CA2174314C

CA2174314C - Electrophilic peptide analogs as inhibitors of trypsin-like enzymes

Info

Publication number: CA2174314C
Application number: CA002174314A
Authority: CA
Inventors: Robert Anthony Galemmo, Jr.; Matthew Mark Abelman; Eugene Cruz Amparo; Robert Madara Knabb; John Matthew Fevig; William Henry Miller; Gregory James Pacofsky; Patricia Carol Weber
Original assignee: DuPont Merck Pharmaceutical Co
Current assignee: Bristol Myers Squibb Pharma Co
Priority date: 1993-10-07
Filing date: 1994-10-06
Publication date: 2000-04-11
Anticipated expiration: 2014-10-06
Also published as: EP0724446A1; IL111175A0; AU7966494A; EP0724446A4; WO1995009634A1

Abstract

This invention relates to electrophilic dipeptide analogs conjugated to an N,N disubstituted .alpha.-amino acid as inhibitors of trypsin-like serine protease enzymes.

Description

WO 95109634 ~ ~PC?lUS9a/11280 Electrophilic Peptide Analogs As Inhibitors of Trypsin-Like Enzymes This invention relates generally to electrophilic peptide analogs as inhibitors of trypsin-like serine proteases. These compounds are dipeptides in which an electrophilic derivative of an a-amino acid is conjugated with an N,N-disubstituted a-amino acid. The N,N- , disubstituted a-amino acid conjugates of the electrophilic amino aci3 analog are derivatives of an amino acid where the a-amino group is alkylated and acylated or diacylated to give alicyclic or cyclic substituents. The electrophilic functional groups used to derivatize these peptide analogs are: boronic acids and their esters, a-mono- and a-perhaloketones, aldehydes, vicinal di- and tricarbonyl compounds, a-mono- and ar-dihalo-~-ketoesters.
Electrophilic tripeptide analogs containing the ((D-phenylalanyl)prolyl)- arginyl- sequence are well known as effective inhibitors of the trypsin-like serine protease thrombin. H-(n)Phe-Pro-ArgCH2C1 was first reported by Kettner.and Shaw (Thromb. Res. 14, 969 (1979)) to be a selective but irreversible inhibitor of human thrombin. A number of studies looking for alternatives to the electrophilic P1 argininechloromethylketones that would SUBSTITUTE SHEET (RULE 26) WO 95109634 PCT/US94111280 ..-~.
yield a reversible protease inhibitor have been reported.
Bajuez et al. (Folia HaematoZ. 109, s. 16 (1982)) found the corresponding aldehyde, n-phenylalanyl-prolyl-arginal, to be a reversible thrombin inhibitor with a Ki = 75 nM for human thrombin. The nitrite analog, n-phenylalanyl-prolyl NHCH((CH2)3NHC(=NH)NH2)-CN, was found to be substantially less potent with a Ki = 700 nM (Kaiser et al., Pharmazie ' 46, 128 (1991)). A retroamide inhibitor, with the D-phenylalanyl-prolyl- sequence and 2-(4-guanidinophenylalanyl)-N-acetyl-2,2-difluoroethylamine substituting for an electrophilic arginine derivative, is a good inhibitor with a Ki of 70 nM for thrombin (Altenburger and Schirlin, Tetrahedron Lett. 32, 7255 (1991)). Cheng et al. claim that the substitution of racemic diphenyl 1-amino-4-methoxybutylphosphonate for an electrophilic arginine derivative gives very good inhibitors with a Ki =
4.8 nM (Tetrahedron Lett. 32, 7333 (1991)). Iwanowicz et al. (Bioorgan. Med. Chem. Lett. 2, 1607 (1992)) has studied the efficacy of (D-phenylalanine)prolyl- conjugated to -NHCH[(CH2)4NH2]CH(OH)C02Me) and -NHCH[(CH2)qNH2JC(=O)C02Me derivatives. The most effective inhibitor of human thrombin reported to date is the boropeptide acetyl-D-phenylalanyl-prolyl-born arginine with a Ki = 0.041 nM
(Kettner et al., J. Biol. Chern. 265, 18289 (1990)).
Walker et al. (Biochem. J. 230, 645 (1985)) published a comparative study of irreversible thrombin inhibitors based on the n-phenylalanyl-prolyl-argininyl sequence confirming the earlier report by Kettner and Shaw (1979).
H-(D)Phe-Pro-ArgCH2C1 was found to be the most effective inhibitor (Ki = 25 nM) while replacing the n-phenylalanine with 4-amino-n-phenylalanine or w-benzoyl-n-lysine gave "
less active analogs. Compounds in development include -(prolyl)arginal derivatives with a variety of unusual P3 amino acids including n-N-methylphenylglycine, Boc-D-fluorophenylglycine as well as constrained cyclized SUBSTITUTE SHEET (RULE 26) '""~~ WO 95109634 ~ 1'~ 4 314 PCTlUS94111280 derivatives of D-phenylglycine and n-phenylalanine (Shaman et. al., J. Med. Chem. 36, 314 (1993)). Balasubramanian et al. (J. Med. Chem. 36, 300 (1993)) has reported an extensive study of replacements for the P3 D-phenylalanine of D-phenylalanyl-prolyl-arginal and found the dihydrocinnamoyl group to be effective, although somewhat less potent.
Patent disclosures in this area have centered around suitably protected peptides composed of natural and unnatural amino acids. In U.S. Patent No. 5,187,157 DuPont Merck has disclosed peptides comprised of C-terminal boronic acid derivatives of lysine, ornithine and arginine as reversible inhibitors of trypsin-like serine proteases, as well as a series of boropeptides active as elastase inhibitors in U.S. Patent No. 4,499,082. In European Patent Application EP 471 651 A2 Sandoz disclosed borolysine and boroarginine peptide analogs containing at least one unnatural hydrophobic a-amino acid substituted with groups such as the trimethylsilyl- or naphthyl-. In U.S. Patent No. 5,106,948 was disclosed a series of boropeptides that are effective as cytotoxic agents. In PCT Application WO 92/07869, Thrombosis Research Institute has disclosed tripeptide analogs containing a P2 proline and an unnatural disubstituted amino acid at P3. A variety of electrophilic and non-electrophilic a-amino acid analogs were claimed as suitable P1 substituents. Tripeptide antithrombotic agents limited to a-alkyl and a aryl or heteroaryl substituted glycines at P3 conjugated to -(prolyl)arginal were been disclosed by Lilly (European Patent Application EP 479 489 A2). Marion Merrell.Dow disclosed a series of activated electrophilic ketone analogs of peptidase substrates useful for inhibiting serine-, carboxylic acid- and metallo- proteolytic enzymes;
compounds are peptides composed of suitably protected a-amino acids conjugated to an electrophilic ketone SUBSTITUTE SHEET (RULE 2b) r WO 95109634 ~ ~ j PCTIUS9~111280 derivative of an oE-amino acid (European Patent Applications EP 417 721 A2, EP 364 344 A2, EP 363 284 A2, EP 195 212 A2). Astra has disclosed a series of a-((trifluoroethyl)oxymethyl)-arginine tripeptides (European Patent Application EP 0 530 167 A). Georgia Tech Research Corporation disclosed peptidyl ketoamides, -ketoacids and -ketoesters as inhibitors of serine and cysteine proteases (WO 92/12140). Boehringer Ingelheim disclosed a series of trifluoromethyl- and a.a-difluoromethyl-øketoesterpeptide derivatives as elastase inhibitors (EP 0 369 391 A2).
The present invention concerns dipeptides which contain an electrophilic derivative of an a-amino acid at P1 conjugated with an N,N-disubstituted a-amino acid at P2.
The electrophilic functional groups used to derivatize the P1 amino acid analog are: boronic acids and their esters, a-mono- and a-perhaloketones, vicinal di- and tricarbonyl compounds, and a,a-dihalo-/~ketoesters . The N,N-disubstituted a-amino acids are derivatives of an amino acid other than proline where the a-amino group is alkylated and acylated or diacylated to give alicyclic or cyclic substituents. As a result these compounds are found to have the advantage of an improved toxicological profile as well as the selectivity and inhibition activity for thrombin required for a useful therapeutic agent.
Summary of the Invention [1] There is provided by this invention a compound of the formula (I):

SUBSTITUTE SHEET (RULE 26) ~~'~ X314 WO 95/09634 ~ PCTIUS94111280 . -.

R3-N-C~N-CH-A
R' ~ Rs H R' (I) or a pharmaceutically acceptable salt, hydrate or prodrug thereof, wherein:
R1 is a) -(C1-C12 alkyl)-X, b) -(C1-C12 alkenyl)-X, or c) -(CH2)q ~ (CH2)pX

a) halogen, b ) -CN, c ) -N02 , d) -CF3, e) -NH2, f ) -NHOR2 , 2 0 g ) -NHC ( =NH ) R2 .

h ) -NHC ( =NH ) NHOH , i ) -NHC ( =NH ) NHNH2 , j) -NHC(=NH)NHCN, -NHC ( =NH ) NHR2 , j) -NHC(=NH)NHCOR2, k) -C(=NHlNHR2, 1) -C(=NH)NHCOR2~

m) -C(=O)NHR2, _5_ SUBSTITUTE SHEET (RULE 26) PCTlU594111280 WO 95/09634 ~ 1 ~ ~ ~ ~ 4 n) -C02R2, o) -OR2, p ) -OCF3 , q) -S(O)rR2~
r ) -SC ( =NH ) NHR2 , or s) -SC(=NH)NHC(=0)R2 ;
R2 is a) hydrogen, or b) C1-C4 alkyl;
R3 is:
a) -C (=O) -aryl, b) -C(=0)-(CH2)p-CR6R~-(CH2)q-aryl, c) -C(=O)-(C2-C5 alkenyl)-aryl, d) -C(=0)-W-CR8R9-aryl, with the proviso that W cannot be a bivalent oxygen atom, e) -C(=0)-CR8R9-W-(CH2)r-aryl, with the proviso that W

cannot be -NR4- or -NC(=O)R4-, f) -C(=O)-heteroaryl, g) -C(=O)-(CH2)p-CR6R~-(CH2)q-heteroaryl, h) -C(=0)-(C2-C5 alkenyl)-heteroaryl, i) -C(=O)-W-CR8R9-heteroaryl, j) -C(=0)-CR8R9-W-(CH2)r-heteroaryl, with the proviso that W cannot be -NR4- or -NC(=O)R4-, k) -C(=0)-heterocycle, 1) -C(=O)-(CH2)p-CR6R~-(CH2)q-heterocycle, m) -C(=O)-(C2-C5 alkenyl)-heterocycle, n) -C(=O)-W-CR8R9-heterocycle, 0) -C(=0)-CR8R9-W-(CH2)r-heterocycle, with the.proviso that W cannot be -NR4- or -NCOR4-, p) -C(=O)-(CH2)t-adamantyl, q) -C(=O)-(CH2)t-(C5-C~ cycloalkyl), r) -C(=0)-(CH2)t-W-(C5-C~ cycloalkyl), s) _S-SUBSTITUTE SHEET (RULE 26) O
HorR'3 ._/
,.
~ (CH2)t-aryl ~ wherei n aryl is limited to phenyl, t) O
H or R'3 'Z'L, ._~
~-, ,.
~ (CH2)p-W-(CH2)q-aryl ~ wherein aryl is limited to phenyl, u) O
/H or R'3 H or R' 3 I
v>
O
\ ~ ~ HorR'3 / \
HorR'3 w) SUBSTITUTE SHEET (RULE 26) WO 95109634 PCTlUS94I11280 ~~~~J~~
O
O
~N (CH2)r ~ H or R'3 ..
x) O \ \
N-S(O)r I
Ra RS H or R'3 with the proviso that R13 cannot be -N(C1-Cq alkyl)2 when A is -C(=O)R14, Y) 2) O
~(CH2)P (CH2)~
(CH2)n Rio-(CH2)a O
N
\ \
H or R 3 / (CH2)r ~\ H or R'3 aa) _g_ SUBSTITUTE SHEET (RULE 26) N W
/H or R'3 bb ) ..
HorR'3 cc) O
i H or R~3 dd) HorR'3 H or H'"
ee) _g_ SUBSTITUTE SHEET (RULE 26) WO 95/09634 PCTlUS94111280 ~1~431~4 N W
~IJ
R~~
O
ff) O O
N W
{CH2)r 9g) s~
hh) H or R~3-ii) SUBSTITUTE SHEET (RULE 26) WO 95109634 ~ , , ; . PCTIUS94/11280 O
H or R'3 ~~i ~\CH=CH-aryl wherein aryl is limted to phenyl;
JJ) -(C(=O)-(CR8R9)-NR11')v-R11:
kk ) - ( C ( =O ) - ( CR8R9 ) -NR11 ' ) ~-C ( =O ) R11;
11 ) - ( C ( =O ) - ( CR$R9 ) -NR11 ' ) v-C ( =S ) Rl1;
mm) O Rye R'8 O
. 1~l oR, R2o r nn) O R,e Rie O
NHR~~
r R2o , 00 ) -C ( =O ) - ( CRaR9 ) -NHS ( O ) rR8 ;
PP) qq) HorR'3 (CH2)P-W-(CH2)q-heteroaryl R4 and R5 are independently selected at each occurrence from the group consisitng of:

O
H or R'3 i, (CHZ)i-heteroaryl or O
SUBSTITUTE SHEET (RULE 26) 3) a) hydrogen, b) C1-Cq alkyl, c) -(C1-Cq alkyl)-aryl, or d) C5-C~ cycloalkyl;
R6, R~, R8 and R9 are independently selected at each occurrence from the group consisting of:
a) hydrogen, b) C1-Cq alkyl, c) C1-Cq alkoxy, d) aryl, e) -(C1-C4 alkyl)-aryl, f) -(C1-Cq alkyl)-heterocycle, g ) -O-aryl , h) -(CH2)p-C02R4,, i) R6 and R~ can be taken together to form a (C2-C~) alkyl, or j) R8 and R9 can be taken together to form a (C2-C~) alkyl;
R10 is:
phenyl, wherein phenyl is optionally substituted with one to three substituents selected from the group consisting of halogen, C1-C4 alkyl, C1-C4 alkoxy, C~-C15 alkylaryl, C-7-C15 alkoxyaryl, methylenedioxy, -N02, -CF3, -SH, -S(0)r-(C1-C4 alkyl), CN, -OH, -NH2, -NH(C1-Cq alkyl), -N(C1-Cq alkyl)2, -NHCOR4, -(CH2)p-C02R4~ -C(=NH)NHR4), -NHC(=NR4)R4, -NHC(=NH)NHR4~
R11 is:
a) C1-Cq alkyl, b) C3-C6 cycloalkyl, C ) -OR4 , d) -NR15R16~

e) -NC(=O)R15R16~

SUBSTITUTE SHEET (RULE 26) l . _ """~ WO 9510963:1 1 '~ 4~ 314 PCTIUS94111280 f ) -NR15C ( =0 ) OR4 , g) aryl, h) -(C1-C4 alkyl)-aryl, i) heteroaryl, S j) -(C1-C4 alkyl)-heteroaryl, k) -(C1-Cq alkyl)-C02R4~
1) heterocycle, m) -(C1-C4 alkyl)heterocycle, n) H or R' 3 l0 (CHZ)t , o) P) 15 q) r) ) H or R~3 R' 8 R' a R~s C
R~s R's ~ a I.
R's or SUBSTITUTE SHEET (RULE 26) p R7s Rya ~
~R»
r R2o .
R3 and R11, when taken together to form a ring bonded to the nitrogen:
a) O
(CH2)q (CHZ)p (CH2)r-H or R'3 b) O
-(CH2)P
( ~ HorR'3 C) O
(CHZ)r ~_ (CH2)P
HorR'3 d) SUBSTITUTE SHEET (RULE 26) ""' WO 95109634 : PCTNS94/11280 '~ ~W
~2)t (CH2)t (CHZ)p H or R'3 , e) ~ H or R~3 f) O
~W
-~~(CH~p g) ~ orR~3 co(cH2)r -CO(CH2)P
, h) SUBSTITUTE SHEET (RULE 26) WO 9510963 ~ ~ ~ ~ ~ 14 PCTlUS94I11280 -CO(CH2)r ' I-I 0~ R~s -CO(CH2)p R11~ is independently selected at each occurrence from the group consisting of:
a) hydrogen;
b) C1-C4 alkyl c) -OR4 d) -NR15R16 a ) -NC ( =O ) R15R16 f) -NR15C(=0)OR4 g) aryl, h) - (C1-Cq alkyl ) -aryl, i) heteroaryl, j) -(C1-C4 alkyl)-heteroaryl, k) -(C1-C4 alkyl)-C02R4-1) heterocycle, m) -(C1-C4 alkyl)heterocycle, R13 is independently selected at each occurrence from the group consisting of:
a) hydrogen b) halogen, c) C1-C4 alkyl, d) C1-C4 alkoxy, e) methylenedioxy, f) -N02, g ) -CF3 , h) -SH, i) -S(0)r-(C1-Cq alkyl), SUBSTITUTE SHEET (RULE 26) z ~ ~ ~~:~

4 , ~ '~ ; PCT/US94111280 t.
j) -CN, k) -OH, 1) -NH2, m) -NH(C1-Cq alkyl), n) -N(C1-C4 alkyl)2, o ) -NHC ( =0 ) R4 , or p) -(CH2)p-C02R4;

q ) -C ( =NH ) NHR4 r) -NHC(=NR4)R4 s) -NHC(=NH)NHR4 R14 is:
a ) -CF3 , b ) -CHF2 , c) -CH2F, d) -CH2C1, e) -C(=O)OR4, f ) -C ( =O ) NR15R16 g) -C (=O) R4, 2 0 h ) -C ( =O ) COOR4 , i) -C(=O)C(=O)NR15R16~
j ) -C ( =O ) C ( =O ) R4 , k) -CY3Y4COOR4, 1 ) _Cy3y4C ( =O) NR15R16 or m) -CY3Y4C(=O)R4;
R15 and R16 are independently selected at each occurrence from the group consisting of:
a) hydrogen, b) C1-C4 alkyl, c) -(C1-C4 alkyl)-aryl, where aryl is defined above, d) C5-C~ cycloalkyl, or ' e) phenyl, unsubstituted or substituted by R13, f) C1-C4 alkoxy;

SUBSTITUTE SHEET (RULE 26) WO 95109634 ~ ~'~ ~ 314 ' PCT/US94I11280 R15 and R16 taken together to form a ring can also include:
a) N\
~J , o r b) -N (CH2)n R1~ is:
a) hydrogen,.
b) C1-C4 alkyl, c) aryl, wherein aryl is defined above, d) -(C1-C4 alkyl)-aryl, wherein aryl is defined above, or e) C5-C~ cycloalkyl;
R18 is a) hydrogen, b) - (C1-CS) alkyl, or c) -(C1-C5) haloalkyl, d) -(C1-C5) alkoxy%
R19 is a) hydrogen, b) -(C1-C5) alkyl, c) halo, or d) -(C1-C5) haloalkyl, a ) -N02 , f) -NR4R5, g) -CN, h) -(Cl-C5) alkoxy;
R2~ is SUBSTITUTE SHEET (RULE 26) ~~.'~4~~4 ' ~ ~ ' ~""~ WO 95109634 PCT/US94/11280 a) hydrogen; or b) -N2 with amine protecting;
A is:
a) -BYlY2, or b) -C (=0) R14, c) C(OH) R14R18;
W is:
a) -0-, b) -S (O) r-, c) -NR4-, or d) -NC ( =O) R4-;
Y1 and Y2 are:

a) -OH, b) -F, c) -NR4R5, d) C1-Cg alkoxy, or when taken together Y1 and Y2 form:

e) a cyclic boron ester where said chain or ring contains from 2 to 20 carbon atoms and, optionally, 1-3 heteroatoms which can be N, S, or O, f) a cyclic boron amide where said chain or ring contains from 2 to 20 carbon atoms and, optionally, 1-3 heteroatoms which can be N, S, or O, g) a cyclic boron amide-ester where said chain ring or contains from 2 to 20 carbon atoms and, optionally, 1-3 heteroatoms which can be N, S, or O;

Y3 and Y4 are a) -OH or SUBSTITUTE SHEET (RULE 26) 2~'~4314 WO 95109634 PCTlUS94111280 b) -F;
n is 0 or l;
p is 0 to 3 ;
q is 0 to 4 ;
r is 0 to 2 ;
t is 1 to 3;
a is 1 to 4 ;
v is 1 to 17.
Specifically preferred compounds of this invention include:
Hydrocinnamoyl-[N-(Phenethyl)-Gly]-boroOrn-C10H16 HC1 Hydrocinnamoyl-[N-(Phenethyl)-Gly]-boro0rn(CH=NH)-C10H16 Hydrocinnamoyl-[N-(Phenethyl)-Gly]-boroOrn(CH=NH)-OH HC1 Hydrocinnamoyl-(N-(Phenethyl)-Gly]-boroArg(CH3)-C10H16 HC1 Hydrocinnamoyl-[N-(N(CH3)2)-Gly]-boroLys-C10H16 HC1 Hydrocinnamoyl-[N-(N(CH3)2)-Gly]-boroLys-OH HC1 Hydrocinnamoyl-[N-(N(CH3)2)-Gly]-boroOrn-C10H16 HC1 Hydrocinnamoyl-(N-(N(CH3)2)-Gly]-boroOrn(CH=NH)-C10H16 HC1 Methanesulfonyl-Sar-[N-(Phenethyl)-Gly]-boroLys-C10H16 HC1 Methanesulfonyl-Sar-[N-(Phenethyl)-Gly]-boroLys-OH HC1 Methanesulfonyl-Gly-[N-(Phenethyl)-Gly]-boroLys-C10H16 HC1 Hydrocinnamoyl-[N-(3-(Trifluoromethyl)-Phenethyl)-Gly]-boroLys-C10H16 HC1 Hydrocinnamoyl-(N-(3-(Trifluoromethyl)-Phenethyl)-Gly]-boroLys-OH HC1 Hydrocinnamoyl-[N-(3-(Methyl)-Phenethyl)-Gly]-boroLys-C10H16 HCl Hydrocinnamoyl-[N-(3-(Methyl)-Phenethyl)-Gly]-boroLys-OH

Succinyl-[N-(3-(Methyl)-Phenethyl)-Gly]-boroLys-C10H16 HC1 SUBSTITUTE SHEET (RULE 26) ;.
""° ' WO 95109634 PCT/US94111280 Hydrocinnamoyl-[N-(2,2-(Dimethyl)-Phenethyl)-Gly]-boroLys-Hydrocinnamoyl-[N-(2-(Cyclopropyl)-Phenethyl)-Gly]-boroLys-Hydrocinnamoyl-[N-(2-(Cyclopropyl)-Phenethyl)-Gly]-boroLys-OH HCl Hydrocinnamoyl-[N-(2-(Cyclopropyl)-Phenethyl)-Gly]-boroOrn(CH=NH)-OH HC1 Hydrocinnamoyl-[N-(2,2-(Diethyl)-Phenethyl)-Gly]-boroLys-Hydrocinnamoyl-Sar-Lys(C(=O)-C(=O)-OH]
(2-(2-Cyano)-Thiophenyl)-Benzoyl-Sar-boroGly[CH2)3-Br]-(2-(2-Cyano)-Thiophenyl)-Benzoyl-Sar-boroGly[CH2)4)-Br]-(2-(2-Cyano)-Thiophenyl)-Benzoyl-Sar-boroIrg-C10H16 HBr (2-(2-Cyano)-Thiophenyl)-Benzoyl-Sar-boroGly[CH2)3-N3]

(2-(2-Cyano)-Thiophenyl)-Benzoyl-Sar-borohomoIrg-C10H16 HBr (2-(2-Cyano)-Thiophenyl)-Benzoyl-Sar-boroGly[CH2)4)-N3]-(2-(2-Cyano)-Thiophenyl)-Benzoyl-Sar-boroOrn-C10H16 HC1 (2-(2-Cyano)-Thiophenyl)-Benzoyl-Sar-borohomoArg-C10H16 HC1 (2-(2-Cyano)-Thiophenyl)-Benzoyl-Sar-boroArg-C10H16 HC1 (2-(2-Cyano)-Thiophenyl)-Benzoyl-Sar-boro0rn(CH=NH)-C10H16 (2-(2-Cyano)-Thiophenyl)-Benzoyl-Sar-boroLys(CH=NH)-C10H16 2-Benzyl-(N-Benzyl)-Sar-boroLys-C10H16 HC1 2-Thiophenyl-Benzoyl-Sar-boroLys(CH=NH)-C10H16 2-(Thiophenyl)-Benzoyl-Sar-boroIrg-C10H16 HBr 2-(Thiophenyl)-Benzoyl-Sar-boroOrn-C10H16 HC1 2-(Thiophenyl)-Benzoyl-Sar-boro0rn(CH=NH)-C10H16 HC1 Pinanediol N-{N-methyl-N-[2-(Thiophenyl)-Benzoyl]Sar}-1-amido-5-thiocyanatobutane boronate SUBSTITUTE SHEET (RULE 26) (2-(2-Cyano)-Thiophenyl)-Benzoyl-Sar-boroLys-C10H16 HC1 Acetyl-Gly[N-(2-(Benzyl)-Benzyl)]-boroLys-C10H16 HC1 Pinanediol N-{N-methyl-N-[2-(pyrrol-1-ylmethyl)-Benzyl]glycyl)-1-amido-5-aminopentaneboronate, hydrochloride salt N-(N-methyl-N-[2-(pyrrol-1-ylmethyl)-Benzyl]glycyl}-1-amido-5-aminopentaneboronic acid, hydrochloride salt 2-(2-(Trifluoromethyl)-Benzyl)-Benzoyl-Sar-Lys-C(=O)-2-(Benzyl)-Benzoyl-Sar-Lys-C(=O)-NHNH2 2 HC1 [3-(Trifluoromethyl)-Benzyl]-Benzoyl-Sar-boroLys-C10H16 HC1 3-(3-(Chloro)-Benzyl)-Benzoyl-Sar-boroLys-C10H16 HCl Hydrocinnamoyl-Sar-Lys(Z)-C(=0)-0-(CH2)2-NH(Z) Hydrocinnamoyl-Sar-Lys-C(=O)-O-(CH2)2-NH2 2 HC1 Hydrocinnamoyl-Sar-Lys(Z)-C(=O)-OCH3 Hydrocinnamoyl-Sar-Lys-C(=O)-OCH3 HC1 Hydrocinnamoyl-Sar-Lys-C(=0)-CH3 HC1 Hydrocinnamoyl-Sar-Lys(Z)-H
Hydrocinnamoyl-Sar-NHCH(CH20H)(CH2)4-NH(Z) Hydrocinnamoyl-Sar-NHCH(CH20H)(CH2)4-NH2 Hydrocinnamoyl-Sar-Lys[CH(OH)(OCH3)-C(=0)-OCH3] HC1 Hydrocinnamoyl-(N-(Cyclopropyl)-Gly]-boroOrn-C10H16 HC1 Hydrocinnamoyl-[N-(Cyclopropyl)-Gly]-boroLys-OH HC1 Hydrocinnamoyl-[N-(Cyclopropyl)-Gly]-boro0rn(CH=NH)-OH HC1 Hydrocinnamoyl-[N-(Cyclopropyl)-Gly]-boro0rn(CH=NH)-C10H16 Hydrocinnamoyl-[N-(Cyclopropyl)-Gly]-boroLys(CH=NH)-C10H16 Hydrocinnamoyl-[N-(Cyclopropyl)-Gly]-boroLys(CH=NH)-OH HC1 Phenoxyacetyl-[N-(Cyclopropyl)-Gly]-boroLys-C10H16 HC1 Thiophenacetyl-[N-(Cyclopropyl)-Gly]-boroLys-C10H16 HC1 Phenoxyacetyl-[N-(Cyclopropyl)-Gly]-boroLys-OH HC1 Thiophenacetyl-[N-(Cyclopropyl)-Gly]-boroLys-OH HC1 Hydrocinnamoyl-[N-(N-(Methyl)-Phenyl)-Gly]-boroLys-C10H16 HCl SUBSTITUTE SHEET (RULE 26) a.,. WO 95/09634 PCT/US94/11280 Hydrocinnamoyl-[N-(N-(Methyl)-Phenyl)-Gly]-boroLys-OH HC1 Hydrocinnamoyl-[N-(N-(Methyl)-Benzyl)-Gly]-boroLys-C10H16 Glutaryl-[N-(Phenethyl)-Gly]-boroLys-OH HC1 Glutaryl(3,3-Dimethyl)-[N-(Phenethyl)-Gly]-boroLys-C10H16 Methyl Glutaryl(3,3-Dimethyl)-[N-(Phenethyl)-Gly]-boroLys-Glutaryl(3,3-Dimethyl)-[N-(Phenethyl)-Gly]-boroLys-OH
Methyl Glutaryl(3,3-Dimethyl)-[N-(Phenethyl)-Gly]-boroLys-Boc-Asp-[N-(Phenethyl)-Gly]-boroLys-ClOHl6 Boc-Glu-[N-(Phenethyl)-Gly]-boroLys-C10H16 Boc-Glu(OCH3)-[N-(Phenethyl)-Gly]-boroLys-C10H16 HC1 Boc-Glu-[N-(Phenethyl)-Gly]-boroLys-OH
Hydrocinnamoyl-(N-(N-(Methyl)-Benzyl)-Gly]-boroLys-OH HC1 Methanesylfonyl-Gly-[N-(N-(Methyl)-Benzyl)-Gly]-boroLys-Methanesulfonyl-Gly-[N-(N-(Methyl)-Benzyl)-Gly]-boroLys-OH

Hydrocinnamoyl-[N-(Succinyl)-Gly]-boroLys-C10H16 Hydrocinnamoyl-[N-(Methyl Succinyl)-Gly]-boroLys-C10H16 HC1 Succinyl-[N-(Phenethyl)-Gly]-boroLys-OH
Methyl Succinyl-[N-(Phenethyl)-Gly]-boroLys-OH HC1 Glutaryl-[N-(Phenethyl)-Gly]-boroLys-C10H16 Methyl Glutaryl-(N-(Phenethyl)-Gly]-boroLys-C10H16 HC1 Methyl Glutaryl-[N-(Phenethyl)-Gly]-boroLys-OH HCl Hydrocinnamoyl-(N-(2-(Cyclopropyl)-Phenethyl)-Gly]-boroArg-Hydrocinnamoyl-[N-(2-(Cyclopentyl)-Phenethyl)-Gly]-boroLys-(2-(2-Cyano)-Thiophenyl)-Benzoyl-Sar-boroArg-OH HC1 Hydrocinnamoyl-[N-(2,2-(Dimethyl)-Phenethyl)-Gly]-boroLys-Hydrocinnamoyl-(N-(2,2-(Dimethyl)-Phenethyl)-Gly]-boroOrn-SUBSTITUTE SHEET (RULE 26) WO 95/9634 PCTlUS94111280 Hydrocinnamoyl-[N-(2,2-(Dimethyl)-Phenethyl)-Gly]-boroArg-Hydrocinnamoyl-[N-(2,2-(Dimethyl)-Phenethyl)-Gly]-boro0rn(CH=NH)-C10H16 HC1 Hydrocinnamoyl-[N-(2,2-(Dimethyl)-Phenethyl)-Gly]-boroArg-Hydrocinnamoyl-[N-(2,2-(Dimethyl)-Phenethyl)-Gly]-boroOrn(CH=NH)-OH HCl Hydrocinnamoyl-[N-(2,2-(Dimethyl)-Phenethyl)-Gly]-boro0rn-Hydrocinnamoyl-[N-(2,2-(Dimethyl)-Phenethyl)-Gly]-boroLys-Hydrocinnamoyl-{N-[2-(3,5-dimethylphenyl)-ethyl]-Gly}-boroOrn-C10H16 HC1 Hydrocinnamoyl-{N-[2-(3,5-dimethylphenyl)-ethyl]-Gly}-boroLys-C10H16 HC1 Hydrocinnamoyl-{N-[2,2-(Dimethyl)-2-(3,5-dimethylphenyl)-ethyl]-Gly}-boroArg-C10H16 HCl Hydrocinnamoyl-(N-[2,2-(Dimethyl)-2-(3,5-dimethylphenyl)-ethyl]-Gly}-boroOrn(CH=NH)-C10H16 HC1 Hydrocinnamoyl-{N-[2-(3,5-dimethylphenyl)-ethyl]-Gly}-boroArg-C10H16 HC1 Hydrocinnamoyl-(N-[2-(3,5-dimethylphenyl)-ethyl]-Gly}-boroOrn(CH=NH)-C10H16 HC1 Hydrocinnamoyl-[N-(Cyclohexyl)-Gly]-boroLys-C10H16 HC1 Hydrocinnamoyl-[N-(Cyclopropyl)-Gly]-boroLys-C10H16 HC1 Hydrocinnamoyl-[N-(Cyclohexyl)-Gly]-boroLys-OH HC1 Hydrocinnamoyl-[N-(Phenethyl)-Gly]-boroOrn(CH=NH)-C10H16 Hydrocinnamoyl-[N-(2-(Cyclopentyl)-Phenethyl)-Gly]-boro0rn(CH=NH)-C10H16 HC1 Hydrocinnamoyl-[N-(2-(Cyclopentyl)-Phenethyl)-Gly]-boroArg-[N-(-C(O)(CH2)2Ph)-N-(CH3)]Gly-boroLys-OH
[N-(-C(O)(CH2)2Ph)-N-(CH2)2Ph]Gly-boroLys-OH

SUBSTITUTE SHEET (RULE 26) "' WO 95/09634 PCT/US94/11280 [N-(-C(O)(CH2)2Ph)-N-Ph]Gly-boroLys-OH
[N-(-C(O)N(CH3)CH2Ph)-N-Ph)Gly-boroLys-OH
[N-(-C(O)Ph-3-CH=CHPh)-N-(CH3)]Gly-boroLys-OH
[N-(-C(O)Ph-3-CHZCH2Ph)-N-(CH3)]Gly-boroLys-OH
[N-(-C(0)Ph-3-SPh-2-OCH3)-N-(CH3)]Gly-boroLys-OH
[N-(-C(O)Ph-2-CH2Ph-2-Ph)-N-(CH3)]Gly-boroLys-OH
[N-(-C(O)Ph-4-CH2Ph)-N-(CH3)]Gly-boroLys-OH
[N-(-C(O)Ph-2-CH2Ph)-N-(CH3)]Gly-boroLys-OH
[N-(-C(0)Ph-3-CH2Ph)-N-(CH3)]Gly-boroLys-OH
[N-(-C(O)Ph-3-CH2Ph-2-CF3)-N-(CH3)]Gly-boroLys-OH
[N-(-C(0)CH2Ph-3,4-C12)-N-(CH3)]Gly-boroLys-OH
[N-(-C(O)(CH2)2Ph)-N-(i-C3H~)]Gly-boroLys-OH
[N-(-C(0)(CH2)2Ph)-N-(C6H12)]Gly-boroLys-OH
[N-(-C(O)(CHZ)2Ph)-N-(N(CH3)Z))Gly-boroLys-OH
[N-(-C(O)CH2Ph)-N-(CH3)]Gly-boroLys-OH
[N-(-C(O)(CH2)3Ph)-N-(CH3)]Gly-boroLys-OH
[N-(-C(0)Ph)-N-(CH3)]Gly-boroLys-OH
[N-(-C(O)(CH2)2Ph)-N-CH2Ph)]Gly-boroLys-OH
[N-(-C(0)(CH2)2Ph-3,4-C12)-N-(CH3)]Gly-boroLys-OH
[N-(-C(O)(CH2)2Ph-4-C1)-N-(CH3)]Gly-boroLys-OH
[N-(-C(0)(CH2)2Ph-4-CH3)-N-(CH3)]Gly-boroLys-OH
[N-(-C(O)(CH2)2Ph-4-OCH3)-N-(CH3))Gly-boroLys-OH
[N-(-C(O)(CH2)2Ph)-N-(CH3)]Gly-boroLys-CipHl6 [N-(-C(O)(CH2)2Ph)-N-(CH2)2Ph]Gly-boroLys-CipHl6 [N-(-C(0)(CHZ)2Ph)-N-Ph]Gly-boroLys-CipHl6 [N- ( -C ( O) N (CH3 ) CH2Ph) -N-Ph) Gly-boroLys-CipHl6 [N-(-C(O)Ph-3-CH=CHPh)-N-(CH3))Gly-boroLys-CipHl6 [N-(-C(O)Ph-3-CH2CH2Ph)-N-(CH3)]Gly-boroLys-CipHl6 [N-(-C(0)Ph-3-SPh-2-OCH3)-N-(CH3)]Gly-boroLys-CipHl6 [N-(-C(0)Ph-2-CH2Ph-2-Ph)-N-(CH3)]Gly-boroLys-CipHl6 [N-(-C(O)Ph-4-CHZPh)-N-(CH3)]Gly-boroLys-CipHl6 [N-(-C(O)Ph-2-CH2Ph)-N-(CH3)]Gly-boroLys-CipHl6 [N-(-C(0)Ph-3-CH2Ph)-N-(CH3)]Gly-boroLys-CipHl6 [N-(-C(O)Ph-3-CH2Ph-2-CF3)-N-(CH3)]Gly-boroLys-CipHl6 [N-(-C(O)CH2Ph-3,4-C12)-N-(CH3))Gly-boroLys-CipHl6 SUBSTITUTE SHEET (RULE 26) WO 95/09634 ~ 1 '~ 4 3 I 4 PCTIUS94/11280 [N-(-C(O)(CH2)2Ph)-N-(i-C3H~)]Gly-boroLys-C1pH16 [N-(-C(O)(CH2)2Ph)-N-(C6H12)]Gly-boroLys-C10H16 [N-(-C(0)CHZPh)-N-(CH3)]Gly-boroLys-C1pH16 [N-(-C(O)(CH2)3Ph)-N-(CH3)]Gly-boroLys-C1pH16 [N-(-C(O)Ph)-N-(CH3)]Gly-boroLys-C1pH16 [N- ( -C (O) (CH2 ) 2Ph) -N-CH2Ph) ] Gly-boroLys-C1pH16 [N-(-C(O)(CH2)2Ph-3,4-C12)-N-(CH3)]Gly-boroLys-C1pH16 [N-(-C(O)(CH2)2Ph-4-C1)-N-(CH3)]Gly-boroLys-C1pH16 [N-(-C(O)(CHZ)2Ph-4-CH3)-N-(CH3)]Gly-boroLys-C1pH16 [N-(-C(O)(CH2)2Ph-4-OCH3)-N-(CH3)]Gly-boroLys-C1pH16 [N-(-C(O)CH3)(D)-Phe[N-(CH3)]Gly-boroLys-C1pH16 [N-(S02CH3](D)-Phe[N-(CH3)]Gly-boroLys-C1pH16 [N-(-C(O)(CH2)2Ph)-N-(CH3)]Gly-Lys-OCH3 [N-(-C(O)(CH2)2Ph)-N-(CH3)]Gly-boroArg-OH
[N-(-C(O)CH2Ph-3,4-C12)-N-(CH3)]Gly-boroArg-OH
[N-(-C(O)(CHZ)2Ph)-N-(CH3)]Gly-boroArg-C1pH16 [N-(-C(O)CH2Ph-3,4-C12)-N-(CH3)]Gly-boroArg-C10H16 [N-(-C(O)CH2Ph-3,4-C12)-N-(CH3)]Gly-boroPhe(mCN)-C1pH16 [N-(-C(O)(CH2)2Ph)-N-(CH3)]Gly-boroOrn(N-methylamidino)-OH
[N-(-C(O)CH2Ph-3,4-C12)-N-(CH3)]Gly-boro0rn(N-methylamidino)-OH
[N-(-C(0)(CH2)2Ph)-N-(CH3)]Gly-boroOrn(N-methylamidino)-[N-(-C(0)CH2Ph-3,4-C12)-N-(CH3)]Gly-boro0rn(N-methylamidino)-C1pH16 [N-(-C(O)(CH2)2Ph)-N-(CH3)]Gly-boroOrn(formamidino)-OH
[N-(-C(O)CH2Ph-3,4-C12)-N-(CH3)]Gly-boroOrn(formamidino)-OH
(N-(-C(0)CH2Ph)-N-(CH3)]Gly-boro0rn(formamidino)-OH
[N-(-C(O)(CH2)2Ph-4-OCH3)-N-(CH3)]Gly-boroOrn(formamidino)-3 a off [N-(-C(O)Ph-4-CH2Ph)-N-(CH3)]Gly-boroOrn(formamidino)-C1pH16 [N-(-C(0)CH2Ph-3,4-C12)-N-(CH3)]Gly-boro0rn(formamidino)-[N-(-C(O)(CH2)2Ph)-N-(OH)]Gly-boroOrn(formamidino)-C1pH16 SUBSTITUTE SHEET (RULE 26) 217~~14'~
°'" WO 95/09634 ~ PCTIU594/11280 (N-(-C(O)(CH2)ZPh-3,4-C12)-N-(CH3)]Gly-boroOrn(formamidino)-C1pH15 [N-(-C(O)(CH2)2Ph)-N-(CH2C(CH2CH3)2Ph)]-Gly-boroLys-OH
[N-(-C(O)(CH2)2Ph)-N-(CH2CH(i-C3H7)Ph)]-Gly-boroLys-OH
[N-(-C(O)(CH2)2Ph)-N-(CH2C(butane-1,4-diyl)Ph)]-Gly boroLys-OH
[N-(-C(O)(CH2)2Ph)-N-(CH2C(CH3)2Ph-3-CH3)]-Gly-boroLys-OH
[N-(-C(O)(CH2)2Ph)-N-(CH2C(CH2CH3)2Ph-3-CH3)]-Gly_ boroLys-OH
[N-(-C(O)(CH2)2Ph)-N-(CH2C(butane-1,4-diyl)Ph)]-Gly-boroArg-OH
[N-(-C(O)(CH2)2Ph)-N-(CH2C(CH3)2Ph-3-N02)]-Gly-boroLys-OH
[N-(-C(O)(CH2)2Ph)-N-(CH2C(CH2CH3)2Ph-3-N02)]-Gly-boroLys-OH
[N-(-C(O)(CH2)2Ph)-N-(CH2CH2Ph-3,5-(CH3)2)]-Gly-boroArg-OH
[N-(-C(O)(CH2)2Ph)-N-(CH2C(CH3)2Ph-3,5-(CH3)2)]-Gly-boroArg-OH
[N-(-C(O)(CH2)2Ph)-N-(CH2C(butane-1,4-diyl)Ph>]-Gly-boro0rn(formamidino)-OH
[N-(-C(O)(CH2)2Ph)-N-(CH2C(CH3)2Ph-3-CH3)]-Gly-boroOrn(formamidino)-OH
[N-(-C(O)(CH2)2Ph)-N-(CH2C(CH2CH3)2Ph-3-CH3-)]-Gly-boro0rn(formamidino)-OH
Illustrative of the preferred compounds of this invention are the following:
[N-(-C(O)(CH2)2Ph)-N-(C2H5)]Gly-boroLys-OH
[N-(-C(O)(CH2)2Ph)-N-(N-C3H~)]Gly-boroLys-OH
[N-(-C(O)(CH2)2Ph)-N-(OH)]Gly-boroLys-OH
[N-(-C(O)(CH2)ZPh)-N-(OCH3)]Gly-boroLys-OH
[N-(-C(O)(CH2)2Ph)-N-(OCH2Ph)]Gly-boroLys-OH

SUBSTITUTE SHEET (RULE 26) WO 95109634 ~ 1 ~ ~ J ~ ~ PCT/US94/11280 [N-(-C(O) (CH2)2Ph)-N-(NH2)]Gly- boroLys-OH

[N-(-C(O) (CHZ)2Ph)-N-(NHBoc)]Gly-boroLys-OH

[N-(-C(0) (CH2)2Ph)-N-(CH2C02H)]Gly-boroLys-OH

[N-(-C(0) (CH2)2Ph)-N-(CH2C02CH3)]Gly-boroLys-OH

(N-(-C(O) (OCH2)Ph)](D)-Phe[N-(CH3)]Gly-boroLys-OH

[N-(-C(O) (OCH2)Ph)](D)-Phe[N-(CH3))Ala-boroLys-OH

[N-(-C(O) (OCH2)Ph)](D)-Phe[N-(Ph)]Gly-boroLys-OH

[N-(-C(0) (OCH2)Ph)](D)-Phe[N-(CH2Ph)]Gly-boroLys-OH

[N-(-C(O) (CH2)2Ph)-N-(C2H5)]Gly-boroLys-C1pH16 (N-(-C(0) (CH2)2Ph)-N-(n-C3H~)]Gly-boroLys-C1pH16 [N-(-C(O) (CH2)2Ph)-N-(OH)]Gly-boroLys-C1pH16 [N-(-C(0) (CH2)2Ph.)-N-(OCH3)]Gly-boroLys-C1pH16 [N-(-C(O) (CHZ)2Ph)-N-(OCHZPh)]Gly-boroLys-C1pH16 [N-(-C(O) (CH2)2Ph)-N-(NH2)]Gly-boroLys-C1pH16 [N-(-C(O) (CH2)2Ph)-N-(NHBoc)]Gly-boroLys-C1pH16 (N-(-C(O) (CH2)2Ph)-N-(CH2C02H)]Gly-boroLys-C1pH16 [N-(-C(O) (CH2)2Ph)-N-(CH2COZCH3)]Gly-boroLys-C1pH16 (N-C02CH2Ph)[Leu-Ser(OtBu)-Asn]4-[N-(CH3)]Gly-boroLys-C1pH16 [Sequence No. 1]
(H)-[Leu-Ser(OtBu)-Asn]4-(N-(CH3)]Gly-boroLys-C1pH16 [Sequence No. 2]
(H)-[Leu-Ser-Asn]q-[N-(CH3)]Gly-boroLys-C1pH16 (Sequence No.
3]
[N-(-C(O)(OCH2Ph)](D)-Phe[N-(CH3)]Gly-boroLys-C1pH16 [N-(-C(0)(CH3)](n)-(/3~yclohexyl)Ala[N-(CH3)]Gly-boroLys-[N-(-C(O)(CH2)2Ph)-N-(CH3)]Gly-Lys-CF3 [N-(-C(O)(CH2)2Ph)-N-(CH2)2Ph]Gly-Lys-CF3 [N-(-C(O) (CH2)2Ph)-N-Ph]Gly-Lys-CF3 [N-(-C(O)N(CH3)CH2Ph)-N-Ph]Gly-Lys-CF3 [N-(-C(0)Ph-3-CH=CHPh)-N-(CH3)]Gly-Lys-CF3 [N-(-C(O)Ph-3-CH2CH2Ph)-N-(CH3)]Gly-Lys-CF3 [N-(-C(0)Ph-3-SPh-3-OCH3)-N-(CH3)]Gly-Lys-CF3 [N-(-C(O)Ph-2-CH2Ph-2-Ph)-N-(CH3)]Gly-Lys-CF3 [N-(-C(0)Ph-4-CH2Ph)-N-(CH3)]Gly-Lys-CF3 SUBSTITUTE SHEET (RULE 26) '"''° WO 95/09634 PCT'IUS94111280 [N-(-C(O)Ph-2-CH2Ph)-N-(CH3)]Gly-Lys-CF3 [N-(-C(O)Ph-3-CH2Ph)-N-(CH3)]Gly-Lys-CF3 [N-(-C(O)Ph-3-CH2Ph-2-CF3)-N-(CH3)]Gly-Lys-CF3 [N-(-C(O)CH2Ph-3,4-C12)-N-(CH3)]Gly-Lys-CF3 [N-(-C(O)(CH2)2Ph)-N-(C2H5)]Gly-Lys-CF3 [N-(-C(0)(CHZ)2Ph)-N-(n-C3H~)]Gly-Lys-CF3 [N-(-C(O)(CH2)2Ph)-N-(i-C3H~)]Gly-Lys-CF3 [N-(-C(O)(CH2)2Ph)-N-(C6H12)]G1Y-LYs-CF3 [N-(-C(O)(CHZ)2Ph)-N-(OH)]Gly-Lys-CF3 [N-(-C(0)(CH2)2Ph)-N-(OCH3)]Gly-Lys-CF3 [N-(-C(O)(CHZ)2Ph)-N-(OCH2Ph)]Gly-Lys-CF3 [N-(-C(O)(CH2)2Ph)-N-(NH2)]Gly-Lys-CF3 [N-(-C(O)(CH2)2Ph)-N-(N(CH3)2)]Gly-Lys-CF3 [N-(-C(O)(CH2)2Ph)-N-(NHBoc)]Gly-Lys-CF3 [N-(-C(O)(CH2)2Ph)-N-(CH2C02H)]Gly-Lys-CF3 [N-(-C(O)(CH2)2Ph)-N-(CH2C02CH3)]Gly-Lys-CF3 [N-(-C(O)CH2Ph)-N-(CH3)]Gly-Lys-CF3 [N-(-C(O)(CH2)3Ph)-N-(CH3)]Gly-Lys-CF3 [N-(-C(O)Ph)-N-(CH3)]Gly-Lys-CF3 [N-(-C(O)(CH2)2Ph)-N-CH2Ph)]Gly-Lys-CF3 [N-(-C(O)(CH2)2Ph-3,4-C12)-N-(CH3)]Gly-Lys-CF3 [N-(-C(O)(CH2)2Ph-4-C1)-N-(CH3)]Gly-Lys-CF3 [N-(-C(O)(CH2)2Ph-4-CH3)-N-(CH3)]Gly-Lys-CF3 [N-(-C(O)(CH2)2Ph-4-OCH3)-N-(CH3)]Gly-Lys-CF3 [N-(-C(O)(CH2)2Ph)-N-(CH2)2Ph]Gly-Lys-OCH3 (N-(-C(0)(CH2)2Ph)-N-Ph]Gly-Lys-OCH3 [N-(-C(O)N(CH3)CH2Ph)-N-Ph)Gly-Lys-OCH3 [N-(-C(0)Ph-3-CH=CHPh)-N-(CH3)]Gly-Lys-OCH3 [N-(-C(O)Ph-3-CH2CH2Ph)-N-(CH3)]Gly-Lys-OCH3 [N-(-C(0)Ph-3-SPh-3-OCH3)-N-(CH3)]Gly-Lys-OCH3 [N-(-C(O)Ph-2-CH2Ph-2-Ph)-N-(CH3)]Gly-Lys-OCH3 [N-(-C(0)Ph-4-CH2Ph)-N-(CH3)]Gly-Lys-OCH3 [N-(-C(O)Ph-2-CH2Ph)-N-(CH3))Gly-Lys-OCH3 (N-(-C(0)Ph-3-CH2Ph)-N-(CH3)]Gly-Lys-OCH3 [N-(-C(O)Ph-3-CH2Ph-2-CF3).-N-(CH3)]Gly-Lys-OCH3 _?9_ SUBSTITUTE SHEET (RULE 26) W O 95/09634 ~ 1 ~ ~ 314 [N-(-C(O)CH2Ph-3,4-C12)-N-(CH3)]Gly-Lys-OCH3 [N-(-C(0) (CH2)2Ph)-N-(C2H5)]G1Y-LYs-OCH3 [N-(-C(O) (CH2)2Ph)-N-(n-C3H~) ]Gly-Lys-OCH3 [N-(-C(O) (CH2)2Ph)-N-(i-C3H~)]Gly-Lys-OCH3 [N-(-C(O) (CH2)2Ph)-N-(C6H12)]Gly-Lys-OCH3 [N-(-C(0> (CH2)2Ph)-N-(OH)]Gly-Lys-OCH3 [N-(-C(O) (CH2)2Ph)-N-(OCH3)]Gly-Lys-OCH3 [N-(-C(0) (CH2)2Ph)-N-(OCH2Ph)]Gly-Lys-OCH3 [N-(-C(O) (CH2)2Ph)-N-(NH2)]Gly-Lys-OCH3 [N-(-C(0) (CH2)2Ph)-N-(N(CH3)2)]Gly-Lys-OCH3 [N-(-C(O) (CH2)2Ph)-N-(NHBoc)]Gly-Lys-OCH3 [N-(-C(0) (CH2)2Ph)-N-(CH2C02H)]Gly-Lys-OCH3 [N-(-C(O) (CH2)2Ph)-N-(CH2C02CH3)]Gly-Lys-OCH3 [N-(-C(O) CH2Ph)-N-(CH3)]Gly-Lys-OCH3 [N-(-C(O) (CH2)3Ph)-N-(CH3)]Gly-Lys-OCH3 [N-(-C(0) Ph)-N-(CH3)]Gly-Lys-OCH3 [N-(-C(O) (CH2)2Ph)-N-CH2Ph)]Gly-Lys-OCH3 [N-(-C(0)(CH2)2Ph-3,4-C12)-N-(CH3)]Gly-Lys-OCH3 [N-(-C(O)(CH2)2Ph-4-C1)-N-(CH3)]Gly-Lys-OCH3 [N-(-C(O)(CH2)2Ph-4-CH3)-N-(CH3)]Gly-Lys-OCH3 [N-(-C(O)(CH2)2Ph-4-OCH3)-N-(CH3)]Gly-Lys-OCH3 [N-(-C(0)(CH2)2Ph)-N-(CH3)]Gly-Lys-C02CH3 [N-(-C(O)(CH2)2Ph)-N-(CH2)2Ph]Gly-Lys-C02CH3 [N-(-C(O)(CH2)2Ph)-N-Ph]Gly-Lys-C02CH3 [N-(-C(O)N(CH3)CH2Ph)-N-Ph]Gly-Lys-C02CH3 [N-(-C(0)Ph-3-CH=CHPh)-N-(CH3)]Gly-Lys-C02CH3 [N-(-C(O)Ph-3-CH2CH2Ph)-N-(CH3)]Gly-Lys-C02CH3 [N-(-C(O)Ph-3-SPh-3-OCH3)-N-(CH3)]Gly-Lys-C02CH3 [N-(-C(O)Ph-2-CH2Ph-2-Ph)-N-(CH3)]Gly-Lys-C02CH3 [N-(-C(0)Ph-4-CH2Ph)-N-(CH3)]Gly-Lys-C02CH3 [N-(-C(O)Ph-2-CH2Ph)-N-(CH3)]Gly-Lys-C02CH3 [N-(-C(O)Ph-3-CH2Ph)-N-(CH3)]Gly-Lys-C02CH3 [N-(-C(O)Ph-3-CH2Ph-2-CF3)-N-(CH3)]Gly-Lys-C02CH3 [N-(-C(O)CH2Ph-3,4-C12)-N-(CH3)]Gly-Lys-C02CH3 [N-(-C(0) (CH2)2Ph)-N-(C2H5) ]Gly-Lys-C02CH3 SUBSTITUTE SHEET (RULE 26) «..... WO 95/09634 , [N-(-C(0)(CH2)2Ph)-N-(n-C3H~)]Gly-Lys-C02CH3 [N-(-C(O)(CH2)2Ph)-N-(i-C3H~)]Gly-Lys-C02CH3 [N-(-C(O)(CH2)2Ph)-N-(C6H12)]G1Y-LYs-C02CH3 [N-(-C(O)(CH2)2Ph)-N-(OH)]Gly-Lys-C02CH3 (N-(-C(0)(CH2)2Ph)-N-(OCH3)]Gly-Lys-C02CH3 [N-(-C(0)(CH2)2Ph)-N-(OCH2Ph)]Gly-Lys-C02CH3 [N-(-C(0)(CH2)2Ph)-N-(NH2)]Gly-Lys-C02CH3 (N-(-C(O)(CH2)2Ph)-N-(N(CH3)2)]Gly-Lys-C02CH3 [N-(-C(0)(CH2)2Ph)-N-(NHBoc)]Gly-Lys-C02CH3 [N-(-C(O)(CH2)2Ph)-N-(CH2C02H)]Gly-Lys-C02CH3 [N-(-C(O)(CH2)2Ph)-N-(CH2C02CH3)]Gly-Lys-C02CH3 [N-(-C(0)CHZPh)-N-(CH3)]Gly-Lys-C02CH3 [N-(-C(0)(CH2)3Ph)-N-(CH3)]Gly-Lys-C02CH3 [N-(-C(O)Ph)-N-(CH3)]Gly-Lys-C02CH3 [N-(-C(O)(CH2)2Ph)-N-CH2Ph)]Gly-Lys-C02CH3 [N-(-C(O)(CH2)2Ph-3,4-C12)-N-(CH3)]Gly-Lys-C02CH3 [N-(-C(0)(CH2)2Ph-4-C1)-N-(CH3)]Gly-Lys-C02CH3 [N-(-C(O)(CH2)2Ph-4-CH3)-N-(CH3)]Gly-Lys-C02CH3 [N-(-C(O)(CH2)2Ph-4-OCH3)-N-(CH3)]Gly-Lys-C02CH3 [N-(-C(0)(CH2)2Ph)-N-(CH2)2Ph]Gly-boroArg-OH
[N-(-C(O)(CH2)2Ph)-N-Ph]Gly-boroArg-OH
[N-(-C(O)N(CH3)CH2Ph)-N-Ph]Gly-boroArg-OH
[N-(-C(O)Ph-3-CH=CHPh)-N-(CH3)JGly-boroArg-OH
[N-(-C(O)Ph-3-CH2CH2Ph)-N-(CH3)]Gly-boroArg-OH
[N-(-C(O)Ph-3-SPh-3-OCH3)-N-(CH3)]Gly-boroArg-OH
[N-(-C(O)Ph-2-CH2Ph-2-Ph)-N-(CH3)]Gly-boroArg-OH
[N-(-C(O)Ph-4-CH2Ph)-N-(CH3)]Gly-boroArg-OH
[N-(-C(O)Ph-2-CH2Ph)-N-(CH3)]Gly-boroArg-OH
[N-(-C(O)Ph-3-CH2Ph)-N-(CH3)]Gly-boroArg-OH
[N-(-C(O)Ph-3-CH2Ph-2-CF3)-N-(CH3)]Gly-boroArg-OH
[N-(-C(O)(CH2)2Ph)-N-(C2H5)]Gly-boroArg-OH
[N-(-C(O)(CH2)2Ph)-N-(n-C3H~)]Gly-boroArg-OH
[N-(-C(O)(CH2)2Ph)-N-(i-C3H~)]Gly-boroArg-OH
[N-(-C(O)(CH2)ZPh)-N-(C6H12)]Gly-boroArg-OH
[N-(-C(O)(CH2)ZPh)-N-(OH)]Gly-boroArg-OH

SUBSTITUTE SHEET (RULE 26) ~1'~ 4314 [N-(-C(O)(CH2)2Ph)-N-(OCH3)]Gly-boroArg-OH
[N-(-C(O)(CH2)2Ph)-N-(OCH2Ph)]Gly-boroArg-OH
[N-(-C(0)(CH2)2Ph)-N-(NH2)]Gly-boroArg-OH
[N-(-C(O)(CH2)2Ph)-N-(N(CH3)2)]Gly-boroArg-OH
[N-(-C(O)(CH2)2Ph)-N-(NHBoc)]Gly-boroArg-OH
[N-(-C(O)(CH2)2Ph)-N-(CH2C02H)]Gly-boroArg-OH
[N-(-C(O)(CH2)2Ph)-N-(CH2C02CH3)]Gly-boroArg-OH
[N-(-C(0)CH2Ph)-N-(CH3)]Gly-boroArg-OH
[N-(-C(O)(CH2)3Ph)-N-(CH3)]Gly-boroArg-OH
[N-(-C(O)Ph)-N-(CH3)]Gly-boroArg-OH
[N-(-C(O)(CH2)2Ph)-N-CH2Ph)]Gly-boroArg-OH
[N-(-C(O)(CH2)2Ph-3,4-C12)-N-(CH3)]Gly-boroArg-OH
[N-(-C(O)(CH2)2Ph-4-C1)-N-(CH3)]Gly-boroArg-OH
[N-(-C(O)(CH2)2Ph-4-CH3)-N-(CH3)]Gly-boroArg-OH
[N-(-C(O)(CH2)2Ph-4-OCH3)-N-(CH3)]Gly-boroArg-OH
[N-(-C(0)(CH2)2Ph)-N-(CH2)2Ph]Gly-boroArg-CipHl6 [N-(-C(O)(CH2)2Ph)-N-Ph]Gly-boroArg-C1aH16 [N-(-C(O)N(CH3)CH2Ph)-N-Ph]Gly-boroArg-CipHl6 [N-(-C(O)Ph-3-CH=CHPh)-N-(CH3)]Gly-boroArg-CipHl6 [N-(-C(O)Ph-3-CH2CH2Ph)-N-(CH3)]Gly-boroArg-CipHl6 [N-(-C(O)Ph-3-SPh-3-OCH3)-N-(CH3)]Gly-boroArg-CipHl6 [N-(-C(O)Ph-2-CH2Ph-2-Ph)-N-(CH3)]Gly-boroArg-CipHl6 [N-(-C(O)Ph-4-CH2Ph)-N-(CH3)]Gly-boroArg-CipHl6 [N-(-C(0)Ph-2-CH2Ph)-N-(CH3)]Gly-boroArg-CipHib [N-(-C(O)Ph-3-CH2Ph)-N-(CH3)]Gly-boroArg-CipHl6 [N-(-C(0)Ph-3-CH2Ph-2-CF3)-N-(CH3)]Gly-boroArg-CipHl6 [N-(-C(O)(CH2)2Ph)-N-(C2H5)]Gly-boroArg-CipHl6 [N-(-C(0)(CH2)2Ph)-N-(n-C3H~)]Gly-boroArg-CipHl6 [N-(-C(O)(CH2)2Ph)-N-(i-C3H~)]Gly-boroArg-CipHl6 [N-(-C(O) (CH2)2Ph)-N-(C6H12) ]Gly-boroArg-CipHl6 [N-(-C(O)(CHZ)2Ph)-N-(OH)]Gly-boroArg-CipHl6 [N-(-C(0)(CH2)2Ph)-N-(OCH3)]Gly-boroArg-C1pH16 [N-(-C(O)(CH2)2Ph)-N-(OCHZPh)]Gly-boroArg-CipHl6 [N-(-C(0)(CH2)2Ph)-N-(NH2)]Gly-boroArg-CipHl6 [N-(-C(O)(CH2)2Ph)-N-(N(CH3)2)]Gly-boroArg-CipHl6 SUBSTITUTE SHEET (RULE 26) ~1'~~314 [N-(-C(0)(CH2)2Ph)-N-(NHBoc>]Gly-boroArg-C1pH16 [N-(-C(0)(CH2)2Ph)-N-(CH2C02H)]Gly-boroArg-C1pH16 [N-(-C(0)(CH2)2Ph)-N-(CH2C02CH3)]Gly-boroArg-C1pH16 [N-(-C(O)CH2Ph)-N-(CH3)]Gly-boroArg-C1pH16 [N-(-C(O)(CH2)3Ph)-N-(CH3)]Gly-boroArg-C1pH16 [N-(-C(O)Ph)-N-(CH3)]Gly-boroArg-C1pH16 [N-(-C(O)(CH2)2Ph)-N-CHZPh)]Gly-boroArg-C1pH16 [N-(-C(O)(CH2)2Ph-3,4-C12)-N-(CH3)]Gly-boroArg-C1pH16 [N-(-C(O)(CH2)2Ph-4-C1)-N-(CH3)]Gly-boroArg-C1pH16 [N-(-C(O)(CH2)2Ph-4-CH3)-N-(CH3)]Gly-boroArg-C1pH16 [N-(-C(O)(CH2)2Ph-4-OCH3)-N-(CH3)]Gly-boroArg-C1pH16 [N- ( -C (O) CH3 ] (D) -Phe [N- (CH3 ) ] Gly-boroArg-C1pH16 (N-(-C(0)CH3](D)-Phe[N-(CH3)]Gly-boroIrg-C1pH16 [N-(-C(O)(CH2)2Ph)-N-(CH3)]Gly-Arg-CF3 [N-(-C(0)(CH2)2Ph)-N-(CH2)2Ph]Gly-Arg-CF3 [N-(-C(O)(CH2)2Ph)-N-Ph]Gly-Arg-CCF3 [N-(-C(O)N(CH3)CH2Ph)-N-Ph]Gly-Arg-CF3 [N-(-C(O)Ph-3-CH=CHPh)-N-(CH3)]Gly-Arg-CF3 [N-(-C(O)Ph-3-CH2CH2Ph)-N-(CH3)]Gly-Arg-CF3 [N-(-C(O)Ph-3-SPh-3-OCH3)-N-(CH3)]Gly-Arg-CF3 [N-(-C(O)Ph-2-CH2Ph-2-Ph)-N-(CH3)]Gly-Arg-CF3 [N-(-C(O)Ph-4-CH2Ph)-N-(CH3)]Gly-Arg-CF3 [N-(-C(0)Ph-2-CH2Ph)-N-(CH3)]Gly-Arg-CF3 [N-(-C(O)Ph-3-CH2Ph)-N-(CH3)]Gly-Arg-CF3 (N-(-C(0)Ph-3-CH2Ph-2-CF3)-N-(CH3)]Gly-Arg-CF3 (N-(-C(O)CH2Ph-3,4-C12)-N-(CH3)]Gly-Arg-CF3 [N-(-C(0)(CH2)2Ph)-N-(C2H5)]Gly-Arg-CF3 [N-(-C(O)(CH2)2Ph)-N-(n-C3H~)]Gly-Arg-CF3 [N-(-C(0)(CH2)2Ph)-N-(i-C3H~)]Gly-Arg-CF3 [N-(-C(O)(CH2)2Ph)-N-(C6H12)]Gly-Arg-CF3 [N-(-C(0)(CH2)2Ph)-N-(OH)]Gly-Arg-CF3 [N-(-C(O)(CH2)2Ph)-N-(OCH3)]Gly-Arg-CF3 [N-(-C(O)(CH2)2Ph)-N-(OCH2Ph)]Gly-Arg-CF3 [N-(-C(O)(CH2)2Ph)-N-(NH2)]Gly-Arg-CF3 [N-(-C(0)(CH2)2Ph)-N-(N(CH3)2)]Gly-Arg-CF3 SUBSTITUTE SHEET (RULE 26) WO 95109634 ~~ 7 4 J ~ ~ PCTlUS94111280 [N-(-C(0)(CH2)2Ph)-N-(NHBoc)]Gly-Arg-CF3 [N-(-C(O)(CH2)2Ph)-N-(CH2C02H)]Gly-Arg-CF3 [N-(-C(O)(CH2)2Ph)-N-(CH2C02CH3)]Gly-Arg-CF3 [N-(-C(O)CH2Ph)-N-(CH3)]Gly-Arg-CF3 [N-(-C(0)(CH2)3Ph)-N-(CH3)]Gly-Arg-CF3 [N-(-C(O)Ph)-N-(CH3)]Gly-Arg-CF3 [N-(-C(O)(CH2)2Ph)-N-CH2Ph)]Gly-Arg-CF3 [N-(-C(O)(CH2)2Ph-3,4-C12)-N-(CH3)]Gly-Arg-CF3 [N-(-C(0)(CH2)2Ph-4-C1)-N-(CH3)]Gly-Arg-CF3 [N-(-C(O)(CH2)2Ph-4-CH3)-N-(CH3)]Gly-Arg-CF3 [N-(-C(0)(CH2)2Ph-4-OCH3)-N-(CH3)]Gly-Arg-CF3 [N-(-C(O)(CH2)2Ph)-N-(CH3)]Gly-Arg-OCH3 [N-(-C(0)(CHZ)2Ph)-N-(CH2)2Ph]Gly-Arg-OCH3 [N-(-C(O)(CHZ)2Ph)-N-Ph]Gly-Arg-OCH3 [N-(-C(O)N(CH3)CH2Ph)-N-Ph]Gly-Arg-OCH3 [N-(-C(O)Ph-3-CH=CHPh)-N-(CH3)]Gly-Arg-OCH3 [N-(-C(0)Ph-3-CH2CH2Ph)-N-(CH3)]Gly-Arg-OCH3 [N-(-C(O)Ph-3-SPh-3-OCH3)-N-(CH3)]Gly-Arg-OCH3 [N-(-C(O)Ph-2-CH2Ph-2-Ph)-N-(CH3)]Gly-Arg-OCH3 [N-(-C(O)Ph-4-CH2Ph)-N-(CH3)]Gly-Arg-OCH3 [N-(-C(0)Ph-2-CH2Ph)-N-(CH3)]Gly-Arg-OCH3 [N-(-C(O)Ph-3-CH2Ph)-N-(CH3)]Gly-Arg-OCH3 [N-(-C(O)Ph-3-CH2Ph-2-CF3)-N-(CH3)]Gly-Arg-OCH3 [N-(-C(O)CH2Ph-3,4-C12)-N-(CH3)]Gly-Arg-OCH3 (N-(-C(0)(CH2)2Ph)-N-(C2H5)]Gly-Arg-OCH3 (N-(-C(O)(CH2)2Ph)-N-(n-C3H~)]Gly-Arg-OCH3 [N-(-C(O)(CH2)2Ph)-N-(i-C3H~)]Gly-Arg-OCH3 [N-(-C(0) (CH2)2Ph)-N-(C6H12) ]G1Y-Arg-OCH3 [N-(-C(0)(CH2)2Ph)-N-(OH)]Gly-Arg-OCH3 [N-(-C(O)(CH2)2Ph)-N-(OCH3)]Gly-Arg-OCH3 [N-(-C(O)(CHZ)2Ph)-N-(OCH2Ph)]Gly-Arg-OCH3 [N-(-C(O)(CH2)2Ph)-N-(NH2)]Gly-Arg-OCH3 [N-(-C(0) (CH2)2Ph)-N-(N(CH3)2) ]Gly-Arg-OCH3 [N-(-C(O)(CH2)2Ph)-N-(NHBoc)]Gly-Arg-OCH3-[N-(-C(O)(CH2)2Ph)-N-(CH2C02H)]Gly-Arg-OCH3 SUBSTITUTE SHEET (RULE 26) ~1'~43h4 , .. ~. , .
. ;, .
WO 95109634 . . ~ , '' = ' ~- PCTIUS94111280 [N-(-C(O)(CH2)ZPh)-N-(CH2C02CH3)]Gly-Arg-OCH3 [N-(-C(O)CH2Ph)-N-(CH3)]Gly-Arg-OCH3 [N-(-C(O)(CH2)3Ph)-N-(CH3)]Gly-Arg-OCH3 [N-(-C(O)Ph)-N-(CH3)]Gly-Arg-OCH3 [N-(-C(O)(CH2)2Ph)-N-CH2Ph)]Gly-Arg-OCH3 [N-(-C(O)(CH2)2Ph-3,4-C12)-N-(CH3)]Gly-Arg-OCH3 [N-(-C(O)(CH2)2Ph-4-C1)-N-(CH3)]Gly-Arg-OCH3 [N-(-C(0)(CH2)2Ph-4-CH3)-N-(CH3)]Gly-Arg-OCH3 [N-(-C(O)(CH2)2Ph-4-OCH3)-N-(CH3)]Gly-Arg-OCH3 [N-(-C(O)(CH2)2Ph)-N-(CH3)]Gly-Arg-C02CH3 [N-(-C(O)(CH2)2Ph)-N-(CH2)2Ph]Gly-Arg-C02CH3 [~N- ( -C ( 0 ) ( CH2 ) 2Ph ) -N-Ph ] Gly-Arg-C02CH3 [N-(-C(O)N(CH3)CH2Ph)-N-Ph]Gly-Arg-C02CH3 [N-(-C(O)Ph-3-CH=CHPh)-N-(CH3)]Gly-Arg-C02CH3 [N-(-C(O)Ph-3-CH2CH2Ph)-N-(CH3)]Gly-Arg-C02CH3 [N-(-C(0)Ph-3-SPh-3-OCH3)-N-(CH3)]Gly-Arg-C02CH3 [N-(-C(O)Ph-2-CH2Ph-2-Ph)-N-(CH3)]Gly-Arg-C02CH3 [N-(-C(O)Ph-4-CH2Ph)-N-(CH3)]Gly-Arg-C02CH3 [N-(-C(O)Ph-2-CH2Ph)-N-(CH3)]Gly-Arg-C02CH3 [N-(-C(0)Ph-3-CHZPh)-N-(CH3)]Gly-Arg-C02CH3 [N-(-C(O)Ph-3-CH2Ph-2-CF3)-N-(CH3)]Gly-Arg-C02CH3 [N-(-C(0)CH2Ph-3,4-C12)-N-(CH3)]Gly-Arg-C02CH3 [N-(-C(O)(CH2)2Ph)-N-(C2H5)]Gly-Arg-C02CH3 [N-(-C(0)(CH2)2Ph)-N-(n-C3H~)]Gly-Arg-C02CH3 [N-(-C(O)(CH2)2Ph)-N-(i-C3H~)]Gly-Arg-C02CH3 [N-(-C(0) (CH2)2Ph)-N-(C6H12) ]GlY-Arg-C02CH3 [N-(-C(O)(CH2)2Ph)-N-(OH)]Gly-Arg-C02CH3 [N-(-C(0)(CH2)2Ph)-N-(OCH3)]Gly-Arg-C02CH3 [N-(-C(0)(CH2)2Ph)-N-(OCH2Ph)]Gly-Arg-C02CH3 [N-(-C(O)(CH2)2Ph)-N-(NH2)]Gly-Arg-C02CH3 [N-(-C(O)(CH2)2Ph)-N-(N(CH3)2)]Gly-Arg-C02CH3 [N-(-C(0)(CH2)2Ph)-N-(NHBoc)]Gly-Arg-COZCH3 (N-(-C(O)(CH2)2Ph)-N-(CH2C02H)]Gly-Arg-C02CH3 [N-(-C(O)(CH2)2Ph)-N-(CH2C02CH3)]Gly-Arg-C02CH3 [N-(-C(O)CH2Ph)-N-(CH3)]Gly-Arg-C02CH3 SUBSTITUTE SHEET (RULE 26) WO 95/09634 ~ PCT/US94111280 [N-(-C(O)(CH2)3Ph)-N-(CH3)]Gly-Arg-C02CH3 [N-(-C(0)Ph)-N-(CH3)]Gly-Arg-C02CH3 [N-(-C(O)(CH2)2Ph)-N-CH2Ph)]Gly-Arg-C02CH3 [N-(-C(O)(CH2)2Ph-3,4-C12)-N-(CH3)]Gly-Arg-C02CH3 [N-(-C(O)(CH2)2Ph-4-C1)-N-(CH3)]Gly-Arg-COzCH3 [N-(-C(0)(CH2)2Ph-4-CH3)-N-(CH3)]Gly-Arg-C02CH3 [N-(-C(0)(CH2)2Ph-4-OCH3)-N-(CH3)]Gly-Arg-C02CH3 [N-(-C(O)(CH2)2Ph)-N-(CH3)]Gly-boroPhe(mCN)-OH
[N-(-C(O)(CH2)2Ph)-N-(CH2)2Ph]Gly-boroPhe(mCN)-OH
(N-(-C(O)(CH2)2Ph)-N-Ph]Gly-boroPhe(mCN)-OH
[N-(-C(0)N(CH3)CH2Ph)-N-Ph]Gly-boroPhe(mCN)-OH
[N-(-C(O)Ph-3-CH=CHPh)-N-(CH3)]Gly-boroPhe(mCN)-OH
[N-(-C(O)Ph-3-CH2CH2Ph)-N-(CH3)]Gly-boroPhe(mCN)-OH
[N-(-C(O)Ph-3-SPh-3-OCH3)-N-(CH3)]Gly-boroPhe(mCN)-OH
[N-(-C(O)Ph-2-CH2Ph-2-Ph)-N-(CH3)lGly-boroPhe(mCN)-OH
[N-(-C(O)Ph-4-CH2Ph)-N-(CH3)]Gly-boroPhe(mCN)-OH
[N-(-C(0)Ph-2-CH2Ph)-N-(CH3)]Gly-boroPhe(mCN)-OH
[N-(-C(O)Ph-3-CH2Ph)-N-(CH3)]Gly-boroPhe(mCN)-OH
[N-(-C(0)Ph-3-CH2Ph-2-CF3)-N-(CH3)]Gly-boroPhe(mCN)-OH
[N-(-C(O)CH2Ph-3,4-C12)-N-(CH3)]Gly-boroPhe(mCN)-OH
[N-(-C(0)(CH2)2Ph)-N-(C2H5)]Gly-boroPhe(mCN)-OH
[N-(-C(O)(CH2)2Ph)-N-(n-C3H~)]Gly-boroPhe(mCN)-OH
[N-(-C(0)(CH2)2Ph)-N-(i-C3H~)]Gly-boroPhe(mCN)-OH
[N-(-C(O)(CH2)2Ph)-N-(C6H12)]Gly-boroPhe(mCN)-OH
[N-(-C(0)(CH2)2Ph)-N-(OH)]Gly-boroPhe(mCN)-OH
[N-(-C(O)(CH2)2Ph)-N-(OCH3)]Gly-boroPhe(mCN)-OH
[N-(-C(0)(CH2)2Ph)-N-(OCH2Ph)]Gly-boroPhe(mCN)-OH
[N-(-C(O)(CH2)2Ph)-N-(NH2)]Gly-boroPhe(mCN)-OH
[N-(-C(0)(CH2)2Ph)-N-(N(CH3)2)]Gly-boroPhe(mCN)-OH
[N-(-C(O)(CH2)2Ph)-N-(NHBoc)]Gly-boroPhe(mCN)-OH
[N-(-C(0)(CH2)2Ph)-N-(CH2C02H)]Gly-boroPhe(mCN)-OH
[N-(-C(O)(CH2)2Ph)-N-(CH2C02CH3)]Gly-boroPhe(mCN)-OH
[N-(-C(O)CH2Ph)-N-(CH3)]Gly-boroPhe(mCN)-OH
(N-(-C(O)(CH2)3Ph)-N-(CH3)]Gly-boroPhe(mCN)-OH
[N-(-C(0)Ph)-N-(CH3)]Gly-boroPhe(mCN)-OH

SUBSTITUTE SHEET (RULE 26) ~~-- WO 95!09634 PCT/US94111280 [N-(-C(0)(CH2)2Ph)-N-CH2Ph)]Gly-boroPhe(mCN)-OH
[N-(-C(O)(CH2)2Ph-3,4-C12)-N-(CH3)]Gly-boroPhe(mCN)-OH
(N-(-C(O)(CH2)2Ph-4-C1)-N-(CH3)]Gly-boroPhe(mCN)-OH
[N-(-C(O)(CH2)2Ph-4-CH3)-N-(CH3)]Gly-boroPhe(mCN)-OH
S [N-(-C(0)(CH2)2Ph-4-OCH3)-N-(CH3)]Gly-boroPhe(mCN)-OH
[N-(-C(O)(CH2)2Ph)-N-(CH3)]Gly-boroPhe(mCN)-CipHl6 [N- ( -C (O) (CH2 ) 2Ph) -N- (CHZ ) 2Ph] Gly-boroPhe (rr~CN) -CipHl6 [N-(-C(0)(CH2)2Ph)-N-Ph]Gly-boroPhe(mCN)-CipHl6 [N-(-C(O)N(CH3)CH2Ph)-N-Ph]Gly-boroPhe(mCN)-CipHl6 [N-(-C(O)Ph-3-CH=CHPh)-N-(CH3)]Gly-boroPhe(mCN)-CipHl6 [N-(-C(O)Ph-3-CH2CH2Ph)-N-(CH3)]Gly-boroPhe(mCN)-CipHl6 (N-(-C(O)Ph-3-SPh-3-OCH3)-N-(CH3)]Gly-boroPhe(mCN)-CipHl6 [N-(-C(O)Ph-2-CH2Ph-2-Ph)-N-(CH3)]Gly-boroPhe(mCN)-CipHl6 [N-(-C(O)Ph-4-CH2Ph)-N-(CH3)]Gly-boroPhe(mCN)-CipHl6 [N-(-C(O)Ph-2-CH2Ph)-N-(CH3)]Gly-boroPhe(mCN)-CipHl6 [N-(-C(O)Ph-3-CH2Ph)-N-(CH3))Gly-boroPhe(mCN)-CipHl6 [N-(-C(O)Ph-3-CH2Ph-2-CF3)-N-(CH3)]Gly-boroPhe(mCN)-CipHl6 [N-(-C(O)(CH2)2Ph)-N-(C2H5)]Gly-boroPhe(mCN)-CipHl6 [N-(-C(O)(CHZ)2Ph)-N-(n-C3H~)]Gly-boroPhe(mCN)-CipHl6 [N-(-C(O)(CH2)2Ph)-N-(i-C3H~)]Gly-boroPhe(mCN)-CipHl6 [N-(-C(O)(CH2)2Ph)-N-(C6H12)]Gly-boroPhe(mCN)-CipHl6 [N-(-C(O)(CH2)2Ph)-N-(OH)]Gly-boroPhe(mCN)-CipHl6 [N-(-C(O)(CH2)2Ph)-N-(OCH3)]Gly-boroPhe(mCN)-CipHl6 [N-(-C(O)(CH2)2Ph)-N-(OCH2Ph)]Gly-boroPhe(mCN)-CipHl6 [N-(-C(O)(CH2)2Ph)-N-(NH2)]Gly-boroPhe(mCN)-CipHl6 [N-(-C(O)(CH2)2Ph)-N-(N(CH3)2)]Gly-boroPhe(mCN)-CipHl6 [N-(-C(O)(CH2)2Ph)-N-(NHBoc)]Gly-boroPhe(mCN)-CipHl6 [N-(-C(0)(CH2)2Ph)-N-(CH2C02H)]Gly-boroPhe(mCN)-CipHl6 [N-(-C(O)(CH2)2Ph)-N-(CH2COZCH3)]Gly-boroPhe(mCN)-CipHl6 [N-(-C(O)CH2Ph)-N-(CH3)]Gly-boroPhe(mCN)-CipHl6 [N-(-C(O)(CH2)3Ph)-N-(CH3)]Gly-boroPhe(mCN)-CipHl6 [N-(-C(O)Ph)-N-(CH3)]Gly-boroPhe(mCN)-CipHl6 [N-(-C(O)(CH2)2Ph)-N-CH2Ph)]Gly-boroPhe(mCN)-CipHl6 [N-(-C(0)(CH2)2Ph-3,4-C12)-N-(CH3)]Gly-boroPhe(mCN)-CipHl6 [N-(-C(O)(CH2)2Ph-4-C1)-N-(CH3)]Gly-boroPhe(mCN)-CipHl6 SUBSTITUTE SHEET (RULE 26) ~1'~4314 [N-(-C(O)(CH2)2Ph-4-CH3)-N-(CH3)]Gly-boroPhe(mCN)-C1pH16 [N-(-C(O)(CH2)2Ph-4-OCH3)-N-(CH3)]Gly-boroPhe(mCN)-C1pH16 (N-(-C(O)(CH2)2Ph)-N-(CH3)]Gly-Phe(mCN)-CF3 [N-(-C(O)(CH2)2Ph)-N-(CH2)2Ph]Gly-Phe(mCN)-CF3 [N-(-C(O)(CH2)2Ph)-N-Ph]Gly-Phe(mCN)-CF3 [N-(-C(O)N(CH3)CH2Ph)-N-Ph]Gly-Phe(mCN)-CF3 [N-(-C(O)Ph-3-CH=CHPh)-N-(CH3)JGly-Phe(mCN)-CF3 [N-(-C(O)Ph-3-CH2CH2Ph)-N-(CH3)]Gly-Phe(mCN)-CF3 [N-(-C(O)Ph-3-SPh-3-OCH3)-N-(CH3))Gly-Phe(mCN)-CF3 [N-(-C(O)Ph-2-CHZPh-2-Ph)-N-(CH3)]Gly-Phe(mCN)-CF3 [N-~(-C (O) Ph-4-CH2Ph) -N- (CH3 ) ] Gly-Phe (mCN) -CF3 [N-(-C(O)Ph-2-CH2Ph)-N-(CH3)]Gly-Phe(mCN)-CF3 [N-(-C(O)Ph-3-CH2Ph)-N-(CH3)]Gly-Phe(mCN)-CF3 [N-(-C(0)Ph-3-CH2Ph-2-CF3)-N-(CH3)]Gly-Phe(mCN)-CF3 (N-(-C(O)CHZPh-3,4-C12)-N-(CH3)]Gly-Phe(mCN)-CF3 [N-(-C(O)(CH2)2Ph)-N-(C2H5)]Gly-Phe(mCN)-CF3 [N-(-C(O)(CH2)2Ph)-N-(n-C3H~)]Gly-Phe(mCN)-CF3 [N-(-C(O)(CH2)2Ph)-N-(i-C3H~)]Gly-Phe(mCN)-CF3 [N-(-C(O)(CH2)2Ph)-N-(C6H12)JG1Y-Phe(mCN)-CF3 [N-(-C(0)(CH2)2Ph)-N-(OH))Gly-Phe(mCN)-CF3 [N-(-C(O)(CH2)2Ph)-N-(OCH3)]Gly-Phe(mCN)-CF3 [N-(-C(O)(CH2)2Ph)-N-(OCHZPh)]Gly-Phe(mCN)-CF3 [N-(-C(O)(CH2)2Ph)-N-(NH2)]Gly-Phe(mCN)-CF3 [N-(-C(0)(CH2)2Ph)-N-(N(CH3)2)]Gly-Phe(mCN)-CF3 [N-(-C(O)(CH2)2Ph)-N-(NHBoc)]Gly-Phe(mCN)-CF3 [N-(-C(O)(CH2)2Ph)-N-(CH2COZH)]Gly-Phe(mCN)-CF3 [N-(-C(O)(CH2)2Ph)-N-(CH2C02CH3)]Gly-Phe(mCN)-CF3 [N-(-C(0)CH2Ph)-N-(CH3)]Gly-Phe(mCN)-CF3 [N-(-C(O)(CH2)3Ph)-N-(CH3))Gly-Phe(mCN)-CF3 [N-(-C(O)Ph)-N-(CH3)]Gly-Phe(mCN)-CF3 [N-(-C(O)(CH2)2Ph)-N-CH2Ph)]Gly-Phe(mCN)-CF3 [N-(-C(0)(CH2)2Ph-3,4-C12)-N-(CH3)]Gly-Phe(mCN)-CF3 [N-(-C(O)(CH2)2Ph-4-C1)-N-(CH3)]Gly-Phe(mCN)-CF3 [N-(-C(O)(CH2)2Ph-4-CH3)-N-(CH3)]Gly-Phe(mCN)-CF3 [N-(-C(O)(CH2)2Ph-4-OCH3)-N-(CH3)]Gly-Phe(mCN)-CF3 SUBSTITUTE SHEET (RULE 26) WO 95109634 ~ 1 ~ 4 ~ ~ 4~ PCTlUS94111280 [N-(-C(O)(CH2)2Ph)-N-(CH3)]Gly-Phe(mCN)-OCH3 [N-(-C(O)(CH2)2Ph)-N-(CH2)2Ph]Gly-Phe(mCN)-OCH3 [N-(-C(0)(CH2)2Ph)-N-Ph]Gly-Phe(mCN)-OCH3 [N-(-C(O)N(CH3)CH2Ph)-N-Ph]Gly-Phe(mCN)-OCH3 [N-(-C(0)Ph-3-CH=CHPh)-N-(CH3)]Gly-Phe(mCN)-OCH3 [N-(-C(O)Ph-3-CH2CH2Ph)-N-(CH3)]Gly-Phe(mCN)-OCH3 [N-(-C(0)Ph-3-SPh-3-OCH3)-N-(CH3)]Gly-Phe(mCN)-OCH3 [N-(-C(O)Ph-2-CH2Ph-2-Ph)-N-(CH3)]Gly-Phe(mCN)-OCH3 [N-(-C(0)Ph-4-CH2Ph)-N-(CH3)]Gly-Phe(mCN)-OCH3 [N-(-C(O)Ph-2-CH2Ph)-N-(CH3)]Gly-Phe(mCN)-OCH3 [N-(-C(0)Ph-3-CH2Ph)-N-(CH3)]Gly-Phe(mCN)-OCH3 [N-(-C(O)Ph-3-CH2Ph-2-CF3)-N-(CH3)]Gly-Phe(mCN)-OCH3 [N-(-C(0)CH2Ph-3,4-C12)-N-(CH3)]Gly-Phe(mCN)-OCH3 [N-(-C(O)(CH2)2Ph)-N-(C2H5)]Gly-Phe(mCN)-OCH3 [N-(-C(0)(CH2)2Ph)-N-(n-C3H~)]Gly-Phe(mCN)-OCH3 [N-(-C(O)(CH2)2Ph)-N-(i-C3H~)]Gly-Phe(mCN)-OCH3 [N-(-C(O)(CH2)2Ph)-N-(C6H12)JG1Y-Phe(mCN)-OCH3 [N-(-C(O)(CH2)2Ph)-N-(OH)]Gly-Phe(mCN)-OCH3 [N-(-C(0)(CH2)2Ph)-N-(OCH3)]Gly-Phe(mCN)-OCH3 [N-(-C(O)(CH2)2Ph)-N-(OCH2Ph)]Gly-Phe(mCN)-OCH3 [N-(-C(0)(CH2)2Ph)-N-(NH2)]Gly-Phe(mCN)-OCH3 [N-(-C(O)(CH2)2Ph)-N-(N(CH3)2)]Gly-Phe(mCN)-OCH3 [N-(-C(0)(CH2)2Ph)-N-(NHBoc)]Gly-Phe(mCN)-OCH3 (N-(-C(O)(CH2)2Ph)-N-(CHzC02H)JGly-Phe(mCN)-OCH3 [N-(-C(0)(CH2)2Ph)-N-(CH2C02CH3)]Gly-Phe(mCN)-OCH3 [N-(-C(O)CH2Ph)-N-(CH3)]Gly-Phe(mCN)-OCH3 [N-(-C(0)(CH2)3Ph)-N-(CH3)]Gly-Phe(mCN)-OCH3 [N-(-C(O)Ph)-N-(CH3)]Gly-Phe(mCN)-OCH3 [N-(-C(O)(CH2)2Ph)-N-CH2Ph)]Gly-Phe(mCN)-OCH3 [N-(-C(0)(CH2)2Ph-3,4-C12)-N-(CH3)]Gly-Phe(mCN)-OCH3 [N-(-C(0)(CH2)ZPh-4-C1)-N-(CH3)]Gly-Phe(mCN)-OCH3 [N-(-C(O)(CH2)2Ph-4-CH3)-N-(CH3)]Gly-Phe(mCN)-OCH3 [N-(-C(O)(CH2)2Ph-4-OCH3)-N-(CH3)]Gly-Phe(mCN)-OCH3 [N-(-C(O)(CH2)2Ph)-N-(CH3)]Gly-Phe(mCN)-COZCH3 [N-(-C(O)(CH2)2Ph)-N-(CH2)2PhJGly-Phe(mCN)-C02CH3 SUBSTITUTE SHEET (RULE 26) ~~ ?43.I4 [N-(-C(0)(CH2)2Ph)-N-Ph]Gly-Phe(mCN)-C02CH3 [N-(-C(O)N(CH3)CH2Ph)-N-Ph]Gly-Phe(mCN)-C02CH3 [N-(-C(O)Ph-3-CH=CHPh)-N-(CH3)]Gly-Phe(rriCN)-C02CH3 [N-(-C(0)Ph-3-CH2CH2Ph)-N-(CH3)]Gly-Phe(mCN)-COZCH3 [N-(-C(0)Ph-3-SPh-3-OCH3)-N-(CH3)]Gly-Phe(mCN)-C02CH3 [N-(-C(O)Ph-2-CH2Ph-2-Ph)-N-(CH3)]Gly-Phe(mCN)-C02CH3 [N-(-C(O)Ph-4-CH2Ph)-N-(CH3)]Gly-Phe(mCN)-C02CH3 [N-(-C(O)Ph-2-CH2Ph)-N-(CH3)]Gly-Phe(mCN)-C02CH3 [N-(-C(O)Ph-3-CH2Ph)-N-(CH3)]Gly-Phe(mCN)-C02CH3 [N-(-C(O)Ph-3-CH2Ph-2-CF3)-N-(CH3)]Gly-Phe(mCN)-C02CH3 [N-(-C(O)CH2Ph-3,4-C12)-N-(CH3)]Gly-Phe(mCN)-C02CH3 [N-(-C(O) (CH2)2Ph)-N-(C2H5)]Gly-Phe(mCN)-C02CH3 [N-(-C(O)(CHZ)2Ph)-N-(n-C3H~)]Gly-Phe(mCN)-C02CH3 [N-(-C(O)(CH2)2Ph)-N-(i-C3H~)]Gly-Phe(mCN)-C02CH3 [N-(-C(O)(CHZ)2Ph)-N-(C6H12)]Gly-Phe(mCN)-C02CH3 [N-(-C(O)(CH2)2Ph)-N-(OH)]Gly-Phe(mCN)-C02CH3 [N-(-C(O)(CH2)2Ph)-N-(OCH3)]Gly-Phe(mCN)-C02CH3 [N-(-C(0)(CH2)2Ph)-N-(OCH2Ph)]Gly-Phe(mCN)-C02CH3 [N-(-C(O)(CH2)2Ph)-N-(NH2)]Gly-Phe(mCN)-C02CH3 [N-(-C(O)(CH2)2Ph)-N-(N(CH3)2)]Gly-Phe(mCN)-C02CH3 [N-(-C(O)(CH2)2Ph)-N-(NHBoc)]G1Y-Phe(mCN)-COZCH3 [N-(-C(0)(CH2)2Ph)-N-(CH2C02H)]Gly-Phe(mCN)-C02CH3 [N-(-C(O)(CH2)2Ph)-N-(CH2C02CH3)]Gly-Phe(mCN)-C02CH3 [N-(-C(0)CH2Ph)-N-(CH3)]Gly-Phe(mCN)-C02CH3 [N-(-C(O)(CH2)3Ph)-N-(CH3)]Gly-Phe(mCN)-C02CH3 [N-(-C(0)Ph)-N-(CH3)]Gly-Phe(mCN)-C02CH3 [N-(-C(O)(CH2)2Ph)-N-CH2Ph)]Gly-Phe(mCN)-C02CH3 [N-(-C(0)(CH2)2Ph-3,4-C12)-N-(CH3)]Gly-Phe(mCN)-C02CH3 [N-(-C(O)(CH2)2Ph-4-C1)-N-(CH3)]Gly-Phe(mCN)-C02CH3 [N-(-C(0)(CH2)2Ph-4-CH3)-N-(CH3)]Gly-Phe(mCN)-C02CH3 [N-(-C(O)(CH2)2Ph-4-OCH3)-N-(CH3)]Gly-Phe(mCN)-C02CH3 [N-(-C(O)(CH2)2Ph)-N-(CH2)2Ph]Gly-boro0rn(N-methylamidino)-OH
[N-(-C(0)(CH2)2Ph)-N-Ph]Gly-boro0rn(N-methylamidino)-OH
[N-(-C!O)N(CH3)CH2Ph)-N-Ph]Gly-boroOrn(N-methylamidino)-OH

