WO 95109634 ~ ~PC?lUS9a/11280
Electrophilic Peptide Analogs As Inhibitors of Trypsin-Like
Enzymes
10
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
-3-
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):
-4-
SUBSTITUTE SHEET (RULE 26)
~~'~ X314
WO 95/09634 ~ PCTIUS94111280
. -.
R4 O
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
X 1S
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)
PCTJUS94/11280
WO 95/09634
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)
WO 95109634 PCTNS94111280
0 0
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
0
N W
~IJ
R~~
O
ff)
O O
N W
{CH2)r
9g)
s~
hh)
H or R~3-
ii)
-10-
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:
-11-
O
H or R'3
i,
(CHZ)i-heteroaryl
or
O
SUBSTITUTE SHEET (RULE 26)
PCT/US94/11280
WO 95/0963)
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~
-12-
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
-13-
SUBSTITUTE SHEET (RULE 26)
PCTIUS94111280
WO 95109634
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)
0
O
-(CH2)P
( ~ HorR'3
C)
O
(CHZ)r
~_ (CH2)P
HorR'3
d)
-1Q-
SUBSTITUTE SHEET (RULE 26)
""' WO 95109634 : PCTNS94/11280
217434
0
'~ ~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)
-15-
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),
-16-
SUBSTITUTE SHEET (RULE 26)
z ~ ~ ~~:~
WO 95/09634 , ~ '~ ; 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;
-17-
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
-18-
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
HC1
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
HC1
Succinyl-[N-(3-(Methyl)-Phenethyl)-Gly]-boroLys-C10H16 HC1
-20-
SUBSTITUTE SHEET (RULE 26)
;.
""° ' WO 95109634 PCT/US94111280
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 HCl
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]-
C10H16
(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]
C10H16
(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 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
HC1
(2-(2-Cyano)-Thiophenyl)-Benzoyl-Sar-boroLys(CH=NH)-C10H16
HC1
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
-21-
SUBSTITUTE SHEET (RULE 26)
WO 95109634 PCT/US94/11280
(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)-
NHNH2 2 HC1
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
HC1
Hydrocinnamoyl-[N-(Cyclopropyl)-Gly]-boroLys(CH=NH)-C10H16
HC1
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
-22-
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
HC1
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-
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-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-
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 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-
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
-23-
SUBSTITUTE SHEET (RULE 26)
WO 95/9634 PCTlUS94111280
Hydrocinnamoyl-[N-(2,2-(Dimethyl)-Phenethyl)-Gly]-boroArg-
C10H16 HC1
Hydrocinnamoyl-[N-(2,2-(Dimethyl)-Phenethyl)-Gly]-
boro0rn(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 HCl
Hydrocinnamoyl-[N-(2,2-(Dimethyl)-Phenethyl)-Gly]-boro0rn-
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 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
HC1
Hydrocinnamoyl-[N-(2-(Cyclopentyl)-Phenethyl)-Gly]-
boro0rn(CH=NH)-C10H16 HC1
Hydrocinnamoyl-[N-(2-(Cyclopentyl)-Phenethyl)-Gly]-boroArg-
C10H16 HC1
[N-(-C(O)(CH2)2Ph)-N-(CH3)]Gly-boroLys-OH
[N-(-C(O)(CH2)2Ph)-N-(CH2)2Ph]Gly-boroLys-OH
-24-
SUBSTITUTE SHEET (RULE 26)
2174314
"' 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
-25-
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)-
C10H16
[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)-
C10H16
