U.S. patent application number 14/025688 was filed with the patent office on 2014-01-09 for piperidinone derivatives as mdm2 inhibitors for the treatment of cancer.
This patent application is currently assigned to AMGEN INC.. The applicant listed for this patent is AMGEN INC.. Invention is credited to Michael David BARTBERGER, Hilary Plake Beck, Xiaoqi Chen, Richard Victor Connors, Jeffrey Deignan, Jason Duquette, John Eksterwicz, Benjamin Fisher, Brian Matthew Fox, Jiasheng Fu, Zice Fu, Ana Gonzalez Buenrostro, Felix Gonzalez Lopez De Turiso, Michael William Gribble, Dann James Gustin, Julie Anne Heath, Xin Huang, Xianyun Jiao, Michael Johnson, Frank Kayser, David John Kopecky, Sujen Lai, Yihong Li, Zhihong Li, Jiwen Liu, Jonathan Dante Low, Brian Stuart Lucas, Zhihua Ma, Lawrence R. McGee, Joel McIntosh, Dustin McMinn, Julio Cesar Medina, Jeffrey Thomas Mihalic, Steven Howard Olson, Yosup Rew, Philip Marley Roveto, Daqing Sun, Xiaodong Wang, Yingcai Wang, Xuelei Yan, Ming Yu, Jiang Zhu.
Application Number | 20140011796 14/025688 |
Document ID | / |
Family ID | 44504412 |
Filed Date | 2014-01-09 |
United States Patent
Application |
20140011796 |
Kind Code |
A1 |
BARTBERGER; Michael David ;
et al. |
January 9, 2014 |
PIPERIDINONE DERIVATIVES AS MDM2 INHIBITORS FOR THE TREATMENT OF
CANCER
Abstract
The present invention provides MDM2 inhibitor compounds of
Formula I, ##STR00001## wherein the variables are defined above,
which compounds are useful as therapeutic agents, particularly for
the treatment of cancers. The present invention also relates to
pharmaceutical compositions that contain an MDM2 inhibitor.
Inventors: |
BARTBERGER; Michael David;
(Sherman Oaks, CA) ; Gonzalez Buenrostro; Ana;
(San Mateo, CA) ; Beck; Hilary Plake; (San Carlos,
CA) ; Chen; Xiaoqi; (Palo Alto, CA) ; Connors;
Richard Victor; (Pacifica, CA) ; Deignan;
Jeffrey; (San Francisco, CA) ; Duquette; Jason;
(Millbrae, CA) ; Eksterwicz; John; (San Francisco,
CA) ; Fisher; Benjamin; (San Mateo, CA) ; Fox;
Brian Matthew; (Brisbane, CA) ; Fu; Jiasheng;
(Foster City, CA) ; Fu; Zice; (Foster City,
CA) ; Gonzalez Lopez De Turiso; Felix; (San Mateo,
CA) ; Gribble; Michael William; (San Francisco,
CA) ; Gustin; Dann James; (Half Moon Bay, CA)
; Heath; Julie Anne; (Orinda, CA) ; Huang;
Xin; (Wellesley, MA) ; Jiao; Xianyun;
(Belmont, WA) ; Johnson; Michael; (San Francisco,
CA) ; Kayser; Frank; (San Francisco, CA) ;
Kopecky; David John; (San Francisco, CA) ; Lai;
Sujen; (Burlingame, CA) ; Li; Yihong;
(Millbrae, CA) ; Li; Zhihong; (Millbrae, CA)
; Liu; Jiwen; (Foster City, CA) ; Low; Jonathan
Dante; (Tarzana, CA) ; Lucas; Brian Stuart;
(San Francisco, CA) ; Ma; Zhihua; (Foster City,
CA) ; McGee; Lawrence R.; (Pacifica, CA) ;
McIntosh; Joel; (Pacifica, CA) ; McMinn; Dustin;
(Pacifica, CA) ; Medina; Julio Cesar; (San Carlos,
CA) ; Mihalic; Jeffrey Thomas; (San Francisco,
CA) ; Olson; Steven Howard; (Millbrae, CA) ;
Rew; Yosup; (Foster City, CA) ; Roveto; Philip
Marley; (San Francisco, CA) ; Sun; Daqing;
(Foster City, CA) ; Wang; Xiaodong; (Millbrae,
CA) ; Wang; Yingcai; (Millbrae, CA) ; Yan;
Xuelei; (Foster City, CA) ; Yu; Ming; (Foster
City, CA) ; Zhu; Jiang; (Palo Alto, CA) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
AMGEN INC. |
Thousand Oaks |
CA |
US |
|
|
Assignee: |
AMGEN INC.
Thousand Oaks
CA
|
Family ID: |
44504412 |
Appl. No.: |
14/025688 |
Filed: |
September 12, 2013 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
|
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13153345 |
Jun 3, 2011 |
8569341 |
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14025688 |
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Current U.S.
Class: |
514/210.2 ;
514/222.2; 514/222.8; 514/227.8; 514/230.5; 514/235.5; 514/236.2;
514/253.12; 514/255.05; 514/256; 514/275; 514/278; 514/291;
514/316; 514/318; 514/321; 514/326; 514/327; 544/105; 544/11;
544/130; 544/3; 544/329; 544/332; 544/336; 544/360; 544/58.2;
546/17; 546/188; 546/198; 546/207; 546/208; 546/209; 546/210;
546/213; 546/216; 546/221; 546/90 |
Current CPC
Class: |
C07D 417/12 20130101;
C07D 498/20 20130101; C07D 407/04 20130101; C07D 491/153 20130101;
C07D 409/12 20130101; A61P 43/00 20180101; C07D 405/04 20130101;
A61P 35/02 20180101; C07D 405/12 20130101; C07D 409/04 20130101;
C07D 221/20 20130101; C07D 401/06 20130101; A61P 29/00 20180101;
C07D 279/02 20130101; C07D 211/76 20130101; A61P 35/00 20180101;
C07D 413/06 20130101; C07D 417/14 20130101; C07D 471/10 20130101;
A61P 31/12 20180101; C07D 407/06 20130101; C07D 491/08 20130101;
A61P 1/04 20180101; C07D 401/12 20130101; A61P 31/04 20180101; C07D
498/08 20130101; C07D 401/04 20130101; C07D 417/06 20130101; C07D
498/14 20130101 |
Class at
Publication: |
514/210.2 ;
546/221; 514/327; 544/130; 514/235.5; 546/208; 514/326; 544/58.2;
514/227.8; 546/209; 514/318; 546/210; 546/17; 514/278; 546/213;
544/360; 514/253.12; 514/236.2; 546/188; 514/316; 546/207; 544/329;
514/256; 544/3; 514/222.2; 544/105; 544/11; 514/222.8; 546/90;
514/291; 546/216; 544/336; 514/255.05; 544/332; 514/275; 546/198;
514/321; 514/230.5 |
International
Class: |
C07D 211/76 20060101
C07D211/76; C07D 417/12 20060101 C07D417/12; C07D 413/06 20060101
C07D413/06; C07D 471/10 20060101 C07D471/10; C07D 409/04 20060101
C07D409/04; C07D 401/04 20060101 C07D401/04; C07D 279/02 20060101
C07D279/02; C07D 491/08 20060101 C07D491/08; C07D 498/08 20060101
C07D498/08; C07D 417/14 20060101 C07D417/14; C07D 491/153 20060101
C07D491/153; C07D 417/06 20060101 C07D417/06; C07D 401/06 20060101
C07D401/06; C07D 405/04 20060101 C07D405/04 |
Claims
1. A compound of Formula I: ##STR01083## or a pharmaceutically
acceptable salt thereof, wherein: Q is a bond or optionally can be
selected from O, NR.sup.7 or S(O).sub.v, when n* is an integer from
1 to 6; Z is C.dbd.O or S(.dbd.O).sub.2; R.sup.a at each occurrence
is independently selected from H, (C.sub.1-C.sub.3)alkyl,
(halo)(C.sub.1-C.sub.3)alkyl, (hydroxy)(C.sub.1-C.sub.3)alkyl,
(alkoxy)(C.sub.1-C.sub.3)alkyl, or cyano; R.sup.b is H, halo,
(C.sub.1-C.sub.3)alkyl, (halo)(C.sub.1-C.sub.3)alkyl,
(hydroxy)(C.sub.1-C.sub.3)alkyl, (alkoxy)(C.sub.1-C.sub.3)alkyl, or
cyano; R.sup.c and R.sup.d are independently selected from H, halo,
(C.sub.1-C.sub.3)alkyl, (C.sub.1-C.sub.3)alkoxy,
(halo)(C.sub.1-C.sub.3)alkyl, (halo)(C.sub.1-C.sub.3)alkoxy,
(alkoxy)(C.sub.1-C.sub.3)alkyl, or (hydroxy)(C.sub.1-C.sub.3)alkyl,
or R.sup.e and R.sup.d may optionally combine to form a
spiro-cycloalkyl or heterocyclo ring system; R.sup.e is (a) H or
halo; or (b) (C.sub.1-C.sub.8)alkyl, (C.sub.3-C.sub.8)cycloalkyl,
(C.sub.3-C.sub.8)heterocyclo, cyano, halogen, hydroxyl, --OR.sup.5,
NR.sup.7R.sup.8, or heterocycloalkyl, any of which may be
optionally substituted with 1 or more R.sup.x groups as allowed by
valence, or R.sup.e and any one of the R' or R'' groups may
optionally combine to form a spiro-cycloalkyl or heterocyclo ring
system, or R.sup.d and any one of the R' or R'' groups may
optionally combine to form a fused cycloalkyl or heterocyclo ring
system, or R.sup.d and R.sup.e may optionally combine to form a
fused cycloalkyl or heterocyclo ring system; R' and R'' at each
occurrence, respectively, are independently H, halo,
(C.sub.1-C.sub.3)alkyl, (C.sub.1-C.sub.3)alkoxy,
(halo)(C.sub.1-C.sub.3)alkyl, (halo)(C.sub.1-C.sub.3)alkoxy,
(alkoxy)(C.sub.1-C.sub.3)alkyl, (hydroxy)(C.sub.1-C.sub.3)alkyl,
--S--(C.sub.1-C.sub.3)alkyl, C(O)(C.sub.1-C.sub.3)alkyl,
--NR.sup.7R.sup.8, or hydroxyl, or R' and R'' bound to the same
carbon atom may optionally combine to form .dbd.O, or R' and R''
bound to the same carbon atom may optionally combine to form a
spiro-fused cycloalkyl or heterocyclo ring system; R.sup.1 is (a)
--COOH, --C(O)OR.sup.10, --C(O)NHOH, --C(O)NH--NH.sub.2,
--C(O)NHS(O).sub.2R.sup.10, --S(O).sub.2NHC(O)R.sup.10,
--S(O).sub.2NR.sup.7R.sup.8, --NR.sup.7C(O)R.sup.10,
--NR.sup.7C(O)OR.sup.5, --C(O)NR.sup.7R.sup.8,
--NR.sup.7S(O).sub.2R.sup.10, --NR.sup.7C(O)NR.sup.7R.sup.8,
--S(O).sub.vR.sup.10, hydroxylalkyl, -cyclopropyl-COOH, or CN; or
(b) heteroaryl or heterocyclo, either of which may be optionally
independently substituted with one or more R.sup.x groups as
allowed by valence; R.sup.2 is (a) --NR.sup.7R.sup.8,
NR.sup.7C(O)OR.sup.10, NR.sup.7C(O)NR.sup.7R.sup.10, or
--C(R.sup.a)R.sup.5R.sup.6; or (b) aryl, heteroaryl, cycloalkyl, or
heterocyclo, any of which may be optionally independently
substituted with one or more R.sup.x groups as allowed by valence;
R.sup.3 and R.sup.4 are independently aryl or heteroaryl, either of
which may be optionally independently substituted with one or more
R.sup.x groups as allowed by valence, or either R.sup.3 and R.sup.a
together with the ring carbon atom to which they are both bonded,
or R.sup.4 and R.sup.b together with the ring carbon atom to which
they are both bonded may optionally combine to form a spiro-fused
bicyclic ring system selected from ##STR01084## wherein K is --O--,
--NR.sup.7--, or --C(.dbd.O)NR.sup.7--; R.sup.5 and R.sup.6 at each
occurrence, respectively, are independently selected from (a) H or
CN; (b) -(alkylene).sub.t-OH, -(alkylene).sub.t-OR.sup.9,
-(alkylene).sub.t-SR.sup.9, -(alkylene).sub.t-NR.sup.10R.sup.11,
-(alkylene).sub.t-C(O)R.sup.9, -(alkylene).sub.t-C(O)OR.sup.9,
-(alkylene).sub.t-OC(O)R.sup.9,
-(alkylene).sub.t-S(O).sub.vR.sup.9,
-(alkylene).sub.t-NHS(O).sub.2R.sup.10,
-(alkylene).sub.t-N(R.sup.1)S(O).sub.2R.sup.10,
-(alkylene).sub.t-S(O).sub.2NR.sup.10R.sup.11,
-(alkylene).sub.t-N(R.sup.11)S(O).sub.2NR.sup.10R.sup.11,
--NR.sup.10C(O)R.sup.9, --C(O)NR.sup.10R.sup.11,
--NR.sup.10S(O).sub.2R.sup.9, S(O).sub.2NR.sup.10, or
NR.sup.10C(O)NR.sup.10R.sup.11; or (c) haloalkyl, haloalkoxy,
C.sub.1-6-alkyl, C.sub.2-6alkenyl, C.sub.2-6-alkynyl,
C.sub.3-8-cycloalkyl, (C.sub.3-8-cycloalkyl)(C.sub.1-3alkyl),
C.sub.4-8-cycloalkenyl, aryl, aryl(C.sub.1-3-alkyl), heteroaryl,
heteroaryl(C.sub.1-3-alkyl), heterocyclo or
heterocyclo(C.sub.1-3-alkyl), any of which may be optionally
independently substituted with one or more R.sup.x groups as
allowed by valence; R.sup.7 and R.sup.8 at each occurrence,
respectively, are independently selected from H, cyano,
--OC.sub.1-6-alkyl, C.sub.1-6-alkyl, halo(C.sub.1-6)-alkyl,
cycloalkyl, C.sub.2-6-alkenyl, C.sub.2-6-alkynyl, aryl, heteroaryl,
heterocyclo, arylalkyl, heteroarylalkyl,
heterocyclo(C.sub.1-10alkyl), or
(C.sub.3-8-cycloalkyl)(C.sub.1-3alkyl), any of which may be
optionally substituted as allowed by valence with one or more
R.sup.x, or R.sup.7 and R.sup.8 may combine to form a
C.sub.4-C.sub.8-heterocyclo ring optionally substituted with one or
more R.sup.x; R.sup.9 is haloalkyl, haloalkoxy, C.sub.1-6-alkyl,
C.sub.2-6alkenyl, C.sub.2-6-alkynyl, C.sub.3-8-cycloalkyl,
(C.sub.3-8-cycloalkyl)(C.sub.1-3alkyl), C.sub.4-8-cycloalkenyl,
aryl, heteroaryl, heterocyclo, or heterocycloalkyl, any of which
may be optionally independently substituted with one or more
R.sup.x groups as allowed by valence; R.sup.10 and R.sup.11 at each
occurrence, respectively, are independently selected from H, alkyl,
haloalkyl, cycloalkyl, alkenyl, alkynyl, aryl, heteroaryl,
heterocyclo, arylalkyl, heteroarylalkyl, heterocycloalkyl, or
cycloalkylalkyl, any of which may be optionally substituted as
allowed by valence with one or more R.sup.x, or R.sup.10 and
R.sup.11 may combine to form a heterocyclo ring optionally
substituted with one or more R.sup.x; R.sup.x at each occurrence is
independently, deuterium, halo, cyano, nitro, oxo, alkyl,
haloalkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, heterocyclo,
aryl, heteroaryl, arylalkyl, heteroarylalkyl, cycloalkylalkyl,
heterocycloalkyl, -(alkylene).sub.t-OR*,
-(alkylene).sub.t-S(O).sub.vR*, -(alkylene).sub.t-NR.sup.+R.sup.++,
-(alkylene).sub.t-C(.dbd.O)R*, -(alkylene).sub.t-C(.dbd.S)R*,
-(alkylene).sub.t-C(.dbd.O)OR*, -(alkylene).sub.t-OC(.dbd.O)R*,
-(alkylene).sub.t-C(.dbd.S)OR*,
-(alkylene).sub.t-C(.dbd.O)NR.sup.+R.sup.++,
-(alkylene).sub.t-C(.dbd.S)NR.sup.+R.sup.++,
-(alkylene).sub.t-N(R.sup.+)C(.dbd.O)NR.sup.+R.sup.++,
-(alkylene).sub.t-N(R.sup.+)C(.dbd.S)NR.sup.+R.sup.++,
-(alkylene).sub.t-N(R.sup.+)C(.dbd.O)R*,
-(alkylene).sub.t-N(R.sup.+)C(.dbd.S)R*,
-(alkylene).sub.t-OC(.dbd.O)NR.sup.+R.sup.++,
-(alkylene).sub.t-OC(.dbd.S)NR.sup.+R.sup.++,
-(alkylene).sub.t-SO.sub.2NR.sup.+R.sup.++,
-(alkylene).sub.t-N(R.sup.+)SO.sub.2R*,
-(alkylene).sub.t-N(R)SO.sub.2NR.sup.+R.sup.++,
-(alkylene).sub.t-N(R.sup.+)C(.dbd.O)OR*,
-(alkylene).sub.t-N(R.sup.+)C(.dbd.S)OR*, or
-(alkylene).sub.t-N(R.sup.+)SO.sub.2R*, wherein said alkyl,
haloalkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, heterocyclo,
aryl, heteroaryl, arylalkyl, heteroarylalkyl, cycloalkylalkyl, and
heterocycloalkyl groups may be further independently substituted
with one or more halo, cyano, oxo, -(alkylene).sub.t-OR*,
-(alkylene).sub.t-S(O).sub.vR*, -(alkylene).sub.t-NR.sup.+R.sup.++,
-(alkylene).sub.t-C(.dbd.O)R*, -(alkylene).sub.t-C(.dbd.S)R*,
-(alkylene).sub.t-C(.dbd.O)OR*, -(alkylene).sub.t-OC(.dbd.O)R*,
-(alkylene).sub.t-C(.dbd.S)OR*,
-(alkylene).sub.t-C(.dbd.O)NR.sup.+R.sup.++,
-(alkylene).sub.t-C(.dbd.S)NR.sup.+R.sup.++,
-(alkylene).sub.t-N(R.sup.+)C(.dbd.O)NR.sup.+R.sup.++,
-(alkylene).sub.t-N(R.sup.+)C(.dbd.S)NR.sup.+R.sup.++,
-(alkylene).sub.t-N(R.sup.+)C(.dbd.O)R*,
-(alkylene).sub.t-N(R.sup.+)C(.dbd.S)R*,
-(alkylene).sub.t-OC(.dbd.O)NR.sup.+R.sup.++,
-(alkylene).sub.t-OC(.dbd.S)NR.sup.+R.sup.++,
-(alkylene).sub.t-SO.sub.2NR.sup.+R.sup.++,
-(alkylene).sub.t-N(R.sup.+)SO.sub.2R*,
-(alkylene).sub.t-N(R)SO.sub.2NR.sup.+R.sup.++,
-(alkylene).sub.t-N(R.sup.+)C(.dbd.O)OR*,
-(alkylene).sub.t-N(R.sup.+)C(.dbd.S)OR*, or
-(alkylene).sub.t-N(R.sup.+)SO.sub.2R*; R* is H, haloalkyl,
haloalkoxy, C.sub.1-6-alkyl, C.sub.2-6alkenyl, C.sub.2-6-alkynyl,
C.sub.3-8-cycloalkyl, C.sub.4-8-cycloalkenyl, aryl, heteroaryl, or
heterocyclo; R.sup.+ and R.sup.++ are independently H, alkyl,
haloalkyl, cycloalkyl, alkenyl, alkynyl, aryl, heteroaryl,
heterocyclo, arylalkyl, heteroarylalkyl, heterocycloalkyl, or
cycloalkylalkyl, or R.sup.+ and R.sup.++ bound to the same nitrogen
atom may optionally combine to form a heterocyclo ring system; m is
1, 2 or 3; n and n* are each independently selected from 0 or an
integer from 1 to 6; p is 0, 1, 2 or 3; t at each occurrence is
independently 0 or an integer from 1 to 6; and v at each occurrence
is independently 0, 1 or 2.
2. The compound of claim 1, or a pharmaceutically acceptable salt
thereof, wherein R.sup.2 is --C(H)R.sup.5R.sup.6,
--NR.sup.7R.sup.8, phenyl or pyridine, wherein the phenyl or the
pyridyl substituted with one or more Rx as allowed by valence.
3. The compound of claim 1, or a pharmaceutically acceptable salt
thereof, wherein R.sup.2 is selected from ##STR01085## ##STR01086##
##STR01087## any of which may be optionally substituted with one or
more R.sup.x groups as allowed by valence.
4. The compound of claim 1 having the structure of Formula IA
##STR01088## or a pharmaceutically acceptable salt thereof, wherein
q and p are each independently 0, 1, 2 or 3.
5. The compound of claim 1 having the structure of Formula IB
##STR01089## or a pharmaceutically acceptable salt thereof, wherein
q and p are each independently 0, 1, 2 or 3.
6. The compound of claim 1 having the structure of Formula IC
##STR01090## or a pharmaceutically acceptable salt thereof, wherein
q and p are each independently 0, 1, 2 or 3.
7. The compound of claim 6, or a pharmaceutically acceptable salt
thereof, wherein R.sup.2 is selected from ##STR01091## ##STR01092##
##STR01093## any of which may be optionally substituted with one or
more R.sup.x groups as allowed by valence.
8. The compound of claim 6, or a pharmaceutically acceptable salt
thereof, wherein R.sup.2 is selected from ##STR01094## ##STR01095##
##STR01096## any of which may be optionally substituted with one or
more R.sup.x groups as allowed by valence; and R.sup.1 is
##STR01097## or a heteroaryl or heterocycle selected from
##STR01098##
9. The compound of claim 6, or a pharmaceutically acceptable salt
thereof, wherein R.sup.2 is selected from ##STR01099## ##STR01100##
##STR01101## any of which may be optionally substituted with one or
more R.sup.x groups as allowed by valence; and R.sup.1 is
##STR01102## or a heteroaryl or heterocycle selected from
##STR01103##
10. The compound of claim 6, or a pharmaceutically acceptable salt
thereof, wherein R.sup.2 is selected from ##STR01104## ##STR01105##
##STR01106## any of which may be optionally substituted with one or
more R.sup.x groups as allowed by valence; and R.sup.1 is
##STR01107## or a heteroaryl or heterocycle selected from
##STR01108##
11. The compound of claim 1 having the structure of Formula ID
##STR01109## or a pharmaceutically acceptable salt thereof.
12. The compound of claim 11, or a pharmaceutically acceptable salt
thereof, wherein Re is H or methyl or ethyl.
13. The compound of claim 1 having the structure of Formula IE
##STR01110## or a pharmaceutically acceptable salt thereof.
14. The compound of claim 13, or a pharmaceutically acceptable salt
thereof, wherein Re is H or methyl or ethyl.
15. The compound of claim 13, or a pharmaceutically acceptable salt
thereof, wherein R.sup.2 is selected from ##STR01111## ##STR01112##
##STR01113## any of which may be optionally substituted with one or
more R.sup.x groups as allowed by valence; and R.sup.1 is
##STR01114## or a heteroaryl or heterocycle selected from
##STR01115##
16. The compound of claim 13, or a pharmaceutically acceptable salt
thereof, wherein R.sup.1 is ##STR01116## or a heteroaryl or
heterocycle selected from ##STR01117## R.sup.2 is ##STR01118## and
R.sup.e is methyl.
17. The compound of claim 13, or a pharmaceutically acceptable salt
thereof, wherein: R.sup.2 is ##STR01119## R.sup.5 is cyclopropyl,
or C.sub.1-6alkyl; R.sup.9 is haloalkyl, haloalkoxy,
C.sub.1-6-alkyl, C.sub.2-6alkenyl, C.sub.2-6-alkynyl,
C.sub.3-8-cycloalkyl, (C.sub.3-8-cycloalkyl)(C.sub.1-3alkyl),
C.sub.4-8-cycloalkenyl, aryl, heteroaryl, or heterocycloalkyl, or
R.sup.9 is haloalkyl, haloalkoxy, C.sub.1-6-alkyl,
C.sub.2-6alkenyl, C.sub.2-6-alkynyl, C.sub.3-8-cycloalkyl,
(C.sub.3-8-cycloalkyl)(C.sub.1-3alkyl), C.sub.4-8-cycloalkenyl,
aryl, heteroaryl, or heterocyclo, any of which may be optionally
independently substituted with one or more R.sup.x groups as
allowed by valence; and R.sup.10 and R.sup.11 at each occurrence,
respectively, are independently selected from H, alkyl, haloalkyl,
cycloalkyl, alkenyl, alkynyl, aryl, heteroaryl, heterocyclo,
arylalkyl, heteroarylalkyl, heterocycloalkyl, or cycloalkylalkyl,
any of which may be optionally substituted as allowed by valence
with one or more R.sup.x, or R.sup.10 and R.sup.11 may combine to
form a heterocyclo ring optionally substituted with one or more
R.sup.x.
18. The compound of claim 13, or a pharmaceutically acceptable salt
thereof, wherein: R.sup.1 is ##STR01120## R.sup.2 is ##STR01121##
and R.sup.e is methyl.
19. A compound, or a pharmaceutically acceptable salt thereof,
selected from:
2-((3R,5R,6S)-1-((S)-1-tert-butoxy-1-oxobutan-2-yl)-5-(3-chlorophen-
yl)-6-(4-chlorophenyl)-2-oxopiperidin-3-yl)acetic acid;
2-((3S,5R,6S)-1-((S)-1-tert-butoxy-1-oxobutan-2-yl)-5-(3-chlorophenyl)-6--
(4-chlorophenyl)-2-oxopiperidin-3-yl)acetic acid;
2-((3R,5R,6S)-5-(3-Chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-ethoxy-1-oxo-
butan-2-yl)-2-oxopiperidin-3-yl)acetic acid;
2-((3R,5R,6S)-5-(3-Chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-ethoxy-4-met-
hyl-1-oxopentan-2-yl)-2-oxopiperidin-3-yl)acetic acid;
2-((3R,5R,6S)-5-(3-Chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-ethoxy-1-oxo-
pentan-2-yl)-2-oxopiperidin-3-yl)acetic acid;
2-((3S,5S,6R)-5-(3-Chlorophenyl)-6-(4-chlorophenyl)-1-((R)-1-ethoxy-1-oxo-
pentan-2-yl)-2-oxopiperidin-3-yl)acetic acid;
2-((3R,5R,6S)-1-((S)-2-tert-Butoxy-1-cyclopropyl-2-oxoethyl)-5-(3-chlorop-
henyl)-6-(4-chlorophenyl)-2-oxopiperidin-3-yl)acetic acid;
2-((3R,5R,6S)-5-(3-Chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-hydroxybutan-
-2-yl)-2-oxopiperidin-3-yl)acetic acid;
2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-cyclopropyl--
2-hydroxyethyl)-2-oxopiperidin-3-yl)acetic acid;
2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-(cyclopropyl-
methoxy)butan-2-yl)-2-oxopiperidin-3-yl)acetic acid;
2-((3R,5R,6S)-5-(3-Chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-methoxybutan-
-2-yl)-2-oxopiperidin-3-yl)acetic acid;
2-((3R,5R,6S)-5-(3-Chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-(2-methoxyet-
hoxy)butan-2-yl)-2-oxopiperidin-3-yl)acetic acid;
2-((3R,5R,6S)-5-(3-Chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-((1-cyanocyc-
lopropyl)methoxy)butan-2-yl)-2-oxopiperidin-3-yl)acetic acid;
2-((3S,5R,6S)-5-(3-Chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-(cyclopropyl-
methoxy)butan-2-yl)-2-oxopiperidin-3-yl)acetic acid;
2-((3S,5R,6S)-5-(3-Chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-methoxybutan-
-2-yl)-2-oxopiperidin-3-yl)acetic acid;
2-((3S,5R,6S)-5-(3-Chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-(2-methoxyet-
hoxy)butan-2-yl)-2-oxopiperidin-3-yl)acetic acid;
2-((3R,5R,6S)-1-((S)-1-((1-carbamoylcyclopropyl)methoxy)butan-2-yl)-5-(3--
chlorophenyl)-6-(4-chlorophenyl)-2-oxopiperidin-3-yl)acetic acid
(isomer 1);
2-((3S,5R,6S)-1-((S)-1-((1-carbamoylcyclopropyl)methoxy)butan-2-yl)-5-
-(3-chlorophenyl)-6-(4-chlorophenyl)-2-oxopiperidin-3-yl)acetic
acid (isomer 2);
2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-(2-hydroxy-2-
-methylpropoxy)butan-2-yl)-2-oxopiperidin-3-yl)acetic acid;
2-((3R,5R,6S)-5-(3-Chlorophenyl)-6-(4-chlorophenyl)-2-oxo-1-((3S)-1,1,1-t-
rifluoro-2-hydroxypentan-3-yl)piperidin-3-yl)acetic acid (isomer
1);
2-((3R,5R,6S)-5-(3-Chlorophenyl)-6-(4-chlorophenyl)-2-oxo-1-((3S)-1,1,1-t-
rifluoro-2-hydroxypentan-3-yl)piperidin-3-yl)acetic acid (isomer
2);
2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-morpholinobu-
tan-2-yl)-2-oxopiperidin-3-yl)acetic acid;
2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-(ethylamino)-
butan-2-yl)-2-oxopiperidin-3-yl)acetic acid;
2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-2-oxo-1-((S)-1-(2,2,2-
-trifluoroethylamino)butan-2-yl)piperidin-3-yl)acetic acid;
2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-2-oxo-1-((S)-1-(pyrro-
lidin-1-yl)butan-2-yl)piperidin-3-yl)acetic acid;
2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-2-oxo-1-((S)-1-(2-oxo-
pyrrolidin-1-yl)butan-2-yl)piperidin-3-yl)acetic acid;
2-((3R,5R,6S)-5-(3-Chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-(1,1-dioxido-
thiomorpholino)butan-2-yl)-2-oxopiperidin-3-yl)acetic acid;
2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-2-oxo-1-((S)-1-(thiaz-
ol-2-ylamino)butan-2-yl)piperidin-3-yl)acetic acid;
2-((3R,5R,6S)-1-((S)-1-acetamidobutan-2-yl)-5-(3-chlorophenyl)-6-(4-chlor-
ophenyl)-2-oxopiperidin-3-yl)acetic acid;
2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-(methylsulfo-
namido) butan-2-yl)-2-oxopiperidin-3-yl)acetic acid;
2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-cyanopentan--
3-yl)-2-oxopiperidin-3-yl)acetic acid;
2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-(methylsulfo-
nyl)pentan-3-yl)-2-oxopiperidin-3-yl)acetic acid;
2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-2-oxo-1-((S)-1-(pyrid-
in-2-yl)pentan-3-yl)piperidin-3-yl)acetic acid;
2-((3R,5R,6S)-5-(3-Chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-(ethylamino)-
-1-oxobutan-2-yl)-2-oxopiperidin-3-yl)acetic acid;
2-((3R,5R,6S)-5-(3-Chlorophenyl)-6-(4-chlorophenyl)-1-((R)-1-(ethylamino)-
-1-oxobutan-2-yl)-2-oxopiperidin-3-yl)acetic acid;
2-((3R,5R,6S)-5-(3-Chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-(5-methyl-1,-
3,4-oxadiazol-2-yl)propyl)-2-oxopiperidin-3-yl)acetic;
2-((3R,5R,6S)-5-(3-Chlorophenyl)-6-(4-chlorophenyl)-1-((R)-1-(5-methyl-1,-
3,4-oxadiazol-2-yl)propyl)-2-oxopiperidin-3-yl)acetic acid;
2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-(cyclopropylmethyl)-
-2-oxopiperidin-3-yl)acetic acid;
2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-(cyclobutylmethyl)--
2-oxopiperidin-3-yl)acetic acid;
2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-(2-ethylbutyl)-2-ox-
opiperidin-3-yl)acetic acid;
2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-(cyclopentylmethyl)-
-2-oxopiperidin-3-yl)acetic acid;
2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((2,2-dimethylcyclo-
pentyl)methyl)-2-oxopiperidin-3-yl)acetic acid;
2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-(cyclohexylmethyl)--
2-oxopiperidin-3-yl)acetic acid;
2-((3S,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-(cyclopropylmethyl)-
-2-oxopiperidin-3-yl)acetic acid;
2-((3S,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-2-oxo-1-propylpiperid-
in-3-yl)acetic acid;
2-((3S,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-(cyclobutylmethyl)--
2-oxopiperidin-3-yl)acetic acid;
2-((3S,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-isobutyl-2-oxopiper-
idin-3-yl)acetic acid;
2-((3S,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-(cyclopentylmethyl)-
-2-oxopiperidin-3-yl)acetic acid;
2-((3S,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-2-oxo-1-(pentan-3-yl)-
piperidin-3-yl)acetic acid; Methyl
2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-(cyclopropylmethyl)-
-2-oxopiperidin-3-yl)acetate;
2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-(cyclopropylmethyl)-
-2-oxopiperidin-3-yl)acetamide; Ethyl
2-(2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-(cyclopropylmeth-
yl)-2-oxopiperidin-3-yl)acetamido)acetate;
2-(2-((3R,5R,6S)-5-(3-Chlorophenyl)-6-(4-chlorophenyl)-1-(cyclopropylmeth-
yl)-2-oxopiperidin-3-yl)acetamido)acetic acid;
2-((3R,5R,6S)-5-(3-Chlorophenyl)-6-(4-chlorophenyl)-1-(cyclopropylmethyl)-
-2-oxopiperidin-3-yl)acetohydrazide;
2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-(cyclopropylmethyl)-
-2-oxopiperidin-3-yl)-N-hydroxyacetamide; (S)-Ethyl
2-((2S,3R,5R)-3-(3-chlorophenyl)-2-(4-chlorophenyl)-5-(2-(methylsulfonami-
do)-2-oxoethyl)-6-oxopiperidin-1-yl)butanoate; (S)-Ethyl
2-((2S,3R,5R)-3-(3-chlorophenyl)-2-(4-chlorophenyl)-5-(2-((3-morpholinopr-
opyl)amino)-2-oxoethyl)-6-oxopiperidin-1-yl)butanoate;
(3R,5R,6S)-3-((1H-Tetrazol-5-yl)methyl)-5-(3-chlorophenyl)-6-(4-chlorophe-
nyl)-1-(cyclopropylmethyl)piperidin-2-one;
(3R,5R,6S)-3-((1,3,4-oxadiazol-2-yl)methyl)-5-(3-chlorophenyl)-6-(4-chlor-
ophenyl)-1-(cyclopropylmethyl)piperidin-2-one;
(3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-(cyclopropylmethyl)-3--
((5-methyl-1,3,4-oxadiazol-2-yl)methyl)piperidin-2-one;
2-((3S,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-(cyclopropylmethyl)-
-2-oxopiperidin-3-yl)-N-(methylsulfonyl)acetamide;
2-((3S,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-(cyclopropylmethyl)-
-2-oxopiperidin-3-yl)acetamide;
(3R,5R,6S)-3-((1H-tetrazol-5-yl)methyl)-5-(3-chlorophenyl)-6-(4-chlorophe-
nyl)-1-(cyclopropylmethyl)piperidin-2-one;
(3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-(cyclopropylmethyl)-3--
((5-methylisoxazol-3-yl)methyl)piperidin-2-one;
2-((2'S,3'R,5'R)-6-chloro-3'-(3-chlorophenyl)-1'-(cyclopropylmethyl)-2,6'-
-dioxospiro[indoline-3,2'-piperidine]-5'-yl)acetic acid;
2-((2'R,3'S,5'S)-6-chloro-3'-(3-chlorophenyl)-1'-(cyclopropylmethyl)-2,6'-
-dioxospiro[indoline-3,2'-piperidine]-5'-yl)acetic acid;
2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(5-chlorothiophen-2-yl)-1-(cyclopropyl-
methyl)-2-oxopiperidin-3-yl)acetic acid;
2-((3S,5R,6S)-5-(3-chlorophenyl)-6-(5-chlorothiophen-2-yl)-1-(cyclopropyl-
methyl)-2-oxopiperidin-3-yl)acetic acid;
2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-ethoxy-1-oxo-
butan-2-yl)-3-methyl-2-oxopiperidin-3-yl)acetic acid;
2-((3R,5R,6S)-1-((S)-1-tert-butoxy-1-oxobutan-2-yl)-5-(3-chlorophenyl)-6--
(4-chlorophenyl)-3-methyl-2-oxopiperidin-3-yl)acetic acid;
2-((3R,5R,6S)-1-((R)-1-tert-butoxy-1-oxobutan-2-yl)-5-(3-chlorophenyl)-6--
(4-chlorophenyl)-3-methyl-2-oxopiperidin-3-yl)acetic acid;
2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-(cyclopropyl-
methoxy)butan-2-yl)-3-methyl-2-oxopiperidin-3-yl)acetic acid;
2-((3S,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-(cyclopropylmethyl)-
-2-oxo-3-(2-(pyrrolidin-1-yl)ethyl)piperidin-3-yl)acetic acid;
2-((3S,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-(cyclopropylmethyl)-
-3-(2-morpholinoethyl)-2-oxopiperidin-3-yl)acetic acid;
2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-2-oxo-1-(pen-
tan-3-yl)piperidin-3-yl)acetic acid;
2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-(cyclopropylmethyl)-
-3-methyl-2-oxopiperidin-3-yl)acetic acid;
2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-isopropyl-3-methyl--
2-oxopiperidin-3-yl)acetic acid;
2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-cyclobutyl-3-methyl-
-2-oxopiperidin-3-yl)acetic acid;
2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-cyclopentyl-3-methy-
l-2-oxopiperidin-3-yl)acetic acid;
(3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-3-((5-oxo-4,5-d-
ihydro-1H-1,2,4-triazol-3-yl)methyl)-1-(pentan-3-yl)piperidin-2-one;
5-(((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-2-oxo-1-(pe-
ntan-3-yl)piperidin-3-yl)methyl)-1,3,4-oxadiazol-2(3H)-one;
2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-2-oxo-1-(pen-
tan-3-yl)piperidin-3-yl)-N-(trifluoromethylsulfonyl)acetamide;
(3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-((3-hydroxy-1H-pyrazol-
-5-yl)methyl)-3-methyl-1-(pentan-3-yl)piperidin-2-one;
(3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-((3-hydroxyisoxazol-5--
yl)methyl)-3-methyl-1-(pentan-3-yl)piperidin-2-one;
5-(((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-2-oxo-1-(pe-
ntan-3-yl)piperidin-3-yl)methyl)oxazolidine-2,4-dione;
3-(((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-2-oxo-1-(pe-
ntan-3-yl)piperidin-3-yl)methyl)-1,2,4-oxadiazol-5(4H)-one;
3-(((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-isopropyl-3-methyl-
-2-oxopiperidin-3-yl)methyl)-1,2,4-oxadiazol-5(4H)-one;
3-(((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-2-oxo-1-(pe-
ntan-3-yl)piperidin-3-yl)methyl)-1,2,4-thiadiazol-5(4H)-one;
3-(((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-isopropyl-3-methyl-
-2-oxopiperidin-3-yl)methyl)-1,2,4-thiadiazol-5(4H)-one;
(3R,5R,6S)-3-((1H-Tetrazol-5-yl)methyl)-5-(3-chlorophenyl)-6-(4-chlorophe-
nyl)-1-isopropyl-3-methylpiperidin-2-one;
2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-ethyl-2-oxo-1-(pent-
an-3-yl)piperidin-3-yl)acetic acid;
(3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-3-(methylsulfon-
ylmethyl)-1-(pentan-3-yl)piperidin-2-one;
2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-(3-cycloprop-
yl-1,2,4-oxadiazol-5-yl)propyl)-3-methyl-2-oxopiperidin-3-yl)acetic
acid;
2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((R)-1-(3-cycloprop-
yl-1,2,4-oxadiazol-5-yl)propyl)-3-methyl-2-oxopiperidin-3-yl)acetic
acid;
2-((3R,5R,6S)-5-(3-Chlorophenyl)-6-(4-chlorophenyl)-3-methyl-1-((S)-1-mor-
pholinobutan-2-yl)-2-oxopiperidin-3-yl)acetic acid;
2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-2-oxo-1-((S)-
-1-(2,2,2-trifluoroethylamino)butan-2-yl)piperidin-3-yl)acetic
acid;
2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-(2,2-dimethy-
lmorpholino)butan-2-yl)-3-methyl-2-oxopiperidin-3-yl)acetic acid;
2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((2S)-1-(2,6-dimeth-
ylmorpholino)butan-2-yl)-3-methyl-2-oxopiperidin-3-yl)acetic acid;
2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-(4-(cyclopro-
pylsulfonyl)piperazin-1-yl)butan-2-yl)-3-methyl-2-oxopiperidin-3-yl)acetic
acid;
2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-1-((S)-
-1-(4-(methylsulfonyl)piperazin-1-yl)butan-2-yl)-2-oxopiperidin-3-yl)aceti-
c acid;
2-((3R,5R,6S)-1-((S)-1-(4-acetylpiperazin-1-yl)butan-2-yl)-5-(3-ch-
lorophenyl)-6-(4-chlorophenyl)-3-methyl-2-oxopiperidin-3-yl)acetic
acid;
2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-(4-(cyclopro-
panecarbonyl)piperazin-1-yl)butan-2-yl)-3-methyl-2-oxopiperidin-3-yl)aceti-
c acid;
3-(((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-1-((-
S)-1-morpholinobutan-2-yl)-2-oxopiperidin-3-yl)methyl)-1,2,4-oxadiazol-5(4-
H)-one;
2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-(5,5--
dimethyl-2-oxooxazolidin-3-yl)butan-2-yl)-3-methyl-2-oxopiperidin-3-yl)ace-
tic acid;
2-((3R,5R,6S)-1-((S)-1-(tert-butylamino)-1-oxobutan-2-yl)-5-(3-c-
hlorophenyl)-6-(4-chlorophenyl)-3-methyl-2-oxopiperidin-3-yl)acetic
acid;
2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((1S,2R,3S)-2,3-dih-
ydroxycyclopentyl)-3-methyl-2-oxopiperidin-3-yl)acetic acid;
2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((1R,2R,3S)-2,3-dih-
ydroxycyclopentyl)-3-methyl-2-oxopiperidin-3-yl)acetic acid;
2-((3R,3'S,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-2-oxo-1'-
-(2,2,2-trifluoroethyl)-1,3'-bipiperidin-3-yl)acetic acid;
2-((3R,3'R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-2-oxo-1'-
-(2,2,2-trifluoroethyl)-1,3'-bipiperidin-3-yl)acetic acid;
2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((1S,3S)-3-hydroxyc-
yclopentyl)-3-methyl-2-oxopiperidin-3-yl)acetic acid;
2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((1S,3R)-3-hydroxyc-
yclopentyl)-3-methyl-2-oxopiperidin-3-yl)acetic acid;
2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-2-oxo-1-((S)-
-tetrahydro-2H-pyran-3-yl)piperidin-3-yl)acetic acid;
2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-2-oxo-1-((R)-
-tetrahydro-2H-pyran-3-yl)piperidin-3-yl)acetic acid;
2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-2-oxo-1-(pyr-
azin-2-yl)piperidin-3-yl)acetic acid;
2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-1-(1-methyl--
1H-pyrazol-4-yl)-2-oxopiperidin-3-yl)acetic acid;
2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-2-oxo-1-(pyr-
imidin-4-yl)piperidin-3-yl)acetic acid;
2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-(2-chloropyrimidin--
4-yl)-3-methyl-2-oxopiperidin-3-yl)acetic acid;
2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-2-oxo-1-(pyr-
imidin-2-yl)piperidin-3-yl)acetic acid;
2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-1-(3-methylp-
yridin-2-yl)-2-oxopiperidin-3-yl)acetic acid;
2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-1-(4-methylp-
yridin-2-yl)-2-oxopiperidin-3-yl)acetic acid;
2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-(dicyclopropylmethy-
l)-3-methyl-2-oxopiperidin-3-yl)acetic acid;
2-((3S,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-(dicyclopropylmethy-
l)-3-methyl-2-oxopiperidin-3-yl)acetic acid;
((3S,4R,6R)-4-(3-chlorophenyl)-3-(4-chlorophenyl)-1,1-dioxido-2-(2-propan-
yl)-1,2-thiazinan-6-yl)acetic acid;
((3S,4R,6S)-4-(3-chlorophenyl)-3-(4-chlorophenyl)-1,1-dioxido-2-(2-propan-
yl)-1,2-thiazinan-6-yl)acetic acid;
((3S,4R,6R)-4-(3-chlorophenyl)-3-(4-chlorophenyl)-6-methyl-1,1-dioxido-2--
(2-propanyl)-1,2-thiazinan-6-yl)acetic acid;
((3S,4R,6S)-4-(3-chlorophenyl)-3-(4-chlorophenyl)-6-methyl-1,1-dioxido-2--
(2-propanyl)-1,2-thiazinan-6-yl)acetic acid;
2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(5-chloropyridin-2-yl)-3-methyl-1-((S)-
-1-morpholinobutan-2-yl)-2-oxopiperidin-3-yl)acetic acid;
2-((3S,5R,6S)-5-(3-Chlorophenyl)-6-(5-chloropyridin-2-yl)-3-methyl-2-oxo--
1-(pentan-3-yl)piperidin-3-yl)acetic acid;
2-((3R,5R,6S)-5-(3-Chlorophenyl)-6-(5-chloropyridin-2-yl)-3-methyl-2-oxo--
1-(pentan-3-yl)piperidin-3-yl)acetic acid;
2-((3S,5R,6S)-5-(3-Chlorophenyl)-6-(5-chloropyridin-2-yl)-3-methyl-2-oxo--
1-(pentan-3-yl)piperidin-3-yl)acetic acid;
2-((3R,5R,6S)-1-((S)-1-tert-butoxy-1-oxobutan-2-yl)-5-(3-chlorophenyl)-6--
(5-chloropyridin-2-yl)-3-methyl-2-oxopiperidin-3-yl)acetic acid; or
2-((3R,5S,6S)-1-((S)-1-tert-butoxy-1-oxobutan-2-yl)-6-(4-chlorophenyl)-5--
(4-chloropyridin-2-yl)-3-methyl-2-oxopiperidin-3-yl)acetic
acid.
20. A compound, or a pharmaceutically acceptable salt thereof,
selected from:
2-((3S,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-(N-met-
hylcyclopropanesulfonamido)butan-2-yl)-2-oxopiperidin-3-yl)acetic
acid;
2-((3S,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-(N-methylcyc-
lopropanesulfonamido)butan-2-yl)-2-oxopiperidin-3-yl)propanoic
acid; (S)-tert-butyl
2-((3R,5R,6S)-3-((1H-tetrazol-5-yl)methyl)-5-(3-chlorophenyl)-6-(4-chloro-
phenyl)-3-methyl-2-oxopiperidin-1-yl)butanoate;
2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-1-((S)-1-(me-
thylsulfonamido)butan-2-yl)-2-oxopiperidin-3-yl)acetic acid;
2-((3R,5R,6S)-5-(3-Chlorophenyl)-6-(4-chlorophenyl)-3-methyl-2-oxo-1-((S)-
-5-oxohexan-3-yl)piperidin-3-yl)acetic acid;
2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((S)-5-hydroxy-5-me-
thylhexan-3-yl)-3-methyl-2-oxopiperidin-3-yl)acetic acid;
2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-2-oxo-1-((3S-
,5S)-6,6,6-trifluoro-5-hydroxy-5-methylhexan-3-yl)piperidin-3-yl)acetic
acid (isomer 1);
2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-2-oxo-1-((3S-
,5R)-6,6,6-trifluoro-5-hydroxy-5-methylhexan-3-yl)piperidin-3-yl)acetic
acid (isomer 2);
2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-1-((S)-1-(N--
methylmethylsulfonamido)butan-2-yl)-2-oxopiperidin-3-yl)acetic
acid;
2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((3S)-5-cyclopropyl-
-6,6,6-trifluoro-5-hydroxyhexan-3-yl)-3-methyl-2-oxopiperidin-3-yl)acetic
acid;
2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((S)-6-hydrox-
y-6-methylheptan-3-yl)-3-methyl-2-oxopiperidin-3-yl)acetic acid;
2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-2-oxo-1-((S)-
-6,6,6-trifluoro-5,5-dihydroxyhexan-3-yl)piperidin-3-yl)acetic
acid;
2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-2-oxo-1-((3S-
)-7,7,7-trifluoro-6-hydroxy-6-methylheptan-3-yl)piperidin-3-yl)acetic
acid (isomer 1);
2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-2-oxo-1-((3S-
)-7,7,7-trifluoro-6-hydroxy-6-methylheptan-3-yl)piperidin-3-yl)acetic
acid (isomer 2);
2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((S)-7-hydroxy-7-me-
thyloctan-3-yl)-3-methyl-2-oxopiperidin-3-yl)acetic acid;
2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-1-((S)-1-(N--
methylcyclopropanesulfonamido)butan-2-yl)-2-oxopiperidin-3-yl)acetic
acid;
2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-(N-cycloprop-
ylmethylsulfonamido)butan-2-yl)-3-methyl-2-oxopiperidin-3-yl)acetic
acid;
2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-2-oxo-1-((3S-
)-6,6,6-trifluoro-5-hydroxyhexan-3-yl)piperidin-3-yl)acetic acid
(isomer 1);
2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-2-oxo-1--
((3S)-6,6,6-trifluoro-5-hydroxyhexan-3-yl)piperidin-3-yl)acetic
acid (isomer 2);
2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((3S)-5-hydroxyhexa-
n-3-yl)-3-methyl-2-oxopiperidin-3-yl)acetic acid (isomer 1);
2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((3S)-5-hydroxyhexa-
n-3-yl)-3-methyl-2-oxopiperidin-3-yl)acetic acid (isomer 2);
2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-2-oxo-1-((S)-
-1-(N-(2,2,2-trifluoroethyl)methylsulfonamido)butan-2-yl)piperidin-3-yl)ac-
etic acid;
2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-(1-
,1-dioxidoisothiazolidin-2-yl)butan-2-yl)-3-methyl-2-oxopiperidin-3-yl)ace-
tic acid;
2-((3R,5R,6S)-5-(3-Chlorophenyl)-6-(4-chlorophenyl)-1-((3S,4R)-5-
-hydroxy-4,5-dimethylhexan-3-yl)-3-methyl-2-oxopiperidin-3-yl)acetic
acid;
2-((3R,5R,6S)-5-(3-Chlorophenyl)-6-(4-chlorophenyl)-1-((3S,4S)-5-hydroxy--
4,5-dimethylhexan-3-yl)-3-methyl-2-oxopiperidin-3-yl)acetic acid;
2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((S)-5-cyano-5-meth-
ylhexan-3-yl)-3-methyl-2-oxopiperidin-3-yl)acetic acid;
2-((3R,5R,6S)-5-(3-Chlorophenyl)-6-(4-chlorophenyl)-3-methyl-2-oxo-1-((S)-
-2-oxopentan-3-yl)piperidin-3-yl)acetic acid;
2-((3R,5R,6S)-5-(3-Chlorophenyl)-6-(4-chlorophenyl)-1-((2S,3S)-2-hydroxyp-
entan-3-yl)-3-methyl-2-oxopiperidin-3-yl)acetic acid;
2-((3R,5R,6S)-5-(3-Chlorophenyl)-6-(4-chlorophenyl)-1-((2S,3S)-2-methoxyp-
entan-3-yl)-3-methyl-2-oxopiperidin-3-yl)acetic acid;
2-((3R,5R,6S)-5-(3-Chlorophenyl)-6-(4-chlorophenyl)-1-((2R,3S)-2-hydroxyp-
entan-3-yl)-3-methyl-2-oxopiperidin-3-yl)acetic acid;
2-((3R,5R,6S)-5-(3-Chlorophenyl)-6-(4-chlorophenyl)-1-((2S,3R)-2-hydroxyp-
entan-3-yl)-3-methyl-2-oxopiperidin-3-yl)acetic acid;
2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((2R,3R)-2-hydroxyp-
entan-3-yl)-3-methyl-2-oxopiperidin-3-yl)acetic acid;
2-((3R,5R,6S)-5-(3-Chlorophenyl)-6-(4-chlorophenyl)-1-((S)-2-hydroxy-2-me-
thylpentan-3-yl)-3-methyl-2-oxopiperidin-3-yl)acetic acid;
2-((3R,5R,6S)-5-(3-Chlorophenyl)-6-(4-chlorophenyl)-1-((3S,4S)-4-hydroxyh-
exan-3-yl)-3-methyl-2-oxopiperidin-3-yl)acetic acid;
2-((3R,5R,6S)-5-(3-Chlorophenyl)-6-(4-chlorophenyl)-1-((3S,4R)-4-hydroxyh-
exan-3-yl)-3-methyl-2-oxopiperidin-3-yl)acetic acid;
2-((3R,5R,6S)-5-(3-Chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-methoxybutan-
-2-yl)-3-methyl-2-oxopiperidin-3-yl)acetic acid;
2-((3R,5R,6S)-5-(3-Chlorophenyl)-6-(4-chlorophenyl)-3-methyl-2-oxo-1-(3S)-
-1,1,1-trifluoro-2-hydroxy-2-methylpentan-3-yl)piperidin-3-yl)acetic
acid;
2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-1-((S)-1-(N--
methylcyclopropanesulfonamido)butan-2-yl)-2-oxopiperidin-3-yl)acetamide;
2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-1-((S)-1-(N--
methylcyclopropanesulfonamido)butan-2-yl)-2-oxopiperidin-3-yl)-N-(methylsu-
lfonyl)acetamide;
2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-1-((S)-1-(N--
methylcyclopropanesulfonamido)butan-2-yl)-2-oxopiperidin-3-yl)-N-(3-hydrox-
ypropyl)acetamide;
2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-1-((S)-1-(N--
methylcyclopropanesulfonamido)butan-2-yl)-2-oxopiperidin-3-yl)-N-(2-hydrox-
yethyl)acetamide;
2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-1-((S)-1-(N--
methylcyclopropanesulfonamido)butan-2-yl)-2-oxopiperidin-3-yl)-N-hydroxyac-
etamide;
2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-1-((-
S)-1-(N-methylcyclopropanesulfonamido)butan-2-yl)-2-oxopiperidin-3-yl)-N-m-
ethoxyacetamide;
2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-1-((S)-1-(N--
methylcyclopropanesulfonamido)butan-2-yl)-2-oxopiperidin-3-yl)-N--((R)-2,3-
-dihydroxypropyl)acetamide;
2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-1-((S)-1-(N--
methylcyclopropanesulfonamido)butan-2-yl)-2-oxopiperidin-3-yl)-N--((S)-2,3-
-dihydroxypropyl)acetamide;
2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-1-((S)-1-(N--
methylcyclopropanesulfonamido)butan-2-yl)-2-oxopiperidin-3-yl)-N-cyanoacet-
amide;
2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-1-((S)-
-1-(N-methylcyclopropanesulfonamido)butan-2-yl)-2-oxopiperidin-3-yl)-N-(2--
(dimethylamino)ethyl)acetamide;
2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-1-((S)-1-(N--
methylcyclopropanesulfonamido)butan-2-yl)-2-oxopiperidin-3-yl)-N-(3,4-dihy-
droxybutyl)acetamide;
2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-(cyclopropan-
esulfonamido)butan-2-yl)-3-methyl-2-oxopiperidin-3-yl)acetic acid;
(S)-2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-1-((S)-1-
-(N-methylcyclopropanesulfonamido)butan-2-yl)-2-oxopiperidin-3-yl)propanoi-
c acid;
2-((3R,5R,6S)-5-(3-Chlorophenyl)-6-(4-chlorophenyl)-1-(3S)-2-(cycl-
opropanesulfonamido)pentan-3-yl)-3-methyl-2-oxopiperidin-3-yl)acetic
acid (isomer 1);
2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-(3S)-2-(cyclopropan-
esulfonamido)pentan-3-yl)-3-methyl-2-oxopiperidin-3-yl)acetic acid
(isomer 2);
2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-1-((2R,3-
S)-2-(1-methylethylsulfonamido)pentan-3-yl)-2-oxopiperidin-3-yl)acetic
acid;
2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-1-((S)-
-1-(N-methylcyclopropanesulfonamido)-1-oxobutan-2-yl)-2-oxopiperidin-3-yl)-
acetic acid;
2-((3R,5R,6S)-5-(3-Chlorophenyl)-6-(4-chlorophenyl)-3-methyl-1-((S)-1-(ne-
opentylamino)-1-oxobutan-2-yl)-2-oxopiperidin-3-yl)acetic acid;
2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-(4,4-dimethy-
l-4,5-dihydrooxazol-2-yl)propyl)-3-methyl-2-oxopiperidin-3-yl)acetic
acid;
2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-2-oxo-1-((S)-
-1-(N-(2,2,2-trifluoroethyl)acetamido)butan-2-yl)piperidin-3-yl)acetic
acid;
2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-(1,1-d-
imethylethylsulfonamido)butan-2-yl)-3-methyl-2-oxopiperidin-3-yl)acetic
acid
2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-(N,2-di-
methylpropan-2-ylsulfonamido)butan-2-yl)-3-methyl-2-oxopiperidin-3-yl)acet-
ic acid;
2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-1-((-
S)-1-(1-methylethylsulfonamido)butan-2-yl)-2-oxopiperidin-3-yl)acetic
acid;
2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-(N-eth-
ylpropan-2-ylsulfonamido)butan-2-yl)-3-methyl-2-oxopiperidin-3-yl)acetic
acid;
2-((3R,5R,6S)-5-(3-Chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-hydrox-
ybutan-2-yl)-3-methyl-2-oxopiperidin-3-yl)acetic acid;
2-((3R,5R,6S)-5-(3-Chlorophenyl)-6-(4-chlorophenyl)-3-methyl-2-oxo-1-((S)-
-1-(trifluoromethylsulfonamido)butan-2-yl)piperidin-3-yl)acetic
acid;
2-((3R,5R,6S)-5-(3-Chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-(4-chlorophe-
nylsulfonamido)butan-2-yl)-3-methyl-2-oxopiperidin-3-yl)acetic
acid;
2-((3R,5R,6S)-5-(3-Chlorophenyl)-6-(4-chlorophenyl)-3-methyl-1-((S)-1-(4--
methylphenylsulfonamido)butan-2-yl)-2-oxopiperidin-3-yl)acetic
acid;
2-((3R,5R,6S)-5-(3-Chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-(2-chlorophe-
nylsulfonamido)butan-2-yl)-3-methyl-2-oxopiperidin-3-yl)acetic
acid;
2-((3R,5R,6S)-5-(3-Chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-(2-methylphe-
nylsulfonamido)butan-2-yl)-3-methyl-2-oxopiperidin-3-yl)acetic
acid;
2-((3R,5R,6S)-5-(3-Chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-(4-methoxyph-
enylsulfonamido)butan-2-yl)-3-methyl-2-oxopiperidin-3-yl)acetic
acid;
2-((3R,5R,6S)-5-(3-Chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-(phenylsulfo-
namido)butan-2-yl)-3-methyl-2-oxopiperidin-3-yl)acetic acid;
2-((3R,5R,6S)-5-(3-Chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-(1-methylcyc-
lopropanesulfonamido)butan-2-yl)-3-methyl-2-oxopiperidin-3-yl)acetic
acid;
2-((3R,5R,6S)-5-(3-Chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-(1,1-dioxido-
benzo[d]isothiazol-2(3H)-yl)butan-2-yl)-3-methyl-2-oxopiperidin-3-yl)aceti-
c acid;
2-((3R,5R,6S)-5-(3-Chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-(3,3--
dimethyl-1,1-dioxidobenzo[d]isothiazol-2(3H)-yl)butan-2-yl)-3-methyl-2-oxo-
piperidin-3-yl)acetic acid;
2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-2-oxo-1-((S)-
-1-(pyridine-3-sulfonamido)butan-2-yl)piperidin-3-yl)acetic acid;
2-((3R,5R,6S)-5-(3-Chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-(4-cyanophen-
ylsulfonamido)butan-2-yl)-3-methyl-2-oxopiperidin-3-yl)acetic acid;
2-((3R,5R,6S)-5-(3-Chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-(3-cyanophen-
ylsulfonamido)butan-2-yl)-3-methyl-2-oxopiperidin-3-yl)acetic acid;
2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-2-oxo-1-((S)-
-1-(pyridine-2-sulfonamido)butan-2-yl)piperidin-3-yl)acetic acid;
2-((3R,5R,6S)-5-(3-Chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-(N,1-dimethy-
lcyclopropanesulfonamido)butan-2-yl)-3-methyl-2-oxopiperidin-3-yl)acetic
acid;
3-((3S,5R,6S)-5-(3-Chlorophenyl)-6-(4-chlorophenyl)-3-methyl-1-((S)-
-1-(N-methylcyclopropanesulfonamido)butan-2-yl)-2-oxopiperidin-3-yl)propan-
oic acid;
3-((3R,5S,6R)-5-(3-Chlorophenyl)-6-(4-chlorophenyl)-3-methyl-1-(-
(S)-1-(N-methylcyclopropanesulfonamido)butan-2-yl)-2-oxopiperidin-3-yl)pro-
panoic acid;
2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-ethyl-1-((S)-1-(N-m-
ethylcyclopropanesulfonamido)butan-2-yl)-2-oxopiperidin-3-yl)acetic
acid;
2-((3S,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methoxy-1-((S)-1-(N-
-methylcyclopropanesulfonamido)butan-2-yl)-2-oxopiperidin-3-yl)acetic
acid;
2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-1-((S)-
-6-methyl-4-oxoheptan-3-yl)-2-oxopiperidin-3-yl)acetic acid;
2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-(ethylsulfon-
yl)pentan-3-yl)-3-methyl-2-oxopiperidin-3-yl)acetic acid;
2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-(isopropylsu-
lfonyl)pentan-3-yl)-3-methyl-2-oxopiperidin-3-yl)acetic acid;
2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-(cyclopropyl-
methylsulfonyl)pentan-3-yl)-3-methyl-2-oxopiperidin-3-yl)acetic
acid;
2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-2-oxo-1-((S)-
-1-(2-oxopyrrolidin-1-yl)butan-2-yl)piperidin-3-yl)acetic acid;
2-((3R,5R,6S)-1-((S)-1-((1R,4R)-2-oxa-5-azabicyclo[2.2.1]heptan-5-yl)buta-
n-2-yl)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-2-oxopiperidin-3-yl-
)acetic acid;
2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-1-((S)-1-((S-
)-3-methylmorpholino)butan-2-yl)-2-oxopiperidin-3-yl)acetic acid;
2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-1-((S)-1-((R-
)-3-methylmorpholino)butan-2-yl)-2-oxopiperidin-3-yl)acetic acid;
2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-(thiomorphol-
ino-1,1-dioxide)butan-2-yl)-3-methyl-2-oxopiperidin-3-yl)acetic
acid;
2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-(3,3-difluor-
oazetidin-1-yl)butan-2-yl)-3-methyl-2-oxopiperidin-3-yl)acetic
acid;
2-((3R,5R,6S)-1-((2S)-1-(8-oxa-3-azabicyclo[3.2.1]octan-3-yl)butan-2-yl)--
5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-2-oxopiperidin-3-yl)acetic
acid;
2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-(3,3-d-
imethylmorpholino)butan-2-yl)-3-methyl-2-oxopiperidin-3-yl)acetic
acid;
2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-(3-hydroxy-3-
-(trifluoromethyl)azetidin-1-yl)butan-2-yl)-3-methyl-2-oxopiperidin-3-yl)a-
cetic acid;
2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-1-((S)-1-(me-
thyl(oxetan-3-yl)amino)butan-2-yl)-2-oxopiperidin-3-yl)acetic acid;
2-((3R,5R,6S)-5-(3-Chlorophenyl)-6-(4-chlorophenyl)-3-methyl-2-oxo-1-((S)-
-1-(2-oxooxazolidin-3-yl)butan-2-yl)piperidin-3-yl)acetic acid;
2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-2-oxo-1-((S)-
-1-(2-oxopyridin-1(2H)-yl)butan-2-yl)piperidin-3-yl)acetic acid;
2-((3R,5R,6S)-5-(3-Chlorophenyl)-6-(4-chlorophenyl)-3-methyl-2-oxo-1-((S)-
-1-(2-oxo-5-(trifluoromethyl)pyridin-1(2H)-yl)butan-2-yl)piperidin-3-yl)ac-
etic acid;
(3R,5R,6S)-3-allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-meth-
yl-1-((S)-1-(pyridin-3-yloxy)butan-2-yl)piperidin-2-one;
2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-2-oxo-1-((1S-
)-1-(tetrahydrofuran-2-yl)propyl)piperidin-3-yl)acetic acid (isomer
1);
2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-2-oxo-1-((1S-
)-1-(tetrahydrofuran-2-yl)propyl)piperidin-3-yl)acetic acid (isomer
2);
2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-2-oxo-1-((1S-
)-1-5-oxotetrahydrofuran-2-yl)propyl)piperidin-3-yl)acetic acid;
2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-2-oxo-1-((1S-
)-1-(tetrahydro-2H-pyran-2-yl)propyl)piperidin-3-yl)acetic acid
(isomer 1);
2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-2-oxo-1--
((1S)-1-(tetrahydro-2H-pyran-2-yl)propyl)piperidin-3-yl)acetic acid
(isomer 2);
2-((3R,5R,6S)-1-((R)-1-(benzo[d]thiazol-2-yl)propyl)-5-(3-chlorophenyl)-6-
-(4-chlorophenyl)-3-methyl-2-oxopiperidin-3-yl)acetic acid;
2-((3R,5R,6S)-1-((S)-1-(benzo[d]thiazol-2-yl)propyl)-5-(3-chlorophenyl)-6-
-(4-chlorophenyl)-3-methyl-2-oxopiperidin-3-yl)acetic acid;
2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-1-((S)-1-(3--
methylisoxazol-5-yl)propyl)-2-oxopiperidin-3-yl)acetic acid;
2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-1-((R)-1-(3--
methylisoxazol-5-yl)propyl)-2-oxopiperidin-3-yl)acetic acid;
2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-(6-chloropyr-
idin-2-yl)propyl)-3-methyl-2-oxopiperidin-3-yl)acetic acid;
2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((R)-1-(6-chloropyr-
idin-2-yl)propyl)-3-methyl-2-oxopiperidin-3-yl)acetic acid;
2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-2-oxo-1-((S)-
-1-(pyridin-2-yl)propyl)piperidin-3-yl)acetic acid;
2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-2-oxo-1-((R)-
-1-(pyridin-2-yl)propyl)piperidin-3-yl)acetic acid;
2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-2-oxo-1-((S)-
-1-(pyridin-2-yl)butyl)piperidin-3-yl)acetic acid;
2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-2-oxo-1-((R)-
-1-(pyridin-2-yl)butyl)piperidin-3-yl)acetic acid;
2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((S)-2-cyclopropyl--
1-(pyridin-2-yl)ethyl)-3-methyl-2-oxopiperidin-3-yl)acetic acid;
2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((R)-2-cyclopropyl--
1-(pyridin-2-yl)ethyl)-3-methyl-2-oxopiperidin-3-yl)acetic acid;
2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-2-oxo-1-((S)-
-1-(pyridin-3-yl)propyl)piperidin-3-yl)acetic acid;
2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-2-oxo-1-((R)-
-1-(pyridin-3-yl)propyl)piperidin-3-yl)acetic acid;
2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-2-oxo-1-((S)-
-1-(pyrazin-2-yl)propyl)piperidin-3-yl)acetic acid;
2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-2-oxo-1-((R)-
-1-(pyrazin-2-yl)propyl)piperidin-3-yl)acetic acid;
2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-2-oxo-1-((S)-
-1-(pyrimidin-2-yl)propyl)piperidin-3-yl)acetic acid;
2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-2-oxo-1-((R)-
-1-(pyrimidin-2-yl)propyl)piperidin-3-yl)acetic acid;
2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-1-((S)-1-(6--
methylpyridin-2-yl)propyl)-2-oxopiperidin-3-yl)acetic acid;
2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-1-((R)-1-(6--
methylpyridin-2-yl)propyl)-2-oxopiperidin-3-yl)acetic acid;
2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-2-oxo-1-((S)-
-1-(pyridin-4-yl)propyl)piperidin-3-yl)acetic acid;
2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-2-oxo-1-((R)-
-1-(pyridin-4-yl)propyl)piperidin-3-yl)acetic acid;
2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-2-oxo-1-((S)-
-1-(6-(trifluoromethyl)pyridin-2-yl)propyl)piperidin-3-yl)acetic
acid;
2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-2-oxo-1-((R)-
-1-(6-(trifluoromethyl)pyridin-2-yl)propyl)piperidin-3-yl)acetic
acid;
2-((3R,5R,6S)-1-((S)-1-(6-bromopyridin-2-yl)propyl)-5-(3-chlorophenyl)-6--
(4-chlorophenyl)-3-methyl-2-oxopiperidin-3-yl)acetic acid;
2-((3R,5R,6S)-1-((R)-1-(6-bromopyridin-2-yl)propyl)-5-(3-chlorophenyl)-6--
(4-chlorophenyl)-3-methyl-2-oxopiperidin-3-yl)acetic acid;
2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-2-oxo-1-((S)-
-1-(thiazol-2-yl)propyl)piperidin-3-yl)acetic acid;
2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-2-oxo-1-((R)-
-1-(thiazol-2-yl)propyl)piperidin-3-yl)acetic acid;
2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-(6-(2-hydrox-
ypropan-2-yl)pyridin-2-yl)propyl)-3-methyl-2-oxopiperidin-3-yl)acetic
acid;
2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((R)-1-(6-(2--
hydroxypropan-2-yl)pyridin-2-yl)propyl)-3-methyl-2-oxopiperidin-3-yl)aceti-
c acid;
2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-(6-cy-
clopropylpyridin-2-yl)propyl)-3-methyl-2-oxopiperidin-3-yl)acetic
acid;
2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((R)-1-(6-cycloprop-
ylpyridin-2-yl)propyl)-3-methyl-2-oxopiperidin-3-yl)acetic acid;
2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-2-oxo-1-((S)-
-3,3,3-trifluoro-1-(pyridin-2-yl)propyl)piperidin-3-yl)acetic acid;
2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-2-oxo-1-((R)-
-3,3,3-trifluoro-1-(pyridin-2-yl)propyl)piperidin-3-yl)acetic acid;
2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-1-((S)-2-met-
hyl-1-(pyridin-2-yl)propyl)-2-oxopiperidin-3-yl)acetic acid;
2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-1-((R)-2-met-
hyl-1-(pyridin-2-yl)propyl)-2-oxopiperidin-3-yl)acetic acid;
(3R,5R,6S)-3-((1H-tetrazol-5-yl)methyl)-5-(3-chlorophenyl)-6-(4-chlorophe-
nyl)-3-methyl-1-(pentan-3-yl)piperidin-2-one;
(3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-((R)-2,3-dihydroxyprop-
yl)-1-((2S,3S)-2-hydroxypentan-3-yl)-3-methylpiperidin-2-one;
(3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-((S)-2,3-dihydroxyprop-
yl)-1-((2S,3S)-2-hydroxypentan-3-yl)-3-methylpiperidin-2-one;
2-((3R,5R,6S)-5-(3-Chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-hydroxybutan-
-2-yl)-3-methyl-2-oxopiperidin-3-yl)cyclopropanecarboxylic acid;
2-((3R,5R,6S)-1-((S)-2-(tert-Butoxy)-1-cyclopropyl-2-oxoethyl)-5-(3-chlor-
ophenyl)-6-(4-chlorophenyl)-2-oxopiperidin-3-yl)acetic acid;
2-((3R,5R,6S)-5-(3-Chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-cyclopropyl--
2-ethoxy-2-oxoethyl)-3-methyl-2-oxopiperidin-3-yl)acetic acid;
2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-cyclopropyl--
2-hydroxyethyl)-3-methyl-2-oxopiperidin-3-yl)acetic acid;
2-((3R,5R,6S)-5-(3-Chlorophenyl)-6-(4-chlorophenyl)-1-((1S,2S)-1-cyclopro-
pyl-2-hydroxybutyl)-3-methyl-2-oxopiperidin-3-yl)acetic acid;
2-((3R,5R,6S)-5-(3-Chlorophenyl)-6-(4-chlorophenyl)-1-((1S,2R)-1-cyclopro-
pyl-2-hydroxybutyl)-3-methyl-2-oxopiperidin-3-yl)acetic acid;
2-((3R,5R,6S)-5-(3-Chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-cyclopropyl--
2-(N-methylcyclopropanesulfonamido)ethyl)-3-ethyl-2-oxopiperidin-3-yl)acet-
ic acid;
2-((3R,5R,6S)-5-(3-Chlorophenyl)-6-(4-chlorophenyl)-1-((S)-2-(cyc-
lopropanesulfonamido)-1-cyclopropylethyl)-3-ethyl-2-oxopiperidin-3-yl)acet-
ic acid;
2-((3R,5R,6S)-5-(3-Chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-cycl-
opropyl-2-(ethylsulfonamido)ethyl)-3-ethyl-2-oxopiperidin-3-yl)acetic
acid;
2-((3R,5R,6S)-5-(3-Chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-cyclop-
ropyl-2-(N-methylcyclopropanesulfonamido)ethyl)-3-methyl-2-oxopiperidin-3--
yl)acetic acid;
2-((3R,5R,6S)-5-(3-Chlorophenyl)-6-(4-chlorophenyl)-1-((1S,2R)-1-cyclopro-
pyl-2-hydroxypropyl)-3-methyl-2-oxopiperidin-3-yl)acetic acid;
2-((3R,5R,6S)-5-(3-Chlorophenyl)-6-(4-chlorophenyl)-1-((1S,2S)-1-cyclopro-
pyl-2-hydroxypropyl)-3-methyl-2-oxopiperidin-3-yl)acetic acid;
2-((3R,5R,6S)-5-(3-Chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-cyclopropyl--
2-(1-methylethylsulfonamido)ethyl)-3-methyl-2-oxopiperidin-3-yl)acetic
acid;
2-((3R,5R,6S)-5-(3-Chlorophenyl)-6-(4-chlorophenyl)-1-((R)-1-cyclop-
ropyl-2-(N-methylcyclopropanesulfonamido)ethyl)-3-methyl-2-oxopiperidin-3--
yl)acetic acid;
2-((3R,5R,6S)-5-(3-Chlorophenyl)-6-(4-chlorophenyl)-1-((2S,3S)-2-hydroxy--
4-methylpentan-3-yl)-3-methyl-2-oxopiperidin-3-yl)acetic acid;
2-((3R,5R,6S)-5-(3-Chlorophenyl)-6-(4-chlorophenyl)-1-((S)-cyclopropyl(py-
ridin-2-yl)methyl)-3-methyl-2-oxopiperidin-3-yl)acetic acid; or
2-((3R,5R,6S)-5-(3-Chlorophenyl)-6-(4-chlorophenyl)-1-((R)-cyclopropyl(py-
ridin-2-yl)methyl)-3-methyl-2-oxopiperidin-3-yl)acetic acid.
21. A compound, or a pharmaceutically acceptable salt thereof,
selected from:
2-(1-(1-tert-butoxy-1-oxobutan-2-yl)-5-(3-chlorophenyl)-6-(4-chloro-
phenyl)-2-oxopiperidin-3-yl)acetic acid;
2-(5-(3-Chlorophenyl)-6-(4-chlorophenyl)-1-(1-ethoxy-1-oxobutan-2-yl)-2-o-
xopiperidin-3-yl)acetic acid;
2-(5-(3-Chlorophenyl)-6-(4-chlorophenyl)-1-(1-ethoxy-4-methyl-1-oxopentan-
-2-yl)-2-oxopiperidin-3-yl)acetic acid;
2-(5-(3-Chlorophenyl)-6-(4-chlorophenyl)-1-(1-ethoxy-1-oxopentan-2-yl)-2--
oxopiperidin-3-yl)acetic acid;
2-(1-(2-tert-Butoxy-1-cyclopropyl-2-oxoethyl)-5-(3-chlorophenyl)-6-(4-chl-
orophenyl)-2-oxopiperidin-3-yl)acetic acid;
2-(5-(3-Chlorophenyl)-6-(4-chlorophenyl)-1-(1-hydroxybutan-2-yl)-2-oxopip-
eridin-3-yl)acetic acid;
2-(5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-(1-cyclopropyl-2-hydroxyethyl)-
-2-oxopiperidin-3-yl)acetic acid;
2-(5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-(1-(cyclopropylmethoxy)butan-2-
-yl)-2-oxopiperidin-3-yl)acetic acid;
2-(5-(3-Chlorophenyl)-6-(4-chlorophenyl)-1-(1-methoxybutan-2-yl)-2-oxopip-
eridin-3-yl)acetic acid;
2-(5-(3-Chlorophenyl)-6-(4-chlorophenyl)-1-(1-(2-methoxyethoxy)butan-2-yl-
)-2-oxopiperidin-3-yl)acetic acid;
2-(5-(3-Chlorophenyl)-6-(4-chlorophenyl)-1-(1-((1-cyanocyclopropyl)methox-
y)butan-2-yl)-2-oxopiperidin-3-yl)acetic acid;
2-(5-(3-Chlorophenyl)-6-(4-chlorophenyl)-1-(1-(cyclopropylmethoxy)butan-2-
-yl)-2-oxopiperidin-3-yl)acetic acid;
2-(5-(3-Chlorophenyl)-6-(4-chlorophenyl)-1-(1-methoxybutan-2-yl)-2-oxopip-
eridin-3-yl)acetic acid;
2-(5-(3-Chlorophenyl)-6-(4-chlorophenyl)-1-(1-(2-methoxyethoxy)butan-2-yl-
)-2-oxopiperidin-3-yl)acetic acid;
2-(1-(1-((1-carbamoylcyclopropyl)methoxy)butan-2-yl)-5-(3-chlorophenyl)-6-
-(4-chlorophenyl)-2-oxopiperidin-3-yl)acetic acid;
2-(5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-(1-(2-hydroxy-2-methylpropoxy)-
butan-2-yl)-2-oxopiperidin-3-yl)acetic acid;
2-(5-(3-chlorophenyl)-6-(4-chlorophenyl)-2-oxo-1-(1,1,1-trifluoro-2-hydro-
xypentan-3-yl)piperidin-3-yl)acetic acid;
2-(5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-(1-morpholinobutan-2-yl)-2-oxo-
piperidin-3-yl)acetic acid;
2-(5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-(1-(ethylamino)butan-2-yl)-2-o-
xopiperidin-3-yl)acetic acid;
2-(5-(3-chlorophenyl)-6-(4-chlorophenyl)-2-oxo-1-(1-(2,2,2-trifluoroethyl-
amino)butan-2-yl)piperidin-3-yl)acetic acid;
2-(5-(3-chlorophenyl)-6-(4-chlorophenyl)-2-oxo-1-(1-(pyrrolidin-1-yl)buta-
n-2-yl)piperidin-3-yl)acetic acid;
2-(5-(3-chlorophenyl)-6-(4-chlorophenyl)-2-oxo-1-(1-(2-oxopyrrolidin-1-yl-
)butan-2-yl)piperidin-3-yl)acetic acid;
2-(5-(3-Chlorophenyl)-6-(4-chlorophenyl)-1-(1-(1,1-dioxidothiomorpholino)-
butan-2-yl)-2-oxopiperidin-3-yl)acetic acid;
2-(5-(3-chlorophenyl)-6-(4-chlorophenyl)-2-oxo-1-(1-(thiazol-2-ylamino)bu-
tan-2-yl)piperidin-3-yl)acetic acid;
2-(1-(1-acetamidobutan-2-yl)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-2-oxop-
iperidin-3-yl)acetic acid;
2-(5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-(1-(methylsulfonamido)
butan-2-yl)-2-oxopiperidin-3-yl)acetic acid;
2-(5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-(1-cyanopentan-3-yl)-2-oxopipe-
ridin-3-yl)acetic acid;
2-(5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-(1-(methylsulfonyl)pentan-3-yl-
)-2-oxopiperidin-3-yl)acetic acid;
2-(5-(3-chlorophenyl)-6-(4-chlorophenyl)-2-oxo-1-(1-(pyridin-2-yl)pentan--
3-yl)piperidin-3-yl)acetic acid;
2-(5-(3-Chlorophenyl)-6-(4-chlorophenyl)-1-(1-(ethylamino)-1-oxobutan-2-y-
l)-2-oxopiperidin-3-yl)acetic acid;
2-(5-(3-Chlorophenyl)-6-(4-chlorophenyl)-1-(1-(5-methyl-1,3,4-oxadiazol-2-
-yl)propyl)-2-oxopiperidin-3-yl)acetic;
2-(5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-(cyclopropylmethyl)-2-oxopiper-
idin-3-yl)acetic acid;
2-(5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-(cyclobutylmethyl)-2-oxopiperi-
din-3-yl)acetic acid;
2-(5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-(2-ethylbutyl)-2-oxopiperidin--
3-yl)acetic acid;
2-(5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-(cyclopentylmethyl)-2-oxopiper-
idin-3-yl)acetic acid;
2-(5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((2,2-dimethylcyclopentyl)meth-
yl)-2-oxopiperidin-3-yl)acetic acid;
2-(5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-(cyclohexylmethyl)-2-oxopiperi-
din-3-yl)acetic acid;
2-(5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-(cyclopropylmethyl)-2-oxopiper-
idin-3-yl)acetic acid;
2-(5-(3-chlorophenyl)-6-(4-chlorophenyl)-2-oxo-1-propylpiperidin-3-yl)ace-
tic acid;
2-(5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-(cyclobutylmethyl)-2--
oxopiperidin-3-yl)acetic acid;
2-(5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-isobutyl-2-oxopiperidin-3-yl)a-
cetic acid;
2-(5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-(cyclopentylmethyl)-2-oxopiper-
idin-3-yl)acetic acid;
2-(5-(3-chlorophenyl)-6-(4-chlorophenyl)-2-oxo-1-(pentan-3-yl)piperidin-3-
-yl)acetic acid; Methyl
2-(5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-(cyclopropylmethyl)-2-oxopiper-
idin-3-yl)acetate;
2-(5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-(cyclopropylmethyl)-2-oxopiper-
idin-3-yl)acetamide; Ethyl
2-(2-(5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-(cyclopropylmethyl)-2-oxopi-
peridin-3-yl)acetamido)acetate;
2-(2-(5-(3-Chlorophenyl)-6-(4-chlorophenyl)-1-(cyclopropylmethyl)-2-oxopi-
peridin-3-yl)acetamido)acetic acid;
2-(5-(3-Chlorophenyl)-6-(4-chlorophenyl)-1-(cyclopropylmethyl)-2-oxopiper-
idin-3-yl)acetohydrazide;
2-(5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-(cyclopropylmethyl)-2-oxopiper-
idin-3-yl)-N-hydroxyacetamide; Ethyl
2-(3-(3-chlorophenyl)-2-(4-chlorophenyl)-5-(2-(methylsulfonamido)-2-oxoet-
hyl)-6-oxopiperidin-1-yl)butanoate; Ethyl
2-(3-(3-chlorophenyl)-2-(4-chlorophenyl)-5-(2-((3-morpholinopropyl)amino)-
-2-oxoethyl)-6-oxopiperidin-1-yl)butanoate;
3-((1H-Tetrazol-5-yl)methyl)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-(cyc-
lopropylmethyl)piperidin-2-one;
3-((1,3,4-oxadiazol-2-yl)methyl)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1--
(cyclopropylmethyl)piperidin-2-one;
5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-(cyclopropylmethyl)-3-((5-methyl--
1,3,4-oxadiazol-2-yl)methyl)piperidin-2-one;
2-(5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-(cyclopropylmethyl)-2-oxopiper-
idin-3-yl)-N-(methylsulfonyl)acetamide;
2-(5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-(cyclopropylmethyl)-2-oxopiper-
idin-3-yl)acetamide;
3-((1H-tetrazol-5-yl)methyl)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-(cyc-
lopropylmethyl)piperidin-2-one;
5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-(cyclopropylmethyl)-3-((5-methyli-
soxazol-3-yl)methyl)piperidin-2-one;
2-(6-chloro-3'-(3-chlorophenyl)-1'-(cyclopropylmethyl)-2,6'-dioxospiro[in-
doline-3,2'-piperidine]-5'-yl)acetic acid;
2-(5-(3-chlorophenyl)-6-(5-chlorothiophen-2-yl)-1-(cyclopropylmethyl)-2-o-
xopiperidin-3-yl)acetic acid;
2-(5-(3-chlorophenyl)-6-(5-chlorothiophen-2-yl)-1-(cyclopropylmethyl)-2-o-
xopiperidin-3-yl)acetic acid;
2-(5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-(1-ethoxy-1-oxobutan-2-yl)-3-m-
ethyl-2-oxopiperidin-3-yl)acetic acid;
2-(1-(1-tert-butoxy-1-oxobutan-2-yl)-5-(3-chlorophenyl)-6-(4-chlorophenyl-
)-3-methyl-2-oxopiperidin-3-yl)acetic acid;
2-(5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-(1-(cyclopropylmethoxy)butan-2-
-yl)-3-methyl-2-oxopiperidin-3-yl)acetic acid;
2-(5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-(cyclopropylmethyl)-2-oxo-3-(2-
-(pyrrolidin-1-yl)ethyl)piperidin-3-yl)acetic acid;
2-(5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-(cyclopropylmethyl)-3-(2-morph-
olinoethyl)-2-oxopiperidin-3-yl)acetic acid;
2-(5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-2-oxo-1-(pentan-3-yl)pi-
peridin-3-yl)acetic acid;
2-(5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-(cyclopropylmethyl)-3-methyl-2-
-oxopiperidin-3-yl)acetic acid;
2-(5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-isopropyl-3-methyl-2-oxopiperi-
din-3-yl)acetic acid;
2-(5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-cyclobutyl-3-methyl-2-oxopiper-
idin-3-yl)acetic acid;
2-(5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-cyclopentyl-3-methyl-2-oxopipe-
ridin-3-yl)acetic acid;
5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-3-((5-oxo-4,5-dihydro-1H-1-
,2,4-triazol-3-yl)methyl)-1-(pentan-3-yl)piperidin-2-one;
5-((5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-2-oxo-1-(pentan-3-yl)p-
iperidin-3-yl)methyl)-1,3,4-oxadiazol-2(3H)-one;
2-(5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-2-oxo-1-(pentan-3-yl)pi-
peridin-3-yl)-N-(trifluoromethylsulfonyl)acetamide;
5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-((3-hydroxy-1H-pyrazol-5-yl)methy-
l)-3-methyl-1-(pentan-3-yl)piperidin-2-one;
5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-((3-hydroxyisoxazol-5-yl)methyl)--
3-methyl-1-(pentan-3-yl)piperidin-2-one;
5-((5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-2-oxo-1-(pentan-3-yl)p-
iperidin-3-yl)methyl)oxazolidine-2,4-dione;
3-((5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-2-oxo-1-(pentan-3-yl)p-
iperidin-3-yl)methyl)-1,2,4-oxadiazol-5(4H)-one;
3-((5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-isopropyl-3-methyl-2-oxopiper-
idin-3-yl)methyl)-1,2,4-oxadiazol-5(4H)-one;
3-((5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-2-oxo-1-(pentan-3-yl)p-
iperidin-3-yl)methyl)-1,2,4-thiadiazol-5(4H)-one;
3-((5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-isopropyl-3-methyl-2-oxopiper-
idin-3-yl)methyl)-1,2,4-thiadiazol-5(4H)-one;
3-((1H-Tetrazol-5-yl)methyl)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-isop-
ropyl-3-methylpiperidin-2-one;
2-(5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-ethyl-2-oxo-1-(pentan-3-yl)pip-
eridin-3-yl)acetic acid;
5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-3-(methylsulfonylmethyl)-1-
-(pentan-3-yl)piperidin-2-one;
2-(5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-(1-(3-cyclopropyl-1,2,4-oxadia-
zol-5-yl)propyl)-3-methyl-2-oxopiperidin-3-yl)acetic acid;
2-(5-(3-Chlorophenyl)-6-(4-chlorophenyl)-3-methyl-1-(1-morpholinobutan-2--
yl)-2-oxopiperidin-3-yl)acetic acid;
2-(5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-2-oxo-1-(1-(2,2,2-trifl-
uoroethylamino)butan-2-yl)piperidin-3-yl)acetic acid;
2-(5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-(1-(2,2-dimethylmorpholino)but-
an-2-yl)-3-methyl-2-oxopiperidin-3-yl)acetic acid;
2-(5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-(1-(2,6-dimethylmorpholino)but-
an-2-yl)-3-methyl-2-oxopiperidin-3-yl)acetic acid;
2-(5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-(1-(4-(cyclopropylsulfonyl)pip-
erazin-1-yl)butan-2-yl)-3-methyl-2-oxopiperidin-3-yl)acetic acid;
2-(5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-1-(1-(4-(methylsulfonyl-
)piperazin-1-yl)butan-2-yl)-2-oxopiperidin-3-yl)acetic acid;
2-(1-(1-(4-acetylpiperazin-1-yl)butan-2-yl)-5-(3-chlorophenyl)-6-(4-chlor-
ophenyl)-3-methyl-2-oxopiperidin-3-yl)acetic acid;
2-(5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-(1-(4-(cyclopropanecarbonyl)pi-
perazin-1-yl)butan-2-yl)-3-methyl-2-oxopiperidin-3-yl)acetic acid;
3-((5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-1-(1-morpholinobutan-2-
-yl)-2-oxopiperidin-3-yl)methyl)-1,2,4-oxadiazol-5(4H)-one;
2-(5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-(1-(5,5-dimethyl-2-oxooxazolid-
in-3-yl)butan-2-yl)-3-methyl-2-oxopiperidin-3-yl)acetic acid;
2-(1-(1-(tert-butylamino)-1-oxobutan-2-yl)-5-(3-chlorophenyl)-6-(4-chloro-
phenyl)-3-methyl-2-oxopiperidin-3-yl)acetic acid;
2-(5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-(2,3-dihydroxycyclopentyl)-3-m-
ethyl-2-oxopiperidin-3-yl)acetic acid;
2-(5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-2-oxo-1'-(2,2,2-trifluo-
roethyl)-1,3'-bipiperidin-3-yl)acetic acid;
2-(5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-(3-hydroxycyclopentyl)-3-methy-
l-2-oxopiperidin-3-yl)acetic acid;
2-(5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-2-oxo-1-(tetrahydro-2H--
pyran-3-yl)piperidin-3-yl)acetic acid;
2-(5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-2-oxo-1-(pyrazin-2-yl)p-
iperidin-3-yl)acetic acid;
2-(5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-1-(1-methyl-1H-pyrazol--
4-yl)-2-oxopiperidin-3-yl)acetic acid;
2-(5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-2-oxo-1-(pyrimidin-4-yl-
)piperidin-3-yl)acetic acid;
2-(5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-(2-chloropyrimidin-4-yl)-3-met-
hyl-2-oxopiperidin-3-yl)acetic acid;
2-(5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-2-oxo-1-(pyrimidin-2-yl-
)piperidin-3-yl)acetic acid;
2-(5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-1-(3-methylpyridin-2-yl-
)-2-oxopiperidin-3-yl)acetic acid;
2-(5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-1-(4-methylpyridin-2-yl-
)-2-oxopiperidin-3-yl)acetic acid;
2-(5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-(dicyclopropylmethyl)-3-methyl-
-2-oxopiperidin-3-yl)acetic acid;
(4-(3-chlorophenyl)-3-(4-chlorophenyl)-1,1-dioxido-2-(2-propanyl)-1,2-thi-
azinan-6-yl)acetic acid;
(4-(3-chlorophenyl)-3-(4-chlorophenyl)-6-methyl-1,1-dioxido-2-(2-propanyl-
)-1,2-thiazinan-6-yl)acetic acid;
2-(5-(3-chlorophenyl)-6-(5-chloropyridin-2-yl)-3-methyl-1-(1-morpholinobu-
tan-2-yl)-2-oxopiperidin-3-yl)acetic acid;
2-(5-(3-Chlorophenyl)-6-(5-chloropyridin-2-yl)-3-methyl-2-oxo-1-(pentan-3-
-yl)piperidin-3-yl)acetic acid;
2-(1-(1-tert-butoxy-1-oxobutan-2-yl)-5-(3-chlorophenyl)-6-(5-chloropyridi-
n-2-yl)-3-methyl-2-oxopiperidin-3-yl)acetic acid; or
2-(1-(1-tert-butoxy-1-oxobutan-2-yl)-6-(4-chlorophenyl)-5-(4-chloropyridi-
n-2-yl)-3-methyl-2-oxopiperidin-3-yl)acetic acid.
22. A compound, or a pharmaceutically acceptable salt thereof,
selected from:
2-(5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-(1-(N-methylcyclopropane-
sulfonamido)butan-2-yl)-2-oxopiperidin-3-yl)acetic acid;
5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-(1-(N-methylcyclopropanesulfonami-
do)butan-2-yl)-2-oxopiperidin-3-yl)propanoic acid; tert-butyl
2-(3-((1H-tetrazol-5-yl)methyl)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-m-
ethyl-2-oxopiperidin-1-yl)butanoate;
2-(5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-1-(1-(methylsulfonamido-
)butan-2-yl)-2-oxopiperidin-3-yl)acetic acid;
2-(5-(3-Chlorophenyl)-6-(4-chlorophenyl)-3-methyl-2-oxo-1-(5-oxohexan-3-y-
l)piperidin-3-yl)acetic acid;
2-(5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-(5-hydroxy-5-methylhexan-3-yl)-
-3-methyl-2-oxopiperidin-3-yl)acetic acid;
2-(5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-2-oxo-1-(6,6,6-trifluor-
o-5-hydroxy-5-methylhexan-3-yl)piperidin-3-yl)acetic acid;
2-(5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-1-(1-(N-methylmethylsul-
fonamido)butan-2-yl)-2-oxopiperidin-3-yl)acetic acid;
2-(5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-(5-cyclopropyl-6,6,6-trifluoro-
-5-hydroxyhexan-3-yl)-3-methyl-2-oxopiperidin-3-yl)acetic acid;
2-(5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-(6-hydroxy-6-methylheptan-3-yl-
)-3-methyl-2-oxopiperidin-3-yl)acetic acid;
2-(5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-2-oxo-1-(6,6,6-trifluor-
o-5,5-dihydroxyhexan-3-yl)piperidin-3-yl)acetic acid;
2-(5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-2-oxo-1-(7,7,7-trifluor-
o-6-hydroxy-6-methylheptan-3-yl)piperidin-3-yl)acetic acid;
2-(5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-(7-hydroxy-7-methyloctan-3-yl)-
-3-methyl-2-oxopiperidin-3-yl)acetic acid;
2-(5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-1-(1-(N-methylcycloprop-
anesulfonamido)butan-2-yl)-2-oxopiperidin-3-yl)acetic acid;
2-(5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-(1-(N-cyclopropylmethylsulfona-
mido)butan-2-yl)-3-methyl-2-oxopiperidin-3-yl)acetic acid;
2-(5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-2-oxo-1-(6,6,6-trifluor-
o-5-hydroxyhexan-3-yl)piperidin-3-yl)acetic acid;
2-(5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-(5-hydroxyhexan-3-yl)-3-methyl-
-2-oxopiperidin-3-yl)acetic acid;
2-(5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-2-oxo-1-(1-(N-(2,2,2-tr-
ifluoroethyl)methylsulfonamido)butan-2-yl)piperidin-3-yl)acetic
acid;
2-(5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-(1-(1,1-dioxidoisothiazolidin--
2-yl)butan-2-yl)-3-methyl-2-oxopiperidin-3-yl)acetic acid;
2-(5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-(5-hydroxy-4,5-dimethylhexan-3-
-yl)-3-methyl-2-oxopiperidin-3-yl)acetic acid;
2-(5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-(5-cyano-5-methylhexan-3-yl)-3-
-methyl-2-oxopiperidin-3-yl)acetic acid;
2-(5-(3-Chlorophenyl)-6-(4-chlorophenyl)-3-methyl-2-oxo-1-(2-oxopentan-3--
yl)piperidin-3-yl)acetic acid;
2-(5-(3-Chlorophenyl)-6-(4-chlorophenyl)-1-(2-hydroxypentan-3-yl)-3-methy-
l-2-oxopiperidin-3-yl)acetic acid;
2-(5-(3-Chlorophenyl)-6-(4-chlorophenyl)-1-(2-methoxypentan-3-yl)-3-methy-
l-2-oxopiperidin-3-yl)acetic acid;
2-(5-(3-Chlorophenyl)-6-(4-chlorophenyl)-1-(2-hydroxypentan-3-yl)-3-methy-
l-2-oxopiperidin-3-yl)acetic acid;
2-(5-(3-Chlorophenyl)-6-(4-chlorophenyl)-1-(2-hydroxy-2-methylpentan-3-yl-
)-3-methyl-2-oxopiperidin-3-yl)acetic acid;
2-(5-(3-Chlorophenyl)-6-(4-chlorophenyl)-1-(4-hydroxyhexan-3-yl)-3-methyl-
-2-oxopiperidin-3-yl)acetic acid;
2-(5-(3-Chlorophenyl)-6-(4-chlorophenyl)-1-(1-methoxybutan-2-yl)-3-methyl-
-2-oxopiperidin-3-yl)acetic acid;
2-(5-(3-Chlorophenyl)-6-(4-chlorophenyl)-3-methyl-2-oxo-1-(1,1,1-trifluor-
o-2-hydroxy-2-methylpentan-3-yl)piperidin-3-yl)acetic acid;
2-(5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-1-(1-(N-methylcycloprop-
anesulfonamido)butan-2-yl)-2-oxopiperidin-3-yl)acetamide;
2-(5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-1-(1-(N-methylcycloprop-
anesulfonamido)butan-2-yl)-2-oxopiperidin-3-yl)-N-(methylsulfonyl)acetamid-
e;
2-(5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-1-(1-(N-methylcyclopr-
opanesulfonamido)butan-2-yl)-2-oxopiperidin-3-yl)-N-(3-hydroxypropyl)aceta-
mide;
2-(5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-1-(1-(N-methylcycl-
opropanesulfonamido)butan-2-yl)-2-oxopiperidin-3-yl)-N-(2-hydroxyethyl)ace-
tamide;
2-(5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-1-(1-(N-methylcy-
clopropanesulfonamido)butan-2-yl)-2-oxopiperidin-3-yl)-N-hydroxyacetamide;
2-(5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-1-(1-(N-methylcycloprop-
anesulfonamido)butan-2-yl)-2-oxopiperidin-3-yl)-N-methoxyacetamide;
2-(5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-1-(1-(N-methylcycloprop-
anesulfonamido)butan-2-yl)-2-oxopiperidin-3-yl)-N-(2,3-dihydroxypropyl)ace-
tamide;
2-(5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-1-(1-(N-methylcy-
clopropanesulfonamido)butan-2-yl)-2-oxopiperidin-3-yl)-N-(2,3-dihydroxypro-
pyl)acetamide;
2-(5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-1-(1-(N-methylcycloprop-
anesulfonamido)butan-2-yl)-2-oxopiperidin-3-yl)-N-cyanoacetamide;
2-(5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-1-(1-(N-methylcycloprop-
anesulfonamido)butan-2-yl)-2-oxopiperidin-3-yl)-N-(2-(dimethylamino)ethyl)-
acetamide;
2-(5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-1-(1-(N-methy-
lcyclopropanesulfonamido)butan-2-yl)-2-oxopiperidin-3-yl)-N-(3,4-dihydroxy-
butyl)acetamide;
2-(5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-(1-(cyclopropanesulfonamido)bu-
tan-2-yl)-3-methyl-2-oxopiperidin-3-yl)acetic acid;
2-(5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-1-(1-(N-methylcycloprop-
anesulfonamido)butan-2-yl)-2-oxopiperidin-3-yl)propanoic acid;
2-(5-(3-Chlorophenyl)-6-(4-chlorophenyl)-1-(2-(cyclopropanesulfonamido)pe-
ntan-3-yl)-3-methyl-2-oxopiperidin-3-yl)acetic acid;
2-(5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-1-(2-(1-methylethylsulf-
onamido)pentan-3-yl)-2-oxopiperidin-3-yl)acetic acid;
2-(5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-1-(1-(N-methylcycloprop-
anesulfonamido)-1-oxobutan-2-yl)-2-oxopiperidin-3-yl)acetic acid;
2-(5-(3-Chlorophenyl)-6-(4-chlorophenyl)-3-methyl-1-(1-(neopentylamino)-1-
-oxobutan-2-yl)-2-oxopiperidin-3-yl)acetic acid;
2-(5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-(1-(4,4-dimethyl-4,5-dihydroox-
azol-2-yl)propyl)-3-methyl-2-oxopiperidin-3-yl)acetic acid;
2-(5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-2-oxo-1-(1-(N-(2,2,2-tr-
ifluoroethyl)acetamido)butan-2-yl)piperidin-3-yl)acetic acid;
2-(5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-(1-(1,1-dimethylethylsulfonami-
do)butan-2-yl)-3-methyl-2-oxopiperidin-3-yl)acetic acid
2-(5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-(1-(N,2-dimethylpropan-2-ylsul-
fonamido)butan-2-yl)-3-methyl-2-oxopiperidin-3-yl)acetic acid;
2-(5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-1-(1-(1-methylethylsulf-
onamido)butan-2-yl)-2-oxopiperidin-3-yl)acetic acid;
2-(5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-(1-(N-ethylpropan-2-ylsulfonam-
ido)butan-2-yl)-3-methyl-2-oxopiperidin-3-yl)acetic acid;
2-(5-(3-Chlorophenyl)-6-(4-chlorophenyl)-1-(1-hydroxybutan-2-yl)-3-methyl-
-2-oxopiperidin-3-yl)acetic acid;
2-(5-(3-Chlorophenyl)-6-(4-chlorophenyl)-3-methyl-2-oxo-1-(1-(trifluorome-
thylsulfonamido)butan-2-yl)piperidin-3-yl)acetic acid;
2-(5-(3-Chlorophenyl)-6-(4-chlorophenyl)-1-(1-(4-chlorophenylsulfonamido)-
butan-2-yl)-3-methyl-2-oxopiperidin-3-yl)acetic acid;
2-(5-(3-Chlorophenyl)-6-(4-chlorophenyl)-3-methyl-1-(1-(4-methylphenylsul-
fonamido)butan-2-yl)-2-oxopiperidin-3-yl)acetic acid;
2-(5-(3-Chlorophenyl)-6-(4-chlorophenyl)-1-(1-(2-chlorophenylsulfonamido)-
butan-2-yl)-3-methyl-2-oxopiperidin-3-yl)acetic acid;
2-(5-(3-Chlorophenyl)-6-(4-chlorophenyl)-1-(1-(2-methylphenylsulfonamido)-
butan-2-yl)-3-methyl-2-oxopiperidin-3-yl)acetic acid;
2-(5-(3-Chlorophenyl)-6-(4-chlorophenyl)-1-(1-(4-methoxyphenylsulfonamido-
)butan-2-yl)-3-methyl-2-oxopiperidin-3-yl)acetic acid;
2-(5-(3-Chlorophenyl)-6-(4-chlorophenyl)-1-(1-(phenylsulfonamido)butan-2--
yl)-3-methyl-2-oxopiperidin-3-yl)acetic acid;
2-(5-(3-Chlorophenyl)-6-(4-chlorophenyl)-1-(1-(1-methylcyclopropanesulfon-
amido)butan-2-yl)-3-methyl-2-oxopiperidin-3-yl)acetic acid;
2-(5-(3-Chlorophenyl)-6-(4-chlorophenyl)-1-(1-(1,1-dioxidobenzo[d]isothia-
zol-2(3H)-yl)butan-2-yl)-3-methyl-2-oxopiperidin-3-yl)acetic acid;
2-(5-(3-Chlorophenyl)-6-(4-chlorophenyl)-1-(1-(3,3-dimethyl-1,1-dioxidobe-
nzo[d]isothiazol-2(3H)-yl)butan-2-yl)-3-methyl-2-oxopiperidin-3-yl)acetic
acid;
2-(5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-2-oxo-1-(1-(pyrid-
ine-3-sulfonamido)butan-2-yl)piperidin-3-yl)acetic acid;
2-(5-(3-Chlorophenyl)-6-(4-chlorophenyl)-1-(1-(4-cyanophenylsulfonamido)b-
utan-2-yl)-3-methyl-2-oxopiperidin-3-yl)acetic acid;
2-(5-(3-Chlorophenyl)-6-(4-chlorophenyl)-1-(1-(3-cyanophenylsulfonamido)b-
utan-2-yl)-3-methyl-2-oxopiperidin-3-yl)acetic acid;
2-(5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-2-oxo-1-(1-(pyridine-2--
sulfonamido)butan-2-yl)piperidin-3-yl)acetic acid
2-(5-(3-Chlorophenyl)-6-(4-chlorophenyl)-1-(1-(N,1-dimethylcyclopropanesu-
lfonamido)butan-2-yl)-3-methyl-2-oxopiperidin-3-yl)acetic acid;
3-(5-(3-Chlorophenyl)-6-(4-chlorophenyl)-3-methyl-1-(1-(N-methylcycloprop-
anesulfonamido)butan-2-yl)-2-oxopiperidin-3-yl)propanoic acid;
2-(5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-ethyl-1-(1-(N-methylcyclopropa-
nesulfonamido)butan-2-yl)-2-oxopiperidin-3-yl)acetic acid;
2-(5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methoxy-1-(1-(N-methylcyclopro-
panesulfonamido)butan-2-yl)-2-oxopiperidin-3-yl)acetic acid;
2-(5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-1-(6-methyl-4-oxoheptan-
-3-yl)-2-oxopiperidin-3-yl)acetic acid;
2-(5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-(1-(ethylsulfonyl)pentan-3-yl)-
-3-methyl-2-oxopiperidin-3-yl)acetic acid;
2-(5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-(1-(isopropylsulfonyl)pentan-3-
-yl)-3-methyl-2-oxopiperidin-3-yl)acetic acid;
2-(5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-(1-(cyclopropylmethylsulfonyl)-
pentan-3-yl)-3-methyl-2-oxopiperidin-3-yl)acetic acid;
2-(5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-2-oxo-1-(1-(2-oxopyrrol-
idin-1-yl)butan-2-yl)piperidin-3-yl)acetic acid;
2-(1-(1-(2-oxa-5-azabicyclo[2.2.1]heptan-5-yl)butan-2-yl)-5-(3-chlorophen-
yl)-6-(4-chlorophenyl)-3-methyl-2-oxopiperidin-3-yl)acetic acid;
2-(5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-1-(1-(3-methylmorpholin-
o)butan-2-yl)-2-oxopiperidin-3-yl)acetic acid;
2-(5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-(1-(thiomorpholino-1,1-dioxide-
)butan-2-yl)-3-methyl-2-oxopiperidin-3-yl)acetic acid;
2-(5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-(1-(3,3-difluoroazetidin-1-yl)-
butan-2-yl)-3-methyl-2-oxopiperidin-3-yl)acetic acid;
2-(1-(1-(8-oxa-3-azabicyclo[3.2.1]octan-3-yl)butan-2-yl)-5-(3-chloropheny-
l)-6-(4-chlorophenyl)-3-methyl-2-oxopiperidin-3-yl)acetic acid;
2-(5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-(1-(3,3-dimethylmorpholino)but-
an-2-yl)-3-methyl-2-oxopiperidin-3-yl)acetic acid;
2-(5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-(1-(3-hydroxy-3-(trifluorometh-
yl)azetidin-1-yl)butan-2-yl)-3-methyl-2-oxopiperidin-3-yl)acetic
acid;
2-(5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-1-(1-(methyl(oxetan-3-y-
l)amino)butan-2-yl)-2-oxopiperidin-3-yl)acetic acid;
2-(5-(3-Chlorophenyl)-6-(4-chlorophenyl)-3-methyl-2-oxo-1-(1-(2-oxooxazol-
idin-3-yl)butan-2-yl)piperidin-3-yl)acetic acid;
2-(5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-2-oxo-1-(1-(2-oxopyridi-
n-1(2H)-yl)butan-2-yl)piperidin-3-yl)acetic acid;
2-(5-(3-Chlorophenyl)-6-(4-chlorophenyl)-3-methyl-2-oxo-1-(1-(2-oxo-5-(tr-
ifluoromethyl)pyridin-1(2H)-yl)butan-2-yl)piperidin-3-yl)acetic
acid;
3-allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-1-(1-(pyridin-3-yl-
oxy)butan-2-yl)piperidin-2-one;
2-(5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-2-oxo-1-(1-(tetrahydrof-
uran-2-yl)propyl)piperidin-3-yl)acetic acid;
2-(5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-2-oxo-1-(1-(5-oxotetrah-
ydrofuran-2-yl)propyl)piperidin-3-yl)acetic acid;
2-(5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-2-oxo-1-(1-(tetrahydro--
2H-pyran-2-yl)propyl)piperidin-3-yl)acetic acid;
2-(1-(1-(benzo[d]thiazol-2-yl)propyl)-5-(3-chlorophenyl)-6-(4-chloropheny-
l)-3-methyl-2-oxopiperidin-3-yl)acetic acid;
2-(5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-1-(1-(3-methylisoxazol--
5-yl)propyl)-2-oxopiperidin-3-yl)acetic acid;
2-(5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-(1-(6-chloropyridin-2-yl)propy-
l)-3-methyl-2-oxopiperidin-3-yl)acetic acid;
2-(5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-2-oxo-1-(1-(pyridin-2-y-
l)propyl)piperidin-3-yl)acetic acid;
2-(5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-2-oxo-1-(1-(pyridin-2-y-
l)butyl)piperidin-3-yl)acetic acid;
2-(5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-(2-cyclopropyl-1-(pyridin-2-yl-
)ethyl)-3-methyl-2-oxopiperidin-3-yl)acetic acid;
2-(5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-2-oxo-1-(1-(pyridin-3-y-
l)propyl)piperidin-3-yl)acetic acid;
2-(5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-2-oxo-1-(1-(pyrazin-2-y-
l)propyl)piperidin-3-yl)acetic acid;
2-(5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-2-oxo-1-(1-(pyrimidin-2-
-yl)propyl)piperidin-3-yl)acetic acid;
2-(5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-(1-(6-methylpyridin-2-y-
l)propyl)-2-oxopiperidin-3-yl)acetic acid;
2-(5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-2-oxo-1-(1-(pyridin-4-y-
l)propyl)piperidin-3-yl)acetic acid;
2-(5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-2-oxo-1-(1-(6-(trifluor-
omethyl)pyridin-2-yl)propyl)piperidin-3-yl)acetic acid;
2-(1-(1-(6-bromopyridin-2-yl)propyl)-5-(3-chlorophenyl)-6-(4-chlorophenyl-
)-3-methyl-2-oxopiperidin-3-yl)acetic acid;
2-(5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-2-oxo-1-(1-(thiazol-2-y-
l)propyl)piperidin-3-yl)acetic acid;
2-(5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-(1-(6-(2-hydroxypropan-2-yl)py-
ridin-2-yl)propyl)-3-methyl-2-oxopiperidin-3-yl)acetic acid;
2-(5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-(1-(6-cyclopropylpyridin-2-yl)-
propyl)-3-methyl-2-oxopiperidin-3-yl)acetic acid;
2-(5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-2-oxo-1-(3,3,3-trifluor-
o-1-(pyridin-2-yl)propyl)piperidin-3-yl)acetic acid;
2-(5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-(2-methyl-1-(pyridin-2--
yl)propyl)-2-oxopiperidin-3-yl)acetic acid;
3-((1H-tetrazol-5-yl)methyl)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-meth-
yl-1-(pentan-3-yl)piperidin-2-one;
5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-(2,3-dihydroxypropyl)-1-(2-hydrox-
ypentan-3-yl)-3-methylpiperidin-2-one;
2-(5-(3-Chlorophenyl)-6-(4-chlorophenyl)-1-(1-hydroxybutan-2-yl)-3-methyl-
-2-oxopiperidin-3-yl)cyclopropanecarboxylic acid;
2-(1-(2-(tert-Butoxy)-1-cyclopropyl-2-oxoethyl)-5-(3-chlorophenyl)-6-(4-c-
hlorophenyl)-2-oxopiperidin-3-yl)acetic acid;
2-(5-(3-Chlorophenyl)-6-(4-chlorophenyl)-1-(1-cyclopropyl-2-ethoxy-2-oxoe-
thyl)-3-methyl-2-oxopiperidin-3-yl)acetic acid;
2-(5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-(1-cyclopropyl-2-hydroxyethyl)-
-3-methyl-2-oxopiperidin-3-yl)acetic acid;
2-(5-(3-Chlorophenyl)-6-(4-chlorophenyl)-1-(1-cyclopropyl-2-hydroxybutyl)-
-3-methyl-2-oxopiperidin-3-yl)acetic acid;
2-(5-(3-Chlorophenyl)-6-(4-chlorophenyl)-1-(1-cyclopropyl-2-(N-methylcycl-
opropanesulfonamido)ethyl)-3-ethyl-2-oxopiperidin-3-yl)acetic acid;
2-(5-(3-Chlorophenyl)-6-(4-chlorophenyl)-1-(2-(cyclopropanesulfonamido)-1-
-cyclopropylethyl)-3-ethyl-2-oxopiperidin-3-yl)acetic acid;
2-(5-(3-Chlorophenyl)-6-(4-chlorophenyl)-1-(1-cyclopropyl-2-(ethylsulfona-
mido)ethyl)-3-ethyl-2-oxopiperidin-3-yl)acetic acid;
2-(5-(3-Chlorophenyl)-6-(4-chlorophenyl)-1-(1-cyclopropyl-2-(N-methylcycl-
opropanesulfonamido)ethyl)-3-methyl-2-oxopiperidin-3-yl)acetic
acid;
2-(5-(3-Chlorophenyl)-6-(4-chlorophenyl)-1-(1-cyclopropyl-2-hydroxypropyl-
)-3-methyl-2-oxopiperidin-3-yl)acetic acid;
2-(5-(3-Chlorophenyl)-6-(4-chlorophenyl)-1-(1-cyclopropyl-2-(1-methylethy-
lsulfonamido)ethyl)-3-methyl-2-oxopiperidin-3-yl)acetic acid;
2-(5-(3-Chlorophenyl)-6-(4-chlorophenyl)-1-(1-cyclopropyl-2-(N-methylcycl-
opropanesulfonamido)ethyl)-3-methyl-2-oxopiperidin-3-yl)acetic
acid;
2-(5-(3-Chlorophenyl)-6-(4-chlorophenyl)-1-(2-hydroxy-4-methylpentan-3-yl-
)-3-methyl-2-oxopiperidin-3-yl)acetic acid; or
2-(5-(3-Chlorophenyl)-6-(4-chlorophenyl)-1-(cyclopropyl(pyridin-2-yl)meth-
yl)-3-methyl-2-oxopiperidin-3-yl)acetic acid.
23. A compound, or a pharmaceutically acceptable salt thereof,
selected from:
2-((3S,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-(N-met-
hylcyclopropanesulfonamido)butan-2-yl)-2-oxopiperidin-3-yl)acetic
acid;
2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-(1,1-dioxido-
isothiazolidin-2-yl)butan-2-yl)-3-methyl-2-oxopiperidin-3-yl)acetic
acid;
2-((3R,5R,6S)-5-(3-Chlorophenyl)-6-(4-chlorophenyl)-1-((2S,3S)-2-hydroxyp-
entan-3-yl)-3-methyl-2-oxopiperidin-3-yl)acetic acid;
2-((3R,5R,6S)-5-(3-Chlorophenyl)-6-(4-chlorophenyl)-1-((2R,3S)-2-hydroxyp-
entan-3-yl)-3-methyl-2-oxopiperidin-3-yl)acetic acid;
2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-(1,1-dimethy-
lethylsulfonamido)butan-2-yl)-3-methyl-2-oxopiperidin-3-yl)acetic
acid
2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-(N,2-dimethy-
lpropan-2-ylsulfonamido)butan-2-yl)-3-methyl-2-oxopiperidin-3-yl)acetic
acid;
2-((3R,5R,6S)-5-(3-Chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-(N,1-d-
imethylcyclopropanesulfonamido)butan-2-yl)-3-methyl-2-oxopiperidin-3-yl)ac-
etic acid;
2-((3R,5R,6S)-5-(3-Chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-cy-
clopropyl-2-(N-methylcyclopropanesulfonamido)ethyl)-3-methyl-2-oxopiperidi-
n-3-yl)acetic acid;
2-((3R,5R,6S)-5-(3-Chlorophenyl)-6-(4-chlorophenyl)-1-((1S,2R)-1-cyclopro-
pyl-2-hydroxypropyl)-3-methyl-2-oxopiperidin-3-yl)acetic acid; or
2-((3R,5R,6S)-5-(3-Chlorophenyl)-6-(4-chlorophenyl)-1-((1S,2S)-1-cyclopro-
pyl-2-hydroxypropyl)-3-methyl-2-oxopiperidin-3-yl)acetic acid.
24. A compound, or a pharmaceutically acceptable salt thereof,
selected from:
2-(5-(3-Chlorophenyl)-6-(4-chlorophenyl)-1-(1-(N-methylcyclopropane-
sulfonamido)butan-2-yl)-2-oxopiperidin-3-yl)acetic acid;
2-(5-(3-Chlorophenyl)-6-(4-chlorophenyl)-1-(1-(1,1-dioxidoisothiazolidin--
2-yl)butan-2-yl)-3-methyl-2-oxopiperidin-3-yl)acetic acid;
2-(5-(3-Chlorophenyl)-6-(4-chlorophenyl)-1-(2-hydroxypentan-3-yl)-3-methy-
l-2-oxopiperidin-3-yl)acetic acid;
2-(5-(3-Chlorophenyl)-6-(4-chlorophenyl)-1-(2-hydroxypentan-3-yl)-3-methy-
l-2-oxopiperidin-3-yl)acetic acid;
2-(5-(3-Chlorophenyl)-6-(4-chlorophenyl)-1-(1-(1,1-dimethylethylsulfonami-
do)butan-2-yl)-3-methyl-2-oxopiperidin-3-yl)acetic acid
2-(5-(3-Chlorophenyl)-6-(4-chlorophenyl)-1-(1-(N,2-dimethylpropan-2-ylsul-
fonamido)butan-2-yl)-3-methyl-2-oxopiperidin-3-yl)acetic acid;
2-(5-(3-Chlorophenyl)-6-(4-chlorophenyl)-1-(1-(N,1-dimethylcyclopropanesu-
lfonamido)butan-2-yl)-3-methyl-2-oxopiperidin-3-yl)acetic acid;
2-(5-(3-Chlorophenyl)-6-(4-chlorophenyl)-1-(1-cyclopropyl-2-(N-methylcycl-
opropanesulfonamido)ethyl)-3-methyl-2-oxopiperidin-3-yl)acetic
acid; or
2-(5-(3-Chlorophenyl)-6-(4-chlorophenyl)-1-(1-cyclopropyl-2-hydroxypropyl-
)-3-methyl-2-oxopiperidin-3-yl)acetic acid.
25. A compound, or a pharmaceutically acceptable salt thereof,
selected from:
2-((3R,5R,6S)-5-(3-Chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-cyclop-
ropyl-2-(thiophene-2-sulfonamido)ethyl)-3-methyl-2-oxopiperidin-3-yl)aceti-
c acid;
2-((3R,5R,6S)-5-(3-Chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-cyclo-
propyl-2-(N-methylthiophene-2-sulfonamido)ethyl)-3-methyl-2-oxopiperidin-3-
-yl)acetic acid;
2-((3R,5R,6S)-5-(3-Chlorophenyl)-6-(4-chlorophenyl)-1-((S)-2-(5-chlorothi-
ophene-2-sulfonamido)-1-cyclopropylethyl)-3-methyl-2-oxopiperidin-3-yl)ace-
tic acid;
2-((3R,5R,6S)-1-((S)-2-(5-Chloro-N-methylthiophene-2-sulfonamido-
)-1-cyclopropylethyl)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-2-oxo-
piperidin-3-yl)acetic acid;
2-((3R,5R,6S)-5-(3-Chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-cyclopropyl--
2-(N-(difluoromethyl)-2-methylpropan-2-ylsulfonamido)ethyl)-3-methyl-2-oxo-
piperidin-3-yl)acetic acid;
2-((3R,5R,6S)-5-(3-Chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-cyclopropyl--
2-(N-(difluoromethyl)ethylsulfonamido)ethyl)-3-methyl-2-oxopiperidin-3-yl)-
acetic acid;
2-((3R,5R,6S)-5-(3-Chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-cyclopropyl--
2-(N-(difluoromethyl)cyclopropanesulfonamido)ethyl)-3-methyl-2-oxopiperidi-
n-3-yl)acetic acid;
1-((3R,5R,6S)-5-(3-Chlorophenyl)-6-(4-chlorophenyl)-1-((S)-2-(cyclopropan-
esulfonamido)-1-cyclopropylethyl)-3-methyl-2-oxopiperidin-3-yl)cyclopropan-
ecarboxylic acid;
2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-cyclopropyl--
2-(N-(2-fluorophenyl)ethylsulfonamido)ethyl)-3-methyl-2-oxopiperidin-3-yl)-
acetic acid;
2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-cyclopropyl--
2-(N-(2-fluorophenyl)methylsulfonamido)ethyl)-3-methyl-2-oxopiperidin-3-yl-
)acetic acid;
2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-cyclopropyl--
2-(N-phenylcyclopropanesulfonamido)ethyl)-3-methyl-2-oxopiperidin-3-yl)ace-
tic acid;
2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-cyc-
lopropyl-2-(N-phenylethylsulfonamido)ethyl)-3-methyl-2-oxopiperidin-3-yl)a-
cetic acid;
2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-cyclopropyl--
2-(ethylsulfonamido)ethyl)-3-methyl-2-oxopiperidin-3-yl)acetic
acid;
2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-cyclopropyl--
2-(N-(3-fluorophenyl)ethylsulfonamido)ethyl)-3-methyl-2-oxopiperidin-3-yl)-
acetic acid;
2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((S)-2-(N-(2-cyanop-
henyl)methylsulfonamido)-1-cyclopropylethyl)-3-methyl-2-oxopiperidin-3-yl)-
acetic acid;
2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-cyclopropyl--
2-(propylsulfonamido)ethyl)-3-methyl-2-oxopiperidin-3-yl)acetic
acid;
2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-cyclopropyl--
2-(N-phenylmethylsulfonamido)ethyl)-3-methyl-2-oxopiperidin-3-yl)acetic
acid;
2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((S)-2-(N-(3--
cyanophenyl)methylsulfonamido)-1-cyclopropylethyl)-3-methyl-2-oxopiperidin-
-3-yl)acetic acid;
2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-cyclopropyl--
2-(N-(pyridin-3-yl)methylsulfonamido)ethyl)-3-methyl-2-oxopiperidin-3-yl)a-
cetic acid;
2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-cyclopropyl--
2-(N-(thiophen-2-ylmethyl)methylsulfonamido)ethyl)-3-methyl-2-oxopiperidin-
-3-yl)acetic acid;
2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-cyclopropyl--
2-(N-(3-methoxybenzyl)methylsulfonamido)ethyl)-3-methyl-2-oxopiperidin-3-y-
l)acetic acid;
2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-cyclopropyl--
2-(phenylmethylsulfonamido)ethyl)-3-methyl-2-oxopiperidin-3-yl)acetic
acid;
2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-cyclop-
ropyl-2-(pyridin-2-ylmethylsulfonamido)ethyl)-3-methyl-2-oxopiperidin-3-yl-
)acetic acid;
2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-cyclopropyl--
2-(pyridin-3-ylmethylsulfonamido)ethyl)-3-methyl-2-oxopiperidin-3-yl)aceti-
c acid;
2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-cyclo-
propyl-2-(N-(pyridin-2-yl)methylsulfonamido)ethyl)-3-methyl-2-oxopiperidin-
-3-yl)acetic acid;
2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-cyclopropyl--
2-(methylsulfonamido)ethyl)-3-methyl-2-oxopiperidin-3-yl)acetic
acid;
2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-cyclopropyl--
2-(N-ethylmethylsulfonamido)ethyl)-3-methyl-2-oxopiperidin-3-yl)acetic
acid;
2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-cyclop-
ropyl-2-(N-isopropylmethylsulfonamido)ethyl)-3-methyl-2-oxopiperidin-3-yl)-
acetic acid;
2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-cyclopropyl--
2-(1-methylethylsulfonamido)ethyl)-3-ethyl-2-oxopiperidin-3-yl)acetic
acid;
2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((S)-2-(cyclo-
butanesulfonamido)-1-cyclopropylethyl)-3-ethyl-2-oxopiperidin-3-yl)acetic
acid;
2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((S)-2-(cyclo-
pentanesulfonamido)-1-cyclopropylethyl)-3-ethyl-2-oxopiperidin-3-yl)acetic
acid;
2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-1-((S)-
-3-methyl-1-(N-methylcyclopropanesulfonamido)butan-2-yl)-2-oxopiperidin-3--
yl)acetic acid;
2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-(cyclopropan-
esulfonamido)-3-methylbutan-2-yl)-3-methyl-2-oxopiperidin-3-yl)acetic
acid;
2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-(ethyl-
sulfonamido)-3-methylbutan-2-yl)-3-methyl-2-oxopiperidin-3-yl)acetic
acid;
2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-(cyclobutane-
sulfonamido)butan-2-yl)-3-methyl-2-oxopiperidin-3-yl)acetic acid;
2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-(N-ethylcycl-
obutanesulfonamido)butan-2-yl)-3-methyl-2-oxopiperidin-3-yl)acetic
acid;
2-((3R,5R,6S)-5-(3-Chlorophenyl)-6-(4-chlorophenyl)-3-methyl-2-oxo-1-((S)-
-1-(phenylsulfonyl)butan-2-yl)piperidin-3-yl)acetic acid;
2-((3R,5R,6S)-5-(3-Chlorophenyl)-6-(4-chlorophenyl)-3-methyl-1-((S)-1-(me-
thylsulfonyl)butan-2-yl)-2-oxopiperidin-3-yl)acetic acid;
2-((3R,5R,6S)-5-(3-Chlorophenyl)-6-(4-chlorophenyl)-3-methyl-2-oxo-1-((S)-
-1-(propylsulfonyl)butan-2-yl)piperidin-3-yl)acetic acid;
2-((3R,5R,6S)-5-(3-Chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-(isobutylsul-
fonyl)butan-2-yl)-3-methyl-2-oxopiperidin-3-yl)acetic acid;
2-((3R,5R,6S)-5-(3-Chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-((cyclopropy-
lmethyl)sulfonyl)butan-2-yl)-3-methyl-2-oxopiperidin-3-yl)acetic
acid;
2-((3R,5R,6S)-5-(3-Chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-((cyclobutyl-
methyl)sulfonyl)butan-2-yl)-3-methyl-2-oxopiperidin-3-yl)acetic
acid;
2-((3R,5R,6S)-5-(3-Chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-(cyclopentyl-
sulfonyl)butan-2-yl)-3-methyl-2-oxopiperidin-3-yl)acetic acid;
2-((3R,5R,6S)-5-(3-Chlorophenyl)-6-(4-chlorophenyl)-3-methyl-1-((S)-1-(ox-
etan-3-ylsulfonyl)butan-2-yl)-2-oxopiperidin-3-yl)acetic acid;
2-((3R,5R,6S)-5-(3-Chlorophenyl)-6-(4-chlorophenyl)-3-methyl-1-((S)-1-(((-
3-methyloxetan-3-yl)methyl)sulfonyl)butan-2-yl)-2-oxopiperidin-3-yl)acetic
acid;
2-((3R,5R,6S)-5-(3-Chlorophenyl)-6-(4-chlorophenyl)-3-methyl-2-oxo--
1-((S)-1-((tetrahydro-2H-pyran-4-yl)sulfonyl)butan-2-yl)piperidin-3-yl)ace-
tic acid;
2-((3R,5R,6S)-5-(3-Chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-((2-
-hydroxy-2-methylpropyl)sulfonyl)butan-2-yl)-3-methyl-2-oxopiperidin-3-yl)-
acetic acid;
2-((3R,5R,6S)-1-((S)-1-((R)-sec-butylsulfonyl)butan-2-yl)-5-(3-chlorophen-
yl)-6-(4-chlorophenyl)-3-methyl-2-oxopiperidin-3-yl)acetic acid;
2-((3R,5R,6S)-1-((S)-1-((S)-sec-butylsulfonyl)butan-2-yl)-5-(3-chlorophen-
yl)-6-(4-chlorophenyl)-3-methyl-2-oxopiperidin-3-yl)acetic acid;
2-((3R,5R,6S)-5-(3-Chlorophenyl)-6-(4-chlorophenyl)-1-((S)-2-(cyclopentyl-
sulfonyl)-1-cyclopropylethyl)-3-methyl-2-oxopiperidin-3-yl)acetic
acid;
2-((3R,5R,6S)-5-(3-Chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-cyclopropyl--
2-(((3-methyloxetan-3-yl)methyl)sulfonyl)ethyl)-3-methyl-2-oxopiperidin-3--
yl)acetic acid;
2-((3R,5R,6S)-5-(3-Chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-cyclopropyl--
2-(phenylsulfonyl)ethyl)-3-methyl-2-oxopiperidin-3-yl)acetic acid;
2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-cyclopropyl--
2-(o-tolylsulfonyl)ethyl)-3-methyl-2-oxopiperidin-3-yl)acetic acid;
2-((3R,5R,6S)-5-(3-Chlorophenyl)-6-(4-chlorophenyl)-1-((S)-2-((2-chloroph-
enyl)sulfonyl)-1-cyclopropylethyl)-3-methyl-2-oxopiperidin-3-yl)acetic
acid;
2-((3R,5R,6S)-5-(3-Chlorophenyl)-6-(4-chlorophenyl)-1-((S)-2-((4-ch-
lorophenyl)sulfonyl)-1-cyclopropylethyl)-3-methyl-2-oxopiperidin-3-yl)acet-
ic acid;
2-((3R,5R,6S)-5-(3-Chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-cycl-
opropyl-2-((4-fluorophenyl)sulfonyl)ethyl)-3-methyl-2-oxopiperidin-3-yl)ac-
etic acid;
2-((3R,5R,6S)-5-(3-Chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-cy-
clopropyl-2-(pyridin-4-ylsulfonyl)ethyl)-3-methyl-2-oxopiperidin-3-yl)acet-
ic acid;
2-((3R,5R,6S)-1-((S)-2-((2-Chloro-4-fluorophenyl)sulfonyl)-1-cycl-
opropylethyl)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-2-oxopiperidi-
n-3-yl)acetic acid;
2-((3R,5R,6S)-5-(3-Chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-cyclopropyl--
2-((cyclopropylmethyl)sulfonyl)ethyl)-3-methyl-2-oxopiperidin-3-yl)acetic
acid;
2-((3R,5R,6S)-5-(3-Chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-cyclop-
ropyl-2-((2,2,2-trifluoroethyl)sulfonyl)ethyl)-3-methyl-2-oxopiperidin-3-y-
l)acetic acid;
2-((3R,5R,6S)-5-(3-Chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-cyclopropyl--
2-((trifluoromethyl)sulfonyl)ethyl)-3-methyl-2-oxopiperidin-3-yl)acetic
acid;
2-((3R,5R,6S)-5-(3-Chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-cyclop-
ropyl-2-(phenylsulfonyl)ethyl)-3-ethyl-2-oxopiperidin-3-yl)acetic
acid;
2-((3R,5R,6S)-5-(3-Chlorophenyl)-6-(4-chlorophenyl)-1-((S)-2-((2-chloroph-
enyl)sulfonyl)-1-cyclopropylethyl)-3-ethyl-2-oxopiperidin-3-yl)acetic
acid;
2-((3R,5R,6S)-5-(3-Chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-cyclop-
ropyl-2-((2-fluorophenyl)sulfonyl)ethyl)-3-ethyl-2-oxopiperidin-3-yl)aceti-
c acid;
2-((3R,5R,6S)-5-(3-Chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-cyclo-
propyl-2-((3-fluorophenyl)sulfonyl)ethyl)-3-ethyl-2-oxopiperidin-3-yl)acet-
ic acid;
2-((3R,5R,6S)-5-(3-Chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-cycl-
opropyl-2-((4-fluorophenyl)sulfonyl)ethyl)-3-ethyl-2-oxopiperidin-3-yl)ace-
tic acid;
2-((3R,5R,6S)-5-(3-Chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-cyc-
lopropyl-2-(propylsulfonyl)ethyl)-3-ethyl-2-oxopiperidin-3-yl)acetic
acid;
2-((3R,5R,6S)-1-((S)-2-(Butylsulfonyl)-1-cyclopropylethyl)-5-(3-chlorophe-
nyl)-6-(4-chlorophenyl)-3-ethyl-2-oxopiperidin-3-yl)acetic acid;
2-((3R,5R,6S)-5-(3-Chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-cyclopropyl--
2-(isopentylsulfonyl)ethyl)-3-ethyl-2-oxopiperidin-3-yl)acetic
acid;
2-((3R,5R,6S)-5-(3-Chlorophenyl)-6-(4-chlorophenyl)-1-((S)-2-(cyclopentyl-
sulfonyl)-1-cyclopropylethyl)-3-ethyl-2-oxopiperidin-3-yl)acetic
acid;
2-((3R,5R,6S)-5-(3-Chlorophenyl)-6-(4-chlorophenyl)-1-((S)-2-(cyclohexyls-
ulfonyl)-1-cyclopropylethyl)-3-ethyl-2-oxopiperidin-3-yl)acetic
acid;
2-((3R,5R,6S)-5-(3-Chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-cyclopropyl--
2-(methylsulfonyl)ethyl)-3-ethyl-2-oxopiperidin-3-yl)acetic acid;
2-((3R,5R,6S)-5-(3-Chlorophenyl)-6-(4-chlorophenyl)-3-methyl-1-((S)-3-met-
hyl-1-((2,2,2-trifluoroethyl)sulfonyl)butan-2-yl)-2-oxopiperidin-3-yl)acet-
ic acid;
2-((3R,5R,6S)-1-((S)-1-(tert-Butylsulfonyl)-3-methylbutan-2-yl)-5-
-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-2-oxopiperidin-3-yl)acetic
acid;
2-((3R,5R,6S)-5-(3-Chlorophenyl)-6-(4-chlorophenyl)-3-methyl-1-((S)-
-3-methyl-1-(methylsulfonyl)butan-2-yl)-2-oxopiperidin-3-yl)acetic
acid;
2-((3R,5R,6S)-5-(3-Chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-(ethylsulfon-
yl)butan-2-yl)-3-methyl-2-oxopiperidin-3-yl)acetic acid;
2-((3R,5R,6S)-5-(3-Chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-(cyclopropyl-
sulfonyl)butan-2-yl)-3-methyl-2-oxopiperidin-3-yl)acetic acid;
2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-(isopropylsu-
lfonyl)butan-2-yl)-3-methyl-2-oxopiperidin-3-yl)acetic acid;
2-((3R,5R,6S)-1-((S)-1-(tert-butylsulfonyl)butan-2-yl)-5-(3-chlorophenyl)-
-6-(4-chlorophenyl)-3-methyl-2-oxopiperidin-3-yl)acetic acid;
2-((3R,5R,6S)-5-(3-Chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-(cyclobutyls-
ulfonyl)butan-2-yl)-3-methyl-2-oxopiperidin-3-yl)acetic acid;
2-((3R,5R,6S)-5-(3-Chlorophenyl)-6-(4-chlorophenyl)-3-ethyl-1-((S)-1-(eth-
ylsulfonyl)butan-2-yl)-2-oxopiperidin-3-yl)acetic acid;
2-((3R,5R,6S)-5-(3-Chlorophenyl)-6-(4-chlorophenyl)-3-ethyl-1-((S)-1-(iso-
propylsulfonyl)butan-2-yl)-2-oxopiperidin-3-yl)acetic acid;
2-((3R,5R,6S)-1-((S)-1-(tert-butylsulfonyl)butan-2-yl)-5-(3-chlorophenyl)-
-6-(4-chlorophenyl)-3-ethyl-2-oxopiperidin-3-yl)acetic acid;
2-((3R,5R,6S)-5-(3-Chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-(cyclobutyls-
ulfonyl)butan-2-yl)-3-ethyl-2-oxopiperidin-3-yl)acetic acid;
2-((3R,5R,6S)-5-(3-Chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-(cyclopropyl-
sulfonyl)butan-2-yl)-3-ethyl-2-oxopiperidin-3-yl)acetic acid;
2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-cyclopropyl--
2-(ethylsulfonyl)ethyl)-3-methyl-2-oxopiperidin-3-yl)acetic acid;
2-((3R,5R,6S)-5-(3-Chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-cyclopropyl--
2-(isopropylsulfonyl)ethyl)-3-methyl-2-oxopiperidin-3-yl)acetic
acid;
2-((3R,5R,6S)-1-((S)-2-(tert-Butylsulfonyl)-1-cyclopropylethyl)-5-(3-chlo-
rophenyl)-6-(4-chlorophenyl)-3-methyl-2-oxopiperidin-3-yl)acetic
acid;
2-((3R,5R,6S)-5-(3-Chlorophenyl)-6-(4-chlorophenyl)-1-((S)-2-(cyclobutyls-
ulfonyl)-1-cyclopropylethyl)-3-methyl-2-oxopiperidin-3-yl)acetic
acid;
2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-cyclopropyl--
2-(cyclopropylsulfonyl)ethyl)-3-methyl-2-oxopiperidin-3-yl)acetic
acid;
2-((3R,5R,6S)-5-(3-Chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-cyclopropyl--
2-(methylsulfonyl)ethyl)-3-methyl-2-oxopiperidin-3-yl)acetic acid;
2-((3R,5R,6S)-5-(3-Chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-cyclopropyl--
2-(tert-pentylsulfonyl)ethyl)-3-methyl-2-oxopiperidin-3-yl)acetic
acid;
2-((3R,5R,6S)-5-(3-Chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-cyclopropyl--
2-((2,4-difluorophenyl)sulfonyl)ethyl)-3-methyl-2-oxopiperidin-3-yl)acetic
acid;
2-((3R,5R,6S)-5-(3-Chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-cyclop-
ropyl-2-(ethylsulfonyl)ethyl)-3-ethyl-2-oxopiperidin-3-yl)acetic
acid;
2-((3R,5R,6S)-5-(3-Chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-cyclopropyl--
2-(isopropylsulfonyl)ethyl)-3-ethyl-2-oxopiperidin-3-yl)acetic
acid;
2-((3R,5R,6S)-1-((S)-2-(tert-Butylsulfonyl)-1-cyclopropylethyl)-5-(3-chlo-
rophenyl)-6-(4-chlorophenyl)-3-ethyl-2-oxopiperidin-3-yl)acetic
acid;
2-((3R,5R,6S)-5-(3-Chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-cyclopropyl--
2-(cyclopropylsulfonyl)ethyl)-3-ethyl-2-oxopiperidin-3-yl)acetic
acid;
2-((3R,5R,6S)-5-(3-Chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-(ethylsulfon-
yl)-3-methylbutan-2-yl)-3-methyl-2-oxopiperidin-3-yl)acetic acid;
2-((3R,5R,6S)-5-(3-Chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-(isopropylsu-
lfonyl)-3-methylbutan-2-yl)-3-methyl-2-oxopiperidin-3-yl)acetic
acid;
2-((3R,5R,6S)-5-(3-Chlorophenyl)-6-(4-chlorophenyl)-1-((S)-3,3-dimethyl-1-
-(methylsulfonyl)butan-2-yl)-3-methyl-2-oxopiperidin-3-yl)acetic
acid;
2-((3R,5R,6S)-5-(3-Chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-(ethylsulfon-
yl)-3,3-dimethylbutan-2-yl)-3-methyl-2-oxopiperidin-3-yl)acetic
acid;
2-((3R,5R,6S)-5-(3-Chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-(isopropylsu-
lfonyl)-3,3-dimethylbutan-2-yl)-3-methyl-2-oxopiperidin-3-yl)acetic
acid;
2-((3R,5R,6S)-5-(3-Chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-cyclopropyl--
2-(pentan-3-ylsulfonyl)ethyl)-3-methyl-2-oxopiperidin-3-yl)acetic
acid;
2-((3R,5R,6S)-5-(3-Chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-((S)-isoprop-
ylsulfinyl)butan-2-yl)-3-methyl-2-oxopiperidin-3-yl)acetic acid;
2-((3R,5R,6S)-5-(3-Chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-((R)-isoprop-
ylsulfinyl)butan-2-yl)-3-methyl-2-oxopiperidin-3-yl)acetic acid;
more polar isomer;
2-((3R,5R,6S)-5-(3-Chlorophenyl)-6-(4-chlorophenyl)-3-methyl-1-((2S,3S)-2-
-(methylsulfonyl)pentan-3-yl)-2-oxopiperidin-3-yl)acetic acid;
2-((3R,5R,6S)-5-(3-Chlorophenyl)-6-(4-chlorophenyl)-3-methyl-1-((2R,3S)-2-
-(methylsulfonyl)pentan-3-yl)-2-oxopiperidin-3-yl)acetic acid;
2-((3R,5R,6S)-5-(3-Chlorophenyl)-6-(4-chlorophenyl)-1-((2S,3S)-2-(ethylsu-
lfonyl)pentan-3-yl)-3-methyl-2-oxopiperidin-3-yl)acetic acid;
2-((3R,5R,6S)-5-(3-Chlorophenyl)-6-(4-chlorophenyl)-1-((2R,3S)-2-(ethylsu-
lfonyl)pentan-3-yl)-3-methyl-2-oxopiperidin-3-yl)acetic acid;
2-((3R,5R,6S)-5-(3-Chlorophenyl)-6-(4-chlorophenyl)-3-methyl-1-((S)-1-(N--
(oxetan-3-yl)sulfamoyl)butan-2-yl)-2-oxopiperidin-3-yl)acetic acid;
2-((3R,5R,6S)-5-(3-Chlorophenyl)-6-(4-chlorophenyl)-3-methyl-1-((S)-1-(N--
((3-methyloxetan-3-yl)methyl)sulfamoyl)butan-2-yl)-2-oxopiperidin-3-yl)ace-
tic acid;
2-((3R,5R,6S)-5-(3-Chlorophenyl)-6-(4-chlorophenyl)-3-methyl-1-(-
(S)-1-(N-(oxetan-3-ylmethyl)sulfamoyl)butan-2-yl)-2-oxopiperidin-3-yl)acet-
ic acid;
2-((3R,5R,6S)-1-((S)-2-(N-(tert-Butyl)sulfamoyl)-1-cyclopropyleth-
yl)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-2-oxopiperidin-3-yl)ace-
tic acid;
2-((3R,5R,6S)-5-(3-Chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-cyc-
lopropyl-2-(N-methylsulfamoyl)ethyl)-3-methyl-2-oxopiperidin-3-yl)acetic
acid;
2-((3R,5R,6S)-5-(3-Chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-cyclop-
ropyl-2-(N,N-dimethylsulfamoyl)ethyl)-3-methyl-2-oxopiperidin-3-yl)acetic
acid;
2-((3R,5R,6S)-5-(3-Chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-cyclop-
ropyl-2-(N-isopropylsulfamoyl)ethyl)-3-methyl-2-oxopiperidin-3-yl)acetic
acid;
2-((3R,5R,6S)-5-(3-Chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-cyclop-
ropyl-2-(morpholinosulfonyl)ethyl)-3-methyl-2-oxopiperidin-3-yl)acetic
acid;
2-((3R,5R,6S)-5-(3-Chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-cyclop-
ropyl-2-(piperidin-1-ylsulfonyl)ethyl)-3-methyl-2-oxopiperidin-3-yl)acetic
acid;
2-((3R,5R,6S)-5-(3-Chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-cyclop-
ropyl-2-(pyrrolidin-1-ylsulfonyl)ethyl)-3-methyl-2-oxopiperidin-3-yl)aceti-
c acid;
2-((3R,5R,6S)-1-((S)-2-(Azetidin-1-ylsulfonyl)-1-cyclopropylethyl)-
-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-2-oxopiperidin-3-yl)acetic
acid;
2-((3R,5R,6S)-5-(3-Chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-cyclop-
ropyl-2-((N,N-dimethylsulfamoyl)amino)ethyl)-3-methyl-2-oxopiperidin-3-yl)-
acetic acid;
2-((3R,5R,6S)-5-(3-Chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-cyclopropyl--
2-((N,N-dimethylsulfamoyl)(methyl)amino)ethyl)-3-methyl-2-oxopiperidin-3-y-
l)acetic acid;
2-((3R,5R,6S)-5-(3-Chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-cyclopropyl--
2-(3-methyl-2,5-dioxoimidazolidin-1-yl)ethyl)-3-methyl-2-oxopiperidin-3-yl-
)acetic acid;
2-((3R,5R,6S)-5-(3-Chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-cyclopropyl--
2-(3,4,4-trimethyl-2,5-dioxoimidazolidin-1-yl)ethyl)-3-methyl-2-oxopiperid-
in-3-yl)acetic acid;
2-((3R,5R,6S)-5-(3-Chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-cyclopropyl--
2-(4,4-dimethyl-2,5-dioxoimidazolidin-1-yl)ethyl)-3-methyl-2-oxopiperidin--
3-yl)acetic acid;
2-((3R,5R,6S)-5-(3-Chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-cyclopropyl--
2-(3-isopropyl-2,2-dioxido-4-oxo-3,4-dihydro-1H-benzo[c][1,2,6]thiadiazin--
1-yl)ethyl)-3-methyl-2-oxopiperidin-3-yl)acetic acid;
2-((3R,5R,6S)-5-(3-Chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-cyclopropyl--
2-(2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)ethyl)-3-methyl-2-oxopiperid-
in-3-yl)acetic acid;
2-((3R,5R,6S)-5-(3-Chloro-4-fluorophenyl)-6-(4-chlorophenyl)-1-isopropyl--
3-methyl-2-oxopiperidin-3-yl)acetic acid;
2-((3R,5R,6S)-5-(3-Chloro-5-fluorophenyl)-6-(4-chlorophenyl)-1-isopropyl--
3-methyl-2-oxopiperidin-3-yl)acetic acid;
2-((3S,5R,6S)-5-(3-Chloro-5-fluorophenyl)-6-(4-chlorophenyl)-1-isopropyl--
3-methyl-2-oxopiperidin-3-yl)acetic acid;
2-((3R,5R,6S)-5-(3-Chloro-5-fluorophenyl)-6-(4-chlorophenyl)-1-((S)-1-(et-
hylsulfonamido)butan-2-yl)-3-methyl-2-oxopiperidin-3-yl)acetic
acid;
2-((3R,5R,6S)-5-(3-Chloro-5-fluorophenyl)-6-(4-chlorophhenyl)-3-methyl-1--
((S)-1-(N-methylethylsulfonamido)butan-2-yl)-2-oxopiperidin-3-yl)acetic
acid;
2-((3R,5R,6S)-5-(3-Chloro-5-fluorophenyl)-6-(4-chlorophenyl)-3-meth-
yl-1-((S)-1-(methylsulfonyl)butan-2-yl)-2-oxopiperidin-3-yl)acetic
acid;
2-((3R,5R,6S)-5-(3-Chloro-5-fluorophenyl)-6-(4-chlorophenyl)-1-((S)-1-(et-
hylsulfonyl)butan-2-yl)-3-methyl-2-oxopiperidin-3-yl)acetic acid;
2-((3R,5R,6S)-5-(3-Chloro-5-fluorophenyl)-6-(4-chlorophenyl)-1-((S)-1-(cy-
clopropylsulfonyl)butan-2-yl)-3-methyl-2-oxopiperidin-3-yl)acetic
acid;
2-((3R,5R,6S)-1-((S)-1-(tert-Butylsulfonyl)butan-2-yl)-5-(3-chloro-5-fluo-
rophenyl)-6-(4-chlorophenyl)-3-methyl-2-oxopiperidin-3-yl)acetic
acid;
2-((3R,5R,6S)-5-(3-Chloro-5-fluorophenyl)-6-(4-chlorophenyl)-1-((S)-1-(is-
opropylsulfonyl)butan-2-yl)-3-methyl-2-oxopiperidin-3-yl)acetic
acid;
2-((3R,5R,6S)-6-(4-Chlorophenyl)-5-(5-chloropyridin-3-yl)-1-((S)-1-(cyclo-
propylsulfonyl)butan-2-yl)-3-methyl-2-oxopiperidin-3-yl)acetic
acid;
2-((3R,5R,6S)-1-((S)-1-(tert-Butylsulfonyl)butan-2-yl)-6-(4-chlorophenyl)-
-5-(5-chloropyridin-3-yl)-3-methyl-2-oxopiperidin-3-yl)acetic acid;
2-((3R,5R,6S)-6-(4-Chlorophenyl)-5-(5-chloropyridin-3-yl)-1-((S)-1-(cyclo-
propanesulfonamido)butan-2-yl)-3-methyl-2-oxopiperidin-3-yl)acetic
acid;
2-((3R,5R,6S)-6-(4-Chlorophenyl)-5-(5-chloropyridin-3-yl)-3-methyl-1-((S)-
-1-(N-methylcyclopropanesulfonamido)butan-2-yl)-2-oxopiperidin-3-yl)acetic
acid;
2-((3R,5R,6S)-5-(3-Chlorophenyl)-6-(5-chloropyridin-2-yl)-1-((S)-1--
(ethylsulfonyl)butan-2-yl)-3-methyl-2-oxopiperidin-3-yl)acetic
acid;
2-((3R,5R,6S)-5-(3-Chlorophenyl)-6-(4-chlorophenyl)-3-methyl-1-((S)-1-((S-
)-morpholin-2-yl)propyl)-2-oxopiperidin-3-yl)acetic acid;
2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-1-((S)-1-((R-
)-morpholin-2-yl)propyl)-2-oxopiperidin-3-yl)acetic acid;
2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-1-((R)-1-((S-
)-morpholin-2-yl)propyl)-2-oxopiperidin-3-yl)acetic acid;
2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-1-((R)-1-((R-
)-morpholin-2-yl)propyl)-2-oxopiperidin-3-yl)acetic acid;
2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-1-((R)-1-((R-
)-morpholin-2-yl)propyl)-2-oxopiperidin-3-yl)acetic acid; or
2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-1-((R)-1-((S-
)-morpholin-2-yl)propyl)-2-oxopiperidin-3-yl)acetic acid;
2-((3S,5R,6S)-5-(3-Chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-(N-methylcyc-
lopropanesulfonamido)butan-2-yl)-3-(2-morpholinoethyl)-2-oxopiperidin-3-yl-
)acetic acid;
2-((3S,5R,6S)-5-(3-Chlorophenyl)-6-(4-chlorophenyl)-3-(2-(1,1-dioxidothio-
morpholino)ethyl)-1-((S)-1-(N-methylcyclopropanesulfonamido)butan-2-yl)-2--
oxopiperidin-3-yl)acetic acid;
2-((3S,5R,6S)-5-(3-Chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-(N-methylcyc-
lopropanesulfonamido)butan-2-yl)-2-oxo-3-(2-(pyrrolidin-1-yl)ethyl)piperid-
in-3-yl)acetic acid;
2-((3S,5R,6S)-5-(3-Chlorophenyl)-6-(4-chlorophenyl)-3-(2-(dimethylamino)e-
thyl)-1-((S)-1-(N-methylcyclopropanesulfonamido)butan-2-yl)-2-oxopiperidin-
-3-yl)acetic acid;
2-((3S,5R,6S)-5-(3-Chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-(N-methylcyc-
lopropanesulfonamido)butan-2-yl)-3-(2-morpholinoethyl)-2-oxopiperidin-3-yl-
)acetamide;
2-((3S,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-(N-methylcyc-
lopropanesulfonamido)butan-2-yl)-3-(2-morpholinoethyl)-2-oxopiperidin-3-yl-
)acetamide;
3S,6S,7R)-7-(3-Chlorophenyl)-6-(4-chlorophenyl)-5-((S)-1-(N-methylcyclopr-
opanesulfonamido)butan-2-yl)-4-oxo-5-azaspiro[2.5]octane-1-carboxylic
acid;
6S,7R)-7-(3-Chlorophenyl)-6-(4-chlorophenyl)-5-((S)-1-(N-methylcycl-
opropanesulfonamido)butan-2-yl)-4-oxo-5-azaspiro[2.5]octane-1-carboxylic
acid;
2-((3R,5R,6S)-5-(3-Chlorophenyl)-6-(4-chlorophenyl)-1-((2S,3S)-1,2--
dihydroxypentan-3-yl)-3-methyl-2-oxopiperidin-3-yl)acetic acid;
2-((3R,5R,6S)-5-(3-Chlorophenyl)-6-(4-chlorophenyl)-1-((2R,3S)-1,2-dihydr-
oxypentan-3-yl)-3-methyl-2-oxopiperidin-3-yl)acetic acid;
2-((3R,5R,6S)-5-(3-Chlorophenyl)-6-(4-chlorophenyl)-1-((2R,3S)-1,2-dihydr-
oxypentan-3-yl)-3-methyl-2-oxopiperidin-3-yl)acetic acid;
2-((3R,5R,6S)-5-(3-Chlorophenyl)-6-(4-chlorophenyl)-1-((2S,3S)-1,2-dihydr-
oxypentan-3-yl)-3-methyl-2-oxopiperidin-3-yl)acetic acid;
2-((3R,5R,6S)-5-(3-Chlorophenyl)-6-(4-chlorophenyl)-1-((1S,2S)-1-cyclopro-
pyl-1-hydroxybutan-2-yl)-3-methyl-2-oxopiperidin-3-yl)acetic acid;
2-((3R,5R,6S)-5-(3-Chlorophenyl)-6-(4-chlorophenyl)-1-((1R,2S)-1-cyclopro-
pyl-1-hydroxybutan-2-yl)-3-methyl-2-oxopiperidin-3-yl)acetic acid;
2-((3S,5R,6S)-5-(3-Chlorophenyl)-6-(4-chlorophenyl)-1-isopropyl-6-methyl--
2-oxopiperidin-3-yl)acetic acid;
2-((3R,5R,6S)-5-(3-Chlorophenyl)-6-(4-chlorophenyl)-1-isopropyl-6-methyl--
2-oxopiperidin-3-yl)acetic acid;
(3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-(1,1-dioxidoiso-
thiazolidin-2-yl)butan-2-yl)-3-((6-methoxypyridin-2-yl)methyl)piperidin-2--
one;
(3R,5R,6S)-5-(3-Chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-(1,1-dioxid-
oisothiazolidin-2-yl)butan-2-yl)-3-((6-methoxypyridin-2-yl)methyl)piperidi-
n-2-one;
(3R,5R,6S)-5-(3-Chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-(1,1-di-
oxidoisothiazolidin-2-yl)butan-2-yl)-3-((6-hydroxypyridin-2-yl)methyl)pipe-
ridin-2-one;
(3R,5R,6S)-5-(3-Chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-(1,1-dioxidoiso-
thiazolidin-2-yl)butan-2-yl)-3-((6-hydroxypyridin-2-yl)methyl)piperidin-2--
one;
(3R,5R,6S)-5-(3-Chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-(1,1-dioxid-
oisothiazolidin-2-yl)butan-2-yl)-3-((6-methoxypyridin-2-yl)methyl)-3-methy-
lpiperidin-2-one;
(3R,5R,6S)-5-(3-Chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-(1,1-dioxidoiso-
thiazolidin-2-yl)butan-2-yl)-3-((6-methoxypyridin-2-yl)methyl)-3-methylpip-
eridin-2-one;
(3R,5R,6S)-5-(3-Chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-(1,1-dioxidoiso-
thiazolidin-2-yl)butan-2-yl)-3-((6-hydroxypyridin-2-yl)methyl)-3-methylpip-
eridin-2-one;
(3R,5R,6S)-5-(3-Chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-(1,1-dioxidoiso-
thiazolidin-2-yl)butan-2-yl)-3-((6-hydroxypyridin-2-yl)methyl)-3-methylpip-
eridin-2-one;
(3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-cyclopropyl-2-(-
ethylsulfonyl)ethyl)-3-(3-hydroxy-2-oxopropyl)-3-methylpiperidin-2-one;
2-((3R,5R,6S)-5-(3-Chlorophenyl)-6-(4-chlorophenyl)-1-(diethylamino)-3-me-
thyl-2-oxopiperidin-3-yl)acetic acid;
2-((3R,5R,6S)-5-(3-Chlorophenyl)-6-(4-chlorophenyl)-1-(dimethylamino)-3-m-
ethyl-2-oxopiperidin-3-yl)acetic acid; or
3S,5S,6R,7aR,10aS)-6-(3-chlorophenyl)-5-(4-chlorophenyl)-3-ethyl-2,7a-dim-
ethylhexahydrofuro[2,3-b]oxazolo[3,2-a]pyridin-9(5H)-one.