SUBSTITUTE SHEET (RULE 26) ~.1'~ 4 3 ~. 4 PCT/US94/11280 ~' WO 95/09634 [N-(-C(O)Ph-3-CH=CHPh)-N-(CH3)]Gly-boroOrn(N-methylamidino)-OH
[N-(-C(O)Ph-3-CH2CH2Ph)-N-(CH3)]Gly-boroOrn(N-methylamidino)-OH
[N-(-C(O)Ph-3-SPh-3-OCH3)-N-(CH3)]Gly-boroOrn(N-methylamidino)-OH
[N-(-C(0)Ph-2-CH2Ph-2-Ph)-N-(CH3)]Gly-boro0rn(N-methylamidino)-OH
[N-(-C(O)Ph-4-CH2Ph)-N-(CH3)]Gly-boroOrn(N-methylamidino)-OH
[N-(-C(O)Ph-2-CH2Ph)-N-(CH3)]Gly-boroOrn(N-methylamidino)-OH
[N-(-C(O)Ph-3-CH2Ph)-N-(CH3)]Gly-boroOrn(N-methylamidino)-OH
[N-(-C(O)Ph-3-CH2Ph-2-CF3)-N-(CH3)]Gly-boroOrn(N-methylamidino)-OH
[N-(-C(O)(CH2)2Ph)-N-(C2H5)]Gly-boro0rn(N-methylamidino)-OH
(N-(-C(O)(CH2)2Ph)-N-(n-C3H~)]Gly-boroOrn(N-methylamidino)-OH
[N-(-C(O)(CH2)2Ph)-N-(i-C3H~)]Gly-boroOrn(N-methylamidino)-OH
[N-(-C(O)(CH2)2Ph)-N-(C6H12)]Gly-boroOrn(N-methylamidino)-OH
[N-(-C(O)(CHZ)2Ph)-N-(OH)]Gly-boroOrn(N-methylamidino)-OH
[N-(-C(O)(CH2)2Ph)-N-(OCH3)]Gly-boroOrn(N-methylamidino)-OH
[N-(-C(0)(CH2)2Ph)-N-(OCH2Ph)]Gly-boro0rn(N-methylamidino)-OH
[N-(-C(O)(CH2)2Ph)-N-(NH2)]Gly-boroOrn(N-methylamidino)-OH
[N-(-C(O)(CH2)2Ph)-N-(N(CH3)2)]Gly-boroOrn(N-methylamidino)-OH
[N-(-C(O)(CH2)2Ph)-N~(NHBoc)]Gly-boroOrn(N-methylamidino)-OH
[N-(-C(O)(CH2)2Ph)-N-(CH2C02H)]Gly-boro0rn(N-methylamidino)-OH
[N-(-C(O)(CH2)2Ph)-N-(CH2C02CH3)]Gly-boroOrn(N-methylamidino)-OH

SUBSTITUTE SHEET (RULE 26) PCTlUS94I11280 [N-(-C(O)CH2Ph)-N-(CH3)]Gly-boroOrn(N-methylamidino)-OH
[N-(-C(O)(CH2)3Ph)-N-(CH3)]Gly-boroOrn(N-methylamidino)-OH
[N-(-C(0)Ph)-N-(CH3)]Gly-boroOrn(N-methylamidino)-OH
(N-(-C(O)(CH2)2Ph)-N-CH2Ph)]Gly-boroOrn(N-methylamidino)-OH
[N-(-C(0)(CH2)2Ph-3,4-C12)-N-(CH3)]Gly-boroOrn(N-methylamidino)-OH
[N-(-C(0)(CH2)2Ph-4-C1)-N-(CH3)]Gly-boro0rn(N-methylamidino)-OH
[N-(-C(O)(CH2)2Ph-4-CH3)-N-(CH3)]Gly-boroOrn(N-methylamidino)-OH
[N-(-C(0)(CH2)2Ph-4-OCH3)-N-(CH3)]Gly-boro0rn(N-methylamidino)-OH
(N-(-C(O)(CH2)2Ph)-N-Ph]Gly-boroOrn(N-methylamidino)-C1pH16 [N-(-C(O)N(CH3)CH2Ph)-N-Ph]Gly-boroOrn(N-methylamidino)-C1oH16 [N-(-C(O)Ph-3-CH=CHPh)-N-(CH3)]Gly-boroOrn(N-methylamidino)-C1pH16 [N-(-C(0)Ph-3-CH2CHZPh)-N-(CH3)]Gly-boro0rn(N-methylamidino)-C1pH16 (N-(-C(O)Ph-3-SPh-3-OCH3)-N-(CH3)]Gly-boroOrn(N-methylamidino)-C1pH16 [N-(-C(O)Ph-2-CH2Ph-2-Ph)-N-(CH3)]Gly-boroOrn(N-methylamidino)-C1pH16 [N-(-C(O)Ph-4-CHZPh)-N-(CH3)]Gly-boroOrn(N-methylamidino)-C1pH16 [N-(-C(O)Ph-2-CH2Ph)-N-(CH3)]Gly-boroOrnlN-methylamidino)-[N-(-C(O)Ph-3-CH2Ph)-N-(CH3)]Gly-boroOrn(N-methylamidino)-[N-(-C(O)Ph-3-CH2Ph-2-CF3)-N-(CH3))Gly-boroOrn(N-methylamidino)-C1pH16 [N-(-C(O)(CH2)2Ph)-N-(C2H5)]Gly-boro0rn(N-methylamidino)-[N-(-C(O)(CH2)2Ph)-N-(n-C3H~)]Gly-boro0rn(N-methylamidino)-SUBSTITUTE SHEET (RULE 26) WO 95/09634 , j; ; PCT/US94111280 [N-(-C(0)(CH2)2Ph)-N-(i-C3H~)]Gly-boro0rn(N-methylamidino)-[N-(-C(0)(CH2)2Ph)-N-(C6H12)]Gly-boroOrn(N-methylamidino)-[N-(-C(0)(CH2)2Ph)-N-(OH)]Gly-boro0rn(N-methylamidino)-[N-(-C(O)(CH2)2Ph)-N-(OCH3)]Gly-boroOrn(N-methylamidino)-[N-(-C(0)(CH2)2Ph)-N-(OCH2Ph)]Gly-boro0rn(N-methylamidino)-C1pH16 [N-(~-C(O)(CH2)2Ph)-N-(NH2)]Gly-boroOrn(N-methylamidino)-[N-(-C(O)(CH2)2Ph)-N-(N(CH3)2)]Gly-boroOrn(N-methylamidino)-C1pH16 [N-(-C(O)(CH2)2Ph)-N-(NHBoc)]Gly-boroOrn(N-methylamidino)-[N-(-C(0)(CH2)2Ph)-N-(CH2C02H)]Gly-boroOrn(N-methylamidino)-C1pH16 [N-(-C(O)(CH2)2Ph)-N-(CH2C02CH3)]Gly-boroOrn(N-methylamidino)-C1pH16 [N-(-C(O)CH2Ph)-N-(CH3)]Gly-boroOrn(N-methylamidino)-C1pH16 [N-(-C(O)(CH2)3Ph)-N-(CH3)]Gly-boroOrn(N-methylamidino)-[N-(-C(O)Ph)-N-(CH3)]Gly-boroOrnlN-methylamidino)-C1pH16 [N-(-C(O)(CH2)2Ph)-N-CH2Ph)]Gly-boroOrn(N-methylamidino)-C1oH16 [N-(-C(O)(CH2)2Ph-3,4-C12)-N-(CH3)]Gly-boroOrn(N-methylamidino)-C1pH16 [N-(-C(O)(CH2)2Ph-4-C1)-N-(CH3)]Gly-boroOrn(N-methylamidino)-C10H16 [N-(-C(O)(CH2)2Ph-4-CH3)-N-(CH3)]Gly-boroOrn(N-methylamidino)-C1pH16 [N-(-C(O)(CH2)2Ph-4-OCH3)-N-(CH3)]Gly-boroOrn(N-methylamidino)-C10H16 [N-(-C(O)(CH2)2Ph)-N-(CH3)]Gly-Orn(N-methylamidino)-CF3 SUBSTITUTE SHEET (RULE 26) [N-(-C(O)(CH2)2Ph)-N-(CH2)2Ph]Gly-Orn(N-methylamidino)-CF3 [N-(-C(0)(CH2)2Ph)-N-Ph]Gly-Orn(N-methylamidino)-CF3 [N-(-C(O)N(CH3)CH2Ph)-N-Ph]Gly-Orn(N-methylamidino)-CF3 [N-(-C(0)Ph-3-CH=CHPh)-N-(CH3)]Gly-Orn(N-methylamidino)-CF3 [N-(-C(O)Ph-3-CH2CH2Ph)-N-(CH3)]Gly-Orn(N-methylamidino)-[N-(-C(O)Ph-3-SPh-3-OCH3)-N-(CH3)]Gly-Orn(N-methylamidino)-[N-(-C(O)Ph-2-CH2Ph-2-Ph)-N-(CH3)]Gly-Orn(N-methylamidino)-[N-(-C(O)Ph-4-CH2Ph)-N-(CH3)]Gly-Orn(N-methylamidino)-CF3 [N-(-C(0)Ph-2-CH2Ph)-N-(CH3)]Gly-Orn(N-methylamidino)-CF3 [N-(-C(O)Ph-3-CH2Ph)-N-(CH3)]Gly-Orn(N-methylamidino)-CF3 [N-(-C(O)Ph-3-CH2Ph-2-CF3)-N-(CH3)]Gly-Orn(N-methylamidino)-CF3 [N-(-C(0)CH2Ph-3,4-C12)-N-(CH3)]Gly-Orn(N-methylamidino)-[N-(-C(O) (CH2)2Ph)-N-(C2H5)]Gly-Orn(N-methylamidino)-CF3 [N-(-C(O) (CH2)2Ph)-N-(n-C3H~)]Gly-Orn(N-methylamidino)-CF3 [N-(-C(0) (CH2)2Ph)-N-(i-C3H~)]Gly-Orn(N-methylamidino)-CF3 (N-(-C(O) (CH2)2Ph)-N-(C6H12)]Gly-Orn(N-methylamidino)-CF3 [N-(-C(0) (CH2)2Ph)-N-(OH)]Gly-Orn(N-methylamidino)-CF3 [N-(-C(0) (CH2)2Ph)-N-(OCH3)]Gly-Orn(N-methylamidino)-CF3 [N-(-C(0) (CH2)2Ph)-N-(OCH2Ph)]Gly-Orn(N-methylamidino)-CF3 [N-(-C(O) (CH2)2Ph)-N-(NH2)]Gly-Orn(N-methylamidino)-CF3 [N-(-C(O) (CH2)2Ph)-N-(N(CH3)2)]Gly-Orn(N-methylamidino)-CF3 [N-(-C(O) (CH2)2Ph)-N-(NHBoc)]Gly-Orn(N-methylamidino)-CF3 [N-(-C(0) (CH2)2Ph)-N-(CH2COZH)]Gly-Orn(N-methylamidino)-CF3 [N-(-C(O) (CH2)2Ph)-N-(CH2C02CH3)]Gly-Orn(N-methylamidino)-(N-(-C(0)CH2Ph)-N-(CH3)]Gly-Orn(N-methylamidino)-CF3 [N-(-C(0)(CH2)3Ph)-N-(CH3)]Gly-Orn(N-methylamidino)-CF3 [N-(-C(O)Ph)-N-(CH3)]Gly-Orn(N-methylamidino)-CF3 [N-(-C(O)(CH2)2Ph)-N-CHZPh)]Gly-Orn(N-methylamidino)-CF3 SUBSTITUTE SHEET (RULE 26) .~.. WO 95109634 PCT/US94111280 [N-(-C(O)(CH2)2Ph-3,4-C12)-N-(CH3)]Gly-Orn(N-methylamidino)-CF3 [N-(-C(O)(CH2)2Ph-4-C1)-N-(CH3)]Gly-Orn(N-methylamidino)-[N-(-C(O)(CH2)2Ph-4-CH3)-N-(CH3)]Gly-Orn(N-methylamidino)-[N-(-C(O)(CH2)2Ph-4-OCH3)-N-(CH3)]Gly-Orn(N-methylamidino)-(N-(-C(O)(CH2)2Ph)-N-(CH3)]Gly-Orn(N-methylamidino)-OCH3 [N-(-C(O)(CH2)2Ph)-N-(CH2)ZPh]Gly-Orn(N-methylamidino)-OCH3 [N-(-C(O)(CH2)2Ph)-N-Ph]Gly-Orn(N-methylamidino)-OCH3 [N-(-C(O)N(CH3)CH2Ph)-N-Ph]Gly-Orn(N-methylamidino)-OCH3 [N-(-C(O)Ph-3-CH=CHPh)-N-(CH3)JGly-Orn(N-methylamidino)-[N-(-C(0)Ph-3-CH2CH2Ph)-N-(CH3)]Gly-Orn(N-methylamidino)-[N-(-C(0)Ph-3-SPh-3-OCH3)-N-(CH3)]Gly-Orn(N-methylamidino)-(N-(-C(0)Ph-2-CH2Ph-2-Ph)-N-(CH3)]Gly-Orn(N-methylamidino)-[N-(-C(O)Ph-4-CH2Ph)-N-(CH3)]Gly-Orn(N-methylamidino)-OCH3 [N-(-C(O)Ph-2-CH2Ph)-N-(CH3)]Gly-Orn(N-methylamidino)-OCH3 [N-(-C(0)Ph-3-CH2Ph)-N-(CH3)]Gly-Orn(N-methylamidino)-OCH3 [N-(-C(O)Ph-3-CH2Ph-2-CF3)-N-(CH3)]Gly-Orn(N-methylamidino)-OCH3 [N-(-C(O)CH2Ph-3,4-C12)-N-(CH3)]Gly-Orn(N-methylamidino)-[N-(-C(O) (CH2)2Ph)-N-(C2H5)]Gly-Orn(N-methylamidino)-OCH3 [N-(-C(O) (CH2)2Ph)-N-(n-C3H~)]Gly-Orn(N-methylamidino)-OCH3 [N-(-C(O) (CH2)2Ph)-N-(i-C3H~)]Gly-Orn(N-methylamidino)-OCH3 [N-(-C(O) (CH2)2Ph)-N-(C6H12)]Gly-Orn(N-methylamidino)-OCH3 [N-(-C(O) (CH2)2Ph)-N-(OH)]Gly-Orn(N-methylamidino)-OCH3 [N-(-C(O) (CH2)2Ph)-N-(OCH3)]Gly-Orn(N-methylamidino)-OCH3 [N-(-C(O) (CH2)2Ph)-N-(OCH2Ph)]Gly-Orn(N-methylamidino)-OCH3 [N-(-C(0) (CH2)2Ph)-N-(NH2))Gly-Orn(N-methylamidino)-OCH3 SUBSTITUTE SHEET (RULE 26) [N-(-C(0)(CH2)2Ph)-N-(N(CH3)2)]Gly-Orn(N-methylamidino)-OCH3 [N-(-C(O)(CH2)2Ph)-N-(NHBoc)]Gly-Orn(N-methylamidino)-OCH3 [N-(-C(O)(CH2)2Ph)-N-(CH2C02H)]Gly-Orn(N-methylamidino)-OCH3 [N-(-C(0)(CH2)2Ph)-N-(CH2C02CH3)]Gly-Orn(N-methylamidino)-[N-(-C(O)CH2Ph)-N-(CH3)]Gly-Orn(N-methylamidino)-OCH3 [N-(-C(0)(CH2)3Ph)-N-(CH3)]Gly-Orn(N-methylamidino)-OCH3 [N-(-C(0)Ph)-N-(CH3)]Gly-Orn(N-methylamidino)-OCH3 [N-(-C(0)(CH2)2Ph)-N-CH2Ph)]Gly-Orn(N-methylamidino)-OCH3 [N-(-C(O)(CH2)2Ph-3,4-C12)-N-(CH3)]Gly-Orn(N-methylamidino)-OCH3 [N-(-C(O)(CH2)2Ph.-4-C1)-N-(CH3)]Gly-Orn(N-methylamidino)-[N-(-C(O)(CH2)2Ph-4-CH3)-N-(CH3)]Gly-Orn(N-methylamidino)-[N-(-C(O)(CH2)2Ph-4-OCH3)-N-(CH3)]Gly-Orn(N-methylamidino)-[N-(-C(0)(CH2)2Ph)-N-(CH3)]Gly-Orn(N-methylamidino)-C02CH3 [N-(-C(O)(CH2)2Ph)-N-(CH2)2Ph]Gly-Orn(N-methylamidino)-[N-(-C(O)(CH2)2Ph)-N-Ph]Gly-Orn(N-methylamidino)-C02CH3 [N-(-C(O)N(CH3)CH2Ph)-N-Ph]Gly-Orn(N-methylamidino)-C02CH3 [N-(-C(O)Ph-3-CH=CHPh)-N-(CH3)]Gly-Orn(N-methylamidino)-[N-(-C(O)Ph-3-CH2CH2Ph)-N-(CH3)]Gly-Orn(N-methylamidino)-[N-(-C(O)Ph-3-SPh-3-OCH3)-N-(CH3)]Gly-Orn(N-methylamidino)-[N-(-C(O)Ph-2-CH2Ph-2-Ph)-N-(CH3)]Gly-Orn(N-methylamidino)-[N-(-C(O)Ph-4-CHZPh)-N-(CH3)]Gly-Orn(N-methylamidino)-[N-(-C(O)Ph-2-CH2Ph)-N-(CH3)]Gly-Orn(N-methylamidino)-SUBSTITUTE SHEET (RULE 26) WO 95/09634 ' ~ ~.'~ 4 31 ~ pCTIUS94111280 [N-(-C(O)Ph-3-CH2Ph)-N-(CH3)]Gly-Orn(N-methylamidino)-[N-(-C(O)Ph-3-CH2Ph-2-CF3)-N-(CH3)]Gly-Orn(N-methylamidino)-C02CH3 [N-(-C(O)CH2Ph-3,4-C12)-N-(CH3)]Gly-Orn(N-methylamidino)-[N-(-C(O)(CH2)2Ph)-N-(C2H5)]Gly-Orn(N-methylamidino)-C02CH3 [N-(-C(0)(CH2)2Ph)-N-(n-C3H~)]Gly-Orn(N-methylamidino)-[N-(-C(0)(CH2)2Ph)-N-(i-C3H~)]Gly-Orn(N-methylamidino)-[N-(-C(O)(CH2)2Ph)-N-(C6H12)]Gly-Orn(N-methylamidino)-C02CH3 [N-(-C(O)(CH2)2Ph)-N-(OH)]Gly-Orn(N-methylamidino)-C02CH3 [N-(-C(0)(CH2)2Ph)-N-(OCH3)]Gly-Orn(N-methylamidino)-C02CH3 [N-(-C(O)(CH2)2Ph)-N-(OCH2Ph)]Gly-Orn(N-methylamidino)-[N-(-C(O)(CH2)2Ph)-N-(NH2))Gly-Orn(N-methylamidino)-C02CH3 [N-(-C(0)(CH2)2Ph)-N-(N(CH3)2)]Gly-Orn(N-methylamidino)-[N-(-C(0)(CH2)2Ph)-N-(NHBoc)]Gly-Orn(N-methylamidino)-[N-(-C(0)(CH2)2Ph)-N-(CH2C02H)]Gly-Orn(N-methylamidino)-[N-(-C(O)(CH2)2Ph)-N-(CH2C02CH3)]Gly-Orn(N-methylamidino)-(N-(-C(O)CH2Ph)-N-(CH3)]Gly-Orn(N-methylamidino)-C02CH3 (N-(-C(O)(CH2)3Ph)-N-(CH3)]Gly-Orn(N-methylamidino)-C02CH3 [N-(-C(0)Ph)-N-(CH3)]Gly-Orn(N-methylamidino)-C02CH3 [N-(-C(O)(CH2)2Ph)-N-CH2Ph)]Gly-Orn(N-methylamidino)-C02CH3 [N-(-C(O)(CH2)2Ph-3,4-C12)-N-(CH3)]Gly-Orn(N-methylamidino)-C02CH3 [N-(-C(0)(CH2)2Ph-4-C1)-N-(CH3)]Gly-Orn(N-methylamidino)-[N-(-C(O)(CH2)2Ph-4-CH3)-N-(CH3)]Gly-Orn(N-methylamidino)-SUBSTITUTE SHEET (RULE 26) WO 95109634 ~ 1'7 4 31 ~ , PCTIUS94I11280 [N-(-C(O)(CH2)2Ph-4-OCH3)-N-(CH3)]Gly-Orn(N-methylamidino)-[N-(-C(0)(CH2)2Ph)-N-Ph]Gly-boroOrn(formamidino)-OH
[N-(-C(0)N(CH3)CH2Ph)-N-Ph]Gly-boroOrn(formamidino)-OH
[N-(-C(0)Ph-3-CH=CHPh)-N-(CH3)]Gly-boroOrn(formamidino)-OH
[N-(-C(0)Ph-3-CH2CH2Ph)-N-(CH3)]Gly-boroOrn(formamidino)-OH
[N-(-C(O)Ph-3-SPh-3-OCH3)-N-(CH3)]Gly-boroOrn(formamidino)-OH
[N-(-C(O)Ph-2-CH2Ph-2-Ph)-N-(CH3)]Gly-boroOrn(formamidino)-OH
[N-(-C(O)Ph-4-CH2Ph)-N-(CH3)]Gly-boroOrn(formamidino)-OH
[N-(-C(O)Ph-2-CH2Ph)-N-(CH3)]Gly-boroOrn(formamidino)-OH
[N-(-C(O)Ph-3-CH2Ph)-N-(CH3)]Gly-boroOrn(formamidino)-OH
[N-(-C(0)Ph-3-CH2Ph-2-CF3)-N-(CH3)]Gly-boroOrn(formamidino)-OH

(N-(-C(O) (CH2)2Ph)-N-(CZHS)]Gly-boroOrn(formamidino)-OH

[N-(-C(O) (CH2)2Ph)-N-(n-C3H~)]Gly-boroOrn(formamidino)-OH

[N-(-C(O) (CH2)2Ph)-N-(i-C3H~)]Gly-boroOrn(formamidino)-OH

[N-(-C(O) (CH2)2Ph)-N-(C6H12)]Gly-boroOrn(formamidino)-OH

[N-(-C(O) (CH2)2Ph)-N-(OH)]Gly-boroOrn(formamidino)-OH

[N-(-C(O) (CH2)2Ph)-N-(OCH3)]Gly-boro0rn(formamidino)-OH

[N-(-C(O) (CH2)2Ph)-N-(OCH2Ph)]Gly-boroOrn(formamidino)-OH

[N-(-C(O) (CH2)2Ph)-N-(NH2)]Gly-boroOrn(formamidino)-OH

[N-(-C(O) (CH2)2Ph)-N-(N(CH3)2)]Gly-boroOrn(formamidino)-OH

(N-(-C(0) (CH2)2Ph)-N-(NHBoc)]Gly-boro0rn(formamidino)-OH

[N-(-C(O) (CH2)2Ph)-N-(CH2C02H)]Gly-boroOrn(formamidino)-OH

[N-(-C(O) (CH2)2Ph)-N-(CH2C02CH3)]Gly-boro0rn(formamidino)-OH

[N-(-C(O) (CH2)3Ph)-N-(CH3)]Gly-boroOrn(formamidino)-OH

[N-(-C(O) Ph)-N-(CH3)]Gly-boroOrn(formamidino)-OH

[N-(-C(O) (CH2)2Ph)-N-CHZPh)]Gly-boroOrn(formamidino.)-OH

[N-(-C(0) (CH2)2Ph-3,4-C12)-N-(CH3)]Gly-boroOrn(formamidino)-OH

(N-(-C(O) (CH2)2Ph-4-C1)-N-(CH3)]Gly-boro0rn(formamidino)-OH

[N-(-C(O) (CH2)2Ph-4-CH3)-N-(CH3)]Gly-boroOrn(formamidino)-OH

SUBSTITUTE SHEET (RULE 26) PCTlUS94111280 [N-(-C(0)(CH2)2Ph)-N-(CH3)]Gly-boro0rn(formamidino)-C1pH16 [N-(-C(O)(CH2)2Ph)-N-(CH2)2Ph]Gly-boroOrn(formamidino)-[N-(-C(O)(CH2)2Ph)-N-Ph]Gly-boroOrn(formamidino)-C1pH16 [N-(-C(O)N(CH3)CHZPh)-N-Ph]Gly-boroOrn(formamidino)-C1pH16 [N-(-C(O)Ph-3-CH=CHPh)-N-(CH3)]Gly-boroOrn(formamidino)-(N-(-C(O)Ph-3-CH2CH2Ph)-N-(CH3)]Gly-boroOrn(formamidino)-[N-(-C(O)Ph-3-SPh-3-OCH3)-N-(CH3)]Gly-boroOrn(formamidino)-[N-(-C(O)Ph-2-CH2Ph-2-Ph)-N-(CH3)]Gly-boroOrn(formamidino)-[N-(-C(O)Ph-3-CH2Ph)-N-(CH3)]Gly-boroOrn(formamidino)-C1pH16 [N-(-C(0)Ph-3-CH2Ph-2-CF3)-N-(CH3)]Gly-boroOrn ( formamidino ) -C10H16 [N-(-C(0)(CH2)2Ph)-N-(C2H5)]Gly-boroOrn(formamidino)-C1pH16 [N-(-C(O)(CH2)2Ph)-N-(n-C3H~)]Gly-boroOrn(formamidino)-(N-(-C(O)(CH2)2Ph)-N-(i-C3H~)]Gly-boroOrn(formamidino)-[N-(-C(O)(CH2)2Ph)-N-(C6H12)]Gly-boroOrn(formamidino)-C1pH16 [N-(-C(0)(CH2)2Ph)-N-(OCH3)]Gly-boro0rn(formamidino)-C1pH16 [N-(-C(O)(CH2)2Ph)-N-(OCH2Ph)]Gly-boroOrn(formamidino)-[N-(-C(O)(CH2)2Ph)-N-(NH2)]Gly-boroOrn(formamidino)-C10H16 (N-(-C(0)(CH2)2Ph)-N-(N(CH3)2)]Gly-boro0rn(formamidino)-[N-(-C(O)(CH2)2Ph)-N-(NHBoc)]Gly-boroOrn(formamidino)-C1pH16 [N-(-C(O)(CH2)2Ph)-N-(CH2C02H)]Gly-boroOrn(formamidino)-[N-(-C(O)(CH2)2Ph)-N-(CH2C02CH3)]Gly-boroOrn(formamidino)-[N-(-C(O)CH2Ph)-N-(CH3)]Gly-boro0rn(formamidino)-C1pH16 [N-(-C(O)(CH2)3Ph)-N-(CH3)]Gly-boro0rn(formamidino)-C1pH16 SUBSTITUTE SHEET (RULE 26) WO 95109634 ~ ~ PCTlUS94111280 (N-(-C(O)Ph)-N-(CH3)]Gly-boroOrn(formamidino)-C1pH16 [N-(-C(0)(CH2)2Ph)-N-CH2Ph)]Gly-boroOrn(formamidino)-C1pH16 [N-(-C(O)(CH2)2Ph-4-C1)-N-(CH3)]Gly-boroOrn(formamidino)-[N-(-C(O)(CH2)2Ph-4-CH3)-N-(CH3)]Gly-boroOrn(formamidino)-[N-(-C(O)(CH2)2Ph-4-OCH3)-N-(CH3)]Gly-boroOrniformamidino)-[N-(-C(O)(CH2)2Ph)-N-(CH3)]Gly-Orn(formamidino)-CF3 [N-(-C(O)(CH2)2Ph)-N-(CHZ)2Ph]Gly-Orn(formamidino)-CF3 [N-(-C(O)(CH2)2Ph)-N-Ph]Gly-Orn(formamidino)-CF3 [N-(-C(O)N(CH3)CH2Ph)-N-Ph]Gly-Orn(formamidino)-CF3 [N-(-C(O)Ph-3-CH=CHPh)-N-(CH3))Gly-Orn(formamidino)-CF3 [N-(-C(0)Ph-3-CH2CH2Ph)-N-(CH3)]Gly-Orn(formamidino)-CF3 [N-(-C(O)Ph-3-SPh-3-OCH3)-N-(CH3)]Gly-Orn(formamidino)-CF3 [N-(-C(O)Ph-2-CH2Ph-2-Ph)-N-(CH3)]Gly-Orn(formamidino)-CF3 [N-(-C(O)Ph-4-CH2Ph)-N-(CH3)]Gly-Orn(formamidino)-CF3 [N-(-C(O)Ph-2-CH2Ph)-N-(CH3)]Gly-Orn(formamidino)-CF3 [N-(-C(O)Ph-3-CH2Ph)-N-(CH3)]Gly-Orn(formamidino)-CF3 [N-(-C(O)Ph-3-CH2Ph-2-CF3)-N-(CH3)]Gly-Orn(formamidino)-CF3 [N-(-C(O)CH2Ph-3,4-C12)-N-(CH3)]Gly-Orn(formamidino)-CF3 [N-(-C(0)(CH2)2Ph)-N-(C2H5)]Gly-Orn(formamidino)-CF3 [N-(-C(O)(CH2)2Ph)-N-(n-C3H~))Gly-Orn(formamidino)-CF3 [N-(-C(0)(CH2)2Ph)-N-(i-C3H~)]Gly-Orn(formamidino)-CF3 (N-(-C(O)(CH2)2Ph)-N-(C6H12)]Gly-Orn(formamidino)-CF3 [N-(-C(0)(CH2)2Ph)-N-(OH)]Gly-Orn(formamidino)-CF3 [N-(-C(O) (CH2)2Ph)-N-(OCH3)]Gly-Orn(formamidino)-CF3 [N-(-C(0) (CH2)2Ph)-N-(OCH2Ph)]Gly-Orn(formamidino)-CF3 [N-(-C(O) (CH2)2Ph)-N-(NH2)]Gly-Orn(formamidino)-CF3 [N-(-C(0) (CH2)2Ph)-N-(N(CH3)2)]Gly-Orn(formamidino)-CF3 [N-(-C(O) (CH2)2Ph)-N-(NHBoc)]Gly-Orn(formamidino)-CF3 [N-(-C(O) (CH2)2Ph)-N-(CH2C02H)]Gly-Orn(formamidino)-CF3 [N-(-C(O) (CH2)2Ph)-N-(CH2C02CH3)]Gly-Orn(formamidino)-CF3 [N-(-C(0) CH2Ph)-N-(CH3)]Gly-Orn(formamidino)-CF3 [N-(-C(O) (CH2)3Ph)-N-(CH3)]Gly-Orn(formamidino)-CF3 SUBSTITUTE SHEET (RULE 26) WO 95109634 ~ 1'~ 4 3 I 4 PCTlUS94111280 [N-(-C(O)Ph)-N-(CH3)]Gly-Orn(formamidino)-CF3 [N-(-C(O)(CH2)2Ph)-N-CH2Ph)]Gly-Orn(formamidino)-CF3 [N-(-C(O)(CH2)2Ph-3,4-C12)-N-(CH3)]G1y-Orn(formamidino)-CF3 [N-(-C(O)(CH2)2Ph-4-C1)-N-(CH3)]Gly-Orn(formamidino)-CF3 [N-(-C(0)(CH2)2Ph-4-CH3)-N-(CH3)]Gly-Orn(formamidino)-CF3 [N-(-C(O)(CH2)2Ph-4-OCH3)-N-(CH3)]Gly-Orn(formamidino)-CF3 [N-(-C(O)(CH2)2Ph)-N-(CH3)]Gly-Orn(formamidino)-OCH3 [N-(-C(O)(CH2)2Ph)-N-(CH2)2Ph]Gly-Orn(formamidino)-OCH3 [N-(-C(0)(CH2)2Ph)-N-Ph]Gly-Orn(formamidino)-OCH3 [N-(-C(O)N(CH3)CH2Ph)-N-Ph]Gly-Orn(formamidino)-OCH3 [N-(-C(O)Ph-3-CH=CHPh)-N-(CH3)]Gly-Orn(formamidino)-OCH3 [N-(-C(O)Ph-3-CH2CH2Ph)-N-(CH3)]Gly-Orn(formamidino)-OCH3 [N-(-C(O)Ph-3-SPh-3-OCH3)-N-(CH3))Gly-Orn(formamidino)-OCH3 [N-(-C(O)Ph-2-CH2Ph-2-Ph)-N-(CH3)]Gly-Orn(formamidino)-OCH3 [N-(-C(O)Ph-4-CHzPh)-N-(CH3)]Gly-Orn(formamidino)-OCH3 [N-(-C(O)Ph-2-CH2Ph)-N-(CH3)]Gly-Orn(formamidino)-OCH3 [N-(-C(0)Ph-3-CH2Ph)-N-(CH3)]Gly-Orn(formamidino)-OCH3 [N-(-C(O)Ph-3-CH2Ph-2-CF3)-N-(CH3)]Gly-Orn(formamidino)-[N-(-C(O)CH2Ph-3,4-C12)-N-(CH3)]Gly-Orn(formamidino)-OCH3 [N-(-C(0)(CH2)2Ph)-N-(CzHS)]Gly-Orn(formamidino)-OCH3 [N-(-C(O)(CH2)2Ph)-N-(n-C3H~)]Gly-Orn(formamidino)-OCH3 [N-(-C(O)(CH2)2Ph)-N-(i-C3H~)]Gly-Orn(formamidino)-OCH3 (N-(-C(0)(CH2)2Ph)-N-(C6H12)]Gly-Orn(formamidino)-OCH3 [N-(-C(0)(CH2)2Ph)-N-(OH)]Gly-Orn(formamidino)-OCH3 [N-(-C(O) (CH2)2Ph)-N-(OCH3)]Gly-Orn(formamidino)-OCH3 [N-(-C(O) (CH2)2Ph)-N-(OCH2Ph)]Gly-Orn(formamidino)-OCH3 [N-(-C(0) (CH2)2Ph)-N-(NH2)]Gly-Orn(formamidino)-OCH3 [N-(-C(0) (CH2)2Ph)-N-(N(CH3)2)]Gly-Orn(formamidino)-OCH3 [N-(-C(O) (CH2)2Ph)-N-(NHBoc)]Gly-Orn(formamidino)-OCH3 [N-(-C(O) (CH2)2Ph)-N-(CH2C02H)]Gly-Orn(formamidino)-OCH3 [N-(-C(O)(CH2)2Ph)-N-(CH2C02CH3)]Gly-Orn(formamidino)-OCH3 [N-(-C(O)CH2Ph)-N-(CH3)]Gly-Orn(formamidino)-OCH3 [N-(-C(O)(CH2)3Ph)-N-(CH3)]Gly-Orn(formamidino)-OCH3 [N-(-C(O)Ph)-N-(CH3)]Gly-Orn(formamidino)-OCH3 SUBSTITUTE SHEET (RULE 26) WO 95/09634 ~~ PCT/US94111280 [N-(-C(O)(CH2)2Ph)-N-CHZPh)]Gly-Orn(formamidino)-OCH3 [N-(-C(O)(CH2)2Ph-3,4-C12)-N-(CH3)]Gly-Orn(formamidino)-OCH3 [N-(-C(0)(CH2)2Ph-4-C1)-N-(CH3)]Gly-Orn(formamidino)-OCH3 [N-(-C(O)(CH2)2Ph-4-CH3)-N-(CH3)]Gly-Orn(formamidino)-OCH3 [N-(-C(O)(CHZ)2Ph-4-OCH3)-N-(CH3)]Gly-Orn(formamidino)-OCH3 [N-(-C(O)(CH2)ZPh)-N-(CH3)]Gly-Orn(formamidino)-C02CH3 [N-(-C(0)(CH2)2Ph)-N-(CH2)2Ph]Gly-Orn(formamidino)-COZCH3 [N-(-C(O)(CH2)2Ph)-N-Ph]Gly-Orn(formamidino)-C02CH3 [N-(-C(0)N(CH3)CH2Ph)-N-Ph]Gly-Orn(formamidino)-C02CH3 [N-(-C(0)Ph-3-CH=CHPh)-N-(CH3)]Gly-Orn(formamidino)-C02CH3 [N-(-C(0)Ph-3-CH2CH2Ph)-N-(CH3)]Gly-Orn(formamidino)-C02CH3 [N-(-C(O)Ph-3-SPh-3-OCH3)-N-(CH3)]Gly-Orn(formamidino)-[N-(-C(O)Ph-2-CH2Ph-2-Ph)-N-(CH3)]Gly-Orn(formamidino)-[N-(-C(O)Ph-4-CH2Ph)-N-(CH3)]Gly-Orn(formamidino)-C02CH3 [N-(-C(O)Ph-2-CH2Ph)-N-(CH3)]Gly-Orn(formamidino)-C02CH3 [N-(-C(0)Ph-3-CH2Ph)-N-(CH3)]Gly-Orn(formamidino)-C02CH3 [N-(-C(0)Ph-3-CH2Ph-2-CF3)-N-(CH3)]Gly-Orn(formamidino)-[N-(-C(O)CH2Ph-3,4-C12)-N-(CH3)]Gly-Orn(formamidino)-C02CH3 [N-(-C(O)(CH2)2Ph)-N-(C2H5)]Gly-Orn(formamidino)-C02CH3 [N-(-C(0)(CH2)2Ph)-N-(n-C3H~)]Gly-Orn(formamidino)-C02CH3 [N-(-C(0)(CH2)2Ph)-N-(i-C3H~)]Gly-Orn(formamidino)-C02CH3 [N-(-C(O) (CHZ)ZPh)-N-(C6H12) ]Gly-Orn(formamidino)-C02CH3 [N-(-C(O)(CH2)2Ph)-N-(OH)]Gly-Orn(formamidino)-C02CH3 [N-(-C(O)(CH2)2Ph)-N-(OCH3)]Gly-Orn(formamidino)-C02CH3 [N-(-C(O)(CH2)2Ph)-N-(OCH2Ph)]Gly-Orn(formamidino)-C02CH3 [N-(-C(O)(CH2)ZPh)-N-(NH2)]Gly-Orn(formamidino)-C02CH3 [N-(-C(O)(CH2)2Ph)-N-(N(CH3)2)]Gly-Orn(formamidino)-C02CH3 [N-(-C(O)(CH2)2Ph)-N-(NHBoc)]Gly-Orn(formamidino)-C02CH3 [N-(-C(O)(CH2)2Ph)-N-(CH2C02H)]Gly-Orn(formamidino)-[N-(-C(O)(CH2)2Ph)-N-(CH2C02CH3)]Gly-Orn(formamidino)-[N-(-C(0)CH2Ph)-N-(CH3)]Gly-Orn(formamidino)-C02CH3 SUBSTITUTE SHEET (RULE 26) WO 9510963.1 ~ PCT/US94111280 (N-(-C(0)(CH2)3Ph)-N-(CH3)]Gly-Orn(formamidino)-C02CH3 [N-(-C(0)Ph)-N-(CH3)]Gly-Orn(formamidino)-C02CH3 [N-(-C(O)(CH2)2Ph)-N-CH2Ph)]Gly-Orn(forrnamidino)-C02CH3 (N-(-C(O)(CH2)2Ph-3,4-C12)-N-(CH3)]Gly-Orn(formamidino)-[N-(-C(0)(CH2)2Ph-4-C1)-N-(CH3)]Gly-Orn(formamidino)-C02CH3 [N-(-C(O)(CH2)2Ph-4-CH3)-N-(CH3)]Gly-Orn(formamidino)-C02CH3 (N-(-C(O)(CH2)2Ph-4-OCH3)-N-tCH3)]Gly-Orn(formamidino)-[N-(-C(O)(CH2)2Ph)-N-(CH2C(propane-1,3-diyl)Ph)]-Gly-boroLys-OH
[N-(-C(O)(CH2)2Ph)-N-(CH2CH(i-C3H~)Ph-3-CH3)]-Gly-boroLys-OH
[N-(-C(O)(CH2)2Ph)-N-(CH2C(ethanediyl)Ph-3-CH3)]-Gly-boroLys-OH
[N-(-C(O)(CH2)2Ph)-N-(CH2C(propane-1,3-diyl)Ph-3-CH3)]-Gly-boroLys-OH
[N-(-C(O)(CH2)2Ph)-N-(CH2C(butane-1,4-diyl)Ph-3-CH3)]-Gly-boroLys-OH
[N-(-C(O)(CH2)2Ph)-N-(CH2C(CH2CH3)2Ph-3,5-(CH3)2)]-Gly-boroLys-OH
(N-(-C(O)(CH2)2Ph)-N-(CH2CH(i-C3H~)Ph-3,5-(CH3)2)]-Gly boroLys-OH
[N-(-C(O)(CH2)2Ph)-N-(CH2C(ethanediyl)Ph-3,5-(CH3)2)1-Gly-boroLys-OH
[N-(-C(0)(CH2)2Ph)-N-(CH2C(propane-1,3-diyl)Ph-3,5-(CH3)2)]-Gly-boroLys-OH
[N-(-C(O)(CH2)2Ph)-N-(CH2C(butane-1,4-diyl)Ph-3,5-(CH3) 2)]-Gly-boroLys-OH
[N-(-C(O)(CH2)2Ph)-N-(CH2CH2Ph-3-NH2)]-Gly-boroLys-OH
[N-(-C(O)(CH2)2Ph)-N-(CH2C(CH3)2Ph-3-NH2)]-Gly-boroLys-OH
[N-(-C(O)(CH2)2Ph)-N-(CH2C(CH2CH3)2Ph-3-NH2)]-Gly-boroLys-OH
[N-(-C(O)(CH2)2Ph)-N-(CH2CH(i-C3H'7)Ph-3-NH2)]-Gly-SUBSTITUTE SHEET (RULE 26) boroLys-OH
[N-(-C(O)(CH2)2Ph)-N-(CH2C(ethanediyl)Ph-3-NH2)]-Gly-boroLys-OH
[N-(-C(O)(CH2)2Ph)-N-(CH2C(propane-1,3-diyl)Ph-3-NH2)]_ Gly-boroLys-OH
[N-(-C(O)(CH2)2Ph)-N-(CH2C(butane-1,4-diyl)Ph-3-NH2)]-Gly-boroLys-OH
[N-(-C(O)(CH2)2Ph)-N-(CH2CH2Ph-3-N02)]-Gly-boroLys-OH
[N-(-C(O)(CH2)2Ph)-N-(CH2CH(i-C3H~)Ph-3-N02))-Gly-boroLys-OH
(N-(-C(0)(CH2)2Ph)-N-(CH2C(ethanediyl)Ph-3-N02)]-Gly -boroLys-OH
[N-(-C(0)(CH2)2Ph)-N-(CH2C(propane-1,3-diyl)Ph-3-N02)]-Gly-boroLys-OH
[N-(-C(O)(CH2)2Ph)-N-(CH2C(butane-1,4-diyl)Ph-3-N02)]-Gly-boroLys-OH
[N-(-C(0)(CH2)2Ph)-N-(CH2CH2Ph)]-Gly-boroArg-OH
[N-(-C(O)(CH2)2Ph)-N-(CH2C(CH2CH3)2Ph)]-Gly-boroArg-OH
[N-(-C(0)(CH2)2Ph)-N-(CH2CH(i-C3H~)Ph)]-Gly-boroArg-OH
[N-(-C(O)(CH2)2Ph)-N-(CH2C(propane-1,3-diyl)Ph)]-Gly-boroArg-OH
[N-(-C(O)(CH2)2Ph)-N-(CH2CH2Ph-3-CH3)]-Gly-boroArg-OH
[N-(-C(O)(CH2)2Ph)-N-(CH2C(CH3)2Ph-3-CH3)]-Gly-boroArg-OH
[N-(-C(0)(CH2)2Ph)-N-(CH2C(CH2CH3)2Ph-3-CH3)]-Gly-boroArg-OH
[N-(-C(0)(CH2)2Ph)-N-(CH2CH(i-C3H~)Ph-3-CH3)]-Gly-boroArg-OH
[N-(-C(0)(CH2)2Ph)-N-(CH2C(ethanediyl)Ph-3-CH3)]-Gly-boroArg-OH
[N-(-C(O)(CH2)2Ph)-N-(CH2C(propane-1,3-diyl)Ph-3-CH3)]-Gly-boroArg-OH
[N-(-C(0)(CH2)2Ph)-N-(CH2C(butane-1,4-diyl)Ph-3-CH3))-Gly-boroArg-OH
[N-(-C(O)(CH2)2Ph)-N-(CH2C(CH2CH3)2Ph-3,5-(CH3)2)]-Gly-SUBSTITUTE SHEET (RULE 26) WO 95/09634 21'~ ~ 3. ~ ~ pCT/US94111280 boroArg-OH
[N-(-C(O)(CH2)2Ph)-N-(CH2CH(i-C3H~)Ph-3,5-(CH3)2)]-Gly-boroArg-OH
[N-(-C(0)(CH2)2Ph)-N-(CH2Cfethanediyl)Ph-3,5-(CH3)2)]-Gly-boroArg-OH
[N-(-C(O)(CH2)2Ph)-N-(CH2C(propane-1,4-diyl)Ph-3,5-(CH3)2)]-Gly-boroArg-OH
[N-(-C(0)(CH2)2Ph)-N-(CH2C(butane-1,4-diyl)Ph-3,5-(CH3) 2)]-Gly-boroArg-OH
[N-(-C(O)(CH2)2Ph)-N-(CH2CH2Ph-3-NH2)]-Gly-boroArg-OH
[N-(-C(O)(CH2)2Ph)-N-(CH2C(CH3)2Ph-3-NH2)]-Gly-boroArg-OH
[N-(-C(O)(CH2)2Ph)-N-(CH2C(CH2CH3)2Ph-3-NH2)]-Gly-boroArg-OH
[N-(-C(O)(CH2)2Ph)-N-(CH2CH(i-C3H~)Ph-3-NH2)]-Gly-boroArg-OH
[N-(-C(O)(CH2)2Ph)-N-(CH2C(ethanediyl)Ph-3-NH2)]-Gly-boroArg-OH
[N-(-C(0)(CH2)2Ph)-N-(CH2C(propane-1,3-diyl)Ph-3-NH2)]-Gly-boroArg-OH
[N-(-C(O)(CH2)2Ph)-N-(CH2C(butane-1,4-diyl)Ph-3-NH2)]-Gly-boroArg-OH
[N-(-C(O)(CH2)2Ph)-N-(CH2CH2Ph-3-N02)]-Gly-boroArg-OH
[N-(-C(O)(CH2)2Ph)-N-(CH2C(CH3)2Ph-3-N02)]-Gly-boroArg -OH
[N-(-C(O)(CH2)2Ph)-N-(CH2C(CH2CH3)2Ph-3-N02)]-Gly-boroArg-OH
[N-(-C(O)(CH2)2Ph)-N-(CH2CH(i-C3H~)Ph-3-N02)]-Gly-boroArg-OH
[N-(-C(O)(CH2)2Ph)-N-(CH2C(ethanediyl)Ph-3-N02)]-Gly-boroArg-OH
[N-(-C(O)(CH2)2Ph)-N-(CH2C(propane-1,3-diyl)Ph-3-N02)]-' Gly-boroArg-OH
[N-(-C(O)(CH2)2Ph)-N-fCH2C(butane-1,4-diyl)Ph-3-N02)]-Gly-boroArg-OH
-55_ SUBSTITUTE SHEET (RULE 26) PCTIUS94l11280 WO 95/09634 ~~ ~ 4 31 ~
[N-(-C(O)(CH2)2Ph)-N-(CH2C(CH2CH3)2Ph)]-Gly-boroOrn (formamidino)-OH
[N-t-C(0)tCH2)2Ph)-N-(CH2CH(i-C3H~)Ph)]-Gly-boro0rn (formamidino)-OH
[N-(-C(0)(CH2)2Ph)-N-(CH2C(propane-1,3-diyl)Ph)]-Gly-boroOrn(formamidino)-OH
[N-(-C(0)(CH2)2Ph)-N-(CH2CH2Ph-3-CH3)]-Gly-boro0rn (formamidino)-OH
[N-t-Ct0)(CH2)2Ph)-N-(CH2CH(i-C3H~)Ph-3-CH3)]-Gly-boroOrn(formamidino)-OH
[N-(-C(0)(CH2)2Ph)-N-(CH2C(ethanediyl)Ph-3-CH3)]-Gly-boroOrn(formamidino)-OH
[N-t-C(O)tCH2)2Ph)-N-(CH2C(propane-1,4-diyl)Ph-3-CH3)]-Gly-boroOrn(formamidino)-OH
[N-t-C(0)(CH2),2Ph)-N-(CH2C(butane-1,4-diyl)Ph-3-CH3)]-Gly-boroOrn(formamidino)-OH
[N-(-Ct0)tCH2)2Ph)-N-(CH2CH2Ph-3,5-(CH3)2)]-Gly-boroOrn(formamidino)-OH
[N-(-C(0)(CH2)2Ph)-N-tCH2C(CH3)2Ph-3,5-(CH3)2)]-Gly_ boroOrn(formamidino)-OH
[N-(-C(0)(CH2)2Ph)-N-(CH2C(CH2CH3)2Ph-3,5-(CH3)2)]-Gly-boroOrn(formamidino)-OH
[N-(-C(0)(CH2)2Ph)-N-tCH2CH(i-C3H~)Ph-3,5-tCH3)2)]-Gly-boroOrn(formamidino)-OH
[N-(-C(0)(CH2)2Ph)-N-(CH2C(ethanediyl)Ph-3,5-(CH3)2 » -Gly-boroOrn(formamidino)-OH
[N-(-C(0)(CH2)2Ph)-N-(CH2Ctpropane-1,3-diyl)Ph-3,5-(CH3)2)]-Gly-boroOrn(formamidino)-OH
[N-(-C(0)(CH2)2Ph)-N-(CH2C(butane-1,4-diyl)Ph-3,5-(CH3) 2)]-Gly-boroOrn(formamidino)-OH
[N-(-C(0)(CH2)2Ph)-N-(CH2C(CH2CH3)2Ph-3-NH2)]-Gly-boroOrn(formamidino)-OH
[N-(-C(O)(CH2)2Ph)-N-(CH2CH(i-C3H7)Ph-3-NH2)]-Gly-boroOrn(formamidino)-OH
_56_ SUBSTITUTE SHEET (RULE 26) ~"~ WO 95109634 ~ , PCT/US94111280 [N-(-C(0)(CH2)2Ph)-N-(CH2C(ethanediyl)Ph-3-NH2)]-Gly-boroOrn(formamidino)-OH
[N-(-C(O)(CH2)2Ph)-N-(CH2C(propane-1,3-diyl)Ph-3-NH2)]-Gly-boroOrn(formamidino)-OH
[N-(-C(O)(CH2)2Ph)-N-(CH2C(butane-1,4-diyl)Ph-3-NH2)]-Gly-boroOrn(formamidino)-OH
[N-t-C(O)(CH2)2Ph)-N-(CH2CH2Ph-3-N02)]-Gly-boroOrn (formamidino)-OH
[N-(-C(O)(CH2)2Ph)-N-(CH2C(CH3)2Ph-3-N02)]-Gly-boroOrn(formamidino)-OH
[N-(-C(O)(CH2)2Ph)-N-(CH2C(CH2CH3)2Ph-3-N02)]-Gly-boroOrn(formamidino)-OH
[N-(-C(O)(CH2)2Ph)-N-(CH2CH(i-C3H7)Ph-3-N02)]-Gly-boroOrn(formamidino>-OH
[N-(-C(O)(CH2)2Ph)-N-(CH2C(ethanediyl)Ph-3-N02)]-Gly-boroOrn(formamidino)-OH
[N-(-C(O)(CH2)2Ph)-N-(CH2C(propane-1,3-diyl)Ph-3-N02)]-Gly-boroOrn(formamidino)-OH
[N-(-C(0)(CH2)2Ph)-N-(CH2C(butane-1,4-diyl)Ph-3-N02)]-Gly-boroOrn(formamidino)-OH
[N-(-C(O)(CH2)2-2-PYridyl)-N-(CH2CH2Ph)]-Gly-boroLys-OH
[N-(-C(O)(CH2)2-2-pyridyl)-N-(CH2C(CH3)2Ph)]-Gly-boroLys-OH
[N-(-C(O)(CH2)2-2-pyridyl)-N-(CH2C(CH2CH3)2Ph)]-Gly-boroLys-OH
[N-(-C(O)(CH2)2-2-pyridyl)-N-(CH2CH(i-C3H7)Ph)]-Gly-boroLys-OH
[N-(-C(O)(CH2)2-2-pyridyl)-N-(CH2C(ethanediyl)Ph)]-Gly-boroLys-OH
[N-(-C(O)(CH2)2-2-pyridyl)-N-(CH2C(propane-1,3-diyl)Ph) ]-Gly-boroLys-OH
[N-(-C(O)(CH2)2-2-pyridyl)-N-(CH2C(butane-1,4-diyl)Ph)]
' -Gly-boroLys-OH
[N-(-C(O)(CH2)2-3-pyridyl)-N-(CH2CH2Ph)]-Gly-boroLys-OH
[N-(-C(0)(CH2)2-3-pyridyl)-N-(CH2C(CH3)2Ph)]-Gly-_57_ SUBSTITUTE SHEET (RULE 26) boroLys-OH
[N-(-C(O)(CH2)2-3-pyridyl)-N-(CH2C(CH2CH3)2Ph)]-Gly-boroLys-OH
[N-(-C(O)(CH2)2-3-pyridyl)-N-(CH2CH(i-C3H~)Ph)]-Gly-boroLys-OH
[N-(-C(O)(CH2)2-3-pyridyl)-N-(CH2C(ethanediyl)Ph)]-Gly-boroLys-OH
[N-(-C(O)(CH2)2-3-pyridyl)-N-(CH2C(propane-1,3-diyl)Ph) ]-Gly-boroLys-OH
[N-(-C(O)(CH2)2-3-pyridyl)-N-(CH2C(butane-1,4-diyl)Ph)]
-Gly-boroLys-OH
[N-(-C(0)(CH2)2Ph-3-OH)-N-(CH2CH2Ph)]-Gly-boroLys-OH
[N-(-C(O)(CH2)2Ph-3-OH)-N-(CH2C(CH3)2Ph)]-Gly-boroLys-OH
[N-(-C(O)(CH2)2Ph-3-OH,)-N-(CH2C(CH2CH3)2Ph)]-Gly-boroLys-OH
[N-(-C(O)(CH2)2Ph-3-OH)-N-(CH2CH(i-C3H~)Ph)]-Gly-boroLys-OH
[N-(-C(0)(CH2)2Ph-3-OH)-N-(CH2C(ethanediyl)Ph)]-Gly-boroLys-OH
[N-(-C(O)(CH2)2Ph-3-OH)-N-(CH2C(propane-1,3-diyl)Ph)]-Gly-boroLys-OH
[N-(-C(O)(CH2)2Ph-3-OH)-N-(CH2C(butane-1,4-diyl)Ph)]-Gly-boroLys-OH
[N-(-C(0)(CH2)2Ph-3-OMe)-N-(CH2CH2Ph)]-Gly-boroLys-OH
[N-(-C(O)(CH2)2Ph-3-OMe)-N-(CH2C(CH3)2Ph)]-Gly-boroLys-OH
[N-(-C(0)(CH2)2Ph-3-OMe)-N-(CH2C(CH2CH3)2Ph)]-Gly-boroLys-OH
[N-(-C(O)(CH2)2Ph-3-OMe)-N-(CH2CH(i-C3H~)Ph)]-Gly-boroLys-OH
[N-(-C(O)(CH2)2Ph-3-OMe)-N-(CH2C(ethanediyl)Ph)]-Gly-boroLys-OH
[N-(-C(O)(CH2)2Ph-3-OMe)-N-(CH2C(propane-1,3-diyl)Ph)]-Gly-boroLys-OH
[N-(-C(O)(CH2)2Ph-3-OMe)-N-(CH2C(butane-1,4-diyl)Ph)]-Gly-boroLys-OH

SUBSTITUTE SHEET (RULE 26) [N-(-C(O)(CH2)2Ph-3-N02)-N-(CH2CH2Ph)]-Gly-boroLys-OH
[N-(-C(O)(CH2)2Ph-3-N02)-N-(CH2C(CH3)2Ph)]-Gly-boroLys-OH
[N-(-C(0)(CH2)2Ph-3-N02)-N-(CH2C(CH2CH3)2Ph)]-Gly-boroLys-OH
[N-(-C(O)(CH2)2Ph-3-N02)-N-(CH2CH(i-C3H~)Ph)]-Gly-boroLys-OH
[N-(-C(0)(CH2)2Ph-3-N02)-N-(CH2C(ethanediyl)Ph)]-Gly-boroLys-OH
[N-(-C(O)(CH2)2Ph-3-N02)-N-(CH2C(propane-1,3-diyl)Ph)]-Gly-boroLys-OH
[N-(-C(0)(CH2)2Ph-3-N02)-N-(CH2C(butane-1,4-diyl)Ph)]-Gly-boroLys-OH
[N-(-C(O)(CH2)2Ph-3-C02H)-N-(CH2CH2Ph)]-Gly-boroLys-OH
[N-(-C(O)(CH2)2Ph-3-C02H)-N-(CH2C(CH3)2Ph)]-Gly-boroLys-OH
[N-(-C(O)(CH2)2Ph-3-C02H)-N-(CH2C(CH2CH3)2Ph)]-Gly-boroLys-OH
[N-(-C(O)(CH2)2Ph-3-C02H)-N-(CH2CH(i-C3H~)Ph)]-Gly-boroLys-OH
[N-(-C(O)(CH2)2Ph-3-C02H)-N-(CH2C(ethanediyl)Ph)]-Gly-boroLys-OH
[N-(-C(O)(CH2)2Ph-3-C02H)-N-(CH2C(propane-1,3-diyl)Ph)]-Gly-boroLys-OH
[N-(-C(O)(CH2)2Ph-3-C02H)-N-(CH2C(butane-1,4-diyl)Ph)]-Gly-boroLys-OH
[N-(-C(0)(CH2)2Ph-3-C02Me)-N-(CH2CH2Ph)]-Gly-boroLys-OH
[N-(-C(O)(CH2)2Ph-3-C02Me)-N-(CH2C(CH3)2Ph)]-Gly-boroLys-OH
[N-(-C(0)(CH2)2Ph-3-C02Me)-N-(CH2C(CH2CH3)2Ph)]-Gly-boroLys-OH
[N-(-C(O)(CH2)2Ph-3-C02Me)-N-(CH2CH(i-C3H~)Ph)]-Gly-boroLys-OH
[N-(-C(0)(CH2)2Ph-3-C02Me)-N-(CH2C(ethanediyl)Ph)]-Gly-boroLys-OH
-59_ SUBSTITUTE SHEET (RULE 26) WO 95/09634 ~ PCT/US94/11280 [N-(-C(O)(CH2)2Ph-3-C02Me)-N-(CH2C(propane-1,3-diyl)Ph)]-Gly-boroLys-OH
[N-(-C(O)(CH2)2Ph-3-C02Me)-N-(CH2C(butane-1,4-diyl)Ph)]-Gly-boroLys-OH
(N-(-C(O)(CH2)2Ph-3-NH2)-N-(CH2CH2Ph)]-Gly-boroLys-OH
[N-(-C(0)(CH2)2Ph-3-NH2)-N-(CH2C(CH3)2Ph)]-Gly-boroLys-OH
[N-(-C(O)(CH2)2Ph-3-NH2)-N-(CH2C(CH2CH3)2Ph)]-Gly-boroLys-OH
[N-(-C(O)(CH2)2Ph-3-NH2)-N-(CH2CH(i-C3H~)Ph)]-Gly-boroLys-OH
[N-(-C(O)(CH2)2Ph-3-NH2)-N-(CH2C(ethanediyl)Ph)]-Gly-boroLys-OH
[N-(-C(O)(CH2)2Ph-3-NH2)-N-(CH2C(propane-1,4-diyl)Ph)]-Gly-boroLys-OH
[N-(-C(O)(CH2)2Ph-3-NH2)-N-(CH2C(butane-1,4-diyl)Ph)]-Gly-boroLys-OH
This invention also provides compositions comprising one or more of the foregoing compounds and methods of using such compositions in the treatment of aberrant proteolysis such as thrombosis in mammals.
Detail Description of the Invention As used throughout the specifications, the following abbreviations for amino acid residues or amino acids apply:
Ala - L-alanine Arg - L-arginine Asn - L-asparagine Asp - L-aspartic acid Cys - L-cysteine Gln - L-glutamine Glu - L-glutamic acid Gly - glycine SUBSTITUTE SHEET (RULE 26) - WO 95I09b3d PCTIUS94111280 His - L-histidine Ile - L-isoleucine Leu - L-leucine Lys - L-lysine Met - L-methionine Phe - L-phenylalanine Pro - L-proline Ser - L-serine Thr - L-threonine Trp - L-tryptophan Tyr ~ - L-tyrosine Val - L-valine Sar - L-sarcosine Irg - L-arginine where the guanidine is replaced with an isothiouronium (-SC(=NH)NH2) The "n" prefix for the foregoing abbreviations indicates the amino acid is in the D-configuration. "D, L"
indicates the amino is present in mixture of the n- and the z-configuration. The prefix "boro" indicates amino acid residues where the carboxyl is replaced by a boronic acid or a boronic acid ester. For example, if R1 is isopropyl and Y1 and Y2 are OH, the C-terminal residue is abbreviated "boroVal-OH" where "-OH" indicates the boronic acid is in the form of the free acid. The pinanediol boronic acid ester and the pinacol boronic acid ester are abbreviated "-C10H16" and "-C6H12", respectively. Examples of other useful diols for esterification with the boronic acids are 1,2-ethanediol, 1,3-propanediol, 1,2-propanediol, 2,3-butanediol, 1,2-diisopropylethanediol, 5,6-decanediol, and 1,2-dicyclohexylethanediol. Other abbreviations are:
formamidino, HC(=NH)-; N-methylamidino, CH3NHC(=NH)-; Z, benzyloxycarbonyl; BSA, benzene sulfonic acid; THF, tetrahydrofuran; Boc-, t-butoxycarbonyl-; Ac-, acetyl; pNA, p-nitro-aniline; DMAP, 4-N,N-dimethylaminopyridine; Tris, SUBSTITUTE SHEET (RULE 26) PCTlUS94111280 Tris(hydroxymethyl)aminomethane; MS, mass spectrometry;
FAB/MS, fast atom bombardment mass spectrometry. LRMS(NH3-CI) and HRMS(NH3-CI) are low and high resolution mass spectrometry, respectively, using NH3 as an ion source.
Thus, an example of the chemical structure based on the nomenclature used herein is:
[N-(-C(O)(CH2)2Ph)-N-(CH3)]Gly-Orn(formamidino)-C02CH3 represents O O
H
N
N ~ ~C02CH3 'H
and [N-(-C(O)(CH2)2Ph-4-OCH3)-N-(CH3)]Gly-boroPhe(mCN)-OH
represents O IH
B
\ N N ~O H

CN
It is understood that many of the compounds of the present invention contain one or more chiral centers and that these stereoisomers may possess distinct physical and biological properties. The present invention comprises all of the stereoisomers or mixtures thereof. If the pure enantiomers or diasteromers are desired, they may be prepared using starting materials with the appropriate stereochemistry, or may be separated from mixtures of undesired stereoisomers by standard techniques, including SUBSTITUTE SHEET (RULE 26) WO 95/U963a PCTlUS94111180 chiral cnromatograpr:~ any =ecrystalization of diastereomeric salts.
The term amine-blocking group" or "amine-protecting groupN as used herein, refers to various aryl, thioacyl, alkyl, sulfonyl, phosphoryl, and phosphinyl groups comprised of 1 to 20 carbon atoms. Substituents on these groups maybe either alkyl, aryl, alkaryl which may contain the heteroatoms, 0, S, and N as a substituent or as inchain component. A number of amine-blocking groups are recognized by those skilled in the art of organic synthesis. Fxampies of suitable groups include forn~yl, acetyl, benzoyl, trifluoroacetyl, and methoxysuccinyl;
aromatic urethane protecting groups, such as, benzyloxycarbonyl; and aliphatic urethane protecting groups, such as t-butoxycarbonyl or adamantyloxyc3rbonyl.
Gross and Meienhofer, eds., The Peptides, Vol 3; 3-88 (1981), Academic Press, New York, and Greene and Wuts Protective Groups in Draanic Synthesis,~315-405 (1991), J.
Wiley and Sons, Inc., New York disclose numerous suitable amine protecting groups.
"Amino acid residues~ as used herein, refers to natural or unnatural amino acids of either n- or L-configuration. Natural amino acids residues are Ala, Arg, Asn, Asp, Cars, Gln, Glu, Gly, His, Ile, Leu, Lys, Met, Phe, Pro, Ser, Thr, Trp, Tyr, and Val. Roberts and Vellaccio, The Peptides, Vol 5; 341-449 11983), Academic Press, New York, discloses numerous suitable unnatural amino acids.
~Amino acids residuesH also refers to various amino acids where sidechain functional groups are coupled with appropriate protecting groups known to those skilled in the art. "The Peptides", Vol 3, 3-88 (1981) discloses numerous suitable protecting groups.

SUBSTITUTE SHEET (RULE 26) As used herein, "alkyl" is intended to include both branched and straight-chain saturated aliphatic hydrocarbon groups having the specified number of carbon atoms.
"Alkoxy" represents an alkyl group of indicated number of carbon atoms attached through an oxygen bridge.
"Cycloalkyl" is intended to include saturated ring groups, including mono-,bi- or poly-cyclic ring systems, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, adamantyl and cyclooctyl, and so forth.
"Alkenyl" is intended to include hydrocarbon chains of either a straight or branched configuration and one or more unsaturated carbon-carbon bonds which may occur in any stable point along the chain, such as ethenyl, propenyl, and the like.
"Halo" or "halogen" as used herein refers to fluoro, chloro, bromo, and iodo.
The term "aryl" is defined as phenyl, fluorenyl, biphenyl and naphthyl, which may be unsubstituted or include optional substitution with one to three substituents.
The term "heteroaryl" is meant to include 5-, 6-, 9-, or 10-membered mono- or bicyclic aromatic rings which can optionally contain from 1 to 3 heteroatoms selected from the group consisting of O, N, and S; said rings) may be unsubstituted or include optional substitution with one to three substituents. Included in the definition of the group heteroaryl, but not limited to, are the following: 2-or 3-, or 4-pyridyl; 2-or 3-furyl; 2- or 3-benzofuranyl;
2-, or 3-thiophenyl; 2- or 3-benzo[b]thiophenyl; 2-, or 3-, or 4-quinolinyl; 1-, or 3-, or 4-isoquinolinyl; 2- or 3-pyrrolyl; 1- or 2- or 3- indolyl; 2-, or 4-, or 5-oxazolyl;
2-benzoxazolyl ; 2- or 4- or 5-imidazolyl; 1- or 2-benzimidazolyl; 2- or 4- or 5-thiazolyl; 2-benzothiazolyl;
3- or 4- or 5-isoxazolyl; 3- or 4- or 5-pyrazolyl; 3- or 4-or 5-isothiazolyl; 3- or 4-pyridazinyl; 2- or 4- or 5-SUBSTITUTE SHEET (RULE 26) WO 95109634 ~ PCTIUS94/11280 pyrimidinyl; 2-pyrazinyl; 2-triazinyl; 3- or 4- cinnolinyl;
1-phthalazinyl; 2- or 4-quinazolinyl; or 2-quinoxalinyl ring. Particularly preferred are 2-, 3-, or 4-pyridyl; 2-, or 3-furyl; 2-, or 3-thiophenyl; 2-, 3-, or 4-quinolinyl;
or 1-, 3-, or 4-isoquinolinyl.
The term "heterocycle" is meant to include 5-, 6-, 9-, or 10-membered mono- or bicyclic rings which can optionally contain from 1 to 3 heteroatoms selected from the group consisting of N, O, or S, with the proviso that proline is excluded from this group; said rings) may be unsubstituted or include optional substitution with one to three substituents. Included in the definition of the group heterocycle, but not limited to, are tetrahydroisoquinoline, tetrahydroquinoline, tetrahydrofuran, tetrahydrothiophene, piperidine, piperazine, morpholine. Particularly preferred are 1-, 3-, or 4-tetrahdroisoquinolinyl.
Unless otherwise specified, the substituents that may be attached to the aryl, heteroaryl or heterocycle rings) may be independently selected at each occurrence from the group consisting of:
halogen, C1-Cq alkyl, C1-C4 alkoxy, methylenedioxy, -N02, -CF3, -SH, -S(O)r-(C1-C4 alkyl), CN, -OH, -NH2, -NH(C1-C4 alkyl), -N(C1-C4 alkyl)2, -C(=NH)NHR4, -NHC(=NR4), -NHC(=NH)NHR4, -NHC(=O)R4, -(CH2)p-C02R4, -NHCO Cl-C4 alkoxy), -NH(C1-C4 alkoxy)2, -N(C1-C4 alkoxy), phenyl which may be unsubstituted or substituted with R13.
By "stable compound" or "stable structure" is meant herein a compound that is sufficiently robust to survive isolation to a useful degree of purity from a reaction ' mixture, and formulation into an efficacious therapeutic agent.

SUBSTITUTE SHEET (RULE 26) WO 9510963 PCTIUS9411128(1 As used herein, pharmaceutically acceptable salt s refer to derivatives of the disclosed compounds wherein the parent compound of formula (I) is modified by making acid or base salts of the compound of formula (I). Examples of pharmaceutically acceptable salts include, but are not limited to, mineral or organic acid salts of basic residues such as amines; alkali or organic salts of acidic residues such as carboxylic acids; and the like.
~Prodrugs° are considered to be any covalently bonded carriers which release the active parent drug according to formula (I) in vivo when such prodrug is administered to a mammalian subject. Prodrugs of the compounds of formula (I) are prepared by modifying functional groups present in the compounds in such a way that the modifications are cleaved, either in routine manipulation or in viva, to the parent compounds. Prodrugs include compounds of formula .
(I) wherein hydroxy,. amine, or sulfhydryl groups are bonded ' to any group that, when administered to a mammalian subject, cleaves to form a free hydroxyl, amino, or sulfhydryl group, respectively. Examples of prodrugs include, but are not limited to,' acetate, formate and benzoate derivatives of alcohol and amine functional groups in the compounds of formula (I); and the like.
Pharmaceutically acceptable salts of the compounds of the invention can be prepared by reacting the free acid or base forms of these compounds with a stoichiometric amount of the appropriate base or acid in water or in an organic solvent, or in a mixture o~ the two; generally, nonaqueous media like ether, ethyl acetate, ethanol, isopropanol, or acetonitrile are preferred. Lists of suitable salts are found in Remington's Pharmaceutical Sciences, 17'h ed., Mack Publishing Company, Easton, PA, 1985, p. 1418.

SUBSTITUTE SHEET (RULE 26) Synthesis The compounds of Formula (I) can be prepared using the reactions and techniques described below, in addition to synthetic procedures described in Applicant's U.S. Patents 5,384,410 and 5,658,885. The reactions are performed in a solvent appropriate to the reagents and materials employed and suitable for the transformations being effected. It will be understood by those skilled in the art of organic synthesis that the functionality present on the molecule should be consistent with the transformations proposed. This will sometimes require a judgment to modify the order of the synthetic steps or to select one particular process scheme over another in order to obtain a desired compound of the invention. It will also be recognized that another major consideration in the planning of any synthetic route in this field is the judicious choice of the protecting group used for protection of the reactive functional groups present in the compounds described in this invention. An authoritative account describing the many alternatives to the trained practitioner is Greene and Wuts, Protective Groups In Organic Synthesis, Wiley and Sons (1991).

Scheme 1 Ra Rs Ra Rs Ra Rs OM -= R~1HN OM -= R1~R3N OM

O
(I
(II) (III) M is a carboxylic acid protecting group The preparation of the required N,N-disubstituted amino acid subunit can be accomplished by the sequence outlined in Scheme 1. A variety of methods for the asymmetric synthesis of the amino acids required for the amino acid ester substrate (II) is reviewed by Morrison and Mosher (Asymmetric Organic Reactions, American Chemical Society, 297-334 (1976) and references there in). The appropriate ester (II), where M is the ester residue, can be conjugated to give the N-substituted intermediate (III) by N-monoalkylation with an alkyl halide related to R11.
Typical conditions for N-monoalkylation include the admixture of an excess of (II), the required alkyl bromide or iodide and a base in an anhydrous polar aprotic solvent, such as acetone, acetonitrile, N,N-dimethylformamide or methyl sulfoxide. The option exists for stirring this mixture at room temperature or heating at temperatures up to the reflux point of the selected solvent. The base added is chosen so that it will not interfere with the ester functionality of (II); among those recommended are non-nucleophilic bases such as sodium hydride or potassium carbonate. Another general route for the preparation of compounds of this type is the reductive amination of (II) with a selected aldehyde related to R11. In this procedure, a mixture of (II) and the aldehyde are heated in an anhydrous non polar solvent, such as benzene, toluene or xylene, with continuous removal of evolved water by drying SUBSTITUTE SHEET (RULE 26) agents or azeotropic distillation. This process causes condensation of the aldehyde with amine (II). The condensation product is reduced to monoalkylated (III) by treatment with a selective hydride reducing agent such as sodium cyanoborohydride or sodium borohydride, according to the method of Getson et. al., J. Heterocycl. Chem. 1, 300 (1964), or by catalytic hydrogenation with platinum, palladium, nickel or Raney nickel in an alcohol solvent like propanol, ethanol or methanol, according to the method of Hudlicky, Reductions In Organic Synthesis, John Wiley and Sons, pp. 134 (1984).
while a number of coupling or acylation methods can be contemplated for the preparation of the disubstituted derivative (IV) from (III), (see Bodanszky and Bodanszky, The Practice of Peptide Synthesis, Springer-Verlag, p. 87-150 (1984)), three methods are preferred. In the first, a solution of (III) in an anhydrous non polar solvent, such as tetrahydrofuran or dichloromethane, at -78°C or higher is treated sequentially with a selected acid chloride related to R3 followed by a trialkylamine base. This mixture is allowed to warm to ambient temperature over several hours if required. The second method is the mixed anhydride procedure of Anderson et al. reported in J. Am.
Chem. Soc. 89, 5012 (1967). In this procedure the alkyl mixed anhydride is generated by dissolving a selected carboxylic acid related to R3 in non-polar anhydrous solvent, such as tetrahydrofuran or dichloromethane, and adding one equivalent of a trialkylamine base. The solution is stirred at -78°C or higher and one equivalent of an alkylchloroformate is added. After formation of the mixed anhydride is complete, a solution of one equivalent each of intermediate (III) and a trialkylamine base is added dropwise. The mixture is stirred with or without cooling until the reaction is complete. The third method preferred for amide formation is the hydroxybenzotriazole /
-SUBSTITUTE SHEET (RULE 26) WO 95109634 PCTIiJS94J11280 dialkylcarbodiimide method of Koing and Geiger in Chem.
Ber. 103, 788 (1970). Thus, to (III) and a selected carboxylic acid related to R3, dissolved in an aprotic solvent like N,N-dimethylformamide, dichloromethane or tetrahydrofuran, at -78°C or higher, is added dialkylcarbodiimide, hydroxybenzotriazole and a trialkylamine base. If necessary, the stirred solution is allowed to thaw to ambient temperature over several hours.
An alternative preparation of N,N-disubstituted amino acids uses a-halo- or ot-sulfonate acylesters such as (V) of Scheme 2. Compound (V) can be treated with a primary amine related to R11 in the presence of a variety of bases like potassium carbonate, triethyl amine or sodium hydride and in solvents such as ethyl ether, acetone or dimethylformamide at temperatures ranging from -78° C to the reflux point of the solvent selected. From this reaction can be isolated the N-alkyl aminoacid ester (III) of Scheme 1; the N-alkyl-N-acylamino acid ester (IV) can be prepared from compound (III) by any of the methods outlined in Scheme 1 and the related discussion hereafter.
The preparation of intermediates which will lead to compounds where R3 and R11 may be taken together to form a cyclic amide or phthalimide is described in Scheme 2. N,N-Disubstituted a-amino acid subunits (VI) which lead to compounds of this type are best derived by reaction of an appropriate a-haloester (V), where J = C1, Br, I.

SUBSTITUTE SHEET (RULE 26) ~ ' i ~ 17 4 31 ~ pCT~S94111280 Scheme 2 Ra Rs Ra Rs OM OM L= ~-N-R"
J ~ ~ L ~ s R

J = Leaving group (V) (VI) M = carboxylic acid protecting group with the alkali metal salt of an amide or phthalimide related to the desired cyclized combination of R3 and R11 in a~polar aprotic solvent according to the method of Daly et. al.in J. Med. Chem. 33, 2818 (1990); Neuberger and Scott, J. Chem. Soc. p 1820 (1954). In a typical preparation the alkali metal salt of the required cyclic amide or phthalimide is generated by adding one equivalent of a strong non-nucleophilic base such as sodium or potassium hydride, a lithium dialkylamine, or lithium trimethyl- or lithium triphenylmethane to a solution of the amide or phthalimide in an anhydrous inert solvent, such as tetrahydrofuran or 1,2-dimethoxyethane, at -78° C or higher. When the salt formation is complete, the solvent is removed by distillation and replaced by the appropriate polar aprotic solvent such as acetonitrile, N,N-dimethylformamide or methylsulfoxide. The appropriate a-chloro- or a-bromoester is introduced and the mixture stirred at room temperature or with heating until the haloester is consumed.
It will be recognized by those skilled in the art of organic synthesis that the acid derivatives of the N,N-disubstituted a-amino acid esters (IV) and (VI) are the required precursors for the preparation of the thrombin inhibitors disclosed in this invention. It is recommended that compounds (IV) and (VI) be prepared as either the benzyl, methyl or t-butyl esters because of the ease with which esters of these types may be converted to their SUBSTITUTE SHEET (RULE 26) W095109634 ~i PCT/US9d111280 corresponding acids. In the case of a benzyl ester (e. g..
(IV) or (VI), where M = -CH2C6H5), hydrogenolysis of an alcohol solution of the compound may be effected under an atmosphere of hydrogen gas in the presence of platinum or palladium on carbon catalyst according to the reported by Hartney and Simonoff, Org. React. VII, 263 (1953); with a methyl ester (IV) or (VI), where M = -CH3, treatment of an ethanol solution of the compound with an aqueous base, such as one equivalent of sodium hydroxide solution, will give the desired acid. The t-butyl ester (IV) or (VI), where M
- -C(CH3)3, is readily cleaved by acid under anhydrous conditions; for example trifluoroacetic acid in dichloromethane solution removes the t-butyl ester of derivatives of (IV) at ambient temperature as reported by Bryan et. al., J. Am. Chem. Soc. 99, 2353 (1977). A number of alternative esters and procedures are detailed in Greene and Wuts (1991).
Scheme 3 illustrates the coupling of the acid derivatives of (IV) or (VI) with boropeptide synthons (VII) or (VIII) to give intermediates (IX) or (X).
Scheme 3 Ra R5 OM +
L
0 O\B~O O
O L
~NH CI (CH2)y N
(CH2)y a (I~ ~ L = R3R~~N' Br Br H R5 Ra (VI) : L = R»-N_ (VII) : y = 3 (IX) : y = 3 (VIII):y=4 (X):y=4 SUBSTITUTE SHEET (RULE 26) .~... WO 95/09634 ~ j PCT/US94111280 The preparation of synthons (VII) and (VIII) has been described by Kettner and Shenvi (EP 293 881 A2). It will be recognized by those skilled in the art of organic synthesis that the methodology described by Kettner and Shenvi can be applied to make homologous boropeptide synthons related to (VII) and (VIII). These homologues may be used in the appropriate processes described herein to prepare the corresponding thrombin inhibitors. The coupling of the carboxylic acid derivative of (IV) or (VI) to boropeptide synthon (VII) or (VIII) has been described previously by Kettner et al. in J. Biol. Chem. 265 ,18289 (1990) and, in general, the standard amino acid coupling protocols detailed by Bodanszky and Bodanszky (1984) are effective for making the compounds of this invention.
Preferred methods are the mixed anhydride procedure of Anderson et al. 11967) and the hydroxybenzotriazole/dialkylcarbodiimide method of Koing and Geiger (1970). In the mixed anhydride procedure, the anhydride is generated by dissolving a carboxylic acid related to (IV) or (VI) in a non polar anhydrous solvent, such as tetrahydrofuran or dichloromethane, and adding one equivalent of a trialkylamine base. The solution is stirred at -78° and up to 0°C, then one equivalent of an alkylchloroformate is added. After formation of the mixed anhydride is complete, a solution of boropeptide synthon (VII) or (VIII) and a trialkylamine base is added. The mixture is stirred for one hour with cooling followed by several hours at ambient temperature. By the hydroxybenzotriazole/dialkylcarbodiimide method, (VII) or (VIII) and the acids of (IV) or (VI) are dissolved in an aprotic solvent, such as N,N-dimethylformamide, dichloromethane or tetrahydrofuran, at -78° or higher. To this solution one equivalent each of dialkylcarbodiimide, hydroxybenzotriazole and a trialkylamine base are added.

SUBSTITUTE SHEET (RULE 26) PCTlUS94/11280 If necessary, the solution is allowed to stir and thaw to ambient temperature over several hours.
A process for the preparation of the boropeptide thrombin inhibitors of this invention from intermediates (IX) and (X) is disclosed in Scheme 4. Compound (IX) serves as a starting point for isothiouronium thrombin inhibitors (XI) and (XII). The boronic ester (XI) is prepared by stirring a solution of (IX) and thiourea in an inert polar solvent, such as an alcohol or N,N-dimethylformamide, at temperatures ranging from ambient to the reflux temperature of the selected solvent. It is understood that a boronic acid ester like compound (XI) is an effective thrombin inhibitor, however, it may be transformed to the corresponding free boronic acid (XII) without a loss of biological activity. Compound (xII) is derived from~the boron ester (XI) by transesterification under equilibrium conditions.

SUBSTITUTE SHEET (RULE 26) WO 95/09634 ~. ~ ! ~ 3 ~ 4 PCT/US94111280 Scheme 4 o~~o O o~ ~o O o~~o NR3R~~ ~ NR3R~~ ~ ~ NR3R~
(CHz)y N ~ ( i Hz)y N ~ (CH )3 N
er I R5 Ra NHz I R5 Ra ~ z I RS a NH H R
(IX) : y = 3 (X111) : y = 3 H2N'~ NH
(x) : y = a (xlv) : y = a (xvl) A O (HO)zB O (HO)zB O
NR3R~~ ~ NR3R~~ ~ NR3R~~
( ~Hz)3 ~ ~ ( i Hz)y ~ ~ (OHz)a H RS Ra NH2 H R5 Ra NH H RS Ra HZN- _ NH (XV) : y = 3 H2N- ' NH
o (XVI): y = 4 (XVIII) (XI) : A =

(X111 : A = BIOHI
Thus stirring ester (XI) with an excess of an alkyl- or aryl boric acid in a biphasic mixture of neutral or acidic water and an immiscible solvent, such as ethyl ether or toluene, gives (XII) after several hours at ambient temperature. The conditions generally preferred use 5 to equivalents of phenylboric acid in ethyl ether/water at 10 neutral pH. Thrombin inhibitors (XIII) to (XVI) are obtained by reduction of an azide intermediate prepared from (IX) or (X). The azide intermediate is prepared by heating either (IX) or (X) with an inorganic azide, such as sodium or potassium azide, in an anhydrous polar aprotic solvent, such as acetone, dimethylformamide or methyl SUBSTITUTE SHEET (RULE 26) WO 95109634 PCTlUS94111280 sulfoxide at temperatures ranging from ambient to 130°C.
Alternatively, phase transfer conditions may be employed to prepare the azide intermediate from (IX) or (X). For example, a tetraalkylammonium azide in a non-polar aprotic solvent, such as tetrahydrofuran or toluene, or a crown ether and inorganic azide in biphasic mixtures of water and an immiscible solvent, such as benzene, toluene or xylene, can be stirred at room temperature or heated up to the reflux point of the selected solvent. The primary amines (XIII) and (XIV) are most conveniently obtained from the catalytic hydrogenation of the azide in an inert solvent, such as an alcohol, ethyl acetate or tetrahydrofuran with a transition metal catalyst such as platinum or palladium on carbon under an atmosphere of hydrogen gas. A variety of alternative methods are also useful and can be found in the monograph by Hudlicky (1984, pp. 76). The acid salt of the resulting amines (XIII) and (XIV) may be formed by the addition of one equivalent of the desired acid to the hydrogenation mixture. Phenylboric acid mediated hydrolysis of esters (XIII) and (XIV) gives the free boronic acid thrombin inhibitors (XV) and (XVI), compounds of formula (I) of the invention.
Compounds containing a primary guanidine or N- alkyl guanidine functionality may be prepared by the alternative process outlined in Scheme 4. As illustrated with primary amine (XIII), the transformation to (XVII) is effected with a guanidinylation agent, such as an S-alkyl thiourea, aminoiminomethane sulfonic acid reported by Miller and Bischoff Synthesis 9, 777 (1986), cyanamide reported by Kettner et al. (1990) or their N-alkyl derivatives. This mixture is stirred at room temperature or higher with a base, such as potassium carbonate, triethylamine or N,N-dimethylaminopyridine in an inert solvent like water, alcohol, N,N-dimethylformamide or acetone. The guanidine boronic acid esters (XVII) can be deesterified to give the SUBSTITUTE SHEET (RULE 26) ., WO 95/09634 PCT/US94111280 corresponding boronic acid (XVIII) by the phenylboric acid procedure described above.
_-;7_ SUBSTITUTE SHEET (RULE 26) ~17431~ .
According to Scheme 5, the bromide (X) is converted to the corresponding alkylnitrile (XIX) upon exposure to the cyanide anion under a variety of conditions.
Scheme 5 o~~o O ~~ O
1 NR3R~~ ~ NR3R»
(CH2)~ N _---r (CH2)a N _---r Br I RS R4 N H R R
(X) (XIX) O~~O O (HO)28 O
~ NR3R~~ ~ NR3Ri~
(CHZ)3 _ N ~ (CHZ)3 ' N
CH ~ RS R° ~H2 ~ RS Ra HzN- ' NH HZN~ NH
) (XXI) Effective methods include the use of potassium or sodium cyanides in polar aprotic solvents, such as N,N-dimethylformamide, methylsulfoxide, acetone or ethylmethyl ketone, at temperatures ranging from ambient up to the reflux point of the selected solvent. More useful, however, are conditions employing phase transfer agents such as tetrabutylammonium cyanide in a nonpolar aprotic solvent such as tetrahydrofuran or toluene, or a biphasic mixture of a crown ether and an inorganic cyanide in water with an immiscible solvent like benzene, toluene or xylene. These mixtures can be stirred at ambient temperature or heated up _78_ SUBSTITUTE SHEET (RULE 26) ~. at ,f ~~c ~ .ii.. '~!
.6-. WO 9510963a PCTlUS94/11280 ~~. ~ ~3~~
to the reflux temperature of the selected solvent. An amidine like (XX) is prepared by first treating nitrile (XIX) with a saturated solution of a mineral acid such as hydrogen chloride in an alcohol solvent at room temperature or lower. The intermediate 0-alkylimidate can be exposed to ammonia, or a primary or secondary amine under anhydrous conditions with or without an inert solvent. As illustrated in Scheme 5, compound (XX) is produced by treating the O-alkylimidate formed from (XIX) with neat anhydrous ammonia at reflux. The free boronic acid (XXI) is obtained by transesterification of (XX) with phenylboric acid in a mixture of water and diethyl ether.
The formamidine substituted boronic acid (xXIII) is prepared from alkylamine (XV) as shown in Scheme 6.
Compounds of (XV> can be stirred with an O-alkyl or O-aryl formimidate from 0°C or up to the reflux temperature of an inert anhydrous solvent such as tetrahydrofuran or N,N-dimethylformamide to give formamidine (XXII). Free boronic acid (XXIII) is produced from (XXII) by the phenylboric acid transesterification protocol.
.79_ SUBSTITUTE SHEET (RULE 26) PCTlUS94111280 Scheme 6 O o ~ B~ O
O NRsR»
NR3R" ~
(CHZ)3 ' N
(CHZ)s I
I ~ 4 NH H RS R4 NHZ H R R ~
H" NH
(XV~
(XXII) (HO)2~ O
NR3R"
(CH2)3 H" NH
(XXIII) As shown in Scheme 7, the N-cyanoguanidine substituted boronic acid (xXVI), can be prepared by the reaction of (XV) with an N-cyanoisourylation agent such as S,S-dimethyl N-cyanoiminodithiocarbonate or O,O-diphenyl N-cyanodiimino-carbonate. In this general process, compounds of Formula (XV) are combined with a selected iminocarbonate in an inert, anhydrous solvent like tetrahydrofuran or N,N-dimethylformamide. The mixture is stirred at 0°C or up to the reflux temperature of the chosen solvent until there is obtained an N-cyano-S-isourea or N-cyano-O-isourea of the Formula (XXIV) similar to that reported by Barpill et al., J. Heterocyclic Chem. 25, 1698 (1988). This intermediate is treated with an amine such as SUBSTITUTE SHEET (RULE 26) Scheme 7 g/ o O ~ s~ O
NR3R~~ ~ NR3R~~
( i Hz)a ~ ~ (CHz)3 NHz H R5 Ra ~ H H RS Ra (XV) X' _ N-CN
(XXIV) wherein X is -SMe, -OPh 0~~0 O . (HO)zB O
NR3R~~ ~ NRsR»
(CHz)3 ' N
(CHz)a ~ ~ -' ~ H H R5 R4 ~H H R Ra ~ HpN N-CN
HZN"- N-CN
(XXV) (XXVI) ammonia, or more generally, an alkylamine or an arylamine with or without an inert solvent like water, tetrahydrofuran or an alcohol at temperatures ranging from 0°C to reflux to give the aminolysis product (XXV).
Treatment of (XXV) as described above with phenylboric acid can provide (xxVl).
The N-hydroxyguanidino inhibitors, as shown in Scheme 8, are prepared by treating amine (XV) with cyanogen bromide or cyanogen chloride followed by hydroxylamine in an inert solvent to yield (XXVII) according to Nakahara et.
al., Tetrahedron 33, 1591 (1977); and Belzecki et al., J.
Chem. Soc. Chem. Commun. p. 806 (1970). Transesterification of (XxVII) by the phenylboric acid method can provide (XXVIII).

SUBSTITUTE SHEET (RULE 26) Scheme 8.

O ~ s~ O
NR3R" ~ NR3R"
(CHz)~N (CHz)a N
I 5~4 NHz H RS R° NH H R R
H2N_ _ N-OH
(XV) (XXVII) (HO)Z~ O
NR3R"
(CHz)s NH H RS R°
HzN- ' N-0H
(XXVIII) A general preparation for the new aromatic boronic acids is illustrated in Scheme 9. Functionalized benzylic anions containing either a halo- or cyano- substituent are obtained with a variety of metalation agents, such as activated zinc metal/CuCN~2LiC1 based on the report of Berk et al. Organometallics 9, 3053 (1990); or use of lithium metal according to Michel et al., J. Organometallic Chem.
204, 1 (1981); or lithium naphthalenide in the presence of zinc chloride based on the report of Zhu et al.,J. Org.
Chem. 56, 1445 (1991) in an inert solvent like tetrahydrofuran or 1,2-dimethoxyethane at temperatures of -78°C or higher. Dichloromethyl boronic acid pinanediol, prepared by the method described by Tsai et al. in Organometallics 2, 1543 (1983), is allowed to react with the transmetallated anion in the selected solvent to give (XXIX). The a-aminoboronic acid, (XXX), can be obtained by treating (XXIX) with the sodium or lithium salt of hexamethyldisilizane in a polar aprotic solvent like SUBSTITUTE SHEET (RULE 26) ~1743I4 :..... WO 95/09634 PCTJUS94/11280 acetone, N,N-dimethylformamide or methyl sulfoxide with heating at temperature up to the reflux point of the selected solvent, if necessary. The trimethylsilyl protecting groups are removed by treatment with Scheme 9.
O~ O O~ O
CHzZnBr CI NHz CI \ \
cN ~~J ~~J
CN CN
(XXIX) (XXX) O
NR3R~~
HO~
R~ Rs A O A
(IV) of (VI) NR3R'~ ~NR3R~~
I Rs Rs 1HY Re~Rs H
i CN ~ NH

(XXXIa) : A = B~ (XXXIIa) (XXXib) : A = B (OH)2 (XXXIIb) anhydrous acid such as gaseous hydrogen chhloride or trifluoroacetic acid in an inert solvent like tetrahydrofuran or dichloromethane at -78°C or higher.
Compound (XXX) was coupled to the N,N-disubstituted a-amino acids (IV) or (VI), using the techniques described in Scheme 3, to give the boronic acid ester (XXXIa).
Transesterification of (XXXIa) by the phenylboric acid protocol (vide infra) gives inhibitor (XXXIb). In Scheme SUBSTITUTE SHEET (RULE 26) WO 95109634 , ~ ~ PCT/US94111280 9, the aromatic nitrite (XXXIa) is converted to the amidine (XXXIIa) by methods described for the synthesis of aliphatic amidine (XX) in Scheme 5. Removal of the pinanediol protecting group of (XXXIIa) gives the free boronic acid derivative (XXXIIb).
As detailed in Scheme 10, compound (XXXIa) is a versatile intermediate that can be hydrogenated to yield the aminomethyl derivative (XXXIIIa) under a variety of conditions (Hudlicky, (1984), pp 173).
Scheme 10.
A
L (XXXIVa) H R' R5 A ~ L (XXXVa) (XXXIVb) H R R
- l CHZNHCH(NH) ' (XXXVb) ~CH2NHC(=N-CN)NHz A A
L L (XXXVIa) L
H R' Rs Fi R' Rs H R' Rs W
~CH NH ~ (XXXVIb) 2 z CHpNHC(=N-OH)NHz CN
O
(XXXllla) : A = B;
(XXXIa) A
L (XXXVIIa) 1 ~ '5 H R R
(XXXlllb) : A = B (OH)Z I ~
~CHZNHC(=NH)NHz (XXXVIIb) wherein L is NR3R~~
Catalysts recommended for this transformation include transition metals like rhodium, Raney nickel, nickel SUBSTITUTE SHEET (RULE 26) y PCT/US94I11280 boride, nickel, platinum or palladium; these reductions occur readily under atmospheres of hydrogen or ammonia at pressures ranging from 1 to 300 atmospheres, at room temperature or higher, and in inert solvents such as water, an alcohol, ethyl acetate or tetrahydrofuran. Furthermore, ' from (XXXIIIa), the formamidino- (XXXIVa), cyanoguanidino-(XXXVa), hydroxyguanidino- (XXXVIa) and guanidino- analogs (XXXVIIa) can prepared by the same procedures described for the aliphatic series in Schemes 4, 6 through 8. The boronic acid esters (XXXIIIa)-(XXXVIIa) can all be trransesterified to the corresponding free boronic acid inhibitors (XXXIIIb)-(XXXVIIb) using the phenyl boronic acid method prviously described.
Aromatic boronic acid inhibitors (XLIa,b), with the guanidine functionality substituted directly on the aromatic nucleus, can be prepared from precursor (XXXVIII) according to Scheme 11. Nitration of the aromatic ring of (XXXVIII) according to the method of Olah and Kuhn, J.
Amer. Chem. Soc. 84, 3684 (1962) can occur readily with agents such as acetyl nitrate, nitrosonium tetrafluoroborate (N02+BF4-) and nitrosonium hexafluorophosphate (N02+PF5-) in inert solvents like tetrahydrofuran or dichloromethane at -78°C or higher. The products of formula (XXXIX) can be reduced to the aniline derivative (LX) by catalytic hydrogenation. The catalysts recommended for this procedure include iron, zinc, platinum oxide, rhodium - platinum oxide, palladium, Raney nickel, copper chromite, and rhenium sulfide. while reduction occurs readily under an atmosphere of hydrogen gas at pressures range from 1 to 350 atmosphere in an inert solvent like water, an alcohol or ethyl acetate, other reagents which may affect this reaction are transfer agents such as hydrazine, formic acid or triethyl formate (Hudlicky, (1984), pp 73).
_g5_ SUBSTITUTE SHEET (RULE 26) WO 95!09634 PCT/US94/11280 2~.'~~~14 Scheme il.
O.B,O O O.B,O O
~NR3R" s >>
N _ ~ N R R ---H Ra R5 N 4 5 R R
(xxxlx) (XXXVIII) N02 O.B.~ ~ ~ A O
NR3R" ~ N~ NR3R"
N ' a 5 H Ra R5 \ H R R
I '~~ I ~~
'NH NHC(=NH)NH2 O
(LX) (LXIa) : A = B, O
(LXIb) : A = B (OH)2 The aniline (LX) can be converted to the phenylguanidine (LXIa) by the procedure described for (XVII) in Scheme 4.
The transformation of (LXIa) to the free boronic acid (LXIb) is effected as in Scheme 4.
The several types of inhibitors disclosed in this invention can be broadly classified by their electrophilic functional group ~, as defined in Formula (I). The -as-SUBSTITUTE SHEET (RULE 26) W O 95109634 ~ 1 '~ 4 314 tr , compounds described below, e the boron containing unlik peptides, utilize a highly rophilic carbon atom elect at g to interact with the active serine of thrombin. The site precursor for the electrophilic carbon inhibitors is the appropriately protected amino id (LXII) of Scheme 12.
ac - Scheme 12 MOZC

MOZC
NPG

H ~ N PG
H

HzNHC(=NH)H

(LXIII) CHZNHC(=N-CN)NHz (LXIV) MOzC MOZC

N PG ~ N PG

H ~ H

CHZNHz CHZNHC(=N-OH)NHz (LXII) (LXV) MOZC
NPG
H
CHZNHC(=NH)NHz (LXVI) D = -(CH2)y- or -(CH2)ø~C6H4(CI~)P.~_ v = 0-10 M = alkyl or benzyl PG = protecting group The preparation of (LXII) can be found in the general chemical literature, one such reference being the review by Morrison and Mosher (1976). According to Scheme 12 various terminal functional groups are available from (XLII) . the _87_ SUBSTITUTE SHEET (RULE 26) ~1'~43f4 formamidino- (XLIII), cyanoguanidino- (XLIV), hydroxyguanidino- (XLV) and guanidino- analogs (XLVI>.
These compounds are prepared by the same procedures described for the boropeptide series in Schemes 4, 6-8.
The preparation of amidine derivative (XLVIII) and phenylguanidines of formula (L) from amino acids (XLVII) and (XLIX) is shown in Scheme 13. The conditions used to prepare amidines of formula (XLVIII) is discussed for (XX) of Scheme 5 while the method for formamidinylation of (XLIX) to give (L) is the same as that described to prepare (XVII) of Scheme 4.
Scheme 13.
MOZC MOZC
NPG ~ NPG

H ~ H

CN CHZ(NH)NHZ

(XLVII) (XLVIII) D = -(CH2)y- or -(CH2)~.~C6Ha(CH2)~-r NPG ~ NPG

H ~ H

NH2 NHC(=NH)NHp (XLIX) (L) D = -(CH2)q.iC6H4_ v=0-10 M = alkyl or benzyl PG = suitable amine protecting group As shown in Scheme 14, appropriately protected derivatives of formulae (XLII)-(L), wherein M is an alkyl _88_ SUBSTITUTE SHEET (RULE 26) WO 95109634 ~ ~ y , PCT/US94111280 or benzyl group can be coupled with N,N-disubstituted acid (IV) or (VI) (wherein M is hydrogen). The methodology to accomplish these transformations is the same as that used to prepare boropeptides (IX) and (X) of Scheme 3. The X
group in compounds of formulae (XLII) through (L) and (LI) in Scheme 14, as well as in compounds illustrated in the Schemes to follow, is a protected version of the terminal functional group X, as defined by Formula (I), unless deprotection is indicated to obtain the final compound of the sequence.
Scheme 14.

