U.S. patent application number 11/500225 was filed with the patent office on 2006-12-07 for aryl and heteroaryl compounds and methods to modulate coagulation.
Invention is credited to Robert C. Andrews, Christopher Behme, Daniel Peter Christen, Devi Reddy Gohimmukkula, Xiao-Chuan Guo, Guoxiang Huang, Adnan M. M. Mjalli, Robert Rothlein, Sameer Tyagi, Tripura Yaramasu.
Application Number | 20060276518 11/500225 |
Document ID | / |
Family ID | 31715822 |
Filed Date | 2006-12-07 |
United States Patent
Application |
20060276518 |
Kind Code |
A1 |
Mjalli; Adnan M. M. ; et
al. |
December 7, 2006 |
Aryl and heteroaryl compounds and methods to modulate
coagulation
Abstract
This invention provides certain compounds, methods of their
preparation, pharmaceutical compositions comprising the compounds,
and their use in treating human or animal disorders. The compounds
of the invention are useful as antagonists, or more preferably,
partial antagonist of factor IX and thus, may be used to inhibit
the intrinsic pathway of blood coagulation. The compounds are
useful in a variety of applications including the management,
treatment and/or control of diseases caused in part by the
intrinsic clotting pathway utilizing factor IX. Such diseases or
disease states include stroke, myocardial infarction, aneurysm
surgery, and deep vein thrombosis associated with surgical
procedures, long periods of confinement, and acquired or inherited
pro-coagulant states.
Inventors: |
Mjalli; Adnan M. M.;
(Jamestown, NC) ; Andrews; Robert C.; (Jamestown,
NC) ; Guo; Xiao-Chuan; (High Point, NC) ;
Christen; Daniel Peter; (High Point, NC) ;
Gohimmukkula; Devi Reddy; (Jamestown, NC) ; Huang;
Guoxiang; (Greensboro, NC) ; Rothlein; Robert;
(Summerfield, NC) ; Tyagi; Sameer; (High Point,
NC) ; Yaramasu; Tripura; (Greensboro, NC) ;
Behme; Christopher; (Jamestown, NC) |
Correspondence
Address: |
KILPATRICK STOCKTON LLP - 41305;CHARLES CALKINS
1001 WEST FOURTH STREET
WINSTON-SALEM
NC
27101
US
|
Family ID: |
31715822 |
Appl. No.: |
11/500225 |
Filed: |
August 7, 2006 |
Related U.S. Patent Documents
|
|
|
|
|
|
Application
Number |
Filing Date |
Patent Number |
|
|
10637900 |
Aug 8, 2003 |
7122580 |
|
|
11500225 |
Aug 7, 2006 |
|
|
|
60402272 |
Aug 9, 2002 |
|
|
|
Current U.S.
Class: |
514/357 ;
514/408; 514/592; 514/602; 514/616 |
Current CPC
Class: |
A61P 29/00 20180101;
C07C 237/42 20130101; C07D 217/02 20130101; C07D 231/12 20130101;
C07D 261/10 20130101; A61P 9/10 20180101; A61P 15/06 20180101; C07C
235/42 20130101; C07D 213/71 20130101; C07D 239/94 20130101; A61P
37/00 20180101; C07C 235/66 20130101; C07D 211/26 20130101; C07D
263/32 20130101; C07C 317/28 20130101; C07C 311/18 20130101; C07C
237/36 20130101; C07C 317/14 20130101; C07C 233/29 20130101; C07C
2601/08 20170501; C07D 409/06 20130101; C07C 235/52 20130101; C07C
233/87 20130101; C07D 285/08 20130101; A61P 9/00 20180101; A61P
13/12 20180101; C07D 213/74 20130101; C07D 317/60 20130101; C07D
217/16 20130101; C07D 231/18 20130101; C07C 2601/04 20170501; C07D
233/84 20130101; A61P 43/00 20180101; C07C 311/44 20130101; A61P
9/06 20180101; C07D 249/08 20130101; C07C 2603/74 20170501; C07D
231/14 20130101; C07D 271/10 20130101; C07D 277/46 20130101; C07D
213/81 20130101; C07D 401/04 20130101; C07C 271/20 20130101; A61P
7/00 20180101; C07C 271/44 20130101; C07D 409/04 20130101; C07C
311/19 20130101; C07C 317/36 20130101; C07C 2601/14 20170501; C07D
307/85 20130101; C07C 237/44 20130101; C07C 257/18 20130101; A61P
41/00 20180101; C07D 295/088 20130101; C07D 413/04 20130101; C07D
207/09 20130101; A61P 9/14 20180101; C07D 207/267 20130101; C07C
2601/02 20170501; C07D 295/155 20130101; C07C 235/60 20130101; C07D
307/66 20130101; C07D 333/70 20130101; C07D 333/38 20130101; C07D
217/22 20130101; C07C 255/60 20130101; A61P 7/02 20180101; C07D
213/30 20130101; C07D 213/70 20130101; C07D 307/79 20130101; C07D
333/24 20130101 |
Class at
Publication: |
514/357 ;
514/408; 514/602; 514/592; 514/616 |
International
Class: |
A61K 31/44 20060101
A61K031/44; A61K 31/40 20060101 A61K031/40; A61K 31/18 20060101
A61K031/18; A61K 31/16 20060101 A61K031/16; A61K 31/175 20060101
A61K031/175 |
Claims
1. A method for the inhibition of the normal biological function of
factor IX comprising administering to a subject in need thereof a
compound of Formula (I): ##STR704## wherein c is equal to 0, 1, or
2; wherein the values of 0, 1, and 2 represent a direct bond,
--CH.sub.2--, and --CH.sub.2--CH.sub.2--, respectively, and
--CH.sub.2-- and --CH.sub.2--CH.sub.2-- are optionally substituted
1 to 4 times with a substituent group independently selected from
the group consisting of: -alkyl, -aryl, -alkylene-aryl,
-arylene-alkyl, -alkylene-arylene-alkyl, --O-alkyl, --O-aryl, and
-hydroxyl; G is: -hydrogen, --CO.sub.2R.sub.1, --CH.sub.2OR.sub.1,
--C(O)--R.sub.1, --C(R.sub.1).dbd.N--O--R.sub.2, or an acid
isostere; wherein R.sub.1 and R.sub.2 are independently selected
from the group consisting of: -hydrogen, -alkyl, -aryl,
-arylene-alkyl, -alkylene-aryl, and -alkylene-arylene-alkyl; V is:
--(CH.sub.2).sub.b--O--(CH.sub.2).sub.a--,
--(CH.sub.2).sub.b--N(R.sub.7)--(CH.sub.2).sub.a--,
--(CH.sub.2).sub.b--O--, --(CH.sub.2).sub.b--N(R.sub.7),
--(CH.sub.2).sub.a--, or a direct bond; in which a is equal to 0,
1, or 2, b is equal to 1 or 2, and R.sub.7 is: -hydrogen, -alkyl,
-aryl, -arylene-alkyl, -alkylene-aryl, or -alkylene-arylene-alkyl;
wherein the alkylene groups of V are optionally substituted 1 to 4
times with a substituent group independently selected from the
group consisting of: -alkyl, -aryl, -alkylene-aryl, -arylene-alkyl,
-alkylene-arylene-alkyl, --O-alkyl, --O-aryl, and -hydroxyl; X is:
--N(R.sub.8)--, --CON(R.sub.8)--, --N(R.sub.8)CO--,
--N(R.sub.8)CON(R.sub.9)--, --OC(O)N(R.sub.8)--,
--SO.sub.2N(R.sub.8)--, or --N(R.sub.8)SO.sub.2N(R.sub.9)--;
wherein R.sub.8 and R.sub.9 are independently selected from the
group consisting of: -hydrogen, -alkyl, -aryl, -arylene-alkyl,
-alkylene-aryl, -alkylene-arylene-alkyl,
-alkylene-cycloalkylene-c(O)-alkylene-aryl,
-alkylene-heterocyclylene-C(O)-alkylene-aryl,
-alkylene-C(H)(R.sub.10)(R.sub.11), and
-alkylene-N-(R.sub.10)(R.sub.11), wherein R.sub.10 is H, alkyl,
alkylene-aryl, alkylene-heteroaryl, aryl, or heteroaryl, and
R.sub.11 is H, -alkyl, -alkylene-aryl, -alkylene-heteroaryl, -aryl,
-heteroaryl, --C(O)--O-alkyl, --C(O)--O-alkylene-aryl,
--C(O)--O-alkylene-heteroaryl, --C(O)-alkyl, --C(O)-alkylene-aryl,
--C(O)-alkylene-heteroaryl, --S(O).sub.2-alkyl, --S(O).sub.2-aryl,
--S(O).sub.2-heteroaryl, --S(O).sub.2-alkylene-aryl,
--S(O).sub.2-alkylene-heteroaryl, --S(O).sub.2--NH-alkyl,
--S(O).sub.2--NH-alkylene-aryl,
--S(O).sub.2--NH-alkylene-heteroaryl, --S(O).sub.2--NH-aryl, or
--S(O).sub.2--NH-heteroaryl; or R.sub.10 and R.sub.11, may be taken
together to form a ring having the
formula--(CH.sub.2).sub.m--Z--(CH.sub.2).sub.n-bonded to the
nitrogen or carbon atom to which R.sub.10 and R.sub.11 are
attached, wherein m and n are, independently, 1, 2, 3, or 4; Z is
--CH.sub.2--, --C(O)--, --O--, --N(H)--, --S--, --S(O)--,
--S(O).sub.2--, --CON(H)--, --NHC(O)--, --NHC(O)N(H)--,
--NH(SO).sub.2--, --S(O.sub.2)N(H)--, --(O)CO--,
--NHS(O).sub.2NH--, --OC(O)--, --N(R.sub.12)--,
--N(C(O)R.sub.12)--, --N(C(O)NHR.sub.12)--,
--N(S(O).sub.2NHR.sub.12)--, --N(SO.sub.2R.sub.12)--, or
--N(C(O)OR,.sub.12)--; wherein R.sub.12 is hydrogen, aryl, alkyl,
or alkylene-aryl; or R.sub.10 and R.sub.11, may be taken together,
with the nitrogen or carbon atom to which they are attached, to
form a heterocyclyl or heteroaryl ring; Ar.sub.1 is an aryl,
heteroaryl, fused cycloalkylaryl, fused cycloalkylheteroaryl, fused
heterocyclylaryl, or fused heterocyclylheteroaryl group optionally
substituted 1 to 7 times, wherein the substituents are
independently selected from the group-consisting of: a) -fluoro; b)
-chloro; c) -bromo; d) -iodo; e) -cyano; f) -nitro; g)
-perfluoroalkyl; h) -D.sub.1-R.sub.13; i) -alkyl; j) -aryl; k)
-heteroaryl; l) -heterocyclyl; m) -cycloalkyl; n) -alkylene-aryl;
o) -alkylene-heteroaryl; p) -alkylene-arylene-D.sub.1-R.sub.13; q)
-alkylene-heteroarylene-D.sub.1-R.sub.13; r)
-alkylene-arylene-aryl; S) -alkylene-heteroarylene-aryl; t)
-alkylene-arylene-heteroaryl u)
-alkylene-arylene-arylene-D.sub.1-R.sub.13; v)
-alkylene-arylene-alkyl; w) -alkylene-heteroarylene-alkyl; x)
-arylene-alkyl; y) -arylene-cycloalkyl; z) -heteroarylene-alkyl;
aa) -arylene-arylene-alkyl; bb) -D.sub.1-alkyl; cc) -D.sub.1-aryl;
dd) -D.sub.1-heteroaryl; ee) -D.sub.1-arylene-D.sub.2-R.sub.14; ff)
-D.sub.1-heteroarylene-D.sub.2-R.sub.14; gg)
-D.sub.1-alkylene-heteroaryl; hh) -D.sub.1-alkylene-aryl; ii)
-D.sub.1-alkylene-arylene-D.sub.2-R.sub.14 jj)
-D.sub.1-alkylene-heteroarylene-D.sub.2-R.sub.14 kk)
-D.sub.1-arylene-alkyl; ll) -D.sub.1-heteroarylene-alkyl; mm)
-D.sub.1-alkylene-arylene-aryl; nn)
-D.sub.1-alkylene-heteroarylene-aryl; oo)
-D.sub.1-arylene-arylene-aryl; pp) -D.sub.1-alkylene-arylene-alkyl;
qq) -D.sub.1-alkylene-heteroarylene-alky ss)
-alkylene-D.sub.1-alkylene-aryl; tt)
-alkylene-D.sub.1-alkylene-arylene-D.sub.2-R.sub.14 uu)
-arylene-D.sub.1-alkyl; vv) -arylene-D.sub.1-cycloalkyl; ww)
-arylene-D.sub.1-heterocyclyl; xx) -alkylene-D.sub.1-aryl; yy)
-alkylene-D.sub.1-heteroaryl; zz)
-alkylene-D.sub.1-arylene-D.sub.2-R.sub.14 aaa)
-alkylene-D.sub.1-heteroarylene-D.sub.2-R.sub.14 bbb)
-alkylene-D.sub.1-heteroaryl; ccc) -alkylene-D.sub.1-cycloalkyl;
ddd) -alkylene-D.sub.1-heterocyclyl; eee)
-alkylene-D.sub.1-arylene-alkyl; fff)
-alkylene-D.sub.1-heteroarylene-alkyl; ggg)
-alkylene-D.sub.1-alkylene-arylene-alkyl; hh)
-alkylene-D.sub.1-alkylene-heteroarylene-alkyl; iii)
-alkylene-D.sub.1-alkyl; jjj) -alkylene-D.sub.1-R.sub.13; kkk)
-arylene-D.sub.1-R.sub.13; lll) -heteroarylene-D.sub.1-R.sub.13;
and mmm) -hydrogen; wherein D.sub.1 is --CH.sub.2--, -alkylene-,
-alkenylene-, -alkylene-S--, --S-alkylene-, -alkylene-O--,
--O-alkylene-, -alkylene-S(O).sub.2--, --S(O).sub.2-alkylene,
--O--, --N(R.sub.15)--, --C(O)--, --CON(R.sub.15)--,
--N(R.sub.15)C(O)--, --N(R.sub.15)CON(R.sub.16)--,
--N(R.sub.15)C(O)O--, --OC(O)N(R.sub.15)--,
--N(R.sub.15)SO.sub.2--, --SO.sub.2N(R.sub.15)--, --C(O)--O--,
--O--C(O)--, --S--, --S(O)--, --S(O).sub.2--,
--N(R.sub.15)SO.sub.2N(R.sub.16)--, ##STR705## and wherein
R.sub.13, R.sub.15, R.sub.16, and R.sub.17 are independently
selected from the group consisting of: -hydrogen, -alkyl, -aryl,
-heteroaryl, -arylene-alkyl, -heteroarylene-alkyl, -alkylene-aryl,
-alkylene-heteroaryl, -alkylene-arylene-alkyl, and
-alkylene-heteroarylene-alkyl; D.sub.2 is --CH.sub.2--, -alkylene-,
-alkenylene-, -alkylene-S--, --S-alkylene-, -alkylene-O--,
--O-alkylene-, -alkylene-S(O).sub.2--, --S(O).sub.2-alkylene,
--O--, --N(R.sub.25)--, --C(O)--, --CON(R.sub.25)--,
--N(R.sub.18)C(O)--, --N(R.sub.18)CON(R.sub.19)--,
--N(R.sub.18)C(O)O--, --OC(O)N(R.sub.18)--,
--N(R.sub.18)SO.sub.2.about., .about.SO.sub.2N(R.sub.18)--,
--C(O)--O--, --O--C(O)--, --S--, --S(O)--, --S(O).sub.2--, or
--N(R.sub.18)SO.sub.2N(R.sub.19)--, wherein R.sub.18 and R.sub.19
are independently selected from the group consisting of: -hydrogen,
-alkyl, -aryl, -arylene-alkyl, -alkylene-aryl, and
-alkylene-arylene-alkyl; and R.sub.14 is -hydrogen, -alkyl, -aryl,
-heteroaryl, -arylene-alkyl, -heteroarylene-alkyl, -alkylene-aryl,
-alkylene-heteroaryl, -alkylene-arylene-alkyl, or
-alkylene-heteroarylene-alkyl; Ar.sub.2 is an aryl or heteroaryl
group optionally substituted 1 to 7 times, wherein the substituents
are independently selected from the group consisting of: a)
-fluoro; b) -chloro; c) -bromo; d) -iodo; e) -cyano; f) -nitro; g)
-perfluoroalkyl; h) -T.sub.1-R.sub.20; i) -alkyl; j) -aryl; k)
-heteroaryl; l) -heterocyclyl; m) -cycloalkyl; n) -alkylene-aryl;
o) -alkylene-arylene-aryl; p) -alkylene-arylene-alkyl; q)
-arylene-alkyl; r) -arylene-aryl; s) -arylene-heteroaryl; t)
-heteroarylene-aryl; u) -heteroarylene-heteroaryl; v)
-heteroarylene-heterocyclyl; w) -arylene-heterocyclyl; x)
-arylene-arylene-alkyl; y) -T.sub.1-alkyl; z) -T.sub.1-aryl; aa)
-T.sub.1-alkylene-aryl; bb) -T.sub.1-alkenylene-aryl; cc)
-T.sub.1-alkylene-heteroaryl; dd) -T.sub.1-alkenylene-heteroaryl;
ee) -T.sub.1-cycloalkylene-aryl; ff)
-T.sub.1-cycloalkylene-heteroaryl; gg)
-T.sub.1-heterocyclylene-aryl; hh)
-T.sub.1-heterocyclylene-heteroaryl; ii) -T.sub.1-arylene-alkyl;
jj) -T.sub.1-arylene-alkenyl; kk) -T.sub.1-alkylene-arylene-aryl;
ll) -T.sub.1-arylene-T.sub.2-aryl; mm)
-T.sub.1-arylene-arylene-aryl; nn) -T.sub.1-alkylene-arylene-alkyl;
oo) -alkylene-T.sub.1-alkylene-aryl; pp) -arylene-T.sub.1-alkyl;
qq) -arylene-T.sub.1-alkylene-aryl; rr)
-T.sub.1-alkylene-T.sub.2-aryl; ss) -T.sub.1-alkylene-aryl; tt)
-alkylene-T.sub.1-heteroaryl; uu) -alkylene-T.sub.1-cycloalkyl; vv)
-alkylene-T.sub.1-heterocyclyl; ww) -alkylene-T-arylene-alkyl; xx)
-alkylene-T.sub.1-alkylene-arylene-alkyl; yy)
-alkylene-T.sub.1-alkyl; zz) -alkylene-T.sub.1-R.sub.20; aaa)
-arylene-T.sub.1-R.sub.20; and bbb) -hydrogen; wherein T.sub.1 is
--CH.sub.2--, --O--, --N(R.sub.21)--, --C(O)--, --CON(R.sub.21)--,
--N(R.sub.21)C(O)--, --N(R.sub.21)CON(R.sub.22)--,
--N(R.sub.21)C(O)O--, --OC(O)N(R.sub.21)--,
--N(R.sub.21)SO.sub.2--, --SO.sub.2N(R.sub.21)--, --C(O)--O--,
--O--C(O)--, --S--, --S(O)--, --S(O.sub.2)--,
--N(R.sub.21)SO.sub.2N(R.sub.22)--, ##STR706## and wherein
R.sub.20, R.sub.21, R.sub.22 and R.sub.23, are independently
selected from the group consisting of: -hydrogen, -alkyl, -alkenyl,
-alkylene-cycloalkyl, -alkynene-heterocyclyl, -aryl, -heteroaryl,
-arylene-alkyl, -alkylene-aryl, -alkylene-arylene-alkyl,
-alkylene-arylene-aryl, -alkylene-arylene-alkylene-aryl,
-alkylene-arylene-O-arylene, and alkylene-arylene-O--alkylene-aryl;
and T.sub.2 is a direct bond, --CH.sub.2--, --O--, --N(R.sub.24)--,
--C(O)--, --CON(R.sub.24)--, --N(R.sub.24)C(O)--,
--N(R.sub.24)CON(R.sub.25)--, --N(R.sub.24)C(O)O--,
--OC(O)N(R.sub.24)--, --N(R.sub.24)SO.sub.2--,
--SO.sub.2N(R.sub.24)--, --C(O)--O--, --O--C(O)--, --S--, --S(O)--,
--S(O).sub.2--, or --N(R.sub.24)SO.sub.2N(R.sub.25)--, wherein
R.sub.24 and R.sub.25 are independently selected from the group
consisting of: -hydrogen, -alkyl, -alkenyl, -alkylene-cycloalkyl,
alkynene-heterocyclyl, -aryl, -heteroaryl, -arylene-alkyl,
-alkylene-aryl, and -alkylene-arylene-alkyl; and wherein the alkyl,
aryl, heteroaryl, alkylene, and arylene groups in Ar.sub.1,
Ar.sub.2, R.sub.1, R.sub.2, R.sub.3, R.sub.4, R.sub.5, R.sub.6,
R.sub.7, R.sub.8, R.sub.9, R.sub.10, R.sub.11, R.sub.12, R.sub.13,
R.sub.14, R.sub.15, R.sub.16, R.sub.17, R.sub.18, R.sub.19,
R.sub.20, R.sub.21, R.sub.22, and R.sub.23 may be optionally
substituted 1 to 4 times with a substituent group independently
selected from the group consisting of: a) -hydrogen; b) -fluoro; c)
-chloro; d) -bromo; e) -iodo; f) -cyano; g) -nitro; h)
-perfluoroalkyl; i) -Q-perfluoroalkyl j) -Q-R.sub.24; k) -Q-alkyl;
l) -Q-aryl; m) -Q-alkylene-aryl; n) -Q-alkylene-NR.sub.25R.sub.26;
and o) -Q-alkyl-W-R.sub.27; wherein Q and W are independently
selected from the group consisting of: --CH.sub.2--, --O--,
--N(R.sub.28)--, --C(O)--, --CON(R.sub.28)--, --N(R.sub.28)C(O)--,
--N(R.sub.28)CON(R.sub.29)--,--N(R.sub.28)C(O)O--,
--OC(O)N(R.sub.28)--,--N(R.sub.28)SO.sub.2--,
SO.sub.2N(R.sub.28)--, --C(O)--O--, --O--C(O)--, and
--N(R.sub.28)SO.sub.2N(R.sub.29)--, wherein R.sub.24, R.sub.25,
R.sub.26, R.sub.27, R.sub.28, and R.sub.29 are independently
selected from the group consisting of: -hydrogen, -alkyl, -aryl,
-arylene-alkyl, -alkylene-aryl, and -alkylene-arylene-alkyl, or a
pharmaceutically acceptable salt thereof.
2. The method of claim 1, wherein said compound of Formula (I) or a
pharmaceutically acceptable salt thereof is administered to said
subject as a pharmaceutical composition comprising a
therapeutically effective amount of said compound and a
pharmaceutically acceptable carrier, excipient, or diluent.
3. The method of claim 1, wherein the compound of Formula (I) or a
pharmaceutically acceptable salt thereof is an antagonist of factor
IX activity.
4. The method of claim 1, wherein said compound of Formula (I) or a
pharmaceutically acceptable salt thereof is a partial antagonist of
factor IX, wherein a partial antagonist comprises a compound that
inhibits less than complete activity at a physiologically tolerable
dose.
5. The method of claim 4, wherein said compound of Formula (I) or a
pharmaceutically acceptable salt thereof inhibits up to 95% of
factor IX activity.
6. The method of claim 4, wherein said compound of Formula (I) or a
pharmaceutically acceptable salt thereof inhibits up to 80% of
factor IX activity.
7. The method of claim 4, wherein said compound of Formula (I) or a
pharmaceutically acceptable salt thereof inhibits up to 50% of
factor IX activity.
8. The method of claim 1, wherein the compound of Formula (I) or a
pharmaceutically acceptable salt thereof antagonizes blood clotting
mediated by factor IX.
9. The method of claim 1, wherein said compound of Formula (I) or a
pharmaceutically acceptable salt thereof is administered in an
amount sufficient to partially antagonize the biological activity
of factor IX in said subject.
10. The method of claim 2, wherein said therapeutically effective
amount at least partially inhibits the intrinsic clotting cascade
in said subject.
11. The method of claim 2, wherein said therapeutically effective
amount preferentially inhibits the intrinsic clotting cascade as
compared to the extrinsic clotting cascade in said subject.
12. The method of claim 2, wherein said therapeutically effective
amount inhibits the intrinsic clotting cascade in said subject by
greater than 80% and inhibits the extrinsic clotting cascade by
less than 50%.
13. The method of claim 2, wherein said therapeutically effective
amount comprises a sufficient amount of the compound of Formula (I)
or a pharmaceutically acceptable salt thereof for treatment or
prevention of factor IX-mediated diseases.
14. The method of claim 1, wherein said pharmaceutical composition
is administered in the form of an oral dosage or parenteral dosage
unit.
15. The method of claim 1, wherein said compound of Formula (I) or
a pharmaceutically acceptable salt thereof is administered as a
dose in a range from about 0.01 to 1,000 mg/kg of body weight per
day.
16. The method of claim 1, wherein said compound of Formula (I) or
a pharmaceutically acceptable salt thereof is administered as a
dose in a range from about 0.1 to 100 mg/kg of body weight per
day.
17. The method of claim 1, wherein said compound of Formula (I) or
a pharmaceutically acceptable salt thereof is administered as a
dose in a range from about 0.5 to 10 mg/kg of body weight per
day.
18. The method of claim 13, wherein said factor IX-mediated disease
is a stroke.
19. The method of claim 13, wherein said factor IX-mediated disease
is deep vein thrombosis.
20. The method of claim 19, wherein said thrombosis is associated
with surgical procedures, long periods of confinement, acquired or
inherited pro-coagulant states including anti-phospholipid antibody
syndrome, protein C deficiency and protein S deficiency, or acute
and chronic inflammation including recurrent miscarriage or
Systemic Lupus Erythmatosis (SLE).
21. The method of claim 13, wherein said factor IX-mediated disease
is clotting associated with the treatment of kidney disease by
hemodialysis and/or venous hemofiltration.
22. The method of claim 13, wherein said factor IX-mediated disease
is cardiovascular disease.
23. The method of claim 22, wherein said cardiovascular disease is
myocardial infarction, arrhythmia, or aneurysm.
24. The method of claim 1, wherein said compound of Formula (I) or
a pharmaceutically acceptable salt thereof is used to replace or
supplement compounds that reduce clotting.
25. The method of claim 2, wherein said pharmaceutical composition
further comprises one or more therapeutic agents.
Description
STATEMENT OF RELATED APPLICATION
[0001] The present application is a divisonal application of U.S.
patent application Ser. No. 10/637,900, filed Aug. 8, 2003, which
claims priority under 35 USC 119 from the U.S. Provisional
Application No. 60/402,272, filed Aug. 9, 2002, entitled "Aryl and
Heteroaryl Compounds and Methods to Modulate Coagulation," the
entirety of which are herein incorporated by reference.
FIELD OF THE INVENTION
[0002] This invention relates to compounds which are antagonists of
the intrinsic clotting pathway by binding to and inhibiting the
function of factor IX.
BACKGROUND OF THE INVENTION
[0003] Hemostasis, the arrest of bleeding from an injured blood
vessel, requires the concerted activity of vascular, platelet, and
plasma factors to eventually form a hemostatic seal or a blood
clot. In normal hemostasis, the combined activity of these factors
is counterbalanced by regulatory mechanisms to limit the
accumulation of platelets and fibrin in the area of injury.
[0004] Upon injury to a blood vessel, vascular factors reduce blood
flow from the blood vessel by local vasoconstriction and
compression of injured vessels. At the same time, platelets adhere
to the site of vessel wall injury and form aggregates called
hemostatic plugs, which form the first key element of the
hemostatic seal. Platelets also release factors that provide
surface membrane sites and components for the formation of
enzyme/cofactor complexes in blood coagulation reactions. Through a
series of interacting and propagating zymogen activations, the
activated form of one plasma factor catalyzes the activation of the
next plasma factor. This cascade of blood coagulation reactions
eventually forms a fibrin clot. The fibrin clot, an insoluble
fibrin matrix that radiates from and anchors the hemostatic plug,
is the second key element of the hemostatic seal
[0005] Specifically, the cascade of blood coagulation reactions
discussed involvse two interdependent pathways, an intrinsic
pathway and an extrinsic pathway. Each pathway ultimately catalyzes
the proteolytic activation of factor X to factor Xa.
[0006] Damage to the blood vessel or a negatively charged surface
initiates blood clotting by the intrinsic pathway. As seen in FIG.
1, the major components of the intrinsic pathway include factor
VIII, a non-enzymatic co-factor, and factors IX and XI, zymogen
serine proteases. The initiation of the intrinsic pathway results
in the activation of factor XI to XIa. Factor XIa, as well as the
presence of the factor VIIa/tissue factor complex involved in the
extrinsic pathway, catalyzes the activation of factor IX to factor
IXa. The presence of factor IXa, in combination with the activated
form of factor VIII on an appropriate phospholipid surface, results
in the formation of a tenase complex (10). The tenase complex
catalyzes the formation of factor Xa from its zymogen, factor
X.
[0007] Exposure of blood to injured tissue initiates blood clotting
by the extrinsic pathway. As is shown in FIG. 1, the major
components of the extrinsic pathway are factor VII, a zymogen
serine protease, and tissue factor, a membrane bound protein.
Tissue factor serves as the requisite non-enzymatic co-factor for
factor VII. The initiation of the extrinsic pathway is thought to
be an autocatalytic event resulting from the activation of factor
VII by trace levels of activated factor VII (factor VIIa), both of
which are bound to newly exposed tissue factor on membrane surfaces
at sites of vascular damage (20). The factor VIIa/tissue factor
complex directly catalyzes the formation of factor Xa from factor
X.
[0008] Once the initial intrinsic or extrinsic cascade results in
the activation of factor X, factor Xa catalyzes the penultimate
step in the blood coagulation cascade, the formation of serine
protease thrombin. As seen in FIG. 2, thrombin formation occurs
when a prothrombinase complex, comprising of factor Xa, the
non-enzymatic co-factor Va and the substrate prothrombin, is
assembled on an appropriate phospholipid surface (30). Once formed,
thrombin functions as part of a feedback loop, controlling the
activation of factors V and VIII. It additionally catalyzes both
the activation of factor VIII and the conversion of fibrinogen to
fibrin. Finally, the factor VIIIa interacts with fibrin to catalyze
the formation of a thrombus, or crosslinked fibrin clot.
[0009] In normal hemostasis, the process of clot formation (blood
coagulation) and clot dissolution (fibrinolysis) is delicately
balanced. A slight imbalance between the processes of clot
formation and dissolution can lead to excessive bleeding or
thrombosis. Many significant disease states are related to abnormal
hemostasis. With respect to the coronary arterial vasculature,
abnormal thrombus formation due to the rupture of an established
atherosclerotic plaque is the major cause of acute myocardial
infarction and unstable angina. Moreover, treatment of an occlusive
coronary thrombus by either thrombolytic therapy or percutaneous
transluminal coronary angioplasty (PTCA) is often accompanied by an
acute thrombotic reclosure of the affected vessel which requires
immediate resolution. With respect to the venous vasculature, a
high percentage of patients undergoing major surgery in the lower
extremities or the abdominal area suffer from thrombus formation in
the venous vasculature which can result in reduced blood flow to
the affected extremity and a predisposition to pulmonary embolism.
Disseminated intravascular coagulopathy commonly occurs within both
vascular systems during septic shock, certain viral infections and
cancer and is characterized by the rapid consumption of coagulation
factors and systemic coagulation which results in the formation of
life-threatening thrombi occurring throughout the vasculature
leading to widespread organ failure.
[0010] Pathogenic thrombosis in the arterial vasculature is a major
clinical concern in today's medicine. It is the leading cause of
acute myocardial infarction which is one of the leading causes of
death in the western world. Recurrent arterial thrombosis also
remains one of the leading causes of failure following enzymatic or
mechanical recanalization of occluded coronary vessels using
thrombolytic agents or percutaneous transluminal coronary
angioplasty (PTCA), respectively [Ross, A. M., Thrombosis in
Cardiovascular Disorder, p. 327, W. B. Saunders Co. (Fuster, V. and
Verstraete, M. edit. 1991); Califf, R. M. and Willerson, J. T., Id.
at p 389]. In contrast to thrombotic events in the venous
vasculature, arterial thrombosis is the result of a complex
interaction between fibrin formation resulting from the blood
coagulation cascade and cellular components, particularly
platelets, which make up a large percentage of arterial thrombi.
Heparin, the most widely used clinical anticoagulant administered
intravenously, has not been shown to be universally effective in
the treatment or prevention of acute arterial thrombosis or
rethrombosis [Prins, M. H. and Hirsh, J., J. Am. Coll. Cardiol.,
67: 3A (1991)].
[0011] Besides the unpredictable, recurrent thrombotic reocclusion
which commonly occurs following PTCA, a profound restenosis of the
recanalized vessel occurs in 30 to 40% of patients 1 to 6 months
following this procedure [Califf, R. M. et al., J. Am. Coll.
Cardiol., 17: 2B (1991)]. These patients require further treatment
with either a repeat PTCA or coronary artery bypass surgery to
relieve the newly formed stenosis. Restenosis of a mechanically
damaged vessel is not a thrombotic process but instead is the
result of a hyperproliferative response in the surrounding smooth
muscle cells which over time results in a decreased luminal
diameter of the affected vessel due to increased muscle mass. Id.
As for arterial thrombosis, there is currently no effective
pharmacologic treatment for the prevention of vascular restenosis
following mechanical recanalization.
[0012] Numerous strategies have been developed for the treatment of
thrombotic disorders. Many antithrombotic therapies are based on
interference in the hemostatic system. This approach carries the
inherent risk of bleeding, since the hemostatic system is no longer
fully responsive to potential injury. Therefore, antithrombotic
benefits are normally associated with antihemostatic risks. In
attempts to improve the benefit-to-risk ratio, antithrombotic
agents are continuously being developed. Various antithrombotic
strategies include administering general inhibitors of thrombin
formation such as heparin or vitamin K antagonists; administering
specific thrombin inhibitors; administering specific factor Xa
inhibitors; and administering inhibitors of platelet activation and
adhesion.
[0013] Evaluation of current antithrombotic strategies in terms of
antithrombotic benefits versus antihemostatic risks reveals that
the benefit-to-risk ratio tends to be more favorable for strategies
that interfere with one specific step rather than in a more general
phase of the hemostatic system [L. A. Harker, Biomedical Progress
vol 8, 1995, 17-26]. For example, the development of inhibitors
specific for factor Xa is an improvement from general and specific
thrombin inhibitors. But, this approach still blocks the common
(intrinsic and extrinsic) pathway of thrombin generation (see FIG.
1), and thereby thrombin-dependent platelet activation. Thus, a
need exists for more specific anti-thrombotic agents that
selectively inhibit one single hemostatic pathway, while leaving
other pathways unaffected.
SUMMARY OF THE INVENTION
[0014] The present invention provides compositions and methods for
the treatment of cardiovascular diseases. More particularly, the
present invention relates to modifying thrombus formation and
growth by administering an agent or agents that inhibit the
clotting activity of factor IX in the intrinsic clotting pathway.
Embodiments of the present invention provide compounds of Formula
(I) as depicted below. Embodiments of the present invention also
provide methods for the preparation of compounds of Formula (I);
pharmaceutical compositions comprising compounds of Formula (I);
and methods for the use of compounds of Formula (I) and
pharmaceutical compositions comprising compounds of Formula (I) in
treating human or animal disorders. Compounds of Formula (I) are
useful as modulators of the intrinsic clotting pathway by
inhibiting the biological activity of factor IX. Compounds of
Formula (I) are useful in a variety of applications including
management, treatment, control, and/or as an adjunct of diseases in
humans caused in part by the intrinsic clotting pathway utilizing
factor IX. Such diseases or disease states include cardiopulmonary
bypass, stroke, myocardial infarction, deep vein thrombosis
associated with surgical procedures or long periods of confinement,
acute and chronic inflammation and clotting associated with
hemodialysis.
BRIEF DESCRIPTION OF THE FIGURES
[0015] The present invention will be described with reference to
the accompanying drawings, wherein:
[0016] FIG. 1 is a diagram depicting the steps involved in the
intrinsic and extrinsic blood clotting cascades, from time of
trauma to the activation of factor X.
[0017] FIG. 2 is a diagram depicting the steps following initial
intrinsic and extrinsic blood clotting cascades, beginning with the
formation of Xa and culminating in the formation of a thrombus.
DETAILED DESCRIPTION
[0018] Two blood coagulation pathways are associated with normal
hemostasis: intrinsic and extrinsic. These two coagulation pathways
converge in the formation of factor Xa. But, these two coagulation
pathways are interdependent because complete elimination of the
intrinsic pathway leads to uncontrolled bleeding. For example, Type
B hemophiliacs completely lack factor IX or factor IX function and
have a phenotype characterized by a severe bleeding disorder. Thus,
the direct factor VIIa/tissue factor activation of factor X, which
bypasses the need for factor VII and factor IX, is insufficient for
normal hemostasis. Conversely, formation of the factor VIIIa/IXa
phospholipid factor X activator (tenase complex) (20) is essential
for normal hemostasis.
[0019] Selective inhibition of the intrinsic pathway of coagulation
with a factor IX antagonist can provide a method to inhibit the
clotting cascade associated with some surgery, stroke, myocardial
infarction and hemodialysis while leaving the clotting pathway
associated with external lesions such as trauma or abscess intact.
Factor IX is primarily associated with the intrinsic clotting
pathway. A specific antagonist of factor IX should have a
therapeutic benefit in diseases associated with intrinsic pathway
clotting by inhibiting intravascular thrombosis. Also, a specific
antagonist of factor IX should not have the side effect of unwanted
or uncontrollable bleeding by impairing extravascular hemostasis
associated with wound healing.
[0020] Some point mutations in factor IX partially inhibit its
function and result in a mild or moderate phenotype manifested as a
non-life threatening bleeding disorder [Bowen, D. J., J. Clin.
Pathol: Mol. Pathol. 55:1-18 (2002)]. These point mutations cause
factor IX to behave as if it were subject to a partial antagonist.
In the presence of a partial antagonist, factor IX should maintain
some activity, even at saturation levels of the partial antagonist.
As a result of the point mutations in factor IX, its activity is
reduced along with clotting associated with the intrinsic pathway,
but some residual activity remains that leaves the extrinsic
pathway intact.
[0021] The present invention provides compositions and methods that
inhibit the clotting activity of factor IX. Inhibition of
hemostasis with agents that selectively inhibit the intrinsic
pathway of factor X activation should leave the extrinsic pathway
intact and allow the formation of small, but hemostatically
important amounts of factor Xa and thrombin.
[0022] Embodiments of the present invention provide compounds of
Formula (I) as depicted below. Embodiments of the present invention
also provide methods of the preparation of compounds of Formula
(I); pharmaceutical compositions comprising compounds of Formula
(I); and methods for the use of compounds of Formula (I) and
pharmaceutical compositions comprising compounds of Formula (I) in
treating human or animal disorders. Compounds of the Formula (I)
are useful as modulators of the intrinsic clotting pathway by
inhibiting the biological activity of factor IX. Compounds of
Formula (I) are useful in a variety of applications including
management, treatment, control, and/or as an adjunct of diseases in
humans caused in part by the intrinsic clotting pathway utilizing
factor IX. Such diseases or disease states include cardiopulmonary
bypass, stroke, myocardial infarction, deep vein thrombosis
associated with surgical procedures or long periods of confinement,
acute and chronic inflammation and clotting associated with
hemodialysis.
[0023] In a first aspect, the present invention provides a compound
comprising at least one moiety of the formula I. Such compounds are
useful in a variety of applications including for the management,
treatment, control, and/or as an adjunct of diseases in humans
caused in part by the intrinsic clotting pathway utilizing factor
IX, will be discussed in more detail below.
[0024] In one aspect, the present invention provides compounds
which are represented by Formula I: ##STR1## wherein c is equal to
0, 1, or 2; wherein the values of 0, 1, and 2 comprise a direct
bond, --CH.sub.2--, and --CH.sub.213 CH.sub.2--, optionally
substituted 1 to 4 times with a substituent group, wherein said
substituent group(s) or the term substituted refers to groups
comprising: -alkyl, -aryl, -alkylene-aryl, -arylene-alkyl,
-alkylene-arylene-alkyl, --O-alkyl, --O-aryl, or -hydroxyl. In
preferred embodiments, c is equal to 0 or 1. In especially
preferred embodiments, c is equal to 0.
[0025] G comprises: -hydrogen, --CO.sub.2R.sub.1, --CH.sub.2O
R.sub.1, --C(O)--R.sub.1, --C(R.sub.1).dbd.N--O--R.sub.2, or an
acid isostere; wherein R.sub.1 and R.sub.2 independently comprise:
-hydrogen, -alkyl, -aryl, -arylene-alkyl, -alkylene-aryl, or
-alkylene-arylene-alkyl. In preferred embodiments, G comprises:
-hydrogen or --CO.sub.2R.sub.1; wherein R.sub.1 comprises:
-hydrogen, -alkyl, or -aryl. In especially preferred embodiments, G
comprises: -hydrogen or --CO.sub.2H.
[0026] V comprises: --(CH.sub.2).sub.b--O--(CH.sub.2).sub.a--,
--(CH.sub.2).sub.b--N(R.sub.7)--(CH.sub.2).sub.a,
--(CH.sub.2).sub.b--O--, --(CH.sub.2).sub.b--N(R.sub.7),
--(CH.sub.2).sub.a--, or a direct bond; in which a is equal to 0,
1, or 2, b is equal to 1 or 2, and R.sub.7 comprises: -hydrogen,
-alkyl, -aryl, -arylene-alkyl, -alkylene-aryl, or
-alkylene-arylene-alkyl; wherein the values of 0, 1, and 2 comprise
a direct bond, --CH.sub.2--, and --CH.sub.2--CH.sub.2--, optionally
substituted 1 to 4 times with a substituent group, wherein said
substituent group(s) or the term substituted refers to groups
comprising: -alkyl, -aryl, -alkylene-aryl, -arylene-alkyl,
-alkylene-arylene-alkyl, --O-alkyl, --O-aryl, or -hydroxyl. In
preferred embodiments, V comprises: --(CH.sub.2).sub.a--,
--(CH.sub.2).sub.b--O--(CH.sub.2).sub.a--, or a direct bond,
wherein a is equal to 1 or 2, and b is equal to 1. In especially
preferred embodiments, V comprises: --(CH2).sub.a-- or a direct
bond, wherein a is equal to 1.
[0027] X comprises: --(R.sub.8)--, --CON(R.sub.8)--,
--(R.sub.8)CO--, --(R.sub.8)CON(R.sub.9)--, --OC(O)N(R.sub.8)--,
--SO.sub.2N(R.sub.8)--, or --(R.sub.8)SO.sub.2N(R.sub.9)--; wherein
R.sub.8 and R.sub.9 independently comprise: -hydrogen, -alkyl,
-aryl, -arylene-alkyl, -alkylene-aryl, -alkylene-arylene-alkyl,
-alkylene-cycloalkylene-C(O)-alkylene-aryl,
-alkylene-heterocyclylene-C(O)-alkylene-aryl,
-alkylene-C(H)(R.sub.10)(R.sub.11), or
-alkylene-N--(R.sub.10)(R.sub.11),
[0028] wherein R.sub.10 comprises H, alkyl, alkylene-aryl,
alkylene-heteroaryl, aryl, or heteroaryl, and R.sub.11 comprises H,
-alkyl, -alkylene-aryl, -alkylene-heteroaryl, -aryl, -heteroaryl,
--C(O)--O-alkyl, --C(O)--O-alkylene-aryl,
--C(O)--O-alkylene-heteroaryl, --C(O)-alkyl, --C(O)-alkylene-aryl,
--C(O)-alkylene-heteroaryl, --S(O).sub.2-alkyl, --S(O).sub.2-aryl,
, --S(O).sub.2-heteroaryl, --S(O).sub.2-alkylene-aryl,
--S(O).sub.2-alkylene-heteroaryl, --S(O).sub.2--H-alkyl,
--S(O).sub.2--NH-alkylene-aryl,
--S(O).sub.2--H-alkylene-heteroaryl, --S(O).sub.2--H-aryl, or
--S(O).sub.2--NH-heteroaryl; [0029] R.sub.10 and R.sub.11 may be
taken together to form a ring having the formula
--(CH.sub.2).sub.m-Z-(CH.sub.2).sub.n-bonded to the nitrogen or
carbon atom to which R.sub.10 and R.sub.11 are attached, wherein m
and n are, independently, 1, 2, 3, or 4; Z independently comprises
--CH.sub.2--, --C(O)--, --O--, --N(H)--, --S--, --S(O)--,
--S(O.sub.2)--, --CON(H)--, --NHC(O)--, --NHC(O)N(H)--,
--NH(SO.sub.2)--, --S(O.sub.2)N(H)--, --(O)CO--,
--NHS(O.sub.2)NH--, --OC(O)--, --N(R.sub.12)--,
--N(C(O)R.sub.12)--, --N(C(O)NHR.sub.12)--,
--N(S(O.sub.2)NHR.sub.12)--, --N(SO.sub.2R.sub.12)--, or
--N(C(O)OR.sub.12)--; or [0030] R.sub.10 and R.sub.11 may be taken
together, with the nitrogen or carbon atom to which they are
attached, to form a heterocyclyl or heteroaryl ring. [0031]
R.sub.12 comprises hydrogen, aryl, alkyl, or alkylene-aryl; In
preferred embodiments, X comprises: --(R.sub.8)--,
--CON(R.sub.8)--, --N(R.sub.8)CO--, or --N(R.sub.8)CON(R.sub.9)--,
wherein R.sub.8 and R.sub.9 independently comprise: -hydrogen,
-alkyl, -aryl, -arylene-alkyl, -alkylene-aryl, or
-alkylene-arylene-alkyl. In especially preferred embodiments, X
comprises: --N(R.sub.8)--, --CON(R.sub.8)--, or --N(R.sub.8)CO--,
wherein R.sub.8 comprises: -hydrogen, -alkyl, -aryl,
-arylene-alkyl, -alkylene-aryl, or -alkylene-arylene-alkyl.
[0032] Ar.sub.1 comprises an aryl, heteroaryl, fused
cycloalkylaryl, fused cycloalkylheteroaryl, fused heterocyclylaryl,
or fused heterocyclylheteroaryl group optionally substituted 1 to 7
times. In preferred embodiments, Ar.sub.1 comprises a mono- or
bicyclic aryl or heteroaryl group optionally substituted 1 to 7
times. In especially preferred embodiments, Ar.sub.1 comprises a
phenyl group having 1 to 5 substituents, wherein the substituents
independently comprise: [0033] a) -fluoro; [0034] b) -chloro;
[0035] c) -bromo; [0036] d) -iodo; [0037] e) -cyano; [0038] f)
-nitro; [0039] g) -perfluoroalkyl; [0040] h) -D.sub.1-R.sub.13;
[0041] i) -alkyl; [0042] j) -aryl; [0043] k) -heteroaryl; [0044] l)
-heterocyclyl; [0045] m) -cycloalkyl; [0046] n) -alkylene-aryl;
[0047] o) -alkylene-heteroaryl; [0048] p)
-alkylene-arylene-D.sub.1-R.sub.13; [0049] q)
-alkylene-heteroarylene-D.sub.1-R.sub.13; [0050] r)
-alkylene-arylene-aryl; [0051] s) -alkylene-heteroarylene-aryl;
[0052] t) -alkylene-arylene-heteroaryl [0053] u)
-alkylene-arylene-arylene-D.sub.1-R.sub.13; [0054] v)
-alkylene-arylene-alkyl; [0055] w) -alkylene-heteroarylene-alkyl;
[0056] x) -arylene-alkyl; [0057] y) -arylene-cycloalkyl; [0058] z)
-heteroarylene-alkyl; [0059] aa) -arylene-arylene-alkyl; [0060] bb)
-D.sub.1-alkyl; [0061] cc) -D.sub.1-aryl; [0062] dd)
-D.sub.1-heteroaryl; [0063] ee) -D.sub.1-arylene-D.sub.2-R.sub.14;
[0064] ff) -D.sub.1-heteroarylene-D.sub.2-R.sub.14; [0065] gg)
-D.sub.1-alkylene-heteroaryl; [0066] hh) -D.sub.1-alkylene-aryl;
[0067] ii) -D.sub.1-alkylene-arylene-D.sub.2-R.sub.14 [0068] jj)
-D.sub.1-alkylene-heteroarylene-D.sub.2-R.sub.14 [0069] kk)
-D.sub.1-arylene-alkyl; [0070] ll) -D.sub.1-heteroarylene-alkyl;
[0071] mm) -D.sub.1-alkylene-arylene-aryl; [0072] nn)
-D.sub.1-alkylene-heteroarylene-aryl; [0073] oo)
-D.sub.1-arylene-arylene-aryl; [0074] pp)
-D.sub.1-alkylene-arylene-alkyl; [0075] qq)
-D.sub.1-alkylene-heteroarylene-alky [0076] ss)
-alkylene-D.sub.1-alkylene-aryl; [0077] tt)
-alkylene-D.sub.1-alkylene-arylene-D.sub.2-R.sub.14 [0078] uu)
-arylene-D.sub.1-alkyl; [0079] vv) -arylene-D.sub.1-cycloalkyl;
[0080] ww) -arylene-D.sub.1-heterocyclyl; [0081] xx)
-alkylene-D.sub.1-aryl; [0082] yy) -alkylene-D.sub.1-heteroaryl;
[0083] zz) -alkylene-D.sub.1-arylene-D.sub.2-R.sub.14 [0084] aaa)
-alkylene-D.sub.1-heteroarylene-D.sub.2-R.sub.14 [0085] bbb)
-alkylene-D.sub.1-heteroaryl; [0086] ccc)
-alkylene-D.sub.1-cycloalkyl; [0087] ddd)
-alkylene-D.sub.1-heterocyclyl; [0088] eee)
-alkylene-D.sub.1-arylene-alkyl; [0089] fff)
-alkylene-D.sub.1-heteroarylene-alkyl; [0090] ggg)
-alkylene-D.sub.1-alkylene-arylene-alkyl; [0091] hh)
-alkylene-D.sub.1-alkylene-heteroarylene-alkyl; [0092] iii)
-alkylene-D.sub.1-alkyl; [0093] jjj) -alkylene-D.sub.1-R.sub.13;
[0094] kkk) -arylene-D.sub.1-R.sub.13; [0095] lll)
-heteroarylene-D.sub.1-R.sub.13; or [0096] mmm) -hydrogen; wherein
D.sub.1 comprises --CH.sub.2--, -alkylene-, -alkenylene-,
-alkylene-S--, --S-alkylene-, -alkylene-O--, --O-alkylene-,
-alkylene-S(O).sub.2--, --S(O).sub.2-alkylene,
[0097] --O--, --N(R.sub.15)--, --C(O)--, --CON(R.sub.15)--,
--N(R.sub.15)C(O)--, --N(R.sub.15)CON(R.sub.16)--,
--N(R.sub.15)C(O)O--, --OC(O)N(R.sub.15)--,
--N(R.sub.15)SO.sub.2--, --SO.sub.2N(R.sub.15)--, --C(O)--O--,
--O--C(O)--, --S--, --S(O)--, --S(O.sub.2)--,
--N(R.sub.15)SO.sub.2N(R.sub.16)--, ##STR2## and wherein R.sub.13,
R.sub.15, R.sub.16, and R.sub.17 independently comprise: -hydrogen,
-alkyl, -aryl, -heteroaryl, -arylene-alkyl, -heteroarylene-alkyl,
-alkylene-aryl, -alkylene-heteroaryl, -alkylene-arylene-alkyl, or
-alkylene-heteroarylene-alkyl.
[0098] D.sub.2 comprises --CH.sub.2--, -alkylene-, -alkenylene-,
-alkylene-S--, --S-alkylene-, -alkylene-O--, --O-alkylene-,
-alkylene-S(O).sub.2--, --S(O).sub.2-alkylene, --O--,
--N(R.sub.25)--, --C(O)--, --CON(R.sub.25)--, --N(R.sub.18)C(O)--,
--N(R.sub.18)CON(R.sub.19)--, --N(R.sub.18)C(O)O--,
--OC(O)N(R.sub.18)--, --N(R.sub.18)SO.sub.2--,
--SO.sub.2N(R.sub.18)--, --C(O)--O--, --O--C(O)--, --S--, --S(O)--,
--S(O.sub.2)--, --N(R.sub.18)SO.sub.2N(R.sub.19)--, and wherein
R.sub.18 and R.sub.19 independently comprise: -hydrogen, -alkyl,
-aryl, -arylene-alkyl, -alkylene-aryl, or
-alkylene-arylene-alkyl.
[0099] R.sub.14 comprises -hydrogen, -alkyl, -aryl, -heteroaryl,
-arylene-alkyl, -heteroarylene-alkyl, -alkylene-aryl,
-alkylene-heteroaryl, -alkylene-arylene-alkyl, or
-alkylene-heteroarylene-alkyl.
[0100] The most preferred embodiments of Ar, are those in which
Ar.sub.1 comprises a mono-substituted phenyl group wherein the
substituent comprises: -aryl, -arylene-alkyl, -D.sub.1-aryl,
-D.sub.1-alkylene-arylene-alkyl, or -arylene-D.sub.1-alkyl; wherein
D.sub.1 comprises --O--, --N(R.sub.15)--, --CON(R.sub.15)--, or
--N(R.sub.15)C(O)--, and wherein R.sub.15 comprises: -hydrogen;
-alkyl; or -aryl.
[0101] Ar.sub.2 comprises an aryl or heteroaryl group optionally
substituted 1 to 7 times. In preferred embodiments, Ar.sub.2
comprises a phenyl, naphthyl, pyridyl, isoquinolyl, pyrimidyl or
quinazolyl group optionally substituted 1 to 7 times. In especially
preferred embodiments, Ar.sub.2 comprises a substituted phenyl,
2-naphthyl, 2-pyridyl, 3-isoquinolyl, 2-pyrimidyl or 2-quinazolyl
group having 1 to 5 substituents wherein the substituents
independently comprise: [0102] a) -fluoro; [0103] b) -chloro;
[0104] c) -bromo; [0105] d) -iodo; [0106] e) -cyano; [0107] f)
-nitro; [0108] g) -perfluoroalkyl; [0109] h) -T.sub.1-R.sub.20;
[0110] i) -alkyl; [0111] j) -aryl; [0112] k) -heteroaryl; [0113] l)
-heterocyclyl; [0114] m) -cycloalkyl; [0115] n) -alkylene-aryl;
[0116] o) -alkylene-arylene-aryl; [0117] p)
-alkylene-arylene-alkyl; [0118] q) -arylene-alkyl; [0119] r)
-arylene-aryl; [0120] s) -arylene-heteroaryl; [0121] t)
-heteroarylene-aryl; [0122] u) -heteroarylene-heteroaryl; [0123] v)
-heteroarylene-heterocyclyl [0124] w) -arylene-heterocyclyl [0125]
x) -arylene-arylene-alkyl; [0126] y) -T.sub.1-alkyl; [0127] z)
-T.sub.1-aryl; [0128] aa) -T.sub.1-alkylene-aryl; [0129] bb)
-T.sub.1-alkenylene-aryl; [0130] cc) -T.sub.1-alkylene-heteroaryl;
[0131] dd) -T.sub.1-alkenylene-heteroaryl; [0132] ee)
-T.sub.1-cycloalkylene-aryl; [0133] ff)
-T.sub.1-cycloalkylene-heteroaryl; [0134] gg)
-T.sub.1-heterocyclylene-aryl; [0135] hh)
-T.sub.1-heterocyclylene-heteroaryl; [0136] ii)
-T.sub.1-arylene-alkyl; [0137] jj) -T.sub.1-arylene-alkenyl; [0138]
kk) -T.sub.1-alkylene-arylene-aryl; [0139] ll)
-T.sub.1-arylene-T.sub.2-aryl; [0140] mm)
-T.sub.1-arylene-arylene-aryl; [0141] nn)
-T.sub.1-alkylene-arylene-alkyl; [0142] oo)
-alkylene-T.sub.1-alkylene-aryl; [0143] pp) -arylene-T.sub.1-alkyl;
[0144] qq) -arylene-T.sub.1-alkylene-aryl; [0145] rr)
-T.sub.1-alkylene-T.sub.2-aryl; [0146] ss) -T.sub.1-alkylene-aryl;
[0147] tt) -alkylene-T.sub.1-heteroaryl; [0148] uu)
-alkylene-T.sub.1-cycloalkyl; [0149] vv)
-alkylene-T.sub.1-heterocyclyl; [0150] ww)
-alkylene-T-arylene-alkyl; [0151] xx)
-alkylene-T.sub.1-alkylene-arylene-alkyl; [0152] yy)
-alkylene-T.sub.1-alkyl; [0153] zz) -alkylene-T.sub.1-R.sub.20;
[0154] aaa) -arylene-T.sub.1-R20; or [0155] bbb) -hydrogen; wherein
T.sub.1 comprises --CH.sub.2--, --O--, --N(R.sub.21)--, --C(O)--,
--CON(R.sub.21)--, --N(R.sub.21)C(O)--,
--N(R.sub.21)CON(R.sub.22)--, --N(R.sub.21)C(O)O--,
--OC(O)N(R.sub.21)--, --N(R.sub.21)SO.sub.2--,
--SO.sub.2N(R.sub.21)--, --C(O)--O--, --O--C(O)--, --S--, --S(O)--,
--S(O.sub.2)--, --N(R.sub.21)SO.sub.2N(R.sub.22)--, ##STR3## and
wherein R.sub.20, R.sub.21, R.sub.22 and R.sub.23, independently
comprise: -hydrogen, -alkyl, -alkenyl, -alkylene-cycloalkyl,
-alkynene-heterocyclyl, -aryl, -heteroaryl, -arylene-alkyl,
-alkylene-aryl, -alkylene-arylene-alkyl, -alkylene-arylene-aryl,
-alkylene-arylene-alkylene-aryl, -alkylene-arylene-O-arylene, or
alkylene-arylene-O-alkylene-aryl; and
[0156] wherein T.sub.2 comprises a direct bond, --CH.sub.2--,
--O--, --N(R.sub.24)--, --C(O)--, --CON(R.sub.24)--,
--N(R.sub.24)C(O)--, --N(R.sub.24)CON(R.sub.25)--,
--N(R.sub.24)C(O)O--, --OC(O)N(R.sub.24)--,
--N(R.sub.24)SO.sub.2--, --SO.sub.2N(R.sub.24)--, --C(O)--O--,
--O--C(O)--, --S--, --S(O)--, --S(O.sub.2)--,
--N(R.sub.24)SO.sub.2N(R.sub.25)--, wherein R.sub.24 and R.sub.25
independently comprise; -hydrogen, -alkyl, -alkenyl,
-alkylene-cycloalkyl, alkynene-heterocyclyl, -aryl, -heteroaryl,
-arylene-alkyl, -alkylene-aryl, and -alkylene-arylene-alkyl.
[0157] The most preferred embodiments of Ar.sub.2 are those in
which Ar.sub.2 comprises a substituted phenyl, 2-naphthyl,
2-pyridyl, 3-isoquinolyl, 2-pyrimidyl or 2-quinazolyl group having
1 to 5 substituents independently comprising: [0158] a) -fluoro;
[0159] b) -chloro; [0160] c) -bromo; [0161] d) -iodo; [0162] e)
-cyano; [0163] f) -nitro; [0164] g) -perfluoroalkyl; [0165] h)
-T.sub.1-R.sub.20; [0166] i) -alkyl; [0167] j) -aryl; [0168] k)
-arylene-alkyl; [0169] l) -T.sub.1-alkyl; [0170] m)
-T.sub.1-alkylene-aryl; [0171] n) -T.sub.1-alkylene-arylene-aryl;
[0172] o) -T.sub.1-alkylene-arylene-alkyl; [0173] p)
-arylene-T.sub.1-alkyl; or [0174] q) -hydrogen; wherein T.sub.1
comprises --CH.sub.2--, --O--, --N(R.sub.21)--, --CON(R.sub.21)--,
or --N(R.sub.21)C(O)--; wherein R.sub.20 and R.sub.21 independently
comprise: -hydrogen, -alkyl, or -aryl.
[0175] The alkyl, aryl, heteroaryl, alkylene, and arylene groups in
Ar.sub.1, Ar.sub.2, R.sub.1, R.sub.2, R.sub.3, R.sub.4, R.sub.5,
R.sub.6, R.sub.7, R.sub.8, R.sub.9, R.sub.10, R.sub.11, R.sub.12,
R.sub.13, R.sub.14, R.sub.15, R.sub.16, R.sub.17, R.sub.18,
R.sub.19, R.sub.20, R.sub.21, R.sub.22, and R.sub.23, may be
optionally substituted 1 to 4 times with a substituent group,
wherein said substituent group(s) or the term substituted refers to
groups comprising: [0176] a) -hydrogen; [0177] b) -fluoro; [0178]
c) -chloro; [0179] d) -bromo; [0180] e) -iodo; [0181] f) -cyano;
[0182] g) -nitro; [0183] h) -perfluoroalkyl; [0184] i)
-Q-perfluoroalkyl [0185] i) -Q-R.sub.24; [0186] k) -Q-alkyl; [0187]
l) -Q-aryl; [0188] m) -Q-alkylene-aryl; [0189] n)
-Q-alkylene-NR.sub.25R.sub.26; or [0190] 0) -Q-alkyl-W--R.sub.27;
wherein Q and W independently comprise: --CH.sub.2--, --O--,
--N(R.sub.28)--, --C(O)--, --CON(R.sub.28)--, --N(R.sub.28)C(O)--,
--N(R.sub.28)CON(R.sub.29)--, --N(R.sub.28)C(O)O--,
--OC(O)N(R.sub.28)--, --N(R.sub.28)SO.sub.2--,
--SO.sub.2N(R.sub.28)--, --C(O)--O--, --O--C(O)--, or
--N(R.sub.28)SO.sub.2N(R.sub.29)--, wherein R.sub.24, R.sub.25,
R.sub.26, R.sub.27, R.sub.28, and R.sub.29 independently comprise:
-hydrogen, -alkyl, -aryl, -arylene-alkyl, -alkylene-aryl, or
-alkylene-arylene-alkyl.
[0191] Also included within the scope of the invention are the
individual enantiomers of the compounds represented by Formula (I)
above as well as any wholly or partially racemic mixtures thereof.
The present invention also covers the individual enantiomers of the
compounds represented by formula above as mixtures with
diastereoisomers thereof in which one or more stereocenters are
inverted.
[0192] In one group of particularly preferred embodiments, the
compounds are represented by Formula (I), in which c is equal to 0;
G comprises: -hydrogen or --CO.sub.2H; V comprises: --CH.sub.2--or
a direct bond; X comprises: --CON(R.sub.8)--, or --N(R.sub.8)CO--
wherein R.sub.8 comprises: -hydrogen; Ar.sub.1 comprises a
mono-substituted phenyl group wherein the substituent comprises:
-aryl, -arylene-alkyl, -D.sub.1-aryl
-D.sub.1-alkylene-arylene-alkyl, or -arylene-D.sub.1-alkyl, wherein
D, comprises --O--, or --N(R.sub.15)--, wherein R.sub.15 comprises:
-hydrogen, -alkyl, or -aryl; and Ar.sub.2 comprises a substituted
phenyl, 2-naphthyl, 2-pyridyl, 3-isoquinolyl, 2-pyrimidyl or
2-quinazolyl group having, 1 to 5 substituents independently
comprising: -hydrogen, -fluoro, -chloro, -bromo, iodo, -cyano,
-nitro, -perfluoroalkyl, -T.sub.1-R.sub.14, -alkyl, -aryl,
-arylene-alkyl, -T.sub.1-alkyl, -T.sub.1-alkylene-aryl, -T.
-alkylene-arylene-aryl, -T.sub.1-alkylene-arylene-alkyl, or
-arylene-T.sub.1-alkyl; wherein T.sub.1 comprises --CH.sub.2--,
--O--, --N(R.sub.21)--, --CON(R.sub.21)--, or --N(R.sub.21)C(O)--;
wherein R.sub.21 comprises: -hydrogen, -alkyl, or -aryl. The alkyl,
aryl, alkylene, and arylene groups in Ar.sub.1, and Ar.sub.2 may be
optionally substituted 1 to 4 times with a substituent group,
wherein said substituent group(s) or the term substituted refers to
groups comprising: -hydrogen, -fluoro, -chloro, -bromo, iodo,
-cyano, -nitro, or -perfluoroalkyl.
[0193] Compounds of the present invention having biological
activity are listed below in Table 1.
