), 3.76 (m, 1H), 5.6 and 5.75 (broad singlets, NH, 1H), 7.0-7.4 (m, 10H).
IR (cm.-', KBr): 1660 (C=O).
MS (%): 279 (parent, 13), 235 ~24), 188 (40), 91 ~100), 44 (31).
The remaining steps were carried out as described in Example 60:
C. 3-Bromo-~Phenyl-7-benzvlhexah~droazeDin-2~ne Oil, mixture of 4 diastereomars, 27% yield.
'H-NMR (~, CDCI3): 1.7-3.2 (series of multiplets, 5H), 2.86 (m, 2H), 3.8 and 4.2(multiplQts, 1H), 4.58 and 4.88 (multiplets, lH), 6.28, 6.55, 6.68 and 6.80 (broad singlets, NH, 1H), 7.~7.4 (m, 10H).
'3C-NMR (~, CDCI3): the 4 diastereomers gav~ many overlapping peaks; 3 of the 4 lactam carbonyls appeared at 170.35, 170.54, and 170.65.
IR (c~n; l, KBr): 1670 (C=O).
MS (%): 358/360 (par~nt, Br'9/BrB' 2/2), 266/268 (98/100), 722 ~2û), 158 (4S), 144 (53)-D. 1-(t-Butvlcarbonylmethvl)-3-bromo~henvl-7-benzvlhe3tahydroazepin-2-one Oil, mixtur~ of 2 diastereomers in a 2/1 ratio, 97% yield.

WO 93/15059 C A 2 l 1 7 3 6 7 PCr/~lS92/1072~ ~

Z1~,'7367 -88-'H-NMR (d, CDCI3): 1.44 and 1.45 (singl~ts, 9H), 1.8-4.3 (series of multiplQts, 8H), 4.9 to 5.4 (multiplets, 1 H), 7.0-7.4 (m, 10H).
IR (cm. ', KBr): 1745 and 1550 (C=O).
MS (%): 392 (parQnt-Br, 2), 372 (30), 256 (100), 200 (70), 180 (98).
E. 1-lt-Butvlcarbonvlmethvl!~azido-~heny!-7-benzylhexahydroazepin-2-one Oil, mixture ot 2 diastereom~rs in a 7/3 ratio, 87% yield.
lH-NMR (~, CDCI3): 1.45 and 1.46 (singlets, 9H), 1.B 4.6 (seriss of multiple~s, 9H), 7.0-7.4 (m, 10H).
IR (cm.-1, KBr): 2107 (N3), 1739 and 1659 (C:=O).
MS (%): 406 ~puent-N2, 2), 350 (10), 259 (13), 91 (17), 57 (16), 32 (100).
F. 1-(t-Butylcarbonylmethyl)-~amino-~phenyl-7-ben~ylhexahydroazepin-2-one Oil, predominantly one diastereomer, 67% yield.
1H-NMR (~, CDCI3): 1.42 and 1.46 (singlets,9H),1.5-2.0 (m,4H),2.32 and 2.71 (multiplets, lH), 3.08 (m, 2H), 3.25 (m, lH), 4.1 (m, lH), 4.10 (AB~" JA~=17, ~v=75), 7.0-7.4 (m, 10H).
13C-NMR (~, CDCI3): (one diastereomer) 28.1,39.1,39-3144.7~ 51.8,54.3,55.4, 63.3, 81.6, 126.7, 126.9, 127.2, 128.5, 128.8, 137.3, 144.6, 169.1, 176Ø
MS (%): 409 (par~nt+1, 2), 262 (42), 132 (100), 91 (30).
G. (1-t-Butoxycarbonylmethyl)-3-(3-tolylureido)-5-phenyl-7-benzylhexahydroazepin-2-one 9% yield, M.P. 10~110C.
lH-NMR (~, CDCI3): 1.41 (s, 9H), 1.S3.2 (series of muttiplets, 7H), 4.15 (AB", JAE,-17, ~v=139), 4.28 (m, lH), 5.24 (m, lH), 6.8 and 7.~7.4 ~m, 16H).
'3C-NMR (~, CDCI3): 21.5, 28.0, 38.2, 39.3, 39.35, 39.4, 44.5, 50.4, 55.6, 81.9,127.0, 127.3, J28~5,128.6, 128.7,128.9,129.0,136.7,138.9,144.4,155.3,168.6,173.
IR (cm. ', KBr): 1740 (CO2R) and 1640 (CONR).
MS (%): 541 (parent, 2), 261 (30), 132 (100), 91 (47).
Anal. calc'd for C33H39N304: C ?3.17, H 7.26, N 7.76. Found: C 72.82, H 7.28, N 7.71.
E)CAMPLE 75 `~~093/l505g CA2 1 17367 Pcr/us92/lo72o ~ ~ ~ t r -8~ 2~-~7367 `

(1 -t-Butoxycarbonv!methyl)-3-~3-methoxyPhenylureido)-5-Phenyl-7-benzylhexahvdro-azeDin-2-one Prepared *om the title compound of Example 74F in analogy with the procedure of Example 60, in 27% yield, M.P. 95-105C.
S 'H-NMR (~, CDCI3): 1.40 (s,9H),1.5-3.2 (series of multiplets, 7H), 3.72 (s, 3H), 4.10 (ABq, J~,~=17, Av=135), 4.28 (m, lH), 5.24 (m, lH),6.5, 6.8 and 7.~7.6 (m,16H).
t3C-NMR (~, CDCI3): 28.0, 38.2, 39.2, 39.3, 39.4, 44.5, 50.4, 55.2, 55.7, 82.0, 105.4,109.2,112.2,126.9,127.0,127.2,127.3,128.5,128.6, t28.7,128.9,129.1,129.2, 129.3, 129.5, 129.6, 136.7, 140A, 144.4, 155.2, 160.2, 168.6, 172.9.
IR (cm;', l(Br): 1740 (CO2R~ and 1640 (CONR?.
MS (%): 557 (parent, 1), 261 (35), 149 (100), 132 (98), 123 (53), 91 (52).
Anal. calc'd for C33H39N305: C 71.07, H 7.05, N 7.53. Found: C 71.30, H 7.10, N7.34.

(1-t-Butoxycarbonylmethyl)-3-(3-chlorophenylureido~-5-~henvl-7-benzylhexahvdroazeDin-2-one Prepared from the title compound of Example 74F in analogy with the procedure of Example 60 in 33% yield, M.P. 95 110C. ~ `
'H-NMR (~, CDCI3): 1.38 (s, 9H), 1.5-3.2 (senes ot multiplets, 7H), 4.10 (AB", J~=17, ~v=138), 4.38 (m, lH), S.28 (m, lH), 6.8-7.8 (m, 16H).
'3C-NMR (~, CDCI3): 28.0, 37.5, 39.1, 39.2, 39.5, 50.3, 55.7, 60.4, 82.1, 117.3,119.4,122.3,122.4,126.5,126.7, tn.o, 127.1,127.2,128.5,12B.6,128.8,128.9,129.2, 129.3, 129.7, 134.4, 136.6, 140.6, 144.2, 155.0, 168.5, 173.6.
IR (cm.-', KBr): 1740 (CO2R) and 1640 (CONR).
MS (%~: 562 (parent, 1), 261 (50), 153 (80), 132 (100), 91 (40).
HRMS calc'd for C32H37N30~CI: 562.24765. Found: 562.24970.
Ana~. calc'd for C32H3~,N30~CI: C 68.38, H 6.46, N 7.48. Found: C 68.37, H
6.76, N 7.02 (-0.46).
E)6~MPLE 77 (t-t-Butoxvcarbonvlmethvl)-3-(3-tolvlureldo~-5-ohenyl-7-cyclohexvlmethyl-hexahydroazel~in-2-one WO 93/15059 ` C A 2 1 ~ 7 3 6~ PCI`/US92/10720 21;173~ 9~
Prepared from (1-t-butoxycarbonylmethyl)-3-amino-S-phenyl-7-cyclohexylmethylhexahydroazepin-2~ne by a procedure analogous to that of Example74 in 47% yield as a foam, mixture of diastereomers.
lH-NMR (~, CDC13): 1.37 (s,9H),0.8-2.3 and 2.64 (series of multiplets,7H),3.18 5 (m, 1H), 3.95 and 4.0 (AB~'s, JA,~=17 and 17, ~v=139 and 150), 4.0-4.1 (m, lH), 5.12 and 5.23 (multiplets, lH), 6.8 and 7.0-7.5 (m, 16H).
'3C-NMR (~, CDCI3): (one diasbreomer) 21.S,26.1,28.0,33.3,33.5,34.6,39.2, 39.3, 39.9, 41.5, 44.9, 46.0, 51.9, 54.2, 81.8, 117.1, 120.8, 123.6, 123.8, 126.3, 126.4, 126.9, 127.2, 128.5, 128.7, 138.7, 139.1, 144.8, 145.6, 155.1, 168.5, 173.3.
IR (cm.-1, I<Br): 1740 (CO2R) and 1640 (CONR).
MS (%): 547 (parent, 1), 243 (15), 184 (50), 141 (30), 136 (100).
Anal. calc'd for C33H"SN30,: C 72.36, H 8.28, N 7.67. Found: C 72.21, H 8.35, N 7.44.
E)CAMPLE 78 (1-t-Butoxvoarbonylmethvl)-3-(3-tolvlureido)-5-Dhenvl-7-cvclohexylhexahydroazepin-2-one Preparedfrom (1-tbutoxyccrbonylmethyl~amino~
phenyl-7-cyclohexylhexahydroazepin-2-one by a procedure analogous to that of Example 74 in 6% yield a~ a 3/1 mb~ture of diastereomers, foam.
lH-NMR (~, CDCI3): 0.8-2.3 (m, 15H), 1.37 (s, 9H), 2.26 (s, 3H), 3.02 and 3.æ
(multiplets, lH), 3.6 (m, lH), 4.01 and 4.1 (AB~,'s, JAI,=17 and 17, AV=216 and 230, 2H), 4.92 and 5.13 (multiplets, lH), 6.7-7.4 (m, 11H).
t3C-NMR (d, CDCI3): (one diastereomer) 21.5, 25.86, 25~90, 26.1, 28.0, 31.5, 39.4, 39.9, 45.8,46.6, 51.6, 63.1, 81.9,117.2,120.8, 120.9,123.6,123.8,126.4,126.9, 127.0, 128.5, 128.6, 128.7, 128.8, 138.8, 139.0, 145.9, 155.1,168.2, 175.5.
IR (cm. ', KBr): 1730 (CO2R) and 1640 (CONR).
MS (%): 533 (parent, 2), 240 (25), 133 (100), 107 (70)l 91 (40).
HRMS calc'd for C32H~3N3O~: 533.3243. Found: 533.æ941.

!1-t-Butoxvcarbonvlmethyl)~methoxvPhenvlureido)~Phenvl-7-cvclohexyl-hexahydroazepin-2-one Cd21 17367 `"VO g3/15059 PCI/US92/10720 '' -91- Zl~

Prepared from (1-t-butoxycarbonylmethyl)-3-~mino-5-phenyl-7-cyclohexylhexahydroazepin-2~ne by a procedure analogous to U~at of Example 74 in 14% yield, as a mixture of diastereomers, foarn.
1H-NMR (~, CDCI3): 0.8-2.3 (m,15H),1.37 (s, 9H),2.6 (m, lH),3.~3.4 (m,1H), 5 3.74 (s, 3H), 3.97 and 4.1 (AB,t's, JA8=17 and 17, ~v=213 and 240, 2H), 4.90 ~nd 5.12 (multiplets, 1 H), 6.5 and 6.~7.4 (m, 11 H).
l3C-NMR (~, CDCI3): (one diastereomer) 25.9,26.3,28.0,31.0,34.9,42.5,45.8, 46.6,51.5,55.2,63.1,64.7, 81.8,109.0,126.2,126.3,126.9,127.0,128.5,128.6,129.5, 129.6, 140.5, 145.9, 147.1, 154.9, 160.2, 168.3, 175.4 10IR (cm. ', KBr): 1730 (CO2R) and 1640 (CONR).
MS (%): 549 (parent, 3.5), 344 (25), 240 (30), 149 (60), 1æ (100).
HRMS calc'd for C32H"3N3~: 549.3192. Found: 549.33256.
EXAMPi~ 80 cis-l -(t-~utvlacetamido~-3-(3-tolylureido)-5-ph~nyl-?-(4-15 fluorophenyl)hexahydroazepin-2-one Prepared from cis-1-(t-butylacetamido)~amino-~phenyl-7-~411uorophenyl)-hexahydroazepin-2-one by a procedure analogous to that of Example 60 in 63% yield, M.P. 22~232C.
'H-NMR (~, CD3SOCD3): 1.16 (singlet, 9H), 2.0 (m, 3H), 2.24 (s, 3H), 2.5 (m, 201H), 3.1~.9 (multiplets, 3H),5.10 (m, lH), 5.34 (m, lH),6.6-7.5 (m,14H),8.95 (bs, lH).
l3C-NMR (~, CD3SOCD3): 21.3,28.4,45.0,50.0,51.6, $8.6,114.7,115.1,115.4, 118.1,121.8,122.4,126.3,126.8,128.5,131.6,131.7,135.5,137.8,140.5,146.2,154.1, 167.2, 173,4.
IR (cm. ', KBr): 1660 (broad, C=O).
25FAB MS (%): ~45 (parent+1, 43), 472 (36), 412 (37), 254 (27), 211 (100).
Anal. calc'd tor C32H3~N"03F-3/4H20: C 68.86, H 6.95, N 10.04. Found: C
68.87, H 6.86j N 9.69.

cis-l-(t-Butvlacetamido)-3 (3-methoxyphenylureido) 5 phenyl-7-(4-~op~e~d,~
30 hexahvdroazeDin-2~ne Prepared from cis-1-(t-butylacetamido)~amino-~phenyl-7-(4-fluorophenyl).
hexahydroazepin-2-one by a procedure anaiogous to that of Example 60 in 54% yield, M.P. 224.~227C.

