Note: Descriptions are shown in the official language in which they were submitted.
WO 95109859 ~ l 7 i 31 i PCT/US94111~)49
~L~
Boropeptide Inhibitors of Thrombin which Contain a
Substituted Pyrrolidine Ring
Field of the Invention
This invention relates to the discovery of novel
and useful a-amino acid analogs, and the
lO pharmaceutically acceFtable salts or prodrugs thereof,
as inhibitors of thrombin. These compounds contain a
disubstituted- pyrrolidine ring con~ugated to an a-amino
acid functionalized with an electrophilic group such as
boronic acids and their esters, a-perhaloketones and
l j aldehydes .
Back~ro1~nd of the Invention
Thrombin plays several criticaI roles in
20 hemostasis, the normal physiological process by which
bleeding from an injured blood vesse' is arrested.
Thrombin cleaves soluble fibrinogen to form insoluble
fibrin in the last proteolytic step of botk the
e~:trinsic and intrinsic pathways of the coagulation
2~ cascade. Fibrin may be further insolubilized through
crosslinking by the thrombin-activated enzyme, factor
XIIIa. In addition, thrombin-induced activation of
platelets leads to their aggregation and the secretion
of additional factors that further accelerate creation
30 of a hemostatic plug. Thrombin also potentiates its own
production by the activation of factors V and VIII.
Recent reviews of the roles of thrombin in coagulation
have been reported by E enton in Ann. N. Y. Acad. Sci .
485, 5-15 (1986), and ~?enton et al. in E3lood Coagulation
3S and ~iorinolysis 2, 69--75 (l99l) .
WO 95l098S9 217 ~ 3 ~ 1 PCTNS94/1 1049
:,
Owing to its mult~ip~e r~o~es in clot ~ormation,
inhibition of thrombin offers a therapeutic opportunity
for development of anticoagulants useful in the
treatment of thrombosis. Specific thrombin inhibitors
5 are anticipated to exhibit few of the adverse side
effects, such zs bleeding and interpatient variability,
caused by anticoagulants currently in clinical use (B.
Furie and B. C. Furie, The New England Journal of
Medicine 326, 800-806 ~1992~ ) .
A number of naturally occurring thrombin inhibitors
have been isolated. These include the marine sponge
natural products Theonella sp. nazumamide A, a linear
tetrapeptide reported by Fusetani et al., Tetrahedron
Lett. 32, 7073-q (1991); Theonella sp. cyclotheonamides
A and B reported by Fusenati et al., J. Am. Chem. Soc.
112, 7053-4 (1990); and Toxadocia cylindrica toxad~ocial
A, a sulfated C47 aldehyde reported by Nakao et al.,
Tetrahedron Lett. 34, 1511. 4 (1993) . Hirudin, a 65
amino acid polypeptide, is responsible for the
antico~gulant activity of the medicinal leech, ~irudo
medicinalis. Recombinant versions of hirudin disclosed
by Brauer et al. in AU-A-45977/85 and compounds
incorporating hirudin fragme~nts that have been disclosed
by Maraganore et al. in PCT application WO91/02750;
DiMaio et al . , J. Med. Chem. 35, 3331-3341 (1992);
DiMaio and Konishi, PCT application WO91/19734; Witting
et al., Biochem. J. 283, 737-7q3 (1992); Krstenansky in
European Patent Application EP 372 503 A2; may be
clinically useful anticoagulants as suggested by Fareed
et al., Blood Coagulation and Fibrinolysis 2, 135-L47
(1991).
Peptide analogs of thrombin substrates and reaction
intermediates also inhibit thrombin. Examples of these
include the tripeptide aldehyde (D)-Phe-Pro-Arg-H,
disclosed by Ba jusz et al., Int. J. Peptide E'rotein Res.
12, 217-221 (1978); a chloromethyl ketone analog (Ac-
wo 95f098S9 ~ 1 7 4 3 i ~ PcrluS94/11û49
he-pro-ArgcH2cl~ disclosed by Kettner and Shaw,
~h~orrb. Res. 14, 969-73 ~1979); polyfluorinated an210gs
such as (D)-phe-pro-Arg-cF2-cF3 disclosed by Kolb et al.,
Al~-B-52881/86; Neises and Ganzhorn, European Patent
Application EP 503 203 Al;
Neises et al., European Patent Application EP 504 064
Al); and boronlc acid analogs (Ac- (D)-Phe-Pro-boroArg,
Kettner and Shenvi, European Patent Application EP 0 293
881 A2; Kettner et al., J. Biol. Chem. 265, 18289-97
(1990). Borolysine, boroornithine and boroarginine
inhibitors that contai]l various amino acid replacements
have also been synthesized and shown to inhibit
thrombin. Representative examples of these compounds
include t-butyloxycarbonyl- (D) -trimethylsilylalanine-Pro-
1~ boroArg-pinanediol, disclosed in Metternich, European
Patent Application EP 971 651 A2; Ac- ~D~
napthylalanine-Pro-boroArg pinanediol ester, disclosed
in Kakkar et al., PCT Application WO 92/07869; N- (t-
butyloxycarbonyl) - ~D)-phenylglycyl- ~L)-prolyl- ~L)-
arginine aldehyde, disclosed in Gesellchen and Shuman,
European Patent Application EP 0 479 489 A2 and J. Med.
Chem. 36, 314-319 (1993); and (HOOC-CH2)2-(L)-,B-
cyclohexylalanine-Pro-Arg-CH2-O-CH2-CF3, disclosed by
Atrash et al., European Patent Application EP 530 16
2~ Al.
Numerous synthetic thrombln inhibitors, many of
which incorporate an arginine or arginine mimic, have
also been disclosed. These include arylsulfonylarginine
amides such as (2~, 4~) -1- [N2- (3-ethyl-1, 2, 3, q-
3G tetrahydro-8-quinolinesulfonyl ) - (L) -arginyl ] -4-methyl-2-
piperidinecarboxylate, disclosed by Okamoto et al., ~.S.
Patent No. 4,258,1g2; Okamoto et al., ~liochem. Piophys.
~es. Commun. 101, 440--446 (1981); Kikumoto et al.,
~iochemistry 23, 85-90 (1984); amidinophenylalanine
derivatives such as (2-naphthylsulfonylglycyl)-4-
amidino-phenylalanyl piperidine disclosed in Stuber and
wo 95,0g859 2 1 7 4 3 1 i - PCr/US94/11049
Dlckneite, European Patent Application EP 508 22a; amino
phenylalanine derivatives, disclosed in Okamolo et 21.,
U.S. Patent No. 4,895,892; 1_[2-[5_
(dimethylamino) naphth-l-ylsulfonamido] -3- (2-
5 imin ohexahydropy r imi di n - 5 -y 1 ) propanoy 1 ] - 4 -
methylpiperidine dihydrochloride, disclosed in Ishikawa
et al., JP 88/227572 and JP 88/227573); and (R) -N- [ (RS) -
1-amidino-3-piperidinylmethyl ] -n- (o-nitro-
benzenesulfonamido) indole-3-propionamide, disclosed in
10 Ackermann et al ., European Patent Application EP 4 68
231) . Isoquinolinyl guanidino benzoate derivatives,
disclosed by Takeshita et al., European Patent
Application EP 435 235 A1; and 2- [3- (4-
amidinophenyl) ]propionic acid derivatives, disclosed by
Mack et al., PCT Application WO 93/01208 also act as
thrombin inhibitors.
Many natural and synthetic thrombin inhibitors
contain a 5-membered pyrrolidine rins. In most cases,
the pyrrolidine rlng is incorporated into the inhibito~
2C as an integral c~mponent of the amino acid proline, a 2-
substituted pyrrolidine, which in turn is bonded to the
remaining atoms of the lnhibitor via amide linkages
None of the clted references describe or suggest the new
thrombin-inhibiting compounds of the presen_ inventio~..
2~ The novel compounds described in the present
invention are substituted at the 4-position of the
pyrrolidine ring. Although Winter et al., in European
Patent Application WO 91/04247, have disclosed that 4-
substituted- lL) -proline can mimic a dipeptide within a
30 larger peptide or protein, and variably substituted
prolines have been incorporated into compounds includinq
bradykinin antagonists disclosed by ~yle et al., J.
Med. '`hem. 34, 2649-2653 (1991); as well as vasopressin
analogs Buku et al., J. Med. Chem. 30, 1509-1512 (1987),
3~ no thrombin inhibitors containing a 5-membered
WO 95109859 PCT/US94/11049
2~L7~311j~
pyrrolidine ring substi tuted in tbe manner described
here: have been disclosed.
Despite considerable research in the area, more
efficacious and specifi,c thrombin inhibitors are needed
5 as potentially valuable therapeutic agents for the
treatment of thrombosis.
Summary of the Invention
[ l ] The present inven~:ion provides novel compounds of
f ormu la ( I ):
R3--V F~11
N~ r~ CH--A
R10_z H R
1 5
or a pharmaceutically acceptable salt or prodrug
thereof, wherein:
~l is
2' a) - (C1-Cl2 alkyl) -X, or
b) - (C2-Cl2 a1 ken~ X, or
c)
(C H2)m
I! , (CH2)n- X
25 X is
-
W095/09859 ~ t y ~ `, . ' PCT/17S9~/110~9
~7~3i1
a) halogen,
b) -CN,
c ) -N0
d) -CF3~
5 e) -S(O)pR2,
f ) -NHR2,
g) -NHS (O) pR2,
h) -NHC (=NH) H,
i ) -NHC (=NH) NHOH,
j) -NHC (=NH) NHCN,
k ) - NHC ( =NH ) NHR2,
1) -NHC (=NH) NHC (=O) R2,
m) -C (=NH) H,
n) -C (=NH) NHR2,
o) -C (=NH) NHC (=O) R2,
p~ -C (=O) NHR2,
q) -C (=O) NHC (=O) R2,
r) -C (=O) oR2,
S) -oR2,
2G t) -OC (=O) R2,
U) -OC ~=O) oR2,
v) -OC (=O) NHR2,
) -OC (=O) NHC (=O) R~,
~.) -SC (=NH) NHR
2~
R2 is
a) hydrogen,
b) -CF3
c) C1-C4 alkyl,
d) - (CH2)q-ary1;
R3 and R10 are independently~selected at each occurrence
from the group consisting of:
a) hydrogen,
b) halogen,-
c) - (CR6R7) tW (CR8R9) u--R9~
WO 95/09859 ~i 1 7 9 3 1 1 PCT/US94/11049
d) - ~CR6R7 ) tW ( CR8R9) u-aryl,
e) - ~CR6R7) tW(CR8F~9) u-heteroaryl,
f ) - (CR6R7) tW (CRBR9) u-heterocycle,
g) -(CR6R7)tW(CR8R9)u-adamantyl,
h) - (CR6R7)tW(CR8R9)U(Cs-c7) cycloalkyl,
5SsS\~
~--W--aryl
i)
~1
ll -J w--heteroaryl
\~
k)
N W
1)
~ 1
N W
~CI~)v
m)
t ~
WO 95/09859 ~ PCT/11594/11049
2~31~
\~W
~d,
rl
~3
R6
W
R5
~ O
lC W
q)
W
r)
W0951098~9 2 1 7~4 3 1 1 PcrluS94/11049
~ ~W
s)
~ ~,N
R3 and R10 when taken together form a ring such as:
a) - (CR6R7) t ~CR8R9) u~W- (CR8R9) U (CR6R7) t;
b) -(CR6R7)tW(CR8R9)u-aryl-(CR8R9)uW(CR6R7)t-;
c) - ~CR6R7) tW(CR8R9) u-heteroaryl- (CR8R9) uW (CR6R7) ~,-;
d) -~CR6R7)tW(CR8~.9)u-heterocycle-(CR8R9)uw~CR6R7)t-;
e ) --~CR6R7 ) tW ~CR8R9) u--W- ~CR8R9 ) u~tq- ~ CR6R7 ) t--;
R~ and R5 are independently selected at each occurrence
from the group consisting of:
a) hydrogen,
b) Cl-C4 alkyl,
c) Cl-C4 alkoxy,
d) Cs-C7 cycloalkyl,
e) pheny1,
f ) benzyl;
R6, R7, R8 and R9 are independently selected at each
occurrence from the group consisting of:
a) hydrogen,
b) C1-C6 alkyl,
c) Cl-C6 alkoxy,
d) C3-Cg cycloalkyl,
e) aryl,
f ) heterocycle,
g ) heteroaryl,
h) -W-aryl,
i) - ~CH2) wC (=O) oR4,
wo 9~109859 2 1 ~ ~ 3 ~ PcTlUS94/lln49
j ) R6 or R7 can alternatively be taken
together with R6 or R7 on an adjacent
carbon atom to form a direct bond,
thereby to form a double or triple bond
between said carbons, or
k) RB or R9 can alternatively be taken
together with RB or R9 on an ad~acent
carbon atom to form a direct bond,
thereby to form a double or triple bond
between said carbons;
R11 is
a) hydrogen,
b) C1-C4 alkyl,
c) Cl-C4 thioalkyl,
d) - (CR6R7) tW (CR8R9) u-aryl,
e) -(CR6R7)tW(CRaR9)u-heteroaryi,
f ) - (CR6R7) tW (CR8R9) u-heterocycle;
g) - (CR6R7) tW (CR8R9) u-R9;
0 Rll ~nd V, when taken together, can also be:
a) keto,
b) =NR10,
c) =C [ (CR6R7) tW (CR8R2) uR9] 2;
d) -(CR6R7)tW(CRBR9)UW-(CR6R7)tW(CRBR9)U-
5 A is
a) -gyly2
b) -C (=O) CF3,
c) -C (=O) CF2CF3,
d) -PO3H2
d) -C (=O) H,
e) -C (=O) -1-piperdinyl,
f ) -C (=O) CH2OCH2CF3,
g) CH2Cl
h) SO2F;5
yl and y2 are
wo 951~9859 2 1 7 ~ 3 i 1 ` Pcr~ss4/1l049
a) -OH,
b) -F,
c ) -NR4R5 -,
d) -C1-Cg alkoxy, or;
S when taken together yl 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,
F ~
f) a cyclic boron amide where said chain or ring
contains from 2 to 20 carbon atoms and,
optionally, 1-3 heteroatoms which c2n be ~, S,
or O,
g) a cyclic boron amide-ester where said chain or
i- ring contains from 2 to 20 carbon atoms and,
optionally, 1-3 heteroatoms which can be N, ~,
or o;
~ can be independently selected at each occurence f~o.
2C the group consisting of:
a) - ~CH2)~
b) -C (=O) -,
c ) --C ~=O) O-,
Q) -C ~=O) NR4-,
2~ e) -O-,
f ) --OC ~=O) -,
g ) -OC (=o~ o-,
h) -OC (=O) NR4-,
i ) -NR4-,
j) -NR4C (=O) -,
k) -NR4C (=O) O-,
1 ) -NR4C ~=O) NR5-,
m) -NR4S (O) p-
n ) -S ~O) p-,
3~ o) -S(O)pO-,
p) _c ~o) pNR~-,
1:
217~311 `
WO 95/09859 ~ '. PC r/US94/1 1049
q) -S (O) pNR4C (=O)--,
r) -S (O) pNR4C (=O) NR5-;
V is selected from the group consisting of:
a) - (CH2)x~~
b) - (CH2) xC (=O) -,
c) - ~CH2) xC (=O) O-,
d) -C (=O) (CH2) x~~
e) -O- (CH2) x~~
f) -O (CH2) xC (=O) -,
g) --O(CH2)XC(=O)o-,
h) -O (CH2) xC (=O) NR4-,
i) -O(CH2)XS~O)p-,
j) - (CH2)XS ~O)p-,
1~ k) - ~CH2) xS ~O) pG-,
1) - (CH2) xS ~O) pNR4-,
m) - (CH2) xS (O) pNR4C (=O) -,
n) --(CH2)Xs(o)pNR4C(=o)NR
o) - (CH2) XNR4-,
2v p) - (CH2) XNR4C (=o) -,
q) - ~CEl.2)XNR4C ~=O) O-,
r ) - ~ CH2 ) XNR4C ~=O) NR5-,
s) - ~CH2) XNR4S (O) p-;
2- z is selected froir. the group consisiting of:
a) - (CH2) x~~
b) --(CH2) yC ~=O) -,
c) --C (=O) ~CH2) X-~
d) - ~CH2) xC ~=O) O-,
e ) - ~CH2 ) xC (=O) NR4-,
f ) - (CH2 ) XNR4-,
g ) - ~ CH2 ) XNR4C ~=O) -,
h ) - ( CH2 ) XNR4C ~ =O) O-,
i) - (CH2) xNR4C (=0) NR5--, =
__ j ) - (CH2) XNR4S (O~ p-,
12
wo 95109859 2 1 7 ~ 3~ 1 . Pcl~nrS94~11049
k) --(CH2) xS (O)p-,
l ~ - (CH2 ) xS (O) pNR4--,
m can be 0 to 4;
n can be 0 to 4
p can be 0 to 2
1 G q can be 0 to 4;
r, s, t, u, and v are independently selected at each
occurrence from 0 to 6,
h and x are independently selected at each occurence
from 0 to 4;
wlth the follohlng provisos:
2~ (a~ when V is (CH2~ x, x cannot be 0 when R3 is
h~ drogen;
(b) when Z is -(cH2~xc(=o~- and -C(=0~ (CH2)X and x is 0,
R C canno~ be halogen.
[2; Preferred compounds of formula lI) are those
compounds wherein:
30 R1 is (C3-C4 alkyl);
X is selected from the group consisting of:
-NHC (=NH) H, -NHC (=NH) NHR2, -NH2 or -SC (=NH) NHR2;
35 R2 is hydrogen or Cl-C4 alkyl.
13
WO 95/09859 21~ L ~ PCr/U594/11049 ,~
[3] More preferred compounds of formula (I) are
compounds of formula (Ia):
R3--V H
~NS fi CH--B
Rl_Z ¦ ¦ `y2
H
(Ia)
or a pharmaceu7 ically acceptable salts or prodrugs
1" 7hereof, wherein:
Rl is (C3-C4 alk~l);
X is selected from the group consisting of:
15 -NP.C (=NH) H, -NHC (=NH) NHR2, -NH2 or -SC (=NH) N~.R-;
R2 is hydrogen or Cl-C4 alkyl; ~
R3 and R10 are independently selected at each oc^~_-rence
2C from the group consisting of:
a ) hydrogen,
b) halogen,
c) - (CR6R7) tW (CR8R9) U-Rg
d) - (CR6R7) tW ~CRaR9) u-~ryl
25 e) -(CR6R7) tW (CR8R9)u-heteroaryl;
R4 and R5 are independently selected at each occurrence
from the group consisting of:
a) hydrogen,
b) C1-C4 alkyl,
14
WO 95/09859 21~ pcr/L7ss4nlo4s
c) C1-C4 alkoxy,
d) phenyl,
e ) benzyl;
R6, R7, RB, R9 are inde~endently selected at each
occurrence from t~le group consisting of:
a) hydrogen
b~ C1-C6 alkyl,
c) aryl,
d) - (CH2) wC (=O) oR4, or;
yl and y2 are
a ) -OH,
b~ -F,
c) -NR4RS-,
d) -C1-Cg alkoxy, or;
when taken together yl and y2 form:
e) a cyclic boron ester where said chain or ring
contains from 2 to 20 carbon atoms and,
optionally, ~-3 heteroatoms which can be N, S,
or O,
f ) a cyclic boron amide where said chain or ring
contains fro~n 2 to 20 carbon atoms and,
optionally, :1-3 heteroatoms which can be N, S,
2~ or O,
g) a cyclic boron amide-ester where said chain or
ring contains from 2 to 20 carbon atoms and,
optionally, 1-3 heteroatoms which can be N, S,
or O;
~' can be independently selected at each occurrence from
the group consisting of: -~
a) - (cH2)
b) -O-,
~5 c) --S (O) p-,
d) --NR4-,
e) -NR4C ~=O) -,
wo gs/og859 ~ ~ 7 4 3~ ~ PCT/US94/11049
f ) -NF~4C (=O) o-
V is selected from the group conslsting of:
a) - (cH2) x~,
b) -O ~cH2) x~,
c) -O~CH2)X~C=O)-,
d) - ~cH2) xS (O) p-,
e) --(CH2) xN~4-
f ) - (CH2) XNR4C (=O) -,
g) - (CH2) XNF~4C ~=O) O-;
Z is selected from the group consisiting of:
a) - ~CH2) xC ~=O) -,
b) -C ~=O) ~CH2) x~~
c) - ~CH2) xC ~=0)0-,
p car, be 0 or 2;
r can be independent ' ~ selected at each occurrence ~rom
0 to 3i
s can be independently selected at each occurrence ~rom
0 to li .
~_ t car. be independent ~ y selected at each occurrence from
0 to 2i
u can be independently selected at each occurrence fro~.
0 to 2;
3(~
w can be independently selected at each occurrence from
0 to 2;
Y. can be independently selected at each occurrence from
0 to 3; with th~ following provisos:
1~
~j WO 95/09859 2 1 7 4 3~ PCI/US94~11049
~a) when V is (CH2) x, x cannot be 0 when R3 is
hydrogen i
~b) when Z is -(cH2)xc~=o)- and -C(=0) (CH2)X and x is 0,
R10 cannot be halogen.
[4] Most preferred compounds of formula (I) are those
compounds of formula (Ia)
lC
R3--V~H
<~ I r~ CH B~y2
R~--Z
(Ia)
or a :pharmaceutically acceptable salt or prodrug
thereof, wherein:
;S
R1 is (C3--C4 alkyl);
X is from the group conslsting o~ :
-NHC (=NH) H, -NHC (=NH)NHR2, -NH2 or -SC (=NH) NHR
2C
R2 is h~d-oge~ o~ C1-C4 alkyl;
R3 is independently selected froml the group consisting
of:
2~ :benzyl, phenyl, phenethyl, (3-phenyl)prcp-1-yl, (2-
methyl-l-phenyl) prop-2-yl, (2-methyl-2-phenyl) prop-
1-yl, 1, l-diphenylmethyl, phenoxymethyl,
phenylsulfonylmethyl, 2- (m-fluorophenyl) ethyl, 2-
(3-pyridyl)ethyl, (m-aminophenyl)methyl, (m-
, -.