[0194] Unless indicated otherwise, the structures of Examples of
compounds of Formula (1) in Table 1 and elsewhere having vacant
connectivity for heteroatoms, such as oxygen and nitrogen, are
assumed to have a hydrogen atom attached thereto. TABLE-US-00001
TABLE 1 Example Structure Name 1 ##STR4## 3-Biphenyl-4-yl-(2S)-
[(isoquinoline-3-carbonyl)- amino]-propionic acid 2 ##STR5##
(2S)-[(Isoquinoline-3- carbonyl)-amino]-3-(4'-
trifluoromethyl-biphenyl-4- yl)-propionic acid 3 ##STR6##
(2S)-[(Isoquinoline-3- carbonyl)-amino]-3-(3;5'-
bistrifluoromethyl-biphenyl-4- yl)-propionic acid 4 ##STR7##
(2S)-[(Isoquinoline-3- carbonyl)-amino]-3-(4'-
methoxy-biphenyl-4-yl)- propionic acid 5 ##STR8##
3-[4-(4'-Cyano-phenoxy)- phenyl]-(2S)-[(isoquinoline-3-
carbonyl)-amino]-propionic acid 6 ##STR9## 3-[4-(4'-Nitro-phenoxy)-
phenyl]-(2S)-[(isoquinoline- 3-carbonyl)-amino]- propionic acid 7
##STR10## 3-(3'-Chloro-4-fluoro- biphenyl-4-yl)-(2S)-
[(isoquinoline-3-carbonyl)- amino]-propionic acid 8 ##STR11##
3-(4'-Cyano-biphenyl-4-yl)- (2S)-[(isoquinoline-3-
carbonyl)-amino]-propionic acid 9 ##STR12## (2S)-[(Isoquinoline-3-
carbonyl)-amino]- 3-(3'-trifluoromethyl- biphenyl-4-yl)-propionic
acid 10 ##STR13## (2S)-[(Isoquinoline-3- carbonyl)-amino]-
3-(3'-nitro-biphenyl-4-yl)- propionic acid 11 ##STR14##
3-Biphenyl-4-yl-(2S)-[(7- bromo-isoquinoline-3-
carbonyl)-amino]-propionic acid 12 ##STR15##
3-Biphenyl-4-yl-(2S)-{[7-(4- trifluoromethyl-phenyl)-
isoquinoIine-3-carbonyl]- amino}-propionic acid 13 ##STR16##
3-Biphenyl-4-yl-(2S)-{[7-(3- chloro-4-fluoro-phenyl)-
isoquinoline-3-carbonyl]- amino}-propionic acid 14 ##STR17##
2-Biphenyl-4-yl-N-(1-bromo- isoquinolin-3-yl)-acetamide 15
##STR18## 2-Biphenyl-4-yl-N-[1 (4- trifluoromethyl-phenyl)-
isoquinolin-3-yl]-acetamide 16 ##STR19##
N-[1(4-aminomethyl-phenyl)- isoquinolin-3-yl]-2-biphenyl-
4-yl-acetamide 17 ##STR20## 3-Biphenyl-4-yl-(2S)-{[4-(2-
biphenyl-4-yl-ethylamino)- quinazoline-2-carbonyl]-
amino}-propionic acid 18 ##STR21## 3-Biphenyl-4-yl-(2S)-{4-
tert-butyl-benzylamino)- quinazoline-2-carbonyl]amino}-propionic
acid 19 ##STR22## 3-Biphenyl-4-yl-(2S)-{[6-(3-
chloro-4-fluoro-phenyl)- pyridine-2-carbonyl]-amino}- propionic
acid 20 ##STR23## 3-Biphenyl-4-yl-(2S)-{[6-(3-
chloro-4-fluoro-phenyl)- pyridine-2-carbonyl]-amino}- propionic
acid 21 ##STR24## 3-Biphenyl-4-yl-(29)-{[6-(4-
trifluoromethoxy-phenyl)- pyridine-2-carbonyl]-amino}- propionic
acid 22 ##STR25## 3-Biphenyl-4-yl-(2S)-{[6-(4-
fluoro-3-methyl-phenyl)- pyridine-2-carbonyl]- amino}-propionic
acid 23 ##STR26## (2S){[6-(4-Amino-phenyl)-
pyridine-2-carbonyl]-amino}- 3-biphenyl-4-yl-propionic acid 24
##STR27## 3-Biphenyl-4-yl-(2S)-{[6-(3- cyano-phenyl)-pyridine-2-
carbonyl]-amino}-propionic acid 25 ##STR28##
3-Biphenyl-4-yl-(2S)-{[6-(4- methanesulfonyl-phenyl)-
pyridine-2-carbonyl]- amino}-propionic acid 26 ##STR29##
3-Biphenyl-4-yl-(2S)-{[6-(4- methoxy-phenyl)-pyridine-2-
carbonyl]-amino}-propionic acid 27 ##STR30##
3-Biphenyl-4-yl-(2S)-{[6-(3- carboxamidinoyl-phenyl)-
pyridine-2-carbonyl]-amino}- propionic acid 28 ##STR31##
3-Biphenyl-4-yl-(2S)-{[6-(4- phenoxy-phenyl)-pyridine-2-
carbonyl]-amino}-propionic acid 29 ##STR32##
3-Biphenyl-4-yl-(2S)-{[6-(4- tert-butyl-phenyl)-pyridine-2-
carbonyl]-amino}-propionic acid 30 ##STR33##
3-Biphenyl-4-yl-(2S)-{[5-(3- chloro-4-fluoro-phenyl)-
pyridine-2-carbonyl]-amino}- propionic acid 31 ##STR34##
3-Biphenyl-4-yl-(2S)-{[5-(4- rifluoromethyl-phenyl)-
pyridine-2-carbonyl]- amino}-propionic acid 32 ##STR35##
3-Biphenyl-4-yl-(2S)-{[5-(4- methoxy-phenyl)-pyridine-2-
carbonyl]-amino}-propionic acid 33 ##STR36##
3-Biphenyl-4-yl-(2S)-{[4-(3- chloro-4-fluoro-phenyl)-
pyridine-2-carbonyl]-amino}- propionic acid 34 ##STR37##
3-Biphenyl-4-yl-(2S)-{[4-(4- methoxy-phenyl)-pyridine-2-
carbonyl]-amino}-propionic acid 35 ##STR38##
3-Biphenyl-4-yl-(2S)-{[4-(4- trifluoromethyl-phenyl)-
pyridine-2-carbonyl]- amino}-propionic acid 36 ##STR39##
3-Biphenyl-4-yl-(2S)-{[4-(3- trifluoromethyl-phenyl)-
pyridine-2-carbonyl]- amino}-propionic acid 37 ##STR40##
3-Hydroxy-napthalene-2- carboxylic acid (2-biphenyl-
4-yl-ethyl)-amide 38 ##STR41## 3-[(3'-Chloro-4'-fluoro)-
biphenyl-4-yl]-(2S)-[(3- hydroxy-naphthalene-2-
carbonyl)-amino]-propionic acid 39 ##STR42##
3-(Biphenyl-4-yl)-(2S)-[(3- hydroxy-napthalene-2-
carbonyl)-amino]-propionic acid 40 ##STR43## (2S)-[(3-Hydroxy-
napthalene-2-carbonyl)- amino]-3-[(3'-nitro)-biphenyl-
4-yl]-propionic acid 41 ##STR44## 3-(Biphenyl-4-yl)-(2S)-[(3'-
chloro-4'-fluoro-4-hydroxy- biphenyl-3-carbonyl)-amino]- propionic
acid methyl ester 42 ##STR45## 3-(Biphenyl-4-yl)-(2S)-[(4'-
trifluoromethyl-4-hydroxy- biphenyl-3-carbonyl)-amino]- propionic
acid methyl ester 43 ##STR46## (2S)-[(3'-Chloro-4'-fluoro-4-
hydroxy-biphenyl-3- carbonyl)-amino]-3-(3'-
trifluoromethyl-biphenyl-4- yl)-propionic methyl ester 44 ##STR47##
3-(4'-Nitro-biphenyl-4-yl)- (2S)-[(4'-trifluoromethyl-4-
hydroxy-biphenyl-3- carbonyl)-amino]-propionic acid methyl ester 45
##STR48## 3-(3'-Trifluoromethyl- biphenyl-4-yl)-(2S)-[(4'-
trifluoromethyl-4-hydroxy- biphenyl-3-carbonyl)-amino]- propionic
acid methyl ester 46 ##STR49## 3-(4'-Trifluoromethyl-
biphenyl-4-yl)-(2S)-[(4'- trifluoromethyl-4-hydroxy-
biphenyl-3-carbonyl)-amino]- propionic acid methyl ester 47
##STR50## 3-Biphenyl-4-yl-(2S)-[(2',4'-
difluoro-4-hydroxy-biphenyl- 3-carbonyl)-amino]-propionic acid 48
##STR51## 3-Biphenyl-4-yl-(2S)-[(4'- chloro-3'-fluoro-4-hydroxy-
biphenyl-3-carbonyl)-amino]- propionic acid methyl ester 49
##STR52## 3-Biphenyl-4-yl-(2S)-[(3'- chloro-4'-fluoro-4-hydroxy-
biphenyl-3-carbonyl)-amino]- propionic acid 50 ##STR53##
3-Blphenyl-4-yl-(2S)-[(4- hydroxy-3'-nitro-biphenyl-3-
carbonyl)-amino}-propionic acid methyl ester 51 ##STR54##
3-Biphenyl-4-yl-(2S)-[(4- hydroxy-4'-trifluoromethoxy-
biphenyl-3-carbonyl)-amino]- propionic acid methyl ester 52
##STR55## (2S)-[(4-Hydroxy-4- trifluoromethyl-biphenyl-3-
carbonyl)-amino}-3-(3'-nitro- biphenyl-4-yl)-propionic acid 53
##STR56## (2S)-[(4-Hydroxy-4'- trifluoromethyl-biphenyl-3-
carbonyl)-amino}-3-(3'-nitro- biphenyl-4-yl)-propionic acid methyl
ester 54 ##STR57## (2S)-[(3'-Chloro-4'-fluoro-4-
hydroxy-biphenyl-3- carbonyl)-amino]-3-(3'-nitro-
biphenyl-4-yl)-propionic acid methyl ester 55 ##STR58##
3-Biphenyl-4-yl-(2S)-[(4'- fluoro-4-hydroxy-biphenyl-3-
carbonyl)-amino]-propionic acid methyl ester 56 ##STR59##
3-Biphenyl-4-yl-(2S)-[(4- hydroxy-4'-methoxy-
biphenyl-3-carbonyl)-amino]- propionic acid methyl ester 57
##STR60## 3-Biphenyl-4-yl-(2S)-[(4'-tert-
butyl-4-hydroxy-biphenyl-3- carbonyl)-amino]-propionic acid methyl
ester 58 ##STR61## (2S)-[(4-Hydroxy-3-nitro-
biphenyl-3-carbonyl)-amino]- 3-(3'-trifluoromethyl-
biphenyl-4-yl)-propionic acid methyl ester 59 ##STR62##
3-(3'-Chloro-4'-fluoro- biphenyl-4-yl)-(2S)-[(4-
hydroxy-3'-nitro-biphenyl- 3-carbonyl)-amino]-propionic acid methyl
ester 60 ##STR63## (2S)-[(4-Amino-4-hydroxy-
biphenyl-3-carbonyl)-amino]- 3-biphenyl-4-yl-propionic acid methyl
ester 61 ##STR64## (2S)-[(3'-Amino-4-hydroxy-
biphenyl-3-carbonyl)-amino]- 3-biphenyl-4-yl-propionic acid methyl
ester 62 ##STR65## 3-Biphenyl-4-yl-(2S)-[(5'-
fluoro-4-hydroxy-2'-methoxy- biphenyl-3-carbonyl)-amino}- propionic
acid methyl ester 63 ##STR66## 3-Biphenyl-4-yl-(2S)-[(3'-
fluoro-4-hydroxy-biphenyl-3- carbonyl)-amino]-propionic acid methyl
ester 64 ##STR67## 3-Biphenyl-4-yl-(2S)-[(4-
hydroxy-3'-trifluoromethyl- biphenyl-3-carbonyl)- amino]-propionic
acid methyl ester 65 ##STR68## 3-Biphenyl-4-yl-(2S)-[(4-
hydroxy-3',5'-bis- trifluoromethyl-biphenyl-3-
carbonyl)-amino]-propionic acid methyl ester 66 ##STR69##
3-Biphenyl-4-yl-(2S)-[(3'- chloro-4-hydroxy-biphenyl-3-
carbonyl)-amino]-propionic acid methyl ester 67 ##STR70##
3-Biphenyl-4-yl-(2S)-[(4- chloro-4-hydroxy-biphenyl-3-
carbonyl)-amino]-propionic acid methyl ester 68 ##STR71##
3-Biphenyl-4-yl-(2S)-[(3',5'- difluoro-4-hydroxy-biphenyl-
3-carbonyl)-amino]-propionic acid methyl ester 69 ##STR72##
3-Biphenyl-4-yl-(2S)-[(4'- fluoro-4-hydroxy-3'-methyl-
biphenyl-3-carbonyl)-amino]- propionic acid methyl ester 70
##STR73## (2S)-[(3'-Chloro-4'-fluoro-4- hydroxy-biphenyl-3-
carbonyl)-amino]-3-(4'- trifluoromethyl-biphenyl-4- yl)-propionic
acid methyl ester 71 ##STR74## (2S)-[(3'-Chloro-4'-fluoro-4-
hydroxy-biphenyl-3- carbonyl)-amino]-3-(4'- methoxy-biphenyl-4-yl)-
propionic acid methyl ester 72 ##STR75## 3-Biphenyl-4-yl-(2S)-[(4-
hydroxy-4'-trifluoromethoxy- biphenyl-3-carbonyl)- amino}-propionic
acid 73 ##STR76## 3-Biphenyl-4-yl-(2S)-[(4'-tert-
butyl-4-hydroxy-biphenyl-3- carbonyl)-amino]-propionic acid 74
##STR77## 3-Biphenyl-4-yl-(2S)-[(4- hydroxy-3',4'-dimethoxy-
biphenyl-3-carbonyl)-amino]- propionic acid methyl ester 75
##STR78## (2S)-(5-Benzo[1,3]dioxol-5- yl-2-hydroxy-benzoylamino)-
3-biphenyl-4-yl-propionic acid methyl ester 76 ##STR79##
3-(3'-Chloro-4'-fluoro- biphenyl-4-yl)-(2S)-[(4-
hydroxy-4'-trifluoromethyl- biphenyl-3-carbonyl)-amino]- propionic
acid methyl ester 77 ##STR80## 3-Biphenyl-4-yl-(2S)-[(4-
hydroxy-4'-methanesulfonyl- biphenyl-3-carbonyl)- amino]-propionic
acid methyl ester 78 ##STR81## (2S)-[(3'-Amino-4-hydroxy-
biphenyl-3-carbonyl)-amino]- 3-(3'-trifluoromethyl- biphenyl-4-yl)-
propionic acid methyl ester
79 ##STR82## 3-(3',5'-Bis-trifluoromethyl-
biphenyl-4-yl)-(2S)-[(3'- chloro-4'-fluoro-4-hydroxy-
biphenyl-3-carbonyl)-amino]- propionic acid methyl ester 80
##STR83## 3-(3',5'-Bis-trifluoromethyl- biphenyl-4-yl)-(2S)-[(4'-
fluoro-4-hydroxy-biphenyl-3- carbonyl)-amino]-propionic acid methyl
ester 81 ##STR84## 3-(3',5'-Bis-trifluoromethyl-
biphenyl-4-yl)-(2S)-[(4- hydroxy-4'-trifluoromethyl-
biphenyl-3-carbonyl)-amino]- propionic acid methyl ester 82
##STR85## (2S)-[(3'-Chloro-4'-fluoro-4- hydroxy-biphenyl-3-
carbonyl)-amino]-3-(3'- trifluoromethyl-biphenyl-4- yl)-propionic
acid 83 ##STR86## (2S)-[(4-Hydroxy-4'- trifluoromethyl-biphenyl-3-
carbonyl)-amino]-3-(3'- trifluoromethoxy-biphenyl-4- yl)-propionic
acid methyl ester 84 ##STR87## (2S)-[(4-Hydroxy-3'-
trifluoromethyl-biphenyl-3- carbonyl)-amino]-3-(3'-
trifluoromethyl-biphenyl-4- yl)-propionic acid methyl ester 85
##STR88## 4'-{(2S)-[(4-Hydroxy-4'- trifluoromethyl-biphenyl-3-
carbonyl)-amino]-2- methoxycarbonyl-ethyl}-5-
nitro-biphenyl-3-carboxylic acid methyl ester 86 ##STR89##
(2S)-[(4-Hydroxy-4'- trifluoromethyl-biphenyl-3-
carbonyl)-amino]-3-(3',4',5'- trimethoxy-biphenyl-4-yl)- propionic
acid methyl ester 87 ##STR90## (2S)-[(3'-Chloro-4'-fluoro-4-
hydroxy-biphenyl-3- carbonyl)-amino]-3-(3'-
trifluoromethoxy-biphenyl-4- yl)-propionic acid methyl ester 88
##STR91## 3-Biphenyl-4-yl-(2S)-[(4- hydroxy-4'-trifluoromethyl-
biphenyl-3-carbonyl)- amino}-propionic acid 89 ##STR92##
(2S)-[(4-Hydroxy-2'- trifluoromethyl-biphenyl-3-
carbonyl)-amino]-3-(2'- trifluoromethyl-biphenyl-4- yl)-propionic
acid methyl ester 90 ##STR93## 3-(3'-Chloro-4'-fluoro-
biphenyl-4-yl)-(2S)-[(3- chloro-4'-fluoro-4-hydroxy-
biphenyl-3-carbonyl)-amino]- propionic acid methyl ester 91
##STR94## (2S)-[(4-Hydroxy-3'-nitro- biphenyl-3-carbonyl)-amino]-
3-(3'-nitro-biphenyl-4-yl)- propionic acid methyl ester 92
##STR95## (2S)-[(4-Hydroxy-3'- trifluoromethyl-biphenyl-3-
carbonyl)-amino]-3-(3'-nitro- biphenyl-4-yl)-propionic acid methyl
ester 93 ##STR96## (2S)-[(4-Hydroxy-3'- trifluoromethyl-biphenyl-3-
carbonyl)-amino]-3-(4'- trifluoromethyl-biphenyl-4- yl)-propionic
acid methyl ester 94 ##STR97## 3-(3'-Chloro-4'-fluoro-
biphenyl-4-yl)-(2S)-[(4- hydroxy-3'-trifluoromethyl-
biphenyl-3-carbonyl)-amino]- propionic acid methyl ester 95
##STR98## 3-Biphenyl-4-yl-(2S)-[(4- hydroxy-2'-trifluoromethyl-
biphenyl-3-carbonyl)- amino]-propionic acid methyl ester 96
##STR99## 3-(3',5'-Bis-trifluoromethyl- biphenyl-4-yl)-(2S)-[(4-
hydroxy-3'-trifluoromethyl- biphenyl-3-carbonyl)-amino]- propionic
acid methyl ester 97 ##STR100## (2S)-[(4-Hydroxy-3'-
trifluoromethyl-biphenyl-3- carbonyl)-amino]-3-(2'-
trifluoromethyl-biphenyl-4- yl)-propionic acid methyl ester 98
##STR101## (2S)-[2-(4-Benzyloxy- benzyloxy)-5-bromo-
benzoylamino]-3-biphenyl-4- yl-propionic acid 99 ##STR102##
3-Biphenyl-4-yl-2S-{[4-(4- tert-butyl-benzyloxy)-3'-
chloro-4'-fluoro-biphenyl-3- carbonyl]-amino}-propionic acid 100
##STR103## (2S)-[5-Bromo-2-(4- trifluoromethyl-benzyloxy)-
benzoylamino]-3-(2'-phenoxy- biphenyl-4-yl)-propionic acid 101
##STR104## (2S)-(5-Bromo-2-heptyloxy- benzoylamino)-3-[2'-(4-
trifluoromethyl-phenoxy)- biphenyl-4-yl]-propionic acid 102
##STR105## (2S)-(5-Chloro-2-heptyloxy- benzoylamino)-3-(4'-
trifluoromethoxy-biphenyl- 4-yl)-propionic acid 103 ##STR106##
3-Biphenyl-4-yl-(2S)-[2-(3,4- bis-benzyloxy-benzyloxy)-5-
bromo-benzoylamino]- propionic acid methyl ester 104 ##STR107##
3-Biphenyl-4-yl-(2S)-[2-(3,4- bis-benzyloxy-benzyloxy)-5-
bromo-benzoylamino]- propionic acid 105 ##STR108##
(2S)-[2-(4-Benzyloxybenzyloxy)- 5-bromo-benzoylamino]-
3-biphenyl-4-yl-propionic acid methyl ester 106 ##STR109##
3-Biphenyl-4-yl-(2S)-[5- bromo-2-(4-bromo-
benzyloxy)-benzoylamino]- propionic acid methyl ester 107
##STR110## 3-Biphenyl-4-yl-(2S)-[5- bromo-2-(4-bromo-
benzyloxy)-benzoylamino]- propionic acid 108 ##STR111##
3-Biphenyl-4-yl-(2S)-[5- bromo-2-(4-tert-butyl-
benzyloxy)-benzoylamino]- propionic acid methyl ester 109
##STR112## 3-Biphenyl-4-yl-(2S)-[5- bromo-2-(4-tert-butyl-
benzyloxy)-benzoylamino]- propionic acid 110 ##STR113##
3-Biphenyl-4-yl-(2S)-[2- (biphenyl-4-ylmethoxy)-5-
bromo-benzoylamino]- propionic acid 111 ##STR114##
3-Biphenyl-4-yl-(2S)-(5- chloro-2-methoxy- benzoylamino)-propionic
acid 112 ##STR115## 3-Biphenyl-4-yl-(2S)-[2-(4-
tert-butyl-benzyloxy)-5- chloro-benzoylamino]- propionic acid 113
##STR116## 3-Biphenyl-4-yl-(2S)-[2-(4- tert-butyl-benzyloxy)-5-(4-
trifluoromethylphenyl)- benzoylamino]-propionic acid 114 ##STR117##
(2S)-[5-Bromo-2-(3-methyl- benzyloxy)-benzoylamino]-3-
(2'-phenoxy-biphenyl-4-yl)- propionic acid methyl ester 115
##STR118## (2S)-[5-Bromo-2-(4-methyl- benzyloxy)-benzoylamino]-3-
(2'-phenoxy-biphenyl-4-yl)- propionic acid 116 ##STR119##
(2S)-[5-Bromo-2-(3-methyl- benzyloxy)-benzoylamino]-3-
(2'-phenoxy-biphenyl-4-yl)- propionic acid 117 ##STR120##
(2S)-[5-Bromo-2-(4-carboxy- benzyloxy)-benzoylamino]-3-
(2'-phenoxy-biphenyl-4-yl)- propionic acid 118 ##STR121##
(2S)-[5-Bromo-2-(4- trifluoromethyl-phenoxy)- benzoylamino]-3-(2'-
phenoxy-biphenyl-4-yl)- propionic acid 119 ##STR122##
(2S)-(5-Bromo-2-heptyloxy- benzoylamin-3-(2'-phenoxy-
biphenyl-4-yl)-propionic acid methyl ester 120 ##STR123##
3-Biphenyl-4-yl-(2S)-(5- bromo-2-heptyloxy- benzoylamino)-propionic
acid methyl ester 121 ##STR124## 3-Biphenyl-4-yl-(2S)-(5-
bromo-2-heptyloxy- benzoylamino)-propionic acid 122 ##STR125##
(2S)-(5-Bromo-2-heptyloxy- benzoylamino)-3-(2'-
phenoxy-biphenyl-4-yl)- propionic acid 123 ##STR126##
3-Biphenyl-4-yl-(2S)-[5- chloro-2-(4-pyrazol-1-yl-
benzyloxy)-benzoylamino]- propionic acid 124 ##STR127##
(2S)-[5-Bromo-2-(4-tert- butyl-benzyloxy)- benzoylamino]-3-(2'-
phenoxy-biphenyl-4-yl)- propionic acid 125 ##STR128##
(2S)-(2-Benzyloxy-5-bromo- benzoylamino)-3-(2'-
phenoxy-biphenyl-4-yl)- propionic acid methyl ester 126 ##STR129##
(2S)-(2-Benzyloxy-5-bromo- benzoylamino)-3-(2'-
phenoxy-biphenyl-4-yl)- propionic acid 127 ##STR130##
(2S)-[5-Bromo-2-(4-bromo- benzyloxy)-benzoylamino]-3-
(2'-phenoxy-biphenyl- 4-yl)-propionic acid 128 ##STR131##
(2S)-(5-Bromo-2-propoxy- benzoylamino)-
3-(2'-phenoxy-biphenyl-4-yl)- propionic acid 129 ##STR132##
(2S)-[(5-Bromo-2,3-dihydro- benzofuran- 7-carbonyl)-amino]-3-(2'-
phenoxy-biphenyl-4-yl)- propionic acid 130 ##STR133##
(2S)-[5-Bromo-2-(3-phenyl- allyloxy)-benzoylamino]-3-
(2'-phenoxy-biphenyl- 4-yl)-propionic acid methyl ester 131
##STR134## (2S)-[5-Bromo-2-(3-phenyl- allyloxy)-benzoylamino]-3-
(2'-phenoxy-biphenyl- 4-yl)-propionic acid 132 ##STR135##
(2S)-[5-Bromo-2-(4- methanesulfonyl-benzyloxy)-
benzoylamino]-3-(2'- phenoxy-biphenyl-4-yl)- propionic acid methyl
ester 133 ##STR136## (2S)-[5-Bromo-2-(4-
methanesulfonyl-benzyloxy)- benzoylamino]-3-(2'-
phenoxy-biphenyl-4-yl)- propionic acid 134 ##STR137##
(2S)-[5-Bromo-2-(3-methyl- butoxy)-benzoylamino]-3-(2'-
phenoxy-biphenyl-4-yl)- propionic acid methyl ester 135 ##STR138##
(2S)-[5-Bromo-2-(3-methyl- butoxy)-benzoylamino]-3-(2'-
phenoxy-biphenyl-4-yl)- propionic acid 136 ##STR139##
(2S)-[2-(Biphenyl-4- ylmethoxy)-5-bromo- benzoylamino]-3-(2'-
phenoxy-biphenyl-4-yl)- propionic acid methyl ester 137 ##STR140##
(2S)-[2-(Biphenyl-4- ylmethoxy)-5-bromo- benzoylamino]-3-(2'-
phenoxy-biphenyl-4-yl)- propionic acid 138 ##STR141##
(2S)-[5-Bromo-2-(4-methoxy- phenoxy)-benzoylamino]-3-
(2'-phenoxy-biphenyl-4-yl)- propionic acid 139 ##STR142##
(2S)-[5-Bromo-2-(4-phenoxy- benzyloxy)- benzoylamino]-3-(2'-
phenoxy-biphenyl-4-yl)- propionic acid 140 ##STR143##
(2S)-[5-Bromo-2-(1-methyl- butoxy)-benzoylamino]-3-(2'-
phenoxy-biphenyl-4-yl)- propionic acid methyl ester 141 ##STR144##
(2S)-[5-Bromo-2-(1-methyl- butoxy)-benzoylamino]-3-(2'-
phenoxy-biphenyl-4-yl)- propionic acid 142 ##STR145##
(2S)-(5-Bromo-2-isopropoxy- benzoylamino)-3-(2'-
phenoxy-biphenyl-4-yl)- propionic acid 143 ##STR146##
(2S)-[5-Bromo-2-(3- trifluoromethyl-phenoxy)- benzoylamino]-3-(2'-
phenoxy-biphenyl-4-yl)- propionic acid 144 ##STR147##
(2S)-(5-Bromo-2-heptyloxy- benzoylamino)-3-[2'-(4-
methoxy-phenoxy)-biphenyl- 4-yl]-propionic acid 145 ##STR148##
(2S)-[5-Bromo-2-(2- morpholin-4-yl-ethoxy)- benzoylamino]-3-(2'-
phenoxy-biphenyl-4-yl)- propionic acid methyl ester 146 ##STR149##
(2S)-{5-Bromo-2-[2-(2- methoxy-ethoxy)-
ethoxy]-benzoylamino}-3-(2'- phenoxy-biphenyl-4-yl)- propionic acid
methyl ester 147 ##STR150## (2S)-(5-Bromo-2-{2-[2-(2-
methoxy-ethoxy)-ethoxy]- ethoxy}-benzoylamino)-3-
(2'-phenoxy-biphenyl-4-yl)- propionic acid methyl ester 148
##STR151## (2S)-(5-Bromo-2-{2-[2-(2- methoxy-ethoxy)-ethoxy]-
ethoxy}-benzoylamino)-3- (2'-phenoxy-biphenyl-4-yl)- propionic acid
methyl ester 149 ##STR152## (2S)-{5-Bromo-2-[2-(2-oxo-
pyrrolidin-1-yl)-ethoxy]- benzoylamino}-3-(2'-
phenoxy-biphenyl-4-yl)- propionic acid methyl ester 150 ##STR153##
(2S)-[5-Bromo-2-(2-phenyl- cyclopropylmethoxy)-
benzoylamino]-3-(2'- phenoxy-biphenyl- 4-yl)-propionic acid 151
##STR154## (2S)-(5-Bromo-2-sec-butoxy- benzoylamino)-3-(2'-
phenoxy-biphenyl-4-yl)- propionic acid 152 ##STR155##
(2S)-(5-Chloro-2-heptyloxy- benzoylamino)-3-(2'-
phenoxy-biphenyl-4-yl)- propionic acid methyl ester 153 ##STR156##
(2S)-(5-Chloro-2-heptyloxy- benzoylamino)-3-(2'-
phenoxy-biphenyl-4-yl)- propionic acid 154 ##STR157##
(2S)-(5-Bromo-2-isobutoxy- benzoylamino)-3-(2'-
phenoxy-biphenyl-4-yl)- propionic acid methyl ester 155 ##STR158##
(2S)-(5-Bromo-2-isobutoxy- benzoylamino)-3-(2'-
phenoxy-biphenyl-4-yl)- propionic acid 156 ##STR159##
(2S)-(5-Bromo-2- ethoxycarbonyloxy- benzoylamino)-3-(2'-
phenoxy-biphenyl-4- yl)-propionic acid methyl ester
157 ##STR160## (2S)-(5-Bromo-2- dimethylcarbamoyloxy-
benzoylamino)-3-(2'- phenoxy-biphenyl-4-yl)- propionic acid methyl
ester 158 ##STR161## (2S)-{5-Bromo-2-[2-(2- methoxy-ethoxy)-
ethoxy]-benzoylamino}-3-(2'- phenoxy-biphenyl-4-yl)- propionic acid
159 ##STR162## (2S)[5-Bromo-2-(4-phenyl-
butoxy)-benzoylamino]-3-(2'- phenoxy-biphenyl-4- yl)-propionic acid
160 ##STR163## (2S)-[5-Bromo-2-(5-phenyl-
pentyloxy)-benzoylamino]-3- (2'-phenoxy-biphenyl-4-yl)- propionic
acid 161 ##STR164## (2S)-[5-Bromo-2-(6-phenyl-
hexyloxy)-benzoylamino]-3- (2'-phenoxy-biphenyl- 4-yl)-propionic
acid 162 ##STR165## (2S)-(5-Bromo-2-heptyloxy-
benzoylamino)-3-[2'-(4- trifluoromethoxy-phenoxy)-
biphenyl-4-yl]-propionic acid 163 ##STR166##
(2S)-(5-Bromo-2-{2-[2-(2- methoxy-ethoxy)-ethoxy]-
ethoxy}-benzoylamino)-3- (2'-phenoxy-biphenyl-4-yl)- propionic acid
164 ##STR167## (2S)-[5-Bromo-2-(2-piperidin-
1-yl-ethoxy)-benzoylamino]- 3-(2'-phenoxy-biphenyl-4-yl)- propionic
acid 165 ##STR168## (2S)-(5-Bromo-2-heptyloxy-
benzoylamino)-3-[2'-(4-tert- butyl-phenoxy)-biphenyl-4-
yl]-propionic acid 166 ##STR169## (2S)-(5-Chloro-2-heptyloxy-
benzoylamino)-3-(4'- trifluoromethyl-biphenyl-4- yl)-propionic acid
167 ##STR170## 3-(3'-Chloro-4'-fluoro-
biphenyl-4-yl)-(2S)-(5-chloro- 2-heptyloxy-benzoylamino)- propionic
acid 168 ##STR171## (2S)-[5-Bromo-2-(3-phenyl-
propoxy)-benzoylamino]-3- (2'-phenoxy-biphenyl-4-yl)- propionic
acid 169 ##STR172## (2S)-{5-Bromo-2-[3-(3,4-
dimethoxy-phenyl)-propoxy]- benzoylamino}-3-(2'-
phenoxy-biphenyl-4-yl)- propionic acid 170 ##STR173##
(2S)-[5-Bromo-2-(3-pyridin- 3-yl-propoxy)- benzoylamino]-3-(2'-
phenoxy-biphenyl-4-yl)- propionic acid 171 ##STR174##
(2S)-[5-Bromo-2-(3-pyridin- 4-yl-propoxy)- benzoylamino]-3-(2'-
phenoxy-biphenyl-4-yl)- propionic acid 172 ##STR175##
(2S)-(5-Bromo-2- dimethylcarbamoyloxy- benzoylamino)-3-(2'-
phenoxy-biphenyl-4-yl)- propionic acid 173 ##STR176##
(2S)-[5-Bromo-2-(3- morpholin-4-yl-propoxy)- benzoylamino]-3-(2'-
phenoxy-biphenyl-4-yl)- propionic acid 174 ##STR177##
(2S)-[5-Bromo-2-(4,4,4- trifluoro-butoxy)- benzoylamino]-3-(2'-
phenoxy-biphenyl-4-yl)- propionic acid 175 ##STR178##
(2S)-(5-Chloro-2-heptyloxy- benzoylamino)-3-(4'-
cyclohexyl-biphenyl-4-yl)- propionic acid 176 ##STR179##
(2S)-(5-Chloro-2-heptyloxy- benzoylamino)-3-(3',4'-
dichloro-biphenyl-4-yl)- propionic acid 177 ##STR180##
(2S)-(5-Bromo-2-butoxy- benzoylamino)-3-(2'-
phenoxy-biphenyl-4-yl)- propionic acid 178 ##STR181##
(2S)-[5-Bromo-2-(2-methyl- butoxy)-benzoylamino}-3-(2'-
phenoxy-biphenyl-4-yl)- propionic acid 179 ##STR182##
(2S)-(5-Bromo-2- cyclopropylmethoxy- benzoylamino)-3-(2'-
phenoxy-biphenyl-4-yl)- propionic acid methyl ester 180 ##STR183##
(2S)-(5-Bromo-2- cyclopropylmethoxy- benzoylamino)-3-(2'-
phenoxy-biphenyl-4-yl)- propionic acid 181 ##STR184##
(2S)-[5-Bromo-2-(4- [1,2,4]triazol-1-yl-benzyloxy)-
benzoylamino]-3-(2'- phenoxy-biphenyl-4-yl)- propionic acid 182
##STR185## (2S)-[5-Bromo-2- (isoquinolin-1-ylmethoxy)-
benzoylamino]-3-(2'- phenoxy-biphenyl-4-yl)- propionic acid 183
##STR186## (2S)-[2-(3-Benzyloxy- benzyloxy)-5-bromo-
benzoylamino]-3-(4'- phenoxy-biphenyl-4-yl)- propionic acid methyl
ester 184 ##STR187## (2S)-[2-(3-Benzyloxy- benzyloxy)-5-bromo-
benzoylamino]-3-(4'- phenoxy-biphenyl-4-yl)- propionic acid 185
##STR188## (2S)-[5-Bromo-2-(4- trifluoromethoxy-benzyloxy)-
benzoylamino]-3-(2'- phenoxy-biphenyl-4-yl)- propionic acid methyl
ester 186 ##STR189## (2S)-[5-Bromo-2-(4-
trifluoromethoxy-benzyloxy)- benzoylamino]-3-(2'-
phenoxy-biphenyl-4-yl)- propionic acid 187 ##STR190##
(2S)-[5-Bromo-2-(4-phenyl- butoxy)-benzoylamino]-3-(4'-
phenoxy-biphenyl-4-yl)- propionic acid methyl ester 188 ##STR191##
(2S)-[5-Bromo-2-(6-phenyl- hexyloxy)-benzoylamino]-3-
(4'-phenoxy-biphenyl-4-yl)- propionic acid methyl ester 189
##STR192## (2S)-(5-Chloro-2-heptyloxy- benzoylamino)-3-(4'-
dimethylamino-biphenyl-4- yl)-propionic acid 190 ##STR193##
(2S)-[5-Bromo-2-(4-phenyl- butoxy)-benzoylamino]-3-(4'-
phenoxy-biphenyl-4-yl)- propionic acid 191 ##STR194##
(2S)-[5-Bromo-2-(6-phenyl- hexyloxy)-benzoylamino]-3-
(4'-phenoxy-biphenyl-4-yl)- propionic acid 192 ##STR195##
(2S)-[5-Bromo-2-(2- cyclohexyl-ethoxy)- benzoylamino]-3-(2'-
phenoxy-biphenyl-4-yl)- propionic acid methyl ester 193 ##STR196##
(2S)-[5-Bromo-2-(2- cyclohexyl-ethoxy)- benzoylamino]-3-(2'-
phenoxy-biphenyl-4-yl)- propionic acid 194 ##STR197##
(2S)-(5-Bromo-2- cyclohexylmethoxy- benzoylamino)-3-(2'-
phenoxy-biphenyl-4-yl)- propionic acid 195 ##STR198##
(2S)-(5-Bromo-2- cyclohexyloxy- benzoylamino)-3-(2'-
phenoxy-biphenyl-4-yl)- propionic acid methyl ester 196 ##STR199##
(2S)-(5-Bromo-2- cyclohexyloxy- benzoylamino)-3-(2'-
phenoxy-biphenyl-4-yl)- propionic acid 197 ##STR200##
N-[2-Hydroxy-4-(4- trifluoromethyl-phenoxy)- phenyl]-2-(3'-methoxy-
biphenyl-4-yl)-acetamide 198 ##STR201## N-[2-Hydroxy-4-(3,4-
dichloro-phenoxy)-phenyl]-2- (4'-trifluoromethyl-biphenyl-
4-yl)-acetamide 199 ##STR202## N-[2-Hydroxy-4-(2,4-
dichloro-6-methyl-phenoxy)- phenyl]-2-(4'-trifluoromethyl-
biphenyl-4-yl)-acetamide 200 ##STR203## N-[2-Hydroxy-4-(2,4-
dichloro-6-methyl-phenoxy)- phenyl]-2-(3'-trifluoromethyl-
biphenyl-4-yl)-acetamide 201 ##STR204## 3-(3'-Chloro-4'-fluoro-
biphenyl-4-yl)-N-[4-(2,4- dichloro-6-methyl-phenoxy)-
2-hydroxy-phenyl]- propionamide 202 ##STR205##
N-[4-(2-Fluoro-6-methoxy- phenoxy)-2-hydroxy-phenyl]-
3-(3'-methoxy-biphenyl-4-yl)- propionamide 203 ##STR206##
N-[4-(2,4-Dichloro-6-methyl- phenoxy)-2-hydroxy-phenyl]-
2-(4'-methoxy-biphenyl-4-yl)- acetamide 204 ##STR207##
2-(3'-Chloro-4'-fluoro- biphenyl-4-yl)-N-[4-(2,4-
dichloro-6-methyl-phenoxy)- 2-hydroxy-phenyl]-acetamide 205
##STR208## 2-Biphenyl-4-yl-N-[2- hydroxy-4-(4'-
methoxy-biphenyl-4-yloxy)- phenyl]-acetamide 206 ##STR209##
2-Biphenyl-4-yl-N-[2- hydroxy-4-(4'-trifluoromethyl-
biphenyl-4-yloxy)-phenyl]- acetamide 207 ##STR210##
N-[4-(3,4-Dichloro-phenoxy)- 2-hydroxy-phenyl]-2-(3'-nitro-
biphenyl-4-yl)-acetamide 208 ##STR211## N-[5-(3-Chloro-phenyl)-
pyridin-2-yl]-2-[4-(3-hydroxy- 4-nitro-phenoxy)-phenyl]- acetamide
209 ##STR212## N-[5-(3,4-Dichloro-phenyl)-
pyridin-2-yl]-2-[4-(3-hydroxy- 4-nitro-phenoxy)-phenyl]- acetamide
210 ##STR213## N-[5-(3-trifluromethyl-
phenyl)-pyridin-2-yl]-2-[4-(3- hydroxy-4-nitro-phenoxy)-
phenyl]-acetamide 211 ##STR214## N-[5-(4-Methoxy-phenyl)-
pyridin-2-yl]-2-[4-(3-hydroxy- 4-nitro-phenoxy)-phenyl]- acetamide
212 ##STR215## 3-Biphenyl-4-yl-(2S)-[(4'-
trifluoromethyl-biphenyl-4- carbonyl)-amino]-propionic acid 213
##STR216## 3-Biphenyl-4-yl-(2S)-[(3'- chloro-4'-fluoro-biphenyl-4-
carbonyl)-amino]-propionic acid 214 ##STR217##
3-Biphenyl-4-yl-(2S)-[(4'- trifluoromethoxy-biphenyl-4-
carbonyl)-amino}-propionic acid 215 ##STR218##
3-Biphenyl-4-yl-(2S)-[(4'- ethyl-biphenyl-4-carbonyl)-
amino]-propionic acid 216 ##STR219## 3-Biphenyl-4-yl-(2S)-[(3'-
ethyl-biphenyl-3-carbonyl)- amino]-propionic acid 217 ##STR220##
3-Biphenyl-4-yl-(2S)-[(4'-tert- butylbiphenyl-3-carbonyl)-
amino}-propionic acid 218 ##STR221## 3-Biphenyl-4-yl-(2S)-[(4'-
methoxy-biphenyl-3- carbonyl)-amino]-propionic acid 219 ##STR222##
3-Biphenyl-4-yl-(2S)-[(4'- methane-sulfonyl-biphenyl-
3-carbonyl)-amino]-propionic acid 220 ##STR223##
3-Biphenyl-4-yl-(2S)-[(4'-tert- butyl-4-chloro-biphenyl-3-
carbonyl)-amino]-propionic acid 221 ##STR224## (2S)-[(4-Chloro-4'-
trifluoromethyl-biphenyl-3- carbonyl)-amino}-3-(4'-
trifluoromethyl-biphenyl-4- yl)-propionic acid 222 ##STR225##
(2S)-[(-4'-Methoxy-biphenyl- 3-carbonyl)-amino}-3-(4'-
methoxyl-biphenyl-4-yl)- propionic acid 223 ##STR226##
3-Biphenyl-4-yl-(2S)-[3-nitro- 4-(3-trifluoromethyl-
phenoxy)-benzoylamino]- propionic acid 224 ##STR227##
3-(4'-Trifluoromethyl- biphenyl-4-yl)-(2S)-[4-(4-
trifluoromethyl-phenoxy)- benzoylamino]-propionic acid 225
##STR228## 3-(4'-Trifluoromethyl- biphenyl-4-yl)-(2S)-[4-(5-
trifluoromethyl-pyridin-2- yloxy)-benzoylamino]- propionic acid 226
##STR229## 3-[4-(4-Trifluoromethyl- phenoxy)-phenyl]-(2S)-[(4'-
trifluoromethyl-biphenyl-4- carbonyl)-amino]-propionic acid 227
##STR230## 3-[4-(4-Cyano-phenoxy)- phenyl]-(2S)-[(4'-
trifluoromethyl-biphenyl-4- carbonyl)-amino]-propionic acid 228
##STR231## 2S-(4-Benzyloxy- benzoylamino)-3-biphenyl-4-
yl-propionic acid 229 ##STR232## 3-Biphenyl-4-yl-(2S)-[(4'-
trifluoromethyl-biphenyl-3- carbonyl)-amino]-propionic acid 230
##STR233## 3-Biphenyl-4-yl-(2S)-[(3- chloro-4'-trifluoromethyl-
biphenyl-4-carbonyl)-amino]- propionic acid 231 ##STR234##
3-Biphenyl-4-yl-(2S)-[4-(4- nitro-phenoxy)- benzoylamino]-propionic
acid 232 ##STR235## 3-Biphenyl-4-yl-(2S)-[4-(3,4-
dimethyl-phenoxy)-3-nitro- benzoylamino]-propionic acid 233
##STR236## 3-Biphenyl-4-yl-(2S)-[(3'- trifluoromethyl-biphenyl-4-
carbonyl)-amino]-propionic acid 234 ##STR237##
3-Biphenyl-4-yl-(2S)-[(3',5'- bis-trifluoromethyl-biphenyl-
4-carbonyl)-amino]-propionic acid 235 ##STR238##
3-Biphenyl-4-yl-(2S)-[(4'-tert- butyl-biphenyl-4-carbonyl)-
amino}-propionic acid 236 ##STR239## 3-Biphenyl-4-yl-(2S)-[(4'-
dimethylamino-biphenyl-4- carbonyl)-amino]-propionic acid 237
##STR240## 3-Biphenyl-4-yl-(2S)-[(4'- methoxy-biphenyl-4-
carbonyl)-amino]-propionic acid 238 ##STR241##
3-Biphenyl-4-yl-2-[(3',4'- dichloro-biphenyl-4-
carbonyl)-amino]-propionic acid 239 ##STR242##
3-Biphenyl-4-yl-(2S)-[(5'- chloro-2'-methoxy-biphenyl-
4-carbonyl)-amino]-propionic acid 240 ##STR243##
(2S)-[(3'-Amino-biphenyl-4- carbonyl)-amino]-3-biphenyl-
4-yl-propionic acid
241 ##STR244## (2S)-[(4'-Trifluoromethoxy-
biphenyl-4-carbonyl)-amino]- 3-(4'-trifluoromethyl-
biphenyl-4-yl)-propionic acid 242 ##STR245##
3-(4'-Trifluoromethoxy- biphenyl-4-yl)-(2S)-[(4'-
trifluoromethyl-biphenyl- 4-carbonyl)-amino]- propionic acid 243
##STR246## 3-(4-Pyridin-4-yl-phenyl)- (2S)-[(4'-trifluoromethyl-
biphenyl-4-carbonyl)-amino]- propionic acid 244 ##STR247##
3-Biphenyl-4-yl-(2S)-[4-(5- trifluoromethyl-pyridin-2-yl)-
benzoylamino]-propionic acid 245 ##STR248##
3-(4-Pyridin-4-yl-phenyl)- (2S)-[4-(5-trifluoromethyl-
pyridin-2-yl)-benzoylamino]- propionic acid 246 ##STR249##
3-(4'-Methanesulfonylamino- biphenyl-4-yl)-(2S)-[(4'-
trifluoromethyl-biphenyl-4- carbonyl)-amino]-propionic acid 247
##STR250## 3-(3'-Chloro-4'-fluoro- biphenyl-4-yl)-(2S)-[(4'-
trifluoromethyl-biphenyl- 4-carbonyl)-amino]-propionic acid 248
##STR251## 3-(4'-Cyano-biphenyl-4-yl)- (2S)-[(4'-trifluoromethyl-
biphenyl-4-carbonyl)- amino]-propionic acid 249 ##STR252##
3-(5-Phenyl-pyridin-2-yl)-2- [(4'-trifluoromethoxy-
biphenyl-4-carbonyl)- amino}-propionic acid 250 ##STR253##
3-(4'-Amino-biphenyl-4-yl)- (2S)-[(4'-trifluoromethyl-
biphenyl-4-carbonyl)-amino]- propionic acid 251 ##STR254##
3-(4'-Dimethylamino- biphenyl-4-yl)-(2S)-[(4'-
trifluoromethyl-biphenyl-4- carbonyl)-amino]-propionic acid 252
##STR255## 3-(4'-Trifluoromethoxy- biphenyl-4-yl)-(2S)-[4-(5-
trifluoromethyl-pyridin-2-yl)- benzoylamino]-propionic acid 253
##STR256## 3-(4'-Trifluoromethyl- biphenyl-4-yl)-(2S)-[4-(s-
trifluoromethyl-pyridin-2- yl)-benzoylamino]-propionic acid 254
##STR257## 3-(4'-Trifluoromethoxy- biphenyl-4-yl)-(2S)-[4-(4-
trifluoromethyl-phenoxy)- benzoylamino]-propionic acid 255
##STR258## 3-Biphenyl-4-yl-(2S)-[4-(4- trifluoromethyl-phenoxy)-
benzoylamino]-propionic acid 256 ##STR259##
3-Biphenyl-4-yl-(2S)-[4-(4- formyl-phenoxy)-
benzoylamino]-propionic acid 257 ##STR260##
3-(5'-Chloro-2'-methoxy- biphenyl-4-yl)-(2S)-[(4'-
trifluoromethyl-biphenyl-4- carbonyl)-amino]-propionic acid 258
##STR261## 3-(4'-Chloro-biphenyl-4-yl)- (2S)-[(4'-trifluoromethyl-
biphenyl-4-carbonyl)-amino]- propionic acid 259 ##STR262##
3-Biphenyl-4-yl-(2R)-[(4'- trifluoromethyl-biphenyl-4-
carbonyl)-amino]-propionic acid 260 ##STR263##
3-(5-Phenyl-pyridin-2-yl)-2- [(4'-trifluoromethyl-biphenyl-
4-carbonyl)-amino]-propionic acid 261 ##STR264##
3-(3'-Acetylamino-biphenyl- 4-yl)-(2S)-[(4'-trifluoromethyl-
biphenyl-4-carbonyl)-amino]- propionic acid 262 ##STR265##
3-(3',4'-Dichloro-biphenyl-4- yl)-(2S)-[(4'-trifluoromethyl-
biphenyl-4-carbonyl)-amino]- propionic acid 263 ##STR266## 3-(5'-
Fluoro-2-methoxy- biphenyl-4-yl)-(2S)-[(4'-
trifluoromethyl-biphenyl-4- carbonyl)-amino]-propionic acid 264
##STR267## 3-[4'-(Acetylamino-methyl)- biphenyl-4-yl]-(2S)-[(4'-
trifluoromethyl-biphenyl-4- carbonyl)-amino]-propionic acid 265
##STR268## 3-(4'-Trifluoromethoxy- biphenyl-4-yl)-(2S)-[4-(5-
trifluoromethyl-pyridin-2- yloxy)-benzoylamino]- propionic acid 266
##STR269## 3-Biphenyl-4-yl-(2S)-[4-(5- trifluoromethyl-pyridin-2-
yloxy)-benzoylamino]- propionic acid 267 ##STR270##
3-[4-(4-Nitro-phenoxy)- phenyl]-(2S)-[(4-
trifluoromethyl-biphenyl-4- carbonyl)-amino}-propionic acid 268
##STR271## 3-[4-(4-Formyl-phenoxy)- phenyl]-(2S)-[(4'-
trifluoromethyl-biphenyl-4- carbonyl)-amino]-propionic acid 269
##STR272## 3-(4-Thiophen-3-yl-phenyl)- (2S)-[(4'-trifluoromethyl-
biphenyl-4-carbonyl)-amino]- propionic acid 270 ##STR273##
3-(4-Thiophen-3-yl-phenyl)- (2S)-[(4'-trifluoromethoxy-
biphenyl-4-carbonyl)-amino]- propionic acid 271 ##STR274##
(2S)-(4-Benzyloxy- benzoylamino)-3-(4'-
trifluoromethoxy-biphenyl-4- yl)-propionic acid 272 ##STR275##
3-(2'- Phenoxy-biphenyl-4-yl)- (2S)-[(4'-trifluoromethyl-
biphenyl-4-carbonyl)-amino]- propionic acid 273 ##STR276##
3-(4'-Phenoxy-biphenyl-4-yl)- (2S)-[(4'-trifluoromethyl-
biphenyl-4-carbonyl)-amino]- propionic acid 274 ##STR277##
3-Biphenyl-4-yl-(2S)-[2-(4- tert-butyl-benzoylamino)-5-
iodo-benzoyl-amino}- propionic acid 275 ##STR278##
3-Biphenyl-4-yl-(2S)-{[4-(4- tert-butyl-benzoylamino)-3'-
trifluoromethyl-biphenyl-3- carbonyl]-amino}-propionic acid 276
##STR279## 3-Biphenyl-4-yl-(2S)-{[4-(4-
tert-butyl-benzoylamino)-4'- nitro-iphenyl-3-carbonyl]-
mino}-propionic acid 277 ##STR280## 3-Biphenyl-4-yl-(2S)-{[4-(4-
tert-butyl-benzoylamino)-3'- chloro-4'-fluoro-biphenyl-3-
carbonyl]-amino}-propionic acid 278 ##STR281##
3-Biphenyl-4-yl-(2S)-[4-(4- tert-butyl-benzoylamino)-5-
(4-chloro-3-trifluromethyl- phenoxy)-benzoylamino]- propionic acid
279 ##STR282## 3-Biphenyl-4-yl-(2S)-[2-(3,5- bis-trifluoromethyl-
benzoylamino)-5-bromo- benzoylamino]-propionic acid 280 ##STR283##
(2S)-[5-bromo-2-(2- cyclopentyl-acetylamino)- benzoylamino]-3-(2'-
phenoxy-biphenyl-4-yl)- propionic acid 281 ##STR284##
(2S)-[5-Bromo-2-(3,3,5- trimethyl-hexanoylamino)-
benzoylamino]-3-(2'- phenoxy-biphenyl-4-yl)- propionic acid 282
##STR285## (2S)-[5-Chloro-2-(4-phenoxy- benzoylamino)-
benzoylamino]-3-(2'- isopropoxy-biphenyl-4-yl)- propionic acid 283
##STR286## 3-Biphenyl-4-yl-(2S)-[2-(4- tert-butyl-benzoylamino)-
benzoylamino]-propionic acid 284 ##STR287##
3-Biphenyl-4-yl-(2S)-[5- chloro-2-(2,4-dichloro- benzoylamino)-
benzoylamino]-propionic acid 285 ##STR288## (2S)-({4-[(Biphenyl-4-
carbonyl)-amino]-3'-chloro- 4'-fluoro-biphenyl-3-
carbonyl}-amino)-3-biphenyl- 4-yl-propionic acid 286 ##STR289##
(2S)-{2-[(Biphenyl-4- carbonyl)-amino]- benzoylamino}-3-(3'-chloro-
4'-fluoro-biphenyl-4-yl)- propionic acid 287 ##STR290##
(2S)-[2-(4-tert-Butyl- benzoylamino)- benzoylamino]-3-(3'-chloro-
4'-fluoro-biphenyl-4-yl)- propionic acid 288 ##STR291##
3-Biphenyl-4-yl-(2S)-[5- bromo-2-(4-tert-butyl- benzoylamino)-
benzoylamino]-propionic acid 289 ##STR292##
3-Biphenyl-4-yl-(2S)-{[4-(4- tert-butyl-benzoylamino)-4'-
cyano-biphenyl-3-carbonyl]- amino}-propionic acid 290 ##STR293##
(2S)-{[4'-Amino-4-(4-tert- butyl-benzoylamino)-
biphenyl-3-carbonyl]-amino}- 3-biphenyl-4-yl-propionic acid 291
##STR294## 3-Biphenyl-4-yl-(2S)-{[4-(4-
tert-butyl-benzoylamino)-3'- cyano-biphenyl-3-carbonyl]-
amino}-propionic acid 292 ##STR295## (2S)-({3-[(Biphenyl-4-
carbonyl)-amino]- naphthalene-2-carbonyl}-
amino)-3-(3'-chloro-4'-fluoro- biphenyl-4-yl)-propionic acid 293
##STR296## (2S)-{[3-(4-tert-Butyl- benzoylamino)-naphthalene-
2-carbonyl]-amino}-3-(3'- chloro-4'-fluoro-biphenyl-4-
yl)-propionic acid 294 ##STR297## (2S)-{[3'-Aminomethyl-4-(4-
tert-butyl-benzoylamino)- biphenyl-3-carbonyl]-amino}-
3-biphenyl-4-yl-propionic acid 295 ##STR298##
3-Biphenyl-4-yl-(2S)-{[4-(4- tert-butyl-benzoylamino)-4'-
carbamimidoyl-biphenyl-3- carbonyl]-amino}-propionic acid 296
##STR299## 3-Biphenyl-4-yl-(2S)-[2-(4- tert-butyl-benzoylamino)-5-
(4-nitro-phenoxy)- benzoylamino]-propionic acid 297 ##STR300##
(2S)-{[4-(4-tert-Butyl- benzoylamino)-3'-
trifluoromethyl-biphenyl-3- carbonyl]-amino}-3-(3'-
trifluoromethyl-biphenyl-4- yl)-propionic acid 298 ##STR301##
(2S)-{[4-(4-tert-Butyl- benzoylamino)-3'-chloro-4'-
fluoro-biphenyl-3-carbonyl]- amino}-3-(3'-chloro-4'-fluoro-
biphenyl-4-yl)-propionic acid 299 ##STR302##
(2S)-{[4-(4-tert-Butyl- benzoylamino)-4'-
trifluoromethyl-biphenyl-3- carbonyl]-amino}-3-(4'-
trifluoromethyl-biphenyl-4- yl)-propionic acid 300 ##STR303##
3-Biphenyl-4-yl-(2S)-[5- bromo-2-(3-phenyl- acryloylamino)-
benzoylamino]-propionic acid 301 ##STR304##
3-Biphenyl-4-yl-(2S)-{5- bromo-2-[(naphthalene-2- carbonyl)-amino]-
benzoylamino}-propionic acid 302 ##STR305##
3-Biphenyl-4-yl-(2S)-[5- bromo-2-(2-cyclopentyl-
acetylamino)-benzoylamino]- propionic acid 303 ##STR306##
3-Biphenyl-4-yl-(2S)-[5- bromo-2-(4-trifluoromethoxy-
benzoylamino)-benzoyl amino}-propionic acid 304 ##STR307##
3-Biphenyl-4-yl-(2S)-[5- bromo-2-(4-phenoxy- butyrylamino)-
benzoylamino]-propionic acid 305 ##STR308##
3-Biphenyl-4-yl-(2S)-{4- bromo-2-[2-(4- tert-butyl-phenoxy)-
acetylamino]-benzoylamino}- propionic acid 306 ##STR309##
(2S)-[2-(4-tert-Butyl- benzoylamino)-5- chloro-benzoylamino]-3-(4'-
phenoxy-biphenyl-4-yl)- propionic acid 307 ##STR310##
2-[5-Bromo-(2S)-(4-tert- butyl-benzoylamino)- benzoylamino]-3-(4'-
phenoxy-biphenyl-4-yl)- propionic acid 308 ##STR311##
3-Biphenyl-4-yl-(2S)-[4- chloro-2-(4-trifluoromethyl-
benzoylamino)-benzoyl amino]-propionic acid 309 ##STR312##
3-Biphenyl-4-yl-(2S)-[2-(4- tert-butyl-benzoylamino)-5-
(4-trifluoromethyl-phenoxy)- benzoylamino]-propionic acid 310
##STR313## 3-Biphenyl-4-yl-(2S)-[2-(4- trifluoromethyl-
benzoylamino)-5-(4- trifluoromethyl-phenoxy)-
benzoylamino]-propionic acid 311 ##STR314##
3-Biphenyl-4-yl-(2S)-[2-(4- tert-butyl-benzoylamino)-4-
(4-trifluoromethyl-phenoxy)- benzoylamino]-propionic acid 312
##STR315## (2S)-[2-(4-tert-Butyl- benzoylamino)-5-
chloro-benzoylamino]-3-(2'- phenoxy-biphenyl-4-yl)- propionic acid
313 ##STR316## (2S)-[5-Chloro-2-(4-phenoxy- benzoylamino)-
benzoylamino]-3-(2'- phenoxy-biphenyl-4-yl)- propionic acid 314
##STR317## (2S)-[2-(4-Benzyloxy- benzoylamino)-5-chloro-
benzoylamino]-3-(2'- phenoxy-biphenyl-4-yl)- propionic acid 315
##STR318## (2S)-(5-Bromo-2- phenylacetylamino- benzoylamino)-3-(2'-
phenoxy-biphenyl-4-yl)- propionic acid 316 ##STR319##
(2S)-[5-Bromo-2-(4-bromo- benzoylamino)- benzoylamino]-3-(2'-
phenoxy-biphenyl-4-yl)- propionic acid 317 ##STR320##
(2S)-{5-Bromo-2-[2-(4-fluoro- phenyl)-acetylamino]-
benzoylamino}-3-(2- phenoxy-biphenyl-4-yl)- propionic acid 318
##STR321## 2-{5-Bromo-(2S)- [(naphthalene-2-carbonyl)-
amino]-benzoylamino}-3-(2'- phenoxy-biphenyl-4-yl)- propionic acid
319 ##STR322## (2S)-{5-Bromo-2- [(naphthalene-1-carbonyl)-
amino]-benzoylamino}-3-(2'- phenoxy-biphenyl-4-yl)- propionic acid
320 ##STR323## (2S)-[5-Chloro-2-(3-phenoxy- benzoylamio)-
benzoylamino]-3-(2'- phenoxy-biphenyl-4-yl)- propionic acid 321
##STR324## -S-[2-(3-Benzyloxy- benzoylamino)-5-chloro-
benzoylamino]-3-(2'- phenoxy-biphenyl-4-yl)- propionic acid
322 ##STR325## (2S)-[5-Bromo-2-(4-phenoxy- benzoylamino)-
benzoylamino]-3-(2'- phenoxy-biphenyl-4-yl)- propionic acid 323
##STR326## (2S)-[5-Bromo-2-(4-hexyl- benzoylamino)-
benzoylamino]-3-(2'- phenoxy-biphenyl-4-yl)- propionic acid 324
##STR327## (2S)-[5-Bromo-2-(4-fluoro- benzoylamino)-
benzoylamino]-3-(2'- phenoxy-biphenyl-4-yl)- propionic acid 325
##STR328## (2S)-{5-Bromo-2- [(thiophene-2-carbonyl)-
amino]-benzoylamino}-3-(2'- phenoxy-biphenyl-4-yl)- propionic acid
326 ##STR329## (2S)-[5-Bromo-2-(2- thiophen-2-yl-acetylamino)-
benzoylamino]-3-(2'- phenoxy-biphenyl-4-yl)- propionic acid 327
##STR330## (2S)-[5-Bromo-2- (cyclopropanecarbonyl-
amino)-benzoylamino]-3-(2'- phenoxy-biphenyl-4-yl)- propionic acid
328 ##STR331## (2S)-[5-Bromo-2- (cyclobutanecarbonyl-
amino)-benzoylamino]-3-(2'- phenoxy-biphenyl-4-yl)- propionic acid
329 ##STR332## (2S)-[5-Bromo-2- (cyclopentanecarbonyl-
amino)-benzoylamino]-3-(2'- phenoxy-biphenyl-4-yl)- propionic acid
330 ##STR333## (2S)-[5-Bromo-2-(2-propyl- pentanoylamino)-
benzoylamino]-3-(2'- phenoxy-biphenyl-4-yl)- propionic acid 331
##STR334## (2S)-[5-Bromo-2-(2-phenoxy- propionylamino)-
benzoylamino]-3-(2'- phenoxy-biphenyl-4-yl)- propionic acid 332
##STR335## (2S)-[2-(3,5-Bis- rifluoromethyl-
benzoylamino)-5-chloro- benzoylamino]-3-(3'-
phenoxy-biphenyl-4-yl)- propionic acid 333 ##STR336##
(2S)-[5-Bromo-2-(3,4,5- trimethoxy-benzoylamino)-
benzoylamino]-3-(2'- phenoxy-biphenyl-4-yl)- propionic acid 334
##STR337## (2S)-{2-[(Adamantane-1- carbonyl)-amino]-5-bromo-
benzoylamino}-3-(2'- phenoxy-biphenyl-4-yl)- propionic acid 335
##STR338## (2S)-(5-Bromo-2-{(1-(4- chloro-phenyl)-
cyclopropanecarbonyl]- amino}-benzoylamino)-3-(2'-
phenoxy-biphenyl-4-yl)- propionic acid 336 ##STR339##
(2S)-(5-Bromo-2-{[1-(2,4- dichloro-phenyl)- cyclopropanecarbonyl]-
amino}-benzoylamino)-3-(2'- phenoxy-biphenyl- 4-yl)-propionic acid
337 ##STR340## (2S)-{5-Bromo-2-[(2,2- dichloro-1-methyl-
cyclopropanecarbonyl)- amino]-benzoylamino}-3-(2'-
phenoxy-biphenyl-4-yl)- propionic acid 338 ##STR341##
(2S)-{5-Chloro-2-[(6-chloro- pyridine-3-carbonyl)-amino]-
benzoylamino}-3-(2'- phenoxy-biphenyl-4-yl)- propionic acid 339
##STR342## (2S)-(5-Chloro-2-{[1-(4- trifluoromethyl-pyrimidin-2-
yl)-piperidine-4-carbonyl]- amino}-benzoylamino)-3-(2'-
phenoxy-biphenyl-4-yl)- propionic acid 340 ##STR343##
(2S)-{5-Bromo-2-[(1-phenyl- cyclopropanecarbonyl)-
amino]-benzoylamino}-3-(2'- phenoxy-biphenyl-4-yl)- propionic acid
341 ##STR344## (2S)-{5-Bromo-2-[(2-phenyl- cyclopropanecarbonyl)-
amino]-benzoylamino}-3-(2'- phenoxy-biphenyl-4-yl)- propionic acid
342 ##STR345## (2S)-[5-Chloro-2-(2-phenoxy- benzoylamino)-
benzoylamino]-3-(2'- phenoxy-biphenyl-4-yl)- propionic acid 343
##STR346## 3-(2'-Benzyloxy-biphenyl-4- yl)-(2S)-[2-(3,5-bis-
trifluoromethyl- benzoylamino)-5-chloro- benzoylamino]-propionic
acid 344 ##STR347## (2S)-{5-Chloro-2-[(6- phenoxy-pyridine-3-
carbonyl)-amino]- benzoylamino}-3- (2'-phenoxy-biphenyl-4-yl)-
propionic acid 345 ##STR348## (2S)-[5-Chloro-2-(4-phenoxy-
benzoylamino)- benzoylamino]-3-(2'- cyclopentyloxy-biphenyl-4-
yl)-propionic acid 346 ##STR349## (2S)-[5-Chloro-2-(4-phenoxy-
benzoylamino)- benzoylamino]-3-[2'-(4- trifluoromethyl-benzyloxy)-
biphenyl-4-yl]-propionic acid 347 ##STR350##
3-[2'-(4-tert-Butyl-benzyloxy)- biphenyl-4-yl]-(2S)-[5-chloro-
2-(4-phenoxy- benzoylamino)- benzoylamino]-propionic acid 348
##STR351## (2S)-[5-Chloro-2-(4- [1,2,3]thiadiazol-4-yl-
benzoylamino)benzoylamin]- 3-(2'-phenoxy-biphenyl-4-yl)- propionic
acid 349 ##STR352## (2S)-{5-Chloro-2-[4-(pyridin-
4-ylmethoxy)-benzoylamino]- benzoylamino}-3-(2'-
phenoxy-biphenyl-4-yl)- propionic acid 350 ##STR353##
(2S)-(5-Chloro-2-{[1-(4- chloro-phenyl)-5-
trifluoromethyl-1H-pyrazole- 4-carbonyl]-amino}-
benzoylamino)-3-(2'- phenoxy-biphenyl-4-yl)- propionic acid 351
##STR354## (2S)-(5-Chloro-2-{[1-(4- chloro-phenyl)-5-propyl-1H-
pyrazole-4-carbonyl]-amino}- benzoylamino)-3-(2'-
phenoxy-biphenyl-4-yl)- propionic acid 352 ##STR355##
(2S)-[5-Bromo-2-(3-phenyl- propionylamino)- benzoylamino]-3-(2'-
phenoxy-biphenyl-4-yl)- propionic acid 353 ##STR356##
(2S)-[2-(3,5-Bis- trifluoromethyl- benzoylamino)-5-chloro-
benzoylamino]-3- [2'-(4-pentyl-phenoxy)- biphenyl-4-yl]-propionic
acid 354 ##STR357## (2S)-{2-[(Benzofuran-2-
carbonyl)-amino]-5-bromo- benzoylamino}-3-(2'-
phenoxy-biphenyl-4-yl)- propionic acid 355 ##STR358##
(2S)-{2-[(Benzo[b]thiophene- 2-carbonyl)-amino]-5-bromo-
benzoylamino}-3-(2'- phenoxy-biphenyl-4-yl)- propionic acid 356
##STR359## (2S)-{5-Bromo-2-[(3-chloro- benzo[b]thiophene-2-
carbonyl)-amino]- benzoylamino}-3-(2- phenoxy-biphenyl-4-yl)-
propionic acid 357 ##STR360## (2S)-{2-[(3,5-Bis-
trifluoromethyl-benzoyl)- pentyl-amino]-5-chloro-
benzoylamino}-3-(2'- phenoxy-biphenyl-4-yl)- propionic acid 358
##STR361## (2S)-{2-[(Biphenyl-4- carbonyl)-(4-methyl-benzyl)-
amino]-5-chloro- benzoylamino}-3-biphenyl-4- yl-propionic acid 359
##STR362## 3-Biphenyl-4-yl-(2S){5- chloro-2-[(3,5-dichloro-
benzoyl)-(4-methyl-benzyl)- amino]-benzoylamino}- propionic acid
360 ##STR363## (2S)-{2-[(Biphenyl-4- carbonyl)-(3-phenyl-propyl)-
amino]-5-chloro- benzoylamino}-3-biphenyl-4- yl-propionic acid 361
##STR364## 3-Biphenyl-4-yl-(2S)-{5- chloro-2-[(2,4-dichloro-
benzoyl)-(3-phenyl-propyl)- amino]-benzoylamino}- propionic acid
362 ##STR365## (2S)-{2-[(Biphenyl-4- carbonyl)-biphenyl-4-
ylmethyl-amino]-5-chloro- benzoylamino}-3-biphenyl-4- yl-propionic
acid 363 ##STR366## 3-Biphenyl-4-yl-(2S)-{2-
[biphenyl-4-ylmethyl-(2,4- dichloro-benzoyl)-amino]-5-
chloro-benzoylamino}- propionic acid 364 ##STR367##
(2S)-{2-[(Biphenyl-4- carbonyl)-(4-isopropyl-
benzyl)-amino]-5-chloro- benzoylamino}-3-biphenyl-4- yl-propionic
acid 365 ##STR368## (2S)-{2-[(Biphenyl-4- carbonyl)-(4-isopropoxy-
benzyl)-amino]-5-chloro- benzoylamino}-3-biphenyl-4- yl-propionic
acid 366 ##STR369## (2S)-{5-Bromo-2-[(2-methyl-
butyl)-(4-phenoxy-benzoyl)- amino}-benzoylamino}-3-(2'-
phenoxy-biphenyl-4-yl)- propionic acid 367 ##STR370##
(2S)-[5-Chloro-2-(5- dibutylamino-naphthalene-1- sulfonylamino)-
benzoylamino]-3-(2- phenoxy-biphenyl-4-yl)- propionic acid methyl
ester 368 ##STR371## (2S)-[5-Bromo-2-(4- tert-butyl-
benzenesulfonylamino)- benzoylamino]-3-(2'- phenoxy-biphenyl-4-yl)-
propionic acid 369 ##STR372## (2S)-[5-Bromo-2-(4-tert- butyl-
benzenesulfonylamino)- benzoylamino]-3-(4'- phenoxy-biphenyl-4-yl)-
propionic acid 370 ##STR373## 3-Biphenyl-4-yl-(2S)-[2-
(3,4-dichloro- benzenesulfonylamino)-5- iodo-benzoylamino]-
propionic acid 371 ##STR374## (2S)-{2-[(Biphenyl-4-
sulfonyl)-(4-methyl-benzyl)- amino]-5-chloro-
benzoylamino}-3-biphenyl- 4-yl-propionic acid 372 ##STR375##
(2S)-[2-(Biphenyl-4- sulfonylamino)-5-chloro-
benzoylamino]-3-biphenyl-4- yl-propionic acid 373 ##STR376##
3-Biphenyl-4-yl-(2S)[2-(4- tert-butyl- benzenesulfonylamino)-5-
iodo-benzoylamino]- propionic acid 374 ##STR377##
3-Biphenyl-4-yl-(2S){[4-(4- tert-butyl- benzenesulfonylamino)-3'-
chloro-4'- fluoro-biphenyl-3-carbonyl]- amino}-propionic acid 375
##STR378## 3-Biphenyl-4-yl-(2S)[5-iodo- 2-(2,4,5-trichloro-
benzenesulfonylamino)- benzoylamino]-propionic acid 376 ##STR379##
3-Biphenyl-4-yl-(2S)-[2-(2,5- dichloro- benzenesulfonylamino)-5-
iodo-benzoylamino]- propionic acid 377 ##STR380##
3-Biphenyl-4-yl-(2S)-[2-(2,4- difluoro- benzenesulfonylamino)-5-
iodo-benzoylamino]- propionic acid 378 ##STR381##
3-Biphenyl-4-yl-(2S)-[5-iodo- 2-(4-propyl- benzenesulfonylamino)-
benzoylamino]-propionic acid 379 ##STR382##
3-Biphenyl-4-yl-(2S)-(5-iodo- 2-pentamethyl- benzenesulfonyl-
amino-benzoylamino)- propionic acid 380 ##STR383##
3-Biphenyl-4-yl-(2S)-[5-iodo- 2-(toluene-4-sulfonylamino)-
benzoylamino]-propionic acid 381 ##STR384##
3-Biphenyl-4-yl-(2S)-[2-(4- bromo- benzenesulfonylamino)-5-
iodo-benzoylamino]- propionic acid 382 ##STR385##
3-Biphenyl-4-yl-(2S)-[5-iodo- 2-(naphthalene-2- sulfonylamino)-
benzoylamino]-propionic acid 383 ##STR386##
3-Biphenyl-4-yl-(2S)-[5- bromo-2-(4-tert-butyl-