W0 93/l505g ~ 1 3 .~3 ~ ~ Pcr/us92/l072r Zl~36~ - -92-lH-NMR (~, CD3SOCD3): 1.16 (singlet,9H),2.0 (m,3H),2.6 (m,1H),3.2-3.9 (m, 3H), 3.70 (s, 3H), 5.10 (m, lH), 5.32 (m, 1H), 6.5 and 6.8-7.S (m, 14H), 9.05 (bs, lH).
'3C-NMR (~, CD3SOCD3): 28.4, 44.9,46.8, 50.0, 51.5, 54.9, 58.5,103.2,106.5, 109.9,115.1,115.4,126.3,126.8,128.5,129.4,131.6,141.8,146.1,154.1,159.7,167.2, 5 173.3.
IR (cm.1, KBr): 1660 (broad, C-O).
FAB MS (%): 561 (parent+1, 25), 488 (30), 412 (28), 254 (27), 211 (100).
Anal. calc'd for C32H37N404-H20: C 66.42, H 6.79, N 9.68. Found: C 66.36, H 6.S7, N 9.42.

cis-1 -(t-Butvlacetamido~-3-(3-chloroDhenylureido)-5-phenvl-7-(4-fluorophenvl)-hexahydroazepin-2-one Prepared from cis-1-(t-butyiacetamido)~amino-5-phenyl-7-~4-~uorophenyl) hexahydroazeptn-2-one by a procedure analogous to Example 60 in 44% yield, M.P.
17~178C.
lH-NMR (~, CD3SOCD3): 1.16 (singlet,9H),2.0 (m,3H),2.6 (m, lH),3.2-3.9 (m, 3H), 5.10 (m, 1H), 5.32 (m, 1H), 6.8-7.6 (m, 14H), 9.27 (bs, 1H).
'3C-NMR (~, CDCI3): 28.45, 44.9, 46.8, 50.0, 51.6, 58.5, 115.1, 115.4, 115.8, 116.8, 120.7, 126.4, 126.8, 128.6, 130.3, 131.6, 131.7, 133.2, 135.4, 142.1, 146.1, 153.9, 167.2, 173.2.
IR (cm. l, KBr): 1660 (broad, C=O).
FAB MS (%): 565 (parent, 20), 492 (26), 412 (27), 254 (20), 211 (100).
Anal. calc'd for C31H34N403FCI-2H20: C 61.94, H 6.37, N s.æ. Found: C
61.93, H 5.73 (-0.64), N 9.09.
HRMS calc'd for C3lH34N403FCI: 564.2790. Found: 564.23444.
_ AMPLE 83 ` cis-1-(t-Butylacetamido)-3-(3~tolylureidol-5-phenyl-7-(4-chlorophenyl)hexahvdroazeDi n-2-one Prepared trom cis-1-(t-butylacetamido)-3-amino-5-phenyl-7-(4-30 chlorophenyl)hexahydroazepin-2-one by a procedure anaiogous to that of Example 60 in 69% yhld, M.P. 22~226C.

o 93~5059 ( ~ A 2 11 7 3 6 7 PCr/US92/10720 9~ 2~3~ -'H-NMR (~ DCI3, TFA): 1.20 (singlet, 9H), 2.0 (m, 1H), 2.3 (m, 3H), 2.33 (sl 3H), 3.30 (m, lH), 3.98 (AB~. JA~3 = 16, ~V=43, 2H~, 5.27 (m, lH), 5.38 (d, J=11, lH), 6.69 (d, J=7, 1H), 6.~7.5 (m, 16H).
'3C-NMR (~, CDCI3, TFA): 22.0, 27.9,38.5, 38.8, 45.6, 52.8, 61.0,112.4,116.1, 5 119.9, 126.6, 127.3, 128.9, 129.5, 129.8, 130.8, 134.9, 143.6, 158, 176.
IR (cm:l, KBr): 1660 (broad, C=O).
FAB MS (%): 561 (parent+1, 47), 488 (30), 454 (20), 428 (25), 227 (28), 157 (100), 119 (46).
Anal. calc'd tor C32H3,N~03CI-l/2H20: C 67.41, H 6.72, N 9.83. Found: C
10 67.77, H 6.57, N 9.44.

cis-l-(t-Butvlacetamido)~(~metho~phenyiureido~-5-phenvl-7-t4chloroDhenyl~-hexahydroaze~in-2-one Prepared from cis-1-(t-butylacetamido)-3-amino-5-phenyl-7-(4-15 chlorophenyl)hexahydroazepin-2-one by a procedur~ ~nalogous to that of Exarnple 60 in 33% yhld, M.~. 130-132C.
lH-NMR (~, CDCI3, TFA): 1.21 (singlet, 9H), 2.~2.4 (multiplets, 4H), 3.29 (m, 1H), 3.82 (s, 3H), 3.89 (A~, J~,3 = 16, ~v=77, 2H), 5.24 (m, lH), 5.39 (d, ~)=11, lH), 6.7-6.9 and 7.1-7.4 (m, 16H).
l3C-NMR (~, CDCI3, TFA): 28.0, 38.7, 38.9, 45.6, 48.3, 52.6, 52.8, 55.5, 60.8, 126.6,127.3,128.9,129.5,130.4,130.5,130.8,136.1,135.6,143.8,160.2,168.8,175.7.
IR (cm.-l, iXBr): 1660 (broad, C=O).
FAB MS (96): 577 (parent, 82),504 (61), 428 (56~,227 (76),119 (100),103 (55).
Anal. calc'd for C32H3,N"O"CI: C 66.60, H 6.46, N 9.71. Found: C 66.83, H
6.46, N 9.51.
i:XAMPLE 85 cis-1-(t-~utylacetamido)-S-(3-chloroph~2nylureldo)-5-phe~
chlorophe~l)hexa-hydroazepin-2~ne Prepared in analogy with -:xample 60 in 52% yield, M.P. 229-231 C.
'H-NMR (~, CDCI3, TFA): 1.21 (singlet, 9H), 2.~2.4 (muitiplets, 4H), 3.29 (m, lH), 3.92 (AB~, JA~ = 16. ~V=65, 2H), 5.27 (d, J=8, lH), 5.43 (d, J=10, lH), 7.1-7.5 (m, 16H).

WO93/150~9 ~A273,~ PCI'/US92/1072~.
, ` '94- :
z~7367 l3C-NMR (~, CDCI3, TFA): 22.0, 27.9, 38.7, 45.6, 48.3, 52.5, 60.9, 71.3, 126.1, 126.6, 127.3, 128.9, 129.5, 130.6, 130.8, 134.9, 135.3, 135.7, 143.7, 176Ø
IR (cm.-', KBr): 1660 (broad, C=0).
FAB MS (%): 581 (parent~1, 63), 508 (61), 428 (36), 227 (65), 157 (81), 119 5 (100).
Anal. calc'd for C3lH3~N"O3CI2-i/3H2O: C 63.37, H 5.95, N 9.54. Found: C
63.74, H 5.99, N 8.87 (-0.6".
HRMS calc'd for C3lH3"N~03CI2: 580.2008. Found: 580.19940.
AMPi~ 86 1 0 cis-1-n-Butylacetami~(3-tolylureido~-5-phenvl-7-(4-tolyl!hexahy~roazeDin-2-one Prepared from cis-1-(t-butylacetamido)-3-amino-5-phenyl-7-(4-toiyl)hexahydroazepin-2-one by a procedure analogous to that of Example 60 in 579~
yield, M.P. 216-218C.
lH-NMR (~, CDCI3, TFA): 1.20 (singlet, 9H), 2.~2.4 (multiplets, 4H), 2.33 (s, 3H), 2.34 (s, 3H), 3.27 (m, 1H), 3.96 (ABq, JAB=16l 1~v=62, 2H), 5.22 (d, J=10, lH), 5.39 (d, J=10, lH), 7.0-7.4(m, 16H).
'3~NMR (~, CDCI3, TFA): 20.9, 22.0, 27.9, 38.5, 38.9, 45.7, 48.2, 52.8, 61.6, 71.3,120.3,124.5,126.6,127.2,128.0,128.9,129.3,129.8,130.0,133.4,134.7,139.7, 20 140.4, 143.9, 176.
IR (cm.-', KBr): 1660 (broad, C=O).
FAB MS (%): 541 (parent~1, 10), 207 (12), 157 (100),119 (24),103 (12).
Anai. calc'dfor C33H~oN403: C 73.30, H 7.46, N 10.36. Found: C 72.90, H 7.37, N 10.11.
i-XAMPLE 87 cis-l -(t-Butvlacetamido)-3-(3-methoxyphenvlurQido)_5-phe~L-,7-~4-tolvl)hexahydroazeDin-2-one Prepared from cis-1-(t-butylacetamido)-3-amino-5-phenyl-7-(4-tolyl)hexahydroazepin-2-one by a procedure anaiogous to that of Example 60 in 40%
30 yield as an amorphous solid.
'H-NMR (~, CDCI3, TFA): 1.19 (singlet, 9H), 2.~2.4 (muitiplets, 4H), 2.34 (s, 3H), 3.29 (m, lH), 3.83 (s, 3H), 3.95 (ABq, JAB-16, ~V=P~1~ 2H), 5.22 (d, J=11, lH), 5.40 (d, J=11, 1H), 6.8 and 7.1-7.4 (m, 16H).

-~VO 93/15059 ` C A 2 1 1 7 3 6 7 PCl`/US92/10720 ' ~q736 9~ , ~:
r ' l3~NMR (~, CDCI3, TFA): 22.0, 27.9, 38.6, 38.9, 45.6, 48.2, 52.7, 55.5, 61.4, 71.2,126.2,126.6,127.2,128.9,129.3,130.0,130.5,130.6,133.4,139.7,143.9,157.2, 169.4, 175.8.
IR (cm. l, KBr): 1660 (broad, C=O).
FAB MS (%): 557 (par~nt+1, 59), 484 (45), 408 (43), 250 (32), 207 (100), 1æ
(33), 105 (43)-Anal. calc'd for C33H~oN40~-H20 C 68.97, H 7.37, N 9.75. Found: C 68.97, H 7.38, N 9.60.

cis-1-(t-Butvlacetamido~-3-(3-3-chloroDhenvlureido)-5-~henvl-7-(4-tolyl)hexahydroazepin-2-one Prepared from cis-1-(t-butylacetamido)-3-amino-5-phenyl-7-(4-tolyl)hexahydroazepin-2-one by a procedure analogous to thd of Example 60 in 41%yield as an amorphous solid.
lH-NMR (~, CDCI3, TFA): 1.20 (singlet,9H),2.0-2.4 (mulbplets,4H),2.34 (s,3H), 3.29 (m, lH), 3.94 (AB", J~, = 16, av=58, 2H), 5.23 (d, J=9, lH), 5.42 (d, J=tl, lH), 7.1-7.5 (m, 16H).
'3C-NMR (~, CDCI3, TFA): 21.0, 27.9, 38.8, 38.9, 45.7, 48.2, S2.S, 61.4, 64.6, 122.2,125.7,126.6,127.2,128.9,129.3,130.0,130.5,133.5,135.2,137.4,139.7,144.0, lS~.4, 169.3, 176Ø
IR (cm. l, i<Br): 1660 (broad, C=O).
FAB MS (%): S61 (parent+1, 44), 488 (34), 408 (28), 207 (67), 157 (100).
Anal. calc'd tor C32H37N~03CI-l/4H20: C 67.95, H 6.68, N 9.91. Found: C
68.12, H 6.47, N 9.52.

cis-l -~t-Butviacetamido~(3-tolvlureido)-5~phenyl-7-(3-tolyl)hexahvdroazepin-2-one Prepared from cis-1-(t-butylacetamido)-3-amino-S-phenyl-7-(3- `
tolyl)hexahydroazepln-2 one by a procedure an~Jogous to that of Example 60 in 56%
yield, M.P. 252-254C.
lH-NMR (~, CDCI3, TFA): 1.20 (singlet, 9H), 2.~2.4 (multipbts, 4H), 2.æ (s~
3H), 2.33 (s, 3H),3.27 (m,1H), 3.93 (AB~" J~,=16, ~v=54, 2H)~ 6.20 (d, J=9, lH), 5.38 (d, J=11, lH~, 7.~7.5 (m, 16H).

WO 93/l~iO59 C A ~ 1 1 7 3 6 7 PCI`/US92/10721 z~ ~36~ -g6-l3C-NMR (~, CDCI3, TFA): 21.1,21.2,28.0,38.7,39.0,45.8; 48.3, S2.6,61.6, 120.4,124.2,126.4,126.7,127.29127.5,123.9,129.2,129.7,130.1,130.2,135.3,136.5, 139.2,140.2,144.0,158,169,175.6.
IR (cm.-l, KBr): 1660 (broad, C=O).
FAB MS (%): S41 (parent+1, 72),468 (63),408 (45),250 (32),207 (100),157 (100),119 (68).
Anal. calc'd for C33H~oN"O3: C 73.30, H 7.4B, N 10.36. Found: C 73.02, H 7.39, N 10.30.
i3~AMPi- E 90 cis-1-(t-Butylacetamido~-3-(3-methoxvphenylureido)-5-phenyl-7-(3-tolyl)hexahydroazepin-2-one Prepared from cis-1 :(t-butylacetamido)-3-amino-5-phenyl-7-(3-tolyl)hexahydroazepin-2-on~ by a procedure anaiogous to that of Example 60 in 76.596 yield as an amorphous solid.
lH-NMR (~, CDCI3, TFA): 1.19 (singlet, 9H), 2.0-2.4 (muitiplets, 4H), 2.32 (s, 3H), 3.28 (m, lH), 3.81 (s, 3H), 4.0 (m, 2H), 5.21 (d, J=9, lH), 5.39 (d, J=11, lH), 6.7-6.9 and 7.1-7.4 (m, 16H).
l3C-NMR (~, CDCI3, TFA): 21.2, 28.0, 38.8, 39.1, 4S.7, 48.2, 52.6, 55.4, 61.6, 71.0,126.4,126.7,127.2,128.9,129.~,130.1,130.5,136.6,139.2,144.1,157,169,176.
IR (cm. l, KBr): 1660 (broad, C=O).
FAB MS (%): ~S7 (parent~t, 34), 484 (39), 408 (32), 207 p5), 119 (100), tO3 (100). ~ ~`
Anai. calc'd for C33H~ON"O"^H20: C 68.97, H 7.37, N 9.75. Found: C 68.73, H 7.95 (-0.58), N 9.42.

cis-l-Lt-Butylacetamido)-3-(3-ch!orophenylureido~-5-phenvl-7-(3-tolyl)hexahvdroazepin-2-one Prepared trom cis-1-(t-butylacetamldo)-3-amino-S-phenyl-7-(3-tolyl)hexahydro~7epin-2-one by a procedura analogous to that of Example 60 in 65%
30 yield as an amorphous solid.
lH-NMR (~, CDCI3, TFA): 1.20 (singlet, 9H), 2.0-2.4 (multiplets, 4H), 2.33 (s, 3H), 3.29 (m, lH), 3.95 (AB~" JAB = 16, ~v=S8, 2H), 5.22 (d, Ja9, lH), 5.44 (d, J=11 lH), 7.1-7.4 ~m, 16H).