~,
WO 95/09859 ~ PCrNS94/1~049
methylphenyl ) methyl, (p-methylphenyl ) methyl, 1-
naphthylmethyl;
R10 is independently selected from the group consisting
5 of:
methyl, t-butoxy, benzyloxy, phenethyl, benzyl,
phenoxymethyl, isopropyl, isoamyl, N-methyl-N-t-
butoxycarbony~Am;n~ -thyl, N-methylaminomethyl, (m-
methyl) phenethyl, (m-fluoro) phenoxymethyl, (m-
lG methyl) phenoxymethyl, (3-pyridyl) ethyl
R11 is hydrogen;
yl and y2 are -
a) -OH,
b) -F,
c) -NR4R5 -,
d) -C1-Cg alkoxy, or;
wher. taken together yl and y2 form:
2~ e) a cycl~ c boron ester where said chain or ring
contains from 2 to 20 carbcn atoms and,
optionally, 1-3 ~ieteroatoms which can be N, S,
or o,
f ) a cyclic boron amide where said chain or ring
2~ contains from 2 to 20 carbon atoms and,
optionally, 1-3 heteroatoms which can be N, S,
or C,
g) a cyclic boron amide-ester where said chain or
ring contains from 2 to 20 carbon atoms and,
3G optionally, 1-3 heteroatoms which c2n be 11, S,
or O;
V is independently selected from the group consisting
of:
'~ O, -OC(=O)-,, S, --NH-;
~i is -C (=O) - . :
~174311
~j WO 95/09859 = = ~ = = ' ` PCII/US9.l/11049
[5] Specifically preferred compounds of formula (I) are
those compounds of formula (Ib):
~--~1
H 2N .~B~o,~
0~ N Ho C H3
/~NJ~ Rl
R3
(Ib)
selected from the list consisting of:
lC
the compound of formula (Ib) wherein R3 is phenyl
and Rl is methyl;
rhe compound of formula (Ib) wherei.. R3 is
_~- phenylmethyl and R]-0 is methyl;
tne compound of formula (Ib) wherein R3 is
phenethyl and B10 is methyl;
the compound of formula (Ib) wherein R3 is 3-
phenylprop-1-yl and R10 is methyl;
the compound of formula (Ib) wherein R3 is 1,1-
dimethyl-2-phenylethyl and R10 is methyl;
the compound of formula (Ib) wherein R3 is 2, 2-
dimethyl-2-phenylethyl and Rl is methyl;
W095/09859 217431i ~ ~ ` PCTNS94/11049 ,~
the compound of formula (Ib) wherein R3 is
diphenylmethyl and R10 is methyl;
the compound of formula (Ib) wherein R3 is
phenoxymethyl and R10 is methyl;
the compound of formula (Ib) wherein R3 is
phenylsulfonylmethyl and R10 is methyl;
the compound of formula (Ib) wherein R3 is (m-
fluorophenyl)ethyl and R10 is methyl;
the com~pound of formula (Ib) wherein R3 is (3-
p~idylel:h~l ) and R10 is methyl;
the compound o~ formula (Ib) wherein R3 is
phenylethyl and R10 is phenethyl.
20 [6~ l~lso specifically preferred compounds of formula
(IJ are those compounds of formula (Ic):
H 2N ~B~
0~,,NH CH3
~N Rl
R3 ~`
~Ic)
selected from the list consisting of:
the compoun~d of formula (Ic) wherein V is sulfur,
R3 is phen~l and R10 is phenmethyl;
~ WO95109859 217~311 PCT/US94/11049
the compound of formula ~Ic) wherein V is oxygen,
R3 is phenylmethyl and RlO is phenethyl;
the compound of formula (Ic) wherein V is oxygen,
R3 is phenylmethyl and RlO is 3-phenylpropyl;
the compound of formula tIc) whereln V is oxygen,
(m-methyl)phenoxymethyl and R10 is 3-phenylpropyl;
the compound of formula (Ic) wherein V is oxygen,
(m-fluoro)phenoxyl~ethyl and RlO is 3-phenylpropyl
the compound of formula (Ic) whereir. V is oxygen,
R3 is phenylmethyl and RlO is (m-
methylphenyl ) ethyl;
the compound of formula (Ic) wherein V is oxygen,
R3 is phenylmethyl and RlO is (m-fluoro)phenethyl;
the compound of formula (Ic) wherein v is oxygen,
R3 is phenylmethyl and RlO is phenoxymethyl;
the compound of formula (Ic) wherein V is oxygen,
R3 is (m-fluorophenyl)methyl and RlO is phenethyl;
the compound of formula (Ic) wherein V is amino, R3
is phenylmethyl and RlO is phenethyl;
the compound of formula ~Ic) wherein V is oxygen,
R3 is phenylmethyl and RlO is methyl;
- the compound of formula (Ic~ wherein V is oxygen,
R3 is phenylmethyl and RlO is 2-propyl;
21
WO 95/09859 ~17 4`3 t 1 ` PCTIUS94/11049 ~
the compound of formula (Ic) wherein v is oxygen,
R3 is phenylmethyl and R10 is isoamyl;
the compound of formula (Ic) wherein V is oxygen,
R3 is (m-methylphenyl)methyl and R10 is methyl;
the compound of formula (Ic) wherein V is oxygen,
R3 is (p-methylphenyl)methyl and R10 is methyl;
the compound of formula (Ic) wherein V is oxygen,
R3 is (l-naphthyl)methyl and R10 is methyl;
the compound of formula (Ic) wherein V is oxygen,
R3 is phenylmeth~ l and R10 is N-methyl-N-t-
butoxycarbonylaminomethyl;
the compound of formula (Ic) wherein V is o~:ygen,
R3 is phenylmethyl and R10 is N-methylaminomethyl.
2Q
[, ] P.lso specific~lly preferred compounds cf formula
( ~ ) are those com~ounds of formula ¢Id):
OH
H 2N ~ O H
O~, N H
~NJ~ R1 o
R3 Y
(Ic)
selected from the list consisting of: -
the compound of formula (Id) wherein V is oxygen,
3C R' is phenylmethyl and R10 is phenethyl;
22
17~311
WO 95/09859 1 Pcr/Uss4/1104s
the compound of formula (Id~ wherein V is oxygen,
R3 is (m-fluorophenyl)methyl and R10 is phenethyl.
the compound of formula (Id) wherein V is oxygen,
R3 is phenylmethyl and R10 (m-methyl) phenethyl;
Detailed DescriDtion of the Invention
The " (D) " prefix for the foregoing abbreviations
lndicates the amino acid is in the (D)-configuration.
"D, L" indicates the ami]lo acid is pre'sent as a mixture
;~ of the (D)- and the (L)-configuration. The prefii: "boro"
indlcates amino acid residues where the carboxyl is
replaced by a boronic acid or a boronic acid ester. For
example, if Rl is isopropyl and yl and y2 are OH, the C-
terminal residue is abbreviated "boroVal-OH" or
20 "~oroValine" where "-OH" indicates the boronic acid is
in the form of the free acid. The pinanediol boronic
acid ester and the pina-ol boronic acid ester are
abbre-~iated "-CloHl6" and "-C6H12", respectively.
E~.amples of other useful diols for esterification hith
~_ the boroni-c acids are 1,2-ethanediol, 1,3-propanediol,
1, 2-propanediol, 2, 3-butanediol, 1, 2-
d isopropylethanediol, ~, 6-decanediol, and 1, 2-
dicyclohexylethanediol. Some common abbreviations used
herein are: CBZ or Z, ]~enzyloxycarbonyl; BSA,
3C benzenesulfonic acid; T~IF, tetrahydrofuran; Boc-, t-
butoxycarbonyl-; Ac-, acetyl; pNA, p-nitroaniline; DMAP,
4-dimethylaminopyridine; HOBT, l-hydroxybenzotriazole
and hydrate thereof; DCC, 1,3-dicyclohexylcarbodimide;
Tris, Tris ~hydroxymethy:L)aminomethane; MS, mass
__ spectrometry; FAB/MS, fast atom bombardment mass
spectrometr~. LRMS and HRMS are low and high resolution
2~
WO 95109859 2 ~ 7 4 31 I PCTIUS94/11049 ~
mass spectrometry, respectively, using ammonla (NH3-CI)
or methane ~CHq-CI) as an ion source.
It is understood that many of the compounds of :the
present invention contain one or more chiral centers and
5 that these stereoisomers may possess distinct physical
and biological properties. ~he 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
lO appropriate stereochemistry, or may be separated from
mixtures of undesired stereoisomers by standard
techniques, including chiral chromatogrsphy and
recrystalli:~ation of diastereomeric salts.
When an~ variable (for example, Rl through RlO, m,
l- n, W, Z, etc. ~ occurs more than one time in any
constituene or ir. formula (I), Dr any other formula
herein, its definition on each occurrence is independen.
of ts definition at every other occurrence.
In the instance that a subscript of a group is 0,
2C it is intended to mean that= the previous group is bonded
directly with the next group in the sequence. For
example, when:
R3 is - (CR6R7) t-w- (CR8R9) u-aryl, snd u is 0
-. is the ssme as:
~_ - (CR6R7 ) t-W-aryl .
As described broadly above for R6 and R7, in the case
"where R6 (R8) or R7 (R9) can alternatively be taken
together with R6 (R8) or R7 (R9) on an ad~acent carbon
atom to form a direct bond", this can only occur when t
3G (u) is greater than l. ~he structure that would result
f rom:
R3 is -(CR6R7)t-W-(CR8R9)u-aryl~ t = 2, u=2,6 and R7 are taken to for a double bond, and R8 and R9
taken to be a triple bond
3_ would be:
-CP6=CR7-W-C_C-aryl .
2~
~ WO 95/09859 2~ ~ 7 4 311 Pcr/uss4nlo4s
The term "amine-blocking group" or "amine-
protecting group" as used herein, refers to va ious
acyl, thioacyl, alkyl, sulfonyl, phosphoryl, and
phosphinyl groups comprised of 1 to 20 carbon atoms.
5 Substituents on these groups may incIude either alkyl,
aryl and alkaryl which l~ay contain the heteroatoms, O,
S, and N as a substituent OI as an inchain component. A
number of amine-blocking groups are recognized by those
skilled in the art of organic synthesis. Examples of
lO suitable groups include formyl, acetyl, benzoyl,
trifluoroacetyl, and methoxysuccinyl; aromatic urethane
protecting groups, such as benzyloxycarbonyl; and
aliphatic urethane protecting groups, such as t-
butoxycarbonyl (also referred to as t-butyloxycarbonyl)
1~ or adamantyloxycarbony'. Gross and Meienhofer, eds.,
~rne Peptides, Vol 3; 3-88 (1981), Academ.ic Press, New
York, and Greene and Wuts Protective Groups in Orga~ic
Synthesis, 315-405 (l991), ~. Wiley and Sons, Inc., Ne
York describe numerous suitable amine protecting groups
2'` and they are incorporated herein by reference for that
purpose .
"Amino acid residues" as used herein, refers to
na.ural or unnatural amino acid of either (D)- or (L)-
configuration. I~atural amino acids residues are Ala,
2_ Arg, Asn, Asp, Cys, Gln, Giu, Gly, ~.is, Ile, Leu, Lys,
Me., Phe, Pro, Ser, Thr, Trp, Tyr, and Val. Roberts anQ
Vellaccio, The Peptides, Vol 5; 341-449 ~1983), Academic
Press, New York, describe numerous suitable unnatural
amino acids for use in this application and is
30 incorporated herein by reference for that purpose.
"Amino acid residue" also refers to various amino
acids where sidechain ful~ctional groups are coupled with
- appropriate protecting groups known to those skilled in
the art. "The Peptides", Vol 3, 3-88 (1981) describes
35 numerous suitable protecting groups and is incorporated
here -. by reference for that purpose.
~7,~31~ ~
Wo 95/098S9 PCr/US94111049
As used herein, "alkyl " is intended to include both
branched and straight-chain saturated aliphatic
hydrocarbon groups having the specif ied 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- and polycyclic 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
ma~ 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,
bipheny1 and naphthyl, which may be unsubstituted or
include optional substitution with one to three
substituents .
2C The term "heteroaryl" is meant to include 5-, 6- or
lO-membered mono- or bicyclic aromatic rings which can
optionall~ contain from 1 t4 3 heteroatoms selected from
the group consisting of O, N, and Si said ring ~s) may be
u-.substituted or include optional substitution with one
to three substituents. Included in the definition of
the group heteroaril, but not limited to, are the
following: 2-, or ~-, or 4-pyrid~-l; 2-or 3-furyl; 2- or
3-benzofuranyl; 2-, or 3-thiophenyl; 2- or 3-
benzo[b]thiophenyl; 2-, or 3-, or 4-quinolinyl; l-,~ or
3-, or 4-isoquinolinyl; 2- or 3-pyrrolyl; l- or 2- or 3-
indolyl; 2-, or 4-, or 5-oxazolyl; 2-benzoxazolyl; 2-
o 4- or 5-imidazolyl; l- or 2- benzimidazolyl; 2- or 4-
or 5-thiazolyl; 2-benzothiazolyl; 3- or 4- or 5-
isQxazolyl; 3- or 4- or 5-pyrazolyl; 3- or 4- or 5-
isothiazolyl; 3- or 4-pyridazinyl; 2- or 4- or 5-
p~rimidinyl; 2-pyra~in~l; 2-triazinyl; 3- or 4-
26
Wo 951098s9 2 1 7 ~ 3 1 1 PCr/USs4/11049
cinnolinyl; l-phthalazinyl; 2- or 4-quinazolinyl; or 2-
quinoxalinyl ring. Pdrticularly preterred are 2-, 3-,
or 4-pyridyl; 2-, or 3-furyl; 2-, or 3-thiophenyl; 2-,
3-, or q-quinolinyl; or l-, 3-, or
4-isoquinolinyl.
The term "heterocycle" is meant to include 5-, 6-
or lO-membered mono- or bicyclic rings which can
optionally contain from l to 3 heteroatoms selected from
the group consisting cf 0, N, and S; said ring(s) may be
unsubstituted or include optional substitution with one
to three substituents. Included in the definition of
the group heterocycle, but not limited to, 2- or 3-
pyrrolidinyl, a 2-, 3-, or 4-piperidin~l, or a l-, 3-,
or 4-tetrahdroisoquinolinyl, l-, 2-, or 9-
lS tetrahydroquinolinyl, 2- or 3-tetrahydrofuranyl, 2- or
3-tetrahydrothiophene, l-, 2-, 3-, or 4-piperazinyl, and
l-, 2-, 3-, or 4-morpholino. Particularly preferred are
l-, 3-, or 4-tetrahdroisoquinolinyl, 2- or 3-
p~rrolidinyl, and 2-, 3- or 4-piperidinyl.
2~ The substituen,s that may be attached to the aryl,
heteroaryl or heterocycle ring (s) m~ be independently
selected at each occurrence from the group consist ing
of:
halogen, -CF3, Cl-C4 alkyl, nitro, phen~ ', cya~o,
2_ - (CH2) rR~ - (CH2) rC (=0) (CH2) sR,
- (CH2) rC (=0) 0 (CH2) sR,
- (CH2~ rC (=0) N [ (CH2,~ sR~] [ (CH2) sR5], met~.~ ienedioxy,
Cl-C4 alkoxy, -CH2) r (CH2) sR4~ - (CH2) rOC (=O) (CH2) sR4
- (CH2) rOC (=0) O(CH2) 3R4,
3C - (CH2) rOC (=0) N [ (CH2) sR4] [ (CH2) sRS] ~
-(CH2)roC(=o)N[(CH2)sR4] [C(=O) (CH2)sRS],
-(CH2)rs(o~p(CH2)sR4, --(CH2)rS(o)p(CH2)sC(=o)R4,
- - (CH2) rS (O) p (CH2) 5C (=O) oR4,
- (CH2) rS (O) pN [ (CH2) sR4] [ (CH2) 5R5],
~_ -(CH2)rS(O)pN[ (CH2)sR4] [C(=0) (CH2)~R5],
~ (C~2) rN [ (CH2) sR4] [ (C}i2) sRS] ~
~, .
WO 95/09859 2 ~ 7 ~ PCT/US94111049
- ~CH2) rN [ (CH2) sR4~ IC (20) (CH2) 8RS] t
--~CH2) rN [ (CH2) sR4] [C (=O) O (CH2) sRS],
-(CH2)rN[ (CH2)sR4]CoN[ (CH2)sR4] [ (CH2)sRS],
- (CH2) rN [ (CH2) sR4] C (=o) -N [ (CH2) sR4 ] [C (=O) (CH2) sRS],
S - (CH2) rN [ (CH2) sR4] [S (O)p(CH2)sRs] .
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 .
As used herein, "pharmaceutically acceptable salts"
refe- to de~ivatives of the disclosed compounds wherein
the parent compound of formula (I) is modified by making
- ac~d or base salts o~ the compound of formula (I) .
E~:amples of pharmaceutically acceptable salts include,
bu~ are no~: limited to, mlneral or organic acid saLts of
basic residues such as amines; alkali or organic salts
of acldic resldues such as carboxylic aclds and the
like .
Pharmaceutically acceptable salts o~ the compounds
o~ the invention can be prepared by reacting the free
acid or base forms of these compounds with a
sloichiometric amount of the appropriate base or acid in
2~ water or in an organic solvent, or in a mixture o~ l:he
two; generally, nonaqueous media like ether, ethyl
acetate, methanol, ethanol, isopropanol, or acetDnitrile
are preferred. Lists of suitable salts are found ln
R~rin~ton's ph~rr~ceutlcal Sciences. 17th ed., Mack
3C Publishing Company, Easton, PA, 198S, p. 1418, the
disclosure of which is hereby incorporated by reference.
"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 IO a mammalian subjecl. Prodrugs of the
2~
Wo 951098~9 2 1 7 4 3 1 `1 ~ ~ PCT/USg~ o~9
compounds of formula (I) are prepared by modifying
functional groups present in the compounds in such a way
that the modlfications are cleaved, either in routine
manipulation or in viv~, to the parent compounds.
5 Prodrugs include compounds of formula (I) wherein
hydroxy, amine, or sulfhydr~ l 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
10 are not limited to, acetate, formate and benzoate
derivatives of alcohol and amine functional groups ln
the compounds of formula (I) .
S~nthesis ~iscussion
1~ Compounds of formula (I) can be preparec using the
synthetic sequences that follow. The solvents employed
are compatible with the reagents selected and the
transforma~ions being performed. It ~ will be understood
by those skilled in the art of organic synthesis that
2C the order of the transformations proposed will be
conslstent with functionality present in the molecules
a~d ma~ require ~udgements during the selection of a
Frocedure for prepara~ ion of a compound of the
invent ion .
2~ The general synthesis of N-acyl-~- (acyloxy) proline
intermediates can be prepared by sequential acylations
of the amine and hydroxyl functionalities and is shown
in Scheme 1.
3G Sche~e 1
WO 95/09859 ~ 1,7i4,3~ PCT/US94/11~49
PhCH20 0 PhCH20 0
~NH HCI ,~ ~N Rto
HO HO
(Il)
PhCH2O O HO~O
R3J~ O R3J~ O
(111) (IV)
Thus, as an example, (1)-4-hydroxyproline benzyl ester
hyàrochloride, which is commercially available, or any
other suitably protected hydroxyproline, can be treated
with a trialkylamine base, typically 9-methylmorpholine,
and an acid chloride (RlOCOCl) to afford acyIation
product (II) selectively. The hydroxyl group can be
converted to a corresponding ester by treatment with a
lC second acid chloride (R3COCl) in the presence of a
tri~lkylamine or heterocyclic amine base, such as
p,~idine, and a suitable catalyst, such as but not
limi~ed to DMAP to generate (III) . The carboxylic acid
o~ the proline moiety can be liberated by hydrogenation
using conditions reported by Hartney and Simonoff, Org.
~eact. VII, 263 (1953) wherein an alcohol solution of
the compound (III) may be affected under an atmosphere
of hydrogen gas using a suitable catalyst, prefe~rably
platinum or palladium on carbon catalyst, to provide
2G (IV)
One may vary the transformations indicated above
depending upon the nature of the groups to be appended.
One may employ alternative methods such as a mixed
anhyd-ide coupling, as reported by Anderson, et al. J.
AJn. Chern. Soc. 89, 5G12 (1967); o~ the DCC/HOB~ protocol
~ wo gsl098s9 2 1 7 ~ 3 1 1 PCr/US94111049
described by Konig, an~ Geiger, Chem. 13er. 103, 788
(1970) to form the requisite amide bond. Also, the
DCC/DMAP esterification procedure, reported by Hassner,
and Alexanian, ~etrahedron Lett. 19, 4475 ~1978) has
proved useful for performing the second acylation
reaction. Finally, one may choose an ester other than
benzyl which might be removed hydrolytically or
photilytically, such as photlytic deprotection. For
example, with a methyl ester of (II), treatment of an
10 alcoholic solution of the compound with a solution of
sodium hydroxide so as to deliver 1 equivalent amount
of NaOH followed by acidification should provide the
carboxylic acid.
The N-acyl-4- ~alkoxy) proline intermediates can
15 prepared as shown in Scheme 2.
S cheme 2
HO O HO O
N-P ~ ~N-~
HO R30~
(V) (Vl)
P=BOC:CBZ
PhCH20 0 HO O
~NH , ~N Rl
R30~ R30~
(Vll) (Vlll)
The hydroxyl function of an N-protected 4-hydroxyproline
(V) can be alkylated according to the method of Smith et
al., J. Med. Cllelr. 31, 875 (1988), by treatment with an
alkali metal hydride, such as but not limited to sodium
2c hydride and an alk:' h21ide (R3X) to give (VI) . Removal
_l
2~7~311
WO95109859 ~ PCTIIIS94111049 ~
,, ~
of the ~ protecting group by an appropriate method know
to one of skill in the art can provlde ~VII): the t-
butyl carbamate can be cleaved upon treating with acid
under anhydrous conditions; for example, trifluoroacetic
5 acid in dichloromethane solution removes the t-butyl
urethane of derivatives of ( LV) at ambient temperature
as reported by Bryan et. al., J. Am. Chem. Soc. 99, 2353
~1977); alternatively anhydrous hydrogen chloride in
dioxane may be used to prepare the HCl salt. Other
l0 methods for protection of the amine are delineated in
Greene and Wuts ~l99l) . The use of benzyl urethane is
also viable where hydrogenation over palladium catalyst
deliveres the free amine (VII) . Acydlation by one of
the methods discussed previously can provide ~VIII) .
The 4-amino and 4-mercaptoproline intermediates
useful for the synthesis of compounds of the formul2
(I), wherein V is S, NH or derivatives thereof, can be
prepared according to Scheme 3. The hydroxyproline
ester (IX), wherein the amine is protected as the BOC or
28 CBZ, can be reacted with carbon tetrachloride/
triphenylphosphine accQrding to the method of ~ebb and
Eigenbrot, J. Org. Chem., 56, 3009 (I991), to provide
the chloride (X) with inversion of stereochemistry. The
chloride can be displaced by a sulfur nucleophile, again
~' witr. inversion o~L sterochemistry in a manner similar to
that reported by Smith et al. (1988) to provide the
displacement producT (XIIb), sulfur-containing pro:line~.
Sim.ilarly, the chlQride can be displaced by sodium
a:zide, ~-hich. is reduced to the primary amine and
3û converted by reductive amination to provide the
displacement products (XIIa), nitrogen-containing
prolines. The R3 group in (XII) used in the
displacement reaction need not be the ultimate R3 of
formula (I); methods for their removal are well known to
3' those skille~ in the art of organic synthesis. Methods
fo- the a~ ,achmen. c~ preferred R3 are described herein .
