Title of Invention

CARBOXYLIC ACID DERIVATIVES THAT INHIBIT THE BINDING OF INTEGRINS TO THEIR RECEPTORS

Abstract The present invention discloses a compound of the structure and pharmaceutical compositions comprising such compound for selectively inhibiting a4ß1 integrin binding in a mammal.
Full Text This invention relates to a carboxylic acid
derivatives that inhibit the binding of integrins to
their receptors and is an improvement in or modification
of an invention disclosed in our co-pending National
Phase Patent application No.IN/PCT/2001/01110.
Field of the Invention
This invention is directed generally to the inhibition of the binding of a4b1 integrin to
its receptors, for example VCAM-1 (vascular cell adhesion molecule-1) and fibronectin. The
invention also relates to compounds that inhibit this binding; to pharmaceutically active
compositions comprising such compounds; and to the use of such compounds either as above,
or in formulations for the control or prevention of disease states in which a4b1 is involved.
Background of the Invention
When a tissue has been invaded by a microorganism or has been damaged, white
blood cells, also called leukocytes, play a major role in the inflammatory response. One of
the most important aspects of the inflammatory response involves the cell adhesion event.
Generally, white blood cells are found circulating through the bloodstream. However, when
a tissue is infected or becomes damaged, the white blood cells recognize the invaded or
damaged tissue, bind to the wall of the capillary and migrate through the capillary into the
affected tissue. These events are mediated by a family of proteins called cell adhesion
molecules.
There are three main types of white blood cells: granulocytes, monocytes and
lymphocytes. The integrin a4b1 (also called VLA-4 for very late antigen-4) is a heterodimeric
protein expressed on the surface of monocytes, lymphocytes and two subclasses of
granulocytes: eosinophils and basophils. This protein plays a key role in cell adhesion
through its ability to recognize and bind VCAM-1 and fibronectin, proteins associated with
the endothelial cells that line the interior wall of capillaries.
Following infection or damage of tissue surrounding a capillary, endothelial cells
express a series of adhesion molecules, including VCAM-1, that are critical for binding the
white blood cells that are necessary for fighting infection. Prior to binding to VCAM-1 or
fibronectin, the white blood cells initially bind to certain adhesion molecules to slow their
flow and allow the cells to "roll" along the activated endothelium. Monocytes, lymphocytes,
basophils and eosinophils are then able to firmly bind to VCAM-1 or fibronectin on the blood
vessel wall via the a4b1 integrin. There is evidence that such interactions are also involved in
transmigration of these white blood cells into the damaged tissue as well as the initial rolling
event itself.
Although white blood cell migration to the site of injury helps fight infection and
destroy foreign material, in many instances this migration can become uncontrolled, with
white blood cells flooding to the scene, causing widespread tissue damage. Compounds
capable of blocking this process, therefore, may be beneficial as therapeutic agents. Thus, it
would be useful to develop inhibitors that would prevent the binding of white blood cells to
VCAM-1 and fibronectin.
Some of the diseases that might be treated by the inhibition of a4b1 binding include,
but are not limited to, atherosclerosis, rheumatoid arthritis, asthma, allergy, multiple sclerosis,
lupus, inflammatory bowel disease, graft rejection, contact hypersensitivity, and type I
diabetes. In addition to being found on some white blood cells, a4b1 is also found on various
cancer cells, including leukemia, melanoma, lymphoma and sarcoma cells. It has been
suggested that cell adhesion involving a4b1 may be involved in the metastasis of certain
cancers. Inhibitors of a4b1 binding may, therefore, also be useful in the treatment of some
forms of cancer.
The isolation and purification of a peptide which inhibits the binding of a4b1 to a
protein is disclosed in U.S. Patent No. 5,510,332. Peptides which inhibit binding are
disclosed in WO 95/15973, EP 0 341 915, EP 0 422 938 Al, U.S. Patent No. 5,192,746 and
WO 96/06108. Novel compounds which are useful for inhibition and prevention of cell
adhesion and cell adhesion-mediated pathologies are disclosed in WO 96/22966, WO
98/04247 and WO 98/04913.
It is therefore an object of the invention to provide novel compounds which are
inhibitors of a4b1 binding, and pharmaceutical compositions including such novel
compounds.
wherein Y, at each occurrence, is independently selected from the group consisting
of C(O), N, CR1, C(R2 )(R3), NR5, CH, O and S;
q is an integer of from 3 to 10;
A is selected from the group consisting of O. S. C(R16)(R17 ) and NR6;
E is selected from the group consisting of CH2, O, S, and
NR7;
J is selected from the group consisting of O, S and NR8;
T is selected from the group consisting of C(O) and (CH2)b wherein b is an integer
of from 0 to 3;
M is selected from the group consisting of C(R9)(R10) and
(CH2)u, wherein u is an integer of from 0 to 3;
L is selected from the group consisting of O, NR11, S, and
(CH2)n wherein n is an integer of 0 or 1;
X is selected from the group consisting of CO2B, PO3H2,
SO3H, SO2NH2, SO2NHCOR12, OPO3H2, C(O)NHC(O)R13,
C(O)NHSO2R14, hydroxyl tetrazolyl and hydrogen;
W is selected from the group consisting of C, CR15 and N: and
B, R1, R2, R3, R4, R5, R6, R7, R8, R9, R10, R11, R12, R13, R14, R15, R16and R17at each
occurrence are independently selected from the group consisting of
hydrogen, halogen, alkyl, alkenyl, alkynyl, alkoxy, alkenoxy,
alkynoxy, thioalkoxy, hydroxyalkyl, aliphatic acyl, -CF3, -CO2H, -SH,
-CN, -NO2, -NH2, -OH, alkynylamino, alkoxycarbonyl, heterocycloyl, carboxy,
-N(C1-C3 alkyl)-C(O)(C1-C3 alkyl), -NHC(O)N(C1-C3 alkyl)C(O)-
NH(C1-C3alkyl), -NHC(O)NH(C1-C6alkyl), -NHSO2(C1-C3 alkyl),
-NHSO2(aryl), alkoxyalkyl, alkylamino, alkenylamino, di(C1-C3)amino,
-C(O)O-(C1-C3)alkyl, -C(O)NH-(C1-C3)alkyl, -C(O)N(C1-C3alkyl)2,
-CH=NOH, -PO3H2, -OPO3H2, haloalkyl, alkoxyalkoxy, carboxaldehyde,
carboxamide, cycloalkyl, cycloalkenyl, cycloalkynyl, cycloalkylalkyl, aryl,
aroyl, aryloxy, arylamino, biaryl, thioaryl, diarylamino, heterocyclyl, alkylaryl,
aralkenyl, aralkyl, alkylheterocyclyl, heterocyclylalkyl, sulfonyl,
-SO2-(C1-C3 alkyl), -SO3-(C1-C3 alkyl), sulfonamido, carbamate, aryloxyalkyl
and -C(O)NH(benzyl) groups;
wherein B, R1, R2, R3, R4, R5, R6, R7, R8, R9, R10, R11, R12, R13, R14,
R15, Rl6 and R17 are unsubstituted or substituted with at least one
electron donating or electron withdrawing group;
wherein when L is NR11, R14 and R11 taken together may form a ring;
and wherein when M is C(R9)(R10), R9 and R10 taken together may
form a ring;
and wherein when A is NR6 and at least one Y is CR1, R1 and R6 taken
together may form a ring;
or a pharmaceutically acceptable salt thereof;
with the proviso that when A is C(R16)(R17), E is not NR7.
For Formula I, presently preferred compounds may have A as NR6; E as NR7; J as O;
M as C(R9)(R10); q as 4 or 5; T as (CH2)b wherein b is 0; L as (CH2)n wherein n is 0; X as
CO2B; W as C or CR15; R4 as aryl, alkylaryl, aralkyl, heterocyclyl, alkylheterccyclyl or
heterocyclylalkyl; and R6, R', R9, R10 and R15 independently as hydrogen or lower alkyl.
More specifically, the compounds of this invention may be described by
Formula II
wherein Y, at each occurrence, is independently selected from the group consisting
of C(O), N, CR1, C(R2 )(R3), NR5, CH, O and S;
q is an integer of from 3 to 7;
T is selected from the group consisting of C(O) and (CH2)b wherein b is an integer of
0 to 3;
L is selected from the group consisting of O, NR11, S, and
(CH2)n wherein n is an integer of 0 or 1;
W is selected from the group consisting of C, CR15 and N; and
B, Rl, R2, R3, R4, R5, R6. R7, R9, R10, R11 and R15 are independently selected from
the group consisting of hydrogen, halogen, alkyl, alkenyl, alkynyl,
alkoxy, alkenoxy, alkynoxy, thioalkoxy, hydroxyalkyl, aliphatic acyl, -CF3,
-CO2H, -SH, -CN, -NO2, -NH2, -OH, alkynylamino, alkoxycarbonyl,
heterocycloyl, carboxy, -N(C1-C3 alkyl)-C(O)(C1-C3 alkyl),
-NHC(O)N(C1-C3 alkyl)C(O)NH(C1-C3alkyl), -NHC(O)NH(C1-C3 alkyl),
-NHSO2(C1-C3 alkyl), -NHSO2(aryl), alkoxyalkyl, alkylamino, alkenylamino,
di(C1-C3)amino, -C(O)O-(C1-C3)alkyl, -C(O)NH-(C1-C3)alkyl, -C(O)N(C1-C3
alkyl)2, -CH=NOH. -PO3H2, -OPO3H2, haloalkyl, alkoxyalkoxy,
carboxaldehyde, carboxamide, cycloalkyl, cycloalkenyl, cycloalkynyl,
cycloalkylalkyl, aryl, aroyl, aryloxy, arylamino, biaryl, thioaryl, diarylamino,
heterocyclyl, alkylaryl, aralkenyl, aralkyl, alkylheterocyclyl, heterocyclylalkyl,
sulfonyl, -SO2-(C1-C3 alkyl), -SO3-(C1-C3 alkyl), sulfonamido, carbamate,
aryloxyalkyl and -C(O)NH(benzyl) groups;
wherein B, R1. R2, R3, R4, R5, R6, R7, R9, R10, R11 and R15 are unsubstituted or
substituted with at least one electron donating or electron withdrawing
group;
wherein when L is NR11, R4 and Rl1 taken together may form a ring;
and wherein R9 and R10 taken together may form a ring;
and wherein when at least one Y is CR1, R1 and R6 taken
together may form a ring;
or a pharmaceutically acceptable salt thereof.
For Formula II, presently preferred compounds may have q as 4 or 5; W as C or CR15;
T as (CH2)b wherein b is 0; L as (CH2)n wherein n is 0; R4 as aryl, alkylaryl, aralkyl,
heterocyclyl, alkylheterocyclyl or heterocyclylalkyl; and R6, R7, R9, R10and R15 as
independently hydrogen or lower alkyl.
More specifically, the compounds of this invention may be described bv Formula HI
wherein Y, at each occurrence, is independently selected from the group
consisting of C(O), N, CR1, C(R2 )(R3), NR5, CH, O and S;
q is an integer of from 2 to 5;
T is selected from the group consisting of C(O) and (CH2)b wherein b is an integer o
0 to 3;
L is selected from the group consisting of O, NR11, S, and
(CH2)n wherein n is an integer of 0 or 1;
R5, R6, R7, R11 and R18 are each independently selected from the group consisting of
alkyl, alkenyl, alkynyl, hydroxyalkyl, aliphatic acyl, alkynylamino,
alkoxycarbonyl, heterocycloyl, -CH=N0H, haloalkyl, alkoxyalkoxy,
carboxaldehyde, carboxamide, cycloalkyl, cycloalkenyl, cycloalkynyl,
cycloalkylalkyl, aryl, aroyl, aryloxy, arylamino, biaryl, thioaryl, diarylamino,
heterocyclyl, alkylaryl, aralkenyl, aralkyl, alkylheterocyclyl, heterocyclylalkyl,
carbamate, aryloxyalkyl, hydrogen and -C(O)NH(benzyl) groups; and
B, R1, R2, R3, R4, R9 and R10 are independently selected from the
group consisting of hydrogen, halogen, alkyl, alkenyl, alkynyl,
alkoxy, alkenoxy, alkynoxy, thioalkoxy, hydroxyalkyl, aliphatic acyl, -CF3,
-CO2H, -SH, -CN, -NO2, -NH2, -OH, alkynylamino, alkoxycarbonyl,
heterocycloyl, carboxy, -N(C1-C3 alkyl)-C(O)(C1-C3 alkyl),
-NHC(O)N(C1-C3 alkyl)C(O)NH(C1-C3alkyl), -NHC(O)NH(C1-C6alkyl),
-NHSO2(C1-C3 alkyl), -NHSO2(aryl), alkoxyalkyl, alkylamino, alkenylamino,
di(C1-C3)amino, -C(O)O-(C1-C3)alkyl, -C(O)NH-
(C1-C33)alkyl, -C(O)N(C1-C3alkyl)2, -CH=NOH, -PO3H2, -OPO3H2, haloalkyl,
alkoxyalkoxy, carboxaldehyde, carboxamide, cycloalkyl, cycloalkenyl,
cycloalkynyl, cycloalkylalkyl, aryl, aroyl, aryloxy, arylamino, biaryl, thioaryl,
diarylamino, heterocyclyl, alkylaryl, aralkenyl, aralkyl, alkylheterocyclyl,
heterocyclylalkyl, sulfonyl, -SO2-(C1-C3 alkyl), -SO3-(C1-C3 alkyl),
sulfonamido, carbamate, aryloxyalkyl and -C(O)NH(benzyl) groups;
wherein B, R1, R2, R3, R4. R5, R6, R7, R9, R10, R11 and R18 are unsubstituted or
substituted with at least one electron donating or electron withdrawing
group;
wherein when L is NR11, R4 and R" taken together may form a ring;
and wherein R9 and R10 taken together may form a ring;
and wherein when at least one Y is CR1, R1 and R6 taken
together may form a ring;
or a pharmaceutically acceptable salt thereof.
For Formula ID, presently preferred compounds may have R18 as hydrogen, alkyl, aryl,
aralkyl, cycloalkyl, alkylheterocyclyl, heterocyclylalkyl or heterocyclyl; T as (CH2)b wherein b
is 0; L as (CH2)n wherein n is 0; Y as CR1 and C(R2 )(R3) and q as 2 or 3.
In Formula HI, the portion of the molecule
and pharmaceutical acceptable salts thereof and pharmaceutical acceptable salts
thereof
wherein R19, R20, R21 and R28 at each occurrence are independently selected from
the group consisting of halogen, alkyl. alkenyl, alkynyl. alkoxy. alkenoxy.
alkynoxy. thioalkoxy. hydroxyalkyl. aliphatic acyl. -CF3. -OH.
-CO2H, -SH. -CN, -NO;. -NH;, alkynylamino, alkoxycarbonyl,
heterocycloyl, carboxy. -N(C1-C3, alkyl)-C(O)(C1-C3 alkyl),
-NHC(O)N(C1-C3 alkyl)C(O)NH(C1-C3alkyl),-NHC(O)NH(C1-C6alkyl),
-NHSO2(C1-C3 alkyl), -NHSO2(aryl), alkoxyalkyl, alkylamino, alkenylamino,
di(C1-C3)amino, -C(O)O-(C1-C3)alkyI. -C(O)NH-(C1-C3)alkyl, -C(O)N(C1-C3
alkyl),, -CH=NOH, -PO3H2, -OPO3H2, haloalkyl, alkoxyalkoxy,
carboxaldehyde, carboxamide, cycloalkyl, cycloalkenyl, cycloalkynyl,
cycloalkylalkyl, aryl. aroyl, aryloxy, arylamino. biaryl, thioaryl, diarylamino,
heterocyclyl, alkylaryl, aralkenyl, aralkyl, alkylheterocyclyl, heterocyclylalkyl,
sulfonyl, -SO:-(C1-C3 alkyl), -SO3-(C1-C3 alkyl),
sulfonamide carbamate, aryloxyalkyl and -C(O)NH(benzyl) groups;
R!8 is selected from the group consisting of alkyl, alkenyl. alkynyl, hydroxyalkyl.
aliphatic acyl. alkynylamino, alkoxycarbonyl, heterocycloyl, -CH=NOH,
haloalkyl, alkoxyalkoxy, carboxaldehyde, carboxamide, cycloalkyl,
cycloalkenyl, cycloalkynyl, cycloalkylalkyl, aryl, aroyl, aryloxy, arylamino,
biaryl, thioaryl, diaiylamino, heterocyclyl, alkylaryl, aralkenyl, aralkyl,
alkylheterocyclyl, heterocyclylalkyl, carbamate, aryloxyalkyl, hydrogen and
-C(O)NH(benzyl) groups;
R22 is selected from the group consisting of hydrogen, halogen, alkyl, alkenyl,
alkynyl, alkoxy, alkenoxy, alkynoxy, thioalkoxy, hydroxyalkyl, aliphatic
acyl, -CF3, -CO2H, -SH, -CN, -NO2, -NH2, -OH, alkynylamino,
alkoxycarbonyl, heterocycloyl, carboxy, -N(C1-C3 alkyl)-C(O)(C1-C3
alkyl), -NHC(O)N(C1-C3 alkyl)C(O)NH(C1-C3alkyl), -NHC(O)NH(C1-C6
alkyl), -NHSO2(C1-C3 alkyl), -NHSO2(aryl), alkoxyalkyl, alkylamino,
alkenylamino, di(C1-C3)amino, -C(O)O-(C1-C3)alkyl,
-C(O)NH-(C1-C3)alkyl, -C(O)N(C1-C3alkyl)2, -CH==NOH, -PO3H2,
-OPO3H2, haloalkyl, alkoxyalkoxy, carboxaldehyde, carboxamide,
cycloalkyl, cycloalkenyl, cycloalkynyl, cycloalkylalkyl, aryl, aroyl, aryloxy,
arylamino, biaryl, thioaryl, diarylamino, heterocyclyl, alkylaryl, aralkenyl,
aralkyl, alkylheterocyclyl, heterocyclylalkyl. sulfonyl, -SO2-(C1-C3 alkyl),
-SO3-(C1-C3 alkyl), sulfonamido, carbamate, aryloxyalkyl and
-C(O)NH(benzyl) groups;
c is an integer of zero to two;
d is an integer of zero to three;
e is an integer of zero to four; and
i is an integer of zero to two.
In one embodiment, R18 is aralkyl; R4 is aryl; T is (CH2)b where b is zero; L is (CH2)n where
n is zero; and, B, R6, R7, R9 and R10 are each independently hydrogen.
More specifically, the compounds of this invention may be described by Formula IV
wherein T is selected from the group consisting of C(O) and (CH2)t wherein b is
integer of from 0 to 3;
L is selected from the group consisting of O, NR , S, and
(CH2)n wherein n is an integer of 0 or 1;
g is an integer of from 0 to 7:
B, R4, R9, R10 and R13 at each occurrence are independently selected from the
group consisting of hydrogen, halogen, alkyl, alkenyl, alkynyl, alkoxy,
alkenoxy, alkynoxy, thioalkoxy, hydroxyalkyl, aliphatic acyl,
-CF3, -CO2H, -SH, -CN, -NO2, -NH2, -OH, alkynylamino,
alkoxycarbonyl, heterocycloyl, carboxy, -N(C1-C3 alkyl)-C(O)(C1-C3
alkyl),
-NHC(O)N(C1-C3 alkyl)C(O)NH(C1-C3alkyl) -NHC(O)NH(C1-C6 alkyl),
-NHSO2(C1-C3 alkyl), -NHSO2(aryl), alkoxyalkyl, alkylamino,
alkenylamino, di(C1-C3)amino, -C(O)O-(C1-C3)alkyl, -C(O)NH-(C1-
C3)alkyl, -C(O)N(C1-C3 alkyl)2, -CH=N0H, -PO3H2, -OPO3H2, haloalkyl,
alkoxyalkoxy, carboxaldehyde, carboxamide, cycloalkyl, cycloalkenyl,
cycloalkynyl, cycloalkylalkyl, aryl, aroyl, aryloxy, arylamino, biaryl,
thioaryl, diarylamino, heterocyclyl, alkylaryl, aralkenyl, aralkyl,
alkylheterocyclyl, heterocyclylalkyl, sulfonyl.
-SO2-(C1-C3 alkyl), -SO3-(C1-C3 alkyl), sulfonamide, carbamate, aryloxyalkyl
and -C(O)NH(benzyl) groups; and
R6, R7, R11 and R18 are each independently selected from the group consisting of alkyl,
alkenyl, alkynyl, hydroxyalkyl, aliphatic acyl, alkynylamino, alkoxycarbonyl,
heterocycloyl, -CH=NOH, haloalkyl, alkoxyalkoxy, carboxaldehyde,
carboxamide, cycloalkyl, cycloalkenyl, cycloalkynyl, cycloalkylalkyl, aryl,
aroyl, aryloxy, arylamino, biaryl, thioaryl, diarylamino, heterocyclyl, alkylaryl,
aralkenyl, aralkyl, alkylheterocyclyl, heterocyclylalkyl, carbamate,
aryloxyalkyl, hydrogen and -C(O)NH(benzyl) groups;
wherein B, R4, R6, R7, R9, R10, R11, R18 and R23 are unsubstituted or substituted
with at least one electron donating or electron withdrawing group;
wherein when L is NR!1, R4 and R11 taken together may form a ring;
and wherein R9 and R10 taken together may form a ring;
or a pharmaceutically acceptable salt thereof.
Presently preferred compounds of the present invention may also be described by
Formula V
wherein h is an integer of zero to five;
B, R9, R10, R24, and R25 are each independently selected from the group consisting
**************************
of hydrogen, halogen, alkyl, alkenyl, alkynyl, alkoxy, alkenoxy, alkynoxy,
thioalkoxy, hydroxyalkyl, aliphatic acyl, -CF3, -CO2H, -SH, -CN, -NO2,
-NH2, -OH, alkynylamino, alkoxycarbonyl, heterocycloyl, carboxy,
-N(C1-C3 alkyl)-C(O)(C1-C3 alkyl),
-NHC(O)N(C1-C3 alkyl)C(O)NH(C1-C3alkyl), -NHC(O)NH(C1-C6 alkyl),
-NHSO2(C1-C3 alkyl), -NHSO2(aryl), alkoxyalkyl, alkylamino,
alkenylamino, di(C1-C3)amino, -C(O)O-(C1-C3)alkyl,
-C(O)NH-(C1-C3)alkyl, -C(O)N(C1-C3alkyl)2, -CH=NOH, -PO3H2,
-OPO3H2, haloalkyl, alkoxyalkoxy, carboxaldehyde, carboxarnide,
cycloalkyl, cycloalkenyl, cycloalkynyl, cycloalkylalkyl, aryl, aroyl,
aryloxy, arylamino, biaryl, thioaryl, diarylamino. heterocyclyl, alkylaryl,
aralkenyl, aralkyl, alkylheterocyclyl, heterocyclylalkyl, sulfonyl,
-SO2-(C1-C3 alkyl), -SO3-(C1-C3 alkyl), sulfonamido, carbamate,
aryloxyalkyl and -C(O)NH(benzyl) groups;
R27, at each occurrence, is independently selected from the group consisting of
halogen, alkyl, alkenyl, alkynyl, alkoxy, alkenoxy, alkynoxy, thioalkoxy,
hydroxyalkyl, aliphatic acyl, -CF3, -CO:H, -SH, -CN, -NO2, -NH2, -OH,
alkynylamino, alkoxycarbonyl, heterocycloyl, carboxy, -N(C1-C3 alkyl)-
C(O)(C1-C3 alkyl), -NHC(O)N(C1-C3 alkyl)C(O)NH(C1-C3alkyl),
-NHC(O)NH(C1-C6 alkyl), -NHSO2(C1-C3 alkyl), -NHSO2(aryl),-N(C1-C3
alkyl)SO2(C1-C3alkyl),-N(C1-C3alkyl)SO2(aryl),-C
alkoxyalkyl,alkylamino, alkenylamino, di(C1-C3)amino, -C(O)O-(C1-
C3)alkyl, -C(O)NH-(C1-C3)alkyl, -C(O)N(C1-C3alkyl)2, -CH=NOH,
-PO3H2, -OPO3H2, haloalkyl, alkoxyalkoxy, carboxaldehyde, carboxamide,
cycloalkyl, cycloalkenyl, cycloalkynyl, cycloalkylalkyl, aryl, aroyl,
aryloxy, arylamino, biaryl, thioaryl, diarylamino, heterocyclyl, alkylaryl,
aralkenyl, aralkyl, alkylheterocyclyl, heterocyclylalkyl, sulfonyl,
-SO2-(C1-C3 alkyl), -SO3-(C1-C3 alkyl), sulfonamido, carbamate,
aryloxyalkyl and -C(O)NH(benzyl) groups;
R6, R' and R18 are each independently selected from the group consisting of
alkyl, alkenyl, alkynyl, hydroxyalkyl, aliphatic acyl, alkynylamino,
alkoxycarbonyl, heterocycloyl, -CH=NOH, haloalkyl, alkoxyalkoxy,
carboxaldehyde, carboxamide, cycloalkyl, cycloalkenyl, cycloalkynyl,
cycloalkylalkyl, aryl, aroyl, aryloxy, arylamino, biaryl, thioaryl, diarylamino,
heterocyclyl, alkylaryl, aralkenyl, aralkyl, alkylheterocyclyl, heterocyclylalkyl,
carbamate, aryloxyalkyl, hydrogen and -C(O)NH(benzyl) groups; and,
R26 is selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl,
hydroxyalkyl, aliphatic acyl, -CF3, alkoxycarbonyl, heterocycloyl, carboxy,
-C(O)O-(C1-C3)alkyl, -C(O)NH-(C1-C3)alkyl, -C(O)NC1-C3alkyl)2, -
PO3H2, haloalkyl, carboxamide, cycloalkyl, cycloalkenyl, cycloalkynyl,
cycloalkylalkyl, aryl, aroyl, biaryl, heterocyclyl, alkylaryl, aralkenyl,
aralkyl, alkylheterocyclyl, heterocyclylalkyl, sulfonyl, -SO2-(C1-C3 alkyl),
sulfonamido, aryloxyalkyl and -C(O)NH(benzyl) groups;
wherein B, R6, R7, R9, R10, R18, R24, R25, R26 and R27 are unsubstituted or
substituted with at least one electron donating or electron withdrawing group;
wherein R1 and R24 taken together may form a ring;
R24 and R25 taken together may form a ring;
R25 and R26 taken together may form a ring;
and wherein R9 and R10 taken together may form a ring;
or a pharmaceutically acceptable salt thereof.
Presently preferred compounds of Formula V have B, R6, R7, R9, R10, R24, R25 and R26 each
independently hydrogen and R18 as substituted or unsubstituted aralkyl.
Other presently preferred compounds of the present invention may be described by
wherein Z, at each occurrence, is independently selected from the group consisting
of C(O), N, CR30, C(R31 )(R32), NR33, CH, O and S;
z is an integer of from 3 to 6;
k is an integer of from 0 to 5;
T is selected from the group consisting of C(O) and (CH2)b wherein b is an
integer of from 0 to 3;
L is selected from the group consisting of O, NR11, S, and
(CH2)n wherein n is an integer of 0 or 1;
R , R , R11, R18 and R33 are each independently selected from the group consisting of
alkyl, alkenyl, alkynyl, hydroxyalkyl, aliphatic acyl, alkynylamino,
alkoxycarbonyl, heterocycloyl, -CH=N0H, haloalkyl, alkoxyalkoxy,
carboxaldehyde, carboxamide, cycloalkyl, cycloalkenyl, cycloalkynyl,
cycloalkylalkyl, aryl, aroyl, aryloxy, arylamino, biaryl, thioaryl, diarylamino,
heterocyclyl, alkylaryl, aralkenyl, aralkyl, alkylheterocyclyl, heterocyclylalkyl,
carbamate, aryloxyalkyl, hydrogen and -C(O)NH(benzyl) groups;
B, R4, R9, R10, R30, R31 and R32 at each occurrence are independently selected from
the group consisting of hydrogen, halogen, alkyl, alkenyl, alkynyl, alkoxy.
alkenoxy, alkynoxy, thioalkoxy, hydroxyalkyl, aliphatic acyl, -CF3,
-CO2H, -SH,-CN, -NO2, -NH2, -OH, alkynylamino, alkoxycarbonyl,
heterocycloyl, carboxy, -N(C1-C3 alkyl)-C(O)(C1-C3 alkyl),
-NHC(O)N(C1-C3 alkyl)C(O)NH(C1-C3alkyl), -NHC(O)NH(C1-C6 alkyl),
-NHSO2(C1-C3 alkyl), -NHSO2(aryl), alkoxyalkyl, alkylamino,
alkenylamino, di(C1-C3)amino, -C(O)O-(C1-C3)alkyl,
-C(O)NH-(C1-C3)alkyl, -C(O)N(C1-C3alkyl)2, -CH=NOH, -PO3H2,
-OPO3H2, haloalkyl, alkoxyalkoxy, carboxaldehyde, carboxamide,
cycloalkyl, cycloalkenyl, cycloalkynyl, cycloalkylalkyl, aryl, aroyl,
aryloxy, arylamino, biaryl, thioaryl, diarylamino, heterocyclyl, alkylaryl,
aralkenyl, aralkyl, alkylheterocyclyl, heterocyclylalkyl, sulfonyl, -S02-(C1-
C3 alkyl), -SO3-(C1-C3 alkyl), sulfonamide carbamate, aryloxyalkyl and
-C(O)NH(benzyl) groups; and,
R29, at each occurrence, is independently selected from the group consisting of
halogen, alkyl, alkenyl, alkynyl, alkoxy, alkenoxy, alkynoxy, thioalkoxy,
hydroxyalkyl, aliphatic acyl, -CF3, -CO2H, -SH, -CN, -NO2, -NH2, -OH,
alkynylamino, alkoxycarbonyl, heterocycloyl, carboxy, -N(C1-C3 alkyl)-
C(O)(C1-C3 alkyl), -NHC(O)N(C1-C3 alkyl)C(O)NH(C1-C3alkyl),
-NHC(O)NH(C1-C6 alkyl), -NHSO2(C1-C3 alkyl), -NHSO2(aryl),
alkoxyalkyl, alkylamino, alkenylamino, di(C1-C3)amino, -C(O)O-(C1-
C3)alkyl, -C(O)NH-(C1-C3)alkyl, -C(O)N(C1-C3alkyl)2, -CH=NOH,
-PO3H2, -OPO3H2, haloalkyl, alkoxyalkoxy, carboxaldehyde,
carboxamide, cycloalkyl, cycloalkenyl, cycloalkynyl, cycloalkylalkyl,
aryl, aroyl, aryloxy, arylamino, biaryl, thioaryl, diarylamino, heterocyclyl,
alkylaryl, aralkenyl, aralkyl, alkylheterocyclyl, heterocyclylalkyl, sulfonyl,
-SO2-(C1-C3 alkyl), -SO3-(C1-C3 alkyl), sulfonamide carbamate,
aryloxyalkyl and -C(O)NH(benzyl) groups;
wherein B, R4, R6, R7, R9, R10, R11, R18, R29, R30, R31 R32 and R33are
unsubstituted or substituted with at least one electron donating or electron
withdrawing group;
wherein when L is NR11, R4 and R11 taken together may form a ring;
and wherein R9 and R10 taken together may form a ring;
or a pharmaceutically acceptable salt thereof.
Some compounds of Formulae I-VI can be prepared from novel intermediates of
Formula VII and Formula VIII.
hydrogen, halogen, alkyl, alkenyl, alkynyl, alkoxy, alkenoxy, alkynoxy,
thioalkoxy, hydroxyalkyl, aliphatic acyl, -CF3, -SH, -OH,
-CO2H, -CN, -NO2, -NH2, alkynylamino, alkoxycarbonyl, heterocycloyl,
carboxy, -N(C1-C3 alkyl)-C(O)(C1-C3 alkyl), -NHC(O)N(C1-C3
alkyl)C(O)NH(C1-C3alkyl), -NHC(O)NH(C1-C6 alkyl), alkylamino,
-NHSO2(C1-C3 alkyl), -NHSO2(aryl), alkoxyalkyl, alkenylamino, di(C1-
C3)amino, -C(O)O-(C1-C3)alkyl, -C(O)NH-(C1-C3)alkyl,
-C(O)N(C1-C3alkyl)2, -CH=NOH, -PO3H2, -OPO3H2, haloalkyl,
alkoxyalkoxy, carboxaldehyde, carboxamide, cycloalkyl, cycloalkenyl,
cycloalkynyl, cycloalkylalkyl, aryl, aroyl, aryloxy, arylamino, biaryl, thioaryl,
diarylamino, heterocyclyl, alkylaryl, aralkenyl, aralkyl, alkylheterocyclyl,
heterocyclylalkyl, sulfonyl, -SO2-(C1-C3 alkyl), -SO3-(C1-C3 alkyl),
sulfonamide, carbamate, aryloxyalkyl and -C(O)NH(benzyl) groups; and
R18 and R34 are each independently selected from the group consisting of alkyl,
alkenyl, alkynyl, hydroxyalkyl, aliphatic acyl, alkynylamino, alkoxycarbonyl,
heterocycloyl, -CH=NOH, haloalkyl, alkoxyalkoxy, carboxaldehyde.
carboxamide, cycloalkyl, cycloalkenyl, cycloalkynyl, cycloalkylalkyl, aryl,
aroyl, aryloxy, arylamino. biaryl, thioaryl, diarylamino, heterocyclyl, alkylaryl,
aralkenyl, aralkyl, alkylheterocyclyl, heterocyclylalkyl, carbamate,
aryloxyalkyl, hydrogen and -C(O)NH(benzyl) groups;
wherein R18, R24, R25 and R34 are unsubstituted or substituted with
at least one electron donating or electron withdrawing
group;
and wherein R24 and R25 taken together may form a ring;
with the proviso that when R24 and R25 taken together form a ring, the ring formed is not
benzene. Presently preferred compounds of Formula VII have R34 as hydrogen; R18 as
aralkyl; and R24 and R25 each indpendently as hydrogen, lower alkyl or lower alkyl wherein
R24 and R25 are taken together to form a ring.
Formula VIII shows presently preferred novel intermediates.
Formula VIII
wherein R24 and R25 are each independently selected from the group consisting of
hydrogen, halogen, alkyl, alkenyl, alkynyl, alkoxy, alkenoxy, alkynoxy,
thioalkoxy, hydroxyalkyl, aliphatic acyl, -CF3, -SH, -OH,
-CO2H, -CN, -NO2, -NH2, alkynylamino, alkoxycarbonyl, heterocycloyl,
carboxy, -N(C1-C3 alkyl)-C(O)(C1-C3 alkyl), -NHC(O)N(C1-C3
alkyl)C(O)NH(C1-C3alkyl), -NHC(O)NH(C1-C6alkyl), -NHSO2(C1-C3
alkyl), -NHSO2(aryl), alkoxyalkyl, alkylamino, alkenylamino, di(C1-
C3)amino, -C(O)O-(C1-C3)alkyl, -C(O)NH-(C1-C3)alkyl, -C(O)N(C1-C3
alkyl)2, -CH=NOH, -PO3H2, -OPO3H2, haloalkyl, alkoxyalkoxy,
carboxaldehyde, carboxamide, cycloalkyl, cycloalkenyl, cycloalkynyl,
cycloalkylalkyl, aryl, aroyl, aryloxy, arylamino, biaryl, thioaryl,
diarylamino, heterocyclyl, alkylaryl, aralkenyl, aralkyl, alkylheterocyclyl,
heterocyclylalkyl, sulfonyl, -SO2-(C1-C3 alkyl), -SO3-(C1-C3 alkyl),
sulfonamido, carbamate, aryloxyalkyl and -C(O)NH(benzyl) groups;
R34 is selected from the group consisting of alkyl, alkenyl, alkynyl, hydroxyalkyl,
aliphatic acyl, alkynylamino, alkoxycarbonyi, heterocycloyl, -CH=NOH,
haloalkyl, alkoxyalkoxy, carboxaldehyde, carboxamide, cycloalkyl,
cycloalkenyl, cycloalkynyl, cycloalkylalkyl, aryl, aroyl, aryloxy, arylamino,
biaryl, thioaryl, diarylamino, heterocyclyl, alkylaryl, aralkenyl, aralkyl,
alkylheterocyclyl, heterocyclylalkyl, carbamate, aryloxyalkyl, hydrogen and
-C(O)NH(benzyl) groups; and,
R35, at each occurrence, is independently selected from the group consisting of
halogen, alkyl, alkenyl, alkynyl, alkoxy, alkenoxy, alkynoxy, thioalkoxy,
hydroxyalkyl, aliphatic acyl, -CF3, -CO2H, -SH, -CN, -NO2, -NH2, -OH,
alkynylamino, alkoxycarbonyl, heterocycloyl, carboxy, -N(C1-C3 alkyl)-
C(O)(C1-C3 alkyl), -NHC(O)N(C1-C3 alkyl)C(O)NH(C1-C3alkyl),
-NHC(O)NH(C1-C6 alkyl), -NHSO2(C1-C3 alkyl), -NHSO2(aryl),
alkoxyalkyl,alkylamino, alkenylamino, di(C1-C3)amino, -C(O)O-(C1-
C3)alkyl, -C(O)NH-(C1-C3)alkyl, -C(O)N(C1-C3alkyl)2, -CH=NOH,
-PO3H2, -OPO3H2, haloalkyl, alkoxyalkoxy, carboxaldehyde, carboxamide,
cycloalkyl, cycloalkenyl, cycloalkynyl, cycloalkylalkyl, aryl, aroyl,
aryloxy, arylamino, biaryl, thioaryl, diarylamino, heterocyclyl, alkylaryl,
aralkenyl, aralkyl, alkylheterocyclyl, heterocyclylalkyl, sulfonyl,
-SO2-(C1-C3 alkyl), -SO3-(C1-C3 alkyl), sulfonamido, carbamate,
aryloxyalkyl and -C(O)NH(benzyl) groups;
wherein R24, R25, R34 and R35 are unsubstituted or substituted with
at least one electron donating or electron withdrawing
group; and,
m is an integer of from 0 to 5. Presently preferred compounds of Formula VIII
have R34 as hydrogen; m as an integer of one to three and R35 at each occurrence as alkyl,
halogen, alkoxy, haloalkyl, sulfonyl, -OH or -CN.
Presently preferred compounds of Formula I include:
(3S)-3-[({[2-methyl-4-(2-methylpropyl)-6-oxo-l-(phenylmethyl)-l,6-dihydro-5-
pyrimidinyl]amino}carbonyl)amino]-3-(4-methylphenyl)propanoic acid, (3S)-3-(1,3-
benzodioxol-5-yl)-3-[( {[2-oxo-1-(phenylmethyl)-4-propyl-1,2-dihydro-3-
pyridinyl]amino}carbonyl)amino]propanoic acid, (3S)-3-{[({1 -[(2-chlorophenyI)methyl]-4-
ethyl-2-oxo-1,2-dihydro-3-pyridinyl} amino)carbonyl]amino} -3-(4-methylphenyl)propanoic
acid, (3S)-3-{[({l-[(2-chlorophenyl)methyl]-2-oxo-4-propyl-l,2-dihydro-3-
pyridinyl}amino)carbonyl]amino}-3-(4-methylphenyl)propanoic acid, (3S)-3-{[({1 -[(2-
chlorophenyl)methyl] -4-methyl-2 -oxo-1,2-dihydro-3 -pyridinyl} amino )carbonyl]amino} -3 -(4-
methylphenyl)propanoic acid, (3S)-3- {[({6-methyl-2-oxo-1 -(phenylmethyl)-4-
[(phenylmethyl)oxy]-1,2-dihydro-3-pyridinyl}amino)carbonyl]amino}-3-(4-
methylphenyl)propanoic acid, (3S)-3-{[({1 -[(2-chlorophenyl)methyl]-2,4-dimethyl-6-oxo-
1,6-dihydro-5-pyrimidinyl}amino)carbonyl]amino}-3-(4-methylphenyl)propanoic acid, (3S)-
3-{[({4-amino-1 -[(2-chlorophenyl)methyl]-6-methyl-2-oxo-1,2-dihydro-3-
pyridinyl}amino)carbonyl]amino}-3-(4-methylphenyl)propanoic acid, (3S)-3- {[({1 -[(2-
chlorophenyl)methyl]-4-methyl-2-oxo-1,2-dihydro-3 -pyridinyl} amino)carbonyl]amino} -3-[4-
(methyloxy)phenyl]propanoic acid, (3S)-3-{[({1 -[(2-chlorophenyl)methyl]-4-methy!-2-oxo-
1,2-dihydro-3-pyridinyl}amino)carbonyl]amino}-3-(3,4-dimethylphenyl)propanoic acid, (3S)-
3- {[({4-amino-1 -[(2-chlorophenyl)methyl]-2-oxo-1,2-dihydro-3-
pyridinyl}amino)carbonyl]amino}-3-(4-methylphenyl)propanoic acid, (3S)-3-{[({1 -[(2-
chlorophenyl)methyl]-4-hydroxy-2-oxo-l,2-dihydro-3-pyridinyl}amino)carbonyl]amino}-3-
(4-methylphenyl)propanoic acid, (3S)-3-[({[ 1 -[(2-chlorophenyl)methyl]-4-( 1,4-oxazinan-4-
yl)-2-oxo-l,2-dihydro-3-pyridinyl]amino}carbonyl)amino]-3-(4-methylphenyl)propanoic
acid, (3S)-3-[({[l-[(2-chlorophenyI)methyl]-2-oxo-4-(propylamino)-1,2-dihydro-3-
pyridinyl]amino}carbonyl)amino]-3-(4-methylphenyl)propanoic acid, (3S)-3-{[({l-[(2-
bromophenyl)methyl]-4-methyl-2-oxo-l,2-dihydro-3-pyridinyl}amino)carbonyl]amino}-3-(4-
methylphenyl)propanoic acid, (3S)-3-{[({l-[(2-chlorophenyl)methyl]-4-hydroxy-2-oxo-l,2-
dihydro-3-pyridinyl}amino)carbonyl]amino[-3-[3-methyl-4-(methyloxy)phenyl]propanoic
acid, (3S)-3-{[({1 -[(2-chlorophenyl)methyl]-2-oxo-4-phenyl-1,2-dihydro-3-
pyridinyl}amino)carbonyI]amino}-3-(4-methylphenyl)propanoic acid, (3S)-3-{[(11-[(2-
chlorophenyl)methyl]-4-[(2-{[2-(methyloxy)ethyl]oxy}ethyl)oxy]-2-oxo-l,2-dihydro-3-
pyridinyl}amino)carbonyl]amino}-3-(4-methylphenyl)propanoic acid, (3S)-3-{[({l-[(2-
chlorophenyl)methyl]-4-hydroxy-6-methyl-2-oxo-l,2-dihydro-3-
yridinyl}amino)carbonyl]amino}-3-(4-methylphenyl)propanoic acid, (3S)-3-{[({1-[(2-
chlorophenyl)methyl]-4-[( 1,1 -dimethylethyl)amino] -2-oxo-1,2-dihydro-3-
pyridinyl}amino)carbonyl]amino}-3-(4-methylphenyl)propanoic acid, (3S)-3-{[({1-[(2-
chlorophenyl)methyl]-4-hydroxy-2-oxo-l,2-dihydro-3-pyridinyl}amino)carbonyl]amino}-3-
phenylpropanoic acid, (3S)-3-{[({ l-[(2-chlorcphenyl)methyl]-4-[4-methyltetrahydro-1(2H)-
pyrazinyl]-2-oxo-1,2-dihydro-3 -pyridinyl}amino)carbonyl]amino}-3-(4-
methylphenyl)propanoic acid, (3S)-3- {[({1 -[(2-chlorophenyl)methyl]-4-hydroxy-2-oxo-1,2-
dihydro-3-pyridinyl}amino)carbonyl]amino}--3-[4-(methyloxy)phenyl]propanoic acid,
(3S)-3-{[({1-[(2-chlorophenyl)methyl]-4-hydroxy-2-oxo-1,2-dihydro-3-
pyridinyl}amino)carbonyl]amino}-3-(3,5-dimethylphenyl)propanoic acid, (3S)-3-{[({1-[(2-
chlorophenyl)methyl]-4-hydroxy-2-oxo-1,2-dihydro-3-pyridinyl}amino)carbonyl]amino}-3-
ß-methylphenytypropanoic acid, (3S)-3-{[({l-[(2-chlorophenyl)methyl]-4-hydroxy-2-oxo-
1,2-dihydro-3-pyridinyl}amino)carbonyl]amino}-3-[3-(methyloxy)phenyl]propanoic acid,
(3S)-3-[3,5-bis(methyloxy)phenyl]-3- {[({1 -[(2-chlorophenyl)methyl]-4-hydroxy-2-oxo-1,2-
dihydro-3-pyridinyl}amino)carbonyl]amino}propanoicacid, (3S)-3-{[({l-[(2-
chlorophenyl)methyl]-4-hydroxy-2-oxo-1,2-dihydro-3-quinolinyl}amino)carbonyl]amino}-3-
(4-methylphenyl)propanoic acid, (3S)-3-{[({1-[(2-chlorophenyl)methyl]-4-hydroxy-2-oxo-
1,2-dihydro-3-pyridinyl}amino)carbonyl]amino}-3-[3-(trifluoromethyl)phenyl]propanoic
acid, (3S)-3-{[({1-[(2-chlorophenyl)methyl]-4-[({ethyl[(ethylamino)carbonyl]
amino}carbonyl)amino]-2-oxo-1,2-dihydro-3 -pyridinyl}amino)carbonyl]amino} -3-(4-
methylphenyl)propanoic acid, (3S)-3-{[({4-( 1 -azetanyl)-1-[(2-chlorophenyl)methyl]-2-oxo-
1,2-dihydro-3-yridinyl}amino)carbonyl]amino}-3-(4-methylphenyl)propanoic acid, (3S)-3-
[({[ 1 -[(2-chlorophenyl)methyl]-4-( {2-[(2- {[2-(methyloxy)ethyl]oxy} ethyl)oxy ]ethyl}
oxy)-2-oxo-1,2-dihydro-3-pyridinyl]amino}carbonyl)amino]-3-(4-methylphenyl)propanoic
acid, (3S)-3-{[({1-[(2-fluorophenyl)methyl]-4-hydroxy-2-oxo-1,2-dihydro-3-
pyridinyl}amino)carbonyl]amino}-3-(4-methylphenyl)propanoic acid, (3S)-3-{[({l-[(2-
chloro-6-fluorophenyl)methyl]-4-hydroxy-2-oxo-1,2-dihydro-3-
pyridinyl}amino)carbonyl]amino}-3-(4-methylphenyl)propanoic acid, (3S)-3-{[({1-[(2-
chlorophenyl)methyl]-5-methyl-2-oxo-1,2-dihydro-3-pyridinyl}amino)carbonyl]ammo}-3-(4-
methylphenyl)propanoic acid, (3S)-3-(1,3-benzodioxol-5-yl)-3-((((2-oxo-l-((4-
(trifluoromethyl)phenyl)methyl)-1,2 dihydro-3-pyridinyl)amino)carbonyl)amino)propanoic
acid, (3S)-3-((((1-((2-chloropheny])methyl)-2-oxo-1,2-dihydro-3-
pyridinyl)amino)carbonyl)amino)-3-(4-methylphenyl)propanoic acid, (3S)-3-((((1-((2-
fluorophenyl)methyl)-2-oxo-1,2-dihydro-3-pyridinyl)amino)carbonyl)ammo)-
3-(4-methylphenyl)propanoic acid, (3S)-3-((((1-((2-bromophenyl)methyl)-2-oxo-1,2-dihydro-
3-pyridinyl)amino)carbonyl)amino)-3-(4-methylphenyl)propanoic acid, (3S)-3-((((1-((2,4-
dichlorophenyl)methyl)-2-oxo-1,2-dihydro-3 -pyridinyl)amino)carbonyl)
amino)-3-(4-methylphenyI)propanoic acid, (3S)-3-((((1 -((2-chloro-6-fluorophenyl)methyl)-2-
oxo-1,2-dihydro-3-pyridinyl)amino)carbonyl)amino)-3-(4-methylphenyl)propanoic acid, (3S)-
3-(((( 1 -((2-chlorophenyl)methyl)-4-hydroxy-2-oxo-1,2-dihydro-3-
pyridinyl)amino)carbonyl)amino)-3-(4-trifluoromethyl)oxy)phenyl)propanoic acid, (3S)-3-
[({[1-(2-chloro-6-methoxybenzyl)-2-oxo-1,2-dihydropyridin-3-yl]amino}carbonyl)amino]-3-
(4-methylphenyl)propanoic acid, 4-{[3-[({[(1S)-2-carboxy-1-(4-
methylphenyl)ethyl]amino}carbonyl)amino]-1-(2-chlorobenzyl)-2-oxo-1,2-dihydropyridin-4-
yl]amino}benzoic acid, (3S)-3-{[({1-(2-chlorobenzyl)-4-[(2,2-dimethylpropanoyl)amino]-2-
oxo-1,2-dihydropyridin-3-yl}amino)carbonyl]amino}-3-(4-methylphenyl)propanoic acid,
(3S)-3-[({[4-{[(tert-butylamino)carbonyl]amino}-1-(2-chlorobenzyl)-2-oxo-1,2-
dihydropyridin-3-yl]amino}carbonyl)amino]-3-(4-methylphenyl)propanoic acid, (3S)-3-[({[1-
(2-cyanobenzyl)-4-hydroxy-2-oxo-1,2-dihydropyridin-3-yl]amino}carbonyl)amino]-3-(4-
methylphenyl)propanoic acid, (3S)-3-[({[1 -(2-chlorobenzyl)-4-hydroxy-2-oxo-1,2-
dihydropyridin-3-yl]am ino}carbonyl)amino]-3-(2,3 -dihydro-1,4-benzodioxin-6-yl)propanoic
acid, (3S)-3-[({[ 1 -(2-chlorobenzyl)-4-hydroxy-2-oxo-1,2-dihydropyridin-3-
yl]amino}carbonyl)amino]-3-(7-methoxy-1,3-benzodioxol-5-yl)propanoic acid, (3S)-3-[({[1-
(2-chlorobenzyl)-4-hydroxy-2-oxo-1,2-dihydropyridin-3-yl]amino}carbonyl)amino}-3-(3-
ethoxy-4-methoxyphenyl)propanoic acid, (3S)-3-[({[1-(2-chlorobenzyl)-4-hydroxy-2-oxo-
1,2-dihydropyridin-3 -yl]amino} carbonyl)amino]-3-(3,4-dimethoxyphenyl)propanoic acid,
(3S)-3-[({[1-(4-chIorobenzyl)-4-hydroxy-2-oxo-1,2-dihydropyridin-3-
yl]amino}carbonyl)amino]-3-(4-methylphenyl)propanoic acid, (3S)-3-[({[1-(2-chloro-6-
methoxybenzyl)-4-hydroxy-2 -oxo-1,2-dihydropyridin-3 -yl]amino}carbonyl)amino]-3-(4-
methylphenyl)propanoic acid, (3S)-3-[({[1 -(2-chlorobenzyl)-4-hydroxy-5-methyl-2-oxo-1,2-
dihydropyridin-3-yl]amino}carbonyl)amino]-3-(4-methylphenyl)propanoic acid, (3S)-3-[({[1-
(2,6-difluorobenzyl)-4-hydroxy-2-oxo-1,2-dihydropyridin-3-yl]amino}carbonyl)amino]-3-(4-
methylphenyl)propanoic acid, (3S)-3-[({[1-(2-chloro-6-methoxybenzyl)-4-hydroxy-2-oxo-
1,2-dihydropyridin-3-yl]amino}carbonyl)amino]-3-(3,5-dimethoxyphenyl)propanoic acid,
(3S)-3-[({[l-(2-chlorobenzyl)-4-hydroxy-2-oxo-1,2-dihydropyridin-3-
yl]amino}carbonyl)amino]-3-(3,4-diethoxyphenyl)propanoic acid, (3S)-3-[({[1-(2-
chlorobenzyl )-4-hydroxy-2 -oxo-1,2 -dihydropyridin-3 -yl] amino}carbony l)amino ]-3-(3-
ethoxyphenyl)propanoic acid, (3S)-3-[({[1-(2-chlorobenzyl)-4-hydroxy-2-oxo-1,2-
dihydropyridin-3-yl]amino}carbonyl)amino]-3-(3-methoxy-4-methylphenyl)propanoic acid,
(3S)-3-[({[1-(2-chlorobenzyl)-4-hydroxy-2-oxo-1,2-dihydropyridin-3-
yl]amino}carbonyl)amino]-3-(3,5-dimethoxy-4-methylphenyl)propanoic acid, (3S)-3-[({[1-
(2-chlorobenzyl)-4-hydroxy-2-oxo-1,2-dihydropyridin-3-yl]amino}carbonyl)amino]-3-(3,4-
dimethylphenyl)propanoic acid, (3S)-3-[({[1-(2-chlorobenzyl)-5-ethyl-4-hydroxy-2-oxo-1,2-
dihydropyridin-3-yl]amino} carbonyl)amino]-3-(4-methylphenyl)propanoic acid, (3S)-3-
{[({1-[2-chloro-5-(trifluoromethyl)benzyl]-4-hydroxy-2-oxo-1,2-dihydropyridin-3-
yl}amino)carbonyl]amino}-3-(4-methylphenyl)propanoic acid, (3S)-3-[({[1-(2-chloro-6-
methoxybenzyl)-4-hydroxy-2-oxo-l ,2-dihydropyridin-3-yl]amino}carbonytyairiino]-3-3-
methylphenyl)propanoic acid, (3S)-3-[({[1-(2-chloro-6-methylbenzyl)-4-hydroxy-5-methyl-2-
oxo-1,2-dihydropyridin-3-yl]amino}carbonyl)amino]-3-(4-methylphenyl)propanoic acid,
(3S)-3-[({[1-(2-chlorobenzyl)-4-hydroxy-2-oxo-2,5,6,7-tetrahydro-1H-cyclopenta[b]pyridin-
3-yl]amino}carbonyl)amino]-3-(4-methylphenyl)propanoic acid, (3S)-3-[({[1-(2,6-
dimethoxybenzyl)-4-hydroxy-2-oxo-1,2-dihydropyridin-3-yl]amino}carbonyl)amino]-3-(4-
methylphenyl)propanoic acid, (3S)-3-[({[1-(2-chlorobenzyl)-4-hydroxy-2-oxo-1,2-
dihydropyridin-3-yl]amino}carbonyl)amino]-3-(3-propoxyphenyl)propanoic acid, (3S)-3-
[({[1-(2-chlorobenzyl)-4-hydroxy-2-oxo-5-propyl-1,2-dihydropyridin-3-
yl]amino}carbonyl)amino]-3-(3-ethoxyphenyl)propanoic acid, (3S)-3-[({[1 -(2-chlorobenzyl)-
4-hydroxy-5,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl]amino}carbonyl)amino]-3-(4-
methylphenyl)propanoic acid, (3S)-3-[({[1-(2-chlorobenzyl)-4-hydroxy-2-oxo-5-propyl-1,2-
dihydropyridin-3-yl]amino}carbonyl)amino]-3-(3,4-diethoxyphenyl)propanoic acid, (3S)-3-
(3-butoxyphenyl)-3-[({[1-(2-chlorobenzyl)-4-hydroxy-2-oxo-1,2-dihydropyridin-3-
yl]aminolcarbonyl)amino]propanoic acid, (3S)-3-{[({1-[2-chloro-5-(methylsulfonyl)benzyl]-
4-hydroxy-2-oxo-1,2-dihydropyridin-3-yl}amino)carbonyl]amino}-3-(4-
methylphenyl)propanoic acid, (3S)-3-[({[1-(2-chlorobenzyl)-4-hydroxy-2-oxo-1,2-
dihydropyridin-3-yl]amino}carbonyl)amino]-3-[3-(2-methoxyethoxy)phenyl]propanoic acid,
(3S)-3-[({[1-(2-chlorobenzyl)-4-hydroxy-2-oxo-1,2-dihydropyridin-3-
yl]amino}carbonyl)amino]-3-(3,4-dipropoxyphenyl)propanoic acid, (3S)-3-[({[]-(2-
chlorobenzyl)-4-hydroxy-2-oxo-1,2-dihydropyridin-3-yl]amino}carbonyl)amino ]-3-[3-
(difluoromethoxy)phenyl]propanoic acid, (3S)-3-[( {[ 1 -(2-chlorobenzyl)-4-hydroxy-5-methyl-
2-oxo-1,2-dihydropyridin-3-yl]amino}carbonyl)amino]-3-(3,4-diethoxyphenyl)propanoic
acid, (3S)-3-[({[1-(2-chlorobenzyl)-4-hydroxy-5-methyl-2-oxo-1,2-dihydropyridin-3-
yl]amino}carbonyl)amino]-3-(3-ethoxyphenyl)propanoic acid, (3S)-3-[({[1-(2-chloro-6-
methylbenzyl)-4-hydroxy-5,6-dimethyl-2-oxo-1,2-dihydropyridin-3-
yl]amino}carbonyl)amino]-3-(3,4-diethoxyphenyl)propanoic acid, (3S)-3-[({[1-(2-chloro-6-
cyanobenzyl)-4-hydroxy-2-oxo-1,2-dihydropyridin-3-yl]amino}carbonyl)amino]-3-(4-
methylphenyl)propanoic acid, 3-[({[1-(2-chlorobenzyl)-4-hydroxy-2-oxo-1,2-dihydropyridin-
3-yl]amino}carbonyl)amino]-3-(2-naphthyl)propanoic acid and (3S)-3-[({[1-(2-
chlorobenzyl)-4-hydroxy-5,6-dimethyl-2-oxo-1,2-dihydropyridin-3-
yl]amino}carbonyl)amino]-3-(3,4-diethoxyphenyl)propanoic acid, (3S)-3-[({[1-(2-chloro-6-
methoxybenzyl)-4-hydroxy-5-methyl-2-oxo-1,2-dihydropyridin-3-yl]amino}carbonyl)amino]-
3-(3,4-diethoxyphenyl)propanoic acid, (3S)-3-[({[1-(2-chlorobenzyl)-4-hydroxy-2-oxo-1,2-
dihydropyridin-3-yl]amino}carbonyl)amino]-3-(3-isopropoxyphenyl)propanoic acid, (3S)-3-
[({[1-(2-chlorobenzyl)-4-hydroxy-5-methyl-2-oxo-1,2-dihydropyridin-3-
yl]amino}carbonyl)amino]-3-(4-methoxyphenyl)propanoic acid, (3S)-3-[({[1-(2-chloro-6-
methylbenzyl)-4-hydroxy-2-oxo-2,5,6,7-tetrahydro-1H-cyclopenta[b]pyridin-3-
yl]amino}carbonyl)amino]-3-(3-ethoxyphenyl)propanoic acid, (3S)-3-[({[1-(2-chloro-6-
ethoxybenzyl)-4-hydroxy-2-oxo-1,2-dihydropyridin-3-yl]amino}carbonyl)amino]-3-(3-
ethoxyphenyl)propanoic acid, (3S)-3-[({[1-(2-chloro-6-ethoxybenzyl)-4-hydroxy-5-methyl-2-
oxo-1,2-dihydropyridin-3-yl]amino}carbonyl)amino]-3-(3-isopropoxyphenyl)propanoic acid.
(3S)-3-[({[1-(2-chloro-6-ethoxybenzyl)-4-hydroxy-2-oxo-2,5,6.7-tetrahydro-1H-
cyclopenta[b]pyridin-3-yl]amino}carbonyl)amino]-3-(3-ethoxyphenyl)propanoic acid. (3S)-3-
[({[1-(2-chloro-6-ethoxybenzyl)-4-hydroxy-5-methyl-2-oxo-1,2-dihydropyridin-3-
yl]amino}carbonyl)amino]-3-(1-methyl-1H-indol-5-y])propanoic acid, (3S)-3-[({[1-(2-chloro-
6-ethoxybenzyl)-4-hydroxy-5-methyl-2-oxo-1,2-dihydropyridin-3-yl]amino}carbonyl)amino]-
3-(2,3-dihydro-1-benzofuran-5-yl)propanoic acid, (3S)-3-[({[1-(2-chloro-6-ethoxybenzyl)-4-
hydroxy-2-oxo-2,5,6,7-tetrahydro-1H-cyclopenta[b]pyridin-3-yl]amino}carbonyl)amino]-3-
(3,5-diethoxyphenyl)propanoic acid, (3S)-3-[({[5-chloro-1-(2-chloro-6-ethoxybenzyl)-4-
hydroxy-2-oxo-1,2-dihydropyridin-3-yl]amino \ carbonyl)amino]-3-(3-
ethoxyphenyl)propanoic acid, (3S)-3-[({[1-(2-chloro-6-ethoxybenzyl)-4-hydroxy-2-oxo-1,2-
dihydropyridin-3-yl]amino}carbonyl)amino]-3-(3-isopropoxyphenyl)propanoic acid, (3S)-3-
[({[1-(2-chloro-6-ethoxybenzyl)-4-hydroxy-2-oxo-2,5,6,7-tetrahydro-1H-
cyclopenta[b]pyridin-3-yl]amino}carbonyl)amino]-3-(3-propoxyphenyl)propanoic acid, (3S)-
3-[( {[ 1 -(2-chloro-6-ethoxybenzyl)-4-hydroxy-2-oxo-2,5,6,7-tetrahydro-1H-
cyclopenta[b]pyridin-3-yl]amino}carbonyl)amino]-3-phenylpropanoic acid, (3S)-3-[({[1-(2-
chlorobenzyl)-4-hydroxy-2-oxo-2.5,6,7-tetrahydro-1H-cyclopenta[b]pyridin-3-
yl]amino}carbony)amino]-3-(1,3-diethyl-2-oxo-2,3-dihydro-1H-benzimidazol-5-
yl)propanoic acid, (3S)-3-[({[1-(2-chloro-6-ethoxybenzyl)-4-hydroxy-5-methyl-2-oxo-1,2-
dihydropyridin-3-yl]amino}carbonyl)amino]-3-[3-(trifluoromethoxy)phenyl]propanoic acid,
(3S)-3-[({[1-(2-chloro-6-ethoxybenzyl)-4-hydroxy-5,6-dimethyl-2-oxo-1,2-dihydropyridin-3-
yl]amino}carbonyl)amino]-3-(3-isopropoxyphenyl)propanoic acid, (3S)-3-[({[1-(2-
chlorobenzyl)-4-hydroxy-2-oxo-2,5,6,7-tetrahydro-1H-cyclopenta[b]pyridin-3-
yl]amino}carbonyl)amino]-3-(1-methyl-1H-indol-5-yl)propanoic acid, (3S)-3-[({[1 -(2-chloro-
6-ethoxybenzyl)-5-cyclopropyl-4-hydroxy-2-oxo-1,2-dihydropyridin-3-
yl]amino}carbonyl)amino]-3-(3-isopropoxyphenyl)propanoic acid, (3S)-3-[({[1-(2-chloro-6-
ethoxybenzyl)-5-cyclopropyl-4-hydroxy-2-oxo-1,2-dihydropyridin-3-
yl]amino}carbonyl)amino]-3-(4-methylphenyl)propanoic acid, (3S)-3-[( {[1-(2-chloro-5-
methoxybenzyl)-4-hydroxy-5-methyl-2-oxo-1,2-dihydropyridin-3-yl]amino} carbonyl)amino]-
3-(4-methylphenyl)propanoic acid, (3S)-3-[({[1-(2-chloro-6-ethoxybenzyl)-4-hydroxy-6-
methyl-2-oxo-1,2-dihydropyridin-3-yl]amino}carbonyl)amino]-3-(3-
isopropoxyphenyl)propanoic acid, (3S)-3-[({[1-(2-chloro-6-ethoxybenzyl)-4-hydroxy-5-
methyl-2-oxo-1,2-dihydropyridin-3 -yl]amino}carbonyl)amino]-3-(1-methyl-1H-indol-6-
yl)propanoic acid, (3S)-3-[({[1-(2-chloro-6-ethoxybenzyl)-4-hydroxy-2-oxo-2,5,6,7-
tetrahydro-1H-cyclopenta[b]pyridin-3-yl]amino}carbonyl)amino]-3-[3-
(cyclopropyloxy)phenyl]propanoic acid, (3S)-3-[({[1-(2-chlorobenzyl)-4-hydroxy-2-oxo-
2,5,6,7-tetrahydro-1H-cyclopenta[b]pyridin-3-yl]amino}carbonyl)amino]-3-[3-
(cyclopropylmethoxy)phenyl]propanoic acid, (3S)-3-[( {[1-(2-chloro-6-ethoxybenzyl)-4-
hydroxy-2-oxo-2,5,6,7-tetrahydro-1H-cyclopenta[b]pyridin-3-yl]amino}carbonyl)amino]-3-
[3-(cyclopropylmethoxy)phenyl]propanoic acid, (3S)-3-[({[1-(2-chlorobenzyl)-4-hydroxy-2-
oxo-2,5,6,7-tetrahydro-1H-cyclopenta[b]pyridin-3-yl]amino}carbonyl)amino]-3-(3,5-
dimethylphenyl)propanoic acid, (3S)-3-{[({1-[(2-chlorophenyl)methyl]-4-hydroxy-2-oxo-
2,5,6,7-tetrahydro-1H-cyclopenta[b]pyridin-3-yl]amino)carbonyl]amino}-3-{3-
[(difluoromethyl)oxy]phenyl}propanoic acid, (3S)-3-{[({1-[(2-chlorophenyl)methyl]-4-
hydroxy-2-oxo-2,5,6,7-tetrahydro-1H-cyclopenta[b]pyridin-3-yl}amino)carbonyl]amino}-3-
{3-[(1,1,2,2-tetrafluoroethyl)oxy]phenyl}propanoic acid, (3S)-3-{[({1-[(2-
chlorophenyl)methyl]-4-hydroxy-2-oxo-2,5,6,7-tetrahydro-1H-cyclopenta[b]pyridin-3-
yl}amino)carbonyl]amino}-3-(1-ethyl-1H-indol-5-yl)propanoic acid and (3S)-3-{[({1 -[(2-
chlorophenyl)methyl]-4-hydroxy-2-oxo-2,5,,6,7-tetrahydro-1H-cyclopenta[b]pyridin-3-
yl}amino)carbonyl]amino}-3-[3-(diethylamino)phenyl]propanoic acid, (3S)-3-[({[1-(2-
chlorobenzyl)-4-hydroxy-5-methyl-2-oxo-1,2-dihydropyridin-3-yl]amino}carbonyl)amino]-3-
(4-methylphenyl)propanoic acid, (3S)-3-[({[1 -(2-chlorobenzyl)-4-hydroxy-2-oxo-2,5,6,7-
tetrahydro-1H-cyclopenta[b]pyridin-3-yl]amino}carbonyl)amino]-3 -(4-
methylphenyl)propanoic acid, (3S)-3-[({[1-(2-chloro-6-ethoxybenzyl)-4-hydroxy-5-methyl-2-
oxo-1,2-dihydropyridin-3-yl]amino}carbonyl)amino]-3-(4-methylphenyl)propanoic acid,
(3S)-3-[( {[1-(2-chloro-6-ethoxybenzyl)-4-hydroxy-5-methyl-2-oxo-1,2-dihydropyridin-3-
yl]amino}carbonyl)amino]-3-(3-ethoxyphenyl)propanoic acid, (3S)-3-[({[1-(2-chlorobenzyl)-
4-hydroxy-2-oxo-2,5,6,7-tetrahydro-1H-cyclopenta[b]pyridin-3-yl]amino} carbonyl)amino]-3-
(3-isopropoxyphenyl)propanoic acid, (3S)-3-[({[1-(2-chloro-6-ethoxybenzyl)-4-hydroxy-5-
methyl-2-oxo-1,2-dihydropyridin-3-yl]amino}carbonyl)amino]-3-(6-methoxy-2-
naphthyl)propanoic acid, (3S)-3-[( {[ 1 -(2-chlorobenzyl)-4-hydroxy-2-oxo-2,5,6,7-tetrahydro-
1H-cyclopenta[b]pyridin-3-yl]amino}carbonyl)amino]-3-(3-methylphenyl)propanoic acid,
(3S)-3-[({[1-(2-chlorobenzyl)-4-hydroxy-5-methyl-2-oxo-1,2-dihydropyridin-3-
yl]amino}carbonyl)amino]-3-[3-(diethylamino)phenyl]propanoic acid, and
(3S)-3-{[({1-[(2-chloro-6-methylphenyl)methyl]-4-hydroxy-2-oxo-2,5,6,7-tetrahydro-1H-
cyclopenta[b Jpyridin-3-yl}amino)carbonyl]amino}-3-( 1-methyl-1H-indol-5-yl)propanoic
acid, (3S)-3-{[({1-[(2-chlorophenyl)methyl]-4-hydroxy-2-oxo-2,5,6,7-tetrahydro-1H-
cyclopenta[b]pyridin-3-yl}amino)carbonyl]amino}-3-{3-
[(methylsulfonyl)amino]phenyl}propanoic acid, (3S)-3-{[( {1-[(2-chloro-6-
methylphenyl)methyl]-4-hydroxy-2-oxo-2,5,6,7-tetrahydro-1H-cyc-openta[b]pyridin-3-
yl}amino)carbonyl]amino}-3-{3-[(methylsulfonyl)amino]phenyl}propanoic acid, (3S)-3-
{[({1-[(2-chlorophenyl)methyl]-4-hydroxy-2-oxo-2,5,6,7-tetrahydio-1H-
cyclopenta[b]pyridin-3-yl}amino)carbonyl]amino}-3-{3-
[methyl(methylsulfonyl)amino]phenyl}propanoic acid, (3S)-3-{[({1-[(2-chloro-6-
methylphenyl)methyl]-4-hydroxy-2-oxo-2,5,6,7-tetrahydro-1H-cyclopenta[b]pyridin-3-
yl}amino)carbonyl]amino}-3-{3-[methyl(methylsulfonyl)amino]phenyl}propanoic acid, (3S)-
3-{[({1-[(2-chlorophenyl)methyl]-4-hydroxy-2-oxo-2,5,6,7-tetrahydro-1H-
cyclopenta[b]pyridin-3-yl}amino)carbonyl]amino}-3-{3-
[ethyl(methylsulfonyl)amino]phenyl}propanoic acid, (3S)-3-{[({1-[(2-chloro-6-
methylphenyl)methyl]-4-hydroxy-2-oxo-2,5,6,7-tetrahydro-1H-cyclopenta[b]pyridin-3-
yl} amino)carbonyl]amino} -3- {3-[ethyl(methylsulfonyl)amino jphenyl} propanoic acid, (3S)-3-
{[({1-[(2-chloro-6-methylphenyl)methyl]-4-hydroxy-2-oxo-2,5,6,7-tetrahydro-1H-
cyclopenta[b]pyridin-3-yl}amino)carbonyl]amino} -3-(1 H-indol-5-yl)propanoic acid and
pharmaceutically acceptable salts thereof of the above compounds.
Presently preferred compounds of Formula VII include:
5-(2-chlorobenzyl)-3,5-dihydro[1,3]oxazolo[4,5-c]pyridine-2,4-dione, 5-(2-chlorobenzyl)-6-
methyl-3,5-dihydro[1,3]oxazolo[4,5-c]pyridine-2,4-dione, 5-(2-fluorobenzyl)-3,5-
dihydro[1,3]oxazolo[4,5-c]pyridine-2,4-dione, 5-(2-chloro-6-fluorobenzyl)-3,5-
dihydro[1,3]oxazolo[4,5-c]pyridine-2,4-dione, 5-benzyl-6-methyl-3,5-
dihydro[1,3]oxazolo[4,5-c]pyridine-2,4-dione, 5-benzyl-3,5-dihydro[1,3]oxazolo[4,5-
c]pyridine-2,4-dione, 5-(2,5-dimethylbenzyl)-3,5-dihydro[1,3]oxazolo[4,5-c]pyridine-2,4-
dione, 5-(2-methylbenzyl)-3,5-dihydro[1,3]oxazolo[4,5-c]pyridine-2,4-dione, 5-(2,4-
dichlorobenzyl)-3,5-dihydro[1,3]oxazolo[4,5-c]pyridine-2,4-dione, 5-(2-methoxybenzyl)-3,5-
dihydro[1,3]oxazolo[4,5-c]pyridine-2,4-dione, 5-(2,5-difluorobenyl)-3,5-
dihydro[1,3]oxazolo[4,5-c]pyridine-2,4-dione, 5-[2-chloro-5-(methylthio)benzyl]-3,5-
dihydro[1,3]oxazolo[4,5-c]pyridine-2,4-dione, 5-(4-fluorobenzyl)-3,5-
dihydro[1,3]Oxazolo[4,5-c]pyridine-2,4-dione, 5-(2-chloro-5-methoxybenzyl)-3,5-
dihydro[1,3]oxazolo[4,5-c]pyridine-2,4-dione, 5-[3,5-bis(trifluoromethyl)benzyl]-3,5-
dihydro[1,3]oxazolo[4,5-c]pyridine-2,4-dione, 5-(4-tert-butylbenzyl)-3,5-
dihydro[ 1,3]oxazolo[4,5-c]pyridine-2,4-dione, 5-(3-chlorobenzyl)-3,5-
dihydro[1,3]oxazolo[4,5-c]pyridine-2,4-dione, 5-(4-chlorobenzyl)-3,5-
dihydro[1,3]oxazolo[4,5-c]pyridine-2,4-dione, 5-[3-(trifluoromethyl)benzyl]-3,5-
dihydro[1,3]oxazolo[4,5-c]pyridine-2,4-dione, 5-(2-bromobenzyl)-3,5-
dihydro[1,3]oxazolo[4,5-c]pyridine-2,4-dione, 5-(3,4-dichlorobenzyl)-3,5-