[N-(-C(O)(CH2)2Ph)-N-(OH)]Gly-boroOrn(formamidino)-C1pH16
-26-
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
-27-
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-
C10H16
[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
-28-
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)
PCT/US94/11280
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
-30-
SUBSTITUTE SHEET (RULE 26)
PCTIUS94111280
«..... 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
-31-
SUBSTITUTE SHEET (RULE 26)
~1'~ 4314
WO 95/09634 PCT/US94/11280
[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
-32-
SUBSTITUTE SHEET (RULE 26)
~1'~~314
WO 95109634 PCT/US94111280
[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
-33-
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
-34-
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
-35-
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
-35-
SUBSTITUTE SHEET (RULE 26)
2174314
~~-- 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
-37-
SUBSTITUTE SHEET (RULE 26)
~1'~4314
WO 95/09634 PCTIUS94/11280
[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
-38-
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
-39-
SUBSTITUTE SHEET (RULE 26)
WO 95/09634 PCTIUS94/11280
~~ ?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
-40-
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
-41-
SUBSTITUTE SHEET (RULE 26)
PCTlUS94I11280
WO 95/09634
[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)-
C10H16
[N-(-C(O)Ph-3-CH2Ph)-N-(CH3)]Gly-boroOrn(N-methylamidino)-
C10H16
[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)-
C10H16
[N-(-C(O)(CH2)2Ph)-N-(n-C3H~)]Gly-boro0rn(N-methylamidino)-
C10H16
-42-
SUBSTITUTE SHEET (RULE 26)
WO 95/09634 , j; ; PCT/US94111280
[N-(-C(0)(CH2)2Ph)-N-(i-C3H~)]Gly-boro0rn(N-methylamidino)-
C10H16
[N-(-C(0)(CH2)2Ph)-N-(C6H12)]Gly-boroOrn(N-methylamidino)-
C10H16
[N-(-C(0)(CH2)2Ph)-N-(OH)]Gly-boro0rn(N-methylamidino)-
C10H16
[N-(-C(O)(CH2)2Ph)-N-(OCH3)]Gly-boroOrn(N-methylamidino)-
C10H16
[N-(-C(0)(CH2)2Ph)-N-(OCH2Ph)]Gly-boro0rn(N-methylamidino)-
C1pH16
[N-(~-C(O)(CH2)2Ph)-N-(NH2)]Gly-boroOrn(N-methylamidino)-
C10H16
[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)-
C10H16
[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)-
C10H16
[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
-43-
SUBSTITUTE SHEET (RULE 26)
WO 95/09634 PCT/US94/11280
[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)-
CF3
[N-(-C(O)Ph-3-SPh-3-OCH3)-N-(CH3)]Gly-Orn(N-methylamidino)-
CF3
[N-(-C(O)Ph-2-CH2Ph-2-Ph)-N-(CH3)]Gly-Orn(N-methylamidino)-
CF3
[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)-
CF3
[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)-
CF3
(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
-44-
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)-
CF3
[N-(-C(O)(CH2)2Ph-4-CH3)-N-(CH3)]Gly-Orn(N-methylamidino)-
CF3
[N-(-C(O)(CH2)2Ph-4-OCH3)-N-(CH3)]Gly-Orn(N-methylamidino)-
CF3
(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)-
OCH3
[N-(-C(0)Ph-3-CH2CH2Ph)-N-(CH3)]Gly-Orn(N-methylamidino)-
OCH3
[N-(-C(0)Ph-3-SPh-3-OCH3)-N-(CH3)]Gly-Orn(N-methylamidino)-
OCH3
(N-(-C(0)Ph-2-CH2Ph-2-Ph)-N-(CH3)]Gly-Orn(N-methylamidino)-
OCH3
[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)-
OCH3
[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
-45-
SUBSTITUTE SHEET (RULE 26)
WO 95109634 PCTIUS94111280
[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)-
OCH3
[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)-
OCH3
[N-(-C(O)(CH2)2Ph-4-CH3)-N-(CH3)]Gly-Orn(N-methylamidino)-
OCH3
[N-(-C(O)(CH2)2Ph-4-OCH3)-N-(CH3)]Gly-Orn(N-methylamidino)-
OCH3
[N-(-C(0)(CH2)2Ph)-N-(CH3)]Gly-Orn(N-methylamidino)-C02CH3
[N-(-C(O)(CH2)2Ph)-N-(CH2)2Ph]Gly-Orn(N-methylamidino)-