32
WO 9S/09859 I ~~ ~ PCT/US94/11049
S chQme 3
Alkyl-O O Alky~-O O
~N P ~N P 1.) depro~ect
HO Cl~~ 2-) R10-Z.CI
(D3 (X)
1.) R3S(-) or
Alkyl-O O 1a.) N3(-)
1b.) reduction HO O
p~V` R10 lC ) aCylation or reduCtiVe aminat!n
Cl 2.) liberateacid
(Xl) (Xlla) V b NHR~
(Xllb) V is SR3
P is a protectin~ group (ie., CBZ, Boc)
These disubstituted prolines (XIIa,b) can be used in an
analogous manner to that of (IV) or ~VIII) described
hereafter
The construction of thrombin inhibitors of the
lC present invention requires the coupling of either of the
aforementioned intermediates, (IV~, (VIII), or (XII)
with a boron-containing fragment followed by
manipulation of the pendant functionalities, as shown in
Scheme q
1~
S cheme 4
_ _
~17~
W0 95/09859 ~ = PCTNS94/11049
O O H
Br ~BO~ Br ~Bo~i3
HCI H2N Me 0~, NH Me
~N--Z-R10
(Xm~ R3-V
H H
N3 ~B,O~j3 H2N ' o~a
0~, NH Me 0~, NH Me
~N--Z-R10 ~N--Z-R10
R3-V (Xv) R3-V
OH
H2N ,BOH
0~, NH
~N--Z-R10
R3-V
Tne synlhesis of borolysine-containing throlrbin
inhibitors (XVII~ begins with the coupling of am.ine
hydrochloride (XIII), disclose~ by Etettner and Shenvi
U.S. Patent l~o. 5.187.197, to provide amide (XIV) . I~.
p-actice, one may choose from several well-known methocs
o prepare ~XIV) in suitably pure form, as purific2tion
o~ this intermediate is oftentimes impractical. One
lC me.hod calls for the cor[bination of (XIII) and the acid
chloride derived from (IV), (VIII) or (XII) in the
presence of an amine base, such as but not limited to
pyridine. Alternatively, one may employ either the
mixed anhydride method, which involves mixing the acid
15 to be coupled with an alkylchloroformate and an tertiary
amine base, such as, but not limited to, ~-butyl
chloroformate and 9-methylmorpholine, followed b~
1'
_
WO 95/09859 ~ ~ 7 4 3 ~ 1 s PCTIUS94~ 149
addition of the amine discussed previously, to- prepare
(XIV) from (IV), (VIII) or (XII); additionally the
DCC/HOBT method may be used to access amines XIV and/or
XII
Conversion of the bromide to the ~; group in Rl of
formula (I) can be accomplished by first reaction of
bromide (X) with an in~arganic azide, such as sodium or
potassium azide, in an anhydrous poLar aprotic solvent,
such as acetone, N,N-dimethylformamide or methyl
sulfoxide at temperatures ranging from ambient to 130~C;
typically reaction witl~ sodium azide in N, N-
dimethylformamide at 6~-70 C for several hours provides
(XV). Subsequent reduction of the azide function to the
amin-e (XVI) is effected by catalytic hydrogenation of
1~ the azide in a solvent, such as an alcohol or ethyl
acetate using a suitable transition metal catalyst under
an atmosphere of hydrogen gas. Reduction of the azide
(XX) in the presence of sulfur-c~ntaining prolines (XV,
where V is S) can be done according to the method of
Knowles et al, ~etrahedron Lett., p. 3663 (1978) to
provide the amines (XXI) . A variety of alternative
me~hods can be found in the monograph by Hudlicky,
Reduct:ions In Or~anic Synthesis, John ~'iley and Sons,
pp. 134 (1984) . The amine (XVI) can be isolated as the
2~ free base or a salt, typically, but not exclusively
hydrochloride or benzenesulfonate; other salts which
impart improved physical properties may be preferred.
The method described by Matteson et al., J. Am.
Chem,. Soc. 102, 7590 (1980) discloses a procedure for
3C removing the pinanediol ester, however, the method
employs reagents which may decompose the desired
product. ~he preferred method for preparation of the
free boronic acid (XVII~ involves transesterification in
the presence of excess phenylboric acid.
_,
W095/09859 ~3~ PCT/US94/11049
The amidine-type analogs, where the X yroup in Rl of
formula (I) is modified, can be prepared as shown in
Scheme 5.
Schcme 5
Br ,B ~ _ Br ~B ~3
HCI NH 2 Me ~, NH Me
(XVIII) ,~N--Z-R 10
R V (X~
O H 0~3
,2~N--Z-R 10 . J~N--Z-R 10
R3-V R V
(XXI) X - NH 2 (XX111) R - NHC(=NH)NH 2
,OH
X B~oH
0~, NH
~C~N--Z-R 10
(XXV) R = NHC(=NH)H
(XXVI) R = NHC(=NH)NH 2
(XXVII) R = NHC(=NH)NHCH 3
The guanidinium analogs can be prepared in a similar
lC manner starting from amine hydrochloride (XVIII) . Amide
bond formation using one of the methods previously
described provides (XIX), which can be converted to the
azide (XX) by nucleophilic displacement of the bromide.
Reduction of the azide using conditions already
36
~17~3~
~ro gslos859 PCT/rTss4/ll04s
descrlbed can provide the amine (XXI) . Preparation of
formamidine (XXII) can be accomplished by reaction of
amine (XXI ) with ethyl formimidate hydrochloride in the
presence of D~qAP according to the method of Ohme and
Schmitz, Angew, Chem mt . Ed 6, 566 (1967) . Elaboration
of (XXI) to guanidine (XXIII) can be accomplished by
reaction with formamidinesulfonic acid in the presence
of DMAP, according to that described in Kim et al.,
Tetrahedron Lett. 29, 3183 (1988), whereas the analogous
N-methylguanidine (XXI~') can be produced when N-methyl-
formamidinesulfonic acid is employed according to the
method of Walter and Rauden, ~iebig Ann. Chem. 722,
98 (lg69) . As before, transesterification wi~h
phenylboric acid yields aclds (XXV) - (XXVIII) .
1~ ~ The compounds of 40rmul2 (I), wherein X is
isothiouronium can be Frepared as shown in Scheme 6.
Schezne 6
(xrx) H r~J~s~~B ~K3
O~, NH Me
~[~N--Z-R
R3-V
(xxvllr)
NH OH
N S , B OH
0~, NH
~N--Z-R~
R3V
(x~a~
2C
~7
W0 95/09859 ~ PCT/US94/11049
~ 31'f`
Starting from intermediate bromide (XIX), the ;~ group in
formula (I) can be introduced directly by displacement
of the halide using thiourea as the nucleophilic ~pecies
thereby providing boronic ester (XXVIII) . As described
5 previously, transesterification using phenylboric acld
yields ~XXIX) .
Ex~ le~
E~r~le 78
Nl-[ (4R)-N-Acetyl-9-(3-phenylpropionyl)oxy-~L)-prolyl]-R-
borolysine, (+)-pinanediol ester
Pa-t A: ~o a solution of (4R) -4-hydroxy- (L)-proline
benzyl ester hydrochloride (2.67 g, 1.04 mol) in
dichloromethane (CH2C12, 50 mL) at 0 C was added 4-
metnylmorpholine (2.50 mL, 2.28 mmol) followed by acetyl
chloride (0.72 mi" 1.09 mmol) . The reaction mixture was
wa~med to roon~ temperature over 12 hours and ethyl
2C acetate (EtOAc, ca. 200 mL) was added. The organic
`~ ayer was washed with saturated aqueous sodium
Dicarbonate (NaHCO3, 1 x 30 mL), water (H2O, 1 x 30 mL),
saturated aqueous sodium chloride (NaCl, 1 x. 30 mL)=,
dried over sodium sulfate (Na2SO4) and concentrated
under reduced pressure . ~he resulting oil (1. 94 g, 71
yield) solidified on standing at room temperature. A
sample o~ (4R) -N-acetyl-4-hydroxy- (L)-prGline benzyl
ester was recrystallized fr.om hexanes:EtOAc to give
white plates, mp 99-102 C (orthorhombic, P212121, a =
3C 9.216, b = 9.315, c 15.420 A) . lH NMR (300 MHz, CDC13)
7.35 (comp, 5H), 5.17 (s, 2H), 4.63 (m, lH), 3.79 (dd,
J= 10.6,4.6 Hz, lH), 3.50 (d, J= 10.6 Hz, lH), 2.29 (d,
J= 4.4 Hz, lH), 2.24 (m, lH), 2.11 (m, lH), 2.09 (s,
3H); LRMS 264 (M+H, base), 281 (M+NH4) i Anal. Calcd for
3c Cl~:il7NO4: C, 63.87; H, 6.51; N, 5.32. Found: C, 63.84i
H, 6.~1; N, 5.3~. ~
38
WO 95/09859 2 1 7 ~ 3 1~1 . PCT/US94/11049
, , ,. " , .
Part B: ~o a solution of the product from Part A (370
mg, 1.41 mmol) and pyridine (0.I7 mL, 2.10 mmol~ in
CH2C12 (14 mL) at 0 C was added 3-phenylpropionyl
chloride (0.23 mL, 1.55 mmol~ . The reaction mixture was
warmed to room temperature over 3 hours and added to
EtOAc (ca. 75 mL~. The organic layer was washed with
sat. aq. NaHCO3 (1 x 25 mL), half-saturated aqueous
copper (II) sulfate (1 x 25 mL), sat. aq. NaCl (1 x 25
mL), dried (Na2SO4) and was concentrated under reduced
pressure. The residue was purified by flash
chromatography, elution with 2 :1 EtOAc-hexanes to give
(4R) -N-acetyl-4- (3-phenylpropionyl) oxy- (L) -proline benzyl
ester (340 mg) as an oil in 61~ yield. lH NMR ~300 MHz,
~_ CDC13) ~ 7.37 (comp, 5~.), 7.28 (m, 2H), 7.19 (m., 3H),
5.30 (m, lH), 5.18 (m., 2H), 4.51 (dd, ~= 8.4, 8 0 Hz,
lH), 3.84 (dd, J= 11.7, 4.7 Hz, lH), 3.46 (d, J= 11.7
H~, lH), 2.93 (t, J= 7.5 Hz, 2H), 2.64 (t, J= 7.5 Hz,
2H) 2.28 ~m, lH), 2.13 (m, lH), 2.03 (s, 3H); LRMS 396
(M+H, base) .
~art C: A so}ution of the product from, Part R (340 mg,
G.~6 mmol) ~ogether with palladium on charcoal (55 mg)
ln me.hanoi (MeO~., 9 mL) was stirred under hydroger. (1
~_ a-rr.) for 2 hours. The reaction mixture was filtered -
,hroug~. a pad Or -Celite with additional MeOH (ca. 10 mL)
and the filtrate was concentrated under reduced pressure
to give (4R)-N-acetyl-4-(3-phenylpropionyl)oxy-~L)-
proline (245 mg) as a foam in 93~ yield. lH NMR (300
3C MHz, CDC13) ~ 7.27 (comp, 5H), 5.28 (m, lH), 4 57 (t, J=
7 7 Hz, lH), 4 38 (br s, lH), 3~76 (dd, J= 11~ 9, 4 5 Hz,
lH), 3~49 (s, lH), 2~95 (., J= 7~3 Hz, 2H), 2 66 (t, J=
7 3 Hz, 2H), 2.56 (m, lH), 2.26 ~m, lH), 2 07 (s, 3H);
LRMS 306 (M+H), 173 (base)
_ _ :
WO 95/09859 ~ PCT/US94111049
~17~311
Part D: To a solution of the product from Part C~ (240
mg, 0.79 mmol) and 9-methylmorpholine (0.26 mL, 2.36
mmol) in tetrahydrofuran (THF, 6 mL) at -20 C was added
i-butyl chloroformate ~0.11 mL, 0.87 mmol) after which
5 the reaction mixture was stirred for 2 minutes. A
solution of ~lR)-5-bromoaminopentane-1-boronic acid ~+)-
pinanediol ester ~299 mg, 0.79 mmol) in l\~,N-
dimethylformamide ~DMF, 2 mL) was added, the reaction
was stirred at -20 C for :15 minutes and warmed to room
10 temperature over 18 hours. The reaction mixture was
poured into EtOAc ~ca. 50 mL) and washed with E2O (3 x
15 mL), and sat. aq. NaCl ~1 x 15 mL) dried ~Na2SO4) and
concentrated under reduced pressure to give ( lR) -5-
bromo- [ (4R) -I~-acetyl-4- ~3-phenylpropionyl) oxy- (L) -
15 Drol~' ]aminopentane-1-boronic acid, (i) -pinanedicl ester
(~75 mg) as an oil in 96~ yield. LRMS 631, 633 ~M+H),
55_ (base) .
.
Part E: A mixture of the product from Part D (470 mg,
0.75 mmol) and sodium azide ~NaN3, 97 mg, 1.50 mmol) in
DM- (8 mL) was heated at 65-70 C for 9 hours. The
mix.ure was poured into EtOAc ~ca. 75 mL) . and washed
w ~h H2O (3 x 20 m~), sat. aq. NaCl ~1 x 20 mL), dried
(Na2SO4), and concentration~under reduced pressure .o
2-- give (lR) -5-azido- [ (4R) -11-acetyl-q- (3-
phe-.ylpropionyl) oxy- (L)-prolyl~ aminopentane-l-boronic
acid, (+)-pinanediol ester. (403 mg) as an oil in 91
yield. LRMS 594 (M+H, base) .
3C Part F: A solution of the product from Part E (388 ms,
0 . 65 mmol) in MeOH (7 mL) together with palladium
hydroxide on charcoal 135 mg) was stirred under hydrogen
(1 atm) for 3 hours. The reaction mixture was filtered
through a pad of Celite with additional MeOH (ca. 10 mL)
and the filtrate was concentrated under reduced pressure
to give 320 mg of the title compound as a foam in 86r
WO 95/lJ9859 2 ~ 7 4 311 PCr/17S9~1nlO49
!
yield. LRMS 568 (M + 1, base); HRMS Cacld for
C31H47BN306: 56~3.3558. Found: 5613.3553.
1:: ~ A 1~,7 1 e 1 5 q
Nl- [ ( qR) -N- ( 3-Phenylproplonyl ) -4- (benzyl ~ oxy- ~L) -prolyl ~ -
R-borolys ine, benzenesulfonate
lo a mlxture of E.~ample 303 (1.95 g, 2.52 mmol~ in
H2O (10 mL~, Et2O (15 mL~, and sufficient MeOH (ca. 1.5
mL) to maintain a clear, biphasic system was added
phenylboric acid (1.54 g, 12.6 mmol). The mixture was
stirred for 14 hours, the layers were separated and the
aqueous phase was eYtracted with Et2O ~5 x 20 mL). The
15 aqueous layer was concentrated under reduced pressure to
give the title compound (1.20 g) as an amorphous powder
in 75t yield. LRMS 482 (Mt~), 464 (base); HRMS Calcd
for C28H39BN3O5 (ethylene gycol ester): 50~3.2983. Found:
503 . 2999 .
~ATn?le 302
Nl - [ ~ 4R) -N- ~ 3-Pheny].propionyl ) -4- ~phenyl ) thio- (L) -
prolyl]-R-borolysine (t-)-pinanediol ester, hydrochloride
Part A: The commercially available starting material,
(4R) -N-BOC-9-hydroxy- (L)-proline methyl ester was
dissolved in CH2C12 ~140 mL) and carbon tetrachloride
~140 mL) and triphenylphosphine (42.56 g, 162.2 mmol)
was added. The mixture was allowed to stir for 2 hours,
30 ethanol (15 mL) was added and stirring was continued for
an additional 16 hours. The mixture was concentrated
- under reduced pressure to 100 mL, cooled to -20 C and
Et2O (200 mL) was added. The resulting precipitate waS
suction filtered and washed with Et2O. The solid was
further purified by flas~ chromatography, elution with
41
~ ~ d, S ,~
WO 95/09859 2 1 7 ~ 3 1 1 PCT/U594111049
1:1 Et20-hexanes gave (4S)-N-BOC-4-chloro-~1.)-prollne
methyl ester (17.03 g) as an oil in 84~ yield. lH NMR
(300 MHz, CDC13) ~ 4.37 (m, 2H), 3.95 (m, lH), 3.75 (s,
3H~, 3.63 (m, lH), 2.63 (m, lH), 2.38 (m, lH), 1.45 (s,
5 9H) .
Part B: A solution of the product from Part A (17.03
q, 64.5 mmol) in trifluoroacetic acid (20 mL) and CH2C12
(20 mL) was stirred 18 hours. The reaction mixture was
concentrated under reduced pressure to give (4S)-4-
10 chloro-(L)-proline methyl ester (18.05 g) as an oil in
quanitative yield. 1H NMR (300 MHz, CDC13) ~ 9 . 75 (comp,
2H), 3.87 (comp, 2H), 3.94 (s, 3H), 2.99 (rrl, lH), 2.77
(m, lH) .
Pa-~ C: A solution of the product from Parl B (30.28
1~ 9, 105 mmol) in CH2C12 (50 mL) was cooled to 0 C and
Et3N (45 . 6 mL, 327 mmol) followed by hydrocinnamoyl
chloride (17.8 mL, 120 mmol) were added slowly in order
to maintain an internal temperature less than 10 C.
After stirring six hours, H2O (50 mL) was added to the
2C reaction mixture. The resulting solution was eY.tracted
witr. CH2C1 2 (3 x 50 mL) . The organics were washed with
r.2C (25 mL), dried with MgSO4 and concentrated under
reduce~ ~pressure to give (4S) -N- (3-phenylpropioryl ) -4-
ch~oro~ )-proline meth~l ester (17.44 g) GS c waxy so_ia
in 54~ yield. LRMS 296.1 ~base, M+H) .
Part D: EtOH (50 mL) was cooled to 0 C and sodium
(0.78 9, 33.8 mmol) was added. After the hydrogen
evolution ceased, thiophenol (3.72 g, 33.8 mmol) was
added and the reaction mixture stirred for 15 minutes at
0 C, and the product from Part C (5 g, 16. 9 mmol) was
added. The stirring was continued for an additional 16
hours at room temperature. The mixture was concentrated
under reduced pressure, diluted with water (20 mL) ano
a idified with lN HCl to pH . `~ eous s~ ~ on was
~174311
Wo 9s~098sg ~ PcrnJS94/11049
extracted with EtOAc (3 x 30 mL), the organics dried
with Na25O4 and concentrated under reduced pressure.
The residue was further purified by flash
chromatosraphy, elution with chromatographed with 1:3
EtOAc-hexanes gave 2 . 06 9 of (9R) -N- (3-phenylpropionyl) -
4- (phenyl) thio- (L) -proline in 25~ yield. LRMS 356.1
(M+H, base).
Part E: Using the method described above for the
preparation of Example 7e, Part D, (lR) -5-bromo- [ (4R)-N-
(3-phenylpropionyl) -4- (phenyl) thio- (L) -
prolyl]aminopentane-l-boronic acid, (+)-pinanediol ester
was isolated (2 . 43 g) as an oil in e5~ yield. LRM5
681.2 683.2 (M+H, base~.
Part F: Using the method described above for Example
7e, Part E, the intermediate (lR) -5-azido- [ (4R) -N- (3-
phenylpropionyl ) -4- (phenyl ) thio- (L) -prolyl ] aminopentane-
1-bo-onic acid, (+)-pir~anediol ester w2S isolated (2.42
g) as ar. oil in quantitative yield.
Part. G: A solution of the product from Part F (2.42 g,
2~ 3.76 mmol) in 1,3-p=opanedithiol (1.62 9, 15 mmol),
trLethylamine (l . 52 g, 15 mmol) and methanol (20 mL~
was s; rred at 50 C for 24 hours. The reaction mixture
wac concentra~ed unde- reduce pressure and purified b~
flash chromatoyraph; through florosil, eluting with 1:9
~-, MeO:;.-CH2Cl2. ~he concentrated residue was dissolved in
diethyl ethe- (10 mL), acidified with 1 equivalent of lN
HCl in Et2O and concentrated to give the title compound
(0 73 5~ as a solid in 31% yield. LRMS 617 . 3 (M+H,
base~ . HRMS Cacld for C3sH4OBN3O45: 617.34583. Found:
3C 617 . 14580 .
E.VRrn~1e 303
4_
WO 95/09859 2 ~ 7 ~ 311 PCT/US94/11049
Nl- [ ~ 4R) -N- ~3-Phenylpropionyl ) -9- ~benzyl ) oxy- (L~ -prolyl ] -
R-borolysine, (+)-pinanediol ester
Part A: A solution of the commercially available
5 starting material, (4R) -N-BOC-4- (benzyl) oxy- (L) -proline,
previously reported by Smith et al., J. Med. Chem. 31,
875 (1988); (2.11 g, 6.57 mmol), in CH2C12 (27 mL) was
treated with anhydrous hydrogen chloride in dioxanes (4
M, 6 . 60 mL) . The reaction mixture was stirred for 18
10 hours, during which time a white precipitate formed. The
reaction was diluted with diethyl ether (Et2O, ca. 100
mL) and the solid material was collected by suction
filtration to afford ~4R) -4- ~benzyl) oxy- (L) -proline
hydrochloride ~1. 60 g) as a white powder in 95~ yield.
T NMR ~300 MHz, DMSO-d6~ ~ 10.2 ~br s, lH~, 7.36 (comp,
SH), 4.52 (s, 2H), 4.37 (dd, J= 10.8,7.5 Hz, lH), 4.31
~m, lH), 3.43 ~dd, J= 12.5,4.4 Hz, lH), 3.33 ~d, J= 12.5
Hz, lH), 2.48 ~m, lH), 2.1~ ~m, lH); LRMS 22Z ~M+H,
base ) .
Part B: ~ suspension of the product from Part A ~1. 5C
g, 5.83 mmol) in CH2C12 (58 mL) at 0 C was treated witr
3-phenylpropionyl chloride (0. 95 mL, 6. 4; mmol) followec
bi 4-methylmorpholine (1. 92 mL, 17 .5 mmol) . The
2_ reaction mixture was warmed to room temperature over 20
hours, treated with 2M aqueous hydrochloric acid ~HCl)
until pH = 2, and added to EtOAc ~ca. 200 mL) . The
organic layer was washed with H2O ~3 x 50 mL), sat. aq.
NaCl ~1 x 50 mL), dried ~MgSO4) and concentrated under
a~ reduced pressure . The resulting solid was
recrystallized from hexanes-EtOAc and gave a first crop
~1.33 g, mp 127-129 C) and a second crop ~0.37 g, mp
122-125 C) of ~4R) -N- ~3-phenylpropionyl) -4- ~benzyl) oxy-
(L~-proline as co,lorless plates in a total of 82~ yield.
3~ ~monoclinic, P21, a - 6.196, b = 9.101, c = 16.477A, ~ =
98 . 98 ) lH NMR ~300 MHz, CDC13) ~ 7 .29 ~comp, lGH),
4~
~ W095/09859 ~174311 - X PCr/Uss4/ll049
q.95 (br s, lH~, 4.69 (dd, J= 8.1,6.2 Hz, lH), 4.50
(ABq, ~Cr.AB = 32.5 Hz, JAB= 11.7 H2, 2H~, 4.20 (quin, J=
4.8 Hz, lH), 3.46 (d, J= 4.8 Hz, 2H~, 2.98 (t, J= 7.7
Hz, 2H~, 2.59 (t, J= 7.4 Hz, 2H), 2.50 (m, lH), 2.23
(ddd, J= 13.5, 8.4, 5.0 Hz, lH)i LRMS 354 (M+H, base);
Anal. Calcd for C21H23NOg: %C, 71.37; %H, 6.56; 96N, 3.96.