Cd21 1 7367 ~,v~o 93/15059 PCI/US92/11~720 -97- ~S~ j."

'3C-NMR (~, CDCI3, TFA): 21.2, 28.0, 38.8, 39.0, 45.7, 48.2, S2.5, 61.7, 71.1, 125.6,126.3, 126.7,127.2,128.9,129.2,130.2, 13a.5,135.2,136.5,139.2,144.0,157, 169, 176.
IR (cm.-', KBr): 1660 (broad, C-O).
FAB MS (%): 561 (parent+1, 30), 488 (75), 408 (43), 250 (S", 207 ~100), 115 (39).
Anal. calc'd tor C32H3,N~03CI-l/4H20: C 67.95, H 6.68, N 9.91. Found: C
67.89, H 6.72, N 9.91.

1 -(t-Butvlacetamido)~(2-methvlDhenvlureido)-5.7~diDhenvlhexahvdro~zeDin-2-one Prepared from the more polar amine diastereomer of 1-(t-butylacetamido)~
amino-5,7-diphenyl-hexahydroazepin-2-one in Example 60 in 26% yield, mp 145-153C.
lH-NMR (~, CD3SOCD3): 1.15 (slnglet, 9H), 1.9-2.1 (m, 3H), 2.17 (s, 3H), 2.61 15 (m, lH), 3.25 (m, lH), 3.51 (AB~" JAII = 16, Dn=214, 2H), 5.10 (m, lH), 5.30 (d, J=10, lH), 6.~7.4 (m, 15H), 7.77 ~d, J=8, lH), 8.17 (s, lH).
l3C-NMR (~, CD3SOCD3): æ.8, 28.5, 45.0, 47.0, 49.9, 51.8, 59.4, 67.3, 120.9, 121.0,1 æ.o, 125.9,126.0,126.3,126.7,126.8,127.2,128.0,128.4,128.5,128.7,129.4, 129.5, 130.1, 131.3, 138.2,139.3, 146.3, 154.4, 167.3, 173.4.
IR (cm.-l, KBr): 1650 (broad, C=O).
FAB MS (%): 527 (parent+1, 90), 454 (75), 394 (45), 193 (100), 157 (67), 119 (54), 91 (66).
Anal. Caic'd. for C32H3"N"03-1/2H20: C 71.75, H 7.34, N 10.46. Found: C
71.84, H 7.10, N 10.27.
O(AMPLE 93 1-(t-Butylacetamido)~(4 chlorophenylureldo~-5.7~iDhemlhexahyd roazepin-2-one Prepared *om the more polar amlne diastereomer of 1-(t-butylacetamido)~

amino-5,7-diphenyl-hexahydroazepin-2-oneln Example60 in 19%yield, mp 16~170C.
'H-NMP~ (~, CDCI3, TFA): 1.18 (singlet, 9H), 2.03 (m, lH), 2.2-2.4 (m, 2H), 3.28 (m, lH), 4.03 (AB~, ~ = 17, Dn=132, 2H), 5.26 (~, J=9, lH), 5.43 (~, .J-11, lH), 7.1-7.4 (m, 17H).

WO 93/15059 C A 2 1 1 7 3 6 7 PCI'/US92/1072 2117367 -9~

l3C-NMR (~, CDCI3, TFA): 27.7, 38.5, 38.6, 45.7, 48.1, 62.9, 53.7, 61.9, 71.6, 124.7,126.5,127.3,128.7,128.9,129.0,129.4,129.6,129.7,129.8,130.0,133.6,136.2, 143.6, 157.4, 169.8, 176.3.
IR (cm.-', KBr): 1650 (broad, C=0).
FAB MS (%): 547 (parent+1, 23), 474 (22), 420 (15), 394 (16), 193 (28), 155 (45), 136 (30 ), 119 (100), 104 (40).
Anal. Cale'd. for C3lH35N~03CI-l/2H20: C 66.96, H 6.52, N 10.07. Found: C
66.65, H 6.33, N g.86.

1 -(t-Butvlacetamldo)~(5-(benztriazolvl)ureido)-5.7-diphenvlhex~hvdroazePi~2-one To a 35 mL round-bottomed flask ecluipped with N2 inlet and eondenser were added 62 mg (0.3B2 mmol) benztriazol~5wboxylie acid, 5 mL dry tetrahydrofuran, 0.090 mL (0.420 mmol) diphenylphosphoryl azide, and 0.060 mL (0.420 mmol) 15 triethylamiM. The reaction was refluxed for 1 hr, eooled briefly, and 150 mg (O.æ
mmol) of 1-(t-butylaeetamido)~amino-5,7-diphenyihexahydroazepin-2-one (the more polar amine diastereomer in Example 60) was added and refluxing eontinued for 14 hr.
The reaction was eooled, filtered to remove a small amou~lt of amide byproduct that had formed, and the filtrate evaporated. The residue was triturded with ehloroform to ~ord a whlte solid, 70 mg (34%), mp 210-æOC.
'H-NMR (~, CDCI3): 1.16 (singlet, 9H), 2.03 (m, lH), 2.2 2.5 (m, 3H), 3.18 (m, - lH), 3.28 (m, lH), 4.01 (AB~" J~" = 16, Dn=108, 2H), 5.2-5.3 ~m, 2H), 5.64 (bs, 1H!, 7.1-7.4 (m, 13H), 7.92 (d, J=9, lH), 8.06 (s, lH), 8.38 (s, lH).
'3C-NMR (~, CDCI3): 27.9, 38.6, 39.0,45.6,48.0,52.5, 5S.4, 61.8,116.1,119.9, 125.2,126.5,127.4,128.9,129.5,129.7,129.9,130.5,135.0,13S.3,140.9,143.7,155.1, 163.0, 169.2, 175.8.
IR (em. l, KBr): 1640 (broad, C=0).
FAB MS (%): S55 (parent+1, 64), 481 (70), S94 (35), 193 (83), 155 (55), 119 (100).
SO HRMS: Cale'd. for C3,H30N~03: 554.2872. Found: 554.28607.

1 -tt-Butylacetamido)~(3.4dimethvlDhenylureido)-5.7~iphenvlhexahvdroazepin-- 2-one:

`-~VO93/15059 CA21 l 7367 PCI'/US92/10720 99 21i7367 :
Prepared as in Example 94, using the more polar isomer o11-(t-buiylacetamido)-~amino-5,7-diphenyl-hexahydroazepin-2-one descri~d in i xample 60, in 48% yield,mp 18~188C.
lH-NMR (~, CDCI3): 1.19 (singlet, 9H), 2.0 (m, lH), 2.14 (s, 3H), 2.15 (s, 3H), 2.2-2.3 (m, 2H), 2.55 (m, lH), 3.20 (m, lH), 3.59 (ABq, J~B = 16, Dn=193,2H), 5.16 (d, J=10, 1H), 5.24 (dd, J=7,10, 1H), 5.38 (s, lH), 6.71 (d, J=6, 1H), 7.0-7.4 (m, 13H), 7.53 (bs, lH).
l3C-NMR (~, CDCI3): 19.0, 19.9, 28.6, 39.3, 39.4, 46.1, 48.2, 51.1, 62.2, 61.2, 117.9,121.8,121.9,126.5,126.6,127.0,128.5,128.6,128.8,128.9,129.4,129.5,130.0, 136.8, 137.1, 138.2, 145.3, 155.4, 167.5, 175Ø
IR (cm. ', KBr): 1660 (broad, C=0).
FAB MS (%): 541 (48, parent+1), 468 (35), 394 (æ), 3Q9 (39), 193 (42), 155 9100), 135 (72), 119 (100), 103 (96).
Anal. Caic'd. for C33H~oN403: C 73.30, H 7.46, N 10.36. Found: C 73.09, H
7.æ, N 10.08.

1-(t-Butvlacetamido)-3-(3-dimethvlaminoDhenylureido)-5.7-diDhenvl-hexahvdroazepin-2-one Prepared as in Example 94, using the more polar isomer of 1-(t-butyia~bmido)-3-amino-5,7-diphenyl-hexahydroazepln-2-one described in Exarnple 60, in 71% yield, mp 145-153C.
ll~NMR (~, CDCI3): 1.18 (singlet,9H),1.98 (m,1H),2.22 (m, 2H), 2.57 (m,1H), 2.87 (s, 6H), 3.20 (m, lH), 3.58 (AB~" J~" = 16, Dn=174, 2H), 5.17 (d, J=10, lH), 5.26 (m, lH), 5.42 (s, lH), 6.3, 6.6, 6.7, 6.9, and 7.0-7.3 (m, 16H), 7.59 (s, lH).
l3C-NMR (~, CDCI3): 28.6, 39.4, 39.5, 40.6, 46.0, 48.3, 51.1, 52.1, 61.2, 104.5,107 7,108.5,108.6,126.6,127.0,128.6,128.8,128~9,129.1,129.3,129.5,138.3,140.1, 145.3, 151.S,155.3, 167.5, 174.9.
IR (cm. ', KBr): 1640 (broad, C=0).
Anal. Calc'd. for C33H~N503-112H20: C 7Q.19, H 7.50, N 12.40. Found: C
69.81, H 7.13, N 12.05.
The hydrochloride salt was formed using HCl in ether and aystalleed from acetone to afford a white solid, mp 190-197C.

WO93/15059 ~A2~ ~ 73b7 PCl`/US92/1072~-Anal. Calc'd. for C33H"l N503 HCI: C 66.93, H 7.15, N 11.83. Found: C 66.60, H7.17, N 11.70.

cis-1 -(t-Butylacetamido)-3-(3-tolylureido)-5-phenyl-7-(3-S methox~henvl)hexahvdro~zepin-2-one Preparedfromthernorepolarisomerof 1-(t-butyiacetamido)~amino-5-phenyi-7-(3-methoxyphenyl)hexahydroazepin-2 one in anaiogy with Exampb 60 in 40% yield, mp 24~;247C.
'H-NMR (~, CDCI3, TFA): 1.19 (singlet, 9H), 1.9-2.4 (muitiplets, 4H), 2.33 (s, 3H), 3.28 (m, lH), 3.81 (s, 3H), 3.97 (AB~" J~" = 17, Dn York=62, 2H), 5.23 (d, J=10, 1H), 5.38 (d, ~1=11, lH), 6.8-7.4 (m, 16H).
'3~NMR (~, CDCI3, TFA): 21.0, 27.9, 38.6, 38.8, 45.6, 48.2, 52.8, 52.9, 55.5, 61.6,114.7,115.9,121.9,124.5,126.6,127.3,128.0,128.9,129.7,130.5,138.0,140.3, 143.8, 158, 169, 175.6.
IR (cm.-', KBr): 1650 (broad, C=0).
FAB MS (%): 557 (parent+1, 30), 484 (45), 266 930), 223 (100), 1æ (45),115 (42), 91 (44).
And. Calc'd. for C33H~oN,~O,~: C 71.20, H 7.24, N 10.07. Found: C 70.98, H
7.51, N 9.83.
EXAI~IPLE 98 cis-1-(t-Butylacetamido)-3-(3-methoxyphenylureido)-5-phenvl-7-(3-methoxv~henyl)hexshydroaze~in-2-one Prepared from the more polar isomer of 1-(t-butylacetamido)~amino~phenyl-7-(3-methoxyphenyl)hexa hydroazepin-2-one in analogy with E~(ampb 60 in 46% yield 25 as an amorphous solid. `
lH-NMR (~, CDCI3, TFA): 1.19 (singlet, 9H), 2.0-2.4 (multiplets, 4H), 3.29 (m, l H), 3.80 (s, 3H), 3.82 ~s, 3H), 3.8-3.9 and 4~0-4.1 (m, 2H), 5.2S (m, l H), 5.38 (m, lH), 6.7-7.0 and 7.1-7.4 (m, 16H).
~ 3C-NMR (IS, CDCI3, TFA): æ.l, 28.0, 38.7, 38.8, 45.6, 47, 52, 55.4, 55.5, 61.5, 30 114.6,115.8,121.~,126.6,127.2,128.9,130.5,143.9 (remaining carbons notvislble in this scan).
IR (cm. ', iCBr): 1670, 1630, 1600 (broad, C=O).

- ~ ~VO 93/150~;9 C A 2 1 1 7 3 6 7 PCl`/US92/10720 -l o~ - 2l~q367 FAB MS (%): 573 ~parent+1, 45), 500 (52), 424 (35), 266 (34), 223 (100), 132 (32), 115 (48), 91 (37).
Anal. Caic'd. for C33H~oN4O5-H2O C 67.10, H 7.17, N 9.48. Found: C 67.01, H 7.23, N 9.20.

c.s-1 -(t-Butvlacetam do)-3-l3-chloroPhenvlureido)-5-DhQnvl-7 -(3-methoxvDhenvl)hexahvdroazeDin-2-one Prepared from the mor~ polàr isomer of 1 -(t-butylacetamido)~amino~phenyl-7-(3-methoxyphenyl)hexahydro~zepin-2-one in analogy with Example S0 in 31% yield as 10 an ~morphous solid.
lH-NMR (ô, CDa3, TFA): 1.20 (singletj 9H), 2.~2.4 (multiplets, 4H), 2.33 (s, 3H), 3.29 (m, lH), 3.81 (s, 3H), 3.96 (AB", JA8 = 17. Dn=~9, 2H), 5.24 (d, J=9, 1H), 5.42 (d, ~1=11, 1H), 6.~7.4 (m, 16H).
'3C-NMR (~, CDCI3, TFA): 22, 28.0, 38.7, 38.8, 45.6, 48.2, 52.5, 55.4, 61.6, 114.7"115.9, 121.8, 125.8, 126.6, 127.2, 128.9, 130.5, 130.6, 138.1, 143.9, 156, 167, 175.
IR (cm. l, KBr): 1670, 1620 (broad, C=O).
FAB MS (%): 577 (parent+1~ 35), ~04 (46), 223 (100),157 p3), 119 (51).
Anal. Calc'd. for C32H3~N~O~CI-H2O: C 64.58, H 6.60, N 9.41. Found: C 67.54, H 6.63, N 9.24.

cis-,1 -(t-Butvl~cetamldo)-3-(3-tolvlureido~-5-Dhenyl-7-(4-trl fluoromethylDhenyl)hexahvdroazepin-2~ne Prepared tromthe more polar isomer of 1 -(t-bu~ylacetamido)~amino-~phenyl-7-(4trifluoromethylphenyi)hexahydro~epin-2~ne in analogywlth Exarnple 60 in 10% yield as an amorphous solid.
NMR (~, CDCI3, TFA): 1.19 (singlet, 9H), 2.~2.4 (mulUplets, 4H), 2.34 (s, 3H), 3.31 (m,1H),3.82 (AB~" J~0 = 16, Dn=36,2H),4.82 and 6.02 (m, lH), 5.3 (m, lH), 7.0-7.7 (m, 16H).
l3C-NMR (~, CDCI3, TFA): 21.1, 28.0, 38.6, 38.8l 43.3, 45.6, 48.4, 52.7, 61.0, 120.7,121.2,124.4,125.0,126.2,126.5,126.6,126.9,127.3,127.7,128.2,128.9,129.7, 130.0, 131.5, 131.9, 134.8, 135.0, 140.3, 140.5, 143.7, 143.9,158, 168, 175.
IR (cm.-', KBr): 1680, 1660, 1640 (broa l. C=O).