26. A compound, or a pharmaceutically acceptable salt thereof,
selected from:
2-(5-(3-Chlorophenyl)-6-(4-chlorophenyl)-1-(1-cyclopropyl-2-(thioph-
ene-2-sulfonamido)ethyl)-3-methyl-2-oxopiperidin-3-yl)acetic acid;
2-(5-(3-Chlorophenyl)-6-(4-chlorophenyl)-1-(1-cyclopropyl-2-(N-methylthio-
phene-2-sulfonamido)ethyl)-3-methyl-2-oxopiperidin-3-yl)acetic
acid;
2-(5-(3-Chlorophenyl)-6-(4-chlorophenyl)-1-(2-(5-chlorothiophene-2-sulfon-
amido)-1-cyclopropylethyl)-3-methyl-2-oxopiperidin-3-yl)acetic
acid;
2-(1-(2-(5-Chloro-N-methylthiophene-2-sulfonamido)-1-cyclopropylethyl)-5--
(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-2-oxopiperidin-3-yl)acetic
acid;
2-(5-(3-Chlorophenyl)-6-(4-chlorophenyl)-1-(1-cyclopropyl-2-(N-(dif-
luoromethyl)-2-methylpropan-2-ylsulfonamido)ethyl)-3-methyl-2-oxopiperidin-
-3-yl)acetic acid;
2-(5-(3-Chlorophenyl)-6-(4-chlorophenyl)-1-(1-cyclopropyl-2-(N-(difluorom-
ethyl)ethylsulfonamido)ethyl)-3-methyl-2-oxopiperidin-3-yl)acetic
acid;
2-(5-(3-Chlorophenyl)-6-(4-chlorophenyl)-1-(1-cyclopropyl-2-(N-(difluorom-
ethyl)cyclopropanesulfonamido)ethyl)-3-methyl-2-oxopiperidin-3-yl)acetic
acid;
1-(5-(3-Chlorophenyl)-6-(4-chlorophenyl)-1-(2-(cyclopropanesulfonam-
ido)-1-cyclopropylethyl)-3-methyl-2-oxopiperidin-3-yl)cyclopropanecarboxyl-
ic acid;
2-(5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-(1-cyclopropyl-2-(N-(2-
-fluorophenyl)ethylsulfonamido)ethyl)-3-methyl-2-oxopiperidin-3-yl)acetic
acid;
2-(5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-(1-cyclopropyl-2-(N-(2-f-
luorophenyl)methylsulfonamido)ethyl)-3-methyl-2-oxopiperidin-3-yl)acetic
acid;
2-(5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-(1-cyclopropyl-2-(N-phen-
ylcyclopropanesulfonamido)ethyl)-3-methyl-2-oxopiperidin-3-yl)acetic
acid;
2-(5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-(1-cyclopropyl-2-(N-phenylethy-
lsulfonamido)ethyl)-3-methyl-2-oxopiperidin-3-yl)acetic acid;
2-(5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-(1-cyclopropyl-2-(ethylsulfona-
mido)ethyl)-3-methyl-2-oxopiperidin-3-yl)acetic acid;
2-(5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-(1-cyclopropyl-2-(N-(3-fluorop-
henyl)ethylsulfonamido)ethyl)-3-methyl-2-oxopiperidin-3-yl)acetic
acid;
2-(5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-(2-(N-(2-cyanophenyl)methylsul-
fonamido)-1-cyclopropylethyl)-3-methyl-2-oxopiperidin-3-yl)acetic
acid;
2-(5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-(1-cyclopropyl-2-(propylsulfon-
amido)ethyl)-3-methyl-2-oxopiperidin-3-yl)acetic acid;
2-(5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-(1-cyclopropyl-2-(N-phenylmeth-
ylsulfonamido)ethyl)-3-methyl-2-oxopiperidin-3-yl)acetic acid;
2-(5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-(2-(N-(3-cyanophenyl)methylsul-
fonamido)-1-cyclopropylethyl)-3-methyl-2-oxopiperidin-3-yl)acetic
acid;
2-(5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-(1-cyclopropyl-2-(N-(pyridin-3-
-yl)methylsulfonamido)ethyl)-3-methyl-2-oxopiperidin-3-yl)acetic
acid;
2-(5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-(1-cyclopropyl-2-(N-(thiophen--
2-ylmethyl)methylsulfonamido)ethyl)-3-methyl-2-oxopiperidin-3-yl)acetic
acid;
2-(5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-(1-cyclopropyl-2-(N-(3-m-
ethoxybenzyl)methylsulfonamido)ethyl)-3-methyl-2-oxopiperidin-3-yl)acetic
acid;
2-(5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-(1-cyclopropyl-2-(phenyl-
methylsulfonamido)ethyl)-3-methyl-2-oxopiperidin-3-yl)acetic acid;
2-(5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-(1-cyclopropyl-2-(pyridin-2-yl-
methylsulfonamido)ethyl)-3-methyl-2-oxopiperidin-3-yl)acetic acid;
2-(5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-(1-cyclopropyl-2-(pyridin-3-yl-
methylsulfonamido)ethyl)-3-methyl-2-oxopiperidin-3-yl)acetic acid;
2-(5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-(1-cyclopropyl-2-(N-(pyridin-2-
-yl)methylsulfonamido)ethyl)-3-methyl-2-oxopiperidin-3-yl)acetic
acid;
2-(5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-(1-cyclopropyl-2-(methylsulfon-
amido)ethyl)-3-methyl-2-oxopiperidin-3-yl)acetic acid;
2-(5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-(1-cyclopropyl-2-(N-ethylmethy-
lsulfonamido)ethyl)-3-methyl-2-oxopiperidin-3-yl)acetic acid;
2-(5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-(1-cyclopropyl-2-(N-isopropylm-
ethylsulfonamido)ethyl)-3-methyl-2-oxopiperidin-3-yl)acetic acid;
2-(5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-(1-cyclopropyl-2-(1-methylethy-
lsulfonamido)ethyl)-3-ethyl-2-oxopiperidin-3-yl)acetic acid;
2-(5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-(2-(cyclobutanesulfonamido)-1--
cyclopropylethyl)-3-ethyl-2-oxopiperidin-3-yl)acetic acid;
2-(5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-(2-(cyclopentanesulfonamido)-1-
-cyclopropylethyl)-3-ethyl-2-oxopiperidin-3-yl)acetic acid;
2-(5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-1-(3-methyl-1-(N-methyl-
cyclopropanesulfonamido)butan-2-yl)-2-oxopiperidin-3-yl)acetic
acid;
2-(5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-(1-(cyclopropanesulfonamido)-3-
-methylbutan-2-yl)-3-methyl-2-oxopiperidin-3-yl)acetic acid;
2-(5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-(1-(ethylsulfonamido)-3-methyl-
butan-2-yl)-3-methyl-2-oxopiperidin-3-yl)acetic acid;
2-(5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-(1-(cyclobutanesulfonamido)but-
an-2-yl)-3-methyl-2-oxopiperidin-3-yl)acetic acid;
2-(5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-(1-(N-ethylcyclobutanesulfonam-
ido)butan-2-yl)-3-methyl-2-oxopiperidin-3-yl)acetic acid;
2-(5-(3-Chlorophenyl)-6-(4-chlorophenyl)-3-methyl-2-oxo-1-(1-(phenylsulfo-
nyl)butan-2-yl)piperidin-3-yl)acetic acid;
2-(5-(3-Chlorophenyl)-6-(4-chlorophenyl)-3-methyl-1-(1-(methylsulfonyl)bu-
tan-2-yl)-2-oxopiperidin-3-yl)acetic acid;
2-(5-(3-Chlorophenyl)-6-(4-chlorophenyl)-3-methyl-2-oxo-1-(1-(propylsulfo-
nyl)butan-2-yl)piperidin-3-yl)acetic acid;
2-(5-(3-Chlorophenyl)-6-(4-chlorophenyl)-1-(1-(isobutylsulfonyl)butan-2-y-
l)-3-methyl-2-oxopiperidin-3-yl)acetic acid;
2-(5-(3-Chlorophenyl)-6-(4-chlorophenyl)-1-(1-((cyclopropylmethyl)sulfony-
l)butan-2-yl)-3-methyl-2-oxopiperidin-3-yl)acetic acid;
2-(5-(3-Chlorophenyl)-6-(4-chlorophenyl)-1-(1-((cyclobutylmethyl)sulfonyl-
)butan-2-yl)-3-methyl-2-oxopiperidin-3-yl)acetic acid;
2-(5-(3-Chlorophenyl)-6-(4-chlorophenyl)-1-(1-(cyclopentylsulfonyl)butan--
2-yl)-3-methyl-2-oxopiperidin-3-yl)acetic acid;
2-(5-(3-Chlorophenyl)-6-(4-chlorophenyl)-3-methyl-1-(1-(oxetan-3-ylsulfon-
yl)butan-2-yl)-2-oxopiperidin-3-yl)acetic acid;
2-(5-(3-Chlorophenyl)-6-(4-chlorophenyl)-3-methyl-(1-(((3-methyloxetan-3--
yl)methyl)sulfonyl)butan-2-yl)-2-oxopiperidin-3-yl)acetic acid;
2-(5-(3-Chlorophenyl)-6-(4-chlorophenyl)-3-methyl-2-oxo-1-(1-((tetrahydro-
-2H-pyran-4-yl)sulfonyl)butan-2-yl)piperidin-3-yl)acetic acid;
2-(5-(3-Chlorophenyl)-6-(4-chlorophenyl)-1-(1-((2-hydroxy-2-methylpropyl)-
sulfonyl)butan-2-yl)-3-methyl-2-oxopiperidin-3-yl)acetic acid;
2-(1-(1-(-sec-butylsulfonyl)butan-2-yl)-5-(3-chlorophenyl)-6-(4-chlorophe-
nyl)-3-methyl-2-oxopiperidin-3-yl)acetic acid
2-(5-(3-Chlorophenyl)-6-(4-chlorophenyl)-1-(2-(cyclopentylsulfonyl)-1-cyc-
lopropylethyl)-3-methyl-2-oxopiperidin-3-yl)acetic acid;
2-(5-(3-Chlorophenyl)-6-(4-chlorophenyl)-1-(1-cyclopropyl-2-(((3-methylox-
etan-3-yl)methyl)sulfonyl)ethyl)-3-methyl-2-oxopiperidin-3-yl)acetic
acid;
2-(5-(3-Chlorophenyl)-6-(4-chlorophenyl)-1-(1-cyclopropyl-2-(phenylsulfon-
yl)ethyl)-3-methyl-2-oxopiperidin-3-yl)acetic acid;
2-(5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-(1-cyclopropyl-2-(o-tolylsulfo-
nyl)ethyl)-3-methyl-2-oxopiperidin-3-yl)acetic acid;
2-(5-(3-Chlorophenyl)-6-(4-chlorophenyl)-1-(2-((2-chlorophenyl)sulfonyl)--
1-cyclopropylethyl)-3-methyl-2-oxopiperidin-3-yl)acetic acid;
2-(5-(3-Chlorophenyl)-6-(4-chlorophenyl)-1-(2-((4-chlorophenyl)sulfonyl)--
1-cyclopropylethyl)-3-methyl-2-oxopiperidin-3-yl)acetic acid;
2-(5-(3-Chlorophenyl)-6-(4-chlorophenyl)-1-(1-cyclopropyl-2-((4-fluorophe-
nyl)sulfonyl)ethyl)-3-methyl-2-oxopiperidin-3-yl)acetic acid;
2-(5-(3-Chlorophenyl)-6-(4-chlorophenyl)-1-(1-cyclopropyl-2-(pyridin-4-yl-
sulfonyl)ethyl)-3-methyl-2-oxopiperidin-3-yl)acetic acid;
2-(1-(2-((2-Chloro-4-fluorophenyl)sulfonyl)-1-cyclopropylethyl)-5-(3-chlo-
rophenyl)-6-(4-chlorophenyl)-3-methyl-2-oxopiperidin-3-yl)acetic
acid;
2-(5-(3-Chlorophenyl)-6-(4-chlorophenyl)-1-(1-cyclopropyl-2-((cyclopropyl-
methyl)sulfonyl)ethyl)-3-methyl-2-oxopiperidin-3-yl)acetic acid;
2-(5-(3-Chlorophenyl)-6-(4-chlorophenyl)-1-(1-cyclopropyl-2-((2,2,2-trifl-
uoroethyl)sulfonyl)ethyl)-3-methyl-2-oxopiperidin-3-yl)acetic acid;
2-(5-(3-Chlorophenyl)-6-(4-chlorophenyl)-1-(1-cyclopropyl-2-((trifluorome-
thyl)sulfonyl)ethyl)-3-methyl-2-oxopiperidin-3-yl)acetic acid;
2-(5-(3-Chlorophenyl)-6-(4-chlorophenyl)-1-(1-cyclopropyl-2-(phenylsulfon-
yl)ethyl)-3-ethyl-2-oxopiperidin-3-yl)acetic acid;
2-(5-(3-Chlorophenyl)-6-(4-chlorophenyl)-1-(2-((2-chlorophenyl)sulfonyl)--
1-cyclopropylethyl)-3-ethyl-2-oxopiperidin-3-yl)acetic acid;
2-(5-(3-Chlorophenyl)-6-(4-chlorophenyl)-1-(1-cyclopropyl-2-((2-fluorophe-
nyl)sulfonyl)ethyl)-3-ethyl-2-oxopiperidin-3-yl)acetic acid;
2-(5-(3-Chlorophenyl)-6-(4-chlorophenyl)-1-(1-cyclopropyl-2-((3-fluorophe-
nyl)sulfonyl)ethyl)-3-ethyl-2-oxopiperidin-3-yl)acetic acid;
2-(5-(3-Chlorophenyl)-6-(4-chlorophenyl)-1-(1-cyclopropyl-2-((4-fluorophe-
nyl)sulfonyl)ethyl)-3-ethyl-2-oxopiperidin-3-yl)acetic acid;
2-(5-(3-Chlorophenyl)-6-(4-chlorophenyl)-1-(1-cyclopropyl-2-(propylsulfon-
yl)ethyl)-3-ethyl-2-oxopiperidin-3-yl)acetic acid;
2-(1-(2-(Butylsulfonyl)-1-cyclopropylethyl)-5-(3-chlorophenyl)-6-(4-chlor-
ophenyl)-3-ethyl-2-oxopiperidin-3-yl)acetic acid;
2-(5-(3-Chlorophenyl)-6-(4-chlorophenyl)-1-(1-cyclopropyl-2-(isopentylsul-
fonyl)ethyl)-3-ethyl-2-oxopiperidin-3-yl)acetic acid;
2-(5-(3-Chlorophenyl)-6-(4-chlorophenyl)-1-(2-(cyclopentylsulfonyl)-1-cyc-
lopropylethyl)-3-ethyl-2-oxopiperidin-3-yl)acetic acid;
2-(5-(3-Chlorophenyl)-6-(4-chlorophenyl)-1-(2-(cyclohexylsulfonyl)-1-cycl-
opropylethyl)-3-ethyl-2-oxopiperidin-3-yl)acetic acid;
2-(5-(3-Chlorophenyl)-6-(4-chlorophenyl)-1-(1-cyclopropyl-2-(methylsulfon-
yl)ethyl)-3-ethyl-2-oxopiperidin-3-yl)acetic acid;
2-(5-(3-Chlorophenyl)-6-(4-chlorophenyl)-3-methyl-(3-methyl-1-((2,2,2-tri-
fluoroethyl)sulfonyl)butan-2-yl)-2-oxopiperidin-3-yl)acetic acid;
2-(1-(1-(tert-Butylsulfonyl)-3-methylbutan-2-yl)-5-(3-chlorophenyl)-6-(4--
chlorophenyl)-3-methyl-2-oxopiperidin-3-yl)acetic acid;
2-(5-(3-Chlorophenyl)-6-(4-chlorophenyl)-3-methyl-1-(3-methyl-1-(methylsu-
lfonyl)butan-2-yl)-2-oxopiperidin-3-yl)acetic acid;
2-(5-(3-Chlorophenyl)-6-(4-chlorophenyl)-1-(1-(ethylsulfonyl)butan-2-yl)--
3-methyl-2-oxopiperidin-3-yl)acetic acid;
2-(5-(3-Chlorophenyl)-6-(4-chlorophenyl)-1-(1-(cyclopropylsulfonyl)butan--
2-yl)-3-methyl-2-oxopiperidin-3-yl)acetic acid;
2-(5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-(1-(isopropylsulfonyl)butan-2--
yl)-3-methyl-2-oxopiperidin-3-yl)acetic acid;
2-(1-(1-(tert-butylsulfonyl)butan-2-yl)-5-(3-chlorophenyl)-6-(4-chlorophe-
nyl)-3-methyl-2-oxopiperidin-3-yl)acetic acid;
2-(5-(3-Chlorophenyl)-6-(4-chlorophenyl)-1-(1-(cyclobutylsulfonyl)butan-2-
-yl)-3-methyl-2-oxopiperidin-3-yl)acetic acid;
2-(5-(3-Chlorophenyl)-6-(4-chlorophenyl)-3-ethyl-1-(1-(ethylsulfonyl)buta-
n-2-yl)-2-oxopiperidin-3-yl)acetic acid;
2-(5-(3-Chlorophenyl)-6-(4-chlorophenyl)-3-ethyl-1-(1-(isopropylsulfonyl)-
butan-2-yl)-2-oxopiperidin-3-yl)acetic acid;
2-(1-(1-(tert-butylsulfonyl)butan-2-yl)-5-(3-chlorophenyl)-6-(4-chlorophe-
nyl)-3-ethyl-2-oxopiperidin-3-yl)acetic acid;
2-(5-(3-Chlorophenyl)-6-(4-chlorophenyl)-1-(1-(cyclobutylsulfonyl)butan-2-
-yl)-3-ethyl-2-oxopiperidin-3-yl)acetic acid;
2-(5-(3-Chlorophenyl)-6-(4-chlorophenyl)-1-(1-(cyclopropylsulfonyl)butan--
2-yl)-3-ethyl-2-oxopiperidin-3-yl)acetic acid;
2-(5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-(1-cyclopropyl-2-(ethylsulfony-
l)ethyl)-3-methyl-2-oxopiperidin-3-yl)acetic acid;
2-(5-(3-Chlorophenyl)-6-(4-chlorophenyl)-1-(1-cyclopropyl-2-(isopropylsul-
fonyl)ethyl)-3-methyl-2-oxopiperidin-3-yl)acetic acid;
2-(1-(2-(tert-Butylsulfonyl)-1-cyclopropylethyl)-5-(3-chlorophenyl)-6-(4--
chlorophenyl)-3-methyl-2-oxopiperidin-3-yl)acetic acid;
2-(5-(3-Chlorophenyl)-6-(4-chlorophenyl)-1-(2-(cyclobutylsulfonyl)-1-cycl-
opropylethyl)-3-methyl-2-oxopiperidin-3-yl)acetic acid;
2-(5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-(1-cyclopropyl-2-(cyclopropyls-
ulfonyl)ethyl)-3-methyl-2-oxopiperidin-3-yl)acetic acid;
2-(5-(3-Chlorophenyl)-6-(4-chlorophenyl)-1-(1-cyclopropyl-2-(methylsulfon-
yl)ethyl)-3-methyl-2-oxopiperidin-3-yl)acetic acid;
2-(5-(3-Chlorophenyl)-6-(4-chlorophenyl)-1-(1-cyclopropyl-2-(tert-pentyls-
ulfonyl)ethyl)-3-methyl-2-oxopiperidin-3-yl)acetic acid;
2-(5-(3-Chlorophenyl)-6-(4-chlorophenyl)-1-(1-cyclopropyl-2-((2,4-difluor-
ophenyl)sulfonyl)ethyl)-3-methyl-2-oxopiperidin-3-yl)acetic acid;
2-(5-(3-Chlorophenyl)-6-(4-chlorophenyl)-1-(1-cyclopropyl-2-(ethylsulfony-
l)ethyl)-3-ethyl-2-oxopiperidin-3-yl)acetic acid;
2-(5-(3-Chlorophenyl)-6-(4-chlorophenyl)-1-(1-cyclopropyl-2-(isopropylsul-
fonyl)ethyl)-3-ethyl-2-oxopiperidin-3-yl)acetic acid;
2-(1-((2-(tert-Butylsulfonyl)-1-cyclopropylethyl)-5-(3-chlorophenyl)-6-(4-
-chlorophenyl)-3-ethyl-2-oxopiperidin-3-yl)acetic acid;
2-(5-(3-Chlorophenyl)-6-(4-chlorophenyl)-1-(1-cyclopropyl-2-(cyclopropyls-
ulfonyl)ethyl)-3-ethyl-2-oxopiperidin-3-yl)acetic acid;
2-(5-(3-Chlorophenyl)-6-(4-chlorophenyl)-1-(1-(ethylsulfonyl)-3-methylbut-
an-2-yl)-3-methyl-2-oxopiperidin-3-yl)acetic acid;
2-(5-(3-Chlorophenyl)-6-(4-chlorophenyl)-1-(1-(isopropylsulfonyl)-3-methy-
lbutan-2-yl)-3-methyl-2-oxopiperidin-3-yl)acetic acid;
2-(5-(3-Chlorophenyl)-6-(4-chlorophenyl)-1-(3,3-dimethyl-1-(methylsulfony-
l)butan-2-yl)-3-methyl-2-oxopiperidin-3-yl)acetic acid;
2-(5-(3-Chlorophenyl)-6-(4-chlorophenyl)-1-(1-(ethylsulfonyl)-3,3-dimethy-
lbutan-2-yl)-3-methyl-2-oxopiperidin-3-yl)acetic acid;
2-(5-(3-Chlorophenyl)-6-(4-chlorophenyl)-1-(1-(isopropylsulfonyl)-3,3-dim-
ethylbutan-2-yl)-3-methyl-2-oxopiperidin-3-yl)acetic acid;
2-(5-(3-Chlorophenyl)-6-(4-chlorophenyl)-1-(1-cyclopropyl-2-(pentan-3-yls-
ulfonyl)ethyl)-3-methyl-2-oxopiperidin-3-yl)acetic acid;
2-(5-(3-Chlorophenyl)-6-(4-chlorophenyl)-1-(1-(isopropylsulfinyl)butan-2--
yl)-3-methyl-2-oxopiperidin-3-yl)acetic acid;
2-(5-(3-Chlorophenyl)-6-(4-chlorophenyl)-3-methyl-1-(2-(methylsulfonyl)pe-
ntan-3-yl)-2-oxopiperidin-3-yl)acetic acid;
2-(5-(3-Chlorophenyl)-6-(4-chlorophenyl)-1-(2-(ethylsulfonyl)pentan-3-yl)-
-3-methyl-2-oxopiperidin-3-yl)acetic acid;
2-(5-(3-Chlorophenyl)-6-(4-chlorophenyl)-3-methyl-1-(1-(N-(oxetan-3-yl)su-
lfamoyl)butan-2-yl)-2-oxopiperidin-3-yl)acetic acid;
2-(5-(3-Chlorophenyl)-6-(4-chlorophenyl)-3-methyl-1-(1-(N-((3-methyloxeta-
n-3-yl)methyl)sulfamoyl)butan-2-yl)-2-oxopiperidin-3-yl)acetic
acid;
2-(5-(3-Chlorophenyl)-6-(4-chlorophenyl)-3-methyl-1-(1-(N-(oxetan-3-ylmet-
hyl)sulfamoyl)butan-2-yl)-2-oxopiperidin-3-yl)acetic acid;
2-(1-(2-(N-(tert-Butyl)sulfamoyl)-1-cyclopropylethyl)-5-(3-chlorophenyl)--
6-(4-chlorophenyl)-3-methyl-2-oxopiperidin-3-yl)acetic acid;
2-(5-(3-Chlorophenyl)-6-(4-chlorophenyl)-1-(1-cyclopropyl-2-(N-methylsulf-
amoyl)ethyl)-3-methyl-2-oxopiperidin-3-yl)acetic acid;
2-(5-(3-Chlorophenyl)-6-(4-chlorophenyl)-1-(1-cyclopropyl-2-(N,N-dimethyl-
sulfamoyl)ethyl)-3-methyl-2-oxopiperidin-3-yl)acetic acid;
2-(5-(3-Chlorophenyl)-6-(4-chlorophenyl)-1-(1-cyclopropyl-2-(N-isopropyls-
ulfamoyl)ethyl)-3-methyl-2-oxopiperidin-3-yl)acetic acid;
2-(5-(3-Chlorophenyl)-6-(4-chlorophenyl)-1-(1-cyclopropyl-2-(morpholinosu-
lfonyl)ethyl)-3-methyl-2-oxopiperidin-3-yl)acetic acid;
2-(5-(3-Chlorophenyl)-6-(4-chlorophenyl)-1-(1-cyclopropyl-2-(piperidin-1--
ylsulfonyl)ethyl)-3-methyl-2-oxopiperidin-3-yl)acetic acid;
2-(5-(3-Chlorophenyl)-6-(4-chlorophenyl)-1-(1-cyclopropyl-2-(pyrrolidin-1-
-ylsulfonyl)ethyl)-3-methyl-2-oxopiperidin-3-yl)acetic acid;
2-(1-(2-(Azetidin-1-ylsulfonyl)-1-cyclopropylethyl)-5-(3-chlorophenyl)-6--
(4-chlorophenyl)-3-methyl-2-oxopiperidin-3-yl)acetic acid;
2-(5-(3-Chlorophenyl)-6-(4-chlorophenyl)-1-(1-cyclopropyl-2-((N,N-dimethy-
lsulfamoyl)amino)ethyl)-3-methyl-2-oxopiperidin-3-yl)acetic acid;
2-(5-(3-Chlorophenyl)-6-(4-chlorophenyl)-1-(1-cyclopropyl-2-((N,N-dimethy-
lsulfamoyl)(methyl)amino)ethyl)-3-methyl-2-oxopiperidin-3-yl)acetic
acid;
2-(5-(3-Chlorophenyl)-6-(4-chlorophenyl)-1-(1-cyclopropyl-2-(3-methyl-2,5-
-dioxoimidazolidin-1-yl)ethyl)-3-methyl-2-oxopiperidin-3-yl)acetic
acid;
2-(5-(3-Chlorophenyl)-6-(4-chlorophenyl)-1-(1-cyclopropyl-2-(3,4,4-trimet-
hyl-2,5-dioxoimidazolidin-1-yl)ethyl)-3-methyl-2-oxopiperidin-3-yl)acetic
acid;
2-(5-(3-Chlorophenyl)-6-(4-chlorophenyl)-1-(1-cyclopropyl-2-(4,4-di-
methyl-2,5-dioxoimidazolidin-1-yl)ethyl)-3-methyl-2-oxopiperidin-3-yl)acet-
ic acid;
2-(5-(3-Chlorophenyl)-6-(4-chlorophenyl)-1-(1-cyclopropyl-2-(3-is-
opropyl-2,2-dioxido-4-oxo-3,4-dihydro-1H-benzo[c][1,2,6]thiadiazin-1-yl)et-
hyl)-3-methyl-2-oxopiperidin-3-yl)acetic acid;
2-(5-(3-Chlorophenyl)-6-(4-chlorophenyl)-1-(1-cyclopropyl-2-(2-oxo-2,3-di-
hydro-1H-benzo[d]imidazol-1-yl)ethyl)-3-methyl-2-oxopiperidin-3-yl)acetic
acid;
2-(5-(3-Chloro-4-fluorophenyl)-6-(4-chlorophenyl)-1-isopropyl-3-met-
hyl-2-oxopiperidin-3-yl)acetic acid;
2-(5-(3-Chloro-5-fluorophenyl)-6-(4-chlorophenyl)-1-isopropyl-3-methyl-2--
oxopiperidin-3-yl)acetic acid;
2-(5-(3-Chloro-5-fluorophenyl)-6-(4-chlorophenyl)-1-(1-(ethylsulfonamido)-
butan-2-yl)-3-methyl-2-oxopiperidin-3-yl)acetic acid;
2-(5-(3-Chloro-5-fluorophenyl)-6-(4-chlorophenyl)-3-methyl-1-(1-(N-methyl-
ethylsulfonamido)butan-2-yl)-2-oxopiperidin-3-yl)acetic acid;
2-(5-(3-Chloro-5-fluorophenyl)-6-(4-chlorophenyl)-3-methyl-(1-(methylsulf-
onyl)butan-2-yl)-2-oxopiperidin-3-yl)acetic acid;
2-(5-(3-Chloro-5-fluorophenyl)-6-(4-chlorophenyl)-1-(1-(ethylsulfonyl)but-
an-2-yl)-3-methyl-2-oxopiperidin-3-yl)acetic acid;
2-(5-(3-Chloro-5-fluorophenyl)-6-(4-chlorophenyl)-1-(1-(cyclopropylsulfon-
yl)butan-2-yl)-3-methyl-2-oxopiperidin-3-yl)acetic acid;
2-(1-(1-(tert-Butylsulfonyl)butan-2-yl)-5-(3-chloro-5-fluorophenyl)-6-(4--
chlorophenyl)-3-methyl-2-oxopiperidin-3-yl)acetic acid;
2-(5-(3-Chloro-5-fluorophenyl)-6-(4-chlorophenyl)-1-(1-(isopropylsulfonyl-
)butan-2-yl)-3-methyl-2-oxopiperidin-3-yl)acetic acid;
2-(6-(4-Chlorophenyl)-5-(5-chloropyridin-3-yl)-1-(1-(cyclopropylsulfonyl)-
butan-2-yl)-3-methyl-2-oxopiperidin-3-yl)acetic acid;
2-(1-(1-(tert-Butylsulfonyl)butan-2-yl)-6-(4-chlorophenyl)-5-(5-chloropyr-
idin-3-yl)-3-methyl-2-oxopiperidin-3-yl)acetic acid;
2-(6-(4-Chlorophenyl)-5-(5-chloropyridin-3-yl)-1-(1-(cyclopropanesulfonam-
ido)butan-2-yl)-3-methyl-2-oxopiperidin-3-yl)acetic acid;
2-(6-(4-Chlorophenyl)-5-(5-chloropyridin-3-yl)-3-methyl-1-(1-(N-methylcyc-
lopropanesulfonamido)butan-2-yl)-2-oxopiperidin-3-yl)acetic acid;
2-(5-(3-Chlorophenyl)-6-(5-chloropyridin-2-yl)-1-(1-(ethylsulfonyl)butan--
2-yl)-3-methyl-2-oxopiperidin-3-yl)acetic acid;
2-(5-(3-Chlorophenyl)-6-(4-chlorophenyl)-3-methyl-1-(1-(morpholin-2-yl)pr-
opyl)-2-oxopiperidin-3-yl)acetic acid;
2-(5-(3-Chlorophenyl)-6-(4-chlorophenyl)-1-(1-(N-methylcyclopropanesulfon-
amido)butan-2-yl)-3-(2-morpholinoethyl)-2-oxopiperidin-3-yl)acetic
acid;
2-(5-(3-Chlorophenyl)-6-(4-chlorophenyl)-3-(2-(1,1-dioxidothiomorpholino)-
ethyl)-1-(1-(N-methylcyclopropanesulfonamido)butan-2-yl)-2-oxopiperidin-3--
yl)acetic acid;
2-(5-(3-Chlorophenyl)-6-(4-chlorophenyl)-1-(1-(N-methylcyclopropanesulfon-
amido)butan-2-yl)-2-oxo-3-(2-(pyrrolidin-1-yl)ethyl)piperidin-3-yl)acetic
acid;
2-(5-(3-Chlorophenyl)-6-(4-chlorophenyl)-3-(2-(dimethylamino)ethyl)-
-1-(1-(N-methylcyclopropanesulfonamido)butan-2-yl)-2-oxopiperidin-3-yl)ace-
tic acid;
2-(5-(3-Chlorophenyl)-6-(4-chlorophenyl)-1-(1-(N-methylcycloprop-
anesulfonamido)butan-2-yl)-3-(2-morpholinoethyl)-2-oxopiperidin-3-yl)aceta-
mide;
7-(3-Chlorophenyl)-6-(4-chlorophenyl)-5-(1-(N-methylcyclopropanesulf-
onamido)butan-2-yl)-4-oxo-5-azaspiro[2.5]octane-1-carboxylic acid;
2-(5-(3-Chlorophenyl)-6-(4-chlorophenyl)-1-(1,2-dihydroxypentan-3-yl)-3-m-
ethyl-2-oxopiperidin-3-yl)acetic acid;
2-(5-(3-Chlorophenyl)-6-(4-chlorophenyl)-1-(1-cyclopropyl-1-hydroxybutan--
2-yl)-3-methyl-2-oxopiperidin-3-yl)acetic acid;
2-(5-(3-Chlorophenyl)-6-(4-chlorophenyl)-1-isopropyl-6-methyl-2-oxopiperi-
din-3-yl)acetic acid;
5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-(1-(1,1-dioxidoisothiazolidin-2-y-
l)butan-2-yl)-3-((6-methoxypyridin-2-yl)methyl)piperidin-2-one;
5-(3-Chlorophenyl)-6-(4-chlorophenyl)-1-(1-(1,1-dioxidoisothiazolidin-2-y-
l)butan-2-yl)-3-((6-hydroxypyridin-2-yl)methyl)piperidin-2-one;
5-(3-Chlorophenyl)-6-(4-chlorophenyl)-1-(1-(1,1-dioxidoisothiazolidin-2-y-
l)butan-2-yl)-3-((6-methoxypyridin-2-yl)methyl)-3-methylpiperidin-2-one;
5-(3-Chlorophenyl)-6-(4-chlorophenyl)-1-(1-(1,1-dioxidoisothiazolidin-2-y-
l)butan-2-yl)-3-((6-hydroxypyridin-2-yl)methyl)-3-methylpiperidin-2-one;
(5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-(1-cyclopropyl-2-(ethylsulfonyl)-
ethyl)-3-(3-hydroxy-2-oxopropyl)-3-methylpiperidin-2-one;
2-(5-(3-Chlorophenyl)-6-(4-chlorophenyl)-1-(diethylamino)-3-methyl-2-oxop-
iperidin-3-yl)acetic acid;
2-(5-(3-Chlorophenyl)-6-(4-chlorophenyl)-1-(dimethylamino)-3-methyl-2-oxo-
piperidin-3-yl)acetic acid; or
6-(3-chlorophenyl)-5-(4-chlorophenyl)-3-ethyl-2,7a-dimethylhexahydrofuro[-
2,3-b]oxazolo[3,2-a]pyridin-9(5H)-one.
27. A compound, or a pharmaceutically acceptable salt thereof,
selected from:
2-((3R,5R,6S)-5-(3-Chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-cyclop-
ropyl-2-(methylsulfonyl)ethyl)-3-methyl-2-oxopiperidin-3-yl)acetic
acid;
2-((3R,5R,6S)-5-(3-Chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-(isopropylsu-
lfonyl)-3-methylbutan-2-yl)-3-methyl-2-oxopiperidin-3-yl)acetic
acid;
2-((3R,5R,6S)-1-((S)-1-(tert-butylsulfonyl)butan-2-yl)-5-(3-chlorophenyl)-
-6-(4-chlorophenyl)-3-methyl-2-oxopiperidin-3-yl)acetic acid;
2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-(isopropylsu-
lfonyl)butan-2-yl)-3-methyl-2-oxopiperidin-3-yl)acetic acid;
2-((3R,5R,6S)-5-(3-Chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-(isopropylsu-
lfonyl)-3,3-dimethylbutan-2-yl)-3-methyl-2-oxopiperidin-3-yl)acetic
acid;
2-((3R,5R,6S)-5-(3-Chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-(ethylsulfon-
yl)-3-methylbutan-2-yl)-3-methyl-2-oxopiperidin-3-yl)acetic acid;
2-((3R,5R,6S)-5-(3-Chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-(ethylsulfon-
yl)butan-2-yl)-3-methyl-2-oxopiperidin-3-yl)acetic acid;
2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-cyclopropyl--
2-(N-phenylcyclopropanesulfonamido)ethyl)-3-methyl-2-oxopiperidin-3-yl)ace-
tic acid; or
2-((3R,5R,6S)-5-(3-Chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-((cyclopropy-
lmethyl)sulfonyl)butan-2-yl)-3-methyl-2-oxopiperidin-3-yl)acetic
acid.
28. A compound, or a pharmaceutically acceptable salt thereof,
selected from:
2-(-5-(3-Chlorophenyl)-6-(4-chlorophenyl)-1-(-1-cyclopropyl-2-(meth-
ylsulfonyl)ethyl)-3-methyl-2-oxopiperidin-3-yl)acetic acid;
2-(-5-(3-Chlorophenyl)-6-(4-chlorophenyl)-1-(-1-(isopropylsulfonyl)-3-met-
hylbutan-2-yl)-3-methyl-2-oxopiperidin-3-yl)acetic acid;
2-(-1-(-1-(tert-butylsulfonyl)butan-2-yl)-5-(3-chlorophenyl)-6-(4-chlorop-
henyl)-3-methyl-2-oxopiperidin-3-yl)acetic acid;
2-(-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-(-1-(isopropylsulfonyl)butan--
2-yl)-3-methyl-2-oxopiperidin-3-yl)acetic acid;
2-(-5-(3-Chlorophenyl)-6-(4-chlorophenyl)-1-(-1-(isopropylsulfonyl)-3,3-d-
imethylbutan-2-yl)-3-methyl-2-oxopiperidin-3-yl)acetic acid;
2-(-5-(3-Chlorophenyl)-6-(4-chlorophenyl)-1-(-1-(ethylsulfonyl)-3-methylb-
utan-2-yl)-3-methyl-2-oxopiperidin-3-yl)acetic acid;
2-(-5-(3-Chlorophenyl)-6-(4-chlorophenyl)-1-(-1-(ethylsulfonyl)butan-2-yl-
)-3-methyl-2-oxopiperidin-3-yl)acetic acid;
2-(-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-(-1-cyclopropyl-2-(N-phenylcy-
clopropanesulfonamido)ethyl)-3-methyl-2-oxopiperidin-3-yl)acetic
acid;
2-(-5-(3-Chlorophenyl)-6-(4-chlorophenyl)-1-(-1-((cyclopropylmethyl)sulfo-
nyl)butan-2-yl)-3-methyl-2-oxopiperidin-3-yl)acetic acid;
2-(-5-(3-Chlorophenyl)-6-(4-chlorophenyl)-1-(-1-cyclopropyl-2-(methylsulf-
onyl)ethyl)-3-methyl-2-oxopiperidin-3-yl)acetic acid;
2-(-5-(3-Chlorophenyl)-6-(4-chlorophenyl)-1-(-1-(isopropylsulfonyl)-3-met-
hylbutan-2-yl)-3-methyl-2-oxopiperidin-3-yl)acetic acid; or
2-(-1-(-1-(tert-butylsulfonyl)butan-2-yl)-5-(3-chlorophenyl)-6-(4-chlorop-
henyl)-3-methyl-2-oxopiperidin-3-yl)acetic acid.
29. A pharmaceutical composition comprising a compound of claim 1,
or a pharmaceutically acceptable salt thereof, together with a
pharmaceutically acceptable exipient, diluent or carrier.
30. A method of treating cancer in a subject in need of said
treatment, the method comprising administering to the subject an
effective dosage amount of a compound of claim 1, or a
pharmaceutically acceptable salt thereof.
Description
CROSS-REFERENCE TO RELATED APPLICATIONS
[0001] This application claims priority of U.S. provisional patent
application No. 61/351,827, filed 4 Jun. 2010, U.S. provisional
application No. 61/352,322, filed 7 Jun. 2010, 61/452,578, filed 14
Mar. 2011 and U.S. non-provisional application Ser. No. 13/153,345,
filed Jun. 3, 2011, the contents of which, now allowed, are
incorporated by reference herein in their entirety.
FIELD OF THE INVENTION
[0002] The present invention relates to compounds that are MDM2
inhibitors that are useful as therapeutic agents, particularly for
the treatment of cancers. The invention also relates to
pharmaceutical compositions that contain an MDM2 inhibitor.
BACKGROUND OF THE INVENTION
[0003] p53 is a tumor suppressor and transcription factor that
responds to cellular stress by activating the transcription of
numerous genes involved in cell cycle arrest, apoptosis,
senescence, and DNA repair. Unlike normal cells, which have
infrequent cause for p53 activation, tumor cells are under constant
cellular stress from various insults including hypoxia and
pro-apoptotic oncogene activation. Thus, there is a strong
selective advantage for inactivation of the p53 pathway in tumors,
and it has been proposed that eliminating p53 function may be a
prerequisite for tumor survival. In support of this notion, three
groups of investigators have used mouse models to demonstrate that
absence of p53 function is a continuous requirement for the
maintenance of established tumors. When the investigators restored
p53 function to tumors with inactivated p53, the tumors
regressed.
[0004] p53 is inactivated by mutation and/or loss in 50% of solid
tumors and 10% of liquid tumors. Other key members of the p53
pathway are also genetically or epigenetically altered in cancer.
MDM2, an oncoprotein, inhibits p53 function, and it is activated by
gene amplification at incidence rates that are reported to be as
high as 10%. MDM2, in turn, is inhibited by another tumor
suppressor, p14ARF. It has been suggested that alterations
downstream of p53 may be responsible for at least partially
inactivating the p53 pathway in p53.sup.WT tumors (p53 wildtype).
In support of this concept, some p53.sup.WT tumors appear to
exhibit reduced apoptotic capacity, although their capacity to
undergo cell cycle arrest remains intact. One cancer treatment
strategy involves the use of small molecules that bind MDM2 and
neutralize its interaction with p53. MDM2 inhibits p53 activity by
three mechanisms: 1) acting as an E3 ubiquitin ligase to promote
p53 degradation; 2) binding to and blocking the p53 transcriptional
activation domain; and 3) exporting p53 from the nucleus to the
cytoplasm. All three of these mechanisms would be blocked by
neutralizing the MDM2-p53 interaction. In particular, this
therapeutic strategy could be applied to tumors that are
p53.sup.WT, and studies with small molecule MDM2 inhibitors have
yielded promising reductions in tumor growth both in vitro and in
vivo. Further, in patients with p53-inactivated tumors,
stabilization of wildtype p53 in normal tissues by MDM2 inhibition
might allow selective protection of normal tissues from mitotic
poisons.
[0005] The present invention relates to compounds capable of
inhibiting the interaction between p53 and MDM2 and activating p53
downstream effector genes. As such, compounds of the present
invention would be useful in the treatment of cancers, bacterial
infections, viral infections, ulcers and inflammation. In
particular, the compounds of the present invention are useful to
treat solid tumors such as: breast, colon, lung and prostate
tumors; and liquid tumors such as lymphomas and leukemias. As used
herein, MDM2 means a human MDM2 protein and p53 means a human p53
protein. It is noted that human MDM2 can also be referred to as
HDM2 or hMDM2.
SUMMARY OF THE INVENTION
[0006] The present invention relates to piperidinone derivatives of
Formula I.
##STR00002##
enantiomers, diastereomers and pharmaceutically acceptable salts
thereof, wherein [0007] Q is a bond or optionally can be selected
from O, NR.sup.7 and S(O).sub.v, when n* is an integer from 1 to 6,
[0008] Z is C.dbd.O or S(.dbd.O).sub.2 [0009] R.sup.a is at each
occurrence independently selected from H, (C.sub.1-C.sub.3)alkyl,
(halo)(C.sub.1-C.sub.3)alkyl, (hydroxy)(C.sub.1-C.sub.3)alkyl,
(alkoxy)(C.sub.1-C.sub.3)alkyl, or cyano; [0010] R.sup.b is H,
halo, (C.sub.1-C.sub.3)alkyl, (halo)(C.sub.1-C.sub.3)alkyl,
(hydroxy)(C.sub.1-C.sub.3)alkyl, (alkoxy)(C.sub.1-C.sub.3)alkyl, or
cyano; [0011] R.sup.e and R.sup.d are independently H, halo,
(C.sub.1-C.sub.3)alkyl, (C.sub.1-C.sub.3)alkoxy,
(halo)(C.sub.1-C.sub.3)alkyl, (halo)(C.sub.1-C.sub.3)alkoxy,
(alkoxy)(C.sub.1-C.sub.3)alkyl, (hydroxy)(C.sub.1-C.sub.3)alkyl;
[0012] or R.sup.e and R.sup.d may optionally combine to form a
spiro-cycloalkyl or heterocyclo ring system; [0013] R.sup.e is (a)
H, or halo; or [0014] (b) (C.sub.1-C.sub.8)alkyl,
(C.sub.3-C.sub.8)cycloalkyl, (C.sub.3-C.sub.8)heterocyclo, cyano,
halogen, hydroxyl, --OR.sup.5, NR.sup.7R.sup.8, heterocycloalkyl,
any of which may be optionally substituted with 1 or more R.sup.x
groups as allowed by valence. [0015] or R.sup.e and any one of the
R' or R'' groups may optionally combine to form a spiro-cycloalkyl
or heterocyclo ring system; [0016] or R.sup.d and any one of the R'
or R'' groups may optionally combine to form a fused cycloalkyl or
heterocyclo ring system; [0017] or R.sup.d and R.sup.e may
optionally combine to form a fused cycloalkyl or heterocyclo ring
system; [0018] R' and R'' at each occurrence, respectively, are
independently H, halo, (C.sub.1-C.sub.3)alkyl,
(C.sub.1-C.sub.3)alkoxy, (halo)(C.sub.1-C.sub.3)alkyl,
(halo)(C.sub.1-C.sub.3)alkoxy, (alkoxy)(C.sub.1-C.sub.3)alkyl,
(hydroxy)(C.sub.1-C.sub.3)alkyl, --S--(C.sub.1-C.sub.3)alkyl,
C(O)(C.sub.1-C.sub.3)alkyl, --NR.sup.7R.sup.8, or hydroxyl [0019]
or R' and R'' bound to the same carbon atom may optionally combine
to form .dbd.O; [0020] or R' and R'' bound to the same carbon atom
may optionally combine to form a spiro-fused cycloalkyl or
heterocyclo ring system [0021] R.sup.1 is [0022] (a) --COOH,
--C(O)OR.sup.10, --C(O)NHOH, --C(O)NH--NH.sub.2,
--C(O)NHS(O).sub.2R.sup.10, --S(O).sub.2NHC(O)R.sup.10,
--S(O).sub.2NR.sup.7R.sup.8, --NR.sup.7C(O)R.sup.10,
--NR.sup.7C(O)OR.sup.5, --C(O)NR.sup.7R.sup.8,
--NR.sup.7S(O).sub.2R.sup.10, or --NR.sup.7C(O)NR.sup.7R.sup.8,
--S(O).sub.vR.sup.10, or CN; [0023] (b) heteroaryl or heterocyclo
either of which may be optionally independently substituted with
one or more R.sup.x groups as allowed by valence; [0024] R.sup.2 is
[0025] (a) --NR.sup.7R.sup.8, NR.sup.7C(O)OR.sup.10,
NR.sup.7C(O)NR.sup.7R.sup.10, or --C(R.sup.a)R.sup.5R.sup.6; [0026]
(b) aryl, heteroaryl, cycloalkyl, or heterocyclo any of which may
be optionally independently substituted with one or more R.sup.x
groups as allowed by valence; [0027] R.sup.3 and R.sup.4 are
independently aryl or heteroaryl, either of which may be optionally
[0028] independently substituted with one or more R.sup.x groups as
allowed by valence; [0029] or either R.sup.3 and R.sup.a together
with the ring carbon atom to which they are both bonded, [0030] or
R.sup.4 and R.sup.b together with the ring carbon atom to which
they are both bonded may optionally combine to form a spiro-fused
bicyclic ring system selected from
##STR00003##
[0031] wherein K is --O--, --NR.sup.7--, or
--C(.dbd.O)NR.sup.7--,
R.sup.5, and R.sup.6 at each occurrence, respectively, are
independently selected from [0032] (a) H and CN; or [0033] (b)
-(alkylene).sub.t-OH, -(alkylene).sub.t-OR.sup.9,
-(alkylene).sub.t-SR.sup.9, -(alkylene).sub.t-NR.sup.10R.sup.11,
-(alkylene).sub.t-C(O)R.sup.9, -(alkylene).sub.t-C(O)OR.sup.9,
-(alkylene).sub.t-OC(O)R.sup.9,
-(alkylene).sub.t-S(O).sub.vR.sup.9,
-(alkylene).sub.t-NHS(O).sub.2R.sup.10,
-(alkylene).sub.t-N(R.sup.11)S(O).sub.2R.sup.10, -(alkylene).sub.t-
[0034] --NR.sup.10C(O)R.sup.9, C(O)NR.sup.10R.sup.11,
NR.sup.10S(O).sub.2R.sup.9, S(O).sub.2NR.sup.10, and
NR.sup.10C(O)NR.sup.10R.sup.11; or [0035] (a) haloalkyl,
haloalkoxy, C.sub.1-6-alkyl, C.sub.2-6alkenyl, C.sub.2-6-alkynyl,
C.sub.3-8-cycloalkyl, (C.sub.3-8-cycloalkyl)(C.sub.1-3alkyl),
C.sub.4-8-cycloalkenyl, aryl, aryl(C.sub.1-3-alkyl)heteroaryl,
heteroaryl(C.sub.1-3-alkyl), heterocyclo and
heterocyclo(C.sub.1-3-alkyl) many of which may be optionally
independently substituted with one or more R.sup.x groups as
allowed by valence; [0036] R.sup.7, and R.sup.8 at each occurrence,
respectively, are independently selected from H, C.sub.1-6-alkyl,
halo(C.sub.1-6)-alkyl, cycloalkyl, C.sub.2-6-alkenyl,
C.sub.2-6-alkynyl, aryl, heteroaryl, heterocyclo, arylalkyl,
heteroarylalkyl, heterocyclo(C.sub.1-10alkyl), and
(C.sub.3-8-cycloalkyl)(C.sub.1-3alkyl), any of which may be
optionally substituted as allowed by valence with one or more
R.sup.x; or R.sup.7 and R.sup.8 may combine to form a
C.sub.4-C.sub.8-heterocyclo ring optionally substituted with one or
more R.sup.x; [0037] R.sup.9 is [0038] haloalkyl, haloalkoxy,
C.sub.1-6-alkyl, C.sub.2-6alkenyl, C.sub.2-6-alkynyl,
C.sub.3-8-cycloalkyl, (C.sub.3-8-cycloalkyl)(C.sub.1-3alkyl),
C.sub.4-8-cycloalkenyl, aryl, heteroaryl, and heterocyclo any of
which may be optionally independently substituted with one or more
R.sup.x groups as allowed by valence; [0039] R.sup.10 and R.sup.11
at each occurrence, respectively, are independently selected from
alkyl, haloalkyl, cycloalkyl, alkenyl, alkynyl, aryl, heteroaryl,
heterocyclo, arylalkyl, heteroarylalkyl, heterocycloalkyl, and
cycloalkylalkyl, any of which may be optionally substituted as
allowed by valence with one or more R.sup.x; [0040] or R.sup.10 and
R.sup.11 may combine to form a heterocyclo ring optionally
substituted with one or more R.sup.x; [0041] R.sup.x at each
occurrence is independently, deuterium, halo, cyano, nitro, oxo,
alkyl, haloalkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl,
heterocyclo, aryl, heteroaryl, arylalkyl, heteroarylalkyl,
cycloalkylalkyl, heterocycloalkyl, -(alkylene).sub.t-OR*,
-(alkylene).sub.t-S(O).sub.vR*, -(alkylene).sub.t-NR.sup.+R.sup.++,
-(alkylene).sub.t-C(.dbd.O)R*, -(alkylene).sub.t-C(.dbd.S)R*,
-(alkylene).sub.t-C(.dbd.O)OR*, -(alkylene).sub.t-OC(.dbd.O)R*,
-(alkylene).sub.t-C(.dbd.S)OR*,
-(alkylene).sub.t-C(.dbd.O)NR.sup.+R.sup.++,
-(alkylene).sub.t-C(.dbd.S)NR.sup.+R.sup.++,
-(alkylene).sub.t-N(R.sup.+)C(.dbd.O)NR.sup.+R.sup.++,
-(alkylene).sub.t-N(R.sup.+)C(.dbd.S)NR.sup.+R.sup.++,
-(alkylene).sub.t-N(R.sup.+)C(.dbd.O)R*,
-(alkylene).sub.t-N(R.sup.+)C(.dbd.S)R*,
-(alkylene).sub.t-OC(.dbd.O)NR.sup.+R.sup.++,
-(alkylene).sub.t-OC(.dbd.S)NR.sup.+R.sup.++,
-(alkylene).sub.t-SO.sub.2NR.sup.+R.sup.++,
-(alkylene).sub.t-N(R.sup.+)SO.sub.2R*,
-(alkylene).sub.t-N(R.sup.+)SO.sub.2NR.sup.+R.sup.++,
-(alkylene).sub.t-N(R.sup.+)C(.dbd.O)OR*,
-(alkylene).sub.t-N(R.sup.+)C(.dbd.S)OR*, or
-(alkylene).sub.t-N(R.sup.+)SO.sub.2R*; [0042] wherein said alkyl,
haloalkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, heterocyclo,
aryl, heteroaryl, arylalkyl, heteroarylalkyl, cycloalkylalkyl, and
heterocycloalkyl groups may be further independently substituted
with one or more halo, cyano, oxo, -(alkylene).sub.t-OR*,
-(alkylene).sub.t-S(O).sub.vR*, -(alkylene).sub.t-NR.sup.+R.sup.++,
-(alkylene).sub.t-C(.dbd.O)R*, -(alkylene).sub.t-C(.dbd.S)R*,
-(alkylene).sub.t-C(.dbd.O)OR*, -(alkylene).sub.t-OC(.dbd.O)R*,
-(alkylene).sub.t-C(.dbd.S)OR*,
-(alkylene).sub.t-C(.dbd.O)NR.sup.+R.sup.++,
-(alkylene).sub.t-C(.dbd.S)NR.sup.+R.sup.++,
-(alkylene).sub.t-N(R.sup.+)C(.dbd.O)NR.sup.+R.sup.++,
-(alkylene).sub.t-N(R.sup.+)C(.dbd.S)NR.sup.+R.sup.++,
-(alkylene).sub.t-N(R.sup.+)C(.dbd.O)R*,
-(alkylene).sub.t-N(R.sup.+)C(.dbd.S)R*,
-(alkylene).sub.t-OC(.dbd.O)NR.sup.+R.sup.++,
-(alkylene).sub.t-OC(.dbd.S)NR.sup.+R.sup.++,
-(alkylene).sub.t-SO.sub.2NR.sup.+R.sup.++,
-(alkylene).sub.t-N(R.sup.+)SO.sub.2R*,
-(alkylene).sub.t-N(R.sup.+)SO.sub.2NR.sup.+R.sup.++,
-(alkylene).sub.t-N(R.sup.+)C(.dbd.O)OR*,
-(alkylene).sub.t-N(R.sup.+)C(.dbd.S)OR*, or
-(alkylene).sub.t-N(R.sup.+)SO.sub.2R*; [0043] R* is [0044]
haloalkyl, haloalkoxy, C.sub.1-6-alkyl, C.sub.2-6alkenyl,
C.sub.2-6-alkynyl, C.sub.3-8-cycloalkyl, C.sub.4-8-cycloalkenyl,
aryl, heteroaryl, and heterocyclo [0045] R.sup.+ and R.sup.++ are
independently H, alkyl, haloalkyl, cycloalkyl, alkenyl, alkynyl,
aryl, heteroaryl, heterocyclo, arylalkyl, heteroarylalkyl,
heterocycloalkyl, and cycloalkylalkyl, [0046] or R.sup.+ and
R.sup.++ bound to the same nitrogen atom may optionally combine to
form a heterocyclo ring system; [0047] m is 1, 2 or 3 [0048] n and
n* are each independently selected from 0 and integers from 1 to 6;
[0049] p is 0, 1, 2 or 3; [0050] t at each occurrence is
independently 0 or an integer from 1 to 6; [0051] v at each
occurrence is independently 0, 1 or 2;
[0052] Preferred compounds within the scope of Formula I include
compounds wherein R.sup.2 is --C(H)R.sup.5R.sup.6 or
--NR.sup.7R.sup.8, phenyl or pyridine, the phenyl or the pyridyl
may be optionally substituted with one or more R.sup.x as allowed
by valence.
[0053] Preferred compounds within the scope of Formula I include
compounds wherein R.sup.2 is R.sup.2 is selected from
##STR00004## ##STR00005## ##STR00006##
and any of which may be optionally substituted with one or more
R.sup.x groups as allowed by valence.
[0054] Preferred compounds within the scope of Formula I include
compounds wherein R.sup.1 is
##STR00007##
or a heterocycle selected from
##STR00008##
(most preferentially
##STR00009##
or a heterocycle selected from
##STR00010##
[0055] Preferred compounds within the scope of Formula I include
compounds of Formula IA:
##STR00011##
enantiomers, diastereomers and pharmaceutically acceptable salts
thereof wherein q and p are each independently 0, 1, 2 or 3.
Preferred compounds of Formula IA include compounds containing
preferred R.sup.1 and R.sup.2 groups previously mentioned.
[0056] Preferred compounds within the scope of Formula I include
compounds of Formula IB:
##STR00012##
enantiomers, diastereomers and pharmaceutically acceptable salts
thereof wherein q and p are each independently 0, 1, 2 or 3.
Preferred compounds of Formula IB include compounds containing
preferred R.sup.1 and R.sup.2 groups previously mentioned
[0057] Preferred compounds within the scope of formula I include
compounds of Formula IC:
##STR00013##
enantiomers, diastereomers and pharmaceutically acceptable salts
thereof wherein q and p are each independently 0, 1, 2 or 3.
Preferred compounds of Formula IC include compounds containing
preferred R.sup.1 and R.sup.2 groups mentioned herein.
[0058] Preferred compounds within the scope of Formulae IA, IB and
IC further include compounds wherein R.sup.2 is selected from
##STR00014## ##STR00015## ##STR00016##
and any of which may be optionally substituted with one or more
R.sup.x groups as allowed by valence.
[0059] In another aspect, aspect A, the present invention provides
compounds of Formula I:
##STR00017##
or a pharmaceutically acceptable salt thereof, wherein:
[0060] Q is a bond or optionally can be selected from O, NR.sup.7
or S(O).sub.v, when n* is an integer from 1 to 6;
[0061] Z is C.dbd.O or S(.dbd.O).sub.2;
[0062] R.sup.a at each occurrence is independently selected from H,
(C.sub.1-C.sub.3)alkyl, (halo)(C.sub.1-C.sub.3)alkyl,
(hydroxy)(C.sub.1-C.sub.3)alkyl, (alkoxy)(C.sub.1-C.sub.3)alkyl, or
cyano;
[0063] R.sup.b is H, halo, (C.sub.1-C.sub.3)alkyl,
(halo)(C.sub.1-C.sub.3)alkyl, (hydroxy)(C.sub.1-C.sub.3)alkyl,
(alkoxy)(C.sub.1-C.sub.3)alkyl, or cyano;
[0064] R.sup.c and R.sup.d are independently selected from H, halo,
(C.sub.1-C.sub.3)alkyl, (C.sub.1-C.sub.3)alkoxy,
(halo)(C.sub.1-C.sub.3)alkyl, (halo)(C.sub.1-C.sub.3)alkoxy,
(alkoxy)(C.sub.1-C.sub.3)alkyl, or (hydroxy)(C.sub.1-C.sub.3)alkyl,
or R.sup.e and R.sup.d may optionally combine to form a
spiro-cycloalkyl or heterocyclo ring system;
[0065] R.sup.e is [0066] (a) H or halo; or [0067] (b)
(C.sub.1-C.sub.8)alkyl, (C.sub.3-C.sub.8)cycloalkyl,
(C.sub.3-C.sub.8)heterocyclo, cyano, halogen, hydroxyl, --OR.sup.5,
NR.sup.7R.sup.8, or heterocycloalkyl, any of which may be
optionally substituted with 1 or more R.sup.x groups as allowed by
valence, or R.sup.e and any one of the R' or R'' groups may
optionally combine to form a spiro-cycloalkyl or heterocyclo ring
system, or R.sup.d and any one of the R' or R'' groups may
optionally combine to form a fused cycloalkyl or heterocyclo ring
system, or R.sup.d and R.sup.e may optionally combine to form a
fused cycloalkyl or heterocyclo ring system;
[0068] R' and R'' at each occurrence, respectively, are
independently H, halo, (C.sub.1-C.sub.3)alkyl,
(C.sub.1-C.sub.3)alkoxy, (halo)(C.sub.1-C.sub.3)alkyl,
(halo)(C.sub.1-C.sub.3)alkoxy, (alkoxy)(C.sub.1-C.sub.3)alkyl,
(hydroxy)(C.sub.1-C.sub.3)alkyl, --S--(C.sub.1-C.sub.3)alkyl,
C(O)(C.sub.1-C.sub.3)alkyl, --NR.sup.7R.sup.8, or hydroxyl, or R'
and R'' bound to the same carbon atom may optionally combine to
form .dbd.O, or R' and R'' bound to the same carbon atom may
optionally combine to form a spiro-fused cycloalkyl or heterocyclo
ring system;
[0069] R.sup.1 is [0070] (a) --COOH, --C(O)OR.sup.10, --C(O)NHOH,
--C(O)NH--NH.sub.2, --C(O)NHS(O).sub.2R.sup.1,
--S(O).sub.2NHC(O)R.sup.10, --S(O).sub.2NR.sup.7R.sup.8,
--NR.sup.7C(O)R.sup.10, --NR.sup.7C(O)OR.sup.5,
--C(O)NR.sup.7R.sup.8, --NR.sup.7S(O).sub.2R.sup.10,
--NR.sup.7C(O)NR.sup.7R.sup.8, --S(O).sub.vR.sup.10, hydroxylalkyl,
-cyclopropyl-COOH, or CN; or [0071] (b) heteroaryl or heterocyclo,
either of which may be optionally independently substituted with
one or more R.sup.x groups as allowed by valence;
[0072] R.sup.2 is [0073] (a) --NR.sup.7R.sup.8,
NR.sup.7C(O)OR.sup.10, NR.sup.7C(O)NR.sup.7R.sup.10, or
--C(R.sup.a)R.sup.5R.sup.6; or [0074] (b) aryl, heteroaryl,
cycloalkyl, or heterocyclo, any of which may be optionally
independently substituted with one or more R.sup.x groups as
allowed by valence;
[0075] R.sup.3 and R.sup.4 are independently aryl or heteroaryl,
either of which may be optionally independently substituted with
one or more R.sup.x groups as allowed by valence, or either R.sup.3
and R.sup.a together with the ring carbon atom to which they are
both bonded, or R.sup.4 and R.sup.b together with the ring carbon
atom to which they are both bonded may optionally combine to form a
spiro-fused bicyclic ring system selected from
##STR00018##
wherein K is --O--, --NR.sup.7--, or --C(.dbd.O)NR.sup.7--;
[0076] R.sup.5 and R.sup.6 at each occurrence, respectively, are
independently selected from (a) H or CN; [0077] (b)
-(alkylene).sub.t-OH, -(alkylene).sub.t-OR.sup.9,
-(alkylene).sub.t-SR.sup.9, -(alkylene).sub.t-NR.sup.10R.sup.11,
-(alkylene).sub.t-C(O)R.sup.9, -(alkylene).sub.t-C(O)OR.sup.9,
-(alkylene).sub.t-OC(O)R.sup.9,
-(alkylene).sub.t-S(O).sub.vR.sup.9,
-(alkylene).sub.t-NHS(O).sub.2R.sup.10,
-(alkylene).sub.t-N(R.sup.1)S(O).sub.2R.sup.10,
-(alkylene).sub.t-S(O).sub.2NR.sup.10R.sup.11,
--NR.sup.10C(O)R.sup.9, --C(O)NR.sup.10R.sup.11,
--NR.sup.10S(O).sub.2R.sup.9, S(O).sub.2NR.sup.1, or
NR.sup.10C(O)NR.sup.10R.sup.11; or [0078] (c) haloalkyl,
haloalkoxy, C.sub.1-6-alkyl, C.sub.2-6alkenyl, C.sub.2-6-alkynyl,
C.sub.3-8-cycloalkyl, (C.sub.3-8-cycloalkyl)(C.sub.1-3alkyl),
C.sub.4-8-cycloalkenyl, aryl, aryl(C.sub.1-3-alkyl), heteroaryl,
heteroaryl(C.sub.1-3-alkyl), heterocyclo or
heterocyclo(C.sub.1-3-alkyl), any of which may be optionally
independently substituted with one or more R.sup.x groups as
allowed by valence;
[0079] R.sup.7 and R.sup.s at each occurrence, respectively, are
independently selected from H, cyano, --OC.sub.1-6-alkyl,
C.sub.1-6-alkyl, halo(C.sub.1-6)-alkyl, cycloalkyl,
C.sub.2-6-alkenyl, C.sub.2-6-alkynyl, aryl, heteroaryl,
heterocyclo, arylalkyl, heteroarylalkyl,
heterocyclo(C.sub.1-10alkyl), or
(C.sub.3-8-cycloalkyl)(C.sub.1-3alkyl), any of which may be
optionally substituted as allowed by valence with one or more
R.sup.x, or R.sup.7 and R.sup.8 may combine to form a
C.sub.4-C.sub.8-heterocyclo ring optionally substituted with one or
more R.sup.x;
[0080] R.sup.9 is haloalkyl, haloalkoxy, C.sub.1-6-alkyl,
C.sub.2-6alkenyl, C.sub.2-6-alkynyl, C.sub.3-8-cycloalkyl,
(C.sub.3-8-cycloalkyl)(C.sub.1-3alkyl), C.sub.4-8-cycloalkenyl,
aryl, heteroaryl, or heterocyclo, any of which may be optionally
independently substituted with one or more R.sup.x groups as
allowed by valence;
[0081] R.sup.10 and R.sup.11 at each occurrence, respectively, are
independently selected from H, alkyl, haloalkyl, cycloalkyl,
alkenyl, alkynyl, aryl, heteroaryl, heterocyclo, arylalkyl,
heteroarylalkyl, heterocycloalkyl, or cycloalkylalkyl, any of which
may be optionally substituted as allowed by valence with one or
more R.sup.x, or R.sup.10 and R.sup.11 may combine to form a
heterocyclo ring optionally substituted with one or more
R.sup.x;
[0082] R.sup.x at each occurrence is independently, deuterium,
halo, cyano, nitro, oxo, alkyl, haloalkyl, alkenyl, alkynyl,
cycloalkyl, cycloalkenyl, heterocyclo, aryl, heteroaryl, arylalkyl,
heteroarylalkyl, cycloalkylalkyl, heterocycloalkyl,
-(alkylene).sub.t-OR*, -(alkylene).sub.t-S(O).sub.vR*,
-(alkylene).sub.t-NR.sup.+R.sup.++, -(alkylene).sub.t-C(.dbd.O)R*,
-(alkylene).sub.t-C(.dbd.S)R*, -(alkylene).sub.t-C(.dbd.O)OR*,
-(alkylene).sub.t-OC(.dbd.O)R*, -(alkylene).sub.t-C(.dbd.S)OR*,
-(alkylene).sub.t-C(.dbd.O)NR.sup.+R.sup.++,
-(alkylene).sub.t-C(.dbd.S)NR.sup.+R.sup.++,
-(alkylene).sub.t-N(R.sup.+)C(.dbd.O)NR.sup.+R.sup.++,
-(alkylene).sub.t-N(R.sup.+)C(.dbd.S)NR.sup.+R.sup.++,
-(alkylene).sub.t-N(R.sup.+)C(.dbd.O)R*,
-(alkylene).sub.t-N(R.sup.+)C(.dbd.S)R*,
-(alkylene).sub.t-OC(.dbd.O)NR.sup.+R.sup.++,
-(alkylene).sub.t-OC(.dbd.S)NR.sup.+R.sup.++,
-(alkylene).sub.t-SO.sub.2NR.sup.+R.sup.++,
-(alkylene).sub.t-N(R.sup.+)SO.sub.2R*,
-(alkylene).sub.t-N(R)SO.sub.2NR.sup.+R.sup.++,
-(alkylene).sub.t-N(R.sup.+)C(.dbd.O)OR*,
-(alkylene).sub.t-N(R.sup.+)C(.dbd.S)OR*, or
-(alkylene).sub.t-N(R.sup.+)SO.sub.2R*, wherein said alkyl,
haloalkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, heterocyclo,
aryl, heteroaryl, arylalkyl, heteroarylalkyl, cycloalkylalkyl, and
heterocycloalkyl groups may be further independently substituted
with one or more halo, cyano, oxo, -(alkylene).sub.t-OR*,
-(alkylene).sub.t-S(O).sub.vR*, -(alkylene).sub.t-NR.sup.+R.sup.++,
-(alkylene).sub.t-C(.dbd.O)R*, -(alkylene).sub.t-C(.dbd.S)R*,
-(alkylene).sub.t-C(.dbd.O)OR*, -(alkylene).sub.t-OC(.dbd.O)R*,
-(alkylene).sub.t-C(.dbd.S)OR*,
-(alkylene).sub.t-C(.dbd.O)NR.sup.+R.sup.++,
-(alkylene).sub.t-C(.dbd.S)NR.sup.+R.sup.++,
-(alkylene).sub.t-N(R.sup.+)C(.dbd.O)NR.sup.+R.sup.++,
-(alkylene).sub.t-N(R.sup.+)C(.dbd.S)NR.sup.+R.sup.++,
-(alkylene).sub.t-N(R.sup.+)C(.dbd.O)R*,
-(alkylene).sub.t-N(R.sup.+)C(.dbd.S)R*,
-(alkylene).sub.t-OC(.dbd.O)NR.sup.+R.sup.++,
-(alkylene).sub.t-OC(.dbd.S)NR.sup.+R.sup.++,
-(alkylene).sub.t-SO.sub.2NR.sup.+R.sup.++,
-(alkylene).sub.t-N(R.sup.+)SO.sub.2R*,
-(alkylene).sub.t-N(R)SO.sub.2NR.sup.+R.sup.++,
-(alkylene).sub.t-N(R.sup.+)C(.dbd.O)OR*,
-(alkylene).sub.t-N(R.sup.+)C(.dbd.S)OR*, or
-(alkylene).sub.t-N(R.sup.+)SO.sub.2R*;
[0083] R* is H, haloalkyl, haloalkoxy, C.sub.1-6-alkyl,
C.sub.2-6alkenyl, C.sub.2-6-alkynyl, C.sub.3-8-cycloalkyl,
C.sub.4-8-cycloalkenyl, aryl, heteroaryl, or heterocyclo;
[0084] R.sup.+ and R.sup.++ are independently H, alkyl, haloalkyl,
cycloalkyl, alkenyl, alkynyl, aryl, heteroaryl, heterocyclo,
arylalkyl, heteroarylalkyl, heterocycloalkyl, or cycloalkylalkyl,
or R.sup.+ and R.sup.++ bound to the same nitrogen atom may
optionally combine to form a heterocyclo ring system;
[0085] m is 1, 2 or 3;
[0086] n and n* are each independently selected from 0 or an
integer from 1 to 6;
[0087] p is 0, 1, 2 or 3;
[0088] t at each occurrence is independently 0 or an integer from 1
to 6; and
[0089] v at each occurrence is independently 0, 1 or 2.
[0090] In another aspect, aspect AA, the present invention provides
compounds of Formula I:
##STR00019##
or a pharmaceutically acceptable salt thereof, wherein:
[0091] Q is a bond or optionally can be selected from O, NR.sup.7
or S(O).sub.v, when n* is an integer from 1 to 6;
[0092] Z is C.dbd.O or S(.dbd.O).sub.2;
[0093] R.sup.a at each occurrence is independently selected from H,
(C.sub.1-C.sub.3)alkyl, (halo)(C.sub.1-C.sub.3)alkyl,
(hydroxy)(C.sub.1-C.sub.3)alkyl, (alkoxy)(C.sub.1-C.sub.3)alkyl, or
cyano;
[0094] R.sup.b is H, halo, (C.sub.1-C.sub.3)alkyl,
(halo)(C.sub.1-C.sub.3)alkyl, (hydroxy)(C.sub.1-C.sub.3)alkyl,
(alkoxy)(C.sub.1-C.sub.3)alkyl, or cyano;
[0095] R.sup.c and R.sup.d are independently selected from H, halo,
(C.sub.1-C.sub.3)alkyl, (C.sub.1-C.sub.3)alkoxy,
(halo)(C.sub.1-C.sub.3)alkyl, (halo)(C.sub.1-C.sub.3)alkoxy,
(alkoxy)(C.sub.1-C.sub.3)alkyl, or (hydroxy)(C.sub.1-C.sub.3)alkyl,
or R.sup.e and R.sup.d may optionally combine to form a
spiro-cycloalkyl or heterocyclo ring system;
[0096] R.sup.e is [0097] (a) H or halo; or [0098] (b)
(C.sub.1-C.sub.8)alkyl, (C.sub.3-C.sub.8)cycloalkyl,
(C.sub.3-C.sub.8)heterocyclo, cyano, halogen, hydroxyl, --OR.sup.5,
NR.sup.7R.sup.8, or heterocycloalkyl, any of which may be
optionally substituted with 1 or more R.sup.x groups as allowed by
valence, or R.sup.e and any one of the R' or R'' groups may
optionally combine to form a spiro-cycloalkyl or heterocyclo ring
system, or R.sup.d and any one of the R' or R'' groups may
optionally combine to form a fused cycloalkyl or heterocyclo ring
system, or R.sup.d and R.sup.e may optionally combine to form a
fused cycloalkyl or heterocyclo ring system;
[0099] R' and R'' at each occurrence, respectively, are
independently H, halo, (C.sub.1-C.sub.3)alkyl,
(C.sub.1-C.sub.3)alkoxy, (halo)(C.sub.1-C.sub.3)alkyl,
(halo)(C.sub.1-C.sub.3)alkoxy, (alkoxy)(C.sub.1-C.sub.3)alkyl,
(hydroxy)(C.sub.1-C.sub.3)alkyl, --S--(C.sub.1-C.sub.3)alkyl,
C(O)(C.sub.1-C.sub.3)alkyl, --NR.sup.7R.sup.8, or hydroxyl, or R'
and R'' bound to the same carbon atom may optionally combine to
form .dbd.O, or R' and R'' bound to the same carbon atom may
optionally combine to form a spiro-fused cycloalkyl or heterocyclo
ring system;
[0100] R.sup.1 is [0101] (a) --COOH, --C(O)OR.sup.10, --C(O)NHOH,
--C(O)NH--NH.sub.2, --C(O)NHS(O).sub.2R.sup.10,
--S(O).sub.2NHC(O)R.sup.10, --S(O).sub.2NR.sup.7R.sup.8,
--NR.sup.7C(O)R.sup.10, --NR.sup.7C(O)OR.sup.5,
--C(O)NR.sup.7R.sup.8, --NR.sup.7S(O).sub.2R.sup.10,
--NR.sup.7C(O)NR.sup.7R.sup.8, --S(O).sub.vR.sup.10, hydroxylalkyl,
-cyclopropyl-COOH, or CN; or [0102] (b) heteroaryl or heterocyclo,
either of which may be optionally independently substituted with
one or more R.sup.x groups as allowed by valence;
[0103] R.sup.2 is [0104] (a) --NR.sup.7R.sup.8,
NR.sup.7C(O)OR.sup.10, NR.sup.7C(O)NR.sup.7R.sup.10, or
--C(R.sup.a)R.sup.5R.sup.6; or [0105] (b) aryl, heteroaryl,
cycloalkyl, or heterocyclo, any of which may be optionally
independently substituted with one or more R.sup.x groups as
allowed by valence;
[0106] R.sup.3 and R.sup.4 are independently aryl or heteroaryl,
either of which may be optionally independently substituted with
one or more R.sup.x groups as allowed by valence, or either R.sup.3
and R.sup.a together with the ring carbon atom to which they are
both bonded, or R.sup.4 and R.sup.b together with the ring carbon
atom to which they are both bonded may optionally combine to form a
spiro-fused bicyclic ring system selected from
##STR00020##
wherein K is --O--, --NR.sup.7--, or --C(.dbd.O)NR.sup.7--;
[0107] R.sup.5 and R.sup.6 at each occurrence, respectively, are
independently selected from [0108] (a) H or CN; [0109] (b)
-(alkylene).sub.t-OH, -(alkylene).sub.t-OR.sup.9,
-(alkylene).sub.t-SR.sup.9, -(alkylene).sub.t-NR.sup.10R.sup.11,
-(alkylene).sub.t-C(O)R.sup.9, -(alkylene).sub.t-C(O)OR.sup.9,
-(alkylene).sub.t-OC(O)R.sup.9,
-(alkylene).sub.t-S(O).sub.vR.sup.9,
-(alkylene).sub.t-NHS(O).sub.2R.sup.10,
-(alkylene).sub.t-N(R.sup.11)S(O).sub.2R.sup.10,
-(alkylene).sub.t-S(O).sub.2NR.sup.10R.sup.11,
-(alkylene).sub.t-N(R.sup.11)S(O).sub.2NR.sup.10R.sup.11,
--NR.sup.10C(O)R.sup.9, --C(O)NR.sup.10R.sup.11,
--NR.sup.10S(O).sub.2R.sup.9, S(O).sub.2NR.sup.10, or
NR.sup.10C(O)NR.sup.10R.sup.11; or [0110] (c) haloalkyl,
haloalkoxy, C.sub.1-6-alkyl, C.sub.2-6alkenyl, C.sub.2-6-alkynyl,
C.sub.3-8-cycloalkyl, (C.sub.3-8-cycloalkyl)(C.sub.1-3alkyl),
C.sub.4-8-cycloalkenyl, aryl, aryl(C.sub.1-3-alkyl), heteroaryl,
heteroaryl(C.sub.1-3-alkyl), heterocyclo or
heterocyclo(C.sub.1-3-alkyl), any of which may be optionally
independently substituted with one or more R.sup.x groups as
allowed by valence;
[0111] R.sup.7 and R.sup.s at each occurrence, respectively, are
independently selected from H, cyano, --OC.sub.1-6-alkyl,
C.sub.1-6-alkyl, halo(C.sub.1-6)-alkyl, cycloalkyl,
C.sub.2-6-alkenyl, C.sub.2-6-alkynyl, aryl, heteroaryl,
heterocyclo, arylalkyl, heteroarylalkyl,
heterocyclo(C.sub.1-10alkyl), or
(C.sub.3-8-cycloalkyl)(C.sub.1-3alkyl), any of which may be
optionally substituted as allowed by valence with one or more
R.sup.x, or R.sup.7 and R.sup.8 may combine to form a
C.sub.4-C.sub.8-heterocyclo ring optionally substituted with one or
more R.sup.x;
[0112] R.sup.9 is haloalkyl, haloalkoxy, C.sub.1-6-alkyl,
C.sub.2-6alkenyl, C.sub.2-6-alkynyl, C.sub.3-8-cycloalkyl,
(C.sub.3-8-cycloalkyl)(C.sub.1-3alkyl), C.sub.4-8-cycloalkenyl,
aryl, heteroaryl, heterocyclo, or heterocycloalkyl, any of which
may be optionally independently substituted with one or more
R.sup.x groups as allowed by valence;
[0113] R.sup.10 and R.sup.11 at each occurrence, respectively, are
independently selected from H, alkyl, haloalkyl, cycloalkyl,
alkenyl, alkynyl, aryl, heteroaryl, heterocyclo, arylalkyl,
heteroarylalkyl, heterocycloalkyl, or cycloalkylalkyl, any of which
may be optionally substituted as allowed by valence with one or
more R.sup.x, or R.sup.10 and R.sup.11 may combine to form a
heterocyclo ring optionally substituted with one or more
R.sup.x;
[0114] R.sup.x at each occurrence is independently, deuterium,
halo, cyano, nitro, oxo, alkyl, haloalkyl, alkenyl, alkynyl,
cycloalkyl, cycloalkenyl, heterocyclo, aryl, heteroaryl, arylalkyl,
heteroarylalkyl, cycloalkylalkyl, heterocycloalkyl,
-(alkylene).sub.t-OR*, -(alkylene).sub.t-S(O).sub.vR*,
-(alkylene).sub.t-NR.sup.+R.sup.++, -(alkylene).sub.t-C(.dbd.O)R*,
-(alkylene).sub.t-C(.dbd.S)R*, -(alkylene).sub.t-C(.dbd.O)OR*,
-(alkylene).sub.t-OC(.dbd.O)R, -(alkylene).sub.t-C(.dbd.S)OR*,
-(alkylene).sub.t-C(.dbd.O)NR.sup.+R.sup.++,
-(alkylene).sub.t-C(.dbd.S)NR.sup.+R.sup.++,
-(alkylene).sub.t-N(R.sup.+)C(.dbd.O)NR.sup.+R.sup.++,
-(alkylene).sub.t-N(R.sup.+)C(.dbd.S)NR.sup.+R.sup.++,
-(alkylene).sub.t-N(R.sup.+)C(.dbd.O)R*,
-(alkylene).sub.t-N(R.sup.+)C(.dbd.S)R*,
-(alkylene).sub.t-OC(.dbd.O)NR.sup.+R.sup.++,
-(alkylene).sub.t-OC(.dbd.S)NR.sup.+R.sup.++,
-(alkylene).sub.t-SO.sub.2NR.sup.+R.sup.++,
-(alkylene).sub.t-N(R.sup.+)SO.sub.2R*,
-(alkylene).sub.t-N(R.sup.+)SO.sub.2NR.sup.+R.sup.++,
-(alkylene).sub.t-N(R.sup.+)C(.dbd.O)OR*,
-(alkylene).sub.t-N(R.sup.+)C(.dbd.S)OR*, or
-(alkylene).sub.t-N(R.sup.+)SO.sub.2R*, wherein said alkyl,
haloalkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, heterocyclo,
aryl, heteroaryl, arylalkyl, heteroarylalkyl, cycloalkylalkyl, and
heterocycloalkyl groups may be further independently substituted
with one or more halo, cyano, oxo, -(alkylene).sub.t-OR*,
-(alkylene).sub.t-S(O).sub.vR*, -(alkylene).sub.t-NR.sup.+R.sup.++,
-(alkylene).sub.t-C(.dbd.O)R*, -(alkylene).sub.t-C(.dbd.S)R*,
-(alkylene).sub.t-C(.dbd.O)OR*, -(alkylene).sub.t-OC(.dbd.O)R*,
-(alkylene).sub.t-C(.dbd.S)OR*,
-(alkylene).sub.t-C(.dbd.O)NR.sup.+R.sup.++,
-(alkylene).sub.t-C(.dbd.S)NR.sup.+R.sup.++,
-(alkylene).sub.t-N(R.sup.+)C(.dbd.O)NR.sup.+R.sup.++,
-(alkylene).sub.t-N(R.sup.+)C(.dbd.S)NR.sup.+R.sup.++,
-(alkylene).sub.t-N(R.sup.+)C(.dbd.O)R*,
-(alkylene).sub.t-N(R.sup.+)C(.dbd.S)R*,
-(alkylene).sub.t-OC(.dbd.O)NR.sup.+R.sup.++,
-(alkylene).sub.t-OC(.dbd.S)NR.sup.+R.sup.++,
-(alkylene).sub.t-SO.sub.2NR.sup.+R.sup.++,
-(alkylene).sub.t-N(R.sup.+)SO.sub.2R*,
-(alkylene).sub.t-N(R.sup.+)SO.sub.2NR.sup.+R.sup.++,
-(alkylene).sub.t-N(R.sup.+)C(.dbd.O)OR*,
-(alkylene).sub.t-N(R.sup.+)C(.dbd.S)OR*, or
-(alkylene).sub.t-N(R.sup.+)SO.sub.2R*;
[0115] R* is H, haloalkyl, haloalkoxy, C.sub.1-6-alkyl,
C.sub.2-6alkenyl, C.sub.2-6-alkynyl, C.sub.3-8-cycloalkyl,
C.sub.4-8-cycloalkenyl, aryl, heteroaryl, or heterocyclo;
[0116] R.sup.+ and R.sup.++ are independently H, alkyl, haloalkyl,
cycloalkyl, alkenyl, alkynyl, aryl, heteroaryl, heterocyclo,
arylalkyl, heteroarylalkyl, heterocycloalkyl, or cycloalkylalkyl,
or R.sup.+ and R.sup.++ bound to the same nitrogen atom may
optionally combine to form a heterocyclo ring system;
[0117] m is 1, 2 or 3;
[0118] n and n* are each independently selected from 0 or an
integer from 1 to 6;
[0119] p is 0, 1, 2 or 3;
[0120] t at each occurrence is independently 0 or an integer from 1
to 6; and
[0121] v at each occurrence is independently 0, 1 or 2.
[0122] In another embodiment, embodiment 2, of the compounds of
Aspect A or AA, or the pharmaceutically acceptable salts thereof,
R.sup.2 is --C(H)R.sup.5R.sup.6, --NR.sup.7R.sup.8, phenyl or
pyridine, wherein the phenyl or the pyridyl may be optionally
substituted with one or more Rx as allowed by valence.
[0123] In another embodiment, embodiment 3, of the compounds of
Aspect A or AA, or the pharmaceutically acceptable salts thereof,
R.sup.2 is selected from
##STR00021## ##STR00022## ##STR00023##
any of which may be optionally substituted with one or more R.sup.x
groups as allowed by valence.
[0124] In another embodiment, embodiment 4, the compounds of Aspect
A or AA have the structure of Formula IA
##STR00024##
or the pharmaceutically acceptable salts thereof, wherein q and p
are each independently 0, 1, 2 or 3.
[0125] In another embodiment, embodiment 5, the compounds of Aspect
A or AA have the structure of Formula IB
##STR00025##
or the pharmaceutically acceptable salts thereof, wherein q and p
are each independently 0, 1, 2 or 3.
[0126] In another embodiment, embodiment 6, the compounds of Aspect
A or AA have the structure of Formula IC
##STR00026##
or the pharmaceutically acceptable salts thereof, wherein q and p
are each independently 0, 1, 2 or 3.
[0127] In another aspect of embodiment 6 (embodiment 7), or the
pharmaceutically acceptable salts thereof, R.sup.2 is selected
from
##STR00027## ##STR00028## ##STR00029##
any of which may be optionally substituted with one or more R.sup.x
groups as allowed by valence.
[0128] In another aspect of embodiment 6 (embodiment 8) or the
pharmaceutically acceptable salts thereof,
R.sup.2 is selected from
##STR00030## ##STR00031## ##STR00032##
any of which may be optionally substituted with one or more R.sup.x
groups as allowed by valence;
and R.sup.1 is
##STR00033##
[0129] or a heteroaryl or heterocycle selected from
##STR00034##
[0130] In another aspect of embodiment 6 (embodiment 9), or the
pharmaceutically acceptable salts thereof,
R.sup.2 is selected from
##STR00035## ##STR00036##
any of which may be optionally substituted with one or more R.sup.x
groups as allowed by valence; and
R.sup.1 is
##STR00037##
[0131] or a heteroaryl or heterocycle selected from
##STR00038##
[0132] In another aspect of embodiment 6 (embodiment 10), or the
pharmaceutically acceptable salts thereof,
R.sup.2 is selected from
##STR00039## ##STR00040##
any of which may be optionally substituted with one or more R.sup.x
groups as allowed by valence; and
R.sup.1 is
##STR00041##
[0133] or a heteroaryl or heterocycle selected from
##STR00042##
[0134] In another embodiment, embodiment 11, the compounds of
Aspect A have the structure of Formula ID
##STR00043##
or a pharmaceutically acceptable salt thereof.
[0135] In another aspect of embodiment 11 (embodiment 12), or the
pharmaceutically acceptable salts thereof, Re is H or methyl or
ethyl.
[0136] In another embodiment, embodiment 13, the compounds of
Aspect A have the structure of Formula IE
##STR00044##
or the pharmaceutically acceptable salts thereof.
[0137] In another aspect of embodiment 13 (embodiment 14), or the
pharmaceutically acceptable salts thereof, R.sup.e is H or methyl
or ethyl.
[0138] In another aspect of embodiment 13 (embodiment 15), or the
pharmaceutically acceptable salts thereof, wherein
R.sup.2 is selected from
##STR00045## ##STR00046##
any of which may be optionally substituted with one or more R.sup.x
groups as allowed by valence; and
R.sup.1 is
##STR00047##
[0139] or a heteroaryl or heterocycle selected from
##STR00048##
[0140] In another aspect of embodiment 13 (embodiment 16), or a
pharmaceutically acceptable salt thereof,
R.sup.1 is
##STR00049##
[0141] or a heteroaryl or heterocycle selected from
##STR00050##
R.sup.2 is
##STR00051##
[0142] and R.sup.e is methyl.
[0143] In another aspect of embodiment 13 (embodiment 17), or a
pharmaceutically acceptable salt thereof:
R.sup.2 is
##STR00052##
[0144] R.sup.5 is cyclopropyl, or C.sub.1-6alkyl; R.sup.9 is
haloalkyl, haloalkoxy, C.sub.1-6-alkyl, C.sub.2-6alkenyl,
C.sub.2-6-alkynyl, C.sub.3-8-cycloalkyl,
(C.sub.3-8-cycloalkyl)(C.sub.1-3alkyl), C.sub.4-8-cycloalkenyl,
aryl, heteroaryl, or heterocycloalkyl, or R.sup.9 is haloalkyl,
haloalkoxy, C.sub.1-6-alkyl, C.sub.2-6alkenyl, C.sub.2-6-alkynyl,
C.sub.3-8-cycloalkyl, (C.sub.3-8-cycloalkyl)(C.sub.1-3alkyl),
C.sub.4-8-cycloalkenyl, aryl, heteroaryl, or heterocyclo, any of
which may be optionally independently substituted with one or more
R.sup.x groups as allowed by valence; and R.sup.10 and R.sup.11 at
each occurrence, respectively, are independently selected from H,
alkyl, haloalkyl, cycloalkyl, alkenyl, alkynyl, aryl, heteroaryl,
heterocyclo, arylalkyl, heteroarylalkyl, heterocycloalkyl, or
cycloalkylalkyl, any of which may be optionally substituted as
allowed by valence with one or more R.sup.x, or R.sup.10 and
R.sup.11 may combine to form a heterocyclo ring optionally
substituted with one or more R.sup.x.
[0145] In another aspect of embodiment 13 (embodiment 18), or a
pharmaceutically acceptable salt thereof,
R.sup.1 is
##STR00053##
[0146] R.sup.2 is
##STR00054##
[0147] and R.sup.e is methyl.
[0148] In another aspect, the present invention provides a
compound, or a pharmaceutically acceptable salt thereof, selected
from: [0149]
2-((3R,5R,6S)-1-((S)-1-tert-butoxy-1-oxobutan-2-yl)-5-(3-chlorophenyl)-6--
(4-chlorophenyl)-2-oxopiperidin-3-yl)acetic acid; [0150]
2-((3S,5R,6S)-1-((S)-1-tert-butoxy-1-oxobutan-2-yl)-5-(3-chlorophenyl)-6--
(4-chlorophenyl)-2-oxopiperidin-3-yl)acetic acid; [0151]
2-((3R,5R,6S)-5-(3-Chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-ethoxy-1-oxo-
butan-2-yl)-2-oxopiperidin-3-yl)acetic acid; [0152]
2-((3R,5R,6S)-5-(3-Chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-ethoxy-4-met-
hyl-1-oxopentan-2-yl)-2-oxopiperidin-3-yl)acetic acid; [0153]
2-((3R,5R,6S)-5-(3-Chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-ethoxy-1-oxo-
pentan-2-yl)-2-oxopiperidin-3-yl)acetic acid; [0154]
2-((3S,5S,6R)-5-(3-Chlorophenyl)-6-(4-chlorophenyl)-1-((R)-1-ethoxy-1-oxo-
pentan-2-yl)-2-oxopiperidin-3-yl)acetic acid; [0155]
2-((3R,5R,6S)-1-((S)-2-tert-Butoxy-1-cyclopropyl-2-oxoethyl)-5-(3-chlorop-
henyl)-6-(4-chlorophenyl)-2-oxopiperidin-3-yl)acetic acid; [0156]
2-((3R,5R,6S)-5-(3-Chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-hydroxybutan-
-2-yl)-2-oxopiperidin-3-yl)acetic acid; [0157]
2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-cyclopropyl--
2-hydroxyethyl)-2-oxopiperidin-3-yl)acetic acid; [0158]
2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-(cyclopropyl-
methoxy)butan-2-yl)-2-oxopiperidin-3-yl)acetic acid; [0159]
2-((3R,5R,6S)-5-(3-Chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-methoxybutan-
-2-yl)-2-oxopiperidin-3-yl)acetic acid; [0160]
2-((3R,5R,6S)-5-(3-Chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-(2-methoxyet-
hoxy)butan-2-yl)-2-oxopiperidin-3-yl)acetic acid; [0161]
2-((3R,5R,6S)-5-(3-Chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-((1-cyanocyc-
lopropyl)methoxy)butan-2-yl)-2-oxopiperidin-3-yl)acetic acid;
[0162]
2-((3S,5R,6S)-5-(3-Chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-(cyclopropyl-
methoxy)butan-2-yl)-2-oxopiperidin-3-yl)acetic acid; [0163]
2-((3S,5R,6S)-5-(3-Chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-methoxybutan-
-2-yl)-2-oxopiperidin-3-yl)acetic acid; [0164]
2-((3S,5R,6S)-5-(3-Chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-(2-methoxyet-
hoxy)butan-2-yl)-2-oxopiperidin-3-yl)acetic acid; [0165]
2-((3R,5R,6S)-1-((S)-1-((1-carbamoylcyclopropyl)methoxy)butan-2-yl)-5-(3--
chlorophenyl)-6-(4-chlorophenyl)-2-oxopiperidin-3-yl)acetic acid
(isomer 1); [0166]
2-((3S,5R,6S)-1-((S)-1-((1-carbamoylcyclopropyl)methoxy)butan-2-yl)-5-(3--
chlorophenyl)-6-(4-chlorophenyl)-2-oxopiperidin-3-yl)acetic acid
(isomer 2); [0167]
2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-(2-hydroxy-2-
-methylpropoxy)butan-2-yl)-2-oxopiperidin-3-yl)acetic acid; [0168]
2-((3R,5R,6S)-5-(3-Chlorophenyl)-6-(4-chlorophenyl)-2-oxo-1-((3S)-1,1,1-t-
rifluoro-2-hydroxypentan-3-yl)piperidin-3-yl)acetic acid (isomer
1); [0169]
2-((3R,5R,6S)-5-(3-Chlorophenyl)-6-(4-chlorophenyl)-2-oxo-1-((3S)--
1,1,1-trifluoro-2-hydroxypentan-3-yl)piperidin-3-yl)acetic acid
(isomer 2); [0170]
2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-morpholinobu-
tan-2-yl)-2-oxopiperidin-3-yl)acetic acid; [0171]
2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-(ethylamino)-
butan-2-yl)-2-oxopiperidin-3-yl)acetic acid; [0172]
2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-2-oxo-1-((S)-1-(2,2,2-
-trifluoroethylamino)butan-2-yl)piperidin-3-yl)acetic acid; [0173]
2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-2-oxo-1-((S)-1-(pyrro-
lidin-1-yl)butan-2-yl)piperidin-3-yl)acetic acid; [0174]
2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-2-oxo-1-((S)-1-(2-oxo-
pyrrolidin-1-yl)butan-2-yl)piperidin-3-yl)acetic acid; [0175]
2-((3R,5R,6S)-5-(3-Chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-(1,1-dioxido-
thiomorpholino)butan-2-yl)-2-oxopiperidin-3-yl)acetic acid; [0176]
2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-2-oxo-1-((S)-1-(thiaz-
ol-2-ylamino)butan-2-yl)piperidin-3-yl)acetic acid; [0177]
2-((3R,5R,6S)-1-((S)-1-acetamidobutan-2-yl)-5-(3-chlorophenyl)-6-(4-chlor-
ophenyl)-2-oxopiperidin-3-yl)acetic acid; [0178]
2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-(methylsulfo-
namido) butan-2-yl)-2-oxopiperidin-3-yl)acetic acid; [0179]
2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-cyanopentan--
3-yl)-2-oxopiperidin-3-yl)acetic acid; [0180]
2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-(methylsulfo-
nyl)pentan-3-yl)-2-oxopiperidin-3-yl)acetic acid; [0181]
2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-2-oxo-1-((S)-1-(pyrid-
in-2-yl)pentan-3-yl)piperidin-3-yl)acetic acid; [0182]
2-((3R,5R,6S)-5-(3-Chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-(ethylamino)-
-1-oxobutan-2-yl)-2-oxopiperidin-3-yl)acetic acid; [0183]
2-((3R,5R,6S)-5-(3-Chlorophenyl)-6-(4-chlorophenyl)-1-((R)-1-(ethylamino)-
-1-oxobutan-2-yl)-2-oxopiperidin-3-yl)acetic acid; [0184]
2-((3R,5R,6S)-5-(3-Chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-(5-methyl-1,-
3,4-oxadiazol-2-yl)propyl)-2-oxopiperidin-3-yl)acetic; [0185]
2-((3R,5R,6S)-5-(3-Chlorophenyl)-6-(4-chlorophenyl)-1-((R)-1-(5-methyl-1,-
3,4-oxadiazol-2-yl)propyl)-2-oxopiperidin-3-yl)acetic acid; [0186]
2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-(cyclopropylmethyl)-
-2-oxopiperidin-3-yl)acetic acid; [0187]
2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-(cyclobutylmethyl)--
2-oxopiperidin-3-yl)acetic acid; [0188]
2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-(2-ethylbutyl)-2-ox-
opiperidin-3-yl)acetic acid; [0189]
2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-(cyclopentylmethyl)-
-2-oxopiperidin-3-yl)acetic acid; [0190]
2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((2,2-dimethylcyclo-
pentyl)methyl)-2-oxopiperidin-3-yl)acetic acid; [0191]
2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-(cyclohexylmethyl)--
2-oxopiperidin-3-yl)acetic acid; [0192]
2-((3S,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-(cyclopropylmethyl)-
-2-oxopiperidin-3-yl)acetic acid; [0193]
2-((3S,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-2-oxo-1-propylpiperid-
in-3-yl)acetic acid; [0194]
2-((3S,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-(cyclobutylmethyl)--
2-oxopiperidin-3-yl)acetic acid; [0195]
2-((3S,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-isobutyl-2-oxopiper-
idin-3-yl)acetic acid; [0196]
2-((3S,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-(cyclopentylmethyl)-
-2-oxopiperidin-3-yl)acetic acid; [0197]
2-((3S,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-2-oxo-1-(pentan-3-yl)-
piperidin-3-yl)acetic acid; [0198] Methyl
2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-(cyclopropylmethyl)-
-2-oxopiperidin-3-yl)acetate; [0199]
2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-(cyclopropylmethyl)-
-2-oxopiperidin-3-yl)acetamide; [0200] Ethyl
2-(2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-(cyclopropylmeth-
yl)-2-oxopiperidin-3-yl)acetamido)acetate; [0201]
2-(2-((3R,5R,6S)-5-(3-Chlorophenyl)-6-(4-chlorophenyl)-1-(cyclopropylmeth-
yl)-2-oxopiperidin-3-yl)acetamido)acetic acid; [0202]
2-((3R,5R,6S)-5-(3-Chlorophenyl)-6-(4-chlorophenyl)-1-(cyclopropylmethyl)-
-2-oxopiperidin-3-yl)acetohydrazide; [0203]
2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-(cyclopropylmethyl)-
-2-oxopiperidin-3-yl)-N-hydroxyacetamide; [0204] (S)-Ethyl
2-((2S,3R,5R)-3-(3-chlorophenyl)-2-(4-chlorophenyl)-5-(2-(methylsulfonami-
do)-2-oxoethyl)-6-oxopiperidin-1-yl)butanoate; [0205] (S)-Ethyl
2-((2S,3R,5R)-3-(3-chlorophenyl)-2-(4-chlorophenyl)-5-(2-((3-morpholinopr-
opyl)amino)-2-oxoethyl)-6-oxopiperidin-1-yl)butanoate; [0206]
(3R,5R,6S)-3-((1H-Tetrazol-5-yl)methyl)-5-(3-chlorophenyl)-6-(4-chlorophe-
nyl)-1-(cyclopropylmethyl)piperidin-2-one; [0207]
(3R,5R,6S)-3-((1,3,4-oxadiazol-2-yl)methyl)-5-(3-chlorophenyl)-6-(4-chlor-
ophenyl)-1-(cyclopropylmethyl)piperidin-2-one; [0208]
(3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-(cyclopropylmethyl)-3--
((5-methyl-1,3,4-oxadiazol-2-yl)methyl)piperidin-2-one; [0209]
2-((3S,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-(cyclopropylmethyl)-
-2-oxopiperidin-3-yl)-N-(methylsulfonyl)acetamide; [0210]
2-((3S,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-(cyclopropylmethyl)-
-2-oxopiperidin-3-yl)acetamide; [0211]
(3S,5R,6S)-3-((1H-tetrazol-5-yl)methyl)-5-(3-chlorophenyl)-6-(4-chlorophe-
nyl)-1-(cyclopropylmethyl)piperidin-2-one; [0212]
(3S,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-(cyclopropylmethyl)-3--
((5-methylisoxazol-3-yl)methyl)piperidin-2-one; [0213]
2-((2'S,3'R,5'R)-6-chloro-3'-(3-chlorophenyl)-1'-(cyclopropylmethyl)-2,6'-
-dioxospiro[indoline-3,2'-piperidine]-5'-yl)acetic acid; [0214]
2-((2'R,3'S,5'S)-6-chloro-3'-(3-chlorophenyl)-1'-(cyclopropylmethyl)-2,6'-
-dioxospiro[indoline-3,2'-piperidine]-5'-yl)acetic acid; [0215]
2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(5-chlorothiophen-2-yl)-1-(cyclopropyl-
methyl)-2-oxopiperidin-3-yl)acetic acid; [0216]
2-((3S,5R,6S)-5-(3-chlorophenyl)-6-(5-chlorothiophen-2-yl)-1-(cyclopropyl-
methyl)-2-oxopiperidin-3-yl)acetic acid; [0217]
2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-ethoxy-1-oxo-
butan-2-yl)-3-methyl-2-oxopiperidin-3-yl)acetic acid; [0218]
2-((3R,5R,6S)-1-((S)-1-tert-butoxy-1-oxobutan-2-yl)-5-(3-chlorophenyl)-6--
(4-chlorophenyl)-3-methyl-2-oxopiperidin-3-yl)acetic acid; [0219]
2-((3R,5R,6S)-1-((R)-1-tert-butoxy-1-oxobutan-2-yl)-5-(3-chlorophenyl)-6--
(4-chlorophenyl)-3-methyl-2-oxopiperidin-3-yl)acetic acid; [0220]
2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-(cyclopropyl-
methoxy)butan-2-yl)-3-methyl-2-oxopiperidin-3-yl)acetic acid;
[0221]
2-((3S,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-(cyclopropylmethyl)-
-2-oxo-3-(2-(pyrrolidin-1-yl)ethyl)piperidin-3-yl)acetic acid;
[0222]
2-((3S,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-(cyclopropylmethyl)-
-3-(2-morpholinoethyl)-2-oxopiperidin-3-yl)acetic acid; [0223]
2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-2-oxo-1-(pen-
tan-3-yl)piperidin-3-yl)acetic acid; [0224]
2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-(cyclopropylmethyl)-
-3-methyl-2-oxopiperidin-3-yl)acetic acid; [0225]
2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-isopropyl-3-methyl--
2-oxopiperidin-3-yl)acetic acid; [0226]
2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-cyclobutyl-3-methyl-
-2-oxopiperidin-3-yl)acetic acid; [0227]
2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-cyclopentyl-3-methy-
l-2-oxopiperidin-3-yl)acetic acid; [0228]
(3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-3-((5-oxo-4,5-d-
ihydro-1H-1,2,4-triazol-3-yl)methyl)-1-(pentan-3-yl)piperidin-2-one;
[0229]
5-(((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-2-ox-
o-1-(pentan-3-yl)piperidin-3-yl)methyl)-1,3,4-oxadiazol-2(3H)-one;
[0230]
2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-2-oxo-1-(pen-
tan-3-yl)piperidin-3-yl)-N-(trifluoromethylsulfonyl)acetamide;
[0231]
(3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-((3-hydroxy-1H-pyrazol-
-5-yl)methyl)-3-methyl-1-(pentan-3-yl)piperidin-2-one; [0232]
(3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-((3-hydroxyisoxazol-5--
yl)methyl)-3-methyl-1-(pentan-3-yl)piperidin-2-one; [0233]
5-(((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-2-oxo-1-(pe-
ntan-3-yl)piperidin-3-yl)methyl)oxazolidine-2,4-dione; [0234]
3-(((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-2-oxo-1-(pe-
ntan-3-yl)piperidin-3-yl)methyl)-1,2,4-oxadiazol-5(4H)-one; [0235]
3-(((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-isopropyl-3-methyl-
-2-oxopiperidin-3-yl)methyl)-1,2,4-oxadiazol-5(4H)-one; [0236]
3-(((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-2-oxo-1-(pe-
ntan-3-yl)piperidin-3-yl)methyl)-1,2,4-thiadiazol-5(4H)-one; [0237]
3-(((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-isopropyl-3-methyl-
-2-oxopiperidin-3-yl)methyl)-1,2,4-thiadiazol-5(4H)-one; [0238]
(3R,5R,6S)-3-((1H-Tetrazol-5-yl)methyl)-5-(3-chlorophenyl)-6-(4-chlorophe-
nyl)-1-isopropyl-3-methylpiperidin-2-one; [0239]
2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-ethyl-2-oxo-1-(pent-
an-3-yl)piperidin-3-yl)acetic acid; [0240]
(3S,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-3-(methylsulfon-
ylmethyl)-1-(pentan-3-yl)piperidin-2-one; [0241]
2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-(3-cycloprop-
yl-1,2,4-oxadiazol-5-yl)propyl)-3-methyl-2-oxopiperidin-3-yl)acetic
acid; [0242]
2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((R)-1-(3-cy-
clopropyl-1,2,4-oxadiazol-5-yl)propyl)-3-methyl-2-oxopiperidin-3-yl)acetic
acid; [0243]
2-((3R,5R,6S)-5-(3-Chlorophenyl)-6-(4-chlorophenyl)-3-methyl-1-((S)-1-mor-
pholinobutan-2-yl)-2-oxopiperidin-3-yl)acetic acid; [0244]
2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-2-oxo-1-((S)-
-1-(2,2,2-trifluoroethylamino)butan-2-yl)piperidin-3-yl)acetic
acid; [0245]
2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-(2,2--
dimethylmorpholino)butan-2-yl)-3-methyl-2-oxopiperidin-3-yl)acetic
acid; [0246]
2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((2S)-1-(2,6-
-dimethylmorpholino)butan-2-yl)-3-methyl-2-oxopiperidin-3-yl)acetic
acid; [0247]
2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-(4-(c-
yclopropylsulfonyl)piperazin-1-yl)butan-2-yl)-3-methyl-2-oxopiperidin-3-yl-
)acetic acid; [0248]
2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-1-((S)-1-(4--
(methylsulfonyl)piperazin-1-yl)butan-2-yl)-2-oxopiperidin-3-yl)acetic
acid; [0249]
2-((3R,5R,6S)-1-((S)-1-(4-acetylpiperazin-1-yl)butan-2-yl)-5-(3-chlorophe-
nyl)-6-(4-chlorophenyl)-3-methyl-2-oxopiperidin-3-yl)acetic acid;
[0250]
2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-(4-(cyclopro-
panecarbonyl)piperazin-1-yl)butan-2-yl)-3-methyl-2-oxopiperidin-3-yl)aceti-
c acid; [0251]
3-(((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-1-((S)-1-mo-
rpholinobutan-2-yl)-2-oxopiperidin-3-yl)methyl)-1,2,4-oxadiazol-5(4H)-one;
[0252]
2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-(5,5--
dimethyl-2-oxooxazolidin-3-yl)butan-2-yl)-3-methyl-2-oxopiperidin-3-yl)ace-
tic acid; [0253]
2-((3R,5R,6S)-1-((S)-1-(tert-butylamino)-1-oxobutan-2-yl)-5-(3-chlorophen-
yl)-6-(4-chlorophenyl)-3-methyl-2-oxopiperidin-3-yl)acetic acid;
[0254]
2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((1S,2R,3S)-2,3-dih-
ydroxycyclopentyl)-3-methyl-2-oxopiperidin-3-yl)acetic acid; [0255]
2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((1R,2R,3S)-2,3-dih-
ydroxycyclopentyl)-3-methyl-2-oxopiperidin-3-yl)acetic acid; [0256]
2-((3R,3'S,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-2-oxo-1'-
-(2,2,2-trifluoroethyl)-1,3'-bipiperidin-3-yl)acetic acid; [0257]
2-((3R,3'R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-2-oxo-1'-
-(2,2,2-trifluoroethyl)-1,3'-bipiperidin-3-yl)acetic acid; [0258]
2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((1S,3S)-3-hydroxyc-
yclopentyl)-3-methyl-2-oxopiperidin-3-yl)acetic acid; [0259]
2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((1S,3R)-3-hydroxyc-
yclopentyl)-3-methyl-2-oxopiperidin-3-yl)acetic acid; [0260]
2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-2-oxo-1-((S)-
-tetrahydro-2H-pyran-3-yl)piperidin-3-yl)acetic acid; [0261]
2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-2-oxo-1-((R)-
-tetrahydro-2H-pyran-3-yl)piperidin-3-yl)acetic acid;
[0262]
2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-2-oxo-
-1-(pyrazin-2-yl)piperidin-3-yl)acetic acid; [0263]
2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-1-(1-methyl--
1H-pyrazol-4-yl)-2-oxopiperidin-3-yl)acetic acid; [0264]
2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-2-oxo-1-(pyr-
imidin-4-yl)piperidin-3-yl)acetic acid; [0265]
2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-(2-chloropyrimidin--
4-yl)-3-methyl-2-oxopiperidin-3-yl)acetic acid; [0266]
2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-2-oxo-1-(pyr-
imidin-2-yl)piperidin-3-yl)acetic acid; [0267]
2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-1-(3-methylp-
yridin-2-yl)-2-oxopiperidin-3-yl)acetic acid; [0268]
2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-1-(4-methylp-
yridin-2-yl)-2-oxopiperidin-3-yl)acetic acid; [0269]
2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-(dicyclopropylmethy-
l)-3-methyl-2-oxopiperidin-3-yl)acetic acid; [0270]
2-((3S,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-(dicyclopropylmethy-
l)-3-methyl-2-oxopiperidin-3-yl)acetic acid; [0271]
((3S,4R,6R)-4-(3-chlorophenyl)-3-(4-chlorophenyl)-1,1-dioxido-2-(2-propan-
yl)-1,2-thiazinan-6-yl)acetic acid; [0272]
((3S,4R,6S)-4-(3-chlorophenyl)-3-(4-chlorophenyl)-1,1-dioxido-2-(2-propan-
yl)-1,2-thiazinan-6-yl)acetic acid; [0273]
((3S,4R,6R)-4-(3-chlorophenyl)-3-(4-chlorophenyl)-6-methyl-1,1-dioxido-2--
(2-propanyl)-1,2-thiazinan-6-yl)acetic acid; [0274]
((3S,4R,6S)-4-(3-chlorophenyl)-3-(4-chlorophenyl)-6-methyl-1,1-dioxido-2--
(2-propanyl)-1,2-thiazinan-6-yl)acetic acid; [0275]
2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(5-chloropyridin-2-yl)-3-methyl-1-((S)-
-1-morpholinobutan-2-yl)-2-oxopiperidin-3-yl)acetic acid; [0276]
2-((3S,5R,6S)-5-(3-Chlorophenyl)-6-(5-chloropyridin-2-yl)-3-methyl-2-oxo--
1-(pentan-3-yl)piperidin-3-yl)acetic acid; [0277]
2-((3R,5R,6S)-5-(3-Chlorophenyl)-6-(5-chloropyridin-2-yl)-3-methyl-2-oxo--
1-(pentan-3-yl)piperidin-3-yl)acetic acid; [0278]
2-((3S,5R,6S)-5-(3-Chlorophenyl)-6-(5-chloropyridin-2-yl)-3-methyl-2-oxo--
1-(pentan-3-yl)piperidin-3-yl)acetic acid; [0279]
2-((3R,5R,6S)-1-((S)-1-tert-butoxy-1-oxobutan-2-yl)-5-(3-chlorophenyl)-6--
(5-chloropyridin-2-yl)-3-methyl-2-oxopiperidin-3-yl)acetic acid; or
[0280]
2-((3R,5S,6S)-1-((S)-1-tert-butoxy-1-oxobutan-2-yl)-6-(4-chlorophenyl)-5--
(4-chloropyridin-2-yl)-3-methyl-2-oxopiperidin-3-yl)acetic
acid.
[0281] In another aspect, the present invention provides a
compound, or a pharmaceutically acceptable salt thereof, selected
from: [0282]
2-((3S,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-(N-methylcyc-
lopropanesulfonamido)butan-2-yl)-2-oxopiperidin-3-yl)acetic acid;
[0283]
2-((3S,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-(N-methylcyc-
lopropanesulfonamido)butan-2-yl)-2-oxopiperidin-3-yl)propanoic
acid; [0284] (S)-tert-butyl
2-((3R,5R,6S)-3-((1H-tetrazol-5-yl)methyl)-5-(3-chlorophenyl)-6-(4-chloro-
phenyl)-3-methyl-2-oxopiperidin-1-yl)butanoate; [0285]
2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-1-((S)-1-(me-
thylsulfonamido)butan-2-yl)-2-oxopiperidin-3-yl)acetic acid; [0286]
2-((3R,5R,6S)-5-(3-Chlorophenyl)-6-(4-chlorophenyl)-3-methyl-2-oxo-1-((S)-
-5-oxohexan-3-yl)piperidin-3-yl)acetic acid; [0287]
2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((S)-5-hydroxy-5-me-
thylhexan-3-yl)-3-methyl-2-oxopiperidin-3-yl)acetic acid; [0288]
2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-2-oxo-1-((3S-
,5S)-6,6,6-trifluoro-5-hydroxy-5-methylhexan-3-yl)piperidin-3-yl)acetic
acid (isomer 1); [0289]
2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-2-oxo-1-((3S-
,5R)-6,6,6-trifluoro-5-hydroxy-5-methylhexan-3-yl)piperidin-3-yl)acetic
acid (isomer 2); [0290]
2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-1-((S)-1-(N--
methylmethylsulfonamido)butan-2-yl)-2-oxopiperidin-3-yl)acetic
acid; [0291]
2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((3S)-5-cycl-
opropyl-6,6,6-trifluoro-5-hydroxyhexan-3-yl)-3-methyl-2-oxopiperidin-3-yl)-
acetic acid; [0292]
2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((S)-6-hydroxy-6-me-
thylheptan-3-yl)-3-methyl-2-oxopiperidin-3-yl)acetic acid; [0293]
2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-2-oxo-1-((S)-
-6,6,6-trifluoro-5,5-dihydroxyhexan-3-yl)piperidin-3-yl)acetic
acid; [0294]
2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-2-oxo-
-1-((3S)-7,7,7-trifluoro-6-hydroxy-6-methylheptan-3-yl)piperidin-3-yl)acet-
ic acid (isomer 1); [0295]
2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-2-oxo-1-((3S-
)-7,7,7-trifluoro-6-hydroxy-6-methylheptan-3-yl)piperidin-3-yl)acetic
acid (isomer 2); [0296]
2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((S)-7-hydroxy-7-me-
thyloctan-3-yl)-3-methyl-2-oxopiperidin-3-yl)acetic acid; [0297]
2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-1-((S)-1-(N--
methylcyclopropanesulfonamido)butan-2-yl)-2-oxopiperidin-3-yl)acetic
acid; [0298]
2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-(N-cy-
clopropylmethylsulfonamido)butan-2-yl)-3-methyl-2-oxopiperidin-3-yl)acetic
acid; [0299]
2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-2-oxo-1-((3S-
)-6,6,6-trifluoro-5-hydroxyhexan-3-yl)piperidin-3-yl)acetic acid
(isomer 1); [0300]
2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-2-oxo-1-((3S-
)-6,6,6-trifluoro-5-hydroxyhexan-3-yl)piperidin-3-yl)acetic acid
(isomer 2); [0301]
2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((3S)-5-hydroxyhexa-
n-3-yl)-3-methyl-2-oxopiperidin-3-yl)acetic acid (isomer 1); [0302]
2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((3S)-5-hydroxyhexa-
n-3-yl)-3-methyl-2-oxopiperidin-3-yl)acetic acid (isomer 2); [0303]
2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-2-oxo-1-((S)-
-1-(N-(2,2,2-trifluoroethyl)methylsulfonamido)butan-2-yl)piperidin-3-yl)ac-
etic acid; [0304]
2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-(1,1-dioxido-
isothiazolidin-2-yl)butan-2-yl)-3-methyl-2-oxopiperidin-3-yl)acetic
acid; [0305]
2-((3R,5R,6S)-5-(3-Chlorophenyl)-6-(4-chlorophenyl)-1-((3S,4R)-5-h-
ydroxy-4,5-dimethylhexan-3-yl)-3-methyl-2-oxopiperidin-3-yl)acetic
acid; [0306]
2-((3R,5R,6S)-5-(3-Chlorophenyl)-6-(4-chlorophenyl)-1-((3S,4S)-5-h-
ydroxy-4,5-dimethylhexan-3-yl)-3-methyl-2-oxopiperidin-3-yl)acetic
acid; [0307]
2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((S)-5-cyano-
-5-methylhexan-3-yl)-3-methyl-2-oxopiperidin-3-yl)acetic acid;
[0308]
2-((3R,5R,6S)-5-(3-Chlorophenyl)-6-(4-chlorophenyl)-3-methyl-2-oxo-1-((S)-
-2-oxopentan-3-yl)piperidin-3-yl)acetic acid; [0309]
2-((3R,5R,6S)-5-(3-Chlorophenyl)-6-(4-chlorophenyl)-1-((2S,3S)-2-hydroxyp-
entan-3-yl)-3-methyl-2-oxopiperidin-3-yl)acetic acid; [0310]
2-((3R,5R,6S)-5-(3-Chlorophenyl)-6-(4-chlorophenyl)-1-((2S,3S)-2-methoxyp-
entan-3-yl)-3-methyl-2-oxopiperidin-3-yl)acetic acid; [0311]
2-((3R,5R,6S)-5-(3-Chlorophenyl)-6-(4-chlorophenyl)-1-((2R,3S)-2-hydroxyp-
entan-3-yl)-3-methyl-2-oxopiperidin-3-yl)acetic acid; [0312]
2-((3R,5R,6S)-5-(3-Chlorophenyl)-6-(4-chlorophenyl)-1-((2S,3R)-2-hydroxyp-
entan-3-yl)-3-methyl-2-oxopiperidin-3-yl)acetic acid; [0313]
2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((2R,3R)-2-hydroxyp-
entan-3-yl)-3-methyl-2-oxopiperidin-3-yl)acetic acid; [0314]
2-((3R,5R,6S)-5-(3-Chlorophenyl)-6-(4-chlorophenyl)-1-((S)-2-hydroxy-2-me-
thylpentan-3-yl)-3-methyl-2-oxopiperidin-3-yl)acetic acid; [0315]
2-((3R,5R,6S)-5-(3-Chlorophenyl)-6-(4-chlorophenyl)-1-((3S,4S)-4-hydroxyh-
exan-3-yl)-3-methyl-2-oxopiperidin-3-yl)acetic acid; [0316]
2-((3R,5R,6S)-5-(3-Chlorophenyl)-6-(4-chlorophenyl)-1-((3S,4R)-4-hydroxyh-
exan-3-yl)-3-methyl-2-oxopiperidin-3-yl)acetic acid; [0317]
2-((3R,5R,6S)-5-(3-Chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-methoxybutan-
-2-yl)-3-methyl-2-oxopiperidin-3-yl)acetic acid; [0318]
2-((3R,5R,6S)-5-(3-Chlorophenyl)-6-(4-chlorophenyl)-3-methyl-2-oxo-1-(3S)-
-1,1,1-trifluoro-2-hydroxy-2-methylpentan-3-yl)piperidin-3-yl)acetic
acid; [0319]
2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-1-((S-
)-1-(N-methylcyclopropanesulfonamido)butan-2-yl)-2-oxopiperidin-3-yl)aceta-
mide; [0320]
2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-1-((S)-1-(N--
methylcyclopropanesulfonamido)butan-2-yl)-2-oxopiperidin-3-yl)-N-(methylsu-
lfonyl)acetamide; [0321]
2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-1-((S)-1-(N--
methylcyclopropanesulfonamido)butan-2-yl)-2-oxopiperidin-3-yl)-N-(3-hydrox-
ypropyl)acetamide; [0322]
2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-1-((S)-1-(N--
methylcyclopropanesulfonamido)butan-2-yl)-2-oxopiperidin-3-yl)-N-(2-hydrox-
yethyl)acetamide; [0323]
2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-1-((S)-1-(N--
methylcyclopropanesulfonamido)butan-2-yl)-2-oxopiperidin-3-yl)-N-hydroxyac-
etamide; [0324]
2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-1-((S)-1-(N--
methylcyclopropanesulfonamido)butan-2-yl)-2-oxopiperidin-3-yl)-N-methoxyac-
etamide; [0325]
2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-1-((S)-1-(N--
methylcyclopropanesulfonamido)butan-2-yl)-2-oxopiperidin-3-yl)-N--((R)-2,3-
-dihydroxypropyl)acetamide; [0326]
2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-1-((S)-1-(N--
methylcyclopropanesulfonamido)butan-2-yl)-2-oxopiperidin-3-yl)-N--((S)-2,3-
-dihydroxypropyl)acetamide; [0327]
2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-1-((S)-1-(N--
methylcyclopropanesulfonamido)butan-2-yl)-2-oxopiperidin-3-yl)-N-cyanoacet-
amide; [0328]
2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-1-((S)-1-(N--
methylcyclopropanesulfonamido)butan-2-yl)-2-oxopiperidin-3-yl)-N-(2-(dimet-
hylamino)ethyl)acetamide; [0329]
2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-1-((S)-1-(N--
methylcyclopropanesulfonamido)butan-2-yl)-2-oxopiperidin-3-yl)-N-(3,4-dihy-
droxybutyl)acetamide; [0330]
2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-(cyclopropan-
esulfonamido)butan-2-yl)-3-methyl-2-oxopiperidin-3-yl)acetic acid;
[0331]
(S)-2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-1-((S)-1-
-(N-methylcyclopropanesulfonamido)butan-2-yl)-2-oxopiperidin-3-yl)propanoi-
c acid; [0332]
2-((3R,5R,6S)-5-(3-Chlorophenyl)-6-(4-chlorophenyl)-1-(3S)-2-(cyclopropan-
esulfonamido)pentan-3-yl)-3-methyl-2-oxopiperidin-3-yl)acetic acid
(isomer 1); [0333]
2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-(3S)-2-(cyclopropan-
esulfonamido)pentan-3-yl)-3-methyl-2-oxopiperidin-3-yl)acetic acid
(isomer 2); [0334]
2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-1-((2R,3S)-2-
-(1-methylethylsulfonamido)pentan-3-yl)-2-oxopiperidin-3-yl)acetic
acid; [0335]
2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-1-((S-
)-1-(N-methylcyclopropanesulfonamido)-1-oxobutan-2-yl)-2-oxopiperidin-3-yl-
)acetic acid; [0336]
2-((3R,5R,6S)-5-(3-Chlorophenyl)-6-(4-chlorophenyl)-3-methyl-1-((S)-1-(ne-
opentylamino)-1-oxobutan-2-yl)-2-oxopiperidin-3-yl)acetic acid;
[0337]
2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-(4,4-dimethy-
l-4,5-dihydrooxazol-2-yl)propyl)-3-methyl-2-oxopiperidin-3-yl)acetic
acid; [0338]
2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-2-oxo-
-1-((S)-1-(N-(2,2,2-trifluoroethyl)acetamido)butan-2-yl)piperidin-3-yl)ace-
tic acid; [0339]
2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-(1,1-dimethy-
lethylsulfonamido)butan-2-yl)-3-methyl-2-oxopiperidin-3-yl)acetic
acid [0340]
2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-(N,2--
dimethylpropan-2-ylsulfonamido)butan-2-yl)-3-methyl-2-oxopiperidin-3-yl)ac-
etic acid; [0341]
2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-1-((S)-1-(1--
methylethylsulfonamido)butan-2-yl)-2-oxopiperidin-3-yl)acetic acid;
[0342]
2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-(N-ethylprop-
an-2-ylsulfonamido)butan-2-yl)-3-methyl-2-oxopiperidin-3-yl)acetic
acid; [0343]
2-((3R,5R,6S)-5-(3-Chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-hydro-
xybutan-2-yl)-3-methyl-2-oxopiperidin-3-yl)acetic acid; [0344]
2-((3R,5R,6S)-5-(3-Chlorophenyl)-6-(4-chlorophenyl)-3-methyl-2-oxo-1-((S)-
-1-(trifluoromethylsulfonamido)butan-2-yl)piperidin-3-yl)acetic
acid; [0345]
2-((3R,5R,6S)-5-(3-Chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-(4-ch-
lorophenylsulfonamido)butan-2-yl)-3-methyl-2-oxopiperidin-3-yl)acetic
acid; [0346]
2-((3R,5R,6S)-5-(3-Chlorophenyl)-6-(4-chlorophenyl)-3-methyl-1-((S)-1-(4--
methylphenylsulfonamido)butan-2-yl)-2-oxopiperidin-3-yl)acetic
acid; [0347]
2-((3R,5R,6S)-5-(3-Chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-(2-ch-
lorophenylsulfonamido)butan-2-yl)-3-methyl-2-oxopiperidin-3-yl)acetic
acid; [0348]
2-((3R,5R,6S)-5-(3-Chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-(2-methylphe-
nylsulfonamido)butan-2-yl)-3-methyl-2-oxopiperidin-3-yl)acetic
acid; [0349]
2-((3R,5R,6S)-5-(3-Chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-(4-me-
thoxyphenylsulfonamido)butan-2-yl)-3-methyl-2-oxopiperidin-3-yl)acetic
acid; [0350]
2-((3R,5R,6S)-5-(3-Chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-(phenylsulfo-
namido)butan-2-yl)-3-methyl-2-oxopiperidin-3-yl)acetic acid; [0351]
2-((3R,5R,6S)-5-(3-Chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-(1-methylcyc-
lopropanesulfonamido)butan-2-yl)-3-methyl-2-oxopiperidin-3-yl)acetic
acid; [0352]
2-((3R,5R,6S)-5-(3-Chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-(1,1--
dioxidobenzo[d]isothiazol-2(3H)-yl)butan-2-yl)-3-methyl-2-oxopiperidin-3-y-
l)acetic acid; [0353]
2-((3R,5R,6S)-5-(3-Chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-(3,3-dimethy-
l-1,1-dioxidobenzo[d]isothiazol-2(3H)-yl)butan-2-yl)-3-methyl-2-oxopiperid-
in-3-yl)acetic acid; [0354]
2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-2-oxo-1-((S)-
-1-(pyridine-3-sulfonamido)butan-2-yl)piperidin-3-yl)acetic acid;
[0355]
2-((3R,5R,6S)-5-(3-Chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-(4-cyanophen-
ylsulfonamido)butan-2-yl)-3-methyl-2-oxopiperidin-3-yl)acetic acid;
[0356]
2-((3R,5R,6S)-5-(3-Chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-(3-cyanophen-
ylsulfonamido)butan-2-yl)-3-methyl-2-oxopiperidin-3-yl)acetic acid;
[0357]
2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-2-oxo-1-((S)-
-1-(pyridine-2-sulfonamido)butan-2-yl)piperidin-3-yl)acetic acid.