Found: %C, 71.39; %H, 6.57; %N, 3.92.
Part C: Using the method described above for the
preparation of Example 78, Part D, (lR) -5-bromo- [ (4R) -N-
(3-phenylpropionyl) -4- (benzyl) oxy- (L) -
prolyl]aminopentane-1-boronic acid ~+)-pinanediol ester
was isolated (2 . 80 g) as an oil in 90~ yield. LRMS
67S, 681 (M+H, base) .
Part D: Using the method described above for Example
78, Par~ E, (lR) -5-azido- [ (4R) -N- (3-phenylpropionyl) -4-
(benzyl)oxy-~L)-prolyl,aminopentane-l-boronic acid (+)-
pinanediol ester was isolated (2.31 g) as an oil in 9g0
2G yieId. LRMS 642 (M+H, base).
Part E: A solution of product from Part D (2.24 g,
3.50 mmol) in MeOH (3~ mL) together with palladium on
charcoal (225 mg) was stirred under hydrogen (1 atm) for
_ 1 hour ~he reaction mixture was filtered through a pad
of Celite with additional MeOH ~ca. 3G m~ ) and the
filtrate was concentrated under reduced pressure to give
a foam which contained a small amount of unreacted
azide. ~his material ~as resubjected to the
3G hydrogenation conditions described above to afford the
title compound (2.GG g) as a white foam in 93~ yield.
LRMS 616 (M+H, base) .
F~r~~le 303a
q
WO 95/09859 ~ 1 7 ~ 31 i PCT/US94/11049
N1- ~ ( 4R) -N- ~ 3-Phenylpropionyl ) -4- (benzyl ) oxy- (L) -prolyl ] -
R-borolysine, (+)-pinanediol ester, benzenesulfonate
A solution of Example 303 (2.00 g, 3.25 mmol) in
5 methanol (25 mL) was treated with a solution of
benzenesulfonic acid (0.514 g, 3.25 mmol) in methanol (8
mL). The mixture was allowed to stand at room
temperature for 15 minutes and concentrated under
reduced pressure to give a foam. The residue was washed
with Et2O (2 x 25 mL), which was decanted, then
dissolved in EtOAc (ca. 20 mL) and triturated with Et2O
(ca. 75 mL) to afford an oily material which was washed
with Et2O (2 x 25 mL). The excess solvent was removed
in vacuo to give the title compound (2 . 00 g) as a powder
ih 79~ yield. LRMS 616 (M+H, base); HRMS Calcd for
C36H51BN3O5: 616.392,. Found: 616.3921.
Ex~le 375
Nl- [ (4R) -N- (3-Phenylpropionyl) -4- (benzyl) amino- (L~ -
prolyl]-R-borolysine, (+)-pinanediol ester,
hydrochloride
Parr ~: A mixture of the product ~rom Example 302,
Part ~ ~3.009, 10.1 mmol~ and NaN3 (3.30 9, 5C.7 mmol)
in D~ (15 mL) was heated to 75 ~C for 18 hours. The
reaction mixture was dissolved in H20 (25 mL) . The
aqueous solution was extracted with Et20 (3 x 25 m.L),
dried with MgSOg and concentrated to give (4R)-N- (3-
phenylpropionyl)-4-aZido-(L)-proline methyl ester (2.13
3G g) as an oil in 83~ yield. 1H NMR (300 MHz, CDC13) ~ -
7.25 (comp, 5H), 4.56 (m, lH), 4.26 (m, lH), 3.77 (s~
3H), 3.75 (m, lH), 3.40 (dd, J = 8, 2 Hz, lH), 2.97 (m,
2H), 2,60 (m, 2H), 2.32 (comp, 2H) . LRMS 303.1 (M+H,
base ) .
46
wossl~)s859 ~ 1 7 4 3 ~ Pcr/us94/11049
Part B: Using the method described above for the
preparation of Example 78, Part E`, (4R) -N- (3-
phenylproplonyl)-4-amil~o-(L)-proline methyl ester was
isolated (2.43 g) as an oil in 85~; yield. lH NMR (300
MHz, CDC13) ~ 7.24 (comp~ 5H), 4.58 (m, lH), 3.79
(m, 2H), 3.73 (s, 3H), 3.01 (m, 3H), 2.60 (m, 2H), 2.12
(m, lH), 1. 94 (m, lH) . LRMS 277 . 1 (M+H, base) .
Part C: A mixture of the product from Part B (l.S1 g,
5.46 mmol), benzaldehyde (0.58 g, 5.46 mmol), potassium
acetate (0.54 g, 5.46 mmol) and 5% palladium on charcoal
(0.21 g) was stirred ill MeOH (25 mL) under hydrogen (3
atm~ for 5 hours. The reaction mixture was filtered
through a pad of Celite with additiona~ MeOH (ca. 10 mL
and the filtrate concentrated under reduced pressure to
give (4R)-N-(3-phenylpropionyl)-4-(benzyl)amino-(L)-
prol.ine methyl ester (2.00 g) as an oil in quantitative
yield. lH NMR (300 MHz, CDC13) ~ 7.27 (comp, 10H), 4.58
(m, lH), 3.73 (comp, 4~1), 3.50 (m, lH), 3.44 (s, 3H),
3.15 (m, lH), 2.96 (t, J = 7 Hz, 2H), 2.55 (m, 2H), 2.09
2C (m, 2H) . LRMS 367.2 ~M+H, base) .
Part D: A solution oF the product from Part C (2.00 g,
5.46 mmol) methano (lS mL) and lN sodiu~. hydroxiQe
( 9 mL) was stirred for 24 hours . The pH of the solutior.
was adjusl:ed to 6 with lN HCl and a white precipitate
2- formeQ. The solid material was collected by suction
filtration to give (9R) -N- (3-phenylpropionyl) -9-
(benzyl)amino-~L)-prOline (1.31 g) as a white powder in
68~ yield. LRMS 353.2 (M+H, base) .
Part. E: Using the method described above for the
30 preparation of Example 78, Part D, (lR) -5-bromo- [ (9R)-N-
( 3-phenylpropionyl ) -9- (benzyl ) amino- ~L) -
prolyl]aminopen,tane-l-boronic acid, (+)-pinanediol este-
was isolated (0.71 g) as an oil in 99~ yield. LRMS
678.3 680.3 (M+E~, base) .
~7
W0 95/098S9 ~ PCT/US94111049
2~74311
Part F: Using the method described above for Example
78, Part E, the intermediate (lR) -5-azido- [ (4R)-N- (3-
phenylpropionyl) -4- (ben2yl) amino- (L) -prolyl ] aminopentane-
l-boronic acid, (+) -pinanediol ester was isolated 10 . 45
9) as an oil in 67% yield.
Part G: A solution of the product from Part F ~0.45 g,
0.70 mmol) in MeOH (5 mL) together with 20% palladium
hydroxide on charcoal (O . 04 g) was stirred under
hydrogen (1 atm) for 4 hours. The reaction mixture was
filtered through a pad of Celite with EtOAc (ca. 10 mL~ . -
The filtrate was concentrated under reduce~i pressure and
purified by flash chromatography through florosil,
eluting with 1: 9 MeOH-CH2C12 . The concentrated residue
;~ was dissolved in Et20 (10 mL), acidified wit}~. 2
equivalents of lN HCl in Et20 and concentrated to ~ive
the title compound (0.27 g) as a oil in 56~ yield.= LRMS
615.4 (M+H, base) .
~A~nle 1 64 1
N1- [ ( 4R) -N- (Benzyloxy) carbonyl-4- (benzyl ) ox~-- (L) -prolyl ] -
R-borothioarginine, (+~-pinanediol ester =
2. Part }~ sing the method described above fo- Example
78, (lR) -4-bromo- [ ~4R) -N- ~benzyloxy) carbon~ l-4-
(benzyl) oxy- (L) -prolyl] aminobutane-l-boronic acid, ~+) -
pinanediol ester (370 mg) was prepared as an oil in 99
yield. LP~MS 667, 669 (M+H), 587 (base) .
Part fi: A mixture of the product from Part A ~365 mg,
0.55 mmol) and thiourea (83 mg, 1.10 mmol) in ethanol
(EtOH, 10 mL) was heated at reflux for 16 hours and
cooled to room temperature. The reaction was poured
into Et20 ~ca. 120 mL) and concentrated under reduced
48
~ Wo 95l098s9 ~3 1 7 ~ 3 1 1 ~ Pcr/r~sg4lllo49
pressure. The residue W25 triturated with Et2O (ca. 50
mL), which was decanted. Purification of the residue by
size exclusion chromatography on Sephadex LH-20, elution
with MeOH, gave a glass which was dissolved in THF (1.5
5 mL) and treated with Et2O ~ca. 20 mL) to give a solid.
The solid was washed with Et2O (ca. 10 mL) and dried to
afford the title compound (125 mg) as a white solid in
31% yield, mp 79-82 C. LP~MS 663 (M+H, base~; H~<MS
Calcd for C35HçgBN4O65: 663.3388. Found: 663.3374.
Based on the representative e~amples detailed --
above, the following compounds of tT~e invention can be
15 prepareQ, as shown in Tables 1-20
.
~c
W0 95/09859 2 1 7 4 3 1 1: ~ PCTIUS94/11049
' ~h~L
OH
N l~ ~B~
OH
0~, N H
RA O ~N--Z--R10
4~(CR8CR9)U--W--(CR6CR7)tJ~O
5 6
Ex.No RA R6 R7 R8 R9 R~0 W Z I u Da~
H - _ _ _ CH3 _ C0 0 0
2 H ~ ~ ~ ~ CH3 CH2 C0 0 0
3 H H H ~ -- CH3 CH2 C0 1 0
4 H H H H H CH3 CH2 C0
HCH3 CH3 ~ ~ CH3 CH2 C0 I 0
6 H - - CH3 CH3 CH3 CH2 C0 0
7 H _ _ Ph H CH3 C0 0
8 H H H - - CH3 0 C0 1 0
9 HCH3 CH3 _ _ CH3 0 C0 1 0
10 H H H ~ ~ CH3 S07 C0 1 0
1 i2-CH3 H H ~ ~ CH3 CH2 C0 1 0
123-CH3 H H ~ ~ CH3 CH2 C0 ~ 0
]32, 3-diCH3 H H ~ ~ CH3 CH2 C0 1 0
142-F H H ~ ~ CH3 CH2 C0 1 0
1~3-F H H ~ ~ CH3 CH2 C0 1 0
164-F H H ~ ~ CH3 CH2 C0 ~ 0
172-NH2 H H ~ ~ CH3 CH2 C0 1 0
183-NH2 H H ~ ~ CH3 CH2 C0 ] 0
192-N02 H H ~ ~ CH3 CH2 C0 1 0
203-N02 H~ H ~ ~ CH3 CH2 C0 ~ I 0
212-N H H ~ ~ CH3 CH2 C0 ] ()
Sr
~,17~311
WO 95109859 PCT/US94/11049
223-N H H - - CH3 CH2 CO l 0
234-N H H - - CH3 CH2 CO l 0
24 H H H _ _ (CH2)2Ph O CO l 0
25 HCH3 CH3 _ (CH2)2ph O CO 0
26 H H H _ _ (CH2)2ph S2 CO l 0
27 H H H _ _ (cH2)2ph CH2 CO l 0
28 HCH3 CH3 _ _ (CH2)2ph CH2 CO l 0
29 H _ _ ~CH3 CH3 (CH2)2Ph CH2 CO 0
302-CH3 H H - _ (CH2)2ph CH2 CO l 0
313-CH3 H H - _ (CH2)2ph CH2 CO l 0
322, 3-diCH3 H H - _ (CH2)2ph CH2 CO I O
332-F H H - _ (CH2)2ph CH2 CO l 0
3~3-F H H - - (CH2)2Ph CH2 CO l 0
354-F H H - - (CH2)2Ph CH2 CO l 0
362-NH2 H H - - (CH2)2ph CH2 CO l 0
373-NH2 H H - - (CH2)2ph CH2 CO I 0
3g2-No2 H H - _ (CH2)2ph CH2 CO l 0
393-NO2 H H - - (CH2)2ph CH2 CO l 0
402-N H H - - (CH2)2ph CH2 CO l 0
413-N H H - _ (CH2)2Ph CH2 CO l 0
424-N H H - _ (CH2)2Ph CH2 CO l 0
43 H H H - - CH2Ph CH2 C(O)O I
4~ HCH3 CH3 _ _ CH7Ph CH2 C(O)O l 0
45 H _ _ CH3 CH3 CH2Ph CH2 C(O)O 0
462-CH3 H H - - CH2Ph CH2 C(O)O l 0
473-CH3 H H _ _ CH2Ph CH2 C(O)O l 0
48'', 3-diCH3 H H - - CH2Ph CH2 C(O)O I O
492-F H H - - CH2Ph CH2 C(O)O I
503-F H H - - CH2Ph CH2 C(O)O l 0
514-F H H - - CH2Ph CH2 C(O)O I
5'2-NH2 H H - - CH2Ph CH2 C(O)O l 0
533-NH2 H H _ _ CH2Ph CH2 C(O)O I
542-NO2 H H - - CH2Ph CH2 C(O)O I
553-NO2 H~ H .- _ CH2Ph CH2 C(O)O I
562-N H H - - CH~)Ph CH2 C(O)O I O
51
W095109859 2?~4~l~ PCTIUS94/11049
573-N H H _ _ CH2Ph CH2 C(O)O ] 0
584-N H H _ _ CH2Ph CH2 C(O)O I O
59 H H H _ _ CH2Ph CH2 C(O)NH ] 0
60 H CH3 CH3 _ CH2Ph CH2 C(O)NH l 0
61 H _ _ CH3 CH3 CH2Ph CH2 C(O)NH 0
622-CH3 H H - = -- CH2Ph CH2 C(O)NH l 0
633-CH3 H H _ = _ CH2Ph CH2 C(O)NH l 0
642, 3-diCH3 H H _ _ CH2Ph CH2 C(O)NH I O
652-F H H _ _ CH2Ph CH2 C(O)NH I
663-F H H _ _ CH2Ph CH2 C(O)NH l 0
674-F H H - - ~ CH2Ph CH2 C(O)NH I
682-NH2 H H -- - CH2Ph CH2 C(O)NH 1 0
693-NH2 H H -- - CH2Ph CH2 C(O)NH I ()
702-N02 H H - - CH2Ph CH2 C(O)N7H I O
7]3-NO2 H H - - CH2Ph CH2 C(O)NH l 0
722-N H H - - CH2Ph CH2 C(O)NH l 0
733-N H H - - CH2Ph CH2 C(O)NH l 0
744-N H H - - CH2Ph CH2 C(O)NH 3 0
75 H H H - - CH2OPh CH2 CO 1 0
WO 95109859 2 1 7 ~ 3 1 1 PCT/US94/11049
Ta~le 2
~0 ~
N ~--~B~o
Oq~NH CH3
~ L (CR8CR8)U--W--(CR6CR7)J~O
s 6
E~NoF~A R6 ~7 R8 R9 R10 W Z I u Da~
76 H _ _ _ _ CH3 -- CO 0 0 A
77 H ~ ~ ~ ~ CH3 CH I CO 0 0 B
78 H H H ~ . ~ CH3 CH2 CO I 0 C
79 H H H H H CH3 CH2 CO I I D
80 HCH3 CH3 ~ ~ CH3 CH2 CO 1 0 E
8I H _ _ ~H3 CH3 CH3 CH2 CO 0 I F
8~ H _ _ Ph H CH3 CO 0 1 G
83 H H H _ _ CH3 O CO 1 0 H
8~ HCH3 CH3 _ _ CH3 o CO l 0
85 H H H ~ ~ CH3 52 CO l 0
862 CH3 H H ~ ~ CH3 CH2 CO ~ 0
873-CH3 H H ~ ~ CH3 CH2 CO ~ 0
882, 3-diC~3 H H ~ ~ CH3 CH2 CO I O
892-F H H ~ ~ CH3 CH2 CO l 0
903-F H H ~ ~ CH3 CH2 CO I 0
914-F H H ~ ~ CH3 CH2 CO 1 0
9'2-NH2 H H ~ CH3 CH 2 CO 1 0
-933-NH2 H H ~ ~ CH3 CH2 CO l 0
9~,~-N02 H H ~ ~ CH3 CH2 CO I O
953-NO2 H' H ~ ~ CH3 CH2 CO ~ 0
962-N H H ~ - CH3 CH~ CO l 0
_ _
WO 95/09859 21 7. 4,~1 1 PCT/US94/11049
973-N H H - - CH3 CH2 CO I 0 K
984-N H H - - CH3 CH2 CO l 0
99 H H H - _ (CH2)2Ph o CO l 0
100 HCH3 CH3 _ (CH2)2Ph O CO 0
101 H H H _ _ (cH2)2ph S2 CO l 0
102 H H H _ _ (CH2)2ph CH2 CO I 0 L
103 HCH3 CH3 _ _ (CH2)2ph CH2 CO l 0
114 H _ _ CH3 CH3 (CH2)2Ph CH2 CO 0
1052-CH3 H H - - (CH2)2ph CH2 CO l 0
1063-CH3 H H - - (CH2)2ph CH2 CO l 0
1072, 3-diCH3 H H - - (cH2)2ph CH2 CO I O
1082-F H H - _ (CH2)2ph CH2 CO l 0
1093-F H H - - (cH2)2ph CH2 CO l 0
1104-F H H - - (CH2)2ph CH2 CO l 0
1112-NH2 H H - - (cH2)2ph CH2 CO . I 0
1123-NH2 H H - _ (CH2)2ph CH2 CO l 0
1132-NO2 H H - _ (cH2)2ph CH2 CO l 0
1143-N2 H H - - (cH2)2ph CH2 CO l 0
1152-N H H - - (CH2)2ph CH2 CO l 0
1163-N H H - -- (cH2)2ph CH2 CO l 0
1~74-N H H - - (cH2)2ph CH2 CO l 0
118 H, H H - - CH2Ph CH~ C(O)O l 0
119 HCH3 CH3 _ CH2Ph CH2 C(O)O ~
120 H _ _ CH3 CH3 CH2Ph CH~ C(O~O
1212-CH3 H H - - CH2Ph CH7 C(O)O I
12~3-CH3 H H - - CH2Ph CH2 C(O)O I
1232, 3-diCH3 H H _ _ CH2Ph CH2 C(O)O I O
1242-F H H - - CH2Ph CH2 C(O)O l 0
1253-F H H - - CH2Ph CH2 C(O)O 1
1264-F H H - - CH2Ph CH2 C(O)O I
1272-NH2 H H - - CH2Ph CH2 C(O)O 1 0
1283-NH2 H H - - CH2Ph CH2 C(O)O I
1292-NO2 H H - - CH2Ph CH2 C(O)O I
1303-NO2 H H _ _ CH2Ph CH2 C(O)O l 0
1312-N H H - - CH2Ph CH2 C(O)O I
5~
WO 95/098S9 2 1 7 4 ~ 1 i PCT/US94/11049
1323-N H H _ _ CH2Ph CH2 C(O)O l 0
1334-N H H _ _ CH2Ph CH2 C(O)O I
131 H H H _ _ CH2Ph CH2 C(O)NH I
135 H CH3 CH3 _ _ CH2Ph CH2 C(O)NH l 0
136 H _ _ CH3 CH3 CH2Ph CH2 C(O)NH 0
1372-CH3 H H _ _ CH2Ph CH2 C(O)NH l 0
1383-CH3 H H _ _ CH2Ph CH2 C(O)NH I
1392, 3-diCH3 H H _ _ CH2Ph CH2 C(O)NH I O
1402-F H H - -- CH2Ph CH2 C(O)NH 1 0
1413-F H H - - CH2Ph CH2 C(O)NH l 0