2 0 C02CH3
[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)-
C02CH3
[N-(-C(O)Ph-3-CH2CH2Ph)-N-(CH3)]Gly-Orn(N-methylamidino)-
C02CH3
[N-(-C(O)Ph-3-SPh-3-OCH3)-N-(CH3)]Gly-Orn(N-methylamidino)-
C02CH3
[N-(-C(O)Ph-2-CH2Ph-2-Ph)-N-(CH3)]Gly-Orn(N-methylamidino)-
C02CH3
[N-(-C(O)Ph-4-CHZPh)-N-(CH3)]Gly-Orn(N-methylamidino)-
C02CH3
[N-(-C(O)Ph-2-CH2Ph)-N-(CH3)]Gly-Orn(N-methylamidino)-
C02CH3
-46-
SUBSTITUTE SHEET (RULE 26)
WO 95/09634 '
~ ~.'~ 4 31 ~ pCTIUS94111280
[N-(-C(O)Ph-3-CH2Ph)-N-(CH3)]Gly-Orn(N-methylamidino)-
C02CH3
[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)-
C02CH3
[N-(-C(O)(CH2)2Ph)-N-(C2H5)]Gly-Orn(N-methylamidino)-C02CH3
[N-(-C(0)(CH2)2Ph)-N-(n-C3H~)]Gly-Orn(N-methylamidino)-
C02CH3
[N-(-C(0)(CH2)2Ph)-N-(i-C3H~)]Gly-Orn(N-methylamidino)-
C02CH3
[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)-
C02CH3
[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)-
C02CH3
[N-(-C(0)(CH2)2Ph)-N-(NHBoc)]Gly-Orn(N-methylamidino)-
C02CH3
[N-(-C(0)(CH2)2Ph)-N-(CH2C02H)]Gly-Orn(N-methylamidino)-
C02CH3
[N-(-C(O)(CH2)2Ph)-N-(CH2C02CH3)]Gly-Orn(N-methylamidino)-
C02CH3
(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)-
C02CH3
[N-(-C(O)(CH2)2Ph-4-CH3)-N-(CH3)]Gly-Orn(N-methylamidino)-
3 5 C02CH3
-47-
SUBSTITUTE SHEET (RULE 26)
WO 95109634 ~ 1'7 4 31 ~ , PCTIUS94I11280
[N-(-C(O)(CH2)2Ph-4-OCH3)-N-(CH3)]Gly-Orn(N-methylamidino)-
C02CH3
[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
-48-
SUBSTITUTE SHEET (RULE 26)
WO 95/09634
PCTlUS94111280
[N-(-C(0)(CH2)2Ph)-N-(CH3)]Gly-boro0rn(formamidino)-C1pH16
[N-(-C(O)(CH2)2Ph)-N-(CH2)2Ph]Gly-boroOrn(formamidino)-
C10H16
[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)-
C10H16
(N-(-C(O)Ph-3-CH2CH2Ph)-N-(CH3)]Gly-boroOrn(formamidino)-
C10H16
[N-(-C(O)Ph-3-SPh-3-OCH3)-N-(CH3)]Gly-boroOrn(formamidino)-
C10H16
[N-(-C(O)Ph-2-CH2Ph-2-Ph)-N-(CH3)]Gly-boroOrn(formamidino)-
C10H16
[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)-
C10H16
(N-(-C(O)(CH2)2Ph)-N-(i-C3H~)]Gly-boroOrn(formamidino)-
C10H16
[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)-
C10H16
[N-(-C(O)(CH2)2Ph)-N-(NH2)]Gly-boroOrn(formamidino)-C10H16
(N-(-C(0)(CH2)2Ph)-N-(N(CH3)2)]Gly-boro0rn(formamidino)-
C10H16
[N-(-C(O)(CH2)2Ph)-N-(NHBoc)]Gly-boroOrn(formamidino)-C1pH16
[N-(-C(O)(CH2)2Ph)-N-(CH2C02H)]Gly-boroOrn(formamidino)-
C10H16
[N-(-C(O)(CH2)2Ph)-N-(CH2C02CH3)]Gly-boroOrn(formamidino)-
C10H16
[N-(-C(O)CH2Ph)-N-(CH3)]Gly-boro0rn(formamidino)-C1pH16
[N-(-C(O)(CH2)3Ph)-N-(CH3)]Gly-boro0rn(formamidino)-C1pH16
-49-
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)-
C10H16
[N-(-C(O)(CH2)2Ph-4-CH3)-N-(CH3)]Gly-boroOrn(formamidino)-
C10H16
[N-(-C(O)(CH2)2Ph-4-OCH3)-N-(CH3)]Gly-boroOrniformamidino)-
C10H16
[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
-50-
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)-
OCH3
[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
-51-
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)-
C02CH3
[N-(-C(O)Ph-2-CH2Ph-2-Ph)-N-(CH3)]Gly-Orn(formamidino)-
C02CH3
[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)-
C02CH3
[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)-
COZCH3
[N-(-C(O)(CH2)2Ph)-N-(CH2C02CH3)]Gly-Orn(formamidino)-
3 5 C02CH3
[N-(-C(0)CH2Ph)-N-(CH3)]Gly-Orn(formamidino)-C02CH3
-52-
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)-
C02CH3
[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)-
C02CH3
[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-
-53-
SUBSTITUTE SHEET (RULE 26)
WO 95109634 PCT/US94111280
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-
-54-
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)
PCT/US94111280
WO 95/09634
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