benzenesulfonylamino)- benzoylamino]-propionic acid 384 ##STR387##
2-[5-Acetylamino-(2S)-(4- tert-butyl- benzenesulfonylamino)-
benzoylamino]-3-biphenyl-4- yl-propionic acid 385 ##STR388##
3-Biphenyl-4-yl-(2R)-[5- bromo-2-(4-tert-butyl-
benzenesulfonylamino)- benzoylamino]-propionic acid methyl ester
386 ##STR389## 3-Biphenyl-4-yl-(2S)-[5- bromo-2-(6-morpholin-4-yl-
pyridine-3-sulfonylamino)- benzoylamino]-propionic acid 387
##STR390## 3-Biphenyl-4-yl-(2S)-[5- bromo-2-(4-vinyl-
benzenesulfonylamino)- benzoylamino]-propionic acid 388 ##STR391##
3-Biphenyl-4-yl-(2S)-[5- bromo-2-(3,4-dichloro-
benzenesulfonylamino)- benzoylamino]-propionic acid 389 ##STR392##
3-Biphenyl-4-yl-(2S)-[5- bromo-2-(4-nitro- benzenesulfonylamino)-
benzoylamino]-propionic acid 390 ##STR393##
3-Biphenyl-4-yl-(2S)-[5- bromo-2-(2-phenyl- ethenesulfonylamino)-
benzoylamino}-propionic acid 391 ##STR394##
3-Biphenyl-4-yl-(2S)-{5- bromo-2-[5-(5-
trifluoromethyl-isoxazol-3-yl)- thiophene-2-sulfonylamino]-
benzoylamino}-propionic acid 392 ##STR395##
3-Biphenyl-4-yl-(2S)-[5- bromo-2-(4-bromo- benzenesulfonylamino)-
benzoylamino]-propionic acid 393 ##STR396##
3-Biphenyl-4-yl-(2S)-[5- bromo-2-(3,4-dimethoxy-
benzenesulfonylamino)- benzoylamino]-propionic acid 394 ##STR397##
(2S)-[2-(4-Acetylamino- benzenesulfonylamino)-5-
bromo-benzoylamino]-3- biphenyl-4-yl-propionic acid 395 ##STR398##
3-Biphenyl-4-yl-(2S)-[5- bromo-2-(4-isopropyl-
benzenesulfonylamino)- benzoylamino]-propionic acid 396 ##STR399##
3-Biphenyl-4-(2S)-[5- bromo-2-(2,5-dichloro- benzenesulfonylamino)-
benzoylamino]-propionic acid 397 ##STR400##
3-Biphenyl-4-yl-(2S)-[5- bromo-2-(2-rifluoromethoxy-
benzenesulfonylamino)- benzoylamino]-propionic acid 398 ##STR401##
(2S)-{5-Bromo-2-(5- dibutylamino-naphthalene- 1-sulfonylamino)-
benzoylamino]-3-(4'- phenoxy-biphenyl-4-yl)- propionic acid 399
##STR402## (2S)-[5-Chloro-2-(5- dibutylamino-naphthalene-1-
sulfonylamino)- benzoylamino]-3-(2'- phenoxy-biphenyl-4-yl)-
propionic acid
400 ##STR403## (2S)-[5-Chloro-2-(5- dimethylamino-naphthalene-
1-sulfonylamino)- benzoylamino]-3-(2'- phenoxy-biphenyl-4-yl)-
propionic acid methyl ester 401 ##STR404## (2S)-[5-Bromo-2-(5-
dimethylamino-naphthalene- 1-sulfonylamino)- benzoylamino]-3-(2'-
phenoxy-biphenyl-4-yl)- propionic acid methyl ester 402 ##STR405##
(2S)-[5-Chloro-2-(5- dimethylamino-naphthalene- 1-sulfonylamino)-
benzoylamino]-3-(2'- phenoxy-biphenyl-4-yl)- propionic acid 403
##STR406## (2S)-[5-Bromo-2-(5- dimethylamino-naphthalene-
1-sulfonylamino)- benzoylamino]-3-(2'- phenoxy-biphenyl-4-yl)-
propionic acid 404 ##STR407## (2S)-[5-Bromo-2-(5-
dimethylamino-naphthalene- 1-sulfonylamino)- benzoylamino]-3-(2'-
phenoxy-biphenyl-4- yl)-propionic acid 405 ##STR408## (2S)-2-
Benzenesulfonylamino- 5-chloro- benzoylamino)-3-(2'-
phenoxy-biphenyl-4-yl)- propionic acid methyl ester 406 ##STR409##
(2S)-2- Benzenesulfonylamino- 5-chloro- benzoylamino)-3-(2'-
phenoxy-biphenyl-4-yl)- propionic acid 407 ##STR410##
(2S)-[5-Chloro-2- (naphthalene-1- sulfonylamino)-
benzoylamino]-3-(2'- phenoxy-biphenyl-4-yl)- propionic acid methyl
ester 408 ##STR411## (2S)-[5-Chloro-2- (naphthalene-1-
sulfonylamino)- benzoylamino]-3-(2'- phenoxy-biphenyl-4-yl)-
propionic acid 409 ##STR412## (2S)-[5-Chloro-2- (naphthalene-2-
sulfonylamino)- benzoylamino]-3-(2'- phenoxy-biphenyl-4-yl)-
propionic acid methyl ester 410 ##STR413## (2S)-[5-Chloro-2-
(naphthalene-2- sulfonylamino)- benzoylamino]-3-(2'-
phenoxy-biphenyl-4-yl)- propionic acid 411 ##STR414##
(2S)-[2-(4-tert-Butyl- benzenesulfonylamino)-5-
chloro-benzoylamino]-3-(2'- phenoxy-biphenyl-4-yl)- propionic acid
methyl ester 412 ##STR415## (2S)-[2-(4-tert-Butyl-
benzenesulfonylamino)-5- chloro-benzoylamino]-3-(2'-
phenoxy-biphenyl-4-yl)- propionic acid 413 ##STR416##
(2S)-[2-(Biphenyl-4- sulfonylamino)-5-chloro- benzoylamino]-3-(2'-
phenoxy-biphenyl-4-yl)- propionic acid methyl ester 414 ##STR417##
(2S)-[2-(Biphenyl-4- sulfonylamino)-5-chloro- benzoylamino]-3-(2'-
phenoxy-biphenyl-4-yl)- propionic acid 415 ##STR418##
(2S)-[5-Chloro-2-(quinoline- 8-sulfonylamino)- benzoylamino]-3-(2'-
phenoxy- biphenyl-4-yl)- propionic acid methyl ester 416 ##STR419##
(2S)-[5-Chloro-2-(quinoline- 8-sulfonylamino)- benzoylamino]-3-(2'-
phenoxy-biphenyl- 4-yl)- propionic acid 417 ##STR420##
(2S)-[5-Chloro-2-(5-chloro- 1,3-dimethyl-1H-pyrazole-
4-sulfonylamino)- benzoylamino)- benzoylamino]-3-(2'-
phenoxy-biphenyl-4- yl)-propionic acid 418 ##STR421##
(2S)-[5-Chloro-2-(1-methyl- 1H-imidazole-4- sulfonylamino)-
benzoylamino]-3- (2'-phenoxy-biphenyl- 4-yl)-propionic acid 419
##STR422## (2S)-[5-Chloro-2-(6-phenoxy- pyridine-3-sulfonylamino)-
benzoylamino]-3-(2'- phenoxy-biphenyl-4-yl)- propionic acid 420
##STR423## (2S)-[5-Chloro-2-(4-pyrazol- 1-yl-benzenesulfonylamino)-
benzoylamino]-3-(2'- phenoxy-biphenyl-4-yl)- propionic acid 421
##STR424## (2S)-[5-Chloro-2-(5-chloro- 1,3-dimethyl-1H-pyrazole-4-
sulfonylamino)- benzoylamino]-3-(2'- phenoxy-biphenyl-4-
yl)-propionic acid methyl ester 422 ##STR425##
(2S)-{5-Chloro-2-[3-(5- methyl-[1,3,4]oxadiazol-2-
yl)-benzenesulfonylamino]- benzoylamino}-3-(2'-
phenoxy-biphenyl-4-yl)- propionic acid methyl ester 423 ##STR426##
(2S)-[5-Chloro-2-(6-phenoxy- pyridine-3-sulfonylamino)-
benzoylamino]-3-(2'- phenoxy-biphenyl-4-yl)- propionic acid methyl
ester 424 ##STR427## (2S)-[5-Chloro-2-(4-pyrazol-
1-yl-benzenesulfonylamino)- benzoylamino]-3-(2'-
phenoxy-biphenyl-4-yl)- propionic acid methyl ester 425 ##STR428##
(2S)-[5-Chloro-2-(1-methyl- 1H-imidazole-4- sulfonylamino)-
benzoylamino]-3- (2'-phenoxy-biphenyl-4-yl)- propionic acid methyl
ester 426 ##STR429## (2S)-[5-Chloro-2-(3,5- dimethyl-isoxazole-4-
sulfonylamino)- benzoylamino]-3- (2'-phenoxy-biphenyl-4-yl)-
propionic acid methyl ester 427 ##STR430## (2S)-[5-Chloro-2-(6-
morpholin-4-yl-pyridine- 3-sulfonylamino)- benzoylamino]-3-(2'-
phenoxy-biphenyl-4-yl)- propionic acid methyl ester 428 ##STR431##
(2S)-[5-Chloro-2-(6- morpholin-4-yl-pyridine- 3-sulfonylamino)-
benzoylamino]-3-(2'- phenoxy-biphenyl-4-yl)- propionic acid 429
##STR432## (2S)-{5-Chloro-2-[5- (2-methylsulfanyl-
pyrimidin-4-yl)-thiophene- 2-sulfonylamino]- benzoylamino}-3-(2'-
phenoxy-biphenyl-4-yl)- propionic acid methyl ester 430 ##STR433##
(2S)-{5-Chloro-2-[5-(2- methylsulfanyl- pyrimidin-4-yl)-thiophene-
2-sulfonylamino]- benzoylamino}-3-(2'- phenoxy-biphenyl-4-yl)-
propionic acid 431 ##STR434## (2S)-{5-Chloro-2-[4-(5-
methyl-[1,3,4]oxadiazol-2- yl)-benzenesulfonylamino]-
benzoylamino}-3-(2'- phenoxy-biphenyl-4-yl)- propionic acid 432
##STR435## 3-Biphenyl-4-yl-(2S)- [2-(2,5-dichloro-
benzenesulfonylamino)-5- iodo-benzoylamino]- propionic acid methyl
ester 433 ##STR436## 3-Biphenyl-4-yl-(2S)- [2-(4-bromo-
benzenesulfonylamino)-5- iodo-benzoylamino]- propionic acid methyl
ester 434 ##STR437## 3-Biphenyl-4-yl-(2S)- [2-(3,5-bis-
trifluoromethyl- benzelesulfonylamino)- 5-chloro-benzoylamino]-
propionic acid 435 ##STR438## (2S)-[5-Chloro-2-(4- oxazol-5-yl-
benzenesulfonylamino)- benzoylamino]-3-(2'- phenoxy-biphenyl-4-yl)-
propionic acid methyl ester 436 ##STR439## (2S)-[5-Chloro-2-(4-
oxazol-5-yl- benzenesulfonylamino)- benzoylamino]-3-(2'-
phenoxy-biphenyl-4- yl)-propionic acid 437 ##STR440##
(2S)-[5-Chloro-2-(4- phenoxy- benzenesulfonylamino)-
benzoylamino]-3-(2'phenoxy-biphenyl-4-yl)- propionic acid methyl
ester 438 ##STR441## (2S)-[5-Chloro-2-(4- phenoxy-
benzenesulfonylamino)- benzoylamino]-4-(2'- phenoxy-biphenyl-4-yl)-
propionic acid 439 ##STR442## (2S)-[5-Chloro-2-(3-nitro-
benzenesulfonylamino)- benzoylamino]-3-(2'- phenoxy-biphenyl-4-yl)-
propionic acid 440 ##STR443## (2S)-[2-(3,5-Bis- trifluoromethyl-
benzenesulfonylamino)-5- chloro-benzoylamino]-3-(2'-
phenoxy-biphenyl-4-yl)- propionic acid methyl ester 441 ##STR444##
(2S)-[2-(3,5-Bis- trifluoromethyl- benzenesulfonylamino)-5-
chloro-benzoylamino]-3-(2'- phenoxy-biphenyl-4-yl)- propionic acid
442 ##STR445## (2S)-[2-(3-Amino- benzenesulfonylamino)-5-
chloro-benzoylamino]-3-(2'phenoxy-biphenyl-4-yl)- propionic acid
methyl ester 443 ##STR446## (2S)-{5-Chloro-2-[5-(2-
methyl-5-trifluoromethyl-2H- pyrazol-3-yl)-thiophene-
2-sulfonylamino]- benzoylamino}-3- (2'-phenoxy-biphenyl-4-yl)-
propionic acid methyl ester 444 ##STR447## (2S)-{5-Chloro-2-[5-(2-
methyl-5-trifluoromethyl-2H- pyrazol-3-yl)-thiophene-
2-sulfonylamino]- benzoylamino}-3- (2'-phenoxy-biphenyl-4-yl)-
propionic acid 445 ##STR448## 3-Biphenyl-4-yl-(2S)-[5-
chloro-2-(5-dibutylamino- napthalene-1- sulfonylamino)-
enzoylamino]-propionic acid methyl ester 446 ##STR449##
3-Biphenyl-4-yl-(2S)-[5- chloro-2-(5-dibutylamino- naphthalene-1-
sulfonylamino)- benzoylamino]- propionic acid 447 ##STR450##
(2S)-[5-Bromo-2-(4- tert-butyl- benzenesulfonylamino)-
benzoylamino]-3-(2'- phenoxy-biphenyl-4-yl)- propionic acid methyl
ester 448 ##STR451## (2S)-[5-Bromo-2-(4- tert-butyl-
benzenesulfonylamino)- benzoylamino]-3-(4'- phenoxy-biphenyl-4-yl)-
propionic acid methyl ester 449 ##STR452## 3-Biphenyl-4-yl-(2S)-{5-
chloro-2-[naphthalen-1- ylmethyl-(4-nitro- benzenesulfonyl)-amino]-
benzoylamino}- propionic acid 450 ##STR453## (2S)-{2-[(Biphenyl-4-
sulfonyl)-(3-methyl-thiophen- 2-ylmethyl)-amino]-5-
chloro-benzoylamino}- 3-biphenyl-4- yl-propionic acid 451
##STR454## (2S)-{2-[(Biphenyl-4- sulfonyl)-(3-phenyl-propyl)-
amino]-5-chloro- benzoylamino}-3- biphenyl-4-yl- propionic acid 452
##STR455## (2S)-{2-[(Biphenyl-4- sulfonyl)-biphenyl-4-
ylmethyl-amino]-5-chloro- benzoylamino}-3- biphenyl-4- yl-propionic
acid 453 ##STR456## (2S)-{2-[(Biphenyl-4- sulfonyl)-naphthalen-1-
ylmethyl-amino]-5-chloro- benzoylamino}-3-biphenyl- 4-yl-propionic
acid 454 ##STR457## (2S)-{2-[(Biphenyl-4- sulfonyl)-(4-isopropyl-
benzyl)-amino]-5-chloro- benzoylamino}-3-biphenyl- 4-yl-propionic
acid 455 ##STR458## 3-Biphenyl-4-yl-(2S)-{2-
[biphenyl-4-ylmethyl-(2,4- dichloro-benzenesulfonyl)-
amino]-5-chloro- benzoylamino}- propionic acid 456 ##STR459##
(2S)-{2-[(Biphenyl-4- sulfonyl)-ethyl-amino]-5-
chloro-benzoylamino}-3- biphenyl-4-yl-propionic acid 457 ##STR460##
(2S)-{2-[(Biphenyl-4- sulfonyl)-ethyl-amino]-5-
iodo-benzoylamino}-3- biphenyl-4-yl- propionic acid 458 ##STR461##
2-{5-Chloro-2-[(naphthalen- 1-ylmethyl)-amino]-
benzoylamino}-3-(4'- trifluoromethyl-biphenyl- 4-yl)-propionic acid
459 ##STR462## (S)-2-{2-[3-(4-tert-Butyl- phenoxy-benzylamino]-5-
chloro-benzoylamino}- 3-(4'- cyclohexyl-biphenyl- 4-yl)-propionic
acid 460 ##STR463## (2S)-{5-Chloro-2- [(naphthalen-1-ylmethyl)-
amino]-benzoylamino}-3- (2'-phenoxy- biphenyl-4-yl)- propionic acid
461 ##STR464## (2S)-{5-Chloro-2 [(naphthalen-2-ylmethyl)-
amino]-benzoylamino}-3- (2'-piperidin- 1-ylmethyl- biphenyl-4-yl)-
propionic acid 462 ##STR465## 2S-[5-Chloro-2-(2-methyl-
butylamino)-benzoylamino]- 3-(2'-phenoxy-biphenyl- 4-yl)-propionic
acid 463 ##STR466## 3-Biphenyl-4-yl-2S-{5-chloro-
2-[(naphthalen-1-ylmethyl)- amino]-benzoylamino}- propionic acid
464 ##STR467## 3-(4'-tert-Butyl-biphenyl-4- yl)-(2S)-{5-chloro-2-
[(naphthalen-1-ylmethyl- amino]-benzoylamino}- propionic acid 465
##STR468## (2S)-{5-Chloro-2- [(naphthalen-1-ylmethyl)-
amino]-benzoylamino}-3-(4'- methanesulfonyl-biphenyl-
4-yl)-propionic acid 466 ##STR469## (2S)-(5-Chloro-2-
hexylamino-benzoylamino)- 3-(4'-trifluoromethyl- biphenyl-4-yl)-
propionic acid 467 ##STR470## (2S)-(5-Chloro-2-
hexylamino-benzoylamino)- 3-(4'-dimethylamino-
biphenyl-4-yl)-propionic acid 468 ##STR471## (2S)-[2-(4-tert-Butyl-
benzylamino)-5-chloro- benzoylamino]-3-(4'- dimethylamino-biphenyl-
4-yl)-propionic acid 469 ##STR472## (2S)-{2-[3-(4-tert-Butyl-
phenoxy)-benzylamino]-5- chloro-benzoylamino}-3-(4'-
dimethylamino-biphenyl-4- yl)-propionic acid 470 ##STR473##
(2S)-{5-Chloro-2- [(naphthalen-1-ylmethyl)- amino]-benzoylamino}-3-
(4'-phenoxy- biphenyl-4-yl)- propionic acid 471 ##STR474##
(2S)-[2-(4-tert-Butyl- benzylamino)-5-chloro- benzoylamino]-3-(4'-
cyclohexyl-biphenyl-4-yl)- propionic acid 472 ##STR475##
(2S)-(5-Chloro-2- heptylamino-benzoylamino)-
3-(4'-phenoxy-biphenyl-4- yl)-propionic acid 473 ##STR476##
(2S)-(5-Chloro-2- heptylamino-benzoylamino)- 3-(4'-cyclohexyl-
biphenyl-4-yl)- propionic acid
474 ##STR477## (2S)-{5-Chloro-2- [(naphthalen-1-ylmethyl)-
amino]-benzoylamino}-3- (4'-cyclohexyl- biphenyl-4-yl)- propionic
acid 475 ##STR478## (2S)-{5-Chloro-2- [(naphthalen-1-ylmethyl)-
amino]-benzoylamino}-3- (4'-pentyl-biphenyl- 4-yl)-propionic acid
476 ##STR479## (2S)-[2-(4-tert-Butyl- benzylamino)-5-iodo-
benzoylamino]-3-(4'- phenoxy-biphenyl-4-yl)- propionic acid 477
##STR480## 3-(4'-Amino-biphenyl-4-yl)- 2S)-{5-chloro-2-
[(naphthalen-1-ylmethyl)- amino]-benzoylamino}- propionic acid 478
##STR481## 3-Biphenyl-4-yl-2S-[2-(4- tert-butyl-benzylamino)-
5-(3,4-dichloro- phenoxy)- benzoylamino]- propionic acid 479
##STR482## 3-Biphenyl-4-yl-2S-[2-(4- tert-butyl-benzylamino)-
5-(3-chloro-4- fluoro-phenoxy)- benzoylamino]- propionic acid 480
##STR483## 3-Biphenyl-4-yl-(2S)-[2-(4- tert-butyl-benzylamino)-5-
(3-trifluoromethyl- phenoxy)-benzoylamino]- propionic acid 481
##STR484## 3-Biphenyl-4-yl-(2S)-[2-(4- tert-butyl-benzylamino)-5-
(2,3,4-trichloro-phenoxy)- benzoylamino]- propionic acid 482
##STR485## 3-Biphenyl-4-yl-(2S)-[2-(4- tert-butyl-benzylamino)-4-
chloro-benzoylamino]- propionic acid 483 ##STR486##
3-Biphenyl-4-yl-(2S)-[2-(4- tert-butyl-benzylamino)-5-(4-
chloro-phenoxy)- benzoylamino]- propionic acid 484 ##STR487##
3-Biphenyl-4-yl-2S-[2-(4-tert- butyl-benzylamino)-5-[4-
chloro-3-fluoro-phenoxy)- benzoylamino]- propionic acid 485
##STR488## 3-Biphenyl-4-yl-(2S)-[2-(4- tert-butyl-benzylamino)-5-
(3,4-dimethoxy-phenoxy)- benzoylamino]- propionic acid 486
##STR489## 3-(2'-Benzyloxy-biphenyl- 4-yl)-(2S)-{5-chloro-
2-[(naphthalen-1- ylmethyl)-amino]- benzoylamino}- propionic acid
487 ##STR490## 3-(3'-Benzyloxy-biphenyl-4- yl)-(2S)-{5-chloro-2-
[(naphthalen-1-ylmethyl)- amino]-benzoylamino}- propionic acid 488
##STR491## (2S)-{5-Chloro-2- [(naphthalen-1-ylmethyl)-
amino]-benzoylamino}- 3-(2'-trifluoromethyl- biphenyl-4-yl)-
propionic acid 489 ##STR492## (2S)-{2-[3-(4-tert-Butyl-
phenoxy)-benzylamino]-5- chloro-benzoylamino}-3-
(2'-phenoxy-biphenyl- 4-yl)-propionic acid 490 ##STR493##
(2S)-[2-(4-tert-Butyl- benzylamino)-5-chloro- benzoylamino]-3-(2'-
phenoxy-biphenyl-4-yl)- propionic acid 491 ##STR494##
(2S)-[5-Bromo-2-(4-tert- butyl-benzylamino)- benzoylamino]-3-(2'-
phenoxy-biphenyl-4-yl)- propionic acid 492 ##STR495##
(2S)-[5-Bromo-2-(2-methyl- pentylamino)-benzoylamino]-
3-(2'-phenoxy-biphenyl- 4-yl)-propionic acid 493 ##STR496##
3-Biphenyl-4-yl-(2S)-{5- chloro-2-[(piperidin-4- ylmethyl)-amino]-
benzoylamino}- propionic acid 494 ##STR497##
3-(2'-Benzyloxy-biphenyl-4- yl)-(2S)-{2-[3-(4-tert-butyl-
phenoxy)-benzylamino]- 5-chloro-benzoylamino}- propionic acid 495
##STR498## 3-(2'-Benzyloxy-biphenyl-4- yl)-(2S)-[2-(4-tert-butyl-
benzylamino)-5-chloro- benzoylamino]- propionic acid 496 ##STR499##
(2S)-[5-Chloro-2-(3-phenoxy- benzylamino)- benzoylamino]-3-(2'-
phenoxy-biphenyl-4-yl)- propionic acid 497 ##STR500##
(2S)-[2-(3,5-Bis- trifluoromethyl-benzylamino)-
5-chloro-benzoylamino]- 3-(2'-phenoxy- biphenyl-4-yl)- propionic
acid 498 ##STR501## (2S)-[5-Chloro-2-(4-phenoxy- benzylamino)-
benzoylamino]-3-(2'- phenoxy-biphenyl-4-yl)- propionic acid 499
##STR502## (2S)-[2-(4-Benzyloxy- benzylamino)-5-chloro-
benzoylamino]-3-(2'- phenoxy-biphenyl-4-yl)- propionic acid 500
##STR503## 3-Biphenyl-4-yl-(2S)-[5-(2- chloro-4-trifluoromethyl-
phenoxy)-2-(2-methyl- butylamino)-benzoylamino]- propionicacid 501
##STR504## (2S)-[3,4-Dichloro-2-(2- methyl-butylamino)-
benzoylamino]-3-(2'- phenoxy-biphenyl-4-yl)- propionic acid 502
##STR505## (2S)-[5-Bromo-2- (cyclohexylmethyl-amino)-
benzoylamino]-3-(2'- phenoxy-biphenyl-4-yl)- propionic acid 503
##STR506## (2S)-(5-Chloro-2- pentylamino-benzoylamino)-
3-(2'-phenoxy-biphenyl- 4-yl)-propionic acid 504 ##STR507##
(2S)-{2-[3-(4-tert-Butyl- phenoxy)-benzylamino]-5-
chloro-benzoylamino}-3- (2'-hydroxy-biphenyl- 4-yl)-propionic acid
505 ##STR508## (2S)-(5-Chloro-2-hexa-2,4- dienylamino-
benzoylamino)-3-(2'- phenoxy-biphenyl-4-yl)- propionic acid 506
##STR509## (2S)-[5-Chloro-2-(3-phenyl- propylamino)-benzoylamino]-
3-(2'-phenoxy-biphenyl- 4-yl)-propionic acid 507 ##STR510##
(2S)-(5-Chloro-2-octylamino-
benzoylamino)-3-(2'phenoxy-biphenyl-4-yl)- propionic acid 508
##STR511## (2S)-(5-Chloro-2- hexylamino-benzoylamino)-
3-(2'-phenoxy-biphenyl-4-yl)- propionic acid 509 ##STR512##
(2S)-[5-Chloro-2-(2,2- dimethyl-propylamino)- benzoylamino]-3-(2'-
phenoxy-biphenyl-4-yl)- propionic acid 510 ##STR513##
(2S)-[5-Chloro-2-(2-methyl- pent-2-enylamino)- benzoylamino]-3-(2'-
phenoxy-biphenyl-4-yl)- propionic acid 511 ##STR514##
(2S)-(5-Chloro-2-ethylamino- benzoylamino)-3-(2'-
phenoxy-biphenyl-4-yl)- propionic acid 512 ##STR515## :
(2S)-(5-Chloro-2- diethylamino-benzoylamino)-
3-(2'-phenoxy-biphenyl-4- yl)-propionic acid 513 ##STR516##
2-(5-Chloro-2-diethylamino- benzoylamino)-3-[3'-(4-
trifluoromethyl-phenoxy)- biphenyl-4-yl]- propionic acid 514
##STR517## (2S)-[5-Chloro-2-(3,5- dimethyl-piperidin-1-yl)-
benzoylamino]-3-(2'- phenoxy-biphenyl-4-yl)- propionic acid 515
##STR518## 3-Biphenyl-4-yl-(2S)-{2-[bis-
(4-benzyloxy-benzyl)-amino]- 5-chloro-benzoylamino}- propionic acid
516 ##STR519## 3-Biphenyl-4-yl-(2S)-[2-(bis- naphthalen-1-ylmethyl-
amino)-5-chloro- benzoylamino]- propionic acid 517 ##STR520##
3-Biphenyl-4-yl-(2S)-[2-(bis- biphenyl-4-ylmethyl-amino)-
5-chloro-benzoylamino]- propionic acid 518 ##STR521##
(2S)-(5-Bromo-2- dibutylamino-benzoylamino)-
3-(2'-phenoxy-biphenyl- 4-yl)-propionic acid 519 ##STR522##
(2S)-(5-Bromo-2- dihexylamino- benzoylamino)-3-(2'-
phenoxy-biphenyl-4-yl)- propionic acid 520 ##STR523##
(2S)-(5-Chloro-2- dipentylamino- benzoylamino)-3-(2'-
phenoxy-biphenyl-4-yl)- propionic acid 521 ##STR524##
(2S)-(5-Chloro-2-piperidin-1- yl-benzoylamino)-3-(2'-
phenoxy-biphenyl-4-yl)- propionic acid 522 ##STR525##
(2S)-(5-Bromo-2- diethylamino-benzoylamino)-
3-(2'-phenoxy-biphenyl- 4-yl)-propionic acid 523 ##STR526##
(2S)-(5-Chloro-2- diethylamino-benzoylamino)- 3-[3'-(3-chloro-4-
fluorophenoxy)-biphenyl)- 4-yl]-propionic acid 524 ##STR527##
(2S)-(5-Bromo-2-piperidin-1- yl-benzoylamino)-3-(2'-
phenoxy-biphenyl-4-yl)- propionic acid 525 ##STR528##
(2S)-(5-Chloro-2- diethylamino-benzoylamino)-
3-[3'-(4-methoxy-phenoxy)- biphenyl-4-yl]- propionic acid 526
##STR529## (2S)-(5-Chloro-2- diethylamino-benzoylamino)-
3-[3'-(4-trifluoromethoxy- phenoxy)-biphenyl-4- yl]-propionic acid
527 ##STR530## 3-[3'-(4-tert-Butyl-phenoxy)-
biphenyl-4-yl]-(2S)-(5- chloro-2-diethylamino- benzoylamino)-
propionic acid 528 ##STR531## (2S)-(5-Bromo-2-
diethylamino-benzoylamino)- 3-[3'-(4-trifluoromethyl-
phenoxy)-biphenyl-4-yl]- propionic acid 529 ##STR532##
(2S)-(5-Bromo-2- diethylamino-benzoylamino)-
3-[3-'(3-fluoro-phenoxy)- biphenyl-4-yl]- propionic acid 530
##STR533## (2S)-(5-Bromo-2- pyrrolidin-1-yl- benzoylamino)-3-(2'-
phenoxy-biphenyl-4-yl)- propionic acid 531 ##STR534##
(2S)-[5-Chloro-2-(4- methyl-piperazin-1-yl)- benzoylamino]-3-(2'-
phenoxy-biphenyl-4-yl)- propionic acid 532 ##STR535##
(2S)-[5-Chloro-2-(4-phenyl- piperazin-1-yl)- benzoylamino]-3-(2'-
phenoxy-biphenyl-4-yl)- propionic acid 533 ##STR536##
(2S)-[5-Chloro-2-(3,4- dihydro-1H-isoquinolin- 2-yl)-benzoylamino]-
3-(2'-phenoxy-biphenyl- 4-yl)-propionic acid 534 ##STR537##
(2S)-(5-Chloro-2-morpholin- 4-yl-benzoylamino)-3-(2'-
phenoxy-biphenyl-4-yl)- propionic acid 535 ##STR538##
(2S)-(2-Azepin-1-yl-5-chloro- benzoylamino)-3-(2'-
phenoxy-biphenyl-4-yl)- propionic acid 536 ##STR539##
(2S)-[5-Chloro-2-(4- trifluoromethyl-piperidin-
1-yl)-benzoylamino]- 3-(2'-phenoxy- biphenyl-4-yl)- propionic acid
537 ##STR540## (2S)-[5-Chloro-2-(4- methylsulfanyl- phenylamino)-
benzoylamino]-3-(2'- phenoxy-biphenyl-4-yl)- propionic acid 538
##STR541## (2S)-[5-Chloro-2-(3-chloro- 4-fluoro-phenylamino)-
benzoylamino]-3-(2'- phenoxy-biphenyl-4-yl)- propionic acid 539
##STR542## (2S)-[5-Bromo-2-(4- trifluoromethyl- phenylamino)-
benzoylamino]-3-(2'- phenoxy-biphenyl-4-yl)- propionic acid 540
##STR543## (2S)-(5-Bromo-2- phenylamino-benzoylamino)-
3-(2'-phenoxy-biphenyl- 4-yl)-propionic acid 541 ##STR544##
(2S)-(5-Chloro-2- phenylamino-benzoylamino)-
3-(2'-phenoxy-biphenyl- 4-yl)-propionic acid 542 ##STR545##
(2S)-[5-Chloro-2-(4- trifluoromethyl- phenylamino)-
benzoylamino]-3-(2'- phenoxy-biphenyl-4-yl)- propionic acid 543
##STR546## (2S)-[5-Chloro-2-(3,5- dimethyl-phenylamino)-
benzoylamino]-3-(2'- phenoxy-biphenyl-4-yl)- propionic acid 544
##STR547## (2S)-[5-Chloro-2-(3- trifluoromethyl- phenylamino)-
benzoylamino]-3-(2'- phenoxy-biphenyl-4-yl)- propionic acid 545
##STR548## (2S)-[5-Chloro-2-(4- methoxy-phenylamino)-
benzoylamino]-3-(2'- phenoxy-biphenyl-4-yl)- propionic acid 546
##STR549## (2S)-[2-(4-tert-Butyl- phenylamino)-5-chloro-
benzoylamino]-3-(2'- phenoxy-biphenyl-4-yl)- propionic acid 547
##STR550## (2S)-[5-Chloro-2-(3,4- difluoro-phenylamino)-
benzoylamino]-3-(2'- phenoxy-biphenyl-4-yl)- propionic acid 548
##STR551## (2S)-[5-Chloro-2-(4-fluoro- 3-methyl-phenylamino)-
benzoylamino]-3-(2'- phenoxy-biphenyl-4-yl)- propionic acid 549
##STR552## (2S)-[5-Chloro-2-(3,4- dichloro-phenylamino)-
benzoylamino]-3-(2'- phenoxy-biphenyl-4-yl)- propionic acid 550
##STR553## (2S)-[5-Chloro-2-(4- trifluoromethoxy- phenylamino)-
benzoylamino]-3-(2'- phenoxy-biphenyl-4-yl)- propionic acid 551
##STR554## (2S)-[5-Chloro-2-(4- methanesulfonyl- phenylamino)-
benzoylamino]-3-(2'- phenoxy-biphenyl-4-yl)- propionic acid 552
##STR555## (2S)-[2-(4-Benzyloxy- phenylamino)-5-chloro-
benzoylamino]-3-(2'- phenoxy-biphenyl-4-yl)- propionic acid 553
##STR556## (2S)-[5-Chloro-2- (naphthalen-1-ylamino)-
benzoylamino]-3-(2'- phenoxy-biphenyl-4-yl)- propionic acid 554
##STR557## (2S)-[5-Chloro-2- (naphthalen-2-ylamino)-
benzoylamino]-3-(2'- phenoxy-biphenyl-4-yl)- propionic acid 555
##STR558## (2S)-[5-(3,5-Bis- trifluoromethyl-
phenylamino)-5-chloro- benzoylamino]-3-(2'- phenoxy-biphenyl-4-yl)-
propionic acid 556 ##STR559## (2S)-[5-Chloro-2-(4-
cyclohexyl-phenylamino)- benzoylamino]-3-(2'-
phenoxy-biphenyl-4-yl)- propionic acid 557 ##STR560##
(2S)-[2-(Biphenyl-4-ylamino)- 5-chloro-
benzoylamino]-3-(2'- phenoxy-biphenyl-4-yl)- propionic acid 558
##STR561## (2S)-[2-(3-Butoxy- phenylamino)-5-chloro-
benzoylamino]-3-(2'- phenoxy-biphenyl-4-yl)- propionic acid 559
##STR562## (2S)-[5-Chloro-2-(4-ethoxy- phenylamino)-
benzoylamino]-3-(2'- phenoxy-biphenyl-4-yl)- propionic acid 560
##STR563## (2S)-[5-Chloro-2-(4-fluoro-3- methoxy-phenylamino)-
benzoylamino]-3-(2'- phenoxy-biphenyl-4-yl)- propionic acid 561
##STR564## (2S)-[5-Chloro-2-(4-chloro- phenylamino)-
benzoylamino]-3-(2'- phenoxy-biphenyl-4-yl)- propionic acid 562
##STR565## (2S)-[5-Chloro-2-(3-chloro- phenylamino)-
benzoylamino]-3-(2'- phenoxy-biphenyl-4-yl)- propionic acid 563
##STR566## (2S)-[5-Chloro-2-(2,4- dichloro-phenylamino)-
benzoylamino]-3-(2'phenoxy-biphenyl-4-yl)- propionic acid 564
##STR567## (2S)-[2-(Benzo[2,3]dioxol-4- ylamino)-4-chloro-
benzoylamino]-3-(2'- phenoxy-biphenyl-4-yl)- propionic acid 565
##STR568## (2S)-[5-Chloro-2-(4-cyano- phenylamino)-
benzoylamino]-3-(2'- phenoxy-biphenyl-4-yl)- propionic acid 566
##STR569## (2S)-[5-Chloro-2-(4-methoxy- 3-methyl-phenylamino)-
benzoylamino]-3-(2'- phenoxy-biphenyl-4-yl)- propionic acid 567
##STR570## (2S)-[5-Chloro-2-(3- isopropyl-phenylamino)-
benzoylamino]-3-(2'- phenoxy-biphenyl-4-yl)- propionic acid 568
##STR571## (2S)-[5-Chloro-2-(4- nitro-phenylamino)-
benzoylamino]-3-(2'- phenoxy-biphenyl-4-yl)- propionic acid 569
##STR572## (2S)-[5-Chloro-2-(4-methyl- 3-nitro-phenylamino)-
benzoylamino]-3-(2'- phenoxy-biphenyl-4-yl)- propionic acid 570
##STR573## (2S)-{[(2-Biphenyl-4-yl- methoxycarbonyl-ethyl)- (4'-
trifluoromethyl-biphenyl- carbonyl)-amino]-methyl}-
(2S)-pyrrolidine-1-carboxylic acid tert-butyl ester 571 ##STR574##
(2S)-(2-{[(2-Biphenyl-4-yl-1- methoxycarbonyl-ethyl)-(4'-
trifluoromethyl-biphenyl-4- carbonyl)-amino]-methyl}-
(2S)-pyrrolidine-1-sulfonyl)- benzoic acid methyl ester 572
##STR575## 3-Biphenyl-4-yl-(2S)-[[(2R)- 1-(2-thiophen-2-yl-acetyl)-
pyrrolidine-2-methyl]-(4'- trifluoromethyl-biphenyl-4-
carbonyl)-amino]-propionic acid 573 ##STR576##
(2S)-[[2-(2-Acetylamino-4- methyl-thiazole-5-
sulfonylamino)-ethyl]-(4'- trifluoromethyl-biphenyl-4-
carbonyl)-amino]-3- biphenyl-4-yl- propionic acid methyl ester 574
##STR577## (2S)-[(Biphenyl-4-carbonyl)-
(2-hydroxy-benzyl)-amino]-3- biphenyl-4-yl-propionic acid 575
##STR578## (2S)-[(Biphenyl-4-carbonyl)-
(4-isopropyl-benzyl)-amino]- 3-biphenyl-4-yl- propionic acid 576
##STR579## 3-Biphenyl-4-yl-(2S)-[(4- isopropyl-benzyl)-
(naphthalene-2-carbonyl)- amino]-propionic acid 577 ##STR580##
3-Biphenyl-4-yl-(2S)-[(4-tert- butyl-benzoyl)-(4-isopropyl-
benzyl)amino]- propionic acid 578 ##STR581##
3-Biphenyl-4-yl-(2S)-[(3,4- dichloro-benzoyl)-(4-
isopropyl-benzyl)-amino]- propionic acid 579 ##STR582##
(2S)-[(Biphenyl-4-carbonyl)- naphthalen-1-ylmethyl-
amino]-3-biphenyl-4-yl- propionic acid 580 ##STR583##
3-Biphenyl-4-yl-(2S)- [(naphthalene-2-carbonyl)-
naphthalen-1-ylmethyl- amino]-propionic acid 581 ##STR584##
3-Biphenyl-4-yl-(2S)-[(4-tert- butyl-benzoyl)-naphthalen-1-
ylmethyl-amino]- propionic acid 582 ##STR585##
3-Biphenyl-4-yl-(2S)-[(3,5- dichloro-benzoyl)-
naphthalen-1-ylmethyl- amino]-propionic acid 583 ##STR586##
3-Biphenyl-4-yl-(2S)- [(naphthalene-1-carbonyl)-
naphthalen-1-ylmethyl- amino]-propionic acid 584 ##STR587##
3-Biphenyl-4-yl-(2S)-[(3,4- dichloro-benzoyl)-
naphthalen-1-ylmethyl- amino]-propionic acid 585 ##STR588##
3-Biphenyl-4-yl-(2S)-[(4- methyl-benzoyl)-naphthalen-
1-ylmethyl-amino]- propionic acid 586 ##STR589##
3-Biphenyl-4-yl-(2S)-[(2,4- dichloro-benzoyl)-
naphthalen-1-ylmethyl- amino]-propionic acid 587 ##STR590##
3-Biphenyl-4-yl-(2S)- [naphthalen-1-yl-methyl-(4-
nitro-benzoyl)-amino]- propionic acid 588 ##STR591##
3-Biphenyl-4-yl-(2S0-[(4- chloro-benzoyl)-naphthalen-
1-ylmethyl-amino]- propionic acid 589 ##STR592##
(2S)-[(Biphenyl-4-carbonyl)- (4-chloro- benzyl)-amino]-3-
biphenyl-4-yl- propionic acid 590 ##STR593##
3-Biphenyl-4-yl-(2S)-[(4- chloro-benzyl)-(3,5-dichloro-
benzoyl)-amino]- propionic acid 591 ##STR594##
(2S)-[(Biphenyl-4-carbonyl)- (5-tert-butyl-2-hydroxy-
benzyl)-amino]-3-biphenyl- 4-yl-propionic acid 592 ##STR595##
Biphenyl-4-carboxylic acid (2S)-{[(biphenyl-4-carbonyl)-
(2-biphenyl-4-yl- 1-carboxy-ethyl)-amino]- methyl}-4-tert-butyl-
phenyl ester 593 ##STR596## 3-Biphenyl-4-yl-(2S)-[(4-
bromo-benzoyl)-(2-tert- butoxycarbonylamino-ethyl)- amino]-
propionic acid 594 ##STR597## 3-Biphenyl-4-yl-(2S)-[(2-tert-
butoxycarbonylamino-ethyl)- (4'-trifluoromethoxy-biphenyl-
4-carbonyl)-amino]- propionic acid 595 ##STR598##
(2S)-[(2-Amino-ethyl)-(4- bromo-benzoyl)-amino]-3- biphenyl-4-yl-
propionic acid methyl ester 596 ##STR599##
(2S)-[(2-Amino-ethyl)-(4- bromo-benzoyl)-amino]-3- biphenyl-4-yl-
propionic acid 597 ##STR600## 3-Biphenyl-4-yl-(2S)-[(4-
chloro-benzyl)-(4'- trifluoromethyl-biphenyl-4- carbonyl)-amino]-
propionic acid 598 ##STR601## (2S)-{2-[(2-Biphenyl-4-yl-
1-carboxy-ethyl)-(4'- trifluoromethyl- biphenyl-4-
carbonyl)-amino]- ethylsulfamoyl}- benzoic acid 599 ##STR602##
3-Biphenyl-4-yl-(2S)-[[(2-(2- methanesulfonyl-
benzenesulfonylamino)- ethyl]-(4'- trifluoromethyl-biphenyl-
4-carbonyl)-amino]- propionic acid 600 ##STR603##
(2S0-{[(2-Biphenyl-4-yl-1- methoxycarbonyl-ethyl)-(4'-
trifluoromethyl-biphenyl-4- carbonyl)-amino]-methyl}-
(2R)-pyrrolidine-1-carboxylic acid tert-butyl ester 601 ##STR604##
(2S)-{2-[(2-Biphenyl-4-yl-1- methoxycarbonyl-ethyl)-(4'-
trifluoromethyl-biphenyl-4- carbonyl)-amino]-
ethylsulfamoyl}-benzoic acid methyl ester 602 ##STR605##
3-Biphenyl-4-yl-(2S)-[[2-(2- methanesulfonyl-
benzenesulfonylamino)- ethyl]-(4'- trifluoromethyl-biphenyl-
4-carbonyl)-amino]-propionic acid methyl ester 603 ##STR606##
3-Biphenyl-4-yl-(2S)-[[2-(4- methanesulfonyl-
benzenesulfonylamino)- ethyl]-(4'-trifluoromethyl-
biphenyl-4-carbonyl)-amino]- propionic acid methyl ester 604
##STR607## 3-Biphenyl-4-yl-(2S)-[[1-(2- methanesulfonyl-
benzenesulfonyl)-(2S)- pyrrolidin-2-ylmethyl]-(4'-
trifluoromethyl-biphenyl-4- carbonyl)-amino]-propionic acid methyl
ester 605 ##STR608## 3-Biphenyl-4-yl-(2S)-[[1-(4- methanesulfonyl-
benzenesulfonyl)-(2S)- pyrrolidin-2-ylmethyl]-(4'-
trifluoromethyl-biphenyl-4- carbonyl)-amino]-propionic acid ester
606 ##STR609## (2S)-{[(2-Biphenyl-4-yl-1- carboxy-ethyl)-(4'-
trifluoromethyl-biphenyl-4- carbonyl)-amino]-methyl}-
(2S)-pyrrolidine-1-carboxylic acid tert-butyl ester 607 ##STR610##
(2S)-{[(2-Biphenyl-4-yl-1- carboxy-ethyl)-(4'-
trifluoromethyl-biphenyl-4- carbonyl)-amino]-methyl}-
(2R)-pyrrolidine-1-carboxylic acid tert-butyl ester 608 ##STR611##
(2S)-(2-{[(2-Biphenyl-4-yl-1- carboxy-ethyl)-(4'-
trifluoromethyl-biphenyl- 4-carbonyl)-amino}-methyl}-
(2S)-pyrrolidine-1-sulfonyl)- benzoic acid methylester 609
##STR612## 3-Biphenyl-4-yl-(2S)-[[1-(2- methanesulfonyl-
benzenesulfonyl)-(2S)- pyrrolidin-2-ylmethyl]-(4'-
trifluoromethyl-biphenyl-4- carbonyl)-amino]- propionic acid 610
##STR613## 3-Biphenyl-4-yl-(2S)-[[1-(4- methanesulfonyl-
benzenesulfonyl)-(2S)- pyrrolidin-2-ylmethyl]-(4'-
trifluoromethyl-biphenyl-4- carbonyl)-amino]- propionic acid 611
##STR614## (2S)-(2-{[(2-Biphenyl-4-yl-1-
methoxycarbonyl-ethyl)--(4'- trifluoromethyl-biphenyl)-4-
carbonyl)-amino]- methyl}-(2R)- pyrrolidine-1-sulfonyl)- benzoic
acid methyl ester 612 ##STR615## 3-Biphenyl-4-yl-(2S)-[[1-
(2-methanesulfonyl- benzenesulfonyl)-(2R)-
pyrrolidin-2-ylmethyl]-(4'- trifluoromethyl-biphenyl-4-
carbonyl)-amino]-propionic acid methyl ester 613 ##STR616##
3-Biphenyl-4-yl-(2S)-[[1- (4-methanesulfonyl-
benzenesulfonyl)-(2R)- pyrrolidin-2-ylmethyl]-(4'-
trifluoromethyl-biphenyl-4- carbonyl)-amino]-propionic acid methyl
ester 614 ##STR617## 3-Biphenyl-4-yl-(2S)-[[1-(2-
thiophen-2-yl-acetyl)-(2R)- pyrrolidin-2-ylmethyl]-
(4'-trifluoromethyl-biphenyl- 4-carbonyl)-amino]-propionic acid
methyl ester 615 ##STR618## (2S)-(2-{[(2-Biphenyl-4-yl-1-
carboxy-ethyl)-(4'- trifluoromethyl-biphenyl-
4-carbonyl)-amino}-methyl]- (2R)-pyrrolidine-1-sulfonyl)- benzoic
acid methyl ester 616 ##STR619## 3-Biphenyl-4-yl-(2S)-[[1-(2-
methanesulfonyl- benzenesulfonyl)-(2R)- pyrrolidin-2-ylmethyl]-(4'-
trifluoromethyl-biphenyl-4- carbonyl)-amino]-propionic acid 617
##STR620## 3-Biphenyl-4-yl-(2S)-[(1- cyclopentanecarbonyl-(2S)-
pyrrolidin-2-ylmethyl)-(4'- trifluoromethyl-biphenyl-4-
carbonyl)-amino]-propionic acid methyl ester 618 ##STR621##
3-Biphenyl-4-yl-(2S)-[(1- cyclopropanecarbonyl-(2R)-
pyrrolidin-2-ylmethyl)-(4'- trifluoromethyl-biphenyl-4-
carbonyl)-amino]-propionic acid methyl ester 619 ##STR622##
3-Biphenyl-4-yl-(2S)-[[1-(4- methanesulfonyl-
benzenesulfonyl)-(2R)- pyrrolidin-2-ylmethyl]-(4'-
trifluoromethyl-biphenyl-4- carbonyl)-amino]- propionic acid 620
##STR623## (2S)-[(1-Acetyl-(2S)- pyrrolidin-2-ylmethyl)-(4'-
trifluoromethyl-biphenyl-4- carbonyl)-amino]-3-biphenyl-
4-yl-propionic acid 621 ##STR624## 3-Biphenyl-4-yl-(2S)-[[1-(2,2-
dimethyl-propionyl)-(2S)- pyrrolidin-2-ylmethyl]-
(4'-trifluoromethyl-biphenyl- 4-carbonyl)-amino}- propionic acid
622 ##STR625## 3-Biphenyl-4-yl-(2S)-[(1- cyclopentanecarbonyl-(2S)-
pyrrolidin-2-ylmethyl)-(4'- trifluoromethyl-biphenyl-4-
carbonyl)-amino]-propionic acid 623 ##STR626##
(2S)-[(1-Acetyl-(2R)- pyrrolidin-2-ylmethyl)-(4'-
trifluoromethyl-biphenyl-4- carbonyl)-amino]-3-biphenyl-
4-yl-propionic acid 624 ##STR627## 3-Biphenyl-4-yl-(2S)-[(1-
cyclopropanecarbonyl-(2R)- pyrrolidin-2-ylmethyl)-(4'-
trifluoromethyl-biphenyl-4- carbonyl)-amino]- propionic acid 625
##STR628## (2S)-[[2-(2-Acetylamino-4- methyl-thiazole-5-
sulfonylamino)-ethyl]-(4'- trifluoromethyl-biphenyl-4-
carbonyl)-amino]-3-biphenyl- 4-yl-propionic acid 626 ##STR629##
3-Biphenyl-4-yl-(2S)-[[2-(5- chloro-1,3-dimethyl-1H-
pyrazole-4-sulfonylamino)- ethyl]-(4'-trifluoromethyl-
biphenyl-4-carbonyl)-amino]- propionic acid 627 ##STR630##
3-Biphenyl-4-yl-(2S)-[[2-(3,5- dimethyl-isoxazole-4-
sulfonylamino)-ethyl]- (4'-trifluoromethyl-biphenyl-
4-carbonyl)-amino]- propionic acid 628 ##STR631##
3-Biphenyl-4-yl-(2S)-[[2-(1,2- dimethyl-1H-imidazole-4-
sulfonylamino)-ethyl]-(4'- trifluoromethyl-biphenyl-4-
carbonyl)-amino]-propionic acid 629 ##STR632##
3-Biphenyl-4-yl-(2S)-[[2-(3,5- dimethyl-isoxazole-4-
sulfonylamino)-ethyl]- (4'trifluoromethyl-biphenyl-
4-carbonyl)-amino]- propionic acid methyl ester 630 ##STR633##
3-Biphenyl-4-yl-(2S)-[[2-(1,2- dimethyl-1H-imidazole-4-
sulfonylamino)-ethyl]-(4'- trifluoromethyl-biphenyl-4-
carbonyl)-amino]- propionic acid methyl ester 631 ##STR634##
3-Biphenyl-4-yl-(2S)-[[2-(5- chloro-1,3-dimethyl-1H-
pyrazole-4-sulfonylamino)- ethyl]-(4'-trifluoromethyl-
biphenyl-4-carbonyl)-amino]- propionic acid methyl ester 632
##STR635## 3-Biphenyl-4-yl-(2S)-[[2-(1- methyl-1H-
imidazole-4-sulfonylamino)- ethyl]-(4'-trifluoromethyl-
biphenyl-4-carbonyl)-amino]- propionic acid 633 ##STR636##
3-Biphenyl-4-yl-(2S)-[[2-(2,4- dimethoxy-benzylamino)-
ethyl]-(4-trifluoromethyl- biphenyl-4-carbonyl)-amino]- propionic
acid 634 ##STR637## 3-Biphenyl-4-yl-(2S)-[(2-tert-
butoxycarbonylamino-ethyl)- (4'-trifluoromethyl-
biphenyl-4-carbonyl)- amino]-propionic acid 635 ##STR638##
2-{[1-(4-Fluoro-phenyl)-5- trifluoromethyl-1H-pyrazole-
4-carbonyl]-amino)-3-(4'- trifluoromethoxy-biphenyl-4-
yl)-propionic acid 636 ##STR639## 2-{(1-(4-Fluoro-phenyl)-5-
trifluoromethyl-1H-pyrazole- 4-carbonyl]-amino}-3-(4'-
trifluoromethyl-biphenyl-4- yl)-propionic acid 637 ##STR640##
3-Biphenyl-4-yl-2-{[1-(4- fluoro-phenyl)-5-
trifluoromethyl-1H-pyrazole- 4-carbonyl]-amino}- propionic acid 638
##STR641## (2S)-{[1-(4-Chloro-phenyl)-5-
trifluoromethyl-1H-pyrazole- 4-carbonyl]-amino}-3-(4'-
trifluoromethyl-biphenyl-4- yl)-propionic acid 639 ##STR642##
3-Biphenyl-4-yl-(2S)-{[1-(4- chloro-phenyl)-5-
trifluoromethyl-1H-pyrazole- 4-carbonyl]-amino}-propionic acid 640
##STR643## (2S)-{[1-(4-Chloro-phenyl)-5-
trifluoromethyl-1H-pyrazole- 4-carbonyl]-amino}-3-(4'-
trifluoromethoxy-biphenyl-4- yl)-propionic acid 641 ##STR644##
2-{[1-(4-Fluoro-phenyl)-5- trifluoromethyl-1H-pyrazole-
4-carbonyl]-amino}-3-(6- phenyl-pyridin-3-yl)- propionic acid 642
##STR645## (2S)-{[1-(4-Nitro-phenyl)-5-
trifluoromethyl-1H-pyrazole- 4-carbonyl]-amino}-3-(4'-
trifluoromethoxy-biphenyl-4- yl)-propionic acid 643 ##STR646##
(2S)-{[1-(4-tert-Butyl-phenyl)- 5-trifluoromethyl-1H-
pyrazole-4-carbonyl]- amino}-3-(4'- trifluoromethoxy-biphenyl-4-
yl)-propionic acid 644 ##STR647## (2S)-[(1-p-Tolyl-5-
trifluoromethyl-1H- pyrazole-4-carbonyl)-amino]-
3-(4'-trifluoromethoxy- biphenyl-4-yl)-propionic acid 645
##STR648## (2S)-{[1-(6-Methoxy- pyridazin-3-yl)-5-
trifluoromethyl-1H-pyrazole- 4-carbonyl]-arnino}-3-(4'-
trifluoromethoxy- biphenyl-4-yl)-propionic acid 646 ##STR649##
(2S)-[(5-Methyl-1-phenyl-1H- pyrazole-4-carbonyl)-amino]-
3-(4'-trifluoromethoxy- biphenyl-4-yl)-propionic acid 647
##STR650## (2S)-{[1-(4-Chloro-phenyl)-5-
trifluoromethyl-1H-pyrazole- 4-carbonyl]-amino)-3-(4'-
trifluoromethoxy-biphenyl- 4-yl)-propionic acid 648 ##STR651##
3-(4'-Trifluoromethoxy- biphenyl-4-yl)-(2S)-{[1-(4-
trifluoromethoxy-phenyl)-5- trifluoromethyl-1H-pyrazole-
4-carbonyl]-amino}- propionic acid 649 ##STR652##
(2S)-{[1-(3-Chloro-4-fluoro- phenyl)-5-
trifluoromethyl-1H-pyrazole- 4-carbonyl]-amino}-3-(4'-
trifluoromethoxy- biphenyl-4-yl)- propionic acid 650 ##STR653##
(2S)-{[1-(4-Chloro-phenyl)- 1H-pyrazole-4-carbonyl]- amino}-3-(4'-
trifluoromethoxy-biphenyl- 4-yl)-propionic acid 651 ##STR654##
(2S)-[(1-Phenyl-5- trifluoromethyl-1H-pyrazole-
4-carbonyl)-amino]-3-(4'- trifluoromethoxy-biphenyl-4-
yl)-propionic acid 652 ##STR655## (2S)-[(1-Phenyl-5-
trifluoromethyl-1H-pyrazole- 4-carbonyl)-amino]-3-(4'-
trifluoromethyl-biphenyl-4- yl)-propionic acid 653 ##STR656##
3-Biphenyl-4-yl-(2S)-[(1- phenyl-5-trifluoromethyl-1H-
pyrazole-4-carbonyl)-amino]- propionic acid 654 ##STR657##
(2S)-{[1-(4-Chloro-phenyl)-5- propyl-1H-pyrazole-4-
carbonyl]-amino}-3-(2'- phenoxy-biphenyl-4-yl)- propionic acid 655
##STR658## 3-(Biphenyl-4-ylmethoxy)- (2S)-[(4'-trifluoromethyl-
biphenyl-4-carbonyl)-amino]- propionic acid 656 ##STR659##
3-[(Biphenyl-4-ylmethyl)- amino]-(2S)-[(4'-
trifluoromethyl-biphenyl-4- carbonyl)-amino]-propionic acid 657
##STR660## 3-(Biphenyl-4-ylmethyl- methyl-amino)-(2S)-[(4'-
trifluoromethyl-biphenyl-4- carbonyl)-amino]-propionic acid 658
##STR661## 3-(Biphenyl-4-ylmethyl- pyridin-4-ylmethyl-amino)-
(2S)-[(4'-trifluoromethyl- biphenyl-4-carbonyl)-amino]- propionic
acid: 659 ##STR662## 3-(Biphenyl-4-ylmethyl-furan-
2-ylmethyl-amino)-(2S)-[(4'- trifluoromethyl-
biphenyl-4-carbonyl)-amino]- propionic acid: 660 ##STR663##
3-[(Biphenyl-4- carbonyl)-amino]-(2S)-[(4'-
trifluoromethyl-biphenyl-4- carbonyl)-amino]-propionic acid: 661
##STR664## (2S),3-Bis-[(4'- trifluoromethyl-biphenyl-4-
carbonyl)-amino]- propionic acid: 662 ##STR665## 3-(Biphenyl-4-
sulfonylamino)-(2S)-[(4'- trifluoromethyl-biphenyl-4-
carbonyl)-amino]- propionic acid
[0195] As used herein, the term "alkyl" refers to a straight or
branched chain hydrocarbon having from one to ten carbon atoms,
optionally substituted with substituents selected from the group
consisting of lower alkyl, lower alkoxy, lower alkylsulfanyl, lower
alkylsulfenyl, lower alkylsulfonyl, oxo, hydroxy, mercapto, amino
optionally substituted by alkyl, carboxy, carbamoyl optionally
substituted by alkyl, aminosulfonyl optionally substituted by
alkyl, silyloxy optionally substituted by alkoxy, alkyl, or aryl,
silyl optionally substituted by alkoxy, alkyl, or aryl, nitro,
cyano, halogen, or lower perfluoroalkyl, multiple degrees of
substitution being allowed. Such an "alkyl" group may containing
one or more O, S, S(O), or S(O).sub.2 atoms. Examples of "alkyl" as
used herein include, but are not limited to, methyl, n-butyl,
t-butyl, n-pentyl, isobutyl, and isopropyl, and the like.
[0196] As used herein, the term "alkylene" refers to a straight or
branched chain divalent hydrocarbon radical having from one to ten
carbon atoms, optionally substituted with substituents selected
from the group consisting of lower alkyl, lower alkoxy, lower
alkylsulfanyl, lower alkylsulfenyl, lower alkylsulfonyl, oxo,
hydroxy, mercapto, amino optionally substituted by alkyl, carboxy,
carbamoyl optionally substituted by alkyl, aminosulfonyl optionally
substituted by alkyl, silyloxy optionally substituted by alkoxy,
alkyl, or aryl, silyl optionally substituted by alkoxy, alkyl, or
aryl, nitro, cyano, halogen, or lower perfluoroalkyl, multiple
degrees of substitution being allowed. Such an "alkylene" group may
containing one or more O, S, S(O), or S(O).sub.2 atoms. Examples of
"alkylene" as used herein include, but are not limited to,
methylene, ethylene, and the like.
[0197] As used herein, the term "alkenyl" refers to a hydrocarbon
radical having from two to ten carbons and at least one
carbon-carbon double bond, optionally substituted with substituents
selected from the group consisting of lower alkyl, lower alkoxy,
lower alkylsulfanyl, lower alkylsulfenyl, lower alkylsulfonyl, oxo,
hydroxy, mercapto, amino optionally substituted by alkyl, carboxy,
carbamoyl optionally substituted by alkyl, aminosulfonyl optionally
substituted by alkyl, silyloxy optionally substituted by alkoxy,
alkyl, or aryl, silyl optionally substituted by alkoxy, alkyl, or
aryl, nitro, cyano, halogen, or lower perfluoroalkyl, multiple
degrees of substitution being allowed. Such an "alkenyl" group may
containing one or more O, S, S(O), or S(O).sub.2 atoms.
[0198] As used herein, the term "alkenylene" refers to a straight
or branched chain divalent hydrocarbon radical having from two to
ten carbon atoms and one or more carbon-carbon double bonds,
optionally substituted with substituents selected from the group
consisting of lower alkyl, lower alkoxy, lower alkylsulfanyl, lower
alkylsulfenyl, lower alkylsulfonyl, oxo, hydroxy, mercapto, amino
optionally substituted by alkyl, carboxy, carbamoyl optionally
substituted by alkyl, aminosulfonyl optionally substituted by
alkyl, silyloxy optionally substituted by alkoxy, alkyl, or aryl,
silyl optionally substituted by alkoxy, alkyl, or aryl, nitro,
cyano, halogen, or lower perfluoroalkyl, multiple degrees of
substitution being allowed. Such an "alkenylene" group may
containing one or more O, S, S(O), or S(O).sub.2 atoms. Examples of
"alkenylene" as used herein include, but are not limited to,
ethene-1,2-diyl, propene-1,3-diyl, methylene-1,1-diyl, and the
like.
[0199] As used herein, the term "alkynyl" refers to a hydrocarbon
radical having from two to ten carbons and at least one
carbon-carbon triple bond, optionally substituted with substituents
selected from the group consisting of lower alkyl, lower alkoxy,
lower alkylsulfanyl, lower alkylsulfenyl, lower alkylsulfonyl, oxo,
hydroxy, mercapto, amino optionally substituted by alkyl, carboxy,
carbamoyl optionally substituted by alkyl, aminosulfonyl optionally
substituted by alkyl, silyloxy optionally substituted by alkoxy,
alkyl, or aryl, silyl optionally substituted by alkoxy, alkyl, or
aryl, nitro, cyano, halogen, or lower perfluoroalkyl, multiple
degrees of substitution being allowed. Such an "alkynyl" group may
containing one or more O, S, S(O), or S(O).sub.2 atoms.
[0200] As used herein, the term "alkynylene" refers to a straight
or branched chain divalent hydrocarbon radical having from two to
ten carbon atoms and one or more carbon-carbon triple bonds,
optionally substituted with substituents selected from the group
consisting of lower alkyl, lower alkoxy, lower alkylsulfanyl, lower
alkylsulfenyl, lower alkylsulfonyl, oxo, hydroxy, mercapto, amino
optionally substituted by alkyl, carboxy, carbamoyl optionally
substituted by alkyl, aminosulfonyl optionally substituted by
alkyl, silyloxy optionally substituted by alkoxy, alkyl, or aryl,
silyl optionally substituted by alkoxy, alkyl, or aryl, nitro,
cyano, halogen, or lower perfluoroalkyl, multiple degrees of
substitution being allowed. Such an "alkynylene" group may
containing one or more O, S, S(O), or S(O).sub.2 atoms. Examples of
"alkynylene" as used herein include, but are not limited to,
ethyne-1,2-diyl, propyne-1,3-diyl, and the like.
[0201] As used herein, "cycloalkyl" refers to a alicyclic
hydrocarbon group optionally possessing one or more degrees of
unsaturation, having from three to twelve carbon atoms, optionally
substituted with substituents selected from the group consisting of
lower alkyl, lower alkoxy, lower alkylsulfanyl, lower
alkylsulfenyl, lower alkylsulfonyl, oxo, hydroxy, mercapto, amino
optionally substituted by alkyl, carboxy, carbamoyl optionally
substituted by alkyl, aminosulfonyl optionally substituted by
alkyl, nitro, cyano, halogen, or lower perfluoroalkyl, multiple
degrees of substitution being allowed. "Cycloalkyl" includes by way
of example cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl,
cycloheptyl, or cyclooctyl, and the like.
[0202] As used herein, the term "cycloalkylene" refers to an
non-aromatic alicyclic divalent hydrocarbon radical having from
three to twelve carbon atoms and optionally possessing one or more
degrees of unsaturation, optionally substituted with substituents
selected from the group consisting of lower alkyl, lower alkoxy,
lower alkylsulfanyl, lower alkylsulfenyl, lower alkylsulfonyl, oxo,
hydroxy, mercapto, amino optionally substituted by alkyl, carboxy,
carbamoyl optionally substituted by alkyl, aminosulfonyl optionally
substituted by alkyl, nitro, cyano, halogen, or lower
perfluoroalkyl, multiple degrees of substitution being allowed.
Examples of "cycloalkylene" as used herein include, but are not
limited to, cyclopropyl-1,1-diyl, cyclopropyl-1,2-diyl,
cyclobutyl-1,2-diyl, cyclopentyl-1,3-diyl, cyclohexyl-1,4-diyl,
cycloheptyl-1,4-diyl, or cyclooctyl-1,5-diyl, and the like.
[0203] As used herein, the term "heterocyclic" or the term
"heterocyclyl" refers to a three to twelve-membered heterocyclic
ring optionally possessing one or more degrees of unsaturation,
containing one or more heteroatomic substitutions selected from S,
SO, SO.sub.2, O, or N, optionally substituted with substituents
selected from the group consisting of lower alkyl, lower alkoxy,
lower alkylsulfanyl, lower alkylsulfenyl, lower alkylsulfonyl, oxo,
hydroxy, mercapto, amino optionally substituted by alkyl, carboxy,
carbamoyl optionally substituted by alkyl, aminosulfonyl optionally
substituted by alkyl, nitro, cyano, halogen, or lower
perfluoroalkyl, multiple degrees of substitution being allowed.
Such a ring may be optionally fused to one or more of another
"heterocyclic" ring(s) or cycloalkyl ring(s). Examples of
"heterocyclic" include, but are not limited to, tetrahydrofuran,
1,4-dioxane, 1,3-dioxane, piperidine, pyrrolidine, morpholine,
piperazine, and the like.
[0204] As used herein, the term "heterocyclylene" refers to a three
to twelve-membered heterocyclic ring diradical optionally having
one or more degrees of unsaturation containing one or more
heteroatoms selected from S, SO, SO.sub.2, O, or N, optionally
substituted with substituents selected from the group consisting of
lower alkyl, lower alkoxy, lower alkylsulfanyl, lower
alkylsulfenyl, lower alkylsulfonyl, oxo, hydroxy, mercapto, amino
optionally substituted by alkyl, carboxy, carbamoyl optionally
substituted by alkyl, aminosulfonyl optionally substituted by
alkyl, nitro, cyano, halogen, or lower perfluoroalkyl, multiple
degrees of substitution being allowed. Such a ring may be
optionally fused to one or more benzene rings or to one or more of
another "heterocyclic" rings or cycloalkyl rings. Examples of
"heterocyclylene" include, but are not limited to,
tetrahydrofuran-2,5-diyl, morpholine-2,3-diyl, pyran-2,4-diyl,
1,4-dioxane-2,3-diyl, 1,3-dioxane-2,4-diyl, piperidine-2,4-diyl,
piperidine-1,4-diyl, pyrrolidine-1,3-diyl, morpholine-2,4-diyl,
piperazine-1,4-diyl, and the like.