[0358]
2-((3R,5R,6S)-5-(3-Chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-(N,1-dimethy-
lcyclopropanesulfonamido)butan-2-yl)-3-methyl-2-oxopiperidin-3-yl)acetic
acid; [0359]
3-((3S,5R,6S)-5-(3-Chlorophenyl)-6-(4-chlorophenyl)-3-methyl-1-((S)-1-(N--
methylcyclopropanesulfonamido)butan-2-yl)-2-oxopiperidin-3-yl)propanoic
acid; [0360]
3-((3R,5S,6R)-5-(3-Chlorophenyl)-6-(4-chlorophenyl)-3-methyl-1-((S)-1-(N--
methylcyclopropanesulfonamido)butan-2-yl)-2-oxopiperidin-3-yl)propanoic
acid; [0361]
2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-ethyl-1-((S)-1-(N-m-
ethylcyclopropanesulfonamido)butan-2-yl)-2-oxopiperidin-3-yl)acetic
acid; [0362]
2-((3S,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methoxy-1-((-
S)-1-(N-methylcyclopropanesulfonamido)butan-2-yl)-2-oxopiperidin-3-yl)acet-
ic acid; [0363]
2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-1-((S)-6-met-
hyl-4-oxoheptan-3-yl)-2-oxopiperidin-3-yl)acetic acid; [0364]
2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-(ethylsulfon-
yl)pentan-3-yl)-3-methyl-2-oxopiperidin-3-yl)acetic acid; [0365]
2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-(isopropylsu-
lfonyl)pentan-3-yl)-3-methyl-2-oxopiperidin-3-yl)acetic acid;
[0366]
2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-(cyclopropyl-
methylsulfonyl)pentan-3-yl)-3-methyl-2-oxopiperidin-3-yl)acetic
acid; [0367]
2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-2-oxo-
-1-((S)-1-(2-oxopyrrolidin-1-yl)butan-2-yl)piperidin-3-yl)acetic
acid; [0368]
2-((3R,5R,6S)-1-((S)-1-((1R,4R)-2-oxa-5-azabicyclo[2.2.1]heptan-5--
yl)butan-2-yl)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-2-oxopiperid-
in-3-yl)acetic acid; [0369]
2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-1-((S)-1-((S-
)-3-methylmorpholino)butan-2-yl)-2-oxopiperidin-3-yl)acetic acid;
[0370]
2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-1-((S)-1-((R-
)-3-methylmorpholino)butan-2-yl)-2-oxopiperidin-3-yl)acetic acid;
[0371]
2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-(thiomorphol-
ino-1,1-dioxide)butan-2-yl)-3-methyl-2-oxopiperidin-3-yl)acetic
acid; [0372]
2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-(3,3--
difluoroazetidin-1-yl)butan-2-yl)-3-methyl-2-oxopiperidin-3-yl)acetic
acid; [0373]
2-((3R,5R,6S)-1-((2S)-1-(8-oxa-3-azabicyclo[3.2.1]octan-3-yl)butan-2-yl)--
5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-2-oxopiperidin-3-yl)acetic
acid; [0374]
2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-(3,3-dimethy-
lmorpholino)butan-2-yl)-3-methyl-2-oxopiperidin-3-yl)acetic acid;
[0375]
2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-(3-hydroxy-3-
-(trifluoromethyl)azetidin-1-yl)butan-2-yl)-3-methyl-2-oxopiperidin-3-yl)a-
cetic acid; [0376]
2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-1-((S)-1-(me-
thyl(oxetan-3-yl)amino)butan-2-yl)-2-oxopiperidin-3-yl)acetic acid;
[0377]
2-((3R,5R,6S)-5-(3-Chlorophenyl)-6-(4-chlorophenyl)-3-methyl-2-oxo-1-((S)-
-1-(2-oxooxazolidin-3-yl)butan-2-yl)piperidin-3-yl)acetic acid;
[0378]
2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-2-oxo-1-((S)-
-1-(2-oxopyridin-1(2H)-yl)butan-2-yl)piperidin-3-yl)acetic acid;
[0379]
2-((3R,5R,6S)-5-(3-Chlorophenyl)-6-(4-chlorophenyl)-3-methyl-2-oxo-1-((S)-
-1-(2-oxo-5-(trifluoromethyl)pyridin-1(2H)-yl)butan-2-yl)piperidin-3-yl)ac-
etic acid; [0380]
(3S,5R,6S)-3-allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-1-((S)--
1-(pyridin-3-yloxy)butan-2-yl)piperidin-2-one;
[0381]
2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-2-oxo-
-1-((1S)-1-(tetrahydrofuran-2-yl)propyl)piperidin-3-yl)acetic acid
(isomer 1); [0382]
2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-2-oxo-1-((1S-
)-1-(tetrahydrofuran-2-yl)propyl)piperidin-3-yl)acetic acid (isomer
2); [0383]
2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-2-oxo-
-1-((1S)-1-5-oxotetrahydrofuran-2-yl)propyl)piperidin-3-yl)acetic
acid; [0384]
2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-2-oxo-
-1-((1S)-1-(tetrahydro-2H-pyran-2-yl)propyl)piperidin-3-yl)acetic
acid (isomer 1); [0385]
2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-2-oxo-1-((1S-
)-1-(tetrahydro-2H-pyran-2-yl)propyl)piperidin-3-yl)acetic acid
(isomer 2); [0386]
2-((3R,5R,6S)-1-((R)-1-(benzo[d]thiazol-2-yl)propyl)-5-(3-chlorophenyl)-6-
-(4-chlorophenyl)-3-methyl-2-oxopiperidin-3-yl)acetic acid; [0387]
2-((3R,5R,6S)-1-((S)-1-(benzo[d]thiazol-2-yl)propyl)-5-(3-chlorophenyl)-6-
-(4-chlorophenyl)-3-methyl-2-oxopiperidin-3-yl)acetic acid; [0388]
2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-1-((S)-1-(3--
methylisoxazol-5-yl)propyl)-2-oxopiperidin-3-yl)acetic acid; [0389]
2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-1-((R)-1-(3--
methylisoxazol-5-yl)propyl)-2-oxopiperidin-3-yl)acetic acid; [0390]
2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-(6-chloropyr-
idin-2-yl)propyl)-3-methyl-2-oxopiperidin-3-yl)acetic acid; [0391]
2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((R)-1-(6-chloropyr-
idin-2-yl)propyl)-3-methyl-2-oxopiperidin-3-yl)acetic acid; [0392]
2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-2-oxo-1-((S)-
-1-(pyridin-2-yl)propyl)piperidin-3-yl)acetic acid; [0393]
2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-2-oxo-1-((R)-
-1-(pyridin-2-yl)propyl)piperidin-3-yl)acetic acid; [0394]
2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-2-oxo-1-((S)-
-1-(pyridin-2-yl)butyl)piperidin-3-yl)acetic acid; [0395]
2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-2-oxo-1-((R)-
-1-(pyridin-2-yl)butyl)piperidin-3-yl)acetic acid; [0396]
2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((S)-2-cyclopropyl--
1-(pyridin-2-yl)ethyl)-3-methyl-2-oxopiperidin-3-yl)acetic acid;
[0397]
2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((R)-2-cyclopropyl--
1-(pyridin-2-yl)ethyl)-3-methyl-2-oxopiperidin-3-yl)acetic acid;
[0398]
2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-2-oxo-1-((S)-
-1-(pyridin-3-yl)propyl)piperidin-3-yl)acetic acid; [0399]
2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-2-oxo-1-((R)-
-1-(pyridin-3-yl)propyl)piperidin-3-yl)acetic acid; [0400]
2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-2-oxo-1-((S)-
-1-(pyrazin-2-yl)propyl)piperidin-3-yl)acetic acid; [0401]
2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-2-oxo-1-((R)-
-1-(pyrazin-2-yl)propyl)piperidin-3-yl)acetic acid; [0402]
2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-2-oxo-1-((S)-
-1-(pyrimidin-2-yl)propyl)piperidin-3-yl)acetic acid; [0403]
2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-2-oxo-1-((R)-
-1-(pyrimidin-2-yl)propyl)piperidin-3-yl)acetic acid; [0404]
2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-1-((S)-1-(6--
methylpyridin-2-yl)propyl)-2-oxopiperidin-3-yl)acetic acid; [0405]
2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-1-((R)-1-(6--
methylpyridin-2-yl)propyl)-2-oxopiperidin-3-yl)acetic acid; [0406]
2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-2-oxo-1-((S)-
-1-(pyridin-4-yl)propyl)piperidin-3-yl)acetic acid; [0407]
2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-2-oxo-1-((R)-
-1-(pyridin-4-yl)propyl)piperidin-3-yl)acetic acid; [0408]
2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-2-oxo-1-((S)-
-1-(6-(trifluoromethyl)pyridin-2-yl)propyl)piperidin-3-yl)acetic
acid; [0409]
2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-2-oxo-
-1-((R)-1-(6-(trifluoromethyl)pyridin-2-yl)propyl)piperidin-3-yl)acetic
acid; [0410]
2-((3R,5R,6S)-1-((S)-1-(6-bromopyridin-2-yl)propyl)-5-(3-chlorophenyl)-6--
(4-chlorophenyl)-3-methyl-2-oxopiperidin-3-yl)acetic acid; [0411]
2-((3R,5R,6S)-1-((R)-1-(6-bromopyridin-2-yl)propyl)-5-(3-chlorophenyl)-6--
(4-chlorophenyl)-3-methyl-2-oxopiperidin-3-yl)acetic acid; [0412]
2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-2-oxo-1-((S)-
-1-(thiazol-2-yl)propyl)piperidin-3-yl)acetic acid; [0413]
2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-2-oxo-1-((R)-
-1-(thiazol-2-yl)propyl)piperidin-3-yl)acetic acid; [0414]
2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-(6-(2-hydrox-
ypropan-2-yl)pyridin-2-yl)propyl)-3-methyl-2-oxopiperidin-3-yl)acetic
acid; [0415]
2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((R)-1-(6-(2-hydrox-
ypropan-2-yl)pyridin-2-yl)propyl)-3-methyl-2-oxopiperidin-3-yl)acetic
acid; [0416]
2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-(6-cycloprop-
ylpyridin-2-yl)propyl)-3-methyl-2-oxopiperidin-3-yl)acetic acid;
[0417]
2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((R)-1-(6-cycloprop-
ylpyridin-2-yl)propyl)-3-methyl-2-oxopiperidin-3-yl)acetic acid;
[0418]
2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-2-oxo-1-((S)-
-3,3,3-trifluoro-1-(pyridin-2-yl)propyl)piperidin-3-yl)acetic acid;
[0419]
2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-2-oxo-1-((R)-
-3,3,3-trifluoro-1-(pyridin-2-yl)propyl)piperidin-3-yl)acetic acid;
[0420]
2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-1-((S)-2-met-
hyl-1-(pyridin-2-yl)propyl)-2-oxopiperidin-3-yl)acetic acid; [0421]
2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-1-((R)-2-met-
hyl-1-(pyridin-2-yl)propyl)-2-oxopiperidin-3-yl)acetic acid; [0422]
(3R,5R,6S)-3-((1H-tetrazol-5-yl)methyl)-5-(3-chlorophenyl)-6-(4-chlorophe-
nyl)-3-methyl-1-(pentan-3-yl)piperidin-2-one; [0423]
(3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-((R)-2,3-dihydroxyprop-
yl)-1-((2S,3S)-2-hydroxypentan-3-yl)-3-methylpiperidin-2-one;
[0424]
(3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-((S)-2,3-dihydroxyprop-
yl)-1-((2S,3S)-2-hydroxypentan-3-yl)-3-methylpiperidin-2-one;
[0425]
2-((3R,5R,6S)-5-(3-Chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-hydroxybutan-
-2-yl)-3-methyl-2-oxopiperidin-3-yl)cyclopropanecarboxylic acid;
[0426]
2-((3R,5R,6S)-1-((S)-2-(tert-Butoxy)-1-cyclopropyl-2-oxoethyl)-5-(3-chlor-
ophenyl)-6-(4-chlorophenyl)-2-oxopiperidin-3-yl)acetic acid; [0427]
2-((3R,5R,6S)-5-(3-Chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-cyclopropyl--
2-ethoxy-2-oxoethyl)-3-methyl-2-oxopiperidin-3-yl)acetic acid;
[0428]
2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-cyclopropyl--
2-hydroxyethyl)-3-methyl-2-oxopiperidin-3-yl)acetic acid; [0429]
2-((3R,5R,6S)-5-(3-Chlorophenyl)-6-(4-chlorophenyl)-1-((1S,2S)-1-cyclopro-
pyl-2-hydroxybutyl)-3-methyl-2-oxopiperidin-3-yl)acetic acid;
[0430]
2-((3R,5R,6S)-5-(3-Chlorophenyl)-6-(4-chlorophenyl)-1-((1S,2R)-1-cyclopro-
pyl-2-hydroxybutyl)-3-methyl-2-oxopiperidin-3-yl)acetic acid;
[0431]
2-((3R,5R,6S)-5-(3-Chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-cyclopropyl--
2-(N-methylcyclopropanesulfonamido)ethyl)-3-ethyl-2-oxopiperidin-3-yl)acet-
ic acid; [0432]
2-((3R,5R,6S)-5-(3-Chlorophenyl)-6-(4-chlorophenyl)-1-((S)-2-(cyclopropan-
esulfonamido)-1-cyclopropylethyl)-3-ethyl-2-oxopiperidin-3-yl)acetic
acid; [0433]
2-((3R,5R,6S)-5-(3-Chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-cyclo-
propyl-2-(ethylsulfonamido)ethyl)-3-ethyl-2-oxopiperidin-3-yl)acetic
acid; [0434]
2-((3R,5R,6S)-5-(3-Chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-cyclo-
propyl-2-(N-methylcyclopropanesulfonamido)ethyl)-3-methyl-2-oxopiperidin-3-
-yl)acetic acid; [0435]
2-((3R,5R,6S)-5-(3-Chlorophenyl)-6-(4-chlorophenyl)-1-((1S,2R)-1-cyclopro-
pyl-2-hydroxypropyl)-3-methyl-2-oxopiperidin-3-yl)acetic acid;
[0436]
2-((3R,5R,6S)-5-(3-Chlorophenyl)-6-(4-chlorophenyl)-1-((1S,2S)-1-cyclopro-
pyl-2-hydroxypropyl)-3-methyl-2-oxopiperidin-3-yl)acetic acid;
[0437]
2-((3R,5R,6S)-5-(3-Chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-cyclopropyl--
2-(1-methylethylsulfonamido)ethyl)-3-methyl-2-oxopiperidin-3-yl)acetic
acid; [0438]
2-((3R,5R,6S)-5-(3-Chlorophenyl)-6-(4-chlorophenyl)-1-((R)-1-cyclopropyl--
2-(N-methylcyclopropanesulfonamido)ethyl)-3-methyl-2-oxopiperidin-3-yl)ace-
tic acid; [0439]
2-((3R,5R,6S)-5-(3-Chlorophenyl)-6-(4-chlorophenyl)-1-((2S,3S)-2-hydroxy--
4-methylpentan-3-yl)-3-methyl-2-oxopiperidin-3-yl)acetic acid;
[0440]
2-((3R,5R,6S)-5-(3-Chlorophenyl)-6-(4-chlorophenyl)-1-((S)-cyclopropyl(py-
ridin-2-yl)methyl)-3-methyl-2-oxopiperidin-3-yl)acetic acid; or
[0441]
2-((3R,5R,6S)-5-(3-Chlorophenyl)-6-(4-chlorophenyl)-1-((R)-cyclopropyl(py-
ridin-2-yl)methyl)-3-methyl-2-oxopiperidin-3-yl)acetic acid.
[0442] In another aspect, the present invention provides a
compound, or a pharmaceutically acceptable salt thereof, selected
from: [0443]
2-(1-(1-tert-butoxy-1-oxobutan-2-yl)-5-(3-chlorophenyl)-6-(4-chlorophenyl-
)-2-oxopiperidin-3-yl)acetic acid; [0444]
2-(5-(3-Chlorophenyl)-6-(4-chlorophenyl)-1-(1-ethoxy-1-oxobutan-2-yl)-2-o-
xopiperidin-3-yl)acetic acid; [0445]
2-(5-(3-Chlorophenyl)-6-(4-chlorophenyl)-1-(1-ethoxy-4-methyl-1-oxopentan-
-2-yl)-2-oxopiperidin-3-yl)acetic acid; [0446]
2-(5-(3-Chlorophenyl)-6-(4-chlorophenyl)-1-(1-ethoxy-1-oxopentan-2-yl)-2--
oxopiperidin-3-yl)acetic acid; [0447]
2-(1-(2-tert-Butoxy-1-cyclopropyl-2-oxoethyl)-5-(3-chlorophenyl)-6-(4-chl-
orophenyl)-2-oxopiperidin-3-yl)acetic acid; [0448]
2-(5-(3-Chlorophenyl)-6-(4-chlorophenyl)-1-(1-hydroxybutan-2-yl)-2-oxopip-
eridin-3-yl)acetic acid; [0449]
2-(5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-(1-cyclopropyl-2-hydroxyethyl)-
-2-oxopiperidin-3-yl)acetic acid; [0450]
2-(5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-(1-(cyclopropylmethoxy)butan-2-
-yl)-2-oxopiperidin-3-yl)acetic acid; [0451]
2-(5-(3-Chlorophenyl)-6-(4-chlorophenyl)-1-(1-methoxybutan-2-yl)-2-oxopip-
eridin-3-yl)acetic acid; [0452]
2-(5-(3-Chlorophenyl)-6-(4-chlorophenyl)-1-(1-(2-methoxyethoxy)butan-2-yl-
)-2-oxopiperidin-3-yl)acetic acid; [0453]
2-(5-(3-Chlorophenyl)-6-(4-chlorophenyl)-1-(1-((1-cyanocyclopropyl)methox-
y)butan-2-yl)-2-oxopiperidin-3-yl)acetic acid; [0454]
2-(5-(3-Chlorophenyl)-6-(4-chlorophenyl)-1-(1-(cyclopropylmethoxy)butan-2-
-yl)-2-oxopiperidin-3-yl)acetic acid; [0455]
2-(5-(3-Chlorophenyl)-6-(4-chlorophenyl)-1-(1-methoxybutan-2-yl)-2-oxopip-
eridin-3-yl)acetic acid; [0456]
2-(5-(3-Chlorophenyl)-6-(4-chlorophenyl)-1-(1-(2-methoxyethoxy)butan-2-yl-
)-2-oxopiperidin-3-yl)acetic acid; [0457]
2-(1-(1-((1-carbamoylcyclopropyl)methoxy)butan-2-yl)-5-(3-chlorophenyl)-6-
-(4-chlorophenyl)-2-oxopiperidin-3-yl)acetic acid; [0458]
2-(5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-(1-(2-hydroxy-2-methylpropoxy)-
butan-2-yl)-2-oxopiperidin-3-yl)acetic acid; [0459]
2-(5-(3-chlorophenyl)-6-(4-chlorophenyl)-2-oxo-1-(1,1,1-trifluoro-2-hydro-
xypentan-3-yl)piperidin-3-yl)acetic acid; [0460]
2-(5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-(1-morpholinobutan-2-yl)-2-oxo-
piperidin-3-yl)acetic acid; [0461]
2-(5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-(1-(ethylamino)butan-2-yl)-2-o-
xopiperidin-3-yl)acetic acid; [0462]
2-(5-(3-chlorophenyl)-6-(4-chlorophenyl)-2-oxo-1-(1-(2,2,2-trifluoroethyl-
amino)butan-2-yl)piperidin-3-yl)acetic acid; [0463]
2-(5-(3-chlorophenyl)-6-(4-chlorophenyl)-2-oxo-1-(1-(pyrrolidin-1-yl)buta-
n-2-yl)piperidin-3-yl)acetic acid; [0464]
2-(5-(3-chlorophenyl)-6-(4-chlorophenyl)-2-oxo-1-(1-(2-oxopyrrolidin-1-yl-
)butan-2-yl)piperidin-3-yl)acetic acid; [0465]
2-(5-(3-Chlorophenyl)-6-(4-chlorophenyl)-1-(1-(1,1-dioxidothiomorpholino)-
butan-2-yl)-2-oxopiperidin-3-yl)acetic acid; [0466]
2-(5-(3-chlorophenyl)-6-(4-chlorophenyl)-2-oxo-1-(1-(thiazol-2-ylamino)bu-
tan-2-yl)piperidin-3-yl)acetic acid; [0467]
2-(1-(1-acetamidobutan-2-yl)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-2-oxop-
iperidin-3-yl)acetic acid; [0468]
2-(5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-(1-(methylsulfonamido)
butan-2-yl)-2-oxopiperidin-3-yl)acetic acid; [0469]
2-(5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-(1-cyanopentan-3-yl)-2-oxopipe-
ridin-3-yl)acetic acid; [0470]
2-(5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-(1-(methylsulfonyl)pentan-3-yl-
)-2-oxopiperidin-3-yl)acetic acid; [0471]
2-(5-(3-chlorophenyl)-6-(4-chlorophenyl)-2-oxo-1-(1-(pyridin-2-yl)pentan--
3-yl)piperidin-3-yl)acetic acid; [0472]
2-(5-(3-Chlorophenyl)-6-(4-chlorophenyl)-1-(1-(ethylamino)-1-oxobutan-2-y-
l)-2-oxopiperidin-3-yl)acetic acid; [0473]
2-(5-(3-Chlorophenyl)-6-(4-chlorophenyl)-1-(1-(5-methyl-1,3,4-oxadiazol-2-
-yl)propyl)-2-oxopiperidin-3-yl)acetic; [0474]
2-(5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-(cyclopropylmethyl)-2-oxopiper-
idin-3-yl)acetic acid; [0475]
2-(5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-(cyclobutylmethyl)-2-oxopiperi-
din-3-yl)acetic acid; [0476]
2-(5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-(2-ethylbutyl)-2-oxopiperidin--
3-yl)acetic acid; [0477]
2-(5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-(cyclopentylmethyl)-2-oxopiper-
idin-3-yl)acetic acid; [0478]
2-(5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((2,2-dimethylcyclopentyl)meth-
yl)-2-oxopiperidin-3-yl)acetic acid; [0479]
2-(5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-(cyclohexylmethyl)-2-oxopiperi-
din-3-yl)acetic acid; [0480]
2-(5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-(cyclopropylmethyl)-2-oxopiper-
idin-3-yl)acetic acid; [0481]
2-(5-(3-chlorophenyl)-6-(4-chlorophenyl)-2-oxo-1-propylpiperidin-3-yl)ace-
tic acid; [0482]
2-(5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-(cyclobutylmethyl)-2-oxopiperi-
din-3-yl)acetic acid; [0483]
2-(5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-isobutyl-2-oxopiperidin-3-yl)a-
cetic acid; [0484]
2-(5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-(cyclopentylmethyl)-2-oxopiper-
idin-3-yl)acetic acid; [0485]
2-(5-(3-chlorophenyl)-6-(4-chlorophenyl)-2-oxo-1-(pentan-3-yl)piperidin-3-
-yl)acetic acid; [0486] Methyl
2-(5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-(cyclopropylmethyl)-2-oxopiper-
idin-3-yl)acetate; [0487]
2-(5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-(cyclopropylmethyl)-2-oxopiper-
idin-3-yl)acetamide; [0488] Ethyl
2-(2-(5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-(cyclopropylmethyl)-2-oxopi-
peridin-3-yl)acetamido)acetate; [0489]
2-(2-(5-(3-Chlorophenyl)-6-(4-chlorophenyl)-1-(cyclopropylmethyl)-2-oxopi-
peridin-3-yl)acetamido)acetic acid; [0490]
2-(5-(3-Chlorophenyl)-6-(4-chlorophenyl)-1-(cyclopropylmethyl)-2-oxopiper-
idin-3-yl)acetohydrazide; [0491]
2-(5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-(cyclopropylmethyl)-2-oxopiper-
idin-3-yl)-N-hydroxyacetamide; [0492] Ethyl
2-(3-(3-chlorophenyl)-2-(4-chlorophenyl)-5-(2-(methylsulfonamido)-2-oxoet-
hyl)-6-oxopiperidin-1-yl)butanoate; [0493] Ethyl
2-(3-(3-chlorophenyl)-2-(4-chlorophenyl)-5-(2-((3-morpholinopropyl)amino)-
-2-oxoethyl)-6-oxopiperidin-1-yl)butanoate; [0494]
3-((1H-Tetrazol-5-yl)methyl)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-(cyc-
lopropylmethyl)piperidin-2-one; [0495]
3-((1,3,4-oxadiazol-2-yl)methyl)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1--
(cyclopropylmethyl)piperidin-2-one; [0496]
5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-(cyclopropylmethyl)-3-((5-methyl--
1,3,4-oxadiazol-2-yl)methyl)piperidin-2-one; [0497]
2-(5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-(cyclopropylmethyl)-2-oxopiper-
idin-3-yl)-N-(methylsulfonyl)acetamide; [0498]
2-(5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-(cyclopropylmethyl)-2-oxopiper-
idin-3-yl)acetamide. [0499]
3-((1H-tetrazol-5-yl)methyl)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-(cyc-
lopropylmethyl)piperidin-2-one; [0500]
5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-(cyclopropylmethyl)-3-((5-methyli-
soxazol-3-yl)methyl)piperidin-2-one; [0501]
2-(6-chloro-3'-(3-chlorophenyl)-1'-(cyclopropylmethyl)-2,6'-dioxospiro[in-
doline-3,2'-piperidine]-5'-yl)acetic acid; [0502]
2-(5-(3-chlorophenyl)-6-(5-chlorothiophen-2-yl)-1-(cyclopropylmethyl)-2-o-
xopiperidin-3-yl)acetic acid; [0503]
2-(5-(3-chlorophenyl)-6-(5-chlorothiophen-2-yl)-1-(cyclopropylmethyl)-2-o-
xopiperidin-3-yl)acetic acid; [0504]
2-(5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-(1-ethoxy-1-oxobutan-2-yl)-3-m-
ethyl-2-oxopiperidin-3-yl)acetic acid; [0505]
2-(1-(1-tert-butoxy-1-oxobutan-2-yl)-5-(3-chlorophenyl)-6-(4-chlorophenyl-
)-3-methyl-2-oxopiperidin-3-yl)acetic acid; [0506]
2-(5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-(1-(cyclopropylmethoxy)butan-2-
-yl)-3-methyl-2-oxopiperidin-3-yl)acetic acid; [0507]
2-(5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-(cyclopropylmethyl)-2-oxo-3-(2-
-(pyrrolidin-1-yl)ethyl)piperidin-3-yl)acetic acid; [0508]
2-(5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-(cyclopropylmethyl)-3-(2-morph-
olinoethyl)-2-oxopiperidin-3-yl)acetic acid; [0509]
2-(5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-2-oxo-1-(pentan-3-yl)pi-
peridin-3-yl)acetic acid; [0510]
2-(5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-(cyclopropylmethyl)-3-methyl-2-
-oxopiperidin-3-yl)acetic acid; [0511]
2-(5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-isopropyl-3-methyl-2-oxopiperi-
din-3-yl)acetic acid; [0512]
2-(5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-cyclobutyl-3-methyl-2-oxopiper-
idin-3-yl)acetic acid; [0513]
2-(5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-cyclopentyl-3-methyl-2-oxopipe-
ridin-3-yl)acetic acid; [0514]
5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-3-((5-oxo-4,5-dihydro-1H-1-
,2,4-triazol-3-yl)methyl)-1-(pentan-3-yl)piperidin-2-one; [0515]
5-((5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-2-oxo-1-(pentan-3-yl)p-
iperidin-3-yl)methyl)-1,3,4-oxadiazol-2(3H)-one; [0516]
2-(5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-2-oxo-1-(pentan-3-yl)pi-
peridin-3-yl)-N-(trifluoromethylsulfonyl)acetamide; [0517]
5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-((3-hydroxy-1H-pyrazol-5-yl)methy-
l)-3-methyl-1-(pentan-3-yl)piperidin-2-one; [0518]
5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-((3-hydroxyisoxazol-5-yl)methyl)--
3-methyl-1-(pentan-3-yl)piperidin-2-one; [0519]
5-((5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-2-oxo-1-(pentan-3-yl)p-
iperidin-3-yl)methyl)oxazolidine-2,4-dione; [0520]
3-((5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-2-oxo-1-(pentan-3-yl)p-
iperidin-3-yl)methyl)-1,2,4-oxadiazol-5(4H)-one; [0521]
3-((5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-isopropyl-3-methyl-2-oxopiper-
idin-3-yl)methyl)-1,2,4-oxadiazol-5(4H)-one; [0522]
3-((5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-2-oxo-1-(pentan-3-yl)p-
iperidin-3-yl)methyl)-1,2,4-thiadiazol-5(4H)-one; [0523]
3-((5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-isopropyl-3-methyl-2-oxopiper-
idin-3-yl)methyl)-1,2,4-thiadiazol-5(4H)-one; [0524]
3-((1H-Tetrazol-5-yl)methyl)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-isop-
ropyl-3-methylpiperidin-2-one; [0525]
2-(5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-ethyl-2-oxo-1-(pentan-3-yl)pip-
eridin-3-yl)acetic acid; [0526]
5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-3-(methylsulfonylmethyl)-1-
-(pentan-3-yl)piperidin-2-one; [0527]
2-(5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-(1-(3-cyclopropyl-1,2,4-oxadia-
zol-5-yl)propyl)-3-methyl-2-oxopiperidin-3-yl)acetic acid; [0528]
2-(5-(3-Chlorophenyl)-6-(4-chlorophenyl)-3-methyl-1-(1-morpholinobutan-2--
yl)-2-oxopiperidin-3-yl)acetic acid; [0529]
2-(5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-2-oxo-1-(1-(2,2,2-trifl-
uoroethylamino)butan-2-yl)piperidin-3-yl)acetic acid; [0530]
2-(5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-(1-(2,2-dimethylmorpholino)but-
an-2-yl)-3-methyl-2-oxopiperidin-3-yl)acetic acid; [0531]
2-(5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-(1-(2,6-dimethylmorpholino)but-
an-2-yl)-3-methyl-2-oxopiperidin-3-yl)acetic acid; [0532]
2-(5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-(1-(4-(cyclopropylsulfonyl)pip-
erazin-1-yl)butan-2-yl)-3-methyl-2-oxopiperidin-3-yl)acetic acid;
[0533]
2-(5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-1-(1-(4-(methylsulfonyl-
)piperazin-1-yl)butan-2-yl)-2-oxopiperidin-3-yl)acetic acid; [0534]
2-(1-(1-(4-acetylpiperazin-1-yl)butan-2-yl)-5-(3-chlorophenyl)-6-(4-chlor-
ophenyl)-3-methyl-2-oxopiperidin-3-yl)acetic acid; [0535]
2-(5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-(1-(4-(cyclopropanecarbonyl)pi-
perazin-1-yl)butan-2-yl)-3-methyl-2-oxopiperidin-3-yl)acetic acid;
[0536]
3-((5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-1-(1-morpholinobutan-2-
-yl)-2-oxopiperidin-3-yl)methyl)-1,2,4-oxadiazol-5(4H)-one; [0537]
2-(5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-(1-(5,5-dimethyl-2-oxooxazolid-
in-3-yl)butan-2-yl)-3-methyl-2-oxopiperidin-3-yl)acetic acid;
[0538]
2-(1-(1-(tert-butylamino)-1-oxobutan-2-yl)-5-(3-chlorophenyl)-6-(4-chloro-
phenyl)-3-methyl-2-oxopiperidin-3-yl)acetic acid; [0539]
2-(5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-(2,3-dihydroxycyclopentyl)-3-m-
ethyl-2-oxopiperidin-3-yl)acetic acid; [0540]
2-(5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-2-oxo-1'-(2,2,2-trifluo-
roethyl)-1,3'-bipiperidin-3-yl)acetic acid; [0541]
2-(5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-(3-hydroxycyclopentyl)-3-methy-
l-2-oxopiperidin-3-yl)acetic acid; [0542]
2-(5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-2-oxo-1-(tetrahydro-2H--
pyran-3-yl)piperidin-3-yl)acetic acid; [0543]
2-(5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-2-oxo-1-(pyrazin-2-yl)p-
iperidin-3-yl)acetic acid; [0544]
2-(5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-1-(1-methyl-1H-pyrazol--
4-yl)-2-oxopiperidin-3-yl)acetic acid; [0545]
2-(5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-2-oxo-1-(pyrimidin-4-yl-
)piperidin-3-yl)acetic acid; [0546]
2-(5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-(2-chloropyrimidin-4-yl)-3-met-
hyl-2-oxopiperidin-3-yl)acetic acid; [0547]
2-(5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-2-oxo-1-(pyrimidin-2-yl-
)piperidin-3-yl)acetic acid; [0548]
2-(5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-1-(3-methylpyridin-2-yl-
)-2-oxopiperidin-3-yl)acetic acid; [0549]
2-(5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-1-(4-methylpyridin-2-yl-
)-2-oxopiperidin-3-yl)acetic acid; [0550]
2-(5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-(dicyclopropylmethyl)-3-methyl-
-2-oxopiperidin-3-yl)acetic acid; [0551]
(4-(3-chlorophenyl)-3-(4-chlorophenyl)-1,1-dioxido-2-(2-propanyl)-1,2-thi-
azinan-6-yl)acetic acid; [0552]
(4-(3-chlorophenyl)-3-(4-chlorophenyl)-6-methyl-1,1-dioxido-2-(2-propanyl-
)-1,2-thiazinan-6-yl)acetic acid; [0553]
2-(5-(3-chlorophenyl)-6-(5-chloropyridin-2-yl)-3-methyl-1-(1-morpholinobu-
tan-2-yl)-2-oxopiperidin-3-yl)acetic acid; [0554]
2-(5-(3-Chlorophenyl)-6-(5-chloropyridin-2-yl)-3-methyl-2-oxo-1-(pentan-3-
-yl)piperidin-3-yl)acetic acid; [0555]
2-(1-(1-tert-butoxy-1-oxobutan-2-yl)-5-(3-chlorophenyl)-6-(5-chloropyridi-
n-2-yl)-3-methyl-2-oxopiperidin-3-yl)acetic acid; or [0556]
2-(1-(1-tert-butoxy-1-oxobutan-2-yl)-6-(4-chlorophenyl)-5-(4-chloropyridi-
n-2-yl)-3-methyl-2-oxopiperidin-3-yl)acetic acid.
[0557] In another aspect, the present invention provides a
compound, or a pharmaceutically acceptable salt thereof, selected
from: [0558]
2-(5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-(1-(N-methylcyclopropanesulfon-
amido)butan-2-yl)-2-oxopiperidin-3-yl)acetic acid; [0559]
5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-(1-(N-methylcyclopropanesulfonami-
do)butan-2-yl)-2-oxopiperidin-3-yl)propanoic acid; [0560]
tert-butyl
2-(3-((1H-tetrazol-5-yl)methyl)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-m-
ethyl-2-oxopiperidin-1-yl)butanoate; [0561]
2-(5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-1-(1-(methylsulfonamido-
)butan-2-yl)-2-oxopiperidin-3-yl)acetic acid; [0562]
2-(5-(3-Chlorophenyl)-6-(4-chlorophenyl)-3-methyl-2-oxo-1-(5-oxohexan-3-y-
l)piperidin-3-yl)acetic acid; [0563]
2-(5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-(5-hydroxy-5-methylhexan-3-yl)-
-3-methyl-2-oxopiperidin-3-yl)acetic acid; [0564]
2-(5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-2-oxo-1-(6,6,6-trifluor-
o-5-hydroxy-5-methylhexan-3-yl)piperidin-3-yl)acetic acid; [0565]
2-(5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-1-(1-(N-methylmethylsul-
fonamido)butan-2-yl)-2-oxopiperidin-3-yl)acetic acid; [0566]
2-(5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-(5-cyclopropyl-6,6,6-trifluoro-
-5-hydroxyhexan-3-yl)-3-methyl-2-oxopiperidin-3-yl)acetic acid;
[0567]
2-(5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-(6-hydroxy-6-methylheptan-3-yl-
)-3-methyl-2-oxopiperidin-3-yl)acetic acid; [0568]
2-(5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-2-oxo-1-(6,6,6-trifluor-
o-5,5-dihydroxyhexan-3-yl)piperidin-3-yl)acetic acid; [0569]
2-(5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-2-oxo-1-(7,7,7-trifluor-
o-6-hydroxy-6-methylheptan-3-yl)piperidin-3-yl)acetic acid; [0570]
2-(5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-(7-hydroxy-7-methyloctan-3-yl)-
-3-methyl-2-oxopiperidin-3-yl)acetic acid; [0571]
2-(5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-1-(1-(N-methylcycloprop-
anesulfonamido)butan-2-yl)-2-oxopiperidin-3-yl)acetic acid; [0572]
2-(5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-(1-(N-cyclopropylmethylsulfona-
mido)butan-2-yl)-3-methyl-2-oxopiperidin-3-yl)acetic acid; [0573]
2-(5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-2-oxo-1-(6,6,6-trifluor-
o-5-hydroxyhexan-3-yl)piperidin-3-yl)acetic acid; [0574]
2-(5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-(5-hydroxyhexan-3-yl)-3-methyl-
-2-oxopiperidin-3-yl)acetic acid; [0575]
2-(5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-2-oxo-1-(1-(N-(2,2,2-tr-
ifluoroethyl)methylsulfonamido)butan-2-yl)piperidin-3-yl)acetic
acid; [0576]
2-(5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-(1-(1,1-dioxidoisothiaz-
olidin-2-yl)butan-2-yl)-3-methyl-2-oxopiperidin-3-yl)acetic acid;
[0577]
2-(5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-(5-hydroxy-4,5-dimethylhexan-3-
-yl)-3-methyl-2-oxopiperidin-3-yl)acetic acid; [0578]
2-(5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-(5-cyano-5-methylhexan-3-yl)-3-
-methyl-2-oxopiperidin-3-yl)acetic acid; [0579]
2-(5-(3-Chlorophenyl)-6-(4-chlorophenyl)-3-methyl-2-oxo-1-(2-oxopentan-3--
yl)piperidin-3-yl)acetic acid; [0580]
2-(5-(3-Chlorophenyl)-6-(4-chlorophenyl)-1-(2-hydroxypentan-3-yl)-3-methy-
l-2-oxopiperidin-3-yl)acetic acid; [0581]
2-(5-(3-Chlorophenyl)-6-(4-chlorophenyl)-1-(2-methoxypentan-3-yl)-3-methy-
l-2-oxopiperidin-3-yl)acetic acid; [0582]
2-(5-(3-Chlorophenyl)-6-(4-chlorophenyl)-1-(2-hydroxypentan-3-yl)-3-methy-
l-2-oxopiperidin-3-yl)acetic acid; [0583]
2-(5-(3-Chlorophenyl)-6-(4-chlorophenyl)-1-(2-hydroxy-2-methylpentan-3-yl-
)-3-methyl-2-oxopiperidin-3-yl)acetic acid; [0584]
2-(5-(3-Chlorophenyl)-6-(4-chlorophenyl)-1-(4-hydroxyhexan-3-yl)-3-methyl-
-2-oxopiperidin-3-yl)acetic acid; [0585]
2-(5-(3-Chlorophenyl)-6-(4-chlorophenyl)-1-(1-methoxybutan-2-yl)-3-methyl-
-2-oxopiperidin-3-yl)acetic acid; [0586]
2-(5-(3-Chlorophenyl)-6-(4-chlorophenyl)-3-methyl-2-oxo-1-(1,1,1-trifluor-
o-2-hydroxy-2-methylpentan-3-yl)piperidin-3-yl)acetic acid; [0587]
2-(5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-1-(1-(N-methylcycloprop-
anesulfonamido)butan-2-yl)-2-oxopiperidin-3-yl)acetamide; [0588]
2-(5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-1-(1-(N-methylcycloprop-
anesulfonamido)butan-2-yl)-2-oxopiperidin-3-yl)-N-(methylsulfonyl)acetamid-
e; [0589]
2-(5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-1-(1-(N-methyl-
cyclopropanesulfonamido)butan-2-yl)-2-oxopiperidin-3-yl)-N-(3-hydroxypropy-
l)acetamide; [0590]
2-(5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-1-(1-(N-methylcycloprop-
anesulfonamido)butan-2-yl)-2-oxopiperidin-3-yl)-N-(2-hydroxyethyl)acetamid-
e; [0591]
2-(5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-1-(1-(N-methyl-
cyclopropanesulfonamido)butan-2-yl)-2-oxopiperidin-3-yl)-N-hydroxyacetamid-
e; [0592]
2-(5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-1-(1-(N-methyl-
cyclopropanesulfonamido)butan-2-yl)-2-oxopiperidin-3-yl)-N-methoxyacetamid-
e; [0593]
2-(5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-1-(1-(N-methyl-
cyclopropanesulfonamido)butan-2-yl)-2-oxopiperidin-3-yl)-N-(2,3-dihydroxyp-
ropyl)acetamide; [0594]
2-(5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-1-(1-(N-methylcycloprop-
anesulfonamido)butan-2-yl)-2-oxopiperidin-3-yl)-N-(2,3-dihydroxypropyl)ace-
tamide; [0595]
2-(5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-1-(1-(N-methylcycloprop-
anesulfonamido)butan-2-yl)-2-oxopiperidin-3-yl)-N-cyanoacetamide;
[0596]
2-(5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-1-(1-(N-methylcycloprop-
anesulfonamido)butan-2-yl)-2-oxopiperidin-3-yl)-N-(2-(dimethylamino)ethyl)-
acetamide; [0597]
2-(5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-1-(1-(N-methylcycloprop-
anesulfonamido)butan-2-yl)-2-oxopiperidin-3-yl)-N-(3,4-dihydroxybutyl)acet-
amide; [0598]
2-(5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-(1-(cyclopropanesulfonamido)bu-
tan-2-yl)-3-methyl-2-oxopiperidin-3-yl)acetic acid; [0599]
2-(5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-1-(1-(N-methylcycloprop-
anesulfonamido)butan-2-yl)-2-oxopiperidin-3-yl)propanoic acid;
[0600]
2-(5-(3-Chlorophenyl)-6-(4-chlorophenyl)-1-(2-(cyclopropanesulfonamido)pe-
ntan-3-yl)-3-methyl-2-oxopiperidin-3-yl)acetic acid; [0601]
2-(5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-1-(2-(1-methylethylsulf-
onamido)pentan-3-yl)-2-oxopiperidin-3-yl)acetic acid; [0602]
2-(5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-1-(1-(N-methylcycloprop-
anesulfonamido)-1-oxobutan-2-yl)-2-oxopiperidin-3-yl)acetic acid;
[0603]
2-(5-(3-Chlorophenyl)-6-(4-chlorophenyl)-3-methyl-1-(1-(neopentylamino)-1-
-oxobutan-2-yl)-2-oxopiperidin-3-yl)acetic acid; [0604]
2-(5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-(1-(4,4-dimethyl-4,5-dihydroox-
azol-2-yl)propyl)-3-methyl-2-oxopiperidin-3-yl)acetic acid; [0605]
2-(5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-2-oxo-1-(1-(N-(2,2,2-tr-
ifluoroethyl)acetamido)butan-2-yl)piperidin-3-yl)acetic acid;
[0606]
2-(5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-(1-(1,1-dimethylethylsulfonami-
do)butan-2-yl)-3-methyl-2-oxopiperidin-3-yl)acetic acid [0607]
2-(5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-(1-(N,2-dimethylpropan-2-ylsul-
fonamido)butan-2-yl)-3-methyl-2-oxopiperidin-3-yl)acetic acid;
[0608]
2-(5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-1-(1-(1-methylethylsulf-
onamido)butan-2-yl)-2-oxopiperidin-3-yl)acetic acid; [0609]
2-(5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-(1-(N-ethylpropan-2-ylsulfonam-
ido)butan-2-yl)-3-methyl-2-oxopiperidin-3-yl)acetic acid; [0610]
2-(5-(3-Chlorophenyl)-6-(4-chlorophenyl)-1-(1-hydroxybutan-2-yl)-3-methyl-
-2-oxopiperidin-3-yl)acetic acid; [0611]
2-(5-(3-Chlorophenyl)-6-(4-chlorophenyl)-3-methyl-2-oxo-1-(1-(trifluorome-
thylsulfonamido)butan-2-yl)piperidin-3-yl)acetic acid; [0612]
2-(5-(3-Chlorophenyl)-6-(4-chlorophenyl)-1-(1-(4-chlorophenylsulfonamido)-
butan-2-yl)-3-methyl-2-oxopiperidin-3-yl)acetic acid; [0613]
2-(5-(3-Chlorophenyl)-6-(4-chlorophenyl)-3-methyl-1-(1-(4-methylphenylsul-
fonamido)butan-2-yl)-2-oxopiperidin-3-yl)acetic acid; [0614]
2-(5-(3-Chlorophenyl)-6-(4-chlorophenyl)-1-(1-(2-chlorophenylsulfonamido)-
butan-2-yl)-3-methyl-2-oxopiperidin-3-yl)acetic acid; [0615]
2-(5-(3-Chlorophenyl)-6-(4-chlorophenyl)-1-(1-(2-methylphenylsulfonamido)-
butan-2-yl)-3-methyl-2-oxopiperidin-3-yl)acetic acid; [0616]
2-(5-(3-Chlorophenyl)-6-(4-chlorophenyl)-1-(1-(4-methoxyphenylsulfonamido-
)butan-2-yl)-3-methyl-2-oxopiperidin-3-yl)acetic acid; [0617]
2-(5-(3-Chlorophenyl)-6-(4-chlorophenyl)-1-(1-(phenylsulfonamido)butan-2--
yl)-3-methyl-2-oxopiperidin-3-yl)acetic acid; [0618]
2-(5-(3-Chlorophenyl)-6-(4-chlorophenyl)-1-(1-(1-methylcyclopropanesulfon-
amido)butan-2-yl)-3-methyl-2-oxopiperidin-3-yl)acetic acid; [0619]
2-(5-(3-Chlorophenyl)-6-(4-chlorophenyl)-1-(1-(1,1-dioxidobenzo[d]isothia-
zol-2(3H)-yl)butan-2-yl)-3-methyl-2-oxopiperidin-3-yl)acetic acid;
[0620]
2-(5-(3-Chlorophenyl)-6-(4-chlorophenyl)-1-(1-(3,3-dimethyl-1,1-dioxidobe-
nzo[d]isothiazol-2(3H)-yl)butan-2-yl)-3-methyl-2-oxopiperidin-3-yl)acetic
acid; [0621]
2-(5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-2-oxo-1-(1-(pyridine-3--
sulfonamido)butan-2-yl)piperidin-3-yl)acetic acid; [0622]
2-(5-(3-Chlorophenyl)-6-(4-chlorophenyl)-1-(1-(4-cyanophenylsulfonamido)b-
utan-2-yl)-3-methyl-2-oxopiperidin-3-yl)acetic acid; [0623]
2-(5-(3-Chlorophenyl)-6-(4-chlorophenyl)-1-(1-(3-cyanophenylsulfonamido)b-
utan-2-yl)-3-methyl-2-oxopiperidin-3-yl)acetic acid; [0624]
2-(5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-2-oxo-1-(1-(pyridine-2--
sulfonamido)butan-2-yl)piperidin-3-yl)acetic acid; [0625]
2-(5-(3-Chlorophenyl)-6-(4-chlorophenyl)-1-(1-(N,1-dimethylcyclopropanesu-
lfonamido)butan-2-yl)-3-methyl-2-oxopiperidin-3-yl)acetic acid;
[0626]
3-(5-(3-Chlorophenyl)-6-(4-chlorophenyl)-3-methyl-1-(1-(N-methylcycloprop-
anesulfonamido)butan-2-yl)-2-oxopiperidin-3-yl)propanoic acid;
[0627]
2-(5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-ethyl-1-(1-(N-methylcyclopropa-
nesulfonamido)butan-2-yl)-2-oxopiperidin-3-yl)acetic acid; [0628]
2-(5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methoxy-1-(1-(N-methylcyclopro-
panesulfonamido)butan-2-yl)-2-oxopiperidin-3-yl)acetic acid; [0629]
2-(5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-1-(6-methyl-4-oxoheptan-
-3-yl)-2-oxopiperidin-3-yl)acetic acid; [0630]
2-(5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-(1-(ethylsulfonyl)pentan-3-yl)-
-3-methyl-2-oxopiperidin-3-yl)acetic acid; [0631]
2-(5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-(1-(isopropylsulfonyl)pentan-3-
-yl)-3-methyl-2-oxopiperidin-3-yl)acetic acid; [0632]
2-(5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-(1-(cyclopropylmethylsulfonyl)-
pentan-3-yl)-3-methyl-2-oxopiperidin-3-yl)acetic acid; [0633]
2-(5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-2-oxo-1-(1-(2-oxopyrrol-
idin-1-yl)butan-2-yl)piperidin-3-yl)acetic acid; [0634]
2-(1-(1-(2-oxa-5-azabicyclo[2.2.1]heptan-5-yl)butan-2-yl)-5-(3-chlorophen-
yl)-6-(4-chlorophenyl)-3-methyl-2-oxopiperidin-3-yl)acetic acid;
[0635]
2-(5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-1-(1-(3-methylmorpholin-
o)butan-2-yl)-2-oxopiperidin-3-yl)acetic acid; [0636]
2-(5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-(1-(thiomorpholino-1,1-dioxide-
)butan-2-yl)-3-methyl-2-oxopiperidin-3-yl)acetic acid; [0637]
2-(5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-(1-(3,3-difluoroazetidin-1-yl)-
butan-2-yl)-3-methyl-2-oxopiperidin-3-yl)acetic acid; [0638]
2-(1-(1-(8-oxa-3-azabicyclo[3.2.1]octan-3-yl)butan-2-yl)-5-(3-chloropheny-
l)-6-(4-chlorophenyl)-3-methyl-2-oxopiperidin-3-yl)acetic acid;
[0639]
2-(5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-(1-(3,3-dimethylmorpholino)but-
an-2-yl)-3-methyl-2-oxopiperidin-3-yl)acetic acid; [0640]
2-(5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-(1-(3-hydroxy-3-(trifluorometh-
yl)azetidin-1-yl)butan-2-yl)-3-methyl-2-oxopiperidin-3-yl)acetic
acid; [0641]
2-(5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-1-(1-(methyl(oxe-
tan-3-yl)amino)butan-2-yl)-2-oxopiperidin-3-yl)acetic acid; [0642]
2-(5-(3-Chlorophenyl)-6-(4-chlorophenyl)-3-methyl-2-oxo-1-(1-(2-oxooxazol-
idin-3-yl)butan-2-yl)piperidin-3-yl)acetic acid; [0643]
2-(5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-2-oxo-1-(1-(2-oxopyridi-
n-1(2H)-yl)butan-2-yl)piperidin-3-yl)acetic acid; [0644]
2-(5-(3-Chlorophenyl)-6-(4-chlorophenyl)-3-methyl-2-oxo-1-(1-(2-oxo-5-(tr-
ifluoromethyl)pyridin-1(2H)-yl)butan-2-yl)piperidin-3-yl)acetic
acid; [0645]
3-allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-1-(1-(pyrid-
in-3-yloxy)butan-2-yl)piperidin-2-one; [0646]
2-(5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-2-oxo-1-(1-(tetrahydrof-
uran-2-yl)propyl)piperidin-3-yl)acetic acid; [0647]
2-(5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-2-oxo-1-(1-(5-oxotetrah-
ydrofuran-2-yl)propyl)piperidin-3-yl)acetic acid; [0648]
2-(5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-2-oxo-1-(1-(tetrahydro--
2H-pyran-2-yl)propyl)piperidin-3-yl)acetic acid; [0649]
2-(1-(1-(benzo[d]thiazol-2-yl)propyl)-5-(3-chlorophenyl)-6-(4-chloropheny-
l)-3-methyl-2-oxopiperidin-3-yl)acetic acid; [0650]
2-(5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-1-(1-(3-methylisoxazol--
5-yl)propyl)-2-oxopiperidin-3-yl)acetic acid; [0651]
2-(5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-(1-(6-chloropyridin-2-yl)propy-
l)-3-methyl-2-oxopiperidin-3-yl)acetic acid; [0652]
2-(5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-2-oxo-1-(1-(pyridin-2-y-
l)propyl)piperidin-3-yl)acetic acid; [0653]
2-(5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-2-oxo-1-(1-(pyridin-2-y-
l)butyl)piperidin-3-yl)acetic acid; [0654]
2-(5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-(2-cyclopropyl-1-(pyridin-2-yl-
)ethyl)-3-methyl-2-oxopiperidin-3-yl)acetic acid; [0655]
2-(5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-2-oxo-1-(1-(pyridin-3-y-
l)propyl)piperidin-3-yl)acetic acid; [0656]
2-(5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-2-oxo-1-(1-(pyrazin-2-y-
l)propyl)piperidin-3-yl)acetic acid; [0657]
2-(5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-2-oxo-1-(1-(pyrimidin-2-
-yl)propyl)piperidin-3-yl)acetic acid; [0658]
2-(5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-1-(1-(6-methylpyridin-2-
-yl)propyl)-2-oxopiperidin-3-yl)acetic acid; [0659]
2-(5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-2-oxo-1-(1-(pyridin-4-y-
l)propyl)piperidin-3-yl)acetic acid; [0660]
2-(5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-2-oxo-1-(1-(6-(trifluor-
omethyl)pyridin-2-yl)propyl)piperidin-3-yl)acetic acid; [0661]
2-(1-(1-(6-bromopyridin-2-yl)propyl)-5-(3-chlorophenyl)-6-(4-chlorophenyl-
)-3-methyl-2-oxopiperidin-3-yl)acetic acid; [0662]
2-(5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-2-oxo-1-(1-(thiazol-2-y-
l)propyl)piperidin-3-yl)acetic acid; [0663]
2-(5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-(1-(6-(2-hydroxypropan-2-yl)py-
ridin-2-yl)propyl)-3-methyl-2-oxopiperidin-3-yl)acetic acid; [0664]
2-(5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-(1-(6-cyclopropylpyridin-2-yl)-
propyl)-3-methyl-2-oxopiperidin-3-yl)acetic acid; [0665]
2-(5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-2-oxo-1-(3,3,3-trifluor-
o-1-(pyridin-2-yl)propyl)piperidin-3-yl)acetic acid; [0666]
2-(5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-(2-methyl-1-(pyridin-2--
yl)propyl)-2-oxopiperidin-3-yl)acetic acid; [0667]
3-((1H-tetrazol-5-yl)methyl)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-meth-
yl-1-(pentan-3-yl)piperidin-2-one; [0668]
5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-(2,3-dihydroxypropyl)-1-(2-hydrox-
ypentan-3-yl)-3-methylpiperidin-2-one; [0669]
2-(5-(3-Chlorophenyl)-6-(4-chlorophenyl)-1-(1-hydroxybutan-2-yl)-3-methyl-
-2-oxopiperidin-3-yl)cyclopropanecarboxylic acid;
[0670]
2-(1-(2-(tert-Butoxy)-1-cyclopropyl-2-oxoethyl)-5-(3-chlorophenyl)-
-6-(4-chlorophenyl)-2-oxopiperidin-3-yl)acetic acid; [0671]
2-(5-(3-Chlorophenyl)-6-(4-chlorophenyl)-1-(1-cyclopropyl-2-ethoxy-2-oxoe-
thyl)-3-methyl-2-oxopiperidin-3-yl)acetic acid; [0672]
2-(5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-(1-cyclopropyl-2-hydroxyethyl)-
-3-methyl-2-oxopiperidin-3-yl)acetic acid; [0673]
2-(5-(3-Chlorophenyl)-6-(4-chlorophenyl)-1-(1-cyclopropyl-2-hydroxybutyl)-
-3-methyl-2-oxopiperidin-3-yl)acetic acid; [0674]
2-(5-(3-Chlorophenyl)-6-(4-chlorophenyl)-1-(1-cyclopropyl-2-(N-methylcycl-
opropanesulfonamido)ethyl)-3-ethyl-2-oxopiperidin-3-yl)acetic acid;
[0675]
2-(5-(3-Chlorophenyl)-6-(4-chlorophenyl)-1-(2-(cyclopropanesulfonamido)-1-
-cyclopropylethyl)-3-ethyl-2-oxopiperidin-3-yl)acetic acid; [0676]
2-(5-(3-Chlorophenyl)-6-(4-chlorophenyl)-1-(1-cyclopropyl-2-(ethylsulfona-
mido)ethyl)-3-ethyl-2-oxopiperidin-3-yl)acetic acid; [0677]
2-(5-(3-Chlorophenyl)-6-(4-chlorophenyl)-1-(1-cyclopropyl-2-(N-methylcycl-
opropanesulfonamido)ethyl)-3-methyl-2-oxopiperidin-3-yl)acetic
acid; [0678]
2-(5-(3-Chlorophenyl)-6-(4-chlorophenyl)-1-(1-cyclopropyl-2-hydrox-
ypropyl)-3-methyl-2-oxopiperidin-3-yl)acetic acid; [0679]
2-(5-(3-Chlorophenyl)-6-(4-chlorophenyl)-1-(1-cyclopropyl-2-(1-methylethy-
lsulfonamido)ethyl)-3-methyl-2-oxopiperidin-3-yl)acetic acid;
[0680]
2-(5-(3-Chlorophenyl)-6-(4-chlorophenyl)-1-(1-cyclopropyl-2-(N-methylcycl-
opropanesulfonamido)ethyl)-3-methyl-2-oxopiperidin-3-yl)acetic
acid; [0681]
2-(5-(3-Chlorophenyl)-6-(4-chlorophenyl)-1-(2-hydroxy-4-methylpent-
an-3-yl)-3-methyl-2-oxopiperidin-3-yl)acetic acid; or [0682]
2-(5-(3-Chlorophenyl)-6-(4-chlorophenyl)-1-(cyclopropyl(pyridin-2-yl)meth-
yl)-3-methyl-2-oxopiperidin-3-yl)acetic acid.
[0683] In another aspect, the present invention provides a
compound, or a pharmaceutically acceptable salt thereof, selected
from: [0684]
2-((3S,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-(N-methylcyc-
lopropanesulfonamido)butan-2-yl)-2-oxopiperidin-3-yl)acetic acid;
[0685]
2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-(1,1-dioxido-
isothiazolidin-2-yl)butan-2-yl)-3-methyl-2-oxopiperidin-3-yl)acetic
acid; [0686]
2-((3R,5R,6S)-5-(3-Chlorophenyl)-6-(4-chlorophenyl)-1-((2S,3S)-2-h-
ydroxypentan-3-yl)-3-methyl-2-oxopiperidin-3-yl)acetic acid; [0687]
2-((3R,5R,6S)-5-(3-Chlorophenyl)-6-(4-chlorophenyl)-1-((2R,3S)-2-hydroxyp-
entan-3-yl)-3-methyl-2-oxopiperidin-3-yl)acetic acid; [0688]
2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-(1,1-dimethy-
lethylsulfonamido)butan-2-yl)-3-methyl-2-oxopiperidin-3-yl)acetic
acid [0689]
2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-(N,2--
dimethylpropan-2-ylsulfonamido)butan-2-yl)-3-methyl-2-oxopiperidin-3-yl)ac-
etic acid; [0690]
2-((3R,5R,6S)-5-(3-Chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-(N,1-dimethy-
lcyclopropanesulfonamido)butan-2-yl)-3-methyl-2-oxopiperidin-3-yl)acetic
acid; [0691]
2-((3R,5R,6S)-5-(3-Chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-cyclopropyl--
2-(N-methylcyclopropanesulfonamido)ethyl)-3-methyl-2-oxopiperidin-3-yl)ace-
tic acid; [0692]
2-((3R,5R,6S)-5-(3-Chlorophenyl)-6-(4-chlorophenyl)-1-((1S,2R)-1-cyclopro-
pyl-2-hydroxypropyl)-3-methyl-2-oxopiperidin-3-yl)acetic acid; or
[0693]
2-((3R,5R,6S)-5-(3-Chlorophenyl)-6-(4-chlorophenyl)-1-((1S,2S)-1-cyclopro-
pyl-2-hydroxypropyl)-3-methyl-2-oxopiperidin-3-yl)acetic acid.
[0694] In another aspect, the present invention provides a
compound, or a pharmaceutically acceptable salt thereof, selected
from: [0695]
2-(5-(3-Chlorophenyl)-6-(4-chlorophenyl)-1-(1-(N-methylcyclopropanesulfon-
amido)butan-2-yl)-2-oxopiperidin-3-yl)acetic acid; [0696]
2-(5-(3-Chlorophenyl)-6-(4-chlorophenyl)-1-(1-(1,1-dioxidoisothiazolidin--
2-yl)butan-2-yl)-3-methyl-2-oxopiperidin-3-yl)acetic acid; [0697]
2-(5-(3-Chlorophenyl)-6-(4-chlorophenyl)-1-(2-hydroxypentan-3-yl)-3-methy-
l-2-oxopiperidin-3-yl)acetic acid; [0698]
2-(5-(3-Chlorophenyl)-6-(4-chlorophenyl)-1-(2-hydroxypentan-3-yl)-3-methy-
l-2-oxopiperidin-3-yl)acetic acid; [0699]
2-(5-(3-Chlorophenyl)-6-(4-chlorophenyl)-1-(1-(1,1-dimethylethylsulfonami-
do)butan-2-yl)-3-methyl-2-oxopiperidin-3-yl)acetic acid [0700]
2-(5-(3-Chlorophenyl)-6-(4-chlorophenyl)-1-(1-(N,2-dimethylpropan-2-ylsul-
fonamido)butan-2-yl)-3-methyl-2-oxopiperidin-3-yl)acetic acid;
[0701]
2-(5-(3-Chlorophenyl)-6-(4-chlorophenyl)-1-(1-(N,1-dimethylcyclopropanesu-
lfonamido)butan-2-yl)-3-methyl-2-oxopiperidin-3-yl)acetic acid;
[0702]
2-(5-(3-Chlorophenyl)-6-(4-chlorophenyl)-1-(1-cyclopropyl-2-(N-methylcycl-
opropanesulfonamido)ethyl)-3-methyl-2-oxopiperidin-3-yl)acetic
acid; or [0703]
2-(5-(3-Chlorophenyl)-6-(4-chlorophenyl)-1-(1-cyclopropyl-2-hydrox-
ypropyl)-3-methyl-2-oxopiperidin-3-yl)acetic acid.
[0704] In another aspect, the present invention provides a
compound, or a pharmaceutically acceptable salt thereof, selected
from: [0705]
2-((3R,5R,6S)-5-(3-Chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-cyclopropyl--
2-(thiophene-2-sulfonamido)ethyl)-3-methyl-2-oxopiperidin-3-yl)acetic
acid; [0706]
2-((3R,5R,6S)-5-(3-Chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-cyclopropyl--
2-(N-methylthiophene-2-sulfonamido)ethyl)-3-methyl-2-oxopiperidin-3-yl)ace-
tic acid; [0707]
2-((3R,5R,6S)-5-(3-Chlorophenyl)-6-(4-chlorophenyl)-1-((S)-2-(5-chlorothi-
ophene-2-sulfonamido)-1-cyclopropylethyl)-3-methyl-2-oxopiperidin-3-yl)ace-
tic acid; [0708]
2-((3R,5R,6S)-1-((S)-2-(5-Chloro-N-methylthiophene-2-sulfonamido)-1-cyclo-
propylethyl)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-2-oxopiperidin-
-3-yl)acetic acid; [0709]
2-((3R,5R,6S)-5-(3-Chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-cyclopropyl--
2-(N-(difluoromethyl)-2-methylpropan-2-ylsulfonamido)ethyl)-3-methyl-2-oxo-
piperidin-3-yl)acetic acid; [0710]
2-((3R,5R,6S)-5-(3-Chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-cyclopropyl--
2-(N-(difluoromethyl)ethylsulfonamido)ethyl)-3-methyl-2-oxopiperidin-3-yl)-
acetic acid; [0711]
2-((3R,5R,6S)-5-(3-Chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-cyclopropyl--
2-(N-(difluoromethyl)cyclopropanesulfonamido)ethyl)-3-methyl-2-oxopiperidi-
n-3-yl)acetic acid; [0712]
1-((3R,5R,6S)-5-(3-Chlorophenyl)-6-(4-chlorophenyl)-1-((S)-2-(cyclopropan-
esulfonamido)-1-cyclopropylethyl)-3-methyl-2-oxopiperidin-3-yl)cyclopropan-
ecarboxylic acid; [0713]
2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-cyclopropyl--
2-(N-(2-fluorophenyl)ethylsulfonamido)ethyl)-3-methyl-2-oxopiperidin-3-yl)-
acetic acid; [0714]
2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-cyclopropyl--
2-(N-(2-fluorophenyl)methylsulfonamido)ethyl)-3-methyl-2-oxopiperidin-3-yl-
)acetic acid; [0715]
2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-cyclopropyl--
2-(N-phenylcyclopropanesulfonamido)ethyl)-3-methyl-2-oxopiperidin-3-yl)ace-
tic acid; [0716]
2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-cyclopropyl--
2-(N-phenylethylsulfonamido)ethyl)-3-methyl-2-oxopiperidin-3-yl)acetic
acid; [0717]
2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-cyclopropyl--
2-(ethylsulfonamido)ethyl)-3-methyl-2-oxopiperidin-3-yl)acetic
acid; [0718]
2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-cyclo-
propyl-2-(N-(3-fluorophenyl)ethylsulfonamido)ethyl)-3-methyl-2-oxopiperidi-
n-3-yl)acetic acid; [0719]
2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((S)-2-(N-(2-cyanop-
henyl)methylsulfonamido)-1-cyclopropylethyl)-3-methyl-2-oxopiperidin-3-yl)-
acetic acid; [0720]
2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-cyclopropyl--
2-(propylsulfonamido)ethyl)-3-methyl-2-oxopiperidin-3-yl)acetic
acid; [0721]
2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-cyclo-
propyl-2-(N-phenylmethylsulfonamido)ethyl)-3-methyl-2-oxopiperidin-3-yl)ac-
etic acid; [0722]
2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((S)-2-(N-(3-cyanop-
henyl)methylsulfonamido)-1-cyclopropylethyl)-3-methyl-2-oxopiperidin-3-yl)-
acetic acid; [0723]
2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-cyclopropyl--
2-(N-(pyridin-3-yl)methylsulfonamido)ethyl)-3-methyl-2-oxopiperidin-3-yl)a-
cetic acid; [0724]
2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-cyclopropyl--
2-(N-(thiophen-2-ylmethyl)methylsulfonamido)ethyl)-3-methyl-2-oxopiperidin-
-3-yl)acetic acid; [0725]
2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-cyclopropyl--
2-(N-(3-methoxybenzyl)methylsulfonamido)ethyl)-3-methyl-2-oxopiperidin-3-y-
l)acetic acid; [0726]
2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-cyclopropyl--
2-(phenylmethylsulfonamido)ethyl)-3-methyl-2-oxopiperidin-3-yl)acetic
acid; [0727]
2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-cyclopropyl--
2-(pyridin-2-ylmethylsulfonamido)ethyl)-3-methyl-2-oxopiperidin-3-yl)aceti-
c acid; [0728]
2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-cyclopropyl--
2-(pyridin-3-ylmethylsulfonamido)ethyl)-3-methyl-2-oxopiperidin-3-yl)aceti-
c acid; [0729]
2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-cyclopropyl--
2-(N-(pyridin-2-yl)methylsulfonamido)ethyl)-3-methyl-2-oxopiperidin-3-yl)a-
cetic acid; [0730]
2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-cyclopropyl--
2-(methylsulfonamido)ethyl)-3-methyl-2-oxopiperidin-3-yl)acetic
acid; [0731]
2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-cyclo-
propyl-2-(N-ethylmethylsulfonamido)ethyl)-3-methyl-2-oxopiperidin-3-yl)ace-
tic acid; [0732]
2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-cyclopropyl--
2-(N-isopropylmethylsulfonamido)ethyl)-3-methyl-2-oxopiperidin-3-yl)acetic
acid; [0733]
2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-cyclopropyl--
2-(1-methylethylsulfonamido)ethyl)-3-ethyl-2-oxopiperidin-3-yl)acetic
acid; [0734]
2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((S)-2-(cyclobutane-
sulfonamido)-1-cyclopropylethyl)-3-ethyl-2-oxopiperidin-3-yl)acetic
acid; [0735]
2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((S)-2-(cycl-
opentanesulfonamido)-1-cyclopropylethyl)-3-ethyl-2-oxopiperidin-3-yl)aceti-
c acid; [0736]
2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-1-((S)-3-met-
hyl-1-(N-methylcyclopropanesulfonamido)butan-2-yl)-2-oxopiperidin-3-yl)ace-
tic acid; [0737]
2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-(cyclopropan-
esulfonamido)-3-methylbutan-2-yl)-3-methyl-2-oxopiperidin-3-yl)acetic
acid; [0738]
2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-(ethylsulfon-
amido)-3-methylbutan-2-yl)-3-methyl-2-oxopiperidin-3-yl)acetic
acid; [0739]
2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-(cycl-
obutanesulfonamido)butan-2-yl)-3-methyl-2-oxopiperidin-3-yl)acetic
acid; [0740]
2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-(N-et-
hylcyclobutanesulfonamido)butan-2-yl)-3-methyl-2-oxopiperidin-3-yl)acetic
acid; [0741]
2-((3R,5R,6S)-5-(3-Chlorophenyl)-6-(4-chlorophenyl)-3-methyl-2-oxo-1-((S)-
-1-(phenylsulfonyl)butan-2-yl)piperidin-3-yl)acetic acid; [0742]
2-((3R,5R,6S)-5-(3-Chlorophenyl)-6-(4-chlorophenyl)-3-methyl-1-((S)-1-(me-
thylsulfonyl)butan-2-yl)-2-oxopiperidin-3-yl)acetic acid; [0743]
2-((3R,5R,6S)-5-(3-Chlorophenyl)-6-(4-chlorophenyl)-3-methyl-2-oxo-1-((S)-
-1-(propylsulfonyl)butan-2-yl)piperidin-3-yl)acetic acid; [0744]
2-((3R,5R,6S)-5-(3-Chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-(isobutylsul-
fonyl)butan-2-yl)-3-methyl-2-oxopiperidin-3-yl)acetic acid; [0745]
2-((3R,5R,6S)-5-(3-Chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-((cyclopropy-
lmethyl)sulfonyl)butan-2-yl)-3-methyl-2-oxopiperidin-3-yl)acetic
acid; [0746]
2-((3R,5R,6S)-5-(3-Chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-((cyc-
lobutylmethyl)sulfonyl)butan-2-yl)-3-methyl-2-oxopiperidin-3-yl)acetic
acid; [0747]
2-((3R,5R,6S)-5-(3-Chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-(cyclopentyl-
sulfonyl)butan-2-yl)-3-methyl-2-oxopiperidin-3-yl)acetic acid;
[0748]
2-((3R,5R,6S)-5-(3-Chlorophenyl)-6-(4-chlorophenyl)-3-methyl-1-((S)-1-(ox-
etan-3-ylsulfonyl)butan-2-yl)-2-oxopiperidin-3-yl)acetic acid;
[0749]
2-((3R,5R,6S)-5-(3-Chlorophenyl)-6-(4-chlorophenyl)-3-methyl-1-((S)-1-(((-
3-methyloxetan-3-yl)methyl)sulfonyl)butan-2-yl)-2-oxopiperidin-3-yl)acetic
acid; [0750]
2-((3R,5R,6S)-5-(3-Chlorophenyl)-6-(4-chlorophenyl)-3-methyl-2-oxo-1-((S)-
-1-((tetrahydro-2H-pyran-4-yl)sulfonyl)butan-2-yl)piperidin-3-yl)acetic
acid; [0751]
2-((3R,5R,6S)-5-(3-Chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-((2-hydroxy--
2-methylpropyl)sulfonyl)butan-2-yl)-3-methyl-2-oxopiperidin-3-yl)acetic
acid; [0752]
2-((3R,5R,6S)-1-((S)-1-((R)-sec-butylsulfonyl)butan-2-yl)-5-(3-chlorophen-
yl)-6-(4-chlorophenyl)-3-methyl-2-oxopiperidin-3-yl)acetic acid;
[0753]
2-((3R,5R,6S)-1-((S)-1-((S)-sec-butylsulfonyl)butan-2-yl)-5-(3-chlorophen-
yl)-6-(4-chlorophenyl)-3-methyl-2-oxopiperidin-3-yl)acetic acid;
[0754]
2-((3R,5R,6S)-5-(3-Chlorophenyl)-6-(4-chlorophenyl)-1-((S)-2-(cyclopentyl-
sulfonyl)-1-cyclopropylethyl)-3-methyl-2-oxopiperidin-3-yl)acetic
acid; [0755]
2-((3R,5R,6S)-5-(3-Chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-cyclo-
propyl-2-(((3-methyloxetan-3-yl)methyl)sulfonyl)ethyl)-3-methyl-2-oxopiper-
idin-3-yl)acetic acid; [0756]
2-((3R,5R,6S)-5-(3-Chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-cyclopropyl--
2-(phenylsulfonyl)ethyl)-3-methyl-2-oxopiperidin-3-yl)acetic acid;
[0757]
2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-cyclopropyl--
2-(o-tolylsulfonyl)ethyl)-3-methyl-2-oxopiperidin-3-yl)acetic acid;
[0758]
2-((3R,5R,6S)-5-(3-Chlorophenyl)-6-(4-chlorophenyl)-1-((S)-2-((2-chloroph-
enyl)sulfonyl)-1-cyclopropylethyl)-3-methyl-2-oxopiperidin-3-yl)acetic
acid; [0759]
2-((3R,5R,6S)-5-(3-Chlorophenyl)-6-(4-chlorophenyl)-1-((S)-2-((4-chloroph-
enyl)sulfonyl)-1-cyclopropylethyl)-3-methyl-2-oxopiperidin-3-yl)acetic
acid; [0760]
2-((3R,5R,6S)-5-(3-Chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-cyclopropyl--
2-((4-fluorophenyl)sulfonyl)ethyl)-3-methyl-2-oxopiperidin-3-yl)acetic
acid; [0761]
2-((3R,5R,6S)-5-(3-Chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-cyclopropyl--
2-(pyridin-4-ylsulfonyl)ethyl)-3-methyl-2-oxopiperidin-3-yl)acetic
acid; [0762]
2-((3R,5R,6S)-1-((S)-2-((2-Chloro-4-fluorophenyl)sulfonyl)-1-cyclo-
propylethyl)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-2-oxopiperidin-
-3-yl)acetic acid; [0763]
2-((3R,5R,6S)-5-(3-Chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-cyclopropyl--
2-((cyclopropylmethyl)sulfonyl)ethyl)-3-methyl-2-oxopiperidin-3-yl)acetic
acid; [0764]
2-((3R,5R,6S)-5-(3-Chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-cyclopropyl--
2-((2,2,2-trifluoroethyl)sulfonyl)ethyl)-3-methyl-2-oxopiperidin-3-yl)acet-
ic acid; [0765]
2-((3R,5R,6S)-5-(3-Chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-cyclopropyl--
2-((trifluoromethyl)sulfonyl)ethyl)-3-methyl-2-oxopiperidin-3-yl)acetic
acid; [0766]
2-((3R,5R,6S)-5-(3-Chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-cyclopropyl--
2-(phenylsulfonyl)ethyl)-3-ethyl-2-oxopiperidin-3-yl)acetic acid;
[0767]
2-((3R,5R,6S)-5-(3-Chlorophenyl)-6-(4-chlorophenyl)-1-((S)-2-((2-chloroph-
enyl)sulfonyl)-1-cyclopropylethyl)-3-ethyl-2-oxopiperidin-3-yl)acetic
acid; [0768]
2-((3R,5R,6S)-5-(3-Chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-cyclopropyl--
2-((2-fluorophenyl)sulfonyl)ethyl)-3-ethyl-2-oxopiperidin-3-yl)acetic
acid; [0769]
2-((3R,5R,6S)-5-(3-Chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-cyclopropyl--
2-((3-fluorophenyl)sulfonyl)ethyl)-3-ethyl-2-oxopiperidin-3-yl)acetic
acid; [0770]
2-((3R,5R,6S)-5-(3-Chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-cyclopropyl--
2-((4-fluorophenyl)sulfonyl)ethyl)-3-ethyl-2-oxopiperidin-3-yl)acetic
acid; [0771]
2-((3R,5R,6S)-5-(3-Chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-cyclopropyl--
2-(propylsulfonyl)ethyl)-3-ethyl-2-oxopiperidin-3-yl)acetic acid;
[0772]
2-((3R,5R,6S)-1-((S)-2-(Butylsulfonyl)-1-cyclopropylethyl)-5-(3-chlorophe-
nyl)-6-(4-chlorophenyl)-3-ethyl-2-oxopiperidin-3-yl)acetic acid;
[0773]
2-((3R,5R,6S)-5-(3-Chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-cyclopropyl--
2-(isopentylsulfonyl)ethyl)-3-ethyl-2-oxopiperidin-3-yl)acetic
acid; [0774]
2-((3R,5R,6S)-5-(3-Chlorophenyl)-6-(4-chlorophenyl)-1-((S)-2-(cycl-
opentylsulfonyl)-1-cyclopropylethyl)-3-ethyl-2-oxopiperidin-3-yl)acetic
acid; [0775]
2-((3R,5R,6S)-5-(3-Chlorophenyl)-6-(4-chlorophenyl)-1-((S)-2-(cyclohexyls-
ulfonyl)-1-cyclopropylethyl)-3-ethyl-2-oxopiperidin-3-yl)acetic
acid; [0776]
2-((3R,5R,6S)-5-(3-Chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-cyclo-
propyl-2-(methylsulfonyl)ethyl)-3-ethyl-2-oxopiperidin-3-yl)acetic
acid; [0777]
2-((3R,5R,6S)-5-(3-Chlorophenyl)-6-(4-chlorophenyl)-3-methyl-1-((S-
)-3-methyl-1-((2,2,2-trifluoroethyl)sulfonyl)butan-2-yl)-2-oxopiperidin-3--
yl)acetic acid; [0778]
2-((3R,5R,6S)-1-((S)-1-(tert-Butylsulfonyl)-3-methylbutan-2-yl)-5-(3-chlo-
rophenyl)-6-(4-chlorophenyl)-3-methyl-2-oxopiperidin-3-yl)acetic
acid; [0779]
2-((3R,5R,6S)-5-(3-Chlorophenyl)-6-(4-chlorophenyl)-3-methyl-1-((S-
)-3-methyl-1-(methylsulfonyl)butan-2-yl)-2-oxopiperidin-3-yl)acetic
acid; [0780]
2-((3R,5R,6S)-5-(3-Chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-(ethy-
lsulfonyl)butan-2-yl)-3-methyl-2-oxopiperidin-3-yl)acetic acid;
[0781]
2-((3R,5R,6S)-5-(3-Chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-(cyclopropyl-
sulfonyl)butan-2-yl)-3-methyl-2-oxopiperidin-3-yl)acetic acid;
[0782]
2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-(isopropylsu-
lfonyl)butan-2-yl)-3-methyl-2-oxopiperidin-3-yl)acetic acid; [0783]
2-((3R,5R,6S)-1-((S)-1-(tert-butylsulfonyl)butan-2-yl)-5-(3-chlorophenyl)-
-6-(4-chlorophenyl)-3-methyl-2-oxopiperidin-3-yl)acetic acid;
[0784]
2-((3R,5R,6S)-5-(3-Chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-(cyclobutyls-
ulfonyl)butan-2-yl)-3-methyl-2-oxopiperidin-3-yl)acetic acid;
[0785]
2-((3R,5R,6S)-5-(3-Chlorophenyl)-6-(4-chlorophenyl)-3-ethyl-1-((S)-1-(eth-
ylsulfonyl)butan-2-yl)-2-oxopiperidin-3-yl)acetic acid; [0786]
2-((3R,5R,6S)-5-(3-Chlorophenyl)-6-(4-chlorophenyl)-3-ethyl-1-((S)-1-(iso-
propylsulfonyl)butan-2-yl)-2-oxopiperidin-3-yl)acetic acid; [0787]
2-((3R,5R,6S)-1-((S)-1-(tert-butylsulfonyl)butan-2-yl)-5-(3-chlorophenyl)-
-6-(4-chlorophenyl)-3-ethyl-2-oxopiperidin-3-yl)acetic acid; [0788]
2-((3R,5R,6S)-5-(3-Chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-(cyclobutyls-
ulfonyl)butan-2-yl)-3-ethyl-2-oxopiperidin-3-yl)acetic acid; [0789]
2-((3R,5R,6S)-5-(3-Chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-(cyclopropyl-
sulfonyl)butan-2-yl)-3-ethyl-2-oxopiperidin-3-yl)acetic acid;
[0790]
2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-cyclopropyl--
2-(ethylsulfonyl)ethyl)-3-methyl-2-oxopiperidin-3-yl)acetic acid;
[0791]
2-((3R,5R,6S)-5-(3-Chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-cyclopropyl--
2-(isopropylsulfonyl)ethyl)-3-methyl-2-oxopiperidin-3-yl)acetic
acid; [0792]
2-((3R,5R,6S)-1-((S)-2-(tert-Butylsulfonyl)-1-cyclopropylethyl)-5--
(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-2-oxopiperidin-3-yl)acetic
acid; [0793]
2-((3R,5R,6S)-5-(3-Chlorophenyl)-6-(4-chlorophenyl)-1-((S)-2-(cyclobutyls-
ulfonyl)-1-cyclopropylethyl)-3-methyl-2-oxopiperidin-3-yl)acetic
acid; [0794]
2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-cyclo-
propyl-2-(cyclopropylsulfonyl)ethyl)-3-methyl-2-oxopiperidin-3-yl)acetic
acid; [0795]
2-((3R,5R,6S)-5-(3-Chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-cyclopropyl--
2-(methylsulfonyl)ethyl)-3-methyl-2-oxopiperidin-3-yl)acetic acid;
[0796]
2-((3R,5R,6S)-5-(3-Chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-cyclopropyl--
2-(tert-pentylsulfonyl)ethyl)-3-methyl-2-oxopiperidin-3-yl)acetic
acid; [0797]
2-((3R,5R,6S)-5-(3-Chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-cyclo-
propyl-2-((2,4-difluorophenyl)sulfonyl)ethyl)-3-methyl-2-oxopiperidin-3-yl-
)acetic acid; [0798]
2-((3R,5R,6S)-5-(3-Chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-cyclopropyl--
2-(ethylsulfonyl)ethyl)-3-ethyl-2-oxopiperidin-3-yl)acetic acid;
[0799]
2-((3R,5R,6S)-5-(3-Chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-cyclopropyl--
2-(isopropylsulfonyl)ethyl)-3-ethyl-2-oxopiperidin-3-yl)acetic
acid; [0800]
2-((3R,5R,6S)-1-((S)-2-(tert-Butylsulfonyl)-1-cyclopropylethyl)-5--
(3-chlorophenyl)-6-(4-chlorophenyl)-3-ethyl-2-oxopiperidin-3-yl)acetic
acid; [0801]
2-((3R,5R,6S)-5-(3-Chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-cyclopropyl--
2-(cyclopropylsulfonyl)ethyl)-3-ethyl-2-oxopiperidin-3-yl)acetic
acid;
[0802]
2-((3R,5R,6S)-5-(3-Chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-(ethy-
lsulfonyl)-3-methylbutan-2-yl)-3-methyl-2-oxopiperidin-3-yl)acetic
acid; [0803]
2-((3R,5R,6S)-5-(3-Chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-(isop-
ropylsulfonyl)-3-methylbutan-2-yl)-3-methyl-2-oxopiperidin-3-yl)acetic
acid; [0804]
2-((3R,5R,6S)-5-(3-Chlorophenyl)-6-(4-chlorophenyl)-1-((S)-3,3-dimethyl-1-
-(methylsulfonyl)butan-2-yl)-3-methyl-2-oxopiperidin-3-yl)acetic
acid; [0805]
2-((3R,5R,6S)-5-(3-Chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-(ethy-
lsulfonyl)-3,3-dimethylbutan-2-yl)-3-methyl-2-oxopiperidin-3-yl)acetic
acid; [0806]
2-((3R,5R,6S)-5-(3-Chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-(isopropylsu-
lfonyl)-3,3-dimethylbutan-2-yl)-3-methyl-2-oxopiperidin-3-yl)acetic
acid; [0807]
2-((3R,5R,6S)-5-(3-Chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-cyclo-
propyl-2-(pentan-3-ylsulfonyl)ethyl)-3-methyl-2-oxopiperidin-3-yl)acetic
acid; [0808]
2-((3R,5R,6S)-5-(3-Chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-((S)-isoprop-
ylsulfinyl)butan-2-yl)-3-methyl-2-oxopiperidin-3-yl)acetic acid;
[0809]
2-((3R,5R,6S)-5-(3-Chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-((R)-isoprop-
ylsulfinyl)butan-2-yl)-3-methyl-2-oxopiperidin-3-yl)acetic acid;
more polar isomer; [0810]
2-((3R,5R,6S)-5-(3-Chlorophenyl)-6-(4-chlorophenyl)-3-methyl-1-((2S,3S)-2-
-(methylsulfonyl)pentan-3-yl)-2-oxopiperidin-3-yl)acetic acid;
[0811]
2-((3R,5R,6S)-5-(3-Chlorophenyl)-6-(4-chlorophenyl)-3-methyl-1-((2R,3S)-2-
-(methylsulfonyl)pentan-3-yl)-2-oxopiperidin-3-yl)acetic acid;
[0812]
2-((3R,5R,6S)-5-(3-Chlorophenyl)-6-(4-chlorophenyl)-1-((2S,3S)-2-(ethylsu-
lfonyl)pentan-3-yl)-3-methyl-2-oxopiperidin-3-yl)acetic acid;
[0813]
2-((3R,5R,6S)-5-(3-Chlorophenyl)-6-(4-chlorophenyl)-1-((2R,3S)-2-(ethylsu-
lfonyl)pentan-3-yl)-3-methyl-2-oxopiperidin-3-yl)acetic acid;
[0814]
2-((3R,5R,6S)-5-(3-Chlorophenyl)-6-(4-chlorophenyl)-3-methyl-1-((S)-1-(N--
(oxetan-3-yl)sulfamoyl)butan-2-yl)-2-oxopiperidin-3-yl)acetic acid;
[0815]
2-((3R,5R,6S)-5-(3-Chlorophenyl)-6-(4-chlorophenyl)-3-methyl-1-((S)-1-(N--
((3-methyloxetan-3-yl)methyl)sulfamoyl)butan-2-yl)-2-oxopiperidin-3-yl)ace-
tic acid; [0816]
2-((3R,5R,6S)-5-(3-Chlorophenyl)-6-(4-chlorophenyl)-3-methyl-1-((S)-1-(N--
(oxetan-3-ylmethyl)sulfamoyl)butan-2-yl)-2-oxopiperidin-3-yl)acetic
acid; [0817]
2-((3R,5R,6S)-1-((S)-2-(N-(tert-Butyl)sulfamoyl)-1-cyclopropylethy-
l)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-2-oxopiperidin-3-yl)acet-
ic acid; [0818]
2-((3R,5R,6S)-5-(3-Chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-cyclopropyl--
2-(N-methylsulfamoyl)ethyl)-3-methyl-2-oxopiperidin-3-yl)acetic
acid; [0819]
2-((3R,5R,6S)-5-(3-Chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-cyclo-
propyl-2-(N,N-dimethylsulfamoyl)ethyl)-3-methyl-2-oxopiperidin-3-yl)acetic
acid; [0820]
2-((3R,5R,6S)-5-(3-Chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-cyclopropyl--
2-(N-isopropylsulfamoyl)ethyl)-3-methyl-2-oxopiperidin-3-yl)acetic
acid; [0821]
2-((3R,5R,6S)-5-(3-Chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-cyclo-
propyl-2-(morpholinosulfonyl)ethyl)-3-methyl-2-oxopiperidin-3-yl)acetic
acid; [0822]
2-((3R,5R,6S)-5-(3-Chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-cyclopropyl--
2-(piperidin-1-ylsulfonyl)ethyl)-3-methyl-2-oxopiperidin-3-yl)acetic
acid; [0823]
2-((3R,5R,6S)-5-(3-Chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-cyclo-
propyl-2-(pyrrolidin-1-ylsulfonyl)ethyl)-3-methyl-2-oxopiperidin-3-yl)acet-
ic acid; [0824]
2-((3R,5R,6S)-1-((S)-2-(Azetidin-1-ylsulfonyl)-1-cyclopropylethyl)-5-(3-c-
hlorophenyl)-6-(4-chlorophenyl)-3-methyl-2-oxopiperidin-3-yl)acetic
acid; [0825]
2-((3R,5R,6S)-5-(3-Chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-cyclo-
propyl-2-((N,N-dimethylsulfamoyl)amino)ethyl)-3-methyl-2-oxopiperidin-3-yl-
)acetic acid; [0826]
2-((3R,5R,6S)-5-(3-Chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-cyclopropyl--
2-((N,N-dimethylsulfamoyl)(methyl)amino)ethyl)-3-methyl-2-oxopiperidin-3-y-
l)acetic acid; [0827]
2-((3R,5R,6S)-5-(3-Chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-cyclopropyl--
2-(3-methyl-2,5-dioxoimidazolidin-1-yl)ethyl)-3-methyl-2-oxopiperidin-3-yl-
)acetic acid; [0828]
2-((3R,5R,6S)-5-(3-Chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-cyclopropyl--
2-(3,4,4-trimethyl-2,5-dioxoimidazolidin-1-yl)ethyl)-3-methyl-2-oxopiperid-
in-3-yl)acetic acid; [0829]
2-((3R,5R,6S)-5-(3-Chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-cyclopropyl--
2-(4,4-dimethyl-2,5-dioxoimidazolidin-1-yl)ethyl)-3-methyl-2-oxopiperidin--
3-yl)acetic acid; [0830]
2-((3R,5R,6S)-5-(3-Chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-cyclopropyl--
2-(3-isopropyl-2,2-dioxido-4-oxo-3,4-dihydro-1H-benzo[c][1,2,6]thiadiazin--
1-yl)ethyl)-3-methyl-2-oxopiperidin-3-yl)acetic acid; [0831]
2-((3R,5R,6S)-5-(3-Chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-cyclopropyl--
2-(2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)ethyl)-3-methyl-2-oxopiperid-
in-3-yl)acetic acid; [0832]
2-((3R,5R,6S)-5-(3-Chloro-4-fluorophenyl)-6-(4-chlorophenyl)-1-isopropyl--
3-methyl-2-oxopiperidin-3-yl)acetic acid; [0833]
2-((3R,5R,6S)-5-(3-Chloro-5-fluorophenyl)-6-(4-chlorophenyl)-1-isopropyl--
3-methyl-2-oxopiperidin-3-yl)acetic acid; [0834]
2-((3S,5R,6S)-5-(3-Chloro-5-fluorophenyl)-6-(4-chlorophenyl)-1-isopropyl--
3-methyl-2-oxopiperidin-3-yl)acetic acid; [0835]
2-((3R,5R,6S)-5-(3-Chloro-5-fluorophenyl)-6-(4-chlorophenyl)-1-((S)-1-(et-
hylsulfonamido)butan-2-yl)-3-methyl-2-oxopiperidin-3-yl)acetic
acid; [0836]
2-((3R,5R,6S)-5-(3-Chloro-5-fluorophenyl)-6-(4-chlorophenyl)-3-met-
hyl-1-((S)-1-(N-methylethylsulfonamido)butan-2-yl)-2-oxopiperidin-3-yl)ace-
tic acid; [0837]
2-((3R,5R,6S)-5-(3-Chloro-5-fluorophenyl)-6-(4-chlorophenyl)-3-methyl-1-(-
(S)-1-(methylsulfonyl)butan-2-yl)-2-oxopiperidin-3-yl)acetic acid;
[0838]
2-((3R,5R,6S)-5-(3-Chloro-5-fluorophenyl)-6-(4-chlorophenyl)-1-((S)-1-(et-
hylsulfonyl)butan-2-yl)-3-methyl-2-oxopiperidin-3-yl)acetic acid;
[0839]
2-((3R,5R,6S)-5-(3-Chloro-5-fluorophenyl)-6-(4-chlorophenyl)-1-((S)-1-(cy-
clopropylsulfonyl)butan-2-yl)-3-methyl-2-oxopiperidin-3-yl)acetic
acid; [0840]
2-((3R,5R,6S)-1-((S)-1-(tert-Butylsulfonyl)butan-2-yl)-5-(3-chloro-
-5-fluorophenyl)-6-(4-chlorophenyl)-3-methyl-2-oxopiperidin-3-yl)acetic
acid; [0841]
2-((3R,5R,6S)-5-(3-Chloro-5-fluorophenyl)-6-(4-chlorophenyl)-1-((S)-1-(is-
opropylsulfonyl)butan-2-yl)-3-methyl-2-oxopiperidin-3-yl)acetic
acid; [0842]
2-((3R,5R,6S)-6-(4-Chlorophenyl)-5-(5-chloropyridin-3-yl)-1-((S)-1-
-(cyclopropylsulfonyl)butan-2-yl)-3-methyl-2-oxopiperidin-3-yl)acetic
acid; [0843]
2-((3R,5R,6S)-1-((S)-1-(tert-Butylsulfonyl)butan-2-yl)-6-(4-chlorophenyl)-
-5-(5-chloropyridin-3-yl)-3-methyl-2-oxopiperidin-3-yl)acetic acid;
[0844]
2-((3R,5R,6S)-6-(4-Chlorophenyl)-5-(5-chloropyridin-3-yl)-1-((S)-1-(cyclo-
propanesulfonamido)butan-2-yl)-3-methyl-2-oxopiperidin-3-yl)acetic
acid; [0845]
2-((3R,5R,6S)-6-(4-Chlorophenyl)-5-(5-chloropyridin-3-yl)-3-methyl-
-1-((S)-1-(N-methylcyclopropanesulfonamido)butan-2-yl)-2-oxopiperidin-3-yl-
)acetic acid; [0846]
2-((3R,5R,6S)-5-(3-Chlorophenyl)-6-(5-chloropyridin-2-yl)-1-((S)-1-(ethyl-
sulfonyl)butan-2-yl)-3-methyl-2-oxopiperidin-3-yl)acetic acid;
[0847]
2-((3R,5R,6S)-5-(3-Chlorophenyl)-6-(4-chlorophenyl)-3-methyl-1-((S)-1-((S-
)-morpholin-2-yl)propyl)-2-oxopiperidin-3-yl)acetic acid; [0848]
2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-1-((S)-1-((R-
)-morpholin-2-yl)propyl)-2-oxopiperidin-3-yl)acetic acid; [0849]
2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-1-((R)-1-((S-
)-morpholin-2-yl)propyl)-2-oxopiperidin-3-yl)acetic acid; [0850]
2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-1-((R)-1-((R-
)-morpholin-2-yl)propyl)-2-oxopiperidin-3-yl)acetic acid; [0851]
2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-1-((R)-1-((R-
)-morpholin-2-yl)propyl)-2-oxopiperidin-3-yl)acetic acid; or
2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-1-((R)-1-((S-
)-morpholin-2-yl)propyl)-2-oxopiperidin-3-yl)acetic acid; [0852]
2-((3S,5R,6S)-5-(3-Chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-(N-methylcyc-
lopropanesulfonamido)butan-2-yl)-3-(2-morpholinoethyl)-2-oxopiperidin-3-yl-
)acetic acid; [0853]
2-((3S,5R,6S)-5-(3-Chlorophenyl)-6-(4-chlorophenyl)-3-(2-(1,1-dioxidothio-
morpholino)ethyl)-1-((S)-1-(N-methylcyclopropanesulfonamido)butan-2-yl)-2--
oxopiperidin-3-yl)acetic acid; [0854]
2-((3S,5R,6S)-5-(3-Chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-(N-methylcyc-
lopropanesulfonamido)butan-2-yl)-2-oxo-3-(2-(pyrrolidin-1-yl)ethyl)piperid-
in-3-yl)acetic acid; [0855]
2-((3S,5R,6S)-5-(3-Chlorophenyl)-6-(4-chlorophenyl)-3-(2-(dimethylamino)e-
thyl)-1-((S)-1-(N-methylcyclopropanesulfonamido)butan-2-yl)-2-oxopiperidin-
-3-yl)acetic acid; [0856]
2-((3S,5R,6S)-5-(3-Chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-(N-methylcyc-
lopropanesulfonamido)butan-2-yl)-3-(2-morpholinoethyl)-2-oxopiperidin-3-yl-
)acetamide; [0857]
2-((3S,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-(N-methylcyc-
lopropanesulfonamido)butan-2-yl)-3-(2-morpholinoethyl)-2-oxopiperidin-3-yl-
)acetamide; [0858]
(1R,3S,6S,7R)-7-(3-Chlorophenyl)-6-(4-chlorophenyl)-5-((S)-1-(N-methylcyc-
lopropanesulfonamido)butan-2-yl)-4-oxo-5-azaspiro[2.5]octane-1-carboxylic
acid; [0859]
(3S,6S,7R)-7-(3-Chlorophenyl)-6-(4-chlorophenyl)-5-((S)-1-(N-methylcyclop-
ropanesulfonamido)butan-2-yl)-4-oxo-5-azaspiro[2.5]octane-1-carboxylic
acid; [0860]
2-((3R,5R,6S)-5-(3-Chlorophenyl)-6-(4-chlorophenyl)-1-((2S,3S)-1,2-dihydr-
oxypentan-3-yl)-3-methyl-2-oxopiperidin-3-yl)acetic acid; [0861]
2-((3R,5R,6S)-5-(3-Chlorophenyl)-6-(4-chlorophenyl)-1-((2R,3S)-1,2-dihydr-
oxypentan-3-yl)-3-methyl-2-oxopiperidin-3-yl)acetic acid; [0862]
2-((3R,5R,6S)-5-(3-Chlorophenyl)-6-(4-chlorophenyl)-1-((2R,3S)-1,2-dihydr-
oxypentan-3-yl)-3-methyl-2-oxopiperidin-3-yl)acetic acid; [0863]
2-((3R,5R,6S)-5-(3-Chlorophenyl)-6-(4-chlorophenyl)-1-((2S,3S)-1,2-dihydr-
oxypentan-3-yl)-3-methyl-2-oxopiperidin-3-yl)acetic acid; [0864]
2-((3R,5R,6S)-5-(3-Chlorophenyl)-6-(4-chlorophenyl)-1-((1S,2S)-1-cyclopro-
pyl-1-hydroxybutan-2-yl)-3-methyl-2-oxopiperidin-3-yl)acetic acid;
[0865]
2-((3R,5R,6S)-5-(3-Chlorophenyl)-6-(4-chlorophenyl)-1-((1R,2S)-1-cyclopro-
pyl-1-hydroxybutan-2-yl)-3-methyl-2-oxopiperidin-3-yl)acetic acid;
[0866]
2-((3S,5R,6S)-5-(3-Chlorophenyl)-6-(4-chlorophenyl)-1-isopropyl-6-methyl--
2-oxopiperidin-3-yl)acetic acid; [0867]
2-((3R,5R,6S)-5-(3-Chlorophenyl)-6-(4-chlorophenyl)-1-isopropyl-6-methyl--
2-oxopiperidin-3-yl)acetic acid; [0868]
(3S,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-(1,1-dioxidoiso-
thiazolidin-2-yl)butan-2-yl)-3-((6-methoxypyridin-2-yl)methyl)piperidin-2--
one; [0869]
(3R,5R,6S)-5-(3-Chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-(1,1-dioxidoiso-
thiazolidin-2-yl)butan-2-yl)-3-((6-methoxypyridin-2-yl)methyl)piperidin-2--
one; [0870]
(3S,5R,6S)-5-(3-Chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-(1,1-dioxidoiso-
thiazolidin-2-yl)butan-2-yl)-3-((6-hydroxypyridin-2-yl)methyl)piperidin-2--
one; [0871]
(3R,5R,6S)-5-(3-Chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-(1,1-dioxidoiso-
thiazolidin-2-yl)butan-2-yl)-3-((6-hydroxypyridin-2-yl)methyl)piperidin-2--
one; [0872]
(3S,5R,6S)-5-(3-Chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-(1,1-dioxidoiso-
thiazolidin-2-yl)butan-2-yl)-3-((6-methoxypyridin-2-yl)methyl)-3-methylpip-
eridin-2-one; [0873]
(3R,5R,6S)-5-(3-Chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-(1,1-dioxidoiso-
thiazolidin-2-yl)butan-2-yl)-3-((6-methoxypyridin-2-yl)methyl)-3-methylpip-
eridin-2-one; [0874]
(3S,5R,6S)-5-(3-Chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-(1,1-dioxidoiso-
thiazolidin-2-yl)butan-2-yl)-3-((6-hydroxypyridin-2-yl)methyl)-3-methylpip-
eridin-2-one; [0875]
(3R,5R,6S)-5-(3-Chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-(1,1-dioxidoiso-
thiazolidin-2-yl)butan-2-yl)-3-((6-hydroxypyridin-2-yl)methyl)-3-methylpip-
eridin-2-one; [0876]
(3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-cyclopropyl-2-(-
ethylsulfonyl)ethyl)-3-(3-hydroxy-2-oxopropyl)-3-methylpiperidin-2-one;
[0877]
2-((3R,5R,6S)-5-(3-Chlorophenyl)-6-(4-chlorophenyl)-1-(diethylamin-
o)-3-methyl-2-oxopiperidin-3-yl)acetic acid; [0878]
2-((3R,5R,6S)-5-(3-Chlorophenyl)-6-(4-chlorophenyl)-1-(dimethylamino)-3-m-
ethyl-2-oxopiperidin-3-yl)acetic acid; or [0879]
(2S,3S,5S,6R,7aR,10aS)-6-(3-chlorophenyl)-5-(4-chlorophenyl)-3-ethyl-2,7a-
-dimethylhexahydrofuro[2,3-b]oxazolo[3,2-a]pyridin-9(5H)-one.
[0880] In another aspect, the present invention provides a
compound, or a pharmaceutically acceptable salt thereof, selected
from: [0881]
2-(5-(3-Chlorophenyl)-6-(4-chlorophenyl)-1-(1-cyclopropyl-2-(thiophene-2--
sulfonamido)ethyl)-3-methyl-2-oxopiperidin-3-yl)acetic acid; [0882]
2-(5-(3-Chlorophenyl)-6-(4-chlorophenyl)-1-(1-cyclopropyl-2-(N-methylthio-
phene-2-sulfonamido)ethyl)-3-methyl-2-oxopiperidin-3-yl)acetic
acid; [0883]
2-(5-(3-Chlorophenyl)-6-(4-chlorophenyl)-1-(2-(5-chlorothiophene-2-
-sulfonamido)-1-cyclopropylethyl)-3-methyl-2-oxopiperidin-3-yl)acetic
acid; [0884]
2-(1-(2-(5-Chloro-N-methylthiophene-2-sulfonamido)-1-cyclopropylethyl)-5--
(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-2-oxopiperidin-3-yl)acetic
acid; [0885]
2-(5-(3-Chlorophenyl)-6-(4-chlorophenyl)-1-(1-cyclopropyl-2-(N-(difluorom-
ethyl)-2-methylpropan-2-ylsulfonamido)ethyl)-3-methyl-2-oxopiperidin-3-yl)-
acetic acid; [0886]
2-(5-(3-Chlorophenyl)-6-(4-chlorophenyl)-1-(1-cyclopropyl-2-(N-(difluorom-
ethyl)ethylsulfonamido)ethyl)-3-methyl-2-oxopiperidin-3-yl)acetic
acid; [0887]
2-(5-(3-Chlorophenyl)-6-(4-chlorophenyl)-1-(1-cyclopropyl-2-(N-(di-
fluoromethyl)cyclopropanesulfonamido)ethyl)-3-methyl-2-oxopiperidin-3-yl)a-
cetic acid; [0888]
1-(5-(3-Chlorophenyl)-6-(4-chlorophenyl)-1-(2-(cyclopropanesulfonamido)-1-
-cyclopropylethyl)-3-methyl-2-oxopiperidin-3-yl)cyclopropanecarboxylic
acid; [0889]
2-(5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-(1-cyclopropyl-2-(N-(2-fluorop-
henyl)ethylsulfonamido)ethyl)-3-methyl-2-oxopiperidin-3-yl)acetic
acid; [0890]
2-(5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-(1-cyclopropyl-2-(N-(2--
fluorophenyl)methylsulfonamido)ethyl)-3-methyl-2-oxopiperidin-3-yl)acetic
acid; [0891]
2-(5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-(1-cyclopropyl-2-(N-phenylcycl-
opropanesulfonamido)ethyl)-3-methyl-2-oxopiperidin-3-yl)acetic
acid; [0892]
2-(5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-(1-cyclopropyl-2-(N-phe-
nylethylsulfonamido)ethyl)-3-methyl-2-oxopiperidin-3-yl)acetic
acid; [0893]
2-(5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-(1-cyclopropyl-2-(ethyl-
sulfonamido)ethyl)-3-methyl-2-oxopiperidin-3-yl)acetic acid; [0894]
2-(5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-(1-cyclopropyl-2-(N-(3-fluorop-
henyl)ethylsulfonamido)ethyl)-3-methyl-2-oxopiperidin-3-yl)acetic
acid; [0895]
2-(5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-(2-(N-(2-cyanophenyl)me-
thylsulfonamido)-1-cyclopropylethyl)-3-methyl-2-oxopiperidin-3-yl)acetic
acid; [0896]
2-(5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-(1-cyclopropyl-2-(propylsulfon-
amido)ethyl)-3-methyl-2-oxopiperidin-3-yl)acetic acid; [0897]
2-(5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-(1-cyclopropyl-2-(N-phenylmeth-
ylsulfonamido)ethyl)-3-methyl-2-oxopiperidin-3-yl)acetic acid;
[0898]
2-(5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-(2-(N-(3-cyanophenyl)methylsul-
fonamido)-1-cyclopropylethyl)-3-methyl-2-oxopiperidin-3-yl)acetic
acid; [0899]
2-(5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-(1-cyclopropyl-2-(N-(py-
ridin-3-yl)methylsulfonamido)ethyl)-3-methyl-2-oxopiperidin-3-yl)acetic
acid; [0900]
2-(5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-(1-cyclopropyl-2-(N-(thiophen--
2-ylmethyl)methylsulfonamido)ethyl)-3-methyl-2-oxopiperidin-3-yl)acetic
acid; [0901]
2-(5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-(1-cyclopropyl-2-(N-(3-methoxy-
benzyl)methylsulfonamido)ethyl)-3-methyl-2-oxopiperidin-3-yl)acetic
acid; [0902]
2-(5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-(1-cyclopropyl-2-(pheny-
lmethylsulfonamido)ethyl)-3-methyl-2-oxopiperidin-3-yl)acetic acid;
[0903]
2-(5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-(1-cyclopropyl-2-(pyridin-2-yl-
methylsulfonamido)ethyl)-3-methyl-2-oxopiperidin-3-yl)acetic acid;
[0904]
2-(5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-(1-cyclopropyl-2-(pyridin-3-yl-
methylsulfonamido)ethyl)-3-methyl-2-oxopiperidin-3-yl)acetic acid;
[0905]
2-(5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-(1-cyclopropyl-2-(N-(pyridin-2-
-yl)methylsulfonamido)ethyl)-3-methyl-2-oxopiperidin-3-yl)acetic
acid; [0906]
2-(5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-(1-cyclopropyl-2-(methy-
lsulfonamido)ethyl)-3-methyl-2-oxopiperidin-3-yl)acetic acid;
[0907]
2-(5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-(1-cyclopropyl-2-(N-ethylmethy-
lsulfonamido)ethyl)-3-methyl-2-oxopiperidin-3-yl)acetic acid;
[0908]
2-(5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-(1-cyclopropyl-2-(N-isopropylm-
ethylsulfonamido)ethyl)-3-methyl-2-oxopiperidin-3-yl)acetic acid;
[0909]
2-(5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-(1-cyclopropyl-2-(1-methylethy-
lsulfonamido)ethyl)-3-ethyl-2-oxopiperidin-3-yl)acetic acid; [0910]
2-(5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-(2-(cyclobutanesulfonamido)-1--
cyclopropylethyl)-3-ethyl-2-oxopiperidin-3-yl)acetic acid; [0911]
2-(5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-(2-(cyclopentanesulfonamido)-1-
-cyclopropylethyl)-3-ethyl-2-oxopiperidin-3-yl)acetic acid; [0912]
2-(5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-1-(3-methyl-1-(N-methyl-
cyclopropanesulfonamido)butan-2-yl)-2-oxopiperidin-3-yl)acetic
acid; [0913]
2-(5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-(1-(cyclopropanesulfona-
mido)-3-methylbutan-2-yl)-3-methyl-2-oxopiperidin-3-yl)acetic acid;
[0914]
2-(5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-(1-(ethylsulfonamido)-3-methyl-
butan-2-yl)-3-methyl-2-oxopiperidin-3-yl)acetic acid; [0915]
2-(5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-(1-(cyclobutanesulfonamido)but-
an-2-yl)-3-methyl-2-oxopiperidin-3-yl)acetic acid; [0916]
2-(5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-(1-(N-ethylcyclobutanesulfonam-
ido)butan-2-yl)-3-methyl-2-oxopiperidin-3-yl)acetic acid; [0917]
2-(5-(3-Chlorophenyl)-6-(4-chlorophenyl)-3-methyl-2-oxo-1-(1-(phenylsulfo-
nyl)butan-2-yl)piperidin-3-yl)acetic acid; [0918]
2-(5-(3-Chlorophenyl)-6-(4-chlorophenyl)-3-methyl-1-(1-(methylsulfonyl)bu-
tan-2-yl)-2-oxopiperidin-3-yl)acetic acid; [0919]
2-(5-(3-Chlorophenyl)-6-(4-chlorophenyl)-3-methyl-2-oxo-1-(1-(propylsulfo-
nyl)butan-2-yl)piperidin-3-yl)acetic acid; [0920]
2-(5-(3-Chlorophenyl)-6-(4-chlorophenyl)-1-(1-(isobutylsulfonyl)butan-2-y-
l)-3-methyl-2-oxopiperidin-3-yl)acetic acid; [0921]
2-(5-(3-Chlorophenyl)-6-(4-chlorophenyl)-1-(1-((cyclopropylmethyl)sulfony-
l)butan-2-yl)-3-methyl-2-oxopiperidin-3-yl)acetic acid; [0922]
2-(5-(3-Chlorophenyl)-6-(4-chlorophenyl)-1-(1-((cyclobutylmethyl)sulfonyl-
)butan-2-yl)-3-methyl-2-oxopiperidin-3-yl)acetic acid; [0923]
2-(5-(3-Chlorophenyl)-6-(4-chlorophenyl)-1-(1-(cyclopentylsulfonyl)butan--
2-yl)-3-methyl-2-oxopiperidin-3-yl)acetic acid; [0924]
2-(5-(3-Chlorophenyl)-6-(4-chlorophenyl)-3-methyl-1-(1-(oxetan-3-ylsulfon-
yl)butan-2-yl)-2-oxopiperidin-3-yl)acetic acid; [0925]
2-(5-(3-Chlorophenyl)-6-(4-chlorophenyl)-3-methyl-(1-(((3-methyloxetan-3--
yl)methyl)sulfonyl)butan-2-yl)-2-oxopiperidin-3-yl)acetic acid;
[0926]
2-(5-(3-Chlorophenyl)-6-(4-chlorophenyl)-3-methyl-2-oxo-1-(1-((tetrahydro-
-2H-pyran-4-yl)sulfonyl)butan-2-yl)piperidin-3-yl)acetic acid;
[0927]
2-(5-(3-Chlorophenyl)-6-(4-chlorophenyl)-1-(1-((2-hydroxy-2-methylpropyl)-
sulfonyl)butan-2-yl)-3-methyl-2-oxopiperidin-3-yl)acetic acid;
[0928]
2-(1-(1-(-sec-butylsulfonyl)butan-2-yl)-5-(3-chlorophenyl)-6-(4-chlorophe-
nyl)-3-methyl-2-oxopiperidin-3-yl)acetic acid [0929]
2-(5-(3-Chlorophenyl)-6-(4-chlorophenyl)-1-(2-(cyclopentylsulfonyl)-1-cyc-
lopropylethyl)-3-methyl-2-oxopiperidin-3-yl)acetic acid; [0930]
2-(5-(3-Chlorophenyl)-6-(4-chlorophenyl)-1-(1-cyclopropyl-2-(((3-methylox-
etan-3-yl)methyl)sulfonyl)ethyl)-3-methyl-2-oxopiperidin-3-yl)acetic
acid; [0931]
2-(5-(3-Chlorophenyl)-6-(4-chlorophenyl)-1-(1-cyclopropyl-2-(pheny-
lsulfonyl)ethyl)-3-methyl-2-oxopiperidin-3-yl)acetic acid; [0932]
2-(5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-(1-cyclopropyl-2-(o-tolylsulfo-
nyl)ethyl)-3-methyl-2-oxopiperidin-3-yl)acetic acid; [0933]
2-(5-(3-Chlorophenyl)-6-(4-chlorophenyl)-1-(2-((2-chlorophenyl)sulfonyl)--
1-cyclopropylethyl)-3-methyl-2-oxopiperidin-3-yl)acetic acid;
[0934]
2-(5-(3-Chlorophenyl)-6-(4-chlorophenyl)-1-(2-((4-chlorophenyl)sulfonyl)--
1-cyclopropylethyl)-3-methyl-2-oxopiperidin-3-yl)acetic acid;
[0935]
2-(5-(3-Chlorophenyl)-6-(4-chlorophenyl)-1-(1-cyclopropyl-2-((4-fluorophe-
nyl)sulfonyl)ethyl)-3-methyl-2-oxopiperidin-3-yl)acetic acid;
[0936]
2-(5-(3-Chlorophenyl)-6-(4-chlorophenyl)-1-(1-cyclopropyl-2-(pyridin-4-yl-
sulfonyl)ethyl)-3-methyl-2-oxopiperidin-3-yl)acetic acid; [0937]
2-(1-(2-((2-Chloro-4-fluorophenyl)sulfonyl)-1-cyclopropylethyl)-5-(3-chlo-
rophenyl)-6-(4-chlorophenyl)-3-methyl-2-oxopiperidin-3-yl)acetic
acid; [0938]
2-(5-(3-Chlorophenyl)-6-(4-chlorophenyl)-1-(1-cyclopropyl-2-((cycl-
opropylmethyl)sulfonyl)ethyl)-3-methyl-2-oxopiperidin-3-yl)acetic
acid; [0939]
2-(5-(3-Chlorophenyl)-6-(4-chlorophenyl)-1-(1-cyclopropyl-2-((2,2,-
2-trifluoroethyl)sulfonyl)ethyl)-3-methyl-2-oxopiperidin-3-yl)acetic
acid; [0940]
2-(5-(3-Chlorophenyl)-6-(4-chlorophenyl)-1-(1-cyclopropyl-2-((trif-
luoromethyl)sulfonyl)ethyl)-3-methyl-2-oxopiperidin-3-yl)acetic
acid; [0941]
2-(5-(3-Chlorophenyl)-6-(4-chlorophenyl)-1-(1-cyclopropyl-2-(pheny-
lsulfonyl)ethyl)-3-ethyl-2-oxopiperidin-3-yl)acetic acid; [0942]
2-(5-(3-Chlorophenyl)-6-(4-chlorophenyl)-1-(2-((2-chlorophenyl)sulfonyl)--
1-cyclopropylethyl)-3-ethyl-2-oxopiperidin-3-yl)acetic acid; [0943]
2-(5-(3-Chlorophenyl)-6-(4-chlorophenyl)-1-(1-cyclopropyl-2-((2-fluorophe-
nyl)sulfonyl)ethyl)-3-ethyl-2-oxopiperidin-3-yl)acetic acid; [0944]
2-(5-(3-Chlorophenyl)-6-(4-chlorophenyl)-1-(1-cyclopropyl-2-((3-fluorophe-
nyl)sulfonyl)ethyl)-3-ethyl-2-oxopiperidin-3-yl)acetic acid; [0945]
2-(5-(3-Chlorophenyl)-6-(4-chlorophenyl)-1-(1-cyclopropyl-2-((4-fluorophe-
nyl)sulfonyl)ethyl)-3-ethyl-2-oxopiperidin-3-yl)acetic acid; [0946]
2-(5-(3-Chlorophenyl)-6-(4-chlorophenyl)-1-(1-cyclopropyl-2-(propylsulfon-
yl)ethyl)-3-ethyl-2-oxopiperidin-3-yl)acetic acid; [0947]
2-(1-(2-(Butylsulfonyl)-1-cyclopropylethyl)-5-(3-chlorophenyl)-6-(4-chlor-
ophenyl)-3-ethyl-2-oxopiperidin-3-yl)acetic acid; [0948]
2-(5-(3-Chlorophenyl)-6-(4-chlorophenyl)-1-(1-cyclopropyl-2-(isopentylsul-
fonyl)ethyl)-3-ethyl-2-oxopiperidin-3-yl)acetic acid; [0949]
2-(5-(3-Chlorophenyl)-6-(4-chlorophenyl)-1-(2-(cyclopentylsulfonyl)-1-cyc-
lopropylethyl)-3-ethyl-2-oxopiperidin-3-yl)acetic acid; [0950]
2-(5-(3-Chlorophenyl)-6-(4-chlorophenyl)-1-(2-(cyclohexylsulfonyl)-1-cycl-
opropylethyl)-3-ethyl-2-oxopiperidin-3-yl)acetic acid; [0951]
2-(5-(3-Chlorophenyl)-6-(4-chlorophenyl)-1-(1-cyclopropyl-2-(methylsulfon-
yl)ethyl)-3-ethyl-2-oxopiperidin-3-yl)acetic acid; [0952]
2-(5-(3-Chlorophenyl)-6-(4-chlorophenyl)-3-methyl-1-(3-methyl-1-((2,2,2-t-
rifluoroethyl)sulfonyl)butan-2-yl)-2-oxopiperidin-3-yl)acetic acid;
[0953]
2-(1-(1-(tert-Butylsulfonyl)-3-methylbutan-2-yl)-5-(3-chlorophenyl)-6-(4--
chlorophenyl)-3-methyl-2-oxopiperidin-3-yl)acetic acid; [0954]
2-(5-(3-Chlorophenyl)-6-(4-chlorophenyl)-3-methyl-1-(3-methyl-1-(methylsu-
lfonyl)butan-2-yl)-2-oxopiperidin-3-yl)acetic acid; [0955]
2-(5-(3-Chlorophenyl)-6-(4-chlorophenyl)-1-(1-(ethylsulfonyl)butan-2-yl)--
3-methyl-2-oxopiperidin-3-yl)acetic acid; [0956]
2-(5-(3-Chlorophenyl)-6-(4-chlorophenyl)-1-(1-(cyclopropylsulfonyl)butan--
2-yl)-3-methyl-2-oxopiperidin-3-yl)acetic acid; [0957]
2-(5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-(1-(isopropylsulfonyl)butan-2--
yl)-3-methyl-2-oxopiperidin-3-yl)acetic acid; [0958]
2-(1-(1-(tert-butylsulfonyl)butan-2-yl)-5-(3-chlorophenyl)-6-(4-chlorophe-
nyl)-3-methyl-2-oxopiperidin-3-yl)acetic acid; [0959]
2-(5-(3-Chlorophenyl)-6-(4-chlorophenyl)-1-(1-(cyclobutylsulfonyl)butan-2-
-yl)-3-methyl-2-oxopiperidin-3-yl)acetic acid; [0960]
2-(5-(3-Chlorophenyl)-6-(4-chlorophenyl)-3-ethyl-1-(1-(ethylsulfonyl)buta-
n-2-yl)-2-oxopiperidin-3-yl)acetic acid; [0961]
2-(5-(3-Chlorophenyl)-6-(4-chlorophenyl)-3-ethyl-1-(1-(isopropylsulfonyl)-
butan-2-yl)-2-oxopiperidin-3-yl)acetic acid; [0962]
2-(1-(1-(tert-butylsulfonyl)butan-2-yl)-5-(3-chlorophenyl)-6-(4-chlorophe-
nyl)-3-ethyl-2-oxopiperidin-3-yl)acetic acid; [0963]
2-(5-(3-Chlorophenyl)-6-(4-chlorophenyl)-1-(1-(cyclobutylsulfonyl)butan-2-
-yl)-3-ethyl-2-oxopiperidin-3-yl)acetic acid; [0964]
2-(5-(3-Chlorophenyl)-6-(4-chlorophenyl)-1-(1-(cyclopropylsulfonyl)butan--
2-yl)-3-ethyl-2-oxopiperidin-3-yl)acetic acid; [0965]
2-(5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-(1-cyclopropyl-2-(ethylsulfony-
l)ethyl)-3-methyl-2-oxopiperidin-3-yl)acetic acid; [0966]
2-(5-(3-Chlorophenyl)-6-(4-chlorophenyl)-1-(1-cyclopropyl-2-(isopropylsul-
fonyl)ethyl)-3-methyl-2-oxopiperidin-3-yl)acetic acid; [0967]
2-(1-(2-(tert-Butylsulfonyl)-1-cyclopropylethyl)-5-(3-chlorophenyl)-6-(4--
chlorophenyl)-3-methyl-2-oxopiperidin-3-yl)acetic acid; [0968]
2-(5-(3-Chlorophenyl)-6-(4-chlorophenyl)-1-(2-(cyclobutylsulfonyl)-1-cycl-
opropylethyl)-3-methyl-2-oxopiperidin-3-yl)acetic acid; [0969]
2-(5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-(1-cyclopropyl-2-(cyclopropyls-
ulfonyl)ethyl)-3-methyl-2-oxopiperidin-3-yl)acetic acid; [0970]
2-(5-(3-Chlorophenyl)-6-(4-chlorophenyl)-1-(1-cyclopropyl-2-(methylsulfon-
yl)ethyl)-3-methyl-2-oxopiperidin-3-yl)acetic acid; [0971]
2-(5-(3-Chlorophenyl)-6-(4-chlorophenyl)-1-(1-cyclopropyl-2-(tert-pentyls-
ulfonyl)ethyl)-3-methyl-2-oxopiperidin-3-yl)acetic acid; [0972]
2-(5-(3-Chlorophenyl)-6-(4-chlorophenyl)-1-(1-cyclopropyl-2-((2,4-difluor-
ophenyl)sulfonyl)ethyl)-3-methyl-2-oxopiperidin-3-yl)acetic acid;
[0973]
2-(5-(3-Chlorophenyl)-6-(4-chlorophenyl)-1-(1-cyclopropyl-2-(ethylsulfony-
l)ethyl)-3-ethyl-2-oxopiperidin-3-yl)acetic acid; [0974]
2-(5-(3-Chlorophenyl)-6-(4-chlorophenyl)-1-(1-cyclopropyl-2-(isopropylsul-
fonyl)ethyl)-3-ethyl-2-oxopiperidin-3-yl)acetic acid; [0975]
2-(1-((2-(tert-Butylsulfonyl)-1-cyclopropylethyl)-5-(3-chlorophenyl)-6-(4-
-chlorophenyl)-3-ethyl-2-oxopiperidin-3-yl)acetic acid; [0976]
2-(5-(3-Chlorophenyl)-6-(4-chlorophenyl)-1-(1-cyclopropyl-2-(cyclopropyls-
ulfonyl)ethyl)-3-ethyl-2-oxopiperidin-3-yl)acetic acid; [0977]
2-(5-(3-Chlorophenyl)-6-(4-chlorophenyl)-1-(1-(ethylsulfonyl)-3-methylbut-
an-2-yl)-3-methyl-2-oxopiperidin-3-yl)acetic acid; [0978]
2-(5-(3-Chlorophenyl)-6-(4-chlorophenyl)-1-(1-(isopropylsulfonyl)-3-methy-
lbutan-2-yl)-3-methyl-2-oxopiperidin-3-yl)acetic acid; [0979]
2-(5-(3-Chlorophenyl)-6-(4-chlorophenyl)-1-(3,3-dimethyl-1-(methylsulfony-
l)butan-2-yl)-3-methyl-2-oxopiperidin-3-yl)acetic acid; [0980]
2-(5-(3-Chlorophenyl)-6-(4-chlorophenyl)-1-(1-(ethylsulfonyl)-3,3-dimethy-
lbutan-2-yl)-3-methyl-2-oxopiperidin-3-yl)acetic acid; [0981]
2-(5-(3-Chlorophenyl)-6-(4-chlorophenyl)-1-(1-(isopropylsulfonyl)-3,3-dim-
ethylbutan-2-yl)-3-methyl-2-oxopiperidin-3-yl)acetic acid; [0982]
2-(5-(3-Chlorophenyl)-6-(4-chlorophenyl)-1-(1-cyclopropyl-2-(pentan-3-yls-
ulfonyl)ethyl)-3-methyl-2-oxopiperidin-3-yl)acetic acid; [0983]
2-(5-(3-Chlorophenyl)-6-(4-chlorophenyl)-1-(1-(isopropylsulfinyl)butan-2--
yl)-3-methyl-2-oxopiperidin-3-yl)acetic acid; [0984]
2-(5-(3-Chlorophenyl)-6-(4-chlorophenyl)-3-methyl-1-(2-(methylsulfonyl)pe-
ntan-3-yl)-2-oxopiperidin-3-yl)acetic acid; [0985]
2-(5-(3-Chlorophenyl)-6-(4-chlorophenyl)-1-(2-(ethylsulfonyl)pentan-3-yl)-
-3-methyl-2-oxopiperidin-3-yl)acetic acid; [0986]
2-(5-(3-Chlorophenyl)-6-(4-chlorophenyl)-3-methyl-1-(1-(N-(oxetan-3-yl)su-
lfamoyl)butan-2-yl)-2-oxopiperidin-3-yl)acetic acid; [0987]
2-(5-(3-Chlorophenyl)-6-(4-chlorophenyl)-3-methyl-1-(1-(N-((3-methyloxeta-
n-3-yl)methyl)sulfamoyl)butan-2-yl)-2-oxopiperidin-3-yl)acetic
acid; [0988]
2-(5-(3-Chlorophenyl)-6-(4-chlorophenyl)-3-methyl-1-(1-(N-(oxetan--
3-ylmethyl)sulfamoyl)butan-2-yl)-2-oxopiperidin-3-yl)acetic
acid;
[0989]
2-(1-(2-(N-(tert-Butyl)sulfamoyl)-1-cyclopropylethyl)-5-(3-chlorop-
henyl)-6-(4-chlorophenyl)-3-methyl-2-oxopiperidin-3-yl)acetic acid;
[0990]
2-(5-(3-Chlorophenyl)-6-(4-chlorophenyl)-1-(1-cyclopropyl-2-(N-methylsulf-
amoyl)ethyl)-3-methyl-2-oxopiperidin-3-yl)acetic acid; [0991]
2-(5-(3-Chlorophenyl)-6-(4-chlorophenyl)-1-(1-cyclopropyl-2-(N,N-dimethyl-
sulfamoyl)ethyl)-3-methyl-2-oxopiperidin-3-yl)acetic acid; [0992]
2-(5-(3-Chlorophenyl)-6-(4-chlorophenyl)-1-(1-cyclopropyl-2-(N-isopropyls-
ulfamoyl)ethyl)-3-methyl-2-oxopiperidin-3-yl)acetic acid; [0993]
2-(5-(3-Chlorophenyl)-6-(4-chlorophenyl)-1-(1-cyclopropyl-2-(morpholinosu-
lfonyl)ethyl)-3-methyl-2-oxopiperidin-3-yl)acetic acid; [0994]
2-(5-(3-Chlorophenyl)-6-(4-chlorophenyl)-1-(1-cyclopropyl-2-(piperidin-1--
ylsulfonyl)ethyl)-3-methyl-2-oxopiperidin-3-yl)acetic acid; [0995]
2-(5-(3-Chlorophenyl)-6-(4-chlorophenyl)-1-(1-cyclopropyl-2-(pyrrolidin-1-
-ylsulfonyl)ethyl)-3-methyl-2-oxopiperidin-3-yl)acetic acid; [0996]
2-(1-(2-(Azetidin-1-ylsulfonyl)-1-cyclopropylethyl)-5-(3-chlorophenyl)-6--
(4-chlorophenyl)-3-methyl-2-oxopiperidin-3-yl)acetic acid; [0997]
2-(5-(3-Chlorophenyl)-6-(4-chlorophenyl)-1-(1-cyclopropyl-2-((N,N-dimethy-
lsulfamoyl)amino)ethyl)-3-methyl-2-oxopiperidin-3-yl)acetic acid;
[0998]
2-(5-(3-Chlorophenyl)-6-(4-chlorophenyl)-1-(1-cyclopropyl-2-((N,N-dimethy-
lsulfamoyl)(methyl)amino)ethyl)-3-methyl-2-oxopiperidin-3-yl)acetic
acid; [0999]
2-(5-(3-Chlorophenyl)-6-(4-chlorophenyl)-1-(1-cyclopropyl-2-(3-met-
hyl-2,5-dioxoimidazolidin-1-yl)ethyl)-3-methyl-2-oxopiperidin-3-yl)acetic
acid; [1000]
2-(5-(3-Chlorophenyl)-6-(4-chlorophenyl)-1-(1-cyclopropyl-2-(3,4,4-trimet-
hyl-2,5-dioxoimidazolidin-1-yl)ethyl)-3-methyl-2-oxopiperidin-3-yl)acetic
acid; [1001]
2-(5-(3-Chlorophenyl)-6-(4-chlorophenyl)-1-(1-cyclopropyl-2-(4,4-dimethyl-
-2,5-dioxoimidazolidin-1-yl)ethyl)-3-methyl-2-oxopiperidin-3-yl)acetic
acid; [1002]
2-(5-(3-Chlorophenyl)-6-(4-chlorophenyl)-1-(1-cyclopropyl-2-(3-isopropyl--
2,2-dioxido-4-oxo-3,4-dihydro-1H-benzo[c][1,2,6]thiadiazin-1-yl)ethyl)-3-m-
ethyl-2-oxopiperidin-3-yl)acetic acid; [1003]
2-(5-(3-Chlorophenyl)-6-(4-chlorophenyl)-1-(1-cyclopropyl-2-(2-oxo-2,3-di-
hydro-1H-benzo[d]imidazol-1-yl)ethyl)-3-methyl-2-oxopiperidin-3-yl)acetic
acid; [1004]
2-(5-(3-Chloro-4-fluorophenyl)-6-(4-chlorophenyl)-1-isopropyl-3-methyl-2--
oxopiperidin-3-yl)acetic acid; [1005]
2-(5-(3-Chloro-5-fluorophenyl)-6-(4-chlorophenyl)-1-isopropyl-3-methyl-2--
oxopiperidin-3-yl)acetic acid; [1006]
2-(5-(3-Chloro-5-fluorophenyl)-6-(4-chlorophenyl)-1-(1-(ethylsulfonamido)-
butan-2-yl)-3-methyl-2-oxopiperidin-3-yl)acetic acid; [1007]
2-(5-(3-Chloro-5-fluorophenyl)-6-(4-chlorophenyl)-3-methyl-1-(1-(N-methyl-
ethylsulfonamido)butan-2-yl)-2-oxopiperidin-3-yl)acetic acid;
[1008]
2-(5-(3-Chloro-5-fluorophenyl)-6-(4-chlorophenyl)-3-methyl-1-(1-(methylsu-
lfonyl)butan-2-yl)-2-oxopiperidin-3-yl)acetic acid; [1009]
2-(5-(3-Chloro-5-fluorophenyl)-6-(4-chlorophenyl)-1-(1-(ethylsulfonyl)but-
an-2-yl)-3-methyl-2-oxopiperidin-3-yl)acetic acid; [1010]
2-(5-(3-Chloro-5-fluorophenyl)-6-(4-chlorophenyl)-1-(1-(cyclopropylsulfon-
yl)butan-2-yl)-3-methyl-2-oxopiperidin-3-yl)acetic acid; [1011]
2-(1-(1-(tert-Butylsulfonyl)butan-2-yl)-5-(3-chloro-5-fluorophenyl)-6-(4--
chlorophenyl)-3-methyl-2-oxopiperidin-3-yl)acetic acid; [1012]
2-(5-(3-Chloro-5-fluorophenyl)-6-(4-chlorophenyl)-1-(1-(isopropylsulfonyl-
)butan-2-yl)-3-methyl-2-oxopiperidin-3-yl)acetic acid; [1013]
2-(6-(4-Chlorophenyl)-5-(5-chloropyridin-3-yl)-1-(1-(cyclopropylsulfonyl)-
butan-2-yl)-3-methyl-2-oxopiperidin-3-yl)acetic acid; [1014]
2-(1-(1-(tert-Butylsulfonyl)butan-2-yl)-6-(4-chlorophenyl)-5-(5-chloropyr-
idin-3-yl)-3-methyl-2-oxopiperidin-3-yl)acetic acid; [1015]
2-(6-(4-Chlorophenyl)-5-(5-chloropyridin-3-yl)-1-(1-(cyclopropanesulfonam-
ido)butan-2-yl)-3-methyl-2-oxopiperidin-3-yl)acetic acid; [1016]
2-(6-(4-Chlorophenyl)-5-(5-chloropyridin-3-yl)-3-methyl-1-(1-(N-methylcyc-
lopropanesulfonamido)butan-2-yl)-2-oxopiperidin-3-yl)acetic acid;
[1017]
2-(5-(3-Chlorophenyl)-6-(5-chloropyridin-2-yl)-1-(1-(ethylsulfonyl)butan--
2-yl)-3-methyl-2-oxopiperidin-3-yl)acetic acid; [1018]
2-(5-(3-Chlorophenyl)-6-(4-chlorophenyl)-3-methyl-1-(1-(morpholin-2-yl)pr-
opyl)-2-oxopiperidin-3-yl)acetic acid; [1019]
2-(5-(3-Chlorophenyl)-6-(4-chlorophenyl)-1-(1-(N-methylcyclopropanesulfon-
amido)butan-2-yl)-3-(2-morpholinoethyl)-2-oxopiperidin-3-yl)acetic
acid; [1020]
2-(5-(3-Chlorophenyl)-6-(4-chlorophenyl)-3-(2-(1,1-dioxidothiomorp-
holino)ethyl)-1-(1-(N-methylcyclopropanesulfonamido)butan-2-yl)-2-oxopiper-
idin-3-yl)acetic acid; [1021]
2-(5-(3-Chlorophenyl)-6-(4-chlorophenyl)-1-(1-(N-methylcyclopropanesulfon-
amido)butan-2-yl)-2-oxo-3-(2-(pyrrolidin-1-yl)ethyl)piperidin-3-yl)acetic
acid; [1022]
2-(5-(3-Chlorophenyl)-6-(4-chlorophenyl)-3-(2-(dimethylamino)ethyl)-1-(1--
(N-methylcyclopropanesulfonamido)butan-2-yl)-2-oxopiperidin-3-yl)acetic
acid; [1023]
2-(5-(3-Chlorophenyl)-6-(4-chlorophenyl)-1-(1-(N-methylcyclopropanesulfon-
amido)butan-2-yl)-3-(2-morpholinoethyl)-2-oxopiperidin-3-yl)acetamide;
[1024]
7-(3-Chlorophenyl)-6-(4-chlorophenyl)-5-(1-(N-methylcyclopropanesu-
lfonamido)butan-2-yl)-4-oxo-5-azaspiro[2.5]octane-1-carboxylic
acid; [1025]
2-(5-(3-Chlorophenyl)-6-(4-chlorophenyl)-1-(1,2-dihydroxypentan-3--
yl)-3-methyl-2-oxopiperidin-3-yl)acetic acid; [1026]
2-(5-(3-Chlorophenyl)-6-(4-chlorophenyl)-1-(1-cyclopropyl-1-hydroxybutan--
2-yl)-3-methyl-2-oxopiperidin-3-yl)acetic acid; [1027]
2-(5-(3-Chlorophenyl)-6-(4-chlorophenyl)-1-isopropyl-6-methyl-2-oxopiperi-
din-3-yl)acetic acid; [1028]
5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-(1-(1,1-dioxidoisothiazolidin-2-y-
l)butan-2-yl)-3-((6-methoxypyridin-2-yl)methyl)piperidin-2-one;
[1029]
5-(3-Chlorophenyl)-6-(4-chlorophenyl)-1-(1-(1,1-dioxidoisothiazolidin-2-y-
l)butan-2-yl)-3-((6-hydroxypyridin-2-yl)methyl)piperidin-2-one;
[1030]
5-(3-Chlorophenyl)-6-(4-chlorophenyl)-1-(1-(1,1-dioxidoisothiazolidin-2-y-
l)butan-2-yl)-3-((6-methoxypyridin-2-yl)methyl)-3-methylpiperidin-2-one;
[1031]
5-(3-Chlorophenyl)-6-(4-chlorophenyl)-1-(1-(1,1-dioxidoisothiazoli-
din-2-yl)butan-2-yl)-3-((6-hydroxypyridin-2-yl)methyl)-3-methylpiperidin-2-
-one; [1032]
(5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-(1-cyclopropyl-2-(ethylsulfonyl)-
ethyl)-3-(3-hydroxy-2-oxopropyl)-3-methylpiperidin-2-one; [1033]
2-(5-(3-Chlorophenyl)-6-(4-chlorophenyl)-1-(diethylamino)-3-methyl-2-oxop-
iperidin-3-yl)acetic acid; [1034]
2-(5-(3-Chlorophenyl)-6-(4-chlorophenyl)-1-(dimethylamino)-3-methyl-2-oxo-
piperidin-3-yl)acetic acid; or [1035]
6-(3-chlorophenyl)-5-(4-chlorophenyl)-3-ethyl-2,7a-dimethylhexahydrofuro[-
2,3-b]oxazolo[3,2-a]pyridin-9(5H)-one.
[1036] In another aspect, the present invention provides a
compound, or a pharmaceutically acceptable salt thereof, selected
from: [1037]
2-((3R,5R,6S)-5-(3-Chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-cyclopropyl--
2-(methylsulfonyl)ethyl)-3-methyl-2-oxopiperidin-3-yl)acetic acid;
[1038]
2-((3R,5R,6S)-5-(3-Chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-(isopropylsu-
lfonyl)-3-methylbutan-2-yl)-3-methyl-2-oxopiperidin-3-yl)acetic
acid; [1039]
2-((3R,5R,6S)-1-((S)-1-(tert-butylsulfonyl)butan-2-yl)-5-(3-chloro-
phenyl)-6-(4-chlorophenyl)-3-methyl-2-oxopiperidin-3-yl)acetic
acid; [1040]
2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-(isop-
ropylsulfonyl)butan-2-yl)-3-methyl-2-oxopiperidin-3-yl)acetic acid;
[1041]
2-((3R,5R,6S)-5-(3-Chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-(isopropylsu-
lfonyl)-3,3-dimethylbutan-2-yl)-3-methyl-2-oxopiperidin-3-yl)acetic
acid; [1042]
2-((3R,5R,6S)-5-(3-Chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-(ethy-
lsulfonyl)-3-methylbutan-2-yl)-3-methyl-2-oxopiperidin-3-yl)acetic
acid; [1043]
2-((3R,5R,6S)-5-(3-Chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-(ethy-
lsulfonyl)butan-2-yl)-3-methyl-2-oxopiperidin-3-yl)acetic acid;
[1044]
2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-cyclopropyl--
2-(N-phenylcyclopropanesulfonamido)ethyl)-3-methyl-2-oxopiperidin-3-yl)ace-
tic acid; or [1045]
2-((3R,5R,6S)-5-(3-Chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-((cyclopropy-
lmethyl)sulfonyl)butan-2-yl)-3-methyl-2-oxopiperidin-3-yl)acetic
acid.