-58-
SUBSTITUTE SHEET (RULE 26)
PCTIUS94111280
WO 95109634
[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
-60-
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,
-61-
SUBSTITUTE SHEET (RULE 26)
PCTlUS94111280
W O 95109634
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
/ CH3 O NH
'H
and [N-(-C(O)(CH2)2Ph-4-OCH3)-N-(CH3)]Gly-boroPhe(mCN)-OH
represents
O IH
B
\ N N ~O H
/ CH3 O
H3C0
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
-52-
SUBSTITUTE SHEET (RULE 26)
WO 95/U963a PCTlUS94111180
217414
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.
-63-
SUBSTITUTE SHEET (RULE 26)
WO 95/09634 PCTIUS94111280
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-
-64-
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.
-65-
SUBSTITUTE SHEET (RULE 26)
WO 9510963 PCTIUS9411128(1
217434
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.
-65-
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).
30
- 67 -
WO 95109634 PCTIUS94I11280
Scheme 1
Ra Rs Ra Rs Ra Rs
OM -= R~1HN OM -= R1~R3N OM
H2N
O 0
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
-68-
SUBSTITUTE SHEET (RULE 26)
WO 95/09634 PCT/US94/11280
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.
-70-
SUBSTITUTE SHEET (RULE 26)
~ ' i
~ 17 4 31 ~ pCT~S94111280
WO 95/09634
Scheme 2
Ra Rs Ra Rs
OM OM L= ~-N-R"
J ~ ~ L ~ s
R
0 O
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
-71-
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
R3
(VIII):y=4 (X):y=4
-72-
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.
-73-
SUBSTITUTE SHEET (RULE 26)
PCTlUS94/11280
WO 95/09634
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.
-74-
SUBSTITUTE SHEET (RULE 26)
WO 95/09634 ~. ~ ! ~ 3 ~ 4 PCT/US94111280
Scheme 4
o~~o O o~ ~o O o~~o
0
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 =
0
(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
-75-
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
-76-
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)
WO 95/09634 PCT/US94111280
~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
0 0
o~~o O ~~ O
1 NR3R~~ ~ NR3R»
(CH2)~ N _---r (CH2)a N _---r
5
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
WO 95109634
Scheme 6
0 0
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
NH H RS R4
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
-80-
SUBSTITUTE SHEET (RULE 26)
WO 95/09634 J PCT/US94111280
Scheme 7
0 0
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).
-81-
SUBSTITUTE SHEET (RULE 26)
PCT/US94111280
WO 95109634
Scheme 8.
0 0 0 0
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
-82-
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
H2N
(XXXIa) : A = B~ (XXXIIa)
1
1
(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
-83-
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
-84-
SUBSTITUTE SHEET (RULE 26)
y PCT/US94I11280
WO 95109634
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
1
O.B.~ ~ ~ A O
NR3R" ~ N~ NR3R"
N ' a 5
H Ra R5 \ H R R
I '~~ I ~~
'NH NHC(=NH)NH2
2
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
PCT/US94I11280
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)
WO 95109634 PCT/US94111280
~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
M02C MOZC
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.
R4 R5 M02C MOZC O
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)
PCT/US94/11280
WO 95/09634
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
I O R3 O D
R3
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,
-90-
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).
-91-
SUBSTITUTE SHEET (RULE 26)
WO 95109634 PCTlUS94111280
X174314
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.