WO 93/150S9 C A 2 117 3 6 7 PCI`/US92/10720-2117~

FAB MS (%): 595 (parent+1, 5), 482 (24), 349 (30), 157 (100), 135 (45), 119 (99). 103 (51).
Anal. Calc'd~ for C33H37N403F3-3/2H20: C 63.75, H 6.49, N 9.01. Found: C
64.01, H 6.44, N 8.74.
EXAMPLE 1û1 c -1-Lt-Butylacetamido2-3-(3-mQthoxyphanvlur-aido)-5-phenvl-7-~4 trifluoromethylphenyl3hexahydroazeDln-2-one PreparQd from the inore polar isomer of 1 -(t-butylacetamido)~arnin~phsnyl-7 (4-trifluoromethylphenyl)hexahydroazepin-2~ne in analogy with Examph 60 in 48% yi~ld 10 as an amorphous solid.
1H-NMP~ (~, CDCI3, TFA): 1.18 (singlet, 9H), 2.~2A (mu~iplets, 411), 3.31 (m, lH), 3.82 (s, 3H), 3.83 (AB~" ~ = 1~, Dn=37, 2H), 4.82 and 5.02 ~m, lH), .~5.4 (m, lH), 6.7-7.7 (m, 16H).
'3C-NMR (~, CDCI3, TFA): 22.1, 28.0, 38.5, 38.7, 43.3, 45.6, 48.4, 55.5, 60.9, 126.2,126.5,126.6,126.9,127.3,128.9, 130.1,130.6, 130.8,140.5,143.7, 144.0,157, 16~, 176.
IR (cm.-~, KBr): 1660, 1640, 1600 (broad, C=O).
FAB MS (%): 611 (parent+1, 4), 498 (17), 349 (20), 157 (100).
Anal. Calc'd. for C33H3,N,,04F3~HzO: C 63.05, H 6.25, N 8.91. Found: C 63.05, H6.11,N8.59.
- ~MPLE 102 cis-l-(t-Butylacetamido!-3-(3-cblo_s~phenylureido)-5-phenyl^7-(4-tr~fluoromethylphenyl)hexahydroazepin-2-one Prepared from the more polar isomer of 1 -(t-butylace~mido)~amino~phenyl-7-(~trffluoromethylphenyl)hexahydroazepin-2~ne in analogy with Example 60 in 34% yield as ~n amorphous solid.
lH-NMR.(~, CDCI3, TFA): 1.19 (singlet, 9H), 2.0-2.4 (multTplets, 4H), 3.33 (m, lH), 3.93 (ABq, JAB = 17, Dn=89, 2H), 5.37 (m, lH), 5.46 (d, J=11, lH), 7.0-7.7 (m, 16H).
l3C-NMR (~, CDCI3, TFA): 27.8, 38.6, 38.7, 45.6, 48.3, 52.6, 53.1, 61.1, 120.4, læ.6,126.2,126.6,127.4,129.0, 130.0,130.6,132.0,135.3,137.0,140.3,143.6, 157, 169, 176.1.
IR (cm.-l, KBr): 1680, 1640 (broad, C=O).

~O 93/1!;059 C A 2 1 1 7 3 6 7 P~/US92/10720 -1 o~ 21l7~

FAB MS (%): 615 (parent+1, 6), 233 t23), 167 (100), 135 (47), 119 (99), 103 (52).
Anal. Calc'd. for C32H3~N~03CIF35/4H~O: C 60.28, H 5.77, N 8.79. Found: C
60.17, H 5.91, N 8.64.

cis-1-(t-ButYlacetamido)-3-(3-to!vlureid~o)-5-Dhenvî-7-(3-fluorophenvl)hexahvdroaze~ir~2~ne Prepar~d from the more polar isomer of 1-(t-butylac~tarnido)~amino~pheny~
7-(3-fluorophenyi)hexahydroazepin-2-one in analogy ~th Exarnph 60 in 39% yield as 10 an arnorphous solid.
1H-NMR (~, CDCI3, TFA): 1.22 (singlet, 9H), 2.0-2.4 (multiplets, 4H), 2.33 (s, 3H), 3.28 (m, lH), 3.87 (ABq, JA" = 16, Dn=43, 2H), 5.21 (d, J=9, lH), 5.32 (d, J=11, 1H), 7.0-7.4 (m, 16H).
'3C-NMR (o', CDCI3, TFA): 21.2, 28.1, 38.8, 38.9, 45.7, 48.3, 52.6, 60.8, 126.7,- 15 127.3, 128.9, 129.6, 144.0, 157, 167, 175 (not all carbons vTsible in this scan).
IR (cm. t, KBr): 1660, 1640 (broad, C=O).
FAB MS (%): 545 (parent+1, 62), 472 (52), 211 (76), 157 (100), 132 (53), 107 (53), 91 (57).
Anai. Calc'd. tor C32H3,N"03F-3/4H20: C 68.86, H 6.95, N 10.04. Found: C
68.87, H 6.83, N 9.73.

cis~ (t-Butylacetamido)-3-~3-methox~phenvlur~ido)-5-phenyl~7-(3-fluoroDhenyl)hexahvdroazepin-2-one Prepared from the more polar isomer of 1 -(t-butylacetarnido)~amino~phenyl-7-(3-fluorophenyl)hexahydroazepin-2-one in analogy wTth Exarnpie 60 in 30% yield as u amorphous solid.
lH-NMR (~, CDCI3, TFA): 1.20 (singlet, 9H), 2.0 2.4 (multiplets, 4H), 3.28 (m, 1H), 3.80 (s, 3H), 3.9 (m, 2H), 5.23 (d, ~1=11, lH), 5.34 (d, J=11, lH), 6.7-6.9 and 7.1-7.4 (m, 16H).
'3C-NMR (~, CDCI3, TFA): 22.2, 28.2, 38.8, 38.9, 45.7, 48.3, 52.5, 55.4, 60.8, 116.5, 126.7, 127.2, 128.9, 143.9, 176 (not all c~ubons visible in this scan).
IR (cm. l, KBr): 167~, 1640 (broad, C=O).
FAB MS (%): 56 (parent~1, 95~ 488 (78), 211 (100),157 (89), lt9 (88).

WO 93/15059 '~ 7 3;6~ PCl`/US92/1072~
.. . .
2~17367 ~

Anal. Calc'd. for C32H3,N404F~l/2H20: C 67.47, H 6.72, N 9.83. Found: C
fi7.20, H 6.70, N 9.14 (~.69).
HRMS CaJc'd. for C32H37N404F: 561.2868. Found: 561.28552.

cis-1-(t-Butyla~etamido)-3-(3-chLorophenvlureido)-5-Dhenyl-7-!3-fluorophenvl!hexahydroazepTn-2-one Prepared from thQ more polar isom~r of 1 -(t-butylacetarnido)~amln~phQnyl7-(~fluorophenyl~hexa hydroazepin-2~ne in analogy with Example 60 in 52% yield as ~n arnorphous solid.
lH-NMP~ (~, CDCI3, TFA): 1.22 (singlet, 9H), 2.~2.4 (multiplets, 4H), 2.33 (s, 3H), 3.29 (m, 1H), 3.g (m, 2H), 5.26 (d, J-11, lH), 5.42 (m, lH), 6.9-7.3 (m,16H).
'3C-NMR 5~, CDCI3, TFA): 22.2, 28.1, 38.8, 39.0, 45.6, 48.4, 52.5, 60.9, 116.6, 125.1, 125.4, 126.6, 126.7, 127.3, 128.9, 130.5, 130.9, 131.0, 135.2, 143.9, 157, 164, 175.
IR (cm. ', K13r~: 1670, 1640 (broad, C=O).
FAB MS (%): 565 (parent+1, 58), 492 t71), 211 (100), lS7 (91), 132 (53(, 115 ~42), 91 (49).
Anal. Calc'd. for C3,H34N"O3CIF-1/2H20: C 64.86, H 6.14, N 9.76. Found: C
64.79, H 5.93, N 9.42.

1-(t-Butylacetamido)-3-~S-methyl. 4-chloroph~nylureido)-5.7-. diPhenylhexahydroaz-epin-2-one Prepared from the more polar isomer of 1 -(t-butylac~tamido)~amino-5,7-phenyl-hexahydroazepin-2~n e in Example 60 in analogy with the procedure given in Ex~nple 94 in 70% yield, mp 16~171 C.
1H-NMR (~, CDCI3): 1.19 (singlct, 9H), 2.0-2.3 (m, 3H), 2.24 (s, 3H), 2.62 (m, lH), 3.17 (m, 1H), 3.S8 (AB~" JA~ = 16, Dn=212, 2H), 6.18 (d, J=11, lH), 6.2 (m, lH), 6.87 (d, J=7,111), 7.~7.4 (m, 1SH), 8.03 (bs, lH).
l3C-NMR (~, CDC.3): 20.1, 2~.6, 38.3, 40.0, 46.3, 48.2, 51.3, 52.4, 61.2,118.3, 126.6,126.9,127.1,127.4,128.6,128.7,128.9,129.0,129.2,129.3,129.4,129.5,136.3, 138.3, 138.4, 145.2, 155.4, 167.6, 175.4.
IR (cm. ', KBr): 1660, 1640 (broad, C=O~.

~VO 93~15059 C ~ 2 1 1 ~ 3 6 7 PCT/US92/10720 -10~ Z~736 FAB MS (%): 561 (parent+1, 22), 488 (37), ~94 (30), 133 (100~,132 (40), 119 (47), 115 (43), 91 (62).
Anal. Calc'd. for C32H3,N4O3CI-1/2H2O: C 67.41, H 6.72, N 9.83. Found: C
67.41, H 6.73, N 9.76.

Butvlac~tamido)~(3 nitroPhenvlur~ldo)-5.?~iPhenvlhexahvdroazepin-2~ne Prepared from the more polar isomer of 1 -(t-butylacetamido~rnino 5,7phenyl-hexahydroazepln-2~ne In Example 60 in 64% yie.d, mp 182-185C.
'~NMP( (~ D3SOCD3~: 1.15 (singlst, 9H), 1.~2.1 (m, 3H), 2.63 (m, lH), 3.3 (m, lH), 3.52 ~ " JA~ = 16, Dn=228, 2H), 5.13 (m, lH), 5.32 (d, J-11, lH), 6.~7.7 (m, 15H), 8.54 (s, lH), 9.56 (s, 1H).
13C-NMR (~, CD3SOCD3): 28.5, 44.9, 47.0, 50.0, 51.6,59.4,126.4,126.8,128.5, 128.7,129.4,139.2,141.8,146.2,148.2,153.8,167.2,173.1.
IR (cm:', KBr): 1660,1640 (broad, C=O).
FAB MS (%): S58 (parcnt+1, 20~, 485 (23), 193 (67), 155 (52), 135 (35), 119 t100), 103 (48), 91 (39).
Anal. Calc'd. for C3,H35N506-2/3H20: C 65.36, H 6.~3, N 12.29. Found: C
65.06, H 6.35, N 11.91.

1-(t-Byty!ac~mido~minoph~nvlureldo)~.7~iPhen~ xahydroaz~in-2~ne Prepared from 1-(~-butylacctamido)~(3-aminophenylur~ido)-5,7-diphenylhe~
ahydroazep~n-2-one in 90% yield by reduction with ~ equ~alents of ammonium formate in ethanol at room temperaturc in the presenc~ ot 10% palladium on carbon, mp 163-168C.
'H-NMR (~, CDCI3): 1.17 (singlet, 9H), 2.~2.3 (m, 3H~, 2.48 (m, lH), 3.18 (m, lH), 3.59 (AB". JA~ = 16, Dn=160,2H),4.08 (bs,2H), 5.1S (d, J=10, lH~,5.21 (m, lH), 5.47 (s, lH~, 6.26 (d, J=7, 1H), 6.7-7.4 (m, 15H), 8.96 (bs, lH).
'3C-NMR (~, CDCb): 28.6, 39.0, 39.6, 46.1, 48.2, 51.2, 62.2~ 60.4, 61.1, 106.6, 109.7,126.6,126.9,127.0,128.4,128.6,128.8,128.9,129.1,129.5,129.7,138.3,140.4, 145.3, 147.3, 165.4, 167.6, 175.1.
IR (cm.-', KBr): 1640 (broad, C=O).
FAB MS ~%): 528 (parent+1, 81), 455 (53), 394 (69), 193 (94), 157 (99~, 119 (1 00).