[1046] In another aspect, the present invention provides a
compound, or a pharmaceutically acceptable salt thereof, selected
from: [1047]
2-(-5-(3-Chlorophenyl)-6-(4-chlorophenyl)-1-(-1-cyclopropyl-2-(methylsulf-
onyl)ethyl)-3-methyl-2-oxopiperidin-3-yl)acetic acid; [1048]
2-(-5-(3-Chlorophenyl)-6-(4-chlorophenyl)-1-(-1-(isopropylsulfonyl)-3-met-
hylbutan-2-yl)-3-methyl-2-oxopiperidin-3-yl)acetic acid; [1049]
2-(-1-(-1-(tert-butylsulfonyl)butan-2-yl)-5-(3-chlorophenyl)-6-(4-chlorop-
henyl)-3-methyl-2-oxopiperidin-3-yl)acetic acid; [1050]
2-(-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-(-1-(isopropylsulfonyl)butan--
2-yl)-3-methyl-2-oxopiperidin-3-yl)acetic acid; [1051]
2-(-5-(3-Chlorophenyl)-6-(4-chlorophenyl)-1-(-1-(isopropylsulfonyl)-3,3-d-
imethylbutan-2-yl)-3-methyl-2-oxopiperidin-3-yl)acetic acid; [1052]
2-(-5-(3-Chlorophenyl)-6-(4-chlorophenyl)-1-(-1-(ethylsulfonyl)-3-methylb-
utan-2-yl)-3-methyl-2-oxopiperidin-3-yl)acetic acid; [1053]
2-(-5-(3-Chlorophenyl)-6-(4-chlorophenyl)-1-(-1-(ethylsulfonyl)butan-2-yl-
)-3-methyl-2-oxopiperidin-3-yl)acetic acid; [1054]
2-(-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-(-1-cyclopropyl-2-(N-phenylcy-
clopropanesulfonamido)ethyl)-3-methyl-2-oxopiperidin-3-yl)acetic
acid; [1055]
2-(-5-(3-Chlorophenyl)-6-(4-chlorophenyl)-1-(-1-((cyclopropylmethy-
l)sulfonyl)butan-2-yl)-3-methyl-2-oxopiperidin-3-yl)acetic acid;
[1056]
2-(-5-(3-Chlorophenyl)-6-(4-chlorophenyl)-1-(-1-cyclopropyl-2-(methylsulf-
onyl)ethyl)-3-methyl-2-oxopiperidin-3-yl)acetic acid; [1057]
2-(-5-(3-Chlorophenyl)-6-(4-chlorophenyl)-1-(-1-(isopropylsulfonyl)-3-met-
hylbutan-2-yl)-3-methyl-2-oxopiperidin-3-yl)acetic acid; or [1058]
2-(-1-(-1-(tert-butylsulfonyl)butan-2-yl)-5-(3-chlorophenyl)-6-(4-chlorop-
henyl)-3-methyl-2-oxopiperidin-3-yl)acetic acid.
[1059] The present invention provides pharmaceutical compositions
comprising a compound of any one of the above aspects or
embodiments, or a pharmaceutically acceptable salt thereof,
together with a pharmaceutically acceptable excipient, diluent or
carrier.
[1060] The present invention also provides method of treating
cancer in a subject in need of said treatment, the method
comprising administering to the subject an effective dosage amount
of a compound according to any one of the above aspects or
embodiments, or a pharmaceutically acceptable salt thereof.
DETAILED DESCRIPTION OF THE INVENTION
[1061] The term "H" denotes a single hydrogen atom. This radical
may be attached, for example, to an oxygen atom to form a hydroxyl
radical.
[1062] Where the term "alkyl" is used, either alone or within other
terms such as "haloalkyl" or "alkylamino", it embraces linear or
branched radicals having one to about twelve carbon atoms. More
preferred alkyl radicals are "lower alkyl" radicals having one to
about six carbon atoms. Examples of such radicals include methyl,
ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl,
tert-butyl, pentyl, isoamyl, hexyl and the like. Even more
preferred are lower alkyl radicals having one or two carbon atoms.
The term "alkylenyl" or "alkylene" embraces bridging divalent alkyl
radicals such as methylenyl or ethylenyl. The term "lower alkyl
substituted with R.sup.2" does not include an acetal moiety. The
term "alkyl" further includes alkyl radicals wherein one or more
carbon atoms in the chain is substituted with a heteroatom selected
from oxygen, nitrogen, or sulfur.
[1063] The term "alkenyl" embraces linear or branched radicals
having at least one carbon-carbon double bond of two to about
twelve carbon atoms. More preferred alkenyl radicals are "lower
alkenyl" radicals having two to about six carbon atoms. Most
preferred lower alkenyl radicals are radicals having two to about
four carbon atoms. Examples of alkenyl radicals include ethenyl,
propenyl, allyl, propenyl, butenyl and 4-methylbutenyl. The terms
"alkenyl" and "lower alkenyl", embrace radicals having "cis" and
"trans" orientations, or alternatively, "E" and "Z"
orientations.
[1064] The term "alkynyl" denotes linear or branched radicals
having at least one carbon-carbon triple bond and having two to
about twelve carbon atoms. More preferred alkynyl radicals are
"lower alkynyl" radicals having two to about six carbon atoms. Most
preferred are lower alkynyl radicals having two to about four
carbon atoms. Examples of such radicals include propargyl, and
butynyl, and the like.
[1065] Alkyl, alkylenyl, alkenyl, and alkynyl radicals may be
optionally substituted with one or more functional groups such as
halo, hydroxy, nitro, amino, cyano, haloalkyl, aryl, heteroaryl,
and heterocyclo and the like.
[1066] The term "halo" means halogens such as fluorine, chlorine,
bromine or iodine atoms.
[1067] The term "haloalkyl" embraces radicals wherein any one or
more of the alkyl carbon atoms is substituted with halo as defined
above. Specifically embraced are monohaloalkyl, dihaloalkyl and
polyhaloalkyl radicals including perhaloalkyl. A monohaloalkyl
radical, for example, may have either an iodo, bromo, chloro or
fluoro atom within the radical. Dihalo and polyhaloalkyl radicals
may have two or more of the same halo atoms or a combination of
different halo radicals. "Lower haloalkyl" embraces radicals having
1 to 6 carbon atoms.
[1068] Even more preferred are lower haloalkyl radicals having one
to three carbon atoms. Examples of haloalkyl radicals include
fluoromethyl, difluoromethyl, trifluoromethyl, chloromethyl,
dichloromethyl, trichloromethyl, pentafluoroethyl,
heptafluoropropyl, difluorochloromethyl, dichlorofluoromethyl,
difluoroethyl, difluoropropyl, dichloroethyl and
dichloropropyl.
[1069] The term "perfluoroalkyl" means alkyl radicals having all
hydrogen atoms replaced with fluoro atoms. Examples include
trifluoromethyl and pentafluoroethyl.
[1070] The term "hydroxyalkyl" embraces linear or branched alkyl
radicals having one to about ten carbon atoms any one of which may
be substituted with one or more hydroxyl radicals. More preferred
hydroxyalkyl radicals are "lower hydroxyalkyl" radicals having one
to six carbon atoms and one or more hydroxyl radicals. Examples of
such radicals include hydroxymethyl, hydroxyethyl, hydroxypropyl,
hydroxybutyl and hydroxyhexyl. Even more preferred are lower
hydroxyalkyl radicals having one to three carbon atoms.
[1071] The term "alkoxy" embraces linear or branched oxy-containing
radicals each having alkyl portions of one to about ten carbon
atoms. More preferred alkoxy radicals are "lower alkoxy" radicals
having one to six carbon atoms. Examples of such radicals include
methoxy, ethoxy, propoxy, butoxy and tert-butoxy. Even more
preferred are lower alkoxy radicals having one to three carbon
atoms. Alkoxy radicals may be further substituted with one or more
halo atoms, such as fluoro, chloro or bromo, to provide
"haloalkoxy" radicals. Even more preferred are lower haloalkoxy
radicals having one to three carbon atoms. Examples of such
radicals include fluoromethoxy, chloromethoxy, trifluoromethoxy,
trifluoroethoxy, fluoroethoxy and fluoropropoxy.
[1072] The term "aryl", alone or in combination, means a
carbocyclic aromatic system containing one or two rings, wherein
such rings may be attached together in a fused manner. The term
"aryl" embraces aromatic radicals such as phenyl, naphthyl,
indenyl, tetrahydronaphthyl, and indanyl. More preferred aryl is
phenyl. An "aryl" group may have 1 or more substituents such as
lower alkyl, hydroxyl, halo, haloalkyl, nitro, cyano, alkoxy, and
lower alkylamino, and the like. Phenyl substituted with
--O--CH.sub.2--O-- forms the aryl benzodioxolyl substituent.
[1073] The term "heterocyclyl" (or "heterocyclo") embraces
saturated, partially saturated and unsaturated
heteroatom-containing ring radicals, where the heteroatoms may be
selected from nitrogen, sulfur and oxygen. It does not include
rings containing --O--O--, --O--S-- or --S--S-- portions. The
"heterocyclyl" group may have 1 to 4 substituents such as hydroxyl,
Boc, halo, haloalkyl, cyano, lower alkyl, lower aralkyl, oxo, lower
alkoxy, amino and lower alkylamino.
[1074] Examples of saturated heterocyclic radicals include
saturated 3 to 6-membered heteromonocyclic groups containing 1 to 4
nitrogen atoms [e.g., pyrrolidinyl, imidazolidinyl, piperidinyl,
pyrrolinyl, piperazinyl]; saturated 3 to 6-membered
heteromonocyclic group containing 1 to 2 oxygen atoms and 1 to 3
nitrogen atoms [e.g., morpholinyl]; saturated 3 to 6-membered
heteromonocyclic group containing 1 to 2 sulfur atoms and 1 to 3
nitrogen atoms [e.g., thiazolidinyl]. Examples of partially
saturated heterocyclyl radicals include dihydrothienyl,
dihydropyranyl, dihydrofuryl and dihydrothiazolyl.
[1075] Examples of unsaturated heterocyclic radicals, also termed
"heteroaryl" radicals, include unsaturated 5 to 6 membered
heteromonocyclyl group containing 1 to 4 nitrogen atoms, for
example, pyrrolyl, imidazolyl, pyrazolyl, 2-pyridyl, 3-pyridyl,
4-pyridyl, pyrimidyl, pyrazinyl, pyridazinyl, triazolyl [e.g.,
4H-1,2,4-triazolyl, 1H-1,2,3-triazolyl, 2H-1,2,3-triazolyl];
unsaturated 5- to 6-membered heteromonocyclic group containing an
oxygen atom, for example, pyranyl, 2-furyl, 3-furyl, etc.;
unsaturated 5 to 6-membered heteromonocyclic group containing a
sulfur atom, for example, 2-thienyl, 3-thienyl, etc.; unsaturated
5- to 6-membered heteromonocyclic group containing 1 to 2 oxygen
atoms and 1 to 3 nitrogen atoms, for example, oxazolyl, isoxazolyl,
oxadiazolyl [e.g., 1,2,4-oxadiazolyl, 1,3,4-oxadiazolyl,
1,2,5-oxadiazolyl]; unsaturated 5 to 6-membered heteromonocyclic
group containing 1 to 2 sulfur atoms and 1 to 3 nitrogen atoms, for
example, thiazolyl, thiadiazolyl [e.g., 1,2,4-thiadiazolyl,
1,3,4-thiadiazolyl, 1,2,5-thiadiazolyl].
[1076] The term heterocyclyl, (or heterocyclo) also embraces
radicals where heterocyclic radicals are fused/condensed with aryl
radicals: unsaturated condensed heterocyclic group containing 1 to
5 nitrogen atoms, for example, indolyl, isoindolyl, indolizinyl,
benzimidazolyl, quinolyl, isoquinolyl, indazolyl, benzotriazolyl,
tetrazolopyridazinyl [e.g., tetrazolo[1,5-b]pyridazinyl];
unsaturated condensed heterocyclic group containing 1 to 2 oxygen
atoms and 1 to 3 nitrogen atoms [e.g. benzoxazolyl,
benzoxadiazolyl]; unsaturated condensed heterocyclic group
containing 1 to 2 sulfur atoms and 1 to 3 nitrogen atoms [e.g.,
benzothiazolyl, benzothiadiazolyl]; and saturated, partially
unsaturated and unsaturated condensed heterocyclic group containing
1 to 2 oxygen or sulfur atoms [e.g. benzofuryl, benzothienyl,
2,3-dihydro-benzo[1,4]dioxinyl and dihydrobenzofuryl]. Preferred
heterocyclic radicals include five to ten membered fused or unfused
radicals. More preferred examples of heteroaryl radicals include
quinolyl, isoquinolyl, imidazolyl, pyridyl, thienyl, thiazolyl,
oxazolyl, furyl and pyrazinyl. Other preferred heteroaryl radicals
are 5- or 6-membered heteroaryl, containing one or two heteroatoms
selected from sulfur, nitrogen and oxygen, selected from thienyl,
furyl, pyrrolyl, indazolyl, pyrazolyl, oxazolyl, triazolyl,
imidazolyl, pyrazolyl, isoxazolyl, isothiazolyl, pyridyl,
piperidinyl and pyrazinyl.
[1077] Particular examples of non-nitrogen containing heteroaryl
include pyranyl, 2-furyl, 3-furyl, 2-thienyl, 3-thienyl,
benzofuryl, and benzothienyl, and the like.
[1078] Particular examples of partially saturated and saturated
heterocyclyl include pyrrolidinyl, imidazolidinyl, piperidinyl,
pyrrolinyl, pyrazolidinyl, piperazinyl, morpholinyl,
tetrahydropyranyl, thiazolidinyl, dihydrothienyl,
2,3-dihydro-benzo[1,4]dioxanyl, indolinyl, isoindolinyl,
dihydrobenzothienyl, dihydrobenzofuryl, isochromanyl, chromanyl,
1,2-dihydroquinolyl, 1,2,3,4-tetrahydro-isoquinolyl,
1,2,3,4-tetrahydro-quinolyl,
2,3,4,4a,9,9a-hexahydro-1H-3-aza-fluorenyl,
5,6,7-trihydro-1,2,4-triazolo[3,4-a]isoquinolyl,
3,4-dihydro-2H-benzo[1,4]oxazinyl, benzo[1,4]dioxanyl,
2,3-dihydro-1H-1.lamda.'-benzo[d]isothiazol-6-yl, dihydropyranyl,
dihydrofuryl and dihydrothiazolyl, and the like.
[1079] The term "heterocyclo" thus encompasses the following ring
systems:
##STR00055## ##STR00056## ##STR00057##
and the like.
[1080] The term "sulfonyl", whether used alone or linked to other
terms such as alkylsulfonyl, denotes respectively divalent radicals
--SO.sub.2--.
[1081] The terms "sulfamyl," "aminosulfonyl" and "sulfonamidyl,"
denotes a sulfonyl radical substituted with an amine radical,
forming a sulfonamide (--SO.sub.2NH.sub.2).
[1082] The term "alknyaminosulfonyl" includes
"N-alkylaminosulfonyl" where sulfamyl radicals are independently
substituted with one or two alkyl radical(s). More preferred
alkylaminosulfonyl radicals are "lower alkylaminosulfonyl" radicals
having one to six carbon atoms. Even more preferred are lower
alkylaminosulfonyl radicals having one to three carbon atoms.
Examples of such lower alkylaminosulfonyl radicals include
N-methylaminosulfonyl, and N-ethylaminosulfonyl.
[1083] The terms "carboxy" or "carboxyl," whether used alone or
with other terms, such as "carboxyalkyl," denotes --CO.sub.2H.
[1084] The term "carbonyl," whether used alone or with other terms,
such as "aminocarbonyl," denotes --(C.dbd.O)--.
[1085] The term "aminocarbonyl" denotes an amide group of the
formula C(.dbd.O)NH.sub.2.
[1086] The terms "N-alkylaminocarbonyl" and
"N,N-dialkylaminocarbonyl" denote aminocarbonyl radicals
independently substituted with one or two alkyl radicals,
respectively. More preferred are "lower alkylaminocarbonyl" having
lower alkyl radicals as described above attached to an
aminocarbonyl radical.
[1087] The terms "N-arylaminocarbonyl" and
"N-alkyl-N-arylaminocarbonyl" denote aminocarbonyl radicals
substituted, respectively, with one aryl radical, or one alkyl and
one aryl radical.
[1088] The terms "heterocyclylalkylenyl" and "heterocyclylalkyl"
embrace heterocyclic-substituted alkyl radicals. More preferred
heterocyclylalkyl radicals are "5- or 6-membered heteroarylalkyl"
radicals having alkyl portions of one to six carbon atoms and a 5-
or 6-membered heteroaryl radical. Even more preferred are lower
heteroarylalkylenyl radicals having alkyl portions of one to three
carbon atoms. Examples include such radicals as pyridylmethyl and
thienylmethyl.
[1089] The term "aralkyl" embraces aryl-substituted alkyl radicals.
Preferable aralkyl radicals are "lower aralkyl" radicals having
aryl radicals attached to alkyl radicals having one to six carbon
atoms. Even more preferred are "phenylalkylenyl" attached to alkyl
portions having one to three carbon atoms. Examples of such
radicals include benzyl, diphenylmethyl and phenylethyl. The aryl
in said aralkyl may be additionally substituted with halo, alkyl,
alkoxy, halkoalkyl and haloalkoxy.
[1090] The term "alkylthio" embraces radicals containing a linear
or branched alkyl radical, of one to ten carbon atoms, attached to
a divalent sulfur atom. Even more preferred are lower alkylthio
radicals having one to three carbon atoms. An example of
"alkylthio" is methylthio, (CH.sub.3S--).
[1091] The term "haloalkylthio" embraces radicals containing a
haloalkyl radical, of one to ten carbon atoms, attached to a
divalent sulfur atom. Even more preferred are lower haloalkylthio
radicals having one to three carbon atoms. An example of
"haloalkylthio" is trifluoromethylthio.
[1092] The term "alkylamino" embraces "N-alkylamino" and
"N,N-dialkylamino" where amino groups are independently substituted
with one alkyl radical and with two alkyl radicals, respectively.
More preferred alkylamino radicals are "lower alkylamino" radicals
having one or two alkyl radicals of one to six carbon atoms,
attached to a nitrogen atom. Even more preferred are lower
alkylamino radicals having one to three carbon atoms. Suitable
alkylamino radicals may be mono or dialkylamino such as
N-methylamino, N-ethylamino, N,N-dimethylamino, and
N,N-diethylamino, and the like.
[1093] The term "arylamino" denotes amino groups, which have been
substituted with one or two aryl radicals, such as N-phenylamino.
The arylamino radicals may be further substituted on the aryl ring
portion of the radical.
[1094] The term "heteroarylamino" denotes amino groups, which have
been substituted with one or two heteroaryl radicals, such as
N-thienylamino. The "heteroarylamino" radicals may be further
substituted on the heteroaryl ring portion of the radical.
[1095] The term "aralkylamino" denotes amino groups, which have
been substituted with one or two aralkyl radicals. More preferred
are phenyl-C.sub.1-C.sub.3-alkylamino radicals, such as
N-benzylamino. The aralkylamino radicals may be further substituted
on the aryl ring portion.
[1096] The terms "N-alkyl-N-arylamino" and "N-aralkyl-N-alkylamino"
denote amino groups, which have been independently substituted with
one aralkyl and one alkyl radical, or one aryl and one alkyl
radical, respectively, to an amino group.
[1097] The term "aminoalkyl" embraces linear or branched alkyl
radicals having one to about ten carbon atoms any one of which may
be substituted with one or more amino radicals. More preferred
aminoalkyl radicals are "lower aminoalkyl" radicals having one to
six carbon atoms and one or more amino radicals. Examples of such
radicals include aminomethyl, aminoethyl, aminopropyl, aminobutyl
and aminohexyl. Even more preferred are lower aminoalkyl radicals
having one to three carbon atoms.
[1098] The term "alkylaminoalkyl" embraces alkyl radicals
substituted with alkylamino radicals. More preferred
alkylaminoalkyl radicals are "lower alkylaminoalkyl" radicals
having alkyl radicals of one to six carbon atoms. Even more
preferred are lower alkylaminoalkyl radicals having alkyl radicals
of one to three carbon atoms. Suitable alkylaminoalkyl radicals may
be mono or dialkyl substituted, such as N-methylaminomethyl,
N,N-dimethyl-aminoethyl, and N,N-diethylaminomethyl, and the
like.
[1099] The term "alkylaminoalkoxy" embraces alkoxy radicals
substituted with alkylamino radicals. More preferred
alkylaminoalkoxy radicals are "lower alkylaminoalkoxy" radicals
having alkoxy radicals of one to six carbon atoms. Even more
preferred are lower alkylaminoalkoxy radicals having alkyl radicals
of one to three carbon atoms. Suitable alkylaminoalkoxy radicals
may be mono or dialkyl substituted, such as N-methylaminoethoxy,
N,N-dimethylaminoethoxy, and N,N-diethylaminoethoxy, and the
like.
[1100] The term "alkylaminoalkoxyalkoxy" embraces alkoxy radicals
substituted with alkylaminoalkoxy radicals. More preferred
alkylaminoalkoxyalkoxy radicals are "lower alkylaminoalkoxyalkoxy"
radicals having alkoxy radicals of one to six carbon atoms. Even
more preferred are lower alkylaminoalkoxyalkoxy radicals having
alkyl radicals of one to three carbon atoms. Suitable
alkylaminoalkoxyalkoxy radicals may be mono or dialkyl substituted,
such as N-methylaminomethoxyethoxy, N-methylaminoethoxyethoxy,
N,N-dimethylaminoethoxyethoxy, and N,N-diethylaminomethoxymethoxy,
and the like.
[1101] The term "carboxyalkyl" embraces linear or branched alkyl
radicals having one to about ten carbon atoms any one of which may
be substituted with one or more carboxy radicals. More preferred
carboxyalkyl radicals are "lower carboxyalkyl" radicals having one
to six carbon atoms and one carboxy radical. Examples of such
radicals include carboxymethyl, and carboxypropyl, and the like.
Even more preferred are lower carboxyalkyl radicals having one to
three CH.sub.2 groups.
[1102] The term "halosulfonyl" embraces sulfonyl radicals
substituted with a halogen radical. Examples of such halosulfonyl
radicals include chlorosulfonyl and fluorosulfonyl.
[1103] The term "arylthio" embraces aryl radicals of six to ten
carbon atoms, attached to a divalent sulfur atom. An example of
"arylthio" is phenylthio.
[1104] The term "aralkylthio" embraces aralkyl radicals as
described above, attached to a divalent sulfur atom. More preferred
are phenyl-C.sub.1-C.sub.3-alkylthio radicals. An example of
"aralkylthio" is benzylthio.
[1105] The term "aryloxy" embraces optionally substituted aryl
radicals, as defined above, attached to an oxygen atom. Examples of
such radicals include phenoxy.
[1106] The term "aralkoxy" embraces oxy-containing aralkyl radicals
attached through an oxygen atom to other radicals. More preferred
aralkoxy radicals are "lower aralkoxy" radicals having optionally
substituted phenyl radicals attached to lower alkoxy radical as
described above.
[1107] The term "heteroaryloxy" embraces optionally substituted
heteroaryl radicals, as defined above, attached to an oxygen
atom.
[1108] The term "heteroarylalkoxy" embraces oxy-containing
heteroarylalkyl radicals attached through an oxygen atom to other
radicals. More preferred heteroarylalkoxy radicals are "lower
heteroarylalkoxy" radicals having optionally substituted heteroaryl
radicals attached to lower alkoxy radical as described above.
[1109] The term "cycloalkyl" includes saturated carbocyclic groups.
Preferred cycloalkyl groups include C.sub.3-C.sub.6 rings. More
preferred compounds include, cyclopentyl, cyclopropyl, and
cyclohexyl.
[1110] The term "cycloalkylalkyl" embraces cycloalkyl-substituted
alkyl radicals. Preferable cycloalkylalkyl radicals are "lower
cycloalkylalkyl" radicals having cycloalkyl radicals attached to
alkyl radicals having one to six carbon atoms. Even more preferred
are "5 to 6-membered cycloalkylalkyl" attached to alkyl portions
having one to three carbon atoms.
[1111] Examples of such radicals include cyclohexylmethyl. The
cycloalkyl in said radicals may be additionally substituted with
halo, alkyl, alkoxy and hydroxy.
[1112] The term "cycloalkenyl" includes carbocyclic groups having
one or more carbon-carbon double bonds including "cycloalkyldienyl"
compounds. Preferred cycloalkenyl groups include C.sub.3-C.sub.6
rings. More preferred compounds include, for example,
cyclopentenyl, cyclopentadienyl, cyclohexenyl and
cycloheptadienyl.
[1113] The term "comprising" is meant to be open ended, including
the indicated component but not excluding other elements.
[1114] A group or atom that replaces a hydrogen atom is also called
a substituent.
[1115] Any particular molecule or group can have one or more
substituent depending on the number of hydrogen atoms that can be
replaced.
[1116] The symbol "--" represents a covalent bond and can also be
used in a radical group to indicate the point of attachment to
another group. In chemical structures, the symbol is commonly used
to represent a methyl group in a molecule.
[1117] The term "therapeutically effective amount" means an amount
of a compound that ameliorates, attenuates or eliminates one or
more symptom of a particular disease or condition, or prevents or
delays the onset of one of more symptom of a particular disease or
condition.
[1118] The terms "patient" and "subject" may be used
interchangeably and mean animals, such as dogs, cats, cows, horses,
sheep and humans. Particular patients are mammals. The term patient
includes males and females.
[1119] The term "pharmaceutically acceptable" means that the
referenced substance, such as a compound of Formula I, or a salt of
a compound of Formula I, or a formulation containing a compound of
Formula I, or a particular excipient, are suitable for
administration to a patient.
[1120] The terms "treating", "treat" or "treatment" and the like
include preventative (e.g., prophylactic) and palliative
treatment.
[1121] The term "excipient" means any pharmaceutically acceptable
additive, carrier, diluent, adjuvant, or other ingredient, other
than the active pharmaceutical ingredient (API), which is typically
included for formulation and/or administration to a patient.
[1122] The compounds of the present invention are administered to a
patient in a therapeutically effective amount. The compounds can be
administered alone or as part of a pharmaceutically acceptable
composition or formulation. In addition, the compounds or
compositions can be administered all at once, as for example, by a
bolus injection, multiple times, such as by a series of tablets, or
delivered substantially uniformly over a period of time, as for
example, using transdermal delivery. It is also noted that the dose
of the compound can be varied over time.
[1123] In addition, the compounds of the present invention can be
administered alone, in combination with other compounds of the
present invention, or with other pharmaceutically active compounds.
The other pharmaceutically active compounds can be intended to
treat the same disease or condition as the compounds of the present
invention or a different disease or condition. If the patient is to
receive or is receiving multiple pharmaceutically active compounds,
the compounds can be administered simultaneously, or sequentially.
For example, in the case of tablets, the active compounds may be
found in one tablet or in separate tablets, which can be
administered at once or sequentially in any order. In addition, it
should be recognized that the compositions may be different forms.
For example, one or more compound may be delivered via a tablet,
while another is administered via injection or orally as a syrup.
All combinations, delivery methods and administration sequences are
contemplated.
[1124] The term "cancer" means a physiological condition in mammals
that is characterized by unregulated cell growth. General classes
of cancers include carcinomas, lymphomas, sarcomas, and
blastomas.
[1125] The compounds of the present invention can be used to treat
cancer. The methods of treating a cancer comprise administering to
a patient in need thereof a therapeutically effective amount of a
compound of Formula I, IA, IB, IC, ID or IE, or a pharmaceutically
acceptable salt thereof.
[1126] The compounds of the present invention can be used to treat
tumors. The methods of treating a tumor comprise administering to a
patient in need thereof a therapeutically effective amount of a
compound of Formula I, IA, IB, IC, ID or IE, or a pharmaceutically
acceptable salt thereof.
[1127] The invention also concerns the use of a compound of the
present invention in the manufacture of a medicament for the
treatment of a condition such as a cancer.
[1128] Cancers which may be treated with compounds of the present
invention include, without limitation, carcinomas such as cancer of
the bladder, breast, colon, rectum, kidney, liver, lung (small cell
lung cancer, and non-small-cell lung cancer), esophagus,
gall-bladder, ovary, pancreas, stomach, cervix, thyroid, prostate,
and skin (including squamous cell carcinoma); hematopoietic tumors
of lymphoid lineage (including leukemia, acute lymphocytic
leukemia, chronic myelogenous leukemia, acute lymphoblastic
leukemia, B-cell lymphoma, T-cell-lymphoma, Hodgkin's lymphoma,
non-Hodgkin's lymphoma, hairy cell lymphoma and Burkett's
lymphoma); hematopoietic tumors of myeloid lineage (including acute
and chronic myelogenous leukemias, myelodysplastic syndrome and
promyelocytic leukemia); tumors of mesenchymal origin (including
fibrosarcoma and rhabdomyosarcoma, and other sarcomas, e.g., soft
tissue and bone); tumors of the central and peripheral nervous
system (including astrocytoma, neuroblastoma, glioma and
schwannomas); and other tumors (including melanoma, seminoma,
teratocarcinoma, osteosarcoma, xenoderoma pigmentosum,
keratoctanthoma, thyroid follicular cancer and Kaposi's sarcoma).
Other cancers that can be treated with a compound of the present
invention include endometrial cancer, head and neck cancer,
glioblastoma, malignant ascites, and hematopoietic cancers.
[1129] Particular cancers that can be treated by the compounds of
the present invention include soft tissue sarcomas, bone cancers
such as osteosarcoma, breast tumors, bladder cancer, Li-Fraumeni
syndrome, brain tumors, rhabdomyosarcoma, adrenocortical carcinoma,
colorectal cancer, non-small cell lung cancer, and acute
myeleogenous leukemia (AML).
[1130] In a particular embodiment of the invention that relates to
the treatment of cancers, the cancer is identified as p53wildtype
(p53.sup.WT). In another particular embodiment, the cancer is
identified as p53.sup.WT and CDKN2A mutant. In another aspect, the
present invention provides a diagnostic for determining which
patients should be administered a compound of the present
invention. For example, a sample of a patient's cancer cells may be
taken and analyzed to determine the status of the cancer cells with
respect to p53 and/or CDKN2A. In one aspect, a patient having a
cancer that is p53.sup.WT will be selected for treatment over
patients having a cancer that is mutated with respect to p53. In
another aspect, a patient having a cancer that is both p53.sup.WT
and has a mutant CDNK2A protein is selected over a patient that
does not have these characteristics. The taking of a cancer cells
for analyses is well known to those skilled in the art. The term
"p53.sup.WT" means a protein encoded by genomic DNA sequence no.
NC.sub.--000017 version 9 (7512445 . . . 7531642)(GenBank); a
protein encoded by cDNA sequence no. NM.sub.--000546 (GenBank); or
a protein having the GenBank sequence no. NP.sub.--000537.3. The
term "CDNK2A mutant" means a CDNK2A protein that in not wildtype.
The term "CDKN2A wildtype" means a protein encoded by genomic DNA
sequence no. 9:21957751-21984490 (Ensembl ID); a protein encoded by
cDNA sequence no. NM.sub.--000077 (GenBank) or NM.sub.--058195
9GenBank) or; or a protein having the GenBank sequence no.
NP.sub.--000068 or NP.sub.--478102.
[1131] The compounds of the present invention can also be used to
treat hyperproliferative disorders such as thyroid hyperplasia
(especially Grave's disease), and cysts (such as hypervascularity
of ovarian stroma, characteristic of polycystic ovarian syndrome
(Stein-Leventhal syndrome)).
[1132] The compounds of the present invention can also be used to
treat the following diseases or conditions: asthma, chronic
obstructive pulmonary disease (COPD), emphysema, psoriasis, contact
dermatitis, conjunctivitis, allergic rhinitis, systemic lupus
erythematosus (SLE), ulcerative colitis, Crohn's disease, multiple
sclerosis, rheumatoid arthritis, inflammatory bowel disease,
Alzheimer's disease, atherosclerosis and Huntington's disease.
[1133] The compounds of the present invention can also be used to
treat inflammatory diseases, hypoxia, ulcers, viral infections,
bacterial infections, and bacterial sepsis.
[1134] The compounds of Formula I, IA, IB, IC, ID or IE, or the
pharmaceutically acceptable salts thereof, may also be administered
in combination with one or more additional pharmaceutically active
compounds/agents. In a particular embodiment, the additional
pharmaceutically active agent is an agent that can be used to treat
a cancer. For example, an additional pharmaceutically active agent
can be selected from antineoplastic agents, anti-angiogenic agents,
chemotherapeutic agents and peptidal cancer therapy agents. In yet
another embodiment, the antineoplastic agents are selected from
antibiotic-type agents, alkylating agents, antimetabolite agents,
hormonal agents, immunological agents, interferon-type agents,
kinase inhibitors, miscellaneous agents and combinations thereof.
It is noted that the additional pharmaceutically active
compounds/agents may be a traditional small organic chemical
molecules or can be macromolecules such as a proteins, antibodies,
peptibodies, DNA, RNA or fragments of such macromolecules.
[1135] Examples of specific pharmaceutically active agents that can
be used in the treatment of cancers and that can be used in
combination with one or more compound of the present invention
include: methotrexate; tamoxifen; fluorouracil; 5-fluorouracil;
hydroxyurea; mercaptopurine; cisplatin; carboplatin; daunorubicin;
doxorubicin; etoposide; vinblastine; vincristine; pacitaxel;
thioguanine; idarubicin; dactinomycin; imatinib; gemcitabine;
altretamine; asparaginase; bleomycin; capecitabine; carmustine;
cladisat. aq. NaCl solution; cyclophosphamine; cytarabine;
decarazine; docetaxel; idarubicin; ifosfamide; irinotecan;
fludarabine; mitosmycin; mitoxane; mitoxantrone; topotecan;
vinorelbine; adriamycin; mithram; imiquimod; alemtuzmab;
exemestane; bevacizumab; cetuximab; azacitidine; clofarabine;
decitabine; desatinib; dexrazoxane; docetaxel; epirubicin;
oxaliplatin; erlotinib; raloxifene; fulvestrant; letrozole;
gefitinib; gemtuzumab; trastuzumab; gefitinib; ixabepilone;
lapatinib; lenalidomide; aminolevulinic acid; temozolomide;
nelarabine; sorafenib; nilotinib; pegaspargase; pemetrexed;
rituximab; dasatinib; thalidomide; bexarotene; temsirolimus;
bortezomib; vorinostat; capecitabine; zoledronic acid; anastrozole;
sunitinib; aprepitant and nelarabine, or a pharmaceutically
acceptable salt thereof.
[1136] Additional pharmaceutically active agents that can be used
in the treatment of cancers and that can be used in combination
with one or more compound of the present invention include:
vascular endothelial growth factor (VEGF) inhibitors, hepatocyte
growth factor/scatter factor (HGF/SF) inhibitors, angiopoietin 1
and/or 2 inhibitors, tumor necrosis factor-related
apoptosis-inducing ligand (TRAIL) agonists, recombinant human apo2
ligand (TRAIL), insulin-like growth factor 1 receptor (IGFR-1)
inhibitors, cFMS inhibitors, HER 2 inhibitors, c-met inhibitors,
aurora kinase inhibitors, CDK 4 and/or 6 inhibitors, and B-raf
inhibitors.
[1137] Further additional pharmaceutically active agents that can
be used in the treatment of cancers and that can be used in
combination with one or more compound of the present invention
include antibody drug conjugates (ADCs) whereby an antibody that
binds to a protein, preferably on a cancer cell, is conjugated
using a linker with a chemical compound that is detrimental to the
cancer cell. Examples of chemical compounds that are detrimental to
a cancer cell include maytansinoids derivatives and auristatin
derivatives.
[1138] Still further additional pharmaceutically active agents that
can be used in the treatment of cancers and that can be used in
combination with one or more compound of the present invention
include: epoetin alfa; darbepoetin alfa; panitumumab;
pegfilgrastim; palifermin; filgrastim; denosumab; ancestim; AMG
102; AMG 319; AMG 386; AMG 479 (Ganitumab); AMG 511, AMG 900, AMG
655 (Conatumumab); AMG 745; AMG 951; and AMG 706 (Motesanib), or a
pharmaceutically acceptable salt thereof.
[1139] In another aspect, the present invention relates to the use
of the compounds of the present invention in combination with one
or more pharmaceutical agent that is an inhibitor of a protein in
the phosphatidylinositol 3-kinase (PI3K) pathway. Combinations of
compounds of the present invention along with inhibitors of
proteins in the PI3K pathway have shown synergy in cancer cell
growth assays, including enhanced apoptosis and cell killing.
Examples of proteins in the PI3K pathway include PI3K, mTOR and PKB
(also known as Akt). The PI3K protein exists in several isoforms
including .alpha., .beta., .delta., or .gamma.. It is contemplated
that a PI3K inhibitor that can be used in combination with a
compound of the present invention can be selective for one or more
isoform. By selective it is meant that the compounds inhibit one or
more isoform more that other isoforms. Selectivity is a concept
well known to those is the art and can be measured with well known
activity in vitro or cell-based assays. Preferred selectivity
includes greater than 2 fold, preferably 10 fold, or more
preferably 100 fold greater selectivity for one or more isoform
over the other isoforms. In one aspect, the PI3K inhibitors that
can be used in combination with compounds of the present invention
is a PI3K a selective inhibitor. In another aspect the compound is
a PI3K .delta. selective inhibitor.
[1140] Examples of PI3K inhibitors that can be used in combination
with one or more compounds of the present invention include those
disclosed in the following: PCT published application no.
WO2010/151791; PCT published application no. WO2010/151737; PCT
published application no. WO2010/151735; PCT published application
no. WO2010151740; PCT published application no. WO2008/118455; PCT
published application no. WO2008/118454; PCT published application
no. WO2008/118468; U.S. published application no. US20100331293;
U.S. published application no. US20100331306; U.S. published
application no. US20090023761; U.S. published application no.
US20090030002; U.S. published application no. US20090137581;
U.S. published application no. US2009/0054405; U.S. published
application no. U.S. 2009/0163489; U.S. published application no.
US 2010/0273764; U.S. published application no. U.S. 2011/0092504;
or PCT published application no. WO2010/108074.
[1141] Preferred PI3K inhibitors for use in combination with
compounds of the present invention include:
##STR00058##
or a pharmaceutically acceptable salt thereof.
[1142] Also preferred is a compound of Formula IIa below, or a
pharmaceutically acceptable salt thereof,
##STR00059##
wherein X.sup.1 is fluorine or hydrogen; Y.sup.1 is hydrogen or
methyl; and Z.sup.1 is hydrogen or methyl.
[1143] Compounds that inhibit both PI3K and mTOR (dual inhibitors)
are known. In still another aspect, the present invention provides
the use of dual PI3K and mTOR inhibitors for use in combination
with a compound of the present invention.
[1144] mTOR is a protein in the PI3K pathway. It is another aspect
of the present invention to use an mTOR inhibitor in combination
with one or more compounds of the present invention. mTOR
inhibitors that can be used in combination with compounds of the
present invention include those disclosed in the following
documents: PCT published application no. WO2010/132598 or PCT
published application no. WO2010/096314.
[1145] PKB (Akt) is also a protein in the PI3K pathway. It is
another aspect of the present invention to use an mTOR inhibitor in
combination with one or more compounds of the present invention.
PKB inhibitors that can be used in combination with compounds of
the present invention include those disclosed in the following
documents: U.S. Pat. No. 7,354,944; U.S. Pat. No. 7,700,636; U.S.
Pat. No. 7,919,514; U.S. Pat. No. 7,514,566; U.S. patent
application publication no. US 2009/0270445 A1; U.S. Pat. No.
7,919,504; U.S. Pat. No. 7,897,619; or PCT published application
no. WO 2010/083246 A1.
[1146] The compounds of the present invention can be used in
combination with CDK4 and/or 6 inhibitors. CDK 4 and/or 6
inhibitors that can be used in combination with compounds of the
present invention include those disclosed in the following
documents: PCT published application no. WO 2009/085185 or U.S.
patent application publication no. US2011/0097305.
[1147] The compounds of the present invention can also be used in
combination with pharmaceutically active agents that treat nausea.
Examples of agents that can be used to treat nausea include:
dronabinol; granisetron; metoclopramide; ondansetron; and
prochlorperazine; or a pharmaceutically acceptable salt
thereof.
[1148] In addition, the compounds of the present invention can be
used in combination with other agents that can be used to treat
cancer such as acemannan; aclarubicin; aldesleukin; alitretinoin;
amifostine; amrubicin; amsacrine; anagrelide; arglabin; arsenic
trioxide; BAM 002 (Novelos); bicalutamide; broxuridine;
celmoleukin; cetrorelix; cladribine; clotrimazole; DA 3030
(Dong-A); daclizumab; denileukin diftitox; deslorelin; dilazep;
docosanol; doxercalciferol; doxifluridine; bromocriptine;
cytarabine; HIT diclofenac; interferon alfa; tretinoin; edelfosine;
edrecolomab; eflornithine; emitefur; epirubicin; epoetin beta;
etoposide phosphate; exisulind; fadrozole; finasteride; fludarabine
phosphate; formestane; fotemustine; gallium nitrate; gemtuzumab
zogamicin; gimeracil/oteracil/tegafur combination; glycopine;
goserelin; heptaplatin; human chorionic gonadotropin; human fetal
alpha fetoprotein; ibandronic acid; interferon alfa; interferon
alfa natural; interferon alfa-2; interferon alfa-2a; interferon
alfa-2b; interferon alfa-N1; interferon alfa-n3; interferon
alfacon-1; interferon alpha natural; interferon beta; interferon
beta-1a; interferon beta-1b; interferon gamma natural; interferon
gamma-1a; interferon gamma-1b; interleukin-1 beta; iobenguane;
irsogladine; lanreotide; LC 9018 (Yakult); leflunomide;
lenograstim; lentinan sulfate; letrozole; leukocyte alpha
interferon; leuprorelin; levamisole+fluorouracil; liarozole;
lobaplatin; lonidamine; lovastatin; masoprocol; melarsoprol;
metoclopramide; mifepristone; miltefosine; mirimostim; mismatched
double stranded RNA; mitoguazone; mitolactol; mitoxantrone;
molgramostim; nafarelin; naloxone+pentazocine; nartograstim;
nedaplatin; nilutamide; noscapine; novel erythropoiesis stimulating
protein; NSC 631570 octreotide; oprelvekin; osaterone; paclitaxel;
pamidronic acid; peginterferon alfa-2b; pentosan polysulfate
sodium; pentostatin; picibanil; pirarubicin; rabbit antithymocyte
polyclonal antibody; polyethylene glycol interferon alfa-2a;
porfimer sodium; raltitrexed; rasburicase; rhenium Re 186
etidronate; RII retinamide; romurtide; samarium (153 Sm)
lexidronam; sargramostim; sizofuran; sobuzoxane; sonermin;
strontium-89 chloride; suramin; tasonermin; tazarotene; tegafur;
temoporfin; teniposide; tetrachlorodecaoxide; thymalfasin;
thyrotropin alfa; toremifene; tositumomab-iodine 131; treosulfan;
tretinoin; trilostane; trimetrexate; triptorelin; tumor necrosis
factor alpha natural; ubenimex; bladder cancer vaccine; Maruyama
vaccine; melanoma lysate vaccine; valrubicin; verteporfin;
virulizin; zinostatin stimalamer; abarelix; AE 941 (Aeterna);
ambamustine; antisense oligonucleotide; bcl-2 (Genta); APC 8015
(Dendreon); dexaminoglutethimide; diaziquone; EL 532 (Elan); EM 800
(Endorecherche); eniluracil; etanidazole; fenretinide; filgrastim
SD01 (Amgen); galocitabine; gastrin 17 immunogen; HLA-B7 gene
therapy (Vical); granulocyte macrophage colony stimulating factor;
histamine dihydrochloride; ibritumomab tiuxetan; ilomastat; IM 862
(Cytran); interleukin-2; iproxifene; LDI 200 (Milkhaus);
leridistim; lintuzumab; CA 125 monoclonal antibody(MAb) (Biomira);
cancer MAb (Japan Pharmaceutical Development); HER-2 and Fc MAb
(Medarex); idiotypic 105AD7 MAb (CRC Technology); idiotypic CEA MAb
(Trilex); LYM-1-iodine 131 MAb (Techniclone); polymorphic
epithelial mucin-yttrium 90 MAb (Antisoma); marimastat; menogaril;
mitumomab; motexafin gadolinium; MX 6 (Galderma); nolatrexed; P 30
protein; pegvisomant; porfiromycin; prinomastat; RL 0903 (Shire);
rubitecan; satraplatin; sodium phenylacetate; sparfosic acid; SRL
172 (SR Pharma); SU 5416 (Pfizer); TA 077 (Tanabe);
tetrathiomolybdate; thaliblastine; thrombopoietin; tin ethyl
etiopurpurin; tirapazamine; cancer vaccine (Biomira); melanoma
vaccine (New York University); melanoma vaccine (Sloan Kettering
Institute); melanoma oncolysate vaccine (New York Medical College);
viral melanoma cell lysates vaccine (Royal Newcastle Hospital); or
valspodar. It is noted that the agents recited above may also be
administered as pharmaceutically acceptable salts when
appropriate.
[1149] The compounds of the present invention may also be used in
combination with radiation therapy, hormone therapy, surgery and
immunotherapy, which therapies are well known to those skilled in
the art.
[1150] Since one aspect of the present invention contemplates the
treatment of the disease/conditions with a combination of
pharmaceutically active compounds that may be administered
separately, the invention further relates to combining separate
pharmaceutical compositions in kit form. The kit comprises two
separate pharmaceutical compositions: a compound of the present
invention, and a second pharmaceutical compound. The kit comprises
a container for containing the separate compositions such as a
divided bottle or a divided foil packet. Additional examples of
containers include syringes, boxes and bags. Typically, the kit
comprises directions for the use of the separate components. The
kit form is particularly advantageous when the separate components
are preferably administered in different dosage forms (e.g., oral
and parenteral), are administered at different dosage intervals, or
when titration of the individual components of the combination is
desired by the prescribing physician or veterinarian.
[1151] An example of such a kit is a so-called blister pack.
Blister packs are well known in the packaging industry and are
being widely used for the packaging of pharmaceutical unit dosage
forms (tablets, capsules, and the like). Blister packs generally
consist of a sheet of relatively stiff material covered with a foil
of a preferably transparent plastic material. During the packaging
process recesses are formed in the plastic foil. The recesses have
the size and shape of the tablets or capsules to be packed. Next,
the tablets or capsules are placed in the recesses and the sheet of
relatively stiff material is sealed against the plastic foil at the
face of the foil which is opposite from the direction in which the
recesses were formed. As a result, the tablets or capsules are
sealed in the recesses between the plastic foil and the sheet.
Preferably the strength of the sheet is such that the tablets or
capsules can be removed from the blister pack by manually applying
pressure on the recesses whereby an opening is formed in the sheet
at the place of the recess. The tablet or capsule can then be
removed via said opening.
[1152] It may be desirable to provide a memory aid on the kit,
e.g., in the form of numbers next to the tablets or capsules
whereby the numbers correspond with the days of the regimen which
the tablets or capsules so specified should be ingested. Another
example of such a memory aid is a calendar printed on the card,
e.g., as follows "First Week, Monday, Tuesday, . . . etc . . .
Second Week, Monday, Tuesday, . . . " etc. Other variations of
memory aids will be readily apparent. A "daily dose" can be a
single tablet or capsule or several pills or capsules to be taken
on a given day. Also, a daily dose of a compound of the present
invention can consist of one tablet or capsule, while a daily dose
of the second compound can consist of several tablets or capsules
and vice versa. The memory aid should reflect this and aid in
correct administration of the active agents.
[1153] In another specific embodiment of the invention, a dispenser
designed to dispense the daily doses one at a time in the order of
their intended use is provided. Preferably, the dispenser is
equipped with a memory-aid, so as to further facilitate compliance
with the regimen. An example of such a memory-aid is a mechanical
counter which indicates the number of daily doses that has been
dispensed. Another example of such a memory-aid is a
battery-powered micro-chip memory coupled with a liquid crystal
readout, or audible reminder signal which, for example, reads out
the date that the last daily dose has been taken and/or reminds one
when the next dose is to be taken.
[1154] The compounds of the present invention and other
pharmaceutically active compounds, if desired, can be administered
to a patient either orally, rectally, parenterally, (for example,
intravenously, intramuscularly, or subcutaneously)
intracisternally, intravaginally, intraperitoneally,
intravesically, locally (for example, powders, ointments or drops),
or as a buccal or nasal spray. All methods that are used by those
skilled in the art to administer a pharmaceutically active agent
are contemplated.
[1155] Compositions suitable for parenteral injection may comprise
physiologically acceptable sterile aqueous or nonaqueous solutions,
dispersions, suspensions, or emulsions, and sterile powders for
reconstitution into sterile injectable solutions or dispersions.
Examples of suitable aqueous and nonaqueous carriers, diluents,
solvents, or vehicles include water, ethanol, polyols (propylene
glycol, polyethylene glycol, glycerol, and the like), suitable
mixtures thereof, vegetable oils (such as olive oil) and injectable
organic esters such as ethyl oleate. Proper fluidity can be
maintained, for example, by the use of a coating such as lecithin,
by the maintenance of the required particle size in the case of
dispersions, and by the use of surfactants.
[1156] These compositions may also contain adjuvants such as
preserving, wetting, emulsifying, and dispersing agents.
Microorganism contamination can be prevented by adding various
antibacterial and antifungal agents, for example, parabens,
chlorobutanol, phenol, sorbic acid, and the like. It may also be
desirable to include isotonic agents, for example, sugars, sodium
chloride, and the like. Prolonged absorption of injectable
pharmaceutical compositions can be brought about by the use of
agents delaying absorption, for example, aluminum monostearate and
gelatin.
[1157] Solid dosage forms for oral administration include capsules,
tablets, powders, and granules. In such solid dosage forms, the
active compound is admixed with at least one inert customary
excipient (or carrier) such as sodium citrate or dicalcium
phosphate or (a) fillers or extenders, as for example, starches,
lactose, sucrose, mannitol, and silicic acid; (b) binders, as for
example, carboxymethylcellulose, alginates, gelatin,
polyvinylpyrrolidone, sucrose, and acacia; (c) humectants, as for
example, glycerol; (d) disintegrating agents, as for example,
agar-agar, calcium carbonate, potato or tapioca starch, alginic
acid, certain complex silicates, and sodium carbonate; (a) solution
retarders, as for example, paraffin; (f) absorption accelerators,
as for example, quaternary ammonium compounds; (g) wetting agents,
as for example, cetyl alcohol and glycerol monostearate; (h)
adsorbents, as for example, kaolin and bentonite; and (i)
lubricants, as for example, talc, calcium stearate, magnesium
stearate, solid polyethylene glycols, sodium lauryl sulfate, or
mixtures thereof. In the case of capsules, and tablets, the dosage
forms may also comprise buffering agents.
[1158] Solid compositions of a similar type may also be used as
fillers in soft and hard filled gelatin capsules using such
excipients as lactose or milk sugar, as well as high molecular
weight polyethylene glycols, and the like.
[1159] Solid dosage forms such as tablets, dragees, capsules,
pills, and granules can be prepared with coatings and shells, such
as enteric coatings and others well known in the art. They may also
contain opacifying agents, and can also be of such composition that
they release the active compound or compounds in a certain part of
the intestinal tract in a delayed manner. Examples of embedding
compositions that can be used are polymeric substances and waxes.
The active compounds can also be in micro-encapsulated form, if
appropriate, with one or more of the above-mentioned
excipients.
[1160] Liquid dosage forms for oral administration include
pharmaceutically acceptable emulsions, solutions, suspensions,
syrups, and elixirs. In addition to the active compounds, the
liquid dosage form may contain inert diluents commonly used in the
art, such as water or other solvents, solubilizing agents and
emulsifiers, as for example, ethyl alcohol, isopropyl alcohol,
ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate,
propylene glycol, 1,3-butylene glycol, dimethylformamide, oils, in
particular, cottonseed oil, groundnut oil, corn germ oil, olive
oil, castor oil, and sesame seed oil, glycerol, tetrahydrofurfuryl
alcohol, polyethylene glycols and fatty acid esters of sorbitan, or
mixtures of these substances, and the like.
[1161] Besides such inert diluents, the composition can also
include adjuvants, such as wetting agents, emulsifying and
suspending agents, sweetening, flavoring, and perfuming agents.
Suspensions, in addition to the active compound, may contain
suspending agents, as for example, ethoxylated isostearyl alcohols,
polyoxyethylene sorbitol and sorbitan esters, microcrystalline
cellulose, aluminum metahydroxide, bentonite, agar-agar, and
tragacanth, or mixtures of these substances, and the like.
[1162] Compositions for rectal administration are preferable
suppositories, which can be prepared by mixing the compounds of the
present invention with suitable non-irritating excipients or
carriers such as cocoa butter, polyethylene glycol or a suppository
wax, which are solid at ordinary room temperature, but liquid at
body temperature, and therefore, melt in the rectum or vaginal
cavity and release the active component.
[1163] Dosage forms for topical administration of a compound of the
present invention include ointments, powders, sprays and inhalants.
The active compound or fit compounds are admixed under sterile
condition with a physiologically acceptable carrier, and any
preservatives, buffers, or propellants that may be required.
Opthalmic formulations, eye ointments, powders, and solutions are
also contemplated as being within the scope of this invention.
[1164] The compounds of the present invention can be administered
to a patient at dosage levels in the range of about 0.1 to about
3,000 mg per day. For a normal adult human having a body weight of
about 70 kg, a dosage in the range of about 0.01 to about 100 mg
per kilogram body weight is typically sufficient. The specific
dosage and dosage range that can be used depends on a number of
factors, including the requirements of the patient, the severity of
the condition or disease being treated, and the pharmacological
activity of the compound being administered. The determination of
dosage ranges and optimal dosages for a particular patient is
within the ordinary skill in the art.
[1165] The compounds of the present invention can be administered
as pharmaceutically acceptable salts, esters, amides or prodrugs.
The term "salts" refers to inorganic and organic salts of compounds
of the present invention. The salts can be prepared in situ during
the final isolation and purification of a compound, or by
separately reacting a purified compound in its free base or acid
form with a suitable organic or inorganic base or acid and
isolating the salt thus formed. Representative salts include the
hydrobromide, hydrochloride, sulfate, bisulfate, nitrate, acetate,
oxalate, palmitiate, stearate, laurate, borate, benzoate, lactate,
phosphate, tosylate, citrate, maleate, fumarate, succinate,
tartrate, naphthylate, mesylate, glucoheptonate, lactobionate, and
laurylsulphonate salts, and the like. The salts may include cations
based on the alkali and alkaline earth metals, such as sodium,
lithium, potassium, calcium, magnesium, and the like, as well as
non-toxic ammonium, quaternary ammonium, and amine cations
including, but not limited to, ammonium, tetramethylammonium,
tetraethylammonium, methylamine, dimethylamine, trimethylamine,
triethylamine, ethylamine, and the like. See, for example, S. M.
Berge, et al., "Pharmaceutical Salts," J Pharm Sci, 66: 1-19
(1977).
[1166] Examples of pharmaceutically acceptable esters of the
compounds of the present invention include C.sub.1-C.sub.8 alkyl
esters. Acceptable esters also include C.sub.5-C.sub.7 cycloalkyl
esters, as well as arylalkyl esters such as benzyl. C.sub.1-C.sub.4
alkyl esters are commonly used. Esters of compounds of the present
invention may be prepared according to methods that are well known
in the art.
[1167] Examples of pharmaceutically acceptable amides of the
compounds of the present invention include amides derived from
ammonia, primary C.sub.1-C.sub.8 alkyl amines, and secondary
C.sub.1-C.sub.8 dialkyl amines. In the case of secondary amines,
the amine may also be in the form of a 5 or 6 membered
heterocycloalkyl group containing at least one nitrogen atom.
Amides derived from ammonia, C.sub.1-C.sub.3 primary alkyl amines
and C.sub.1-C.sub.2 dialkyl secondary amines are commonly used.
Amides of the compounds of the present invention may be prepared
according to methods well known to those skilled in the art.
[1168] The term "prodrug" means compounds that are transformed in
vivo to yield a compound of the present invention. The
transformation may occur by various mechanisms, such as through
hydrolysis in blood. A discussion of the use of prodrugs is
provided by T. Higuchi and W. Stella, "Prodrugs as Novel Delivery
Systems," Vol. 14 of the A.C.S. Symposium Series, and in
Bioreversible Carriers in Drug Design, ed. Edward B. Roche,
American Pharmaceutical Association and Pergamon Press, 1987.
[1169] To illustrate, if the compound of the invention contains a
carboxylic acid functional group, a prodrug can comprise an ester
formed by the replacement of the hydrogen atom of the acid group
with a group such as (C.sub.1-C.sub.8 alkyl,
(C.sub.2-C.sub.12)alkanoyloxymethyl, 1-(alkanoyloxy)ethyl having
from 4 to 9 carbon atoms, 1-methyl-1-(alkanoyloxy)ethyl having from
5 to 10 carbon atoms, alkoxycarbonyloxymethyl having from 3 to 6
carbon atoms, 1-(alkoxycarbonyloxy)ethyl having from 4 to 7 carbon
atoms, 1-methyl-1-(alkoxycarbonyloxy)ethyl having from 5 to 8
carbon atoms, N-(alkoxycarbonyl)aminomethyl having from 3 to 9
carbon atoms, 1-(N-(alkoxycarbonyl)aminomethyl having from 4 to 10
carbon atoms, 3-phthalidyl, 4-crotonolactonyl,
gamma-butyrolacton-4-yl,
di-N,N--(C.sub.1-C.sub.2)alkylamino(C.sub.2-C.sub.3)alkyl (such as
.beta.-dimethylaminoethyl), carbamoyl-(C.sub.1-C.sub.2)alkyl,
N,N-di(C.sub.1-C.sub.2)alkylcarbamoyl-(C.sub.1-C.sub.2)alkyl and
piperidino-, pyrrolidino- or morpholino(C.sub.2-3)alkyl.
[1170] Similarly, if a compound of the present invention comprises
an alcohol functional group, a prodrug can be formed by the
replacement of the hydrogen atom of the alcohol group with a group
such as (C.sub.1-C.sub.6)alkanoyloxymethyl,
1-((C.sub.1-C.sub.6)alkanoyloxy)ethyl,
1-methyl-1-((C.sub.1-C.sub.6)alkanoyloxy)ethyl,
(C.sub.1-C.sub.6)alkoxycarbonyloxymethyl,
N--(C.sub.1-C.sub.6)alkoxycarbonylaminomethyl, succinoyl,
(C.sub.1-C.sub.6)alkanoyl, .alpha.-amino(C.sub.1-C.sub.4)alkanoyl,
arylacyl and .alpha.-aminoacyl, or
.alpha.-aminoacyl-.alpha.-aminoacyl, where each .alpha.-aminoacyl
group is independently selected from the naturally occurring
L-amino acids, --P(O)(OH).sub.2,
--P(O)(O(C.sub.1-C.sub.6)alkyl).sub.2 or glycosyl (the radical
resulting from the removal of a hydroxyl group of the hemiacetal
form of a carbohydrate).
[1171] The compounds of the present invention may contain
asymmetric or chiral centers, and therefore, exist in different
stereoisomeric forms. It is contemplated that all stereoisomeric
forms of the compounds as well as mixtures thereof, including
racemic mixtures, form part of the present invention. In addition,
the present invention contemplates all geometric and positional
isomers. For example, if the compound contains a double bond, both
the cis and trans forms (designated as S and E, respectively), as
well as mixtures, are contemplated.
[1172] Mixture of stereoisomers, such as diastereomeric mixtures,
can be separated into their individual stereochemical components on
the basis of their physical chemical differences by known methods
such as chromatography and/or fractional crystallization.
Enantiomers can also be separated by converting the enantiomeric
mixture into a diastereomeric mixture by reaction with an
appropriate optically active compound (e.g., an alcohol),
separating the diastereomers and converting (e.g., hydrolyzing) the
individual diastereomers to the corresponding pure enantiomers.
Also, some compounds may be atropisomers (e.g., substituted
biaryls).
[1173] The compounds of the present invention may exist in
unsolvated as well as solvated forms with pharmaceutically
acceptable solvents such as water (hydrate), ethanol, and the like.
The present invention contemplates and encompasses both the
solvated and unsolvated forms.
[1174] It is also possible that compounds of the present invention
may exist in different tautomeric forms. All tautomers of compounds
of the present invention are contemplated. For example, all of the
tautomeric forms of the tetrazole moiety are included in this
invention. Also, for example, all keto-enol or imine-enamine forms
of the compounds are included in this invention.
[1175] Those skilled in the art will recognize that the compound
names and structures contained herein may be based on a particular
tautomer of a compound. While the name or structure for only a
particular tautomer may be used, it is intended that all tautomers
are encompassed by the present invention, unless stated
otherwise.
[1176] It is also intended that the present invention encompass
compounds that are synthesized in vitro using laboratory
techniques, such as those well known to synthetic chemists; or
synthesized using in vivo techniques, such as through metabolism,
fermentation, digestion, and the like. It is also contemplated that
the compounds of the present invention may be synthesized using a
combination of in vitro and in vivo techniques.
[1177] The present invention also includes isotopically-labelled
compounds, which are identical to those recited herein, but for the
fact that one or more atoms are replaced by an atom having an
atomic mass or mass number different from the atomic mass or mass
number usually found in nature. Examples of isotopes that can be
incorporated into compounds of the invention include isotopes of
hydrogen, carbon, nitrogen, oxygen, phosphorous, fluorine and
chlorine, such as .sup.2H, .sup.3H, .sup.13C, .sup.14C, .sup.15N,
.sup.16O, .sup.17O, .sup.18O, .sup.31P, .sup.32P, .sup.35S,
.sup.18F, and .sup.36Cl. In one aspect, the present invention
relates to compounds wherein one or more hydrogen atom is replaced
with deuterium (.sup.2H) atoms.
[1178] Compounds of the present invention that contain the
aforementioned isotopes and/or other isotopes of other atoms are
within the scope of this invention. Certain isotopically-labelled
compounds of the present invention, for example those into which
radioactive isotopes such as .sup.3H and .sup.14C are incorporated,
are useful in drug and/or substrate tissue distribution assays.
Tritiated, i.e., .sup.3H, and carbon-14, i.e., .sup.14C, isotopes
are particularly preferred for their ease of preparation and
detection. Further, substitution with heavier isotopes such as
deuterium, i.e., .sup.2H, can afford certain therapeutic advantages
resulting from greater metabolic stability, for example increased
in vivo half-life or reduced dosage requirements and, hence, may be
preferred in some circumstances. Isotopically labelled compounds of
this invention can generally be prepared by substituting a readily
available isotopically labelled reagent for a non-isotopically
labelled reagent.
[1179] The compounds of the present invention may exist in various
solid states including crystalline states and as an amorphous
state. The different crystalline states, also called polymorphs,
and the amorphous states of the present compounds are contemplated
as part of this invention.
[1180] In synthesizing compounds of the present invention, it may
be desirable to use certain leaving groups. The term "leaving
groups" ("LG") generally refer to groups that are displaceable by a
nucleophile. Such leaving groups are known in the art. Examples of
leaving groups include, but are not limited to, halides (e.g., I,
Br, F, Cl), sulfonates (e.g., mesylate, tosylate), sulfides (e.g.,
SCH.sub.3), N-hydroxsuccinimide, N-hydroxybenzotriazole, and the
like. Examples of nucleophiles include, but are not limited to,
amines, thiols, alcohols, Grignard reagents, anionic species (e.g.,
alkoxides, amides, carbanions) and the like.
[1181] All patents, published patent applications and other
publications recited herein are hereby incorporated by
reference.
[1182] The examples presented below illustrate specific embodiments
of the present invention. These examples are meant to be
representative and are not intended to limit the scope of the
claims in any manner. Unless otherwise noted, when a percent is
used herein with respect to a solid, the percent is by weight with
respect to the referenced solid composition. When a percent is used
herein with respect to a liquid, the percent is by volume with
respect to the referenced solution.
[1183] .sup.1H-NMR spectra were typically acquired on a Bruker
Avance III 500 spectrometer system (Bruker, Bilerica, Mass.)
operating at a .sup.1H frequency of 500.13 MHz, equipped with a
Bruker 5 mm PABBI probe with a z-axis gradient; or on a Bruker
Avance II 400 spectrometer operating at a .sup.1H frequency of
400.23 MHz, equipped with a Bruker 5 mm PABBO probe with a z-axis
gradient. Samples were typically dissolved in 500 .mu.L of either
DMSO-d.sub.6 or CD.sub.3OD for NMR analysis. .sup.1H chemical
shifts are referenced to the residual solvent signals from
DMSO-d.sub.6 at .delta. 2.50 and CD.sub.3OD at .delta. 3.30.
[1184] Significant peaks are tabulated and typically include:
number of protons, multiplicity (s, singlet; d, doublet; dd,
doublet of doublets; t, triplet; q, quartet; m, multiplet; br s,
broad singlet) and coupling constant(s) in Hertz.
[1185] Electron Ionization (EI) mass spectra were typically
recorded on an Agilent Technologies 6140 Quadrupole LC/MS mass
spectrometer. Mass spectrometry results are reported as the ratio
of mass over charge, sometimes followed by the relative abundance
of each ion (in parentheses). Starting materials in the Examples
below are typically either available from commercial sources such
as Sigma-Aldrich, St. Louis, Mo., or via literature procedures.
The following abbreviations may be used herein: [1186] .about.
about [1187] +ve or pos. ion positive ion [1188] .DELTA. heat
[1189] Ac acetyl [1190] Ac.sub.2O acetic anhydride [1191] aq
aqueous [1192] AcOH acetic acid [1193] Bn benzyl [1194] Boc
tert-butyloxycarbonyl [1195] BSA bovine serum albumin [1196] Bu
butyl [1197] Bz benzoyl [1198] Calcd or Calc'd calculated [1199]
Conc. concentrated [1200] CSA camphor-10-sulfonic acid [1201] d
day(s) [1202] DBU 1,8-diazabicyclo[5.4.0]undec-7-ene [1203] DCE
dichloroethane [1204] DCM dichloromethane [1205] DEA diethylamine
[1206] Dess-Martin periodinane; [1207] Dess-Martin reagent
1,1,1-triacetoxy-1,1-dihydro-1,2-benziodoxol-3-(1H)-one [1208] DIEA
or DIPEA diisopropylethylamine [1209] DMAP 4-dimethylaminopyridine
[1210] DME 1,2-dimethoxyethane [1211] DMF N,N-dimethylformamide
[1212] DMSO dimethyl sulfoxide [1213] dr diastereomeric ratio
[1214] DTT dithiothreitol [1215] DVB divinylbenzene [1216] EDC
N-Ethyl-N'-(3-dimethylaminopropyl)carbodiimide [1217] eq equivalent
[1218] ESI or ES electrospray ionization [1219] Et ethyl [1220]
Et.sub.2O diethyl ether [1221] Et.sub.3N triethylamine [1222] EtOAc
ethyl acetate [1223] EtOH ethyl alcohol [1224] g gram(s) [1225] h
hour(s) [1226] HATU
O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium
hexafluorophosphate [1227] HBTU
O-benzotriazole-N,N,N',N'-tetramethyl-uronium-hexafluorophosphate
[1228] Hex hexanes [1229] HMPA hexamethylphosphoramide [1230] HOAt
1-hydroxy-7-azabenzotriazole [1231] HOBt hydroxybenzotriazole
[1232] HPLC high pressure liquid chromatography [1233] IPA or iPrOH
isopropyl alcohol [1234] Jones reagent solution of
chromium(IV)oxide and sulfuric acid in water [1235] KHMDS potassium
hexamethyldisilazide [1236] KOAc potassium acetate [1237] LCMS,
LC-MS or LC/MS liquid chromatography mass spectrometry [1238] LDA
lithium diisopropylamide [1239] LHMDS or LiHMDS lithium
hexamethyldisilazide [1240] L-Selectride.RTM. lithium
tri-sec-butylborohydride (Sigma-Aldrich, St. Louis) [1241] M molar
(mol L.sup.-1) [1242] m/z mass divided by charge [1243] mCPBA
m-chloroperoxybenzoic acid [1244] Me methyl [1245] MeCN
acetonitrile [1246] MeI iodomethane [1247] MeOH methyl alcohol
[1248] mg milligram(s) [1249] min minute(s) [1250] mL milliliter(s)
[1251] M mole(s) [1252] MS mass spectrometry [1253] MsCl
methanesulfonyl chloride [1254] MTBE or MtBE methyl tert-butyl
ether [1255] m/z mass-to-charge ratio [1256] NaHMDS sodium
hexamethyldisilazide [1257] NaOtBu sodium tert-butoxide [1258] NBS
N-bromosuccinimide [1259] nBuLi n-butyl lithium [1260] NMO
N-methylmorpholine-N-oxide [1261] NMP 1-methyl-2-pyrrolidinone
[1262] NMR nuclear magnetic resonance [1263] N-Selectride.RTM.
sodium tri-sec-butylborohydride (Sigma-Aldrich, St. Louis) [1264]
PBS phosphate buffered saline [1265] PMB paramethoxybenzyl [1266]
Pr propyl [1267] ppm parts per million [1268] rac racemic [1269]
RP-HPLC or RPHPLC reversed phase high pressure liquid
chromatography [1270] RT or rt room temperature [1271] sat. or
sat'd or satd saturated [1272] SFC supercritical fluid
chromatography [1273] TBAF tetrabutylammonium fluoride [1274] TBDMS
tert-butylidimethylsilyl [1275] TBDMS-Cl tert-butyldimethylsilyl
chloride [1276] TBDPS tert-butyldiphenylsilyl [1277] TEMPO
(2,2,6,6-tetramethylpiperidin-1-yl)oxidanyl [1278] tert or t
tertiary [1279] TFA trifluoroacetic acid [1280] THF tetrahydrofuran
[1281] TIPS triisopropylsilyl [1282] TLC thin layer chromatography
[1283] TMS trimethylsilyl or trimethylsilane [1284] TPAP
tetrapropylammonium perruthenate [1285] t.sub.R retention time
[1286] tBuOH tert-butyl alcohol [1287] v/v volume per volume
EXAMPLES
General Synthetic Schemes
[1288] Compounds of the present invention generally can be prepared
beginning with commercially available starting materials and using
synthetic techniques known to those of skill in the art. Outlined
below are some reaction schemes suitable for preparing compounds of
the present invention. Further exemplification is found in the
specific examples provided.
##STR00060##
[1289] As shown in Scheme 1, compounds of the present invention
wherein R.sup.a and R.sup.b are both H, can be prepared by reacting
a suitably substituted aryl acetic acid 1 and an aryl carboxylic
acid 2 in an organic solvent or mixture of solvents (including
aqueous mixtures) in the presence of a base, such as LHMDs or KHMDS
to provide, after workup, a compound of formula 3. Treatment of 3
with methyl acrylate in the presence of a base, such as tBuOK
results in the formation of a 4,5-substituted 5-oxopentanoate,
which can be reduced with a reducing reagent such as NaBH.sub.4 or
LiBEt.sub.3H in a suitable solvent such as THF, diethylether or
dimethoxyethane to produce racemic compound 4. 5 can in turn be
obtained from 4 by converting the alcohol into a toluenesulfonate,
methanesulfonate, or trifluoromethanesulfonate, followed by
reaction with sodium azide in a suitable solvent such as, for
example, DMF, DME or acetone. The azide can be reduced to a primary
amine by a number of reducing agents including NaBH.sub.4, H.sub.2
and a catalyst, triphenylphosphine and trimethylphoshine, which in
turn, upon treatment with a base, such as LiOH, K.sub.2CO.sub.3 or
NaHCO.sub.3 in an aqueous mixture with a suitable organic solvent,
such as THF will cyclize to the piperidin-2-one 6. Individual
enantiomers of racemic 6 can be separated by chiral HPLC using, for
example, a Chiralcel.RTM. OD-H 20 mm I.D..times.250 mm column
(Daicel Chemical Industries LTD, Fort Lee, N.J.) using 40%
isopropyl alcohol/hexane as the eluent.
##STR00061##
[1290] As shown in Scheme 2, the piperidin-2-one 6 can be further
modified, for example by arylating or alkylating the nitrogen by
methods well known to those of ordinary skill in the art. For
example, reacting 6 with an alkyl halide in the presence of a base
such as sodium hydride in a solvent such as DME, DMF or THF will
accomplish this transformation. 7 may be further alkylated by
treatment with a base such as lithium diisopropylamide or lithium
hexamethyldisilazide in a suitable solvent such as THF, followed by
reaction with an alkylating agent, such as an alkyl halide, alkyl
methanesulfonate, alkyl trifluoromethanesulfonate, or alkyl
toluenesulfonate to give intermediate 8. If desired, the sequence
may be repeated to give compounds of the general formula 9. LG is a
leaving group.
[1291] As shown in Scheme 3, the group attached to the nitrogen can
potentially be removed to give intermediate 16. For example
treating a 2,4-dimethoxybenzyl derivative with TFA accomplishes
such a transformation. Similar transformations are well documented
(see e.g. P. G. M. Wuts and T. W. Greene, "Greene's protective
groups in organic synthesis", 4.sup.th ed., John Wiley & Sons,
New York, (2007)). Resubjecting compound 16 to alkylation
conditions similar to the ones described above will give 17.
##STR00062##
[1292] As further shown in Scheme 3, if one of the alkyl groups
contains a double bond, this double bond can be converted into a
carboxylic acid 11 by a number of methods known to those of
ordinary skill in the art. For example, reacting 10 with a solution
of periodate containing KMnO.sub.4 or RuCl.sub.3 (see e.g. R. U.
Lemieux, E. von Rudloff, Can. J. Chem., 38, 1703, (1955)) will
accomplish this transformation. The carboxylic acid 11 can, in
turn, be converted into other groups such as an amide or hydrazide
by methods well known to those of ordinary skill in the art. For
example, the carboxylic acid 11 can be activated by condensation
with a variety of coupling reagents, including hydroxybenzotriazole
(HOBt) and N-hydroxysuccinimide (HOSu), for example, using
dicyclohexylcarbodiimide (DCC) or a similar carbodiimide reagent or
a wide variety of reagents such as those developed for formation of
peptide bonds. Conditions for such reactions are well known to
those of ordinary skill in the art. The activated intermediate, an
ester of HOBt or HOSu, for example, can then be condensed with a
wide variety of nucleophiles such as amines or alcohols.
[1293] Scheme 3 shows the conversion of a compound of formula 11
into an amide 12 by this sequence. Using ammonia as the
nucleophile, compound 13 is obtained. Dehydration of the amide 13
to a nitrile 14 can be accomplished by a variety of methods.
Phosphorous pentoxide is a common dehydrating reagent for this
reaction, but many others are known to those skilled in the art
(see e.g. R. C. Larock; Comprehensive Organic Transformations,
2.sup.nd ed., John Wiley & Sons, New York, pp. 1983, (1999)).
The nitrile can, in turn, be converted into other groups such as a
tetrazole by reacting the nitrile with an azide, such as sodium
azide, lithium azide or hydrazoic acid in a solvent such as DMF or
water.
##STR00063##
[1294] As shown in Scheme 4, the acid 11 can also be used to
produce heterocyclic derivatives, such as, for example,
[1,3,4]-oxadiazoles 18, [1,2,4]-oxadiazol-5(4H)-ones 19, and
[1,2,4]-oxadiazoles 20 by methods well known to those of ordinary
skill in the art. For example, converting the acid 11 into an
diacylhydrazide, followed by treatment with a base at elevated
temperature will provide 18. In another example 11 is converted
into a nitrile as described in Scheme 3, which is treated with
hydroxylamine. Reaction with 1,1'-carbonyldiimidazole in the
presence of a base, such as DBU, generates 19 In yet another
example, 11 reacts with a N-hydroxycarboxamidine derivative in the
presence of 1,1'-carbonyldiimidazole, followed by treatment with
tetrabutylammonium fluoride to give 20.
##STR00064##
[1295] As shown in Scheme 5, a compound of formula 16 can also be
dihydroxylated to give 21. Osmiumtetroxide in the presence of a
second oxidizing agent such as 4-methylmorpholine-4-oxide in a
suitable solvent will accomplish such a transformation. 21 can be
converted into 22 by reaction with acetone or 2,2-dimethoxypropane
in the presence of an acid, such as methanesulfonic acid,
p-toluenesulfonic caid or camphorsulfonic acid. Compound 22 can
then be N-arylated or N-alkylated by a variety of methods well
known to those of ordinary skill in the art, such as treating 22
with an alkylhalide, alkylmethanesulfonate or alkyltoluenesulfonate
in the presence of a base such as butyllithium or sodium hydride in
a solvent such as DME, DMF or THF. Treating 23 with an acid such as
HCl or H.sub.2SO.sub.4 in the presence of water will give the diol
24, which can be cleaved to the aldehyde 25 by a variety of
oxidizing agents, such as periodic acid or lead tetraacetate (see
e.g. Haines, A. H. Methods for the Oxidation of Organic Compounds,
Vol 2.; p 277, Academic Press, NY, (1988)). The aldehyde 25 can be
converted into the acid 26 by strong oxidizing agents including
CrO.sub.3 or a solution of periodate containing RuCl.sub.3.
##STR00065##
[1296] Scheme 6 illustrates an alternative method for the
preparation of intermediate compounds of general structure 35. This
intermediate can be used to make additional compounds in this
invention. Here, a
(4S,5S)-2-allyl-2-chloro-3,4-dimethyl-5-phenyl-1,3,2-oxazasilolidine
of the general formula 28 is formed by the reaction of 27 (prepared
as described in J. Am. Chem. Soc. 124, 7920, (2002) with an alkene
in the presence of Grubb's catalyst. Reaction with imine 29, which
is prepared by the reaction of 2-(aminomethyl)phenol with an
aldehyde using conditions well known to those skilled in the art,
will yield compound 30 (See also J. Am. Chem. Soc. 129, 14552,
(2007)). Intermediate 30 can in turn be converted into compound 31,
by reacting consecutively with acetic anhydride in the presence of
a base such as triethylamine, toluenesulfonic acid and oxalyl
chloride in the presence of propylene glycol as described in Org.
Letters, 11, 433, (2009), for example. Homoallyl amine 31 can
optionally be further modified, for example by arylating or
alkylating the nitrogen by methods well known to those of ordinary
skill in the art. For example, the reaction of 31 with a ketone or
aldehyde in the presence of a reducing agent such as sodium
borohydride, sodium cyanoborohydride or sodium
triacetoxyborohydride in a solvent such as DME, DMF or THF will
accomplish this transformation. 32 can be acylated or sulfonylated
by conditions well known to those of ordinary skill in the art to
yield 33. 33 can be cyclized to 34 by a Ring Closing Metathesis
(RCM) reaction. Catalysts suitable for such transformations are
known to those of skill in the art (see e.g. (a) Grubbs, R. H.
Handbook of Metathesis; Wiley-VCH: Weinheim, (2003); (b) Angew.
Chem., Int. Ed., 42, 1900, (2003)) and include Grubbs 1.sup.st
generation and Grubbs 2.sup.nd generation catalysts. Catalytic
hydrogenation of 34 using, for example, a palladium, platinum or
iridium catalyst in a solvent such as DCM, THF, methanol, or an
aqueous mixture containing an alcohol or THF as a co-solvent, for
example, is used to reduce the double bond, producing compound
35.
##STR00066##
[1297] Compounds of the present invention may also be prepared via
the lactone route illustrated in Scheme 7. Aryl benzyl ketones 3,
commercially available or prepared by Dieckmann condensation or by
coupling an aryl methyl ketone 41 with a bromoaryl compound 42, can
be condensed with acrylate esters 43 including methacrylate,
ethacrylate, etc., to form the keto ester 44. Stereoselective
reduction occurs with sodium borohydride in methanol to form
racemic 45 as a mixture of epimers at the R.sup.e position.
Alternatively, this reduction can be carried out via dynamic
kinetic resolution (see, Chen, et. al., Organic Process Research
& Development, 2007, 11, 616-623 and references contained
therein) to give enantioenriched 46, also as a mixture of epimers
at the R'' position. In this process, isopropyl esters are produced
by transesterification. Hydrolysis to the carboxylic acid 47
followed by lactonization affords the racemic or enantioenriched
lactone 48 as a mixture of diastereomers at the R.sup.e position.
The diastereomers as a mixture can be enolized with strong base
such as LiHMDS or LDA to give a common enolate which is alkylated
with allyl bromide to afford lactone 49 as a single diastereomer.
(see Example 261 Step E). Condensation of racemic lactone 49 with
enantiopure aminoalcohols 50 results in diastereomeric
hydroxylamides 51 which can be converted into oxazolines 52,
oxazolinium salts 53 or hydroxylactams 54. Separation of the
diastereomers can generally be done on any of these intermediates
by normal phase silica chromatography. Alternatively, condensation
of enantioenriched lactone 49 with enantioenriched amino alcohols
50 leads to enhanced enantiopurity of the resulting 51, 52, 53 or
54. For example 94% ee lactone combined with 98% ee amino alcohol
results in the major diastereomer of 99.94% ee.
[1298] Hydroxylactam 54 (R.sup.5=Et, cPr) has been prepared by
alternate procedures (see Example 91 Step B; and Example 252 Step
A) and used as an intermediate for many of the compounds of the
present invention (equivalent to lactam 10 of Scheme 3). Using the
lactone procedure, additional examples (R.sup.5=iPr [Example 261,
Step H], tBu, etc.) can be prepared. Additionally, aminoalcohols
containing two adjacent stereocenters (i.e., R.sup.6 not H) can be
incorporated into this route. The oxazolinium salt 53 is also a
versatile intermediate. It can be intercepted with various
nucleophiles such as azide, thiols or sulfinate salts to form
lactams 56, leading to amines, amides, sulfonamides and sulfones.
The allyl group of oxazolinium salt 53 can be oxidized to the
carboxylic acid oxidation state with minimal complication from the
primary or secondary alcohol center which is tied up in the
oxazoline ring. The resulting orthoamide 57 releases the lactam
carboxylate 58 under mild hydrolysis conditions. Thus lactone 49
[R.sup.3=pClPh, R.sup.4=mClPh, R.sup.e=Me] and
(2S,3S)-3-aminopentan-2-ol [WO2007/110649A2] were combined. The
corresponding oxazoline 52 [R.sup.3=pClPh, R.sup.4=mClPh,
R.sup.e=Me R.sup.5=Et, R.sup.6=Me] was formed by dehydration under
Dean-Stark conditions in toluene with ammonium molybdate as a
catalyst. Treatment with triflic anhydride in dichloromethane with
lutidine at -50.degree. C. gave oxazolinium salt 53 [R.sup.3=pClPh,
R.sup.4=mClPh, R.sup.e=Me R.sup.5=Et, R.sup.6=Me]. Oxidation with
KMnO.sub.4 in dichloromethane/water facilitated by
tetrabutylammonium chloride gave after workup and hydrolysis with
sodium bicarbonate solution in isopropyl acetate at 70.degree. C.,
compound 58 [R.sup.3=pClPh, R.sup.4=mClPh, R.sup.e=Me R.sup.5=Et,
R.sup.6=Me] identical to material prepared in Example 152.
Example 1
##STR00067##
[1299]
2-((3R,5R,6S)-1-((S)-1-tert-butoxy-1-oxobutan-2-yl)-5-(3-chlorophen-
yl)-6-(4-chlorophenyl)-2-oxopiperidin-3-yl)acetic acid
Step A. 2-(3-Chlorophenyl)-1-(4-chlorophenyl)ethanone
##STR00068##
[1301] To a solution of 2-(3-chlorophenyl)acetic acid (10 g, 58.6
mmol) in THF (58 ml) was added 117 mL of a 1M solution of sodium
bis-(trimethylsilyl)amide in THF slowly over 1 h at -78.degree. C.
After being stirred at -78.degree. C. for 40 min, a solution of
methyl 4-chlorobenzoate (10 g, 58.6 mmol) in THF (35 ml) was added
over a period of 10 min. The reaction was stirred at -78.degree. C.
for 3 h, then allowed to warm to 25.degree. C., and stirred an
additional 2 h until completion. The reaction was quenched with
saturated aqueous NH.sub.4Cl solution and most of the THF was
removed under reduced pressure. The residue was extracted with
ethyl acetate (2.times.100 ml). The combined organic layers were
washed with sat. NaCl solution, dried over Na.sub.2SO.sub.4,
filtered and the filtrate was concentrated. The product was
recrystallized from ether/pentane to provide the title compound as
a white solid.
Step B. Methyl
4-(3-chlorophenyl)-5-(4-chlorophenyl)-5-oxopentanoate
##STR00069##
[1303] To a solution of 52.1 g (197 mmol) of
2-(3-chlorophenyl)-1-(4-chlorophenyl)ethanone (Example 1, Step A)
and methyl acrylate (19.5 ml, 216 mmol) in 360 mL of THF was added
20 mL of a 1M solution of potassium tert-butoxide in THF slowly at
0.degree. C. over a period of 20 min (reaction solution temp kept
<10.degree. C.). The reaction was allowed to warm to ambient
temperature. After being stirred at rt for 1 h, the reaction was
concentrated under reduced pressure, diluted with water and
extracted with ethyl acetate. The combined organic layers were
washed with sat. NaCl solution, dried over Na.sub.2SO.sub.4,
filtered and the filtrate was concentrated. Purification of the
residue by flash chromatography on silica gel (eluent:15%
EtOAc/hexanes) provided the title compound as a colorless liquid. R
is CH.sub.3.
Step C. (4S,5S)-Methyl
4-(3-chlorophenyl)-5-(4-chlorophenyl)-5-hydroxy pentanoate and
(4R,5R)-Methyl 4-(3-chlorophenyl)-5-(4-chlorophenyl)-5-hydroxy
pentanoate
##STR00070##
[1305] To a solution of 75.1 g (213 mmol) of methyl
4-(3-chlorophenyl)-5-(4-chlorophenyl)-5-oxopentanoate (Example 1,
Step B) in MeOH (0.71 .mu.L, c=0.3 M) at 0.degree. C. was added
sodium borohydride (8058 mg, 213 mmol) in several small portions.
After being stirred at 0.degree. C. for 30 min, the reaction
mixture was quenched with ice-cold H.sub.2O, concentrated under
reduced pressure, and extracted with EtOAc. The combined organic
layers were washed (sat. aq. NaCl solution), dried over
Na.sub.2SO.sub.4, filtered and the filtrate was concentrated.
Purification of the residue by flash chromatography on silica gel
(eluent: 20 to 30% EtOAc/hexanes, gradient elution) provided a
racemic mixture of the title compounds as a colorless liquid.
Step D. (4S,5R)-Methyl
5-azido-4-(3-chlorophenyl)-5-(4-chlorophenyl)pentanoate and
(4R,5S)-Methyl
5-azido-4-(3-chlorophenyl)-5-(4-chlorophenyl)pentanoate
##STR00071##
[1307] To a solution of 63.1 g (179 mmol) of (4S,5S)-methyl
4-(3-chlorophenyl)-5-(4-chlorophenyl)-5-hydroxy pentanoate and
(4R,5R)-methyl 4-(3-chlorophenyl)-5-(4-chlorophenyl)-5-hydroxy
pentanoate (Example 1, Step C) and triethylamine (49.8 ml, 357
mmol) in DCM (600 mL, 0.3 M) was added methanesulfonyl chloride (18
ml, 232 mmol) at 0.degree. C. dropwise over a period of 10 min. The
reaction was stirred at 0.degree. C. for 40 min and monitored by
TLC for completion. Then the reaction was quenched with ice-cold
water, extracted (3.times.DCM), and washed with sat aq. NaCl
solution. The combined organic layers were dried
(Na.sub.2SO.sub.4), and concentrated under the reduced
pressure.
[1308] The crude mesylate synthesized above was dissolved in DMF
(350 mL, 0.5 M) and sodium azide (58 g, 893 mmol) was added in
several portions. The mixture was heated to 100.degree. C. and
after being stirred at 100.degree. C. for 30 min, the reaction
mixture was cooled to room temperature, diluted with water and
extracted with EtOAc. The combined organic layers were washed (sat.
aq. NaCl solution), dried over Na.sub.2SO.sub.4, filtered and the
filtrate was concentrated. Purification of the residue by flash
chromatography on silica gel (eluent: 5 to 20% EtOAc/hexanes,
gradient elution) provided the title compound as a colorless
liquid.
Step E.
(5R,6S)-5-(3-Chlorophenyl)-6-(4-chlorophenyl)piperidin-2-one
##STR00072##
[1310] To a solution of 45.9 g (121 mmol) of methyl
5-azido-4-(3-chlorophenyl)-5-(4-chlorophenyl)pentanoate (Example 1,
Step D) in THF/H.sub.2O (4:1, 375 mL) was added 152 mL of a 1M
solution of trimethylphosphine in THF (152 mmol). After being
stirred for 1 h at 25.degree. C., most of the THF was removed under
reduced pressure. The residue was basified (ice-cold 2 M LiOH) and
the product was extracted with methylene chloride. The combined
organic layers were washed with sat. NaCl solution, dried over
Na.sub.2SO.sub.4, filtered and the filtrate was concentrated under
reduced pressure to provide a white solid.
[1311] This solid was dissolved in MeOH/saturated aq. NaHCO.sub.3
(4:1, 2.4 L, c=0.05 M) and the reaction was heated to reflux for 3
h. Excess organic solvent was removed under reduced pressure, the
residue was diluted with water and extracted (2.times.10%
MeOH/DCM). The combined organic layers were washed with sat. NaCl
solution, dried over Na.sub.2SO.sub.4, filtered and the filtrate
was concentrated under reduced pressure to provide
trans-5-(3-chlorophenyl)-6-(4-chlorophenyl)piperidin-2-one as a
mixture of stereoisomers. Individual stereoisomers were separated
by chiral HPLC (flowrate: 18 ml/min on a Chiralcel.RTM. OD-H 20 mm
I.D..times.250 mm, 5 mic column (Daicel Inc., Fort Lee, N.J.),
using 40% isopropyl alcohol/hexane as the eluent) to to give the
title compound (t.sub.R=8.2 min) as a white solid.
[1312] [.alpha.].sub.D=+158 (T=23.4.degree. C., c=1.12, MeOH);
.sup.1H NMR (400 MHz, CHLOROFORM-d) .delta. ppm 7.21 (2H, d, J=8.2
Hz), 7.09-7.19 (3H, m), 7.04-7.01 (1H, m), 6.97 (2H, d, J=8.2 Hz),
6.80-6.77 (1H, m), 5.83 (1H, s, br), 4.51 (1H, d, J=9.8 Hz),
2.94-2.77 (1H, m), 2.74-2.60 (2H, m), 2.34-2.20 (1H, m), 2.17-2.08
(1H, m); MS (ESI) 320.0 [M+H].sup.+.
[1313] Also obtained by the above method was the enantiomer of the
title compound,
(5S,6R)-5-(3-chlorophenyl)-6-(4-chlorophenyl)piperidin-2-one:
t.sub.R=12.4 min; [.alpha.].sub.D=-156 (T=23.4.degree. C., c=1.13,
MeOH).
Step F. tert-butyl
(2S)-2-((2S,3R)-3-(3-chlorophenyl)-2-(4-chlorophenyl)-6-oxo-1-piperidinyl-
)butanoate and tert-butyl
(2R)-2-((2S,3R)-3-(3-chlorophenyl)-2-(4-chlorophenyl)-6-oxo-1-piperidinyl-
)butanoate
##STR00073##
[1315] To a solution of 13.5 g (42.2 mmol) of
(5R,6S)-5,6-bis(4-chlorophenyl)piperidin-2-one (Example 1, Step E)
in 140 mL of DMF was added 4.22 g (105 mmol) of a dispersion of 60%
sodium hydride in mineral oil at 0.degree. C. After being stirred
for 20 min, tert-butyl 2-bromobutanoate (28.2 g, 126 mmol) was
added at 0.degree. C. and the resulting solution was stirred at
25.degree. C. for 1.5 h until completion of the reaction. Then sat.
aq. NH.sub.4Cl solution was added and the mixture was extracted
with ethylacetate. The combined organic layers were washed with
water and sat. NaCl solution, dried over Na.sub.2SO.sub.4, filtered
and the filtrate was concentrated under reduced pressure.
Purification of the residue by flash chromatography on silica gel
(eluent: 20 to 50% EtOAc/hexanes, gradient elution) provided
tert-butyl
(2S)-2-((2S,3R)-3-(3-chlorophenyl)-2-(4-chlorophenyl)-6-oxo-1-piperidinyl-
)butanoate as the faster eluting minor isomer:
[1316] .sup.1H NMR (400 MHz, CHLOROFORM-d) .delta. ppm 7.22 (2H, d,
J=8.2 Hz), 7.20-7.10 (2H, m), 7.08 (2H, t, J=8.2 Hz) 6.99-6.96 (1H,
m), 6.77-6.73 (1H, m), 4.48 (1H, d, J=9.4 Hz), 3.24 (1H, t, J=7.0
Hz), 3.04-2.94 (1H, m), 2.72-2.58 (2H, m), 2.25-2.00 (3H, m),
1.93-1.82 (1H, m), 1.45 (9H, s), 0.98 (3H, t, J=7.4 Hz); MS (ESI)
462.1 [M+H].sup.+.
[1317] Further Elution Provided
[1318] tert-butyl
(2R)-2-((2S,3R)-3-(3-chlorophenyl)-2-(4-chlorophenyl)-6-oxo-1-piperidinyl-
)butanoate as the slower eluting major isomer.
[1319] .sup.1H NMR (400 MHz, CHLOROFORM-d) .delta. ppm 7.24 (2H, d,
J=8.2 Hz), 7.18-7.10 (2H, m), 7.01 (2H, d, J=82 Hz), 7.02-6.98 (1H,
m), 6.82-6.78 (1H, m), 5.83 (1H, s), 4.54 (1H, d, J=9.8 Hz), 3.09
(1H, dd, J=8.2, 4.3 Hz), 3.05-2.99 (1H, m), 2.70-2.64 (2H, m),
2.28-2.18 (2H, m), 2.08-2.02 (1H, m), 1.48 (9H, s), 0.57 (3H, t,
J=7.4 Hz); MS (ESI) 462.1 [M+H].sup.+.
Step G. tert-Butyl
(2S)-2-((3S,5R,6S)-3-allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-2-oxopip-
eridin-1-yl)butanoate and. tert-Butyl
(2S)-2-((3R,5R,6S)-3-allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-2-oxopip-
eridin-1-yl)butanoate
##STR00074##
[1321] To a solution of 1.45 g (3.14 mmol) of tert-butyl
(2S)-2-((2S,3R)-3-(3-chlorophenyl)-2-(4-chlorophenyl)-6-oxo-1-piperidinyl-
)butanoate (Example 1, Step F) and allyl bromide (0.326 mL, 3.76
mmol) in 12.5 mL of THF was added dropwise at -78.degree. C. 3.3 mL
of a 1 M solution of lithium bis(trimethylsilyl)-amide in THF (3.3
mmol). After being stirred at -78.degree. C. for 3 h, the reaction
was quenched with sat. aqueous NH.sub.4Cl solution, extracted with
ethyl acetate. The combined organic layers were washed with sat.
NaCl solution, dried over Na.sub.2SO.sub.4, filtered and the
filtrate was concentrated under reduced pressure. Purification of
the residue by flash chromatography on silica gel (50 g SiO.sub.2,
eluent: 5 to 20% EtOAc/hexanes, gradient elution) provided
tert-butyl
(2S)-2-((3R,5R,6S)-3-allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-2-oxopip-
eridin-1-yl)butanoate as the faster eluting major isomer.
[1322] .sup.1H NMR (400 MHz, CHLOROFORM-d) .delta. ppm 7.27-7.24
(2H, m), 7.21-7.12 (2H, m), 7.11-7.00 (3H, m), 6.93-6.87 (1H, m),
5.90-5.77 (1H, m), 5.19-5.09 (2H, m), 4.64 (1H, d, J=8.6 Hz),
3.21-3.10 (2H, m), 2.80-2.71 (1H, m), 2.70-2.63 (1H, m), 2.56-2.48
(1H, m), 2.30-2.15 (2H, m), 2.07-1.99 (1H, m), 1.60-1.48 (1H, m),
1.47 (9H, s), 0.61 (3H, t, J=7.6 Hz); MS (ESI) 446.0
[M+H].sup.+.
[1323] Further Elution Provided
[1324] tert-butyl
(2S)-2-((3S,5R,6S)-3-allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-2-oxopip-
eridin-1-yl)butanoate as the slower eluting, minor isomer.
[1325] .sup.1H NMR (400 MHz, CHLOROFORM-d) .delta. ppm 7.23 (2H, d,
J=8.2 Hz), 7.19-7.07 (2H, m), 7.01-6.95 (3H, m), 6.77-6.72 (1H, m),
5.95-5.77 (1H, m), 5.16-4.99 (2H, m), 4.51 (1H, d, J=10.6 Hz),
3.13-3.04 (1H, m), 2.94 (1H, dd, J=7.8, 4.3 Hz), 2.87-2.77 (1H, m),
2.68-2.58 (1H, m), 2.39-2.27 (2H, m), 2.16-1.95 (2H, m), 1.54-1.50
(1H, m), 1.51 (9H, s), 0.55 (3H, t, J=7.4 Hz); MS (ESI) 446.0
[M+H].sup.+.
Step H.
2-((3R,5R,6S)-1-((S)-1-tert-Butoxy-1-oxobutan-2-yl)-5-(3-chlorophe-
nyl)-6-(4-chlorophenyl)-2-oxopiperidin-3-yl)acetic acid
##STR00075##
[1327] To a rapidly stirring solution of 842 mg (1.67 mmol) of
tert-butyl
(2S)-2-((3S,5R,6S)-3-allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-2-oxopip-
eridin-1-yl)butanoate (Example 1, Step G) in a mixture of 7 mL of
water, 5 mL of acetonitrile and 5 mL of CCl.sub.4 was added sodium
periodate (1.43 g, 6.70 mmol), followed by ruthenium(III) chloride
hydrate (37.8 mg, 0.168 mmol). After being stirred vigorously for
18 h, the reaction was acidified (10% citric acid) and diluted with
EtOAc. The reaction mixture was filtered through celite and the
filtrate was extracted with EtOAc. The combined organic layers were
washed with sat. NaCl solution, dried over Na.sub.2SO.sub.4,
filtered and the filtrate was concentrated under reduced pressure.
The residue was purified by reversed phase preparatory HPLC
(Gemini.TM. Prep C18 5 .mu.m column, Phenomenex, Torrance, Calif.;
eluent: 60 to 80% acetonitrile+0.1% TFA in water+0.1% TFA, gradient
elution) to give the title compound as a white solid.
[1328] .sup.1H NMR (400 MHz, CHLOROFORM-d) .delta. ppm 7.35 (2H, d,
J=8.6 Hz), 7.27-7.24 (3H, m), 7.22-7.16 (1H, m), 7.18 (2H, d, J=8.6
Hz), 4.85 (1H, d, J=5.1 Hz), 3.36 (1H, dd, J=8.6, 3.5 Hz),
3.18-3.14 (1H, m), 2.92-2.80 (2H, m), 2.79-2.72 (1H, m), 2.32-2.18
(2H, m), 2.15-2.06 (1H, m), 1.63-1.50 (1H, m), 1.44 (9H, s), 0.67
(3H, t, J=7.4 Hz); MS (ESI) 520.2 [M+H].sup.+, 518.0
[M-H].sup.-.
Example 2
##STR00076##
[1330]
2-((3S,5R,6S)-1-((S)-1-tert-Butoxy-1-oxobutan-2-yl)-5-(3-chlorophen-
yl)-6-(4-chlorophenyl)-2-oxopiperidin-3-yl)acetic acid The title
compound was prepared from (S)-tert-butyl
2-((3R,5R,6S)-3-allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-2-oxopiperidi-
n-1-yl)butanoate (Example 1, Step G) by the procedure described in
Example 1, Step H.
[1331] .sup.1H NMR (500 MHz, CHLOROFORM-d) .delta. ppm 7.27-7.26
(2H, m), 7.12-7.16 (1H, m), 7.13-7.10 (1H, m), 7.02-6.94 (3H, m),
6.74-6.71 (1H, m), 4.51 (1H, d, J=10.8 Hz), 3.18-3.08 (2H, m),
3.06-2.96 (2H, m), 2.47 (1H, dd, J=15.4, 3.2 Hz), 2.35-2.25 (1H,
m), 2.24-2.12 (2H, m), 1.52-1.57 (1H, m), 1.51 (9H, s), 0.56 (3H,
t, J=7.5 Hz); MS (ESI) 520.2 [M+H].sup.+, 518.0 [M-H].
[1332] The following examples 3 to 6 were prepared as described in
Example 1, substituting tert-butyl 2-bromobutanoate in step F, with
the appropriate amount of ethyl 2-bromobutanoate,
[1333] ethyl 2-bromo-3-methylpentanoate, ethyl 2-bromopentanoate,
and ethyl 2-bromo-2-cyclopropylacetate, respectively.
Example 3
##STR00077##
[1334]
2-((3R,5R,6S)-5-(3-Chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-ethoxy-
-1-oxobutan-2-yl)-2-oxopiperidin-3-yl)acetic acid
[1335] .sup.1H NMR (400 MHz, CHLOROFORM-d) .delta. ppm 7.42-7.33
(3H, m), 7.32-7.28 (3H, m), 7.27-7.24 (2H, m), 4.91 (1H, d, J=3.5
Hz), 4.23-4.10 (2H, m), 3.54 (1H, dd, J=8.6, 3.5 Hz), 3.22-3.16
(1H, m), 2.84-2.73 (3H, m), 2.38-2.30 (2H, m), 2.05-1.97 (1H, m),
1.60-1.50 (1H, m), 1.27 (3H, t, J=7.4 Hz), 0.70 (3H, t, J=7.4 Hz);
MS (ESI) 491.8 [M+H].sup.+, 489.9 [M-H].sup.-.
Example 4
##STR00078##
[1336]
2-((3R,5R,6S)-5-(3-Chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-ethoxy-
-4-methyl-1-oxopentan-2-yl)-2-oxopiperidin-3-yl)acetic acid
[1337] .sup.1H NMR (400 MHz, CHLOROFORM-d) .delta. ppm 0.34 (d,
J=6.7 Hz, 3H), 0.77 (d, J=6.7 Hz, 3H), 1.13 (m, 1H), 1.28 (t, J=7.1
Hz, 3H), 1.30-1.44 (m, 1H), 1.98 (m, 1H), 2.32-2.47 (m, 2H), 2.75
(m, 1H), 2.79-2.86 (m, 2H), 3.14-3.19 (m, 1H), 3.66 (dd, J=9.2, 2.4
Hz, 1H), 4.11-4.24 (m, 2H), 4.95 (m, 1H), 7.23-7.34 (m, 5H),
7.36-7.41 (m, 3H), MS (ESI) 520.2 [M+H].sup.+. 518.0
[M-H].sup.-.
Example 5
##STR00079##
[1338]
2-((3R,5R,6S)-5-(3-Chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-ethoxy-
-1-oxopentan-2-yl)-2-oxopiperidin-3-yl)acetic acid and
2-((3S,5S,6R)-5-(3-Chlorophenyl)-6-(4-chlorophenyl)-1-((R)-1-ethoxy-1-oxo-
pentan-2-yl)-2-oxopiperidin-3-yl)acetic acid
[1339] The compounds described in Example 5 were derived from
racemic piperidinone which was prepared in Example 1, Step E.
[1340] .sup.1H NMR (400 MHz, CHLOROFORM-d) .delta. ppm 7.40-7.37
(3H, m), 7.31-7.27 (3H, m), 7.27-7.24 (2H, m), 4.92 (1H, d, J=3.5
Hz), 4.20-4.10 (2H, m), 3.60 (1H, dd, J=8.6, 3.5 Hz), 3.20-3.15
(1H, m), 2.83-2.72 (3H, m), 2.40-2.30 (2H, m), 2.03-1.97 (1H, m),
1.44-1.37 (1H, m), 1.27 (3H, t, J=7.2 Hz), 1.26-1.17 (1H, m),
0.92-0.80 (1H, m), 0.54-0.78 (3H, t, J=7.4 Hz); MS (ESI) 506.0
[M+H].sup.+, 504.0 [M-H].sup.-.
Example 6
##STR00080##
[1341]
2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-cyclop-
ropyl-2-ethoxy-2-oxoethyl)-2-oxopiperidin-3-yl)acetic acid
[1342] .sup.1H NMR (400 MHz, CHLOROFORM-d) .delta. ppm 0.08 (1H,
m), 0.34 (1H, m), 0.47 (1H, m), 0.58 (1H, m), 1.06 (1H, m), 1.13
(3H, t, J=7.1 Hz), 1.83 (1H, m), 2.19 (1H, m), 2.50-2.63 (2H, m),
2.74 (1H, dd, J=16, 6.8 Hz), 3.08 (1H, m), 3.42 (1H, d, J=10.8 Hz),
3.97 (2H, m), 5.20 (1H, s), 7.08 (1H, m), 7.15-7.25 (7H, m); MS
(ESI) 504.1 [M+H].sup.+.
Example 7
##STR00081##
[1343]
2-((3R,5R,6S)-5-(3-Chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-hydrox-
ybutan-2-yl)-2-oxopiperidin-3-yl)acetic acid
[1344] To a solution of 300 mg (0.61 mmol) of
2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-ethoxy-1-oxo-
butan-2-yl)-2-oxopiperidin-3-yl)acetic acid (Example 3) in 12 mL of
Et.sub.2O was added lithium tetrahydroborate (39.8 mg, 1.83 mmol)
at 0.degree. C. After being stirred for 20 min, methanol (37.0
.mu.l, 914 .mu.mol) was added at 0.degree. C. and the resulting
solution was stirred at 25.degree. C. for 2 h. The reaction was
quenched (10% citric acid), extracted (2.times.EtOAc) and washed
(1.times.sat. aq. NaCl solution). The combined organic layers were
washed with sat. NaCl solution, dried over Na.sub.2SO.sub.4,
filtered and the filtrate was concentrated under reduced pressure.
Purification by reversed phase preparatory HPLC (Gemini.TM. Prep
C18 5 .mu.m column, Phenomenex, Torrance, Calif.; eluent: 35 to 75%
acetonitrile+0.1% TFA in water+0.1% TFA, gradient elution) provided
the title compound as a white foam.
[1345] .sup.1H NMR (400 MHz, CHLOROFORM-d) .delta. ppm 7.42-7.37
(3H, m), 7.34-7.27 (4H, m), 7.18-7.13 (1H, m), 4.89 (1H, d, J=2.7
Hz), 3.99-3.90 (1H, m), 3.78 (1H, dd, J=11.5, 3.3 Hz), 3.32-3.23
(1H, m), 3.13-3.07 (1H, m), 2.88-2.65 (3H, m), 2.35-2.25 (1H, m),
2.12-2.03 (1H, m), 1.95-1.84 (1H, m), 1.58-1.46 (1H, m), 0.71 (3H,
t, J=7.4 Hz); MS (ESI) 450.1 [M+H].sup.+, 448.0 [M-H].sup.-.
Example 8
##STR00082##
[1346]
2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-cyclop-
ropyl-2-hydroxyethyl)-2-oxopiperidin-3-yl)acetic acid
[1347] The title compound was prepared from
2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-cyclopropyl--
2-ethoxy-2-oxoethyl)-2-oxopiperidin-3-yl)acetic acid (Example 6) as
described in Example 7.
[1348] .sup.1H NMR (400 MHz, CHLOROFORM-d) .delta. ppm 0.23 (m,
1H), 0.36 (m, 1H), 0.65-0.69 (m, 2H), 0.95 (m, 1H), 1.90 (m, 1H),
2.40 (m, 1H), 2.68 (m, 1H), 2.80 (2H, d, J=5.3 Hz), 3.13 (1H, m),
3.48 (m, 1H), 3.60-3.85 (m, 2H), 5.32 (s, 1H), 7.20 (m, 1H),
7.27-7.40 (m, 3H), 7.40-7.43 (m, 4H); MS (ESI) 462.1
[M+H].sup.+.
Example 9
##STR00083##
[1349]
2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-(cyclo-
propylmethoxy)butan-2-yl)-2-oxopiperidin-3-yl)acetic acid
Step A. (S)-Ethyl
2-((2S,3R)-3-(3-chlorophenyl)-2-(4-chlorophenyl)-6-oxopiperidin-1-yl)buta-
noate
##STR00084##
[1351] To a solution of 15 g (46.8 mmol) of
((5R,6S)-5-(3-Chlorophenyl)-6-(4-chlorophenyl)piperidin-2-one
(Example 1, Step E) in 140 mL of DMF was added 3.75 g (94 mmol) of
a dispersion of 60% sodium hydride in mineral oil at 0.degree. C.
After being stirred for 20 min, ethyl 2-bromobutanoate (17.2 mL,
117 mmol) was added at 0.degree. C. and the resulting solution was
stirred at 25.degree. C. for 12 h until completion of the reaction.
Then sat. aq. NH.sub.4Cl solution was added and the mixture was
extracted with ethyl acetate. The combined organic layers were
washed with water and sat. NaCl solution, dried over
Na.sub.2SO.sub.4, filtered and the filtrate was concentrated under
reduced pressure. Purification of the residue by flash
chromatography on silica gel (eluent:30% EtOAc/hexanes, gradient
elution) provided the title compound as the faster eluting
isomer.
Step B. (S)-Ethyl
2-((3S,5R,6S)-3-allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-2-oxopiperidi-
n-1-yl)butanoate
##STR00085##
[1353] To a solution of 0.62 g (1.4 mmol) of (S)-ethyl
2-((2S,3R)-3-(3-chlorophenyl)-2-(4-chlorophenyl)-6-oxopiperidin-1-yl)buta-
noate (Example 9, Step A) and allyl bromide (0.14 ml, 1.7 mmol) in
THF (6.0 mL, 0.25 M) was added lithium bis(trimethylsilyl)-amide
(1M solution in THF, 1.5 ml, 1.5 mmol) at -78.degree. C. The
reaction was allowed to warm to R.T., then was quenched (sat.
aqueous NH.sub.4Cl) and extracted with EtOAc. The combined organic
layers were washed with water and sat. NaCl solution, dried over
Na.sub.2SO.sub.4, filtered and the filtrate was concentrated under
reduced pressure. Purification of the residue by flash
chromatography on silica gel (15 to 20% EtOAc/Hex, gradient
elution) provided the title compound as the slower eluting isomer
as a colorless oil.
Step C.
(3S,5R,6S)-3-allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1--
hydroxybutan-2-yl)piperidin-2-one
##STR00086##
[1355] To a solution of 256 mg (0.54 mmol) of (S)-ethyl
2-((3S,5R,6S)-3-allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-2-oxopiperidi-
n-1-yl)butanoate (Example 9, Step B) in Et.sub.2O (5.5 mL) was
added lithium borohydride of 90% purity (17.6 mg, 0.809 mmol) at
0.degree. C. After being stirred at 0.degree. C. for 10 min, the
reaction was quenched (ice cold 10% citric acid), extracted
(2.times.EtOAc) and washed (sat. aq. NaCl solution). The combined
organic layers were washed with sat. NaCl solution, dried over
Na.sub.2SO.sub.4, filtered and the filtrate was concentrated under
reduced pressure. Purification by chromatography on silica gel
(eluent 30% to 50% EtOAc/Hexanes, a gradient elution) provided the
title compound.
Step D.
(3S,5R,6S)-3-allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1--
(cyclopropylmethoxy)butan-2-yl)piperidin-2-one
##STR00087##
[1357] To a solution of
(3S,5R,6S)-3-Allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-hydroxy-
butan-2-yl)piperidin-2-one (98 mg, 0.227 mmol) in DMF (1.10 mL) was
added 60% sodium hydride in mineral oil (27.2 mg, 0.680 mmol) at
0.degree. C. After being stirred at 0.degree. C. for 2 min,
(bromomethyl)cyclopropane (47.3 .mu.L, 0.680 mmol) was added. The
mixture was stirred at 0.degree. C. for 2 h and then warmed to rt.
Then the reaction was stirred at rt overnight. The reaction was
quenched (sat aq. NH.sub.4Cl), extracted (2.times.EtOAc) and washed
(sat. aq. NaCl solution). The combined organic layer was dried
(Na.sub.2SO.sub.4) and concentrated under reduced pressure.
Purification by chromatography on silica gel (10% to 20%
EtOAc/Hexanes gradient) provided
(3S,5R,6S)-3-allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((R)-1-(cyclop-
ropylmethoxy)butan-2-yl)piperidin-2-one as the less polar isomer
and the title compound as the more polar stereoisomer.
Step E.
2-((3R,5R,6S)-5-(3-Chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-(cycl-
opropylmethoxy)butan-2-yl)-2-oxopiperidin-3-yl)acetic acid
##STR00088##
[1359]
(3S,5R,6S)-3-allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-(-
cyclopropylmethoxy)butan-2-yl)piperidin-2-one was converted into
the carboxylic acid by a procedure similar to the one described in
Example 1, Step H. Purification by reversed phase preparatory HPLC
(Gemini.TM. Prep C18 5 .mu.m column, Phenomenex, Torrance, Calif.;
eluent: 50 to 80% acetonitrile+0.1% TFA in water+0.1% TFA, gradient
elution) provided the title compound as a white solid.
[1360] .sup.1H NMR (400 MHz, CHLOROFORM-d) .delta. ppm 7.39 (2H, d,
J=8.2 Hz), 7.38-7.36 (1H, m), 7.33-7.28 (3H, m), 7.23 (2H, d, J=8.2
Hz), 5.09 (1H, d, J=2.0 Hz), 4.17-4.07 (1H, m), 3.47-3.40 (2H, m),
3.23-3.15 (m, 2H), 3.12-3.08 (1H, m), 2.85 (1H, dd, J=15.8, 8.8
Hz), 2.66-2.55 (2H, m), 2.22-2.12 (1H, m), 2.07-1.99 (1H, m),
1.95-1.85 (1H, m), 1.62-1.54 (1H, m), 1.07-1.00 (1H, m), 0.65 (3H,
t, J=7.4 Hz), 0.60-0.52 (2H, m), 0.24-0.18 (2H, m); MS (ESI) 504.1
[M+H].sup.+, 502.1 [M-H].sup.-.
[1361] The following Examples 10 to 12 were prepared from
(3R,5R,6S)-3-allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-hydroxy-
butan-2-yl)piperidin-2-one (Example 9, Step C) by procedures
similar to those described in Example 9, Steps D and E,
substituting (bromomethyl)cyclopropane in step D for the
appropriate amount of methyliodide, 2-methoxyethylbromide, and
1-(bromomethyl)cyclopropanecarbonitrile, respectively.
TABLE-US-00001 ##STR00089## Example R 10 ##STR00090## 11
##STR00091## 12 ##STR00092##
Example 10
##STR00093##
[1362]
2-((3R,5R,6S)-5-(3-Chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-methox-
ybutan-2-yl)-2-oxopiperidin-3-yl)acetic acid
[1363] 1H NMR (400 MHz, CHLOROFORM-d) .delta. ppm 7.52-7.48 (1H,
m), 7.40 (2H, d, J=8.2 Hz), 7.31-7.28 (2H, m), 7.27-7.24 (1H, m),
7.24-7.27 (2H, m), 5.05 (1H, s), 4.08 (1H, t, J=9.6 Hz), 3.39 (3H,
s), 3.34 (1H, dd, J=9.8, 3.1 Hz), 3.20-3.10 (2H, m), 2.88-2.78 (1H,
m), 2.64-2.55 (2H, m), 2.25-2.16 (1H, m), 2.10-2.00 (1H, m),
1.90-1.81 (1H, m), 1.56-1.50 (1H, m), 0.65 (3H, t, J=7.4 Hz); MS
(ESI) 464.0 [M+H].sup.+, 462.1 [M-H].sup.-.
Example 11
##STR00094##
[1364]
2-((3R,5R,6S)-5-(3-Chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-(2-met-
hoxyethoxy)butan-2-yl)-2-oxopiperidin-3-yl)acetic acid
[1365] .sup.1H NMR (400 MHz, CHLOROFORM-d) .delta. ppm 7.41-7.35
(3H, m), 7.28-7.26 (2H, m), 7.25-7.21 (3H, m), 5.09 (1H, d, J=2.7
Hz), 4.17-4.10 (1H, m), 3.74-3.65 (1H, m), 3.60-3.52 (3H, m), 3.44
(1H, dd, J=10.4, 3.3 Hz), 3.35 (3H, s), 3.25-3.15 (1H, m),
3.12-3.07 (1H, m), 2.91-2.80 (1H, m), 2.71-2.58 (2H, m), 2.21-2.12
(1H, m), 2.05-1.89 (2H, m), 1.61-1.52 (1H, m), 0.64 (3H, t, J=7.6
Hz); MS (ESI) 508.1 [M+H].sup.+, 506.0 [M-H].sup.-.
Example 12
##STR00095##
[1366]
2-((3R,5R,6S)-5-(3-Chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-((1-cy-
anocyclopropyl)methoxy)butan-2-yl)-2-oxopiperidin-3-yl)acetic
acid
[1367] .sup.1H NMR (400 MHz, CHLOROFORM-d) .delta. ppm 7.43-7.30
(3H, m), 7.28-7.20 (4H, m), 7.18-7.10 (1H, m), 5.04 (1H, d, J=3.9
Hz), 4.13 (1H, t, J=9.4 Hz), 3.52-3.43 (2H, m), 3.42-3.33 (1H, m),
3.32-3.24 (1H, m), 3.13-3.05 (1H, m), 2.92-2.75 (2H, m), 2.72-2.60
(1H, m), 2.20-2.10 (1H, m), 2.10-1.90 (1H, m), 1.64-1.49 (1H, m),
1.35-1.25 (2H, m), 1.00-0.90 (2H, m), 0.71-0.57 (3H, m); MS (ESI)
529.2 [M+H].sup.+, 527.0 [M-H].sup.-.
[1368] Examples 13-15 were prepared from
(3R,5R,6S)-3-allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-cyclopr-
opyl-2-hydroxyethyl)piperidin-2-one in a process similar to that
described for Example 9, Step D and E.
TABLE-US-00002 ##STR00096## Example R.sup.1 13 ##STR00097## 14
##STR00098## 15 ##STR00099##
Example 13
2-((3S,5R,6S)-5-(3-Chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-(cyclopropylm-
ethoxy)butan-2-yl)-2-oxopiperidin-3-yl)acetic acid
[1369] 1H NMR (400 MHz, CHLOROFORM-d) .delta. ppm 7.25 (2H, d,
J=8.6 Hz), 7.22-7.18 (1H, m), 7.15-7.11 (1H, m), 7.08-7.04 (1H, m),
6.96 (2H, d, J=8.6 Hz), 6.77-6.73 (1H, m), 4.69 (1H, d, J=10.2 Hz),
4.03 (1H, t, J=9.8 Hz), 3.42-3.33 (2H, m), 3.28-3.22 (1H, m),
3.10-2.90 (4H, m), 2.50 (1H, dd, J=15.3, 3.1 Hz), 2.20-2.10 (1H,
m), 2.01-2.01 (1H, m), 1.92-1.80 (1H, m), 1.65-1.53 (1H, m),
1.16-1.08 (1H, m), 0.66-0.60 (2H, m), 0.53 (3H, t, J=7.6 Hz),
0.28-0.24 (2H, m); MS (ESI) 504.1 [M+H].sup.+, 502.1
[M-H].sup.-.
Example 14
2-((3S,5R,6S)-5-(3-Chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-methoxybutan--
2-yl)-2-oxopiperidin-3-yl)acetic acid
[1370] 1H NMR (400 MHz, CHLOROFORM-d) .delta. ppm 0.55 (t, J=7.53
Hz, 3H), 1.49-1.60 (m, 1H), 1.77-1.91 (m, 1H), 2.02-2.15 (m, 2H),
2.51 (dd, J=15.26, 3.33 Hz, 1H), 2.89-2.99 (m, 1H), 2.99-3.09 (m,
2H), 3.09-3.17 (m, 1H), 3.29 (dd, J=9.68, 4.21 Hz, 1H), 3.34 (s,
3H), 3.90 (t, J=9.49 Hz, 1H), 4.57 (d, J=9.98 Hz, 1H), 6.75 (d,
J=7.43 Hz, 1H), 6.97 (d, J=8.41 Hz, 2H), 7.00 (t, J=1.76 Hz, 1H),
7.14 (t, J=7.73 Hz, 1H), 7.17-7.22 (m, 1H), 7.25 (d, J=8.41 Hz,
2H).
Example 15
2-((3S,5R,6S)-5-(3-Chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-(2-methoxyeth-
oxy)butan-2-yl)-2-oxopiperidin-3-yl)acetic acid
[1371] .sup.1H NMR (400 MHz, CHLOROFORM-d) .delta. ppm 7.24 (2H, d,
J=8.2 Hz), 7.21-7.16 (1H, m), 7.14-7.09 (1H, m), 7.05-7.03 (1H, m),
6.97 (2H, d, J=8.2 Hz), 6.75-6.71 (1H, m), 4.66 (1H, d, J=10.6 Hz),
4.09 (1H, t, J=9.8 Hz), 3.70-3.55 (4H, m), 3.47 (3H, s), 3.44 (1H,
dd, J=9.8, 4.3 Hz), 3.05-2.90 (4H, m), 2.53 (1H, dd, J=15.1, 2.5
Hz), 2.28-2.15 (1H, m), 2.05-1.97 (1H, m), 1.92-1.82 (1H, m),
1.65-1.55 (1H, m), 0.50 (3H, t, J=7.6 Hz); MS (ESI) 508.1
[M+H].sup.+, 506.0 [M-H].sup.-.
Example 16
##STR00100##
[1372]
2-((3R,5R,6S)-1-((S)-1-((1-carbamoylcyclopropyl)methoxy)butan-2-yl)-
-5-(3-chlorophenyl)-6-(4-chlorophenyl)-2-oxopiperidin-3-yl)acetic
acid
[1373] A solution of 10 mg (0.02 mmol)
2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-((1-cyanocyc-
lopropyl)methoxy)butan-2-yl)-2-oxopiperidin-3-yl)acetic acid
(Example 11) and potassium hydroxide (3.2 mg, 0.06 mmol) in t-BuOH
(189 .mu.L) was stirred at 85.degree. C. for 24 h. The reaction was
acidified (10% citric acid) and extracted (2.times.EtOAc). The
combined organic layers were washed with sat. NaCl solution, dried
over Na.sub.2SO.sub.4, filtered and the filtrate was concentrated
under reduced pressure. Purification by reversed phase preparatory
HPLC (Gemini.TM. Prep C18 5 .mu.m column, Phenomenex, Torrance,
Calif.; eluent: 35 to 75% acetonitrile+0.1% TFA in water+0.1% TFA,
gradient elution) provided the title compound.
[1374] .sup.1H NMR (400 MHz, CHLOROFORM-d) .delta. ppm 0.67 (m,
5H), 1.34 (m., 2H), 1.54 (m., 1H), 1.87-2.18 (m, 4H), 2.65 (m, 1H),
2.71-2.90 (m, 2H), 3.08 (m, 1H), 3.38-3.64 (m, 4H), 3.94 (m, 1H),
4.84 (m, 1H),6.35 (br.s., 1H), 6.91 (br. s., 1H) 7.13 (m, 1H)
7.21-7.38 (m, 7H). MS (ESI) 547.2 [M+H].sup.+, 545.0
[M-H].sup.-.
[1375] Further elution provided Example 17.
Example 17
##STR00101##
[1376]
2-((3S,5R,6S)-1-((S)-1-((1-carbamoylcyclopropyl)methoxy)butan-2-yl)-
-5-(3-chlorophenyl)-6-(4-chlorophenyl)-2-oxopiperidin-3-yl)acetic
acid
[1377] 1H NMR (400 MHz, CHLOROFORM-d) .delta. ppm 7.26-7.21 (2H,
m), 7.17-7.12 (2H, m), 7.06 (1H, br, s), 6.95-6.90 (2H, m),
6.88-6.80 (1H, s), 6.79-6.76 (1H, m), 6.74 (1H, br, s), 4.63 (1H,
d, J=10.2 Hz), 4.10-4.00 (1H, m), 3.33-3.10 (3H, m), 3.02-2.92 (2H,
m), 2.90-2.78 (1H, m), 2.70-2.60 (1H, m), 2.44-2.34 (1H, m),
2.00-1.90 (1H, m), 1.85-1.75 (1H, m), 1.65-1.55 (1H, m), 1.43-1.35
(2H, m), 0.85-0.73 (2H, m), 0.63-0.52 (3H, m); MS (ESI) 547.2
[M+H].sup.+, 545.0 [M-H].sup.-.
Example 18
##STR00102##
[1378]
2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-(2-hyd-
roxy-2-methylpropoxy)butan-2-yl)-2-oxopiperidin-3-yl)acetic
acid
Step A. Ethyl
2-((S)-2-((3S,5R,6S)-3-allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-2-oxop-
iperidin-1-yl)butoxy)acetate
##STR00103##
[1380] To a solution of 203 mg (0.47 mmol) of
(3S,5R,6S)-3-allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-hydroxy-
butan-2-yl)piperidin-2-one (Example 9, Step B) and
rhodium(II)acetate dimmer (10.4 mg, 0.047 mmol) in CH.sub.2Cl.sub.2
(1.90 mL) was added dropwise ethyl diazoacetate (286 .mu.L, 2.35
mmol) at 25.degree. C. After being stirred at 25.degree. C. for 14
h, the reaction was concentrated under reduced pressure and
purified by chromatography on silica gel (20% to 30% EtOAc/Hexanes,
gradient elution) to provide the title compound as a colorless
liquid:
Step B.
(3S,5R,6S)-3-allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1--
(2-hydroxy-2-methylpropoxy)butan-2-yl)piperidin-2-one
##STR00104##
[1382] To a solution of ethyl
2-((S)-2-((3S,5R,6S)-3-allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-2-oxop-
iperidin-1-yl)butoxy)acetate (69.0 mg, 0.133 mmol) in THF (2.22 mL)
was added methylmagnesium bromide, 1.4M in Toluene/THF, (0.38 mL,
0.532 mmol) at 0.degree. C. After being stirred at 25.degree. C.
for 3 h, the reaction was quenched (sat. aq. NH.sub.4Cl), and
extracted with EtOAc. The combined organic layers were washed with
sat. NaCl solution, dried over Na.sub.2SO.sub.4, filtered and the
filtrate was concentrated under reduced pressure. Purification by
chromatography on silica gel (20% to 50% EtOAc/Hexanes, gradient
elution) provided the title compound as a colorless liquid.
Step C.
2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-(2-hy-
droxy-2-methylpropoxy)butan-2-yl)-2-oxopiperidin-3-yl)acetic
acid
[1383] To a rapidly stirring solution of
(3S,5R,6S)-3-allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-(2-hydr-
oxy-2-methylpropoxy)butan-2-yl)piperidin-2-one (51.0 mg, 0.101
mmol) in a mixture of water (361 .mu.L), acetonitrile (241 .mu.L),
and CCl.sub.4 (241 .mu.L) was added sodium periodate (86 mg, 0.404
mmol), followed by ruthenium(III) chloride hydrate (2.28 mg, 10.1
.mu.mol). After being stirred vigorously for 18 h, the reaction was
acidified (10% citric acid) and diluted (EtOAc). The mixture was
filtered through Celite.RTM. (J. T. Baker, Phillipsberg, N.J., J.
T. Baker, Phillipsberg, N.J., diatomaceous earth) and the filtrate
was extracted with EtOAc. The combined organic layers were washed
with sat. NaCl solution, dried over Na.sub.2SO.sub.4, filtered and
the filtrate was concentrated under reduced pressure. Purification
by reversed phase preparatory HPLC (Gemini.TM. Prep C18 5 .mu.m
column, Phenomenex, Torrance, Calif.; eluent: 50 to 76%
acetonitrile+0.1% TFA in water+0.1% TFA, gradient elution) provided
the title compound as a white solid.
[1384] .sup.1H NMR (400 MHz, CHLOROFORM-d) .delta. ppm 0.64-0.74
(t, J=7.6 Hz, 3H), 1.21 (d, J=3.7 Hz, 6H), 1.58 (ddd, J=14.0, 7.6,
4.4 Hz, 1H), 1.84-1.99 (m, 2H), 2.21 (m, 1H), 2.64-2.83 (m, 3H),
3.04-3.15 (m, 1H), 3.19 (d, J=9.2 Hz, 1H), 3.29 (d, J=9.2 Hz, 1H),
3.38 (m, 1H), 3.41-3.55 (m, 1H), 3.98 (t, J=8.6 Hz, 1H), 4.98 (d,
J=2.9 Hz, 1H) 7.12-7.20 (m, 1H), 7.21-7.34 (m, 5H), 7.34-7.41 (m,
2H); MS (ESI) 522.1 [M+H].sup.+. 520.2 [M-H].sup.-.
Example 19
##STR00105##
[1385]
2-((3R,5R,6S)-5-(3-Chlorophenyl)-6-(4-chlorophenyl)-2-oxo-1-((3S)-1-
,1,1-trifluoro-2-hydroxypentan-3-yl)piperidin-3-yl)acetic acid
(Isomer 1)
Step A.
(S)-2-((3S,5R,6S)-3-allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-2--
oxopiperidin-1-yl)butanal
##STR00106##
[1387] To a solution of oxalyl dichloride (166 .mu.L, 1.87 mmol) in
DCM (4.16 mL) at -60.degree. C. was added a solution of DMSO (222
.mu.L, 3.12 mmol) in DCM (4.16 mL) under N.sub.2. After about 20
min, a solution of 540 mg (1.25 mmol) of
(3S,5R,6S)-3-allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-hydroxy-
butan-2-yl)piperidin-2-one (Example 9, Step B) in 4.2 mL of DCM was
added, and the resulting solution was stirred for 15 min.
Triethylamine (872 .mu.L, 6.24 mmol) was then added. After being
stirred at -60.degree. C. for 5 min, the reaction was allowed to
warm to rt, and 5 mL of water was added. The solution was extracted
(2.times.DCM), washed (sat. aq. NaCl solution), dried (MgSO.sub.4)
and concentrated under the reduced pressure to give the crude title
compound containing 20% starting material (SM).
Step B.
(3S,5R,6S)-3-allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((3S)-1-
,1,1-trifluoro-2-hydroxypentan-3-yl)piperidin-2-one
##STR00107##
[1389] A solution of
(S)-2-((3S,5R,6S)-3-allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-2-oxopipe-
ridin-1-yl)butanal (80 mg, 0.186 mmol) and
trimethyl(trifluoromethyl)silane (82 .mu.L, 0.558 mmol) in THF (929
.mu.L) was treated at 0.degree. C. with 1 M tetrabutylammonium
fluoride in THF (93 .mu.L, 0.093 mmol). After being stirred for 1
h, three additional equivalents of trimethyl(trifluoromethyl)silane
(82 .mu.L, 0.558 mmol) and 1 M tetrabutylammonium fluoride in THF
(93 .mu.L, 0.093 mmol) were added to the reaction at 0.degree. C.
and the reaction was stirred for 14 h. The reaction mixture was
diluted (EtOAc), washed (1.times.H.sub.2O and 1.times.sat. aq. NaCl
solution), dried (Na.sub.2SO.sub.4), and concentrated under reduced
pressure. Purification by reverse phase preparatory HPLC
(Gemini.TM. Prep C18 5 .mu.m column, Phenomenex, Torrance, Calif.;
eluent: 60 to 90% acetonitrile+0.1% TFA in water+0.1% TFA, gradient
elution) provided two compounds which are diastereomers at the
secondary alcohol.
Step C.
2-((3R,5R,6S)-5-(3-Chlorophenyl)-6-(4-chlorophenyl)-2-oxo-1-((3S)--
1,1,1-trifluoro-2-hydroxypentan-3-yl)piperidin-3-yl)acetic acid
[1390] The title compound was prepared from a single diastereomer
of
(3S,5R,6S)-3-allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((3S)-1,1,1-tr-
ifluoro-2-hydroxypentan-3-yl)piperidin-2-one by a procedure similar
to the one described in Example 18, Step C.
[1391] .sup.1H NMR (400 MHz, CHLOROFORM-d) .delta. ppm 0.53 (t,
J=7.5 Hz, 3H), 1.66 (m, 1H), 1.97-2.05 (m, 1H), 2.18 (m, 1H),
2.32-2.45 (m, 1H), 2.68-2.83 (m, 2H), 2.94-3.05 (m, 1H), 3.15-3.25
(m, 1H), 4.42 (m, 1H), 4.69 (d, J=3.9 Hz, 1H), 6.95-7.02 (m, 1H),
7.12 (m, 1H), 7.22-7.37 (m, 5H), 7.37-7.46 (m, 2H); MS (ESI) 518.0
[M+H]. 516.0 [M-H].sup.-.
Example 20
##STR00108##
[1392]
2-((3R,5R,6S)-5-(3-Chlorophenyl)-6-(4-chlorophenyl)-2-oxo-1-((3S)-1-
,1,1-trifluoro-2-hydroxypentan-3-yl)piperidin-3-yl)acetic acid
(Isomer 2)
[1393] To a rapidly stirring solution of 6.3 mg (0.013 mmol) of
(3S,5R,6S)-3-allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((3S)-1,1,1-tr-
ifluoro-2-hydroxypentan-3-yl)piperidin-2-one (Example 19, Step B,
the diastereomer not used for Example 19 Step B)) (6.30 mg, 0.013
mmol) in a mixture of water (108 .mu.L), acetonitrile (71.9 .mu.L),
and CCl.sub.4 (71.9 .mu.L) was added sodium periodate (10.7 mg,
0.050 mmol), followed by ruthenium(III) chloride hydrate (0.284 mg,
1.26 .mu.mol). After being stirred vigorously for 18 h, the
reaction was acidified (10% citric acid) and diluted (EtOAc). The
reaction mixture was filtered through Celite.RTM. (J. T. Baker,
Phillipsberg, N.J., J. T. Baker, Phillipsberg, N.J., diatomaceous
earth). The filtrate was extracted (2.times.EtOAc). The combined
organic layers were washed with sat. NaCl solution, dried over
Na.sub.2SO.sub.4, filtered and the filtrate was concentrated under
reduced pressure. Purification by reversed phase preparatory HPLC
(Gemini.TM. Prep C18 5 .mu.m column, Phenomenex, Torrance, Calif.;
eluent: 45 to 70% acetonitrile+0.1% TFA in water+0.1% TFA, gradient
elution) provided the title compound as a white solid.
[1394] .sup.1H NMR (400 MHz, CHLOROFORM-d) .delta. ppm 0.44-0.72
(m, 3H); 1.28-1.46 (m, 1H), 2.15-2.28 (m, 2H), 2.45-2.55 (m, 1H),
2.89-3.05 (m, 3H), 3.10-3.18 (m, 2H), 4.02-4.16 (m, 1H), 4.56 (d,
J=7.8 Hz, 1H), 6.84-6.93 (m, 1H), 7.01-7.04 (m, 1H), 7.08-7.14 (m,
2H), 7.17-7.20 (m, 2H), 7.32-7.38 (m, 2H); MS (ESI) 518.0
[M+H].sup.+. 516.0 [M-H].sup.-.
Example 21
##STR00109##
[1395]
2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-morpho-
linobutan-2-yl)-2-oxopiperidin-3-yl)acetic acid
Step A. (S)-ethyl
2-((3R,5R,6S)-3-(2-tert-butoxy-2-oxoethyl)-5-(3-chlorophenyl)-6-(4-chloro-
phenyl)-2-oxopiperidin-1-yl)butanoate
##STR00110##
[1397] To a stirred solution of 1.14 g (2.3 mmol) of
2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-ethoxy-1-oxo-
butan-2-yl)-2-oxopiperidin-3-yl)acetic acid (Example 3) in DCM
(21.0 mL) was added sulfuric acid (0.247 mL, 4.63 mmol) followed by
isobutylene (4.42 mL, 46.3 mmol) at -78.degree. C. The reaction
vessel was sealed and the mixture was slowly warmed to rt and
vigorously stirred for 3 days. After cooling to -78.degree. C., the
tube was opened and the reaction was quenched with aqueous
saturated NaHCO.sub.3 to pH 8. The organic solvent was removed
under reduced pressure, and the remaining mixture was extracted
(2.times.EtOAc). The combined organic layers were washed with sat.
NaCl solution, dried over Na.sub.2SO.sub.4, filtered and the
filtrate was concentrated under reduced pressure. The residue was
purified by chromatography on silica gel (eluent: 20 to 35%
EtOAc/hexanes) to provide the title compound as a foam.
Step B. tert-butyl
2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-hydroxybutan-
-2-yl)-2-oxopiperidin-3-yl)acetate
##STR00111##
[1399] To a solution of (S)-ethyl
2-((3R,5R,6S)-3-(2-tert-butoxy-2-oxoethyl)-5-(3-chlorophenyl)-6-(4-chloro-
phenyl)-2-oxopiperidin-1-yl)butanoate (1.94 g, 3.54 mmol, Example
21, Step A) in Et.sub.2O (35.4 mL) was added 90% lithium
borohydride (0.154 g, 7.07 mmol) at 0.degree. C. After being
stirred at 0.degree. C. for 30 min, the reaction was quenched (ice
cold 10% citric acid), extracted (2.times.EtOAc) and washed (sat.
aq. NaCl solution). The combined organic layers were washed with
sat. NaCl solution, dried over Na.sub.2SO.sub.4, filtered and the
filtrate was concentrated under reduced pressure. Purification by
chromatography on silica gel (50% to 100% EtOAc/Hexanes, gradient
elution) provided the title compound.
Step C. tert-butyl
2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-2-oxo-1-((S)-1-oxobut-
an-2-yl)piperidin-3-yl)acetate
[1400] To a solution of oxalyl chloride (0.261 mL, 2.99 mmol) in
DCM (5.87 mL) at -60.degree. C. was added a solution of DMSO (0.512
mL, 5.98 mmol) in DCM (5.87 mL) under N.sub.2. After being stirred
for 20 min, a solution of tert-butyl
2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-hydroxybutan-
-2-yl)-2-oxopiperidin-3-yl)acetate (1.01 g, 1.99 mmol, Example 21,
Step B) in DCM (5.87 mL) was added, and the resulting solution was
stirred for 15 min. To this solution was added triethylamine (1.39
mL, 9.97 mmol). After being stirred at -60.degree. C. for 5 min,
the reaction was allowed to warm to rt, and quenched (H.sub.2O).
The solution was extracted (3.times.DCM) and washed (H.sub.2O and
sat. aq. NaCl solution). The combined organic layers were washed
with sat. NaCl solution, dried over Na.sub.2SO.sub.4, filtered and
the filtrate was concentrated under reduced pressure to give the
title compound.
Step D. tert-butyl
2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-morpholinobu-
tan-2-yl)-2-oxopiperidin-3-yl)acetate
##STR00112##
[1402] To a solution of tert-butyl
2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-2-oxo-1-((S)-1-oxobut-
an-2-yl)piperidin-3-yl)acetate (0.050 g, 0.099 mmol, Example 21,
Step C) and morpholine (0.013 mL, 0.149 mmol) in DCE (1.0 mL) was
added sodium triacetoxyhydroborate (0.063 g, 0.297 mmol) at
0.degree. C. After being stirred at 25.degree. C. for 18 h, the
reaction was quenched by adding ice-cold saturated aqueous
NaHCO.sub.3 and extracted (2.times.DCM) and the combined organic
layers were washed (1.times.sat. aq. NaCl solution) and
concentrated under the reduced pressure. This was used in next step
without further purification.
Step E.
2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-morph-
olinobutan-2-yl)-2-oxopiperidin-3-yl)acetic acid
[1403] To a round-bottomed flask with tert-butyl
2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-morpholinobu-
tan-2-yl)-2-oxopiperidin-3-yl)acetate (0.057 g, 0.099 mmol; Example
21, Step D) in DCM (1 mL) was added TFA (1.129 g, 9.90 mmol) at
0.degree. C. The ice-bath was removed and the mixture was stirred
at rt for 3 h. The solvent was removed. Purification by reversed
phase preparatory HPLC (Gemini.TM. Prep C18 5 .mu.m column,
Phenomenex, Torrance, Calif.; eluent: 10 to 90% acetonitrile+0.1%
TFA in water+0.1% TFA, gradient elution) provided the title
compound as a white powder.
[1404] .sup.1H NMR (400 MHz, CHLOROFORM-d) .delta. ppm 0.99 (m,
3H), 1.60-2.43 (m., 4H), 2.60-2.86 (m, 5H), 3.11-3.40 (m, 2H),
3.83-4.04 (m, 5H), 4.43 (m, 2H), 4.90 (m, 1H), 7.01 (m, 1H) 7.12
(m, 1H) 7.20-7.36 (m, 2H) 7.46 (m., 4H); MS (ESI) 519.1
[M+H].sup.+. 517.2 [M-H].sup.-
[1405] Examples 22 to 27 were prepared in a process similar to that
described for Example 21, substituting morpholine in step D for the
appropriate amine.