-92-
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)
1
Ra Rs H
0 = (CH2)~.~2 or (CHZ)qC6Ha(CH2)p N C(=O)CHJ2
R~~N
R3 O
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
-93-
SUBSTITUTE SHEET (RULE 26)
WO 95109634 PCTIUS94I11280
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) .
-94-
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
WO 95/09634
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).
-96-
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.
-99-
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
OH X OCH3
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.
-100-
SUBSTITUTE SHEET (RULE 26)
~"""'~ WO 95109634 ~ ~ 3 ~.4~. , '~ ; .., PCTIUS94I11280
Scheme 22.
CH2C12 1) Oxalychloiide
-10°C 2)DMS
3)TEA
O HO OCH3
X OCH3 X OCH3
i n ~ O ~n ~ O
N H MeOH N H
p Rt
3
LXXI11 R4 Rs N- R 4 N- R3
R R Rs Rii
LiOH
MeOH/H20
RT
O
X OH
O
NH
O
N- R3
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.
-101-
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
CH2C12 N H BOC
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.
-102-
SUBSTITUTE SHEET (RULE 26)
WO 95/09634 PCT/US94111280
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~
NH O NH2 O
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.
-103-
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
4
O . R5 O
HO ~
-..~ N~ ~
l , ~,~
XCI
1
X~~A
In
NH
O
R3
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
-104-
SUBSTITUTE SHEET (RULE 26)
WO 95109634 PCT/US94111280
~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)
WO 95109634 PCT/US94111280
X174314
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.
-106-
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
4
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
R4
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,
-107-
SUBSTITUTE SHEET (RULE 26)
WO 95/09634 PCT/US94111280
~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
-108-
SUBSTITUTE SHEET (RULE 26)
WO 95109634 PCTIUS94I11280
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
-109-
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.
-110-
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
-112-
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-
-113-
SUBSTITUTE SHEET (RULE 26)
PCT/US94111280
WO 95109634
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
-114-
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
-115-
SUBSTITUTE SHEET (RULE 26)
WO 95109634 PCT/US94/11280
~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.
20
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:
-116-
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 .
-117-
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),
-119-
SUBSTITUTE SHEET (RULE 26)
WO 95/0963.1 PC17OS94/11Z80
2174314
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 ~ -
-120-
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-
-121-
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.
-122-
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
-123-
SUBSTITUTE SHEET (RULE 26)
WO 95/09634 PCT/US94111280
~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
-124-
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
-125-
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.
-126-
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.
-127-
SUBSTITUTE SHEET (RULE 26)
~1'~~~L~
WO 95109634 PCT/US94/11280
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
-128-
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-
-129-
SUBSTITUTE SHEET (RULE 26)
WO 95/09634 PCTIUS94I11280
~~'~~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.
-130-
SUBSTITUTE SHEET (RULE 26)
WO 95109634 217 4 314 PCTIUS94I11280
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
-131-
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)+.
5
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
-132-
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)+.
-133-
SUBSTITUTE SHEET (RULE 26)
PCTIUS94/11280
WD 95/09634
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
-134-
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.
-135-
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-
-136-
SUBSTITUTE SHEET (RULE 26)
X174314
""'"' 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-
-137-
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
-138-
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
-139-
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
-140-
SUBSTITUTE SHEET (RULE 26)
PCTlUS94/11280
W O 95/09634
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
-141-
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
-142-
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
-143-
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
-144-
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
-145-
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 .
-146-
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
-147-
SUBSTITUTE SHEET (RULE 26)
WO 95/09634 PCT/US94/11280
~'~ 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
-148-
SUBSTITUTE SHEET (RULE 26)
WO 95109634 PCT/US94111280
~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
-149-
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
-150-
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) +.
-151-
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
-152-
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
-153-
SUBSTITUTE SHEET (RULE 26)
WO 95/09634 PCT/US94111280
~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
-154-
SUBSTITUTE SHEET (RULE 26)
PCT/US94111280
WO 95/09634
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.