dihydro[1,3]oxazolo[4,5-c]pyridine-2,4-dione, 5-(4-methylbenzyl)-3,5-
dihydro[1,3]oxazolo[4,5-c]pyridine-2,4-dione, 5-(2-chloro-6-methoxybenzyl)-3,5-
dihydro[1,3]oxazolo[4,5-c]pyridine-2,4-dione, 5-[4-(trifluoromethyl)benzyl]-3,5-
dihydro[1,3]oxazolo[4,5-c]pyridine-2,4-dione, 5-(3-methylbenzyl)-3,5-
dihydro[1,3]oxazolo[4,5-c]pyridine-2,4-dione, 5-(pyridin-2-ylmethyl)-3,5-
dihydro[1,3]oxazolo[4,5-c]pyridine-2,4-dione, 5-(2-chlorobenzyl)-7-methyl-3,5-
dihyuro[1,3]oxazolof[4,5-c]pyridine-2,4-dione, 5-(2,4-difluorobenzyl)-3,5-
dihydro[1, 3]oxazolo[4,5-c]pyridine-2,4-dione, 5-(2,6-difluorobenzyl)-3,5-
dihydro[1,3]oxazolo[4,5-c]pyridine-2,4-dione, 5-[3-(trifluoromethoxy)benzyl]-3,5-
dihydro[1,3]oxazolo[4,5-c]pyridine-2,4-dione, 5-[4-(trifluoromethoxy)benzyl]-3,5-
dihydro[1,3]oxazolo[4,5-c]pyridine-2,4-dione, 5-[2-(trifluoromethyl)benzyl]-3,5-
dihydro[1,3]oxazolo[4,5-c]pyridine-2,4-dione, 5-(3-methoxybenzyl)-3,5-
dihydro[ 1,3]oxazolo[4,5-c]pyridine-2,4-dione, 5-(2,3-dichlorobenzyl)-3,5-
dihydro[1,3]oxazolo[4,5-c]pyridine-2,4-dione, 5-(3,5-dimethylbenzyl)-3,5-
dihydro[1,3]oxazolo[4,5-c]pyridine-2,4-dione, 5-(2-chlorobenzyl)-7-pentyl-3,5-
dihydro[1,3]oxazolo[4,5-c]pyridine-2,4-dione, 5-(2,4-dichlorobenzyl)-7-methyl-3,5-
dihydro[1,3]oxazolo[4,5-c]pyridine-2,4-dione, 5-(2-chlorobenzyl)-7-ethyI-3,5-
dihydro[1,3]oxazolo[4,5-c]pyridine-2,4-dione, 7-butyl-5-(2-chlorobenzyl)-3,5-
dihydro[1,3]oxazolo[4,5-c]pyridine-2,4-dione, 5-[2-chloro-5-(trifIuoromethyl)benzyl]-3,5-
dihydro[1,3]oxazolo[4,5-c]pyridine-2,4-dione, 5-(2,6-dichlorobenzyl)-3,5-
dihydro[1,3]oxazolo[4,5-c]pyridine-2,4-dione, 5-(2-chloro-5-fluorobenzyl)-3,5-
dihydro[1,3]oxazolo[4,5-c]pyridine-2,4-dione, 5-(2-chloro-6-methylbenzyl)-7-methyl-3,5-
dihydro[1,3]oxazolo[4,5-c]pyridine-2,4-dione, 5-(4-chlorobenzyl)-7-methyl-3,5-
dihydro[1,3]oxazolo[4,5-c]pyridine-2,4-dione, 5-(2-chlorobenzyl)-5,6,7,8-tetrahydro-2H-
cyclopenta[b][1,3]oxazolo[5,4-d]pyridine-2,4(3H)-dione, 7-methyl-5-[4-
(methylsulfonyl)benzyl]-3,5-dihydro[1,3]oxazolo[4,5-c]pyridine-2,4-dione, 5-(4-
methoxybenzyl)-3,5-dihydro[1,3]oxazolo[4,5-c]pyridine-2,4-dione, 5-(2-chlorobenzyl)-7-
propyl-3,5-dihydro[1,3]oxazolo[4,5-c]pyridine-2,4-dione, 4-[(2,4-dioxo-2,3-
dihydro[ 1,3]oxazolo[4,5-c]pyridin-5(4H)-yl)methyl]-N,N-dimethylbenzenesulfonamide, 5-
(mesitylmethyl)-3,5-dihydro[1,3]oxazolo[4,5-c]pyridine-2,4-dione, 5-(2-chlorobenzyl)-
3,5,6,7,8,9-hexahydro[1,3]oxazoIo[4,5-c]quinoline-2,4-dione, 5-(2-chlorobenzyl)-7-ethyl-6-
methyl-3,5-dihydro[1,3]oxazolo[4,5-c]pyridine-2,4-dione, 5-[2-(methylthio)benzyl]-3,5-
dihydro[1,3]oxazolo[4,5-c]pyridine-2,4-dione, 2-[(2,4-dioxo-2,3-dihydro[1,3]oxazolo[4,5-
c]pyridin-5(4H)-yl)methyl]-N,N-dimethylbenzenesulfonamide, 5-(2,6-dimethoxybenzyl)-3,5-
dihydro[1,3]oxazolo[4,5-c]pyridine-2,4-dione, 5-[2-(trifluoromethoxy)benzyl]-3,5-
dihydro[1,3]oxazolo[4,5-c]pyridine-2,4-dione, 5-(2-chlorobenzyl)-6,7-dimethyl-3,5-
dihydro[1,3]oxazolo[4,5-c]pyridine-2,4-dione, 5-[2-chloro-5-(methylsulfonyl)benzyl]-3,5-
dihydro[1,3]oxazolo[4,5-c]pyridine-2,4-dione, 5-(4-chloro-2-methoxybenzy])-3,5-
dihydro[1,3]oxazolo[4,5-c]pyridine-2,4-dione, 5-(2-chlorobenzyl)-5,6,7,8,9,10-hexahydro-
2H-cyclohepta[b][1,3]oxazolo[5,4-d]pyridine-2,4(3H)-dione, 5-[2-(difluoromethoxy)benzyl]-
3,5-dihydro[1,3]oxazolo[4,5-c]pyridine-2,4-dione, 7-methyl-5-[( 1R)-1-phenylethyl]-3,5-
dihydro[1,3]oxazolo[4,5-c]pyridine-2,4-dione, 5-(4-chlorobenzyl)-7-propyl-3,5-
dihydro[1,3]oxazolo[4,5-c]pyridine-2,4-dione, 5-[2-(methylsulfonyl)benzyl]-3,5-
dihydro[1,3]oxazolo[4,5-c]pyridine-2,4-dione, 5-(2,6-dimethylbenzyl)-3,5-
dihydro[1,3]oxazolo[4,5-c]pyridine-2,4-dione, 3-chloro-2-[(2,4-dioxo-2,3-
dihydro[1,3]oxazolo[4,5-c]pyridin-5(4H)-yl)methyl]benzonitrile, 5-(2-chloro-6-
methylbenzyl)-6,7-dimethyl-3,5-dihydro[1,3]oxazolo[4,5-c]pyridine-2,4-dione, 2-[(2,4-dioxo-
2,3-dihydro[1,3]oxazolo[4,5-c]pyridin-5(4H)-yl)methyl]benzonitrile, 5-(2-chloro-6-
methoxybenzyl)-7-methyl-3,5-dihydro[1,3]oxazolo[4,5-c]pyridine-2,4-dione, 5-[3-
(methylthio)benzyl]-3,5-dihydro[1,3]oxazolo[4,5-c]pyridine-2,4-dione, 5-(2-chlorobenzyl)-7-
cyclopropyl-3,5-dihydro[1,3]oxazolo[4,5-c]pyridine-2,4-dione, 5-(3-chlorobenzyl)-7-methyl-
3,5-dihydro[1,3]oxazolo[4,5-c]pyridine-2,4-dione, 5-(2,6-dichlorobenzyl)-7-methyl-3,5-
dihydro[1,3]oxazolo[4,5-c]pyridine-2,4-dione, 7-methyl-5-(4-methylbenzyl)-3,5-
dihydro[1,3]oxazolo[4,5-c]pyridine-2,4-dione, 5-(3,5-dimethoxybenzyl)-7-rnethyl-3,5-
dihydro[1,3]oxazolo[4,5-c]pyridine-2,4-dione, 5-(2,6-difluorobenzyl)-7-methyl-3,5-
dihydro[1,3]oxazolo[4,5-c]pyridine-2,4-dione, 5-[3-(methylsulfonyl)benzyl]-3,5-
dihydro[1,3]oxazolo[4,5-c]pyridine-2,4-dione, 5-(2-chloro-6-ethoxybenzyl)-3,5-
dihydro[1,3]oxazolo[4,5-c]pyridine-2,4-dione, 5-(2-chloro-6-ethoxybenzyl)-7-methyl-3,5-
dihydro[1,3]oxazolo[4,5-c]pyridine-2,4-dione, 5-(2-fluoro-6-methoxybenzyl)-7-methyl-3,5-
dihydro[1,3]oxazolo[4,5-c]pyridine-2,4-dione, 5-(2-chloro-6-methoxybenzyl)-7-propyl-3,5-
dihydro[1,3]oxazolo[4,5-c]pyndine-2,4-dione, 5-(5-chloro-2-fluorobenzyl)-7-methyl-3,5-
dihydro[1,3]oxazolo[4,5-c]pyridine-2,4-dione, 5-(2-chlorobenzyl)-7-isopropyl-3,5-
dihydro[1,3]oxazolo[4,5-c]pyridine-2,4-dione. 5-(5-fluoro-2-methylbenzyl)-7-methyl-3.5-
dihydro[1,3]oxazolo[4,5-c]pyridine-2,4-dione, 7-methyl-5-[(lS)-1-phenylethyl]-3,5-
dihydro[ 1,3]oxazolo[4,5-c]pyridine-2,4-dione, 5-(2-chloro-5-isopropoxybenzyl)-7-methyl-
3,5-dihydro[1,3]oxazolo[4,5-c]pyridine-2,4-dione, 5-(5-acetyl-2-methoxybenzyl)-3,5-
dihydro[1,3]oxazolo[4,5-c]pyridine-2,4-dione, 5-(2-chlorobenzyl)-7-methyl-3,5-
dihydro[1,3]oxazolo[4,5-d]pyridazine-2,4-dione, 5-[2-fluoro-6-(trifluoromethyl)benzyl]-7-
methyl-3,5-dihydro[1,3]oxazolo[4,5-c]pyridine-2,4-dione, 5-(2-chloro-6-methylbenzyl)-
5,6,7,8-tetrahydro-2H-cyclopenta[b][1,3]oxazolo[5,4-d]pyridine-2,4(3H)-dione, 5-(2-chloro-
6-ethoxybenzyl)-7-ethyl-3,5-dihydro[ 1,3]oxazolo[4,5-c]pyridine-2,4-dione, 5-(2-chloro-6-
propoxybenzyl)-7-methyl-3,5-dihydro[1,3]oxazolo[4,5-c]pyridine-2,4-dione, 5-(2-chloro-6-
isobutoxybenzyl)-7-methyl-3,5-dihydro[1,3]oxazolo[4,5-c]pyridine-2,4-dione, 5-(2-chloro-6-
ethoxybenzyl)-5,6,7,8-tetrahydro-2H-cyclopenta[b][1,3]oxazolo[5,4-d]pyridine-2,4(3H)-
dione, 5-(2-chloro-6-isopropoxybenzyl)-7-methyl-3,5-dihydro[1,3]oxazolo[4,5-c]pyridine-
2,4-dione, 5-[2-chloro-6-(2,2,2-trifluoroethoxy)benzyl]-7-methyl-3,5-
dihydro[1,3]oxazolo[4,5-c]pyridine-2,4-dione, 5-(2-chloro-6-ethoxybenzyl)-7-methyl-3,5-
dihydro[1,3]oxazolo[4,5-c]pyridcizine-2,4-dione, 5-[2-chloro-6-(2-methoxyethoxy)benzyl]-
5,6,7,8-tetrahydro-2H-cyclopenta[b][1,3]oxazolo[5,4-d]pyridine-2,4(3H)-dione, 5-(2-chloro-
6-ethoxybenzyl)-6,7-dimethyl-3,5-dihydro[1,3]oxazolo[4,5-c]pyridine-2,4-dione, 5-(2-chloro-
6-ethoxybenzyl)-7-ethyl-6-methyl-3,5-dihydro[1,3]oxazolo[4,5-c]pyridine-2,4-dione, 5-(2-
chlorobenzyl)-7-ethyl-3,5-dihydro[1,3]oxazolo[4,5-d]pyridazine-2,4-dione, 5-(2-chloro-6-
ethoxybenzyl)-7-propyl-3,5-dihydro[ 1,3]oxazolo[4,5-c]pyridine-2,4-dione, 5-(2-chloro-6-
ethoxybenzyl)-7-cyclopropyl-3,5-dihydro[1,3]oxazolo[4,5-c]pyridine-2,4-dione, 5-(2-chloro-
5-propoxybenzyl)-7-methyl-3,5-dihydro[1,3]oxazolo[4.5-c]pyridine-2,4-dione, 5-(2-chloro-5-
methoxybenzyl)-7-methyl-3,5-dihydro[1,3]oxazolo[4,5-c]pyridine-2,4-dione, 5-(2-chloro-6-
ethoxybenzyl)-6-methyl-3,5-dihydro[1,3]oxazolo[4,5-c]pyridine-2,4-dione, 5-(2-chloro-5-
ethoxybenzyl)-7-methyl-3,5-dihydro[1,3]oxazolo[4,5-c]pyridine-2,4-dione, 5-[2-chloro-5-
(piperidin-1-ylsulfonyl)benzyl]-7-methyl-3,5-dihydro[1,3]oxazolo[4,5-c]pyridine-2,4-dione,
5-[2-chloro-5-(pyrrolidin-1-ylsulfonyl)benzyl]-7-methyl-2,4-dihydro[1,3]oxazolo[4,5-
c]pyridine-2,4-dione, 5-[2-chloro-6-(cyclopentylmethoxy)benzyl]-7-methyl-3,5-
dihydro[1,3]oxazolo-2,4-c]pyridine-2,4-dione, 5-[2-(benzyloxy)-6-chlorobenzyl]-7-methyl-
3,5-dihydro[1,3]oxazolo[4,5-c]pyridine-2,4-dione, 5-(2,3-dichloro-6-ethoxybenzyl)-5,6,7,8-
tetrahydro-2H-cyclopenta[b][1,3]oxazolo[5,4-d]pyridine-2,4(3H)-dione, 5-[2-chloro-5-
(trifluoromethyl)benzyl]-7-methyl-3,5-dihydro[1,3]oxazolo[4,5-c]pyridine-2,4-dione and 5-
(2-chloro-5-fluorobenzyl)-7-methyl-3,5-dihydro[1,3]oxazolo[4,5-c]pyridine-2,4-dione.
Derivatives such as esters, carbamates, aminals, amides, opiical isomers and pro-drugs
are also contemplated.
The present invention also relates to pharmaceutical compositions comprising a
physiologically acceptable diluent and at least one compound of the present invention.
The present invention further relates to a process of inhibiting the binding of
a4ß1 integrin to VCAM-1 comprising exposure of a cell expressing a4ß1 integrin to a cell
expressing VCAM-1 in the presence of an effective inhibiting amount of a compound
of the present invention. The VCAM-1 may be on the surface of a vascular endothelial cell,
an antigen presenting cell, or other cell type. The a4ß1 may be on a white blood cell such as a
monocyte, lymphocyte, granulocyte; a stem cell; or any other cell that naturally expresses
a4ß1.
The invention also provides a method for treating disease states mediated by
a4ß1 binding which comprises administration of an effective amount of a compound of the
present invention, either alone or in formulation, to an afflicted patient.
Detailed Description of the Invention
Definitions of Terms
The term "alkyl" as used herein, alone or in combination, refers to C1-C12 straight or
branched, substituted or unsubstituted saturated chain radicals derived from saturated
hydrocarbons by the removal of one hydrogen atom, unless the term alkyl is preceded by a
Cx-Cy designation. Representative examples of alkyl groups include methyl, ethyl,
n-propyl, iso-propyl, n-butyl, sec-butyl, iso-butyl, and tert-butyl among others.
The term "alkenyl" as used herein, alone or in combination, refers to a substituted or
unsubstituted straight-chain or substituted or unsubstituted branched-chain alkenyl radical
containing from 2 to 10 carbon atoms. Examples of such radicals include, but are not limited
to, ethenyl, E- and Z-pentenyl, decenyl and the like.
The term "alkynyl" as used herein, alone or in combination, refers to a substituted or
unsubstituted straight or substituted or unsubstituted branched chain alkynyl radical
containing from 2 to 10 carbon atoms. Examples of such radicals include, but are not limited
to ethynyl, propynyl, propargyl, butynyl, hexynyl, decynyl and the like.
The term "lower" modifying "alkyl", "alkenyl", "alkynyl" or "alkoxy" refers to a C1-
C6 unit for a particular functionality. For example lower alkyl means C1-C6 alkyl.
The term "aliphatic acyl" as used herein, alone or in combination, refers to radicals of
formula alkyl-C(O)-, alkenyl-C(O)- and alkynyl-C(O)- derived from an aikane-, alkene- or
alkyncarboxylic acid, wherein the terms "alkyl", "alkenyl" and "alkynyl" are as defined
above. Examples of such aliphatic acyl radicals include, but are not limited to, acetyl,
propionyl, butyryl, valeryl, 4-methylvaleryl, acryloyl, crotyl, propiolyl and methylpropiolyl,
among others.
The term "cycloalkyl" as used herein refers to an aliphatic ring system having 3 to 10
carbon atoms and 1 to 3 rings, including, but not limited to cyclopropyl, cyclopentyl,
cyclohexyl, norbomyl, and adamantyl among otners. Cycloalkyl groups can be unsubstituted
or substituted with one, two or three substituents independently selected from lower alkyl,
haloalkyl, alkoxy, thioalkoxy, amino, alkylamino, dialkylamino, hydroxy, halo, mercapto,
nitro, carboxaldehyde, carboxy, alkoxycarbonyl and carboxamide.
"Cycloalkyl" includes cis or trans forms. Furthermore, the substituents may either be
in endo or exo positions in the bridged bicyclic systems.
The term '"cycloalkenyl" as used herein alone or in combination refers to a cyclic
carbocycle containing from 4 to 8 carbon atoms and one or more double bonds. Examples of
such cycloalkenyl radicals include, but are not limited to, cyclopentenyl. cyclohexenyl,
cyclopentadienyl and the like.
The term "cycloalkylalkyl" as used herein refers to a cycloalkyl group appended to a
lower alkyl radical, including, but not limited to cyclohexylmethyl.
The term "halo" or "halogen" as used herein refers to I, Br, Cl or F.
The term "haloalkyl" as used herein refers to a lower alkyl tadical, to which is
appended at least one halogen substituent. for example chloromethyl, fluoroethyl,
trifiuoromethyl and pentafluoroethyl among others.
The term "alkoxy" as used herein, alone or in combination, refers to an alkyl ether
ladical, wherein the term "alkyl" is as defined above. Examples of suitable alkyl ether
radicals include, but are not limited to, methoxy, ethoxy, n-propoxy, iso-propoxy, n-butoxy,
iso-butoxy, sec-butoxy, tert-butoxy and the like.
The term "alkoxyalkyl" as used herein, refers to Ry-O-Rz, wherein Ry is lower alkyl as
defined above, and Rz is alkylene (-(CH2)w-) wherein w is an integer of from one to six.
Representative examples include methoxymethyl, methoxyethyl, and ethoxyethyl among
others.
The term "alkenoxy" as used herein, alone or in combination, refers to a radical of
formula alkenyl-O, provided that the radical is not an enol ether, wherein the term "alkenyl"
is as defined above. Examples of suitable alkenoxy radicals include, but are not limited to,
allyloxy, E- and Z- 3-methyl-2-propenoxy and the like.
The term "alkynoxy" as used herein, alone or in combination, refers to a radical of
formula alkynyl-O, provided that the radical is not an -ynol ether. Examples of suitable
alkynoxy radicals include, but are not limited to, propargyloxy, 2-butynyloxy and the like.
The term "carboxy" as used herein refers to -C(O)O-.
The term "thioalkoxy" refers to a thioether radical of formula alkyl-S-, wherein
"alkyl" is as defined above.
The term "sulfonamide" as used herein refers to -SO2NH2.
The term "carboxaldehyde" as used herein refers to -C(O)R wherein R is hydrogen.
The terms "carboxamide" or "'amide" as used herein refer to -C(O)NRaRb wherein Ra
and Rb are each independently hydrogen, alkyl or any other suitable substituent.
The term "alkoxyalkoxy" as used herein refers to RcO-RdO- wherein Rc is lower
alkyl as defined above and Rd is alkylene wherein alkylene is -(CH2)n- wherein n' is an integer
from 1 to 6. Representative examples of alkoxyalkoxy groups include methoxymethoxy,
ethoxymethoxy, t-butoxymethoxy among others.
The term "alkylamino" as used herein refers to ReNH- wherein Re is a lower alkyl
group, for example, ethylamino, butylamino, among others.
The term "alkenylamino" as used herein, alone or in combination, refers to a radical of
formula alkenyl-NH-or (alkenyl)2N-, wherein the term "alkenyl" is as defined above,
provided that the radical is not an enamine. An example of such alkenylamino radical is the
allylamino radical.
The term "alkynylamino" as used herein, alone or in combination, refers to a radical
of formula alkynyl-NH- or (alkynyl)2N- wherein the term "alkynyl" is as defined above,
provided that the radical is not an amine. An example of such alkynylamino radicals is the
propargyl amino radical.
The term "dialkylamino" as used herein refers to Rt-RgN- wherein Rf and Rg are
independently selected from lower alkyl, for example diethylamino, and methyl propylamine
among others.
The term "alkoxycarbonyl" as used herein refers to an alkoxyl group as previously
defined appended to the parent molecular moiety through a carbonyl group. Examples of
alkoxycarbonyl include methoxycarbonyl, ethoxycarbonyl, and isopropoxycarbonyl among
others.
The term "aryl" or "aromatic" as used herein alone or in combination refers to a
substituted or unsubstituted carbocyciic aromatic group having about 6 to 12 carbon atoms
such as phenyl, naphthyl, indenyl, indanyl, azulenyl, fluorenyl and anthracenyl; or a
heterocyclic aromatic group containing at least one endocyclic N, O or S atom such as furyl,
thienyl, pyridyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, 2-pyrazolinyl,
pyrazolidinyl, isoxazolyl, isothiazolyl, 1,2,3-oxadiazolyl, 1,2,3-triazolyl, 1,3,4-thiadiazolyl,
pyridazinyl, pyrimidinyl, pyrazinyl. 1,3,5-triazinyl, 1,3,5-trifhianyl, indolizinyl, indolyl,
isoindolyl, 3H-indolyl, indolinyl, benzo[b]furanyl, 2,3-dihydroberizofuranyl,
benzo[b]thiophenyl, 1H-indazolyl, benzimidazolyl, benzthiazolyl, purinyl, 4H-quinolizinyl,
isoquinolinyl, cinnolinyl, phthalazinyl, quinazolinyl, quinoxalinyl, 1,8-naphthridinyl,
pteridinyl, carbazolyl, acridinyl, phenazinyl, phenothiazinyl, phenoxyazinyl, pyrazolo[1,5-
c]triazinyl and the like. "Aralkyl" and "alkylaryl" employ the term "alkyl" as defined above.
Rings may be multiply substituted.
The term "aralkyl" as used herein, alone or in combination, refers to an aryl
substituted alkyl radical, wherein the terms "alkyl" and "aryl" are as defined above.
Examples of suitable aralkyl radicals include, but are not limited to. phenylmethyl, phenethyl,
phenylhexyl, diphenylmethyl pyridylmethyl, tetrazolyl methyl, furylmethyl, imidazolyl
methyl indolvlmethyl, thienylpropyl and the like.
The term "aralkenyl" as used herein, alone or in combination, refers to an aryl
substituted alkenyl radical, wherein the terms "aryl" and "alkenyl" are as defined above.
The term "arylamino" as used herein, alone or in combination, refers to a radical of
formula aryl-NH-, wherein "aryl" is as defined above. Examples of arylamino radicals
include, but are not limited to, phenylamino(anilido), naphthlamino, 2-, 3-, and 4-
pyridylamino and the like.
The term "benzyl" as used herein refers to C6H5-CH2-.
The term "biaryl" as used herein, alone or in combination, refers to a radical of
formula aryl-aryl, wherein the term "aryl" is as defined above.
The term "thioaryl" as used herein, alone or in combination, refers to a radical of
formula aryl-S-, wherein the term "aryl" is as defined above. An example of a thioaryl radical
is the thiophenyl radical.
The term "aroyl" as used herein, alone or in combination, refers to a radical of
formula aryl-CO-, wherein the term "aryl" is as defined above. Examples of suitable
aromatic acyl radicals include, but are not limited to, benzoyl, 4-halobenzoyl, 4-
carboxybenzoyl, naphthoyl, pyridylcarbonyl and the like.
The term "heterocyclyl" as used herein, alone or in combination, refers to a non-
aromatic 3- to 10- membered ring containing at least one endocyclic N, O, or S atom. The
heterocycle may be optionally aryl-fused. The heterocycle may also optionally be substituted
with at least one substituent which is independently selected from the group consisting of
hydrogen, halogen, hydroxyl, amino, nitro, trifluoromethyl, trifluoromethoxy, alkyl, aralkyl,
alkenyl, alkynyl, aryl, cyano, carboxy, carboalkoxy, carboxyalkyl, oxo, arylsulfonyl and
aralkylaminocarbonyl among others.
The term "alkylheterocyclyl" as used herein refers to an alkyl group as previously
defined appended to the parent molecular moiety through a heterocyclyl group, including
but not limited to 2-methyl-5-thiazolyl, 2-methyl-1-pyrrolyl and 5-ethyl-2-thienyl.
The term "heterocyclylalkyl" as used herein refers to a heterocyclyl group as previously
defined appended to the parent molecular moiety through an alkyl group, including but not
limited to 2-thienylmethyl, 2-pyridinylmethyl and 2-(1-piperidinyl) ethyl.
The term "heterocycloyl" as used herein refers to radicals of the formula heterocyclyl-
C(O)-, wherein the term "hetercyclyl" is as defined above.
The term "aminal" as used herein refers to a hemi-acetal of the structure
RhC(NR1Rj)(NRkRl)- wherein Rh, Ri, Rj, Rk and Rl are each independently hydrogen,
alkyl or any other suitable substituent.
The term "ester" as used herein refers to -C(O)Rm, wherein Rm is hydrogen, alkyl or
any other suitable substituent.
The term "carbamate" as used herein refers to compounds based on carbamic acid
NH2C(O)OH.
The term "optical isomers" as used herein refers to compounds which differ only in
the stereochemistry of at least one atom, including enantiomers, diastereomers and racemates.
Use of the above terms is meant to encompass substituted and unsubstituted
moieties. Substitution may be by one or more groups such as alcohols, ethers., esters,
amides, sulfones, sulfides, hydroxyl, nitro, cyano, carboxy, amines, heteroatoms, lower
alkyl, lower alkoxy, lower alkoxycarbonyl, alkoxyalkoxy, acyloxy, halogens,
trifluoromethoxy, trifluoromethyl, alkyl, aralkyl, alkenyl, alkynyl, aryl, cyano, carboxy,
carboalkoxy, carboxyalkyl, cycloalkyl, cycloalkylalkyl, heterocyclyl, alkylheterocyclyl,
heterocyclylalkyl, oxo, arylsulfonyl and aralkylaminocarbonyl or any of the substituents of
the preceding paragraphs or any of those substituents either attached directly or by suitable
linkers. The linkers are typically short chains of 1-3 atoms containing any combination of
-C-, -C(O)-, -NH-, -S-, -SCO)-, -O-, -C(O)O- or -S(O)O-. Rings may be substituted
multiple times.
The terms "electron-withdrawing" or "electron-donating" refer to the ability of a
substituent to withdraw or donate electrons relative to that of hydrogen if hydrogen occupied
the same position in the molecule. These terms are well-understood by one skilled in the art
and are discussed in Advanced Organic Chemistry by J, March, 1985, pp. 16-18, incorporated
herein by reference. Electron withdrawing groups include halo, nitro, carboxyl, lower
alkenyl, lower alkynyl, carboxaldehyde, carboxyamido, aryl, quaternary ammonium,
trifluoromethyl, sulfonyl and aryl lower alkanoyl among others. Electron donating groups
include such groups as hydroxy, lower alkyl, amino, lower alkylamino, di(lower alkyl)amino,
aryloxy, mercapto, lower alkylthio, lower alkylmercapto, and disulfide among others. One
skilled in the art will appreciate that the aforesaid substituents may have electron donating or
electron withdrawing properties under different chemical conditions. Moreover, the present
invention contemplates any combination of substituents selected from the above-identified
groups.
The most preferred electron donating or electron withdrawing substituents are halo,
nitro, alkanoyl, carboxaldehyde, arylalkanoyl, aryloxy, carboxyl, carboxamide, cyano,
sulfonyl, sulfoxide, heterocyclyl, guanidine. quaternary ammonium., lower alkenyl, lower
alkynyl, sulfonium salts, hydroxy, lower alkoxy, lower alkyl, amino, lower alkylamino,
di(lower alkyl)amino, amine lower alkyl mercapto, mercaptoalkyl, alkylthio, carboxy lower
alkyl, arylalkoxy, alkanoylamino, alkanoyl(lower alkyl)amino, lower alkylsufonylamino,
arylsulfonylamino, alkylsulfonyl(lower alkyl)amino, arylsulfonyl(lower alkyDamino, lower
alkylcarboxamide, didower alkyDcarboxamide, sulfonamide, lower alkylsulfonamide,
didower alkyDsulfonamide, lower alkylsulfonyl, arylsulfonyl and alkyldithio.
As used herein, the term "composition" is intended to encompass a product
comprising the specified ingredients in the specified amounts, as well as any product which
results, directly or indirectly, from a combination of the specified ingredients in the specified
amounts.
As used herein, the term "mammals" includes humans and other animals.
The ring defined by Y in Formulae I, II and III can be a mono-cyclic heterocycle or
aromatic ring, or can be a bicyclic ring.
The dotted lines used in Formulae I, II, III, IV and VI indicate that the bond at that
location can be either single or double. The bond between the atoms Yand W for example
can be a single or double bond if Y and/or W is a substitutent such as N, C or CH. Therefore,
the ring defined by Y in the Formulae can be either saturated or unsaturated, depending upon
which W and/or Y is selected. In Formulae IV and VI, the dotted line indicates that the
nitrogen -containing ring optionally contains double bonds at the indicated locations.
In the Formulae, certain R groups potentially substitute their associated rings a
number of times. R19, R20, R21, R23, R27, R28, R29 and R25 may each substitute their
associated rings more than once. For example for R9, when c is zero, the associated ring is
unsubstituted, having hydrogens at the C-2 and C-4 positions; and for R23, when g is zero,
hydrogens are at the C-2 - C-5 positions.
Suitable substituents for the aryl, alkyl, cycloalkyl, heterocyclyl groups or the ring defined
by Y and W in the formulae described above, when present, include alcohols, amines,
heteroatoms, or any combination of aryl, alkoxy, alkoxyalkoxy, alkyl, cycloalkyl or
heterocyclyl groups either attached directly, or via suitable linkers. The linkers are typically
short chains of 1-3 atoms containing any combination of C, C=O, CO2, O, N, S, S=O, SO2, as
for example ethers, amides, amines, ureas, sulfamides, sulfonamides, among others.
For example, R1, R2, R3, R5, R6, R7 and R8 in the above formulae may independently
be, but are not limited to: hydrogen, alkyl, phenyl, thienylmethyl, isobutyl, n-butyl, 2-
thienylmethyl, 1,3-thiazol-2-yl-methyl, benzyl, thienyl, 3-pyridinylmethyl, 3-methyl-1-
benzothiophen-2-yl, allyl, 3-methoxybenzyl, propyl, 2-ethoxyethyl, cyclopropylmethyl,
benzylsulfanylmethyl, benzylsulfonylmethyl, phenylsulfanylmethyl,
phenethylsulfanylmethyl, 3-phenylpropylsulfanylmethyl, 4-((2-
toluidinocarbonyl)amino)benzyl, 2-pyridinylethyl, 2-(1H-indol-3-yl)ethyl, 1H-
benzimidazol-2-yl, 4-piperidinylmethyl, 3-hydroxy-4-methoxybenzyl, 4-
hydroxyphenethyl, 4-aminobenzyl, phenylsulfonylmethyl, 4-(acetylamino)phenyl, 4-
methoxyphenyl, 4-aminophenyl, 4-chlorophenyl, (4-(benzylsulfonyl)amino)phenyl, (4-
(methylsulfonyl)amino)phenyl, 2-aminophenyl, 2-methylphenyl, isopropyl, 2-oxo-1-
pyrrolidinyl, 3-(methylsulfanyl)propyl, (propylsulfanyl)methyl, octylsulfanylmethyl, 3-
aminophenyl, 4-((2-toluidinocarbonyl)amino)phenyl, 2-((methylbenzyl)amino)benzyl,
methylsulfanylethyl, hydroxy, chloro, fluoro, bromo, ureido, amino,
methanesulfonylamino, acetylamino, ethylsulfanylmethyl, 2-chlorobenzyl, 2-
bromobenzyl, 2-fluorobenzyl, 2-chloro-6-fluorobenzyl, 2-chloro-4-fluorobenzyl, 2,4-
dichlorobenzyl, 2-chloro-6-methoxybenzyl, 2-cyanobenzyl, 2,6-difluorobenzyl, 2-chloro-
5-(trifluoromethyl)benzyl, 2-chloro-6-methylbenzyl, 2,6-dimethoxybenzyl. 2-chloro-5-
(methylsulfonyl)benzyl, 2-chloro-6-cyanobenzyl, 2-chloro-6-ethoxybenzyl, 2-chloro-5-
methoxybenzyl, 2-chloro-5-fluorobenzyl, 5-chloro-2-fluorobenzyl, ethyl, propyl, butyl,
pentyl, cyclopropyl, tert-butylamino, propylamino, 4-methyl-1-piperazinyl, 1-azetidinyl,
4-morpholino, (4-carboxyphenyl)amino, pivaloylamino, ((tert-
butylamino)carbonyl)amino, trifluoromethyl, benzyloxy, 2-(2-methoxyethoxy)ethoxy, 2-
(2-(2-methoxyethoxy)ethoxy)ethoxy and 2-(2-(2-(2-
methoxyethoxy)ethoxy)ethoxy)ethoxy.
The R4 substituent for the formulae above may be, but is not limited to 1,3-
benzodioxol-5-yl, 1-naphthyl, thienyl, 4-isobutoxyphenyl, 2,6-dimethylphenyl,
allyloxyphenyl, 3-bromo-4-methoxyphenyl, 4-butoxyphenyl, 1-benzofuran-2-yl, 2-
thienylmethyl, phenyl, methylsulfanyl, phenylsulfanyl, phenethylsulfanyl, 4-bromo-2-
thienyl, 3-methyl-2-thienyl, 4-methylphenyl, 3,5-bis(methyloxy)phenyl, 4-
(methyloxy)phenyl, 4-fluorophenyl, 3-(methyloxy)phenyl, 3,4,5-tris(methyloxy)phenyl,
2,3-dihydTo-l-benzofuran-5-yl, 3-fluorophenyl, 4-(trifiuoromethyl)phenyl, 4-fluoro-3-
(trifluoromethyl)phenyl, 4-(1,1-dimethylethyl)phenyl, 3,5-dimethylphenyl, 4-
hydroxyphenyl, 3,4-dimethylphenyl, 3-methyl-4-(methyloxy)phenyl, 4-hydroxy-3-
methylphenyl, 3-methylphenyl, 2,3-dihydro-inden-5-yl, 2-methylphenyl, 2,6-
bis(methyloxy)phenyl, 2,6-dihydroxyphenyl, 4-chlorophenyl, 3-chIorophenyl, 3,4-
dichlorophenyl, 4-((trifluoromethyl)oxy)phenyl, 4-ethylphenyl, 4-(ethyloxy)phenyl,
methyl, 2-propyl, 4,5-dihydro-l,3-oxazol-2-yl, 3-(trifluoromethyl)phenyl, 4-
(trifluoromethoxy)phenyl, 2,3-dihydro-1,4-benzodioxin-6-yl, 7-methoxy-1,3-
benzodioxol-5-yl, 3-ethoxy-4-methoxyphenyl, 3,4-dimethoxyphenyl, 3,4-diethoxyphenyl,
3-ethoxyphenyl, 3-methoxy-4-methylphenyl, 3,5-dimethoxy-4-methylphenyl, 3-
propoxyphenyl, 3-butoxyphenyl, 3-(2-methoxyethoxy)phenyl, 3,4-dipropoxyphenyl, 3-
(difluoromethoxy)phenyl, 2-naphthyl, 3-isopropoxyphenyl, 1 -methyl-1H-indol-5-yl, 2,3-
dihydro-1-benzofuran-5-yl, 1,3-diethyl-2-oxo-2,3-dihydro-1H-benzimidazol-5-yl, 3-
(trifluoromethoxy)phenyl, 1-methyl-1H-indol-6-yl, 3-(cyclopropoxy)phenyl, 3-
(cyclopropylmethoxyjphenyl, 3-(difluoromethoxy)phenyl, 3-( 1,1,2,2-
tetrafluoroethoxy)phenyl, 1-ethyl-1H-indol-5-yl, 3-(diethylamino)phenyl, 6-methoxy-2-
naphthyl, 3-[(methylsulfonyl)amino]phenyl, 3-[methyl(methylsulfonyl)amino]phenyl, 3-
[ethyl(methylsulfonyl)amino]phenyl, 1H-indol-5-yl, 3-fluoro-4-methoxyphenyl and 3-
(difluoromethyl)phenyl.
Two independent R1, R2, R3 or R5 groups taken together may be linked to form a
ring.
R4 and R11 may be linked to form a ring such as 1-pyrrolidino, 1-piperidino, 4-methyl-1-
piperazino, 4-acetyl-1-piperazino and 4-morpholino among others.
R9 and R10 may be linked to form a ring such as cyclopropyl, cyclobutyl, cyclopentyl,
and cyclohexyl among others.
Abbreviations
Abbreviations which have been used in the schemes and the examples which follow
are: BOC for t-butyloxycarbonyl; DMF for dimethylformamide; THF for tetrahydrofuran;
DME for dimethoxyethane; DMSO for dimethylsulfoxide; NMM for N-methyl
morpholine; DIPEA for diisopropylethylamine; CDI for 1,1'-carbonyldiimidazole; TBS
for TRIS-buffered saline; Ms for methanesulfonyl, TMEDA for N,N,N',N'-
tetramethylethylenediamine, DCE for 1,2-dichloroethane, NCS for N-chlorosuccinimide,
NBS for N-bromosuccinimide, DPPA for diphenylphosphorylazide, DEAD for diethyl
azodicarboxylate, m-CPBA for 3-chloroperoxybenzoic acid, TFAA for trifiuoroacetic
anhydride, DCM for dichloromethane, LHMDS for lithium bis(trimethylsilyl)amide and
Cbz for benzyloxycarbonyl. Amino acids are abbreviated as follows: C for L-cysteine; D
for L-aspartic acid; E for L-glutamic acid; G for glycine; H for L-histidine; I for L-
isoleucine; L for L-leucine; N for L-asparagine; P for L-proline; Q for L-glutamine; S for
L-serine; T for L-threonine; V for L-valine and W for L-tryptophan.
Examples of the procedures that may be used to synthesize compounds of the
Formulae described above are shown in the Schemes which follow. A detailed
description of the representative compounds of the present invention is set forth in the
Examples below.
The compounds of the present invention can be used in the form of pharmaceutically
acceptable salts derived from inorganic or organic acids. The phrase "pharmaceutically
acceptable salt" means those salts which are, within the scope of sound medical judgement,
suitable for use in contact with the tissues of humans and lower animals without undue
toxicity, irritation, allergic response and the like and are commensurate with a reasonable
benefit/risk ratio. Pharmaceutically acceptable salts are well-known in the art. For example,
S. M. Berge et al. describe pharmaceutically acceptable salts in detail in J. Pharmaceutical
Sciences. 1977, 66: 1 et seq. The salts can be prepared in situ during the final isolation and
purification of the compounds of the invention or separately by reacting a free base function
with a suitable organic acid. Representative acid addition salts include, but are not limited to
acetate, adipate, alginate, citrate, aspartate, benzoate, benzenesulfonate, bisulfate, butyrate,
camphorate, camphorsulfonate, digluconate, glycerophosphate, heinisulfate, heptanoate,
hexanoate, fumarate, hydrochloride, hydrobromide, hydroiodide, 2-hydroxyethansulfonate
(isothionate), lactate, maleate, methanesulfonate, nicotinate, 2-naphthalenesulfonate, oxalate,
palmitoate, pectinate, persulfate, 3-phenylpropionate, picrate, pivalate, propionate, succinate,
tartrate, thiocyanate, phosphate, glutamate, bicarbonate, p-toluenesulfonate and undecanoate.
Also, the basic nitrogen-containing groups can be quaternized with such agents as lower alkyl
halides such as methyl, ethyl, propyl, and butyl chlorides, bromides and iodides; dialkyl
sulfates like dimethyl, diethyl, diburyl and diamyl sulfates; long chain halides such as decyl,
lauryl, myristyl and stearyl chlorides, bromides and iodides; arylalkyl halides like benzyl and
phenethyl bromides and others. Water or oil-soluble or dispersible products are thereby
obtained. Examples of acids which can be employed to form pharmaceutically acceptable
acid addition salts include such inorganic acids as hydrochloric acid, hydrobromic acid,
sulphuric acid and phosphoric acid and such organic acids as oxalic acid, maleic acid, succinic
acid and citric acid.
Basic addition salts can be prepared in situ during the final isolation and
purification of compounds of this invention by reacting a carboxylic acid-containing
moiety with a suitable base such as the hydroxide, carbonate or bicarbonate of a
pharmaceutically acceptable metal cation or with ammonia or an organic primary,
secondary or tertiary amine. Pharmaceutically acceptable salts include, but are not limited
to, cations based on alkali metals or alkaline earth metals such as lithium, sodium,
potassium, calcium, magnesium and aluminum salts and the like and nontoxic quaternary
ammonia and amine cations including ammonium, tetramethylammonium,
tetraethylammonium, methylammonium, dimethylammonium, trimethylammonium,
triethylammonium, diethylammonium, and ethylammonium among others. Other
representative organic amines useful for the formation of base addition salts include
ethylenediamine, ethanolamine, diethanolamine, piperidine, piperazine and the like.
Dosage forms for topical administration of a compound of this invention include
powders, sprays, ointments and inhalants. The active compound is mixed under sterile
conditions with a pharmaceutically acceptable carrier and any needed preservatives, buffers or
propellants which can be required. Opthalmic formulations, eye ointments, powders and
solutions are also contemplated as being within the scope of this invention.
Actual dosage levels of active ingredients in the pharmaceutical compositions of
this invention can be varied so as to obtain an amount of the active compound(s) which is
effective to achieve the desired therapeutic response for a particular patient, compositions
and mode of administration. The selected dosage level will depend upon the activity of
the particular compound, the route of administration, the severity of the condition being
treated and the condition and prior medical history of the patient being treated. However,
it is within the skill of the art to start doses of the compound at levels lower than required
to achieve the desired therapeutic effect and to gradually increase the dosage until the
desired effect is achieved.
When used in the above or other treatments, a therapeutically effective amount of
one of the compounds of the present invention can be employed in pure form or, where
such forms exist, in pharmaceutically acceptable salt, ester or prodrug form.
Alternatively, the compound can be administered as a pharmaceutical composition
containing the compound of interest in combination with one or more pharmaceutically
acceptable excipients. The phrase "therapeutically effective amount" of the compound of
the invention means a sufficient amount of the compound to treat disorders, at a
reasonable benefit/risk ratio applicable to any medical treatment. It will be understood,
however, that the total daily usage of the compounds and compositions of the present
invention will be decided by the attending physician within the scope of sound medical
judgement. The specific therapeutically effective dose level for any particular patient will
depend upon a variety of factors including the disorder being treated and the severity of
the disorder; activity of the specific compound employed; the specific composition
employed; the age, body weight, general health, sex and diet of the patient; the time of
administration, route of administration, and rate of excretion of the specific compound
employed; the duration of the treatment; drugs used in combination or coincidental with
the specific compound employed; and like factors well known in the medical arts. For
example, it is well within the skill of the art to start doses of the compound at levels lower
than required to achieve the desired therapeutic effect and to gradually increase the
dosage until the desired effect is achieved.
The total daily dose of the compounds of this invention administered to a human
or lower animal may range from about 0.0001 to about 1000 mg/kg/day. For purposes of
oral administration, more preferable doses can be in the range of from about 0.001 to
about 5 mg/kg/day. If desired, the effective daily dose can be divided into multiple doses
for purposes of administration; consequently, single dose compositions may contain such
amounts or submultiples thereof to make up the daily dose.
The present invention also provides pharmaceutical compositions that comprise
compounds of the present invention formulated together with one or more non-toxic
pharmaceutically acceptable carriers. The pharmaceutical compositions can be specially
formulated for oral administration in solid or liquid form, for parenteral injection or for rectal
administration.
The pharmaceutical compositions of this invention can be administered to humans
and other mammals orally, rectally, parenterally , intracisternally, intravaginally,
intraperitoneally, topically (as by powders, ointments or drops), bucally or as an oral or
nasal spray. The term "parenterally," as used herein, refers to modes of administration
which include intravenous, intramuscular, intraperitoneal, intrasternal, subcutaneous and
intraarticular injection and infusion.
In another aspect, the present invention provides a pharmaceutical composition
comprising a component of the present invention and a physiologically tolerable diluent.
The present invention includes one or more compounds as described above formulated
into compositions together with one or more non-toxic physiologically tolerable or
acceptable diluents, carriers, adjuvants or vehicles that are collectively referred to herein
as diluents, for parenteral injection, for intranasal delivery, for oral administration in solid
or liquid form, for rectal or topical administration, among others.
The compositions can also be delivered through a catheter for local delivery at a
target site, via an intracoronary stent (a tubular device composed of a fine wire mesh), or
via a biodegradable polymer. The compounds may also be complexed to ligands, such as
antibodies, for targeted delivery.
Compositions suitable for parenteral injection may comprise physiologically
acceptable, sterile aqueous or nonaqueous solutions, dispersions, suspensions or
emulsions and sterile powders for reconstitution into sterile injectable solutions or
dispersions. Examples of suitable aqueous and nonaqueous carriers, diluents, solvents or
vehicles include water, ethanol, polyols (propyleneglycol, polyethyleneglycol, glycerol,
and the like), vegetable oils (such as olive oil), injectable organic esters such as ethyl
oleate, and suitable mixtures thereof.
These compositions can also contain adjuvants such as preserving, wetting,
emulsifying, and dispensing agents. Prevention of the action of microorganisms can be
ensured by various antibacterial and antifungal agents, for example, parabens,
chlorobutanol, phenol, sorbic acid, and the like. It may also be desirable to include
isotonic agents, for example sugars, sodium chloride and the like. Prolonged absorption
of the injectable pharmaceutical form can be brought about by the use of agents delaying
absorption, for example, aluminum monostearate and gelatin.
Suspensions, in addition to the active compounds, may contain suspending agents,
as for example, ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan
esters, microcrystalline cellulose, aluminum metahydroxide, bentonite, agar-agar and
tragacanth, or mixtures of these substances, and the like.
In some cases, in order to prolong the effect of the drug, it is desirable to slow the
absorption of the drug from subcutaneous or intramuscular injection. This can be
accomplished by the use of a liquid suspension of crystalline or amorphous material with
poor water solubility. The rate of absorption of the drug then depends upon its rate of
dissolution which, in turn, may depend upon crystal size and crystalline form.
Alternatively, delayed absorption of a parenterally administered drug form is
accomplished by dissolving or suspending the drug in an oil vehicle.
Injectable depot forms are made by forming microencapsule matrices of the drug
in biodegradable polymers such as polylactide-polyglycolide. Depending upon the ratio
of drug to polymer and the nature of the particular polymer employed, the rate of drug
release can be controlled. Examples of other biodegradable polymers include
poly(orthoesters) and poly(anhydrides). Depot injectable formulations are also prepared
by entrapping the drug in liposomes or microemulsions which are compatible with body
tissues.
The injectable formulations can be sterilized, for example, by filtration through a
bacterial-retaining filter or by incorporating sterilizing agents in the form of sterile solid
compositions which can be dissolved or dispersed in sterile water or other sterile
injectable medium just prior to use.
Solid dosage forms for oral administration include capsules, tablets, pills, powders
and granules. In such solid dosage forms, the active compound may be mixed with at
least one inert, pharmaceutically acceptable excipient or carrier, such as sodium citrate or
dicalcium phosphate and/or a) fillers or extenders such as starches, lactose, sucrose,
glucose, mannitol and silicic acid; b) binders such as carboxymethylcellulose, alginates,
gelatin, polyvinylpyrrolidone, sucrose and acacia; c) humectants such as glycerol; d)
disintegrating agents such as agar-agar, calcium carbonate, potato or tapioca starch,
alginic acid, certain silicates and sodium carbonate; e) solution retarding agents such as
paraffin; f) absorption accelerators such as quaternary ammonium compounds; g) wetting
agents such as cetyl alcohol and glycerol monostearate; h) absorbents such as kaolin and
bentonite clay and i) lubricants such as talc, calcium stearate, magnesium stearate, solid
polyethylene glycols, sodium lauryl sulfate and mixtures thereof. In the case of capsules,
tablets and pills, the dosage form may also comprise buffering agents.
Solid compositions of a similar type may also be employed as fillers in soft and
hard-filled gelatin capsules using such excipients as lactose or milk sugar as well as high
molecular weight polyethylene glycols and the like.
The solid dosage forms of tablets, dragees, capsules, pills and granules can be
prepared with coatings and shells such as enteric coatings and other coatings well-known
in the pharmaceutical formulating art. They may optionally contain opacifying agents and
may also be of a composition such that they release the active ingredient(s) only, or
preferentially, in a certain part of the intestinal tract, optionally, in a delayed manner.
Examples of embedding compositions which can be used include polymeric substances
and waxes.
The active compounds can also be in micro-encapsulated form, if appropriate,
with one or more of the above-mentioned excipients.
Liquid dosage forms for oral administration include pharmaceutically acceptable
emulsions, solutions, suspensions, syrups and elixirs. In addition to the active
compounds, the liquid dosage forms may contain inert diluents commonly used in the art
such as, for example, water or other solvents, solubilizing agents and emulsifiers such as
ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl
benzoate, propylene glycol, 1,3-butylene glycol, dimethyl formamide, oils (in particular,
cottonseed, groundnut, corn, germ, olive, castor and sesame oils), glycerol,
tetrahydrofurfuryl alcohol, polyethylene glycols and fatty acid esters of sorbitan and
mixtures thereof.
Besides inert diluents, the oral compositions may also include adjuvants such as
wetting agents, emulsifying and suspending agents, sweetening, flavoring and perfuming
agents.
Compositions for rectal or vaginal administration are preferably suppositories
which can be prepared by mixing the compounds of this invention with suitable non-
irritating excipients or carriers such as cocoa butter, polyethylene glycol or a suppository
wax which are solid at room temperature but liquid at body temperature and therefore
melt in the rectum or vaginal cavity and release the active compound.
Compounds of the present invention can also be administered in the form of
liposomes. As is known in the art, liposomes are generally derived from phospholipids or
other lipid substances. Liposomes are formed by mono- or multi-lamellar hydrated liquid
crystals which are dispersed in an aqueous medium. Any non-toxic, physiologically
acceptable and metabolizable lipid capable of forming liposomes can be used. The
present compositions in liposome form can contain, in addition to a compound of the
present invention, stabilizers, preservatives, excipients and the like. The preferred lipids
are natural and synthetic phospholipids and phosphatidyl cholines (lecithins) used
separately or together.
Methods to form liposomes are known in the art. See, for example, Prescott, Ed.,
Methods in Cell Biology, Volume XIV, Academic Press, New York, N.Y. (1976), p. 33 et
seq.
The term "pharmaceutically acceptable prodrugs" as used herein represents those
prodrugs of the compounds of the present invention which are, within the scope of sound
medical judgement, suitable for use in contact with the tissues of humans and lower
animals without undue toxicity, irritation, allergic response, and the like, commensurate
with a reasonable benefit/risk ratio, and effective for their intended use, as well as the
zwitterionic forms, where possible, of the compounds of the invention. Prodrugs of the
present invention may be rapidly transformed in vivo to the parent compound of the above
formula, for example, by hydrolysis in blood. A thorough discussion is provided in T.
Higuchi and V. Stella, Pro-drugs as Novel Delivery Systems. V. 14 of the A.C.S.
Symposium Series, and in Edward B. Roche, ed., Bioreversible Carriers in Drug Design.
American Pharmaceutical Association and Pergamon Press (1987), hereby incorporated
by reference.
Compounds of the present invention that are formed by in vivo conversion of a
different compound that was administered to a mammal are intended to be included
within the scope of the present invention.
Compounds of the present invention may exist as stereoisomers wherein
asymmetric or chiral centers are present. These stereoisomers are "R" or "S" depending
on the configuration of substituents around the chiral carbon atom. The present invention
contemplates various stereoisomers and mixtures thereof. Stereoisomers include
enantiomers and diastereomers, and mixtures of enantiomers or diastereomers. Individual
stereoisomers of compounds of the present invention may be prepared synthetically from
commercially available starting materials which contain asymmetric or chiral centers or
by preparation of racemic mixtures followed by resolution well-known to those of
ordinary skill in the art. These methods of resolution are exemplified by (1) attachment
of a mixture of enantiomers to a chiral auxiliary, separation of the resulting mixture of
diastereomers by recrystallization or chromatography and liberation of the optically pure
product from the auxiliary or (2) direct separation of the mixture of optical enantiomers
on chiral chromatographic columns.
The compounds of the invention can exist in unsolvated as well as solvated forms,
including hydrated forms, such as hemi-hydrates. In general, the solvated forms, with
pharmaceutically acceptable solvents such as water and ethanol among others are
equivalent to the unsolvated forms for the purposes of the invention.
In another aspect, the present invention contemplates a process of inhibiting the
binding of a4b1 integrin to VCAM-1. A process of the present invention can be used either
in vitro or in vivo. In accordance with a process of the present invention, a cell expressing
a4b1 integrin is exposed to a cell expressing VCAM-1 in the presence of an effective
inhibiting amount of a compound of the present invention.
A cell expressing a4b1 integrin can be a naturally occurring white blood cell, mast
cell or other cell type that naturally expresses a4b1 on the cell surface, or a cell
transfected with an expression vector that contains a poly-nucleotide (e.g., genomic DNA
or cDNA) that encodes a4b1 integrin. In an especially preferred embodiment,
a4b1 integrin is present on the surface of a white blood cell such as a monocyte, a
lymphocyte or a granulocyte (e.g., an eosinophil or a basophil).
A cell that expresses VCAM-1 can be a naturally occurring cell (e.g. an
endothelial cell) or a cell transfected with an expression vector containing a
polynucleotide that encodes VCAM-1. Methods for producing transfected cells that
express VCAM-1 are well known in the art.
Where VCAM-1 exists on the surface of cell, the expression of that VCAM-1 is
preferably induced by inflammatory cytokines such as tumor necrosis factor-a
interleukin-4 and interleukin-1b.
Where the cells expressing a4b1 integrin and VCAM-1 are in a living organism, a
compound of the present invention is administered in an effective amount to the living
organism. Preferably, the compound is in a pharmaceutical composition of this invention.
A process of the present invention is especially useful in treating diseases associated