OM + ~ L
L ~ NH2 ~ NH
RS a O D-X Q-- X R
(IV) : L = R3R~~N- (XLII)-(L) (LI) wherein X is terminal (VI) : L = R~L N- functional group (protected) It is understood that the protecting group(s> used should compatible with the conditions of the process discussed; a good source for information on protecting group chemistry is Greene and Wuts (1991).
The preparation of the thrombin inhibitors trihalomethyl ketone (LIII) and a-ketoester (LIV) are shown in Scheme 15. The coupled ester (LI), wherein M is alkyl or benzyl can be converted to the acid (M is hydrogen) by ' the methodology appropriate for the particular ester functionality as described in Greene and Wuts (1984). The aldehyde (LII) can be prepared by selective reduction of the acid (LI, M is hydrogen) to the primary alcohol followed by oxidation.
_gg_ SUBSTITUTE SHEET (RULE 26) Scheme 15.
R4 Rs H R4 Rs H R4 Rs H
' CHO ~ C(=O)~ 3 R"N COpM ~ R» Rat I
I ~ I 3 O
R3 O p R3 O ~ R
X
X
(LI) (LII) (LIII) J can be Fluorine Ra Rs H R4 Rs H
C(-0)C02CH3 ~CH(OH)C(SEty~ R~~N
R~~ ~N

X X
(LIV) (LV) To obtain the primary alcohol, the acid can be transformed to the mixed anhydride by condensation of the trialkylammonium salt of the acid with an alkyl- or arylchloroformate in an inert non-polar solvent such as tetrahydrofuran, 1,2-dimethoxyethane or toluene at-78°C to room temperature. The solution of the resulting mixed anhydride is filtered and reduced to the peptidyl alcohol with an excess of a borohydride reducing agent in a compatible solvent like water or an alcohol at -78°C to room temperature according to the method of Rodriguez et.
al., Tetrahedron Lett. 32, 923 (1991). The peptidyl alcohol can be oxidized to aldehyde (LII) without over oxidation by a variety of procedures, as detailed by Hudlicky in Oxidations in Organic Chemistry, American Chemical Society, p. 114 (1991); the preferred methods include Swern oxidation described by Omura and Swern, Tetrahedron 34, 1651 (1978); and the Pfitzner-Moffat oxidation described by Fearon et al.in J. Med. Chem. 30, 1617 (1987). A two step protocol reported by Edwards, SUBSTITUTE SHEET (RULE 26) '"'" WO 95/09634 ~ 1 "7 4 314 PCTIUS94111280 the trifluoromethyl ketones (LIII) (J is fluorine) from aldehyde (LII). In this procedure a metallated trifluoromethyl anion is generated from an excess of trifluoromethyliodide or -bromide and an active metal such as zinc, magnesium, lithium or cadmium in inert, anhydrous solvents like tetrahydrofuran or N,N-dimethylformamide at temperatures of -100°C up to the reflux point of the solvent. Alternatively, the metalated trifluoromethyl anion may be generated by the transmetallation of trifluoromethyliodide or -bromide with an organometallic compound such as a Grignard reagent or alkyllithium compound in an inert solvent like tetrahydrofuran, hexane or ether at temperatures ranging from -78°C up to the reflux point of the selected solvent. Aldehyde (LII) can be added to the solution of the metalated trifluoromethyl anion to form the trifluoroethanol derivative at temperatures of -100°C or higher. To obtain the trifluoromethyl ketone (LIII) where J is fluoro, the alcohol is oxidized by the Pfitzner-Moffat or Swern procedure. Removal of the protecting groups) on terminal group X by the appropriate method will provide the thrombin inhibitors of formulae (LIII).
Trihalomethyl analogs of (LIII), where J is fluoro can also be prepared from aldehyde (LII) by a different method.
The trihalomethyl ketones are prepared by treating aldehyde (LII) with either the trimethylsilyl trihaloacetate or the potassium or sodium trihaloacetate in a polar solvent such as an alcohol, N,N-dimethylformamide or methylsulfoxide with or without a base such as a trialkyl amine, potassium carbonate or sodium hydroxide at temperatures of -78°C or higher according to the method of Beaulieu, Tetrahedron Lett. 32, 1031 (1991); Shell Int. Res., European Patent Application EP 16504 ). The resulting a,a,a-trihaloethanol is oxidized and group x can be deprotected as above to give the thrombin inhibitors or formulae (LIII).

SUBSTITUTE SHEET (RULE 26) WO 95109634 PCTlUS94111280 The a-ketoester thrombin inhibitors, exemplified by (LV), are prepared according to a route disclosed by Iwanowicz et. al. in Bioorgan. Med. Chem. Lett. 12, 1607 (1992). The tris(ethylthio)methyl anion is added to the peptidyl aldehyde (LII) in a solvent such as tetrahydrofuran, 1,2-dimethoxyethane or toluene at -100°C
or higher to give the alcohol (LIV). The a-hydroxyl, ester is generated from (LIV) by treatment with a mixture of mercuric salts, such as mercuric chloride and mercuric oxide, in an alcohol or water. Swern or Pfitzner-Moffat oxidation of the a-hydroxyl ester followed by the deprotection of substituent X protecting group provides thrombin inhibitors of formula (LV).
Another method for the preparation of compound (LV) substitutes a 1-lithio-1-alkoxyethene or 1-magnesio-1-alkoxyethene for the tris(ethylthio)methyl anion of Scheme 15 in an addition reaction with peptidyl aldehyde (LII).
There can be obtained an adduct analogus to the tris(ethylthio)hydroxyethyl compound (LIV) when excess 1-magnesio- or 1-lithio-1-alkoxyethene anion is stirred at temperatures ranging from -100 °C to ambient temperature with (LII) in anhydrous solvents such as diethyl ether or tetrhydrofuran. This alkoxyolefin product may then be transformed to (LV) by oxidative cleavage with reagents such as ozone or periodate in an inert solvent such as a halohydrocarbon, lower alkyl ketone, an alcohol or water at temperatures ranging from -100 °C to ambient temperature, followed by oxidation of the intervening a-hydroxyester and deprotection as described above.
The preparation of the a,a-dihalomethylketone thrombin inhibitors of this invention is outlined in Scheme 16.

SUBSTITUTE SHEET (RULE 26) .~~ WO 95/09634 PCT/US94111280 ~1"~ 4314 Scheme 16.
Ra Rs I Ra Rs I
CHO CH(OH)CHJZ
R~~N R~~N
13 ~ Q I3 ~ Q
R O I R
X X
(LII) (LVI) Ra Rs H
0 = (CH2)~.~2 or (CHZ)qC6Ha(CH2)p N C(=O)CHJ2 R~~N

I
X
(LVI I) The a,a-dihalomethylketone (LVII), where J is fluoro can be prepared from the aldehyde (LII) by selective reaction of the aldehyde with the anion of the corresponding dihalomethane. The metalated dihalomethane anion is generated from one equivalent each of a strong hindered base, such as lithium tetramethylpiperidide or tertbutyllithium, and the selected dihalomethane in an anhydrous, inert solvent like tetrahydrofuran or 1,2-dimethoxyethane at -100°C or higher according to the method of Taguchi et. al. Bull. Chem. Soc. ~Tpn., 50, 1588 (1977).
The metalated dihalomethane anion can be added to the aldehyde (LII) at -100°C or higher. Alternatively, the dihalomethane anion is generated from a dihalomethyl(trimethyl)silane and an anhydrous fluoride ion source such as tris(diethylamino)sulfonium difluoromethyl silicate in an inert solvent like benzene, acetonitrile or tetrahydrofuran at -78°C or higher, then (LII) can be added to give dihaloethanol (LVI) according to the method of SUBSTITUTE SHEET (RULE 26) 21?4~1~
Fujita and Hiyama, J. Am. Chem. Soc. 107, 4085 (1985).
The resulting dihaloethanol can be oxidized to ketone (LVII) by the Swern or Pfitzner-Moffat procedure. Removal of the protecting groups) on substituent X of (LVII) gives the a,a-dihalomethylketone thrombin inhibitors.
a-Halomethylketone thrombin inhibitors can be prepared by the process illustrated in Scheme 17.
The acid chloride (LVIII) can be prepared from acid (LI), wherein M is hydrogen or its trialkylammonium, sodium or potassium salt with a chlorinating agent such as thionyl chloride, oxalyl chloride or dichloromethylmethyl ether in a solvent like tetrahydrofuran or dichloromethane with or without a catalytic amount of N,N-dimethylformamide at -78°C or higher. Alternatively, the mixed anhydride of (LI) may be prepared as described for (LI) in Scheme 15.
Compound (LVIII) or the mixed anhydride of (LI) can be treated with an ether solution of diazomethane and either anhydrous hydrogen fluoride or hydrogen chloride gas according to that described by McPhee and Klingsbury, Org.
Synth. Coll. III, 119 (1955); or hydrogen bromide according to the method Miescher and Kaji, Helv. Chim.
Acta. 24, 1471 (1941) .

SUBSTITUTE SHEET (RULE 26) ~

~"' WO 95/09634 ~ 1'~ 4 314 pCT/US94/11280 S ..
Scheme 17.
Ra Rs I Ra RS I
C02M C(O)CI
R"N ~ ~ R
Ra O O R3 O
X X
(LVI11) Ra RS H
C(O)CH2,J
R" I3 ~ o R
Q = ~CH2)t~12 a~ (CH2)qCsH4(CH2)P X
(LIX) Selection of the hydrogen fluoride gas will give the a-fluoromethylketone analog, (LIX) wherein J is fluoro; and hydrogen chloride gas gives the a-chloromethylketone analog (LIX) wherein J is chloro. Deprotection of X gives the corresponding thrombin inhibitors of (LIX).
The general preparative route for the a,b-diketoester, -amide and -ketone thrombin inhibitors of this invention is exemplified in Scheme 18. Compound (LVIII) or the mixed anhydride of (LI) can be reacted with a Wittig reagent such as methyl (triphenyl-phosphoranylidene)acetate in a solvent like tetrahydrofuran or acetonitrile at temperatures ranging from 0°C to the reflux point of the solvent to give (LX). Oxidative cleavage of the phosphoranylidene (LX) with an oxidizing agent like ozone or OXONETM in an inert solvent such as tetrahydrofuran, dichloromethane or water at temperatures of -78°C or, higher gives the vicinal _95_ SUBSTITUTE SHEET (RULE 26) PCTlUS94111280 tricarbonyl compound (LXI), analogous to that described by Wasserman and vu, Tetrahedron Lett. 31, 5205 (1990).
Cleavage of the protecting group can provide thrombin inhibitors of formula (LXI).
Scheme 18.
Ra Rs H Ra Rs H
R~~N N C(O)M R N N'/C(O)C(=PPh3)C02CH3 R3 O 0 Rs O Gl X X
(LX) (LI) : M = OH
(LVIII) : M = CI
Q = (CH2)~.~2 or (CH2)qC6H4(CH2)p R4 R5 H
NYC (O)C(O)C02CH3 R~~N~
Rs O GZ
X
(LXI) The preparative routes for the synthesis of the a-mono- and a,a-dihalo-b-ketoester -amide and ketone thrombin inhibitors of this invention are summarized in Scheme 19.
The exemplified b-ketoester (LXII) is available from the acid derivative (LI). The acid (LI) can be treated with carbonyl diimidazole in an inert solvent such as tetrahydrofuran or dichloromethane at 0°C or higher to form the acyl imidazole. This acyl imidazole, or the mixed anhydride of (LI), can be further reacted with lithioethylacetate in solvents such as 1,2-dimethoxyethane or tetrahydrofuran/hexane at temperatures ranging from -100°C to ambient temperature, according to the method of Dow, ~T. Org. Chem. 55, 386 (19901 to give b-ketoester (LXII).

SUBSTITUTE SHEET (RULE 26) 2.1743/4 WO 95/09634 \ PCTlUS94/11280 Scheme 19.
Ra Rs I Ra Rs I
C02M C(O)CH2C02CH3 R,1I ~ ~ R'1I
Rs O ~ Rs d X X
(LI) : M = H (LXII) Ra Rs H
I
N C(O)C(J)zC02CH3 R~~N
Ra O O
X
(LXIII) : J = H, halogen O = (CH2)~_~2 or (CH2)qC6Ha(CH2)P (LXIV) : J = dihalogen Compound (LXII) serves as a substrate for both mono- and dihalogenation. The a-monochloro analog of (LXIII), where J
is each chlorine and hydrogen, can be prepared by controlled halogrenation reactions with reagents like N-chlorosuccinimide or thionyl chloride in an inert halogenated solvent and at temperatures ranging from -20°C
to the reflux point of the selected solvent according to the methods of Uhle, ~T. Am. Chem. Soc. 83, 1460 (1961); and DeKimpe et. al., Synthesis 2, 188 (1987). The a,a-dihalo analog (LXIV) where J is chloro is available from halogenation with molecular chlorine in a halogenated solvent at temperatures of -20°C or higher according to the method of Bigelow and Hanslick, Org. Syn. Coll. II, 244 (1943). Reagents such as N-_97_ SUBSTITUTE SHEET (RULE 26) WO 95/09634 ' PCT/US94111280 fluorobis((trifluoromethyl)sulfonyl]imide are useful for the preparation of mono- and difluoro analogs (LXIII) and (LXIV) by reacting the appropriate stoichiometry of this reagent with (LXII) in a halogenated solvent at temperatures of -78°C or higher according to the method of Resnati and DesMarteau, J. Org. Chem. 56, 4925 (1991).
Deprotection of substituent X of the halogenation products (LXIII) and (LXIV) can provide the corresponding thrombin inhibitors.
Compounds of formula (LXII) also serves as a substrate for the preparation of tricarbonyl derivatives such as (LXI) (Scheme 18). Condensation of (LXII) with an aldehyde, such as benzaldehyde, gives an b-ene-a,g-dione.
This ene-dione can be oxidatively cleaved with reagents like ozone or periodate to give tricarbonyl analog (LXI).
The preparation of the mono- and dihalomethylketone thrombin inhibitors is outlined in Scheme 20. The intermediates formed in the preparation of the a-mono- and a,a-dihalo-b-ketoester thrombin inhibitors of Scheme 19 can be used in these preparations.
Scheme 20.
Ra Rs H Ra Rs H
I N C(O)CHJp C(O)C(J2)C02CH3 R~~N R~~N
Rs O ~ R3 O
X X
(LXIII) : J = halogen. H (LIX) : J = dihalogen (LXIV) : J = dihalogen (LVII) : J = halogen, H
The decarboxylation of these halogenation products, (LXIII) and (LXIV), can be effected by saponification of the ester with mild aqueous base such as potassium carbonate or sodium hydroxide in water miscible solvents like an _98_ SUBSTITUTE SHEET (RULE 26) WO 95109634 ~ 1 '~ 4 3 i 4 PCT/US94/11280 alcohol, tetrahydrofuran or N,N-dimethylformamide, followed by adjusting the pH to a range of 4 to 6. This mixture can be either stirred at ambient temperatures or heated at various temperatures up to the reflux point of the solvent chosen until the formation of (LVII) or (LIX) is complete and is similar to that reported in Matsuda et. al., Tetrahedron Lett. 30, 4259 (1989). Removal of protecting groups) can provide thrombin inhibitors corresponding to (LVII) or (LIX).
Compounds of the present invention wherein the electrophilic group A is an a-hydroxy ester are prepared according to Scheme 21. The appropriate amino acid (LXVI) is reduced to the corresponding alcohol (LxVII) via NaBH4 treatment of the mixed anhydride. (LXVII) is then oxidized to the aldehyde (LXVIII) utilizing a Swern oxidation.
(LXVIII) is converted to the thiocarbinol (XIX) via a lithiated orthoethylthioformate followed by conversion to the a-hydroxy methyl ester (LXX) upon treatment with mercuric salts. (LXX) is readily converted to the peptides of the invention via coupling with (IV) (M=H) to form (LXXI) under the conditions described in Scheme 3.

SUBSTITUTE SHEET (RULE 26) WO 95109634 PCTlUS94111280 ~1'~4314 Scheme 21.
O 1)IBCF OH 1) Oxalychloride 2)NMM 2)DMS
X OH 3)NaBHs ~ X 3)TEA
+ CH.,C1., n ~ 4)H30 n NHBOC -IO°c NHBOC DME
n = 2,3 -40°c LXVII
LXVI
THF O H
X -78°c X 1)HgO/HeCI., \H 1)n-BuLi n R MeOH
n NHBOC 2)HC(SEt)~ NHBOC Rt LXVIII 3)H30+ LXIX
OH

OCH3 n O
NH
n O LXXI
O N_ Ra NHBOC Ra RS R~ i The preparation of compounds of the present invention wherein A is an a-keto ester, a-keto acid or a-keto ester hemiacetal is shown in Scheme 22. (LXXI) is converted to the a-keto ester LXXIII via a Swern Oxidation. (LXXIII) is further elaborated to hemiketal (LXXIV) by treating with methanol or to (LXXV) by treatment with hydroxide.

SUBSTITUTE SHEET (RULE 26) ~"""'~ WO 95109634 ~ ~ 3 ~.4~. , '~ ; .., PCTIUS94I11280 Scheme 22.
CH2C12 1) Oxalychloiide -10°C 2)DMS
3)TEA

i n ~ O ~n ~ O
N H MeOH N H
p Rt LXXI11 R4 Rs N- R 4 N- R3 R R Rs Rii LiOH
MeOH/H20 RT
O
X OH
O
NH
O

LXXV R4 Rs R' ~
The compounds of the present invention wherein A is an alkyl carbinol (LXXVII) or an alkyl ketone (LXXVIII) are prepared according to Scheme 23. (LXVIII) is treated with an alkyl-CeCl2 to form the alkyl carbinol (LXXVII) which is then subjected to the Swern oxidation to yield the alkyl ketone (LXXVIII). (LXXVIII) is then further elaborated to the peptide compounds of the present invention (LXXX) by following the conditions outlined in Scheme 3.

SUBSTITUTE SHEET (RULE 26) WO 95109634 ~~ PCTIUS94I11280 Scheme 23.
1 )RLi "
LXVIII 2)CeCl3 X
3)H30+~ n R
THF NHBOC
_~g°c LXXVII
1) Oxalychloride 2)DMS X
R
3)TEA n I 0°c LXXVIII
R = alkyl O
n = 2,3 X
n ~ R
NH
O
N_Rs R4 R5 R> >
Compounds of the present invention wherein R3 is an optionally substituted thiophenylbenzoyl group (LXXXIII) are prepared according to Scheme 24. The desired thiophenol (LXXXII) is coupled to the bromobenzoic acid via a copper promoted coupling reaction to form (LXXXIII).
(LXXXIII) is then coupled to (IV) (M=H) under the conditions outlined in Scheme 3 to form (LXXXIV) which is then coupled to (LXXXVI) under the conditions outlined in Scheme 3 to form (LXXXV). It is understood that (LXxxv) need not be in final form and that any or all of the functional groups present may be converted to their desired final form using methods known to the skilled artisan.

SUBSTITUTE SHEET (RULE 26) Scheme 24.
1)Br O
/ SH -I ~ OH O OH
2)KOH
\ R 3Cu° / I S ~\
/
R
LXXXffI
X A X A R~i Ra O N R~

R
O~N I \ ~ ~I S~\ OH
R Ra R» /
S
i R- L~XXIV
Compounds of the present invention wherein R3 is an optionally substituted benzylbenzoyl group are prepared according to Scheme 25. An optionally substituted bromophenyl compound (LXXXVII) is converted to its phenyl lithium derivative and reacted with a bromobenzaldehyde to form the optionally substituted diphenylmethyl carbinol (LXXXVIII). (LXXXVIII) is further reduced to the substituted diphenylmethane (LXXXIX) with Et3SiH. (LXXXIX) is converted to XC. XC is then further elaborated to XCI and XCII by following the appropriate outline in previous schemes.

SUBSTITUTE SHEET (RULE 26) WO 95/09634 _ PCTIUS94/11280 9chamo 25 Br 1 ) t-BuLi 2) CHO OH
Br ~ 1)Et~SiH
I i w Z)rFA
.~~ . I I , ...-..
~.v RT
R Br L~DtXVII LXJO~CVIII
. / \ 1) t-BuLi l I -~.
I ~~ ~HO+ CO H
R z XC

O . R5 O
HO ~
-..~ N~ ~
l , ~,~
XCI

X~~A
In NH
O

XCZI
Inhibitors which contain a substituted phenethyl group as R11 are easily prepared according to Scheme 26. The appropriate phenylacetate (XCIV) is readily dialkylated with an excess of s small, unbranched alkyl halide (R18-X) and a suitable base such as potassium tert-butoxide to form an a,a-bisalkylated ester (XCVa). Reduction of XCVa to the SUBSTITUTE SHEET (RULE 26) ~1'~ 4314 primary alcohol may accomplished with many hydride reducing agents, a preferred agent being lithium aluminum hydride.
Oxidation of the alcohol under Swern conditions or with pyridinium chlorochromate affords the aldehyde (XCV).
(xCV) is best coupled to the appropriate glycine derivative by reductive amination, a preferred procedure being reduction with sodium cyanoborohydride. The resulting amine (XCVI) is then coupled with R3 by any of several standard amide bond forming reactions familiar to those 0 skilled in the art. A preferred method involves treating the amine with the appropriate acid chloride in the presence of a tertiary amine base, such as N-methylmorpholine or triethylamine. Saponification of the ester affords the carboxylic acid (XCVII).
75 The acid (XCVIIJ is then coupled to (LXxxVI) and elaborated to the inhibitors of the present invention by following the procedures outlined in Schemes 3, 4, and 5.
~ 105-SUBSTITUTE SHEET (RULE 26) Scheme 26.
O OEt Me02C R~ a R~ a Ra 1) RIgX, base \~ C H O R5 NH2 . HCI
(I
NaCNBH
R ' 2) reduction R 3 MeOH, pH 6 XCVa O OEt O O H
4 Ra R 1 ) R3X, base R
Rs N H 2) KOH _ ~~ I R~ N R3 MeOH/H20 R Ris R~s R R~e Rya XCVIa XCVIIa X~~ A
~' ~n NH
Ra XCVIIIa R
(\~ I Rs NR3 R \R Rye Inhibitors which contain a 1,w-alkanediyl substituted phenethyl group (XCVb) as R11 are easily prepared according to Scheme 27. This procedure is similar to that of Scheme 26, except that a 1,w-bifunctional alkylating agent (X-R18_ X) instead of a monofunctional alkylating agent (R1$-X).
In this manner, inhibitors of the present invention with the general formula (xCVIIIb) may be prepared.

SUBSTITUTE SHEET (RULE 26) WO 95/09634 ~ 1 ~ 4 3 I 4 pCT~S94/11280 Scheme 27.
O OEt Me02C
R
1) XR18X, base \~ C H O Rs NH2 . HCI
/. I /~ NaCNBH
R 2) reduction R
XCIV 3) fOl XCVb MeOH, pH 6 O OEt O OH

R R4 1) R3X. hale R R L~~XVI
Rs N H 2) KOH - , ~~ I R5 N R3 MeOH/Hz0 ~j~
R C~ R
~C~"~2)n (CH2)n XCVIb X _ A XCVBb Yn O NH

R XCVIIIb Rs NR3 /~
R
(CH2)n Inhibitors'in which R3 is an acylalkyl terminated by a carboxylic acid or ester (CI) are prepared by the general route described in Scheme 28. Reaction of a suitably substituted cyclic anhydride (C) with an alkoxide such as sodium benzyl oxide affords a mono-protected diacid tCI).
(CI) is then coupled to an appropriate N-alkylglycine derivative ((IV), (M=H) by any of a number of methods known to the skilled artisan. The choice of ester groups should allow for selective deprotection of the glycine carboxylate. Preferred ester groups are methyl or ethyl on the glycine carboxylate and benzyl on the acylalkyl chain, SUBSTITUTE SHEET (RULE 26) ~1'~~~1~
so that saponification gives the acid (CII). (CII) is then converted to the final products (CIII) following methods described in previous schemes.
Scheme 28.
R5 Ra O~ O O O 1) Me02C~NHR~i O
R~ ~R NaOBn ~ /R ~ coupling agent HO
OBn 2 a . base R R R ) 9 C CI
X A
O OH
R5 OII R OII ~ On NH CIII
4 N~/~~~\~OBn 5 O R O
R ~ R n R R ~
R> > 4 N~~~~~'~~OBn CII R ~ R n R
R~ i Tntermediate 1 N-Methyl-N-[(3-phenyl)propionyl]glycine Part A: To hydrocinnamic acid (10.0 g, 66.7 mmol) and 4-methylmorpholine (6.74 g, 66.7 mmol) in tetrahydrofuran (THF, 200 mL) at 0°C was added n-butylchloroformate. The reaction was maintained at 0°C for 15 minutes, and the hydrochloride salt of sarcosine ethyl ester (10.23 g, 66.7 mmol) followed by triethylamine (Et3N, 16.84 g, 166.8 mmol) was added. The reaction was allowed to thaw to ambient temperature and stirred for 18 hours. After this time, the solvent was removed and the residue partitioned between aqueous hydrochloric acid (HC1, 1 N, 200 mL) and ethyl acetate (EtOAc, 200 mL). The aqueous acid phase was extracted with additional EtOAc (200 mL), the combined SUBSTITUTE SHEET (RULE 26) organic extracts were washed with HCl (1 N, 100 mL), saturated sodium bicarbonate (NaHCO3, 100 mL) and brine (100 mL). The organic phase was dried over sodium sulfate and evaporated to give ethyl N-methyl-N-[(3-phenyl)propionyl]glycine (11.81 g, 71o yield). This material was used in the next step without further purification.
Part B: To a solution of ethyl N-methyl-N-[(3-phenyl)propionyl]glycine (11.81 g, 47.4 mmol) in ethanol (300 mL) was added aqueous sodium hydroxide (NaOH, 1 N, 94.8 mL, 94.8 mmol). The reaction was stirred at ambient temperature for 18 hour, afterwhich the solvent was removed by distillation in vacuo. The residue was dissolved in HC1 (1 N, 100 mL) and the solution extracted with methylene chloride (CH2C12, 2 x 100 mL). The extracts were dried over sodium sulfate (Na2S04), evaporated and the resulting solid (9.42 g) was recrystallized from EtOAc to give the title compound (7.14 g, 68~ yield) as a solid (mp: 123 - 126 °C).
Examr~le 21.1.3 Pinanediol N-{N-methyl-N-[(3-phenyl)propionyl]glycyl?-1-amido-5-aminopentaneboronate, benzenesulfonic acid salt Part A: A mixture of Intermediate 1 (0.31 g, 1.5 mmol), pinanediol 1-amino-5-bromopentaneboronate (0.57 g, 1.85 mmol>, 1-hydroxybenzotriazole (0.20 g, 1.5 mmol), 4-methylmorpholine (0.17 mL, 1.5 mmol), and 1,3-dicyclohexylcarbodiimide (DCC, 0.33 g,1.5 mmol) were - 30 stirred in dry CH2C12 at 0°C for 1 hour. The reaction was thawed to ambient temperature and stirred an additional 18 hour. After this time, the reaction mixture was diluted with CH2C12 (25 mL) and filtered. The filtrate was washed with aqueous citric acid (10 0) and saturated NaHC03 (25 mL
each), dried (Na2S04) and evaporated. The intermediate SUBSTITUTE SHEET (RULE 26) ~1743I4 WO 95/09634 PCTIUS94l11280 pinanediol N-{N-methyl-N-[(3-phenyl)propionyl]glycyl}-1-amido-5-bromopentaneboronate (0.75 g, 92o yield) was carried on to the next step without further purification.
Part B: The intermediate from Part A (0.75 g, 1.4 mmol) was heated with sodium azide (NaN3, 0.15 g, 2.3 mmol) in N,N-dimethylformamide (DMF, 10 mL) at 100°C for 2 hours.
The reaction mixture was partitioned between water (H20) and EtOAc (25 mL each), and the EtOAc layer was washed with additional H20 (6 x 15 mL). The organic layer was dried (Na2SOq) and evaporated to give pinanediol N-{N-methyl-N-[(3-phenyl)propionyl]glycyl}-1-amido-5-azidopentaneboronate (0.67 g) in 95o yield.
Part C: The azide from Part B (0.48 g, 0.9 mmol) was dissolved in methanol (MeOH, 15 mL) with benzenesulfonic acid (0.15 g, 0.9 mmol) and Pearlman's catalyst (palladium hydroxide on carbon, 0.05 g). This mixture was shaken under an atmosphere of 50 psi of hydrogen for 18 hours at ambient temperature. The reaction mixture was purged with nitrogen and the catalyst was removed by filtration through.a pad of diatomaceous earth. The clear filtrate was evaporated and pinanediol N-{N-methyl-N-[(3-phenyl)propionyl]glycyl}-1-amido-5-aminopentaneboronate was obtained as its benzenesulfonate salt (0.51 g) in 88o yield. High Res Mass Spec: found (M+H)+ 484.334758; calculated (M+H)+ _ 484.334663.
Intermediate 2 N-[(2-Phenyl)ethyl]-N-[(3-phenyl)propionyl]glycine Part A: A mixture of benzyl glycinate, p-toluenesulfonic acid salt (2.68 g, 7.94 mmol), (2-phenyl)bromoethane (0.98 g, 5.29 mmol), and solid NaHC03 (1.56 g, 18.5 mmol) in acetonitrile (25 mL) were heated at reflux for 18 hour.

SUBSTITUTE SHEET (RULE 26) °

"~"° WO 95109634 , v y , + PCT/US94/11280 The reaction was concentrated and diluted with EtOAc (25 mL). The organic solution was washed with H20 (25 mL) and brine (25 mL), dried (Na2S04) and concentrated in vacuo.
The residue was purified by elution through a pad of silica gel with a gradient mixture of hexane:EtOAc. The intermediate benzyl N-((2-phenyl)ethyl]-glycinate (0.82 g) was obtained in 38o yield. Low Res MS: (M+H)+ = 270.
Part B: A mixture of intermediate from Part A (0.82 g, 3.04 mmol) and 4-methylmorpholine (0.62 g, 6.08 mmol) in THF (15 mL) at 0°C was added hydrocinnamoyl chloride (0.51 g, 3.04 mmol). The reaction was thawed to ambient temperature and stirred for 1 hour. The reaction mixture was diluted with EtOAc (50 mL), washed with HC1 (100, 25 mL) and NaHC03 (saturated, 25 mL), dried (MgS04) and evaporated. The intermediate benzyl N-((2-phenyl)ethyl]-N-[(3-phenyl)-propionyl]glycinate (1.2 g) prepared was used in the next procedure without further purification. LRMS:
(M+NH3)+ = 419.0, (M+H)+ = 402.1.
Part B A methanol solution (20 mL) of benzyl N-[(2-phenyl)ethyl]-N-((3-phenyl)propionyl]glycinate (1.3 g, 3.24 mmol) and palladium on carbon (10a, 180 mg) was stirred under 1 atmosphere of hydrogen gas for 18 hours. The reaction was purged with nitrogen and filtered through a pad of diatomaceous earth and evaporated to give N-[(2-phenyl)ethyl]-N-[(3-phenyl)propionyl]glycine (1.0 g) in quantitative yield. LRMS . (M+NH3)+ = 326.
' 30 Example 23.1.3 Pinanediol N-{N-[(2-phenyl)ethyl]-N-[(3-. phenyl)propionyl]glycyl}-1-amido-S-aminopentaneboronate, hydrochloride salt -111- .
SUBSTITUTE SHEET (RULE 26) WO 95109634 ~ ~ ~ PCTIUS94111280 Part A: To a solution of N-((2-phenyl)ethyl]-N-[(3-phenyl)propionyl]glycine (1.0 g 3.24 mmol) and 4-methylmorpholine (0.66 g, 6.48 mmol) in THF (15 mL) at 0°C
was added isobutylchloroformate (0.44 g, 3.24 mmol). The reaction was stirred for 15 min at 0°C, pinanediol 1-amino-5-bromopentaneboronate (1.23 g, 3.24 mmol) was added followed by additional 4-methylmorpholine (0.33 g, 3.24 mmol)and the reaction was stirred at ambient temperature for 18 hours. The reaction was diluted with EtOAc (50 mL), washed sequentially with HC1 (100) and NaHC03 (saturated) and brine (25 mL each), then dried over magnesium sulfate (MgS04) and evaporated. The residue was purified by flash chromatography (silica gel) using 3:1 EtOAc:hexane to give pinanediol N-{N-[(2-phenyl)ethyl]-N-[(3-phenyl)propionyl]glycyl)-1-amido-5-bromopentaneboronate (0.8 g) in 43o yield. LRMS: (M+H)* = 637/638, (M-HBr)* _ 557.
Part B: The intermediate pinanediol N-{N-[(2-phenyl)ethyl]-N-[(3-phenyl)propionyl]glycyl)-1-amido-5-bromopentaneboronate (0.8 g, 1.4 mmol) and NaN3 (0.11 g, 1.7 mmol) in DMF (10 mL) was stirred at 100°C for 2 h. The cooled reaction mixture was diluted with EtOAc (50 mL), then it was washed with H20 (6 x 20 mL) and dried (MgS04).
The EtOAc solution was evaporated to give pinanediol N-{N-[(2-phenyl)ethyl]-N-[(3-phenyl)propionyl]glycyl}-1-amido-5-azidopentaneboronate (0.7 g) in 86o yield. LRMS . (M+H)* _ 600.
Part C: A mixture of the product from Part B (0.7 g, 1.2 mmol) and Pearlman's catalyst (0.1 g) in HC1 (1.2 N, 1 mL, 1.2 mmol) and MeOH (20 mL) was stirred under an atmosphere of hydrogen (1 atm) for 2 hours. The reaction mixture was purged with nitrogen, filtered through a pad of diatomaceous earth and evaporated. The residue was dried SUBSTITUTE SHEET (RULE 26) .. WO 95109634 ~ PCT/US94/11280 w by azeotropic distillation with benzene and triturated with hexane to give the title compound (0.45 g> as a yellow powder in 67o yield. LRMS: (M+H)+ = 574.4 .
Example 8.1.3 N-(N-[(2-Phenyl)ethyl]-N-[(3-phenyl)propionyl)glycyl}-1-amido-5-aminopentaneboronic acid, hydrogen chloride salt A mixture of Example 23.1.3 (0.45 g, 0.8 mmol) in diethyl ether(Et20): H20 (15 mL:lS mL) was stirred with phenylboric acid (0.45 g, 3.7 mmol) at ambient temperature for 18 hours. The phases were separated, the Et20 layer was discarded, and the H20 layer was washed with Et20 (15 mL) and 1:1 hexane:EtOAc (15 mL). The H20 solution was concentrated by distillation under reduced pressure anddried by azeotropic distillation with toluene. The dried residue was dissolved in a minimal amount of CH2C12 and the title compound was precipitated from solution by the addition of hexane. LRMS: (M+H of glycerol ester)+ _ 496.
Intermediate 3 N-methyl-N-[(3,4-dichlorophenyl)acetyl]glycine The title compound was prepared from commercially available sarcosine ethyl ester and 3,4-dichlorophenylacetic acid according to the procedure of Intermediate 1.
Example 50 Pinanediol N-(N-methyl-N-[(3,4-dichlorophenyl) acetyl]glycyl}-1-amido-4-formamidinobutaneboronate, hydrochloride salt Part A: By substituting pinanediol 1-amino-4-bromobutaneboronate for pinanediol 1-amino=5-SUBSTITUTE SHEET (RULE 26) bromopentaneboronate and coupling with Intermediate 3 according to the procedure in Example 21.1.3, Parts A-C, the amino intermediate was prepared.
Part B: To an ethanol solution (20 mL) of the product from Part A (600 mg, 1.2 mmol) was added ethylformimidate hydrogen chloride (400 mg, 3.62 mmol) and 4-dimethylamino pyridine (DMAP, 442 mg, 3.62 mmol). This mixture was heated at reflux for 5 hours, and the reaction mixture was evaporated. The residue was chromatographed (Sephedex LH
20, MeOH elutant) to give the title compound as a yellow solid. LRMS: (M+H)+ = 551.
Example 51 Pinanediol N-ZN-methyl-N-[(3,4-dichlorophenyl) acetyl]glycyl]-1-amido-4-guanidinobutaneboronate, hydrochloride salt Part A: The intermediate from Example 50, Part A
hydrochloride salt (1.0 g, 2 mmol), formamidine sulfonic acid (0.496 g, 4 mmol) and DMAP (0.488 g, 4 mmol) in ethanol (50 mL) were heated at reflux for 3 hours. The reaction was cooled to ambient temperature, filtered through a pad of Celite, rinsed with chloroform (CHC13) and evaporated. The residue was dissolved in CHC13 and washed with HC1 (0.1 N) and brine, dried and evaporated. The title compound was obtained as a white solid. HRMS calcd for C26H3gBN504C12:582.247216+; found: 566.247905.
Intermediate 4 Pinanediol 1-amino-2-(3-cyanophenyl)ethylboronate, hydrochloride salt SUBSTITUTE SHEET (RULE 26) -~"'° WO 95/09634 ~ 1'~ 4 314 PCTJUS94/11280 Part A: The intermediate, C1-CH(CH2-(m-cyanophenyl)]B02-C1oH16, was prepared from m-cyanobenzyl bromide and dichloromethyl boronate pinanediol. Zinc dust (1.0 g) in THF (1 mL) was cooled to 0-5°C and a solution of m-cyanobenzyl bromide (1.37 g, 7.0 mmol) in THF (7 mL) was added dropwise (5 sec/drop). The reaction mixture was allowed to stir at 5°C for 2 hours. A mixture consisting . of lithium bromide (Liar, 1.22 g, 14 mmol), copper(I) cyanide (CuCN, 0.63 g, 7.0 mmol) and THF (6 mL> was placed in a 50 mL flask and cooled to -40°C; the benzylic organozinc reagent was added by cannulation. The mixture was allowed to warm to -20°C and stir for 5 minutes.
Following cooling to -78°C, neat dichloromethyl boronic acid pinanediol (1.47 g, 5.6 mmol) was added dropwise and the resulting mixture was stirred at -78°C for 2 h, and additionally at room temperature for 2 days. Aqueous ammonium chloride (NH4C1, saturated, 20 mL) was added to the mixture and the aqueous solution was extracted with Et20 (3 x 20 mL). The combined organic layers was dried over anhydrous MgSOq and evaporated in vacuo to give crude compound (1.8 g). Purification was carried out using silica gel chromatography where the column was stepwise eluted with hexane (100 mL) and then 15o ether in hexane (200 mL) to give the desired product (0.53 g) in 27o yield.
LRMS(NH3-CI) m/e for M+NH4+ calcd. for C1gH23N02BC1: 361.2;
found: 361.1.
Part B: To a solution of hexamethyldisilazane (0.21 mL, 0.98 mmol) in THF (2 mL) at -78°C was added n-butyllithium (1.45 M, 0.67 mL, 0.98 mmol). The solution was allowed to slowly warm to room temperature to ensure the anion generation was complete and recooled to -78°C, upon which a solution of product from Part A (0.33 g, 0.98 mmol) in THF
(2 mL) was added. The mixture was allowed to warm to room temperature and to stir overnight. The volatiles were SUBSTITUTE SHEET (RULE 26) ~1'~431~
evaporated and hexane (8 mL) was added to give a suspension. Anhydrous hydrogen chloride in dioxane (4.1 N, 1.5 mL, 6.0 mmol) was added at -78°C and the mixture was slowly warmed to room temperature and stirred for 2 hour.
Additional hexane (6 mL) was added and crude product was isolated as a precipitate. This product was dissolved in CHC13 and insoluble material was removed by filtration.
The filtrate was evaporated at a reduced pressure to give an oil t-0.2 g). Final purification was achieved by chromatography on a column of SephedexT"'' LH 20 column using MeOH as a solvent. H-boroPhe(m-CN)-C1pH16~HC1 was obtained as an oil (0.12 g) in 34o yield. HRMS(NH3-CI) m/e (M+H)+
calcd. for C19H26BN202: 325.2087; found: 325.2094.

example 52 Pinanediol N-{N-methyl-N-[(3,4 dichlorophenyl)acetyl]glycyl}-1-amido-2-(3 cyanophenyl)ethylboronate Part A: To Intermediate 3 (0.77 g, 2.8 mmol) and 4-methylmorpholine (0.28 g, 2.8 mmol) in THF (50 mL) at -20°C
was added isobutylchloroformate (0.38 g, 2.8 mmol). After minutes at -20°C, the cold solution was added to a -20°C
solution of Intermediate 4 (1.0 g, 2.8 mmol) and Et3N (0.28 g, 2.8 mmol) in CHC13 (50 mL). This mixture was maintained at -20°C for 5 hours and stirred at ambient temperature for 18 hours. The reaction was filtered and concentrated in vacuo. The residue was dissolved in EtOAc, washed with HC1 (0.1N), saturated NaHC03 and brine. After the solution was dried and evaporated, the resulting yellow solid was applied to a column of Florisil and the desired product eluted with a gradient of CHC13: MeOH (Oo MeOH to 7o MeOH).
The title compound was obtained as a white solid. HRMS:

SUBSTITUTE SHEET (RULE 26) ~°"~ WO 95/09634 PCT/US94I11280 ~1"~ 4314 k. ., calcd. (M+H)+ for C3pH35BN30qC12: 582.209768; found:
582.209631.
Example 53 Pinanediol N-(N-methyl-N-[(3-phenyl)propionyl]glycyl}-1 amido-4-(N-methylguanidino)butylboronate, hydrochloride salt Part A: Pinanediol N-{N-methyl-N-[(3-phenyl)propionyl]glycyl}-1-amido-4-aminobutylboronate, hydrochloride salt was prepared by the method outlined for Example 21.1.3, wherein pinanediol 1-amino-4-bromobutylboronate hydrochloride was used instead of pinanediol 1-amino-5-bromopentane-boronate hydrochloride.
Part B: To a solution of the product from Part A (0.45 g, 0.89 mmol) in ethanol (10 mL) was added DMAP (0.22 g, 1.78 mmol). After 15 minutes at room temperature, N-methylaminoiminomethanesulfonic acid (0.25 g, 1.78 mmol) was added and the resulting suspension stirred at reflux for 5 hours. The reaction was cooled to room temperature, filtered, the precipitate washed with CHC13 and the combined filtrate concentrated under vacuum. The resulting oil was dissolved in CHC13 (40 mL> and the organic solution washed with ice cold HC1 (0.1 M, 1x10 mL), ice cold H20 (1x10 mL), brine and dried (MgS04). The filtered solution was concentrated in vacuo to give of the desired N-methyl guanidino compound (0.35 g) in 70o yield. The material was purified through a florisil column using 10% MeOH/CHC13 as eluant to give the purified product (0.22 g); LRMS: (M+H)+:
526 .

SUBSTITUTE SHEET (RULE 26) WO 95109634 PGTIUS94111=80 2~743~4 FxamDle 54 Ac-ID)Phe-Sar-boroLys-OH
Part A: Boc-(DIPhe-OH (6.9 g, 26 mmoles)was dissolved in THF (50 mL) and 4-methylmorpholine (2.86 mL, 26 mmoles) was added. The solution was cooled to -20°C and isobutylchloroformate (3.38 ml, 26 mmoles) was added.
After stirring 5 minutes at -20°C, the mixture was added to a cold solution of H-Sar-Hzl~toluenesulfonic acid dissolved in CHC13 (50 mL), followed by Et3N (3.6 mL, 26 mmoles).
The mixture was allowed to stir for 1 hour at -20°C and 2 h at room temperature. The solids were removed by filtration and the solvent was removed by evaporation. The residue was dissolved in EtOAC and was washed with HCl (0.20 N), NaHCO3 (5%), and brine. The solution was dried over anhydrous Na2S04, filtered, and evaporated to yield Boc-In)Phe-Sar-O-Bzl as thick oil (10.4 g).
Part B: The product from Part A 110.4 g) was dissolved in MeOH 1100 mL) and the sample was hydrogenated for 2 hour on a Parr apparatus in the presence of palladium on carbon (i0%, 0.5 g). The catalysis was removed by filtration and solvent was evaporated to yield Boc-(D)Phe-Sar-OH as a foam (7.8 g) .
Part C: The mixed anhydride of product from Part B (4.42 g, 13.1 mmoles) was prepared as previously described and coupled to NH2-CH[(CH2)qBr1802C10H16~HC1 (5.0 g, 13.1 mmoles) using the procedure described in Part A. The crude product 17.7 g) was purified by chromatography of a 4.2 g portion on a 2.5 x 100 cm column of Sephedex'" LH-20 using MeOH as a solvent to give Boc-(D)Phe-Sar-NH-CH[(CHa),-Br) BOzCloHls .
.11a-SUBSTITUTE SHEET (RULE 26) WO 95109634 ~ 1 ~ 4 ~ i ,~ PCTIUS94111280 Part D: The product from Part C 13.5 g, 5.8 mmoles) was dissolved in anhydrous HC1 in dioxane (4.1 N, 50 mL) and was stirred for 1 hour at room temperature. Solvent and excess HC1 were removed by evaporation. The residue was triturated with hexane to yield H-(D)Phe-Sar-NH-CH((CH2)4-Br]B02C1pH16~HC1 (2.9 g).
Part E: The product from Part D (2.9 g, 4.8 mmoles) was dissolved in 30 mL of a 500 (v/v) solution of dioxane:
water and acetic anhydride (0.92 ml, 9.7 mmoles) was added.
NaHC03 (0.81 g, 9.7 mmoles) was added and the solution was allowed to stir 45 minutes at room temperature. Acetic acid (3 ml) was added and solution was concentrated approximately 50o by evaporation. It was diluted to 100 mL
with EtOAc and was washed with NaHC03 (50), HC1 (0.2 N), and brine. The organic phase was dried over anhydrous Na2S04, filtered, and evaporated to yield Ac-(D)Phe-Sar-NH-CH[(CH2)q-Br]B02C1OH16 as a foam (2.7 g). HRMS calcd for C2gH43N305BBr (M+H): 604.2557; found: 604.2558.
Part F: The product from Part E (2.5 g, 4.1 mmoles) and NaN3 (0.54 g, 8.3 mmoles) were dissolved in DMF (5 mL) and heated at 100°C for 1 hour. The reaction was allowed to cool and was diluted with EtOAc (100 mL). The organic phase was washed with H20 and saturated brine, dried over Na2S04, filtered, and evaporated to yield Ac-(D)Phe-Sar-NH-CH[(CH2)4-N3]B02C1pH16 as a white foam (2.2 g).
Part G: The product from Part F (2.0 g, 3.5 mmoles) was dissolved in MeOH (100 mL) and was hydrogenated on a Parr apparatus in the presence of HCl in dioxane (4.1 N, 1.3 ml, 5.3 mmoles) and palladium on carbon (100, 0.5 g). The catalysis was removed by filtration and solvent was removed by evaporation. The product, Ac-(n)Phe-Pro-boroLys-C1pH16~HC1 (Ac-(D)Phe-Sar-NH-CH[(CH2)4-NH2]B02C1pH16~HC1), SUBSTITUTE SHEET (RULE 26) WO 95/0963.1 PC17OS94/11Z80 was purified by chromatography on 2.5 X 100 cm column of LH-20 in MeOH to yield 1.8 g.
Part H: The product from Part G (1.5 g, 2.5 mmoles) and phenyl boronic acid (1.5 g, 12 mmoles) was dissolved in H2o and Et20 (15 ml each). The mixture was stoppered and allowed to stir for 3 hour at room temperature. The phases were separated and the aqueous phase was Washed extensively with Et20. The aqueous phase was evaporated, dried in vacuo., and triturated with Et20 to yield the title compound (0.98 g). An analytical sample was prepared as the pinacol ester by treating 4 mg of the boronic acid with 2 equivalents of pinacol in 1.4 ml of MeOH for 5 minutes and evaporating solvent. HRMS calcd.for the pinacol ester C25H41N4058 lM+H): 489.3248. found: 489.3242.
Example 55 Pinanediol N-(N-2-propyl-N-[(3-phenyl>propionyl)glycyl)-1-amido-5-aminopentaneboronate, hydrochloride salt Part A: A mixture of glycine methyl ester hydrochloride 13.83 g, 30.5 mmol), acetone (1.77 g, 30.5 mmol) and NaOH
11.22 g, 30.5 mmol) in MeOH (200 mL) was stirred under an atmosphere of hydrogen (1 atm) in the presence of palladium on carbon (10%, 0.4 g) for 29 hours. The reaction was flushed with nitrogen and filtered through a Celite'" pad, acidified with HC1 (1N), dried (MgSO,) and evaporated.
Trituration of the residue with Et,O gave N-2-propylglycine methyl ester hydrochloride (1.0 g) as an off-white solid; LRMS
(M+H)* = 132.1.
Part B: To the hydrochloride salt prepared above (1.0 g, 5.97 mmol) and hydrocinnamic acid (0.9 g, 5.97 mmol) in DMF
( 20 mL ) was added O-benzotriazole-h~, N, N ~ , N ~ -SUBSTITUTE SHEET (RULE 26) WO 95109634 217 4 3 i 4 . . PCTlUS94111280 tetramethyluronium hexafluorophosphate (2.26 g, 5.97 mmol) followed by N,N-diisopropylethylamine (1.69 g, 13.1 mmol).
The reaction was stirred at ambient temperature for 48 hours. The reaction mixture was diluted with 1:1 EtOAc:hexane and washed with H20 (2 x), HC1 (10~) , saturated NaHC03 and brine. The solution was dried (MgS04), evaporated, and combined with an additional material obtained by the same acylation procedure. The combined batches were purified by flash chromatography on silica gel with 2:1 hexane:EtOAc as the eluent. There was obtained N-2-propyl-N-[(3-phenyl)propionyl]glycine methyl ester (2.8 g); LRMS (M+H>+ = 264Ø
Part C: A mixture of the ester from Part B (2.8 g, 10.52 mmol) and LiOH monohydrate in THF:H20 (20 mL:lO mL) was stirred at ambient temperature for 18 hours. The reaction was diluted with H20 and washed with 1:1 hexane:EtOAc and the organic washings were discarded. The aqueous layer was acidified with HC1 (l00) and extracted with EtOAc. The EtOAc extract was washed with brine, dried (MgSOq) and evaporated to give N-2-propyl-N-[(3-phenyl)propionyl]glycine (2.0 g); LRMS (M+H)+ = 250.1.
Part D: N-2-propyl-N-[(3-phenyl)propionyl)glycine was reacted with pinanediol 1-amino-5-bromopentaneboronate according to the procedure of Example 23.1.3 to prepare pinanediol N-{N-2-isopropyl-N-[(3-phenyl)propionyl]glycyl}-1-amido-5-bromopentaneboronate; LRMS (M+H)+ = 575/577.
Part E-F: This material was reacted with NaN3 according to the procedure in Example 23.1.3 to give pinanediol N-{N-2-isopropyl-N-[(3-phenyl)propionyl]glycyl}-1-amido-5-azidopentaneboronate; LRMS (M+H)+ = 538.3. The azide was hydrogenated under the conditions in Example 23.1.3 to give the title compound, pinanediol N-{N-2-propyl-N-[(3-SUBSTITUTE SHEET (RULE 26) WO 95109634 *~ '~'~' (~ ~ ~ ~ PCTlUS94/11280 phenyl)propionyl]-glycyl}-1-amido-5-aminopentaneboronate hydrochloride; LRMS (M+H)+ = 512.
Example 56 N-{N-2-propyl-N-[(3-phenyl)propionyl]glycyl]-1-amido 5-aminopentaneboronic acid, hydrochloride salt Part A: N-{N-2-propyl-N-[(3-phenyl)propionyl]glycyl}-1-amido-5-aminopentane-boronic acid, hydrochloride salt, was prepared from pinanediol N-{N-2-propyl-N-[(3-phenyl)propionyl]glycyl]-1-amido-5-aminopentaneboronate, hydrochloride salt by the procedure of Example 8.1.3; LRMS
(M+H-H20)+ = 360.1, (M+H-2H20)+ = 342Ø
Examr~le 57 Pinanediol N-(N-methyl-N-[2-(methylphenyl)benzoyl]glycyl]
1-amido-5-aminopentaneboronate, hydrochloride salt Part A: A mixture of 2-(methylphenyl)benzoic acid (3.09 g, 14.55 mmol), sarcosine ethyl ester hydrochloride salt (2.23 g, 14.55 mmol), DCC (3.0 g, 14.55 mmol), HOST (1.97 g, 14.55 mmol) and Et3N (1.47 g, 14.55 mmol) in THF (50 mL) were stirred at ambient temperature for 48 hours. The reaction was evaporated and the residue dissolved in EtOAc.
The EtOAc solution was washed with HCl (100), saturated NaHC03 and brine, and dried (MgS04). The EtOAc solution was filtered through a plug of silica gel follwoed by a second filtration through a plug of neutral alumina.
Evaporation of the solution gave N-methyl-N-[2-(methylphenyl)benzoyl]glycine ethyl ester (4.5 g); LRMS
(M+H)+ = 312.2.

SUBSTITUTE SHEET (RULE 26) ..~,. WO 95!09634 ~ ~.'~ 4 ~ I 4 ~ PCTlUS94111280 Part B: N-methyl-N-[2-(methylphenyl)benzoyl]glycine ethyl ester (4.5 g, 14.45 mmol) and KOH (2.43 g, 43.4 mmol) in MeOH/H20 (200 mL/50 mL) were heated at reflux for 45 minutes. The solvent was removed and the residue dissolved in H20. The aqueous solution was washed with Et20 and acidified with HC1 (10%). The acidified aqueous layer was extracted with EtOAC, the EtOAc extract was washed with brine (2 x), dried over (MgS04) and evaporated. There was obtained N-methyl-N-[2-(methylphenyl)benzoyl)glycine (2.0 g); LRMS (M+H)+ = 284.1, (M+NH4)+ = 301.1 Part C-E: Pinanediol N-{N-methyl-N-[2-(methylphenyl)benzoyl)glycyl}-1-amido-5-bromopentaneboronate was prepared by reaction of N-methyl-N-[2-(methylphenyl)benzoyl)glycine with pinanediol 1-amino-5-bromopentaneboronate according to the procedure of Example 23.1.3; LRMS (M+H)+ = 611.2. Pinanediol N-{N-methyl-N-[2-(methylphenyl)benzoyl)glycyl}-1-amido-5-bromopentaneboronate was reacted withe NaN3 by under the conditions detailed above to give pinanediol N-{N-methyl-N-[2-(methylphenyl)benzoyl]glycyl}-1-amido-5-azidopentaneboronate; LRMS (M+H)+ = 572.4. Hydrogenation of the azide was effected by the conditions previously described to give the title compound, pinanediol N-{N-methyl-N-[2-(methylphenyl)benzoyl]glycyl}-1-amido-5-amino-pentaneboronate, hydrochloride acid salt; LRMS (M+H)+
546.3.
Example 35.5.3 Part A: Trimethylsilyl cyanide (5.80 mL, 44.0 mmol) was added dropwise to a solution of benzaldehyde (3.10 g, 29.0 mmol) and zinc iodide 1280 mg, 8.80 mmol) at 0 °C. The reaction mixture was warmed to room temperature over 18 h SUBSTITUTE SHEET (RULE 26) ~1~~3~4 then treated with saturated aqueous NaHC03 (ca. 100 mL).
The layers were separated and the aqueous was extracted with EtOAc (2 x 75 mL). The combined organics were washed with saturated aqueous NaCl (1 x 50 mL), dried (Na2S04), and concentrated under reduced pressure to give 3.78 g of 2-[(trimethylsilyl)oxy]-phenylacetonitrile as an oil, which was carried on without purification.
Lithium aluminum hydride (2.10 g, 55.0 mmol) was added in portions over 15 min to a solution of [2 -(trimethylsilyl)oxy]-phenylacetonitrile (3.75 g, 18.3 mmol) in anhydrous THF (75 mL) at 0 °C. The reaction was quenched by the sequential addition of H20 (2.10 mL), 10~
aqueous NaOH (2.10 mL), and H20 (6.30 mL) then dried (Na2S04) and filtered through a pad of Celite using EtOAc (ca. 75 mL). The filtrate was concentrated under reduced pressure to provide an oil which was purified by flash chromatography, elution with 9:1 CH2C12-MeOH containing 2~
Et3N, to give 2-hydroxy-1-phenethylamine (2.40 g) as an oil in 95~ yield. (1H NMR, 300 MHz) d 7.32 (comp, 5H), 4.66 (dd, 1H, J = 7.8, 4.0 Hz), 3.03 (dd, 1H, J = 12.5, 4.0 Hz).
2.83 (dd, 1H, J = 12.5, 9.1 Hz), 2.46 (br s, 3H). LRMS 155 (M+NH4), 138 (M+H).
Part B: Phosgene (6.0 mL of a 1.93 M solution in toluene (PhCH3), 12.0 mmol) was added to a solution of 2-hydroxy-1-phenethylamine (1.18 g, 8.60 mmol) in PhCH3 (100 mL) at 0 °C followed by the dropwise additon of Et3N (1.80 mL, 13.0 mmol). The reaction mixture was warmed to room temperature over 48 h and poured into EtOAc (ca. 200 mL). The layers were separated and the aqueous was extracted with EtOAc (1 x 50 mL). The combined organics were washed with saturated aqueous NaCl (1 x 100 mL), dried (Na2S04) and concentrated under reduced pressure to give 5-phenyl-2-oxazolidinone (1.05 g) as a solid in 75% yield. (1H NMR, 300 MHz) d 7.39 (comp, 5H), 5.69 (br s, 1H), 5.63 (dd, 1H, J = 8.4, 8.1 SUBSTITUTE SHEET (RULE 26) ~1"1434 .....- WO 95/09634 PCT/US94/11280 Hz), 3.99 (dd, 1H, J = 8.4, 8.1 Hz), 3.55 (dd, 1H, J = 8.4, 8.1 Hz). LRMS 181 (M+NHq), 164 (M+H).
Part C: A solution of 5-phenyl-2-oxazolidinone (500 mg, 3.1 mmol) in anhydrous THF was added dropwise to a ' suspension of NaH (91 mg, 3.7 mmol) in anhydrous THF at 0 °C. The reaction mixture was warmed to room temperature over 30 min then heated at reflux for 15 min. Methyl bromoacetate (0.32 mL, 3.4 mmol) was added and the mixtue was heated at reflux for 2h. The reaction mixture was cooled to room temperature and quenched with H20 (ca. 20 mL). The aqueous, was extracted with EtOAc (2 x 75 mL).
The combined organics were washed with saturated aqueous NaCl (1 x 50 mL), dried (MgSOq), and concentrated under reduced pressure to give an oil which was purified by flash chromatography, elution with 3:1 EtOAc-hexanes, to provide 2-[3-(5-phenyl-2-oxazolidino))-acetic acid, methyl ester (545 mg) as an oil in 76o yield. (1H NMR, 300 MHz) c3 7.42 (comp, 5H), 5.56 (dd, 1H, J = 8.4, 8.1 Hz), 4.10 (d, 2H, J
- 3.0 Hz), 4.06 (dd, 1H, J = 8.4, 8.1 Hz), 3.78 (s, 3H), 3.64 (dd, 1H, J = 8.4, 8.1 Hz). LRMS 253 (M+NH4, base), 236 (M+H).
Part D: A solution of 2-[3-(5-phenyl-2-oxazolidino)]acetic acid, methyl ester (540 mg, 2.30 mmol) in MeOH (10 mL) and H20 (10 mL) was treated with NaOH (138 mg, 3.40 mmol) and heated at reflux for 15 min. The reaction mixture was cooled to room temperature, acidified to pH 2 with 2M aqueous HC1, and extracted with EtOAc (3 x 50 mL). The combined organics were washed with saturated aqueous NaCl (1 x 25 mL), dried (MgS04), and concentrated to give 2-[3-(5-Phenyl-2-oxazolidino)]acetic Acid (505 mg) as an oil in 99o yield. (1H NMR, 300 MHz) d 7.41 (comp, 5H), 5.57 (dd, 1H, J = 8.0, 8.0 Hz), 4.15 (s, 2H), 4-.05 SUBSTITUTE SHEET (RULE 26) WO 95/09634 ~ ~ ~ ~ ~ PCTIUS94l11280 (dd, 1H, J = 8Ø 8.0 Hz), 3.65 (dd, 1H, J = 8.0, 8.0 Hz).
LRMS 239 (M+NH4, base), 222 (M+H).
Part E: Triethylamine (0.23 mL, 1.60 mmol> was added to a mixture of (2R)-4-bromo-1-aminobutane-1-boronic acid, (+)-pinanediol ester hydrochloride (540 mg, 1.47 mmol), HOBT
(200 mg, 1.47 mmol), DCC (300 mg, 1.47 mmol), and 2-[3-(5-phenyl-2-oxazolidino)]acetic acid (325 mg, 1.47 mmol) in anhydrous THF (12 mL) and anhydrous DMF (3 mL) at 0 °C.
The reaction mixture was warmed to room temperature over 18 h, diluted with Et20 (ca. 30 mL), and filtered through Celite with additional Et20 (ca. 50 mL). The filtrate was washed with H20 (3 x 25 mL), saturated aqueous NaCl (1 x 25 mL), dried (NaZSOq), and concentrated under reduced pressure to give (2R)-2-[[3-(5-phenyl-2-oxazolidino)]-acetamido)-4-bromo-1-aminobutane-1-boronic acid, (+)-pinanediol ester (770 mg) as a foam in 98o yield. LRMS
535, 533 (M+H) 453 (base).
Part F: A solution of (2R)-2-[[3-(5-phenyl-2-oxazolidino)]-acetamido]-4-bromo-1-aminobutane-1-boronic acid, (+)-pinanediol ester (770 mg, 1.45 mmol) and thiourea (220 mg, 2.90 mmol) in EtOH (15 mL) was heated at reflux for 36 hours then cooled to room temperature and diluted with Et20 (ca. 100 mL) which was decanted. The residue was purified by size exclusion chromatography on Sephadex LH -20, elution~with MeOH, to give a foam. The foam was dissolved in 5 mL of anhydrous THF and treated with Et20 (ca. 30 mL) to give a solid that was washed with Et20 (ca.
10 mL) and dried to afford the title compound (180 mg) as a white powder in 21o yield, mp 93 - 96 °C. LRMS 529 (M+1, base); HRMS Calcd for C26H3gBN405S: 529.2656. Found:
529.2644.

SUBSTITUTE SHEET (RULE 26) ,. WO 95109634 ,, PCTlUS94111280 Example 35.6.2 A solution of (2R)-2-((3-(5-phenethyl-2-oxazolidino)]-acetamido]-4-bromo-1-aminobutane-1-boronic acid, (+)-pinanediol ester (710 mg, 1.27 mmol) was prepared by an analogous method to that reported for Example 35.5.3, however substituting hydrocinnamaldehyde for benzaldehyde.
Further reaction with thiourea (190 mg, 2.50 mmol) in EtOH
(13 mL) was heated at reflux for 36 h then cooled to room temperature and diluted with Et20 (ca. 200 mL) which was decanted. The residue was purified by size exclusion chromatography on Sephadex LH - 20, elution with MeOH, to give a foam. The foam was dissolved in 5 mL of anhydrous THF and treated with Et20 (ca. 40 mL) to give a solid that was washed with Et20 (ca. 10 mL) and dried to afford the title compound (150 mg) as a white powder in 19~ yield, mp 93 - 96 °C. LRMS 557 (M+H, base); HRMS Calcd for C2gHq2BNq05S: 557.2969. Found: 557.2965.
Example 59 Part A: A mixture of 1,8-napthalic anhydride (1.0 g, 5.1 mmol), glycine (0.42g, 5.6 mmol) and camphorsulfonic acid (ca. 100 mg) was suspended in absolute EtOH (60 mL) and DMF (20 mL). The reaction mixture was heated at reflux for 72 h, then the solvent removed by distillation in vacuo.
The residue was diluted with H20 (10 mL), acidified with HC1 (1~1) to pH = 3 and the resulting solid was isolated by filtration and air dried. There was obtained N,N-(1,8-napthyldiimido)-glycine (1.22 g) in 95o yield. LRMS .
(M+H)+ = 256 ; mp 278-279 °C.

SUBSTITUTE SHEET (RULE 26) ~1'~~~L~

An alternative to the above prepartion of N,N-(1,8-napthyldiimido)glycine would be to react the sodium salt of 1,8-napthalic phthalimide with ethyl bromoacetate in dimethylformamide at 60°C. The resulting ester can then be hydrolyzed with 1N_ sodium hydroxide in ethanol solution to give the title compound.
Part B: N,N-(1,8-Napthyldiimido)glycine (0.56 g, 2.1 mmol) and N-methylmorpholine (0.53 mL, 4.82 mmol) were dissolved in THF (10 mL) and DMF (1 mL) then cooled to -20 oC. Isobutylchloroformate (0.31 mL, 2.32 mmol) was added to the cold solution and the reaction was stirred at -20 oC
for 20 min. After this time a THF suspension (5 mL) of pinanediol 1-amino-9-bromobutane-boronate hydrochloride salt (0.80 g, 2.19 mmol) was added to the mixture and the reaction was allowed to warm to room temperature over 3 h.
The reaction was partitioned between H20 (10 mL) and EtOAc (15 mL). The organic layer was washed with H20 (3 x 15 mL), then with saturated NaHC03 (15 mL), and brine (15 mL).
After the solution was dried (MgSOg) and evaporated under reduced pressure, there was obtained pinanediol N-[N,N-(1,8-napthyl-diimido)glycyl]-1-amido-4-bromobutaneboronate (1.2 g) in 98o yield. LRMS: (M+H)+ = 568.
Part C: To a solution of pinanediol N-[N,N-(1,8-napthyldiimido)glycyl]-1-amido-4-bromobutaneboronate (1.0 g, 1.76 mmol) in MeOH (30 mL) was added thiourea (0.27 g, 3.53 mmol). The reaction mixture was heated at reflux for 4h, then was allowed to cool to ambient temperature and the solvent was removed by distillation. The resulting viscous liquid was dissolved in a minimal amount of MeOH
and passed through a short column (35 g, LH-20 Sephadex) by elution with MeOH. Product containing fractions were combined and concentrated in vacuo, then the resulting foam was dissolved in a minimal amount of MeOH and triturated SUBSTITUTE SHEET (RULE 26) WO 95/0963) \ PCT/US94111280 with Et20. After solvent was decanted, the residue was rinsed with additional Et20 and placed under vacuum. There was obtained pinanediol N-[N,N-(1,8-napthyldiimido)glycyl]-1-amido-4-S-thiourylbutane-boronate hydrogen bromide (1.0 g) as an amorphous foam in 1000 yield. LRMS: (M+H)+ = 563.
Part D: To a solution of pinanediol N-[N,N-(1,8-napthyldiimido)glycyl]-1-amido-4-bromobutaneboronate (1.218, 2.13 mmol) in DMF (10 mL) was added NaN3 (0.28 g, 4.27 mmol). The reaction mixture was heated at 65 oC for 8 h, then it was allowed to cool to room temperature and partitioned between H20 (15 mL) and EtOAc (20 mL). The layers were separated and the organic phase was washed with H20 (3x20 mL) and brine (20 mL). This solution was dried (MgS04) and concentrated in vacuo to give pinanediol N-[N,N-(1,8-napthyldiimido)glycyl]-1-amido-4-azidobutaneboronate (0.92 g) in 82o yield. LRMS: (M+H)+
530.
Part D: A suspension of the azide prepared above (1.19g, 2.25 mmol) and 10~ Pd/C (100 mg) in MeOH (15 mL) was placed under an atmosphere of H2 (1 atm). The reaction mixture was stirred at room temperature for 5 h, then purged with a stream of N2. The catalyst was removed by filtration through a pad of diatomaceous earth and the filtrate was concentrated under reduced pressure to give pinanediol N-[N,N-(1,8-napthyldiimido)glycyl]-1-amido-4-amino-butaneboronate (1.1 g) in 85o yield. LRMS: (M+H)+ = 504.
Part E: To a solution of pinanediol N-[N,N-(1,8-napthyldiimido)glycyl]-1-amido-4-aminobutaneboronate (0.51 g, 1.01 mmol) in pyridine (10 mL) was added aminoiminomethanesulfonic acid (0.13 g, 1.01 mmol). The reaction mixture was heated at reflux for 4 h, then was concentrated in vacuo to give pinanediol N-[N,N-(1,8-SUBSTITUTE SHEET (RULE 26) ~~'~~3~4 napthyldiimido)glycyl]-1-amido-4-guanidinobutane-boronate sulfonic acid salt (0.21 g) in 35o yield.
Part F: Pinanediol N-[N,N-(1,8-napthyldiimido)glycyl]-1-amido-4-guanidinobutane-boronate sulfonic acid salt (0.21 g, 0.35 mmol) was dissolved in MeOH (2 mL) and Et2o (10 mL). A single portion of phenylboric acid (0.218, 1.76 mmol) was added to the solution followed by H20 (10 mL) and this mixture was stirred for 15 h. The phases were separated and the aqueous layer was washed with Et20 (6 x 10 mL). The aqueous layer was concentrated in vacuo and the resulting residue was placed under vacuum to give N-[N,N-(1,8-napthyldiimido)-glycyl]-1-amido-4-guanidinobutane-boronic acid as the sulfonic acid salt (0.16 g) in quantitative yield.
The following compounds were prepared according to the methods outlined in the Synthesis and Experimental sections. Appropriate physical data to characterize the compounds are provided:
Examt~le 52.1.2 Hydrocinnamoyl-(N-(3-methylphenethyl)-Gly]-boroLys-OH
hydrochloride salt.
Part A. Preparation of 3-methylphenethyl bromide.
To a solution of 3-methylphenethyl alcohol (5.0 g, 36.7 mmol) in methylene chloride at Oo C was added triphenylphosphine (10.6 g, 40.4 mmol) and carbon tetrabromide (13.4 g, 40.4 mmol). The mixture was allowed to stir with warming to 25o C for 16 h. The solvent was removed in vacuo and the residue was taken up in ether and filtered through a pad of silica gel. The solvent was removed in vacuo to afford 7.0 g (95a) of the title bromide.

SUBSTITUTE SHEET (RULE 26) Part B. Preparation of N-(3-methylphenethyl)-Gly-OMe.
To a solution of 3-methylphenethyl bromide (7.0 g, 35.0 mmol) in acetonitrile was added glycine methyl ester hydrochloride (6.6 g, 52.5 mmol) and sodium bicarbonate (10.3 g, 122.5 mmol). The resulting mixture was allowed to ' stir at 80o C for 16 h. The reaction mixture was allowed to cool to 25° C and then was diluted with ethyl acetate.
The mixture was washed with water and brine, dried lMgS04), and concentrated to afford the title compound. MS (CI):
m/z 208 (M+H)+. Part C. Preparation of hydrocinnamoyl-[N-(3-methylphenethyl)-Gly]-OMe.
To a solution of N-(3-methylphenethyl)-Gly-OMe (3.15 g, 15.2 mmol) in THF at Oo C was added N-methylmorpholine (3.34 mL, 30.4 mmol) and hydrocinnamoyl chloride (2.26 mL, 15.2 mmol). The mixture was allowed to stir with warming to 25° C for 6 h. The solvent was removed in vacuo and the residue was taken up in ethyl acetate and washed with loo aq HC1, sat'd aq NaHCO3 and brine. The organic layer was dried (MgS04) and concentrated to afford 4.4 g (860) of the title compound. MS (CI): m/z 340 (M+H)+.
Part D. Preparation of Hydrocinnamoyl-[N-(3-methylphenethyl>-Gly]-OH.
To a solution of hydrocinnarnoyl-[N-(3-methylphenethyl)-Gly)-OMe (4.4 g, 13.0 mmol) in 50 mL of 2:1 THF/H20 was added lithium hydroxide monohydrate (0.65 g, 15.6 mmol).
The reaction mixture was allowed to stir at 25° C for 4 h and then the THF was removed in vacuo. The basic solution - was extracted with 1:1 hexanes/ethyl acetate and the organic layer was discarded. The aqueous layer was SUBSTITUTE SHEET (RULE 26) WO 95109634 . PCT/US94111280 21743~~
acidified with concentrated HC1 and then was extracted with ethyl acetate. The ethyl acetate layer was washed with brine, dried (MgS04) and concentrated to afford the title compound as a white solid. MS (CI): m/z 326 (M+H)+.

Part E. Preparation of Hydrocinnamoyl-[N-(3-methylphenethyl)-Gly]-boroLys-OH hydrochloride salt.
The carboxylic acid hydrocinnamoyl-[N-(3-methylphenethyl)-Gly]-OH was elaborated to the title compound according to the procedures described herein. MS
(ES) : m/z 454 .4 (M+H) +.
Example 53 . t _ ~
Hydrocinnamoyl-(N-(2,2-dimethyl)-phenethyl-Gly]
boroLys-OH hydrochloride salt Part A. Preparation of Methyl 2,2-(dimethyl)-2-phenylacetate.
To a cooled (-78o C) solution of methyl phenylacetate 11.0 g, 6.7 mmol) in THF was added methyl iodide (0:91 m;, 14.7 mmol) followed by potassium tert-butoxide (14.7 mL of a 1.0 M solution in THF; 14.7 mmol).
The reaction mixture was allowed to stir while slowly warming to 25o C. After 1 h the reaction was quenched by addition c: saturated aq NH4C1, diluted with ethyl acetate and washed with brine. The organics were dried (MgSOq) and concentrated to afford 1.1 g (92%) of the title compound.
Part B. Preparation of 2,2-(Dimethyl)-2-phenylethyl alcohol.
To a cooled (Oo C) solution of 1M lithium aluminum SUBSTITUTE SHEET (RULE 26) WO 95/0963. PCTIUS9d/11280 ~.._ 21743~~
hydride in ether (31.1 mL, 31.1 mmol) was added methyl 2,2-(dimethyl)-2-phenylacetate (5.54 g, 31.1 mmol) as a solution in ether. The reaction mixture was allowed to warm to 25o C and was stirred for 3 h. The mixture was cooled to Oo C and was quenched by slow sequential addition of 1.2 mL of water, 1.2 mL of 15% aq NaOH and 3.6 mL of water. The resulting slurry was stirred vigorously with 'warming to 25o C far 1 h, and then was dried lMgS04).
filtered and concentrated to afford 3.8 g I81%) of the title compound.
Part C. Preparation of 2,2-(Dimethyl)-2-phenylacetaldehyde.
To a solution of 2,2-Idimethyl)-2-phenylethyl alcohol I3.8 g, 25.1 mmol) in methylene chloride was added pyridinium chlorochromate (16.2 g, 75.3 mmol) and the resulting mixture was stirred vigorously at 25o C for 4h.
The mixture was filtered through a pad of layered silica gel (bottom)/Celite/Florasil'" (top) and concentrated to~give 2~ the title aldehyde.
Part D. Preparation of N-I2,2-dimethyl)-phenethyl-Gly-OEt To a solution of glycine ethyl ester hydrochloride r ll.? g, 12.3 mmol) in methanol was added sodium cyanoborohydride (0.77 g, 12.3 mmoll and 2,2-ldimethyl)-2-phenylacetaldehyde I2.0 g, 13.5 mmol). Glacial acetic acid was added if necessary to maintain the pH at 5-6. The mixture was allowed to stir at 25o C for 16 h. The reaction was quenched by addition of excess satd. aq. K2C03 and then was diluted with ethyl acetate. The layers were separated and the organic layer was washed with brine I2x), dried (MgS04) and concentrated to afford 2.5 g (86%) of the title compound. MS ICI): m/z 236 (M+H)+.

SUBSTITUTE SHEET (RULE 26) Part E. Preparation of Hydrocinnamoyl-N-(2,2-dimethyl)-phenethyl-Gly-OEt.
To a cooled (0° C) solution of N-(2,2-dimethyl)-phenethyl-Gly-OEt (2.4 g, 10.1 mmol) in THF was added N-methylmorpholine (2.22 mL, 20.2 mmol) followed by hydrocinnamoyl chloride (1.50 mL, 10.1 mmol). The resulting solution was allowed to warm to 25° C and was stirred for 3h. The THF was removed in vacuo and the residue was taken up in ethyl acetate and washed with l00 aq HC1, satd. aq. NaHC03 and brine. The organics were dried (MgS04) and concentrated. The residue was purified by silica gel flash chromatography (solvent gradient 7:1 hexanes/ethyl acetate to 3:1 hexanes/ethyl acetate) to afford 2.0 g (540) of the title compound. MS (CI): m/z 368 (M+H)+.
Part F. Preparation of Hydrocinnamoyl-N-(2,2-dimethyl)-phenethyl-Gly-OH.
To a solution of hydrocinnamoyl-N-(2,2-dimethyl)-phenethyl-Gly-OEt (1.5 g, 4.1 mmol) in 25 mL of 1:1 methanol/water was added potassium hydroxide (0.34 g, 6.1 mmol). The reaction mixture was allowed to stir at reflux far 1 h and then was allowed to cool to 25° C and the methanol was removed in vacuo. The basic aqueous solution was extracted with 1:1 hexanes/ethyl acetate and the organic layer was discarded. The aqueous layer was acidified with concentrated HC1 and then was extracted with ethyl acetate. The ethyl acetate layer was washed with brine, dried (MgS04) and concentrated to afford the title compound as a white solid. MS (CI): m/z 340 (M+H)+.
Part G. Preparation of Hydrocinnamoyl-[N-(2,2-dimethyl)-phenethyl-Gly)-boroLys-OH hydrochloride salt.
The carboxylic acid hydrocinnamoyl-N-(2,2-dimethyl)-phenethyl-Gly-OH was elaborated to the title compound SUBSTITUTE SHEET (RULE 26) """ WO 95/09634 ~ 17 4 3 I c~ _ ; , . ~ : pCT/US94/11280 according to the procedures described in Example ???. MS
(ES): m/z 468.4 (M+H)+.
Example 1.1.3 N-{N-methyl-N-((3-phenyl)propionyl]glycyl}-1-amido-4-(guanidino)butylboronate, hydrochloride salt; LRMS (M+H, ethylene glycol ester)+ = 404.
m N-{N-methyl-N-benzoylglycyl}-1-amido-5-aminopentaneboronate, hydrochloride salt; HRMS calcd .
(M+H, ethylene glycol ester)+ = 348.209462, obs.: (M+H, ethylene glycol ester)+ = 348.208428.
Example 6.1.2 N-{N-methyl-N-[phenylacetyl]glycyl}-1-amido-5-aminopentaneboronic acid, hydrochloride salt; LRMS (M+H, ethylene glycol ester)+ = 362.
xample 6.1.3 N-{N-methyl-N-[(3-phenyl)propionyl]glycyl}-1-amido-5-aminopentaneboronate; HRMS (M+H)+ calcd: 376.240762, found . 376.240727.
Hxam~le a . 1 . 2 N-{N-phenyl-N-[phenylacetyl]glycyl}-1-amido-5-aminopentaneboronate, hydrochloride salt; HRMS calcd:
(M+H, ethylene glycol ester)+ = 424.240762, obs.: (M+H, ethylene glycol ester)+ = 424.242097.
Exam ple 9.1.3 N-{N-phenyl-N-[(3-phenyl)propionyl]glycyl}-1-amido-5-aminopentaneboronate, hydrochloride salt; HRMS calcd .
(M+H, ethylene glycol ester)+ = 438.256412, obs.: (M+H, ethylene glycol ester)+ = 438.256557.

SUBSTITUTE SHEET (RULE 26) WO 95109634 PCTlUS94111280 ~1'~43~4 Example 15.1.3 Pinanediol N-tN-methyl-N-[(3-phenyl)propionyl]glycyl}-1-amido-4-(guanidino)butylboronate, hydrochloride salt;
LRMS (M+H)+ = 512.3.
Example 21.1.1 Pinanediol N-{N-methyl-N-benzoylglycyl}-1-amido-5-aminopentaneboronate, hydrochloride salt; HRMS calcd .
(M+H)+ = 456.303362, obs.: (M+H)+ = 456.302964.
Example 21.1.2 Pinanediol N-(N-methyl-N-[phenylacetyl]glycyl}-1 amido-5-aminopentaneboronate, hydrochloride salt; LRMS
(M+H)+ = 470.
Example 21.9.1 Pinanediol N-{N-methyl-N-[2-(phenyl)benzoyl]glycyl?-1-amido-5-amino-pentaneboronate, hydrochloride acid salt;
LRMS (M+H)+ = 532.3.
~xamnle 24.1.2 Pinanediol N-tN-phenyl-N-[phenylacetyl]glycyl}-1 amido-5-aminopentaneboronate, hydrochloride salt; HRMS
calcd: (M+H)+ = 532.334663, obs.: (M+H)+ = 532.334090.
Example 24.1.3 Pinanediol N-{N-phenyl-N-[(3-phenyl)propionyl]glycyl}-1-amido-5-aminopentaneboronate, hydrochloride salt; HRMS
calcd: (M+H)+ = 546.350313, obs: (M+H)+ = 546.352069.
Fxam~le 24.59.1 Pinanediol N-{N-phenyl-N-(N'-methyl-N'-methylphenyl)aminocarbonyl]glycyl}-1-amido-4-SUBSTITUTE SHEET (RULE 26) ""'"' WO 95109634 PCTIUS94111280 isothiouroniumbutylboronate , HRMS (M+H)+ calcd:
606.338533, found: 606.329421.
Fxam~le X6.1.3 Pinanediol N-{N-methyl-N-[(3-phenyl)propionyl]glycyl}-1-amido-4-isothiouroniumbutylboronate; HRMS (M+H)+ calcd:
529.301983, found: 529.302078.
Example 26.9.1_ Pinanediol N-{N-methyl-N-((2-phenyl)benzoyl]glycyl}-1-amido-4-isothiouroniumbutylboronate; HRMS (M+H)+ calcd:
.577.301983, found: 577.302704.
xamgle 26.9.3 Pinanediol N-{N-methyl-N-[!3-(2-phenyl>phenyl)propionyl]glycyl}-1-amido-4-isothiouroniumbutylboronate ; HRMS (M+H)+ calcd: 605.3333, found: 605.3325.
~xamnle 26.12.1 Pinanediol N-(N-methyl-N-[(3-!2-phenyl)phenyl)propionyl]glycyl}-1-amido-4-isothiouroniumbutylboronate ; HRMS (M+H)+ calcd: 606.3285, found: 606.3294.
Example 27.1.3 Pinanediol N-{N-[(4-hydroxyphenyl)methyl]-N-[(3-phenyl)propionyl]-glycyl}-1-amido-4-isothiouroniumbutylboronate; HRMS (M+H)+ calcd: 621.328198, found: 621.329437.
Exam~l a 2 8 . 1. 3 Pinanediol N-{N-[(2-phenyl)ethyl)-N-[(3-phenyl)propionyl]glycyl}-1-amido-4-SUBSTITUTE SHEET (RULE 26) WO 95109634 ~ ~ ' PCTlUS94111280 isothiouroniumbutylboronate; HRMS (M+H)+ calcd: 619.348934, found: 619.348587.
~~xamgle 29.1.3 Pinanediol N-~N-phenyl-N-[(3-phenyl)propionyl]glycyl}-1-amido-4-isothiouroniumbutylboronate; HRMS (M+H)+ calcd:
591.317633, found: 591.316620.
mph Pinanediol N-{N-[(naphth-2-yl)methyl]-N-[(3-phenyl)propionyl]glycyl}-1-amido-4-isothiouroniumbutylboronate; HRMS (M+H)+ calcd: 655.348934, found: 655.347870.
Examr~le 36 6 1 Pinanediol N-(2-[(2-oxo-4-methylphenyl)-4,5-(H)oxazol-3-yl]acetyl}-1-amido-4-isothiouroniumbutylboronate ; mp.
120-130 °C ; Anal calcd. for C27H3gBN405S HBr oC: 52.02;
oH: 6.47; oN: 8.99; %B: 1.73; found: %C: 52.01; oH: 6.43,;
oN: 8.84; oB: 1.75.
Examr~le 49.1.1 Hydrocinnamoyl-[N-(Phenethyl)-Gly]-boroOrn-C10H16 HC1; MS
(ESI) (M+H)+ 560.4.
~'xample 49.1.2 Hydrocinnamoyl-[N-(Phenethyl)-Gly]-boro0rn(CH=NH)-C10H16 HC1; MS (NH3-CI) (M+H)+ 587.7.
xam°le 49.1.3 Hydrocinnamoyl-[N-(Phenethyl)-Gly]-boro0rn(CH=NH)-OH HC1;
MS (ESI) (M+H)+ 453.1.
Example 49.2.1 SUBSTITUTE SHEET (RULE 26) ~""'- WO 95/09634 ~ PCT/US94/11280 Hydrocinnamoyl-[N-(Phenethyl)-Gly]-boroArg(CH3)-C10H16 HC1;
MS lESI) (M+H)+ 616.4.
Example 50.1.1 Hydrocinnamoyl-[N-(N(CH3)2)-Gly]-boroOrn-C10H16 HC1; MS
(ESI) (M+H)+ 499.2 Example 50.1.2 Hydrocinnamoyl-[N-(N(CH3)2)-Gly]-bOrOOrn(CH=NH)-C10H16 HC1;
MS (ESI) !M+H)+ 526.1 Example 50.1.3 Hydrocinnamoyl-[N-(NlCH3)2)-Gly]-boroLys-C10H16 HC1; MS
(NH3-CI) (M+H)+ 513.5.
Example 51.1.1 Hydrocinnamoyl-[N-(3-(Trifluoromethyl)-Phenethyl)-Gly]-boroLys-C10H16 HC1; MS (ESI) (M+H)+ 642.5 Example 51.1.2 Hydrocinnamoyl-[N-(3-(Methyl)-Phenethyl)-Gly]-boroLys-C10H16 HC1; MS (ESI) (M+H)+ 588.4 Example 52.1.1 Hydrocinnamoyl-[N-(3-(Trifluoromethyl)-Phenethyl)-Gly]-boroLys-OH HC1; MS lESI) (M+H)+ 534 for ethylene glycol ester.
EXAMPLE 61.1.1 Hydrocinnamoyl-Sar-Lys[C(0)C02H]
Part A: Preparation of Na-t-Boc-Ne-Cbz-lysine[N(OMe)Me]
A flask was charged 150 ml of anhydrous CH2C12 followed by the addition of Na-t-boc-NE-Cbz-lysine (15.00 grams, 39.43 mmol), N-methylmorpholine (13.0 ml, 118.29 SUBSTITUTE SHEET (RULE 26) WO 95109634 ~ ~ PCTIUS94111280 mmol) and was cooled to -78°c followed by the addition of isobutylchloroformate (5.11 ml, 39.43 mmol). The mixture was stirred for 1 hr at which time the N,O-Dimethylhydroxylamine hydrochloride was added, stirred for 1 hr. and allowed to warm to room temperature. The solvent was removed in vacuo, the residue diluted with EtOAc and washed with loo aq HC1, sat'd aq NaHC03 and brine. After drying (MgS04), the solution was filtered through a pad of silica gel and the solvent removed in vacuo to give the product (16.32 g). MS: ESI, m/z 424.2 (M+H)+.
Part B: Preparation of Part A: Na-t-boc-Ne-Cbz-lysinal A flask was charged with 200 ml of anhydrous THF
followed by the addition of Na-t-boc, NE-Cbz lysine[N(OMe)Me] (4.00 gr, 9.44 mmol), cooled to 0°c and followed by the addition of Lithium aluminum hydride (450 mg, 11.80 mmol). The solution was stirred for 30 min. and was slowly quenched with a sat'd KHS03 solution (2.25 gr, 16.53 mmol). The volatiles were removed in vacuo and the residue dissolved in EtOAc and washed with loo aq HC1, sat'd aq NaHC03 and brine. After drying (MgS04), the solution was filtered through a pad of silica gel and the solvent removed in vacuo to give the product (3.29 grams) MS: ESI, m/z 365.2 (M+H)+.
Part C: Preparation of Na-t-boc, Ne-Cbz lysine[C(OH)C02CH3]
A flask was charged with 150 ml of anhydrous THF
followed by the addition of orthoethylthioformate (6.82 gr, 34.77 mmol), cooled tb -78°c and lithiated with n-butyllithium (2.5 M, 14.0 ml, 34.7 mmol). After stirring for 20 min., Na-t-boc-NE-Cbz-lysinal was added as a THF
solution via cannula and continued to stir at -78°c for and additional 4 hrs; the solution was quenched using sat'd NH4C1 and the volatiles removed in vacuo. The residue was SUBSTITUTE SHEET (RULE 26) PCTlUS94/11280 dissolved in EtOAc and washed twice with brine, dried over MgS04, filtered and dried in vacuo. The residue was dissolved in 95o MeOH followed by the addition of Hg0 (12.57 gr, 58.06 mmol) and HgCl2 (40.8 gr, 150.2 mmol) and stirred at rt. for 3 hrs. The solution was filtered through a pad of celite and the volatiles removed in vacuo followed by the addition of chloroform, the solution filtered and the volatiles removed in vacuo. The residue was dissolved in EtOAc and washed with l0a aq HC1, sat'd aq NaHC03 and brine. After drying (MgS04), the solution was filtered through a pad of silica gel and the solvent removed in vacuo. The residue was purified by flash chromatography to give the product (1.49 grams) MS: CI m/z 425.2 (M+H)+
Part D: Preparation of NE-Cbz-lysine[C(OH)C02CH3] TFA salt Na-t-boc-Ne-Cbz-lysine[C(OH)C02CH3] (1.49 gr, 3.51 mmol) was dissolved in 50 ml of neat TFA and the reaction monitored by TLC. The volatiles were removed in vacuo and the residue dissolved in a minimum amount of CH2C12 followed by the addition of Et20, cooled to -78°c and the product ppt. out with hexane (1.36 gr). MS: CI m/z 325.0 (M+H)+.
Part E: Preparation of Hydrocinnamoyl-Sar-ethyl ester Hydrocinnamic acid was added to 100 ml of anhydrous CH2C12 followed by the addition of N-methylmorpholine (44.0 ml, 400.0 ml), and cooled to -78°c. To the resulting solution was added isobutylchloroformate (17.3 ml, 133.17 mmol) and stirred for 1 hr. The sarcosine ethyl ester hydrochloride (20.00 gr, 133.17 mmol) was added and the solution stirred for and additional hr at -78°c and allowed to warm to rt. The volatiles were removed in vacuo and the residue was dissolved in EtOAc and washed with l0a aq HC1, sat'd aq NaHC03 and brine. After drying (MgS04), the SUBSTITUTE SHEET (RULE 26) WO 95/09634 ~ ~ j PCTIUS94111280 solution was filtered through a pad of silica gel and the solvent removed in vacuo (31.56 gr) MS: CI m/z 250.0 (M+H)+.
Part F: Preparation of Hydrocinnamoyl-Sar-OH
Hydrocinnamoyl-Sar-ethyl ester (31.57 gr, 126.63 mmol) and KOH (21.32 gr, 380 mmol) were combined in a 50/50 methanol-water solution and stirred at rt, the reaction was monitored by TLC. The methanol was removed in vacuo and the organics were extracted using EtOAc. The aq extract was acidified with a l0a HC1 solution and the organics extracted with EtOAc and washed with brine. After drying (MgS04), the solution was filtered and the solvent removed in vacuo to a white solid. MS: CI m/z 222.0 (M+H)+.
Part G: Preparation of Hydrocinnamoyl-Sar-NE-Cbz-lysine[C(OH)C02CH3]
Hydrocinnamoyl-Sar-OH (690 mg, 3.10 mmol), NE-Cbz lysine[C(OH)C02CH3] TFA salt (1.36 gr, 3.10 mmol), N-Methyl morpholine (1.0 ml, 9.3 mmol), HOBT (420 mg, 3.10 mmol) and 1-(3-Dimethyl amino propyl)-3 ethyl carbodiimide (600 mg, 3.10 mmol) were dissolved in SO ml of anhydrous DMF and stirred overnight at rt. The resulting solution was diluted with 300 ml of EtOAc and washed repeatedly with brine. The organic were dried over MgS04, filtered through a pad of silica gel, and the volatiles dried in vacuo to an oil (1.08 gr). MS: CI m/z 528.4 (M+H)+.
Part H: Preparation of Hydrocinnamoyl-Sar-NE-Cbz-lysine[C(0)C02CH3]
Anhydrous CH2C12 (100 ml) was charged with oxalylchloride (20 ml 2.25 mmol) and cooled to -40°c; this was followed by the addition of anhydrous DMSO (.35 ml, 4.91 mmol) and stirred for 20 min. Hydrocinnamoyl-Sar-NE-Cbz-lysine(C(OH)C02CH3] (1.08 gr, 2.04 mmol) was added as a SUBSTITUTE SHEET (RULE 26) - WO 95109634 PCTlUS94/11280 CH2C12 solution and stirred for an additional 20 minutes.
Triethylamine (1.42 ml, 10.23 mmol) was added to the resulting solution and stirred for an additional 20 min.
The volatiles were removed in vacuo and the resulting residue subject to flash chromatography yielding the product as an oil.(73 gr) MS: CI m/z 526.4 (M+H)+.
Part I: Preparation of Hydrocinnamoyl-Sar-NE-Cbz-lysine[C(O)C02H) Hydrocinnamoyl-Sar-NE-Cbz lysine[C(O)C02CH3] (.73 gr, 1.39 mmol) and LiOH (150 mg, 3.48 mmol) were combined in a 50/50 mixture of methanol/water, stirred at rt and the reaction monitored by TLC. The volatiles were removed in vacuo, the residue dissolved in EtOAC and acidified with 10% HC1. The organics were dried (MgS04) and the volatiles removed in vacuo to yield .57 gr of product MS: CI m/z 468.2 (M+H-C02)+.
Part J: Hydrocinnamoyl-Sar-Lys[C(O)C02H]
Hydrocinnamoyl-Sar-Ne-Cbz-lysine(C(O)C02H] (570 mg, 1.11 mmol) was dissolved in 100 ml of methanol followed by the addition of 20% Pd/C catalyst (60 mg) and stirred under 1 atm. of HZ at rt for 3 hrs. The solution was filtered through a pad of celite and the volatiles removed in vacuo to give the product MS: CI m/z 380.3 (M+H)+
Example 53.1.2 Hydrocinnamoyl-(N-(2-(Cyclopropyl)-Phenethyl)-Gly]-boroLys-OH HC1; MS (ESI) (M+H)+ 466.3 Examx~le 53.2.1 Hydrocinnamoyl-(N-(N-(Methyl)-Phenyl)-Gly)-boroLys-OH HC1;
MS (ESI) (M+H)+ 441.3 Example 53.2.2 SUBSTITUTE SHEET (RULE 26) WO 95/09634 PCTlUS94I11280 ~~~~~~4 Hydrocinnamoyl-[N-(N-(Methyl)-Benzyl)-Gly]-boroLys-OH HC1;
MS (ESI) (M+H)+ 455.4 Example 53.4.3 Hydrocinnamoyl-[N-(Cyclohexyl)-Gly]-boroLys-OH HC1; MS
(ESI) (M+H)+ 418.3 Fxam~le 54.1.1 Hydrocinnamoyl-[N-(2,2-(Dimethyl)-Phenethyl)-Gly]-boroLys C10H16 HC1; MS (ESI) (M+H)+ 616.3 Example 54.1.2 Hydrocinnamoyl-[N-(2-(Cyclopropyl)-Phenethyl)-Gly]-boroLys-C10H16 HC1; MS (NH3CI) (M+H)+ 600.5 Example 54.1.3 Hydrocinnamoyl-[N-(2,2-(Diethyl)-Phenethyl)-Gly]-boroLys-C10H16 HC1; MS (ESI) (M+H)+ 630 example 54.2.1 Hydrocinnamoyl-[N-(N-(Methyl)-Phenyl)-Gly]-boroLys-C10H16 HC1; MS (NH3CI) (M+H)+ 575.4 Rxam~le 54.2.2 Hydrocinnamoyl-[N-(N-(Methyl)-Benzyl)-Gly]-boroLys-C10H16 HC1; MS (NH3CI) (M+H)+ 589.4 Example 54.2.3 Hydrocinnamoyl-[N-(Succinyl)-Gly]-boroLys-C10H16; MS (ESI) (M+H)+ 542.5 Example 54.3.1 Hydrocinnamoyl-[N-(Methyl Succinyl)-Gly]-boroLys-C10H16 HC1; MS (ESI) (M+H)+ 556.5 SUBSTITUTE SHEET (RULE 26) ~.~ 743 ~
WO 95109634 PCTlUS94/11280 ~a i , .. i. .'; !
Examr~le 54.3.2 Hydrocinnamoyl-[N-(2-(Cyclopentyl)-Phenethyl)-Gly]-boroLys-C10H16 HC1; MS (ESI) (M+H)+ 628.3 Examy~le 54.3.3 Hydrocinnamoyl-[N-(2,2-(Dimethyl)-Phenethyl)-Gly]-boroLys-C10H16 HC1; MS (ESI) (M+H)+ 630.4 Fxamole 54.4.1 Hydrocinnamoyl-{N-[2-(3,5-dimethylphenyl)-ethyl]-Gly}-boroLys-C10H16 HC1; MS (ESI) (M+H)+ 602.4 Example 54.4.2 Hydrocinnamoyl-[N-(Cyclopropyl)-Gly]-boroLys-C10H16 HC1;
MS (NH3CI) (M+H)+ 510.3 Example 54.4.3 Hydrocinnamoyl-(N-(Cyclohexyl)-Gly]-boroLys-C10H16 HC1; MS
(NH3CI) (M+H)+ 552.4 Example 55.1.1 Hydrocinnamoyl-(N-(2,2-(Dimethyl)-Phenethyl)-Gly]-boroArg-OH HC1; MS (ESI) (M+H)+ 496.4 D-xamole 56.1.1 Hydrocinnamoyl-[N-(2,2-(Dimethyl)-Phenethyl)-Gly]-boroArg-C10H16 HC1; MS (ESI) (M+H)+ 630.4 E~amole 56.1.2 Hydrocinnamoyl-[N-(2-(Cyclopropyl)-Phenethyl)-Gly]-boroArg-C10H16 HC1; MS (ESII (M+H)+ 628.3 Example 56.3.3 Hydrocinnamoyl-{N-[2,2-(Dimethyl)-2-(3,5-dimethylphenyl)-ethyl]-Gly}-boroArg-C10H16 HC1; MS (ESI) (M+H)+ 658.4 SUBSTITUTE SHEET (RULE 26) WO 95/09634 ~ ~ ~ ~ ~ ~ ~~ PCTIUS94111280 Example 56.4.1 Hydrocinnamoyl-{N-[2-(3,5-dimethylphenyl)-ethyl)-Gly}-boroArg-C10H16 HCl; MS (ESI) (M+H)+ 630.4 Example 57.1.1 Hydrocinnamoyl-[N-(2,2-(Dimethyl)-Phenethyl)-Gly]-boroOrn(CH=NH)-OH HC1; MS (ESI) (M+H)+ 481.2 1p Example 57.1.2 Hydrocinnamoyl-(N-(2-(Cyclopropyl)-Phenethyl)-Gly]-boroOrn(CH=NH)-OH HC1; MS (ESI) (M+H)+ 479 Example 57.4.2 Hydrocinnamoyl-[N-(Cyclopropyl)-Gly]-boroOrn(CH=NH)-OH HCl;
MS (ESI) (M+H)+ 389.3 Example 58 N-{N-methyl-N-(2-(methylphenyl)benzoyl]glycyl}-1-amido-5 aminopentaneboronic acid, hydrochloride salt Using the procedure of Example 8.1.3, however using pinanediol N-{N-methyl-N-[2-(methylphenyl)benzoyl] glycyl}-1-amido-5-aminopentaneboronate, hydrochloride salt, the title compound was prepared; LFNlS (M -H20)+ = 394.1, (M
-2H20)+ = 376.1.
Example 58.1.1 Hydrocinnamoyl-[N-(2,2-(Dimethyl)-Phenethyl)-Gly]-boroOrn(CH=NH)-C10H16 HC1; MS (ESI) (M+H)+ 615.4 Example 58.3.3 Hydrocinnamoyl-{N-[2,2-(Dimethyl)-2-(3,5-dimethylphenyl)-ethyl]-Gly}-boroOrn(CH=NH)-C10H16 HC1; MS (ESI) (M+H)+
643.4 .