-155-
SUBSTITUTE SHEET (RULE 26)
WO 95/09634 PCTIUS94/11280
~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
-156-
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
-157-
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
-158-
SUBSTITUTE SHEET (RULE 26)
~i~ 4~,~.4
PCTJUS94111280
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
-159-
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
-160-
SUBSTITUTE SHEET (RULE 26)
WO 95/09634 PCTIUS94I11280
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
-161-
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)
WO 95/09634 PCT/US94111280
~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-
2-
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
IG3
SUBSTITUTE SHEET (RULE 26)
WO 95/09634 PCT/US94111280
~~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
I / 1
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
1
/47
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)
PCTIUS94111280
.-. WO 95109634
20 -C(Uhn-1'hSPh -C'(O)C'Ii~lm-Ph -C(U)C1I~CH?lm-PhSPh)
4
. -C(O)p-PhSPh -C(U)CIi~(P-PhSPh)-C(O)CI-I2CH2(P-PhSPh
21 )
4
. -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-
23
. 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)
25
. -C(U)cyclopentvl -C(O)CH~(cvcloPcntyl)-C(O)CH~CH~((cyclopentyl)
4
26
. 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-
2-
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)
WO 95109634 PCT/US94/11280
~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-
0 0
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)
WO 95/09634 PCT/US94/11280
,,
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)
1
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
WO 95109634
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~_~
WO 95/09634 PCT/US94/11280
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
0
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)
1
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)
1
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-
2-
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-
3-
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
0 0
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)
WO 95/09634 PCT/US94111280
~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)
1
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)
1
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)
PCT/US94I11280
WO 95109634
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)
PCTIUS94I11280
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)
X174314
'~° 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)
/S3
SUBSTITUTE SHEET (RULE 26)
~~~~J~~~
WO 95109634 PCTIUS94II1280
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
1
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-
3-
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
WO 95/09634 PCT/US94111280
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 =
CH3
.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
WO 95/09634
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-
2-
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)
X98
SUBSTITUTE SHEET (RULE 26)
4 ~ ~ ~ PCTlUS94I11280
WO 95109634
23 -C(U)Cl-12(m-I'hC112SPh)-C(U)CH2CH2(m-
-C(U)m-I'hCII2S1'h
17
. PhCH~SPh)
24 -C(O)p-1'hCl-I2SPh-C(U)Cll2(P-PhCII2SPh)-C(O)CH2CH2(p-
17
. PhCH~SPh)
25 -C(U)adurt><'tntyl-C(U)ClI2(advn:uUyl)-C'(O)CH2CH2(adamanry
17
. -C(Okyclopentyl -C(O)CI-h(cvclopentyl)-C(O)CHZCH2((cycloPentyl)
26
17
. -C(O)cyclohexvl -C(U)CII~(cvclohexvl)-C(U)CI-i2CH2(cyclohexyl)
27
17
. -C(O)CH2U(cvclopentyl)-Cl0)Cll~Nl-I(cvclopentyl)-C(O)CH2S(cyclopenty
28
17
. 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
33
. -C(O)furart-3-yl -C'(O)CII~(furtn-3-yl)-C(O)CH2CH2(furan-3-yl)
34
17
. -C(U)Uuonhen-2-Y1 -C(O)CI1~(Uuophen-2-yl)-C(O)CH~CH2(U~iophen-2-yl)
17
35
. -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)-
17
. 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)
1
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 ~
WO 95/09634 PCT/US94/11280
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
3
. -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
5
. -C(O)o-PItCH~CU01-I-C(U)m-PhCI-12CUUH -C(U)P-PhCH2COOH
18
6
. -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
WO 95/09634 4
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-
3-
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)
WO 95/09634 PCTIUS94/11280
~~ 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)
1
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-
2-
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)
WO 95/09634 PCT/US94I11280
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 =
CH3
.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-
21
. PhCH2SPh )
23 -C(U)m-I'hCH2SPh -C(O)CII2(m-I'hCll2SPh)-C(O)CI-I2CH2(m-
21
. 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
2
22
. -C(U)o-PhOH -C(O)m-PhOLI -C(0) -PhOH
22
3
. -C(Uk~-PhCI-I2pH -C(U)m-PhCH2pH -C(O)p-PhCH20H
4
22
. -C(O)o-PhCOOH -C(C))m-Ph COOH -C(O) -PhCOOH
22
. -C(O?o-PhCH2CUOH -C(U)m-PhCH~COOH -C(O)p-PhCH2COOH
6
22
. -C(O)naphth-1-yl -C(U)CI~~(naphth-1-vl)-C(O)CH2CH2(napth-1-yl)
7
22
. l -C(O)CH2CH2(napth-2-yl)
2
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)-
9 -C