with uncontrolled migration of white blood cells to damaged tissue. Such diseases
include, but are not limited to, asthma, atherosclerosis, rheumatoid arthritis, allergy,
multiple sclerosis, lupus, inflammatory bowel disease, graft rejection, contact
hypersensitivity, type I diabetes, leukemia, and brain cancer. Administration is
preferably accomplished via intravascular, subcutaneous, intranasal, transdermal or oral
delivery.
The present invention also provides a process of selectively inhibiting the binding
of a4b1 integrin to a protein comprising exposing the integrin to the protein in the
presence of an effective inhibiting amount of a compound of the present invention. In a
preferred embodiment, the a4b1 integrin is expressed on the surface of a cell, either
naturally occurring or a cell transformed to express a4b1 integrin.
The protein to which the a4b1 integrin binds can be expressed either on a cell
surface or be part of the extracellular matrix. Especially preferred proteins are fibronectin
or invasin.
The ability of compounds of the present invention to inhibit binding is described in
detail hereinafter in the Examples. These Examples are presented to describe preferred
embodiments and utilities of the invention and are not meant to limit the invention unless
otherwise stated in the claims appended hereto.
The ability of compounds of the present invention to inhibit binding is described
in detail hereinafter in the Examples. These Examples are presented to describe preferred
embodiments and utilities of the invention and are not meant to limit the invention unless
otherwise stated in the claims appended hereto.
Example 1
Synthesis of (3S)-3- {[({1 -[(2-chlorophenyl)methyl]-4-ethyl-2-oxo-1,2-dihydro-3-
pyridinyl}amino)carbonyl]amino} -3-(4-methylphenyl)propanoic acid (10).
Step One: Compound 1 (20.8 g, 135 mmol) was dissolved in methanol (270 mL)
and palladium on carbon (10 % Pd dry weight basis, Degussa type E101 NE/W, ~50%
water content, 5.75 g, 2.7 mmol Pd) was added. The atmosphere was replaced with
hydrogen (toggle between vacuum and hydrogen from a balloon five times), the mixture
was stirred overnight, then filtered. The filtrate was concentrated under vacuum and the
residue was taken up in a 1:1 hexanes:ethyl acetate mixture and washed with a 4:1
mixture of water and saturated NaHCO3, saturated NaHCO3 and brine. The organic layer
was dried over MgSO4 and filtered and the filtrate was concentrated under reduced
pressure to give compound 2 (12.43 g, 74%) as a white solid. This material was used
without purification.
Step Two: Compound 2 (2.64 g, 21.3 mmol) was dissolved in dichloroniethane
(50 mL) and chilled to 0 °C. The cold solution was treated sequentially with
triethylamine (3.6 mL, 25.6 mmol) and trimethylaceryl chloride (2.90 mL, 23.4 mmol).
The solution was stirred at room temperature for 6 hours, then refluxed overnight. The
mixture was partitioned between dichloromethane and aqueous NaOH (2N). The organic
layer was washed with brine, dried over MgSO4 and filtered and the filtrate was
concentrated to give compound 3 (3.33 g, 75%).
Step Three: Compound 3 (0.50 g, 2.4 mmol) was dissolved in dry THF, (9.6 mJL)
and TMEDA (1.1 mL, 7.2 mmol) under a dry nitrogen atmosphere. The resulting
solution was chilled to between -20 and -10 °C and treated sequentially with n-
butyllithium (1.6 M in hexanes 2.25 mL) and t-butyllithium (1.7 M in pentane, 2.1 mL)
dropwise via syringe. After 30 minutes the bath temperature was allowed to come to -5 to
0 °C and treated with ethyl iodide via a syringe (0.77 mL, 9.6 mmol). The solution was
stirred at 0 °C for 2 hours, then room temperature overnight. The mixture was quenched
with methanol and concentrated to dryness. The residue was purified by filtering through
silica gel, eluting with 3:1 hexanes:ethyl acetate and then recrystallizing from hexanes to
yield compound 4 (0.32 g, 56%).
Step Four: Compound 4 (0.32 g, 1.3 mmol) was dissolved in glacial acetic acid
(4.5 mL) and treated with potassium iodide (0.65 g, 3.9 mmol). The resulting mixture was
heated in an oil bath regulated at 115°C for 1.0 hour. The mixture was cooled, diluted
with water and adjusted to pH 6 using 2N NaOH and 2N HCl. The mixture was extracted
with chloroform (4 times). The combined extracts were washed with aqueous sodium
thiosulfate, dried over MgSO4 and filtered. The filtrate was concentrated under reduced
pressure to give compound 5 (0.25 g, 86%) as a white solid. This material was used
without further purification.
Step Five: Compound 5 (0.25 g, 1.1 mmol) was dissolved in THF (45 mL) and
treated dropwise with a solution of potassium bis(trimethylsilyl)amide (0.5 M in toluene,
2.7 mL) at 0 °C. The resulting solution was treated with 2-chlorobenzylbromide (0.16
mL, 1.2 mmol) and the solution was allowed to warm to room temperature overnight.
The mixture was partitioned between 2N HCl and ethyl acetate. The organic layer was
washed with brine, dried over MgSO4 and filtered. The filtrate was concentrated under
reduced pressure and the residue was purified by chromatography (SiO2, gradient elution
4:1 switching to 2:1 hexanes:ethyl acetate) to give compound 6 (0.16 g, 41%).
Step Six: Compound 6 (0.16 g, 0.46 mmol) was suspended in 1:1
watenconcentrated HCl (4.6 mL). The suspension was brought to reflux for 4 hours,
during which time the compound dissolved. The mixture was cooled, diluted with water
and extracted with diethyl ether. The aqueous layer adjusted basic with excess saturated
sodium bicarbonate solution, and the mixture was extracted with ethyl acetate. The
extracts were combined, washed with brine, dried over MgSO4 and filtered. The filtrate
was concentrated under reduced pressure to give compound 7 (0.081 g, 67%).
Step Seven: Compound 7 (0.080 g, 0.30 mmol) was dissolved in 1,2-dichloroethane
(1.2 mL) and DIPEA (0.115 mL, 0.66 mmol) and chilled to 0 °C The cold solution was
treated rapidly with a solution of phosgene (1.93 M in toluene, 0.170 mL, 0.33 mmol). After
30 minutes a solution of compound 8 (0.068 g, 0.33 mmol) in 1,2-dichloroethane (0.5 mL)
was added rapidly via syringe. The resulting mixture was heated to 55 °C. for 1 hour. The
mixture was partitioned between dichloromethane and 2N HCl. The organic layer was
washed with saturated aqueous NaHCO3 and brine, dried over MgSO4 and filtered. The
filtrate was concentrated to give compound 9 (0.110 g, 74%).
Step Eight: Compound 9 (0.11 g, 0.22 mmol) was dissolved in 2:1 THF:H2O
(0.88 mL) and treated with a solution of 2N NaOH (0.33 mL). Methanol was added
dropwise until a homogeneous solution was obtained. The mixture was stirred for 20
minutes, diluted with water and washed with ethyl ether. The aqueous layer v/as acidified
with 2N HCl and extracted with ethyl acetate. The ethyl acetate layer was washed with
brine, dried over MgSO4 and filtered. The filtrate was concentrated to give (3S)-3-{[({1-
[(2-chlorophenyl)methyl]-4-ethyl-2-oxo-l,2-dihydro-3-
pyridinyl}amino)carbonyl]amino}-3-(4-methylphenyl)propanoic acid (10, 0.095 g, 92%).
Example 2
Synthesis of (3S)-3-{[({6-methyl-2-oxo-1-(phenylmethyl)-4-[(phenylmethyl)oxy]-1,2-
dihydro-3-pyridinyl}amino)carbonyl]amino}-3-(4-methylphenyl)propanoic acid (15).
Step One: To a suspension of compound 11 (1.0 g, 5.9 mmol) and K2CO3 (2.40 g
17.6 mmol) in acetone (50 mL) was added benzylbromide (2.31 g, 13.5 mmol). After
refiuxing overnight, the reaction was cooled and the mixture was partitioned between
ethyl acetate and saturated NaHCO3. The organic layer was washed with dilute HCl and
brine, dried over MgSO4 and filtered and the filtrate was concentrated to give compound
12 (1.60 g, 80%).
Step Two: Compound 12 (0.30 g, 0.86 mmol), zinc powder (0.30 g, 4.6 mmol)
and saturated aqueous NH4Cl (0.30 mL) were mixed in MeOH (18 mL). This mixture
was allowed to stir at room temperature for 1 hour before additional zinc (0.30 g, 4.6
mmol) was added. The resulting heterogeneous mixture was refluxed overnight. After
filtration of the hot mixture and concentration of the filtrate under reduced pressure, the
residue was dissolved in ethyl acetate and washed with saturated aqueous NaHCO3 and
brine. The organic layer was dried over MgSO4 and filtered and the filtrate was
concentrated under reduced pressure to give compound 13 (0.18 g, 66%).
Step Three: Compound 13 (0.30 g, 0.94 mmol.) and DIPEA (0.40 mL, 2.3 mmol.)
were dissolved in CH2Cl2 and the mixture was cooled to 0 °C. Phosgene (1.9 M in
toluene, 0.55 mL, 1.0 mmol) was added to the solution dropwise. The reaction mixture
was stirred at 0 °C for 15 minutes before compound 8 (0.19 g, 0.94 mmol) in CH2Cl2 (2
mL) was added. The resulting solution was stirred at room temperature overnight then
poured into ethyl acetate and washed with saturated aqueous NaHCO3, 1 N HCl and
brine. The organic layer was dried over MgSO4 and filtered and the filtrate was
concentrated under reduced pressure. The residue was purified by flash chromatography
on silica gel, eluting with 1:1 increasing to 1:2 hexanes:ethyl acetate to give compound 14
(0.33 g, 64%).
Step Four: A solution of compound 14 ( 0.33 g, 0.6 mmol) in THF (6 mL) was
treated with 2N NaOH (2 mL). MeOH was added until homogeneous solution was
achieved. The reaction mixture was stirred at room temperature for 30 minutes and
poured into H2O (50 mL). The aqueous layer was washed with diethyl ether (twice), and
then acidified with 1N HCl. The aqueous layer was extracted with ethyl acetate (twice).
The combined ethyl acetate extracts were washed with brine (twice), dried over MgSO4
and filtered. The filtrate was concentrated under reduced pressure to give (3S)-3-{[({6-
methyl-2-oxo-1-(phenylmethyl)-4-[(phenylmethyl)oxy]-1,2-dihydro-3-
pyridinyl}amino)carbonyl]amino}-3-(4-methylphenyl)propanoic acid (15, 0.26 g, 90%) as
an off-white solid. Melting point: 124-126 °C.
Example 3
Synthesis of (3S)-3-{[({4-amino-1-[(2-chlorophenyl)methyl]-6-methyl-2-oxo-1,2-
dihydro-3-pyridinyl}amino)carbonyl]amino}-3-(4-methylphenyl)propanoic acid (22).
Step One: To a solution of compound 11 (10.00 g, 58.8 mmol) in anhydrous DMF
(120 mL) at 0 °C was added NaH (60% dispersion in mineral oil, 5.40 g, 135 mmol). The
mixture was stirred at 0 °C for 15 minutes before the addition of 2-chlorobenzylchloride
(12.3 g, 76.4 mmol). After stirring at 55 °C overnight, the mixture was poured into ice-
water and washed with Et2O twice. The aqueous layer was acidified and filtration of the
resulting precipitate gave compound 16 (14.7 g, 85%).
Step Two: To a flask containing compound 16 (8.00 g, 28.6 mmol) sealed with a
rubber septum and balloon at room temperature under dry nitrogen atmosphere, POCl3
(30.0 ml, 322 mmol) was added via syringe. The nitrogen line was removed and the
reaction mixture was stirred overnight at 70 °C, then poured over ice (300ml) and stirred
for 30 minutes. The resulting mixture was extracted with dichloromethane (300 ml) and
the organic phase was dried over MgSO4 and filtered. The filtrate was concentrated under
reduced pressure to give compound 17 (7.3g, 86%) as a dark brown solid.
Step Three: To a 250 ml flask equipped with condenser and rubber septum fitted
with a balloon, a solution of compound 17 (2.1g, 7.05 mmol), methanol (55ml) and
aqueous ammonium hydroxide (28-30%, 70.0 ml, 1.14 mol) were added at room
temperature. The reaction mixture was heated to 65 °C for 60 hours open only to the
balloon. The mixture was filtered and the filtrate was concentrated under reduced
pressure to yield compound 18 (1.5 g, 76%) as a brown solid.
Step Four: To a solution of compound 18 (0.3g, 1.02 mmol) in methanol (50 ml)
at room temperature, saturated aqueous ammonium chloride (2 ml) and zinc dust (0.30 g,
4.6 mmol) were added sequentially. After stirring 30 minutes at room temperature,
additional zinc was added (0.30 g, 4.6 mmol) and the reaction mixture was refluxed
overnight. The reaction mixture was filtered hot and the filtrate was concentrated under
reduced pressure. The residue was partitioned between ethyl acetate and 1N NaOH. The
solution was filtered and the aqueous phase extracted with ethyl acetate. The combined
organic phases were dried over MgSO4 and filtered. The filtrate was concentrated under
reduced pressure to yield compound 19 (0.2 lg, 78%) as a brown solid.
Step Five: A solution of compound 19 (0.10 g, 0.38 mmol), NMM (0.040 mL,
0.38 mmol) and compound 20 (0.14 g, 0.38 mmol) in anhydrous DMF (5 mL) was heated
to 50 °C overnight. The mixture was cooled and diluted with ethyl acetate (60 mL). The
organic layer was washed with 0.5N NaOH (3 x 30 mL) and brine, dried over MgSO4 and
filtered. The filtrate was concentrated under reduced pressure and the residue was
purified by flash chromatography on silica gel, eluting with 9:1 increasing to 17:3
CHCl3:MeOH to give compound 21 (0.120 g, 65%) as a yellow foam.
Step Six: A solution of compound 21 (0.120 g, 0.25 mmol) in THF (6 mL) was
treated with 2N NaOH (2 mL). Methanol was added until a homogeneous solution was
achieved. The reaction mixture was stirred at room temperature for 30 minutes and
poured into H2O (50 mL). The aqueous layer was washed with diethyl ether (twice), and
then acidified with 1N HCl. The aqueous layer was extracted with ethyl acetate (twice).
The combined ethyl acetate extracts were washed with brine (twice), dried over MgSO4
and filtered. The filtrate was concentrated under reduced pressure to give (3S)-3-{[({4-
amino-1 -[(2-chlorophenyl)methyl]-6-methyl-2-oxo-1,2-dihydro-3-pyridinyl}amino)-
carbonyl]amino}-3-(4-methylphenyl)propanoic acid (22, 0.100 g, 89%) as an off-white
solid. Melting point: 145-147 °C.
Example 4
Synthesis of (3S)-3-[({[1-[(2-chlorophenyl)methyl]-4-(methyloxy)-2-oxo-1,2-dihydro-
3-pyridinyl]amino}carbonyl)amino]-3-(4-methylphenyl)propanoic acid.
Step One: To a solution of compound 23 (10.00 g, 64.0 mmol) in anhydrous DMF
(130 mL) at 0°C was added NaH (60% dispersion in mineral oil, 5.90 g, 147 mmol). The
mixture was stirred at 0 °C for 15 minutes before the addition of 2-chlorobenzylchloride
(13.4 g, 83.3 mmol). After stirring at 55 °C overnight, the mixture was poured into ice
water and washed with Et2O (twice). The aqueous layer was acidified and filtration of the
resulting precipitate gave compound 24 (13.5 g, 75%).
Step Two: A suspension of compound 24 (1.0 g, 3.6 mmol), K2CO3 (0.85 g, 6.2
mmol) and Mel (1.18 g, 8.3 mmol) in acetone (20 mL) was refluxed overnight. The
reaction mixture was diluted with ethyl acetate and washed with saturated aqueous
NaHCO3, 1N HCl and brine. The organic layer was dried over MgSO4 and filtered and
the filtrate was concentrated under reduced pressure to give Compound 25 (0.74 g, 70%).
(3S)-3-[({[1-[(2-chlorophenyl)methyl]-4-(methyloxy)-2-oxo-1,2-dihydro-3-
pyridinyl]amino}carbonyl)amino]-3-(4-methylphenyl)propanoic acid was prepared from
compound 25 according to procedures described in Example 3. MS: Calculated: (M+H)+
= 469.93; Found: (M+H)+ = 470.01.
Example 5
Synthesis of (3S)-3-{[({1 -[(2-chlorophenyl)methyl]-4-fluoro-2-oxo-1,2-dihydro-3-
pyridinyl}amino)carbonyl]amino}-3-(4-methylphenyl)propanoic acid.
Step One: Compound 3 (0.65 g, 3.1 mmol) was dissolved in dry THF (12.4 mL)
and TMEDA (0.90 mL, 6 mmol) under a dry nitrogen atmosphere. The resulting solution
was chilled to between -15 and -10 °C and n-butyllithium (1.6 M in hexanes, 7.75 mL,
12.4 mmol) was added dropwise via syringe. After 1.5 hours, a solution of N-
fiuorobenzenesulfonimide (1.07g, 3.4 mmol) in THF (5 mL) was added to the cold
solution rapidly via syringe. The solution was stirred at 0 °C for 1 hour, then room
temperature for 3 hours. The mixture was quenched with water and extracted with
chloroform (4 times). The combined organic extracts were washed with brine, dried over
MgSO4 and filtered. The filtrate was concentrated under reduced pressure and the residue
was purified by chromatography, (SiO2, plug gel, using 4:1 switching to 3:1 hexanes:ethyl
acetate) to yield compound 26 (0.177g, 25%).
(3S)-3-{[({1-[(2-Chlorophenyl)methyl]-4-fluoro-2-oxo-1,2-dihydro-3-
pyridinyl}amino)carbonyl]amino}-3-(4-methylphenyl)propanoic acid was prepared from
Compound 26 according to procedures described in Example 1. MS: Calculated:
(M+H)+ = 458.12; Found: (M+H)+= 458.01.
Example 6
Synthesis of (3S)-4-chloro-3-{[({1-[(2-chlorophenyl)methyl]- 2-oxo-1,2-dihydro-
3 -pyridinyl} amino)carbonyl]amino} -3 -(4-methylphenyl)propanoi c acid.
Step One: Compound 3 (0.65 g, 3.1 mmol) was dissolved in THF (21 mL) and
TMEDA (1.20 mL, 7.75 mmol) and chilled to -15 °C. The solution was treated with n-
butyllithium (1.6 M in hexanes, 4.8 mL, 7.8 mmol). The mixture was maintained between
-20 and -10 °C for 1 hour, then cooled to -78 °C. Solid N-chlorosuccinimide
(0.45 g, 3.4 mmol) was added while the apparatus was under a positive flow of nitrogen.
The reaction was allowed to gradually warm to room temperature then stirred overnight.
The mixture was quenched with water and extracted with chloroform (4 times). The
organic layers were combined, dried over MgSO4 and filtered. The filtrate was
concentrated under reduced pressure and the residue was recrystallized from hexanes to
give compound 27 (0.25 g, 33%).
(3S)-4-Chloro-3-{[({1 -[(2-chlorophenyl)methyl]- 2-oxo-1,2-dihydro-3-
pyridinyl}amino)carbonyl]amino}-3-(4-methylphenyl)propanoic acid was prepared from
compound 27 according to procedures described in Example 1.
Example 7
Synthesis of (3S)-4-bromo-3-{[({1-[(2-chlorophenyl)methyl]- 2-oxo-1,2-dihydro-
3-pyridinyl}amino)carbonyl]amino} -3-(4-methylphenyl)propanoic acid.
Step One: Compound 3 (2.00g, 9.6 mmol) was dissolved in dry THF (32 mL) and
TMEDA (2.20 mL, 14.4 mmol) under a dry nitrogen atmosphere. The resulting solution
was chilled to between -20 and -10 °C and n-butyl lithium (1.60 M in hexanes, 18.0 mL,
28.8 mmol) was added dropwise via syringe. Upon completion of the addition, the
solution was chilled to -78 °C and bromine (0.49 mL, 10.5 mmol) was added dropwise
via syringe. The solution was allowed to warm slowly to room temperature overnight,
then was quenched with water and extracted with chloroform. The organic layer was
dried over MgSO4 and filtered and the filtrate was concentrated under reduced pressure.
The residue was recrystallized from hexanes to give compound 28 (1.32 g, 48%) as a
tannish white solid.
(3S)-4-Bromo-3-{[({1-[(2-chlorophenyl)methyl]-2-oxo-1,2-dihydro-3-
pyridinyl}amino)carbonyl]amino}-3-(4-methylphenyl)propanoic acid was prepared from
compound 28 according to procedures described in Example 1.
Example 8
Synthesis of (3S)-3-{[({1-[(2-chlorophenyl)methyl]-4-hydroxy-2-oxo-1,2-
dihydro-3-pyridinyl}amino)carbonyl]amino}-3-(4-methylphenyl)propanoic acid (32).
Step One: To a solution of compound 24 (1.5 g, 5.3 mmol) in methanol (50 ml) at
room temperature, saturated ammonium chloride (1.5 mL) and zinc dust (1.5 g, 23 mmol)
were added sequentially. After stirring 30 minutes at room temperature, additional zinc
dust (1.5 g, 23 mmol) was added and the reaction mixture was re fluxed overnight. The
reaction mixture was filtered while hot and the filtrate was concentrated under reduced
pressure. HCl (1 N) was added to the resulting residue until the pH was approximately 4
and the resulting precipitate was collected by filtration to give compound 29 (0.80 g,
57%) as a brown solid.
Step Two: A solution of compound 29 (0.26 g, 1.0 mmol) and CDI (0.25 g, 1.6
mmol) in DMF (10 mL) was heated to 70 °C overnight. After cooling to room
temperature, the mixture was diluted with ethyl acetate and washed with 1N HCl (3
times) and brine. The organic layer was dried over MgSO4 and filtered and the filtrate
was concentrated under reduced pressure to give compound 30 (0.14 g, 50%) as a brown
solid.
Step Three: A solution of compound 30 (0.1 g, 0.36 mmol) and compound 8 (0.082 g,
0.40 mmol) in anhydrous DMF (5 mL) was heated to 70 °C overnight. The mixture was
cooled, diluted with ethyl acetate and washed with 1N HCl (3 times) and brine. The organic
layer was dried over MgSO4 and filtered and the filtrate was concentrated under reduced
pressure. The residue was purified by flash chromatography (SiO2), eluting with 9:1
CHCl3:MeOH to give compound 31 (0.17 g, 97%).
Step Four: A solution of compound 31 (0.170 g, 0.35 mmol) in THF (3 mL) was
treated with 2N NaOH (1 mL). Methanol was added until a homogeneous solution was
achieved. The reaction mixture was stirred at room temperature for 30 minutes and
poured into H2O (50 mL). The aqueous layer was washed with diethyl ether (twice), and
then acidified with 1N HCl. The aqueous layer was extracted with ethyl acetate (twice).
The combined ethyl acetate extracts were washed with brine (twice), dried over MgSO4
and filtered. The filtrate was concentrated under reduced pressure to give (3S)-3-{[({1-
[(2-chlorophenyl)methyl]-4-hydroxy-2-oxo-1,2-dihydro-3-
pyridinyl}amino)carbonyl]amino}-3-(4-methylphenyl)propanoic acid (32, 0.150 g, 94%)
as an off-white solid. Melting point: 113-115 °C.
Example 9
Synthesis of (3S)-3-{[({1-[(2-chlorophenyl)methyl]-2-oxo-4-phenyl-1,2-dihydro-
3-pyridinyl}amino)carbonyl]amino}-3-(4-methylphenyl)propanoic acid.
Step One: Compound 33 (prepared from compound 28 according to procedures
described in Example 1, 0.20 g, 0.50 mmol) was dissolved in DMF (1.8 mL) and water
(0.7 mL) and treated with K3PO4 (0.39 g, 1.86 mmol) and phenyl boronic acid (0.113 g,
0.93 mmol). The resulting mixture was deoxygenated (switching between vacuum and
nitrogen 5 times), then tetrakis(triphenylphosine)palladium(0) (8.7 mg, 0.050 mmol) was
added. The mixture was deoxygenated as before and heated at 90 °C overnight. The
mixture was cooled, diluted with water and extracted with ethyl acetate (2 times). The
combined extracts were washed with brine, dried over MgSO4 and filtered through silica
gel and concentrated under reduced pressure. The residue was suspended in 1:1
water:concentrated HCl (2 mL) and acetonitrile (0.5 mL). The suspension was brought to
reflux for 1 hour, then cooled, and partitioned between ethyl acetate and saturated
aqueous NaHCO3. The ethyl acetate layer was washed with brine, dried over MgSO4,
filtered, and concentrated under reduced pressure. The residue was purified by flash
chromatography (SiO2, 3:1 hexanes/ethyl acetate) to give compound 34 (0.115 g, 94%).
This material was used without purification.
(3S)-3- {[({1-[(2-Chlorophenyl)methyl]-2-oxo-4-phenyl-1,2-dihydro-3-
pyridinyl}amino)carbonyl]amino}-3-(4-methylphenyl)propanoic acid was prepared from
Compound 34 according procedures described in Example 1. 1H NMR (400 MHz,
CD3OD): d 2.25 (s, 3H), 2.50 (m, 2H), 4.89 (t, J = 5.9 Hz, 1H), 5.34 (s, 2H), 6.40 (d, J =
7.0HZ, 1H), 7.0 (d, J = 8.0 Hz, 2H), 7.10 (d, J = 8.0 Hz, 2H), 7.18 (m, 1H), 7.28 (m, 2H),
7.35 (m, 3H), 7.43 (m, 1H), 7.49 (m, 3H).
Example 10
Synthesis of (3S)-3-[({[2-methyl-4-(2-methylpropyl)-6-oxo-1-(phenylmethyl)-1,6-
dihydro-5-pyrimidinyl]amino}carbonyl)amino]-3-(4-methylphenyl)propanoic acid (43).
Step One: Compound 35 (2.00 g 18.2 mmol) was dissolved in 30 mL of dry
methanol. To this was added benzylamine (1.97 g 18.2 mmol) and triethylamine (2.0 g
20.0 mmol). The reaction mixture was stirred at 50 °C for 3 hours, and then concentrated
under reduced pressure. The residue was partitioned between H2O and CH2Cl2. The
organic layer was dried over MgSO4 and filtered and the filtrate was concentrated under
reduced pressure to give compound 36 (2.3 g, 82%).
Step Two: To a solution of compound 37 (3.50 g, 26.5 mmol) in ethanol (10 mL)
and pyridine (5 mL) was added isovaleraldehyde (2.8 mL 27 mmol) and piperidine (1
mL). The reaction mixture was heated to reflux for 3 hours and concentrated under
reduced pressure. The residue was partitioned between 2N HCl (15 mL) and ethyl acetate
(30 mL). The organic layer was dried over MgSO4, and filtered and the filtrate was
concentrated under reduced pressure. The residue was purified by silica gel
chromatography, eluting with 2:1 hexanes:ethyl acetate to give compound 38 (3.6 g,
67%).
Step Three: A solution of compound 38 (2.5 g, 12.48 mmol) and compound 36
(2.52 g, 13.7 mmol) in dry methanol (25 mL) was heated to vigorous reflux for 3 hours,
cooled and concentrated under reduced pressure. The residue was chromatographed on
silica gel eluting with 2:1 hexanes:ethylacetate to give compound 39 (2.75 g, 69%).
Step Four: To a solution of compound 39 (2.5 g, 7.9 mmol) in CCl4 (15 mL) was
added NBS (1.4 g, 8.0 mmoL), K2CO3 (11.0 g, 80.0 mmol), and benzoyl peroxide (50 mg,
0.20 mmol). The reaction mixture was heated to reflux for 1 hour, cooled to room
temperature, diluted with H2O and extracted with CH2Cl2. The organic layer was dried
over MgSO4 and filtered and the filtrate was concentrated under reduced pressure. The
residue was chromatographed on silica gel eluting with 3:1 hexanes:ethyl acetate to give
compound 40 (0.62 g, 25%).
Step Five: Compound 40 (0.60 g, 1.9 mmol) was treated with 2N NaOH (5mL)
and THF (3 mL). The resulting mixture was stirred at room temperature for 2 hours,
acidified with 2N HCl and extracted with ethyl acetate. The organic layer was dried over
MgSO4 and filtered and the filtrate was concentrated under reduced pressure to give
compound 41 (560 mg, 98%).
Step Six: To a solution of compound 41 (0.56 g, 1.86 mmol) in dry benzene (10
mL), diphenylphosphorylazide (0.56 g, 2.0 mmol) and triethylamine (2.02 g, 2.0 mmol)
were added. The reaction mixture was heated to 90 °C for 1 hour then a solution of
compound 8 (0.39 g, 1.9 mmol) in benzene (2 mL) was added. The reaction was stirred
at 90 °C for an additional 1 hour, cooled to room temperature, diluted with 10% aqueous
ammonium chloride and extracted with ethyl acetate. The organic layer was dried over
MgSO4 and filtered and the filtrate was concentrated under reduced pressure. The residue
was chromatographed on silica gel, eluting with 7:3 ethyl acetate:hexane to give
compound 42 (0.38 g, 40%).
Step Seven: To a solution of compound 42 (0.35 g 0.7 mmol) in 1:1 mixture of
THF:MeOH (8 mL) was added 2N NaOH (8 mL). The reaction was stirred at room
temperature for 3 hours, acidified with 2N HCl (10 mL) and extracted with ethyl acetate
(20 mL). The organic layer was dried over MgSO4 and filtered and the filtrate was
concentrated under reduced pressure to give (3S)-3-[({[2-methyl-4-(2-methylpropyl)-6-
oxo-1-(phenylmethyl)-1,6-dihydro-5-pyrimidinyl]amino}carbonyl)amino]-3-(4-
methylphenyl)propanoic acid (43, 250 mg, 75%). MS: Calculated: (M+H)+ = 477.25 m/z;
Found: (M+H)+ = 477.17 m/z.
Example 11
Synthesis of (3S)-3-[({[2-methyl-6-oxo-1-(phenylmethyl)-1,6-dihydro-5-
pyrimidinyl]ammo}carbonyl)amino]-3-(4-methylphenyl)propanoic acid
Step One: A solution of compound 36 (2.3 g , 15.5 mmol) and compound 44 (3.36
g, 15.5 mmol) in absolute ethanol (35 mL) was refluxed for 3 hours and concentrated.
The residue was chromatographed on silica gel, eluting with 1:1 ethyl acetate:hexane to
give compound 45 (1.87 g, 55% yield).
(3S)-3-[({[2-Methyl-6-oxo-1-(phenylmethyl)-1,6-dihydro-5-
pyrimidinyl]amino}carbonyl)amino]-3-(4-methylphenyl)propanoic acid was prepared
from compound 45 according to procedures described in Example 10. 1H NMR (400
MHz, CD3OD) d 2.28 (s, 3H), 2.35 (s, 3H), 2.57 (m, 2H), 5.16 (m, 1H), 5.30 (s, 2H), 7.13
(m, 4H), 7.30 (m, 5H), 8.50 (s, 1H).
Example 12
Synthesis of (3S)-3-{[({1-[(2-chlorophenyl)methyl]-4-[({ethyl[(ethylamino)
carbonyl]amino}carbonyl)amino]-2-oxo-1,2-dihydro-3-
pyridinyl}amino)carbonyl]amino}-3-(4-methylphenyl)propanoic acid.
Step One: To a solution of compound 46 (prepared according to procedures
described in Example 3, 0.50 g, 1.8 mmol) in THF (10 mL) at 0 °C was added NaH (60%
dispersion in mineral oil, 0.23 g, 5.1 mmol). The mixture was stirred for 10 minutes at 0
°C, then ethyl isocyanate (0.65 g, 9.15 mmol) was added. The mixture was stirred at
room temperature over the weekend, was quenched with 1 N HCl and extracted with
ethyl acetate. The organic layer was dried over MgSO4 and filtered and the filtrate was
concentrated under reduced pressure to give compound 47 (0.60 g). This material was
used without purification.
(3S)-3-{[({1-[(2-Chlorophenyl)methyl]-4-[({ethyl[(ethylamino)carbonyl]
amino}carbonyl)amino]-2-oxo-1,2-dihydro-3-pyridinyl}amino)carbonyl] amino}-3-(4-
methylphenyl)propanoic acid was prepared from compound 47 according to procedures
described in Example 3. Melting point: 128-130°C.
Example 13
Synthesis of (3S)-3-{[({1-[(2-chlorophenyl)methyl]-4-hydroxy-2-oxo-1,2-
dihydro-3-quinolinyl}amino)carbonyl]amino}-3-(4-methylphenyl)propanoic acid.
Step One: To a solution of compound 48 (2.00 g, 9.70 mmol) in anhydrous DMF
(25 mL) at 0 °C was added NaH (60% dispersion in mineral oil, 0.89 g, 22 mmol). The
mixture was stirred at 0 °C for 15 minutes before the addition of 2-chlorobenzylchloride
(2.03 g, 12.6 mmol). After stirring at 55 °C overnight, the mixture was poured into ice-
water and washed with Et2O (twice). The aqueous layer was acidified and filtration of the
resulting precipitate gave compound 49 (3.45 g). This material was used without
purification.
(3S)-3- {[({1-[(2-chlorophenyl)methyl]-4-hydroxy-2-oxo-1,2-dihydro-3-
quinolinyl}amino)carbonyl]amino}-3-(4-methylphenyl)propanoic acid was prepared from
compound 49 according to procedures described in Example 8. Melting point: 134-136
°C.
Example 14
Synthesis of (3S)-3-{[({1-[(2-chlorophenyl)methyl]-5-methyl-2-oxo-1,2-dihydro-
3-pyridinyl}amino)carbonyl]amino} -3-(4-methylphenyl)propanoic acid (56).
Step One: To a suspension of compound 51 (1.67 g, 9.81 mmol) in DMF (33 mL)
at room temperature under a dry, nitrogen atmosphere, 2-chlorobenzylamine (1.30 mL,
10.8 mmol) and EDCl (2.35 g, 12.3 mmol) were added sequentially. The resulting
mixture was vigorously stirred at room temperature for 5 hours, diluted with ethyl acetate
and washed with 2 N HCl, H2O (3 times), saturated aqueous NaHCO3 and brine. The
organic layer was dried over MgSO4 and filtered and the filtrate was concentrated under
reduced pressure to give compound 52 (2.55 g, 100%) as a pale yellow solid.
Step Two: A solution of compound 52 (555 mg, 2.17 mmol) and 3-
dimethylamino-2-methylpropenal (738 mg, 6.5 mmol) in absolute ethanol (4.3 mL) and
glacial acetic acid (0.22 mL) was heated to reflux overnight. The resulting mixture was
cooled to room temperature, diluted with ethyl acetate and washed with 2 N HCl (twice),
H2O and brine. The organic layer was dried over MgSO4 and filtered and the filtrate was
concentrated under reduced pressure. The pressure was purified by chromatography on
silica gel, eluting with 7:3 increasing to 1:1 hexanes:ethyl acetate and finally 19:19:2
hexanes:ethyl acetate:methanol to yield compound 53 (182 mg, 27%) as a yellow oil.
Step Three: To a solution of compound 53 (167 mg, 0.55 mmol) in THF (3 mL), 2
N NaOH (1 mL) and methanol (2 mL) were added. The resulting mixture was stirred for
15 minutes, diluted with H2O and extracted with ethyl ether. The aqueous layer was
acidified with 2 N HCl and extracted with ethyl acetate. The ethyl acetate layer was
washed with H2O and brine, dried over MgSO4 and filtered. The filtrate was concentrated
under reduced pressure to give compound 54 (139 mg, 91%) as a white solid.
Step Four: To a suspension of compound 54 (175 mg, 0.63 mmol) in THF (6.7
mL) and DIPEA (0.23 mL, 1.34 mmol) at room temperature under a dry, nitrogen
atmosphere, DPPA (0.29 mL, 1.34 mmol) was added via syringe. The resulting mixture
was stirred at room temperature for 15 minutes, then heated to reflux for 3.5 hours. The
mixture was allowed to cool to room temperature and a solution of compound 8 (278 mg,
1.34 mmol) in THF (6.0 mL) was added via cannula along with a THF (0.7 mL) rinse.
The resulting mixture was stirred at room temperature overnight, diluted with ethyl
acetate and washed with 2 N HCl (twice), saturated aqueous NaHCO3 and brine. The
organic layer was dried over MgSO4 and filtered and the filtrate was concentrated under
reduced pressure. The residue was purified by silica gel chromatography, eluting with 7:3
then 3:2 and finally 1:1 hexanes:ethyl acetate to yield compound 55 (60 mg, 20%) as a
colorless oil.
Step Five: To a solution of compound 55 (60 mg, 0.12 mmol) in THF (3 mL),
0.192 N NaOH (0.65 mL, 0.12 mmol) and methanol (2 mL) were added. The resulting
mixture was stirred at room temperature for 24 hours, then was diluted with H2O. The
organic solvents were removed under reduced pressure and the resulting aqueous mixture
was extracted with ethyl ether. The aqueous phase was lyophilized to give (3S)-3-{[({1-
[(2-chlorophenyl)methyl]-5-methyl-2-oxo-l,2-dihydro-3-
pyridinyl}amino)carbonyl]amino}-3-(4-methylphenyl)propanoic acid, sodium salt (56, 56
mg, 95%) as an off-white solid. MS: Calculated for (C24H23ClN3O4)-: 452.14 m/z;
Found: 451.99 m/z.
Example 15
Synthesis of (3S)-3-(l,3-benzodioxol-5-yl)-3-[({[2-oxo-1-(2-thienylmethyl)-1,2-
dihydro-3-pyridinyl]amino}carbonyl)amino]propanoic acid (62).
Step One: To a solution of 2-thiophenemethanol (1.015 g, 8.89 mmol) in CH2Cl2
(17.8 ml) cooled to 0°C under a dry nitrogen atmosphere, triethylamine (2.98 ml, 21.4
mmol) and methanesulfonyl chloride (0.69 ml, 8.9 mmol) were added sequentially by
syringe. The resulting mixture was stirred at 0°C for 15 minutes, then 2-hydroxy-3-
nitropyridine (1.496 g, 10.7 mmol) and 4-dimethylaminopyridine (catalytic) were added.
The mixture was allowed to gradually warm to room temperature and then was stirred
overnight. The mixture was diluted with ethyl acetate and washed with 2N HCl, H2O,
saturated NaHCO3 and brine. The organic phase was dried over MgSO4 and filtered and
the filtrate was concentrated under reduced pressure to give 58 (395 mg) as a yellow
waxy solid. This material was used without purification.
Step Two: To a solution of 58 (330 mg, 1.40 mmol) in glacial acetic acid (6.6 ml)
at room temperature under a dry nitrogen atmosphere, iron powder (154 mg, 2.8 mmol,
-325 mesh) was added. The resulting solution was heated to 60°C in an oil bath with
vigorous stirring for 20 minutes. The mixture was cooled to room temperature, diluted
with ethyl acetate and filtered through Celite. The filtrate was washed with H2O.
saturated NaHCO3 and brine. The organic phase was dried over MgSO4 and filtered and
the filtrate was concentrated under reduced pressure. The residue was filtered through
silica gel, eluting with 1:1 hexanes:ethyl acetate increasing to 1:3 hexanes:ethyl acetate to
yield 59 (188 mg, 12% for two steps) as a greenish solid.
Step Three: To a solution of 59 (111 mg, 0.54 mmol) in CH2Cl2 (2.7 ml) cooled to
0°C under a dry nitrogen atmosphere, N,N-diisopropylethylamine (0.23 ml, 1.30 mmol)
and phosgene (0.31 ml, 1.9M in toluene, 0.59 mmol) were added sequentially by syringe.
The resulting mixture was stirred at 0°C for 15 minutes, then a solution of ß-amino ester
60 (167 mg, 0.70 mmol) in CH2Cl2 (2.7 ml) was added by cannula along with a CH2Cl2
rinse (1.0 ml). The resulting mixture was allowed to warm to room temperature, was
stirred for 2 hours, was diluted with ethyl acetate and washed with 2N HCl, H2O,
saturated NaHCO3 and brine. The organic phase was dried over MgSO4 and filtered and
the filtrate was concentrated under reduced pressure. The residue was purified by silica
gel chromatography, eluting with 1:1 hexanes:ethyl acetate to yield 61 (231 mg, 91%) as
a purple foam.
Step Four: To a solution of ester 61 (227 mg, 0.48 mmol) in THF (6 ml) at room
temperature, NaOH (2 ml, 2N in H2O, 4 mmol) and methanol (enough to give a clear
solution, approximately 2 ml) were added. The resulting mixture was stirred for 15
minutes, then was diluted with water and extracted with ether. The aqueous phase was
acidified with HCl (2N) and extracted with ethyl acetate. The organic phase was washed
with brine, dried over MgSO4 and filtered and the filtrate was concentrated under reduced
pressure to give 62 (191 mg, 90%) as a white solid. 1H NMR (400 MHz, CD3SOCD3) d
2.63 (d, J = 7.3 Hz, 2H), 4.99 (dt, J = 8.4, 7.3 Hz, 1H), 5.30 (s, 2H), 5.98 (m, 2H), 6.21
(dd, J = 7.5, 7.0 Hz, 1H), 6.78 (dd, J = 8.1, 1.6 Hz, 1H), 6.85 (d, J = 8.1 Hz, 1H), 6.88 (d,
J= 1.6 Hz, 1H), 6.97 (dd, J = 5.1, 3.5 Hz, 1H), 7.17 (dd, J = 3.5, 1.1 Hz, 1H), 7.35 (dd, J
= 7.0, 1.8 Hz, 1H), 7.44 (dd, J = 5.1, 1.1 Hz, 1H), 7.67 (d, J = 8.4 Hz, 1H), 7.94 (dd, J =
7.5, 1.8 Hz, 1H), 8.40 (s, 1H).
Example 16
Synthesis of (3S)-3-(1,3-benzodioxol-5-yl)-3-[({[(3S)-2-oxo-1-(2-
thienylmethyl)hexahydro-3-pyridinyl]amino}carbonyl)amino]propanoic acid (68).
Step One: To a solution of N-a-tert-butoxycarbonyl-N-d-benzyloxycarbonyl-L-
ornithine 63 (1.00 g, 2.73 mmol) and cesium carbonate (1.33 g, 4.1 mmol) in DMF (10
ml) at room temperature under a dry nitrogen atmosphere, iodomethane (0.22 ml, 3.3
mmol) was added by syringe. The resulting mixture was stirred at room temperature for
18 hours then was diluted with ethyl acetate and washed with H2O, 10% Na2S2O5,
saturated NaHCO3 and brine. The organic phase was dried over MgSO4 and filtered and
the filtrate was concentrated under reduced pressure to give ester 64 (1.21g) as a pale
yellow oil. This material contained DMF but was used without purification.
Step Two: To a solution of 64 (0.86 g of crude material prepared in previous
procedure, 1.94 mmol theoretical) in methanol (10 ml) at 0°C under a dry nitrogen
atmosphere, palladium on charcoal (300 mg, 10% Pd, Degussa type E101 NE/W, wet,
50% water by weight) was added. The nitrogen atmosphere was replaced by hydrogen
(alternate five times between vacuum and hydrogen supplied by balloon) and the mixture
was stirred at 0°C for 30 minutes then filtered directly into a flask containing 2-
thiophenecarboxaldehyde (177 mg, 1.58 mmol). The mixture was concentrated (water
bath at room temperature) and the residue was taken up in dichloroethane (6 ml). To this
solution, sodium triacetoxyborohydride (479 mg, 2.26 mmol) was added and the mixture
was stirred for 2 hours, diluted with ethyl acetate and washed with saturated NaHCO3 (2
times) and brine. The organic phase was dried over MgSO4 and filtered and the filtrate
was concentrated under reduced pressure. The residue was filtered through silica gel,
eluting with 7:3 hexanes:ethyl acetate to yield lactam 65 (75 mg, 12% for two steps) as a
colorless oil.
Step Three: To a flask containing 65 (89 mg, 0.29 mmol) sealed with a rubber
septum at room temperature under a dry nitrogen atmosphere, HCl (7.2 ml, 4.0M in
dioxane, 28.8 mmol) was added by syringe. The nitrogen needle was removed and the
mixture in the sealed flask was stirred overnight. The mixture was diluted with CH2Cl2
and washed with saturated NaHCO3. The organic phase was dried over MgSO4 and
filtered and the filtrate was concentrated under reduced pressure to give amine 66 (60
mg, 100%) as a light yellow oil. This material was used without purification.
Step Four: To a solution of ß-amino ester 60 (75 mg, 0.32 mmol) in CH2Cl2 (0.6
ml) at room temperature under a dry nitrogen atmosphere, carbonyldiimidazole (51 mg,
0.32 mmol) was added. The resulting mixture was stirred at room temperature for 5
minutes and a solution of amine 66 (60 mg, 0.29 mmol) in CH2Cl2 (0.6 ml) was added by
cannula along with a CH2Cl2 (0.2 ml) rinse. The resulting mixture was stirred at room
temperature for 3 days, then was diluted with ethyl acetate and washed with 2N HCl (2
times), H2O, saturated NaHCO3 and brine. The organic phase was dried over MgSO4 and
filtered and the filtrate was concentrated under reduced pressure. The residue was filtered
through silica gel, eluting with 1:1 hexanes:ethyl acetate increasing to 2:3 hexanes:ethyl
acetate to yield urea 67 (110 mg, 80%).
Step Five: To a solution of urea 67 (108 mg, 0.23 mmol) in THF (3 ml) at room
temperature, NaOH (1 ml, 2N in H2O, 2 mmol) and methanol (enough to give a clear
solution, approximately 2 ml) were added. The resulting mixture was stirred for 15
minutes, then was diluted with water and extracted with ether. The aqueous phase was
acidified with HCl (2N) and extracted with ethyl acetate. The ethyl acetate layer was
washed with brine, dried over MgSO4 and filtered and the filtrate was concentrated under
reduced pressure to give 68 (92 mg, 90%) as a white foam. 1H NMR (400 MHz,
CD3SOCD3) d 1.45 (m, 1H), 1.76 (m, 2H), 2.62 (m, 2H), 3.25 (m overlapping H2O, 2H),
4.01 (m, 1H), 4.59 (d, J = 15.0 Hz, 1H), 4.68 (d, J = 15.0 Hz, 1H), 4.96 (m, 1H), 5.97 (s,
2H), 6.24 (d, J = 6.6 Hz, 1H), 6.71 (d, J = 8.4 Hz, 1H), 6.75 (dd, J = 8.1, 1.5 Hz, 1H),
6.82 (d, J = 8.1 Hz, 1H), 6.85 (d, J= 1.5 Hz, 1H), 6.97 (dd, J = 5.1, 3.3 Hz, 1H), 7.03 (dd,
J = 3.3, 1.5 Hz, 1H), 7.42 (dd, J = 5.1, 1.5 Hz, 1H), 12.06 (br. s, 1H).
Example 17
Synthesis of (3S)-3-(1,3-benzodioxol-5-yl)-3-[({[(3S)-2-oxo-1-(2-
thienylmethyl)tetrahydro-1H-pyrrol-3-yl]amino}carbonyl)amino]propanoic acid (74).
Step One: To a solution of N-tert-butoxycarbonyl-L-aspartic acid a-benzylester
(2.10 g, 6.5 mmol) in dimethoxyethane (15 ml) cooled to -15°C (bath temperature) under
a dry nitrogen atmosphere, 4-methylmorpholine (0.71 ml, 6.5 mmol) and isobutyl
chloroformate (0.84 ml, 6.5 mmol) were added sequentially by syringe. The resulting
mixture was stirred for 2 minutes, then was filtered, washing the solid cake with
dimethoxyethane (10 ml). The filtrate was recooled to -15°C (bath temperature) and a
solution of sodium borohydride (370 mg, 9.7 mmol) in H2O (3 ml) was added followed
immediately by the addition of H2O (100 ml). The mixture was extracted with ethyl
acetate (3 times) and the organic layers were combined and washed with cold (0°C) HCl
(0.2N), H2O, saturated NaHCO3 and brine. The resulting organic layer was dried over
MgSO4 and filtered and the filtrate was concentrated under reduced pressure to give 69
(2.50 g) as a colorless oil. This material contains some of the unreduced mixed-
anhydride but was used without purification.
Step Two: To a solution of oxalyl chloride (2.4 ml, 2.0 M in CH2Cl2, 4.8 mmol) in
CH2Cl2 (30 ml) cooled to -65°C under a dry nitrogen atmosphere, a solution of
methylsulfoxide (0.55 ml, 7.8 mmol) in CH2Cl2 (8 ml) was added by syringe. The
resulting mixture was stirred at -65°C for 15 minutes, then a solution of alcohol 69
(1.00 g, 3.2 mmol) in CH2Cl2 (29 ml) was added by cannula along with a CH2Cl2 (3 ml)
rinse. The mixture was stirred at -65°C for 3 hours, then was allowed to warm to -20°C
(bath temperature). Triethylamine (0.96 ml, 6.9 mmol) was added, followed by H2O (20
ml). The aqueous layer was extracted with CH2Cl2 and the combined organic phases
were dried over MgSO4 and filtered. The filtrate was concentrated under reduced
pressure to give aldehyde 70 as a white solid. This material was used immediately
without purification.
Step Three: To a solution of the crude aldehyde 70 (3.2 mmol theoretical) and 2-
aminomethylthiophene (402 mg, 3.55 mmol) in dichloroethane (13 ml) at room
temperature under a dry nitrogen atmosphere, sodium triacetoxyborohydride (959 mg, 4.5
mmol) was added. The resulting mixture was stirred at room temperature overnight, then
was diluted with ethyl acetate and washed with saturated NaHCO3 and brine. The organic
phase was dried over MgSO4 and filtered and the filtrate was concentrated under reduced
pressure. The residue was purified by silica gel chromatography, eluting with 1:1
hexanes:ethyl acetate to yield lactam 71 (220 mg, 23% for 3 steps) as a white solid.
Step Four: To a solution of 71 (220 mg, 0.74 mmol) in dioxane (1.5 ml) sealed with a
rubber septum at room temperature under a dry nitrogen atmosphere, HCl (1.50 ml, 4.0M in
dioxane, 6.0 mmol) was added by syringe. The nitrogen needle was removed and the mixture
in the sealed flask was stirred for 5 hours. The mixture was diluted with CH2Cl2 and washed
with saturated NaHCO3. The organic phase was dried over MgSO4 and filtered and the
filtrate was concentrated under reduced pressure to give amine 72 (129 mg, 89%) as a light
yellow oil. This material was used without purification.
Step Five: To a solution of amine 72 (123 mg, 0.63 mmol) in CH2Cl2 (1.5 ml) at
room temperature under a dry nitrogen atmosphere, carbonyldiimidazole (112 mg, 0.69
mmol) was added. The resulting mixture was stirred at room temperature for 5 minutes
and a solution of ß-amino ester 60 (164 mg, 0.69 mmol) in CH2Cl2 (0.8 ml) was added by
cannula along with a CH2Cl2 (0.2 ml) rinse. The resulting mixture was stirred at room
temperature overnight, then was diluted with ethyl acetate and washed with 2N HCl (2
times), H2O, saturated NaHCO3 and brine. The organic phase was dried over MgSO4 and
filtered and the filtrate was concentrated under reduced pressure. The residue was filtered
through silica gel, eluting with 49:1 chloroform:methanol to yield urea 73 (230 mg, 80%)
as a colorless oil which slowly solidified on standing.
Step Six: To a solution of urea 73 (230 mg, 0.50 mmol) in THF (3 ml) at room
temperature, NaOH (1 ml, 2N in H2O, 2 mmol) and methanol (1 ml) were added. The
resulting mixture was stirred for 1 hour, then was diluted with water and extracted with
ether. The aqueous phase was acidified with HCl (2N) and extracted with ethyl acetate.
The ethyl acetate layer was washed with brine, dried over MgSO4 and filtered and the
filtrate was concentrated under reduced pressure to give 74 (181 mg, 84%) as a white
foam. 1H NMR (400 MHz, CD3SOCD3) IH), 1.64 (m, 1H), 2.30 (m, 1H), 2.64 (m, 2H),
3.20 (m, 2H), 4.17 (dd, J = 8.8, 8.4 Hz, 1H), 4.56 (s, 2H), 4.96 (m, 1H), 5.97 (s, 2H), 6.30
(d, J = 7.0 Hz, 1H), 6.58 (d, J = 8.8 Hz, 1H), 6.77 (m, 1H), 6.80-6.90 (m, 2H), 6.96-7.04
(m, 2H), 7.45 (dd, J = 5.1, 0.7 Hz, 1H), 12.10 (br. s, 1H).
Example 18
Synthesis of (3S)-3-[({[5-chloro-2-hydroxy-3-
(phenylmethyl)phenyl]amino}carbonyl)amino]-3-(4-methylphenyl)propanoic acid.
Step One: To a mixture of 2-phenylmethyl-3-chlorophenol (5.00 g, 22.9 mmol) in
Et2O (20 mL) and 6N HCl (50 mL), KNO3 (2.30 g, 22.9 mmol) and NaNO2 (20 mg,
catalytic) were added sequentially. The resulting mixture was stirred for 2 hours, diluted
with water and extracted with ethyl acetate. The organic layer was washed with water
and brine, dried over MgSO4 and filtered. The filtrate was concentrated under reduced
pressure to give 99 (6.0 g, 100%).
Step Two: To a solution of 99 (6.0 g, 22.8 mmol) in methanol (360 mL), zinc
powder (6.0 g, 92 mmol) and setuated aqueous NH4Cl (6 mL) were added. The resulting
heterogeneous mixture was refluxed overnight. After filtration of the hot mixture and
concentration of the filtrate under reduced pressure, the residue was dissolved in ethyl
acetate and washed with saturated aqueous NaHCO3 and brine. The organic layer was
dried over MgSO4 and filtered and the filtrate was concentrated under reduced pressure to
give compound 100 (2.93 g, 55%).
Step Three: To a solution of 25 (0.20 g, 0.96 mmol) in CH2Cl2 at 0 °C, DIPEA
(0.40 mL, 2.4 mmol) and phosgene (1.93 M in toluene, 0.60 mL, 1.2 mmol) were added
sequentially. The resulting mixture was allowed to warm to room temperature, stirred for
20 minutes, then recooled to 0 °C. To this mixture, a solution of 100 (0.25 g, 1.1 mmol)
in CH2Cl2 was added dropwise. The resulting mixture was allowed to warm to room
temperature overnight, was diluted with water and was extracted with CH2Cl2. The
organic layer was washed with water and brine, dried over MgSO4 and filtered. The
filtrate was concentrated under reduced pressure and the residue was purified by silica gel
chromatography, eluting with 9:1 and increasing to 5:1 hexanes:ethyl acetate to give 101
(60 mg, 12%).
(3S)-3-[({[5-Chloro-2-hydroxy-3-(phenylmethyl)phenyl]amino}carbonyl)amino]-
3-(4-methylphenyl)propanoic acid was prepared from 101 by procedures described in
Example 1. 1H NMR (400 MHz, CD3SO2CD3) d 2.26 (s, 3H), 2.58 (dd, J = 15.8, 6.6 Hz,
1H), 2.67 (dd, J = 15.8, 8.4 Hz, 1H), 3.49 (s, 2H), 4.88 (m, 1H), 7.00-7.70 (m, 13H),
11.95(br. s, 1H).
Example 19
Synthesis of (3S)-3-(1,3-benzodioxol-5-yl)-3-[({butyl[2,5-dioxo-1-
(phenylmethyl)tetrahydro-1H-pyrrol-3-yl]amino}carbonyl)amino]propanoic acid.
Step One: A solution of N-benzylmaleimide (2.60 g, 13.9 mmol) and n-
butylamine (1.00 g, 13.7 mmol) in THF (15 mL) was stirred at room temperature
overnight and concentrated under reduced pressure. The residue was purified by silica
gel chromatography, eluting with 4:1 increasing to 2:1 hexanes:ethyl acetate to give 102
(3.25 g, 90%).
(3S)-3-(1,3-Benzodioxol-5-yl)-3-[({butyl[2.5-dioxo-1-(phenylmethyl)tetrahydro-1H-
pyrrol-3-yl]amino}carbonyl)amino]propanoic acid was prepared from 102 according to
procedures described in Example 1. MP: 80-85 °C.
Example 20
Synthesis of (3S)-3-(1,3-benzodioxol-5-yl)-3-[({[1-(cyclopentylmethyl)-2-oxo-1,2-
dihydro-3-pyridinyl]amino}carbonyl)amino]propanoic acid.
Step One: To a solution of 2-hydroxy-3-nitropyridine (200 mg, 1.4 mmol) in
CH2Cl2 (14 mL) at 0°C under a nitrogen atmosphere, cyclopentanemethanol (178 mg,
1.78 mmol) was added followed by triphenylphosphine (551 mg, 2.1 mmol). The
solution was stirred at 0 °C for 15 minutes and diethyl azodicarboxylate (366 mg, 2.1
mmol) was added dropwise via syringe. The reaction was allowed to stir at 0 °C for one
hour and then at room temperature overnight. The mixture was quenched with methanol
(20 mL) and washed with water (twice). The aqueous layer was extracted with
dichloromethane and the combined organic layers were dried over magnesium sulfate and
filtered. The filtrate was concentrated and the residue was purified by silica gel