1424-F H H _ _ CH2Ph CH2 C(O)NH l 0
1432-NH2 H H _ _ CH2Ph CH2 C(O)NH l 0
1~3-NH2 H H _ _ CH2Ph CH2 C(O)NH l 0
1452 NO2 H H - - CH2Ph CH2 C(O)NH l 0
1463-NO~ H H _ _ CH2Ph CH~ C(O)NH I O
1472-N H H - - CH2Ph CH2 C(O)NH l 0
1483-N H H _ _ CH2Ph CH2 C(O)NH l 0
1494-N H H - - CH2Ph CH2 C(O)NH l 0
150 H H H - - CH2oph CH~ CO l O
~5
WO 95/09859 2 ~ 7 4; 3 f ~: PCT/US94111049
Table 3
,OH
H 2 N B~
OH
Oq~ N H
4~(CH ) `~ R6 R7 ~RB
s 6
E7uNo RA RB R6 R7 z V W u Da~
151 H H H H C(O)O O - I
15' H H H H CO O CH2 0
153 H H CH3 CH3 CO S =CH2 o~
15~ H H H H CO CH2 1 ~3SA
sal~,M
155 H 2'- CH3 H H CO CH2
156 H 3'-CH3 H H CO O CH2 I N
157 H 2, 3-diCH3 H H CO CH2
158 H 2'-F H H CO O CH2
159 H 3'-F H H CO o , CH2
160 H 2'-N H H CO O CH2
16~ H 3'-1~ H H CO O CH,
~673-CH3 H H H CO O CH2
1633-CH3 2~-CH3 H H CO O CH2
16~3-CH3 3 CH3 H H CO O CH2
1653-CH3 2', 3'-diCH3 H H CO CH2
1663-CH3 2'-F H H CO CH2
1673-CH3 3'-F H H CO O CH2
1683-CH3 2'-1~ H H CO CH2
1693-CH3 3'-N H H CO O CH2
1702-F H H H CO O CH2
1712-F ~-CH3 H H CO CH2
5~
WO95109859 2i74~ PCT/US94/11049
172 2-F 3~-CH3 H H CO CH2
173 2-F 2', 3'-diCH3 H H CO O CH2
174 2-F 2'-F H H CO CH2
175 2-F 3'-F H H CO O CH2
176 2-F 2'-N H H CO CH2
177 2-F 3:N H H CO CH2
178 3-F H H H CO O CH2 1 O
179 3-F 2~-CH3 H H CO CH2
170 3-F 3~-CH3 H H CO CH2
181 3-F 2', 3'-diCH3 H H CO CH2
182 3-F 2'-F H H CO CH2
183 3-F 3'-F H H CO CH2
181 3-F 2'-N H H CO CH2
185 3-F 3'-N H H CO O CH2
186 3-NH2 H H H CO O CH2
187 3-NH2 2~-CH3 H H CO CH2
188 3-NH2 3~-CH3 H H CO CH2
189 3-NH2 2', 3'-diCH3 H H CO O CH2
19O 3-NH2 2'-F H H CO CH2
191 3-NH2 3'-F H H CO CH2
192 3-NH2 2'-N H H CO CH2
193 3-NH2 3'-N H H CO O CH2
19~ 3-NO2 H H H CO CH2
195 3-NO2 2~-CH3 H H CO CH2
196 3-NO2 3~-CH3 H H CO O CH2 3
197 3-NO2 2', 3-diCH3 H H CO O CH2
198 3-NO2 2'-F H H CO O CH2
199 3-NO2 3'-F H H CO CH2
2CO 3-NO2 2'-N H H CO O CH2
201 3-N2 3'-N H H CO CH2
202 2-N H H H CO CH2
203 2-N 2~-CH3 1 i H CO CH2
204 2-N 3'-CH3 } i H CO O CH2
205 2-N 2', 3'.diCH3 1~ H CO CH2
206 2-N 2'-F ~; H CO O CH2
57
WO 95/09859 2 ~ 7 g~l PCTII~S94/11049
2072-N 3'-F H H CO O CH2
2082-N 2'-N H H CO O CH2
2092-N 3'-N H H CO O CH2
2103-N' H H H CO o CH2
2113-N 2'-CH3 H H CO CH2
2123-N 3~-CH3 H H CO CH2
2133-N 2', 3'-diCH3 H H CO O CH2
2143-N 2'-F H H CO O CH2
2153-N 3'-F H H CO O CH2
2163-N 2'-N H H CO CH2
2~73-N 3'-N H H CO CH2
2184-N H H H CO CH2
2194-N' 2'-CH3 H H CO CH2
2204-1`.' 3~-CH3 H H CO O CH2
2714-1`: 2', 3'-diCH3 H H CO O CH2
2224_1~: 2'-F H H CO O CH2
2234-N' 3'-F H H CO CH2
22~4-N' 2'-N H H CO O CH2
2254-N 3'-N H H CO O CH~ I
226 H H H H CO O O 0--
227 H H CH3 CH3 CO S O 0
228 H H H H CO O O
229 H 2'- CH3 H H CO O O
230 H 3'-CH3 H H CO O O
231 H 2'~ 3'-diCH3 H H CO O O
23 H2'-F H H CO O O
233 H 3'-F H H CO O O
234 H 2'-N H H CO O O
235 H 3'-N H H CO O O
2363-CH3 H H H CO O O I ~ -
2373-CH3 2'-CH3 H H CO O O 1,
2383-CH3 3~-CH3 H H CO O O
2393-CH3 2', 3-diCH3 H H CO O O I
2403-CH3 ~'-F H H CO O O
2413-CH3 3'-F H H CO O O
58
WO 95109859 2 1 7 4 3:1 ~ PCT/US94/11049
o
242 3-CH3 2'-N H H CO O O
243 3-CH3 3'-N H H CO O O
244 2-F H H H CO O O
245 2-F 2'-CH3 H H CO O O
246 2-F 3 CH3 H H CO O O
247 2-F 2', 3'-diCH3 H H CO O O
248 2-F 2'-F H H CO O O
249 2-F 3'-F H H CO O O
250 2-F 2'-N H H CO O O
251 2-F 3'-N H H CO O O
252 3-F H H H CO O O
253 3-F 2'-CH3 H H CO O O
25, 3-F 3~-CH3 H H CO O O
255 3-F 2', 3'-diCH3 H H CO O O
256 3-F 2'-F H H CO O O
257 3-F 3'-F H H CO O O
258 3-F 2:N H H CO O O
259 3-F 3'-N H H CO O O
260 3-NH2 H H H CO O O
261 3-NH2 2~-CH3 H H CO O O
26'' 3-NH2 3~-CH3 H H CO O O
263 3-NH2 2, 3-diCH3 H H CO O O
26~ 3-NH2 Z-F H H CO O O
265 3-NH2 3'-F H H CO O O
266 3-NH2 2'-N H H CO O O
267 3-NH2 3'-N H H CO O O
268 3-N2 H H H CO O O
269 3-NO2 2~-CH3 H H CO O O
270 3-NO2 3~-CH3 H H CO O O
27i 3-N2 2, 3-diCH3 H H CO O O
272 3-NO2 2'-F H H CO O O
273 3-NO2 3'-F H H CO O O
27~ 3-NO2 2'-N H H CO O O
275 3-NO2 '3:~' H H CO O O
276 2-N H H H CO O O
5~
W095/09859 21~5~i3~ i PCr/lJS94/11049
2772-N 2'-CH3 H H C0 0 0
2782-N 3~-CH3 H H C0 0 0
2792-N 2', 3'-diCH3 H H C0 0 0
2802-N 2'-F H H C0 0 0
2812-N 3'-F H H C0 0 0
2822-N 2'-N H H C0 0 0
2832-N 3'-N H H C0 0 0
2843-N H H H C0 0 0
2853-N 2~-CH3 H H C0 0 0
2863-N 3~-CH3 H H C0 0 0
2873-N 2', 3'-diCH3 H H C0 0 0
2883-N 2'-F H H C0 0 0
2893-N 3'-F H H C0 0 0
2903-N 2'-N H H C0 0 0
2913-N 3'-N H H C0 0 0
2924-N H H H C0 0 0
2934-N' 2~-CH3 H H C0 0 0
2914-N 3~-CH3 H H C0 0 0
2954-N 2', 3'-diCH3 H H C0 0 0
2964-N 2'-F H H C0 0 0
2974-N 3'-F H H C0 0 0
2984-N , 2'-N H H C0 0 0
2994-N' 3'-N H H C0 0 0
Table 9
w~gsl098s9 S~174311 PCT~7S94/11049
i
O ~
H2N ~ ,~B,
O~,NH r H3
~ N--Z~,W~_
E~.No RA RB R6 R7 z V W u Da~
300 H H H H C(O)O O - I
301 H H H H CO O CH2 0
302 H H H H CO S CH2 o P
303 H H H H CO O CH2 I Q
303a H H H H CO O CH2 I BSA
sal~
30~ H 2~- CH3 H H CO O CH2
305 H 3'-CH3 H H CO O CH2 I R
306 H 2, 3-diCH3 H H CO O CH2
307 H 2'-F H H CO O CH2
308 H 3'-F H H CO O CH2
309 H 2'-~' H H CO O CH2
310 H 3'-N H H CO O CH2 I S
3~ i 3-CH3 H H H CO O CH2
312 3-CH3 2~-CH3 H H CO O CH2
313 3-CH3 3~-CH3 H H CO CH2
314 3-CH3 2, 3-diCH3 H H CO O CH2
315 3-CH3 2'-F H H CO O CH2
316 3-CH3 3'-F H H CO O CH2
317 3-CH3 2'-N H H CO O CH2
318 3-CH3 ,3~ H H CO O CH2
319 2-F H H H CO O CH2
. I
WO 95/09859 ;~ ~ 7 4 3 ~ i PCT/llS94/11049
320 2-F 2'-CH3 H H CO CH2
321 2-F 3~-CH3 H H CO CH2
322 2-F 2', 3'-diCH3 H H CO O CH2
323 2-F 2'-F H H CO CH2
324 2-F 3'-F H H CO CH2
325 2-F 2'-N H H CO o CH2
326 2-F 3'-N H H CO O CH2
327 3-F H H H CO O CH2 I T
328 3-F 2'-CH3 H H CO o CH2
329 3-F 3~-CH3 H H CO O CH2
330 3-F 2'~ 3'-diCH3 H H CO CH2
331 3-F 2'-F H H CO CH2
332 3-F 3'-F H H CO O CH2
333 3-F 2'-N H H CO CH2
334 3-F 3'-N H H CO O CH2
335 3-NH2 H H H CO O CH2 1 U
336 3-NH2 2~-CH3 H H CO CH2
337 3-NH2 3~-CH3 H H CO CH2
338 3-NH2 2', 3-diCH3 H H CO O CH2
339 3-NH2 2'-F H H CO O CH2
340 3-NH2 3'-F H H CO O CH, I
343 3-NH2 2'-N H H CO O CH2 ]
34'2 3-NH2 3'-N~ H H CO CH2
343 3-NO2 H H H CO O CH ~ I
34~ 3-NO2 2'-CH3 H H CO CH2
345 3-NO2 3~-CH3 H H CO O CH2
346 3-N2 2', 3-diCH3 H H CO O CH2
347 3-NO2 2'-F H H CO O CH2
348 3-N2 3'-F H H CO O CH2
345 3-N02 2'-N H H CO CH2
350 3-NO2 3'-N H H CO CH2
351 2-N H H H CO CH2
352 2-N 2'-CH3 H H CO O CH2
353 2-N 3~-CH3 H H CO CH2
35~ 2-N 2', 3'-diCH3 H H CO CH2
62
WO95/09859 ~ 43~ PCTIUS94J11049
355 2-N 2'-F H H CO O CH2
356 2-N 3'-F H H CO O CH2
357 2-N 2'-N H H CO O CH2
358 2-N 3'-N H H CO CH2
359 3-N H H H CO CH2
360 3-N 2'-CH3 H H CO O CH2
361 3-N 3~-CH3 H H CO CH2
362 3-N 2', 3'-diCH3 H H CO O CH2
363 3-N 2'-F H H CO CH2
364 3-N 3'-F H H CO CH2
365 3-N 2'-N H H CO O CH2
366 3-N 3'-N H H CO O CH2
367 4-N H H H CO O CH7
36~ 4~N 2~-CH3 H H CO O CH~ I
369 4-N 3~-CH3 H H CO CH2
370 4-N 2', 3'-diCH3 H H CO O CH~ I
37~ 4-N 2'-F H H CO O CH2
372 4-N 3'-F H ' H CO CH2
373 4-N 2'-N H H CO O CH2
374 4-N 3'-N H H CO CH2
375 H H H H CO NH CH2
376 H H H H CO O (cH2 I K
CH2)
377 H H H H CO O O I ~'
37~ H 2: CH3 H H CO O O
379 H 3~-CH3 H H CO O O ] ~;
380 H 2', 3'-diCH3 H H CO O O
38~ H 2'-F H H CO O O
38' H 3'-F H H CO O O I W~'
383 H 2'-N H H CO O O
384 H 3'-N H H CO O O
385 3-CH3 H H H CO O O
386 3-CH3 2~-CH3 H H CO O O
387 3-CH3 3,-CH3 H H CO O O
39~ 3-CH3 2', 3'-diCH3 H H CO O O
63
2174311
WO 95/09859 .~ PC'r/llS94/11049
399 3-CH3 2'-F H H CO O O
390 3-CH3 3'-F H H CO O O
391 3-CH3 2'-N H H CO O O
392 3-CH3 3'-N H H CO O O
393 2-F H H H CO O O
394 2-F 2'-CH3 H H CO O O
395 2-F 3~-CH3 H H CO O O
396 2-F 2', 3'~iCH3 H H CO O O
397 2-F 2'-F H H CO 0 O
398 2-F 3'-F H H CO O O
399 2-F 2'-N H H CO 0 O
400 2-F 3'-N H H CO 0 O
401 3-F H H H CO O O
40'' 3-F 2'-CH3 H H CO 0 O
403 3-F 3~-CH3 H H CO 0 O
40~ 3-F 2', 3'-diCH3 H H CO 0 O
405 3-F 2'-F H H CO O O
40~ 3-F 3'-F H H CO 0 O
407 3-F 2'-N H H CO O 0
408 3-F 3'-N H H CO 0 O
409 3-NH2 H H H CO 0 0
410 3-NH~ 2'-CH3 H H CO 0 0
411 3-l`.H . 3~-CH3 H H CO 0 O
412 3-NH2 2', 3-diCH3 H H CO 0 O
413 3-NH2 2'-F H H CO 0 0
414 3-NH2 3'-F H H CO 0 0
415 3-NH2 2'-N H H CO 0 O
416 3-NH2 3'-N H H C0 0 O
417 3-NO2 H H H CO 0 O
418 3-NO2 2'-CH3 H H C0 0 0
419 3-NO2 3~-CH3 H H CO 0 O
420 3-NO2 2', 3-diCH3 H H C0 0 O
421 3-N2 2'-F H H C0 0 O
422 3-NO2 '3'-F H H C0 0 O
423 3-NO2 2'-N H H C0 0 O
64
Wo 9St09859 217 ~ 311 PCr/U594/lla49
424 3-No2 3'-N H H CO O O
425 2-N H H H CO O O
426 2-N 2'~CH3 H H CO O O
427 2-N 3~-CH3 H H CO O O
428 2-N 2', 3'~iCH3 H H CO O O
429 2-N 2'-F H H CO O O
430 2-N 3'-F H H CO O O
431 2-N 2'-N H H CO O O
432 2-N 3'-N H H CO O O
433 3-N H H H CO O O
434 3-N 2~-CH3 H H CO O O
435 3-N 3~-CH3 H H CO O O
436 3-~' '', 3'-diCH3 H H CO O O
437 3-18' 2'-F H H CO O O
438 3-N 3'-F H H CO O O
439 3-N 2'-N H H CO O O
440 3-N 3'-N H H CO O O
441 4-~' H H H CO O O
442 4-N 2:CH3 H H CO O O
443 4-N' 3~-CH3 H H CO O O
444 4-N 2, 3-diCH3 H H CO O O
445 4-N 2'-F H H CO O O
446 4-N 3'-F H H CO O O
447 4-~ 2'-N H H CO O O
448 4-~' 3'-N H H CO O O
Table 5
5~
~1 74 ~. i
WO 95/09859 311 PCT/US94/11049
NH pH
RX J~ N ~\I~B~o H
Oq~ N H
RA o ~N--Z--R10
3 2
4~ 3~(CR8CR7u--W--(CR6CR7)~ ~O
s 6
Ex.No RA R6 R7 R8 R9 R10 W Z ~ u RX Da~a
449 H H H ~ ~ CH3 CH~ CO I 0 H
450 H CH3 CH3 ~ ~ ~ CH3 CH2 CO l 0 H
45~ H _ _ CH3 CH3 CH3 CH2 CO 0 l H
452 H H H _ _ CH3 O CO l 0 H
453 H CH3 CH3 - -.. CH3 O CO l 0 H
45~ H H H ~ ~ CH3 SO2 CO l 0 H
4553-CH3 H H ~ -- CH3 CH2 CO ~ 0 H
4563-F H H ~ ~ CH3 CH2 CO I 0 H
4573-NH2 H H ~ ~ CH3 CH2 CO l 0 H
4532-N H H ~ ~ CH3 CH2 CO l 0 H
4593-CH3 H H - - (CH2)2Ph CH2 CO l 0 H
4603-F H H - - (CH2)2Ph CH2 CO l 0 H
4613-NH2 H H - - (CH2)2Ph CH~ CO l 0 H
46"2-N H H - - (CH2)2Ph CH2 CO I O H
4633-CH3 H H - - CH2Ph CH2 C(O)O 1 ~ H
46~3-F H H - - CH2Ph CH2 C(O)O l 0 H
4653-NH2 H H - - CH2Ph CH2 C(O)O l 0 H
4662-N H H - - CH2Ph CH2 C(O)O 1 0 H
4673-CH3 H H - - CH2Ph CH2 C(O)NH I 0 H
4683-F H H - -= CH2Ph CH2 C(O)NH I 0 H
4693-NH2 H H - -- CH2Ph CH2 C(O)NH I 0 H
4702-N H ~ H - -- CH2Ph CH2 C(O)NH I 0 H
471 H H H ~ ~ CH3 CH, CO l H2N
66
21743~
WO 95/098S9 - - = = PCT/[IS94111049
472 H CH3 CH3 - - CH3 CH2 CO 1 H2N
473 H _ _ CH3 CH3 CH3 CH2 CO I H2N
474 H H H - - CH3 O CO I H2N
475 H CH3 CH3 _ _ CH3 O CO ] H2N
476 H H H - - CH3 SO2 CO I H2N
4773-CH3 H H - - CH3 CH2 CO I H2N
4783-F H H - - CH3 CH2 CO I H2N
4793-NH2 H H - - CH3 CH2 CO I H2N
4802-N H H - - CH3 CH2 CO 1 H2N
4813-CH3 H H - -- (CH2)2Ph CH2 CO I H2N
4823-F H H - - (CH2)2Ph CH2 CO I H2N
4833-NH2 H H - - (CH2)2Ph CH2 CO I H2N
4842-N H H - - (CH2)2Ph CH2 CO I H2N
4853-CH3 H H - - CH2Ph CH2 C(O)O I H2N
4863-F H H - - CH2Ph CH2 C(O)O I H2N
4873-NH2 H H - - CH2Ph CH2 C(O)O I H2N
4882-N H H - - CH2Ph CH2 C(O)O I H2N
4893-CH3 H H - - CH2Ph CH2 C(O)NH I H2N
4903-F H H - - CH2Ph CH2 C(O)NH I H2~
4913-NH2 H H - - CH2Ph CH2 C(O)NH I H2N
4922-N H H - - CH2Ph CH2 C(O)NH I H2N
493 H H H - - CH3 CH2 CO I o CH3NH
49~ H CH3 CH3 - - CH3 CH~ CO I 0 CH3NH
495 H _ _ CH3 CH3 CH3 CH- CO o I CH3NH
496 H H H _ _ CH3 O CO I o CH3NH
497 H CH3 CH3 _ _ _CH3 O CO I o CH3NH
498 H H H - - CH3 SO2 CO I 0 CH3NH
4993-CH3 H H - - CH3 CH2 CO I o CH3NH
5003-F H H - - CH3 CH2 CO I o CH3NH
5013-NH2 H H - - CH3 CH2 CO l 0 CH3NH
5022-N H H - - CH3 CH2 CO I o CH3NH
5033-CH3 H H - - (CH2)2Ph CH2 CO I o CH3NH
50~3-F H H - - (CH2)2Ph CH2 CO I o CH3NH
5053-NH2 H ' H - - (CH2)2Ph CH2 CO l 0 CH3NH
5062-N' H H - - (CH2)2Ph CH2 CO I 0 CH3NH
6~
Wo 95/09859 217 4 3 11 PCrNS94/11049
5073-CH3 H H - _ CH2Ph CH2 C(O~O I 1~ CH3NH
5083-F H H - - CH2Ph CH2 C(O)O I o CH3NH
5093-NH2 H H ~ ~ ~ CH2Ph CH2 C(O)O I 0 CH3NH
5102-N H H - - CH2Ph CH2 C(O)O I o CH3NH
5113-CH3 H H - -- CH2Ph CHz C(O)NH 1 o CH3NH
5123-F H H - - CH2Ph CH2 C(O)NH I o CH3NH
5133-NH2 H H - - CH2Ph CH2 C(O)NH I o CH3NH
5142-N H H - - CH2Ph CH2 C(O)NH I o CH3NH
Table 6
N H B, ~3
Oq~NH CH,
RA o ~N--Z--R10
4~ (CR8CR9)U--W--(CR6CR7)J~O
s 6
Ex.No RA R6 R7 RR R9 R10 W Z ~ u i~; Da~
515 H H H ~ -- CH3 CH~ CO i 0 H
516 H CH3 CH3 ~ CH3 CH~ ~o I 0 H
517 H - _ CH3 CH3 CH3 CH2 CO 0 1 H
51~ H H H _ _ CH3 O CO ~ 0 H
519 H CH3 CH3 _ _ CH3 O CO ] 0 H
520 H H H ~ ~ CH3 SO2 CO I 0 H
5213-CH3 H H ~ ~ CH3 CH2 CO I 0 H
5Z3-F H H ~ ~ CH3 CH2 CO I 0 H
5233-NH2 H H ~ ~ CH3 CH2 CO I 0 H
5242-N H H ~ ~ CH3 CH, CO I 0 H
5253-CH3 H H - -- (CH2)2Ph CH2 CO I 0 H
6~3
21~4311
WO 95109859 . . ~ PCT/US94/11049
~ . . ~ ,.