TABLE-US-00003 ##STR00113## Example R.sup.1 22 ##STR00114## 23
##STR00115## 24 ##STR00116## 25 ##STR00117## 26 ##STR00118## 27
##STR00119##
Example 22
2-((3RS,5RS,6SR)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((SR)-1-(ethylami-
no)butan-2-yl)-2-oxopiperidin-3-yl)acetic acid (prepared from
racemic intermediate)
[1406] .sup.1H NMR (400 MHz, CHLOROFORM-d) .delta. ppm 0.91-1.13
(t, J=7.8 Hz, 3H), 1.28 (t, J=7.14 Hz, 3H), 1.55-1.65 (m, 1H),
1.76-1.86 (m, 1H), 1.95-2.05 (m, 1H), 2.31-2.59 (m, 2H), 2.73-2.85
(m, 2H), 2.90-3.09 (m, 5H), 4.78-4.82 (m, 1H), 4.88-5.02 (m, 1H),
6.90-6.98 (m, 1H), 7.04-7.12 (m, 1H), 7.20-7.30 (m, 3H), 7.36-7.42
(m, 2H), 7.45-7.56 (m, 1H); MS (ESI) 477.1 [M+H].sup.+, 475.1
[M-H].sup.-.
Example 23
2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-2-oxo-1-((S)-1-(2,2,2--
trifluoroethylamino)butan-2-yl)piperidin-3-yl)acetic acid
[1407] .sup.1H NMR (400 MHz, CHLOROFORM-d) .delta. ppm 0.96 (t,
J=7.3 Hz, 3H), 1.62-1.74 (m, 1H), 1.79-1.98 (m, 2H), 2.41-2.51 (m,
1H), 2.61-2.75 (m, 2H), 3.01-3.21 (m, 4H), 3.74-3.91 (m, 2H), 4.57
(m, 1H), 4.89 (d, J=2.9 Hz, 1H), 6.96-7.02 (m, 1H), 7.12 (m, 1H),
7.24-7.31 (m, 2H), 7.36-7.49 (m, 4H); MS (ESI) 531.1 [M+H].sup.+,
529.0 [M-H].sup.-.
Example 24
2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-2-oxo-1-((S)-1-(pyrrol-
idin-1-yl)butan-2-yl)piperidin-3-yl)acetic acid
[1408] .sup.1H NMR (400 MHz, CHLOROFORM-d) .delta. ppm 0.93 (m.,
3H), 1.67-1.75 (m, 2H), 2.03-2.39 (m., 7H), 2.74-2.91 (m, 6H),
3.09-3.17 (m, 2H), 3.86 (m, 1H), 4.05 (m, 1H), 4.86 (m, 1H),
6.82-7.04 (m, 1H) 7.09 (m, 1H) 7.25 (m, 2H) 7.44 (m, 4H); MS (ESI)
503.2 [M+H].sup.+, 501.1 [M-H].sup.-.
Example 25
2-((3RS,5RS,6SR)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-2-oxo-1-((SR)-1-(2--
oxopyrrolidin-1-yl)butan-2-yl)piperidin-3-yl)acetic acid (prepared
from racemic intermediate.)
[1409] Ethyl 4-aminobutanoate hydrochloride was used at the amine.
After reductive amination the intermediate was cyclized by heating
to 120.degree. C. in acetic acid and toluent to provide the title
compound.
[1410] .sup.1H NMR (400 MHz, CHLOROFORM-d) .delta. ppm 0.93 (m.,
3H), 1.67 (m, 1H), 1.82 (m, 1H), 2.07-2.20 (m., 5H), 2.44-2.46 (m,
3H), 2.71-3.06 (m, 3H), 3.20-3.30 (m, 2H), 3.40-3.55 (m, 3H), 3.69
(m, 1H), 4.70 (m, 1H), 6.99-7.04 (m, 1H) 7.12-7.16 (m, 3H)
7.24-7.27 (m, 2H) 7.35 (m, 2H); MS (ESI) 517.2 [M+H].sup.+.
Example 26
2-((3R,5R,6S)-5-(3-Chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-(1,1-dioxidot-
hiomorpholino)butan-2-yl)-2-oxopiperidin-3-yl)acetic acid
[1411] .sup.1H NMR (400 MHz, CHLOROFORM-d) .delta. ppm 0.85 (m.,
3H) 1.71 (m, 2H) 1.83-1.98 (m, 1H) 2.37 (m, 1H) 2.58 (m, 1H)
2.63-2.83 (m, 2H) 3.04-3.15 (m, 3H), 3.25-3.35 (m., 6H) 3.43-3.64
(m, 2H) 4.88 (m, 1H) 7.09 (m., 1H) 7.19 (m, 1H) 7.29 (m, 2H)
7.34-7.50 (m, 4H); MS (ESI) 567.1 [M+H].sup.+, 565.2
[M-H].sup.-.
Example 27
2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-2-oxo-1-((S)-1-(thiazo-
l-2-ylamino)butan-2-yl)piperidin-3-yl)acetic acid
[1412] .sup.1H NMR (500 MHz, ACETONITRILE-d.sub.3) .delta. ppm 0.58
(t, J=7.2 Hz, 3H), 1.52-1.64 (m, 1H), 1.73-1.89 (m, 1H), 1.98-2.05
(m, 1H), 2.05-2.16 (m, 1H), 2.67-2.81 (m, 1H), 2.81-2.92 (m, 2H),
3.11-3.32 (m, 2H), 3.50 (m, 1H), 3.68 (m, 1H), 4.81 (d, J=6.8 Hz,
1H), 6.72-6.79 (m, 1H), 7.04-7.12 (m, 1H), 7.14 (s, 1H), 7.17-7.23
(m, 2H), 7.25 (d, J=4.4 Hz, 1H), 7.29-7.41 (m, 4H); MS (ESI) 530.0
[M-H].sup.-.
Example 28
##STR00120##
[1413]
2-((3RS,5RS,6SR)-1-((SR)-1-acetamidobutan-2-yl)-5-(3-chlorophenyl)--
6-(4-chlorophenyl)-2-oxopiperidin-3-yl)acetic acid (racemic)
Step A.
(3SR,5RS,6SR)-3-allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((SR-
)-1-(4-methoxybenzylamino)butan-2-yl)piperidin-2-one
[1414] To a solution of 79 mg (0.184 mmol) of
(SR)-2-((3SR,5RS,6SR)-3-allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-2-oxo-
piperidin-1-yl)butanal (racemate of Example 19, Step A) and
4-methoxybenzylamine (35.7 .mu.L, 0.275 mmol) in 1.8 mL of
dichloroethane was added sodium triacetoxyborohydrate (117 mg,
0.551 mmol) at 0.degree. C. in several portions. After being
stirred at 25.degree. C. for 18 h, the reaction was quenched by
adding ice-cold saturated aqueous NaHCO.sub.3 and extracted
(2.times.DCM) and the combined organic layers were washed with sat.
NaCl solution, dried over Na.sub.2SO.sub.4, filtered and the
filtrate was concentrated under reduced pressure. Purification by
flash chromatography on silica (0% to 3% MeOH/DCM with 1% aq.
NH.sub.4OH) provided the title compound as a yellow film.
Step B.
(3SR,5RS,6SR)-3-allyl-1-((SR)-1-aminobutan-2-yl)-5-(3-chlorophenyl-
)-6-(4-chlorophenyl)piperidin-2-one
[1415] To a solution of
(3SR,5RS,6SR)-3-allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((SR)-1-(4--
methoxybenzylamino)butan-2-yl)piperidin-2-one (88 mg, 0.160 mmol)
in acetonitrile (1899 .mu.L) and water (380 .mu.L) was added ceric
ammonium nitrate (350 mg, 0.638 mmol) at 25.degree. C. The reaction
was monitored by LCMS and HPLC and on completion was diluted with
0.5 M aq. NaOH and EtOAc and the resulting emulsion was filtered
through a pad of Celite.RTM. (J. T. Baker, Phillipsberg, N.J., J.
T. Baker, Phillipsberg, N.J., diatomaceous earth). The filtrate was
extracted with ethyl acetate and the combined organic layers were
washed with sat. NaCl solution, dried over Na.sub.2SO.sub.4,
filtered and the filtrate was concentrated under reduced pressure
to provide the crude product which was used n subsequent steps
without further purification.
Step C.
N--((SR)-2-((3SR,5RS,6SR)-3-allyl-5-(3-chlorophenyl)-6-(4-chloroph-
enyl)-2-oxopiperidin-1-yl)butyl)acetamide
[1416] To a solution of 53 mg (0.123 mmol) of
(3SR,5RS,6SR)-3-allyl-1-((RS)-1-aminobutan-2-yl)-5-(3-chlorophenyl)-6-(4--
chlorophenyl)piperidin-2-one (Step B) in DMF (307 .mu.L) was added
acetic anhydride (116 .mu.L, 1.229 mmol) at 25.degree. C. After
being stirred at 25.degree. C. for 14 h the reaction was quenched
(H.sub.2O) and extracted (2.times.EtOAc). The combined organic
layers were washed with sat. NaCl solution, dried over
Na.sub.2SO.sub.4, filtered and the filtrate was concentrated under
reduced pressure. Separation by reversed phase HPLC (50 to 80%
AcCN/H.sub.2O in 25 min, 2 injections, t.sub.R=15.683 min) provided
the title compound as a yellow solid.
Step D.
2-((3RS,5RS,6SR)-1-((SR)-1-acetamidobutan-2-yl)-5-(3-chlorophenyl)-
-6-(4-chlorophenyl)-2-oxopiperidin-3-yl)acetic acid
[1417] The oxidation of
N--((SR)-2-((3SR,5RS,6SR)-3-allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-2-
-oxopiperidin-1-yl)butyl)acetamide to the title compound was
carried out as described in Example 1, Step H to give the title
compound as white solid.
[1418] .sup.1H NMR (500 MHz, CHLOROFORM-d) .delta. ppm 0.80 (t,
J=7.4 Hz, 3H) 1.62-1.75 (m, 1H), 1.84-1.97 (m, 2H), 2.07 (s, 3H),
2.36-2.49 (m, 1H), 2.64-2.80 (m, 2H), 3.02-3.16 (m, 2H), 3.16-3.31
(m, 1H), 3.32-3.40 (m, 1H), 3.74-3.90 (m, 1H), 4.76-4.82 (m, 1H),
7.04-7.08 (m, 1H), 7.16-7.19 (m, 1H), 7.22-7.30 (m, 2H), 7.32-7.38
(m, 4H); MS (ESI) 491.0 [M+H].sup.+, 489.1 [M-H].sup.-.
Example 29
##STR00121##
[1419]
2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-(methy-
lsulfonamido) butan-2-yl)-2-oxopiperidin-3-yl)acetic acid
Step A.
N--((S)-2-((3S,5R,6S)-3-allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl-
)-2-oxopiperidin-1-yl)butyl)methanesulfonamide
[1420] To a solution of 69 mg (0.16 mmol) of
(3S,5R,6S)-3-allyl-1-((S)-1-aminobutan-2-yl)-5-(3-chlorophenyl)-6-(4-chlo-
rophenyl)piperidin-2-one (Example 28, Step B from the non-racemic
precursor described in Example 19, Step A) in 1.6 mL of DCM was
added methanesulfonyl chloride (13.7 .mu.L, 0.175 mmol) and
pyridine (38.7 .mu.L, 0.478 mmol) successively at 0.degree. C.
After being stirred at rt for 14 h the reaction mixture was
acidified with 10% aq. citric acid and extracted (2.times.DCM). The
combined organic layers were washed with sat. NaCl solution, dried
over Na.sub.2SO.sub.4, filtered and the filtrate was concentrated
under reduced pressure. Purification by reversed phase HPLC (40 to
90% MeCN/H.sub.2O in 45 min, 2 injections, t.sub.R=25.94 min)
provided the title compound as a yellow solid.
Step B.
2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-(meth-
ylsulfonamido) butan-2-yl)-2-oxopiperidin-3-yl)acetic acid
[1421] The title compound was prepared as described in Example 28,
Step D, using
N--((S)-2-((3S,5R,6S)-3-allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-
-2-oxopiperidin-1-yl)butyl)methanesulfonamide (Step A).
[1422] .sup.1H NMR (500 MHz, CHLOROFORM-d) .delta. ppm 0.67 (t,
J=7.6 Hz, 3H), 1.51-1.61 (m, 1H), 1.88-1.92 (m, 1H), 2.13-2.26 (m,
2H), 2.79-2.89 (m, 2H), 2.89-2.95 (m, 1H), 2.98 (s, 3H), 3.02-3.10
(m, 1H), 3.17-3.21 (m, 1H), 3.42-3.52 (m, 1H), 4.85 (d, J=5.4 Hz,
1H), 5.27 (br. s., 1H), 7.02-7.10 (m, 1H), 7.10-7.15 (m, 1H),
7.18-7.30 (m, 4H), 7.34 (d, J=8.6 Hz, 2H); MS (ESI) 527.0
[M+H].sup.+, 525.1 [M-H].sup.-.
Example 30
##STR00122##
[1423]
2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-cyanop-
entan-3-yl)-2-oxopiperidin-3-yl)acetic acid
Step A. tert-butyl
2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-cyanopent-1--
en-3-yl)-2-oxopiperidin-3-yl)acetate
[1424] To a solution of diethyl cyanomethylphosphonate (62.4 .mu.L,
0.396 mmol) and DMPU (239 .mu.L, 1.98 mmol) in THF (661 .mu.L) was
added 60% sodium hydride as suspension in mineral oil (11.89 mg,
0.297 mmol) at 0.degree. C. The mixture was stirred for 30 min, and
then treated with a solution of 100 mg (0.2 mmol) of tert-butyl
2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-2-oxo-1-((R)-1-oxobut-
an-2-yl)piperidin-3-yl)acetate (Example 21, Step C) in THF (661
.mu.L). After being stirred for 12 h, the reaction was quenched
with water, extracted (2.times.EtOAc) and the combined organic
layers were washed with sat. NaCl solution, dried over
Na.sub.2SO.sub.4, filtered and the filtrate was concentrated under
reduced pressure. Purification of the residue by flash
chromatography on silica gel (10 to 20% EtOAc/Hex, a gradient
elution) provided the of the title compound as a mixture of E- and
Z-isomers.
[1425] MS (ESI) 527.2 [M+H].sup.+.
Step B. tert-butyl
2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-cyanopentan--
3-yl)-2-oxopiperidin-3-yl)acetate
[1426] To a solution of 56 mg (0.106 mmol) of tert-butyl
2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-cyanopent-1--
en-3-yl)-2-oxopiperidin-3-yl)acetate (Example 30, Step A) in 3.5 mL
of EtOH) was added 10% palladium on activated carbon (11.30 mg,
10.62 .mu.mol). Then the reaction mixture was subjected to regular
hydrogenation with hydrogen. After being stirred under a hydrogen
atmosphere at rt for 2 h, the catalyst was filtered using a short
plug of silica gel. The plug was washed several times with EtOAc.
The combined filtrates were concentrated under reduced pressure to
provide the crude title compound as a colorless film which was used
in the subsequent reaction without further purification. MS (ESI)
529.2 [M+H]+.
Step C.
2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-cyano-
pentan-3-yl)-2-oxopiperidin-3-yl)acetic acid
[1427] To a solution of 57 mg (0.11 mmol) of tert-butyl
2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-cyanopentan--
3-yl)-2-oxopiperidin-3-yl)acetate (Example 30, Step B) in DCM (359
.mu.L) was added trifluoroacetic acid (415 .mu.L, 5.38 mmol) at
0.degree. C. After being stirred at 25 C for 2 h, solvents were
removed under reduced pressure and the residual TFA was removed by
azeotroping with toluene under reduced pressure three times.
Separation of the crude product by reversed phase HPLC (45 to 70%
AcCN/H.sub.2O in 30 min, 3 time runs, t.sub.R=18.52 min) provided
the title compound as a white solid.
[1428] .sup.1H NMR (400 MHz, CHLOROFORM-d) .delta. ppm 7.37 (2H, d,
J=8.6 Hz), 7.27-7.25 (2H, m), 7.21 (2H, d, J=8.6 Hz), 7.15-7.12
(1H, m), 7.04-6.98 (1H, m), 4.74 (1H, d, J=5.3 Hz), 3.42-3.32 (1H,
m), 3.13-3.08 (1H, m), 3.08-3.00 (1H, m), 2.99-2.92 (1H, m),
2.85-2.77 (1H, m), 2.43-2.33 (2H, m), 2.23-2.15 (2H, m), 2.13-2.03
(1H, m), 1.94-1.77 (2H, m), 1.64-1.54 (1H, m), 0.64 (3H, t, J=7.4
Hz); MS (ESI) 473.0 [M+H].sup.+, 471.1 [M-H].sup.-.
[1429] Examples 31 and 32 were prepared in a process similar to
that described for Example 30, using the appropriately substituted
phosphonates in Step A:
Example 31
##STR00123##
[1430]
2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-(methy-
lsulfonyl)pentan-3-yl)-2-oxopiperidin-3-yl)acetic acid
[1431] .sup.1H NMR (400 MHz, CHLOROFORM-d) .delta. ppm 0.71 (t,
J=8.0 Hz, 3H), 1.58-1.69 (m, 1H), 1.82 (m, 1H), 1.98-2.17 (m, 3H),
2.20-2.34 (m, 1H), 2.83-3.13 (m, 10H), 4.80-4.84 (m, 1H), 7.00-7.07
(m, 1H), 7.13-7.18 (m, 1H), 7.23-7.32 (m, 4H), 7.34-7.41 (m, 2H);
MS (ESI) 526.2 [M+H].sup.+.
Example 32
##STR00124##
[1432]
2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-2-oxo-1-((S)-1--
(pyridin-2-yl)pentan-3-yl)piperidin-3-yl)acetic acid
[1433] .sup.1H NMR (400 MHz, CHLOROFORM-d) .delta. ppm 0.89 (t,
J=7.5 Hz, 3H), 1.60-1.79 (m, 4H), 1.90-1.98 (m, 1H), 2.53 (m, 1H),
2.61-2.69 (m, 1H), 2.72-2.79 (m, 1H), 2.90-3.03 (m, 2H), 3.07-3.12
(m, 1H), 3.19-3.28 (m, 1H), 4.15 (m, 1H), 4.80-4.81 (m, 1H),
7.01-7.07 (m, 1H), 7.15 (s, 1H), 7.22-7.35 (m, 4H), 7.40-7.47 (m,
1H), 7.59 (d, J=7.82 Hz, 1H), 7.75 (t, J=6.75 Hz, 1H), 8.28 (t,
J=7.92 Hz, 1H), 8.85-8.89 (m, 1H); MS (ESI) 525.1 [M+H].sup.+
Example 33
##STR00125##
[1434]
2-((3R,5R,6S)-5-(3-Chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-(ethyl-
amino)-1-oxobutan-2-yl)-2-oxopiperidin-3-yl)acetic acid and
2-((3R,5R,6S)-5-(3-Chlorophenyl)-6-(4-chlorophenyl)-1-((R)-1-(ethylamino)-
-1-oxobutan-2-yl)-2-oxopiperidin-3-yl)acetic acid
Step A.
(R)-2-((3S,5R,6S)-3-allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-2--
oxopiperidin-1-yl)butanoic acid
[1435] To a solution of 320 mg (0.64 mmol) of tert-butyl
(2S)-2-((3S,5R,6S)-3-allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-2-oxopip-
eridin-1-yl)butanoate (Example 1, Step G) in DCM (3184 .mu.L) was
added trifluoroacetic acid (2453 .mu.L, 31.8 mmol) at 0.degree. C.
After being stirred at 25 C for 3 h, solvents were removed under
reduced pressure and the residual TFA was removed by azeotroping
with toluene under reduced pressure 3-times to provide the title
compound as a pale yellow foam which was used in the subsequent
reaction without further purification.
Step B.
(S)-2-((3S,5R,6S)-3-allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-2--
oxopiperidin-1-yl)-N-ethylbutanamide
[1436] A solution of 107 mg (0.24 mmol) of
(S)-2-((3S,5R,6S)-3-allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-2-oxopipe-
ridin-1-yl)butanoic acid (Example 33, Step A) and ethylamine (31.4
.mu.L, 0.479 mmol) in DCM (539 .mu.L) and DMF (59.9 .mu.L) was
treated at 0.degree. C. with
N1-((ethylimino)methylene)-N3,N3-dimethylpropane-1,3-diamine
hydrochloride (138 mg, 0.719 mmol),
3H-[1,2,3]triazolo[4,5-b]pyridin-3-ol (98 mg, 0.719 mmol), and
sodium bicarbonate (60.4 mg, 0.719 mmol), successively. Then the
reaction was stirred at 25.degree. C. for 12 h. The reaction was
diluted (1 N aq. HCl), extracted (2.times.EtOAc), the combined
organic layers were washed with sat. aq. NaCl and
NaHCO.sub.3-solutions, dried over Na.sub.2SO.sub.4, filtered and
the filtrate was concentrated under reduced pressure. Purification
by chromatography on silica gel (30% to 40% EtOAc/Hexanes, a
gradient elution) provided the title compound as a mixture of
diastereomers (dr=5:1) as a white solid: MS (ESI) 473.2
[M+H].sup.+.
Step C.
2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-(ethy-
lamino)-1-oxobutan-2-yl)-2-oxopiperidin-3-yl)acetic acid and
2-((3R,5R,6S)-5-(3-Chlorophenyl)-6-(4-chlorophenyl)-1-((R)-1-(ethylamino)-
-1-oxobutan-2-yl)-2-oxopiperidin-3-yl)acetic acid
[1437]
2-((3S,5R,6S)-3-allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-2-oxopi-
peridin-1-yl)-N-ethylbutanamide (Example 33, Step B) was converted
to the acid as described in Example 1, Step H to give the title
compounds as a mixture of diastereomers (dr=5:1).
[1438] .sup.1H NMR (400 MHz, CHLOROFORM-d) .delta. ppm 0.81 (t,
J=7.8 Hz, 3H), 1.10 (t, J=7.2 Hz, 3H), 1.65-1.75 (m, 1H), 1.87 (m,
1H), 2.24-2.41 (m, 2H), 2.57-2.66 (m, 1H), 2.70 (dd, J=16.8, 5.09
Hz, 1H), 2.98 (dd, J=16.9, 5.58 Hz, 1H), 3.04-3.26 (m, 3H), 3.97
(dd, J=10.37, 4.89 Hz, 1H), 5.05-5.10 (m, 1H), 7.06-7.19 (m, 2H),
7.19-7.24 (m, 1H) 7.24-7.38 (m, 5H); MS (ESI) 491.0 [M+H].sup.+.
489.1 [M-H].sup.-.
Example 34
##STR00126##
[1439]
2-((3R,5R,6S)-5-(3-Chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-(5-met-
hyl-1,3,4-oxadiazol-2-yl)propyl)-2-oxopiperidin-3-yl)acetic acid
and
2-((3R,5R,6S)-5-(3-Chlorophenyl)-6-(4-chlorophenyl)-1-((R)-1-(5-methyl-1,-
3,4-oxadiazol-2-yl)propyl)-2-oxopiperidin-3-yl)acetic acid
Step A.
(S)--N'-acetyl-2-((3S,5R,6S)-3-allyl-5-(3-chlorophenyl)-6-(4-chlor-
ophenyl)-2-oxopiperidin-1-yl)butanehydrazide
[1440] A solution of 95 mg (0.213 mmol) of
(S)-2-((3S,5R,6S)-3-allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-2-oxopipe-
ridin-1-yl)butanoic acid (Example 33, Step A) and acetic hydrazide
(23.65 mg, 0.319 mmol) in DCM (479 .mu.L) and DMF (53.2 .mu.L) was
treated at 0.degree. C. with
N1-((ethylimino)methylene)-N3,N3-dimethylpropane-1,3-diamine
hydrochloride (122 mg, 0.638 mmol),
3H-[1,2,3]triazolo[4,5-b]pyridin-3-ol (87 mg, 0.638 mmol), and
sodium bicarbonate (53.6 mg, 0.638 mmol) at 0.degree. C.,
successively. Then the reaction was stirred at 25.degree. C. for 12
h. The reaction was diluted with 1 N aq. HCl and extracted
(2.times.EtOAc). The combined organic layers were washed with sat.
aq. NaCl and NaHCO.sub.3-solutions, dried over Na.sub.2SO.sub.4,
filtered and the filtrate was concentrated under reduced pressure.
Purification by chromatography on silica gel (60% to 80%
EtOAc/Hexanes, gradient elution) provided the title compound as a
colorless film. MS (ESI) 502.1 [M+H].sup.+.
Step B.
(3S,5R,6S)-3-allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1--
(5-methyl-1,3,4-oxadiazol-2-yl)propyl)piperidin-2-one
[1441] A solution of 58 mg (0.115 mmol) of
(S)--N'-acetyl-2-((3S,5R,6S)-3-allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl-
)-2-oxopiperidin-1-yl)butanehydrazide (Example 34, Step A) and
Burgess' reagent (110 mg, 0.462 mmol) in dichloroethane (1154
.mu.L) was heated in the microwave at 120.degree. C. for 30 min.
Then the reaction mixture was diluted with water and extracted with
DCM. The combined organic layers were washed with sat. aq. NaCl and
NaHCO.sub.3-solutions, dried over Na.sub.2SO.sub.4, filtered and
the filtrate was concentrated under reduced pressure. Separation by
reversed phase HPLC (55 to 90% MeCN/H.sub.2O in 35 min, 29 mg
injection each time) provided the title compound as a colorless
film. MS (ESI) 484.1 [M+H].sup.+.
Step C.
2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-(5-me-
thyl-1,3,4-oxadiazol-2-yl)propyl)-2-oxopiperidin-3-yl)acetic
acid
[1442]
(3S,5R,6S)-3-allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-(-
5-methyl-1,3,4-oxadiazol-2-yl)propyl)piperidin-2-one (Example 34,
Step B) was converted to the acid as described in Example 1, Step H
to give the title compound as a mixture of diastereomers
(dr=10:1).
[1443] .sup.1H NMR (400 MHz, CHLOROFORM-d) .delta. ppm 0.81 (t,
J=7.8 Hz, 3H), 1.93-2.04 (m, 2H), 2.25 (m, 1H), 2.26 (s, 3H),
2.33-2.44 (m, 1H), 2.83-2.94 (m, 3H), 3.12 (d, J=2.3 Hz, 1H),
5.08-5.18 (m, 1H), 5.60 (br. s., 1H), 7.07 (d, J=8.2 Hz, 2H),
7.18-7.23 (m, 1H), 7.26 (m, 1H), 7.28 (m, 1H), 7.30-7.35 (m, 3H);
MS (ESI) 502.1 [M+H].sup.+, 500.0 [M-H].sup.-.
Example 35
##STR00127##
[1444]
2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-(cyclopropylm-
ethyl)-2-oxopiperidin-3-yl)acetic acid
Step A.
(5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-(cyclopropylmethyl-
)piperidin-2-one
##STR00128##
[1446] To a solution of 1.5 g (4.7 mmol) of
(5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)piperidin-2-one
(Example 1, Step E) in 9.4 mL of DMF was added sodium hydride (60%
suspension in mineral oil, 244 mg, 6.1 mmol) at 0.degree. C. The
reaction was stirred at 0.degree. C. for 20 min and then treated
with cyclopropylmethyl bromide (759 .mu.l, 5621 .mu.mol). After
being stirred at 25.degree. C. for 5 h, the reaction was quenched
(sat. aqueous NH.sub.4Cl), extracted (2.times.EtOAc). The combined
organic layers were washed with sat. aq. NaCl and
NaHCO.sub.3-solutions, dried over Na.sub.2SO.sub.4, filtered and
the filtrate was concentrated under reduced pressure. Purification
of the residue by flash chromatography on silica gel (30 to 50%
EtOAc/hexanes, gradient elution) provided the title compound as a
colorless foam.
Step B.
(3S,5R,6S)-3-allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-(cyclop-
ropylmethyl)piperidin-2-one
##STR00129##
[1448] To a solution of
(5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-(cyclopropylmethyl)piperi-
din-2-one (1481 mg, 3957 .mu.mol; Example 35, Step A) and allyl
bromide (360 .mu.l, 4155 .mu.mol) in THF (16 mL, 0.25 M) was added
dropwise lithium bis(trimethylsilyl)amide (1M solution in THF, 4352
.mu.l, 4352 .mu.mol) at -78.degree. C. After being stirred at
-78.degree. C. for 3 h, the reaction was quenched (sat. aqueous
NH.sub.4Cl), extracted (2.times.EtOAc). The combined organic layers
were washed with sat. aq. NaCl solution, dried over
Na.sub.2SO.sub.4, filtered and the filtrate was concentrated under
reduced pressure. Purification of the residue by flash
chromatography (SiO.sub.2, 20 to 30% EtOAc/Hex, gradient elution)
provided the title compound as a mixture of stereoisomers.
[1449] Individual stereoisomers were separated by HPLC on a
Chiralcel OD column (eluent:25% iPA/hexanes).
Step C.
2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-(cyclopropyl-
methyl)-2-oxopiperidin-3-yl)acetic acid
[1450]
(3S,5R,6S)-3-allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-(cyclopr-
opylmethyl)piperidin-2-one (Example 35, Step B) was converted to
the acid as described in Example 1, Step H to give the title
compound as a white solid.
[1451] .sup.1H NMR (400 MHz, CHLOROFORM-d) .delta. ppm 7.48-7.46
(1H, m), 7.40 (2H, d, J=8.6 Hz), 7.31-7.35 (2H, m), 7.22-7.26 (1H,
m), 7.13 (2H, d, J=8.6 Hz), 5.17 (1H, s), 4.24 (1H, dd, J=14.1, 6.7
Hz), 3.23-3.19 (1H, m), 2.96-2.78 (1H, m), 2.64-2.50 (2H, m), 2.36
(1H, dd, J=14.1, 7.8 Hz), 2.17-2.08 (1H, m), 1.93-1.83 (1H, m),
1.29-1.17 (1H, m), 0.77-0.69 (1H, m), 0.67-0.58 (1H, m), 0.37-0.25
(2H, m); MS (ESI) 432.1 [M+H].sup.+, 429.9 [M-H].sup.-.
[1452] Examples 36 to 40 were prepared in a process similar to that
described for Example 35, substituting (bromomethyl)cyclopropane in
Step A for the appropriate amount of alkylbromide or
alkyliodide.
TABLE-US-00004 ##STR00130## Example R.sup.1 36 ##STR00131## 37
##STR00132## 38 ##STR00133## 39 ##STR00134## 40 ##STR00135##
Example 36
2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-(cyclobutylmethyl)-2-
-oxopiperidin-3-yl)acetic acid
[1453] .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. ppm 1.62-1.74 (m,
1H), 1.75-1.84 (m, 2H), 1.84-2.01 (m, 2H), 2.03-2.17 (m, 2H),
2.18-2.29 (m, 1H), 2.53 (dd, J=13.69 and 7.24 Hz, 1H), 2.57-2.63
(m, 1H), 2.63-2.70 (m, 1H), 2.69-2.76 (m, 1H), 2.76-2.85 (m, 1H),
3.04-3.17 (m, 1H), 4.25 (dd, J=13.69 and 7.63 Hz, 1H), 4.76-4.89
(m, 1H), 7.07-7.17 (m, 1H), 7.22 (d, J=8.61 Hz, 2H), 7.27-7.31 (m,
3H), 7.39 (d, J=8.61 Hz, 2H). MS (ESI) 446.2 [M+H].sup.+.
Example 37
2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-(2-ethylbutyl)-2-oxo-
piperidin-3-yl)acetic acid
[1454] .sup.1H NMR (400 MHz, CHLOROFORM-d) .delta. ppm 7.37 (2H, d,
J=8.4 Hz), 7.27 (2H, m), 7.18 (1H, s), 7.15 (2H, d, J=8.4 Hz), 7.03
(1H, m), 4.67 (1H, d, J=7.5 Hz), 3.29 (1H, m), 3.09-2.97 (3H, m),
2.72 (1H, dd, J=15.4, 3.7 Hz), 2.20-2.00 (2H, m), 1.83 (1H, m),
1.68 (1H, m), 1.55-1.40 (2H, m), 0.89 (3H, t, J=8.0 Hz), 0.55 (3H,
t, J=8 Hz); MS (ESI) 448.1 [M-H].sup.-.
Example 38
2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-(cyclopentylmethyl)--
2-oxopiperidin-3-yl)acetic acid
[1455] .sup.1H NMR (400 MHz, CHLOROFORM-d) .delta. ppm 7.42 (2H, d,
J=8.4 Hz), 7.31 (2H, m), 7.24 (1H, s), 7.20 (2H, d, J=8.4 Hz), 7.11
(1H, m), 4.93 (1H, s), 3.87 (1H, m), 3.16 (1H, m), 2.81 (1H, dd,
J=16.4, 7.8 Hz), 2.68 (1H, dd, J=16.4, 3.9 Hz), 2.57 (1H, m), 2.12
(1H, m), 2.00 (1H, m), 1.90-1.65 (6H, m), 1.55-1.40 (2H, m); MS
(ESI) 446.0 [M-H].sup.-.
Example 39
2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((2,2-dimethylcyclop-
entyl)methyl)-2-oxopiperidin-3-yl)acetic acid
[1456] .sup.1H NMR (400 MHz, CHLOROFORM-d) .delta. ppm 7.41 (2H, d,
J=8.2 Hz), 7.39 (1H, m), 7.35-7.27 (3H, m), 7.13 (2H, d, J=8.2 Hz),
4.93 (1H, s), 4.45 (1H, m), 3.20 (2H, m), 3.00 (1H, dd, J=16.8, 8.0
Hz), 2.51 (1H, dd, J=16.8, 3.3 Hz), 2.10 (1H, m), 1.90 (1H, m),
1.65-1.35 (5H, m), 0.88 (3H, s), 0.53 (3H, s); MS (ESI) 474.1
[M-H].sup.-.
Example 40
2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-(cyclohexylmethyl)-2-
-oxopiperidin-3-yl)acetic acid
[1457] .sup.1H NMR (400 MHz, CHLOROFORM-d) .delta. ppm 7.41 (2H, d,
J=8.6 Hz), 7.35-7.27 (3H, m), 7.18 (2H, d, J=8.6 Hz), 7.14 (1H, m),
4.95 (1H, s), 3.08 (1H, m), 2.90 (1H, dd, J=15.8, 9.2 Hz), 2.65
(1H, m), 2.51 (1H, dd, J=15.8, 2.7 Hz), 2.10 (1H, m), 1.90-1.55
(4H, m), 1.35-1.20 (8H, m); MS (ESI) 460.4 [M-H].sup.-.
Example 41
##STR00136##
[1458]
2-((3S,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-(cyclopropylm-
ethyl)-2-oxopiperidin-3-yl)acetic acid
[1459]
(3R,5R,6S)-3-allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-(cyclopr-
opylmethyl)piperidin-2-one (Example 35, Step B) was converted to
the acid as described in Example 1, Step H to give the title
compound as a white solid.
[1460] .sup.1H NMR (400 MHz, CHLOROFORM-d) .delta. ppm 7.24 (2H, d,
J=8.2 Hz), 7.23-7.19 (1H, m), 7.17-7.12 (1H, t, J=7.4 Hz), 7.01
(1H, s), 6.86 (2H, d, J=8.2 Hz), 6.74 (1H, d, J=7.4 Hz), 4.63 (1H,
d, J=10.2 Hz), 3.92 (1H, dd, J=14.1, 6.3 Hz), 3.12-2.92 (3H, m),
2.60 (1H, dd, J=15.5, 3.3 Hz), 2.34 (1H, dd, J=14.1, 7.4 Hz),
2.29-2.08 (2H, m), 0.95-0.85 (1H, m), 0.55-0.47 (1H, m), 0.46-0.39
(1H, m), 0.15-(-)0.02 (2H, m); MS (ESI) 432.0 [M+H].sup.+, 429.9
[M-H].sup.-.
Example 42
2-((3S,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-2-oxo-1-propylpiperidi-
n-3-yl)acetic acid
##STR00137##
[1461] Step A.
(3R,5R,6S)-3-allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)piperidin-2-one
##STR00138##
[1463] A 100 mL flame-dried round-bottomed flask equipped with a
magnetic stir bar was charged with
(5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)piperidin-2-one (1.32
g, 4.12 mmol) (Example 1, Step E) and anhydrous THF (41.2 mL). This
solution was cooled to 0.degree. C. under argon and BuLi (3.30 mL,
8.24 mmol) was added. After 10 minutes allyl bromide (0.357 mL,
4.12 mmol) was added. After an additional 45 minutes the reaction
was quenched by the addition of sat. aq. NH.sub.4Cl and the layers
were separated. The aqueous layer was extracted with EtOAc twice
and the organics were pooled, washed with sat. aq. NaCl solution,
dried (MgSO.sub.4), filtered and concentrated in vacuo to provide a
colorless oil. Purification using a Combiflash Companion (flash
column chromatography, Teledyne Isco, Lincoln, Nebr.) with a 120 g
SiO.sub.2 column and eluting with 10 to 100% EtOAc/hexanes provided
the title compound.
[1464] .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. ppm 2.07 (m, 1H),
2.15 (m, 1H), 2.45 (m, 1H), 2.69 (m, 1H), 2.80 (m, 1H), 2.88 (m,
1H), 4.49 (d, J=10.3 Hz, 1H), 5.13 (m, 2H), 5.82 (br s, 1H), 5.84
(m, 1H), 6.77 (m, 1H), 6.95 (d, J=8.4 Hz, 2H), 7.01 (m, 1H), 7.12
(t, J=7.7 Hz, 1H), 7.18 (m, 1H), 7.21 (d, J=8.6 Hz, 2H).
##STR00139##
Step B.
(3R,5R,6S)-3-allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-propyl-
piperidin-2-one
[1465] To a solution of
(3R,5R,6S)-3-allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)piperidin-2-one
(Example 42, Step A) (70 mg, 0.19 mmol) in 430 .mu.L of DMF was
added sodium hydride (60% suspension in mineral oil, 20 mg, 0.51
mmol) at 0.degree. C. The reaction was stirred at 0.degree. C. for
15 min and then treated with 1-bromopropane (53 .mu.L, 0.58 mmol).
After being stirred at 25.degree. C. for 4 h, the reaction was
quenched with sat. aqueous NaHCO.sub.3 and extracted
(2.times.EtOAc). The combined organic layers were washed with sat.
aq. NaCl and NaHCO.sub.3-solutions, dried over Na.sub.2SO.sub.4,
filtered and the filtrate was concentrated under reduced pressure.
Purification of the residue by silica gel prep plate (25%
EtOAc/hexanes) provided the title compound as a colorless
solid.
Step C.
2-((3S,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-2-oxo-1-propyl-
piperidin-3-yl)acetic acid
[1466] The title compound was obtained from
(3R,5R,6S)-3-allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-propylpiperidi-
n-2-one (Example 42, Step B) by a procedure similar to the one
described in Example 1, Step H. Purification by silica gel prep
plate (5% MeOH/DCM) provided the title compound as a white
solid.
[1467] .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. ppm 0.78 (t,
J=7.34 Hz, 3H) 1.33-1.45 (m, 1H) 1.45-1.57 (m, 1H) 2.05-2.21 (m,
2H) 2.48 (ddd, J=13.89, 9.39 and 5.09 Hz, 1H) 2.60 (dd, J=15.94 and
4.79 Hz, 1H) 2.96 (dd, J=16.04 and 7.43 Hz, 1H) 2.97-3.02 (m, 1H)
3.02-3.12 (m, 1H) 3.75 (ddd, J=13.69, 9.68 and 6.36 Hz, 1H) 4.41
(d, J=10.17 Hz, 1H) 6.66-6.76 (m, 1H) 6.87 (d, J=8.41 Hz, 2H) 6.97
(t, J=1.66 Hz, 1H) 7.12 (t, J=7.83 Hz, 1H) 7.16-7.20 (m, 1H) 7.23
(d, J=8.41 Hz, 2H). MS (ESI) 420.2 [M+H].sup.+.
Example 43
2-((3S,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-(cyclobutylmethyl)-2-
-oxopiperidin-3-yl)acetic acid
##STR00140##
[1468] Step A.
(5R,6S)-3-allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-(cyclobutylmethyl-
)piperidin-2-one
##STR00141##
[1470] To a solution of
(3R,5R,6S)-3-allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)piperidin-2-one
(Example 42, Step A) (70 mg, 0.19 mmol) in 430 .mu.L of DMF was
added sodium hydride (60% suspension in mineral oil, 20 mg, 0.51
mmol) at 0.degree. C. The reaction mixture was stirred at 0.degree.
C. for 15 min and after treatment with (bromomethyl)cyclobutane (66
.mu.L, 0.58 mmol) the reaction mixture was heated to 70.degree. C.
for 15 h. The reaction mixture was cooled to room temperature,
quenched with sat. aqueous NaHCO.sub.3 and extracted
(2.times.EtOAc). The combined organic layers were washed with sat.
aq. NaCl and NaHCO.sub.3-solutions, dried over Na.sub.2SO.sub.4,
filtered and the filtrate was concentrated under reduced pressure.
Purification of the residue by silica gel prep plate (25%
EtOAc/hexanes) provided the title compound as a colorless
solid.
Step B.
2-((3S,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-(cyclobutylm-
ethyl)-2-oxopiperidin-3-yl)acetic acid
[1471] The title compounds were prepared from
(5R,6S)-3-allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-(cyclobutylmethyl-
)piperidin-2-one (Example 43, Step A) as described in Example 1
Step H and purified by reversed phase HPLC on an Eclipse column
(45-60% acetonitrile/water, gradient elution) to provide the title
compound as a white solid.
[1472] .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. ppm 1.52-1.69 (m,
2H), 1.72-1.90 (m, 2H), 1.91-2.09 (m, 3H), 2.14 (t, J=12.52 Hz,
1H), 2.42 (dd, J=13.50 and 7.43 Hz, 1H), 2.46-2.57 (m, 1H), 2.62
(dd, J=16.43 and 6.85 Hz, 1H), 2.86-3.01 (m, 2H), 3.01-3.12 (m,
1H), 4.05 (dd, J=13.50 and 7.24 Hz, 1H), 4.38 (d, J=9.98 Hz, 1H),
6.70 (d, J=7.43 Hz, 1H), 6.84 (d, J=8.22 Hz, 2H), 6.97 (s, 1H),
7.12 (t, J=7.83 Hz, 1H), 7.16-7.20 (m, 1H), 7.22 (d, J=8.22 Hz,
2H). MS (ESI) 446.2 [M+H].sup.+.
Example 44
2-((3S,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-isobutyl-2-oxopiperi-
din-3-yl)acetic acid
##STR00142##
[1473] Step A.
(3R,5R,6S)-3-allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-isobutylpiperi-
din-2-one
##STR00143##
[1475] To a solution of
(3R,5R,6S)-3-allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)piperidin-2-one
(Example 42, Step A) (78 mg, 0.22 mmol) in 480 .mu.L of DMF was
added potassium tert-butoxide (40 mg, 0.54 mmol) at 0.degree. C.
The reaction mixture was stirred at 0.degree. C. for 15 min and
then treated with 1-bromo-2-methylpropane (82 .mu.L, 0.76 mmol).
After being stirred at 25.degree. C. for 4 h, the reaction was
quenched with sat. aqueous NaHCO.sub.3 and extracted
(2.times.EtOAc). The combined organic layers were washed with sat.
aq. NaCl and NaHCO.sub.3-solutions, dried over Na.sub.2SO.sub.4,
filtered and the filtrate was concentrated under reduced pressure.
Purification of the residue by silica gel prep plate (25%
EtOAc/hexanes) provided the title compound as a colorless
solid.
Step B.
2-((3S,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-isobutyl-2-o-
xopiperidin-3-yl)acetic acid
[1476] The title compound was prepared from
(3R,5R,6S)-3-allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-isobutylpiperi-
din-2-one (Example 44, Step A) as described in Example 1, Step H to
provide a white solid.
[1477] .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. ppm 0.83 (d,
J=6.65 Hz, 3H), 0.85 (d, J=6.85 Hz, 3H), 1.93 (dq, J=8.39 and 6.66
Hz, 1H), 2.06-2.16 (m, 2H), 2.17-2.24 (m, 1H), 2.60 (dd, J=15.85
and 4.30 Hz, 1H), 2.90-2.97 (m, 1H), 2.97-3.03 (m, 1H), 3.04-3.13
(m, 1H), 3.86 (dd, J=13.69 and 8.80 Hz, 1H), 4.41 (d, J=10.17 Hz,
1H), 6.68-6.76 (m, 1H), 6.84 (d, J=8.41 Hz, 2H), 6.96 (t, J=1.76
Hz, 1H), 7.14 (t, J=7.82 Hz, 1H), 7.18-7.22 (m, 1H), 7.24 (m, 2H).
MS (ESI) 434.2 [M+H].sup.+.
Example 45
2-((3S,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-(cyclopentylmethyl)--
2-oxopiperidin-3-yl)acetic acid
##STR00144##
[1478] Step A.
(3R,5R,6S)-3-allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-(cyclopentylme-
thyl)piperidin-2-one
##STR00145##
[1480] The title compound was prepared from
(3R,5R,6S)-3-allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)piperidin-2-one
(Example 42, Step A) and (bromomethyl)cyclopentane as described in
Example 44, Step A. Purification of the residue by silica gel prep
plate (25% EtOAc/hexanes) provided the title compound as a
colorless solid.
Step B.
2-((3S,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-(cyclopentyl-
methyl)-2-oxopiperidin-3-yl)acetic acid
[1481] The title compound was prepared from
(3R,5R,6S)-3-allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-(cyclopentylme-
thyl)piperidin-2-one (Example 45, Step A) as described in Example
1, Step H to provide a white solid.
[1482] .sup.1H NMR (500 MHz, CDCl.sub.3) .delta. ppm 1.02-1.10 (m,
1H), 1.12-1.19 (m, 1H), 1.46-1.57 (m, 2H), 1.59-1.71 (m, 4H),
2.04-2.21 (m, 3H), 2.32 (dd, J=13.69 and 6.85 Hz, 1H), 2.60 (dd,
J=15.77 and 4.03 Hz, 1H), 2.92-3.01 (m, 2H), 3.06 (dd, J=11.98 and
7.09 Hz, 1H), 4.02 (dd, J=13.69 and 8.56 Hz, 1H), 4.48 (d, J=10.03
Hz, 1H), 6.72 (d, J=7.82 Hz, 1H), 6.84 (d, J=8.31 Hz, 2H),
6.93-7.00 (m, 1H), 7.14 (t, J=7.70 Hz, 1H), 7.18-7.22 (m, 1H), 7.24
(m, 2H). MS (ESI) 460.2 [M+H].sup.+.
Example 46
2-((3S,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-2-oxo-1-(pentan-3-yl)p-
iperidin-3-yl)acetic acid
##STR00146##
[1483] Step A.
(3R,5R,6S)-3-allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-(pentan-3-yl)p-
iperidin-2-one
##STR00147##
[1485] To a solution of
(3R,5R,6S)-3-allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)piperidin-2-one
(Example 42, Step A) (440 mg, 1.221 mmol) in 3-bromopentane (3196
.mu.L, 25.6 mmol) under nitrogen at rt was added a dispersion of
60% sodium hydride in mineral oil (244 mg, 6.11 mmol). Evolution of
gas was observed. The reaction was stirred at room temperature for
10 min and then heated to 120.degree. C. under N.sub.2 for 19 h.
The reaction mixture was cooled to room temperature and quenched
with sat. NH.sub.4Cl. The layers were separated and the organic
layer was dried over Na.sub.2SO.sub.4 and concentrated under
reduced pressure. The residue was purified by flash chromatography
on silica gel (eluent: 0 to 25% EtOAc in hexanes) to give the title
compound (375 mg, 71% yield) as a mixture of diastereomers.
Step B.
2-((3S,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-2-oxo-1-(penta-
n-3-yl)piperidin-3-yl)acetic acid
[1486] The title compound was prepared from
(5R,6S)-3-allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-ethyl-1-(pentan-3-
-yl)piperidin-2-one (Example 46, Step A) as described in Example 1
Step H. Purification by reversed phase preparatory HPLC (eluent: 0
to 100% MeCN+0.1% TFA in water+0.1% TFA, over 20 minutes) provided
the title compound.
[1487] .sup.1H NMR (400 MHz, CHLOROFORM-d) .delta. ppm 0.55 (t,
J=7.53 Hz, 3H) 0.94 (t, J=7.34 Hz, 3H) 1.32-1.54 (m, 2H) 1.85 (tt,
J=14.38 and 7.24 Hz, 2H) 2.04-2.12 (m, 1H) 2.18 (q, J=12.72 Hz, 1H)
2.66 (dd, J=16.14 and 4.40 Hz, 1H) 2.85-3.01 (m, 2H) 3.01-3.17 (m,
2H) 4.33 (d, J=9.98 Hz, 1H) 6.71 (d, J=7.63 Hz, 1H) 6.90-7.01 (m,
3H) 7.09-7.22 (m, 2H) 7.23-7.26 (m, 1H) 10.11 (br. s., 1H). Mass
spectrum (ESI) m/z=448 [M+H].sup.+.
Example 47
##STR00148##
[1488] Methyl
2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-(cyclopropylmethyl)-
-2-oxopiperidin-3-yl)acetate
[1489] To a suspension of 250 mg (0.578 mmol) of
2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-(cyclopropylmethyl)-
-2-oxopiperidin-3-yl)acetic acid (Example 35) in MeOH (3 mL) was
added thionyl chloride (78.0 .mu.l, 1070 .mu.mol) dropwise at
0.degree. C. After being stirred at 25.degree. C. for 14 h, the
reaction was diluted (EtOAc), basified (sat NaHCO.sub.3), extracted
(2.times.EtOAc). The combined organic layers were washed with sat.
aq. NaCl solution, dried over Na.sub.2SO.sub.4, filtered and the
filtrate was concentrated under reduced pressure to provide the
title compound as a colorless liquid.
[1490] .sup.1H NMR (400 MHz, CHLOROFORM-d) .delta. ppm 7.53-7.49
(1H, m), 7.39 (2H, d, J=8.6 Hz), 7.31-7.28 (2H, m), 7.27-7.22 (3H,
m), 5.12 (1H, s), 4.25-4.18 (1H, m), 3.69 (3H, s), 3.20-3.14 (1H,
m), 2.85-2.82 (1H, m), 2.69-2.63 (1H, m), 2.60-2.53 (1H, m),
2.33-2.20 (2H, m), 1.85-1.77 (1H, m), 1.20-1.15 (1H, m), 0.70-0.63
(1H, m), 0.61-0.53 (1H, m), 0.30-0.20 (2H, m); MS (ESI) 445.9
[M+H].sup.+.
Example 48
##STR00149##
[1491]
2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-(cyclopropylm-
ethyl)-2-oxopiperidin-3-yl)acetamide
[1492] In a sealed tube, 60 mg (134 .mu.mol) of methyl
2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-(cyclopropylmethyl)-
-2-oxopiperidin-3-yl)acetate (Example 47) and 4.8 mL of a solution
of ammonia in methanol (7N, 3.4 mmol) were stirred at 25.degree. C.
for 5 days. Then NaCN (3 mg) was added and the resulting solution
was stirred at 50.degree. C. for 3 days. Excess NH.sub.3 and MeOH
were removed under reduced pressure. Separation by reversed phase
HPLC (10 to 90% AcCN/H.sub.2O in 45 min) provided the title
compound as a white solid.
[1493] .sup.1H NMR (400 MHz, CHLOROFORM-d) .delta. ppm 7.52-7.45
(1H, m), 7.37 (2H, d, J=8.2 Hz), 7.33-7.29 (2H, m), 7.26-7.22 (1H,
m), 7.17 (2H, d, J=8.6 Hz), 6.40 (1H, br. s.), 5.42 (1H, br. s.),
5.11 (1H, br. s.), 4.21 (1H, dd, J=14.1, 6.3 Hz), 3.20-3.16 (1H,
m), 2.77-2.70 (1H, m), 2.60-2.48 (2H, m), 2.33-2.25 (2H, m),
1.92-1.85 (1H, m), 1.22-1.15 (1H, m), 0.72-0.64 (1H, m), 0.62-0.54
(1H, m), 0.32-0.20 (2H, m); MS (ESI) 430.9 [M+H].sup.+.
Example 49
##STR00150##
[1494] Ethyl
2-(2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-(cyclopropylmeth-
yl)-2-oxopiperidin-3-yl)acetamido)acetate
[1495] A solution of 40 mg (93 .mu.mol) of
2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-(cyclopropylmethyl)-
-2-oxopiperidin-3-yl)acetic acid (Example 35) and ethyl
2-aminoacetate hydrochloride (14 mg, 102 .mu.mol) in DMF (0.31 mL)
was treated at 0.degree. C. with
N1-((ethylimino)methylene)-N3,N3-dimethylpropane-1,3-diamine
hydrochloride (27 mg, 139 .mu.mol),
3H-[1,2,3]triazolo[4,5-b]pyridin-3-ol (19 mg, 139 .mu.mol), and
sodium hydrogencarbonate (23 mg, 278 .mu.mol), successively. After
being stirred at 25.degree. C. for 12 h, the reaction was diluted
with water and extracted with EtOAc. The combined organic layers
were successively washed with 10% aq. citric acid solution, sat.
aq. NaHCO.sub.3 solution and sat. aq. NaCl solution, dried over
Na.sub.2SO.sub.4, filtered and the filtrate was concentrated under
reduced pressure. Purification of the residue by flash
chromatography (SiO.sub.2, 40% to 60% EtOAc/Hexanes, gradient
elution) provided the title compound as a colorless film.
[1496] .sup.1H NMR (400 MHz, CHLOROFORM-d) .delta. ppm 7.51-7.47
(1H, m), 7.35 (2H, d, J=8.6 Hz), 7.32-7.28 (2H, m), 7.26-7.24 (1H,
m), 7.16 (2H, d, J=8.2 Hz), 6.89 (1H, br, s), 5.11 (1H, s),
4.27-4.18 (3H, m), 4.11-3.98 (2H, m), 3.20-3.15 (1H, d, J=1.6 Hz),
2.83-2.72 (1H, m), 2.63-2.55 (2H, m), 2.32-2.16 (2H, m), 1.95-1.87
(1H, m), 1.29 (3H, t, J=7.0 Hz), 1.22-1.12 (1H, m), 0.72-0.62 (1H,
m), 0.60-0.52 (1H, m), 0.30-0.18 (2H, m); MS (ESI) 516.8
[M+H].sup.+.
Example 50
##STR00151##
[1497]
2-(2-((3R,5R,6S)-5-(3-Chlorophenyl)-6-(4-chlorophenyl)-1-(cycloprop-
ylmethyl)-2-oxopiperidin-3-yl)acetamido)acetic acid
[1498] To a solution of 38 mg (73 .mu.mol) of ethyl
2-(2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-(cyclopropylmeth-
yl)-2-oxopiperidin-3-yl)acetamido)acetate (Example 49) in 0.75 mL
of MeOH/THF/H.sub.2O (2/2/1) was added a 2M solution of lithium
hydroxide in water (70 .mu.l, 141 .mu.mol) at 25.degree. C. and the
mixture was stirred for 10 h. The reaction was acidified (1N aq.
HCl) and extracted with DCM (2.times.). The combined organic layers
were successively washed with 10% aq. citric acid solution and sat.
aq. NaCl solution, dried over Na.sub.2SO.sub.4, filtered and the
filtrate was concentrated under reduced pressure. Purification of
the residue by reversed phase HPLC (10 to 90% AcCN/H.sub.2O with
0.1% TFA in 45 min) provided the title compound as a white
solid.
[1499] .sup.1H NMR (400 MHz, CHLOROFORM-d) .delta. ppm 7.37-7.34
(1H, m), 7.35 (2H, d, J=8.2 Hz), 7.27-7.25 (1H, m), 7.23-7.19 (1H,
m), 7.17-7.14 (1H, m), 7.08 (2H, d, J=8.2 Hz), 5.00 (1H, d, J=3.9
Hz), 4.18-4.08 (2H, m), 4.07-3.99 (1H, m), 3.23-3.18 (1H, m),
2.83-2.75 (2H, m), 2.72-2.64 (1H, m), 2.35-2.23 (2H, m), 2.05-1.95
(1H, m), 1.16-1.05 (1H, d, J=1.2 Hz), 0.68-0.60 (1H, m), 0.58-0.50
(1H, m), 0.27-0.13 (2H, m); MS (ESI) 488.8 [M+H].sup.+, 486.9
[M-H].sup.-.
Example 51
##STR00152##
[1500]
2-((3R,5R,6S)-5-(3-Chlorophenyl)-6-(4-chlorophenyl)-1-(cyclopropylm-
ethyl)-2-oxopiperidin-3-yl)acetohydrazide
[1501] To a solution of 120 mg (0.27 mmol) of methyl
2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-(cyclopropylmethyl)-
-2-oxopiperidin-3-yl)acetate (Example 47) in EtOH was added
hydrazine, monohydrate (135 .mu.l, 2688 .mu.mol). After being
refluxed for 14 h, the reaction was concentrated, diluted
(H.sub.2O) and extracted (2.times.EtOAc). The combined organic
layers were washed with sat. aq. NaCl solution, dried over
Na.sub.2SO.sub.4, filtered and the filtrate was concentrated under
reduced pressure. Purification of the residue by flash
chromatography on silica gel (5% MeOH/CH.sub.2Cl.sub.2, gradient
elution) provided the title compound as a white solid.
[1502] .sup.1H NMR (400 MHz, CHLOROFORM-d) .delta. ppm 7.52-7.46
(1H, m), 7.37 (2H, d, J=8.6 Hz), 7.33-7.28 (2H, m), 7.26-7.22 (1H,
m), 7.15 (2H, d, J=8.6 Hz), 5.10 (1H, s), 4.20 (1H, dd, J=14.1, 6.7
Hz), 3.20-3.15 (1H, m), 2.71-2.63 (1H, m), 2.60-2.48 (2H, m),
2.31-2.18 (1H, m), 1.92-1.82 (1H, m), 1.20-1.10 (1H, dt, J=7.9, 3.3
Hz), 0.70-0.63 (1H, m), 0.59-0.52 (1H, m), 0.30-0.18 (2H, m); MS
(ESI) 445.9 [M+H].sup.+.
Example 52
##STR00153##
[1503]
2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-(cyclopropylm-
ethyl)-2-oxopiperidin-3-yl)-N-hydroxyacetamide
[1504] A solution of 30 mg (0.07 mmol) of
2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-(cyclopropylmethyl)-
-2-oxopiperidin-3-yl)acetic acid (Example 35) in DMF (0.5 mL,
c=0.14 M) was treated with
N1-((ethylimino)methylene)-N3,N3-dimethylpropane-1,3-diamine
hydrochloride (0.03 g, 0.1 mmol),
3H-[1,2,3]triazolo[4,5-b]pyridin-3-ol (0.02 g, 0.1 mmol),
hydroxylamine hydrochloride (0.006 ml, 0.1 mmol) and sodium
hydrogencarbonate (0.02 g, 0.2 mmol) successively. After being
stirred at 25.degree. C. for 12 h, the reaction was diluted with
water and extracted with EtOAc. The combined organic layers were
successively washed with sat. aq. NaHCO.sub.3 solution and sat. aq.
NaCl solution, dried over Na.sub.2SO.sub.4, filtered and the
filtrate was concentrated under reduced pressure. The residue was
purified by reversed phase HPLC (10 to 90% AcCN/H.sub.2O with 0.1%
TFA in 45 min) to give the title compound as a white solid.
[1505] .sup.1H NMR (400 MHz, CHLOROFORM-d) .delta. ppm 7.45 (1H,
s), 7.41-7.16 (5H, m), 7.16-6.98 (2H, m), 5.10 (1H, br. s.),
4.26-4.13 (1H, m), 3.25-3.17 (1H, m), 2.65 (3H, br. s.), 2.30 (2H,
dd, J=14.1, 7.8 Hz), 1.91 (1H, br. s.), 1.15 (1H, d, J=2.0 Hz),
0.77-0.65 (1H, m), 0.65-0.51 (1H, m), 0.37-0.14 (2H, m).
Example 53
##STR00154##
[1506] (S)-Ethyl
2-((2S,3R,5R)-3-(3-chlorophenyl)-2-(4-chlorophenyl)-5-(2-(methylsulfonami-
do)-2-oxoethyl)-6-oxopiperidin-1-yl)butanoate
[1507] Methanesulfonamide (0.02 g, 0.2 mmol),
N-ethyl-N-isopropylpropan-2-amine (0.05 ml, 0.3 mmol),
di(1H-imidazol-1-yl)methanone (0.04 g, 0.2 mmol) and
2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((R)-1-ethoxy-1-oxo-
butan-2-yl)-2-oxopiperidin-3-yl)acetic acid (Example 3, 0.030 g,
0.06 mmol) were combined in 2 mL of THF. After being stirred at
25.degree. C. for 12 h, sat. NH.sub.4Cl solution was added and the
reaction mixture was extracted with EtOAc. The combined organic
layers were successively washed with sat. aq. NaHCO.sub.3 solution
and sat. aq. NaCl solution, dried over Na.sub.2SO.sub.4, filtered
and the filtrate was concentrated under reduced pressure. The
residue was purified by reversed phase HPLC (10 to 90%
AcCN/H.sub.2O with 0.1% TFA in 45 min) to give the title compound
as a white solid.
[1508] .sup.1H NMR (400 MHz, CHLOROFORM-d) .delta. ppm 7.45-7.33
(3H, m), 7.33-7.21 (5H, m), 4.88 (1H, d, J=3.9 Hz), 4.27-4.10 (2H,
m), 3.48 (1H, dd, J=8.8, 3.3 Hz), 3.30 (3H, s), 3.20 (1H, dd,
J=4.7, 0.8 Hz), 3.04-2.74 (2H, m), 2.72-2.59 (1H, m), 2.48-2.28
(2H, m), 2.03 (1H, s), 1.63-1.46 (1H, m), 1.28 (3H, t, J=7.2 Hz),
0.69 (3H, t, J=7.4 Hz).
Example 54
##STR00155##
[1509] (S)-Ethyl
2-((2S,3R,5R)-3-(3-chlorophenyl)-2-(4-chlorophenyl)-5-(2-((3-morpholinopr-
opyl)amino)-2-oxoethyl)-6-oxopiperidin-1-yl)butanoate
[1510] The title compound was prepared as described in Example 49,
using
2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((R)-1-ethoxy-1-oxo-
butan-2-yl)-2-oxopiperidin-3-yl)acetic acid (Example 3) as starting
material.
[1511] .sup.1H NMR (400 MHz, CHLOROFORM-d) .delta. ppm 7.34 (2H, d,
J=8.6 Hz), 7.30-7.16 (5H, m), 7.11-7.03 (1H, m), 4.73 (1H, d, J=5.5
Hz), 4.14 (2H, q, J=7.3 Hz), 4.09-3.92 (4H, m), 3.67-3.51 (2H, m),
3.50-3.40 (1H, m), 3.39-3.30 (2H, m), 3.25 (1H, dd, J=8.8, 3.3 Hz),
3.22-3.12 (2H, m), 2.98-2.50 (5H, m), 2.33-2.03 (5H, m), 1.52-1.37
(0H, m), 1.26 (3H, t, J==7.2 Hz), 0.60 (3H, t, J=7.4 Hz).
Example 55
##STR00156##
[1512]
(3R,5R,6S)-3-((1H-Tetrazol-5-yl)methyl)-5-(3-chlorophenyl)-6-(4-chl-
orophenyl)-1-(cyclopropylmethyl)piperidin-2-one
Step A.
2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-(cyclopropyl-
methyl)-2-oxopiperidin-3-yl)acetonitrile
##STR00157##
[1514] A solution of 136 mg (0.315 mmol) of
2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-(cyclopropylmethyl)-
-2-oxopiperidin-3-yl)acetamide (Example 48) and triethylamine (220
.mu.l, 1576 .mu.mol) in 5 mL of THF was treated with
trifluoroacetic anhydride (111 .mu.l, 788 .mu.mol) at 0.degree. C.
After being stirred at 0.degree. C. for 2 h, the reaction was
quenched (sat. NH.sub.4Cl), extracted (2.times.EtOAc) and washed
(sat. aq. NaCl solution). The combined organic layer were dried
(Na.sub.2SO.sub.4) and concentrated under the reduced pressure.
[1515] After being stirred at 0.degree. C. for 2 h, sat. NH.sub.4Cl
solution was added and the reaction mixture was extracted with
EtOAc. The combined organic layers were washed with sat. aq. NaCl
solution, dried over Na.sub.2SO.sub.4, filtered and the filtrate
was concentrated under reduced pressure. Purification of the
residue by flash chromatography (SiO.sub.2, 20-25% EtOAc/Hexanes)
provided the title compound which was used without further
purification.
Step B.
(3R,5R,6S)-3-((1H-Tetrazol-5-yl)methyl)-5-(3-chlorophenyl)-6-(4-ch-
lorophenyl)-1-(cyclopropylmethyl)piperidin-2-one
[1516] To a solution of 136 mg (0.33 mmol) of
2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-(cyclopropylmethyl)-
-2-oxopiperidin-3-yl)acetonitrile (Example 55, Step A) in 1.8 mL of
DMF was added ammonium chloride (176 mg, 3290 .mu.mol) and sodium
azide (214 mg, 3290 .mu.mol). The resulting mixture was stirred at
90.degree. C. for 4 days. Then, the reaction was acidified (aq. 10%
citric acid) and extracted (2.times.EtOAc). The combined organic
layers were washed with sat. aq. NaCl solution, dried over
Na.sub.2SO.sub.4, filtered and the filtrate was concentrated under
reduced pressure. Separation by reversed phase HPLC (60-90%
AcCN/H.sub.2O in 30 min) provided the title compound as a white
solid.
[1517] .sup.1H NMR (400 MHz, CHLOROFORM-d) .delta. ppm 7.51-7.48
(1H, s), 7.35 (2H, d, J=8.2 Hz), 7.32-7.28 (2H, m), 7.25-7.21 (1H,
m), 6.86 (2H, d, J=8.2 Hz), 5.14 (1H, s), 4.23 (1H, dd, J=14.1, 6.7
Hz), 3.40 (1H, dd, J=15.3, 3.1 Hz), 3.28-3.20 (1H, m), 3.15 (1H,
dd, J=15.1, 8.0 Hz), 2.60-2.52 (1H, m), 2.33 (1H, dd, J=14.1, 8.2
Hz), 2.26-2.18 (2H, br. s.), 2.04-1.93 (1H, m), 1.25-1.15 (1H, m),
0.77-0.70 (1H, m), 0.68-0.59 (1H, m), 0.36-0.24 (2H, m); MS (ESI)
456.0[M+H].sup.+, 453.9[M-H].sup.-.
Example 56
##STR00158##
[1518]
(3R,5R,6S)-3-((1,3,4-oxadiazol-2-yl)methyl)-5-(3-chlorophenyl)-6-(4-
-chlorophenyl)-1-(cyclopropylmethyl)piperidin-2-one
[1519] To a solution of 20 mg (45 .mu.mol) of
2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-(cyclopropylmethyl)-
-2-oxopiperidin-3-yl)acetohydrazide (Example 51) in 0.2 mL of
toluene was added ethyl formimidate hydrochloride (6.4 mg, 58
.mu.mol). The reaction mixture was heated to reflux for 14 h and
then the reaction was concentrated under reduced pressure.
Separation by reversed phase HPLC (10 to 90% AcCN/H.sub.2O in 40
min) provided the title compound as a colorless film.
[1520] .sup.1H NMR (400 MHz, CHLOROFORM-d) .delta. ppm 8.35 (1H,
s), 7.50-7.45 (1H, m), 7.37 (2H, d, J=8.6 Hz), 7.34-7.28 (2H, m),
7.26-7.22 (1H, m), 7.13 (2H, d, J=8.6 Hz), 5.13 (1H, s), 4.22-4.17
(1H, m), 3.38-3.35 (2H, m), 3.24-3.18 (1H, m), 2.80-2.72 (1H, m),
2.35-2.28 (1H, m), 2.25-2.18 (1H, m), 1.96-1.86 (1H, m), 1.21-1.12
(1H, m), 0.70-0.62 (1H, m), 0.61-0.54 (1H, m), 0.30-0.20 (2H, m);
MS (ESI) 456.0[M+H].sup.+.
Example 57
##STR00159##
[1521]
(3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-(cyclopropylmeth-
yl)-3-((5-methyl-1,3,4-oxadiazol-2-yl)methyl)piperidin-2-one
[1522] To a solution of 40 mg (90 .mu.mol) of
2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-(cyclopropylmethyl)-
-2-oxopiperidin-3-yl)acetohydrazide (Example 51) in 0.2 mL of
toluene was added methyl acetimidate hydrochloride (13 mg, 116
.mu.mol). The reaction mixture was heated to reflux for 14 h and
then the reaction was concentrated under reduced pressure.
Separation by reversed phase HPLC (10 to 90% AcCN/H.sub.2O in 45
min) provided the title compound as a colorless film.
[1523] .sup.1H NMR (400 MHz, CHLOROFORM-d) .delta. ppm 7.47-7.45
(1H, s), 7.38 (2H, d, J=8.6 Hz), 7.33-7.29 (2H, m), 7.24-7.19 (1H,
m), 7.15 (2H, d, J=8.6 Hz), 5.12-5.10 (1H, m), 4.18 (1H, dd,
J=14.1, 6.7 Hz), 3.38-3.23 (2H, m), 3.22-3.18 (1H, m), 2.80-2.72
(1H, m), 2.54 (3H, s), 2.36-2.22 (2H, m), 1.94-1.88 (1H, m),
1.20-1.10 (1H, m), 0.70-0.63 (1H, m), 0.60-0.52 (1H, m), 0.30-0.20
(2H, m); MS (ESI) 469.9 [M+H].sup.+.
Example 58
##STR00160##
[1524]
2-((3S,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-(cyclopropylm-
ethyl)-2-oxopiperidin-3-yl)-N-(methylsulfonyl)acetamide
[1525] To a solution of
2-((3S,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-(cyclopropylmethyl)-
-2-oxopiperidin-3-yl)acetic acid (Example 41) (83 mg, 0.192 mmol),
methanesulfonamide (22.59 mg, 0.230 mmol) and
4-dimethylaminopyridine (1.057 mg, 0.00865 mmol) in DCM (2 mL) was
added diisopropylethylamine (80 .mu.L, 0.461 mmol). The reaction
mixture was stirred at room temperature for one minute before
adding bromo-tris-pyrrolidino-phosphonium hexafluorophosphate (125
mg, 0.269 mmol). The reaction mixture was stirred at room
temperature for 3 hours. The reaction was quenched with 1N HCl and
the aqueuos layer was extracted with DCM (10 mL). The combined
organic layers were washed with 1N HCl, 1N NaOH, sat. aq. NaCl
solution and concentrated under reduced pressure. The residue was
purified by reversed phase preparatory HPLC (column: Gemini-NX
C.sub.18 5 .mu.m column; Phenomonex, Torrance, Calif.; eluent: 0 to
100% MeCN+0.1% TFA in water+0.1% TFA, over 20 minutes) to afford
the title compound.
[1526] .sup.1H NMR (400 MHz, CHLOROFORM-d) .delta. ppm -0.06-0.04
(m, 1H) 0.06-0.16 (m, 1H) 0.43 (dd, J=8.51 and 4.60 Hz, 1H)
0.47-0.60 (m, 1H) 0.88 (d, J=6.26 Hz, 1H) 2.09-2.18 (m, 1H) 2.29
(dt, J=14.04 and 6.77 Hz, 2H) 2.62 (dd, J=15.26 and 3.52 Hz, 1H)
2.90 (dd, J=15.26 and 7.63 Hz, 1H) 3.02 (t, J=2.64 Hz, 1H) 3.14 (d,
J=3.72 Hz, 1H) 3.32 (s, 3H) 3.93 (dd, J=14.28 and 6.26 Hz, 2H) 4.64
(d, J=10.17 Hz, 1H) 6.74 (d, J=7.63 Hz, 1H) 6.85-6.91 (m, 2H) 7.00
(d, J=1.76 Hz, 1H) 7.10-7.26 (m, 4H). Mass Spectrum (ESI) m/z=509
[M+H].sup.+.
Example 59
2-((3S,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-(cyclopropylmethyl)--
2-oxopiperidin-3-yl)acetamide
##STR00161##
[1527] Step A. Methyl
2-((3S,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-(cyclopropylmethyl)-
-2-oxopiperidin-3-yl)acetate
##STR00162##
[1529] To a solution of
2-((3S,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-(cyclopropylmethyl)-
-2-oxopiperidin-3-yl)acetic acid (Example 41) (500 mg, 1.156 mmol)
in 10% MeOH in DCM (10 mL) was added (trimethylsilyl)diazomethane
(2.0 M in diethyl ether) (1 mL). The yellow colored reaction
mixture was stirred at room temperature for 30 min. The reaction
was concentrated under reduced pressure and was purified by flash
chromatography on silica gel (eluent: 0 to 50% EtOAc in hexanes) to
give the title compound as a clear oil.
Step B.
2-((3S,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-(cyclopropyl-
methyl)-2-oxopiperidin-3-yl)acetamide
##STR00163##
[1531] A sealed tube was charged with methyl
2-((3S,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-(cyclopropylmethyl)-
-2-oxopiperidin-3-yl)acetate (Example 59, Step A) (109 mg, 0.244
mmol), ammonia, 7N solution in methanol (2 ml, 14.00 mmol) and
sodium cyanide (1.197 mg, 0.024 mmol). The tube was sealed and
heated to 50.degree. C. The pressure reached 35 kilopascals after 1
hour. The reaction was stirred at 50.degree. C. for 18 h. The
reaction was cooled to rt and anhydrous ammonia (gas) was bubbled
through the solution for ten minutes at room temperature. The
reaction mixture was capped and heated to 50.degree. C. for 18 h.
The reaction was cooled to rt and anhydrous ammonia (gas) was
bubbled through the solution for twenty minutes at room
temperature. The reaction mixture was capped and heated to
50.degree. C. for 2 days. The crude reaction was concentrated under
reduced pressure and purified by reversed phase preparatory HPLC
(column: Gemini-NX C.sub.18 5 um column; Phenomonex, Torrance,
Calif.; eluent: 0 to 100% MeCN+0.1% TFA in water+0.1% TFA, over 20
minutes) to afford the title compound.
[1532] .sup.1H NMR (400 MHz, CHLOROFORM-d) .delta. ppm -0.05-0.04
(m, 1H) 0.06-0.15 (m, 1H) 0.36-0.45 (m, 1H) 0.46-0.56 (m, 1H)
0.79-0.93 (m, 1H) 2.11-2.20 (m, 1H) 2.29 (dt, J=13.99, 6.90 Hz, 1H)
2.64-2.73 (m, 1H) 2.75-2.83 (m, 1H) 2.96-3.13 (m, 2H) 3.91 (dd,
J=14.09, 6.46 Hz, 1H) 4.63 (d, J=9.98 Hz, 1H) 6.41 (br. s., 1H)
6.75 (dt, J=7.58, 1.59 Hz, 2H) 6.83-6.90 (m, 2H) 7.01 (t, J=1.96
Hz, 1H) 7.10-7.26 (m, 4H). Mass Spectrum (ESI) m/z=431
[M+H].sup.+.
Example 60
(3S,5R,6S)-3-((1H-tetrazol-5-yl)methyl)-5-(3-chlorophenyl)-6-(4-chlorophen-
yl)-1-(cyclopropylmethyl)piperidin-2-one
##STR00164##
[1533] Step A.
(3S,5R,6S)-3-((1H-tetrazol-5-yl)methyl)-5-(3-chlorophenyl)-6-(4-chlorophe-
nyl)piperidin-2-one
##STR00165##
[1535] A 100 mL round-bottomed flask was placed under vacuum and
heated with a heat gun to ensure dryness. The flask was allowed to
cool to room temperature and a solution of 500 mg (1.56 mmol) of
(5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)piperidin-2-one
(Example 1, Step E) in THF (12 mL) under argon was added and cooled
to 0.degree. C. Butyllithium (1.6M in hexanes, 2440 .mu.L, 3.90
mmol) was added followed by 5-chloromethyl-1H-tetrazole (185 mg,
1.561 mmol) and the reaction mixture was stirred for 15 minutes at
0.degree. C. The reaction was quenched with saturated ammonium
chloride solution and extracted with ethyl acetate. The aqueous
layer was acidified with 1M HCl. The aqueous layer was extracted
with ethyl acetate (2.times.30 mL) and the combined organic layers
were washed with sat. aq. NaCl solution, dried over sodium sulfate,
and concentrated under reduced pressure. The residue was purified
by reversed phase preparatory HPLC (column: Gemini-NX C.sub.18 5 um
column; Phenomonex, Torrance, Calif.; eluent: 0 to 100% MeCN+0.1%
TFA in water+0.1% TFA, over 25 minutes) to afford the title
compound.
Step B.
(3S,5R,6S)-3-((1H-tetrazol-5-yl)methyl)-5-(3-chlorophenyl)-6-(4-ch-
lorophenyl)-1-(cyclopropylmethyl)piperidin-2-one
[1536] A solution of
(3S,5R,6S)-3-((1H-tetrazol-5-yl)methyl)-5-(3-chlorophenyl)-6-(4-chlorophe-
nyl)piperidin-2-one (Example 60, Step A) (65 mg, 0.162 mmol) in DMF
(1.6 mL) was cooled to 0.degree. C. and sodium tert-butoxide (31.1
mg, 0.323 mmol) was added. The reaction mixture was stirred at
0.degree. C. for ten minutes before adding
(bromomethyl)cyclopropane (78 .mu.L, 0.808 mmol). The reaction
mixture was warmed to room temperature and stirred for 16 hours,
quenched with saturated ammonium chloride and diluted with water
and ethyl acetate. The aqueous layer was extracted with ethyl
acetate and the organic layers were combined, washed with 1M LiCl,
sat. aq. NaCl solution, dried over sodium sulfate, and concentrated
under reduced pressure. The residue was purified by reversed phase
preparatory HPLC (column: Gemini-NX C.sub.18 5 um column;
Phenomonex, Torrance, Calif.; eluent: 0 to 100% MeCN+0.1% TFA in
water+0.1% TFA, over 20 minutes) to afford the title compound.
[1537] .sup.1H NMR (400 MHz, CHLOROFORM-d) .delta. ppm -0.08-0.02
(m, 1H) 0.11 (dt, J=9.44 and 4.77 Hz, 1H) 0.38-0.46 (m, 1H) 0.50
(td, J=8.31 and 4.50 Hz, 1H) 0.78-0.89 (m, 1H) 2.18-2.28 (m, 2H)
2.31-2.41 (m, 1H) 2.96-3.07 (m, 2H) 3.29 (dd, J=14.87 and 7.82 Hz,
1H) 3.47-3.56 (m, 1H) 3.89 (dd, J=14.09 and 6.46 Hz, 1H) 4.58 (d,
J=9.98 Hz, 1H) 6.71-6.76 (m, 1H) 6.80-6.87 (m, 2H) 6.98 (d, J=1.76
Hz, 1H) 7.12-7.18 (m, 1H) 7.19-7.25 (m, 3H). Mass Spectrum (ESI)
m/z=456 [M+H].sup.+.
Example 61
(3S,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-(cyclopropylmethyl)-3-(-
(5-methylisoxazol-3-yl)methyl)piperidin-2-one
##STR00166##
[1539] The title compound was prepared from
(5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)piperidin-2-one
(Example 1, Step E),3-(bromomethyl)-5-methylisoxazole, and
(bromomethyl)cylopropane as described in Example 60.
[1540] .sup.1H NMR (400 MHz, CHLOROFORM-d) .delta. ppm -0.05-0.04
(m, 1H) 0.05-0.14 (m, 1H) 0.32-0.41 (m, 1H) 0.42-0.51 (m, 1H)
0.79-0.94 (m, 1H) 2.04-2.09 (m, 2H) 2.28 (dd, J=14.28 and 7.24 Hz,
1H) 2.37 (d, J=0.59 Hz, 3H) 2.86-3.04 (m, 3H) 3.33-3.41 (m, 1H)
3.93 (dd, J=14.18 and 6.55 Hz, 1H) 4.56 (d, J=9.98 Hz, 1H) 5.92 (d,
J=0.78 Hz, 1H) 6.70 (dt, J=7.58 and 1.30 Hz, 1H) 6.80-6.86 (m, 2H)
6.95 (t, J=1.76 Hz, 1H) 7.06-7.11 (m, 1H) 7.13-7.17 (m, 1H)
7.17-7.23 (m, 2H). Mass Spectrum (ESI) m/z=469 [M+H].sup.+.
Example 62
(rac)
2-((2'S,3'R,5'R)-6-chloro-3'-(3-chlorophenyl)-1'-(cyclopropylmethyl)-
-2,6'-dioxospiro[indoline-3,2'-piperidine]-5'-yl)acetic acid
##STR00167##
[1541] Step A. 1-(3-chlorophenyl)pent-4-en-1-one
##STR00168##
[1543] To a solution of 3-chlorobenzoyl chloride (7 ml, 54.7 mmol)
in THF (60 mL) was added copper (I) iodide (0.521 g, 2.73 mmol).
The slurry was cooled to -10.degree. C. and 3-butenylmagnesium
bromide (0.5M in THF) (112 ml, 55.8 mmol) was added dropwise via
cannula over 30 min. The reaction mixture was stirred at
-10.degree. C. for 1 h and then warmed to room temperature. The
reaction mixture was concentrated to 25 mL and diluted with 100 mL
DCM and 100 mL 1M HCl. The layers were separated and the organic
layer was filtered. The filtrate was washed with sat. NaHCO.sub.3,
dried over Na.sub.2SO.sub.4 and concentrated under reduced
pressure. The residue was purified by flash chromatography on
silica gel (eluent: 0 to 50% DCM in hexanes) to give the title
compound.
Step B.
6-chloro-3-(1-(3-chlorophenyl)pent-4-enylidene)indolin-2-one
##STR00169##
[1545] To a mixture of 1-(3-chlorophenyl)pent-4-en-1-one (Example
62, Step A) (14.86 g, 76 mmol) and 6-chloroindolin-2-one (12.79 g,
76 mmol) in toluene (50 mL) at room temperature was added
pyrrolidine (6.31 mL, 76 mmol). The slurry was heated at reflux
with a Dean Stark trap for 6 h. The reaction mixture was cooled to
room temperature and concentrated under reduced pressure. The
residue was purified by flash chromatography on silica gel (eluent:
10 to 20% EtOAc in hexanes) to give the title compound.
Step C. 6-chloro-3-(1-(3-chlorophenyl)pent-4-enyl)indolin-2-one
##STR00170##
[1547] To a yellow slurry of
6-chloro-3-(1-(3-chlorophenyl)pent-4-enylidene)indolin-2-one
(Example 62, Step B) (12.81 g, 37.2 mmol) in MeOH (200 mL) at room
temperature was slowly added sodium borohydride (1.689 g, 44.7
mmol). Evolution of gas was observed. The yellow reaction mixture
was stirred at room temperature for 30 min. Additional sodium
borohydride (1.689 g, 44.7 mmol) was slowly added and the reaction
mixture was stirred at room temperature for 1 h. The reaction
mixture was poured into water (200 mL). A precipitate formed and
the mixture was sonicated for 15 min then filtered. The filtrate
was concentrated under reduced pressure to 36 mL and then extracted
with EtOAc twice. The organic layers were combined, dried over
Na.sub.2SO.sub.4 and concentrated under reduced pressure to provide
the title compound.
Step D.
3-bromo-6-chloro-3-(1-(3-chlorophenyl)pent-4-enyl)indolin-2-one
##STR00171##
[1549] To a solution of
6-chloro-3-(1-(3-chlorophenyl)pent-4-enyl)indolin-2-one (Example
62, Step C (13.0 g, 37.5 mmol) in THF (200 mL) (previously degassed
with Ar) at -78.degree. C. under Ar was added
N1,N1,N2,N2-tetramethylethane-1,2-diamine (11.79 mL, 79 mmol)
(previously degassed with Ar) and butyllithium (1.6 M in hexanes)
(49.3 mL, 79 mmol) (previously degassed with Ar) via addition
funnel. The light brown reaction mixture was stirred at -78.degree.
C. for 30 min., wrapped in foil and recrystallized
1-bromopyrrolidine-2,5-dione (6.68 g, 37.5 mmol) in THF (50 mL)
(previously degassed with Ar) was added via cannula. After the
addition the reaction was quenched immediately with sat. potassium
phosphate mono basic and warmed to room temperature. The mixture
was extracted with EtOAc twice. The organic layers were combined,
dried over Na.sub.2SO.sub.4 and concentrated under reduced
pressure. The residue was purified by flash chromatography on
silica gel (eluent: 0 to 10% EtOAc in hexanes) to give the title
compound as a 1:1.7 ratio of diastereomers.
Step E.
4-(3-bromo-6-chloro-2-oxoindolin-3-yl)-4-(3-chlorophenyl)butanoic
acid
##STR00172##
[1551] To a rapidly stirred solution of
3-bromo-6-chloro-3-(1-(3-chlorophenyl)pent-4-enyl)indolin-2-one
(Example 62, Step D) (7.74 g, 18.21 mmol) in
H.sub.2O/CCl.sub.4/MeCN (1.5/1/1) (80 mL/50 mL/50 mL) was added
sodium periodate (15.58 g, 72.8 mmol) and ruthenium(III) chloride
hydrate (0.205 g, 0.910 mmol). The reaction mixture was stirred
vigorously for 30 min and the reaction monitored by TLC. The
reaction mixture was acidified (10% citric acid) and extracted with
EtOAc. The organic layer was washed with sat. aq. NaCl solution,
dried over Na.sub.2SO.sub.4 and concentrated under reduced
pressure. The residue was purified by flash chromatography on
silica gel (eluent: 30 to 70% EtOAc in hexanes) to give the title
compound.
Step F. methyl
4-(3-bromo-6-chloro-2-oxoindolin-3-yl)-4-(3-chlorophenyl)butanoate
##STR00173##
[1553] To a solution of
4-(3-bromo-6-chloro-2-oxoindolin-3-yl)-4-(3-chlorophenyl)butanoic
acid (Example 62, Step E) (5.38 g, 12.14 mmol) in MeOH (120 mL) at
room temperature was added one drop of concentrated sulfuric acid.
The reaction mixture was stirred at room temperature for 18 h and
then concentrated under reduced pressure. The residue was purified
by flash chromatography on silica gel (eluent: 0 to 50% EtOAc in
hexanes) to give the title compound.
Step G. (rac) (S)-methyl
4-((S)-6-chloro-3-(cyclopropylmethylamino)-2-oxoindolin-3-yl)-4-(3-chloro-
phenyl)butanoate and (rac) (R)-methyl
4-((S)-6-chloro-3-(cyclopropylmethylamino)-2-oxoindolin-3-yl)-4-(3-chloro-
phenyl)butanoate
##STR00174##
[1555] A solution of methyl
4-(3-bromo-6-chloro-2-oxoindolin-3-yl)-4-(3-chlorophenyl)butanoate
(Example 62, Step F) (110 mg, 0.241 mmol) in DCE (4 mL) was heated
at reflux. Cesium carbonate (157 mg, 0.481 mmol) and
cyclopropylmethylamine hydrochloride (25.9 mg, 0.241 mmol) in DCE
(1 mL) were added in one portion. The reaction mixture was heated
at reflux for 5 h and then cooled to room temperature. The reaction
mixture was filtered through celite and washed with DCM. The
filtrate was concentrated and the diastereomeric pairs were
separated by flash chromatography on silica gel (eluent: 20 to 60%
EtOAc in hexanes) to give the title compounds. The more polar
isomer is used in Example 62, Step H.
Step H. (rac)
(2'S,3'R)-6-chloro-3'-(3-chlorophenyl)-1'-(cyclopropylmethyl)spiro[indoli-
ne-3,2'-piperidine]-2,6'-dione
##STR00175##
[1557] A solution of (rac) (R)-methyl
4-((S)-6-chloro-3-(cyclopropylmethylamino)-2-oxoindolin-3-yl)-4-(3-chloro-
phenyl)butanoate (Example 62, Step G, more polar isomer) in DCM was
washed with sat NaHCO.sub.3, dried over Na.sub.2SO.sub.4 and
concentrated under reduced pressure. The residue was dissolved in
distilled xylene (5 mL) and the reaction mixture was heated to
135.degree. C. for 24 h. The reaction mixture was cooled to room
temperature and concentrated under reduced pressure. The residue
was purified by flash chromatography on silica gel (eluent: 20 to
60% EtOAc in hexanes) to give the title compound.
Step I. (rac)
(2'S,3'R)-6-chloro-3'-(3-chlorophenyl)-1'-(cyclopropylmethyl)-1-((2-(trim-
ethylsilyl)ethoxy)methyl)spiro[indoline-3,2'-piperidine]-2,6'-dione
##STR00176##
[1559] To a solution of (rac)
(2'S,3'R)-6-chloro-3'-(3-chlorophenyl)-1'-(cyclopropylmethyl)spiro[indoli-
ne-3,2'-piperidine]-2,6'-dione (Example 62, Step H) (114 mg, 0.274
mmol) in DMF (2 mL) at 0.degree. C. was added a dispersion of 60%
sodium hydride in mineral oil (10.98 mg, 0.274 mmol) followed by
(2-(chloromethoxy)ethyl)trimethylsilane (48.4 .mu.L, 0.274 mmol).
The reaction mixture was stirred at 0.degree. C. for 30 min and
then warmed to room temperature and stirred at room temperature for
24 h. The reaction mixture was poured into ice water and extracted
with EtOAc. The organic layer was washed with 1M LiCl, sat. aq.
NaCl solution, dried over Na.sub.2SO.sub.4 and concentrated under
reduced pressure. The residue was purified by flash chromatography
on silica gel (eluent: 0 to 50% EtOAc in hexanes) to give the title
compound.
Step J. (rac)
(2'S,3'R,5'S)-5'-allyl-6-chloro-3'-(3-chlorophenyl)-1'-(cyclopropylmethyl-
)-1-((2-(trimethylsilyl)ethoxy)methyl)spiro[indoline-3,2'-piperidine]-2,6'-
-dione
##STR00177##
[1561] To a solution of (rac)
(2'S,3'R)-6-chloro-3'-(3-chlorophenyl)-1'-(cyclopropylmethyl)-1-((2-(trim-
ethylsilyl)ethoxy)methyl)spiro[indoline-3,2'-piperidine]-2,6'-dione
(Example 62, Step I) (97 mg, 0.178 mmol) in THF (1 mL) at
-78.degree. C. under Ar was added freshly prepared LDA (1.0 M in
THF) (178 .mu.L, 0.178 mmol). The reaction color turned yellowish
orange. The reaction was stirred at -78.degree. C. for 30 min then
distilled allyl bromide (15.39 .mu.L, 0.178 mmol) was added. The
reaction was stirred at -78.degree. C. for 10 min then warmed to
0.degree. C. The reaction was quenched with sat. NH.sub.4Cl and
warmed to room temperature. The mixture was diluted with EtOAc and
the layers were separated. The organic layer was dried over
Na.sub.2SO.sub.4 and concentrated under reduced pressure. The
residue was purified by flash chromatography on silica gel (eluent:
0 to 25% EtOAc in hexanes) to give the title compound.
Step K. (rac)
2-((2'S,3'R,5'R)-6-chloro-3'-(3-chlorophenyl)-1'-(cyclopropylmethyl)-2,6'-
-dioxo-1-((2-(trimethylsilyl)ethoxy)methyl)spiro[indoline-32'-piperidine]--
5'-yl)acetic acid
##STR00178##
[1563] To a rapidly stirred solution of (rac)
(2'S,3'R,5'S)-5'-allyl-6-chloro-3'-(3-chlorophenyl)-1'-(cyclopropylmethyl-
)-1-((2-(trimethylsilyl)ethoxy)methyl)spiro[indoline-3,2'-piperidine]-2,6'-
-dione (Example 62, Step J) (46 mg, 0.079 mmol) in
H.sub.2O/CCl.sub.4/MeCN (0.75 ml/0.5 mL/0.5 mL) was added sodium
periodate (67.2 mg, 0.314 mmol) and ruthenium(III) chloride hydrate
(1.771 mg, 7.85 .mu.mol). The reaction mixture was stirred
vigorously for 19 h and then acidified (10% citric acid) and
filtered through a plug of celite and washed with EtOAc. The
filtrate was transferred to a separatory funnel and extracted with
EtOAc. The organic layer was dried over Na.sub.2SO.sub.4 and
concentrated under reduced pressure to provide the title
compound.
Step L. (rac)
2-((2'S,3'R,5'R)-6-chloro-3'-(3-chlorophenyl)-1'-(cyclopropylmethyl)-1-(h-
ydroxymethyl)-2,6'-dioxospiro[indoline-3,2'-piperidine]-5'-yl)acetic
acid
##STR00179##
[1565] To a solution of (rac)
2-((2'S,3'R,5'R)-6-chloro-3'-(3-chlorophenyl)-1'-(cyclopropylmethyl)-2,6'-
-dioxo-1-((2-(trimethylsilyl)ethoxy)methyl)spiro[indoline-3,2'-piperidine]-
-5'-yl)acetic acid (Example 62, Step K) (47 mg, 0.078 mmol) in DCM
(0.8 mL) at room temperature was added 0.2 mL TFA. The reaction
mixture was stirred at room temperature for 19 h before
concentrating under reduced pressure. The residue was purified by
flash chromatography on silica gel (eluent: 50 to 100% EtOAc in
hexanes) to give the title compound.
Step M. (rac)
2-((2'S,3'R,5'R)-6-chloro-3'-(3-chlorophenyl)-1'-(cyclopropylmethyl)-2,6'-
-dioxospiro[indoline-3,2'-piperidine]-5'-yl)acetic acid
##STR00180##
[1567] To a solution of (rac)
2-((2'S,3'R,5'R)-6-chloro-3'-(3-chlorophenyl)-1'-(cyclopropylmethyl)-1-(h-
ydroxymethyl)-2,6'-dioxospiro[indoline-3,2'-piperidine]-5'-yl)acetic
acid (Example 62, Step L) (12.6 mg, 0.025 mmol) in MeOH (1 mL) at
room temperature was added DIEA (8.74 .mu.L, 0.050 mmol). The
reaction mixture was stirred at room temperature for 1 h. The
reaction was quenched with 10% citric acid and concentrated under
reduced pressure. The residue was purified by reversed phase
preparatory HPLC (column: Gemini-NX C.sub.18 5 um column;
Phenomonex, Torrance, Calif.; eluent: 0 to 100% MeCN+0.1% TFA in
water+0.1% TFA) to give the title compound.
[1568] .sup.1H NMR (400 MHz, ACETONITRILE-d.sub.3) .delta. ppm
-0.25--0.18 (1H, m) -0.12--0.04 (1H, m) 0.20-0.34 (2H, m) 0.66-0.77
(1H, m) 1.64-1.73 (1H, m) 2.68 (1H, dd, J=14.3 and 7.0 Hz)
2.73-2.81 (1H, m) 2.86-3.02 (1H, m) 3.12-3.33 (3H, m) 3.53-3.65
(1H, m) 6.61 (1H, d, J=1.8 Hz) 6.79-6.91 (2H, m) 7.08 (1H, t, J=7.8
Hz) 7.11-7.20 (2H, m) 7.49 (1H, d, J=8.2 Hz) 8.29 (1H, br s). Mass
Spectrum (ESI) m/z=473 [M+H].sup.+.
Example 63
##STR00181##
[1569]
2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(5-chlorothiophen-2-yl)-1-(cyclo-
propylmethyl)-2-oxopiperidin-3-yl)acetic acid
Step A. 2-(3-Chlorophenyl)-1-(5-chlorothiophen-2-yl)ethanone
##STR00182##
[1571] To a 500-mL round-bottomed flask was added silica gel 60 (21
g, 350 mmol) and the flask was heated with a heat gun under high
vacuum for 30 min. The system was cooled to room temperature and
phosphorus pentoxide (8.75 mL, 148 mmol) was added. The mixture was
stirred at 110.degree. C. (oil bath) under high vacuum for 120 min.
The mixture was allowed to cool to room temperature.
3-chlorophenylacetic acid (15.6 g, 91 mmol), 2-chlorothiophene
(33.8 mL, 366 mmol) and DCE (50 mL) were added. The reaction
mixture was stirred at reflux for 4 hours. LCMS analysis showed the
reaction was complete. The reaction mixture was allowed to cool to
room temperature. The reaction mixture was diluted with ether (300
mL) and filtered. The organic solution was concentrated under
reduced pressure. The residue was triturated with hexane to afford
the title compound as an off-white solid. The hexane mother liquid
was concentrated and purified by flash chromatography (SiO.sub.2, 0
to 30% EtOAc/Hex, a gradient elution) provided another batch of the
title compound as a light yellow solid. Mass Spectrum (ESI) m/z=271
(M+1).
Step B. rac. Methyl
4-(3-chlorophenyl)-5-(5-chlorothiophen-2-yl)-5-oxopentanoate
##STR00183##
[1573] To a solution of 7.35 g (27.1 mmol) of
2-(3-chlorophenyl)-1-(5-chlorothiophen-2-yl)ethanone (Example 63,
Step A) and acrylic acid methyl ester (2.81 mL, 31.2 mmol) in DCM
(60 mL) was added 1,8-diazabicyclo[5.4.0]undec-7-ene (4.05 mL, 27.1
mmol) in DCM (10 mL) slowly at 0.degree. C. over 20 min. Then the
reaction was allowed to warm to ambient temperature. After being
stirred at 25.degree. C. for two days, the reaction mixture was
diluted with DCM and washed with 2N HCl, water and sat. aq. NaCl
solution. The organic extract was dried over Na.sub.2SO.sub.4. The
solution was filtered and concentrated in vacuo to give the crude
material as light yellow oil. The crude material was absorbed onto
a plug of silica gel and purified by chromatography through a
pre-packed silica gel column (220 g), eluting with a gradient of 0%
to 30% EtOAc in hexane, to provided the title compound as a
light-yellow oil. Mass Spectrum (ESI) m/z=357 (M+1).
Step C. rac (4S,5S)(4R,5R) methyl
4-(3-chlorophenyl)-5-(5-chlorothiophen-2-yl)-5-hydroxypentanoate
##STR00184##
[1575] To a solution of 8.20 g (22.95 mmol) of methyl
4-(3-chlorophenyl)-5-(5-chlorothiophen-2-yl)-5-oxopentanoate
(Example 63, Step B) in MeOH (100 mL) was added sodium borohydrate
(0.809 mL, 22.95 mmol) portion-wise at 0.degree. C. Then the
reaction was stirred at 0.degree. C. for 30 min. LCMS analysis
showed the reaction went to completion. Ice-water was added to
quench the reaction. The reaction mixture was concentrated under
reduced pressure to remove most of MeOH. The residue was extracted
with DCM (3.times.100 mL). The combined organic layers were washed
with sat. aq. NaCl solution, dried over Na.sub.2SO.sub.4, and
concentrated under reduced pressure. Purification of the residue by
flash chromatography (TLC, SiO.sub.2, 20 to 30% EtOAc/hexanes,
gradient elution) provided the title compound as a colorless
oil.
Step D. rac.
(4S,5R)(4R,5S)-methyl-5-azido-4-(3-chlorophenyl)-5-(5-chlorothiophen-2-yl-
)pentanoate
##STR00185##
[1577] To a solution of 1.18 g (3.28 mmol) of racemic
(4S,5S)(4R,5R)-methyl
4-(3-chlorophenyl)-5-(5-chlorothiophen-2-yl)-5-hydroxypentanoate
(Example 63, Step C) in toluene (10 mL) was added
1,8-diazabicyclo[5.4.0]undec-7-ene (0.639 mL, 4.27 mmol) over 5 min
at 0.degree. C. with stirring. To the above solution,
diphenylphosphoryl azide (0.852 mL, 3.94 mmol) was added dropwise
over a period of 8 min. The reaction mixture was stirred at
0.degree. C. to rt for 14 hours and monitored by LCMS analysis. The
reaction mixture was diluted (sat. aq. NH.sub.4Cl), extracted
(3.times.EtOAc), and washed (2.times.sat. aq. NaCl solution). The
combined organic layers were dried (Na.sub.2SO.sub.4) and
concentrated under reduced pressure. The crude material was
dissolved in small amount of DCM for chromatography. The insoluble
material was removed by filtration and the solution was absorbed
onto a plug of silica gel and purified by chromatography through a
Redi-Sep pre-packed silica gel column (40 g), eluting with a
gradient of 0% to 60% EtOAc in hexane, to provide the racemic title
compound as a colorless oil.
[1578] Mass Spectrum (ESI) m/z=406 (M+23).
Step E.
(5R,6S)-5-(3-chlorophenyl)-6-(5-chlorothiophen-2-yl)piperidin-2-on-
e
##STR00186##
[1580] To a solution of 7.8 g (20.3 mmol) of racemic
(4S,5R)(4R,5S)-methyl
5-azido-4-(3-chlorophenyl)-5-(5-chlorothiophen-2-yl)pentanoate
(Example 63, Step D) in THF/H.sub.2O (4/1, 75 mL) was added
trimethylphosphine, 1.0M solution in tetrahydrofuran (24.36 mL,
24.36 mmol). After being stirred for 1 h at 23.degree. C., LCMS
analysis showed reaction was complete. Most of THF was removed
under reduced pressure and the residue was basified (ice-cold 2 M
LiOH) and the product was extracted (3.times.DCM) and washed
(2.times.sat. aq. NaCl solution). The combined organic layers were
dried (Na.sub.2SO.sub.4) and concentrated under reduced pressure to
provide a crude mixture of amines as a yellow solid.
[1581] The crude amine from above was dissolved in MeOH/saturated
aq. NaHCO.sub.3(4/1, 60 mL, c=0.04 M) and the reaction was refluxed
for 3 h. After LCMS analysis showed the reaction to be complete,
excess solvent was removed under reduced pressure, the residue was
diluted (water), extracted (2.times.10% MeOH/DCM), and washed
(1.times.sat. aq. NaCl solution). The combined organic layers were
dried (Na.sub.2SO.sub.4) and concentrated under reduced pressure to
provide the crude title compound.
[1582] The crude material was absorbed onto a plug of silica gel
and purified by chromatography through a pre-packed silica gel
column (220 g), eluting with a gradient of 20% to 100% EtOAc in
CH.sub.2Cl.sub.2, to provide the racemic title compound as a white
solid.
[1583] Individual enantiomers of the racemic
(5R,6S)(5S,6R)-5-(3-chlorophenyl)-6-(5-chlorothiophen-2-yl)piperidin-2-on-
e were separated by chiral SFC on a 250.times.30 mm Chiralcel AS-H
column with 50 g/min MeOH (+20 mM NH.sub.3)+50 g/min CO.sub.2 on
Thar 350 SFC (Thar Technologies, Inc., Pittsburg, Pa.). Outlet
pressure=100 bar; Temp.=46.degree. C.; Wavelength=245 nm. Run
time=20 min.; cycle time=17 min. The title compound
(5R,6S)-5-(3-chlorophenyl)-6-(5-chlorothiophen-2-yl)piperidin-2-one
was obtained as the faster eluting isomer.
[1584] .sup.1H NMR (400 MHz, CHLOROFORM-d) .delta. ppm 7.18-7.24
(2H, m), 7.10 (1H, m), 6.93-6.95 (1H, m) 6.23 (1H, d, J=4 Hz), 6.42
(1H, d, J=4 Hz), 6.09 (1H, s), 4.73 (1H, d, J=8 Hz), 2.87-2.94 (1H,
m), 2.60-2.65 (2H, m), 2.05-2.25 (2H, m); Mass Spectrum (ESI)
m/z=326 (M+1); [.alpha.].sub.D=+165.8 (T=24.7.degree. C., c=0.104,
CHCl.sub.3)
[1585] Also obtained by the above method was the enantiomer of the
title compound,
(5S,6R)-5-(3-chlorophenyl)-6-(5-chlorothiophen-2-yl)piperidin-2-
-one as the slower eluting isomer.
[1586] [.alpha.].sub.D=-158 (T=24.8.degree. C., c=0.104,
CHCl.sub.3)
Step F. rac.
(5R,6S)(5S,6R)-5-(3-chlorophenyl)-6-(5-chlorothiophen-2-yl)-1-(cyclopropy-
lmethyl)piperidin-2-one
##STR00187##
[1588] The title compound was prepared from racemic (5R,6S),
(5S,6R)-5-(3-chlorophenyl)-6-(5-chlorothiophen-2-yl)piperidin-2-one
(Example 63, Step E) as described in Example 35, Step A.
[1589] .sup.1H NMR (400 MHz, CHLOROFORM-d) .alpha. ppm 7.34 (1H, br
s), 7.25-7.30 (2H, m), 7.13-7.17 (1H, m), 6.74 (1H, d, J=4 Hz),
6.56 (1H, d, J=4 Hz), 5.06 (1H, d, J=4 Hz), 4.13-4.19 (1H, m),
3.19-3.23 (1H, m), 2.46-2.60 (3H, m), 2.23-2.29 (1H, m), 2.01-2.10
(1H, m), 1.05-1.13 (1H, m), 0.59-0.66 (1H, m), 0.49-0.56 (1H, m),
0.27-0.33 (1H, m), 0.18-0.24 (1H, m). Mass Spectrum (ESI) m/z=380
(M+1).
Step G. (3R,5R,6S)
(3S,5S,6R)-3-Allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-(cyclopropylme-
thyl)piperidin-2-one and (3S,5R,6S)
(3R,5S,6R)-3-allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-(cyclopropylme-
thyl)piperidin-2-one
##STR00188##
[1591] The title compounds were prepared from racemic
((5R,6S)(5S,6R)-5-(3-chlorophenyl)-6-(5-chlorothiophen-2-yl)-1-(cycloprop-
ylmethyl)piperidin-2-one (Example 63, Step F) as described in
Example 1, Step G and were obtained as a mixture of stereoisomers.
The individual racemic stereoisomers were separated by silica gel
chromatography.
[1592] The title compound (3R,5R,6S)
(3S,5S,6R)-3-allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-(cyclopropylme-
thyl)piperidin-2-one was obtained as the faster eluting isomer
(less polar isomer) by silica gel chromatography.
[1593] .sup.1H NMR (400 MHz, CHLOROFORM-d) .delta. ppm 7.16-7.23
(2H, m), 7.10-7.12 (1H, m), 6.60 (1H, d, J=4 Hz), 6.32 (1H, d, J=4
Hz), 5.75-5.84 (1H, m), 5.05-5.12 (2H, m), 4.76 (1 h, d, J=8 Hz),
3.98-4.03 (1H, m), 3.04-3.10 (1H, m), 2.75-2.81 (1H, m), 2.51-2.63
(2H, m), 2.35-2.42 (1H, m), 2.05-2.11 (1H, m), 1.89-1.99 (1H, m),
0.88-0.98 (1H, m), 0.49-0.56 (1H, m), 0.39-0.46 (1H, m), 0.19-0.25
(1H, m), 0.07-0.13 (1H, m). Mass Spectrum (ESI) m/z=420 (M+1).
[1594] The title compound (3S,5R,6S)
(3R,5S,6R)-3-allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-(cyclopropylme-
thyl)piperidin-2-one was obtained as the slower eluting isomer on
silica gel chromatography.
[1595] .sup.1H NMR (400 MHz, CHLOROFORM-d) .delta. ppm 7.42 (1H, br
s) 726-7.31 (1H, m), 7.19-7.23 (1H, m),6.79 (1H, d, J=4 Hz), 6.60
(1H, d, J=4 Hz), 5.70-5.80 (1H, m), 5.06-5.15 (3H, m), 4.18-4.23
(1H, m), 3.26-3.29 (1H, m), 2.62-2.68 (1H, m), 2.41-2.51 (2H, m),
2.31-2.38 (1H, m), 2.15-2.22 (1H, m), 1.92-1.98 (1H, m), 1.11-1.21
(1H, m), 0.63-0.69 (1H, m), 0.54-0.60 (1H, m), 0.24-0.34 (2H, m).
Mass Spectrum (ESI) m/z=420 (M+1).
Step H.
2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(5-chlorothiophen-2-yl)-1-(cycl-
opropylmethyl)-2-oxopiperidin-3-yl)acetic acid
##STR00189##
[1597] The title compound was prepared from racemic
(3R,5R,6S)(3S,5S,6R)-3-allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-(cyc-
lopropylmethyl)piperidin-2-one (Example 63, Step G) as described in
Example 1, Step H and resolved by chiral SFC on a CHRALCEL.RTM. OJ
column (Daicel, Fort Lee, N.J.). It was obtained as the slower
eluting isomer.
[1598] .sup.1H NMR (400 MHz, CHLOROFORM-d) .delta. ppm 7.45 (1H, br
s) 7.31-7.34 (2H, m), 7.23-7.35 (1H, m),6.84 (1H, d, J=4 Hz), 6.74
(1H, d, J=4 Hz), 5.27 (1H, br s), 4.22-4.27 (1H, m), 3.33 (1H, br
s), 2.76-2.84 (1H, m), 2.52-2.63 (3H, m), 2.31-2.36 (1H, m),
1.96-2.02 (1H, m), 1.15-1.24 (1H, m), 0.71-0.77 (1H, m), 0.60-0.67
(1H, m), 0.34-0.40 (1H, m), 0.27-0.33 (1H, m). Mass Spectrum (ESI)
m/z=438 (M+1).
Example 64
2-((3S,5R,6S)-5-(3-chlorophenyl)-6-(5-chlorothiophen-2-yl)-1-(cyclopropylm-
ethyl)-2-oxopiperidin-3-yl)acetic acid
##STR00190##
[1600] The title compound was prepared from racemic
(3R,5R,6S)(3S,5S,6R)-3-allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-(cyc-
lopropylmethyl)piperidin-2-one (Example 63, Step G) as described in
Example 1, Step H and resolved by chiral SFC on an AD column. It
was obtained as the slower eluting isomer on a CHIRALCEL.RTM.
(Daicel, Fort Lee, N.J.) AD column.
[1601] .sup.1H NMR (400 MHz, CHLOROFORM-d) .delta. ppm 7.17-7.24
(2H, m), 7.09-7.10 (1H, m), 6.90-6.92 (1H, m), 6.62 (1H, d, J=4
Hz), 6.35 (1H, d, J=4 Hz), 4.80 (1H, d, J=12 Hz), 3.94-3.99 (1H,
m), 3.11-3.18 (1H, m), 2.99-3.16 (1H, m), 2.54-2.66 (2H, m),
2.09-2.22 (2H, m), 0.87-0.98 (1H, m), 0.50-0.57 (1H, m), 0.40-0.47
(1H, m), 0.18-0.24 (1H, m), 0.07-0.13 (1H, m). Mass Spectrum (ESI)
m/z=438 (M+1).
Example 65
##STR00191##
[1602]
2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-ethoxy-
-1-oxobutan-2-yl)-3-methyl-2-oxopiperidin-3-yl)acetic acid
Step A. (S)-Ethyl
2-((3R,5R,6S)-3-allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-2-oxopiperidi-
n-1-yl)butanoate and (S)-Ethyl
2-((3S,5R,6S)-3-allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-2-oxopiperidi-
n-1-yl)butanoate
##STR00192##
[1604] To a solution of 362 mg (833 .mu.mol) of (S)-Ethyl
2-((2S,3R)-3-(3-chlorophenyl)-2-(4-chlorophenyl)-6-oxopiperidin-1-yl)buta-
noate (Example 9, Step A) and allyl bromide (87 .mu.l, 1000
.mu.mol) in THF (3.30 mL, 0.25 M) was added dropwise lithium
bis(trimethylsilyl)amide (1M solution in THF; 875 .mu.l, 875
.mu.mol) at -78.degree. C. After being stirred at -78.degree. C.
for 3 h, the reaction was quenched (sat. aqueous NH.sub.4Cl),
extracted (2.times.EtOAc). The combined organic layers were washed
with water and sat. aq. NaCl solution, dried over Na.sub.2SO.sub.4,
filtered and the filtrate was concentrated under reduced pressure.
Purification of the residue by chromatography (12 g SiO.sub.2, 15
to 20% EtOAc/Hex, a gradient elution) provided the title compounds
as a mixture of stereoisomers.
Step B. (2S)-Ethyl
2-((3S,5R,6S)-3-allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-2-ox-
opiperidin-1-yl)butanoate and (2S)-Ethyl
2-((3R,5R,6S)-3-allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-2-ox-
opiperidin-1-yl)butanoate
##STR00193##
[1606] To a solution of 0.66 g (1.39 mmol) of (S)-ethyl
2-((5R,6S)-3-allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-2-oxopiperidin-1-
-yl)butanoate (Example 65, Step A; mixture of diastereomers) and
iodomethane (0.592 g, 4.17 mmol) in 15 mL of THF was added LHMDS
(1.0M solution in THF; 4.17 mL, 4.17 mmol) at RT. After being
stirred for 12 h, the reaction was quenched (sat. aqueous
NH.sub.4Cl), extracted (2.times.EtOAc). The combined organic layers
were washed with water and sat. aq. NaCl solution, dried over
Na.sub.2SO.sub.4, filtered and the filtrate was concentrated under
reduced pressure. Purification of the residue by reversed phase
preparatory HPLC (Gemini.TM. Prep C18 5 .mu.m column, Phenomenex,
Torrance, Calif.; eluent: 10 to 90% acetonitrile+0.1% TFA in
water+0.1% TFA, gradient elution) gave the title compound as a
mixture of stereoisomers.
Step D.
2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-ethox-
y-1-oxobutan-2-yl)-3-methyl-2-oxopiperidin-3-yl)acetic acid
##STR00194##
[1608] To a rapidly stirring solution of 0.28 g (0.573 mmol) of
(2S)-ethyl
2-((5R,6S)-3-allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-2-oxopi-
peridin-1-yl)butanoate (Example 65, Step B; mixt. of diastereomers)
in H.sub.2O/CCl.sub.4/MeCN (4.0/2.0/2.0, 8.0 mL) was added sodium
periodate (0.490 g, 2.29 mmol), followed by ruthenium(III) chloride
hydrate (0.013 g, 0.057 mmol). After being stirred vigorously for
12 h, the reaction was acidified (10% citric acid) and diluted with
EtOAc. The insoluble material was removed by filtration through a
pad of Celite.RTM. (J. T. Baker, Phillipsberg, N.J., diatomaceous
earth). The filtrate was extracted (2.times.EtOAc). The combined
organic layers were washed with water and sat. aq. NaCl solution,
dried over Na.sub.2SO.sub.4, filtered and the filtrate was
concentrated under reduced pressure. The residue was purified by
reversed phase preparatory HPLC (Gemini.TM. Prep C18 5 .mu.m
column, Phenomenex, Torrance, Calif.; eluent: 10 to 90%
acetonitrile+0.1% TFA in water+0.1% TFA, gradient elution) to give
the title compound as the first eluting isomer as a white
powder.
[1609] .sup.1H NMR (400 MHz, CHLOROFORM-d) .delta. ppm 0.59 (t,
J=7.6 Hz, 3H), 1.28 (t, J=7.2 Hz, 3H), 1.44 (s, 3H), 1.50-1.64 (m,
1H), 2.10-2.19 (m, 1H), 2.19-2.37 (m, 2H), 2.86 (q, J=14.5 Hz, 2H),
3.19-3.35 (m, 2H), 4.11-4.27 (m, 2H), 4.58 (d, J=10.5 Hz, 1H), 6.77
(m, 1H) 6.93-7.05 (m, 3H) 7.05-7.17 (m, 2H) 7.20-7.33 (m, 2H); MS
(ESI) 506.2 [M+H].sup.+. 504.1 [M-H].sup.-.
Example 66
##STR00195##
[1610]
2-((3S,5R,6S)-1-((S)-1-tert-butoxy-1-oxobutan-2-yl)-5-(3-chlorophen-
yl)-6-(4-chlorophenyl)-3-methyl-2-oxopiperidin-3-yl)acetic acid
Step A. (S)-tert-butyl
2-((2S,3R)-3-(3-chlorophenyl)-2-(4-chlorophenyl)-6-oxopiperidin-1-yl)buta-
noate
##STR00196##
[1612] The title compound was synthesized as described in Example
9, Step A, substituting ethyl 2-bromobutanoate for t-butyl
2-bromobutanoate. Purification by flash chromatography on silica
gel (30% EtOAc/Hexanes) provided the title compound as the faster
eluting component as a white foam.
Step B. (2S)-tert-butyl
2-((2S,3R)-3-(3-chlorophenyl)-2-(4-chlorophenyl)-5-methyl-6-oxopiperidin--
1-yl)butanoate
##STR00197##
[1614] To a solution of 11.2 g (24.2 mmol) of (S)-tert-butyl
2-((2S,3R)-3-(3-chlorophenyl)-2-(4-chlorophenyl)-6-oxopiperidin-1-yl)buta-
noate (Example 66, Step A) and iodomethane (1.813 mL, 29.1 mmol) in
THF (120.0 mL) was added a lithium bis(trimethylsilyl)amide, (1M
solution in THF; 26.6 mL, 26.6 mmol) at -78.degree. C. The reaction
was allowed to warm to R.T., then was quenched (sat. aqueous
NH.sub.4Cl) and extracted (2.times.EtOAc). The combined organic
layers were washed with water and sat. aq. NaCl solution, dried
over Na.sub.2SO.sub.4, filtered and the filtrate was concentrated
under reduced pressure. The residue was absorbed onto a plug of
silica gel and purified by chromatography on silica gel, eluting
with a gradient of 10% to 30% EtOAc in hexane, to provide the title
compound as a mixture of stereoisomers.
Step C. (2S)-tert-butyl
2-((5R,6S)-3-allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-2-oxopi-
peridin-1-yl)butanoate
##STR00198##
[1616] To a solution of 10.2 g (21.4 mmol) of (2S)-tert-butyl
2-((2S,3R)-3-(3-chlorophenyl)-2-(4-chlorophenyl)-5-methyl-6-oxopiperidin--
1-yl)butanoate (Example 66, Step B, mixture of diastereomers) and
allyl bromide (7.24 mL, 86 mmol) in THF (210 mL) was added LHMDS,
(1.0M solution in THF; 64.2 mL, 64.2 mmol) at R.T. Let it stir at
R.T. for 5 min. Then the reaction mixture was heated at 50.degree.
C. for 3 h. Sat. aq. NH.sub.4Cl solution was added and the mixture
was extracted with CH.sub.2Cl.sub.2. The combined organic layers
were washed with water and sat. aq. NaCl solution, dried over
MgSO.sub.4, filtered and the filtrate was concentrated under
reduced pressure. The residue was purified by chromatography,
eluting with a gradient of 0% to 20% EtOAc in hexane, to provide
the title compound as a mixture of stereoisomers at C-3.
Step D.
2-((3S,5R,6S)-1-((S)-1-tert-butoxy-1-oxobutan-2-yl)-5-(3-chlorophe-
nyl)-6-(4-chlorophenyl)-3-methyl-2-oxopiperidin-3-yl)acetic
acid
##STR00199##
[1618] (2S)-tert-butyl
2-((5R,6S)-3-allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-2-oxopi-
peridin-1-yl)butanoate (Example 66, Step C, mixture of
diastereomers) was converted to the acid by a procedure similar to
the one described in Example 65, Step D. The crude product was
purified by reversed phase preparatory HPLC (Gemini.TM. Prep C18 5
.mu.m column, Phenomenex, Torrance, Calif.; eluent: 10 to 90%
acetonitrile+0.1% TFA in water+0.1% TFA, gradient elution) to give,
the title compound as the first eluting isomer.
[1619] .sup.1H NMR (400 MHz, CHLOROFORM-d) .delta. ppm 0.54 (t,
J=7.5 Hz, 3H), 1.41-1.55 (m, 14H), 2.07-2.17 (m, 1H), 2.25 (d,
J=13.5 Hz, 1H), 2.28-2.42 (m, 1H), 2.81 (d, J=15.4 Hz, 1H),
2.93-3.03 (m, 2H), 3.24 (ddd, J=13.3, 10.5, 3.1 Hz, 1H), 4.58 (d,
J=10.5 Hz, 1H), 6.76 (m, 1H) 6.97-7.06 (m, 3H) 7.08-7.20 (m, 2H)
7.25 (s, 2H); MS (ESI) 534.1 [M+H].sup.+. 532.0 [M-H].sup.-.
[1620] Further elution provided Example 67.
Example 67
##STR00200##
[1621]
2-((3R,5R,6S)-1-((S)-1-tert-butoxy-1-oxobutan-2-yl)-5-(3-chlorophen-
yl)-6-(4-chlorophenyl)-3-methyl-2-oxopiperidin-3-yl)acetic acid
[1622] .sup.1H NMR (400 MHz, CHLOROFORM-d) .delta. ppm 1.00 (t,
J=7.5 Hz, 3H), 1.43 (s, 9H), 1.50 (s, 3H), 1.93-2.27 (m, 4H), 2.79
(d, J=15.3 Hz, 1H), 3.04 (d, J=15.5 Hz, 1H), 3.15-3.29 (m, 2H),
4.52 (d, J=10.4 Hz, 1H), 6.68-6.78 (m, 1H), 6.90-6.98 (m, 1H),
7.05-7.29 (m, 6H); MS (ESI) 534.1 [M+H].sup.+. 532.0
[M-H].sup.-.
Example 68
##STR00201##
[1623]
2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-(cyclo-
propylmethoxy)butan-2-yl)-3-methyl-2-oxopiperidin-3-yl)acetic
acid
Step A.
(5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-hydroxybuta-
n-2-yl)piperidin-2-one
##STR00202##
[1625] To a solution of 3 g (6.9 mmol) of (S)-ethyl
2-((2S,3R)-3-(3-chlorophenyl)-2-(4-chlorophenyl)-6-oxopiperidin-1-yl)buta-
noate (Example 9, Step A) in 45 mL of Et.sub.2O was added lithium
tetrahydroborate (0.334 g, 13.81 mmol) at 0.degree. C. After being
stirred at 0.degree. C. for 50 min, the reaction was quenched (ice
cold 10% citric acid) and extracted (2.times.EtOAc). The combined
organic layers were washed with water and sat. aq. NaCl solution,
dried over MgSO.sub.4, filtered and the filtrate was concentrated
under reduced pressure. Purification by flash chromatography on
silica gel (eluent: 30% to 60% EtOAc/Hexanes, gradient elution)
provided the title compound.
Step B.
(5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-(cyclopropy-
lmethoxy)butan-2-yl)piperidin-2-one
##STR00203##
[1627] To a solution of 1.48 g (3.77 mmol) of
(5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-hydroxybutan-2-yl)-
piperidin-2-one (Example 68, Step A) and bromomethylcyclopropane
(0.828 mL, 7.54 mmol) in DMF (20 mL) was added sodium t-butoxide
(0.544 g, 5.66 mmol) at 0.degree. C. The mixture was stirred at
0.degree. C. for 2 h and then warmed to rt. Then the reaction was
stirred at rt for 14 h. The reaction was quenched with sat. aqueous
NH.sub.4Cl solution and extracted with EtOAc. The combined organic
layers were washed with water and sat. aq. NaCl solution, dried
over MgSO.sub.4, filtered and the filtrate was concentrated under
reduced pressure. Purification by flash chromatography on silica
gel (eluent: 20%-40% EtOAc/Hexanes, gradient elution) provided the
title compound as a colorless oil.
Step C.
(5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-(cyclopropy-
lmethoxy)butan-2-yl)-3-methylpiperidin-2-one
##STR00204##
[1629] To a solution of 0.325 g (0.73 mmol) of
(5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-(cyclopropylmethox-
y)butan-2-yl)piperidin-2-one (Example 68, Step B) and iodomethane
(0.055 mL, 0.874 mmol) in THF (7.0 mL) was added lithium
bis(trimethylsilyl)amide (1M solution in THF, 0.8 mL, 0.8 mmol) at
-78.degree. C. The reaction was allowed to warm to R.T., then was
quenched with sat. aqueous NH.sub.4Cl solution and extracted with
EtOAc. The combined organic layers were washed with water and sat.
aq. NaCl solution, dried over MgSO.sub.4, filtered and the filtrate
was concentrated under reduced pressure. The crude material was
absorbed onto a plug of silica gel and purified by chromatography
on silica gel, eluting with a gradient of 10% to 30% EtOAc in
hexane, to provide the title compound as a mixture of C-3
stereoisomers, as indicated by *.
Step D.
(3S,5R,6S)-3-allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1--
(cyclopropylmethoxy)butan-2-yl)-3-methylpiperidin-2-one
##STR00205##
[1631] To a solution of 0.2 g (0.434 mmol) of
(5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-(cyclopropylmethox-
y)butan-2-yl)-3-methylpiperidin-2-one (Example 68, Step C, mixture
of diastereomers) and allyl bromide (0.147 mL, 1.737 mmol) in THF
(5 mL) was added LHMDS, (1.0M solution in THF, 1.3 mL, 1.3 mmol) at
RT. Let it stir at RT for 5 min. Then the reaction mixture was
heated at 50.degree. C. for 3 h. The reaction mixture was diluted
with satd. NH.sub.4Cl. and extracted with CH.sub.2Cl.sub.2. The
combined organic layers were washed with water and sat. aq. NaCl
solution, dried over MgSO.sub.4, filtered and the filtrate was
concentrated under reduced pressure. The crude material was
purified by chromatography, eluting with a gradient of 0% to 20%
EtOAc in hexane, to provide the title compound as a colorless
oil.
Step E.
2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-(cycl-
opropylmethoxy)butan-2-yl)-3-methyl-2-oxopiperidin-3-yl)acetic
acid
[1632]
(3S,5R,6S)-3-Allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-(-
cyclopropylmethoxy)butan-2-yl)-3-methylpiperidin-2-one (Example 68,
Step E) was converted to the acid by a procedure similar to the one
described in Example 1, Step H, to provide the title compound.
[1633] .sup.1H NMR (400 MHz, CHLOROFORM-d) .delta. ppm 0.20-0.33
(m, 2H), 0.51 (t, J=7.5 Hz, 3H), 0.57-0.70 (m, 2H), 1.05-1.17 (m,
1H), 1.44 (s, 3H), 1.48-1.62 (m, 1H), 1.82-1.95 (m, 1H), 2.01 (dd,
J=13.9, 3.3 Hz, 1H), 2.20 (t, J=13.5 Hz, 1H), 2.72 (d, J=15.1 Hz,
1H), 2.95-3.12 (m, 3H), 3.24-3.40 (m, 3H), 3.95 (t, J=9.8 Hz, 1H),
4.69 (d, J=10.0 Hz, 1H), 6.72-6.80 (m, 1H), 6.94-7.07 (m, 3H),
7.07-7.21 (m, 2H), 7.25 (d, J=8.61 Hz, 2H);
Example 69
##STR00206##
[1634]
2-((3S,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-(cyclopropylm-
ethyl)-2-oxo-3-(2-(pyrrolidin-1-yl)ethyl)piperidin-3-yl)acetic
acid
Step A.
(5R,6S)-3-Allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-(cycloprop-
ylmethyl)-3-(2-(triisopropylsilyloxy)ethyl)piperidin-2-one
##STR00207##
[1636] To a solution of 3.70 g (8.9 mmol) of a mixture of C-3
diastereomers of
(5R,6S)-3-allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-(cyclopropylmethy-
l)piperidin-2-oneoxopentanoate (Example 35, Step B) and 20.7 g (63
mmol) of (2-iodoethoxy)triisopropylsilane in dry, degassed THF (60
mL) was added 54.5 mL (54.5 mmol) of a 1 M solution of lithium
bis(trimethylsilyl)amide in THF slowly via syringe over 6 min.
After 10 min, the orange solution was warmed to 40.degree. C. and
stirred for an additional 2.25 h. The reaction was cooled to room
temperature, quenched with saturated aqueous ammonium chloride, and
extracted with EtOAc (3.times.). The combined organic layers were
dried over Na.sub.2SO.sub.4, filtered and the filtrate was
concentrated. Purification of the residue by flash chromatography
on silica gel (2-25% EtOAc/hexanes, gradient elution) provided the
title compound (mixture of C-3 epimers) as a light yellow oil.
Step B.
2-((5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-(cyclopropylmet-
hyl)-2-oxo-3-(2-(triisopropylsilyloxy)ethyl)piperidin-3-yl)acetaldehyde
##STR00208##
[1638] To a solution of 1.28 g (2.08 mmol) of
(5R,6S)-3-allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-(cyclopropylmethy-
l)-3-(2-(triisopropylsilyloxy)ethyl)piperidin-2-one (Example 69,
Step A, mixture of diastereomers) in THF (50 mL) and water (17.5
mL) was added a catalytic amount of osmium tetroxide. After 25 min,
1.34 g (6.25 mmol) of sodium periodate was added. The resulting
light brown slurry was stirred for 19 h and then was filtered
through a fritted funnel. The filtrate was partially concentrated
under reduced pressure, then was diluted with water and extracted
with ethyl acetate (2.times.). The combined organic layers were
washed with saturated aqueous sodium thiosulfate and then saturated
aqueous sodium chloride. The organic layer was dried over
Na.sub.2SO.sub.4, filtered and the filtrate was concentrated. The
crude title compound (mixture of C-3 epimers) was used directly in
the next step.
Step C. Synthesis of
(5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-(cyclopropylmethyl)-3-(2--
(pyrrolidin-1-yl)ethyl)-3-(2-(triisopropylsilyloxy)ethyl)piperidin-2-one
##STR00209##
[1640] A mixture of 1.02 g (1.66 mmol) of crude
2-((5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-(cyclopropylmethyl)-2--
oxo-3-(2-(triisopropylsilyloxy)ethyl)piperidin-3-yl)acetaldehyde
(Example 69, Step B, mixture of diastereomers), 0.55 mL (6.6 mmol)
of pyrrolidine, 880 mg (4.15 mmol) of sodium triacetoxyborohydride
and 285 .mu.L (4.98 mmol) of acetic acid was suspended in a mixture
of 1,2-dichloroethane (36 mL) and DMF (12 mL). After being stirred
at room temperature for 20 h, the reaction mixture was quenched
with saturated aqueous sodium bicarbonate and extracted with DCM
(3.times.). The combined organic layers were dried over
Na.sub.2SO.sub.4, filtered and the filtrate was concentrated. The
crude title compound (mixture of C-3 epimers) was used directly in
the next step.
Step D.
(5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-(cyclopropylmethyl-
)-3-(2-hydroxyethyl)-3-(2-(pyrrolidin-1-yl)ethyl)piperidin-2-one
##STR00210##
[1642] To an ice-cooled solution of 1.12 g (1.66 mmol) of crude
(5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-(cyclopropylmethyl)-3-(2--
(pyrrolidin-1-yl)ethyl)-3-(2-(triisopropylsilyloxy)ethyl)piperidin-2-one
(Example 69, Step C, mixture of diastereomers) in THF (55 mL) added
8.3 mL (8.3 mmol) of a 1M solution of TBAF in THF. After being
stirred at room temperature for 1.5 h, the reaction mixture was
quenched with water and extracted with EtOAc (3.times.). The
combined organic layers were dried (Na.sub.2SO.sub.4), and
concentrated under the reduced pressure. Purification of the
residue by flash chromatography on silica gel (3-30% MeOH/DCM,
gradient elution) provided the title compound (mixture of C-3
epimers) as a light yellow oil.
Step E.
2-((3S,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-(cyclopropyl-
methyl)-2-oxo-3-(2-(pyrrolidin-1-yl)ethyl)piperidin-3-yl)acetic
acid
[1643] An ice-cooled solution of 2.05 g (20.5 mmol) of chromium(VI)
oxide in water (4 mL) was treated with 1.75 mL (32.7 mmol) of
sulfuric acid via syringe. The mixture was diluted with additional
water (4 mL) and stored at 0.degree. C. at prior to use. In a
separate flask, 105 mg (0.21 mmol) of
(5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-(cyclopropylmethyl)-3--
(2-hydroxyethyl)-3-(2-(pyrrolidin-1-yl)ethyl)piperidin-2-one
(Example 69, Step D, mixture of diastereomers) was dissolved in
acetone (20 mL) and then treated with Jones reagent (see above)
slowly via pipette at room temperature. After 30 min, the resulting
dark red solution was heated at 55.degree. C. for an additional
17.5 h. The reaction was concentrated under reduced pressure, then
was diluted with water and extracted with ethyl acetate (4.times.).
The organic layers were over Na.sub.2SO.sub.4, filtered and the
filtrate was concentrated. Purification of the residue by reversed
phase prep. HPLC (Sunfire Prep C.sub.18 OBD 10 .mu.m column
(Waters, Milford, Mass.), gradient elution of 40% MeCN in water to
55% MeCN in water over a 35 min period, where both solvents contain
0.1% TFA) provided the title compound (single enantiomer) as a
white solid. [Note that the desired C-3 (3S) epimer is the less
polar epimer and elutes off second].
[1644] .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. ppm 11.11 (1H, br
s), 7.18-7.24 (2H, m), 7.08-7.18 (2H, m), 6.99 (1H, br s),
6.77-6.87 (3H, m), 4.61 (1H, dd, J=10.1 Hz, 4.7 Hz), 3.72-3.86 (3H,
m), 3.61 (1H, br s), 3.36 (1H, br s), 3.13 (1H, br s), 2.75-2.97
(4H, m), 2.20-2.35 (2H, m), 1.99-2.22 (7H, m), 0.84 (1H, br s),
0.36-0.54 (2H, m), -0.05-0.13 (2H, m). Mass Spectrum (ESI) m/z=529
(M+1).
Example 70
##STR00211##
[1645]
2-((3S,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-(cyclopropylm-
ethyl)-3-(2-morpholinoethyl)-2-oxopiperidin-3-yl)acetic acid
Step A.
(5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-(cyclopropylmethyl-
)-3-(2-hydroxyethyl)-3-(2-morpholinoethyl)piperidin-2-one
##STR00212##
[1647] A mixture of 94 mg (0.15 mmol) of crude
2-((5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-(cyclopropylmethyl)-2--
oxo-3-(2-(triisopropylsilyloxy)ethyl)piperidin-3-yl)acetaldehyde
(Example 69, Step B, mixture of diastereomers), 66 .mu.L (0.76
mmol) of morpholine, 97 mg (0.46 mmol) of sodium
triacetoxyborohydride and 30 .mu.L (0.53 mmol) of acetic acid was
suspended in a mixture of 1,2-dichloroethane (6 mL) and DMF (2 mL).
After being stirred at room temperature for 20 h, the reaction
mixture was quenched with saturated aqueous sodium bicarbonate and
extracted with DCM (3.times.). The combined organic layers were
dried over Na.sub.2SO.sub.4, filtered and the filtrate was
concentrated. Purification of the residue by reversed phase
preparatory HPLC (SunFire.TM. Prep C.sub.18 OBD 10 .mu.m column
(Waters, Milford, Mass.), gradient elution of 50% MeCN in water to
90% MeCN in water over a 30 min period, where both solvents contain
0.1% TFA) provided the title compound (mixture of C-3 epimers)
along with the corresponding TIPS ether (mixture of C-3 epimers)
and the corresponding trifluoroacetate (mixture of C-3 epimers) as
a colorless oil.
[1648] This mixture was dissolved in THF (5 mL) and treated with
0.76 mL (0.76 mmol) of a 1M solution of TBAF in THF. After being
stirred at room temperature for 3.5 h, the reaction mixture was
quenched with water and extracted with EtOAc (3.times.). The
combined organic layers were dried (Na.sub.2SO.sub.4), and
concentrated under the reduced pressure. Purification of the
residue by flash chromatography on silica gel (8-35% MeOH/DCM,
gradient elution) provided the title compound (mixture of C-3
epimers) as a white solid.
Step B.
2-((3S,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-(cyclopropyl-
methyl)-3-(2-morpholinoethyl)-2-oxopiperidin-3-yl)acetic acid
[1649] An ice-cooled solution of 403 mg (4.03 mmol) of chromium(VI)
oxide in water (1 mL) was treated with 343 .mu.L (6.44 mmol) of
sulfuric acid via syringe. The solution was diluted with additional
water (1 mL) and stored at 0.degree. C. at prior to use. In a
separate flask,
(5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-(cyclopropylmethyl)-3-(2--
hydroxyethyl)-3-(2-morpholinoethyl)piperidin-2-one (Example 70,
Step A, mixture of diastereomers) was dissolved in acetone (5 mL)
and then treated with Jones reagent (see above) slowly via pipette
at room temperature. After 30 min, the resulting dark red solution
was heated at 55.degree. C. for an additional 17 h. The reaction
was concentrated under reduced pressure, then was diluted with
water and extracted with ethyl acetate (3.times.). The organic
layers were over Na.sub.2SO.sub.4, filtered and the filtrate was
concentrated. Purification of the residue by reversed phase prep.
HPLC (SunFire.TM. Prep C.sub.18 OBD 10 .mu.m column (Waters,
Milford, Mass.), gradient elution of 40% MeCN in water to 60% MeCN
in water over a 35 min period, where both solvents contain 0.1%
TFA) provided the title compound (single enantiomer) as a white
solid. [Note that the desired (3S)C-3 epimer is the less polar
epimer and elutes off second].
[1650] .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. ppm 12.05 (1H, br
s), 6.95-7.26 (5H, m), 6.76-6.88 (3H, m), 4.64 (1H, d, J=10.0 Hz),
4.23 (1H, br s), 3.76-4.10 (5H, m), 3.43-3.65 (2H, m), 3.08-3.34
(2H, m), 2.78-3.01 (3H, m), 2.41-2.76 (2H, m), 2.26-2.39 (2H, m),
2.08-2.24 (2H, m), 0.85 (1H, br s), 0.33-0.55 (2H, m), -0.10-0.15
(2H, m). Mass Spectrum (ESI) m/z=545 (M+1).
Example 71
##STR00213##
[1651]
2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-2-oxo--
1-(pentan-3-yl)piperidin-3-yl)acetic acid
Step A.
(5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-(2,4-dimethoxybenz-
yl)piperidin-2-one
##STR00214##
[1653] Thionyl chloride (116 mL, 1586 mmol) was added dropwise over
1 hour to a turbid solution of (2,4-dimethoxyphenyl)methanol (97.00
g, 577 mmol) and pyridine (93 mL, 1153 mmol) in anhydrous Et.sub.2O
(1153 mL) at 0.degree. C. under nitrogen with mechanical stirring.
After 1 hour the reaction mixture was poured into 2 L of ice water
and the layers were separated. The aqueous layer was extracted with
Et.sub.2O (2.times.1 L) and the organics were pooled, washed with
ice water (1.2 L), cold 5:1 sat. aq. NaCl solution/sat. aq.
NaHCO.sub.3 (1.2 L), dried (MgSO.sub.4), filtered and most of the
ether was removed in vacuo at 12.degree. C. Benzene (300 mL) was
added and the mixture was concentrated at 12.degree. C. until 100
mL of benzene remained to provide a solution of
1-(chloromethyl)-2,4-dimethoxybenzene.
[1654] 80 g (250 mmol) of
(5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)piperidin-2-one
(Example 1, Step E) was added in portions over 20 minutes to a
mixture of NaH (19.98 g, 500 mmol) in anhydrous DMF (400 mL) at
0.degree. C. under nitrogen. After the addition was complete the
ice bath was removed and the mixture was stirred at rt for 1 hour
before cooling the solution to 0.degree. C. To the cooled solution
was added a solution of 1-(chloromethyl)-2,4-dimethoxybenzene (107
g, 575 mmol) in benzene and the reaction mixture was allowed to
warm to rt. After 16 hours the reaction mixture was poured into ice
water (2 L) and extracted with EtOAc (3.times.1 L). The organics
were pooled, washed with water (3.times.1 L), sat. aq. NaCl
solution (1 L), dried (MgSO.sub.4), filtered and concentrated in
vacuo to provide a thick yellow oil. Purification on the Combiflash
XL (flash column chromatography, Teledyne Isco, Lincoln, Nebr.)
using four stacked 330 g columns and one 1.5 kg column and eluting
with 35-40-45-50-55% EtOAc/hexanes provided a very pale yellow oil.
This was dissolved in benzene and the solvent removed in vacuo and
dried under vacuum for 2 days to provide the title compound as a
white foam (105.8 g, 90%).
Step B.
(5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-(2,4-dimethoxybenz-
yl)-3-methylpiperidin-2-one
##STR00215##
[1656] A solution of
(5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-(2,4-dimethoxybenzyl)pipe-
ridin-2-one (Example 71, Step A) (140.34 g, 298 mmol) in anhydrous
THF (994 mL) was degassed by bubbling argon through the solution
for 20 minutes while it cooled to -78.degree. C. Iodomethane (23.32
mL, 373 mmol) was added followed by the addition of LHMDS (328 mL,
328 mmol) over 15 minutes. The reaction mixture was stirred for 15
minutes at -78.degree. C. and then the reaction was removed from
the cold bath and stirred at rt for 12 hours. The reaction was
quenched by the addition of sat. aq. NH.sub.4Cl and the layers were
separated. The aqueous layer was extracted with EtOAc (2.times.500
mL) and the organics were pooled, washed with sat. aq. NaCl
solution, dried (MgSO.sub.4), filtered and concentrated in vacuo to
provide an orange oil. Purification (wet loaded with small amount
of DCM) using the Combiflash Companion XL (flash column
chromatography, Teledyne Isco, Lincoln, Nebr.) with a 1.5 kg
SiO.sub.2 column and eluting with 4 L each of 15-20-25-30-35%
EtOAc/hexanes provided the title compound as a thick very pale
yellow oil and a 3.7:1 mixture of C-3 diastereomers.
Step C.
(5R,6S)-3-allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-(2,4-dimet-
hoxybenzyl)-3-methylpiperidin-2-one
##STR00216##
[1658] A solution of
(5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-(2,4-dimethoxybenzyl)-3-m-
ethylpiperidin-2-one (Example 71, Step B, mixture of C-3
diastereomers) (117.0 g, 242 mmol) in anhydrous THF (966 mL) was
degassed by bubbling argon through the solution for 20 minutes.