. -C(O)m-biPhenvl -C(U)Cl-12(m-biphenyl)-C(O)CH2CH2(m-biphenyl)
22
. -C(O)p-hiphenyl -C(O)Cl i~(p-biphenyl)-C(O)C1~2CH2(p-biphenyl)
12
22
. ' 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)
22
. -C(U)m-l'hNHph -C(O)Cli2(m-I'hNllPh)-C'(O)CH2CH2(m-PhNHPh)
17
22
. -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
0 0
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)
1
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-
2-
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
1
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)
1
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)
217 4 314 PCTJUS94/11280
WO 95/09634
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-
2-
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)
WO 95/09634 PCTJU594111280
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)
WO 95/09634 PCT/US94I11280
~~ 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)
PCT/US94111280
WO 95109634
~'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-
3-
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
0 0
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)
1
'
'
27.7 -C(U)naphtlrl-vl -v -C(O)CH~CH2(napQr2-yl)
lh(naphU~-
(U)C
-C
l
2
'
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)
WO 95/09634 PCT/US94111280
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-
2-
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
WO 95/09634
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)
WO 95109634 PCT/US94111280
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
WO 95109634 PCTIUS94I11280
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)
WO 95109634 PCT/US94111280
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)
WO 95109634 PCT/US94111280
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)
WO 95109634 PCT/US94111280
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
0 0
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
0 0
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-
0 0
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)
WO 95/09634 ~ 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 O N 0
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)
X174314
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)
PCTIUS94111280
W O 95109634
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-
2-
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~
WO 95/09634 PCTIUS94/11280
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
40
2
. -C(U)o-Ph0lI -C(U)m-PhUII -C(U) -PhOH
40
3
. -C(O)o-I'ItCI-I~UI~-('(())m-I'hCII~UII-C'(U)P-1'hC1120H
40
4
. -C(O)o-l'hC001-1 -C'((m-I'hC'()UII -C(()) -PhCOOH
40
. COOH
-PhCH
-C(U)
40 -C(O)o-PhCIhCUUII-C(U)tn-PhCIi~CU0112
6 P
. -C(U)naphth-1-yl -C(U)CI1~(naPhth-1-vl)-C'(O)CI-hCH2(napQt-1-yl)
40
7
. -C(O)CH~CH~(napth-2-yl)
40 -C(U)naphUt-2-yl -C(OlCll~(naPltlh-2-y!
8
. -C(O)a-hiPhenvl -C(U)C'.I1~(a-hiphenyl)-C(U)CII2CH2(o-hiphenyl)
40
9
. -C(U)m-hiphenvl -C(U)C'Ih(m-hiphenvl)-C'(O)CH~CH~(m-biphenyl)
40
. -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)
13
. -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)
16
. -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)
WO 95/09634 PCTIUS94111280
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-
3-
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)
PCT1US94111280
W O 95/09634
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)
WO 95/09634 PCT/US94111280
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 =
CH3
.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
WO 95109634
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-
2-
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)
WO 95/09634 PCT/US94/11280
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)
WO 95/09634 PCTIUS94111280
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)
WO 95/09634 PCT/US94/11280
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)
WO 95109634 PCTIUS94/11280
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
0
SUBSTITUTE SHEET (RULE 26)
6 PCTIUS94/11280
WO 95/09634
~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)
WO 95109634 PCT/US94111280
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
1
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~~~~
WO 95109634 PCT/US94111280
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)
WO 95/09634 PCT/US9-1111280
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)
WO 95109634 PCT/US94111280
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)
ZCH3
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)
PCTIUS94111280
W O 95109634
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)
PCTIUS94111280
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
1 5 10
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
1 5 10
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
1 5 10
Gly
SUBSTITUTE SHEET (RULE 26)
WO 95/09634 PCT/US94111280
~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)
PCTIUS94/11280
W O 9510963
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
W O 95109634
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)
17 4 314 PCTIUS94111280
W O 95109634 M
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)
WO 95/09634 PCT/US94111280
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)