WO 93/15059 C A 2 1 1 7 3 6 7 PCr/US92/1072~-2~i} ~ 1 06-Anal. Calc'd. for C3,H37N5O3CI-H2O: C 68.23, H 7.20, N 12.83. Found: C 68.73 ~+0.50), H 7.07, N 12.43.

l-(t-Butvlacetamido~-3-(3-acetvlaminophenvlureido~-5,7-diphe nylhexahydroazeDin-2~r:e Prepared from l-(t-butylacetamidoI-3-(3-aminoph~nylureido)-5,7-diphenylhexahydroazepin-2-one 70% yield by ~cetylation ~nth acaffc anhydridQ in pyridine at r~ux for 14 hr, mp 195~205C.
lH-NMR (~, CD3SOCD3): 1.15 (singlet, 9H),1.~2.0 (m, 3H), 2.57 ~m, lH), 3.17 (m, 1H),3.51 (ABq, JAB = 16, Dn=228, 2H), 5.01 (m, 1H), 5.30 (d, J=10, lH), 6.7-7.4 (m, 15H), 7.67 (s,111), 9.01 (s, 1 H), 9.82 (bs, l H).
'3C-NMR (~, CD3SOCD3): 24.0, 28.5, 45.1,47.0, 49.9, 51.6, 59.4,112.0, 112.3, 126.3,126.8,128.0,128.1,128.5,128.7,128.8,129.3,129.4,129.5,134.6,139.3,139.7, 140.8, 146.3, 154.1, 167.3, 168.2, 173.3.
IR (cm.-l, KBr): 1660, 1~40 (broad, C=O).
FAB MS (%): 570 (parent+1, 25), 497 (29),193 (42),157 (100),119 (34).
Anal. Caic'd. ~or C33H3,~N5O" H2O: C 67.44, H 7.03, N 11.92. Found: C 67.31, H 7.08, N 11.71.
E)(AMPLE 110 1-(t-Butvlacetamido!-3-(3-methvlsulfonvlaminophenvlureido~-5 ,7-diDhenvlhexahydroaze,oin-2~ne Prepared from 1-(t-butylacetamido)-3-(3-aminoph~nylureido)-5,7-diphenylhaxahydroazepin-2-one in 69% yield by reaction with methanesuifonyl chloride in pyridine at room temperature, mp 185-192C.
lH-NMR (~, CD3SOCD3): 1.15 (singlet, 9H),1.8-2.0 (m, 3H), 2.57 (m, lH), 2.94 (s, 3H), 3.20 (m, lH), 3.50 (AB~" JA~ = 16, Dn=231, 2H), 5.09 (d, J=11, lH), 5.30 (d, J=10, lH), 6.6-7.4 (m, 16H), 9.11 (s, lH), 9.62 (s, 3H).
'3C-NMR (~, CD3SOCD3): 28.5,45.0,47.0,49.9,51.5,59.4,108.3,126.8,126.9, 128.0,12~.4, 128.5,128.6,128.7,129.3,129.4,129.5, ~29.6,139.3,141.4,146.3,153.6,3~ 167.3, 173.2.
IR (cm.-l, I<Br): 1640 (broad, C=O).
FAB MS (%): 606 (parent+1, 47), 533 ~64), 193 (100), 119 (63), 91 (59).

- ~vo 93/1~059 C A 2 1 1 7 3 6 7 PCI`/US92/10720 -1~)7- 2~36~7 Anat. Catc'd. for C32H39NsO5S-112H20: C 62.52, H 6.56, N 11.39, S 5.22.
Found: C 62.12, H 6.80, N 11.08, S 5.32.

l-(t-Butvlacetamido)-3-(3-(N-methvlureido~Dhenylureido)-5.7-5 diphenylhexahvdroaze~in-2-one Prepared from 1-(t-butylacetamido)-3-(3-aminophenylureid~)-5,7-diphenylhexahydroazepin-2-one in 45% ~eld by reaction unth mettlylisocy~nate in r~uxing tetrahydro~ran for 18 hr, mp 18~195C.
'H-NMR (~, CDCI3): 1.10 (singlet, 9H), 1.9-2.2 (m, 3H), 2.5 (m, lH), 2.60 (bs, 10 3H), 3.04 and 3.8 (multiplets, 2H), 3.28 (m, lH), 5.~5.2 (broad muttipl~t, 2H), 5.4-5.6 ~broad muttiplet, 2H), 6.~7.4 (m, 15H), 7.6 (bs, lH), 8.1 (bs, lH).
'3C-NMR (~, CDCI3~: 26.6, 28.5, 46.0, 61.1, 126.9, 127.0, 128.4, 128.6, 128.7, 128.8, 128.9, 129.0, 129.5, 129.6, remaining carbons not visible in thi~ ~can.
IR (cm. ', KBr): 1640 (broad, C=Q).
FAB MS (%): 585 (parent+1, 26), 512 (60),193 (100), 115 (42), 91 ~58).
Anal. Calc'd. for C33H~oN"O"-H20: C 65.76, H 7.02, N 13.94. Found: C 65.94, H 6.74, N 13.58.
E)(AMPLE 112 N~ MethvlcyclQhexvl) 2-L3-bromo-2:oxo-5-(phenvl)-2.3.4.5-tetrahydro-1 H-20 (l!benzazepin-l-vl! ethanoic acTd amide Prepar~d in analogywith Example 1 using N~ nethylcyclohexyl~ iodoacet~rnide toalkylate~brom~2~x~(phenyl)-2,3,4,~te~rahydro-1 H-(1)benz~zepinein75%yleld, mp 16~168C.
1H-NMR (~, CDCI3): 1.35 (s, 9H), 1.46 (s, 3H), 1.2-1.5 and 1.~2.1 (m, 10H), 2.6225 and 2.79 (muttiplets for 2 diastereomers, 1H~, 2.92 (m, lH), 4.24.7 (m, 4H), 6.0 and 6.11 (singlets, lH), 6.~7.4 (m, 9H).
l3C-I~IMR (~, CDCI3): 121.9, 22.0, 25.5, 26.4, 36.3, 36.9, 43.0, 43.1, 44.1, 44.8, 47.1, 53.7, 54.8, 55.1, 56.5, 123.2, 127.5, 127.6, 127.7, 127.8, 128.0, 128.1, 128.7, 128.8, 129.0, 137.5, 137.7, 139.0, 140.7, 141.1, 167.1, 168.2, 168.7.
IR (cm:l, ICBr): 1660 broad (C=O).
MS (%): 468/470 (parent~or BrJ9/Br~',1/1), 276 (50),250 (51),165 (40),97 (38), 55 (100). ' WO 93/15059 ` C ~ 2 1 1 7 3 6 7 PCI/US~2tlO72~-2~l7~
. ., ,. -lo~

N-(1-Methvlcyclohexyl) 2 ~3-azido-2-oxo-5-(phenyl)-2.3.4.5-tetrahydro-1 H-(1)benz~e pin-1-yll et anoic acid amide Prepared in analogy with Exarnple 1 in 419~ yield as an oil.
lH-NMR (~, ~DCI3): 1.29 (s, 9H), 1.43 (s, 3H), 1.1~1.6 and 1.~2.0 (m, 10H), 5 2.76 (m,1 H~,2.92 (m,1 H),3.09 (AB", JAB-1 5, dn=317,2H),3.97 (m,1 H),4.20 (ml 1 H), 6.t8 (bs, lH3, 6.~7.5 (m, 9H). ;
'3C-NMR (~, CDCI3): 21.8, 22.0, 25.5, 26.4, 35.7, 35.8, 36.0, 36.1, 36.3, 36.9, 37.0, 43.7, 53.4, 54.7, 58.4, 125.5, 125.6, 125.7, 125.8, 125.9, 126.0, 126.2, 126.5, 126.6,126.7,127.3,127.5,127.6,127.7,128.0,128.5,128.7,129.2,129.3,130.3,130.4, 10 137.9, 141.0, 141.1, 168.0, 170Ø
IR (cm. ', KBr): 2100 (N3) and 1675 broad (C=O). ;
FAB MS (%): 432 (parent+1, 32), 406 pO), 319 (100), 293 (92), 194 (90), 91 (92).
HRMS Calc'd. for C25H2~N5O2: 43t.2315. Found: 431.23135.
N~ Methylcyclohexyl) 2-r3-amino-2-oxv-5-(phenvl1-2.3.4!5-tetrahydro-1 H-l)benzaze pin-1-ylJ ethanoic acid amide Prepared in analogy with Example 1 in 69% yield as a white foam.
l H-NMR (~, CDCI3): 1.26 (s,9H),1.39 (s,3H),1.~1.7 and 1.~2.0 (m,1 OH),2.22 (bs, 2H), NH~), 2.5 (m, lH), 2.78 (m, lH), 3.08 (ABq, JAe=16, dn=305, 2H), 3.48 (m, lH), 4.10 (m, lH), 6.10 (bs, 1H), 6.~7.4 (m, 9H~.
13C-NMR (~, CDCI3): 21.9, 25.5, 26.4, 31.5, 36.2, 36.8, 39.7, 44.5, 50.7, 53.4, 54.4,125.3,125.4,125.5,126.2,127.2,128.3,128.5,128.8,130.2,138.7,141.6,141.~, 168.3, 175.1.
IR (cm.-', KBr): 1660 broad (C=O).
FAB MS (%): 406 (parent+1, 84), 293 (100), 237 (38), 194 (43).
HRMS Calc'd. for C25H3lN302: 405.2409. Found: 405.23807.
N~ Methylcyclohexvl) 2-~(3-ethylphenyl)ureido)-2-oxo-5-(phenyl~2~3.4.5-tetrahvdro-1H-(1)benzazQpin-1-yl1 ethanoic acid arnide Preparsd from N~ methylcyclohexyl) 2-[~amino-2~xo-5-(phenyl)-2,3,4,~
tetrahydro-lH-~1)benzazepin 1-yllethanoicacidamideasinExarnplel,mpl30-140C, 94% yield.

~0 93/lSoSg C A 2 1 1 7 3 6 7 PCI`/US92/10720 -10~ 21i~ 7 'H-NMR (~, CDCI3): 1.16 (t, J=8, 3H),1.28 (s,9H),1.37 ($, 3H),1.2-1.5 (m, 6H), 1.~2.0 (m, 4H), 2.54 (q, J=8, 2H), 2.9 and 3.1 (m, 2H), 3.24 (AB~" JAE,=16, dn=297, 2H), 4.æ (d, J=8, 1H), 4.66 (m, lH), 5.90 (bs, 1H), 6.~7.4 (m,13H), 7.71 (bs, 1H).
'3C-NMR (~, CDCI3): 15.6, 21.9, 22.0, 25.4, 26.1, 28.9, 36.4, 36.6, 37.3, 44.4, 5 50.1, 53.8, 54.0, 117.2, 119.6, 119.7, 122.5, 124.9, 125.0, 126.3, 126.4, 127.8, 127.9, 128.4,128.8,128.9,129.0,130.7,130.8,138.3,139.1,141.2,141.8,145.3,155.4,167.7, 173Ø
IR (cm. l, KBr): 1650 broad (C=O). ~-FAB MS (9~): 553 (parent+1, 32), 440 (68), 293 (84), æo (82), 194 (100), 91 10 (56).
Anal. Calc'd. for C3~H~oN"031/4H20: C 73.29, H 7.33, N 10.05. Found: C
73.30, H 7.15, N 10.25.

N~ M~thvlcvclohexyl)2-l3-(3-(3-chloroDhenvl)ureidol-2-oxo-5-(Dhenvl)-2.3.4.5-15 tetrahvdro-1 H-(1)benzazeDin-1-yll ethanoic acid amide Prepared from N-(1 rnethylcyclohexyl) 2-13~mino-2oxo-S-(phenyl)-2,3,4,5-tetrahydro-lH-(1)benzazepin-1-yl] ethanoic acid arnide as in Example 107, mp 215-æooc,~ 84% yield.
'H-NMR ~, CDCI3): 1.28 (s, 9H),1.36 (s, 3H), 1.2-1.6 (m, 6H),1.8-2.0 (m,4H), 20 2.9-3.0 (m, 2H), 3.33 (AB~" JA,=16, dn=284, 2H),4.26 (d, J=7, lH), 4.63 (m, lH), 5.79 (bs, lH), 6.6-7.6 (m, 13H), 7.99 (bs, lH).
'3C-NMR (~, CDCI3): æ.o, 22.1, 25.4, 25.9, 36.4, 36.7, 36.9, 44.5, 53.4, 54.1, 117.1,119.1,122.2,124.4,124.5,126.3,126.5,126.6,127.8,128.4,129.1,129.6,130.8, 134.3, 138.2, 140.7, 141.1, 141.7, 155.1, 167.4, 173.2.
IR (crn. l, KBr): 1650 broad (C=O).
FAB MS (%): 559/561 (parent+1, Cl35/CI37 21/8), 446 (69), 293 (55), 237 (58), 220 (92), 1a4 (100), 97 (80).
Anal. Calo'd. for C32H~5N~O,CI: C 68.74, H 6.31, N 10.02. Found: C 68.40, H
6.19, N 9.82.

N-(1-Methvlcvclohexvl~ 2-13-(3-(3-tolvl)ureido)-2-oxo~(Phenyl~-2.3.4.~tetra-hvdro-1H-(1)benzazeDin-1-vI~ ethanoic acid amide .. .