SUBSTITUTE SHEET (RULE 26) w WO 95/0963.1 PCTIUS9:1/11280 ' '.
Example 58.4.1 Hydrocinnamoyl-{N-[2-(3,5-dimethylphenyl)-ethyl]-Gly}-boro0rn(CH=NH)-C10H16 HC1; MS (ESI) (M+H)+ 615.4 Example 58.4.2 Hydrocinnamoyl-[N-(Cyclopropyl)-Gly]-boroOrn(CH=NH)-C10H16 HC1; MS (NH3CI) (M+H)+ 524.3 Example 59.1.1 Hydrocinnamoyl-[N-(2,2-(Dimethyl)-Phenethyl)-Gly]-boroLys-OH HC1; MS (ESI) (M+H)+ 482.2 Example 59.4.2 Hydrocinnamoyl-[N-(Cyclopropyl)-Gly]-boroLys-OH HC1; MS
(ESI) (M+H)+ 376.2 Example 60 Pinanediol N-{N-[(naphth-1-yl)methyl]-N-[(3-phenyl)propionyl]glycyl}-1-amido-4-isothiouroniumbutylboronate; HRMS (M+H)+ calcd: 655.348934, found: 655.349243.
Example 60.1.1 Hydrocinnamoyl-[N-(2,2-(Dimethyl)-Phenethyl)-Gly]-boroOrn-C10H16 HC1; MS (NH3DCI) (M+H)+ 602.5 Examble 60.3.3 Hydrocinnamoyl-[N-(2,2-(Dimethyl)-Phenethyl)-Gly]-boroOrn C10H16 HC1; MS (ESI) (M+H)+ 616.4 Example 60.4.1 Hydrocinnamoyl-{N-[2-(3,5-dimethylphenyl)-ethyl]-Gly}-boroOrn-C10H16 HC1; MS (ESI> (M+H)+ 588.3 SUBSTITUTE SHEET (RULE 26) ~'~ 1~31,.~
Examgle 60.4.2 Hydrocinnamoyl-[N-(Cyclopropyl)-Gly]-boroOrn-C10H16 HC1;
MS (NH3CI) (M+H)+ 496.3 Example 61 Pinanediol N-(N-methyl-N-[(3-phenyl-2-(phenyl)methyl)propionyl)-glycyl}-1-amido-5-aminopentylboronate; HRMS (M+H)+ calcd: 560.365963, found:
560.364426.
Examgle 61 1 1 Hydrocinnamoyl-Sar-Lys[C(=O)-C(=O)-OH]; MS: ESI m/z 380.3 (M+H)+
~5 EXAMPLE 62.3.3 2-(2-cyanothiophenyl)-benzoyl-Sar-BoroArg C1pH16-HC1 Part A: Preparation of 2-(2-cyanothiophenyl>benzoyl-Sar-ethyl ester 2-(2-cyanothiophenyl)benzoic acid (5.00 gr, 19.58 mmol), sarcosine ethyl ester hydrochloride (3.00 gr, 19.58 mmol), triethylamine (8.2 ml, 58.75 mmol), HOBT (2.64 gr, 19.58 mmol) and 1,3-diisopropylcarbodiimide f3.0 ml, 19.58 mmol) were combined in 100 ml of anhydrous CH2C12 and stirred at rt overnight. The volatiles were removed in vacuo, the organics dried over MgS04, filtered and concentrated. The product was purified by flash chromatography (4.93 gr) MS: CI m/z 355.1 (M+H)+.
Part B: Preparation of 2-(2-cyanothiophenyl)benzoyl-Sar-OH
2-(2-cyanothiophenyl)benzoyl-Sar-ethyl ester (4.93 gr, 14.03 mmol) and KOH (790 mg, 14.03 mmol) were combined in 75 ml of a 50/50 methanol-water solution and stirred at rt, the reaction was monitored by TLC. The methanol was removed in vacuo and the organics were diluted with EtOAc SUBSTITUTE SHEET (RULE 26) ~1'~4314 and extracted with H20. The aq extract was acidified with a loo HCl solution and the organics extracted with EtOAc, washed with brine. After drying (MgS04), the solution was filtered and the solvent removed in vacuo to a white solid.
MS: CI m/z 327.0 (M+H)+
Part C: Preparation of 2-(2-cyanothiophenyl)benzoyl-Sar-NH-CH[(CH2)3Br]B02-C1pH16 2-(2-cyanothiophenyl)benzoyl-Sar-OH (4.23 gr, 12.96 mmol) and NMM (4.3 ml, 38.9 mmol) were dissolved in 150 ml of anhydrous CH2C12 and stirred at -78°c. This was followed by the addition of isobutylchloroformate(1.70 ml, 12.96 mmol) and stirred for 1 hr, at which time NH2CH[(CH2)3Br]B02-C1pH16~ HC1 (4.75 gr, 12.96 mmol) was added and stirred for an additional hr. and allowed to warm to rt. The volatiles were removed in vacuo, the residue was dissolved in EtOAc and the organics were washed with sat'd NaHC03, 10~ HC1 and brine. The residue was dried (MgS04) and filtered through a pad of florisil and concentrated in vacuo to give the product (6.01 gr) MS: CI
m/z 558.2 (M-HBr)+
Part D: Preparation of 2-(2-cyanothiophenyl)benzoyl-Sar-NH-CH[(CH2)3N3]BOZ-C1pH16 2-(2-cyanothiophenyl)benzoyl-Sar-NH-CH[(CH2)3Br]B02-C1oH16 (6.01 gr, 9.21 mmol) and NaN3 (1.80 gr, 27.64 mmol) were combined in 75 ml of DMF and stirred for 3 hrs. at 110°c. The solution was diluted with EtOAc and washed repeatedly with brine. The organics were dried over MgS04 and filtered through a pad of florisil and concentrated in vacuo to give the product (5.38 gr).MS: ESI m/z 601.4 (M+H)+
Part E: Preparation of 2-(2-cyanothiophenyl)benzyloyl-Sar-boro0rn-C10H16~HC1 SUBSTITUTE SHEET (RULE 26) WO 95/09b34 ~ 1 ~ (~ ~ ~ ;~ PCT/U594111280 To a solution of 2-(2-cyanothiophenyl)benzyloyl-Sar-NH-CH[(CH2)3N3]B02-C1pH16 (5.38 gr, 8.96 mmol) in MeOH (75 ml) was added 20o Pd/C catalyst (600 mg>. The mixture was stirred under 1 atm of HZ for 2 hrs and then filtered through a pad of celite and concentrated to give the product MS: CI m/z 575.2 (M+H)+.
Part F: Preparation of 2-(2-cyanothiophenyl)benzyloyl-Sar-boroArg-C1pH16~HC1 2-(2-cyanothiophenyl)benzyloyl-Sar-boroOrn-C1pH16~HC1 (1.77 gr, 2.90 mmol), DMAP (710 mg, 5.79 mmol) and H2NC(NH)S03H (720 mg, 5.79 mmol) were combined in 50 ml of absolute EtOH and refluxed overnight. The volatiles were removed and the residue dissolved in CH3C1 and washed with 10o HC1 and brine. The organics were dried (NaS04) and concentrated to give the product MS: CI m/z 617.3 (M+H)+.
Example 61.2.1 Hydrocinnamoyl-Sar-Lys-C(=O)-OCH3 HC1; MS: CI m/z 364.2 (M+H)+
Example 61.2.3 Hydrocinnamoyl-Sar-Lys-C(=O)-CH3 HC1; MS: CI m/z 348.2 (M+H)+
Example 61.4.1 Hydrocinnamoyl-Sar-Lys(CH(OH)(OCH3)-C(=O)-OCH3] HC1; MS:
CI m/z 392.3(M+H)+
Example 62 Pinanediol N-{N-methyl-N-[(3,4-dichlorophenyl)acetyl]glycyl}-1-amido-5-aminopentaneboronate, hydrochloride salt; LRMS (M+H)+ _ 538.
Example 62.1.3 SUBSTITUTE SHEET (RULE 26) ..~- WO 95109634 ~ 1 '7 4 314 : : ' PCT/US94I11280 DM-6666-c (2-(2-Cyano)-Thiophenyl)-Benzoyl-Sar-boroIrg-C10H16 HBr;
MS: DCI m/z 648.(M+H)+
Example 62.2.2 (2-(2-Cyano)-Thiophenyl)-Benzoyl-Sar-borohomoIrg-C10H16 HBr: MS: ESI m/z 634.4 (M+H)+
Example 62.3.2 (2-(2-Cyano)-Thiophenyl)-Benzoyl-Sar-borohomoArg-C10H16 HC1; MS: DCI m/z 631. (M+H)+
EXAMPLE 64.2.3 2-(3-chlorobenzyl)-benzoyl-Sar-Borolys C1pH16~HC1 Part A: Preparation of,2-bromo-3'-chloro Biphenyl methanol Anhydrous THF (400 ml) was charged with 3-(chloro) bromo benzene (19.63 ml, 167.13 mmol), cooled to -78°c, lithiated with n-BuLi (2.5 M, 66.85 ml, 167.13 mmol) and stirred for 20 minutes. 2-bromobenzaldehyde (19.51 ml, 167.13 mmol) was added and stirred for an additional 30 minutes and allowed to warm to rt. The solution was quenched with sat'd NH4C1 and the volatiles removed in vacuo. The residue was dissolved in EtOAc and washed with brine; the organics were dried over MgS04, filtered through a pad of silica and the volatiles dried in vacuo. The product was purified by flash chromatography (38.8 gr) MS:
CI m/z 281.0 (M+H-H20)+
Part B: Preparation of 2-bromo-3'-chloro Biphenyl methane ' 30 2-bromo-3'-chloro Biphenyl methanol (38.8 gr, 130.35 mmol) and triethylsilane (31.23 ml, 195.53 mmol) were combined in 200 ml of TFA and stirred overnight at rt. The volatiles were removed in vacuo and the residue purified by flash chromatography (33.32 grams) MS: CI m/z 283.0 (M+H) +.

SUBSTITUTE SHEET (RULE 26) ~x~~3f WO 95109634 " PCTIUS94/11280 Part C: Preparation of 3-chlorobenzylbenzoic acid 2-bromo-3'-chloro diphenyl methane was dissolved in 250 ml of anhydrous THF, cooled to -78°c and lithiated with n-BuLi (2.5 M, 47.5 ml, 118.34 mmol). After stirring for 30 minutes, C02 was slowly bubbled in for 15 minutes and the solution warmed to rt. The volatiles were removed in vacuo and the residue dissolved in H20 and the organics removed with EtOAc, the aq. layer was acidified with 10%
HC1, the organics extracted with EtOAc, washed with brine, dried (MgSOq) and the volatiles removed in vacuo to a white solid MS: CI m/z 264.0 (M+H)+.
Part D: Preparation of 2-(3-chlorobenzyl)benzoyl-Sar ethyl ester 3-chlorobenzylbenzoic acid (10.28 gr, 41.67 mmol), sarcosine ethyl ester hydrochloride (6.40 gr, 41.67 mmol), 1-(3-Dimethyl amino propyl)-3 ethyl carbodiimide (8.0 gr, 41.67 mmol), NMM (13.75 ml, 125.0 mmol> and DMAP (1.27 gr, 10.42 mmol) were combined in anhydrous CH2C12 and~stirred at rt overnight. The volatiles were removed in vacuo, the residue dissolved in EtOAc, washed with 10o aq HC1, sat'd aq NaHC03 and brine. After drying (MgSOq), the solution was filtered through a pad of silica gel and the solvent removed in vacuo to give the product (3.19 grams) MS: CI, m/z 346.0 (M+H)+.
Part E: Preparation of 2-(3-chlorobenzyl)benzoyl-Sar-OH
3-chlorobenzylbenzoyl-Sar ethyl ester (3.19 gr, 9.22 mmol) and KOH (2.0 gr, 36.90 mmol) were combined in 75 ml of a 50/50 methanol-water solution and stirred at rt, the reaction was monitored by TLC. The MeOH was removed in vacuo and the organics were diluted with EtOAc and extracted with H20. The aq extract was acidified with a 10% HC1 solution and the or~anics extracted with EtOAc and SUBSTITUTE SHEET (RULE 26) WO 95109634 ~ 1'~ 4 ~ ~. 4 ~ ,° pCT/US94111280 washed with brine. After drying (MgSOq), the solution was filtered and the solvent removed in vacuo to a white solid.
MS: CI m/z 318.0 (M+H)+
Part F: Preparation of 2-(3-chlorobenzyl)benzyloyl-Sar-NH-CH((CH2)qBr]B02-C1pH16 3-chlorobenzylbenzoyl-Sar-OH (2.66 gr, 8.37 mmol) and NMM (2.76 ml, 25.11 mmol) were dissolved in anhydrous CH2C12 and stirred at -78°c. This was followed by the addition of isobutylchloroformate (1.1 ml, 8.37 ml) and stirred for 1 hr, at which time NH2CH[(CH2)qBr]B02-C1pH16' HC1 (3.19 gr, 8.37 mmol) was added and stirred for an additional hr. and allowed to warm to rt. The volatiles were removed in vacuo, the residue was dissolved in EtOAc and the organics were washed with sat'd NaHC03, 10% HC1 and brine. The residue was dried (MgSOq), filtered through a pad of florisil and concentrated in vacuo to give the product (.4.45 gr) MS: CI m/z 645.5 (M+H)+
Part G: Preparation of 2-(3-chlorobenzyl)benzyloyl-Sar-NH-CH[(CH2)qN3]B02-C1pH16 3-chlorobenzylbenzyloyl-Sar-NH-CH[(CH2)qBr]B02-C1pH16 (4.45 gr, 6.91 mmol) and NaN3 (1.34 gr, 20.73 mmol) were combined in 50 ml of DMF and stirred for 3 hrs. at 110°c.
The solution was diluted with EtOAc and washed repeatedly with brine. The organics were dried over MgSOq and filtered through a pad of florisil and concentrated in vacuo to give the product (3.33 gr) MS: DCI m/z 623.0 (M+NHq ) +
Part H: Preparation of 2-(3-chlorobenzyl)benzyloyl-Sar-borolys-C1pH16'HC1 To a solution of 3-chlorobenzylbenzyloyl-Sar-NH-CH[(CH2)qN3]B02-C1pH16 (3.33 gr, 5.49 mmol) in MeOH (75 ml) was added 20o Pd/C catalyst (300 mg>. The mixture was SUBSTITUTE SHEET (RULE 26) ~1~43~~~;
stirred under 1 atm of H2 for 2 hrs and then filtered through a pad of celite and concentrated to give the product MS: CI m/z 580.5 (M+H>+.
Example 62.4.1 (2-(2-Cyano)-Thiophenyl)-Benzoyl-Sar-bOrOOrn(CH=NH)-C10H16 HC1; MS: ESI m/z 602.3 (M+H)*
~,xamgle 62.4.2 (2-(2-Cyano)-Thiophenyl)-Benzoyl-Sar-boroLys(CH=NH)-C10H16 HCl; MS: ESI m/z 616.2 (M+H)*
Example 62.4.3 (2-(2-Cyano)-Thiophenyl)-Benzoyl-Sar-boroLys-C10H16 HC1;
MS: CI m/z 589.3 (M+H)*
Examg,l a 6 3 Pinanediol N-tN-methylphenyl-N-[(3-phenyl)propionyl]glycyl}-1-amido-5-aminopentaneboronate, hydrochloride salt; HFNlS calcd: (M+H)* = 560.365963, obs:
(M+H)* = 560.366107.
Example 63.1.3 2-(Thiophenyl)-Benzoyl-Sar-boroIrg-C10H16 HBr; MS: CI m/z 567.2 (M-H2NCN)*
Examgle 63.3.1 2-(Thiophenyl)-Benzoyl-Sar-boroOrn-C10H16 HC1; MS: CI m/z 550.3 (M+H)*
Example 63.4.1 2-(Thiophenyl)-Benzoyl-Sar-boro0rn(CH=NH)-C10H16 HC1; MS:
CI m/z 577.3 (M+H)*
Exam~l a E 3 . 4 . 2 SUBSTITUTE SHEET (RULE 26) 2-Thiophenyl-Benzoyl-Sar-boroLys(CH=NH)-C10H16; MS: CI
m/z 564.2 (M-HCN)+
Examr~le 63.5.1 Pinanediol N-{N-methyl-N-[2-(Thiophenyl)-Benzoyl]Sar}-1-amido-5-thiocyanatobutane boronate; MS: CI m/z 592.2 (M+H)+
Example 64 N-(N-methylphenyl-N-[(3-phenyl)propionyl]glycyl}-1-amido-5-aminopentaneboronate, hydrochloride salt; HRMS
calcd (M+H, ethylene glycol ester)+ = 452.272062, obs.:
(M+H, ethylene glycol ester)+ = 452.270496.
~.xamole 64.1.1 2-Benzyl-(N-Benzyl)-Sar-boroLys-C10H16 HC1; MS: CI m/z 532.5 (M+H)+
Example 64.1.2 Acetyl-Gly[N-(2-(Benzyl)-Benzyl)]-boroLys-C10H16 HC1; MS:
CI m/z 560.4 (M+H)+
Example 64.1.3 Pinanediol N-{N-methyl-N-[2-(pyrrol-1-ylmethyl)-Benzyl]glycyl}-1-amido-5-aminopentaneboronate, hydrochloride salt; MS: CI m/z 535.3 (M+H)+
Example 64.2.2 [3-(Trifluoromethyl)-Benzyl]-Benzoyl-Sar-boroLys-C10H16 HC1; MS: CI m/z 614.3 (M+H)+
Example 65 Piananediol N-(N-methyl-N-[(4-phenyl)butanoyl]glycyl}-1-amido-5-aminopentaneboronate, hydrochloride salt; HRMS
calcd: (M+H)+ = 498.350313, obs.: (M+H)+ = 498.350585.

SUBSTITUTE SHEET (RULE 26) ~1'~431~~
Example 65.1.3 N-{N-methyl-N-[2-(pyrrol-1-ylmethyli-Benzyl]glycyl)-1-amido-5-aminopentaneboronic acid, hydrochloride salt; MS:
ESI m/z 601.3 (M+H)+
Example 66 N-{N-methyl-N-[(4-phenyl)butanoyl]glycyl}-1-amido-5-aminopentaneboronate, hydrochloride salt; HRMS calcd: (M+H, ethylene glycol ester)+ = 390.256412, obs.: (M+H, ethylene glycol ester)+ = 390.257428.
Example 66.1.1 Glutaryl-[N-(Phenethyl)-Gly]-boroLys-OH HC1; MS (ESI) (M+H)+ 422.3 Example 66.1.2 Glutaryl(3,3-Dimethyl)-[N-(Phenethyl)-Gly]-boroLys-OH; MS
(ESI) (M+H)+ 450.5 Example 66.1.3 Methyl Glutaryl(3,3-Dimethyl)-[N-(Phenethyl)-Gly]-boroLys-OH HC1; MS (CDI) (M+H)+ 490 Example 66.3.2 Methanesulfonyl-Gly-[N-(N-(Methyl)-Benzyl)-Gly]-boroLys-OH
HC1; MS (ESI) (M+H)+ 458.3 Example 67 Pinanediol N-{N-methyl-N-[N-methanesulphonyl-D-phenylalanyl]glycyl}-1-amido-5-aminopentaneboronate, hydrochloride salt; HRMS calcd: (M+H)+ = 577.323113, obs.:
(M+H)+ = 577.322891.
Example 67.1.2 SUBSTITUTE SHEET (RULE 26) WO 95109634 ~ ~ ~ ~ ~ ~ ~ PCTIU594111280 Glutaryl(3,3-Dimethyl)-[N-(Phenethyl)-Gly]-boroLys-C10H16;
MS (ESI) (M+H)+ 584.6 Example 67.1.3 Methyl Glutaryl(3,3-Dimethyl)-[N-(Phenethyl)-Gly]-boroLys-C10H16 HC1; MS (ESI) (M+H)+ 598.6 Example 67.3.2 Methanesylfonyl-Gly-[N-(N-(Methyl)-Benzyl)-Gly]-boroLys-C10H16 HC1; MS (ESI) (M+H)+ 592.3 Example 68 N-(N-methyl-N-[N-methanesulphonyl-D-phenylalanyl]glycyl}-1-amido-5-aminopentaneboronate, hydrochloride salt; HRMS calcd: (M+H, ethylene glycol ester)+ = 469.229212, obs.: (M+H, ethylene glycol ester)+ _ 469.228962.
Example 68.2.1 Boc-Glu-[N-(Phenethyl)-Gly]-boroLys-OH
Example 68.3.1 Succinyl-[N-(Phenethyl)-Gly]-boroLys-OH; MS (ESI) (M+H)+
408.3 ~xam~le 68.3.3 Methyl Succinyl-[N-(Phenethyl)-Gly]-boroLys-OH HC1; MS
(ESI) (M+H)+ 422.3 Example 68.4.1 Methyl Glutaryl-[N-(Phenethyl)-Gly]-boroLys-OH HC1; MS
(ESI) (M+H)+ 336.3 Example 68.4.2 SUBSTITUTE SHEET (RULE 26) ~1743~~~
WO 95109634 ' PCT/US94111280 Methanesulfonyl-Sar-[N-(Phenethyl)-Gly]-boroLys-OH HC1; MS
(ESI) (M+H)+ 457.0 Example 69 Pinanediol N-tN-methyl-N-[3-(4-methylphenyl)propionyl]glycyl}-1-amido-5-aminopentaneboronate, hydrochloride salt; HRMS calcd:
(M+H)+ = 498.350313, obs.: (M+H)+ = 498.349676.
Example 59.1.1 Glutazyl-(N-(Phenethyl)-Gly]-boroLys-C10H16; MS (ESI) (M+H)+ 556.4 Example 69.2.1 Boc-Glu-[N-(Phenethyl).-Gly]-boroLys-C10H16; MS (ESI) (M+H)+ 671.6 Example 69.2.2 Boc-Asp-[N-(Phenethyl)-Gly]-boroLys-C10H16; MS (ESI) (M+H)+ 657.6 Example 69.2.3 Boc-Glu(OCH3)-[N-(Phenethyl)-Gly]-boroLys-C10H16 HC1; MS
(ESI) (M+H)+ 685.6 example 69.3.2 Methanesulfonyl-Gly-[N-(Phenethyl)-Gly]-boroLys-C10H16 HC1;
MS (NH3CI) (M+H)+ 577 Examr~le 69.4.1 Methyl Glutaryl-[N-(Phenethyl)-Gly]-boroLys-C10H16 HC1; MS
(ESI) (M+H)+ 570.5 Example 69.4.2 SUBSTITUTE SHEET (RULE 26) ~i~ 4~,~.4 WO 95109634 _ Methanesulfonyl-Sar-[N-(Phenethyl)-Gly]-boroLys-C10H16 HC1;
MS (NH3CI) (M+H)+ 591.4 Example 70 N-{N-methyl-N-[3-(4-methylphenyl)propionyl]glycyl}-1-amido-5-aminopentaneboronate, hydrochloride salt; HRMS
calcd: (M+H, ethylene glycol ester)+ = 390.256412, obs.:
(M+H, ethylene glycol ester)+ = 390.256960.
Example 71 Pinanediol N-{N-methyl-N-[2-(methyl(4-methoxyphenyl))benzoyl]glycyl}-1-amido-5-amino-pentaneboronate, hydrochloride acid salt; LRMS (M+H)+ _ 576.3.
example 72 Pinanediol N-{N-methyl-N-[2-(methyl(4-methylphenyl))benzoyl]glycyl}-1-amido-5-amino-pentaneboronate, hydrochloride acid salt; LRMS (M+H)+ _ 560.5.
Example 72.1.3 Hydrocinnamoyl-[N-(N(CH3)2)-Gly]-boroLys-OH HC1; MS (ESI) (M+H)+ 379.0 Example 73 Pinanediol N-{N-((O-tert-butyl)methylenecarboxylate)-N-[(3-phenyl)propionyl]-glycyl}-1-amido-5-aminopentaneboronate, hydrochloride salt; LRMS (M+H)+ _ 584.
Example 73.1.2 Succinyl-[N-(3-(Methyl)-Phenethyl)-Gly]-boroLys-C10H16 HC1;
MS (ESI) (M+H)+ 556 SUBSTITUTE SHEET (RULE 26) WO 95109634 PCTlUS94l11280 i~1 ~ ~3~4 Example 74 Pinanediol N-{N-methyl-N-[(3-phenyl)propionyl]glycyl}-1-amido-4-(formamidino)butylboronate, hydrochloride salt;
LRMS (M+H)+ = 497.
Example 75 N-{N-methyl-N-((3-phenyl)propionyl)glycyl}-1-amido-4-(N- methylguanidino)butylboronate, hydrochloride salt; LRMS
(M+H, ethylene glycol ester)+ = 418.3.
Example 75.3.1 (2-(2-Cyano)-Thiophenyl)-Benzoyl-Sar-boroArg-OH HC1; MS
(ESI) (M+H)+ 483.1 Example 76 N-{N-methyl-N-[(3-phenyl)propionyl)glycyl}-1-amido-4-(formamidino)butylboronate, hydrochloride salt; LRMS (M+H, ethylene glycol ester)+ = 389.2.
Example 76.1.1 Hydrocinnamoyl-[N-(Cyclopropyl)-Gly]-boroLys(CH=NH)-OH HC1;
MS (ESI) (M+H)+ 403.0 Example 77.1.1 Hydrocinnamoyl-[N-(Cyclopropyl)-Gly)-boroLys(CH=NH)-C10H16 HC1; MS (NH3CI) (M+H)+ 537.3 Example 78._1.2 Phenoxyacetyl-[N-(Cyclopropyl)-Gly]-boroLys-OH HC1; MS
(ESI) (M+H)+ 378.3 Examz~l a 7 8 . 1. 3 Thiophenacetyl-[N-(Cyclopropyl)-Gly]-boroLys-OH HC1; MS
(ESI) (M+H)+ 394.2 SUBSTITUTE SHEET (RULE 26) Fxamr~le 79.1.2 Phenoxyacetyl-(N-(Cyclopropyl)-Gly]-boroLys-C10H16 HC1; MS
(NH3CI) (M+H)+ 512.3 Fxamn~e 79.1.3 Thiophenacetyl-[N-(Cyclopropyl)-Gly]-boroLys-C10H16 HC1;
' MS (NH3CI) (M+H)+ 528.3 SUBSTITUTE SHEET (RULE 26) WO 95/09634 ~ ~ ~ PCTIUS94J11280 Tables 1-79 H H H H
A Y- A R1 1- ~ ~ A Y- ~ A
Ra o Ra o X ~ ~ X
X X
Formula I Formula II Formula III Formula IV
Table 1 Formula I : A = -B(OH)2 ; X = guanidinyl ; R3 = table below ; R11 = CH3 .1 .2 .3 1.1 -C(O)Ph -C(O)CH~Ph -C(O)CH~CH2Ph 1.2 -C(O)CH~OPh -C(O)CI-hNHPh -C(O)CH~SPh 1.3 -Cl0)o-PhOH -Cl0)m-I'hOI-I -C(O) -PhOH

1.4 -C(O)o-PhCI-I20H -C(O)m-PhCH~OIi -C(O)p-PhCH20H

1.5 -C(O)o-PhCOOli -C(O)rn-PhCOOH -C(O) -PhCOOH

1.6 -C(O)o-PhCH2COOH -C(O)m-PhCH~COOH -C(O)p-PhCH2COOH

1.7 -C(O)naphth-1-yl -C(O)CH~(naphth-1-yl)-C(O)CH2CH2(napth-1-yl) 1.8 -C(O)naphth-2-yl -C(O)CH2(naphth-2-vl-C(O)CH2CH2(napth-2-yl) 1.9 -C(O)o-biphenyl -C(O)CH2(o-biphenyl)-C(O)CH2CH2(o-biphenyl) 1.10 -C(O)m-biphenyl -C(O)CH2(m-biphenyl)-C(O)CH2CH2(m-biphenyl) 1.12 -C(O)p-biphenyl -C(O)CH2(p-biphenyl)-C(O)CH2CH2(p-biphenyl) 1.13 -C(O)o-PhOPh -C(O)CIi2(o-PhOPh) -C(O)CH2CH2(o-PhOPh) 1.14 -C(O)m-PhOPh -C(O)CH2(m-PhOPh) -C(O)CH2CH2(m-PhOPh) 1.15 -C(O)p-PhOPh -C(O)CI-I2(p-PhOPh -C(O)CH~CH2(p-PhOPh) ) 1.16 -C(O)o-PhNHPh -C(O)CH2(o-PhNHPh) -C(O)CH~CH2(o-PhNHPh) 1.17 -C(O)m-PhNI-IPh -C(O)CH2(m-PhNI-IPh)-C(O)CH2CH2(m-PhNHPh) 1.18 -C(O)p-PhNHPh -C(O)CH2(p-PhNHPh) -C(O)CH2CH2(p-PhNHPh) 1.19 -C(O)o-PhSPh -C(O)CI-I~(o-1'hSPh)-C(O)CH2CH2(o-PhSPh) 1.20 -C(O)m-PhSPh -C(O)CII2(m-PhSPh) -C(O)CH2CH2(m-PhSPh) 1.21 -C(O)P-PhSPh -C(O)CH2(p-PhSPh -C(O)CH~CH2(p-PhSPh) ) 1.22 -C(0)o-PhCH2SPh -C(O)CI-I2(o-PhCH2SPh)-C(O)CH2CH2(o-PhCH2SPh) 1.23 -C(O)m-PhCH2SPh -C(O)Cl-12(m-PhCH2SPh)-C(O)CH2CH2(m-PhCH2SPh) 1.24 -C(O)p-PhCH2SPh -C(O)Cl-12(p-PhCH2SPh)-C(O)CH2CH2(p-PhCH2SPh) 1.25 -C(O)adarrutntvl -C(O)CH2(adamwuvl) -C(O)CH2CH2(adamantyl) 1.26 -C(O)cvclopentyl -C(O)C132(cvclopenrvl)-C(O)CH2CH2((cyclopentyl) 1.27 -C(O)cyclohexvl -C(O)Cl-12(cyclohexyl)-C(O)CH2CH~(cvclohexyl) 1.28 -C(O)CI-I20(cvclopentyl)-C'(O)C1~2M-I(cyclopentyl)-C(O)CH2S(cyclopentvl) 1.29 -C(O)CH20(cvclohexvl)-C(O)CH2N1I(cvclohexvl)-C(O)CI-I2S(cyclohexyl) 1.30 -C(O)pvridin-2-vl -C(O)C112(pyridin-2-vl)-C(O)CH2CH2(pvridin-2-yl) 1.31 -C(O)pyridin-3-yl -C(O)CI12(pyridin-3-yl)-C(O)CH2CH2(pyridin-3-yl) 1.32 -C(O)pytidin-4-yl -C(O)CIh(pyridin-4-yl)-C(O)CH~CH~(pvridin~-vl) 1.33 -C(O)furu~-2-vl -C(O)CI-i~(lltrm-2-vl)-C(O)CH~CH2(furan-2-yl) 1.34 -C(O)furan-3-yl -C(O)CII~lfuran-3-yl)-C(O)CI-hCH2(furan-3-yl) /G~
SUBSTITUTE SHEET (RULE 26) ~1743~.4 1.35 -C(O)thionhen-2-yl -C(O)CH~(thioPhen-2-vl) -C(O)CH~CH~(thioPhen-2-yl) 1.36 -C(O)thio~hen-2-yl -C(O)CH~(thioPhen-2-vl) -C(OICH~CH~(thioPhen-2-yl) 1.37 -C(O)imidazo-2-yl -C(O)CH~(imidazo-2-vl) -C(O)CH2CH~(imidazo-2-yl) 1.38 -C(Ok~xazo-2-yl -C(O)CH~(oxazo-2-yl) -C(O1CH~CH~(oxazo-2-yl) 1.39 -C(O)thioazo-2-vl -C(O)CH~(thioazo-2-vi) -C(O)CH~CH~(thioazo-2-vl) 1.40 -C(O)henzofuran-2-yl -C(O)CH2(hcnzofuran-2-yl) -C(O)CH2CH2(benzofuran-2-vl) 1.41 -C(O)benzoftuan-3-yl -C(U)Crl2(benzoftuan-3-yl) -C(O)CH2CH2(benzofuran-3-vl) 1.42 -C(O)benzothiophen-2-yl -C(O)CH2(benzothiophen-2-yl) -C(0)CHZCH2(benzothiophen-2-vl) 1.43 -C(O)thiophen-2-vl -C(U)CH2(thio~hen-2-vl) -C(O)CH~CH2(thiaphen-2-yl) 1.44 -C(O)benzimidazo-2-yl -C(O)CH2(henzimidazo-2-yl) -C(O)CH2CH2(benzimidazo-2-vl) 1.45 -C(O)benzoxazo-2-yl -C(O)CH2(henzoxazo-2-yl) -C(O)CH2CH2(benzoxazo-2-vl) 1.46 -C(O)benzothiazo-2-yl -C(U)CH2(benzothiazo-2-yl) -C(O)CH2CH2(benzothiazo-vl) 1.47 -C(O)o-Ph(P(O)Pln) -C(O)m-Ph(P(U)Ph~) -C(O)p-I'h(P(O)Ph3) 1.48 -C(O)Ph-2-(fluoren-9-vl) -C'(O)Ph-3-(fluoren-9-vl) -C(O)Ph-4-(fluoren-9-vl) 1.49 -C(O)N-indolin-2-one -Cl0)indolin-2-vl -C'.(U)indol-2-vl 1.50 -C(O)cyclopentyl-2-(Ph) -C(U)cyclohexyl-2- (Ph) C(O)C(CH3)2NHS02(naphth -2-vl) 1.51 -C(O)pytrolidin-3-yl-4-(Ph) -C(O)tetrahydrofuran-3-yl-4-(Ph) -C(O)tetrahydrothiophen-3-yl-4-(Ph) 1.52 -C(O)tetrahydmnaphth-1-yl -C(O)tetrahvdmna~hth-2-yl -C(O)cyclopropyl-2,2-(Ph2) 1.53 -C(O)tetrahydmisoquinolin-1- -C(O)tetrahydroisoquinolin-3-yl -C(O)Cl-I2((2-oxo)indolin-3 yl vl) 1.54 -C(O)CH2(N-benzimidazol-2- -C(O)CIi2(N-henzoxazol-2-one) -C(U)CH2(N-benzothiazol-2-one) one) 1.55 -C(O)CH2(N-dihydrounidazol- -C(U)CH2(N-dihydrooxazol-2- -C(U)CH2(N-dihydrothiazol-2-2-one) one) one) 1.s6 ~co- ~co-1~ N O !~ N O l~ N 1 ' ~~ i i 1.57 O O O
a a a -OC..N NH -OC~N O -OC~N S
1.58 -OC O -OC, -OC O -r,N ~ I ~ CNJ t,NUO
U
N
~I
1.59 -C(O)N(CH~)CI-I2Ph -C(U)N(C'21i5)ClI2Ph -C(O)N(C3H7)CH2Ph SUBSTITUTE SHEET (RULE 26) ~~74~1~4 1.60 -C(O)pytidin-3-Yl-S-(Ph ) -C(U)Ph-3-(Cli~(U~ioOhen-2-vl)) -C(O)Ph-3-(CH2Ph) 1.61 -C(O)C(CH~)20Ph -C(U)CII(C~I-I~)UPh -C(O)CH~OCH~Ph 1.62 -C(O)CH~O(o-PhCH201I) -C(O)Cl-I2U(m-PhCH~OH) -C(O)CH20(p-PhCH20H) 1.63 -C(O)CH20(o-PhC001-I) -C(O)CI-hO(tn-I'hCOOH) -C(O)CH~U(p-PhCOOH) 1.64 -C(O)CH~O(o-PhCOOCI-I~) -C(O)CH~O(m-PhCUOCH~) -C(O)CIi~U(P-PhCOOCH~) 1.65 -C(O)CH~U(o-PhCH~CUU)-I) -C(O)C'I-i2U(m-1'hCl-hCOOH) -C(U)CH2U(p-PhCH2COOH) 1.66 _pC O
~NUo J
/ \
Table 2 Formula I : A = -B(OH)2 ; X = guanidinYl ; R3 = t~nble below ; R11 = -CI-I2(p-PhOH).
~ .3 .~

2.1 -C(O)Ph -C(O)C'.I-I~I'h -CIOlCH2C1-l2Ph 2.2 -C(O)CI~~OPh -C(O)CI-hNI-IPh -C(O)CH2SPh 2.3 -C(O)o-PhOH -C(U)m-I'hOI-I -C(U) -PhOH

2.4 -C(U)o-Ph CH20I-I -C(U)m-I'hC1120H -C(O)P-PhCH20H

2.5 -C(O)o-PhCOOH -C(O)m-PhCOOIi -Cl0) -PhCOOH

2.6 -C(O)o-PhCH2COOH -C(U)m-PhCI-12COOH-C(O)p-PhCH2COOH

2.7 -C(O)naphUrl-yl -C(U)CH~(naPhth-I-yl)-C(O)CH2CH2(napth-1-vl) 2.8 -C(O)naphth-2-yl -C(O)CH2(naphth-2-yl-C(O)CH~CH2(napth-2-yl) 2.9 -C(O)o-biphenyl -C(O)Cl-h(o-biphenyl)-C(U)CH2CH2(o-biphenyl) 2.10 -C(O)m-biphenyl -C(O)CH2(tn-biphenyl)-C(O)CI~2CH2(m-biphenyl) 2.12 -C(O)p-biphenyl -C(U)CI-1~(p-biphenyl)-C(O)CH2CH2(p-biphenyl) 2.13 -C(Ok>-PhOPh -C(O)C1h(o-I'hOPh -C(O)CH2CH2(o-PhOPh) ) 2.14 -C(O)m-I'hOPh -C(O)CH~(tn-PhOPh)-C(O)CH2CH?(m-PhOPh) 2.15 -C(O)P-PhOPh -C(O)CH~(P-1'hOPh -C(O)CH~CH2(p-PhOPh) ) 2.16 -C(O)o-PhNHPh -C'(O)CH2(o-('hNl-IPh)-Cl0)CH2CH2(o-PhNHPh) 2.17 -C(O)m-1'hNl-II'h -C(O)C'I-I~(m-PhNI-IPh)-C(U)CI-12CH2(m-PhNHPh) 2.18 -C(U)p-PhNHPh -C(U)CI-12(p-PhNI-iPh)-C(O)CH2CH2(p-PhNHPh) 2.19 -C(O)o-PhSPh -C(O)C1 h(o-I'hSPh)-C(O)CH2CH2(o-PhSPh) 2.20 -C(O)m-PhSPh -C(U)CH2(m-PhSPh) -C(O)CH2CH2(m-PhSPh) 2.21 -C(O)s-PhSPh -C(O)CIh(p-PhSPh) -C(O)CH2CH2(p-PhSPh) 2.22 -C(U)o-PhCH2SPh -C(O)CII2(o-I'hCII~SPh)-C(O)CH2CH2(o-PhCH2SPh) 2.23 -C(U)tn-PhCH2SPh -C(U)Cl-I2(tn-PhCH2SPh)-C(O)CH2CH2(m-PhCI-hSPh ) 2.24 -C(U)p-PhCI~I~SPh -C(U)CI-12(p-PhCII~SPh)-C(O)CH2CH2(p-PhCH2SPh) 2.25 -C(O)aclarri<~ntyl -C(O)CI-t2(adamarrtvl)-C(U)CH2CH2(adartrantvl) 2.26 -C(O)cyclopentvl -C(O)C'I-12(cyclopentvl)-C(O)CI-I2CI-12((cyclopentyl) 2.27 -C(O)cvclohexyl -C(U)Cl h(cvclohexyl)-C(U)CH2CI-I2(cyclohexyl) 2.28 -C(O)CH~U(cvclopentvl)-Cl0)C1U~NL1(cvclopentvl)-C(O)CH2S(cyclopentyl) 2.29 -C(O)CH~O(cvclohexvl)-C'(U)CI-I2NLI(cvclohexvl)-C(U)CI-I2S(cvclohexyl) 2.30 -C(O)pytidin-2-vl -C(U)CI-h(pytidin-2-yl)-C(O)CI-hCI-I2(pyridin-2-yl) 2.31 -C(O)pyridin-3-yl -C'(O)CH~lpyriclin-3-vl)-C'.(U)CI-I~CH~(pvridin-3-yl) / (o'~
SUBSTITUTE SHEET (RULE 26) ,;~.. WO 95/09634 ~ PCTIUS94111280 2.32 -C(U)P~din-4-vl -C(U)Cl-h(Pyridinjl-vl) -C(U)C11~CH7(Pyridin-4-yl) 2.33 -C(O)furm-2-vl. -C(O)Clt~(furan-2-yl) -C(UlC)-i~CH~(furan-2-yl) 2.34 -C(O)furm-3-yl -C(O)CH?(furv~-3-yl) -C(O)CH~CH~(furan-3-yl) 2.35 -C(O)Utio~hen-2-v1 -C(U)CH~(U~ioPhen-2-yl) -C(U)CH~CH~(thiophen-2-yl) 2.36 -C(O)thiophen-2-yl -C(O)CI-I~(UiioPhen-2-yl) -C(O)CH~CH~(thiophen-2-yl) 2.37 -C(O)imidazo-2-v_ I -C(O1CI-I~(imidazo-2-vl) -C(O)CH~CH~(imidazo-2-yl) 2.38 -C(O)oxazo-2-vl -C(U)CII2(oxazo-2-yl) -C(O)CH?CH?(oxazo-2-yl) 2.39 -C(O)thioazo-2-vl -C(O)CH2(Uiioazo-2-yl) -C(O)CH~CH~(U~ioazo-2-yl) 2.40 -C(O)benzofuracr2-yl -C(O)CH2(hcnzofurzn-2-yl) -C(O)CH2CH2(benzofuran-2-vl) 2.41 -C(O)henzofuran-3-yl -C(O)CH2(hcnzofuran-3-yl) -C(O)CI-I2CH2(benzofuran-3-vl) 2.42 -C(U)henzoUuoPhen-2-yl -C(O)CH2(hcnzothiophen-2- -yl) C(O)CH2CH2(benzothiophen-2-vl) 2.43 -C(O)Uiiophen-2-yl -C(O)CI-!~(thiophen-2-yl) -C(O)CH~CH~(thioPhen-2-yl) 2.44 -C(U)benzunid azer2-yl -C(O)CI I?(hcwzimid~tzo-2-yl) -C(O)CH2CH2(benzimidazo-2-vl ) 2.45 -C(O)benzoxazo-2-yl -C(U)CI-I2(bcnzoxazo-2-yl) -C(U)CH2CH2(benzoxazo-2-vl) 2.46 -C(O)txnzothi~zo-2-yl -C(O)CIU 2(benzoU~iazo-2-yl) -C(U)CH2CFI2(benzothiazo-Z-vl) 2.47 -C(O)o-Ph(P(U)Ph~) -C(U)m-Ph(P(O)Ph3) -C(U)p-Ph(P(O)Ph3) 2.4R -C(O)Ph-2-(Ilunren-9-vl) -C(O)Ph-3-(fluoren-9-vl) -C(O)Ph-4-(fluoren-9-vl) 2.49 -C(O)N-indolin-2-cme -C(O)ind~lin-2-vl -C(O)indol-2-vl 2.50 -C(O)C(C1I3)2N1-IS02(n<lnhU~- -C(U)cycloPentyl-2-(Ph) -C(U)cyclohexyl-2-(Ph) 2-vl) 2.51 -C(O)ryrrolidin-3-yl~-(Ph) -C(U)tctrihydrofuran-3-yl~- -C(O)tetrahydroUiiophen-3-yl-(Ph ) 4..(Ph) 2.52 -C(O)tetrahvdronaphUi-1-vl -C(U)tctr~hvdmnaphU~-2-yl -C(O)cvclopropyl-2,2-(Ph2) 2.53 -C(O)tetr~hydroisoquinolin-1-yl -C(U)tetrahydroisoquinolin-3- -C(O)CH2((2-oxo)indolin-3 yl vl) 2.54 -C(O)CI-12(N-henzimidazol-2- -C(O)Cl-i2(N-bcnzoxazol-2- -C(U)CH2(N-benzothiazol-2-onel cane) one) 2.55 -C(O)CH2(N-dihydroimidazol- -C(U)Cl h(N-dihydrooxazol-2- -C(U)Cl-I2(N-dihydmthiazol-2-2-one) one) one) 2.56 rC0- ~CO-O
I~ N O I~ N I~ N I~
i i 2.57 p O O
-OC~.N~NH -OC~NUO -OC~N~S
~ lo.~
SUBSTITUTE SHEET (RULE 26) ., ~17~~i~v.
WO 9510963:1 PCTlUS9al11280 2.58 -OC O -OCR -OC O
IN / I \ CN~ lNllp U
/\ N /\
\I
2.59 -C(O)N(CH3)CH~Ph -C(O)N(C21I5)CI-I2Ph -C(O)N(C3H~)CH2Ph 2.60 -C(O)~yridin-3-yl-5-(Ph) -C(O)Ph-3-(CI~i2(U~iophen-2- -C(O)Ph-3-(CH2Ph) vl)) 2.61 -C(O)C(CH3)20Ph -C(O)Cl1(C2II5)OPh -C(O)CH~OCH~Ph 2.62 -C(O)CH20(o-PhCH~OH) -C(O)CII~O(m-PhCH~UH) -C(O)CII20(p-PhCH?OH) 2.63 -C(O)CH~OIo-PhCOOH) -C(O)CIi~O(m-PhCOOI-i) -C(O)CH20(P-PhCOOH) 2.64 -C(O)CH~O(o-PhCOOCH3) -C(O)CH2U(m-I'hCOOCH3) -C(O)CH20(P-PhCOOCH3) 2.65 -C(O)CH20(o-PhCH2CUOH) -C(U)CII20(m- -C(O)CH20(P-PhCH2COOH) PIICH~COOI i) 2.66 _ p C p ~N~O
J
/ \
Table 3 Formula I : A = -B(OH)2 ; X = aulrudmyl : R3 = t~~ble helow ; R11 = -CH2CIi2Ph.
.1 .2 .3 3.1 -C(O)Ph -C(O)CH2Ph -C(O)CH~CH2Ph 3.2 -C(O)Cl-I20Ph -C(O)ClI2NiIPh -C(O)CH2SPh 3.3 -C(O)o-Ph01-I -C(O)m-Ph01-I -C(Ol PhOH

3.4 -C(0)o-PhCH~OH -C(O>m-PhCH~OtI -C(O)P-PhCI-hOH

3.5 -C(O)o-Ph C001-I -C(U)m-PhC0013 -C(O) -PhCOOH

3.6 -C(O)o-PhCI-hCOOIi -C(O)m-PhCI-hCOOIi-C(O)P-PhCH~COOH

3.7 -C(O)naPhUl-I-vl -C(U)Cl i~(naPhU~-I-vl)-C(O)CI I~CH~(napU~-1-vl) 3.8 -C(U)naPhUl-2-vl -C(U)Cll~(naPluh-2-vl-C(O)CH~CII~(napU~-2-vl) 3.9 -C(O)o-hiPhenyl -C(U)CII~(o-hiPhenvl)-C(O)CH~CH~(o-hiphenvl) 3.10 -C(O)m-hiPhenvl -C(U)CIh(m-hiPhenvl)-C(O)CH2CH2(m-hiphenyl) 3.12 -C(O)P-hiPhenvl -C(O)CI-h(P-hiphenvl)-C(O)CH2CH2(p-biphenyl) 3.13 -C(O)o-PhOPh -C(U)CI-I2(o-PhOPh)-C(U)CH~CH2(crPhOPh) 3.14 -C(Olm-PhOPh -C(U)CH2(m-PhOPh) -C(U)CH~CH2(m-PhOPh) 3.15 -C(O)P-PhOPh -C(O)CI1~(P-PhOPh)-C(O)CH2CH2(P-PhOPh) 3.16 -C(O)o-1'hNHPh -C(0)CI-I~(o-PhIVI-IPh)-C(O)CH~CH2(o-PhNHPh) 3.17 -C(O)m-PhNI-IPh -C(O)CIl2(m-I'IiNIIPh)-C(O)CH2CH2(m-PhNHPh) 3.18 -C(O)P-PhNl3Ph -C'(U)CI12(P-1'IIIVtIPh)-C(U)CH2CH2(P-PhNHPh ) 3.19 -C(O)o-PhSPh -C(U)C1I~(o-PhSPh)-C(U)CH2CH2(o-PhSPh) 3.20 -C(O)m-PhSPh -C'.(U)C'll~(m-PhSPh)-C(O)CI-I~CH~(m-PhSPh) 3.21 -C(O)P-PhSPh -C(O)C13~(~-1'hSPh)-C(O)CH2Cli2(P-PhSPh) 3.22 -C(O)o-PhCIi~SPh -C(O)CIh(o-I'hC:II~SPIO-C(0)Cl-I~CH~(o-PhCHZSPh) ((c~
SUBSTITUTE SHEET (RULE 26) ~1'~ 4314 , W0 95/09634 ~ PCTlUS94111280 3.23 -C(O)m-PhCH2SPh -C(O)CII2(tn-PhCI-l2SPh) -C(O)CH2CH2(m-PhCH2SPh) 3.24 -C(U)P-PhCHZSPh -C(O)CI1~(r-1'hCl-i~Sl'h) -C(O)CIi2CH?(P-PhCH2SPh) 3.25 -C(O)adatruvrttyl -C(O)CH?(ad.un~ttttyl) -C(O)CI-hCI-h(adamantyl) 3.26 -C(O)cvcloPentvl -C(U)CIh(cvcloPentvl) -C(U)CH~CH~((cvcloPentyl) 3.27 -C(O)cvclohexyl -C(O)CH~(cyclohexyl) -C(O)CH~CH~(cyclohexyl) 3.28 -C(O)CH~O(cvcloPentyl) -C(O)CII~M-1(cvcloPentvi) -C(O)CH~S(cvcloPentvl) 3.29 -C(O)CH20(cyclohexvl) -C'(O)CH2N1-1(cyclohexvl) -C(O)CH2S(cyclohexyl) 3.30 -C(O)Pyridin-2-yl -C(O)CI12(Pyridin-2-yl) -C(O)CH2CH2(ryridin-2-yl) 3.31 -C(O)Pytidin-3-yl -C(U)Cli~(Pytidin-3-vl) -C(U)CH2CH2(pytidin-3-vl) 3.32 -C(O)Pyridin-4-yl -C(O)CH~(Pyridin.ll-yi) -C(O)CH~CH2(pvridin-4-yl) 3.33 -C(O)ftirart-2-yl -C(O)CH~(furtn-2-yl) -C(U)CH~CH~(furan-2-vl) 3.34 -C(O)furan-3-yl -C(U)CH2(furtn-3-yl) -C(O)CI-12CH2(furan-3-yl) 3.35 -C(O)Utionhen-2-yl -C(O)Clf~(diiorhen-2-vl) -C(U)CH~CH2(thioPhen-2-yl) 3.36 -C(O)thiophen-2-vl -C(O)CII~(tluoPhcn-2-vl) -C(U)CH~CH~(d~ioPhen-2-yl) 3.37 -C(U)imid<~tzo-2-v_ I -C(O)Cl-i~(imidazo-2-yl) -C(O)CH~CHZ(imidazo-2-yl) 3.38 -C(O)oxazo-2-vl -C(O)CH~(oxazo-2-yl) -C(O)CH~CH?(oxazo-2-yl) 3.39 -C(U)thioazo-2-yl -C(U)CH?(tluouzo-2-yl) -C(O)CH~CH~(thioazo-2-yl) 3.40 -C(U)benzofuran-2-yl -C:(O)Cl-I2(benzofurm-2-yl) -C(O)CH2CH2(benzofuran-2-vl) 3.41 -C(U)benzofuratr3-yl -C(U)Cl-12(hcnzofuran-3-yl) -C(O)CH2CH2(benzofuran-3-vl) 3.42 -C(O)benzoUiiophen-2-yl -C(U)CI-12(benzothiophen-2- -yl) C(O)CH2CI-I2(benzothiophen-2-vl) 3.43 -C(O)thiophen-2-vl -C(O)Clh(thionhen-2-yl) -C(O)CH~CH~(d~iophen-2-yl) 3.44 -C(O)henzimidazo-2-yl -C(U)Cl-I2(henzimidazo-2-yl) -C(U)CH2CH2(benzimidazo-2-vl) 3.45 -C(U)benzoxazo-2-yl -C(U)CI-I2(benzoxazo-2-yl) -C(O)CH2CH2(henzoxazo-2-vi) 3.46 -C(O)benzothuzzo-2-yl -C(O)CIH2(henzothiozo-2-yl) -C(U)CH2C1-12(benzothiazo-2-vl) 3.47 -C(O)o-Plt(P(O)Ph~) -C(U)tn-Ph(P(O)Ph~) -C(O)P-Ph(P(O)Ph3) 3.4R -Cl0)Ph-2-((luoren-9-vl) -C(U)I'h-:I-(nttoren-9-vn -C(O)Ph-4-(tluoren-9-vl) 3.49 -C(O)N-intlolin-2-one -C(U)indolin-2-vl -C(U)intlol-2-vl 3.50 -C(O)C(CH3)2NHSU2(naphth- -C(U)cyclo rentyl-2-(Ph ) -C(U)cyclohexyl-2-(Ph) 2-vl) 3.51 -C(U)rytrolidin-3-yl-4-(Ph) -C(U)tctrahydrofurm-3-yl-4- -C(U)tetrthydrothiophen-3-yl-(Ph) 4-(Ph) 3.52 -C(O)tetrahyclinnaphth-1-vl -C(U)tctrahvdmnanhth-2-yi -C(U)cvcloPropyl-2.2-(Ph2) 3.53 -C(O)tetrthydroiu~quinolin-1-yl -C(U)tctrahydroisoquinolin-3- -C(O)CH2((2-oxo)indolin-3-yl vl) 3.54 -C(O)CH2(N-hcnzimiduzol-2- -C(U)CI-l2(N-bcnzoxazol-2- -C(O)CH2(N-henzothiazol-2-one) one) one) 3.55 -C(O)C1-i2(N-diltydmitnidazoi- -C(U)CI-i2(N-dihydmoxazol-2- -C(O)CH2(N-dihydrothiazol-2-one) one) 2-one) 3.56 rC0- ~CO-O
l~ N O l_~ N w N w SUBSTITUTE SHEET (RULE 26) WO 95109634 ~,, ~, ~ ~ J ~ l~' PCTIUS94111280 3.57 O O O
a _OC''N NH -OC~N~O -OC~NUS
3.58 -OC O -OCR -OC O
IN ~ I ' CN~ 1NJ10 U
N
'I
3.59 -C(O)N(CH~)CI-I2Ph -C(U)N(C~HS)CH2Ph -C'(O)N(C3H7)CH2Ph 3.60 -C(O)pyridin-3-yl-5-(Ph) -C(U)Ph-3-(CH2(thiophen-2- -C(O)Ph-3-(CH2Ph) vl)) 3.61 -C(O)C(CI-I~)20Ph -C(U)CII(C~1-IS)UPh -C(O)CH20CH2Ph 3.62 -C(O)CH2U(o-PhCIIZOH) -C(O)CIi2U(m-PhCH~OH) -Cl0)CI-i~0(P-PhCH~OHI
3.63 -C(O)CH20(o-Ph COOH) -C(O)CI I~U(m-PhCOOH) -C(O)C1I2U(p-PhCOOH) 3.64 -C(O)CH~O(o-PhCUOCII~) -C(O)C'1-1~U(m-PhCOOCII~) -C(U)CH2Ul~-PhCOOCH~) 3.65 -C(U)CH2U(o-PhCI-I?COUII) -C(O)CII2U(m- -C(U)CH2U(p-PhCH2CUOH) !'hCI I ~COOI-I ) 3.66 _ O C O
~NxO
able 4 Formula I : A = -B(OI-1)2 ; X = guanidinyl ; R3 = table below ; Ril = -Ph.

.1 2 .3 ~

4.1 -C(O)Ph -C(U)CI-hPh -C(O)CH~CH~Ph 4.2 -C(O)CH~OPh -C(O)CId~NH1'h -C(O)C)-I?SPh 4.3 -C(U)o-PhOH - -C(U)m-PhUII -C(O) -PhOH

4.4 -C(U)o-PhCH~UII -C(U)m-PhCIhUI~ -C(U)p-PhCH20H

4.5 -C(O)n-PhC001-i -C'(O)m-PhC00I-I -C(Ol -PhCOOH

4.6 -C(O)o-PhCI-i~COOH -C(U)m-I'hCI-I~COUH-C(U)p-PhCH7COOH

4.7 -C(U)naphth-1-vl -C(O)Cll~(naPhth-1-yl)-C(O)CH2CI~I~(nand~-1-yl) 4.8 -C(O)naPhti~-2-yl -C(O)Cll~lna~hth-2-yl-C(O)CI-I2CH2(napth-2-yl) 4.9 -C(U)o-hiphenvl -C(O)CII~(o-biphenyl)-C(O)CH~CH~(o-hiphenvl) 4.10 -C(U)m-biphenyl -C(O)CIh(m-biphenyl)-C(O)CH~CH2(m-biphenyl) 4.12 -C(U)p-biphenyl -C(O)CII~(p-biphenyl)-C(U)CI-I2CH2(p-hiphenvl) ' 4.13 -C(O)o-PhOPh -C(U)CI I~(o-PhOPh-C(O)CI-I2CH2(o-PhOPh) ) 4.14 -C(O)m-I'hOPh -C'(O)C'.l-l~(m-PhOPh)-C(O)CH~CH2(m-PhOPh) 4.15 -C(O)p-PhOPh -('(O)CI1~(p-I'hUl'h)-C(O)CH2CI-1?(p-PhOPh ) 4.16 -C(O)o-I'hNI-IE'h -C'(U)C11~(o-I'hNtIPh)-C(O)CH2CH~(o-PhNHPh) 4.17 -C(O)m-1'hNI-IPh -C(O)CII~(m-PUNI-IPh)-C(U)CH~CHZ(m-PhNHPh) 4.18 -C(U)p-PhNI-IPh -C(O)C11~(p-PhIVHPh)-C(O)CH?CH2(p-PhNHPh) 4.19 -C(O)o-PhSPh -C(U)C'1-I~(o-I'hSPh)-C(U)Cl-I?CH?(o-PhSPh) leg SUBSTITUTE SHEET (RULE 26) .-. WO 95109634 20 -C(Uhn-1'hSPh -C'(O)C'Ii~lm-Ph -C(U)C1I~CH?lm-PhSPh) . -C(O)p-PhSPh -C(U)CIi~(P-PhSPh)-C(O)CI-I2CH2(P-PhSPh 21 ) . -C(O)o-PhC1-hSPh -C(O)CIi~(o-PhCI-I~SPh)-C(U)CH~CH2(o-PhCH2SPh) 4.22 4 -C(O)m-PhCH2SPh -C(O)C1I2(m-PhCI-I2SPh)-C(U)CH2CH2(m-. PhCI-hSPh ) 4.24 -C(O)p-PhCH~SPh -C(O)CH~(P-PhCH~SPh)-C(O)CH~CH2(P-PhCH~SPh) 4 -C(U)adamantyl -C(U)CI-I2(adacnantyl)-C(O)CH~CH?(adamantyl) . -C(U)cyclopentvl -C(O)CH~(cvcloPcntyl)-C(O)CH~CH~((cyclopentyl) . clohexyl) (c C(O)CH~CH

4.27 -C(O)cvclohexvl -C(O)Cli~(cvclohexyl)2 y -4.28 -C(O)CI-hO(cvclopentvi)-C(U)CH~NI-1(cvcloPentvl)-C(U)Cl-hS(cvclopentyl) 4.29 -C(O)CH?O(cyclohexvl)-C(O)CI-I~NI-I(cyclohexyl)-C(O)CH?S(cyclohexyl) 4.30 -C(O)pyridin-2-yl -C(O)CI-1~(Pyridin-2-vl)-C(O)CH2CH2(pyridin-2-yl) 4.31 -C(O)pyridin-3-yl -C(O)CIh(Pyridin-3-yl)-C(O)CH?CH2(ryridin-3-yl) 4.32 -C(O)Pvri~in-4-v_ -C(U)CII2(Pyridin-4-vl)-C(U)CH~CH2(pyridin-4-yl) l 4.33 -C(O)furan-2-yl -C(O)Clhlfuran-2-yl)-C(O)CH2CH2(furan-2-yl) 4.34 -C(O)furm-3-yl -C(U)CII2(furnn-3-yl)-C(O)CH~CH2(furan-3-yl) 4.35 -C(O)U~ioPhen-2-vl -C(O)CH~(U~ioPhen-2-vl)-C(O)CH~CH~(thiophen-2-yl) 4.36 -C(O)U~ioPhen-2-vl -C(O)C'.H~(tl~ioPhen-2-vl)-C(U)CH~CH~(thioPhen-2-yl) 4.37 -C(U)imidazo-2-yl -C'.(U)CII~(imidazo-2-vl)-C(U)Cl-hCH2(imidazo-2-yl) 4.38 -C(O)oxazo-2-vl -C(U)Cll~(oxazo-2-yl)-C(O)CH~CH~(oxazo-2-yl) 4.39 -C(O)thioazo-2-vl -C(U)CI~2(Uiioazo-2-yl)-C(U)CH~CH~(Uiioazo-2-yl) 4.40 -C(O)henzolurur2-yl-C(O)CH2(bcnzofuran-2-yl)-C(U)CH2CH2(benzofuran-2-I) 4.41 -C(U)benzofuran-3-yl-C(O)CII2(benzofurut-3-yl)-C(O)CH2CH2(benzofuran-3-vl) 4.42 -C(U)henzoUuoPhcn-2-yl-C(U)CH2(henzothiophen-2--yl) C(O)CH2CI-I2(benzothioPhen-2-vl) 4.43 -C(O)Uuophen-2-yl -C(U)CI h(UtioPhen-2-vl)-C(O)CH~CH2(thioPhen-2-yl) 4.44 -C(O)benzimidazo-2-yl-C(U)CH2(benzimidazo-2-yl)-C(O)CH2CH2(benzimidazo-2-vl) 4.45 -C(O)henzox~zo-2-yl-C(O)CI12(hcnzoxazo-2-yl)-C(U)CHZCI-12(benzoxazo-2-vl) 4.46 -C(O)tx:nzoU~iazo-2-yl-C(U)C112(bcnzoU~iazo-2-yl)-C(O)C1I2CH2(benzothiazo-vl) 4.47 -Cl0)o-I'h(P(O)Ph~)-C(U)m-Ph(P(U )Ph3)-C(O)P-Ph(P(O)Ph3) 4.4R -C(OIPh-2-(lluorcn-9-vl)-C'(O)Ph-3-(lluoren-9-vl)-C(O)I'h-4-(t7uoren-9-I) 4.49 -C(O)N-indolin-2-cme-C'(U)indolin-2-vl-C(O)indol-2-vl 4.50 -C(O)C(CH3)?NIiSU?(narl~U~--C(O)cyclopentyl-2-(Ph)-C(O)cyclohexyl-2-(Ph) 2-vl) 4.51 -C(O)pyrolidin-3-yl-4-(Ph)-C(U)tetrahydroftuan-3-yl~--C(U)teuahydroUiiophen-3-yl-(Ph ) 4-(Ph) 4.52 -C(U)tctrahvdronaPhUi-1-vl-C(O)uu-.ihvdronaPhU~-2-yl-C(U)cvcloproPyl-2,2-(Ph2) 4.53 -C(U)tctrthydmisoquinolin-1-yl-C(U)tctrahydmiaoquinolin-3--C(U)CI-12((2-oxo)indolin-3-vl vl) 4.54 -C(O)CI72(N-tx:nzunidazol-2--C(U)Cl-I2(N-bcnzox~zol-2--C(O)CH2(N-benzothiazol-2-one) one) one) 4.55 -C(O)C1I2(N-dihydmimidazol--C(U)CII2(N-~lihydrcx~x~zol-2--C(U)CI-i2(N-dihydmthiazol-2-2-one) one) one) ;~ (~9 SUBSTITUTE SHEET (RULE 26) ~174~314 4.56 rC0- rC0-O
N O I ~ N ~ N
I i i ~ / \ I i I i ~I
4.57 O O O
-OC''NUNH -OC~N~O -OC~N~S
4.58 -OC O -OCR -OC O
IN ~ 1 ~ CN~ lNUO
/\ ~ N /\
~I
4.SO -C(U)N(CI-I3)CIhPh -C(UlN(C?Ii5)CH?Ph -C(U)N(C~H~)CH?Ph 4.60 -C(U)pyridiu-3-yl-S-(Ph ) -C'.(O)1'h-3-(CII?(thiophen-2- -C(U)Ph-3-(CH2Ph) vl)) 4.61 -C(O)C(CI-I3)ZOl'h -C(U)Cli(C'~115)OI'h -C(O)CH?OCH?Ph 4.62 -C(O)CH~U(o-PhCI-I20H) -C(O)CI-I2U(m-l'hCH~OIi) -C(U)CH~O(P-PhCH?OH) 4.63 -C(O)CI-hU(o-I'hC001-i) -C(O)CI-hU(m-I'hCUUF-I) -C(O)Cl-hU(P-PhCOOH) 4.64 -C(O)CH20(o-PhCUUCH3) -C(O)CFI2U(m-PhCUOCH3) -C(O)CH20(P-PhCOOCH3) 4.65 -C(O)CH2U(o-PhCI-I2CUOH ) -C(O)CHI2U(m- -C(O)CH20(P-PhCH2COOH) PhCH2COOH) 4~~ -OC O
~NUO
J
/ \
~ rl D
SUBSTITUTE SHEET (RULE 26) '°° WO 95109634 ~ 1 '~ 4 3 Z 4 PCT~S94/11280 Table 5 Formula I : A = -B(OH)2 ; X = guanidinyl ; R3 = table below ; R11 = -CH2(naphth-2-yl).
~ .3 5.1 -C(O)Ph .1 -C(O)CH~I'h -C(OlCH2CH2Ph 5.2 -C(O)C>-I20Ph -C(U)CI-I2NHPh -C(O)CH2SPh 5.3 -C(O>n-PhOH -C(O)rn-PhOH -C(O) -PhOH
5.4 -C(U>o-PhCH20H -C(O)m-PhCH201-i -C(O)P-PhCH20H

5.5 -C(Ok~-PhCOOH -C(O)m-PhCOOH -C(O) PhCOOH
5.6 -C(O)o-PhCH2COOH -C(U)m-PhCH~COOH -C(O)p-PhCH~COOH
5.7 -C(U)naphth-1-yl -C(O)CH2(naphtlr-1-vl)-C(OlCH2CH~(napth-1-yl) 5.8 -C(O)naphth-2-yl -C(U)CI-I2(naphth-2-yl-C(O)CH2CH2(napth-2-yl) 5.9 -C(Ok~-biphenyl -C(O)CH~(o-hiPhenvl)-C(O)CH2CH2(o-biphenyl) 5.10 -C(O)m-biphenyl -L(O)CI-I2lm-biphenyl)-C(O)CH2CH2(m-biphenyl) 5.12 -C(O)p-biphenyl -C(O)Cl-1~(p-biphenyl)-C(O)CH2CH2(P-biphenyl) 5.13 -C(O)o-PhOPh -C(O)Cli~(o-PhOPh -C(O)CH2CH~(o-PhOPh) ) 5.14 -C(U)m-PhOPh -C(U)('I1~(m-I'h01'h)-C(O)CII2CH2(tn-PhOPh) 5.15 -C(O)s-PhOPIr -C(O)CI-I2(p-PhUPh)-C(O)CH2CH2(p-PhOPh) 5.16 -C(O)o-I'hNHPh -C(O)CI~~(ml'hNHPh)-C(O)CFi2CH2(o-PhNHPh) 5.17 -C(O)m-PhNHPh -C(O)Cll2(m-PhNIIPh)-C(O)CI-I2CH2(m-PhNHPh) 5.18 -C(O)p-PhNHPh -C(O)C112(p-PhNHPh)-C(O)CI-i2CI-12(p-PhNHPh) 5.19 -C(0)o-PhSPh -C(U)C1I~(o-PhSPh)-C(U)CH2CH2(o-PhSPh) 5.20 -C(O)m-PhSPh -C(O)CI-I~(m-PhSPh)-C(O)CH2CH2lm-PhSPh) 5.21 -C(O)p-PhSPh -C(O)CH2(p-PhSPh -C(U)CH2CH2(p-PhSPh) ) 5.22 -C(O)o-PhCI-I2SPh -C(U)CI-12(o-PhCII2SPh)-C(U)CH2CH2(o-PhCH2SPh) 5.23 -C(O)m-PhCIU2SPh -C(U)CH2(m-PhC'H2SPh)-C(O)CH2CH2(m-PhCH2SPh) 5.24 -C(O)P-I'hCli2SPh -C(U)CII2(P-PhCIi2SPh)-C(O)CH2CH2(P-PhCI-I2SPh) 5.25 -C(O)adarrtantyl -C(O)CHI2(adamantyl)-C(O)CH~CH2(adamantvl) 5.26 -C(O)cvclopentvl -C(O)C'.H~lcvclopentvl)-C(O)CII~CH~((cvclopentvl) 5.27 -C(U)cvclohexyl -C(O)C'.tl~(cvclohexvl)-C(O)CI-I2CH2(cyclohexvl>
-5.28 -C(U)Cl-120(cyclopentvl)-C(U)C1I2NIi(cvclopentyl)-C(O)CH2S(cvcloPentvl) 5.29 -C(O)CH2U(cvclohexyl)-C(O)CIi~NII(eyclohexyl)-C(O)CH2S(cyclohexyl) 5.30 -C(O)pyridin-2-vl -C(O)('lI~(pyridin-2-yl)-C(O)CH~CH2(pyridin-2-yl) 5.31 -C(O)pyridin-3-yl -C(U)C1I~(pyridin-3-yl)-C(O)CH~CH2(pyridin-3-yl) 5.32 -C(O)Pyridin-4-yl -C(U)C112(pyridin-4-yl)-C(O)CH2CH2(pyridin-4-yl) 5.33 -C(0)furan-2-yl -C(O)CI12(furan-2-vl)-C(U)CH2CH2(furan-2-vl) 5.34 -C(O)furan-3-yl -C(U)Cl-I~(furan-3-yl)-C(U)CI-I2CH2(fur<an-3-vl) 5.35 -C(O)thiophen-2-yl-C(O)ClI2(thioPhen-2-yl)-C(O)CH2CH2(thiophen-2-vl) 5.36 -C(U)thiophen-2-yl-C(U)CH2(tlioph -C(U)CH2CI-12(thiophen-2-en-2-yl) vll 5.37 -C(0)imidazo-2-yl -C(O)CH~(itnidazn-2-vl)-C(O)CH~CHZ(imidazo-2-yl) 5.38 -C(O)oxazo-2-vl -C(O)Cl-I~(oxazo-2-yl)-C(O)CH~CH2(oxazo-2-vl) 5.39 -C(O)thioazo-2-vl -C(O)C11~(thioazo-2-yl)-C(O)CH~CH~(thioazo-2-yl) SUBSTITUTE SHEET (RULE 26) WO 95109634 ~, ~ ~ ~ ~ ~ -~ PCTIUS94/11280 5.40 -C(O)henzofurun-2-yl -C(U)C'I-I2(tx:nzofuran-2-yl) -C(O)CH2CH2(benzofutan-2-vl) 5.41 -C(O)benzofur<vt-3-yl -C(O)CI-I2(henzofuran-3-yl) -C(O)CH2CH2(henzot'uran-3-vl) 5.42 -C(O)benzothiophen-2-yl -C(U)CIi2(henzothiophen-2- -yl) C(O)CH2CH2(benzothiophen -2-vl) 5.43 -C(O)thiophen-2-yl -C(U)CH2(U~iophen-2-yl) -C(O)CH2CH2(thiophen-2-vl) 5.44 -C(O)henzimidazo-2-yl -C(U)CH2(henzimidazo-2-yl) -C(O)CH2CH2(benzimidazo-2-vl) 5.45 -C(O)henzoxazo-2-yl -C(O)CI-12(benzoxazo-2-yl) -C(O)CH2CI-I2(benzoxazo-2-vl) 5.46 -C(O)henzothiazo-2-yl -C(U)CH2(henzothiazo-2-yl) -C(O)CH2CH2(henzothiazo-2-vl) 5.47 -C(O)o-Ph(P(U)Ph3) -C(U)m-Ph(P(U)Ph3) -C(O)P-Ph(P(O)Ph3) 5.48 -C(O)Ph-2-lt7u~ren-9-vl) -C'(U)Ph-3-(tlunren-9-vl) -C(UIPh-4-(lluoren-9-vl) 5.4~J -C(O)N-indolin-2-one -C(U)indolin-2-vl -C(O)incl~l-2-vl 5.50 -C(U)cyclopentyl-2-(Ph) -C(U)cyclohexyl-2-(Ph) C(O)C(CH3)2NIiS02(naPhth -2-vl) 5.51 -C(U)Pytrolidin-3-yl-4-(Ph) -C(U)tetr~hydrofuram-3-yl-4- -C(U)tetrahydroU~iophen-3-(Ph) vl~-(Ph) 5.52 -C(O)tetrattydrona~hth-1-vl -C'(U)tetrahvdmnaphth-2-yl -C(U)cvclopropyl-2.2-(Ph2) 5.53 -C(O)tetrattydroistxluinolin- -C(U)tetrW ydroisoquinolin-3- -C(O)C1~I2((2-oxo)indolin-3 I-yl yl vl) 5.54 -C(O)CH2(N-henzimidazol- -C(U)CI-f2(N-henzoxazol-2- -C(O)CH2(N-benzothiazol-2-2-one) one) one) 5.55 -C(O)CH2(N- -C(U)CI-I2(N-dihydrooxazol- -C(O)CH2(N-dihydrothiazol-dihvdroimidttzol-2-one) 2-one) 2-one) 5.56 rC0- ~CO-O O
I~ N Iv N Iw N Iw ,I ~ ~ ~ i i 5.57 O O O
-OC~-NUNH -OC~NU0 -OC~N~S
5.58 -OC O -OCR -OC O
IN ~ I \ ~N~ 1N110 N
\I
5.5> -C(O)N(CH~)CH~Ph -C'(U)N(C'~I15)CIIZPh -C(O)N(C3H7)CH2Ph 5.60 -C(O)pyridin-3-yl-5-(Ph) -C(O)1'h-3-(CIi2(thioPhen-2- -C(U)Ph-3-(CH2Ph) vl)) 5.61 -C(O)C(CII~)~Ol'h -C(C))Cll(C~115)UPh -C(O)CH~UCH2Ph ma SUBSTITUTE SHEET (RULE 26) WO 95/09634 ~ 17 4 314 pCTlUS94111280 5.62 -C(O)CI-I~O(o-f'hCII~UH) -C(O)CFI~OIm-PhCI-hOII) -_C(O)CI-I?U(p-PhCH20H) 5.63 -C(O)CH2U(o-PhCOOH) -C(O)CH?O(m-PhCOUH) -C(U)C~120(P-PhCOOH) 5.64 -C(O)CH~O(o-PhCOOClI~) -C(O)CH~U(m-PhCOOCH~) -C(O)CIi20(p-PhCOOCH3) 5.65 -C(O)CH2U(o- -C(O)CIi20(m- -C(O)CH20(p-PhCH~COOH) PhCH~COOH) PhCH~COOH) 5.66 _pC p ~NxO
J
Tahe6 Formula I : A = -B(OH)2 ; X = -CH2NH2 ; R3 = table below ; R11 = CH3 .1 ~ .3 .

6.1 -C(O)Ph -C(O)CH~I'h -C(U)CH7CH2Ph 6.2 -C(O)CII~OPh -C(O)CH~NIiPh -C(U)CH~SPh 6.3 -C(O)o-PhOH -C'(O)m-Ph01-I -C(U) -PhOH

6.4 -C(O)o-PhCH~OI-I -C(U)m-PhCH~OII -C(O)p-PhCH20H

6.5 -C(U)o-PhC001-I -C'.(O)m-PhCU01-i -C(O) -Ph COOH

6.6 -C(O)o-PhCH2COOH -C(U)tn-PhCIi~CUUH-C(U)P-PhCH2COOH

6.7 -C(O)naphth-1-yl -C(O)CH~(naPhth-1-yl)-C(O)CH2CH2(napth-1-yl) 6.8 -C(O)naphU~-2-vl -C(O)CH~(nanhth-2-yl-C(O)CH2CH2(napth-2-yl) 6.9 -C(O)o-biphenyl -C(O)CIi~(o-hiphenvl)-C(O1CII~CH~(o-biphenyl) 6.10 -C(O)m-hiphenvl -C(O)CH~(m-biphenyl)-C(O)CH2CH2(m-biphenyl) 6.12 -C(O)p-biphenyl -C(U)C1~2(r-hinhenyl)-C(O)C1~2CH2(r-hiPhenyl) 6.13 -C(U)o-PhOPh -C(U)Cl-i~(o-I'h01'h)-C(O)CH?CH~(o-PhOPh) 6.14 -C(O)m-PhOPh -C(U)CH~(m-PhOPh) -C(O)CI-I2CH2(m-PhOPh) 6.15 -C(O)p-PhOPh -C(O)CH~(p-I'hUPh -C(O)CH2CH2(p-PhOPh) ) 6.16 -C(O)o-PhNHPh -C(U)CI-1~(o-PhNIIPh-C(U)CIi~CIi?(o-PhNHPh) ) 6.17 -C(O)m-PhNHPh -C(U)CH~(m-PhNliPh)-C(O)CIi~CH~lm-PhNHPh) 6.18 -C(U)p-I'hNHPh -C(U)CII~(p-PhNIIPh)-C(O)CH~CH2(p-PhNHPh) 6.19 -C(O)o-PhSPh -C'.(O)C'.1-i~(o-1'hSPh)-C(U)CH~CIi2(o-PhSPh) 6.20 -C(O)m-PhSPh -C(O)CI-12(tn-PhSPh)-C(O)CH~CH2(m-PhSPh) 6.21 -C(O)p-PhSPh -C(U)CI-I~(p-PhSPh)-C(O)CH~CH2(p-PhSPh) 6.22 -C(O)o-PhCH2SPh -C(U)CH2(o-PhCH2SPh)-C(U)CH2CH2(o-PhCH2SPh) 6.23 -C(O)m-PhCH2SPh -C(U)C1~2(m-PhCH2SPh)-C(U)CH2CH2(m-PhCH~SPh) 6.24 -C(O)P-PhCII2SPh -C(O)CII2(P-1'hC1-I2SPh-C(U)CH2CH2(P-) PhCH~SPh) 6.25 -C(O)adamantvl -C(O)C11~(aclamantvl)-C(O)CH?CIi2(adamantyl) 6.26 -C(U)cvclopentvi -C(U)CH~(cvcloPentvl)-C(0)CH~CIi2((cvclopentyl) 6.27 -C(O)cvclohexvl -C(U)CII~(cvclohexvl)-C(O)CH~CH2(cyclohexyl) 6.28 -C(O)C11~0(cvclopentvl)-C(O)CIU~NI1(cvclopentyl)-C(U)CH~S(cyclopentyl) 6.29 -C(U)CII~U(cvclohexvl)-C(U)CHI~NIIlcvclohexvl)-C(U)CH~S(evclohexyl) 6.30 -C(O)pyridin-2-vl -C(U)CI-I~(pyriclin-2-yl)-C(U)CH~CI-I2(pYridin-2-yl) ,' '73 SUBSTITUTE SHEET (RULE 26) WO 95/09634 ~ ~ ~ ~ PCTIUS94/11280 6.31 -C(O)pyridin-3-vl -C(U)CHI~(pyridin-3-vl) -C(U)CH~CH~IPyridin-3-vl) 6.32 -C(O)pyridin-4-yl -C(O)Cl-I~(pyridin-4-vl) -C(O)Cti~CH2(pyridin-4-vl) 6.33 -C(O)furan-2-yl -C(O)CH2(fut<an-2-yl) -C(U)CI~2CH2(furan-2-yl) 6.34 -C(O)furan-3-vl -C(U)Cl-I~(furan-3-yl) -C(O)CH2CH~(furan-3-yl) 6.35 -C(O)thiophen-2-yl -C(U)CH2(thiophen-2-yl) -C(O)CH2CH2(thiophen-2-vl) 6.36 -C(O)thiophen-2-yl -C(U)CH2(thiophcn-2-yl) -C(O)CH2CH2(thiophen-2-1) 6.37 -C(O)imidazo-2-v_ 1 -C(O)CHI~(imidazo-2-yl) -C(O)CH~CH~(imidazo-2-yl) 6.38 -C(O)oxazo-2-yl -C(U)CH2(oxazo-2-yl) -C(O)CH~CH2(oxazo-2-yl) 6.39 -C(O)thioazo-2-yl -C(U)CH~(thioazo-2-yl) -C(O)CH~CH2(thioazo-2-yl) 6.40 -C(O)benzofuratr2-yl -C(O)CI-i2(henzofurtn-2-yl) -C(O)CH2CH2(benzofuran-2-vl) 6.41 -C(O)henzofuratr3-yl -C(O)CI-I2(hcnzofuran-3-yl) -C(O)CH2CH2(henzofuran-3-vll 6.42 -C(O)henzothiophcn-2-yl -C(U)C'1-I2(tx.nzothiophen-2- -yl) C(U)CI-i2CH2(benzothiophen -2-vl) 6.43 -C(U)thiophen-2-yl -C(U)C'.112(thiophen-2-yl) -C(U)CH2CH2(thiophen-2-vl) 6.44 -C(O)benzimidazo-2-yl -C(U)CI-12(hcnzimidazo-2-yl) -C(O)CH2CH2(henzimidazo-2-vl) 6.45 -C(O)benzoxazo-2-yl -C(U)ClI2(henzoxazo-2-yl) -C(O)CH2CH2(henzoxazo-2-YI) 6.46 -C(O)henzothiazo-2-yl -C(U)CI-I2(henzothiazo-2-yl) -C(O)CH2CH2(benzothiazo-2-vl) 6.47 -C(O)o-Ph(P(U)Ph3) -C(U)m-I'h(P(U)Ph3) -C(U)p-Plt(P(U)Ph3) 6.4R -C(O)Ph-2-(tluoren-~J-vl) -C(O)Ph-3-(fluoren-9-vl) -C(O)Ph-4-(fluoren-9-vl) 6.49 -C(O)N-indolin-2-one -C(U)indolin-2-vl -C(O)indol-2-vl 6.50 -C(U)cyclopentyl-2-(Ph) -C(U)cyclohexyl-2-(Ph) C(O)C(CIi3)2NHS02(naphth -2-vll 6.51 -C(O)pyrrolidin-3-yl-4-(Ph) -C(O)tctrahydrofurm-3-yl-4- -C(U)tetrahydrothiophen-3-(Ph) vl-4-(Ph) 6.52 -C(O)tetrahvdronaPhth-1-yl -C(O)tctrahvdronanhth-2-yl -C(U)cvclopropyl-2.2-(Ph2) 6.53 -C(U)tetrahydroiscx.luinolin- -C(U)tctrahydroisoyuinolin-3- -C(O)CI-I2((2-oxo)indolin-3 1-vl yl Il 6.54 -C(O)C)-12(N-henzimidazol- -C(O)CH2(N-henzoxazol-2- -C(U)C1-I2(N-henzothiazol-2-2-one) one) one) 6.55 -C(O)CII2(N- -C(U)C1I2(N-dihydrooxazol- -C(U)C)-I2(N-dihydrothiazol-dihvdroimidazol-2-one) 2-one) 2-one) 6.s6 ~co- ~co-N l ~ N y N y ,1 ~ ~~ i i 6.57 O O O
-OC~~ N~ N H -OC~ Nu0 -OC~ NHS
SUBSTITUTE SHEET (RULE 26) ~~.'~4~1~
WO 95/09634 PCT/US9.1/11280 6.58 -OC O -OCR -OC p --IN ~ I ' CN~ 1NJ10 N
6.59 -C(O)N(CH~)CH2Ph -C(U)N(C~IiS)CI-I~1'h -C(O)N(C3H7)CH2Ph 6.60 -C(O)pyridin-3-yl-5-(Ph) -C(U)Ph-3-(Cli2(thiophen-2- -C(O)Ph-3-(CH2Ph) vl)) 6.61 -C(O)C(CH3)20Ph -C(O)CII(C2H5)OPh -C(O)CH20CH2Ph 6.62 -C(O)CH20(o-PhCH20H) -C(O)CI-I2U(m-PhCI-I~OH) -C(O)CH20(P-PhCH~OH) 6.63 -C(O)CI-i~0(o-PhCOUH) -C(0)CH~U(m-1'hC00H) -C(U)CH20(P-PhC00H) 6.64 -C(O)CH~O(o-PhCOOCI1~) -C(O)CH~O(m-1'hCOUCII~) -C(O)CH20(P-PhCOOCH3) 6.65 -C(O)CH20(o- -C(O)C1I2U(m- -C(U)CH20(P-PhCH~C001-I) PhCI I~CUOH) PhCH2COOH) 6.66 - O C~ O
~Nuo J
able 7 Formula I : A = -B(OH)2 ; X = -CI-i2NH2 ; R3 = table below ; R11 = -CH2(P-PhOH).