[0205] As used herein, the term "aryl" refers to a benzene ring or
to an optionally substituted benzene ring system fused to one or
more optionally substituted benzene rings, optionally substituted
with substituents selected from the group consisting of lower
alkyl, lower alkoxy, lower alkylsulfanyl, lower alkylsulfenyl,
lower alkylsulfonyl, di(lower alkyl)aminoalkyl, aminoalkyl, oxo,
hydroxy, mercapto, amino optionally substituted by alkyl, carboxy,
tetrazolyl, carbamoyl optionally substituted by alkyl,
aminosulfonyl optionally substituted by alkyl, acyl, aroyl,
heteroaroyl, acylamino, acyloxy, aroyloxy, heteroaroyloxy,
alkoxycarbonyl, silyloxy optionally substituted by alkoxy, alkyl,
or aryl, silyl optionally substituted by alkoxy, alkyl, or aryl,
nitro, cyano, halogen, or lower perfluoroalkyl, multiple degrees of
substitution being allowed. Examples of aryl include, but are not
limited to, phenyl, 2-naphthyl, 1-naphthyl, 1-anthracenyl, and the
like.
[0206] As used herein, the term "arylene" refers to a benzene ring
diradical or to a benzene ring system diradical fused to one or
more optionally substituted benzene rings, optionally substituted
with substituents selected from the group consisting of lower
alkyl, lower alkoxy, lower alkylsulfanyl, lower alkylsulfenyl,
lower alkylsulfonyl, di(lower alkyl)aminoalkyl, aminoalkyl, oxo,
hydroxy, mercapto, amino optionally substituted by alkyl, carboxy,
tetrazolyl, carbamoyl optionally substituted by alkyl,
aminosulfonyl optionally substituted by alkyl, acyl, aroyl,
heteroaroyl, acylamino, acyloxy, aroyloxy, heteroaroyloxy,
alkoxycarbonyl, silyloxy optionally substituted by alkoxy, alkyl,
or aryl, silyl optionally substituted by alkoxy, alkyl, or aryl,
nitro, cyano, halogen, or lower perfluoroalkyl, multiple degrees of
substitution being allowed. Examples of "arylene" include, but are
not limited to, benzene-1,4-diyl, naphthalene-1,8-diyl, and the
like.
[0207] As used herein, the term "heteroaryl" refers to a five- to
seven-membered aromatic ring, or to a polycyclic heterocyclic
aromatic ring, containing one or more nitrogen, oxygen, or sulfur
heteroatoms, where N-oxides and sulfur monoxides and sulfur
dioxides are permissible heteroaromatic substitutions, optionally
substituted with substituents selected from the group consisting of
lower alkyl, lower alkoxy, lower alkylsulfanyl, lower
alkylsulfenyl, lower alkylsulfonyl, oxo, hydroxy, mercapto, amino
optionally substituted by alkyl, carboxy, tetrazolyl, carbamoyl
optionally substituted by alkyl, aminosulfonyl optionally
substituted by alkyl, acyl, aroyl, heteroaroyl, acyloxy, aroyloxy,
heteroaroyloxy, alkoxycarbonyl, silyloxy optionally substituted by
alkoxy, alkyl, or aryl, silyl optionally substituted by alkoxy,
alkyl, or aryl, nitro, cyano, halogen, or lower perfluoroalkyl,
multiple degrees of substitution being allowed. For polycyclic
aromatic ring systems, one or more of the rings may contain one or
more heteroatoms. Examples of "heteroaryl" used herein are furan,
thiophene, pyrrole, imidazole, pyrazole, triazole, tetrazole,
thiazole, oxazole, isoxazole, oxadiazole, thiadiazole, isothiazole,
pyridine, pyridazine, pyrazine, pyrimidine, quinoline,
isoquinoline, quinazoline, benzofuran, benzothiophene, indole, and
indazole, and the like.
[0208] As used herein, the term "heteroarylene" refers to a five-
to seven-membered aromatic ring diradical, or to a polycyclic
heterocyclic aromatic ring diradical, containing one or more
nitrogen, oxygen, or sulfur heteroatoms, where N-oxides and sulfur
monoxides and sulfur dioxides are permissible heteroaromatic
substitutions, optionally substituted with substituents selected
from the group consisting of lower alkyl, lower alkoxy, lower
alkylsulfanyl, lower alkylsulfenyl, lower alkylsulfonyl, oxo,
hydroxy, mercapto, amino optionally substituted by alkyl, carboxy,
tetrazolyl, carbamoyl optionally substituted by alkyl,
aminosulfonyl optionally substituted by alkyl, acyl, aroyl,
heteroaroyl, acyloxy, aroyloxy, heteroaroyloxy, alkoxycarbonyl,
silyloxy optionally substituted by alkoxy, alkyl, or aryl, silyl
optionally substituted by alkoxy, alkyl, or aryl, nitro, cyano,
halogen, or lower perfluoroalkyl, multiple degrees of substitution
being allowed. For polycyclic aromatic ring system diradicals, one
or more of the rings may contain one or more heteroatoms. Examples
of "heteroarylene" used herein are furan-2,5-diyl,
thiophene-2,4-diyl, 1,3,4-oxadiazole-2,5-diyl,
1,3,4-thiadiazole-2,5-diyl, 1,3-thiazole-2,4-diyl,
1,3-thiazole-2,5-diyl, pyridine-2,4-diyl, pyridine-2,3-diyl,
pyridine-2,5-diyl, pyrimidine-2,4-diyl, quinoline-2,3-diyl, and the
like.
[0209] As used herein, the term "fused cycloalkylaryl" refers to a
cycloalkyl group fused to an aryl group, the two having two atoms
in common, and wherein the aryl group is the point of substitution.
Examples of "fused cycloalkylaryl" used herein include 5-indanyl,
5,6,7,8-tetrahydro-2-naphthyl, ##STR666## and the like.
[0210] As used herein, the term "fused cycloalkylarylene" refers to
a fused cycloalkylaryl, wherein the aryl group is divalent.
Examples include ##STR667## and the like.
[0211] As used herein, the term "fused arylcycloalkyl" refers to an
aryl group fused to a cycloalkyl group, the two having two atoms in
common, and wherein the cycloalkyl group is the point of
substitution. Examples of "fused arylcycloalkyl" used herein
include 1-indanyl, 2-indanyl, 1-(1,2,3,4-tetrahydronaphthyl),
##STR668## and the like.
[0212] As used herein, the term "fused arylcycloalkylene" refers to
a fused arylcycloalkyl, wherein the cycloalkyl group is divalent.
Examples include ##STR669## and the like.
[0213] As used herein, the term "fused heterocyclylaryl" refers to
a heterocyclyl group fused to an aryl group, the two having two
atoms in common, and wherein the aryl group is the point of
substitution. Examples of "fused heterocyclylaryl" used herein
include 3,4-methylenedioxy-1-phenyl, ##STR670## and the like
[0214] As used herein, the term "fused heterocyclylarylene" refers
to a fused heterocyclylaryl, wherein the aryl group is divalent.
Examples include ##STR671## and the like.
[0215] As used herein, the term "fused arylheterocyclyl" refers to
an aryl group fused to a heterocyclyl group, the two having two
atoms in common, and wherein the heterocyclyl group is the point of
substitution. Examples of "fused arylheterocyclyl" used herein
include 2-(1,3-benzodioxolyl), ##STR672## and the like.
[0216] As used herein, the term "fused arylheterocyclylene" refers
to a fused arylheterocyclyl, wherein the heterocyclyl group is
divalent. Examples include ##STR673## and the like.
[0217] As used herein, the term "fused cycloalkylheteroaryl" refers
to a cycloalkyl group fused to a heteroaryl group, the two having
two atoms in common, and wherein the heteroaryl group is the point
of substitution. Examples of "fused cycloalkylheteroaryl" used
herein include 5-aza-6-indanyl, ##STR674## and the like.
[0218] As used herein, the term "fused cycloalkylheteroarylene"
refers to a fused cycloalkylheteroaryl, wherein the heteroaryl
group is divalent. Examples include ##STR675## and the like.
[0219] As used herein, the term "fused heteroarylcycloalkyl" refers
to a heteroaryl group fused to a cycloalkyl group, the two having
two atoms in common, and wherein the cycloalkyl group is the point
of substitution. Examples of "fused heteroarylcycloalkyl" used
herein include 5-aza-1-indanyl, ##STR676## and the like.
[0220] As used herein, the term "fused heteroarylcycloalkylene"
refers to a fused heteroarylcycloalkyl, wherein the cycloalkyl
group is divalent. Examples include ##STR677## and the like.
[0221] As used herein, the term "fused heterocyclylheteroaryl"
refers to a heterocyclyl group fused to a heteroaryl group, the two
having two atoms in common, and wherein the heteroaryl group is the
point of substitution. Examples of "fused heterocyclylheteroaryl"
used herein include 1,2,3,4-tetrahydro-beta-carbolin-8-yl,
##STR678## and the like.
[0222] As used herein, the term "fused heterocyclylheteroarylene"
refers to a fused heterocyclylheteroaryl, wherein the heteroaryl
group is divalent. Examples include ##STR679## and the like.
[0223] As used herein, the term "fused heteroarylheterocyclyl"
refers to a heteroaryl group fused to a heterocyclyl group, the two
having two atoms in common, and wherein the heterocyclyl group is
the point of substitution. Examples of "fused
heteroarylheterocyclyl" used herein
include-5-aza-2,3-dihydrobenzofuran-2-yl, ##STR680## and the
like.
[0224] As used herein, the term "fused heteroarylheterocyclylene"
refers to a fused heteroarylheterocyclyl, wherein the heterocyclyl
group is divalent. Examples include ##STR681## and the like.
[0225] As used herein, the term "acid isostere" refers to a
substituent group which will ionize at physiological pH to bear a
net negative charge. Examples of such "acid isosteres" include but
are not limited to heteroaryl groups such as but not limited to
isoxazol-3-ol-5-yl, 1H-tetrazole-5-yl, or 2H-tetrazole-5-yl. Such
acid isosteres include but are not limited to heterocyclyl groups
such as but not limited to imidazolidine-2,4-dione-5-yl,
imidazolidine-2,4-dione-1-yl, 1,3-thiazolidine-2,4-dione-5-yl, or
5-hydroxy-4H-pyran-4-on-2-yl.
[0226] As used herein, the term "direct bond", where part of a
structural variable specification, refers to the direct joining of
the substituents flanking (preceding and succeeding) the variable
taken as a "direct bond".
[0227] As used herein, the term "alkoxy" refers to the group
R.sub.aO--, where R.sub.a is alkyl.
[0228] As used herein, the term "alkenyloxy" refers to the group
R.sub.aO--, where R.sub.a is alkenyl.
[0229] As used herein, the term "alkynyloxy" refers to the group
R.sub.aO--, where R.sub.a is alkynyl.
[0230] As used herein, the term "alkylsulfanyl" refers to the group
R.sub.aS--, where R.sub.a is alkyl.
[0231] As used herein, the term "alkenylsulfanyl" refers to the
group R.sub.aS--, where R.sub.a is alkenyl.
[0232] As used herein, the term "alkynylsulfanyl" refers to the
group R.sub.aS--, where R.sub.a is alkynyl.
[0233] As used herein, the term "alkylsulfenyl" refers to the group
R.sub.aS(O)--, where R.sub.a is alkyl.
[0234] As used herein, the term "alkenylsulfenyl" refers to the
group R.sub.aS(O)--, where R.sub.a is alkenyl.
[0235] As used herein, the term "alkynylsulfenyl" refers to the
group R.sub.aS(O)--, where R.sub.a is alkynyl.
[0236] As used herein, the term "alkylsulfonyl" refers to the group
R.sub.aSO.sub.2--, where R.sub.a is alkyl.
[0237] As used herein, the term "alkenylsulfonyl" refers to the
group R.sub.aSO.sub.2--, where R.sub.a is alkenyl.
[0238] As used herein, the term "alkynylsulfonyl" refers to the
group R.sub.aSO.sub.2--, where R.sub.a is alkynyl.
[0239] As used herein, the term "acyl" refers to the group
R.sub.aC(O)--, where R.sub.a is alkyl, alkenyl, alkynyl,
cycloalkyl, cycloalkenyl, or heterocyclyl.
[0240] As used herein, the term "aroyl" refers to the group
R.sub.aC(O)--, where R.sub.a is aryl.
[0241] As used herein, the term "heteroaroyl" refers to the group
R.sub.aC(O)--, where R.sub.a is heteroaryl.
[0242] As used herein, the term "alkoxycarbonyl" refers to the
group R.sub.aOC(O)--, where R.sub.a is alkyl.
[0243] As used herein, the term "acyloxy" refers to the group
R.sub.aC(O)O--, where R.sub.a is alkyl, alkenyl, alkynyl,
cycloalkyl, cycloalkenyl, or heterocyclyl.
[0244] As used herein, the term "aroyloxy" refers to the group
R.sub.aC(O)O--, where R.sub.a is aryl.
[0245] As used herein, the term "heteroaroyloxy" refers to the
group R.sub.aC(O)O--, where R.sub.a is heteroaryl.
[0246] As used herein, the term "optionally" means that the
subsequently described event(s) may or may not occur, and includes
both event(s) which occur and events that do not occur.
[0247] As used herein, the term "substituted" refers to
substitution with the named substituent or substituents, multiple
degrees of substitution being allowed unless otherwise stated.
[0248] As used herein, the terms "contain" or "containing" can
refer to in-line substitutions at any position along the above
defined alkyl, alkenyl, alkynyl or cycloalkyl substituents with one
or more of any of O, S, SO, SO.sub.2, N, or N-alkyl, including, for
example, --CH.sub.2--O--CH.sub.2--,
--CH.sub.2--SO.sub.2--CH.sub.2--, --CH.sub.2--NH--CH.sub.3 and so
forth.
[0249] Whenever the terms "alkyl" or "aryl" or either of their
prefix roots appear in a name of a substituent (e.g.
arylalkoxyaryloxy) they shall be interpreted as including those
limitations given above for "alkyl" and "aryl". Alkyl or cycloalkyl
substituents shall be recognized as being functionally equivalent
to those having one or more degrees of unsaturation. Designated
numbers of carbon atoms (e.g. C.sub.1-10) shall refer independently
to the number of carbon atoms in an alkyl, alkenyl or alkynyl or
cyclic alkyl moiety or to the alkyl portion of a larger substituent
in which the term "alkyl" appears as its prefix root.
[0250] As used herein, the term "oxo" shall refer to the
substituent .dbd.O.
[0251] As used herein, the term "halogen" or "halo" shall include
iodine, bromine, chlorine and fluorine.
[0252] As used herein, the term "mercapto" shall refer to the
substituent --SH.
[0253] As used herein, the term "carboxy" shall refer to the
substituent --COOH.
[0254] As used herein, the term "cyano" shall refer to the
substituent --CN.
[0255] As used herein, the term "aminosulfonyl" shall refer to the
substituent --SO.sub.2NH.sub.2.
[0256] As used herein, the term "carbamoyl" shall refer to the
substituent --C(O)NH.sub.2.
[0257] As used herein, the term "sulfanyl" shall refer to the
substituent --S--.
[0258] As used herein, the term "sulfenyl" shall refer to the
substituent --S(O)--.
[0259] As used herein, the term "sulfonyl" shall refer to the
substituent --S(O).sub.2--.
[0260] The compounds can be prepared readily according to the
following reaction Schemes (in which variables are as defined
before or are defined) using readily available starting materials,
reagents and conventional synthesis procedures. In these reactions,
it is also possible to make use of variants which are themselves
known to those of ordinary skill in this art, but are not mentioned
in greater detail.
[0261] The present invention also provides a method for the
synthesis of compounds useful as intermediates in the preparation
of compounds of Formula (I) along with methods for the preparation
of compounds of Formula (I).
[0262] Scheme I describes the synthesis of an intermediate of
structure (4).
[0263] Ar.sub.3 and Ar.sub.4 are, independently, groups such as,
but not limited to, a heteroaryl, heteroarylene, arylene, or aryl
ring system.
[0264] As shown in Scheme l, in one embodiment, bromo- or
iodo-substituted aryl alanine methyl ester (or amino acid
esterified in linkage to Wang resin) (1) is treated with a
carboxylic acid in the presence of a coupling reagent, such as, but
not limited to, diisopropyl carbodiimide (DIC) to form the amide
(2). The resulting amide is then subjected to coupling with an
arylboronic acid in the presence of a catalyst such as but not
limited to tetrakis(triphenylphosphine)palladium (0), in the
presence of base such as, but not limited to, sodium carbonate to
form compound (3). The methyl ester (3) is hydrolyzed using a base
such as, but not limited to, LiOH to provide the free carboxylic
acid (4), where Ar.sub.1 and Ar.sub.2 are as defined for Formula
(I). ##STR682##
[0265] Scheme II describes the preparation of a compound of
structure (4).
[0266] Ar.sub.3 and Ar.sub.4 are, independently, groups such as but
not-limited to a heteroaryl, heteroarylene, arylene, or aryl ring
system.
[0267] As shown in Scheme II, in another embodiment, an aryl
hydroxy amino acid methyl ester (or amino acid esterified in
linkage to Wang resin) (5) is treated with a carboxylic acid
Ar.sub.2--CO.sub.2H in the presence of a coupling reagent such as,
but not limited to, diisopropyl carbodiimide (DIC) to form the
amide (6). The resulting amide is then subjected to: 1)
nucleophilic substitutions with an optionally substituted
electron-deficient fluoroaromatic or fluoroheteroaromatic in the
presence of base such as, but not limited to, potassium carbonate;
or 2) coupling with an aryl bromide, or heteroaryl bromide, and
copper iodide in the presence of a base including, but not limited
to, cesium carbonate to form compound (7). The methyl ester in (7)
is hydrolyzed using a base such as LiOH to provide the free
carboxylic acid (4), where Ar.sub.1 and Ar.sub.2 are as defined for
Formula (I) ##STR683##
[0268] Scheme III describes the preparation of a compouind of
formula (4).
[0269] Ar.sub.5 and Ar.sub.6 are, independently, groups such as but
not limited to a heteroaryl, heteroarylene, arylene, or aryl ring
system.
[0270] As shown in Scheme III, in another embodiment, an amino acid
methyl ester (or, alternately, an amino acid esterified in linkage
to Wang resin) (8) is treated with a bromo-substituted aryl
carboxylic acid in the presence of a coupling reagent such as, but
not limited to, diisopropyl carbodiimide (DIC) to form the amide
(9). The resulting amide then is subjected to coupling with an
arylboronic acid or heteroarylboronic acid in the presence of a
catalyst such as but not limited to
tetrakis(triphenylphosphine)palladium(0), in the presence of base
such as, but not limited to, sodium carbonate to form compound
(10). The methyl ester (10) is hydrolyzed using a base such as, but
not limited to, LiOH to provide the free carboxylic acid (4), where
Ar.sub.1 and Ar.sub.2 are as defined for Formula (I) ##STR684##
[0271] Scheme IV describes the synthesis of a compound of formula
(4).
[0272] Ar.sub.3, Ar.sub.7, Ar.sub.5 and Ar.sub.6 are,
independently, groups such as but not limited to a heteroaryl,
heteroarylene, arylene, or aryl ring system.
[0273] As shown in Scheme IV, in another embodiment, a bromo or
iodo aryl alanine methyl ester (or amino acid esterified in linkage
to Wang resin) (11) is subjected to coupling with an arylboronic
acid in the presence of a catalyst such as but not limited to
tetrakis(triphenylphosphine)palladium(0), in the presence of base
such as but not limited to sodium carbonate to form compound (12).
The resulting compound is treated with a bromo- or iodo-substituted
aryl carboxylic acid in the presence of a coupling reagent such as,
but not limited to, diisopropyl carbodiimide (DIC) to form the
amide (13). The resulting amide is then subjected to coupling with
a arylboronic acid or heteroarylboronic acid in the presence of a
catalyst such as but not limited to
tetrakis(triphenylphosphine)palladium(0), in the presence of base
such as, but not limited to, sodium carbonate, and the product
methyl ester is hydrolyzed using a base such as LiOH to provide the
free carboxylic acid (4), where Ar.sub.1 and Ar.sub.2 are as
defined for Formula (I). ##STR685## ##STR686## ##STR687##
[0274] Scheme V describes the preparation of a compound of formula
(16).
[0275] Ar.sub.3 and Ar.sub.7 are, independently, groups such as but
not limited to a heteroaryl, heteroarylene, arylene, or aryl ring
system.
[0276] Pol is a functionalized polymeric support, such as but not
limited to Wang Resin.
[0277] As shown in Scheme V, in another embodiment, a hydroxy aryl
ester loaded onto the Wang Bromo resin or Merrifield resin using
base such as, but not limited to, sodium methoxide in DMA, and
hydrolyzed to give (14), is coupled with a bromo- or
iodo-subsituted aryl amino acid methyl ester (11) in the presence
of a coupling reagent such as, but not limited to, diisopropyl
carbodiimide (DIC) to give the amide (15). The resulting amide (15)
is then subjected to a coupling with an arylboronic acid or
heteroarylboronic acid in the presence of a catalyst such as but
not limited to tetrakis(triphenylphosphine)palladium(0), in the
presence of base such as, but not limited to, sodium carbonate
followed by cleavage from the resin with TMSBr/TFA/DCM (1:1:1) or a
similar suitable cleavage cocktail to yield the desired product
(16), where Ar.sub.1 and Ar.sub.2 are as defined for Formula (I)
##STR688## ##STR689##
[0278] Scheme VI describes the preparation of a compound of formula
(19).
[0279] Ar.sub.6 and Ar.sub.8 are, independently, groups such as but
not limited to a heteroaryl, heteroarylene, arylene, or aryl ring
system.
[0280] Pol is a functionalized polymeric support, such as but not
limited to Wang Resin.
[0281] As shown in Scheme VI, in another embodiment, a hydroxy aryl
ester loaded onto the Wang Bromo resin, Merrifiend resin, or other
suitable support using base such as, but not limited to, sodium
methoxide in DMA, is hydrolyzed to give (17), and is coupled with
an amino acid methyl ester (8) in the presence of a coupling
reagent such as, but not limited to, diisopropyl carbodiimide (DIC)
to give the amide (18). The resulting amide (18) is then subjected
to a coupling with an arylboronic acid or heteroarylboronic acid in
the presence of a catalyst such as but not limited to
tetrakis(triphenylphosphine)palladium(0), in the presence of base
such as, but not limited to, sodium carbonate, and is then cleaved
from the resin with TMSBr/TFA/DCM (1:1:1) or a similar suitable
cleavage cocktail to yield the desired product (19), where Ar.sub.1
and Ar.sub.2 are as defined for Formula (I). ##STR690##
[0282] Scheme VlI describes the synthesis of a compound of formula
(23).
[0283] Ar.sub.3, Ar.sub.7, and Ar.sub.6 are, independently, groups
such as but not limited to a heteroaryl, heteroarylene, arylene, or
aryl ring system.
[0284] Pol is a functionalized polymeric support, such as but not
limited to Wang Resin.
[0285] As shown in Scheme VII, in another embodiment, a bromo
hydroxy aryl ester (20) loaded onto Wang Bromo resin, Merrifield
resin, or other suitable support using base such as, but not
limited to, sodium methoxide in DMF, is then subjected to a
coupling with an arylboronic acid or heteroarylboronic acid in the
presence of a catalyst such as but not limited to
tetrakis(triphenylphosphine)palladium(0), in the presence of base
such as, but not limited to, sodium carbonate, followed by
hydrolysis of the product ester to yield the acid (21). The
resulting carboxylic acid (21) is then subjected to coupling with a
bromo- or iodo-substituted aryl amino acid methyl ester (11) in the
presence of a coupling reagent such as, but not limited to,
diisopropyl carbodiimide (DIC) to give the amide (22). The
resulting amide (22) is then subjected to a coupling with an
arylboronic acid or heteroaryl boronic acid in the presence of a
catalyst such as but not limited to
tetrakis(triphenylphosphine)plladium(0), in the presence of base
such as, but not limited to, sodium carbonate followed by cleavage
from the resin with TMSBr/TFA/DCM (1:1:1) or a similar cleavage
cocktail to yield the desired product (23), where Ar.sub.1 and
Ar.sub.2 are as defined for Formula (I). ##STR691##
[0286] Scheme VIII describes the preparation of a compound of
formula (29).
[0287] Ar.sub.7, Ar.sub.9, Ar.sub.10, and Ar.sub.11 are,
independently, groups such as but not limited to a heteroaryl,
heteroarylene, arylene, or aryl ring system.
[0288] As shown in Scheme VIII, in another embodiment, a fluoro
nitro phenol (24) loaded onto a polymer such as Wang Bromo resin
using base such as, but not limited to, sodium methoxide in DMA, is
then treated with a hydroxy aryl compound (25) in the presence of
base, followed by reduction of the nitro group to give the free
amine (26).
[0289] The resulting amine (26) is then subjected to coupling with
a bromo- or iodo-substituted aryl acid (27) in the presence of a
coupling reagent such as, but not limited to, diisopropyl
carbodiimide (DIC) to give the amide (28). The resulting amide (28)
is then subjected to a coupling with an arylboronic acid or
heteroarylboronic acid in the presence of a catalyst such as but
not limited to tetrakis(triphenylphosphine)palladium(0), in the
presence of base such as, but not limited to, sodium carbonate
followed by cleavage from the resin with TMSBr/TFA/DCM (1:1:1) or a
similar suitable cleavage cocktail to yield the desired product
(29), where Ar.sub.1 and Ar.sub.2 are as defined for Formula (I).
##STR692##
[0290] Scheme IX describes the preparation of a compound of formula
(32).
[0291] Ar.sub.6, Ar.sub.12, and Ar.sub.13 are, independently,
groups such as but not limited to a heteroaryl, heteroarylene,
arylene, or aryl ring system.
[0292] PG.sub.1 is an amino protecting group such as
allyloxycarbonyl or tert-butoxycarbonyl.
[0293] As shown in Scheme IX, In another embodiment, an aryl amino
acid methyl ester (8) is reacted with an iodo-subsituted aryl amino
carboxylic acid (the amino group of which may be protected with an
amino protecting group PG.sub.1) in the presence of a coupling
reagent such as, but not limited to, diisopropyl carbodiimide (DIC)
giving the amide (30). The amino group of the amide (30) may be
then deprotected, if desired, by treatment with, in the case of
PG.sub.1 as tert-butoxycarbonyl, TFA, and is then treated with an
aroyl chloride in the presence of a base such as pyridine or TEA to
give the iodo amide (31). The amide (31) is subjected to coupling
with an arylboronic acid or heteroaryl boronic acid in the presence
of a catalyst such as but not limited to
tetrakis(triphenylphosphine)palladium(0), in the presence of base
such as, but not limited to, sodium carbonate. Hydrolysis of the
product methyl ester with an alkaline reagent such as LiOH provides
compound (32), where Ar.sub.1 and Ar.sub.2 are as defined for
Formula (I). ##STR693##
[0294] In Scheme X, in another embodiment, a beta ketoester (33)
may be treated with a reagent such as triethyl orthoformate of
triethyl orthoacetate in the presence of acetic anhydride and heat
to afford the ethoxy olefin derivative (34). R.sub.41 is a group
such as but not limited to aryl, heteroaryl, or alkyl. The
derivative (34) may be treated with a hydrazine derivative (35) to
afford the pyrazole (36). Hydrolysis of the ester of (36) with
aqueous alkali and mild acidification with a weak acid such as
aqueous citric acid affords (37). ##STR694##
[0295] In Scheme XI, in another embodiment, is described the
derivitization of aniline and amine nitrogen atoms. L.sub.1 is
either a direct bond or a group such as an alkylene group. An amide
derivative (38) may be prepared substantially in like manner as
(30) and may be deprotected to afford (39). For example, where
PG.sub.1 is a tert-butoxycarbonyl group, treatment of (38) with TFA
followed by neutralization affords (39). (39) may be treated with
R.sub.44--C(O)OH in the presence of a coupling agent such as HBTU
or DCC to afford (40), or R.sub.44--COCl in the presence of a weak
base such as triethylamine, to afford (40). (39) may be treated
with an aldehyde or ketone and a reducing agent such as sodium
cyanoborohydroide or sodium triacetoxyborohydride to afford (42).
(39) may be treated with a sulfonyl chloride R.sub.44SO.sub.2Cl in
the presence of a weak base such as triethylamine or pyridine to
afford (43). (39) may also be treated with an activated aromatic
halide such as 4-fluorobenzonitrile in the presence of a weak base
such as DIEA, in a solvent such as DMF, at a temperature of from
25.degree. C. to 120.degree. C., to afford the product of ipso
halide displacement (41). Other activated or electron--deficient
heteroaryl or aryl groups may be employed in this reaction.
Alternately, where L.sub.1 is a direct bond, the aniline may be
arylated by treatment of (39) with cuprous acetate and
Ar.sub.14--B(OH).sub.2, and a weak base such as triethylamine, in a
solvent such as DCM or 1,2-dichloroethane, to afford (41).
[0296] The derivative (42) may be reductively aminated a second
time in the manner described above. (42) may also be acylated or
sulfenylated as described above to afford (45) and (46),
respectively. ##STR695##
[0297] Scheme XII describes an additional embodiment. In Scheme
XII, an amino ester and a protected phenolic aryl carboxylic acid
or similar species are coupled as in Scheme 1. The protecting group
PG.sub.2 is removed, where PG.sub.2 is a hydroxyl or alcohol
protecting group. For example, where PG.sub.2 is a
tert-butyldimethylsilyl group, treatment of (49) with
tetrabutylammonium fluoride in THF affords (50). (50) may be
treated with a reagent such as but not limited to potassium
carbonate and an alkyl halide R.sub.47--X, where R.sub.47 is a
group such as alkyl or substituted alkyl and X is a group such as
bromo or iodo, to afford (51). Alternately, where R.sub.47 is an
activated or unactivated aromatic or heteroaromatic ring system and
X is fluoro, treatment of (50) with R.sub.47--X in the presence of
a base such as but not limited to potassium carbonate in a solvent
such as DMF, at a temperature of 25.degree. C. to 120.degree. C.,
affords (51). Hydrolysis of the ester as described previously
affords (52). ##STR696##
[0298] Scheme XIII describes another embodiment. L.sub.3 is a group
such as -alkylene-. The amino ester (53) may be coupled with a
carboxylic acid as described in Scheme I to afford 54. The
protecting group PG.sub.3 may be removed. Where J is NH and
PG.sub.3 is, for example, a tert-butoxycarbonylamino group,
treatment of (54) with TFA or HCl in dioxane solvent affords the
amine salt (55). Where J is O and PG.sub.3 is, for example, a
benzyl group, treatment of (54) with a reagent such as but not
limited to palladium on carbon in a solvent such as methanol or
ethanol under a hydrogen atmosphere affords (55). Where J is S and
PG.sub.3 is, for example, a trityl group, treatment of (54) with
catalytic HCl or other acid in a solvent such as methanol under a
nitrogen atmosphere affords (55). (55) where J is O or S may be
alkylated with a reagent R.sub.48--X, where R.sub.48 is
(un)substituted alkyl and X is bromo or iodo or chloro, by reacting
(55) with a base such as sodium hydride in a solvent such as THF or
DMF and treating the reaction mixture with R.sub.48--X. The
resulting compounds (56) and (57) may be processed on to compounds
of formula (I). Additionally, (56) may be oxidized to the sulfoxide
or sulfone, respectively, by treatment with one or two equivalents
of an oxidizing agent such as m-chloroperbenzoic acid in a solvent
such as DCM or 1,2-dichloroethane. (55) may be treated with a
carboxylic acid R.sub.49--COOH and a coupling agent such as DCC
under conditions described previoulsy to afford (59), where L.sub.4
is --C(O)--. Alternately, (55) may be treated with a sulfonyl
chloride R.sub.49--SO.sub.2Cl in the presence of a base such as TEA
or pyridine to afford (59), where L.sub.4 is --SO.sub.2--. The
amine (55) may be reductively aminated employing a ketone or
aldehyde under conditions described previously to afford (58), and
(58) may be reductively aminated with a ketone or aldehyde to
afford (60). Alternately, the amine (58) may be sulfenylated or
acylated as described above to afford (61), where L.sub.4 is
--SO.sub.2--or --(O)--. ##STR697##
[0299] The term "amino protecting group" as used herein refers to
substituents of the amino group commonly employed to block or
protect the amino functionality while reacting other functional
groups on the compound. Examples of such amino-protecting groups
include the formyl group, the trityl group, the phthalimido group,
the trichloroacetyl group, the chloroacetyl, bromoacetyl and
iodoacetyl groups, urethane-type blocking groups such as
benzyloxycarbonyl, 4-phenylbenzyloxycarbonyl,
2-methylbenzyloxycarbonyl, 4-methoxybenzyloxycarbonyl,
4-fluorobenzyloxycarbonyl, 4-chlorobenzyloxycarbonyl,
3-chlorobenzyloxycarbonyl, 2-chlorobenzyloxycarbonyl,
2,4-dichlorobenzyloxycarbonyl, 4-bromobenzyloxycarbonyl,
3-bromobenzyloxycarbonyl, 4-nitrobenzyloxycarbonyl,
4-cyanobenzyloxy-carbonyl, 2-(4-xenyl)iso-propoxycarbonyl,
1,1-diphenyleth-1-yloxycarbonyl, 1,1-diphenylprop-1-yloxycarbonyl,
2-phenylprop-2-yloxycarbonyl, 2-(p-toluyl)prop-2-yloxycarbonyl,
cyclopentanyloxycarbonyl, 1-methylcyclopentanyloxycarbonyl,
cyclohexanyloxycarbonyl, 1-methylcyclohexanyloxycarbonyl,
2-methylcyclohexanyloxycarbonyl,
2-(4-toluylsulfonyl)ethoxycarbonyl,
2(methylsulfonyl)ethoxycarbonyl,
2-(triphenylphosphino)ethoxycarbonyl, 9-fluorenylmethoxycarbonyl
("FMOC"), t-butoxycarbonyl ("BOC"),
2-(trimethylsilyl)ethoxycarbonyl, allyloxycarbonyl,
1-(trimethylsilylmethyl)prop-1-enyloxycarbonyl,
5-benzisoxalylmethoxycarbonyl, 4-acetoxybenzyloxycarbonyl,
2,2,2-trichloroethoxycarbonyl, 2-ethynyl-2-propoxycarbonyl,
cyclopropylmethoxycarbonyl, 4-(decyloxy)benzyloxycarbonyl,
isobornyloxycarbonyl, 1-piperidyloxycarbonyl and the like; the
benzoylmethylsulfonyl group, the 2-(nitro)phenylsulfenyl group, the
diphenylphosphine oxide group and like amino-protecting groups. The
species of amino-protecting group employed is not critical so long
as the derivatized amino group is stable to the condition of
subsequent reaction(s) on other positions of the compound of
Formula (I) and can be removed at the desired point without
disrupting the remainder of the molecule. Preferred
amino-protecting groups are the allyloxycarbonyl, the
t-butoxycarbonyl, 9-fluorenylmethoxycarbonyl, and the trityl
groups. Similar amino-protecting groups used in the cephalosporin,
penicillin and peptide art are also embraced by the above terms.
Further examples of groups referred to by the above terms are
described by J. W. Barton, "Protective Groups In Organic
Chemistry", J. G. W. McOmie, Ed., Plenum Press, New York, N.Y.,
1973, and T. W. Greene, "Protective Groups in Organic Synthesis",
John Wiley and Sons, New York, N.Y., 1981. The related term
"protected amino" or "protected amino group" defines an amino group
substituted with an amino-protecting group discussed above.
[0300] The term "hydroxyl protecting group" as used herein refers
to substituents of the alcohol group commonly employed to block or
protect the alcohol functionality while reacting other functional
groups on the compound. Examples of such alcohol-protecting groups
include the 2-tetrahydropyranyl group, 2-ethoxyethyl group, the
trityl group, the trichloroacetyl group, urethane-type blocking
groups such as benzyloxycarbonyl, and the trialkylsilyl group,
examples of such being trimethylsilyl, tert-butyldimethylsilyl,
phenyldimethylsilyl, triiospropylsilyl and thexyldimethylsilyl. The
choice of of alcohol-protecting group employed is not critical so
long as the derivatized alcohol group is stable to the condition of
subsequent reaction(s) on other positions of the compound of the
formulae and can be removed at the desired point without disrupting
the remainder of the molecule. Further examples of groups referred
to by the above terms are described by J. W. Barton, "Protective
Groups In Organic Chemistry", J. G. W. McOmie, Ed., Plenum Press,
New York, N.Y., 1973, and T. W. Greene, "Protective Groups in
Organic Synthesis", John Wiley and Sons, New York, N.Y., 1981. The
related term "protected hydroxyl" or "protected alcohol" defines a
hydroxyl group substituted with a hydroxyl-protecting group as
discussed above.
[0301] The term "carboxyl protecting group" as used herein refers
to substituents of the carboxyl group commonly employed to block or
protect the --OH functionality while reacting other functional
groups on the compound. Examples of such alcohol-protecting groups
include the 2-tetrahydropyranyl group, 2-ethoxyethyl group, the
trityl group, the allyl group, the trimethylsilylethoxymethyl
group, the 2,2,2-trichloroethyl group, the benzyl group, and the
trialkylsilyl group, examples of such being trimethylsilyl,
tert-butyldimethylsilyl, phenyldimethylsilyl, triiospropylsilyl and
thexyldimethylsilyl. The choice of carboxyl protecting group
employed is not critical so long as the derivatized alcohol group
is stable to the condition of subsequent reaction(s) on other
positions of the compound of the formulae and can be removed at the
desired point without disrupting the remainder of the molecule.
Further examples of groups referred to by the above terms are
described by J. W. Barton, "Protective Groups In Organic
Chemistry", J. G. W. McOmie, Ed., Plenum Press, New York, N.Y.,
1973, and T. W. Greene, "Protective Groups in Organic Synthesis",
John Wiley and Sons, New York, N.Y., 1981. The related term
"protected carboxyl" defines a carboxyl group substituted with a
carboxyl-protecting group as discussed above.
[0302] The general procedures used in the methods of the present
invention are described below.
General Experimental:
[0303] LC-MS data was obtained using gradient elution on a Waters
600 controller equipped with a 2487 dual wavelength detector and a
Leap Technologies HTS PAL Autosampler using an YMC Combiscreen
ODS-A 50.times.4.6 mm column. A three minute gradient was run from
25% B (97.5% acetonitrile, 2.5% water, 0.05% TFA) and 75% A (97.5%
water, 2.5% acetonitrile, 0.05% TFA) to 100% B. The mass
spectrometer used was a Micromass ZMD instrument. All data was
obtained in the positive mode unless otherwise noted. .sup.1H NMR
data was obtained on a Varian 400 MHz spectrometer.
Common Names and Definitions for Resin Reagents Used in the
Disclosure are;
[0304] Merrifield p-Chloromethyl polystyrene [0305]
Hydroxy-Merrifield p-Hydroxymethyl polystyrene [0306] Wang
(4-Hydroxymethyl)phenoxymethyl polystyrene [0307] Wang carbonate
4-(p-nitrophenyl carbonate) phenoxymethyl polystyrene [0308] Rink
Resin 4-(2',4'-Dimethoxyphenyl-Fmco-aminomethyl)-phenoxy
polystyrene resin [0309] Wang Bromo Resin
(4-Bromomethyl)phenoxymethyl polystyrene [0310] THP Resin
3,4-Dihydro-2H-pyran-2-ylmethoxymethyl polystyrene Aldehyde Resin
can Refer to the Following:
[0311] 4-Benzyloxybenzaldehyde polystyrene
[0312] 3-Benzyloxybenzaldehyde polystyrene
[0313] 4-(4-Formyl-3-methoxyphenoxy)butyryl-aminomethyl
polystyrene
[0314] 2-(4-Formyl-3-methoxyphenoxy)ethyl polystyrene
[0315] 2-(3,5-dimethoxy-4-formylphenoxy)ethoxy-methyl
polystyrene
[0316] 2-(3,5-dimethoxy-4-formylphenoxy)ethoxy polystyrene
[0317] (3-Formylindolyl)acetamidomethyl polystyrene
[0318] (4-Formyl-3-methoxyphenoxy) grafted
(polyethyleneglycol)-polystyrene; or
[0319] (4-Formyl-3-methoxyphenoxy)methylpolystyrene.
Abbreviations Used in the Examples are as Follows:
[0320] APCI=atmospheric pressure chemical ionization [0321]
BOC=tert-butoxycarbonyl [0322]
BOP=(1-benzotriazolyloxy)tris(dimethylamino)phosphonium
hexafluorophosphate [0323] d=day [0324] DIAD=diisopropyl
azodicarboxylate [0325] DCC=dicyclohexylcarbodiimide [0326]
DCE=1,2-dichloroethane [0327] DCM=dichloromethane [0328]
DIC=diisopropylcarbodiimide [0329] DIEA=diisopropylethylamine
[0330] DMA=N,N-dimethylacetamide [0331] DMAP=dimethylaminopyridine
[0332] DME 32 1,2 dimethoxyethane [0333] DMF=N,N-dimethylformamide
[0334] DMPU=1,3-dimethypropylene urea [0335] DMSO=dimethylsulfoxide
[0336] EDC=1-ethyl-3-(3-dimethylaminopropyl)-carbodiimide
hydrochloride [0337] EDTA=ethylenediamine tetraacetic acid [0338]
ELISA=enzyme-linked immunosorbent assay [0339] ESI=electrospray
ionization [0340] ether=diethyl ether [0341] EtOAc=ethyl acetate
[0342] FBS fetal bovine serum [0343] g gram [0344] h hour [0345]
HBTU=O-benzotriazol-1-yl-N,N,N',N'-tetramethyluronium
hexafluorophosphate [0346] HMPA=hexamethylphosphoric triamide
[0347] HOBt=1-hydroxybenzotriazole [0348] Hz=hertz [0349]
i.v.=intravenous [0350] kD=kiloDalton [0351] L=liter [0352]
LAH=lithium aluminum hydride [0353] LDA=lithium diisopropylamide
[0354] LPS=lipopolysaccharide [0355] M=molar [0356] m/z=mass to
charge ratio [0357] mbar=millibar [0358] MeOH=methanol [0359]
mg=milligram [0360] min=minute [0361] mL=milliliter [0362]
mM=millimolar [0363] mmol=millimole [0364] mol=mole [0365]
mp=melting point [0366] MS=mass spectrometry [0367] N=normal [0368]
NMM=N-methylmorpholine, 4-methylmorpholine [0369] NMR=nuclear
magnetic resonance spectroscopy [0370] p.o.=per oral [0371]
PBS=phosphate buffered saline solution [0372] PMA=phorbol myristate
acetate [0373] ppm=parts per million [0374] psi=pounds per square
inch [0375] R.sub.t=relative TLC mobility [0376] rt=room
temperature [0377] s.c.=subcutaneous [0378] SPA=scintillation
proximity assay [0379] TEA=triethylamine [0380] TFA=trifluoroacetic
acid [0381] THF=tetrahydrofuran [0382] THP=tetrahydropyranyl [0383]
TLC=thin layer chromatography [0384] TMSBr=bromotrimethylsilane,
trimethylsilylbromide T.sub.r=retention time
[0385] Thus, in an embodiment, the following compounds were
synthesized according to the Schemes described herein.
General Procedure A:
[0386] To a solution of a carboxylic acid (1.0-1.5 mmol) in DMF (6
mL) was added an amino acid methyl ester (1.0-1.5 mmol), HBTU
(1.0-1.5 mmol), and DIEA (2.0-3.0 mmol) and the mixture was stirred
overnight. After completion of the reaction, sufficient amount of
water was added and the mixture was extracted with ethyl acetate
(3.times.15 ml). The combined organic layer was washed with water
and brine, and then dried over sodium sulfate. The solvent was
removed in vacuum to afford the amide, which was used for further
transformation without further purification or purified by flash
chromatography.
General Procedure B:
[0387] To a mixture of phenol and the aryl fluoride (2 eq) in DMF
was added solid potassium carbonate (10 eq), and the mixture was
heated at 80.degree. C. for 12 h. After completion of the reaction,
sufficient amount of water was added, and the mixture was extracted
with ethyl acetate. The combined organic layer was washed with
water and brine, dried over sodium sulfate. The solvent was removed
in vacuum and the crude material obtained was purified by flash
chromatography to afford the desired aryl ethers.
General Procedure C:
[0388] To a solution of ester in THF, CH.sub.3OH (4:1), 2N-lithium
hydroxide solution (5 eq) was added, and the resulting reaction
mixture was stirred at 0.degree. C. for 30 minutes and then warmed
to room temperature. After completion of the reaction, 2N HCl was
used to neutralize the base, extracted with ethyl acetate, the
organic layer was washed with brine, dried over sodium sulfate, and
the solvent was removed in vacuum to afford the product.
General Procedure D:
[0389] To a solution of phenyl bromide in DME or Toluene were added
corresponding boronic acid (5 eq), Pd (PPh.sub.3).sub.4 (0.5% eq),
2N Na.sub.2CO.sub.3 solution (5 eq). The mixture was heated at
75.degree. C. for 12 h. After completion of the reaction, solvent
was evaporated in vacuo. During the reaction, most of the ester was
hydrolyzed to the corresponding acid. Therefore, crude product so
obtained was re-esterfied by dissolving it in CH.sub.3OH containing
1% of HCl. The mixture was refluxed for 6 h and after the
completion of the reaction, the reaction mixture was concentrated
under reduced pressure. The residue was purified by column
chromatography (silica, CH.sub.2Cl.sub.2) to provide the desired
ester. The resulting ester was hydrolyzed as described in procedure
C yielding the acid.
General Procedure E:
[0390] To a solution of an aniline (1.0 mmol) in DCE (10 mL) was
added an aldehyde (2.0-2.2 mmol), acetic acid (3.0 mmol) and sodium
triacetoxyborohydride (2.5 mmol) or sodium cyanoborohydride and the
mixture was stirred overnight. After completion of the reaction, 50
mL of DCM was added and the organic layer was washed with saturated
sodium bicarbonate solution and brine, and then dried over sodium
sulfate. The solvent was removed in vacuum to afford the amine,
which was purified by flash chromatography.
General Procedure F:
[0391] To a solution of an aniline (1.0 mmol) in DCM (10 mL) was
added a sulfonyl chloride (1.0 mmol), and pyridine (10.0 mmol) and
the mixture was stirred overnight. After completion of the
reaction, 50 mL of DCM was added and the organic layer was washed
with 1 N HCl, saturated sodium bicarbonate solution and brine, and
then dried over sodium sulfate. The solvent was removed in vacuum
to afford the sulfonamide, which was purified by flash
chromatography.
General Procedure G:
[0392] A flask is charged with phenol or aniline (1.0 equiv),
Cu(OAc).sub.2 (1.0 equiv), arylboronic acid (1.0-3.0), and powdered
4 A.sup.0 molecular sieves. The reaction mixture is diluted with
CH.sub.2Cl.sub.2 to yield a solution approximately 0.1 M in phenol
or aniline, and the Et.sub.3N (5.0 equiv) is added. After stirring
the colored heterogeneous reaction mixture for 24 h at 25.degree.
C. under ambient atmosphere, the resulting slurry is filtered and
the diaryl ether or diaryl amine is isolated from the organic
filtrate by flash chromatography.
General Procedure H:
[0393] To a solution of a phenol (1.0 mmol) in DMF (5 mL) was added
an alkyl halide (1.2 mmol) (a catalytic amount of Nal is added for
alkyl chlorides), and potassium carbonate (2.5 mmol) and the
mixture heated at 70.degree. C. overnight. After completion of the
reaction, 5 mL of ethyl acetate and 5 mL of water was added. The
organic layer was washed with water, and then dried over sodium
sulfate. The solvent was removed in vacuum to afford the ether,
which was purified by flash chromatography.
General Procedure I:
[0394] To a solution of ester in THF was added lithium hydroxide
(3-4 eq), water, and methanol. The ratio of THF/water/methanol is
4:1:1. The reaction mixture was stirred at RT for 1-1.5 h. A 10%
solution of citric acid was added to adjust the pH between 6-7.
Ethyl acetate was added and the organic layer is separated. The
aqueous layer was extracted with ethyl acetate twice. The combined
organic layer was washed with brine, dried (Na.sub.2SO.sub.4), and
concentrated under reduced pressure to give the product.
General Procedure J:
[0395] To a stirring solution of an aniline (2 mmol) dissolved in
DCM containing pyridine (4 mmol), was added acid chloride (2.5
mmol) at 0.degree. C. The reaction mixture was stirred at rt for 3
h, extracted with DCM, washed with 1M HCl and brine evaporation
followed by column chromatography purification gave amide.
[0396] The above general methods are for illustration only;
Alternative conditions that may optionally be used include: Use of
alternative solvents, alternative stoichiometries of reagents,
alternative reaction temperatures and alternative methods of
purification.
Synthesis of 4'-Trifluoromethyl-biphenyl-4-carboxylic acid
[0397] ##STR698##
[0398] The title compound was made as described in general
procedure D using 4-bromo benzoic acid (10 g, 49.4 mmol),
4-trifluoromethyl phenylboronic acid (14.17 g, 74.61 mmol),
palladium tetrakis-triphenylphosphine (5.7 g, 4.974 mmol) and 2N
Na.sub.2CO.sub.3 aq. solution (150 mL, 149.2 mmol) in 500 ml of
Toluene. After the reaction is complete, the reaction mixture was
neutralized with 2N HCl then filtered. The resulting solid was
dissolved in ethyl acetate then passed through a short column of
silica gel giving 9.7 g (75%) of the compound as a white solid.
Synthesis of Amino Acids
(2S)-Amino-3-(2'-phenoxy-biphenyl-4-yl)-propionic acid methyl
ester
[0399] ##STR699##
[0400] The title compound was prepared following the procedure D
using (L)-4-bromophenylalanine (8.55 g, 35.0 mmol), 2-phenoxyphenyl
boronic acid (10.00 g, 46.73 mmol), and palladium
tetrakis-triphenylphosphine (4.0 g, 10% mmol)) and 2N
Na.sub.2CO.sub.3 aq. solution (70 mL, 140 mmol) in 140 ml of DME.
After removal of solvents, the solid was washed with ether to
afford the title compound as the HCl salt (10.0 g, 26.20 mmol, 75%
yield).
(2S)-Amino-3-(4'-trifluoromethoxy-biphenyl-4-yl)-propionic acid
methyl ester
[0401] ##STR700##
[0402] The title compound was prepared following the procedure D
using (L)-4-bromophenylalanine (8.0 g, 32.7 mmol),
4-trifluoromethoxybenzene boronic acid (10.1 g, 49.1 mmol),
palladium tetrakis-triphenylphosphine (3.7 g, 3.2 mmol), and
Na.sub.2CO.sub.3 (2.0 N, 80.0 mL, 160 mmol) in DME (300 mL). After
removal of solvent, the solid was washed with ether to afford the
title compound as the HCl salt (10.8 g, 28.7 mmol, 88% yield).
(2S)-Amino-3-(4'-trifluoro-biphenyl-4-yl)-propionic acid methyl
ester
[0403] ##STR701##
[0404] The title compound was prepared exactly following the
procedure D using (L)-4-bromophenylalanine (9.0 g, 36.8 mmol),
4-trifluoromethylbenzene boronic acid(10.48 g, 55.2 mmol),
palladium tetrakis-triphenylphosphine (4.25 g, 3.6 mmol), and
aqueous Na.sub.2CO.sub.3 (2.0 N, 90.0 mL, 185 mmol) in DME (300
mL). After removal of solvent, the solid was washed with ether to
afford the title compound as the HCl salt (10.5 g, 29.2 mmol, 79%
yield).
EXAMPLE 1
3-Biphenyl-4-yl-(2S)-[(isoquinoline-3-carbonyl)-amino]-propionic
acid
[0405] 2-L-amino-3-biphenyl-4-yl-propionic acid methyl ester (100
mg, 0.1 mmol) was reacted with isoquinoline-3-carboxylic acid (78
mg, 0.5 mmol) as described in general procedure A. The resulting
compound was hydrolyzed according to general procedure C to afford
the title product (132 mg, 81%) as a white solid.
[0406] .sup.1H-NMR (400 MHz, CD.sub.3COCD.sub.3): 3.38(dd, 1H),
3.47 (dd, 1H), 5.09 (m, 1H), 7.32 (m, 1H), 7.42 (m, 4H), 7.60 (m,
4H), 7.82 (m, 1H), 7.89 (m, 1H), 8.17 (m, 1H), 8.23 (m, 1H), 8.58
(s, 1H), 8.76 (m, 1H), 9.30 (d, 1H); LC/MS (m/z):
397(M+1).sup.+.
EXAMPLE 2
(2S)-[(Isoquinoline-3-carbonyl)-amino]-3-(4'-trifluoromethyl-biphenyl-4-yl-
)-propionic acid
[0407]
3-(4-Bromo-phenyl)-(2S)-[(isoquinoline-3-carbonyl)-amino]-propioni-
c acid methyl ester (720 mg, 90%) was prepared starting from
2-L-amino-3-(4-bromo-phenyl)-propionic acid methyl ester (500 mg,
1.9 mmol) and isoquinoline -3-carboxylic acid (400 mg, 2.3 mmol)
according to general procedure A.
[0408] The resulting amide (100 mg, 0.24 mmol) was reacted with
4-trifluoromethylphenyl boronic acid (95 mg, 0.5 mmol) as described
in general procedure D yielding the title compound (80 mg, 80%) as
a white solid.
[0409] .sup.1H-NMR(400 MHz, CDCl.sub.3): 3.33(m, 2H), 5.08 (m, 1H),
7.11 (d, 1H), 7.36 (t, 2H), 7.49 (m, 1H), 7.61 (s, 2H), 7.77 (m,
3H), 8.00 (m, 3H), 8.60 (d, 1H), 8.75 (m, 1H), 9.16 (s, 1H); LC/MS
(m/z): 465(M+1).sup.+.
EXAMPLE 3
(2S)-[(Isoquinoline-3-carbonyl)-amino]-3-(3,5'-bistrifluoromethyl-biphenyl-
-4-yl)-propionic acid
[0410]
3-(4-Bromo-phenyl-(2S)-[(isoquinoline-3-carbonyl)-amino]-propionic
acid methyl ester (100 mg, 0.24 mmol) prepared as in example 2 was
reacted with 3,5-bis(trifluoromethyl)phenyl boronic acid (129 mg,
0.5 mmol) as described in general procedure D to afford the title
compound (100 mg, 79%) as a white solid.
[0411] .sup.1H-NMR(400 MHz, CDCl.sub.3): 3.36(dd, 1H), 3.48 (dd,
1H), 5.18 (m, 1H), 7.40 (d, 2H), 7.51 (d, 2H), 7.74 (m, 2H), 7.79
(m, 1H), 7.94 (m, 2H), 8.00 (m, 2H), 8.59 (s, 1H), 8.74 (d, 1H),
9.14 (s, 1H); LC/MS (m/z): 533(M.sup.++1).sup.+.
EXAMPLE 4
(2S)-[(Isoquinoline-3-carbonyl)-amino]-3-(4'-methoxy-biphenyl-4-yl)-propio-
nic acid
[0412]
3-(4-Bromo-phenyl-(2S)-[(isoquinoline-3-carbonyl)-amino]-propionic
acid methyl ester (100 mg, 0.24 mmol) prepared as in example 2 was
reacted with 4-methoxyphenyl boronic acid (76 mg, 0.5 mmol) as
described in general procedure D yielding the title compound (84
mg, 82%) as a white solid.
[0413] .sup.1H-NMR(400 MHz, CDCl.sub.3): 3.32(m, 2H), 3.81 (s, 3H),
5.12 (m, 1H), 6.91 (m ,1H), 7.11 (d, 1H), 7.26 (m, 2H), 7.32 (m,
2H), 7.46 (m, 2H), 7.74 (m ,3H), 7.98 (m, 2H), 8.59 (d, 1H), 8.74
(m, 1H), 9.14 (s, 1H); LC/MS (m/z): 427(M+1).sup.+.
EXAMPLE 5
3-[4-(4'-Cyano-phenoxy)-phenyl]-(2S)-[(isoquinoline-3-carbonyl)-amino]-pro-
pionic acid
[0414]
3-(4-Hydroxyphenyl)-(2S)-[(isoquinoline-3-carbonyl)-amino]-propion-
ic acid methyl ester (807 mg, 90%) was prepared from
(2S)-amino-3-(4-hydroxy-phenyl)-propionic acid methyl ester (500
mg, 3.0 mmol) and isoquinoline -3-carboxylic acid (530 mg, 2.3
mmol) according to general procedure A.
[0415] The resulting amide (100 mg, 0.28 mmol) was reacted with
4-cyano fluorobenzene (36 mg, 0.30 mmol) as described in general
procedure B. The resulting aryl ether was hydrolyzed as described
in general procedure C yielding the title compound (47 mg, 72%) as
a white solid. .sup.1H-NMR(400 MHz, CDCl.sub.3): 3.30(dd,1H), 3.44
(dd, 1H), 5.10 (m, 1H), 6.96 (m, 3H), 7.27 (m, 1H), 7.31 (d, 2H),
7.53 (d, 2H), 7.77 (m, 2H), 7.99 (d, 1H), 8.05 (d,1H), 8.59 (s,
1H), 8.70 (d, 1H), 9.15 (s, 1H); LC/MS (m/z): 438(M+1).sup.+.
EXAMPLE 6
[0416]
3-[4-(4'-Nitro-phenoxy)-phenyl]-(2S)-[(isoquinoline-3-carbonyl)-am-
ino]-propionic acid
[0417]
3-(4-Hydroxy-phenyl)-(2S)-[(isoquinoline-3-carbonyl)-amino]-propio-
nic acid methyl ester (50 mg, 0.15 mmol) prepared as in example 5
was reacted with 4-nitro-fluorobenzene (42 mg, 0.30 mmol) as
described in general procedure B and hydrolyzed as described in
general procedure C yielding the title compound (49 mg, 71 %) as a
light yellow solid. LC/MS (m/z): 456 (M+1).sup.+
[0418] By analogous methods to those described above the following
Examples were synthesized. TABLE-US-00002 LC/MS EXAMPLE NAME (m/z)
7 3-(3'-Chloro-4'-fluoro-biphenyl-4-yl)-(2S)- 449
[(isoquinoline-3-carbonyl)-amino]-propionic acid 8
3-(4'-Cyano-biphenyl-4-yl)-(2S)-[(isoquinoline- 422
3-carbonyl)-amino]-propionic acid 9
(2S)-[(Isoquinoline-3-carbonyl)-amino]-3-(3'- 465
trifluoromethyl-biphenyl-4-yl)-propionic acid 10
(2S)-[(Isoquinoline-3-carbonyl)-amino]-3-(3'- 442
nitro-biphenyl-4-yl)-propionic acid
EXAMPLE 11
3-Biphenyl-4-yl-(2S)-[(7-bromo-isoquinoline-3-carbonyl)-amino]-propionic
acid
[0419] To a solution of 4-bromophthalic acid (3.0 g, 12.24 mmol) in
30 mL of THF was added a solution of borane-THF complex (1.0 M)
dropwise at 0.degree. C. The solution was warmed to rt and stirred
for 3 h. The reaction mixture was quenched by addition of HCl (2N)
at 0.degree. C. The product was extracted with ethyl acetate and
washed with sat. NaCl, dried over Na.sub.2SO.sub.4, and
concentrated under reduced pressure to afford 2.8 g (100%) of
4-bromo-2-hydroxymethylbenzyl alcohol as a colorless oil. .sup.1H
NMR (CDCl.sub.3) 7.28 (m, 2 H), 7.26 (m, 1H), 4.69 (s, 4 H), 2.80
(bs, 2 H).
[0420] To a solution of oxalyl chloride (2.37 mL, 4.607 mmol) in
DCM (20 mL) was added dropwise DMSO (1.95 mL) at -78.degree. C. The
mixture was stirred at -78.degree. C. for 30 min and a solution of
the diol (1.00 g, 4.607 mmol) was added dropwise. The reaction
mixture was stirred for 2 hr and TEA (11.5 mL) was added. The
reaction mixture was warmed to rt and water was added. The organic
layer was separated and washed with sat. NaCl, dried over
Na.sub.2SO.sub.4, and concentrated under reduced pressure to give
4-bromo-benzene-1,2-dicarbaldehyde as a yellow oil (0.450 g,
46%).
[0421] A mixture of 4-bromo-benzene-1,2-dicarbaldehyde (0.450 g,
2.137 mmol), diethylamino malonate (0.452 g, 2.137 mmol), and
sodium ethoxide (0.218 g, 3.20 mmol) in anhydrous ethanol (15 mL)
was refluxed for 4 hr. The solution was cooled to rt and
concentrated under reduced pressure. The crude residue was purified
by flash column chromatography (silica gel, 0.5% MeOH in
CHCl.sub.3) to obtain 0.460 g (78%) of the
7-bromo-isoquinoline-3-carboxylic acid ethyl ester which was
hydrolyzed according to general procedure C yielding the 0.350 g
(85%) of 7-bromo-isoquinoline-3-carboxylic acid as a white solid.
LC/MS (m/z): 253 (M+1).sup.+.
[0422] (2S)-amino-3-biphenyl-4yl-propionic acid methyl ester (340
mg, 13.9 mmol) was reacted with 7-bromo-isoquinoline-3-carboxylic
acid (350 mg, 13.9 mmol) as described in general procedure A. The
resulting compound was hydrolyzed by following general procedure C
yielding the title compound (132 mg, 81%) as a white solid.
EXAMPLE 12
3-Biphenyl-4-yl-(2S)-{[7-(4-trifluoromethyl-phenyl)-isoquinoline-3-carbony-
l]-amino}-propionic acid
[0423] Example 11 (50 mg, 0.1 mmol) was reacted with
4-trifluoromethylphenyl boronic acid (42.5 mg, 0.3 mmol) as
described in general procedure D yielding the title compound (45
mg, 80%) as a white solid.
[0424] .sup.1H-NMR (400 MHz, CDCl.sub.3): 8.94 (s, 1 H), 8.75 (3s,
1 H), 8.67 (m, 1 H), 8.47 (m, 1 H), 7.82 (m, 2 H), 7.51 (m, 12 H),
5.07 (m, 1 H), 3.28 (m, 2 H); LC/MS (m/z): 541 (M+1).sup.+.
EXAMPLE 13
3-Biphenyl-4-yl-(2S)-{[7-(3-chloro-4-fluoro-phenyl)-isoquinoline-3-carbony-
l]-amino}-propionic acid
[0425] Example 11 (50 mg, 0.1 mmol) was reacted with
3-chloro-4-fluoro-phenyl boronic acid (109 mg, 0.3 mmol) as
described in general procedure D yielding the title compound (45
mg, 80%) as a white solid.
[0426] .sup.1H-NMR (400 MHz, CDCl.sub.3): 9.11 (s, 1 H), 8.74 (s, 1
H), 8.58 (m, 1 H), 8.01 (m, 1 H), 7.82-7.26 (m, 13 H), 5.13 (m, 1
H), 3.44 (m, 2 H); LC/MS (m/): 541 (M+1).sup.+.
EXAMPLE 14
2-Biphenyl-4-yl-N-(1-bromo-isoquinolin-3-yl)-acetamide
[0427] To a solution of 4-biphenylacetic acid (1.0 g, 4.7 mmol) in
10 ml of anhydrous DMF was added HBTU (2.1 g, 5.7 mmol) and 1.0 ml
of DIEA. The mixture was stirred at room temperature for 10 min,
and then 1-bromo-3-isoquinolinamine (0.68 g, 4.7 mmol) was added.
After stirring over night, the mixture was poured into water,
acidified with 10% citric acid, and extracted with ethyl acetate.
The organic extracts were washed with water and brine, dried over
Na.sub.2SO.sub.4. After the condensation of the solvent, the
residue was purified by flash column chromatography (SiO.sub.2, 1:1
hexane:ethyl aceate) to provide the title compound (1.7 g, 86%) as
a light yellow solid.
[0428] .sup.1H-NMR (400 MHz, CDCl.sub.3): 3.83 (s, 3H), 7.33-7.37
(m, 1H), 7.42-7.48 (m, 4H), 7.52-7.58 (m, 1H), 7.60-7.64 (m, 4H),
7.65-7.70 (m, 1H), 7.80 (d, 1H,), 7.61 (s, 1H), 8.18 (d, 1H), 8.56
(s, 1H); LC/MS (m/z) 418 (M+1).sup.+.
EXAMPLE 15
2-Biphenyl-4-yl-N-[1
(4-trifluoromethyl-phenyl)-isoquinolin-3-yl]-acetamide
[0429] A mixture of Example 14 (0.1 g, 0.24 mmol),
3-trifluoromethylphenylboronic acid (0.14 g, 0.72 mmol), Pd
(PPh.sub.3).sub.4 (0.028 g, 0.024 mmol) and 2N Na.sub.2CO.sub.3
solution (0.1 ml) in DME was heated at 75.degree. C. for 12 h under
nitrogen. The reaction mixture was cooled, and the solvent was
evaporated. The resulting residue was purified by flash column
chromatography (SiO.sub.2, 10% ethyl acetate in hexane) to provide
the title compound (0.1 g, 87%) as a light yellow solid.
[0430] .sup.1H-NMR(400 MHz, CDCl.sub.3): 3.85(s, 3H), 7.34-7.39 (m,
1H), 7.42-7.46 (m, 5H), 7.56-7.67 (m, 6H), 7.77 (d, 1H), 7.8 (d,
1H), 7.85-7.91 (m, 3H), 8.15 (s, 1H), 8.65 (s, 1H); LC/MS (m/z):
483 (M+1).sup.+.
EXAMPLE 16
N-[1(4-aminomethyl-phenyl)-isoquinolin-3-yl]-2-biphenyl-4-yl-acetamide
[0431] The title compound was prepared (0.1 g, 85%) from Example 14
(0.1 g, 0.24 mmol) employing 4-amino methyl phenylboronic acid (0.1
g, 0.72 mmol) as described in Example 15. LC/MS (m/z): 444
(M+1).sup.+.
EXAMPLE 17
3-Biphenyl-4-yl-(2S)-{[4-(2-biphenyl-4-yl-ethylamino)-quinazoline-2-carbon-
yl]-amino}-propionic acid
[0432] 2.18 g (10 mmol) of 2-ethoxycarbonylquinazolin-4-one was
suspended in 20 ml of phosphorus oxychloride. The mixture was
refluxed for one hour, and the solvent was removed by rotary
evaporation. The resulting residue was dissolved in ethyl acetate,
and the obtained solution was washed with saturated sodium
bicarbonate solution three times, dried over anhydrous sodium
sulfate, filtered, and evaporated to give 2.13 g (90% mmol) of
2-ethoxycarbonyl-4-chloroquinazoline as a pale-yellow solid. LC/MS
(m/z 237 (M+1).sup.+.
[0433] 236 mg (1.0 mmol) of 2-ethoxycarbonyl-4-chloroquinazoline
obtained above, 210 mg (1.05 mmol) of biphenylethylamine and 1.0 ml
(5.74 mmol) of diisopropylethylamine were mixed with 10 ml of
isopropyl alcohol. The mixture was refluxed for 12 hours. The
residue obtained after removing the solvent was purified by
chromatography (5% ethyl acetate in DCM) to give 360 mg (0.9 mmol)
of 2-ethoxycarbonyl-4-biphenylethylaminoquinazoline as a white
solid. The ethyl ester was hydrolyzed according to general
procedure C yielding the 295 mg (90%) of
4-biphenylethylaminoquinazoline-2-carboxylic acid as a white solid.
LC/MS (m/z): 398 (M+1).sup.+.
[0434] To 200 mg(.about.0.2 mmol) of Wang resin (1.1 mmol/g) loaded
with L-4-biphenylalanine were added 220 mg of (0.6 mmol)
4-biphenylethylaminoquinazoline-2-carboxylic acid, 0.6 mL (0.6
mmol) of 1.0 M DIC in DMF, 0.6 mL (0.6 mmol) of 1.0 M HOBt in DMF,
and a catalytic amount of DMAP. The resulting mixture was left on
shaker overnight. The resin was washed with DMF, MeOH, DCM three
times of each and cleaved with 20% TFA in DCM. The residue obtained
after removing the solvent was purified by chromatography (10%
methanol in DCM) to give 72 mg (60%) of the title compound.