526 3-F H H - - (CH2)2Ph CH2 CO I 0 H
527 3-NH2 H H - - (CH2)2Ph CH2 CO I 0 H
528 2-N H H - - (CH2)2Ph CH2 CO I 0 H
529 3-CH3 H H - - CH2Ph CH2 C(O)O I 0 H
530 3-F H H - - CH2Ph CH2 C(O)O I H
531 3-NH2 H H _ _ CH2Ph CH2 C(O)O I 0 H
532 2-N H H - - CH2Ph CH2 C(O)O I 0 H
533 3-CH3 H H - - CH2Ph CH2 C(O)NH I 0 H
534 3-F H H - - CH2Ph CH2 C(O)NH l 0 H
535 3-NH2 H H - - CH2Ph CH2 C(O)NH I 0 H
536 2-N H H - - CH2Ph CH2 C(O)NH i 0 H
537 H H H - - CH3 CH2 CO I H21~'
538 H CH3 CH3 - - CH3 CH2 CO I H2N
539 H _ _ CH3 CH3 CH3 CH~ CO I H2N
540 H H H - - CH3 O CO I H2~
541 H CH3 CH3 _ _ CH3 O CO I H2N
542 H H H - - CH3 SO~ CO ] H2N
543 3-CH3 H H - - CH3 CH2 CO I H2N
544 3-F H H - - CH3 CH, CO ~ H2N
545 3-NH2 H H - - CH3 CH2 CO I H2~
546 2-N H H - - CH3 CH2 CO 1 H2N
547 3-CH3 H H - - (CH2)2Ph CH2 CO I H2r~
548 3-F H H - - (CH2)2Ph CH2 CO I H2N
549 3-NH2 H H - - (CH2)2Ph CH7 CO I O H~18
550 2-N H H - _ (CH2)2Ph CH2 CO I O H7!~
551 3-CH3 H H - - CH2Ph CH2 C(O)O I H21
552 3-F H H - - CH2Ph CH2 C(O)O I H2r~
553 3-NH2 H H - - CH2Ph CH7 C(O)O I O H7N
554 2-N H H - - CH2Ph CH2 C(O)O I O H7N
555 . 3-CH3 H H - - CH2Ph CH2 C(O)NH I H2N
556 3-F H H - - CH2Ph CH2 C(O)NH I O H7N
557 3-NH2 H H - - CH2Ph CH2 C(O)NH I H2N
558 2-N H H - - CH2Ph CH2 C(O)NH I O H7N
559 H H ~ H - - CH3 CH2 CO ] o CH3NH
560 H CH3 CH3 - CH3 CH2 CO l 0 CH3NH
69
W0 9S/098~9 ~ PCT/US94/11049
561. H _ _ CH3 CH3 CH3 CH2 CO o I CH3NH
562 H H H - _ CH3 O CO I 0 CH3NH
563 H CH3 CH3 _ CH3 O CO I 0 CH3NH
56~ H H H ~ ~ CH3 SO2 CO I 0 CH3NH
5653-CH3 H H ~ ~ CH3 CH2 CO 1 0 CH3NH
5663-F H H ~ ~ CH3 CH2 CO I 0 CH3NH
5673-NH2 H H ~ - CH3 CH2 CO I o CH3NH
5682-N H H ~ ~ CH3 CH2 CO 1 0 CH3NH
5693-CH3 H H - - (CH2)2Ph CH2 CO I 0 CH3NH
5703-F H H - - (CH2)2Ph CH2 CO 1 0 CH3NH
5713-NH2 H H - - (CH2)2Ph CH2 CO I o CH3NH
5722-N H H - - (CH2)2Ph CH2 CO I 0 CH3NH
5733-CH3 H H - - CH2Ph CH2 C(O)O I o CH3NH
5743-F H H - - CH2Ph CH2 C(O)O I o CH3NH
5753-NH~ H H - - CH2Ph CH2 C(O)O I 0 CH3NH
5762-N H H - - CH2Ph CH2 C(O)O I 0 CH3NH
5773-CH3 H H - - CH2Ph CH2 C(O)NH I o CH3NH
5783-F H H - - CH2Ph CH2 C(O)NH I 0 CH3NH
5793-NH2 H H - - CH2Ph CH2 C(O)NH I o CH3NH
5802-N H H - - CH2Ph CH2 C(O)NH I o CH3NH
Table 7
,O H
H2N /\~B~
OH
0~, N H
4 ~ ( C H2)U--V
55~ 6
7G
~WO 95/09859 217 4 31~ PCT/US94/11049
Ex No. RA R10 z V 11 D~a
581 H CH3 CO O 0
5823-CH3 CH3 CO O 0
5834-CH3 CH3 CO O 0
5842 F CH3 CO O 0
5853-F CH3 CO O 0
5864 F CH3 CO O 0
5873-NH2 CH3 CO O 0
5884-NH2 CH3 C0 O 0
58g3-N2 c]~3 CO O 0
5904-NO2 C] i3 C0 0 0
5913-N C1~3 C0 O 0
5924-N C1~3 C0 0 0
593 H C~3 CO S 0
5943-CH3 C}~3 C0 S 0
5954-CH3 C~3 CO S 0
5962-F C~3 CO S 0
5973-F C113 CO S 0
5984-F C1~3 CO S 0
5993-NH2 C~13 CO S 0
6004-NH2 c~l3 CO S (]
6013-N02 C~13 CO S ()
60"4-N2 C~3 C0 S 0
6033-N CH3 CO S ()
60~4-N CH3 CO S ()
605 H CH(CH3)2 C0 O 0
6063-CH3 CH(CH3)2 C0 0 0
6074-CH3 CH(CH3)2 CO O 0
6082-F CH(CH3)2 C0 O 0
60g3-F CH(CH3)2 CO O 0
6104-F CH(C1~3)2 CO O 0
6113-NH2 CH(C3~3)2 CO O 0
6124-NH2 CHlcl~3)2 CO O 0
6133-NO2 . CH(Cl~3)2 CO O 0
6144-NO2 CH(C1i3)2 CO O 0
71
WO 95/09859 217 4 ~ PCT/US94/11049
615 3-N CH(CH3)2 CO O 0
616 4-N CH(CH3)2 CO O O
617 H CH(CH3)2 CO S O
618 3-CH3 CH(CH3)2 CO S 0
619 4-CH3 CH(cH3)2 CO S O
620 2-F CH(CH3)2 CO S O
621 3-F CH(CH3)2 CO S 0
622 4-F CH(cH3)2 CO S 0
623 3-NH2 CH(CH3)2 CO S O
624 4-NH2 CH(CH3)2 CO S 0
625 3-N2 CH(cH3)2 CO S 0
626 4-N2 CH(cH3)2 CO S U
677 3-N CH(CH3)2 CO S O
6'8 4-18 CH(cH3)2 CO S O
629 H CH2CH2CH(CH3)2 CO O 0
630 3-CH3 CH2CH2CH(cH3)2 CO O 0
631 4-CH3 CH2CH2CH(CH3)2 CO O O
632 2-F CH2CH2CH(cH3)2 CO O O
633 3-F CH2CH2CH(CH3)2 CO O 0
634 4-F CH2CH2CH(CH3)2 CO O 0
635 3-NH2 CH2CH2CH(CH3)2 CO O 0
636 4-NH2 CH2CH2CH(CH3)2 CO O O
637 3-N2 CH2CH2CH(cH3)2 CO O 0
638 4-N2 CH2CH2CH(CH3)2 CO O 0
639 3-N CH2CH2CH(CH3)2 CO O O
640 4-N CH2CH2CH(CH3)2 CO O 0
641 H CH2CH2CH(CH3)2 CO S 0
642 3-CH3 CH2CH2CH(cH3)2 CO S O
643 4~CH3 CH2CH2CH(CH3)2 CO S 0
644 2-F CH2CH2CH(cH3)2 CO S 0
645 3-F CH2CH2CH(CH3)2 CO S 0
646 4-F CH2CH2CH(CH3)2 CO S O
647 3-NH2 CH2CH2CH(CH3)2 CO S 0
648 4-NH2 , CH2CH2CH(CH3)2 CO S 0
649 3-N2 CH2CH2CH(CH3)2 CO S O
72
,317~3~1
WC~ 95109859 ~ ~ ~ PCT/US94/11049
650 4-NO2 CH2CH2CH(CH3)2 CO S 0
65~ 3-N CH2CH2CH(cH3~2 CO S 0
652 4-N CH2CH2CH(CH3)2 CO S 0
653 H CH3 CO O
654 3-CH3 CH3 CO O
655 4-CH3 CH3 CO O
656 2-F CH3 CO O
657 3-F CH3 CO O
65g 4-F CH3 CO O
659 3-NH2 CH3 CO O
660 4-NH2 C H3 CO O
661 3-NO2 CH3 CO O
662 4-NO2 CH3 CO O
663 3-N c~3 CO O
66`l 4-N C~3 CO O
665 H C1~3 CO S
666 3 CH3 Cli3 CO S
667 4 CH3 C1~3 CO S
668 2-F Cli3 CO S
669 3-F C]~3 CO S
670 4-F C1~3 CO S
671 3-NH2 C~i3 CO S
67' 4-NH2 C~3 CO S
673 3-NO2 C~i3 CO S
674 4-N2 C~3 CO S
675 3-N C~3 CO S
676 4-N C~3 CO= S
677 H C~13 CO NH
678 3-CH3 C~3 CO NH
679 4-CH3 C113 CO NH
680 2-F C~13 CO NH
681 3-F C~13 CO NH
682 4-F C}13 CO NH
683 3-NH2 C}13 CO NH
68~ 4-NH2 CH3 CO N'H
.
WO 95/09859 21 7 ~ 3 1 1 PCT/US94/11049
685 3-N2 CH3 CO NH
686 4-N2 CH3 CO NH
687 3-N CH3 CO NH
688 4-N CH3 CO NH
689 H CH(CH3)2 CO O
690 3-CH3 CH(CH3)2 CO O
691 4-CH3 CH(cH3)2 CO O
692 2-F CH(CH3)2 CO O
693 3-F CH(cH3)2 CO O
694 4-F CH(cH3)2 CO O
695 3-NH2 CH(CH3)2 CO O
696 4-NH2 CH(cH3)2 CO O
697 3-NO2 CH(CH3)2 CO O
698 4-NO2 CH(CH3)2 CO O
699 3-N CH(CH3)2 CO O
700 4-N CH(cH3)2 CO O
701 H CH(cH3)2 CO S 3
70'' 3-CH3 CH(CH3)2- CO S
703 4-CH3 CH(cH3)2 CO S
704 2-F CH(CH3)2 CO S
705 3-F CH(CH3)2 CO S
706 4-F CH(CH3)2 CO S
707 3-NH2 CH(cH3)2 CO S
708 4-NH2 CH(CH3)2 CO S
709 3-NO2 CH(cH3)2 CO S
710 4-NO2 CH(cH3)2 CO S
711 3-N CH(cH3)2 CO S
712 4-N CH(cH3)2 CO S
713 H CH(CH3)2 CO NH
714 3-CH3 CH(cH3)2 CO NH
715 4-CH3 CH(cH3)2 CO NH
716 2-F CH(CH3)2 CO NH
717 3-F CH(cH3)2 CO NH
718 4-F CH(CH3)2 CO NH
719 3-NH2 CH(CH3)2 CO NH
7~
~17~
WO 95/09859 - ' - PC'r/US9411 1049
1~ ~ "~
720 4-NH2 CHl,CH3)2 C0 NH
721 3 N2 CH~CH3)2 CO NH
7Z 4-NO2 CH~CH3)2 CO NH
723 3-N CH(CH3)2 CO NH
724 4-N CH(cH3)2 CO NH
725 H CH2CH2CH(CH3)2 CO O
726 3-CH3 CH2CH2CH(CH3)2 C0 0
727 4-CH3 CH2CH2CH(CH3)2 CO O
728 2-F CH2CH2CH(cH3)2 CO O
729 3-F CH2CH2CH(CH3)2 CO O
730 4-F CH2CH2CH(cH3)2 CO O
731 3-NH2 CH2CH2CH(cH3)2 CO O
732 4.NH2 CH2CH2CH(cH3)2 CO O
733 3-N02 CH2CH2CH(CH3)2 C0 O
7~ 4-NO2 CH2CH2CH(CH3)2 CO 0
735 3-N CH~CH2CH(CH3)2 CO O
736 4-N CH2CH2CH(CH3)2 C0 0 3
737 H CH2CH2~H(CHi)2 CO S
738 3-CH3 CH2CH2CH(CH3)2 C0 S
739 4-CH3 CH7CH2CH(CH3)2 CO S
740 2-F CH2CH2CH(CH3)2 CO S
741 3-F CH2CH2CH(CH3)2 CO S 3
74q 4-F CH2CH~CH(CH3)7 CO S
743 3-NH2 CH2CH2CH(cH3)2 CO S
744 4-NH~ CH2CH2CH(CH3)2 CO S 3
745 3-NO2 CH2CH2CH(CH3)2 CO S
746 4 N2 CH2CH2CH(CH3)2 CO S
747 3-N CH2CH2CH(CH3)2 CO S
748 4-N CH2CH2CH(cH3)2 CO . S
749 H CH2CH2CH(cH3)2 C0 NH
750 3-CH3 CH2CH2CH(cH3)2 CO NH
751 4-CH3 CH2CH2CH(CH3)2 C0 NH
752 2-F CH2CH2CH(cH3)2 CO NH
753 3-F , CH2CH2CH(CH3)2 CO NH
75~ 4-F CH~CH2CH(cH3)2 C0 NH
7 '-
WO95/09859 ~1 7~3~ii ;` ' PCr~S94/11049
755 3-NH2 CH2CH2CH(CH3)2 CO NH
756 4-NH2 CH2CH2CH(CH3)2 CO NH
757 3-NO2 CH2CH2CH(cH3)2 CO NH
758 4-No2 CH2CH2CH(cH3)2 CO NH
759 3-N CH2CH2CH(CH3)2 CO NH
760 4-N CH2CH2CH(cH3)2 CO NH
761 H cH2NH(cH3) CO O
762 H CH2N(CH3)CO2C(CH3)3 CO O
~able 8
0 ~1
H2N ~
0~, N H C 113
RA < N--Z--R10
,=1~
4 ~ ( C H2)u--V
s 6
Ex. No. RA R10 z ~, u Da~a
763 H CH3 CO O 0
764 3~CH3 CH3 CO O 0
765 4-CH3 CH3 CO O 0
766 2-F CH3 CO O 0
767 3-F CH3 CO O 0 ~: ~
768 4-F CH3 CO O 0
769 3-NH2 CH3 CO O 0
770 4-NH2 CH3 CO O 0
771 3-NO~ ' CH3 CO O 0
772 4-NO2 CH3 CO O . 0
,~17~311~
WO 95/09859 ~ - PCI'117594/11049
773 3-N CH3 CO O 0
774 4-N CH3 CO O 0
775 H CH3 CO S 0
776 3-CH3 CH3 CO S 0
777 4-CH3 CH3 CO S 0
778 2-F CH3 CO S 0
779 3-F CH3 CO S 0
780 4-F CH3 CO S 0
781 3-NH2 CH3 CO S 0
782 4-NH2 CH3 CO S 0
783 3-NO2 CH3 CO S 0
784 4-N2 CH3 CO S 0
785 3-N CH3 CO S 0
786 4-N CH3 CO S 0
787 H CH(CH3)2 CO O 0
78g 3-CH3 CH(CH3)2 CO O 0
789 4-CH3 CH(CH3)2 CO O 0
790 2-F CH(CH3)2 CO O 0
791 3-F CH(CH3)2 CO O 0
792 4-F CH(CH3)2 CO O 0
793 3-NH2 CH~CH3)2 CO O 0
79~ 4-NH2 CH(CH3)2 CO O 0
795 3-NO2 CH(CH3)2 CO O 0
796 4-N2 CH(CH3)~ CO O 0
797 348 CH(cH3)~ CO O 0
798 4-N CH(I_H3 ~ CO~ O 0
799 H CH(CH3)2 CO S 0
800 3-CH3 CH(I-H3)2 CO S 0
80~ 4-CH3 CH(I-H3)2 CO S 0
802 2-F CH(CH3)2 CO S 0
803 3-F CH(CH3)2 CO S 0
804 4-F CH(I~H3)2 CO S 0
805 3-NH2 CH(CH3)2 CO S 0
806 4-NH2 . CH(CH3)2 CO S 0
807 3-N02 CH(CH3);~ CO S O
_ 7
~,
WO 95/09859 æ~ S i PCTNS94/11049
80~ 4 N2 CH(CH3)2 CO S 0
809 3-N CH(CH3)2 CO S 0
810 4-N CH(CH3)2 CO S 0
81~ H CH2CH2CH(CH3)2 CO O 0
812 3-CH3 CH2CH2CH(CH3)2 CO O 0
813 4-CH3 C~2CH2CH(cH3)2 CO O 0 t
814 2-F CH2CH2CH(CH3)2 CO O 0
815 3-F CH2CH2CH(CH3)2 CO O 0
816 4-F CH2CH2CH(CH3)2 CO O 0
817 3-NH2 CH2CH2CH(CH3)2 CO O 0
818 4-NH2 CH2CH2CH(CH3)2 CO O 0
819 3 N2 CH2CH2CH(CH3)2 CO O 0
820 4 N2 CH2CH2CH(CH332 CO O 0
8~1 3-N CH2CH2CH(CH3)2 CO O 0
822 4-N CH2CH2CH(CH3)2 CO O 0
823 H CH2CH2CH(CH3)2 CO S 0
82~ 3-CH3 CH2CH2CH(CH3 j2 CO S 0
875 4-CH3 CH2CH2CH(CH3)2 CO S 0
826 2-F CH2CH2CH(CH3)2 CO S 0
877 3 F CH2CH2CH(CH3)2 CO S 0
828 4-F CH2CH2CH(CH3)2 CO S 0
829 3-NH2 CH2CH2CH(CH3)2 CO S 0
830 4-NH2 CH2CH2CH(CH3)7 CO S 0
831 3 N2 CH2CH2CH(CH3~2 CO S 0
83~ 4-N02 CH2CH2CH(CH3j2 CO S 0
833 3-N CH2CH2CH(CH3)2 CO S 0
834 4-N CH2CH2CH(CH3)2 CO S 0
835 H CH3 CO O l Z
836 3-CH3 CH3 CO O I AA
837 4-CH3 CH3 CO O I BB
838 2-F CH3 CO O
839 3-F CH3 CO O
840 4-F CH3 CO O
841 3-NH2 CH3 CO O
84' 4-NH2 CH3 CO O
78
wogs/ogXs9 217~311 P~US94n}049
843 3-N2 CH3 CO O
844 4-NO2 CH3 CO O
845 3-N CH3 CO O
- 846 4-N CH3 CO O
847 H CH3 CO S
848 3-CH3 CH3 CO S
849 4-CH3 CH3 CO S
850 2-F CH3 CO S
851 3-F CH3 CO S
852 4-F CH3 CO S
853 3-NH2 CH3 CO S
854 4-NH2 CH3 CO S
855 3 N2 CH3 CO S
856 4-NO~ CH3 CO S
857 3-N' CH3 CO S
858 4-~' Cli3 CO S
859 H C1~3 CO NH
860 3-CH3 cl~3 CO NH
86l 4-CH3 C~3 CO NH
862 2-F C}~3 CO NH
863 3-F C~3 CO NH
86~ 4-F C~13 CO NH
865 3-NH~ C~3 CO NH
866 4-NH2 C~13 CO NH
867 3-N'O~ C~3 CO NH
868 4-N2 C~13 CO NH
869 3-N CH3 CO NH
870 4-N C~13 CO NH
871 H CH(CH3)2 CO O I CC
872 3-CH3 CH(CH3)2 CO O
873 4-CH3 CH(CH3)2 CO O
874 2-F CH(C1~3)2 CO O
875 3-F CH(Cli3)2 CO O
876 4-F . CH(C1l3)2 CO O
877 3-NH2 CH(Cli3)2 CO O
7 9
WO9~i/098~9 ii " ~ PCT/US94/11049
878 4-NH2 CH(cH3)2 CO O
879 3-N2 CH(cH3)2 CO O
880 4-N2 CH(CH3k CO O
881 3-N CH(CH3k CO O
882 4-N CH(CH3k CO O
883 H CH(CH3k CO S
884 3-CH3 CH(CH3k CO S
885 4-CH3 CH(CH3k CO S
886 2-F CH(CH3k CO S
887 3-F CH(CH3)2 CO S
888 4-F CH(cH3)2 CO S
889 3-NH2 CH(CH3)2 CO S
890 4-NH2 CH(CH3)2 CO S
891 3-N2 CH(CH3)~ CO . S . I
892 4-N2 CH(CH3)2 CO S
893 3-N CH(cH3)2 CO S
89~ 4-N CH(cH3)2 CO S
895 H CH(CH3)2 CO NH
896 3-CH3 CH(cH3)2 CO NH
897 4-CH3 CH(CH3)2 CO NH
898 2-F CH(cH3)2 CO NH
899 3-F CH(cH3)2 CO NH
900 4-F CH(CH3k CO NH
901 3-NH2 CH(CH3) ~ CO NH
90~ 4-NH2 CH(CH3 H CO .. NH
903 3-NO2 CH(cH3)2 CO NH
904 4-NO2 CH(CH3)2 CO NH
90~ 3-N CH(cH3)2 CO NH
906 4-N CH(CH3k CO NH
907 H CH2CH2CH(CH3)2 CO O I DD
908 3-CH3 CH2CH2CH(cH3)2 CO O
909 4-CH3 CH2CH2CH(CH3)2 CO O
910 2-F CH2CH2CH(CH3)2 CO O
911 3-F CH2CH2CH(cH3)2 CO O
912 4-F CH~CH2CH(cH3)2 CO O
&Q
~ ~17~311
Wo 9s/09859 ~ ' PCT/US94/11049
9l3 3-NH2 CH2C~H2CH(CH3)2 CO O
914 4-NH2 CH2CIi2CH(cH3)2 CO O
915 3-NO2 CH2C112CH(CH3)2 CO O
9 l 6 4-NO2 CH2C}~2CH(CH3)2 CO O
9l7 3-N CH2C~2CH(cH3)2 CO O
9l8 4-N CH2C~2CH(CH3)2 CO O
9l9 H CH2C~I2CH(CH3)2 CO S
920 3-CH3 CH2CH2CH(CH3)2 CO S
921 4-CH3 CH2CH2CH(CH3)2 CO S
922 2-F CH2CH:2CH(CH3)2 CO S
923 3-F CH2CH2CH(cH3)2 CO S
924 4-F CH2CH2CH(CH3)2 CO S
925 3-NH2 CH2CH2CH(CH3)2 CO S
926 4-NH2 CH2CH2CH(cH3)2 CO S
927 3-NO2 CH2CH2CH(cH3)2 CO S
928 4-N2 CH2CH 2CH(CH3)2 CO S
929 3-N CH2CH2CH(CH3)2 CO S
930 4-N CH2CHCH(cH3)2 CO S
931 H CH2CH2CH(cH3)2 CO NH
932 3-CH3 CH2CH2CH(CH3)2 CO NH
933 4-CH3 CH2CH2CH(CH3)2 CO NH
934 2-F CH2CH2CH(CH3)2 - CO NH
935 3-F CH2CH2CH(CH3)2 CO NH
936 4-F CH2CH2CH(CH3)2 CO NH
937 3-NH2 CH2CH2~H(CH3)2 CO NH
938 4-NH2 CH2CH2CH(cH3)2 CO NH
939 3-NO2 CH2CH2CH(cH3)2 CO NH
940 4-NO2 CH2CH2CH(CH3)2 CO NH
941 3-N CH2CH2CH(cH3)2 CO NH
94' 4-N CH2CH2CH(cH3)2 CO NH
943 H CH2NI~(CH3) CO O I EE
94~ H CH2N(CH3)CO2c(cH3)3 CO O I FF
Table 5
81
W095/09859 ~t ~i?ti3~' pCT/US94111049
OH
H 2 N ~ O H
0~, N H
~N-- --R10
o
R3--O~`
E~ No. R3 R10 Da~a
945 CH3 CH3
946 (H3C)3c CH3
9~7 CH3
Q~ ,
94
8 C H2 CH3
949 CH3 CH2CH2Ph
950 ~H3C~3C CH2CH2Ph
951
C ~ CH2CH2Ph
95- C H2 CH2CH2Ph
82
W09sl098s9 2 17 ~ 3 1 I PCI/US94~11049
~able 10
,0
H2N-- ~B~
Oq~N H CH3
~N ~ R 1 0
~
R3--O
Ex No. R3 R10 Da~a
953 CH3 CH3
954 (H3C~3C CH3 GG
955
I ~ CH3 HH
956
C ~ CH3
957 CH3 CH2CH2Ph
958 (H3C)3C CH2CH2Ph 11
959
C ~ CH2CH2Ph JJ
960 C ~ CH~CH2Ph
8 _
WO95/09859 ~ ~17~ `; PCT/US94/11049
Table 11
N H O H
RX~ N --B`o H
O~, N H
4 ~ ( C H2) `~ R6 R7 ~ RB
5 6
RX = H2N
ExNo. RA RB R6 R7 z V W u Daa
961 H H H H C(O)O O - I
962 H H H H CO O CH2 0
963 H H H H CO S CH2 0
96~ H H H H CO O CH2
965 H 2~- CH3 H H CO O CH2
966 H 3' CH3 H H CO O CH2
967 H .2', 3'-diCH3 H H CO O CH2
968 H 2'-F H H CO O CH2
969 H 3'-F H H CO O CH2 ]
970 H 2'-N H H CO O CH2
971 H 3'-N H H CO O CH~ I
972 3-CH3 H H H CO O CH2
973 3~CH3 2'-CH3 H H CO O CH2
974 3-CH3 3~-CH3 H H CO O CH2
975 3-CH3 2, 3-diCH3 H H CO o CH2
976 3-CH3 2'-F H H CO O CH2
977 3-CH3 3'-F H H CO o CH2
978 3-CH3 2'-N H H CO O CH2
979 3-CH3 3~ ~ H H CO O CH- I
980 2-F H H H CO O CH2
84
WO95109859 ~ 743~1 : PCT~'US94/11049
~ ;
981 2-F 2'-CH3 H H CO CH2
982 2-F 3~-CH3 H H CO CH2
983 2-F 2', 3'-diCH3 H H CO O CH2
984 2-F 2'-F H H CO O CH2
985 2-F 3'-F H H CO O CH2
986 2-F 2'-N H H CO O CH2
987 2-F 3'-N H H CO O CH2
988 3-F H H H CO O CH2 ] KK
989 3-F 2~-CH3 H H CO O CH2
990 3-F 3.-CH3 H H CO O CH2
991 3-F 2', 3'-diCH3 H H CO O CH2
992 3-F 2'-F H H CO CH2
993 3-F 3'-F H H CO O CH2
99~ 3-F 2'-N H H CO O CH2
995 3-F 3'-N' H H CO O CH2
996 3-NH2 H H H CO CH2
997 3-NH2 2'-CH3 H H CO CH2
998 3-NH2 3~-CH3 H H CO O CH2
999 3-NH2 2, 3 -diCH3 H H CO CH2
1000 3-NH2 2'-F H H CO O CH2
lool 3-NH2 3'-F H H CO O CH2
1002 3-NH2 2'-N H H CO O CH2
1003 3-NH2 3'-N' H H CO o CH2 . I
100l 3-NO2 H H H CO CH2
1005 3-NO2 2~-CH3 H H CO CH2
1006 3-N2 3~-CH3 H H CO CH2
1007 3-NO2 2', 3'-diCH3 H H CO CH2
1008 3-NO2 2'-F H H CO O CH2
1009 3-NO2 3'-F H H CO CH2
1010 3-NO2 2'-N H H CO CH2
1011 3-N2 3'-N H H CO CH2
1012 2-N H H H CO CH2
1013 2-N 2~-CH3 H H CO CH2
1014 2-N' 3~-CH3 H H CO CH2