C~21 1 7367 WO 93/15059 PCI/US92/1072(~ ~

Z~i 1 1 o--Prepared from N~ methylcyclohexyl) 2-l~amino-2~xo-5-(phenyi)-2,3,4,~
tetrahydro-lH-(1)benzazepin-1-yll ethanoic acid amide as in Example 107, mp 220-225C, 85% yield. -'H-NMR (~, CDCI3): 1.28 (s, 9H),1.38 (s, 3H),1.2-1.5 (m, 6H),1.8-2.0 (m, 4H), 5 2.23 (s, 3H), 2.8 (m,1H), 3.06 (m,1H), 3.22 (AB~" J~,~=16, dn=297, 2H), 4.23 (d, J=8, 1H), 4.65 (m, 1H), 5.90 (bs, 1H), 6.5-7.4 (m, 13H), 7.68 (bs, lH).
'3GNMR (~, CDCI3): 21.5, 21.9, 22.0, 25.5, 26.1, 36.4, 37.2, 44.4, 50.1, 53.8, 53.9,116.9,117.0,120.6,123.7,124.9,126.3,126.5,127.8,128.3,128.5,128.7,129.0, 129.1, 130.7, 130.8, 138.~, 138.8, 139.0, 141.2, 141.8, 155.3, 167.6, 172.9.
IR (cm. ', l<Br): 1650 broad (C=0).
FAB MS (%): 539 (parent+1, 60), 426 (82), 293 (92), 220 (94), 194 (100), 119 (73), 97 (71), 91 (99).
E)(AMPLE 115 ~
2-(Cyclohexvll-2~henvlethanol :- :--To a 500 mL round-bottomed flask equipped with condenser and N2 inlet were added 15 g (68.8mmol) o~phenylcyclohexylacetic acid,110 mLdrytetr~hydrofuran, and 137 mL (275 mmol) of a 2M solution of borane-methyl sulfide in tetrahydrofuran. The solution was refluxed 60 hr, cooled, and evaporated. The residue was taken up carefully in 200 mL ethanol, treated wtth 2 g sodium carbonate, and refluxed 3 hr. The 20 reaction was cooled, evaporated, taken up in ethyl acetatelwater, separated, and the aqueous phase extracted wlth fresh ~thyl acetate. The organic layers were combtned, washed wtth brtne, drted over sodium sulfate, and evaporated to an oil which solidtfted on standtng. The yield was 12.27 g (87%).
'H-NMR (~, CDCI3): 0.7-1.9 (m,11H), 2.54 (m,1H), 3.7-3.9 (m,2H), 7.1-7.3 (m, 25 5H).
2-(Cvclohexyl~-2-Dhenvlethanol tosvlate To a~125 mL round-bottomed 11ask were added 12.27 g (60.15 mmol) 2-(cyclohexyl)-2-phcnylethanol and 30 mL dry pyridine. The reaction was cooled to 0C, and 13.78 g (72.18 mmol) tosyl chloride added. The reaction was let stand at 0C for 30 14 hr, poured into water, and ex~cted into ether. The ether layer was washed with 3 portions ot lN hydrochloric acid, 3 portions of saturated aqueous sodium bicarbonab solution, 2 portions w~ater, and brine, dried over sodium sulhte, and evaporated. The -`~O 93/150~9 C A 2 1 1 7 3 6 7 PCI`/US92/10720 - 2~

residue was slurried in ethanol and collected by filtration to afford a white solid, mp 9 100C, 13.1 9 (61%).
lH-NMR (~, CDCI3): 0.6-1.7 (mr 1 lH), 2.40 (s, 3H), 2.64 (m, lH), 4.1~.3 (m, 2H), 6.9-7.5 (m, 5H).
IR (cm.-', KBr): 2940 (C-H) and 1600 (C=C).
MS (%): 186 (100, parent for elimination of tosic acid), 104 (95), 91 ~70).
Anai. Calc'd. for C2lH2~,O3S: C 70.35, H 7.31. Found: C 70.æ, H 7.33.

2-(Cvclohexyl)-2-Phenvl-1 -iodoethane To a 250 mL round-bottomed flask equipped with condenser and N2 inlet were added 13.9 9 (39.4 mmol) 2-(cyclohcxyl)-2-phenyl~thanol tosylate, 80 mL aceton~ and 6.49 9 (43.3 mmol) sodium iodide. The reaction was reflux~i 36 hr, cooled, and ~vaporated. The residue was taken up in ethyl ac~tate, washad with water and aqueous sodium bisulffle solu~on, dried over sodium sulfate, and evaporated to an oil, 12.11 9 (98%), which was used directly in the naxt step.
lH-NMR (~, CDCI3): 0.7-1.9 (m, 11H), 2.60 (m, 1H), 3.4 and 3.6 (m, 2H), 7.~7.3 (m, SH).
Diethvl-(2-~cvclohexyl)-2-phenvlethyl)malonate To a 500 mL round-bottomed flask equipped with condenser and N2 inlet were added 3.05 9 (77.1 mmol) sodium hydride, which was washed with hexane and th~
hexane pipQtted off, and 100 mL dry tetrahydrohran. To the stirring suspension was added a solution of 12.34 9 (77.1 mmol) diethyl maionate in 50 mL drytetrahydrofuran dropwise over 30 min. Once gas evolution had ceased, a solution of 12.11 9 (38.S7 mmol) 2-(cyclohexyl)-2-phenyl-1-iodoethane in 40 mL dry t~trahydrofuran was added, 25 and the reaction refluxed 3 days. The reaction was concentrated, poured into 1N
hydrochloric acid, and extracted twice into ethyl acetate. The combined organic layer was washed with water, 3 porUons of aqueous sodium bisul~'tte solution, and brine, dried over sodium sulfate, and evaporatcd. The residue was chromatographed on silica gel using hexane/ethyi aQetate as eluant to afford an oil, 12.53 9 (87%).
lH-NMR (~, CDCI3): 0.~2.0 (m, 12H), 1.12 (t, J-7, 3H), 1.20 (t, J=7, 3H), 2.24 (m, lH), 2.32 (m, lH), 2.95 (dd, J=4,10, lH), 3.98 (m, 2H), 4.15 (m, 2H), 6.~7.2 (m, 5H)-WO93/15059 C~ 2 1 1 i73b~ PCr/USs2/10720 2~ 67 ` -1 12-l3C-NMR (~, CDCI3~: 13.9, t4.1, 26.4, 26.5, 3t.1, 31.2, 32.0, 43.3, 49.7, 50.3, 61.0, 61.2, 126.3,12R.2, 128.5, 142.6, 169.4, 169.6.
IR (cm.-', KBr): 1738 (C=O).
MS (%): 346 (parent, 12), 160 (100), 114 (60), 28 (59).
HRMS Calc'd. for C2lH3004: 346.2136. Found: 346.21838.
~Cvclohexvl-~Dhenylbutanoic acid To a 250 mL round-bottomed flask equipped with condenser and N2 inlet were added 12.53 9 (36.2 mmol) diethyl-(2-(cycloh~xyl)-2-phenylcthyl)malonate,80 mLacetic acid, and 25 mL 6N hydrochloric acid. The r~action was refluxed 20 hr, cooled, poured 10 into water, and extracted into ethyl acetate. The organic phas~ was washed with water and brine, dried over sodium suffate, and evaporated. Evaporation ~rom heptane removed traces of water to afford an oil, 9.78 g (99% crude yield).
H-N.\IIR (~, CDCI3): 0.~2.3 (m, 16H), 7.~7.3 (m, 5H).
l3C-NMR (~, C:DCI3): 26.5, 27.7, 31.2, 31.3, 32.6, 43.2, 51.6, 126.2, 128.3, t28.5,143.3, 180.8.
IR (cm.-l, KBr): 1720 (C=0).
MS (%~: 246 (parent, 13), 173 (45), 163 (52), 117 (78), 1~4 (100), 91 (79), 55 (48).
HRMS Calc'd. for C,~,H2202: 246.1614. Found: 246.15968.
The remaining steps were carried out as described for the analogous compounds inExample 22:
Cyclohexyl-1.2.3.~tetrahvdronaphth-1-one Prepared as an oil in 74% yi~ld.
lH-NMR (~, CDCI3?: 1.9-2.1 (m,5H),1.~1.8 (m,6H),2.0-2.2 (m,2H),2.42.7 (m, 3H), 7.~7.3 (m, 3H), 7.88 (m, lH).
'3C-NMR (~, CDCI3): 24.3,26.3,26.5,30.5,35.0,39.9,44.0,126.6,127.4,129.2, 132.3, 132.6, 147.3, 198.6.
IR (cm.1, ~CBr): 1690 (C=0).
MS (96): 228 (parent, 7), 146 (100), 55 (20).
HRMS CaWd. tor Cl"H20O: 228.1509. Found: 228.15016.
~CYclohexvl-1.2.3.~tetrahydronaphth-1~nQ oxime Prepared as a solid, mp 12~123C in 71% yield.

CA21 i 7367 ~093/1~059 PCI`~US92/10720 Zl~

lH-NMR (~, CDCl3): 0.~1.7 (m,11H),1.88 (m, lH), 2.12 (m, lH), 2.39 (m,1H), 2.79 (m, 2H), 7.0-7.3 (m, 3H), 7.77 (m, tH).
l3C-NMR (~, CDCl3): 20.5,22.4,26.3, 26.4,31.0, 32.0,38.8,44.9,124.6,126.6, 128.i~, 129.7, 129.9, 143.2, 155.6.
IR (cm. t, KBr): 1640 (weak) (C=N).
Anal. Calc'd. for C,~,H2,NO: C 78.97, H 8.70, N 5.75. Found: C 78.83, H 8.74, N S.64.
5-Cyclohexv1-2.3.4.5-t~trahydr~1 H-(1)benzaze~in-2~ne Prepared as a white solid, mp 12~128C, in 80% yield.
'H-NMR (~, CDC13): 0.6-2.0 (m,12H), 2.2-2.4 (m, 3H),2.59 (m,1H), 6.~7.2 (m, 4H), 8.80 (bs, lH).
l3C-NMR (~, CDCl3): 26.3, 26.4, 31.0, 31.6, æ.5, 32.7, 38.7,45.8,122.4,125.3, 126.9, 128.6, 136.3, 138.2, 176.1.
IR (cm.-1, KBr): 1680 (C=O).
MS (%): 243 (40, parent), 160 (tO0), 132 (32), 118 (37).
Anal. Calc'd. for CloH2lNO: C 78.97, H 8.70, N 5.75. Found: C 78.77, H 8.71, N 5.66.
~Bromo-~cyclohexvl-2.3.4.5-t~trahydro-1 H-(1 ~benzazeDin-2-one Prepared as a white solid, mp 104 107C, in i54% yield.
'H-NMR (~, CDCl3): 0.6-2.0 (m, 11H), 2.25 (m, lH), 2.69 (m, 2H), 4.37 (dd, J=7,11, lH), 7.~7.3 (m, 4H), 8.90 (bs, lH).
'3C: NMR (~, CDCl3): 26.1, 26.4, 30.3, 32.3,38.0,44.2, 44.9,48.0,123.1,126.5, 126.9, 127.2, 135.3, 137.3, 169.6.
N-t-Butyl 2-~3-bromo-2-oxo-~cvc!o_e~yl-2.3,~L5.-tetrahvdro-1 H-~1 Ibenzazepin 25 -1-yl1ethanoic acid amide ``
~repared as a mixture of diaster~omers, which separated into the less polar isomer, mp 18~189.5C,36% yield, and the mor~ polar isomer, mp 190.5~192C,58%
yield. `
Less polar isomer:
lH-NMR (~, CDCl3): 0.42.0 (m, 11H), 1.36 (s, 9H), 2.39 (m, lH), 2.61 (m, 2H), 4.01 (AB~" JAE =15, Dn=381,2H), 4.59 (dd, J=8,12, lH), 6.25 (bs, lH), 6.9-7.4 (m,4H~.
l3~NMR (~, CDCl3): 26.1, 26.2, 28.7, æ.2, æ.5, 40.1, 4~.5, 47.4, 50.3, 51.5, 55.7, 124.7, 127.5, 12B.6, 131.4, 136.0, 141.4, 167.6, 168.6.

WO 93~15059 C A ~ I 1 7 3 6 7 PCr/US92/10720 ~ . . ;
2~7367 -1 14-More polar isomer:
lH-NMR (~, CDCI3): 0.~1.9 (m,11H), 1.31 (s, 9H), 2.06 (m, 1H), 2.65 (m, 2H), 4.26 (ABq, JA,~=15, Dn=32, 2H), 4.2 (m, lH), 6.22 (bs, lH), 7.1-7.3 (m, 4H).
'3C-NMR (~, CDCI3): 26.0, 26.3, 26.4, 28.7, 30.3, 32.0, 37.7, 43.7, 45.4, 48.1, 6 51.4, 54.8, 123.6,126.1, 127.5, 127.6, 127.7~ 136.2, 142.0, 167.1, 168.4.
N-tert-But~-r3-azido-2~xo-~c~clohexyl-2.3.4.~tetrahydro-1 H-(~benzazepin-l -yll ethanoic acid amide Prepared *om the mor~ polar diastereomer in the previous step in 4796 yield, mp 13~139C.
1H-NMR (~, CDCI3): 0.4-2.0 (m,11H), 1.34 (s, 9H), 2.22 (m, lH), 2.43 (m, 2H), 3.84 (m, 1H~, 4.04 (ABq, J~8=15, Dn=291, 2H), 6.32 (bs, 1H), 7.~7.4 (ml 4H).
l3C-NMR (~, CDCI3): 26.0, 26.1, 26.2, 28.6, 32.2, 32.5, 36.6, 40.2, 47.7, 51.5, 55.1, 58.4, 124.6,127.4, 128.6, 131.3, 136.4,140.7,167.7, 170.8.
N-t~-Butyl 2-r3 amin~2~x~5~cloh2xv~2.3.4~tetrahydr~1 ~tl )benzazeDi~l-15 vll ethanoic acid amide Prepared as a solid, mp 10~115C, in quantitative yield.
lH-NMR (~, CDCI3): 0.~1.7 (m, 10H), 1.31 (s, 9H), 1-.98 (m lH), 2.18 (m, lH~, 2.39 (m, lH),2.62 (m, lH),3.79 (m, lH),4.08 (ABq, ~=lS, Dn=364,2H), 5.5 (bs,2H),6.61 (bs, lH), 7.~7.3 (m, 4H).
l3~NMR (~, CDCI3): 25.9, 26.2, 28.7, 32.2, 32.3, 37.7, 39.9, 47.9, 50.6, 51.7, 54.1, 124.1, 127.3, 128.5, 131.6, 136.6, 140.4, 167.7, 172.1.
N-tert-Butvl 2-~(~(Stoh/l)ureido)-2-oxo-5 cvclohex~l-2.3.4.5-tetr~hydro-1 H-(l)benzazepin-l-~ll ethanoic acid amide Prapared as a white solid, mp 22~228C, 67% yield.
lH-NMR (~, CDCI3): 0.54 (m,1H), 0.~1.8 (m, 9H),1.35 (s, 9H), 2.~2.2 (m, 2H), 2.49 (m, lH), 2.64 (m, lH), 4.17 (ABq, ~IAB=16, Dn=408, 2H), 4.52 (m, lH), 6.23 (d, .)=7, lH), 6.28 (s, lH), 6.7-7.3 (m, 8H), 7.62 (s, 1H).
'3C-NMR (~, CDCI3): 21.4, 26.1, 26.2, 26.3, 28.7, 32.S, 32.5, 37.6, 40.4, 48.2, 50.6, 51.8, 54.0, 116.8, 120.5, 123.4, 123.5, 127.3, 128.4, 128.5, t28.6, 131.~, 136.7, 13B.6, 139.0, 140.9, 155.5,167.5, 174.1.

te1t-Butvl 2-~(3-(~chloro~henyl)ureido)-2~xo~cYdohexyl 213.4.5-tetrahydr~
1 H-(l )benzæepi~1-vll ethanoic acid amid_ WO 93/lSOS9 C A 2 1 1 7 3 6 7 PCl-/US92/10720 Z~1736'7 r~~ rJ, ,~ ~ ~

Prepared from N-tert-butyl 2-[~amino-2-oxo-S-cyclohexyl-2,3,4,5-tetrahydro-1 H-(1)benza zepin-1-yl] ethanoic acid arnide as in Example 115 as a white solid, mp æ~
226C, 48% yield.
lH-NMR (~, CDCI3): 0.52 (m, 1H), 0.8-1.8 (m, 9H), 1.37 (s, 9H), 1.98 (m, lH), 5 2.13 (m, lH), 2.48 (m, lH), 2.58 (m, lH), 4.23 (AB," ~e=16, Dn= 408, 2H), 4.48 (m, lH), 6.28 (s, 1H), 6.39 (~, J=7, 1H), 6.8-7.3 (m, 7H), 7.55 (s, 1H), 8.01 (s, 1H).
l3C-NMR (~, CDCI3): 26.1, 26.2, 28.7, æ.3, 32.5, 37.2, 40.3, 48.2j 50.7, 52.1, 53.6,116.9,118.9,119.0,122.1,123.0,127.4,128.6,129.4,131.8,134.2,136.6,140.5, 140.7, 155.2, 167.4, 174.5.