[0435] .sup.1H NMR (400 MHz, CD.sub.3OD): 2.91 (t, 2H), 3.30-3.36
(m, 2H), 3.90-4.00 (m, 2H), 4.98 (t, 1H), 7.06 (d, 2H), 7.12-7.21
(m, 4H), 7.22-7.31 (m, 9H), 7.33-7.38 (m, 3H), 7.72 (td, 1H),
7.90-7.96 (m, 2H), 8.22 (d, 1H); LC/MS (m/z): 593 (M+1).sup.+.
EXAMPLE 18
3-Biphenyl-4-yl-(2S)-{[4-tert-butyl-benzylamino)-quinazoline-2-carbonyl]-a-
mino}-propionic acid
[0436] 4-tert-butyl benzyl aminoquinazoline-2-carboxylic acid (290
mg, 90%) was synthesized from 236 mg (1.0 mmol) of
2-ethoxycarbonyl-4-chloroquinazoline, 210 mg (1.05 mmol) of
4-tert-butyl benzylamine and 1.0 ml (5.74 mmol) of
diisopropylethylamine as described in Example 17.
[0437] 4-tert-butyl benzyl aminoquinazoline-2-carboxylic acid (290
mg, 0.6 mmol) so obtained was reacted with 200 mg (.about.0.2 mmol)
of Wang resin (1.1 mmol/g) loaded with L-4-biphenylalanine as
described in Example 17 yielding the title compound (70 mg, 60%).
LC/MS (m/z) 559 (M+1).sup.+.
EXAMPLE 19
3-Biphenyl-4-yl-(2S)-{[6-(3-chloro-4-fluoro-phenyl)-pyridine-2-carbonyl]-a-
mino}-propionic acid
[0438]
3-Biphenyl-4-yl-(2S)-[(6-bromo-pyridine-2-carbonyl)-amino]-propion-
ic acid methyl ester (1.5 g, 90%) was prepared by following general
procedure A from commercially available 5-bromo picolinic acid
(0.95 g, 4.7 mmol) and (2S)-amino-3-biphenyl-4-yl-propionic acid
methyl ester (1.0 g, 3.9 mmol).
[0439] The above compound (80 mg, 0.20 mmol) was reacted with
3-chloro-4-fluoro phenylboronic acid (87 mg, 0.5 mmol) as described
in general procedure D yielding
3-Biphenyl-4-yl-2-{[6-(3-chloro-4-fluoro-phenyl)-pyridine-2-carbonyl]-ami-
no}-propionic acid (75 mg, 79%) as a light yellow solid. LC/MS
(m/z): 475 (M+1).sup.+.
EXAMPLE 20
3-Biphenyl-4-yl-(2S)-{[6-(3-chloro-4-fluorophenyl)-pyridine-2-carbonyl]-am-
ino}-propionic acid
[0440]
Biphenyl-4-yl-(2S)-[(6-bromo-pyridine-2-carbonyl)-amino]-propionic
acid methyl ester (80 mg, 0.20 mmol) was reacted with 4-trifluoro
methyl phenylboronic acid (87 mg, 0.5 mmol) as described in general
procedure D to afford the title compound (75 mg, 79%) as a light
yellow solid. LC/MS (m/z): 475 (M+1).sup.+.
[0441] By analogous methods to those described above the following
compounds were synthesized. TABLE-US-00003 LC/MS EXAMPLE NAME (m/z)
21 3-Biphenyl-4-yl-(2S)-{[6-(4-trifluoromethoxy- 507
phenyl)-pyridine-2-carbonyl]-amino}-propionic acid 22
3-Biphenyl-4-yl-(2S)-{[6-(4-fluoro-3-methyl- 455
phenyl)-pyridine-2-carbonyl]- amino}-propionic acid 23
(2S){[6-(4-Amino-phenyl)-pyridine-2-carbonyl]- 438
amino}-3-biphenyl-4-yl-propionic acid 24
3-Biphenyl-4-yl-(2S)-{[6-(3-cyano-phenyl)- 448
pyridine-2-carbonyl]-amino}-propionic acid 25
3-Biphenyl-4-yl-(2S)-{[6-(4-methanesulfonyl- 501
phenyl)-pyridine-2-carbonyl]- amino}-propionic acid 26
3-Biphenyl-4-yl-(2S)-{[6-(4-methoxy-phenyl)- 453
pyridine-2-carbonyl]-amino}-propionic acid 27
3-Biphenyl-4-yl-(2S)-{[6-(3-carbamimidoyl- 465
phenyl)-pyridine-2-carbonyl]-amino}-propionic acid 28
3-Biphenyl-4-yl-(2S)-{[6-(4-phenoxy-phenyl)- 515
pyridine-2-carbonyl]-amino}-propionic acid 29
3-Biphenyl-4-yl-(2S)-{[6-(4-tert-butyl-phenyl)- 479
pyridine-2-carbonyl]-amino}-propionic acid
EXAMPLE 30
3-Biphenyl-4-yl-(2S)-{[5-(3-chloro-4-fluoro-phenyl)-pyridine-2-carbonyl]-a-
mino}-propionic acid
[0442]
3-Biphenyl-4-yl-(2S)-[(5-bromo-pyridine-2-carbonyl)-amino]-propion-
ic acid methyl ester (1.5 g, 90%) was prepared by following general
procedure A from commercially available 5-bromo picolinic acid (0.9
g, 4.7 mmol) and (2S)-amino-3-biphenyl-4-yl-propionic acid methyl
ester (1.0 g, 3.9 mmol).
[0443] The above compound (80 mg, 0.20 mmol) was reacted with
3-chloro-4-fluoro phenylboronic acid (87 mg, 0.5 mmol) as described
in general procedure D yielding the title compound (75 mg, 79%) as
a light yellow solid. LC/MS (m/z): 475(M+1).sup.+.
[0444] By analogous methods to those described above the following
compounds were synthesized. TABLE-US-00004 EXAMPLE NAME LC/MS(m/z)
31 3-Biphenyl-4-yl-(2S)-{[5-(4-trifluoromethyl- 491
phenyl)-pyridine-2-carbonyl]- amino}-propionic acid 32
3-Biphenyl-4-yl-(2S)-{[5-(4-methoxy- 453
phenyl)-pyridine-2-carbonyl]- amino}-propionic acid
EXAMPLE 33
3-Biphenyl-4-yl-(2S)-{[4-(3-chloro-4-fluoro-phenyl)-pyridine-2-carbonyl]-a-
mino}-propionic acid
[0445]
3-Biphenyl-4-yl-(2S)-[(4-chloro-pyridine-2-carbonyl)-amino]-propio-
nic acid methyl ester (1.26 g, 85%) was prepared by following
general procedure A from commercially available 4-chloro picolinic
acid (0.7 g, 4.4 mmol) and (2S)-amino-3-biphenyl-4-yl-propionic
acid methyl ester (1.0 g, 3.9 mmol).
[0446] The above compound (80 mg, 20 mmol) was reacted with
3-chloro4-fluoro phenylboronic acid (70 mg, 0.40 mmol) as described
in general procedure D yielding the title compound (48 mg, 51%) as
a white solid. LC/MS (m/z): 475 (M+1).sup.+.
EXAMPLE 34
3-Biphenyl-4-yl-(2S)-{[4-(4-methoxy-phenyl)-pyridine-2-carbonyl]-amino}-pr-
opionic acid
[0447]
3-Biphenyl-4-yl-(2S)-[(4-chloro-pyridine-2-carbonyl)7amino]-propio-
nic acid methyl ester (80 mg, 0.20 mmol) was reacted with 4-methoxy
phenylboronic acid (61 mg, 0.40 mmol) as described in general
procedure D to afford the title compound (42 mg, 46%) as a light
yellow solid. LC/MS (m/z): 453 (M+1).sup.+.
[0448] By analogous methods to those described above the following
compounds were synthesized TABLE-US-00005 EXAMPLE NAME LC/MS(m/z)
35 3-Biphenyl-4-yl-(2S)-{[4-(4- 491 trifluoromethyl-phenyl)-
pyridine-2-carbonyl]-amino}-propionic acid 36 3-Biphenyl-4-yl-(2S)-
491 {[4-(3-trifluoromethyl-phenyl)-
pyridine-2-carbonyl]-amino}-propionic acid
EXAMPLE 37
3-Hydroxy-naphthalene-2-carboxylic acid
(2-biphenyl-4yl-ethyl)-amide
[0449] To 40.40 g (200 mmol) of Methyl 3-hydroxy-2-naphthoate, 11.0
g (220 mmol) of sodium methoxide in 500 mL of anhydrous DMA was
added 13.30 g (71 mmol) of Merrifield resin. The mixture was heated
at 110.degree. C. overnight. The resin was washed with H.sub.2O
DMF, MeOH, DCM three times each, and dried. The resulting
resin-bound methyl naphthoate was hydrolyzed with
LiOH/H.sub.2O/THF/ethanol at rt for 3 days.
[0450] To 1.0 g (2.5 mmol) of above resulting resin-bound naphthoic
acid was added mixture of 1.5 g (7.5 mmol) of
4-bromophenethylamine, 7.5 mL (7.5 mmol) of 1.0 M DIC in DMF, 7.5
mL (7.5 mmol) of 1.0 M HOBt in DMF, and a catalytic amount of DMAP.
The resulting mixture was left on a shaker overnight. The resin was
washed with DMF, MeOH, DCM three times of each to give the
resin-bound N-2-(4-bromophenyl)ethyl-3-hydroxyl-2-naphthamide.
[0451] To 0.05 g (0.1 mmol) of above resin-bound
N-2-(4-Bromophenyl)ethyl-3-hydroxyl-2-naphthamide in 2.0 mL of DME
were added 36.6 mg (0.3 mmol) of phenylboronic acid, 30 mg (0.03
mmol) of Pd(PPh.sub.3).sub.4, and 0.3 mL (0.6 mmol) of 2N
Na.sub.2CO.sub.3 solution. The mixture was heated to 80.degree. C.
for 12 h. The resin was washed with H.sub.2O DMF, MeOH, DCM three
times of each and cleaved with TMSBr/TFA/DCM (1:1:5) at rt for 4 h.
The residue obtained after removing the solvent was purified by
chromatography (100% methylene chloride) to give 22 mg (60%) of the
title compound.
[0452] .sup.1H NMR (400 MHz, CDCl.sub.3): 3.04 (t, 2H), 3.82 (dd,
2H), 6.60 (m, 1H), 7.28-7.38 (m, 5H), 7.43-7.49 (m, 3H), 7.59-7.61
(m, 4H), 7.67-7.70 (m, 2H), 7.81 (s, 1H), 11.75 (s, 1H); LC/MS
(m/z): 368 (M+1).sup.+.
EXAMPLE 38
3-[(3'-Chloro-4'-fluoro)-biphenyl-4-yl]-(2S)-[(3-hydroxy-naphthalene-2carb-
onyl)-amino]-propionic acid
[0453] To 1.0 g (2.5 mmol) of resin-bound naphthoic acid obtained
in Example 37 was added 1.95 g (7.5 mmol) of L-4-bromophenylalanine
methyl ester, 7.5 mL (7.5 mmol) of 1.0 M DIC in DMF, 7.5 mL (7.5
mmol) of 1.0 M HOBt in DMF, and a catalytic amount of DMAP. The
resulting mixture was left on a shaker overnight. The resin was
washed with DMF, MeOH, DCM three times of each to give resin-bound
3-(4-bromophenyl)
ethyl-2-[3-(hydroxy-napthalene-2-carbonyl)amino]-propionic acid
methyl ester.
[0454] To 0.05 g (0.1 mmol) of the above resin-bound
3-(4-bromophenyl)ethyl-(2S)-[3-(hydroxy-napthalene-2-carbonyl)-amino]-pro-
pionic acid methyl ester in 2.0 mL of DME were added 52.0 mg (0.3
mmol) of 3-chloro-4-fluorophenylboronic acid, 30 mg (0.03 mmol) of
Pd(PPh.sub.3).sub.4, and 0.3 mL (0.6 mmol) of 2N Na.sub.2CO.sub.3
solution. The mixture was heated to 80.degree. C. for 12 h. The
resin was washed with H.sub.2O, DMF, MeOH, DCM three times of each
and cleaved with TMSBr/TFA/DCM (1:1:5) at rt for 4 h. The residue
obtained after removing the solvent was purified by chromatography
(DCM) to give 30 mg (60%) of
3-[(3'-Chloro-4'-fluoro)-biphenyl-4-yl]-(2S)-[(3-hydroxy-napthalene-2-car-
bonyl)-amino]-propionic acid methyl ester which was hydrolyzed as
described in general procedure C yielding the title compound (28.5
mg, 100%). LC/MS (m/z) 464 (M+1).sup.+.
EXAMPLE 39
3-(Biphenyl-4-yl)-(2S)-[(3-hydroxy-napthalene-2-carbonyl)-amino]-propionic
acid
[0455] The title compound (26 mg, 65%) was prepared from 0.05 g
(0.1 mmol) of resin-bound
3-(4-bromophenyl)ethyl-(2S)-[3-(hydroxy-napthalene-2-carbonyl)-amino]-pro-
pionic acid methyl ester and 36.0 mg (0.3 mmol) of phenyl boronic
acid as described in Example 38. LC/MS (m/z): 412 (M+1).sup.+.
EXAMPLE 40
(2S)-[(3-Hydroxy-napthalene-2-carbonyl)-amino]-3-[(3'-nitro)-biphenyl-4-yl-
]-propionic acid
[0456] The title compound (27 mg, 60%) was prepared from 0.05 g
(0.1 mmol) of resin-bound
3-(47-bromophenyl)ethyl-(2S)-[3-(hydroxy-napthalene-2-carbonyl)-amino]-pr-
opionic acid methyl ester and 50.0 mg (0.3 mmol) of 3-nitro-phenyl
boronic acid as described in Example 38. LC/MS (m/z): 457
(M+1).sup.+.
EXAMPLE 41
3-(Biphenyl-4-yl)-(2S)-[(3'-chloro-4'-fluoro-4-hydroxy-biphenyl-3-carbonyl-
)-amino]-propionic acid methyl ester
[0457] To 1.0 g (2.5 mmol) of resin-bound 5-bromo-2-hydroxy-benzoic
acid obtained by a similar procedure as in Example 37 were added
1.92 g (7.5 mmol) of (2S)-amino-3-biphenyl-4yl-propionic acid
methyl ester, 7.5 mL (7.5 mmol) of 1.0 M DIC in DMF, 7.5 mL (7.5
mmol) of 1.0 M HOBt in DMF, and a catalytic amount of DMAP. The
resulting mixture was left on a shaker overnight. The resin was
washed with DMF, MeOH, DCM three times of each to give resin-bound
3-(biphenyl-4-yl)-(2S)-(5-bromo-4-hydroxy-benzoylamino)-propionic
acid methyl ester.
[0458] To 0.05 g (0.1 mmol) of above resin-bound
3-(biphenyl-4-yl)-(2S)-(5-bromo-4-hydroxy-benzoylamino)-propionic
acid methyl ester in 2.0 mL of DME were added 52.0 mg (0.3 mmol) of
3-chloro-4-fluorophenylboronic acid, 30 mg (0.03 mmol) of
Pd(PPh.sub.3).sub.4, and 0.3 mL (0.6 mmol) of 2N Na.sub.2CO.sub.3
solution. The mixture was heated to 80.degree. C. for 12 h. The
resin was washed with H.sub.2O, DMF, MeOH, DCM three times of each
and cleaved with TMSBr/TFA/DCM (1:1:5) at rt for 4 h. The residue
obtained after removing the solvent was purified by chromatography
(DCM) to give 35 mg (70%) of title compound LC/MS (m/z): 490
(M+1).sup.+.
EXAMPLE 42
3-(Biphenyl-4-yl)-(2S)-[(4'-trifluoromethyl-4-hydroxy-biphenyl-3-carbonyl)-
-amino]-propionic acid methyl ester
[0459] The resin-bound
3-(biphenyl-4-yl)-(2S)-(5-bromo-4-hydroxy-benzoyl-amino)-propionic
acid methyl ester (50 mg, 0.1 mmol) obtained as in Example 37 was
reacted with 4-trifluoromethyl phenyl boronic acid (56.7 mg, 0.3
mmol) as generally described in Example 41 to provide the title
compound (36 mg, 70%) as a white solid. LC/MS (m/z): 520
(M+1).sup.+.
EXAMPLE 43
(2S)-[(3'-Chloro-4'-fluoro-4-hydroxy-biphenyl-3-carbonyl)-amino]-3-(3'-tri-
fluoromethyl-biphenyl-4-yl)-propionic acid methyl ester
[0460] To 2.50 g (5.0 mmol) of resin-bound methyl
5-bromo-2-hydroxy-benzoate obtained by a similar procedure as in
Example 37 in 30 mL of DME were added 2.60 g (15 mmol) of
3-chloro-4-fluorophenylboronic acid, 1.12 g (1.0 mmol) of
Pd(PPh.sub.3).sub.4, and 15 mL (30.0 mmol) of 2N Na.sub.2CO.sub.3
solution. The mixture was heated to 80.degree. C. for 12 h. The
resin was washed with H.sub.2O, DMF, MeOH, DCM three times of each,
and was hydrolyzed by LiOH/H.sub.2O/THF/ethanol at rt for 3 days to
give the resin-bound
3'-chloro-4'-fluoro-4-hydroxy-biphenyl-3-carboxylic acid.
[0461] To 1.5 g (2.5 mmol) of above resin-bound
3'-chloro-4'-fluoro-4-hydroxy-biphenyl-3-carboxylic acid were added
1.95 g (7.5 mmol) of L-4-bromophenylalanine methyl ester, 7.5 mL
(7.5 mmol) of 1.0 M DIC in DMF, 7.5 mL (7.5 mmol) of 1.0 M HOBt in
DMF, and catalytic amount of DMAP. The resulting mixture was left
on a shaker overnight. The resin was washed with DMF, MeOH, DCM
three times of each to give resin-bound
3-(4-bromo-phenyl)-2-[(3'-Chloro-4'-fluoro-4-hydroxy-biphenyl-3-carbonyl)-
-amino]-propionic acid methyl ester.
[0462] To 0.05 g (0.1 mmol) of above resin-bound
3-(4-bromo-phenyl)-(2S)-[(3'-Chloro-4'-fluoro-4-hydroxy-biphenyl-3-carbon-
yl)-amino]-propionic acid methyl ester in 2.0 mL of DME were added
58.0 mg (0.3 mmol) of 3-(trifluoromethyl)phenylboronic acid, 30 mg
(0.03 mmol) of Pd(PPh.sub.3).sub.4, and 0.3 mL (0.6 mmol) of 2N
Na.sub.2CO.sub.3 solution. The mixture was heated at 80.degree. C.
for 12 h. The resin was washed with H.sub.2O, DMF, MeOH, DCM three
times of each and cleaved with TMSBr/TFA/DCM (1:1:5) at rt for 4 h.
The residue obtained after removing the solvent was purified by
chromatography (100% DCM) to give 29 mg (50%) of the title
compound. LC/MS (m/z): 572 (M+1).sup.+.
EXAMPLE 44
[0463]
3-(4'-Nitro-biphenyl-4-yl)-(2S)-[(4'-trifluoromethyl-4-hydroxy-bip-
henyl-3-carbonyl)-amino]-propionic acid methyl ester
[0464] The resin-bound
3-(4-bromo-phenyl)-(2S)-[(4'-trifluoromethyl-4-hydroxy-biphenyl-3-carbony-
l)-amino]-propionic acid methyl ester (50 mg, 0.1 mmol) prepared as
generally described in Example 37 was reacted with 4-nitro-phenyl
boronic acid (50.1 mg, 0.3 mmol) by adapting the procedureas
described in Example 43 to give title compound (28.2 mg, 50%).
LC/MS (m/z): 565 (M+1).sup.+.
EXAMPLE 45
3-(3'-Trifluoromethyl-biphenyl-4-yl)-(2S)-[(4'-trifluoromethyl-4-hydroxy-b-
iphenyl-3-carbonyl)-amino]-propionic acid methyl ester
[0465] The resin-bound
3-(4-bromo-phenyl)-(2S)-[(4'-trifluoromethyl-4-hydroxy-biphenyl-3-carbony-
l)-amino]-propionic acid methyl ester (50 mg, 0.1 mmol) prepared as
described in above Example 44 was reacted with
3-trifluoromethyl-phenyl boronic acid (57.2 mg, 0.3 mmol) by
following as generally described in Example 44 to give title
compound (29.2 mg, 50%). LC/MS (m/z): 588 (M+1).sup.+.
EXAMPLE 46
3-(4'-Trifluoromethyl-biphenyl-4-yl)-(2S)-[(4'-trifluoromethyl-4-hydroxy-b-
iphenyl-3-carbonyl)-amino]-propionic acid methyl ester
[0466] The resin-bound
3-(4-bromo-phenyl)-(2S)-[(4'-trifluoromethyl-4-hydroxy-biphenyl-3-carbony-
l)-amino]-propionic acid methyl ester (50 mg, 0.1 mmol) prepared as
generally described in Example 37 was reacted with
4-trifluoromethyl-phenyl boronic acid (57.2 mg, 0.3 mmol) by
adapting the procedure in Example 45 to give the title compound
(29.2 mg, 50%).
[0467] .sup.1H NMR (400 MHz, CDCl.sub.3): 3.30-3.42 (m, 2H), 3.84
(s, 3H), 5.11 (dd, 1H), 6.82 (d, 1H), 7.10 (d, 1H), 7.43-7.45 (m,
2H), 7.53-7.57 (m, 4H), 7.60-7.70 (m, 6H); LC/MS (m/z): 588
(M+1).sup.+.
[0468] By analogous methods to those described above the following
Examples were synthesized; TABLE-US-00006 LC/MS EXAMPLE NAME (m/z)
47 3-Biphenyl-4-yl-(2S)-[(2',4'-difluoro-4-hydroxy- 488
biphenyl-3-carbonyl)-amino]-propionic acid 48
3-Biphenyl-4-yl-(2S)-[(4'-chloro-3'-fluoro-4- 504
hydroxy-biphenyl-3-carbonyl)-amino]- propionic acid methyl ester 49
3-Biphenyl-4-yl-(2S)-[(3'-chloro-4'-fluoro-4- 490
hydroxy-biphenyl-3-carbonyl)-amino]- propionic acid 50
3-Biphenyl-4-yl-(2S)-[(4-hydroxy-3'-nitro- 499
biphenyl-3-carbonyl)-amino]-propionic acid methyl ester 51
3-Biphenyl-4-yl-(2S)-[(4-hydroxy-4'- 536
trifluoromethoxy-biphenyl-3-carbonyl)-amino]- propionic acid methyl
ester 52 (2S)-[(4-Hydroxy-4'-trifluoromethyl-biphenyl- 553
3-carbonyl)-amino]-3-(3'-nitro-biphenyl-4-yl)- propionic acid 53
(2S)-[(4-Hydroxy-4'-trifluoromethyl-biphenyl- 566
3-carbonyl)-amino]-3-(3'-nitro-biphenyl-4-yl)- propionic acid
methyl ester 54 (2S)-[(3'-Chloro-4'-fluoro-4-hydroxy-biphenyl- 551
3-carbonyl)-amino]-3-(3'-nitro-biphenyl-4-yl)- propionic acid
methyl ester 55 3-Biphenyl-4-yl-(2S)-[(4'-fluoro-4-hydroxy- 470
biphenyl-3-carbonyl)-amino]-propionic acid methyl ester 56
3-Biphenyl-4-yl-(2S)-[(4-hydroxy-4'-methoxy- 482
biphenyl-3-carbonyl)-amino]-propionic acid methyl ester 57
3-Biphenyl-4-yl-(2S)-[(4'-tert-butyl-4-hydroxy- 508
biphenyl-3-carbonyl)-amino]-propionic acid methyl ester 58
(2S)-[(4-Hydroxy-3'-nitro-biphenyl-3- 567
carbonyl)-amino]-3-(3'-rifluoromethyl- biphenyl-4-yl)-propionic
acid methyl ester 59
3-(3'-Chloro-4'-fluoro-biphenyl-4-yl)-(2S)-[(4- 551
hydroxy-3'-nitro-biphenyl-3-carbonyl)-amino]- propionic acid methyl
ester 60 (2S)-[(4'-Amino-4-hydroxy-biphenyl-3- 467
carbonyl)-amino]-3-biphenyl-4-yl-propionic acid methyl ester 61
(2S)-[(3'-Amino-4-hydroxy-biphenyl-3- 467
carbonyl)-amino]-3-biphenyl-4-yl-propionic acid methyl ester 62
3-Biphenyl-4-yl-(2S)-[(5'-fluoro-4-hydroxy-2'- 500
methoxy-biphenyl-3-carbonyl)-amino]- propionic acid methyl ester 63
3-Biphenyl-4-yl-(2S)-[(3'-fluoro-4-hydroxy- 470
biphenyl-3-carbonyl)-amino]-propionic acid methyl ester 64
3-Biphenyl-4-yl-(2S)-[(4-hydroxy-3'- 520
trifluoromethyl-biphenyl-3-carbonyl)-amino]- propionic acid methyl
ester 65 3-Biphenyl-4-yl-(2S)-[(4-hydroxy-3',5'-bis- 588
trifluoromethyl-biphenyl-3-carbonyl)-amino]- propionic acid methyl
ester 66 3-Biphenyl-4-yl-(2S)-[(3'-chloro-4-hydroxy- 486
biphenyl-3-carbonyl)-amino]-propionic acid methyl ester 67
3-Biphenyl-4-yl-(2S)-[(4'-chloro-4-hydroxy- 486
biphenyl-3-carbonyl)-amino]-propionic acid methyl ester 68
3-Biphenyl-4-yl-(2S)-[(3',5'-difluoro-4-hydroxy- 488
biphenyl-3-carbonyl)-amino]-propionic acid methyl ester 69
3-Biphenyl-4-yl-(2S)-[(4'-fluoro-4-hydroxy-3'- 483
methyl-biphenyl-3-carbonyl)-amino]-propionic acid methyl ester 70
(2S)-[(3'-Chloro-4'-fluoro-4-hydroxy-biphenyl- 572
3-carbonyl)-amino]-3-(4'-trifluoromethyl- biphenyl-4-yl)-propionic
acid methyl ester 71 (2S)-[(3'-Chloro-4'-fluoro-4-hydroxy-biphenyl-
534 3-carbonyl)-amino]-3-(4'-methoxy-biphenyl-4- yl)-propionic
acidmethyl ester 72 3-Biphenyl-4-yl-(2S)-[(4-hydroxy-4'- 522
trifluoromethoxy-biphenyl-3-carbonyl)-amino]- propionic acid 73
3-Biphenyl-4-yl-(2S)-[(4'-tert-butyl-4-hydroxy- 494
biphenyl-3-carbonyl)-amino]-propionic acid 74
3-Biphenyl-4-yl-(2S)-[(4-hydroxy-3',4'- 512
dimethoxy-biphenyl-3-carbonyl)-amino]- propionic acid methyl ester
75 (2S)-(5-Benzo[1,3]dioxol-5-yl-2-hydroxy- 496
benzoylamino)-3-biphenyl-4-yl-propionic acid methyl ester 76
3-(3'-Chloro-4'-fluoro-biphenyl-4-yl)-(2S)-[(4- 572
hydroxy-4'-trifluoromethyl-biphenyl-3- carbonyl)-amino]-propionic
acid methyl ester 77 3-Biphenyl-4-yl-(2S)-[(4-hydroxy-4'- 530
methanesulfonyl-biphenyl-3-carbonyl)- amino]-propionic acid methyl
ester 78 (2S)-[(3'-Amino-4-hydroxy-biphenyl-3- 535
carbonyl)-amino]-3-(3'-trifluoromethyl- biphenyl-4-yl)-propionic
acid methyl ester 79
3-(3',5'-Bis-trifluoromethyl-biphenyl-4-yl)-(2S)- 640
[(3'-chloro-4'-fluoro-4-hydroxy-biphenyl-3-
carbonyl)-amino]-propionic acid methyl ester 80
3-(3',5'-Bis-trifluoromethyl-biphenyl-4-yl)-(2S)- 606
[4'-fluoro-4-hydroxy-biphenyl-3-carbonyl)- amino]-propionic acid
methyl ester 81 3-(3',5'-Bis-trifluoromethyl-biphenyl-4-yl)-(2S)-
656 [(4-hydroxy-4'-trifluoromethyl-biphenyl-3- carbonyl)-amino]-
propionic acid methyl ester 82
(2S)-[(3'-Chloro-4'-fluoro-4-hydroxy-biphenyl- 558
3-carbonyl)-amino]-3-(3'-trifluoromethyl- biphenyl-4-yl)-propionic
acid 83 (2S)-[(4-Hydroxy-4'-trifluoromethyl-biphenyl- 604
3-carbonyl)-amino]-3-(3'-trifluoromethoxy- biphenyl-4-yl)-propionic
acid methyl ester 84 (2S)-[(4-Hydroxy-3'-trifluoromethyl-biphenyl-
588 3-carbonyl)-amino]-3-(3'-trifluoromethyl-
biphenyl-4-yl)-propionic acid methyl ester 85
4'-{(2S)-[(4-Hydroxy-4'-trifluoromethyl- 623
biphenyl-3-carbonyl)-amino]-2-
methoxycarbonyl-ethyl}-5-nitro-biphenyl-3- carboxylic acid methyl
ester 86 (2S)-[(4-Hydroxy-4'-trifluoromethyl-biphenyl- 610
3-carbonyl)-amino]-3-(3',4',5'-trimethoxy- biphenyl-4-yl)-propionic
acid methyl ester 87 (2S)-[(3'-Chloro-4'-fluoro-4-hydroxy-biphenyl-
588 3-carbonyl)-amino]-3-(3'-trifluoromethoxy-
biphenyl-4-yl)-propionic acid methyl ester 88
3-Biphenyl-4-yl-(2S)-[(4-hydroxy-4'- 506
trifluoromethyl-biphenyl-3-carbonyl)- amino]-propionic acid 89
(2S)-[(4-Hydroxy-2'-trifluoromethyl-biphenyl- 588
3-carbonyl)-amino]-3-(2'-trifluoromethyl- biphenyl-4-yl)-propionic
acid methyl ester 90
3-(3'-Chloro-4'-fluoro-biphenyl-4-yl)-(2S)-[(3'- 556
chloro-4'-fluoro-4-hydroxy-biphenyl-3- carbonyl)-amino]-propionic
acid methyl ester 91 (2S)-[(4-Hydroxy-3'-nitro-biphenyl-3- 542
carbonyl)-amino]-3-(3'-nitro-biphenyl-4-yl)- propionic acid methyl
ester 92 (2S)-[(4-Hydroxy-3'-trifluoromethyl-biphenyl- 565
3-carbonyl)-amino]-3-(3'-nitro-biphenyl-4-yl)- propionic acid
methyl ester 93 (2S)-[(4-Hydroxy-3'-trifluoromethyl-biphenyl- 588
3-carbonyl)-amino]-3-(4'-trifluoromethyl- biphenyl-4-yl)-propionic
acid methyl ester 94
3-(3'-Chloro-4'-fluoro-biphenyl-4-yl)-(2S)-[(4- 572
hydroxy-3'-trifluoromethyl-biphenyl-3- carbonyl)-amino]-propionic
acid methyl ester 95 3-Biphenyl-4-yl-(2S)-[(4-hydroxy-2'- 520
trifluoromethyl-biphenyl-3-carbonyl)-amino]- propionic acid methyl
ester 96 3-(3',5'-Bis-trifluoromethyl-biphenyl-4-yl)-(2S)- 656
[(4-hydroxy-3'-trifluoromethyl-biphenyl-3-
carbonyl)-amino]-propionic acid methyl ester 97
(2S)-[(4-Hydroxy-3'-trifluoromethyl-biphenyl- 588
3-carbonyl)-amino]-3-(2'-trifluoromethyl- biphenyl-4-yl)-propionic
acid methyl ester
EXAMPLE 98
(2S)-[2-(4-Benzyloxy-benzyloxy)-5-bromo-benzoylamino]-3-biphenyl-4-yl-prop-
ionic acid
[0469]
3-Biphenyl-4-yl-(2S)-(5-bromo-2-hydroxy-benzoylamino)-propionic
acid methyl ester (2.75 g, 35%) was prepared from
(2S)-amino-3-biphenyl-4-yl-propionic acid methyl
ester-hydrochloride (5.0 g, 17.2 mmol), 5-bromo-2-hydroxy-benzoic
acid (3.7 g, 17.2 mmol) as described in general procedure A except
for an adapted work-up. After reaction completion, the reaction
mixture was poured onto 150 mL of 1N HCl and 150 mL of EtOAc. The
organic layer was washed with 1N HCl, saturated sodium bicarbonate,
dried over sodium sulfate and evaporated. The crude material was
purified over silica gel (7:3, DCM-hexanes).
[0470]
(2S)-[2-(4-Benzyloxy-benzyloxy)-5-bromo-benzoylamino]-3-biphenyl-4-
-yl-propionic acid methyl ester (302 mg, 50%) was prepared from
(2S)-3-Biphenyl-4-yl-2-(5-bromo-2-hydroxy-benzoylamino)-propionic
acid methyl ester (400 mg, 0.92 mmol) and 4-benzyloxybenzyl
chloride (256 mg, 0.39) as described in general procedure H and
purified over silica gel (8:2, DCM-hexanes).
[0471]
(2S)-[2-(4-Benzyloxy-benzyloxy)-5-bromo-benzoylamino]-3-biphenyl-4-
-yl-propionic acid methyl ester (60 mg, 0.092 mmol) was dissolved
in 5 mL of THF-MeOH (4-1), cooled to 0.degree. C. and 1.1 equiv of
2 N LiOH added. After 30 minutes, 2.2 additional equiv of 2N LiOH
was added and the reaction stirred for 30 minutes. The reaction was
worked up according to general procedure C to give
(2S)-[2-(4-Benzyloxy-benzyloxy)-5-bromo-benzoylamino]-3-biphenyl-4-yl-pro-
pionic acid (35 mg, 60%).
[0472] .sup.1H-NMR(400 MHz, DMSO-d.sub.6): 2.90 (m, 1H), 3.17 (m,
1H), 4.69 (m, 1H), 4.98 (s, 2H), 5.18 (s, 2H), 6.92 (m, 2H), 7.21
(m, 3H), 7.33 (m, 10H), 7.53 (d, 2H), 7.61 (m, 3), 7.84 (d, 1H),
8.51(d, 1H); LC/MS (m/z): 638.1 (M+2).sup.+.
EXAMPLE 99
3-Biphenyl-4-yl-(2S)-{[4-(4-tert-butyl-benzyloxy)-3'-chloro-4'-fluoro-biph-
enyl-3-carbonyl]-amino}-propionic acid
[0473] 5-Bromo-2-(4-t-butyl-benzyloxy)-benzoic acid methyl ester
(338 mg, 90%) was made from 5-bromosalicilic acid methyl ester (230
mg, 1.0 mmol) and t-butyl-benzyl bromide (226 mg, 1.0 mmol)
following general procedure H, then hydrolyzed as in general
procedure C to give the corresponding acid (310 mg, 95%). The above
acid (40 mg, 0.11 mmol) was reacted with biphenyl alanine methyl
ester (44 mg, 0.15 mmol) as described in general procedure A to
give
3-biphenyl-4-yl-(2S)-[2-(4-t-butyl-benzyloxy)-5-bromo-benzoylamino]-propi-
onic acid methyl ester. The methyl ester (60 mg, 0.1 mmol) so
obtained was reacted with 3-chloro-4-fluorophenyl boronic acid (35
mg, 0.2 mmol) as described in general procedure D to provide the
(2S)-[(3'-chloro-4'-fluoro-4-tert-butyl-benzyloxy-biphenyl-3-carbonyl)-am-
ino]-3-biphenyl-4-yl-propionic acid methyl ester (52 mg, 80%). The
ester was hydrolyzed following general procedure C to give the
title compound (48 mg, 95%).
[0474] .sup.1H NMR (400 MHz, CDCl.sub.3): 1.27 (s, 9H), 2.89 (m,
1H), 3.30 (m, 1H), 4.93 (m, 1H), 5.11 (m, 2H), 7.00 (m, 2H),
7.26-7.60 (m, 17H), 8.41(d, 1H), 8.58 (d, 1H); LC/MS (m/z): 636
(M+1).sup.+.
EXAMPLE 100
(2S)-[5-Bromo-2-(4-trifluoromethylbenzyloxy)-benzoylamine]-3-(2'-phenoxybi-
phenyl-4-yl)-propionic acid
[0475] 5-Bromo-salicylic acid (2.16 g, 10 mmol) was first
transformed into 2-acetyl-5-bromo-salicylic acid (252 g, 98%) with
acetyl chloride (2.34 g, 30 mmol) and pyridine (3.95 g, 50 mmol) in
DCM. The above acid (1.29 g, 5.0 mmol) was converted into acid
chloride by using oxyl chloride (1.97 g, 15 mmol) and catalytic
amount of DMF in DCM, then 2-phenoxy-biphenyl alanine (1.45 g, 5.0
mmol) and DIEA (0.77 g, 6.0 mmol) were added to the acid chloride
to form
(2S)-[5-Bromo-2-hydroxybenzoylamine]-3-(2'-phenoxybiphenyl-4-yl)-propioni-
c acid methyl ester (1.92 g, 85%). The above methyl ester (50 mg,
0.092 mmol) was reacted with 4-trifluoromethyl benzyl bromide (44
mg, 0.18 mmol) as described in general procedure H to provide
(2S)-[5-Bromo-2-(4-trifluoromethylbenzyloxy)-benzoylamine]-3-(2'-phenoxyb-
iphenyl-4-yl)-propionic acid methyl ester (55 mg, 85%). The ester
was hydrolyzed following general procedure C to give the title
compound (52 mg, 96%).
[0476] .sup.1H NMR (400 MHz, CDCl.sub.3): 3.03, 3.22 (ABX, 2H),
4.92 (m, 3H), 6.64 (d, 1H), 6.76 (m, 2H), 6.85(dd, 1H), 6.93 (m,
2H), 7.00 (d, 2H), 7.07-7.24 (m, 7H), 7.39 (m, 4H), 8.22 (d, 1H),
8.26 (d, 1H); LC/MS (m/z): 690 (M+1).sup.+.
EXAMPLE 101
(2S)-(5-Bromo-2-heptyloxy-benzoylamino)-3-[2'-(4-trifluoromethyl-phenoxy)--
biphenyl-4-yl]-propionic acid
[0477] 5-Bromo-2-heptyloxy-benzoic acid was prepared by reacting
5-bromo-2-hydroxy-benzoic acid methyl ester (1.0 g, 4.32 mmol) with
iodoheptane (1.46 g, 6.49 mmol) as per general procedure H with
potassium carbonate (1.5 g, 10.8 mmol) added. The ester thus
obtained was subjected to hydrolysis as per general procedure C to
yield the 5-Bromo-2-heptyloxy-benzoic acid (0.950 gm, 70%).
[0478] (2S)-Amino-3-(2'-hydroxy-biphenyl-4-yl)-propionic acid was
prepared from 4-bromophenylalanine (5.0 g, 20.48 mmol),
2-hydroxyphenylboronic acid (4.23 g, 30.72 mmol) and Pd
(PPh.sub.3).sub.4 (2.36 g, 2.038 mmol) as per procedure D to yield
the corresponding amino acid which was further esterified with
methanolic solution of anhydrous HCl to yield the corresponding HCl
salt of the (2S)-Amino-3-(2'-hydroxy-biphenyl-4-yl)-propionic acid
methyl ester (5.0 g, 90% crude yield).
[0479] 5-Bromo-2-heptyloxy-benzoic acid (0.231 g, 0.738 mmol) and
the (2S)-amino-3-(2'-hydroxy-biphenyl-4-yl)-propionic acid methyl
ester (0.200 g, 0.738 mmol) were then combined as per general
procedure A with HBTU (0.335 g, 0.885 mmol) and
diisopropylethylamine (0.285 g, 2.21 mmol) to yield the
(2S)-(5-bromo-2-heptyloxy-benzoylamino)-3-(2'-hydroxy-biphenyl-4-yl)-prop-
ionic acid methyl ester (0.200 g, 50%).
[0480] The title compound was the prepared from
(2S)-(5-bromo-2-heptyloxy-benzoylamino)-3-(2'-hydroxy-biphenyl-4-yl)-prop-
ionic acid methyl ester (0.080 g, 0.140 mmol) and
4-trifluoromethylphenylboronic acid (0.050 g, 0.281 mmol) as per
general procedure G to give
(2S)-(5-bromo-2-heptyloxy-benzoylamino)-3-[2'-(4-trifluoromethyl-phenoxy)-
-biphenyl-4-yl]-propionic acid methyl ester which was further
hydrolyzed as per general procedure C to give the title compound
(0.020 g, 30% yield). .sup.1H-NMR(400 MHz, CDCl.sub.3): 1.14(t,
3H), 1.53 (m, 8H), 1.92(m, 2H), 3.6(m, 2H), 4.2(m, 2H), 5.21(m,
1H), 7.12(d, 1H), 7.22(m, 2H), 7.36(d, 1H), 7.5(d, 2H), 7.58(m,
2H), 7.66(m, 1H), 7.78 (m, 6H), 8.62 (S, 1H), 8.9 (bs, 1H). LC/MS
(m/z): 700.2(M+2).
EXAMPLE 102
2S-(5-Chloro-2-heptyloxy-benzoylamino)-3-(4'-trifluoromethoxy-biphenyl-4-y-
l)-propionic acid
[0481] 5-Chloro-2-hydroxy-benzoic acid (2.5 g, 28.97 mmol) was
coupled with 2-amino-3-(4-bromo-phenyl)-propionic acid methyl ester
hydrochloride (4.26 g, 28.96 mmol) with HBTU (6.59 g, 34.76 mmol)
and diisopropylethylamine (8 ml, 86.91 mmol) as per general
procedure A to yield the corresponding
3-(4-Bromo-phenyl)-(2S)-(5-chloro-2-hydroxy-benzoylamino)-propionic
acid methyl ester in 50% yield.
[0482] The above hydroxy compound (0.500 g, 1.21 mmol) was then
alkylated with heptyliodide (0.410 g, 1.815 mmol) and potassium
carbonate (0.050 g, 3.025 mmol) as per general procedure H to yield
the
3-(4-bromo-phenyl)-(2S)-(5-chloro-2-heptyloxy-benzoylamino)-propionic
acid methyl ester (0.500 g, 80%)
[0483] The title compound was then prepared from
3-(4-bromo-phenyl)-(2S)-(5-chloro-2-heptyloxy-benzoylamino)-propionic
acid methyl ester (0.090 g, 0.176 mmol) and trifluoromethyl boronic
acid (0.067 g, 0.352 mmol) with Pd (PPh.sub.3) (0.020 g, 0.0176
mmol) and 2 N Na.sub.2CO.sub.3 (0.528 ml, 0.528 mmol) as per
general procedure D to yield the
(2S)-(5-chloro-2-heptyloxy-benzoylamino)-3-(4'-trifluoromethoxy-
-biphenyl-4-yl)-propionic acid methyl ester which was further
hydrolyzed as per general procedure C to give the title compound
(0.050 g, 50%)%). .sup.1H-NMR(400 MHz, CDCl.sub.3): 1.11(t, 3H),
1.44(m, 8H), 1.87(m, 2H), 3.65(dddd, 2H), 4.27(m, 2H), 5.50(m, 1H),
7.18(m, 2H), 7.4(d, 1H), 7.57(m, 4H), 7.68-7.85(m, 4H), 8.52 (S,
1H), 8.98 (bs, 1H). LC/MS (m/z): 578.2(M+2).
[0484] By analogous methods to those described above the following
compounds were synthesized. TABLE-US-00007 EXAMPLE NAME LC/MS (m/z)
103 3-Biphenyl-4-yl-(2S)-[2-(3,4-bis-benzyloxy- 757
benzyloxy)-5-bromo-benzoylamino]-propionic acid methyl ester 104
3-Biphenyl-4-yl-(2S)-[2-(3,4-bis-benzyloxy 743
benzyloxy)-5-bromo-benzoylamino]-propionic acid 105
(2S)-[2-(4-Benzyloxybenzyloxy)-5-bromo 651
benzoylamino]-3-biphenyl-4-yl-propionic acid methyl ester 106
3-Biphenyl-4-yl-(2S)-[5-bromo-2-(4-bromo- 624
benzyloxy)-benzoylamino]-propionic acid methyl ester 107
3-Biphenyl-4-yl-(2S)-[5-bromo-2-(4-bromo- 610
benzyloxy)-benzoylamino]-propionic acid 108
3-Biphenyl-4-yl-(2S)-[5-bromo-2-(4-tert-butyl- 601
benzyloxy)-benzoylamino]-propionic acid methyl ester 109
3-Biphenyl-4-yl-(2S)-[5-bromo-2-(4-tert-butyl- 587
benzyloxy)-benzoylamino]-propionic acid 110
3-Biphenyl-4-yl-(2S)-[2-(biphenyl-4-ylmethoxy)-5- 607
bromo-benzoylamino]-propionic acid 111
3-Biphenyl-4-yl-(2S)-(5-chloro-2-methoxy-benzoyl 410
amino)-propionic acid 112
3-Biphenyl-4-yl-(2S)-[2-(4-tert-butyl-benzyloxy)-5- 542
chloro-benzoylamino]-propionic acid 113
3-Biphenyl-4-yl-(2S)-[2-(4-tert-butyl-benzyloxy)-5- 636
(4-trifluoromethylphenyl)-benzoylamino]-propionic acid 114
(2S)-[5-Bromo-2-(3-methyl-benzyloxy)- 652
benzoylamino]-3-(2'-phenoxy-biphenyl-4-yl)- propionic acid methyl
ester 115 (2S)-[5-Bromo-2-(4-methyl-benzyloxy)- 637
benzoylamino]-3-(2'-phenoxy-biphenyl-4-yl)- propionic acid 116
(2S)-[5-Bromo-2-(3-methyl-benzyloxy)- 637
benzoylamino]-3-(2'-phenoxy-biphenyl-4-yl)- propionic acid 117
(2S)-[5-Bromo-2-(4-carboxy-benzyloxy)- 667
benzoylamino]-3-(2'-phenoxy-biphenyl-4-yl)- propionic acid 118
(2S)-[5-Bromo-2-(4-trifluoromethyl-phenoxy)- 677
benzoylamino]-3-(2'-phenoxy-biphenyl-4-yl)- propionic acid 119
(2S)-(5-Bromo-2-heptyloxy-benzoylamin-3-(2'- 645
phenoxy-biphenyl-4-yl)-propionic acid methyl ester 120
3-Biphenyl-4-yl-(2S)-(5-bromo-2-heptyloxy- 553
benzoylamino)-propionic acid methyl ester 121
3-Biphenyl-4-yl-(2S)-(5-bromo-2-heptyloxy- 539
benzoylamino)-propionic acid 122
(2S)-(5-Bromo-2-heptyloxy-benzoylamino)-3-(2'- 631
phenoxy-biphenyl-4-yl)-propionic acid 123
3-Biphenyl-4-yl-(2S)-[5-chloro-2-(4-pyrazol-1-yl- 552
benzyloxy)-benzoylamino]-propionic acid 124
(2S)-[5-Bromo-2-(4-tert-butyl-benzyloxy)- 679
benzoylamino]-3-(2'-phenoxy-biphenyl-4-yl)- propionic acid 125
(2S)-(2-Benzyloxy-5-bromo-benzoylamino)-3-(2'- 637
phenoxy-biphenyl-4-yl)-propionic acid methyl ester 126
(2S)-(2-Benzyloxy-5-bromo-benzoylamino)-3-(2'- 623
phenoxy-biphenyl-4-yl)-propionic acid 127
(2S)-[5-Bromo-2-(4-bromo-benzyloxy)- 702
benzoylamino]-3-(2'-phenoxy-biphenyl- 4-yl)-propionic acid 128
(2S)-(5-Bromo-2-propoxy-benzoylamino)- 575
3-(2'-phenoxy-biphenyl-4-yl)-propionic acid 129
(2S)-[(5-Bromo-2,3-dihydro-benzofuran- 559
7-carbonyl)-amino]-3-(2'-phenoxy-biphenyl-4-yl)- propionic acid 130
(2S)-[5-Bromo-2-(3-phenyl-allyloxy)- 663
benzoylamino]-3-(2'-phenoxy-biphenyl- 4-yl)-propionic acid methyl
ester 131 (2S)-[5-Bromo-2-(3-phenyl-allyloxy)- 649
benzoylamino]-3-(2'-phenoxy-biphenyl- 4-yl)-propionic acid 132
(2S)-[5-Bromo-2-(4-methanesulfonyl-benzyloxy)- 715
benzoylamino]-3-(2'-phenoxy-biphenyl-4-yl)- propionic acid methyl
ester 133 (2S)-[5-Bromo-2-(4-methanesulfonyl-benzyloxy)- 701
benzoylamino]-3-(2'-phenoxy-biphenyl-4-yl)- propionic acid 134
(2S)-[5-Bromo-2-(3-methyl-butoxy)-benzoylamino]- 617
3-(2'-phenoxy-biphenyl-4-yl)-propionic acid methyl ester 135
(2S)-[5-Bromo-2-(3-methyl-butoxy)-benzoylamino]- 603
3-(2'-phenoxy-biphenyl-4-yl)-propionic acid 136
(2S)-[2-(Biphenyl-4-ylmethoxy)-5-bromo- 713
benzoylamino]-3-(2'-phenoxy-biphenyl-4-yl)- propionic acid methyl
ester 137 (2S)-[2-(Biphenyl-4-ylmethoxy)-5-bromo- 699
benzoylamino]-3-(2'-phenoxy-biphenyl-4-yl)- propionic acid 138
(2S)-[5-Bromo-2-(4-methoxy-phenoxy)- 639
benzoylamino]-3-(2'-phenoxy-biphenyl- 4-yl)-propionic acid 139
(2S)-[5-Bromo-2-(4-phenoxy-benzyloxy)- 715
benzoylamino]-3-(2'-phenoxy-biphenyl-4-yl)- propionic acid 140
(2S)-[5-Bromo-2-(1-methyl-butoxy)-benzoylamino]- 617
3-(2'-phenoxy-biphenyl-4- yl)-propionic acid methyl ester 141
(2S)-[5-Bromo-2-(1-methyl-butoxy)-benzoylamino]- 603
3-(2'-phenoxy-biphenyl-4- yl)-propionic acid 142
(2S)-(5-Bromo-2-isopropoxy-benzoylamino)-3-(2'- 575
phenoxy-biphenyl-4-yl)-propionic acid 143
(2S)-[5-Bromo-2-(3-trifluoromethyl-phenoxy)- 677
benzoylamino]-3-(2'-phenoxy-biphenyl-4-yl)- propionic acid 144
(2S)-(5-Bromo-2-heptyloxy-benzoylamino)- 661
3-[2'-(4-methoxy-phenoxy)-biphenyl-4-yl]-propionic acid 145
(2S)-[5-Bromo-2-(2-morpholin-4-yl-ethoxy)- 660
benzoylamino]-3-(2'-phenoxy-biphenyl-4-yl)- propionic acid methyl
ester 146 (2S)-{5-Bromo-2-[2-(2-methoxy-ethoxy)- 649
ethoxy]-benzoylamino}-3-(2'-phenoxy-biphenyl-4- yl)-propionic acid
methyl ester 147 (2S)-(5-Bromo-2-{2-[2-(2-methoxy-ethoxy)-ethoxy]-
693 ethoxy}-benzoylamino)-3- (2'-phenoxy-biphenyl-4-yl)-propionic
acid methyl ester 148
(2S)-(5-Bromo-2-{2-[2-(2-methoxy-ethoxy)-ethoxy]- 658
ethoxy}-benzoylamino)-3- (2'-phenoxy-biphenyl-4-yl)-propionic acid
methyl ester 149 (2S)-{5-Bromo-2-[2-(2-oxo-pyrrolidin-1- 658
yl)-ethoxy]-benzoylamino}-3-(2'-phenoxy-biphenyl- 4-yl)-propionic
acid methyl ester 150
(2S)-[5-Bromo-2-(2-phenyl-cyclopropylmethoxy)- 663
benzoylamino]-3-(2'-phenoxy-biphenyl-4-yl)- propionic acid 151
(2S)-(5-Bromo-2-sec-butoxy-benzoylamino)-3-(2'- 589
phenoxy-biphenyl-4-yl)-propionic acid 152
(2S)-(5-Chloro-2-heptyloxy-benzoylamino)-3-(2'- 600
phenoxy-biphenyl-4-yl)-propionic acid methyl ester 153
(2S)-(5-Chloro-2-heptyloxy-benzoylamino)-3-(2'- 586
phenoxy-biphenyl-4-yl)-propionic acid 154
(2S)-(5-Bromo-2-isobutoxy-benzoylamino)-3-(2'- 603
phenoxy-biphenyl-4-yl)-propionic acid methyl ester 155
(2S)-(5-Bromo-2-isobutoxy-benzoylamino)-3-(2'- 588
phenoxy-biphenyl-4-yl)-propionic acid 156
(2S)-(5-Bromo-2-ethoxycarbonyloxy- 619
benzoylamino)-3-(2'-phenoxy-biphenyl-4- yl)-propionic acid methyl
ester 157 (2S)-(5-Bromo-2-dimethylcarbamoyloxy- 618
benzoylamino)-3-(2'-phenoxy-biphenyl-4-yl)- propionic acid methyl
ester 158 (2S)-{5-Bromo-2-[2-(2-methoxy-ethoxy)- 635
ethoxy]-benzoylamino}-3-(2'-phenoxy-biphenyl-4- yl)-propionic acid
159 (2S)[5-Bromo-2-(4-phenyl-butoxy)-benzoylamino]- 665
3-(2'-phenoxy-biphenyl-4-yl)-propionic acid 160
(2S)-[5-Bromo-2-(5-phenyl-pentyloxy)- 679
benzoylamino]-3-(2'-phenoxy-biphenyl-4-yl)- propionic acid 161
(2S)-[5-Bromo-2-(6-phenyl-hexyloxy)- 693
benzoylamino]-3-(2'-phenoxy-biphenyl-4-yl)- propionic acid 162
(2S)-(5-Bromo-2-heptyloxy-benzoylamino)-3-[2'-(4- 715
trifluoromethoxy-phenoxy)- biphenyl-4-yl]-propionic acid 163
(2S)-(5-Bromo-2-{2-[2-(2-methoxy-ethoxy)-ethoxy]- 679
ethoxy}-benzoylamino)-3-(2'-phenoxy-biphenyl-4- yl)-propionic acid
164 (2S)-[5-Bromo-2-(2-piperidin-1-yl-ethoxy)- 644
benzoylamino]-3-(2'-phenoxy-biphenyl-4-yl)- propionic acid 165
(2S)-(5-Bromo-2-heptyloxy-benzoylamino)-3-[2'-(4- 687
tert-butyl-phenoxy)-biphenyl-4-yl]-propionic acid 166
(2S)-(5-Chloro-2-heptyloxy-benzoylamino)-3-(4'- 562
trifluoromethyl-biphenyl-4-yl)-propionic acid 167
3-(3'-Chloro-4'-fluoro-biphenyl-4-yl)-(2S)-(5-chloro- 546
2-heptyloxy-benzoylamino)-propionic acid 168
(2S)-[5-Bromo-2-(3-phenyl-propoxy)- 651
benzoylamino]-3-(2'-phenoxy-biphenyl-4-yl)- propionic acid 169
(2S)-{5-Bromo-2-[3-(3,4-dimethoxy-phenyl)- 711
propoxy]-benzoylamino}-3-(2'-phenoxy-biphenyl-4- yl)-propionic acid
170 (2S)-[5-Bromo-2-(3-pyridin-3-yl-propoxy)- 652
benzoylamino]-3-(2'-phenoxy-biphenyl-4-yl)- propionic acid 171
(2S)-[5-Bromo-2-(3-pyridin-4-yl-propoxy)- 652
benzoylamino]-3-(2'-phenoxy-biphenyl-4-yl)- propionic acid 172
(2S)-(5-Bromo-2-dimethylcarbamoyloxy- 604
benzoylamino)-3-(2'-phenoxy-biphenyl-4-yl)- propionic acid 173
(2S)-[5-Bromo-2-(3-morpholin-4-yl-propoxy)- 660
benzoylamino]-3-(2'-phenoxy-biphenyl-4-yl)- propionic acid 174
(2S)-[5-Bromo-2-(4,4,4-trifluoro-butoxy)- 643
benzoylamino]-3-(2'-phenoxy-biphenyl-4-yl)- propionic acid 175
(2S)-(5-Chloro-2-heptyloxy-benzoylamino)-3-(4'- 576
cyclohexyl-biphenyl-4-yl)-propionic acid 176
(2S)-(5-Chloro-2-heptyloxy-benzoylamino)-3-(3',4'- 562
dichloro-biphenyl-4-yl)-propionic acid 177
(2S)-(5-Bromo-2-butoxy-benzoylamino)-3-(2'- 589
phenoxy-biphenyl-4-yl)-propionic acid 178
(2S)-[5-Bromo-2-(2-methyl-butoxy)-benzoylamino]- 603
3-(2'-phenoxy-biphenyl-4-yl)-propionic acid 179
(2S)-(5-Bromo-2-cyclopropylmethoxy- 601
benzoylamino)-3-(2'-phenoxy-biphenyl-4-yl)- propionic acid methyl
ester 180 (2S)-(5-Bromo-2-cyclopropylmethoxy- 587
benzoylamino)-3-(2'-phenoxy-biphenyl-4-yl)- propionic acid 181
(2S)-[5-Bromo-2-(4-[1,2,4]triazol-1-yl-benzyloxy)- 690
benzoylamino]-3-(2'-phenoxy-biphenyl-4-yl)- propionic acid 182
(2S)-[5-Bromo-2-(isoquinolin-1-ylmethoxy)- 674
benzoylamino]-3-(2'-phenoxy-biphenyl-4-yl)- propionic acid 183
(2S)-[2-(3-Benzyloxy-benzyloxy)-5-bromo- 743
benzoylamino]-3-(4'-phenoxy-biphenyl-4-yl)- propionic acid methyl
ester 184 (2S)-[2-(3-Benzyloxy-benzyloxy)-5-bromo- 728
benzoylamino]-3-(4'-phenoxy-biphenyl-4-yl)- propionic acid 185
(2S)-[5-Bromo-2-(4-trifluoromethoxy-benzyloxy)- 721
benzoylamino]-3-(2'-phenoxy-biphenyl-4-yl)- propionic acid methyl
ester 186 (2S)-[5-Bromo-2-(4-trifluoromethoxy-benzyloxy)- 707
benzoylamino]-3-(2'-phenoxy-biphenyl-4-yl)- propionic acid 187
(2S)-[5-Bromo-2-(4-phenyl-butoxy)-benzoylamino]- 679
3-(4'-phenoxy-biphenyl-4-yl)-propionic acid methyl ester 188
(2S)-[5-Bromo-2-(6-phenyl-hexyloxy)- 707
enzoylamino]-3-(4'-phenoxy-biphenyl-4-yl)- propionic acid methyl
ester 189 (2S)-(5-Chloro-2-heptyloxy-benzoylamino)-3-(4'- 537
dimethylamino-biphenyl-4-yl)-propionic acid 190
(2S)-[5-Bromo-2-(4-phenyl-butoxy)-benzoylamino]- 665
3-(4'-phenoxy-biphenyl-4-yl)-propionic acid 191
(2S)-[5-Bromo-2-(6-phenyl-hexyloxy)- 693
benzoylamino]-3-(4'-phenoxy-biphenyl- 4-yl)-propionic acid 192
(2S)-[5-Bromo-2-(2-cyclohexyl-ethoxy)- 657
benzoylamino]-3-(2'-phenoxy-biphenyl-4-yl)- propionic acid methyl
ester 193 (2S)-[5-Bromo-2-(2-cyclohexyl-ethoxy)- 643
benzoylamino]-3-(2'-phenoxy-biphenyl-4-yl)-
propionic acid 1944 (2S)-(5-Bromo-2-cyclohexylmethoxy- 629
benzoylamino)-3-(2'-phenoxy-biphenyl-4-yl)- propionic acid 195
(2S)-(5-Bromo-2-cyclohexyloxy-benzoylamino)-3- 629
(2'-phenoxy-biphenyl-4-yl)-propionic acid methyl ester 196
(2S)-(5-Bromo-2-cyclohexyloxy-benzoylamino)-3- 615
(2'-phenoxy-biphenyl-4-yl)-propionic acid
EXAMPLE 197
N-[2Hydroxy-4-(4-trifluoromethyl-phenoxy)-phenyl]-2-(3'-methoxy-biphenyl-4-
-yl)-acetamide
[0485] To 4.0 g (4.0 mmol) of resin-bound 5-fluoro-2-nitro-phenol
obtained by a similar procedure as s in Example 37 in 8.0 mL of DMF
were added 1.31 g (8.0 mmol) of 4-hydroxybenzotrifluoride, and 1.20
g (8.0 mmol) of K.sub.2CO.sub.3. The mixture was heated to
110.degree. C. for 12 h. The resin was washed with H.sub.2O, DMF,
MeOH, DCM three times of each, and was reduced by SnCl.sub.2
hydrate in NMP at rt for 4 h to give the resin-bound
2-amino-5-(4-trifluoromethyl-phenoxy)-phenol.
[0486] To 3.0 g (2.5 mmol) of above resin-bound
2-amino-5-(4-trifluoromethyl-phenoxy)-phenol were added 1.62 g (7.5
mmol) of 4-bromophenylacetic acid, 7.5 mL (7.5 mmol) of 1.0 M DIC
in DMF, 7.5 mL (7.5 mmol) of 1.0 M HOBt in DMF, and a catalytic
amount of DMAP. The resulting mixture was left on a shaker
overnight. The resin was washed with DMF, MeOH, DCM three times of
each to give resin-bound
2-(4-bromo-phenyl)-N-[2-Hydroxy-4-(4-trifluoromethyl-phenoxy)-phenyl]-ace-
tamide.
[0487] To 120 mg (0.1 mmol) of above resin-bound
2-(4-bromo-phenyl)-N-[2-Hydroxy-4-(4-trifluoromethyl-phenoxy)-phenyl]-ace-
tamide in 2.0 mL of DME were added 46.0 mg (0.3 mmol) of
3-methoxyphenylboronic acid, 30 mg (0.03 mmol) of
Pd(PPh.sub.3).sub.4, and 0.3 mL (0.6 mmol) of 2N Na.sub.2CO.sub.3
solution. The mixture was heated to 80.degree. C. for 12 h. The
resin was washed with H.sub.2O, DMF, MeOH, DCM three times of each
and cleaved with TMSBr/TFA/DCM (1:1:5) at rt for 4 h. The residue
obtained after removing the solvent was purified by chromatography
(100% methylene chloride) to give 25 mg (50%) of the title
compound. LC/MS (m/z) 494 (M+1).sup.+.
EXAMPLE 198
N-[2-Hydroxy-4-(3,4-dichloro-phenoxy)-phenyl]-2-(4'-trifluoromethyl-biphen-
yl-4-yl)-acetamide
[0488] The resin-bound
2-(4-bromo-phenyl)-N-[2-Hydroxy-4-(3,4-dichloro-phenoxy)-phenyl]-acetamid-
e (120 mg, 0.1 mmol) prepared as described in Example 197 was
reacted with 4-trifluoromethyl-phenyl boronic acid (56.7 mg, 0.3
mmol) as generally described in Example 197 to afford (26.9 mg,
50%) the title compound.
[0489] .sup.1H NMR (400 MHz, CDCl.sub.3):. 3.88 (s, 2H), 6.48 (dd,
1H), 6.66(d, 1H), 6.79-6.85 (m, 2H), 7.05 (d, 1H), 7.36 (d, 2H),
7.46-7.48 (m, 2H), 7.66-7.68 (m, 2H), 7.71 (m, 4H), 8.92 (s, 1H);
LC/MS (m/z): 532 (M+1).sup.+.
EXAMPLE 199
N-[2-Hydroxy-4-(2,4-dichloro-6-methyl-phenoxy)-phenyl]-2-(4'-trifluorometh-
yl-biphenyl-4-yl)-acetamide
[0490] The resin-bound
2-(4-bromo-phenyl)-N-[2-Hydroxy-4-(3,4-dichloro-6-methyl-phenoxy)-phenyl]-
-acetamide (120 mg, 0.1 mmol) prepared as described in Example 197
was reacted with 4-trifluormethyl-phenyl boronic acid (56.7 mg, 0.3
mmol) as generally described in Example 197 to afford (27.5 mg,
50%) of title compound.
[0491] .sup.1H NMR (400 MHz, CDCl.sub.3): 2.13 (s, 3H), 3.86 (s,
2H), 6.33 (dd, 1H), 6.36 (d, 1H), 6.69 (d, 1H), 7.15 (d, 1H, 7.29
(d, 1H), 7.45 (d, 2H), 7.64-7.71 (m, 6H), 8.92 (s, 1H); LC/MS
(m/z): 546 (M+1).sup.+.
EXAMPLE 200
N[2-Hydroxy-4-(2,4-dichloro-6-methyl-phenoxy)-phenyl]-2-(3'-trifluoromethy-
l-biphenyl-4-yl)-acetamide
[0492] The resin-bound
2-(4-bromo-phenyl)-N-[2-Hydroxy-4-(3,4-dichloro-6-methyl-phenoxy)-phenyl]-
-acetamide (120 mg, 0.1 mmol) prepared as described in Example 197
was reacted with 3-trifluormethyl-phenyl boronic acid (56.7 mg, 0.3
mmol) as generally described in Example 197 to afford (27.5 mg,
50%) of title compound.
[0493] .sup.1H NMR (400 MHz, CDCl.sub.3): 2.13 (s, 1H), 3.86 (s,
2H), 6.33 (dd, 1H), 6.37 (d, 1H), 6.69 (d, 1H), 7.15 (m, 1H), 7.30
(d, 1H), 7.45 (dd, 2H), 7.59-7.65 (m, 4H), 7.78 (m, 1H), 7.84 (s,
1H), 8.84 (s, 1H); LC/MS (m/z): 546 (M+1).sup.+.
[0494] By analogous methods to those described above the following
compounds were synthesized TABLE-US-00008 LC/MS EXAMPLE NAME (m/z)
201 3-(3'-Chloro-4'-fluoro-biphenyl-4-yl)-N-[4-(2,4- 544
dichloro-6-methyl-phenoxy)-2-hydroxy-phenyl]- propionamide 202
N-[4-(2-Fluoro-6-methoxy-phenoxy)-2-hydroxy- 488
phenyl]-3-(3'-methoxy-biphenyl-4-yl)- propionamide 203
N-[4-(2,4-Dichloro-6-methyl-phenoxy)-2- 508
hydroxy-phenyl]-2-(4'-methoxy-biphenyl-4-yl)- acetamide 204
2-(3'-Chloro-4'-fluoro-biphenyl-4-yl)-N-[4-(2,4- 530
dichloro-6-methyl-phenoxy)-2-hydroxy-phenyl]- acetamide 205
2-Biphenyl-4-yl-N-[2-hydroxy-4-(4'- 502
methoxy-biphenyl-4-yloxy)-phenyl]-acetamide 206
2-Biphenyl-4-yl-N-[2-hydroxy-4-(4'- 540
trifluoromethyl-biphenyl-4-yloxy)-phenyl]- acetamide 207
N-[4-(3,4-Dichloro-phenoxy)-2-hydroxy-phenyl]- 508
2-(3'-nitro-biphenyl-4-yl)-acetamide
EXAMPLE 208
N-[5-(3-Chloro-phenyl)-pyridin-2-yl]-2-[4-(3-hydroxy-4-nitro-phenoxy)-phen-
yl]-acetamide
[0495] To 4.0 g (4.0 mmol) of resin-bound 5-fluoro-2-nitro-phenol
prepared as generally described in Example 37 in 8.0 mL of DMF were
added 1.34 g (8.0 mmol) of methyl 4-hydroxyphenylacetate, and 1.20
g (8.0 mmol) of K.sub.2CO.sub.3. The mixture-was heated to
110.degree. for 12 h. The resin was washed with H.sub.2O, DMF,
MeOH, DCM three times of each, and was hydrolyzed by
LiOH/H.sub.2O/THF/ethanol at rt for 12 h to give the resin-bound
[4-(3-hydroxy-4-nitro-phenoxy)-phenyl]-acetic acid.