.1 .2 .3 7.1 -C(O)Ph -C(U)C1~12Ph -C(O)CH2CH2Ph 7.2 -C(O)C1I~OPh -C(U)C11~NI1Ph -C(O)CH2SPh 7.3 -C(Ok~-PhOH -C'(U)m-I'h01-I -C(U) PhOH

7.4 -C(Ok>-PhCIi~OH -C(U)tn-PhClI~011 -C(U)(~-PhCH20H

7.5 -C(Olo-1'hC001-I -C'(U )m-1'hCU011 -C(U) PhCOOH

7.6 -C(O)o-PhCH~COOII -C(Okn-I'hCl-I~COOII-C(U)s-PhCH2COOH

7.7 -C(U)naPhth-1-vl -C(U)CH~(naphth-1-vl)-C(U)CH2CH~(naPth-1-vl) 7.R -C(U)n~tphth-2-yl -C(UlCll~(naphth-2-vl-C(U)CIt2CH?(naPth-2-yl) 7.9 -C(U)o-hinhenvl -C(O)Cli~(o-hi~henvl)-C(O)CH~CH2(o-biPhenvl) 7.10 -C(U)m-bi~henvl -C(U)CIi2(tn-biPhenvl)-C(U)CH2CH2(m-hiPhenvl) 7.12 -C(O)s-biphenyl -C(O)CH2(P-hinhenyl)-C(O)CII~CH2(p-biphenyl) 7.13 -C(O)o-1'hOPh -ClU)CII2(o-PhOPh)-C(O)CH~CH2(o-PhOPh) 7.14 -C(O)m-Ph01'h -C(U )CI-I~(tn-PhOPh-C(U)CH2CH2(m-PhOPh) ) 7.15 -C(0)n-PhOPh -C(U)CH2(r-PhUPh) -C(U)CH~CH2(P-PhOPh) 7.16 -C(U)o-PhNI-IPh -C(U)CI-I~(o-1'hNI-IPh-C(O)CH2CH2(o-PhNHPh) ) 7.17 -C(Uhn-PliNIIPh -C'(O)Cll~(m-PhNIIPh)-C(U)CH2CH2(m-PhNHPh) 7.18 -C!U)~-PhNHPh -C(O)Cl-I~(P-PhNIIPh)-C(O)CH2CH2(P-PhNHPh) 7.19 -C(O)o-PhSPh -C(O)CII~(o-I'hSl'h)-C(U)CII2CH2(o-PhSPh) 7.20 -C(U)m-PhSPh -C(O)C1-I~(m-1'1~51'h)-C(U)CI-I2CHI~(m-PhSPh) 7.21 -C(U)0-I'hSl'h -C(U)CII~(~-PhSI'h)-C(O)CH~CH~(P-1'hSPh) 7.22 -C(O)o-PhCI-I~SI'h-C(U)C1-12(o-I'hCII~SPh)-C(U)CH2CH2(o-PhCI-I~SPh) / 7.~
SUBSTITUTE SHEET (RULE 26) ,, 7.23 -C(O)m-PhCH2Sl'h -C(U)CI-I2(m-PhCH2SPh)-C(U)CI-I2CH2(m-PhCtI~SPh) 7.24 -C(U)p-PhCH2SPh -C(O)CH2(P-PhCI-I2SPh)-C(O)CH2CH2(p-PhCH~SPh) 7.25 -C(O)adamantvl -C(U)CH~(adaunantvl)-C(O)CH2CH2(adamantvl) 7.26 -C(O)cvclopentvl -C(O)CIi~(cvcloPentvl)-C(O)CI~~CH2((cvclopentvl) 7.27 -C(O)cyclohexyl -C(O)CH~(cvclohexyl)-C(O)CH~CH2(cvclohexv_ 1) 7.28 -C(O)CH20(cvclorentvl)-L(O)CI-I~NI1(cvclopentvl)-C(O)CH2S(cvclopentvl) 7.29 -C(U)CH~O(cvclohexvl)-C(O)C13~NH(cvclnhexvl)-C(O)CH~S(cyclohexvl) 7.30 -C(U)pyridin-2-vl -G(U)CH2(Pyridin-2-yl)-C(0)CH2CH?(Pytidin-2-yl) 7.31 -C(O)pyridin-3-yl -C(O)CH2(Pyridin-3-vl)-C(O)CH2CH2(pyridin-3-vl) 7.32 -C(U)wridin-4-v_ -C(U)CH2(Pyridin-4-yl)-C(O)CH2CH2(pyidin-4-yl) 7.33 -C(U)furan-2-yl -C(U)CH~(furan-2-yl)-C(U)CH~CH2(furan-2-yl) 7.34 -C(O)furan-3-yl -C(U)CI1~(furan-3-yl)-C(O)CH2CH2(furan-3-vl) 7.35 -C(U)thiophen-2-yl-C(U)CH2(Uiiophen-2-yl)-C(O)CH2CH2(thiophen-2-vl) 7.36 -C(O)Utiophen-2-yl-C(O)CIt2(Utiophen-2-yl)-C(O)Cl-i2CH2(thiophen-2-vl) 7.37 -C(O)imidazo-2-vl -C(U)CII2(imidazo-2-vl)-C(O)CH~CH~(imidazo-2-yl) .

7.38 -C(O)oxazo-2-vl -C(U)CII2(oxazo-2-yl)-C(U)CIi?CH2(oxazo-2-vl) ' 7.39 -C(O)thioazo-2-yl -C(U)CIi~(thioazo-2-vl)-C(O)CI-I2CH~(thioazo-2-yl) 7.40 -C(U)benzofurvt-2-yl-ClU)C)-i2(lxnzofuran-2-yl)-C(U)Cr12CH2(benzofuran-2-vl) 7.41 -C(O)benzofurm-3-yl-C(U)CrI2(henzofurau-3-yl)-C(O)CH2CH2(benzofuran-3-vl) 7.42 -C(O)benzoUuo~hcn-2-yl-C(O)CI-I2(henzoUtiophen-2-yl) C(O)CH2CH2(benzoUtiophen -2-vl) 7.43 -C(O)thiophen-2-yl-C(U)CI-I2(Utiophen-2-yl)-C(U)CH2CI-i2(thiophen-2-vl) 7.44 -C(O)benzimidazo-2-yl-C(U)ClI2(henzimidazo-2-yl)-C(O)CH2CH2(henzimidazo-2-vl) 7.45 -C(U)bcnzoxazo-2-yl-C(U)C112(benzoxazo-2-yl)-C(U)Cii2CH2(benzoxazo-2-vl) 7.46 -C(U)henzothiazo-2-yl-C(U)C112(henzothiazo-2-yl)-C(O)CI-I2CH2(benzothiazo-2-vl) 7.47 -C(U)o-Ph(P(U)Ph3)-C(U)m-I'h(P(O)1'h3)-C(U)p-Ph(P(O)Ph3) 7.48 -C(O)Ph-2-(tluoren-9-vl)-C(U)I'h-3-ftluoren-9-vl)-C(U)Ph-4-(fluoren-9-vl) 7.49 -C(O)N-indnlin-2-one-C(())ind~lin-2-vl-C(U)indol-2-vl 7.50 -C(U)cycloPen tyl-2-(Ph)-C(U)cyclohexyl-2-(Ph) C(O)C(CI-I3)2NI-IS02(naphth -2-vl) 7.51 -C(O)pytrolidin-3-yl-=t-(Ph)-C(U)tetrahydrofuran-3-yl-4--C(U)tetrahydrothiophen-3-(Ph) vl-4-lPh) 7.52 -C(O)tetralmdrona~hU~-1-vl-C(U)tctrahvdrona~hth-2-vl-C(U)cvclopropyl-2,2-(Ph2) 7.53 -C(U)tetrahydroistxluinolin--C(U)tetrahydroisoyuinolin-3--C(U)CH2((2-oxo)indolin-3-1-yl vl vl) 7.54 -C(O)CI-I2(N-benzimidazol--C(U)CII2(N-henzoxazol-2--C(O)CtI2(N-benzothiazol-2-2-one) one) one) 7.55 -C(O)CH2(N- -C(U)CII2(N-dihydrooxazol--C(O)CH2(N-dihydrothiazol-dihvdroimidazol-2-one)2-one). 2-one) /'7~
SUBSTITUTE SHEET (RULE 26) PCTlUS94/11280 7.56 NCO- rCO-O
w N O I ~ N w N w I ~ i ~ / \ I ~ I ~
7.57 O O O
-OCrNUNH -OC~N~O -OC~NUS
7.58 -OC O -OCR -OC O
~N CN' ~NUO
Ji ~ ~ N /
~I
7.59 -C(O)N(CI~I~)CH~Ph -C(U)N(C'.~I-i5)C1121'h -C(O)NfC3H7)CH2Ph 7.60 -C(O)pyridin-3-yl-5-(t'h) -C(O)Ph-3-(CI-I2(thiophen-2- -C(O)Ph-3-(CH2Ph) vl)) 7.61 -C(O)C(CH3)~OPh -C(U)Cl-I(C2H5)UPh -C(O)CH20CH2Ph 7.62 -C(U)CH~O(o-I'hCH~UH) -C(U)Ct-I2U(m-PhC'.Ii2UH) -C(U)CH2U(p-PhCH20H) 7.63 -C(O)CH~O(o-PhCOOH) -C(U)CII2U(m-PhC:001I) -C(O)CI-I20(P-PhCOOHI
7.64 -C(O)Crl2U(o-PhCOOCII~) -C(U)CII20(m-PhCOUCI-I3) -C(O)C1i20(p-PhCOOCH3) 7.65 -C(O)CH20(o- -C(U)CH2O(m- -C(O)CH20(P-PhCH2COOH) PhCI-I2COOH) PhCIi2COOH) 7.66 -OC O
~NUo /~
Formula I : A = -B(OI-I)2 : X = CI12NII2; R3 = table below : R11 = -CI I2CI-I2Ph.
.2 .3 8.1 -C(O)Ph -C(U)CH~Ph -C(O)CH2CI~~Ph 8.2 -Cf0)CH~OPh -C(O)CII~NHPh -C(U)CH2SPh 8.3 -Cf0)o-PhOH -C'.(U)m-PhOI-I -C(U) PhOH

8.4 -C(O)o-PhCH~UH -C'(U)m-PhCI-I~Uri -C(O)P-PhCH~OH

8.5 -C(O)o-PhCOOH -C(U)m-1'hCUOH -C(U) -Ph COOH

8.6 -C(O)o-PhCH~CU01I -C(U)tn-PhCI-1~CUUH-C(O)P-PhCH~COOH

8.7 -C(O)naPhth-1-vl -C(O)CII2(naPhth-1-yl)-C(U)CII~CH2(napth-1-yl) 8.8 -C(O)narhth-2-yl -C(O)CII~(naPhth-2-vl-C(U)CH~CH2(napth-2-yl) 8.9 -C(O)o-biPhenvl -C(O)CII~(o-hiPhenvl)-C(O)CIi2CI-i~(o-hiphenvl) ~

8.10 -C(U)m-hiPhenvl -C(U)C'H~(m-hiPhenyl)-C(U)CU~CH2(m-biphenyl) 8.12 -C(O)P-hiPhenyl -L(O)CII~(P-hiPhenvl)-C(O)CH2CH2(P-hiPhenyl) 8.13 -C(O)o-PhOPh -C(U)CII~(o-I'hUPh)-C(O)Cl12CH2(o-PhOPh) 8.14 -C(O)m-PhOPh -C(U)CI1~(m-I'hUPh)-C(U)Cl-I?CH2(m-PhOPh) I '7'~
SUBSTITUTE SHEET (RULE 26) ~~~~j~_~

8.15 -C(U)P-PhOPh -C(O)C11?(~-PhOPh)-C(U)CrI~CH~(P-i'hOPh) 8.16 -C(U)o-I'hNl-IPh -C(U)CI1~(o-I'hNIIPh)-C(U)CHI~CH~(o-PhNHPh) 8.17 -C(O)m-PhNHPh -C(U)Cl-l~(m-PhNHI'h)-C(U)CH~CH~(m-PhNHPh) 8.18 -C(O)P-PhNHPh -C'(O)CH~(P-1'hNliI'h-C(U)CrI~CH~(P-PhNHPh) ) 8.19 -C(O)o-PhSPh -C(U)CH~Io-PhSPh> -C(U)CH~CH~(o-PhSPh) 8.20 -C(O)m-PhSPh -C(O)CH2(m-I'hSPh)-C(O)Cr12CH2(m-PhSPh) 8.21 -C(O)P-PhSPh -C(O)CH~(P-1'hSl'h-C(U)CH~CH~(P-PhSPh) ) 8.22 -C(U)o-PhCH2SPh -C(O)CH2(o-PhCrI2SPh)-C(O)CH2CH2(o-PhCI-I2SPh) 823 -C(O)m-PhCH2SPh -C(O)CI-I2(tn-PhCII2SPh)-C(O)CH2CI-i2(m-PhCH~SPh) 8.24 -C(U)p-!'hCl-I2SPh-C(U)Crl2(p-PhCri2SPh)-C(U)CH2CH2(p-PhCH2SPh) 8.25 -C(U)adaunanrvl -C(U)CrI~(adamantyl)-C(U)cH~CH~(adamantyn 8.26 -C(U)cycloPentyl -C(U)CII~(cyclopentyl)-C(O)CH2CH2((cvclopentyl) 8.27 -C(O)cvclohexyl -C(O)Crl~(cvclohexyl)-C(O)CH~CH~(cvclohexvl) .

8.28 -C(O)CII2U(cvcloretitvl>-C(U)CIT~NIi(cvclopentvl)-C(U)CH?S(cvcloPentvl) 8.29 -C(UICI-I~O(cvclohexyl)-C(U)C'.II~NI1(cvclohexvl)-C(U)CIi?S(cyclohexyl) 8.30 -C(U)Pyridin-2-vl -C(U)CI-I2(pyridin-2-vl)-C(U)CH~CH2(pyridin-2-vI) 8.31 -C(O)pvridin-3-yl -C(U)CI~I~(Pyridin-3-yl)-C(UICH~CH2(Pyridin-3-vl) 8.32 -C(O)Pyridin-4-yl -C(U)CI-I~(pyridin-4-yl)-C(O)CH2CH2(Pyridin-4-yl) 8.33 -C(O)furan-2-yl -C(U)CII~(furan-2-vl)-C(O)CI-I2CH~(furan-2-vl) 8.34 -C(O)furan-3-yl -C(O)CI-I~(furan-3-yl)-C(O)CH~CH~(furan-3-vl) 8.35 -C(O)thioPhen-2-yl-C(O)CII2(thioPhen-2-yl)-C(U)CH2C1-i2(duophen-2-vl) 8.36 -C(O)U~iopt~en-2-yl-C(U)Cli2(thiophen-2-yl)-C(U)CH2CIi2(thiophen-2-vl) 8.37 -C(O)imidazo-2-yl -C(U)CII~(imidazo-2-yl)-C(O)CrI2CH2(imidazo-2-yl) 8.38 -C(O)oxazo-2-yl -C(U)CH~(oxazo-2-vl)-C(U)CH~CH2(oxazo-2-yl) 8.39 -C(O)thioazo-2-yl -C(U)C11~(tluoazo-2-vl)-C(O)CIi~CH~(thioazo-2-yl) 8.40 -C(O)henzofuran-2-yl-C(U)Cti2(hcnzofuran-2-yl)-C(U)CH2Cri2(benzofuran-2-vl) 8.41 -C(O)henzolurm-3-yl-C(U)CI-12(hcnzoluran-3-yl)-C(U)ClI2CIi2(henzofuran-3-vll 8.42 -C(U)henzothioPhen-2-yl-C(U)C112(tx:nzothiophen-2-yl) C(U)CH2CH2(henzothiophen -2-vl) 8.43 -C(O)thiophen-2-yl-C(U )Cl-12(tluoPhen-2-yl)-C(O)Cli2CH2(thiophen-2-vl) 8.44 -C(O)benzimidazc~-2-yl-C(U)C112(henzimidazo-2-yl)-C(O)CH2CH2(benzimidazo-2-v1) 8.45 -C(O)henzoxazo-2-yl-C(U)C112(henzoxazo-2-yl)-C(U)Cri2CH2(henzoxazo-2-vl) 8.46 -C(O)henzothi~zo-2-yl-C(U)Cli2(Ixnzothiazo-2-yl)-C(U)CI-I2CH2(henzothiazo-2-vl) 8.47 -C(U)o-Ph(P(U)Ph~)-C(U)m-Ph(P(U)Ph~)-C.((p-Ph(P(O)Ph~) 8.48 -C'(U )Ph-2-(fluoren-~)-vl)-('((>)Ph-~i-l(luorcn-~)-vl)-C(CI'h-4-(tluoren-9-vl) 8.49 -C'(U)N-indolin-2-one-C((indolin-2-vl -C((indol-2-vl /'78' SUBSTITUTE SHEET (RULE 26) WO 95109634 ' PCT/US94I11280 8.50 -C(U)cycl0pentyl-2-(Ph) -C(U)cyclohexyl-2-(Ph) C(O)C(CI-I3)2NIISU2(naPhth -2-vl) 8.s1 -C(O)pyrrolidin-3-yl-4-(Ph) -C(U)tetrthydrofuran-3-yl-4- -C(U)tetrahydrothiophen-3-(Ph) vl-4-(Phl 8.52 -C(O)tetrahvdronlPhU~-1-vl -C'(U )tetrahvdronaPhth-2-vl -C'(O)cyclOPmPyI-2.2-lPh2) 8.s3 -C(U)tetrthydroisoyuinolin- -C(U)tetrahydrois0quinolin-3- -C(O)CH2((2-oxo)indolin-3 1-yl yl vl) 8.s4 -C(O)C1I2(N-henzimidazol- -C(O)Cli2(N-benz0xazol-2- -C(O)CH2(N-benzothiazol-2-2-one) one) one) 8.ss -C(O)CH2(N- -C(O)CH2(N-dihydrooxaz0l- -C(U)CH2(N-dihydrothiazol-dihvdroimidlz~l-2-one) 2-one) 2-one) 8.s6 ~co- ~~o- ~ o N O I~ N I~ N I~
i ~ ~ ~ \ i i ' I
8.57 O O O
a -OC'' Nu N H -OC~ NCO -OC~ N
8.58 -OC O -OCl -OC O
~N CN' ~NUO
Ji i N
~I
8.59 -C(O)N(CH~)ClI2Ph -C(U)N(C21-IS)CH2Ph -C(O)N(C3H7)CH2Ph 8.60 -C(U)~yridin-3-yl-5-(Ph) -C(U)Ph-3-(CIi2(thioPhen-2- -C(U)Ph-3-(CH2Ph) vl)) 8.61 -C(O)C(CH~)20Ph -C(U)CI-I(C~IIS)OPh -C(OICH~OCH2Ph 8.62 -C(U)CI-I~O(o-PhCI-I~UiI) -C'(O)CII~U(m-I'hCl-I~OH) -C(U)CH2U(p-PhClI20H) 8.63 -C(OICI-I~U(o-Ph COUI I) -C(O)Cli~()(m-PhCU01-I) -C(U)Cl-i~0(p-PhCOOH) 8.64 -C(o)CH~o(o-PhC.OUCII~) -C'(U)CI-I~UCm-I'hC'.OOC1-i~) -C(U)CH2U(P-I'hCOOCH~) 8.65 -C(O)CI-120(0- -C(O)C1I2U(m- -C(O)CH20(It-PhCH2COOH) PhCI hCOOII) PhCI2COOH) 8.66 -pC O
~NUo J
Table 9 Formula I : A = -B(OIi)2 ; X = CI-12NI12: R3 = table hcl0w : R11 = -Ph.
9.1 -C(U)Ph -c(U~c11~1'n ~ -C(O)CH2C1-l2Ph '7 9 SUBSTITUTE SHEET (RULE 26) WO 95/09634 ~ ~ PCT/US94I11280 4 3 .~ 4 9.2 -C(O)CIU~OPh -C(U)C'I-12NI-1Ph -C(U)Cli?SPh 9.3 -C(U)o-1'hOH -C(())m-I'h011 -C(U) -PhOI-I

9.4 -C(O)o-PhCI-I~OII -C(U)m-I'hCII~OH -C(U)P-PhCH~OH

9.5 -C(O)o-PhCOOIi -C(U)m-1'hC'001-I -C(( -PhCOOH

9.6 -C(0)o-PhCH~COUI-I-ClU)m-I'hCH~COOII-C(U)P-PhCH~COOH

9.7 -C(O)naphUt-1-vl -C(U)CI-I~(naPhth-I-vl)-C(O)CH~CH~(napth-1-yl) 9.8 -C(O)naphth-2-vl -C(O)CIi~(naPhth-2-vl-C(O)CI-I~CH2(napd~-2-y 9.9 -C(O)o-biphenyl -C(U)Cl-I~(o-hiphenvl)-C(U)CH~CH~(o-biphenyl) 9.10 -C(O)m-biphenyl -C(O)CI-I~(m-hiphenvl)-C(O)CH~CH~(m-biphenyl) 9.12 -C(O)P-biphenyl -C(O)CI-I2(p-hiphenvl)-C(O)CH2CH2(p-biphenyl) 9.13 -C(Ok~-PhOPh -C(O)CII~(o-PhOPh)-C(O)CH2CH2(o-PhOPh) 9.14 -C(O)m-PhOPh -C(O)CI-l2(m-PhUPh)-C(O)CH~CH~Im-PhOPh) 9.15 -C(O)p-PhOPh -C(O)CH~(p-I'hUPh)-C(U)CH2CH2(P-PhOPh) 9.16 -C(OkrPhNI-IPh -C(O)CII~(o-PhNI-IPh)-C(O)CH~CH2(o-PhNHPh) 9.17 '-C(O)tn-I'hNHPh -C(U)CII~(m-1'hNliPh-C(O)CH2CH2(m-PhNHPh) ) 9.18 -C(U)P-PhNI-IPh -C(U)CII?(P-I'hNIIPh)-C(U)CH?Ct-12(p-PhNHPh) 9.19 -C(U)o-PhSPh -C(U)C'11~(o-PhSPh)-C(O)CI-i~CH2(o-PhSPh) 9.20 -C(U)m-PhSPh -C(U)Cll~(m-I'hSPh)-C'(U)CI-I2CH2(m-PhSPh) 9.21 -C(U)p-PhSPh -C'.(O)Cll~(P-PhSPh)-C(O)CH~CH2(P-PhSPh) 9.22 -C(O)o-PhCH2SPh -C(U)Cli2(o-PhCI-I2SPh)-C(U)CII2CH2(o-PhCH2SPh) 9.23 -C(U)m-PhCI-I2SPh -C(U)CI12(tn-I'hCII2SPh-C(O)CH2CIi2(m-) PhCI-I2SPh ) 9.24 -C(O)p-PhCI-I2SPh -C(U)CI12(p-1'hCl -C(O)CH2CH2(p-I2SPh ) PhCI-I2SPh) 9.25 -C(O)adatnantvl -C'(U )CII2(adamantyl)-C(O)CH2CH2(adatnantyl) 9.26 -C(O)cyclopentyl -C(U)CI-I~(cyclopentyl)-C(O)CH2CH2((cyclopentyl) 9.27 -C(O)cyclohexyl -C(O)CII~(cvclohexvl)-C(0)CtI2CH2(cvclohexyl) 9.28 -C(O)CH~O(cyclopentvl)-C(U)C1I~N1-1(cvcl~Pentyl)-C(U)CH2S(cyclopentyl) 9.29 -C(O)CH~O(cvclohexyl)-C'.(CCII~NIi(cvclohexvl)-C(U)CH2S(cyclohexyl) 9.30 -C(O)pyridin-2-yl -C(U)CII~(Pyridin-2-vl)-C(U)CI-I2CH2(pyridin-2-yl) 9.31 -C(O)pvridin-3-vl -Cl0)Cll~(Pyriclin-3-vl)-C(O)CIi~CH2(Pyridin-3-vl) 9.32 -C(O)Pvridin-4-v_ -C(U)Cll~(Pyriclin-4-vl)-C(U)CH~CH2(pyridin-4-vl) 9.33 -C(O)furan-2-vl -C(U)Cll~(f~uran-2-vl)-C(U)C11~CH~(furan-2-yl) 9.34 -C(O)furan-3-yl -C(O)CII~(fhran-3-vl)-C(O)CII~CH2(furan-3-yl) 9.35 -C(O)Wiophen-2-yl -C(U)CI12(Uuophen-2-yl)-C(U)CH2C1-I2(thiophen-2-vl) 9.36 -C(U)thiophen-2-yl-C(U)C112(thiophcn-2-yl)-C(O)CH2CH2(thiophen-2-vl) 9.37 -C!O)imidazo-2-v_ -C'(U)CI-I~(imiclazo-2-yl)-C(U)CH2CH2(imidazo-2-yl) 9.38 -C(O)oxazo-2-vl -C(U)C'.II~(oxazo-2-vl)-C(U)C1I2CH2(oxazo-2-yl) 9.39 -C(O)thioazo-2-vl -C(U)CII~(thioazn-2-vl)-C(O)CH2CH2(thioazo-2-vl) 9.40 -C(O)henzofurut-2-yl-C(O)CHZ(lxxnzofurati-2-yl)-C(U)Cl-I2CH2(benzofuran-2-vl) 9.41 -C(U)henzofuran-3-yl-C(U)CII~(tx;nzoCuran-3-yl)-C(U)CI-I2C1-!2(henzofuran-3-vl) 9.42 -C(U)henzothiophrn-2-vl-('(U)C112(tx:nz<rihiophen-2-yl) C(O)CI-I2CI-I2(henzothiophen -2-vl) SUBSTITUTE SHEET (RULE 26) """ WO 95!09634 PCTIUS94111280 ~17~~I
9.43 -C(U)tltiophen-2-yl -C(U)CI-I2(thioPhen-2-yl) -C(U)CI-I2CI-i2(thiophen-2-_ vl) 9.44 -C(U)henzimidazo-2-yl -C(0)Cl-I2(benzimidazt>-2-yl) -C(U)Cti2CH2(benzimidazo-2-vl) 9.45 -C(O)henzoxazo-2-yl -C(U)CI-I2(henzoxazo-2-yl) -C(O)CH2CH2(benzoxazo-2-vl) 9.46 -C(O)benzothiazo-2-yl -C(U)CI-I2(henzothiazo-2-yl) -C(O)CH2CH2(benzothiazo-2-vl) 9.47 -C(O)o-Ph(P(U)Ph3) -C(O)tn-Ph(P(O)Ph3) -C(O)(t-Ph(P(O)Ph3) 9.48 -C(O)Ph-2-(fluoren-9-vl) -C(OIPh-3-(lluoren-9-vl) -C(O)Ph-4-(fluoren-9-vl) 9.49 -C(O)N-indolin-2-one -C(O)indolin-2-vl -C(O)indol-2-vl 9.50 -C(U)cycloltentyl-2-(Ph) -C(U)cyclohexyl-2-(Ph) C(O)C(CH3)2NI-IS02(naphth -2-vl ) 9.51 -C(U)Itytrolidin-3-yl-4-(Ph) -C(U)tetrahydrofuran-3-yl-4- -C(O)tetrahydrothiophen-3-(Ph ) vl-4-(Ph) 9.52 -C(O)tetrahvdron~phtlt-1-vl -C'(U)tctrahvdronaohth-2-vl -C(U)cvcloProPyl-2.2-(Ph2) 9.53 -C(U)tetrahydroisoytiinolin- -C(U)tetrahydroisoyuinolin-3- -C(O)CH2((2-oxo)indolin-3 1-yl vl vl) 9.54 -C(O)CI-I2(N-henzimidazol- -C(O)CH2(N-henzoxazol-2- -C(U)Cl-12(N-benzothiazol-2-2-one) one! one>
9.55 -C(O)CH2(N- ., -C(U)CH~_(N-dihydrooxazol- -C(U)CH2(N-dihydrothiazol-dihvdrounidazol-2-one) 2-one) 2-one) 9.56 NCO- NCO- ~ p I~ N O l ~ N O w N w I ~. / ~ li li 9.57 p O O
a -OC''NUNH -OC~N~O -OC~N S
9.58 -OC O -OCR -OC O
~N ~ I ~_ CN' ~NxO
N
~I
9.59 -C(O)N(CH~)CII~I'h -C(U)N(C~IIS)CIUZPh -C(U)N(C~H7)CH2Ph 9.60 -C(O)Pyridin-3-yl-5-(Ph) -C(U)Ph-3-(CI-I2(thioPhen-2- -C(U)Ph-3-(CH2Ph) vl)) 9.61 -C(O)C(CI-I~)20Ph -C(U)CII(C?IIS)OPh -C(O)CH2UCH2Ph 9.62 -C(O)CI-I~O(o-PhCH~OIf) -C(U)CI1~U(tn-PhChi2UH) -C(O)CH2U(It-PhCH20H) 9.63 -C(O)CH~OIo-P1~CU011) -C(U)CII~U(tn-PhCOOrI) -C(O)CH~U(P-PhCOOH) 9.64 -C(O)CIi~U(o-PItCUUCII~) -C(U)CII~U(m-I'hC:OOCI-I~) -C(U)Cl-1~0(p-PhCOOCH3) 9.65 -C(O)CI-I20(o- -C(O)C1I~U(m- -C(O)CH20(P-PhCH~C0011) PlO'I I~C'001-I) PhCI-f~COOH) l 8' l SUBSTITUTE SHEET (RULE 26) WO 95/09634 ~ 1 ~ PCTIUS94111280 9.66 -OC O
~NxO
J
SUBSTITUTE SHEET (RULE 26) ~1743i4 r~'"~ WO 95109634 PCTJUS94I11280 Table 10 Formula I : A _ -B(OH)2 ; X = -CH2N112: R3 = table below : RI I = -CH2(naphUt-2-yl).
.1 '' .3 .

10.1 -C(O)Ph -C(O)CH~Ph -C(O)CI-I2CH2Ph 10.2 -C(O)CH20Ph -C(O)CI-i2M~Ph -L(O)CI-I2SPh 10.3 -C(O)o-PhOH -C(U)m-Ph01-I -C(O) -PhOH
10.4 -C(O)o-PhCH2O1-I -C(O)m-PhCII?OH -C(U)p-PhCH20H
10.5 -C(O)o-PhCOOH -C(U)m-I'hC'OOH -C(O) PhCOOH
10.6 -C(Okt-PhCH2COOli-C(O)m-PhCli?CUUH -C(O)p-PhCH2COOH
10.7 -C(U)naphth-1-yl -C(O)CI-12(naphtJt-1-yl)-C(O)CH~CH~(napth-1-yl) 10.8 -C(O)naphth-2-yl -C(O)CH~(naphth-2-vl-C(O)CF-12CH2(napth-2-yl) 10.9 -C(U)o-biphenyl -C(O)CH~(o-hiphenvl)-C(O)CH2CH2(o-hiphenvl) 10.10 -C(O)m-biphenyl -C(O)CH~(m-biphenyl)-C(O)CI-hCH2(m-biphenyl) 10.12 -C(U)p-hiphenvl -C(O)Cll2(p-biphenyl)-C(U)CH~CH~(p-biphenyl) 10:13 -C(0)o-PhOPIt -C(O)Cli2(o-PhOPh) -C(O)CIi2CH~(o-PhOPh) 10.14 -C(O)m-PhUPh -C(O)CI-I~(m-PhOPh)-C(O)CH~CH~(m-PhOPh) IO.1S -C(U)P-PhOPh -C(U)CII~(p-l'hUl'h)-C(U)CH~CH2(p-PhOPh) 10.16 -C(O)o-1'hNI-lPlt-C(U)Cl~~(trPItNHI'h)-C(O)C1 hCIl2(o-PhNHPh) 10.17 -C(O)m-PhNHPh -C(U)CII2(m-PhNI-IPh)-C(U)CH2CH2(m-PhNHPh) 10.18 -C(O)p-PhNHPIt -C(U)CH2(p-PhNI-IPh)-C(O)CH2CI-I2(p-PhNHPh) 10.19 -C(U)o-PhSPh -C(U)Cl-I2(o-l'hSPh)-C(O)CH~CH2(o-PhSPh) 10.20 -C(O)m-PhSPh -C(U)CH~(m-PhSPh -C(O)CH~CH2(m-PhSPh) ) 10.21 -C(O)p-PhSPh -C(U)ClI2(p-PhSPh -C(O)CH~CH2(p-PhSPh) ) 10.22 -C(O)o-PhCH2SPh -C(O)Cli2(o-PhCI-i2SPh)-C(O)CH2CH2(o-PhCH2SPh) 10.23 -C(O)m-PhClI2SPh -C(O)CH2(tn-PhCH2SPh)-C(O)CH2CH2(m-PhCH2SPh) 10.24 -C(O)p-PhCII2SPh -C(U)CIl2(p-PhC112SPh)-C(U)CI-I2CH2(p-PhC'H2SPh) 10.25 -Cl0)adamantyl -C(O)CI12(adatrtarnvl)-C(O)CH~CH2(adamantvl) 10.26 -Cl0)cvclopentvl -C:(U)Cl h(cyclopentvl)-C(O)CH~CIi2((cvclopentyl) 10.27 -C(U)cvclohexvl -C(O)CII~(cvclohexvl)-C(O)CH~CH?(cyclohexyl) 10.28 -C(U)ChhU(cyclopentvl)-C(U)CI-hM-1(cvclopentvl)-C(O)CH2S(evclopentyl) 10.29 -C(O)CI-hO(cvclohexyl)-C(O)Cli~Nll(cvclohexvl)-C(O)CH2S(cyclohexyl) 10.30 -C(O)pvtidin-2-vl-C(O)CI-h(pyridin-2-vl)-C(U)CI-I2CH2(pyridin-2-vl) 10.31 -C(O)pyridin-3-vl-C(U)CH2(pyridin-3-yi)-C(U)CH2CH2(pyridin-3-yl) 10.32 -C(O)pytidin-4-yl-C'-(O)Cl-l2(pyridin-4-vll-C(O)CH2CH2(pvridin-4-yl) 10.33 -C(O)furttt-2-vl -C(U)CII~(Curur2-yl)-C(O)CH~CH2(furatt-2-yl) 10.34 -C(O)t-urm-3-yl -C(U)CIU~(lurtn-3-yl)-C(U)CII2CI-I2(fmatt-3-vl) 10.35 -C(O)thiophen-2-vl-C(U)CIh(thiophen-2-vl)-C(U)C112CIi~(thiophen-2-yl) 10.36 -C(O)tttiophen-2-vl-C(U)CIi~(Utiophen-2-yl)-C(U)CH~CH2(thiophen-2-yl) 10.37 -C(O)unidazo-2-yl-C(U)CIh(imidazo-2-yl)-C(U)CH2C)-h(imidazo-2-yl) 10.38 -C(O)oxazo-2-yl -C(U)CI i~(oxvo-2-vl)-C:(U)CH~CI I~(oxazo-2-yl) 10.39 -C(O)thi~~.o-2-vl-C'(O)CH~(thiovo-2-vl)-C(U)CH~CH~(thioazo-2-yl) 10.40 -C(O)benzoFuran-2-Y1-C(U)CII2(hcnzofurm-2-yl)-C(O)CIi2CI-I2(tx:nzofuran-vl) SUBSTITUTE SHEET (RULE 26) WO 95/09634 ~ ~ ~ ~ PCT/US94/11280 10.41 -C(U)benzofur~ur3-yl -C(U)C:H2(he;nzolurm-3-yl) -C(U)Cl-f2CH2(henzofuran-v1) 10.42 -C(0)henzothiophen-2-yl -C(O)C112(henzothiophen-2- -yl) C(O)CH2CH2(benzothiophen -2-vl) 10.43 -C(O)ihiophen-2-vl -C(O)Cll~(thiophen-2-yl) -C(O)CH~CH2(thiophen-2-vl) 10.44 -C(O)henzimidazo-2-yl -C(O)CH2(henzanidazo-2-yl) -C(U)CI~2CH2(benzimidazo-2-vl) 10.45 -C(O)benzoxazo-2-yl -C(U)ClI2(henzoxazo-2-yl) -C(O)CH2CH2(benzoxazo-2-vl) 10.46 -C(O)benzothiazo-2-yl -C(O)CI-12(benzothi~~zo-2-yl) -C(O)CIi2CH2(benzothiazo-2-vl) 10.47 -C(O)o-Ph(P(O)Ph~) -C(O)m-Ph(P(O)Ph~) -C(U)p-Ph(P(O)Ph~) 10.48 -C(O)Ph-2-(fluoren-9-vl) -C(O)Ph-3-(fluoren-9-vl) -C(O)Ph-4-(fluoren-9-vl) 10.49 -C(0)N-indolin-2-one -C(O)itulolin-2-vl -Cl0)indol-2-vl 10.50 -C(U)cyclopentyl-2-(Ph) -C(U)cyclohexyl-2-(Ph) C(O)C(CH3)2NI-iS02(naphth -2-vl) 10.51 -C(U)pyrrolidin-3-yl~-(Ph ) -C(())teuahydrofurur3-yl-.i- -C(U)tctrahycirothiophen-3-yl-(Ph ) 4-(Ph ) 10.52 -C(U)tetrahvcironaPhtl-1-vl -C(OhetrahvdronaPhUr2-vl -C(U)cvclonropyl-2.2-(Phi) 10.53 -C(U)tetrahydroiaoyuinolin-1- -C(U)tetrahydroi,oquinolin-3- -C(U)CH2((2-oxo)indolin-3 yl yl vl) 10.54 -C(O)CH2(N-benzunidazol-2- -C(O)CII2(N-henzoxlzol-2- -C(U)CH2(N-benzothiazol-2-one) one) one) 10.55 -C(O)CI-I2(N-dihydmimidazol- -C(O)C1-12(N-dihyclr~x~xazol-2- -C(U)CH2(N-dihydrothiazol-2-one) one) 2-one) 10.56 rC0- ~CO-O O
l~ N y N lw i i 10.57 O O O
a -OC~-N NFi -OC~N~O -OC~N~S
10.58 -pC O -OC, -OC O
~N ~ I. CN1 ~NUo /v ~I
10.59 -C(O)N(CH~)CII~I'h -C(O)N(C?I15)CI-1~1'h -C(4)N(C3H7)CH2Ph 10.60 -C(U)pyridin-3-yl-5-(Ph ) -C(U)I'h-3-(CI-12(U~iophen-2- -C(O)Ph-3-(CI-l2Ph) vl)) 10.61 -C(O)C(CI-I3)20Ph -C(O)('.II(C~I-15)OPh -C(UICI-I~OCH2Ph 10.62 -C(O)CI-I~U(o-1'hCIhUII) -C(U)CI-I~O(m-PhCI-hOH) -C(U)CI-I20(p-PhCH~OH) 10.63 -C(O)CII~O(o-1'h COUI l) -C(U)ChhU(m-I'hCOUH) -C(O)CH2U(p-PhCOOH) 10.64 -C(U)CIi~U(o-PhCUUCI-i~) -C(U)CII~U(tn-PhCUUCH~) -C(U)CH20(P-PhCOOCH~) r g~/
SUBSTITUTE SHEET (RULE 26) WO 95/09634 ~ ~'l ~ 3 .~ ~ PCT/US94111280 10.65 -C(O)CH2U(o-PhCH?CUOII) -C(U)Ctt2U(m- -C(U)CI-120(p-PhCH2COOH) PhCIi~COOI-I) 10.66 _ p C O
~NUO
J
/ \
Table ll Formula I : A = -B(OH)2 ; X = -SC(=NI-I)N112 ; R3 = table below : R11 = CH3 -' .1 ~ .3 .

11.1 -C(O)Ph -C(O)CH~Ph -C(O)CtI2CH2Ph 11.2 -C(O)CH~OPh -C(U)CI-i~NI-IPh -C(O)CH?SPh 11.3 -C(O)o-PhOtI -C(U)tn-PhOFi -C'(U) 1'hOH
11.4 -C(O)o-PhCH~UH -C(U)tn-I'hCH~OH -C(U)P-PhCH?UH

11.5 -C(O)o-Ph C'.001-I-C'(U)m-I'hC'OOH -C(U) -PhCOOH
11.6 -Cl0)o-PhCH~C001i -C(U)m-PhC1-I2CUUlI-C(O)P-PhCH2COOH

11.7 -C(O)naphth-1-yl -C(O)Clh(naPhUt-1-yl)-C(U)CH~CH~(naPth-1-yl) 11.8 -C(O)naphth-2-yl -C(U)CII~(m~Phth-2-vl-C(O)CH~CH2(naPth-2-yl) 11.9 -C(O)o-biphenyl -C(U)CH2(o-biphenyl)-C(O)CH2CH2(o-biphenyl) 11.10-C(O)m-biphenyl -C(O)CIi2(m-biphenyl)-C(O)CH~CH2(m-biphenyl) 11.12-C(O)p-biphenyl -C(U)CI-I2(P-biphenyl)-C(O)CH~CH2(p-biphenyl) 11.13-C(O)o-PhOPh -C(O)CH2(o-PhOPh) -C(O)CH2CH2(o-PhOPh) 11.14-C(O)m-PhOPh -C(O)CH~(m-PhOPh) -C(O)CH2CH2(m-PhOPh) 11.15-C(O)p-PhOPh -C(U)CH~(P-PhUPh) -C(O)CH~CH2(P-PhOPh) 11.16-C(Ok~-PhNI~Ph -C(U)C112(o-PItNHPh)-C(O)CH~CH2(o-PhNHPh) 11.17-C(O)m-PhNtiPh -C(U)CII2(m-PhNtIPh)-C'.(O)CI~I~CH2(m-PhNHPh) 11.18-C(O)P-PhNIIPh -C(U)CIi~(p-I'hNlil'h-C(O)CIi~CH2(P-PhNHPh) ) 11.19-C(O)o-PhSPh -C(O)CIi2(o-PhSPh)-C(U)CH~CH2(o-PhSPh) 11.20-C(O)m-PhSPh -C(U)CtI2(m-I'hSPh)-C(O)Cti2CH2(m-PhSPh ) 11.21-C(U)P-PhSPh -C(O)CII~(P-I'hSl'h)-C(O)CH~CH2(P-PhSPh) 11.22-C(O)o-PhCI-i2S1'h-C(U)Ctl2(o-PhCH2SPh-C(O)CH2CH2(o-) PhCH2SPh) 11.23-C(O)m-PhCII2SPh -C(U)C112(m-PhCi-l2SPh-C(0)CH2CH2(m-) PhCI-hSPh) 11.24-C(O)P-PhCtI2SPh -C(U)CH2(P-I'hCII2SPh)-C(O)CH2CH2(p-PhCH~SPh) 11.25-C(U)adartaarttyl -C(U)CI1?(acl~~tm~~ntyl)-C(U)CIi2CH2(adamantyl) 11.26-C(O)cvclopentvl -C(U)CtI~(cvcloPentyl)-C(O)CH2CH2((cycloPentyl) 11.27-C(O)cvclohexvl -C(U)CI-I~(cyclohexyl)-C(U)CI-hCrI2(cvclohexyl) 11.28-C(O)CI~1~0(cvclopentvl)-C(U)CII~NII(cyclopentvl)-C(O)CII2S(cycloPentyl) 11.29-C(O)GH?O(cyctohexvl)-C(U)Cf2NF1(cyclohexyl)-C(O)CI-IZS(cyclohexyl) 11.30-C(O)Pytidin-2-vl -C'(U)CI h(Pytidin-2-yl)-C(U)CI-I2CH?(Pytidin-2-yl) 11.31-C(O)pvridin-3-vl -ClO)C!-1~(Pyridin-3-yl)-C(O)CH~CH2(Pyridin-3-yl) 11.32-C(O)Pvtidin-4-vl -C(U)Cll~(pyridin-4-yl)-C(O)CI-I~CH2(pytidin-4-yl) /

11.33-C(O)I'urtn-2-vl -C(U)C'11~(furnn-2-vl)-C(U)CH~Cth(furut-2-vl) / $'.~
SUBSTITUTE SHEET (RULE 26) WO 95!09634 PCT/US94111280 ~17~3~4 11.34 -C(U)1'urtn-3-yl -C(U)CI1~(furan-3-vl) -C(U)CH2CH2(furan-3-vl) 11.35 -C(U)thiophen-2-vl -C(U)CIU~(thioPhcn-2-yl) -C(O)CH~CH2(thiophen-2-yl) 11.36 -C(O)thionhen-2-yl -C(U)CIh(thioPhcn-2-yl) -C(U)CH~CH2(thiophen-2-vl) 11.37 -C(O)itnidazo-2-v_ l -C(U)CII~(uniclazo-2-vl) -C(O)CH~CH2(imidazo-2-yl) 11.38 -C(O)oxazo-2-vl -C'(O)CI h(oxazo-2-vl) -C(O)CH~CH~(oxazo-2-vl) 11.31 -C(U)thioazo-2-yl -C(O)CI-t~(tluo~zo-2-yl) -C(U)CH~CH~(thioazo-2-yl) 11.40 -C(O)benzofuru~-2-yl -C(U)CH2(henzofuru~-2-yl) -C(O)CH2CH2(benzofuran-2-vl) 11.41 -C(U)henzofurair3-yl -C(U)CI-I2(henzofurm-3-yl) -C(O)CH2CH2(henzofuran-3-vl) 11.42 -C(O)henzothiophen-2-yl -C(U)CII2(henzothiophen-2- -Y1) C(U)CH2CH2(benzothiophen -2-vl) 11.43 -C(O)thiophen-2-yl -C(O)CI-i~(thioPhen-2-vl) -C(O)CI~~CH~(thiophen-2-yl) 11.44 -C(O)henzimidazo-2-yl -C(O)CI-I2(henzunidazo-2-yl) -C(U)CI-I2CH2(benzi,midazo-2-vl) 11..45 -C(O)henzoxzzo-2-yl -C(U)CH2(hcnzoxazn-2-yl) -C(O)CH2CH2(benzoxazo-2-vl) 11.46 -C(U)benzothiazo-2-yl -C(U)Cl-12(bcnzoU~i~zo-2-yl) -C(O)CH2CH2(henzothiazo-2-vl) 11.47 -C(O)o-Ph(P(U)I'h3) -C(U)m-Ph(P(U)1'h3) -C(U)P-l'h(P(O)Ph3) 11.48 -C(O)Ph-2-ltluoren-9-vl) '-C'((»Ph-3-(tluoren-~~-vl) -C(U)Ph~-((luoren-9-vl) 11.49 -C(O)N-indolin-2-one -('.(C))indolin-2-vl -C(U)indol-2-vl 11.50 -C(U)cyclopentyl-2-(Ph) -C(UkYclohexyl-2-(Ph) C(O)C(CI-I3)2NI-IS02(naPhth -2-vl) 11.51 -C(O)pyrmlidin-3-yl~t-(Ph) -C(U)tetrthydrofurm-3-yl~- -C(O)tenahydrothiophen-3-yl-(Ph) 4-(Ph) 11.52 -C(U)tetrW ydmna~hth-1-yl -C(O)tctrihvdronurhth-2-vl -C(O)cyclopronyl-2,2-(Ph2) 11.53 -C(O)tetrahydroiuwyuinolin-1- -C(U)tctr~tlrydroisc~uinolin-3- -C(U)CH2((2-oxo)indolin-3 yl yl vl) 11.54 -C(O)CI-i2(N-henzimidazol-2- -C(U)CI12(N-bcnzox~zol-2- -C(U)CH2(N-henzothiazol-2-one) one) one!
11.55 -C(O)C112(N-dihydrounid~rzol- -C(U)C112(N-~ihydrcx~xazol-2- -C(O)CH2(N-dihydrothiazol-2-one! one) 2-one) II.56 ~co- ~co- ~ o N l ~ N y N y ,l ' ~ ~ i i 11.57 p O O
-OC'-N~NH -OC~N~O -OC~N~S
SUBSTITUTE SHEET (RULE 26) ~1'~4~I4 11.58 -0C O - .OCR -0C O
~N ~ 1. CNJ ~NUo U
N
~I
11.59 -C(O)N(CH3)CIl2Ph -C(U)N(C21-i5)C:I-i2Ph -C(O)N(C3H7)CH2Ph 11.60 -C(O)Pyridin-3-yl-5-(Ph) -C(O)Ph-3-(CII2(tluophen-2- -C(O)Ph-3-(CH2Ph) vl)) 11.61 -C(U)C(CH3)20Ph -C(U)CI-i(C2115)OPh -C(O)CH20CH2Ph 11.62 -C(O)CI-hOfo-PhCI-I~OH) -C(U)CH~O(m-PhCH~0lI) -C(O)CH20(P-PhCH20H) 11.63 -C(O)CH~O(o-PhCOOH) -C(UICI-hU(m-PhCUOI-I) -C(O)CH2U(P-PhCOOH) 11.64 -C(O)CH20(o-PhCOOCH3) -C(O)CII~O(m-PhCOOCH~) -C(O)CH20(P-PhCOOCH3) 11.65 . -C(O)CH20(o-I'hCl-I2CUU1I) -C(U)CI-i20(m- -C(U)CH20(p-Ph CH2COOH) PhCI-I~COOH) 11..66 -OC 0 ~N~O
J
Table 12 Formula I : A = -B(OH)2 ; X = -SC(=NH)NH2 ; R3 = table below ; R11 = -CtI2(P-Ph OH).

.1 .2 12.1 -C(O)Ph -C(U)CI-hPh -C(O)CH2CH2Ph 12.2 -C(O)CI-hOPh -C(U)CI-hNltl'h -C(O)CH~SPh 12.3 -C(U)o-PhOH -('(())m-Ph01-I -C(U) -1'hOH

12.4 -C(U)o-I'hCI-I~UII -C(O)m-l'hClhOI-I -C(U)P-PhCH20H

12.5 -C(O)o-I'hC'.OO11 -Cl(m-I'hCU0lI -C(< -Ph COOH

12.6 -C(U)o-I'hCIhCUUJI -C(()>m-!'hCII~CUUI~-C(U)P-Ph CI-12COOH

12.7 -C(O)naphth-1-vl -C(U)CI-I2lnarhU~-1-yl)-C(O)CH2CH2fnaPth-1-vl) 12.8 -C(U)naphth-2-vl -C(U)CH2(naphth-2-yl-C(O)CH2CH2(naPth-2-vl) 12.9 -C(O)o-hiPhenvt -C(O)CII~(o-hiPhenvl)-C(U)CH2CH~(o-biPhenvl) 12.1()-C(O)m-hiPhenvl -('(O)('.li~(m-hiPhenvl)-C(O)CH~CH~(m-hiPhenvl) 12.12-C(O)P-hiPhenyl -C(O)CI1~(P-hiphenvl)-C(O)CH2CH2(P-hiPhenyl) 12.13-Cl0>o-Ph OPh -C(U)CI h(o-1'hUPh)-C(O)CI-I~CH~(o-PhOPh) 12.14-C(U)m-I'hUPh -C(U)CI-h(m-I'hOPh)-C(U)CI-hCH2(m-PhOPh) 12.15-C(O)P-PhOPh -C(U)CII~IP-l'hUPh)-C(O)CI-I2CH2(P-PhOPh) 12.16-C(U)o-PhNHPh -C'(O)CI-I~(o-PhNIII'h)-C(U)CH2CH2(o-PhNHPh) 12.17-C(U)tn-PhNIIPh -C(O)Cli~(m-!'hIVIIPh-C(U)CH2Cli2(m-PhhlHPh) ) 12.18-C(U)P-PhNI~Ph -CfU)C'.112(P-I'hNIIPh)-C(O)CH2CH2(P-PItNHPh) 12.19-C(O)o-I'hSPh -C(O)Cll~(o-l'hSPh)-C(U)CH2CH~(o-PhSPh) 12.20-C(Ohn-PhSPh -C((Cf I~(m-1'hSl'h)-C(O)CH~CH2(m-PhSPh) 12.21-C(OlP-I'hSPh -C(O)CIi~(P-l'hSPh-C(O)CH2CH2(P-PhSPh) ) 12.22-C(O)o-PhCH~SPh -C'(U)('1l~(o-PhCII~SPh)-C(O)CH2CI-h(o-PhCH~SPh) l g7 SUBSTITUTE SHEET (RULE 26) WO 95/09634 ~' ~ ~ ~ ~ ~ ~ PCT/US94/11280 12.23-C(O)m-PhC112SPh -C(U)C112(m-PhCI-I2SPh)-C(O)CH2CH2(m-PhCI-hSPh ) 12.24-C(U)p-PhCI-i~SPlt-C'.(U)('.H~(P-PhCII~SPh)-C(O)CIhCIl2(p-PhCH2SPh) 12.25-C(O)adamantvl -C(U)CII~(aciwn.~ntvl)-C(O)CH2Cli~(adamantyl) 12.26-C(O)cvclonentyl -C(U)CII~(cvcloPentvl)-C(O)CH~CH2((cvclonentyl) 12.27-C(O)cvclohexvl -C(U)CIi~(cvclnhexvl)-C(O)CH~CH~(cvclohexvl) 12.28-C(O)CH~O(cyclopentvl)-C(U )CI-hNII(cvcloPentvl>-C(O)CH~S(cyclopentyl) 12.29-C(O)CH2U(cvclohexvl)-C(U)CI-I~NI-I(cvclohexvl)-C(U)CH2S(cyclohexvl) 12.30-C(O)Pvridin-2-yl -C(U)Cl-I~(Py~din-2-vl)-C(U)CH?CH2(pytidin-2-yl) 12.31-C(O)pvridin-3-yl -C(U)CI-1~(Pyridin-3-vl)-C(O)CH2CH2(pyridin-3-yl) 12.32-C(O)ryridin-4-v_ -C(O)Cl-I2(pyridin-4-vl)-C(O)CH2CH2(Pyriclin-4-yl) 12.33-C(O)furan-2-yl -C(O)CII~(furut-2-vl)-C(O)CH2CI-h(furan-2-yl) 12.34-C(O)furan-3-vl -C(U)CI-I~(furan-3-vl)-C(U)CH~CII2(ftuatt-3-yl) 12.35-C(O)Utionhen-2-yl-C(U)CII2(Utiophen-2-vl)-C(U)CH~CH~(thioPhen-2-yl) .

12.36-C(O)Uuo~hen-2-yl -C'(U)CII2(Uiiophen-2-yl)-C(U)CH2CH2(thiophen-2-yl) 12.37-C(O)imidazo-2-v_ -C(U)CIh(imiduzo-2-vl)-C(O)CH2CH2(imidazo-2-yl) 12.38-C(U)oxazo-2-vl -C'.(O)Cl-1~(oxazo-2-vl>-C(U)CI-I~CH~(oxazo-2-vl) 12.39-C(O)U~ioazo-2-v! -C'(( Clh(Uuoazo-2-yl)-C(U)CH~CH~lthioazo-2-yl) 12.40-C(U)benzofuran-2-yl-C(U)CI12(tKnzoturut-2-yl)-C(U)CI-12CH2(benzofuran-2-vl) 12.41-C(U)henzofurm-3-yl-C(U)C:Ii2(hcnzolurut-3-yp-C(O)CH2CH2(henzofutan-3-vl) 12.42-C(O)henzoUtiorhen-2-yl-C(U)CIi2(henzoUtiophen-2-yl) C(O)CH2CI-I2(benzothiophen-2-vl) 12.43-C(O)Utiophen-2-yl-C(U )CIIZ(UtioPhen-2-yl)-C(O)CH2CH~(thiophen-2-yl) 12.44-C(O)bcnzimicJazo-2-yl-C(U)C'.lI2(henzimicl~>zo-2-yl)-C(O)CII2CH2(benzimidazo-2-vl) 12.45-C(O)benzoxazo-2-yl-C(O)ClI2(hcnzoxazo-2-yU-C(U)ClI2CIi2(henzoxazo-2-vl) 12.46-C(O)tx:nzoU~iazo-2-yl-C(O)C:I1~(hcnzoU~iazo-2-yl)-C(O)Clf2CH2(benzothiazo-2-vl) 12.47-C(U)o-Ph(P(U)1'h~)-C'(U)m-I'h(t'(U)Ph~)-C(O)p-Ph(P(O)Ph~) 12.48-ClU)Ph-2-(Iluoren-9-vl)-C(U)Ph-:1-lfluoren-9-vl)-C(O)1'h-4-(Iluoren-9-vll 12.49-C(O)N-indolin-2-one-C(())incle~lin-2-vl-C(U)inciol-2-vl 12.50-C(U)C(CH3)2NIISU2(narhUt--C(U)cyclopcntyl-2-(Ph) -C(U)cyclohexyl-2-(Ph) 2-vl) 12.51-C(O)(tywolidin-3-yl-4-(Ph)-C:(O)tcu~thydrofm;ut-3-yl-4--C(U)tetrahydmUtiophen-3-yl_ (Ph) 4-(Ph ) 12.52-C(U)tetrahvdronaPhtlr-C((>)teu:~hvdrona0tnh-2-vl-C(O)cyclopropyl-2.2-(Ph2) 1-vl 12.53-C(O)tetrahydroisoquinolin-1-yl-C(U)tetrahyeJroisoquinolin-3--C(U)CH2((2-oxo)indolin-3-vl vl) 12.54-C(U)CI-12(N-t>Lnzimi~l:~zol-2--C(U)Crl2(N-benzoxtzol-2--C(U)CH2(N-benzothiazol-2-onel one) one) 12.55-C(U)CH2(N-dihydmimidaznl--C(U)CI12(N-dihydrooxazol-2--C(U)CI-12(N-dihydmthiazol-2-2-onel one) one) ;g~
SUBSTITUTE SHEET (RULE 26) .~ ~ ~ 4 31 ~: PCTIUS94111280 ~°""'~ WO 95109634 12.56 rC0- rC0-O
N O 1 ~ N w N w li ~1 ~ ,\ li li O O
12.57 p a -OC~.NuNH -OC~N~O -OC~N S
12.58 -OC O -OCR OC O
IN CN1 ~NUO
J
/ \ ~ N / \
~I
12.59 -C(U)N(CI-t~)CH~I'h -C(U)N(C21I5)CII?Ph -C(O)N(C3H7)CH?Ph 12.60 -C(U)pyridin-3-yl-5-(Ph) -C(U)I'h-3-(CI f?(U~ioPhen-2- -C(O)Ph-3-(CH2Ph) vl)) 12.61 -C(O)C(CH3)2UPh -C(U)CI-((C21I5)OPh -Cl0)CH20CH2Ph 12.62 -C(U)CH~O(o-PhC1i20H) -C(U)CH~U(m-PhCH~OH) -C(O)CH20(P-PhCH20H) 12.63 -C(O)CH~U(o-PhCOOH) -C(0)CH~U(m-1'hCOOH) -C(O)CH?O(P-PhCOOH) 12.64 -C(O)CI-I~U(o-PhCOOC'.H~) -C(U)CII~Uhn-PhCUOCI-1~) -C(O)CH2U(P-PhCOOCH~) 12.65 -C(O)CI-I2U(o-PhCII2CU0Ii) -C(U)CIi2U(m- -C(O)CI~20(P-PhCH2COOH) PhCH~COOH) 12.66 _ O C O
~NxO
J
/ \
Table 13 Formula I : A = -B(OI-I)2 : a = -SC(=MI)NI12 ; R3 = Othle hclow ; R11 = -CH2ChI2Ph.
.l 2 .3 .

13.1 -C(U)Ph -C(U)CIl2Ph -C(O)CH2CH2Ph 13.2 -C(O)CIhUI'h -C(O)C'.1-I~M tPh -C(U)C1I2SPh 13.3 -C(O)o-PhOH -ClU)tn-PhOH -C(O) PhOH

13.4 -C(O)o-PhCl-i~UH -C(U)m-PhCII~UIU -C(U)P-PhCI-120I-I

13.5 -C(O)o-PhCOOI-I -C(U)tn-PhCUOH -C(U) -PhCOOH

13.6 -C(O)o-PhC1hC001-I -C(U)m-I'hCII~CUOH-C(O)P-PhCH2COOH

13.7 -C(U)naPhtlrl-vl -C(U)C'1-I2(naPhth-I-vl)-C(O)CI-I2C1-I2(naPth-I-yl) 13.8 -C(O)naPhth-2-vl -C(U)CII~(naPhth-2-yl-C(U)CH~CH~(n~Pth-2-v1) 13.9 -C(O)o-hiPhenvl -C'(U)CII~(o-hiPhenyl)-C(O)CI-I~CH~(o-hiphenvl) 13.10-C(Ohn-biPhenvl -C(U)C'.I h(m-hiPhenyl)-C(U)CId~CI-i2(m-hiPhenyl) 13.12-C(O)P-hiphenvl -C'(O)C'11~(P-hiPhenvl)-C(U)ClhCH2(P-biphenyl) 13.13-C(U)o-1'hUPh -C(O)C'11~(~-f'hOPh)-ClU)CII~Crl2(o-PhOPh) SUBSTITUTE SNEET (RULE 26) WO 95109634 ~ ~ ~ ~ ,~ PCT/US9.~111280 13.14-C(U)tn-PhUPh -C(U)C'11~(m-l'hUI'h)-C(U)C:II?CH~Im-PhOPh ) 13.15-C(U)~-I'hUPh -C'.(U)Cll~(P-1'h01'h)-C(U)Cl-I~CI-hlP-PhOPh) 13.16-C(U)o-PhNIIPh -C'(O)Clh(o-I'hNIIPh)-Cl0)CI-I~CH~(o-PhNHPh) 13.17-C(Ohn-PhNHPh -C'(U)Cli~(m-PhN1-II'h)-C(O)CH~CH~(m-PhNHPh) 13.18-C(U)p-PhNHPh -C'.(U)C'.1-l~(P-PhNIIPh)-C(U)CH~CH~(P-PhNHPh) 13.19-C(U)o-PhSPh -C(U)CII~(o-I'hSl'h)-C(O)CH~CH~(o-PhSPh) 13.20-C(U)m-PhSPh -C(O)CI-h(m-PhSPh)-C(O)CH2CH2(m-PhSPh) 13.21-C(O)s-PhSPh -C(U)CH2(P-PhSPh) -C(O)CH~CH2(P-PhSPh) 13.22-C(U)o-PhCH~SPh -C(U)CII~Io-PhCII2SPh)-C(U)CH2CH~(o-PhCH2SPh) 13.23-C(U)m-PhCH2SPh -C(O)CI-t2(m-PhCH2SPh)-C(O)CH2CH2(m-PhCH2SPh) 13.24-C(U)ri-PhCH~SPh -C(U)CH2(P-PhCI-I~SPh)-C(O)CH~CH~(p-PhCH~SPh) 13.25-C(O)adamantvl -C(UICIl~(adamantvl)-C(O)CH~CH~(adamantvl) 13.26-C(O)cycloPentvl -C(O)CH~(cyclolxntvl)-C(O)CH~CH2((cvclopentyl) 13.27-C(O)cvclohexvl -C(U)CH2(cyclohexyt)-C(U)CH?CH?(cyclohexyl) 13.28-C(U)CI I~Olcyclonemvl)-C(U)CI hNI I(cvcloPentvl)-C(U)CH~S(evclopentvl) 13.29-C(O)C1I~U(cvclohexvl)-C'(O)Cl?N1I(cyclohexyl)-C(U)CIi2S(cyclohexyl) 13.30-C(U)P~ditr2-vl -C(U)CII~tPyidin-2-vl)-C(U)CH~CH~(Pvridin-2-vl) 13.31-C(O)Pvndnr3-vl -C(O)Cll~(Pyridin-3-vl)-C(O)CH~CH~(Pyridin-3-yl) 13.32-C(O)pvridin-4-vl -C'.(U)CII~(Pyridin-4-vl)-C(U)CH~CH2(Pvtidin-4-vp -13.33-C(O)turm-2-vl -C'(U)CI-i~(furan-2-vl)-C(O)CH~CH2(furan-2-y1) 13.34-C(O)furan-3-yl -C'(U)CH2(furtn-3-yl)-C(U)CH2CH2(furan-3-yl) 13.35-C(U)thioPhen-2-vl -C(U)Clh(thiophcn-2-yl)-C(O)CH~CH2(thioPhen-2-yl) 13.36-C(O)thioPhen-2-yl -C(U)CI-I~(thioPhen-2-yl)-C(U)CH~CH~(thioPhen-2-y1) 13.37-C(O)imidazo-2-v_ -C(O)Cli~(imidazo-2-yl)-C(U)CI-hCH~(imidazo-2-yl) I

13.38-C(O)oxazo-2-yl -C(O)C1U~(oxazo-2-yl)-C(U)CI-hCI-I2(oxuzo-2-yl) 13.39-C(O)thio<uzo-2-yl -C(U)CIh(thioazo-2-yl)-C(O)CH2CII2(thioazo-2-yl) 13.40-C(O)henzofurln-2-yl-C(O)CII2(tx;nzofuran-2-yl)-C(U)CH2CII2(henzofutan-2-vl) 13.41-C(O)henzoftunn-3-yl-C(U)CH2(hc;nzofurut-3-yl)-C(U)CI-I2CH2(henzofuran-3-vl) 13.42-C(0)henzothio~hen-2-yl-C(O)CII2(benzoU~iophen-2-yl) C(O)CI-I?CI I2(benzothiophen-2-vl) 13.43-C(U)thionhen-2-vl -ClU)CIU~(thioPhetr2-vl)-C(U)CI-hCII~(thio~hen-2-yl) 13.44-C(U)lxnzitnidazo-2-yl-C(U)C112(hcnzunid.'tzo-2-yl)-C(U)CH2CH2lhcnzimidazo-2-vl) 13.45-C(U)hcnzoxazo-2-yl-C(U)CII2(hcnzoxazo-2-yl)-C:(U)CH2C)-I2(henzoxazo-2-vl) 13.46-C(U)henzotltiazo-2-yl-C(U)CI-t2(hcnzothiazcr2-yl)-C(O)CH2CIi2(benzothiazo-2-vl) 13.47-C(O)o-Ph(P(O)I'h~)-C(U)m-I'h(P(U)Ph~)-C(O)Y-Ph(P(O)Ph~) 13.48-C(O)Ph-2-l(lunrcn-9-vl)-CtC))1'h-3-(fluorcn-9-vl)-C(O)1'h-4-(fluoren-9-vl) 13.49-C(O)N-indolin-2-onr-C(U)incinlin-2-vl-C(O)indnl-2-vl 13.50-C(O)C(CI-i3)2NIISU2(naPhth--C'.(U)cyclolxntyl-2-(Ph)-C(U)cyclohexyl-2-(Ph) 2-vl ) 13.51-C(U)Pyrmlidin-3-yt-4-(Ph)-C(O)tcunhydrofur;tn-3-yl-4--C(U)tetrahydmthiophen-3-yl-(Ph) 4-(Ph ) 13.52-C(U)tetr.dmdmn,ylulrl-vl-C(U)tcu.chvclronaPhth-2-vl-C(U)cycloProPy1-2.2-(Ph2) l ~t'o SUBSTITUTE SHEET (RULE 26) 13.53 -C(U)tetrtthydroisoquinolin-1-yl -('(U)tcu~ah aoquinolin-3- -C H2((2-oxo)indolin-3-vl vl) 13.54 -C(U)CH2(N-henzimiduzol-2- -C(U)CI-I2(N-henzoxazo!-2- -C(O)CH2(N-henzothiazol-2-onel one) one) 13.55 -C(O)Cl-i2(N-dihydrounidazol- -C(U)CH2(N-dihycli~ooxazol-2- -C(O)CH2(N-dihydrothiazol-2-2-onel one) one) 13.56 rC0- rC0-O
N O / ~ N w N w !i ti O O
13.57 O a -OC~N11NH _OC''N11O -OC..N S
13.58 -OC O -OC, O ' a _ ~N ~ !~ N N O
\ ~ CN_ / \
~I
13.59 -C(0)N(CI-I3)ClI2Ph -C(U)N(C21i5)CH2Ph -C(O)N(C3>-I7)CH2Ph 13.60 -C(O)Pyridin-3-yl-5-(Ph ) -C(U)I'h-3-(Cl I2(U~ioPhen-2- -C(U)Ph-3-(CH2Ph) 1)) 13.61 -C(U)C(C1I3)~UPh -C(U)CII(C21I5)OPh -C(U)CI-hUCH2Ph 13.62 -C(U)CI-12U(o-PhCH~UII) -C(O)C1-1~U(m-l'hCI~h01-I) -C(O)CH2U(p-PhCH20H) 13.63 -C(O)CIi~O(o-PhCOOI-I) -C(U)CII~UIm-PhCUOH) -C(U)CH20(P-PhCOOH) 13.64 -C(O)CI-hO(o-PhCUC~H~) -C(0)C13~0(m-PhCUOCIi~) -C(O)CH?U(P-PhC00CH3) 13.65 -C(O)Cl-I2U(o-PhCII2CUU1-I) -C(O)CI12U(m- -C(O)CH2U(p-PhCH2COOH) PhCI I~CUOI I) 13.66 -OC O
~NxO
J
/ \
~ ~r SUBSTITUTE SHEET (RULE 2b) WO 95109634 ' Table 14 Formula I : A = -B(OH)2 ; X = -SC(=NH)NlI2; R3 = table below ; R11 = -Ph.
.l ' .3 .

14.1 -C(O)Ph -C(O)CH~Ph -C(O)CH2CH~Ph 14.2 -C(O)CII20Ph -C(U)CI-I?NHPh -C(O)CI-I2SPh 14.3 -C(O)o-PhOH -C(U)m-PhOI-I -C(O) -PhOH

14.4 -C(O)o-PhCH20H -C(U)m-PhCII20fI -C(O)P-PhCH20H

14.5 -C(O)o-PhCUOH -C(O)m-PhCUUH -C(0) -PhC00H

14.6 -C(Ok~-PhCH2COOH -C(U)m-PhCH2CU01-i -C(O)p-PhCH2COOH

14.7 -C(O)naphth-I-vl -C(O)CI-12(naphth-I-vl)-C(O)CH~CH~(naPth-1-yl) 14.8 -C(O)naphth-2-yl -C(O)CH~(narhth-2-vl-C(O)CH2CH2(naPth-2-yl) 14.9 -C(O)o-biphenyl -C(O)CH~(o-biphenyl)-C(O)CH2CH2(o-hiphenvl) 14.10-C(O)m-biphenyl -C(O)C'.H~(m-biphenyl)-C(O)CH2CH~(m-biphenyl) 14.12-C(O)p-biphenyl -C(U)CII~(p-biphenyl)-C(0)CI-I2CH2(P-biphenyl) 14.13-C(O)o-PhOPh -L(O)CI1~(o-PhUPh) -C(O)CH2CH~(o-PhOPh) 14.14-C(U)m-PhOPh -C(O)Cll~(m-1'hUPh)-C(O)CI-I~CH~(m-PhOPh) 14.15-C(0)p-PhOPh -C(O)CH~(p-l'h01'h)-C(O)CH2CH2(p-PhOPh ) 14.16-C(U)o-PhNHPh -C(U)Cl i~(o-1'hNIIPh-C(O)CH2CH2(o-PhNHPh) ) 14.17-C(U)m-1'hNI-IPh -C(O)CI12(m-I'hNHPh)-C(O)CH2CH2(m-PhNHPh) 14.18-C(O)p-PhNHPh -C(U)CH2(p-I'hNIiPh)-C(U)CH2CH2(p-PhNHPh) 14.19-C(O)o-PhSPh -C(U)CIU2(o-PhSPh) -C(O)CH2CH2(o-PhSPh) 14.20-C(O)m-PhSPh -C(U)CI~~(m-PhSPh) -C(O)CH2CH2(m-PhSPh) 14.21-C(U)p-PhSPh -C(O)Cli2(p-PhSPh) -C(O)CH~CH2(p-PhSPh) 14.22-C(O)o-PhCH2SPh -C(U)Cli2(o-PhCI-I2SPh)-C(O)CH2CH2(o-PhCH2SPh) 14.23-C(U)m-PhCIi2SPh -C(U)CI-12(tn-PhCII2SPh)-C(O)CH2CH2(m-PhCH2SPh) 14.24-C(U)p-PhCH2SPh -C(U)CI12(P-PhClI2SPh-C(O)CH2CH2(p-) PhCH2SPh) 14.25-C(O)adatnantvl -ClU)CII~(aclomlntvl)-C(O)Cl-hCH2(adaunantyl) 14.26-C(0)cvclopentvl -C(U)Clh(cvclepcntyl)-C(0)CI-I2CH~((cycloPentvl) 14.27-C(U)cvclohexvl -C(U)Clh(cvclohexvl)-C(O)CI-hCH2(cyclohexyl) 14.28-C(O)CH~U(cvclopentyl)-C(U)CI-i~NII(cyclopentyl)-C(O)CI-f2S(cvclopentyl) 14.29-C(O)CH2U(cvclohexvl)-C(O)CIhNIi(cvclohexyl)-C(O)CH2S(cyclohexyl) 14.30-C(U)pyridin-2-yl -C(U)Cli~(pytidin-2-yl)-C(U)ClhClI2(pvridin-2-yl) 14.31-C(O)pytidin-3-yl -C(U)CI h(pyridin-3-vl)-C(O)CH2CH~(pyridin-3-yl) 14.32-C(O)pytidin-4-v_ -C(U)CII~(pyridin-4-vl)-C(O)CH2CH~(pyridin-4-yl) l 14.33-C(O)furan-2-yl -C(U)CIh(furnn-2-vl)-C(O)CH2CH~(futart-2-yl) 14.34-C(O)furlrt-3-yl -C(U)CI-I~(fur<tn-3-yl)-C(O)Cl-IZCH2(fttran-3-yl) 14.35-C(O)duophen-2-vl -C(O)Cll~(d~iophen-2-vl)-C(O)CH2CH~(thiophen-2-yl) 14.36-C(O)thiophen-2-vl-C(U)Clh(thiophen-2-yl)-C(U)CI-I~CH~(thiophen-2-yl) 14.37-C(U)imitJazo-2-yl-C(O)C1~I~(itnidazo-2-vl)-C(O)CI-i2CH2(imidazo-2-yl) 14.38-C(O)oxazo-2-vl -C(O)CIi~(oxazo-2-yl)-C(O)CH2CH~(oxazo-2-vl) 14.3 -C(O)thioazo-2-yl -C(U)C1h(thiowo-2-vl)-C(O)CH2CH~(d~ioazo-2-yl) 14.40-C(U)benzofurut-2-yl-C(O)C1I2(tx:nzolur<vr2-yl)-C(O)CI-i2CH2(henzofuran-2-vl) I ~~
SUBSTITUTE SHEET (RULE 26) '~° WO 95/09634 PCTIUS94/11280 14.41 -C(O)benzoftuutt-3-yl -C(U)CI12(benzofuran-3-yl) -C(O)CIi2C112(benzofuran-3-vll 14.42 -C(O)benzoUiio~hen-2-yl -C(U)CIi2(benzoUtioPhen-2-yl) -C(O)CH_~CH2(henzothiophen -2-vll 14.43 -C(O)U~ioPhcn-2-vl -C(O)C'.H~(thioPhen-2-vl) -C(O)CH~CH~(thiophen-2-yl) 14.44 -C(O)benzitnidazo-2-yl -C(U)CII2(hcnzimidnzc>-2-yl) -C(O)CH2CH2(benzimidazo-2-vll 14.45 -C(O)benzoxazo-2-yl -C(O)C112(benzoxzzo-2-yl) -C(U)Cli2Crt2(benzoxazo-2-vl) 14.46 -C(U)henzoUtiazo-2-yl -C(O)C112(benzoUtiazo-2-yl) -C(O)CH2CH2(benzothiazo-2-vl) 14.47 -C(O)o-Ph(P(O)Ph3) -C(U)m-Ph(P(U)Ph3) -C(O)p-Ph(P(O)Ph3) 14.48 -C(O)Ph-2-(iluoren-9-vl) -C(O)Ph-3-(tlu~ren-~)-vl) -C'(O)Ph-4-(fluoren-9-vl) 14.49 -C(O)N-indolin-2-one -C'(U)imlelin-2-vl -C(U)indol-2-vl 14.50 -C(O)C(CIi3)2NHS02(naphUt- -C(U)cyclopcmyl-2-(Ph) -C(U)cyclohexyl-2-(Ph) 2-vll 14.51 -C(O)Pytmlidin-3-yl-4-(Ph) -C(U)tctrU~ydrofurm-3-yl~-(Ph) -C(U)tetrahydrothiophen-3-yl-4-(Phl 14.52 -C(O)tetrahvdmna~hUi-I-Yl -C'(U)tcu-uhvdronaPl~U~-2-yl -C(U)cyclopmpyl-2.2-(Ph2) 14.53 -C(O)tetralrydroisc>uuinolin-1-yl -C(U)tcuahydroisoquinolin-3-yl -C(O)CH2((2-oxo)indolin-3-vl) 14.54 -C(O)CH2(N-benzimidazol-2- -C(O)CI~I2(N-benzoxazol-2-one) -C(U)CI12(N-benzothiazol-2-one) one) 14.55 -C(O)C112(N-dUtydroimidazol- -C(O)C112(N-dihydrcx~xazol-2- -C(O)CH2(N-dihydmthiazol-2-onel cite) 2-one) 14.56 rC0- ~CO-O
w N O 1 ~ N w N w I ~ ~ ~ ~ \ I i I i 14.57 O O O
-OC''N~NH -OC~N~O -OC~N~S
14.58 _OC O -OCR -OC O
IN ~ I w CN1 1N110 /\
N /\
14.59 -C(U)N(CH~)CII~Ph -C(O)N(C~IIS)C112Ph -C(U)N(C3H7)CH2Ph 14.60 -C(O)PYridin-3-vl-5-(I'h ) -C(O)Ph-3-(C'.I1~(U~iophen-2-vl)) -C(O)Ph-3-(CH2Ph) 14.61 -C(U)C(CH~)2UI'h -C(UICI-I(C21-IS)OPh -C(O)CI-I20CH2Ph 14.62 -C(O)C11~0(o-PhCI-i~0I1) -('.(O)CFI~U(m-PhCI~~OH) -C(O)Cli2CXp-PhCI-I20H) 14.63 -C(O)CIhU(o-t'hC'UUI-1) -C'(O)C'II~UIm-PhCUUIi) -C(U)CH2U(r-PhCOOH) 14.64 -C(U)CII~U(o-I'hCOC)<'.1I3) -C:(O)CI12U(m-PhCOCxH3> -C(U)CH2U(p-PhCC~CH~) 14.65 -C(O)CI-i~0(o-I'hCII~C'UUII) -C(O)CI1~()(m-PhCII~CUUII) -C(U)CII~O(~-PhCH~COOH) SUBSTITUTE SHEET (RULE 26) ~~~~J~~~

14.66 -pC O
~NxO
J
/ \
Table 5 Formula I : A = -B(OI-I)2 ; X = -SC(=NH)NH2 ; R3 = table below ; RI I = -CH2(naphth-2-yl).

.1 2 .3 .

15.1 -C(O)Ph -C(O)CIhPh -C(O)CH2CH2Ph 15.2 -C(U)CH~OPh -C(U)CI-I~NI-IPh -C(O)CI~2SPh 15.3 -C(o)o-PhOI-1 -C'(())m-PhOli -C'(O) -PhOil 15.4 -C(O)o-PhCH~UI1 -C(U)m-t'hC'.1-I~UI!-C(O)P-P1~CH~OH

15.5 -C(O)o-PhCOOI-I -C(Ohn-PhC0011 -C(O) -PhCOOH

15.6 -C(O)o-PhCH~C001I -C(O)m-PhCI-hCUOH -C(O)P-PhCH~COOH

15.7 -C(U)naphth-1-vl -C(U)Clh(naphtlrl-vl)-C(O)CH~CH2(napth-1-vl) 15.8 -C(O)naphth-2-vi -C(O)CH2(naphth-2-yl-C(O)CH~CH~(napth-2-yl) 15.9 -C(O)o-bi0henvl -C(U)CIi~(o-biPhenvl)-C(O)CH~CH~(o-hiphenvl) 15.10-C(O)m-hiphenvl -C(O)CI-h(m-biphenyl)-C(O)CIi2CH2(m-biphenyl) 15.12-C(O)P-biphenyl -C(U)CIi2(P-biphenyl)-C(O)CH2CH2(P-biphenyl) 15.13-C(O)o-PhUPh -C(O)CI1~(o-PhOPh -C(O)CH2CH~(o-PhOPh) ) 15.14-C(O)m-PhOPh -C(U)CIh(m-I'hOPh) -C(U)CH2CH2(m-PhOPh) 15.15-C(O)p-PhOPh -C(O)C1I2(p-PhUPh) -C(O)CH~CH2(p-PhOPh) 15.16-C(O)o-PhNIiPh -C(U)CII~(o-1'hNHPh)-C(O)CH~CH2(o-PhIVHPh) 15.17-C(U)m-PhNI-iPh -C(U)CIi2(m-PhNHPh -C(O)CI-hC112(m-PhNHPh) ) 15.18-C(O)p-PhNHPh -C(U)CI-l2(P-PhNlll'h)-C(U)CH2CH2(P-PhNHPh) 15.19-C(U)o-PhSPh -C(O)CI1~(o-PhSPh -C(O)CH~CH2(o-PhSPh) ) 15.20-C(0)m-PhSPh -C(O)CI-12(tn-PhSPh)-C(O)CH2CI-I2(m-PhSPh) 15.21-C(U)p-PhSPh -C(U)Cll~(p-I'hSPh -C(O)CH2CH2(P-PhSPh) ) 15.22-C(U)o-PhCII2S1'h -C(U)ClI2lu-I'h -C(O)C'II2C132(o-CIi2SPh) PhCI-I~SPh) 15.23-C(U)m-1'hCH2S1'h -C(U)CI12(m-I'hC'.112SPh-C(U)CH2CH2(m-) PhCH2SPh) 15.24-C(U)P-PhClI2SPh -C(U)CI12(P-I'hCII2SPh)-C(O)CI-I2CH2(p-PhCH2SPh ) 15.25-C(O)adamantvl -C(U)CII~(ad~unantyl)-C(O)CH2CH2(adamantyl) 15.26-C(O)cvclopentvl -C(U )CI-12(cvcloPmtvl)-C(O)CH~CH2((cvclopentyl) 15.27-C(O)cvclohexvl -C(U)CI12(cvclohexvl)-C(O)CH?CH~(cyclohexvl) 15.28-C(O)CH~U(cycloPenlvl)-C(U)Cl-I~NII(cvclopentvl)-C(O)CH~S(cycloPentyl) 15.29-C(U)CH~O(cvclohcxvl)-C(O)CI-I~Ni Ilcvclohexvl)-C(O)ClI2S(cyclohexyl) 15.30-C(O)pytidin-2-yl -C(o)CI-1~(~yridin-2-vl)-C(U)CH2CH2(pyridin-2-yl) 15.31-C(O)Pytidin-3-vl -C(O)CII~(Pyridin-3-vl)-C'(O)CI-hCH2(pyridin-3-yl) 15.32-C(U)pyridin~-v_ -C(O)C1I~(pyridin-4-vl)-C(O)Cl-hCI-I2(pyridin-4-yp 15.33-Cl0)furan-2-yl -C(U)C'11~(fur~n-2-yl)-C'(U)CIU~CI-I~(furu~-2-yl) 15.34-C(o)iuru~-3-vl -CCU)CII~curtn-3-yl)-C'(U)CFI~CH~(furan-3-yl) 15.35-C(U)thioPhcn-2-yl-C(U)C'I1~(thi<yhen-2-vl)-C(U)CH~CI-I2(thiophen-2-yl) !9y SUBSTITUTE SHEET (RULE 26) ~7~31.~
WO 9510963.1 PCTIUS94/11280 15.36 -C(U)Uiio~hen-2-yl -C(U)CII~(Uuonhen-2-vl) -C(O)CH~CH~(thiophen-2-yl) 15.37 -C(O)unidatzo-2-yl - -C(U)C)h(imiclvo-2-yl) -C(O)CH2CH2(imidazo-2-yl) 15.38 -C(O)oxazo-2-yl -C(U)C'.1-I2(oxazo-2-yl) -C(O)CH~CH~(oxazo-2-yl) 15.39 -C(O)thioazo-2-vl -C(U)Cli2(Utioazo-2-yl) -C(O)CH~CH~(thioazo-2-yl) 15.40 -C(U)henzofuru~-2-yl -C(O)CH2(lx~nzofuran-2-yl) -C(O)CH2CH2(benzofuran-2-vl) 15.41 -C(O)henzofuran-3-yl -C(U)CI-h(henzofttran-3-yl) -C(O)CH2CH2(henzoft>ran-vl) 15.42 -C(O)henzoUuorhen-2-yl -C(U)CII2(hcnzoUuoPhcn-2-yl) -C(O)CH2CH2(henzothiophen -2-v1) 15.43 -C(O)Utiophen-2-vl -C'.(U)C'.II~(UuoPhen-2-yl) -C(O)CH~CH2(Uiiophen-2-yl) 15.44 -C(U)henzimidazo-2-yl -C(U)CI-I2(lxnzitnidazo-2-yl) -C(U)CH2CH2(henzimidazo-2-vl) 15.45 -C(O)henzoxazo-2-yl -C(U)CI12(henzoxazo-2-yl) -C.(O)CH2CH2(henzoxazo-2-vl ) 15.46 -C(O)benzoUiiazo-2-yl -C!U)CII2(benzoU~iazo-2-yl) -C(O)CH2CH2(henzoUtiazo-2-vl) 15.47 -C(U)o-Ph(P(O)Ph3) -C(U)m-1'h(P(U)I'h3) -C(U)(t-Ph(P(U)Ph3) 15.48 -C(O)Ph-2-(Iluoren-~)-vl) -C'(C»I'h-3-(lluoren-9-vl) -C'(O)Ph-4-(tluoren-9-vll 15.49 -C(O)N-indolin-2-one -C(U)indotin-2-vl -C(())ind~l-2-vl 15.50 -C(O)C(CH3)2NI-ISU2lnaPhUt- -C(U)cycla~entyl-2-(Ph) -C(U)cyclohexyl-2-(Ph) 2-vl) 15.51 -C(O)Pyrrolidin-3-yl-4-(Ph) -C'.(U)tetrahydmf uru~-3-yl~-(1'h) -C(U)tetralrydrothiophen-3-yl-4-(Ph) 15.52 -C(O)tetrW ydmnanhtlrl-vl -C(U)tetrnhydmnaPhU~-2-yl -C(O)cyclonmpyl-2.2-(Ph2) 15.53 -C(O)tetrahydroisoquinolin-1-yl -C(U)tctrahydroisoquinolin-3-yl -C(O)CH2((2-oxo)indolin-3-vl) 15.54 -C(O)CrI2(N-hc:nzimidazol-2- -C(U)Cl-12(N-henzoxazol-2-one) -C(O)CH2(N-henzothiazol-2-one) onel 15.55 -C(O)Cl-I~(N-dihydmimi~~>zol- -C(U)CII2(N-dihydrooxazol-2- -C(O)CHZ(N-clihydrothiazol-2-one) nne) 2-one) 15.56 NCO- ~CO-I ~ N O __ ~ \ N O p N p i i 15.57 O O O
-OC~.N~NH -OC~NU0 -OC~N~S
15.58 -OC O -OCR -OC O -.
IN ~ I ' ~N~ 1N110 N
15.59 -C(U)N(C'.1I~)CII~1'h -C'(O)N(C~_115)C11~1'h -C(U)N(C3H7)CH2Ph 15.60 -C(U)~yridin-3-vl-5-(Ph) -C(U)l'h-3-(C'11~(U~iophen-2-vl» -C(U)I'h-3-(Cli~Ph) ~ 93~
SUBSTITUTE SHEET (RULE 26) ~~ 74J1 15.61 -C(O)C:(Cll~)~UI'h -C'(U)C1I(C'?Ii5)OPh -C(U)CIi20CH2Ph 15.62 -C(O)CI-I2U(o-PhC11~011) -C(U)CIi~U(m-I'hC)-I~OI-I) -C(U)CIi20lP-PhCH20H) 15.63 -C(U)CH2U(o-PhCOUII) -C(U)CI-hO(m-Ph('.OUII) -C(U)CIi~U(P-PhCOOH) 15.64 -C(U)CI-I~U(o-PhCUUCH~) -C(U)C'I-i~U(tn-1'hCUOCH~) -C(O)CH20(p-PhCOOCH3) 15.65 -C(O)CH~U(o-PhCI-I~CUOII) -C(O)C'H~U(m-PhCH~COUIi) -C(O)CH~U(P-PhCH2COOH) 15.66 -OC O
~nluo J
Table 16 Formula I : A = -B(pinacieJiol) ; X = guanidinyl ; R3 = table below ; R11 =

.I 2 .3 ~

16.1 -c(o)Ph -c(cncl~~l'1~ -c(o)cH2c1-hPh 16.2 -C(O)CH~OPh -C(U)CII~M-I1'h -C(U)CI-I?SPh 16.3 -C(UIo-PhOH -C(U)m-I'h(1 -C(O) -PhOH

16.4 -C(U)o-PhCI-I2~Ii -C(U)m-PhCH~OII -C(O)P-PhCI-120H

16.5 -C(O)o-PhCU01-I -C(U)m-1'hCOOI~ -C(O) -PhCOOH

16.6 -C(U)o-PhCI hCUUH -C(U)m-I'hCIhCUOH -C(O)P-PhCH2COOH

16.7 -C(O)naphth-1-yl -C(O)CI12(naphdrl-yl)-C(O)CH2CI-I2(napth-1-yl) 16.8 -C(O)naphth-2-vl -C(O)CIi2(naphth-2-vl-C(O)CH2CH2(napth-2-yp 16.9 -C(O)o-biphenyl -C(O)CI-1~(c~-biphenyl)-C!O)CH2CH~(o-biphenyl) 16.10-C(O)m-biphenyl -C(U)CIV~(m-biphenyl)-C(O)CH~CH~(m-biphenyl) 16.12-C(O)p-biphenyl -C'.(O)Cll~(p-biphenyl)-C(0)CH~CH2(p-biphenyl) 16.13-C(Ok~-PhOPh -C(O)CI-I2(o-1'hUPh-C(O)CH2CH2(o-PhOPh) ) 16.14-C(O)m-PhOPh -C'.(U)CH~(m-PhOPh -C(O~H2CH2(m-PhOPh) ) 16.15-C(U)p-PhOPh -C(O)Cll~(p-1'hOPh)-C(O)CH2CH2(p-PhOPh) 16.16-C(O)o-PhNHPh -C(O)CII~(o-PhNI-IPh)-C'(O)CIi~CH2(o-PhNHPh) 16.17-C(U)m-PhNI-IPh -C'.(U)Cll~lm-PhIVHPh)-C(U)CH~CH2(m-PhNHPh) 16.18-C(U)n-I'hN1-tl'h -C'.(U)CII~(p-PhNllPh)-C(O)CI-hCII2(p-PhNHPh) -16.19-C(O)o-1'hSPh -C(O)C1I~(o-1'hSI'h)-C(U)CI-I2CH2(o-PhSPh) 16.20-C(U)m-PhSPh -C(O)CI-h(m-I'hSPh)-C(O)CI~2CH2(m-PhSPh) 16.21-C(U)p-PhSPh -C(U)Cli~(p-I'hSPh)-C(U)CH2CH2(p-PhSPh) 16.22-C(U)o-PhCI-I2S1'h-C(U)CI12(o-1'hCH2SPh)-C(O)CH2CH2(o-PhCH2SPh) 16.23-C{U)tn-PhC112SPh -C(U)CI-12(m-I'hCt-I2SPh)-C(O)CH2CH2(m-PhCH~SPh) 16.24-C{U)p-PhCI-I2S1'h-C(U)C112(p-PhCII2SPh)-C(O)CI-I2CH2(P-PhCH2SPh) 16.25-C(U)acl~rri<~ntvl-C(O)CI12(~ultunantvl)-C(O)CH2CH2(adarrtantyl) 16.26-C(O)cvclopentvl -C(U)Cl h(cvclopcntvl)-C(o)CI~2CHZ((cyclopentyn 16.27-C(U)cvclohexyl -C'(U)C'll~(c~clohex~~n-C(O)Cli2CH2(cvclohexvl) 16.28-C(o)Crl~o(cvclopentvn-C'(U )C'.I hNl -C(O)C:1-I2S(evclopentyl) l(cvclopentyl) 16.29-C(O)CIhO(cvclohexvl)-C'(U)C'.II~N1I(cvclohexvl)-C(U)CH~S(cvclohexyl) 16.30-C(U)pyridin-2-vl -C:(U)CII~(pynclin-2-vl)-C(U)CI-I2CH2(pytidin-2-vl) 'hv SUBSTITUTE SHEET (RULE 26) PCTIUS94l11280 16.31 -C(U)~YnJin-3-vl -C(O)CI1~(Pyriclin-3-vl) -C(O)CH~CH~(Pvridin-3-yl) 16.32 -C(O)Pyridin-4-vl -Cl0)CII~(Pyiclin-4-vl) -C(O)CH~CH2(Pvridin-4-yl) 16.33 -C(U)fururt-2-yl. -C(O)Cllz(furan-2-vl) -C(O)CH~CH~(ftuan-2-vl) 16.34 -C(O)furut-3-yl -C(U)CH12(furut-3-yl) -C(O)CI~2CH?(furan-3-yl) 16.35 -C(O)U~iophen-2-vl -C(U)CIj~(U~io~hcn-2-vl) -C(O)CH~CH~(thiophen-2-yl) 16.36 -C(O)U~iorhen-2-vl -C(O)Clh(UtinPhen-2-yl) -C(U)CH~CH~(Uiionhen-2-yp 16.37 -C(U)imitlazo-2-yl -C(U)CH2(imiUazo-2-vl) -C(O)CH~CH~(imidazo-2-yl) 16.38 -C(O)oxazo-2-yl -C(U)CI-I?(oxazc~-2-yl) -C(O)Cl-I2CH2(oxazo-2-yl) 16.39 -C(U)thioazo-2-yl -C(O)CII~(diicrtzo-2-vl) -C(U)CH~CH2(thioazo-2-yl) 16.40 -C(O)benzofurm-2-yl -C(U)Cl-i2(henzofurm-2-yl) -C(O)CH2CH2(benzofuran-2-vl) 16.41 -C(O)henzofutan-3-yl -C(U)CII2(henzoftuatr3-yl) -C(O)CH2CH2(henzofuran-3-vl) 16.42 -C(O)hcnzoUiioPhen-2-yl -C(U)CII2(hcnzoUuophen-2-yl) -C(0)CI-I?CH2(benzothiophen -2-vl) 16.43 -C(U)Uun~hen-2-yl -C'(U)CII~(Uii~rthcn-2-vl) -C(O)CI-I~CIi~(thiophen-2-yl) 16.44 -C(O)henzuruUazo-2-yl -C(U)C'I12(txnzimicJazo-2-yl) -C(U)C1I2CH2(benzimidazo-2-vl) 16.45 -C(U)henzoxuzo-2-yl -('(C»C112(hcnzox.~zo-2-yl) -C(U)CH2CI-I2(benzoxazo-vl ) 16.46 -C(O)tx.nznUOtzo-2-yl -C(U)Cli?(hcnzoU~iazo-2-yl) -C(O)CH2CH2(benzodiiazo-2-vl) 16.47 -C(O)o-Ph(P(O)Ph~) -C(U)m-Ph(1'(U)I'h3) -C(U)P-Ph(P(O)Ph3) 16.48 -C(O)Ph-2-(tluoren-9-vl) -C(UIPh-3-(lluoren-9- 1) -C(O)Ph-4-(fluoren-9-vl) 16.49 -C(O)N-indolin-2-one -C(O)imlolin-2-vl -C(U)ind~l-2-vl 16.50 -C(O)C(CH3)2NIiSU2(naphth- -C(U)cyclopentyl-2-(Ph) -C(U)cyclohexyl-2-(Ph) 2- 1) 16.51 -C(O)pyrolidin-3-yl-4-(Ph) -C(U)tcuuhyclrofurv~-3-yl-4-(Ph) -C(U)tetrahydrothiophen-3-yl_ 4-(Ph) 16.52 -C(U)tetrW vdronaplnlt-1-yl -C(U)tetrthvdronaPhUr2-vl -C(O)cycloPmpyl-2.2-(Ph2) 16.53 -C(O)teu-ahydroisoyuinolin-I-yl -C(U)tctrahyJroiuxluinolin-3-yl -C(O)CI12((2-oxo)indolin-3-vl ) 16.54 -C(O)CI-I2(N-tx:nzimiUazol-2- -C(U)CI1~(N-txnzoxatzol-2-one) -C(U)CII2(N-henzothiazol-2-one) one) 16.55 -C(O)CI-I?(N-diltydroimiUttzul- -C(U)CI1~_(N-clihy0rcx~xazol-2- -C(U)CH2(N-dihydrothiazol-2-one) one) 2-one) 16.56 rC0- ~CO-O
N O I ~ N ~ N
I~ I~
16.57 O O a -OC~.N~NH -OC~NUO -OC~N S
SUBSTITUTE SHEET (RULE 26) WO 9510963:1 ~ ~ PCT/US94/11280 16.58 -pC p -pC~ -~C
IN ~ 1 ' CN1 1N110 NJ
16.59 -C(U)N(CI-I~)CIhPh -C(U)N(C~115)Cl-I2PU -C(O)N(C3H7)CH?Ph 16.60 -C(O)Pyridin-3-vl-S-(Ph) -C'(U)1'h-3-(CII~(thioPhen-2-yl)) -C(O)Ph-3-(CH2Ph) 16.61 -C(O)C(CH3)2UI'h -C(O)CII(C~IIS)OPh -C(O)Cl-120CH2Ph 16.62 -C(O)CI-hO(o-PhC11201-I) -C(O)CII~UIm-PhCH~UH) -C(O)CH20(p-PhCH20H) 16.63 -C(O)Cl-I2U(o-PhCOOH) -C(O)CH2U(m-I'hCOOH) -C(O)CH20(p-PhCOOH) 16.64 -C(U)CH~U(o-PhCOUCH~) -C(U1CH~U(m-PItC00CH~) -C(O)CH?O(p-PhC00CH3) 16.65 -C(O)CH~OIo-I'hCH~CUUII) -C(O)CII~U(m-I'hCH~CUUII) -C(O)CH~O(P-PhCH2COOH) 16.66 -pC O
~NxO
J
Table 17 Focmu4~ I : A = -B(pinanedial) ; X = guanidinyl : R3 = table below ; R11 = -CI-12(p-PhOH).