1015 2-N' 2', 3'-diCH3 H H CO O CH, I
WO 95/098S9 2 1 7~ 31 i ~ ~ t . PCT/US94/11049
1016 2-N 2'-F H H CO O CH
1017 2-N 3'-F H H CO CH
1018 2-N 2'-N H H CO CH
1019 2N 3'-N H H CO CH
1020 3-N H H H CO CH
1021 3-N 2'-CH3 H H CO o CH
1022 3-N 3~-CH3 H H CO O CH
1023 3-N 2', 3'-diCH3 H H CO O CH
1024 3-N 2'-F H H CO CH
1025 3-N 3'-F H H CO O CH
1026 3-N 2'-N H H CO O CH
1027 3-N 3'-N H H CO CH
1028 4-N H H H CO CH
10~9 4-N 2'-CH3 H H CO CH
1030 4-N 3~-CH3 H H CO CH
1031 4-N 2', 3'-diCH3 H H CO CH
103' 4-N 2'-F H H CO CH
1033 4-N 3'-F H H CO O CH
103~ 4-N 2'-1`: H H CO O CH
1035 4-N 3'-1~ H H CO CH
1036 H H H H CO O O
1037 H H CH3 CH3 CO S O
1038 H H H H CO O O
1039 H 2'- CH3 H H CO O O
1040 H 3'-CH3 H H CO O O
1041 H 2', 3'-diCH3 H H CO O O
1042 H 2'-F H H CO O O
1043 H 3'-F H H CO O O
1044 H 2'-N H H CO O O
1045 H 3'-N H H CO O O
1046 3-CH3 H H H CO O O
1047 3-CH3 2'-CH3 H H CO O O
1048 3-CH3 3~-CH3 H H CO O O
1049 3-CH3 2', 3',diCH3 H H CO O O
1050 3-CH3 2'-F H H CO O O
1~6
2174311
-- wo 9S/09859 ' PCIrUS94rllO49
1051 3-CH3 3'-F H H CO O O
10S2 3-CH3 2'-N H H CO O O
1053 3-CH3 3'-N H H CO O O
105~ 2-F H H H CO O O
1055 2-F 2~-CH3 H H CO O O
1056 2-F 3r-CH3 H H CO O O
1057 2-F 2', 3'-diCH3 H H CO O O
1058 2-F 2'-F H H CO O O
1059 2-F 3'-F H H CO O O
1060 2-F 2'-N H H CO O O
1061 2-F 3:N H H CO O O
106' 3-F H H H CO O O
1063 3-F 2~-CH3 H H CO O O
106~ 3-F 3 CH3 H H CO O O
1065 3-F 2', 3'-diCH3 H H CO O O
1066 3-F 2'-F H H CO O O
1067 3-F 3'-F H H CO O O
1068 3-F 2'-N H ' H CO O O
1069 3-F 3'-N' H H CO O O
1070 3-NH2 H H H CO O O
1071 3-NH2 2'-CH3 H H CO O O
107' 3-NH2 3~-CH3 H H CO O O
1073 3-NH2 2, 3 -diCH3 H H CO O O
107~ 3-NH2 2'-F H H CO O O
1075 3-NH2 3'-F H H CO O O
1076 3-NH2 2'-N H H CO O O
1077 3-NH2 3'-N H H CO O O
1078 3-NO2 H H H CO O O
1079 3-NO2 2'-CH3 H H CO O O
1080 3-NO2 3 CH3 H H CO O O
1081 3-N2 2, 3-diCH3 H H CO O O
108q 3-NO2 2'-F H H CO O O
1083 3-NO2 3'-F H H CO O O
108~ 3'N2 2'-N H H CO O O
1085 3-N02 3:N H H CO O O
~7
W0 95/09859 ' i~ é PCT/US94/11049
1086 2-N H H H CO O O
1087 2-N 2~-CH3 H H CO O O
1088 2-N 3~-CH3 H H CO O O
~089 2-N 2', 3'-diCH3 H H CO O O
1090 2-N 2'-F H H CO O O
1091 2-N 3'-F H H CO O O
1092 2-N 2'-N H H CO O O
1093 2-N 3'-N H H CO O O
1094 3-N ~ H H H CO O O
1095 3-N 2'-CH3 H H CO O O
1096 3-N 3~-CH3 H H CO O O
1097 3-N 2', 3'-diCH3 H H CO O O
1098 3-N 2'-F H H CO O O
1099 3-N 3'-F H H CO O O
]100 3-~ 2'-N H H CO O O I
1101 3-N 3'-N H H CO O o
1102 4-N' H H H CO O O
1103 4-N 2'-CH3 H ~ H CO O O
110~ 4-N 3~-CH3 H H CO O O
1105 4-N' 2', 3'-diCH3 H H CO O O
1106 4-N 2'-F H H CO O O
1107 4-N 3'-F H H CO O O
1108 4-N 2'-N H H CO O O
1109 4-~ 3'-N H H CO O O
Table 12
1i8
Wo 95~9859 ~17 ~ 311 Pcr/Uss4nl04s
N H ,0
Oq~ N H C 1-13
RA ~ R6 R7 ~R
s
RX = H21`1
E~No, RA RB R6 R7 z V W u Da a
1110 H H H H C(O)O O - - I
1111 H H H H CO O CH2 0
1112 H H H H CO S CH7 0
1il3 H H H H CO CH2 1 1 l ~
1114 H 2'- CH3 H H CO O CH2
1115 H 3'-CH3 IB H CO CH2
1116 H 2 . 3-diCH3 H H CO CH2
1117 H 2'-F 1~ H CO O CH7
1118 H . 3'-F 1~ H CO CH2
1119 H 2'-N }i H CO CH2
1120 H 3'-N ~ H CO CH2
1]21 3-CH3 H ~I H CO CH2
1122 3-CH3 2'-CH3 ~I H CO O CH2
1123 3-CH3 3~-CH3 ~! H CO CH2
1124 3-CH3 2',3'-diCH3 ~I H CO CH2
1125 3-CH3 2'-F H H CO CH2
1126 3-CH3 3'-F H H CO O CH7
1127 3-CH3 2'~N H' H CO CH2
-1128 3-CH3 3'-N H H CO CH2
1129 2-F H H H CO CH2
1130 2-F 2~-CH3 H H CO CH2
1131 2-F 3~-CH3 H H CO CH2
89
WO95/09859 1 7,~3~1 PCT/I~S94/11049
L J
1132 2-F 2', 3'-diCH3 H H CO O CH2
1133 2-F 2'-F H H CO O CH2
1134 2-F 3'-F H H CO O CH2
1135 2-F 2'-N H H CO CH2
1136 2-F 3'-N H H CO CH2
1137 3-F H H H CO O CH2 I MM
1138 3-F 2'-CH3 H H CO O CH2
1139 3-F 3~-CH3 H H CO O CH2
1140 3-F 2', 3'-diCH3 H H CO O CH2
1141 3-F 2'-F H H CO CH2
1142 3-F 3'-F H H CO O CH2
1143 3-F 2'-N H H CO O CH2
1144 3-F 3'-N H H CO CH2
1145 3-NH2 H H H CO O CH2
1146 3-NH2 2'-CH3 H H CO CH2
1147 3-NH2 3~-CH3 H H CO CH2
1148 3-NH2 2, 3-diCH3 H H CO o CH2
1149 3-NH2 2'-F H H CO CH2
1150 3-NH2 3'-F H H CO o CH2
1151 3-NH2 2'-N H H CO CH2
115'' 3-NH2 3'-N H H CO CH2
1153 3-N2 H H H CO CH2
115~ 3-N2 2'-CH3 H H CO O CH2
1155 3-NO2 2',3'-diCH3 H H CO CH2
1156 3-N2 2'-F H H CO O CH2 ]
1157 3-N2 3'-F H H CO CH2
1158 3-N2 2'-N H H CO O CH2
59 3-NO2 3~-N H H CO O CH2
1160 2-N H H H CO O CH2
1161 2-N 2'-CH3 H H CO O CH2
1162 2-N 3~-CH3 H H CO O CH2
1163 2-N 2', 3'-diCH3 H H CO O CH2
1164 2-N 2'-F H H CO CH2
1165 2-N 3'-F H H CO O CH2
W095109859 21 7~3~1 PcrNsg4/ll049
1166 2-N 2'-N H H C0 0 CH
1167 2-N 3'-N H H C0 0 CH
1168 3-N H H H C0 CH
1169 3-N 2~-CH3 H H C0 0 CH
1170 3-N 3~-CH3 H H C0 CH
1171 3-N 2', 3'-diCH3 H H C0 CH
1172 3-N 2'-F H H C0 CH
1173 3-N 3'-F H H C0 0 CH
1174 3-N 2'-N H H C0 0 CH
1175 3-N 3'-N H H CO CH
1176 4-N H H H C0 0 CH
1177 4-N 2'-CH3 H H C0 0 CH7
1178 4-N 3~-CH3 H H C0 0 CH
1179 4-N 2',3'-diCH3 H H C0 0 CH
1180 4-N 2'-F H H C0 0 CH
1181 4-N 3'-F H H C0 CH
118' 4-N 2'-N H H C0 0 CH
1183 4-N 3'-N H H C0 0 CH
118~ H H H H C0 0 0
1185 H H CH3 CH3 C0 S 0
1186 H H H H C0 0 0
1187 H 2'- CH3 H H C0 0 0
~188 H 3'-CH3 H H C0 0 0
1189 H 2',3'-dicH3 H H CO O O
1190 H 2'-F H H C0 0 0
1191 H 3'-F H H CO O O
1192 H 2'-N H H C0 0 0
1193 H 3'-N H H C0 0 0
1194 3-CH3 H H H C0 0 0
1195 3-CH3 2~-CH3 H H C0 0 0
1196 3-CH3 3~-CH3 H H C0 0 0
1197 3-CH3 2, 3-diCH3 H H C0 0 0
1198 3-CH3 2'-F H H C0 0 0
91
WO 9510g859 21 7 4 3 il PCT/US94/11049
1199 3-CH3 3'-F H H CO O O
1200 3-CH3 2'-N H H CO O O
]201 3-CH3 3'-N H H CO O O
1202 2-F H H H CO O O
1203 2-F 2'-CH3 H H CO O O
1204 2-F 3'-CH3 H H CO O O
1205 2-F 2', 3'-diCH3 H H CO O O
1206 2-F 2'-F H H CO O O
1207 2-F 3'-F H H CO O O
1208 2-F 2'-N H H CO O O
1209 2-F 3'-N H H CO O O
1210 3-F H H H CO O O
1211 3-F 2'-CH3 H H CO O O 3
1212 3-F 3~-CH3 H H CO O O
1213 3-F 2', 3'-diCH3 H H CO O O
1214 3-F 2'-F H H CO O O
1215 3-F 3'-F H H CO O O
1216 3-F 2'-N' H H CO O O
1217 3-F 3'-N H H CO O O
1218 3-NH2 H H H CO O O
1219 3-NH2 2~-CH3 H H CO O O
1220 3-NH2 3~-CH3 H H CO O O ]~
12'1 3-NH7 ' 2', 3'-diCH3 H H CO O O
12" 3-NH, 2'-F H H CO O O
1223 3-NH~ 3'-F H H CO O O
122~ 3-~'H2 2'-N' H H CO O O
1225 3-NH2 3'-N H H CO O O
1226 3-NO2 H H H CO O O
1227 3-N2 2'-CH3 H H CO O O
1228 3-NO2 3~-CH3 H H CO O O
1229 3-N2 2', 3'-diCH3 H H CO O O
1230 3-N2 2'-F H H CO O O :1=
1231 3-NO2 3'-F H H CO O O ' I
~232 3-N2 ,2'-N H H CO O O
1233 3-N2 3'-N H H CO O O
92
74311
W09sl098S9 Xl PCr/USs4/11049
~J ,
1234 2-N H H H CO O O
1235 2-N 2'-CH3 H H CO 0 O
1236 2-N 3~-CH3 H H CO O 0
1237 2-N 2', 3'-diCH3 H H CO O O
1238 2-N 2'-F H H CO O O
1239 2-N 3'-F H H CO O O
1240 2-N 2'-N H H CO O O
1241 2-N 3'-N H H CO O O
1242 3-N H H H CO O O
1243 3-N 2~-CH3 H H C0 O O
1244 3-N 3~-CH3 H H C0 O O
1245 3-N 2', 3'-diCH3 H H C0 O O
1246 3-N 2'-F H H CO O O
1247 3-N 3'-F H H CO O O
1248 3-N 2'-N H H CO O O
1249 3-N 3'-N H H C0 O O
1250 4-N H H H C0 O 0
1251 4-N 2~-CH3 H H CO O 0
125'2 4-N 3~-CH3 H H CO O O
1253 4-N 2', 3'-diCH3 H H CO 0 O
1254 4-N 2'-F H H CO O O
1255 4-N 3'-F H H CO O O
1256 4-N' 2'-N H H C0 O O
1257 4-N 3'-N H H CO O 0
Table 13
93
311 ~i ~
WO 95/09859 ' i - i - . PCI/~S94/11049
NH OH
RXJ~N ~ OH
0~, N H
RA ~N--Z--R10
3 2 \J
/= =\ i.~
4~(CHz)u--V
5 6
RX = H2N
E~ No. RA R10 z V u Dala
1258 H CH3 CO O 0
1259 3-CH3 CH3 CO O 0
1260 4-CH3 CH3 CO O 0
1261 2-F CH3 CO O 0
1262 3-F CH3 CO O 0
1263 4-F CH3 CO O 0
126~ 3-NH2 CH3 CO O 0
1265 4-NH2 CH3 CO O 0
1266 3-NOi CH3 CO O 0
1267 4-NO2 CH3 CO O 0
1268 3-N CH3 CO O 0
1269 4-1~ CH3 CO O 0 : :
1270 H CH3 CO S 0
1271 3-CH3 CH3 CO S 0
1272 4-CH3 CH3 CO S 0
1273 2-F CH3 CO S 0
1274 3-F CH3 CO S 0
1275 4-F CH3 CO S 0
1276 3-NH2 CH3 CO S 0
1277 4-NH2 CH3 CO S 0
1278 34~l02 CH3 CO S O
99
WO 95/09859 ~ ' ' PCT/~Sg4~11049
1279 4 N2 CH3 CO S 0
1280 3-N CH3 CO S 0
1281 4-N CH3 CO S 0
1282 H CH(CH3k CO O 0
1283 3-CH3 CHl(CH3k CO O 0
1284 4-CH3 CH(CH3)2 CO O 0
1285 2-F CH(CH3)2 CO O 0
1286 3-F CH(CH3k CO O 0
1287 4-F CH(CH3k CO O 0
1288 3-NH2 CH(CH3k CO O 0
1289 4-NH2 CH~C~3k CO O 0
1290 3-NO2 CH~CH3)2 CO O 0
1291 4-N2 CH~CH3k CO O 0
129' 3-N CH(CH3)2 CO O 0
1293 4-N CH(CH3)2 CO O 0
129l H CH(CH3k CO S O
1295 3~CH3 CH(CH3)2 CO S 0
1296 4-CH3 CH(I'`H3)2- CO S O
1297 2-F CH(CH3)2 CO S 0
1298 3-F CH(CH3)2 CO S 0
1299 4-F CH(CH3k CO S 0
1300 3-NH2 CH(CH3)2 CO S 0
1301 4-NH2 CH(CH3)2 CO S 0
130' 3-N2 CH(CH3k CO S 0
1303 4-NO2 CH(CH3)2 CO S 0
130~ 3-N CH(CH3k CO S 0
1305 4-N CH(CH3)2 CO S 0
1306 H CH2CH2CH(CH3)2 CO O 0
1307 3-CH3 CH2CH2CH(CH3)2 CO O 0
1308 4-CH3 CH2CH2CH(CH3)2 CO O 0
1309 2-F CH2CH2CH(cH3)2 CO O 0
1310 3-F CH2CH2CH(CH3)2 CO O 0
1311 4-F CH2CH2CH(CH3)2 CO O 0
1312 3-NH2 , CH2CH2CH(CH3)2 CO O 0
1313 4-NH2 CH2CH2CH(cH3)2 CO O 0
' ~ ' t. ~ } .
WO 95/09859 PCT/I~S94/1 1049
~7~31~
1314 3-N2 CH2CH2CH(cH3)2 CO O 0
1315 4-N2 CH2CH2CH(CH3)2 CO O 0
1316 3-N CH2CH2CH(CH3)2 CO O 0
1317 4-N CH2CH2CH(CH3)2 CO O 0
1318 H CH2CH2CH(CH3)2 CO S 0
1319 3-CH3 CH2CH2CH(cH3)2 CO S 0
1320 4-CH3 CH2CH2CHtcH3)2 CO S 0
1321 2-F CH2CH2CH(CH3)2 CO S 0
1322 3-F CH2CH2CH~CH3)2 CO S 0
1323 4-F CH2CH2CH(CH3)2 CO S 0
1324 3-NH2 CH2CH2CH(cH3)2 CO S 0
1325 4-NH2 CH2CH2CH(CH3)2 CO S 0
1326 3-NO2 CH2CH2CH(CH3)2 CO S 0
1327 4-N2 CH2CH2CH(CH3)2 CO S 0
1328 3-N CH2CH2CH(CH3)2 CO S 0
1329 4-N CH2CH2CH(CH3)2 CO S 0
1330 H CH3 CO O
1331 3-CH3 CH3 CO O
1332 4-CH3 CH3 CO O
1333 2-F CH3 CO O
1334 3-F CH3 CO O
i335 4-F CH3 CO O
1336 3-NH2 CH3 CO O
1337 4-NH2 CH3 CO O
1338 3-N2 CH3 CO O
339 4-NO2 CH3 CO O
1340 3-N CH3 CO O
134~ 4-~ CH3 CO O
1342 H CH3 CO S
1343 3-CH3 CH3 CO S
1344 4-CH3 CH3 CO S
1345 2-F CH3 CO S
1346 3-F CH3 CO S
1347 4-F ~ CH3 CO S
1348 3-NH~ CH3 CO S
5~:
~43~1
WO 95109859 PCT/US94/11049
1349 4-NH2 CH3 CO S
1350 3-NO2 CH3 CO S
1351 4-N2 CH3 CO S
1352 3-N CH3 CO S
1353 4-N CH3 CO S
1354 H CH3 CO NH
1355 3-CH3 CH3 CO NH
1356 4-CH3 CH3 CO NH
1357 2-F CH3 CO NH
1358 3-F CH3 CO NH
1359 4-F CH3 CO NH
1360 3-NH2 CH3 CO NH
1361 4-NH2 CH3 CO ~'H
136' 3-N2 CHj CO NH
1363 4-N2 CH3 CO NH
136~ 3-N CH3 CO NH
1365 4-N CH3 CO NH
1366 H CH(CH3)2 CO: O
1367 3-CH3 CH(CH3~2 CO O
1368 4-CH3 CH(CH3)~ CO O
1369 2-F CH(CH3)2 CO. O
1370 3-F CH(CH3)2 CO O
1371 4-F CH(cH3)2 CO O
137' 3-NH2 CH(CH3)2 CO O
1373 4-NH2 CH(cH3)2 CO O
137~ 3-NO2 CH(cH3)2 CO O
1375 4-N2 CH(CH3)2 CO O
1376 3-N CH(cH3)2 CO O
1377 4-N CH(CH3)2 CO O
1378 H CH(CH3)2 CO S
1379 3-CH3 CH(CH3)2 CO S
1380 4-CH3 CH(CH3)2 CO S
1381 2-F CH(cH3)2 CO S
1387 3-F , CH(CH3)2 CO S
1383 4-F CH(CH3)2 CO S
g _
W0 95/09859 ~ , PCTIUS94111049
~17~31~
~384 3-NH2 CH(cH3)2 CO S
1385 4-NH2 CH(cH3)2 CO S
1386 3-N2 CH(cH3)2 CO S
1387 4-N2 CH(cH3)2 CO S
1388 3-N CH(CH3)2 CO S
1389 4-N CH(cH3)2 CO S
1390 H CH(CH3)2 CO NH
1391 3-CH3 CH(cH3)2 CO NH
1392 4-CH3 CH(CH3k CO NH
1393 2-F CH(cH3)2 CO NH
1394 3-F CH(CH3)2 CO NH
1395 4-F CH(cH3)2 CO NH
1396 3-NH2 CH(cH3)2 CO NH
1397 4-NH2 CH(CH3)2 CO NH
1398 3-N02 CH(cH3)2 CO NIH
1399 4-N2 CH(cH3)2 CO NH
1400 3-N CH(cH3)2 CO NH
1401 4-N CH(CH3)2 CO NH
140' H CH2CH2CH(CH3)2 CO O
1403 3-CH3 CH2CH2CH(CH3)2 CO O
140~ 4-CH3 CH2CH2CH(CH3)2 CO O
1405 2-F CH2CH2CH(CH3)2 CO O
1406 3-F CH2CH2CH(CH3)2 CO O
1407 4-F CH2CH2CH(cH3)2 CO O
1408 3-NH2 CH2CH2CH(CH3)2 CO O
1409 4-NH2 CH2CH2CH(cH3)2 CO O
1410 3-NO2 CH2CH2CH(cH3)2 CO O
1411 4-NO2 CH2CH2CH(CH3)2 CO O
1412 3-N CH2CH2CH(cH3)2 CO O
1413 4-N CH2CH2CH(CH3)2 CO O
1414 H CH2CH2CH(CH3)2 CO S
1415 3-CH3 CH2CH2CH(cH3)2 CO S
1416 4-CH3 CH2CH2CH(cH3)2 CO S
1417 2-F , CH2CH2CH(cH3)2 CO S
1418 3-F CH2CH7CH(CH3)2 CO S
CC
WO95109859 21~43~1 PCr/US94/11049
1419 4-F CH2CH2CH(cH3)2 CO S
1420 3-NH2 CH2CH2CH(cH3)2 CO S
1421 4-NH2 CH2CH2CH(cH3)2 CO S
1422 3-N2 CH2C1~2CH(cH3)2 CO S
1423 4-N2 CH2C1~2CH(cH3)2 CO S
1424 3-N CH2C1~2CH(CH3)2 CO S
1425 4-N CH2C}~2CH(cH3)2 CO S
1426 H CH2C~2CH(CH3)2 CO NH
1427 3-CH3 CH2C}~2CH(cH3)2 CO NH
428 4 CH3 CH2C~12CH(CH3)2 CO NH
~429 2-F CH2C~12CH(CH3)2 CO NH
1430 3-F CH2C~12CH(cH3)2 CO NH
~431 4-F CH~C~12CH(CH3)~ CO NH
1432 3-NH2 CH2CH2CH(cH3)2 CO ~'H
1433 4-NH2 CH-~CH2CH(CH3)2 CO NH
43~ 3-NO2 CH2CH2CH(CH3)2 CO NH
1435 4-NO2 CH2CH2CH(CH3)2 CO NH
1436 3-N CH2CH2CH(CH3)2 CO NH
1437 4-N CH2CH2CH(cH3)2 CO NH
1438 H CH2l~H(cH3) CO O
1439 H CH2N(CH3)CO2C(CH3)3 CO O
TA~3~ 14
NH 0
R~J~N ' o--
Oq~ N H C H3
RA /~N--Z--R10
3,=l=~2 V
/ \
4~(CH2)L--V
~i 6
~,
A I ^ '
WO 95/098S9 2~ 1 7 ~ 3 1 1 PCTIUS94111049 ~
`` RX = H2N
Ex No. RA R10 z V u Dala
1440 H CH3 CO O 0
1441 3-CH3 CH3 CO O 0
1442 4-CH3 CH3 CO O 0
1443 2-F CH3 CO O 0
1444 3-F CH3 CO O 0
1445 4-F CH3 CO O 0
1446 3-NH2 CH3 CO O 0
1447 4-NH2 CH3 CO O 0
1448 3-NO2 CH3 CO O 0
1449 4-N2 CH3 CO O 0
1450 3-N CH3 CO O 0
1451 4-N' CH3 CO O 0
145'' H CH3 CO S O
1453 3-CH3 CH3 CO S 0
1454 4-CH3 CH3 CO S 0
1455 2-F CH3 CO S 0
1456 3-F CH3 CO S 0
1457 4-F CH3 CO S 0
1458 3-NH2 CH3 CO S 0
1459 4-NH2 CH3 CO S 0
1460 3-NO2 CH3 CO S 0
146~ 4-NO~ CH3 CO S 0
146'' 3-N CH3 CO S ()
1463 4-N CH3 CO S O
1464 H CH(CH3)2 CO O 0
1465 3-CH3 CH(CH3)2 CO O 0
1466 4-CH3 CH(CH3)2 CO O 0
1467 2-F CH(cH3)2 CO O 0
~468 3-F CH(CH3)2 CO O 0
1469 4-F CH(cH3)2 CO O 0
1470 3-NH2 CH(CH3)2 CO O 0
1471 4-NH2 CH(CH3)2 CO O 0
C_
217~311
WO95/09859 PCr~US94~11049
1472 3-NO2 CH(CH3)2 CO O 0
1473 4-N2 CH~(CH3)2 CO O 0
1474 3-N CH(CH3)2 CO O 0
1475 4-N CH(CH3)2 CO O 0
1476 H CH(CH3)2 CO S 0
1477 3-CH3 CH(CH3)2 CO S 0
1478 4-CH3 CH(CH3k CO S 0
1479 2-F CH(CH3)2 : CO S 0
1480 3-F CH(CH3)2 CO S 0
1481 4-F CHI~CH3)2 CO S 0
1482 3-NH2 CH(CH3)2 CO S 0
1483 4-NH2 CH(CH3)2 CO S 0
1484 3-NO2 CH(cH3)7 CO S 0
1485 4-NO2 CH(CH3)2 CO S 0
1486 3-N CH(CH3)~ CO S ()
~487 4-N CH(CH3)2 CO S 0
1488 H CH2cH2cH(cH3)7 CO O ()
1489 3-CH3 CH2CH2CH(CH3)2 CO O ()
1490 4-CH3 CH2CH2CH(CH3)2 CO O 0
149~ 2-F CH2CH2CH(CH3)2 CO O 0
~492 3-F CH2CH2CH(CH3)2 CO O 0
1493 4-F CH2CH2CH(CH3)2 CO O 0
149~ 3-NH2 CH2CH2CH(CH3)2 CO O 0
1495 4-NH2 CH2CH2CH(CH3)7 CO O ()
1496 3-N2 CH2CH2CH(cH3)2 CO O ()
1497 4-N02 CH2CH21`-H(CH3)2 CO O 0
1498 3-N CH2CH21-H(CH3)2 CO O 0
1499 4-N CH2CH2CH(CH3)2 CO O 0
1500 H CH2CH2CH(CH3)2 CO S 0
1501 3-CH3 CH2CH2CH(CH3)2 CO~ S 0
1502 4-CH3 CH2CH2CH(CH3)2 CO S 0
1503 2-F CH2CH2CH(CH3)2 CO S 0
1504 3-F CH2CH2CH(CH3)2 CO S 0
1505 4-F CH2CH2CH(CH3)2 CO S 0
1506 3-NH2 CH2CH2CH(cH3)2 CO ~ S 0
101
~174311
" . i .