chromatography, eluting with 1:1 hexanes:ethyl acetate to afford 103 (299 mg, 96% yield)
as a yellow solid.
(3S)-3-(l,3-Benzodioxol-5-yl)-3-[({[1-(cyclopentylmethyl)-2-oxo-1,2-dihydro-3-
pyridinyl]amino}carbonyl)amino]propanoic acid was prepared from 103 according to
procedures described in Example 1. 1H NMR (400 MHz, CDCl3): d 1.2-1.7 (m, 8H), 2.34 (m,
1H), 2.81 (dd, J = , 1H), 2.95 (dd, J = , 1H), 3.92 (d, J = 7.7 Hz, 2H), 5.30 (m, 1H), 5.92 (m,
2H), 6.30 (t, J = 7.1 Hz, 1H), 6.68-7.00 (m, 5H), 8.33 (d, J = 7.7 Hz, 1H), 8.89 (s, 1H).
Example 21
Synthesis of (3S)-3-(1,3-benzodioxol-5-yl)-3-{[({3-[(2-thiophenylmethyl)amino]
phenyl}amino)carbonyl]amino} propanoic acid.
Step One: To a solution of 2-thiophenecarboxaldehyde (0.48 g, 4.0 mmol) in
dichloromethane was added 3-nitroaniline (0.51 g, 3.7 mmol). The solution was
concentrated to dryness and brought up in 1,2-dichloroethane (16 mL). Molecular sieves
(3A, 1.1 g) were added followed by NaBH(OAc)3 (1.01 g, 4.8 mmol). The solution was
stirred overnight at room temperature, diluted with chloroform and washed with water.
The organic layer was dried over MgSO4 and filtered and the filtrate was concentrated
under reduced pressure to give 104 (0.72 g, 84%).
Step Two: To a solution of 104 (0.30 g, 1.3 mmol) in CH2Cl2 (5.2 mL) and
triethylamine (0.215 mL, 1.5 mmol) at 0 °C was added trifluoroacetic anhydride (0.193
mL, 1.4 mmol). The solution was stirred 15 minutes at 0 °C, the ice bath was removed
and the mixture was stirred for an additional 15 minutes. The mixture was diluted with
CH2Cl2, washed with 2N HCl, water and brine. The organic layer was dried over Na2SO4
and filtered and the filtrate was concentrated under reduced pressure to give 105 (0.38 g,
100 %) as a yellow solid.
Step Three: To a solution of 105 (0.38 g, 1.4 mmol) in ethanol (2.6 mL) and acetic
acid (2.6 mL) at room temperature, Fe powder (0.36 g, 6.5 mmol) was added and the
suspension was stirred vigorously at 40 °C until TLC indicated complete consumption of
105. The mixture was filtered through Celite, washing with chloroform. The filtrate was
diltuted with saturated sodium bicarbonate and the chloroform layer was dried over
Na2SO4 and filtered. The filtrate was concentrated under reduced pressure and the residue
was purified by chromatography on silica gel (gradient elution 6:1 to 4:1 hexanes:ethyl
acetate) to give compound 106 (0.102 g, 25%)
(3S)-3-(1,3-Benzodioxol-5-yl)-3-{[({3-[(2-thiophenylmethyl)amino]phenyl}
amino)carbonyl]amino}propanoic acid was prepared from 106 according to procedures
described in Example 1, 1H NMR (400 MHz, CD3SO2CD3) d 2.50 (m, 2H overlapping
DMSO), 4.37 (d, J = 5.9 Hz, 2H), 4.94 (m, 1H), 5.94 (m, 2H), 6.06 (t, J = 5.8 Hz, 1H), 6.16
(m, 1H), 6.59 (d, J = 8.8 Hz, 1H), 6.78 (m, 3H), 6.85 (dd, J = 8.8, 7.7 Hz, 1H), 6.90 (s, 1H),
6.94 (dd, J = 5.2, 3.7 Hz, 1H), 7.00 (d, J = 3.3 Hz, 1H), 7.33 (dd, J = 5.1, 1.1 Hz, 1H), 8.5 (s,
1H).
Example 22
Synthesis of 3-(1,3-benzodioxol-5-yl)-2,2-difluoro-3-[({[2-oxo-1-(2-
thiophenylmethyl) 1,2-dihydro-3-pyridinyl]amino} carbonyl)amino]propanoic acid.
Step One: To a solution of (1S,2R,5S)-(+)-menthyl (R)-p-toluenesulfinate (3.00 g,
10.2 mmol) in THF (25.5 mL) chilled to -78 °C, lithium bis(trimethylsilyl)amide (1.0 M in
THF, 15.3 mL) was added dropwise over 15 minutes. The resulting mixture was stirred at
room temperature for 6 hours, then chilled to 0 °C. Piperonal (3.06 g, 20.4 mmol) and CsF
(3.10 g, 20.4 mmol) were added rapidly and the suspension stirred 36 hours at room
temperature. The reaction was quenched with saturated NH4Cl and extracted with ethyl
acetate. The organic layer was washed with brine, dried over Na2SO4 and filtered and the
filtrate was concentrated under reduced pressure. The residue was recrystallized from
hexanes and dichloromethane to give compound 108 (1.36 g, 46 %)
Step Two: Ethyl bromodifluoroacetate (0.78 mL, 6.1 mmol) was added to a
suspension of Zn dust (2.00 g, 30.5 mmol) in THF (20.2 mL) and refluxed for 15 minutes.
The suspension was chilled to 0 ° C and 108 (0.87 g, 3.0 mmol) was added. The suspension
was allowed to warm to room temperature and stirred overnight. The mixture was quenched
with a minimum amount of saturated NH4Cl and extracted with ethyl acetate. The organic
layer was washed with saturated aqueous NaHCO3 and brine, dried over Na2SO4 and filtered.
The filtrate was concentrated under reduced pressure and the residue was purified by
chromatography on silica gel (gradient elution 6:1 to 4:1 hexanes:ethyl acetate to give 109
(0.607 g, 61% at 80% conversion).
Step Three: To a solution of 109 (0.700 g, 1.70 mmol) in methanol (4.3 mL) at 0
°C, trifluoroacetic acid (0.26 mL 3.4 mmol) was added. The solution was stirred at 0 °C
for 2 hours, then concentrated to dryness under reduced pressure, while maintaining the
external temperature below 30 °C. The residue was taken up in diethyl ether and washed
with 2N HCl (2 times). The combined aqueous layers were carefully basified with excess
saturated NaHCCb and extracted with diethyl ether. The ether layer was dried over
MgSO4 and filtered and the filtrate was concentrated under reduced pressure to give 110
(0.326 g, 80 %).
3-(1,3-Benzodioxol-5-yl)-2,2-difluoro-3-[( {[2-oxo-1-(2-thiophenylmethyl)-1,2-
dihydro-3-pyridinyl]aminolcarbonyl)amino]propanoic acid was prepared from 110
according to procedures described in Example 1. MS: Calculated (M-H)- = 476.07;
Found (M-H)- = 476.00.
Example 23
Synthesis of (3S)-3-(1,3-benzodioxol-5-yl)-3-({[9-oxo-8-(phenylmethyl)-
2,3,4,5,8,9-hexahydro-1H-pyrido[3,4-b]azepin-1-yl]carbonyl}amino)propanoic acid.
Step One: To a solution of 3 (0.74 g, 3.6 mmol) in THF (14.4 mL) and TMEDA
(1.60 mL, 10.8 mmol) at -20 °C, n-butyllithium (1.6 M in hexanes, 3.4 mL, 5.4 mmol)
and tert-butyllithium (1.7M in pentane, 2.5 mL, 4.3 mmol) were sequentially added
dropwise by syringe. The temperature was allowed to warm to between -10 and 0 °C and
maintained there for 2 hours. To the resulting mixture, 1,4-dibromobutane (1.75 mL,
14.7 mmol) was added rapidly and the solution was allowed to warm to room temperature
and stirred for 4 days. The reaction was quenched with water and extracted with CHCl3 (3
times). The combined extracts were washed with brine, dried over NaSO4 and filtered.
The filtrate was concentrated under reduced pressure and the residue was purified by
chromatography on silica gel, eluting with 4:1 hexanes:ethyl acetate to give 111 (0.4lg,
44%).
(3S)-3-(l,3-Benzodioxol-5-yl)-3-({[9-oxo-8-(phenylmethyl)-2,3,4,5,8,9-
hexahydro-lH-pyrido[3,4-b]azepin-1-yl]carbonyl}amino)propanoic acid was prepared
from 111 according to the procedures described in Example 4. MS: Calculated (M-H)" =
488.18; Found (M-H)- = 488.21.
Example 24
Synthesis of (3S)-3-{[({1-[(2-chlorophenyl)methyl]-2-oxo-1,2-dihydro-3-
pyridinyl}amino)carbonyl]amino}-3-(4-hydroxyphenyl)propanoic acid.
Step One: To a solution of 112 (prepared according to procedures described in
Example 15, 0.19 g, 0.39 mmol) in CH2Cl2 at 0 °C under nitrogen, BBr3 (1.0 M in
CH2Cl2, 1.2 mL, 1.2 mmol) was added by syringe. The mixture was allowed to gradually
warm to room temperature and then stirred overnight. The mixture was diluted with
water and stirred for 30 minutes and further diluted with saturated aqueous NaHCO3. The
organic layer was washed with water and the aqueous layers were combined and acidified
with 2N HCl and extracted with ethyl acetate (3 times). The combined ethyl acetate
layers were dried over MgSO4 and filtered and the filtrate was concentrated under
reduced pressure to yield (3S)-3-{[({1-[(2-chlorophenyl)methyl]-2-oxo-1,2-dihydro-3-
pyridinyl}amino)carbonyl]amino}-3-(4-hydroxyphenyl)propanoic acid (113, 120 mg,
70%). 1H NMR (400 MHz, CD3SO2CD3) d 2.95 (d, J = 5.2 Hz, 2H), 5.28 (s, 2H), 5.35
(ddd, J = 9.2, 4.8, 4.4 Hz, 1H), 6.33 (t, J = 7.1 Hz, 1H), 6.60 (d, J = 8.8 Hz, 2H), 7.04 (m,
5H), 7.22 (m, 3H), 7.37 (dd, J = 7.7, 1.5 Hz, 1H), 8.35 (dd, J = 7.6, 1.5 Hz, 1H), 8.80 (s,
1H).
Example 25
Synthesis of (3S)-3-[({[1-(2-chlorobenzyl)-4-hydroxy-5-methyl-2-oxo-1,2-
dihydropyridin-3-yl]amino}carbonyl)amino]-3-(4-methylphenyl)propanoic acid, 119.
Step One: To a suspension of sodium hydride (3.6 g of 60% dispersion in mineral oil,
90 mmol) in THF (300 mL) under a dry nitrogen atmosphere, TMEDA (13.2 mL, 87.5 mmol)
was added and the mixture was cooled to -20 °C. Methyl propionylacetate (9.60 mL, 76.5
mmol) was added dropwise and the solution was stirred for an additional 15 minutes. A
solution of n-butyllithium (90 mL, 1.6M in hexanes, 144 mmol) was added dropwise and the
resulting mixture was stirred at -20 °C for 15 minutes. Methyl formate
(6.0 mL, 97 mmol) was then added rapidly and the mixture was allowed to stir for 15 minutes
before quenching with HCl (2 N, 250 mL). The reaction was diluted with diethyl ether (150
mL) and the organic layer was washed twice more with water. The aqueous layers were
combined and sodium chloride was added until saturated. This mixture was extracted with
ethyl acetate (3 times). The original ether layer was washed with saturated sodium
bicarbonate solution and water. The combined aqueous washes were acidified with excess
HCl (2 N), saturated with sodium chloride and extracted with ethyl acetate (3 times). All of
the ethyl acetate extracts were combined and dried over MgSCV The resulting mixture was
vacuum filtered through coarse silica gel and the filtrate was concentrated under reduced
pressure to give 114 (8.27g, 68%) as a light yellow oil. This material was used without
further purification.
Step Two: To a solution of 114 (3.95g, 25.0 mmol) in anhydrous methanol (225mL)
at room temperature, a solution of 2-chlorobenzylamine (4.2 g, 30 mmol) in anhydrous
methanol (25 mL) was added dropwise from an addition funnel. The solution was heated at
45 °C overnight then refluxed for two hours. The reaction mixture was cooled to room
temperature and concentrated to dryness. The residue was brought up in dichloromethane and
filtered. The solid was collected and dried under vacuum to give 115 ( 2.20 g 35%) as a light
yellow solid.
Step Three: To a suspension of 115 (840 mg, 3.4 mmol) in glacial acetic acid (11 mL)
at room temperature, NaNO2 (46 mg, 0.67 mmol), water (0.92 mL) and HNO3 (70%, 0.85
mL, 13.4 mmol) were added sequentially. The resulting bright yellow solution was stirred at
room temperature overnight, then was diluted with CH2CI2 and water. The aqueous phase
was extracted with CH2CI2, the organic layers were combined and washed with water (3
times) and brine. The organic layer was dried over MgSC^ and filtered and the filtrate was
concentrated under reduced pressure to give 116 (910 mg, 92%) as a bright yellow solid.
This material was used without purification.
Step Four: To a solution of 116 (910 mg, 3.1 mmol) in DMF (10 .3 mL) at room
temperature under a dry nitrogen atmosphere, Zn powder (909 mg, 13.9 mmol) and
triethylamine hydrochloride (2340 mg, 17.0 mmol) were added. The resulting mixture was
heated to 55 °C for 2 hours, then was cooled to room temperature. To the resulting mixture,
CDI (1002 mg, 6.18 mmol) was added as a solid. Upon addition, gas evolution occurred.
The mixture was then heated to 80 °C for 1 hour, cooled to room temperature, and diluted
with CH2Cl2 and HCl (2 N). The aqueous phase was extracted with CH2Cl2, the organic
layers were combined and washed with water (4 times) and brine. The organic layer was
dried over MgSO4 and filtered and the filtrate was concentrated under reduced pressure to
give 117 (920 mg) as a yellow solid. This material contained a small amount of DMF and
was used without purification.
Step Five: A suspension of 117 (920 mg crude material, 3.i mmol tneoretical) and 8
(800 mg, 3.86 mmol) in 21 ml THF under a dry nitrogen atmosphere was heated to 55 °C
overnight, cooled to room temperature and then diluted with ethyl acetate. The resulting
mixture was washed twice with HCl (2N) and brine and the organic layer was dned over
MgSO4 and filtered. The filtrate was concentrated under reduced pressure and the resulting
residue was purified by silica gel chromatography, eluting with 7:3 hexanes:ethyl acetate to
give 118 (1098 mg, 71% for two steps) as a pale yellow foam.
Step Six: To a solution of 118 (1091 mg. 2 19 mmol) in THF (18 ml) as room
temperature. sodium hydroxide (2 N, 6 mL) and methanol (12 mL) were added. The mixture
was stirred fo: 20 minutes, then was diluted with water and extracted with ethyl ether. The
equeous phase was acidified with HCl (2 N) and extracted with ethyl acetate. The ethyl
acetate layer was washed with water and brine, dried over MgSO4 and filtered. The filtrate
was concentrated under reduced pressure to give (3S)-3-[({[1-(2-chlorobenzyl)-4-hydroxy-5-
rnethyl-2-oxG-1,2-dihydropyridin-3-yl]amino}carbonyl)amino]-3-(4-mcthylphenyl)propanoic
acid, 119, (1045 rng, quantitative; as a white ibam MS: Calculated (M-H)- = 468.13 m/z;
bound (M-H) - 467.99 m/z.
Example 26
Synthesis of (3S)-3-[({[4-hydroxy-2-cxo-1-(pyridin-2-ylmethyl)-1.2-dihydropyridin-
3-yl]ammo}carbonyl)amino]-3-(4-methyiphenyl)propanoic acid.
Step One: To a solution of 23 (0.50 g, 3.2 mmol) in DMSO (12.5 mi) at room
temperature, powdered KOH (0.89g, 16 mmol) was added and the mixture was stirred for 1.5
hours. To the resulting mixture, 2-picolylchloride hydrochloride (0.63g, 3.8 mmol) was added
as a solid and the mixture was stirred overnight. At this point, triethylamine hydrochloride
(3.52 g, 25.6 mmol) and DMF (5 mL) were added followed by zinc powder (1.04 g, 16.0
mmol). The mixture was heated to 80 °C for 2 hours then cooled to room temperature. To
this mixture, CDI (1.00 g, 6.2 mmol) was added and the resulting mixture was heated to 80
°C overnight. The mixture was diluted with ethyl acetate and saturated aqueous NaHCO3.
The organic layer was dried over MgSO4 and filtered and the filtrate was concentrated under
reduced pressure. The residue was filtered through a pad of silica gel, eluting with 9:1
CHCl3:CH3OH to give 120 (0.14 g, 18%).
(3S)-3-[({4-Hydroxy-2-oxo-1-(pyridin-2-ylmethyl)-1,2-dihydropyridin-3-
yl]amino}carbonyl)amino]-3-(4-methylphenyl)propanoic acid was prepared from 120
according to procedures described in Example 25. MS: Calculated (M-H)- = 421.15 m/z;
Found (M-H)- = 421.06 m/z.
Example 27
Synthesis of (3S)-3-{[({1 -[1-chloro-5-(methylsulfonyl)benzyl]-4-hydroxy-2-oxo-1,2-
dihydropyridin-3-yl}amino)carbonyl]amino}-3-(4-methylphenyl)propanoic acid.
Step One: To a solution of 121 (prepared from 23 according to procedures described
in Example 4, 220 mg, 0.67 mmol) in anhydrous CH2Cl2 (14 mL) cooled to 0 °C under a dry,
nitrogen atmosphere, m-CPBA (610 mg, 3.6 mmol) was added. The resulting mixture was
allowed to warm to room temperature and stirred for 4 hours. The reaction was diluted with
water (50 ml) and the aqueous phase was extracted with CH2Cl2 (2 times). The combined
organic layers were dried over MgSO4 and filtered and the filtrate was concentrated under
reduced pressure. The residue was purified by silica gel chromatography, eluting with 9:1
CHCl3:MeOH to give 122 (219 mg, 91% yield) as a yellow solid.
(3S)-3- {[({1-[2-Chloro-5-(methylsulfonyl)benzyl]-4-hydroxy-2-oxo-1,2-
dihydropyridin-3-yl}amino)carbonyl]amino}-3-(4-methylphenyl)propanoic acid was prepared
from 122 according to procedures described in Example 25. MS: Calculated (M-H)' = 532.10 m/z; Found (M-H)" = 531.94 m/z. Example 28
Synthesis of (3S)-3-[( {[ 1 (2-chloro-6-methoxybetizyl)-4-hydroxy-2-oxo-1,2-dihydropyridin-3-yl]amino}carbonyl)amino]-3-(3-methylphenyl)propanoic acid.
Step One: To a solution of the 123 (70 mg, 0.13 mmol) in anhydrous CH2C12 (3 mL), stirring under a nitrogen atmosphere, ZnBr2 (200 mg, 0.82 mmol) was added. The solution was stirred at 0 °C for one hour. The reaction mixture was allowed to warm to room temperature and was stirred overnight. At this point, water (50 ml) was added and the mixture was stirred for an additional three hours. The layers were separated and the aqueous layer was extracted with CH2Cl2 (2 times). The combined organic layers were dried over MgSO4 and filtered and the filtrate was concentrated under reduced pressure to give (3S)-3-[({[ 1 -(2-chloro-6-methoxybenzyl)-4-hydroxy-2-oxo-1,2-dihydropyridin-3 -yl]amino}carbonyl)amino]-3-(3-methylphenyl)propanoic acid, 124 (60 mg, 95% yield). MS: Calculated (M-H)" = 484.13 m/z; Found (M-H)" = 484.00 m/z. Example 29
Synthesis of (3S)-3-[({[l-(2-chlorobenzyl)-4-hydroxy-2-oxo-5-propyl-l,2-dihydropyridin-3-yl]amino}carbonyl)amino]-3-(4-methylphenyl)propanoic acid.
Step One: A mixture of malonyl dichloride (25.0 g, 177 mmol) and valeronitrile (25.0 g, 300.7 mmol) under an anhydrous atmosphere was vigorously stirred at room temperature for 24 hours. Diethyl ether (50 mL) was added to the resulting heterogeneous mixture. The precipitate was collected and washed with diethyl ether to give 125•HCl as a white solid (20.2 g, 64%).
Step Two: To a suspension of 125•HCl (6.10 g, 27.2 mmol) in EtOH (100 mL), triethylamine (5.8 g, 57.3 mmol) and palladium on carbon (10 % Pd dry weight basis, Degussa type E101 NE/W, -50% water content, 3.5 g, 1.6 mmol Pd) were added. The atmosphere was replaced with hydrogen (toggle between vacuum and hydrogen from a
balloon five times) and the mixture was stirred overnight, then filtered. The filtrate was concentrated under reduced pressure to give 126*2Et3NHCl (11.0 g, 94%). This material was used without further purification.
(3S)-3-[( {[ 1 -(2-Chlorobenzyl)-4-hydroxy-2-oxo-5-propyl-1,2-dihydropyridin-3-yl]amino}carbonyl)amino]-3-(4-methylphenyl)propanoic acid was prepared from 126.2Et3NHCl according to procedures described in Example 25. MS: Calculated (M-H)" = 496.16 m/z; Found (M-H)" = 495.94 m/z. Example 30
Synthesis of (3S)-3-[({[ 1 -(2-chlorobenzyl)-4-hydroxy-2-oxo-2,5,6,7-tetrahydro-1H-cyclopenta[b]pyridin-3-yl]amino}carbonyl)amino]-3-(4-methylphenyl)propanoic acid.
Step One: To a solution of ethyl 2-oxocyclopentanecarboxylate (3.30 g, 21.1 mmol) in toluene (45 ml), 4-chlorobenzyiamine (2.56 mL, 21.1 mmol) was added. The resulting mixture was refluxed overnight with azeotropic removal of water via a Dean-Stark trap. The reaction mixture was concentrated under reduced pressure to give 127 (5.90 g, 99%) as a red oil. This material was used without purification.
Step Two: To a solution of 127 (11.0 g, 39.3 mmol) in anhydrous THF (75 mL) cooled to 0 °C under a dry, nitrogen atmosphere, NaH (60% dispersion in mineral oil, 1.73 g, 43.2 mmol) was added. The reaction was stirred for 10 minutes at 0 °C, then acetyl chloride (3.9 mL, 55 mmol) was added. The reaction mixture was allowed a) gradually warm to room temperature, then was stirred overnight. The resulting mixture was concentrated under reduced pressure and a mixture of ice water (200 mL) and HC1 (1 N, 200 mL) was added to the residue. This mixture was extracted with ethyl acetate (300 mL) and the ethyl acetate layer was dried over MgSO4 and filtered. The filtrate was concentrated under reduced pressure to give 128 (13.4 g) as a brown oil. This material contained mineral oil but was used without purification.
Step Three: To a solution of crude 128 (13.4 g, 39.3 mmol theoretical) in anhydrous THF (50 ml) cooled to 0 °C under a dry, nitrogen atmosphere, lithium
bis(trimethylsilyl)amide (1.0 M in THF, 125 mL, 125 mmol) was added slowly via syringe. The reaction mixture was allowed to warm to room temperature, then was stirred overnight. The mixture was concentrated under reduced pressure and the residue was triturated with ethyl acetate/hexane and filtered. The solid was washed with HC1 (1 N, 250 ml) and water (500 ml) to give 129 (5.48g, 48% for two steps) as a brown solid.
(3S)-3-[( {[ 1 -(2-Chlorobenzyl)-4-hydroxy-2-oxo-2,5,6,7-tetrahydro-1H-cyclopenta[b]pyridin-3-yl]ammo}carbonyl)amino]-3-(4-methylphenyl)propanoic acid was synthesized from 129 according to procedures described in Example 25. MS: Calculated (M+H)+ = 496.16 m/z; Found (M+H)+ = 495.99 m/z. Example 31
Synthesis of (3S)-3-[({[4- {[(tert-butylarnino)carbonyl]amino}-1 -(2-chlorobenzyl)-2-oxo-l,2-dihydropyridin-3-yl]amino}carbonyl)amino]-3-(4-methylphenyl)propanoic acid.
Step One: To a solution of 46 (500 mg, 1.79 mmol) in anhydrous THF (10 mL) cooled to 0 °C under a dry nitrogen atmosphere, NaH (60% dispersion in mineral oil, 210 mg, 5.37 mmol) was added and the resulting mixture was stirred for 20 minutes. To this mixture, tert-butyl isocyanate (0.31 mL, 2.68 mmol) was added and the reaction mixture was allowed to warm to room temperature, then was stirred for 2 days. The reaction mixture was quenched with water and extracted twice with ethyl acetate. The organic layers were combined, dried over MgSO4 and filtered and the filtrate was concentrated under reduced pressure to give 130 (660 mg, 97%) as a brown solid.
(3S)-3-[( {[4- {[(tert-butylamino)carbonyl]amino} -1 -(2-chlorobenzyl)-2-oxo-1,2-dihydropyridin-3-yl]amino}carbonyl)amino]-3-(4-methylphenyl)propanoic acid was prepared from 130 according to procedures described in Example 3. MS: Calculated (M-H)" = 552.20
m/z; Found (M-H)" = 551.89 m/z.
Synthetic procedures similar to those described above may be utilized to
obtain the compounds of Tables 2, 3, 4 and 5.
Example 32
Synthesis of (3S)-3-[({[5-chloro-l-(2-chlorobenzyl)-4-hydroxy-2-oxo-l,2-dihydropyridin-3-yl]amino}carbonyl)amino]-3-(4-methylphenyl)propanoic acid.
Step One: To a solution of 31 (350 mg, 0.72 mmol) in CH2CI2 at room temperature under a dry nitrogen atmosphere, sulfurylchloride (1.0 M in CH2CI2, 0.65 mL, 0.65 mmol) was added by syringe. The resulting mixture was stirred at room temperature for 1 hour, then was partitioned between CH2Cl2 and water. The organic layer was washed with brine and dried over MgSO4 and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel chromatography, eluting with 8:1, then 4:1 and finally 1:1 hexanes:ethyl acetate to give 131 (240 mg, 64%).
(3S)-3-[( {[5-Chloro-l -(2-chlorobenzyl)-4-hydroxy-2-oxo-1,2-dihydropyridin-3-yl]amino}carbonyl)amino]-3-(4-methylphenyl)propanoic acid was synthesized from 131 according to procedures described in Example 1. MS: Calculated (M-H)~ = 488.08; Found (M-H)' = 487.97. Example 33
Synthesis of (3S)-3-[({[ 1 -(2-chlorobenzyl)-4-hydroxy-5-methyl-2-oxo-l,2-dihydropyridin-3-yl]amino}carbonyl)amino]-3-(2',6'-dimethoxy-l, l'-biphenyl-4-yl)propanoic acid.
Step One: To a solution of (R)-(+)-N-benzyl-a-methylbenzyl amine (5.07 g, 24 mmol) in THF (85 mL) under nitrogen in a flame-dried flask, cooled to -78 °C, .sec-buryllithium (1.3 M solution in cyclohexane, 18.0 mL, 23.4 mmol) was added dropwise over a 30 minute period. The mixture was stirred an additional 30 minutes at -78 °C, then a solution off-butyl 4-bromocinnamate (5.1 g, 20 mmol) in THF (20 mL) was added dropwise and the mixture was allowed to come to room temperature overnight. The reaction was quenched by addition of saturated ammonium chloride (-50 mL) and the organic layer was washed with saturated sodium chloride, dried over MgSO4 then filtered. The filtrate was concentrated under reduced pressure and the residue was purified by silica gel chromatography eluting with hexanes and increasing to 3:1 hexanes:ethyl acetate to give 132 (4.33 g, 47%) as a pale yellow oil.
Step Two: To a solution of 132 (7.4 g, 15 mmol) and 2,6-dimethoxyphenyl boronic acid (4.9 g, 27 mmol) in DME (100 mL) at room temperature under a dry, nitrogen
atmosphere, finely-powdered potassium phosphate (8.0 g, 37.5 mM) and dichlorobis(triphenylphosphine)palladium (0) (0.5 g, 0.75 mmol) were added. The mixture was deoxygenated (toggle between vacuum and nitrogen gas 5 times) and then heated to reflux for 8 hours. The mixture was then cooled and filtered through Celite® 521, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel chromatography, eluting with hexanes increasing to 3:1 hexanes:ethyl acetate to give 133 (7.8 g, 95%yield).
Step Three: To a solution of 133 (3.39 g, 6.1 mmol) in ethanol (80 mL) in a 250 mL flask, acetic acid (0.5 mL) and palladium on carbon (10% Pd dry weight basis, water content -50%, Degussa type E101 NE/W, 2.5 g, 1.2 mmol Pd) were added sequentially. The mixture was stirred under a hydrogen atmosphere from a balloon for 36 hours. The reaction mixture was filtered through Celite 521 and the filtrate was concentrated under reduced pressure. The residue was recrystallized from ethyl acetate to give 134.HOAc (1.0 g, 71%) as a white solid.
(3S)-3-[( {[ 1 -(2-chlorobenzyl)-4-hydroxy-5-methyl-2-oxo-1,2-dihydropyridin-3-yl]amino}carbonyl)amino]-3-(2',6'-dimethoxy-l,l'-biphenyl-4-yl)propanoic acid was synthesized from 134.HOAc by procedures described in Example 25. MS: Measured (M+H)+ - 592.04; Calculated (M+H)+ = 592.19. Example 34
Synthesis of (3S)-3-[({[2-(2-chloro-6-ethoxybenzyl)-5-hydroxy-6-methyl-3-oxo-2,3-dihydropyridazin-4-yl]amino}carbonyl)amino]-3-(3-ethoxyphenyl)propanoic acid.
Step One: To a solution of sodium z-butoxide (65 g, 0.642 mol) in THF (1 L), at room temperature under a dry nitrogen atmosphere, ethanol (250 mL, 5.35 mol) was added over a 10 minute period. To the resulting solution, 2-chloro-6-fluorobenzonitrile (100 g, 0.642 mol) was added in portions. The reaction mixture was stirred at room temperature for 30 minutes and then reduced to a volume of approximately 250 mL under reduced pressure. The resulting mixture was poured into chloroform and water and the layers separated. The organic layer was washed with water (twice) and brine, dried over MgSO4 and filtered. The filtrate was concentrated under reduced pressure to afford a light yellow solid. This material was recrystallized from hexanes to provide the 2-chloro-6-ethoxybenzonitrile, 135, (101 g, 87 % yield) as a white crystalline solid.
Step Two: To a solution of 2-chloro-6-ethoxybenzonitrile, 135, (93.2 g, 0.513 mol) in THF (350 mL) at room temperature under a dry nitrogen atmosphere was added borane in THF (1.0 M, 620 mL, 0.62 mol). The resulting mixture was heated to reflux for 3 hours and then cooled to room temperature. Water (250 mL) was added very slowly to the solution allowing for the evolution of hydrogen. Concentrated HC1 (50 mL) was then added over several minutes and the solution was heated to 50 °C for 2 hours. The mixture was cooled and partitioned between chloroform and water. The aqueous layer was washed 6 times with chloroform. The combined organic fractions were washed with HC1 (1 M) and this organic layer was discarded. Chloroform was added to the combined aqueous layers and solid KOH was added until the aqueous phase was basic (pH > 9). The aqueous layer washed with chloroform an additional five times. The organic fractions were combined and washed with water, brine, and dried over MgSO4 and silica gel (2 g). This mixture was filtered and the filtrate was concentrated under reduced pressure to give 2-chloro-6-ethoxybenzylamine, 136, (60.1 g, 64% yield) as a light yellow oil.
Step Three: To a solution of 2-chloro-6-ethoxybenzylamine, 136, (7.30 g, 39.3 mmol) in glacial acetic acid (50 mL) and acetic anhydride (50 mL) at room temperature, sodium nitrite (6.00 g, 85.7 mmol) was added in small portions. The resulting mixture was stirred at room temperature overnight then was poured into ice water and extracted with ethyl acetate. The organic layer was washed with aqueous NaOH (IN, 2 X 100 mL) and brine (twice). The organic layer was dried over Na2SO4 and filtered and the filtrate was concentrated under reduced pressure to give 137 (9.00 g, 100%) as a light yellow solid.
Step Four: To a solution of 137 (9.00 g, 39.3 mmol) and tetrabutylammonium bromide (1.0 g, 3.1 mmol) in THF (50 ml) et room temperature, aqueous NaOH (2N, 50 mL, 100 mmol) was slowly added and the mixture was heated to 45 °C overnight. The reaction mixture was cooled to room temperature, then was diluted with water and extracted with ethyl acetate. The organic layer was washed with brine, dried over Na2SO4 and filtered and the filtrate was concentrated under reduced pressure to give 138 (7.08 g, 96% yield).
Step Five: To a solution of 138 (7.08 g, 37.9 mmol) in CH2C12 (55 mL) at room temperature under a dry nitrogen atmosphere, a solution of SOCh (9.0 mL, 120 mmol) in CH2C12 (30 mL) was added dropwise. The resulting mixture was stirred at room temperature overnight, then was poured into ice water. The aqueous layer was extracted with CH2C12 and
the combined organic layers were washed with aqueous NaOH (IN, twice), water (3 times) and brine (twice). The organic layer was dried over Na2SO4 and filtered and the filtrate was concentrated under reduced pressure to give 2-chloro-6-ethoxybenzylchloride, 139, (6.69 g, 86% yield) as a viscous, brown oil.
Step Six: A solution of 2-chloro-6-ethoxybenzychloride, 139, (6.90 g, 253.7 mmol) and hydrazine (21.60 g, 673 mmol) in MeOH (22 mL) was stirred at room temperature for 3 hours. The mixture was then partitioned between CH2Cl2 and water. The organic layer was dried over MgSO4 and filtered and the filtrate was concentrated under reduced pressure to give 140 (6.18 g, 92%).
Step Seven: To a suspension of ethyl pyruvate (3.85 mL, 33.7 mmol) and MgSCU in CHCI3 (65 mL), a solution of 140 (6.14 g, 30.6 mmol) in CHC13 (30 mL) was slowly added. The resulting mixture was stirred at room temperature overnight. The resulting mixture was filtered and the filtrate was concentrated under reduced pressure to give 141 (8.43 g, 92%). This material was used in the next step without purification.
Step Eight: To a solution of 141 (8.43 g, 28.2 mmol) in dry THF (110 mL)cooled to 0 °C under a dry nitrogen atmosphere, sodium hydride (60% dispersion in mineral oil, 1.88 g, 47.1 mmol) was added in one portion. The resulting mixture was stirred at 0 °C for 30 minutes, then methyl malonylchloride (6.63 g, 47.10 mmol) was slowly added. The mixture was allowed to warm to room temperature, stirred overnight, carefully quenched with water then extracted with ethyl acetate (twice). The organic layers were combined, washed with brine, dried over MgSO4 and filtered. The filtrate was concentrated under reduced pressure to give 142 (14.29 g). This material was used in the next step without further purification.
Step Nine: To a solution of crude 142 (14.29 g) in dry DMF (60 mL) cooled to 0 °C under a dry nitrogen atmosphere, sodium hydride (60% dispersion in mineral oil, 2.90 g, 72.2 mmol) was added in one portion. This solution was heated to 60 °C overnight, cooled down in an ice bath, then shaken with hexane. The layers were separated and the DMF layer was poured into ice water. The mixture was acidified (pH 1) by adding HC1 (2N). The precipitate was collected by filtration the dissolved in ethyl acetate. The organic solution was dried over MgSO4 and filtered and the filtrate was concentrated to give 143 (8.42 g, 85% yield for two steps).
Step Ten: A solution of 143 (8.42 g, 23.9 mmol) in dioxane (100 mL) and aqueous HC1 (60 mL, 5.2 N) was refluxed overnight. The mixture was cooled to room temperature, diluted with water and extracted with ethyl acetate. The organic layer was washed with brine, dried over MgSO4 and filtered. The filtrate was concentrated under reduced pressure and the residue was purified by silica gel chromatography eluting with 1:1 ethyl acetate:hexanes, then ethyl acetate and finally 9:1 ethyl acetate:methanol to give 144 (2.0 g, 28%).
Synthesis of (3S)-3-[({[2-(2-chloro-6-ethoxybenzyl)-5-hydroxy-6-methyl-3-oxo-2,3-dihydropyridazin-4-yl]amino} carbonyl)amino] -3 -(3 -ethoxyphenyljpropanoic ac id was prepared from 144 by procedures provided in Example 25. MS: Measured (M+H)+ = 545.05; Calculated (M+H)+ = 545.18. Example 35
Synthesis of (3S)-3-[({[l-(2-chlorobenzyl)-4-hydroxy-2-oxo-2,5,6,7-tetrahydro-lH-cyclopenta[b]pyridin-3 -yl] amino} carbonyl)amino] -3 -(1,3 -diethyl-2-oxo-2,3 -dihydro-1H-benzimidazol-5-yl)propanoic acid.
Step One: An ice-cold mixture of sodium hydride (8.00 g, 60% dispersion in mineral oil, 200 mmol) and 145 (8.94g, 66.6 mmol) in DMF (250 mL) under a dry nitrogen atmosphere was allowed to gradually warm to room temperature. To the resulting mixture, iodoethane (16 ml, 200 mmol) was added and the mixture was stirred at room temperature overnight. The reaction mixture was poured into ice and extracted with ethyl acetate. The organic layer was washed with water and brine, dried over Na2SO4 and filtered. The filtrate was concentrated under reduced pressure and the residue was taken up in hexanes and filtered. The resulting brown solid was dried under reduced pressure to give 146 (9.00 g, 71% yield). This material was used without purification.
Step Two: A mixture of DMF (3.6 g, 49 mmol) and POC13 (9.6 mL, 100 mmol) was stirred at room temperature under a dry nitrogen atmosphere for 1 hour. The flask containing this mixture was then placed in a 45 °C oil bath and 146 (7.6 g, 40 mmol) was added in small portions. The oil bath temperature was raised to 70 °C and the mixture was stirred overnight, then cooled to room temperature. The mixture was diluted with water and extracted with ethyl acetate. The organic layer was washed with water and brine, dried over Na2SO4 and filtered. The filtrate was concentrated under reduced pressure to give a 7:3 mixture of 147:146 (6.69 g). This material was used without purification.
Step Three: To a solution of the 147:146 mixture obtained above (2.2 g) in ethanol (2.2 mL), malonic acid (1.16 g, 11.2 mmol), pyridine (0.44 mL) and piperidine (0.99 mL) were added sequentially. The resulting mixture was heated to reflux for 6 hours, then cooled to room temperature. The mixture was diluted with aqueous NaOH (IN) and extracted with ethyl acetate (4 times). The aqueous phase was acidified to pH 3 with HC1 (IN) and the resulting suspension was filtered, washing the solid with water. The white solid was collected and dried under reduced pressure to give 148 (1.69 g, 49% for two steps).
(3 S)-3-[( {[ 1 -(2-chlorobenzyl)-4-hydroxy-2-oxo-2,5,6,7-tetrahydro-1H-cyclopenta[b]pytidin-3-yl]amino}carbonyl)amino]-3-(l,3-diethyl-2-oxo-2,3-dihydro-lH-benzimidazol-5-yl)propanoic acid was prepared from 148 by procedures described in Examples 33 and 25. MS: Measured (M+H)+ = 594.05; Calculated (M+H)+ = 594.21. Example 36
Synthesis of give (3S)-3-[( {[ 1 -(2-chloro-6-ethoxybenzyl)-4-hydroxy-5-methyl-2-oxo-1,2-dihydropyridin-3-yl]amino}carbonyl)amino]-3-(4-methylphenyl)propanoic acid, 153.
Step One: To a solution of 114 (20.3 g, 129 mmol) in anhydrous methanol (430 mL) at room temperature under a dry nitrogen atmosphere, 2-chloro-6-ethoxybenzylamine, 136, (31.1 g, 168 mmol) was added. The solution was heated at 45 °C for 1 hour then refluxed overnight. The reaction mixture was cooled to room temperature and concentrated to dryness. The residue was brought up in dichloromethane and filtered. The solid was collected and dried under vacuum to give 149 (14.7 g, 39%),
Step Two: To a suspension of 149 (11.02 g, 37.8 mmol) in glacial acetic acid (126 mL) at room temperature, Na.NO2 (522 mg, 7.6 mmol), water (10.5 mL) and HNO3 (70%, 9.6 mL, 151.2 mmol) were added sequentially. The resulting bright yellow solution was stirred at room temperature overnight, then was diluted with CH2CI2 and water. The aqueous phase was extracted with CH2Cl2, the organic layers were combined and washed with water (3 times) and brine. The organic layer was dried over MgSO4 and filtered and the filtrate was concentrated under reduced pressure. The residue was recrystallized from CH2Cl2/ethyl acetate to give 150 (10.9 g, 85%) as a bright yellow solid.
Step Three: To a solution of 150 (10.9 g, 32.2 mmol) in DMF (107 mL) at room temperature under a dry nitrogen atmosphere, Zn powder (9.48 g, 145 mmol) and triethylamine hydrochloride (24.4 g, 177 mmol) were added. The resulting mixture was
heated to 55 °C for 1 h, then was cooled to room temperature. To the resulting mixture, CDI (10.4 g, 64.4 mmol) was added as a solid. Upon addition, gas evolution occurred. The mixture was then heated to 80 °C for 2 hours, cooled to room temperature and poured into HC1 (2 N, 1L). The resulting suspension was stirred for 20 minutes and then was diluted with water (1L) and filtered. The solid was resuspended in water (1L) and then filtered. The solid was dried under vacuum to give 151 (10.78 g, 100% yield) as a white powder.
Step Four: A mixture of 151 (10.68 g, 31.9 mmol) and 8 (8.27 g, 39.9 mmol) in DMF (64 mL) under a dry nitrogen atmosphere was heated to 55 °C overnight, cooled to room temperature and then diluted with ethyl acetate. The resulting mixture was washed with HC1 (2N), water (4 times) and brine and the organic layer was dried over MgSCU and filtered. The filtrate was concentrated under reduced pressure and the resulting residue was purified by silica gel chromatography, eluting with 7:3 hexanes:ethyl acetate to give 152 (14.2 g, 82%) as a pale yellow foam.
Step Five: To a solution of 152 (11.60 g, 21.4 mmol) in THF (138 mL) at room temperature, aqueous sodium hydroxide (2 N, 46 mL) and methanol (92 mL) were added. The mixture was stirred for 20 minutes, then was diluted with water and extracted with ethyl ether. The aqueous phase was acidified with HC1 (2 N) and extracted with ethyl acetate. The ethyl acetate layer was washed with water and brine, dried over MgSO4 and filtered. The filtrate was concentrated under reduced pressure to give (3S)-3-[({[l-(2-chloro-6-ethoxybenzyl)-4-hydroxy-5-methyl-2-oxo-l,2-dihydropyridin-3-yl]amino}carbonyl)amino]-3-(4-methylphenyl)propanoic acid, 153, (10.82, 98% yield) as a light tan foam. MS: Calculated (M-H)" = 512.16; Measured (M-H)" = 512.03. Example 37
Synthesis of (3S)-3-| ({[ 1 -(2-chloro-6-ethoxybenzyl)-4-hydroxy-5-rnethyl-2-oxo-l ,2-dihydropyridin-3-yl]ammo} carbonyl)amino]-3-(3-ethoxyphenyl)propanoic acid, 156.
Step One: A mixture of 151 (8.40 g, 28.8 mmol) and 154 (8.2 g, 35 mmol) in DMF (100 mL) under a dry nitrogen atmosphere was heated to 55 °C overnight, cooled to room temperature and then diluted with ethyl acetate. The resulting mixture was washed with HC1 (2N), water (4 times) and brine and the organic layer was dried over MgSO4 and filtered. The
filtrate was concentrated under reduced pressure and the resulting residue was purified by silica gel chromatography, eluting with 8:2 increasing to 1:1 hexanes:ethyl acetate to give 155 (11.1 g, 67% yield).
Step Two: To a solution of 155 (9.12 g, 15.9 mmol) in THF (100 mL) at room temperature, aqueous sodium hydroxide (1 N, 88 mL) and methanol (63 mL) were added. The mixture was stirred for 20 minutes, then was diluted with water and extracted with ethyl ether. This ether layer was discarded. The aqueous phase was acidified with HC1 (2 N) and extracted with ethyl ether (4 times). The organic layers were washed with water and brine, dried over MgSCu and filtered. The filtrate was concentrated under reduced pressure to give (3S)-3-[({[l-(2-chloro-6-ethoxybenzyl)-4-hydroxy-5-methyl-2-oxo-l,2-dihydropyridin-3-yl]amino}carbonyl)amino]-3-(3-ethoxyphenyl)propanoic acid, 156, (8.13 g, 93%) as a white foam. MS: Calculated (M+Hf = 544.19; Measured (M+H)+ = 544.04. Example 38
Synthesis of (3S)-3-[({[l-(2-chloro-6-ethoxybenzyl)-4-hydroxy-5-methyl-2-oxo-l,2-dihydropyridin-3-yl]amino}carbonyl)amino]-3-(6-methoxy-2-naphthyl)propanoic acid, 159. Step One: A mixture of 151 (110 mg, 0.29 mmol), 157 (130 mg, 0.34mmol) and NMM (0.50 mL, 4.5 mmol) in DMF (1.0 mL) under a dry nitrogen atmosphere was heated to 55 °C overnight, cooled to room temperature and then diluted with ethyl acetate. The resulting mixture was washed with HC1 (2N), water (4 times) and brine and the organic layer was dried over MgSO4 and filtered. The filtrate was concentrated under reduced pressure and the resulting residue was purified by silica gel chromatography, eluting with 1:1 hexanes:ethyl acetate to give 158 (130 mg, 73% yield).
Step Two: To a solution of 158 (130 mg, 0.21 mmol) in THF (3 mL) at room temperature, aqueous sodium hydroxide (2 N, 1 mL) and methanol (2 mL) were added. The mixture was stirred for 20 minutes, then was diluted with water and extracted with ethyl ether. The aqueous phase was acidified with HC1 (2 N) and extracted with ethyl acetate. The ethyl acetate layer was washed with water and brine, dried over MgSO4 and filtered. The filtrate was concentrated under reduced pressure to give (3S)-3-[({[l-(2-chloro-6-ethoxybenzyl)-4-hydroxy-5-methyl-2-oxo-l,2-dihydropyridin-3-yl]amino}carbonyl)amino]-3-(6-methoxy-2-naphthyl)propanoic acid, 159, (90 mg, 74% yield). MS: Measured (M+H)+ = 580.07; Calculated (M+H)+ = 580.19.
Example 39
Synthesis of (3S)-3-[( {[ 1 -(2-chlorobenzyl)-4-hydroxy-2-oxo-2,5,6,7-tetrahydro-1H-cyclopenta[b]pyridin-3-yl]amino}carbonyl)amino]-3-(3-isopropoxyphenyl)propanoic acid, 164.
Step One: To a suspension of 129 (5.30 g, 19.2 mmol) in glacial acetic acid (64 mL) at room temperature, NaNO2 (266 mg, 3.9 mmol), water (5.3 mL) and HNO3 (70%, 4.9 mL, 77 mmol) were added sequentially. The resulting bright yellow solution was stirred at room temperature overnight, then was poured into water and filtered, washing with water. The yellow solid was dried under reduced pressure to give 160 (5.35 g, 87%).
Step Two: To a solution of 160 (5.35 g, 16.7 mmol) in DMF (56 mL) at room temperature under a dry nitrogen atmosphere, Zn powder (4.88 g, 74.7 mmol) and triethylamine hydrochloride (12.6 g, 91.5 mmol) were added. The resulting mixture was heated to 55 °C for 1 h, then was cooled to room temperature. To the resulting mixture, CDI (5.41 g, 33.4 mmol) was added as a solid. Upon addition, gas evolution occurred. The mixture was then heated to 80 °C for 2 hours, cooled to room temperature and poured into HC1 (2 N, 500 mL). The resulting suspension was stirred for 20 minutes and then was diluted with water (500 mL) and filtered. The solid was resuspended in water (500 mL) and then filtered. The solid was dried under vacuum to give 161 (5.0 g, 95% yield) as a white powder.
Step Three: A mixture of 161 (6.14 g, 19.4 mmol) and 162 (5.12 g, 20.3 mmol) in DMF (90 mL) under a dry nitrogen atmosphere was heated to 80 °C overnight, cooled to room temperature and then diluted with ethyl acetate. The resulting mixture was washed with HC1 (2 N), water (4 times) and brine and the organic layer was dried over MgSO4 and filtered. The filtrate was concentrated under reduced pressure and the resulting residue was purified by silica gel chromatography, eluting with 7:3 hexanes:ethyl acetate to give 163 (8.90 g, 81%) as a pale yellow foam.
Step Four: To a solution of 163 (8.69 g, 15.3 mmol) in THF (35 mL) at room temperature, aqueous sodium hydroxide (2 N, 30 mL) and methanol (30 mL) were added. The mixture was stirred overnight, then was diluted with water and extracted with ethyl ether. The aqueous phase was acidified with HC1 (2 N) and extracted with ethyl acetate. The ethyl acetate layer was washed with water and brine, dried over MgSCU and filtered. The filtrate was concentrated under reduced pressure to give (3S)-3-[({[l-(2-chlorobenzyl)-4-hydroxy-2-
oxo-2,5,6,7-tetrahydro-lH-cyclopenta[b]pyridin-3-yl]amino}carbonyl)amino]-3-(3-isopropoxyphenyl)propanoic acid, 164, (7.50 g, 91% yield). MS: Measured (M+H)+ = 540.09; Calculated (M+H)+ = 540.19. Example 40
Synthesis of (3S)-3-[({[ 1 -(2-chlorobenzyl)-4-hydroxy-2-oxo-2,5,6,7-teitrahydro-l H-cyclopenta[b]pyridin-3-yl]amino}carbonyl)amino]-3-(4-chloro-3-isopropoxyphenyl)propanoic acid.
Step One: To a mixture of 162 (200 mg, 0.80 mmol) in glacial acetic acid (1.65 mL) cooled to 0 °C under a dry nitrogen atmosphere, a mixture of SO2Cl2 (1.2 mL, 15 mmol) in glacial acetic acid (1.0 mL) was added dropwise by syringe. The resulting mixture was stirred at 0 °C for 30 minutes then was warmed to room temperature. After stirring for an additional 4 hours, the mixture was recooled to 0 °C and quenched by careful addition of saturated aqueous NaHCC>3. The mixture was extracted with ethyl acetate and the organic layer was washed with saturated aqueous NaHCC>3, dried over MgSO4 and filtered. The filtrate was concentrated under reduced pressure and the residue was purified by silica gel chromatography, eluting with 2:1 hexanes:ethyl acetate to give 165 (148 mg, 65%).
(3S)-3-[( {[ 1 -(2-chlorobenzyl)-4-hydroxy-2-oxo-2,5,6,7-tei[rahydro-1H-cyclopenta[b]pyridin-3-yl]amino}carbonyl)amino]-3-(4-chloro-3-
isopropoxyphenyl)propanoic acid was prepared from 165 according to procedures described in Examples 25 and 30. MS: Calculated (M-H)" = 586.15; Found (M-H)" = 585.92. Example 41
Synthesis of (3S)-3-({[(l-{[2-chloro-6-tetrahydro-l(2H)-pyridinylphenyl]methyl}-4-hydroxy-5-methyl-2-oxo-1,2-dihydro-3-pyridinyl)amino]carbonyl}amino)-3-(4-methylphenyl)propanoic acid.
Step One: To a suspension of 166 (0.35 g, 1.06 mmol, prepared according to procedures described in Examples 34 and 25) in methanol (7 mL) and water (3.5 mL) cooled to 0 °C, glacial acetic acid (189 µL, 3.2 mmol) and sodium nitrite (178 mg, 2.65 mmol) were added sequentially. The mixture was allowed to slowly warm to room temperature overnight and then was diluted with chloroform and water. The pH of the aqueous phase was checked to ensure a pH of 4-5. The organic layer was washed with brine, dried over MgSO4
and filtered and the filtrate was concentrated under reduced pressure to give 167 (0.35g, 92%) as a yellow solid.
(3 S)-3-( {[(1 - {[2-chloro-6-tetrahydro-1 (2H)-pyridinylphenyl]methyl} -4-hydroxy-5-methyl-2-oxo-1,2-dihydro-3 -pyridinyl)amino]carbonyl} amino)-3 -(4-methylphenyl)propanoic acid was synthesized from 167 according to the procedures described in Example 25. MS: Calculated (M-H)" = 551.21; Found (M-H)" = 551.06. Example 42
Synthesis of (3S)-3-{[({l-[(2-chlorophe.-«yl)methyl]-4-hydroxy-5-methyl-2-oxo-l,2-dihydro-3-pyridinyl}amino)carbonyl]amino}-3-[3-(difluoromethyl)phenyl]propanoic acid.
Step One: To a solution of 3-bromobenzaldehyde, 168, (3.00 g, 16 2 mmol) in DMF (69 mL) under a dry nitrogen atmosphere, palladium acetate (73 mg, 0.32 mmol), tri-o-tolylphosphine (197 mg, 0.65 mmol), ethyl acrylate (2.20 mL, 20.3 mmol) and triethylamine (4.50 mL, 32.4 mmol) were added. The system was deoxygenated (toggle between vacuum and nitrogen five times), the mixture was heated to 125 °C for 19 hours and then cooled to room temperature. The reaction was poured into water and extracted with ether. The organic layer was washed with HC1 (4N) and brine, dried over MgSO4 and filtered. The filtrate was concentrated under reduced pressure to give 169 (2.74g, 83%), which was used without further purification.
Step Two: To a flask containing 169 (1.00 g, 4.9 mmol) under a dry nitrogen atmosphere, (dimethylamino)sulfur trifluoride (0.96 mL, 9.8 mmol) was added by syringe. The mixture was heated to 90 °C behind a blast shield for 25 minutes then was cooled to room temperature. The resulting mixture was diluted with CH2Cl2 and washed with saturated aqueous NaHCO3 and H2O. The organic layer was dried over MgSCO4 and filtered and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel chromatography, eluting with 1:5 ethyl actetate:hexanes to give 170 (0.62 g, 56%).
Step Three: To a solution of (R)-(+)-N-benzyl-a-methylbenzylamine (0.70 g, 3.3 mmol) in THF (6.7 mL) cooled to -78 °C under a dry nitrogen atmosphere, sec-BuLi (4.22 mL, 1.3M in cyclohexane, 5.5 mmol) was added dropwise. The resulting mixture was stirred at -78 °C for 30 minutes and then a solution of 170 (0.62 g, 2.74 mmol) in THF (3.4 mL) was added dropwise by syringe. The mixture was. stirred at -78 °C for 5 hours and then quenched
with glacial AcOH (2 mL) in THF (5 mL). The reaction mixture was warmed to room temperature, poured into a 1:1 mixture of saturated aqueous NaHCO3EtOAc. The organic layer was washed with H2O (2 times) and brine, dried over MgSO4 and filtered. The filtrate was concentrated under reduced pressure and the residue was purified by silica gel chromatography, eluting with 1:5 ethyl actetate:hexanes to give 171 (1.2 g, 100%). This material still contained minor impurities but was used without further purification.
Step Four: To a solution of 171 (0.50 g, 1.14 mmol) in EtOH (10 mL) at room temperature under a dry nitrogen atmosphere, Pd/C (10% Pd dry weight basis, 50% water by weight, Degussa type E101 NE/W, 0.25 g) and glacial AcOH (0.5 mL) were added. The atmosphere was replaced by hydrogen (toggle between vacuum and hydrogen from a balloon five times) and the mixture was heated to 35 °C for 6 hours. The reaction was cooled to room temperature, filtered through a plug of Celite® 52land the filtrate was concentrated under reduced pressure. The residue was diluted with CHCI3 and washed with saturated aqueous NaHCO3. The aqueous layer was extracted with CHCI3 (2 times) and the combined organic layers were dried over MgSO4 and filtered. The filtrate was concentrated under reduced pressure and the residue was purified by silica gel chromatography, eluting with 1:10 MeOH:CHCl3 to give 172 (] 80 mg, 67%).
(3S)-3- {[({1 -[(2-chlorophejiyl)methyl]-4-hydroxy-5-methyl-2-oxo-1,2-dihydro-3-pyridinyl}amino)carbonyl]amino} -3-[3-(difluorornethyl)phenyl]propanoic acid was synthesized from 172 according to procedures described in Example 25. MS: Calculated (M-H)" = 504.11; Found (M-H)' = 503.96. Example 43
The procedures described in Examples 3, 4, 8, 25, 26, 27, 29, 30, 34, 36, 39 and 41 were utilized to synthesize several compounds of general Formla VII and general Formula Vin, by varying starting materials. In Table 1 shown below, characterization data is provided for compounds synthesized.