.l _2 .3 17.1 -C(O)Ph -('(O)Cli~Ph -C(O)ClhCH2Ph 17.2 -C(O)C1I~UPh -('(U)CII~NII1'h -C(O)CH2SPh 17.3 -C(O)o-I'hOH -C'(( ))m-I'h01 -C'(O) -PhOH
I

17.4 -C(O)o-1'hCl-I2UH -C(U)tn-Ph('.I-1~U1-I-C(U)p-PhCH20H

17.5 -C(Ulo-PhCOOi-I -('(())m-PhCU01-I -C(O) -Ph COOH

17.6 -C(O)o-PhCI-1~C0011-C(U>m-PhCII~CUOH -C(U)p-I'hCH~COOH

17.7 -C(U)naPhtJrl-vl -C'.(())Cll~(narhU~-I-vl)-C(O)C)-hCH2(napth-1-yl) 17.8 -C(U)naPhth-2-vl -('(U)C'll~(napluh-2-yl-C(O)CH~CH~(naPth-2-vl) 17.9 -C(U)o-hi~henvl -Cl0)C'll~(o-hiphenvl)-C(O)CH~CH~(o-biphenyl) 17.10-C(0)m-biphenyl -C'(C))CII~(m-biphenyl)-C(O)CH~CH~(m-biphenyl) 17.12-C(O)p-hiPhenvl -('(U)C'II~(p-biphenyl)-C(O)CH~CI-i~(p-biphenyl) 17.13-C(O)o-PhOPh -('(U)CIi~(o-PhOPh)-C(U)CI-1~CH~(o-PhOPh ) 17.14-C(O)m-1'hUI'h -C(())CII~(m-1'hOPh-C(U)CH~CI-I2(m-PhOPh) ) 17.15-C(O)p-PhOPh -C'(O)CI1~(p-PhUPh)-C(U)CH~CH2(p-PhOPh ) 17.16-C(O)o-PhNI-ll'1 -C'(U)('II~(o-I'hNl-IPh)-C(U)CH~CH2(o-PhNHPh) 17.17-C(U)m-PhNI-IPh -C(U)C'11~(m-PhNIIPh-C(0)CH~CH?(m-PhNHPh) ) 17.18-C(O)s-PhNIIPh -C(<))CII~(P-I'iihllll'h)-C(O)CI-I2CH2(p-PhNHPh) 17.19-C(U)o-PhSPh -C'(U)CI1~(o-I'hSI'h)-C(O)CH~CH2(o-PhSPh) 17.20-C(O)m-PhSPh -C(O)CI1~(m-PhSPh) -C(O)CH~CH2(m-PhSPh) 17.21-C(O)~-PhSPh -C(U)C'11~(p-PhSI'h)-C(O)C1I~CI-h(P-PhSPh) 17.22-C(U)o-I'ttCl-I_~Sl'h-('.(U)C11~(o-I'hCII~SI'IO-C(U)CIi2CH2(o-PhCII2SPh) SUBSTITUTE SHEET (RULE 26) 4 ~ ~ ~ PCTlUS94I11280 23 -C(U)Cl-12(m-I'hC112SPh)-C(U)CH2CH2(m--C(U)m-I'hCII2S1'h . PhCH~SPh) 24 -C(O)p-1'hCl-I2SPh-C(U)Cll2(P-PhCII2SPh)-C(O)CH2CH2(p-. PhCH~SPh) 25 -C(U)adurt><'tntyl-C(U)ClI2(advn:uUyl)-C'(O)CH2CH2(adamanry . -C(Okyclopentyl -C(O)CI-h(cvclopentyl)-C(O)CHZCH2((cycloPentyl) . -C(O)cyclohexvl -C(U)CII~(cvclohexvl)-C(U)CI-i2CH2(cyclohexyl) . -C(O)CH2U(cvclopentyl)-Cl0)Cll~Nl-I(cvclopentyl)-C(O)CH2S(cyclopenty . l -C(O)CI-I~S(cyclohexyl) 29 -C(O)ClhO(evclohexyl)) 17 -C(U)CH~NI-f(cyclohexy . l -C(U)CH2CH2(pyridin-2-yl) 30 -C(O)~yridin-2-vl ) 17 -C(U)C112(pytidin-2-y . l -C(O)CH2CH2(pyridin-3-yl) 31 -C(U)PYndin-3-yl ) 17 -C(U)CI-i2(Pytidin-3-y . -C(O)CH2CH2(pytidin-4-yl) 32 I -C(U)CIH((tyridin-4-yl) 17 -C(O)pYtidin-4-v . _ -C(O)('.li~(furan-2-vl)-C(O)CH~CH2(furan-2-yl) 17 -C(O)furan-2-yl . -C(O)furart-3-yl -C'(O)CII~(furtn-3-yl)-C(O)CH2CH2(furan-3-yl) . -C(U)Uuonhen-2-Y1 -C(O)CI1~(Uuophen-2-yl)-C(O)CH~CH2(U~iophen-2-yl) . -C(O)U~iophen-2-vl-C(UICI-I~(U~ioPhen-2-y1)-C(O)CH2C1-h(thioPhen-2-yl) 17.36 17.37 -C(O)itnidazo-2-yl-C(U)C'Ih(imidazcr2-vl)-C(O)CH~CI-12(imidazo-2-yl) 17.38 -C(O)oxazo-2-yl -C:((CI h(oxazo-2-yl)-C(O)CH2C1-1~(oxazo-2-yl) 17.39 -C(O)Uiicrtzo-2-vl-C(U)C'.11~(Uiio~zo-2-vl)-C(U)CH~CH2(thioazo-2-yp 17.40 -C(U)hcnzofurtn-2-yl-C(U)C.H2(hcnzoCttrtn-2-yl)-C(U)CH2CH2(henzofuran-2-vl) 17.41 -C(O)henzolmam-3-yl-C(U)Cl-12(henzofurur3-yl)-C(O)CH2CH2(henzofuran-3-Vl) 42 -C(O)benzoU~ionhen-2-yl-C(U)CI12(hcnzoUiiophen-2-yl)-. C(O)CH2CH2(benzothiophen -2-vl) 17.43 -C(O)Utiophen-2-yl-C:(U)CII~(U~ioPhen-2-yl)-C(O)CI-12CH2(thiophen-2-yl) 17.44 -C(O)lx;nzitrudazo-2-yl-C(U)ClI2(hcnzimidnzcr2-y-C(O)CH2CH2(henzimidazo-2-vl) 17.45 -C(O)henzoxazo-2-yl-C(U )CII2(henzoxazo-2-yl)-C(O)CH2C112(henzoxazo-2-vl) 17.46 -C(O)henzoUii~zo-2-yl-C(U)C'.1i2(henzoUti<tzo-2-yl)-C(O)CH2CH2(benzoU~iazo-2-vl) 17.47 -C(U)o-Ph(P(O)Ph~)-C'.((m-1'lOP(U)l'h~)-C(U)(~-I'h(P(U)Ph~) 17.48 -C'(U)Ph-2-(iluoren-~)-vl)-('.(())Ph-3-(fluoren-~)-vl)-C(U)Ph-4-ltluoren-9-vl) 17.49 -C(OlN-indolin-2-one-('((>)indolin-2-vl -C(U)indol-2-vl 17.50 -C(U)C(CI-I3)2N11SU2(naphU~--C'.(U)cyclolxmyl-2-(Ph)-C(U)cyclohexyl-2-(Ph) 2-vl>

17.51 -C(U)pytmlidin-3-Yl-4-(Ph)-C(O)tetrthydrofurvr3-yl-4-(P1O-C(O)tetrahydrothiophen-3-yl-4-(Phl 17.52 -C(UhetrnhvdronaPhth-1-vl-C'(O)tcUahvdronaphU~-2-vl-C(U)cvclopropyl-2.2-(Ph2) I

17.53 -C(O)tctralrydroisoquinolin-1-yl-C'.(U)tcuahydroiscxauinolin-3-yl-C(O)CH2((2-oxo)indolin-3-vi) 17.54 -C(U)C112(N-hcnzimidazol-2--C(U)C112(N-ix:nzoxazol-2-one)-C(O)CH2(N-henzothiazol-2-one) one) 17.55 -C(O)C'.1I2(N-dihydrouniclt~zol--C(U)C:I1?(N-dihydrc~xazol-2--C(O)CI-I2(N-dihydroUtiazol-2-one) cme) 2-onel ~S9 SUBSTITUTE SHEET (RULE 2fi) WO 95109634 ~ ~ PCTIUS94/11280 17.s6 NCO- ~co- ~ o N O ! ~ N O w N w i ~ I ~ / \ l i l i 17.57 O O O
.OC~-N~NH -OC~N~O -OC~NUS
17.58 -OC O -OCR -OC O
~N ~ I. CN~ ~NUo /~ ~ N /~
~I
17.59 -C(O)N(CH~)CI-I~l'h -C'(U)N(C'~115)Clhl'h -C(O)N(C~I-I7)CH~Ph 17.60 -C(O)wridin-3-vl-5-(Ph) -C(U)1'h-3-(C'.I-1~(U~ioPhen-2-vl)) -C(U)Plr-3-(CI-i?Ph) 17.61 -C(U)C(CH3)2Ul'h -C'.(U)CII(C'~115)UI'h -C(O)CH~UCI-I2Ph 17.62 -C(O)CH~O(o-1'hCl-1~011) -C(U)CIt~U(m-PhCi-hUl-I) -C(U)CI-hU(p-PhCH~OH) 17.63 -C(O)CIhU(o-1'hCUUII> -C(U)CI-!~U(m-PhCOUI~) -C(U)CH20(P-PhCOUH) 17.64 -C(O)CH~U(o-PIUUCH~) -C(O)CII~U(rn-PhCOC)CH~) -C(O)CI-I2U(p-PhCC~CH~) 17.65 -C(O)CIhU(o-1'hCI-hCOOI-I) -C(U)CI-I~U(tn-I'hCII~COOII) -C(O)CH~OIp-PhCH2COOH) 17.66 -OC O
~NxO
J
a vo SUBSTITUTE SHEET (RULE 26) .~ ~ ~'~ 4 ~ 1 ~

Table 18 Formula I : A = -B(PinaneJiol) : X = gumtidinyl : R3 r table below ; R11 = -CH~CH2Ph.

1 2 .3 .

18 . -C(U)Cll~Ph -C(O)CH~CH7Ph 1 -C(O)Ph . -C(0)CH~OPIt -C(O)C1I~NI-lPh -C(O)CH2SPh 18.2 18 -C(O)o-Ph01-I -C'(U)m-I'hOH -C(O) -PhOH

. -C(O)o-PhCH~OH -C(U)m-PhCH~OH -C(O)P-PhCH?OH
18.4 I -C(O)o-I'hCOOI.I -('(U)m-l'hCOOH -C(O) -PhCOOH
R

. -C(O)o-PItCH~CU01-I-C(U)m-PhCI-12CUUH -C(U)P-PhCH2COOH

. -C(U)naPhUt-1-yl -C(O)CIh(naPhth-1-yl)-C(O)CH?CH2(napth-1-yl) 18.7 18.8 -C(O)naphUt-2-vl -C(U)Cll~(naPluh-2-vl-C(O)CH~CH~(napth-2-yl) 18.0 -C(O)o-hirhenyl -C(U)CI-1~(a-biphenyl)-C(U)CH2CH2(o-biphenyl) 18.10-C(O)m-biphenyl -C(O)C'll~lm-biphenyl)-C(O)CH~CH2(m-biphenyl) 18.12-C(U)P-hiPhenvl -C:(O)CII~(P-biphenyl)-C(O)CH~CH?(P-biphenyl) 18.13-C(U)o-PhUPh -C(())CIi~(o-PhOPh) -C(O)CH~CH2(o-PhOPh) 18.14-C(U)tn-1'hOPh -C'.co)C'Il~an-PhOPh)-C(O)CH~CH~(m-PhOPh) 18.15-C(U)P-PhOPh -C(U)Clh(p-PhOPh) -C(U)CH~CH2(p-PhOPh) 18.16-C(O)o-PhNI-IPh -C(O)CU~(o-PhNIiPh -C'.(U)CH~CH~(o-PhNHPh ) ) 18.17-C(O)m-PhNI-IPh -C(O)C112(m-t'hNIIPh)-C(U)CI-I2CH2(m-PhNHPh) 18.18-C(O)P-I'hNlil'h -C(O)Cll~(P-I'hNIiIh)-C(O)CH~CH2(p-PhNHPh) 18.19-C(U)o-1'hSPh -C(O)Cl-1~(o-PhSPh) -C(O)CH2CH2(o-PhSPh) 18.20-C(O)m-PhSPh -C(O)Cli~(m-PhSPh) -C(O)CH2CH2(m-PhSPh) 18.21-C(O)P-PhSPIt -C(U)CI-1~(p-1'hSPh)-C(O)CI-hCH2(p-PhSPh) 18.22-C(U)o-PhC1I2S1'h -C(U)CH2(o-PhCI-I2SPh)-C(O)CH2CH2(o-PhCH~SPIt) 18.23-C(U)m-PhCI-I2Sl'h -C(O)CII2(m-PhCH2SPh)-C(U)CH2CH2(m-PhCH2SPh ) 18.24-C(U)p-PhCIi2SPh -C(U)CI12(p-1'hCli2SPh)-C(O)CIi2CH2(P-PhCIi~SPh) 18.25-C(U)aJitmantvl -('(U)C'I1~(a~lantantyl)-C'(o)CH?Cll?(adamantyl) 18.26-C(O)cycloPentvl -C'(O)Cll~(cvclopentvl)-C(O)CH~CH~((cyclopentyl) 18.27-C(O)evclohexvl -C'(U)CII~(cvclohexvl)-C(U)CH~CH~(cyclohexyl) 18.28-C(O)CII~O(rvrloPcntvl)-C(U)C:IhI~~I~IlcvcloPentyl)-C(O)CIi~S(cyclopentyl) 18.29-C(U)C11?U(cyclnhexvl)-C(O)CII~NI1(cychthexvl)-C(U)CI-I2S(cyclohexyl) 18.30-C(O)Pvtidin-2-yl -C(())CII2(Pyridin-2-vl)-C(O)CH~CH2(pyridin-2-yl) 18.31-C(O)Pvndin-3-vl -C(U)CII?(Pyticlin-3-vl)-C(O)CH2CH2(pvridin-3-yl) 18.32-C(o)Py~clin-4-vl -C(O)C'II~(Pyriaut-4-vl)-C(UlCH2CH2(Pytidin-4-yl) ' 18.33-C(O)furan-2-vl -C(O)('I1~(furut-2-vl)-C(O)CH~CH2(furut-2-yl) 18.34-C(O)furut-3-vl -C(U)Cll~lfuran-3-yl)-C(O)CII~CII2(furvt-3-yl) 18.35-C(O)UtioPhcn-2-yl -C(C))C'11~(Utiophcn-2-yl)-C(o)CIU~CI-1~(thiophen-2-yp 18.36-C.(O)tltioPhcn-2-vl-C'(())C'II~(thiophen-2-v!)-C(O)CI-12CII2(thiophen-2-yl) 18.37-C(U)imidazo-2-yl -C'(O)('I h(imidaio-2-vl)-C'(O)CI-hCIIZ(imidozo-2-yl) 18.38-C(O)oxnzo-2-vl -('(U)C'I hloxazo-2-yl)-C(O)CI-12CI12(oxazo-2-yl) 18.3>-C(U)Uuoazo-2-vl -C(U)C11~(U~ioa~o-2-yl)-C(U)CH~CH2(thioazo-2-yl) 18.40-C(O)hc'nzoCurut-2-yl-C(O)CH~_(hcn-rot~uuut-2-yl)-C(O)CI-I2CI-12(henzofuran-2-vl) ~, o l SUBSTITUTE SHEET (RULE 26) WO 95109634 ~ ~ PCT/US94/11280 18.41 -C(U)hcnzofuran-3-yl - -C(U)C'.I12(txnzolhrm-3-yl) -C(U)CH_~CH2(benzoturan-3-vl ) 18.42 -C(O)henzothinnhcn-2-yl -C:(O)CI12(hcnzothiophen-2-yl) -C(O)CH2CH2(benzothiophen -2-vl) 18.43 -C(U)thiophen-2-vl -C(O)C'.II~(thinPhen-2-yl) -C(O)CH~CH~(thiophen-2-yl) 18.44 -C(O)henzimidazo-2-yl -C(O)Cll2(hcnzimidazo-2-yl) -C(O)CH2CH2(benzimidazo-2-vl) 18.45 -C(O)henzoxazo-2-yl -C(U)Cl-I2(tx:nzoxazo-2-yD -C(O)CH2CH2(henzoxazo-2-vl) 18.46 -C(U)hellZUllllaZO-2-yl -C(O)CI-I2(henzothiazo-2-yl) -C(O)CI-I2CH2(henzothiazo-2-vl) 18.47 -C(U)o-Ph(P(O)Ph3) -C(U )tn-l'h(P(U )!'h3) -C(O)p-Ph(P(O)Ph~) 18.48 -C(O)Ph-2-(lluoren-9-vl) -C'(())I'h-3-(l7uoren-9-vl) -C(U)Ph-4-lfluoren-9-vl) 18.49 -C'(O)N-inclnlin-2-one -('l(»inciolin-2-vl -C(U)indol-2-vl 18.50 -C(O)C(CI-13)2NIISU2(naPhth- -C(U )cycloPcntyl-2-(Ph) -C(U)cyclohexyl-2-(Ph) 2-vl) 18.51 -C(U)PYrroli~in-3-yl-=i-(1'1~) -C(U)tcuahyclrofuru~-3-yl-:l-(Ply -C(O)tetrahyclrothiophen-3-yl-4-(Phl 18.52 -C(U)tetrahvdronaPhth-1-yl -('(U)teuuhyclrona~hth-2-yl -C(U)cvcioProPyl-2.2-(Ph2) 18.53 -C(O)tetrahydroiu~quinolin-1-yl -C(U)teunhydroisoyuinolin-3-yl -C(O)CH2((2-oxo)indolin~3-vll 18.54 -C(U)C)-i2(N-henzunidazol-2- -C(U)CII2(N-henzoxazol-2-one) -C(O)CH2(N-henzothiazol-2-one) one) 18.55 -C(O)CI-12(N-~ihyclroimidazol- -C(U)ClI2(N-~ihylrcx~xazol-2- -C(U)CH2(N-dihydrothiazol-2-one) one) 2-one) 18.56 rC0- rC0-O O
N l~ N Iw N y ~~ i i 18.57 O O O
-Otr'-NUNH -OC~N~O -OC~NUS
18.58 -OC O -OCR -OC O
~N ~ ! ~ CN' ~NxO
/\
N /\
~I
18.59 -C(O)N(CII~)Cl-l2Ph -C(U)N(C'2115)Cll~Ph -C(O)N(C~H7)CI-I2Ph 18.60 -C(O)P)n'idin-3-vl-5-(Ph ) -C(U )1'h-3-lC(1~(thioPhen-2-vl» -C(U)Ph-3-(CH2Ph ) 18.61 -C(O)C(CH3)~UPh -C(())CIl(C21I5)OPh -C(U)CHhOCH2Ph 18.62 -C(U)CI-hO(o-1'hCI-I~UII) -C(U)CII~U(m-I'1~CII~U1I) -C(U)CI-hU(P-PhCH20H) 18.63 -C(U)CII~U(o-1'hC'UUII) -C(O)C'I1~U~m-I'hC:UUII) -C(U)CH2U(P-PhCOOH) 18.64 -C(U)CII~U(o-PhC()()CI-I~) -C(U)C'II~U(m-!'hCUUCH~) -C(U)CII2U(P-PhCOOCH3) 18.65 -C(O)CI-I~U(o-I'1WII~C'UUII) -C(U)C'II~()(m-1'hC'1-I~CUUII) -C(U)CH~O(P-PhCH2COOH) aoy SUBSTITUTE SHEET (RULE 26) WO 95109634 '!' PCT/US94/11280 18.66 _pC O
~N~O
J
/ \
a-o3 SUBSTITUTE SHEET (RULE 26) PCTlUS94111280 ha 9 Formula I : A = -B(Pinanediol) : X = ~uanidinyl : R3 = table below ; R11 = -Ph.
.I .2 .3 19.1 -C(O)Ph -C(U)CH~Ph -C(U)CH~CH2Ph 19.2 -C(O)CI-I~OPh -C(O)CI12NHI'h -C(O)CH2SPh 19.3 -C(O)o-PhOH -C(O)m-I'hOll -C(O) -PhOH

19.4 -C(O)o-PhCI-I201I -C(O)m-PhC>-1~OH -C(U)p-PhCH20H

19.5 -C(O)o-Ph COOII -C(O)m-PhCUOI-I -C(O) -PhCOOH

19.6 -C(O)o-PhCH2COOH -C(U )m-PhCI-I2COOH-C(O)p-PhCH2COOH

19.7 -C(O)naphth-1-yl -C(O)CI-I~(naPhth-1-yl)-C(O)CH2CH2(napth-1-yl) 19.8 -C(O)naphth-2-vl -C(O)CH~(naPhth-2-vl-C(OK'.H~CH2(napth-2-yl) 19.9 -C(O)o-biphenyl -C(O)CI-1~(o-biPhenvl)-C(O)CH2CH2(o-biphenyl) 19.10-C(O)m-hiphenvl -C(U)Cli~(m-biphenyl)-C(O)C1~2CH2(m-hiPhenvl) 19.12-C(O)p-biphenyl -C(U)C1I2(p-hiphenvl)-C(O)CH~CH2(P-biphenyl) 19.13-C(O)o-PhOPh -C(O)CII~(o-PhOPh)-C(O)CH2CH~(o-PhOPh) 19.14-C(U)m-PhOPh -C(U)C1U~(m-PhUPh)-ClU)CFI~CH~(m-PhOPh) 19.15-C(U)p-PhOPh -C'(O)CI I~(r-PhOPh)-C'(O)CH~CH~(p-PhOPh ) 19.16-C(U)o-PhNHPh -C.(U)CH2(o-I'hNIIPh)-C(U)CH?CH2(o-PhNHPh) 19.17-C(O)m-PhNI-II'h -C(O)CI-I~(m-I'hNl-IPh)-C(O)CI-i2CH2(m-PhNHPh) 19.18-C(O)p-PhNHPh -C(O)CI-I~(p-PhNHPh)-C(O)CH2CH2(p-PhNHPh) 19.19-C(U)o-PhSPh -C(U)CII2(o-PhSPh)-C(O)CH2CH2(o-PhSPh) 19.20-C(U)m-PhSPh -C(O)CI12(m-PhSPh)-C(O)CH2CH2(m-PhSPh) 19.21-C(U)p-PhSPh -C(O)CI-I2(P-1'hSPh)-C(O)CIi2CH2(p-PhSPh) 19.22-C(U)o-PhCI-i2SPh -C(U)CIi2(o-PhCI-hSPh)-C(0)CH2CH2(o-PhCH2SPh) 19.23-C(O)m-PhCI-I2SPh -C(O)C1I2(m-Ph -C(O)CH2CH2(m-Cl-I2SPh ) PhCH2SPh) 19.24-C(O)(~-PhCIi~SPh -C(U)CII~(P-l'hCIhSPh)-C(U)CH2CI-12(p-PhCH2SPh) 19.25-C(O)adamatuvl -C(U)C112(adatnmttyl)-C(U)CH2CH2(adamantyl) 19.26-C(O)cvclopentvl -C(O)CII~(cyclopentyl)-C(U)CH2CH2((cyclopentyl) 19.27-C(O)cvrlohexvl -ClU)C1-I~(cyclohexvl)-C(0)CH2CH~(cvclohexv_ 1) 19.28-C(O)CII~O(cvclopcntvl>-('(U)C11~NII(cvclopentvl)-C(O)CI-I2S(cvclopcntvl) 19.29-C(O)CII2O(cvclohexvl)-C(O)C112NH(cyclohexyl)-C(O)CH2S(cyclohexyl) 19.30-C(O)pvridin-2-vl -C(U)CII~(pyridin-2-yl)-C(O)CH~CH2(pyridin-2-yl) 19.31-C(O)pyridin-3-yl -C(O)CII~(pyridin-3-vl)-C(U)CH2CH2(pyridin-3-yl) 19.32-C(O)~yridin-4-vl -C(U)C'I-IZ(Pyridin-4-yl)-C(U)CH~CH2(Pyridin-4-vl) .

19.33-C(U)furan-2-yl -C(O)CII~(fm.~tn-2-yl)-C(U)CH~CH2(furan-2-yl) 19.34-C(U)furan-3-vl -CIUICII~(furan-3-vl)-C(O)CH2CI-h(furan-3-yl) 19.35-C(O)thioPhen-2-yl -C(U)CI-I2(UtioPhen-2-yl)-C(O)CH2CH2(thiophen-2-vl) 19.36-C(O)thiophen-2-yl -C(U)C'.1-I2(thiopheu-2-yl)-C(O)CH2C1-I2(thiophen-2-vl) 19.37-C(U)imidazo-2-vl -C'(U)CIi2(imidazo-2-yl)-C(U)CH2CH2(imidazo-2-yl) .

19.38-C(O)oxazo-2-vl -C'(O)CIi~(oxazo-2-yl)-C(O)CH2CH2(oxazo-2-yl) 19.39-C(O)thioazo-2-vl -C(O)CII~(tluoazo-2-vl)-C(U)CI-I2CH~(thioazo-2-yl) 19.40-C(O)benzofurv~-2-yl-C(U)CII~(tx:nzofur~u~-2-yl)-C(U)CII2CH2(benzofuran-2-vl) ~ D
SUBSTITUTE SHEET (RULE 26) ~"°° WO 95109634 ~ 1'~ 4 314 pCT~S94111280 19.41 -C(U)bcnzofurm-3-yl -C(O)ChI2(bcnzoturan-3-yl) -C(U)CI-I2CH2(benzofuran-vl) 19.42 -C(U)benzoUuophen-2-yl -C(O)CI-I2(bcnzoUtioPhen-2- -yl) C(0)CH2CH2(benzothiophen -2-vl ) 19.43 -C(O)Utiophen-2-yl -C(O)CH2(UuoPhcn-2-yl) -C(U)CH2CH2(thiophen-2-vl) 19.44 -C(O)benzimidazo-2-yl -C'.(O)CH2(bcnzimidazo-2-yl) -C(O)CH2CH2(benzimidazo-2-vl) 19.45 -C(O)bcnzoxazo-2-yl -C(U)Cli2(henzoxazo-2-yl) -C(O)CH2CH2(benzoxazo-2-v1) 19.46 -C(O)benzothiazo-2-yl -C(O)CH2(benzoU~iazo-2-yl) -C(O)CH2C112(benzothiazo-2-vl) 19.47 -C(O)o-Ph(P(O)Ph3) -C(U)m-Ph(P(O)Ph~) -C(O)P-Ph(P(O)Ph3) 19.48 -C(O)Ph-2-(fluoren-9-vl) -C(U)I'h-:~-(tluoren-9-vl) -C(O)Ph-4-(fluoren-9-vl) 19.49 -C(O)N-indolin-2-one -('(U)indolin-2-vl -C(U)indol-2-vl 19.50 -C(O)C(CIi3)ZNI~1SU2(naphth- -C(U)cycloPentyl-2-(Ph) -C(O)cyclohexyl-2-(Ph) 2-vl) 19.51 -C(U)pyrrolidin-3-yl-4-(Ph) -C(O)tctrahydrolurm-3-yl-4- -C(U)tetrahydroUtiophen-3-(Ph) vl-4-(Phl 19.52 -C(O)tetrahvdronaphth-1-yl -C(U)tetrahvdronaphth-2-vl -C(O)cvclopmPyl-2.2-(Ph2) 19.53 -C(O)tetrahydroisoyuinolin-1- -C(U)tctrthydroisoquinolin- -C(U)CH2((2-oxo)indolin-3-yl 3-yl 1) 19.54 -C(O)CH2(N-henzimidazol-2- -C(U)C1I2(N-bcnzoxazol-2- -C(O)CH2(N-benzothiazol-2-one) one) one) 19.55 -C(O)C1~2(N-dihydroimidazol- -C(U)CI-12(N-dihydrooxazol- -C(U)CH2(N-dihydrothiazol-2-one) 2-one) 2-one) 19.s6 ~co. ~co- ~ o I w N O 1 v N O w N w i i l ~ / \ l i I i 19.57 p O O
N~
-OC~. NH -OC~NU0 -OC~N~S
19.58 -Ol O -OC1 -OC O
N ~ 1 ~ CN1 ~NuO
/\ ~ N /\
~I
19._59 -C(O)N(CIi~)CI-l2Ph -C(U)N(C~IU 5)CII~Ph -C(O)N(C3H7)CH2Ph 19.60 -C(O)Oyridin-3-yl-5-(Ph) -C(U)I'h-3-(CH2(thioPhen-2- -C(U)1'h-3-(CH2Ph) vl)) 19.61 -C(U)C(C'.I-I~)~Ul'lr -C'(())CII(C'~IIS)OI'h -C(U)CH20Cl-l2Ph 19.62 -C(O)CII~U(o-I'hClI~OlI) -C(U)CII~U(m-1'hCl-hOH) -C(O)CH~O(P-PhCH20H) 19.63 -C(O)CI1~U(o-I'hC'.0011) -C(U)CII~U(m-PhCOUII) -C(O)CH?O(P-PhCUOH) 19.64 -C(O)CI-(~U(o-I'hCUUC113) -C'(O)C1-I~U(m-1'hCOUC113) -C(U)Cl)~O(P-PhCOOCH3) a~
SUBSTITUTE SHEET (RULE 26) ~~ 7~3.
19.65 -C(O)CI-I20(o-PhCli2C001-1) -C(U)C112U(tn- -C(U)CH2U(p PhCH~COOH) PhCH~COOH) 19.66 -p C p J
Tahle 2(120 Formula I : A = -B(pinanediol) ; X = guanidinyl ; R3 = tahle below ; R11 = -CH2(naphth-2-yl).

.1 .2 .3 20.1 -C(O)Ph -C(U)CH2Ph -C(O)CH2CH2Ph 20.2 -C(O)CH20Ph -C(U)CH2NIIPh -C(O)CII2SPh 20.3 -C(Co-PhOH -ClU)m-PhUII -C(O) PhOH

20.4 -C(Uk~-PhCH2U11 -C'(Cm-l'hCtl~01-i-C(U)p-1'hCH~OH

20.5 -C(U)o-PhCU01-I -('.(0)m-1'hCUUIi -C(U) -PhC00H

20.6 -C(O)o-PhCH~COOH -C(O)m-Ph('.li2COOli-C(U)p-PhCH2COOH

20.7 -C(O)naphth-1-vl -C(O)Cli~(narl~U~-1-vl)-Cl0)CH2CH~(napth-1-yl) 20.8 -C(O)naphth-2-yl -C(O)CH2(naphtlt-2-vl-C(O)CH2CH2(napth-2-yl) 20.9 -C(Ok~-biphenyl -C(O)CI~2(o-hiphenyl)-C(O)CH2CH2(o-biphenyl) 20.10-C(O)m-biphenyl -C(O)CI-I2(m-biphenyl)-C(O)CH2CH2(m-biphenyl) 20.12-C(O)p-biphenyl -C(U)CII2(p-biphenyl)-C(U)CI-I2CI-i2(p-biphenyl) 20.13-C(U)o-PhOPh -C(U)CI-I2(o-PhOPh)-C(O)CH2CH2(o-PhOPh) 20.14-C(O)m-PhOPh -C(O)Cli~(m-PhUPh)-C(U)CI-I2CH2(m-PhOPh) 20.15-C(O)n-PItOPh -C(U)C:II2(p-PhOPh)-C(O)CI-I2CH2(p-PhOPh) 20.16-C(O)o-PhNHPh -C'(U)CIi2(o-1'hNIiPh)-C(O)CH2CH2(o-PhNHPh) 20.17-C(O)tn-I'ItNI-iPh -C(U)Cl-I~(m-PhNlI1'h)-C(O)CI-1~CH~(m-PhNHPh) 20.18-C(U)p-PhNI-IPh -C(U)C1I~(p-PhNI-IPh-C(O)CH2CH2(p-PhNHPh) ) 20.19-C(O)o-PhSI'h -C(U)CI-I~(o-I'hSPh)-C(O)CH~CH2(o-PhSPh) 20.20-C(O)m-PhSPh -C(U)CI-1~(m-PhSPh)-C(O)CH~CH~(m-PhSPh) 20.21-C(O)n-PhSPh - -C(O)C1-I~(p-1'hSPh)-C(U)CH2CH2(p-PnSPh) 20.22-C(U)o-PhCI-I~SPh -C(U)CII~(o-1'hCIhSI'h)-C(O)CH2CH2lo-PUCH~SPh) 20.23-C(0)m-PhCI-I2SPh -C(O)CI-IZ(m-PhCI~I2SPh)-C(0)CH2CH2(m-PhCIi2SPh) 20.24-C(U)p-PhCH~SPh -C(U)CII~(p-1'hCII2SPh)-C(U)CI-I2CH2lp-PhC1-l2SPh) 20.25-C(U)adaunantvl -C(U)CI-I~(aclamantyl)-C(O)CH~CH2(adamantyl) 20.26-C(O)cvclopentvl -C'(O)C1-!~(cvclopentvl)-C(O)CH~CH~((cvclopentyl) 20.27-C(O)cyclohexyl -C(O)C'1-1~(cvclohexyl)-C(O)CH~CI-i~(cyclohexyl) 20.28-C(U)CH~U(cvciopcntvl)-C(U)C1I~N1I(cvclopcntyl)-C(0)CH2S(cyclopentyl) ~

20.29-C(O)CH~U(cvclohexvl)-C(O)CIhNIi(cvclohexvl)-C(O)CH~S(evclohexyl) 20.30-C(U)pyridin-2-vl -C(O)CI-I~(pyridin-2-vl)-C(U)CH~CH2(pyridin-2-yl) 20.31-C(O)pyridin-3-vl -C(O)CII~(pyriclin-3-vl)-C(O)CH~CH2(pyridin-3-yl) 20.32-C(U)wridin-4-v_ -C'(U)Ci-I~(pyriclin-4-vl>-C'.(O)CH~CH2(pyridin-4-yl) 20.33-C(U)1'uran-2-yl -C(O)CII~(furan-2-vl)-C(O)Cli2CI-I2(furan-2-vl) 20.34-C(O)furan-3-vl -C(())C'.H~(Curan-3-vl)-C(O)CH~CH~(furan-3-vl) ao~
SUBSTITUTE SHEET (RULE 26) ,.~~. WO 95109634 ; PCT/US94111280 20.35 -C(O)thiophen-2-yl -C(U)CIi2(thiophen-2-yl> -C(O)CH2CH2(thiophen-2-vl) 20.36 -C(O)thiophen-2-yl -C(O)ClI2(thiophen-2-yl) -C(O)CH2CH2(thiophen-2-vl) 20.37 -C(O)imidazo-2-vl -C(U)CI-h(imidazo-2-vl) -C(O)CI-I2CH2(imidazo-2-yl) 20.38 -C(O>oxazo-2-yl' -C(O)CI-I?(oxazo-2-yl) -C(O)CH?CH2(oxazo-2-yl) 20.39 -C(U)thioazo-2-yl -C(U)C11~(thioazo-2-yl) -C(O)CH~CH2(thioazo-2-yl) 20.40 -C(O)henzofuran-2-yl -C(O)CII2(hcnzofuran-2-yl) -C(O)CH2CH2(benzofttratt-vl) 20.41 -C(O)benzofuran-3-yl -C(O)CH2(benzofuran-3-yl) -C(O)CH2CH2(benzofuran-3-vl) 20.42 -C(O)benzothiophen-2-yl -C(O)CI12(benzothiophen-2- -yl ~ C(O)CH2CH2(benzothiophen -2-vl) 20.43 -C(O)U~iophen-2-yl -C(U)C1I?(tluophen-2-yl) -C(O)CH2CH2(thiophen-2-vl) 20.44 -C(O)henzimidazo-2-yl -C(U)CII2(henzimidazo-2-yl) -C(U)CH2CH2(benzimidazo-2-vl) 20.45 -C(U)henzoxazo-2-yl -C(U)CIi2(henzoxazo-2-yl) -C(U)CH2CH2(benzoxazo-2-vl) 20.46 -C(O)benzothiazo-2-yl -C(U)ClI2(benzothiazo-2-yl) -C(O)CH2CI-12(benzothiazo-2-vl) 20.47 -C(U)o-Ph(P(O)Ph~l -C(U)m-Ph(1'(U)Ph3) -C(U)p-Ph(P(O)Ph3) 20.48 -Cl0)Ph-2-(fluoren-9-vl) -C(U)1'h-3-(iluoren-9-vl) -C(O)Ph-4-(fluoren-9-vl) 20.49 -C(O)N-indolin-2-one -C(U)indolin-2-vl -C(O)indol-2-vl 20.50 -C(O)C(CH3)2N)~ISU2(ttaphth- -C(U)cyclopentyl-2-(Ph) -C(O)cyclohexyl-2-(Ph) 2-vl) 20.51 -C(O)pyrrolidin-3-yl-4-(Ph) -C(O)tetrahydmfuran-3-yl-4- -C(O)tetrahydrothiophen-3-(Ph) vl-4-(Ph) 20.52 -C(O)tetrahvdronaphth-1-vl -C(O)tetrahvdmnaphth-2-yl -C(U)cyclopmpyl-2.2-(Ph2) 20.53 -C(O)tetrahydroisoquinolin-1- -C;(U)tetrahydroisoquinolin- -C(U)CH2((2-oxo)indolin-3-yl 3-yl vl) 20.54 -C(O)CH2(N-benzimidazol-2- -C(U)C1I2(N-henzoxazol-2- -C(U)CI-12(N-benzothiazol-2-onel one) one) 20.55 -C(O)CI-I2(N-dihydroimidazol- -C'.(U)CIU~(N-dihydrooxazol- -C(U)CI-i2(N-dihydrothiazol-2-onel 2-cane) 2-one) 20.56 rC0- ICO-N O
O l ~ N y N y /\
20.57 O O O
-OC~.N~NH -OC~NU0 -OC~N~S
a o ?' SUBSTITUTE SHEET (RULE 26) 20.58 -OC O -OCR - -OC O
~N . 1. ~N, ~NUo /\ ~ N /\
\I
20.59 -C(O)N(CH3)Ctf2Ph -C(O)N(C21I5)ClhPh -C(O)N(C3I-I7)CH2Ph 20.60 -C(O)Pyridin-3-yl-5-(Ph) -C(U)Ph-3-(C1I2(tlrioPhen-2- -C(O)Ph-3-(CH2Ph) vl)) 20.61 -C(O)C(CH3)20Ph -C(O)CH(CZtiS)OPh -C(OlCH20CH2Ph 20.62 -C(O)CH20(o-PhCII~OII) -C(O)CtI~U(m-PhCH~OH) -C(O)CH20(P-PhCH20H) 20.63 -C(O)CH20(o-PhCUOH) -C(O)CI-hO(m-PhCOOtI) -C(O)CH2U(P-PhCOOH) 20.64 -C(O)CH~U(o-PhCOOCH3) -C(U)C11~U(m-PhCOOCIi~) -C(O)CH~O(P-PhCOOCH3) 20.65 ~-C(O)CI-I2U(o-PhCtI2CUUlI) -C(U)C112U(m- -C(O)CH20(p-PhCH~COOIi) PhCH~COOtI) 20.66 _ p C O
~NRO
J
/ \
Table 21 Formula I : A = -B(rinanedie~l) ; X = -CIi2N1 I2 ; R3 = table helow ; R11 =

.1 .2 .3 21.1 -C(O)Ph -C(U)CII2Ph -C(O)CI-I2CH2Ph 21.2 -C(O)CI-120Ph -C(U)CH~NtIPh -C(O)CH~SPh 21.3 -C(O)o-Ph01-i -C(U)m-PhOI-1 -C(O) -PhOH

21.4 -C(O)o-PhCH201I -C(U)m-1'hC11~01~ -C(U)P-PhCH20H

21.5 -ClU)o-PhCOOtI -C(U)m-I'hC()UI-I -C(O) -PhCOOH

21.6 -C(O)o-PhCH~CUUI-I-C(U)m-I'hCl-I~COUI-I-C(O)P-PhCH2COOH

21.7 -C(O)naplUh-1-vl -C(U)Ctt~(naphth-I-vl)-C(O)CH2CH2(napth-1-vl) 21.8 -C(O)naphth-2-vl -C(U)C'II~(n,rPhth-2-vl-C(U)CH~CtI2(naPth-2-yl) 21.9 -C(O)o-hiPhenvl -C(U)CII~(o-hiphenyl)-C(O)CH~CH2(o-biphenyl) 21.10-C(O)m-hiphenvl -C'(C))C'.11~(m-hiPhenvl)-C(O)CH2CIi2(m-biphenyl) 21.12-C(0)P-hiphenvl -C(O)C.1-I~(p-hiphcnvl)-C(O)CH2CH2(p-biphenyl) 21.13-C(O)o-PhOPh -C(U)Ctl~(o-PhOPh) -C(U)CH2CH2(o-PhOPh) 21.14-C(O)m-PhOPh -C(U)CII~(m-1'h01'h)-C(U)CH~CH~(m-PhOPh) 21.15-C(O)P-PhOPh -C(O)CH~(P-PhUPh) -C(U)CH2CH2(p-PhOPh) 21.16-C(O)o-PhNIiPh -C(O)Cli~(o-PhNHPh)-C(O)CH2CI-I2(o-PhNHPh) 21.17-C(O)m-PhNHPh -C(U)CII~(m-PhNI-IPh-C(O)CI-I2CI12(m-PhNHPh) ) 21.18-C(O)P-PhNI-IPh -C(U)C1I~(P-PhNI-iPh)-C(0)CH?CH2(p-PhNHPh) 21.19-C(O)o-PhSPh -C'(U)C'Il~(o-PhSPh)-C(O)CtI2CH~(o-PhSPh) 21.20-C(U)m-PhSPh -C(Ol('li~(rn-PhSPh)-C(O)CtI2Clh(m-PhSPh) 21.21-C(U)P-1'hSl'h -C(U)C,II~(p-I'hSPh)-C(U)CI-I~CH2(p-PhSPh) a ors SUBSTITUTE SHEET (RULE 26) ,... WO 95109634 ~ 1'~ 43 ~ 4 PCTlUS94111280 22 -C(O)o-I'hCI-I2SPh -C(U)CH?(o-l'hCII2SPh)-C(U)CH2CH2(o-. PhCH2SPh ) 23 -C(U)m-I'hCH2SPh -C(O)CII2(m-I'hCll2SPh)-C(O)CI-I2CH2(m-. PhCH~SPh) 21.24-C(O)p-PhCH2SPh -C(U)CII2(p-PhCH2SPh)-C(O)CH2CH2(p-PhCH~SPh) 21.25-C(O)adamantyl -C(U)Cli~(adamantyl)-C(O)CH~CH~(adamantyl) 21.26-C(Okvclopentyl -C(O)CII~(cvclopentvl)-C(O)CH~CH2((cyclopentyl) 21.27-C(O)cyclohexyl -C(O)CI1~(cvclohexvl)-C(O)CH2CH2(cyclohexyl) 21.28-C(O)CH~O(cvciopentvl)-C(O)CI-I~NII(cvclonentyl)-C(U)CH2S(cyclopentyl) 21.29-C(O)CH2U(cyclohexyl)-C(U)CI-I~NI-i(cyclohexyl)-C(O)CH2S(cyclohexyl) 21.30-C(U)ryridin-2-yl -C(O)CI-I2(Pyridin-2-yl)-C(O)CH2CH2(pyridin-2-yl) 21.31-C(O)pyridin-3-yl -C(O)CH~(pyridin-3-vl)-C(O)CH~CH2(pYridin-3-yl) 21.32-C(O)Pyridin-4-vl -C(O)CI-I~(pyridin-4-vl)-C(O)CH~CH~(pyridin-4-yl) -21.33-C(O)furan-2-vl -C'(U)C'l12(Curan-2-yl)-C(U)CH~CH2(furan-2-yl) 21.34-C(O)Curan-3-vl -C'(U)C'II~lCuran-3-yl)-C(U)CI-I~CH2(futan-3-yl) 21.35-C(O)thiophen-2-yl -C(U)C112(thiophen-2-yl)-C(O)CH2CH2(thiophen-2-vl) 21.36-C(U)U~iophen-2-yl -C'.(U)C11?(thiophen-2-yl)-C(U)CH2C1-i2(thiophen-2-vl) 21.37-C(O)imidazo-2-yl -C(U)Cll~(imidazo-2-yl)-C(O)Cli~Ci-I2(imidazo-2-yl) 21.38-C(U)oxazo-2-vl -ClU)C'II~(oxazo-2-vl)-C(O)CH2CH2(oxazo-2-yl) 21.39-C(O)thioazo-2-yl -C(O)C112(thioazo-2-yl)-C(O)CH2CI-I2(thioazo-2-yl) 21.40-C(O)benzofurv~-2-yl-C(U)CI-i2(henzofuran-2-yl)-C(O)CH2CH2(benzofuran-2-vl) 21.41-C(O)benzofuran-3-yl-C(U)CIi2(txnzofur~n-3-yl)-C(O)CH2CH2(benzofuran-3-vl) 21.42-C(O)henzothiophen-2-yl-C(O)Cl-12(tx;nzothiophen-2-yl)-C(O)CH2CH2(benzothiophen -2-vl) 21.43-C(U)thiophen-2-yl -C(U)CII2(tluophcn-2-yl)-C(U)CI-I2Cli2(thiophen-2-vl) 21.44-C(O)henzimidazo-2-yl-C'.(U)C1-12(tx;nzimidazo-2-yl)-C(O)CH2CH2(benzimidazo-2-vl) 21.45-C(U)henzoxazo-2-yfi-C(U)C1121t>Lnzoxazo-2-yl)-C(O)CH2CH2(benzoxazo-2-vl) 21.46-C(O)henzothiazo-2-yl-C(U)CI12(henzothiazo-2-yl)-C(O)CH2CH2(benzothiazo-2-vl) 21.47-C(O)o-Ph(P(O)Ph3) -C(U)m-l'h(P(O)I'h~)-C(O)p-Ph(P(O)Ph3) 21.48-C(O)Ph-2-lfluoren-9-vl)-C'(U )t'h-3-(Iluoren-9-vl)-C(O)Ph-4-(fluoren-9-vl) 21.49-C(O)N-indolin-2-one-C(U)indolin-2-vl -C(U)indol-2-vl 21.50-C(O)C(Cl-I3)~NIiSU2(naphU~--C'(U)cyclorentyl-2-(I'h)-C(O)cyclohexyl-2-(Ph) 2-vl) 21.51-C(O)nyrrolidin-3-yl-.~-(Ph)-C(U)tetrahydroluran-:~-yl-4--C(O)tetrahydrothiophen-3-(Ph) vl-4-(Ph) 21.52-C(O)teu~ahvclronaPhth-1-vl-C'(U)tetrahvdronaPhth-2-vl-C(U)cyclopropyl-2.2-(Ph2) 21.53-C(O)tetrWydroiscxpinolin-1--C(U)tctrahyclroisoquinolin-3-yl-C(O)CI-I2((2-oxo)indolin-3-yl vl) 21.54-C(O)CH2(N-hcnzimidazol-2--C'(U)C112(N-hcnzoxazol-2-one)-C(U)CH2(N-benzothiazol-2-one) one) ao~
SUBSTITUTE SHEET (RULE 26) WO 95/09634 ~ PCT/US94111280 21.55 -C(U)CH2(N-dihydroimidazol- -C(U)CI12(N-dihydrooxazol-2- -C(O)Cli2(N-dihydrothiazol-2-one) one) 2-one) 21.56 rC0- rC0-N O l ~ N O ~ N
I i i ~ / 1 I i I i 'I
21.57 O O O
-OC''N~NH -OC~NU0 -OC~N~S
21.58 -OC O -OCR -OC O
~N ~ 1 ~ CN1 ~N~O
/ \ ~ N / \
~I
21.59 -C(U)N(CFI~)CII~Ph -('.(U)N(C'.~US)CI-I~PIt -C(O)N(C3I-I7)CH2Ph 21.60 -C(O)pyridin-3-yl-5-(Ph) -C(U)1'h-3-(CI12(thiophen-2- -C(O)Ph-3-(CH2Ph) vl)) 21.61 -C(O)C(CH3)2UPh -C(U)Cl-i(C~IIS)UPh -C(U)CI-I20CH2Ph 21.62 -C(O)CH~O(o-PhCH20I-I) -C(O)CIi~O(m-Ph CI-hOli) -C(O)CH~O(It-PhCH20H) 21.63 -C(O)CH~U(o-PhCUOII) -C(O)CII~O(m-PhCUOII) -C(O)CH20(It-PhCOOH) 21.64 -C(O)CH~U(o-PhCOOCH3) -C(O)C.'II~U(m.Plt('UOCH3) -C(O)CH2U(P-PhCOOCH3) 21.65 -C(U)CH2U(o-PhCI-I2COUI-I) -C(U)CII2U(m-PhCII2CUOlI) -C(O)CIi20(P-PhC3-I2COOH) 21.66 .OC O
~NUO
J
\
a/~
SUBSTITUTE SHEET (RULE 26) -""'" WO 9510963:1 '~ 1~ 431 ~ PCTlUS94l11280 h ' Formula I : A = -B(pinanediol) ; X = -CH2N112 ; R3 = tahle below ; R11 = -CH2(p-PhOH).
1 ~ - .3 .

1 _. -C(U)CI-i~Ph -C(O)CH2CH2Ph 22 -C(O)Ph . -C(O)CH~OPh -C(O)C112NHPh -C(O)CfI2SPh . -C(U)o-PhOH -C(O)m-PhOLI -C(0) -PhOH

. -C(Uk~-PhCI-I2pH -C(U)m-PhCH2pH -C(O)p-PhCH20H

. -C(O)o-PhCOOH -C(C))m-Ph COOH -C(O) -PhCOOH

. -C(O?o-PhCH2CUOH -C(U)m-PhCH~COOH -C(O)p-PhCH2COOH

. -C(O)naphth-1-yl -C(U)CI~~(naphth-1-vl)-C(O)CH2CH2(napth-1-yl) . l -C(O)CH2CH2(napth-2-yl) 22 -C(O)n~phth-2-yl -y 8 -C(O)CH2(naphth-. ' C(O)CH2CH?(o-biphenyl) 22 -C(O)o-biphenyl (O)CI-I~(o-biphenyl)-. -C(O)m-biPhenvl -C(U)Cl-12(m-biphenyl)-C(O)CH2CH2(m-biphenyl) . -C(O)p-hiphenyl -C(O)Cl i~(p-biphenyl)-C(O)C1~2CH2(p-biphenyl) . ' CH?(o-PhOPh) -C(O)CH

13 -C(O)o-PhOPh hOPh) ~
22 -C(U)CII~(o-1 . h CH~(m-PhOPh) ' (O)CH
-C' 14 -C(Ulm-PhOPh ) .
22 hOP ~
-C(U)C.H~(m-1 . -C(U)p-PhOPh -C(U)CI1~(p-Ph01'h)-C(UICH~CH~(p-PhOPh) 22.15 16 -C(O)o-PhNI-IPIt -C(U)CII~(o-I'hNIiPh)-C(O)CI-I2CH2(o-PhNHPh) . -C(U)m-l'hNHph -C(O)Cli2(m-I'hNllPh)-C'(O)CH2CH2(m-PhNHPh) . -C(O)p-PhNHPh -C(U)CI-12(p-I'hNHPh)-C(O)CI-I2CH2(p-PhNHPh) 22.18 22.19-C(Ok~-PhSPh -C(U)Cl-I~(o-PhSPh)-C(U)CH2CH2(o-PhSPh) 22.20-C(O)m-PhSPh -C(U)CII~(m-PhSPh) -Cl0)CH2CH2(m-PhSPh) 22.21-C(O)P-I'hSPh -C'.(U)CII~(p-I'hSPh)-C(O)CH2CH2(p-PhSPh) 22.22-C(O)o-PhCI-I2SPh -C(U)C112(o-PhCH2SPh)-C(O)CH2CH2(o-PhCH2SPh) 22.23-C(O)m-PhClI2SPh -C(O)C1I2(m-PhCI-I2SPh-C(O)ClI2CH2(m-) PhCH2SPh) 22.24-C(O)p-PhCI-I2SPh -C(U)CI12(p-PhCIi2SPh)-C(O)CH2CH2(p-PhCH2SPh) 22.25-C(O)adaunantvl -C(U)CI1~(aclamantvl)-C(O)CH~CH~(adamantyl) 22.26-C(O)cvclopentvl -('.(U)Cll~(cvclopcntvl)-C(U)CH2CH~((cvclopentyl) 22.27-C(O)cvclohexvi -C(U)C11~(cvclohexvl)-C(O)CH~CH~(cvclohexvl) 22.28-C(O)C11~U(cyclopentvl)-C(O)CII~NII(evclopentvl)-C(U)CH2S(evclopentvl) 22.29-C(O)CH~U(cyclohexvl)-C(U)('.ll~Nll(cyclohexyl)-C(O)CH2S(cyclohexyl) 22.30-C(O)pYridin-2-vl -C(O)Cli~(pyritlin-2-yl)-C(O)CH2CH~(pyridin-2-yl) 22.31-C(O)PYn~in-3-vl -C(U)CI-12(pyridin-3-vl)-C(O)CH~CI~~(pytidin-3-yl) 22.32-C(O)pYtidin-4-vl -C(U)Cll~(pyridin-4-yl)-C(U)CH2CH~(pYtidin-4-yl) /

22.33-C(O)furan-2-yl -C(U)CII~(furan-2-vl)-C(U)CH~CH2(furan-2-yl) 22.34-C(U)furan-3-yl -C(U)CH2(furan-3-yl)-C(U)CH2CH~(furtn-3-yl) 22.35-C(O)thiophen-2-yl -C(U)CI12(tltiophen-2-yl)-C(U)CH2CI12(thiophen-2-vl>

22.36-C(U)thiophcn-2-yl -C(U)CII2(thiophen-2-yl)-C(U)Cl-I2CH2(thiophen-2-vl) 22.37-C(O)imidazo-2-yl -C(U)CIf~(imiclazo-2-yl)-C(U)CH~CH~(imidazo-2-yl) 22.38-C(O)oxazo-2-yl -C(CC11?(oxazo-2-yl>-C(O)CH2CH2(oxazo-2-yl) 22.39-C(U)thioazo-2-vl -C(U)('.11~(thioazc-2-yl)-C(O)CH?CH~(thioazo-2-Yl) SUBSTITUTE SHEET (RULE 26) '~ ~t .
WO 95109634 ~~ ~ ~ ~ .f ~ PCT/US94111280 22.40 -C(O)benzoiuran-2-yl -C(U)C1I2(tx:nzoturv~-2-yl) -C(U)CH2CH2(henzofuran-2-vl) 22.41 -C(O)benzofuran-3-yl -C.(U)CI12(tx:nzoturatt-3-yl) -C(O)CH2CH2(henzofuran-3-vl) 22.42 -C(O)benzoUtiophen-2-yl -C(O)CH2(benzoU~iophen-2-yl) -C(U)CH2CH2(benzothiophen -2-vl) 22.43 -C(O)thiophen-2-yl -C(U)CIi2(thioPhen-2-yl) -C(O)CH2CH2(thiophen-2-vl) 22.44 -C(O)benzimidazo-2-yl -C(U)CH2(henzimidazo-2-yl) -C(O)CH2CH2(benzimidazo-2-vi) 22.45 -C(U)benzoxazo-2-yl -C(U)CH2(benzoxazo-2-yl) -C(U)CI-i2CH2(benzoxazo-2-vl) 22.46 -C(O)benzothiazo-2-yl -C(U)CH2(bcnzoUiittzo-2-yl) -C(U)CH2CH2(henzothiazo-2-vl) 22.47 -C(U)o-Ph(P(O)Ph~) -C(O)m-I'h(P(U)Ph~) -C(U)P-Ph(P(O)Ph3) 22.48 -C(O)Ph-2-(tluoren ~)-vl) -C(UIPh-:~-(lluorcn-9-vl) -C(O)Ph-4-(lluoren-9-vl) 22.49 -C(U)N-indolin-2-one -C(U)intlolin-2-vl -Cl0)indol-2-vl 22.50 -C(O)C(CU3)2N11SU2(naPhUt- -C(U)cycloPentyl-2-(Ph ) -C(O)cyclohexyl-2-(Ph) 2-vl) 22.51 -C(O)Pyrrolidin-3-yl-~~-(I'h) -C(U)tetrahydrofurun-3-yl-4- -C(O)tetrahydrothiophen-3-(Ph ) vl-4-(Phl 22.52 -C(O)tetrahydron~PhU~-1-yl -C(U)tetrahvdronaPhth-2-yl -C(O)cvclopropyl-2,2-(Ph2) 22.53 -C(O)tetrahydroisoquinolin-I- -C(U)tetrthydroisoyuinolin-3-yl -C(O)CH2((2-oxo)indolin-3 yl vl) 22.54 -C(O)CI-I2(N-benzimidazol-2- -C(U)CH2(N-henzoxazol-2-one) -C(O)CI-i2(N-benzothiazol-2-one) one) 22.55 -C(O)CH2(N-dihydroimidazol- -C(U)C112(N-dihydrooxazoi-2- -C(O)CI-I2(N-dihydrothiazol-2-one) one) 2-one) 22.s6 ~co- ~co- ~ o N I~ N Iw N y ~~ i i 22.57 p O O
-OC~-N~NH -OC~N~O -OC~NUS
22.58 -O ' O -OCR -OC O
N ~ I ~ CN_ ~NUO
/v ~ N /
~I
22.5> -C(U)N(CH~)CI-I2Ph -C(U)N(C'21I5)CII2Ph -C(O)N(C31-I7)CH2Ph 22.60 -C(U)Pyridin-3-yl-5-(Ph) -C(U)1'h-3-(CI12(thiophen-2- -C(U)Ph-3-(CH2Ph) vl)) 22.61 -C(U)C(C)-I~)~UPh -C(U)Cll(C~IIS)OPh -C(U)CH~OCH2Ph 22.62 -C(O)CH~U(o-PW'.11~OII) -C'(U)C'1I~U(m-PhCli~Ul1) -C(U)CH~U(P-PhCH~OH) ar ~-SUBSTITUTE SHEET (RULE 26) .:r, ,.,~.. WO 95/09634 ~ PCTIUS94111280 22.63 -C(O)CH~U(o-PIOOII) -C(O)C'II?()lm-PhCU01-I) -C(O)C)-I~U(P-PhCOOH) 22.64 -C(O)CII~U(o-PhCOOCI-I~) -C(O)CIi~U(m-PhCOUCII~) -C(U)CHI2U(P-PhCOOCH3) 22.65 -C(O)CI-I2U(o-PhCIi~C001I) -C(O)CII2U(m-P1~C1I2COUH) -C(O)CH2O(P-I'hCI-I~COOH) 22.66 _ p C O
~NxO
J
SUBSTITUTE SHEET (RULE 26) WO 95/09634 ~ ' PCT/U594/11280 ~~. 1~~~
Table 23 Formula I : A = -B(pinanediol) : X = CI1?NI-I2; R3 = table below ; R11 = -CH2CH2Ph.
.l - ~ .3 .

23.1 -C(O)Ph -C(O)CI-I?Ph -C(O)CH2CH2Ph 23.2 -C(O)CI-hOPh -C(O)C1I~NHI'h -C(O)CI-I2SPh 23.3 -C(O)o-PhOIi -C(U)m-Ph0lI -C(U) -PhOH

23.4 -C(0)o-PhCH~OH -C(O)rn-PhCIhU>-1 -C(O)p-PhCH20H

23.5 -C(U)o-PhCOOIi -C(O)rn-PhCOOIi -C(O) PhCOOH

23.6 -C(O)o-PhCIi2COOH -C(U>m-PhCIhCOOIi -C(O)p-PhCH~COOH

23.7 -C(O)naphth-1-yl -C'(U )CI h(naphUr-1-yl)-C(O)CH~CH~(napth-1-yl) 23.8 -C(O)naphUr-2-yl -C(O)CII~(nanhth-2-vl-C(O)CH~CH~(napth-2-yl) 23.9 -C(O)o-biphenyl -C(O)C)-I~(o-biphenyl)-C(U)CH2CH2(o-biphenyl) 23.10-C(O)m-biphenyl -C(O)CIh(m-biphenyl)-C(O)CHZCH2(m-biphenyl) 23.12-C(O)p-biphenyl -C(O)CH~(p-biphenyl)-C(O)CH2CH~(p-biphenyl) 23.13-C(O)o-PhUPh -C(O)CII~(o-PhUI'h)-C(O)CH2CH2(o-PhOPh) 23.14-C(O)m-Ph01'h -C(O)CI1~(m-PhUPh)-C(U)CH~CH~(m-PhOPh) 23.15-C(U)P-PhOPh -C(U)CII~(p-1'h0l'h)-C(O)CI-I2CH2(p-PhOPh) 23.16-C(O)o-I'hNliPh -C'(O)C11~(o-1'hNl-IPh)-C(O)CI-I2CH2(o-PhNHPh) 23.17-C(O)m-PhNIIPh -C(U)Cli?(m-PhIVIII'h)-C(O)CH2CH~(m-PhNHPh) 23.18-C(O)P-PhNt-IPh -C(U)C.11~(p-1'hNHPh)-C(O)CIi2CH2(p-1'hNHPh ) 23.19-C(O)o-PhSPh -C(U)CFI2(o-PhSPh)-C(O)CH~CH2(o-PhSPh) 23.20-C(O)m-PhSPh -C(O)CIi2(m-PhSPh)-C(O)CH?CH~(m-PhSPh) 23.21-C(O)P-I'hSPh -C(O)Cl-I2(p-1'hSPh)-C(O)CH2CH2(p-PhSPh) 23.22-C(O)o-PhCII2SPh -C(U)Cli2(o-l'hCH2SPh>-C(O)CH2CH2(o-PhCH2SPh) 23.23-C(O)m-PhCIi2SPh -C(U)CIi2(m-PhCH2SPh)-C(O)CH2CH2(m-PhCH2SPh) 23.24-C(O)p-PhCH~SPh -C(U)Cll~(p-PhCI-I2SPh-C(U)CH2CH2(p-PhCH2SPh) ) 23.25-C(O)ad<vnantvl -C'.(O)Cl f2(adarri<lntyl)-C(O)CH2CIi2(ad<rnantyl) 23.26-C(O)cycloPcntvl -C(O)Cli~(cvcloPcntvl)-C(O)CIhCH~((cycloPentyl) 23.27-C(O)cvclohexvl -C(O)CII~(cvclohexvl)-C(U1CI-i2CH~(cvclohexyl) 23.28-C(U)CI-I~U(cvclopentvl)-C(U)CII~NIi(cvclopenrvl)-C(O)CH~S(cvclopentvl) 23.29-C(O)CII2U(cvclohexvl)-C(U)CIhNl1(cyclohexyl)-C(O)CI-I2S(cyclohexyl) 23.30-C(O)Pyridin-2-vl -C(U)CIi2(pytidin-2-vl)-C(O)CH2CH2(pyridin-2-vl) 23.31-C(O)pvridin-3-vl -C(U)C'I12(pyridin-3-vl)-C(U)CI-I2CH~(pvridin-3-yl) 23.32-C(O)Pytidin.~-v_ -C(U)CI t~(pyidin-4-yl>-C(U)Cl-i2CH2(pyridin-4-yl) 23.33-C(0)furut-2-yl -C(O)C'.1 (~(fman-2-vl)-C(U)CH~CH~(furrt-2-yl) 23.34-C(O)fur~rt-3-yl -C(U)CII~(furu~-3-yl)-C(O)CH~CH~(furan-3-yl) 23.35-C(O)U~iophen-2-yl-C(O)C'1t~(Uuophcn-2-vi)-C(U)C)hClh(thiophen-2-yl) 23.36-C(O)U~ioPhen-2-vl-C'.(U)CIh(thiophen-2-yl)-C(O)CH~CIi~(U~iophen-2-yl) 23.37-ClU)imidazo-2-v_ -C(O)CI I~(unidazcr2-vl)-Cl0)CH2CH2(imidazo-2-vl) l 23.38-C(O)oxazo-2-vl -C(U)CIh(oxvo-2-yl)-C(U)CI-12CH2(oxazo-2-yl) 23.39-C(O)U~ic~lzo-2-yl-C'(O)(:H~(Uuoazo -C(U)CH~CH2(U~ioazo-2-yl) ?-vl) 23.40-C(O)henzoluru~-2-yl-C(U)C'.II2(bcnzoturan-2-yl)-C(U)Cl-I2CH2(henzofutan-vl) 23.41-C(O)benzoiurm-3-yl-C(U)C'II2(txnzolurur3-yl)-C(0)CH2C1-12(benzofutan-3-vl) a~~r SUBSTITUTE SHEET (RULE 26) ",~.. WO 95109634 PCT/US94111280 23.42 -C(U)henzotltiophen-2-yl -C(U)CII2(hcnzothioPhen-2- -yl) C(O)CH2CH2(benzothiophen-2-vl ) 23.43 -C(U)thionhen-2-vl -C(U)Cl h(thionhen-2-vl) -C(U)CH~CH~(thiophen-2-vl) 23.44 -C(O)henzimidazo-2-yl -C(U)CI-12(henzimidazo-2-yl) -C(O)CH2C1-I2(benzimidazo-2-vl) 23.45 -C(U)benzoxazo-2-yl -C(O)C1I2(tx;nzoxazo-2-yl) -C(U)CH2CH2(henzoxazo-2-vl) 23.46 -C(O)benzothiazo-2-yl -C(O)Cl i2(henzoU~i~zo-2-yl) -C(O)CH2CH2(benzothiazo-2-vl) 23.47 -C(U)o-I'h(P(U)I'h~) -C(Uhn-Ph(l'(O)Ph3) -C(U)p-Ph(P(O)Ph3) 23.48 -C(O)Ph-2-(tluorcn-9-vl) -C(O)1'h-3-(Iluoren-9-vl) -C(O)Ph-4-(fluoren-9-vl) 23.49 -C(O)N-indolin-2-one -C(O)indolin-2-vl -C(O)indol-2-vl 23.50 -C(O)C(CH3)2NHS02(naPhth- -C(U)cycloPcntyl-2-(Ph) -C(Ukyclohexyl-2-(Ph) 2-vl) 23.51 -C(O)pyrrolidin-3-yl-4-(Ph) -C(U)tetrthydrofurm-3-yl-4- -C(U)tetrahydrothiophen-3-yl-(Ph) 4-(Ph) 23.52 -C(O)tetrW vcironuPhth-1-vl -C(U)teuahvdmnaPhth-2-yl -C(U)cvcloPropyl-2.2-(Ph2) 23.53 -C(O)tetrW ydroisoquinolin-I-yl -C(U)tctrahydroisocluinolin-3- -C(U)CH2((2-oxo)indolin-3-yl vll 23.54 -C(O)CH2(N-henzitnidazol-2- -C(U)CI12(N-henzoxlzol-2- -C(O)CH2(N-henzothiazol-2-onel one) one) 23.55 -C(O)CI-I2(N-dihyJrounidazol- -C(U)C112(N-dihydrooxazol-2- -C(O)CH2(N-dihydrothiazol-2-2-one) one) one) 23.s6 ~co- - ~co- ~ o N O I ~ N O ~ N
l i i ~ / \ l i l i 'I
23.57 O O O
-OC'' N~ N H -OC~ NCO -OC~ NHS
23.58 -OC O -OCR -OC O
IN i I ~ ~N~ INkO
U
/\ _ N
~I
23.59 -C(O)N(CII~)CII~Ph -C(U)N(C~11S)C'IhPh -C(U)N(C~I17)CI-l~Ph 23.60 -C(O)Pyt7din-3-yl-5-(Ph) -C(U)1'h-:1-(CII2(thiophen-2- -C(O)Ph-3-(Cl~2Ph) vl)) 23.61 -C(U)C(CH3)~UPh -C(U)CII(C~115)UPh -C(O)CH~UCH~I'h 23.62 -C(U)CII~O(o-PhCN~01-I) -C(U )CII2U(m-I'hCH2011) -C(U)CI~~U(P-PhCH20H) 23.63 -C(U)C11~U(c~-1'hCUUH) -ClU)CII~U(m-1'hCUUI-I) -C(O)CH2U(P-PhCOOH) 23.64 -C(O)CI-hU(o-PhCUUCH~) -C(U)CI-hU(m-PhCUUCII~) -C'(U)CH2U(P-PhCOC)CH~) 23.65 -C(O)C132U(o-PhC112CUUII) -C'(O)CI12U(m- -C(U)Cl-I2U(P-PhCH2COOH) PhC'11~C'001-I) o7.h SUBSTITUTE SHEET (RULE 26) WO 95109634 ~ L r " PCTIUS94111280 23.66 -OC 0 ~NUO
J
Table 24 Formula I : A = -B(pinuttediol) ; X = CH2N1-I2: R3 = table below ; R11 = -Ph.
.1 ~2 ,_ _ .3 24.1 -C(O)Ph -C(U)CI-I~Ph -C(O)CH~CH2Ph 24.2 -C(U)CI-hOPh -C(O)C1I~NI-IPh -C(O)CH2SPh 24.3 -C(U)o-PhOII -C(Cm-I'h01-i -C'lC -Ph01-I

24.4 -C(O)o-PhCF1~01-I -C(U)rn-PhCll?UH -C(O)p-PhCI-I2Ul-I

24.5 -C(O)o-I'h CUOI -C'l( m-I'hC'UOH -C(U) -Ph COOH

24.6 -C(U)o-PhCN~CU011 -C(Uhn-I'hCl1~C0011-C(O)p-PhCH2C00N

24.7 -C(U)naphth-1-vl -C(U)CIh(naphth-1-vl)-C(O)CH~CH2(napth-1-vl) 24.8 -C(O)na~htlr2-yl -C(U)C'II~(naPhth-2-yl-C(O)C1I2CH~(napth-2-yl) 24.9 -C(O)crhiphenvl -C(O)ClI2(o-hiphenvl)-C(O)CH~CH2(o-biphenyl) 24.10-C(O)m-hi~henyl -C(O)CI-I~(m-hiphenvl)-C(O)CH~CH~(m-biphenyl) 24.12-C(U)p-biphenyl -C(O)Clt2(p-biphenyl)-C(O)CH2C1-12(p-biphenyl) 24.13-C(Ok~-PhOPh -C(U)CI-h(o-PhUPh)-C(O)ClI?CH?(o-PhUPh) 24.14-C(U)m-I'hOPh -C(O)CIh(m-PhUPh) -C(O)CH2CH2(m-PhOPh) 24.15-C(O)p-PhOPh -C(U)CI hlp-PhOPh)-C(O)CH2CH2lp-PhOPh) 24.16-C(O)o-PhNI-iPh -C(O)CII~(o-1'hNl-IPh)-C(O)CH2CH2(o-PhNHPh) 24.17-C(O)m-PhNI-IPh -C(U)CH~(m-PhNllPh)-C(U)CH~CH2(m-PhNHPh) 24.18-C(O)p-PhNHPh -C(O)CIU~(p-I'ltNlIPh-C(O)CH?CH2(p-PhNHPh) ) 24.19-C(O)o-PhSPh -C(O)C'1-I~(o-1'hSPh)-Cl0)CH2CH~(o-PhSPh) 24.20-C(U)m-PhSPh -C'(U)CH~lrn-PhSPh)-C(O)CH~C1I2(m-PhSPh) 24.21-C(O)p-I'hSPh -C(U)C11~(p-I'hSI'h)-C(O)CI-hCH2(p-PhSPh ) 24.22-C'.(O)o-I'hCIi~SI'h_-C(U)C11~O-I'hCH~SPh)-C(O)CI-i~Cll2lo-I'hCH2SPh) 24.23-C(U)m-PhCH2SPh -C(U)ClI2(m-PhCII2SI'h)-C(U)CH2CH2(m-PhCIi~SPh) 24.24-C(O)p-l'hCI-I2S1'h-C(U)CII?(p-PhCII~SPh)-C(O)CIi2CH2(p-PhCH2SPh) 24.25-C(O)aclaut><nntyl -C(U)C:II~(adamantvl)-C(O)CH2CH2(adamantyl) 24.26-C(O)cyclopentvl -C'(O)CII~(cvclopentvl)-C(U)CIhCI-i2((cyclopentyl) 24.27-C(O)cvclohexvl -C(U)CI12(cvclnhexvl)-C(U)CH2CH2(cyclohexyl) 24.28-C(O)CHZO(cyclopentvl)-C(U)CII~NII(evclopentvl)-C(O)CH~S(cyclopentyl) 24.29-C(U)CI-hU(cvclohexvl)-C(U)CII~NII(cvclohexvl>-C(U)CI~~Slcvclohexyl) /

24.30-C(U)PYridin-2-yl -('(U)CII~(pytidin-2-yl)-C(O)CH~CH2(pyridin-2-yl) 24.31-C(O)Pv>idin-3-vl -C'(U)CII~(pyridin-3-yl)-C(U)CI-I2CH2(pyridin-3-yl) 24.32-C(O)pvtidin-4-v_ -C(O)Cl-1~(py>iclin-4-vl)-C(0)CH~CH2(pvridin-4-yl) 24.33-C(O)furm-2-vl -C(O)CII2(furm-2-v-C(U)CH2CH2(furan-2-y 24.34-C(0)furur3-yl -C(U)CII~(furtn-3-vl)-C(O)CI-I2CH~(furan-3-yl) 24.35-C(O)thio~hen-2-vl -C(U)C'.II~(thi~phen-2-vl)-C(O)CI~~CH~(thiophen-2-yl) 24.36-C(O)thio~hen-2-yl -C(O)CII~(thicyhcn-2-yl)-C'(U)CH2CI-i~(thiophen-2-vl) al ~
SUBSTITUTE SHEET (RULE 26) V
24.37 -C(O)imidazo-2-yl -ClU)('I t~(imidazo-2-vl) -C.(O)C1~~CH~(imidazo-2-yl) 24.38 -C(O)oxazo-2-yl -C(O)CII?(ox~o-2-yl) -C(O)CH2CH?(oxazo-2-yl) 24.39 -C(O)U~ioazo-2-vl -C(O)C'II~(Uuoazo-2-vl) -C(O)CH~CH~(thioazo-2-vl) 24.40 -C(U)hcnzoftuutr2-yl -C(U)CI12(Ixnzofurut-2-yl) -C(O)CI-12CH2(benzofutan-vl) 24.41 -C(O)benzofurvt-3-yl -C(O)C112(henzofur:tn-3-yl) -C(O)C1-I2CH2(benzofuran-3-vl) 24.42 -C(U)benzoUuoPhen-2-yl -C(U)C)-I2(hcnzothiophen-2- -yl) C(O)CH2CH2(benzothiophen-2-vl) 24.43 -C(O)thiophen-2-yl -C(O)CI-12(Utiophen-2-yl) -C(O)CH~CH~(thiophen-2-yl) 24.44 -C(U)benzitnidazo-2-yl -C(O)Cl-I2(benzitnid<nzo-2-yl) -C(O)CH2CH2(benzimidazo-2-vl) 24.45 -C(O)benzoxazo-2-yl -C(U)CIi2(hcnzoxZZO-2-yl) -C(U)CIi2C1-I2(benzoxazo-2-vl) 24.46 -C(O)henzoUii~zo-2-yl -C(U)Cll2(henzothiazo-2-yl) -C(O)CH2CH2(benzothiazo-2-vl) 24.47 -C(U)o-1'h(P(U)l'h~) -C(U)m-I'h(I'(U)Ph~) -C(U)(t-Ph(P(O)Ph3) 24.48 -C(O)Ph-2-(Iluorcnn-9-vl) -C(U)Ph-;-(tiuoren-~)-vl) -C(U)Ph-4-(Iluoren-9-vl) 24.49 -C(O)N-indolin-2-one -Cl())inclolin-2-vl -C(U)indol-2-vl 24.50 -C(O)C(CH3)2NIISU2(naphUt- -C(U)cyclolxntyl-2-(Ph ) -C(U)cyclohexyl-2-(Ph) 2-vl) 24.51 -C(O)pyrrolidin-3-yl-4-(Ph) -C(U)tetrihydrofuran-3-yl-4- -C(U)tetrthydmthiophen-3-yl-(Ph) 4-(Ph) 24.52 -C(U)tetrahydrtni<lPhtlrl-yl -C(U)tetrthydronaphtlr2-yl -C(O)cyclorroryl-2.2-(Ph2) 24.53 -C(O)tetrahydroisoquinolin-1-yl -C(U)tetrthydroiscxluinolin-3- -C(U)Cl-12((2-oxo)indolin-3-yl vt) 24.54 -C(U)CH2(N-tx;nzunidazol-2- -C(O)CH2(lV-henzoxazol-2- -C(O)C~I2(N-benzothiazol-2-one) cite) one) 24.55 -C(U)CIi2(N-dihydroimidazol- -C(U)CI-12(N-dihydrcxtxazol-2- -C(O)CH2(N-dihydrothiazol-2-2-one) onc) one) 24.56 rC0- ~CO-w N O I v N O N
l i i ~ / ~ l i l i ~I
24.57 p O O
-OC''NUNH -OC~NU0 -OC~NUS
24.58 -OC O -OCl -OC O
IN ~ 1 ' CN1 1N110 JU
N
\1 24.50 -C(O)N(CI-I~)Cl-hPh -C(U)N(('~I15)C1121'h -C(U)N(C~li7)CH~Ph 24.60 -C(O)nyridin-3-yl-5-(1'h) -C(U)1'h-3-(C'll2(Utiophen-2- -C(U)Ph-3-(CH2Ph) vl)) ail SUBSTITUTE SHEET (RULE 26) WO 95/09634 ~ PCT/US94/11280 217431, _ 24.61 -c(o)c(cH3)2oPh -c(o)cll(c~115)oI'h -c(o)cH~ocH~Pn 24.62 -C(O)CI-hO(o-PhCI-I~OII) -C(U)CII2U(m-PI~CIt~UII) -C(U)CIi20(P-PhCH20H) 24.63 -C(O)CH~O(o-I'hCU01-i) -C(U)CI1~0(m-I'hCOUI-I) -ClU)CI-I~U(P-PhCOOH) 24.64 -C(O)CIt~U(o-PhCU(X'.II;) -C(U)CII~U(rn-I'UCUUCII~) -C(O)CH2U(P-I'hCOCXrH3) 24.65 -C(O)CH2U(o-PhCII2CUO1-I) -C(O)CH20(m- -C(O)CH20(P-PhCIi2COOH) PIrCH~C0011) 24.66 - p C O
~NUo J
/ \
Table 25 Formula I : A = -B(Pinanediol) ; X = -CII?NI I2; R3 = t~~hle below ; R11 = -CI-i2(naphth-2-yl).
.1 ' .3 2s.1 -c(o)Ph -c(o)cl hPh -c(o)cH~cH~Ph 2s.2 -c(o)crl~oP~, -c(o)crl~M-IPh -c(o)cH~sPh 2s.3 -c(o)o-Phol-1 -C((m-1'hOII -('(U) -PhOH

25.4 -C(O)o-PhCI-I2UHI -C(U)rn-I'hCl hOH -C(U)P-PhCH~OH

2s.5 -C(U)c~-PhCOOH -C(U)m-I'hCUU1 -C(U) PhCOOH
i 25.6 -C(Uk~-PhCH~CUOH -C(U )m-I'hC1~12COUl-C(O)s-PhCH~COOH
t 2s.7 -C(O)na~httrl-vl -C(O)C112(naPhth-1-yl)-C(U)CH~CH~(napth-1-yl) 25.8 -C(O)naPhth-2-yl -C'.(U)CI12(n~Phth-2-yl-C(U)CH~CI-i2(napth-2-yl) 25.9 -C(O)o-hirhenyl -C(O)Cli~(o-hiPhenyl)-C(O)CH2Clh(o-hiphenyl) 25.10-C(U)m-biphenyl -C(U)CIh(m-hirhenyl)-C(O)CH~CH~(m-biphenyl) 25.12-C(U)s-biphenyl -C'.(U)C112(r-hiPhenyl)-C(U)CI-i2CH2(P-biphenyl) 25.13-C(O)o-PhOPh -C'(O)CI i~(o-1'hOPh-C(O)CH2CH2(o-PhOPh) ) 25.14-C(O)m-1'h01'h -C(U)C1I2(m-l'hOPh-C(O)Cli2CH2(m-PhOPh) ) 2s.ls-C(U)p-PhOPh -C(U)C112(~-I'h01'h-C(O)CH2CH2(P-PhOPh) ) 25.16-C(Olo-I'hNHPh -C(U)C'.11~(o-I'hNIIPh)-C(O)CI-ICI-I~(o-PhNHPh) 25.17-C(U)m-I'hNlil'h -C'(O)('li~(m-PhNliPh)-C(O)CI-I~CH~(m-PhIVHPh) 2s.18-C(U)s-PhNHI'h -C'.(U )C'l h(P-I'hNl-C(O)CIi~CH2(p-PhNHPh) ll'h) 2s.19-C(U)o-PhSPh -C(U)CIU~(o-1'hSPh)-C(O)CH~CH2(o-PhSPh) 2s.20-C(O)m-PhSPh -C(U)Cli2(m-PhSPh)-C(O)CH2CH2(m-PhSPh) 25.21-C(O)P-PhSPh -C'.!U)CI t~(~-PhSPh)-C(O)CH~CH?(P-PhSPh) 25.22-C(O)o-PhCIhSPh -C'.((pCII~(o-1'hCI-hSPh)-C(O)CH2CH2(o-PhCH2SPh) 25.23-C(O)m-PhCl-i2SPh -C(O)CI-I2(m-I'hCll2SPh)-C(U)CH2CH2(m-PhCH~SPh) 25.24-C(O)P-PhCI-hSPh -C(O)CII2(P-I'hCII~SPh)-C(U)CH2CH2(p-PhCH2SPh) 2s.2s-C(O)adaraurtvl -C:(O)Cl-12(acL~mantyl)-C(O)CH~CH?(adamantyl) 25.26-C(O)cvclopentvl -C(U)CI h(cvcloPcntvl)-C(O)CH2CH~((cvclopentvl) 25.27-C(O)cvclohexvl -C'(C))Clt~(rvclohexvl)-C(U)CII~C1I~(cvclohexvl) 25.28-C(O)CIhU(cvcloPentvl)-C'(C))C'IhNII(cvcloPentvl)-C(U)CIhS(cvclohentyl) 2s.29-C(O)Cl-hU(cvcloh -C(())CII~IvTII(cvclohexvl)-C(O)CI-hS(cvclohexyl) exyl) 2s.30-C(U)~Yriclin-2-yl -C'(())C'It~(Pyiclin-2-vl)-C(O)C112CH~(Pvridin-2-yl) I2s.31-C(U)nwidin-3-vl -C'(U)C11~(Pyticlin-3-vl)-C(U)CH~CIi~(pyridin-3-yl) am SUBSTITUTE SHEET (RULE 2b) 25.32 -C(U)P)'nJin-4-vl -C((»C'1l~(wricJin-4-vl) -C(O)CH~CH2(nvridin-4-yl) 25.33 -C(O)furnn-2-vl -C'(U1C11~(furut-2-vl) -C(O)CH2CH2(fttran-2-yl) 25.34 -C(O)fttrtn-3-yl -C(U)Cll~(furtn-3-yl) -C(O)CH2CH2(furan-3-yl) 25.35 -C(O)Utiophen-2-yl -C(O)CI1~(Utiolthcn-2-v!) -C(U)CH~CH2(thiolthen-2-yl) 25.36 -C(O)tltioPhen-2-vl -C(O)CI-1~(Utio~hen-2-vl) -C(O)Cl-i~CH~(thioPhen-2-yl) 25.37 -C(O)imiJ~~zo-2-yl -C(U)CH~(irniclazo-2-yl) -C(U)CH~CH~(imiclazo-2-yl) 25.38 -C(U)oxazo-2-yl -C(U)CH2(ox:tzo-2-yl) -C(O)CH2CH2(ox:tzo-2-yl) 25.39 -C(O)lhio:tzo-2-yl -C(O)C112(Utioazo-2-yl) -C(O)CH2Chi2(thioazo-2-yl) 25.40 -C(O)henzoftiratt-2-yl -C(U)CI-12(txnzofurut-2-yl) -C(O)CH2CH2(benzofutan-2-vl) 25.41 -C(O)hc:nzofurut-3-yl -C(U )ClI2(henzofuran-3-yl) -C(U)CI-I2CH2(henzofutan-3-vl) 25.42 -C(O)henzoUtiophcn-2-yl -C(U)CIi2(henzoUtiophen-2- -yl) C(O)CH2CH2(benzothiophen-2-vl) 25.43 .-C(O)UtioOhen-2-vl -C(O)CI1~(Utionhen-2-vl) -C(U)CH~CH~(Utiophen-2-yl) 25.44 -C(O)henzimid:tzo-2-yl -C(U)CI12(tx:nzimid:tzo-2-yl) -C(U)CH2CH2(henzimidazo-2-vl) 25.45 -C(U)henzoxuzo-2-yl -C:(O)CII2(henzoxazo-2-y!) -C(U)CH2CH2(henzoxazo-2-vl) 25.46 -C(U)lx:nzoUtiazcr2-yl -C(U)CIl2(hcnzoUti~zcr2-yl) -C(U)C1-I2CH2(henzothiazo-2-vl) 25.47 -C(U)o-Ph(P(O)I'h~) -C(U)m-1'h(P(U)Ph3) -C(U)P-Ph(P(O)Ph3) 25.48 -C(U)I'h-2-(tluorc:n-9-vl) -('(U)I'h-3-(iluoren-9-vl) -C(U)Phll-(nuoren-9-vl) 25.49 -C(O)N-indolin-2-one -Clt»inclolin-2-v1 -C(U )indol-2-vl 25.50 -C(O)C(CI-i3)2N1ISU2(naphUt- -CtU)cycloltemyl-2-(Ph) -C(U)cyclohexyl-2-(Ph) 2-vl) 25.51 -C(O)pytrolidin-3-yl-4-(Ph) -C(U)tctrthydmfur:tn-3-yl-4- -C(O)tetrahyc)rothiophen-3-yl-(Ph) 4-(Ph) 25.52 -C(O)tetrNtyclmna~hUr I-vl -C(U)tetrthvJronaPhUt-2-vl -C(O)cycloproPyl-2.2-(Ph2) 25.53 -C(O)tetrahydmicoquinolin-1-yl -C(U)tctraltyJroiaoquinolin-3- -C(U)CfI2((2-oxo)indolin-3-vl vl) 25.54 -C(U)ChI2(N-tx:nzimidazol-2- -C(U)C112(N-hcnzoxazol-2- -C(U)C1~2(N-benzothiazol-2-one) one) one) 25.55 -C(U)CII2(N-dihydroimicJvol- -C'(U)t'.112(N-dihyclrcxtx:tzol-2- -C(O)C'1I2(N-dihyJrothiazol-2-2-one) one) one) 25.56 rC0- rC0- ~ p O
w N O I v N w N w ,.
~I
25.57 p O O
-OC''NUNH -OC~NU0 -OC~N~S
ass SUBSTITUTE SHEET (RULE 26) ~~ 74 ~I 4 25.58 -OC O -OCR -OC O
IN ~ I ~ ~N~ INkO
/\ ~ N /\
25.59 -C(O)N(CI-I~)CI~I~Ph -C(U)N(C?I-15)CH2Ph -C(U)N(C3H7)CH2Ph 25.60 -C(O)pyridin-3-yl-5-(Ph) -C(U)l'h-3-(CIi2(thiophen-2- -C(O)Ph-3-(CIi2Ph) vl)) 25.61 -C(O)C(CI-I3)201'h -C(U)Cli(C?1-I5)OPh -C(U)CH?OCH2Ph 25.62 -C(O)CI-I~U(o-PhCI-i~OH) -C'(U)CI-I~O(m-1'hCl-1~U1I) -C(O)CI-I2U(P-PhCH20H) 25.63 -C(O)CI-I~O(o-1'hCUUI-I) -C(())CIt2U(rn-1'hCOOI-I) -C(O)CH20(p-PhCOOH) 25.64 -C(O)CIhO(o-PhCUUClI~) -C(U)C'IhUhn-PhCUUCI-I~) -C(O)CH~O(P-PhCOOCH~) 25.65 -C(O)CH2U(o-PhCII2CUUI~) -C(O)C1120(rn- -C(U)CH2U(p-PhCH2COOH) 1'hCOI~C'OOI-I) 25.66 -OC O
~N~O
J
/ \
a~~
SUBSTITUTE SHEET (RULE 26) ~'ahle 26 Formula I : A = -B(pinanediol) ; X = -SC(=NI I)NI I2 ; R3 = tahle helow ; R11 = CN3 .1 ' .3 ~

26.1 -C(O)Ph -C(U)Ctl2Ph -C(O)ClI2CH?Ph 26.2 -C(O)CH~OPh -C(U)Cl-I~M-IPh -C(O)CIi~SPh 26.3 -C(O)o-PhUH -C(U)m-1'hOH -C(U) -PhOH
26.4 -C(O)o-PhCI-I201-I -C(O)tn-PhCIl201U -C(0)p-PhCH20H

26.5 -C(O)o-PhCOOrI -C'(U)m-1'hCOUH -C(U) -PhCOOH
26.6 -C(O)o-PhCH2COUH -C(U)m-I'hCH2COU1-I-C(O)p-PhCH2COOH
26.7 -C(O)naphth-1-vl -C(O)CH~(naphth-I-yl)-C(O)CH~CHZ(napth-1-yl) 26.8 -C(O)naphth-2-vl -C(O)CI-1~(naPhth-2-vl-C(O)CI-hCH2(napth-2-yl) 26.9 -C(U)o-hiphenvl -C(O)Cli~(c~-hiphenvl)-C(O)CH2CH2(o-biphenyl) 26.10-C(O)m-hiphenvl -C(U)CI-h(m-hiphenyl)-C(U)CH2CH2(m-biphenyl) 26.12-C(O)p-hiphenvl -C(O)CII~(p-hiphenvl)-C(U)CH~CH2(p-biphenyl) 28.13-C(0)o-PhOPIt -('(O)Cl l~(o-PhOPh-C(U)CH~CH2(o-PhOPh) ) 26.14-C(O)m-PhOPh -C(U)Cll~(m-l'hOPh)-C(U)CH~CH?(m-PhOPh) 26.15-C(O)p-PhOPh -C(U)C'Il~lp-PhUI'h)-C(O)CIhClI2(p-PhOPh) 26.16-C(U)o-I'hNl-IPIt -C(U)CIl2lo-PhNliPh)-C(O)CH~CI-12(o-PhNHPh) 26.17-C(U)tn-PhNl3Ph -C(U)CHZ(m-I'hNl-IPh)-C(U)C:Fi~CH2(m-PhNHPh) 26.18-C(U)p-I'hNI-IPh -C(U)C112(p-PhNI-IPh)-C(O)CH~CH2(p-PhNHPh) 26.19-C(O)o-PhSPh -C(O)CII~(o-PhSPh)-C(U)CH2CH2(o-PhSPh) 26.20-C(O)m-PhSPh -C'(U)Cli2tm-I'hSPh-C(U)CH2CH2(m-PhSPh) ) 26.21-C(O)p-PhSPh -C'.(O)CH~(p-PhSPh)-C(U)CIi~CH2(p-PhSPh) 26.22-C(U)o-PhCII2SPh -C'.(U)CH~(o-I'hClhSPh)-C(O)CI-I2CH2(o-PhCH2SPh) 26.23-C(U)m-PhCH2SPh -C(U)C112(m-PhCII2SPh)-C(O)CI-I2CH2(m-PhCI-hSPh) 26.24-C(U)P-PhCII2SPh -C(U)CI12(p-PhCII~SPh)-C(U)CH2CH2(p-PhCH2SPh) 26.25-C(U)acilrr><~ntvt -C(U)CI-h(adwnantvl)-C(O)CH2CH~(adamantyl) 26.26-C(O)cvclopentyl -C(U)CI-h(cvclopentyl)-C(U)CI-hCH2((cyclopentyl) 26.27-C(O>cvclohexvl -C(U)C'.II~(cvrlohexvl)-C(U)CH~CH2(cyclohexvl) 26.28-C(O)CI-I~O(cvclopentvl)-('.(U)C'11~NI1(evclnpentvl)-C(O)C>-l~Stcvclopentyl) 26.29-C(U)CI-h()(cvrlohexvl)-C(U)CII~N1I(ryclohexvl)-C'(U><'.li2S(cyclohexyl) 26.30-C(O)pvri~in-2-vl -C(U)CII~(pyri~in-2-yl)-C(U)CH2CH2(pyridin-2-yl) 26.31-C(O)p~~in-3-vl -C(U)CII2(pyndin-3-yl)-C(U)Cl-hCH2(pyridin-3-yl) 26.32-C(O)pyriclin-4-vl -C(O)CI-I~(pyridin-4-vl)-C(O)CH2CH2(pyridin-4-yl) .