N-tert-Butyi 2-r3-~3-~ethvlDhenvl)ureido)-2-oxo-5-cycloh~xvl-2.3.4.5-tetra-hvdro-l H-~l )benzazepin-1 -yll ethanoic acid amide Prepared from N-brt-butyl 2-l~amino-2 oxo-S-cyclohexyl-2,3,4,5-tetrahydro-1 H-(l)benza zepin-l-yll ethanoic acid amide as in Lxample 115 as a white solid, mp 145-15 155C, 61 % yield.
lH-NMR (~, CDCI3): 0.48 (m, lH), 0.7-1.7 (m, 9H), 1.30 (t, J=7.5, 3H), 1.35 (s, 9H), 1.9-2.1 (m, 2H), 2.47 (q, J=7.5, 2H), 2.62 (m, 1H), 4.1~ (AB~" J~"=16, Dn=4Q4, 2H), 4.50 (m, lH), 6.2S (d, J=7, 1H), 6.26 (s, 1H), 6.7-7.3 (m, 8H), 7.63 (s, 1H).
'3C-NMR (ô, CDCI3): 15.6, 26.1, 26.2, 26.3, 28.7, 28.9, 32.3, æ.5, 37.7, 40.4, ;
20 48.2, 50.5, 51.8, 54.1, 117.1, 119.4, 119.5, 122.4, 123.4, 123.5, 127.3, 128.5, 128.7, 131.7, 136.7, 139.0, 140.9, 145.1, 155.4, 167.6, 176Ø
i3CAMPLE 118 4(4FiuoroDhenyl)~4hydroxycyclohexanone ethvhneketai Prepared in analogy with J. Med. Chem., 1992, 35, 320-324 as follows: To a 25 1 L round-bottomed flask equipped with N"nlct were added 46.8 9 (0.30 mol) cyclohexane-1,4~ione monoethylene ketal and 500 mL dry tetrahydrofuran. The soluUon was cooled to -78C, and 150 mL of a 2.0 M solution (0.30 mol) ot 4- ``
... .
fluorophenylmagnesium bromide in ether was added dropwise over 30 min, then the reaction was stirred for 10 min and warrned to room temperature. The reaction was 30 poured hto ice/water, the layers separahd, and the aqueous phase extracted wnh ether. The combined organic phase was dried over sodhm suifate and evaporated toa an oil, which was triturated with ether to a white, low-meiting solid, 24.3 9 (32%).

WO 93/150S9 C ~ 7 PCI/US92/10720 .
21~367 lH-NMR (~, CDCI3): 1.~1.8 (m, 4H), 2.05 ~m, 4H), 3.95 (bs, 4H), 6.96 (m, 2H), 7.61 (m, 2H).
l3C-NMR (~, CDCI3): 30.7, 36.7, 64.2, 64.4, 72.1, 108.3, 114.8, 115.1, 12~.2, 126.3, 144.
MS (%): 234 ~7, par~nt-H20), 123 (15), 99 (100), 86 (60).

~Fluoro~h~nyl)cvclohexanone A solution of 5.0 9 (19.8 mmol) ~(~fluorophenyl) 4 hydroxycyclohexanone e~hylene ketal in 170 mL dioxana was treated with 5.0 9 10% palladium~r~carbon 10 under 35 p.s.i. hydrogen for 24 hr, then tilter~d through Cel~R to remove the catalyst.
The filtrate was treated ~nth 100 mL water and 3.5 mL concentrat~d hydrochloric acid, and stirred at room temperatur~ for 24 hr. The solution was evaporated, the pH
adjusted to 8 wiU~ saturated aqueous sodium bicarbonate solution, and extracted u~th m~thylene chloride. The organic layer was driad over sodium suHata amd evaporat~d.
15 The residue was chromatographed on silica gel using methylena chloride as elu~nt to afford 2.9 g (~4%) of an oil.
'H-NMR (~, CDCI3): 1.83 (m, 2H), 2.12 (m, 2H), 2.42 ~m, 4H), 2.96 (m, lH), 6.
7.2 (m, 4H)-'3~NMR (~, CDCI3): 34.1, 35.1, 41.3, 42.0, 115.2, 115.S, 128.0, 128.1, 140.4, 140.5, 159.9, 163.1, carbonyl carbon not ~isible in this scan.
IR (cm. l, CHCI3): 1705 (C=0).
MS (%): 192 (90~,135 (60),122 (100),109 (65), 57 (15).
HRMS Calc'd. for Cl2Hl3FO: 192.0947. Found: 192.0983.
The remainder of the synthesis was carried out as described in Exarnple 60:
2-Chloro~(~fluoroDhenvllcyclohexanone Prepared as an oil in 93% yield.
tH-NMR (~, CDCI3): 1.~3.7 (series o~ multipl~ts,7H), 4.67 u~d 5.34 (multiplets, .... .
1 H), 6.8-7.2 (m, 4H).
l3C-NMR (~, CDCI3): 33.4, 33.9,34.3, 35.9, 40.4, 42.8, 45.5, 63.2,115.5,115.7, 30 128.0, 128.1, 128.2, 128.3, carbonyl carbon not visible In thls scan.
MS (%~: 226 (55, parent), 171 (85), 122 (100), 109 (95), 55 (45).
2-Phenyl~(~fluoroPhenyl)cyclohexanQne Prepared as an oil in 29% yield.

-`~0 93/15059 C ~ 2 I 1 7 3 6 7 PCI/US92/10720 -11 7- 211736~

1H-NMR (~, CDCI3): 2.~2.4 (m, 4H), 2.64 (rn, 2H), 33.24 (m, 1tJ), 3.79 (dd, J-5,13, 1H), 6.~7.4 (m, 9H).
MS (%): 268 (100, parent), 224 (90), 135 (65), 122 (95), 109 (75), 91 (99).
2-Phenyl 4-(4-fluoroPhenyl)cyclohexanone oxime Prepared as a light yellow solid, mp 192-194C, in 64% yield.
1H-NMR (~, DMS0-d~ 1.5-2.2 (m, 4H), 3.02 (m, 1H), 3.42 (m, 1H), 3.66 (dd, J=4,13, 1H), 7.~7.3 (m, 9H).
'3C-NMR (~, DMSO-do): 24.1, 32.7,41.3,42.3,48.3,114.9,115.1,126.0,127.7, 128.5, 128.6, 128.9, 141.5, 142.0, 158.7, 159.12, 162.3.
$(4F3yoropheny~ phenyl-hexahydroazepin-2-one Prepsred as a light yellow foam in 53% yield.
~H-NMR (~, CDCI3j: 1.8-2.2 (m, 4H), 2.70 (m, 2H), 2.93 ~m, 1H), 4.58 (m, 1H), 5.72 (bs, 1H) N~), 6~7.4 (m, 9H).
l3C-NMR (~, CDCI3): 30.5, 36.2, 45.4, 46.2, 47.8, 58.0, 115~3, 11S.6, 115.7, 116.0, 125.5, 126.3, 127.6, 128.0, 128.4, 129.2, 141.8, 141.9, 163.1, 176.4.
FAB MS (%): 284 (100, parent+1), 180 (37), 109 (10), 91 (11).
~Bromo-5-(~fluorophenyl!-7-pheny!-hexahydroazepin-2~ne Prepared as a mixture of diastereomers as a toarn in 63% yield.
lH-NMR (~, CDCI3): 2.0-2.6 (m, 4H), 3.12 (m, 1H), 4.50 (m,1H), 4.86 and 4.98 (multiplets tor the diastereomers at the ~position, 1 H), 5.87 (bs, 1H) NO, 6.9-7.4 (m, .
9H)-l3C-NMR (~S, CDCI3): 42.0, 42.6, 44.1, 46.2, 47.2, 50.3, 57.3, 57.6, 59.1, 115.5, `~
115.8, 126.2, 128.0, 128.1, 128.8, 129.4, 140.1, 141.0, 160.1,163.3, 169.6.
IR (cm. l, KBr~: 1670 (C=O).
N-ft-Butyl)-2-oxo-3-bromo-5-(4-fluoroDhenyl)-7-phenvl-hexahydroazepin-1-yl ethanoic amide Prepared as a mixture of diastereomers as a foam in 73% yield.
lH-NMR (~, CDCI~` l .27 and 1.29 (singlets tor the t NO dlastereomers,9H), 2.0-2.6 (m, 4H), 3.1 (m, lH), :~.56 (m, 1H), 5.02 (m, lH), 5.44 (m,111), 6.9-7.3 (m, 9H).
N-~t-Butvl~-2-oxo-3-azido-5-~4-fluorophenvQ-7-phenvl-hexahydroazeDin-1-vl ethanoic unide Prepared as a mixture of diasterbomers as a foam in % yield.

WO 93/lSOS9 ~ A 2 I 1 7 3 6 7 PCI/US92/1072(~-`

-118- ' lH-NMR (~, CDCIJ: 1.28 and 1.36 (singlets, 9H), 2.0-2.3 (m, 3H), 2.5 (m, lH), 3.10 (m, lH), 3.51 and 3.79 (AB~,'s, JAB=15~ Dn=238 and æ6, 2H), 4.1 and 4.52 (multiplets, 1 H), 4.90 and 5.09 (multiplets, 1 H), 5.50 and 5.90 (singlets, 1 H), 6.9-7.5 (m 9H).
l3~NMR (~, CDCI3): 28.7, 28.8, 37.1, 37.6, 39.2, 40.5, 45.4, 48.3, 51.5, 52.1, 60.9, 61.2, 62.0, 115.5, 115.8, 125.9, 128.1, 128.S, 128.4, 128.~, 129.0, 129.4, 137.9, 140.1, 167.5, 170.7, 172.2.
N-(t-Butyl)-2-oxo-3-amino-5-(4-~luoroDhenyl)-7-phenyl-hexahydroazepin~
ethanoic amide Prepared as a ham in % yi~id.
lH-NMR (~, CD30D): 1.21 (s, 9H), 2.0-2.3 (m, 3H), 2.70 (m, 1H), 3.30 (bs over a multiplet, 3H), 3.73 (AB~, JAE,=17, Dn=178, 2H), 4.80 (d, J=ll, lH), 5.23 (d, ~
lH), 6.9-7.4 (m, 9H). ~`
N-(t-Bllqf)-?-ox-o-~(3-tolylureido)-5-(4nuoroDhenyl~7-phen~hexahydroazepin 15 vl ethanoic amide Prepared as an amorphous solid in 62 % yield.
lH-NMi~ (~, CDCI3,TFA): 1.20 (s, 9H), 1.9-2.4 (m, 4H), 2.33 (s, 3H), 3.26 (m, lH), 3.~4.0 (m, 3H), 5.23 (m, 1H), 5.37 (m, 1H), 6.9-7.5 (m, 15H).

~t-Butyl)-2-oxo-3-(3-chlorophenvlureido)-5-(4-fluoroDhenvl)-7-phenvl-hexahvdroazepin-l-vl ethanoic amide Prepared from N-(t-butyi)-2-oxo~amino-5-(4-fluorophenyl)-7-pheny~hexahy droazepin-l-yl ethanoic amide as in Example 118 as an amorphous solid in 54.5 %
yield.
1H-NMR (~, CDCI3,TFA): 1.20 (s, 9H), 2.00 (m, lH), 2.2-2.5 (m, 3H), 3.29 (m, lH), 3.86 (m, lH), 3.91 (AB", J~"=16, Dn=42, 2H), 5.25 (d, J=ll, lH), 5.41 (d, J=ll, 1H), 6.9-7.4 Im, 1SH).

:~ N-(t-Butyl)-2-oxo-3-(3-methoxvphenvlureido)-5-~4-fluorophenyl)-7-phenyl-~; 30 hexahvdroazepin-l-yl ethanoicamide Prepared from N-(tbutyl)-2-oxo~amino~(~uorophenyl)-7-phenyl-hexahy droazepin-1-yi ethanoic amide as in Example 118 as an amorphous solid in 55 % yieid.

~o 93/lSOS9 C ~1 2 I ~ 7 3 6 7 PCI`/US92/10720 t `
-lt~

tH-NMR (~, CDCI3,TFA): 1.19 (s, 9H), 1.97 (m, 1H), 2.2~2.5 (m, 3H), 3.29 (m, lH), 3.82 (s, 3H), 3.83 (m, lH), 3.92 (A8~t, JA8=17, Dn=51, 2H), 5.23 (d, J=11, lH), 5.38 (d, J=ll, lH), 6.7-7.4 (m, 15H).
.