5-(2-methoxybenzyl)-3,5- (CDC13) S 3.87 (s, 1H), 5.24 (s, 2H), 6.36 (d, J
dihydro[l,3]oxazolo[4,5- = 7.5 Hz, 1H), 6.88 (d, J = 8.1 Hz, 1H), 6.97
c]pyridine-2,4-dione (m, 1H), 7.30 (m, 1H), 7.45 (d, J = 7.5 Hz,
1H), 7.55 (m, 1H), 10.75 (br. s, 1H).
5-(2,5-difluorobenzyl)-3,5- (CDCI3) 5 5.26 (s, 2H), 6.46 (d, J = 7.4 Hz,
dihydro[l,3]oxazolo[4,5- 1H), 6.96-7.05 (m, 2H), 7.30-7.37 (m, 1H),
c]pyridine-2,4-dione 7.39 (m, 1H), 10.68 (br. s, 1H).
5-[2-chloro-5- (CD3SO2CD3) 5 2.41 (s, 3H),_5.24 (s, 2H),
(methylthio)benzyl]-3,5- 6.65 (d, J = 7.2 Hz, 1H), 6.83 (d, J = 2.6 Hz,
dihydro[l,3]oxazolo[4,5- 1H), 7.25 (dd, J= 8.0, 2.6 Hz, 2H), 7.45 (d, J =
c]pyridine-2,4-dione 8.0 Hz, 1H), 7.62 (d, J = 7.2 Hz, 1H), 12.01
(br. s, 1H).
5-(4-fluorobenzyl)-3,5- (CD3SO2CD3) 5 5.18 (s, 2H), 6.61 (d, J = 7.4
dihydro[l,3]oxazolo[4,5- Hz, 1H), 7.14-7.2 (m, 2H), 7.35-7.39 (m, 2H),
c]pyridine-2,4-dione 7.74 (d, J = 7.3 Hz, 1H), 11.96 (br. s, 1H).
5-(2-chloro-5-methoxybenzyl)- (CD3SO2CD3) 8 3.69 (s, 3H), 5.22 (s, 2H),
3,5-dihydro[l,3]oxazolo[4,5- 6.42 (d, J = 2.9 Hz, 1H), 6.65 (d, J = 7.3 Hz,
c]pyridine-2,4-dione 1H), 6.94 (dd, J = 8.8, 2.9 Hz, 1H), 7.43 (d, J
= 8.8 Hz, 1H), 7.62 (d, J = 7.3 Hz, 1H), 12.05
(br. s, 1H).
5-[3,5- (CD3SO2CD3) 5 5.36 (s, 2H), 6.69 (d, J = 7.5
bis(trifluoromethyl)benzyl]- Hz, 1H), 7.91 (d, J = 7.5 Hz, 1H), 8.08 (s,
3,5-dihydro[l,3]oxazolo[4,5- 3H), 12.04 (br. S, 1H). c ]pyridine-2,4-dione
5-(4-tert-butylbenzyl)-3,5- (CD3SO2CD3) 6 1.24 (s, 9H), 5.15 (s, 2H),
dihydro[l,3]oxazolo[4,5- 6.61 (d, J = 7.3 Hz, 1H), 7.23 (d, J = 8.4 Hz,
c]pyridine-2,4-dione 2H), 7.35 (d, J = 8.4 Hz, 2H), 7.74 (d, J = 7.3
Hz, 1H), 12.02 (br. s, 1H).
5-(3-chlorobenzyl)-3,5- (CD3SO2CD3) 5 5.20 (s, 2H), 6.63 (d, J = 7.4
dihydro[l,3]oxazolo[4,5- Hz, 1H), 7.25 (m, 1H), 7.35-7.39 (m, 3H),
c]pyridine-2,4-dione 7.76 (d, J = 7.4 Hz, 1H), 11.97 (br. s, 1H).
5-(4-chlorobenzyl)-3,5- (CD3SO2CD3) 5 5.19 (s, 2H), 6.62 (d, J = 7.3
dihydro[l,3]oxazolo[4,5- Hz, 1H), 7.29-7.33 (m, 2H), 7.37-7.42 (m,
c]pyridine-2,4-dione 2H), 7.73 (d, J = 7.3 Hz, 1H), 11.97 (br. s,
1H).
5-[3-(trifluoromethyl)benzyl]- n.d. 3,5-dihydro[ 1,3]oxazolo[4,5-c]pyridine-2,4-dione
5-(2-bromobenzyl)-3,5- (CD3SO2CD3) 5 5.23 (s, 2H), 6.68 (d, J = 7.4
dihydro[l,3]oxazolo[4,5- Hz, 1H), 6.79 (m, 1H), 7.26 (m, 1H), 7.34 (m,
c]pyridine-2,4-dione 1H), 7.64 (d, J = 7.4 Hz, 1H), 7.68 (m, 1H),
12.02 (br. s, 1H).
5-(3,4-dichlorobenzyl)-3,5- (CD3SO2CD3) 6 5.19 (s, 2H), 6.64 (d, J = 7.3
dihydro[l,3]oxazolo[4,5- Hz, 1H), 7.29 (m, 1H), 7.61 (m, 2H), 7.77 (d,
c]pyridine-2,4-dione J = 7.3 Hz, 1H), 11.98 (br. s, 1H).
5-(4-methylbenzyl)-3,5- (CD3SO2CD3) 5 2.27 (s, 3H), 5.14 (s, 2H),
dihydro[1.3]oxazolo[4,5- 6.59 (d, J = 7.5 Hz. 1H), 7.14 (d, J = 8.2 Hz,
c]pyridine-2,4-dione 2H), 7.20 (d, J = 8.2 Hz, 2H1, 7.69 (d, J = 7.5
Hz, 1H), 11.95(br. s, 1H).
5-(2-chloro-6-methoxybenzyl)- (CD3SO2CD3) 5 3.80 (s, 3H), 5.23 (s, 2H),
3,5-dihydro[l,3]oxazolo[4,5- 6.48 (d, J = 7.4 Hz, 1H), 7.05-7.15 (m, 3H),
c]pyridine-2,4-dione 7.42 (m, 1H), 11.95 ( br. s, 1H).
5-[4-(trifluoromethyl)benzyl]- (CD3SO2CD3) 5 5.30 (s, 2H), 6.65 (d, J = 7.3
3,5-dihydro[l,3]oxazolo[4,5- Hz, 1H), 7.48 (d, J = 8.0 Hz. 2H), 7.71 (d, J =
c]pyridine-2,4-dione 8.0 Hz, 2H), 7.76 (d, J = 7.3 Hz, 1H), 11.96
(br. s, 1H).
5-(3-methylbenzyl)-3,5- (CD3SO2CD3) 5 2.27 (s, 3H), 5.15 (s, 2H),
dihydro[l,3]oxazolo[4,5- 6.62 (d, J = 7.3 Hz, 1H), 7.10 (m, 4H), 7.72
c]pyridine-2,4-dione (d, J = 7.3 Hz, 1H), 12.53 (br. s, 1H).
5-(pyridin-2-ylmethyl)-3,5- (CD3SO2CD3) 8 5.29 (s, 2H), 6.62 (d, J = 7.3
dihydro[l,3]oxazolo[4,5- Hz, 1H), 7.22-7.33 (m, 2H), 7.71 (d. J = 7.3
cjpyridine-2,4-dione Hz, 1H), 7.79 (m, 1H), 8.50 (m, 1H), 11.96
(br. s, 1H).
5-(2-chlorobenzyl)-7-methyl- (CD3SO2CD3) 5 2.10 (s, 3H), 5.23 (s, 2H),
3,5-dihydro[l,3]oxazolo[4,5- 6.86 (dd, J = 7.7, 1.5 Hz, 1H), 7.31 (m, 2H),
c]pyridine-2,4-dione 7.50 (m, 2H), 12.01 (br s, 1H).
5-(2,4-difluorobenzyl)-3,5- (CD3SO2CD3) 8 5.21 (s, 2H), 6.63 (d, J = 7.3
dihydro[l,3]oxazolo[4,5- Hz, 1H), 7.02-7.07 (m, 1H), 7.20-7.29 (m,
c]pyridine-2,4-dione 2H), 7.65 (d, J = 7.3 Hz, 1H), 11.97 (br. s,
1H).
5-(2,6-difluorobenzyl)-3,5- (CD3SO2CD3) 8 5.25 (s, 2H), 6.58 (d, J = 7.3
dihydro[l,3]oxazolo[4,5- Hz, 1H), 7.02-7.12 (m, 2H) 7.38-7.55 (m,
c]pyridine-2,4-dione 1H), 7.63 (d, J = 7.3 Hz, 1H), 11.91 (br. s,
1H).
5-[3- (CD3SO2CD3) 8 5.24 (s, 2H), 6.64 (d, J = 7.3
(trifluoromethoxy)benzyl]-3,5- Hz, 1H), 7.22-7.35 (m, 3H), 7.46 (t, J = 7.7
dihydro[l,3]oxazolo[4,5- Hz, 1H), 7.78 (d, J = 7.3 Hz, 1H), 11.99 (br. s,
c]pyridine-2,4-dione 1H).
5-[4- (CD3SO2CD3) 8 5.23 (s, 2H), 6.63 (d, J = 7.3
(trifluoromethoxy)benzyl]-3,5- Hz, 1H), 7.29-7.45 (m, 4H), 7.76 (d, J = 7.3
dihydro[l,3]oxazolo[4,5- Hz, 1H), 11.98 (br. s, 1H). c]pyridine-2,4-dione
5-[2-(trifluoromethyl)benzyl]- (CD3SO2CD3) 8 5.40 (s, 2H), 6.73 (d, J = 7.3
3,5-dihydro[l,3]oxazolo[4,5- Hz, 1H), 6.81 (d, J = 7.5 Hz, 1H), 7.51 (1, J =
c]pyridine-2,4-dione 7.5 Hz, 1H), 7.61 (t, J = 7.5 Hz, 1H), 7.70 (d,
J = 7.3 Hz, 1H), 7.80 (d, J = 7.5 Hz, 1H),
12.04 (br. s, 1H).
5-(3-methoxybenzyl)-3,5- n. d.
dihydro[l,3]oxazolo[4,5-c]pyridine-2,4-dione
5-(2,3-dichlorobenzyl)-3,5- n. d.
dihydro[l,3]oxazolo[4,5-
c]pyridine-2,4-dione
5-(3,5-dimethylbenzyl)-3,5- (CD3SO2CD3) 8 2.23 (s, 6H), 5.11 (s, 2H),
dihydro[l,3]oxazolo[4,5- 6.61 (d, J = 7.3 Hz, 1H), 6.91 (m, 3H), 7.69
c]pyridine-2,4-dione (d, J = 7.3 Hz, 1H), 12.00 (br. s, 1H).
5-(2-chlorobenzyl)~7-pentyl- (CD3SO2CD3) 8 0.86 (t, J = 6.2 Hz, 3H), 1.27
3,5-dihydro[l,3]oxazolo[4,5- (m, 6H), 1.65 (t, J = 6.7 Hz, 2H), 5.24 (s, 2H),
c]pyridine-2,4-dione 6.83 (d, J = 6.6 Hz, 1H), 7.24-7.34 (m, 2H),
7.48 (s, 1H), 7.50 (d, J = 7.7 Hz, 1H), 12.00
(br. s, 1H).
5-(2,4-dichlorobenzyl)-7- (CD3SO2CD3) 8 2.10 (s, 3H), 5.19 (s, 2H),
methyl-3,5- 6.87 (d, J = 8.4 Hz, 1H), 7.38 (dd, J = 8.4, 2.2
dihydro[l,3]oxazolo[4,5- Hz, 1H), 7.50 (s, 1H), 7.69 (d, J = 2.2 Hz,
c]pyridine-2,4-dione 1H), 12.02 (br. s, 1H).
5-(2-chlorobenzyl)-7-ethyl-3,5- (CD3SO2CD3) 5 1.17 (t, J = 7.5 Hz, 3H), 2.50
dihydro[l,3]oxazolo[4,5- (m, 2H overlapping DMSO), 5.25 (s, 2H),
c]pyridine-2,4-dione 6.84 (m, 1H), 7.30 (m, 2H), 7.49 (m, 2H),
12.02 (br. s, 1H).
7-butyl-5-(2-chlorobenzyl)- (CD3SO2CD3) 8 0.87 (t, J = 7.3 Hz, 3H), 1.28
3,5-dihydro[l,3]oxazolo[4,5- (m, 4H), 1.54 (t, J = 7.1 Hz, 2H), 5.24 (s, 2H),
c]pyridine-2,4-dione 6.83 (d, J = 6.8 Hz, 1H), 7.24-7.34 (m, 2H),
7.48-7.56 (m, 2H), 12.00 (br. s, 1H).
5-[2-chloro-5- (CD3SO2CD3) 8 5.33 (s, 2H), 6.68 (d, J = 7.3
(trifluoromethyl)benzyl]-3,5- Hz, 1H), 7.35 (s, 1H), 7.69-7.79 (m, 3H),
dihydro[l,3]oxazolo[4,5- 11.96 (br. s, 1H). c]pyridine-2,4-dione
5-(2,6-dichlorobenzyl)-3,5- (CD3SO2CD3) 8 5.38 (s, 2H), 6.53 (d, J = 7.4
dihydro[l,3]oxazolo[4,5- Hz, 1H), 7.07 (d, J = 7.7 Hz, 1H), 7.45-7.50
c]pyridine-2,4-dione (m, 1H), 7.52-7.59 (m, 2H), 11.99 (br. s, 1H).
5-(2-chloro-5-fluorobenzyl)- (CD3SO2CD3) 8 5.27 (s, 2H), 6.67 (d, J = 7.3
3,5-dihydro[l,3]oxazolo[4,5- Hz, 1H), 6.72 (dd, J = 7.3, 3.2 Hz, 1H), 7.21-
c]pyridine-2,4-dione 7.23 (m, 1H), 7.55-7.59 (m, 1H), 7.65 (d, J =
7.3 Hz, 1H), 12.00 (br. s, 1H).
5-(2-chloro-6-methylbenzyl)-7- (CDC13) 8 2.07 (s, 3H), 2.29 (s, 3H), 5.48 (s,
methyl-3,5- 2H), 6.63 (s, 1H), 7.16 (d, J = 7.7 Hz, 1H),
dihydro[l,3]oxazolo[4,5- 7.25 (t, J = 7.7 Hz, 1H), 7.34 (d, J = 7.7 Hz,
c]pyridine-2,4-dione 1H), 11.33 (br. S, 1H).
5-(4-chlorobenzyl)-7-methyl- (CD3SO2CD3) 8 2.08 (s, 3H), 5.14 (s, 2H),
3,5-dihydro[l,3]oxazolo[4,5- 7.31 (d, J = 8.4 Hz, 2H), 7.41 (d, J = 8.4 Hz,
c]pyridine-2,4-dione 2H), 7.58 (s, 1H), 12.03 (br. s, 1H).
5-(2-chlorobenzyl)-5,6,7,8- (CD3SO2CD3) 8 2.04 (m, 2H), 2.80 (m, 4H),
tetrahydro-2H- 5.28 (s, 2H), 6.68 (d, J = 7.3 Hz, 1H), 7.18-
cyclopenta[b][l,3]oxazolo[5,4- 7.34 (m, 2H), 7.51 (d, J = 7.7 Hz, 1H), 1 ] .92
d]pyridine-2,4(3H)-dione (br. s, 1H).
7-methyl-5-[4- (CD3SO2CD3) 5 2.11 (s, 3H), 2.58 (s, 3H),
(methylsulfonyl)benzyl]-3,5- 5.28 (s, 2H), 7.58 (d, J = 7.3 Hz, 2H), 7.64 (s,
dihydro[l,3]oxazolo[4,5- 1H), 7.91 (d, J = 7.3 Hz, 2H), 12.06 (br. s,
c]pyridine-2,4-dione 1H).
5-(4-methoxybenzyl)-3,5- (CD3SO2CD3) 6 3.73 (s, 3H), 5.10 (s, 2H),
dihydro[l,3]oxazolo[4,5- 6.56 (br. d, J = 5.9 Hz, 1H), 6.89 (d, J = 8.8
c]pyridine-2,4-dione Hz, 2H), 7.27 (d, J = 8.8 Hz, 2H), 7.67 (br. m,
1H), 12.06 (br. s, 1H).
5-(2-chlorobenzyl)-7-propyl- (CD3SO2CD3) 5 0.88 (t, J = 7.4 Hz, 3H), 1.57
3,5-dihydro[l,3]oxazolo[4,5- (m, 2H), 2.46 (m, 2H), 5.24 (s, 2H), 6.84 (d, J
c]pyridine-2,4-dione =6.2 Hz, 1H), 7.26-7.38 (m, 2H), 7.48 (sr,
1H), 7.50 (d, J = 7.7 Hz, 1H), 12.00 (br. s,
1H).
4-[(2,4-dioxo-2,3- (CD3SO2CD3) 5 2.55 (s, 6H), 5.31 (s, 2H),
dihydro[l,3]oxazolo[4,5- 6.67 (d, J = 7.3 Hz, 1H), 7.43-7.51 (m, 2H),
c]pyridin-5(4H)-yl)methyl]- 7.66-7.74 (m, 2H), 7.77 (d, J = 7.3 Hz, 1H),
N,N- 12.00 (br. s, 1H). dimethylbenzenesulfonamide
5-(mesitylmethyl)-3,5- (CDC13) 6 2.19 (s, 6H), 2.30 (s, 3H), 5.25 (s,
dihydro[l,3]oxazolo[4,5- 2H), 6.31 (d, J = 7.3 Hz, 1H), 6.73 (d, J = 7.3
c]pyridine-2,4-dione Hz, 1H), 6.94 (s, 2H), 11.01 (br. s, 1H).
5-(2-chlorobenzyl)-3,5,6,7,8,9- (CD3SO2CD3) 5 1.64 (m, 4H), 2.50 (m, 4H),
hexahydro[l,3]oxazolo[4,5- 5.34 (s, 2H), 6.59 (d, J = 8.1 Hz, 1H), 7.25-
c]quinoline-2,4-dione 7.34 (m, 2H), 7.51 (d, J = 7.7 Hz, 1H), 11.92
(br. s, 1H).
5-(2-chlorobenzyl)-7-ethyl-6- (CD3SO2CD3) 5 1.10 (t, J = 7.4 Hz, 3H), 2.22
methyl-3,5- (s, 3H), 2.56 (m, 2H), 5.40 (s, 2H), 6.58 (d, J
dihydro[l,3]oxazolo[4,5- = 7.0 Hz, 1H), 7.23-7.34 (m, 2H), 7.52 (d, J =
c]pyridine-2,4-dione 8.1 Hz, 1H), 11.92 (br. s, 1H).
5-[2-(methylthio)benzyl]-3,5- (CD3SO2CD3) 5 2.52 (s, 3H), 5.19 (s, 2H),
dihydro[l,3]oxazolo[4,5- 6.63 (d, J = 7.3 Hz, 1H), 6.76 (d, J = 7.7 Hz,
c]pyridine-2,4-dione 1H), 7.09-7.17 (m, 1H), 7.29-7.37 (m, 2H),
7.55 (d, J = 7.3 Hz, 1H), 11.99 (s, 1H).
2-[(2,4-dioxo-2,3- (CD3SO2CD3) 5 2.81 (s, 6H), 5.54 (s, 2H),
dihydro[l,3]oxazolo[4,5- 6.71 (d, J = 7.3 Hz, 1H), 6.81 (d, J = 7.3 Hz,
c]pyridin-5(4H)-yl)methyl]- 1H), 7.49-7.61 (m, 2H), 7.69 (d, J = 7.3 Hz,
N,N- 1H), 7.85 (d, J = 7.3 Hz, 1H), 12.05 (br. s,
dimethylbenzenesulfonamide 1H).
5-(2,6-dimethoxybenzyl)-3,5- (CD3SO2CD3) 5 3.76 (s, 6H), 5.07 (s, 2H),
dihydro[l,3]oxazolo[4,5- 6.43 (d, J = 7.7 Hz, 1H), 6.73 (d, J = 8.4 Hz,
c]pyridine-2,4-dione 2H), 7.00 (d, J = 7.7 Hz, 1H), 7.37 (t, J = 8.4
Hz, 1H), 11.92(br. s, 1H).
5-[2- (CD3SO2CD3) 5 5.27 (s, 2H), 6.65 (d, J = 7.3
(trifluoromethoxy)benzyl]-3,5- Hz, 1H), 7.08 (dd, J = 7.3, 1.4 Hz, 1H), 7.30-
dihydro[l,3]oxazolo[4,5- 7.49 (m, 3ri), 7.63 (d, J = 7.3 Hz. 1H), 1 i.99
c]pyridine-2,4-dione (br. s, 1H).
5-(2-chlorobenzyl)-6,7- (CD3SO2CD3) 5 2.12 (s, 3H), 2.19 (s, 3H),
dimethyl-3,5- 5.40 (s, 2H), 6.59 (d, J = 6.6 Hz, 1H), 7.25-
dihydro[l,3]oxazolo[4,5- 7.34 (m, 2H), 7.52 (d, J = 7.7 Hz, 1H), 11.91
c]pyridine-2,4-dione (br. s, 1H).
5-[2-chloro-5 (CD3SO2CD3) 5 3.20 (s, 3H). 5.35 (s, 2H),
(methylsulfonyl)benzyl]-3,5- 6.70 (d, J = 7.3 Hz, 1H), 7.55 (m, 1H), 7.69
dihydro[l,3]oxazolo[4,5- (m, iH), 7 90 (m, 2H), 12.04 (br. s, 1H). c ] pyridine-2,4-dione
5-(4-chloro-2-methoxybenzyl)- (CD3SO2CD3) 5 3.86 (s, 3H), 5.09 (s, 2H),
3,5-dihydro[l,3]oxazolo[4,5- 6.60 (d, J = 7.3 Hz, IH), 6.90-6.98 (m, 2H),
c]pyridine-2,4-dione 7.12 (d, J = 2.2 Hz, IH), 7.59 (d, J = 7.3 Hz,
IH), 11.95 (br. s, IH).
5-(2-chlorobenzyl)- (CD3SO2CD3) 5 1.34 (m, 2H), 1.56 (m, 2H),
5,6,7,8,9,10-hexahydro-2H- 1.69 (m, 2H), 2.70 (m, 4H), 5.45 (s, 2H), 6.69
cyclohepta[b][l,3]oxazolo[5,4- (d, J = 6.6 Hz, IH), 7.24-7.35 (m, 2H), 7.52
d]pyridine-2,4(3H)-dione (d, J = 7.7 Hz, IH), 11.91 (br. s, IH).
5-[2- (CD3SO2CD3) 5 5.21 (s, 2H), 6.64 (dr J = 7.3
(difluoromethoxy)benzyl]-3,5- Hz, IH), 7.02 (d, J = 7.3 Hz, IH), 7.20-7.25
dihydro[l,3]oxazolo[4,5- (m, 2H), 7.27 (t, J = 74.0 Hz, IH), 7.62 (d, J =
c]pyridine-2.4-dione 7.3 Hz, IH), 12.00 (br. s, IH).
7-methyl-5-[(lR)-l- (CD3SO2CD3) 5 1.72 (d, J = 7.3 Hz, 3H), 2.07
phenylethyl]-3,5- (s, 3H), 6.27 (q, J = 7.3 Hz, 1H), 7.27-7.40
dihydro[l,3]oxazolo[4,5- (m, 6H), 11.95 (br. s, IH). c]pyridine-2,4-dione
5-(4-chlorobenzyl)-7-propyl- (CD3SO2CD3) 8 0.89 (t, J == 7.3 Hz, 3H), 1.54
3,5-dihydro[l,3]oxazolo[4,5- (m, 2H), 2.44 (t, J = 7.7 Hz, 2H), 5.15 (s, 2H),
c]pyridine-2,4-dione 7.30 (d, J = 8.4 Hz, 2H), 7.39 (d, J = 8.4 Hz,
2H), 7.57 (s, 1H), 11.97 (br. s, 1H).
5-[2-(methylsulfonyl)benzyl]- (CD3SO2CD3) 5 3.43 (s, 3H), 5.60 (s, 2H),
3,5-dihydro[l,3]oxazolo[4,5- 6.75 (d, J = 7.3 Hz, 1H), 7.49-7.61 (m, 2H),
c]pyridine-2,4-dione 7.65-7.70 (m, 2H) 7.89-7.91 (m, 1H), 12.02
(br. s, 1H).
5-(2,6-dimethylbenzyl)-3,5- (CD3SO2CD3) 5 2.21 (s, 6H), 5.16 (s, 2H),
dihydro[l,3]oxazolo[4,5- 6.47 (d, J = 7.3 Hz, 1H), 6.80 (d, J = 7.3 Hz,
c]pyridine-2,4-dione 1H), 7.09-7.22 (m, 3H), 12.00 (br. s, 1H).
3-chloro-2-[(2,4-dioxo-2,3- (CD3SO2CD3) 5 5.38 (s, 2H), 6.61 (d, 7.4 Hz,
dihydro[l,3]oxazolo[4,5- 1H), 7.55 (t, J = 8.0 Hz, 1H), 7.62 (d, J = 7.4
c]pyridin-5(4H)- Hz, 1H), 7.82 (d, J = 8.0 Hz, 1H), 7.87 (d, J =
yl)methyl]benzonitrile 8.0 Hz, 1H), 11.96 (br. sf 1H).
5-(2-chloro-6-methylbenzyl)- (CD3SO2CD3) 5 2.06 (s, 3H), 2.09 (s, 3H),
6,7-dimethyl-3,5- 2.10 (s, 3H), 5.58 (s, 2H), 7.13 (d, J = 7.7 Hz,
dihydro[l,3]oxazolo[4,5- 1H), 7.20 (t, J = 7.7 Hz, 2H), 7.27 (d, J = 7.7
c]pyridine-2,4-dione Hz, 1H), 11.84 (br. s, 1H).
2-[(2,4-dioxo-2,3- (CD3SO2CD3) 5 5.40 (s, 2H), 6.70 (d, J = 7.4
dihydro[ 1,3]oxazolo[4,5- Hz, 1H), 7.11 (d, J = 7.7 Hz, 1H), 7.50 (t, J =
c]pyridin-5(4H)- 7.7 Hz, 1H), 7.66 (td, J = 7.7, 1.1 Hz, 1H),
yl)methyl]benzonitrile 7.74 (d, J = 7.4 Hz, 1H), 7.88 (dd, J = 7.7, 1.1
Hz, 1H), 12.01 (br. s, 1H).
5-(2-chloro-6-methoxybenzyl)- (CD3SO2CD3) 5 2.01 (s, 3H), 3.81 (s, 3H),
7-methyl-3,5- 5.21 (s, 2H), 6.86 (s, 1H), 7.11 (m, 2H), 7.41
dihydro[l,3]oxazolo[4,5- (t, J = 8.2 Hz, 1H), 11.96 (br. s, 1H). c]pyridine-2,4-dione
5-[3-(methylthio)benzyl]-3,5- (CD3SO2CD3) 5 2.45 (s, 3H), 5.16 (s, 2H),
dihydro[l,3]oxazolo[4,5- 6.61 (d, J = 7.3 Hz, 1H), 7.04 (d, J = 7.3 Hz,
c]pyridine-2,4-dione 1H), 7.16-7.34 (m, 3H), 7.73 (d, J = 7.3 Hz,
1H), 11.97(br. s, 1H).
5-(2-chlorobenzyl)-7- (CD3SO2CD3) 5 0.70 (m, 2H), 0.87 (m, 2H),
cyclopropyl-3,5- 1.79 (m, 1H), 5.22 (s, 2H), 6.79 (d, J = 7.3
dihydro[l,3]oxazolo[4,5- Hz, 1H), 7.31 (m, 1H), 7.45 (s, 1H), 7.50 (d, J
c]pyridine-2,4-dione = 7.7 Hz, 1H), 12.01 (br. s, 1H).
5-(3-chlorobenzyl)-7-methyl- (CD3SO2CD3) S 2.09 (d, J == 1.1 Hz, 3H), 5.15
3,5-dihydro[l,3]oxazolo[4,5- (s, 2H), 7.26 (m, 1H), 7.33-7.41 (m, 3H), 7.59
c]pyridine-2,4-dione (q, J = 1.1 Hz, 1H), 11.97 (br. s, 1H).
5-(2,6-dichlorobenzyl)-7- (CD3SO2CD3) 5 2.03 (d, J = 1.1 Hz, 3H), 5.36
methyl-3,5- (s, 2H), 6.87 (q, J = 1.1 Hz, 1H), 7.46 (dd, J =
dihydro[l,3]oxazolo[4,5- 8.8, 7.4 Hz, 1H), 7.56 (d, J = 7.4 Hz, 1H),
c]pyridine-2,4-dione 7.57 (d, J = 8.8 Hz, 1H), 11.99 (br. s, 1H).
7-methyl-5-(4-methylbenzyl)- (CD3SO2CD3) 5 2.07 (s, 3H), 2.27 (s, 3H),
3,5-dihydro[l,3]oxazolo[4,5- 5.10 (s, 2H), 7.08-7.23 (m, 4H), 7.52 (s, 1H),
c]pyridine-2,4-dione 11.95 (br. s, 1H).
5-(3,5-dimethoxybenzyl)-7- (CD3SO2CD3) 5 2.09 (s, 3H), 3.71 (s, 6H),
methyl-3,5- 5.06 (s, 2H), 6.42 (t, J = 2.2 Hz, 1H), 6.46 (d,
dihydro[l,3]oxazolo[4,5- J = 2.2 Hz, 2H), 7.51 (s, 1H), 11.96 (br. s,
c]pyridine-2,4-dione 1H).
5-(2,6-difluorobenzyl)-7- (CD3SO,CD3) 5 2.09 (d, J = 1.1 Hz, 3H), 5.21
methyl-3,5- (s, 2H), 7.04-7.13 (m, 2H), 7.38-7.47 (m, 2H),
dihydro[l,3]oxazolo[4,5- 11.91 (br. s, 1H). c]pyridine-2,4-dione
5-[3-(methylsulfonyl)benzyl]- (CD3SO2CD3) 5 3.20 (s, 3H), 5.31 (s, 2H),
3,5-dihydro[l,3]oxazolo[4,5- 6.66 (d, J = 7.3 Hz, 1H), 7.5-7.7 (m, 2H), 7.81
c]pyridine-2,4-dione (d, J = 7.3 Hz, 1H), 7.83-7.96 (m, 2H), 11.99
(br. s, 1H).
5-(2-chloro-6-ethoxybenzyl)- (CD3SO2CD3) 5 1.25 (t, J = 7.0 Hz, 3H), 4.05
3,5-dihydro[l,3]oxazolo[4,5- (q, J = 7.0 Hz, 2H), 5.25 (s, 2H), 6.49 (d, J =
c]pyridine-2,4-dione 7.3 Hz, 1H), 7.06 (d, J = 8.4 Hz, 1H), 7.10 (d,
J = 8.1 Hz, 1H), 7.12 (d, J = 7.3 Hz, 1H), 7.37 (dd, J = 8.4, 8.1 Hz, 1H), 11 95 (br. s, 1H).
5-(2-chloro-6-ethoxybenzyl)-7- (CD3SO2CD3) 5 1.25 (t, J = 7.0 Hz, 3H), 2.02
methyl-3,5- (s, 3H), 4.04 (q, J = 7.0 Hz, 2H), 5.23 (s, 2H),
dihydro[l,3]oxazolo[4,5- 6.97 (s, 1H), 7.04 (d, J = 8.4 Hz, 1H), 7.09 (d,
c]pyridine-2,4-dione J = 8.0 Hz, 1H), 7.36 (dd, J = 8.4, 8.0 Hz,
1H), 11.93 (br. s, 1H).
5-(2-fluoro-6-methoxybenzyl)- (CD3SO2CD3) 8 2.05 (s, 3H), 3.82 (s, 3H),
7-methyl-3,5- 5.12 (s, 2H), 6.82 (dd, J = 9.5, 8,4 Hz, 1H),
dihydro[l,3]oxazolo[4,5- 6.91 (d, J = 8.4 Hz, 1H), 7.18 (s, 1H), 7.37
c]pyridine-2,4-dione (td, J = 8.4, 6.6 Hz, 1H), 11.89 (br. s, 1H).
5-(2-chloro-6-methoxybenzyl)- (CD3SO2CD3) 5 0.82 (t, J = 7.3 Hz, 3H), 1.47
7-propyl-3,5- (sextet, J = 7.3 Hz, 2H), 2.38 (t, J = 7.3 Hz,
dihydro[l,3]oxazolo[4,5- 2H), 3.80 (s, 3H), 5.21 (s, 2H), 6.89 (s, 1H),
c]pyridine-2,4-dione 7.08-7.13 (m, 2H), 7.40 (t, J = 8.3 Hz, 1H),
11.93(br. s, 1H).
5-(5-chloro-2-fluorobenzyl)-7- (CD3SO2CD3) 6 2.10 (s, 3H), 5.18 (s, 2H),
methyl-3,5- 7.20 (dd, J = 6.6, 3.0 Hz, 1H), 7.29 (dd, J =
dihydro[l,3]oxazolo[4,5- 9.6, 8.8 Hz, 1H), 7.42 (ddd, J = 8.8, 4.4, 3.0
c]pyridine-2,4-dione Hz, 1H), 7.51 (s, 1H), 11.96 (br. s, 1H).
5-(2-chlorobenzyl)-7- (CD3SO2CD3) 5 1.23 (d, J = 7.0 Hz, 6H), 2.92
isopropyl-3,5- (m, 1H), 5.25 (s, 2H), 6.83 (dd, J = 7.4, 2.2
dihydro[l,3]oxazolo[4,5- Hz, 1H), 7.27-7.35 (m, 2H), 7.49 (s, 1H), 7.51
c]pyridine-2,4-dione (dd, J = 7.3, 1.8 Hz, 1H), 12.01 (br. s, 1H).
5-(5-fluoro-2-methylbenzyl)-7- (CD3SO2CD3) 5 2.10 (d, J = 1.1 Hz, 3H), 2.30
methyl-3,5- (s, 3H), 5.13 (s, 2H), 6.55 (dd, J = 9.9, 2.6 Hz,
dihydro[l,3]oxazolo[4,5- 1H), 7.01 (td, J = 8.4, 2.6 Hz, 1H), 7.25 (dd, J
c]pyridine-2,4-dione = 8.4, 5.9 Hz, 1H), 7.42 (q, 1.1 Hz, 1H), 11.99
(br. s, 1H).
7-methyl-5-[(lS)-l- (CD3SO2CD3) 5 1.72 (d, J = 7.3 Hz, 3H), 2.07
phenylethyl]-3,5- (s, 3H), 6.27 (q, J = 7.3 Hz, 1H), 7.27-7.40
dihydro[ 1,3]oxazolo[4,5- (m, 6H), 11.95 (br. s, 1H). c]pyridine-2,4-dione
5-(2-chloro-5- (CD3SO2CD3) 5 1.20 (d, J = 6.0 Hz, 6H), 2.11
isopropoxybenzyl)-7-methyl- (s, 3H), 4.50 (m, 1H), 5.16 (s, 2H), 6.34 (d, J
3,5-dihydro[l,3]oxazolo[4,5- = 3.0 Hz, 1H), 6.91 (dd, J = 8.8, 3.0 Hz, 1H),
c]pyridine-2,4-dione 7.38 (d, J = 8.8 Hz, 1H), 7.47 (s, 1H), 12.01
(br. s, 1H).
5-(5-acetyl-2-methoxybenzyl)- (CD3SO2CD3) 6 2.47 (s, 3H), 3.93 (s, 3H),
3,5-dihydro[l,3]oxazolo[4,5- 5.16 (s, 2H), 6.62 (d, J = 7.3 Hz, 1H), 7.16 (d,
c]pyridine-2,4-dione J = 8.4 Hz, 1H), 7.59 (d, J = 2.2 Hz, 1H); 7.63
(d, J = 7.3 Hz, 1H), 7.97 (dd, J = 8.4, 2.2 Hz,
1H), 11.96(br. s, 1H).
5-(2-chlorobenzyl)-7-methyl- (CD3SO2CD3) 5 2.29 (s, 3H), 5.39 (s, 2H),
3,5-dihydro[l,3]oxazolo[4,5- 7.00 (d, J = 7.4 Hz, 1H), 7.26-7.37 (m, 2H),
d]pyridazine-2,4-dione 7.51 (d, J = 7.7 Hz, 1H), 12.80 (br. s, 1H).
5-[2-fluoro-6- (CD3SO2CD3) 5 2.04 (s, 3H), 5.33 (s, 2H),
(trifluoromethyl)benzyl]-7- 7.05 (s, 1H), 7.51-7.72 (m, 3H), 11.98 (br. s,
methyl-3,5- 1H).
dihydrof 1,3]oxazolo[4,5-c]pyridine-2,4-dione
5-(2-chloro-6-methylbenzyl)- (CD3SO2CD3) 5 2.02 (m, 2H), 2.21 (s, 3H),
5,6,7,8-tetrahydro-2H- 2.64-2.80 (m, 4H), 5.42 (s, 2H), 7.05-7.33 (m,
cyclopenta[b][l,3]oxazolo[5,4- 3H), 11.81 (br. s, 1H). d]pyridine-2,4(3H)-dione
5-(2-chloro-6-ethoxybenzyl)-7- (CD3SO2CD3) 5 1.08 (t, J = 7.7 Hz, 3H), 1.25 ethyl-3,5- (t, J = 7.0 Hz, 3H), 2.44 (q, J = 7.7 Hz, 2H),
dihydro[l,3]oxazolo[4,5- 4.05 (q, J = 7.0 Hz, 2H), 5.23 (s, 2H), 6.99 (s,
c]pyridine-2,4-dione 1H), 7.05 (d, J = 8.4 Hz, 1H), 7.09 (d, J = 8.1
Hz, 1H), 7.36 (dd, J = 8.4, 8.1 Hz, 1H), 11.93
(br. s, 1H).
5-(2-chloro-6-propoxybenzyl)- (CD3SO2CD3) 5 0.88 (t, J = 7.3 Hz, 3H), 1.66
7-methyl-3,5- (m, 2H), 2.01 (d, J = 1.1 Hz, 3H), 3.95 (t, J =
dihydro[l,3]oxazolo[4,5- 6.2 Hz, 2H), 5.24 (s, 2H), 6.91 (q, J = 1.1 Hz,
c]pyridine-2,4-dione 1H), 7.03 (d, J = 8.4 Hz, 1H), 7.10 (d, J == 8.1
Hz, 1H), 7.37 (dd, J = 8.4, 8.1 Hz, 1H), 11.95
(br. s, 1H).
5-(2-chloro-6- (CD3SO2CD3) S 0.89 (d, J = 7.0 Hz, 6H), 1.95
isobutoxybenzyl)-7-methyl- (m, 1H), 2.00 (s, 3H), 3.79 (d, J = 6.2, 2H),
3,5-dihydro[l,3]oxazolo[4,5- 5.25 (s, 2H), 6.85 (s, 1H), 7.06 (d, J = 8.4 Hz,
c]pyridine-2,4-dione 1H), 7.11 (d, J = 8.1 Hz, 1H), 7.38 (dd, J =
8.4,8.1 Hz, 1H), 11.97 (br. s, 1H).
5-(2-chloro-6-ethoxybenzyl)- (CD3SO2CD3) 8 1.10 (t, J = 7.0 Hz, 3H), 2.06
5,6,7,8-tetrahydro-2H- (m, 2H), 2.70-2.92 (m, 4H), 3.90 (q, J = 7.0
cyclopenta[b][l,3]oxazolo[5,4- Hz, 2H), 5.33 (s, 2H), 6.93 (d, J = 8.4 Hz, d]pyridine-2,4(3H)-dione 1H), 7.03 (d, J = 8.1 Hz, 1H), 7.26 (dd, J =
8.4,8.1 Hz, 1H), 11.75(br. s, 1H).
5-(2-chloro-6- (CD3SO2CD3) 5 1.16 (d, J = 6.2 Hz, 6H), 2.02
isopropoxybenzyl)-7-methyl- (s, 3H), 4.67 (m, 1H), 5.21 (s, 2H), 6.94 (s,
3,5-dihydro[l,3]oxazolo[4,5- 1H), 7.07 (d, J = 8.0 Hz, 2H), 7.34 (t, J = 8.0
c]pyridine-2,4-dione Hz, 1H), 11.93 (br. s, 1H).
5-[2-chloro-6-(2,2,2- (CD3SO2CD3) 8 2.01 (s, 3H), 4.82 (q, J = 8.8
trifluoroethoxy)benzyl]-7- Hz, 2H), 5.24 (s, 2H), 6.94 (s, 1H), 7.19 (d, J
methyl-3,5- = 8.4 Hz, 1H), 7.22 (d, J = 8.1 Hz, 1H), 7.43
dihydro[l,3]oxazolo[4,5- (dd, J = 8.4, 8.1 Hz, 1H), 11.92 (br. s, 1H). c]pyridine-2,4-dione
5-(2-chloro-6-ethoxybenzyl)-7- (CD3SO2CD3) 6 1.19 (t, J = 7.0 Hz, 3H), 2.19
methyl-3,5- (s, 3H), 3.99 (q, J = 7.0 Hz, 2H), 5.41 (s, 2H),
dihydro[l,3]oxazolo[4,5- 6.98 (d, J = 8.4 Hz, 1H), 7.05 (d, J = 8.0 Hz,
d]pyridazine-2,4-dione 1H), 7.30 (dd, J = 8.4, 8.0 Hz, 1H), 12.70 (br.
s, 1H).
5-[2-chloro-6-(2- (CD3SO2CD3) 5 2.06 (m, 2H), 2.74-2.90 (m,
methoxyethoxy)benzyl]- 4H), 3.20 (s, 3H), 3.47 (1, J = 4.4 Hz, 2H),
5,6,7,8-tetrahydro-2H- 4.01 (t, J = 4.4 Hz, 2H), 5.33 (s, 2H), 6.98 (d,
cyclopenta[b][l,3]oxazolo[5,4- J = 8.0 Hz, 1H), 7.04 (d, J = 8.0 Hz, 1.H), 7.27
d]pyridine-2,4(3H)-dione (t, J = 8.0 Hz, 1H), (br. s, 1H).
5-(2-chloro-6-ethoxybenzyl)- (CD3SO2CD3) 5 1.03 (t, J = 7.0 Hz, 3H), 2.06
6,7-dimethyl-3,5- (s, 3H), 2.22 (s, 3H), 3.84 (q, J = 7.0 Hz, 2H),
dihydro[l,3]oxazolo[4,5- 5.48 (s, 2H), 6.92 (d, 8.4 Hz, lHj, 7.03 (d, J =
c]pyridine-2,4-dione 8.1 Hz, 1H), 7.24 (dd, J - 8.4, 8.1 Hz, 1H),
11.76(br.s, 1H).
5-(2-chloro-6-ethoxybenzyl)-7- (CD3SO2CD3) 5 1.06 (m, 6H), 2.24 (s, 3H),
ethyl-6-methyl-3,5- 2.48-2.56 (m overlapping DMSO, 2H), 3.85
dihydro[l,3]oxazolo[4,5- (q, J = 7".O Hz, 2H), 5.48 (s, 2H), 6.92 (d, 8.4
c]pyridine-2,4-dione Hz, 1H), 7.03 (d, J = 8.1 Hz, 1H), 7.24 (dd, J
= 8.4, 8.1 Hz, 1H), 11.77 (br.s, 1H).
5-(2-chlorobenzyl)-7-ethyl-3,5- (CD3SO2CD3) 5 1.18 (t, J = 7.5 Hz, 3H), 2.70
dihydro[l,3]oxazolo[4,5- (q, J = 7.5 Hz, 2H), 5.38 (s, 2H), 7.0-7.6 (m,
d]pyridazine-2,4-dione 4H), 12.77 (br. s, 1H).
5-(2-chloro-6-ethoxybenzyl)-7- (CD3SO2CD3) 5 0.82 (t, J = 7.3 Hz, 3H), 1.24
propyl-3,5- (t, J = 7.0 Hz, 3H), 1.48 (m, 2H), 2.37 (t, J =
dihydro[l,3]oxazolo[4,5- 7.3 Hz, 2H), 4.05 (q, J = 7.0 Hz, 2H), 5.23 (s,
c]pyridine-2,4-dione 2H), 6.93 (s, 1H), 7.05 (d, J = 8.4 Hz, 1H),
7.09 (d, J = 8.1 Hz. 1H), 7.36 (dd, J = 8.4, 8.1 Hz, 1H), 11.94 (br.s, 1H).
5-(2-chloro-6-ethoxybenzyl)-7- (CD3SO2CD3) 5 0.55 (m, 2H), 0.81 (m, 2H), cyclopropyl-3,5- 1.26 (t, J = 7.0 Hz, 3H), 1.72 (m, 1H), 4.05 (q,
dihydro[l,3]oxazolo[4,5- J = 7.0 Hz, 2H), 5.22 (s, 2H), 6.95 (s, 1H),
c]pyridine-2,4-dione 7.05 (d, J = 8.4 Hz, 1H), 7.09 (d, J = 8.1 Hz,
1H), 7.36 (dd, J = 8.4, 8.1 Hz, 1H), 11.93 (br.
s, 1H).
5-(2-chloro-5-propoxybenzyl)- (CD3SO2CD3) 5 0.92 (t, J = 7.3 Hz, 3H), 1.66
7-methyl-3,5- (m, 2H), 2.10 (s, 3H), 3.85 (m, 2H), 5.17 (s,
dihydro[l,3]oxazolo[4,5- 2H), 6.41 (d, J = 3.3 Hz, 1H), 6.91 (dd, J =
c]pyridine-2,4-dione 8.8, 3.3 Hz, 1H), 7.39 (d, J = 8.8 Hz, 1H),
7.45 (s, 1H), 12.00 (br. s, 1H).
5-(2-chloro-5-methoxybenzyl)- (CD3SO2CD3) 5 2.10 (s, 3H), 3.9 (s, 3H), 5.18
7-methyl-3,5- (s, 2H), 6.42 (d, J = 3.0 Hz, 1H), 6.93 (dd, J =
dihydro[l,3]oxazolo[4,5- 8.8, 3.0 Hz, 1H), 7.42 (d, J = 8.8 Hz, 1H),
c]pyridine-2,4-dione 7.44 (s, 1H), 12.00 (br. s, 1H).
5-(2-chloro-6-ethoxybenzyl)-6- (CD3SO2CD3) 5 1.07 (t, J = 7.0 Hz, 3H), 2.32 methyl-3,5- (s, 3H), 3.87 (q, J = 7.0 Hz, 2H), 5.42 (s, 2H),
dihydro[l,3]oxazolo[4,5- 6.44 (s, 1H), 6.92 (d, J = 8.4 Hz, 1H), 7.03 (d,
c]pyridine-2,4-dione J = 8.1 Hz, 1H), 7.24 (dd, J = 8.4, 8.1 Hz,
1H), 11.74 (br. s, 1H).
5-(2-chloro-5-ethoxybenzyl)-7- (CD3SO2CD3) 5 1.26 (t, J = 7.0 Hz, 3H), 2.10 methyl-3,5- (s, 3H), 3.94 (q, J = 7.0 Hz, 2H), 5.17 (s, 2H),
dihydro[l,3]oxazolo[4,5- 6.38 (d, J = 2.9 Hz, 1H), 6.91 (dd, J = 8.8, 2.9
c]pyridine-2,4-dione Hz, 1H), 7.39 (d, J = 8.8 Hz, 1H), 7.44 (s,
1H), 11.99(br. s, 1H).
5-[2-chloro-5-(piperidin-l - (CD3SO2CD3) 5 1.35 (m, 2H), 1.47 (m, 4H),
ylsulfonyl)benzyl]-7-methyl- 2.10 (s, 3H), 2.81 (m, 4H), 5.30 (s, 2H), 7.18
3,5-dihydro[l,3]oxazolo[4,5- (d, J = 2.2 Hz, 1H), 7.57 (s, 1H), 7.67 (dd, J =
c]pyridine-2,4-dione 8.4, 2.2 Hz, 1H), 7.78 (d, J = 8.4 Hz, 1H),
12.07 (br. s, 1H).
5-[2-chloro-5-(pyrrolidin-l- (CD3SO2CD3) 5 1.62 (m, 4H), 2.11 (s, 3H),
ylsulfonyl)benzyl]-7-methyl- 3.05 (m, 4H), 5.30 (s, 2H), 7.30 (s, 1H), 7.57
3,5-dihydro[l,3]oxazolo[4,5- (s, 1H), 7.75-7.82 (m, 2H), 12.08 (br. s, 1H). c]pyridine-2,4-dione
5-[2-chloro-6- (CD3SO2CD3) 5 1.22 (m, 2H), 1.51 (m, 4H),
(cyclopentylmethoxy)benzyl]- 1.68 (m, 2H), 2.00 (s, 3H), 2.20 (m, 1H), 3.89
7-methyl-3,5- (d, J = 7.0 Hz, 2H), 5.24 (s, 2H), 6.86 (s, 1H),
dihydro[l,3]oxazolo[4,5- 7.07 (d, J = 8.4 Hz, 1H), 7.11 (d, J = 8.1 Hz,
c]pyridine-2,4-dione 1H), 7.37 (dd, J = 8.4, 8.1 Hz, 1H), 11.97 (br.
s, 1H).
5-[2-(benzyloxy)-6- (CD3SO2CD3) 5 1.90 (s, 3H), 5.15 (s, 2H),
chlorobenzyl]-7-methyl-3,5- 5.25 (s, 2H), 6.84 (s, 1H), 7.13 (d, J = 8.1 Hz,
dihydro[l,3]oxazolo[4,5- 1H), 7.19 (d, J = 7.7 Hz, 1H), 7.30-7.37 (m,
c]pyridine-2,4-dione 5H), 7.39 (dd, J = 8.1, 7.7 Hz, 1H), 11.91 (br.
s, 1H).
5-(2,3-dichloro-6- (CD3SO2CD3) 5 1.10 (t, J = 7.0 Hz, 3H), 2.09
ethoxybenzyl)-5,6,7,8- (m, 2H) 2.80 (m, 2H), 2.89 (m, 2H), 3.92 (q, J
tetrahydro-2H- = 7.0 Hz, 2H), 5.33 (s, 2H), 6.98 (d, J = 8.8
cyclopenta[b][l,3]oxazolo[5,4- Hz, 1H), 7.50 (d, J = 8.8 Hz, 1H), 11.71 (br. s,
d]pyridine-2,4(3H)-dione 1H).
5-[2-chloro-5- (CD3SO2CD3) 8 2.11 (s, 3H), 5.29 (s, 2H),
(trifluoromethyl)benzyl]-7- 7.34 (s, 1H), 7.54 (s, 1H), 7.72-7.79 (m, 2H),
methyl-3,5- 12.00 (br. s, 1H).
dihydro[l,3]oxazolo[4,5-c]pyridine-2,4-dione
5-(2-chloro-5-fluorobenzyl)-7- (CD3SO2CD3) 5 2.11 (s, 3H), 5.20 (s, 2H),
methyl-3,5- 6.71 (dd, J = 9.4, 2.9 Hz, 1H), 7.22 (td, J =
dihydro[l,3]oxazolo[4,5- 8.4, 2.9 Hz, 1H), 7.49 (s, 1H), 7.57 (dd, J =
c]pyridine-2,4-dione 8.4, 5.2 Hz, 1H), 11.99 (br. s, 1H).
Example 42
A procedure in which a 26-amino acid peptide containing the CS1 sequence of fibronectin with an N-terminal Cys (CDELPQLVTLPHPNLHGPEILDVPST) was coupled to maleimide activated ovalbumin was used to determine the efficacy of the compounds synthesized. Bovine serum albumin (BSA) and CS1 conjugated ovalbumin were coated onto 96-well polystyrene plates at 0.5 µg/ml in TBS (50 mM TRIS, pH 7.5; 150 mM NaCl) at 4°C for 16 hours. The plates were washed three times with TBS and blocked with TBS containing 3% BSA at room temperature for 4 hours. Blocked plates were
washed three times in binding buffer (TBS; 1 mM MgCl2; 1 mM CaCl2; 1 mM MnCl2)) prior to assay. Ramos cells fluorescently labeled with calcein AM were resuspended in binding buffer (107 cells/ml) and diluted 1:2 with same buffer with or without compound. 100 µM of compound was added. The cells were added immediately to the wells (2.5 x 105 cells/well) and incubated for 30 minutes at 37°C. Following three washes with binding buffer, adherent cells were lysed and quantitated using a fluorometer. The results are shown in Tables 2-7. IC5o is defined as the dose required to give 50% inhibition, measured in µM for Tables 2 and 4. The lower the IC50 value and the greater the percentage of inhibition, the more efficient the compound is at prevention of cell adhesion.
(3S)-3-{[({l-[(2,4-dichlorophenyl)methyl]-4- 30 Calculated (M-H)" = 486.10 m/z;
methyl-2-oxo-1,2-dihydro-3- Found (M-H)" = 485.95 m/z.
pyridinyl} amino)carbonyl]amino} -3-(4-methylphenyl)propanoic acid
(3S)-3-{[({4-amino-l-[(2-chlorophenyl)methyl]- 10 Calculated (M-H)" = 467.15 m/z; 6-methyl-2-oxo-l,2-dihydro-3- Found (M-H)' = 467.14 m/z.
pyridinyl} amino)carbonyl]amino} -3 -(4-methylphenyl)propanoic acid
(3S)-3-[({[l-[(2-chlorophenyl)methyl]-4- 20 Calculated (M-H)- = 468.13 m/z;
(methyloxy)-2-oxo-l ,2-dihydro-3- Found (M-H)" = 467.97 m/z.
pyridmyl]amino}carbonyl)amino]-3-(4-methylphenyl)propanoic acid
(3S)-3-{[({4-chloro-l-[(2-chlorophenyl)methyl]- 20 Calculated (M-H)" = 472.08 m/z; 2-oxo-l,2-dihydro-3- Found (M-H)" = 471.91 m/z.
pyridinyl} amino)carbonyl]amino} -3-(4-methylphenyl)propanoic acid
(3S)-3-{[({l-[(2-chlorophenyl)methyl]-4-methyl- 15 Calculated (M-H)" = 482.15 m/z; 2-oxo-l,2-dihydro-3- Found (M-H)" == 481.93 m/z.
pyridinyl}amino)carbonyl]amino}-3-[3-methyl-4-(methyloxy)phenyl]propanoic acid
(3S)-3-{[({ l-[(2-chlorophenyl)methyl]-4-methyl- 3 Calculated (M+H)" = 470.15 m/z; 2-oxo-l,2-dihydro-3- Found (M+H)+ = 470.01 m/z.
pyridinyl}amino)carbonyl]amino}-3-[4-(methyloxy)phenyl]propanoic acid
(3S)-3-{[({l-[(2-chlorophenyl)methyl]-4-methyl- 10 Calculated (M+Hf = 468.17 m/z; 2-oxo-l ,2-dihydro-3- Found (M+H)+ = 468.05 m/z.
pyridinyl }amino)carbonyl]amino} -3 -(3,4-dimethylphenyl)propanoic acid
(3S)-3-{[({4-amino-l-[(2-chlorophenyl)methyl]- 10 Calculated (M-H)" = 453.13 m/z; 2-oxo-l,2-dihydro-3- Found (M-H)' = 453.01 m/z.
pyridinyl} amino)carbonyl]amino} -3 -(4-methylphenyl)propanoic acid
(3S)-3-{[({l-[(2-chlorophenyl)methyl]-4-fluoro- 15 Calculated (M-H)" = 456.12 m/z; 2-oxo-l,2-dihydro-3- Found (M-H)" = 455.94 m/z.
pyridinyl}amino)carbonyl]amino}-3-(4-methylphenyl)propanoic acid
(3S)-3-[({[l-[(2-chlorophenyl)methyl]-2-oxo-4- 20 Calculated (M-H)" = 529.16 m/z; (phenylamino)-l,2-dihydro-3- Found (M-H)' = 529.02 m/z.
pyridinyl]amino}carbonyl)amino]-3-(4-methylphenyl)propanoic acid
(3S)-3-[({[l-[(2-chlorophenyl)methyl]-2-oxo-4- 15 Calculated (M-H)" = 530.16 m/z; (2-pyridinylamino)-l,2-dihydro-3- Found (M-H)" = 529.99 m/z.
pyridinyl]amino}carbonyl)amino]-3-(4-methylphenyl)propanoic acid
(3S)-3-{[({l-[(2-chlorophenyl)methyl]-4- 10 Calculated (M-H)" ==454.11 m/z;
hydroxy-2-oxo-l ,2-dihydro-3- Found (M-H)" = 454.05 m/z.
pyridinyl} amino)carbonyl] amino} -3 -(4-methylphenyl)propanoic acid
(3S)-3-{[({l-[(2-chlorophenyl)methyl]-2-oxo-4- 15 Calculated (M-H)* = 544.17 m/z; [(2-pyridinylmethyl)amino]-l,2-dihydro-3- Found (M-H)" = 544.03 m/z.
pyridinyl} amino)carbonyl]amino} -3 -(4-methylphenyl)propanoic acid
(3S)-3-{[({l-[(2-chlorophenyl)methyl]-2-oxo-4- 20 Calculated (M-H)" = 544.17 m/z; [(3-pyridinylmethyl)amino]-l,2-dihydro-3- Found (M-H)" = 544.02 m/z.
pyridinyl} amino)carbonyl]amino} -3-(4-methylphenyl)propanoic acid
(3S)-3-[({[l-[(2-chlorophenyl)methyl]-4-(l,4- 1 Calculated (M-H)" = 523.17 m/z;
oxazinan-4-yl)-2-oxo-l,2-dihydro-3- Found (M-H)" = 523.02 m/z.
pyridinyl] amino} carbonyl)amino] -3 -(4-methylphenyl)propanoic acid
(3S)-3-[({[l-[(2-chlorophenyl)methyl]-2-oxo-4- 10 Calculated (M-H)" = 495.18 m/z; (propylamino)-l ,2-dihydro-3- Found fM-H)" = 495.04 m/z.
pyridinyl] amino} carbonyl)amino ] - 3 -(4-methylphenyl)propanoic acid
(3S)-3-{[({l-[(2-fluorophenyl)methyl]-4-methyl- 20 Calculated (M-H)" = 436.17 m/z; 2-oxo-l,2-dihydro-3- Found (M-H)" = 435.99 m/z.
pyridinyl}amino)carbonyl]amino}-3-(4-methylphenyl)propanoic acid
(3S)-3-{[({l-[(2,6-dichlorophenyl)methyl]-4- 20 Calculated (M-H)" = 486.10 m/z;
methyl-2-oxo-l,2-dihydro-3- Found (M-H)' = 485.95 m/z.
pyridinyl}amino)carbonyl]amino}-3-(4-methylphenyl)propanoic acid
(3R)-3- {[({1 -[(2-chlorophenyl)methyl]-4-methyl- 300 Calculated (M-H)" = 376.11 m/z; 2-oxo-l ,2-dihydro-3- Found (M-H)" = 376.00 m/z.
pyridinyl} amino)carbonyl] amino} butanoic acid
(3S)-3-{[({ l-[(2-bromophenyl)methyl]-4-methyl- 10 Calculated (M-H)" = 496.09 m/z; 2-oxo-l,2-dihydro-3- Found (M-H)" = 495.87 m/z.
pyridinyl}amino)carbonyl]amino}-3-(4-methylphenyl)propanoic acid
(3S)-3-[({[4-methyl-2-oxo-l-(phenylmethyl)-l,2- 30 Calculated (M-H)" = 418.17 m/z; dihydro-3-pyridinyl]amino}carbonyl)amino]-3-(4- Found (M-H)" = 417.96 m/z.
methylphenyl)propanoic acid
(3S)-3-{[({l-[(2-chlorophenyl)methyl]-4- 8 Calculated (M-H)" = 484.12 m/z;
hydroxy-2-oxo-l ,2-dihydro-3- Found (M-H)" = 484.03 m/z.
pyridinyl} amino)carbonyl] amino} -3 - [3 -methyl-4-(methyloxy)phenyl]propanoic acid
(3S)-3-{[({l-[(2-chlorophenyl)methyl]-2-oxo-4- 10 Calculated (M-H)" = 514.15 m/z; phenyl-1,2-dihydro-3- Found (M-H)" = 514.00 m/z.
pyridinyl}amino)carbonyl]amino}-3-(4-methylphenyl)propanoic acid
(3S)-3-{[({4-bromo-l-[(2-chlorophenyl)methyl]- 20 Calculated (M-H)" = 516.03 m/z; 2-oxo-l,2-dihydro-3- Found (M-H)" = 515.90 m/z.
pyridinyl} amino)carbonyl]amino} -3 -(4-methylphenyl)propanoie acid
(3S)-3-(l,3-benzodioxol-5-yl)-3-{[({l-[(2- 20 Calculated (M-H)"-484.09 m/z;
chlorophenyl)methyl]-4-hydroxy-2-oxo-l,2- Found (M-H)" = 484.03 m/z.
dihydro-3-p>Tidinyl}amino)carbonyl]amino}propanoic acid
(3S)-3-{[({l-[(2-chlorophenyl)methyl]-4-[(2-{[2- 2 Calculated (M-H)" = 556.18 m/z; (methyloxy)ethyl]oxy}ethyl)oxy]-2-oxo-l,2- Found (M-H)" = 556.03 m/z.
dihydro-3-pyridinyl}amino)carbonyl]amino}-3-(4-methylphenyl)propanoic acid
(3S)-3-{[({l-[(2-chlorophenyl)methyl]-4- 15 Calculated (M-H)" = 468.13 m/z;
hydroxy-6-methyl-2-oxo-1,2-dihydro-3- Found (M-H)" = 468.05 m/z.
pyridinyl} amino)carbonyl] amino} -3 -(4-methylphenyl)propanoic acid
(3S)-3-{[({l-[(2-chlorophenyl)methyl]-4-[(l,l- 3 Calculated (M-H)" = 509.20 m/z;
dimethylethyl)amino]-2-oxo-l,2-dihydro-3- Found (M-H)" = 509.06 m/z.
pyridinyl} amino)carbonyl]amino} -3 -(4-methylphenyl)propanoic acid
(3S)-3-{[({l-[(2-chlorophenyl)methyl]-4- 10 Calculated (M-H)" =440.10 m/z;
hydroxy-2-oxo-l ,2-dihydro-3- Found (M-H)" = 440.04 m/z.
pyridinyl} amino)carbonyl]amino} -3-phenylpropanoic acid
(3S)-3-{[({l-[(2-chlorophenyl)methyl]-4-[4- 3 Calculated (M-H)" =536.20 m/z;
methyltetrahydro-l(2H)-pyrazinyl]-2-oxo-l,2- Found (M-H)" = 536.12 m/z.
dihydro-3 -pyridinyl} amino)carbonyl] amino} -3 -(4-methylphenyl)propanoic acid
(3S)-3-{[({l-[(2-chlorophenyl)methyl]-4- 5 Calculated (M-H)" = 470.11 m/z;
hydroxy-2-oxo-l,2-dihydro-3- Found (M-H)' = 470.05 m/z.
pyridinyl}amino)carbonyl]arnino}-3-[4-(methyloxy)phenyl]propanoic acid
(3S)-3-{[({l-[(2-chlorophenyl)methyl]-4- 20 Calculated (M-H)" = 530.13 m/z;
hydroxy-2-oxo-l,2-dihydro-3- Found (M-H)' = 530.05 m/z.
pyridinyl} amino )carbonyl]amino}-3-[3,4,5-tris(methyloxy)phenyl]propanoic acid
(3S)-3-{[({l-[(2-chlorophenyl)methyl]-4- 15 Calculated (M-H)" = 468.13 m/z;
hydroxy-2-oxo-1,2-dihydro-3- Found (M-H)" = 468.08 m/z.
pyridinyl} amino)carbonyl]amino}-3-(3,5-dimethylphenyl)propanoic acid
(3S)-3-{[({l-[(2-chlorophenyl)methyl]-4-[(3- 15 Calculated (M-H)" = 534.15 m/z;
methyl-5-isoxazolyl)amino]-2-oxo-l,2-dihydro-3- Found (M-H)" = 534.01 m/z.
pyridinyl} amino)carbonyl] amino} -3 -(4-methylphenyl)propanoic acid
(3S)-3-{[({l-[(2-chlorophenyl)methyl]-4- 20 Calculated (M-H)" = 454.17 m/z;
hydroxy-2-oxo-1,2-dihydro-3- Found (M-H)" = 454.04 m/z.
pyridinyl}amino)carbonyl]amino}-3-(3-methylphenyl)propanoic acid
(3S)-3-{[({l-[(2-chlorophenyl)methyl]-4- 5 Calculated (M-H)" = 470.11 m/z;
hydroxy-2-oxo-1,2-dihydro-3- Found (M-H)' = 470.03 m/z.
pyridinyl} amino)carbonyl]amino} -3-[3-(methyloxy)phenyl]propanoic acid
(3S)-3-[3,5-bis(methyloxy)phenyl]-3-{[({l-[(2- 3 Calculated (M-H)" =500.12 m/z;
chlorophenyl)methyl]-4-hydroxy-2-oxo-1,2- Found (M-H)" = 500.07 m/z.
dihydro-3-
pyridinyl} amino)carbonyl]amino} propanoic acid
(3S)-3- {[({1 -[(2-chlorophenyl)methyl]-4- 8 Calculated (M-H)" = 504.13 m/z; hydroxy-2-oxo-1,2-dihydro-3- Found (M-H)" = 504.06 m/z.
quinolinyl} amino)carbonyl] amino} -3 -(4-methylphenyl)propanoic acid
(3S)-3-{[({l-[(2-chlorophenyl)methyl]-4- 20 Calculated (M-H)" = 508.04 m/z;
hydroxy-2-oxo-1,2-dihydro-3- Found (M-H)" = 508.09 m/z.
pyridinyl}amino)carbonyl]amino}-3-[3-(trifluoromethyl)phenyl]propanoic acid
(3S)-3-{[({l-[(2-chlorophenyl)methyl]-4- 2 Calculated (M-H)" = 595.21 m/z;
[({ethyl[(ethylamino)carbonyl]amino}carbonyl) Found (M-H)" = 594.97 m/z.
amino]-2-oxo-l ,2-dihydro-3-pyridinyl}amino)carbonyl]amino}-3-(4-methylphenyl)propanoic acid
(3S)-3-{[({4-(l-azetanyl)-l-[(2- 5 Calculated (M-H)'= 493.16 m/z;
chlorophenyl)methyl]-2-oxo-l,2-dihydro-3- Found (M-H)" = 493.05 m/z.
pyridinyl} amino)carbonyl]amino} -3 -(4-methylphenyl)propanoic acid
(3S)-3-{[({l-[(2-chlorophenyl)methyl]-4- 30 Calculated (M-H)" = 458.09 m/z;
hydroxy-2-oxo-l,2-dihydro-3- Found (M-H)" = 458.03 m/z.
pyridinyl} amino)carbonyl]amino} -3 -(4-fluorophenyl)propanoic acid
(3S)-3-{[({l-[(2-chlorophenyl)methyl]-4- 40 Calculated (M-H)" = 458.09 m/z;
hydroxy-2-oxo-1,2-dihydro-3- Found (M-H)' = 458.06 m/z.
pyridinyl}amino)carbonyl]amino}-3-(3-fluorophenyl)propanoic acid
(3S)-3-[({[l-[(2-chlorophenyl)methyl]-4-({2-[(2- 2 Calculated (M-H)" = 600.21 m/z; {[2-(methyloxy)ethyl]oxy}ethyl)oxy]ethyl}oxy)- Found (M-H)" = 600.10 m/z.
2-oxo-1,2-dihydro-3-pyridinyl]amino}carbonyl)amino]-3-(4-methylphenyl)propanoic acid
(3S)-3-{[({l-[(2-chlorophenyl)methyl]-4- 25 Calculated (M-H)" = 508.09 m/z;
hydroxy-2-oxo-l,2-dihydro-3- Found (M-H)" = 508.02 m/z.
pyridinyl}amino)carbonyl]amino}-3-[4-(trifluoromethyl)phenyl]propanoic acid
(3S)-3-{[({l-[(2-fluorophenyl)methyl]-4- 30 Calculated (M-H)" = 438.15 m/z;
hydroxy-2-oxo-l,2-dihydro-3- Found (M-H)" = 438.07 m/z.
pyridinyl} amino)carbonyl] amino} -3 -(4-methylphenyl)propanoic acid
(3S)-3-{[({l-[(2-chloro-6-fluorophenyl)methyl]- 10 Calculated (M-H)" = 472.11 m/z; 4-hydroxy-2-oxo-l ,2-dihydro-3- Found (M-H)" = 472.06 m/z.
pyridinyl}amino)carbonyl]amino}-3-(4-methylphenyl)propanoic acid
(3S)-3-{[({l-[(2-chlorophenyl)methyl]-4- 400 Calculated (M-H)" = 496.16 m/z;
hydroxy-2-oxo-1,2-dihydro-3- Found (M-H)' = 496.11 m/z.
pyridinyl} amino)carbonyl]ammo} -3 -[4-( 1,1 -dimethylethyl)phenyl]propanoic acid
(3S)-3-{[({l-[(2-chlorophenyl)methyl]-5-methyl- 70 Calculated (M-H)" = 452.14 m/z; 2-oxo-l,2-dihydro-3- Found (M-H)" = 451.99 m/z.
pyridinyl}amino)carbonyl]amino}-3-(4-methylphenyl)propanoic acid
3-(4-chlorophenyl)-3-{[({l-[(2- 30 Calculated (M-H)" = 474.06 m/z;
chlorophenyl)methyl]-4-hydroxy-2-oxo-l,2- Found (M-H)" = 474.07 m/z.
dihydro-3-
pyridinyl} amino)carbonyl] amino} propanoic acid
(3S)-3-[({[2-methyl-6-oxo-l-(phenylmethyl)-4- 25 Calculated (M+H)+ = 498.22 m/z; (2-pyridinyl)-1,6-dihydro-5- Found (M+H)+ = 498.10 m/z.
pyrimidinyl] amino} carbonyl)amino]-3-(4-methylphenyl)propanoic acid
3-(3-chlorophenyl)-3-{[({l-[(2- 30 Calculated (M-H)" = 474.06 m/z;
chlorophenyl)methyl]-4-hydroxy-2-oxo-l,2- Found (M-H)" = 474.03 m/z.
dihydro-3-pyridinyl}amino)carbonyl]amino}propanoic acid
3-{[({l-[(2-chlorophenyl)methyl]-4-hydroxy-2- 40 Calculated (M-H)" = 508.02 m/z; oxo-l,2-dihydro-3- Found (M-H)" = 507.97 m/z.
pyridinyl}amino)carbonyl]amino}-3-(3,4-dichlorophenyl)propanoic acid
(3S)-3-(l,3-benzodioxol-5-yl)-3-({[(l-{[4- 3 Calculated (M-H)" = 464.14 m/z;
(methyloxy)phenyl]methyl}-2-oxo-l ,2-dihydro- Found (M-H)' = 464.03 m/z.
3-pyridinyl)amino]carbonyl}amino)propanoic acid
(3S)-3-(l,3-benzodioxol-5-yl)-3-{[({l-[(3- 1.5 Calculated (M-H)" = 448.15 m/z;
methylphenyl)methyl]-2-oxo-1,2-dihydro-3 - Found (M-H)" = 448.04 m/z.
pyridinyl} amino)carbonyl]amino} propanoic acid
(3S)-3-[3,5-bis(methyloxy)phenyl]-3-[({[2-oxo- 0.7 Calculated (M-H)" = 456.12 m/z;
1 -(2-thiophenylmethyl)-1,2-dihydro-3- Found (M-H)" = 456.00 m/z.
pyridinyl]amino}carbonyl)amino]propanoic
acid
(3S)-3-[4-(methyloxy)phenyl]-3-[{ {[2-oxo-l-(2- 0.8 Calculated (M-H)" = 426.11 m/z;
thiophenylmethyl)-1,2-dihydro-3- Found (M-H)" = 426.00 m/z.
pyridinyl]amino} carbonyl)amino]propanoic
acid
(3S)-3-[({[2-oxo-l-(2-thiophenylmethyl)-l,2- 2.5 Calculated (M-H)" = 464.09 m/z;
dihydro-3-pyridinyl]amino}carbonyl)amino]-3- Found. (M-H)" = 463.99 m/z.
[3-(trifluoromethyl)phenyl]propanoic acid
(3S)-3-(l,3-benzodioxol-5-yl)-3-[({[3- 50 Calculated (M-H)" = 419.12 m/z;
(phenyloxy)phenyl]amino}carbonyl)amino] Found (M-H)" = 418.97 m/z.
propanoic acid
(3S)-3-(l,3-benzodioxol-5-yl)-3-{[({3-[(2- 5 Calculated (M-H)" = 438.11 m/z;
thiophenylmethyl)amino]phenyi}amino)carbony Found (M-H)" = 438.00 m/z.
1] amino} propanoic acid
(3S)-3-(l,3-benzodioxol-5-yl)-3-{[({!-[(3- 0.8 Calculated (M-H)" = 468.09 m/z;
chlorophenyl)methyl]-2-oxo-1,2-dihydro-3- Found (M-H)" = 468.01 m/z.
pyridinyl} amino)carbonyl]amino}propanoic acid
(3S)-3-(l,3-benzodioxol-5-yl)-3-({[(2-oxo-l- 0.8 Calculated (M-H)" = 502.12 m/z;
{[3-(trifluoromethyl)phenyl]methyl}-l,2- Found (M-H)" = 502.03 m/z.
dihydro-3-
pyridinyl)amino]carbonyl} amino )propanoic
acid
(3S)-3-(4-fluorophenyl)-3-[({[2-oxo-l-(2- 1.6 Calculated (M-H)" = 414.09 m/z;
thiophenylmethyl)-1,2-dihydro-3- Found (M-H)" = 414.01 m/z.
pyridinyl]amino}carbonyl)amino]propanoic acid
(3S)-3-(l,3-benzodioxol-5-yl)-3-{[({l-[(4- 3 Calculated (M-H)" = 468.09 m/z;
chlorophenyl)methyl]-2-oxo-l ,2-dihydro-3- Found (M-H)' = 467.99 m/z.
pyridinyl} amino)carbonyl]amino} propanoic acid
(3S)-3-(l,3-benzodioxol-5-yl)-3-({[(l-{[2- 0.5 Calculated (M-H)" = 464.14 m/z;
(methyloxy)phenyl]methyl}-2-oxo-l,2-dihydro- Found (M-H)" = 464.04 m/z.
3-pyridinyl)amino]carbonyl}amino)propanoic acid
(3S)-3-[3-(methyloxy)phenyl]-3-[({[2-oxo-l-(2- 1.4 Calculated (M-H)" = 426.11 m/z; thiophenylmethyl)-1,2-dihydro-3- Found (M-H)" = 426.02 m/z.
pyridinyl]amino} carbonyl)amino]propanoic acid
(3S)-3-[({[2-oxo-l-(2-thiophenylmethyl)-l,2- 1 Calculated (M-H)' = 396.10 m/z;
dihydro-3-pyridinyl]amino}carbonyl)amino]-3- Found (M-H)" = 396.01 m/z.
phenylpropanoic acid
(3S)-3-[({[2-oxo-l-(2-thiophenylmethyl)-l,2- 0.3 Calculated (M-H)" = 486.13 m/z;
dihydro-3-pyridinyl]amino}carbonyl)amino]-3- Found (M-H)" = 485.98 m/z.
[3,4,5-tris(methyloxy)phenyl]propanoic acid
(3S)-3-(l,3-benzodioxol-5-yl)-3-{[({l-[(2- 0.3 Calculated (M-H)" = 468.08 m/z; chlorophenyl)methyl]-2-oxo-l,2-dihydro-3- Found (M-H)" = 468.03 m/z.
pyridinyl} amino)carbonyl]amino} propanoic acid
(3S)-3-(l,3-benzodioxol-5-yl)-3-{[({l-[(4- 2 Calculated (M-H)" = 452.12 m/z;
fluorophenyl)methyl]-2-oxo-1,2-dihydro-3- Found (M-H)" = 452.00 m/z.
pyridinyl} amino)carbonyl ] amino} propanoic acid
3-(l,3-benzodioxol-5-yl)-2,2-difluoro-3-[({[2- >100 Calculated (M-H)' = 476.07 m/z; oxo-1 -(2-thiophenylmethyl)-1,2-dihydro-3- Found (M-H)" = 476.00 m/z.
pyridinyl]amino} carbonyl)amino]propanoic acid
(3S)-3-(l,3-benzodioxol-5-yl)-3-{[({2-oxo-l- 14 Calculated (M-H)' = 478.16 m/z;
[3-(phenyloxy)propyl]-l,2-dihydro-3- Found (M-H)" = 478.09 m/z.
pyridinyl} amino)carbonyl]amino} propanoic acid
(3S)-3-(l,3-benzodioxol-5-yl)-3-{[({l-[(3,5- 5 Calculated (M-H)' = 502.05 m/z;
dichlorophenyl)methyl]-2-oxo-l,2-dihydro-3- Found (M-H)" = 501.94 m/z.
pyridinyl}amino)carbonyl]amino}propanoic acid
(3S)-3-(l,3-benzodioxol-5-yl)-3-[({[l- 6 Calculated (M-H)" = 426.16 m/z;
(cyclopentylmethyl)-2-oxo-l,2-dihydro-3- Found (M-H)" = 426.09 m/z.
pyridinyl]amino} carbonyl)amino]propanoic acid
(3S)-3-(l,3-benzodioxol-5-yl)-3-{[({2-oxo-l- 15 Calculated (M-H)" = 454.09 m/z;
[2-(2-thiophenyl)ethyl]-l,2-dihydro-3- Found (M-H)" = 453.99 m/z.
pyridinyl}amino)carbonyl]amino}propanoic acid
(3S)-3-{[({l-[(2-chlorophenyl)methyl]-2-oxo- 0.1 Ca^ulated (M+H)+ = 440.14 m/z; 1,2-dihydro-3- Found (M+H)+ = 440.09 m/z.
pyridinyl} amino)carbonyl] amino} -3 -(4-methylphenyl)propanoic acid
(3S)-3-(2,3-dihydro-l-benzofuran-5-yl)-3-[({[2- 0.14 Calculated (M-H)'==438.11 m/z; oxo-l-(2-thiophenylmethyl)-l,2-dihydro-3- Found (M-H)" = 437.99 m/z.
pyridinyl]amino} carbonyl)aminojpropanoic acid
(3S)-3-(3-fluorophenyl)-3-[( {[2-oxo-l-(2- 3 Calculated (M-H)" == 414.09 m/z;
thiophenylmethyl)-l,2-dihydro-3- Found (M-H)" = 413.99 m/z.
pyridinyl]amino}carbonyl)amino]propanoic acid
(3S)-3-[({[2-oxo-l-(2-thiophenylmethyl)-l,2- 1.5 Calculated (M-H)" = 464.09 m/z;
dihydro-3-pyridinyl]amino}carbonyl)amino]-3- Found (M-H)" = 463.99 m/z.
[4-(trifluoromethyl)phenyl]propanoic acid
(3S)-3-(l,3-benzodioxol-5-yl)-3-[({[6-oxo-l- 0.5 Calculated (M-H)" == 434.13 m/z;
(phenylmethyl)-l ,6-dihydro-3- Found (M-H)" = 434.02 m/z.
pyridinyl]amino}carbonyl)amino]propanoic acid
(3S)-3-[4-fluoro-3-(trifluoromethyl)phenyl]-3- 0.35 Calculated (M-H)"= 482.08 m/z;
[({[2-oxo-1-(2-thiophenylmethyl)-1,2-dihydro- Found (M-H)" = 481.97 m/z.
3-pyridinyl]amino}carbonyl)amino]propanoic
acid
(3S)-3-[4-(l,l-dimethylethyl)phenyl]-3-[({[2- 2 Calculated (M-H)" = 452.16 m/z;
oxo-1 -(2-thiophenylmethyl)-1,2-dihydro-3- Found (M-H)" = 452.02 m/z.
pyridinyl]amino}carbonyl)amino]propanoic
acid
(3S)-3-(l,3-benzodioxol-5-yl)-3-[({butyl[2,5- 70 Calculated (M-H)" = 494.19 m/z;
dioxo-l-(phenylmethyl)tetrahydro-lH-pyrrol-3- Found (M-H)" = 494.12 m/z.
yl]amino}carbonyl)amino]propanoic acid
(3S)-3-{[({1 -[(2-chlorophenyl)methyl]-2-oxo- 0.04 Calculated (M+H)+ = 516.16 m/z; 1,2-dihydro-3- Found (M+H)+ = 516.02 m/z.
pyridinyl} amino)carbonyl] amino} -3 - [3,4,5 -tris(methyloxy)phenyl]propanoic acid
(3S)-3-{[({1 -[(2,6-dichlorophenyl)methyl]-2- 0.2 Calculated (M+H)" = 474.10 m/z;
oxo-i,2-dihydro-3- Found (M+H)+ = 474.04 m/z.
pyridinyl}amino)carbonyl]amino}-3-(4-methylphenyl)propanoic acid
(3S)-3-{[({l-[(2-chlorophenyl)methyl]-2-oxo- 0.2 Calculated (M+H)+ = 512.10 m/z; l,2-dihydro-3- Found (M+H)+ = 512.04 m/z.
pyridinyl} amino)carbonyl] amino} -3-[4-fluoro-3-(trifluoromethyl)phenyl]propanoic acid
(3S)-3-{[({l-[(2-fluorophenyl)methyl]-2-oxo- 0.1 Calculated (M-H)" = 422.15 m/z;
1,2-dihydro-3- Found (M-H)" = 422.01 m/z.
pyridinyl} amino )carbonyl]amino} -3 -(4-methylphenyl)propanoic acid
(3S)-3-(4-methylphenyl)-3-{[({l-[(2- 0.1 Calculated (M-H)" = 418.18 m/z;
methylphenyl)methyl]-2-oxo-1,2-dihydro-3- Found (M-H)" = 418.02 m/z.
pyridinyl}amino)carbonyl]amino}propanoic acid
(3S)-3-{[({l-[(2-bromophenyl)methyl]-2-oxo- 0.05 Calculated (M+H)+ = 484.09 m/z; 1,2-dihydro-3- Found (M+H)+ = 484.03 m/z.
pyridinyl} amino)carbonyl] amino} -3 -(4-methylphenyl)propanoic acid
(3S)-3-{[({l-[(2,4-dichlorophenyl)methyl]-2- 0.4 Calculated (M+H)+ = 474.10 m/z;
oxo-1,2-dihydro-3- Found (M+H)+ = 474.05 m/z.
pyridinyl} amino)carbonyl]amino} -3-(4-methylphenyl)propanoic acid
(3S)-3-{[({l-[(2-chlorophenyl)methyl]-2-oxo- 0.04 Calculated (M-H)'= 466.11 m/z; 1,2-dihydro-3- Found (M-H)" = 466.00 m/z.
pyridinyl} amino)carbonyl] amino} -3 -(2,3 -dihydro-1 -benzofiiran-5-yl)propanoic acid
(3R)-3-(l,3-benzodioxol-5-yl)-3-{[({l-[(2- 2 Calculated (M-H)" = 468.09 m/z;
chlorophenyl)methyl]-2-oxo-l,2-dihydro-3- Found (M-H)" = 467.97 m/z.
pyridinyl} amino)carbonyl] amino} propanoic acid
(3S)-3-(4-methylphenyl)-3-({[(2-oxo-l-{[2- 1 Calculated (M+H)" = 474.10 m/z;
(trifluoromethyl)phenyl]methyl}-l,2-dihydro-3- Found (M+Hf = 474.09 m/z.
pyridinyl)amino]carbonyl} amino)propanoic acid
(3S)-3-{[({l-[(2,5-dichlorophenyl)methyl]-2- 0.15 Calculated (M+H)" = 474.10 m/z;
oxo-1,2-dihydro-3- Found (M+Hf = 474.04 m/z.
pyridinyl} amino)carbonyl]amino} -3-(4-methylphenyl)propanoic acid
(2R)-2-{[({l-[(2-chlorophenyl)methyl]-2-oxo- 50 Calculated (M-H)" = 424.10 m/z;
1,2-dihydro-3- Found (M-H)" = 423.99 m/z.
pyridinyl} amino)carbonyl]amino} -3 -phenylpropanoic acid
(2R)-2-{[({l-[(2-chlorophenyl)methyl]-2-oxo- 80 Calculated (M-H)" = 410.08 m/z;
1,2-dihydro-3- Found (M-H)" = 409.95 m/z.
pyridinyl}amino)carbonyl]amino}-2-phenylethanoic acid
(3S)-3-{[({l-[(2-chlorophenyl)methyl]-2-oxo- 0.1 Calculated (M-H)" = 452.14 m/z; 1,2-dihydro-3- Found (M-H)" = 451.96 m/z.
pyridinyl} amino)carbonyl]amino} -3 -(3,5 -dimethylphenyl)propanoic acid
(3S)-3-{[({l-[(2-chlorophenyl)methyl]-2-oxo- 0.1 Calculated (M-H)" = 424.10 m/z; 1,2-dihydro-3- Found (M-H)" = 424.07 m/z.
pyridinyl} amino)carbonyl]amino} -3-phenylpropanoic acid
(3S)-3-{[({l-[(2-chlorophenyl)methyl]-2-oxo- 0.1 Calculated (M-H)" = 454.11 m/z; 1,2-dihydro-3- Found (M-H)" = 454.01 m/z.
pyridinyl}amino)carbonyl]amino}-3-[4-(methyloxy)phenyl]propanoic acid
(3S)-3-{[({l-[(2-chlorophenyl)methyl]-2-oxo- 0.1 Calculated (M-H)" = 440.10 m/z; 1,2-dihydro-3- Found (M-H)" = 440.00 m/z.
pyridinyl} amino)carbonyl]amino}-3-(4-hydroxyphenyl)propanoic acid
(3S)-3-({[(l-{[3-(methyloxy)phenyl]methyl}-2- 0.2 Calculated (M-H)" = 434.17 m/z; oxo-l,2-dihydro-3- Found (M-H)" = 434.01 m/z.
pyridinyl)amino]carbonyl} amino)-3-(4-methylphenyl)propanoic acid
(3S)-3-{[({l-[(2-bromophenyl)methyl]-2-oxo- 0.08 Calculated (M-H)" = 558.09 m/z; 1,2-dihydro-3- Found (M-H)" - 557.87 m/z.
pyridinyl} amino)carbonyl]amino}-3-[3,4,5-tris(methyloxy)phenyl]propanoic acid
(3S)-3-{[({l-[(2-chlorophenyl)methyl]-2-oxo- 0.09 Calculated (M+H)+ = 454.15 m/z; 1,2-dihydro-3- Found (M+H)+ = 454.07 m/z.
pyridinyl}amino)carbonyl]amino}-3-(3,4-dimethylphenyl)propanoic acid
(3S)-3-[({[5-chloro-2-hydroxy-3- 8 Calculated (M-H)" = 437.12 m/z;
(phenylmethyl)phenyl]amino}carbonyl)amino]- Found (M-H)" = 437.06 m/z.
3-(4-methylphenyl)propanoic acid
(3S)-3-(4-methylphenyl)-3-[({[3- 10 Calculated (M-H)" = 387.17 m/z;
(phenylmethyl)phenyl]amino}carbonyl)amino] Found (M-H)" = 387.00 m/z.
propanoic acid
(3S)-3-{[({l-[(2-chlorophenyl)methyl]-2-oxo- 0.04 Calculated (M-H)" = 468.13 m/z; 1,2-dihydro-3- Found (M-H)" = 468.01 m/z.
pyridinyl} amino)carbonyl]amino}-3-[3-methyl-4-(methyloxy)phenyl]propanoic acid
(3S)-3-{[({l-[(2-chlorophenyl)methyl]-2-oxo- 0.07 Calculated (M-H)" = 454.11 m/z; 1,2-dihydro-3- Found (M-H)' = 454.00 m/z.
pyridinyl}amino)carbonyl]amino}-3-(4-hydroxy-3 -methylphenyl)propanoic acid
(3S)-3-{[({l-[(2,3-dichlorophenyl)methyl]-2- 0.35 Calculated (M-H)' = 472.08 m/z; oxo-1,2-dihydro-3- Found (M-H)' = 471.94 m/z.
pyridinyl} amino)carbonyl]amino} -3-(4-methylphenyl)propanoic acid
(3S)-3-[({[l-([l,l'-biphenyl]-2-ylmethyl)-2- 2.5 Calculated (M-H)' = 480.19 m/z;
oxo-1,2-dihydro-3- Found (M-H)" = 480.05 m/z.
pyridinyl]amino} carbonyl)amino] -3 -(4-methylphenyl)propanoic acid
(3S)-3-{[({l-[(2-chlorophenyl)methyl]-2-oxo- 0.2 Calculated (M-H)" = 438.12 m/z; 1,2-dihydro-3- Found (M-H)' = 438.00 m/z.
pyridinyl} amino)carbonyl] amino} -3 -(3 -methylphenyl)propanoic acid
(3S)-3-{[({l-[(2-chlorophenyl)methyl]-2-oxo- 3 Calculated (M-H)" = 438.12 m/z;
1,2-dihydro-3- Found (M-H)" = 437.99 m/z.
pyridinyl} amino)carbonyl]amino} -3-(2-methylphenyl)propanoic acid
(3S)-3-{[({l-[(2-chlorophenyl)methyl]-2-oxo- 0.3 Calculated (M-H)" = 464.13 m/z; l,2-dihydro-3- Found (M-H)' = 464.03 m/z.