[0496] To 3.0 g (2.5 mmol) of above resin-bound
[4-(3-hydroxy-4-nitro-phenoxy)-phenyl]-acetic acid were added 1.30
g (7.5 mmol) of 2-amino-5-bromopyridine, 7.5 mL (7.5 mmol) of 1.0 M
DIC in DMF, 7.5 mL (7.5 mmol) of 1.0 M HOBt in DMF, and catalytic
amount of DMAP. The resulting mixture was left on a shaker
overnight. The resin was washed with DMF, MeOH, DCM three times of
each to give resin-bound
N-(5-bromo-pyridin-2-yl)-2-[4-(3-hydroxy-4-nitro-phenoxy)-phenyl]-acetami-
de
[0497] To 120 mg (0.1 mmol) of above resin-bound bound
N-(5-bromo-pyridin-2-yl)-2-[4-(3-hydroxy-4-nitro-phenoxy)-phenyl]-acetami-
de in 2.0 mL of DME were added 48.0 mg (0.3 mmol) of
3-chlorophenylboronic acid, 30 mg (0.03 mmol) of
Pd(PPh.sub.3).sub.4, and 0.3 mL (0.6 mmol) of 2N Na.sub.2CO.sub.3
solution. The mixture was heated to 80.degree. C. for 12 h. The
resin was washed with H.sub.2O, DMF, MeOH, DCM three times of each
and cleaved with TMSBr/TFA/DCM (1:1:5) at rt for 4h. The residue
obtained after removing the solvent was purified by chromatography
(silica gel, DCM) to give 20 mg (40%) of the title compound.
[0498] .sup.1H NMR (400 MHz, CDCl.sub.3): 3.81 (s, 2H), 6.51-6.55
(m, 1H), 6.60-6.63 (m, 1H), 7.11-7.13 (m, 2H), 7.26-7.45 (m, 5H),
7.52 (m,1H), 7.91 (dd,1H), 8.08 (m, 1H), 8.34 (d, 1H), 8.43 (m,
1H), 10.89 (s, 1H); LC/MS (m/z): 476 (M+1).sup.+.
EXAMPLE 209
N-[5-(3,4-Dichloro-phenyl)-pyridin-2-yl]-2-[4-(3-hydroxy-4-nitro-phenoxy)--
phenyl]-acetamide
[0499] The resin-bound
N(5-bromo-pyridin-2-yl)-2-[4-(3-hydroxy-4-nitro-phenoxy)-phenyl]-acetamid-
e (120 mg, 0.1 mmol) was reacted with 3,4-dichloro-phenyl boronic
acid (57 mg, 0.3 mmol) as described in example 208 to afford 25 mg
(45%) of the title compound. LC/MS (m/z): 510 (M+1).sup.+.
EXAMPLE 210
N-[5-(3-Trifluromethyl-phenyl)-pyridin-2-yl]-2-[4-(3-hydroxy-4-nitro-pheno-
xy)-phenyl]-acetamide
[0500] The resin-bound
N-(5-bromo-pyridin-2-yl)-2-[4-(3-hydroxy-4-nitro-phenoxy)-phenyl]-acetami-
de (120 mg, 0.1 mmol) was reacted with 3-trifluoromethyl-phenyl
boronic acid (57 mg, 0.3 mmol) as described in example 208 to
afford 22.9 mg (45%) of the title compound.
[0501] .sup.1H NMR (400 MHz, CDCl.sub.3): 3.72 (s, 2H), 3.89 (s,
3H), 6.52 (m, 1H), 6.58-6.63 (m, 1H), 7.07-7.11 (m, 2H), 7.48-7.50
(m, 2H), 7.66-7.78 (m, 4H), 8.06-8.09 (m, 1H), 8.25 (dd, 1H), 8.43
(dd, 1H), 8.72 (d, 1H), 10.90 (s, 1H); LC/MS (m/z): 510
(M+1).sup.+.
EXAMPLE 211
N-[5-(4-Methoxy-phenyl)-pyridin-2-yl]-2-[4-(3-hydroxy-4-nitro-phenoxy)-phe-
nyl]-acetamide
[0502] The resin-bound
N-(5-bromo-pyridin-2-yl)-2-[4-(3-hydroxy-4-nitro-phenoxy)-phenyl]-acetami-
de (120 mg, 0.1 mmol) was reacted with 4-methoxy-phenyl boronic
acid (45 mg, 0.3 mmol) as described in example 208 to afford 21.2
mg (45%) of the title compound.
[0503] .sup.1H NMR (400 MHz, CDCl.sub.3): 3.87 (s, 3H), 3.88 (s,
2H), 6.52 (d, 1H), 6.61 (dd, 1H), 7.01-7.03 (m ,2H), 7.08-7.10 (m,
2H), 7.46-7.56 (m, 4H), 8.08 (d, 1H), 8.16 (dd, 1H), 8.36 (dd, 1H),
8.62 (d, 1H), 10.89 (s, 1H); LC/MS (m/z): 472. (M+1).sup.+.
EXAMPLE 212
3-Biphenyl-4-yl-(2S)-[(4'-trifluoromethyl
-biphenyl-4-carbonyl)-amino]-propionic acid
[0504] (2S)-Amino-3-biphenyl-4-yl-propionic acid methyl ester (1.0
g mg, 4.1 mmol) was reacted with 4-bromo-benzoic acid (1.07 g mg,
5.3 mmol) as described in general procedure A yielding
3-biphenyl-4-yl-(2S)-[(5-bromo-benzoyl-amino)-propionic acid (1.48
g, 85%).
[0505] 3-Biphenyl-4-yl-(2S)-[(5-bromo-benzoylamino)-propionic acid
(100 mg, 0.23 mmol) was reacted with 4-trifluoromethyl phenyl
boronic acid (0.133 mg, 0.69 mmol) by following general procedure D
yielding the title compound (98 mg, 85%) as a white solid.
[0506] .sup.1H-NMR(400 MHz, DMSO-d.sub.6): 3.07-3.25(m, 2H),
4.63-4.69 (m, 1H), 7.26-7.32 (m, 1H), 7.39-7.42 (m, 4H), 7.56-7.62
(m, 4H), 7.1-7.84 (m, 4H), 7.81-7.84 (m, 4H), 7.92-7.95 (m, 4H),
8.86 (d, 1H); LC/MS (m/z): 490 (M+1).sup.+.
EXAMPLE 213
3-Biphenyl-4-yl-(2S)-[(3'-chloro-4'-fluoro-biphenyl-4-carbonyl)-amino]-pro-
pionic acid
[0507] 3-Biphenyl-4-yl-(2S)-[(5-bromo-benzoyl-amino)-propionic acid
(100 mg, 0.23 mmol) was reacted with 3-chloro-4-fluoro-phenyl
boronic acid (0.123 mg, 0.69 mmol) by following general procedure D
to afford title compound (89 mg, 80%) as a white solid. .sup.1H NMR
(400 MHz, CD.sub.3COCD.sub.3): 4.05 (dd, 2H), 5.00 (m, 1H), 7.32
(m, 1H), 7.44 (m, 4H), 7.62 (m, 4H), 7.71 (m, 1H), 7.74 (m, 2H),
7.84 (m, 1H), 7.96 (m, 3H). LC/MS (m/z) (M+1).sup.+.
EXAMPLE 214
3-Biphenyl-4-yl-(2S)-[(4'-trifluoromethoxy-biphenyl-4-carbonyl)-amino]-pro-
pionic acid
[0508] 3-Biphenyl-4-yl-(2S)-[(5-bromo-benzoyl-amino)-propionic acid
(100 mg, 0.23 mmol) was reacted with
4-trifluoromethoxyphenylboronic acid (0.145 mg, 0.69 mmol) by
following general procedure D yielding the title compound (101 mg,
85%) as a white solid:
[0509] .sup.1H-NMR(400 MHz, DMSO-d.sub.6): 3.08-3.15 (m, 1H),
3.20-3.25 (m, 1H), 4.62-4.68 (m, 1H), 7.28-7.32 (m, 1H ), 7.39-7.46
(m, 6H), 7.55-7.61 (m, 4H), 7.77 (d, 2H), 7.82 (d, 2H), 7.92 (d,
2H), 8.84 (d, 1H); LC/MS (m/z): 524 (M+1).sup.+.
EXAMPLE 215
3-Biphenyl-4-yl-(2S)-[(4'-ethyl-biphenyl-4-carbonyl)-amino]-propionic
acid
[0510] 3-Biphenyl-4-yl-(2S)-[(5-bromo-benzoyl-amino)-propionic acid
(100 mg, 0.23 mmol) was reacted with 4-ethyl phenyl boronic acid
(0.145 mg, 0.69 mmol) by following general procedure D yielding the
title compound (101 mg, 85%) as a white solid. LC/MS (m/z): 450
(M+1).sup.+.
EXAMPLE 216
3-Biphenyl-4-yl-(2S)-[(3'-ethyl-biphenyl-3-carbonyl)-amino]-propionic
acid
[0511] (2S)-amino-3-biphenyl-4yl-propionic acid methyl ester (1.0 g
mg, 4.1 mmol) was reacted with 3-bromo-benzoic acid (1.07 g mg, 5.3
mmol) as described in general procedure A yielding
3-biphenyl-4-yl-(2S)-(3-bromo-benzoylamino)-propionic acid (1.48 g,
85%).
[0512] 3-Biphenyl-4-yl-(2S)-[(3-bromo-benzoyl-amino)-propionic acid
(100 mg, 0.23 mmol) was reacted with 4-ethyl phenyl boronic acid
(0.145 mg, 0.69 mmol) by following general procedure D yielding the
title compound (101 mg, 85%) as a white solid.
[0513] .sup.1H-NMR(400 MHz, DMSO-d.sub.6): 1.22 (t, 3H), 2.61 (q,
2H), 3.25-3.30 (m, 1H), 3.37-3.39 (m, 1H), 5.06-5.08 (m, 1H), 6.75
(d, 1H, J=6.4Hz), 7.15 (d, 2H), 7.24-7.26 (m, 2H), 7.30-7.33 (m,
1H), 7.36-7.43 (m, 5H), 7.49 (t, 4H), 7.60 (d, 1H), 7.64 (d, 1H),
7.85 (s, 1H); LC/MS (m/z): 450 (M+1).sup.+.
EXAMPLE 217
3-Biphenyl-4-yl-(2S)-[(4'-tert-butyl-biphenyl-3-carbonyl)-amino]-propionic
acid
[0514] 3-Biphenyl-4-yl-(2S)-[(3-bromo-benzoyl-amino)-propionic acid
(100 mg, 0.23 mmol) was reacted with 4-tert-butyl phenyl boronic
acid (0.125 mg, 0.69 mmol) by following general procedure D
yielding the title compound (95 mg, 85%) as a white solid.
.sup.1H-NMR(400 MHz, DMSO-d.sub.6): 1.31 (s, 9H), 3.34-3.42 (m,
1H), 3.42-3.46 (m, 1H), 5.10-5.14 (m, 1H), 6.62 (bs, 1H), 7.25 (s,
1H), 7.28 (d, 1H), 7.31-7.35 (m, 1H), 7.37-7.43 (m, 4H), 7.44-7.49
(m, 3H), 7.52-7.56 (m, 4H), 7.64 (d, 1H), 7.70-7.72 (m, 1H), 7.4
(s, 1H); LC/MS (m/z): 478 (M+1).sup.+.
EXAMPLE 218
3-Biphenyl-4-yl-(2S)-[(4'-methoxy-biphenyl-3-carbonyl)-amino]-propionic
acid
[0515] 3-Biphenyl-4-yl-(2S)-[(3-bromo-benzoyl-amino)-propionic acid
(100 mg, 0.23 mmol) was reacted with 4-methoxy-phenyl boronic acid
(0.106 mg, 0.69 mmol) by following general procedure D yielding the
title compound (85 mg, 80%) as a white solid.
[0516] .sup.1H-NMR(400 MHz, DMSO-d.sub.6): 3.26-3.31 (m, 1H),
3.39-3.40 (m, 1H), 3.77 (s, 3H), 5.02-5.04 (m, 1H), 6.73 (bs, 1H),
6.85 (d, 1H), 7.79 (m, 17H); LC/MS (m/z): 452 (M+1).sup.+.
EXAMPLE 219
3-Biphenyl-4-yl-(2S)-[(4'-methane-sulfonyl-biphenyl-3-carbonyl)-amino]-pro-
pionic acid
[0517] 3-Biphenyl-4-yl-(2S)-[(3-bromo-benzoyl-amino)-propionic acid
(100 mg, 0.23 mmol) was reacted with 4-methanesulfonyl-phenyl
boronic acid (0.141 mg, 0.69 mmol) by following general procedure D
yielding the title compound (102 mg, 87%) as a light yellow
solid.
[0518] .sup.1H-NMR(400 MHz, CDCl.sub.3): 3.11-3.17 (m, 1H),
3.26-3.30 (m, 1H,), 4.69-4.74 (m, 1H), 7.30-7.34 (m, 1H), 7.58-7.63
(m, 5H), 7.87-7.93 (m, 2H), 7.98-8.05 (m, 4H), 8.14 (s, 1H), 8.97
(d, 1H); LC/MS (m/z): 500 (M+1).sup.+.
EXAMPLE 220
3-Biphenyl-4-yl-(2S)-[(4'-tert-butyl-4-chloro-biphenyl-3-carbonyl)-amino]--
propionic acid
[0519] (2S)-Amino-3-biphenyl-4yl-propionic acid methyl ester (1.0 g
mg, 4.1 mmol) was reacted with 5-bromo-2-chloro-benzoic acid (1.07
g mg, 5.3 mmol) as described in general procedure A yielding
3-biphenyl-4-yl-(2S)-(5-bromo-2-chloro-benzoyl-amino)-propionic
acid (1.5 g, 85%) as white solid.
[0520]
3-Biphenyl-4-yl-(2S)-[(2-chloro-5-bromo-benzoyl-amino)-propionic
acid (100 mg, 0.23 mmol) was reacted with 4-trifluoromethyl-phenyl
boronic acid (0.141 mg, 0.69 mmol) by following general procedure D
yielding the title compound (114 mg, 75%) as a white solid.
[0521] .sup.1H-NMR(400 MHz, DMSO-d.sub.6): 2.98-3.02 (m, 1H),
3.24-3.28 (m, 1H), 4.71-4.73 (m, 1H), 7.25 (d, 1H), 7.31-7.34 (m,
1H), 7.38-7.41 (m, 4H), 7.56-7.60 (m, 5H), 7.70 (d, 2H), 7.74-7.77
(m, 3H), 8.9 (d, 1H); LC/MS (m/z): 524 (M+1).sup.+.
EXAMPLE 221
(2S)-[(4-Chloro-4'-trifluoromethyl-biphenyl-3-carbonyl)-amino]-3-(4'-trifl-
uoromethyl-biphenyl-4-yl)-propionic acid
[0522] (2S)-Amino-3-(4-bromo-phenyl)-propionic acid methyl ester
(1.0 g mg, 3.8 mmol) was reacted with 5-bromo-2-chloro-benzoic acid
(1.09 g mg, 4.5 mmol) as described in general procedure A yielding
(2S)-(5-bromo-2-chloro-benzoyl-amino)-3-(4-bromo-phenyl)-propionic
acid (1.35 g, 75%).
[0523]
(2S)-(5-Bromo-2-chloro-benzoyl-amino)-3-(4-bromo-phenyl)-propionic
acid (100 mg, 0.21 mmol) was reacted with
4-trifluoromethyl-phenyl-boronic acid (243 mg, 1.2 mmol) by
following general procedure D yielding the title compound (114 mg,
75%) as a light yellow solid.
[0524] .sup.1H-NMR(400 MHz, DMSO-d.sub.6): 3.01-3.04 (m, 1H),
3.27-3.29 (m, 1H), 4.74-4.76 (m, 1H), 7.17 (d, 1H), 7.46 (d, 2H),
7.57 (d, 1H ), 7.64 (d, 2H, J=8 Hz), 7.67-7.82 (m, 9H), 8.91 (d,
1H, J=8.4 Hz); LC/MS (m/z): 592 (M+1).sup.+.
EXAMPLE 222
(2S)-[(-4'-Methoxy-biphenyl-3-carbonyl)-amino]-3-(4'-methoxyl-biphenyl-4-y-
l)-propionic acid
[0525] (2S)-Amino-3-(4-bromo-phenyl)-propionic acid methyl ester
(1.0 g, 3.8 mmol) was reacted with 3-bromo-benzoic acid (0.91 g ,
4.5 mmol) as described in general procedure A yielding
(2S)-(3-bromo-benzoyl-amino)-3-(4-bromo-phenyl)-propionic acid
methyl ester (1.38 g, 81%).
[0526] (2S)-(3-Bromo-benzoyl-amino)-3-(4-bromo-phenyl)-propionic
acid methyl ester (100 mg, 0.22 mmol) was reacted with
4-methoxy-phenyl-boronic acid (204 mg, 1.4 mmol) according to
general procedure D yielding the title compound (90 mg, 83%) as a
white solid.
[0527] .sup.1H-NMR (400 MHz, DMSO-d.sub.6): 3.08 (m, 1H), 3.22 (m,
1H), 3.74 (s, 3H), 3.76 (s, 3H), 4.38 (m, 1H), 6.96-7.01 (m, 3H),
7.25 (d, 2H), 7.43-7.48 (m, 3H), 7.52 (d, 2H), 7.62-7.07 (m, 3H),
7.70 (d, 1H), 7.87 (s, 1H), 8.10 (d, 1H); LC/MS (m/z): 482
(M+1).sup.30.
EXAMPLE 223
3-Biphenyl-4-yl-(2S)-[3-nitro-4-(3-trifluoromethyl-phenoxy)-benzoylamino]--
propionic acid
[0528] ##STR702##
[0529] 3-Nitro-4-(3-trifluoromethyl-phenoxy)-benzoic acid (530 mg,
81%) was prepared from 4-fluoro-3-nitro-benzoic acid (370 mg, 2.0
mmol) and 3-trifluoromethyl phenol (324 mg, 2.0 mmol) as in general
procedure B. To Wang resin (60 mg, 0.06 mmol, 1.1 mmol/g) loaded
with 4-L-biphenylalanine were added 82 mg of (0.25 mmol)
3-nitro-4-(3-trifluoromethyl-phenoxy)-benzoic acid (82 mg, 0.25
mmol), 1.0 M DIC (1.5 mL, 1.5 mmol) in DMF, 1.0 M HOBt (1.5 mL, 1.5
mmol) in DMF, and a catalytic amount of DMAP. The resulting mixture
was left on shaker overnight. The resin was washed with DMF, MeOH,
DCM three times of each and cleaved with 20% TFA in DCM. The
residue obtained after removing the solvent was purified by
chromatography to give the title compound (26 mg, 79%).
[0530] .sup.1H NMR (400 MHz, CDCl.sub.3): 3.35, 3.40 (ABX, 2H),
5.18 (dd, 1H), 6.64 (d, 1H), 7.03 (dd, 2H), 7.28 (m, 1H), 7.34 (m,
2H), 7.42 (m, 2H), 7.55 (m, 5H), 7.91 (dd, 1H), 8.21 (dd, 1H), 8.36
(d, 1H), 8.69 (d, 1H); LC/MS (m/z): 551 (M+1).sup.+.
EXAMPLE 224
[0531]
3-(4'-Trifluoromethyl-biphenyl-4-yl)-(2S)-[4-(4-trifluoromethyl-ph-
enoxy)-benzoylamino]-propionic acid ##STR703##
[0532] 4-(4-Trifluoromethyl-phenoxy)benzoic acid (474 mg, 80%) was
prepared from 1-fluoro-4-trifluoromethyl benzene (328 mg, 2.0 mmol)
and 4-hydroxy benzoic acid methyl ester (304 mg, 2.0 mmol)
following general procedure B, then hydrolyzed following general
procedure C to give the corresponding acid (450 mg, 80%).
3-(4'-Trifluoromethyl-biphenyl-4-yl)-(2S)-[4-(4-trifluoromethyl-phenoxy)--
benzoylamino]-propionic acid methyl ester (121 mg, 82%) was
prepared starting from the above acid (70 mg, 0.25 mmol) and
2-amino-3-(4'-trifluoromethyl-biphenyl-4-yl)-(2S)-propionic acid
methyl ester (108 mg, 0.30 mmol) according to general procedure A.
The ester was hydrolyzed following general procedure C to give the
title compound (105 mg, 89%) .sup.1H NMR (400 MHz, CDCl.sub.3):
3.40 (m, 2H), 5.10 (m, 1H), 6.58 (m, 1H), 7.08 (m, 4H), 7.33 (m,
2H), 7.64 (m, 10H); LC/MS (m/z): 574 (M+1).sup.+.
EXAMPLE 225
3-Biphenyl-4-yl-(2S)-[4-(5-trifluoromethyl-pyridin-2-yloxy)-benzoylamino]--
propionic acid
[0533] 5-(Trifluoromethyl)-2-pyridinol (1.63 g, 10 mmol) was
reacted with 4-fluorobenzaldehyde-(1.24 g, 10 mmol) as described in
general procedure B. The resulting compound was oxidized by
AgNO.sub.3 (20 mmol) in 2N NaOH aq. solution (20 mL, 40 mmol) to
afford 4-(5-(trifluoromethyl-pyridin-2-yloxy)-benzoic acid (5.10 g,
80%) as a white solid.
[0534] 2-L-amino-3-biphenyl-4-yl-propionic acid methyl ester (128
mg, 0.5 mmol) was reacted with above
4-(5-(trifluoromethyl-pyridin-2-yloxy)-benzoic acid (142 mg, 0.5
mmol) as described in general procedure A. The resulting compound
was hydrolyzed according to general procedure C to afford the title
product (225 mg, 80%) as a white solid..sup.1H-NMR(400 MHz,
CDCl.sub.3): 3.21 (dd, 1H), 3.36 (dd, 1H), 5.02 (dd, 1H), 6.74(d,
1H), 7.39-7.27 (m, 8H), 7.56-7.48 (m, 5H),7.67 (s,1H), 7.79 (d,
2H); LC/MS (m/z): 507(M+1).sup.+.
EXAMPLE 226
3-[4-(4-Trifluoromethyl-phenoxy)-phenyl]-(2S)-[(4'-trifluoromethyl-bipheny-
l-4-carbonyl)-amino]-propionic acid
[0535]
3-(4-Hydroxy-phenyl)-(2S)-[(4'-trifluoromethyl-biphenyl-4-carbonyl-
)-amino]-propionic acid methyl ester (664 mg, 75%) was prepared
starting from 4'-trifluoromethyl-biphenyl-4-carboxylic acid (532
mg, 2.0 mmol) and tyrosine methyl ester (462 mg, 2.0 mmol)
according to general procedure A. The above compound (443 mg, 1.0
mmol) was treated with 1-fluoro-4-trifluorobenzene (246 mg, 1.5
mmol) following general procedure B to give
3-[4-(4-trifluoromethyl-phenoxy)-phenyl]-(2S)-[(4'-trifluoromethyl-biphen-
yl-4-carbonyl)-amino]-propionic acid methyl ester (305 mg, 52%).
The ester was hydrolyzed following general procedure C to give the
title compound (296 mg, 99%). .sup.1H NMR (400 MHz, CDCl.sub.3):
3.22, 3.36 (ABX, 2H), 5.04 (dd, 1H), 6.56 (d, 1H), 6.94 (m, 4H),
7.17 (m, 2H), 7.49 (d, 2H), 7.63 (m, 6H), 7.76 (d, 2H); LC/MS
(m/z): 574 (M+1).sup.+.
EXAMPLE 227
3-[4-(4-Cyano-phenoxy)-phenyl]-(2S)-[(4'-trifluoromethyl-biphenyl-4-carbon-
yl)-amino]-propionic acid
[0536]
3-(4-Hydroxy-phenyl)-(2S)-[(4'-trifluoromethyl-biphenyl-4-carbonyl-
)-amino]-propionic acid methyl ester (664 mg, 75%) was prepared
starting from 4'-trifluoromethyl-biphenyl-4-carboxylic acid (532
mg, 2.0 mmol) and tyrosine methyl ester (462 mg, 2.0 mmol)
according to general procedure A. The above compound (443 mg, 1.0
mmol) was treated with 1-fluoro-4-cyanobenzene (181 mg, 1.5 mmol)
following general procedure B to give
3-[4-(4-cyano-phenoxy)-phenyl]-(2S)-[(4'-trifluoromethyl-biphenyl-
-4-carbonyl)-amino]-propionic acid methyl ester (360 mg, 66%). The
ester was hydrolyzed following general procedure C to give the
title compound (345 mg, 99%)
[0537] .sup.1H NMR (400 MHz, CDCl.sub.3): 3.28, 3.44 (ABX, 2H),
5.12 (dd, 1H), 6.65 (d, 1H), 6.99 (m, 4H), 7.28 (m, 2H), 7.58 (d,
2H), 7.69 (m, 6H), 7.84 (d, 2H); LC/MS (m/z): 530 (M+1).sup.+.
EXAMPLE 228
(2S)-(4-Benzyloxy-benzoylamino)-3-biphenyl-4-yl-propionic acid
[0538] 2-L-amino-3-biphenyl-4-yl-propionic acid methyl ester (255
mg, 1.0 mmol) was reacted with 4-(benzyloxy)-benzoic acid (228 mg,
1.0 mmol) as described in general procedure A. The resulting
compound was hydrolyzed according to general procedure C to afford
the title product (370 mg, 82%) as a white solid. .sup.1H-NMR(400
MHz, CDCl.sub.3): 3.31 (dd, 1H), 3.40 (dd, 1H), 5.09-5.05 (m, 3H),
6.56 (d, 1H), 6.96 (d, 2H), 7.36-7.32 (m, 2H), 7.43-7.38 (m, 6H),
7.57-7.52 (m, 4H), 7.67 (d, 2H); LC/MS (m/z): 452(M+1).sup.+.
[0539] By analogous methods to those described above the following
compounds were synthesized TABLE-US-00009 LC/MS EXAMPLE NAME (m/z)
229 3-Biphenyl-4-yl-(2S)-[(4'-trifluoromethyl- 490
biphenyl-3-carbonyl)-amino]-propionic acid 230
3-Biphenyl-4-yl-(2S)-[(3-chloro-4'- 524
trifluoromethyl-biphenyl-4-carbonyl)-amino]- propionic acid 231
3-Biphenyl-4-yl-(2S)-[4-(4-nitro-phenoxy)- 483
benzoylamino]-propionic acid 232
3-Biphenyl-4-yl-(2S)-[4-(3,4-dimethyl- 511
phenoxy)-3-nitro-benzoylamino]-propionic acid 233
3-Biphenyl-4-yl-(2S)-[(3'-trifluoromethyl- 490
biphenyl-4-carbonyl)-amino]-propionic acid 234
3-Biphenyl-4-yl-(2S)-[(3',5'-bis-trifluoromethyl- 558
biphenyl-4-carbonyl)-amino]-propionic acid 235
3-Biphenyl-4-yl-(2S)-[(4'-tert-butyl-biphenyl-4- 478
carbonyl)-amino]-propionic acid 236
3-Biphenyl-4-yl-(2S)-[(4'-dimethylamino- 465
biphenyl-4-carbonyl)-amino]-propionic acid 237
3-Biphenyl-4-yl-(2S)-[(4'-methoxy-biphenyl-4- 452
carbonyl)-amino]-propionic acid 238
3-Biphenyl-4-yl-2-[(3',4'-dichloro-biphenyl-4- 490
carbonyl)-amino]-propionic acid 239
3-Biphenyl-4-yl-(2S)-[(5'-chloro-2'-methoxy- 486
biphenyl-4-carbonyl)-amino]-propionic acid 240
(2S)-[(3'-Amino-biphenyl-4-carbonyl)-amino]- 437
3-biphenyl-4-yl-propionic acid 241
(2S)-[(4'-Trifluoromethoxy-biphenyl-4- 574
carbonyl)-amino]-3-(4'-trifluoromethyl- biphenyl-4-yl)-propionic
acid 242 3-(4'-Trifluoromethoxy-biphenyl-4-yl)-(2S)- 574
[(4'-trifluoromethyl-biphenyl- 4-carbonyl)-amino]-propionic acid
243 3-(4-Pyridin-4-yl-phenyl)-(2S)-[(4'- 491
trifluoromethyl-biphenyl-4-carbonyl)-amino]- propionic acid 244
3-Biphenyl-4-yl-(2S)-[4-(5-trifluoromethyl- 491
pyridin-2-yl)-benzoylamino]-propionic acid 245
3-(4-Pyridin-4-yl-phenyl)-(2S)-[4-(5- 492
trifluoromethyl-pyridin-2-yl)-benzoylamino]- propionic acid 246
3-(4'-Methanesulfonylamino-biphenyl-4-yl)- 583
(2S)-[(4'-trifluoromethyl-biphenyl- 4-carbonyl)-amino]-propionic
acid 247 3-(3'-Chloro-4'-fluoro-biphenyl-4-yl)-(2S)-[(4'- 542
trifluoromethyl-biphenyl- 4-carbonyl)-amino]-propionic acid 248
3-(4'-Cyano-biphenyl-4-yl)-(2S)-[(4'- 515
trifluoromethyl-biphenyl-4-carbonyl)- amino]-propionic acid 249
3-(5-Phenyl-pyridin-2-yl)-2-[(4'- 507
trifluoromethoxy-biphenyl-4-carbonyl)- amino]-propionic acid 250
3-(4'-Amino-biphenyl-4-yl)-(2S)-[(4'- 505
trifluoromethyl-biphenyl-4-carbonyl)-amino]- propionic acid 251
3-(4'-Dimethylamino-biphenyl-4-yl)-(2S)-[(4'- 533
trifluoromethyl-biphenyl-4-carbonyl)-amino]- propionic acid 252
3-(4'-Trifluoromethoxy-biphenyl-4-yl)-(2S)-[4- 575
(5-trifluoromethyl-pyridin-2-yl)-benzoylamino]- propionic acid 253
3-(4'-Trifluoromethyl-biphenyl-4-yl)-(2S)-[4-(5- 559
trifluoromethyl-pyridin-2-yl)-benzoylamino]- propionic acid 254
3-(4'-Trifluoromethoxy-biphenyl-4-yl)-(2S)-[4- 590
(4-trifluoromethyl-phenoxy)-benzoylamino]- propionic acid 255
3-Biphenyl-4-yl-(2S)-[4-(4-trifluoromethyl- 506
phenoxy)-benzoylamino]-propionic acid 256
3-Biphenyl-4-yl-(2S)-[4-(4-formyl-phenoxy)- 466
benzoylamino]-propionic acid 257
3-(5'-Chloro-2'-methoxy-biphenyl-4-yl)-(2S)- 554
[(4'-trifluoromethyl-biphenyl-4-carbonyl)- amino]-propionic acid
258 3-(4'-Chloro-biphenyl-4-yl)-(2S)-[(4'- 524
trifluoromethyl-biphenyl-4-carbonyl)-amino]- propionic acid 259
3-Biphenyl-4-yl-(2R)-[(4'-trifluoromethyl- 490
biphenyl-4-carbonyl)-amino]-propionic acid 260
3-(5-Phenyl-pyridin-2-yl)-2-[(4'-trifluoromethyl- 491
biphenyl-4-carbonyl)-amino]-propionic acid 261
3-(3'-Acetylamino-biphenyl-4-yl)-(2S)-[(4'- 547
trifluoromethyl-biphenyl-4-carbonyl)-amino]- propionic acid 262
3-(3',4'-Dichloro-biphenyl-4-yl)-(2S)-[(4'- 558
trifluoromethyl-biphenyl-4-carbonyl)-amino]- propionic acid 263
3-(5'-Fluoro-2'-methoxy-biphenyl-4-yl)-(2S)- 538
[(4'-trifluoromethyl-biphenyl-4-carbonyl)- amino]-propionic acid
264 3-[4'-(Acetylamino-methyl)-biphenyl-4-yl]- 561
(2S)-[(4'-trifluoromethyl-biphenyl-4-carbonyl)- amino]-propionic
acid 265 3-(4'-Trifluoromethoxy-biphenyl-4-yl)-(2S)-[4- 591
(5-trifluoromethyl-pyridin- 2-yloxy)-benzoylamino]-propionic acid
266 3-Biphenyl-4-yl-(2S)-[4-(5-trifluoromethyl- 507
pyridin-2-yloxy)-benzoylamino]-propionic acid 267
3-[4-(4-Nitro-phenoxy)-phenyl]-(2S)-[(4'- 553
trifluoromethyl-biphenyl-4-carbonyl)-amino]- propionic acid 268
3-[4-(4-Formyl-phenoxy)-phenyl]-(2S)-[(4'- 534
trifluoromethyl-biphenyl-4-carbonyl)-amino]- propionic acid 269
3-(4-Thiophen-3-yl-phenyl)-(2S)-[(4'- 496
trifluoromethyl-biphenyl-4-carbonyl)-amino]- propionic acid 270
3-(4-Thiophen-3-yl-phenyl)-(2S)-[(4'- 512
trifluoromethoxy-biphenyl-4-carbonyl)-amino]- propionic acid 271
(2S)-(4-Benzyloxy-benzoylamino)-3-(4'- 536
trifluoromethoxy-biphenyl-4-yl)-propionic acid 272
3-(2'-Phenoxy-biphenyl-4-yl)-(2S)-[(4'- 537
trifluoromethyl-biphenyl-4-carbonyl)-amino]- propionic acid 273
3-(4'-Phenoxy-biphenyl-4-yl)-(2S)-[(4'- 582
trifluoromethyl-biphenyl-4-carbonyl)-amino]- propionic acid
EXAMPLE 274
3-Biphenyl-4-yl-(2S)-[2-(4-tert-butyl-benzoylamino)-5-iodo-benzoyl-amino]--
propionic acid
[0540]
(2S)-(2-Amino-5-iodo-benzoyl-amino)-3-biphenyl-4-yl-propionic acid
methyl ester (1.53 g, 80%) was prepared from
(2S)-amino-3-biphenyl-4-yl-propionic acid methyl ester (1.0 g, 4.1
mmol), 5-iodo-2-amino-benzoic acid (1.23 g, 4.9 mmol) as described
in general procedure A.
[0541]
3-Biphenyl-4-yl-(2S)-[2-(4-tert-butyl-benzoylamino)-5-iodo-benzoyl-
-amino]-propionic acid methyl ester was prepared as a white solid
from (2S)-(2-amino-5-iodo-benzoyl-amino)-3-biphenyl-4-yl-propionic
acid methyl ester (1.0 g, 2 mmol) prepared above, pyridine (1.58 g,
4 mmol), t-butyl-benzoyl chloride (1.20 g, 2.5 mmol) as described
in general procedure K. The title compound (1.23 g, 100%) as a
white solid ((1.23 g, 100%) was obtained after hydrolysis according
to general procedure C
[0542] .sup.1H-NMR(400 MHz, DMSO-d.sub.6): 1.26 (s, 9H), 3.09-3.19
(m, 1H), 3.21-3.29 (m, 1H), 4.74-4.76 (m, 1H), 7.27-7.29 (m, 1H),
7.42-7.39 (m, 4H),. 7.44-7.57 (m, 7H), 7.67-7.77 (m, 3H), 7.99 (s,
1H), 8.54 (d, 1H), 9.32 (d, 1H), 11.98 (s, 1H); LC/MS (m/z): 647
(M+1).sup.+.
EXAMPLE 275
3-Biphenyl-4-yl-(2S)-{[4-(4-tert-butyl-benzoylamino)-3'-trifluoromethyl-bi-
phenyl-3-carbonyl]-amino}-propionic acid
[0543] Example 274 (100 mg, 0.15 mmol) was reacted with
3-trifluoromethyl phenyl boronic acid (87.5 mg, 4.5 mmol) as
described in general procedure D yielding the title compound (92
mg, 90%) as white solid. LC/MS (m/z): 665 (M+1).sup.+.
EXAMPLE 276
3-Biphenyl-4-yl-(2S)-{[4-(4-tert-butyl-benzoylamino)-4'-nitro-biphenyl-3-c-
arbonyl]-amino}-propionic acid
[0544] Example 274 (100 mg, 0.15 mmol) was reacted with
4-nitro-phenyl boronic acid (77 mg, 4.5 mmol) as described in
general procedure D yielding the title compound (92 mg, 90%) as
white solid. LC/MS (m/z): 642 (M+1).sup.+.
EXAMPLE 277
3-Biphenyl-4-yl-(2S)-{[4-(4-tert-butyl-benzoylamino)-3'-chloro-4'-fluoro-b-
iphenyl-3-carbonyl]-amino}-propionic acid
[0545] Example 274 (100 mg, 0.15 mmol) was reacted with
3-chloro-4-fluoro-phenyl boronic acid (80 mg, 4.5 mmol) as
described in general procedure D yielding the title compound (95
mg, 95%) as a white solid.
[0546] .sup.1H-NMR(400 MHz, DMSO-d.sub.6): 1.28 (s, 9H), 3.09-3.19
(m, 1H), 3.21-3.29 (m, 1H), 4.74-4.76 (m, 1H), 7.27-7.29 (m, 1H),
7.32-7.44 (m, 6H), 7.44-7.57 (m, 7H), 7.50-7.59 (m, 2H), 7.71-7.77
(m, 2H), 7.80-7.86 (m, 2H), 7.88-7.90 (m, 3H), 8.3 (s, 2H), 8.7 (d,
1H), 9.38 (d, 1H), 12.00 (s, 1H); LC/MS (m/z): 647 (M+1).sup.+.
EXAMPLE 278
3-Biphenyl-4-yl-(2S)-[4-(4-tert-butyl-benzoylamino)-5-(4-chloro-3-trifluro-
methyl-phenoxy)-benzoylamino]-propionic acid
[0547] Example 274 (100 mg, 0.15 mmol), 4-chloro-3-trifluoromethyl
phenol (60.4 mg, 0.3 mmol), cesium carbonate (0.3 mmol), Cul (0.15
mmol) were added to 10 mL of toluene containing 4 .ANG. molecular
sieves. The mixture was degassed and filled with nitrogen three
times. This mixture was then heated to reflux under nitrogen and
followed by HPLC until completion of the reaction. The reaction
with diluted with toluene and filtered. The toluene was evaporated,
and the residue was dissolved in ethyl acetate washed with 2M HCl
and then saturated NaCl. The title compound (70 mg, 65%) was
isolated by flash chromatography (silica, 1% MeOH in DCM) as a
white solid. .sup.1H-NMR(400 MHz, CDCl.sub.3): 1.35 (s, 9H),
3.22-3.27 (m, 1H), 3.32-3.37 (m, 1H, 5.03-5.13 (m, 1H), 6.69 (d,
1H), 6.98-7.01 (m, 1H), 7.13-7.18 (m, 4H), 7.28-7.53 (m, 10H), 7.93
(d, 1H), 8.85 (d, 1H), 11.72 (s, 1H); LC/MS (m/z): 715
(M+1).sup.+.
EXAMPLE 279
3-Biphenyl-4-yl-(2S)-[2-(3,5-bis-trifluoromethyl-benzoylamino)-5-bromo-ben-
zoylamino]-propionic acid
[0548] To a solution of fmoc-L-biphenylalanine (40.0 mmol) in DMF
(40 mL) was added Wang resin (16.0 mmol), HOBt (40.0 mmol) in DMF
(40 mL), DIC (40.0 mmol) in DMF (40 mL) and DMAP (0.40 mmol) and
the mixture was shaken overnight. The reaction mixture was drained
and the resin washed with DMF, methanol and DCM (3.times.150 mL
each solvent).
[0549] The resulting resin-bound fmoc-L-biphenylalanine was
deprotected with 20% piperidine in DMF (150 mL) for 2hours. The
reaction mixture was drained and washed with DMF, methanol and DCM
(3.times.150 mL each solvent).
[0550] To the resin-bound L-biphenylalanine (12 mmol), a solution
of 2-amino-5-bromobenzoic acid (30 mmol) in DMF (30 mL), HOBt (30
mmol) in DMF (30 mL) and DIC (30 mmol) in DMF (30 mL) were added
and the mixture was shaken overnight. The reaction mixture was
drained and washed with DMF, methanol and DCM (3.times.150 mL each
solvent).
[0551] To the resin-bound
(S)-2-(2-amino-5-bromo-benzoylamino)-3-biphenyl-4-yl-propionic acid
(0.12 mmol) was added a solution of
3,5-bis-(trifluoromethyl)benzoyl chloride (0.3 mmol) and pyridine
(0.3 mmol) and the mixture agitated for 72 hours. The reaction
mixture was drained and washed with DMF, methanol and DCM
(3.times.5 mL each solvent).
[0552] Resin bound
(S)-3-biphenyl-4-yl-2-[2-(3,5-bistrifluoromethyl-benzoylamino)-5-bromo-be-
nzoylamino]propionic acid was treated with 20% TFA in DCM (2 mL)
for 1 hour. The filtrate was collected and evaporated to give
(S)-3-biphenyl-4-yl-2-[2-(3,5-bis(trifluoromethyl)-benzoylamino)-5-bromo--
benzoylamino]propionic acid (0.0412 g, 50%). The product was
purified via chromatography (silica, DCM/ethyl acetate). LC/MS
(m/z): 680 (M+1).sup.+.
EXAMPLE 280
(2S)-[5-Bromo-(2S)-(2-cyclopentyl-acetylamino)-benzoylamino]-3-(2'-phenoxy-
-biphenyl-4-yl)-propionic acid
[0553]
(S)-(2-Amino-5-bromo-benzoylamino)-3-(2'-phenoxy-biphenyl-4-yl)-pr-
opionic acid methyl ester (1.53 g, 80%) was prepared from
(2S)-Amino-3-(2'-phenoxy-biphenyl-4-yl)-propionic acid methyl ester
HCl salt (1.0 g, 2.6 mmol, 5-bromo-2-amino-benzoic acid (0.5 g, 2.9
mmol) as described in general procedure A.
[0554]
(S-)(2-Amino-5-bromo-benzoylamino)-3-(2'-phenoxy-biphenyl-4-yl)-pr-
opionic acid methyl ester (0.2 g,0.04 mmoml) in 5 ml of DCM was
reacted with cyclopentyl acetyl chloride (82.6 mg, 0.06 mmol) and
pyridine (60 mg, 0.08 mmol) as described in general procedure K.
The resulting ester was hydrolyzed according to the general
procedure C to afford the title compound (0.2 g, 83.3%) as a white
solid. LCMS: 642 (M+1).sup.+. .sup.1H NMR (CDCl.sub.3): 1.1-1.26
[m, 3H], 1.5-1.75 [m, 3H], 1.8-1.90 [m, 2H], 2.2-2.41 [m, 2H], 2.48
[d, 1H], 3.1-3.4 [m, 2H], 5.0-5.1 [m, 1H], 6.6 [d, 1H], 6.89-6.97
[m, 4H], 7.18-7.26 [m, 6H], 7.43-7.52 [m, 5H], 8.48 (d, 1), 10.73
(s, 1H).
EXAMPLE 281
(2S)-[5-Bromo-2-(3,3,5-trimethyl-hexanoylamino)-benzoylamino]-3-(2'-phenox-
y-biphenyl-4-yl)-propionic acid
[0555] A solution of
(2S)-(2-amino-5-bromo-benzoylamino)-3-(2'-phenoxy-biphenyl-4-yl)-propioni-
c acid methyl ester (54.5 mg, 0.10 mmol) from example 294 in 1 mL
dry CH.sub.2Cl.sub.2 was treated with 3,5,5-trimethylhexanoyl
chloride(1.2 eq., 23 microL, 0.12 mmol) and pyridine (1.5 eq., 12
microL, 0.15 mmol) in succession and stirred under an atmosphere of
dry N.sub.2 for one hour, then concentrated in vacuo. The crude
residue was purified by flash column chromatography (hexanes,
EtOAc) to afford the desired amide,
(2S)-[5-Bromo-2-(3,3,5-trimethyl-hexanoylamino)-benzoylamino]-3-(2'-pheno-
xy-biphenyl-4-yl)-propionic acid methyl ester, in quantitative
yield (68 mg, 100%). The methyl ester (20 mg, 29 micromol) was
dissolved in 2.0 mL THF and 0.5 mL MeOH and saponified with 2N
aqueous LiOH solution (0.25 mL), as described in general procedure
C, to afford the title compound,
(2S)-[5-Bromo-2-(3,3,5-trimethyl-hexanoylamino)-benzoylamino]-3-(2'-pheno-
xy-biphenyl-4-yl)-propionic acid (20 mg, 100%), as a white solid.
LCMS 673 (M+1).sup.+. .sup.1H NMR (400 MHz, CDCl.sub.3) 10.74 [s,
1H], 8.51 [d, 1H], 7.51 [m, 3H], 7.43 [m, 2H], 7.27-7.30 [m, 2H],
7.16-7.26 [m, 5H], 6.98 [d, 2H], 6.88 [d, 2H], 5.03 [dd, 1H], 3.28
[dq, 2H], 2.36 [m, 1H], 2.14 [m, 1H], 1.11-125 [m, 3H], 0.92 [s,
3H], 0.91 [d, 6H].
EXAMPLE 282
(2S)-[5-Chloro-2-(4-phenoxy-benzoylamino)-benzoylamino]-3-(2'-isopropoxy-b-
iphenyl-4-yl)-propionic acid
[0556] 2-Amino-5-chloro-benzoic acid (0.702 g, 4.09 mmol) was
coupled with 2-Amino-3-(4-bromo-phenyl)-propionic acid methyl ester
hydrochloride (1 g, 4.09 mmol) using HBTU (1.86 g, 4.908 mmol) and
diisopropylethylamine (1.32 ml, 10.22 mmol) as per general
procedure A to yield the
2-(2-amino-5-chloro-benzoylamino)-3-(4-bromo-phenyl)-propionic acid
methyl ester in 60% yield.
[0557] The above compound (0.500 g, 1.21 mmol) was reacted with
4-phenoxy-benzoyl chloride (0.337 g, 1.45 mmol) in dry
dichloromethane at 0.degree. C. as described in general procedure J
to get
3-(4-Bromo-phenyl)-2-[5-chloro-2-(4-phenoxy-benzoylamino)-benzoylamino]-p-
ropionic acid methyl ester (0.590 g, 80%).
[0558] The above compound (0.100 g, 0.164 mmol) was then subjected
to Suzuki coupling with 2-isopropoxyphenylboronic acid (0.059 g,
0.328 mmol) and with Pd (PPh.sub.3) (0.0189 g, 0.016 mmol) and 2N
Na.sub.2CO.sub.3 (0.410 ml, 0.410 mmol) as per general procedure D
to yield
(2S)-[5-chloro-2-(4-phenoxy-benzoylamino)-benzoylamino]-3-(2'-isopropoxy--
biphenyl-4-yl)-propionic acid methyl ester which was further
hydrolyzed as per general procedure C to give the title compound
(0.050g, 50%)%). .sup.1H-NMR(400 MHz, CDCl.sub.3): 1.56(d, 6H),
3.65(dddd, 2H), 4.76(m, 1H), 5.42(m, 1H), 7.30-7.38(m, 6H),
7.39-7.58(m, 8H), 7.59-7.83(m, 6H), 8.27 (m, 2H), 9.01(d, 1H).
LC/MS (m/z): 649(M+1).
[0559] By analogous methods to those described above the following
compounds were synthesized. TABLE-US-00010 LC/MS EXAMPLE NAME (m/z)
283 3-Biphenyl-4-yl-(2S)-[2-(4-tert-butyl- 521
benzoylamino)-benzoylamino]-propionic acid 284
3-Biphenyl-4-yl-(2S)-[5-chloro-2-(2,4-dichloro- 567
benzoylamino)-benzoylamino]-propionic acid 285
(2S)-({4-[(Biphenyl-4-carbonyl)- 669 amino]-3'-chloro-
4'-fluoro-biphenyl-3-carbonyl}-amino)-3- biphenyl-4-yl-propionic
acid 286 (2S)-{2-[(Biphenyl-4-carbonyl)-amino]- 593
benzoylamino}-3-(3'-chloro-4'-fluoro-biphenyl-4- yl)-propionic acid
287 (2S)-[2-(4-tert-Butyl-benzoylamino)- 573
benzoylamino]-3-(3'-chloro-4'-fluoro-biphenyl-4- yl)-propionic acid
288 3-Biphenyl-4-yl-(2S)-[5-bromo-2-(4-tert-butyl- 600
benzoylamino)-benzoylamino]- propionic acid 289
3-Biphenyl-4-yl-(2S)-{[4-(4-tert-butyl- 622
benzoylamino)-4'-cyano-biphenyl-3-carbonyl]- amino}-propionic acid
290 (2S)-{[4'-Amino-4-(4-tert-butyl-benzoylamino)- 612
biphenyl-3-carbonyl]-amino}-3-biphenyl-4-yl- propionic acid 291
3-Biphenyl-4-yl-(2S)-{[4-(4-tert-butyl- 622
benzoylamino)-3'-cyano-biphenyl-3-carbonyl]- amino}-propionic acid
292 (2S)-({3-[(Biphenyl-4-carbonyl)-amino]- 643
naphthalene-2-carbonyl}-amino)-3-(3'-chloro-4'-
fluoro-biphenyl-4-yl)-propionic acid 293
(2S)-{[3-(4-tert-Butyl-benzoylamino)- 623
naphthalene-2-carbonyl]-amino}-3-(3'-chloro-4'-
fluoro-biphenyl-4-yl)-propionic acid 294
(2S)-{[3'-Aminomethyl-4-(4-tert-butyl- 626
benzoylamino)-biphenyl-3-carbonyl]-amino}-3-
biphenyl-4-yl-propionic acid 295
3-Biphenyl-4-yl-(2S)-{[4-(4-tert-butyl- 639
benzoylamino)-4'-carbamimidoyl-biphenyl-3-
carbonyl]-amino}-propionicacid 296
3-Biphenyl-4-yl-(2S)-[2-(4-tert-butyl- 658
benzoylamino)-5-(4-nitro-phenoxy)- benzoylamino]-propionic acid 297
(2S)-{[4-(4-tert-Butyl-benzoylamino)-3'- 733
trifluoromethyl-biphenyl-3-carbonyl]-amino}-3-
(3'-trifluoromethyl-biphenyl-4-yl)-propionic acid 298
(2S)-{[4-(4-tert-Butyl-benzoylamino)-3'-chloro-4'- 701
fluoro-biphenyl-3-carbonyl]-amino}-3-(3'-chloro-
4'-fluoro-biphenyl-4-yl)-propionic acid 299
(2S)-{[4-(4-tert-Butyl-benzoylamino)-4'- 733
trifluoromethyl-biphenyl-3-carbonyl]-amino}-3-
(4'-trifluoromethyl-biphenyl-4-yl)-propionic acid 300
3-Biphenyl-4-yl-(2S)-[5-bromo-2-(3-phenyl- 570
acryloylamino)-benzoylamino]-propionic acid 301
3-Biphenyl-4-yl-(2S)-{5-bromo-2- 594 [(naphthalene-2-
carbonyl)-amino]-benzoylamino}-propionic acid 302
3-Biphenyl-4-yl-(2S)-[5-bromo-2-(2-cyclopentyl- 550
acetylamino)-benzoylamino]-propionic acid 303
3-Biphenyl-4-yl-(2S)-[5-bromo-2-(4- 628
trifluoromethoxy-benzoylamino)-benzoylamino]- propionic acid 304
3-Biphenyl-4-yl-(2S)-[5-bromo-2-(4-phenoxy- 602
butyrylamino)-benzoylamino]-propionic acid 305
3-Biphenyl-4-yl-(2S)-{5-bromo-2-[2-(4- 630
tert-butyl-phenoxy)-acetylamino]-benzoylamino}- propionic acid 306
(2S)-[2-(4-tert-Butyl-benzoylamino)-5- 647
chloro-benzoylamino]-3-(4'-phenoxy-biphenyl-4- yl)-propionic acid
307 2-[5-Bromo-(2S)-(4-tert-butyl-benzoylamino)- 692
benzoylamino]-3-(4'-phenoxy-biphenyl-4-yl)- propionic acid 308
3-Biphenyl-4-yl-(2S)-[4-chloro-2-(4- 567
trifluoromethyl-benzoylamino)-benzoylamino]- propionic acid 309
3-Biphenyl-4-yl-(2S)-[2-(4-tert-butyl- 681
benzoylamino)-5-(4-trifluoromethyl-phenoxy)-
benzoylamino]-propionic acid 310
3-Biphenyl-4-yl-(2S)-[2-(4-trifluoromethyl- 693
benzoylamino)-5-(4-trifluoromethyl-phenoxy)-
benzoylamino]-propionic acid 311
3-Biphenyl-4-yl-(2S)-[2-(4-tert-butyl- 681
benzoylamino)-4-(4-trifluoromethyl-phenoxy)-
benzoylamino]-propionic acid 312
(2S)-[2-(4-tert-Butyl-benzoylamino)-5- 647
chloro-benzoylamino]-3-(2'-phenoxy-biphenyl-4- yl)-propionic acid
313 (2S)-[5-Chloro-2-(4-phenoxy-benzoylamino)- 683
benzoylamino]-3-(2'-phenoxy-biphenyl-4-yl)- propionic acid 314
(2S)-[2-(4-Benzyloxy-benzoylamino)-5-chloro- 697
benzoylamino]-3-(2'-phenoxy-biphenyl-4-yl)- propionic acid 315
(2S)-(5-Bromo-2-phenylacetylamino- 650
benzoylamino)-3-(2'-phenoxy-biphenyl-4-yl)- propionic acid 316
(2S)-[5-Bromo-2-(4-bromo-benzoylamino)- 715
benzoylamino]-3-(2'-phenoxy-biphenyl-4-yl)- propionic acid 317
(2S)-{5-Bromo-2-[2-(4-fluoro-phenyl)- 668
acetylamino]-benzoylamino}-3-(2'-phenoxy- biphenyl-4-yl)-propionic
acid 318 2-{5-Bromo-(2S)-[(naphthalene-2-carbonyl)- 686
amino]-benzoylamino}-3-(2'-phenoxy-biphenyl-4- yl)-propionic acid
319 (2S)-{5-Bromo-2-[(naphthalene-1-carbonyl)- 686
amino]-benzoylamino}-3-(2'-phenoxy-biphenyl-4- yl)-propionic acid
320 (2S)-[5-Chloro-2-(3-phenoxy-benzoylamino)- 683
benzoylamino]-3-(2'-phenoxy-biphenyl-4-yl)- propionic acid 321
-S-[2-(3-Benzyloxy-benzoylamino)-5-chloro- 697
benzoylamino]-3-(2'-phenoxy-biphenyl-4-yl)- propionic acid 322
(2S)-[5-Bromo-2-(4-phenoxy-benzoylamino)- 728
benzoylamino]-3-(2'-phenoxy-biphenyl-4-yl)- propionic acid 323
(2S)-[5-Bromo-2-(4-hexyl-benzoylamino)- 720
benzoylamino]-3-(2'-henoxy-biphenyl-4-yl)- propionic acid 324
(2S)-[5-Bromo-2-(4-fluoro-benzoylamino)- 654
benzoylamino]-3-(2'-phenoxy-biphenyl-4-yl)- propionic acid 325
(2S)-{5-Bromo-2-[(thiophene- 642 2-carbonyl)-amino]-
benzoylamino}-3-(2'-phenoxy-biphenyl-4-yl)- propionic acid 326
(2S)-[5-Bromo-2-(2-thiophen-2-yl-acetylamino)- 656
benzoylamino]-3-(2'-phenoxy-biphenyl-4-yl)- propionic acid 327
(2S)-[5-Bromo-2-(cyclopropanecarbonyl-amino)- 600
benzoylamino]-3-(2'-phenoxy-biphenyl-4-yl)- propionic acid 328
(2S)-[5-Bromo-2-(cyclobutanecarbonyl-amino)- 614
benzoylamino]-3-(2'-phenoxy-biphenyl-4-yl)- propionic acid 329
(2S)-[5-Bromo-2-(cyclopentanecarbonyl- 628
amino)-benzoylamino]-3-(2'-phenoxy-biphenyl-4- yl)-propionic acid
330 (2S)-[5-Bromo-2-(2-propyl-pentanoylamino)- 658
benzoylamino]-3-(2'-phenoxy-biphenyl-4-yl)- propionic acid 345
(2S)-[5-Bromo-2-(2-phenoxy-propionylamino)- 680
benzoylamino]-3-(2'-phenoxy-biphenyl-4-yl)- propionic acid 332
(2S)-[2-(3,5-Bis-rifluoromethyl-benzoylamino)-5- 727
chloro-benzoylamino]-3-(3'-phenoxy-biphenyl-4- yl)-propionic acid
333 (2S)-[5-Bromo-2-(3,4,5-trimethoxy- 726
benzoylamino)-benzoylamino]-3-(2'-phenoxy- biphenyl-4-yl)-propionic
acid 334 (2S)-{2-[(Adamantane-1-carbonyl)-amino]-5- 694
bromo-benzoylamino}-3-(2'-phenoxy-biphenyl-4- yl)-propionic acid
335 (2S)-(5-Bromo-2-{[1-(4-chloro-phenyl)- 710
cyclopropanecarbonyl]-amino}-benzoylamino)-3-
(2'-phenoxy-biphenyl-4-yl)-propionic acid 336
(2S)-(5-Bromo-2-{[1-(2,4-dichloro-phenyl)- 744
cyclopropanecarbonyl]-amino}-benzoylamino)-3- (2'-phenoxy-biphenyl-
4-yl)-propionic acid 337 (2S)-{5-Bromo-2-[(2,2-dichloro-1-methyl-
682 cyclopropanecarbonyl)-amino]-benzoylamino}-3-
(2'-phenoxy-biphenyl-4- yl)-propionic acid 338
(2S)-{5-Chloro-2-[(6-chloro-pyridine-3-carbonyl)- 626
amino]-benzoylamino}-3-(2'-phenoxy-biphenyl-4- yl)-propionic acid
339 (2S)-(5-Chloro-2-{[1-(4- 744 trifluoromethyl-pyrimidin-
2-yl)-piperidine-4-carbonyl]- amino}-enzoylamino)-
3-(2'-phenoxy-biphenyl-4-yl)-propionic acid 340
(2S)-{5-Bromo-2-[(1-phenyl- 676
cyclopropanecarbonyl)-amino]-benzoylamino}-3-
(2'-phenoxy-biphenyl-4-yl)-propionic acid 341
(2S)-{5-Bromo-2-[(2-phenyl- 676
cyclopropanecarbonyl)-amino]-benzoylamino}-3-
(2'-phenoxy-biphenyl-4-yl)-propionic acid 342
(2S)-[5-Chloro-2-(2-phenoxy-benzoylamino)- 683
benzoylamino]-3-(2'-phenoxy-biphenyl-4-yl)- propionic acid 343
3-(2'-Benzyloxy-biphenyl-4-yl)-(2S)-[2-(3,5-bis- 741
trifluoromethyl-benzoylamino)-5-chloro- benzoylamino]-propionic
acid 344 (2S)-{5-Chloro-2[(6-phenoxy-pyridine-3- 684
carbonyl)-amino]-benzoylamino}-3-
(2'-phenoxy-biphenyl-4-yl)-propionic acid 345
(2S)-[5-Chloro-2-(4-phenoxy-benzoylamino)- 675
benzoylamino]-3-(2'-cyclopentyloxy-biphenyl-4- yl)-propionic acid
346 (2S)-[5-Chloro-2-(4-phenoxy-benzoylamino)- 765
benzoylamino]-3-[2'-(4-trifluoromethyl-
benzyloxy)-biphenyl-4-yl]-propionic acid 347
3-[2'-(4-tert-Butyl-benzyloxy)- 753 biphenyl-4-yl]-(2S)-
[5-chloro-2-(4-phenoxy-benzoylamino)- benzoylamino]-propionic acid
348 (2S)-[5-Chloro-2-(4-[1,2,3]thiadiazol-4-yl- 675
benzoylamino)benzoylamino]-3-(2'-phenoxy- biphenyl-4-yl)-propionic
acid 349 (2S)-{5-Chloro-2-[4-(pyridin-4-ylmethoxy)- 698
benzoylamino]-benzoylamino}-3-(2'-phenoxy- biphenyl-4-yl)-propionic
acid 350 (2S)-(5-Chloro-2-{[1-(4-chloro-phenyl)-5- 759
trifluoromethyl-1H-pyrazole-4-carbonyl]-amino}-
benzoylamino)-3-(2'-phenoxy-biphenyl-4-yl)- propionic acid 351
(2S)-(5-Chloro-2-{[1-(4-chloro-phenyl)-5-propyl- 733
1H-pyrazole-4-carbonyl]-amino}-benzoylamino)-
3-(2'-phenoxy-biphenyl-4-yl)-propionic acid 352
(2S)-[5-Bromo-2-(3-phenyl-propionylamino)- 664
benzoylamino]-3-(2'-phenoxy-biphenyl-4-yl)- propionic acid 353
(2S)-[2-(3,5-Bis-trifluoromethyl-benzoylamino)- 796
5-chloro-benzoylamino]-3-[2'-(4-pentyl-
phenoxy)-biphenyl-4-yl]-propionic acid 354
(2S)-{2-[(Benzofuran-2-carbonyl)-amino]-5- 676
bromo-benzoylamino}-3-(2'-phenoxy-biphenyl-4- yl)-propionic acid
355 (2S)-{2-[(Benzo[b]thiophene-2-carbonyl)-amino]- 692
5-bromo-benzoylamino}-3-(2'-phenoxy-biphenyl- 4-yl)-propionic acid
356 (2S)-{5-Bromo-2-[(3-chloro-benzo[b]thiophene-2- 726
carbonyl)-amino]-benzoylamino}-3-(2'-phenoxy-
biphenyl-4-yl)-propionic acid
EXAMPLE 357
(2S)-{(3,5-Bis-trifluoromethyl-benzoyl)-pentyl-amino]-5-chloro-benzoylamin-
o}-3-(2'-phenoxy-phenyl-4-yl)-propionic acid
[0560] (2S)-amino-3-(2'-phenoxy-biphenyl-4-yl-propionic acid methyl
ester (192 mg, 0.5 mmol), which was prepared in the general section
of syntheses of amino acids, was reacted with 5-bromoanthranilic
acid (90 mg, 0.5 mmol) as described in general procedure A. The
resulting crude compound was alkylated by valeraldehyde (86 mg, 1.0
mmol) as described in general reductive amination procedure E. The
purified compound was reacted with 3,5-bis(trifluoromethyl)benzoyl
chloride (210 mg, 0.75 mmol) as described in general procedure F.
The resulting compound was hydrolyzed according to general
procedure C to afford the title product (200 mg, 50%) as a white
solid. .sup.1H-NMR(400 MHz, CDCl.sub.3): 0.86 (t, 3H), 3.71-2.91
(m, 8H), 4.29-4.23 (m, 1H), 4.85 (broad, 1H), 5.09-4.99 (m, 1H),
6.91-6.87 (m, 2H), 7.03-6.96 (m, 2H), 7.30-7.15 (m, 8H), 7.59-7.35
(m, 4H), 8.11-7.91 (m, 2H), 8.52 (s, 1H) LC/MS (m/z):
797(M+1).sup.-.
EXAMPLE 358
(2S)-{2-[(Biphenyl-4-carbonyl)-(4-methyl-benzyl)-amino]-5-chloro-benzoylam-
ino}-3-biphenyl-4-yl-propionic acid
[0561] To the resin-bound L-biphenylalanine (1.2 mmol) which was
made in example 279, a solution of 2-amino-5-chloro benzoic acid
(3.0 mmol), HOBt (30 mmol), DIC (30 mmol) and DMAP (0.03 mmol) in
DMF (30 mL) were added and the mixture was shaken overnight. The
reaction mixture was drained and washed with DMF, methanol and DCM
(3.times.150 mL each solvent).
[0562] To the resin-bound
(2S)-(2-amino-5-chloro-benzoylamino)-3-biphenyl-4-yl-propionic acid
(0.12 mmol) synthesized above was suspended in DCE (5 mL) was added
4-methyl benzaldehyde (0.6 mmol), acetic acid (0.6 mmol) and sodium
cyanoborohydride (1.2 mmol) and the mixture was shaken overnight.
Upon completion of the reaction, the reaction mixture was drained
and washed with DMF, methanol and DCM (3.times.5 mL each
solvent).
[0563] To the resin-bound
3-Biphenyl-4-yl-(2S)-[5-chloro-2-(4-methyl-benzylamino)-benzoylamino]-pro-
pionic acid (0.12 mmol) was added a solution of Biphenyl-4-carbonyl
chloride (0.3 mmol) and pyridine (0.3 mmol) and the mixture
agitated for 24 hours. The reaction mixture was drained and washed
with DMF, methanol and DCM (3.times.5mL each solvent).
[0564] Resin bound
2S-{2-[(Biphenyl-4-carbonyl)-(4-methyl-benzyl)-amino]-5-chloro-benzoylami-
no}-3-biphenyl-4-yl-propionic acid was treated with 20% TFA in DCM
(2 mL) for 1 hour. The filtrate was collected and evaporated to
give 10 mg of the title compound with 95% purity. LC/MS (m/z): 679
(m+1).sup.+
[0565] By analogous methods to those described above the following
Examples were synthesized. TABLE-US-00011 LC/MS EXAMPLE NAME (m/z)
359 3-Biphenyl-4-yl-(2S){5-chloro-2-[(3,5-dichloro- 671
benzoyl)-(4-methyl-benzyl)-amino]- benzoylamino}-propionic acid 360
(2S)-{2-[(Biphenyl-4-carbonyl)-(3-phenyl- 693
propyl)-amino]-5-chloro-benzoylamino}-3- biphenyl-4-yl-propionic
acid 361 3-Biphenyl-4-yl-(2S)-{5-chloro-2-[(2,4- 685
dichloro-benzoyl)-(3-phenyl-propyl)-amino]- benzoylamino}-propionic
acid 362 (2S)-{2-[(Biphenyl-4-carbonyl)-biphenyl-4- 741
ylmethyl-amino]-5-chloro-benzoylamino}-3- biphenyl-4-yl-propionic
acid 363 3-Biphenyl-4-yl-(2S)-{2-[biphenyl-4-ylmethyl- 733
(2,4-dichloro-benzoyl)-amino]-5-chloro- benzoylamino}-propionic
acid 364 (2S)-{2-[(Biphenyl-4-carbonyl)-(4-isopropyl- 707
benzyl)-amino]-5-chloro-benzoylamino}-3-
biphenyl-4-yl-propionicacid 365
(2S)-{2-[(Biphenyl-4-carbonyl)-(4-isopropoxy- 723
benzyl)-amino]-5-chloro-benzoylamino}-3- biphenyl-4-yl-propionic
acid 366 (2S)-{5-Bromo-2-[(2-methyl-butyl)-(4- 798
phenoxy-benzoyl)-amino]-benzoylamino}-3-
(2'-phenoxy-biphenyl-4-yl)-propionic acid
EXAMPLE 367
(2S)-[5-Chloro-2-(5-dibutylamino-naphthalene-1-sulfonylamino)-benzoylamin
o]-3-(2'-phenoxy-biphenyl-4-yl)-propionic acid methyl ester
[0566] A solution of
2-(2-amino-5-chloro-benzoylamino)-3-(2'-phenoxy-biphenyl-4-yl)-propionic
acid (0.05 g, 0.1 mmol) [ prepared by reacting
(2S)-amino-3-(2'-phenoxy-biphenyl4-yl) propionic acid methyl ester
hydrochloride salt and 2-amino-5-chlorobenzoic acid by general
procedure A ] in CH.sub.2Cl.sub.2 was treated with (0.035 g, 0.1
mmol) of bansyl chloride according to the general procedure F.
Product was purified by flash column chromatography on silicagel
using ethyl acetate hexanes to give product as pale yellow solid
(0.06 g, 74.0% yield).
[0567] .sup.1HNMR (400 MHz, CDCl.sub.3) :0.8 (t, 6H), 1.14-1.28 (m,
4H), 1.34-1.44 (m, 4H), 2.98-3.11 (m, 5H), 3.16 (dd, 1H), 3.73 (s,
3H), 4.91 (dd, 1H), 6.42 (d,1H), 6.88 (d, 2H), 6.93-7.20 (m, 4H),
7.16-7.32 (m, 7H), 7.40-7.47 (m, 4H), 7.54-7.61 (m, 2H), 8.24-8.29
(m, 1H), 8.35 (d, 1H), 8.56 (d, 1H), 11.11 (s, 1H).
[0568] LC/MS (m/z): 818.3 (M+1).sup.+.
EXAMPLE 368
(2S)-[5-Bromo-2-(4-tert-butyl-benzenesulfonylamino)-benzoylamino]-3-(2'-ph-
enoxy-biphenyl-4-yl)-propionic acid
[0569] A solution of
2-(2-amino-5-bromo-benzoylamino)-3-(2'-phenoxy-biphenyl-4-yl)-propionic
acid (0.06 g, 0.11 mmol) [prepared by reacting
(2S)-amino-3-(2'-phenoxy-biphenyl-4-yl) propionic acid methyl ester
hydrochloride salt and 2-amino-5-bromobenzoic acid by general
procedure A]] in CH.sub.2Cl.sub.2 was treated with of
4-tert-butylbenzenesulfonyl chloride (0.025 g, 0.11 mmol) according
to the general procedure F. Product was purified by flash column
chromatography on silicagel using ethyl acetate hexanes to give
product as white solid (0.065 g, 79.6% yield).