Claims (17)

1. A compound of the formula I

or II

wherein Y1 and Y2 are independently selected from the group consisting of phenyl, hydrogen, thienyl, pyridyl, furyl, pyrimidyl, (C3-C8) straight or branched alkyl and (C3-C8) cycloalkyl, wherein said phenyl, thienyl, pyridyl, furyl, and pyrimidyl may optionally substituted with one or two substituents independently selected from the group consisting of halo (e.g., chloro, fluoro, bromo or iodo), (C1-C8) alkyl, (C1-C8) alkoxy, nitro, amino and trifluoromethyl, and wherein said cycloalkyl may optionally be substituted with one or two substituents independently selected from (C1-C8) alkyl; with the proviso that one of Y1 and Y2 must be other than hydrogen;
W is hydrogen, methyl, ethyl, chlorine, fluorine, methoxy or trifluoromethyl;
Z1 and Z2 are independently selected from the group consisting of halo, (C1-C8) alkyl, (C1-C8) thioalkyl, (C1-C8) alkoxy, trifluoromethyl, (C1-C8) carboalkoxy, cyano, methylamino, diethylamino, isopropylamino, t-butylamino, methylsulfonylamino, acetylamino, amino and nitro;
R1 is phenyl, CO2R2, SO4NR3R6 or CONR4R5, wherein said phenyl may optionally be substituted with one or two substituents independently selected from the group -120a-consisting of halo, (C1-C6) alkyl, (C1-C?) alkoxy, nitro, amino and trifluoromethyl, and wherein R2, R3, and R6 are independently selected from hydrogen, (C3-C12) alkyl and fused, saturated, carbocyclic systems containing two or three rings, and R4 and R5 are independently selected from hydrogen, benzyl, (C3-C12)alkyl and fused, saturatedcarbocyclic systems containing two or three rings.

or a pharmaceutically acceptable salt thereof.

2. A compound according to claim 1, wherein said compound is a compound of the formula I wherein either both of Y1 and Y2 are phenyl or one of Y1 and Y2 is cyclohexyl, or a pharmaceutically acceptable salt of said compound.

3. A compound according to claim 1, wherein said compound is a compound of the formula II wherein Y1 is phenyl, or a pharmaceutically acceptable salt of said compound.

4. A compound according to claim 1, wherein said compound is selected from the group consisting of:
tert-butyl-2-[3-((3-chlorophenyl)ureido)-2-oxo-7-cyclohexyl-hexahydrozapin-1-yl]ethanoate;
tert-butyl-2-[3-((3-tolyl)ureido)-2-oxo-7-cyclohexyl-hexahydroazepin-1-yl]ethanoate;
(1-adamantyl)-2-[3-((3-chlorophenyl)ureido)-2-oxo-7-cyclohexyl-hexahydroazepin-1-yl]ethanoate;
(2-adamantyl)-2-[3-((3-chlorophenyl)ureido)-2-oxo-7-cyclohexyl-hexahydroazepin-1-yl]ethanoate;
(1-adamantyl)-2-[3-((3-tolyl)ureido)-2-oxo-7-cyclohexyl-hexahydroazepin-1-yl]ethanoate;
(2-adamantyl)-2-[3-((3-tolyl)ureido)-2-oxo-7-cyclohexyl-hexahydroazepin-1-yl]ethanoate;
tert-butyl-2-[3-((3-chlorophenyl)ureido)-2-oxo-6,7-diphenyl-hexahydroazepin-1-yl]ethanoate;
(1-adamantyl)-2-[3-((3-methoxyphenyl)ureido)-2-oxo-7-cyclohexyl-hexahydroazepin-1-yl]ethanoate;
(2-adamantyl)-2-[3-((3-methoxyphenyl)ureido)-2-oxo-7-cyclohexyl-hexahydroazepin-1-yl]ethanoate;
tert-butyl-2-[3-((3-chlorophenyl)ureido)-2-oxo-6,7-diphenyl-hexahydroazepin-1-yl]ethanoate;
tert-butyl-2-[3-((3-tolyl)ureido)-2-oxo-6,7-diphenyl-hexahydroazepin-1-yl]ethanoate;

tert-butyl-2-[3-((3-methoxyphenyl)ureido)-2-oxo-5,7-diphenyl-hexahydroazepin-1-yl] ethanoate;
(1-adamantyl)-2-[3-((3-chlorophenyl)ureido)-2-oxo-5,7-diphenyl-hexahydroazepin-1-yl]ethanoate;
N-tert-butyl 2-[3-(3-(3-chlorophenyl)ureido)-2-oxo-5-phenyl-2,3,4,5-tetrahydro-1H-(1)benzazepin-1-yl] ethanoic acid amide;
N-tert-butyl 2-[3-(3-(3-tolyl)ureido)-2-oxo-5-phenyl-2,3,4,5-tetrahydro-1H-(1)benzazepin-1-yl] ethanoic acid amide;
N-tert-butyl 2-[3-(3-(3-methoxyphenyl)ureido)-2-oxo-5-phenyl-2,3,4,5-tetrahydro-1H-(1)benzazepin-1-yl] ethanoic acid amide;
N-tert-butyl 2-[3-(3-(3-thiomethylphenyl)ureido)-2-oxo-5-phenyl-2,3,4,5-tetrahydro-1H-(1)benzazepin-1-yl] ethanoic acid amide;
N,N-di(2-propyl) 2-[3-(3-(3-chlorophenyl)ureido)-2-oxo-5-phenyl-2,3,4,5-tetrahydro-1H-(1)benzazepin-1-yl] ethanoic acid amide;
N,N-di(2-propyl) 2-[3-(3-(3-tolyl)ureido)-2-oxo-5-phenyl-2,3,4,5-tetrahydro-1H-(1)benzazepin-1-yl] ethanoic acid amide;
N,N-di(2-propyl) 2-[3-(3-(3-methoxyphenyl)ureido)-2-oxo-5-phenyl-2,3,4,5-tetrahydro-1H-(1)benzazepin-1-yl] ethanoic acid amide;
N,N-di(2-propyl) 2-[3-(3-(3-thiomethylphenyl)ureido)-2-oxo-5-phenyl-2,3,4,5-tetrahydro-1H-(1)benzazepin-1-yl] ethanoic acid amide;
tert-butyl 2-[3-(3-(3-chlorophenyl)ureido)-2-oxo-5-phenyl-2,3,4,5-tetrahydro-1H-(1)benzazepin-1-yl] ethanoate;
tert-butyl 2-[3-(3-(3-tolyl)ureido)-2-oxo-5-phenyl-2,3,4,5-tetrahydro-1H-(1)benzazepin-1-yl] ethanoate; and tert-butyl 2-[3-(3-(3-methoxyphenyl)ureido)-2-oxo-5-phenyl-2,3,4,5-tetrahydro-1H-(1)benzazepin-1-yl] ethanoate;

5. A pharmaceutical composition for treating or preventing a condition selected from the group consisting of pain, gastrointestinal disorders and central nervous system disorders in a mammal, comprising (a) an amount of a compound according to any one of claims 1 through 4 effective in preventing or treating such condition and (b) a pharmaceutically acceptable carrier.

6. A use of a compound according to any one of claims 1 through 4 in preparing a pharmaceutical composition for treating or preventing a condition selected from the group consisting of pain, gastrointestinal disorders, and central nervous system disorders in a mammal.

7. A pharmaceutical composition for antagonizing the effects of cholecystokinin in a mammal, comprising (a) a CCK-B
antagonizing effective amount of a compound according to any one of claims 1 through 4 and (b) a pharmaceutically acceptable carrier.

8. A use of a compound according to any one of claims 1 through 4 in preparing a pharmaceutical composition for antagonizing the effects of cholecystokinin in a mammal.

9. A compound of the formula:

123a XVI

wherein R7 is CH2R1;
R1 is hydrogen, phenyl, CO2R2, SO2NR3R6 or CONR4R5, wherein said phenyl may optionally be substituted with one or two substituents independently selected from the group consisting of halo, (C1-C6) alkyl, (C1-C6) alkoxy, nitro, amino and trifluoromethyl, and wherein R2, R3, and R6 are independently selected from hydrogen, (C3-C12) alkyl and fused, saturated, carbocyclic systems containing two or three rings, and R4 and R5 are independently selected from hydrogen, benzyl, (C3-C12) alkyl and fused, saturated carbocyclic systems containing two or three rings;
R8 is bromine, amino or azido;
W is hydrogen, methyl, ethyl, chlorine, fluorine, methoxy or trifluoromethyl; and Y1 and Y2 are independently selected from the group consisting of hydrogen, phenyl, thienyl, pyridyl, furyl, pyrimidyl, (C3-C8) straight or branched alkyl and (C5-C8) cycloalkyl, wherein said phenyl, thienyl, pyridyl, furyl, and pyrimidyl may optionally be substituted with one or two substituents independently selected from halo (e.g., chloro, fluoro, bromo or iodo), (C1-C6) alkyl, (C1-C6) alkoxy, nitro 123b amino and trifluoromethyl, and wherein said cycloalkyl may optionally be substituted with one or two substituents independently selected from (C1-C6) alkyl; with the proviso that one of Y1 and Y2 must be other than hydrogen.

10. A process for preparing a compound of the formula I

wherein Y1 and Y2 are independently selected from the group consisting of phenyl, hydrogen, thienyl, pyridyl, furyl, pyrimidyl, (C3-C8) straight or branched alkyl and (C5-C8) cycloalkyl, wherein said phenyl, thienyl, pyridyl, furyl, and pyrimidyl may optionally substituted with one or two substituents independently selected from halo (e.g., chloro, fluoro, bromo or iodo), (C1-C6) alkyl, (C1-C6) alkoxy, nitro, amino and trifluoromethyl, and wherein said cycloalkyl may optionally be substituted with one or two substituents independently selected from (C1-C6) alkyl; with the proviso that one of Y1 and Y2 must be other than hydrogen;
Z1 and Z2 are independently selected from the group consisting of halo, (C1-C6) alkyl, (C1-C6) thioalkyl, (C1-C6) alkoxy, trifluoromethyl, (C1-C6) carboalkoxy, cyano, methylamino, diethylamino, isopropylamino, t-butylamino, methylsulfonylamino, acetylamino, amino and nitro;
R1 is phenyl, CO2R2, SO2NR3R6 or CONR4R5, wherein said phenyl may optionally be substituted with one or two substituents independently selected from halo, (C1-C6) alkyl, (C1-C6) alkoxy, nitro, amino and trifluoromethyl, and wherein R2, R3, and R6 are independently selected from hydrogen, (C3-C12) alkyl and fused, saturated carbocyclic systems containing two or three rings, and R4 and R5 are independently selected from hydrogen, benzyl, (C3-C12)alkyl and fused, saturated carbocyclic systems containing two or three rings;
or a pharmaceutically acceptable salt thereof;
comprising reactring a compound of the formula IX

wherein R1, Y1 and Y2 are defined as above, with an isocyanate of the formula C6H4Z1Z2NCO, wherein Z1 and Z2 are defined as above.

11. A process according to claim 10, wherein said compound of the formula IX is obtained by reducing an azide of the formula VIII

wherein Y1, Y2 and R1 are defined as in claim 10.

12. A process for preparing a compound of the formula II

wherein Y1 and Y2 are independently selected from the group consisting of phenyl, hydrogen, thienyl, pyridyl, furyl, pyrimidyl, (C3-C8) straight or branched alkyl and (C6-C9) cycloalkyl, wherein said phenyl, thienyl, pyridyl, furyl, and pyrimidyl may optionally substituted with one or more substituents independently selected from halo (e.g., chloro, fluoro, bromo or iodo), (C1-6) alkyl, (C1-C6) alkoxy, nitro, amino and trifluoromethyl, and wherein said cycloalkyl may optionally be substituted with one or two substituents independently selected from (C1-C6) alkyl; with the proviso that one of Y1 and Y2 must be other than hydrogen;
W is hydrogen, methyl ethyl, chlorine, fluorine, methoxy or trifluoromethyl;
Z1 and Z2 are independently selected from the group consisting of halo, (C1-C6) alkyl, (C1-C6) thioalkyl, (C1-C6) alkoxy, trifluoromethyl, (C1-C6) carboalkoxy, cyano, methylamino, diethylamino, isopropylamino, 1-butylamino, methylsulfonylamino, acetylamino, amino and nitro;
R1 is phenyl; CO2R2, SO2NR3R6 or CONR4R5, wherein said phenyl may optionally be substituted with one or two substituents independently selected from halo, (C1-C6) alkyl, (C1-C6) alkoxy, nitro, amino and trifluoromethyl, and wherein R2, R3, and R6 are independently selected from hydrogen, (C3-C12) alkyl and fused, saturated carbocyclic systems containing two or three rings, and R4 and R5 are independently selected from hydrogen, benzyl, (C3-C12) alkyl and fused, saturated carbocyclic systems containing two or three rings;
or a pharmaceutically acceptable salt thereof;
comprising reacting a compound of the formula XV

-126a-wherein R1, Y1 and Y2 are defined as in claim 10 and W is defined as above, with an isocyanate of the formula C6H4Z1Z2NCO, wherein Z1 and Z2 are defined as in claim 10.

13. A process according to claim 12, wherein said compound of the formula XV is obtained by reducing an azide of the formula XIV

wherein R1, Y1 and Y2 are defined as in claim 10 and W is defined as in claim 12.

14. A process for preparing a compound of the formula IB

wherein R1 is CO2H and Y1, Y2, Z1 and Z2 are defined as in claim 10, comprising hydrolyzing a compound of the formula IA

wherein R1 is CO2R2, R2 is defined as in claim 10 except that R2 is other than hydrogen, and Y1, Y2, Z1 and Z2 are defined as in claim 10.

15. A process for preparing a compound of the formula IA

wherein R1 is CONR4R5 and R4, R5, Y1, Y2, Z1 and Z2 are defined as in claim 10, comprising reacting a compound of the formula IB, as defined in claim 14, with an amine of the formula NHR4R5, wherein R4 and R5 are defined as in claim 10.

16. A process for preparing a compound of the formula IIB

wherein R1 is CO2H, Y1, Y2, Z1 and Z2 are defined as in claim 10 and W is defined as in claim 12, comprising hydrolyzing a compound of the formula IIA

wherein R1 is CO2R2, R2 is defined as in claim 10 except that R2 is other than hydrogen, Y1, Y2, Z1 and Z2 are defined as in claim 10 and W is defined as in claim 12.

17. A process for preparing a compound of the formula IIA

wherein R1 is CONR4R5, Y1, Y2, Z1 and Z2 are defined as in claim 10 and W is defined as in claim 12, comprising reacting a compound of the formula IIB, as defined in claim 16, with an amine of the formula NHR4R5 wherein R4 and R5 are defined as in claim 10.