pyridinyl} amino)carbonyl]amino} -3-(2,3-dihydro-1 H-inden-5-yl)propanoic acid
(3S)-3-{[({l-[(2-cyanophenyl)methyl]-2-oxo- 0.1 Calculated (M+H)+= 431.18 m/z;
1,2-dihydro-3- Found (M+H)+ = 431.09 m/z.
pyridinyl}amino)carbonyl]amino}-3-(4-methylphenyl)propanoic acid
(3S)-3-[2,6-bis(methyloxy)phenyl]-3-{[({l-[(2- 6 Calculated (M-H)" = 484.14 m/z; chlorophenyl)methyl]-2-oxo-l,2-dihydro-3- Found (M-H)" = 483.96 m/z.
pyridinyl} amino)carbonyl]amino}propanoic acid
(3S)-3-{[({1 -[(3-hydroxyphenyl)methyl]-2-oxo- 0.2 Calculated (M+H)+ = 420.18 m/z; 1,2-dihydro-3- Found (M+H)+ = 422.05 m/z.
pyridinyl} amino)carbonyl]amino} -3 -(4-methylphenyl)propanoic acid
(3S)-3-[({[2-methyl-6-oxo-l-(phenylmethyl)- 0.1 Calculated (M-H)" = 419.17 m/z; 1,6-dihydro-5- Found (M-H)" = 419.03 m/z.
pyrimidinyl]amino}carbonyl)amino]-3-(4-methylphenyl)propanoic acid
(3S)-3-{[({ l-[(2-chlorophenyl)methyl]-4-oxo- 0.1 Calculated (M-H)' = 438.12 m/z; l,4-dihydro-3- Found (M-H)" = 438.10 m/z.
pyridinyl} amino)carbonyl] amino} -3 -(4-methylphenyl)propanoic acid
(3S)-3-(4-methylphenyl)-3-{[({l-[(2- 1 Calculated (M+H)+ = 451.17 m/z; nitrophenyl)methyl]-2-oxo-l ,2-dihydro-3- Found (M+H)+ = 451.07 m/z.
pyridinyl} amino )carbonyl]amino} propanoic acid
(3S)-3-(4-methylphenyl)-3-{[({l-[(4- 1 Calculated (M+H)+ = 451.17 m/z;
nitrophenyl)methyl]-2-oxo-1,2-dihydro-3- Found (M+H)+ = 451.09 m/z.
pyridinyl}amino)carbonyl]amino}propanoic acid
(3S)-3-{[({l-[(2-chlorophenyl)methyl]-2-oxo- 3 Calculated (M-H)" = 456.10 m/z;
1,2-dihydro-3- Found (M-H)" = 456.04 m/z.
pyridinyl} amino)carbonyl]amino}-3-(2,6-dihydroxyphenyl)propanoic acid
(3S)-3-{[({l-[(2,6-difluorophenyl)methyl]-2- 0.3 Calculated (M-H)" = 440.14 m/z;
oxo-1,2-dihydro-3- Found (M-H)" = 440.00 m/z.
pyridinyl} amino)carbonyl]amino} -3-(4-methylphenyl)propanoic acid
(3S)-3-{[({l-[(2,4-difluorophenyl)methyl]-2- 1.3 Calculated (M-H)" = 440.14 m/z;
oxo-l,2-dihydro-3- Found (M-H)" = 439.96 m/z.
pyridinyl} amino)carbonyl]amino} -3 -(4-methylphenyl)propanoic acid
(3S)-3-{[({l-[(2,5-difluorophenyl)methyl]-2- 0.8 Calculated (M-H)" = 440.14 m/z;
oxo-l,2-dihydro-3- Found (M-H)" = 439.96 m/z.
pyridinyl} amino)carbonyl] amino} -3 -(4 -methylphenyl)propanoic acid
(3S)-3-{[({l-[(2-chlorophenyl)methyl]-2- 0.09 Calculated (M-H)" = 453.13 m/z; methyl-6-oxo-1,6-dihydro-5- Found (M-H)' = 453.00 m/z.
pyrimidinyl}amino)carbonyl]amino}-3-(4-methylphenyl)propanoic acid
(3S)-3-{[({l-[(2-chloro-6- 0.1 Calculated (M-H)" = 456.11 m/z;
fluorophenyl)methyl]-2-oxo-l,2-dihydro-3- Found (M-H)' = 455.94 m/z.
pyridinyl} amino)carbonyl]amino} -3-(4-methylphenyl)propanoic acid
(3S)-3-{[({l-[(2-bromo-5- 0.5 Calculated (M-H)'= 500.06 m/z;
fluorophenyl)methyl]-2-oxo-l,2-dihydro-3- Found (M-H)" = 499.91 m/z.
pyridinyl}amino)carbonyl]amino}-3-(4-methylphenyl)propanoic acid
(3S)-3-{[({l-[(2-chloro-4- 0.35 Calculated (M-H)" = 456.11 m/z;
fluorophenyl)methyl]-2-oxo-l,2-dihydro-3- Found (M-H)" = 455.93 m/z.
pyridmyl}amino)carbonyl]amino}-3-(4-methylphenyl)propanoic acid
(3S)-3-{[({l-[(2-bromophenyl)methyl]-2-oxo- 0.2 Calculated (M-H)" == 512.08 m/z; 1,2-dihydro-3- Found (M-H)" = 511.96 m/z.
pyridinyl} amino)carbonyl] amino} -3 - [ 3 -methyl-4-(methyloxy)phenyl]propanoic acid
(3S)-3-{[({l-[(3,5-dimethyl-4- 3 Calculated (M-H)' = 423.17 m/z;
isoxazolyl)methyl]-2-oxo-l,2-dihydro-3- Found (M-H)' = 423.02 m/z.
pyridinyl} amino)carbonyl]amino} -3 -(4-methylphenyl)propanoic acid
(3S)-3-(4-methylphenyl)-3-{[({2-oxo-l-[(2,4,6- 2.5 Calculated (M-H)" ==446.21 m/z; trimethylphenyl)methyl]-1,2-dihydro-3- Found (M-H)" = 446.08 m/z.
pyridinyl} amino)carbonyl]amino}propanoic acid
(3S)-3-(4-methylphenyl)-3-{[({l-[(2-methyl- 1 Calculated (M-H)" ==425.13 m/z;
l,3-thiazol-4-yl)methyl]-2-oxo-l,2-dihydro-3- Found (M-H)" = 424.99 m/z.
pyridinyl} amino)carbonyl]amino} propanoic acid
(3S)-3-({[(l-{[4-(l,l- 6 Calculated (M-H)" = 460.22 m/z;
dimethylethyl)phenyl]methyl}-2-oxo-l,2- Found (M-H)* = 460.07 m/z.
dihydro-3-pyridinyl)amino]carbonyl}amino)-3-(4-methylphenyl)propanoic acid
(3S)-3-[({[l-(l,3-benzoxazol-2-ylmethyl)-2- >10 Calculated (M-H)" = 445.15 m/z; oxo-1,2-dihydro-3- Found (M-H)" = 445.01 m/z.
pyridinyl]amino}carbonyl)amino]-3-(4-methylphenyl)propanoic acid
(3S)-3-({[(l-{2-[(2-hydroxyphenyl)amino]-2- >10 Calculated (M-H)" = 463.16 m/z; oxoethyl}-2-oxo-l,2-dihydro-3- Found (M-H)" = 463.06 m/z.
pyridinyl)amino] carbonyl} amino)-3 -(4-methylphenyl)propanoic acid
(3S)-3-{[({l-[(2-chloro-6-nitrophenyl)methyl]- 4 Calculated (M-H)" = 483.11 m/z; 2-oxo-l,2-dihydro-3- Found (M-H)" = 483.01 m/z.
pyridinyl}amino)carbonyl]amino}-3-(4-methylphenyl)propanoic acid
(3S)-3-{[({l-[(5-chloro-2- 2.5 Calculated (M-H)" = 456.11 m/z;
fluorophenyl)methyl]-2-oxo-l ,2-dihydro-3- Found (M-H)' = 456.00 m/z.
pyridinyl} amino)carbonyl]amino} -3-(4-methylphenyl)propanoic acid
(3S)-3-{[({l-[(2-amino-6- 2 Calculated (M-H)" = 453.13 m/z;
chlorophenyl)methyl]-2-oxo-l,2-dihydro-3- Found (M-H)" = 453.02 m/z.
pyridinyl} amino)carbonyl] amino} -3 -(4-methylphenyl)propanoic acid
(3S)-3-({[(l-{[2-fluoro-4- 3 Calculated (M-H)" = 490.14 m/z;
(trifluoromethyl)phenyl]methyl}-2-oxo-1,2- Found (M-H)' = 489.99 m/z.
dihydro-3-pyridinyl)amino]carbonyl} amino)-3 -(4-methylphenyl)propanoic acid
(3S)-3-{[({l-[(5-chloro-2-thiophenyl)methyl]-2- 1.3 Calculated (M-H)" = 444.08 m/z; oxo-l,2-dihydro-3- Found (M-H)" = 443.97 m/z.
pyridinyl} amino)carbonyl]amino} -3 -(4-methylphenyl)propanoic acid
(3S)-3-{[({l-[(2-bromo-5-nitrophenyl)methyl]- 2 Calculated (M-H)" = 527.06 m/z; 2-oxo-l,2-dihydro-3- Found (M-H)" = 526.95 m/z.
pyridinyl}amino)carbonyl]amino}-3-(4-methylphenyl)propanoic acid
3-(4-chlorophenyl)-3-{[({l-[(2- 0.03 Calculated (M-H)" == 474.06 m/z;
chlorophenyl)methyl]-4-hydroxy-2-oxo-1,2- Found (M-H)" = 474.07 m/z.
dihydro-3-
pyridinyl} amino)carbonyl] amino} propanoic
acid
(3S)-3-[({[2-methyl-6-oxo-l-(phenylmethyl)-4- 0.025 Calculated (M+H)+ = 498.22 m/z; (2-pyridinyl)-l ,6-dihydro-5- Found (M+H)+ = 498.10 m/z.
pyrimidinyl]amino}carbonyl)amino]-3-(4-methylphenyl)propanoic acid
(3S)-3-{[({l-[(5-amino-2- 0.08 Calculated (M-H)" = 497.08 m/z;
bromophenyl)methyl]-2-oxo-l ,2-dihydro-3- Found (M-H)" = 497.02 m/z.
pyridinyl}amino)carbonyl]amino}-3-(4-methylphenyl)propanoic acid
(3S)-3-{[({l-[(2,5-dimethylphenyl)methyl]-2- 0.15 Calculated (M-H)" = 432.19 m/z; oxo-l,2-dihydro-3- Found (M-H)' = 432.04 m/z.
pyridinyl}amino)carbonyl]amino}-3-(4-methylphenyl)propanoic acid
3-(3-chlorophenyl)-3-{[({l-[(2- 0.03 Calculated (M-H)' = 474.06 m/z;
chlorophenyl)methyl]-4-hydroxy-2-oxo-l,2- Found (M-H)" = 474.03 m/z.
dihydro-3-pyridinyl} amino) carbonyl]amino}propanoic acid
3-{[({l-[(2-chlorophenyl)methyl]-4-hydroxy-2- 0.04 Calculated (M-H)" = 508.02 m/z; oxo-l,2-dihydro-3- Found (M-H)' = 507.97 m/z.
pyridinyl} amino )carbonyl] amino }-3-(3,4-dichlorophenyl)propanoic acid
(3S)-3-({[(l-{[5-(acetylamino)-2- 0.2 Calculated (M-H)" = 539.09 m/z;
bromophenyl]methyl}-2-oxo-l,2-dihydro-3- Found (M-H)" = 539.02 m/z.
pyridinyl)amino]carbonyl}amino)-3-(4-methylphenyl)propanoic acid
(3S)-3-[({[l-({2-bromo-5- 0.25 Calculated (M-H)" = 575.06 m/z;
[(methylsulfonyl)amino]phenyl}methyl)-2-oxo- Found (M-H)" = 575.01 m/z.
l,2-dihydro-3-
pyridinyl]amino}carbonyl)amino]-3-(4-
methylphenyl)propanoic acid
3-(4-chlorophenyl)-3-{[({l-[(2- 0.4 Calculated (M-H)" = 458.07 m/z;
chlorophenyl)methyl]-2-oxo-l,2-dihydro-3- Found (M-H)" = 457.96 m/z.
pyridinyl} amino)carbonyl] amino} propanoic acid
3-(3-chlorophenyl)-3-{[({l-[(2- 1 Calculated (M-H)" = 458.07 m/z;
chlorophenyl)methyl]-2-oxo-l,2-dihydro-3- Found (M-H)" = 457.93 m/z.
pyridinyl} amino)carbonyl]amino} propanoic acid
3-{[({l-[(2-chlorophenyl)methyl]-2-oxo-l,2- 1 Calculated (M-H)' = 492.03 m/z;
dihydro-3-pyridmyl}arnino)carbonyl]amino}-3- Found (M-H)' = 491.85 m/z.
(3,4-dichlorophenyl)propanoic acid
(3S)-3-{[({l-[(2-bromo-4- 1 Calculated (M-H)" = 516.03 m/z;
chlorophenyl)methyl]-2-oxo-l,2-dihydro-3- Found (M-H)" = 515.91 m/z.
pyridinyl} amino)carbonyl]amino} -3-(4-methylphenyl)propanoic acid
(3S)-3-{[({l-[(4-chlorophenyl)methyl]-2-oxo- 2 Calculated (M-H)" = 438.12 m/z;
1,2-dihydro-3- Found (M-H)' = 437.88 m/z.
pyridinyl}amino)carbonyl]amino}-3-(4-methylphenyl)propanoic acid
(3S)-3-{[({l-[(2-chlorophenyl)methyl]-4- 0.035 Calculated (M-H)" = 498.14 m/z;
hydroxy-2-oxo-l,2-dihydro-3- Found (M-H)" = 498.05 m/z.
pyridinyl} amino)carbonyl]amino}-3 - [2,3-dimethyl-4-(methyloxy)phenyl ]propanoic acid
(3S)-3-{[({l-[(2-chlorophenyl)methyl]-4- 0.015 Calculated (M-H)" = 524.08 m/z;
hydroxy-2-oxo-1,2-dihydro-3- Found (M-H)" = 524.03 m/z.
pyridinyl} amino)carbonyl]amino} -3- {4-[(trifluoromethyl)oxy]phenyl}propanoic acid
(3R)-3-[({[l-[(2-chlorophenyl)methyl]-4-(l,4- 0.1 Calculated (M-H)" = 489.19 m/z; oxazinan-4-yl)-2-oxo-1,2-dihydro-3- Found (M-H)" = 489.13 m/z.
pyridinyl]amino}carbonyl)amino]-5-methylhexanoic acid
(3S)-3-[({[4-hydroxy-6-methyl-2-oxo-l- 0.035 Calculated (M-H)' = 434.17 m/z;
(phenylmethyl)-l ,2-dihydro-3- Found (M-H)" = 434.08 m/z.
pyridinyl]amino}carbonyl)amino]-3-(4-methylphenyl)propanoic acid
(3S)-3-{[({l-[(2-chlorophenyl)methyl]-2-oxo-4- 0.030 Calculated (M-H)" = 559.14 m/z; [(propylsulfonyl)amino]-l,2-dihydro-3- Found (M-H)" = 559.04 m/z.
pyridinyl}amino)carbonyl]amino}-3-(4-methylphenyl)propanoic acid
(3S)-3-{[({1 -[(2-chlorophenyl)methyl]-4- 0.025 Calculated (M-H)" = 468.13 m/z;
hydroxy-2-oxo-l ,2-dihydro-3- Found (M-H)" = 468.06 m/z.
pyridinyl}amino)carbonyl]amino}-3-(4-ethylphenyl)propanoic acid
(3S)-3- {[({1 -[(2-chlorophenyl)methyl]-4- 0.02 Calculated (M-H)" = 484.13 m/z;
hydroxy-2-oxo-l,2-dihydro-3- Found (M-H)" = 484.06 m/z.
pyridinyl}amino)carbonyl]amino}-3-[4-(ethyloxy)phenyl]propanoic acid
(3S)-3-[({[4-hydroxy-2-oxo-l-(phenylmethyl)- 0.030 Calculated (M-H)" = 420.16 m/z; 1,2-dihydro-3- Found (M-H)" = 420.08 m/z.
pyridinyl]amino}carbonyl)amino]-3-(4-methylphenyl)propanoic acid
(3S)-3-[({[l-(3-chlorobenzyl)-2-oxo-l,2- 0.5 Calculated (M-H)" =
dihydropyridin-3-yl]amino}carbonyl)amino]-3-(4- 438.12 m/z; Found (M-H)"
methylphenyl)propanoic acid =438.01 m/z.
(3S)-3-[({[ 1 -(2-chloro-6-methoxybenzyl)-2-oxo- 0.1 Calculated (M-H)" =
l,2-dihydropyridin-3-yl]amino}carbonyl)amino]-3- 468.13 m/z; Found (M-H)"
(4-methylphenyl)propanoic acid = 468.08 m/z.
(3S)-3-[({[l-(2-chlorobenzyl)-4-hydroxy-2-oxo- 0.035 Calculated (M-H)" =
1,2-dihydropyridin-3-yl]amino}carbonyl)amino]-3- 498.14 m/z; Found (M-H)'
(4-methoxy-3,5-dimethylphenyl)propanoic acid = 497.94 m/z.
4-{[3-[({[(lS)-2-carboxy-l-(4- 0.004 Calculated (M-H)' =
methylphenyl)ethyl]amino}carbonyl)amino]-l-(2- 573.15 m/z; Found (M-H)"
chlorobenzyl)-2-oxo-l,2-dihydropyridin-4- = 572.92 m/z. yl]amino}benzoic acid
(3S)-3-{[({l-(2-chlorobenzyl)-4-[(2,2- 0.01 Calculated (M-H)" =
dimethylpropanoyl)amino]-2-oxo-1,2- 537.19 m/z; Found (M-H)"
dihydropyridin-3-yl}amino)carbonyl]amino}-3-(4- = 536.88 m/z. methylphenyl)propanoic acid
(3S)-3-[({[l-(2-chloro-5-methoxybenzyl)-2-oxo- 0.09 Calculated (M-H)" =
1,2-dihydropyridin-3-yl]amino}carbonyl)amino]-3- 468.13 m/z; Found (M-H)"
(4-methylphenyl)propanoic acid = 467.99 m/z.
(3R)-3-[({[l-(2-chlorobenzyl)-4-hydroxy-2-oxo- 0.19 Calculated (M-H)" =
l,2-dihydropyridin-3- 378.09 m/z; Found (M-H)"
yl]amino}carbonyl)amino]butanoic acid = 378.01 m/z.
(3S)-3-[({[4-{[(tert-butylamino)carbonyl]amino}-l- 0.01 Calculated (M-H)" =
(2-chlorobenzyl)-2-oxo-l,2-dihydropyridin-3- 552.20 m/z; Found (M-H)"
yl]amino}carbonyl)amino]-3-(4- = 551.89 m/z. methylphenyl)propanoic acid
(3S)-3-[({[l-(2-chloro-5-hydroxybenzyl)-2-oxo- 0.25 Calculated (M-H)" =
l,2-dihydropyridin-3-yl]amino}carbonyl)amino]-3- 454.12 m/z; Found (M-H)"
(4-methylphenyl)propanoic acid = 454.03 m/z.
(3S)-3-[({[l-(2-cyanobenzyl)-4-hydroxy-2-oxo-l,2- 0.009 Calculated (M-H)" =
dihydropyridin-3-yl]amino}carbonyl)amino]-3-(4- 445.15 m/z; Found (M-H)"
methylphenyl)propanoic acid = 445.01 m/z.
(3S)-3-[({[l-(2,4-dichlorobenzyl)-4-hydroxy-2-oxo- 0.06 Calculated (M-H)" =
l,2-dihydropyridin-3-yl]amino}carbonyl)amino]-3- 488.08 m/z; Found (M-H)"
(4-methylphenyl)propanoic acid = 487.96 m/z.
(3S)-3-[({[4-hydroxy-l-(2-methoxybenzyl)-2-oxo- 0.08 Calculated (M-H)' =
1,2-dihydropyridin-3-yl]amino}carbonyl)amino]-3- 450.17 m/z; Found (M-H)"
(4-methylphenyl)propanoic acid = 450.02 m/z.
(3S)-3-[({[l-(2-chlorobenzyl)-4-hydroxy-2-oxo- 0.08 Calculated (M-H)' =
1,2-dihydropyridin-3-yl]amino}carbonyl)amino]-3- 498.14 m/z; Found (M-H)"
(4-methoxy-2,5-dimethylphenyl)propanoic acid = 497.95 m/z.
(3S)-3-[( {[1 -(2-chloro-6-hydroxybenzyl)-2-oxo- 0.1 Calculated (M-H)' =
1,2-dihydropyridin-3-yl]amino}carbonyl)amino]-3- 454.12 m/z; Found (M-H)"
(4-methylphenyl)propanoic acid = 454.05 m/z.
(3S)-3-[({[l-(3-tert-butyl-2-hydroxybenzyl)-2-oxo- 4 Calculated (M-H)" =
l,2-dihydropyridin-3-yl]amino}carbonyl)amino]-3- 476.02 m/z; Found (M-H)"
(4-methylphenyl)propanoic acid = 476.00 m/z.
(3R)-3-[({[l-(2-chlorobenzyl)-4-hydroxy-2-oxo- 0.3 Calculated (M-H)' =
l,2-dihydropyridin-3-yl]amino}carbonyl)amino]-3- 454.17 m/z; Found (M-H)"
(4-methylphenyl)propanoic acid = 454.05 m/z.
(3S)-3-[( {[ 1 -(2-chlorobenzyl)-4-hydroxy-2-oxo- 0.015 Calculated (M-H)" =
l,2-dihydropyridin-3-yl]amino}carbonyl)amino]-3- 468.13 m/z; Found (M-H)'
(3-ethylphenyl)propanoic acid = 467.95 m/z.
(3S)-3-[( {[ 1 -(2-chlorobenzyl)-4-hydroxy-2-oxo- 0.01 Calculated (M-H)' =
l,2-dihydropyridin-3-yl]amino}carbonyl)amino]-3- 498.10 m/z; Found (M-H)'
(2,3-dihydro-l ,4-benzodioxin-6-yl)propanoic acid = 497.85 m/z.
(3S)-3-[({[l-(2,5-difluorobenzyl)-4-hydroxy-2-oxo- 0.015 Calculated (M-H)" =
l,2-dihydropyridin-3-yl]amino}carbonyl)amino]-3- 456.14 m/z; Found (M-H)"
(4-methylphenyl)propanoic acid = 455.96 m/z.
(3S)-3-[({[l-(2-chlorobenzyl)-4-hydroxy-2-oxo- 30 Calculated (M-H)" =
1,2-dihydropyridin-3-yl]amino}carbonyl)amino]-4- 468.13 m/z; Found (M-H)"
(4-methylphenyl)butanoic acid = 467.87 m/z.
(3S)-3-{[({l-[2-chloro-5-(methylthio)benzyl]-4- 0.015 Calculated (M-H)" =
hydroxy-2-oxo-l,2-dihydropyridin-3- 500.10 m/z; Found (M-H)"
yl}amino)carbonyl]amino}-3-(4- = 499.92 m/z. methylphenyl)propanoic acid
(3S)-3-[({[l-(2-chlorobenzyl)-4-hydroxy-2-oxo- 0.005 Calculated (M-H)' =
1,2-dihydropyridin-3-yl]amino}carbonyl)amino]-3- 514.10 m/z; Found (M-H)"
(7-methoxy-l,3-benzodioxol-5-yl)propanoic acid = 513.86 m/z.
(3S)-3-[({[l-(2-chlorobenzyl)-4-hydroxy-2-oxo- 0.002 Calculated (M-H)" =
1,2-dihydropyridin-3-yl]amino}carbonyl)amino]-3- 514.13 m/z; Found (M-H)'
(3-ethoxy-4-methoxyphenyl)propanoic acid =513.90 m/z.
(3S)-3-[({[l-(2-chlorobenzyl)-4-hydroxy-2-oxo- 0.015 Calculated (M-H)' =
1,2-dihydropyridin-3-yl]amino}carbonyl)amino]-3- 488.10 m/z; Found (M-H)'
(3-fluoro-4-methoxyphenyl)propanoic acid = 487.92 m/z.
(3S)-3-[({[ 1 -(2-chlorobenzyl)-4-hydroxy-2-oxo- 0.002 Calculated (M-H)" =
l,2-dihydropyridin-3-yl]amino}carbonyl)amino]-3- 500.12 m/z; Found (M-H)"
(3,4-dimethoxyphenyl)propanoic acid == 500.01 m/z.
(3S)-3-[({[l-(4-fluorobenzyl)-4-hydroxy-2-oxo-l,2- 0.022 Calculated (M-H)" =
dihydropyridin-3-yl]amino}carbonyl)amino]-3-(4- 438.18 m/z; Found (M-H)"
methylphenyl)propanoic acid == 438.00 m/z.
(3S)-3-[({[l-(2-methoxybenzyl)-2-oxo-l,2- 0.25 Calculated (M-H)" =
dihydropyridin-3-yl]amino}carbonyl)amino]-3-(4- 434.17 m/z; Found (M-H)'
methylphenyl)propanoic acid == 433.95 m/z.
(3S)-3-[({[l-(2-chlorobenzyl)-4-hydroxy-2-oxo- 0.05 Calculated (M-H) =
l,2-dihydropyridin-3-yl]amino}carbonyl)amino]-3- 468.13 m/z; Found (M-H)"
(2,5-dimethylphenyl)propanoic acid == 467.94 m/z.
(3S)-3-[({[l-(2-chloro-5-methoxybenzyl)-4- 0.012 Calculated (M-H)" =
hydroxy-2-oxo-1,2-dihydropyridin-3- 484.13 m/z; Found (M-H)"
yl]amino}carbonyl)amino]-3-(4- ==484.03 m/z. methylphenyl)propanoic acid
(3S)-3-{[({l-[3,5-bis(trifluoromethyl)benzyl]-4- 0.3 Calculated (M-H)" =
hydroxy-2-oxo-l ,2-dihydropyridin-3- 556.13 m/z; Found (M-H)"
yl}amino)carbonyl]amino}-3-(4- = 555.95 m/z. methylphenyl)propanoic acid
(3S)-3-[({[l-(4-tert-butylbenzyl)-4-hydroxy-2-oxo- 0.03 Calculated (M-H)" =
l,2-dihydropyridin-3-yl]amino}carbonyl)amino]-3- 476.22 m/z; Found (M-H)"
(4-methylphenyl)propanoic acid = 476.05 m/z.
(3S)-3-[({[l-(3-chlorobenzyl)-4-hydroxy-2-oxo- 0.015 Calculated (M-H)" =
l,2-dihydropyridin-3-yl]amino}carbonyl)amino]-3- 454.12 m/z; Found (M-H)'
(4-methylphenyl)propanoic acid = 453.99 m/z.
(3S)-3-[({[l-(4-chlorobenzyl)-4-hydroxy-2-oxo- 0.007 Calculated (M-H)" =
1,2-dihydropyridin-3-yl]amino}carbonyl)amino]-3- 454.12 m/z; Found (M-H)"
(4-methylphenyl)propanoic acid = 454.00 m/z.
(3S)-3-{[({4-hydroxy-2-oxo-l-[3- 0.017 Calculated (M-H)" =
(trifluoromethyl)benzyl]-l,2-dihydropyridin-3- 488.14 m/z; Found (M-H)"
yl}amino)carbonyl]amino}-3-(4- = 487.99 m/z. methylphenyl)propanoic acid
(3S)-3-[( {[1 -(2-bromobenzyl)-4-hydroxy-2-oxo- 0.015 Calculated (M-H)" =
l,2-dihydropyridin-3-yl]amino}carbonyl)amino]-3- 498.07 m/z; Found (M-H)"
(4-methylphenyl)propanoic acid = 497.97 m/z.
(3S)-3-[({[l-(3,4-dichlorobenzyl)-4-hydroxy-2-oxo- 0.045 Calculated (M-H)' =
l,2-dihydropyridin-3-yl]amino}carbonyl)amino]-3- 488.08 m/z; Found (M-H)"
(4-methylphenyl)propanoic acid = 487.96 m/z.
(3S)-3-[({[4-hydroxy-l-(4-methylbenzyl)-2-oxo- 0.025 Calculated (M-H)" =
1,2-dihydropyridin-3-yl]amino}carbonyl)amino]-3- 434.17 m/z; Found (M-H)"
(4-methylphenyl)propanoic acid = 434.05 m/z.
(3S)-3-[({[l-(2-chloro-6-methoxybenzyl)-4- 0.003 Calculated (M-H)" =
hydroxy-2-oxo-1,2-dihydropyridin-3- 484.13 m/z; Found (M-H)"
yl]amino}carbonyl)amino]-3-(4- =484.02 m/z. methylphenyl)propanoic acid
(3S)-3-{[({4-hydroxy-2-oxo-l-[4- 0.02 Calculated (M-H)" =
(trifluoromethyl)benzyl]-l,2-dihydropyridin-3- 488.14 m/z; Found (M-H)"
yl}amino)carbonyl]amino}-3-(4- =487.99 m/z. methylphenyl)propanoic acid
(3S)-3-[({[l-(2-chlorobenzyl)-4-hydroxy-2-oxo- 0.02 Calculated (M-H)" =
l,2-dihydropyridin-3-yl]amino}carbonyl)amino]-3- 524.08 m/z; Found (M-H)"
[3-(trifluoromethoxy)phenyl]propanoic acid =523.91 m/z.
(3S)-3-[({[4-hydroxy-l-(3-methylbenzyl)-2-oxo- 0.055 Calculated (M-H)" =
1,2-dihydropyridin-3-yl]amino}carbonyl)amino]-3- 434.17 m/z; Found (M-H)"
(4-methylphenyl)propanoic acid = 433.99 m/z.
(3S)-3-[({[4-hydroxy-2-oxo-l-(pyridin-2-ylmethyl)- 0.045 Calculated (M-H)" =
1,2-dihydropyridin-3-yl]amino}carbonyl)amino]-3- 421.15 m/z; Found (M-H)"
(4-methylphenyl)propanoic acid = 421.06 m/z.
(3S)-3-[({[l-(2-chlorobenzyl)-4-hydroxy-5-methyl- 0.005 Calculated (M-H)" =
2-oxo-l,2-dihydropyridin-3- 468.13 m/z; Found (M-H)"
yl]amino}carbonyl)amino]-3-(4- = 467.99 m/z. methylphenyl)propanoic acid
(3S)-3-[({[l-(2,4-difluorobenzyl)-4-hydroxy-2-oxo- 0.03 Calculated (M-H)" =
1,2-dihydropyridin-3-yl]amino}carbonyl)amino]-3- 456.14 m/z; Found (M-H)"
(4-methylphenyl)propanoic acid =456.01 m/z.
(3S)-3-[({[l-(2,6-difluorobenzyl)-4-hydroxy-2-oxo- 0.008 Calculated (M-H)" =
1,2-dihydropyridin-3-yl]amino}carbonyl)amino]-3- 456.14 m/z; Found (M-H)"
(4-methylphenyl)propanoic acid = 456.01 m/z.
(3S)-3-{[({4-hydroxy-2-oxo-l-[3- 0.045 Calculated (M-H)" =
(trifluoromethoxy)benzyl]-1,2-dihydropyridin-3- 504.14 m/z; Found (M-H)"
yl}amino)carbonyl]amino}-3-(4- == 503.98 m/z. methylphenyl)propanoic acid
(3S)-3-{[({4-hydroxy-2-oxo-l-[4- 0.025 Calculated (M-H)-=
(trifluoromethoxy)benzyl]-l,2-dihydropyridin-3- 504.14 m/z; Found (M-H)"
yl}amino)carbonyl]amino}-3-(4- == 503.98 m/z. methylphenyl)propanoic acid
(3S)-3-[({[ 1 -(2-chloro-6-methoxybenzyl)-4- 0.0015 Calculated (M-H)" =
hydroxy-2-oxo-1,2-dihydropyridin-3- 530.13 m/z; Found (M-H)"
yl]amino}carbonyl)amino]-3-(3,5- = 529.91 m/z. dimethoxyphenyl)propanoic acid
3-[({[l-(2-chlorobenzyl)-4-hydroxy-2-oxo-l,2- 0.05 Calculated (M-H)" =
dihydropyridin-3-yl]amino}carbonyl)amino]-3-(2- 430.08 m/z; Found (M-H)"
furyl)propanoic acid = 429.94 m/z.
(3S)-3-{[({4-hydroxy-2-oxo-l-[2- 0.02 Calculated (M-H)" =
(trifluoromethyl)benzyl]-l,2-dihydropyridin-3- 488.14 m/z; Found (M-H)"
yl}amino)carbonyl]amino}-3-(4- = 487.96 m/z. methylphenyl)propanoic acid
(3R)-3-[({[l-(2-chlorobenzyl)-4-hydroxy-2-oxo- 0.15 Calculated (M-H)" =
l,2-dihydropyridin-3-yl]amino}carbonyl)amino]-4- 468.13 m/z; Found (M-H)"
(4-methylphenyl)butanoic acid = 467.99 m/z.
(3S)-3-[({[l-(2-chlorobenzyl)-4-hydroxy-2-oxo- 0.0008 Calculated (M-H)" =
1,2-dihydropyridin-3-yl]amino}carbonyl)amino]-3- 528.15 m/z; Found (M-H)"
(3,4-diethoxyphenyl)propanoic acid = 527.96 m/z.
(3S)-3-[({[l-(2-chlorobenzyl)-4-hydroxy-2-oxo- 0.003 Calculated (M-H)" =
l,2-dihydropyridin-3-yl]amino}carbonyl)amino]-3- 484.12 m/z; Found (M-H)"
(3-ethoxyphenyl)propanoic acid =483.94 m/z.
(3S)-3-[({[4-hydroxy-l-(3-methoxybenzyl)-2-oxo- 0.04 Calculated (M-H)" =
l,2-dihydropyridin-3-yl]amino}carbonyl)amino]-3- 450.17 m/z; Found (M-H)"
(4-methylphenyl)propanoic acid =450.00 m/z.
(3S)-3-[({[l-(2,3-dichlorobenzyl)-4-hydroxy-2-oxo- 0.13 Calculated (M-H)" =
l,2-dihydropyridin-3-yl]amino}carbonyl)amino]-3- 488.08 m/z; Found (M-H)"
(4-methylphenyl)propanoic acid =487.92 m/z.
(3S)-3-[({[l-benzyl-2-oxo-5-(trifluoromethyl)-l,2- 1.5 Calculated (M-H)" =
dihydropyridin-3-yl]amino}carbonyl)amino]-3-(4- 472.15 m/z; Found (M-H)"
methylphenyl)propanoic acid = 471.89 m/z.
(3S)-3-[({[l-(3,5-dimethylbenzyl)-4-hydroxy-2- 0.06 Calculated (M-H)" =
oxo-l,2-dihydropyridin-3- 448.19 m/z; Found (M-H)"
yl]amino}carbonyl)amino]-3-(4- =448.02 m/z. methylphenyl)propanoic acid
(3S)-3-[({[l-(2-chloro-6-methoxybenzyl)-4- 0.04 Calculated (M-H)" =
hydroxy-2-oxo-l,2-dihydropyridin-3- 554.09 m/z; Found (M-H)'
yl]amino}carbonyl)amino]-3-[4- =: 553.98 m/z. (trifluoromethoxy)phenyl]propanoic acid
(3S)-3-[({[l-(2-chlorobenzyl)-4-hydroxy-2-oxo- 0.003 Calculated (M-H)" =
l,2-dihydropyridin-3-yl]amino}carbonyl)amino]-3- 484.13 m/z; Found (M-H)'
(3-methoxy-4-methylphenyl)propanoic acid = 483.95 m/z.
(3S)-3-[({[l-(2-chlorobenzyl)-4-hydroxy-2-oxo- 0.003 Calculated (M-H)" =
l,2-dihydropyridin-3-yl]amino}carbonyl)amino]-3- 514.14 m/z; Found (M-H)"
(3,5-dimethoxy-4-methylphenyl)propanoic acid = 513.95 m/z.
(3S)-3-[({[l-(2-chlorobenzyl)-4-hydroxy-2-oxo-5- 0.04 Calculated (M-H)" =
pentyl-1,2-dihydropyridin-3- 524.20 m/z; Found (M-H)"
yl]amino}carbonyl)amino]-3-(4- = 523.98 m/z. methylphenyl)propanoic acid
(3S)-3-[({[l-(2-chlorobenzyl)-4-hydroxy-2-oxo- 0.005 Calculated (M+H)= 468.13
l,2-dihydropyridin-3-yl]amino}carbonyl)amino]-3- m/z; Found (M+H)+ =
(3,4-dimethylphenyl)propanoic acid 467.99 m/z.
(3S)-3-[({[l-(2,4-dichlorobenzyl)-4-hydroxy-5- 0.02 Calculated (M-H)" =
methyl-2-oxo-1,2-dihydropyridin-3- 502.09 m/z; Found (M-H)"
yl]amino}carbonyl)amino]-3-(4- = 501.89 m/z. methylphenyl)propanoic acid
[2-({[l-(2-chlorobenzyl)-4-hydroxy-2-oxo-l,2- >10 Calculated (M-H)" =
dihydropyridin-3-yl]amino}carbonyl)-l-(4- 455.11 m/z; Found (M-H)"
methylphenyl)hydrazino]acetic acid = 454.97 m/z.
(3S)-3-[({[l-(2-chlorobenzyl)-5-ethyl-4-hydroxy-2- 0.01 Calculated (M-H)" =
oxo-1,2-dihydropyridin-3- 482.15 m/z; Found (M-H)"
yl]amino}carbonyl)amino]-3-(4- = 482.00 m/z. methylphenyl)propanoic acid
3-[({[l-(2-chlorobenzyl)-4-hydroxy-2-oxo-l,2- 0.05 Calculated (M-H)" =
dihydropyridin-3-yl]amino}carbonyl)amino]-3- 441.09 m/z; Found (M-H)"
pyridin-3-ylpropanoic acid = 441.00 m/z.
(3S)-3-[({[5-butyl-l-(2-chlorobenzyl)-4-hydroxy-2- 0.025 Calculated (M-H)" =
oxo-l,2-dihydropyridin-3- 510.18 m/z; Found (M-H)"
yl]amino}carbonyl)amino]-3-(4- = 509.98 m/z. methylphenyl)propanoic acid
(3S)-3-{[({l-[2-chloro-5-(trifluoromethyl)benzyl]- 0.01 Calculated (M-H)' =
4-hydroxy-2-oxo-l,2-dihydropyridin-3- 522.10 m/z; Found (M-H)"
yl}amino)carbonyl]amino}-3-(4- = 521.97 m/z. methylphenyl)propanoic acid
(3S)-3-[({[l-(2-chloro-6-methoxybenzyl)-4- 0.005 Calculated (M-H)" =
hydroxy-2-oxo-1,2-dihydropyridin-3- 484.13 m/z; Found (M-H)"
yl]amino}carbonyl)amino]-3-(3- = 484.00 m/z. methylphenyl)propanoic acid
(3S)-3-[({[l-(2,6-dichlorobenzyl)-4-hydroxy-2-oxo- 0.013 Calculated (M-H)" =
l,2-dihydropyridin-3-yl]amino}carbonyl)amino]-3- 488.08 m/z; Found (M-H)"
(4-methylphenyl)propanoic acid =487.91 m/z.
(3S)-3-[({[l-(2-chloro-5-fluorobenzyl)-4-hydroxy- 0.014 Calculated (M-H)" =
2-oxo-l,2-dihydropyridin-3- 472.11 m/z; Found (M-H)"
yl]amino}carbonyl)amino]-3-(4- = 471.96 m/z. methylphenyl)propanoic acid
(3S)-3-[({[l-(2-chloro-6-methylbenzyl)-4-hydroxy- 0.01 Calculated (M-H)' =
5-methyl-2-oxo-1,2-dihydropyridin-3- 482.15 m/z; Found (M-H)"
yl]amino}carbonyl)amino]-3-(4- = 481.98 m/z. methylphenyl)propanoic acid
(3S)-3-[({[l-(4-chlorobenzyl)-4-hydroxy-5-methyl- 0.02 Calculated (M-H)" =
2-oxo-l,2-dihydropyridin-3- 468.13 m/z; Found (M-H)"
yl]amino}carbonyl)amino]-3-(4- = 467.94 m/z. methylphenyl)propanoic acid
(3S)-3-[({[l-(2-chlorobenzyl)-4-hydroxy-2-oxo- 0.003 Calculated (M+H)+ =
2,5,6,7-tetrahydro-lH-cyclopenta[b]pyridin-3- 496.16 m/z; Found
yl]amino}carbonyl)amino]-3-(4- (M+H)+ = 495.99 m/z. methylphenyl)propanoic acid
(3S)-3-{[({4-hydroxy-5-methyl-l-[4- 0.02 Calculated (M-H)" =
(methylsulfonyl)benzyl]-2-oxo-l,2-dihydropyridin- 512.15 m/z; Found (M-H)"
3-yl}amino)carbonyl]amino}-3-(4- =511.96 m/z. methylphenyl)propanoic acid
(3S)-3-[({[4-hydroxy-l-(4-methoxybenzyl)-2-oxo- 0.02 Calculated (M-H)" =
1,2-dihydropyridin-3-yl]amino}carbonyl)amino]-3- 450.17 m/z; Found (M-H)"
(4-methylphenyl)propanoic acid = 449.99 m/z.
(3S)-3-[({[l-(2-chlorobenzyl)-4-hydroxy-2-oxo-5- 0.02 Calculated (M-H)" =
propyl-l,2-dihydropyridin-3- 496.16 m/z; Found (M-H)"
yl]amino}carbonyl)amino]-3-(4- = 495.94 m/z. methylphenyl)propanoic acid
(3S)-3-({[(l-{4-[(dimethylamino)sulfonyl]benzyl}- 0.035 Calculated (M-H)" =
4-hydroxy-2-oxo-l,2-dihydropyridin-3- 527.16 m/z; Found (M-H)'
yl)amino]carbonyl}amino)-3-(4- = 526.96 m/z. methylphenyl)propanoic acid
(3S)-3-[({[4-hydroxy-l-(mesitylmethyl)-2-oxo-l,2- 0.06 Calculated (M-H)' =
dihydropyridin-3-yl]amino}carbonyl)amino]-3-(4- 462.20 m/z; Found (M-H)"
methylphenyl)propanoic acid = 462.02 m/z.
(3S)-3-[({[ 1 -(2-chlorobenzyl)-4-hydroxy-2-oxo- 0.02 Calculated (M-H)" =
l,2,5,6,7,8-hexahydroquinolin-3- 508.16 m/z; Found (M-H)"
yl]amino}carbonyl)amino]-3-(4- == 507.96 m/z. methylphenyl)propanoic acid
(3S)-3-[({[l-(2-chlorobenzyl)-5-ethyl-4-hydroxy-6- 0.025 Calculated (M-H)" =
methyl-2-oxo-l ,2-dihydropyridin-3- 496.16 m/z; Found (M-H)"
yl]amino}carbonyl)amino]-3-(4- = 495.96 m/z. methylphenyl)propanoic acid
(3S)-3-[({[l-(2-chlorobenzyl)-4-hydroxy-2-oxo- 0.4 Calculated (M-H)" =
1,2-dihydropyridin-3- 468.13 m/z; Found (M-H)"
yl]amino}carbonyl)(methyl)amino]-3-(4- ==467.85 m/z. methylphenyl)propanoic acid
(3S)-3-{[({4-hydroxy-l-[2-(methylthio)benzyl]-2- 0.02 Calculated (M-H)" =
oxo-l,2-dihydropyridin-3- 466.14 m/z; Found (M-H)"
yl}amino)carbonyl]amino}-3-(4- == 465.97 m/z. methylphenyl)propanoic acid
(3S)-3-({[(l-{2-[(dimethylamino)sulfonyl]benzyl}- 0.03 Calculated (M-H)' =
4-hydroxy-2-oxo-l,2-dihydropyridin-3- 527.16 m/z; Found (M-H)"
yl)amino]carbonyl}amino)-3-(4- = 526.97 m/z. methylphenyl)propanoic acid
(3S)-3-[({[l-(2,6-dimethoxybenzyl)-4-hydroxy-2- 0.01 Calculated (M-H)' =
oxo-1,2-dihydropyridin-3- 480.18 m/z; Found (M-H)"
yl]amino}carbonyl)amino]-3-(4- = 480.00 m/z. methylphenyl)propanoic acid
(3S)-3-{[({4-hydroxy-2-oxo-l-[2- 0.025 Calculated (M-H)" =
(trifluoromethoxy)benzyl]-1,2-dihydropyridin-3- 504.14 m/z; Found (M-H)"
yl}amino)carbonyl]amino}-3-(4- == 503.96 m/z. methylphenyl)propanoic acid
(3R)-3-[({[l-(2-chlorobenzyl)-4-hydroxy-2-oxo- 0.35 Calculated (M-H)" =
l,2-dihydropyridin-3-yl]amino}carbonyl)amino]-4- 522.10 m/z; Found (M-H)"
[3-(trifluoromethyl)phenyl]butanoic acid = 521.95 m/z.
(3S)-3-[({[l-(2-chlorobenzyl)-4-hydroxy-2-oxo- 0.003 Calculated (M-H)" =
1,2-dihydropyridin-3-yl]amino}carbonyl)amino]-3- 498.14 m/z; Found (M-H)"
(3-propoxyphenyl)propanoic acid = 497.97 m/z.
(3S)-3-[({[l-(2-chlorobenzyl)-4-hydroxy-2-oxo-5- 0.003 Calculated (M+H)+ =
propyl-l,2-dihydropyridin-3- 528.19 m/z; Found
yl]amino}carbonyl)amino]-3-(3- (M+H)+ = 528.02 m/z. ethoxyphenyl)propanoic acid
(3S)-3-[({[l-(2-chlorobenzyl)-4-hydroxy-5,6- 0.006 Calculated (M-H)" =
dimethyl-2-oxo-1,2-dihydropyridin-3- 482.15 m/z; Found (M-H)"
yl]amino}carbonyl)amino]-3-(4- =481.95 m/z. methylphenyl)propanoic acid
(3S)-3-[({[l-(2-chlorobenzyl)-4-hydroxy-2-oxo-5- 0.005 Calculated (M-H)' =
propyl-1,2-dihydropyridin-3- 570.20 m/z; Found (M-H)*
yl]amino}carbonyl)amino]-3-(3,4- = 569.98 m/z. diethoxyphenyl)propanoic acid
(3S)-3-(3-butoxyphenyl)-3-[({[l-(2-chlorobenzyl)- 0.005 Calculated (M+H)+ =
4-hydroxy-2-oxo-l ,2-dihydropyridin-3- 514.17 m/z; Found
yl]amino}carbonyl)amino]propanoic acid (M+H)+ = 514.00 m/z.
(3S)-3-{[({l-[2-chloro-5-(methylsulfonyl)benzyl]- 0.003 Calculated (M-H)" =
4-hydroxy-2-oxo-1,2-dihydropyridin-3- 532.10 m/z; Found (M-H)"
yl}amino)carbonyl]amino}-3-(4- = 531.94 m/z. methylphenyl)propanoic acid
(3R)-3-[({[l-(2-chlorobenzyl)-4-hydroxy-2-oxo- 0.08 Calculated (M-H)' =
1,2-dihydropyridin-3-yl]amino}carbonyl)amino]-4- 468.13 m/z; Found (M-H)'
(2-methylphenyl)butanoic acid =: 468.03 m/z.
(3S)-3-[({[l-(2-chlorobenzyl)-4-hydroxy-2-oxo- 0.003 Calculated (M-H)" =
l,2-dihydropyridin-3-yl]amino}carbonyl)amino]-3- 514.14 m/z; Found (M-H)"
[3-(2-methoxyethoxy)phenyl]propanoic acid = 513.95 m/z.
(3S)-3-[({[l-(4-chloro-2-methoxybenzyl)-4- 0.025 Calculated (M-H)" =
hydroxy-2-oxo-l,2-dihydropyridin-3- 484.13 m/z; Found (M-H)"
yl]amino}carbonyl)amino]-3-(4- =483.93 m/z. methylphenyl)propanoic acid
(3S)-3-[({[l-(2-chlorobenzyl)-4-hydroxy-2-oxo- 0.003 Calculated (M-H)" =
l,2-dihydropyridin-3-yl]amino}carbonyI)amino]-3- 556.18 m/z; Found (M-H)"
(3,4-dipropoxyphenyl)propanoic acid = 555.94 m/z.
(3S)-3-[({[l-(2-chlorobenzyl)-4-hydroxy-2-oxo- 0.12 Calculated (M-H)" =
2,5,6,7,8,9-hexahydro-lH-cyclohepta[b]pyridin-3- 522.18 m/z; Found (M-H)"
yl]amino}carbonyl)amino]-3-(4- = 521.98 m/z. methylphenyl)propanoic acid
(3S)-3-[({[l-(2-chlorobenzyl)-4-hydroxy-2-oxo- 12 Calculated (M-H)" =
1,2-dihydropyridin-3-yl]amino}carbonyl)amino]- 530.15 m/z; Found (M-H)"
4,4-diphenylbutanoic acid = 529.92 m/z.
(3S)-3-{[({1 -[2-(difluoromethoxy)benzyl]-4- 0.075 Calculated (M-H)" =
hydroxy-2-oxo-1,2-dihydropyridin-3- 486.15 m/z; Found (M-H)"
yl}amino)carbonyl]amino}-3-(4- = 486.00 m/z. methylphenyl)propanoic acid
(3S)-3-{[({4-hydroxy-5-methyl-2-oxo-l-[(lR)-l- 4 Calculated (M-H)" =
phenylethyl]-l,2-dihydropyridin-3- 448.19 m/z; Found (M-H)"
yl}amino)carbonyl]amino}-3-(4- = 447.99 m/z. methylphenyl)propanoic acid
(3S)-3-[({[l-(4-chlorobenzyl)-4-hydroxy-2-oxo-5- 0.03 Calculated (M-H)" =
propyl-1,2-dihydropyridin-3- 496.16 m/z; Found (M-H)"
yl]amino}carbonyl)amino]-3-(4- = 495.96 m/z. methylphenyl)propanoic acid
(3S)-3-[({[l-(2-chlorobenzyl)-4-hydroxy-2-oxo- 0.05 Calculated (M-H)" =
1,2-dihydropyridin-3-yl]amino}carbonyl)amino]-3- 496.16 m/z; Found (M-H)"
(3,4-diethylphenyl)propanoic acid =495.98 m/z.
(3S)-3-[({[l-(2-chlorobenzyl)-4-hydroxy-2-oxo- 0.05 Calculated (M-H)" =
l,2-dihydropyridin-3-yl]amino}carbonyl)amino]-3- 476.08 m/z; Found (M-H)"
(3,5-difluorophenyl)propanoic acid = 475.93 m/z.
3-[({[l-(2-chlorobenzyl)-4-hydroxy-2-oxo-l,2- 0.02 Calculated (M-H)" =
dihydropyridin-3-yl]amino}carbonyl)amino]-3-(2- 490.12 m/z; Found (M-H)"
naphthyl)propanoic acid = 489.97 m/z.
3-[({[l-(2-chlorobenzyl)-4-hydroxy-2-oxo-l,2- 0.025 Calculated (M+H)+ =
dihydropyridin-3-yl]amino}carbonyl)amino]-3-(5- 446.11 m/z; Found
methyl-2-furyl)propanoic acid (M+H)+ = 446.08 m/z.
(3S)-3-[({[l-(2-chlorobenzyl)-4-hydroxy-2-oxo- 0.025 Calculated (M-H)" =
l,2-dihydropyridin-3-yl]amino}carbonyl)amino]-3- 584.21 m/z; Found (M-H)"
(3,4-dibutoxyphenyl)propanoic acid = 583.98 m/z.
(3S)-3-{[({4-hydroxy-l-[2- 0.035 Calculated (M+H)+ =
(methylsulfonyl)benzyl]-2-oxo-l,2-dihydropyridin- 500.15 m/z; Found
3-yl}amino)carbonyl]amino}-3-(4- (M+H)" = 500.01 m/z. methylphenyl)propanoic acid
3-[({[l-(2-chlorobenzyl)-4-hydroxy-2-oxo-l,2- 0.2 Calculated (M-H)" =
dihydropyridin-3-yl]amino}carbonyl)amino]-3-(l- 490.12 m/z; Found (M-H)'
naphthyl)propanoic acid =489.91 m/z.
(3S)-3-[({[l-(4-chlorobenzyl)-4-hydroxy-2-oxo-5- 0.03 Calculated (M-H)" =
propyl-1,2-dihydropyridin-3- 526.17 m/z; Found (M-H)'
yl]amino}carbonyl)amino]-3-(3- = 525.95 m/z. ethoxyphenyl)propanoic acid
(3S)-3-[({[ 1 -(4-chlorobenzyl)-4-hydroxy-2-oxo-5- 0.015 Calculated (M-H)" =
propyl-l,2-dihydropyridin-3- 570.20 m/z; Found (M-H)"
yl]amino}carbonyl)amino]-3-(3,4- = 569.97 m/z. diethoxyphenyl)propanoic acid
(3S)-3-[({[l-(2,6-dimethylbenzyl)-4-hydroxy-2- 0.035 Calculated (M-H)" =
oxo-l,2-dihydropyridin-3- 448.19 m/z; Found (M-H)"
yl]amino}carbonyl)amino]-3-(4- = 448.02 m/z. methylphenyl)propanoic acid
(3S)-3-[3,5-bis(trifluoromethyl)phenyl]-3-[({[l-(2- 0.22 Calculated (M-H)" =
chlorobenzyl)-4-hydroxy-2-oxo-l,2-dihydropyridin- 576.08 m/z; Found (M-H)"
3-yl]amino}carbonyl)amino]propanoic acid = 575.91 m/z.
(3S)-3-[({[l-(2-chlorobenzyl)-4-hydroxy-2-oxo- 0.006 Calculated (M-H)' =
l,2-dihydropyridin-3-yl]amino}carbonyl)amino]-3- 506.09 m/z; Found (M-H)"
[3-(difluoromethoxy)phenyl]propanoic acid = 505.93 m/z.
(3R)-3-[({[l-(2-chlorobenzyl)-4-hydroxy-2-oxo- 0.225 Calculated (M-H)" =
l,2-dihydropyridin-3-yl]amino}carbonyl)amino]-4- 455.11 m/z; Found (M-H)"
pyridin-2-ylbutanoic acid = 455.09 m/z.
(3S)-3-[({[ 1 -(2-chlorobenzyl)-4-hydroxy-5-methyl- 0.0006 Calculated (M-H)" =
2-oxo-l,2-dihydropyridin-3- 542.17 m/z; Found (M-H)"
yl]amino}carbonyl)amino]-3-(3,4- = 542.06 m/z. diethoxyphenyl)propanoic acid
(3S)-3-[({[l-(2-chlorobenzyl)-4-hydroxy-5-methyl- 0.002 Calculated (M-H)" =
2-oxo-l,2-dihydropyridin-3- 499.15 m/z; Found (M-H)"
yl]amino}carbonyl)amino]-3-(3- =498.07 m/z. ethoxyphenyl)propanoic acid
(3S)-3-[({[l-(2-chlorobenzyl)-4-hydroxy-5-methyl- 0.020 Calculated (M+H)+ =
2-oxo-l ,2-dihydropyridin-3- 500.16 m/z; Found
yl]amino}carbonyl)amino]-3-(3-methoxy-4- (M+H)+ = 500.02 m/z. methylphenyl)propanoic acid
3-[({[l-(2-chlorobenzyl)-4-hydroxy-5-methyl-2- 0.030 Calculated (M-H)' =
oxo-l,2-dihydropyridin-3- 504.13 m/z; Found (M-H)"
yl]amino}carbonyl)amino]-3-(2-naphthyl)propanoic = 504.04 m/z. acid
(3S)-3-[({[ 1 -(2-chloro-6-methylbenzyl)-4-hydroxy- 0.015 Calculated (M-H)" =
5,6-dimethyl-2-oxo-l,2-dihydropyridin-3- 526.17 m/z; Found (M-H)"
yl]amino}carbonyl)amino]-3-(3- = 525.95 m/z. ethoxyphenyl)propanoic acid
(3S)-3-[({[l-(2-chloro-6-methylbenzyl)-4-hydroxy- 0.025 Calculated (M-H)" =
5,6-dimethyl-2-oxo-l,2-dihydropyridin-3- 526.17 m/z; Found (M-H)"
yl]amino}carbonyl)amino]-3-(3-methoxy-4- = 525.97 m/z. methylphenyl)propanoic acid
(3S)-3-[({[l-(2-chloro-6-methylbenzyl)-4-hydroxy- 0.004 Calculated (M-H)" =
5,6-dimethyl-2-oxo-l,2-dihydropyridin-3- 570.20 m/z; Found (M-H)"
yl]amino}carbonyl)amino]-3-(3,4- = 570.00 m/z. diethoxyphenyl)propanoic acid
(3S)-3-[({[l-(2-chloro-6-cyanobenzyl)-4-hydroxy- 0.007 Calculated (M-H)" =
2-oxo-l ,2-dihydropyridin-3- 479.11 m/z; Found (M-H)"
yl]amino}carbonyl)amino]-3-(4- = 478.90 m/z. methylphenyl)propanoic acid
(3S)-3-[({[l-(2-chloro-6-methylbenzyl)-4-hydroxy- 0.03 Calculated (M-H)" =
5,6-dimethyl-2-oxo-l,2-dihydropyridin-3- 496.16 m/z; Found (M-H)"
yl]amino}carbonyl)amino]-3-(4- = 495.97 m/z. methylphenyl)propanoic acid
(3S)-3-[({[ 1 -(2-chlorobenzyl)-4-hydroxy-5,6- 0.015 Calculated (M-H)" =
dimethyl-2-oxo-l ,2-dihydropyridin-3- 512.16 m/z; Found (M-H)"
yl]amino}carbonyl)amino]-3-(3-methoxy-4- = 511.95 m/z. methylphenyl)propanoic acid
(3S)-3-[({[l-(2-chlorobenzyl)-4-hydroxy-5,6- 0.003 Calculated (M-H)" =
dimethyl-2-oxo-l,2-dihydropyridin-3- 556.18 m/z; Found (M-H)"
yl]amino}carbonyl)amino]-3-(3,4- = 555.99 m/z. diethoxyphenyl)propanoic acid
(3S)-3-{[({4-hydroxy-l-[3-(meihylthio)benzyl]-2- 20 Calculated (M-H)' =
oxo-1,2-dihydropyridin-3- 466.14; Found (M-H)' =
yl}amino)carbonyl]amino}-3-(4- 466.04. methylphenyl)propanoic acid
(3S)-3-[({[l-(2-chlorobenzyl)-4-hydroxy-5-methyl- 15 Calculated (M-H)" =
2-oxo-l,2-dihydropyridin-3- 482.15; Found (M-H)' =
yl]amino} carbonyl)amino]-3-(3,4- 482.02. dimethylphenyl)propanoic acid
(3S)-3-[({[l-(2-chloro-6-methoxybenzyl)-4- 3 Calculated (M-H)" =
hydroxy-5-methyl-2-oxo-l,2-dihydropyridin-3- 512.16; Found (M-H)" =
yl]amino}carbonyl)amino]-3-(3,4- 512.03. dimethylphenyl)propanoic acid
(3 S)-3-[( {[ 1 -(2-chlorobenzyl)-5-cyclopropyl-4- 20 Calculated (M+H)+ =
hydroxy-2-oxo-l ,2-dihydropyridin-3- 496.16; Found (M+H)+ =
yl]amino} carbonyl)amino]-3-(4- 496.05. methylphenyl)propanoic acid
(3S)-3-[({[l-(4-chlorobenzyl)-4-hydroxy-2-oxo- 50 Calculated (M-H)" =
2,5,6,7-tetrahydro-lH-cyclopenta[b]pyridin-3- 494.15; Found (M-H)" =
yl]amino}carbonyl)amino]-3-(4- 494.02. methylphenyl)propanoic acid
(3S)-3-[({[l-(3-chlorobenzyl)-4-hydroxy-5-methyl- 20 Calculated (M-H)' =
2-oxo-l,2-dihydropyridin-3- 468.13; Found (M-H)" =
yl]amino}carbonyl)amino]-3-(4- 468.02. methylphenyl)propanoic acid
(3S)-3-[({[l-(2,6-dichlorobenzyl)-4-hydroxy-5- 20 Calculated (M-H)" =
methyl-2-oxo-l,2-dihydropyridin-3- 502.09; Found (M-H)" =
yl]amino}carbonyl)amino]-3-(4- 501.92. methylphenyl)propanoic acid
(3S)-3-[({[4-hydroxy-5-methyl-l-(4-methylbenzyl)- 150 Calculated (M-H)" =
• 2-oxo-l,2-dihydropyridin-3- 448.19; Found (M-H)" =
yl]amino}carbonyl)amino]-3-(4- 448.05. methylphenyl)propanoic acid
3-(l -benzofiiran-2-yl)-3-[( {[ 1 -(2-chlorobenzyl)-4- 140 Calculated (M-H)" =
hydroxy-2-oxo-1,2-dihydropyridin-3- 480.10; Found (M-H)' =
yl]amino}carbonyl)amino]propanoic acid 479.96.
(3S)-3-[({[l-(2-chlorobenzyl)-4-hydroxy-2-oxo- 3 Calculated (M-H)" =
2,5,6,7-tetrahydro-lH-cyclopenta[b]pyridin-3- 524.16; Found (M-H)' =
yl]amino}carbonyl)amino]-3-(3- 523.95. ethoxyphenyl)propanoic acid
3-[( {[ 1 -(2-chlorobenzyl)-4-hydroxy-2-oxo-1,2- 15 Calculated (M -H)" =
dihydropyridin-3-yl]amino}carbonyl)amino]-3-(6- 520.13; Found (M-H)" =
methoxy-2-naphthyl)propanoic acid 520.00.
(3S)-3-[({[l-(3,5-dimethoxybenzyl)-4-hydroxy-5- 70 Calculated (M-H)" =
methyl-2-oxo-l,2-dihydropyridin-3- 494.19; Found (M-H)' =
yl]amino}carbonyl)amino]-3-(4- 494.04. methylphenyl)propanoic acid
(3S)-3-[({[l-(2,6-difluorobenzyl)-4-hydroxy-5- 25 Calculated (M-H)' =
methyl-2-oxo-l,2-dihydropyridin-3- 470.15; Found (M-H)" =
yl]amino}carbonyl)amino]-3-(4- 470.03. methylphenyl)propanoic acid
(3 S)-3-[( {[ 1 -(2-chlorobenzyl)-4-hydroxy-2-oxo- 3 Calculated (M+H)+ =
2,5,6,7-tetrahydro-lH-cyclopenta[b]pyridin-3- 570.20; Found (M+H)+ =
yl]amino} carbonyl)amino]-3 -(3,4- 5 70.00. diethoxyphenyl)propanoic acid
(3S)-3-{[({4-hydroxy-l-[3-(methylsulfonyl)benzyl]- 25 Calculated (M-H)" =
2-oxo-1,2-dihydropyridin-3- 498.13; Found (M-H)" =
yl}amino)carbonyl]amino}-3-(4- 498.01. methylphenyl)propanoic acid
(3S)-3-[({[ 1 -(2-chloro-6-raethylben2yl)-4-hydroxy- 3 Calculated (M-H)" =
5-methyl-2-oxo-l,2-dihydropyridin-3- 556.19; Found (M-H)" =
yl]amino}carbonyl)amino]-3-(3,4- 556.02. diethoxyphenyl)propanoic acid
(3S)-3-[({[l-(2-chloro-6-methylbenzyl)-4-hydroxy- 4 Calculated (M-H)' =
5-methyl-2-oxo-1,2-dihydropyridin-3- 512.16; Found (M-H)" =
yl] amino} carbonyl)amino] -3 -(3 - 512.02. ethoxyphenyl)propanoic acid
(3S)-3-[({[l-(2-chloro-6-methylbenzyl)-4-hydroxy- 45 Calculated (M-H)" =
5-methyl-2-oxo-1,2-dihydropyridin-3- 496.16; Found (M-H)" =
yl]amino}carbonyl)amino]-3-(3,4- 496.01. dimethylphenyl)propanoic acid
(3S)-3-[({[l-(2-chloro-6-methylbenzyl)-4-hydroxy- 25 Calculated (M-H)" =
5-methyl-2-oxo-1,2-dihydropyridin-3- 512.16; Found (M-H)" =
yl]amino}carbonyl)amino]-3-(3-methoxy-4- 511.97. methylphenyl)propanoic acid
3 -[({[ 1 -(2-chlorobenzyl)-4-hydroxy-2-oxo-1,2- 115 Calculated (M-H)" =
dihydropyridin-3-yl]amino}carbonyl)amino]-3-(4,5- 458.11; Found (M-H)" =
dimethyl-2-furyl)propanoic acid 457.99.
3-[({[l-(2-chlorobenzyl)-4-hydroxy-2-oxo-l,2- 160 Calculated (M-H)' =
dihydropyridin-3-yl]amino} carbonyl)amino]-3-(4- 520.13; Found (M-H)" =
methoxy-l-naphthyl)propanoic acid 519.97.
(3R)-3-[({[l-(2-chlorobenzyl)-4-hydroxy-2-oxo-l,2- 115 Calculated (M-H)' =
dihydropyridin-3-yl]amino}carbonyl)amino]-5- 468.13; Found (M-H)" =
phenylpentanoic acid 467.98.
(3S)-3-[({[l-(2-chlorobenzyl)-4-hydroxy-2-oxo-l,2- 12 Calculated (M-H)" =
dihydroquinolin-3-yl]amino}carbonyl)amino]-3-(3- 534.14; Found (M-H)" =
ethoxyphenyl)propanoic acid 533.94.
(3S)-3-[({[l-(2-chlorobenzyl)-4-hydroxy-2-oxo- 18 Calculated (M+H)+ =
2,5,6,7-tetrahydro-lH-cyclopenta[b]pyridin-3- 510.18; Found (M+H)+ =
yl]amino}carbonyl)amino]-3-(3,4- 510.06. dimethylphenyl)propanoic acid
(3S)-3-[({[l-(2-chloro-6-ethoxybenzyl)-4-hydroxy- 7 Calculated (M+H)+ =
2-oxo-l,2-dihydropyridin-3- 500.16; Found (M+Hf =
yl]amino}carbonyl)amino]-3-(4- 500.06. methylphenyl)propanoic acid
(3S)-3-[({[l-(2-chloro-6-ethoxybenzyl)-4-hydroxy- 3 Calculated (M-H)" =
S-methyl^-oxo-l^-dihydropyridin-S- 512.16; Found (M-H)" =
yl]amino}carbonyl)amino]-3-(4- 512.03. methylphenyl)propanoic acid
(3S)-3-[({[l-(2-chlorobenzyl)-5-cyclopropyl-4- 14 Calculated (M+H)+ =
hydroxy-2-oxo-l,2-dihydropyridin-3- 526.17; Found (M+H)"1" =
yl]amino}carbonyl)amino]-3-(3- 526.01. ethoxyphenyl)propanoic acid
(3S)-3-[({[l-(2-chlorobenzyl)-5-cyclopropyl-4- 6 Calculated (M+H)+ =
hydroxy-2-oxo-l ,2-dihydropyridin-3- 570.20; Found (M+Hf =
yl]amino}carbonyl)amino]-3-(3,4- 570.04. diethoxyphenyl)propanoic acid
(3S)-3-[({[l-(2-chlorobenzyl)-4-hydroxy-2-oxo-l,2- 30 Calculated (M-H)" =
dihydropyridin-3-yl]amino}carbonyl)amino]-3-[4- 506.09; Found (M-H)" =
(difluoromethoxy)phenyl]propanoic acid 505.96.
3-[({[l-(2-chlorobenzyl)-4-hydroxy-2-oxo-l,2- 105 Calculated (M-H)" =
dihydropyridin-3-yl]amino}carbonyl)amino]-3- 491.11; Found (M-H)" =
quinolin-2-ylpropanoic acid 490.96.
(3S)-3-[( {[ 1 -(2-fluoro-6-methoxybenzyl)-4-hydroxy- 10 Calculated (M-H)" =
5-methyl-2-oxo-l ,2-dihydropyridin-3- 482.17;
yljamino} carbonyl)amino]-3-(4- Found (M-H)" = 482.02. methylphenyl)propanoic acid
(3 S)-3-[( {[ 1 -(2-chloro-6-methoxybenzyl)-4- 15 Calculated (M+H)+ =
hydroxy-2-oxo-5-propyl-l,2-dihydropyridin-3- 528.19; Found (M+H)+ -
yl]amino}carbonyl)amino]-3-(4- 528.04. methylphenyl)propanoic acid
(3S)-3-[({[l-(2-chloro-6-methoxybenzyl)-4- 7 Calculated (M+H)+ =
hydroxy-2-oxo-5-propyl-l,2-dihydropyridin-3- 558.20; Found (M+H)+ =
yl]amino}carbonyl)amino]-3-(3- 558.07. ethoxyphenyl)propanoic acid
(3S)-3-[({[l-(5-chloro-2-fluorobenzyl)-4-hydroxy-5- 15 Calculated (M-H)" =
methyl-2-oxo-l,2-dihydropyridin-3- 486.12; Found (M-H)' =
yl]amino}carbonyl)amino]-3-(4- 486.00. methylphenyl)propanoic acid
(3S)-3-[({[l-(2-chlorobenzyl)-4-hydroxy-2-oxo-l,2- 14 Calculated (M-H)" =
dihydroquinolin-3-yl]amino}carbonyl)amino]-3-(3- 534.14; Found (M-H)" =
methoxy-4-methylphenyl)propanoic acid 533.95.
(3S)-3-[({[l-(2-chlorobenzyl)-4-hydroxy-2-oxo-l,2- 4 Calculated (M-H)" =
dihydroquinolin-3-yl]amino}carbonyl)amino]-3- 578.17; Found (M-H)" =
(3,4-diethoxyphenyl)propanoic acid 577.99.
(3S)-3-[({[l-(2-chlorobenzyl)-4-hydroxy-2-oxo-l,2- 25 Calculated (M-H)" =
dihydroquinolin-3-yl]amino}carbonyl)amino]-3- 518.15; Found (M-H)' =
(3,4-dimethylphenyl)propanoic acid 517.96.
(3S)-3-[( {[ 1 -(2-chlorobenzyl)-4-hydroxy-2-oxo-l ,2- 150 Calculated (M+H)+ =
dihydropyridin-3-yl]amino}carbonyl)amino]-3- 443.11; Found (M+H)+ =
pyridin-2-ylpropanoic acid 443.03.
(3S)-3-[({[l-(2-chlorobenzyl)-4-hydroxy-2-oxo-l,2- 3 Calculated (M-H)" =
dihydropyridin-3-yl]amino}carbonyl)amino]-3-(3- 498.14; Found (M-H)" =
isopropoxyphenyl)propanoic acid 498.04.
(3S)-3-[({[l-(2-chlorobenzyl)-4-hydroxy-2-oxo-l,2- 7 Calculated (M-H)" =
dihydropyridin-3-yl]amino}carbonyl)amino]-3-(3,5- 528.15; Found (M-H)" =
diethoxyphenyl)propanoic acid 528.02.
(3 S)-3-[( {[ 1 -(2-chlorobenzyl)-4-hydroxy-5- 60 Calculated (M+H)+ =
isopropyl-2-oxo-l ,2-dihydropyridin-3- 498.18; Found (M+H)+ =
yl]amino}carbonyl)amino]-3-(4- 498.05. methylphenyl)propanoic acid
(3S)-3-[({[l-(5-fluoro-2-methylbenzyl)-4-hydroxy- 20 Calculated (M+H)+ =
5-methyl-2-oxo-l,2-dihydropyridin-3- 468.19; Found (M+H)+ =
yl]amino}carbonyl)amino]-3-(4- 468.07. methylphenyl)propanoic acid
(3S)-3-{[({4-hydroxy-5-methyl-2-oxo-l-[(lS)-l- 1500 Calculated (M+H)+ =
phenylethyl]-l,2-dihydropyridin-3- 450.20; Found (M+Hf =
yl}amino)carbonyl]amino}-3-(4- 450.07. methylphenyl)propanoic acid
(3S)-3-[({[l-(2-chloro-6-methoxybenzyl)-4- 3 Calculated (M+H)+-
hydroxy-2-oxo-5-propyl-l,2-dihydropyridin-3- 602.23; Found (M+H)+ =
yl]amino}carbonyl)amino]-3-(3,4- 602.04. diethoxyphenyl)propanoic acid
(3S)-3-[({[l-(2-chloro-5-isopropoxybenzyl)-4- 7 Calculated (M-H)' =
hydroxy-5-methyl-2-oxo-l ,2-dihydropyridin-3- 526.17; Found (M-H)" =
yl]amino}carbonyl)amino]-3-(4- 526.04. methylphenyl)propanoic acid
(3S)-3-[({[l-(2-chloro-6-methoxybenzyl)-4- 15 Calculated (M+Hf =
hydroxy-2-oxo-5-propyl-l,2-dihydropyridin-3- 558.20; Found (M+H)T =
yl] amino} carbonyl)amino]-3-(3 -methoxy-4- 558.05. methylphenyl)propanoic acid
(3S)-3-[({[l-(2-chloro-6-ethoxybenzyl)-4-hydroxy- 2 Calculated (M+H)" =
5-methyl-2-oxo-l,2-dihydropyridin-3- 544.19; Found (M+H)+ =
yl]amino} carbonyl)amino]-3-(3- 544.04. ethoxyphenyl)propanoic acid
(3S)-3-[({[l-(5-acetyl-2-methoxybenzyl)-4-hydroxy- 33 Calculated (M-H)" =
2-oxo-l,2-dihydropyridin-3- 492.18; Found (M-H)' =
yl] amino} carbonyl)amino]-3 -(4- 492.04. methylphenyl)propanoic acid
3-[({[l-(2-chloro-6-methylbenzyl)-4-hydroxy-5- 35 Calculated (M-H)" =
methyl-2-oxo-l,2-dihydropyridin-3- 548.16; Found (M-H)" =
yl]amino}carbonyl)amino]-3-(6-methoxy-2- 548.01. naphthyl)propanoic acid
(3S)-3-[({[l-(2-chloro-6-methoxybenzyl)-4- 17 Calculated (M+H)f =
hydroxy-2-oxo-5-propyl-l,2-dihydropyridin-3- 542.21; Found (M+H)+ =
yl]amino}carbonyl)amino]-3-(3,4- 542.05. dimethylphenyl)propanoic acid
(3S)-3-[({[l-(2-chlorobenzyl)-4-hydroxy-2-oxo-l,2- 3 Calculated (M-H)' =
dihydropyridin-3-yl]amino}carbonyl)amino]-3-(l- 493.13; Found (M-H)" =
methyl-1 H-indol-5-yl)propanoic acid 492.95.
(3S)-3-[({[2-(2-chlorobenzyl)-5-hydroxy-6-methyl- 18 Calculated (M+H)+ =
3-oxo-2,3-dihydropyridazin-4- 471.14; Found (M+H)+ =
yl]amino}carbonyl)amino]-3-(4- 471.00. methylphenyl)propanoic acid
(3S)-3-[({[l-(2-chlorobenzyl)-4-hydroxy-5-methyl- 5 Calculated (M-H)' =
2-oxo-l,2-dihydropyridin-3- 534.14; Found (M-H)' =
yl]amino}carbonyl)amino]-3-(6-methoxy-2- 533.91. naphthyl)propanoic acid
(3S)-3-[({[2-(2-chloroben2yl)-5-hydroxy-6-methyl- 5 Calculated (M+H)+ =
3-oxo-2,3-dihydropyridazin-4- 501.15; Found (M+H)+ =
yl]amino}carbonyl)amino]-3-(3- 501.01. ethoxyphenyl)propanoic acid
3-[( {[ 1 -(2-chlorobenzyl)-4-hydroxy-2-oxo-1,2- 30 Calculated (M+H)+ =
dihydropyridin-3-yl]amino}carbonyl)amino]-3- 448.07; Found (M+H)+ =
thien-2-ylpropanoic acid 447.97.
(3S)-3-[({[5-chloro-l-(2-chlorobenzyl)-4-hydroxy-2- 6 Calculated (M-H)" =
oxo-1,2-dihydropyridin-3- 488.08; Found (M-H)" =
yl]amino}carbonyl)amino]-3-(4- 487.97. methylphenyl)propanoic acid
(3S)-3-(3-butoxyphenyl)-3-[({[ 1 -(2-chlorobenzyl)-4- 20 Calculated (M-H)" =
hydroxy-2-oxo-2,5,6,7-tetrahydro-lH- 552.19; Found (M-H)" =
cyclopenta[b]pyridin-3- 552.01. yl]amino} carbonyl)amino]propanoic acid
(3S)-3-[({[l-(2-chlorobenzyl)-4-hydroxy-2-oxo-l,2- 5 Calculated (M-H)" =
dihydropyridin-3-yl]amino}carbonyl)amino]-3-[3- 524.16; Found (M-H)" =
(cyclopentyloxy)phenyl]propanoic acid 524.00.
(3S)-3-[({[2-(2-chlorobenzyl)-5-hydroxy-6-methyl- 3 Calculated (M+H)+ =
3-oxo-2,3-dihydropyridazin-4- 545.18; Found (M+H)+ =
yl]amino}carbonyl)amino]-3-(3,4- 544.98. diethoxyphenyl)propanoic acid
(3S)-3-[({[ 1 -(2-chlorobenzyl)-4-hydroxy-5-methyl- 3 Calculated (M-H)" =
2-oxo-l,2-dihydropyridin-3- 507.14; Found (M-H)" =
yl] amino} carbonyl)amino] -3 -(1 -methyl-1 H-indol-5 - 5 06.94. yl)propanoic acid
(3S)-3-[({[2-(2-chlorobenzyl)-5-hydroxy-6-methyl- 10 Calculated (M+H)+ =
3-oxo-2,3-dihydropyridazin-4- 545.18; Found (M+H)+ =
yl]amino}carbonyl)amino]-3-(3,5- 545.01. diethoxyphenyl)propanoic acid
(3S)-3-[({[l-(2-chlorobenzyl)-4-hydroxy-5-methyl- 70 Calculated (M-H)" =
2-oxo-l,2-dihydropyridin-3- 538.10; Found (M-H)' =
yl]amino}carbonyl)amino]-3-[4- 537.95. (trifluoromethoxy)phenyl]propanoic acid
(3S)-3-[({[ 1 -(2-chlorobenzyl)-4-hydroxy-5-methyl- 10 Calculated (M-H)" =
2-oxo-1,2-dihydropyridin-3- 538.10; Found (M-H)' =
yl]amino}carbonyl)amino]-3-[3- 537.95. (trifluoromethoxy)phenyl]propanoicacid
(3S)-3-[({[l-(2-chlorobenzyl)-4-hydroxy-5-methyl- 4 Calculated (M+H)+ =
2-oxo-l,2-dihydropyridin-3- 486.14; Found (M+H)+ =
yl]amino}carbonyl)amino]-3-(4- 486.04. methoxyphenyl)propanoic acid
(3S)-3-[({[l-(2"-chlorobenzyl)-4-hydroxy-2-oxo-l,2- 15 Calculated (M-H)" =
dihydropyridin-3-yl]amino}carbonyl)amino]-3-(6- 520.13; Found (M-H)" =
methoxy-2-naphthyl)propanoic acid 520.03.
(3S)-3-{[({1 -[2-fluoro-6-(trifluoromethyl)benzyl]-4- 100 Calculated (M-H)" =
hydroxy-5-methyl-2-oxo-1,2-dihydropyridin-3- 520.15; Found (M-H)" =
yl} amino)carbonyl]amino} -3 -(4- 519.97. methylphenyl)propanoic acid
(3S)-3-[({[l-(2-chlorobenzyl)-4-hydroxy-5-methyl- 10 Calculated (M-H)' =
2-oxo-l,2-dihydropyridin-3- 522.10; Found (M-H)" =
yl]amino}carbonyl)amino]-3-[3- 521.96. (trifluoromethyl)phenyl]propanoic acid
(3S)-3-[({[ 1 -(2-chlorobenzyl)-4-hydroxy-5-methyl- 3 Calculated (M-H)" =
2-oxo-l,2-dihydropyridin-3- 484.13; Found (M-H)" =
yl]amino}carbonyl)amino]-3-(3- 484.00. methoxyphenyl)propanoic acid
(3S)-3-[({[l-(2-chloro-6-methylbenzyl)-4-hydroxy- 20 Calculated (M+H)+ =
2-oxo-2,5,6,7-tetrahydro-lH-cyclopenta[b]pyridin-3- 510.18; Found (M+H)1" =
yl]amino}carbonyl)amino]-3-(4- 510.05. methylphenyl)propanoic acid
(3S)-3-[({[l-(2-chloro-6-methylbenzyl)-4-hydroxy- 4 Calculated (M+H)+ =
2-oxo-2,5,6,7-tetrahydro-lH-cyclopenta[b]pyridin-3- 540.19; Found (M+H)+ =
yl]amino}carbonyl)amino]-3-(3- 540.10. ethoxyphenyl)propanoic acid
(3S)-3-[({[l-(2-chlorobenzyl)-4-hydroxy-2-oxo- 3 Calculated (M+H)+ =
2,5,6,7-tetrahydro-1 H-cyclopenta[b]pyridin-3- 540.19; Found (M+H)+ =
yl]amino}carbonyl)amino]-3-(3- 540.09. isopropoxyphenyl)propanoic acid
(3S)-3-[({[l-(2-chloroben2yl)-4-hydroxy-5-methyl- 3 Calculated (M-H)' =
2-oxo-1,2-dihydropyridin-3- 542.17; Found (M-H)" =
yl]amino}carbonyl)amino]-3-(3,5- 542.00. diethoxyphenyl)propanoic acid
(3S)-3-[({[l-(2-chloro-6-ethoxybenzyl)-5-ethyl-4- 4 Calculated (M-H)" =
hydroxy-2-oxo-l,2-dihydropyridin-3- 556.19; Found (M-H)" =
yl]amino}carbonyl)amino]-3-(3- 556.01. ethoxyphenyl)propanoic acid
(3S)-3-[({[l-(2-chloro-6-ethoxybenzyl)-4-hydroxy- 3 Calculated (M+H)+ =
2-oxo-1,2-dihydropyridin-3- 5 30.17; Found (M+H)+ =
yl]amino}carbonyl)amino]-3-(3- 530.04. ethoxyphenyl)propanoic acid