Allyl bromide (105 mL, 1208 mmol) was added followed by the
addition of LHMDS (725 mL, 725 mmol) over 20 minutes. The reaction
mixture was heated at 40.degree. C. under argon for 5 hours. The
reaction mixture was cooled to rt. and the reaction was quenched by
the addition of sat. aqueous NH.sub.4Cl (500 mL) and the layers
were separated. The aqueous layer was extracted with EtOAc
(2.times.1 L) and the organics were pooled, washed with sat. aq.
NaCl solution (1 L), dried (MgSO.sub.4), filtered and concentrated
in vacuo to provide a red oil (180 g). Purification using the
Biotage system (Charlotte, N.C.) with a 1.5 kg SiO.sub.2 column and
eluting with 10-30% EtOAc/hexanes provided the title compound as a
very pale yellow oil as a 3.7:1 mixture of (3S):(3R)
diastereomers.
Step D.
(3S,5R,6S)-3-allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methylp-
iperidin-2-one
##STR00217##
[1660] A solution of
(5R,6S)-3-allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-(2,4-dimethoxyben-
zyl)-3-methylpiperidin-2-one (Example 71, Step C, mixture of
diastereomers) (105.87 g, 202 mmol) in TFA (778 mL, 1.01E+04 mmol)
was heated at 50.degree. C. for 2 hours before concentrating the
reaction mixture in vacuo. The residue was azeotroped with hexanes
to remove all of the TFA. The deep purple oil containing some
residue was taken up in a minimum amount of DCM, filtered and
washed liberally with DCM. The filtrate was concentrated in vacuo
to provide a dark purple oil. Purification (wet packed with a
minimum amount of DCM) using the Biotage Isolera (Biotage,
Charlotte, N.C.) with a 1.5 kg column and eluting with 25-40%
EtOAc/hexanes provided the title compound as a white solid.
[1661] .sup.1H NMR (500 MHz, CDCl.sub.3) .delta. ppm 1.30 (s, 3H),
2.06 (m, 2H), 2.52 (dd, J=13.7 and 7.1 Hz, 1H), 2.60 (dd, J=13.7
and 7.8 Hz, 1H), 3.06 (m, 1H), 4.50 (d, J=10.7 Hz, 1H), 5.17 (m,
2H), 5.81 (br s, 1H), 5.86 (m, 1H), 6.77 (d, J=7.6 Hz, 1H), 6.96
(d, J=8.3 Hz, 2H), 7.00 (s, 1H), 7.12 (t, J=7.7 Hz, 1H), 7.17 (m,
1H), 7.20 (d, J=8.3 Hz, 2H). [ ].sup.22.sub.D+182.2.degree. (c
1.55, CHCl.sub.3).
Step E.
(3S,5R,6S)-3-allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl--
1-(pentan-3-yl)piperidin-2-one
##STR00218##
[1663] To a suspension of 1.81 g (4.8 mmol) of
(3S,5R,6S)-3-allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methylpiperidi-
n-2-one (Example 71, Step D) in 3-bromopentane (17.6 mL) added 967
mg (60 wt. % in mineral oil, 24.2 mmol) of sodium hydride. The
resulting milky white slurry was heated at 120.degree. C. for 20 h,
and then more 3-bromopentane (5.1 mL) was added. After an
additional 24 h at 120.degree. C., the reaction was cooled to room
temperature and quenched with saturated aqueous ammonium chloride.
The mixture was extracted with ethyl acetate (3.times.) and the
combined organic layers were dried over Na.sub.2SO.sub.4, filtered
and the filtrate was concentrated. Purification of the residue by
flash chromatography on silica gel (2 to 26% EtOAc/hexanes,
gradient elution) provided the title compound as a white solid.
Step F. Synthesis of
2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-2-oxo-1-(pen-
tan-3-yl)piperidin-3-yl)acetic acid
[1664] To a solution of 725 mg (1.63 mmol) of
(3S,5R,6S)-3-allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-1-(pent-
an-3-yl)piperidin-2-one (Example 3, Step A) in a mixture of
acetonitrile (4 mL), carbon tetrachloride (4 mL) and water (5.9 mL)
added 1.40 g (6.53 mmol) of sodium periodate followed by 44 mg
(0.20 mmol) of ruthenium(III) chloride hydrate. The dark brown
biphasic mixture was stirred vigorously at room temperature for 21
h, and then was acidified with 1 N HCl. The mixture was diluted
with EtOAc and filtered through a pad of Celite.RTM. (J. T. Baker,
Phillipsberg, N.J., diatomaceous earth). After filtration, the
layers were separated and the aqueous layer was extracted with
EtOAc (1.times.). The combined organic layers were washed with
saturated aqueous sodium chloride (1.times.), then were dried over
Na.sub.2SO.sub.4, filtered and the filtrate was concentrated.
Purification of the residue by flash chromatography on silica gel
(0 to 25% MeOH/DCM, gradient elution) provided the title compound
as a white solid.
[1665] .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. ppm 7.06-7.27 (5H,
m), 6.90-7.01 (2H, m), 6.68 (d, 1H, J=7.8 Hz), 4.34 (1H, d, J=10.4
Hz), 3.00-3.15 (2H, m), 2.63-2.79 (2H, m), 2.15-2.27 (1H, m),
1.85-2.03 (3H, m), 1.51 (s, 3H), 1.38-1.51 (2H, m), 0.95 (3H, t,
J=7.4 Hz), 0.50 (3H, t, J=7.4 Hz). Mass Spectrum (ESI) m/z=462
(M+1).
[1666] Examples 72-75 were prepared in a process similar to that
described for Example 71, substituting 3-bromopentane in Step E for
the appropriate amount of alkylhalide.
TABLE-US-00005 ##STR00219## Example R.sup.1 72 ##STR00220## 73
##STR00221## 74 ##STR00222## 75 ##STR00223##
Example 72
2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-(cyclopropylmethyl)--
3-methyl-2-oxopiperidin-3-yl)acetic acid
[1667] .sup.1H NMR (400 MHz, CHLOROFORM-d) .delta. ppm 7.29 (2H, d,
J=8.6 Hz), 7.12-7.24 (3H, m), 6.90 (2H, d, J=8.6 Hz), 6.88-6.82
(1H, m), 4.80 (1H, d, J=8.4 Hz), 4.02 (1H, dd, J=14.1, 6.8 Hz),
3.11-3.03 (1H, m), 2.98 (1H, d, J=15.5 Hz), 2.68 (1H, d, J=15.5
Hz), 2.37 (1H, dd, J=14.1, 7.4 Hz), 2.23-2.14 (1H, m), 2.13-2.05
(1H, m), 1.39 (3H, s), 1.03-0.94 (1H, m), 0.62-0.46 (2H, m),
0.23-0.08 (1H, m); MS (ESI) 446.0 [M+H].sup.+, 444.1
[M-H].sup.-.
Example 73
2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-isopropyl-3-methyl-2-
-oxopiperidin-3-yl)acetic acid
[1668] .sup.1H NMR (400 MHz, CHLOROFORM-d) .delta. ppm 7.27 (2H, d,
J=7.8 Hz), 7.14-7.20 (2H, m), 7.02 (1H, s), 6.97 (2H, d, J=7.8 Hz),
6.75 (1H, d, J=7.6 Hz), 4.49 (1H, d, J=9.0 Hz), 3.45 (1H, m), 3.08
(1H, m), 2.98 (1H, d, J=15.2 Hz), 2.77 (1H, d, J=15.2 Hz), 2.08
(2H, m), 1.38 (3H, s), 1.24 (6H, t, J=6.7 Hz); MS (ESI) 434.0
[M+H].sup.+.
Example 74
2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-cyclobutyl-3-methyl--
2-oxopiperidin-3-yl)acetic acid
[1669] 1H NMR (400 MHz, CHLOROFORM-d) .delta. ppm 7.15-7.26 (3H,
m), 7.17 (1H, m), 7.04 (1H, s), 6.65-6.79 (3H, m), 4.65 (1H, d,
J=8.8 Hz), 3.85 (1H, m), 3.05 (1H, d, J=15.8 Hz), 2.85 (1H, m),
2.60 (1H, d, J=15.8 Hz), 2.45 (1H, m), 2.20 (1H, m), 1.90-2.2.20
(2H, m), 1.65 (1H, m), 1.42-1.55 (3H, m), 1.42 (3H, s); MS (ESI)
446.0 [M+H].sup.+.
Example 75
2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-cyclopentyl-3-methyl-
-2-oxopiperidin-3-yl)acetic acid
[1670] 1H NMR (400 MHz, CHLOROFORM-d) .delta. ppm 7.28 (2H, d,
J=8.3 Hz), 7.14-7.25 (2H, m), 7.06 (1H, s), 6.93 (2H, d, J=8.3 Hz),
6.80 (1H, d, J=7.6 Hz), 4.63 (1H, d, J=8.1 Hz), 3.40 (1H, m), 3.03
(1H, d, J=15.7 Hz), 3.02 (1H, m), 2.62 (1H, d, J=15.7 Hz),
1.75-2.13 (7H, m), 1.26-1.45 (3H, m), 1.33 (3H, s); MS (ESI) 460.1
[M+H].sup.+.
Example 76
##STR00224##
[1671]
(3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-3-((5-oxo-
-4,5-dihydro-1H-1,2,4-triazol-3-yl)methyl)-1-(pentan-3-yl)piperidin-2-one
Step A.
2-(2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-2--
oxo-1-(pentan-3-yl)piperidin-3-yl)acetyl)hydrazinecarboxamide
##STR00225##
[1673] To a solution of 320 mg (0.69 mmol) of
2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-2-oxo-1-(pen-
tan-3-yl)piperidin-3-yl)acetic acid (Example 71, Step F) and 921 mg
(2.42 mmol) of HOBt in DMF (13 mL) was added 0.58 mL (4.15 mmol) of
triethylamine. After stirring at room temperature for 40 min, added
270 mg (2.42 mmol) of semicarbazide hydrochloride. The resulting
dark red solution was stirred at room temperature for 2.5 h, and
then was concentrated under reduced pressure. Purification of the
residue by reversed phase prep. HPLC (Sunfire.TM. Prep C.sub.18 OBD
10 .mu.m column (Waters, Milford, Mass.), gradient elution of 40%
MeCN in water to 90% MeCN in water over a 30 min period, where both
solvents contain 0.1% TFA) provided the title compound as a light
yellow solid.
Step B.
(3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-3-((5-ox-
o-4,5-dihydro-1H-1,2,4-triazol-3-yl)methyl)-1-(pentan-3-yl)piperidin-2-one
[1674] 259 mg (0.50 mmol) of
2-(2-((3R,5R,6S)-5-(3-Chlorophenyl)-6-(4-chlorophenyl)-3-methyl-2-oxo-1-(-
pentan-3-yl)piperidin-3-yl)acetyl)hydrazinecarboxamide (Example 76,
Step A) was suspended in 2 N aqueous sodium hydroxide (16 mL) and
heated at reflux for 3.25 h. Upon cooling to room temperature, the
mixture was acidified with conc. HCl until strongly acidic and then
extracted with EtOAc (3.times.). The combined organic layers were
dried over Na.sub.2SO.sub.4, filtered and the filtrate was
concentrated. Purification of the residue by reversed phase prep.
HPLC (Sunfire.TM. Prep C.sub.18 OBD 10 .mu.m column (Waters,
Milford, Mass.), gradient elution of 40% MeCN in water to 75% MeCN
in water over a 30 min period, where both solvents contain 0.1%
TFA) provided the title compound as a white solid.
[1675] .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. ppm 10.36 (1H, br
s), 9.35 (1H, br s), 7.20-7.27 (3H, m), 7.05-7.17 (2H, m),
6.86-6.95 (2H, m), 6.68 (1H, d, J=7.8 Hz), 4.34 (1H, d, J=10.5 Hz),
2.90-3.09 (3H, m), 2.68-2.76 (1H, m), 2.21 (1H, t, J=13.8 Hz), 2.05
(1H, dd, J=13.9 Hz, 2.9 Hz) 1.85-1.99 (2H, m), 1.37-1.52 (2H, m),
1.36 (3H, s), 0.94 (3H, t, J=7.4 Hz), 0.50 (3H, t, J=7.5 Hz). Mass
Spectrum (ESI) m/z=501 (M+1), 523 (M+23).
Example 77
##STR00226##
[1676]
5-(((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-2-oxo-
-1-(pentan-3-yl)piperidin-3-yl)methyl)-1,3,4-oxadiazol-2(3H)-one
[1677] A solution of 56 mg (0.19 mmol) of triphosgene in DCM (1 mL)
was added dropwise to a solution of 62 mg (0.13 mmol) of
2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-2-oxo-1-(pen-
tan-3-yl)piperidin-3-yl)acetohydrazide (obtained as a byproduct in
Example 76, Step B) and 170 .mu.L (0.98 mmol) of
diisopropylethylamine in DCM (4 mL). The resulting light yellow
solution was stirred at room temperature for 18 h, then was
quenched with saturated aqueous sodium bicarbonate and extracted
with EtOAc (3.times.). The combined organic layers were dried over
Na.sub.2SO.sub.4, filtered and the filtrate was concentrated.
Purification of the residue by reversed phase preparative HPLC
(Sunfire.TM. Prep C.sub.18 OBD 10 .mu.m column, (Waters, Milford,
Mass.) gradient elution of 40% MeCN in water to 75% MeCN in water
over a 30 min period, where both solvents contain 0.1% TFA)
provided the title compound as a white solid.
[1678] .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. ppm 9.68 (1H, br
s), 7.08-7.27 (4H, m), 6.90-7.01 (3H, m), 6.70 (1H, d, J=7.4 Hz),
4.35 (1H, d, J=10.4 Hz), 3.01-3.15 (3H, m), 2.70-2.79 (1H, m), 2.15
(1H, t, J=13.8 Hz), 2.01 (1H, dd, J=13.8 Hz, 3.1 Hz) 1.82-1.95 (2H,
m), 1.35-1.57 (2H, m), 1.43 (3H, s), 0.93 (3H, t, J=7.4 Hz), 0.51
(3H, t, J=7.4 Hz). Mass Spectrum (ESI) m/z=502 (M+1).
Example 78
##STR00227##
[1679]
2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-2-oxo--
1-(pentan-3-yl)piperidin-3-yl)-N-(trifluoromethylsulfonyl)acetamide
[1680] To a solution of 47 mg (0.10 mmol) of
2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-2-oxo-1-(pen-
tan-3-yl)piperidin-3-yl)acetic acid (Example 71, Step F) in DMF (4
mL) was added 64 mg (0.34 mmol) of EDC, 48 mg (0.36 mmol) of HOBt,
and a catalytic amount of DMAP. After 30 min, 45.5 mg (0.30 mmol)
of trifluoromethanesulfonamide was added. The resulting light
yellow solution was stirred at room temperature for 3 h, and then
was concentrated under reduced pressure. Purification of the
residue by reversed phase prep. HPLC (Sunfire.TM. Prep C.sub.18 OBD
10 .mu.m column (Waters, Milford, Mass.), gradient elution of 50%
MeCN in water to 90% MeCN in water over a 30 min period, where both
solvents contain 0.1% TFA) provided the title compound as a white
solid.
[1681] .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. ppm 7.25-7.32 (3H,
m), 7.16-7.20 (1H, m), 7.11 (t, 1H, J=7.8 Hz), 6.92-7.00 (2H, m),
6.67 (d, 1H, J=7.6 Hz), 4.35 (1H, d, J=10.4 Hz), 3.19 (d, 1H,
J=15.7 Hz), 2.97-3.06 (1H, m), 2.73-2.83 (1H, m), 2.68 (1H, d,
J=15.7 Hz), 2.26 (1H, t, J=13.8 Hz), 1.86-2.08 (3H, m), 1.52 (3H,
s), 1.39-1.52 (2H, m), 0.95 (3H, t, J=7.4 Hz), 0.50 (3H, t, J=7.4
Hz). Mass Spectrum (ESI) m/z=593 (M+1), 615 (M+23).
Example 79
##STR00228##
[1682]
(3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-((3-hydroxy-1H-p-
yrazol-5-yl)methyl)-3-methyl-1-(pentan-3-yl)piperidin-2-one
Step A.
2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-2-oxo-
-1-(pentan-3-yl)piperidin-3-yl)acetaldehyde
##STR00229##
[1684] To a solution of 240 mg (0.54 mmol) of
(3S,5R,6S)-3-allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-1-(pent-
an-3-yl)piperidin-2-one (Example 71, Step E) in THF (8 mL) and
water (2.8 mL) added a catalytic amount of osmium tetroxide. After
1.25 h, 323 mg (1.51 mmol) of sodium periodate were added. The
resulting light brown slurry was stirred at room temperature for
18.5 h, and then filtered through a fritted funnel. The filtrate
was partially concentrated under reduced pressure, then was diluted
with water and extracted with ethyl acetate (2.times.). The
combined organic layers were washed with saturated aqueous sodium
thiosulfate and then saturated aqueous sodium chloride. The organic
layer was dried over Na.sub.2SO.sub.4, filtered and the filtrate
was concentrated. The crude title compound was used directly in the
next step.
Step B. Ethyl
4-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-2-oxo-1-(pen-
tan-3-yl)piperidin-3-yl)-3-oxobutanoate
##STR00230##
[1686] To a suspension of 160 mg (0.36 mmol) of
2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-2-oxo-1-(pen-
tan-3-yl)piperidin-3-yl)acetaldehyde (Example 79, Step A) and 20.4
mg (0.11 mmol) of tin(II) chloride in DCM (6 mL) was added 104
.mu.L (1.00 mmol) of ethyl diazoacetate via syringe over 3 min. The
resulting yellow slurry was stirred at room temperature for 14.25
h, then was quenched with 1 N HCl and extracted with EtOAc
(2.times.). The combined organic layers were washed with 1 N HCl
(1.times.), then were dried over Na.sub.2SO.sub.4, filtered and the
filtrate was concentrated. Purification of the residue by reversed
phase prep. HPLC (Sunfire.TM. Prep C.sub.18 OBD 10 .mu.m column
(Waters, Milford, Mass.), gradient elution of 55% MeCN in water to
85% MeCN in water over a 30 min period, where both solvents contain
0.1% TFA) provided the title compound as a light yellow oil.
Step C.
(3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-((3-hydroxy-1H--
pyrazol-5-yl)methyl)-3-methyl-1-(pentan-3-yl)piperidin-2-one
[1687] To a solution of 42 mg (0.08 mmol) of ethyl
4-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-2-oxo-1-(pen-
tan-3-yl)piperidin-3-yl)-3-oxobutanoate (Example 79, Step B) in
ethanol (4 mL) was added 36 .mu.L (0.48 mmol) hydrazine monohydrate
(64-65% weight percent hydrazine). The resulting colorless solution
was heated at 65.degree. C. for 3.5 h, and then was concentrated
under reduced pressure. Purification of the residue by reversed
phase prep. HPLC (Sunfire Prep C.sub.18 OBD 10 .mu.m column,
gradient elution of 45% MeCN in water to 80% MeCN in water over a
30 min period, where both solvents contain 0.1% TFA) provided the
title compound as a white solid.
[1688] .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. ppm 7.23-7.30 (3H,
m), 7.18-7.22 (1H, m), 7.12 (1H, t, J=7.7 Hz), 6.90-6.96 (2H, m),
6.67 (1H, d, J=7.8 Hz), 5.66 (1H, s), 4.34 (1H, d, J=10.6 Hz), 3.42
(1H, d, J=15.9 Hz), 3.02-3.11 (1H, m), 2.82 (1H, d, J=15.9 Hz),
2.68-2.77 (1H, m), 2.36 (1H, t, J=13.9 Hz), 1.87-2.03 (3H, m),
1.40-1.51 (2H, m), 1.36 (3H, s), 0.96 (3H, t, J=7.4 Hz), 0.50 (3H,
t, J=7.5 Hz). Mass Spectrum (ESI) m/z=500 (M+1), 522 (M+23).
Example 80
##STR00231##
[1689]
(3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-((3-hydroxyisoxa-
zol-5-yl)methyl)-3-methyl-1-(pentan-3-yl)piperidin-2-one
[1690] To an ice-cooled slurry of 65 mg (0.12 mmol) of ethyl
4-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-2-oxo-1-(pen-
tan-3-yl)piperidin-3-yl)-3-oxobutanoate (Example 79, Step B) in
water (2 mL) was added 53.5 mg (0.77 mmol) of hydroxylamine
hydrochloride and 62 mg (1.55 mmol) of sodium hydroxide. After 5
min, THF (1 mL) and MeOH (1 mL) were added. The resulting cloudy
light yellow solution was stirred at 0.degree. C. for 20 min, then
was warmed to room temperature and stirred for an additional 6 h.
The reaction was acidified by dropwise addition of conc. HCl until
strongly acidic, then was diluted with water and extracted with
EtOAc (4.times.). The combined organic layers were dried over
Na.sub.2SO.sub.4, filtered and the filtrate was concentrated.
Purification of the residue by reversed phase prep. HPLC
(Sunfire.TM. Prep C.sub.18 OBD 10 .mu.m column (Waters, Milford,
Mass.), gradient elution of 55% MeCN in water to 85% MeCN in water
over a 30 min period, where both solvents contain 0.1% TFA)
provided the title compound as a white solid.
[1691] .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. ppm 7.20-7.27 (3H,
m), 7.14-7.20 (1H, m), 7.11 (1H, dt, J=7.8 Hz, 3.8 Hz), 6.89-7.01
(3H, m), 6.70 (1H, d, J=7.4 Hz), 4.33 (1H, dd, J=10.5 Hz, 3.4 Hz),
3.59-3.78 (2H, m), 3.13-3.23 (1H, m), 3.07 (1H, dd, J=14.1 Hz, 3.1
Hz), 2.66-2.77 (2H, m), 2.15-2.26 (1H, m), 1.96-2.04 (1H, m),
1.78-1.94 (2H, m), 1.40-1.51 (1H, m), 1.41 (3H, s), 0.93 (3H, dt,
J=7.4 Hz, 3.5 Hz), 0.51 (3H, dt, J=7.5 Hz, 3.6 Hz). Mass Spectrum
(ESI) m/z=501 (M+1).
Example 81
##STR00232##
[1692]
5-(((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-2-oxo-
-1-(pentan-3-yl)piperidin-3-yl)methyl)oxazolidine-2,4-dione
Step A.
(3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-(2,3-dihydroxyp-
ropyl)-3-methyl-1-(pentan-3-yl)piperidin-2-one
##STR00233##
[1694] To a solution of 298 mg (0.67 mmol) of
(3S,5R,6S)-3-allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-1-(pent-
an-3-yl)piperidin-2-one (Example 71, Step E) in a mixture of
acetone (11.5 mL) and water (4 mL) added a catalytic amount of
osmium tetroxide. After 4 min, 275 mg (2.35 mmol) of
N-methylmorpholine-N-oxide was added. The resulting brown solution
was stirred at room temperature for 3.5 h, and then was partitioned
between water and DCM (3.times.). The combined organic layers were
dried over Na.sub.2SO.sub.4, filtered and the filtrate was
concentrated. Purification of the residue by flash chromatography
on silica gel (1 to 20% MeOH/DCM, gradient elution) provided the
title compound (mixture of alcohol epimers) as a yellow oil.
Step B.
3-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-2-oxo-
-1-(pentan-3-yl)piperidin-3-yl)-2-hydroxypropanoic acid
##STR00234##
[1696] A mixture of 142 mg (0.30 mmol) of
(3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-(2,3-dihydroxypropyl)--
3-methyl-1-(pentan-3-yl)piperidin-2-one (Example 81, Step A) and 28
mg (0.18 mmol) of TEMPO in a mixture of acetonitrile (6 mL) and
sodium phosphate-sodium hydroxide buffer (pH 6.7, 4.5 mL) at
35.degree. C. was treated simultaneously with a solution of 105 mg
(1.16 mmol) of sodium chlorite in water (1.2 mL) and a solution of
106 L (0.07 mmol) of bleach solution (ca. 0.7 N) in water (0.6 mL)
over 10 min. The resulting dark orange solution was stirred at
35.degree. C. for 1.75 h, and then was partitioned between 1 N HCl
and EtOAc (3.times.). The combined organic layers were dried over
Na.sub.2SO.sub.4, filtered and the filtrate was concentrated.
Purification of the residue by reversed phase prep. HPLC
(Sunfire.TM. Prep C.sub.18 OBD 10 .mu.m column (Waters, Milford,
Mass.), gradient elution of 60% MeCN in water to 80% MeCN in water
over a 30 min period, where both solvents contain 0.1% TFA)
provided the title compound (mixture of alcohol epimers) as a white
solid.
Step C.
3-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-2-oxo-
-1-(pentan-3-yl)piperidin-3-yl)-N-(2,4-dimethoxybenzyl)-2-hydroxypropanami-
de
##STR00235##
[1698] To a solution of 43 mg (0.09 mmol) of
3-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-2-oxo-1-(pen-
tan-3-yl)piperidin-3-yl)-2-hydroxypropanoic acid (Example 81, Step
B) in DMF (5 mL) was added 67 mg (0.18 mmol) of HATU, 58.5 mg (0.35
mmol) of 2,4-dimethoxybenzylamine and 36 .mu.L (0.26 mmol) of
triethylamine. The resulting yellow solution was stirred at room
temperature for 1.1 h, and then was partitioned between saturated
aqueous sodium bicarbonate and EtOAc (2.times.). The combined
organic layers were dried over Na.sub.2SO.sub.4, filtered and the
filtrate was concentrated. The crude title compound (mixture of
alcohol epimers) was used directly in the next step.
Step D.
(S)-3-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-2-
-oxo-1-(pentan-3-yl)piperidin-3-yl)-2-hydroxypropanamide and
(R)-3-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-2-oxo-1--
(pentan-3-yl)piperidin-3-yl)-2-hydroxypropanamide
##STR00236##
[1700] A solution of 56 mg (0.09 mmol) of
3-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-2-oxo-1-(pen-
tan-3-yl)piperidin-3-yl)-N-(2,4-dimethoxybenzyl)-2-hydroxypropanamide
(Example 81, Step C) in trifluoroacetic acid (2.3 mL) was heated at
50.degree. C. for 2.5 h, and then was concentrated under reduced
pressure. Purification of the residue by reversed phase prep. HPLC
(Sunfire.TM. Prep C.sub.18 OBD 10 .mu.m column (Waters, Milford,
Mass.), gradient elution of 50% MeCN in water to 75% MeCN in water
over a 30 min period, where both solvents contain 0.1% TFA)
provided the two title compounds (in each case the stereochemistry
at alcohol stereocenter is arbitrarily assigned) each as a light
green solid.
Step E.
5-(((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-2-ox-
o-1-(pentan-3-yl)piperidin-3-yl)methyl)oxazolidine-2,4-dione
[1701] To a solution of 10.3 mg (0.02 mmol) of
(S)-3-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-2-oxo-1--
(pentan-3-yl)piperidin-3-yl)-2-hydroxypropanamide (Example 81, Step
D) in MeOH (2.5 mL) was added 0.50 mL (1.22 mmol) of sodium
ethoxide (21 wt. % solution in ethanol) and 1.20 mL (9.90 mmol) of
diethyl carbonate. The resulting mixture was heated at reflux for
15 min, and then was concentrated under reduced pressure. The
residue was partitioned between 0.5 M HCl and EtOAc (3.times.). The
combined organic layers were dried over Na.sub.2SO.sub.4, filtered
and the filtrate was concentrated. Purification of the residue by
reversed phase prep. HPLC (Sunfire.TM. Prep C.sub.18 OBD 10 .mu.m
column (Waters, Milford, Mass.), gradient elution of 60 MeCN in
water to 80 MeCN in water over a 30 min period, where both solvents
contain 0.1% TFA) provided the title compound (mixture of ether
epimers) as a white solid.
[1702] .sup.1H NMR (400 MHz, CDCl.sub.3, mixture of epimers)
.delta. ppm 8.90 (1H, br s, major epimer), 8.83 (1H, br s, minor
epimer), 7.20-7.27 (3H, m), 7.15-7.20 (1H, m), 7.11 (1H, dt, J=7.7
Hz, 1.9 Hz), 6.94-7.02 (2H, m), 6.71 (1H, d, J=7.6 Hz), 5.37 (1H,
t, J=10.0 Hz), 4.33 (1H, d, J=10.4 Hz), 2.67-2.79 (1H, m),
2.67-2.79 (1H, m, major epimer) 2.41 (1H, dd, J=15.2 Hz, 8.6 Hz,
minor epimer), 1.82-2.31 (6H, m), 1.48-1.61 (1H, m), 1.35-1.45 (1H,
m), 1.45 (3H, s, minor epimer), 1.44 (s, 3H, major epimer), 0.94
(3H, t, J=7.4 Hz), 0.52 (3H, t, J=7.5 Hz). Mass Spectrum (ESI)
m/z=517 (M+1), 539 (M+23).
Example 82
3-(((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-2-oxo-1-(pen-
tan-3-yl)piperidin-3-yl)methyl)-1,2,4-oxadiazol-5(4H)-one
##STR00237##
[1703] Step A.
2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-2-oxo-1-(pen-
tan-3-yl)piperidin-3-yl)acetamide
##STR00238##
[1705] To an ice-cooled solution of 1.15 g (2.49 mmol) of
2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-2-oxo-1-(pen-
tan-3-yl)piperidin-3-yl)acetic acid (Example 71, Step F) in THF
(12.5 mL) was added 383 .mu.L (3.48 mmol) of N-methylmorpholine and
392 .mu.L (2.98 mmol) of isobutyl chloroformate. The resulting
off-white slurry was stirred at 0.degree. C. for 2 h, and then 336
.mu.L (28% ammonia in water, 4.97 mmol) of ammonium hydroxide was
added. After an additional 3 h at 0.degree. C., the reaction was
quenched with saturated aqueous ammonium chloride and extracted
with EtOAc (3.times.). The combined organic layers were dried over
Na.sub.2SO.sub.4, filtered and the filtrate was concentrated. The
crude title compound was used directly in the next step.
Step B.
2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-2-oxo-
-1-(pentan-3-yl)piperidin-3-yl)acetonitrile
##STR00239##
[1707] To an ice-cooled solution of 1.15 g (2.49 mmol) of
2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-2-oxo-1-(pen-
tan-3-yl)piperidin-3-yl)acetamide (Example 82, Step A) in THF (21
mL) was added 1.73 mL (12.4 mmol) of triethylamine and 865 .mu.L
(6.22 mmol) of TFA. The resulting tan solution was stirred at
0.degree. C. for 2.75 h, then was warmed to room temperature and
stirred for an additional 2 h. The reaction was recooled to
0.degree. C., quenched with 1 N citric acid, and then extracted
with EtOAc (3.times.). The combined organic layers were dried over
Na.sub.2SO.sub.4, filtered and the filtrate was concentrated. The
combined organic layers were washed with saturated aqueous sodium
chloride (1.times.), then were dried over Na.sub.2SO.sub.4,
filtered and the filtrate was concentrated. Purification of the
residue by flash chromatography on silica gel (5 to 35%
EtOAc/hexanes, gradient elution) provided the title compound as a
white solid.
Step C.
2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-2-oxo-
-1-(pentan-3-yl)piperidin-3-yl)-N'-hydroxyacetimidamide
##STR00240##
[1709] To a suspension of 1.49 g (20.6 mmol) of hydroxylamine
hydrochloride in DMSO (10 mL) was added 2.88 mL (20.6 mmol) of
triethylamine. The slurry was stirred for 5 min and then filtered
twice through cotton, rinsing with THF, to remove the solids. The
filtrate was partially concentrated under reduced pressure to
remove THF, and then was added to a flask containing 915 mg (2.06
mmol) of
2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-2-oxo-1-(pen-
tan-3-yl)piperidin-3-yl)acetonitrile (Example 82, Step B). The
resulting yellow solution was heated at 75.degree. C. for 22 h, and
then was partitioned between water and EtOAc. The organic layer was
dried over Na.sub.2SO.sub.4, filtered and the filtrate was
concentrated. Purification of the residue by flash chromatography
on silica gel (1 to 7% MeOH/DCM, gradient elution) provided the
title compound as a white solid.
Step D.
3-(((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-2-ox-
o-1-(pentan-3-yl)piperidin-3-yl)methyl)-1,2,4-oxadiazol-5(4H)-one
##STR00241##
[1711] To a solution of 385 mg (0.81 mmol) of
2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-2-oxo-1-(pen-
tan-3-yl)piperidin-3-yl)-N'-hydroxyacetimidamide (Example 82, Step
C) in dioxane (12.5 mL) was added 211 .mu.L (1.41 mmol) of DBU and
262 mg (1.62 mmol) of 1,1'-carbonyldiimidazole. The resulting
colorless solution was heated at 100.degree. C. for 25 min, and
then was quenched with water and extracted with EtOAc. The organic
layer was washed with saturated aqueous sodium chloride, and then
was dried over Na.sub.2SO.sub.4, filtered and the filtrate was
concentrated. Purification of the residue by reversed phase prep.
HPLC (Sunfire.TM. Prep C.sub.18 OBD 10 .mu.m column (Waters,
Milford, Mass.), gradient elution of 55% MeCN in water to 80% MeCN
in water over a 35 min period, where both solvents contain 0.1%
TFA) provided the title compound as a white solid.
[1712] .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. ppm 10.39 (1H, br
s), 7.22-7.27 (3H, m), 7.18 (1H, d, J=8.1 Hz), 7.12 (1H, t, J=7.8
Hz), 6.87-6.98 (2H, m), 6.68 (1H, d, J=7.6 Hz), 4.35 (1H, d, J=10.3
Hz), 3.19 (1H, d, J=15.4 Hz), 3.05 (1H, ddd, J=13.3 Hz, 10.5 Hz,
2.6 Hz), 2.82 (1H, d, J=15.4 Hz), 2.69-2.78 (1H, m), 2.31 (1H, t,
J=13.8 Hz), 2.06 (1H, dd, J=13.9 Hz, 2.7 Hz), 1.84-2.00 (2H, m),
1.39-1.51 (2H, m), 1.38 (3H, s), 0.95 (3H, t, J=7.5 Hz), 0.50 (3H,
t, J=7.5 Hz). Mass Spectrum (ESI) m/z=502 (M+1), 524 (M+23).
Example 83
3-(((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-isopropyl-3-methyl--
2-oxopiperidin-3-yl)methyl)-1,2,4-oxadiazol-5(4H)-one
##STR00242##
[1714] The title compound was prepared by methods similar to those
described in Example 82. .sup.1H NMR (400 MHz, CDCl.sub.3) .delta.
ppm 10.38 (1H, br s), 7.24-7.32 (2H, m), 7.18-7.23 (m, 1H), 7.15
(1H, dt, J=7.8 Hz, 3.6 Hz), 7.04 (1H, br s), 6.90 (2H, d, J=5.4
Hz), 6.76 (1H, d, J=7.1 Hz), 4.52 (1H, dd, J=8.6 Hz, 3.2 Hz),
3.40-3.50 (1H, m), 3.09 (1H, dd, J=15.3 Hz, 2.8 Hz), 2.99-3.06 (1H,
m), 2.78 (1H, dd, J=15.3 Hz, 3.1 Hz), 2.18 (1H, dt, J=11.9 Hz, 3.2
Hz), 2.05-2.13 (1H, m), 1.22-1.27 (m, 9H). Mass Spectrum (ESI)
m/z=474 (M+1).
Example 84
##STR00243##
[1715]
3-(((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-2-oxo-
-1-(pentan-3-yl)piperidin-3-yl)methyl)-1,2,4-thiadiazol-5(4H)-one
[1716] To a solution of 83 mg (0.17 mmol) of
2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-2-oxo-1-(pen-
tan-3-yl)piperidin-3-yl)-N'-hydroxyacetimidamide (Example 82, Step
C) in THF (4 mL) was added 50 mg (0.28 mmol) of
1,1'-thiocarbonyldiimidazole. The resulting yellow solution was
stirred at room temperature for 1 h, and then was quenched with
water and extracted with EtOAc. The organic layer was dried over
Na.sub.2SO.sub.4, filtered and the filtrate was concentrated. The
residue was dissolved in THF (4.5 mL), and 69 .mu.L (0.56 mmol) of
boron trifluoride etherate was added via syringe. The resulting
light yellow solution was stirred at room temperature for 2.5 h,
and then was quenched with water and extracted with EtOAc. The
organic layer was dried over Na.sub.2SO.sub.4, filtered and the
filtrate was concentrated. Purification of the residue by reversed
phase prep. HPLC (Sunfire Prep C.sub.18 OBD 10 .mu.m column,
gradient elution of 55% MeCN in water to 85% MeCN in water over a
35 min period, where both solvents contain 0.1% TFA) provided the
title compound as a white solid.
[1717] .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. ppm 10.94 (1H, br
s), 7.20-7.27 (3H, m), 7.13-7.18 (1H, m), 7.09 (1H, t, J=7.7 Hz),
6.85-6.95 (2H, m), 6.66 (1H, d, J=7.6 Hz), 4.34 (1H, d, J=10.2 Hz),
3.09 (1H, d, J=14.8 Hz), 2.87-3.01 (2H, m), 2.68-2.77 (1H, m), 2.25
(1H, t, J=13.5 Hz), 2.04-2.13 (1H, m), 1.87-2.04 (2H, m), 1.39-1.51
(2H, m), 1.38 (3H, s), 0.95 (3H, t, J=7.4 Hz), 0.50 (3H, t, J=7.4
Hz). Mass Spectrum (ESI) m/z=518 (M+1), 540 (M+23).
Example 85
##STR00244##
[1718]
3-(((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-isopropyl-3--
methyl-2-oxopiperidin-3-yl)methyl)-1,2,4-thiadiazol-5(4H)-one
[1719] The title compound was prepared by methods similar to those
described in Example 84. .sup.1H NMR (400 MHz, CDCl.sub.3) .delta.
ppm 10.89 (1H, br s), 7.24-7.30 (2H, m), 7.18-7.22 (m, 1H), 7.15
(1H, t, J=7.8 Hz), 7.04 (1H, br s), 6.86 (2H, d, J=8.3 Hz), 6.77
(1H, d, J=7.8 Hz), 4.53 (1H, d, J=8.3 Hz), 3.41-3.50 (1H, m),
2.90-3.04 (3H, m), 2.05-2.19 (2H, m), 1.27 (6H, dd, J=6.6 Hz, 6.6
Hz), 1.23 (s, 3H). Mass Spectrum (ESI) m/z=490 (M+1), 512
(M+23).
Example 86
##STR00245##
[1720]
(3R,5R,6S)-3-((1H-Tetrazol-5-yl)methyl)-5-(3-chlorophenyl)-6-(4-chl-
orophenyl)-1-isopropyl-3-methylpiperidin-2-one
[1721] The title compound was prepared from
2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-isopropyl-3-methyl--
2-oxopiperidin-3-yl)acetic acid (Example 73) as described in
Example 51.
[1722] .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. ppm 1.20 (s, 3H),
1.27 (d, J=6.9 Hz, 3H), 1.29 (d, J=6.8 Hz, 3H), 2.20 (m, 2H), 3.08
(m, 1H), 3.41 (d, J=15.7 Hz, 1H), 3.47 (m, 1H), 3.50 (d, J=15.6 Hz,
1H), 4.52 (d, J=8.8 Hz, 1H), 6.78 (m, 3H), 7.06 (m, 1H), 7.16 (m,
1H), 7.23 (m, 3H). Mass spectrum (ESI) m/z 458.0 [M+H].sup.+.
Example 87
2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-ethyl-2-oxo-1-(penta-
n-3-yl)piperidin-3-yl)acetic acid
##STR00246##
[1723] Step A.
(5R,6S)-3-allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-ethyl-1-(pentan-3-
-yl)piperidin-2-one
##STR00247##
[1725] To a solution of
(3R,5R,6S)-3-allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)piperidin-2-one
(Example 42, Step A) (440 mg, 1.221 mmol) in 3-bromopentane (3196
.mu.L, 25.6 mmol) under nitrogen at rt was added a dispersion of
60% sodium hydride in mineral oil (244 mg, 6.11 mmol). Evolution of
gas was observed. The reaction was stirred at room temperature for
10 min and then heated to 120.degree. C. under N.sub.2 for 19 h.
The reaction mixture was cooled to room temperature and quenched
with sat. NH.sub.4Cl. The layers were separated and the organic
layer was dried over Na.sub.2SO.sub.4 and concentrated under
reduced pressure. The residue was purified by flash chromatography
on silica gel (eluent: 0 to 25% EtOAc in hexanes) to give the title
compound as a mixture of diastereomers.
Step B.
(5R,6S)-3-allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-ethyl-1-(p-
entan-3-yl)piperidin-2-one
##STR00248##
[1727] To
(5R,6S)-3-allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-(pentan--
3-yl)piperidin-2-one (Example 87, Step A) (125 mg, 0.290 mmol) was
added toluene (15 mL) and the mixture was concentrated under
reduced pressure. This step was repeated three times. Inhibitor
free THF (1 mL) was added and the mixture was cooled to -78.degree.
C. Freshly prepared LDA (1.0M in THF) (290 .mu.L, 0.290 mmol) was
added and the reaction turned a golden-yellow color. The reaction
was warmed to 0.degree. C. for 30 min and the reaction color turned
orange. The reaction was cooled to -78.degree. C. and ethyl iodide
(281 .mu.L, 3.49 mmol) was added. The reaction mixture was warmed
to 0.degree. C. and stirred for 30 min. The reaction was quenched
with sat. NH.sub.4Cl, warmed to room temperature, diluted with
EtOAc and the layers were separated. The organic layer was dried
over Na.sub.2SO.sub.4 and concentrated under reduced pressure. The
residue was purified by flash chromatography on silica gel (eluent:
0 to 10% EtOAc in hexanes) to give the title compound as a 1:1
mixture of diastereomers.
Step C.
2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-ethyl-2-oxo--
1-(pentan-3-yl)piperidin-3-yl)acetic acid
[1728] The title compound was prepared from
(5R,6S)-3-allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-ethyl-1-(pentan-3-
-yl)piperidin-2-one (Example 87, Step B) as described in Example
42, Step C. Purification by reversed phase preparatory HPLC
(eluent: 0 to 100% MeCN+0.1% TFA in water+0.1% TFA) provided the
title compound as the first eluting diastereomer.
[1729] .sup.1H NMR (500 MHz, CHLOROFORM-d) .delta. ppm 0.50 (3H, t,
J=7.5 Hz) 0.95 (3H, t, J=7.5 Hz) 1.00 (3H, t, J=7.5 Hz) 1.29-1.45
(2H, m) 1.45-1.53 (1H, m) 1.84-2.01 (4H, m) 2.30 (1H, t, J=13.8 Hz)
2.72-2.80 (2H, m) 3.03-3.11 (2H, m) 4.34 (1H, d, J=10.3 Hz) 6.69
(1H, d, J=7.6 Hz) 6.95 (2H, br s) 7.05-7.20 (2H, m) 7.08-7.17 (2H,
m) 7.22-7.25 (1H, m). Mass Spectrum (ESI) m/z=476 [M+H].sup.+.
Example 88
(3S,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-3-(methylsulfony-
lmethyl)-1-(pentan-3-yl)piperidin-2-one
##STR00249##
[1730] Step A. (5R,6S)-methyl
5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-(2,4-dimethoxybenzyl)-3-methyl-2--
oxopiperidine-3-carboxylate
##STR00250##
[1732] LHMDS (5.42 mL, 5.42 mmol) was added to a solution of
(5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-(2,4-dimethoxybenzyl)-3-m-
ethylpiperidin-2-one (Example 71, Step B) (1.75 g, 3.61 mmol) in
anhydrous THF (14.45 mL) at rt under argon. After 5 minutes
dimethyl dicarbonate (1.159 mL, 10.84 mmol) was added. After 4
hours TLC indicated that a significant amount of product had formed
but some starting material remained. Additional LHMDS (5.42 mL,
5.42 mmol) was added followed by dimethyl dicarbonate (1.159 mL,
10.84 mmol). After 2.5 hours the reaction was quenched by the
addition of sat. aq. NH.sub.4Cl and the layers were separated. The
aqueous layer was extracted with EtOAc twice and the organics were
pooled, washed with sat. aq. NaCl solution, dried (MgSO.sub.4),
filtered and concentrated in vacuo to provide a yellow oil.
Purification using a 120 g SiO.sub.2 column and eluting with 25 to
40% EtOAc/hexanes provided the title compound as a colorless oil as
a mixture of isomers.
Step B.
(5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-(2,4-dimethoxybenz-
yl)-3-(hydroxymethyl)-3-methylpiperidin-2-one
##STR00251##
[1734] 2M lithium borohydride (1.078 mL, 2.157 mmol) was added to a
solution of (5R,6S)-methyl
5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-(2,4-dimethoxybenzyl)-3-methyl-2--
oxopiperidine-3-carboxylate (Example 88, Step A) (1.17 g, 2.157
mmol) in anhydrous THF (21.57 mL) and anhydrous ether (20 mL) at
0.degree. C. under nitrogen. The reaction was quenched after 58
hours with the addition of sat. aq. NH.sub.4Cl and the layers were
separated. The aqueous layer was extracted with EtOAc twice and the
organics were pooled, washed with sat. aq. NaCl solution, dried
(MgSO.sub.4), filtered and concentrated in vacuo to provide a
colorless oil. Purification using a 80 g SiO.sub.2 column and
eluting with 35 to 65% EtOAc/hexanes provided the title compound as
a .about.30:1 mixture of isomers.
Step C.
((5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-(2,4-dimethoxyben-
zyl)-3-methyl-2-oxopiperidin-3-yl)methyl
4-methylbenzenesulfonate
##STR00252##
[1736] DMAP (0.015 g, 0.120 mmol) was added to a solution of
(5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-(2,4-dimethoxybenzyl)-3-(-
hydroxymethyl)-3-methylpiperidin-2-one (Example 88, Step B) (0.616
g, 1.197 mmol) and tosyl-Cl (0.457 g, 2.395 mmol) in pyridine (5.99
mL) at rt. The reaction mixture was heated at 100.degree. C. for 5
hours before removing the solvent in vacuo to provide a beige oil.
Purification using a 80 g SiO.sub.2 column and eluting with 25 to
55% EtOAc/hexanes provided the title compound as a colorless oil as
a 33:1 mixture of isomers.
Step D.
(3S,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-(2,4-dimethoxyb-
enzyl)-3-methyl-3-(methylthiomethyl)piperidin-2-one
##STR00253##
[1738] Sodium thiomethoxide (0.193 g, 2.76 mmol) was added to a
solution of
((5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-(2,4-dimethoxybenzyl)-
-3-methyl-2-oxopiperidin-3-yl)methyl 4-methylbenzenesulfonate
(Example 88, Step C) (0.738 g, 1.104 mmol) in anhydrous DMF (5.52
mL) at rt under nitrogen. The reaction mixture was heated at
50.degree. C. for 8 hours before being cooled to rt, diluted with
water and extracted with ether three times. The organics were
pooled, washed with water three times, sat. aq. NaCl solution,
dried (MgSO.sub.4), filtered and concentrated in vacuo to provide a
colorless oil. Purification using a 40 g SiO.sub.2 column and
eluting with 15 to 40% EtOAc/hexanes provided the title compound as
a colorless foam.
Step E.
(3S,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-3-(methy-
lthiomethyl)piperidin-2-one
##STR00254##
[1740] A solution of
(3S,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-(2,4-dimethoxybenzyl)--
3-methyl-3-(methylthiomethyl)piperidin-2-one (Example 88, Step D)
(0.406 g, 0.746 mmol) in TFA (6.00 mL) was heated at 50.degree. C.
under nitrogen for 2 hours. The reaction mixture was concentrated
in vacuo to provide a purple oil. Purification using a 40 g
SiO.sub.2 column and eluting with 35 to 60% EtOAc/hexanes provided
the title compound as a white solid.
Step F.
(3S,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-3-(methy-
lthiomethyl)-1-(pentan-3-yl)piperidin-2-one
##STR00255##
[1742] NaH (0.076 g, 1.900 mmol) was added to a solution of
(3S,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-3-(methylthiome-
thyl)piperidin-2-one (Example 88, step E) (0.150 g, 0.380 mmol) in
3-bromopentane (1.42 mL, 11.41 mmol) at rt under nitrogen. The
reaction mixture was heated at 120.degree. C. for 24 hours, cooled
to rt, diluted with water and extracted with DCM three times. The
organics were pooled, washed with sat. aq. NaCl solution, dried
(MgSO.sub.4), filtered and concentrated in vacuo to provide a
yellow oil. Purification using a 24 g SiO.sub.2 column and eluting
with 15% EtOAc/hexanes provided the title compound as a colorless
syrup.
Step G.
(3S,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-3-(methy-
lsulfonylmethyl)-1-(pentan-3-yl)piperidin-2-one
##STR00256##
[1744] 3-Chloroperbenzoic acid (0.054 g, 0.242 mmol) was added to a
solution of
(3S,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-3-(methylthiome-
thyl)-1-(pentan-3-yl)piperidin-2-one (Example 88, Step F) (0.045 g,
0.097 mmol) in DCM (0.969 mL) at 0.degree. C. The reaction mixture
was stirred at rt for 1 hour, washed with sat. NaHCO.sub.3, sat.
aq. NaCl solution, dried (MgSO.sub.4), filtered and concentrated in
vacuo to provide a colorless oil. Purification using a 4 g
SiO.sub.2 ISCO column and eluting with 25 to 75% EtOAc/hexanes
provided the title compound as a colorless glass.
[1745] .sup.1H NMR (500 MHz, CDCl.sub.3) .delta. ppm 0.49 (t, J=7.6
Hz, 3H), 0.95 (t, J=7.5 Hz, 3H), 1.39 (m, 1H), 1.54 (s, 3H), 1.56
(m, 1H), 1.89 (m, 2H), 2.10 (m, 1H), 2.57 (dd, J=14.4 and 3.1 Hz,
1H), 2.72 (m, 1H), 3.05 (s, 3H), 3.24 (d, J=13.9 Hz, 1H), 3.63 (m,
1H), 3.82 (d, J=13.9 Hz, 1H), 4.40 (d, J=10.7 Hz, 1H), 6.78 (m,
1H), 7.02 (br s, 1H), 7.06 (m, 2H), 7.10 (m, 2H), 7.20 (m, 2H).
Mass spectrum (ESI) m/z 496.2 [M+H].sup.+.
Example 89
2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-(3-cyclopropy-
l-1,2,4-oxadiazol-5-yl)propyl)-3-methyl-2-oxopiperidin-3-yl)acetic
acid
##STR00257##
[1746] Step A.
2-((3S,5R,6S)-3-allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-2-ox-
opiperidin-1-yl)butanoic acid
##STR00258##
[1748] LiOH (0.267 g, 11.13 mmol) in water (2.6 mL) was added to a
solution of methyl
2-((3S,5R,6S)-3-allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-2-ox-
opiperidin-1-yl)butanoate (Example 65, Step B) (0.528 g, 1.113
mmol) in MeOH (7.5 mL) at rt. The reaction mixture was heated at
80.degree. C. for 14 hours, cooled to rt and acidified to pH=1 with
3M HCl. The mixture was extracted with EtOAc three times and the
organics were pooled, washed with sat. aq. NaCl solution, dried
(MgSO.sub.4), filtered and concentrated in vacuo to provide a white
solid. Purification using a 40 g SiO.sub.2 column and eluting with
35-60% EtOAc/hexanes provided the title compound as a mixture of
isomers.
Step B.
N'-(2-((3S,5R,6S)-3-allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3--
methyl-2-oxopiperidin-1-yl)butanoyloxy)cyclopropanecarboximidamide
##STR00259##
[1750] 1,1'-Carbonyldiimidazole (0.104 g, 0.639 mmol) was added to
a solution of
2-((3S,5R,6S)-3-allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-2-ox-
opiperidin-1-yl)butanoic acid (Example 89, Step A) (0.196 g, 0.426
mmol) in dichloromethane (1.703 mL) at rt and stirred for 22 hours
before adding n-hydroxycyclopropanecarboxamidine (0.064 g, 0.639
mmol). After 6 hours the reaction mixture was adsorbed onto silica
and purified using a 12 g SiO.sub.2 ISCO column and eluting with 35
to 60% EtOAc/hexanes to provide a 2:1 mixture of isomers.
Step C.
(3S,5R,6S)-3-allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1--
(3-cyclopropyl-1,2,4-oxadiazol-5-yl)propyl)-3-methylpiperidin-2-one
and
(3S,5R,6S)-3-allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((R)-1-(3-cycl-
opropyl-1,2,4-oxadiazol-5-yl)propyl)-3-methylpiperidin-2-one
##STR00260##
[1752] A solution of tetrabutylammonium fluoride (1.0M in THF,
1.880 mL, 1.880 mmol) was added to a solution of
N'-(2-((3S,5R,6S)-3-allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl--
2-oxopiperidin-1-yl)butanoyloxy)cyclopropanecarboximidamide
(Example 89, Step B) (0.204 g, 0.376 mmol) in THF (3.76 mL) at rt.
After 2 hours the reaction mixture was concentrated in vacuo and
purified using a 24 g SiO.sub.2 column eluting with 25%
Et.sub.2O/hexames to provide
(3S,5R,6S)-3-allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-(3-cycl-
opropyl-1,2,4-oxadiazol-5-yl)propyl)-3-methylpiperidin-2-one.
[1753] Further elution provided
(3S,5R,6S)-3-allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((R)-1-(3-cycl-
opropyl-1,2,4-oxadiazol-5-yl)propyl)-3-methylpiperidin-2-one.
Step D.
2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-(3-cy-
clopropyl-1,2,4-oxadiazol-5-yl)propyl)-3-methyl-2-oxopiperidin-3-yl)acetic
acid
##STR00261##
[1755] The title compound was prepared from
(3S,5R,6S)-3-allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-(3-cycl-
opropyl-1,2,4-oxadiazol-5-yl)propyl)-3-methylpiperidin-2-one
(Example 89, Step C), as described in Example 42 Step C.
Purification using a 4 g SiO.sub.2 column and eluting with 35 to
100% EtOAc/hexanes provided the title compound as a colorless
film.
[1756] .sup.1H NMR (500 MHz, CDCl.sub.3) .delta. ppm 0.84 (t, J=7.5
Hz, 3H), 0.89 (m, 2H), 1.01 (m, 2H), 1.25 (m, 1H), 1.43 (s, 3H),
1.95 (m, 1H), 1.98 (m, 1H), 2.20 (m, 2H), 2.37 (m, 1H), 2.90 (m,
2H), 3.26 (m, 1H), 4.60 (t, J=6.9 Hz, 1H), 4.63 (d, J=10.3 Hz, 1H),
6.76 (m, 1H), 6.90 (m, 2H), 7.00 (br s, 1H), 7.10 (t, J=7.9 Hz,
1H), 7.16 (m, 3H). Mass spectrum (ESI) m/z 542.2 [M+H].sup.+.
Example 90
2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((R)-1-(3-cyclopropy-
l-1,2,4-oxadiazol-5-yl)propyl)-3-methyl-2-oxopiperidin-3-yl)acetic
acid
##STR00262##
[1758] The title compound was prepared from
(3S,5R,6S)-3-allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((R)-1-(3-cycl-
opropyl-1,2,4-oxadiazol-5-yl)propyl)-3-methylpiperidin-2-one
(Example 89, Step C) as described in Example 42, Step C.
[1759] .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. ppm 0.85-1.05 (m,
3H) 1.09 (t, J=7.6 Hz, 3H), 1.44 (s, 3H), 2.01 (m, 1H), 2.19 (m,
1H), 2.26 (m, 3H), 2.83 (d, J=14.7 Hz, 1H), 2.91 (d, J=14.7 Hz,
2H), 3.32 (m, 1H), 3.95 (t, J=7.2 Hz, 1H), 4.57 (d, J=10.4 Hz, 1H),
6.73 (m, 1H), 6.98 (m, 1H), 7.09 (t, J=7.8 Hz, 1H), 7.16 (m, 2H),
7.20 (m, 3H). Mass spectrum (ESI) m/z 542.2 [M+H].sup.+.
Example 91
2-((3R,5R,6S)-5-(3-Chlorophenyl)-6-(4-chlorophenyl)-3-methyl-1-((S)-1-morp-
holinobutan-2-yl)-2-oxopiperidin-3-yl)acetic acid
##STR00263##
[1760] Step A. (S)-Methyl
2-((3S,5R,6S)-3-allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-2-ox-
opiperidin-1-yl)butanoate
##STR00264##
[1762] To a solution of
(3S,5R,6S)-3-allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methylpiperidi-
n-2-one (Example 71, Step D) (4.00 g, 10.7 mmol) in 45 mL of DMF
was added a dispersion of 60% sodium hydride in mineral oil (1.71
g, 42.7 mmol) at 0.degree. C. After being stirred for 20 min,
methyl 2-bromobutanoate (6.15 mL, 53.4 mmol) was added at 0.degree.
C. and the resulting solution was stirred at 25.degree. C. for 12 h
until completion of the reaction. Then sat. aq. NH.sub.4Cl solution
was added and the mixture was extracted with ethyl acetate. The
combined organic layers were washed with water and sat. aq. NaCl
solution, dried over Na.sub.2SO.sub.4, filtered and the filtrate
was concentrated under reduced pressure. Purification of the
residue by flash chromatography on silica gel (eluent: 0 to 100%
MTBE/hexanes, gradient elution), followed by separation of
individual stereoisomers by chiral SFC (flowrate: 65 mL/min on a
ChiralPak.RTM. AD-H column (Diacel Inc., Fort Lee, N.J.) using 3:1
heptanes/IPA (0.1% DEA)/CO.sub.2 as the eluent) provided the title
compound as the faster eluting isomer.
[1763] .sup.1H NMR (400 MHz, CHLOROFORM-d) .delta. ppm 7.23 (2H, d,
J=8.4 Hz), 7.06-7.17 (2H, m), 7.00 (3H, t, J=1.8 Hz), 6.77 (1H, d,
J=7.6 Hz), 5.79-5.94 (1H, m), 5.20 (1H, d, J=4.7 Hz), 5.17 (1H, s),
4.56 (1H, d, J=10.8 Hz), 3.73 (3H, s), 3.25-3.37 (1H, m), 3.18 (1H,
dd, J=7.6 Hz, 4.9 Hz), 2.61 (2H, d, J=7.4 Hz), 2.20-2.34 (1H, m),
2.09-2.19 (1H, m), 1.99 (1H, d, J=3.1 Hz), 1.57-1.72 (1H, m), 1.24
(3H, s), 0.61 (3H, t, J=7.5 Hz); Mass Spectrum (ESI) m/z=474.1
[M+H].sup.+.
[1764] Further Elution Provided:
(R)-Methyl
2-((3S,5R,6S)-3-allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-m-
ethyl-2-oxopiperidin-1-yl)butanoate
##STR00265##
[1765] as the slower eluting isomer.
[1766] .sup.1H NMR (400 MHz, CHLOROFORM-d) .delta. ppm 7.22 (2H, d,
J=8.0 Hz), 6.99-7.19 (4H, m), 6.95 (1H, t, J=1.8 Hz), 6.71 (1H, d,
J=7.6 Hz), 5.81-5.95 (1H, m), 5.19 (1H, d, J=2.7 Hz), 5.16 (1H, d,
J=1.0 Hz), 4.48 (1H, d, J=10.6 Hz), 3.67 (3H, s), 3.24-3.32 (1H,
m), 3.20 (1H, dd, J=7.8 Hz, 6.1 Hz), 2.61-2.72 (1H, m), 2.49-2.60
(1H, m), 1.91-2.21 (4H, m), 1.27 (3H, s), 1.00 (3H, t, J=7.5 Hz);
MS (ESI) m/z=474.1 [M+H].sup.+.
Step B.
(3S,5R,6S)-3-Allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((R)-1--
hydroxybutan-2-yl)-3-methylpiperidin-2-one
##STR00266##
[1768] To a solution of (S)-methyl
2-((3S,5R,6S)-3-allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-2-ox-
opiperidin-1-yl)butanoate and (R)-methyl
2-((3S,5R,6S)-3-allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-2-ox-
opiperidin-1-yl)butanoate (1.73 g, 3.64 mmol) (mixture of
stereoisomers from Example 91, Step A) in 27 mL of Et.sub.2O and 9
mL of THF was added a solution of lithium tetrahydroborate in THF
(0.238 mL, 7.28 mmol) at 0.degree. C. The resulting solution was
stirred at 25.degree. C. for 2 h. The reaction was quenched (10%
citric acid), extracted (2.times.EtOAc) and washed (1.times.Sat.
aq. NaCl solution). The combined organic layers were washed with
sat. aq. NaCl solution, dried over Na.sub.2SO.sub.4, filtered and
the filtrate was concentrated under reduced pressure. The residue
was purified by flash chromatography on silica gel (eluent: 0-60%
EtOAc in hexanes) to give the title compound as the faster eluting
isomer.
[1769] .sup.1H NMR (400 MHz, CHLOROFORM-d) .delta. ppm 0.99 (t,
J=7.4 Hz, 3H), 1.29 (s, 3H), 1.79-2.03 (m, 4H), 2.62 (d, J=7.4 Hz,
2H), 2.80-2.85 (m, 1H), 3.05-3.16 (m, 1H), 3.40-3.49 (m, 2H), 4.33
(d, J=10.4 Hz, 1H), 5.13-5.22 (m, 2H), 5.79-5.95 (m, 1H), 6.7 (d,
J=7.6 Hz, 1H), 6.85-6.97 (m, 3H), 7.08-7.15 (m, 1H), 7.17-7.19 (m,
1H), 7.23 (d, J=8.6 Hz, 2H); Mass Spectrum (ESI) m/z=446 (M+1).
[1770] Further Elution Provided:
(3S,5R,6S)-3-Allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-hydroxyb-
utan-2-yl)-3-methylpiperidin-2-one
##STR00267##
[1771] as the slower eluting isomer.
[1772] .sup.1H NMR (400 MHz, CHLOROFORM-d) .delta. ppm 0.68 (t,
J=7.5 Hz, 3H), 1.27 (s, 3H), 1.38-1.52 (m, 1H), 1.90-2.08 (m, 4H),
2.61 (d, J=7.4 Hz, 2H), 3.10-3.25 (m, 2H), 3.59-3.68 (m, 2H), 4.46
(d, J=10.2 Hz, 1H), 5.18 (dd, J=13.7, 1.8 Hz, 2H), 5.79-5.93 (m,
1H), 6.72 (d, J=7.6 Hz, 1H), 6.93-7.04 (m, 2H), 7.09-7.13 (m, 1H),
7.15-7.20 (m, 1H), 7.24 (d, J=8.6 Hz, 2H); Mass Spectrum (ESI)
m/z=446 (M+1).
Step C.
(S)-2-((3S,5R,6S)-3-Allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3--
methyl-2-oxopiperidin-1-yl)butanal
##STR00268##
[1774] To a solution of 218 mg (0.49 mmol) of
(3S,5R,6S)-3-allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-hydroxy-
butan-2-yl)-3-methylpiperidin-2-one (Example 91, Step B) in a
mixture of water (13.20 .mu.L, 0.733 mmol) and DCM (4883 .mu.L) was
added 1,1,1,-tris(acetoxy)-1,1-dihydro-1,2-benziodoxol-3-(1H)one
("Dess Martin periodinane") (311 mg, 0.733 mmol) at ambient
temperature. The reaction was monitored by LCMS, and several small
portions of additional periodinane were added until the reaction
was complete. The reaction was quenched (2 mL, 1 M
Na.sub.2S.sub.2O.sub.3), extracted (2.times.DCM), and the combined
organic layers were washed with sat. NaHCO.sub.3 solution
(2.times.), sat NaCl solution, dried over Na.sub.2SO.sub.4,
filtered and the filtrate was concentrated under reduced pressure.
Purification of the residue by flash chromatography on silica gel
(eluent: 20 to 35% EtOAc/hexanes, gradient elution) provided the
title compound.
Step D.
(3S,5R,6S)-3Allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-1-
-((S)-1-morpholinobutan-2-yl)piperidin-2-one
##STR00269##
[1776] To a solution of 100 mg (0.225 mmol) of
(S)-2-((3S,5R,6S)-3-allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl--
2-oxopiperidin-1-yl)butanal (Example 91, Step C) in DCE (2420
.mu.L) was added morpholine (200 .mu.L, 2.297 mmol), acetic acid
(1.288 .mu.L, 0.023 mmol) and sodium triacetoxyborohydride (95 mg,
0.450 mmol). The reaction mixture was stirred at room temperature
for 18 hours. The reaction was quenched with sat. sodium
bicarbonate solution and extracted with DCM (2.times.10 mL). The
combined organic layers were washed with sat NaCl solution, dried
over Na.sub.2SO.sub.4, filtered and the filtrate was concentrated
under reduced pressure to afford the crude title compound as an
oil.
Step E.
2-((3R,5R,6S)-5-(3-Chlorophenyl)-6-(4-chlorophenyl)-3-methyl-1-((S-
)-1-morpholinobutan-2-yl)-2-oxopiperidin-3-yl)acetaldehyde
##STR00270##
[1778] To a round-bottomed flask charged with
(3S,5R,6S)-3-allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-1-((S)--
1-morpholinobutan-2-yl)piperidin-2-one (Example 91, Step D) (125
mg, 0.242 mmol) was added THF (2 mL). Approximately 1 mL water was
added dropwise until the solution became and remained cloudy with
gentle stirring. t-BuOH (0.350 mL) was added dropwise until the
solution became homogeneous. NMO (42.6 mg, 0.364 mmol) was added
followed by osmium tetroxide, 4 wt. %, in water (1 drop from glass
Pasteur pipette). The reaction mixture was stirred at room
temperature for 16 hours. An additional drop of osmium tetroxide, 4
wt. %, in water was added. After 5 hours, two additional drops of
osmium tetroxide, 4 wt. %, in water were added and the reaction
mixture was stirred at room temperature for an additional 16 hours.
Sodium periodate (145 mg, 0.679 mmol) was added and the reaction
mixture was stirred at room temperature for 2 hours. The reaction
mixture was diluted with ethyl acetate (10 mL) and water (10 mL)
and filtered. The aqueous layer of the filtrate was extracted with
additional ethyl acetate (10 mL) and the combined organic layers
were washed with sat. aq. NaCl solution, dried over sodium sulfate,
filtered and the filtrate was concentrated under reduced pressure
to provide the title compound.
Step F.
2-((3R,5R,6S)-5-(3-Chlorophenyl)-6-(4-chlorophenyl)-3-methyl-1-((S-
)-1-morpholinobutan-2-yl)-2-oxopiperidin-3-yl)acetic acid
##STR00271##
[1780] To a solution of
2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-1-((S)-1-mor-
pholinobutan-2-yl)-2-oxopiperidin-3-yl)acetaldehyde (Example 91,
Step E) (125 mg, 0.242 mmol) in acetone (2 mL) was added 3 mL of a
mixture of CrO.sub.3 in water (2 mL) and concentrated
H.sub.2SO.sub.4 (1 ml). The reaction mixture was stirred at room
temperature for 2 hours and then diluted with water (10 mL) and
ethyl acetate (10 mL) and the layers were separated. The aqueous
layer was extracted with additional ethyl acetate (10 mL). The
combined organic layers were concentrated under reduced pressure.
The residue was purified by reversed phase preparatory HPLC
(column: Gemini-NX C.sub.18 5 um column; Phenomonex, Torrance,
Calif.; eluent: 0 to 100% MeCN+0.1% TFA in water+0.1% TFA) to
provide the title compound.
[1781] .sup.1H NMR (400 MHz, CHLOROFORM-d) .delta. ppm 0.57 (t,
J=7.53 Hz, 1H) 1.26 (s, 1H) 1.39 (s, 3H) 1.54-1.70 (m, 1H)
1.72-1.89 (m, 1H) 2.02-2.27 (m, 3H) 2.49 (br. s., 2H) 2.69 (br. s.,
2H) 2.82 (m, 2H) 3.02 (br. s., 2H) 3.13-3.30 (m, 2H) 3.74-3.93 (m,
4H) 4.47-4.72 (m, 1H) 6.75 (d, J=7.82 Hz, 1H) 6.96 (t, J=1.86 Hz,
1H) 7.01 (br. s., 1H) 7.04-7.17 (m, 3H) 7.22 (d, J=8.41 Hz, 2H).
Mass Spectrum (ESI) m/z=533 [M+H].sup.+.
[1782] Examples 92-94 were prepared from
(3S,5R,6S)-3-allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-cyclopr-
opyl-2-hydroxyethyl)piperidin-2-one by procedures similar to those
described in Example 91, substituting morpholine in step D for the
appropriate amount of amine
TABLE-US-00006 ##STR00272## Example R = 92 ##STR00273## 93
##STR00274## 94 ##STR00275##
Example 92
2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-2-oxo-1-((S)--
1-(2,2,2-trifluoroethylamino)butan-2-yl)piperidin-3-yl)acetic
acid
[1783] .sup.1H NMR (400 MHz, CHLOROFORM-d) .delta. ppm 0.56 (t,
J=7.43 Hz, 3H) 1.23-1.35 (m, 1H) 1.44 (s, 3H) 1.48-1.65 (m, 2H)
1.77-1.91 (m, 1H) 2.02-2.11 (m, 1H) 2.13-2.25 (m, 1H) 2.59-2.71 (m,
1H) 2.73-2.84 (m, 1H) 2.90-3.24 (m, 5H) 4.60 (d, J=10.17 Hz, 1H)
6.69-6.77 (m, 1H) 6.91-7.05 (m, 3H) 7.06-7.13 (m, 1H) 7.13-7.18 (m,
1H) 7.23 (d, J=8.22 Hz, 2H). Mass Spectrum (ESI) m/z=545
[M+H].sup.+.
Example 93
2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-(2,2-dimethyl-
morpholino)butan-2-yl)-3-methyl-2-oxopiperidin-3-yl)acetic acid
[1784] .sup.1H NMR (400 MHz, CHLOROFORM-d) .delta. ppm 0.49 (t,
J=7.34 Hz, 3H) 1.21-1.30 (m, 4H) 1.34 (s, 3H) 1.37 (s, 3H) 1.42 (s,
3H) 1.51-1.68 (m, 1H) 1.86 (dd, J=14.48 and 7.24 Hz, 1H) 2.08-2.22
(m, 2H) 2.30 (br. s., 1H) 2.35-2.48 (m, 2H) 2.74-2.84 (m, 1H)
2.86-2.94 (m, 1H) 3.00-3.22 (m, 2H) 3.68-3.91 (m, 2H) 4.57 (d,
J=10.37 Hz, 1H) 6.68 (d, J=7.63 Hz, 1H) 6.91-7.00 (m, 2H) 7.03-7.11
(m, 1H) 7.14 (d, J=7.24 Hz, 2H) 7.23 (d, J=7.43 Hz, 2H). Mass
Spectrum (ESI) m/z=561 [M+H].sup.+.
Example 94
2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((2S)-1-(2,6-dimethy-
lmorpholino)butan-2-yl)-3-methyl-2-oxopiperidin-3-yl)acetic
acid
[1785] The crude product was purified by reversed phase preparatory
HPLC (column: Gemini-NX C.sub.18 5 um column; Phenomonex, Torrance,
Calif.; eluent: 0 to 100% MeCN+0.1% TFA in water+0.1% TFA) to
provide a 4:1 ratio of diastereomers of undetermined configuration
at the positions indicated by *.
[1786] .sup.1H NMR (400 MHz, CHLOROFORM-d) .delta. ppm 1.02 (br.
s., 1H) 1.24 (d, J=6.06 Hz, 6H) 1.35-1.49 (m, 4H) 2.02-2.44 (m, 4H)
2.68 (s, 1H) 2.79-2.89 (m, 2H) 3.20-3.32 (m, 2H) 3.37-3.49 (m, 1H)
3.80-4.00 (m, 2H) 4.10 (br. s., 3H) 4.23-4.34 (m, 1H) 4.41-4.58 (m,
1H) 4.91-5.10 (m, 1H) 6.89-6.98 (m, 2H) 6.99-7.15 (m, 4H) 7.20-7.30
(m, 2H). Mass Spectrum (ESI) m/z=561 [M+H].sup.+.
Example 95
2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-(4-(cycloprop-
ylsulfonyl)piperazin-1-yl)butan-2-yl)-3-methyl-2-oxopiperidin-3-yl)acetic
acid
##STR00276##
[1787] Step A. tert-butyl
4-((S)-2-((3S,5R,6S)-3-allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-meth-
yl-2-oxopiperidin-1-yl)butyl)piperazine-1-carboxylate
##STR00277##
[1789] The title compound was prepared from
(S)-2-((3S,5R,6S)-3-allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl--
2-oxopiperidin-1-yl)butanal (Example 91, Step C) and tert-butyl
piperazine-1-carboxylate according to the procedure described in
Example 91 Step D.
Step B.
(3S,5R,6S)-3-allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl--
1-((S)-1-(piperazin-1-yl)butan-2-yl)piperidin-2-one
##STR00278##
[1791] To a solution of tert-butyl
4-((S)-2-((3S,5R,6S)-3-allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-meth-
yl-2-oxopiperidin-1-yl)butyl)piperazine-1-carboxylate (Example 95,
Step A) (187 mg, 0.304 mmol in DCM (2.4 mL) was added TFA (600
.mu.L, 7.79 mmol). The reaction mixture was stirred at room
temperature for 16 hours before concentrating under reduced
pressure. The residue was taken up in DCM (15 mL) and washed with
sat. sodium bicarbonate solution (10 mL) and saturated sodium
chloride solution (10 mL). The organic layer was dried over sodium
sulfate, filtered and the filtrate concentrated under reduced
pressure to afford the title compound as a white foam.
Step C.
(3S,5R,6S)-3-allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1--
(4-(cyclopropylsulfonyl)piperazin-1-yl)butan-2-yl)-3-methylpiperidin-2-one
##STR00279##
[1793] To a solution of
(3S,5R,6S)-3-allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-1-((S)--
1-(piperazin-1-yl)butan-2-yl)piperidin-2-one (Example 95, Step B)
(60 mg, 0.117 mmol) in DCE (1.2 mL) was added cyclopropanesulfonyl
chloride (23.76 .mu.L, 0.233 mmol) followed by
diisopropylethylamine (40.6 .mu.L, 0.233 mmol). The reaction
mixture was stirred at room temperature for 16 hours, diluted with
water (10 mL) and the layers were separated. The aqueous layer was
extracted with DCM (2.times.10 mL). The combined organic layers
were washed with saturated NaCl solution (10 mL), dried over sodium
sulfate, filtered, and the filtrate concentrated under reduced
pressure to afford the title compound as a solid.
Step D.
2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-(4-(c-
yclopropylsulfonyl)piperazin-1-yl)butan-2-yl)-3-methyl-2-oxopiperidin-3-yl-
)acetic acid
[1794] To a 10 mL round-bottomed flask charged with
(3S,5R,6S)-3-allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-(4-(cyc-
lopropylsulfonyl)piperazin-1-yl)butan-2-yl)-3-methylpiperidin-2-one
(Example 23, Step C) (85.1 mg, 0.138 mmol) was added THF
(.about.800 uL) followed by water (.about.600 uL, until the
reaction remains cloudy with gentle stirring) followed by tBuOH
(.about.200 uL, until the reaction becomes translucent). NMO (24.17
mg, 0.206 mmol) was added followed by 5 drops of osmium tetroxide,
4 wt. %, in water (33.6 .mu.L, 0.138 mmol) via pasteur pipette. The
reaction was stirred at rt over night before adding Jones reagent
(0.154 mL). The reaction was stirred at room temperature for 2
hours, diluted with water (15 mL) and extracted with ethyl acetate
(3.times.15 mL). The combined organic layers are washed with water
(3.times.20 mL), saturated sodium chloride solution (20 mL), dried
over sodium sulfate, filtered and the filtrate concentrated under
reduced pressure. The residue was purified by reversed phase
preparatory HPLC (column: Gemini-NX C.sub.18 5 um column;
Phenomonex, Torrance, Calif.; eluent: 0 to 100% MeCN+0.1% TFA in
water+0.1% TFA, over 20 minutes) to give the title compound.
[1795] .sup.1H NMR (400 MHz, CHLOROFORM-d) .delta. ppm 0.92-1.25
(m, 10H) 1.43 (s, 3H) 1.85 (br. s., 1H) 2.08 (d, J=13.50 Hz, 1H)
2.16-2.30 (m, 1H) 2.40 (d, J=5.87 Hz, 2H) 2.52 (br. s., 2H)
2.69-2.79 (m, 2H) 2.79-2.92 (m, 2H) 3.21-3.34 (m, 2H) 3.83 (br. s.,
3H) 4.51 (br. s., 1H) 6.67 (br. s., 1H) 6.91-7.01 (m, 2H) 7.03-7.09
(m, 2H) 7.11-7.18 (m, 3H). Mass Spectrum (ESI) m/z=636
[M+H].sup.+.
Example 96
2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-1-((S)-1-(4-(-
methylsulfonyl)piperazin-1-yl)butan-2-yl)-2-oxopiperidin-3-yl)acetic
acid
##STR00280##
[1797] The title compound was prepared from
(3S,5R,6S)-3-allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-1-((S)--
1-(piperazin-1-yl)butan-2-yl)piperidin-2-one (Example 95, Step B)
and methanesulfonyl chloride as described in Example 95, Steps C
and D.
[1798] .sup.1H NMR (400 MHz, CHLOROFORM-d) .delta. ppm 1.04 (br.
s., 3H) 1.42 (s, 3H) 1.85 (br. s., 2H) 2.00-2.13 (m, 1H) 2.14-2.28
(m, 1H) 2.56 (br. s., 3H) 2.66-2.77 (m, 3H) 2.85 (d, J=14.48 Hz,
2H) 2.90-2.99 (m, 3H) 3.27 (t, J=10.27 Hz, 3H) 3.80 (br. s., 3H)
4.51 (br. s., 1H) 6.63-6.71 (m, 1H) 6.97 (s, 2H) 7.03-7.10 (m, 2H)
7.11-7.17 (m, 3H). Mass Spectrum (ESI) m/z=610 [M+H].sup.+.
Example 97
2-((3R,5R,6S)-1-((S)-1-(4-acetylpiperazin-1-yl)butan-2-yl)-5-(3-chlorophen-
yl)-6-(4-chlorophenyl)-3-methyl-2-oxopiperidin-3-yl)acetic acid
##STR00281##
[1799] Step A.
(3S,5R,6S)-1-((S)-1-(4-acetylpiperazin-1-yl)butan-2-yl)-3-allyl-5-(3-chlo-
rophenyl)-6-(4-chlorophenyl)-3-methylpiperidin-2-one
##STR00282##
[1801] To a solution of
(3S,5R,6S)-3-allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-1-((S)--
1-(piperazin-1-yl)butan-2-yl)piperidin-2-one (Example 95, Step B)
(80 mg, 0.155 mmol) in DCE (1.5 mL) was added acetyl chloride (22.1
.mu.L, 0.31 mmol) followed by diisopropylethylamine (54.1 .mu.L,
0.311 mmol). The reaction mixture was stirred at room temperature
for 16 hours and then concentrated under reduced pressure to
provide the title compound.
Step B.
2-((3R,5R,6S)-1-((S)-1-(4-acetylpiperazin-1-yl)butan-2-yl)-5-(3-ch-
lorophenyl)-6-(4-chlorophenyl)-3-methyl-2-oxopiperidin-3-yl)acetic
acid
[1802] The title compound was prepared from
(3S,5R,6S)-1-((S)-1-(4-acetylpiperazin-1-yl)butan-2-yl)-3-allyl-5-(3-chlo-
rophenyl)-6-(4-chlorophenyl)-3-methylpiperidin-2-one
[1803] (Example 97, Step A) as described in Example 95, Step D. The
residue was purified by reversed phase preparatory HPLC (column:
Gemini-NX C.sub.18 5 um column; Phenomonex, Torrance, Calif.;
eluent: 0 to 100% MeCN+0.1% TFA in water+0.1% TFA, over 20 minutes)
to give the title compound.
[1804] .sup.1H NMR (400 MHz, CHLOROFORM-d) .delta. ppm 0.94-1.18
(m, 3H) 1.42 (s, 3H) 1.77-1.98 (m, 1H) 2.12 (s, 4H) 2.23 (s, 2H)
2.48-2.63 (m, 3H) 2.67 (s, 3H) 2.84 (br. s., 3H) 3.16-3.35 (m, 2H)
3.83-4.05 (m, 3H) 4.43-4.61 (m, 1H) 6.62-6.75 (m, 1H) 6.97 (s, 2H)
7.07 (d, J=7.83 Hz, 2H) 7.10-7.17 (m, 3H). Mass Spectrum (ESI)
m/z=574 [M+H].sup.+.
Example 98
2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-(4-(cycloprop-
anecarbonyl)piperazin-1-yl)butan-2-yl)-3-methyl-2-oxopiperidin-3-yl)acetic
acid
##STR00283##
[1806] The title compound was prepared from
(3S,5R,6S)-3-allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-1-((S)--
1-(piperazin-1-yl)butan-2-yl)piperidin-2-one (Example 95, Step B)
and cyclopropanecarbonyl chloride as described in Example 97.
[1807] .sup.1H NMR (400 MHz, CHLOROFORM-d) .delta. ppm 0.79-0.91
(m, 6H) 1.02 (br. s., 6H) 1.43 (s, 3H) 1.65-1.75 (m, 2H) 2.11 (br.
s., 2H) 2.17-2.30 (m, 2H) 2.51 (br. s., 3H) 2.65 (s, 2H) 2.80-2.88
(m, 2H) 3.29 (t, J=11.44 Hz, 2H) 6.98 (s, 2H) 7.06 (t, J=7.83 Hz,
2H) 7.10-7.16 (m, 2H) 7.19-7.26 (m, 2H). Mass Spectrum (ESI)
m/z=600 [M+H].sup.+.
Example 99
3-(((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-1-((S)-1-mor-
pholinobutan-2-yl)-2-oxopiperidin-3-yl)methyl)-1,2,4-oxadiazol-5(4H)-one
##STR00284##
[1809] The title compound was prepared from
2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-1-((S)-1-mor-
pholinobutan-2-yl)-2-oxopiperidin-3-yl)acetic acid (Example 91)
using a similar procedure as the one described for Example 82. The
crude product was purified by flash chromatography on silica gel
(eluent: 0 to 10% MeOH in DCM) to give the title compound.
[1810] .sup.1H NMR (400 MHz, CHLOROFORM-d) .delta. ppm 0.56 (t,
J=7.34 Hz, 3H) 1.29 (br. s., 1H) 1.30-1.38 (m, 3H) 1.57 (ddd,
J=13.99, 7.53 and 3.91 Hz, 1H) 1.81 (dt, J=14.48 and 7.43 Hz, 1H)
2.09 (dd, J=13.99 and 3.03 Hz, 1H) 2.18 (d, J=9.98 Hz, 1H)
2.22-2.32 (m, 1H) 2.46 (d, J=3.72 Hz, 2H) 2.66 (br. s., 2H) 2.90
(d, J=15.06 Hz, 1H) 2.95-3.21 (m, 4H) 3.74-3.89 (m, 4H) 4.59 (d,
J=10.17 Hz, 1H) 6.72 (d, J=7.63 Hz, 1H) 6.84-6.99 (m, 3H) 7.08-7.13
(m, 1H) 7.14-7.18 (m, 1H) 7.23 (d, J=8.22 Hz, 2H). Mass Spectrum
(ESI) m/z=573 [M+H].sup.+.
Example 100
2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-(5,5-dimethyl-
-2-oxooxazolidin-3-yl)butan-2-yl)-3-methyl-2-oxopiperidin-3-yl)acetic
acid
##STR00285##
[1811] Step A.
(3S,5R,6S)-3-allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-(2-hydr-
oxy-2-methylpropylamino)butan-2-yl)-3-methylpiperidin-2-one
##STR00286##
[1813] The title compound was prepared as described in Example 91,
Step D and using and using 1-amino-2-methylpropan-2-ol (Tyger
Scientific, Inc., Ewing, N.J.).
Step B.
3-((S)-2-((3S,5R,6S)-3-allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-
-3-methyl-2-oxopiperidin-1-yl)butyl)-5,5-dimethyloxazolidin-2-one
##STR00287##
[1815] To a solution of 42 mg (0.081 mmol) of
(3S,5R,6S)-3-allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-(2-hydr-
oxy-2-methylpropylamino)butan-2-yl)-3-methylpiperidin-2-one
(Example 100, Step A) in dioxane (2705 .mu.L) was added
carbonyldiimidazole (132 mg, 0.812 mmol). The reaction was heated
to 100.degree. for 6 h. Purification of the residue by reversed
phase HPLC (Sunfire.TM. Prep C.sub.18 OBD 10 .mu.m column (Waters,
Milford, Mass.) (eluent: 60 to 85% MeCN/water (0.1% TFA), gradient
elution) provided the title compound.
Step C.
2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-(5,5--
dimethyl-2-oxooxazolidin-3-yl)butan-2-yl)-3-methyl-2-oxopiperidin-3-yl)ace-
tic acid
[1816] To a rapidly stirring solution of 20 mg (0.037 mmol) of
3-((S)-2-((3S,5R,6S)-3-allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-meth-
yl-2-oxopiperidin-1-yl)butyl)-5,5-dimethyloxazolidin-2-one (Example
100, Step B) in a mixture of CCl4 (210 .mu.L), MeCN (210 .mu.L),
and water (315 .mu.L) was added sodium periodate (31.5 mg, 0.147
mmol), followed by catalytic ruthenium(III) chloride hydrate (4.15
mg, 0.018 mmol). When complete by LCMS monitoring, acidified the
reaction with citric acid and diluted with chloroform. Insoluble
material was removed by filtration through celite. Extracted to
ethyl acetate and the combined organic layer was washed with sat.
NaCl, dried over Na.sub.2SO.sub.4, filtered and the filtrate was
concentrated in vacuo. Purification of the residue by reversed
phase HPLC (Sunfire.TM. Prep C.sub.18 OBD 10 .mu.m column (Waters,
Milford, Mass.) (eluent: 60 to 80% MeCN/water (0.1% TFA), gradient
elution) provided the title compound as a white powder.
[1817] .sup.1H NMR (500 MHz, CHLOROFORM-d) .delta. ppm 0.55 (t,
J=7.21 Hz, 2H) 0.94 (br. s., 2H) 1.27 (d, J=2.93 Hz, 1H) 1.33 (d,
J=2.69 Hz, 1H) 1.52 (t, 7H) 1.88-1.99 (m, 2H) 2.34 (t, J=13.82 Hz,
1H) 2.71 (d, J=14.92 Hz, 2H) 2.95-3.12 (m, 4H) 3.29-3.39 (m, 2H)
4.44 (d, J=10.27 Hz, 1H) 6.73 (d, J=7.58 Hz, 1H) 6.95 (s, 2H) 7.11
(t, J=7.70 Hz, 1H) 7.13-7.20 (m, 1H). Mass Spectrum (ESI) m/z=561
(M+1).
Example 101
2-((3R,5R,6S)-1-((S)-1-(tert-butylamino)-1-oxobutan-2-yl)-5-(3-chloropheny-
l)-6-(4-chlorophenyl)-3-methyl-2-oxopiperidin-3-yl)acetic acid
##STR00288##
[1818] Step A.
2-((3S,5R,6S)-3-allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-2-ox-
opiperidin-1-yl)butanoic acid
##STR00289##
[1820] To a 15-mL round-bottomed flask was added (S)-tert-butyl
2-((3S,5R,6S)-3-allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-2-ox-
opiperidin-1-yl)butanoate (420 mg, 0.813 mmol) (Example 1, Step F)
and anisole (444 .mu.L, 4.07 mmol), followed by TFA (4066 .mu.L)
which had been pre-cooled to 0.degree. C. The reaction mixture was
stirred at 0.degree. C. for 1 h, diluted with 50 ml of ether, and
the combined organics were washed with 20 ml water, NaHCO.sub.3/sat
NaCl solution until neutral, then dried over Na.sub.2SO.sub.4,
filtered and the filtrate was concentrated. Purification of the
residue by flash chromatography on silica gel (eluent: 0 to 20%
EtOAc/hexanes, gradient elution) provided the title compound.
[1821] 1H NMR (400 MHz, CHLOROFORM-d) .delta. ppm 7.25 (1H, s),
7.07-7.19 (2H, m), 7.00 (3H, br. s.), 6.76 (1H, d, J=7.4 Hz),
5.77-5.93 (1H, m), 5.15-5.25 (2H, m), 4.58 (1H, d, J=10.8 Hz), 3.35
(1H, br. s.), 3.23-3.33 (1H, m), 2.62 (2H, d, J=7.2 Hz), 2.27 (1H,
dquin, J=14.6, 7.5, 7.5, 7.5, 7.5 Hz), 2.14 (1H, t, J=13.5 Hz),
1.99 (1H, dd, J=13.7, 2.9 Hz), 1.50-1.64 (1H, m), 1.29 (3H, s),
0.66 (3H, t, J=7.4 Hz).
Step B.
2-((5R,6S)-3-allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl--
2-oxopiperidin-1-yl)-N-tert-butylbutanamide
##STR00290##
[1823] To a solution of
2-((3S,5R,6S)-3-allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-2-ox-
opiperidin-1-yl)butanoic acid (81 mg, 0.176 mmol) (Example 101,
Step A) in dry DMF (880 .mu.L) with 3 eq TEA (73.6 .mu.L, 0.528
mmol) at 00 was added 2 eq HATU (134 mg, 0.352 mmol). The reaction
was stirred at 00 for 5 min, followed by addition of t-butyl amine
(25.7 mg, 0.352 mmol). It was stirred for 30 min at 00, quenched
with sat. NaHCO.sub.3 and extracted to EtOAc. The combined organic
layers were washed with sat. NaCl solution, dried over
Na.sub.2SO.sub.4, filtered and the filtrate was concentrated.
Purification of the residue by flash chromatography on silica gel
(eluent: 0-30% EtOAc/hexanes, gradient elution) provided the title
compound as a mixture of stereoisomers.
Step C.
2-((3R,5R,6S)-1-((S)-1-(tert-butylamino)-1-oxobutan-2-yl)-5-(3-chl-
orophenyl)-6-(4-chlorophenyl)-3-methyl-2-oxopiperidin-3-yl)acetic
acid
[1824] The title compound was prepared from
(5R,6S)-5-(3-chlorophenyl)-6-(5-chloropyridin-2-yl)piperidin-2-one
(Example 101, Step B) as described in Example 1, Step H. The crude
product was purified by reversed phase preparatory HPLC
(Sunfire.TM. Prep C.sub.18 OBD 10 .mu.m column (Waters, Milford,
Mass.) (eluent: 55% acetonitrile, water, 0.1% TFA, gradient
elution).
[1825] .sup.1H NMR (500 MHz, CHLOROFORM-d) .delta. ppm 0.71 (t,
J=7.46 Hz, 3H), 1.32 (s, 9H), 1.40 (s, 3H), 1.60-1.71 (m, 1H),
2.07-2.25 (m, 3H), 2.86 (d, J=2.20 Hz, 2H), 3.16 (ddd, J=12.65,
9.60, 3.42 Hz, 1H), 3.67 (dd, J=8.80, 5.62 Hz, 1H), 4.70 (d, J=9.78
Hz, 1H), 6.78 (d, J=7.58 Hz, 1H), 6.97 (s, 1H), 6.98-7.05 (m, 3H),
7.11 (t, J=7.83 Hz, 1H), 7.14-7.19 (m, 1H), 7.21 (d, J=8.56 Hz,
2H). Mass Spectrum (ESI) m/z=533 (M+1).
Example 102
2-((3R,5R,6S)-5-(3-Chlorophenyl)-6-(4-chlorophenyl)-1-((1S,2S,3R)-2,3-dihy-
droxycyclopentyl)-3-methyl-2-oxopiperidin-3-yl)acetic acid
##STR00291##
[1826] Step A.
(3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-(2,3-dihydroxypropyl)--
3-methylpiperidin-2-one
##STR00292##
[1828] To a solution of 4 g (10.69 mmol) of
(3S,5R,6S)-3-allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methylpiperidi-
n-2-one (Example 71, Step D) in 100 mL of THF was added water (60
mL) followed by 4-methylmorpholine 4-oxide (1.878 g, 16.03 mmol).
The cloudy reaction mixture became clear within 5 min and
osmium(VIII) oxide (4% aq) (0.340 mL, 0.053 mmol) was added and the
reaction mixture remained clear. The reaction mixture was stirred
at room temperature for 18 h. Osmium(VIII) oxide (4% aq) (0.1 mL)
was added and the reaction mixture was stirred at room temperature
for 24 h. Sat NaCl solution was added and the mixture was extracted
with EtOAc. The organic layers were combined, dried over
Na.sub.2SO.sub.4, filtered and the filtrate was concentrated to
give the title compound as a 1:1 ratio of diastereomers.
Step B.
(3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-((2,2-dimethyl--
1,3-dioxolan-4-yl)methyl)-3-methylpiperidin-2-one
##STR00293##
[1830] To a solution of
(3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-(2,3-dihydroxypropyl)--
3-methylpiperidin-2-one (Example 102, Step A) (4.900 g, 12.00 mmol)
and 2,2-dimethoxypropane (14.76 mL, 120 mmol) in
N,N-dimethylformamide (34 mL) at room temperature was added CSA
(0.279 g, 1.200 mmol) and the reaction mixture was allowed to stir
for 1 hr at room temperature. The reaction was quenched with sodium
bicarbonate (100 mL) and EtOAc (100 mL). The layers were separated
and the organic layer was washed three times with sat. sodium
carbonate (100 mL). The aqueous layers were combined and were
extracted with EtOAc (200 mL). The organic layers were combined,
washed with sat. aq. NaCl solution, dried with sodium sulfate,
filtered, and concentrated under reduced pressure to provide the
title compound.
Step C.
(3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-(cyclopent-2-en-
yl)-3-((2,2-dimethyl-1,3-dioxolan-4-yl)methyl)-3-methylpiperidin-2-one
##STR00294##
[1832] To
(3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-((2,2-dimethy-
l-1,3-dioxolan-4-yl)methyl)-3-methylpiperidin-2-one (Example 102,
Step B) (0.909 g, 2.027 mmol) was added toluene (15 mL) and the
mixture was concentrated under reduced pressure. This step was
repeated three times. Inhibitor free THF (20 mL) was added and the
solution was cooled to -78.degree. C. Butyllithium in pentane
(2.0M) (1.014 mL, 2.027 mmol) was added dropwise and the reaction
mixture remained colorless. The reaction mixture warmed to
0.degree. C. and the reaction color turned very light yellow. nBuLi
in pentane (2.0M) was added dropwise until the reaction mixture
remained bright yellow. The reaction mixture was cooled to
-78.degree. C. and freshly prepared 3-bromocyclopent-1-ene (0.4 g,
2.72 mmol) in THF (2 mL) was added dropwise. The reaction mixture
was wrapped in foil and warmed to 0.degree. C. The reaction mixture
was stirred at 0.degree. C. for 1 h and then at rt for 2 days. The
reaction was quenched with sat. NH.sub.4Cl and extracted with
EtOAc. The organic layer was dried over Na.sub.2SO.sub.4 and
concentrated under reduced pressure. The residue was purified by
flash chromatography on silica gel (eluent: 0 to 100% EtOAc in
hexanes) to give the title compound as a colorless film.
Step D.
(3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-(cyclopent-2-en-
yl)-3-(2,3-dihydroxypropyl)-3-methylpiperidin-2-one
##STR00295##
[1834] To a solution of
(3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-(cyclopent-2-enyl)-3-(-
(2,2-dimethyl-1,3-dioxolan-4-yl)methyl)-3-methylpiperidin-2-one
(Example 28, Step C) (310 mg, 0.603 mmol) in THF (3 mL) at room
temperature was added aq. HCl (1 M) (3013 .mu.L, 3.01 mmol). The
reaction mixture was stirred at room temperature for 19 h. The
reaction mixture was diluted with EtOAc and the layers were
separated. The organic layer was washed with sat. NaHCO.sub.3, sat.
aq. NaCl solution and dried over Na.sub.2SO.sub.4 and concentrated
under reduced pressure to provide the title compound.
Step E.
2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-(cyclopent-2-
-enyl)-3-methyl-2-oxopiperidin-3-yl)acetaldehyde
##STR00296##
[1836] To a solution of
(3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-(cyclopent-2-enyl)-3-(-
2,3-dihydroxypropyl)-3-methylpiperidin-2-one (Example 102, Step D)
(286 mg, 0.603 mmol) in THF (3 mL) and water (3 mL) was added
sodium periodate (258 mg, 1.206 mmol) at room temperature. The
slurry was stirred at room temperature for 1 h and then diluted
with EtOAc and the layers were separated. The organic layer was
washed with sat. Na.sub.2S.sub.2O.sub.3 and sat. aq. NaCl solution
and dried over Na.sub.2SO.sub.4 and concentrated under reduced
pressure to provide the title compound.
Step F.
2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-(cyclopent-2-
-enyl)-3-methyl-2-oxopiperidin-3-yl)acetic acid
##STR00297##
[1838] To
2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-(cyclopent-
-2-enyl)-3-methyl-2-oxopiperidin-3-yl)acetaldehyde (Example 102,
Step E) (267 mg, 0.604 mmol) in acetone (4 mL) was added freshly
prepared Jones reagent (0.5 mL) at rt. The reaction mixture was
stirred at room temperature for 15 min. before it was diluted with
EtOAc and washed with water and sat. aq. NaCl solution. The organic
layer was dried over Na.sub.2SO.sub.4 and concentrated under
reduced pressure. The residue was purified by flash chromatography
on silica gel (eluent: 50 to 100% EtOAc in hexanes) to give the
title compound as a colorless film as a 3.6:1 mixture of
diastereomers.
Step G.
2-((3R,5R,6S)-5-(3-Chlorophenyl)-6-(4-chlorophenyl)-1-((1S,2S,3R)--
2,3-dihydroxycyclopentyl)-3-methyl-2-oxopiperidin-3-yl)acetic
acid
[1839] To a solution of
2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-(cyclopent-2-enyl)--
3-methyl-2-oxopiperidin-3-yl)acetic acid (Example 102, Step F) (94
mg, 0.205 mmol) in THF (1.0 mL) was added water (0.25 mL) and tBuOH
(0.2 mL) at room temperature. NMO (36.0 mg, 0.308 mmol) was added
followed by osmium tetroxide (4% aq) (1.303 .mu.L, 0.205 .mu.mol).
The reaction mixture was stirred at room temperature for 24 h.
Water (10 mL) was added and the mixture was extracted with DCM
twice. The organic layers were combined and dried over
Na.sub.2SO.sub.4 and concentrated under reduced pressure. The
residue, containing a mixture of three stereoisomers, was purified
by reversed phase preparatory HPLC (column: Gemini-NX C.sub.18 5 um
column; Phenomonex, Torrance, Calif.; eluent: 30 to 50% MeCN+0.1%
TFA in water+0.1% TFA, over 20 minutes) to provide the title
compound as the first eluting isomer.
[1840] .sup.1H NMR (400 MHz, CHLOROFORM-d) .delta. ppm 1.21-1.36
(3H, m), 1.38 (3H, s), 1.53-1.56 (2H, m), 2.20-2.02 (3H, m), 2.22
(1H, t, J=13.2 Hz), 2.62-2.78 (1H, m), 2.85-3.00 (1H, m), 3.00-3.13
(1H, m), 4.06-4.17 (1H, m), 4.35 (1H, br s), 4.70 (1H, d, J=8.8
Hz), 6.76-6.88 (1H, m), 6.93-7.12 (4H, m), 7.12-7.25 (3H, m). Mass
Spectrum (ESI) m/z=492 [M+H].sup.+.
[1841] Further elution provided as the last eluting isomer Example
103.
Example 103
2-((3R,5R,6S)-5-(3-Chlorophenyl)-6-(4-chlorophenyl)-1-((1R,2R,3S)-2,3-dihy-
droxycyclopentyl)-3-methyl-2-oxopiperidin-3-yl)acetic acid
##STR00298##
[1843] .sup.1H NMR (400 MHz, CHLOROFORM-d) .delta. ppm 1.19-1.38
(1H, m) 1.38-1.50 (3H, m) 1.38-1.50 (1H, m) 1.71-1.98 (2H, m)
2.06-2.27 (3H, m) 2.33 (1H, d, J=8.2 Hz) 2.70-2.79 (1H, m)
2.79-2.90 (1H, m) 3.20-3.37 (2H, m) 3.40 (1H, d, J=5.1 Hz) 3.86
(1H, br. s.) 4.50 (1H, d, J=10.2 Hz) 6.67-6.77 (1H, m) 6.93-7.07
(1H, m) 7.06-7.19 (3H, m) 7.23 (3H, d, J=8.6 Hz). Mass Spectrum
(ESI) m/z=492 [M+H].sup.+.
Example 104
2-((3R,3'S,5R,6S)-5-(3-Chlorophenyl)-6-(4-chlorophenyl)-3-methyl-2-oxo-1'--
(2,2,2-trifluoroethyl)-1,3'-bipiperidin-3-yl)acetic acid or
2-((3R,3'R,5R,6S)-5-(3-Chlorophenyl)-6-(4-chlorophenyl)-3-methyl-2-oxo-1'-
-(2,2,2-trifluoroethyl)-1,3'-bipiperidin-3-yl)acetic acid
##STR00299##
[1844] Step A.
2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-(1,5-dioxopentan-2--
yl)-3-methyl-2-oxopiperidin-3-yl)acetic acid
##STR00300##
[1846] To a solution of
2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-(2,3-dihydroxycyclo-
pentyl)-3-methyl-2-oxopiperidin-3-yl)acetic acid (Example 102, Step
F) (110 mg, 0.223 mmol) in THF (3 mL) and water (3 mL) was added
sodium periodate (134 mg, 0.626 mmol) at room temperature. The
reaction mixture was stirred at room temperature for 45 min and was
diluted with EtOAc and the layers were separated. The organic layer
was washed with sat. aq. Na.sub.2S.sub.2O.sub.3 solution, sat. aq.
NaCl solution, dried over Na.sub.2SO.sub.4 and concentrated under
reduced pressure to provide the title compound.
Step B.
2-((3R,3'S,5R,6S)-5-(3-Chlorophenyl)-6-(4-chlorophenyl)-3-methyl-2-
-oxo-1'-(2,2,2-trifluoroethyl)-1,3'-bipiperidin-3-yl)acetic acid or
2-((3R,3'R,5R,6S)-5-(3-Chlorophenyl)-6-(4-chlorophenyl)-3-methyl-2-oxo-1'-
-(2,2,2-trifluoroethyl)-1,3'-bipiperidin-3-yl)acetic acid (Isomer
1)
[1847] To a solution of
2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-(1,5-dioxopentan-2--
yl)-3-methyl-2-oxopiperidin-3-yl)acetic acid (Example 104, Step A)
(55 mg, 0.112 mmol) in DCE (1 mL) was added
2,2,2-trifluoroethanamine (9.24 .mu.L, 0.118 mmol) and sodium
triacetoxyborohydride (76 mg, 0.359 mmol) at room temperature. The
cloudy reaction mixture was stirred at room temperature for 2 h.
The reaction mixture was concentrated under reduced pressure,
diluted with DCM and washed with sat. aq. NaHCO.sub.3 solution and
sat. aq. NaCl solution. The layers were separated and the aqueous
layer was extracted three times with DCM. The organic layers were
combined, dried over Na.sub.2SO.sub.4 and concentrated under
reduced pressure. The residue was purified by reversed phase
preparatory HPLC (column: Gemini-NX C.sub.18 5 um column;
Phenomonex, Torrance, Calif.; eluent: 40% MeCN+0.1% TFA in
water+0.1% TFA, over 20 minutes) and concentrated in vacuo to
provide the first eluting diastereomer. The residue was dissolved
in DCM (1 mL) and HCl in ether (IM) (1 mL) was added and the
solvent was removed under reduced pressure to provide the
hydrochloride salt of one of the title compounds as the first
eluting isomer.
[1848] .sup.1H NMR (400 MHz, CHLOROFORM-d) .delta. ppm 0.73-1.00
(4H, m), 1.13-1.53 (6H, m), 1.58-1.84 (2H, m), 1.98-2.13 (1H, m),
2.24-2.44 (1H, m), 2.67-2.99 (3H, m), 3.17-3.32 (1H, m), 4.22 (2H,
t, J=6.0 Hz), 6.65-6.91 (1H, m), 7.00 (1H, d, J=0.6 Hz), 7.05-7.24
(4H, m), 7.48-7.59 (1H, m), 7.63-7.79 (1H, m). Mass Spectrum (ESI)
m/z=557 [M+H].sup.+.
[1849] Further elution and concentration in vacuo provided example
105.
Example 105
2-((3R,3'S,5R,6S)-5-(3-Chlorophenyl)-6-(4-chlorophenyl)-3-methyl-2-oxo-1'--
(2,2,2-trifluoroethyl)-1,3'-bipiperidin-3-yl)acetic acid or
2-((3R,3'R,5R,6S)-5-(3-Chlorophenyl)-6-(4-chlorophenyl)-3-methyl-2-oxo-1'-
-(2,2,2-trifluoroethyl)-1,3'-bipiperidin-3-yl)acetic acid (Isomer
2)
##STR00301##
[1851] The residue was dissolved in DCM (1 mL) and HCl in ether
(1M) (1 mL) was added and the solvent was removed under reduced
pressure to provide the hydrochloride salt of one of the title
compounds as the second eluting isomer.
[1852] .sup.1H NMR (400 MHz, CHLOROFORM-d) .delta. ppm 0.73-1.08
(7H, m), 1.13-1.50 (7H, m), 1.69 (6H, d, J=6.1 Hz), 7.54 (4H, dd,
J=5.7 and 3.3 Hz), 7.72 (4H, dd, J=5.7 and 3.3 Hz).
[1853] Mass Spectrum (ESI) m/z=557 [M+H].sup.+.
Example 106
2-((3R,5R,6S)-5-(3-Chlorophenyl)-6-(4-chlorophenyl)-1-((1S,3S)-3-hydroxycy-
clopentyl)-3-methyl-2-oxopiperidin-3-yl)acetic acid or
2-((3R,5R,6S)-5-(3-Chlorophenyl)-6-(4-chlorophenyl)-1-((1S,3R)-3-hydroxyc-
yclopentyl)-3-methyl-2-oxopiperidin-3-yl)acetic acid
##STR00302##
[1854] Step A.
(5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-(cyclopent-2-enyl)piperid-
in-2-one
##STR00303##
[1856] To a solution of 3.25 g (10.16 mmol) of
(5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)piperidin-2-one
(Example 1, Step E) in DMF (150 mL) at 0.degree. C. was added a
dispersion of 60% sodium hydride in mineral oil (1.016 g, 25.4
mmol). Evolution of gas was observed. The cloudy reaction mixture
was stirred at 0.degree. C. for 20 min before adding
3-bromocyclopent-1-ene (4.48 g, 30.5 mmol). The cloudy reaction
mixture warmed to room temperature and stirred at room temperature
for 18 h. The reaction was quenched with sat. aq. NH.sub.4Cl
solution, diluted with EtOAc and the layers were separated. The
organic layer was washed with 1M LiCl, sat. aq. NaCl solution,
dried over Na.sub.2SO.sub.4 and concentrated under reduced
pressure. The residue was purified by flash chromatography on
silica gel (eluent: 25 to 100% EtOAc in hexanes) to give the title
compound as a 5:2 mixture of diastereomers.
Step B.
(5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-(3-hydroxycyclopen-
tyl)piperidin-2-one
##STR00304##
[1858] To a solution of
(5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-(cyclopent-2-enyl)piperid-
in-2-one (Example 106, Step A) (394 mg, 1.020 mmol) in THF (10 mL)
was added borane tetrahydrofuran complex (1.0 m in THF) (1020
.mu.L, 1.020 mmol). Evolution of gas was observed. The reaction was
stirred at room temperature for 30 min. before adding aq. NaOH (6
M) (1.25 mL) and 30% H.sub.2O.sub.2 (1.25 mL). The reaction mixture
became cloudy and was stirred at room temperature for 1 h. The
reaction mixture was extracted with EtOAc. The organic layers were
washed with sat. aq. NaCl solution and dried over Na.sub.2SO.sub.4.
The residue was purified by flash chromatography on silica gel
(eluent: 40 to 100% EtOAc in hexanes) to give the title compound as
a mixture of diastereomers.
Step C.
(5R,6S)-1-((1S,3S)-3-((tert-Butyldimethylsilyl)oxy)cyclopentyl)-5--
(3-chlorophenyl)-6-(4-chlorophenyl)piperidin-2-one or
(2S,3R)-1-((1S,3R)-3-((tert-Butyldimethylsilyl)oxy)cyclopentyl)-3-(3-chlo-
rophenyl)-2-(4-chlorophenyl)piperidine
##STR00305##
[1860] To a solution of
(5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-(3-hydroxycyclopentyl)pip-
eridin-2-one (Example 106, Step B) (175 mg, 0.433 mmol) in DMF (4
mL) at room temperature was added TBDMS-Cl (71.8 mg, 0.476 mmol)
and imidazole (29.5 mg, 0.433 mmol). The reaction mixture was
stirred at room temperature for 18 h. Additional imidazole (29.5
mg, 0.433 mmol) and TBDMS-Cl (71.8 mg, 0.476 mmol) were added. The
reaction mixture was stirred at room temperature for 18 h and was
then diluted with EtOAc, washed with aq. IM LiCl solution, 1M HCl
and sat. aq. Na.sub.2CO.solution. The organic layer was dried over
Na.sub.2SO.sub.4 and concentrated under reduced pressure. The
residue was purified by flash chromatography on silica gel (eluent:
0 to 100% EtOAc in hexanes) to give the title compound as the major
single isomer.
Step D.
(5R,6S)-1-((1S,3S)-3-(tert-Butyldimethylsilyloxy)cyclopentyl)-5-(3-
-chlorophenyl)-6-(4-chlorophenyl)-3-methylpiperidin-2-one or
(2S,3R)-1-((1S,3R)-3-((tert-Butyldimethylsilyl)oxy)cyclopentyl)-3-(3-chlo-
rophenyl)-2-(4-chlorophenyl)-5-methylpiperidine
##STR00306##
[1862] To
(5R,6S)-1-((1S,3S)-3-((tert-Butyldimethylsilyl)oxy)cyclopentyl)--
5-(3-chlorophenyl)-6-(4-chlorophenyl)piperidin-2-one or
(2S,3R)-1-((1S,3R)-3-((tert-Butyldimethylsilyl)oxy)cyclopentyl)-3-(3-chlo-
rophenyl)-2-(4-chlorophenyl)piperidine from above (Example 106,
Step C) (104 mg, 0.201 mmol) was added toluene (15 mL) and the
mixture was concentrated under reduced pressure. This step was
repeated three times. The residue was dissolved in inhibitor free
THF (2 mL) that was previously degassed with Ar and the mixture was
cooled to 0.degree. C. under Ar. Methyliodide (13.79 .mu.L, 0.221
mmol) was added followed by LHMDS (previously degassed with Ar)
(1.0M in THF) (221 .mu.L, 0.221 mmol). The reaction mixture was
warmed to room temperature and stirred under Ar for 24 h.
Additional LHMDS (1.0 M in THF) (221 .mu.L, 0.221 mmol) was added
and the reaction mixture was stirred at room temperature for 1 h.
The reaction was quenched with sat. aq. NH.sub.4Cl solution and
extracted with EtOAc. The organic layers were dried over
Na.sub.2SO.sub.4, filtered and the filtrate was concentrated in
vacuo to provide the title compound.
Step E.
(5R,6S)-3-Allyl-1-((1S,3S)-3-((tert-butyldimethylsilyl)oxy)cyclope-
ntyl)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methylpiperidin-2-one
or
(2S,3R)-5-Allyl-1-((1S,3R)-3-((tert-butyldimethylsilyl)oxy)cyclopentyl)-3-
-(3-chlorophenyl)-2-(4-chlorophenyl)-5-methylpiperidine
##STR00307##
[1864] To
(5R,6S)-1-((1S,3S)-3-(tert-Butyldimethylsilyloxy)cyclopentyl)-5--
(3-chlorophenyl)-6-(4-chlorophenyl)-3-methylpiperidin-2-one or
(2S,3R)-1-((1S,3R)-3-((tert-Butyldimethylsilyl)oxy)cyclopentyl)-3-(3-chlo-
rophenyl)-2-(4-chlorophenyl)-5-methylpiperidine from above (Example
106, Step D) (107 mg, 0.201 mmol) was added toluene (15 mL) and the
mixture was concentrated under reduced pressure. This step was
repeated three times. The residue was dissolved in inhibitor free
THF (2 mL) that was previously degassed with Ar and the mixture was
cooled to 0.degree. C. under Ar. Distilled allyl bromide (87 .mu.L,
1.004 mmol) and LHMDS (1M in THF) (502 .mu.L, 0.502 mmol) were
added and the reaction mixture was warmed to room temperature and
stirred at room temperature for 1 h before heating the reaction
mixture at 50.degree. C. under Ar overnight. The reaction mixture
was cooled to room temperature and additional allyl bromide (87
.mu.L, 1.004 mmol) and LHMDS (1.0 M in THF) (502 .mu.L, 0.502 mmol)
were added and the reaction mixture was heated to 60.degree. C. for
6 h under Ar. The reaction mixture was cooled to room temperature
and the reaction was quenched with sat. NH.sub.4Cl solution and
extracted with EtOAc. The organic layers were dried over
Na.sub.2SO.sub.4 and concentrated under reduced pressure. The
residue was purified by flash chromatography on silica gel (eluent:
0 to 20% MTBE in hexanes) to give the title compound as a mixture
of diastereomers.
Step F.
2-((5R,6S)-1-((1S,3S)-3-(tert-Butyldimethylsilyloxy)cyclopentyl)-5-
-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-2-oxopiperidin-3-yl)acetic
acid or
2-((5R,6S)-1-((1S,3R)-3-((tert-Butyldimethylsilyl)oxy)cyclopentyl-
)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methylpiperidin-3-yl)acetic
acid
##STR00308##
[1866] The title compound was prepared from
(5R,6S)-3-Allyl-1-((1S,3S)-3-((tert-butyldimethylsilyl)oxy)cyclopentyl)-5-
-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methylpiperidin-2-one or
(2S,3R)-5-Allyl-1-((1S,3R)-3-((tert-butyldimethylsilyl)oxy)cyclopentyl)-3-
-(3-chlorophenyl)-2-(4-chlorophenyl)-5-methylpiperidine from above
(Example 106, Step E) as described in Example 95, Step D.
Step G.
2-((3R,5R,6S)-5-(3-Chlorophenyl)-6-(4-chlorophenyl)-1-((1S,3S)-3-h-
ydroxycyclopentyl)-3-methyl-2-oxopiperidin-3-yl)acetic acid or
2-((3R,5R,6S)-5-(3-Chlorophenyl)-6-(4-chlorophenyl)-1-((1S,3R)-3-hydroxyc-
yclopentyl)-3-methyl-2-oxopiperidin-3-yl)acetic acid
[1867] To a solution of
2-((5R,6S)-1-((1S,3S)-3-(tert-Butyldimethylsilyloxy)cyclopentyl)-5-(3-chl-
orophenyl)-6-(4-chlorophenyl)-3-methyl-2-oxopiperidin-3-yl)acetic
acid or
2-((5R,6S)-1-((1S,3R)-3-((tert-Butyldimethylsilyl)oxy)cyclopentyl)-5-(3-c-
hlorophenyl)-6-(4-chlorophenyl)-3-methylpiperidin-3-yl)acetic acid
from above (Example 106, Step F) (31 mg, 0.052 mmol) in THF (1.0
mL) was added 1.0M TBAF in THF (262 .mu.L, 0.262 mmol) at room
temperature. The reaction mixture was stirred at room temperature
for 19 h before being concentrated under reduced pressure. The
residue was purified by reversed phase preparatory HPLC (column:
Gemini-NX C.sub.18 5 um column; Phenomonex, Torrance, Calif.;
eluent: 45 to 75% MeCN+0.1% TFA in water+0.1% TFA) to give the
title compound.
[1868] .sup.1H NMR (400 MHz, CHLOROFORM-d) .delta. ppm 1.31 (3H,
s), 1.49-1.65 (3H, m), 1.65-1.90 (3H, m), 2.06-2.19 (3H, m),
2.68-2.78 (1H, m), 3.05-3.18 (1H, m), 2.88 (1H, d, J=15.1 Hz),
3.35-3.54 (1H, m), 4.41-4.49 (1H, m), 4.68 (1H, d, J=8.0 Hz), 6.85
(1H, dt, J=7.4 and 1.7 Hz), 6.95-7.00 (2H, m), 7.09 (1H, t, J=1.9
Hz), 7.15-7.26 (2H, m), 7.30 (2H, d, J=8.6 Hz). Mass Spectrum (ESI)
m/z=476 [M+H].sup.+.
Example 107
2-((3R,5R,6S)-5-(3-Chlorophenyl)-6-(4-chlorophenyl)-3-methyl-2-oxo-1-((S)--
tetrahydro-2H-pyran-3-yl)piperidin-3-yl)acetic acid or
2-((3R,5R,6S)-5-(3-Chlorophenyl)-6-(4-chlorophenyl)-3-methyl-2-oxo-1-((R)-
-tetrahydro-2H-pyran-3-yl)piperidin-3-yl)acetic acid
##STR00309##
[1869]
2-((3R,5R,6S)-5-(3-Chlorophenyl)-6-(4-chlorophenyl)-3-methyl-2-oxo--
1-((S)-tetrahydro-2H-pyran-3-yl)piperidin-3-yl)acetic acid or
2-((3R,5R,6S)-5-(3-Chlorophenyl)-6-(4-chlorophenyl)-3-methyl-2-oxo-1-((R)-
-tetrahydro-2H-pyran-3-yl)piperidin-3-yl)acetic acid
##STR00310##
[1870] Step A.
2-((2S,3R)-3-(3-chlorophenyl)-2-(4-chlorophenyl)-6-oxopiperidin-1-yl)pent-
anedial
##STR00311##
[1872] To a solution of 454 mg (1.175 mmol) of
(5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-(cyclopent-2-enyl)piperid-
in-2-one (Example 104, Step A) in THF (6 mL) was added water
dropwise (3.5 mL) and tBuOH (0.2 mL). 4-methylmorpholine 4-oxide
(207 mg, 1.763 mmol) was added followed by 4% aq. osmium(VIII)
oxide (37.3 .mu.L, 5.88 .mu.mol). The reaction mixture was stirred
at room temperature for 18 h. Sodium periodate (704 mg, 3.29 mmol)
was added and the cloudy reaction mixture was stirred at room
temperature for 90 min. Water (4 mL) was added and the mixture was
filtered and washed with EtOAc. The filtrate was diluted with EtOAc
and the layers were separated. The combined organic layers were
washed with sat. Na.sub.2S.sub.2O.sub.3, sat. aq. NaCl solution,
dried over Na.sub.2SO.sub.4 and concentrated in vacuo to provide
the title compound.
Step B.
(5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-(1,5-dihydroxypent-
an-2-yl)piperidin-2-one
##STR00312##
[1874] To a solution of
2-((2S,3R)-3-(3-chlorophenyl)-2-(4-chlorophenyl)-6-oxopiperidin-1-yl)pent-
anedial (Example 107, Step A) (492 mg, 1.176 mmol) in MeOH (11 mL)
was added sodium borohydride (89 mg, 2.352 mmol) at room
temperature. Evolution of gas was observed. The reaction mixture
was stirred at room temperature for 15 min and then concentrated
under reduced pressure. The residue was purified by flash
chromatography on silica gel (eluent: 50 to 100% EtOAc in hexanes
and then 10% MeOH in DCM) to give the title compound.
Step C.
(5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-(tetrahydro-2H-pyr-
an-3-yl)piperidin-2-one
##STR00313##
[1876] To a solution of
(5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-(1,5-dihydroxypentan-2-yl-
)piperidin-2-one (Example 107, Step B) (192 mg, 0.455 mmol) in THF
(5 mL) at room temperature was added triphenylphosphine (119 mg,
0.455 mmol) followed by the dropwise addition of diisopropyl
azodicarboxylate (89 .mu.L, 0.455 mmol). The reaction mixture
turned light yellow during the addition and then became colorless
within 5 min. The reaction mixture was stirred at room temperature
for 1 h. The reaction mixture was diluted with EtOAc and washed
with sat. aq. NaCl solution. The organic layer was dried over
Na.sub.2SO.sub.4 and concentrated in vacuo. The residue was
purified by flash chromatography on silica gel (eluent: 0 to 100%
EtOAc in hexanes) to give the title compound as a mixture of
diastereomers.
Step D.
(5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-1-(tetrahyd-
ro-2H-pyran-3-yl)piperidin-2-one
##STR00314##
[1878] The title compound was prepared from
(5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-(tetrahydro-2H-pyran-3-yl-
)piperidin-2-one (Example 107, Step C) as described in Example 71,
Step B.
Step E.
(5R,6S)-3-allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-1-(-
tetrahydro-2H-pyran-3-yl)piperidin-2-one
##STR00315##
[1880] The title compound was prepared as a mixture of
stereoisomers from
(5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-1-(tetrahydro-2H-p-
yran-3-yl)piperidin-2-one (Example 107, Step D) as described in
Example 71 Step C.
Step F.
2-((3R,5R,6S)-5-(3-Chlorophenyl)-6-(4-chlorophenyl)-3-methyl-2-oxo-
-1-((S)-tetrahydro-2H-pyran-3-yl)piperidin-3-yl)acetic acid Or
2-((3R,5R,6S)-5-(3-Chlorophenyl)-6-(4-chlorophenyl)-3-methyl-2-oxo-1-((R)-
-tetrahydro-2H-pyran-3-yl)piperidin-3-yl)acetic acid
[1881] The title compound was prepared from
(5R,6S)-3-allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-1-(tetrahy-
dro-2H-pyran-3-yl)piperidin-2-one (Example 107, Step E) as
described previously in Example 42, Step C. The residue was
purified by reversed phase preparatory HPLC (column: Gemini-NX
C.sub.18 5 um column; Phenomonex, Torrance, Calif.; eluent: 0 to
100% MeCN+0.1% TFA in water+0.1% TFA) to give the title compound as
a single, but unassigned stereoisomer.
[1882] .sup.1H NMR (400 MHz, CHLOROFORM-d) .delta. ppm 1.40 (3H,
s), 1.49-1.84 (3H, m), 2.01-2.16 (3H, m), 2.39 (1H, dd, J=12.3 and
4.3 Hz), 2.66-2.77 (1H, m), 2.90-3.10 (2H, m), 3.22-3.33 (1H, m),
3.48 (1H, br. s.), 3.69-3.79 (1H, m), 4.24 (1H, t, J=10.5 Hz), 4.42
(1H, d, J=9.4 Hz), 6.72 (1H, d, J=7.6 Hz), 6.89-7.04 (3H, m),
7.06-7.26 (4H, m). Mass Spectrum (ESI) m/z=476 [M+H].sup.+.
Example 108
2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-2-oxo-1-(pyra-
zin-2-yl)piperidin-3-yl)acetic acid
##STR00316##
[1883] Step A.
(3S,5R,6S)-3-allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-1-(pyra-
zin-2-yl)piperidin-2-one
##STR00317##
[1885]
(3S,5R,6S)-3-allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methylpi-
peridin-2-one (Example 71, Step D) (100 mg, 0.27 mmol),
2-iodopyrazine (170 .mu.L, 0.80 mmol) and cesium carbonate (220 mg,
0.67 mmol) were dissolved in 2.7 mL of 1,4-dioxane. The reaction
vessel was flushed with argon, copper (I) iodide (5.1 mg, 27
.mu.mol) and TMEDA (11 .mu.L, 80 .mu.mol) were added, and the
reaction mixture was allowed to stir at 110.degree. C. for 15
hours. The reaction mixture was cooled to room temperature,
quenched with water and extracted (2.times.EtOAc). The combined
organic layers were washed with sat. aq. NaCl solution, dried over
Na.sub.2SO.sub.4, filtered and the filtrate was concentrated under
reduced pressure. Purification of the residue by flash
chromatography on silica gel (0 to 50% EtOAc/hexanes) provided the
title compound as a colorless solid.
Step B.
2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-2-oxo-
-1-(pyrazin-2-yl)piperidin-3-yl)acetic acid
[1886] The title compound was prepared from
(3S,5R,6S)-3-allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-1-(pyra-
zin-2-yl)piperidin-2-one (Example 108, Step A) as described in
Example 42 Step C to provide a white solid.
[1887] .sup.1H NMR (400 MHz, MeOD) .delta. ppm 1.42 (s, 3H),
2.30-2.39 (m, 1H), 2.39-2.49 (m, 1H), 2.60 (d, J=14.67 Hz, 1H),
3.07 (d, J=12.52 Hz, 1H), 3.71-3.81 (m, 1H), 5.50 (d, J=10.76 Hz,
1H), 6.96-7.03 (m, 2H), 7.04-7.11 (m, 3H), 7.12-7.17 (m, 2H), 7.19
(br. s., 1H), 8.16 (br. s., 1H), 8.30 (s, 1H), 8.62 (br. s., 1H).
MS (ESI) 470.2 [M+H].sup.+.
Example 109
2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-1-(1-methyl-1-
H-pyrazol-4-yl)-2-oxopiperidin-3-yl)acetic acid
##STR00318##
[1888] Step A.
(3S,5R,6S)-3-allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-1-(1-me-
thyl-1H-pyrazol-4-yl)piperidin-2-one
##STR00319##
[1890]
(3S,5R,6S)-3-allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methylpi-
peridin-2-one (Example 71, Step D) (90 mg, 0.24 mmol),
1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole
(125 mg, 0.60 mmol), diacetoxycopper (44 mg, 0.24 mmol) and
N,N-dimethylpyridin-4-amine (88 mg, 0.72 mmol) were dissolved in
1.2 mL of toluene. Sodium bis(trimethylsilyl)amide (480 .mu.L, 0.48
mmol) was added and the reaction apparatus was outfitted with a
reflux condenser and was allowed to stir at 115.degree. C. for 13
hours. The reaction mixture was cooled to room temperature,
quenched with water and extracted (2.times.EtOAc). The combined
organic layers were washed with sat. aq. NaCl solution, dried over
Na.sub.2SO.sub.4, filtered and the filtrate was concentrated under
reduced pressure. Purification of the residue by flash
chromatography (0 to 60% EtOAc/hexanes) provided the title compound
as a colorless solid.
Step B.
2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-1-(1--
methyl-1H-pyrazol-4-yl)-2-oxopiperidin-3-yl)acetic acid
[1891] The title compound was prepared from
(3S,5R,6S)-3-allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-1-(1-me-
thyl-1H-pyrazol-4-yl)piperidin-2-one (Example 108, Step A) as
described in Example 42, Step C to provide a white solid.
[1892] .sup.1H NMR (400 MHz, MeOD) .delta. ppm 1.42 (s, 3H),
2.25-2.33 (m, 1H), 2.31-2.44 (m, 1H), 2.60 (d, J=12.91 Hz, 1H),
3.01 (d, J=13.30 Hz, 1H), 3.47-3.59 (m, 1H), 3.68 (s, 3H), 5.06 (d,
J=10.37 Hz, 1H), 6.95-7.05 (m, 3H), 7.09 (d, J=8.41 Hz, 2H),
7.12-7.20 (m, 3H), 7.24 (s, 1H), 7.49 (s, 1H). MS (ESI) 472.2
[M+H].sup.+.
Example 110
2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-2-oxo-1-(pyri-
midin-4-yl)piperidin-3-yl)acetic acid
##STR00320##
[1893] Step A. 1-(Pyrimidin-4-yloxy)-1H-benzo[d][1,2,3]triazole
##STR00321##
[1895] To a solution of pyrimidin-4-ol (350 mg, 3.6 mmol) and
(1H-benzo[d][1,2,3]triazol-1-yloxy)tris(dimethylamino)phosphonium
hexafluorophosphate(V) (1.9 g, 4.4 mmol) in 24 mL of acetonitrile
was added 2,3,4,6,7,8,9,10-octahydropyrimido[1,2-a]azepine (820
.mu.L, 5.5 mmol) dropwise at room temperature. After the reaction
mixture was stirred for 1 hour, the reaction solvent was removed
under reduced pressure. Purification of the residue by flash
chromatography (0 to 70% EtOAc/hexanes) provided the title compound
as a light yellow solid.
Step B.
(3S,5R,6S)-3-allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl--
1-(pyrimidin-4-yl)piperidin-2-one
##STR00322##
[1897] To a solution of
(3S,5R,6S)-3-allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methylpiperidi-
n-2-one (Example 71, Step D) (100 mg, 0.27 mmol) in 1.3 mL of DMSO
was added sodium hydride (60% suspension in mineral oil, 13 mg,
0.32 mmol) at room temperature. The reaction mixture was stirred
for 5 minutes, and was treated with
1-(pyrimidin-4-yloxy)-1H-benzo[d][1,2,3]triazole (Example 110, Step
A) (170 mg, 0.80 mmol). The reaction mixture was stirred at
110.degree. C. for 13 hours. The reaction mixture was cooled to
room temperature, quenched with water and extracted
(2.times.EtOAc). The combined organic layers were washed with sat.
aq. NaCl solution, dried over Na.sub.2SO.sub.4, filtered and the
filtrate was concentrated under reduced pressure. Purification of
the residue by flash chromatography (0 to 45% EtOAc/hexanes)
provided the title compound as a colorless solid.
Step C.
2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-2-oxo-
-1-(pyrimidin-4-yl)piperidin-3-yl)acetaldehyde
##STR00323##
[1899] To a solution of
(3S,5R,6S)-3-allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-1-(pyri-
midin-4-yl)piperidin-2-one (Example 110, Step B) (60 mg, 0.13 mmol)
in a mixture of tetrahydrofuran (2.7 mL) and water (880 .mu.L) was
added osmium tetroxide (1.7 mg, 6.6 .mu.mol). After 5 minutes,
sodium periodate (89 mg, 0.46 mmol) was added and the reaction
mixture was stirred for 14 hours. The reaction mixture was filtered
through Celite.RTM. (J. T. Baker, Phillipsberg, N.J., diatomaceous
earth) and washed with EtOAc and water. The organic layer was
washed with sat. aq. NaCl solution, dried over Na.sub.2SO.sub.4,
filtered and the filtrate was concentrated under reduced pressure.
Purification of the residue by flash chromatography (0 to 75%
EtOAc/hexanes, gradient elution) provided the title compound as a
colorless solid.
Step D.
2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-2-oxo-
-1-(pyrimidin-4-yl)piperidin-3-yl)acetic acid
[1900] To a solution of
2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-2-oxo-1-(pyr-
imidin-4-yl)piperidin-3-yl)acetaldehyde (Example 110, Step C) (25
mg, 55 .mu.mol) in a mixture of 2-methylpropan-2-ol (1.0 mL) and
2-methyl-2-butene (55 .mu.L, 2.0 M soln in THF, 0.11 mmol) was
added a solution of sodium chlorite (37 mg, 0.55 mmol) and sodium
dihydrogen phosphate (4.8 mg, 50 .mu.mol) in 550 .mu.L of water at
room temperature. The reaction mixture was stirred for 1 hour
before it was quenched with water and extracted (2.times.EtOAc).
The combined organic layers were washed with sat. aq. NaCl
solution, dried over Na.sub.2SO.sub.4, filtered and the filtrate
was concentrated under reduced pressure. Purification of the
residue by silica gel prep plate (10% MeOH/DCM) provided the title
compound as a colorless solid.
[1901] .sup.1H NMR (500 MHz, CDCl.sub.3) .delta. ppm 1.43 (s, 3H),
2.21-2.27 (m, 1H), 2.29-2.36 (m, 1H), 2.84-2.95 (m, 2H), 3.34-3.42
(m, 1H), 5.71 (d, J=9.78 Hz, 1H), 6.85-6.92 (m, 3H), 7.01 (d,
J=8.31 Hz, 2H), 7.10-7.16 (m, 2H), 7.18-7.22 (m, 1H), 7.63 (d,
J=5.38 Hz, 1H), 8.49 (d, J=5.38 Hz, 1H), 8.82 (s, 1H). MS (ESI)
470.2 [M+H].sup.+.
Example 111
2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-(2-chloropyrimidin-4-
-yl)-3-methyl-2-oxopiperidin-3-yl)acetic acid
##STR00324##
[1902] Step A.
(3S,5R,6S)-3-allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-(2-chloropyrim-
idin-4-yl)-3-methylpiperidin-2-one
##STR00325##
[1904] To a solution of
(3S,5R,6S)-3-allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methylpiperidi-
n-2-one (Example 71, Step D) (100 mg, 0.27 mmol) in 1.1 mL of DMSO
was added sodium hydride (60% suspension in mineral oil, 32 mg,
0.80 mmol) at room temperature. The reaction mixture was stirred
for 15 minutes, and was treated with 2,4-dichloropyrimidine (200
mg, 1.3 mmol). The reaction mixture was stirred at 60.degree. C.
for 5 hours. The reaction mixture was cooled to room temperature
and quenched with water and extracted (2.times.EtOAc). The combined
organic layers were washed with sat. aq. NaCl solution, dried over
Na.sub.2SO.sub.4, filtered and the filtrate was concentrated under
reduced pressure. Purification of the residue by silica gel prep
plate (50% EtOAc/hexanes) provided the title compound as a
colorless solid.
Step B.
2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-(2-chloropyr-
imidin-4-yl)-3-methyl-2-oxopiperidin-3-yl)acetaldehyde
##STR00326##
[1906] The title compound was prepared from
(3S,5R,6S)-3-allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-(2-chloropyrim-
idin-4-yl)-3-methylpiperidin-2-one (Example 111, Step A) as
described in Example 110, Step C to provide a white solid.
Step C.
2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-(2-chloropyr-
imidin-4-yl)-3-methyl-2-oxopiperidin-3-yl)acetic acid
[1907] The title compound was prepared from
2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-(2-chloropyrimidin--
4-yl)-3-methyl-2-oxopiperidin-3-yl)acetaldehyde (Example 111, Step
B) as described in Example 110 Step D to provide a white foam.
[1908] .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. ppm 1.48 (s, 3H),
2.29 (d, J=3.91 Hz, 1H), 2.33 (d, J=12.52 Hz, 1H), 2.86 (d, J=14.87
Hz, 1H), 3.06 (d, J=14.67 Hz, 1H), 3.31-3.41 (m, 1H), 5.65 (d,
J=10.37 Hz, 1H), 6.83-6.87 (m, 1H), 6.88-6.93 (m, 2H), 7.04-7.07
(m, 1H), 7.07-7.10 (m, 2H), 7.15 (m, 1H), 7.18-7.23 (m, 1H), 7.70
(d, J=5.67 Hz, 1H), 8.39 (d, J=5.7 Hz, 1H). MS (ESI) 504.0
[M+H].sup.+.
Example 112
2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-2-oxo-1-(pyri-
midin-2-yl)piperidin-3-yl)acetic acid
##STR00327##
[1910] The title compound was prepared from
(3S,5R,6S)-3-allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methylpiperidi-
n-2-one (Example 71, Step D) and 2-chloropyrimidine as described in
Example 111, followed by conversion to the acid as described in
Example 71, Step F.
[1911] .sup.1H NMR (500 MHz, CDCl.sub.3) .delta. ppm 1.49 (s, 3H),
2.34-2.40 (m, 2H), 2.94 (d, J=14.18 Hz, 1H), 3.10 (d, J=13.45 Hz,
1H), 3.50 (td, J=10.88 and 3.91 Hz, 1H), 5.46 (d, J=10.27 Hz, 1H),
6.89 (d, J=7.34 Hz, 1H), 6.93-7.01 (m, 5H), 7.11 (t, J=8.19 Hz,
1H), 7.14-7.18 (m, 2H), 8.56 (d, J=4.9 Hz, 2H). MS (ESI) 470.2
[M+H].sup.+.
Example 113
2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-1-(3-methylpy-
ridin-2-yl)-2-oxopiperidin-3-yl)acetic acid
##STR00328##
[1912] Step A.
(3S,5R,6S)-3-allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-1-(3-me-
thyl-5-nitropyridin-2-yl)piperidin-2-one
##STR00329##
[1914] The title compound was prepared from
(3S,5R,6S)-3-allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methylpiperidi-
n-2-one (Example 71, Step D) and 2-chloro-3-methyl-5-nitropyridine
as described in Example 111, Step A to provide a light-yellow
solid.
Step B.
(3S,5R,6S)-3-allyl-1-(5-amino-3-methylpyridin-2-yl)-5-(3-chlorophe-
nyl)-6-(4-chlorophenyl)-3-methylpiperidin-2-one
##STR00330##
[1916]
(3S,5R,6S)-3-allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-1-
-(3-methyl-5-nitropyridin-2-yl)piperidin-2-one (Example 113, Step
A) (120 mg, 0.23 mmol) and tin(II) chloride dihydrate (260 mg, 1.1
mmol) were dissolved in 2.3 mL of ethyl acetate. The reaction
apparatus was outfitted with a reflux condenser and was stirred at
90.degree. C. for 4 hours. The reaction mixture was cooled to room
temperature, quenched with 1M NaOH and extracted (2.times.EtOAc).
The combined organic layers were washed with sat. aq. NaCl
solution, dried over Na.sub.2SO.sub.4, filtered and the filtrate
was concentrated under reduced pressure. Purification of the
residue by flash chromatography (0 to 90% EtOAc/Hex, gradient
elution) provided the title compound as a colorless solid.
Step C.
(3S,5R,6S)-3-allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl--
1-(3-methylpyridin-2-yl)piperidin-2-one
##STR00331##
[1918] To a solution of
(3S,5R,6S)-3-allyl-1-(5-amino-3-methylpyridin-2-yl)-5-(3-chlorophenyl)-6--
(4-chlorophenyl)-3-methylpiperidin-2-one (Example 113, Step B) (89
mg, 0.185 mmol) in 1,4-dioxane (4.0 mL) and acetic acid (0.50 mL)
was added 3.0M HCl (730 .mu.L, 2.2 mmol) at 0.degree. C. After the
reaction was stirred for 5 minutes, hydrogen peroxide (6% wt aq.,
95 .mu.L, 0.185 mmol) was added dropwise, followed by sodium
nitrite (46 mg, 0.74 mmol). The reaction mixture was stirred for 2
hours at 0.degree. C. The reaction mixture was warmed to room
temperature, quenched with 1M NaOH and extracted (2.times.EtOAc).
The combined organic layers were washed with sat. aq. NaCl
solution, dried over Na.sub.2SO.sub.4, filtered and the filtrate
was concentrated under reduced pressure. Purification of the
residue by flash chromatography (0 to 55% EtOAc/Hex, gradient
elution) provided the title compound as a colorless solid.
Step D.
2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-1-(3--
methylpyridin-2-yl)-2-oxopiperidin-3-yl)acetaldehyde
##STR00332##
[1920] The title compound was prepared from
(3S,5R,6S)-3-allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-1-(3-me-
thylpyridin-2-yl)piperidin-2-one (Example 113, Step C) as described
in Example 110, Step C to provide a white solid.
Step E.
2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-1-(3--
methylpyridin-2-yl)-2-oxopiperidin-3-yl)acetic acid
[1921] The title compound was prepared from
2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-1-(3-methylp-
yridin-2-yl)-2-oxopiperidin-3-yl)acetaldehyde (Example 113, Step D)
as described in Example 110 Step D to provide a white foam.
[1922] .sup.1H NMR (500 MHz, CDCl.sub.3) .delta. ppm 1.54 (s, 3H),
2.12 (s, 3H), 2.29 (dd, J=14.31 and 3.06 Hz, 1H), 2.50 (t, J=13.82
Hz, 1H), 2.92-3.01 (m, 1H), 3.07-3.17 (m, 1H), 3.56-3.67 (m, 1H),
5.51 (d, J=11.00 Hz, 1H), 6.90-7.02 (m, 5H), 7.05-7.15 (m, 4H),
7.45 (d, J=7.09 Hz, 1H), 8.30 (d, J=3.67 Hz, 1H). MS (ESI) 483.2
[M+H].sup.+.
Example 114
2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-1-(4-methylpy-
ridin-2-yl)-2-oxopiperidin-3-yl)acetic acid
##STR00333##
[1923] Step A.
(3S,5R,6S)-3-allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-1-(4-me-
thylpyridin-2-yl)piperidin-2-one
##STR00334##
[1925] The title compound was prepared from
(3S,5R,6S)-3-allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methylpiperidi-
n-2-one (Example 71, Step D) and 2-chloro-4-methyl-5-nitropyridine
as described in Example 113 Steps A-C to provide a white solid.
Step B.
2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-1-(4--
methylpyridin-2-yl)-2-oxopiperidin-3-yl)acetic acid
[1926] To a solution of
(3S,5R,6S)-3-allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-1-(4-me-
thylpyridin-2-yl)piperidin-2-one (Example 114, Step A) (73 mg, 0.16
mmol) in 780 .mu.L of tetrahydrofuran was added water (1.0 mL),
followed by 2-methylpropan-2-ol (100 .mu.L) at room temperature.
The reaction mixture was treated with 4-methylmorpholine 4-oxide
(28 mg, 0.24 mmol), followed by osmium tetroxide (2.0 mg, 7.8
.mu.mol) and was stirred at room temperature for 2 hours. The
reaction mixture was treated with a 1.25 M solution of Jones
reagent (190 .mu.L, 0.24 mmol) at room temperature and was stirred
at room temperature for 1 hour. The reaction was quenched with
water and extracted (3.times.EtOAc). The combined organic layers
were washed with sat. aq. NaCl solution, dried over
Na.sub.2SO.sub.4, filtered and the filtrate was concentrated under
reduced pressure. Purification of the residue by HPLC on an Eclipse
column (Agilent Technologies, Santa, Clara, Calif.) (20 to 80%
acetonitrile/water, gradient elution) provided the title compound
as a colorless solid.