WO 95/09859 { ~ PCTIUS94/11049
1507 4-NH2 CH2CH2CH(cH3)2 CO S 0
1508 3-NO2 CH2CH2CH(CH3)2 CO S 0
1509 4-N2 CH2CH2CH(CH3)2 CO S 0
1510 3-N CH2CH2CH(CH3)2 CO S 0
1511 4-N CH2CH2CH(CH3)2 CO S 0
1512 H CH3 CO O
1513 3-CH3 CH3 CO O
1514 4-CH3 CH3 CO O
1515 2-F CH3 CO O
1516 3-F CH3 CO O
1517 4-F CH3 CO O
1518 3-NH2 CH3 CO O ]
1519 4-NH2 CH3 CO O
1520 3-NO2 CH3 CO O
15 ~ 4-NO2 CH3 CO O
1523-N CH3 CO O
1523 4-18 CH3 CO O
152~ H CH3 CO S
1525 3-CH3 CH3 CO S
1526 4-CH3 CH3 CO S
1527 2-F CH3 CO S
~523 3-F CH3 CO S
1529 4-F CH3 CO S
1530 3-NH2 CH3 CO S
153~ 4-NH~ CH3 CO S
1532 3-N2 CH3 CO S
1533 154-NO2 CH3 CO S
1534 3-N CH3 CO S
1535 4-N CH3 CO S
1536 H CH3 CO NH
1537 3-CH3 CH3 CO NH
1538 4-CH3 CH3 CO NH
~539 2-F CH3 CO NH
1540 3-F CH3 CO NH
154~ 4-F CH3 CO NH
102
wo gslog8~9 2 17 43~ PCT/U594/11049
.
1542 3-NH2 C~i3 CO NH
1543 4-NH2 C~13 CO NH
1544 3-N2 c~l3 CO NH
1545 4-N2 C~13 CO NH
1546 3-N C~13 CO NH
1547 4-N C~13 CO NH
1548 H CH(CH3)2 CO O
1549 3-CH3 CH(CH332 CO O
1550 4-CH3 CH(cH332 CO O
1551 2-F CH(CH332 CO O
~552 3-F CH(cH3)2 CO O
1553 4-F CH(cH3)2 CO O
155~ 3-NH2 CH(CH3k CO O
1555 4-NH2 CH(cH3)2 CO O
1556 3-NO2 CH(cH3)2 CO O
1557 4-N2 CH(CH332 CO O
1558 3-N CH(CH332 CO O
1559 4-N CH(CH3)2 CO O
156(3 H CH(cH3)2 CO S
1561 3-CH3 CH(cH3)2 CO S
156'2 4-CH3 CH(cH3)2 CO S
1563 2-F CH(cH3)2 CO S
156~ 3-F CH(CH3)~ CO S
1565 4-F - CH(CH3) CO S
1566 3-NH2 CH(cH3)2 CO S
1567 4-NH2 CH(cH3)2 CO S
1568 3-N2 CH(CH3)~ CO S
1569 4-N2 CH(CH3)2 CO S
1570 3-N CH(CH3)2 CO S
1571 4-N CH(CH3k CO S
1572 H CH(CH3k CO NH
1573 3-CH3 CH(CH3)2 CO NH
1574 4-CH3 CH(CH3k CO NH
1575 2-F CH(cH3)2 CO NH
1576 3-F CH(CH3)2 CO NH
10?
~ r ~
.,. 1 ~ . ~ ..
WO 95/09859 ~ PCT/T~S94/11049
15774-F CH(CH3)2 CO NH
15783-NH2 CH(cH3)2 CO NH
15794-NH2 CH(CH3)2 CO NH
15803-NO2 CH(cH3)2 CO NH
15814-NO2 CH(cH3~2 CO NH
15823-N CH(cH3)2 CO NH
15834-N CH(cH3~2 CO NH
1584 H CH2CH2CH(CH3k CO O
15853-CH3 CH2CH2CH(CH3)2 CO O
15864-CH3 CH2CH2CH(cH3)2 CO O
15872-F CH2CH2CH(CH3)2 CO O
15883-F CH2CH2CH(CH3)2 CO O
15894-F CH2CH2CH(cH3)2 CO O .
15903-NH2 CH2CH2CH(CH3)2 CO O
15914-NH2 CH2CH2CH(CH3)2 CO O
159'2 3-NO~ CH2CH2CH(CH3)2 CO O
15934-NO2 CH2CH2CH(c.H3)2 CO O
159~3-N CH2CH2CH(CH3)2 CO O
15954-N CH2CH2CH(CH3)2 CO O
1596 H CH2CH2CH(CH3)2 CO S
15973-CH3 CH2CH2CH(CH3)2 CO S
15984-CH3 CH2CH2CH(cH3)2 CO S
15992-F CH2CH2CH(CH3)2 CO S
16003-F CH2CH2CH(CH3)2 CO S
16014-F CH2CH2CH(cH3)2 CO S
16023-NH2 CH2CH2CH(CH3)2 CO S
16034-NH2 CH2CH2CH(CH3)2 CO S
16(~3-N2 CH2CH2CH(CH3)2 CO S
16054-No2 CH2CH2CH(CH3)2 CO S
16063-N CH2CH2CH(CH3)2 CO S 1 r
16074-N CH2CH2CH(cH332 CO S
1608 H CH2CH2CH(CH3)2 CO NH
16093-CH3 CH2CH2CH(CH3)2 CO NH
16104-CH3 CH~CH2CH(CH3)2 CO Nll
161~2-F CH~CH2CH(cH3)2 CO NH
;0~
~17~311
WO 95/098sg PCT~Uss4/1 1049
1612 3 ~ CH2CH2CH(CH3)2 CO NH
1613 4-F CH2CH2CH(CH3)2 CO NH
1614 3-NH2 CH2CH2CH(cH3)2 CO NH
1615 4-NH2 CH2CH2CH(cH3)2 CO NH
1616 3-NO2 CH2CH2CH(cH3)2 CO NH
1617 4-NO2 CH2CH2CH(CH3)2 CO NH
1618 3-N CH2CH2CH(cH3)2 CO NH
1619 4-N CH2CH2CH(CH3)2 CO NH
1620 H CH2NH(CH3) CO O
1621 H CH2N(cH3)co2c(cH3)3 CO O
Table 15
NH OH
RXJ~ H ~B~o H
Oq~ N H
~N--Z---Rl
R3--O
~X = ~21~, Z=C~=O)
Ex No. R3 R10 Da~a
1622 CH3 CH3
1623 (H3c)3c CH3
1624
C ~ CH3
105
WogS/098S9 21~3~ pCrNS94/11049
1 625 - : -
~o~C Hz CH3
16~6 CH3 t,'H2CH2Ph
1627 (H3C)3C CH2CH2Ph
1628
f ~ CH2CH~Ph
0~
1629
~,C H2 CH2CH2Ph
Ta~le 1 6
RXJ~ N ,B ~3
O~,NH C~
<~N--Z--R 10
R3 0
RX = ~2N, Z=C~=O)
No. R3 R10 Da~a
~630 CH3 CH3
1631 (H3c)3c C~3
~1743~1 `
WO 951098S9 PCTIUS94/1 1049
1632
d~ CH3
1633
C,C 1~2 CH3
1634 CH3 CH2CH2Ph
1635 (H3C)3C CH2CH2Ph
1636
C ~ CH2CH2Ph
CC
1637
CC~ H2 ' CH2CH2Ph
~able 17
H N~S~ ~
0~ N H C H3
N--Z--R10
O
10-
Wo 95/098S9 3~ PCT/US94/11049
Ex No. R3 Rll R10 z Da;
163B H H CH2Ph C(O)O NN
163 9 PhCH2 H C(CH3)3 C(O)O OO
1640 PhCH2 H CH3 CO PP
16 41 PhCH2 H CH2Ph C(O)O OO
Table 18
O ~
H2N~ B` ~3
Oq~NH CH3
~N--Z--R10
R
S R3--g
Ex No. R3 R l l R 1 0 z Dala
singlc bond CH2CH2Ph CO . RR
TABLE l 5
u
N H B~ ~3
Oq~ N H C H3
~N--Z--Rl
R3--O
WO95109859 æ~3ll PCr/US94/11049
Ex No. R3 R10 z R~
1643 CH2Ph CH2CH2Ph CO NHCH3 SS
1644 CH2Ph CH2CH2Ph CO H lT
Table 20
NH OH
RXJ~1 ' OH
0~ N H
~N--Z--R10
R3--O
Ex No. R3 R10 Z Rx Da~a
1645 CH2Ph CH2CH2Ph CO NHCH3 Ul I
1646 CH2Ph CH2CH2Ph CO H VV
O ~
HR~S Calcd for C29H4.B~3O6: 540.3245. Found:
540 .3248 .
B HRMS Calcd for C30H44BN3O6: 554.3401. Found:
55~.3404.
C HR~S Calcd for C31H47BN3O6: 568.3558. Found:
5 68 . 3558 .
D HRMS Calcd for C29H42BN3O6: 540.3245. Found:
540 . 3248 .
20 ~ HRMS Calcd for C33~51BN3O6: 596.3871. Found:
596 . 3870 .
105
WO 95/09859 ~ PCr/U594/11049
F HRMS Calcd ~or C33H51BN3O6: 596.3871. Founà:
596 .3857 .
G HRMS Calcd for C36H48BN306: 630.3714. Found:
630 .3709 .
5 H HRMS Calcd for C30H44BN3O7: 570.3351. Found:
570 . 3353 .
I LF~MS Calcd for C3~H45BN3O8S: 618.3. Found: 618.q.
J HRMS Calcd for C31H468FN3O6: 586.3464. Found:
586. 3456 .
10 K HRMS Calcd for C30H46BN4O6: 569.3510. Found:
569 . 3501 .
L HRMS Calcd for C3~H52BN3O6: 6sa . 4027 . Found:
658 . 4036.
M HRMS Calcd for C28H39BN3O5 (ethylene glycol ester):
508.2983. Found: 508.2999.
N HRMS Calcd for C27H39BN3O5 (ethylene glycol ester~:
522.3139. Found: 522.3123.
O LRMS Calcd for C26H36BFN3O5 (ethylene glycol ester~:
526. Found: 526.
20 P HP~qS Calcd for C35H49BN3045: 618.3537. Founa:
61 8 . 3537 .
HRMS Calcd for C36H51BN3O5: 616.3922. Found:
616.3910. : :
R HRMS Calcd for C37H~3BN305: 630.4078. Found:
630 . 4060 .
S HR~.S Calcd for C35H50BN4O5: 617.3874. Found:
617 . 387 6 .
T LRMS Calcd for C36H50BFN3Os: 634. Found: 634.5.
U LRMS Calcd for C36H52BN4O5: 631. Found: 631.3.
30 V HRMS Calcd for C37H53BN305: 630 . qO78 . Found:
630 . 4071 .
W HRMS Calcd for C36H48BN3O6: 618.3714. Found:
618 . 3713 .
X HRMS Calcd for C36H51BN3O6: 632.3871. Found:
3~ 632.3857.
llr
wo gs~og~sg ~ 1 7 4 3 1 I PCI/lJS94/11049
Y LFcMS Calcd for C36H51BN4O4: 615. Found: 615.5.
Z HRMS Calcd for CzgH~4BN405: 526.3452. Found:
526.3460.
AA HRMS Calcd for C30H46BN305: 540.3609. Found:
540 . 3604 .
BB HRMS Calcd for C30E~q7BN3O5: 540.3609. Found:
540.3620 .
CC HRMS Calcd for C31E~4gBN3Os: 554.3765. Found:
554 . 37 69 .
DD HRMS Calcd for C33El53BN407: 582.4078. Found:
582 . 4 071 .
EE ~EcMS Calcd for C30P.48BNgO5: 555.3718. Found:
555 . 3735 .
FF HE`cMS Calcd for C35E156BN4O7: 655.4242. Found:
655 . 4234 .
GG HRMS Calcd for C26H47BN3O5: 492.3609. Found:
4 5~ . 3600 .
Hl'. HRMS Calcd for C33Ei47BN305: 576.3609. Found:
576 . 3593 .
II HRMS Calcd for C33H53BN305: 582.4078. Found:
582 . 4092 .
JJ HFcMS Calcd for C40Hs3BN3Os: 666.4078. Found:
666 . 408~ .
~E' LRMS Calcd for C26H36BFN505: 528.3. Found: 528.3.
2_ , L HRMS Calcd for C36HslBNsos: 64~ .39~,. Found:
6~ ~ . 3 977 .
MM LRMS Calcd for C36H50BFN5O5: 662. Found: 662.
NN HRMS Calcd for C28H~l2BN4O6S: 573.2918. Found:
573 . 2919 . '~
OO HFcMS Calcd for C32HsoBN4O6S: 629.3544. Found:
62 9 . 3524 .
PP HR~IS Calcd for C29H42BN3O5S: 571.3126. Found:
571 . 3138 .
QQ HRMS Calcd for C35Ei48BN4O6S: 663.3388. Found:
663.3374.
i ~ 1
WO 95/09859 ~ PCTIUS94/1 l049
RR HRMS Calcd for C29H43BN3O5: 524.3300. Found:
524 . 3305 .
SS LRMS Calcd for C37Hs3BNsOs: 653. Found: 658
TT LRMS Calcd for C36Hs~BN4Os: 629. Found: 629
5 UU LRMS Calcd for C27H3gBNsOs: S24. Found: S~4
W LRMS Calcd for C26H36BN4Os: 495. Found: 49S
WW HRMS Calcd for C3sH4~BFN3O6: 636.3620. Found:
63 6 . 3612 .
Ut; lity
The compounds of formula (I) are useful as
inhibitors of serine proteases and notably human
thrombin, plasma kallikrein and plasmin. Because of
their inhibitory action, these compounds are indic~ted
for use in the preYention or treatment of physiologica' ,
reactions, blood coagulatiQn and inflammatior., calalyzed
b~ the aforesaid class of er.zymes.
Inhibition constants were determined by the melhod
described by Kettner et al. in J. ~iol. ~hem. 265,
18289-18297 (1990~, herein incorporated by reference.
In these assays, thrombin-mediated hydrolysis cf the
chromogenic substrate S2238 (Helena Laboratories,
Beaumont, TX) was monitored spectrophotometrically.
Aad~ tion of an inhibitor to the assay miY.Iure resul~s lr
~- decreased absorbance and is indicative of thrombin
inhibition. Human thrombin (Enzyme Research
Laboratories, Inc., South Bend, Il~ al a concentratior.
of 0.2 nM in 0.10 M sodium phosphate buffer, pH 7.S,
0.20 ~ NaCl, and 0 S'i polyethylene glycol 6000, was
~0 incubated with various substrate concentrations ranging
from 0.20 to 0.02 mM. After 25 to 30 minuteS of ~
incubation, thrombin activity was assayed by moni1:0rins
the rate of increase in absorbance at 9405 nm which
arises owing to substrate hydrolysis. Inhibition
constants were derived from reciprocal plots of tbe
1 ~
~ WO9~1098S9 21 7~31`~. PCr/U594/11049
re~ction velocity as a function of substrate
concentration using the standard method of Lineweaver
and Burk.
Using the methodology described above,
5 representative compounds of this invention were
evaluated and found to exhib t a Ki of less than l mM,
thereby confirming the utility of the compounds of the
invention as effective thrombin inhibitors.
The ability of the compounds to inhibit coagulation
lO was assayed in normal rabbit piasma which was prepared
by diluting blood l:lO with 3.2~ aqueous citric acid
followed by centrifugation. Bovine thrombin was
obtained from Sigma and diluted to 2~ NIH units/mL.
Plasma ( 0.2 mL) and buffe~ (0.05 m~, O.lO M
l~ ~ris[hydroxymethyl~-aminomethane hydrochloride, pH 7.4,
o . 9~ (w/v) sodium chloride, and 2 . 5 mg/mL bovine serum
albumin) containing inhibitor were incubated 3 min at 37
C in a fibrameter. Reactions were ~initiated by adding
thrombin (0.05 mL) T:O achieve a final concentration of 4
20 NIH units/mL. ~he effectiveness of compounds as
antiGoagulants is reported as the level of inhibitor
req~ired to prolong clotting to that observed for 2 NIH
units/mL of .thrombin in the absence of inhibitor. In
this assay then, better inhibitors req~ire lower
2~ concentrations to dela~ clot formatlon. Representative
compounds of this invention were evaluated and found to
be active.
Since the ~ :~.pounds of formula (I) have anti-
thromoogeniC proper~ies, they may be employed when an
30 anti-thrombogenic agent is indicated, such as for the
control of the coagulation of the fibrinolysis system
in mammals or they may be added to blood for the
purpose of preventing coagulation of the blood due to
contact with blood collecting or distribution
3' containers, tubing or apparatus.
113
WO9S/09859 ~ 3 1~.; PCr/US94111049
Generally, these compounds may be administered
orally, parenterally or intravenousl ~ to a host to
obtain an anti-thrombogenic effect. The dosage of the
active compound depends on the mammalian species, body
5 weight, age, and mode of administration as determined
by one skilled in the art. In the case of large
mammals such as humans, the compounds may be
administered alone or in combination with
pharmaceutical carriers or diluents at a dose of from
l0 0.02 to 15 mg/kg to obtain the anti-thrombogenic
effect, and may be given as a single dose or in
divided doses or as a sustained release formulation.
Pharmaceutical carriers or diluents are well known and
include sugars, s~arches and water, which may be used to
15 make tablets, capsules, injectable solutions or the like
which can serve as suitable dosage forms for
administration of the compounds of this invention.
Rem;nqton's Pharmaceutlcal Sciences, A. Osol, is a
standard reference teY.t which discloses sui~able
20 pharmaceutical carriers and dosage forms. The
disclosure of this text is hereby incorporated by
reference for a more complete teaching of suit:able
dosage forms for administration of the compounds of this
invention .
11