(3S)-3-[({[l-(2-chlorobenzyl)-4-hydroxy-5-methyl- 15 Calculated (M-H)' =
2-oxo-l,2-dihydropyridin-3- 538.17; Found (M-H)" =
yl]amino}carbonyl)amino]-3-[3- 538.03. (cyclopentyloxy)phenyl]propanoic acid
3-(l,l'-biphenyl-4-yl)-3-[({[l-(2-chlorobenzyl)-4- 130 Calculated (M-H)' =
hydroxy-5-methyl-2-oxo-l,2-dihydropyridin-3- 530.15; Found (M-H)" =
yl]amino}carbonyl)amino]propanoic acid 529.96.
(3S)-3-[({[l-(2-chlorobenzyl)-4-hydroxy-2-oxo- 30 Calculated (M+Hf =
2,5,6,7-tetrahydro-lH-cyclopenta[b]pyridin-3- 580.15; Found (M+H)+ =
yl]amino}carbonyl)amino]-3-[3-(2,2,2- 580.02. trifluoroethoxy)phenyl]propanoic acid
(3S)-3-[({[l-(2-chloroben2yl)-4-hydroxy-5-methyl- 15 Calculated (M+H)+ =
2-oxo-l,2-dihydropyridin-3- 554.13; Found (M+H)+ =
yl]amino}carbonyl)amino]-3-[3-(2,2,2- 554.00. trifluoroethoxy)phenyl]propanoic acid
(3S)-3-[({[l-(2-chlorobenzyl)-4-hydroxy-5-methyl- 3 Calculated (M+Hf =
2-oxo-l,2-dihydropyridin-3- 514.17; Found (M+Hf =
yl]amino}carbonyl)amino]-3-(3- 514.05. isopropoxyphenyl)propanoic acid
(3S)-3-[({[l-(2-chloro-6-ethoxybenzyl)-4-hydroxy- 4 Calculated (M+H)" =
5-methyl-2-oxo-l,2-dihydropyridin-3- 558.20; Found (M+H)+ =
yl]amino} carbonyl)amino]-3-(3 - 558.05. isopropoxyphenyl)propanoic acid
(3S)-3-[({[l-(2-chlorobenzyl)-4-hydroxy-5-methyl-2- 40 Calculated (M+H)+ =
oxo-1,2-dihydropyridin-3-yl]amino}carbonyl)amino]- 592.19; Found (M+H)^
3-(2',6'-dimethoxy-l, 1 '-biphenyl-4-yl)propanoic acid = 592.04.
(3S)-3-[({[l-(2-chlorobenzyl)-4-hydroxy-5-methyl-2- 30 Calculated (M+H)+ =
oxo-1,2-dihydropyridin-3-yl]amino}carbonyl)amino]- 509.16; Found (M+H)"
3-(l-methyl-lH-indol-7-yl)propanoic acid = 509.03.
(3S)-3-[({[l-(2-chloro-6-ethoxybenzyl)-4-hydroxy-2- 2 Calculated (M+H)+ =
oxo-2,5,6,7-tetrahydro-lH-cyclopenta[b]pyridin-3- 570.20; Found (M+H)+
yl]amino}carbonyl)amino]-3-(3- = 570.09. ethoxyphenyl)propanoic acid
(3S)-3-[({[l-(2-chloro-6-propoxybenzyl)-4-hydroxy- 5 Calculated (M+H)+ =
5-methyl-2-oxo-1,2-dihydropyridin-3 - 5 5 8.20; Found (M+H)+
yl]amino}carbonyl)amino]-3-(3- =558.03. ethoxyphenyl)propanoic acid
(3S)-3-[({[l-(2-chloro-6-isobutoxybenzyl)-4- 14 Calculated (M+H)+ =
hydroxy-5-methyl-2-oxo-l ,2-dihydropyridin-3- 572.22; Found (M+H)+
yl]amino}carbonyl)amino]-3-(3- = 572.05. ethoxyphenyl)propanoic acid
(3S)-3-[( {[ 1 -(2-chloro-6-isopropoxybenzyl)-4- 7 Calculated (M+H)+ =
hydroxy-5-methyl-2-oxo-l,2-dihydropyridin-3- 558.20; Found (M+H)+
yl]amino}carbonyl)amino]-3-(3- == 558.03. ethoxyphenyl)propanoic acid
(3S)-3-{[({l-[2-chloro-6-(2,2,2- 4 Calculated (M+H)+=
trifluoroethoxy)benzyl]-4-hydroxy-5-methyl-2-oxo- 598.16; Found (M+H)+
l,2-dihydropyridin-3-yl}amino)carbonyl]amino}-3- = 597.99. (3-ethoxyphenyl)propanoic acid
3-[( {[1 -(2-chlorobenzyl)-4-hydroxy-5-methyl-2-oxo- 15 Calculated (M+H)+ =
1,2-dihydropyridin-3-yl]amino}carbonyl)amino]-3- 502.12; Found (M+H)+
[4-(methylthio)phenyl]propanoic acid = 501.98.
(3S)-3-[({[l-(2-chloro-6-ethoxybenzyl)-4-hydroxy-2- 2 Calculated (M+H)+ =
oxo-2,5,6,7-tetrahydro-lH-cyclopenta[b]pyridin-3- 606.20; Found (M+H)+
yI]amino}carbonyl)amino]-3-(6-methoxy-2- = 606.04. naphthyl)propanoic acid
(3S)-3-[({[l-(2-chlorobenzyl)-4-hydroxy-5-methyl-2- 6 Calculated (M+H)+ =
oxo-1,2-dihydropyridin-3-yl]amino}carbonyl)amino]- 498.14; Found (M+H)+
3-(2,3-dihydro-l-benzofuran-5-yl)propanoic acid = 498.02.
(3S)-3-[({[l-(2-chloro-6-ethoxybenzyl)-4-hydroxy-5- 3 Calculated (M+H)+ =
methyl-2-oxo-l ,2-dihydropyridin-3- 553.19; Found (M+H)"
yl]amino}carbonyl)amino]-3-(l-methyl-lH-indol-5- = 553.05. yl)propanoic acid
(3S)-3-[({[l-(2-chloro-6-ethoxybenzyl)-4-hydroxy-5- 2 Calculated (M+H)+ =
methyl-2-oxo-l ,2-dihydropyridin-3- 542.17; Found (M+H)+
yl]amino}carbonyl)amino]-3-(2,3-dihydro-l- = 542.06. benzofuran-5-yl)propanoic acid
(3S)-3-[({[l-(2-chloro-6-ethoxybenzyl)-4-hydroxy-2- 3 Calculated (M+H)+ =
oxo-2,5,6,7-tetrahydro-lH-cyclopenta[b]pyridin-3- 614.22; Found (M+H)+
yl]amino}carbonyl)amino]-3-(3,5- =614.11. diethoxyphenyl)propanoic acid
(3S)-3-[({[l-(2-chloro-6-isopropoxybenzyl)-4- 4 Calculated (M+H)+ =
hydroxy-5-methyl-2-oxo-1,2-dihydropyridin-3- 558.20; Found (M+H)+
yl]amino}carbonyl)amino]-3-(3- = 558.02. ethoxyphenyl)propanoic acid
(3S)-3-[({[l-(2-chloro-6-ethoxybenzyl)-4-hydroxy-5- 3 Calculated (M+H)+ =
methyl-2-oxo-l,2-dihydropyridin-3- 558.20; Found (M+H)+
yl]amino}carbonyl)amino]-3-(3- = 558.07. propoxyphenyl)propanoic acid
(3S)-3-(3-butoxyphenyl)-3-[({[l-(2-chloro-6- 4 Calculated (M+H)+ =
ethoxybenzyl)-4-hydroxy-5-methyl-2-oxo-l,2- 572.22; Found (M+H)+
dihydropyridin-3- = 572.04. yl]amino}carbonyl)amino]propanoic acid
(3S)-3-[({[5-chloro-l-(2-chloro-6-ethoxybenzyl)-4- 3 Calculated (M+H)+ =
hydroxy-2-oxo-l,2-dihydropyridin-3- 564.13; Found (M+H)+
yl]amino}carbonyl)amino]-3-(3- = 563.99. ethoxyphenyl)propanoic acid
(3S)-3-[({[l-(2-chloro-6-ethoxybenzyl)-4-hydroxy-2- 3 Calculated (M+H)+
oxo-l,2-dihydropyridin-3-yl]amino}carbonyl)amino]- =544.19; Found
3-(3-isopropoxyphenyl)propanoic acid (M+H)+ = 544.06.
(3S)-3-[({[l-(2-chlorobenzyl)-4-hydroxy-2-oxo- 2 Calculated (M+H)+
2,5,6,7-tetrahydro-lH-cyclopenta[b]pyridin-3- =524.16; Found
yl]amino}carbonyl)amino]-3-(2,3-dihydro-l - (M+H)+ = 524.03. benzofuran-5-yl)propanoic acid
(3S)-3-[({[2-(2-chloro-6-ethoxybenzyl)-5-hydroxy-6- 7 Calculated (M+H)+ =
methyl-3-oxo-2,3-dihydropyridazin-4- 515.19; Found (M+H)+
yl]amino}carbonyl)amino]-3-(4- = 515.05. methylphenyl)propanoic acid
(3S)-3-[({[l-(2-chloro-6-ethoxyben2yl)-4-hydroxy-2- 3 Calculated (M+H)+ =
oxo-2,5,6,7-tetrahydro-lH-cyclopenta[b]pyridin-3- 584.21; Found (M+H)+
yl]amino}carbonyl)amino]-3-(3- = 584.10. propoxyphenyl)propanoic acid
(3S)-3-[({[2-(2-chloro-6-ethoxybenzyl)-5-hydroxy-6- 3 Calculated (M+H)+ =
methyl-3-oxo-2,3-dihydropyridazin-4- 545.18; Found (M+H)+
yl]amino}carbonyl)amino]-3-(3- = 545.05. ethoxyphenyl)propanoic acid
(3S)-3-[({[2-(2-chloro-6-ethoxybenzyl)-5-hydroxy-6- 2 Calculated (M+H)+ =
methyl-3-oxo-2,3-dihydropyridazin-4- 559.20; Found (M+H)+
yl]amino}carbonyl)amino]-3-(3- = 559.04. isopropoxyphenyl)propanoic acid
(3S)-3-[({[l-(2-chloro-6-ethoxybenzyl)-4-hydroxy-2- 6 Calculated (M+H)+ =
oxo-2,5,6,7-tetrahydro-lH-cyclopenta[b]pyridin-3- 610.23; Found (M+H)+
yl]amino}carbonyl)amino]-3-[3- = 610.14. (cyclopentyloxy)phenyl]propanoic acid
(3S)-3-[({[l-(2-chlorobenzyl)-4-hydroxy-2-oxo- 7 Calculated (M+H)+ =
2,5,6,7-tetrahydro-lH-cyclopenta[b]pyridin-3- 566.21; Found (M+H)+
yl]amino}carbonyl)amino]-3-[3- = 566.09. (cyclopentyloxy)phenyl]propanoic acid
(3S)-3-[({[l-(2-chloro-6-ethoxybenzyl)-4-hydroxy-2- 2 Calculated (M+H)+ =
oxo-2,5,6,7-tetrahydro-lH-cyclopenta[b]pyridin-3- 526.17; Found (M+H)1"
yl]amino}carbonyl)amino]-3-phenylpropanoic acid = 526.07.
(3S)-3-[({[l-(2-chlorobenzyl)-4-hydroxy-2-oxo- 8 Calculated (M+H)+ =
2,5,6,7-tetrahydro-lH-cyclopenta[b]pyridin-3- 482.15; Found (M+H)+
yl]amino}carbonyl)amino]-3-phenylpropanoic acid =482.07.
(3S)-3-[({[l-(2-chloro-6-methylbenzyl)-4-hydroxy-5- 5 Calculated (M+H)+ =
methyl-2-oxo-l ,2-dihydropyridin-3- 512.16; Found (M+H)+
yl]amino}carbonyl)amino]-3-(2,3-dihydro-l- = 512.03. benzofuran-5-yl)propanoic acid
(3S)-3-[({[l-(2-chlorobenzyl)-4-hydroxy-2-oxo- 4 Calculated (M+H)+ =
2,5,6,7-tetrahydro-1 H-cyclopenta[b]pyridin-3- 594.21; Found (M+H)+
yl]amino}carbonyl)amino]-3-(l,3-diethyl-2-oxo-2,3- = 594.05. dihydro-1 H-benzimidazol-5-yl)propanoic acid
(3S)-3-[({[l-(2-chloro-6-ethoxybenzyl)-4-hydroxy-5- 3 Calculated (M+H)+ =
methyl-2-oxo-l,2-dihydropyridin-3- 568.15; Found (M+H)+
yl]amino}carbonyl)amino]-3-[3- = 568.00. (trifluoromethyl)phenyl]propanoic acid
(3S)-3-[({[l-(2-chloro-6-ethoxybenzyl)-4-hydroxy-5- 4 Calculated (M+H)+ =
methyl-2-oxo-l,2-dihydropyridin-3- 584.14; Found (M+H)+
yl]amino}carbonyl)amino]-3-[3- = 584.01. (trifluoromethoxy)phenyl]propanoic acid
(3S)-3-{[({l-[2-chloro-6-(2-methoxyethoxy)benzyl]-4- 6 Calculated (M-H)' =
hydroxy-2-oxo-2,5,6,7-tetrahydro-lH- 568.18; Found (M-H)"
cyclopenta[b]pyridin-3-yl}amino)carbonyl]amino}-3- = 568.03. (4-methylphenyl)propanoic acid
(3S)-3-{[({1 -[2-chloro-6-(2-methoxyethoxy)benzyl]-4- 4 Calculated (M-H)" =
hydroxy-2-oxo-2,5,6,7-tetrahydro-lH- 598.19; Found (M-H)"
cyclopenta[b]pyridin-3-yl} amino)carbonyl]amino} -3- =598.01. (3-ethoxyphenyl)propanoic acid
(3S)-3-[({[l-(2-chlorobenzyl)-4-hydroxy-2-oxo-2,5,6,7- 4 Calculated (M+H)+ =
tetrahydro-lH-cyclopenta[b]pyridin-3- 538.17; Found (M+H)+
yl]amino}carbonyl)amino]-3-[3- = 538.09. (cyclopropyloxy)phenyl]propanoic acid
(3S)-3-[({[l-(2-chloro-6-ethoxybenzyl)-4-hydroxy-5,6- 4 Calculated (M-H)' =
dimethyl-2-oxo-l,2-dihydropyridin-3- 556.19; Found (M-H)'
yl]amino}carbonyl)amino]-3-(3- = 556.02. ethoxyphenyl)propanoic acid
(3S)-3-[({[l-(2-chloro-6-ethoxybenzyl)-4-hydroxy-5,6- 4 Calculated (M-H)' =
dimethyl-2-oxo-l ,2-dihydropyridin-3- 526.17; Found (M-H)"
yl]amino}carbonyl)amino]-3-(4- = 526.02. methylphenyl)propanoic acid
(3S)-3-[({[l-(2-chloro-6-ethoxybenzyl)-5-ethyl-4- 4 Calculated (M-H)" =
hydroxy-6-methyl-2-oxo-l,2-dihydropyridin-3- 570.20; Found (M-H)"
yl]amino}carbonyl)amino]-3-(3- = 570.04. ethoxyphenyl)propanoic acid
(3S)-3-[({[l-(2-chloro-6-ethoxybenzyl)-5-ethyl-4- 4 Calculated (M-H)" =
hydroxy-6-methyl-2-oxo-l ,2-dihydropyridin-3- 540.19; Found (M-H)"
yl]amino}carbonyl)amino]-3-(4- = 540.05. methylphenyl)propanoic acid
(3S)-3-[({[l-(2-chlorobenzyl)-4-hydroxy-5-methyl-2- 25 Calculated (M+H)+ =
oxo-1,2-dihydropyridin-3-yl]amino}carbonyl)amino]-3- 562.09; Found (M+H)+
(2'-methoxy-l,l'-biphenyl-4-yl)propanoic acid = 562.17.
(3S)-3-[({[ 1 -(2-chloro-6-ethoxybenzyl)-4-hydroxy-5,6- 3 Calculated (M-H)" =
dimethyl-2-oxo-l,2-dihydropyridin-3- 570.20; Found (M-H)"
yl]amino}carbonyl)amino]-3-(3- = 570.00. isopropoxyphenyl)propanoic acid
(3S)-3-[({[ 1 -(2-chloro-6-ethoxybenzyl)-4-hydroxy-5,6- 4 Calculated (M-H)" =
dimethyl-2-oxo-l,2-dihydropyridin-3- 512.16; Found (M-H)"
yljamino}carbonyl)amino]-3-phenylpropanoic acid =512.01.
(3S)-3-[({[l-(2-chloro-6-ethoxybenzyl)-5-ethyl-4- 5 Calculated (M-H)~ =
hydroxy-6-methyl-2-oxo-1,2-dihydropyridin-3- 584.22; Found (M-H)"
yl]amino}carbonyl)amino]-3-(3- = 584.03. isopropoxyphenyl)propanoic acid
(3S)-3-[({[ 1 -(2-chloro-6-ethoxybenzyl)-5-ethyl-4- 4 Calculated (M-H)" =
hydroxy-6-methyl-2-oxo-l,2-dihydropyridin-3- 526.17; Found (M-H)"
yl]amino}carbonyl)amino]-3-phenylpropanoic acid = 526.00.
(3S)-3-[({[l-(2-chloro-6-ethoxybenzyl)-4-hydroxy-5- 6 Calculated (M-H)" =
methyl-2-oxo-1,2-dihydropyridin-3- 592.19; Found (M-H)"
yl]amino}carbonyl)amino]-3-(6-ethoxy-2- = 592.00. naphthyl)propanoic acid
(3S)-3-[({[2-(2-chlorobenzyl)-6-ethyl-5-hydroxy-3-oxo- 22 Calculated (M-H)" =
2,3-dihydropyridazin-4-yl]amino}carbonyl)amino]-3- 483.14; Found (M-H)"
(4-methylphenyl)propanoic acid =483.03.
(3S)-3-[({[l-(2-chlorobenzyl)-4-hydroxy-2-oxo-2,5,6,7- 15 Calculated (M-H)" =
tetrahydro-lH-cyclopenta[b]pyridin-3- 536.20; Found (M-H)"
yl]amino}carbonyl)amino]-3-(3- =535.99. isobutylphenyl)propanoic acid
(3S)-3-[({[l-(2-chlorobenzyl)-4-hydroxy-5-methyI-2- 4 Calculated (M+H)+ =
oxo-l,2-dihydropyridin-3-yl]amino}carbonyl)amino]-3- 509.16; Found (M+H)*
(1-methyl-lH-indol-6-yl)propanoic acid = 509.05.
(3S)-3-[({[l-(2-chloro-6-methylbenzyl)-4-hydroxy-2- 4 Calculated (M-H)" =
oxo-2,5,6,7-tetrahydro-lH-cyclopenta[b]pyridin-3- 550.17; Found (M-H)*
yl]amino}carbonyl)amino]-3-[3- = 550.01. (cyclopropyloxy)phenyl]propanoic acid
(3S)-3-[({[l-(2-chlorobenzyl)-4-hydroxy-2-oxo-2,5,6,7- 15 Calculated (M-H)' =
tetrahydro-1 H-cyclopenta[b]pyridin-3- 574.17; Found (M-H)"
yl]amino}carbonyl)amino]-3-(6-ethoxy-2- = 574.02. naphthyl)propanoic acid
(3S)-3-[({[l-(2-chloro-6-ethoxybenzyl)-4-hydroxy-2- 23 Calculated (M-H)' =
oxo-5-propyl-l,2-dihydropyridin-3- 526.17; Found (M-H)-
yl]amino}carbonyl)amino]-3-phenylpropanoic acid = 526.04.
(3S)-3-[({[l-(2-chloro-6-ethoxybenzyl)-4-hydroxy-2- 22 Calculated (M-H)" =
oxo-5-propyl-l,2-dihydropyridin-3- 584.22; Found (M-H)"
yl]amino}carbonyl)amino]-3-(3- = 584.09. isopropoxyphenyl)propanoic acid
(3S)-3-[({[l-(2-chloro-6-ethoxybenzyl)-4-hydroxy-2- 20 Calculated (M-H)" =
oxo-5-propyl-1,2-dihydropyridin-3- 540.19; Found (M-H)"
yl]amino}carbonyl)amino]-3-(4- = 540.05. methylphenyl)propanoic acid
(3S)-3-[({[l-(2-chloro-6-ethoxybenzyl)-4-hydroxy-2- 6 Calculated (M-H)" =
oxo-5-propyl-l,2-dihydropyridin-3- 570.20; Found (M-H)"
yl]amino}carbonyl)amino]-3-(3- = 570.04. ethoxyphenyl)propanoic acid
(3S)-3-[({[l-(2-chlorobenzyl)-4-hydroxy-2-oxo-l,2- 40 Calculated (M-H)" =
dihydropyridin-3-yl]amino}carbonyl)amino]-3-(4'- 530.15; Found (M-H)"
methyl-1,1 '-biphenyl~4-yl)propanoic acid = 530.02.
(3S)-3-[({[l-(2-chloroben2yl)-4-hydroxy-2-oxo-2,5,6,7- 4 Calculated (M-H)" =
tetrahydro-lH-cyclopenta[b]pyridin-3- 533.16; Found (M-H)"
yl]amino}carbonyl)amino]-3-(l-methyl-lH-indol-5- = 533.00. yl)propanoic acid
(3S)-3-[({[l-(2-chloro-6-ethoxybenzyl)-5-cyclopropyl- 3 Calculated (M-H)' =
4-hydroxy-2-oxo-l,2-dihydropyridin-3- 582.20; Found (M-H)"
yl]amino}carbonyl)amino]-3-(3- = 582.07. isopropoxyphenyl)propanoic acid
(3S)-3-[({[l-(2-chloro-6-ethoxybenzyl)-5-cyclopropyl- 3 Calculated (M-H)' =
4-hydroxy-2-oxo-l ,2-dihydropyridin-3- 538.17; Found (M-H)"
yl]amino}carbonyl)amino]-3-(4- = 538.06. methylphenyl)propanoic acid
(3S)-3-[({[l-(2-chloro-5-propoxybenzyl)-4-hydroxy-5- 6 Calculated (M-H)" =
methyl-2-oxo-1,2-dihydropyridin-3- 526.17; Found (M-H)"
yl]amino}carbonyl)amino]-3-(4- = 526.05. methylphenyl)propanoic acid
(3S)-3-[({[l-(2-chloro-5-methoxybenzyl)-4-hydroxy-5- 3 Calculated (M-H)' =
methyl-2-oxo-l,2-dihydropyridin-3- 498.14; Found (M-H)'
yl]amino}carbonyl)amino]-3-(4- = 498.01. methylphenyl)propanoic acid
3-[( {[ 1 -(2-chloro-6-ethoxybenzyl)-4-hydroxy-5-methyl- 13 Calculated (M-H)" =
2-oxo-l ,2-dihydropyridin-3-yl]amino}carbonyl)amino]- 548.16; Found (M-H)"
3-(2-naphthyl)propanoic acid = 548.01.
3-[({[l-(2-chloro-6-ethoxybenzyl)-4-hydroxy-5-methyl- 8 Calculated (M-H)" =
2-oxo-l,2-dihydropyridin-3-yl]amino}carbonyl)amino]- 576.12; Found (M-H)"
3-[4-(methylsulfonyl)phenyl]propanoic acid = 576.00.
(3S)-3-[({[l-(2-chlorobenzyl)-4-hydroxy-2-oxo-l,2- 27 Calculated (M-H)' =
dihydropyridin-3-yl]amino}carbonyl)amino]-3-(3'- 560.16; Found (M-H)'
ethoxy-1,1 '-biphenyl-4-yl)propanoic acid = 560.04.
(3S)-3-[({[l-(2-chloro-6-methylbenzyl)-4-hydroxy-2- 20 Calculated (M-H)' =
oxo-2,5,6,7-tetrahydro-lH-cyclopenta[b]pyridin-3- 564.19; Found (M-H)"
yl]amino}carbonyl)amino]-3-[3- = 564.00. (cyclobutyloxy)phenyl]propanoic acid
(3S)-3-[({[ 1 -(2-chlorobenzyl)-4-hydroxy-2-oxo-2,5,6,7- 17 Calculated (M-H)" =
tetrahydro-lH-cyclopenta[b]pyridin-3- 550.17; Found (M-H)"
yl]amino}carbonyl)amino]-3-[3- = 550.02. (cyclobutyloxy)phenyl]propanoic acid
(3S)-3-[({[l-(2-chloro-6-ethoxybenzyl)-4-hydroxy-6- 3 Calculated (M-H)' =
methyl-2-oxo-l,2-dihydropyridin-3- 556.19; Found (M-H)'
yl]amino}carbonyl)amino]-3-(3- = 556.05. isopropoxyphenyl)propanoic acid
3-[({[ 1 -(2-chlorobenzyl)-4-hydroxy-5-methyl-2-oxo- 10 Calculated (M-H)" =
l,2-dihydropyridin-3-yl]amino}carbonyl)amino]-3-(3- 523.17; Found (M-H)"
pyrrolidin-l-ylphenyl)propanoic acid = 522.99.
3-[({[l-(2-chlorobenzyl)-4-hydroxy-5-methyl-2-oxo- 22 Calculated (M-H)" =
1,2-dihydropyridin-3-yl]amino}carbonyl)amino]-3-(3- 537.19; Found (M-H)"
piperidin-l-ylphenyl)propanoic acid = 537.08.
(3S)-3-[({[l-(2-chloro-6-me%lbenzyl)-4-hydroxy-2- 22 Calculated (M-H)" =
oxo-2,5,6,7-tetrahydro-lH-cyclopenta[b]pyridin-3- 580.22; Found (M-H)"
yl]amino}carbonyl)amino]-3-[3-(l- = 580.04. ethylpropoxy)phenyl]propanoic acid
(3S)-3-[({[l-(2-chlorobenzyl)-4-hydroxy-2-oxo-2,5,6,7- 20 Calculated (M-H)" =
tetrahydro-lH-cyclopenta[b]pyridin-3- 566.20; Found (M-H)"
yl]amino}carbonyl)amino]-3-[3-(l- = 566.01. ethylpropoxy)phenyl]propanoic acid
(3S)-3-(4-chloro-3-isopropoxyphenyl)-3-[( {[1 -(2- 23 Calculated (M-H)' =
chloro-6-methylbenzyl)-4-hydroxy-2-oxo-2,5,6,7- 586.15; Found (M-H)"
tetrahydro-lH-cyclopenta[b]pyridin-3- = 585.92. yl]amino}carbonyl)amino]propanoic acid
(3S)-3-[({[l-(2-chlorobenzyl)-4-hydroxy-2-oxo-2,5,6,7- 38 Calculated (M-H)" =
tetrahydro-lH-cyclopenta[b]pyridin-3- 572.14; Found (M-H)"
yl]amino}carbonyl)amino]-3-(4-chloro-3- = 572.00. isopropoxyphenyl)propanoic acid
(3S)-3-[({[l-(2-chlorobenzyl)-4-hydroxy-2-oxo-l,2- 30 Calculated (M-H)" =
dihydropyridin-3-yl]amino}carbonyl)amino]-3-(3'- 530.15; Found (M-H)"
methyl-l,l'-biphenyl-4-yl)propanoic acid = 530.02.
(3S)-3-[({[l-(2-chlorobenzyl)-4-hydroxy-2-oxo-2,5,6,7- 3 Calculated (M-H)" =
tetrahydro-lH-cyclopenta[b]pyridin-3- 533.16; Found (M-H)"
yl]amino}carbonyl)amino]-3-(l-methyl-lH-indol-6- = 532.97. yl)propanoic acid
(3S)-3-[({[l-(2-chloro-6-ethoxybenzyl)-4-hydroxy-5- 3 Calculated (M-H)" =
methyl-2-oxo-l ,2-dihydropyridin-3- 551.17; Found (M-H)"
yl]amino}carbonyl)amino]-3-(l-methyl-lH-indol-6- = 551.02. yl)propanoic acid
(3S)-3-[({[l-(2-chlorobenzyl)-4-hydroxy-5-methyl-2- 23 Calculated (M-H)" =
oxo-1,2-dihydropyridin-3-yl]amino}carbonyl)amino]-3- 560.16; Found (M-H)'
(4'-methoxy-1,1 '-biphenyl-4-yl)propanoic acid = 560.01.
(3S)-3-[({[l-(2-chlorobenzyl)-4-hydroxy-5-methyl-2- 55 Calculated (M+H)+ =
oxo-l,2-dihydropyridin-3-yl]amino}carbonyl)amino]-3- 546.18; Found (M+H)+
(2'-methyl-1,1 '-biphenyl-4-yl)propanoic acid =546.11.
(3S)-3-[({[l-(2-chlorobenzyl)-4-hydroxy-2-oxo-2,5,6,7- 3 Calculated (M-H)" =
tetrahydro-lH-cyclopenta[b]pyridin-3- 560.16; Found (M-H)'
yl]amino}carbonyl)arnino]-3-(6-methoxy-2- = 560.00. naphthyl)propanoic acid
(3S)-3-(4-chloro-3-ethoxyphenyl)-3-[({[l-(2-chloro-6- 25 Calculated (M-H)" =
methylben2yl)-4-hydroxy-2-oxo-2,5,6,7-tetrahydro-lH- 572.14; Found (M-H)"
cyclopenta[b]pyridin-3- = 571.94. yl]amino} carbonyl)amino]propanoic acid
(3S)-3-[({[ 1 -(2-chlorobenzyl)-4-hydroxy-2-oxo-2,5,6,7- 30 Calculated (M-H)" =
tetrahydro-lH-cyclopenta[b]pyridin-3- 558.12; Found (M-H)"
yl]amino}carbonyl)amino]-3-(4-chloro-3- = 557.77'. ethoxyphenyl)propanoic acid
(3S)-3-[({[l-(2-chloro-6-ethoxybenzyl)-4-hydroxy-2- 4 Calculated (M+H)T =
oxo-2,5,6,7-tetrahydro-lH-cyclopenta[b]pyridin-3- 582.24; Found (M+H)+
yl]amino}carbonyl)amino]-3-(3- = 582.10. isobutylphenyl)propanoic acid
(3S)-3-[({[l-(2-chloro-5-ethoxybenzyl)-4-hydroxy-5- 4 Calculated (M+H)+ =
methyl-2-oxo-l,2-dihydropyridin-3- 514.17; Found (M+H)+
yl]amino}carbonyl)amino]-3-(4- = 514.08. methylphenyl)propanoic acid
3-[({[ 1 -(2-chlorobenzyl)-4-hydroxy-5-methyl-2-oxo- 134 Calculated (M+H)+ ==
l,2-dihydropyridin-3-yl]amino}carbonyl)amino]-3-[4- 534.11; Found (M+H)+
(methylsulfonyl)phenyl]propanoic acid = 534.07.
(3S)-3-[({[l-(2-chlorobenzyl)~4-hydroxy-2-oxo-2,5,6,7- 225 Calculated (M+H)+ =
tetrahydro-lH-cyclopenta[b]pyridin-3- 594.09; Found (M+H)"
yl]amino}carbonyl)amino]-3-(2,4-dichloro-3- = 593.98. ethoxyphenyl)propanoic acid
(3S)-3-{[({l-[2-chloro-5-(piperidin-l- 27 Calculated (M-H)" =
ylsulfonyl)benzyl]-4-hydroxy-5-methyl-2-oxo-1,2- 615.17; Found (M-H)"
dihydropyridin-3-yl} amino)carbonyl]amino} -3-(4- = 615.04. methylphenyl)propanoic acid
(3S)-3-{[({l-[2-chloro-5-(pyrrolidin-l- 15 Calculated (M-H)" =
ylsulfonyl)benzyl]-4-hydroxy-5-methyl-2-oxo-l,2- 601.15; Found (M-H)"
dihydropyridin-3-yl}amino)carbonyl]amino}-3-(4- = 601.03. methylphenyl)propanoic acid
(3S)-3-[({[l-(2-chloro-6-ethoxybenzyl)-4-hydroxy-2- 2 Calculated (M+H)+ =
oxo-2,5,6,7-tetrahydro-1 H-cyclopenta[b]pyridin-3- 582.20; Found (M+H)+
yl]amino}carbonyl)amino]-3-[3- = 582.10. (cyclopropyloxy)phenyl]propanoic acid
(3S)-3-{[({l-[2-chloro-6-(cyclopentylmethoxy)benzyl]- 20 Calculated (M-H)" =
4-hydroxy-5-methyl-2-oxo-1,2-dihydropyridin-3- 566.20; Found (M-H)'
yl}amino)carbonyl]amino}-3-(4- = 566.09. methylphenyl)propanoic acid
(3S)-3-{[({l-[2-(benzyloxy)-6-chlorobenzyl]-4- 10 Calculated (M-H)" =
hydroxy-5-methyl-2-oxo-l,2-dihydropyridin-3- 574.17; Found (M-H)"
yl} amino)carbonyl]amino} -3-(4- = 5 74.01. methylphenyl)propanoic acid
(3S)-3-[({[l-(2-chlorobenzyl)-4-hydroxy-2-oxo-2,5,6,7- 3 Calculated (M+H)+ =
tetrahydro-1 H-cyclopenta[b]pyridin-3 - 604.16; Found (M+H)+
yl]amino}carbonyl)amino]-3-(3-chloro-4,5- = 604.02. diethoxyphenyl)propanoic acid
(3S)-3-[({[l-(2-chloro-6-methylbenzyl)-4-hydroxy-2- 500 Calculated (M+H)+ =
oxo-2,5,6,7-tetrahydro-lH-cyclopenta[b]pyridin-3- 652.14; Found (M+H)+
yl]amino}carbonyl)amino]-3-(2,4-dichloro-3,5- = 651.98. diethoxyphenyl)propanoic acid
(3S)-3-[({[l-(2-chlorobenzyl)-4-hydroxy-2-oxo-2,5,6,7- 450 Calculated (M+H)+ =
tetrahydro-lH-cyclopenta[b]pyridin-3- 638.12; Found (M+H)+
yl]amino}carbonyl)amino]-3-(2,4-dichloro-3,5- = 637.97. diethoxyphenyl)propanoic acid
(3S)-3-[({[l-(2-chlorobenzyl)-4-hydroxy-2-oxo-2,5,6,7- 9 Calculated (M+H)+ =
tetrahydro-lH-cyclopenta[b]pyridi;, 3- 552.19; Found (M+H)+
yl]amino}carbonyl)amino]-3-[3- = 552.10. (cyclopropylmethoxy)phenyl]propanoic acid
(3S)-3-[({[l-(2-chloro-6-ethoxybenzyl)-4-hydroxy-2- 4 Calculated (M+H)+ =
oxo-2,5,6,7-tetrahydro-lH-cyclopenta[b]pyridin-3- 596.21; Found (M+H)+
yl]amino}carbonyl)amino]-3-[3- = 596.11. (cyclopropylmethoxy)phenyl]propanoic acid
(3S)-3-[({[l-(2-chloro-6-methylbenzyl)-4-hydroxy-2- 10 Calculated (M+H)+ =
oxo-2,5,6,7-tetrahydro-lH-cyclopenta[b]pyridin-3- 566.20; Found (M+H)+
yl]amino}carbonyl)amino]-3-[3- = 566.12. (cyclopropylmethoxy)phenyl]propanoic acid
(3S)-3-[({[l-(2-chlorobenzyl)-4-hydroxy-5-methyl-2- 13 Calculated (M-H)" =
oxo-1,2-dihydropyridin-3-yl]amino}carbonyl)amino]-3- 544.16; Found (M-H)"
(2,4-diethoxypyrimidin-5-yl)propanoic acid = 544.00.
(3S)-3-[({[l-(2,3-dichloro-6-ethoxybenzyl)-4-hydroxy- 5 Calculated (M-H)" =
2-oxo-2,5,6,7-tetrahydro-lH-cyclopenta[b]pyridin-3- 572.13; Found (M-H)"
yl]amino}carbonyl)amino]-3-(4- = 571.97. methylphenyl)propanoic acid
(3S)-3-[3-(cyclopropylmethoxy)phenyl]-3-[({[ 1 -(2,3- 7 Calculated (M-H)" =
dichloro-6-ethoxybenzyl)-4-hydroxy-2-oxo-2,5,6,7- 628.16; Found (M-H)"
tetrahydro-1 H-cyclopenta[b]pyridin-3 - =627.98. yl]amino} carbonyl)amino]propanoic acid
(3S)-3-[({[l-(2,3-dichloro-6-ethoxybenzyl)-4-hydroxy- 3 Calculated (M-H)" =
2-oxo-2,5,6,7-tetrahydro-lH-cyclopenta[b]pyridin-3- 602.15; Found (M-H)"
yl]amino}carbonyl)amino]-3-(3- = 601.99. ethoxyphenyl)propanoic acid
(3S)-3-[({[l-(2,3-dichloro-6-ethoxybenzyl)-4-hydroxy- 5 Calculated (M-H)" =
2-oxo-2,5,6,7-tetrahydro-lH-cyclopenta[b]pyridin-3- 616.16; Found (M-H)"
yl]amino}carbonyl)amino]-3-(3- = 616.01. isopropoxyphenyl)propanoic acid
(3S)-3-({[[ 1 -(2-chlorobenzyl)-4-methoxy-2-oxo-l,2- 2000 Calculated (M-H)" =
dihydropyridin-3-yl](methyl)amino]carbonyl}amino)-3- 482.14; Found (M-H)"
(4-methylphenyl)propanoic acid = 482.07.
(3S)-3-[({[l-(2-chlorobenzyl)-4-hydroxy-5-methyl-2- 15 Calculated (M-H)" =
oxo-l,2-dihydropyridin-3-yl]amino}carbonyl)amino]-3- 560.16; Found (M-H)"
(2'-methoxy-l,r-biphenyl-3-yl)propanoic acid = 559.98.
3-[({[l-(2-chlorobenzyl)-4-hydroxy-5-methyl-2-oxo- 20 Calculated (M-H)" =
l,2-dihydropyridin-3-yl]amino}carbonyl)amino]-3-(5- 458.11; Found (M-H)"
methyl-2-furyl)propanoic acid = 457.99.
3-[({[l-(2-chloro-6-methylbenzyl)-4-hydroxy-5-methyl- 43 Calculated (M+H)+ =
2-oxo-l,2-dihydropyridin-3-yl]amino}carbonyl)amino]- 548.13; Found (M+H)+
3-[4-(methylsulfonyl)phenyl]propanoic acid = 548.07.
3-[({[l-(2-chlorobenzyl)-4-hydroxy-2-oxo-2,5,6,7- 5 Calculated (M-H)" =
tetrahydro-1 H-cyclopenta[b]pyridin-3- 470.11; Found (M-H)"
yl]amino}carbonyl)amino]-3-(2-fiiryl)propanoic acid = 469.96.
3-[({[l-(2-chlorobenzyl)-4-hydroxy-5-methyl-2-oxo- 4 Calculated (M-H)" =
l,2-dihydropyridin-3-yl]amino}carbonyl)amino]-3-(2- 444.10; Found (M-H)"
furyl)propanoic acid = 443.91.
(3S)-3-[({[l-(2-chlorobenzyl)-4-hydroxy-2-oxo-2,5,6,7- 18 Calculated (M-H)" =
tetrahydro-lH-cyclopenta[b]pyridin-3- 548.12; Found (M-H)"
yl]amino}carbonyl)amino]-3-[4- = 548.00. (trifluoromethyl)phenyl]propanoic acid
(3S)-3-[({[l-(2-chlorobenzyl)-4-hydroxy-2-oxo-2,5,6,7- 5 Calculated (M-H)' =
tetrahydro-1 H-cyclopenta[b]pyridin-3 - 494.15; Found (M-H)~
yl]amino}carbonyl)amino]-3-(3- = 494.02. methylphenyl)propanoic acid
(3S)-3-[({[l-(2-chlorobenzyl)-4-hydroxy-2-oxo-2,5,6,7- 10 Calculated (M-H)" =
tetrahydro-lH-cyclopenta[b]pyridin-3- 548.12; Found (M-H)"
yl]amino}carbonyl)amino]-3-[3- = 547.99. (trifluoromethyl)phenyl]propanoic acid
(3S)-3-[({[l-(2-chlorobenzyl)-4-hydroxy-2-oxo-2,5,6,7- 9 Calculated (M-H)" =
tetrahydro-lH-cyclopenta[b]pyridin-3- 508.16; Found (M-H)"
yl]amino}carbonyl)amino]-3-(3,5- = 508.02. dimethylphenyl)propanoic acid
(3S)-3-[3)5-bis(trifluoromethyl)phenyl]-3-[({[l-(2- 130 Calculated (M-H)" =
chlorobenzyl)-4-hydroxy-2-oxo-2,5,6,7-tetrahydro-lH- ol5.11; Found (M-H)"
cyclopenta[b]pyridin-3- = 615.99. yl]amino}carbonyl)amino]propanoic acid
(3S)-3- {[({1 -[2-chloro-5-(trifluoromethyl)benzyl]-4- 6 Calculated (M-H)" =
hydroxy-5-methyl-2-oxo-l,2-dihydropyridin-3- 536.12; Found (M-H)'
yl}amino)carbonyl]amino}-3-(4- = 535.99. methylphenyl)propanoic acid
(3S)-3-[({[l-(2-chloro-5-fluorobenzyl)-4-hydroxy-5- 5 Calculated (M-H)" =
methyl-2-oxo-l,2-dihydropyridin-3- 486.12; Found (M-H)"
yl]amino}carbonyl)amino]-3-(4- = 485.97. methylphenyl)propanoic acid
(3S)-3-[({[l-(2-chlorobenzyl)-4-hydroxy-5-methyl-2- 2 Calculated (M-H)" =
oxo-l,2-dihydropyridin-3-yl]amino}carbonyl)amino]-3- 525.19; Found (M-H)"
[3-(diethylamino)phenyl]propanoic acid = 525.00.
3-(l,l'-biphenyl-4-yl)-3-[({[l-(2-chlorobenzyl)-4- 30 Calculated (M-H)" =
hydroxy-2-oxo-2,5,6,7-tetrahydro-lH- 556.16; Found (M-H)"
cyclopenta[b]pyridin-3- = 555.99. yl]amino}carbonyl)amino]propanoic acid
(3S)-3-[({[l-(2-chlorobenzyl)-4-hydroxy-2-oxo-2,5,6,7- 8 Calculated (M+H)+ =
tetrahydro-1 H-cyclopenta[b]pyridin-3- 522.17; Found (M+H)+
yl]amino}carbonyl)amino]-3-(2,3-dihydro-lH-inden-5- = 522.03. yl)propanoic acid
(3S)-3-[({[ 1 -(2-chloro-6-methylbenzyl)-4-hydroxy-2- 10 Calculated (M+H)+ =
oxo-2,5,6,7-tetrahydro-lH-cyclopenta[b]pyridin-3- 536.19; Found (M+H)+
yl]amino}carbonyl)amino]-3-(2,3-dihydro-lH-inden-5- = 536.08. yl)propanoic acid
N-{l-[(2-chlorophenyl)methyl]-4-hydroxy-5-methyl- 6000 Calculated (M+H)+ =
2-oxo-l,2-dihydro-3-pyridinyl}-N'-[(lS)-l-(4- 494.17; Found (M+H)+
methylphenyl)-2-(lH-l,2,3,4-tetraazol-5-yl)ethyl]urea = 494.01.
(3S)-3-[l,l'-biphenyl]-3-yl-3-{[({l-[(2- 17 Calculated (M-H)" =
chlorophenyl)methyl]-4-hydroxy-2-oxo-2,5,6,7- 556.16; Found (M-H)"
tetrahydro-lH-cyclopenta[b]pyridin-3- = 556.01. yl} amino)carbonyl]amino} propanoic ac id
(3S)-3-{[({l-[(2-chlorophenyl)methyl]-4-hydroxy-2- 13 Calculated (M-H)" =
oxo-2,5,6,7-tetrahydro-lH-cyclopenta[b]pyridin-3- 564.11; Found (M-H)"
yl}amino)carbonyl]amino}-3-{4- = 564.01. [(trifluoromethyl)oxy]phenyl}propanoicacid
(3S)-3-{[({l-[(2-chlorophenyl)methyl]-4-hydroxy-2- 13 Calculated (M-H)" =
oxo-2,5,6,7-tetrahydro-lH-cyclopenta[b]pyridin-3- 546.12; Found (M-H)'
yl}amino)carbonyl]amino}-3-{4- = 545.97. [(difluoromethyl)oxy]phenyl}propanoic acid
(3S)-3-{[({l-[(2-chlorophenyl)methyl]-4-hydroxy-2- 10 Calculated (M-H)" =
oxo-2,5,6,7-tetrahydro-lH-cyclopenta[b]pyridin-3- 564.11; Found (M-H)"
yl}amino)carbonyl]amino}-3-{3- = 563.98. [(trifluoromethyl)oxy]phenyl}propanoic acid
(3S)-3- {[({1 -[(2-chlorophenyl)methyl]-4-hydroxy-2- 5 Calculated (M-H)" =
oxo-2,5,6,7-tetrahydro-lH-cyclopenta[b]pyridin-3- 546.12; Found (M-H)"
yl}amino)carbonyl]amino}-3-{3- = 546.01. [(difluoromethyl)oxy]phenyl}propanoic acid
(3S)-3- {[({1 -[(2-chlorophenyl)methyl]-4-hydroxy-2- 4 Calculated (M-H)" =
oxo-2,5,6,7-tetrahydro-lH-cyclopenta[b]pyridin-3- 596.12; Found (M-H)"
yl}amino)carbonyl]amino}-3-{3-[(l, 1,2,2- = 596.02. tetrafluoroethyl)oxy]phenyl}propanoic acid
(3S)-3-{[({l-[(2-chlorophenyl)methyl]-4-hydroxy-2- 11 Calculated (M-H)" =
oxo-2,5,6,7-tetrahydro-lH-cyclopenta[b]pyridin-3- 538.17; Found (M-H)"
yl}amino)carbonyl]amino}-3-[3,5-dimethyl-4- = 538.04. (methyloxy)phenyl]propanoic acid
(3S)-3- {[({1 -[(2-chlorophenyl)methyl]-4-hydroxy-2- 5 Calculated (M+Hf =
oxo-2,5,6,7-tetrahydro-lH-cyclopenta[b]pyridin-3- 549.19; Found (M+H)+
yl}amino)carbonyl]amino}-3-(l-ethyl-lH-indol-5- = 549.02. yl)propanoic acid
(3S)-3-{[({l-[(2-chlorophenyl)methyl]-4-hydroxy-2- 7 Calculated (M-H)" =
oxo-2,5,6,7-tetrahydro-lH-cyclopenta[b]pyridin-3- 516.11; Found (M-H)"
yl}amino)carbonyl]amino}-3-(3,5- = 516.01. difluorophenyl)propanoic acid
(3 S)-3 - {[({1 -[(2-chlorophenyl)methyl] -4-hydroxy-2- 3 Calculated (M-H)" =
oxo-2,5,6,7-tetrahydro-lH-cyclopenta[b]pyridin-3- 528.13; Found (M-H)"
yl}amino)carbonyl]amino}-3-[3-fluoro-4- = 528.00. (methyloxy)phenyl]propanoic acid
(3 S)-3 - {[({1 -[(2-chlorophenyl)methyl] -4-hydroxy-2- 17 Calculated (M-H)" =
oxo-2,5,6,7-tetrahydro-lH-cyclopenta[b]pyridin-3- 522.18; Found (M-H)"
yl}amino)carbonyl]amino}-3-(4- = 522.04. propylphenyl)propanoic acid
(3S)-3-{[({1 -[(2-chloro-6-methylphenyl)methyl]-4- 20 Calculated (M-H)" =
hydroxy-2-oxo-2,5,6,7-tetrahydro-lH- 536.20; Found (M-H)"
cyclopenta[b]pyridin-3-yl}amino)carbonyl]amino}-3- = 536.06. (4-propylphenyl)propanoic acid
(3S)-3-{[({l-[(2-chlorophenyl)methyl]-4-hydroxy-5- 267 Calculated (M-H)" =
methyl-2-oxo-l,2-dihydro-3- 468.13; Found (M-H)"
pyridinyl}amino)carbonyl]amino}-3-(2- = 468.00. methylphenyl)propanoic acid
(3S)-3-{[({1 -[(2-chlorophenyl)methyl]-4-hydroxy-2- 25 Calculated (M+H)+ =
oxo-2,5,6,7-tetrahydro-lH-cyclopenta[b]pyridin-3- 522.18; Found (M+H)+
yl}amino)carbonyl]amino}-3-(4- = 522.04. cyclopropylphenyl)propanoic acid
(3S)-3-{[({l-[(2-chlorophenyl)methyl]-4-hydroxy-5- 22 Calculated (M-H)" =
methyl-2-oxo-l,2-dihydro-3- 505.13; Found (M-H)"
pyridinyl}amino)carbonyl]amino}-3-(3- = 504.98. quinolinyl)propanoic acid
(3S)-3-{[({l-[(2-chlorophenyl)methyl]-4-hydroxy-2- 22 Calculated (M-H)" =
oxo-2,5,6,7-tetrahydro-lH-cyclopenta[b]pyridin-3- 531.14; Found (M-H)"
yl}amino)carbonyl]amino}-3-(3-quinolinyl)propanoic = 530.99. acid
3-({[(l-{[2-chloro-6-(ethyloxy)phenyl]methyl}-4- 8 Calculated (M-H)" =
hydroxy-5-methyl-2-oxo-l,2-dihydro-3- 488.12; Found (M-H)"
pyridinyl)amino]carbonyl}amino)-3-(2- = 487.98. furanyl)propanoic acid
(3S)-3-[2,4-bis(ethyloxy)-5-pyrimidinyl]-3-{[({l-[(2- 15 Calculated (M-H)" =
chlorophenyl)methyl]-4-hydroxy-2-oxo-2,5,6,7- 570.18; Found (M-H)"
tetrahydro-1 H-cyclopenta[b]pyridin-3 - =570.14. yl}amino)carbonyl]amino}propanoic acid
(3S)-3-{[({l-[(2-chloro-6-methylphenyl)methyl]-4- 19 Calculated (M+H)+ =
hydroxy-2-oxo-2,5,6,7-tetrahydro-lH- 536.20; Found (M+H)+
cyclopenta[b]pyridin-3-yl}amino)carbonyl]amino}-3- = 536.07. (4-cyclopropylphenyl)propanoic acid
(3R)-3-{[({1 -[(2-chlorophenyl)methyl]-4-hydroxy-2- 15 Calculated (M-H)" =
oxo-2,5,6,7-tetrahydro-lH-cyclopenta[b]pyridin-3- 418.12; Found (M-H)'
yl}amino)carbonyl]amino}butanoic acid =418.00.
(3S)-3- {[({1 -[(2-chlorophenyl)methyl]-4-hydroxy-2- 8 Calculated (M-H)' =
oxo-2,5,6,7-tetrahydro-lH-cyclopenta[b]pyridin-3- 508.16; Found (M-H)"
yl}amino)carbonyl]amino}-3-(4- = 508.06. ethylphenyl)propanoic acid
(3S)-3-{[({l-[(2-chlorophenyl)methyl]-4-hydroxy-2- 17 Calculated (M-H)' =
oxo-2,5,6,7-tetrahydro-lH-cyclopenta[b]pyridin-3- 522.17; Found (M-H)"
yl}amino)carbonyl]amino}-3-[4-(l- = 522.06. methylethyl)phenyl]propanoic acid
(3S)-3-{[({l-[(2-chlorophenyl)methyl]-4-hydroxy-5- 30 Calculated (M-H)" =
methyl-2-oxo-l,2-dihydro-3- 482.14; Found (M-H)"
pyridinyl}amino)carbonyl]amino}-3-(4- = 482.00. ethylphenyl)propanoic acid
(3S)-3-{[({l-[(2-chlorophenyl)methyl]-4-hydroxy-5- 175 Calculated (M-H)' =
methyl-2-oxo-1,2-dihydro-3- 496.16; Found (M-H)"
pyridinyl}amino)carbonyl]amino}-3-[4-(l- = 496.01. methylethyl)phenyl]propanoic acid
(3S)-3-{[({l-[(2-chlorophenyl)methyl]-4-hydroxy-5- 6 Calculated (M-H)" =
methyl-2-oxo-1,2-dihydro-3- 510.14; Found (M-H)"
pyridinyl}amino)carbonyl]amino}-3-[4- = 510.00. (cyclopropyloxy)phenyl]propanoic acid
(3S)-3-{[({l-[(2-chlorophenyl)methyl]-4-hydroxy-5- 12 Calculated (M-H)" =
methyl-2-oxo-1,2-dihydro-3- 496.16; Found (M-H)"
pyridinyl}amino)carbonyl]amino}-3-(4- = 495.99. propylphenyl)propanoic acid
3-{[({1 -[(2-chlorophenyl)methyl]-4-hydroxy-5- 35 Calculated (M-H)" =
methyl-2-oxo-1,2-dihydro-3- 494.15; Found (M-H)"
pyridinyl}amino)carbonyl]amino}-3-(4- = 494.01. cyclopropylphenyl)propanoic acid
(3S)-3-{[({l-[(2-chlorophenyl)methyl]-4-hydroxy-5- 18 Calculated (M-H)" =
methyl-2-oxo-1,2-dihydro-3- 494.15; Found (M-H)"
pyridinyl}amino)carbonyl]amino}-3-(2,3-dihydro- = 494.02. lH-inden-5-yl)propanoic acid
(3S)-3-{[({l-[(2-chlorophenyl)methyl]-4-hydroxy-2- 13 Calculated (M-H)" =
oxo-2,5,6,7-tetrahydro-lH-cyclopenta[b]pyridin-3- 597.19; Found (M-H)"
yl}amino)carbonyl]amino}-3-(9-ethyl-9H-carbazoi-3- = 597.01. yl)propanoic acid
(3S)-3-{[({1 -[(2-chlorophenyl)methyl]-4-hydroxy-5- 23 Calculated (M-H)" =
methyl-2-oxo-1,2-dihydro-3- 571.17; Found (M-H)"
pyridinyl}amino)carbonyl]amino}-3-(9-ethyl-9H- = 570.99. carbazol-3-yl)propanoic acid
(3S)-3-{[({l-[(2-chloro-6-methylphenyl)methyl]-4- 3 Calculated (M-H)" =
hydroxy-2-oxo-2,5,6,7-tetrahydro-lH- 547.17; Found (M-H)'
cyclopenta[b]pyridin-3-yl}amino)carbonyl]amino}-3- = 547.04. (1 -methyl-1 H-indol-5-yl)propanoic acid
(3S)-3-{[({l-[(2-chloro-6-methylphenyl)methyl]-4- 3 Calculated (M-H)" =
hydroxy-2-oxo-2,5,6,7-tetrahydro-lH- 560.14; Found (M-H)"
cyclopenta[b]pyridin-3-yl}amino)carbonylJamino}-3- = 560.03. {3-[(difluoromethyl)oxy]phenyl}propanoic acid
(3S)-3-{[({l-[(2-chlorophenyl)methyl]-4-hydroxy-5- 25 Calculated (M-H)" =
methyl-2-oxo-l,2-dihydro-3- 574.17; Found (M-H)"
pyridinyl}amino)carbonyl]amino}-3-[2- = 574.00. (ethyloxy)[ 1,1 '-biphenyl]-4-yl]propanoic acid
(3S)-3-{[({l-[(2-chlorophenyl)methyl]-4-hydroxy-2- 20 Calculated (M-H)" =
oxo-2,5,6,7-tetrahydro-lH-cyclopenta[b]pyridin-3- 600.19; Found (M-H)"
yl}amino)carbonyl]amino}-3-[2-(ethyloxy)[l,l'- = 600.01. biphenyl]-4-yl]propanoic acid
(3S)-3-{[({l-[(2-chlorophenyl)methyl]-4-hydroxy-5- 20 Calculated (M-H)" =
methyl-2-oxo-1,2-dihydro-3- 544.16; Found (M-H)"
pyridinyl}amino)carbonyl]amino}-3-(2'-methyl[l,l'- = 544.04. biphenyl]-3-yl)propanoic acid
(3S)-3-{[({l-[(2-chlorophenyl)methyl]-4-hydroxy-5- 18 Calculated (M-H)" =
methyl-2-oxo-1,2-dihydro-3- 544.16; Found (M-H)"
pyridinyl}amino)carbonyl]amino}-3-(3'-methyl[l,l'- = 544.00. biphenyl]-3-yl)propanoic acid
(3S)-3-({[(l-{[2-chloro-6-tetrahydro-l(2H)- 90 Calculated (M-H)" =
pyridinylphenyl]methyl}-4-hydroxy-5-methyl-2-oxo- 551.21; Found (M-H)"
1,2-dihydro-3-pyridinyl)amino]carbonyl} amino)-3-(4- = 551.06. methylphenyl)propanoic acid
(3S)-3- {[({1 -[(2-chlorophenyl)methyl]-4-hydroxy-5- 23 Calculated (M-H)" =
methyl-2-oxo-1,2-dihydro-3- 544.16; Found (M-H)"
pyridinyl}amino)carbonyl]amino}-3-(4'-methyl[l,r- = 543.99. biphenyl]-3-yl)propanoic acid
(3S)-3-{[({l-[(2-chlorophenyl)methyl]-4-hydroxy-2- 3 Calculated (M-H)" =
oxo-2,5,6,7-tetrahydro-lH-cyclopenta[b]pyridin-3- 551.21; Found (M-H)"
yl}amino)carbonyl]amino}-3-[3- = 551.05. (diethylamino)phenyl]propanoic acid
(3S)-3- {[({1 -[(2-chlorophenyl)methyl]-4-hydroxy-5- 20 Calculated (M-H)" =
methyl-2-oxo-1,2-dihydro-3- 504.11; Found (M-H)"
pyridinyl}amino)carbonyl]amino}-3-[3- = 503.96. (difluoromethyl)phenyl]propanoic acid
(3S)-3- {[({1 -[(2-chlorophenyl)methyl]-4-hydroxy-2- 16 Calculated (M-H)" =
oxo-2,5,6,7-tetrahydro-lH-cyc1openta[b]pyridin-3- 498.12; Found (M-H)"
yl}amino)carbonyl]amino}-3-(3- = 498.02. fluorophenyl)propanoic acid
(3S)-3-{[({1 -[(2-chlorophenyl)methyl]-4-hydroxy-2- 9 Calculated (M-H)* =
oxo-2,5,6,7-tetrahydro-lH-cyclopenta[b]pyridin-3- 498.12; Found (M-H)"
yl}amino)carbonyl]amino}-3-(4- = 498.01. fluorophenyl)propanoic acid
N- {1 -[(2-chlorophenyl)methyl]-4-hydroxy-5-methyl- > 10000 Calculated (M-H)" =
2-oxo-l,2-dihydro-3-pyridinyl}-N'-[(R)-phenyl(lH- 464.12; Found (M-H)"
1,2,3,4-tetraazol-5-yl)methyl]urea = 464.01.
(3S)-3-{[({l-[(2-chloro-6-methylphenyl)methyl]-4- 4 Calculated (M-H)" =
hydroxy-5-methyl-2-oxo-l,2-dihydro-3- 521.16; Found (M-H)"
pyridinyl}amino)carbonyl]amino}-3-(1-methyl-1H- = 521.00. indol-5-yl)propanoic acid
(3S)-3-{[({l-[(2-chloro-6-methylphenyl)methyl]-4- 10 Calculated (M-H)" =
hydroxy-2-oxo-2,5,6,7-tetrahydro-lH- 565.14; Found (M-H)"
cyclopenta[b]pyridin-3-yl}amino)carbonyl]amino}-3- = 565.04. [3 -(diethylamino)phenyl]propanoic acid
(3S)-3-{[({l-[(2-chloro-6-methylphenyl)methyl]-4- 4 Calculated (M-H)" =
hydroxy-2-oxo-2,5,6,7-tetrahydro-lH- 508.16; Found (M-H)"
cyclopenta[b]pyridin-3-yl}amino)carbonyl]amino}-3- = 508.03. (3-methylphenyl)propanoic acid
(3S)-3-{[({1 -[(2-chloro-6-methylphenyl)methyl]-4- 17 Calculated (M-H)" =
hydroxy-2-oxo-2,5,6,7-tetrahydro-lH- 494.15; Found (M-H)'
cyclopenta[b]pyridin-3-yl}amino)carbonyl]amino}-3- = 494.09. phenylpropanoic acid
(3S)-3-{[({l-[(2-chlorophenyl)methyl]-4-hydroxy-2- 8 Calculated (M-H)' =
oxo-2,5,6,7-tetrahydro-lH-cyclopenta[b]pyridin-3- 496.13; Found (M-H)"
yl}amino)carbonyl]amino}-3-(3- = 495.99. hydroxyphenyl)propanoic acid
(3S)-3-{[({l-[(2-chlorophenyl)methyl]-4-hydroxy-5- 9 Calculated (M-H)" =
methyl-2-oxo-1,2-dihydro-3- 470.11; Found (M-H)"
pyridinyl}amino)carbonyl]amino}-3-(3- = 469.98. hydroxyphenyl)propanoic acid
(3S)-3- {[({1 -[(2-chlorophenyl)methyl]-4-hydroxy-5- 50 Calculated (M-H)" =
methyl-2-oxo-1,2-dihydro-3- 558.18; Found (M-H)-
pyridinyl}amino)carbonyl]amino}-3-(3',5'- = 558.00. dimethyl [ 1,1 '-biphenyl]-3-yl)propanoic acid
(3S)-3-{[({l-[(2-chlorophenyl)methyl]-4-hydroxy-5- 15 Calculated (M-H)" =
methyl-2-oxo-l,2-dihydro-3- 455.12; Found (M-H)-
pyridinyl}amino)carbonyl]amino}-3-phenylpropanoic = 454.00. acid
(3S)-3-{[({l-[(2-chlorophenyl)methyl]-4-hydroxy-2- 3 Calculated (M-H)" =
oxo-2,5,6,7-tetrahydro-lH-cyclopenta[b]pyridin-3- 573.12; Found (M-H)-
yl} amino)carbonyl] amino}-3-{3- =572.98. [(methylsulfonyl)amino]phenyl} propanoic acid
(3S)-3- {[({1 -[(2-chloro-6-methylphenyl)methyl]-4- 3 Calculated (M-H)" =
hydroxy-2-oxo-2,5,6,7-tetrahydro-i H- 587.14; Found (M-H)-
cyclopenta[bJpyridin-3-yl}amino)carbonyl]amino}-3- = 586.98. {3-[(methylsulfonyl)amino]phenyl}propanoic acid
(3S)-3-{[({1 -[(2-chlorophenyl)methyl]-4-hydroxy-2- 4 Calculated (M-H)" =
oxo-2,5,6,7-tetrahydro-1 H-cyclopenta[b]pyridin-3- 530.13; Found (M-H>
yl}amino)carbonyl]amino}-3-[3- = 530.03. (difluoromethyl)phenyl]propanoic acid
(2S,3S)-3-{[({l-[(2-chlorophenyl)methyl]-4-hydroxy- 1500 Calculated (M-H)" =
5-methyl-2-oxo-l,2-dihydro-3- 482.15; Found (M-H)-
pyridinyl}amino)carbonyl]amino}-2-methyl-3-(4- = 481.99. methylphenyl)propanoic acid
(3S)-3-{[({1 -[(2-chloro-6-methylphenyl)methyl]-4- 15 Calculated (M-H)" =
hydroxy-2-oxo-2,5,6,7-tetrahydro-lH- 522.18; Found (M-H)-
cyclopenta[b]pyridin-3-yl}amino)carbonyl]amino}-3- = 522.04. (4-ethylphenyl)propanoic acid
(3S)-3- {[({1 -[(2-chlorophenyl)methyl]-4-hydroxy-2- 3 Calculated (M-H)" =
oxo-2,5,6,7-tetrahydro-lH-cyclopenta[b]pyridin-3- 550.17; Found (M-H)-
yl}amino)carbonyl]amino}-3-(2,2-dimethyl-2,3- = 550.05. dihydro-1 -benzofuran-5-yl)propanoic acid
(3S)-3-{[({1 -[(2-chloro-6-methylphenyl)methyl]-4- 3 Calculated (M-H)" =
hydroxy-2-oxo-2,5,6,7-tetrahydro-lH- 542.15; Found (M-H)-
cyclopenta[b]pyridin-3-yl}amino)carbonyl]amino}-3- = 542.00. [3-fluoro-4-(methyloxy)phenyl]propanoic acid
(3S)-3-{[({l-[(2-chloro-6-methylphenyl)methyl]-4- 11 Calculated (M-H) =
hydroxy-2-oxo-2,5,6,7-tetrahydro-lH- 578.13; Found (M-H)-
cyclopenta[b]pyridin-3-yl}amino)carbonyl]amino}-3- = 578.02. {3 -[(trifluoromethyl)oxy]phenyl} propanoic acid
(3S)-3-{[({l-[(2-chlorophenyl)methyl]-4-hydroxy-2- 1.6 Calculated (M-H)" =
oxo-2,5,6,7-tetrahydro-lH-cyclopenta[b]pyridin-3- 587.14; Found (M-H)-
yl}amino)carbonyl]amino}-3-{3- = 586.99. [methyl(methylsulfonyl)amino]phenyl} propanoic acid
(3S)-3-{[({1 -[(2-chloro-6-methylphenyl)methyl]-4- 1.3 Calculated (M-H)" =
hydroxy-2-oxo-2,5,6,7-tetrahydro-1H- 601.15; Found (M-H)-
cyclopenta[b]pyridin-3-yl}amino)carbonyl]amino}-3- = 601.00. {3-[methyl(methylsulfonyl)amino]phenyl}propanoic acid
(3S)-3-{[({l-[(2-chlorophenyl)methyl]-4-hydroxy-2- 1 Calculated (M-H)" =
oxo-2,5,6,7-tetrahydro-lH-cyclopenta[b]pyridin-3- 601.15; Found (M-H)-
yl}amino)carbonyl]amino}-3-{3- = 601.00. [ethyl(methylsulfonyl)amino]phenyl}propanoic acid
(3S)-3-{[({l-[(2-chloro-6-methylphenyl)methyl]-4- 1 Calculated (M-H)" =
hydroxy-2-oxo-2,5,6,7-tetrahydro-lH- 615.17; Found (M-H)-
cyclopenta[b]pyridin-3-yl}amino)carbonyl]amino}-3- = 615.04. {3-[ethyl(methylsulfonyl)amino]phenyl}propanoic acid
(3S)-3-{[({1 -[(2-chlorophenyl)methyl]-4-hydroxy-5- 25 Calculated (M-H)' =
methyl-2-oxo-l,2-dihydro-3- 548.14; Found (M-H)-
pyridinyl}amino)carbonyl]amino}-3-(2'-fluoro[l,r- = 547.96. biphenyl]-3-yl)propanoic acid
(3S)-3-{[({l-[(2-chlorophenyl)methyl]-4-hydroxy-5- 157 Calculated (M-H)" =
methyl-2-oxo-l,2-dihydro-3- 598.14; Found (M-H)-
pyridinyl}amino)carbonyl]amino}-3-[2'- = 597.97. (trifluoromethyl)f 1,1 '-biphenyl]-3-yl]propanoic acid
(3S)-3-{[({l-[(2-chlorophenyl)methyl]-4-hydroxy-5- 10 Calculated (M-H)" =
methyl-2-oxo-l,2-dihydro-3- 472.11; Found (M-H)-
pyridinyl}amino)carbonyl]amino}-3-(2- = 471.98. fluorophenyl)propanoic acid
(3S)-3-{[({l-[(2-chloro-6-methylphenyl)methyl]-4- 2 Calculated (M-H)- =
hydroxy-2-oxo-2,5,6,7-tetrahydro-lH- 533.16; Found (M-H)-
cyclopenta[b]pyridin-3-yl} amino)carbonyl]amino} -3- =533.01. (lH-indol-5-yl)propanoic acid
(3S)-3-{[({l-[(2-chloro-6-methylphenyl)methyl]-4- 11 Calculated (M-H)" =
hydroxy-2-oxo-2,5,6,7-tetrahydro-1H- 530.13; Found (M-H)-
cyclopenta[b]pyridin-3-yl}amino)carbonyl]amino}-3- = 530.00. (3,5-difluorophenyl)propanoic acid
SEQUENCE LISTING
(1) GENERAL INFORMATION:
(i) APPLICANT: Biediger, Ronald J.; Chen, Qi; Decker, E. Radford; Holland, George W.; Kassir, Jamal M.; Li, Wen; Market, Robert V.; Scott, Ian L.; Wu, Chengde; and Li, Jian.
(ii) TITLE OF INVENTION: Carboxylic Acid Derivatives that Inhibit the Binding of Integrins to their Receptors
(iii) NUMBER OF SEQUENCES: 1
(iv) CORRESPONDENCE ADDRESS:
(A) ADDRESSEE: Rockey, Milnamow & Katz, Ltd.
(B) STREET: 180 N. Stetson Avenue, 2 Prudential Plaza, Suite 47
(C) CITY: Chicago
(D) STATE: Illinois
(E) COUNTRY: U.S A.
(F) ZIP: 60601
(v) COMPUTER READABLE FORM:
(A) MEDIUM TYPE: Floppy disk
(B) COMPUTER: IBM PC compatible
(C) OPERATING SYSTEM: PC-DOS/MS-DOS
(D) SOFTWARE: Patentln Release #1.0, Version #1.30
(vi) CURRENT APPLICATION DATA:
(A) APPLICATION NUMBER:
(B) FILING DATE:
(C) CLASSIFICATION:
(viii) ATTORNEY/AGENT INFORMATION:
(A) NAME: Katz, Martin L.
(B) REGISTRATION NUMBER: 25,011
(C) REFERENCE/DOCKET NUMBER: TEX4542P0402US
(ix) TELECOMMUNICATION INFORMATION:
(A) TELEPHONE: 312-616-5400
(B) TELEFAX: 312-616-5460
(2) INFORMATION FOR SEQ ID NO: 1: (i) SEQUENCE CHARACTERISTICS:
(A) LENGTH: 26 amino acids
(B) TYPE: amino acid
(C) STRANDEDNESS: single
(D) TOPOLOGY: linear
(ii) MOLECULE TYPE: protein
(xi) SEQUENCE DESCRIPTION: SEQ ID NO: 1:
Cys Asp Glu Leu Pro Gin Leu Val Thr Leu Pro His Pro Asn Leu His
15 10 15
Gly Pro Glu lie Leu Asp Val Pro Ser Thr
20 25 I
All references cited are hereby incorporated by reference.
The present invention is illustrated by way of the foregoing description and examples. The foregoing description is intended as a non-limiting illustration, since many variations will become apparent to those skilled in the art in view thereof. It is intended that all such variations within the scope and spirit of the appended claims be embraced thereby.
Changes can be made in the composition, operation and arrangement of the method of the present invention described herein without departing from the concept and scope of the invention as defined in the following claims:
i
wherein T is selected from the group consisting of C(O) and (CH2)b wherein b is an the
integer of 0 to 3 ;
L is selected from the group consisting of O, NR", S, and (CH2)n wherein n is
an the integer of 0 to 1 ;
B, R4 R5, R6, R7, R9, R10 and R11 at each occurrence are independently selected from the group consisting of hydrogen, halogen, hydroxyl, alkyl, alkenyl, alkynyl, alkoxy, alkenoxy, alkynoxy, thioalkoxy, hydroxyalkyl, aliphatic acyl, -CF3, nitro, amino, cyano, carboxy, -N(C1-C3 alkyl)-C(O)(C1-C3 alkyl), -NHC(O)N(C1-C3 alkyl)C(O)NH(C1-C3 alkyl), NHC(O)NH(C1-C6 alkyl), alkylamino, alkenylamino, di(C1-C3)arnino, -C(O)O-(C1-C3)alkyl, -C(O)NH-(C1-C3)alkyl, -C(O)N(C1-C3 alkyl)2, -CH=NOH, -PO3H2, -OPO3H2, haloalkyl, alkoxyalkoxy, carboxaldehyde, carboxamide, cycloalkyl, cycloalkenyl, cycloalkynyl, cycloalkylalkyl, aryl, aroyl, aryloxy, arylamino, biaryl, thioaryl, diarylamino, heterocyclyl, alkylaryl, aralkenyl, aralkyl, alkylheterocyclyl, heterocyclylalkyl, sulfonyl, -SQr (C1-C3 alkyl), -SO3-(C1-C3 alkyl), sulfonamido, carbamate, aryloxyalkyl and -C(O)NH(benzyl) groups ;
wherein B, R 4, R5, R6, R7, R9, R10 and R" are unsubstituted or substituted with at least one electron donating or electron withdrawing group ;
wherein when L is NR", R4 and R" taken together may form a ring ; and wherein R9 and R'° taken together may form a ring ; and wherein when A is NR6 and at least one Y is CR\ R1 and R6
taken together may form a ring ;
R19 is selected from the group consisting of hydrogen, halogen, hydroxyl, alkyl, alkenyl, alkynyl, alkoxy, alkenoxy, alkynoxy, thioalkoxy, hydroxyalkyl, aliphatic acyl, -CF3, nitro, amino, cyano, carboxy, -N (C1-C3 alkyl)-C(O)(C1-C3 alkyl), -NHC(O)N(C1-C3 alkyl)C(O)NH(G-C3 alkyl), NHC(O)NH(C1-C6 alkyl), alkylamino, alkenylamino, di(d-
C3)amino, -C(O)O-(C1-C3)alkyl, -C(O)NH-(C1-C3)alkyl, -C(O)N(C1-C3 alkyl)2, -CH-NOH, -PO3H2, -OPO3H2, haloalkyl, alkoxyalkoxy, carboxaldehyde, carboxamide, cycloalkyl, cycloalkenyl, cycloalkynyl, cycloalkylalkyl, aryl, aroyl, aryloxy, arylamino, biaryl, thioaryl, diarylamino, heterocyclyl, alkylaryl, aralkenyl, aralkyl, alkylheterocyclyl, heterocyclylalkyl, sulfonyl, -SO2-(C1-C3 alkyl), -SO3-(C1-C3 alkyl), sulfonamido, carbamate, C6-C12 aryloxy(C1-C12) alkyl and -C(O)NH(benzyl) groups ;
d is an integer of zero to three ;
or a pharmaceutically acceptable salt thereof.
2. A compound, as claimed in claim 1, which is a derivative thereof selected from the group consisting of esters, carbamates, aminals, amides and optical isomers, and pro-drugs.
3. A compound, as claimed in claim 1, having the structure
wherein h is an integer of zero to five;
B, R", R'°, R24and R25 are each independently selected from the group consisting
of hydrogen, halogen, hydroxyl, alkyl, alkenyl, alkynyl, alkoxy, alkenoxy, alkynoxy, thioalkoxy, hydroxyalkyl, aliphatic acyl, -CF3, nitro, amino, cyano, carboxy, -N(C1-C3 alkyl)-C(O)(C1-C3 alkyl), -NHC(O)N (C,-C3 alkyl)C(O)NH(C1-C3 alkyl), NHC(O)NH(C1-C6 alkyl), alkylamino, alkenylamino, di(C1-C3)amino, -C(O)O-(C1-C3)alkyl, -C(O) NH-(C1-C3)alkyl, -C(O)N(C1-C3 alkyl)2, -CH=NOH, -PO3H2, -OPO3H2, haloalkyl, alkoxyalkoxy, carboxaldehyde, carboxamide, cycloalkyl, cycloalkenyl, cycloalkynyl, cycloalkylalkyl, aryl, aroyl, aryloxy, arylamino, biaryl, thioaryl, diarylamino, heterocyclyl, alkylaryl, aralkenyl, aralkyl, alkylheterocyclyl, heterocyclylalkyl, sulfonyl, -SQr (C1-C3 alkyl), -SO3-(C1-C3 alkyl), sulfonamido, carbamate, aryloxyalkyl and -C(O)NH(benzyl) groups ;
R27 at each occurrence is independently selected from the group consisting of halogen, hydroxyl, alkyl, alkenyl, alkynyl, alkoxy, alkenoxy, alkynoxy, thioalkoxy, hydroxyalkyl, aliphatic acyl, -CF3, nitro, amino, cyano, carboxy, -N(C1-C3 alkyl)-C(O)(C1-C3 alkyl), -NHC(O)N(C1-C3 alkyl)C (O)NH(C1-C3 alkyl), NHC(O)NH(C1-C6 alkyl), alkylamino, alkenylamino, di(C1-C3)amino, -C(O)O-(C1-C3)alkyl, -C(O)NH-(C1-C3) alkyl, -C(O)N(Ci-C3 alkyl)2, -CH=NOH, -PO3H2, -OPO3H2, haloalkyl, alkoxyalkoxy, carboxaldehyde, carboxamide, cycloalkyl, cycloalkenyl, cycloalkynyl, cycloalkylalkyl, aryl, aroyl, aryloxy, arylamino, biaryl, thioaryl, diarylamino, heterocyclyl, alkylaryl, aralkenyl, aralkyl, alkylheterocyclyl, heterocyclylalkyl, sulfonyl, -SQ2-(C1-C3 alkyl), -SO3-(C1-C3 alkyl), sulfonamido, carbamate, aryloxyalkyl and -C(O)NH (benzyl) groups;
R6, R7 and R18 are each independently selected from the group consisting of alkyl, alkenyl, alkynyl, hydroxyalkyl, aliphatic acyl, alkylamino, alkynylamino, alkoxycarbonyl, heterocycloyl, -CH=NOH, haloalkyl, alkoxyalkoxy, carboxaldehyde, carboxamide, cycloalkyl, cycloalkenyl, cycloalkynyl, cycloalkylalkyl, aryl, aroyl, aryloxy, arylamino, biaryl,
thioaryl, diarylamino, heterocyclyl, alkylaryl, aralkenyl, aralkyl, alkylheterocyclyl, heterocyclylalkyl, carbamate, aryloxyalkyl, hydrogen and -C(O)NH(benzyl) groups ; and
wherein B, R6, R7, R9, R10, R24, R 25and R26 are unsubstituted or substituted with at least one electron donating or electron withdrawing group ; wherein R18 and R24 taken together may form a ring ; R24 and R25 taken together may form a ring ; R25 and R26 taken together may form a ring; and wherein R9 and R10 taken together may form a ring ; or a pharmaceutically acceptable salt thereof.
4. The compound, as claimed in claim 3, wherein B, R6, R7, R9, R10, R24 R25 and R26 are each independently hydrogen and R18 is substituted of unsubstituted aralkyl.
5. A compound, as claimed in claim 3, which is a derivative thereof selected from the group consisting of esters, carbamates, aminals, amides and optical isomers, and pro-drugs.
6. (3S)-3-[( {[ 1 -(2-chlorobenzyl)-4-hydroxy-5-rnethyl-2-oxo-1,2-dihydropyridin-3-yl] amino}carbonyl)amino]-3-(4-methylphenyl)propanoic acid or a pharmaceutically acceptable salt thereof.
7. (3S)-3-[({[l-(2-chlorobenzyl)-4-hydroxy-2-oxo-2,5,6,7-tetrahydro-lH-cyclopenta [b]pyridin-3-yl]amino}carbonyl)amino]-3-(4-methylphenyl)propanoic acid or a pharmaceutically acceptable salt thereof.
8. (3S)-3-[( {[ l-(2-chlorobenzyl)-4-hydroxy-5-methyl-2-oxo-1 ,2-dihydropyridin-3-yl] amino}carbonyl)amino]-3-[3-(diethylamino)phenyl]propanoic acid or a pharmaceutically acceptable salt thereof.
9. A pharmaceutical composition comprising :
a compound as claimed in any of claims 1, 3 - 5 or 6 - 8 or a pharmaccutically acceptable salt thereof, in a pharmaceutically acceptable carrier.
10. A pharmaceutical composition for selectively inhibiting a4ß1 integral binding in a mammal comprising a therapeutic amount of a compound as claimed in any of claims 1, 3 - 5 or 6 - 8 or a pharmaceutically acceptable salt thereof.
The present invention discloses a compound of the structure
and pharmaceutical compositions comprising such compound for selectively inhibiting a4ß1 integrin binding in a mammal.