[0570]
2-[5-Bromo-2-(4-t-butyl-benzenesulfonylamino)-benzoylamino]-3-(2'--
phenoxy-biphenyl-4-yl) propionic acid methyl ester (0.04 g, 0.054
mmol) was treated with LiOH (2 eq, 1N aqueous solution) according
to the general procedure C to give 0.034 g (87.0%) of
2-[5-Bromo-2-(4-t-butyl-benzenesulfonylamino)-benzoylamino]-3-(2'-phenoxy-
-biphenyl-4-yl) propionic acid.
[0571] .sup.1HNMR (400 MHz, DMSO-d6): 1.2 (s, 9H) 3.04 (dd, 1H),
3.21 (dd, 1H), 4.58-4.70 (M, 1H), 6.83-6.87 (m, 2H), 6.94-6.99 (m,
2H), 7.20-7.39 (m, 6H), 7.42-7.49 (m, 4H), 7.51-7.56 (m, 2H),
7.64-7.72 (m, 3H), 7.86 (d, 1H), 9.29 (d, 1H), 11.38 (s, 1H), 13.06
(s, 1H) LC/MS (m/z): 727.1 (M+1).sup.+.
EXAMPLE 369
(2S)-[5-Bromo-2-(4-tert-butyl-benzenesulfonylamino)-benzoylamino]-3-(4'-ph-
enoxy-biphenyl-4-yl)-propionic acid
[0572] To a mixture of (L)-4-bromophenylalanine (8.55, 35.0 mmol),
2-phenoxyphenyl boronic acid (10.00 g, 46.73 mmol), and palladium
tetrakis-triphenylphosphine (4.0 g, 10% mmol) were added DME (140
mL) and 2N Na.sub.2CO.sub.3 aq. solution (70 mL, 140 mmol). The
resulting mixture was heated at 90.degree. C. under N.sub.2 for 20
h. While the reaction solution was hot, the aqueous layer was
removed and the top organic layer was concentrated. The residue was
neutralized with HCl and washed with diethyl ether, and then, was
dissolved in methanol and the insoluble solid was removed by
filtration. The methanol filtrate was refluxed with HCl/Ether for 6
h. After removal of solvents, the solid was washed with ether to
afford (2S)-amino-3-(4'-phenoxy-biphenyl-4-yl-propionic acid methyl
ester in HCl salt form (11.0 g, 28.65 mmol, 82% yield).
[0573] (2S)-amino-3-(4'-phenoxy-biphenyl-4-yl-propionic acid methyl
ester (192 mg, 0.5 mmol) was reacted with 5-bromoanthranilic acid
(110 mg, 0.5 mmol) as described in general procedure A. The
resulting crude compound was sulfonylated by
4-tert-butylbenzenesulfonyl chloride (175 mg, 0.75 mmol) as
described in general procedure F. The resulting compound was
hydrolyzed according to general procedure C to afford the title
product (219 mg, 60%) as a white solid. .sup.1H-NMR(400 MHz,
CDCl.sub.3): 1.25 (s, 9H), 3.25 (dd, 1H), 3.35 (dd, 1H), 5.01 (dd,
1H), 6.62 (d, 1H), 7.05-7.03 (m, 4H), 7.12(t,1H), 7.21 (d, 2H),
7.45-7.33 (m, 6H), 7.54-7.49 (m, 5H), 7.60 (d, 2H), 10.61 (s, 1H)
LC/MS (m/z): 727(M+1).sup.+.
EXAMPLE 370
3-Biphenyl-4-yl-(2S)-[2-(3,4-dichloro-benzenesulfonylamino)-5-iodo-benzoyl-
amino]-propionic acid
[0574] To the resin-bound L-biphenylalanine (1.2 mmol) which was
made in example 279, a solution of 2-amino-5-iodo benzoic acid (3.0
mmol), HOBt (30 mmol), DIC (30 mmol) and DMAP (0.03 mmol) in DMF
(30 mL) were added and the mixture was shaken overnight. The
reaction mixture was drained and washed with DMF, methanol and DCM
(3.times.150 mL each solvent).
[0575] To the resin-bound
(2S)-(2-amino-5-iodo-benzoylamino)-3-biphenyl-4-yl-propionic acid
(0.12 mmol) was added a solution of 3,4-dichloro benzenesulfonyl
chloride (0.3 mmol) and pyridine (0.3 mmol) in 5 ml of DCM and the
mixture agitated for 24 hours. The reaction mixture was drained and
washed with DMF, methanol and DCM (3.times.5 mL each solvent).
[0576] Resin bound
3-Biphenyl-4-yl-(2S)-[2-(3,4-dichloro-benzenesulfonylamino)-5-iodo-benzoy-
lamino]-propionic acid was treated with 20% TFA in DCM (2mL) for 1
hour. The filtrate was collected and evaporated to give 10 mg of
the title compound with 95% purity. LC/MS (m/z): 695
(m+1).sup.+
EXAMPLE 371
(2S)-{2-[(Biphenyl-4-sulfonyl)-(4-methyl-benzyl)-amino]-5-chloro-benzoylam-
ino}-3-biphenyl-4-yl-propionic acid
[0577] To the resin-bound
3-Biphenyl-4-yl-(2S)-[5-chloro-2-(4-methyl-benzylamino)-benzoylamino]-pro-
pionic acid (0.12 mmol) prepared in example 358 was added a
solution of biphenyl-4-sulfonyl chloride (0.3 mmol) and pyridine
(0.3 mmol) and the mixture agitated for 72 hours. The reaction
mixture was drained and washed with DMF, methanol and DCM
(3.times.5 mL each solvent).
[0578] Resin bound
(2S)-{2-[(biphenyl-4-sulfonyl)-(4-methyl-benzyl)-amino]-5-chloro-benzoyla-
mino}-3-biphenyl-4-yl-propionic acid was treated with 20% TFA in
DCM (2 mL) for 1 hour. The filtrate was collected and evaporated to
give 10 mg of the title compound with 95% purity. LC/MS (m/z): 715
(m+1).sup.+
[0579] By analogous methods to those described above the following
compounds were synthesized. TABLE-US-00012 LC/MS EXAMPLE NAME (m/z)
372 (2S)-[2-(Biphenyl-4-sulfonylamino)-5- 611
chloro-benzoylamino]-3-biphenyl-4-yl- propionic acid 373
3-Biphenyl-4-yl-(2S)[2-(4-tert-butyl- 683
benzenesulfonylamino)-5-iodo- benzoylamino]-propionic acid 374
3-Biphenyl-4-yl-(2S){[4-(4-tert-butyl- 685
benzenesulfonylamino)-3'-chloro-4'-fluoro-
biphenyl-3-carbonyl]-amino}-propionic acid 375
3-Biphenyl-4-yl-(2S)[5-iodo-2-(2,4,5- 729
trichloro-benzenesulfonylamino)-benzoylamino]- propionic acid 376
3-Biphenyl-4-yl-(2S)-[2-(2,5-dichloro- 695
benzenesulfonylamino)-5-iodo- benzoylamino]-propionic acid 377
3-Biphenyl-4-yl-(2S)-[2-(2,4-difluoro- 663
benzenesulfonylamino)-5-iodo- benzoylamino]-propionic acid 378
3-Biphenyl-4-yl-(2S)-[5-iodo-2-(4-propyl-
benzenesulfonylamino)-benzoylamino]- propionic acid 379
3-Biphenyl-4-yl-(2S)-(5-iodo-2- 697
pentamethylbenzenesulfonylamino- benzoylamino)-propionic acid 380
3-Biphenyl-4-yl-(2S)-[5-iodo-2-(toluene-4-
sulfonylamino)-benzoylamino]-propionic acid 381
3-Biphenyl-4-yl-(2S)-[2-(4-bromo- 706 benzenesulfonylamino)-5-iodo-
benzoylamino]-propionic acid 382 3-Biphenyl-4-yl-(2S)-[5-iodo-2-
677 (naphthalene-2-sulfonylamino)- benzoylamino]-propionic acid 383
3-Biphenyl-4-yl-(2S)-[5-bromo-2-(4-tert- 636
butyl-benzenesulfonylamino)- benzoylamino]-propionic acid 384
2-[5-Acetylamino-(2S)-(4-tert-butyl- 614
benzenesulfonylamino)-benzoylamino]-3- biphenyl-4-yl-propionic acid
385 3-Biphenyl-4-yl-(2R)-[5-bromo-2-(4-tert- 650
butyl-benzenesulfonylamino)- benzoylamino]-propionic acid methyl
ester 386 3-Biphenyl-4-yl-(2S)-[5-bromo-2-(6- 665
morpholin-4-yl-pyridine-3-sulfonylamino)- benzoylamino]-propionic
acid 387 3-Biphenyl-4-yl-(2S)-[5-bromo-2-(4-vinyl- 606
benzenesulfonylamino)-benzoylamino]- propionic acid 388
3-Biphenyl-4-yl-(2S)-[5-bromo-2-(3,4- 648
dichloro-benzenesulfonylamino)- benzoylamino]-propionic acid 389
3-Biphenyl-4-yl-(2S)-[5-bromo-2-(4-nitro- 625
benzenesulfonylamino)-benzoylamino]- propionic acid 390
3-Biphenyl-4-yl-(2S)-[5-bromo-2-(2-phenyl- 608
ethenesulfonylamino)-benzoylamino]- propionic acid 391
3-Biphenyl-4-yl-(2S)-{5-bromo-2-[5-(5- 721
trifluoromethyl-isoxazol-3-yl)-thiophene-2-
sulfonylamino]-benzoylamino}-propionic acid 392
3-Biphenyl-4-yl-(2S)-[5-bromo-2-(4-bromo- 659
benzenesulfonylamino)-benzoylamino]- propionic acid 393
3-Biphenyl-4-yl-(2S)-[5-bromo-2-(3,4- 640
dimethoxy-benzenesulfonylamino)- benzoylamino]-propionic acid 394
(2S)-[2-(4-Acetylamino- 637 benzenesulfonylamino)-5-bromo-
benzoylamino]-3-biphenyl-4-yl-propionic acid 395
3-Biphenyl-4-yl-(2S)-[5-bromo-2-(4- 622
isopropyl-benzenesulfonylamino)- benzoylamino]-propionic acid 396
3-Biphenyl-4-yl-(2S)-[5-bromo-2-(2,5- 648
dichloro-benzenesulfonylamino)- benzoylamino]-propionic acid 397
3-Biphenyl-4-yl-(2S)-[5-bromo-2-(2- 664
rifluoromethoxy-benzenesulfonylamino)- benzoylamino]-propionic acid
398 (2S)-[5-Bromo-2-(5-dibutylamino- 849
naphthalene-1-sulfonylamino)-
benzoylamino]-3-(4'-phenoxy-biphenyl-4- yl)-propionic acid 399
(2S)-[5-Chloro-2-(5-dibutylamino- 804 naphthalene-1-sulfonylamino)-
benzoylamino]-3-(2'-phenoxy-biphenyl-4- yl)-propionic acid 400
(2S)-[5-Chloro-2-(5-dimethylamino- 734
naphthalene-1-sulfonylamino)-
benzoylamino]-3-(2'-phenoxy-biphenyl-4- yl)-propionic acid methyl
ester 401 (2S)-[5-Bromo-2-(5-dimethylamino- 780
naphthalene-1-sulfonylamino)-
benzoylamino]-3-(2'-phenoxy-biphenyl-4- yl)-propionic acid methyl
ester 402 (2S)-[5-Chloro-2-(5-dimethylamino- 720
naphthalene-1-sulfonylamino)-
benzoylamino]-3-(2'-phenoxy-biphenyl-4- yl)-propionic acid 403
(2S)-[5-Bromo-2-(5-dimethylamino- 765 naphthalene-1-sulfonylamino)-
benzoylamino]-3-(2'-phenoxy-biphenyl-4- yl)-propionic acid 404
(2S)-[5-Bromo-2-(5-dibutylamino- 849 naphthalene-1-sulfonylamino)-
benzoylamino]-3-(2'-phenoxy-biphenyl-4- yl)-propionic acid 405
(2S)-(2-Benzenesulfonylamino-5-chloro- 641
benzoylamino)-3-(2'-phenoxy-biphenyl-4- yl)-propionic acid methyl
ester 406 (2S)-(2-Benzenesulfonylamino-5-chloro- 627
benzoylamino)-3-(2'-phenoxy-biphenyl-4- yl)-propionic acid 407
(2S)-[5-Chloro-2-(naphthalene-1- 691
sulfonylamino)-benzoylamino]-3-(2'-
phenoxy-biphenyl-4-yl)-propionic acid methyl ester 408
(2S)-[5-Chloro-2-(naphthalene-1- 677
sulfonylamino)-benzoylamino]-3-(2'-
phenoxy-biphenyl-4-yl)-propionic acid 409
(2S)-[5-Chloro-2-(naphthalene-2- 691
sulfonylamino)-benzoylamino]-3-(2'-
phenoxy-biphenyl-4-yl)-propionic acid methyl ester 410
(2S)-[5-Chloro-2-(naphthalene-2- 677
sulfonylamino)-benzoylamino]-3-(2'-
phenoxy-biphenyl-4-yl)-propionic acid 411 (2S)-[2-(4-tert-Butyl-
697 benzenesulfonylamino)-5-chloro- benzoylamino]-3-(2'-
phenoxy-biphenyl-4-yl)-propionic acid methyl ester 412
(2S)-[2-(4-tert-Butyl- 683 benzenesulfonylamino)-5-chloro-
benzoylamino]-3-(2'-phenoxy-biphenyl-4- yl)-propionic acid 413
(2S)-[2-(Biphenyl-4-sulfonylamino)-5-chloro- 717
benzoylamino]-3-(2'-phenoxy- biphenyl-4-yl)-propionic acid methyl
ester 414 (2S)-[2-(Biphenyl-4-sulfonylamino)-5- 703
chloro-benzoylamino]-3-(2'-phenoxy- biphenyl-4-yl)-propionic acid
415 (2S)-[5-Chloro-2-(quinoline-8- 692
sulfonylamino)-benzoylamino]-3-(2'-
phenoxy-biphenyl-4-yl)-propionic acid methyl ester 416
(2S)-[5-Chloro-2-(quinoline-8- 678
sulfonylamino)-benzoylamino]-3-(2'-
phenoxy-biphenyl-4-yl)-propionic acid 417
(2S)-[5-Chloro-2-(5-chloro-1,3-dimethyl-1H- 679
pyrazole-4-sulfonylamino)-benzoylamino]-3-
(2'-phenoxy-biphenyl-4-yl)-propionic acid 418
(2S)-[5-Chloro-2-(1-methyl-1H-imidazole- 631
4-sulfonylamino)-benzoylamino]-3-
(2'-phenoxy-biphenyl-4-yl)-propionic acid 419
(2S)-[5-Chloro-2-(6-phenoxy-pyridine-3- 720
sulfonylamino)-benzoylamino]-3-(2'-
phenoxy-biphenyl-4-yl)-propionic acid 420
(2S)-[5-Chloro-2-(4-pyrazol-1-yl- 693
benzenesulfonylamino)-benzoylamino]-3-
(2'-phenoxy-biphenyl-4-yl)-propionic acid 421
(2S)-[5-Chloro-2-(5-chloro-1,3-dimethyl-1H- 693
pyrazole-4-sulfonylamino)-benzoylamino]-3- (2'-phenoxy-biphenyl-4-
yl)-propionic acid methyl ester 422
(2S)-{5-Chloro-2-[3-(5-methyl-[1,3,4]oxadiazol- 723
2-yl)-benzenesulfonylamino]-
benzoylamino}-3-(2'-phenoxy-biphenyl-4- yl)-propionic acid methyl
ester 423 (2S)-[5-Chloro-2-(6-phenoxy-pyridine-3- 734
sulfonylamino)-benzoylamino]-3-(2'-
phenoxy-biphenyl-4-yl)-propionic acid methyl ester 424
(2S)-[5-Chloro-2-(4-pyrazol-1-yl- 707
benzenesulfonylamino)-benzoylamino]-3-
(2'-phenoxy-biphenyl-4-yl)-propionic acid methyl ester 425
(2S)-[5-Chloro-2-(1-methyl-1H-imidazole-4- 645
sulfonylamino)-benzoylamino]-3-(2'-
phenoxy-biphenyl-4-yl)-propionic acid methyl ester 426
(2S)-[5-Chloro-2-(3,5-dimethyl-isoxazole-4- 660
ulfonylamino)-benzoylamino]-3-(2'- phenoxy-biphenyl-4-yl)-propionic
acid ethyl ester 427 (2S)-[5-Chloro-2-(6-morpholin-4-yl-pyridine-
727 3-sulfonylamino)-benzoylamino]-3-(2'-
phenoxy-biphenyl-4-yl)-propionic acid methyl ester 428
(2S)-[5-Chloro-2-(6-morpholin-4-yl-pyridine- 713
3-sulfonylamino)-benzoylamino]-3-(2'-
phenoxy-biphenyl-4-yl)-propionic acid 429
(2S)-{5-Chloro-2-[5-(2-methylsulfanyl- 771
pyrimidin-4-yl)-thiophene-2-sulfonylamino]-
benzoylamino}-3-(2'-phenoxy-biphenyl-4- yl)-propionic acid methyl
ester 430 (2S)-{5-Chloro-2-[5-(2-methylsulfanyl- 757
pyrimidin-4-yl)-thiophene-2-sulfonylamino]-
benzoylamino}-3-(2'-phenoxy-biphenyl-4- yl)-propionic acid 431
(2S)-{5-Chloro-2-[4-(5-methyl- 709 [1,3,4]oxadiazol-2-yl)-
benzenesulfonylamino]-benzoylamino}-3-
(2'-phenoxy-biphenyl-4-yl)-propionic acid 432
3-Biphenyl-4-yl-(2S)-[2-(2,5-dichloro- 709
benzenesulfonylamino)-5-iodo- benzoylamino]-propionic acid methyl
ester 433 3-Biphenyl-4-yl-(2S)-[2-(4-bromo- 720
benzenesulfonylamino)-5-iodo- benzoylamino]-propionic acid methyl
ester 434 3-Biphenyl-4-yl-(2S)-[2-(3,5-bis- 671
trifluoromethyl-benzenesulfonylamino)-5-
chloro-benzoylamino]-propionic acid 435
(2S)-[5-Chloro-2-(4-oxazol-5-yl- 708
benzenesulfonylamino)-benzoylamino]-3-
(2'-phenoxy-biphenyl-4-yl)-propionic acid methyl ester 436
(2S)-[5-Chloro-2-(4-oxazol-5-yl- 694
benzenesulfonylamino)-benzoylamino]-3-(2'-
phenoxy-biphenyl-4-yl)-propionic acid 437
(2S)-[5-Chloro-2-(4-phenoxy- 733
benzenesulfonylamino)-benzoylamino]-3-
(2'-phenoxy-biphenyl-4-yl)-propionic acid methyl ester 438
(2S)-[5-Chloro-2-(4-phenoxy- 719
benzenesulfonylamino)-benzoylamino]-3-
(2'-phenoxy-biphenyl-4-yl)-propionic acid 439
(2S)-[5-Chloro-2-(3-nitro- 672
benzenesulfonylamino)-benzoylamino]-3-
(2'-phenoxy-biphenyl-4-yl)-propionic acid 440
(2S)-[2-(3,5-Bis-trifluoromethyl- 777
benzenesulfonylamino)-5-chloro-
benzoylamino]-3-(2'-phenoxy-biphenyl-4- yl)-propionic acid methyl
ester 441 (2S)-[2-(3,5-Bis-trifluoromethyl- 763
benzenesulfonylamino)-5-chloro-
benzoylamino]-3-(2'-phenoxy-biphenyl-4- yl)-propionic acid 442
(2S)-[2-(3-Amino-benzenesulfonylamino)- 656
5-chloro-benzoylamino]-3-(2'-phenoxy-
biphenyl-4-yl)-propionic acid methyl ester 443
(2S)-{5-Chloro-2-[5-(2-methyl-5- 795
trifluoromethyl-2H-pyrazol-3-yl)-thiophene-
2-sulfonylamino]-benzoylamino}-3-
(2'-phenoxy-biphenyl-4-yl)-propionic acid methyl ester 444
(2S)-{5-Chloro-2-[5-(2-methyl-5- 781
trifluoromethyl-2H-pyrazol-3-yl)-thiophene-
2-sulfonylamino]-benzoylamino}-3-
(2'-phenoxy-biphenyl-4-yl)-propionic acid 445
3-Biphenyl-4-yl-(2S)-[5-chloro-2-(5- 726
dibutylamino-naphthalene-1-sulfonylamino)- enzoylamino]-propionic
acid methyl ester 446 3-Biphenyl-4-yl-(2S)-[5-chloro-2-(5- 712
dibutylamino-naphthalene-1-sulfonylamino)- benzoylamino]-propionic
acid 447 (2S)-[5-Bromo-2-(4-tert-butyl- 742
benzenesulfonylamino)-benzoylamino]-3-
(2'-phenoxy-biphenyl-4-yl)-propionic acid methyl ester 448
(2S)-[5-Bromo-2-(4-tert-butyl- 742 benzenesulfonylamino)-
benzoylamino]-3-(4'-phenoxy- biphenyl-4-yl)-propionic acid methyl
ester 449 3-Biphenyl-4-yl-(2S)-{5-chloro-2- 720
[naphthalen-1-ylmethyl-(4-nitro-
benzenesulfonyl)-amino]-benzoylamino}- propionic acid 450
(2S)-{2-[(Biphenyl-4-sulfonyl)-(3-methyl- 721
thiophen-2-ylmethyl)-amino]-5-chloro-
benzoylamino}-3-biphenyl-4-yl-propionic acid 451
(2S)-{2-[(Biphenyl-4-sulfonyl)-(3-phenyl- 729
propyl)-amino]-5-chloro-benzoylamino}-3- biphenyl-4-yl-propionic
acid 452 (2S)-{2-[(Biphenyl-4-sulfonyl)-biphenyl-4- 777
ylmethyl-amino]-5-chloro-benzoylamino}-3- biphenyl-4-yl-propionic
acid 453 (2S)-{2-[(Biphenyl-4-sulfonyl)-naphthalen-1- 751
ylmethyl-amino]-5-chloro-benzoylamino}-3- biphenyl-4-yl-propionic
acid 454 (2S)-{2-[(Biphenyl-4-sulfonyl)-(4-isopropyl- 753
benzyl)-amino]-5-chloro-benzoylamino}-3- biphenyl-4-yl-propionic
acid 455 3-Biphenyl-4-yl-(2S)-{2-[biphenyl-4- 769
ylmethyl-(2,4-dichloro-benzenesulfonyl)-
amino]-5-chloro-benzoylamino}-propionic acid 456
(2S)-{2-[(Biphenyl-4-sulfonyl)-ethyl-amino]- 639
5-chloro-benzoylamino}-3-biphenyl-4-yl- propionic acid 457
(2S)-{2-[(Biphenyl-4-sulfonyl)-ethyl-amino]- 731
5-iodo-benzoylamino}-3-biphenyl-4-yl- propionic acid
EXAMPLE 458
2-{5-Chloro-2-[(naphthalen-1-ylmethyl)-amino]-benzoylamino}-3-(4'-trifluor-
omethyl-biphenyl-4-yl)-propionic acid
[0580] A solution of 2-amino-5-chlorobenzoic acid (0.58 g, 3.37
mmol) in DMF (7.0 mL) was reacted with (L)-4-bromophenylalanine
methyl ester hydrochloride (1.00 g, 3.37 mmol), HBTU (1.20 g, 3.37
mmol), and DIEA (1.80 mL, 10.13 mmol) by the general procedure A.
The crude product was purified by flash column chromatography on
silica gel using DCM(+50% hexane) followed by DCM to give 0.890 g
(64%) of
2-(2-amino-5-chloro-benzoylamino)-3-(4-bromo-phenyl)-propionic acid
methyl ester as a white solid. A solution of
2-(2-amino-5-chloro-benzoylamino)-3-(4-bromo-phenyl)-propionic acid
methyl ester (0.600 g, 1.45 mmol) in DME (10.0 mL) was reacted with
4-trifluoromethylbenzene boronic acid (0.55 g, 2.91 mmol),
Pd(PPh.sub.3).sub.4 (0.70 g, 0.14 mmol), and Na.sub.2CO.sub.3 (2.0
N, 3.50 mL, 3.64 mmol) by the general procedure D to form 0.850 g
of
2-(2-amino-5-chloro-benzoylamino)-3-(4'-trifluoromethyl-biphenyl-4-yl)-pr-
opionic acid methyl ester as a brown oil.
[0581] A solution of
2-(2-amino-5-chloro-benzoylamino)-3-(4-bromo-phenyl)-propionic acid
methyl ester (0.830 g, 1.74 mol) in DCE (15 mL) was reacted with
1-naphthaldehyde (0.244 g, 3.50 mmol), sodium triacetoxyborohydride
(0.553 g, 2.61 mmol), and acetic acid/DCM(1.0 M, 2.0 mL) by the
general procedure E. The crude product was purified by flash column
chromatography on silica gel using DCM (+35% hexane) to give 0.580
g (54%) of
2-{5-Chloro-2-[(naphthalen-1-ylmethyl)-amino]-benzoylamino}-3-(4-
'-trifluoromethyl-biphenyl-4-yl)-propionic acid methyl ester as a
colorless oil. This ester was treated with LiOH (0.123 g, 2.92
mmol) by the general procedure J to give 0.405 g (92%) of the title
compound.
2-{5-chloro-2-[(naphthalen-1-ylmethyl)-amino]-benzoylamino)-3-(4'-trifluo-
romethyl-biphenyl-4-yl)-propionic acid as a white solid. LCMS 603
(M+1).sup.+. .sup.1H NMR (DMSO-d.sub.6) 8.62 [d, 1 H], 8.10 [m, 1
H], 8.03 [m, 1 H], 7.92 [m, 1 H], 7.81 (m, 2 H], 7.72 [m, 2 H],
7.59 [m, 3 H], 7.50 [m, 2 H], 7.38 [m, 3 H], 7.23 [dd, 1 H], 6.67
[d, 1 H], 4.47 [m, 1 H], 3.25 [dd, 1 H], 3.16 [s, 2 H], 3.07 [m, 1
H].
EXAMPLE 459
(2S)-{2-[3-(4-tert-Butyl-phenoxy)-benzylamino]-5-chloro-benzoylamino}-3-(4-
'-cyclohexyl-biphenyl-4-yl)-propionic acid
[0582]
(2S)-(2-Amino-5-chloro-benzoylamino)-3-biphenyl-4-yl-propionic acid
methyl ester was prepared following General Procedure A using
2-amino-5-chloro-benzoic acid (1.751 g, 98%, 10 mmol),
(S)-2-amino-3-(4-bromo-phenyl)-propionic acid methyl ester
hydrochloride salt (2.95 g, 10 mmol), HBTU (4.55 g, 12 mmol) and
DIEA (6.33 mL, 99%, 36 mmol) in DMF (60 mL). Purification by flash
chromatography (ethyl acetate/hexanes 1:3, 1:2, 1:1.5) gave solid
(3.48 g, 8.45 mmol, 85% yield).
[0583]
(2S)-(2-Amino-5-chloro-benzoylamino)-3-(4'-cyclohexyl-biphenyl-4-y-
l)propionic acid methyl ester compound was prepared following
General Procedure D using
(S)-2-(2-amino-5-chloro-benzoylamino)-3-(4-bromo-phenyl)-propionic
acid methyl ester (1.803 g, 4.38 mmol), 4-cyclohexyl-benzene
boronic acid (1.61 g, 98%, 7.88 mmol), palladium
tetrakis-triphenylphosphine (0.462 g, 0.4 mmol), and aqueous
Na.sub.2CO.sub.3 (2.0 N, 16 mL, 32 mmol) in DME (32 mL). The
mixture was heated at 80.degree. C. for 14 h. Purification by flash
chromatography (ethyl acetate/hexanes 1:3,1:2) gave product as a
red solid (2.01 g, 4.09 mmol, 93% yield).
[0584] Reductive amination was carried out using (2S)
-(2-amino-5-chloro-benzoylamino)-3-(4'-cyclohexyl-biphenyl-4-yl)propionic
acid methyl ester (123 mg, 0.25 mmol),
3-(4-tert-butyl-phenoxy)-benzaldehyde (130 mg, 98%, 0.5 mmol),
acetic acid (0.7 mmol), sodium triacetoxyborohydride (131 mg, 97%,
0.6 mmol) and DCE (2.5 mL). The mixture was stirred for 7 h.
Purification by flash chromatography (ethyl acetate/hexanes 1:9)
gave the title compound as colorless oil (139 mg, 0.19 mmol, 76%
yield).
[0585] The title compound was prepared following General Procedure
C using
(S)-2-{2-[3-(4-tert-Butyl-phenoxy)-benzylamino]-5-chloro-benzoylami-
no)-3-(4'-cyclohexyl-biphenyl-4-yl)-propionic acid methyl ester
(135 mg, 0.19 mmol), LiOH(aq) (2.0 N, 0.22 mL, 0.44 mmol), THF (4
mL) and MeOH (1 mL). The mixture was stirred at 0.degree. C. for 12
h. The product was obtained as off-white solid (115 mg, 0.16 mmol,
84% yield).
[0586] .sup.1H-NMR (400 MHz, DMSO-d.sub.6): 12.82 (s, 1H), 8.77(d,
1H), 8.06(t, 1H), 7.62(d, 1H), 6.75 -7.54(m, 17H), 6.54(d, 1H),
4.59(ddd, 1H), 4.33(d, 2H), 3.08-3.31 (m, 3H), 1.33-1.79(m, 10H),
1.24(s, 9H); LC-MS m/z: 715 (M+1).sup.+.
EXAMPLE 460
(2S)-{5-Chloro-2-[(naphthalen-1-ylmethyl)-amino]-benzoylamino}-3-(2'-pheno-
xy-biphenyl-4-yl)-propionic acid
[0587] 2-Amino-5-chlorobenzoic acid methyl ester (1.85 g, 10.0
mmol) was treated with 1-napthaldehyde (1.56 g, 10.0 mmol) and
sodium triacetoxyborohydride (4.23 g, 20.0 mmol) in
1,2-dichloroethane as described in general procedure E to give
5-chloro-2-[(napthalen-1yl-methyl)-amino]-benzoic acid methyl ester
(2.54 g, 78%). This methyl ester (2.0 g, 6.13 mmol) was treated
with LiOH (2 eq, 1N aqueous solution) according to the general
procedure C gave 5-chloro-2-[(napthalen-1yl-methyl)-amino]-benzoic
acid (1.64 g, 86.0%).
[0588] 5-Chloro-2-[(napthalen-1-yl-methyl)-amino]-benzoic acid (0.1
g, 0.32 mmol) was treated with
(2S)-amino-3-(2'-phenoxy-biphenyl-4-yl) propionic acid methyl ester
hydrochloride salt (0.123 g, 0.32 mmol) according to the general
procedure A to give
2-{5-Chloro-2-[(naphthalene-1-yl-methyl)-amino]-3-(2'phenoxy-biphenyl-4-y-
l)-propionic acid methyl ester (0.155 g, 75.6%). This methyl ester
(0.15 g, 0.23 mmol) was treated with LiOH (2 eq, 1N aqueous
solution) according to the general procedure C to give
2-{5-chloro-2-[(naphthalene-1-yl-methyl)-amino]-3-(2'phenoxy-biphenyl-4-y-
l)-propionic acid (0.13 g, 90.0%) as white solid. .sup.1HNMR (400
MHz, DMSO-d.sub.6): 3.36 (dd, 1H), 3.46 (dd, 1H), 4.79-4.88 (m,
1H), 5.10 (d, 2H), 7.01 (d, 1H), 7.18 (d, 2H), 7.26(d, 1H), 7.33
(t, 7.90(m, 14H), 7.96(d, 1H), 8.10-8.20 (m,1H), 8.22-8.30 (m, 1H),
8.32-8.48 (m,2H), 9.07(d, 1H), 13.10 (s, 1H). LC/MS (m/z): 627.2
(M+1).sup.+.
EXAMPLE 461
(2S)-{5-Chloro-2-[(naphthalen-2-ylmethyl)-amino]-benzoylamino)-3-(2'-piper-
idin-1-ylmethyl-biphenyl-4-yl)-propionic acid
[0589] The
(2S)-(2-Amino-5-chloro-benzoylamino)-3-(4-bromo-phenyl)-propionic
acid methyl ester (0.400 g, 0.972 mmol) was made according to the
procedure for Example 282 and this was subjected to reductive
amination with naphthalene-2-carbaldehyde (0.227 g, 1.45 mmol) and
sodium triacetoxyborohydride (0.515 g, 2.43 mmol) as per general
procedure E to yield the
3-(4-Bromo-phenyl)-2-{5-chloro-2-[(naphthalen-2-ylmethyl)-amino-
]-benzoylamino}-propionic acid methyl ester (0.428 g, 80%).
[0590] The above compound (0.360 g, 0.653 mmol) was then subjected
to Suzuki coupling with 2-(formylphenyl) boronic acid (0.195 g,
1.306 mmol) and Pd (PPh.sub.3) (0.075 g, 0.0653 mmol) and 2N
Na.sub.2CO.sub.3 (2.0 ml, 1.956 mmol) as per general procedure D to
yield
(2S)-{5-Chloro-2-[(naphthalen-2-ylmethyl)-amino]-benzoylamino}-3-(2'-form-
yl-biphenyl-4-yl)-propionic acid methyl ester (0.244 g, 65%).
[0591] The title compound was hen prepared by reductive amination
on
(2S)-{5-chloro-2-[(naphthalen-2-ylmethyl)-amino]-benzoylamino}-3-(2'-form-
yl-biphenyl-4-yl)-propionic acid methyl ester (0.100 g, 0.173 mmol)
with piperidine (0.0345 g, 0.347 mmol) as per general procedure E
to give the
(2S)-{5-chloro-2-[(naphthalen-2-ylmethyl)-amino]-benzoylamino}-3-(2'-pipe-
ridin-4-ylmethyl-biphenyl-4-yl)-propionic acid methyl ester which
was further hydrolyzed as per general procedure C to give the title
compound (0.56 g,50%). LC/MS (m/z): 632(M+1).
[0592] By analogous methods to those described above the following
compounds were synthesized. TABLE-US-00013 LC/MS EXAMPLE NAME (m/z)
462 2S-[5-Chloro-2-(2-methyl-butylamino)- 557
benzoylamino]-3-(2'-phenoxy-biphenyl-4- yl)-propionic acid 463
3-Biphenyl-4-yl-2S-{5-chloro-2- 535
[(naphthalen-1-ylmethyl)-amino]- benzoylamino}-propionic acid 464
3-(4'-tert-Butyl-biphenyl-4-yl)-(2S)-{5- 591
chloro-2-[(naphthalen-1-ylmethyl)-amino]- benzoylamino}-propionic
acid 465 (2S)-{5-Chloro-2-[(naphthalen-1- 613
ylmethyl)-amino]-benzoylamino}-3-(4'-
methanesulfonyl-biphenyl-4-yl)-propionic acid 466
(2S)-(5-Chloro-2-hexylamino- 547
benzoylamino)-3-(4'-trifluoromethyl- biphenyl-4-yl)-propionic acid
467 (2S)-(5-Chloro-2-hexylamino- 522
benzoylamino)-3-(4'-dimethylamino- biphenyl-4-yl)-propionic acid
468 (2S)-[2-(4-tert-Butyl-benzylamino)-5- 584
chloro-benzoylamino]-3-(4'- dimethylamino-biphenyl-4-yl)-propionic
acid 469 (2S)-{2-[3-(4-tert-Butyl-phenoxy)- 676
benzylamino]-5-chloro-benzoylamino}-3-
(4'-dimethylamino-biphenyl-4-yl)-propionic acid 470
(2S)-{5-Chloro-2-[(naphthalen-1- 627
ylmethyl)-amino]-benzoylamino}-3-(4'-
phenoxy-biphenyl-4-yl)-propionic acid 471
(2S)-[2-(4-tert-Butyl-benzylamino)-5- 623
chloro-benzoylamino]-3-(4'-cyclohexyl- biphenyl-4-yl)-propionic
acid 472 (2S)-(5-Chloro-2-heptylamino- 585
benzoylamino)-3-(4'-phenoxy-biphenyl-4- yl)-propionic acid 473
(2S)-(5-Chloro-2-heptylamino- 575
benzoylamino)-3-(4'-cyclohexyl-biphenyl- 4-yl)-propionic acid 474
(2S)-{5-Chloro-2-[(naphthalen-1- 617
ylmethyl)-amino]-benzoylamino}-3-(4'-
cyclohexyl-biphenyl-4-yl)-propionic acid 475
(2S)-{5-Chloro-2-[(naphthalen-1- 605
ylmethyl)-amino]-benzoylamino}-3-(4'-
pentyl-biphenyl-4-yl)-propionic acid 476
(2S)-[2-(4-tert-Butyl-benzylamino)-5-iodo- 725
benzoylamino]-3-(4'-phenoxy-biphenyl-4- yl)-propionic acid 477
3-(4'-Amino-biphenyl-4-yl)-2S)-{5-chloro- 550
2-[(naphthalen-1-ylmethyl)-amino]- benzoylamino}-propionic acid 478
3-Biphenyl-4-yl-2S-[2-(4-tert-butyl- 667
benzylamino)-5-(3,4-dichloro-phenoxy)- benzoylamino]-propionic acid
479 3-Biphenyl-4-yl-2S-[2-(4-tert-butyl- 651
benzylamino)-5-(3-chloro-4-fluoro- phenoxy)-benzoylamino]-propionic
acid 480 3-Biphenyl-4-yl-(2S)-[2-(4-tert-butyl- 667
benzylamino)-5-(3-trifluoromethyl- phenoxy)-benzoylamino]-propionic
acid 481 3-Biphenyl-4-yl-(2S)-[2-(4-tert-butyl- 701
benzylamino)-5-(2,3,4-trichloro-phenoxy)- benzoylamino]-propionic
acid 482 3-Biphenyl-4-yl-(2S)-[2-(4-tert-butyl- 541
benzylamino)-4-chloro-benzoylamino]- propionic acid 483
3-Biphenyl-4-yl-(2S)-[2-(4-tert-butyl- 633
benzylamino)-5-(4-chloro-phenoxy)- benzoylamino]-propionic acid 484
3-Biphenyl-4-yl-2S-[2-(4-tert-butyl- 651
benzylamino)-5-(4-chloro-3-fluoro- phenoxy)-benzoylamino]-propionic
acid 485 3-Biphenyl-4-yl-(2S)-[2-(4-tert-butyl- 659
benzylamino)-5-(3,4-dimethoxy-phenoxy)- benzoylamino]-propionic
acid 486 3-(2'-Benzyloxy-biphenyl-4-yl)-(2S)-{5- 641
chloro-2-[(naphthalen-1-ylmethyl)- amino]-benzoylamino}-propionic
acid 487 3-(3'-Benzyloxy-biphenyl-4-yl)-(2S)-{5- 641
chloro-2-[(naphthalen-1-ylmethyl)- amino]-benzoylamino}-propionic
acid 488 (2S)-{5-Chloro-2-[(naphthalen-1- 603
ylmethyl)-amino]-benzoylamino}-3-(2'-
trifluoromethyl-biphenyl-4-yl)-propionic acid 489
(2S)-{2-[3-(4-tert-Butyl-phenoxy)- 725
benzylamino]-5-chloro-benzoylamino}-3-
(2'-phenoxy-biphenyl-4-yl)-propionic acid 490
(2S)-[2-(4-tert-Butyl-benzylamino)-5- 633
chloro-benzoylamino]-3-(2'-phenoxy- biphenyl-4-yl)-propionic acid
491 (2S)-[5-Bromo-2-(4-tert-butyl- 678
benzylamino)-benzoylamino]-3-(2'- phenoxy-biphenyl-4-yl)-propionic
acid 492 (2S)-[5-Bromo-2-(2-methyl-pentylamino)- 616
benzoylamino]-3-(2'-phenoxy-biphenyl-4- yl)-propionic acid 493
3-Biphenyl-4-yl-(2S)-{5-chloro-2- 492
[(piperidin-4-ylmethyl)-amino]- benzoylamino}-propionic acid 494
3-(2'-Benzyloxy-biphenyl-4-yl)-(2S)-{2-[3- 739
(4-tert-butyl-phenoxy)-benzylamino]-5-
chloro-benzoylamino}-propionic acid 495
3-(2'-Benzyloxy-biphenyl-4-yl)-(2S)-[2-(4- 647
tert-butyl-benzylamino)-5-chloro- benzoylamino]-propionic acid 496
(2S)-[5-Chloro-2-(3-phenoxy- 669 benzylamino)-benzoylamino]-3-(2'-
phenoxy-biphenyl-4-yl)-propionic acid 497
(2S)-[2-(3,5-Bis-trifluoromethyl- 713
benzylamino)-5-chloro-benzoylamino]-3-
(2'-phenoxy-biphenyl-4-yl)-propionic acid 498
(2S)-[5-Chloro-2-(4-phenoxy- 669 benzylamino)-benzoylamino]-3-(2'-
phenoxy-biphenyl-4-yl)-propionic acid 499
(2S)-[2-(4-Benzyloxy-benzylamino)-5- 683
chloro-benzoylamino]-3-(2'-phenoxy- biphenyl-4-yl)-propionic acid
500 3-Biphenyl-4-yl-(2S)-[5-(2-chloro-4- 625
trifluoromethyl-phenoxy)-2-(2-methyl-
butylamino)-benzoylamino]-propionic acid 501
(2S)-[3,5-Dichloro-2-(2-methyl- 591
butylamino)-benzoylamino]-3-(2'- phenoxy-biphenyl-4-yl)-propionic
acid 502 (2S)-[5-Bromo-2-(cyclohexylmethyl- 628
amino)-benzoylamino]-3-(2'-phenoxy- biphenyl-4-yl)-propionic acid
503 (2S)-(5-Chloro-2-pentylamino- 557
benzoylamino)-3-(2'-phenoxy-biphenyl-4- yl)-propionic acid 504
(2S)-{2-[3-(4-tert-Butyl-phenoxy)- 649
benzylamino]-5-chloro-benzoylamino}-3-
(2'-hydroxy-biphenyl-4-yl)-propionic acid 505
(2S)-(5-Chloro-2-hexa-2,4-dienylamino- 567
benzoylamino)-3-(2'-phenoxy-biphenyl-4- yl)-propionic acid 506
(2S)-[5-Chloro-2-(3-phenyl-propylamino)- 605
benzoylamino]-3-(2'-phenoxy-biphenyl-4- yl)-propionic acid 507
(2S)-(5-Chloro-2-octylamino- 599
benzoylamino)-3-(2'-phenoxy-biphenyl-4- yl)-propionic acid 508
(2S)-(5-Chloro-2-hexylamino- 571
benzoylamino)-3-(2'-phenoxy-biphenyl-4- yl)-propionic acid 509
(2S)-[5-Chloro-2-(2,2-dimethyl- 557
propylamino)-benzoylamino]-3-(2'- phenoxy-biphenyl-4-yl)-propionic
acid 510 (2S)-[5-Chloro-2-(2-methyl-pent-2- 569
enylamino)-benzoylamino]-3-(2'-phenoxy- biphenyl-4-yl)-propionic
acid 511 (2S)-(5-Chloro-2-ethylamino- 515
benzoylamino)-3-(2'-phenoxy-biphenyl-4- yl)-propionic acid
EXAMPLE 512
(2S)-(5-Chloro-2-diethylamino-benzoylamino)-3-(2'-phenoxy-biphenyl-4-yl)-p-
ropionic acid
[0593]
(2S)-(2-Amino-5-chloro-benzoylamino)-3-(2'-phenoxy-biphenyl-4-yl)--
propionic acid methyl ester was prepared (0.6 g, 80%) from
(2S)-Amino-3-(2'-phenoxy-biphenyl-4-yl)-propionic acid methyl ester
(0.5 g, 1.5 mmol), 5-chloro-2-amino-benzoic acid (0.28 g, 1.65
mmol) as desribed in general procedure A.
[0594]
(2S)-(2-Amino-5-chloro-benzoylamino)-3-(2'-phenoxy-biphenyl-4-yl)--
propionic acid methyl ester (0.5 g, 1.0 mmol), was reacted with
acetaldehyde (0.175 g, 3.0 mmol), sodium cyanoboro hydride (10 ml
1.0M solution in THF, 10 mmol), in DCM (50 ml) as described in the
general procedure E. The crude product was purified by flash column
chromatography on silica gel using DCM as an eluent to give ester
wich was hydrolyzed by following the general procedure I to give
0.4 g (69% of over all) of the title compound. LCMS: 543
(M+1).sup.+. .sup.1H NMR (CDCl.sub.3) [t, 6H], 2.88 [q, 4 H], 3.45
[m, 1H], 3.58 [m, 1 H], 5.12 [m, 1H], 7.17-7.7 [m, 16 H], 8.48 [d,
1 H], 1i.57 [s, 1H].
EXAMPLE 513
2-(5-Chloro-2-diethylamino-benzoylamino)-3-[3'-(4-trifluoromethyl-phenoxy)-
-biphenyl-4-yl]-propionic acid
[0595] A solution of (L)-4-bromophenylalanine (7.0 g, 28.6 mmol) in
DME(100 mL) was reacted with 3-hydroxyphenyl boronic acid(5.14 g,
37.2 mmol), palladium tetrakis-triphenylphosphine (3.3 g, 2.8
mmol), and Na.sub.2CO.sub.3(2.0 N, 43.0 mL, 86 mmol) by the general
procedure D. After removal of solvent, the solid was washed with
ether and DCM to afford
2-amino-3-(3'-hydroxy-biphenyl-4-yl)propionic acid methyl ester in
HCl salt form (8.20 g, 31.9 mmol, 93% yield).
[0596] A solution of 2-amino-5-chloro-benzoic acid (1.95 g, 11.38
mmol) in DMF (10.0 mL) was reacted with
2-amino-3-(3'-hydroxy-biphenyl-4-yl)propionic acid methyl ester
(3.50 g, 11.38 mmol), HBTU (3.98 g, 10.50 mmol), and DIEA (6.08 mL,
34.15 mmol) by the general procedure A. The crude product was
purified by flash column chromatography on silical gel using DCM
(+15% hexane) and increasing the gradient to DCM and finally DCM
(+0.25% methanol) to give 1.75 g, (36%) of
2-(2-amino-5-chloro-benzoylamino)-3-(3'-hydroxy-biphenyl-4-yl)propioni-
c acid methyl ester as a white solid. LCMS: 425 (M+1).sup.+.
[0597] A solution
2-(2-amino-5-chloro-benzoylamino)-3-(3'-hydroxy-biphenyl-4-yl)propionic
acid methyl ester (0.850 g, 2.00 mmol) was reacted with
acetaldehyde (0.350 g, 6.01 mmol), sodium triacetoxyborohydride
(0.850 g, 4.00 mmol), and acetic acid/DCM (1.0 M, 3.00 mL) by the
general procedure E. The crude product was purified by flash column
chromatography on silica gel using DCM (+15% hexane) and increasing
the gradient to DCM and finally DCM (+0.25% methanol) to give 0.540
g, (56%) of the phenolic etser.
[0598] A solution of this phenolic ester (0.240 g, 0.49 mmol) in.
DCM (5.0 mL) was, reacted with copper acetate (0.100 g, 0.54 mmol),
and 4-trifluoromethylbenzene boronic acid (0.236 g, 1.24 mmol), and
triethyl amine (0.350 mL) by the general procedure G. The crude
product was purified by the flash column chromatography on silica
gel using DCM (+5% hexane) to give 0.133 g, (43%) of
2-(5-Chloro-2-diethylamino-benzoylamino)-3-[3'-(4-trifluoromethyl-phenoxy-
)-biphenyl-4-yl]-propionic acid methyl ester. This ester (0.110 g,
0.17 mmol) was reacted with LiOH (0.030 g, 0.70 mmol) by the
general procedure J to give 0.095 g (89%) of
2-(5-Chloro-2-diethylamino-benzoylamino)-3-[3'-(4-trifluoromethyl-phenoxy-
)-biphenyl-4-yl]-propionic acid as a white solid. LCMS: 612
(M+1).sup.+. .sup.1H NMR (CDCl.sub.3) 11.56 [s, 1 H], 8.28 [d, 1
H], 7.59 [d, 2 H], 7.42 [dd, 1 H], 7.35 [dd, 1 H], 7.28 [m, 4 H],
7.19 [t, 1 H], 7.15 [d, 1 H], 7.02 [dd, 1 H], 7.00 [dd, 1 H], 5.05
[m, 1 H], 3.32 [m, 2 H], 2.79 [q, 4 H], 0.69 [t, 6 H].
EXAMPLE 514
[0599] To a solution of 5-chloro-2-fluoro-benzonitrile (0.700 g,
4.499 mmol) in anhydrous DMF (8.0 mL) was added
3,5-dimethylpiperdine (0.713 g, 6.299 mmol) and cesium carbonate
(4.30 g, 13.497 mmol). The reaction mixture was heated at 80 C for
2 h. Upon cooling to rt, water and ethylacetate was added. The
organic layer was separated and the aqueous layer was extracted
twice with ethyl acetate. To the combined organic layer was added
ether and the organic layer was washed with water and brine, dried
(Na2SO4) and concentrated under reduced pressure to give 1.15
g(96%) of 5-chloro-2-(3,5-dimethyl-piperidin-1-yl)-benzonitrile as
solid. LCMS 249(M+1).sup.+. The compound was >98% purity and was
hence used directly for the next step
[0600] To a solution of
5-chloro-2-(3,5-dimethyl-piperidin-1-yl)-benzonitrile (1.05 g,
4.220 mmol) in Diethylene glycol monomethyl ether (2.50 mL) was
added KOH (0.947 g, 16.883 mmol) and water (0.750 ml). The reaction
was heated at 130-135.degree. C. overnight. Upon cooling to rt,
water and ethyl acetate was added. the organic layer was discarded
and the aqueous layer is acidified to pH.about.6-7. The aqueous
layer was then extracted with ethyl acetate three times. The
combined organic layer was washed with water, brine, dried
(Na2SO4), and concentrated to give required
5-chloro-2-(3,5-dimethyl-piperidin-1-yl)-benzoic acid (0.850 g,
75%) as an off white solid. LCMS 268(M+1).sup.+.
[0601] A solution of
5-chloro-2-(3,5-dimethyl-piperidin-1-yl)-benzoic acid (0.250 g,
0.933 mmol) in DMF (4.0 mL) was reacted with
(2S)-amino-3-(2'-phenoxy-biphenyl-4-yl)-propionic acid methyl ester
hydrochloride (0.360 g, 0.933 mmol), HBTU (0.355 g, 0.933 mmol),
and DIEA (0.500 mL, 2.800 mmol) by the general procedure A. The
crude product was purified by flash column chromatography on silica
gel using DCM(+20% hexane) to give 0.435 g (62%) of
2-[5-Chloro-2-(3,5-dimethyl-piperidin-1-yl)-benzoylamino]-3-(2'-phenoxy-b-
iphenyl-4-yl)-propionic acid methyl ester. A solution of this ester
(0.200 g, 0.334 mmol) in THF (4.0 mL) was reacted with LiOH (0.050
g, 1.172 mmol) by the general procedure I to give 0.182 g (93%) of
2-[5-Chloro-2-(3,5-dimethyl-piperidin-1-yl)-benzoylamino]-3-(2'-phenoxy-b-
iphenyl-4-yl)-propionic acid as a white solid. LCMS: 584
(M+1).sup.+. .sup.1H NMR (CDCl.sub.3) 11.20 [d,1 H], 8.21 [d, 1H],
7.45 [m,2 H], 7.39[m, 2 H], 7.23 [m, 8 H], 7.02 [m, 2 H], 6.86 [m,
2 H], 4.90 [m, 1 H], 3.38 [dd, 5.60 Hz, 1H], 3.26 [dd, 1 H], 2.80
[m, 2 H], 2.16 [t, 1 H], 2.04 [t, 1 H], 1.70 [m, 2 H], 1.43 [m, 1
H], 0.76 [m, 6 H], 0.58 [m, 1 H].
[0602] By analogous methods to those described above the following
compounds were synthesized. TABLE-US-00014 LC/MS EXAMPLE NAME (m/z)
515 3-Biphenyl-4-yl-(2S)-{2-[bis-(4-benzyloxy- 787
benzyl)-amino]-5-chloro-benzoylamino}- propionic acid 516
3-Biphenyl-4-yl-(2S)-[2-(bis-naphthalen-1- 675
ylmethyl-amino)-5-chloro-benzoylamino]- propionic acid 517
3-Biphenyl-4-yl-(2S)-[2-(bis-biphenyl-4- 727
ylmethyl-amino)-5-chloro-benzoylamino]- propionic acid 518
(2S)-(5-Bromo-2-dibutylamino- 644
benzoylamino)-3-(2'-phenoxy-biphenyl-4- yl)-propionic acid 519
(2S)-(5-Bromo-2-dihexylamino- 700
benzoylamino)-3-(2'-phenoxy-biphenyl-4- yl)-propionic acid 520
(2S)-(5-Chloro-2-dipentylamino- 627
benzoylamino)-3-(2'-phenoxy-biphenyl-4-yl)- propionic acid 521
(2S)-(5-Chloro-2-piperidin-1-yl-benzoylamino)- 555
3-(2'-phenoxy-biphenyl-4-yl)- propionic acid 522
(2S)-(5-Bromo-2-diethylamino-benzoylamino)- 588
3-(2'-phenoxy-biphenyl-4-yl)-propionic acid 523
(2S)-(5-Chloro-2-diethylamino-benzoylamino)- 595
3-[3'-(3-chloro-4-fluoro-phenoxy)- biphenyl-4-yl]-propionic acid
524 (2S)-(5-Bromo-2-piperidin-1-yl- 600
benzoylamino)-3-(2'-phenoxy-biphenyl-4-yl)- propionic acid 525
(2S)-(5-Chloro-2-diethylamino- 573
benzoylamino)-3-[3'-(4-methoxy-phenoxy)- biphenyl-4-yl]-propionic
acid 526 (2S)-(5-Chloro-2-diethylamino- 627
benzoylamino)-3-[3'-(4-trifluoromethoxy-
phenoxy)-biphenyl-4-yl]-propionic acid 527
3-[3'-(4-tert-Butyl-phenoxy)-biphenyl-4-yl]- 599
(2S)-(5-chloro-2-diethylamino- benzoylamino)-propionic acid 528
(2S)-(5-Bromo-2-diethylamino- 656
benzoylamino)-3-[3'-(4-trifluoromethyl-
phenoxy)-biphenyl-4-yl]-propionic acid 529
(2S)-(5-Bromo-2-diethylamino- 606
benzoylamino)-3-[3'-(3-fluoro-phenoxy)- biphenyl-4-yl]-propionic
acid 530 (2S)-(5-Bromo-2-pyrrolidin-1-yl- 586
benzoylamino)-3-(2'-phenoxy-biphenyl-4-yl)- propionic acid 531
(2S)-[5-Chloro-2-(4-methyl-piperazin-1-yl)- 570
benzoylamino]-3-(2'-phenoxy-biphenyl-4- yl)-propionic acid 532
(2S)-[5-Chloro-2-(4-phenyl-piperazin-1-yl)- 632
enzoylamino]-3-(2'-phenoxy-biphenyl-4-yl)- propionic acid 533
(2S)-[5-Chloro-2-(3,4-dihydro-1H- 603
isoquinolin-2-yl)-benzoylamino]-3-(2'-
phenoxy-biphenyl-4-yl)-propionic acid 534
(2S)-(5-Chloro-2-morpholin-4-yl- 557
benzoylamino)-3-(2'-phenoxy-biphenyl-4- yl)-propionic acid 535
(2S)-(2-Azepan-1-yl-5-chloro- 569
benzoylamino)-3-(2'-phenoxy-biphenyl-4- yl)-propionic acid 536
(2S)-[5-Chloro-2-(4-trifluoromethyl- 623
piperidin-1-yl)-benzoylamino]-3-(2'-
phenoxy-biphenyl-4-yl)-propionic acid
EXAMPLE 537
(2S)-[5-Chloro-2-(4-methylsulfanyl-phenylamino)-benzoylamino]-3-(2'-phenox-
y-biphenyl-4-yl)-propionic acid
[0603] A solution of
(2S)-(2-amino-5-chloro-benzoylamino)-3-(2'-phenoxy-biphenyl-4-yl)-propion-
ic acid (0.154 g, 0.307 mmol), prepared by reacting
(2S)-amino-3-(2'-phenoxy-biphenyl-4-yl)-propionic acid methyl ester
and 2-amino-5-chlorobenzoic acid by the general procedure-A) was
reacted with 4-(methylthio)phenylboronic acid (0.130 g, 0.768
mmol), copper acetate (0.084 g, 0.460 mmol), and triethyl amine
(0.215 mL, 1.535 mmol) by the general procedure G. The crude
product was purified by flash column chromatography on silica gel
using DCM (+25% hexane) to give 0.075 g (39%) of
2-[5-chloro-2-(4-methylsulfanyl-phenylamino)-benzoylamino]-3-(2'-
-phenoxy-biphenyl-4-yl)-propionic acid methyl ester as a colorless
oil. This ester was treated with LiOH (0.019 g, 0.441 mmol) by the
general procedure I to give 0.049 g (92%) of
2-[5-chloro-2-(4-methylsulfanyl-phenylamino)-benzoylamino]-3-(2'-phenoxy--
biphenyl-4-yl)-propionic acid. LCMS: 610 (M+1).sup.+. .sup.1H NMR
(CDCl.sub.3) 8.94 [bs, 1H], 7.49 [d, 2 H], 7.47 [d, 1 H], 7.22 [m,
10 H], 7.06 [d, 2 H], 6.99 [d, 2 H], 6.88 [d, 2 H], 6.50 [d, 1 H],
4.99 [m, 1 H], 3.30 [m, 2 H], 2.45 [s, 3 H].
EXAMPLE 538
2S-[5-Chloro-2-(3-chloro-4-fluoro-phenylamino)-benzoylamino]-3-(2'-phenoxy-
-biphenyl-4-yl)-propionic acid
[0604]
(2S)-(2-amino-5-chloro-benzoylamino)-3-(2'-phenoxy-biphenyl-4-yl)--
propionic acid (0.154 g, 0.307 mmol) prepared above was reacted
with 3-Cl, 4-F-phenyl boronic acid (0.13g, 0.77 mmol), copper
acetate (0.084 g, 0.460 mmol), and triethyl amine (0.215 mL, 1.535
mmol) as described in the general procedure G. The crude product
was purified by column chromatography using DCM as an eluent then
hydrolyzed as described in the general proceudure I to get the
title compound (20 mg, 10%) as a light yellow solid. LCMS:
615(M+1).sup.+. .sup.1H NMR (CDCl.sub.3) 3.12 [m, 1H], 3.39 [m,
1H], 4.84 [m, 1H], 6.61 [m,1H], 6.79-7.58 [m, 19H], 8.88 [s,
1H].
[0605] By analogous methods to those described above the following
compounds were synthesized. TABLE-US-00015 LC/MS EXAMPLE NAME (m/z)
539 (2S)-[5-Bromo-2-(4-trifluoromethyl- 676
phenylamino)-benzoylamino]-3-(2'-phenoxy- biphenyl-4-yl)-propionic
acid 540 (2S)-(5-Bromo-2-phenylamino-benzoylamino)- 608
3-(2'-phenoxy-biphenyl-4-yl)-propionic acid 541
(2S)-(5-Chloro-2-phenylamino-benzoylamino)- 563
3-(2'-phenoxy-biphenyl-4-yl)-propionic acid 542
(2S)-[5-Chloro-2-(4-trifluoromethyl- 631
phenylamino)-benzoylamino]-3-(2'-phenoxy- biphenyl-4-yl)-propionic
acid 543 (2S)-[5-Chloro-2-(3,5-dimethyl-phenylamino)- 591
benzoylamino]-3-(2'-phenoxy-biphenyl-4-yl)- propionic acid 544
(2S)-[5-Chloro-2-(3-trifluoromethyl- 631
phenylamino)-benzoylamino]-3-(2'-phenoxy- biphenyl-4-yl)-propionic
acid 545 (2S)-[5-Chloro-2-(4-methoxy-phenylamino)- 593
benzoylamino]-3-(2'-phenoxy-biphenyl-4-yl)- propionic acid 546
(2S)-[2-(4-tert-Butyl-phenylamino)-5-chloro- 619
benzoylamino]-3-(2'-phenoxy-biphenyl-4-yl)- propionic acid 547
(2S)-[5-Chloro-2-(3,4-difluoro-phenylamino)- 599
benzoylamino]-3-(2'-phenoxy-biphenyl-4-yl)- propionic acid 548
(2S)-[5-Chloro-2-(4-fluoro-3-methyl- 595
phenylamino)-benzoylamino]-3-(2'-phenoxy- biphenyl-4-yl)-propionic
acid 549 (2S)-[5-Chloro-2-(3,4-dichloro-phenylamino)- 631
benzoylamino]-3-(2'-phenoxy-biphenyl-4-yl)- propionic acid 550
(2S)-[5-Chloro-2-(4-trifluoromethoxy- 647
phenylamino)-benzoylamino]-3-(2'-phenoxy- biphenyl-4-yl)-propionic
acid 551 (2S)-[5-Chloro-2-(4-methanesulfonyl- 641
phenylamino)-benzoylamino]-3-(2'-phenoxy- biphenyl-4-yl)-propionic
acid 552 (2S)-[2-(4-Benzyloxy-phenylamino)-5-chloro- 669
benzoylamino]-3-(2'-phenoxy-biphenyl-4-yl)- propionic acid 553
(2S)-[5-Chloro-2-(naphthalen-1-ylamino)- 613
benzoylamino]-3-(2'-phenoxy-biphenyl-4-yl)- propionic acid 554
(2S)-[5-Chloro-2-(naphthalen-2-ylamino)- 613
benzoylamino]-3-(2'-phenoxy-biphenyl-4-yl)- propionic acid 555
(2S)-[2-(3,5-Bis-trifluoromethyl-phenylamino)-5- 699
chloro-benzoylamino]-3-(2'-phenoxy-biphenyl- 4-yl)-propionic acid
556 (2S)-[5-Chloro-2-(4-cyclohexyl-phenylamino)- 645
benzoylamino]-3-(2'-phenoxy-biphenyl-4-yl)- propionic acid 557
(2S)-[2-(Biphenyl-4-ylamino)-5-chloro- 639
benzoylamino]-3-(2'-phenoxy-biphenyl-4-yl)- propionic acid 558
(2S)-[2-(3-Butoxy-phenylamino)-5-chloro- 635
benzoylamino]-3-(2'-phenoxy-biphenyl-4-yl)- propionic acid 559
(2S)-[5-Chloro-2-(4-ethoxy-phenylamino)- 607
benzoylamino]-3-(2'-phenoxy-biphenyl-4-yl)- propionic acid 560
(2S)-[5-Chloro-2-(4-fluoro-3-methoxy- 611
phenylamino)-benzoylamino]-3-(2'-phenoxy- biphenyl-4-yl)-propionic
acid 561 (2S)-[5-Chloro-2-(4-chloro-phenylamino)- 597
benzoylamino]-3-(2'-phenoxy-biphenyl-4-yl)- propionic acid 562
(2S)-[5-Chloro-2-(3-chloro-phenylamino)- 597
benzoylamino]-3-(2'-phenoxy-biphenyl-4-yl)- propionic acid 563
(2S)-[5-Chloro-2-(2,4-dichloro-phenylamino)- 631
benzoylamino]-3-(2'-phenoxy-biphenyl-4-yl)- propionic acid 564
(2S)-[2-(Benzo[1,3]dioxol-5-ylamino)-5-chloro- 607
benzoylamino]-3-(2'-phenoxy-biphenyl-4-yl)- propionic acid 565
(2S)-[5-Chloro-2-(4-cyano-phenylamino)- 588
benzoylamino]-3-(2'-phenoxy-biphenyl-4-yl)- propionic acid 566
(2S)-[5-Chloro-2-(4-methoxy-3-methyl- 607
phenylamino)-benzoylamino]-3-(2'-phenoxy- biphenyl-4-yl)-propionic
acid 567 (2S)-[5-Chloro-2-(3-isopropyl-phenylamino)- 605
benzoylamino]-3-(2'-phenoxy-biphenyl-4-yl)- propionic acid 568
(2S)-[5-Chloro-2-(4-nitro-phenylamino)- 608
benzoylamino]-3-(2'-phenoxy-biphenyl-4-yl)- propionic acid 569
(2S)-[5-Chloro-2-(4-methyl-3-nitro- 622
phenylamino)-benzoylamino]-3-(2'-phenoxy- biphenyl-4-yl)-propionic
acid
EXAMPLE 570
(2S)-{[2-Biphenyl-4-yl-methoxycarbonyl-ethyl)-(4'-trifluoromethyl-biphenyl-
-carbonyl)-amino]-methyl}-(2S)-pyrrolidine-1-carboxylic acid
tert-butyl ester
[0606] To a solution of
2-biphenyl-4-yl-(1S)-(methoxycarbonyl)ethylammonium chloride (1.337
g, 4.58 mmol) and (2S)-formyl-pyrrolidine-1-carboxylic acid
tert-butyl ester (1.0 eq., 9.13 mg, 4.58 mmol) in a mixture of 25
mL methanol and 25 mL THF was added glacial acetic acid (1.5 eq.,
0.40 mL, 6.87 mmol) and the mixture was stirred at ambient
temperature for ten minutes. To this was added a 1.0 N solution of
NaCNBH.sub.3 in THF (1.5 eq., 6.87 mL, 6.87 mmol) in small portions
and the reaction mixture was stirred at r.t. overnight. The solvent
was removed and the residue was dissolved in water and DCM and
partitioned. The organic portion was dried over Na.sub.2SO.sub.4,
filtered and concentrated. The crude product was purified by flash
column chromatography (2:1 EtOAc;Hexanes, EtOAc) to provide
(2S)-[(2-biphenyl-4-yl-(1S)-1-methoxycarbonyl-ethylamino)-methyl]-
-pyrrolidine-1-carboxylic acid tert-butyl ester (1.440 g, 72%) as a
clear colorless oil.
[0607] A portion of the product (584 mg, 1.33 mmol), dissolved in
13 mL dry CH.sub.2Cl.sub.2, was subsequently condensed with
4'-trifluoromethyl-biphenyl-4-carbonyl chloride (1.2 eq., 455 mg,
1.60 mmol) (synthesized from
4'-trifluoromethyl-biphenyl-4-carboxylic acid by heating at reflux
in a neat solution of thionyl chloride, followed by removal of
excess reagent and volatiles in vacuo) in dry CH.sub.2Cl.sub.2 (13
mL), in the presence of triethylamine (3.0 eq., 3.99 mmol, 0.56 mL)
at 0.degree. C. The reaction was stirred at that temperature and
gradually allowed to warm to ambient temperature until the reaction
was shown to be complete by TLC. The solvent was removed and the
crude residue was purified by flash column chromatography (1:1
EtOAc: hexanes) to afford the title compound,
(2S)-{[(2-biphenyl-4-yl-(1
S)-methoxycarbonyl-ethyl)-(4'-trifluoromethyl-biphenyl-4-carbonyl)-amino]-
-methyl}-(2S)-pyrrolidine-1-carboxylic acid tert-butyl ester (600
mg, 76%), as a white solid. LCMS 687 (M+1).sup.+.
EXAMPLE 571
(2S)-(2-{[(2-Biphenyl-4-yl-1-methoxycarbonyl-ethyl)-(4'-trifluoromethyl-bi-
phenyl-4
carbonyl)-amino]-methyl}-(2S)-pyrrolidine-1-sulfonyl)-benzoic acid
methyl ester
[0608] Into a dry flask was placed 2-(2S)-{[(2-biphenyl-4-yl-(1
S)-methoxycarbonyl-ethyl)-(4'-trifluoromethyl-biphenyl-4-carbonyl)-amino]-
-methyl}-pyrrolidine-1-carboxylic acid tert-butyl ester (333 mg,
0.485 mmol) (for preparation, see Example 570), and the flask was
capped and purged with dry N.sub.2. The flask was then charged with
5 mL of 4N HCl/dioxane and stirred at rt for about one hour. The
solvent was removed and the crude product was rinsed with ether and
dried in vacuo to afford 302 mg (100%) of the desired product,
(2S)-{[(2-biphenyl-4-yl-(1S)-methoxycarbonyl-ethyl)-(4'-trifluoromethyl-b-
iphenyl-4-carbonyl)-amino]-methyl}-pyrrolidinium; chloride, which
was used without further purification.
[0609] The amine hydrochloride (40 mg, 64 micromol) was dissolved
in anhydrous acetonitrile (2 mL) and to this was added
2-chlorosulfonyl-benzoic acid methyl ester (3.0 eq., 50 mg, 0.193
mmol), pyridine (0.2 mL) and DMAP (0.1 eq., 0.8 mg, 6.4 micromol)
and the reaction carried out as described in general procedure F.