26.33-C(O)furtn-2-vl -C'.fU)C'.11~(f'urut-2-vl)-C(U)CH~CH2(furan-2-yl) 26.34-C(O)fnrtrt-3-yl -C.(U)CII~(furtn-3-yl)-C(U)Cli2CH2(furan-3-vl) 26.35-C(O)thiophen-2-vl -C(O)C'.II~(thionhen-2-vl)-C(U)CH~CH2(thiophen-2-yl) 26.36-C(U)tluophcn-2-vl -C(O)CII~(thiaphen-2-yl)-C(O)CH~CH~(thiophen-2-yl) 26.37-C(O)imidwo-2-yl -C(U)CI h(irnidazc>-2-yl)-C(O)CH~CH2(imidazo-2-yl) 26.38-C(O)ox~zo-2-yl -C(U)CII~(oxazo-2-yl)-C:(U)CI-12CI-12(oxazo-2-yl) 26.39-C(U)thio~zo-2-vl -C'(U)Cl hlthiowo-2-vl)-C'.(U)CI-hCH2(Uiioazo-2-yl) 26.40-C(U)lxnzofurur2-yl-C(O)CI12(hcnzofuran-2-yl)-C(U)CIU2CH2(henzofutan-2-vl) 26.41-C(U)henzolirrur-s-yl-C'.(U)CII2(hcn-rolitrur3-yl)-C(U)CII2CH2(henzofuran-vl) a ar SUBSTITUTE SHEET (RULE 26) WO 95/09634 ~ ~ ~ PCTIUS9-1/11280 26.42 -C(U)henzoUiio~hen-2-yl -C(U)C'112(henzothioPhen-2- -yl) C(O)CI~2CH2(benzothiophen-2-vl) 26.43 -C(O)U~ionhen-2-yl -C(U)CII~(thio~hen-2-vl) -C(U)CH~CI~~(thionhen-2-vl) 26.44 -C(O)henzanidnzn-2-yl -C'(O)CI-i2(tx:nzimiUazo-2-yl) -C(O)CH2CH2(benzimidazo-2-vl) 26.45 -C(O)henzoxazo-2-yl -C(U)CI-i2(hcnzoxazo-2-yl) -C(O)CH2CH2(benzoxazo-2-vll 26.46 -C(O)lx;nzothiazcr2-yl -C(U)CIi2(bcnzoU~iazo-2-yl) -C(U)CH2CH2(benzothiazo-2-vl) 26.47 -C(O)o-Ph(P(O)Ph~) -C(Uhn-1'h(I'(O)Ph~) -C(O)r-Ph(I'(O)Ph3) 26.48 -C(O)Ph-2-(Ilttorcn-9-vl) -C(O)Ph-3-((luorcn-9-vl) -C(O)Ph-4-(Iluoren-9-vl) 26.49 -C(O)N-indolin-2-one -C(())indolin-2-vl -C((> indol-2-vl 26.50 -C(O)C(CH3)2NIISU2(naPhU~- -C(U)cyclonentyl-2-(Ph) -C(U)cyclohexyl-2-(Ph) 2-vl) 26.51 -C(U)pYm~lidin-3-yl-4-(Ph) -C(U)teuahydrofurm-3-yljl- -C(U)teUahytirothiophen-3-yl_ (Ph) 4-(Ph ) 26.52 -C(U)tetrahvdrona~hU~-1-vl -C:(U)tcln~hvclronaphU~-2-vl -C'(U)cvclopro~yl-2.2-(Ph2) 26.53 -C(U)tetrW ycL~oiu~quinolin-1-yl -C(O)tetrahydroiwxluinolin-3- -C(U)CII2((2-oxo)indolin-3 yl vl) 26.54 -C(O)CH2(N-hcnzimiUazol-2- -C.(U)C'112(N-bcnzoxazol-2- -C(U)Ctl2(N-henzothiazol-2-one) one) one) 26.55 -C(O)CH2(N-clihyclroimi~azol- -C(O)C112(N-clihydrooxazol-2- -C(U)CH2(N-dihydmthiazol-2-2-one) one) one) 26.s6 ~co- ~co- ~ o N r~ N ~~ N
,I ' ~ ~ i i 26.57 O O O
a a a _OC'~ N N H -OC~ N O -OC~ N
26.58 -OC O -OCl -OC O
IN ~ I w CN~ lNJtlO
N
~I
26.59 -C(O)N(CH~)C'.II~Ph -C(())N(C~IIS)Cl-hPh -C(U)N(C~H7)CH2Ph 26.60 -C(O)pyridin-3-yl-5-(I'h ) -C(U)I'h-3-(CI12(thioPhen-2- -C(U)Ph-3-(CH2Ph) vl)) 26.61 -C(O)C(Ctl3)~OPh -C:(U)CI1(C'.~115)OPh -C(O)CH~OCI-I2Ph 26.62 -C(O)CI-i~U(o-1'hCII~UI-i) -C(U)C'.IhU(tn-I'hCl-hUH) -C(O)CH~U(P-PhCH20H) 26.63 -C(O)CH~O(o-Ph C001-I) -C(U)C11~U(m-PhCOOIi) -C(O)CH~O(P-PhCOOH) 26.64 -C(U)CI-hU(o-PhCUUCI-1~) -C(U)C'.11~0(m-PhCOUCI-f~) -C(U)CH~U(P-PhCOOCH3) 26.65 -C(O)CI-I20(o-PhC112CUO1I) -C(U)C:li2U(m- -C(U)CH20(p-PhCH2COOH) PhCI I~COOI I) aaa SUBSTITUTE SHEET (RULE 26) WO 95109634 ' PCT/US94111280 1~ 4314 26.66 -OC O
~N~O
J
/ \
able 27 Formula I : A = -B(pinanediol) ; X = -SC(=NI-I)NI-I2 ; R3 = table below ; R11 = -CH2(p-PhOH).
.1 ., .~ .3 27.1 -C(O)Ph -C(U)ClhPh .~ -C(O)CH2CH2Ph 27.2 -C(U)CII~UPh -C(C))Cll~Mil'h -C(0)CH?SPh 27.3 -C(U)o-PhOI~ -C'(< m-I'hOt l -C(U) -Ph01-1 27.4 -C(U)o-PhCH~UII -C'(Cm-1'h('I-12U1-i-C(U)p-PhCII~OH
27.5 -C(U)o-1'hCOUiU -C((rn-PhC()UII -C(U) -I'hCOOH
OIi -PhCH?COOII
' -C(U) 27.6 -C(O)o-PhCIi~C'UUI1hC1-I~CU p -C(())m-I -C(U)CH2CH2(napth-1-yl) l) ' ' 27.7 -C(U)naphtlrl-vl -v -C(O)CH~CH2(napQr2-yl) lh(naphU~-(U)C
-C
l ' 27.8 -C(U)nrrphtlr2-vl -v .
.(O)CII~(narlUh- -C(U)CH2CH2(o-hiphenyl) -C
l ' 27.1 -C(O)~rbiPhenvl ) -C'.(U~H~CH2(m-biphenyl) 27.10-C(O)m-biphenyl l-12(crhirhcny CH2(p-biphenyl) -C(())( C(O)CH
-C(U)('l h(m-biphenyl) 27.12-C(O)p-hiphenyl -C(O)C112(p-biphenyl)2 27.13-C(O)o-PhOPh -C(O)CII2(o-l'h01'h)-27.14-C(U)tn-I'hOPh -C(U)Cl l~(m-I'hUPh-C(O)CH~CH2(crPhOPh) 27.15-C(U)p-PhOPh ) -C(U)CI-I2Ct-I2(m-PhOPh) 27.16-C(O)o-PhN1IP11 -C(U)CI1~(p-PhOPh)-C(U)CH2CH2(p-PhOPh) 27.17-C(O)m-PhNHPh -C(U)CH~(o-PhNI-IPh)-C(U)CH~CH2(o-PhNHPh) 27.18-C(O)p-1'hNHPh -C(U)CII~(m-PhNliPh)-C(O)CI-12CH2(m-PhNHPh) 27.10-C(O)o-PhSPh -C((CI-h(p-PhNI-II'h)-C(O)CH2CH2(p-PhNHPh) 27.20-C(O)m-PhSPh -ClU)CII~(crPhSPh)-C(U)CH2CH2(o-PhSPh) 27.21-C(U)p-PhSPh -C(U)CI-h(m-l'hSPh)-C(U)CII?CH~(m-PhSPh) 27.22-C(O)o-PhCH~SPh -C(U)CII?(p-I'hSPh)-C(U)CI-I2CII2(p-PhSPh) -C(())C'.Fl~lcrl'hC'II~SPh)-C(O)CH~CH~(o-PhCH~SPh) 27.23-C(U)m-1'hC112SP1r -C'.(U)C'.112(m-t'hCIV2S1'h-C(O)Cl-i?CH2(m-) PhCI I~SPh) 27.24-C(U)p-PhCII2Sl'h -C(U)CI1~(p-I'hCl-I~SI'h)-C(U)CIi~CH2(p-1'hCH?SPh) 27.25-c(orularri<~ntvl -C(())CI~I~(aclamlntyl)-C(U)ClI2C1-IZ(adamvttyl) 27.26-C(U)cvcloPentYl -('(O)Cll~(ryclopentyl)-C(U)CI-f2CH2((cyclopentyl) 27.27-C(U)cvclohexyl -C(O)Cll~(cvclohexvl)-C(O)CH~CH2(cyclohexyl) 27.28-C(U)CI1~0(cvclopcntvl)-C(O)CIhNIi(cvclopentvl)-C(U)CH~S(cyclopentyl) 27.20-C(O)Cl-I2U(cyclohexvl)-C(U)C'.II~NII(cyclohexvl)-C(U)Cli2S(cyclohexyl) 27.30-C(0)pyridin-2-vl -C(CCl h(pyrldin-2-yl)-C(U)CH~CH2(pyridin-2-yl) 27.31-C(U)pyridin-3-yl -C'.(U)C'I i2(pyndin-3-yl)-C(U)CH~CH2(pyridin-3-yl) 27.32-C(O)Pvridin-4-v_ -C(U)Cll~(pYri~lin-4-vl)-C(U)CI-i2CH2(pyridin-4-yD
27.331 -('(())C'.11~(fur~m-?-vl)-C(O)CFI2CH~(furan-2-yl) 27.34-C(U)furrn-2-vl -C'.(U)C'11?(furm-3-yl)-C(U)CH?CI-I2(furan-3-yl) 27.35-C(O)furan-3-vl -C(<))('lt~(U~iorhen-2-vl)-C(U)CH~CH~(thiophen-2-yl) 27.36-C(O)thiophcn-2-vl -('(())('II~(thiophc:n-2-vl)-C(U)CH2CH2(thiophen-2-yp 27.37-C(O)thiophen-2-vl -C'((Clh(irnida-ro-2-yl)-C(U)CH~CIU2(imidazo-2-yl) -C(O)imidwcr2-vl a a.~
SUBSTITUTE SHEET (RULE 26) 27.38 -C(U)oxazo-2-vl -C'(U)('l f~(oxaro-2-vl) -C'(U)CH~CrI2(oxazo-2-vl) 27.39 -C(O)Utioazo-2-vl -C'(U)('11~(thioazo-2-vl) -C(O)CIi~CH2(Utioazo-2-yl) 27.40 -C(U)henzolur<tn-2-yl -C(U)C'.112(tmnzoCutart-2-yl) -C(U)CI-I2CI-I2(benzofuran-2-vl) 27.41 -C(U)henzoCuratt-3-yl -C(U)C112(hc~nzoturut-3-yl) -C(U)CH2CH2(benzot'utatt-3-vl) 27.42 -C(O)henzothiophen-2-yl -C(U)C112(henzothioPhen-2- -yl) C(O)CI-I2CH2(benzothiophen-2-vl) 27.43 -C(U)UtioPhen-2-vl -C(U)CI h(UtioPhen-2-vl) -C(O)C>~I2CH~(thiophen-2-yl) 27.44 -C(O)benzimiJ<azo-2-yl -C(U)CI-I2(hcnzimicfazo-2-yl) -C(U)CH2CH2(benzimidazo-2-vll 27.45 -C(O)henzoxazo-2-yl -C(U)C'.II2(hcnzoxazo-2-yl) -C(O)CII2C1-I2(henzoxazo-1>
27.46 -C(U)lx:nznUti<vzo-2-yl -C(U)Cll2(henzoUtiatzo-2-yl) -C(U)CH2CH2(henzothiazo-2-vl) 27.47 -C(O)«-Ph(P(U)1'h~) -C'(<»m-!'h(l'(U )Ph3) -C(U)lt-Ph(P(U)Ph3) 27.48 -C(U)Ph-2-(Iluoren-9-vl) -('(())Ph-3-(llunren-9-vl) -('(U)Phli-(tluoren-9-vl) 27.49 -C(O)N-inJolin-2-one -('((»itulolin-2-vl -C'(U)inJol-2-vl 27.50 -C(U)C(CH3)2NI-ISU2(naphUt_ -C.(U)cyclolxntyl-2-(1'h) -C(U)cyclohexyl-2-(Ph) 2-vl) 27.51 -C(O)pyrrolidin-.3-y1.4-(1'h)- -C(U )tctrthydroCurtu-3-yl-4- -C(U)tetrthydrothiophen-3-yl_ (Ph) 4-lPh) 27.52 -C(U)tetrttitvdronalthUt-I-vl -C'(())tctrthvdronalthth-2-vl -C(U)cycloProPyl-2.2-(Ph2) 27.53 -C(OhetraUtydroivoquinolin-1-yl -C(U)tctrahydroisoquinolin-3- -C(U)CH2((2-oxo)indolin-3-yl vl) 27.54 -C(U)CII2(N-hcnzimiJazol-2- -C(U )CI12(N-hcnzoxazol-2- -C(U)CI-12(N-henzothiazol-2-one) true) one) 27.55 -C(O)CHI2(N-dihydroimiJazol- -C(U)CI h_(N-JihyJrcxtxazol-2- -C(O)C1~2(N-dihydrothiazol-2-2-one) one) one) 27.56 NCO- ~CO-O O
N I ~ N 1 w N 1 w ,l ~ , ~ i i 27.57 p 0 0 -OC~.NUNH -OCrNUO -OC~NUS
27.58 -OC p -OCl -OC O
~N . 1. ~N) tNUo N
~1 27.59 -C(U)N(C'I1~)Cll~l'h -C(())NlC'~fl;)('.lhl'h -('(U)N(C~1I7)CH~Ph 27.60 -C(U)Pyridin-3-yl-5-(I'h) -C(U)1'h-:i-(('112(UtioPh en-2- -C:(U)I'h-3-(CH2Ph) vl)) 27.61 -C(U)C(CI-I~)~()1'h -C'(U)CII(('~ll;)UI'h -C(U)CH2UCIi~Ph as s~
SUBSTITUTE SHEET (RULE 2fi) PCT/US94l11280 27.62 -C(OICI-I~U(o-I'liC'1-I~UIII -C'((»C,11~()(m-l'IW1-I~UII) -C'(O)CFI~U(P-PhCH20H) 27.63 -C(O)CII~O(o-1'hCUUI-I) -C(U)C112(Om-PWOUI1) -C(U)CI-I2U(r-PhCOOH) 27.64 -C(O)CH~U(o-I'hCUOC'.113) -C(C»C:lt?U(m-1'hCUOCI-I~) -C(U)CH~O(P-PhCOOCH3) 27.65 -C(U)CH2U(o-I'hCl12CU01-I) -C(U)C:II2UUn- -C(U)CFI2U(p-PhCH2COOH) PhCI hCU01 Il 27 .66 _ p C O
~NUo J
a SUBSTITUTE SHEET (RULE 26) Table 2828 Formula I : A =-B(pinanediol) ; X = -SC(=NII)N112 ; R3 = table hclow ; R11 = -CH2CH2Ph.
.l .2 .3 28.1 -C(O)Ph -C(U)C'.I (~Ph -C(O)CH~CH2Ph 28.2 -C(O)CH~OPh -C(O)CH~NUIPh -C(O)CH~SPh 28.3 -C(O)o-PhOH -C(())m-I'h01-I -C(O) -PhOH

28.4 -C(O)o-PhCIhOH -C(U)tn-PUCH~OI-I -C(O)p-PhCH?OH

28.5 -C(O)o-PhC001I -C(U)m-1'hC001I -C(O) PhCOOH

28.6 -C(U)o-PhCI-hCOOH-C(O)m-PhCH2CU0I-I-C(O)p-PhCH2COOH

28.7 -C(O)naphth-1-yl -C(U)CII~(naphd~-I-yl)-C(O)CH~CH~(napth-1-yl) 28.8 -C(O)nanhth-2-yt -C(O)CH2(naphth-2-yl-C(O)CH~CH2(napth-2-yl) 28.9 -C(O)o-biphenyl -C(O)CI-I~(~-biphenyl)-C(O)CH2CH~(o-biphenyl) 28.10 '-C(O)m-hiphenvl -C(U)CI1~(m-biphenyl)-C(O)CH2CH~(m-biphenyl) 28.12 -C(U)p-biphenyl -C(O)CI1~(p-biphenyl)-C(U)CI-I2CH2(p-biphenyl) 28.13 -C(O)o-PhOPh -C(U)CH~(o-I'hOPh -C(O)CH~CH~(o-PhOPh) ) 28.14 -C(O)m-PhOPh -C(O)CI-I~(m-I'hUPh)-C(O)CI-I~CI-I~(m-PhOPh) 28.15 -C(O)s-PhOI'h -C(U)CI-12(p-1'hOPh-C(U)CH2CH~(p-PhOPh) ) 28.16 -C(U)o-I'hNI-II'h-C(U)CI-I~(c~-I'hNIIPh)-C(U)CI-I2CI-I?(o-PhNHPh) 28.17 -C(O)m-1'hNiIl'h -C(O)CI12(m-1'hNI-IPh)-C(O)CH2CH2(m-PhNHPh) 28.18 -C(O)s-PhNIIPh -C(O)CI-I2(p-I'hNIiPh)-C(O)CH2CH2(p-PhNHPh) 28.19 -C(O)o-PhSPh -C(U)Cll~(o-PhSPh)-C(O)CH~CH2(o-PhSPh) 28.20 -C(O)m-PhSPh -C(U)CH~(m-PhSPh) -C(O)CH~CH2(m-PhSPh) 28.21 -C(O)p-PhSPh -C(U)CI12(p-PhSPh)-C(O)CH2CH2(p-PhSPh) 28.22 -C(O)o-PhCIi2SPh -C(U)CH2(o-I'hCH2SPh)-C(U)CH2CH2(o-PhCH2SPh) 28.23 -C(O)m-PhCH2SPh -C(O)CI-I2(m-PhC112SPh)-C(U)CH2CH2(m-PhCI-I2SPh) 28.24 -C(O)p-1'hCI-l2SPh-C(U)CII2(P-l'hC112SPh)-C(O)CI-I2CH2(p-PhCII2SPh) 28.25 -C(O)adarrtantvl -C' .(U)Cll~ladamantvl)-C(U)CH~CH~(adnmantvl) 28.26 -C(O)cyclopentvl -C(U)CII~(cvclopentyl>-C(O)CIi~CI-I~((cvclopentvl) 28.27 -C(U)cvclohexvl -C'(O)CII~(cvclohexvl)-C(U)CIi~CH2(cvclohexvl) 28.28 -C(U)CH~O(cvclopcntvl)-C'.(U)CII~N11(cvclcycntvl)-ClU)CI-12S(cyclopentyl) 28.29 -C(O)Clt2U(cvclohexyl)-C(U)CII~NII(cvclohexyl)-C(U)CH2S(cvclohexvl) 28.30 -C(O)pyridin-2-vl-C(U)CIi2(pyridin-2-vl)-C(O)Cl-I2CH2(pyridin-2-yl) 28.31 -C(O)pyridin-3-yl-C'(U)CI12(pyridin-3-vl)-C:(U)Cl-12CH~(pyridin-3-yl) 28.32 -C(O)pyridin-4-vl-C'(O)CIi~(pyriclin-4-vl)-C(O)CH2CH2(pyridin-4-vl) J

28.33 -C(O)furan-2-yl -C(U)CHZ(furan-2-vl>-C(O)CI~2Cli2(furan-2-vl) 28.34 -C(O)furan-3-vl -C(O)CIi2(furan-3-vl)-C(O1CH?C1~2(furan-3-yt) 28.35 -C(O)thiophen-2-yl-C(U)C112(Uiiophen-2-yl)-C(O)CH2CH2(thiophen-2-vl) 28.36 -C(U)Uiiophen-2-yl-C(U)C1I2(Utiophcn-2-yl)-C(O)CH2CI-12(Wiophen-2-vl) 28.37 -C(O)imidazo-2-_vl-C(O)CI1~(imiclazo-2-yl)-C(O)C1-I2CH2(imidazo-2-yl) 28.38 -C(O)oxazo-2-vl -C(U)C112(oxazo-2-yl)-C(O)CH2CH2(oxazo-2-yl) 28.39 -C(O)U~ioazo-2-vl-C(O)Cll~(U~ioarn-2-vl)-C(U)CH~CH~lthioazo-2-yl) aa~
SUBSTITUTE SHEET (RULE 26) ~1'~ X314 28.40 -C(O)henzofurm-2-yl -C(U)CIi2(henzofura~i-2-yl) -C(O)CH2CH2(henzofuran-2-vl) 28.41 -C(O)benzofuran-3-Yl -C(O)CH2(henzofuran-3-yl) -C(O)CH2CH2(benzofuran-3-v1) 28.42 -C(U)henzothioPhen-2-yl -C(U)CII2(hcnzothioPhen-2- -yl) C(O)CH2CH2(benzothiophen -2-vl) 28.43 -C(U)thiophen-2-yl -C(U)C1~I2(thiophen-2-yl) -C(O)CH2CI-I2(thiophen-2-vl) 28.44 -C(O)benzimidazo-2-yl -C(O)CH2(tx;nzimidazo-2-yl) -C(U)CH2CH2(benzimidazo-2-vl) 28.45 -C(O)henzoxazo-2-yl -C(U)ClI2(henzoxazo-2-yl) -C(U)C>-I2CH2(benzoxazo-2-vl) 28.46 -C(O)bcnzothiazo-2-yl -C(U)CI-l2(tx;nzothiazo-2-yl) -C(U)CH2CH2(benzothiazo-2-vl) 28.47 -C(U)o-Ph(P(O)Ph3) -C(U)m-Ph(P(O)Ph~l -C(O)p-Ph(P(O)Ph3) 28.48 -C(O)Ph-2-(fluoren-9-vl) -C'(U)Ph-3-(lluomn-~)-vl) -C(O)Ph-4-(fluoren-9-vl) 28.49 -C(O)N-indnlin-2-ona -C(U)indolin-2-vl -C(Ulindol-2-vl 28.50 -C(O)cyclopentyl-2-(Ph ) -C(O)cyclohexyl-2-(Ph ) C(U)C(C113)2NI-iS02(naphth -2-vl) 28.51 -C(O)pyrrolidin-3-yl-4-(Ph) -C(U)tctrahydroCuran-3-yl-~l- -C(U)tetrahydrothiophen-3-' (Ph ) vl~i-(Ph) 28.52 -C(O)tetrahvdron~Pluh-1-vl -C(U)tctrahvclrona~hth-2-vl -C(O)cycloproPyl-2.2-(Phi) 28.53 -C(O)tetralrydroiroquinolin- -C(O)tetr~hydroisoquinolin-3- -C(O)CH2((2-oxo)indolin-3 1-yl yl 1) 28.54 -C(O)CI-I2(N-benzimidazol- -C(U)CII2(N-hcnzoxazol-2- -C(U)CH2(N-benzothiazol-2-2-one) one) one) 28.55 -C(O)CH2(N- -C(O)CH2(N-dihydrooxazol- -C(O)CH2(N-dihydrothiazol-dihvdroimidazol-2-one) 2-one) 2-one) 28.56 rC0- ~CO-O
~ N O I ~ N ~ N
I ~ ~ ~~ ~ \ 1 i I i I
28.57 O O O
-OC''N~NH -OC~N~O -OC~N~S
28.58 -OC p _pC~ -OC O
IN . CN~ 1N110 /\ ~ N /\
~I
28.59 -C(U)N(Cll~)CI-hPh -C(U)I~T(C'~115)C117Ph -C(U)N(C3H7)CH2Ph 28.60 -C(U)PYriclin-3-yl-5-(Ph) -C(O)I'h-3-(Clt2(thioPhen-2- _C(U)Ph-3-(CH2Ph) vl)) 28.61 -C(U)C(CH~)20I'h -C(O)CII(C~I15)OI'h -C(O)CH20CH2Ph a~ ~
SUBSTITUTE SHEET (RULE 26) 28.62 -C(O)CIt~U(o-PhCI-I~UII) -(:(U)CIi~U(m-Pl'11~U31) -C(U)CIi~O(P-PhCH~OIi) 28.63 -C(O)CH20(o-I'hCOUIi) -C(O)CI-I~UIm-I'hC'.UUII) -C(U)Cl1?U(p-PhCOOH) 28.64 -C(O)CII~O(o-PhCUOCI-l~) -C(O)Cll~Ulm-PhCOOCI-I~) -C(O)C1i70(P-PhCOOCH3) 28.65 -C(O)CH20(o- -C(U)CI-I2U(m- -C(U)C1I2U(p-PhCH~CUOIi) PhCIi~C()Ol () PhCI-I~C'OOH) 28.66 -pC
~NRO
J
Table 29 Formula I : A = -B(pinancdinl) : X = -SC(=NI1)NI l~: R3 = table below ; R11 = -Ph.

l - '' .3 .~

29.1 -C(O)I'h -C(U)(:II~Pn -C(U)CI-l~Crl~l'h 29.2 -C(O)C)-I~UI'h -C'(CC1I~NIII'h -C'.(U)CII~S!'h 29.3 -ClU)o-PhOII -('(()lm-I'h(>II -C(( -1'hOI-I

29.4 -C(O)o-PhCII201I -C(Cm-1'hCII~UII -C(U)p-PhCH20H

29.5 -C(O)o-PhCOOI-I -C'(U)m-I'hC'001-I-C(C -PhCOOH

29.6 -C(U)o-PhCII~CUUII-C(U)m-I'hCII2CUOli-C(O)P-I'hCH2COOH

29.7 -C(O)napluh-1-vl -C(O)CI-1~(naPhUt-1-yl)-C(U)CI-I2CI~12(napdt-1-yl) 29.8 -C(O)naphth-2-yl -C(U)Cl-I~(naPhU~-2-yl-C(O)CHZCHZ(napth-2-yl) 29.9 -C(U)o-biphenyl -C(U)CII~(o-biphenyl)-C(U)CH~CI-I~(o-biphenyl) 29.10-C(U)m-biphenyl -C(())('1-I~(m-biphenyl)-C(O)CII2CH2(m-hiphenvl) 29.12-C(O)p-hiPhenyl -C(O)('.I-1~(P-biphenyl)-C(U)CI-I2CI-12(p-biphenyl) 29.13-C(U)o-l'hOPh -C(U)CII~(o-1'hUl'h)-C(U)CI-I?CH?(o-PhUPh) 29.14-C(U)m-PhOPh -C(U)C'll~(m-1'hOPh)-C(U)C1I~CH~(m-PhOPh) 29.15-C(U)p-l'h01'h -C(U)('.I-12(p-1'hUPh)-C(O)Cl-I~CH2(p-PhOPh) 29.16-C(U)o-PhNIIPh -C(O)CI1~(o-I'hNIiPh)-C(U)CIi~CII~(o-PhNHPh) 29.17-C(U)m-I'hNIIPh -C:(U)CII~(m-PhNIiPh)-C(O)CII~CH2(m-PhNHPh) 29.18-C(U)P-PhNHPh -C(U)('li~(P-1'hNI-IPh)-C(O)Cl-I?CH~(P-PhNHPh) 29.19-C(O)o-PhSPh -C(O)C'.11~(~-1'hSPh)-C(U)CI-I2CIi2(o-PhSPh) 29.20-C(O)m-PhSPh -('(())('tI~(m-PhSI'h)-C(U)CII~CII?lm-PhSPh) 29.21-C(U)p-PhSI'h -C:(U)C1I~(p-I'hSPh)-C(U)C'H~CH2(p-PhSPh) 29.22-C(U)o-PhCll2Sl'h -C(())('.II2(o-1'hC112SPh)-C(U)CH2CI-I2(o-l'hCIhSPh) 29.23-C(U)tn-1'hCII~SI'h-C(U)('.II~(m-l'hC'.112SPh)-C(U)Cli2Cli2(m-PhCII~SPh) 29.24-C(U)p-PhC112SPh -C'.(O )CII2(p-I'hClI2S1'h)-C(U)CI-I2CH2(p_ I'hCIi2SPh) 29.25-C(U)adamamvl -('(U)Cll~ladamantyl)-C(U)CH~CI-I2(adamantyl) 29.26-C(U)cvelopen tvl -C'(U)C'.I1~(cvrlopentvl)-C:(U)C1I~CH2((cvclopentyl) 29.27-C(0)cvclohexvl -C(())CII~(rvdohcxvl)-C(U)CII~CH~(cvclohexyl) 29.28-C(O)CII~U(cvrlopcntvl)-C(O)C11~NI1(cvclopemvl)-C(U)CIf~S(cvclopentvl) 29.29-C(O)C'1-I~U(cvclohexvl)-C(())C11~N11(rvclc>hexvl)-C(U)C11~S(cvclohexyl) 29.30-C(U)pYridin-2-vl -C'(())C'11~(Pyriclin-?-vl)-C'(O)C'.ll~CIIZ(pyridin-2-yl) ~ a e' SUBSTITUTE SHEET (RULE 26) 29.31 -C(U)PYridin-3-vl -C'(U)C'If~(Pyridin-3-vl) -C(U)CH~CH2(pyridin-3-yl) 29.32 -C(O)pyridin-4-v_ I -C'(U)C'I1~(pyridin-4-vl) -C(U)CI-I~CH2(pyridin-4-yl) 29.33 -C(O)furan-2-vl -C'(())('11~(furan-2-vl) -C(U)CII~CH?(furan-2-yl) 29.34 -C(O)furan-3-vl -C'(U)CI-I~(furan-3-vl) -C(U)CIi~CH~(furan-3-yl) 29.35 -C(O)thiophen-2-yl -C:(U)CI12(Utiophen-2-yl) -C(U)CH2CH2(Utiophen-2-vl) 29.36 -C(O)Utiophen-2-yl -C(U)CII2(Utiophen-2-yl) -C(U)CH2CH2(Utiophen-2-vl) 29.37 -C(Ulimidazn-2-v_ 1 -C(U)C'.li~(imidttzo-2-yl> -C(U)CH~CH~(imidazo-2-yl) 29.38 -C(U)oxazo-2-vl -C(U)Cli~(oxazn-2-yl) -C(U)CI-i~CH~(oxazo-2-yl) 29.39 -C(Olthiolzo-2-vl -C(U)CI1~(thioazo-2-yl) -C(U)CH2CH2(thioazo-2-yp 29.40 -C(U)henzot-uratt-2-yl -C(O)Cli2(bcnzofur~n-2-yl) -C(U)C>-12CH2(benzofuran-2-vl) 29.41 -C(O)hcnzofuran-3-yl -C(U)Cll~_(hcnzofur<m-3-yl) -C(U)CI-I2CI-I2(hcnzofutan-3-vl) 29.42 -C(U)henzoUtiophctt_2-yl -C(U )Clt2(tx;nzothiophen-2- -yl) C(U )CI12C1I2(henzothiophen -2-vll 29.43 -C(U)thiophen-2-y1 -C(U)C'If~_(Utiophcn-2-yl) -C(U)CIi2CIi2(Utiophen-2-vl) 29.44 -C(O)hcnzimidato-2-yl -CfU)C112(hcnzimidttzc>~2-yl) -C:(U)C132CFI2(benzimidazo-2-vll 29.45 -C(U)henzoxvo-2-yl -C(U)Cll2(hcnzoxazo-2-yl) -C(U)CI-I2CH2(henzoxazo-2-vl) 29.46 -C(O)henzothiazo-2-yl -C(U)C1I2(hcnzothiazo-2-yl) -C(U)C)-I2CH2(henzoUtiazo-2-vl) 29.47 -C(O)o-I'h(P(U )1'h3) -C(U)m-1'h(1'(())Ph3) -C(U)p-Ph(P(O)Ph3) 29.48 -C(U)Ph-2-(Iluorcn-9-vl) -('(())1'h-3-(fluctrcn-9-vl) -C(U)Ph-4-(Iluoren-9-vl) 29.49 -C(O)N-inclolin-2-one -C(())indotin-2-v1 -C(U)indol-2-vl 29.50 -C(U)cyclo~cntyl-2-(Ph) -C(O)cyclohexyl-2-(Ph) C(O)C(CI-I3)2N1 ISU2(naphUt -2-vl) 29.51 -C(U)pyrrolidin-3-yt-~.l-(I'h) -C(U)tctrahydrofuran-3-yl-4- -C(U)tetrahydroUtioplten-3-(Ph) vl-4-(Ph) 29.52 -C(U )tetr:UtydronaPhth-1-vl -C(())tctrthvdrcmaPhth-2-vl -C'(U
)cvclopropvl-2.2-(Ph2) 29.53 -C(U)teuwhydroiscxluinolitt- -C'(U)tcuwhydroisoquinolin-3- -C'(U)CII2((2-oxo)indolin-3 1-vl Yl vl) 29.54 -C(U)Cli2(N-hcnzimidazol- -C'.(())C'.112(A'-henzoxazol-2- -C'.(U)ClI2(N-henzoWiazol-2-2-one) one) one) 29.55 -C(O)CIU 2(N- -C'.(U)CI12(N-dihydrooxazol- -C(O)CI-12(N-dUtydroUtiazol-dihvdroimid~zol-2_one) 2-onc) 2-onel 29.56 NCO- ~CO-O
w N O l ~ N w N w I ~ ~ ~ / \ I ~ I i ~I
29.57 O O O
-OC'"N~NH -OC~N~O -OCrN~S
a~9 SUBSTITUTE SHEET (RULE 26) 29.58 -OC O -OCR -OC O
IN ~ I w CN1 1Nj10 /\ ~ N /\
~I
29.59 -C(O)N(CI-I3)C1I21'h -C(O)N(C2115)CI-I2Ph -C(U)N(C3H7)CH2Ph 29.60 -C(O)Pyridin-3-yl-5-(Ph) -C(O)t'h-3-(CI-12(thioPhen-2- -C(O)Ph-3-(CH2Ph) vl»
29.61 -C(O)C(CI-I3)2UI'h -C(O)CII(C?IIS)OPh -C(O)C)-I2OCIi2Ph 29.62 -C(O)CI-I2U(o-1'hCII2UlI) -C(U)CII~U(tn-I'hCH~UII) -C(U)CI-120(P-PhCH20H) 29.63 -C(O)CII~U(o-PhCOUH) -C(U)CII~O(m-I'hCUOH) -C(O)CI-I~O(P-PhCOOH) 29.64 -C(O)CH~U(o-PhCOUCIU~) -C(O)CII~O(m-I'hC'.OOCII~) -C(O)CI-I2O(P-PhCOOCH~) 29.65 -C(O)CI-I2U(o- -C(U)CII2U(m- -C(O)Cl-I20(P-PhCI-I~_COOH) PhCII2C'OUI1) PhCIi2COOH) 29.66 -p C O
~N~O
J
/ \
TaHle 30 Formula I : A = -B(Pinanediol) ; X = -SC(=NII)NI I2 ; R3 = table below ; Rll =
-CI-I2(naPhth-2-yl).

.1 .2 .3 30.1-C(O)Ph -C(O)C'.1121'h -C(U)CI~2CH2Ph 30.2-C(O)C>-I~OPh -C(())C1I~NIIPh -C(O)CI-I~SPh 30.3-C(O)o-PhOH -C(C))tn-I'hOII -C(U) PhOH

30.4-C(O)o-PhCII~UII -C(U)m-I'hC11~0I-I-C(U)P-1'hCl-I201-i 30.5-C(O)o-1'h('UOII -C'((m-I'h('()UH -C(( -Ph C'UOFI

30.6-C(O)o-PhCII~CO()IU-C(U )m-l'h('.II~CUUII-C(U)P-1'hC1-I~COOH

30.7-C(U)naPhth-I-vl -C'(U)('.l-I~(naPhU~-1-vl)-C'(U)CII~ChI~(naPth-1-yl) _ 30.8-C(U )naPhth-2-vl -C(U)('.II~(naPhth-2-vl-C(O)CH~C)-I~(naPth-2-yl) 30 -C(O)o-hiPhenvl -C(C))CI-1~(c~-hiPhcnvl)-C(O)CI~i~CI~~(o-hiPhenyl) ~) 30.10-C(O)m-hinhenyl -C(O)CII~(m-hiPhenvl)-C(O)CHI~CIl2(m-hiPhenyl) 30.12-C(O)P-hiPhenvl -('.(())CII~(P-hiPhcnvl)-C(U)CI-I2CI12(P-hiPhenvl) 30.13-C(O)o-1'hOPh -C(U)Cll~(o-t'hUPh)-C(O)CI-I2CH2(o-PhOPh) 30.14-C(U)m-Ph01'h -C'(())Cll~lm-I'hUl'h)-C(O )CH2CI-I2(m-Ph OPh) 30.15-C(U)P-Ph01'h -('(U)CIU~(P-PhUI'h)-C(O)C'.I-I~CH~(P-PhUPh) 30.16-C(U)o-PhNI-IPh -ClU)CII~(o-1'hNl-11'h-C(U )CH2C1-i~(o-I'hNHPh) ) 30.17-C'(O)m-PhNI-I1'h -('.(O)CII~(m-I'hNrll'h)-C(O)CH2CH~(m-1'hNHPh) 30.18-C(U)P-PhNIIPh -C'(<))C'1I~(P-l'hNlll'h)-C(U)CI12CI-I2(P-PhNI-IPh) 30.19-C(O)o-PhSI'h -C'(U)C'll~(o-t'hSl'h)-C(())C'.H~CI12(o-PhSPh) 30.20-C(U)m-1'hSl'h -('(U)C'II~(m-l'hSl'h)-C(U)CIhCH2(m-PhSPh) 30.21-C(UlP-I'hSl'h -C'(())C'II~(P-I'hSl'h)-C(U)CH~CI-I~(P-PhSPh ) 30.22-C(Oh~-PhCII~_SI'h-('.(U)C'll2(o-1'hC'II2SPh)-C(U)C112CH2(o-PhCI I~SPh) ~3v SUBSTITUTE SHEET (RULE 26) PCTlUS94111280 .~.». WO 95/09634 30.23-C(O)m-I'hC1i2S1'h-C(U)Cll~_(m-I'hC'112SPh)-C(O)CIi2CH2(m-PhCIi~SPh) 30.24-C(U)P-PhCH2SI'h -C'(U)C11?(P-1'hCH2SPh)-L(O)CI-I2CH2(P-PhCI-I~SPh) 30.25-C(U)adttmantyl -C'((C'li~(uclamantvl)-C'(U)CH~CHZ(adamantyl) 30.26-C(O)cvcloPentyl -C(U)Cll~(cyclo~cmvl)-C'(U)CIi~CH~((cvclopentyl) 30.27-C(O)cvclohexvl -C(()>C'IU ~(cvclcrhexvl)-C(U)Cl-i~CH~(cyclohexyl) 30.28-C(U)CII~U(cvcloPentvl)-C'.(U)CII~NII(cvclo~entvl)-C(U)CI-I2S(cvcloPentyl) 30.29-C(O)CI-I2U(cyclohexyl)-C(U)C1I~NII(cyclohexvl)-C(U)CI-I2S(cyclohexyl) 30.30-C(O)Pvridin-2-vl -C(U)C1I2(Pyridin-2-vl)-C(O)CH2Cli2(Pyridin-2-yl) 3031 -C(O)Pyridin-3-vl -C(U)C'>-I~(Pyri~iin-3-vl)-C(U)CH2CH2(pyridin-3-yl) 30.32-C(O)PYnUin-4-yl -C(U)CII~(Pyritlin-4-vl)-C'(U)CH~CH2(Pyridin-4-yl) 30.33-C(O)furan-2-yl -C(O)CII~(Curan-2-vl)-C(U)C11~CH~(furan-2-vl) 30.34-C(O)furan-3-yl -C'(UlC'I1~(Iurnn-:~-vl)-C(U)CI-I2CH2(furan-3-yl) 30.35-C(U)Urioph cn-2-yl-C(U)C112(UuoPhcn-2-yl)-C(U)CI-I2CI-i2(thioPhen-2-vl ) 30.36-C(U)thioPhcn-2-y1-('((>)('I1~_(tlucyhcn-2-yl)-C(O)Cl-I2C1-l2(UrioPhen-2-vl) 30.37-C(U)imiclazo-2-vl-('(())('.ll~(irniclazo-2-vl)-C(O)CI~I2Clt~(imidazo-2-yl) 30.38-C(O)oxazo-2-vl -('(())CI1~(oxaio-2-vl)-C(U)CH2CIi2(oxazo-2-yl) 30.39-C(U)thiozzo-2-v1 -C'.(U)Cll~(Uuoazt>-2-yl)-C(U)CII2CH2(thioazo-2-yl) 30.40-C(U)henzofuraa-2-yl-C(U)C112(tx:nzofurm-2-yl)-C(O)CH2CI-i2(henzofuran-2-vl) 30.41-C(O)henzofuratn-3-yl-C(U)CI-12(hc:nzoFuran-3-yl)-C(U)C1~2CH2(benzofuran-3-vl) 30.42-C(O)henzoUrioPhen-2-yl-C(U)CII2(henzothioPhcn-2--yl) C(O)CH2CH2(benzothiophen -2-vl) 30.43-C(U)Uriophen-2-yl-C(U)C'l12(thioPhen-2-yl)-C(U)Chi2C'I-12(thiophen-2-vl) 30.44-C(O)hcnzimicJazt>2-yl-C(U)C'112(tx:nzimidazo-2-yl)-C(O)C1-l2Cli2(henzimidazo-2-vl) 30.45-C(U)hcnzoxazo-2-yl-C(U)CII~_(hcnzoxw-_c-2-yl)-C(U)CI-I2CH2(benzoxazo-2-vl) 30.46-C(O)henzothivo-2-),I-C(U)C'II~_(henzothiazo-2-yl)-C(U)CI-I2CH2(benzoUii~zo-2-vl) 30.47-C(O)o-1'h(1'(U -C'((m-1'h(1'(U)1'h3)-C(O)P-I'h(P(O)Ph3) )1'h3) 30.48-C(UIPh-2-(Iluoren-~)-vl)-C'(())1'h-;-(Iluc~r<n-cJ-vl)-C'(U)i'h-4-(tluoren-9-vl) 30.49-C(U)N-intictlin-2-orn-('(())intlolin-2-vl-('(U)indol-2-vl 30.50 -C(U)cycloPcmyl-2-(Ph)-C(U)cyclohexyl-2-(Ph) C(O)C(CIi3)2NI
ISU2(naPhUr -2-vl ) 30.51-C(U)Pyrrolidin-3-yl-4-(l'h)-('((>)tctrahytirofur:m-3-yl-4--C(U)tctrahydrothiophen-3-(1'h) vl-4-(Ph) 30.52-C(U)tetrW vdron~Phtlr-1-vl-('(())tctrahvtirotutPluh-2-vl-C(U
)cvcloproPyl-2.2-(Ph2) 30.53-C(O)tctrahydroisotluinolin--C'(())tctrahytlrc~ic<xpinnlin-3--C(O)CI-i2((2-oxo)indolin-3-1-vl vl vl) 30.54-C(U)CIl2(N-hcnzimiUazcrl--C(U)('.11~(A~-hcnroxazol-2--C(U)CI12(N-henzoUriazol-2-2-one) one) one) 30.55-C(O)C112(N- -C'.(())C'lt~_(N-~iihy~rooxazol--C'(U)CI-I~(N-clihydroU~iazol-dihvclroitnitla~ol-?-one)2-one) 2-one) air SUBSTITUTE SHEET (RULE 26) WO 95/09634 ~ ~ ~ ~ j ~ ~ PCTlUS94111280 3o.s6 ~co- ~co- ~ o N l ~ N I w N l w ' ~' i i 30.57 p O O
N~
_OC~- N H -OC~ NCO -OC~ NHS
30.58 -OC p -OCR -OC 0 ~N ~ t ~ CNJ tNuO
/~
N
~I
30.59 -C(o)N(CI1~)CII~1'1, -C((»N(('~II~)cnl~ln, -CCU)N(C~I-i,)cll~Ph 30.60 -C(U)Pyridin-3-yl-5-(t'h) -C(U)1'h-;-(C'.Il~(thioPhcn-2- -C'(U)1'h-3-(CI-f2Ph) vl)) 30.61 -C(O)C(Cll~)~Ul'h -C(<»C'I1(C'~I15)UI'h -C(U)CI-I?UCH~Ph 30.62 -C(O)CHI~O(o-PhCII~OI-I) -('(O)Cll~()(m-I'hCII~OH) -C(O)CIi~U(p-PhCH20H) 30.63 -C(O)CI-I~U(o-1'hCUOH) -C(O)CII~U(m-I'hCOOII) -C(O)C112U(p-PhCOOH) 30.64 -C(O)C1I20(o-1'hCUUCIt3) -C(O)CII~O(m-I'hCOOCI-13) -C(O)CH20(P-PhCOOCH3) 30.65 -C(O)CH2U(o- -C(U)CI12U(m- -C(U)CI-I2U(p-PhCH2COOH ) PhCI I ~COOI-1 ) PhCI-h COON) 30.66 -OC O
~NUo J
1) Formula II : A = -B(UH)2 ; \ = gu<u,idinyl : Y = tahle helow.
.I 2 .3 31.1 -C(U)C1I2(N-hcnzirnidazol- -C'.(O)('.ll~_(N-hcnzoxazol-2- -C(U)C112(N-henzoU,iazol-2-2-one) onc) one) 31.2 -C(O)CI-12(N- -C(U)CII_~(N-Jihydrooxazol- -C(O)CI-I2(N-dihydrodiiazol-dihvdr~imidazc,l-2-one) 2-onc) 2-one) 31.3 ~co- ~co- ~ o N t~ N 1wN 1w i i ~-3 a SUBSTITUTE SHEET (RULE 26) ~1"~4314 WO 95109634 ~ PCTlUS94/11280 31.4 O O O
a -OC~ Nu N H -OC~ NCO -OC~ N
31.5 -OC O -OCR _OC O
~N i w CN1 1N~0 JI
/v ~ N /v 31.6 .OC O -OC O
~ N p ~ N JO
a 33 SUBSTITUTE SHEET (RULE 26) WO 95109634 PCTlUS94/11280 ~1'~4~~~
ah Formula II : A = -B(OH)2 ; \ _ -C1-I2NI I~ ; l' = table below.
.1 2 .3 32.1 -C(O)CH2(N-benzimidazol- -C'(U)C112(N-bcnzoxazol-2- -C(O)CH2(N-benzothiazol-2-2-one) one) one) 32.2 -C(O)CH2(N- -C(O)C1I2(N-dihydrooxazol- -C(O)CH2(N-dihydrothiazol-dihvdroimidazol-2-one) 2-one) 2-one) 32.3 ~co- ~co-N ! ~ N y N y ,1 ~ ,~ i i 32.4 O O O
-OC~N~NH _OC~N~O -OC~N~S
32.5 -pC O -OCR -OC O
~N ~ .I. CNJ tNuO
/\ U
N
~I
32.6 -OC O
~NUo J
/ \
Table 33 Formula II : A = -B(OlI)2 : \ _ -SC(=NI I)NI I2 ; Y = table below.
.1 .2 .3 33.1 -C(O)CH2(N-bcnzimidazol-2- -C(U)C1I~(N-benzoxazol-2- -C(O)CH2(N-benzothiazol-2-one) one> ~ one) 33.2 -C(O)C1I2(N-dihydroimitlazol- -C'.(U)C112(N-~lihydrooxazol- -C(U)CH2(N-dihydrothiazol-2-one) 2-one) 2-one) 33.3 ~co- ~co- ~ o N O N O
~ N
i i a~~
SUBSTITUTE SHEET (RULE 26) 34 ~ 17 4 31 ~ pCT/US94111280 .1 L .3 34.1 -C(O)CH2(N-bcnzimidazol-2- -C(U)CII~(N-bcnzoxazol-2- -C(U)CI-I2(N-bcnzothiazol-2-one) one) onel 34.2 -C(O)CfI2(N-dihydroimidazol- -C(U )CI12(N-dihydrooxazol- -C(O)CH2(N-dihydrothiazol-2-one) 2-one) 2-one) 34.3 rC0- ~co- ~ o N O l ~ N O ~ N w i il ~ / 1 li 34.4 0 0 0 -OC''NUNH -OC~N~O -OC~N~S
34.5 _OC O -OCR -OC O
~N . I. ~N~ ~NUo N /~
~I
34.6 _OC O
~NUO
J
a 3s 33.4 O O O
a -OC~.N~NH -OC~N~O -OC~N S
33.5 -OC p -OCR -OC O
IN CN_ ~NxO
,i N
~I
33.6 -OC O
~NUo J
Table 34 Formula II : A = -B(pinmecliol) ; X = guanidinyl ; Y = table below.
SUBSTITUTE SHEET (RULE 26) WO 95/09634 ~ , PCTIUS94/11280 Table 35 Formula II : A = -B(Pinanediol) ; X = -CI I~NI I2 : Y = t~~hlc hc:low.
.1 2 .3 35.1 -C(O)CH2(N-hcnzimi~:uol-2- -C(WCII2(N-hcnzoxazol-2- -C(O)CH~(N-benzothiazol-2-one) one) one) 35.x -C(U)C>-f~(N-dihydrc~imich~zc71- -C'.(O)CII?(N-~iihyclrooxazc~l- -C(0)CI°I2(N-dihydrothiazal-2-onel 2-one) 2-one) 35.3 rC0- NCO- ~ p N
1 ~ ~ ~ / \ I ~ I ~
~I
35.4 -OC~ Nu N H -OC~ NCO -OC~N~S
3$~5 -OC O -OCR -OC O
IN ~ I ' CN~ 1N110 /\
N
35.6 -pC O
~NUo J
Table 36 Formula II : A = -B(Pin<mediol) ; X = -SC'(=Nl I)NI I~ : Y = gable below.
.1 ? .3 36.1 -C(U)C1I2(N-benzimicl~ot- -('(U)CI1~(N-hcnzoxazol-2- -C(U)CIi2(N-henzothiazol-2-2-onc) onc) one) 36.2 -C(U)CH2(N- -C(U)CII~_(A'-dihydrooxazol- -C(U)CIi2(N-dihydrothiazol-dihvdroimicl~~ol-2-onr) 2-onc) 2-one) 36.3 rC0- rC0-N O ! ~ N O N
I~ ~I / \ I~ I~
a3~
SUBSTITUTE SHEET (RULE 26) WO 95109634 PCTlUS94l11280 36.4 O O O
a -OC''N~NH -OC~NUO -OC~N
36.5 -OC O -OC1 -OC O
IN / i ' CN1 1N110 \ ~ NJ / \
~1 36.6 _ O C O
~NxO
J
/ \
SUBSTITUTE SHEET (RULE 26) ~1 ~4~~ ~
WO 95109634 PCT/~JS94I11280 Formula III : A = -B(OI-I)2 : X = -CN : R3 = t~~hle below : RI I = CI-13 .1 ~ ~ .,~
, 37.1 -C(O)Ph -C(U >CII~Ph -C(O)CH2CH~Ph 37.2 -C(O)CH~OPh -C(U)CII~NIII'h -C(O)CH2SPh 37.3 -C(O)o-Ph0lI -C((>)m-1'hUII -C(U) -PhOH

37.4 -C(U)o-PhCH20II -C(U)m-PhCI hUl1 -C(U)P-PhCH20H

37.5 -C(O)o-PhCUOI-I -C((m-PhC'OUII -C(U) -PhCOOH

37.6 -C(Okt-PhCH~COUH -C(U)m-1'hCII~CUUH-C(U)P-PhCH2COOH

37.7 -C(O)naPhth-1-yl -C(U)Clh(naPhUt-1-yl)-C(O)CfI~CH~(naPth-1-yl) 37.8 -C(O)naphUt-2-yl -C(U)CII~(narhth-2-vl-C(O)CIi~CH2(napth-2-vl) 37.9 -C(O)o-hiPhenyl -C(O)C112(o-biphenyl)-C(U)CH~CH~(o-hiphenvl) 37.10-C(O)m-hiPhenvl -('(U)CI h(m-hiPhenvl)-C(O)Cl-hCH2(m-biphenyl) 37.12-C(O)P-hiPhenyl -C(U)Cl-12(P-hiPhenyl)-C(O)CI-I2CH2(P-biPhenvl) 37.13-C(O)o-PhUPh -('.(U)CII~(o-I'hUPh)-C(U)CIi~CH2(o-PhOPh) 37.14-C(O)m-Ph01'h -C(U)C1I~(m-Ph01'h)-C(U)CH~CH?(m-PhOPh) 37.15-C(U)s-PhOPh -C'(U)CII~(P-l'hUl'h)-C(U)CH2C1-I2(p-PhOPh) 37.16-C(Ukt-PhNHPh -C(O)C1I~O-I'hNIIPh)-C(U)CH~CH2(o-PhNHPh) 37.17-C(U)m-PhNI-IPh -('(U )CII~(m-t'hNhIPh)-C(O)CI-12CH2(m-PhNHPh) 37.18-C(U)P-PhN)-IPh -C(U)CII~(P-PhNIII'h)-C(U)CH2CH2(P-PhNHPh) 37.19-C(O)o-PhSPh -C(U)CI1~(o-1'hSPh-C(U)CIi~CH~(o-PhSPh) ) 37.20-C(O)m-PhSPh -C(())C11~(m-I'hSPh)-C(U)CH~CH~(m-PhSPh) 37.21-C(O)P-PhSPh -C(U )C112(P-PhSPh)-C(U)CH~CH2(P-PhSPh) 37.22-C(O)o-PhC112SPh -C(U)C)12(o-I'h('.112SPh-C(U)CH2CH2(o-) PhCH~SPh) 37.23-C(U)ni=1'ht.l-I2S1'h-C(t_5)C1I'2(t5i-1'1iC112S1'ly)-C(())Cll2Cli2(m-PhCII2SPh) 37.24-C(O)p-PhCII2SPh -C(U)Cl-12(P-PhC112SPh-C(U)C1I2CH2(p-) PhGli2 S Ph ) 37.25-C(U)adamantyl -C'(U)CII~(acl:un:uttvl)-C(O)CIhCH~(adamantyl) 37.26-C(O)cycloPentvl -C'(CCIh(cvcloftentyl)-C(O)Cli2CI-I2((cvcloPentyl) 37.27-C(U)evclohexyl -C'.(<))t:'11~(cvclohexvl)-C(O)CH?CIi2(cvclohexvl) 37.28-C(U)C)-I~O(cvclctPcntvl)-('.(U)C'IhNIIlcvrhtPcntvl)-C(U)CII~S(cvciopentvl) 37.29-C(O)('.I-hU(cvclohexyl)-C'(U)('.Ii~Nli(cvclohexvl>-C(U)CI12S(cyclohexvl) 37.30-C(U)Pyridin-2-vl -C(O)CII~(ItYtidin-2-vl)-C(U)CI-I?CH2(Pytidin-2-yl) 37.31-C(U)PyriUin-3-yl -C(U)CI12(PYridin-3-vl)-C(U)CI-hC132(PYndin-3-yl) 37.32-C(U)Pvridin-4-yl -C(())CII~(Pyriclin-4-vl)-C(U)CH~CH2(Pyridin-4-yl) 37.33-C(O)fttrut-2-yl -C(U)CII~(lurut-2-yl)-C(U)CH~CI-I2(furan-2-yl) 37.34-C(O)furan-3-vl -C(U)Cll~(turan-3-vl)-C(O)CII2CH2(futan-3-vl) 37.35-C(U)UtioPhen-2-vl-C'(U)('.ll~(UuoPhen-2-yl)-C(O)CH2CH2(thioPhen-2-yl) 37.36-C(O)thiophen-2-vl-C(U)Cll~(UtioPhen-2-vl)-C(U)CH2CH2(thiophen-2-yl) 37.37-C(U)itniduzo-2-yl-C(U)C'l h(itnidazo-2-yl)-C(U)CH~CH2(imidazo-2-yl) 37.38-C(O)oxazo-2-vl -C(U)C'.Ih(oxaro-2-vl)-C(U)CI-hCH2(oxazo-2-yl) 37.39-C(O)Utictazo-2-vl-C((.>)C'II~(Uticrtzo-2-vl)-C(U)(:1-hCI-I2(lhioazo-2-yl) 37.40-C(U)henzofurnn-2-Yl-C(O)C112(hcnzolutan-2-yl)-C(U)CH2Chi2(henzoftuan-2-~sl) 37.41-C-(U)h~;nzotur<tn-3-YI-C'((J)('II9(hcnxofuvtn-;~-Yf)-C(())C'.I-IZCl~2(bt;naotut~rt-3-vl) a3$
SUBSTITUTE SHEET (RULE 26) 37.42 -C(U)henzotltio~hen-2-yl -C'(U)C112(hrnzothioPhcn-2- - -yl) C(U)CI-12CH2(benzothiophen -2-vl) 37.43 -C(U)tltioph en-2-yl -C(O)CI I~(thiolthcn-2-vl) -C(O)CH~CI3~lthiolthen-2-yl) 37.44 -C(O)tx:nzimidazo-2-yl -C(U)CII~(hcnzimic)azo-2-yl) -C(O)CH2CH2(henzimidazo-2-vll 37.45 -C(U)hcnzoxazo-2-yl -C(O)Cll2(hcnzox~tzo-2-yl) -C(0)CH2CH2(benzoxazo-2-vl) 37.46 -C(O)henzothiuzo-2-yl -C:(O)Cl-i2(hcnzothit~zo-2-yl) -C(O)CI-I2CH2(benzothiazo-2-vl) 37.47 -C(O)o-Ph(P(O)Ph~) -C(U)m-Ph(1'(U)Ph3) -C(U)P-1'h(P(O)Ph3) 37.48 -C(OIPh-2-(Iluoren-9-vl) -C'(O)Ph-:l-(tlnorcn-9-vlt -C(())I'h-4-ltluoren-9-vl) 37.49 -C(O)N-indolin-2-one -C(Ulitxltttin-2-vl -C(())indol-2-vl 37.50 -C(U)cyclopcntyl-2-(1'h) -C(O)cyclohexyl-2-(Ph) C(O)C(CF~I3)2M~SU2(naphth -2-vl) 37.51 -C{O)pyirolidin-3-yl-4-lPh) -C(U)tcunhydrulurm-3-yl-:l- -C(U)tcuahydroUtioPhen-3-yl-(Ph ) 4-(Plt) 37.52 -C(O)tetrattvdmnaPhtlrl-vl -C(O)tctrattvclrctn,yhth-2-vl -C(U)cycloProPyl-2;1-(Ph2) 37.53 -C(U)tetrahydroisoquinolin-1- -C(U)tctrahydroiu>yuinolin-3- -C(O)CI-12((2-oxo)indolin-3 vl Yl vl) 37.54 -C(U)CH2(N-hcnzimiduzol-2- -C'.(U)C:ll~_(N-hcnzoxazol-2- -C'.(U)CI12(N-hcnzathiazol-2-<me) onel one) 37.55 -C(O)C112(N-dihydroimidazol- -C'.((>)C'.112(N-dihyclrcx~xazol-2- -C(U)CI-12(N-dihydrothiazol-2-one) one) 2-one) 37.56 rCp- ~CO-N O I ~ N O w N w i i I ~ / ~ I i I i 37.57 O O O
-OC''NUNH -OC~N~O -OC~N~S
37.58 -OC O -OC1 -OC O
~N . 1. ~N~ ~NUo N
~I
37.59 -C(O)N(CII~)CI~I~I'h -C(U)N(C'.2115)CIh1'h -C(O)N(C3I-t7)CH2Ph 37.60 -C{U)Pyudin-3-yl-5-(Ph ) -C(U)I'h-3-(CI12(tltioPhcn-2- -C(U)I'h-3-(CI-I2Ph) vl)) 37.61 -C(U)C(CHI~)~Ul'h -C(())('ll(('~115)UPh -C(O)Cl-hOCI-l2Ph 37.62 -C(O)C112U(o-1'hCll~Oll) -('(())Cll~<)(m-I'hC11~01I) -C(O)C'.1-I~O(P-PhCH20H) 37.63 -C(O)('.1I~<)(o-1'h('OUII) -C'(U)Cll~c>tm-I'hC'UUII) -C(U)C'H~U(p-PhCUOH) 37.64 -C(0)C11~U(o-1'h('U(X'.II~) -('(())C'II~()lm-l'ItC'OU(:11~) -ClU)CI-I2U(It-I'hC00CH3) 37.65 -C(U)CI12U(o-1'hCII2COUII) -C'(())C112U(tn- -C(U)CI12U(p-PhCli2COOH) 1'h C'11~C'UOl I) a39 SUBSTITUTE SHEET (RULE 26) WO 95109634 ~ 17 4 3 .t ~ PCT/US94I11280 37.66 -O C O
~N~O
J
/ \
Tahle 38 Formula III : A = -B(OIi)2 ; X = -CN ; R3 = tahle below ; R11 = -CI-I2CH2Ph.
.1 ~ .3 .~

38.1 -C(O)Ph -C(U)Clhl'h -C(O)CH~Cri2Ph 38.2 -C(O)CH~UI'h -C(U)C1 hNlil'h -C(U)CI-i~SPh 38.3 -C(O)o-PhOII -C((m-1'hUll -('(U) -PhUH

38.4 -C(O)n-PhCtl~Oti -C(U)rn-PICII~OII-C(U)p-PhCI-I2UH

38.5 -C(U)o-PhCU011 -C(( m-I'h('( -C(U) -I'h COOH
)( )11 38.6 -C(U)o-PhCli~('()Ol-I-C(U)m-I'h('11~C'UOIl-C(O)p-PhCI-hCOOH

38.7 -C(U)n.yhth-I-vl -C(U)('Il~(n,yhth-I-vl>-C(O)CH~CH~(napU~-1-vl) 38.8 -C(O)naPhtlr-2-vl -('(U)CII~(nylUh-2-vl-C(O)CI-i~CH~(napth-2-yl) 38.9 -C(U)o-bi~henvl -C'.(U)C112(o-hi~henvl)-C(U)CI-hCH2(o-biPhenvl) 38.10-C(U)m-bi henyl -C'.(C))CII~(mhiphcnyl)-C(U)CH~CH~(m-hi hsdnyl) 38.12-C:(C33t~-3~tisi~c~sY1_~=((~)CII'~(fr -Cf(~3C~t~CH~(P-I~iPI~e~~I) hiF~t~cr~vl) 38.13-C(4)o-1'hC)Ph -C'(O)tal~(c~-i'lrUl'h)-C(C))C'.)'hCN2(o-PhbPh 38.14-C(U)m-PhOPh -C'.(U)C'.ll~(m-1'hOPh)-C'.(U)CI1~CI-I2(m-PhOPh) 38.15-C(U)P-PhUPh -C(U)C112(P-PhUPh)-C(U)CI-hCI-12(P-PhOPh) 38.16-C(U)o-I'hNI-II'h -C(U)('II~(o-1'hlVlll'h)-C(U)CH~CH2(o-PhNHPh) 38.17-C(U)m-PhNIIPh -C(U)CIIZ(m-PhlYI-1Ph)-C(U)CH2CII2(m-PhNHPh) 38.18-C(U)P-PhNHPh -C(O)Cll~(P-I'hNIIPh)-C(U)C1~2C1~2(p-PhNHPh) 38.10-C(O)o-PhSPh -C(U)CI-I2lo-I'hSPh)-C(U)CH~CH2(o-PhSPh) 38.20-C(U)m-I'hSPh -('.(O)Cl l~(m-f'hSPh-C(O)CH~CH~(m-PhSPh) ) 38.21-C(U)P-PhSPh -C(())C'lI~(P-I'hSPh)-C(U)CI-i~CH~(P-PhSPh) 38.22-C(U)o-PhCII~SPh -('l())('II~(o-1'hCl-I~S1'h)-C(O)CH~CIh(o-PhCH25Ph) 38.23-C(U)m-1'hCl-i2SPh -C(U)('.II2(m-1'h('.11251'h)-C(U)CH2CH2(m-PhCH~SPh) 38.24-C(O)(~-PhCI-I~SPtr-C'(())('11~(~-1'hC'.II~SPh)-C(U)CIf~CI-I~(p-PhCI-i~SPh) 38.25-C(O)adamantvl -C(())('.II~(ad.unantyl)-C(())CI-12CI-i2(adnmantyl) 38.26-C(U)cvclorcmvl -('(<>)C'.11~(cvrlo~Cmvl)-C(O)Cli~C1-I~((cycloPentyl) 38.27-C(U)cvclohcxvl -('.(())('11~(cvclohcxvl)-C(O)CIi~CFi~(cyclohexyl) 38.28-C(O)('.11~0(cyclo~entvl)-('(())('II~IVII(cvcloPentvl)-C(U)CI-I~S(cvcloPentyl) 38.29-C(O)CIi20(cvclohexvl)-(:((>)CII~NII(cvclohexyl>-C(U)CI-hS(cvclohexyl) 38.30-C(U)Pytidin-2-yl -('.(U)Cl h(Pyridin-2-vl)-C(O)C>-I~CH2(Pyridin-2-yl) 38.31-C(O)(~yridin-3-vl -('.(())C'.lhlPyridin-3-yl)-C(U)CH~Cfi?lPvridin-3-yl) 38.32-C(U)Pvridin-4-vl -C(U)CII~(Pyriclin~l-vl)-C(U)CIhCH2(Pyridin-4-yl) .

38.33-C(U)furan-2-vl -C'.(U)CII~(furut-2-yl)-C(U)CH~CH2(furan-2-yl) 38.34-C(U)furan-3-vl -('(())('11~(Im<m-3-vl)-C(O)CI-i~CH~(furan-3-yl) 38.35-C(U)thiophcn-2-vl -('(())('Il~(tl~ioPhcn-2-yl)-('(U)CII~CI-I~(thioPhen-2-yl) 38.36-C(U)tJtio~hen-2-yl-(,((>)('ll~(thio~hen-2-vl)-C(O)CI12CH~(thioPhen-2-yl) 38.37-C(U)imidaro-2-vl -C'(())('.ll~(irnici;~zo-2-vl)=C(U)CI-hCHZ(imidazo-2-yl) -38.3x-c(on~x~>7r~-~_vl -c(())Cll~(a~<~.r,-2-vl>-c(U)cH~crl~(oxaZO-2-yn aya SUBSTITUTE SHEET (RULE 26) ~1'~43I~
WO 95!09634 , , PCT/US94111280 38.39 -C(U)Uiin;tzo-2-vl -C'(C))C112(Uuoa7o-2-yl) -C(U)C1I~C1-i2(U~ioazo-2-yl) 38.40 -C(U)tK'ilZOlllIiln-2-yl -C:(O)C1I~_(tx:nzofurv~-2-yl) -C(U)Cl-I2CH2(benzofuran-2-vl) 38.41 -C(O)hc:nzofurtn-3-yl -('(U)CII2(hcnzolurut-3-yl) -C(U)C1U
2CH?(henzofutan-3-vl) 38.42 -C(O)henzotltioPhen-2-yl -C(O)CI12(hcnzothioPhen-2- -yl) C(O)CH2CH2(benzothiophen-2-vl) 38.43 -C(O)thio~hen-2-Y1 -C(O)C1I~(U~ioPhen-2-yl) -C(O)CI-I2CH2(U~ioPhen-2-yl) 38.44 -C(O)henzimidazo-2-yl -C(U)Cli2(lxnzimidazo-2-yl) -C(O)CH2CH2(benzimidazo-2-vl) 38.45 -C(O)henzoxazo-2-yl -C(U)CII2(henzoxazo-2-yl) -C(O)CH2CH2(benzoxazo-2-vl) 38.46 -C(U)hcnzoU~iazo-2-yl -C(U)CI12(benzoU~ilzo-2-yl) -C(O)CH2Cl-!2(benzothiazo-2-vl) 38.47 -C(U)o-Ph(P(U)!'h~) -C:(C»m-1'h(I'(U)I'h~> -C(O)P-PtOP(O)Ph3) 38.48 -C(O)Ph-2-(fluorcn-c)-vl> -('lC»I'h-:l-(Ilu~ren-9-vl) -C(OIPh-4-(fluoren-9-vl) 38.49 -C(O)N-inclolin-2-one -C'(())indolin-2-vl -C(U)inclol-2-vl 38.50 -C(U)C(C1I3)2NIISU2(naPhth- -('(U)cyclolxnt)~l-2-(l'h) -C(U)cyclohexyl-2-(Ph) 2-v»
38.51 -C(U)PYrn~lidin-3-yl-4-(1'lO -C(U)tctrahydrofumn-3-yl-4- -C(O)tetrahyciroU~iophen-3-yt_ (Ph) 4-(Ph) 38.52 -C(O)tetr:~hydronaphUr 1-vl -C(U )tetrthvclronaphth-2-vl -C(U)cyclorroPyl-2.2-(Ph2) 38.53 -C(O)tcirahydroisoquinolin-1-yl -C'(U)tctrahydmiccxluinolin-3- -C(U)CI-I2((2-oxo)indolin-3-yl vl) 38.54 -C(U)C12(N-henzimidazol-2- -C(U)CII2(N-hcnzoxvol-2- -C(O)C1-12(N-henzothiazol-2-onel one) one) 38.55 -C(O)C132(N-JihydroimiUazol- -C(U)CII2(N-dihydrooxazol-2- -C(U)CH2(N-dihydrothiazol-2-2-one) one) one) 38.56 rCp-- rC0-O
I~ N O ! ~ N ~ N
38.57 O O O
-OC~.N~NH -OC~NU0 -OC~N~S
38.58 -OC O -OC, -OC O
IN / I ' CN~ lNllO
/v ~ N /\
~I
38.50 -C(O)N(CII~)C'112Ph -C(U)N(C'311;)C112Ph -C(U )N(C31I7)CH2Ph 38.60 -C(O)Pvridin-;-yl-5-(Ph) -C:(())l'lr3-(Cll_~(thioPhcn-?- -C(O)Ph-3-(CH2Ph) vl)) 38.61 -C(O)C'(CI1~)~<)l'U -C'((»CII(C.~I15)OI'h -C(U)CI-12UCI-I?Ph 38.62 -C(U)CH~()(o-l'lO'll~()11) -C'l())C'I1~(>(m-1'hC'II~UII) -C'(U)CIhU(P-PhCII201-I) 38,63 -C(U)C(-I~U(o-I'h('()UII) -('(())C'II~U(m-l'h('U()II) -C'lU)CH~U(r-PhCUOH) a ~~
SUBSTITUTE SHEET (RULE 26) WO 95/0963 PCT/US9:1/11280 38.64 -C(0)Cl-I~U(o-1'hC'OUCI1~) -C'(U)CII~UIm-l'hC',U()C'II~) -C(U)CIhU(p-1'hC0(~H3) 38.65 -C(O)CI12U(o-I'hCII2COUl1) -C(U)CI12U(m- -C(U)CH2U(p-PhCH2COOH) PhC'11~C'UUI I) 38.66 . p C p ~NUO
J
/ \
h 9 Formula III : A = -B(0II)2 ; a = -CI-i2NI l2 ; R3 = table below ; Rl l = CI-I3 .1 2 .3 .

39.1 -C(O)Ph -C(U)('I1~1'h -C(U)CH2CH2Ph 39.2 -C(O)C1I~OPtt -C((7)C'I1~N111'h -C(U)CI-hSPh 39.3 -C(U)o-Ph011 -C(())m-1'hUl-1 -C(U) PhOH

39.4 -C(U)o-1'hCll~Ul1-C'(())m-t'hCll~01-I-C'(U)p-l'hCH~OH

39.5 -Cl0)o-I'hCOUI -Cl( m-1'hCU(71V -C(( -I'hCOOH
I

39.6 -C(O)o-f'hCH~C'0011-ClU)m-PUCIf~COUFi-C(U)p-I'hCH~CC~H

39.7 -C(O)naphtlrl-yl -.C(U)C'Ih(naphth-1-vl)-C(U)CH2CH2(napth-I-vl) 39.8 -C(O)naphtlt-2-vl-C'(U)C'II2(napluh-2-vl-C(U)CH2C1I~(napth-2-yl) 39.9 -C(O)o-hiphenvl -C(O)C'II~(o-hiphenvl)-C(U)CI-I2CH2(crhiphenyl) 39.10-C(O)rn-hiphenvl -C'.(U)C'II~(m-hiphenyl)-C(U)CH~CH2(m-biphenyl) 39.12-C(O)p-hiphenvl -('(CC'lh(p-hiphenvl)-L(O)CI-I2CI-I2(p-biphenyl) 39.13-C(O)o-PhOPh -C(U)CI-I~(o-I'hUPh)-C(U)CH~CH2(o-PhOPh) 39.14-C(U)m-PhUPh -C(U )Ctl2(rn-1'hUPh)-C(O)CI-I2CH~(m-PhOPh ) 39.15-C(O)P-PhOPh -C(U)CI-12(p-I'hOPh)-C(U)CH2CH2(p-PhOPh) 39.16-C(U)o-PhNI-II'h -C'.(U)C'.II~(o-I'hNIIPh)-C(U)CH~CH2(o-PhNHPh) 39.17-C(Ohn-PhNI-IPh -C((>)Cli~(rn-I'hNHPh)-C'(U)CH~CI-t~(m-PhNHPh) 39.18-C(U)p-PhNllPh -C(U)C'II~(p-I'hNIIPh)-C(U)CI-I~CH~(p-PhNI-IPh) 39.19-C(U)o-PhSPh -C(U)CIh(o-I'hSPh)-C(O)CI-hCI-h(o-PhSPh) 39.20-C(U)rn-1'hSl'h -C'(())C'11~(m-l'hSl'h)-C'lU)C'II~CIi~(m-PhSPh) 39.21-C(U)P-PhSI'h -('(())C'I1~(p-l'h51'h)-C'(U)CI-hCl-12(p-I'hSPh) 39.22-C(U)o-PhClI2Sl'h-C'(U)C'112(o-I'hC1I2S1'h)-C(U)CH2CH2(o-PItC)-I2SPh) 39.23-C(Ohn-I'hCI12S1'h-C(U)C112(m-!'hC'.II2SPh-C(U)CI~2CH2(m-) PltCN2SPli) _ ~i~'24_C~~~p-I'ItCI-I2S1'h-C(U)Cll2(p-l'hCII2SPh)-C(U)CI-i2CH2(p-PhGI-hSPh) 39.25-C(O)acl<~mantvl -C'(0)C'll~(acl:unantvl)-C(U)CI-hCH2(aclarrtanryl) 39.26-C(O)cvcloPentvl -C'(<CII~(cvclopentyl)-C(O)CH2C1-I~((cyclopentvl) 39.27-C(O)cvclohexvl -C(U)CII~(cvclohexvl)-C'(U)CI-l2CIi2(cyclohexyl) 39.28-C'.(O)CI-i~U(cvrlopcntvl)-('(())C11~h1II(rvclnpentvl)-C(U)CI2S(cyclopentyi) 39.29-C(O)Cl-f~U(cvclahexvl)-C'(U)CII~NII(rvclohexvl)-C'(U
)C'.112S(cyclohexyl) 39.30-C(U)pyridin-2-vl-C(U)C'.II~(pyiclin-2-vl)-C(U)CIhCI-12(pyridin-2-yl) 39.31-C(U)pvridin-3-vl-C(U)CII~(pytidin-3-yl)-C(())CII~CI-I2(Pytidin-3-yl) 39.32-C(O)Pvriclin-~l-vl-('l())CII~(pyriclin-a-vl)-C(U)CII?CH2(Pytidin-4-vl) ~

39.33-C(O)turur2-vl -C'((>)C'II~(litrm-2-vl>-C((>)C'IhCH2(furm-2-yl) rya SUBSTITUTE SHEET (RULE 26) 17 4 3 I ~ PCT/US94/11280 ..~.. W O 95/09634 39.34 -C(U)furm-3-yl -C'(()ICII~(turnn-3-yl) -C(U)CII?CH2(fman-3-vl>
39.35 -C(U)U~ioPhen-2-vl -C'(())('.ll~(U~inPhan-2-vl) -C(U)CI-hCH2(thiophen-2-yl) 39.36 -C(O)thio~hen-2-vl -C'(U)CI1~(U~io~hen-2-vl) -C(U)CIhCI~12(thioPhen-2-yl) 39.37 -C(U)imiUazo-2-v_ 1 -C'(U )CI i~(imidazo-2-vl) -C:(U)CH~CH~(imidlza2-yl) 39.38 -C(O)oxazo-2-yl -('(())C'11~(ox~~o-2-vl) -C(U)CH2CI-!2(oxazo-2-yl) 39.39 -C(O)U~ioazo-2-yl -C'(())('II~(Uiioazo-2-vl) -C(O)C'.II~CH?(Uuoazo-2-yl) 39.40 -C(O)hcnzofuru~-2-yl -C(U)Cli2(tx:nzolurm-2-yl) -C(U)ChI2CH2(bcnzofuran-vl) 39.41 -C(U)henzoluran-3-yl -C'(U)CII2(hc:nzofuran-3-)'1) -C(U)CH2Cli2(bcnzofuran-3-vl) 39.42 -C(O)benzoUuoPhen-2-yl -C(U)CIi2(henzothiophen-2- -yl) C(O)CI-I2CH2(benzothiophen -2-vl) 39.43 -C(O)UiioPhen-2-yl -('(O)CII~(U~ioPhrn-2-vl) -C(U)CIhCH~(thiophen-2-yl) 39.44 -C(O)henzuniclazc~-2-yl -C'(O)CII2(Ixnzimi~Llzo-2-yl) -C(U)CI~2CH2(benzimidazo-2-vl) 39.45 . -C(U)henzoxvo-2-yl -C'(U)('I1~_(hcnzoxazo-2-yl) -C(U)CII2CIi2(benzoxazo-2-v l) 39.46 -C(U)hcnzothiazo-2-yl -C'(U)Cll~_lhrnzothiuzo-2-yl) -C(U)CII2C'.l-12(hcnzoUtiazo-2-vl) 39.47 -C(O)o-Ph(I'(U)1'h~) -('(())m-!'hll'((>)t'h~) -C(U)(~-1'h(P(U)I'h~) 39.48 -C(U )1'h-2-(Iluomn-~)-vl) -Cl(>)I'h-3-(I lumen-9-vl) -C'(())1'h-4-(tluoren-9-vll 39.49 -C'(U)N-indolin-2-one -C'(())inUolin-2-vl -C'(U)inclol-2-vl 39.50 -C.(U)cyclolx:ntyl-2-(I'h ) -C(U)cyclohexyl-2-(Ph) C(O)C(Cl I3)2Nl ISU2(naPhth -2-vl) 39.51 -C(U)pywolidin-3-yl-4-(Ph) -C'(U)tctrihydrofuran-3-yl-4- -C(U)tetrahyclrothiophen-3-yl_ (Ph) 4-(Ph) 39.52 -C(O)tetruhydronarhth-1-yl -C'(U)tctrthycirona~luh-2-yl -C(U)cvcloProPyl-2.2-(Ph2) 39.53 -C(O)tctr.U~ydroiu~yuinolin-I- -C(U)tctrahycirois~xluinolin-3- -C(U)CIl2((2-oxo)indolin-3 yl yl vl) 39.54 -C(U)CII2(N-hcnzimicl:~zol-2- -C'.(U)C'11~_(N-hcnzoxazol-2- -C(U)CII2(N-benzothiazol-2-onel one) one) 39.55 -C(U)CH2(N-dihydrounidvol_ _C'(U)Cll~_(N-tlihydrooxazol-2- -C(U)CH2(N-(iihydrothiazol-2-one) one) 2-one) 39.56 fC0- rC0-w N O I v N O w N w I ~ i ~ / \ I ~ I J
'I
39.57 O O O
-OC~.N~NH -OC~N~O -OC~N~S
39.58 -OC O -OCR -OC O -.
IN / I w ~N~ lNJllO
N /\
y a y3 SUBSTITUTE SHEET (RULE 26) ~1743I~

39.59 -C(O)N(C'1I3)Clhl'h ~ -('(())N(('~Its)C'.Il~f'h -C(U)N(C~H7)CH~Ph 39.60 -C(O)pyridin-3-yl-5-(Ph) -C'(U )I'h-3-(C'.II~(U~ioPhcn-?- -C(U)1'h-3-(CI-I2Ph) vl)) 39.61 -C(O)C(CH3)~Ul'h -C'(U)C'I-I(C~II~)U!'h -C(U)CI-I~UCH2Ph 39.62 -C(O)CH~U(o-PhCIhOI-Il -('(O)CII~U(m-l'hCII~OII) -C(U)C11?UlP-PhCH~OH) 39.63 -C(O)CH~U(o-I'h COOIf) -C(U)CIhU(m-Ph COU11) -C(O)C>-I~U(r-PhCOOH) 39.64 -C(O)Cl-hU(o-PhCOUCII~) -C(O)CII~U(m-PhCOOC'II~) -C(U)CI-hO(P-PhCUOCH3) 39.65 -C(O)Cl-I20(o-P1~CI-I~CUOII) -C'(U)C:11~U(m- -C(U)ClI?U(P-PhCH2COOH) I'hCI i~C'OOI I) 39.66 -OC O
~NxO
J
~ 5~5~
SUBSTITUTE SHEET (RULE 26) "'' WO 95/09634 PCTIUS94l11280 '~17~31 ~
1, o Formula III : A = -B(OII)2 ; ~ = CII~N1 t~: lt3 = tahlc below : R11 = -CH2C1-I2Ph.
1 '_ .3 ~

40 . -c(o)CI1~1'1, -c(o)cH~crl~Ph 1 -c(o)Ph . -C(O)CI-hOPh -C'(O)t:Il~NIII'lt -C(U)Cl-I?SPh . -C(U)o-Ph0lI -C(U)m-PhUII -C(U) -PhOH

. -C(O)o-I'ItCI-I~UI~-('(())m-I'hCII~UII-C'(U)P-1'hC1120H

. -C(O)o-l'hC001-1 -C'((m-I'hC'()UII -C(()) -PhCOOH

. COOH
-PhCH
-C(U) 40 -C(O)o-PhCIhCUUII-C(U)tn-PhCIi~CU0112 . -C(U)naphth-1-yl -C(U)CI1~(naPhth-1-vl)-C'(O)CI-hCH2(napQt-1-yl) . -C(O)CH~CH~(napth-2-yl) 40 -C(U)naphUt-2-yl -C(OlCll~(naPltlh-2-y!

. -C(O)a-hiPhenvl -C(U)C'.I1~(a-hiphenyl)-C(U)CII2CH2(o-hiphenyl) . -C(U)m-hiphenvl -C(U)C'Ih(m-hiphenvl)-C'(O)CH~CH~(m-biphenyl) . -C(U)P-biphenyl -C(U)CIh(P-biphenyl)-C(O)ClhCH2(p-biphenyl) 40.12 40 -C(U)o-PhOI'lt -C(U)('.11~(o-t'h(>t'h)-C(O)CH2C1i2(o-PItOPIt) . -C(O)m-PhOI'!t -C(O)('11~(tn-1'hUPh)-C'(U)CIi~CH~(m-PhOPh) 40.14 40.15 -C(U)P-1'hUl'h -('((C:ll~(P-I'h()Ph)-C(U)C11~C:1-i~(p-PhOPh) 40 -C(U)o-l'hNlt!'h -C'((('I1~(o-l'hN111'h)-C(U)CIU~CIi?(a-PhNHPh) . -C(U)m-l'hNHhh -C(())C'11~(rn-1'hNllPh-C(U)Cl-I2CH2(m-PhNHPh 40.17 ) ) 40.18 -C(U)p-1'hNIII'h -('.(O)Cll~(P-I'ltNlll'h)-ClU)Cli2CI-I2(p-PhNHPh) 40.19 -C(U)o-PhSPIt -('(U)C'If~(o-PhSPh)-C(O)CII~CH~(o-PhSPh) 40.20 -C(U)m-I'hSPit -C:(())CII~(m-l'hSl'h)-C(U)CH~CH~(m-PhSPh) 40.21 -C(U)P-PhSPIt -C:(U)C1h(p-I'hSPh)-C(O)CI-I2C112(P-PhSPh) 40.22 -C(U)o-PhCli2SPh -C(U)C112(o-1'hC.112SPh)-C(O)CI-I2CH2(o-PhCH~SPh) 40.23 -C(U)m-PhChI2SPh -C(U)CII2(m-PhC112S1'h)-C(U)CH2CH2(m-PhCI I2SPh) 40.24 -C(U)p-PhC112SPh -C(U)Cll~_(p-1'hC112SPh)-C(U)CrI2CH2(P-PhCII~SPh) 40.25 -C(U)acdmantvl -C'(U)Chh(acJtunantvl)-C'(O)Cl-hCIi2(adamvuyl) 40.26 -C(U)evclopentvl -C(())('I1~(cvclolxntvl)-C(U)CII~CI-I~((cyclaltentyl) 40.27 -C(Ccyclahexvl -('(U)('Il~lcvriahexvl)-C'.(())CIhCH~(cvclohexvl) 40.28 -C(O)C'.II~U(cvclopcntvll-C(U)('ll~Nl1(cvcloPcntvl)-C(O)CIhS(cvclopentyl) 40.29 -C(U)CI-hU(cvclohexvi)-C'.(U)C'11~N11(cvclohexvl)-C(O)CI1~S(evelahexyl) 40.30 -C(O)Pvtidin-2-vl-C(())C'.I1~(Pytictiu-2-yl>-C'(U)ClhCH2(pvridin-2-yl) 40.31 -C(O)pvtidin-3-yl-C(())('Il~(Pyticlin-3-yl)-C(U)C1i2C1-I2(PYndin-3-yl) 40.32 -C(U)Pvtidin~-vl -C(U)Cl t~(pytidin-4-vl)-C(O)CH~CIi~(pytidin-4-yl) .

40.33 -C(O)fur<tn-2-vl -C(U)CI I~(t'umn-2-vl>-C(U)Cl hCl-I2(futart-2-yl) 40.34 -C(U)furut-3-vl -C(())C'II~(Iuran-3-vl)-('(U)Cl-hClh(furatt-3-yl) 40.35 -C(U)tltiaphen-2-vl-C'(U)C'11~(tltioPhen-2-yl)-C(U)ClhCli2(thiaphen-2-yl) 40.36 -C(O)tltioPhen-2-yl-('(U)Cll~(tltioPhen-2-yl)-C(O)CI-hCH2(thiophen-2-yl) 40.37 -C(U)imicLlzo-2-vl-C'((Clh(imiUazct-2-vl)-(~(O)C1I2C1-h(imidaza-2-yl) .

40.38 -C(U)oxaro-2-vl -C'.(())C'.II~(oxaro-2-vl)-C(O)CII2CH2(axazo-2-yl) 40.39 -C(U)tltioazo-2-yl-(:(<))C'.11~(dtinaro-2-yl)-C(U)CIhC>-12(thioazo-2-yl) 40.40 -C(O)hcnzaCutnn-2-yl-('(U)('I1~_(bcttrttCurut-?-yl)-C(U)CH~CH2(henzofutan-2-vl) 40.41 -C(U)tmnzoCurtn-3-yl-C'.(())Cll~(t,cnzofurut-3-yl)-C(O)C1i2C1I2(hcnzofttran-3-vl) ~~i a SUBSTITUTE SHEET (RULE 26) 40.4? -C(U)hcnzoUtioPhcn-2-vl -C'(<>)C'11_~ihcnr,mhio~hcn-2-yl) C(O)CEI2C1 I2(hcnzothiophen _?_~,l) 40.43 -C(O)U~ioOhen-2-vl -C(O)Cll~(Utio~hcn-2-vl) -C(U)CI-hClh(Utiolthen-2-yl) 40.44 -C(U)henzitnicLtzo-2-yl -C'(U)Cll2(hcnzitnicLvo-2-yl) -C(U)CH2C1~2(lxnzimidaz~-2-vl) 40.45 -C(O)henzoxazo-2-yl -C(U)CI-12(tx:nzoxuzo-2-yl) -C(O)CI-I2CI-I2(henzoxazo-2-vl) 40.46 -C(O)henzoU~iazo-2-yl -C'(U)C:112(henzoUti<<tzo-2-yl) -C(U)CII2CH2(henzothiazo-2-vl) 40.47 -C(O)o-I'h(P(U)Ph~) -C(U )m-I'h(!'(O)I'h~) -C(U)P-Ph(P(0)Ph3) 40.48 -C(O)Ph-2-(fluoren-9-vl) -C(<))1'h-3-(ilnoren-9-vl) -C(U)Ph-4-(tluoren-9-vl) 40.49 -C(U)N-indolin-2-one -C'(())intlolin-2-vl -('.(C))indol-2-vl 40.50 -C'.(U)cycloltentyl-2-(Ph) -C(U)cyclohexyl-2-(Ph) C(O)C(CI I3)2NHIS02(naPhUl -2-vl) 40.51 -C(U)Pywolitlin-3-yl~-(t'h) -C'.(U)tctrthyclrofut.ut-3-yl-~- -C(O)tetr~hydroU~ioPhen-3-yl_ (1'h) 4-(Ph) 40.52 -C(O)tetr<titvclrona~htlt-1-vl -C(O)teunhvctrcma~lnh-2-vl -C'(U)cvcloltroPyl-2.2-(Ph2) 40.53 -C(O)tetrthydroisoquinolin-1- -C(U)tcuaUtyclroixtxluinolin-3- -C'(U)CI-I2((2-oxo)indolin-3 yl vl vl) 40.54 -C(O)CI12(N-hcnzimicl.~ol-2- -C'(U)CI12(N-hrnzoxazol-2- -C'(U)CII2(N-hcnzoUtiazol-2-one) .one) one) 40.55 -C(U)Cl-I2(N-Jihydroimitiwol- -C'(U )C112(N-~lihycJt~cxtxazol-2- -C(U)CI~I2(N-dihydroU~iazol-2-one) one) 2-one) 40.56 rC0- ~CO-O O
p N ~ ~ N y N Iw i i 40.57 p O O
-OCR N~ N H -OC~ Nu0 -OC~ NHS
40.58 _OC O -OCR -OC O
IN ~ 1 \ ~N~ 1N110 U N
i~
'I
40.50 -C(O)N(CH~)CI I2Ph -C(U )N(C'2115)C'I hPh -C:(U)N(C~lI7)C)-I2Ph 40.60 -C(O)Pyridin-3-yl-5-(I'h) -C(U )1'h-3-(C'.I1?(U~ioPhen-2- -C(O)1'h-3-(CH2Ph) vl)) 40.61 -C(U)C(CI-I~)~U('h -C((>)C'1 ((C'.~115)UI'h -C(U)CH~OCH2Ph 40.62 -C(O)CI-hO(o-I'hCII~UII) -C(U)C'.II~()(m-1'hCIhUli) -C(U )CI-120(P-PhCH20H) 40.63 -C(O)C1~~U(<t-1'hC()UIf) -('(())C'II~U(m-I'hCUOII) -C(U)CI-I~OIP-PhCOOH) 40.64 -C(U)CIhU(o-t'hC()UC'.It~) -('(())C'll~<)(m-l'hCUUCIi~) -C'.(U)CII~U(P-PhCUOCH~) 40.65 -C(U)CI-I2U(o-1'hC112('.UUII) -C'.(U)CII2UOn- -C(U)CII2U(P-PhCH2COOH) I'hCl I~CUUII) SUBSTITUTE SHEET (RULE 26) "°' WO 95/09634 PCT/US94111280 ~1 ~43I4 40.66 -OC O
~NUo J
/ \
able 41 Formula III : A = -B(Pinane~iol) ; X = -CN ; R3 = table below ; R11 = CH3 .1 2 .3 -41.1 -C(O)PI1 -C(U)CII~I'h -C(U)CI-I2CH2Ph 41.2 -C(O)CII~UPh -('((>)CIt~Mtl'h -C(U)Cl-I2SPh 41.3 -C(UlcrPhUll -('(U)m-I'h(>I1 -C(( -PhOH

41.4 -C(UOrPh('.II~UII -('(U)m-I'h('.11~()tl-C(U)P-PhCH20H

41.5 -C(O)crPhCUUI-1 -C'((m-I'hC'()()II-C(( -1'hCOOH

41.6 -C(U)o-PhCIhCUUII -C(())m-1'hC'.1I~('OUII-C'(U)0-l'hCH~C001-I

41.7 -C(O)naphtlrl-vl -('.!())('ll~(n;yhth-1-vl)-C(U)CI-I2CH2(nanth-1-yl) 41.8 -C(U)narhth-2-vl -C(U)('ll~lnyloh-2-vl-C(U)CI-I~CIi~(naPth-2-yl) 41.9 -C(U)o-hiPhcnvl -C((('li~(o-hi~hcnyl)-C(U)CI-I~CIf2(o-hiphenvl) 41.10-C(O)m-hiPhenvl -C'(())C'.11~(m-hi~henvl)-C(U )CI-I2CH2(m-hiPhenvl) 41.12-C(O)~-hinhcnyl -C(<))CI1~(n-hiphcnvl)-C(U)ClI2Cl-I2(P-hiPhenvl) 41.13-C(Ok~-PhUPIt -C(())('.ll~(crl'h()Ph)-C(O)CH~CH2(o-PhOPh) 41.14-C(U)m-PhUI'h -('(U)('I-1~(m-I'hUl'h)-C(U)Cl-hCI-I2(m-PhOPh) 41.15-C(U)0-1'hUl'lt -('.(())CII~(P-I'hUl'h-C(U)Cl-I2CI-I2(P-PhOPh) ) 41.16-C(0)o-1'hNIiPh -C'.(())CII~(o-I'hNlll'h-C(U)CI-I2CH2(crPhNHPh ) ) 41.17-C(O)m-PhNI-IPh -('(U )Cll~(m-I'hNIlPh)-C(U)CH2CIi2(m-PhNHPh) 41.18-C(U)P-PhMll'h -C(())Cll~(P-PhNlll'h)-C(U)CI12CH2(p-PhNHPh) 41.19-C(U)o-PhSI'h -C(O)C11~(o-1'hSl'h)-C'(U)CI-hC>-I2(o-PhSPh) 41.20-C(U)m-PhSI'h -('(())('ll2(m-PhSPh-C(UICI-I2C1I2(m-PhSPh) ) 41.21-C(U)0-PhSI'h -('l())('I1~(~-I'hSl'h-C'(U)C:1I~CHI~(P-1'hSPh) ) 41.22-C(U)o-PhCll~_Sl't~-('(())('.II~_(o-1'lO'II~_Sl'h)-C(U)CrI2('.H2(o_ PhCI-I~SPh) 41.23-C(U)m-PhC112S1'h -('(())('Il~_(m-1'h('112S1'h)-C'.(U)CI12C1I2(m-PhCIi~SPh) 41.24-C(O)P-PhCII2Sl'h -('.(U)C'112(~-l'hC112S1'h)-C(U)CII2CH2(p-PhCI3~SPh) 41.25-C(Uladan<vnvl -('(())C'11~(;Wunarnvl)-C(U)Cl-IZCI-I2(adamantvl) 41.26-C(U)cvckyentvl -C((Cl hlcvrlnlxntvl)-C(( CI-hCIi2((cycloPentyl) 41.27-C(O)cyclohexvl -C'(())cll~(cvclohexvl)-C(o)CH~CH2(cyclohexyn 41.28-C(o)Cll~o(cvcloPentvl)-('(())CII~NII(cvcl~Pentvl)-C((('II~S(cyclo~entyl) 41.29-C(O)CI-hU(cvclohcxvl>-('((>)('II~NII(cvclohexv_-C'(U)CI-I2S(cvclohexyl) 1) 41.30-C(O)wridin-2-y1 -C'(U)CII~(~yrulin-2-yl)-C(U)CIi2C1I2(Pycidin-2-yl) 41.31-C(U)PvriQin-3-vl -('(U)('I1~(~yiclin-3-yl)-C((CI-12C1-I2(nyr;din-3-yl) 41.32-C(U)PvnJin-~t-v_ -('(( ))('l l~(~yiclin-4-vll-C(U)('.I-I~CI-I~(Pyridin-4-yl) I

41.33-C(O)Curm-2-vl -('((>)('Il~(lurtn-2-vl)-C(U)CI-I2CH2(furan-2-yl) 41.34-C'(U)1-umn-3-yl -('((('Il~(Cm<m-3-vl)-C'(U)C1I2CII2(furan-3-vl) 41.35-C(U)thinOhcn-2-vl-('(())('ll~(thi<yhm-2-vl>-C(())ClI2CFI2(thioPhen-2-yl) ~Y'7 SUBSTITUTE SHEET (RULE 26) WO 95/09634 PCTlUS94111280 41.36 -C'(U)Uti<yhcn-2-vl -('(())('fl~(tl~icyhcn-?_vp -('(U)C'fI~CI-I~lUtioPlten-2-vl) 41.37 -C(U)unidazo-2-vI -('(())C'II~(imici:v.o-2-vl) -C'(U)C'lhC'I-h(itniUazo-2-yl) 41.38 -C(U)oxttzo-2-vl -C'(())('.ll~loxaict-2-vl) -C'(U)CH~CI-I~(oxazo-2-yl) 41.3 -C(U)Utioazo-2-vl -C(O)('Il~(thioarc>-2-vl) -C'l0)C'H~CIi~(Utioazo-2-yl) 41.40 -C(U)henzoturu~-2-yl -C(O)C'I12(hcnzoturan-2-yl) -C'(U)Cl-I~CH2(benzofuran-2-v»
41.41 -C(O)henzofurm-3-yl -C(O)CII~(tx;nzolurut-3-yl) -C(U)CI-I2CH2(benzofuran-vl) 41.42 -C(U)hcnzotltiophcn-2-yl -C(U)C.1I~_(bcnzoUtiophen-2- -yl) C(U)CI I_~CH2(henzothiophen -2-vl) 41.43 -C(O)UtioPltcn-2-yl -C'.(U)C'.II~(Utioltlten-2-yl) -C(U)CN7CIi2(UtioPhen-2-yl) 41.44 -C(O)henzimiUsvet-2-yl -C'(U)CIi~(ttcnzunictozo-2-yl) -C(U)CI12CI-I2(henzimidazo-2-vl) 41.45 -C(U)hcnzoxa-rct-2-yl -('(())Cll~(ttenzoxa~o-2-yl) -C(U)CII~CH~(benzoxazo-2-vl) 41.46 -C(U)tx~nzcttltia-rct-2-Yl -('(<))Cll?(hcnroUtinco-2-yl) -C(U)CI-I2CH2(henzothiazo-2-vl) 41.47 -C(U )o-Ph(P(U)!'h3) -('(Uhn-1'h(I'(())1'h~) -('((>)It-I'h(l'(U)I'h~) 41.4F, -C(U)I'h-2-(llctoren-~)-vl) -('((»I'h-;-(Iluorun ~)-vll -C(()ll'h-4-(tluctren-9-vl) 41.40 -C'(U)N-inelctlin-2-one -('(())inclolin-2-vl -('((»inelol-2-vl 41.50 -('(U)cycloltc:ntyl-2-(Ph) -C(U)cyclohexyl-2-(Ph) C(O)C(Cl-I3)2Nl ISO~(naPhUt -2-vl) 41.51 -C(U)PYrroliclin-3-yl-4-(I'h) -C'(())tcuahyclroiuru~-3-yl-4- -C(U)teu~altydroUtiophen-3-yl_ (Ph) 4-(Ph) 41.52 -C(U)IctrnltvclrcnutPhth-1-yl -('(())tcunhyclrcuutPhth-2-yl -C(U)cycloPmPyl-2.2-(Ph2) 41.53 -C(U)tctrtltydmiKtcluinolin-1- -C'.(U)tctrsvhyclroiaocluinolin-3- -C(U)CH2((2-oxo)indolin-3 yl vl vl) 41.54 -C(O)CII2(N-henzimicl.~tzol-2- -C'.(U)Clh(N-hcnzoxazol-2- -C(U)CII2(N-hcnzothiazol-2-one) ctne ) one) 41.55 -C(U)C'112(N-clihyclruitniJ~~zol- -('(())CI1~(N-dihyclrooxazol-2- -C(U)CI-i2(N-diltydrotltia2ol-2-one) cntc) 2-onel 41.56 rC0- ~CO-O O
N ~ ~ N ~ N
i ~ I ~ / \ I ~ I i 41.57 O O O
-OC~-NUNH -OC~NU0 -OC~N~S
41.58 -OC O -OCR -OC O
IN ~ I ~ ~N~ lNUO
\ ~ N
~l 41.59 -C(U)N(C'.ll~)('ll~I'h -('(())N(C'~1-IS)('11~1'h -('(U)N(C3U7)CH?Ph a ~r~r SUBSTITUTE SHEET (RULE 26) WO 95/09634 ~ 17 4 31 ~ PCTIUS94/11280 41.60 -C'(U)ItyriUin-3-yl-5-(1'h) -C'(U)l'h-;-(C'll2nlti<yhen-2- -('(())I'h-~-(C'11~1'it) vl)) 41.61 -C(U)C(CII~)~UPh -C'l())Cll(('~II~)UI'h -C'(U)C'.II~OC1i21'h 41.62 -C(U)CII~U(o-!'hC'll~Ull) -('l<))('I-I~U(m-t'h('II~UII) -C'(U)C'II~U(P-PhCH?OH) 41.63 -C(O)Cl-I~U(o-I'hC001I> -('(())CII~U(m-1'hC:UUIU) -C(U)CII~U((~-PItCOOHI
41.64 -C(O)CI-I~U(o-1'hC()UCI-i~) -C'(U)C'II~U(m-PhC'OUC'.H~) -C(O)CI1~0(P-PhCOOCH~) 41.65 -C(O)CI-I2U(o-PhCI-I~_C'UUII) -C'.(U)CIi2U(nt- -C(U)CII2U(P-PltCH2C(~I-n PhCI I ~CUOI Il 41.66 _pC 0 ~NUO
J
~-~9 SUBSTITUTE SHEET (RULE 26) h ' Formula III : A = -B(Pinanediol) ; a = -C'N ; R3 = table below : R11 = -CI-12C1I2Ph.
.1 2 .3 .