Documents:

IN-PCT-2001-1211-KOL-CERTIFIED COPIES(OTHER COUNTRIES).pdf

IN-PCT-2001-1211-KOL-CORRESPONDENCE 1.1.pdf

IN-PCT-2001-1211-KOL-CORRESPONDENCE 1.2.pdf

IN-PCT-2001-1211-KOL-CORRESPONDENCE 1.3.pdf

IN-PCT-2001-1211-KOL-CORRESPONDENCE-1.4.pdf

IN-PCT-2001-1211-KOL-CORRESPONDENCE.pdf

IN-PCT-2001-1211-KOL-FORM 27.pdf

IN-PCT-2001-1211-KOL-FORM-27.pdf

in-pct-2001-1211-kol-granted-abstract.pdf

in-pct-2001-1211-kol-granted-assignment.pdf

in-pct-2001-1211-kol-granted-claims.pdf

in-pct-2001-1211-kol-granted-correspondence.pdf

in-pct-2001-1211-kol-granted-description (complete).pdf

in-pct-2001-1211-kol-granted-examination report.pdf

in-pct-2001-1211-kol-granted-form 1.pdf

in-pct-2001-1211-kol-granted-form 18.pdf

in-pct-2001-1211-kol-granted-form 2.pdf

in-pct-2001-1211-kol-granted-form 3.pdf

in-pct-2001-1211-kol-granted-form 5.pdf

in-pct-2001-1211-kol-granted-gpa.pdf

in-pct-2001-1211-kol-granted-reply to examination report.pdf

in-pct-2001-1211-kol-granted-specification.pdf

in-pct-2001-1211-kol-granted-translated copy of priority document.pdf

IN-PCT-2001-1211-KOL-OTHERS 1.1.pdf

IN-PCT-2001-1211-KOL-PA 1.1.pdf

IN-PCT-2001-1211-KOL-PA-CERTIFIED COPIES.pdf

IN-PCT-2001-1211-KOL-PA.pdf


Patent Number 225456
Indian Patent Application Number IN/PCT/2001/1211/KOL
PG Journal Number 46/2008
Publication Date 14-Nov-2008
Grant Date 12-Nov-2008
Date of Filing 20-Nov-2001
Name of Patentee TEXAS BIOTECHNOLOGY CORPORATION
Applicant Address SUITE 1920, 7000 FANNIN, HOUSTON, TX 77030
Inventors:
# Inventor's Name Inventor's Address
1 BIEDIGER RONALD J 17002 E. COPPER LAKES COURT HOUSTON, TX 77095
2 HOLLAND GEORGE W 10 ACORN PLACE, NORTH CALDWELL NJ 07006
3 WU CHENGDE 2511 LANSING CIRCLE, PEARLAND TX 77584
4 CHEN QI 2607 PARKBRIAR LANE, PEARLAND TX 77584
5 KASSIR JAMAL M 2121 HEPBURN, APT. #713, HOUSTON TX 77054
6 LI WEN 1954 WINROCK, APT. #234, HOUSTON TX 77057
7 MARKET ROBERT V 2215 ST. JAMES PLACE, PEARLAND TX 77581
8 SCOTT IAN L 25 LEA DRIVE, DELANSON, NY 12053
PCT International Classification Number A61K 31/215, 31/335
PCT International Application Number PCT/US00/12303
PCT International Filing date 2000-05-05
PCT Conventions:
# PCT Application Number Date of Convention Priority Country
1 NA