The crude product was purified by flash column chromatography to
afford 40 mg (79%) of the title compound,
2-(2S)-{[(2-Biphenyl-4-yl-(1S)-methoxycarbonyl-ethyl)-(4'-trifluoromethyl-
-biphenyl-4-carbonyl)-amino]-methyl}-pyrrolidine-1-sulfonyl)-benzoic
acid methyl ester. LC/MS 785 (M+1).sup.+.
EXAMPLE 572
3-Biphenyl-4-yl-(2S)-[[(2R)-1-(2-thiophen-2-yl-acetyl)-pyrrolidine-2-methy-
l]-(4'-trifluoromethyl-biphenyl-4-carbonyl)-amino]-propionic
acid
[0610] The synthesis of the title compound proceeds through the
intermediacy of
(2S)-{[(2-biphenyl-4-yl-(1S)methoxycarbonyl-ethyl)-(4'-trifluoromethyl-bi-
phenyl-4-carbonyl)-amino]-methyl}-(2R)-pyrrolidinium chloride,
similar in all respects to the intermediate in the synthesis of
Example 570,
(2S)-{([(2-biphenyl-4-yl-(1S)-methoxycarbonyl-ethyl)-(4'trifluoromethyl-b-
iphenyl-4-carbonyl)-amino]-methyl)-(2S)-pyrrolidinium chloride, in
all respects except for the stereochemical orientation at the
2-position of the pyrrolidine ring. Thus, the synthesis of this
intermediate proceeds as described in Examples 570 and 571 with the
exception that (2S)-formyl-pyrrolidine-1-carboxylic acid tert-butyl
ester is replaced with (2R)-formyl-pyrrolidine-1-carboxylic acid
tert-butyl ester in the first step of the sequence.
[0611] To a solution of
(2S)-{[(2-biphenyl-4-yl-(1S)methoxycarbonyl-ethyl)-(4'-trifluoromethyl-bi-
phenyl-4-carbonyl)-amino]-methyl}-(2R)-pyrrolidinium chloride (15
mg, 24 micromol) in dry CH.sub.2Cl.sub.2 under dry N.sub.2 at
0.degree. C. was added 2-thiophene acetyl chloride (3.0 eq., 72
.mu.mol, 8.9 .mu.L)followed by triethylamine (5.0 eq., 0.12 mmol,
17 .mu.L) and the mixture was stirred at 0.degree. C. for one hour,
then the solvent was removed. The residue was purified by flash
column chromatography (4:1 EtOAc:hexanes) to yield the purified
amide,
3-biphenyl-4-yl-(2S)-[[1-(2-thiophen-2-yl-acetyl)-pyrrolidin-(2R)-ylmethy-
l]-(4'trifluoromethyl-biphenyl-4-carbonyl)-amino]-propionic acid
methyl ester (17 mg, 100%). The ester was saponified according to
general procedure C. Thus,
3-biphenyl-4-yl-(2S)-[[1-(2-thiophen-2-yl-acetyl)-pyrrolidin-(2R)-ylmethy-
l]-(4'trifluoromethyl-biphenyl-4-carbonyl)-amino]-propionic acid
methyl ester (16 mg, 23 .mu.mol) was dissolved in 1 mL of a 4:1
mixture of THF and methanol and cooled to 0.degree. C. for the
addition of 0.1 mL of 2 N aq. LiOH. The reaction furnished the
title compound,
3-Biphenyl-4-yl-(2S)-[[1-(2-thiophen-2-yl-acetyl)-pyrrolidin-(2R)-ylmethy-
l]-(4'-trifluoromethyl-biphenyl-4-carbonyl)-amino]-propionic acid
(14 mg, 100%) LCMS: 697 (M+1).sup.+.
EXAMPLE 573
(2S)-[[2-(2-Acetylamino-4-methyl-thiazole-5-sulfonylamino)-ethyl]-(4'-trif-
luoromethyl-biphenyl-4-carbonyl)-amino]-3-biphenyl-4-yl-propionic
acid methyl ester
[0612] To a solution of
2-biphenyl-4-yl-(1S)-methoxycarbonyl-ethyl-ammonium chloride
(1.833g, 6.28 mmol) and (2-oxo-ethyl)-carbamic acid tert-butyl
ester (1.0 eq., 1.00 g, 6.28 mmol), dissolved in a mixture of 25 mL
each of THF and methanol, was added glacial acetic acid (2.0 eq.,
0.72 mL, 12.56 mmol), and after stirring for 10 minutes,
NaCNBH.sub.3 in small portions. The reaction mixture was stirred
overnight at rt then the volatiles were removed in vacuo. The crude
residue was purified by flash column chromatography (3:2
EtOAc:hexanes) to afford the desired secondary amine,
3-Biphenyl-4-yl-(2S)-(2-tert-butoxycarbonylamino-ethylamino)-propionic
acid methyl ester (775 mg, 31%).
[0613] This secondary amine (803 mg, 2.02 mmol) was reacted with
4'-rifluoromethyl-biphenyl-4-carbonyl chloride (1.24 eq., 713 mg,
2.50 mmol) (see Example 591 for preparation) in 40 mL anhydrous
CH.sub.2Cl.sub.2 in the presence of triethylamine (3.0 eq., 0.84
mL, 6.06 mmol) at 0.degree. C. for one hour, then the mixture was
allowed to warm to ambient temperature and stirred overnight. The
volatiles were removed in vacuo and the residue was purified by
flash column chromatography (1:1 EtOAc:hexanes) to afford
3-biphenyl-4-yl-(2S)-[(2-tert-butoxycarbonylamino-ethyl)-(4'-trifluoromet-
hyl-biphenyl-4-carbonyl)-amino]-propionic acid methyl ester (996
mg, 76%). A portion of this compound (395 mg, 0.61 mmol) was placed
in a dry flask, capped with a septum and purged with dry N.sub.2.
The flask was charged with 10 mL of 4N HCl/dioxane solution and
stirred at r.t. for 1 hour, at which point the reaction was shown
to be complete by TLC. The volatiles were removed and the residue
was dissolved in ether and triturated with hexanes. The crude
product,
2-[(2-biphenyl-4-yl-(1S)-methoxycarbonyl-ethyl)-(4'-trifluoromethyl-biphe-
nyl-4-carbonyl)-amino]-ethyl-ammonium chloride (356 mg, 100%) was
used without further purification.
[0614] To a mixture of
2-[(2-biphenyl-4-yl-(1S)-methoxycarbonyl-ethyl)-(4'-trifluoro-methyl-biph-
enyl-4-carbonyl)-amino]-ethyl-ammonium chloride (40 mg, 69 .mu.mol)
and 2-acetyl-amino-4-methyl-thiazole-5-sulfonyl chloride (3.0 eq.,
52.4 mg, 0.21 mmol), in 2 mL anhydrous CH.sub.2Cl.sub.2 at
0.degree. C., was added pyridine (5.0 eq., 28 .mu.L, 0.34 mmol) and
DMAP (0.1 eq., 0.8 mg, 6.9 .mu.mol) and the mixture was allowed to
gradually warm to ambient temperature and stirred overnight. The
solvent was removed and the residue was purified by flash column
chromatography (EtOAc) to afford the title compound,
(2S)-[[2-(2Acetylamino-4-methyl-thiazole-5-sulfonylamino)-ethyl]-(4'-trif-
luoromethyl-biphenyl-amino]4carbonyl)-amino]3-biphenyl-4-yl-propionic
acid methyl ester (42 mg, 80%). LCMS 765 (M+1).sup.+.
[0615] By analogous methods to those described above the following
compounds were synthesized. TABLE-US-00016 LC/MS EXAMPLE NAME (m/z)
574 (2S)-[(Biphenyl-4-carbonyl)-(2-hydroxy- 528
benzyl)-amino]-3-biphenyl-4-yl- propionic acid 575
(2S)-[(Biphenyl-4-carbonyl)-(4- 554
isopropyl-benzyl)-amino]-3-biphenyl-4- yl-propionic acid 576
3-Biphenyl-4-yl-(2S)-[(4-isopropyl- 528
benzyl)-(naphthalene-2-carbonyl)- amino]-propionic acid 577
3-Biphenyl-4-yl-(2S)-[(4-tert-butyl- 534
benzoyl)-(4-isopropyl-benzyl)amino]- propionic acid 578
3-Biphenyl-4-yl-(2S)-[(3,4-dichloro- 546
benzoyl)-(4-isopropyl-benzyl)-amino]- propionic acid 579
(2S)-[(Biphenyl-4-carbonyl)-naphthalen- 562
1-ylmethyl-amino]-3-biphenyl-4-yl- propionic acid 580
3-Biphenyl-4-yl-(2S)-[(naphthalene-2- 536
carbonyl)-naphthalen-1-ylmethyl- amino]-propionic acid 581
3-Biphenyl-4-yl-(2S)-[(4-tert-butyl- 542
benzoyl)-naphthalen-1-ylmethyl-amino]- propionic acid 582
3-Biphenyl-4-yl-(2S)-[(3,5-dichloro- 554
benzoyl)-naphthalen-1-ylmethyl-amino]- propionic acid 583
3-Biphenyl-4-yl-(2S)-[(naphthalene-1- 536
carbonyl)-naphthalen-1-ylmethyl- amino]-propionic acid 584
3-Biphenyl-4-yl-(2S)-[(3,4-dichloro- 554
benzoyl)-naphthalen-1-ylmethyl-amino]- propionic acid 585
3-Biphenyl-4-yl-(2S)-[(4-methyl- 500
benzoyl)-naphthalen-1-ylmethyl-amino]- propionic acid 586
3-Biphenyl-4-yl-(2S)-[(2,4-dichloro- 554
benzoyl)-naphthalen-1-ylmethyl-amino]- propionic acid 587
3-Biphenyl-4-yl-(2S)-[naphthalen-1-ylmethyl- 531
(4-nitro-benzoyl)-amino]- propionic acid 588
3-Biphenyl-4-yl-(2S)-[(4-chloro- 520
benzoyl)-naphthalen-1-ylmethyl-amino]- propionic acid 589
(2S)-[(Biphenyl-4-carbonyl)-(4-chloro- 546
benzyl)-amino]-3-biphenyl-4-yl- propionic acid 590
3-Biphenyl-4-yl-(2S)-[(4-chloro-benzyl)- 538
(3,5-dichloro-benzoyl)-amino]-propionic acid 591
(2S)-[(Biphenyl-4-carbonyl)-(5-tert-butyl- 584
2-hydroxy-benzyl)-amino]-3-biphenyl-4- yl-propionic acid 592
Biphenyl-4-carboxylic acid (2S)- 764
{[(biphenyl-4-carbonyl)-(2-biphenyl-4-yl-
1-carboxy-ethyl)-amino]-methyl}-4-tert- butyl-phenyl ester 593
3-Biphenyl-4-yl-(2S)-[(4-bromo- 568
benzoyl)-(2-tert-butoxycarbonylamino- ethyl)-amino]-propionic acid
594 3-Biphenyl-4-yl-(2S)-[(2-tert- 649
butoxycarbonylamino-ethyl)-(4'-
trifluoromethoxy-biphenyl-4-carbonyl)- amino]-propionic acid 595
(2S)-[(2-Amino-ethyl)-(4-bromo- 482
benzoyl)-amino]-3-biphenyl-4-yl- propionic acid methyl ester 596
(2S)-[(2-Amino-ethyl)-(4-bromo- 468
benzoyl)-amino]-3-biphenyl-4-yl- propionic acid 597
3-Biphenyl-4-yl-(2S)-[(4-chloro-benzyl)- 614
(4'-trifluoromethyl-biphenyl-4-carbonyl)- amino]-propionic acid 598
(2S)-{2-[(2-Biphenyl-4-yl-1-carboxy- 717
ethyl)-(4'-trifluoromethyl-biphenyl-4-
carbonyl)-amino]-ethylsulfamoyl}- benzoic acid 599
3-Biphenyl-4-yl-(2S)-[[2-(2- 751 methanesulfonyl-
benzenesulfonylamino)-ethyl]-
(4'-trifluoromethyl-biphenyl-4-carbonyl)- amino]-propionic acid 600
(2S)-{[(2-Biphenyl-4-yl-1- 687 methoxycarbonyl-ethyl)-(4'-
trifluoromethyl-biphenyl-4-carbonyl)-
amino]-methyl}-pyrrolidine-1-carboxylic acid tert-butyl ester 601
(2S)-{2-[(2-Biphenyl-4-yl-1-methoxycarbonyl- 745
ethyl)-(4'-trifluoromethyl-biphenyl-
4-carbonyl)-amino]-ethylsulfamoyl}- benzoic acid methyl ester 602
3-Biphenyl-4-yl-(2S)-[[2-(2- 765 methanesulfonyl-
benzenesulfonylamino)-ethyl]-
(4'-trifluoromethyl-biphenyl-4-carbonyl)- amino]-propionic acid
methyl ester 603 3-Biphenyl-4-yl-(2S)-[[2-(4- 765
methanesulfonyl-benzenesulfonylamino)- ethyl]-
(4'-trifluoromethyl-biphenyl-4-carbonyl)- amino]-propionic acid
methyl ester 604 3-Biphenyl-4-yl-(2S)-[[1-(2- 805
methanesulfonyl-benzenesulfonyl)-
pyrrolidin-2-ylmethyl]-(4'-trifluoromethyl-
biphenyl-4-carbonyl)-amino]-propionic acid methyl ester 605
3-Biphenyl-4-yl-(2S)-[[1-(4-methanesulfonyl- 805
benzenesulfonyl)-pyrrolidin-2-
ylmethyl]-(4'-trifluoromethyl-biphenyl-4-
carbonyl)-amino]-propionic acid methyl ester 606
(2S)-{[(2-Biphenyl-4-yl-1-carboxy-ethyl)- 673
(4'-trifluoromethyl-biphenyl-4-carbonyl)-
amino]-methyl}-pyrrolidine-1-carboxylic acid tert-butyl ester 607
(2S)-{[(2-Biphenyl-4-yl-1-carboxy-ethyl)- 673
(4'-trifluoromethyl-biphenyl-4-carbonyl)-
amino]-methyl}-pyrrolidine-1-carboxylic acid tert-butyl ester 608
(2S)-(2-{[(2-Biphenyl-4-yl-1-carboxy- 771
ethyl)-(4'-trifluoromethyl-biphenyl-
4-carbonyl)-amino]-methyl}-pyrrolidine- 1-sulfonyl)-benzoic acid
methylester 609 3-Biphenyl-4-yl-(2S)-[[1-(2- 791
methanesulfonyl-benzenesulfonyl)-
pyrrolidin-2-ylmethyl]-(4'-trifluoromethyl-
biphenyl-4-carbonyl)-amino]-propionic acid 610
3-Biphenyl-4-yl-(2S)-[[1-(4- 791 methanesulfonyl-benzenesulfonyl)-
pyrrolidin-2-ylmethyl]-(4'-trifluoromethyl-
biphenyl-4-carbonyl)-amino]-propionic acid 611
(2S)-(2-{[(2-Biphenyl-4-yl-1- 785 methoxycarbonyl-ethyl)-(4'-
trifluoromethyl-biphenyl-4-carbonyl)- amino]-methyl}-
pyrrolidine-1-sulfonyl)-benzoic acid methyl ester 612
3-Biphenyl-4-yl-(2S)-[[1-(2- 805 methanesulfonyl-benzenesulfonyl)-
pyrrolidin-2-ylmethyl]-(4'-trifluoromethyl-
biphenyl-4-carbonyl)-amino]-propionic acid methyl ester 613
3-Biphenyl-4-yl-(2S)-[[1-(4- 805 methanesulfonyl-benzenesulfonyl)-
pyrrolidin-2-ylmethyl]-(4'-trifluoromethyl-
biphenyl-4-carbonyl)-amino]-propionic acid methyl ester 614
3-Biphenyl-4-yl-(2S)-[[1-(2-thiophen-2- 711
yl-acetyl)-pyrrolidin-2-ylmethyl]-
(4'-trifluoromethyl-biphenyl-4-carbonyl)- amino]-propionic acid
methyl ester 615 (2S)-(2-{[(2-Biphenyl-4-yl-1-carboxy- 771
ethyl)-(4'-trifluoromethyl-biphenyl-
4-carbonyl)-amino]-methyl}-pyrrolidine- 1-sulfonyl)-benzoic acid
methyl ester 616 3-Biphenyl-4-yl-(2S)-[[1-(2- 791
methanesulfonyl-benzenesulfonyl)-
pyrrolidin-2-ylmethyl]-(4'-trifluoromethyl-
biphenyl-4-carbonyl)-amino]-propionic acid 617
3-Biphenyl-4-yl-(2S)-[(1- 683 cyclopentanecarbonyl-pyrrolidin-2-
ylmethyl)-(4'-trifluoromethyl-biphenyl-4-
carbonyl)-amino]-propionic acid methyl ester 618
3-Biphenyl-4-yl-(2S)-[(1- 655 cyclopropanecarbonyl-pyrrolidin-2-
ylmethyl)-(4'-trifluoromethyl-biphenyl-4-
carbonyl)-amino]-propionic acid methyl ester 619
3-Biphenyl-4-yl-(2S)-[[1-(4- 791 methanesulfonyl-benzenesulfonyl)-
pyrrolidin-2-ylmethyl]-(4'-trifluoromethyl-
biphenyl-4-carbonyl)-amino]-propionic acid 620
(2S)-[(1-Acetyl-pyrrolidin-2-ylmethyl)- 615
(4'-trifluoromethyl-biphenyl-4-carbonyl)-
amino]-3-biphenyl-4-yl-propionic acid 621
3-Biphenyl-4-yl-(2S)-[[1-(2,2-dimethyl- 657
propionyl)-pyrrolidin-2-ylmethyl]-
(4'-trifluoromethyl-biphenyl-4-carbonyl)- amino]-propionic acid 622
3-Biphenyl-4-yl-(2S)-[(1- 669 cyclopentanecarbonyl-pyrrolidin-2-
ylmethyl)-(4'-trifluoromethyl-biphenyl-4-
carbonyl)-amino]-propionic acid 623
(2S)-[(1-Acetyl-pyrrolidin-2-ylmethyl)- 615
(4'-trifluoromethyl-biphenyl-4-carbonyl)-
amino]-3-biphenyl-4-yl-propionic acid 624 3-Biphenyl-4-yl-(2S)-[(1-
641 cyclopropanecarbonyl-pyrrolidin-2-
ylmethyl)-(4'-trifluoromethyl-biphenyl-4-
carbonyl)-amino]-propionic acid 625
(2S)-[[2-(2-Acetylamino-4-methyl- 751
thiazole-5-sulfonylamino)-ethyl]-(4'-
trifluoromethyl-biphenyl-4-carbonyl)-
amino]-3-biphenyl-4-yl-propionic acid 626
3-Biphenyl-4-yl-(2S)-[[2-(5-chloro-1,3- 725
dimethyl-1H-pyrazole-4-sulfonylamino)-
ethyl]-(4'-trifluoromethyl-biphenyl-4- carbonyl)-amino]-propionic
acid 627 3-Biphenyl-4-yl-(2S)-[[2-(3,5-dimethyl- 692
isoxazole-4-sulfonylamino)-ethyl]-
(4'-trifluoromethyl-biphenyl-4-carbonyl)- amino]-propionic acid 628
3-Biphenyl-4-yl-(2S)-[[2-(1,2-dimethyl- 691
1H-imidazole-4-sulfonylamino)-ethyl]-
(4'-trifluoromethyl-biphenyl-4-carbonyl)- amino]-propionic acid 629
3-Biphenyl-4-yl-(2S)-[[2-(3,5-dimethyl- 706
isoxazole-4-sulfonylamino)-ethyl]-
(4'-trifluoromethyl-biphenyl-4-carbonyl)- amino]-propionic acid
methyl ester 630 3-Biphenyl-4-yl-(2S)-[[2-(1,2-dimethyl- 705
1H-imidazole-4-sulfonylamino)-ethyl]-
(4'-trifluoromethyl-biphenyl-4-carbonyl)- amino]-propionic acid
methyl ester 631 3-Biphenyl-4-yl-(2S)-[[2-(5-chloro-1,3- 739
dimethyl-1H-pyrazole-4-sulfonylamino)-
ethyl]-(4'-trifluoromethyl-biphenyl-4- carbonyl)-amino]-propionic
acid methyl ester 632 3-Biphenyl-4-yl-(2S)-[[2-(1-methyl-1H- 677
imidazole-4-sulfonylamino)-ethyl]-(4'-
trifluoromethyl-biphenyl-4-carbonyl)- amino]-propionic acid 633
3-Biphenyl-4-yl-(2S)-[[2-(2,4-dimethoxy- 683
benzylamino)-ethyl]-(4'-trifluoromethyl-
biphenyl-4-carbonyl)-amino]-propionic acid 634
3-Biphenyl-4-yl-(2S)-[(2-tert- 633 utoxycarbonylamino-ethyl)-(4'-
rifluoromethyl--biphenyl-4-carbonyl)- amino]-propionic acid
EXAMPLE 635
2-{[1-(4-Flouro-phenyl)-5-trifluoromethyl-1H-pyrazole-4-carbonyl]-amino}-3-
-(4'-trifluoromethoxy-biphenyl-4-yl)-propionic acid
[0616] A solution of hydrazine (1.00 mmol), ethyl
2-(ethoxymethylene)-4,4,4-trifluoroacetate (1.00 mmol), and DIEA
(1.00 mmol) in anhydrous acetonitrile was stirred at rt for 2 h.
The reaction mixture was concentrated under reduced pressure and
purified by flash column chromatography to give the desired ester
as a white solid. This ester was then hydrolyzed by general
procedure J to give the desired
1-(4-Fluoro-phenyl)-5-trifluoromethyl-1H-pyrazole-4-carboxylic acid
as a white solid.
[0617] A solution of above acid in DMF (3.0 mL) was reacted with
(2S)-amino-3-(4'-trifluoromethoxy-biphenyl-4-yl)propionic acid
methyl ester Hydrochloride (0.300 g, 0.797 mmol), HBTU (0.300 g,
0.797 mmol), and DIEA (0.425 mL, 2.40 mmol) as described in general
procedure A. The crude compound was purified by flash column
chromatography on silica gel using CHCl.sub.3 as the mobile phase
to give 0.290 g (61%) of
2-{[1-(4-fluoro-phenyl)-5-trifluoromethyl-1H-pyrazole-4-carbonyl]-amino)--
3-(4'-trifluoromethoxy-biphenyl-4-yl)-propionic acid methyl ester.
A solution of this ester (0.140 g, 0.235 mmol) in THF (4.0 mL) was
treated with LiOH (0.035 g) by general procedure I to afford (0.125
g, 92%) of the title compound
2-{[1-(4-Fluoro-phenyl)-5-trifluoromethyl-1H-pyrazole-4-carbonyl]-amino-3-
-(4'-trifluoromethyl-biphenyl-4-yl)-propionic acid as a white
solid. LCMS: 582 (M+1).sup.+. .sup.1H NMR (DMSO-d.sub.6) 8.94 [d, 1
H], 8.07 [s, 1 H], 7.76 [m, 2 H], 7.57 [m, 4 H], 7.42 [m, 6 H],
4.64 [m, 1 H], 3.22 [m, 1 H], 3.05 [m, 1 H].
EXAMPLE 636
2-{[1-(4-Fluoro-phenyl)-5-trifluoromethyl-1H-pyrazole-4-carbonyl]-amino}-3-
-(4'-trifluoromethyl-biphenyl-4-yl)-propionic acid
[0618] A solution of
1-(4-Fluoro-phenyl)-5-trifluoromethyl-1H-pyrazole-4-carboxylic acid
(0.300 g, 1.097 mmol, prepared in example 635) in DMF (4.0 mL) was
reacted with
(2S)-amino-3-(4'-trifluoromethyl-biphenyl-4-yl)propionic acid
methyl ester Hydrochloride (0.394 g, 1.097 mmol), HBTU (0.416 g,
1.097 mmol), and DIEA (0.585 mL, 3.29 mmol) as described in general
procedure A. The crude compound was purified by washing with ethyl
ether to give 0.300 g(47%) of
2-{[1-(4-Fluoro-phenyl)-5-trifluoromethyl-1H-pyrazole-4-carbonyl]-amino}--
3-(4'-trifluoromethyl-biphenyl-4-yl)-propionic acid methyl ester. A
solution of this ester (0.125 g, 0.215 mmol) in THF (4.0 mL) was
treated with LiOH (0.031 g) by general procedure I to afford (0.105
g, 87%) the title compound
2-{[1-(4-Fluoro-phenyl)-5-trifluoromethyl-1H-pyrazole-4-carbonyl]-amino}--
3-(4'-trifluoromethyl-biphenyl-4-yl)-propionic acid as a white
solid. LCMS: 565 (M+1).sup.+. .sup.1H NMR (DMSO-d.sub.6) 8.9? [d, 1
H], 8.39 [s, 1 H], 8.18 [d, 2 H], 8.09 [d, 2 H], 7.96 [d, 2 H],
7.87 [m, 2 H], 7.71 [m, 4 H], 4.83 [m, 1 H], 3.58 [m, 1 H], 3.36
[m, 1 H].
EXAMPLE 637
(2S)-{[1-(4-Fluoro-phenyl)-5-trifluoromethyl-1H-pyrazole-4-carbonyl]-amino-
)-3-(4'-trifluoromethyl-biphenyl-4-yl)-propionic acid
[0619] A solution of
1-(4-fluoro-phenyl)-5-trifluoromethyl-1H-pyrazole-4-carboxylic acid
(0.200 g, 0.731 mmol, prepared in example 635) in DMF (4.0 mL) was
reacted with 2-L-amino-3-biphenyl-4-yl-propionic acid methyl ester
hydrochloride (0.213 g, 0.731 mmol), HBTU (0.277 g, 0.731 mmol),
and DIEA (0.450 mL, 2.566 mmol) as described in general procedure
A. The crude compound was purified by flash column chromatography
on silica gel using CHCl.sub.3 (+10% hexane) to give 0.150 g(41%)
of
3-biphenyl-4-yl-2-{[1-(4-fluoro-phenyl)-5-trifluoromethyl-1H-pyrazole-4-c-
arbonyl]-amino}-propionic acid methyl ester. A solution of this
ester (0.085 g, 0.166 mmol) in THF (3.0 mL) was treated with LiOH
(0.025 g) by general procedure I to afford (0.070 g, 85%) of the
title compound
3-Biphenyl-4-yl-2-{[1-(4-fluoro-phenyl)-5-trifluoromethyl-1H-pyrazole-4-c-
arbonyl]-amino}-propionic acid as a white solid. LCMS: 498
(M+1).sup.+. .sup.1H NMR (DMSO-d.sub.6) 8.94 [d, 1 H], 8.08 [s, 1
H], 7.58 [m, 6 H], 7.42 [m, 7 H], 4.63 [m, 1 H], 3.22 [m, 1 H].
3-Biphenyl-4-yl-(2S)-{[1-(4-fluoro-phenyl)-5-trifluoromethyl-1H-pyrazole-4-
-carbonyl]-amino}-propionic acid
[0620] By analogous methods to-those described above the following
compounds were synthesized. TABLE-US-00017 EXAMPLE NAME LC/MS(m/z)
638 (2S)-{[1-(4-Chloro-phenyl)-5- 582
trifluoromethyl-1H-pyrazole-4-carbonyl]-
amino}-3-(4'-trifluoromethyl-biphenyl-4-yl)- propionic acid 639
3-Biphenyl-4-yl-(2S)-{[1-(4-chloro-phenyl)- 514
5-trifluoromethyl-1H-pyrazole-4-carbonyl]- amino}-propionic acid
640 (2S)-{[1-(4-Chloro-phenyl)-5- 598
trifluoromethyl-1H-pyrazole-4-carbonyl]-
amino}-3-(4'-trifluoromethoxy-biphenyl-4- yl)-propionic acid 641
2-{[1-(4-Fluoro-phenyl)-5-trifluoromethyl- 499
1H-pyrazole-4-carbonyl]-amino}-3-(6- phenyl-pyridin-3-yl)-propionic
acid 642 (2S)-{[1-(4-Nitro-phenyl)-5-rifluoromethyl- 609
1H-pyrazole-4-carbonyl]-amino}-3-(4'- trifluoromethoxy-biphenyl-4-
yl)-propionic acid 643 (2S)-{[1-(4-tert-Butyl-phenyl)-5- 620
trifluoromethyl-1H-pyrazole-4-carbonyl]-
amino}-3-(4'-trifluoromethoxy-biphenyl-4- yl)-propionic acid 644
(2S)-[(1-p-Tolyl-5-trifluoromethyl-1H- 578
pyrazole-4-carbonyl)-amino]-3-(4'-
trifluoromethoxy-biphenyl-4-yl)-propionic acid 645
(2S)-{[1-(6-Methoxy-pyridazin-3-yl)-5- 596
trifluoromethyl-1H-pyrazole-4-carbonyl]-
amino}-3-(4'-trifluoromethoxy- biphenyl-4-yl)-propionic acid 646
(2S)-[(5-Methyl-1-phenyl-1H-pyrazole-4- 510
carbonyl)-amino]-3-(4'-trifluoromethoxy- biphenyl-4-yl)-propionic
acid 647 (2S)-{[1-(4-Chloro-phenyl)-5- 598
trifluoromethyl-1H-pyrazole-4-carbonyl]-
amino}-3-(4'-trifluoromethoxy-biphenyl- 4-yl)-propionic acid 648
3-(4'-Trifluoromethoxy-biphenyl-4-yl)-(2S)- 648
{[1-(4-trifluoromethoxy-phenyl)-5-
trifluoromethyl-1H-pyrazole-4-carbonyl]- amino}-propionic acid 649
(2S)-{[1-(3-Chloro-4-fluoro-phenyl)-5- 616
trifluoromethyl-1H-pyrazole-4-carbonyl]-
amino}-3-(4'-trifluoromethoxy-biphenyl-4- yl)-propionic acid 650
(2S)-{[1-(4-Chloro-phenyl)-1H-pyrazole-4- 530
carbonyl]-amino}-3-(4'-trifluoromethoxy- biphenyl-4-yl)-propionic
acid 651 (2S)-[(1-Phenyl-5-trifluoromethyl-1H- 564
pyrazole-4-carbonyl)-amino]-3-(4'-
trifluoromethoxy-biphenyl-4-yl)-propionic acid 652
(2S)-[(1-Phenyl-5-trifluoromethyl-1H- 548
pyrazole-4-carbonyl)-amino]-3-(4'-
trifluoromethyl-biphenyl-4-yl)-propionic acid 653
3-Biphenyl-4-yl-(2S)-[(1-phenyl-5- 480
trifluoromethyl-1H-pyrazole-4-carbonyl)- amino]-propionic acid 654
(2S)-{[1-(4-Chloro-phenyl)-5-propyl-1H- 580
pyrazole-4-carbonyl]-amino}-3-(2'- phenoxy-biphenyl-4-yl)-propionic
acid
EXAMPLE 655
3(Biphenyl-4-ylmethoxy)-(2S)-[(4'-trifluoromethyl-biphenyl-4-carbonyl)-ami-
no]-propionic acid
[0621] To a solution of
2-tert-Butoxycarbonylamino-3-hydroxy-propionic acid methyl ester
(0.400 g, 1.82 mmol) in dimethylformamide (15 ml) was added sodium
hydride (65%)(0.145 g, 3.64 mmol) at 0.degree. C. after the
evolution of hydrogen gas ceased, the freshly distilled benzyl
bromide (0.449 g, 1.82 mmol) was added to the solution. The
reaction mixture was stirred at 25-30.degree. C. for 5 hr to give a
clear solution. The solvent was then removed under reduced pressure
below 40.degree. C. The residue was dissolved in water (30 ml) and
the solution extracted with ethyl acetate(two 20 ml portions). The
combined organic layers were further washed with brine and dried
over anhydrous sodium sulfate. The ethyl acetate was then removed
under reduced pressure to give the
3-(biphenyl-4-ylmethoxy)-(2S)-tert-butoxycarbonylamino-propionic
acid methyl ester as colorless oil (0.421 g, 60%). LC/MS (m/z):
386(M+1).
[0622] To
3-(Biphenyl-4-ylmethoxy)-(2S)-tert-butoxycarbonylamino-propioni- c
acid methyl ester (0.421 gms, 1.1 mmol) was added 2 ml of 4M HCl in
dioxane (8.8 mmol) and stirred for 30 min. The HCl was then removed
under reduced pressure and the residue was then triturated with
dichloromethane and hexane for 2-3 times and the solvents were
removed under reduced pressure to yield the HCl salt of the
compound (2S)-amino-3-(biphenyl-4-ylmethoxy)-propionic acid methyl
ester hydrochloride as a white solid (0.300 g, 90%). LC/MS (m/z):
286(M+1).
[0623] (2S)-Amino-3-(biphenyl-4-ylmethoxy)-propionic acid methyl
ester hydrochloride (0.150 g, 0.483 mmol) was reacted with
4'-trifluoromethyl-biphenyl-4-carboxylic acid (0.136 g, 0.483 mmol)
as described in general procedure A yielding the
3-(biphenyl-4-ylmethoxy)-(2S)-[(4'-trifluoromethyl-biphenyl-4-carbonyl)-a-
mino]-propionic acid methyl ester. The resulting compound was then
hydrolyzed by following the general procedure C to yield the title
compound (0.200 g, 80%).
[0624] .sup.1H-NMR(400 MHz, CDCl.sub.3): 4.2(m, 2H), 4.9 (S, 2H),
5.1 (m, 1H), 7.72(m, 1H), 7.74 (m, 4H), 7.94 (m, 4H), 8.17 (m, 4H),
8.28 (d, 2H), 8.34 (d, 2H), 8.62 (S, 1H), 9.3 (d, 1H); LC/MS (m/z):
520.2 (M+1).sup.+.
EXAMPLE 656
3-[(Biphenyl-4-ylmethyl)-amino]-(2S)-[(4'-trifluoromethyl-biphenyl-4-carbo-
nyl)-amino]-propionic acid
[0625] (2S)-amino-3-tert-butoxycarbonylamino-propionic acid methyl
ester hydrochloride (0.200 g, 0.785 mmol) was reacted with
4'-trifluoromethyl-biphenyl-4-carboxylic acid (0.208 g, 0.785 mmol)
as described in general procedure A yielding
3-tert-butoxycarbonylamino-(2S)-[(4'-trifluoromethyl-biphenyl-4-carbonyl)-
-amino]-propionic acid methyl ester (0.313 g, 85%). LC/MS (m/z):
367(M+1).
[0626] To
3-tert-butoxycarbonylamino-(2S)-[(4'-trifluoromethyl-biphenyl-4-
-carbonyl)-amino]-propionic acid methyl ester (0.313 g, 0.671 mmol)
was added 2 ml of 4M HCl in dioxane (3.3 mmol) and stirred for 30
min. The HCl was then removed under reduced pressure and the
residue was then triturated with dichloromethane and hexane for 2-3
times and the solvents were removed under reduced pressure to yield
the HCl salt of the compound
3-amino-(2S)-[(4'-trifluoromethyl-biphenyl-4-carbonyl)-amino]-propionic
acid methyl ester hydrochloride as a white solid (0.300 g, 90%).
LC/MS (m/z): 267(M+1).
[0627]
3-Amino-(2S)-[(4'-trifluoromethyl-biphenyl-4-carbonyl)-amino]-prop-
ionic acid methyl ester hydrochloride (0.200 g, 0.493 mmol) was
subjected to reductive amination as per general procedure E with
biphenyl-4-carbaldehyde (0.080 g, 0.444 mmol) and sodium
triacetoxyborohydride (0.208 g, 0.986 mmol) to yield the
3-[(biphenyl-4-ylmethyl)-amino]-(2S)-[(4'-trifluoromethyl-biphenyl-4-carb-
onyl)-amino]-propionic acid methyl ester which was further
hydrolyzed as per general procedure C to yield
3-[(biphenyl-4-ylmethyl)-amino]-(2S)-[(4'-trifluoromethyl-biphenyl-4-carb-
onyl)-amino]-propionic acid (0.190 g, 70%).
[0628] .sup.1H-NMR(400 MHz, DMSOd.sub.6): 3.9(m, 2H) 4.6(m, 2H),
5.2 (m, 1H), 7.72(m, 1H), 7.78 (m, 2H), 7.98 (m, 4H), 8.05 (bd,
2H), 8.19 (m, 4H), 8.27 (d, 2H), 8.40 (d, 2H), 8.7 (S, 1H), 9.5(d,
1H); LC/MS (m/z): 519.3(M+1).
EXAMPLE 657
3-(Biphenyl-4-ylmethyl-methyl-amino)-(2S)-[(4'-trifluoromethyl-biphenyl-4--
carbonyl)-amino]-propionic acid
[0629]
3-[(Biphenyl-4-ylmethyl)-amino]-(2S)-[(4'-trifluoromethyl-biphenyl-
-4-carbonyl)-amino]-propionic acid methyl ester (0.050 g, 0.093
mmol) prepared as per the above listed example 656 was subjected to
reductive amination as per procedure E with formaldehyde (0.010 ml,
0.093 mmol) and sodium triacetoxyborohydride (0.039 gms, 0.1 86
mmol) to yield the corresponding
3-(Biphenyl-4-ylmethyl-methyl-amino)-(2S)-[(4'-trifluoromethyl-biphenyl-4-
-carbonyl)-amino]-propionic acid methyl ester which was then
hydrolyzed as per general procedure C to yield the title compound
(0.040 g, 80%)..sup.1H-NMR(400 MHz, DMSOd.sub.6): 3.17(s, 3H), 3.9
(m, 2H), 4.76 (m,2H), 5.31(s,1H), 7.69(m, 1H), 7.77 (m, 2H), 7.97
(m, 4H), 8.05 (bd, 2H), 8.19 (m, 4H), 8.27 (d, 2H), 8.40 (d, 2H),
9.5(s,1H); LC/MS (m/z): 533.3(M+1).
EXAMPLE 658
3-(Biphenyl-4-ylmethyl-pyridin-4-ylmethyl-amino)-(2S)-[(4'-trifluoromethyl-
-biphenyl-4-carbonyl)-amino]-propionic acid
[0630]
3-[(Biphenyl-4-ylmethyl)-amino]-(2S)-[(4'-trifluoromethyl-biphenyl-
-4-carbonyl)-amino]-propionic acid methyl ester (0.050 g, 0.093
mmol) prepared as per the above listed example 656 was subjected to
reductive amination as per procedure E with 4-pyridine carbaldehyde
(0.010 ml, 0.093 mmol) and sodium triacetoxyborohydride (0.039 gms,
0.186 mmol) to yield the corresponding
3-(Biphenyl-4-ylmethyl-pyridin-4-yl
methyl-amino)-(2S)-[(4'-trifluoromethyl-biphenyl-4-carbonyl)-amino]-propi-
onic acid methyl ester which was then hydrolyzed as per general
procedure C to yield the title compound (0.040 g, 80%).
.sup.1H-NMR(400 MHz, DMSOd.sub.6): 3.3 (m, 2H), 4.001 (s, 4H),
5.18(m, 1H), 7.62-7.75 (m, 8H), 7.8-7.93 (m, 4H), 8.17 (m, 4H),
8.27 (m, 4H), 8.77 (d, 2H), 9.1 (d, 1H), 8.7 (S, 1H); LC/MS (m/z):
610.4(M+1).
EXAMPLE 659
3-(Biphenyl-4-ylmethyl-furan-2-ylmethyl-amino)-(2S)-[(4'-trifluoromethyl-b-
iphenyl-4-carbonyl)-amino]-propionic acid
[0631]
3-[(Biphenyl-4-ylmethyl)-amino]-(2S)-[(4'-trifluoromethyl-biphenyl-
-4-carbonyl)-amino]-propionic acid methyl ester (0.050 g, 0.093
mmol) prepared as per the above listed example 657 and was
subjected to reductive amination as per procedure E with
furan-27-carbaldehyde (0.009 g, 0.093 mmol) and sodium
triacetoxyborohydride (0.039 gms, 0.186 mmol) to yield the
corresponding
3-(biphenyl-4-ylmethyl-furan-2-ylmethyl-amino)-(2S)-[(4'-trifluoromethyl--
biphenyl-4-carbonyl)-amino]-propionic acid methyl ester which was
then hydrolyzed as per general procedure C to yield the title
compound (0.030 g, 60%)..sup.1H-NMR(400 MHz, DMSOd.sub.6): 3.21(m,
2H), 4.0 (m, 3H), 6.7(d, 1H), 7.6 (m, 2H), 7.8 (m, 8H), 8.24 (m,
8H); LC/MS (m/z): 599.3(M+1).
EXAMPLE 660
3-[(Biphenyl-4-carbonyl)-amino]-(2S)-[(4'-trifluoromethyl-biphenyl-4-carbo-
nyl)-amino]-propionic acid
[0632] The
3-amino-(2S)-[(4'-trifluoromethyl-biphenyl-4-carbonyl)-amino]-propionic
acid methyl ester hydrochloride (0.100 g, 0.273 mmol) prepared as
per the above listed Example 656 was reacted with
biphenylcarboxylic acid as per general procedure A to yield the
corresponding
3-[(biphenyl-4-carbonyl)-amino]-(2S)-[(4'-trifluoromethyl-biphenyl-4-carb-
onyl)-amino]-propionic acid methyl ester which was then hydrolyzed
as per general procedure C to yield the title compound (0.095 g,
65%)..sup.1H-NMR(400 MHz, DMSOd.sub.6): 4.16(m, 2H), 4.98 (m, 1H),
7.71(m, 2H), 7.79 (m, 2H), 8.08 (dd, 4H), 8.2-8.4 (m, 9H), 9.16 (m,
1H), 9.2(d,1H); LC/MS (m/z): 533.2(M+1).
EXAMPLE 661
(2S)-2,3-Bis-[(4'-trifluoromethyl-biphenyl-4-carbonyl)-amino]-propionic
acid
[0633] (2S)-2,3-Diamino-propionic acid methyl ester (0.080 g, 0.421
mmol) was reacted with 4'-trifluoromethyl-biphenyl-4-carboxylic
acid (0.224 g, 0.841 mmol) as described in general procedure A
yielding the corresponding
(2S)-3-bis-[(4'-trifluoromethyl-biphenyl-4-carbonyl)-amino]-propionic
acid methyl ester which was then hydrolyzed as per general
procedure C to yield the title compound (0.150 g, 60%).
.sup.1H-NMR(400 MHz, DMSOd.sub.6): 4.16(m, 2H), 5.0 (m, 1H),
8.17(m, 8H), 8.28(m, 8H), 9.18 (m, 1H), 9.21 (d, 1H);LC/MS (m/z):
601.2(M+1).
EXAMPLE 662
3-(Biphenyl-4-sulfonylamino)-(2S)-[(4'-trifluoromethyl-biphenyl-4-carbonyl-
)-amino]-propionic acid
[0634] To
3-amino-(2S)-[(4'-trifluoromethyl-biphenyl-4-carbonyl)-amino]-p-
ropionic acid methyl ester hydrochloride (0.1 00 g, 0.273 mmol)
prepared as per the above listed example 656 was added dry
dichloromethane (10 ml) followed by diisopropylethylamine (0.095 g,
0.738 mmol) and stirred for 10 min. To this mixture at 0.degree. C.
was added Biphenyl-4-sulfonyl chloride (0.062 g, 0273 mmol) and the
reaction was stirred at ambient temperature. After 2 hrs the
reaction mixture was diluted with dichloromethane and washed with
water (20 ml) followed by brine (20 ml). The organic layers were
collected and dried over sodium sulfate and concentrated under
reduced pressure to yield the
3-(Biphenyl-4-sulfonylamino)-2-[(4'-trifluoromethyl-biphenyl-4-carbony
I)-amino]-propionic acid methyl ester which was then hydrolyzed as
per procedure C to yield the title compound (0.045 g, 50%).
.sup.1H-NMR(400 MHz, DMSOd.sub.6): 3.65 (m, 2H), 4.85 (m, 1H),
7.78(m, 4H), 8.02 (d, 2H), 8.17 (m, 7H), 8.27 (m, 4H), 8.62 (S,
1H), 8.9 (bs, 1H). LC/MS (m/z): 569.1(M+1).
Biological Assay
[0635] The following assay methods are utilized to identify
compounds of Formula (I) that are effective in antagonizing the
function of factor IX. Compounds of Formula (I) are effective in
antagonizing the function of factor IX and are useful as inhibitors
of the intrinsic clotting pathway.
General Assay Procedure
Factor IXa Florescence Based Molecular Assay:
[0636] Method where a Fluorescent product is generated based on
factor IXa cleaving the substrate
CH.sub.3SO.sub.2-(D)-CHG-Gly-Arg-AMC AcOH (methyl
sulfonyl-D-cyclohexylglycyl-glycyl-arginine-7-amino-4-methylcouma-
rid monoacetate) available from Centerchem, Inc.
[0637] 12 .mu.L of 4.times. compound dilutions (final 1% DMSO) is
incubated for 10 min at room temp with 24 .mu.L FIXa
(HCIXA-0050Haemotologic Technologies Inc. Essex Junction, Vt.) 3.9
units/mL in Buffer containing 80% Ethylene glycol, 10 mM
CaCl.sub.2, 200 mM NaCl, and 100 mM Tris (pH 7.4). The reaction is
started by the addition of 12 .mu.L of 0.5 mM FIXa substrate
(Pefa-10148 from Pentapharm Basel, Switzerland). After incubating
the reaction for 10 min at room temp, the plate is read in a
Spectromax Gemini fluorescence plate reader with and exitation
wavelenth of 340 nm and an emmision wavelength of 440 nm. From the
varying concentrations of test compound, IC.sub.50's are then
calculated. The Examples in Table 1 inhibit Factor IX in this assay
with IC.sub.50 of less than 30 micromolar.
Factor IXa In Vitro Clotting Assay:
[0638] Method where inhibition of clotting using citrated human
plasma with exogenous human factor IXa is measured by
turbidity.
[0639] Potential inhibitors of factor IX are added to a mixture of
citrated human plasma, Cephalin, and human factor IX to give a
final concentration of 0.8 U/ml. The mixture is allowed to incubate
at 30.degree. C. for 10 minutes. Clotting is initiated by the
addition of 10 mM CaCl.sub.2. The optical density is measured at
405 nm for 5 minutes. Relative IC.sub.50's as well as maximum
efficacy are calculated.
[0640] A first control assay is performed using a mixture of
citrated human plasma, Cephalin, and human factor IX. A second
control assay is performed using a mixture of citrated human plasma
and Cephalin. Clotting for the two control assays is initiated by
the addition of CaCl.sub.2, and the optical density is measured at
405 nm for 5 minutes.
[0641] Analysis of graphs of optical denisty versus time for the
two control assays and various concentrations of compounds of
Formula (I) demonstrates that factor IX decreases the time for
Ca.sup.+2 induced clotting of human serum. Analysis also
demonstrates that compounds of Formula (I) prolong the Ca.sup.+2
induced clotting time in the presence of factor IX.
[0642] Factor Xa in vitro clotting assays were performed using
compounds of Formula (I) under the same or similar conditions as
the factor IXa in vitro clotting assay. These data demonstrate that
compounds of Formula (I) are partial inhibitors or partial
antagonists of factor IX. For example, where a range of
concentrations of a compound of Formula (I) in the presence of
factor IX prolong the Ca.sup.+2 induced clotting time from 700
seconds to 1500 seconds, the same range of concentrations of a
compound of Formula (I) in the presence of factor Xa did not alter
the Ca.sup.+2 induced clotting time from 200 seconds.
[0643] The invention further provides pharmaceutical compositions
comprising the factor IX modulating compounds of the invention. The
term "pharmaceutical composition" is used herein to denote a
composition that may be administered to a mammalian host, e.g.,
orally, topically, parenterally, by inhalation spray, or rectally,
in unit dosage formulations containing conventional non-toxic
carriers, diluents, adjuvants, vehicles and the like. The term
"parenteral" as used herein, includes subcutaneous injections,
intravenous, intramuscular, intracisternal injection, or by
infusion techniques.
[0644] The term "factor IX" is used herein to refer to blood
coagulation factor IX, including both activated and non-activated
forms thereof.
[0645] The term "therapeutically effective amount" is used herein
to denote that amount of a drug or pharmaceutical agent that will
elicit the therapeutic response of an animal or human that is being
sought.
[0646] The pharmaceutical compositions containing a compound of the
invention may be in a form suitable for oral use, for example, as
tablets, troches, lozenges, aqueous, or oily suspensions,
dispersible powders or granules, emulsions, hard or soft capsules,
or syrups or elixirs. Compositions intended for oral use may be
prepared according to any known method, and such compositions may
contain one or more agents selected from the group consisting of
sweetening agents, flavoring agents, coloring agents, and
preserving agents in order to provide pharmaceutically elegant and
palatable preparations. Tablets may contain the active ingredient
in admixture with non-toxic pharmaceutically-acceptable excipients
which are suitable for the manufacture of tablets. These excipients
may be for example, inert diluents, such as calcium carbonate,
sodium carbonate, lactose, calcium phosphate or sodium phosphate;
granulating and disintegrating agents, for example corn starch or
alginic acid; binding agents, for example, starch, gelatin or
acacia; and lubricating agents, for example magnesium stearate,
stearic acid or talc. The tablets may be uncoated or they may be
coated by known techniques to delay disintegration and absorption
in the gastrointestinal tract and thereby provide a sustained
action over a longer period. For example, a time delay material
such as glyceryl monostearate or glyceryl distearate may be
employed. They may also be coated by the techniques described in
U.S. Pat. Nos. 4,356,108; 4,166,452; and 4,265,874, to form osmotic
therapeutic tablets for controlled release.
[0647] Formulations for oral use may also be presented as hard
gelatin capsules where the active ingredient is mixed with an inert
solid diluent, for example, calcium carbonate, calcium phosphate or
kaolin, or a soft gelatin capsules wherein the active ingredient is
mixed with water or an oil medium, for example peanut oil, liquid
paraffin, or olive oil.
[0648] Aqueous suspensions may contain the active compounds in
admixture with excipients suitable for the manufacture of aqueous
suspensions. Such excipients are suspending agents, for example
sodium carboxymethylcellulose, methylcellulose,
hydroxypropylmethylcellulose, sodium alginate,
polyvinylpyrrolidone, gum tragacanth and gum acacia; dispersing or
wetting agents may be a naturally-occurring phosphatide such as
lecithin, or condensation products of an alkylene oxide with fatty
acids, for example polyoxyethylene stearate, or condensation
products of ethylene oxide with long chain aliphatic alcohols, for
example, heptadecaethyl-eneoxycetanol, or condensation products of
ethylene oxide with partial esters derived from fatty acids and a
hexitol such as polyoxyethylene sorbitol monooleate, or
condensation products of ethylene oxide with partial esters derived
from fatty acids and hexitol anhydrides, for example polyethylene
sorbitan monooleate. The aqueous suspensions may also contain one
or more coloring agents, one or more flavoring agents, and one or
more sweetening agents, such as sucrose or saccharin.
[0649] Oily suspensions may be formulated by suspending the active
ingredient in a vegetable oil, for example arachis oil, olive oil,
sesame oil or coconut oil, or in a mineral oil such as a liquid
paraffin. The oily suspensions may contain a thickening agent, for
example beeswax, hard paraffin or cetyl alchol. Sweetening agents
such as those set forth above, and flavoring agents may be added to
provide a palatable oral preparation. These compositions may be
preserved by the addition of an anti-oxidant such as ascorbic
acid.
[0650] Dispersible powders and granules suitable for preparation of
an aqueous suspension by the addition of water provide the active
compound in admixture with a dispersing or wetting agent,
suspending agent and one or more preservatives. Suitable dispersing
or wetting agents and suspending agents are exemplified by those
already mentioned above. Additional excipients, for example,
sweetening, flavoring, and coloring agents may also be present.
[0651] The pharmaceutical compositions of the invention may also be
in the form of oil-in-water emulsions. The oily phase may be a
vegetable oil, for example, olive oil or arachis oil, or a mineral
oil, for example a liquid paraffin, or a mixture thereof. Suitable
emulsifying agents may be naturally-occurring gums, for example gum
acacia or gum tragacanth, naturally-occurring phosphatides, for
example soy bean, lecithin, and esters or partial esters derived
from fatty acids and hexitol anhydrides, for example sorbitan
monooleate, and condensation products of said partial esters with
ethylene oxide, for example polyoxyethylene sorbitan monooleate.
The emulsions may also contain sweetening and flavoring agents.
[0652] Syrups and elixirs may be formulated with sweetening agents,
for example glycerol, propylene glycol, sorbitol or sucrose. Such
formulations may also contain a demulcent, a preservative and
flavoring and coloring agents. The pharmaceutical compositions may
be in the form of a sterile injectible aqueous or oleaginous
suspension. This suspension may be formulated according to the
known methods using suitable dispersing or wetting agents and
suspending agents described above. The sterile injectable
preparation may also be a sterile injectable solution or suspension
in a non-toxic parenterally-acceptable diluent or solvent, for
example as a solution in 1,3-butanediol. Among the acceptable
vehicles and solvents that may be employed are water, Ringer's
solution, and isotonic sodium chloride solution. In addition,
sterile, fixed oils are conveniently employed as solvent or
suspending medium. For this purpose, any bland fixed oil may be
employed using synthetic mono- or diglycerides. In addition, fatty
acids such as oleic acid find use in the preparation of
injectables.
[0653] The compositions may also be in the form of suppositories
for rectal administration of the compounds of the invention. These
compositions can be prepared by mixing the drug with a suitable
non-irritating excipient which is solid at ordinary temperatures
but liquid at the rectal temperature and will thus melt in the
rectum to release the drug. Such materials include cocoa butter and
polyethylene glycols, for example.
[0654] For topical use, creams, ointments, jellies, solutions of
suspensions, etc., containing the compounds of the invention are
contemplated. For the purpose of this application, topical
applications shall include mouth washes and gargles. The compounds
of the present invention may also be administered in the form of
liposome delivery systems, such as small unilamellar vesicles,
large unilamellar vesicles, and multilamellar vesicles. Liposomes
may be formed from a variety of phospholipids, such as cholesterol,
stearylamine, or phosphatidylcholines.
[0655] Also provided by the present invention are prodrugs of the
invention.
[0656] Pharmaceutically-acceptable salts of the compounds of the
present invention, where a basic or acidic group is present in the
structure, are also included within the scope of the invention. The
term "pharmaceutically acceptable salts" refers to non-toxic salts
of the compounds of this invention which are generally prepared by
reacting the free base with a suitable organic or inorganic acid or
by reacting the acid with a suitable organic or inorganic base.
Representative salts include the following salts: Acetate,
Benzenesulfonate, Benzoate, Bicarbonate, Bisulfate, Bitartrate,
Borate, Bromide, Calcium Edetate, Camsylate, Carbonate, Chloride,
Clavulanate, Citrate, Dihydrochloride, Edetate, Edisylate,
Estolate, Esylate, Fumarate, Gluceptate, Gluconate, Glutamate,
Glycollylarsanilate, Hexylresorcinate, Hydrabamine, Hydrobromide,
Hydrocloride, Hydroxynaphthoate, Iodide, Isethionate, Lactate,
Lactobionate, Laurate, Malate, Maleate, Mandelate,
Methanesulfonate, Methylbromide, Methylnitrate, Methylsulfate,
Monopotassium Maleate, Mucate, Napsylate, Nitrate,
N-methylglucamine, Oxalate, Pamoate (Embonate), Palmitate,
Pantothenate, Phosphate/diphosphate, Polygalacturonate, Potassium,
Salicylate, Sodium, Stearate, Subacetate, Succinate, Tannate,
Tartrate, Teoclate, Tosylate, Triethiodide, Trimethylammonium and
Valerate. When an acidic substituent is present, such as --COOH,
there can be formed the ammonium, morpholinium, sodium, potassium,
barium, calcium salt, and the like, for use as the dosage form.
When a basic group is present, such as amino or a basic heteroaryl
radical, such as pyridyl, an acidic salt, such as hydrochloride,
hydrobromide, phosphate, sulfate, trifluoroacetate,
trichloroacetate, acetate, oxlate, maleate, pyruvate, malonate,
succinate, citrate, tartarate, fumarate, mandelate, benzoate,
cinnamate, methanesulfonate, ethanesulfonate, picrate and the like,
and include acids related to the pharmaceutically-acceptable salts
listed in the Journal of Pharmaceutical Science, 66, 2 (1977) p.
1-19.
[0657] Other salts which are not pharmaceutically acceptable may be
useful in the preparation of compounds of the invention and these
form a further aspect of the invention.
[0658] In addition, some of the compounds of Formula (I) may form
solvates with water or common organic solvents. Such solvates are
also encompassed within the scope of the invention.
[0659] Thus, in another aspect of the present invention, there is
provided a pharmaceutical composition comprising a therapeutically
effective amount of a compound of Formula (I), or a
pharmaceutically acceptable salt, solvate, or prodrug therof, and
one or more pharmaceutically acceptable carriers, excipients, or
diluents. In an embodiment of the pharmaceutical composition, the
compound of Formula (I) is an antagonist of factor IX activity. In
another embodiment of the pharmaceutical composition, the compound
of Formula (I) is a partial antagonist of factor IX activity,
wherein a partial antagonist comprises a compound that inhibits
less than complete activity at a physiologically tolerable dose. In
another embodiment of the pharmaceutical composition, the compound
of Formula (I) is a partial antagonist of factor IX activity,
wherein the compound of Formula (I) inhibits up to 95% of factor IX
activity. In another embodiment of the pharmaceutical composition,
the compound of Formula (I) is a partial antagonist of factor IX
activity, wherein the compound of Formula (I) inhibits up to 80% of
factor IX activity. In another embodiment of the pharmaceutical
composition, the compound of Formula (I) is a partial antagonist of
factor IX activity, wherein the compound of Formula (I) inhibits up
to 50% of factor IX activity. In another embodiment of the
pharmaceutical composition, the compound of Formula (I) antagonizes
blood clotting mediated by factor IX.
[0660] In another aspect of the present invention, there is
provided a pharmaceutical composition comprising a therapeutically
effective amount of a compound of Formula (I), or a
pharmaceutically acceptable salt, solvate, or prodrug therof, and
one or more pharmaceutically acceptable carriers, excipients, or
diluents, wherein said therapeutically effective amount of Formula
(I) preferentially inhibits the intrinsic clotting cascade as
compared to the extrinsic clotting cascade. In an embodiment of the
pharmaceutical composition, said therapeutically effective amount
of Formula (I) inhibits the intrinsic clotting cascade by greater
than 80% and inhibits the extrinsic clotting cascade by less than
50%. In another embodiment of the pharmaceutical composition, said
therapeutically effective amount of Formula (I) comprises an amount
sufficient to achieve and maintain a sustained blood level that at
least partially antagonizes factor IX biological activity.
Preferably, said sustained blood level comprises a concentration
ranging from about 0.01 .mu.M to 2 mM, more preferably from about 1
.mu.M to 300 .mu.M, and even more preferably from about 20 .mu.M to
about 100 .mu.M.
[0661] In another aspect of the present invention, there is
provided a pharmaceutical composition comprising a therapeutically
effective amount of a compound of Formula (I), or a
pharmaceutically acceptable salt, solvate, or prodrug therof, and
one or more pharmaceutically acceptable carriers, excipients, or
diluents, wherein said therapeutically effective amount comprises a
sufficient amount of the compound of Formula (I) to at least
partially inhibit the biological activity of factor IX in a
subject, a sufficient amount of the compound of Formula (I) for at
least partial amelioration of at least one factor IX-mediated
disease, or a sufficient amount of the compound of Formula (I) to
at least partially inhibit the intrinsic clotting cascade in a
subject. In an embodiment of the pharmaceutial composition, said
factor IX-mediated disease comprises stroke. In another embodiment
of the pharmaceutial composition, said factor IX-mediated disease
comprises deep vein thrombosis. In another embodiment of the
pharmaceutial composition, said factor IX-mediated disease
comprises deep vein thrombosis, wherein said thrombosis is
associated with surgical procedures, long periods of confinement,
acquired or inherited pro-coagulant states including
anti-phospholipid antibody syndrome, protein C deficiency and
protein S deficiency, or acute and chronic inflammation including
recurrent miscarriage or Systemic Lupus Erythmatosis (SLE). In
another embodiment, said factor IX-mediated disease comprises
excessive clotting associated with the treatment of kidney diseases
by hemodialysis and/or venous hemofiltration. In another
embodiment, said factor IX-mediated disease comprises
cardiovascular disease. In another embodiment, said factor
IX-mediated disease comprises cardiovascular disease, wherein said
cardiovascular disease comprises myocardial infarction, arrhythmia,
or aneurysm.
[0662] In another aspect, the present invention provides a
pharmaceutical composition comprising a therapeutically effective
amount of the compound of Formula (I), and one or more
pharmaceutically acceptable carriers, excipients, or diluents,
wherein said pharmaceutical composition is used to replace or
supplement compounds that reduce clotting.
[0663] In another aspect, the present invention provides a
pharmaceutical composition comprising a therapeutically effective
amount of the compound of Formula (I), and one or more
pharmaceutically acceptable carriers, excipients, or diluents,
further comprising one or more therapeutic agents.
[0664] In another aspect, the present invention provides a method
for the inhibition of the normal biological function of factor IX
comprising administering to a subject in need thereof a compound of
Formula (I). In embodiment of the method, said compound of Formula
(I) is an antagonist of factor IX activity. In another embodiment
of the method, said compound of Formula (I) antagonizes blood
clotting mediated by factor IX. In another embodiment of the
method, said compound of Formula (I) is administered in an amount
sufficient to partially antagonize the biological activity of
factor IX in said subject. In another embodiment of the method,
said compound of Formula (I) is an antagonist of factor IX
activity. In another embodiment of the method, said compound of
Formula (I) antagonizes blood clotting mediated by factor IX. In
another embodiment of the method, said compound of Formula (I) is
administered in an amount sufficient to partially antagonize the
biological activity of factor IX in said subject. In another
embodiment of the method, said pharmaceutical composition is
administered in the form of an oral dosage or parenteral dosage
unit. In another embodiment of the method, said compound of Formula
(I) is administered as a dose in a range from about 0.01 to 1,000
mg/kg of body weight per day. In another embodiment of the method,
said compound of Formula (I) is administered as a dose in a range
from about 0.1 to 100 mg/kg of body weight per day. In another
embodiment of the method, said compound of Formula (I) is
administered as a dose in a range from about 0.5 to 10 mg/kg of
body weight per day. In another embodiment, said compound of
Formula (I) is used to replace or supplement compounds that reduce
clotting.
[0665] In another aspect, the present invention provides a method
for the inhibition of the normal biological function of factor IX
comprising administering to a subject in need thereof a compound of
Formula (I), wherein said compound of Formula (I) is administered
to said subject as a pharmaceutical composition comprising a
therapeutically effective amount of said compound of Formula (I)
and one or more pharmaceutically acceptable carriers, excipients,
or diluents. In an embodiment of the method, said therapeutically
effective amount of the compound of Formula (I) comprises a
sufficient amount of the compound of Formula (I) to at least
partially inhibit the intrinsic clotting cascade in said subject.
In another embodiment of the method, said therapeutically effective
amount of Formula (I) preferentially inhibits the intrinsic
clotting cascade as compared to the extrinsic clotting cascade. In
another embodiment of the method, said therapeutically effective
amount of Formula (I) inhibits the intrinsic clotting cascade by
greater than 80% and inhibits the extrinsic clotting cascade by
less than 50%. In another embodiment of the method, said
therapeutically effective amount of the compound of Formula I
comprises an amount sufficient to achieve and maintain a sustained
blood level that at least partially antagonizes factor IX
biological activity. Preferably, said sustained blood level
comprises a concentration ranging from about 0.01 .mu.M to 2 mM,
more preferably from about 1 .mu.M to 300 .mu.M, and even more
preferably from about 20 .mu.M to about 100 .mu.M. In another
embodiment of the method, said pharmaceutical composition further
comprises one or more therapeutic agents.
[0666] In another aspect, the present invention provides a method
for the inhibition of the normal biological function of factor IX
comprising administering to a subject in need thereof a compound of
Formula (I), wherein said compound of Formula (I) is a partial
antagonist of factor IX, wherein a partial antagonist comprises a
compound that inhibits less than complete activity at a
physiologically tolerable dose. In an embodiment of the method,
said compound of Formula (I) inhibits up to 95% of factor IX
activity. In another embodiment of the method, said compound of
Formula (I) inhibits up to 80% of factor IX activity. In another
embodiment of the method, said compound of Formula (I) inhibits up
to 50% of factor IX activity.
[0667] In another aspect, the present invention provides a method
for the inhibition of the normal biological function of factor IX
comprising administering to a subject in need thereof a compound of
Formula (I), wherein said compound of Formula (I) is administered
to said subject as a pharmaceutical composition comprising a
therapeutically effective amount of said compound of Formula (I)
and one or more pharmaceutically acceptable carriers, excipients,
or diluents, wherein said therapeutically effective amount of the
compound of Formula (I) comprises a sufficient amount of the
compound of Formula (I) for treatment or prevention of factor
IX-mediated diseases. In an embodiment of the method, said factor
IX-mediated disease comprises stroke. In another embodiment of the
method, said factor IX-mediated disease comprises deep vein
thrombosis. The thrombosis may be associated with surgical
procedures, long periods of confinement, acquired or inherited
pro-coagulant states including anti-phospholipid antibody syndrome,
protein C deficiency and protein S deficiency, or acute and chronic
inflammation including recurrent miscarriage or Systemic Lupus
Erythmatosis (SLE). In another embodiment of the method, said
factor IX-mediated disease comprises clotting associated with the
treatment of kidney disease by hemodialysis and/or venous
hemofiltration. In another embodiment of the method, said factor
IX-mediated disease comprises cardiovascular disease. The
cardiovascular disease may be associated myocardial infarction,
arrhythmia,or aneurysm.
[0668] In a further aspect of the present invention, the factor IXa
modulators of the invention are utilized in adjuvant therapeutic or
combination therapeutic treatments with other known therapeutic
agents.
[0669] The term "treatment" as used herein, refers to the full
spectrum of treatments for a given disorder from which the patient
is suffering, including alleviation of one, most of all symptoms
resulting from that disorder, to an outright cure for the
particular disorder or prevention of the onset of the disorder.
[0670] The following is a non-exhaustive listing of adjuvants and
additional therapeutic agents which may be utilized in combination
with the factor IXa antagonists of the present invention: [0671] 1.
Analgesics: Aspirin [0672] 2. NSAIDs (Nonsteroidal
anti-inflammatory drugs): Ibuprofen, Naproxen, Diclofenac [0673] 3.
DMARDs (Disease-Modifying Antirheumatic drugs): Methotrexate, gold
preparations, hydroxychloroquine, sulfasalazine [0674] 4. Biologic
Response Modifiers, DMARDs: Etanercept, Infliximab
Glucocorticoids
[0675] In a further preferred embodiment, the present invention
provides a method of treating or preventing a factor IXa mediated
diseases, the method comprising administering to a subject in need
thereof, a therapeutically effective amount of a compound of
Formula (I) alone or in combination with therapeutic agents
selected from the group consisting of antibiotics, hormones,
biologic response modifiers, analgesics, NSAIDs, DMARDs,
glucocorticoids, thrombolytic agents, antidepressants, and
anticonvulsants.
[0676] Generally speaking, the compound of the present invention,
preferably Formula (I), is administered at a dosage level of from
about 0.01 to 1000 mg/kg of the body weight of the subject being
treated, with a preferred dosage range between 0.01 and 100 mg/kg,
most preferably 0.5 to 10 mg/kg of body weight per day. The amount
of active ingredient that may be combined with the carrier
materials to produce a single dosage will vary depending upon the
host treated and the particular mode of administration. For
example, a formulation intended for oral administration to humans
may contain 1 mg to 2 grams of a compound of Formula (I) with an
appropriate and convenient amount of carrier material which may
vary from about 5 to 95 percent of the total composition. Dosage
unit forms will generally contain between from about 5 mg to about
500 mg of active ingredient. This dosage has to be individualized
by the clinician based on the specific clinical condition of the
subject being treated. Thus, it will be understood that the
specific dosage level for any particular patient will depend upon a
variety of factors including the activity of the specific compound
employed, the age, body weight, general health, sex, diet, time of
administration, route of administration, rate of excretion, drug
combination and the severity of the particular disease undergoing
therapy.
[0677] While the invention has been described and illustrated with
reference to certain preferred embodiments therof, those skilled in
the art will appreciate that various changes, modifications and
substitutions can be made therein without departing from the spirit
and scope of the invention. For example, effective dosages other
than the preferred dosages as set forth herein may be applicable as
a consequence of variations in the responsiveness of the mammal
being treated for factor IXa-mediated disease(s). Likewise, the
specific pharmacological responses observed may vary according to
and depending on the particular active compound selected or whether
there are present pharmaceutical carriers, as well as the type of
formulation and mode of administration employed, and such expected
variations or differences in the results are contemplated in
accordance with the objects and practices of the present
invention.
* * * * *