[1927] .sup.1H NMR (500 MHz, CDCl.sub.3) .delta. ppm 1.49 (s, 3H),
2.23 (s, 3H), 2.28 (dd, J=14.2 and 3.2 Hz, 1H), 2.42 (t, J=13.45
Hz, 1H), 2.96 (m, 1H), 3.04 (m, 1H), 3.39 (ddd, J=12.9, 10.2 and
3.1 Hz, 1H), 5.57 (d, J=10.3 Hz, 1H), 6.81 (d, J=5.1 Hz, 1H),
6.86-6.92 (m, 3H), 6.99 (d, J=8.1 Hz, 2H), 7.08-7.13 (m, 2H),
7.13-7.18 (m, 2H), 8.13 (d, J=5.1 Hz, 1H). MS (ESI) 483.2
[M+H].sup.+.
Example 115
2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-(dicyclopropylmethyl-
)-3-methyl-2-oxopiperidin-3-yl)acetic acid
##STR00335##
[1928] Step A. (Z)-2-((4-chlorobenzylideneamino)methyl)phenol
##STR00336##
[1930] To a stirred suspension of 2-(aminomethyl)phenol, (4.0 g,
32.5 mmol) in ethanol (65 mL) was added 4-chlorobenzaldehyde (3.86
mL, 32.8 mmol). The resulting reaction mixture was stirred at rt
for 3 h. The solvent was removed and 100 ml of toluene was added
and concentrated in vacuum twice. The resulting imine was dried
under vacuum overnight and used in the next step without further
purification.
[1931] .sup.1H NMR (500 MHz, DMSO-d6) .delta. ppm 9.47 (1H, br.
s.), 8.44 (1H, s), 7.79 (2H, d, J=8.6 Hz), 7.51 (2H, d, J=8.6 Hz),
7.16 (1H, dd, J=7.3, 1.6 Hz), 7.08 (1H, td, J=7.6, 1.6 Hz),
6.72-6.87 (2H, m), 4.71 (2H, s).
Step B.
2-(((1S,2R)-2-(3-chlorophenyl)-1-(4-chlorophenyl)but-3-enylamino)m-
ethyl)phenol
##STR00337##
[1933] To a solution of 1.42 g (5.3 mmol)
(4S,5S)-2-allyl-2-chloro-3,4-dimethyl-5-phenyl-[1,3,2]-oxazasilolidine
(prepared according to J. Am. Chem. Soc. 124, 7920, 2002) and
1-chloro-3-vinylbenzene (1.69 g, 12.21 mmol) in DCM (12 mL) and DCE
(12 mL) was added 0.173 g (0.2 mmol) of
1,3-bis-(2,4,6-trimethylphenyl)-2-(imidazolidinylidene)(dichlorophenylmet-
hylene)(tricyclohexylphosphine)ruthenium ("Grubb's 2nd Generation
Catalyst"). The resulting mixture was degassed two times and then
heated to reflux for 8 h. The reaction mixture was cooled to room
temperature. The imine, from above (Step A) (1.0 g, 4.07 mmol) was
added. The reaction mixture was heated to reflux for 14 h, and then
cooled to rt and quenched by adding 8 ml of ethanol. The reaction
mixture was diluted with ethyl acetate (120 ml) and washed with
water (30 ml) and sat. NaCl solution (30 ml). The combined organic
layers were dried over MgSO.sub.4, filtered and the filtrate was
concentrated. The residue was purified by chromatography on silica
gel, (eluent: hexane/ethyl acetate 90/10-65/35) to give the title
compound.
[1934] .sup.1H NMR (500 MHz, ACETONITRILE-d3) .delta. ppm 7.52 (2H,
d, J=8.3 Hz), 7.23-7.37 (3H, m), 7.10-7.17 (3H, m), 7.06 (1H, d,
J=8.1 Hz), 6.92-7.03 (2H, m), 6.88 (1H, td, J=7.5, 1.0 Hz), 6.14
(1H, dt, J=16.4, 9.8 Hz), 5.72 (1H, d, J=16.4 Hz), 5.47 (1H, dd,
J=9.8, 1.2 Hz), 4.35-4.47 (1H, m), 4.25-4.35 (1H, m), 4.05 (1H, d,
J=13.4 Hz), 3.78 (1H, d, J=13.4 Hz). MS (ESI) [M+H].sup.+,
398.0.
Step C.
2-((N-((1S,2R)-2-(3-chlorophenyl)-1-(4-chlorophenyl)but-3-enyl)ace-
tamido)methyl)phenyl acetate
##STR00338##
[1936] To a solution of 1.1 g (2.76 mmol) of
2-(((1S,2R)-2-(3-chlorophenyl)-1-(4-chlorophenyl)but-3-enylamino)methyl)p-
henol (Example 115, Step B) and triethylamine (0.85 mL, 6.08 mmol)
in a mixture of THF (5.0 mL) and DCM (5.0 mL) was added acetic
anhydride (0.55 mL, 5.80 mmol) at 0.degree. C. The temperature of
the reaction was slowly allowed to rise to room temperature and the
mixture was stirred at ambient temperature overnight. When LCMS
indicated completion of the reaction, 100 ml of ethyl acetate was
added and the combined organics were washed consecutively with
water (30 ml), citric acid (30 ml, IM), NaHCO.sub.3 solution (30
ml) and sat. NaCl solution (30 ml), dried over MgSO.sub.4, filtered
and the filtrate was concentrated to give the title compound. The
crude product was used without further purification.
[1937] .sup.1H NMR (400 MHz, CHLOROFORM-d) .delta. ppm 7.05-7.14
(4H, m), 6.91-7.05 (6H, m), 6.88 (1H, d, J=7.4, Hz), 6.81 (1H, t,
J=7.5 Hz), 6.42 (1H, m), 5.95 (1H, dt, J=16.8, 9.6 Hz), 4.97-5.18
(2H, m), 4.24-4.45 (2H, m), 4.05 (1H, q, J=7.0 Hz), 2.31 (3H, s),
1.91 (3H, s). MS (ESI) [M+H].sup.+, 482.0.
Step D.
N-((1S,2R)-2-(3-chlorophenyl)-1-(4-chlorophenyl)but-3-enyl)acetami-
de
##STR00339##
[1939] A solution of 1.05 g (2.18 mmol) of
2-((N-((1S,2R)-2-(3-chlorophenyl)-1-(4-chlorophenyl)but-3-enyl)acetamido)-
methyl)phenyl acetate (Example 115, Step C) and toluenesulfonic
acid monohydrate (1.66 g, 8.71 mmol) in toluene (15.0 mL) was
heated to reflux for about 2 h. 120 ml of ethyl acetate was added,
and the combined organics were washed consecutively with
NaHCO.sub.3 solution and sat. NaCl solution, dried over MgSO.sub.4,
filtered and the filtrate was concentrated. The crude mixture was
purified by preparative HPLC to give the title compound.
[1940] .sup.1H NMR (500 MHz, CHLOROFORM-d) .delta. ppm 7.08-7.15
(2H, m), 7.02-7.08 (2H, m), 6.92 (3H, t, J=8.6, Hz), 6.81 (1H, dd,
J=3.5, 2.1 Hz), 5.83-6.07 (2H, m), 5.04-5.21 (3H, m), 3.48 (1H, t,
J=9.3 Hz), 1.97 (3H, s). MS (ESI) [M+H].sup.+, 334.0.
Step E.
(1S,2R)-2-(3-chlorophenyl)-1-(4-chlorophenyl)but-3-en-1-amine
##STR00340##
[1942] To a mixture of 4.1 g (12.27 mmol) of
N-((1S,2R)-2-(3-chlorophenyl)-1-(4-chlorophenyl)but-3-enyl)acetamide
(Example 115, Step D) and pyridine (1.20 mL, 14.72 mmol) in THF
(35.0 mL) was added 1.2 mL (13.5 mmol) of oxalyl chloride at
0.degree. C. The resulting light yellow slurry was stirred at
0.degree. C. for 1.5 h. 1,2-dihydroxypropane (1.80 mL, 24.53 mmol)
was added in one portion and the reaction was warmed to rt. The
mixture was treated with ethanol (16.0 ml) followed by 6 N HCl
(16.0 ml). The reaction mixture was heated at 55.degree. C. for 10
min and then cooled down to rt. When LCMS indicated that most SM
was consumed, 200 ml of ethyl acetate was added, and the organic
layer was washed consecutively with NaHCO.sub.3 solution and sat.
NaCl solution, dried over MgSO.sub.4, filtered and the filtrate was
concentrated. The crude mixture was purified by flash
chromatography on silica gel to give the title compound.
[1943] .sup.1H NMR (400 MHz, CHLOROFORM-d) .delta. ppm 7.21 (3H, d,
J=8.4 Hz), 7.03-7.17 (3H, m), 6.96 (1H, s), 6.79 (1H, ddd, J=6.2,
2.2, 2.0 Hz), 5.98 (1H, dt, J=16.8, 9.8 Hz), 5.39 (1H, d, J=16.8
Hz), 5.24 (1H, d, J=10.2 Hz), 4.14 (1H, d, J=11.2 Hz), 3.76 (1H, t,
J=10.2 Hz). MS (ESI) [M+H].sup.+, 292.1.
Step F.
(1S,2R)-2-(3-chlorophenyl)-1-(4-chlorophenyl)-N-(dicyclopropylmeth-
yl)but-3-en-1-amine
##STR00341##
[1945] To a solution of 2.0 g (6.84 mmol) of
(1S,2R)-2-(3-chlorophenyl)-1-(4-chlorophenyl)but-3-en-1-amine
(Example 115, Step E), dicyclopropyl ketone (7.54 mL, 68.4 mmol),
and acetic acid (1.96 mL, 34.2 mmol) in methanol (25.0 mL) was
added sodium cyanoborohydride (1.44 mL, 27.4 mmol) at rt. The
resulting mixture was stirred at 50.degree. C. for 2 days. Acetic
acid (1.5 ml) and sodium cyanoborohydride (0.6 g) were added again
and heating was continued overnight. 200 ml of ethyl acetate was
added, and the organic layer was washed consecutively with
K.sub.2CO.sub.3 solution and sat. NaCl solution, dried over
K.sub.2CO.sub.3, filtered and the filtrate was concentrated under
reduced pressure at 60.degree. C. The mixture was purified by flash
chromatography on silica gel (eluent: DCM/MeOH, 95/5) to give the
title compound.
[1946] .sup.1H NMR (400 MHz, CHLOROFORM-d) .delta. ppm 7.20-7.41
(4H, m), 7.04-7.20 (2H, m), 6.92-7.04 (1H, m), 6.80 (1H, dt, J=7.0,
1.6 Hz), 6.11 (1H, ddd, J=16.8, 10.0, 9.8 Hz), 5.63 (1H, d, J=16.8
Hz), 5.52 (1H, d, J=10.0 Hz), 4.47 (1H, d, J=10.8 Hz), 4.06 (1H, t,
J=10.0 Hz), 1.79 (1H, t, J=9.4 Hz), 1.08-1.24 (1H, m), 0.91-1.08
(2H, m), 0.50-0.78 (3H, m), 0.29-0.50 (2H, m), 0.24 (1H, dq, J=9.9,
5.0 Hz), 0.09 (1H, ddd, J=9.9, 5.2, 5.0 Hz). MS (ESI) [M+H].sup.+,
386.0.
Step G.
N-((1S,2R)-2-(3-chlorophenyl)-1-(4-chlorophenyl)but-3-enyl)-N-(dic-
yclopropylmethyl)acrylamide
##STR00342##
[1948] To a solution of 2.1 g (5.44 mmol) of
(1S,2R)-2-(3-chlorophenyl)-1-(4-chlorophenyl)-N-(dicyclopropylmethyl)but--
3-en-1-amine (Example 115, Step F) and triethylamine (1.89 mL,
13.59 mmol) in THF (30.0 mL) was added acryloyl chloride (0.66 mL,
8.15 mmol) at 0.degree. C. The resulting reaction mixture was
stirred at rt for 2 h. When LCMS indicated completion of the
reaction, 100 ml of ethyl acetate was added and the combined
organics were washed consecutively with water (10 ml), citric acid
(10 ml, 1M), NaHCO.sub.3 solution (10 ml) and sat. NaCl solution
(30 ml), dried over MgSO.sub.4, filtered and the filtrate was
concentrated. The crude product was purified by flash
chromatography on silica gel (eluent: hexane/ethyl acetate, 90/10
to 20/80) to give the title compound.
[1949] .sup.1H NMR (500 MHz, CHLOROFORM-d) .delta. ppm 7.28 (3H,
br. s.), 6.94-7.17 (5H, m), 6.87 (1H, br. s.), 6.42 (1H, m.), 6.20
(2H, ddd, J=16.9, 9.8, 9.5 Hz), 5.58 (1H, d, J=10.3 Hz), 5.18 (1H,
d, J=16.9 Hz), 5.06 (2H, dd, J=10.3, 1.3 Hz), 2.72 (1H, br. s.),
1.19-1.41 (1H, m), 0.77-1.00 (2H, m), 0.63 (3H, d, J=5.6 Hz), 0.50
(1H, br. s.), 0.43 (1H, d, J=4.6 Hz), 0.20 (1H, br. s.), -0.28 (1H,
br. s.). MS (ESI) [M+H].sup.+, 440.0.
Step H.
(5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-(dicyclopropylmeth-
yl)-5,6-dihydropyridin-2(1H)-one
##STR00343##
[1951] To a solution of 2.1 g (4.77 mmol) of
N-((1S,2R)-2-(3-chlorophenyl)-1-(4-chlorophenyl)but-3-enyl)-N-(dicyclopro-
pylmethyl)acrylamide (Example 115, Step G) in 50 mL of DCE was
added 160 mg of
1,3-bis-(2,4,6-trimethylphenyl)-2-(imidazolidinylidene)(dichlorophe-
nylmethylene)(tricyclohexylphosphine)ruthenium ("Grubb's 2nd
Generation Catalyst"). The resulting mixture was degassed two times
and then heated to 70.degree. C. for 18 h. Another 160 mg of
Grubb's 2nd Generation Catalyst was added at that time and heating
was continued for another 18 h. The reaction mixture was cooled to
room temperature. The solvent was removed and the residue was
purified by chromatography on silica gel (eluent: hexane/ethyl
acetate, 90/10 to 20/80) to give the title compound.
[1952] .sup.1H NMR (500 MHz, CHLOROFORM-d) .delta. ppm 7.13-7.36
(8H, m), 6.42 (1H, d, J=9.8 Hz), 6.27 (1H, ddd, J=9.8, 6.1, 1.3
Hz), 4.91 (1H, s), 3.67 (1H, d, J=6.1 Hz), 3.28-3.44 (1H, m), 0.42
(1H, ddd, J=8.9, 4.6, 4.5 Hz), 0.26-0.37 (3H, m), 0.12-0.26 (3H,
m), -0.07-0.02 (1H, m), -0.24--0.12 (1H, m), -0.34--0.24 (1H, m).
MS (ESI) [M+H].sup.+, 412.1.
Step I.
(5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-(dicyclopropylmeth-
yl)piperidin-2-one
##STR00344##
[1954] A solution of
(5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-(dicyclopropylmethyl)-5,6-
-dihydropyridin-2(1H)-one (Example 115, Step H, 0.826 g, 2.003
mmol) and (1,5-cyclooctadiene)(pyridine)
(tricyclohexylphosphine)iridium (i) hexafluorophosphate (0.129 g,
0.160 mmol) in DCM (60.0 ml) was saturated with hydrogen. The
resulting mixture was stirred at rt under a hydrogen atmosphere for
2 h, then another 66.0 mg of (1,5-cyclooctadiene)(pyridine)
(tricyclohexylphosphine)iridium (i) hexafluorophosphate were added.
Stirring under hydrogen atmosphere was continued until LCMS
indicated complete saturation of the double bond. The solvent was
removed and the crude mixture was purified by chromatography on
silica gel (eluting with ethyl acetate:hexane, 10:90) to give the
title compound.
[1955] .sup.1H NMR (400 MHz, CHLOROFORM-d) .delta. ppm 7.11-7.32
(7H, m), 6.98-7.11 (1H, m), 4.96 (1H, d, J=4.7 Hz), 3.26 (1H, m.),
2.92-3.15 (1H, m), 2.60 (2H, t, J=6.9 Hz), 2.09 (1H, dddd, J=14.1,
7.3, 7.1, 4.9 Hz), 1.83-2.01 (1H, m), 0.80-0.94 (1H, m), 0.45-0.61
(1H, m), 0.12-0.41 (6H, m), 0.05 (1H, dt, J=9.7, 4.8, Hz),
-0.19--0.04 (1H, m). MS (ESI) [M+H].sup.+, 414.0.
Step J.
(5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-(dicyclopropylmeth-
yl)-3(R,S)-methylpiperidin-2-one
##STR00345##
[1957] The title compound was prepared form
(5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-(dicyclopropylmethyl)pipe-
ridin-2-one (Example 115, Step I) as described in Example 68, Step
C. The crude product was purified by chromatography on silica gel
(eluent:ethyl acetate:hexane, 10:90) to give the title compound as
colorless oil.
[1958] .sup.1H NMR (500 MHz, CHLOROFORM-d) .delta. ppm 7.16 (2H, d,
J=8.6 Hz), 7.00-7.14 (6H, m), 4.95 (1H, d, J=2.2 Hz), 3.21 (1H, br.
s.), 2.85-2.99 (1H, m), 2.40 (1H, dt, J=10.3, 7.1 Hz), 1.68-1.87
(2H, m), 1.21 (3H, s), 1.04-1.17 (1H, m), 0.86 (1H, d, J=4.2 Hz),
0.35-0.51 (1H, m), 0.12-0.28 (4H, m), -0.04-0.12 (2H, m),
-0.34--0.15 (1H, m).
Step K.
(3S/3R,5R,6S)-3-allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-(dic-
yclopropylmethyl)-3-methylpiperidin-2-one
##STR00346##
[1960] The title compound was obtained as a mixture of
stereoisomers by using a procedure similar to the one described in
Example 68, Step D.
[1961] .sup.1H NMR (400 MHz, CHLOROFORM-d) .delta. ppm 7.06-7.23
(4H, m), 6.91-7.06 (3H, m), 6.69-6.86 (1H, m), 5.79-5.98 (1H, m),
5.03-5.26 (2H, m), 4.81 (1H, d, J=9.6 Hz), 3.03-3.22 (1H, m),
2.49-2.78 (2H, m), 1.88-2.01 (2H, m), 1.46 (1H, s), 1.21 (2H, s),
0.98-1.16 (1H, m), 0.44-0.71 (3H, m), 0.19-0.44 (3H, m), -0.11-0.19
(3H, m). MS (ESI) [M+H].sup.+, 468.2.
Step L.
2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-(dicycloprop-
ylmethyl)-3-methyl-2-oxopiperidin-3-yl)acetic acid
##STR00347##
[1963] A mixture of diastereomers of
(3S/3R,5R,6S)-3-allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-(dicyclopro-
pylmethyl)-3-methylpiperidin-2-one (Example 115, Step K) was
converted to a distereomeric mixture of the acids by a procedure
similar to the one described in Example 71, Step F. Individual
steroisomers were separated by reverse phase prep. HPLC
(Sunfire.TM. Prep C.sub.18 OBD 10 .mu.m column (Waters, Milford,
Mass.), gradient elution of 40% MeCN in water to 80% MeCN in water
over a 30 min period, where both solvents contain 0.1% TFA) to give
the title compound as the faster eluting isomer.
[1964] .sup.1H NMR (400 MHz, CHLOROFORM-d) .delta. ppm 7.98 (1H,
dd, J=7.6, 6.5 Hz), 7.00-7.29 (7H, m), 6.86 (1H, d, J=7.4 Hz), 4.93
(1H, d, J=8.2 Hz), 4.33 (1H, d, J=5.1 Hz), 3.09-3.15 (1H, m), 3.03
(1H, d, J=15.1 Hz), 2.69-2.80 (1H, m), 2.08-2.17 (2H, m), 1.35 (3H,
s), 1.14-1.21 (1H, m), 0.53-0.73 (2H, m), 0.41-0.51 (2H, m),
0.27-0.40 (2H, m), 0.02-0.21 (3H, m). MS (ESI) [M+H].sup.+,
486.2.
[1965] Further elution and concentration in vacuo provided Example
116.
Example 116
2-((3S,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-(dicyclopropylmethyl-
)-3-methyl-2-oxopiperidin-3-yl)acetic acid
##STR00348##
[1967] The title compound was obtained from procedure 115 as the
slower eluting isomer.
[1968] .sup.1H NMR (500 MHz, CHLOROFORM-d) .delta. ppm 7.10-7.33
(6H, m), 6.95-7.03 (2H, m), 6.73-6.83 (1H, m), 4.80 (1H, d, J=9.8
Hz), 3.18-3.23 (1H, m), 2.84 (1H, t, J=13.4 Hz), 2.72-2.79 (1H, m),
2.63-2.72 (1H, m), 2.32-2.39 (1H, m), 1.77 (1H, dd, J=13.2, 3.4
Hz), 1.64-1.68 (3H, m), 1.14 (1H, m), 0.64-0.70 (1H, m), 0.52-0.58
(1H, m), 0.44-0.49 (2H, m), 0.27-0.33 (2H, m), 0.13-0.18 (2H, m),
-0.01 (1H, m). MS (ESI) [M-H], 484.0.
Example 117
((3S,4R,6R)-4-(3-chlorophenyl)-3-(4-chlorophenyl)-1,1-dioxido-2-(2-propany-
l)-1,2-thiazinan-6-yl)acetic acid
##STR00349##
[1969] Step A.
(E)-N-((1S,2R)-2-(3-chlorophenyl)-1-(4-chlorophenyl)but-3-enyl)-2-phenyle-
thenesulfonamide
##STR00350##
[1971] To a solution of 5.33 g (18.24 mmol) of
(1S,2R)-2-(3-chlorophenyl)-1-(4-chlorophenyl)but-3-en-1-amine
(Example 115, Step E) in DCM (45.0 mL) was added
N,N-diisopropylethylamine (4.8 mL, 27.5 mmol), followed by
trans-beta-styrenesulfonyl chloride (4.17 g, 20.58 mmol). The
resulting solution was stirred at ambient temperature under an
N.sub.2 atmosphere. After being stirred for 3.25 hours, the
reaction was diluted with water and extracted with DCM. The
combined organic layers were washed with sat. aq. NaCl solution,
dried over Na.sub.2SO.sub.4, filtered and the filtrate was
concentrated. Purification by flash chromatography on silica gel (0
to 40% EtOAc in hexanes gradient) provided the title compound as a
yellow solid.
[1972] .sup.1H NMR (500 MHz, CHLOROFORM-d) .delta. 7.30-7.41 (m,
3H), 7.12-7.17 (m, 2H), 7.05-7.11 (m, 5H), 6.97-7.03 (m, 3H),
6.82-6.89 (m, 1H), 6.17 (d, J=15.41 Hz, 1H), 6.06-6.15 (m, 1H),
5.21-5.40 (m, 2H), 5.13 (d, J=5.62 Hz, 1H), 4.60 (dd, J=5.87, 9.29
Hz, 1H), 3.54 (t, J=9.17 Hz, 1H). MS (ESI) 480.0 [M+Na].sup.+.
Step B.
(3S,4R)-4-(3-chlorophenyl)-3-(4-chlorophenyl)-3,4-dihydro-2H-1,2-t-
hiazin
##STR00351##
[1974] To a degassed solution of 7.29 g (15.90 mmol) of
(E)-N-((1S,2R)-2-(3-chlorophenyl)-1-(4-chlorophenyl)but-3-enyl)-2-phenyle-
thenesulfonamide (Example 117, Step A) in a 1:1 mixture of DCM (350
mL) and DCE (350 mL) was added Grubbs First Generation (1.20 g,
1.434 mmol). The resulting solution was stirred at 70.degree. C.
for 20 hours. After cooling to room temperature, the reaction was
concentrated under reduced pressure. Purification by flash
chromatography on silica gel (0 to 2% MeOH in DCM gradient)
provided the title compound.
[1975] .sup.1H NMR (500 MHz, CHLOROFORM-d) .delta. 7.20-7.29 (m,
J=8.80 Hz, 3H), 7.11-7.19 (m, 1H), 7.02 (d, J=8.31 Hz, 2H), 6.99
(t, J=0.71 Hz, 1H), 6.86 (dd, J=2.69, 10.76 Hz, 1H), 6.79 (d,
J=7.58 Hz, 1H), 6.44 (dd, J=2.20, 11.00 Hz, 1H), 5.14 (d, J=11.00
Hz, 1H), 4.86 (t, J=10.76 Hz, 1H), 3.76 (td, J=2.35, 10.70 Hz, 1H).
MS (ESI) 376.0 [M+Na].sup.+.
Step C.
(3S,4R)-4-(3-chlorophenyl)-3-(4-chlorophenyl)-1,2-thiazinan
##STR00352##
[1977] A solution of 4.14 g (11.69 mmol) of
(3S,4R)-4-(3-chlorophenyl)-3-(4-chlorophenyl)-3,4-dihydro-2H-1,2-thiazin
(Example 117, Step B) in dichloromethane (63.0 mL) was purged with
argon three times, and then Crabtree's catalyst (835.2 mg, 1.027
mmol) was added to the reaction mixture. The reaction was purged
again with argon, and then a hydrogen atmosphere was placed over
the reaction. The solution was stirred at ambient temperature for
15 hours, at which point the reaction was concentrated down to an
oil. Purification by flash chromatography on silica gel (0 to 4%
MeOH in DCM gradient) provided the title compound as a tan
solid.
[1978] .sup.1H NMR (500 MHz, CHLOROFORM-d) .delta. 7.16-7.22 (m,
2H), 7.08-7.14 (m, 2H), 6.99-7.07 (m, 3H), 6.82-6.88 (m, 1H), 4.67
(dd, J=5.01, 10.88 Hz, 1H), 4.55 (d, J=4.65 Hz, 1H), 3.25-3.39 (m,
2H), 2.89-3.04 (m, 1H), 2.67 (dddd, J=6.60, 10.39, 12.50, 14.52 Hz,
1H), 2.39 (qd, J=3.67, 14.43 Hz, 1H). MS (ESI) 378.0
[M+Na].sup.+.
Step D.
(3S,4R)-4-(3-chlorophenyl)-3-(4-chlorophenyl)-2-(2-propanyl)-1,2-t-
hiazinan
##STR00353##
[1980] To a solution of 1.21 g (3.40 mmol) of
(3S,4R)-4-(3-chlorophenyl)-3-(4-chlorophenyl)-1,2-thiazinan
(Example 117, Step C) in DMF (8.5 mL) was added cesium carbonate
(4.31 g, 13.23 mmol), followed by 2-iodopropane (2.9 mL, 29.0
mmol). The resulting mixture was heated at 85.degree. C. for 23
hours. After cooling to room temperature, the reaction mixture was
diluted with water and extracted with ethyl acetate. The combined
organic layers were washed with sat. NaCl solution, dried over
Na.sub.2SO.sub.4, filtered and the filtrate was concentrated.
Purification by flash chromatography on silica gel (0 to 2% MeOH in
DCM gradient) provided the title compound as a white solid.
[1981] .sup.1H NMR (500 MHz, CHLOROFORM-d) .delta. 7.13-7.19 (m,
3H), 7.04-7.12 (m, 3H), 7.00 (t, J=1.83 Hz, 1H), 6.75 (d, J=7.58
Hz, 1H), 4.51 (d, J=10.76 Hz, 1H), 3.81 (td, J=6.94, 13.75 Hz, 1H),
3.40-3.49 (m, 1H), 3.25-3.39 (m, 2H), 2.53 (ddt, J=6.85, 11.49,
13.45 Hz, 1H), 2.23 (tdd, J=2.96, 6.54, 13.94 Hz, 1H), 1.36 (d,
J=6.85 Hz, 3H), 1.07 (d, J=7.09 Hz, 3H). MS (ESI) 420.0
[M+Na].sup.+.
Step E.
(3S,4R,6R/6S)-4-(3-chlorophenyl)-3-(4-chlorophenyl)-2-(2-propanyl)-
-6-(2-propen-1-yl)-1,2-thiazinan
##STR00354##
[1983] To a degassed solution of 211.7 mg (0.531 mmol) of
(3S,4R)-4-(3-chlorophenyl)-3-(4-chlorophenyl)-2-(2-propanyl)-1,2-thiazina-
n (Example 117, Step D) in THF (2.5 mL) was added allyl iodide
(0.25 mL, 2.74 mmol). The resulting solution was heated to
50.degree. C. After 10 minutes, a 1 M solution of lithium
bis(trimethylsilyl)-amide in THF (0.86 mL, 0.860 mmol) was added
dropwise, over one minute. After heating at 50.degree. C. for 20
hours, the reaction was cooled to room temperature, quenched with
water (2 mL), and then concentrated under reduced pressure.
Purification by flash chromatography on silica gel (0 to 100% DCM
in hexanes gradient) provided the title compounds as a white solid.
The .sup.1H NMR showed a 91:9 mixture of R/S allyl epimers.
[1984] A degassed solution of 98.6 mg (0.225 mmol) of the epimeric
mixture in THF (5 mL) was heated to 60.degree. C. After 10 minutes,
a 1 M solution of lithium bis(trimethylsilyl)-amide in THF (1.0 mL,
1.00 mmol) was added. The resulting solution was then stirred at
60.degree. C. for 45 minutes, at which point methanol (275.0 .mu.L,
6.80 mmol) was then added. The solution was heated for another 45
minutes at 60.degree. C. Upon cooling to room temperature, the
reaction was quenched with methanol (5 mL), then concentrated under
reduced pressure. The material was purified by reverse-phase
preparative HPLC using an Agilent Eclipse Plus C18 column (Agilent
Technologies, Santa, Clara, Calif.), 0.1% TFA in MeN/H.sub.2O,
gradient 30% to 95% over 25 minutes to provide the title compounds,
as a white solid. The .sup.1H NMR showed .about.2:1 mixture of
epimers. Individual stereoisomers were separated by SFC
(Chiralcel.RTM. AD-H column (Diacel, Fort Lee N.J.), 30 mm
I.D..times.250 mm, using 12 g/min of a 20 mM solution of NH.sub.3
in isopropyl alcohol and 68 g/min of CO.sub.2 as the eluent) to
give
(3S,4R,6S)-4-(3-chlorophenyl)-3-(4-chlorophenyl)-2-(2-propanyl)-6-(2-prop-
en-1-yl)-1,2-thiazinan (t.sub.R=1.62 min) as a white solid.
[1985] .sup.1H NMR (500 MHz, CHLOROFORM-d) .delta. ppm 7.16-7.21
(m, 1H), 7.06-7.15 (m, 5H), 7.00 (t, J=1.59 Hz, 1H), 6.72 (d,
J=7.58 Hz, 1H), 5.71-5.88 (m, 1H), 5.11-5.24 (m, 2H), 4.34 (d,
J=11.00 Hz, 1H), 3.99-4.11 (m, 1H), 3.46 (ddd, J=13.33, 10.76, 3.06
Hz, 1H), 3.32-3.43 (m, 1H), 2.85-2.96 (m, 1H), 2.43-2.61 (m, 2H),
2.00 (dt, J=13.94, 2.45 Hz, 1H), 1.35 (d, J=6.85 Hz, 3H), 1.00 (d,
J=7.09 Hz, 3H). MS (ESI) 460.0 [M+Na].sup.+.
[1986] Also obtained was
(3S,4R,6R)-4-(3-chlorophenyl)-3-(4-chlorophenyl)-2-(2-propanyl)-6-(2-prop-
en-1-yl)-1,2-thiazinan (t.sub.R=1.87 min) as a white solid.
[1987] .sup.1H NMR (500 MHz, CHLOROFORM-d) .delta. ppm 7.16 (d,
J=8.31 Hz, 2H), 7.10-7.14 (m, 1H), 7.04-7.10 (m, 3H), 6.99 (t,
J=1.59 Hz, 1H), 6.74 (d, J=7.58 Hz, 1H), 5.76 (dddd, J=16.84,
10.24, 8.13, 6.11 Hz, 1H), 5.10-5.22 (m, 2H), 4.57 (d, J=11.00 Hz,
1H), 3.59 (dt, J=13.94, 6.97 Hz, 1H), 3.30-3.41 (m, J=11.49, 9.66,
4.71, 4.71 Hz, 1H), 3.26 (ddd, J=12.65, 10.82, 3.42 Hz, 1H),
2.84-2.98 (m, 1H), 2.21-2.33 (m, 2H), 2.04-2.19 (m, 1H), 1.36 (d,
J=6.85 Hz, 3H), 1.13 (d, J=6.85 Hz, 3H). MS (ESI) 460.0
[M+Na].sup.+.
Step F.
((3S,4R,6R)-4-(3-chlorophenyl)-3-(4-chlorophenyl)-1,1-dioxido-2-(2-
-propanyl)-1,2-thiazinan-6-yl)acetic acid
##STR00355##
[1989] The title compound was obtained from
(3S,4R,6S)-4-(3-chlorophenyl)-3-(4-chlorophenyl)-2-(2-propanyl)-6-(2-prop-
en-1-yl)-1,2-thiazinan (Example 117, Step E) by a procedure similar
to the one described in Example 71, Step F. Purification by
reversed phase preparative HPLC using an Agilent Eclipse Plus C18
column (Agilent Technologies, Santa, Clara, Calif.), 0.1% TFA in
MeCN/H.sub.2O, gradient 30% to 95% over 25 minutes, provided the
title compound as a white solid.
[1990] .sup.1H NMR (500 MHz, CHLOROFORM-d) .delta. ppm 7.12-7.19
(m, 3H), 7.04-7.12 (m, 3H), 6.99 (br. s., 1H), 6.73 (d, J=7.58 Hz,
1H), 4.38 (d, J=11.00 Hz, 1H), 3.91-4.05 (m, 1H), 3.84 (br. s.,
1H), 3.39-3.49 (m, 1H), 3.24 (d, J=17.12 Hz, 1H), 2.88 (dd,
J=17.12, 10.27 Hz, 1H), 2.66-2.79 (m, 1H), 2.02 (d, J=12.72 Hz,
1H), 1.32-1.40 (m, 3H), 1.03 (d, J=6.85 Hz, 3H). MS (ESI) 478.0
[M+Na].sup.+.
Example 118
((3S,4R,6S)-4-(3-chlorophenyl)-3-(4-chlorophenyl)-1,1-dioxido-2-(2-propany-
l)-1,2-thiazinan-6-yl)acetic acid
##STR00356##
[1992] The title compound was prepared from
(3S,4R,6R)-4-(3-chlorophenyl)-3-(4-chlorophenyl)-2-(2-propanyl)-6-(2-prop-
en-1-yl)-1,2-thiazinan (Example 117, Step E) as described in
Example 117, Step F.
[1993] .sup.1H NMR (500 MHz, CHLOROFORM-d) .delta. ppm 7.07 (d,
J=6.85 Hz, 2H), 6.94-7.05 (m, 4H), 6.90 (br. s., 1H), 6.65 (d,
J=7.34 Hz, 1H), 4.48 (d, J=11.00 Hz, 1H), 3.70-3.79 (m, 1H),
3.48-3.57 (m, 1H), 3.22-3.32 (m, 1H), 3.10 (dd, J=17.12, 4.65 Hz,
1H), 2.46 (dd, J=17.12, 8.80 Hz, 1H), 2.22-2.34 (m, 1H), 2.07 (d,
J=12.47 Hz, 1H), 1.25 (d, J=6.60 Hz, 3H), 1.01 (d, J=6.60 Hz, 3H).
MS (ESI) 478.0 [M+Na].sup.+.
Example 119
((3S,4R,6R)-4-(3-chlorophenyl)-3-(4-chlorophenyl)-6-methyl-1,1-dioxido-2-(-
2-propanyl)-1,2-thiazinan-6-yl)acetic acid
##STR00357##
[1994] Step A. Synthesis of
(3S,4R,6S)-4-(3-chlorophenyl)-3-(4-chlorophenyl)-6-methyl-2-(2-propanyl)--
6-(2-propen-1-yl)-1,2-thiazinan
##STR00358##
[1996] To a degassed solution of diisopropylamine (300 .mu.L, 2.123
mmol) in THF (1.0 ml) was added dropwise at -78.degree. C.
n-butyllithium, 2.5 M in hexanes (800 .mu.L, 2.000 mmol). After
stirring the solution at -78.degree. C. for 10 min, the reaction
was warmed to room temperature. In a separate flask, a degassed
solution of 111.9 mg (0.255 mmol) of
(3S,4R,6R)-4-(3-chlorophenyl)-3-(4-chlorophenyl)-2-(2-propanyl)-6-(2-prop-
en-1-yl)-1,2-thiazinan (Example 117, Step E) and methyl iodide (0.6
ml, 9.62 mmol) in THF (1.0 ml) was heated to 50.degree. C. After
five minutes, the LDA solution was added dropwise to the other
flask, and stirring continued for 14 hours at 50.degree. C. Upon
cooling to room temperature, the reaction was quenched with water
(3 mL), then concentrated under reduced pressure. Purification by
reverse-phase preparative HPLC using an Agilent Eclipse Plus C18
column (Agilent Technologies, Santa, Clara, Calif.), 0.1% TFA in
CH.sub.3CN/H.sub.2O, gradient 60% to 80% over 25 minutes provided
the title compound as a white solid.
[1997] .sup.1H NMR (500 MHz, CHLOROFORM-d) .delta. ppm 7.18 (br.
s., 2H), 7.03-7.14 (m, 4H), 6.96 (d, J=1.71 Hz, 1H), 6.72 (d,
J=7.34 Hz, 1H), 5.64-5.93 (m, 1H), 5.18-5.28 (m, 2H), 4.45 (d,
J=10.76 Hz, 1H), 3.61-3.75 (m, 1H), 3.30-3.44 (m, 1H), 2.82-2.90
(m, 1H), 2.74-2.82 (m, 1H), 2.17-2.32 (m, 1H), 2.02 (dd, J=13.94,
3.18 Hz, 1H), 1.42 (s, 3H), 1.34 (d, J=6.85 Hz, 3H), 1.11 (d,
J=6.85 Hz, 3H). MS (ESI) 474.1 [M+Na].sup.+.
Step B.
((3S,4R,6R)-4-(3-chlorophenyl)-3-(4-chlorophenyl)-6-methyl-1,1-dio-
xido-2-(2-propanyl)-1,2-thiazinan-6-yl)acetic acid
##STR00359##
[1999] The title compound was prepared from
(3S,4R,6S)-4-(3-chlorophenyl)-3-(4-chlorophenyl)-6-methyl-2-(2-propanyl)--
6-(2-propen-1-yl)-1,2-thiazinan (Example 119, Step A) as described
in Example 1, Step F.
[2000] .sup.1H NMR (500 MHz, CHLOROFORM-d) .delta. ppm 7.08 (d,
J=7.34 Hz, 2H), 6.92-7.03 (m, 4H), 6.87 (br. s., 1H), 6.63 (d,
J=7.34 Hz, 1H), 4.41 (d, J=11.00 Hz, 1H), 3.41-3.52 (m, 1H),
3.29-3.36 (m, 1H), 3.25 (d, J=14.92 Hz, 1H), 2.93 (d, J=15.16 Hz,
1H), 2.21-2.36 (m, 2H), 1.51 (s, 3H), 1.23 (d, J=6.60 Hz, 3H), 1.05
(d, J=6.60 Hz, 3H). MS (ESI) 492.1 [M+Na].sup.+.
Example 120
((3S,4R,6S)-4-(3-chlorophenyl)-3-(4-chlorophenyl)-6-methyl-1,1-dioxido-2-(-
2-propanyl)-1,2-thiazinan-6-yl)acetic acid
##STR00360##
[2001] Step A.
(3S,4R,6R)-4-(3-chlorophenyl)-3-(4-chlorophenyl)-6-methyl-2-(2-propanyl)--
1,2-thiazinan
##STR00361##
[2003] To a degassed solution of 239.9 mg (0.602 mmol) of
(3S,4R)-4-(3-chlorophenyl)-3-(4-chlorophenyl)-2-(2-propanyl)-1,2-thiazina-
n (Example 117, Step D) in THF (2.0 mL) was added iodomethane (60.0
.mu.l, 0.960 mmol), followed by dropwise addition of a 1 M solution
of lithium bis(trimethylsilyl)-amide in THF (640.0 .mu.l, 0.640
mmol). After stirring at room temperature for 17 hours, the
reaction was quenched with MeOH (3 mL), then concentrated under
reduced pressure. Purification by flash chromatography on silica
gel (0 to 70% DCM in hexanes gradient) provided the title compound
as a white solid. The .sup.1H NMR showed 6% of the 6S epimer was
also isolated.
[2004] .sup.1H NMR (500 MHz, CHLOROFORM-d) .delta. ppm 7.14-7.18
(m, 2H), 7.04-7.13 (m, 4H), 6.95-7.01 (m, 1H), 6.71-6.77 (m, 1H),
4.57 (d, J=10.76 Hz, 1H), 3.54-3.63 (m, 1H), 3.39-3.51 (m, 1H),
3.23-3.39 (m, 1H), 2.14-2.27 (m, 2H), 1.42 (d, J=6.85 Hz, 3H),
1.34-1.38 (m, 3H), 1.13 (d, J=6.85 Hz, 3H). MS (ESI) 434.0
[M+Na].sup.+.
Step B.
(3S,4R,6R)-4-(3-chlorophenyl)-3-(4-chlorophenyl)-6-methyl-2-(2-pro-
panyl)-6-(2-propen-1-yl)-1,2-thiazinan
##STR00362##
[2006] To a degassed solution of 174.7 mg (0.424 mmol) of
(3S,4R,6R)-4-(3-chlorophenyl)-3-(4-chlorophenyl)-6-methyl-2-(2-propanyl)--
1,2-thiazinan (Example 120, Step A) in THF (1.5 mL) was added allyl
iodide (0.55 mL, 6.02 mmol). The resulting solution was heated to
60.degree. C. for 10 minutes, then a 1 M solution of lithium
bis(trimethylsilyl)-amide in THF (2.0 mL, 2.00 mmol) was added
dropwise, over one minute. After heating at 60.degree. C. for 17
hours, the reaction was cooled to room temperature, quenched with
water (2 mL), and then concentrated under reduced pressure.
Purification by reverse-phase preparative HPLC using an Agilent
Eclipse Plus C18 column (Agilent Technologies, Santa, Clara,
Calif.), 0.1% TFA in MeCN/H.sub.2O, gradient 40% to 95% over 25
minutes, provided the title compound as a white solid.
[2007] .sup.1H NMR (500 MHz, CHLOROFORM-d) .delta. ppm 7.15-7.20
(m, 2H), 7.03-7.13 (m, 4H), 6.97 (s, 1H), 6.73 (d, J=7.34 Hz, 1H),
5.72-5.89 (m, 1H), 5.22 (d, J=4.65 Hz, 1H), 5.19 (s, 1H), 4.47 (d,
J=10.76 Hz, 1H), 3.56-3.69 (m, 1H), 3.31-3.42 (m, 1H), 2.69 (dd,
J=13.82, 7.21 Hz, 1H), 2.55 (dd, J=13.82, 7.70 Hz, 1H), 2.38 (t,
J=13.45 Hz, 1H), 1.87 (dd, J=13.94, 3.18 Hz, 1H), 1.61 (s, 3H),
1.33 (d, J=6.85 Hz, 3H), 1.12 (d, J=6.85 Hz, 3H). MS (ESI) 474.1
[M+Na].sup.+.
Step C.
((3S,4R,6S)-4-(3-chlorophenyl)-3-(4-chlorophenyl)-6-methyl-1,1-dio-
xido-2-(2-propanyl)-1,2-thiazinan-6-yl)acetic acid
##STR00363##
[2009] The title compound was prepared from
(3S,4R,6R)-4-(3-chlorophenyl)-3-(4-chlorophenyl)-6-methyl-2-(2-propanyl)--
6-(2-propen-1-yl)-1,2-thiazinan (Example 120, Step B) as described
in Example 1, Step F.
[2010] .sup.1H NMR (500 MHz, CHLOROFORM-d) .delta. ppm 7.15-7.23
(m, 2H), 7.03-7.14 (m, 4H), 6.97 (br. s., 1H), 6.73 (d, J=6.60 Hz,
1H), 4.47 (d, J=10.52 Hz, 1H), 3.59-3.73 (m, 1H), 3.42 (t, J=11.74
Hz, 1H), 2.95-3.03 (m, 1H), 2.84-2.93 (m, 1H), 2.47 (t, J=13.08 Hz,
1H), 2.28 (d, J=13.94 Hz, 1H), 1.79 (br. s., 3H), 1.30-1.39 (m,
3H), 1.02-1.14 (m, 3H). MS (ESI) 492.1 [M+Na].sup.+.
Example 121
2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(5-chloropyridin-2-yl)-3-methyl-1-((S)--
1-morpholinobutan-2-yl)-2-oxopiperidin-3-yl)acetic acid
##STR00364##
[2011] Step A. Methyl 5-chloropicolinate
##STR00365##
[2013] To a solution of 5-chloropyridin-2-carboxylic acid (309 g,
1.96 mol) in anhydrous MeOH (2 L) was slowly added thionyl chloride
(299.7 mL, 4.12 mol, 2.1 eq) at room temperature (cloudy solution
became clear brown solution during the addition of thionyl
chloride). After the addition was complete, the reaction mixture
was heated to 50.degree. C. and stirred at this temperature
overnight. The solvent and excess thionyl chloride were removed
under reduced pressure and the crude product was azeotroped with
toluene twice. The resulting solid was transferred to a filter
funnel and washed with saturated aqueous NaHCO.sub.3 until the
filtrate was basic. The resulting solid was dissolved in
dichloromethane (2 L) and washed with saturated aqueous
NaHCO.sub.3. The organics were dried over sodium sulfate, filtered
and the filtrate was concentrated to provide the title compound as
an off-white solid.
Step B. 2-(3-Chlorophenyl)-1-(5-chloropyridin-2-yl)ethanone
##STR00366##
[2015] To a solution of 3-chlorophenylacetic acid (326.5 g, 1.91
mol, 0.95 eq) in THF (1.82 L) at -78.degree. C. was slowly added
NaHMDS (1M solution in THF, 3.82 L, 3.82 mol, 2 eq) over 2 h 45 min
while keeping the temperature below -65.degree. C. After the
addition was complete, the reaction mixture was stirred for 30 min
at -78.degree. C. A solution of methyl 5-chloropicolinate (326.5 g,
1.91 mol, Example 121, Step A) in THF (0.9 L) was added to the
above solution at -78.degree. C. over 30 min. The reaction was
stirred for another 1 h and then allowed to warm to ambient
temperature overnight. The reaction mixture was slowly transferred
into a sat. aq. ammonium chloride solution (4 L), extracted with
ethyl acetate (2.times.8 L), and then the combined organic layers
were dried over Na.sub.2SO.sub.4, filtered and the filtrate was
concentrated. Purification of the residue by flash chromatography
on silica gel (eluent: DCM) provided the title compound as a white
solid.
Step C. methyl
4-(3-chlorophenyl)-5-(5-chloropyridin-2-yl)-5-oxopentanoate
##STR00367##
[2017] To a solution of 368.5 g (1.39 mol) of
2-(3-chlorophenyl)-1-(5-chloropyridin-2-yl)ethanone (Example 121,
Step B) in dioxane (1.5 L) at 80.degree. C. was added DBU (207 mL,
1.39 mole, 1 eq), followed by dropwise addition of methyl acrylate
(124.7 mL, 1.39 mol, 1 eq) at 80.degree. C. The reaction was
stirred at 80.degree. C. for 1 h 30 min and then allowed to cool to
ambient temperature. It was quenched with 2 M aqueous HCl solution
(56.5 eq) and then basified to pH 7 with saturated aqueous
NaHCO.sub.3. The aqueous layer was extracted with EtOAc (2.times.4
L). The combined organic layers were dried over Na.sub.2SO.sub.4,
filtered and the filtrate was evaporated. Purification by flash
chromatography on silica gel (eluent: 40 to 100% DCM/hexanes)
provided the title compound as a yellow liquid.
Step D. (4R,5R)Methyl
4-(3-chlorophenyl)-5-(5-chloropyridin-2-yl)-5-hydroxy pentanoate
and (4S,5S)-methyl
4-(3-chlorophenyl)-5-(5-chloropyridin-2-yl)-5-hydroxypentanoate
##STR00368##
[2019] To a solution of
2-(3-chlorophenyl)-1-(5-chloropyridin-2-yl)ethanone (459.5 g, 1.3
mol, Example 121, Step C) in anhydrous MeOH (1.5 L) was portionwise
added sodium borohydride (14.8 g, 0.392 mol, 0.3 eq) at 0-5.degree.
C. The reaction was stirred at same temperature for 30 min then
quenched with ice-water. The methanol was removed under reduced
pressure. The residue was dissolved in ethyl acetate and washed
with water. The aqueous layer was extracted with ethyl acetate
(3.times.2 L). The combined organic layers were washed with
sat.
[2020] NaCl solution, dried over Na.sub.2SO.sub.4, filtered and the
filtrate was concentrated under reduced pressure. Purification of
the residue by flash chromatography on silica gel (eluent: 10 to
70% EtOAc/hexanes, gradient elution) provided the title compound as
a yellow liquid.
Step E. (4R,5S)Methyl
5-azido-4-(3-chlorophenyl)-5-(5-chloropyridin-2-yl)pentanoate and
(4S,5R)-methyl
5-azido-4-(3-chlorophenyl)-5-(5-chloropyridin-2-yl)pentanoate
##STR00369##
[2022] To a solution of (4R,5R)-methyl
4-(3-chlorophenyl)-5-(5-chloropyridin-2-yl)-5-hydroxypentanoate
(432 g, 1.22 mol, Example 121, Step D) and triethylamine (340 mL,
2.4 mol, 2 eq) in DCM (2.4 L) was added dropwise methanesulfonyl
chloride (123.21 mL, 1.59 mol, 1.3 eq) at 0-5.degree. C. The
reaction was stirred at 0-5.degree. C. for 30 min, then quenched
slowly with ice water and extracted with DCM (2.times.2 L). The
combined organic layers were washed with sat. aq. NaCl solution,
dried over MgSO.sub.4, filtered and the filtrate was concentrated
under reduced pressure.
[2023] The crude mesylate thus obtained was dissolved in DMF (1.5
L) and to it was added sodium azide (300 g, 4.6 mol, 3.8 eq). The
reaction mixture was heated to 90.degree. C. (internal temperature)
for 2 h. It was allowed to cool to ambient temperature. The
reaction mixture was diluted with water (2 L) and extracted with
ethyl acetate (2.times.4 L). The combined organic layers were
washed with sat. NaCl solution (2 L), dried over Na.sub.2SO.sub.4,
filtered and the filtrate was concentrated under reduced pressure.
The crude azide was carried directly to the next step without
further purification.
Step F.
(5R,6S)-5-(3-Chlorophenyl)-6-(5-chloropyridin-2-yl)piperidin-2-one
##STR00370##
[2025] Crude (4R,5S)-methyl
5-azido-4-(3-chlorophenyl)-5-(5-chloropyridin-2-yl)pentanoate (463
g, 1.22 mol, Example 121, Step E) was dissolved in 2.5 L THF/water
(4:1). Trimethyl phosphine (1 M in THF, 1.46 L, 1.46 mol, 1.2 eq)
was added slowly at 0-5.degree. C. The reaction was stirred for 30
min and then basified with 2.0 M aqueous LiOH solution to pH 12.
The reaction mixture was stirred for another 30 min, and extracted
to ethyl acetate (2.times.5 L). The combined organic layers were
washed with sat. NaCl solution, dried over Na.sub.2SO.sub.4,
filtered and the filtrate was concentrated under reduced
pressure.
[2026] Purification of the residue by flash chromatography on
silica gel (eluent: 20-90% EtOAc/hexanes, gradient elution)
followed by recrystallization from EtOAc/hexanes provided trans
5-(3-chlorophenyl)-6-(5-chloropyridin-2-yl)piperidin-2-one as a
mixture of stereoisomers. Individual stereoisomers were separated
by chiral HPLC (flowrate: 100 ml/min on a Chiralcel.RTM. OD-H 10 cm
I.D..times.50 cm, 20 mic column (Daicel Chemical Industries LTD),
using 25% isopropyl alcohol/hexane as the eluent) to give the title
compound (t.sub.R=17-25 min, earlier eluting peak) as a white
solid.
[2027] .sup.1H NMR (300 MHz, CDCl.sub.3) .delta. 8.49 (d, J=2.34
Hz, 1H), 7.52 (dd, J=2.35 and 8.21 Hz, 1H), 7.20-7.17 (m, 2H), 7.07
(s, 1H), 6.93-6.88 (m, 2H), 6.11 (s, 1H), 4.70 (d, J=9.37 Hz, 1H),
3.20-3.13 (m, 1H), 2.61 (q, J=5.27 and 8.2 Hz, 2H), 2.26-2.04 (m,
2H). Mass Spectrum (ESI) m/z=321 (M+1).
Step G. (S)-Ethyl
2-((2S,3R)-3-(3-chlorophenyl)-2-(5-chloropyridin-2-yl)-6-oxopiperidin-1-y-
l)butanoate
##STR00371##
[2029] To an ice-cooled solution of 9.93 g (30.9 mmol) of
(5R,6S)-5-(3-chlorophenyl)-6-(5-chloropyridin-2-yl)piperidin-2-one
(Example 121, Step F) in DMF (65 mL) was added 2.47 g (60 wt. % in
mineral oil, 61.8 mmol) of sodium hydride. The resulting yellow
slurry was stirred at 0.degree. C. for 5 min, then was warmed to
room temperature and stirred for an additional 12 min. The reaction
was re-cooled to 0.degree. C. and 11.4 mL (77 mmol) of ethyl
2-bromobutyrate was added slowly via syringe over 10 min. The
resulting orange slurry was warmed to room temperature and stirred
for 4.75 h, and then was quenched with saturated aqueous ammonium
chloride. The mixture was extracted with ethyl acetate (3.times.),
and the combined organic layers were washed with water (2.times.)
and sat. aq. NaCl solution (1.times.). The organic layer was dried
over Na.sub.2SO.sub.4, filtered and the filtrate was concentrated.
Purification of the residue by flash chromatography on silica gel
(38 to 40% EtOAc/hexanes, gradient elution) provided the title
compound as a light yellow solid.
Step H.
(5R,6S)-5-(3-chlorophenyl)-6-(5-chloropyridin-2-yl)-1-((S)-1-hydro-
xybutan-2-yl)piperidin-2-one
##STR00372##
[2031] To an ice-cooled solution of 3.95 g (10.0 mmol) of (S)-ethyl
2-((2S,3R)-3-(3-chlorophenyl)-2-(5-chloropyridin-2-yl)-6-oxopiperidin-1-y-
l)butanoate (Example 121, Step G) in ether (100 mL) was added 486
mg (90%, 20.1 mmol) of lithium borohydride. The resulting light
yellow slurry was stirred at 0.degree. C. for 3 h, and then was
warmed to room temperature and stirred for an additional 3 h. The
reaction was re-cooled to 0.degree. C. and quenched by cautious
addition of 1 N HCl until bubbling subsided. The mixture was
extracted with EtOAc (3.times.), and the combined organic layers
were washed with saturated aqueous sodium chloride (1.times.). The
organic layer was dried over Na.sub.2SO.sub.4, filtered and the
filtrate was concentrated. Purification of the residue by flash
chromatography on silica gel (1 to 7% MeOH/DCM, gradient elution)
provided the title compound as a white solid.
Step I.
(5R,6S)-1-((S)-1-(tert-butyldiphenylsilyloxy)butan-2-yl)-5-(3-chlo-
rophenyl)-6-(5-chloropyridin-2-yl)piperidin-2-one
##STR00373##
[2033] To a solution of 2.03 g (5.2 mmol) of
(5R,6S)-5-(3-chlorophenyl)-6-(5-chloropyridin-2-yl)-1-((S)-1-hydroxybutan-
-2-yl)piperidin-2-one (Example 121, Step H) and 877 mg (12.9 mmol)
of imidazole in DMF (32 mL) was added 1.9 mL (7.3 mmol) of
tert-butyldiphenylsilyl chloride. The resulting light yellow
solution was stirred at room temperature for 4.5 h. The reaction
was partitioned between water and EtOAc (2.times.), and then the
combined organic layers were dried over Na.sub.2SO.sub.4, filtered
and the filtrate was concentrated. Purification of the residue by
flash chromatography on silica gel (0 to 4% MeOH/DCM, gradient
elution) provided the title compound as a white solid.
Step J.
(5R,6S)-1-((S)-1-(tert-butyldiphenylsilyloxy)butan-2-yl)-5-(3-chlo-
rophenyl)-6-(5-chloropyridin-2-yl)-3-methylpiperidin-2-one
##STR00374##
[2035] To a -78.degree. C. solution of 3.19 g (5.05 mmol) of
(5R,6S)-1-((S)-1-(tert-butyldiphenylsilyloxy)butan-2-yl)-5-(3-chloropheny-
l)-6-(5-chloropyridin-2-yl)piperidin-2-one (Example 121, Step I)
and 347 .mu.L (5.55 mmol) of methyl iodide in dry, degassed THF (40
mL) was added 6.82 mL (6.82 mmol) of a 1 M solution of lithium
bis(trimethylsilyl)amide in THF slowly via syringe over 2 min. The
yellow solution was warmed to 0.degree. C. and stirred for 1.5 h,
and then was warmed to room temperature and stirred for an
additional 15 min. The reaction was quenched with saturated aqueous
ammonium chloride, and extracted with EtOAc (3.times.). The
combined organic layers were dried over Na.sub.2SO.sub.4, filtered
and the filtrate was concentrated. Purification of the residue by
flash chromatography on silica gel (0-15% MeOH/DCM, gradient
elution) provided the title compound (mixture of C-3 epimers) as a
white solid.
Step K.
(5R,6S)-3-allyl-1-((S)-1-((tert-butyldiphenylsilyl)oxy)butan-2-yl)-
-5-(3-chlorophenyl)-6-(5-chloropyridin-2-yl)-3-methylpiperidin-2-one
##STR00375##
[2037] To a solution of 2.95 g (4.57 mmol) of
(5R,6S)-1-((S)-1-(tert-butyldiphenylsilyloxy)butan-2-yl)-5-(3-chloropheny-
l)-6-(5-chloropyridin-2-yl)-3-methylpiperidin-2-one (Example 121,
Step J) and 7.91 mL (91.0 mmol) of allyl bromide in dry, degassed
THF (22 mL) was added 68.6 mL (68.6 mmol) of a 1 M solution of
lithium bis(trimethylsilyl)amide in THF slowly via syringe over 6
min at room temperature. After 10 min, the orange solution was
warmed to 50.degree. C. and stirred for 24 h. At this time, 11.4 mL
(11.4 mmol) of a 1 M solution of lithium bis(trimethylsilyl)amide
in THF and 790 .mu.L (0.79 mmol) of allyl bromide were added. The
reaction was stirred for an additional 6.25 h at 50.degree. C., and
then was cooled to room temperature and quenched with saturated
aqueous ammonium chloride. The mixture was extracted with EtOAc
(3.times.), and the combined organic layers were dried over
Na.sub.2SO.sub.4, filtered and the filtrate was concentrated.
Purification of the residue by flash chromatography on silica gel
(2 to 25% EtOAc/hexanes, gradient elution) provided the title
compound (mixture of C-3 epimers) as a light yellow solid.
Step L.
(5R,6S)-3-Allyl-5-(3-chlorophenyl)-6-(5-chloropyridin-2-yl)-1-((S)-
-1-hydroxybutan-2-yl)-3-methylpiperidin-2-one
##STR00376##
[2039] To an ice-cooled solution of 1.30 g (1.90 mmol) of
(5R,6S)-3-allyl-1-((S)-1-(tert-butyldiphenylsilyloxy)butan-2-yl)-5-(3-chl-
orophenyl)-6-(5-chloropyridin-2-yl)-3-methylpiperidin-2-one
(Example 121, Step K) in THF (55 mL) was added 11.37 mL (11.37
mmol) of a 1 M solution of TBAF in THF. The orange solution was
warmed to room temperature and stirred for 3.75 h. The reaction was
partitioned between 1 M HCl and EtOAc (2.times.), and then the
combined organic layers were washed with water (2.times.). The
organic layer was dried over Na.sub.2SO.sub.4, filtered and the
filtrate was concentrated. Purification of the residue by flash
chromatography on silica gel (0 to 10% MeOH/DCM, gradient elution)
provided the title compound as a light yellow solid.
Step M.
(S)-2-((5R,6S)-3-Allyl-5-(3-chlorophenyl)-6-(5-chloropyridin-2-yl)-
-3-methyl-2-oxopiperidin-1-yl)butanal
##STR00377##
[2041] To a solution of 197 mg (0.44 mmol) of
(5R,6S)-3-allyl-5-(3-chlorophenyl)-6-(5-chloropyridin-2-yl)-1-((S)-1-hydr-
oxybutan-2-yl)-3-methylpiperidin-2-one (Example 121, Step L) in DCM
(6 mL) was added 12 .mu.L (0.66 mmol) of water and 280 mg (0.66
mmol) of Dess-Martin periodinane. The resulting light yellow slurry
was warmed to room temperature and stirred for 50 min. The reaction
was quenched with saturated aqueous sodium thiosulfate, diluted
with water, and extracted with DCM (2.times.). The combined organic
layers were washed with saturated aqueous sodium bicarbonate
(1.times.) and saturated aqueous sodium chloride (1.times.), and
then were dried over Na.sub.2SO.sub.4, filtered and the filtrate
was concentrated. Purification of the residue by flash
chromatography on silica gel (0 to 7% MeOH/DCM, gradient elution)
provided the title compound as a light yellow solid.
Step N.
(3S,5R,6S)-3-Allyl-5-(3-chlorophenyl)-6-(5-chloropyridin-2-yl)-3-m-
ethyl-1-((S)-1-morpholinobutan-2-yl)piperidin-2-one
##STR00378##
[2043] The title compound was prepared from
(S)-2-((3S,5R,6S)-3-allyl-5-(3-chlorophenyl)-6-(5-chloropyridin-2-yl)-3-m-
ethyl-2-oxopiperidin-1-yl)butanal (Example 121, Step M) as
described in Example 91, Step A. Purification of the crude product
by flash chromatography on silica gel (3 to 10% MeOH/DCM, gradient
elution) provided the title compound as a white solid.
Step O.
2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(5-chloropyridin-2-yl)-3-methyl-
-1-((S)-1-morpholinobutan-2-yl)-2-oxopiperidin-3-yl)acetaldehyde
##STR00379##
[2045] To a solution of 42 mg (0.08 mmol) of
(3S,5R,6S)-3-allyl-5-(3-chlorophenyl)-6-(5-chloropyridin-2-yl)-3-methyl-1-
-((S)-1-morpholinobutan-2-yl)piperidin-2-one (Example 121, Step N)
in THF (6 mL) and water (2 mL) added a catalytic amount of osmium
tetroxide. After 3 min, 87 mg (0.41 mmol) of sodium periodate was
added. The resulting white slurry was stirred at room temperature
for 4.25 h, and then filtered through a fritted funnel. The
filtrate was partially concentrated under reduced pressure, and
then was diluted with a mixture of water and saturated aqueous
sodium chloride and extracted with ethyl acetate (2.times.). The
combined organic layers were washed with saturated aqueous sodium
thiosulfate and then saturated aqueous sodium chloride. The organic
layer was dried over Na.sub.2SO.sub.4, filtered and the filtrate
was concentrated. Purification of the residue by reversed phase
prep. HPLC (Sunfire.TM. Prep C.sub.18 OBD 10 .mu.m column (Waters,
Milford, Mass.), gradient elution of 35% MeCN in water to 75% MeCN
in water over a 35 min period, where both solvents contain 0.1% TFA
provided the title compound as a white solid.
Step P.
2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(5-chloropyridin-2-yl)-3-methyl-
-1-((S)-1-morpholinobutan-2-yl)-2-oxopiperidin-3-yl)acetic acid
##STR00380##
[2047] To a solution of 16 mg (0.03 mmol) of
2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(5-chloropyridin-2-yl)-3-methyl-1-((S)-
-1-morpholinobutan-2-yl)-2-oxopiperidin-3-yl)acetaldehyde (Example
121, Step O) and 1.0 mL (9.4 mmol) of 2-methyl-2-butene in t-BuOH
(3 mL) was added a solution of 28 mg (0.31 mmol) of sodium chlorite
and 4.6 mg (0.03 mmol) of sodium dihydrogenphosphate dihydrate in
water (1.6 mL). The resulting mixture was stirred at room
temperature for 2 h, and then was quenched with 1 M HCl and
extracted with EtOAc (3.times.). The combined organic layers were
dried over Na.sub.2SO.sub.4, filtered and the filtrate was
concentrated. Purification of the residue by reversed phase prep.
HPLC (Sunfire.TM. Prep C.sub.18 OBD 10 .mu.m column (Waters,
Milford, Mass.), gradient elution of 35% MeCN in water to 60% MeCN
in water over a 35 min period, where both solvents contain 0.1% TFA
provided the title compound as a white solid.
[2048] .sup.1H NMR (400 MHz, CD.sub.3OD) .delta. ppm 8.69 (1H, d,
J=2.4 Hz), 7.65 (1H, dd, J=8.3 Hz, 2.5 Hz), 7.14-7.22 (2H, m),
7.01-7.08 (2H, m), 6.88-6.95 (1H, m), 4.85-4.90 (1H, buried d),
3.94-4.09 (4H, m), 3.42-3.53 (1H, m), 3.07-3.24 (2H, m), 2.88-3.01
(2H, m), 2.73 (1H, d, J=13.7 Hz), 2.38 (1H, t, J=13.9 Hz), 2.10
(1H, dd, J=13.9 Hz. 3.5 Hz), 1.80-1.92 (1H, m), 1.41 (3H, s),
1.39-1.47 (2H, m), 1.13 (3H, dd, J=6.5 Hz, 4.9 Hz), 0.93-1.05 (3H,
br s). Mass Spectrum (ESI) m/z=534 (M+1).
Example 122
2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(5-chloropyridin-2-yl)-3-methyl-2-oxo-1-
-(pentan-3-yl)piperidin-3-yl)acetic acid
##STR00381##
[2049] Step A.
(5R,6S)-5-(3-Chlorophenyl)-6-(5-chloropyridin-2-yl)-1-(pentan-3-yl)piperi-
din-2-one
##STR00382##
[2051] To a degassed solution of
(5R,6S)-5-(3-chlorophenyl)-6-(5-chloropyridin-2-yl)piperidin-2-one
(1.00 g, 3.11 mmol, Example 121, Step F), 3-bromopentane (6.0 ml,
48.1 mmol) and tetrabutylammonium iodide (3.45 g, 9.34 mmol) in dry
DMF (5.2 ml) was added 1.25 g (31 mmol) of a dispersion of 60%
sodium hydride in mineral oil at 0.degree. C. The reaction was
heated to 900 for 8 h. Sat. aq. NaHCO.sub.3/NaCl solution was added
and the mixture was extracted with ethyl acetate. The organic
layers were washed with water and sat. NaCl solution, dried over
Na.sub.2SO.sub.4, filtered and the filtrate was concentrated under
reduced pressure. Purification of the residue by flash
chromatography on silica gel (eluent: 25 to 50% EtOAc/hexanes which
had been sparged with NH.sub.3 gas, gradient elution) provided the
title compound.
Step B.
(5R,6S)-3-Allyl-5-(3-chlorophenyl)-6-(5-chloropyridin-2-yl)-3-meth-
yl-1-(pentan-3-yl)piperidin-2-one
##STR00383##
[2053] The title compound was prepared from
(5R,6S)-5-(3-chlorophenyl)-6-(5-chloropyridin-2-yl)-1-(pentan-3-yl)piperi-
din-2-one (Example 122, Step A) by a procedure similar to the one
described in Example 121, Steps J and K and was obtained as a
mixture of epimers at C-3.
Step C.
2-((3R,5R,6S)-5-(3-Chlorophenyl)-6-(5-chloropyridin-2-yl)-3-methyl-
-2-oxo-1-(pentan-3-yl)piperidin-3-yl)acetic acid
##STR00384##
[2055] The title compound was obtained from
(5R,6S)-3-allyl-5-(3-chlorophenyl)-6-(5-chloropyridin-2-yl)-3-methyl-1-(p-
entan-3-yl)piperidin-2-one (149 mg, 0.335 mmol, mixture of
stereoisomers at C-3, Example 122, Step B) by a procedure similar
to the one described in Example 71, Step F. Purification by
reversed phase preparatory HPLC (eluent: 50% MeCN/water (0.1% TFA),
isocratic elution) using a Sunfire.TM. C18 OBD column, 10 uM,
(30.times.150 mm), Waters Corp (Milford, Mass.) provided the title
compound as the more polar, major isomer.
[2056] .sup.1H NMR (500 MHz, CHLOROFORM-d) .delta. ppm 0.53 (t,
J=7.46 Hz, 3H), 0.93 (t, J=7.46 Hz, 3H), 1.20-1.34 (m, 1H),
1.34-1.46 (m, 1H), 1.49 (s, 3H), 1.62-1.78 (m, 1H), 1.83 (ddd,
J=14.61, 7.58, 7.40 Hz, 1H), 1.99 (dd, J=13.69, 3.18 Hz, 1H), 2.22
(t, J=13.57 Hz, 1H), 2.72 (d, J=15.89 Hz, 1H), 2.88-2.99 (m, 1H),
3.35 (d, J=15.89 Hz, 1H), 3.43 (ddd, J=13.14, 9.72, 3.06 Hz, 1H),
4.50 (d, J=9.78 Hz, 1H), 6.76 (dt, J=7.58, 1.22 Hz, 1H), 6.84 (d,
J=8.07 Hz, 1H), 6.98 (t, J=1.83 Hz, 1H), 7.14 (t, J=7.70 Hz, 1H),
7.53 (dd, J=8.07, 2.45 Hz, 1H), 8.60 (d, J=2.20 Hz, 1H). Mass
Spectrum (ESI) m/z=463 (M+1).
Example 123
2-((3S,5R,6S)-5-(3-Chlorophenyl)-6-(5-chloropyridin-2-yl)-3-methyl-2-oxo-1-
-(pentan-3-yl)piperidin-3-yl)acetic acid
##STR00385##
[2058] The title compound was obtained in Example 122, Step C as
the less polar, minor isomer.
[2059] .sup.1H NMR (500 MHz, CHLOROFORM-d) .delta. ppm 0.51 (t,
J=7.46 Hz, 3H), 0.94 (t, J=7.46 Hz, 3H), 1.33-1.55 (m, 3H), 1.73
(s, 3H), 1.73-1.82 (m, 3H), 2.24 (t, J=13.69 Hz, 1H), 2.49 (d,
J=15.16 Hz, 1H), 2.88 (d, J=14.92 Hz, 1H), 3.62 (ddd, J=13.88,
10.21, 3.55 Hz, 1H), 4.42 (d, J=10.03 Hz, 1H), 6.70-6.82 (m, 2H),
6.96 (t, J=1.83 Hz, 1H), 7.09-7.24 (m, 2H), 7.52 (dd, J=8.07, 2.45
Hz, 1H), 8.62 (d, J=2.45 Hz, 1H). Mass Spectrum (ESI) m/z=463
(M+1).
Example 124
2-((3R,5R,6S)-1-((S)-1-tert-butoxy-1-oxobutan-2-yl)-5-(3-chlorophenyl)-6-(-
5-chloropyridin-2-yl)-3-methyl-2-oxopiperidin-3-yl)acetic acid
##STR00386##
[2060] Step A.
(5R,6S)-5-(3-chlorophenyl)-6-(5-chloropyridin-2-yl)-1-(2,4-dimethoxybenzy-
l)piperidin-2-one
##STR00387##
[2062] To a solution of 6.72 g (20.92 mmol) of
(5R,6S)-5-(3-chlorophenyl)-6-(5-chloropyridin-2-yl)piperidin-2-one
(Example 121, Step F) in DMF (.about.0.5M) at 0.degree. C. was
slowly added a dispersion of 60% sodium hydride in mineral oil
(2.51 g, 62.8 mmol). The reaction was stirred 0.degree. C. for 30
min, followed by addition of 1-(chloromethyl)-2,4-dimethoxybenzene
(7.81 g, 41.8 mmol). Upon completion, the reaction was quenched at
0.degree. C. with a small excess of acetic acid (4.79 mL, 84 mmol).
It was neutralized with sat. aq. NaHCO.sub.3 solution and extracted
with ethyl acetate. The organic layer was dried over
Na.sub.2SO.sub.4, filtered and the filtrate as concentrated under
reduced pressure to yield a reddish oil. Purification by flash
chromatography on silica gel (eluent: 0 to 30% ethyl acetate/DCM,
gradient elution) provided the title compound as a pale yellow
oil.
[2063] .sup.1H NMR (500 MHz, CHLOROFORM-d) .delta. ppm 1.81-1.93
(m, 1H), 2.00-2.11 (m, 1H), 2.38-2.50 (m, 1H), 2.50-2.61 (m, 1H),
3.30 (dt, J=6.60, 4.16 Hz, 1H), 3.63 (s, 3H), 3.74 (d, J=14.43 Hz,
1H), 3.80 (s, 3H), 4.86 (d, J=4.40 Hz, 1H), 5.23 (d, J=14.43 Hz,
1H), 6.37 (d, J=2.20 Hz, 1H), 6.44 (dd, J=8.31, 2.45 Hz, 1H), 6.84
(d, J=7.58 Hz, 1H), 6.90-7.00 (m, 2H), 7.08 (t, J=7.83 Hz, 1H),
7.11-7.16 (m, 1H), 7.18 (d, J=8.31 Hz, 1H), 7.61 (dd, J=8.31, 2.45
Hz, 1H), 8.56 (d, J=2.45 Hz, 1H). Mass Spectrum (ESI) m/z=471
(M+1).
Step B.
(3S,5R,6S)-3-allyl-5-(3-chlorophenyl)-6-(5-chloropyridin-2-yl)-1-(-
2,4-dimethoxybenzyl)-3-methylpiperidin-2-one and
(3R,5R,6S)-3-allyl-5-(3-chlorophenyl)-6-(5-chloropyridin-2-yl)-1-(2,4-dim-
ethoxybenzyl)-3-methylpiperidin-2-one
##STR00388##
[2065] The title compound was prepared from
(5R,6S)-5-(3-chlorophenyl)-6-(5-chloropyridin-2-yl)-1-(2,4-dimethoxybenzy-
l)piperidin-2-one (Example 124, Step A) by a procedure similar to
the ones described in Example 121, Steps J and K and was obtained
as a mixture of epimers at C-3.
Step C.
(3S,5R,6S)-3-allyl-5-(3-chlorophenyl)-6-(5-chloropyridin-2-yl)-3-m-
ethylpiperidin-2-one
[2066]
(5R,6S)-3-allyl-5-(3-chlorophenyl)-6-(5-chloropyridin-2-yl)-1-(2,4--
dimethoxybenzyl)-3-methylpiperidin-2-one (3.6 g, 6.85 mmol, mixture
of C-3 epimers, Example 124, Step B) was dissolved in TFA (26.4 mL,
343 mmol) and the reaction was heated to 700 for 1.5 h. It was then
cooled to ambient temperature and the TFA was removed by
concentration under reduced pressure. The product was azeotroped
with heptanes, dissolved in DCM and the organic layer was washed
with sat. aq. NaHCO.sub.3 solution and sat. NaCl solution.
Purification by flash chromatography on silica gel (eluent: 35 to
45% EtOAc/hexanes which had been NH.sub.3 sparged, gradient
elution) provided the title compound as the more polar isomer as a
white solid: (R.sub.f in 75% EtOAc/Hexanes=0.44).
[2067] .sup.1H NMR (500 MHz, CHLOROFORM-d) .delta. ppm 0.67-0.84
(m, 1H), 1.10-1.25 (m, 3H), 1.60 (br. s., 1H), 1.85-2.04 (m, 2H),
2.32-2.50 (m, 1H), 2.56 (d, J=8.31 Hz, 1H), 3.19-3.33 (m, 1H),
4.56-4.66 (m, 1H), 4.99-5.14 (m, 2H), 5.68-5.84 (m, 1H), 5.89 (br.
s., 1H), 6.72-6.84 (m, 2H), 6.92-7.01 (m, 1H), 7.01-7.12 (m, 2H),
7.12-7.23 (m, 1H), 7.35-7.48 (m, 1H), 8.31-8.48 (m, 1H). Mass
Spectrum (ESI) m/z=375 (M+1).
Step D. (S) tert-Butyl
2-((3S,5R,6S)-3-allyl-5-(3-chlorophenyl)-6-(5-chloropyridin-2-yl)-3-methy-
l-2-oxopiperidin-1-yl)butanoate
##STR00389##
[2069] To a solution of
(3S,5R,6S)-3-allyl-5-(3-chlorophenyl)-6-(5-chloropyridin-2-yl)-3-methylpi-
peridin-2-one (77 mg, 0.205 mmol, Example 124, Step C) in DMF (0.3
mL) was added slowly 9.5 mg (0.24 mmol) of a dispersion of 60%
sodium hydride in mineral oil followed by tert-butyl
2-bromobutanoate (92 mg, 0.410 mmol). The reaction was stirred at
ambient temperature overnight, quenched with MeOH/HOAc, was diluted
with EtOAc and water and extracted to EtOAc. The organics were
dried over Na.sub.2SO.sub.4, filtered and the filtrate was
concentrated. Purification by reversed phase preparatory HPLC
(Sunfire.TM. Prep C18 OBD 10 .mu.m column (Waters, Milford, Mass.)
(eluent: 70% acetonitrile, water, 0.1% TFA) provided the title
compound, as well as its stereoisomer, (R)-tert-butyl
2-((3S,5R,6S)-3-allyl-5-(3-chlorophenyl)-6-(5-chloropyridin-2-yl)-3-methy-
l-2-oxopiperidin-1-yl)butanoate.
Step E. (S)-tert-butyl
2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(5-chloropyridin-2-yl)-3-methyl-2-oxo--
3-(2-oxoethyl)piperidin-1-yl)butanoate
##STR00390##
[2071] The example was prepared from (S)-tert-butyl
2-((3S,5R,6S)-3-allyl-5-(3-chlorophenyl)-6-(5-chloropyridin-2-yl)-3-methy-
l-2-oxopiperidin-1-yl)butanoate (Example 124, Step D) as described
in Example 121, Step O. Purification of the residue by reversed
phase preparatory HPLC(Sunfire.TM. Prep C18 OBD 10 .mu.m column
(Waters, Milford, Mass.) (eluent: 55 to 75% acetonitrile, water,
0.1% TFA, gradient elution) provided the title compound as a white
solid after lyophilization.
Step F.
2-((3R,5R,6S)-1-((S)-1-tert-butoxy-1-oxobutan-2-yl)-5-(3-chlorophe-
nyl)-6-(5-chloropyridin-2-yl)-3-methyl-2-oxopiperidin-3-yl)acetic
acid
##STR00391##
[2073] The title compound was prepared from (S)-tert-butyl
2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(5-chloropyridin-2-yl)-3-methyl-2-oxo--
3-(2-oxoethyl)piperidin-1-yl)butanoate (Example 124, Step E) as
described in Example 121, Step P.
[2074] .sup.1H NMR (500 MHz, CHLOROFORM-d) .delta. ppm 0.46 (t,
J=7.46 Hz, 2H), 1.09-1.28 (m, 2H), 1.28-1.42 (m, 2H), 1.42-1.46 (m,
2H), 1.49 (s, 7H), 1.71-1.90 (m, 3H), 1.93-2.04 (m, 1H), 2.12-2.29
(m, 2H), 2.89-2.97 (m, 1H), 2.99 (dd, J=7.70, 4.28 Hz, 1H),
3.01-3.09 (m, 1H), 3.61 (ddd, J=13.02, 9.84, 3.55 Hz, 1H), 4.73 (d,
J=10.27 Hz, 1H), 6.83 (d, J=7.58 Hz, 1H), 6.94 (d, J=8.31 Hz, 1H),
7.03 (s, 1H), 7.11 (t, J=7.70 Hz, 1H), 7.14-7.18 (m, 1H), 7.56 (dd,
J=8.31, 2.45 Hz, 1H), 8.61 (d, J=2.45 Hz, 1H). Mass Spectrum (ESI)
m/z=535 (M+1).
Example 125
2-((3R,5S,6S)-1-((S)-1-tert-butoxy-1-oxobutan-2-yl)-6-(4-chlorophenyl)-5-(-
4-chloropyridin-2-yl)-3-methyl-2-oxopiperidin-3-yl)acetic acid
##STR00392##
[2075] Step A.
1-(4-Chlorophenyl)-2-(4-chloropyridin-2-yl)ethanone
##STR00393##
[2077] To a solution of 4-chloro-2-methylpyridine (23.07 g, 181
mmol) and methyl 4-chlorobenzoate (30.8 g, 181 mmol) in dry THF
(500 mL) at 0.degree. C. was added 1 M LiHMDS in THF (63.5 g, 380
mmol) slowly via a dropping funnel. When complete, the reaction was
quenched with NaHCO.sub.3 solution, concentrated under reduced
pressure, and extracted with ethyl acetate. The combined organics
were dried over Na.sub.2SO.sub.4, filtered and the filtrate was
concentrated under reduced pressure to provide the title
compound.
Step B. (4R,5R)-methyl
5-(4-chlorophenyl)-4-(4-chloropyridin-2-yl)-5-hydroxypentanoate and
(4S,5S)-methyl
5-(4-chlorophenyl)-4-(4-chloropyridin-2-yl)-5-hydroxypentanoate
##STR00394##
[2079] To a solution of
1-(4-chlorophenyl)-2-(4-chloropyridin-2-yl)ethanone (42.0 g, 158
mmol) and DBU (28.5 mL, 189 mmol, Example 125, Step A) in dioxane
(316 mL) at 80.degree. C. was added methyl acrylate (15.73 mL, 174
mmol), dropwise. The reaction was stirred at 80.degree. C. for 30
min, at which time more methyl acrylate (2.86 mL, 31 mmol) was
added. When the reaction was complete, it was cooled to 0.degree.
C. Methanol (500 mL) was added slowly, the reaction was cooled to
0.degree. C. and NaBH.sub.4 (5.97 g, 158 mmol) was slowly added.
The solution was concentrated under reduced pressure, and
partitioned between ethyl acetate and 1 N NaOH. The organic layer
was concentrated under reduced pressure. Purification by flash
chromatography on silica gel (eluent: EtOAc/hexanes which had been
NH.sub.3 sparged, gradient elution) provided the title
compound.
Step C. (4S,5S)-methyl
5-azido-5-(4-chlorophenyl)-4-(4-chloropyridin-2-yl)pentanoate and
(4R,5R)-methyl
5-azido-5-(4-chlorophenyl)-4-(4-chloropyridin-2-yl)
##STR00395##
[2081] The title compound mixture was prepared from methyl
5-(4-chlorophenyl)-4-(4-chloropyridin-2-yl)-5-hydroxypentanoate
(Example 125, Step B) as described in Example 121, Step E, using
2.0 eq of NaN.sub.3 at 100.degree. C. The residue was purified by
flash chromatography on silica gel (eluent: 15 to 45% ethyl
acetate/hexanes, gradient elution).
Step D.
(5S,6S)-6-(4-chlorophenyl)-5-(4-chloropyridin-2-yl)piperidin-2-one
##STR00396##
[2083] The title compound mixture was prepared from (4S,5S)-methyl
5-azido-5-(4-chlorophenyl)-4-(4-chloropyridin-2-yl)pentanoate
(racemic compound mixture) (Example 125, Step C) as described in
Example 121, Step F. The crude product was first purified by flash
chromatography on silica gel (eluent: 5 to 40% ethyl acetate/DCM,
gradient elution), then individual stereoisomers were separated by
chiral HPLC (250.times.30 mm AS-H column with 50 g/min IPA (0.2%
DEA)+50 g/min CO.sub.2 on Thar 350 SFC (Thar Technologies,
Pittsburg, Pa.)) to give the title compound as the faster eluting
stereoisomer.
[2084] .sup.1H NMR (500 MHz, CHLOROFORM-d) .delta. ppm 1.60 (br.
s., 3H), 2.07 (dddd, J=13.60, 5.84, 2.93, 2.81 Hz, 2H), 2.30-2.46
(m, 2H), 2.54-2.72 (m, 4H), 2.96 (ddd, J=12.10, 9.54, 2.81 Hz, 2H),
3.50 (s, 1H), 4.98 (d, J=10.03 Hz, 2H), 5.78 (br. s., 2H), 6.81 (d,
J=1.71 Hz, 2H), 7.03 (d, J=8.31 Hz, 4H), 7.09-7.17 (m, 2H), 7.21
(d, J=8.07 Hz, 4H), 8.46 (d, J=5.38 Hz, 2H), Mass Spectrum (ESI)
m/z=321 (M+1), (t.sub.R=7.1 min on 40% iPrOH/Hexanes on Chiracel OD
analytical column)
Step E.
(5S,6S)-6-(4-chlorophenyl)-5-(4-chloropyridin-2-yl)-1-(2,4-dimetho-
xybenzyl)piperidin-2-one or
(5R,6R)-6-(4-chlorophenyl)-5-(4-chloropyridin-2-yl)-1-(2,4-dimethoxybenzy-
l)piperidin-2-one
##STR00397##
[2086] The title compound mixture was prepared from
(5S,6S)-6-(4-chlorophenyl)-5-(4-chloropyridin-2-yl)piperidin-2-one
or
(5R,6R)-6-(4-chlorophenyl)-5-(4-chloropyridin-2-yl)piperidin-2-one
(Example 125, Step D and 1-(chloromethyl)-2,4-dimethoxybenzene
using a similar procedure to that described in Example 124, Step
A.
Step F.
(3S,5S,6S)-3-allyl-6-(4-chlorophenyl)-5-(4-chloropyridin-2-yl)-1-(-
2,4-dimethoxybenzyl)-3-methylpiperidin-2-one and
(3R,5S,6S)-3-allyl-6-(4-chlorophenyl)-5-(4-chloropyridin-2-yl)-1-(2,4-dim-
ethoxybenzyl)-3-methylpiperidin-2-one
##STR00398##
[2088] The title compound was prepared as a mixture of
stereoisomers from
(5S,6S)-6-(4-chlorophenyl)-5-(4-chloropyridin-2-yl)-1-(2,4-dimethoxybenzy-
l)-3-methylpiperidin-2-one (Example 125, Step E) using a similar
procedure to that described in Example 121, Steps J and K.
Step G.
(5R,6S)-5-(3-chlorophenyl)-6-(5-chloropyridin-2-yl)piperidin-2-one
##STR00399##
[2090] The title compound was prepared as a mixture of
stereoisomers at the C3 position from
(5S,6S)-6-(4-chlorophenyl)-5-(4-chloropyridin-2-yl)-1-(2,4-dimethoxybenzy-
l)-3-methylpiperidin-2-one (Example 125, Step F) in a similar
procedure to that described in Example 124, Step C, followed by
purification on silica gel, except that the reaction was warmed to
ambient temperature rather than 70.degree. and the eluents were 0
to 3% MeOH/DCM.
Step H. tert-butyl
2-((3S,5S,6S)-3-allyl-6-(4-chlorophenyl)-5-(4-chloropyridin-2-yl)-3-methy-
l-2-oxopiperidin-1-yl)butanoate and tert-butyl
2-((3R,5S,6S)-3-allyl-6-(4-chlorophenyl)-5-(4-chloropyridin-2-yl)-3-methy-
l-2-oxopiperidin-1-yl)butanoate
##STR00400##
[2092] To a solution of 100 mg, (0.266 mmol) of
(5S,6S)-3-allyl-6-(4-chlorophenyl)-5-(4-chloropyridin-2-yl)-3-methylpiper-
idin-2-one (Example 125, Step G; mixture of stereoisomers) in dry
DMF (533 .mu.L) at ambient temperature was added a dispersion of
60% sodium hydride in mineral oil (15.99 mg, 0.400 mmol). The
mixture was sonicated at 40.degree. C. for 10 min, followed by
addition of tert-butyl 2-bromobutanoate (119 mg, 0.533 mmol).
Stirred at ambient temperature for 24 h, then added 2 eq more NaH,
and stirred overnight. The reaction was quenched with a small
amount of 10% HOAc in MeOH, diluted with EtOAc and water and
extracted to EtOAc.times.3. The combined organics were dried over
Na.sub.2SO.sub.4, filtered and the filtrate was concentrated under
reduced pressure. Purification of the residue by preparatory
RP-HPLC (Sunfire.TM. Prep C18 OBD 10 .mu.m column (Waters, Milford,
Mass., gradient elution of 55% MeCN in water to 75% MeCN in water
over a 35 min period, where both solvents contain 0.1% TFA) yielded
a mixture of 4 epimers including the title compound and the other 3
epimers. After HPLC, the product containing fractions were
concentrated under reduced pressure, and extracted to ethyl
acetate. The combined organics were dried over Na.sub.2SO.sub.4,
filtered and the filtrate was concentrated.
Step I.
2-((3R,5S,6S)-1-((S)-1-tert-butoxy-1-oxobutan-2-yl)-6-(4-chlorophe-
nyl)-5-(4-chloropyridin-2-yl)-3-methyl-2-oxopiperidin-3-yl)acetic
acid
##STR00401##
[2094] The title compound was prepared from
(5R,6S)-5-(3-chlorophenyl)-6-(5-chloropyridin-2-yl)piperidin-2-one
(Example 125, Step H) as described in Example 121, Steps O and P.
Purification of the residue by reversed phase HPLC (Sunfire.TM.
Prep C18 OBD 10 .mu.m column (Waters, Milford, Mass.) (eluent: 55%
MeCN/water (0.1% TFA) provided the title compound as a white
solid.
[2095] .sup.1H NMR (500 MHz, CHLOROFORM-d) .delta. ppm 0.56 (t,
J=7.46 Hz, 3H), 1.43 (s, 3H), 1.45-1.57 (m, 11H), 2.17-2.35 (m,
3H), 2.78-2.92 (m, 2H), 3.09 (dd, J=7.70, 3.79 Hz, 1H), 3.57-3.66
(m, 1H), 5.00 (d, J=10.51 Hz, 1H), 7.02 (d, J=1.71 Hz, 1H), 7.11
(d, J=7.34 Hz, 2H), 7.20 (dd, J=5.50, 1.83 Hz, 1H), 7.24 (d, J=8.56
Hz, 2H), 8.41 (d, J=5.38 Hz, 1H). Mass Spectrum (ESI) m/z=535
(M+1).
Example 126
2-((3S,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-(N-methylcycl-
opropanesulfonamido)butan-2-yl)-2-oxopiperidin-3-yl)acetic acid
##STR00402##
[2096] Step A. (S)-Methyl
2-((3R,5R,6S)-3-allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-2-oxopiperidi-
n-1-yl)butanoate
##STR00403##
[2098] To a solution of 1.3 g (3.61 mmol) of
(3R,5R,6S)-3-allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)piperidin-2-one
(Example 42, Step A) in DMF (14.43 mL) at 0.degree. C. was added a
dispersion of 60% sodium hydride in mineral oil (0.361 g, 9.02
mmol). The grey slurry was stirred at 0.degree. C. for 30 minutes.
Then methyl 2-bromobutanoate (1.246 mL, 10.83 mmol) was added. The
mixture was warmed to room temperature and stirred at room
temperature for 1 h. The mixture was quenched with sat. NH.sub.4Cl.
The mixture was extracted with ethyl acetate. The organic layer was
washed with water, 1 M LiCl (2.times.), and sat. aq. NaCl solution.
The organic layer was dried over Na.sub.2SO.sub.4 filtered and the
filtrate was concentrated under reduced pressure. The residue was
purified by flash chromatography on silica gel (80 g column;
eluent: 10 to 35% EtOAc in hexanes) to give the title compound as
the less polar, major diastereomer.
Step B.
(3R,5R,6S)-3-allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1--
hydroxybutan-2-yl)piperidin-2-one
##STR00404##
[2100] To a solution of 710 mg (1.542 mmol) (S)-methyl
2-((3R,5R,6S)-3-allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-2-oxopiperidi-
n-1-yl)butanoate (Example 126, Step A) in Et.sub.2O (15 mL) was
added lithium borohydride (67.2 mg, 3.08 mmol) at 0.degree. C.
Evolution of gas was observed. The resulting white slurry was
stirred at 0.degree. C. for 60 min. The mixture was quenched with
ice cold 1 M HCl. Evolution of gas was observed. The mixture was
warmed to room temperature and extracted with EtOAc. The organic
layer was washed with sat. aq. NaCl solution, dried over
Na.sub.2SO.sub.4, filtered, and the filtrate was concentrated under
reduced pressure. The residue was purified by flash chromatography
on silica gel (24 g column; eluent: 20 to 40% EtOAc in hexanes) to
give the title compound.
Step C.
(S)-2-((3R,5R,6S)-3-allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-2--
oxopiperidin-1-yl)butanal
##STR00405##
[2102] To a mixture of 2.00 g (4.63 mmol)
(3R,5R,6S)-3-allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-hydroxy-
butan-2-yl)piperidin-2-one (Example 126, Step B) in water (0.125 g,
6.94 mmol) and DCM (50 mL) was added Dess-Martin periodinane (2.94
g, 6.94 mmol) at ambient temperature. After being stirred for 1 h
(no SM detected by TLC), the reaction was quenched by addition of
10 mL of 0.5 M Na.sub.2S.sub.2O.sub.3, extracted with DCM, and
washed with sat. aq. NaHCO.sub.3 solution and sat. aq. NaCl
solution. The combined organic layers were dried over
Na.sub.2SO.sub.4, filtered and the filtrate was concentrated under
reduced pressure. Purification of the residue by chromatography on
silica gel (80 g SiO.sub.2, 5 to 20% EtOAc/hexanes) provided the
title compound as a white foam.
Step D.
(3R,5R,6S)-3-allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-(1-(met-
hylamino)butan-2-yl)piperidin-2-one
##STR00406##
[2104] To a solution of 1.67 g (3.88 mmol) of
(S)-2-((3R,5R,6S)-3-allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-2-oxopipe-
ridin-1-yl)butanal (Example 126, Step C) and acetic acid (6.60 mL,
116 mmol) in DCE (40 mL) was added 2 M methylamine in THF (19.40
mL, 38.8 mmol) and sodium triacetoxy hydroborate (3.29 g, 15.52
mmol) at room temperature. The reaction was stirred for 2 days. The
reaction was quenched with sat aq. NaHCO.sub.3, extracted with
EtOAc, and the combined organic layers were washed with 1N NaOH and
sat. aq. NaCl solution, dried over Na.sub.2SO.sub.4 and
concentrated under reduced pressure to provide the title compound
as a pale yellow oil, which was used without further purification
in the next step.
Step E.
N-(2-((3R,5R,6S)-3-allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-2-o-
xopiperidin-1-yl)butyl)-N-methylcyclopropanesulfonamide
##STR00407##
[2106] To a solution of the free amine made in Example 126, step D
(1.67 g, 3.75 mmol) in DCE (15 mL) was added pyridine (6.06 mL,
75.0 mmol) and cyclopropanesulfonyl chloride (3.85 mL, 37.5 mmol)
successively at 40.degree. C. The reaction was stirred at
40.degree. C. for 14 h. After that time additional 10 eq. pyridine
and 10 eq. cyclopropanesulfonyl chloride were added. The reaction
was stirred at 40.degree. C. for 14 h. The reaction was acidified
with 10% citric acid and extracted with EtOAc. The combined organic
layers were washed with saturated aq. NaHCO.sub.3 solution and sat.
aq. NaCl solution, dried over Na.sub.2SO.sub.4, and concentrated
under reduced pressure. Purification by chromatography on silica
gel (SiO.sub.2, 25 g; eluent: 20% to 40% EtOAc/Hexanes) provided
the title compound as a white foam.
Step F.
2-((3S,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-(N-me-
thylcyclopropanesulfonamido)butan-2-yl)-2-oxopiperidin-3-yl)acetic
acid
[2107]
N-(2-((3R,5R,6S)-3-allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-2-ox-
opiperidin-1-yl)butyl)-N-methylcyclopropanesulfonamide (Example
126, Step D) was converted to the acid by a procedure similar to
the one described in Example 1, Step H, to provide the crude title
compound. The crude material was absorbed onto a plug of silica gel
and purified by chromatography, eluting with 60% to 80% EtOAc in
hexane, to provide a colorless oil. This was purified by reverse
phase preparatory HPLC (eluent: 10 to 90% acetonitrile, water, 0.1%
TFA, gradient elution) to provide the title compound as the second
eluting peak from reverse-phase-HPLC) as a white solid after
lyophilization.
[2108] .sup.1H NMR (400 MHz, CHLOROFORM-d) .delta. ppm 0.51 (t,
J=7.53 Hz, 3H), 0.96-1.11 (m, 2H), 1.17-1.32 (m, 2H), 1.61 (ddd,
J=14.28, 7.83, 3.91 Hz, 1H), 1.88-2.02 (m, 2H), 2.31-2.47 (m, 3H),
2.68-2.77 (m, 1H), 2.81 (br. s., 1H), 2.86-3.10 (m, 2H), 2.92 (s,
3H), 3.23 (dd, J=15.45, 10.17 Hz, 1H), 4.67 (d, J=10.56 Hz, 1H),
6.86 (m, 1H), 6.94 (m, 3H), 7.11-7.20 (m, 2H), 7.23-7.32 (m, 2H);
Mass Spectrum (ESI) m/z=567.2 (M+1).
Example 127
2-((3S,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-(N-methylcycl-
opropanesulfonamido)butan-2-yl)-2-oxopiperidin-3-yl)propanoic
acid
##STR00408##
[2109] Step A.
(3R,5R,6S)-3-allyl-1-((S)-1-((tert-butyldiphenylsilyl)oxy)butan-2-yl)-5-(-
3-chlorophenyl)-6-(4-chlorophenyl)piperidin-2-one
##STR00409##
[2111] To a solution of 615 mg (1.422 mmol)
(3R,5R,6S)-3-allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-hydroxy-
butan-2-yl)piperidin-2-one (Example 126, Step B) in DMF (4741
.mu.L) at 0.degree. C. was added 1H-imidazole (97 mg, 1.422 mmol)
followed by tert-butylchlorodiphenylsilane (473 .mu.L, 1.849 mmol).
The mixture was stirred at 0.degree. C. for 15 min and then warmed
to room temperature. The mixture was stirred at room temperature
for 30 min and then quenched with sat. NH.sub.4Cl. The mixture was
extracted with EtOAc and the organic layer was washed with water, 1
M LiCl, and sat. aq. NaCl solution. The mixture was dried over
Na.sub.2SO.sub.4 and concentrated under reduced pressure. The
residue was purified by flash chromatography on silica gel (24 g
column; eluent: 0 to 30% EtOAc in hexanes) to give the title
compound.
Step B.
2-((3S,5R,6S)-1-((S)-1-((tert-butyldiphenylsilyl)oxy)butan-2-yl)-5-
-(3-chlorophenyl)-6-(4-chlorophenyl)-2-oxopiperidin-3-yl)acetic
acid
##STR00410##
[2113] To a solution of
(3R,5R,6S)-3-allyl-1-((S)-1-(tert-butyldiphenylsilyloxy)butan-2-yl)-5-(3--
chlorophenyl)-6-(4-chlorophenyl)piperidin-2-one (816 mg, 1.216
mmol; Example 127, Step A) in water/acetonitrile/CCl.sub.4 (7 mL/5
mL/5 mL) at room temperature was added sodium periodate (1041 mg,
4.87 mmol) and ruthenium chloride hydrate (27.4 mg, 0.122 mmol).
The mixture was stirred vigorously at room temperature for 3 h. The
mixture was diluted with EtOAc and acidified with 1 M HCl. Sat. aq.
NaCl solution was added and the mixture was filtered to remove the
emulsion. The layers of the filtrate were separated. The organic
layer was dried over Na.sub.2SO.sub.4 and concentrated under
reduced pressure. The residue was purified by flash chromatography
on silica gel (24 g column; eluent: 0 to 50% EtOAc in hexanes) to
give the title compound.
Step C. Methyl
2-((3S,5R,6S)-1-((S)-1-((tert-butyldiphenylsilyl)oxy)butan-2-yl)-5-(3-chl-
orophenyl)-6-(4-chlorophenyl)-2-oxopiperidin-3-yl)acetate
##STR00411##
[2115] To a solution of
2-((3S,5R,6S)-1-((S)-1-(tert-butyldiphenylsilyloxy)butan-2-yl)-5-(3-chlor-
ophenyl)-6-(4-chlorophenyl)-2-oxopiperidin-3-yl)acetic acid (741
mg, 1.076 mmol; Example 127, Step B) in 10 mL of a 10% solution of
MeOH in DCM at room temperature was added TMS-diazomethane (2.0M in
ether) (807 .mu.L, 1.614 mmol). Evolution of gas was observed and
the yellow mixture was stirred at room temperature for 45 min. More
TMS-diazomethane (2.0M in ether) (807 .mu.L, 1.614 mmol) was added
and the reaction was stirred at room temperature for 45 min. The
mixture was concentrated under reduced pressure. The residue was
purified by flash chromatography on silica gel (24 g column;
eluent: 0 to 30% EtOAc in hexanes) to give the title compound.
Step D. Methyl
2-((3S,5R,6S)-1-((S)-1-((tert-butyldiphenylsilyl)oxy)butan-2-yl)-5-(3-chl-
orophenyl)-6-(4-chlorophenyl)-2-oxopiperidin-3-yl)propanoate
##STR00412##
[2117] Methyl
2-((3S,5R,6S)-1-((S)-1-((tert-butyldiphenylsilyl)oxy)butan-2-yl)-5-(3-chl-
orophenyl)-6-(4-chlorophenyl)-2-oxopiperidin-3-yl)acetate (Example
127, Step C) was azetroped with toluene 3.times. and then dissolved
in THF (14 mL) under Ar and the mixture was cooled to -78.degree.
C. HMPA (236 .mu.L, 1.356 mmol) and LHMDS (1.0M in THF) (1356
.mu.L, 1.356 mmol) were added under Ar at -78.degree. C. The
mixture was stirred at -78.degree. C. for 30 min. The mixture color
turned light yellow. Then iodomethane (110 .mu.L, 1.763 mmol) was
added and the reaction mixture was allowed to slowly warm to room
temperature. The mixture was quenched with sat. NH.sub.4Cl and the
layers were separated. The combined organic layers were dried over
Na.sub.2SO.sub.4 and concentrated under reduced pressure. The
residue was purified by flash chromatography on silica gel
(2.times.50 g stacked VersaPak I-style, Spherical, Supelco,
Bellenfonte, Pa.; eluent: 20 to 30% MtBE in hexanes) to give the
title compound as the less polar, major diastereomer. The retention
time of the less polar diastereomer is 0.871 min (80-100% MeCN+0.1%
TFA in water+0.1% TFA, over 1 minute). The retention time of the
more polar diastereomer is 0.841 min (80 to 100% MeCN+0.1% TFA in
water+0.1% TFA, over 1 minute).
Step E. Methyl
2-((3S,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-hydroxybutan-
-2-yl)-2-oxopiperidin-3-yl)propanoate
##STR00413##
[2119] To a solution of methyl
2-((3S,5R,6S)-1-((S)-1-((tert-butyldiphenylsilyl)oxy)butan-2-yl)-5-(3-chl-
orophenyl)-6-(4-chlorophenyl)-2-oxopiperidin-3-yl)propanoate (285
mg, 0.398 mmol) (the less polar isomer from step D) in THF (1988
.mu.L) was added TBAF (1.0M in THF) (1590 .mu.L, 1.590 mmol). The
mixture was stirred at room temperature for 16 h. The mixture was
quenched with 1 M HCl and diluted with EtOAc. The organic layer was
washed with sat. aq. NaCl solution, dried over Na.sub.2SO.sub.4 and
concentrated under reduced pressure. The residue was purified by
flash chromatography on silica gel (11 g VersaPak I-style,
Spherical, Supelco, Bellenfonte, Pa.; eluent: 50 to 75% MtBE in
hexanes) to give the title compound.
Step F. Methyl
2-((3S,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-(N-methylcyc-
lopropanesulfonamido)butan-2-yl)-2-oxopiperidin-3-yl)propanoate
##STR00414##
[2121] A flask, containing a solution of methyl
2-((3S,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-hydroxybutan-
-2-yl)-2-oxopiperidin-3-yl)propanoate (195 mg, 0.408 mmol; Example
127, Step E) and N-methylcyclopropanesulfonamide (165 mg, 1.223
mmol) in toluene (2038 .mu.L) was evacuated and backfilled with Ar
(5.times.). Then cyanomethylenetributylphosphorane (321 .mu.L,
1.223 mmol) was added. The light brownish orange mixture was heated
to 70.degree. C. for 2 h. More N-methylcyclopropanesulfonamide (134
mg, 0.991 mmol) was added and the mixture was heated to 70.degree.
C. for 2 h. The mixture was heated to reflux overnight and then
cooled to room temperature. The mixture was diluted with EtOAc and
sat. aq. NaCl solution. The layers were separated. The organic
layer was dried over Na.sub.2SO.sub.4 and concentrated under
reduced pressure. The residue was purified by flash chromatography
on silica gel (4 g column eluent: 0 to 100% EtOAc in hexanes) to
give the title compound.
Step G.
2-((3S,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-(N-me-
thylcyclopropanesulfonamido)butan-2-yl)-2-oxopiperidin-3-yl)propanoic
acid
[2122] To a solution of methyl
2-((3S,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-(N-methylcyc-
lopropanesulfonamido)butan-2-yl)-2-oxopiperidin-3-yl)propanoate (56
mg, 0.094 mmol; Example 127, Step F) in MeOH/THF/H.sub.2O (1 mL/1
mL/2 mL) was added LiOH (3 M in water) (157 .mu.L, 0.470 mmol) at
room temperature. The slurry was heated to .about.100.degree. C.
for 3 h. The mixture was cooled to room temperature, acidified with
1 M HCl and extracted with EtOAc (2.times.). The organic layers
were combined, dried over Na.sub.2SO.sub.4, filtered and the
filtrate was concentrated under reduced pressure. The colorless
film was purified by reverse phase preparatory HPLC (column:
Gemini-NX C.sub.18 5 um column; Phenomonex, Torrance, Calif.;
eluent: 0 to 100% MeCN+0.1% TFA in water+0.1% TFA, over 20 minutes)
to give the title compound.
[2123] .sup.1H NMR (400 MHz, CHLOROFORM-d) .delta. ppm 0.50 (t,
J=6.65 Hz, 3H), 0.95-1.07 (m, 2H), 1.20-1.26 (m, 5H), 1.40 (dd,
J=10.96, 7.24 Hz, 1H), 1.52-1.66 (m, 1H), 1.85-1.93 (m, 1H),
1.96-2.00 (m, 1H), 2.22-2.36 (m, 2H), 2.70-2.79 (m, 1H), 2.88-3.07
(m, 6H), 3.13 (quin, J=7.19 Hz, 1H), 4.67 (d, J=10.56 Hz, 1H),
6.89-6.92 (m, 1H), 6.94-7.01 (m, 3H), 7.14-7.18 (m, 2H), 7.25 (d,
J=8.41 Hz, 2H); Mass Spectrum (ESI) m/z=603 (M+23), 581 (M+1).
Example 128
(S)-tert-butyl
2-((3R,5R,6S)-3-((1H-tetrazol-5-yl)methyl)-5-(3-chlorophenyl)-6-(4-chloro-
phenyl)-3-methyl-2-oxopiperidin-1-yl)butanoate
##STR00415##
[2124] Step A. (S)-tert-butyl
2-((3R,5R,6S)-3-(2-amino-2-oxoethyl)-5-(3-chlorophenyl)-6-(4-chlorophenyl-
)-3-methyl-2-oxopiperidin-1-yl)butanoate
##STR00416##
[2126] A solution of
2-((3R,5R,6S)-1-((S)-1-tert-butoxy-1-oxobutan-2-yl)-5-(3-chlorophenyl)-6--
(4-chlorophenyl)-3-methyl-2-oxopiperidin-3-yl)acetic acid (230 mg,
0.430 mmol; Example 67) in DMF (4.3 mL) was treated with
N-(3-dimethyaminopropyl)-N'-ethylcarbodiimide hydrochloride (165
mg, 0.86 mmol), 1-hydroxy-7-azabenzotriazole (117 mg, 0.86 mmol)
and NaHCO.sub.3 (72.3 mg, 0.861 mmol) successively. After being
stirred at rt for 0.5 h, 7 M ammonia in methanol (6.2 mL, 4.30
mmol) was added dropwise and the reaction was stirred overnight.
Then, the reaction was diluted (water), extracted (2.times.EtOAc),
and washed (1.times. saturated NaHCO.sub.3, and 2.times.sat. aq.
NaCl solution). The combined organic layers were dried
(Na.sub.2SO.sub.4) and concentrated under reduced pressure.
Purification by RP-HPLC (45 to 70% MeCN/H.sub.2O (0.1% TFA), a
gradient elution) provided the title compound as a white solid.
Step B. (S)-tert-butyl
2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-(cyanomethyl)-3-met-
hyl-2-oxopiperidin-1-yl)butanoate
##STR00417##
[2128] A solution of (S)-tert-butyl
2-((3R,5R,6S)-3-(2-amino-2-oxoethyl)-5-(3-chlorophenyl)-6-(4-chlorophenyl-
)-3-methyl-2-oxopiperidin-1-yl)butanoate (105 mg, 0.197 mmol;
Example 128, Step A) and triethylamine (137 .mu.L, 0.984 mmol) in
THF (3.3 mL) was treated with 2,2,2-trifluoroacetic anhydride (69.8
.mu.L, 0.492 mmol) at 0.degree. C. After being stirred at 0.degree.
C. for 3 h, the reaction was quenched (10% citric acid), extracted
(2.times.EtOAc) and washed (sat. aq. NaCl solution). The combined
organic layers were dried (Na.sub.2SO.sub.4) and concentrated under
reduced pressure. Purification of the residue by chromatography on
silica gel (12 g SiO.sub.2, 20 to 50% EtOAc/Hex, a gradient
elution) provided the title compound as a colorless foam.
Step C. (S)-tert-butyl
2-((3R,5R,6S)-3-((1H-tetrazol-5-yl)methyl)-5-(3-chlorophenyl)-6-(4-chloro-
phenyl)-3-methyl-2-oxopiperidin-1-yl)butanoate
[2129] To a solution of (S)-tert-butyl
2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-(cyanomethyl)-3-met-
hyl-2-oxopiperidin-1-yl)butanoate (101 mg, 0.196 mmol; Example 128,
Step B) in DMF (0.50 mL) was added sodium azide (127 mg, 1.96 mmol)
and NH.sub.4Cl (105 mg, 1.96 mmol). The resulting mixture was
stirred at 90.degree. C. for 5 days. Then, the reaction was
quenched (aq. 10% citric acid), extracted (2.times.EtOAc), and
washed (3.times.sat. aq. NaCl solution). The combined organic layer
was dried (Na.sub.2SO.sub.4) and concentrated under reduced
pressure. Purification by RP-HPLC (60 to 85% AcCN/H.sub.2O,
gradient elution) provided the title compound as a white solid.
[2130] .sup.1H NMR (400 MHz, CHLOROFORM-d) .delta. ppm 7.23-7.26
(2H, m), 7.09-7.19 (2H, m), 7.01 (1H, t, J=1.9 Hz), 6.92 (2H, d,
J=8.6 Hz), 6.75-6.80 (1H, m), 4.60 (1H, d, J=10.8 Hz), 3.44-3.63
(2H, m), 3.27 (1H, br. s.), 3.15 (1H, dd, J=8.3, 3.4 Hz), 2.29-2.42
(2H, m), 2.24 (1H, d, J=3.3 Hz), 1.49-1.52 (8H, m), 1.34-1.40 (1H,
m), 1.32 (3H, s), 0.55 (3H, t, J=7.4 Hz); MS (ESI) 558.1
[M+H].sup.+, 556.2 [M-H].sup.-.
Example 129
2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-1-((S)-1-(met-
hylsulfonamido)butan-2-yl)-2-oxopiperidin-3-yl)acetic acid
##STR00418##
[2131] Step A.
(3R,5R,6S)-3-allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-((4-met-
hoxybenzyl)amino)butan-2-yl)-3-methylpiperidin-2-one
##STR00419##
[2133] To a solution of
(S)-2-((3R,5R,6S)-3-allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl--
2-oxopiperidin-1-yl)butanal (300 mg, 0.675 mmol; Example 91, Step
C) and (4-methoxyphenyl)methanamine (131 .mu.L, 1.01 mmol) in DCE
(4.5 mL) was added sodium triacetoxyborohydride (429 mg, 2.03 mmol)
at 0.degree. C. in several portions. After being stirred at
25.degree. C. for 18 h, the reaction was quenched by adding
ice-cold saturated aqueous NaHCO.sub.3 and extracted (2.times.DCM).
The combined organic layers were washed (1.times.sat. aq. NaCl
solution) and concentrated under reduced pressure to provide the
title compound as a yellow film. The product was used in the next
step without further purification.
Step B.
(S)-2-((3S,5R,6S)-3-Allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3--
methyl-2-oxopiperidin-1-yl)butan-1-ammonium
2,2,2-trifluoroacetate
##STR00420##
[2135] To a solution of
(3S,5R,6S)-3-allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-(4-meth-
oxybenzylamino)butan-2-yl)-3-methylpiperidin-2-one (370 mg, 0.654
mmol; Example 129, Step A) in acetonitrile (8.0 mL) and water (1.6
mL) was added ceric ammonium nitrate (2.87 g, 5.23 mmol) at
25.degree. C. After being stirred at rt for 2 days, the reaction
was quenched (sat. aq. NaCl solution), extracted (3.times.EtOAc),
and washed (1.times.sat. aq. NaCl solution). The combined organic
layers were dried (Na.sub.2SO.sub.4) and concentrated under reduced
pressure. Purification by RP-HPLC (35 to 70% MeCN/H.sub.2O (0.1%
TFA), a gradient elution) provided the title compound as a pale
yellow powder.
Step C.
N--((S)-2-((3S,5R,6S)-3-Allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl-
)-3-methyl-2-oxopiperidin-1-yl)butyl)methanesulfonamide
##STR00421##
[2137]
(S)-2-((3S,5R,6S)-3-allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-m-
ethyl-2-oxopiperidin-1-yl)butan-1-aminium 2,2,2-trifluoroacetate
(74 mg, 0.14 mmol; Example 129, Step B) was dissolved in DCM at
0.degree. C. and 2 N lithium hydroxide (0.34 mL, 0.68 mmol) was
added and the resulting solution was stirred for 5 min at 0.degree.
C. The solution was extracted (2.times.DCM), washed (sat. aq. NaCl
solution), dried (Na.sub.2SO.sub.4), and concentrated under reduced
pressure to give the free amine. To a solution of the free amine
from above in DMF (0.34 mL) was added methanesulfonyl chloride (53
.mu.L, 0.68 mmol) and pyridine (66 .mu.L, 0.820 mmol) successively
at 0.degree. C. After being stirred at 25.degree. C. for overnight,
the reaction was acidified (10% citric acid) and extracted
(2.times.EtOAc) and washed (sat. aq. NaCl solution). The combined
organic layers were dried (Na.sub.2SO.sub.4), and concentrated
under reduced pressure. Purification by RP-HPLC (45 to 80%
MeCN/H.sub.2O (0.1% TFA), a gradient elution) provided the title
compound as a white powder.
Step D.
2-((3R,5R,6S)-5-(3-Chlorophenyl)-6-(4-chlorophenyl)-3-methyl-1-((S-
)-1-(methylsulfonamido)butan-2-yl)-2-oxopiperidin-3-yl)acetic
acid
[2138] To a rapidly stirring solution of
N--((S)-2-((3S,5R,6S)-3-allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-met-
hyl-2-oxopiperidin-1-yl)butyl)methanesulfonamide (34 mg, 0.064
mmol; Example 91, Step C) in a mixture of water (0.55 mL),
acetonitrile (0.37 mL), and CCl.sub.4 (0.37 mL) was added sodium
periodate (55 mg, 0.26 mmol) and ruthenium(III) chloride hydrate
(1.5 mg, 6.5 .mu.mol). After being stirred vigorously for 20 h, the
reaction was acidified (10% citric acid) and diluted with EtOAc.
The insoluble material was removed by filtering through a pad of
Celite.RTM. (J. T. Baker, Phillipsberg, N.J., diatomaceous earth).
The filtrate was extracted (2.times.EtOAc) and washed (sat. aq.
NaCl solution). The combined organic layers were dried
(Na.sub.2SO.sub.4) and concentrated under reduced pressure.
Purification by RP-HPLC (40 to 70% MeCN/H.sub.2O (0.1% TFA), a
gradient elution) provided the title compound as a white foam.
[2139] .sup.1H NMR (400 MHz, CHLOROFORM-d) .delta. ppm 7.25 (2H, d,
J=8.2 Hz), 7.10-7.18 (2H, m), 7.00-7.10 (2H, m), 6.97 (1H, s), 6.83
(1H, d, J=7.2 Hz), 4.99-5.20 (1H, m), 4.87-4.97 (1H, m), 4.74 (1H,
d, J=10.4 Hz), 3.44-3.65 (1H, m), 3.10-3.33 (2H, m), 3.02-3.09 (1H,
m), 2.99 (3H, s), 2.96 (1H, s), 2.77 (1H, s), 2.36 (1H, s),
1.94-2.05 (1H, m), 1.77-1.92 (1H, m), 1.52-1.59 (1H, m), 1.50 (3H,
s), 0.58 (3H, t, J=7.3 Hz); MS (ESI) 541.0 [M+H].sup.+, 539.0
[M-H].sup.-.
Example 130
2-((3R,5R,6S)-5-(3-Chlorophenyl)-6-(4-chlorophenyl)-3-methyl-2-oxo-1-((S)--
5-oxohexan-3-yl)piperidin-3-yl)acetic acid
##STR00422##
[2140] Step A.
(S)-3-((3S,5R,6S)-3-allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl--
2-oxopiperidin-1-yl)pentanal
##STR00423##
[2141] (Methoxymethyl)triphenylphosphonium chloride was dried at
80.degree. C. under vacuum for 3 h. To a solution of the dried
(methoxymethyl)triphenylphosphonium chloride (1.96 g, 5.71 mmol) in
THF (10 mL) was added 0.5 M KHMDS in toluene (10.2 mL, 5.08 mmol)
at -78.degree. C. The color of the solution turned blood red in
color. After stirring at 0.degree. C. for 30 min., a solution of
(S)-2-((3S,5R,6S)-3-allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl--
2-oxopiperidin-1-yl)butanal (Example 91, Step C; 564 mg, 1.27 mmol)
in THF (10.1 mL) was added at 0.degree. C. dropwise. After being
stirred at rt for overnight, the reaction was quenched (sat
NH.sub.4Cl solution), extracted (2.times.EtOAc), and washed (sat.
aq. NaCl solution). The combined organic layers were dried
(Na.sub.2SO.sub.4) and concentrated under reduced pressure.
Purification by chromatography on silica gel (SiO.sub.2, 40 g, 15%
and 20% EtOAc/Hexanes) provided the vinyl ether
(3S,5R,6S)-3-allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((S,E)-1-metho-
xypent-1-en-3-yl)-3-methylpiperidin-2-one. To a solution of
(3S,5R,6S)-3-allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((S,E)-1-metho-
xypent-1-en-3-yl)-3-methylpiperidin-2-one prepared above in
acetonitrile (7.8 mL) was added 3 N hydrochloric acid (4.4 mL, 13
mmol) and the resulting solution was stirred at rt for 1.5 h. Then,
the reaction was extracted (2.times.EtOAc), and washed (sat. aq.
NaCl solution). The combined organic layers were dried
(Na.sub.2SO.sub.4) and concentrated under reduced pressure to
provide the title compound as a pale yellow film.
Step B.
(3S,5R,6S)-3-allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((3S)-5-
-hydroxyhexan-3-yl)-3-methylpiperidin-2-one
##STR00424##
[2143] To a solution of
(S)-3-((3S,5R,6S)-3-allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl--
2-oxopiperidin-1-yl)pentanal (540 mg, 1.18 mmol; Example 130, Step
A) in THF (12 mL) was added 1.4 M methylmagnesium bromide in
toluene and THF (75:25) (2.52 mL, 3.53 mmol) at 0.degree. C. Then
the reaction was allowed to warm to rt and stirred for 3 h. The
reaction was quenched (sat NH.sub.4Cl solution), extracted
(2.times.EtOAc), and washed (sat. aq. NaCl solution). The combined
organic layers were dried (Na.sub.2SO.sub.4) and concentrated under
reduced pressure to provide the crude title compound as a mixture
of diastereomers.
Step C.
2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-2-oxo-
-1-((S)-5-oxohexan-3-yl)piperidin-3-yl)acetic acid
[2144] The title compound was obtained from
(3S,5R,6S)-3-allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((S)-5-hydroxy-
hexan-3-yl)-3-methylpiperidin-2-one (90 mg, 0.19 mmol; Example 130
Step B) as described in Example 71, Step F as a white foam.
[2145] .sup.1H NMR (400 MHz, CHLOROFORM-d) .delta. ppm 7.23-7.27
(2H, m), 7.06-7.17 (4H, m), 7.00 (1H, t, J=1.8 Hz), 6.81 (1H, s),
4.92 (1H, d, J=10.8 Hz), 3.54-3.63 (1H, m), 3.07 (3H, d, J=15.7
Hz), 2.67 (1H, d, J=15.8 Hz), 2.50-2.60 (1H, m), 2.19 (3H, s), 2.12
(1H, s), 1.97-2.07 (1H, m), 1.88-1.96 (1H, m), 1.39 (3H, s),
1.21-1.32 (1H, m), 0.37 (3H, t, J=7.5 Hz); MS (ESI) 490.0
[M+H].sup.+, 488.0 [M-H].sup.-.
Example 131
2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((S)-5-hydroxy-5-met-
hylhexan-3-yl)-3-methyl-2-oxopiperidin-3-yl)acetic acid
##STR00425##
[2146] Step A.
(3S,5R,6S)-3-allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-1-((S)--
5-oxohexan-3-yl)piperidin-2-one
##STR00426##
[2148] The title compound was prepared from
(3S,5R,6S)-3-allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((S)-5-hydroxy-
hexan-3-yl)-3-methylpiperidin-2-one (100 mg, 0.21 mmol; Example
130, Step B) by a procedure similar to the one described in Example
129, Step C.
Step B.
(3S,5R,6S)-3-allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((S)-5--
hydroxy-5-methylhexan-3-yl)-3-methylpiperidin-2-one
##STR00427##
[2150] To a solution of
(3S,5R,6S)-3-allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-1-((S)--
5-oxohexan-3-yl)piperidin-2-one (90 mg, 0.19 mmol; Example 131,
Step A) in THF (1.9 mL) was added 1.4 M methylmagnesium bromide in
toluene and THF (75:25) (408 .mu.L, 0.571 mmol) at 0.degree. C.
Then the reaction was allowed to warm to rt and stirred for 4 h.
The reaction was quenched (sat NH.sub.4Cl solution), extracted
(2.times.EtOAc), and washed (sat. aq. NaCl solution). The combined
organic layer was dried (Na.sub.2SO.sub.4) and concentrated under
reduced pressure and purification of the residue by chromatography
on silica gel (12 g SiO.sub.2, 30% and 35% EtOAc/Hex) provided the
title compound as a colorless foam.
Step C.
2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((S)-5-hydro-
xy-5-methylhexan-3-yl)-3-methyl-2-oxopiperidin-3-yl)acetic acid
[2151] The title compound was obtained from
(3S,5R,6S)-3-allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((S)-5-hydroxy-
-5-methylhexan-3-yl)-3-methylpiperidin-2-one (73 mg, 0.15 mmol;
Example 131, Step B) by a procedure similar to the one described in
Example 71, Step F as a white foam.
[2152] .sup.1H NMR (400 MHz, CHLOROFORM-d) .delta. ppm 7.25 (2H, d,
J=7.8 Hz), 6.98-7.18 (4H, m), 6.95 (1H, t, J=1.8 Hz), 6.70 (1H, d,
J=7.6 Hz), 4.90-5.38 (2H, m), 4.67-4.81 (1H, m), 3.51 (1H, s),
2.98-3.13 (2H, m), 2.70 (1H, d, J=15.1 Hz), 2.19 (1H, t, J=13.8
Hz), 1.93 (2H, d, J=13.3 Hz), 1.48 (4H, s), 1.16-1.28 (7H, m), 0.53
(3H, br. s.); MS (ESI) 506.0 [M+H].sup.+, 504.0 [M-H].sup.-.
Example 132
2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-2-oxo-1-((3S)-
-6,6,6-trifluoro-5-hydroxy-5-methylhexan-3-yl)piperidin-3-yl)acetic
acid (Isomer 1)
##STR00428##
[2153] Step A.
(3S,5R,6S)-3-allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-1-((3S,-
5S)-6,6,6-trifluoro-5-hydroxy-5-methylhexan-3-yl)piperidin-2-one
and
(3S,5R,6S)-3-allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-1-((3S,-
5R)-6,6,6-trifluoro-5-hydroxy-5-methylhexan-3-yl)piperidin-2-one
##STR00429##
[2155] To a solution of
(3S,5R,6S)-3-allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-1-((S)--
5-oxohexan-3-yl)piperidin-2-one (120 mg, 0.254 mmol; Example 131,
Step A) in THF (2.5 mL) was added trimethyl(trifluoromethyl)silane
(113 .mu.L, 0.762 mmol) at 0.degree. C. and the reaction was
stirred for 5 min. Then 1 M TBAF in THF (381 .mu.L, 0.381 mmol) was
added slowly at 0.degree. C. After being stirred at 0.degree. C.
for 20 min, the reaction was allowed to warm to rt. After being
stirred at rt for 40 min the reaction was quenched (sat aq.
NH.sub.4Cl), extracted (2.times.DCM), and washed (2.times.sat.
NaHCO.sub.3 and 1.times.sat. aq. NaCl solution). The combined
organic layers were dried (Na.sub.2SO.sub.4) and concentrated under
reduced pressure. Purification of the residue by chromatography on
silica gel (12 g SiO.sub.2, 13% and 24% EtOAc/Hex) provided a less
polar isomer and a more polar isomer.
(3S,5R,6S)-3-Allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-1-((3S)--
6,6,6-trifluoro-5-hydroxy-5-methylhexan-3-yl)piperidin-2-one (less
polar isomer)
[2156] .sup.1H NMR (400 MHz, CHLOROFORM-d) .delta. ppm 7.24 (2H, d,
J=8.2 Hz), 7.15-7.20 (1H, m), 7.07-7.14 (1H, m), 6.88-7.06 (3H, m),
6.69 (1H, d, J=7.4 Hz), 5.77-5.92 (1H, m), 5.09-5.23 (2H, m),
4.44-4.59 (1H, m), 3.13 (1H, br. s.), 2.62 (2H, d, J=7.4 Hz),
1.84-2.05 (3H, m), 1.64-1.82 (2H, m), 1.33 (3H, s), 1.25-1.31 (5H,
m), 0.72-0.94 (3H, m); MS (ESI) 542.0 [M+H].sup.+.
(3S,5R,6S)-3-Allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-1-((3S)--
6,6,6-trifluoro-5-hydroxy-5-methylhexan-3-yl)piperidin-2-one (more
polar isomer)
[2157] .sup.1H NMR (400 MHz, CHLOROFORM-d) .delta. ppm 7.22-7.27
(2H, m), 7.14-7.20 (1H, m), 7.09-7.14 (1H, m), 6.90-7.08 (3H, m),
6.70 (1H, d, J=7.4 Hz), 5.86 (1H, dd, J=17.4, 9.6 Hz), 5.12-5.22
(2H, m), 4.44-4.56 (1H, m), 3.06-3.21 (1H, m), 1.83-2.03 (2H, m),
1.53-1.82 (3H, m), 1.37-1.49 (1H, m), 1.29 (3H, s), 1.23 (3H, d,
J=14.5 Hz), 0.62-0.94 (3H, m); MS (ESI) 542.0 [M+H].sup.+.
Step B.
2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-2-oxo-
-1-((3S)-6,6,6-trifluoro-5-hydroxy-5-methylhexan-3-yl)piperidin-3-yl)aceti-
c acid (isomer 1)
[2158] The title compound was obtained from the less polar isomer
of
(3S,5R,6S)-3-allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-1-((3S)-
-6,6,6-trifluoro-5-hydroxy-5-methylhexan-3-yl)piperidin-2-one
prepared in Step A by a procedure similar to the one described in
Example 71, Step F as a white foam.
[2159] .sup.1H NMR (400 MHz, CHLOROFORM-d) .delta. ppm 7.24-7.27
(2H, m), 7.14-7.19 (1H, m), 6.96-7.12 (3H, m), 6.93 (1H, t, J=1.7
Hz), 6.68 (1H, d, J=7.6 Hz), 4.58-4.67 (1H, m), 2.98-3.14 (2H, m),
2.71-2.81 (1H, m), 2.17 (1H, s), 2.02 (2H, s), 1.52-1.70 (1H, m),
1.48 (3H, s), 1.34 (5H, s), 0.19-0.93 (3H, m); MS (ESI) 558.0
[M+H].sup.+, 560.0 [M-H].sup.-.
Example 133
2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-2-oxo-1-((3S)-
-6,6,6-trifluoro-5-hydroxy-5-methylhexan-3-yl)piperidin-3-yl)acetic
acid (Isomer 2)
##STR00430##
[2161] The title compound was obtained from the more polar isomer
of
(3S,5R,6S)-3-allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-1-((3S)-
-6,6,6-trifluoro-5-hydroxy-5-methylhexan-3-yl)piperidin-2-one (48
mg, 0.088 mmol; Example 132, Step A) by a procedure similar to the
one described in Example 71, Step F as a white foam.
[2162] .sup.1H NMR (400 MHz, CHLOROFORM-d) .delta. ppm 7.25 (2H,
br. s.), 6.96-7.19 (4H, m), 6.93 (1H, t, J=1.8 Hz), 6.69 (1H, d,
J=7.6 Hz), 4.60-4.70 (1H, m), 3.01 (2H, s), 2.75 (1H, d, J=15.1
Hz), 2.11-2.21 (1H, m), 2.02 (2H, s), 1.77-1.93 (1H, m), 1.48 (6H,
s), 1.35 (3H, br. s.), 0.39-0.71 (3H, m); MS (ESI) 560.0
[M+H].sup.+, 558.0 [M-H].sup.-.
Example 134
2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-1-((S)-1-(N-m-
ethylmethylsulfonamido)butan-2-yl)-2-oxopiperidin-3-yl)acetic
acid
##STR00431##
[2163] Step A.
(3S,5R,6S)-3-allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-1-((S)--
1-(methylamino)butan-2-yl)piperidin-2-one
##STR00432##
[2165] To a solution of
(S)-2-((3S,5R,6S)-3-allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl--
2-oxopiperidin-1-yl)butanal (70 mg, 0.16 mmol; Example 91, Step C)
and acetic acid (271 .mu.L, 4.73 mmol) in C1CH.sub.2CH.sub.2Cl (2.6
mL) was added 2 M methylamine in THF (788 .mu.L, 1.58 mmol) and
sodium triacetoxyborohydride (100 mg, 0.47 mmol) at rt. After being
stirred at rt for 3 h, the reaction was quenched (sat aq.
NaHCO.sub.3), extracted (2.times.EtOAc), and washed (sat. aq. NaCl
solution). The combined organic layers were dried
(Na.sub.2SO.sub.4) and concentrated under reduced pressure to
provide the crude title compound as a pale yellow film. The product
was used in the next step without further purification.
Step B.
N--((S)-2-((3S,5R,6S)-3-allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl-
)-3-methyl-2-oxopiperidin-1-yl)butyl)-N-methylmethanesulfonamide
##STR00433##
[2167] To a solution of
(3S,5R,6S)-3-allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-1-((S)--
1-(methylamino)butan-2-yl)piperidin-2-one (72 mg, 0.16 mmol;
Example 134 Step A) in DMF (0.40 mL) was added methanesulfonyl
chloride (61 .mu.L, 0.79 mmol) and pyridine (76 .mu.L, 0.95 mmol)
successively at 0.degree. C. After being stirred at 25.degree. C.
for overnight, the reaction was acidified (10% citric acid) and
extracted (2.times.EtOAc). The combined organic layers were washed
(sat. aq. NaCl solution), dried (Na.sub.2SO.sub.4), and
concentrated under reduced pressure. Separation by RP-HPLC (50 to
85% MeCN/H.sub.2O (0.1% TFA) a gradient elution) provided the title
compound as a pale yellow film.
Step C.
2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-1-((S-
)-1-(N-methylmethylsulfonamido)butan-2-yl)-2-oxopiperidin-3-yl)acetic
acid
[2168] The title compound was prepared from
N--((S)-2-((3S,5R,6S)-3-allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-met-
hyl-2-oxopiperidin-1-yl)butyl)-N-methylmethanesulfonamide (Example
134, Step B) described in Example AB, Step G.
[2169] .sup.1H NMR (400 MHz, CHLOROFORM-d) .delta. ppm 7.21-7.27
(2H, m), 7.10-7.17 (2H, m), 6.92-7.07 (3H, m), 6.87 (1H, dd, J=6.5,
1.8 Hz), 4.78 (1H, d, J=10.6 Hz), 4.12-4.27 (1H, m), 2.97-3.15 (2H,
m), 2.84-2.90 (1H, m), 2.85 (3H, s), 2.84 (3H, s), 2.63-2.77 (2H,
m), 2.43 (1H, t, J=13.9 Hz), 1.88-1.97 (2H, m), 1.55-1.68 (1H, m),
1.51 (3H, s), 0.50 (3H, t, J=7.5 Hz); MS (ESI) 555.1 [M+H].sup.+,
553.0 [M-H].sup.-.
Example 135
2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((3S)-5-cyclopropyl--
6,6,6-trifluoro-5-hydroxyhexan-3-yl)-3-methyl-2-oxopiperidin-3-yl)acetic
acid
##STR00434##
[2170] Step A.
(3S,5R,6S)-3-allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((3S)-1-cyclop-
ropyl-1-hydroxypentan-3-yl)-3-methylpiperidin-2-one
##STR00435##
[2172] To a solution of
(S)-3-((3S,5R,6S)-3-allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl--
2-oxopiperidin-1-yl)pentanal (160 mg, 0.349 mmol; Example 130, Step
A) in THF (3.5 mL) was added 0.5 M cyclopropylmagnesium bromide in
THF (2.09 mL, 1.05 mmol) at 0.degree. C. Then the reaction was
allowed to warm to rt and stirred for 3.5 h. The reaction was
quenched (sat NH.sub.4Cl solution), extracted (2.times.EtOAc), and
washed (sat. aq. NaCl solution). The combined organic layers were
dried (Na.sub.2SO.sub.4) and concentrated under reduced pressure to
provide the title compound as a mixture of two diastereomers. The
crude product was used in the next step without further
purification.
Step B.
(3S,5R,6S)-3-allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1--
cyclopropyl-1-oxopentan-3-yl)-3-methylpiperidin-2-one
##STR00436##
[2174] To a solution of
(3S,5R,6S)-3-allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-cyclopr-
opyl-1-hydroxypentan-3-yl)-3-methylpiperidin-2-one prepared above
in Step A (175 mg, 0.350 mmol) and water (9.5 .mu.L, 0.52 mmol) in
DCM (3.9 mL) was added Dess-Martin periodinane (222 mg, 0.524 mmol)
at rt. After being stirred at rt for 40 min, the reaction was
quenched (1 M aq. Na.sub.2S.sub.2O.sub.3), extracted (2.times.DCM),
and washed (2.times.sat. NaHCO.sub.3 and 1.times.sat. aq. NaCl
solution). The combined organic layers were dried
(Na.sub.2SO.sub.4) and concentrated under reduced pressure.
Purification of the residue by chromatography on silica gel (12 g
SiO.sub.2, 15% and 25% EtOAc/Hex) provided the title compound as a
colorless film.
Step C.
(3S,5R,6S)-3-allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((3S,5S-
)-5-cyclopropyl-6,6,6-trifluoro-5-hydroxyhexan-3-yl)-3-methylpiperidin-2-o-
ne and
(3S,5R,6S)-3-allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((3S,5R)-
-5-cyclopropyl-6,6,6-trifluoro-5-hydroxyhexan-3-yl)-3-methylpiperidin-2-on-
e
##STR00437##
[2176] To a solution of
(3S,5R,6S)-3-allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-cyclopr-
opyl-1-oxopentan-3-yl)-3-methylpiperidin-2-one prepared above in
Step B (132 mg, 0.265 mmol) in THF (2.6 mL) was added
trimethyl(trifluoromethyl)silane (117 .mu.L, 0.794 mmol) at
0.degree. C. and the reaction was stirred for 5 min. Then 1 M
tetrabutylammonium fluoride in THF (397 .mu.L, 0.397 mmol) was
added slowly at 0.degree. C. Then the reaction was allowed to warm
to rt. After being stirred for 3 h, additional
trimethyl(trifluoromethyl)silane (234 .mu.L, 1.59 mmol) and 1 M
tetrabutylammonium fluoride in THF (794 .mu.L, 0.794 mmol) were
added at 0.degree. C. and the reaction was allowed to warm to rt.
After being stirred at rt for 15 h, the reaction was quenched (sat.
aq. NaCl solution), extracted (2.times.EtOAc), and washed (sat. aq.
NaCl solution). The combined organic layers were dried
(Na.sub.2SO.sub.4) and concentrated under reduced pressure.
Purification of the residue by chromatography on silica gel (12 g
SiO.sub.2, 6% and 13% EtOAc/Hex) provided one of the title
compounds as the less polar isomer and another one of the title
compounds as the more polar isomer, successively.
(3S,5R,6S)-3-allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((3S)-5-cyclopr-
opyl-6,6,6-trifluoro-5-hydroxyhexan-3-yl)-3-methylpiperidin-2-one
(less polar isomer)
[2177] .sup.1H NMR (400 MHz, CHLOROFORM-d) .delta. ppm 7.24 (2H, d,
J=8.2 Hz), 7.15-7.20 (1H, m), 7.07-7.14 (1H, m), 6.88-7.06 (3H, m),
6.69 (1H, d, J=7.4 Hz), 5.77-5.92 (1H, m), 5.09-5.23 (2H, m),
4.44-4.59 (1H, m), 3.13 (1H, br. s.), 2.62 (2H, d, J=7.4 Hz),
1.84-2.05 (3H, m), 1.64-1.82 (2H, m), 1.33 (3H, s), 1.25-1.31 (5H,
m), 0.72-0.94 (3H, m);
[2178] MS (ESI) 568.2 [M+H].sup.+.
(3S,5R,6S)-3-allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((3S)-5-cyclopr-
opyl-6,6,6-trifluoro-5-hydroxyhexan-3-yl)-3-methylpiperidin-2-one
(more polar isomer)
[2179] .sup.1H NMR (400 MHz, CHLOROFORM-d) .delta. ppm 7.22-7.27
(2H, m), 7.14-7.20 (1H, m), 7.09-7.14 (1H, m), 6.90-7.08 (3H, m),
6.70 (1H, d, J=7.4 Hz), 5.86 (1H, dd, J=17.4, 9.6 Hz), 5.12-5.22
(2H, m), 4.44-4.56 (1H, m), 3.06-3.21 (1H, m), 1.83-2.03 (2H, m),
1.53-1.82 (3H, m), 1.37-1.49 (1H, m), 1.29 (3H, s), 1.23 (3H, d,
J=14.5 Hz), 0.62-0.94 (3H, m); MS (ESI) 568.2 [M+H].sup.+.
Step D.
2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((3S)-5-cycl-
opropyl-6,6,6-trifluoro-5-hydroxyhexan-3-yl)-3-methyl-2-oxopiperidin-3-yl)-
acetic acid
[2180] The title compound was prepared from
(3S,5R,6S)-3-allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((3S)-5-cyclop-
ropyl-6,6,6-trifluoro-5-hydroxyhexan-3-yl)-3-methylpiperidin-2-one
(Example 135, Step C, more polar product) by a procedure similar to
the one described in Example 71, Step F.
[2181] .sup.1H NMR (400 MHz, CHLOROFORM-d) .delta. ppm 7.00-7.04
(2H, m), 6.91-6.96 (1H, m), 6.84-6.90 (1H, m), 6.67-6.84 (3H, m),
6.46 (1H, d, J=7.6 Hz), 4.29-4.45 (1H, m), 2.76-2.91 (2H, m), 2.51
(1H, d, J=15.1 Hz), 1.84-1.96 (1H, m), 1.69-1.79 (1H, m), 1.48-1.67
(1H, m), 1.12-1.35 (6H, m), 0.62-0.81 (1H, m), 0.01-0.51 (8H, m);
MS (ESI) 586.2 [M+H].sup.+, 584.0 [M-H].sup.-.
Example 136
2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((S)-6-hydroxy-6-met-
hylheptan-3-yl)-3-methyl-2-oxopiperidin-3-yl)acetic acid
##STR00438##
[2182] Step A.
(S)-4-((3S,5R,6S)-3-allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl--
2-oxopiperidin-1-yl)hexanal
##STR00439##
[2184] The title compound was prepared form
(S)-3-((3S,5R,6S)-3-allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl--
2-oxopiperidin-1-yl)pentanal (106 mg, 0.231 mmol; Example 130, Step
A) by a procedure similar to the one described in Example 130, Step
A.
Step B.