42.1 -C(0)Ph -C(O)CII~I'h -C(O)CII~CtI2Ph 42.2 -C(O)CH~UPh -C(U)ClI~NIII'h -C(O)CH2SPh 42.3 -C(O)o-1'h01~ -C(Cm-I'hUll -C(U) -PhUH

42.4 -C(O)o-1'hCII~OH -C(U)m-I'hCl-I~UII-Cl0)P-PhCI-I20H

42.5 -C(O)o-PhCOUI-I -C(U)m-Ph COU11 -C(U) -PhCOUH

42.6 -C(O)o-Ph CIi~COOII-C'(U)m-PhCI hCU01-I-C(O)P-Ph Cl-I~COOH

42.7 -C(O)naphth-I-yl -C(O)CH~(naPhth-1-vl)-C(U)Cl-I~CH~(nanth-1-yl) 42.8 -C(O)nanhth-2-yl -C(O)CII~(naPhth-2-vl-C(O)CH~CH2(naPth-2-yl) 42.9 -C(O)o-hiPltenvl -C(O)C'I-1~(o-hiPhenvl)-C(O)CH~CH~(o-hiphenvl) 42.10-C(U)tn-biphenyl -C(U)CI1~(m-hiPhenvl)-C(U)CH~CH~(m-hiphenvl) 42.12-C(U)P-hiPhenvl -C(O)C'.I1~(P-hiPhenvl)-C(U)CI-I~CH~(P-biphenyl) 42.13-C(O)o-PhUPIt -C'.((C11~(o-I'hOPh)-C(O)CII~CH?(o-PhOPh) 42.14-C(U)m-I'hUl'h -C'(O)C11~(m-l'h0l'h)-C(O)CII~CI-I~(m-PhOPh) 42.15-C(U)s-1'hOI'h -C'(U)C11~(P-I'hUl'h)-C(O)CI-I~CH2(P-PhOPh) 42.16-C(U)o-PhNIIPh -C(())C'll~(o-1'hNllPh)-C(U)C'.H~CH~(o-PhNHPh) 42.17-C(U)m-PhNI-11'h -C'((C112(m-1'hNlil'h)-(:(U)CEI~CHZ(m-PhNHPh) 42.18-C(U)P-PhNIIPh -C'(U)CI12(P-I'hNIIPh-C'(U)CH2CI-12(p-PhNHPh) ) 42.19-C(O)o-1'hSPh -C(U)C'.H~(o-PhSI'h-C(U)CH2CH2(o-PhSPh) ) 42.20-C(O)m-I'hSPh -C(O)C'If~hn-1'hSl'h)-C(O)CIi2CH2(m-PhSPh) 42.21-C(O)s-PhSPh -C(U)CI1~(P-PhSPh)-C(U)CH2CH2(p-PhSPh) 42.22-C(O)o-PhCH2SPh -C(U)CII2(o-I'hC112SPh)-C(U)CI-12CH2(o_ PhCII2SPh ) 42.23-C(U)m-PhCII2SI'h-C'.(U)C112(m-I'hCII2SPh)-C(U)CII2CH2(m-PhCI-I~SPh) 42.24-C(U)P-I'hCl12S1'h-C'(U)C'.II2(P-1'hC'.1I2SPh-C(U)CII2CII2(P-) PhCI-I~SPh ) 42.25-C(O)ad.unantvl -('(())C'11~(~ulam~ntvl)-C(O)Cll?CI-I?(adamantyl) 42.26-C(O)cvcto~entvl -C'.(C>)C'II~(cvcloPentvl)-C(O)C'.I-I~CH~((cyclnpentyl) 42.27-C(U)cvclohcxvl -C(())CI1~(cvclohexvl)-C(U)CI-I~CEI2(cvclohexyl) 42.28-C(U)CII~U(cvcloPmtvf)-('.(())CI1~NII(cycloPcntyl)-C(O)C112S(cycloPentyl) 42.29-C(U)CII~O(cvclohexvl)-C'.(U)C'I1~NII(cvclohexvl)-C(O)CH~S(cvclohexyl) 42.30-C(U)Pvridin-2-yl-C(O)C11~(pyri~in-2-vl)-C(U)CI-IZCH2(Pyridin-2-yl) 42.31-C(O)Pyridin-3-vl-C(C>)Cll~(Pyritlin-3-yl)-C(U)CII2CIi2(Pyridin-3-yl) 42.32-C(O)Pyridin-4-v_-C(U)C'Il~(Pyritiin-4-vl)-C(U)CIi~CH2(Pyridin-4-yl) I

42.33-C(U)furan-2-yl -C'(U)CII~(titran-2-vl)-C(O)CII2CH2(furart-2-vl) 42.34-C(U)furan-3-vl -C'(())CII~(titr,tn-3-vl)-C:(O)CI-I2CFI2(furan-3-yl) 42.35-C(U)thiophcn-2-yl-C'(U)('ll~(tliuPhcn-2-yl)-C(U)C'li2Cli2(thiophen-2-vl) 42.36-C(O)thiophen-2-yl-('.(U)CII~_Itl~ioPhcn-2-yl)-C(U)CII2CI-I2(thiophen-2-vl) 42.37-C(U)imidttzo-2-vl-C'((>)C'Il~(imi~laro-2-vl)-C(O)CIi2CH~(imiclttzo-2-yl) .

42.38-C(O)oxazo-2-vl -C(O)C'II~(oxar.o-2-vl)-C(U)CI-I~CH~(oxazo-2-vl) 42.39-C(O)thioazo-2-vl-C'(())(~Il~(thicriro-2-vl)-C(())CIi~CH~(thioazo-2-yl) ~-O
SUBSTITUTE SHEET (RULE 26) ..~.~ PCT/US94111280 WO 95109634 ~ 1 ~ 4 ~, ~. 4 , 42.40 -C(O)benzoturam-2-yl -C(U)CII2(hcnzofuran-2-yl) -C(U)CI-t2CH2(benzofuran-2_vl) 42.41 -C(U)hcnzofurun-3-yl -C(O)CI1~_(hcnzoluran-3-yl) -C(O)CII2CI-12(henzofuran-~-vll 42.42 -C(U)hcnzothinphen-2-yl -C(U)ClI?(hcnzothiophen-2- -yl) C(O)CH2CH2(henzothiophen -2-vl) 42.43 -C(U)thiophen-2-yl -C(U)C112(tltioPhen-2-yl) -C(O)CI12C1-12(thioPhen-2-vl) 42.44 -C(U)henzimi~azo-2-yl -C(U)CI12(tx:nzimid<tzo-2-yl) -C(U)CH2CH2(henzimidazo-2-vl) 42.45 -C(U)henzoxazo-2-yl -C(U)CI12(Ix~nzoxazo-2-yl) -C(U)CI-12CH2(henzoxazo-2-vl) 42.46 -C(U)henzothiazo-2-yl -C'.(U)Cll2(henzothiazo-2-yl) -C(U)CH2CH2(benzothiazo-2-vl) 42.47 -C(O)o-Ph(1'(U)I'h~) -C(Uhn-l'h(P(U)I'h3) -C(U)P-Ph(P(O)Ph3) 42.48 -C(O)Ph-2-(tluoren-9-vl) -C'((»Ph-3-llluorcn-9-vl) -C(U)Ph-4-(tluoren-9-vl) 42.49 -C(O)N-inciolin-2-one -C((»itulolin-2-vl -C'(C»indol-2-vl 42.50 -('.(U)cycloPcntyl-2-(Ph) -C(U)cyclohexyl-2-(Ph) C(O)C(CH3)2NI1SU2(naPhtlt -2-vl) 42.51 -C(U)OytrolicJin-,3-yl-4-(l'h) -C:(U)tetmhytlrofur<ut-3-yl-4- -C(U)tetraltydrotltiophen-3-(Ph) vl-4-(Ph) 42.52 -C(U)tetrtchyctronaPhth-1-vl -C'(U)tctrahvdronaPhth-2-yl -C(U)cycloProltyl-2.2-(Ph2) 42.53 -C(U)tetrahydroisoquinolin- -C(U)tetrahydroisocluinolin-3- -C(U)CI-I2((2-oxo)indolin-3 1-yl vl vl) 42.54 -C(O)CH2(N-hcnzimid.czol- -C'.(U)CII2(N-hcnzoxazol-2- -C(U)CIi2(N-benzothiazol-2-one) one) 2-one) 42.55 -C(O)CH2(N- -C(U)CIi2(N-dihydrooxazol- -C(O)CI-I2(N-dihydrothiazol-elihvdroimici~~ol-2-one) 2-onc) 2-one) 42.56 rC0- NCO- ~ p N O l ~ N O ~ N
I i ~ ~ / \ I i I i ~I
42.57 O O O
-OC'-NU N H -OC~ NCO -OC~ NHS
42.58 -OC O -OCR -OC O
~N ~ I w CN1 ~NxO
NJ / \
~I
42.59 -C(O)N(C:II~)Cll~l'h -('(())1\(('~115)CI1~!'h -C'(O)N(C3EI7)CI-i~Ph 42.60 -C(U)Pyridin-3-yl-5-(I'h) -C'.(U)I'h-3-(C'II2(thioPhen-2- -C'.(U)l'h-3-(CI-I2Ph) vl)) 42.61 -C(O)C:(CII~)~()1'h -C'(U)C'11(('2115)UPh -C'(O)C1I2UCl-I2Ph a ,s-~
SUBSTITUTE SHEET (RULE 26) 42.62 -C(O)CIi~U(o-l'lO'.11~U11) -C'.(())CII~U(m-I'hCII~UII) -C(U)CH~U(P-PhCH20H) 42.63 -C(O)C1120(x-PhC0011) -C:(U)C'I~U(m-I'h C0011) -C(O)CI-I~O(P-PhCOOII) 42.64 -C(0)CI-I~U(o-PItCUUCIl3) -C'(O)C'II~U(m-I'hC'UOCI-I3) -C(O)CII2U(n-PhC00CH3) 42.65 -C(O)CH20(o- -C(O)CII~U(m- -C(U)C1I20(p-PhCH~COOH) PhC'I I~C'UUI I) PhC'I I~COOIi) 42.66 -pC~ O
~NRO
J
/ \
ahle 43 Formula III : A = -B(pinv~eclial) : X = -CI I2NI-I~ : R3 = 4lhle hclow : R11 =

.1 ~ .3 .

43.1 -C(U)Ph -C'((>)('II~1'h -C'(U)CI-I7CH2Ph 43.2 -C(O)C'.1I~OPh -C'(U)CII~NIII'h -C(U)CI-I~SPh 43.3 -('(U)o-I'h()11 -C'(())rn-1'h()II -C'(( -PhUH

43.4 -C(O>o-PhC:I-I2Uil-.C'(U)m-l'h('.II~UII-C'.(U)p-PhC1i20H

43.5 -C(U)o-I'h C'OUII -('((1m-1'h C'UC)II-C'.(( -Ph COOH

43.6 -C(O)o-PhCI-I2CUO1-I-C(U )m-1'hCl t~CUOI~-C(O)P-PhCI~?COOH

43.7 -C(U)naPhth-1-vl -C(U)C'.i12(naphtlt-1-yl)-C(U)ClhCH2(napth-1-yl) 43.8 -C(U)naPltth-2-vl -C(U)C112(naPhth-2-yl-C(O)ClhCH2(naPih-2-yl) 43.9 -C(0)o-hiphenyl -C(U)C11~(o-biphenyl)-C(U)CH~CH2(o-biphenyl) 43.10-C(O)m-hiphenvl -C((.))('.II~(m-hiphenvl)-C(U)CH~CH~(m-biphenyl) 43.12-C(O)P-hinhenyl -C:(())C'lI~(P-hiPhcnyl)-C(U)CI-I2CH2(P-hiPhenyp 43.13-C(U)o-PhOPh -C'(U)C'lI~(o-PhUI'h)-C(U)CI-I2CH~(o-PhOPh ) 43.14-C(U)m-I'hOPh -C(U)C11~(m-i'hUl'h)-C(O)C1I2CH2(m-PhOPh) 43.15-C(U)P-!'hOPh -C'.(())CII~(p-I'h01'h)-C(O)CH~CI~I?(p-PhUPh) 43.16-C(0)~-PhN1-II'h -C'(O)C'li~(o-I'hNIII'h-C(U)('.II~CH~(o-PhNHPh) ) 43.17-C(Uhn-PhNIIPh -C'(())CII~(m-l'hNIIPh)-C(U)CH~CH~(m-PhNHPh ) 43.18-C(U)P-I'hNliPh -C'(U)C'lf~(P-PhNItI'h)-C(U)CI-I~CH2(P-PhNHPh) -43.19-C(U)o-PhSI'h -C'(U)Cll~(<rl'hSl'h)-C(U)CII~CH?(o-PhSPh) 43.20-C(O)m-1'hSPh -C((C'Il~(m-PhSPh)-C(U)CH~CH?(m-PhSPh) 43.21-C(U)P-PhSPh -C(U)CII~(p-I'hSl'h)-C(O)CH2CH2(p-PhSPh ) 43.22-C(U)o-PhCI-I2SPh -C(U)CI1~_(o-I'hC112SPh-C(U)CI-l2CIi2(o-) 1'hCII2SPh) 43.23-C(U)m-Ph C112SPh -C(O)C'.11~_(m-1'hCII2S1'h)-C(U)CI12CH2(m-I'hC'.II~SPh) 43.24-C'.(U)p-PhCli~_SI'h-('(U)C'112(P-PhCII2SI'h)-C(U)C1I2C1I2(P-PhCH~SPh) 43.25-C(U)adarnantvl -C(U)C'II~(,rcl,rm~uitvl)-C(O)CII2CH2(acUvnantyl) 43.26-C(U)cvcloPentvl -C'(())('II~(cvcloPentvl)-C(O)CI-I~CI-I~((cyclopentyl) 43.27-C(U)cvclohcxvl -C'(O)C'Il~(cvclohcxvl)-C(U)C'II~CH2(cyclohexvl) 43.28-C(O)CII~U(cvcloPcntvl)-C(O)CII~NII(cvclopcntvl)-C(U)CII~S(cycloPentyl) 43.29-C(U)CII20(cvclohexvl)-C'(O)C'II~NII(rvclohexvl)-C(U)CI-I~S(cyclohexyl) 43.30-C(U)Pvridin-2-vl -('(())C'II~(pyriclin-2-vl)-C(U)C11?CH2(pyridin-2-yl) a J~S
SUBSTITUTE SHEET (RULE 26) .,~,. ' ' v PCTJUS94111280 z17431~
43.31 -C(U)Pyridin-3-yl -('(())C'il~tryriclin-3-yl) -C'.(O)C'.II~C'11~(Pyridin-3-yl) 43.32 -C(U)Pvridin-4-v_ 1 -C'(U)C:II~(Pyridin-4-vl) -C(O)CIU~CI~12(Pyridin-4-yl) 43.33 -C(U)lur;ur2-vl -C'(U)C'II~(turan-2-vl) -C:(U)CII~CI-I~(furan-2-yl) 43.34 -C(O)furan-3-vl -('(U)('II~(Cur;m-3-vl) -C'(U)C1I7CH2(furan-3-yl) 43.35 -C(O)thiophen-2-yl -C(U)C1I2(tltioPhcn-2-yl) -C(U)CI-I2CI-I2(thiophen-2-vl) 43.36 -C(U)thiophen-2-yl -C(U)CII~_(tltio0ten-2-yl) -C(U)C1I2C1-i2(thiophen-2-vl) 43.37 -C(O)imidazo-2-yl -C(U)C11~(imidazc~-2-vl) -C(O)CH~CH~(imidazo-2-yl) 43.38 -C(O)oxazo-2-yl -C(U)CI12(oxazo-2-yl) -C(U)CH2CH~(oxazo-2-yl) 43.39 -C(O)thioazo-2-yl -C'lU)CII~(tltioazo-2-vl) -C(U)CII~CI~~(duoazo-2-yl) 43.40 -C(O)henzofur;ut-2-yl -C'.(U)C:11~(bcnzofuran-2-yl) -C'.(U)C112CII2(henzofutan-2-vl) 43.41 -C(O)hcnzofwan-3-yl -C(())C~ll?(hcnzoluran-3-yl) -C(U)Cli2C1I2(benzofuran-3-vl) 43.42 -C(U)hcnzothioPhcn-2-yl -C(U)C'.II2(hc:ni.othioPhcn-2_ _ yl ) C(U)CI I~CH2(benzothioPhen -2-vl) 43.43 -C(U)thiophcn-2-yl -('(U)C'11~_(thio~hcn-2-yl) -C(U)CI-12CH2(thiophen-2-vl) 43.44 -C(U)benzimicl~~o-2-yl -('(())C'.I12(hcnzimidaro-2-yl) -C(U)C'H2CH2(benzimidazo-2-vl) 43.45 -C(O)henzoxazo-2-yl -C(U)C112(hc;nzoxazo-2-yl) -C'.(U)CI-12CH2(benzoxazo-vl) 43.46 -C(O)henzothiazo-2-yl -('.(U)C'.112(txnzothiazo-2-yl) -C(U)CII2C1I2(benzothiazo-2-vl) 43.47 -C(U)o-I'h(P(U)Ph3) -C(())tn-1'h(P(())1'ly) -C(U)P-PIOP(U)Ph~) 43.48 -C(OIPh-2-(lluorcn-~)-vl) -C'(())I'h-3-(Iluorcn-~l-vl) -C(U)Ph-4-(tlu~ren-9-vl) 43.49 -C(U)N-indolin-2-one -('(())itulolin-2-vl -('.(U)inclol-2-vl 43.50 -('.(U)cycloPcntyl-2-(1'h) -C(U)cyclohexyl-2-(Ph) C(O)C(CH13)2NI ISU2(naPhth -2-vl) 43.51 -C(O)PyrroliJiu-;-yl-4-(I'h) -C(U )tctr;thyclroturan-3-yl-4- -C(U)telr;~ltydrothioPhen-3-(Ph) vl-4-(Ph) 43.52 -C(U)tetr;tlmclremaPhth-1-vl -('(())tetrahvilrc»t;tPhth-2-vl -('.(())cvcloProPyl-2.2-(Ph2) 43.53 -C(U)tctraltydroisoduinolin- -C(UHctrahydroiaoduinolin-;- -C'(U)Cli~_((2-oxo)indolin-3 1_yl yl vl) 43.54 -C(U)CI12(N-hcnzimidazol- -C(U)('.ll~_(N-hcnzoxazol-2- -C'(U)CI-I2(N-benzothiazol-2-2-one) cme) one) 43.55 -C(O)CI12(N- -C'.(( ))('112(J~'-clihydrooxazol- -C(U)C112(N-dihydrothiazol-dihvdrnimicl~zol-2-one) 2-one) 2-one) 43.56 NCO- rC0-O
I~ N O I ~ N I~ N I~
i i 43.57 - O O O
-OC'' N~ N H -OC~ NCO -OC~ NHS
asj SUBSTITUTE SHEET (RULE 26) 43.58 -OC p -OCR -OC O
~N ~ 1. CNJ ~NUo /\ ~ N /\
~I
43.5 -C(O)N(CII~)CI1~1'h -C'(U)N(C~IIS)C'.11~1'h -C(U)N(C~I-17)CH2Ph 43.60 -C(O)Pyridin-3-yl-S-(Ph) -C(U)1'h-3-(CI12(thiophcn-2- -C(U)1'h-3-(CH2Ph) vl)) 43.61 -C(U)C(CH3)2UPh -C(U)CII(C~I-I5)Ul'h -C(U)CII~OC>-I2Ph 43.62 -C(O)CH~U(o-PhCII~UII) -C(U)CII~U(m-1'hCII~UII) -C(U)CI-I~U(p-PhCH20H) 43.63 -C(U)CH~O(o-PhCUUI-I) -C(O)C'II~(>(m-1'hCU011) -C(U)CII~O(P-PhCOOH) 43.64 -C(U)CII~O(o-l'hC()UC1U~) -C(())C'II~U(m-1'hCUUC'11;) -C(U)CH2U(P-PhCOOCH~) 43.65 -C(U)CI(2U(o- -('(())C'II~()(nt- -C(U)C'.I-I2U(P-PhCII~COOIi) PhCII~('()C)11) 1'h C'I-I2C'OOH) 43.66 -pC
~NUO
J
/ \
Table 44 Formula III : A = -B(Pinancdiol) : a = CI12NI12: lt3 = table hclow : K11 = -CI12CI-I2Ph.
.1 2 .3 .

44.1 -C(U )Plt -C(O)CII~PIt -C(U)C112CI-I2Ph 44.2 -C(O)CI-l2UPh -C'(U)Cll~Nll1'h -C(U)CH2SPh 44.3 -C(O)o-PhC)II -C'((m-1'hC)11 -C(o) l'h01~

44.4 -C(O)o-Ph ClI2UlI -('.(())m-I'h('.I -C(U)P-PhCH20H
I~UIi 44.5 -C(o)o-l'hCUUI -('(( ))rn-I'h('( -C(U) -Ph COUH
( )C>l l 44.6 -C(O)o-PhCIi~C'.UOII-C(U)m-1'h('11~C'UUII-C(U)P-PhCI-I~COOI-I

44.7 -C(U)naPhth-1-vl -('(U)C11~(naPltth-1-vl)-C'.(O)C'.II~CIi~(naPtlt-1-yl) 44.R -C(U)naphth-2-v1 -('(())('11~(naPhth-2-vl-C'(())CII2CH2(naPUt-2-yl) 44.9 -C(o)o-hiPhcnyl -C'((C'11~(o-hiPhcnvl)-C:(U)CI-12CH~(o-hiphenvl) 44.10-C(O)m-hiphcnvl -C'(U)Clf~(m-hiPhenvl)-C(U)CH~CH~(m-biphenyl) 44.12-C(U>p-hiphenvl -C'(())('11~(P-biphenyl)-C(U)Cl-i~CI-12(P-hiphenvl) 44.13-C(O)o-l'h01'h -C'(())('.II~(o-1'hUI'h)-C(o)CI-I~CH2(o-PhOPh) 44.14-C(Ohn-Ph01'h -C'.(U)C'.11~(m-Ph()1'h)-C(U)CII2C1-I2(m-PhOPh) 44.15-C(O)P-I'hOPh -('.(< CI1~(P-1'hUPh-C(U)CI32CI-I2(p-PhOPh) ) 44.16-C(Okt-1'hNIUPh -C'((>)C'.11~(o-1'hNIIPh-C'.(U)CHI~CH2(o-PhNHPh ) ) 44.17-C(O)m-I'hNl~Ph -C(C('.11~(m-I'hNIIPh)-C(U)CII2CIi2(m-PhNHPh) 44.18-C(U)P-PhNI-IPh -('(C))C'Il~(P-1'hIvTIII'h)-C(U)CH2CI-12(P-PhNHPh) 44.11-C(O)o-PhSI'h -('(())('II~(o-I'hSl'h)-C'(CCII~CI-1~(o-I'hSPh) 44.20-C(Uhn-1'hSl'h -('(())('.Il~lm-I'hSl'h)-C(U)CII~CH~(m-PhSPh) 44.21-C(U)n-PhSPh -C'(<))('Il~(P-I'h11'h)-('.(O)Cl-I~CII~(P-1'hSPh) 44.22-C(U)o-I'h('ll~_Sl'h-C'(())('112(u-I'IO'II~_SI'h)-C'.(U)C'.II2CII2(o-PhCH2SPh) SUBSTITUTE SHEET (RULE 26) WO 9510963:1 ~ 1'~ 4 314 pC.L~S9q111280 44.23-C(U)m-I'hC'.II2S1'h-C'(U)CII~_(m-1'hCIl2Sl'h)-C'(U)Cf12CH2(m-PhCIhSPh ) 44.24-C(O)P-I'hC112S1'11-C(U)C112(P-t'hCII2SI'h)-C(U)C1I2CH2(t,-PhCIi~SPh) 44.25-C(O)adamantyl -C(U)C'11~(adamanty!)-C(U)C.I-I2CIi2(adamantyl) 44.26-C(O)cvclo~entvl -C(U)CII~(cyclo~entvl)-Cl0)CI-I~CH~((cvcloPentyl) 44.27-C(U)cvclohexvl -C(U)C:II~(rvclohexvl)-C(U)C11~C1-I~(cvclohexvl) 44.28-C(U)CI-I~U(cvclcycntvl)-C'(U)CII~NII(cvcll~Pcntvl)-C(U)CIi~S(cyclopentyl) 44.2J-C(O)C'.IdU(cyclohexvl)-C(())CII~NII(cyclohexyl)-C(U)CII2S(cyciohexyp 44.30-C(U)Pyridin-2-vl -C(U )C112(Pyridin-2-yl)-C(O)CI-I~CH2(pyridin-2-yl) 44.31-C(O)Pyridin-3-vl -C'(())C1I~(Pyridin-3-vl)-C(O)CI-I~CI-12(Pyridin-3-yl) 44.32-C(U)Pyridin-4-v_ -C((CII~(pyridin-4-vl)-C(U)C'.II~CH2(pyridin-4-yl) I

44.33-C(O)furan-2-yl -C'(U)CII~(furtn-2-vl)-C(O)CH~CI-i~(fumn-2-vl) 44.34-C(O)furan-3-yl -('(())C'll~(fvrsm-3-yl)-C(U)ClI2Chi2(furan-3-yl) 44.35-C(U)thioPhen-2-yl-('(U)C11~_(thio~hen-2-yl)-C(O)CI-I2CH2(thiophen-2-vl) 44.36-C(O)thiophen-2-yl-('(())CI1~_(tltioPhcn-2-yl)-C(O)CII2CH2(thiophen-2-vl) 44.37-C(U)imidwo-2-v_ -('(())('ll~(imiclar.c>-2-vl)-C'(U)('.I-I~Cli2(imidazo-2-yl) I

44.38-C(U)oxuzo-2-v1 -C(())('II~W xurc,-2-vl)-C(U)CIi~CI-12(oxazo-2-yl) 44.3 -C(U)thioazo-2-vl -('(U)('11~(thioaru-2-vl)-('(())Cl-I~CI-I2(thioazo-2-yl) 44.40-C(O)henzofurut-2-yl-C'((CI12(tx;nroluran-2-yl)-C(U)C1I2CH2(benzofuran-2-vl) 44.41-C(O)henzofurun-3-yl-C'.(U)('II~(tkn-roCur~ut-3-yl)-C'.(O)CII2CH2(henzofutan-3-vl) 44.42-C(O)henzothioPhcn-2-yl-('.(U)CIl_~(bcnrothioPhen-2-_ yl) C(U )CH2C1-I2(henzothiophen -2-vt) 44.43-C(O)thiophcn-2-yl-C(U)CII2(tltioPhcn-2-yl)-C(U)CH2CI-12(thiophen-2-vl) 44.44-C(U)henzimidazo-2-yl-('.(U)C11~_(henzimidazo-2-yl)-C(U)CI-I2CI-I2(henzimidazo-2-vl) 44.45-C(U )hcnznxaru.2-yl-('(C))('Il~_(hc:n~oxaio-2-yl)-C(U)CI12C1-12(henzoxazo-2-vl) 44.46-C( U)hcnzothiaro-2-yl-('(())('112(txncothiazc~-2-yl)-C(U)CH2CI-i2(benzothiazo-2-vl) 44.47-C(U)o-1'h(I'(U)1'h~)-('((m-1'h(P(U)!'h3)-C(O)P-I'h(P(O)Ph3) 44.48-C((Ph-2-(lluorcn-~)-vl)-('((Ph-:~-(fluoren-~)-vl)-C(U)Ph-4-(fluoren-9-vl) 44.49-C(U)N-indolin-2-one-C((incilin-2-vl -C(())indol-2-vl 44.50 -C(U>cyclopcntyl-2-(Ph)-C(Ukyclohexyl-2-(Ph) C(O)C(C113)2NI
ISU?(nuPhth -2-vl ) 44.51-C(U)Pytroiidin-3-yl-=t-(I'h)-('(())tctrahyclroluran-3-yl-4_-C(U)tetruhydrothioPhen-3-(!'h) vl-4-(l'h) 44.52-C(U)tetrlhvdr<uuyhth-I-vl-C'(l)>mtrahvclrcm.yhlh-2-p-C'(U)cyclproPyl-2.2-(Ph2) 44.53-C(U)tctrahydroiscxluinolin--('(U)tctrahylrctiscxluinolin-3--C(O)CH2((2-oxo)indolin-3-1-vl vl vl) 44.54-C(U)Cll~(N-hcniimiclarui--('.(())('112(N-hcn-C(U)C112(N-henzothiazol-2-ioxazol-2-2-one) one) one) 44.55-L(O)CI12(N- -C(U )C'II~_(N-~iihydrcx~xazoi--C'(O)Cl-I2(N-dihydrothiazol-dihvclroimiH,v.nl-2-~nr)2-one) 2-one) a s.~
SUBSTITUTE SHEET (RULE 26) 44.56 NCO- rC0-O
N O I ~ N ~ N
' I
~I
44.57 O O O
-OC~.N~NH -OC~NU0 -OC~N~S
44.58 -OC O -OCR -OC O
IN ~ I w ~N~ 1NJ10 N
~I
44.59 -C(O)N(C'II~)('ll~l'h -('(())N(('~1I5)C'II~I'h -C'(C))N(C'~I17)CH~Ph 44.60 -C(U)pyridin-3-YI-S-(1'h) -C'(U)!'h-3-(C'll?(thioPhcn-?- -C(U)1'h-:~-(Cli2Ph ) vl)) 44.61 -C(O)C(Cll;)~UI'h -C'(U)C'II(C'~IIS)UPh -C(U)CII~OCI-i~Ph 44.62 -C(O)CI-I~OIo-!'hC'II~(>ll) -C.(<))CIt~()tm-1'hC'11~OII> -C:(U)C:I-I~U(P-PhCH20H) 44.63 -C(O)CII~U(o-PhC'UOII) -C'((>)C'II~U(m-l'hC'UOI-I) -C(O)CI-I~U(p-PhCOOH) 44.64 -C(U)CIW U(o-I'hC()(:)CIi3) -('.(<)>('II~U(m-Ph('U()C11~) -C(U)CIi20(n-PhCOOCH~) 44.65 -C(O)CH20(o- -C'.(U)C'.1I2U(m- -C(U)C112U(P-PhC1-I2COOI-I) Ph('I I2COOI I) PhC.I-12C.OOH) 44.66 -O C O
~NUo i~
Tahle 45 Formula IV : A = -B(UI-I)2 ; \ _ -C'.N : 1' = t.~hlc hclow.
.1 ~ .3 45.1 -C(O)C1-I2(N-hcnzimi~azc~l- -C:(U)C'II~_(N-hcnzoxazol-2- -C(O)CI-I2(N-henzothiazol-2-2-one) onc) one) 45.2 -C(U)ClI2(N- -C'(U)Cll2(N-clihydrooxazol- -C.(U)CIi2(N-dihydrothiazol-dihvdroimicla~ol-2_onc) ?-onr) 2-one) 45.3 NCO- rC0-O O
N I~ N Iw N Iw ' , ~ i i ~ s~
SUBSTITUTE SHEET (RULE 26) ~I'~4314 '°"° WO 95/09634 PCT/US9-1/11280 O O
45.4 0 a -OC''N~NH -OC~N~O -OC~N S
45.5 -OC O -OCl -OC O
IN ~ ~ N ~NxO
/ \ I' CN' / \
'I
45.6 -OC 0 ~NUO
J
/ \
Tahle 46 Formula IV : A = -B(Ul I)~ : X = -C'I hNI l~ : 1' = tahlc hclow.
.1 ' .3 46.1 -C(U)CI12(N-hcnzimiclazc~l- -C(U)C11~_(N-hcnzoxazol-2- -C'(U)C112(N-henzothiazol-2-2-one) onc) one) 46.2 -C(O)C112(N- -C(U)CII~(N-dihyJrooxazol- -C(U)Cl-I2(N-dihydrothiazol-dihvdroirnida~ol-2-onc) 2-one) 2-one) 46.3 rC0- rC0-N O I ~ N O w N w ~ I ~ ~ \ I ~ I ~
46.4 O O 0 -OC'' N~ N H -OC~ NUO -OC~ NHS
46.5 -O i O -OCR -OC 0 N ~ l ~ CN' ~NxO
\ ~ NJ / \
'I
46.6 . O C O
~NuO
J
/ \
a .~~
SUBSTITUTE SHEET (RULE 26) Tahle 47 Formula IV : A = -B(pinanediol) : X = -C'N :1' = urhlc hclrnv.
.1 ~ .3 47.1 -C(U)CII2(N-benzimid~~~>t- -C((~)C'Il~_(N-henr.ox<rzol-2- -C'(U)C'II~(N-henzoUiiazol-2-2-one) onc) one) 47.2 -C(O)C1I2(N- -C'.((~)C'.112(N-clihydrcx~xazol- -C(U)C'II2(N-dihydrothiazol-dihvdmirnidazol-2_onc) 2-one> 2-onc) 47.3 (CO- ~CO-O
I ~ N O I ~ N I ~ N I ~
i ~ ' ~ ~ i i ~I
47.4 p O O
-OC''N~NH -OC~NU0 -OC~N~S
47.5 -pC O -OCR -OC O
~N . I. ~N~ ~NUo /\ U
N /\
~I
47.6 _ O C O
~NxO
J
/ \
07 Jest SUBSTITUTE SHEET (RULE 26) ~174.3~~
'°'"" WO 95109634 PCT/US94/11280 Table 48 Formula IV : A = -B(pin:umdiol) : X = -CI I~N11~ : Y = u~hlc hcloH~.
.1 ~ .3 48.1 -C(O)CH~(N-henzimidazol-2- -C(U)CI12(N-hcnzoxazol-2- -C(U)CI-I2(N-benzothiazol-2-one) one) one) 48.2 -C(U)CH2(N-dihy~roimicJn~ol- -C(U)Cll~_(N-clihylrc>oxazol- -('(O)CIi2(N-dihydrothiazol-2-onc) 2-one) 2-one) 48.3 rC0- NCO- ~ p O
w N O I ~ N w N w I i i ~ / \ I i I i ~I
48.4 O O O
-OC~NUNH -OC~NU0 -OC~N~S
48.5 -OC O -OCR -OC O
~N CN' ~N~O
/ \ ~ N / \
~I
48.6 -OC O
~NUo i\
as-s SUBSTITUTE SHEET (RULE 26) Table 49 Formula I: A = -B(pinanediol); X = See Table below; R3 =
hydrocinnamoyl; R11 = -CH~CH2Ph Example .1 .2 .3 No.

4 9 . -NH2 -NHCH ( =r~lH -CH2NHC ( =NH
1 ) H ) NH2 49.2 -NHC(=NH)NH2 -CH~NH2 Table 50 Formula I: A = -B(pinanediol); X = See Table below; R3 =
hydrocinnamoyl; R11 = -N(CH3)2 Example .1 .2 .3 No.

50.1 -NH2 -NHCH(=NH)H -CH~NH~

0 . -CH2NHC ( =NH -NHC ( =T?H ) 2 I ) NH2 I NH2 Table 51 Formula I: A = -B(pinanediol); X = -CH2NH2; R3 =
hydrocinnamoyl; R11 = See Table below Example .1 .2 .3 No.

51.1 -CH2(m-PhCF3) -CH~(m-PhCH3) Table 52 Formula I: A = -B(OH)2; X = -CH~NH2; R3 = hydrocinnamoyl;
R11 = See Table below SUBSTITUTE SHEET (RULE 26) ~1743L4 Example .1 .2 .3 No.

52.1 -CHZ(m-PhCF3) -CH?(m-PhCH3) Table 53 Formula I: A = -B(OH)2; X = -CH2NH2; R3 = hydrocinnamoyl;
R11 = See Table below Example .1 .2 .3 No.

53.1 -(2,2-dimethyl- -(2,2- -(2,2-diethyl-2-phenyl)ethyl ethanediyl-2- 2-phenyl)ethyl phenvl)ethvl 53.2 -N-phenyl-N- -N-ben2yl-N- -C(=O)CH2CH2C02H

methyl methyl 53.3 -C(=O)CH2CH2- -(2,2- -[2,2-dimethyl-C02CH3 butanediyl-2- 2-(3,5-phenyl)ethyl dimethyl)-henvl)ethvl 53.4 -2-(3,5- -cyclopropyl -cyclohexyl dimethyl)phenyl ethyl Table 54 Formula I: A = -B(pinanediol); X = -CH2NH2; R3 =
hydrocinnamoyl; R11 = See Table below Example .1 .2 .3 No.

54.1 -(2,2-dimethyl- -(2,2- -(2,2-diethyl-2-phenyl)ethyl ethanediyl-2- 2-phenyl)ethyl phenvl)ethvl a ~~
SUBSTITUTE SHEET (RULE 26) 54.2 -N-phenyl-N- -N-benzyl-N- -C(=O)CH2CH2C02H
methyl methyl 54.3 -C(=O)CH2CH2- -(2,2- -[2,2-dimethyl-C02CH3 butanediyl-2- 2-(3,5-phenyl)ethyl dimethyl)-henvl]ethyl 54.4 -2-(3,5- -cyclopropyl -cyclohexyl dimethyl)phenyl ethyl Table 55 Formula I: A = -B(OH)2; X = -NHC(=NH)NH2; R3 -hydrocinnamoyl; R11 = See Table below Example .1 .2 .3 No.

55.1 -(2,2-dimethyl- -(2,2- -(2,2-diethyl-2-phenyl)ethyl ethanediyl-2- 2-phenyl)ethyl nhenvl)ethvl 55.2 -N-phenyl-N- -N-benzyl-N- -C(=0)CH2CH2C02H

methyl methyl 55.3 -C(=O)CH2CH2- -(2,2- -[2,2-dimethyl-COZCH3 butanediyl-2- 2-(3,5-phenyl)ethyl dimethyl)-phenvl]ethyl 55.4 -2-(3,5- -cyclopropyl -cyclohexyl dimethyl)phenyl ethyl Table 56 Formula I: A = -B(pinanediol); X = -NHC(=NH)NH2; R3 =
hydrocinnamoyl; R11 = See Table below J~a SUBSTITUTE SHEET (RULE 26) ''1'~~3I4 WO 95109634 ~ PCTIUS94111280 Example .1 .2 .3 No.

56.1 -(2,2-dimethyl- -(2,2- -(2,2-diethyl-2-phenyl)ethyl ethanediyl-2- 2-phenyl)ethyl ohenvl)ethvl 56.2 -N-phenyl-N- -N-benzyl-N- -C(=O)CH2CH2C02H

methyl methyl 56.3 -C(=0)CH2CH2- -(2,2- -(2,2-dimethyl-Co2CH3 butanediyl-2- 2-(3,5-phenyl)ethyl dimethyl)-~henvl]ethvl 56.4 -2-(3,5- -cyclopropyl -cyclohexyl dimethyl)phenyl ethyl Table 57 Formula I: A = -E(OH)2; X = -NHC(=NH)H; R3 =
hydrocinnamoyl; R11 = See Table below Example .1 .2 .3 No.

57.1 -(2,2-dimethyl- -(2,?- -(2,2-diethyl-2-phenyl)ethyl ethanediyl-2- 2-phenyl)ethyl phen,~1 ) eth 57.2 -N-phenyl-N- -N-benzyl-N- -C(=O)CH2CH2C02H

methyl methyl 5?.3 -C(=0)CH2CH?- -(2,2- -(2,2-dimethyl-C02CH3 butanediyl-2- 2-(3,5-phenyl)ethyl dimethyl)-~henvl]ethvl ~L3 SUBSTITUTE SHEET (RULE 26) ~~~4~~~~

57.4 -2-(3,5- -cyclopropyl -cyclohexyl dimethyl)phenyl ethyl Table 58 Formula I: A = -B(pinanediol); X = -NHC(=NH)H; R3 =
hydrocinnamoyl; R11 = See Table below Example .1 .2 .3 No.

58.1 -(2,2-dimethyl- -(2,2- -(2,2-diethyl-2-phenyl)ethyl ethanediyl-2- 2-phenyl)ethyl nhenvl)ethvl 58.2 -N-phenyl-N- -N-benzyl-N- -C(=O)CH2CH2C02H
.

methyl methyl 58.3 -C(=O)CH2CH2- -(2,2- -[2,2-dimethyl-C02CH3 butanediyl-2- 2-(3,5-phenyl)ethyl dimethyl)-~henvl)ethvl 58.4 -2-(3,5- -cyclopropyl -cyclohexyl dimethyl)phenyl ethyl Table 59 Formula I: A = -B(OH)2; X = -NH2; R3 = hydrocinnamoyl; R11 =
See Table below Example .1 .2 .3 No.

59.1 -(2,2-dimethyl- -(2,2- -(2,2-diethyl-2-phenyl)ethyl ethanediyl-2- 2-phenyl)ethyl r~henvl > ethyl a c,~
SUBSTITUTE SHEET (RULE 26) 59.2 -N-phenyl-N- -N-ben~yl-N- -C(=O)CH2CH2C02H
methyl methyl 59.3 -C(=0)CH2CH2- -(2,2- -[2,2-dimethyl-C02CH3 butanediyl-2- 2-f3,5-phenyl>ethyl dimethyl)-phenvl]ethyl 59.4 -2-(3,5- -cyclopropyl -cyclohexyl dimethyl)phenyl ethyl Table 60 Formula I: A = -B(pinanediol>; x = -NH2; R3 =
hydrocinnamoyl; R11 = See Table below Example .1 .2 .3 No.

60.1 -(2,2-dimethyl- -(2,2- -(2,2-diethyl-2-phenyl)ethyl ethanediyl-2- 2-phenyl)ethyl phenyl)ethyl 60.2 -N-phenyl-N- -N-benzyl-N- -C(=O)CH2CH2C02H

methyl methyl 60.3 -C(=O)CH~CHZ- -(2,2- -[2,2-dimethyl-C02CH; butanediyl-2- 2-(3,5-phenyl)ethyl dimethyl)-phenvl]ethyl 60.4 -2-(3,5- -cyclopropyl -cyclohexyl dimethyl)phenyl ethyl Table 61 Formula I: A = See Table belo~-~; X = -CH?NH2; R3 =
hydrocinnamoyl; R11 = -CH3 a ~s-SUBSTITUTE SHEET (RULE 26) WO 95/09634 ~ 1 '~ ~ 314 PCTJUS94111280 Example.1 .2 ~3 No.

61.1 -C(=O)COZH -C(=O)OCH2CH2- -C(=O)OCH2CH2-NHCbz NH2 61.2 -C(=O)OCH3 HCL -C(=O)OCH3 tree -C(=O)CH3 base 61.3 -CH20H -CH20H; X = -C(=O)OH; X =

-CH~NHCbz -CH~NHCbz 61.4 -C(OH)(OCH3)- -C(=0)NHNH2 C(=O)OCHz Table 62 Formula I: A = -B(pinariediol); X = See Table below; R3 =
2-(2-cyanothiophenyl>-benzoyl; R11 = -CH3 Example.1 .2 .3 No.

62.1 -Br -CH~Br -SC(=NH)NH2 62.2 -N3 -CH~SC(=NH)NH2 -CH2N3 62.3 -NH2 -CH~NHC(=NH)NH2 -NHC(=NH)NH2 62.4 -NHC(=1'IH)H -CH~NHC(=NH)H -CH~NH~

62.4 -SCN

Table 63 Formula I: A = -B(pinanediol); X = See Table below; R3 =
2-(thiophenyl)benzoyl; R11 = -CH3 Example .1 .2 No.

63.1 -Br -CH~Br -SC(=NH)NH2 63.2 -N3 -CH~SC(=NH)NH~ -CH~N3 a c, ~
SUBSTITUTE SHEET (RULE 26) ,~~ ~'~ 4 314 pCTIUS94I11280 WO 9510963.1 63 . -NI-i~ -CH~r': ( -NH -NHC ( =NH ) NH2 3 ) NH-~

63.4 -NHC(=NH)H -CH~NHC(=NH)H -CH~NH?

63.5 -SCN

Table 64 Formula I: A = -B(pinanediol); X = -CH?NH2; R3 = See Table below; R11 = -CH3 Example .1 .2 .3 No.

64.1 2-(benzyl)- 2-(benzyl)- 2-(pyrrol-1-benzyl benzyl; R11 = ylmethyl)benzyl -C(=0)CH

64.2 2-(2- 3-(3-trifluoro- 3-(3-methylbenzyl)- methylbenzyl)- chlorobenzyl)-benzovl benzovl benzovl 64.3 2-(2-cyano-benzvl)benzovl Table 65 Formula I: A = -B(OH)2; X = -CH?NH~; Rj = See Table below;
R11 = -CH3 Example .1 .2 .3 No.

65.1 2-(benzyl)- 2-(benzyl)- 2-(pyrrol-1-benzyl benzyl; R11 = ylmethyl)benzyl -C ( =0 ) CH

65.2 2-(2- 3-(3-trifluoro- 3-(3-methylbenzyl)- methylbenzyl)- chlorobenzyl)-benzovl benzovl benzovl a~~
SUBSTITUTE SHEET (RULE 26) 65.3 2-(2-cyano-benzvl)benzovl Table 66 Formula I: A = -B(OH)2; X = -CH2NH2; R3 = See Table below;
R11 = -N (CH3 ) CH2Ph Example .1 .2 .3 No.

66.1 -C(=0)CH2CH2- -C(=O)CH2C- -C(=0)CH2C-CH2C02H (CH3)?CH~COzH (CH3)2CH~C02CH3 66.2 -C(=O)CH- -C(=O)CH- -C(=0)CH-(NHBOC)- (NHBOC)CHZC02H (NHBOC)-CH2CH~CO~H CH~CH~C02CH3 66.3 -C(=O)CH2CH2C02H-C(=O)CH2NH- -C(=O)CH2CH2-S(O)2CH3 CO~CH3 66.4 -C(=O)CH2CH2- -C(=O)CH2N-CH~C02CH3 ( CH3 ) S ( O
) 2CH3 Table 67 Formula I: A = -B(pinanediol); X = -CH~NH2; R3 = See Table below; R11 = -N(CH3)CH2Ph Example .1 .2 .3 No.

67.1 -C(=O)CH2CH2- -C(=O)CH2C- -C(=O)CH2C-CH2C02H (CH3)2CH~C02H (CH3)2CHZC02CH3 67.2 -C(=O)CH- -C(=O)CH- -C(=O)CH-(NHBOC)- (NHBOC)CH~C02H (NHBOC)-CH2CH~CO~H CH2CH~COZCH3 67.3 -C(=O)CH2CH2C02H-C(=O)CH2NH- -C(=O)CH2CH2-S(O)~CH~ CO~CH3 a ~~
SUBSTITUTE SHEET (RULE 26) ~1'~43I 4 ~"'""' WO 95109634 PCT/US94/11280 67.4 -C(=0)CH2CH2- -C(=O)CH2N-I

CH~CO~CH3 ( CH3 ) S ( O
) 2CH3 Table 68 Formula I: A = -B(OH)2; X = -CH2NH2; R3 = See Table below;
R11 = -CH2CH2Ph Example .1 .2 .3 No.

68.1 -C(=0)CH2CH2- -C(=O)CH2C- -C(=O)CH2C-CHZCO~H (CH3)2CH~C02H (CH3)2CH~C0?CH3 68.2 -C(=O)CH- -C(=O)CH- -C(=O)CH-(NHBOC)- (NHBOC)CH2C02H (NHBOC)-CH~CH~CO~H CH2CHZC02CH3 68.3 -C(=O)CH2CH2C02H-C(=O)CH2NH- -C(=O)CH2CH2-S ( O ) 2CH3 C02CH3 68.4 -C(=O)CH2CH2- -C(=O)CH2N-CH2CO~CH3 (CH3 ) S (O) Table 69 Formula I: A = -B(pinanediol); X = -CH2NH2; R3 = See Table below; R11 = -CH?CH2Ph Example .1 .2 .3 No.

69.1 -C(=0)CH2CH2- -C(=O)CH2C- -C(=0)CH2C-CH~CO~H (CH3)2CH2C02H (CH3)2CH2C02CH3 69.2 -c(=o)cH- -c(=o)cH- -c(=o)cH-(NHBOC)- (NHBOC)CH2C02H (NHBOC)-CH~CH~CO~H CH2CH~CO~CH3 69.3 -C(=O)CH2CH2C02H-C(=O)CH2NH- -C(=O)CH2CH2-S(O)2CH~ C02CH3 ~ ~9 SUBSTITUTE SHEET (RULE 26) 69.4 -C(=0)CH2CH2- -C(=0)CH2N-CH~CO~CH3 (CH3)S(O)2CH3 Table 70 Formula I: A = See Table below; X = -CH2NH2; R3 - 2-(benzyl)benzoyl; R11 = -CH3 Example .1 .2 .3 No.

70.1 -C(=0>C02H -C(=0)OCH2CH2- -C(=0)OCH2CH2-NHCbz NHS

70.2 -C(=O)OCH3 HCL -C(=O)OCH3 free -C(=O)CH3 base 70.3 -CH20H -CH20H; X = -C(=0)OH; X =

-CH2NHCbz -CH2NHCbz 70.4 -C(OH)(OCH3)- -C(=O)NHNH2 C(=O)OCH3 Table 71 Formula I: A = See Table below; X = -CH2NH2; R3 = 2-(2-trifluoromethylbenzyl)benzoyl; R11 = -CH3 Example .1 .2 .3 No.

71.1 -C(=0)C02H -C(=0)OCH2CH2- -C(=0)OCH2CH2-NHCbz NH2 71.2 -C(=0)OCH3 HCL -C(=O)OCH3 free -C(=0)CH3 base 71.3 -CH20H -CH20H; X = -C(=0)OH; X =

-CH~NHCbz -CH~NHCbz 71.4 -C(OH)(OCH3)- -C(=O)NHNH2 C(=O)OCH3 a 70 SUBSTITUTE SHEET (RULE 26) WO 95109634 ~ 17 4 3 I 4 Table 72 Formula I: A = -B(OH)2; X = See Table below; R3 =
hydrocinnamoyl; R11 = -N(CH3)2 Example .1 .2 .3 No.

72.1 -NH2 -NHCH(=NH)H -CH2NH2 72.2 -CH2NHC(=NH)NH2 -NHC(=NH)NH?

Table 73 Formula I: A = -B(pinanediol); X = -CH?NH2; R3 =
-C(=O)CHZCH2C02H; R11 = See Table below Example .1 .2 .3 No.

73.1 -CH~(m-PhCF3) -CH2(m-PhCH3) Table 74 Formula I: A = -B(pinanediol); X = -NHC(=NH)NH2; R3 = See Table below; R11 = -CH3 Example .1 .2 .3 No.

?4.1 2-(benzyl)- 2-(benzyl)- 2-(pyrrol-1-benzyl benzyl; R11 = ylmethyl)benzyl -C ( =0 ) CH

74.2 2-(2- 3-(3-trifluoro- 3-(3-methylbenzyl>- methylbenzyl)- chlorobenzyl)-benzovl benzovl benzovl a 7~
SUBSTITUTE SHEET (RULE 26) PCTlUS94l11280 WO 95/09634 ~ ~ ~ ~ J
74.3 2-(2-cyano-benzvl)benzovl Table 75 Formula I: A = -B(OH)2; X = -NHC(=NH)NH2; R3 = See Table below; R11 = -CH3 Example .1 .2 .3 No .

75.1 2-(benzyl)- 2-(benzyl)- 2-(pyrrol-1-benzyl benzyl; R11 = ylmethyl)benzyl -C(=O)CH

75.2 2-(2- 3-(3-trifluoro- 3-(3-methylbenzyl)- methylbenzyl)- chlorobenzyl)-benzovl benzovl benzovl 75.3 2-(2-cyano-benzvl>benzovl Table 76 Formula I: A = -B(OH)2; X = -CH2NHC(=NH)H; R3 = See Table below; R11 = -cyclopropyl Example .1 .2 .3 No.

76.1 hvdrocinnamovl -C(=O)CHZOPh -C(=0)CH2SPh Table 77 Formula I: A = -B(pinanediol); X = -CH2NHC(=NH)H; R3 = See Table below; R11 = -cyclopropyl a7~
SUBSTITUTE SHEET (RULE 26) f'"'~ WO 95/09634 ~ PCTIUS94/11280 ~1'~43~.j~
Example .1 .2 .3 No.

77.1 hvdrocinnamovl -C(=O)CH~OPh -C(=O)CHZSPh Table 78 Formula I: A = -B(OH)2% X = -CH2NH2; R3 = See Table below;
R11 = -cyclopropyl Example .1 .2 .3 No.

78.1 hvdrocinnamovl -C(=O)CH~OPh -C(=O)CH~SPh Table 79 Formula I: A = -B(pinanediol); X = -CH2NH2; R3 = See Table below; R11 = -cyclopropyl Example .1 .2 .3 NO.

79.1 hvdrocinnamovl -C(=O)CH~OPh -C(=O)CH2SPh SEQUENCE LISTING
(1) GENERAL INFORMATION:
(i) APPLICANT: GalemmO, et al.
(ii) TITLE OF INVENTION: ELECTROPHILIC PEPTIDE ANALOGS
AS INHIBITORS OF TRYPSIN LIKE ENZYMES
(iii) NUMBER OF SEQUENCES: 3 (iv) CORRESPONDENCE ADDRESS:
(A) ADDRESSEE: THE DUPONT MERCK PHARMACEUTICAL
COMPANY
(B) STREET: 1007 MARKET STREET
LEGAL DEPARTMENT
(C) CITY: WILMINGTON
(D) STATE: DE
(E) COUNTRY: U.S.A.
a h3 SUBSTITUTE SHEET (RULE 26) WO 95/0963:1 ~ ~ PCTIUS94111280 (F) ZIP: 19898 (v) COMPUTER
READABLE
FORM:

(A) MEDIUM TYPE: 3.50 INCH DISK

(B) COMPUTER: APPLE MACINTOSH

(C) OPERATING SYSTEM: APPLE MACINTOSH

(D) SOFTWARE: MICROSOFT WORD

(vi) CURRENT
APPLICATION
DATA:

(A) APPLICATION NUMBER: N/A

(B) FILING DATE: HEREWITH

(C) CLASSIFICATION:

(viii)ATTORNEY/AGENT
INFORMATION:

(A) NAME: REINERT, NORBERT F.

(B) REGISTRATION NUMBER: 18,926 (C) REFERENCE/DOCKET NUMBER: DM-6666 (ix) TELECOMMUNICATION
INFORMATION:

(A) TELEPHONE: 302-892-8867 (B) TELEFAX: 302-892-8536 (2 ) INFORNLATION FOR SEQ ID NO: 1 (i) SEQUENCE CHARACTERISTICS:
(A) LENGTH: 14 (B) TYPE: amino acid (C) TOPOLOGY: linear (ii) MOLECULAR TYPE: peptide (vi) ORIGINAL SOURCE: synthetic (ix) FEATURE:
(D) OTHER INFORMATION: thrombin inhibitor (xi) SEQUENCE DESCRIPTION: SEQ ID N0:1:
Leu Ser Asn Leu Ser Asn Leu Ser Asn Leu Ser Asn Gly a ~Y
SUBSTITUTE SHEET (RULE 26) ~I74314 WO 95109634 PCTIUS9a111280 ( 2 ) INFORNL=.TION FOR SEQ I~ NO: 2 (i) SEQUENCE CHARACTERISTICS:
(A) LENGTH: 14 (B) TYPE: amino acid (C) TOPOLOGY: linear (ii) MOLECULAR TYPE: peptide (vi) ORIGINAL SOURCE: synthetic (ix) FEATURE:
(D) OTHER INFORMATION: thrombin inhibitor (xi) SEQUENCE DESCRIPTION: SEQ ID N0:2:
Leu Ser Asn Leu Ser Asn Leu Ser Asn Leu Ser Asn Gly (2) INFORMATION FOR SEQ ID N0:3:
(i) SEQUENCE CHARACTERISTICS:
(A) LENGTH: 14 (B) TYPE: amino acid (C) TOPOLOGY: linear (ii) MOLECULAR TYPE: peptide (vi) ORIGINAL SOURCE: synthetic (ix) FEATURE:
(D) OTHER INFORMATION: thrombin inhibitor (xi) SEQUENCE DESCRIPTION: SEQ ID N0:3:
Leu Ser Asn Leu Ser Asn Leu Ser Asn Leu Ser Asn Gly SUBSTITUTE SHEET (RULE 26) ~1'~43~~
The compounds which are described in the present invention represent a novel class of potent, reversible inhibitors of trypsin-like enzymes. Trypsin-like enzymes are a group of proteases which hydrolyzed peptide bonds at basic residues liberating either a C-terminal arginyl or lysyl residue. Among these are enzymes of the blood coagulation and fibrinolytic system required for hemostasis. They are Factors II, X, VII, IX, XII, kallikrein, tissue plasminogen activators, urokinase-like plasminogen activator, and plasmin. Enzymes of the complement system, acrosin (required for fertilization), pancreatic trypsin are also in this group. Elevated levels of proteolysis by these proteases can result in disease states. For example, consumptive coagulopathy, a condition marked by a decrease in the blood levels of enzymes of both the coagulation system, the fibrinolytic system and accompanying protease inhibitors is often fatal.
Intervention by a synthetic inhibitor would clearly be valuable. More specifically, proteolysis by thrombin is required for blood clotting. Inhibition of thrombin results in an effective inhibitor of blood clotting.
The importance of an effective inhibitor of thrombin is underscored by the observation that conventional anticoagulants such as heparin (and its complex with the protein inhibitor, antithrombin III) are ineffective in blocking arterial thrombosis associated with myocardial infractions and other clotting disorders. However, a low molecular weight thrombin inhibitor, containing a different functionality, was effective in blocking arterial thrombosis (Hanson and Harker, Proc. Natl. Acad. Sci. U.S.A. 85, 3184 (1988).
Therefore, we have chosen to demonstrate utility of compounds in the inhibition of thrombin, both as in a ~~
SUBSTITUTE SHEET (RULE 26) buffered solutions and in plasma. Specifically, the compounds have utility as drugs for the treatment of diseases arising from elevated thrombin activity such as myocardial infarction, and as reagents used as anticoagulants in the processing of blood to plasma for diagnostic and other commercial purposes.
Compounds of the present invention are expected to be effective in the control of aberrant proteolysis and a number of accompanying disease states such as inflammation, pancretitis, and heritary angioedema.
The effectiveness of compounds of the present invention as inhibitors of blood coagulation proteases was determined using purified human proteases and synthetic substrates following procedures similar to those described in Kettner et al. (1990).
For these assays, the rate of enzymatic (thrombin, Factor Xa, and Factor VIIa) hydrolysis of chromogenic substrates (52238 (H-D-Phe-Pip-Arg-pNA), 52222, and S2288, respectively; Kabi Pharmacia, Franklin, OH) was measured both in the absence and presence of compounds of the present invention. Hydrolysis of the substrate resulted in the release of pNA, which was monitored spectrophotometrically by measuring the increase in absorbance at 405 nM. A decrease in the rate of absorbance change at 405 nm in the presence of inhibitor is indicative of enzyme inhibition. The results of this assay are expressed as inhibitory constant, Ki.
Thrombin and Xa determinations were made in 0.10 M
sodium phosphate buffer, pH 7.5, containing 0.20 M
NaCl, and 0.5 ~ PEG 8000. VIIa determinations were made in 0.05 M tris buffer, pH 7.6, containing 0.10 M
NaCl, 4 mM CaCl2, and 0.1~ bovine serum albumin. The Michaelis constant, Km, for substrate hydrolysis was determined at 25 °C using the method-of Lineweaver and Burk. ' a 77 SUBSTITUTE SHEET (RULE 26) WO 95109634 PCTlUS94111280 Values of Ki were determined by allowing 0.2 - 0.5 nM human thrombin or human factor Xa (Enzyme Research Laboratories, South Bend, IN) , or 50 nM human factor VIIa (BiosPacific, Emeryville, CA) react with the substrate (0.20 mM - 1 mM) in the presence of inhibitor. Reactions were allowed to go for 30 minutes and the velocities (rate of absorbance change vs time) were measured in the time frame of 25-30 minutes. The following relationship was used to calculate Ki values.
vo-vs I
vs Ki (1 + S/Km) where:
vo is the velocity of the control in the absence of inhibitor;
vs is the velocity in the presence of inhibitor;
I is the concentration of inhibitor;
Ki is the dissociation constant of the enzyme:
inhibitor complex;
S is the concentration of substrate;
Km is the Michaelis constant.
Using the methodology described above, representative compounds of this invention were evaluated and found to exhibit a Ki of less 500 N.M
thereby confirming the utility of compounds of the invention as effective inhibitors of human blood coagulation proteases. The results of these assays are summarized in Table 80, where +++ indicates a Ki < 500 nM; ++ indicates a Ki < 50,000 nM; and + indicates a Ki 500,000 < nM; - indicates inactive.
Table 80. Ki values for inhibition of Serine Proteases by compounds of the present invention.
a '~$
SUBSTITUTE SHEET (RULE 26) ~~ 1'~ ~ 3 I 4 pCT/US94111280 Ex Thrombin Factor Factor I~50 No. Xa VIIa Thrombin time 49.1.1+++ ++ inactive NT

49.1.2+++ NT NT +++

49.1.3+++ +++ NT +++

49.2.1+++ +++ NT ++

50.1.1NT NT NT NT

50.1.2+++ NT NT +++

50.1.3+++ NT NT NT

51.1.1+++ +++ ++ NT

51.1.2+++ NT NT NT

52.1.1+++ +++ ++ NT

52.1.2+++ +++ ++ +++

53.1.1+++ +++ +++ +++

53.1.2+++ +++ +++ +++

53.2.1+++ NT NT ++

53.2.2+++ +++ +++ NT

53.4.3+++ ++ +++ NT

54.1.1+++ NT NT NT

54.1.2+++ ++ +++ +++

54.1.3+++ ++ +++ NT

54.2.1+++ NT NT ++

54.2.2+++ NT NT ++

54.2.3+++ ++ ++ NT

54.3.1+++ ++ ++ NT

54.3.2+++ ++ +++ NT

54.3.3NT ++ +++ NT

54.4.1NT ++ ++ NT

54.4.2+++ ++ +++ +++

54.4.3+++ ++ +++ ++

55.1.1+++ +++ +++ NT

56.1.1+++ +++ +++ NT

56.1.2+++ +++ +++ NT

56.3.3+++ +++ +++ NT

56.4.1NT NT NT NT

a ~9 SUBSTITUTE SHEET (RULE 26) WO 95109634 PCTlUS94111280 57.1.1 +++ +++ +++ NT

57.1.2 +++ +++ +++ NT

57.4.2 +++ ++ NT +++

58.1.1 +++ +++ +++ NT

58.3.3 NT NT NT NT

58.4.1 NT NT NT NT

58.4.2 ++ NT NT NT

59.1.1 +++ ++ +++ NT

59.4.2 +++ ++ NT +++

60.1.1 +++ ++ NT NT

60.3.3 +++ ++ ++ NT

60.4.1 +++ ++ ++ NT

60.4.2 +++ NT NT NT

61.1.1 +++ ++ ++ NT

61.1.2 ++ Inactive Inactive NT

61.1.3 ++ ++ Inactive NT

61.2.1 ++ ++ ++ NT

61.2.2 ++ Inactive Inactive NT

61.2.3 NT Inactive Inactive NT

61.3.1 ++ Inactive Inactive NT

61.3.2 ++ Inactive Inactive NT

61.3.3 ++ ++ inactive NT

61.4.1 +++ ++ ++ ++

62.1.1 ++ ++ ++ NT

62.1.2 ++ ++ ++ NT

62.1.3 +++ +++ +++ NT

62.2.1 ++ ++ ++ NT

62.2.2 +++ +++ ++ NT

62.2.3 ++ ++ ++ NT

62.3.1 ++ ++ ++ NT

62.3.2 +++ +++ ++ NT

62.3.3 +++ +++ +++ NT

62.4.1 +++ +++ +++ NT

62.4.2 +++ +++ ++ NT

62.4.3 +++ +++ ++ ++

~ ~o SUBSTITUTE SHEET (RULE 26) 63.1.3 +++ +++ ++ NT

63.3.1 +++ ++ inactive NT

63.4.1 +++ +++ ++ +++

63.4.2 +++ +++ ++ ++

63.5.1 ++ ++ inactive NT

64.1.1 +++ ++ ++ Inactive 64.1.2 +++ ++ +++ NT

64.1.3 +++ NT NT ++

64.2.2 +++ +++ ++ NT

64.2.3 +++ +++ +++ NT

65.1.3 +++ NT NT ++

66.1.1 +++ +++ ++ ++

66.1.2 +++ NT ++ NT

66.1.3 +++ NT ++ NT

66.3.2 +++ +++ +++ +++

67.1.2 +++ ++ ++ NT

67.1.3 +++ +++ ++ NT

67.3.2 +++ NT NT NT

68.2.1 +++ ++ ++ NT

68.3.1 +++ ++ ++ NT

68.3.3 +++ ++ ++ ++

68.4.1 +++ +++ ++ ++

68.4.2 +++ NT NT NT

69.1.1 +++ +++ ++ ++

69.2.1 +++ NT +++ NT

69.2.2 +++ NT +++ NT

69.2.3 +++ NT ++ NT

69.3.2 +++ +++ +++ +++

69.4.1 +++ ++ ++ NT

69.4.2 +++ NT NT NT

70.4.2 ++ ++ inactive NT

71.4.2 ++ NT NT NT

72.1.3 +++ NT NT +++

73.1.2 +++ +++ ++ NT

75.3.1 NT NT +++ NT

~ 8'I
SUBSTITUTE SHEET (RULE 26) 7 4 3 ~ ~ 7 6 . 1 . 1 +++ NT NT NT

77.1.1 +++ NT NT NT

78.1.2 +++ NT NT +++

78.1.3 +++ NT NT +++

79.1.2 +++ NT NT +++

79.1.3 +++ NT NT +++

a ~3.
SUBSTITUTE SHEET (RULE 26)

Claims

WHAT IS CLAIMED IS:

1. A compound of formula (I):

or a pharmaceutically acceptable salt, hydrate or prodrug thereof, wherein:

R1 is a) -(C1-C12 alkyl)-X, b) -(C1-C12 alkenyl)-X, or c) X is a) halogen, b -CN, c) -NO2, d) -CF3, e) -NH2, f) -NHOR2, g) -NHC(=NH)R2, h) -NHC(=NH)NHOH, i) -NHC(=NH)NHHH2, j) -NHC(=NH)NHCN.

) -NHC(=NH)NHR2, j) -NHC(=NH)NHCOR2, k) -C(=NH)NHR2, l) -C(=NH)NHCOR2, m) -C(=O)NHR2, n) -CO2R2, o) -OR2, p) -OCF3, q) -S(O)r R2, r) -SC(=NH)NHR2 , or s) -SC(=NH)NHC(=O)R2;

R2 is a) hydrogen, or b) C1-C4 alkyl;

R3 is a) -C(=O)-aryl, b) -C(=O)-(CH2)p-CR6R7-(CH2)q-aryl, c) -C(=O)-(C2-C5 alkenyl)-aryl, d) -C(=O)-W-CR8R9-aryl, with the proviso that W
cannot be a bivalent oxygen atom, e) -C(=O)-CR8R9-W-(CH2)r-aryl, with the proviso that W cannot be -NR4- or -NC(=O)R4-, f) -C(=O)-heteroaryl, g) -C(=O)-(CH2)p-CR6R7-(CH2)q-heteroaryl, h) -C(=O)-(C2-C5 alkenyl)-heteroaryl, i) -C(=O)-W-CR8R9-heteroaryl, j) -C(=O)-CR8R9-W-(CH2)r-heteroaryl, with the proviso that W cannot be -NR4- or -NC(=O)R4-, k) -C(=O)-heterocycle, l) -C(=O)-(CH2)p-CR6R7-(CH2)q-heterocycle, m) -C(=O)-(C2-C5 alkenyl)-heterocycle, n) -C(=O)-W-CR8R9-heterocycle, o) -C(=O)-CR8R9-W-(CH2)r-heterocycle, with the proviso that W cannot be -NR4- or -NCOR4-, p) -C(=O)-(CH2)t-adamantyl, q) -C(=O)-(CH2)t-(C5-C7 cycloalkyl), r) -C(=O)-(CH2)t-W-(C5-C7 cycloalkyl), S) ,wherein aryl is limited to phenyl, t) ,wherein aryl is limited to phenyl, u) v) with the proviso that R13 cannot be -N(C1-C4 alkyl)2 when A is -C(=O)R14, a ~~

, wherein aryl is limted to phenyl;

jj) -(C(=O)-(CR8R9)-NR11')v-R11;
kk) -(C(=O)-(CR8R9)-NR11')v-C(=O)R11;
ll) -(C(=O)-(CR8R9)-NR11')v-C(=S)R11;
mm) nn) oo) -C(=O)-(CR8R9)-NHS(O)r R8;
pp) or ;

qq) R4 and R5 are independently selected at each occurrence from the group consisitng of:

a) hydrogen, b) C1-C4 alkyl, c) -(C1-C4 alkyl)-aryl, or d) C5-C7 cycloalkyl;
R6, R7, R8 and R9 are independently selected at each occurrence from the group consisting of:
a) hydrogen, b) C1-C4 alkyl, c) C1-C4 alkoxy, d) aryl, e) -(C1-C4 alkyl)-aryl, f) -(C1-C4 alkyl)-heterocycle, g) -O-aryl, h) -(CH2)p-CO2R4, i) R6 and R7 can be taken together to form a (C2-C7) alkyl, or j) R8 and R9 can be taken together to form a (C2-C7) alkyl;

R10 is:
phenyl, wherein phenyl is optionally substituted with one to three substituents selected from the group consisting of halogen, C1-C4 alkyl, C1-C4 alkoxy, C7-C15 alkylaryl, C7-C15 alkoxyaryl, methylenedioxy, -NO2, -CF3, -SH, -S(O)r-(C1-C4 alkyl), CN, -OH, -NH2, -NH(C1-C4 alkyl), -N(C1-C4 alkyl)2, -NHCOR4, -(CH2)p-CO2R4:

R11 is:

a) C1-C4 alkyl, b) C3-C6 cycloalkyl, c) -OR4, d) -NR15R16, e) -NC(=O)R15R16, f) -NR15C(=O)OR4, g) aryl, h) -(C1-C4 alkyl)-aryl, i) heteroaryl, j) -(C1-C4 alkyl)-heteroaryl, k) -(C1-C4 alkyl)-CO2R4, l) heterocycle, m) -(C1-C4 alkyl)heterocycle, n) R3 and R11, when taken together to form a ring bonded to the nitrogen:
a) ~ .s~

R4 and R11, when taken together, form - (CH2)2 - ;
R11' is independently selected at each occurrence from the group consisting of:
a) hydrogen;
b) C1-C4 alkyl c) -OR4 d) -NR15R16 e) -NC(=O)R15R16 f) -NR15C(=O)OR4 g) aryl, h) -(C1-C4 alkyl)-aryl, i) heteroaryl, j) -(C1-C4 alkyl)-heteroaryl, k) -(C1-C4 alkyl)-CO2R4, l) heterocycle, m) -(C1-C4 alkyl)heterocycle, R13 is independently selected at each occurrence from the group consisting of:
a) hydrogen b) halogen, c) C1-C4 alkyl, d) C1-C4 alkoxy, e) methylenedioxy, f) -NO2, g) -CF3.

h) -SH, i) -S(O)r-(C1-C4 alkyl), j) -CN, k) -OH, l) -NH2, m) -NH(C1-C4 alkyl), n) -N(C1-C4 alkyl)2, o) -NHC(=O)R4, or p) -(CH2)p-CO2R4:

R14 is:
a) -CF3, b) -CHF2, c) -CH2F, d) -CH2C1, e) -C(=O)OR4, f) -C(=O)NR15R16 9) -C(=O)R4, h) -C(=O)COOR4, i) -C(=O)C(=O)NR15R16, j) -C(=O)C(=O)R4, k) -CY3Y4COOR4, l) -CY3Y4C(=O)NR15R16, or m) -CY3Y4C(=O)R4:

R15 and R16 are independently selected at each occurrence from the group consisting of:
a) hydrogen, b) C1-C4 alkyl, c) -(C1-C4 alkyl)-aryl, d) C5-C7 cycloalkyl, or e) phenyl, unsubstituted or substituted by R13 R15 and R16, when taken together, form a ring selected from:
a) R17 is:
a) hydrogen, b) C1-C4 alkyl, c) aryl, d) -(C1-C4 alkyl)-aryl, or e) C5-C7 cycloalkyl;

R18 is:
a) hydrogen, b) -(C1-C5) alkyl, or c) -(C1-C5) haloalkyl, d) -(C1-C5) alkoxy;

R19 is:
a) hydrogen, b) -(C1-C5) alkyl, c) halo, or d) -(C1-C5) haloalkyl, e) -NO2, f) -NR4R5, g) -CN, h) -(C1-C5) alkoxy;

R20 is a) hydrogen; or b) -N2 with amine protecting;

A is:
a) -BY1Y2, or b) -C(=O)R14, c) C(OH)R14R18;

W is a) -O-, b) -S(O)r-, c) -NR4-, or d) -NC(=O)R4-;
Y1 and Y2 are a) -OH, b) -F, c) -NR4R5, d) C1-C8 alkoxy, or when taken together Y1 and Y2 form:
e) a cyclic boron ester where said chain or ring contains from 2 to 20 carbon atoms and, optionally, 1-3 heteroatoms which is N, S, or O, f) a cyclic boron amide where said chain or ring contains from 2 to 20 carbon atoms and, optionally, 1-3 heteroatoms which is N, S, or O, g) a cyclic boron amide-ester where said chain or ring contains from 2 to 20 carbon atoms and, optionally, 1-3 heteroatoms which is N, S, or O;
Y3 and Y4 are a) -OH or b) -F;
n is 0 or 1;
p is 0 to 3;

q is 0 to 4;
r is 0 to 2 ;
t is 1 to 3 ;
v is 1 to 17;

wherein aryl is defined as phenyl, fluorenyl, biphenyl and naphthyl, which may be unsubstituted or include optional substitution with one to three substituents;
heteroaryl is 2-, or 3-, or 4-pyridyl; 2-or 3-furyl;
2- or 3-benzofuranyl; 2-, or 3-thiophenyl; 2- or 3-benzo[b]thiophenyl; 2-, or 3-, or 4-quinolinyl; 1-, or 3-, or 4-isoquinolinyl; 2- or 3-pyrrolyl; 1- or 2- or 3- indolyl; 2-, or 4-, or 5-oxazolyl; 2-benzoxazolyl ;
2- or 4- or 5-imidazolyl; 1- or 2- benzimidazolyl;
2- or 4- or 5-thiazolyl; 2-benzothiazolyl; 3- or 4- or 5-isoxazolyl; 3- or 4- or 5-pyrazolyl; 3- or 4- or 5-isothiazolyl; 3- or 4-pyridazinyl; 2- or 4- or 5-pyrimidinyl; 2-pyrazinyl; 2-triazinyl; 3- or 4-cinnolinyl; 1-phthalazinyl; 2- or 4-quinazolinyl; or 2-quinoxalinyl ring; said ring(s) may be unsubstituted or include optional substitution with one to three substituents;

heterocycle is tetrahydroisoquinoline, tetrahydroquinoline, tetrahydrofuran, tetrahydrothiophene, piperidine, piperazine, morpholino; said ring(s) may be unsubstituted or include optional substitution with one to three substituents;
the substituents that may be attached to the aryl, heteroaryl and heterocycle ring(s) may be independently selected at each occurrence from the group consisting of:
halogen, C1-C4 alkyl, C1-C4 alkoxy, methylenedioxy, -NO2, -CF3, -SH, -S(O)r-(C1-C4 alkyl), CN, -OH, -NH2, -NH(C1-C4 alkyl), -N(C1-C4 alkyl)2, -NHC(=O)R4, -(CH2)p-CO2R4, phenyl which may be unsubstituted or substituted with R13.

2. A compound of claim 1 wherein:
A is -BY1Y2;
heteroaryl is 2-, 3-, or 4-pyridyl; 2-, or 3-furyl; 2-, or 3-thiophenyl; 2-, 3-, or 4-quinolinyl; or 1-, 3-, or 4-isoquinolinyl which may be unsubstitued or include optional substitution with one to three substituents;
heterocycle is 1-, 3-, or 4-tetrahydroisoquinolinyl, 2- or 3-pyrrolidinyl, and 2-, 3- or 4-piperidinyl which may be unsubstituted or include optional substitution with one to three substituents.

3. A compound of claim 2 selected from the group consisting of:
Hydrocinnamoyl-[N-(Phenethyl)-Gly]-boroOrn-C10H16 HC1 Hydrocinnamoyl-[N-(Phenethyl)-Gly]-boroOrn(CH=NH)-Hydrocinnamoyl-[N-(Phenethyl)-Gly]-boroOrn(CH=NH)-OH

Hydrocinnamoyl-[N-(Phenethyl)-Gly]-boroArg(CH3)-C10H16 Hydrocinnamoyl-[N-(N(CH3)2)-Gly]-boroLys-C10H16 HC1 Hydrocinnamoyl-[N-(N(CH3)2)-Gly]-boroLys-OH HC1 Hydrocinnamoyl-[N-(N(CH3)2)-Gly]-boroOrn-C10H16 HC1 Hydrocinnamoyl-[N-(N(CH3)2)-Gly]-boroOrn(CH=NH)-C10H16 Methanesulfonyl-Sar-[N-(Phenethyl)-Gly]-boroLys-C10H16 Methanesulfonyl-Sar-[N-(Phenethyl)-Gly]-boroLys-OH HC1 Methanesulfonyl-Gly-[N-(Phenethyl)-Gly)-boroLys-C10H16 Hydrocinnamoyl-(N-(3-(Trifluoromethyl)-Phenethyl)-Gly]-boroLys-C10H16 HC1 Hydrocinnamoyl-[N-(3-(Trifluoromethyl)-Phenethyl)-Gly]-boroLys-OH HC1 Hydrocinnamoyl-[N-(3-(Methyl)-Phenethyl)-Gly]-boroLys-Hydrocinnamoyl-[N-(3-(Methyl)-Phenethyl)-Gly]-boroLys-Succinyl-[N-(3-(Methyl)-Phenethyl)-Gly]-boroLys-C10H16 Hydrocinnamoyl-(N-(2,2-(Dimethyl)-Phenethyl)-Gly]-boroLys-OH HC1 Hydrocinnamoyl-[N-(2-(Cyclopropyl)-Phenethyl)-Gly]-boroLys-C10H16 HC1 Hydrocinnamoyl-[N-(2-(Cyclopropyl)-Phenethyl)-Gly]-boroLys-OH HC1 Hydrocinnamoyl-[N-(2-(Cyclopropyl)-Phenethyl)-Gly]-boroOrn(CH=NH)-OH HC1 Hydrocinnamoyl-[N-(2,2-(Diethyl)-Phenethyl)-Gly]-boroLys-C10H16 HC1 Hydrocinnamoyl-Sar-Lys[C(=O)-C(=O)-OH]
(2-(2-Cyano)-Thiophenyl)-Benzoyl-Sar-boroGly[CH2)3-Br]-(2-(2-Cyano)-Thiophenyl)-Benzoyl-Sar-boroGly[CH2)4)-Br]-C10H16 (2-(2-Cyano)-Thiophenyl)-Benzoyl-Sar-boroIrg-C10H16 HBr (2-(2-Cyano)-Thiophenyl)-Benzoyl-Sar-boroGly[CH2)3-N3]

(2-(2-Cyano)-Thiophenyl)-Benzoyl-Sar-borohomoIrg-C10H16 HBr (2-(2-Cyano)-Thiophenyl)-Benzoyl-Sar-boroGly[CH2)4)-N3]-C10H16 (2-(2-Cyano)-Thiophenyl)-Benzoyl-Sar-boroOrn-C10H16 HCl (2-(2-Cyano)-Thiophenyl)-Benzoyl-Sar-borohomoArg-C10H16 HCl (2-(2-Cyano)-Thiophenyl)-Benzoyl-Sar-boroArg-C10H16 HCl (2-(2-Cyano)-Thiophenyl)-Benzoyl-Sar-boroOrn(CH=NH)-C10H16 HCl (2-(2-Cyano)-Thiophenyl)-Benzoyl-Sar-boroLys(CH=NH)-C10H16 HCl 2-Benzyl-(N-Benzyl)-Sar-boroLys-C10H16 HCl 2-Thiophenyl-Benzoyl-Sar-boroLys(CH=NH)-C10H16 2-(Thiophenyl)-Benzoyl-Sar-boroIrg-C10H16 HBr 2-(Thiophenyl)-Benzoyl-Sar-boroOrn-C10H16 HCl 2-(Thiophenyl)-Benzoyl-Sar-boroOrn(CH=NH)-C10H16 HCl Pinanediol N-(N-methyl-N-(2-(Thiophenyl)-Benzoyl]Sar}-1-amido-5-thiocyanatobutane boronate (2-(2-Cyano)-Thiophenyl)-Benzoyl-Sar-boroLys-C10H16 HCl Acetyl-Gly[N-(2-(Benzyl)-Benzyl)]-boroLys-C10H16 HCl Pinanediol N-{N-methyl-N-[2-(pyrrol-1-ylmethyl)-Benzyl]glycyl}-1-amido-5-aminopentaneboronate, hydrochloride salt N-{N-methyl-N-[2-(pyrrol-1-ylmethyl)-Benzyl]glycyl}-1-amido-5-aminopentaneboronic acid, hydrochloride salt2-(2-(Trifluoromethyl)-Benzyl)-Benzoyl-Sar-Lys-C(=O)-NHNH2 2 HCl 2-(Benzyl)-Benzoyl-Sar-Lys-C(=O)-NHNH2 2 HCl [3-(Trifluoromethyl)-Benzyl]-Benzoyl-Sar-boroLys-C10H16 HCl 3-(3-(Chloro)-Benzyl)-Benzoyl-Sar-boroLys-C10H16 HCl Hydrocinnamoyl-Sar-Lys(Z)-C(=O)-O-(CH2)2-NH(Z) Hydrocinnamoyl-Sar-Lys-C(=O)-O-(CH2)2-NH2 2 HCl Hydrocinnamoyl-Sar-Lys(Z)-C(=O)-OCH3 Hydrocinnamoyl-Sar-Lys-C(=O)-OCH3 HCl Hydrocinnamoyl-Sar-Lys-C(=O)-CH3 HCl Hydrocinnamoyl-Sar-Lys(Z)-H
Hydrocinnamoyl-Sar-NHCH(CH2OH)(-CH2)4-NH(Z) Hydrocinnamoyl-Sar-NHCH(CH2OH)(CH2)4-NH2 Hydrocinnamoyl-Sar-Lys[CH(OH)(OCH3)-C(=O)-OCH3] HC1 Hydrocinnamoyl-(N-(Cyclopropyl)-Gly]-boroOrn-C10H16 HC1 Hydrocinnamoyl-[N-(Cyclopropyl)-Gly]-boroLys-OH HC1 Hydrocinnamoyl-[N-(Cyclopropyl)-Gly]-boroOrn(CH=NH)-OH

Hydrocinnamoyl-[N-(Cyclopropyl)-Gly]-boroOrn(CH=NH)-Hydrocinnamoyl-[N-(Cyclopropyl)-Gly]-boroLys(CH=NH)-Hydrocinnamoyl-[N-(Cyclopropyl)-Gly]-boroLys(CH=NH)-OH

Phenoxyacetyl-[N-(Cyclopropyl)-Gly]-boroLys-C10H16 HC1 Thiophenacetyl-[N-(Cyclopropyl)-Gly]-boroLys-C10H16 HC1 Phenoxyacetyl-[N-(Cyclopropyl)-Gly]-boroLys-OH HC1 Thiophenacetyl-[N-(Cyclopropyl)-Gly]-boroLys-OH HC1 Hydrocinnamoyl-[N-(N-(Methyl)-Phenyl)-Gly]-boroLys-Hydrocinnamoyl-[N-(N-(Methyl)-Phenyl)-Gly]-boroLys-OH

Hydrocinnamoyl-[N-(N-(Methyl)-Benzyl)-Gly]-boroLys-Glutaryl-[N-(Phenethyl)-Gly]-boroLys-OH HC1 Glutaryl(3,3-Dimethyl)-[N-(Phenethyl)-Gly]-boroLys-Methyl Glutaryl(3,3-Dimethyl)-[N-(Phenethyl)-Gly]-boroLys-C10H16 HC1 Glutaryl(3,3-Dimethyl)-[N-(Phenethyl)-Gly]-boroLys-OH
Methyl Glutaryl(3,3-Dimethyl)-[N-(Phenethyl)-Gly]-boroLys-OH HC1 Boc-Asp-[N-(Phenethyl)-Gly]-boroLys-C10H16 Boc-Glu-[N-(Phenethyl)-Gly]-boroLys-C10H16 Boc-Glu(OCH3)-[N-(Phenethyl)-Gly]-boroLys-C10H16 HC1 Boc-Glu-[N-(Phenethyl)-Gly]-boroLys-OH
Hydrocinnamoyl-[N-(N-(Methyl)-Benzyl)-Gly]-boroLys-OH

Methanesylfonyl-Gly-[N-(N-(Methyl)-Benzyl)-Gly]-boroLys-C10H16 HC1 Methanesulfonyl-Gly-[N-(N-(Methyl)-Benzyl)-Gly]-boroLys-OH HC1 Hydrocinnamoyl-[N-(Succinyl)-Gly]-boroLys-C10H16 Hydrocinnamoyl-[N-(Methyl Succinyl)-Gly]-boroLys-C10H16 Succinyl-[N-(Phenethyl)-Gly]-boroLys-OH
Methyl Succinyl-[N-(Phenethyl)-Gly]-boroLys-OH HC1 Glutaryl-[N-(Phenethyl)-Gly]-boroLys-C10H16 Methyl Glutaryl-[N-(Phenethyl)-Gly]-boroLys-C10H16 HC1 Methyl Glutaryl-[N-(Phenethyl)-Gly]-boroLys-OH HC1 [N-(-C(O)(CH2)2Ph)-N-(CH2CH2Ph)]-Gly-boroLys-OH
[N-(-C(O)(CH2)2Ph)-N-(CH2C(CH3)2Ph)]-Gly-boroLys-OH
[N-(-C(O)(CH2)2Ph)-N-(CH2C(ethanediyl)Ph)]-Gly-boroLys-OH
Hydrocinnamoyl-(N-(2-(Cyclopropyl)-Phenethyl)-Gly]-boroArg-C10H16 HC1 Hydrocinnamoyl-[N-(2-(Cyclopentyl)-Phenethyl)-Gly]-boroLys-C10H16 HC1 (2-(2-Cyano)-Thiophenyl)-Benzoyl-Sar-boroArg-OH HC1 Hydrocinnamoyl-[N-(2,2-(Dimethyl)-Phenethyl)-Gly]-boroLys-C10H16 HC1 Hydrocinnamoyl-[N-(2,2-(Dimethyl)-Phenethyl)-Gly]-boroOrn-C10H16 HC1 Hydrocinnamoyl-[N-(2,2-(Dimethyl)-Phenethyl)-Gly]-boroLys-OH HC1 Hydrocinnamoyl-[N-(2,2-(Dimethyl)-Phenethyl)-Gly]-boroArg-C10H16 HC1 Hydrocinnamoyl-[N-(2,2-(Dimethyl)-Phenethyl)-Gly]-boroOrn(CH=NH)-C10H16 HC1 Hydrocinnamoyl-[N-(2,2-(Dimethyl)-Phenethyl)-Gly]-boroArg-OH HC1 Hydrocinnamoyl-[N-(2,2-(Dimethyl)-Phenethyl)-Gly]-boroOrn(CH=NH)-OH HC1 Hydrocinnamoyl-[N-(2,2-(Dimethyl)-Phenethyl)-Gly]-boroOrn-C10H16 HC1 Hydrocinnamoyl-[N-(2,2-(Dimethyl)-Phenethyl)-Gly]-boroLys-C10H16 HC1 Hydrocinnamoyl-(N-[2-(3,5-dimethylphenyl)-ethyl]-Gly)-boroOrn-C10H16 HC1 Hydrocinnamoyl-(N-[2-(3,5-dimethylphenyl)-ethyl]-Gly)-boroLys-C10H16 HC1 Hydrocinnamoyl-(N-[2,2-(Dimethyl)-2-(3,5-dimethylphenyl)-ethyl]-Gly)-boroArg-C10H16 HC1 Hydrocinnamoyl-(N-[2,2-(Dimethyl)-2-(3,5-dimethylphenylphethyl]-Gly]-boroOrn(CH=NH)-C10H16 Hydrocinnamoyl-(N-[2-(3,5-dimethylphenyl)-ethyl]-Gly)-boroArg-C10H16 HC1 Hydrocinnamoyl-(N-[2-(3,5-dimethylphenyl)-ethyl]-Gly)-boroOrn(CH=NH)-C10H16 HC1 Hydrocinnamoyl-[N-(Cyclohexyl)-Gly]-boroLys-C10H16 HC1 Hydrocinnamoyl-[N-(Cyclopropyl)-Gly]-boroLys-C10H16 HC1 Hydrocinnamoyl-[N-(Cyclohexyl)-Gly]-boroLys-OH HC1

4. A pharmaceutical composition comprising a pharmaceutically suitable carrier and a therapeutically effective amount of a compound of claim 1.

5. A pharmaceutical composition comprising a pharmaceutically suitable carrier and a therapeutically effective amount of a compound of claim 2.

6. A pharmaceutical composition comprising a pharmaceutically suitable carrier and a therapeutically effective amount of a compound of claim 3.

7. Use of an effective amount of a compound of Claim 1 in the treatment of a physiological disorder in a warm blooded animal catalysed by trypsin-like enzymes.

8. Use of an effective amount of a compound of Claim 2 in the treatment of a physiological disorder in a warm blooded animal catalysed by trypsin-like enzymes.

9. Use of an effective amount of a compound of Claim 3 in the treatment of a physiological disorder in a warm blooded animal catalysed by trypsin-like enzymes.