(3S,5R,6S)-3-allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((3S)-6-
-hydroxyheptan-3-yl)-3-methylpiperidin-2-one
##STR00440##
[2186] The title compound was prepared from
(S)-4-((3S,5R,6S)-3-allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl--
2-oxopiperidin-1-yl)hexanal (84 mg, 0.18 mmol; Example 136, Step A)
by a procedure similar to the one described in Example 130, Step B
as a colorless film. The crude product was used in the next step
without further purification
Step C.
(3S,5R,6S)-3-allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl--
1-((S)-6-oxoheptan-3-yl)piperidin-2-one
##STR00441##
[2188] The title compound was prepared from a mixture of
(3S,5R,6S)-3-allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((S)-6-hydroxy-
heptan-3-yl)-3-methylpiperidin-2-one prepared above in Step B by a
procedure similar to the one described in Example 129, Step C.
Step D.
(3S,5R,6S)-3-allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((S)-6--
hydroxy-6-methylheptan-3-yl)-3-methylpiperidin-2-one
##STR00442##
[2190] To a solution of
(3S,5R,6S)-3-allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-1-((S)--
6-oxoheptan-3-yl)piperidin-2-one prepared above in Step C (78 mg,
0.16 mmol) in THF (1.6 mL) was added 1.4 M methylmagnesium bromide
in toluene and THF (75:25) (344 .mu.L, 0.481 mmol) at 0.degree. C.
Then the reaction was allowed to warm to rt and stirred for 2 h.
The reaction was quenched (sat NH.sub.4Cl solution), extracted
(2.times.EtOAc), and washed (sat. aq. NaCl solution). The combined
organic layer was dried (Na.sub.2SO.sub.4) and concentrated under
reduced pressure. Purification of the residue by chromatography on
silica gel (12 g SiO.sub.2, 33% and 43% EtOAc/Hex) provided the
title compound as a colorless foam.
Step E.
2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((S)-6-hydro-
xy-6-methylheptan-3-yl)-3-methyl-2-oxopiperidin-3-yl)acetic
acid
[2191] The title compound was prepared from
(3S,5R,6S)-3-allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((S)-6-hydroxy-
-6-methylheptan-3-yl)-3-methylpiperidin-2-one (Example 136, Step D)
by a procedure similar to the one described in Example 71, Step
F.
[2192] .sup.1H NMR (400 MHz, CHLOROFORM-d) .delta. ppm 7.25 (2H, d,
J=8.4 Hz), 7.16 (1H, dd, J=1.9, 1.1 Hz), 7.11 (1H, d, J=7.6 Hz),
6.94 (3H, t, J=1.8 Hz), 6.70 (1H, d, J=7.6 Hz), 5.01-5.25 (2H, m),
4.37 (1H, d, J=10.4 Hz), 3.06 (2H, d, J=15.3 Hz), 2.93-3.03 (1H,
m), 2.71 (1H, d, J=15.3 Hz), 2.20 (1H, s), 2.02 (1H, s), 1.78-1.97
(2H, m), 1.37-1.56 (7H, m), 1.22 (6H, d, J=5.5 Hz), 0.55 (3H, t,
J=7.5 Hz); MS (ESI) 520.2 [M+H].sup.+, 518.0 [M-H].sup.-.
Example 137
2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-2-oxo-1-((S)--
6,6,6-trifluoro-5,5-dihydroxyhexan-3-yl)piperidin-3-yl)acetic
acid
##STR00443##
[2193] Step A.
(3S,5R,6S)-3-allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-1-((3S)-
-6,6,6-trifluoro-5-hydroxyhexan-3-yl)piperidin-2-one
##STR00444##
[2195] To a solution of
(S)-3-((3S,5R,6S)-3-allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl--
2-oxopiperidin-1-yl)pentanal (100 mg, 0.218 mmol; Example 130, Step
A) in THF (2.2 mL) was added trimethyl(trifluoromethyl)silane (97
.mu.L, 0.66 mmol) at 0.degree. C. and the reaction was stirred for
5 min. Then 1 M TBAF in THF (327 .mu.L, 0.327 mmol) was added
slowly at 0.degree. C. After being stirred at 0.degree. C. for 40
min, the reaction was quenched (sat. aq. NaCl solution), extracted
(2.times.EtOAc), and washed (sat. aq. NaCl solution). The combined
organic layers were dried (Na.sub.2SO.sub.4) and concentrated under
reduced pressure. Purification of the residue by chromatography on
silica gel (12 g SiO.sub.2, 13% and 23% EtOAc/Hex) provided the
title compound as a mixture of two diastereomers.
Step B.
(3S,5R,6S)-3-allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl--
1-((S)-6,6,6-trifluoro-5,5-dihydroxyhexan-3-yl)piperidin-2-one
##STR00445##
[2197] To a solution of
(3S,5R,6S)-3-allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-1-((S)--
6,6,6-trifluoro-5-hydroxyhexan-3-yl)piperidin-2-one prepared above
in Step A (100 mg, 0.189 mmol) in DCM (2.1 mL) was added water (17
.mu.L, 0.95 mmol) and Dess-Martin periodinane (161 mg, 0.378 mmol)
at rt and the resulting solution was stirred overnight. The
reaction was quenched (1 M aq. Na.sub.2S.sub.2O.sub.3), extracted
(2.times.DCM), and washed (2.times.sat. NaHCO.sub.3 and
1.times.sat. aq. NaCl solution). The combined organic layers were
dried (Na.sub.2SO.sub.4) and concentrated under reduced pressure to
provide the title compound as a colorless film. The product was
used in the next step without further purification.
Step C.
2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-2-oxo-
-1-((S)-6,6,6-trifluoro-5,5-dihydroxyhexan-3-yl)piperidin-3-yl)acetic
acid
[2198] The title compound was prepared from
(3S,5R,6S)-3-allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-1-((S)--
6,6,6-trifluoro-5,5-dihydroxyhexan-3-yl)piperidin-2-one (Example
137, Step B) by a procedure similar to the one described in Example
71, Step F.
[2199] .sup.1H NMR (400 MHz, CHLOROFORM-d) .delta. ppm 7.29 (2H,
br. s.), 7.06-7.20 (4H, m), 6.97 (1H, s), 6.76-6.82 (1H, m), 4.74
(1H, d, J=10.6 Hz), 3.88-3.98 (1H, m), 3.09-3.19 (2H, m), 2.96 (1H,
s), 2.78 (2H, s), 2.08 (3H, s), 1.38 (4H, s), 0.42 (3H, t, J=7.5
Hz); MS (ESI) 562.1 [M+H].sup.+, 560.0 [M-H].sup.-.
Example 138
2-((3R,5R,6S)-5-(3-Chlorophenyl)-6-(4-chlorophenyl)-3-methyl-2-oxo-1-((3S)-
-7,7,7-trifluoro-6-hydroxy-6-methylheptan-3-yl)piperidin-3-yl)acetic
acid (Isomer 1)
##STR00446##
[2200] Step A.
(3S,5R,6S)-3-allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-1-((3S,-
6R)-7,7,7-trifluoro-6-hydroxy-6-methylheptan-3-yl)piperidin-2-one
and
(3S,5R,6S)-3-allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-1-((3S,-
6S)-7,7,7-trifluoro-6-hydroxy-6-methylheptan-3-yl)piperidin-2-one
##STR00447##
[2202] To a solution of
(3S,5R,6S)-3-allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-1-((S)--
6-oxoheptan-3-yl)piperidin-2-one (169 mg, 0.347 mmol; Example 136,
Step C) in THF (3.5 mL) was added trimethyl(trifluoromethyl)silane
(154 .mu.L, 1.04 mmol) at 0.degree. C. and the reaction was stirred
for 5 min. Then 1 M TBAF in THF (521 .mu.L, 0.521 mmol) was added
slowly at 0.degree. C. Then the reaction was allowed to warm to rt.
After being stirred at rt for 1.5 h, the reaction was quenched
(water), extracted (2.times.EtOAc), and washed (water and sat. aq.
NaCl solution). The combined organic layers were dried
(Na.sub.2SO.sub.4) and concentrated under reduced pressure.
Purification of the residue by chromatography on silica gel (40 g
SiO.sub.2, 13%, 23% and 33% EtOAc/Hex) provided one of the title
compounds as the less polar isomer and another one of the title
compounds as the more polar isomer, successively
(3S,5R,6S)-3-allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-1-((3S)--
7,7,7-trifluoro-6-hydroxy-6-methylheptan-3-yl)piperidin-2-one (less
polar isomer)
[2203] .sup.1H NMR (400 MHz, CHLOROFORM-d) .delta. ppm 7.22 (2H, d,
J=8.2 Hz), 7.07-7.20 (2H, m), 6.91 (3H, t, J=1.8 Hz), 6.65-6.74
(1H, m), 5.82-5.97 (1H, m), 5.13-5.24 (2H, m), 4.33 (1H, d, J=10.6
Hz), 3.78-3.99 (1H, m), 3.10-3.26 (1H, m), 2.64 (2H, dd, J=7.4, 4.5
Hz), 1.91-2.04 (2H, m), 1.68-1.78 (1H, m), 1.62 (3H, t, J=7.3 Hz),
1.33-1.46 (1H, m), 1.29 (4H, s), 1.25 (3H, s), 0.94-1.13 (1H, m),
0.84 (3H, t, J=7.3 Hz); MS (ESI) 556.2 [M+H].sup.+.
(3S,5R,6S)-3-allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-1-((3S)--
7,7,7-trifluoro-6-hydroxy-6-methylheptan-3-yl)piperidin-2-one (more
polar isomer)
[2204] .sup.1H NMR (400 MHz, CHLOROFORM-d) .delta. ppm 7.23 (2H, d,
J=8.4 Hz), 7.08-7.20 (2H, m), 6.89-7.01 (3H, m), 6.68-6.75 (1H, m),
5.84 (1H, s), 5.13-5.23 (2H, m), 4.28 (1H, d, J=10.4 Hz), 3.09-3.22
(2H, m), 2.62 (2H, d, J=7.2 Hz), 1.90-2.05 (2H, m), 1.73-1.84 (2H,
m), 1.53-1.66 (3H, m), 1.35-1.48 (1H, m), 1.31 (3H, s), 1.24-1.29
(4H, m), 0.66 (3H, t, J=7.4 Hz); MS (ESI) 556.2 [M+H].sup.+.
Step B.
2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-2-oxo-
-1-((3S)-7,7,7-trifluoro-6-hydroxy-6-methylheptan-3-yl)piperidin-3-yl)acet-
ic acid (Isomer 1)
[2205] The title compound was prepared from
(3S,5R,6S)-3-allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-1-((3S)-
-7,7,7-trifluoro-6-hydroxy-6-methylheptan-3-yl)piperidin-2-one
(Example 138, Step A, less polar product) by a procedure similar to
the one described in Example 71, Step F.
[2206] .sup.1H NMR (400 MHz, CHLOROFORM-d) .delta. ppm 7.23 (2H, d,
J=8.0 Hz), 7.14-7.19 (1H, m), 7.07-7.13 (1H, m), 7.01 (2H, br. s.),
6.92 (1H, t, J=1.7 Hz), 6.69 (1H, d, J=7.6 Hz), 5.57-5.68 (1H, m),
4.38 (1H, d, J=10.4 Hz), 3.52 (1H, s), 3.17 (1H, br. s.), 2.77-3.02
(2H, m), 2.05-2.24 (2H, m), 1.75 (2H, dd, J=11.8, 6.6 Hz),
1.53-1.65 (1H, m), 1.48 (3H, s), 1.34-1.45 (3H, m), 1.29 (3H, s),
0.71 (3H, t, J=7.3 Hz); MS (ESI) 574.2 [M+H].sup.+, 572.0
[M-H].sup.-.
Example 139
2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-2-oxo-1-((3S)-
-7,7,7-trifluoro-6-hydroxy-6-methylheptan-3-yl)piperidin-3-yl)acetic
acid (Isomer 2)
##STR00448##
[2208] The title compound was prepared from
(3S,5R,6S)-3-allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-1-((3S)-
-7,7,7-trifluoro-6-hydroxy-6-methylheptan-3-yl)piperidin-2-one
(Example 138, Step A, more polar product) by a procedure similar to
the one described in Example 71, Step F.
[2209] .sup.1H NMR (400 MHz, CHLOROFORM-d) .delta. ppm 7.25 (2H,
s), 7.16-7.21 (1H, m), 7.09-7.15 (1H, m), 7.01 (2H, d, J=4.1 Hz),
6.93 (1H, t, J=1.7 Hz), 6.72 (1H, d, J=7.6 Hz), 5.66-5.74 (1H, m),
4.34 (1H, d, J=10.2 Hz), 3.09-3.27 (2H, m), 2.98 (1H, d, J=14.5
Hz), 2.74 (1H, d, J=14.5 Hz), 2.14-2.24 (1H, m), 2.02-2.08 (1H, m),
1.81 (2H, dd, J=14.3, 7.2 Hz), 1.52-1.70 (3H, m), 1.50 (3H, s),
1.29-1.38 (1H, m), 1.27 (3H, s), 0.64 (3H, t, J=7.3 Hz); MS (ESI)
574.2 [M+H].sup.+, 572.0 [M-H].sup.-.
Example 140
2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((S)-7-hydroxy-7-met-
hyloctan-3-yl)-3-methyl-2-oxopiperidin-3-yl)acetic acid
##STR00449##
[2210] Step A.
(S)-5-((3S,5R,6S)-3-allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl--
2-oxopiperidin-1-yl)heptanal
##STR00450##
[2212] The title compound was prepared from
(S)-4-((3S,5R,6S)-3-allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl--
2-oxopiperidin-1-yl)hexanal (147 mg, 0.311 mmol; Example 136, Step
A) by a procedure similar to the one described in Example 130, Step
A.
Step B.
(3S,5R,6S)-3-allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((3S)-7-
-hydroxyoctan-3-yl)-3-methylpiperidin-2-one
##STR00451##
[2214] To a solution of
(S)-5-((3S,5R,6S)-3-allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl--
2-oxopiperidin-1-yl)heptanal prepared above in Step A (138 mg,
0.284 mmol) in THF (2.8 mL) was added 1.4 M methylmagnesium bromide
in toluene and THF (75:25) (608 .mu.L, 0.851 mmol) at 0.degree. C.
Then the reaction was allowed to warm to rt and stirred for 2 h.
The reaction was quenched (sat NH.sub.4Cl solution), extracted
(2.times.EtOAc), and washed (sat. aq. NaCl solution). The combined
organic layer was dried (Na.sub.2SO.sub.4) and concentrated under
reduced pressure to provide the title compound as a colorless
film.
Step C.
(3S,5R,6S)-3-allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl--
1-((S)-7-oxooctan-3-yl)piperidin-2-one
##STR00452##
[2216] The title compound was prepared from
(3S,5R,6S)-3-allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((S)-7-hydroxy-
octan-3-yl)-3-methylpiperidin-2-one prepared above in Step B (143
mg, 0.285 mmol) by a procedure similar to the one described in
Example 131, Step A as a white solid.
Step D.
(3S,5R,6S)-3-allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((S)-7--
hydroxy-7-methyloctan-3-yl)-3-methylpiperidin-2-one
##STR00453##
[2218] To a solution of
(3S,5R,6S)-3-allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-1-((S)--
7-oxooctan-3-yl)piperidin-2-one prepared above in Step C (122 mg,
0.244 mmol) in THF (2.4 mL) was added 1.4 M methylmagnesium bromide
in toluene and THF (75:25) (522 .mu.L, 0.731 mmol) at 0.degree. C.
Then the reaction was allowed to warm to rt and stirred for 2 h.
The reaction was quenched (sat NH.sub.4Cl solution), extracted
(2.times.EtOAc), and washed (sat. aq. NaCl solution). The combined
organic layers were dried (Na.sub.2SO.sub.4) and concentrated under
reduced pressure and purification of the residue by chromatography
on silica gel (12 g SiO.sub.2, 30% and 40% EtOAc/Hex) provided the
title compound as a colorless foam.
Step E.
2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((S)-7-hydro-
xy-7-methyloctan-3-yl)-3-methyl-2-oxopiperidin-3-yl)acetic acid
[2219] The title compound was prepared from
(3S,5R,6S)-3-allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((S)-7-hydroxy-
-7-methyloctan-3-yl)-3-methylpiperidin-2-one (Example 140, Step D)
by a procedure similar to the one described in Example 71, Step
F.
[2220] .sup.1H NMR (400 MHz, CHLOROFORM-d) .delta. ppm 7.23 (2H, d,
J=8.0 Hz), 7.05-7.18 (2H, m), 6.92-7.05 (3H, m), 6.70 (1H, d, J=7.6
Hz), 4.42 (1H, d, J=10.4 Hz), 3.05-3.18 (2H, m), 3.00 (1H, d,
J=15.1 Hz), 2.72 (1H, d, J=15.1 Hz), 2.11-2.26 (1H, m), 1.97-2.08
(1H, m), 1.79-1.92 (1H, m), 1.64-1.79 (1H, m), 1.50-1.59 (2H, m),
1.48 (3H, s), 1.34-1.45 (3H, m), 1.28-1.33 (1H, m), 1.27 (3H, s),
1.25 (3H, s), 0.56 (3H, t, J=7.4 Hz); MS (ESI) 534.1 [M+H].sup.+,
532.2 [M-H].sup.-.
Example 141
2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-1-((S)-1-(N-m-
ethylcyclopropanesulfonamido)butan-2-yl)-2-oxopiperidin-3-yl)acetic
acid
##STR00454##
[2222] The title compound was prepared from
(3S,5R,6S)-3-allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-1-((S)--
1-(methylamino)butan-2-yl)piperidin-2-one (Example 134, Step A) by
procedures similar to those described in Example 134, Steps B and
C, substituting methanesuflonylchloride in Step B for the
appropriate amount of cyclopropylsulfonyl chloride.
[2223] .sup.1H NMR (400 MHz, CHLOROFORM-d) .delta. ppm 7.24 (2H,
br. s.), 7.10-7.17 (2H, m), 6.80-7.09 (4H, m), 4.79 (1H, d, J=10.8
Hz), 4.13-4.30 (1H, m), 2.99-3.12 (2H, m), 2.89 (4H, s), 2.64-2.81
(2H, m), 2.45 (1H, t, J=13.8 Hz), 2.33 (1H, s), 1.88 (2H, dd,
J=13.9, 2.7 Hz), 1.54-1.66 (1H, m), 1.50-1.54 (3H, m), 1.22 (2H, d,
J=4.5 Hz), 1.02 (2H, dd, J=8.0, 3.9 Hz), 0.51 (3H, t, J=7.4 Hz); MS
(ESI) 581.0 [M+H].sup.+, 579.0 [M-H].sup.-.
Example 142
2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-(N-cyclopropy-
lmethylsulfonamido)butan-2-yl)-3-methyl-2-oxopiperidin-3-yl)acetic
acid
##STR00455##
[2225] The title compound was prepared from
(S)-2-((3S,5R,6S)-3-allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl--
2-oxopiperidin-1-yl)butanal (Example 91, Step C) by procedures
similar to those described in Example 134, Step A-C, substituting
methylamine in Step A for the appropriate amount of
cyclopropylamine.
[2226] .sup.1H NMR (400 MHz, CHLOROFORM-d) .delta. ppm 7.22-7.27
(2H, m), 7.11-7.18 (2H, m), 6.81-7.06 (4H, m), 4.81 (1H, d, J=10.6
Hz), 4.25-4.41 (1H, m), 3.08 (2H, d, J=15.5 Hz), 2.95 (3H, s),
2.81-2.90 (1H, m), 2.73-2.80 (1H, m), 2.67 (1H, d, J=15.5 Hz), 2.52
(2H, s), 1.95-2.14 (1H, m), 1.77-1.88 (1H, m), 1.53 (4H, s),
0.70-0.92 (3H, m), 0.59-0.69 (1H, m), 0.50 (3H, t, J=7.5 Hz); MS
(ESI) 581.0 [M+H].sup.+, 579.0 [M-H].sup.-.
Example 143
2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-2-oxo-1-((3S)-
-6,6,6-trifluoro-5-hydroxyhexan-3-yl)piperidin-3-yl)acetic acid
(Isomer 1)
##STR00456##
[2227] Step A.
(3S,5R,6S)-3-allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-1-((3S,-
5S)-6,6,6-trifluoro-5-hydroxyhexan-3-yl)piperidin-2-one and
(3S,5R,6S)-3-allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-1-((3S,-
5R)-6,6,6-trifluoro-5-hydroxyhexan-3-yl)piperidin-2-one
##STR00457##
[2229] To a solution of
(S)-3-((3S,5R,6S)-3-allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl--
2-oxopiperidin-1-yl)pentanal (139 mg, 0.303 mmol; Example 130, Step
A) in THF (3.0 mL) was added trimethyl(trifluoromethyl)silane (134
.mu.L, 0.910 mmol) at 0.degree. C. and the reaction was stirred for
5 min. Then 1 M TBAF in THF (455 .mu.L, 0.455 mmol) was added
slowly at 0.degree. C. Then, the reaction was allowed to warm to
rt. After being stirred at rt for 1.5 h, the reaction was quenched
(sat. aq. NaCl solution), extracted (2.times.EtOAc), and washed
(sat. aq.
[2230] NaCl solution). The combined organic layers were dried
(Na.sub.2SO.sub.4) and concentrated under reduced pressure.
Purification of the residue by chromatography on silica gel (24 g
SiO.sub.2, 6% and 16% EtOAc/Hex) provided one of the title
compounds as the less polar isomer and another one of the title
compounds as the more polar isomer, successively.
(3S,5R,6S)-3-allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-1-((3S)--
6,6,6-trifluoro-5-hydroxyhexan-3-yl)piperidin-2-one (less polar
isomer)
[2231] .sup.1H NMR (400 MHz, CHLOROFORM-d) .delta. ppm 7.15-7.26
(3H, m), 7.11 (1H, t, J=7.7 Hz), 6.93 (3H, t, J=1.9 Hz), 6.68 (1H,
dt, J=7.6, 1.5 Hz), 5.83-5.95 (1H, m), 5.17-5.26 (2H, m), 4.38 (1H,
d, J=10.4 Hz), 3.69-3.81 (1H, m), 3.11-3.22 (1H, m), 2.66 (2H, d,
J=7.6 Hz), 1.92-2.12 (3H, m), 1.72-1.89 (1H, m), 1.49-1.60 (1H, m),
1.25-1.37 (5H, m), 1.00 (1H, none), 0.92-1.07 (3H, m); MS (ESI)
528.1 [M+H].sup.+.
(3S,5R,6S)-3-allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-1-((3S)--
6,6,6-trifluoro-5-hydroxyhexan-3-yl)piperidin-2-one (more polar
isomer)
[2232] .sup.1H NMR (400 MHz, CHLOROFORM-d) .delta. ppm 7.24 (2H,
dd, J=7.4, 1.4 Hz), 7.15-7.20 (1H, m), 7.11 (1H, t, J=7.8 Hz),
6.90-7.05 (3H, m), 6.70 (1H, dt, J=7.5, 1.5 Hz), 5.79-5.92 (1H, m),
5.13-5.22 (2H, m), 4.43 (1H, d, J=10.4 Hz), 3.90 (1H, ddd, J=11.1,
6.6, 2.2 Hz), 3.09-3.22 (1H, m), 2.53-2.71 (2H, m), 1.90-2.05 (2H,
m), 1.56-1.86 (4H, m), 1.22-1.32 (4H, m), 0.79 (3H, t, J=7.4 Hz);
MS (ESI) 528.1 [M+H].sup.+.
Step B.
2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-2-oxo-
-1-((3S,5S)-6,6,6-trifluoro-5-hydroxyhexan-3-yl)piperidin-3-yl)acetic
acid (Isomer 1)
[2233] The title compound was prepared from
(3S,5R,6S)-3-allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-1-((3S)-
-6,6,6-trifluoro-5-hydroxyhexan-3-yl)piperidin-2-one (Step A, less
polar product) by a procedure similar to the one described in
Example 71, Step F.
[2234] .sup.1H NMR (400 MHz, CHLOROFORM-d) .delta. ppm 7.06-7.27
(6H, m), 6.94 (1H, t, J=1.7 Hz), 6.68 (1H, d, J=7.6 Hz), 4.58-5.15
(3H, m), 4.42 (2H, d, J=10.4 Hz), 3.88-4.01 (1H, m), 3.19-3.28 (1H,
m), 2.86 (2H, d, J=12.7 Hz), 2.03-2.24 (2H, m), 1.71-1.89 (1H, m),
1.54-1.66 (1H, m), 1.50 (3H, s), 1.26-1.40 (1H, m), 0.97 (3H, br.
s.); MS (ESI) 546.0 [M+H].sup.+, 544.0 [M-H].sup.-.
Example 144
2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-2-oxo-1-((3S)-
-6,6,6-trifluoro-5-hydroxyhexan-3-yl)piperidin-3-yl)acetic acid
(Isomer 2)
##STR00458##
[2236] The title compound was prepared from
(3S,5R,6S)-3-allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-1-((3S)-
-6,6,6-trifluoro-5-hydroxyhexan-3-yl)piperidin-2-one (Example 143,
Step A; more polar product) by a procedure similar to the one
described in Example 71, Step F.
[2237] .sup.1H NMR (400 MHz, CHLOROFORM-d) .delta. ppm 7.23-7.27
(2H, m), 7.08-7.20 (2H, m), 6.93-7.08 (3H, m), 6.70 (1H, dt, J=7.7,
1.4 Hz), 4.49 (1H, d, J=10.4 Hz), 3.88-4.01 (1H, m), 3.51 (1H, s),
3.10-3.22 (1H, m), 2.95 (1H, d, J=14.5 Hz), 2.75 (1H, d, J=14.5
Hz), 2.20 (1H, t, J=13.8 Hz), 1.99-2.08 (1H, m), 1.95 (1H, d, J=2.3
Hz), 1.77 (1H, dd, J=14.3, 7.2 Hz), 1.52-1.70 (2H, m), 1.48 (3H,
s), 0.72 (3H, t, J=7.5 Hz); MS (ESI) 546.0 [M+H].sup.+, 544.0
[M-H].sup.-.
Example 145
2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((3S)-5-hydroxyhexan-
-3-yl)-3-methyl-2-oxopiperidin-3-yl)acetic acid (Isomer 1)
##STR00459##
[2239] To a solution of
2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-2-oxo-1-((S)-
-5-oxohexan-3-yl)piperidin-3-yl)acetic acid (24 mg, 0.049 mmol;
Example 130) in ether (0.40 mL) and MeOH (0.10 mL) was added sodium
borohydride (9.26 mg, 0.245 mmol) at 0.degree. C. Then the reaction
was allowed to warm to rt. After being stirred at rt for 1 h, the
reaction was quenched (10% citric acid) and extracted
(2.times.EtOAc). The combined organic layer was washed (sat. aq.
NaCl solution), dried (Na.sub.2SO.sub.4), and concentrated under
reduced pressure. Purification by RP-HPLC (30 to 70% MeCN/H.sub.2O
(0.1% TFA), a gradient elution) provided the title compound as the
more polar isomer.
[2240] .sup.1H NMR (400 MHz, CHLOROFORM-d) .delta. ppm 7.22-7.27
(2H, m), 7.07-7.19 (2H, m), 6.95-7.06 (3H, m), 6.71 (1H, dt, J=7.6,
1.6 Hz), 4.57 (1H, d, J=10.2 Hz), 3.77-3.89 (1H, m), 2.99-3.15 (2H,
m), 2.69 (1H, d, J=14.9 Hz), 2.23 (1H, t, J=13.6 Hz), 1.81-1.99
(2H, m), 1.52-1.64 (1H, m), 1.47 (3H, s), 1.39 (1H, d, J=2.0 Hz),
1.19 (3H, d, J=6.3 Hz), 0.60 (3H, t, J=7.4 Hz); MS (ESI) 492.1
[M+H].sup.+, 490.0 [M-H].sup.-.
Example 146
2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((3S)-5-hydroxyhexan-
-3-yl)-3-methyl-2-oxopiperidin-3-yl)acetic acid (Isomer 2)
##STR00460##
[2242] Further elution from Example 145 provided the title compound
as the less polar isomer.
[2243] .sup.1H NMR (400 MHz, CHLOROFORM-d) .delta. ppm 7.04-7.27
(5H, m), 6.91-7.04 (2H, m), 6.70 (1H, dt, J=7.7, 1.5 Hz), 4.47 (1H,
d, J=10.4 Hz), 3.75 (1H, ddd, J=12.4, 6.1, 0.7 Hz), 3.15-3.27 (1H,
m), 2.96 (1H, d, J=14.5 Hz), 2.76 (1H, d, J=14.7 Hz), 2.18 (1H, t,
J=13.8 Hz), 2.02-2.09 (1H, m), 1.59-1.71 (2H, m), 1.50 (3H, s),
1.26 (1H, dd, J=16.8, 6.8 Hz), 1.08-1.21 (2H, m), 0.99-1.07 (3H,
m), 0.89 (3H, br. s.); MS (ESI) 492.1 [M+H].sup.+, 490.0
[M-H].sup.-.
Example 147
2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-2-oxo-1-((S)--
1-(N-(2,2,2-trifluoroethyl)methylsulfonamido)butan-2-yl)piperidin-3-yl)ace-
tic acid
##STR00461##
[2244] Step A.
(3S,5R,6S)-3-allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-1-((S)--
1-((2,2,2-trifluoroethyl)amino)butan-2-yl)piperidin-2-one
##STR00462##
[2246] To a solution of
(S)-2-((3S,5R,6S)-3-allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl--
2-oxopiperidin-1-yl)butanal (104 mg, 0.234 mmol; Example 130, Step
A) in C1CH.sub.2CH.sub.2Cl (3.9 mL) was added
2,2,2-trifluoroethylamine (74 .mu.L, 0.94 mmol) and sodium
triacetoxyborohydride (248 mg, 1.17 mmol) at rt. After being
stirred at rt overnight, the reaction was quenched (sat aq.
NaHCO.sub.3), extracted (2.times.EtOAc), and washed (sat. aq. NaCl
solution). The combined organic layers were dried
(Na.sub.2SO.sub.4) and concentrated under reduced pressure to
provide the title compound as a white solid. The product was used
in the next step without further purification.
Step B.
N--((S)-2-((3S,5R,6S)-3-allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl-
)-3-methyl-2-oxopiperidin-1-yl)butyl)-N-(2,2,2-trifluoroethyl)methanesulfo-
namide
##STR00463##
[2248] To a solution of
(3S,5R,6S)-3-allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-1-((S)--
1-(2,2,2-trifluoroethylamino)butan-2-yl)piperidin-2-one prepared
above in Step A (60.9 mg, 0.115 mmol) in DCE (770 .mu.L) was added
DMAP (70.5 mg, 0.577 mmol) and methanesulfonyl chloride (35.9
.mu.L, 0.462 mmol) successively at rt. After being stirred at rt
for 3 h, pyridine (46.7 .mu.L, 0.577 mmol), methanesulfonyl
chloride (35.9 .mu.L, 0.462 mmol), and DCE (0.77 mL) were added and
the resulting solution was stirred for 15 h.
[2249] The reaction was quenched (sat. NH.sub.4Cl), and extracted
(3.times.DCM). The combined organic layers were washed (water and
sat. aq. NaCl solution), dried (Na.sub.2SO.sub.4), and concentrated
under reduced pressure. Separation by RP-HPLC (10 to 90%
MeCN/H.sub.2O (0.1% TFA), a gradient elution) provided the title
compound as a yellow solid.
Step C.
2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-2-oxo-
-1-((S)-1-(N-(2,2,2-trifluoroethyl)methylsulfonamido)butan-2-yl)piperidin--
3-yl)acetic acid
[2250] The title compound was prepared from
N--((S)-2-((3S,5R,6S)-3-allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-met-
hyl-2-oxopiperidin-1-yl)butyl)-N-(2,2,2-trifluoroethyl)methanesulfonamide
(Step B) by a procedure similar to the one described in Example 71,
Step F.
[2251] .sup.1H NMR (400 MHz, CHLOROFORM-d) .delta. ppm 7.21-7.28
(2H, m), 7.11-7.20 (2H, m), 6.74-7.10 (4H, m), 4.65 (1H, d, J=10.8
Hz), 4.32-4.50 (1H, m), 4.11 (1H, d, J=7.8 Hz), 3.48-3.65 (1H, m),
2.94-3.19 (6H, m), 2.79-2.92 (1H, m), 2.75 (1H, d, J=14.7 Hz), 2.42
(1H, t, J=13.9 Hz), 1.85-2.12 (2H, m), 1.50 (4H, s), 0.48 (3H, t,
J=7.4 Hz);
[2252] MS (ESI) 623.0 [M+H].sup.+, 621.0 [M-H].sup.-.
Example 148
2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-(1,1-dioxidoi-
sothiazolidin-2-yl)butan-2-yl)-3-methyl-2-oxopiperidin-3-yl)acetic
acid
##STR00464##
[2253] Step A.
N--((S)-2-((3S,5R,6S)-3-allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-met-
hyl-2-oxopiperidin-1-yl)butyl)-3-chloropropane-1-sulfonamide
##STR00465##
[2255]
(3S,5R,6S)-3-Allyl-1-((S)-1-aminobutan-2-yl)-5-(3-chlorophenyl)-6-(-
4-chlorophenyl)-3-methylpiperidin-2-one 2,2,2-trifluoroacetate (76
mg, 0.14 mmol; Example 129, Step B) was dissolved in DCM, basified
(1 N LiOH), extracted (3.times.DCM), and washed (sat. aq. NaCl
solution). The combined organic layers were dried
(Na.sub.2SO.sub.4) and concentrated under reduced pressure to
provide the free amine. To a solution of the free amine in DCE
(0.68 mL) was added pyridine (55 .mu.L, 0.68 mmol) and
3-chloropropane-1-sulfonyl chloride (96 mg, 0.54 mmol) successively
at rt. The reaction was stirred at rt for 5 h. Then additional
pyridine (55 .mu.L, 0.68 mmol) and 3-chloropropane-1-sulfonyl
chloride (96 mg, 0.54 mmol) was added. After being stirred
overnight, the reaction was quenched (10% citric acid), extracted
(3.times.EtOAc), and washed (saturated aq. NaHCO.sub.3 and sat. aq.
NaCl solution). The combined organic layers were dried
(Na.sub.2SO.sub.4), and concentrated under reduced pressure.
Separation by RP-HPLC (10 to 90% MeCN/H.sub.2O (0.1% TFA), gradient
elution) provided the title compound as a yellow solid.
Step B.
(3S,5R,6S)-3-allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1--
(1,1-dioxidoisothiazolidin-2-yl)butan-2-yl)-3-methylpiperidin-2-one
##STR00466##
[2257] To a solution of
N--((S)-2-((3S,5R,6S)-3-allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-met-
hyl-2-oxopiperidin-1-yl)butyl)-3-chloropropane-1-sulfonamide
prepared above in Step A (36.1 mg, 0.062 mmol) in DMF (1.2 mL) was
added DBU (46.4 .mu.L, 0.308 mmol) at rt. After being stirred at rt
overnight, the reaction was quenched (10% citric acid), extracted
(3.times.EtOAc), and washed (saturated aq. NaHCO.sub.3 and sat. aq.
NaCl solution). The combined organic layers were dried
(Na.sub.2SO.sub.4) and concentrated under reduced pressure to
provide the title compound as a pale brown film.
Step C.
2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-(1,1--
dioxidoisothiazolidin-2-yl)butan-2-yl)-3-methyl-2-oxopiperidin-3-yl)acetic
acid
[2258] The title compound was prepared from
(3S,5R,6S)-3-allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-(1,1-di-
oxidoisothiazolidin-2-yl)butan-2-yl)-3-methylpiperidin-2-one (Step
B)) by a procedure similar to the one described in Example 71, Step
F.
[2259] .sup.1H NMR (400 MHz, CHLOROFORM-d) .delta. ppm 7.27 (2H, d,
J=8.0 Hz), 7.10-7.19 (2H, m), 6.97-7.10 (3H, m), 6.83 (1H, d, J=7.4
Hz), 4.87 (1H, d, J=0.6 Hz), 3.33 (2H, t, J=6.6 Hz), 3.24 (2H, t,
J=7.5 Hz), 3.09 (2H, d, J=15.3 Hz), 2.96 (2H, d, J=2.3 Hz), 2.74
(1H, d, J=15.3 Hz), 2.37-2.51 (3H, m), 1.90-2.02 (2H, m), 1.53 (4H,
s), 0.49 (3H, t, J=7.5 Hz); MS (ESI) 567.1 [M+H].sup.+, 565.0
[M-H].sup.-.
Example 149
2-((3R,5R,6S)-5-(3-Chlorophenyl)-6-(4-chlorophenyl)-1-((3S,4R)-5-hydroxy-4-
,5-dimethylhexan-3-yl)-3-methyl-2-oxopiperidin-3-yl)acetic acid or
2-((3R,5R,6S)-5-(3-Chlorophenyl)-6-(4-chlorophenyl)-1-((3S,4S)-5-hydroxy--
4,5-dimethylhexan-3-yl)-3-methyl-2-oxopiperidin-3-yl)acetic
acid
##STR00467##
[2260] Step A.
(3S,5R,6S)-3-Allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-1-((S)--
2-oxopentan-3-yl)piperidin-2-one
##STR00468##
[2262] To a solution of oxalyl dichloride (78 .mu.L, 0.87 mmol) in
DCM (1.5 mL) at -60.degree. C. was added a solution of DMSO (93
.mu.L, 1.30 mmol) in DCM (1.5 mL) under N.sub.2. After being
stirred for 2 min, a solution of
(3S,5R,6S)-3-allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((3S)-2-hydrox-
ypentan-3-yl)-3-methylpiperidin-2-one prepared in example 151, Step
C (200 mg, 0.434 mmol) in DCM (1.5 mL) was added and the resulting
solution was stirred for 15 min. at -60.degree. C. Then,
triethylamine (305 .mu.L, 2.17 mmol) was added to the reaction
solution. After being stirred at rt for 20 min, the reaction was
quenched (water), extracted (2.times.EtOAc), and washed
(2.times.sat. aq. NaCl solution). The combined organic layers were
dried (Na.sub.2SO.sub.4) and concentrated under reduced pressure.
Purification by combi flash (SiO.sub.2, 24 g, 20% and 30%
EtOAc/Hexanes) provided the title compound as a colorless foam.
Step B.
((3S,5R,6S)-3-Allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-
-methoxy-2-methylpent-1-en-3-yl)-3-methylpiperidin-2-one
##STR00469##
[2263] (Methoxymethyl)triphenylphosphonium chloride was dried at
80.degree. C. under vacuum for 2 h. To a solution of the dried
(methoxymethyl)triphenylphosphonium chloride (673 mg, 1.96 mmol) in
THF (3.5 mL) was added 0.5 M KHMDS in toluene (3.49 mL, 1.75 mmol)
at -78.degree. C. The solution resulted in a blood red color. After
addition, the reaction was stirred at 0.degree. C. for 30 min and a
solution of
(3S,5R,6S)-3-allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-1-((S)--
2-oxopentan-3-yl)piperidin-2-one prepared above in Step B (200 mg,
0.436 mmol) in THF (3.5 mL) was added dropwisely at 0.degree. C.
The reaction was allowed to warm to rt and stirred for 1.5 h. Then
the reaction was quenched (sat NH.sub.4Cl solution), extracted
(2.times.EtOAc), and washed (brine). The combined organic layers
were dried (Na.sub.2SO.sub.4) and concentrated under reduced
pressure. Purification by combi flash (SiO.sub.2, 24 g, 15% and 20%
EtOAc/Hexanes) provided the title compound as a colorless film.
Step C.
(2S,3S)-3-((3S,5R,6S)-3-Allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl-
)-3-methyl-2-oxopiperidin-1-yl)-2-methylpentanal and
(2R,3S)-3-((3S,5R,6S)-3-Allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-met-
hyl-2-oxopiperidin-1-yl)-2-methylpentanal
##STR00470##
[2265] To a solution of
(3S,5R,6S)-3-allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-methoxy-
-2-methylpent-1-en-3-yl)-3-methylpiperidin-2-one prepared above in
Step B (179 mg, 0.368 mmol) in acetonitrile (3.7 mL) was added 3 N
hydrochloric acid (1.5 mL, 4.5 mmol) at rt. After being stirred at
rt for 1.5 h, the reaction was extracted (2.times.EtOAc), and
washed (2.times. brine). The combined organic layers were dried
(Na.sub.2SO.sub.4) and concentrated under reduced pressure provided
the title compounds as a mixture of stereoisomers (dr=7:3) as a
pale yellow film.
Step D.
(3S,5R,6S)-3-allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl--
1-((3S,4R)-4-methyl-5-oxohexan-3-yl)piperidin-2-one and
(3S,5R,6S)-3-allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-1-((3S,-
4S)-4-methyl-5-oxohexan-3-yl)piperidin-2-one
##STR00471##
[2267] To a solution of
(2S,3S)-3-((3S,5R,6S)-3-allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-met-
hyl-2-oxopiperidin-1-yl)-2-methylpentanal and
(2R,3S)-3-((3S,5R,6S)-3-allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-met-
hyl-2-oxopiperidin-1-yl)-2-methylpentanal prepared above in Step C
(177 mg, 0.375 mmol) in THF (3.076 ml) was added 1.4 M
methylmagnesium bromide in toluene and THF (75:25) (0.803 ml, 1.12
mmol) at 0.degree. C. Then the reaction was allowed to warm to rt
and stirred for 2 h. The reaction was quenched (sat NH.sub.4Cl
solution), extracted (2.times.EtOAc), and washed (brine). The
combined organic layer was dried (Na.sub.2SO.sub.4) and
concentrated under the reduced pressure to provide a crude
secondary alcohol product. To a solution of the crude secondary
alcohol product (183 mg, 0.375 mmol) in DCM (4.2 mL) was added
water (14 .mu.L, 0.75 mmol) and dess-martinperiodinane (196 mg,
0.462 mmol) successively. After being stirred art for overnight,
the reaction was quenched (1 M aq. Na.sub.2S.sub.2O.sub.3),
extracted (2.times.DCM), and washed (2.times.sat. NaHCO.sub.3 and
1.times. brine). The combined organic layers were dried
(Na.sub.2SO.sub.4) and concentrated under reduced pressure.
Purification of the residue by chromatography on silica gel (24 g
SiO.sub.2, 13%, 27% and 37% EtOAc/Hex) provided a less polar and
more polar isomer, successively.
[2268] Less polar isomer: .sup.1H NMR (400 MHz, CHLOROFORM-d)
.delta. ppm 7.25 (2H, d, J=8.0 Hz), 7.03-7.17 (4H, m), 6.94-6.99
(1H, m), 6.81-6.87 (1H, m), 5.12-5.23 (2H, m), 4.58 (1H, d, J=10.8
Hz), 3.14 (1H, s), 2.66 (1H, s), 2.58 (2H, d, J=7.4 Hz), 2.22 (3H,
s), 1.81 (1H, d, J=4.3 Hz), 1.75 (1H, d, J=7.2 Hz), 1.51-1.65 (2H,
m), 1.19 (3H, s), 1.00 (3H, d, J=7.2 Hz), 0.30 (3H, t, J=7.7 Hz);
MS (ESI) 486.1 [M+H].sup.+.
[2269] More polar isomer: .sup.1H NMR (400 MHz, CHLOROFORM-d)
.delta. ppm 7.22-7.27 (2H, m), 7.01-7.17 (4H, m), 6.89-6.95 (1H,
m), 6.71 (1H, dt, J=7.5, 1.3 Hz), 5.81-5.93 (1H, m), 5.17-5.25 (2H,
m), 4.32 (1H, d, J=10.8 Hz), 3.50 (1H, br. s.), 3.23-3.32 (1H, m),
3.06 (1H, br. s.), 2.60-2.66 (2H, m), 2.13-2.20 (3H, m), 1.91-2.01
(2H, m), 1.64-1.70 (2H, m), 1.28-1.32 (3H, m), 1.13 (3H, d, J=7.0
Hz), 0.34 (3H, t, J=7.5 Hz); MS (ESI) 486.1 [M+H].sup.+.
Step E.
(3S,5R,6S)-3-Allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((3S,4R-
)-5-hydroxy-4,5-dimethylhexan-3-yl)-3-methylpiperidin-2-one or
(3S,5R,6S)-3-Allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((3S,4S)-5-hyd-
roxy-4,5-dimethylhexan-3-yl)-3-methylpiperidin-2-one
##STR00472##
[2271] To a solution of the less polar isomer prepared above in
example 149, step D (96 mg, 0.20 mmol) in THF (2.0 mL) was added
1.4 M methylmagnesium bromide in toluene and THF (75:25) (423
.mu.L, 0.592 mmol) at 0.degree. C. Then the reaction was allowed to
warm to rt and stirred for overnight. The reaction was quenched
(sat NH.sub.4Cl solution), extracted (2.times.EtOAc), and washed
(brine). The combined organic layers were dried (Na.sub.2SO.sub.4)
and concentrated under reduced pressure. Purification of the
residue by combi-flash (12 g SiO.sub.2, 30% EtOAc/Hex) provided the
title compound as a single isomer.
Step F.
2-((3R,5R,6S)-5-(3-Chlorophenyl)-6-(4-chlorophenyl)-1-((3S,4R)-5-h-
ydroxy-4,5-dimethylhexan-3-yl)-3-methyl-2-oxopiperidin-3-yl)acetic
acid or
2-((3R,5R,6S)-5-(3-Chlorophenyl)-6-(4-chlorophenyl)-1-((3S,4S)-5-hydroxy--
4,5-dimethylhexan-3-yl)-3-methyl-2-oxopiperidin-3-yl)acetic
acid
##STR00473##
[2273] The title compound was prepared from
(3S,5R,6S)-3-allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((3S,4R)-5-hyd-
roxy-4,5-dimethylhexan-3-yl)-3-methylpiperidin-2-one or
(3S,5R,6S)-3-allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((3S,4S)-5-hyd-
roxy-4,5-dimethylhexan-3-yl)-3-methylpiperidin-2-one (Example 149,
Step E) by a procedure similar to the one described in example 129,
Step D.
[2274] .sup.1H NMR (400 MHz, CHLOROFORM-d) .delta. ppm 7.01-7.27
(6H, m), 6.96 (1H, t, J=1.7 Hz), 6.70 (3H, d, J=7.6 Hz), 4.59 (1H,
d, J=9.8 Hz), 3.63-3.91 (1H, m), 3.14 (1H, s), 2.98 (1H, d, J=14.5
Hz), 2.72 (1H, d, J=14.5 Hz), 1.98-2.21 (2H, m), 1.84-1.96 (1H, m),
1.56-1.69 (2H, m), 1.48 (3H, s), 1.15 (3H, s), 1.06 (3H, s), 0.75
(3H, br. s.), 0.28 (3H, br. s.); MS (ESI) 520.2 [M+H].sup.+, 518.2
[M-H].sup.-.
Example 150
2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((S)-5-cyano-5-methy-
lhexan-3-yl)-3-methyl-2-oxopiperidin-3-yl)acetic acid
##STR00474##
[2275] Step A. (2S)-methyl
2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-(2,3-dihydroxypropy-
l)-3-methyl-2-oxopiperidin-1-yl)butanoate
##STR00475##
[2277] To a solution of (S)-methyl
2-((3S,5R,6S)-3-allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-2-ox-
opiperidin-1-yl)butanoate (1.06 g, 2.23 mmol; Example 91, Step A)
and 4-methylmorpholine 4-oxide (393 mg, 3.35 mmol) in DCM (15.800
mL) was added osmium(VIII) oxide polymer-bound, 1% DVB (56.8 mg,
2.234 .mu.mol). After being vigorously stirred at rt for 2 days,
additional osmium(VIII) oxide polymer-bound, 1% DVB (56.8 mg, 2.23
mol) was added and the resulting solution was vigorously stirred at
rt for 2 days. The resin was filtered and washed (DCM). The
combined organic layers were washed (sat. aq. NaCl solution), dried
(Na.sub.2SO.sub.4), and concentrated under reduced pressure.
Purification by chromatography on silica gel (SiO.sub.2, 40 g, 53%
and 63% EtOAc/Hexanes) provided the title compound.
Step B. (2S)-methyl
2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-((2,2-dimethyl-1,3--
dioxolan-4-yl)methyl)-3-methyl-2-oxopiperidin-1-yl)butanoate
##STR00476##
[2279] To a solution of (S)-methyl
2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-(2,3-dihydroxypropy-
l)-3-methyl-2-oxopiperidin-1-yl)butanoate prepared above in Step A
(749 mg, 1.47 mmol) in DCM (8.2 mL) was added p-toluenesulfonic
acid monohydrate (14.0 mg, 0.074 mmol) and 2,2-dimethoxypropane
(8.15 mL, 66.3 mmol). After being stirred at rt for 3 h, the
reaction mixture was concentrated under reduced pressure and the
residue was dissolved (EtOAc and sat. aq. NaHCO.sub.3) and
extracted (3.times.EtOAc). The combined organic layers were washed
(sat. aq. NaCl solution), dried (Na.sub.2SO.sub.4), and
concentrated under reduced pressure. Purification by chromatography
on silica gel (SiO.sub.2, 40 g, 27% and 37% EtOAc/Hexanes) provided
the title compound as a colorless film.
Step C.
(3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-((2,2-dimethyl--
1,3-dioxolan-4-yl)methyl)-1-((S)-1-hydroxybutan-2-yl)-3-methylpiperidin-2--
one
##STR00477##
[2281] To a solution of (2S)-methyl
2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-((2,2-dimethyl-1,3--
dioxolan-4-yl)methyl)-3-methyl-2-oxopiperidin-1-yl)butanoate
prepared above in Step B (734 mg, 1.34 mmol) in ether (12.2 mL) was
added lithium borohydride (58.3 mg, 2.68 mmol) at 0.degree. C.
After being stirred at 0.degree. C. for 30 min, the reaction was
quenched (ice cold 10% citric acid), extracted (2.times.EtOAc) and
washed (sat. aq. NaCl solution). The combined organic layers were
dried (Na.sub.2SO.sub.4) and concentrated under reduced pressure
provided the title compound as a colorless film. The product was
used in the next step without further purification.
Step D.
(2S)-2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-((2,2-d-
imethyl-1,3-dioxolan-4-yl)methyl)-3-methyl-2-oxopiperidin-1-yl)butanal
##STR00478##
[2283] The title compound was prepared form
(3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-((2,2-dimethyl-1,3-dio-
xolan-4-yl)methyl)-1-((S)-1-hydroxybutan-2-yl)-3-methylpiperidin-2-one
(Example 150, Step C) by a procedure similar to the one described
in Example 91, Step C.
Step E.
(4S)-4-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-((2,2-d-
imethyl-1,3-dioxolan-4-yl)methyl)-3-methyl-2-oxopiperidin-1-yl)hex-2-ene
nitrile
##STR00479##
[2285] To a solution of diethyl cyanomethylphosphonate (126 .mu.L,
0.799 mmol) and DMPU (481 .mu.L, 3.99 mmol) in THF (1.33 mL) was
added 60% sodium hydride in mineral oil (24.0 mg, 0.599 mmol) at
0.degree. C. The mixture was stirred for 30 min, and then treated
with a solution of
(2S)-2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-((2,2-dimethyl-
-1,3-dioxolan-4-yl)methyl)-3-methyl-2-oxopiperidin-1-yl)butanal
prepared above in Step D (207 mg, 0.399 mmol) in THF (1.33 mL).
After being stirred for 4 h, the reaction was quenched (water),
extracted (2.times.EtOAc), and washed (sat. aq. NaCl solution). The
combined organic layers were dried (Na.sub.2SO.sub.4) and
concentrated under reduced pressure. Purification of the residue by
chromatography on silica gel (24 g SiO.sub.2, 30 to 40% EtOAc/Hex,
gradient elution) provided the title compound as a colorless
liquid.
Step F.
(4S)-4-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-((2,2-d-
imethyl-1,3-dioxolan-4-yl)methyl)-3-methyl-2-oxopiperidin-1-yl)hexanenitri-
le
##STR00480##
[2287] To a solution of
(4S)-4-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-((2,2-dimethyl-
-1,3-dioxolan-4-yl)methyl)-3-methyl-2-oxopiperidin-1-yl)hex-2-enenitrile
prepared above in Step E (208 mg, 0.384 mmol) in EtOH (12.8 mL) was
added 10% palladium on activated carbon (40.9 mg, 0.038 mmol). Then
the reaction mixture was subjected to regular hydrogenation with
hydrogen (0.774 mg, 0.384 mmol). After being stirred at rt for 1.5
h, the catalyst was filtered using a short plug of silica-gel and
washed (EtOAc). The combined organic solutions were concentrated
under reduced pressure. Purification by combi flash (flash column
chromatography, Teledyne Isco, Lincoln, Nebr.) (SiO.sub.2, 24 g,
35% and 40% EtOAc/Hexanes) provided the title compound as a
colorless film.
Step G.
(4S)-4-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-((2,2-d-
imethyl-1,3-dioxolan-4-yl)methyl)-3-methyl-2-oxopiperidin-1-yl)-2,2-dimeth-
ylhexanenitrile
##STR00481##
[2289] To a solution of
(4S)-4-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-((2,2-dimethyl-
-1,3-dioxolan-4-yl)methyl)-3-methyl-2-oxopiperidin-1-yl)hexanenitrile
prepared in Step F (120 mg, 0.221 mmol) in THF (1.10 mL) was added
2 M lithium diisopropylamide (552 .mu.L, 1.10 mmol) at -78.degree.
C. After being stirred for 5 min at -78.degree. C., iodomethane (94
.mu.L, 1.51 mmol) was added and the resulting solution was stirred
at -78.degree. C. for 30 min. Then the reaction was allowed to warm
to rt and stirred for overnight. The reaction was quenched (aq.
sat. NH.sub.4Cl) and extracted (2.times.EtOAc) and the combined
organic layers were washed (sat. aq. NaCl solution), dried
(Na.sub.2SO.sub.4), and concentrated under reduced pressure.
Purification by chromatography on silica gel (SiO.sub.2, 30% and
40% EtOAc/hex) provided a mixture of dimethylated product and
monomethylated product, which was resubjected to the methylation
conditions described below.
[2290] To a solution of the crude product from the previous
reaction in THF (1.10 mL) was added 2 M lithium diisopropylamide in
heptane/THF/ethylbenzene (552 .mu.L, 1.10 mmol) at -78.degree. C.
After being stirred for 5 min at -78.degree. C., iodomethane (94
.mu.L, 1.51 mmol) was added and the resulting solution was stirred
at -78.degree. C. for 30 min. Then the reaction was allowed to warm
to rt and stirred for overnight. The reaction was quenched (aq.
sat. NH.sub.4Cl) and extracted (2.times.EtOAc) and the combined
organic layers were washed (sat. aq. NaCl solution), dried
(Na.sub.2SO.sub.4), and concentrated under reduced pressure.
Purification by RP-HPLC purification (60 to 90% MeCN/H.sub.2O (0.1%
TFA), gradient elution) provided the title compound.
Step H.
(4S)-4-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-(2,3-di-
hydroxypropyl)-3-methyl-2-oxopiperidin-1-yl)-2,2-dimethylhexanenitrile
##STR00482##
[2292] To a solution of
(4S)-4-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-((2,2-dimethyl-
-1,3-dioxolan-4-yl)methyl)-3-methyl-2-oxopiperidin-1-yl)-2,2-dimethylhexan-
enitrile prepared above in Step G (77 mg, 0.135 mmol) in THF (2.69
mL) was added 3 N hydrochloric acid in water (1.35 .mu.L, 4.04
mmol) at rt. After being stirred at rt for 4 h, the reaction was
diluted (sat. aq. NaCl) and extracted (2.times.EtOAc). The combined
organic layers were washed (sat. aq. NaCl solution), dried
(Na.sub.2SO.sub.4), and concentrated under reduced pressure to
provide the title compound as a colorless foam.
Step I.
2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((S)-5-cyano-
-5-methylhexan-3-yl)-3-methyl-2-oxopiperidin-3-yl)acetic acid
[2293] The title compound was prepared from
(4S)-4-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-(2,3-dihydroxy-
propyl)-3-methyl-2-oxopiperidin-1-yl)-2,2-dimethylhexanenitrile
prepared above in Step H by a procedure similar to the one
described in Example 71, Step F.
[2294] .sup.1H NMR (400 MHz, CHLOROFORM-d) .delta. ppm 7.27 (2H,
s), 7.00-7.20 (4H, m), 6.97 (1H, t, J=1.7 Hz), 6.82 (1H, dt, J=7.4,
1.4 Hz), 4.82 (1H, d, J=10.6 Hz), 3.12 (1H, s), 3.01 (1H, d, J=15.1
Hz), 2.75 (3H, d, J=15.1 Hz), 2.54 (1H, s), 2.03-2.12 (1H, m), 2.01
(1H, s), 1.90 (1H, dd, J=14.0, 2.6 Hz), 1.52 (3H, s), 1.43 (3H, s),
1.35-1.41 (1H, m), 1.31 (3H, s), 1.23 (1H, d, J=13.9 Hz), 0.33 (3H,
t, J=7.3 Hz); MS (ESI) 515.0 [M+H].sup.+, 513.0 [M-H].sup.-.
Example 151
2-((3R,5R,6S)-5-(3-Chlorophenyl)-6-(4-chlorophenyl)-3-methyl-2-oxo-1-((S)--
2-oxopentan-3-yl)piperidin-3-yl)acetic acid
##STR00483##
[2295] Step A.
(3S,5R,6S)-3-Allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-hydroxy-
butan-2-yl)-3-methylpiperidin-2-one
##STR00484##
[2297] To a solution of 1004 g (1.47 mol) of
(3S,5R,6S)-3-allyl-1-((S)-1-((tert-butyldiphenylsilyl)oxy)butan-2-yl)-5-(-
3-chlorophenyl)-6-(4-chlorophenyl)-3-methylpiperidin-2-one (Example
185, Step E) in THF (3.0 L) was added 2.50 L (2.50 mol) of a 1 M
solution of TBAF in THF over a 10 min period. The orange solution
was stirred at room temperature for 4 h. The reaction was quenched
with 1 N HCl (3 L) and extracted with EtOAc (3.times.). The
combined organic layers were washed with a 3:1 mixture of water and
saturated aqueous sodium chloride (4.times.) and then saturated
aqueous sodium chloride (1.times.). The organic layer was dried
over Na.sub.2SO.sub.4, filtered and the filtrate was concentrated.
Purification of the residue by chromatography (Biotage.RTM.
Snap.TM. column; Biotage, LLC, Charlotte, N.C.), 10 to 50%
EtOAc/hexanes, where the EtOAc contains 2% MeCN, gradient elution)
provided the title compound as a white foam.
Step B.
(S)-2-((3S,5R,6S)-3-Allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3--
methyl-2-oxopiperidin-1-yl)butanal
##STR00485##
[2299] To a solution of 428 g (959 mmol) of
(3S,5R,6S)-3-allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-hydroxy-
butan-2-yl)-3-methylpiperidin-2-one (Example 151, Step A) in
dichloromethane (4.55 L) was added 25.9 mL (1.44 mol) of water. A
solution of 610 g (1.44 mol) of Dess-Martin periodinane in
dichloromethane (4.55 L) was added slowly over a 25 min period so
as to maintain an internal reaction temperature not exceeding
25.degree. C. The white slurry was stirred for 2.5 h and then was
quenched by cautious, slow addition of saturated aqueous sodium
thiosulfate (5.2 L) so as to maintain an internal reaction
temperature below 30.degree. C. Water was added and the mixture was
extracted with dichloromethane (3.times.). The combined organic
layers were washed with saturated aqueous sodium bicarbonate
solution (4.times.) and then saturated aqueous sodium chloride
(1.times.), dried over Na.sub.2SO.sub.4, filtered and the filtrate
was concentrated to afford a yellow oily solid. A mixture of ethyl
ether and DCM were added, and precipitated solids were filtered
off. The precipitation/filtration process was repeated. The
filtrate was concentrated to provide the title compound as a white
solid. The crude product was used directly in the next step.
Step C.
(3S,5R,6S)-3-Allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((3S)-2-
-hydroxypentan-3-yl)-3-methylpiperidin-2-one
##STR00486##
[2301] To a 0.degree. C. solution of 399 g (899 mmol) of
(S)-2-((3S,5R,6S)-3-allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl--
2-oxopiperidin-1-yl)butanal (Example 151, Step B) in THF (9 L) was
added 1.93 L (2.70 mol) of a 1.4 M solution of methylmagnesium
bromide 75:25 in toluene/tetrahydrofuran slowly over a 30 min
period so as to maintain an internal reaction temperature below
6.degree. C. The yellow solution was warmed to room temperature and
stirred for 1.5 h. At this time the reaction was cooled to
0.degree. C. and quenched by cautious, slow addition of saturated
aqueous ammonium chloride (4.6 L) so as to maintain an internal
reaction temperature below 15.degree. C. The mixture was warmed to
room temperature, ethyl acetate was added, and the layers were
separated. The aqueous layer was extracted with EtOAc (2.times.).
The combined organic layers were washed with water (1.times.) and
then saturated aqueous sodium chloride (1.times.), dried over
Na.sub.2SO.sub.4, filtered and the filtrate was concentrated to
afford a yellow oil. Purification of the residue by chromatography
on silica (Biotage.RTM. Snap.TM. column; Biotage, LLC, Charlotte,
N.C.), 5% acetone/5% EtOAc/90% hexanes grading to 5% acetone/29%
EtOAc/66% hexanes) provided the title compound as a white
solid.
Step D.
2-((3R,5R,6S)-5-(3-Chlorophenyl)-6-(4-chlorophenyl)-3-methyl-2-oxo-
-1-((S)-2-oxopentan-3-yl)piperidin-3-yl)acetic acid
[2302] Ruthenium(III) chloride hydrate (1.404 g, 6.23 mmol) was
added to a solution of
(3S,5R,6S)-3-allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((3S)-2-hydrox-
ypentan-3-yl)-3-methylpiperidin-2-one (Example 151, Step C) (130.30
g, 283 mmol) and NaIO.sub.4 (61.5 g) in EtOAc (630 mL), CH.sub.3CN
(630 mL) and water (935 mL) at 18.degree. C. The remaining
NaIO.sub.4 (307.5 g) was added in five portions over 2.5 hours
while maintaining the temperature below 26.degree. C. 15 minutes
after the final addition of NaIO.sub.4 the cooling bath was removed
and the reaction mixture was stirred at ambient temperature for 50
minutes. The tan reaction mixture was filtered using a Buchner
funnel and washed with EtOAc (500 mL) and CH.sub.3CN (500 mL). The
layers were separated and the aqueous layer was extracted with
EtOAc twice. The organics were pooled, washed with 10% aq.
NaHSO.sub.3 (3.times.1 L), brine (1 L), dried (Na.sub.2SO.sub.4),
decanted and concentrated in vacuo to provide a green oil. The
material was dissolved in a minimum amount of DCM and purified
using two 1.5 kg Biotage.RTM. Snap.TM. columns (Biotage, LLC,
Charlotte, N.C.) and eluting with 10-50% (15% MeOH/acetone)/hexanes
to provide a light pink foam (109.67 g).
[2303] .sup.1H NMR (400 MHz, CHLOROFORM-d) .delta. ppm 7.25 (2H, d,
J=8.2 Hz), 6.93-7.18 (5H, m), 6.73-6.80 (1H, m), 4.47 (1H, d,
J=10.6 Hz), 3.28 (1H, ddd, J=13.4, 10.5, 3.0 Hz), 3.16 (1H, dd,
J=7.0, 5.5 Hz), 2.73-3.00 (2H, m), 2.28-2.40 (1H, m), 2.18-2.25
(1H, m), 2.16 (3H, s), 2.11-2.15 (1H, m), 1.83 (1H, ddd, J=14.3,
7.8, 5.7 Hz), 1.47 (3H, s), 0.64 (3H, t, J=7.5 Hz); MS (ESI) 476.2
[M+H].sup.+.
Example 152
2-((3R,5R,6S)-5-(3-Chlorophenyl)-6-(4-chlorophenyl)-1-((2S,3S)-2-hydroxype-
ntan-3-yl)-3-methyl-2-oxopiperidin-3-yl)acetic acid
##STR00487##
[2305] To a solution of 3.86 g (8.13 mmol) of
2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-2-oxo-1-((S)-
-2-oxopentan-3-yl)piperidin-3-yl)acetic acid (Example 151) in THF
(102 mL) was added a 1 M solution of sodium
tri-sec-butylborohydride (N-Selectride.RTM., Aldrich, St. Louis,
Mo.) in THF (16.26 mL, 16.26 mmol) at -78.degree. C. dropwise over
a period of 5 min. After being stirred at -78.degree. C. for 30
min, the reaction was allowed to warm to rt. The reaction was
stirred at rt for 2 h, the reaction was quenched (sat. NH.sub.4Cl
solution), extracted (3.times.EtOAc) and washed (3.times. ice-cold
1 N aq. HCl and 3.times. saturated aqueous sodium chloride). The
combined organic layers were dried over Na.sub.2SO.sub.4, filtered
and the filtrate was concentrated under reduced pressure. The crude
material was purified by chromatography on a Biotage Isolera flash
purification system (Biotage, Charlotte, N.C.) (2.times.1500 g
columns, using a gradient from 10-30% (15% MeOH/acetone) in
hexanes. The purified material was then recrystallized from 3:1
hexane/acetone (8 mL/g) to provide the title compound.
[2306] .sup.1H NMR (500 MHz, DMSO-d.sub.6) .delta. ppm 0.30 (t,
J=7.6 Hz, 3H), 1.00 (d, J=6.3 Hz, 3H), 1.26 (s, 3H), 1.41-1.49 (m,
1H), 1.55-1.64 (m, 1H), 2.04-2.15 (m, 2H), 2.29-2.33 (m, 1H), 2.48
(d, J=13.7 Hz, 1H), 2.87 (d, J=13.7 Hz, 1H), 3.35-3.40 (m, 1H),
4.01-4.06 (m, 1H), 4.77 (d, J=10.9 Hz, 1H), 4.80 (br. s, 1H),
6.93-6.95 (m, 1H), 7.08-7.10 (m, 1H), 7.17-7.27 (m, 4H), 7.33 (d,
J=8.4 Hz, 2H), 12.42 (br s, 1H); MS (ESI) 478.2 [M+H].sup.+, 476.2
[M-H].sup.-. [.alpha.].sub.D=+110.degree. (T=23.degree. C., MeOH,
c=0.51).
[2307] Alternatively the title compound can be prepared from
(3S,5R,6R)-3-allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyltetrahyd-
ro-2H-pyran-2-one as prepared in Example 261 step F.
[2308] To a 10 mL round-bottom reaction flask was added
(3S,5R,6R)-3-allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyltetrahyd-
ro-2H-pyran-2-one (750 mg, 1.998 mmol), (2S,3S)-3-aminopentan-2-ol
hydrochloride (837 mg, 6.00 mmol, reference: J. Org. Chem., 2003,
68 (26), 9948), and triethylamine (1966 .mu.l, 13.99 mmol). The
vessel was fitted with a reflux condensor and heated to 85 to
95.degree. C. for 2 d. The reaction was cooled to RT and diluted
with ethyl acetate and washed with 1N HCl (2.times.20 mL) and
brine. The organic layer was dried over MgSO.sub.4, filtered, and
concentrated. Purification by column chromatography using 40 to 50%
ethyl acetate in hexanes afforded
(S)-2-((2R,3R)-2-(3-chlorophenyl)-3-(4-chlorophenyl)-3-hydroxypropyl)-N-(-
(2S,3S)-2-hydroxypentan-3-yl)-2-methylpent-4-enamide.
[2309] .sup.1H NMR (500 MHz, DMSO-d.sub.6) .delta. 7.17 (m, 2H),
7.16 (m, 1H), 7.14-7.08 (series of m, 2H), 6.97 (m, 2H), 6.88 (br
d, J=6.9 Hz, 1H), 5.96 (d, J=8.3 Hz, 1H), 5.65 (ddt, J=17.4, 10.2,
7.2 Hz, 1H), 5.07 (dd J=10.3, 1.0 Hz, 1H), 5.02 (d, J=17.6, 1H),
4.75 (t, J=4.2 Hz, 1H), 3.79 (m, 1H), 3.66 (ddd, J=8.8, 5.9, 4.2
Hz, 1H), 3.30 (d, J=3.4 Hz, 1H), 3.03 (dt, J=6.9, 5.4 Hz, 1H), 2.37
(dd, J=13.9, 7.3 Hz, 1H), 2.32 (dd, J=14.7, 5.6 Hz, 1H), 2.12 (dd,
J=13.7, 7.1 Hz, 1H), 2.01 (d, J=4.7 Hz, 1H), 1.83 (dd, J=14.7, 7.3
Hz, 1H), 1.58 (m, 1H), 1.42 (ddq, J=14.9, 8.6, 7.3 Hz), 1.14 (s,
3H), 1.14 (d, J=6.4 Hz, 3H), 0.90 (t, J=7.3 Hz, 3H) ppm. LC/MS
(M+H)=478.2.
[2310] To a solution of
(S)-2-((2R,3R)-2-(3-chlorophenyl)-3-(4-chlorophenyl)-3-hydroxypropyl)-N-(-
(2S,3S)-2-hydroxypentan-3-yl)-2-methylpent-4-enamide (127 mg, 0.265
mmol) in toluene (5309 .mu.l) was added ammonium molybdate
((NH.sub.4).sub.2MoO.sub.4) (5.20 mg, 0.027 mmol) and heated to
reflux under Dean-Stark conditions overnight. The reaction was
cooled to room temperature, diluted with ethyl acetate and washed
with sat. NaHCO.sub.3 and brine. The organics were dried over
MgSO.sub.4, filtered and concentrated. Purification by column
chromatography using 20 to 40% ethyl acetate in hexanes afforded
(1R,2R,4S)-2-(3-chlorophenyl)-1-(4-chlorophenyl)-4-((4S,5S)-4-ethyl-5-met-
hyl-4,5-dihydrooxazol-2-yl)-4-methylhept-6-en-1-ol.
[2311] .sup.1H NMR (500 MHz, DMSO-d.sub.6) .delta. 7.25 (m, 2H),
7.12 (m, 2H), 7.07 (br s, 1H), 7.05 (m, 2H), 6.96 (br d, J=6.8 Hz,
1H), 5.53 (ddt, J=17.4, 10.3, 7.4 Hz, 1H), 5.42 (d, J=4.2 Hz, 1H),
4.95 (m, 2H), 4.66 (t, J=4.9 Hz, 1H), 3.56 (dq, J=7.6, 6.1 Hz, 1H),
3.12 (q, J=7.1 Hz, 1H), 2.90 (ddd, (9.5, 5.1, 2.3 Hz, 1H), 2.20 (m,
2H), 1.93 (dd, J=13.7, 7.8 Hz, 1H), 1.75 (dd, J=14.3, 2.2 Hz, 1H),
1.11 (m, 1H), 1.10 (d, J=6.4 Hz, 3H), 0.98 (m, 1H), 0.97 (s, 3H),
0.75 (t, J=7.6 Hz, 3H) ppm. LC/MS (M+H)=460.2.
[2312] To a solution of
(1R,2R,4S)-2-(3-chlorophenyl)-1-(4-chlorophenyl)-4-((4S,5S)-4-ethyl-5-met-
hyl-4,5-dihydrooxazol-2-yl)-4-methylhept-6-en-1-ol (80 mg, 0.174
mmol) in CH.sub.2Cl.sub.2 (1737 .mu.l) at -50.degree. C. was added
2,6-lutidine (46.4 .mu.l, 0.400 mmol) followed by
trifluoromethanesulfonic anhydride solution, 1 M in methylene
chloride (191 .mu.l, 0.191 mmol). The reaction was stirred at
-50.degree. C. for 30 min and then treated with an additional 25 uL
of trifluoromethanesulfonic anhydride solution, 1 M in methylene
chloride, then 2 mL of sat. CuSO.sub.4. The reaction was warmed to
rt and extracted with dichloromethane. The organic phase was dried
over MgSO.sub.4, filtered and concentrated. Purification by column
chromatography using 40 to 80% acetone in hexanes afforded
(2S,3S,5S,6R,8S)-8-allyl-6-(3-chlorophenyl)-5-(4-chlorophenyl)-3-ethyl-2,-
8-dimethyl-2,3,5,6,7,8-hexahydrooxazolo[3,2-a]pyridin-4-ium
triflate.
[2313] .sup.1H NMR (500 MHz, DMSO-d6) .delta. 7.55-7.05 (series of
m, 8H), 5.88 (ddt, J=17.3, 10.0, 7.8 Hz, 1H), 5.36 (dd, J=17.1, 2.0
Hz, 1H), 5.31 (d, J=10.8 Hz, 1H), 5.28 (dd, J=10.0, 2.0 Hz, 1H),
5.18 (quintet, J=6.1 Hz, 1H), 4.10 (td, J=6.6, 2.7 Hz, 1H), 3.98
(ddd, J=13.7, 11.2, 3.4 Hz, 1H), 2.80 (ABX, J.sub.AB=13.7 Hz,
J.sub.AX=7.3 Hz, 1H), 2.73 (ABX J.sub.AB=13.7 Hz, J.sub.BX=7.8 Hz,
1H), 2.49 (m, 1H), 2.41 (t, J=13.7 Hz, 1H), 2.00 (dd, J=13.9, 3.7
Hz, 1H), 1.55 (d, J=6.1 Hz, 1H), 1.31 (s, 3H), 0.95 (dqd, J=14.2,
7.8, 3.0 Hz, 1H), 0.58 (t, J=7.3 Hz, 1H), 0.47 (ddq, J=13.7, 6.3,
6.3 Hz, 1H) ppm. LC/MS (M+=442.2).
[2314] To a solution of
(2S,3S,5S,6R,8S)-8-allyl-6-(3-chlorophenyl)-5-(4-chlorophenyl)-3-ethyl-2,-
8-dimethyl-2,3,5,6,7,8-hexahydrooxazolo[3,2-a]pyridin-4-ium
triflate (60 mg, 0.101 mmol) in 1 mL dichloromethane at 0.degree.
C. was added tetra-n-butylammonium chloride (2.81 mg, 10.13
.mu.mol) and acetic acid (116 .mu.l, 2.025 mmol). To this was added
KMnO.sub.4 (32.0 mg, 0.203 mmol) in 1 mL water followed by a 1 mL
water rinse. An additional 10 eq. acetic acid were added followed
by an additional 16 mg KMnO.sub.4 in 1 mL water. This was repeated
once more. A total of 4 eq KMnO.sub.4 and 40 eq. acetic acid were
added.
[2315] The reaction was quenched with 1 mL of sat.
Na.sub.2S.sub.2O.sub.3 solution and diluted with ethyl acetate. The
layers were separated and the organic phase was washed once with
brine, dried over MgSO.sub.4, filtered and concentrated to afford
crude
(2S,3S,5S,6R,7aR)-6-(3-chlorophenyl)-5-(4-chlorophenyl)-3-ethyl-2,7a-dime-
thylhexahydrofuro[2,3-b]oxazolo[3,2-a]pyridin-9(5H)-one. This crude
residue was redissolved in 2 mL isopropyl acetate and treated with
2 mL sat. NaHCO.sub.3 and heated to 70.degree. C. After 2 h, the
reaction was cooled to 0.degree. C. and treated with 10% acetic
acid to a pH of about 3. The reaction was diluted with ethyl
acetate and washed once with 10% acetic acid solution, dried over
MgSO.sub.4, filtered, and concentrated. Purification by column
chromatography using 10 to 50% of (15% MeOH/acetone) in hexanes
afforded
2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((2S,3S)-2-hydroxyp-
entan-3-yl)-3-methyl-2-oxopiperidin-3-yl)acetic acid.
Example 153
2-((3R,5R,6S)-5-(3-Chlorophenyl)-6-(4-chlorophenyl)-1-((2S,3S)-2-methoxype-
ntan-3-yl)-3-methyl-2-oxopiperidin-3-yl)acetic acid
##STR00488##
[2316] Step A. Methyl
2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((2S,3S)-2-hydroxyp-
entan-3-yl)-3-methyl-2-oxopiperidin-3-yl)acetate
##STR00489##
[2318] To a solution of 260 mg (0.543 mmol) of
2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((2S,3S)-2-hydroxyp-
entan-3-yl)-3-methyl-2-oxopiperidin-3-yl)acetic acid (Example 152)
in 5 mL of THF was added 60% sodium hydride (217 mg, 5.43 mmol) at
0.degree. C. After being stirred at 0.degree. C. for 20 min,
iodomethane (271 uL, 4.35 mmol) was added. The reaction was allowed
to warm to ambient temperature, and stirred for an additional 3 h
until completion. The reaction was quenched with saturated aqueous
NH.sub.4Cl solution, extracted with EtOAc (2.times.25 mL). The
combined organic layers were washed with saturated NaCl, dried over
MgSO.sub.4, filtered and the filtrate was concentrated to provide
the title compound.
Step B. Methyl
2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((2S,3S)-2-methoxyp-
entan-3-yl)-3-methyl-2-oxopiperidin-3-yl)acetate
##STR00490##
[2320] To a solution of 50 mg (0.102 mmol) of methyl
2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((2S,3S)-2-hydroxyp-
entan-3-yl)-3-methyl-2-oxopiperidin-3-yl)acetate (Example 153, Step
A) in 0.3 mL of DMF was added 60% sodium hydride (20.31 mg, 0.508
mmol) at 25.degree. C. After being stirred at 25.degree. C. for 20
min, iodomethane (25.4 uL, 0.406 mmol) was added. The reaction was
stirred for an additional 30 min and was quenched with saturated
aqueous NH.sub.4Cl solution, extracted with EtOAc (2.times.25 mL).
The combined organic layers were washed with saturated NaCl, dried
over MgSO.sub.4, filtered and the filtrate was concentrated.
Purification of the residue by flash chromatography on silica gel
(eluent: 20 to 60% EtOAc/hexanes) provided the title compound.
Step C.
2-((3R,5R,6S)-5-(3-Chlorophenyl)-6-(4-chlorophenyl)-1-((2S,3S)-2-m-
ethoxypentan-3-yl)-3-methyl-2-oxopiperidin-3-yl)acetic acid
[2321] To a solution of methyl
2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((2S,3S)-2-methoxyp-
entan-3-yl)-3-methyl-2-oxopiperidin-3-yl)acetate (34 mg, 0.067
mmol; Example 153, Step B) in THF/MeOH/H.sub.2O (1/1/1, 0.48 mL)
was added 2 M lithium hydroxide (67 uL, 0.134 mmol) at rt. After
being stirred at rt for 4 h, the reaction was quenched saturated
aqueous NH.sub.4Cl and extracted (2.times.DCM) and the combined
organic layers were washed (1.times.sat. aq. NaCl solution) and
concentrated under the reduced pressure. Purification of the
residue by flash chromatography on silica gel (eluent: 70 to 100%
EtOAc/hexanes) provided the title compound.
[2322] .sup.1H NMR (400 MHz, CHLOROFORM-d) .delta. ppm 0.38 (t,
J=8.0 Hz, 3H), 1.05 (d, J=4.0 Hz, 1H), 1.48 (s, 3H), 1.65 (m, 1H),
1.75 (m, 1H), 2.00 (dd, J=12.0, 4 Hz, 1H), 2.21 (m, 1H), 2.48 (m,
1H), 2.70 (d, J=16.0 Hz, 1H), 3.06-3.15 (m, 2H), 3.41 (s, 3H), 3.94
(m, 1H), 4.63 (d, J=12.0 Hz, 1H), 6.75 (d, J=8.0 Hz, 1H), 6.90-7.05
(m, 3H), 7.05-7.15 (m, 2H), 7.25 (d, J=8.0 Hz, 2H); MS (ESI) 492.1
[M+H].sup.+.
Example 154
2-((3R,5R,6S)-5-(3-Chlorophenyl)-6-(4-chlorophenyl)-1-((2R,3S)-2-hydroxype-
ntan-3-yl)-3-methyl-2-oxopiperidin-3-yl)acetic acid
##STR00491##
[2324] A solution of
2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-2-oxo-1-((S)-
-1-oxobutan-2-yl)piperidin-3-yl)acetic acid (71 mg, 0.154 mmol)
(Example 210, Step A) in THF (2 mL) was sparged with argon for 5
minutes. The mixture was cooled to 0.degree. C. and methylmagnesium
chloride, 3.0 M solution in tetrahydrofuran (0.113 ml, 0.339 mmol)
was added at such a rate that the internal temperature did not get
above 4.degree. C. The mixture was stirred at 0.degree. C. for 45
minutes. The mixture was quenched with sat. aq. NH.sub.4Cl solution
and extracted with EtOAc. The combined organic layers were dried
over Na.sub.2SO.sub.4, filtered and the filtrate was concentrated.
The residue was purified by flash chromatography on silica gel
(2.times.4 g stacked columns, eluent: 5 to 15% isopropanol/hexanes)
to give the title compound as the more polar diastereomer.
[2325] .sup.1H NMR (400 MHz, CHLOROFORM-d) .delta. ppm 0.55 (t,
J=7.63 Hz, 3H), 1.18 (d, J=6.65 Hz, 3H), 1.44 (s, 3H), 1.63-1.77
(m, 1H), 1.99-2.18 (m, 3H), 2.61-2.71 (m, 1H), 2.81 (d, J=14.28 Hz,
1H), 2.92 (d, J=14.48 Hz, 1H), 3.24 (td, J=10.22, 5.77 Hz, 1H),
4.11-4.22 (m, 1H), 4.45 (d, J=10.17 Hz, 1H), 6.74 (dt, J=7.53, 1.61
Hz, 1H), 6.93-7.05 (m, 3H), 7.07-7.14 (m, 1H), 7.15-7.20 (m, 1H),
7.24-7.31 (m, 2H). Mass Spectrum (ESI) m/e=478.1 (M+1).
Example 155
2-((3R,5R,6S)-5-(3-Chlorophenyl)-6-(4-chlorophenyl)-1-((2S,3R)-2-hydroxype-
ntan-3-yl)-3-methyl-2-oxopiperidin-3-yl)acetic acid (isomer 1)
##STR00492##
[2326] Step A.
(R)-2-((3S,5R,6S)-3-Allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl--
2-oxopiperidin-1-yl)butanal
##STR00493##
[2328] The title compound was prepared from
(3S,5R,6S)-3-allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((R)-1-hydroxy-
butan-2-yl)-3-methylpiperidin-2-one by a procedure similar to the
one described in Example 91, Step B. The product was used in the
next step without further purification.
Step B.
(3S,5R,6S)-3-allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((3R)-2-
-hydroxypentan-3-yl)-3-methylpiperidin-2-one
##STR00494##
[2330] The title compound was prepared from
(R)-2-((3S,5R,6S)-3-allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl--
2-oxopiperidin-1-yl)butanal (Example 155, Step A) as described in
Example 149, Step A. Purification by flash chromatography
(SiO.sub.2, 40 g, 10% to 25% EtOAc/hexanes) provided the title
compound as a mixture of two diastereomers at the newly formed
stereocenter.
Step C.
2-((3R,5R,6S)-5-(3-Chlorophenyl)-6-(4-chlorophenyl)-3-methyl-2-oxo-
-1-((R)-2-oxopentan-3-yl)piperidin-3-yl)acetic acid
##STR00495##
[2332] The title compound was prepared from
(3S,5R,6S)-3-allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((3R)-2-hydrox-
ypentan-3-yl)-3-methylpiperidin-2-one (0.210 g, 0.456 mmol; Example
155, Step B) by a procedure similar to the one described in Example
71, Step F.
Step D.
2-((3R,5R,6S)-5-(3-Chlorophenyl)-6-(4-chlorophenyl)-1-((2S,3R)-2-h-
ydroxypentan-3-yl)-3-methyl-2-oxopiperidin-3-yl)acetic acid
[2333] To a solution of
2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-2-oxo-1-((R)-
-2-oxopentan-3-yl)piperidin-3-yl)acetic acid (0.150 g, 0.315 mmol,
Example 155, Step C) in THF/MeOH (3/1, 4 mL) was added sodium
borohydride (0.060 g, 1.574 mmol) at room temperature. After being
stirred at room temperature for 1 h, the reaction was acidified
with sat. aq. NH.sub.4Cl solution and extracted with EtOAc. The
combined organic layers were washed with sat. aq. NaCl solution,
dried over MgSO.sub.4, filtered and the filtrate was concentrated
under reduced pressure. The crude material was purified by reversed
phase preparatory HPLC (eluent: 10-90% acetonitrile, water, 0.1%
TFA, gradient elution) to give a mixture of two isomers (dr=93:7).
Individual stereoisomers were separated by chiral HPLC
(250.times.30 mm CHIRALPAK.RTM. IC column (CHIRAL TECHNOLOGIES,
INC., West Chester, Pa., USA) with 46 g/min ispropylamine+(20 .mu.M
NH.sub.3)+84 g/min CO.sub.2 on Thar 350 SFC (Thar Technologies,
Inc., Pittsburg, Pa.)) to give the title compound as the faster
eluting stereoisomer.
[2334] .sup.1H NMR (400 MHz, CHLOROFORM-d) .delta. ppm 0.61 (d,
J=6.65 Hz, 3H), 0.99-1.08 (t, J=7.34 Hz, 3H), 1.18-1.37 (m, 1H),
1.45-1.60 (m, 4H), 1.99-2.21 (m, 3H), 2.69 (dd, J=11.15, 3.72 Hz,
1H), 2.82-2.90 (m, 1H), 3.18-3.30 (m, 1H), 3.69-3.79 (m, 1H), 4.34
(d, J=10.56 Hz, 1H), 6.71 (d, J=7.63 Hz, 1H), 6.88-7.04 (m, 2H),
7.04-7.20 (m, 3H), 7.20-7.32 (m, 2H). MS (ESI) 478.0
[M+H].sup.+.
[2335] Further elution provided Example 156.
Example 156
2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((2R,3R)-2-hydroxype-
ntan-3-yl)-3-methyl-2-oxopiperidin-3-yl)acetic acid
##STR00496##
[2337] Example 155, Step D; slower eluting isomer from chiral
HPLC.
[2338] .sup.1H NMR (400 MHz, CHLOROFORM-d) .delta. ppm 0.81 (d,
J=6.46 Hz, 3H), 1.01 (t, J=7.43 Hz, 3H), 1.47 (s, 3H), 1.64 (m,
1H), 1.82-1.95 (m, 1H), 2.13-2.25 (m, 2H), 2.73-2.84 (m, 2H), 2.93
(d, J=14.87 Hz, 1H), 3.37 (m, 1H), 3.93 (m, 1H), 4.45 (d, J=10.56
Hz, 1H), 6.72 (d, J=7.43 Hz, 1H), 6.96 (m, 1H), 7.02-7.17 (m, 4H),
7.21 (m, 2H); Mass Spectrum (ESI) m/z=478.0 (M+1).
Example 157
2-((3R,5R,6S)-5-(3-Chlorophenyl)-6-(4-chlorophenyl)-1-((S)-2-hydroxy-2-met-
hylpentan-3-yl)-3-methyl-2-oxopiperidin-3-yl)acetic acid
##STR00497##
[2339] Step A.
(3S,5R,6S)-3-allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((S)-2-hydroxy-
-2-methylpentan-3-yl)-3-methylpiperidin-2-one
##STR00498##
[2341] To a solution of
(3S,5R,6S)-3-allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-1-((S)--
2-oxopentan-3-yl)piperidin-2-one (0.100 g, 0.218 mmol; Example 149,
Step B) in THF (4 mL) was added a solution of methylmagnesium
bromide, 1.4M in toluene (0.104 g, 0.873 mmol) at 0.degree. C. The
reaction was allowed to warm to room temperature. After being
stirred at room temperature for 4 h, another 1 eq. of MeMgBr was
added and stirred for another 2 h. The reaction was quenched w/sat
NH.sub.4Cl solution, and extracted with EtOAc. The combined organic
layers were washed with sat. aq. NaCl solution, dried over
MgSO.sub.4, filtered and the filtrate was concentrated under
reduced pressure. The crude material was absorbed onto a plug of
silica gel and purified by chromatography on silica gel, eluting
with 40% EtOAc/hexanes, to provide the title compound as a
light-yellow oil.
Step B.
2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((S)-2-hydro-
xy-2-methylpentan-3-yl)-3-methyl-2-oxopiperidin-3-yl)acetic
acid
[2342] The title compound was prepared from
(3S,5R,6S)-3-allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((S)-2-hydroxy-
-2-methylpentan-3-yl)-3-methylpiperidin-2-one (Example 157, Step A)
by a procedure similar to the one described in Example 71, Step
F.
[2343] .sup.1H NMR (400 MHz, CHLOROFORM-d) .delta. ppm 0.37 (t,
J=7.63 Hz, 3H) 1.10 (s, 3H) 1.35 (s, 3H) 1.50 (s, 3H) 1.68 (ddd,
J=15.21, 7.78, 4.01 Hz, 1H) 2.10-2.31 (m, 3H) 2.44-2.55 (m, 1H)
2.78-2.95 (m, 2H) 3.24-3.37 (m, 1H) 4.40 (d, J=10.56 Hz, 1H) 6.73
(dt, J=7.53, 1.52 Hz, 1H) 6.95 (m, 1H) 7.01-7.21 (m, 4H) 7.21-7.38
(m, 2H). MS (ESI) 492.2 [M+H].sup.+.
Example 158
2-((3R,5R,6S)-5-(3-Chlorophenyl)-6-(4-chlorophenyl)-1-((3S,4S)-4-hydroxyhe-
xan-3-yl)-3-methyl-2-oxopiperidin-3-yl)acetic acid or
2-((3R,5R,6S)-5-(3-Chlorophenyl)-6-(4-chlorophenyl)-1-((3S,4R)-4-hydroxyh-
exan-3-yl)-3-methyl-2-oxopiperidin-3-yl)acetic acid
##STR00499##
[2344] Step A.
(3S,5R,6S)-3-Allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((S)-4-hydroxy-
hexan-3-yl)-3-methylpiperidin-2-one
##STR00500##
[2346] The title compound was prepared from
(S)-2-((3S,5R,6S)-3-allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl--
2-oxopiperidin-1-yl)butanal (Example 91, Step C) and ethylmagnesium
bromide as described in Example 149, Step A. The crude material was
used in the next step without further purification
Step B.
2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-2-oxo-
-1-((S)-4-oxohexan-3-yl)piperidin-3-yl)acetic acid
##STR00501##
[2348] The title compound was prepared from
(3S,5R,6S)-3-allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((S)-4-hydroxy-
hexan-3-yl)-3-methylpiperidin-2-one (Example 158, Step A) as
described in Example 71, Step F.
Step C.
2-((3R,5R,6S)-5-(3-Chlorophenyl)-6-(4-chlorophenyl)-1-((3S)-4-hydr-
oxyhexan-3-yl)-3-methyl-2-oxopiperidin-3-yl)acetic acid
[2349] To a solution of
2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-2-oxo-1-((S)-
-4-oxohexan-3-yl)piperidin-3-yl)acetic acid (0.038 g, 0.077 mmol;
Example 158, Step B) in a mixture of THF and methanol (4:1, 5 mL)
was added sodium borohydride (9 mg, 0.24 mmol) at 0.degree. C. Then
the reaction was allowed to warm to room temperature. After being
stirred at room temperature for 1.5 h, another 2 eq. of sodium
borohydride were added and stirred for another 0.5 h. The reaction
was acidified (10% citric acid) and extracted (2.times.EtOAc). The
combined organic layers were washed (sat. aq. NaCl solution), dried
(MgSO.sub.4), and concentrated under reduced pressure. The crude
material was purified by reverse phase preparatory HPLC (eluent: 10
to 90% acetonitrile, water, 0.1% TFA, gradient elution) to give the
title compound as the first eluting fraction as a white solid after
lyophilization.
[2350] .sup.1H NMR (400 MHz, CHLOROFORM-d) .delta. ppm 0.55 (t,
J=7.53 Hz, 3H) 0.91 (t, J=7.34 Hz, 3H) 1.38 (m, 1H) 1.44 (s, 3H)
1.54 (m, 1H) 1.72 (m, 1H) 2.00-2.25 (m, 3H) 2.73-2.79 (m, 1H) 2.82
(d, J=14.48 Hz, 1H) 2.92 (d, J=14.48 Hz, 1H) 3.26 (m, 1H) 3.87-3.93
(m, 1H) 4.43 (d, J=10.17 Hz, 1H) 6.75 (dt, J=7.53, 1.52 Hz, 1H)
6.95-7.07 (m, 3H) 7.12 (t, J=7.73 Hz, 1H) 7.17 (m, 1H) 7.25-7.35
(m, 2H). MS (ESI) 492.2 [M+H].sup.+.
Example 159
2-((3R,5R,6S)-5-(3-Chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-methoxybutan--
2-yl)-3-methyl-2-oxopiperidin-3-yl)acetic acid
##STR00502##
[2351] Step A.
(3S,5R,6S)-3-allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-methoxy-
butan-2-yl)-3-methylpiperidin-2-one
##STR00503##
[2353] To a solution of 50 mg (0.112 mmol) of
(3S,5R,6S)-3-allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-hydroxy-
butan-2-yl)-3-methylpiperidin-2-one (Example 91, Step B) in 0.5 mL
of THF was added 60% sodium hydride (8.96 mg, 0.244 mmol) at
0.degree. C. After being stirred at 0.degree. C. for 30 min,
iodomethane (14.01 uL, 0.244 mmol) was added. The reaction was
allowed to warm to 25.degree. C., and stirred for an additional 2 h
until completion. The reaction was quenched with saturated aqueous
NH.sub.4Cl solution, extracted with EtOAc (2.times.25 mL). The
combined organic layers were washed with saturated NaCl solution,
dried over MgSO.sub.4, filtered and the filtrate was concentrated
to provide the title compound.
Step B.
2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-metho-
xybutan-2-yl)-3-methyl-2-oxopiperidin-3-yl)acetic acid
[2354] The title compound was prepared from
(3S,5R,6S)-3-allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-methoxy-
butan-2-yl)-3-methylpiperidin-2-one (Example 159, Step A) by a
procedure similar to the one described in Example 71, Step F. The
residue was purified by reverse phase preparatory HPLC (MeCN in
water with 0.1% TFA, gradient elution) to give the title compound
as a white solid.
[2355] .sup.1H NMR (400 MHz, CHLOROFORM-d) .delta. ppm 0.50 (t,
J=8.0 Hz, 3H), 1.42 (s, 3H), 1.50 (m, 1H), 1.93 (m, 1H), 2.02 (dd,
J=12.0, 4.0 Hz, 1H), 2.18 (dd, J=12.0, 12.0 Hz, 1H), 2.71 (d,
J=16.0 Hz, 1H), 3.05 (d, J=12.0 Hz, 1H), 2.90-3.10 (m, 2H), 3.31
(dd, J=8.0, 4.0 Hz, 1H), 3.38 (s, 3H), 3.93 (t, J=12.0 Hz, 1H),
4.61 (d, J=8.0 Hz, 1H), 6.78 (d, J=8.0 Hz, 1H), 7.01 (d, J=8.0 Hz,
2H), 7.05 (s, 1H), 7.12 (t, J=8.0 Hz, 1H), 7.17 (d, J=8.0 Hz, 1H),
7.26 (d, J=8.0 Hz, 2H); MS (ESI) 478.0 [M+H].sup.+.
Example 160
2-((3R,5R,6S)-5-(3-Chlorophenyl)-6-(4-chlorophenyl)-3-methyl-2-oxo-1-((3S)-
-1,1,1-trifluoro-2-hydroxy-2-methylpentan-3-yl)piperidin-3-yl)acetic
acid
##STR00504##
[2356] Step A.
(3S,5R,6S)-3-Allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-1-((3S)-
-1,1,1-trifluoro-2-hydroxy-2-methylpentan-3-yl)piperidin-2-one
##STR00505##
[2358] A solution of
(3S,5R,6S)-3-allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-1-((S)--
2-oxopentan-3-yl)piperidin-2-one (30 mg, 0.065 mmol; Example 149,
Step B) and trimethyl(trifluoromethyl)silane (48.5 .mu.L, 0.327
mmol) in THF (0.5 mL) was treated with 1 M tetrabutylammonium
fluoride solution in THF (196 .mu.L, 0.196 mmol) at 0.degree. C.
After being stirred for 2 h, the reaction mixture was extracted
with EtOAc. The combined organic layers were washed with water and
saturated NaCl solution, dried over Na.sub.2SO.sub.4, filtered and
the filtrate was concentrated. The residue was purified by the
flash chromatography on silica gel (eluent: 10 to 20% EtOAc/Hexane,
gradient elution) to provide the title compound as the major
product.
Step B.
2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-2-oxo-
-1-((3S)-1,1,1-trifluoro-2-hydroxy-2-methylpentan-3-yl)piperidin-3-yl)acet-
ic acid
[2359] The title compound was prepared from
(3S,5R,6S)-3-allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-1-((3S)-
-1,1,1-trifluoro-2-hydroxy-2-methylpentan-3-yl)piperidin-2-one
(Example 160, Step A) by a procedure similar to the one described
in Example 71, Step F.
[2360] .sup.1H NMR (400 MHz, CHLOROFORM-d) .delta. ppm 0.33 (t,
J=8.0 Hz, 3H), 1.47 (s, 3H), 1.52 (s, 3H), 1.70 (m, 1H), 2.10-2.25
(m, 3H), 2.89 (d, J=8.0 Hz, 2H), 2.95 (t, J=8.0, 1H), 3.43 (m, 1H),
4.40 (d, J=12.0 Hz, 1H), 6.75 (d, J=8.0 Hz, 1H), 6.95 (m, 1H),
7.08-7.20 (m, 3H), 7.26-7.40 (m, 3H); MS (ESI) 545.2
[M+H].sup.+.
Example 161
2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-1-((S)-1-(N-m-
ethylcyclopropanesulfonamido)butan-2-yl)-2-oxopiperidin-3-yl)acetamide
##STR00506##
[2362] A solution of
2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-1-((S)-1-(N--
methylcyclopropanesulfonamido)butan-2-yl)-2-oxopiperidin-3-yl)acetic
acid (0.055 g, 0.095 mmol; Example 141) in DMF (2.0 mL) was treated
with HBTU (0.072 g, 0.189 mmol),
N.sup.1-((ethylimino)methylene)-N.sup.3,N.sup.3-dimethylpropane-1,3-diami-
ne hydrochloride (0.036 g, 0.189 mmol) and sodium hydrogencarbonate
(0.016 g, 0.189 mmol) successively. Let it stir for 0.5 h. 7.0M
ammonia in methanol (0.135 mL, 0.946 mmol) was added dropwise.
After being stirred at room temperature for 18 h, the reaction was
diluted with water, extracted (2.times.EtOAc), and washed (1.times.
saturated NaHCO.sub.3, and 2.times.sat. aq. NaCl solution). The
combined organic layers were dried over Na.sub.2SO.sub.4, filtered
and the filtrate was concentrated under reduced pressure. The
residue was purified by reverse phase preparatory HPLC (eluent: 10
to 90% acetonitrile, water, 0.1% TFA, gradient elution) to give the
title compound as a white solid after lyophilization.
[2363] .sup.1H NMR (400 MHz, CHLOROFORM-d) .delta. ppm 0.52 (t,
J=7.53 Hz, 3H) 0.97-1.07 (m, 2H) 1.18-1.25 (m, 2H) 1.47 (s, 3H)
1.59-1.62 (m, 1H) 1.84-2.06 (m, 2H) 2.33 (ddd, J=8.02, 4.79, 3.23
Hz, 1H) 2.43 (t, J=13.8 Hz, 1H) 2.65-2.80 (m, 2H) 2.81-2.95 (m, 5H)
3.17 (ddd, J=13.74, 10.91, 2.93 Hz, 1H) 4.80 (d, J=10.76 Hz, 1H)
6.78 (br. s., 1H) 6.86-6.90 (m, 1H) 6.97-7.01 (m, 1H) 7.10-7.15 (m,
2H) 7.24 (d, J=7.82 Hz, 4H) 7.42 (br. s., 1H); Mass Spectrum (ESI)
m/z=580.2 (M+1).
Example 162
2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-1-((S)-1-(N-m-
ethylcyclopropanesulfonamido)butan-2-yl)-2-oxopiperidin-3-yl)-N-(methylsul-
fonyl)acetamide
##STR00507##
[2365] A solution of
2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-1-((S)-1-(N--
methylcyclopropanesulfonamido)butan-2-yl)-2-oxopiperidin-3-yl)acetic
acid (0.045 g, 0.077 mmol) (Example 141) in THF (2.0 mL) was
treated with methanesulfonamide (0.029 g, 0.310 mmol),
N-ethyl-N-isopropylpropan-2-amine (0.050 g, 0.387 mmol) and
1,1'-carbonyldiimidazole (0.050 g, 0.310 mmol), successively. The
mixture was heated to reflux for 48 h, quenched with sat.NH.sub.4Cl
solution and extracted with EtOAc. The combined organic layers were
dried over MgSO.sub.4, filtered and the filtrate was concentrated
under reduced pressure. The residue was purified by reverse phase
preparatory HPLC (eluent: 10 to 90% acetonitrile, water, 0.1% TFA,
gradient elution) to give the title compound as a white solid after
lyophilization.
[2366] .sup.1H NMR (400 MHz, CHLOROFORM-d) .delta. ppm 0.52 (t,
J=7.53 Hz, 3H) 0.96-1.08 (m, 2H) 1.15-1.28 (m, 2H) 1.50 (s, 3H)
1.61 (ddd, J=14.33, 7.68, 3.62 Hz, 1H) 1.92 (dd, J=13.69, 2.93 Hz,
1H) 1.96-2.10 (m, 1H) 2.34 (tt, J=8.02, 4.79 Hz, 1H) 2.49 (t,
J=13.89 Hz, 1H) 2.65 (d, J=14.87 Hz, 1H) 2.73 (dd, J=14.48, 2.35
Hz, 1H) 2.87 (s, 3H) 2.98-3.08 (m, 2H) 3.32 (s, 3H) 4.79 (d,
J=10.56 Hz, 1H) 6.84-6.90 (m, 1H) 6.94-7.07 (m, 1H) 7.08-7.16 (m,
2H) 7.19-7.32 (m, 4H)
[2367] Examples 163-170 were prepared from
2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-1-((S)-1-(N--
methylcyclopropanesulfonamido)butan-2-yl)-2-oxopiperidin-3-yl)acetic
acid (Example 141) by using the following general procedure using
the appropriate amine, unless noted otherwise.
[2368] A mixture of
2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-1-((S)-1-(N--
methylcyclopropanesulfonamido)butan-2-yl)-2-oxopiperidin-3-yl)acetic
acid (0.020 g, 0.034 mmol; Example 141), corresponding amine (1.2
eq.), N-ethyl-N-isopropylpropan-2-amine (3.3 eq.) and
(1H-benzo[d][1,2,3]triazol-1-yloxy)tripyrrolidin-1-ylphosphonium
hexafluorophosphate (V) (1.05 eq.) in 2 ml of DCM was stirred at
room temperature for 5 h. The solvent was removed under reduced
pressure, and the residue was purified by reverse phase HPLC
(40-90% water/acetonitrile gradient with 0.1% TFA). Desired
fractions were then collected and concentrated to give pure
product.
TABLE-US-00007 ##STR00508## Example R Amine used 163 ##STR00509##
3-Aminopropan-1-ol 164 ##STR00510## 2-Aminoethanol 165 ##STR00511##
Hydroxylamine 166 ##STR00512## O-Methyl- hydroxylamine 167
##STR00513## (R)-3-Aminopropane- 1,2-diol 168 ##STR00514##
(S)-3-Aminopropane- 1,2-diol 169 ##STR00515## Monosodium cyanamide
170 ##STR00516## N.sup.1,N.sup.1-Dimethylethane- 1,2-diamine
Example 163
2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-1-((S)-1-(N-m-
ethylcyclopropanesulfonamido)butan-2-yl)-2-oxopiperidin-3-yl)-N-(3-hydroxy-
propyl)acetamide
[2369] .sup.1H NMR (400 MHz, MeOH-d.sub.4) .delta. ppm 0.54 (t,
J=7.63 Hz, 3H), 1.00-1.19 (m, 4H), 1.39 (s, 3H), 1.65-2.13 (m, 5H),
2.25-2.36 (m, 1H), 2.48-2.61 (m, 2H), 2.81-2.95 (m, 6H), 3.25-3.43
(m, 3H), 3.61 (t, J=6.26 Hz, 1H), 4.13-4.26 (br, 1H), 4.44 (s, 1H),
4.82 (d, J=10.76 Hz, 1H), 6.97-7.07 (m, 2H), 7.11-7.22 (m, 4H),
7.27-7.347 (m, 2H). Mass Spectrum (ESI) m/z=638.2 (M+1).
Example 164
2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-1-((S)-1-(N-m-
ethylcyclopropanesulfonamido)butan-2-yl)-2-oxopiperidin-3-yl)-N-(2-hydroxy-
ethyl)acetamide
[2370] .sup.1H NMR (400 MHz, MeOH-d.sub.4) .delta. ppm 0.51 (t,
J=7.53 Hz, 3H), 0.95-1.15 (m, 4H), 1.38 (s, 3H), 1.60-1.74 (m, 1H),
1.79-1.92 (m, 1H), 2.02-2.11 (m, 1H), 2.22-2.33 (m, 1H), 2.49-2.58
(m, 2H), 2.78-2.93 (m, 6H), 3.37-3.39 (m, 2H), 3.53-3.64 (m, 2H),
4.10-4.24 (m, 1H), 4.39-4.49 (m, 1H), 4.79 (d, J=10.76 Hz, 1H),
6.95-7.05 (m, 2H), 7.10-7.21 (m, 4H), 7.24-7.32 (m, 2H). Mass
Spectrum (ESI) m/z=624.4 (M+1).
Example 165
2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-1-((S)-1-(N-m-
ethylcyclopropanesulfonamido)butan-2-yl)-2-oxopiperidin-3-yl)-N-hydroxyace-
tamide
[2371] .sup.1H NMR (400 MHz, MeOH-d.sub.4) .delta. ppm 0.53 (t,
J=7.53 Hz, 3H), 1.00-1.16 (m, 4H), 1.38 (s, 3H), 1.70 (ddd,
J=14.23, 7.78, 4.21 Hz, 1H), 1.88 (ddd, J=14.28, 8.51, 7.34 Hz,
1H), 2.09-2.16 (m, 1H), 2.17-2.22 (m, 1H), 2.24-2.39 (m, 2H),
2.52-2.60 (m, 1H), 2.77-2.88 (m, 2H), 2.92 (s, 3H), 3.37-3.44 (m,
1H), 4.20 (br 1H), 4.82 (d, J=10.76 Hz, 1H), 7.01-7.09 (m, 2H),
7.13-7.22 (m, 4H), 7.30 (d, J=8.02 Hz, 2H). Mass Spectrum (ESI)
m/z=618 (M+1).
Example 166
2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-1-((S)-1-(N-m-
ethylcyclopropanesulfonamido)butan-2-yl)-2-oxopiperidin-3-yl)-N-methoxyace-
tamide
[2372] .sup.1H NMR (400 MHz, CHLOROFORM-d) .delta. ppm 0.50 (t,
J=7.53 Hz, 3H), 0.96-1.07 (m, 2H), 1.17-1.28 (m, 2H), 1.43 (s, 3H),
1.55-1.65 (m, 1H), 1.87-2.00 (m, 1H), 2.07-2.13 (dd, J=13.79, 2.64
Hz, 1H), 2.28-2.42 (m, 2H), 2.63-2.77 (m, 3H), 2.88 (br, 4H), 3.26
(ddd, J=13.89, 10.66, 3.03 Hz, 1H), 3.82 (s, 3H), 4.25 (br, 1H),
4.77 (d, J=10.76 Hz, 1H), 6.88-6.92 (m, 1H), 6.99-7.05 (m, 2H),
7.10-7.14 (m, 2H), 7.18-7.30 (m, 3H). Mass Spectrum (ESI) m/z=632
(M+1).
Example 167
2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-1-((S)-1-(N-m-
ethylcyclopropanesulfonamido)butan-2-yl)-2-oxopiperidin-3-yl)-N--((R)-2,3--
dihydroxypropyl)acetamide
[2373] .sup.1H NMR (500 MHz, CHLOROFORM-d) .delta. ppm 0.51 (t,
J=6.6 Hz, 3H), 1.01 (t, J=8.3 Hz, 2H), 1.21 (br. s., 2H), 1.40-1.48
(m, 3H), 1.58 (dd, J=7.8, 3.9 Hz, 1H), 1.81-1.99 (m, 2H), 2.28-2.36
(m, 1H), 2.37-2.49 (m, 1H), 2.52-2.64 (m, 1H), 2.67-2.77 (m, 1H),
2.84 (br. s., 2H), 2.88 (s, 4H), 2.90-3.05 (m, 7H), 3.11-3.23 (m,
2H), 3.47 (br. s., 2H), 3.55-3.72 (m, 2H), 3.89 (br. s., 1H), 4.25
(br. s., 1H), 4.76 (d, J=10.3 Hz, 1H), 6.85-6.92 (m, 1H) 6.98 (br.
s., 2H), 7.00-7.06 (m, 1H), 7.13 (br. s., 3H), 7.20-7.26 (m,
2H).
Example 168
2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-1-((S)-1-(N-m-
ethylcyclopropanesulfonamido)butan-2-yl)-2-oxopiperidin-3-yl)-N--((S)-2,3--
dihydroxypropyl)acetamide
[2374] .sup.1H NMR (500 MHz, CHLOROFORM-d) .delta. ppm 0.43-0.58
(m, 3H), 1.01 (t, J=7.6 Hz, 2H), 1.16-1.24 (m, 2H), 1.41-1.45 (m,
1H), 1.45-1.49 (m, 2H), 1.49 (s, 1H), 1.54-1.66 (m, 1H), 1.79-1.95
(m, 2H), 2.28-2.36 (m, 1H), 2.38-2.49 (m, 1H), 2.55 (d, J=13.7 Hz,
1H), 2.72 (s, 5H), 2.74 (s, 4H,), 2.84 (d, J=13.2 Hz, 2H), 2.88 (s,
3H), 3.11-3.25 (m, 2H), 3.28-3.39 (m, 1H), 3.51-3.59 (m, 1H),
3.59-3.76 (m, 2H), 3.92 (br. s., 1H), 4.18-4.31 (m, 1H), 4.70-4.81
(m, 1H), 6.90 (d, J=5.1 Hz, 1H) 6.92-7.01 (m, 2H,), 7.10-7.16 (m,
2H), 7.20-7.26 (m, 2H).
Example 169
2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-1-((S)-1-(N-m-
ethylcyclopropanesulfonamido)butan-2-yl)-2-oxopiperidin-3-yl)-N-cyanoaceta-
mide
[2375] A mixture of
2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-1-((S)-1-(N--
methylcyclopropanesulfonamido)butan-2-yl)-2-oxopiperidin-3-yl)acetic
acid (0.030 g, 0.052 mmol; Example 141),
N,N'-dicyclohexylcarbodiimide (10.64 mg, 0.052 mmol) and
N-hydroxysuccinimide (5.94 mg, 0.052 mmol) in 3 mL of THF was
stirred while cooling with an ice bath for 3 h. The reaction
mixture was filtered and the filtrate was added dropwise to a
solution of monosodium cyanamide (10.90 mg, 0.170 mmol) in 2 mL of
water at an ice bath temperature. The reaction mixture was stirred
at room temperature for 12 h. Solvents were removed and the residue
was purified by reverse phase HPLC (40 to 90% water/acetonitrile
gradient with 0.1% TFA). Desired fractions were then collected and
concentrated to give the title compound.
[2376] .sup.1H NMR (500 MHz, CHLOROFORM-d) .delta. ppm 0.52 (t,
J=7.6 Hz, 3H), 0.98-1.10 (m, 2H), 1.17-1.30 (m, 2H), 1.49-1.53 (m,
3H), 1.54-1.61 (m, 1H), 1.91-2.03 (m, 1H), 2.35 (tt, J=8.0, 4.7 Hz,
1H), 2.56 (t, J=13.8 Hz, 1H), 2.60-2.66 (m, 1H), 2.71-2.77 (m, 1H),
2.80-2.87 (m, 1H), 2.87-2.91 (m, 3H), 2.91-3.01 (m, 1H), 3.18 (d,
J=16.1 Hz, 1H), 4.19-4.32 (m, 1H), 4.79 (d, J=10.8 Hz, 1H), 6.84
(dt, J=7.1, 1.6 Hz, 1H), 6.92-6.96 (m, 1H), 7.11-7.18 (m, 2H),
11.77 (br. s., 1H).
Example 170
2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-1-((S)-1-(N-m-
ethylcyclopropanesulfonamido)butan-2-yl)-2-oxopiperidin-3-yl)-N-(2-(dimeth-
ylamino)ethyl)acetamide
[2377] .sup.1H NMR (400 MHz, MeOH-d.sub.4) .delta. ppm 0.52 (t,
J=7.53 Hz, 3H), 1.01-1.21 (m, 4H), 1.47 (s, 3H) 1.62-1.85 (m, 2H),
1.90 (dd, J=13.50, 3.13 Hz, 1H), 2.42 (t, J=13.69 Hz, 1H),
2.51-2.62 (m, 2H), 2.80-2.91 (m, 3H, 2.93 (s, 3H), 3.03 (s, 6H),
3.38-3.50 (m, 2H), 3.29-3.39 (m, 2H), 3.84 (ddd, J=15.01, 7.38,
4.79 Hz, 1H), 4.21 (dd, J=13.89, 10.56 Hz, 1H), 4.80 (d, J=10.76
Hz, 1H), 7.00-7.12 (m, 2H) 7.15-7.25 (m, 4H) 7.33 (d, J=6.85 Hz,
2H).
[2378] Mass Spectrum (ESI) m/z=651.2 (M+1).
Example 171
2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-1-((S)-1-(N-m-
ethylcyclopropanesulfonamido)butan-2-yl)-2-oxopiperidin-3-yl)-N-(3,4-dihyd-
roxybutyl)acetamide
##STR00517##
[2380] To a solution of
N-(but-3-enyl)-2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-meth-
yl-1-((S)-1-(N-methylcyclopropanesulfonamido)butan-2-yl)-2-oxopiperidin-3--
yl)acetamide (0.030 g, 0.047 mmol; Example 170) in 1 mL of
THF/H.sub.2O (4:1) was added osmium(VIII) oxide (0.030 mL, 2.363
.mu.mol), followed by 4-methylmorpholine-4-oxide (8.31 mg, 0.071
mmol). The reaction mixture was stirred at room temperature for 12
h. Solvents were removed and the residue was purified by reverse
phase HPLC (40 to 90% water/acetonitrile gradient with 0.1% TFA).
Desired fractions were then collected and concentrated to give the
title compound.
[2381] .sup.1H NMR (400 MHz, CHLOROFORM-d) .delta. ppm 0.51 (t,
3H), 1.00 (t, J=7.24 Hz, 2H), 1.21 (d, J=4.11 Hz, 2H), 1.42 (br.
s., 3H), 1.61 (br. s., 2H), 1.75-2.10 (m, 2H) 2.26-2.44 (m, 2H)
2.52-2.80 (m, 7H) 2.88 (s, 3H), 3.21 (br. s., 2H), 3.45-3.85 (m,
4H), 4.23 (br. s., 1H), 4.76 (d, J=10.56 Hz, 1H), 6.90 (br. s.,
1H), 6.95-7.04 (m, 2H), 7.07-7.15 (m, 3H) 7.23 (d, J=7.04 Hz, 2H).
Mass Spectrum (ESI) m/z=668 (M+1).
Example 172
2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-(cyclopropane-
sulfonamido)butan-2-yl)-3-methyl-2-oxopiperidin-3-yl)acetic
acid
##STR00518##
[2383] The title compound was prepared by a procedure similar to
the one described in Example 129, using the equivalent amount of
cyclopropanesulfonyl chloride instead of methanesulfonyl chloride
in Step C. Purification of the residue by reverse phase preparatory
HPLC (eluent: 10 to 90% acetonitrile, water, 0.1% TFA, gradient
elution) provided the title compound as a white solid after
lyophilization of the collected fractions.
[2384] .sup.1H NMR (400 MHz, CHLOROFORM-d) .delta. ppm 0.54 (t,
J=7.53 Hz, 3H) 0.92-1.08 (m, 2H) 1.08-1.23 (m, 2H) 1.39-1.64 (m,
4H) 1.77-1.92 (m, 1H) 1.96-2.07 (m, 1H) 2.28-2.49 (m, 2H) 2.77 (d,
J=14.28 Hz, 1H) 2.92 (d, J=14.09 Hz, 1H) 3.01-3.28 (m, 3H) 3.61 (m,
1H) 4.76 (d, J=10.56 Hz, 1H) 6.78-6.90 (m, 1H) 6.90-7.18 (m, 5H)
7.23 (m, 2H).
Example 173
(S)-2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-1-((S)-1--
(N-methylcyclopropanesulfonamido)butan-2-yl)-2-oxopiperidin-3-yl)propanoic
acid
##STR00519##
[2385] Step A. Methyl
2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-1-((S)-1-(N--
methylcyclopropanesulfonamido)butan-2-yl)-2-oxopiperidin-3-yl)acetate
##STR00520##
[2387] To a solution of
2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-1-((S)-1-(N--
methylcyclopropanesulfonamido)butan-2-yl)-2-oxopiperidin-3-yl)acetic
acid (0.055 g, 0.095 mmol; Example 141) in 1 mL of MeOH and 4 mL of
benzene was added a 2.0 M solution of (trimethylsilyl)diazomethane
in diethyl ether (0.095 mL, 0.189 mmol) at 0.degree. C. The
reaction mixture was stirred at 0.degree. C. for 0.5 h and was then
concentrated. The crude material was purified by reverse phase
preparatory HPLC (eluent: 10 to 90% acetonitrile, water, 0.1% TFA,
gradient elution) to provide the title compound as a white powder
after lyophilization of the pooled collected fractions.
Step B. (S)-Methyl
2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-1-((S)-1-(N--
methylcyclopropanesulfonamido)butan-2-yl)-2-oxopiperidin-3-yl)propanoate
##STR00521##
[2389] To a solution of methyl
2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-1-((S)-1-(N--
methylcyclopropanesulfonamido)butan-2-yl)-2-oxopiperidin-3-yl)acetate
(0.040 g, 0.067 mmol) from Step A above and HMPA (0.012 mL, 0.067
mmol) in anhydrous THF (1 mL) was added LDA, 2.0M in THF (0.037 mL,
0.074 mmol) at -78.degree. C. Let it stir for 0.5 h at -78.degree.
C. Then iodomethane (0.057 mL, 0.913 mmol) was added. After
stirring for 1 h, the reaction was quenched with sat. aq.
NH.sub.4Cl solution and extracted with EtOAc. The organics were
pooled, washed with sat. aq. NaCl solution, dried (MgSO.sub.4),
filtered and the filtrate was concentrated under the reduced
pressure to provide a yellow oil. This was used in the next step
without further purification.
Step C.
S)-2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-1--
((S)-1-(N-methylcyclopropanesulfonamido)butan-2-yl)-2-oxopiperidin-3-yl)pr-
opanoic acid
[2390] To a solution of (S)-methyl
2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-1-((S)-1-(N--
methylcyclopropanesulfonamido)butan-2-yl)-2-oxopiperidin-3-yl)propanoate
(0.041 g, 0.067 mmol) from Step B above in MeOH/THF/H.sub.2O (1
mL/1 mL/2 mL) was added lithium hydroxide (8.02 mg, 0.335 mmol).
The mixture was heated to 60.degree. C. for 14 h. The reaction
mixture was acidified with 1N HCl and extracted with EtOAc
(.times.2). The organics were pooled, washed with sat. aq. NaCl
solution, dried (MgSO.sub.4), filtered and the filtrate was
concentrated under reduced pressure to provide a colorless film.
The crude material was purified by reverse phase preparatory HPLC
(eluent: 10 to 90% acetonitrile, water, 0.1% TFA, gradient elution)
to provide the title compound as the first eluting peak.
[2391] .sup.1H NMR (400 MHz, CHLOROFORM-d) .delta. ppm 0.52 (t,
J=7.53 Hz, 3H) 0.97-1.06 (m, 2H) 1.20-1.26 (m, 2H) 1.41 (s, 3H)
1.43-1.51 (m, 3H) 1.57-1.70 (m, 1H) 1.88-2.04 (m, 2H) 2.26-2.38 (m,
2H) 2.78-2.97 (m, 5H) 3.13 (q, J=7.11 Hz, 1H) 3.32 (ddd, J=13.55,
10.51, 3.13 Hz, 1H) 4.86 (d, J=10.56 Hz, 1H) 6.88-7.03 (m, 3H)
7.10-7.16 (m, 2H) 7.24 (m, 3H).
Example 174
2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((3S)-2-(cyclopropan-
esulfonamido)pentan-3-yl)-3-methyl-2-oxopiperidin-3-yl)acetic acid
(Isomer 1)
##STR00522##
[2392] Step A.
N-((2S,3S)-3-((3S,5R,6S)-3-allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3--
methyl-2-oxopiperidin-1-yl)pentan-2-yl)cyclopropanesulfonamide and
N-((2R,3S)-3-((3S,5R,6S)-3-allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3--
methyl-2-oxopiperidin-1-yl)pentan-2-yl)cyclopropanesulfonamide
##STR00523##
[2394] To a solution of
(3S,5R,6S)-3-allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((3S)-2-hydrox-
ypentan-3-yl)-3-methylpiperidin-2-one (0.053 g, 0.115 mmol; mixture
of stereoisomers; Example 149, Step A) and cyclopropanesulfonamide
(0.042 g, 0.345 mmol) in toluene (2 mL) was added
cyanomethylenetri-n-butylphosphorane (0.093 mL, 0.345 mmol) at room
temperature under an argon atmosphere, which solution was then
stirred at 110.degree. C. for 2 days. Then the reaction was
quenched (sat NH.sub.4Cl), extracted (3.times.EtOAc) and the
combined extracts were washed (2.times. water and 1.times.sat. aq.
NaCl solution). The combined organic layer was dried
(Na.sub.2SO.sub.4) and concentrated under reduced pressure. The
crude material was purified by reversed phase preparatory HPLC
(eluent: 10 to 90% acetonitrile, water, 0.1% TFA, gradient elution)
to provide the title compounds as two separate fractions.
Step B.
2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((2S,3S)-2-(-
cyclopropanesulfonamido)pentan-3-yl)-3-methyl-2-oxopiperidin-3-yl)acetic
acid
[2395] The title compound was prepared from
N--((S)-3-((3S,5R,6S)-3-allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-met-
hyl-2-oxopiperidin-1-yl)pentan-2-yl)cyclopropanesulfonamide
(Example 174, Step A, faster eluting isomer) by a procedure similar
to the one described in Example 71, Step F.
[2396] .sup.1H NMR (400 MHz, CHLOROFORM-d) .delta. ppm 0.67 (t,
J=7.43 Hz, 3H) 0.92-1.04 (m, 2H) 1.04-1.19 (m, 2H) 1.22 (d, J=6.85
Hz, 3H) 1.50 (s, 3H) 1.79-1.93 (m, 1H) 1.96-2.09 (m, 2H) 2.28-2.42
(m, 2H) 2.77 (d, J=13.89 Hz, 1H) 2.92-2.96 (m, 2H) 3.14-3.31 (m,
1H) 4.54 (d, J=10.37 Hz, 1H) 6.80 (m, 1H) 6.91-7.19 (m, 5H)
7.21-7.27 (m, 2H)
Example 175
2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((3S)-2-(cyclopropan-
esulfonamido)pentan-3-yl)-3-methyl-2-oxopiperidin-3-yl)acetic acid
(isomer 2)
##STR00524##
[2398] The title compound was prepared from
N-((3S)-3-((3S,5R,6S)-3-allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-met-
hyl-2-oxopiperidin-1-yl)pentan-2-yl)cyclopropanesulfonamide
(Example 174, Step A, slower eluting isomer) by a procedure similar
to the one described in Example 71, Step F.
[2399] .sup.1H NMR (400 MHz, CHLOROFORM-d) .delta. ppm 0.45-0.53
(m, 3H) 0.97-1.12 (m, 2H) 1.18 (m, 1H) 1.23-1.32 (m, 5H) 1.52 (s,
3H) 1.70 (m, 1H) 1.92 (m, 2H) 2.40-2.54 (m, 2H) 2.74 (d, J=15.06
Hz, 1H) 3.02 (d, J=15.06 Hz, 1H) 3.14 (m, 1H) 4.85 (d, J=10.56 Hz,
1H) 6.84 (m, 1H) 6.99 (m, 1H) 7.08-7.17 (m, 2H) 7.25 (m, 4H)
Example 176
2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-1-((3S)-2-(1--
methylethylsulfonamido)pentan-3-yl)-2-oxopiperidin-3-yl)acetic
acid
##STR00525##
[2401] The title compound was prepared from
(3S,5R,6S)-3-allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((3S)-2-hydrox-
ypentan-3-yl)-3-methylpiperidin-2-one (mixture of stereoisomers;
Example 149, Step A) and propane-2-sulfonamide by a procedure
similar to the one described in Example 174.
[2402] .sup.1H NMR (400 MHz, CHLOROFORM-d) .delta. ppm 0.47 (t,
J=7.83 Hz, 3H) 1.20 (d, J=6.85 Hz, 3H) 1.41 (dd, J=14.87, 6.85 Hz,
6H) 1.51-1.60 (s, 3H) 1.60-1.73 (m, 1H) 1.80-2.00 (m, 2H) 2.50 (t,
J=13.89 Hz, 1H) 2.72-2.81 (d, J=14.67 Hz, 1H) 2.97 (d, J=14.67 Hz,
1H) 3.07-3.23 (m, 2H) 4.85 (d, J=10.96 Hz, 1H) 6.87 (m, 1H)
6.97-7.07 (m, 1H) 7.07-7.19 (m, 2H) 7.19-7.33 (m, 4H).
Example 177
2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-1-((S)-1-(N-m-
ethylcyclopropanesulfonamido)-1-oxobutan-2-yl)-2-oxopiperidin-3-yl)acetic
acid
##STR00526##
[2403] Step A.
2-((3S,5R,6S)-3-Allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-2-ox-
opiperidin-1-yl)butanoic acid
##STR00527##
[2405] To a stirred solution of methyl
2-((3S,5R,6S)-3-allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-2-ox-
opiperidin-1-yl)butanoate (200 mg, 0.42 mmol; Example 91, Step A)
in THF (5 mL) was added sodium hydroxide (506 mg, 12.65 mmol) in
water (5 mL) and the reaction was heated at reflux for about 12 h.
After this time the reaction was cooled to rt and partitioned
between EtOAc (80 mL) and 1.0 M HCl (20 mL). The separated aqueous
layer was extracted with EtOAc (30 mL) and the combined organic
layers were dried over MgSO.sub.4, filtered and the filtrate was
evaporated in vacuo to give the title compound as a white
solid.
[2406] Mass Spectrum (ESI) m/z=460.0 (M+1).
Step B.
(S)-2-((3S,5R,6S)-3-allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3--
methyl-2-oxopiperidin-1-yl)-N-(cyclopropylsulfonyl)butanamide
##STR00528##
[2408] To a stirred solution of
2-((3S,5R,6S)-3-allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-2-ox-
opiperidin-1-yl)butanoic acid (140 mg, 0.304 mmol; Example 177,
Step A) in DMF (2 mL) was added bromotripyrrolidin-1-ylphosphonium
hexafluorophosphate (V) (354 mg, 0.76 mmol) and
N,N-diisopropylethylamine (0.11 mL, 0.61 mmol) and the reaction was
stirred at rt for 3 hours. After this time the reaction was
partitioned between EtOAc (60 mL) and 1.0 M aq. LiCl solution (20
mL). The separated organic layer was dried over MgSO.sub.4,
filtered and evaporated in vacuo. Column chromatography (SiO.sub.2,
hexanes:EtOAc, 1:0 to 1:1) gave the title compound. Mass Spectrum
(ESI) m/z=563.0 (M+1).
Step C.
(S)-2-((3S,5R,6S)-3-allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3--
methyl-2-oxopiperidin-1-yl)-N-(cyclopropylsulfonyl)-N-methylbutanamide
##STR00529##
[2410] To a stirred solution of
(S)-2-((3S,5R,6S)-3-allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl--
2-oxopiperidin-1-yl)-N-(cyclopropylsulfonyl)butanamide (8 mg, 0.014
mmol; Example 177, Step B) in DMF (1.0 mL) was added potassium
carbonate (2.9 mg, 0.021 mmol) and iodomethane (1.1 .mu.L, 0.017
mmol) at rt. The reaction was stirred for 1 hour. After this time
more iodomethane (1.1 .mu.L, 0.017 mmol) and potassium carbonate
(2.9 mg, 0.021 mmol) was added and the reaction was stirred at rt
for 60 hours. After this time the reaction was partitioned between
EtOAc (20 mL) and 1.0 M LiCl (5 mL). The separated organic layer
was washed with 1.0 M LiCl (5 mL), dried over MgSO.sub.4, filtered
and evaporated in vacuo to give the title compound.
[2411] Mass Spectrum (ESI) m/z=577.0 (M+1).
Step D.
2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-1-((S-
)-1-(N-methylcyclopropanesulfonamido)-1-oxobutan-2-yl)-2-oxopiperidin-3-yl-
)acetic acid
[2412] The title compound was prepared from
2-((3S,5R,6S)-3-allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-2-ox-
opiperidin-1-yl)-N-(cyclopropylsulfonyl)-N-methylbutanamide
(Example 177, Step C) by a procedure similar to the one described
in Example 71, Step F.
[2413] .sup.1H NMR (400 MHz, CHLOROFORM-d) .delta. ppm 7.30 (2H, d,
J=8.4 Hz), 7.15-7.25 (4H, m), 6.94 (2H, d, J=7.6 Hz), 4.79-4.93
(2H, m), 3.31 (3H, s), 3.08-3.17 (1H, m), 2.92 (1H, d, J=15.1 Hz),
2.70 (1H, d, J=14.7 Hz), 2.08-2.19 (2H, m), 1.72 (2H, t, J=7.5 Hz),
0.92-1.39 (8H, m), 0.84-0.91 (3H, m). Mass Spectrum (ESI) m/z=595.0
(M+1).
Example 178
2-((3R,5R,6S)-5-(3-Chlorophenyl)-6-(4-chlorophenyl)-3-methyl-1-((S)-1-(neo-
pentylamino)-1-oxobutan-2-yl)-2-oxopiperidin-3-yl)acetic acid
##STR00530##
[2414] Step A.
2-((3S,5R,6S)-3-Allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-2-ox-
opiperidin-1-yl)butanoic acid
##STR00531##
[2416] To a stirred solution of
2-((3S,5R,6S)-3-allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-2-ox-
opiperidin-1-yl)butanoic acid (110 mg, 0.24 mmol; Example 177, Step
A or Example 1, Step F) and DIEA (0.050 ml, 0.287 mmol) in dry DMF
(1195 .mu.L) at 0.degree. C. was added HATU (109 mg, 0.287 mmol).
The reaction was stirred at 0.degree. 5 min, followed by addition
of 2 eq. of neopentyl amine (55.9 .mu.L, 0.478 mmol; TCI America).
The reaction solution was stirred at 0.degree. C. for 10 min until
complete by LCMS, then filtered. Purification of the solution by
reverse phase preparatory HPLC (Sunfire.TM. Prep C18 OBD 10 .mu.m
column (Waters, Milford, Mass.), gradient elution of 70 to 100%
MeCN in water over a 35 min period, where both solvents contain
0.1% TFA) provided the title compounds as an epimeric mixture.
Step B.
2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-1-((S-
)-1-(neopentylamino)-1-oxobutan-2-yl)-2-oxopiperidin-3-yl)acetic
acid
[2417] The title compound was obtained from
2-((3S,5R,6S)-3-allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-2-ox-
opiperidin-1-yl)-N-neopentylbutanamide (88 mg, 0.166 mmol) (Example
178, Step A) by a procedure similar to the one described in Example
71, Step F, followed by purification of the residue by reverse
phase HPLC (eluens: 55% MeCN/water (0.1% TFA), isocratic elution)
using a Sunfire C18 OBD column, 10 uM, (30.times.150 mm), Waters
Corp (Milford, Mass.).
[2418] .sup.1H NMR (500 MHz, CHLOROFORM-d) .delta. ppm 0.79 (t,
J=7.46 Hz, 3H), 0.93 (s, 9H), 1.26 (s, 2H), 1.43 (s, 3H), 1.78
(dquin, J=14.38, 7.29, 7.29, 7.29, 7.29 Hz, 1H), 2.08-2.23 (m, 3H),
2.81 (dd, J=13.20, 5.14 Hz, 1H), 2.88 (s, 2H), 3.09 (dd, J=13.20,
6.60 Hz, 1H), 3.17 (ddd, J=12.78, 9.72, 3.67 Hz, 1H), 3.92 (t,
J=7.34 Hz, 1H), 4.63 (d, J=9.78 Hz, 1H), 6.75 (d, J=7.58 Hz, 1H),
6.94-7.00 (m, 3H), 7.10 (t, J=7.70 Hz, 2H), 7.13-7.24 (m, 3H). Mass
Spectrum (ESI) m/z=547 (M+1).
Example 179
2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-(4,4-dimethyl-
-4,5-dihydrooxazol-2-yl)propyl)-3-methyl-2-oxopiperidin-3-yl)acetic
acid
##STR00532##
[2419] Step A.
2-((3S,5R,6S)-3-allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-2-ox-
opiperidin-1-yl)-N-(1-hydroxy-2-methylpropan-2-yl)butanamide
##STR00533##
[2421] To a solution of
2-((3S,5R,6S)-3-allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-2-ox-
opiperidin-1-yl)-N-(1-hydroxy-2-methylpropan-2-yl)butanamide
(Example 177, Step A) and 5 eq. of 2-amino-2-methylpropan-1-ol (80
.mu.L, 0.836 mmol; Sigma-Aldrich) in DMF (1672 .mu.L) at 0.degree.
C. was added 1.2 eq HATU (76 mg, 0.201 mmol). The reaction solution
was stirred for 1 hour, at which time the reaction was judged to be
complete by LCMS. The reaction mixture was diluted with EtOAc (50
mL) and washed with NaHCO.sub.3 (20 mL), 1N HCl, and water. The
combined organic layers were dried over Na.sub.2SO.sub.4, filtered
and the filtrate was concentrated to give the crude material as a
clear solution (residual DMF present). The product was used in the
next step without further purification.
Step B.
(3S,5R,6S)-3-allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1--
(4,4-dimethyl-4,5-dihydrooxazol-2-yl)propyl)-3-methylpiperidin-2-one
##STR00534##
[2423] To a cold (-78.degree. C.) solution of
2-((3S,5R,6S)-3-allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-2-ox-
opiperidin-1-yl)-N-(1-hydroxy-2-methylpropan-2-yl)butanamide (89
mg, 0.167 mmol; Example 179, Step A: epimeric mixture) in DCM (1674
.mu.L) was added 3 eq. of diethylaminosulfur trifluoride (26.5
.mu.L, 0.201 mmol) dropwise. The reaction mixture was stirred at
-78.degree. C. for 20 min. Anhydrous K.sub.2CO.sub.3 (1.5 equiv)
was then added in one portion and the mixture was allowed to warm
to ambient temperature. The reaction was poured into saturated
aqueous NaHCO.sub.3, and the biphasic mixture was extracted with
EtOAc.times.2. The combined organic extracts were dried over
MgSO.sub.4, filtered, and the filtrate was concentrated under
reduced pressure. Purification of the residue by flash
chromatography on silica gel (eluent: 0 to 20% ethyl
acetate/hexane) provided the title compound.
[2424] .sup.1H NMR (500 MHz, CHLOROFORM-d) .delta. ppm 0.76 (t,
J=7.46 Hz, 3H), 1.08 (s, 3H), 1.15 (s, 3H), 1.24 (s, 3H), 1.67 (s,
1H), 1.82 (dt, J=14.43, 7.21 Hz, 1H), 1.89-1.96 (m, 1H), 2.00-2.11
(m, 1H), 2.21 (dt, J=14.31, 7.27 Hz, 1H), 2.61 (d, J=7.58 Hz, 2H),
3.21 (ddd, J=13.14, 10.09, 3.18 Hz, 1H), 3.64 (d, J=7.83 Hz, 1H),
3.90 (d, J=7.83 Hz, 1H), 4.12 (t, J=6.85 Hz, 1H), 4.54 (d, J=10.27
Hz, 1H), 5.16 (s, 1H), 5.18 (d, J=3.18 Hz, 1H), 5.81-5.93 (m, 1H),
6.75 (d, J=7.58 Hz, 1H), 7.00 (s, 3H), 7.10 (t, J=7.70 Hz, 1H),
7.15 (d, J=8.07 Hz, 1H), 7.20 (d, J=8.31 Hz, 2H). Mass Spectrum
(ESI) m/z=513 (M+1).
[2425] Further elution provided the other epimer:
(3S,5R,6S)-3-allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((R)-1-(4,4-di-
methyl-4,5-dihydrooxazol-2-yl)propyl)-3-methylpiperidin-2-one.
[2426] .sup.1H NMR (500 MHz, CHLOROFORM-d) .delta. ppm 0.96 (t,
J=7.46 Hz, 3H), 1.19 (s, 3H), 1.27 (s, 3H), 1.30 (s, 3H), 1.65 (br.
s., 1H), 1.86-2.06 (m, 4H), 2.60 (qd, J=14.06, 7.70 Hz, 2H), 3.20
(ddd, J=13.27, 10.09, 3.30 Hz, 1H), 3.79-3.89 (m, 2H), 3.89-3.95
(m, 1H), 4.49 (d, J=10.03 Hz, 1H), 5.15 (s, 1H), 5.18 (d, J=3.91
Hz, 1H), 5.82-5.95 (m, 1H), 6.72 (d, J=7.58 Hz, 1H), 6.97 (t,
J=1.83 Hz, 1H), 7.08-7.13 (m, 1H), 7.13-7.23 (m, 3H). Mass Spectrum
(ESI) m/z=513 (M+1).
Step C.
2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-(4,4--
dimethyl-4,5-dihydrooxazol-2-yl)propyl)-3-methyl-2-oxopiperidin-3-yl)aceti-
c acid
[2427] The title compound was obtained from
(3S,5R,6S)-3-allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-(4,4-di-
methyl-4,5-dihydrooxazol-2-yl)propyl)-3-methylpiperidin-2-one (53
mg, 0.103 mmol; Example 179, Step B) by a procedure similar to the
one described in Example 71, Step F.
[2428] .sup.1H NMR (500 MHz, CHLOROFORM-d) .delta. ppm 0.74 (t,
J=7.46 Hz, 3H) 1.08 (s, 3H) 1.14 (s, 3H) 1.41 (s, 3H) 1.74 (dt,
J=14.31, 7.03 Hz, 1H) 2.04-2.12 (m, 1H) 2.12-2.30 (m, 2H) 2.76 (d,
J=14.43 Hz, 1H) 2.88 (d, J=14.18 Hz, 1H) 3.24 (ddd, J=12.59, 9.66,
3.18 Hz, 1H) 3.66 (d, J=8.07 Hz, 1H) 3.88 (d, J=8.07 Hz, 1H) 4.16
(t, J=6.72 Hz, 1H) 4.60 (d, J=9.78 Hz, 1H) 6.78 (d, J=7.58 Hz, 1H)
6.99-7.06 (m, 2H) 7.10 (t, J=7.82 Hz, 2H) 7.14-7.18 (m, 1H) 7.22
(d, J=8.31 Hz, 2H). Mass Spectrum (ESI) m/z=531 (M+1).
Example 180
2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-2-oxo-1-((S)--
1-(N-(2,2,2-trifluoroethyl)acetamido)butan-2-yl)piperidin-3-yl)acetic
acid
##STR00535##
[2429] Step A.
N--((S)-2-((3S,5R,6S)-3-allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-met-
hyl-2-oxopiperidin-1-yl)butyl)-N-(2,2,2-trifluoroethyl)acetamide
##STR00536##
[2431] The title compound was obtained by acetylating
(3S,5R,6S)-3-allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-1-((S)--
1-((2,2,2-trifluoroethyl)amino)butan-2-yl)piperidin-2-one (Example
147, Step A) by a procedure similar to the one described in Example
28, Step C.
Step B.
2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-2-oxo-
-1-((S)-1-(N-(2,2,2-trifluoroethyl)acetamido)butan-2-yl)piperidin-3-yl)ace-
tic acid
[2432] The title compound was obtained from
N--((S)-2-((3S,5R,6S)-3-allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-met-
hyl-2-oxopiperidin-1-yl)butyl)-N-(2,2,2-trifluoroethyl)acetamide
(Example 180, Step A) by a procedure similar to the one described
in Example 71, Step F.
[2433] .sup.1H NMR (400 MHz, CHLOROFORM-d) .delta. ppm 0.52 (t,
J=8.0 Hz, 3H), 1.50 (s, 3H), 1.61 (m, 1H), 1.87 (m, 1H), 1.90-2.40
(m, 3H), 2.27 (s, 3H), 2.77 (d, J=16.0 Hz, 1H), 3.00 (d, J=16.0 Hz,
1H), 3.10-3.30 (m, 2H), 3.43 (m, 1H), 3.85-4.05 (m, 3H), 4.40 (d,
J=8.0 Hz, 1H), 6.71 (d, J=8.0 Hz, 1H), 6.92 (s, 1H), 7.01 (m, 2H),
7.05-7.20 (m, 2H), 7.25 (d, J=8.0 Hz, 2H).
Example 181
2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-(1,1-dimethyl-
ethylsulfonamido)butan-2-yl)-3-methyl-2-oxopiperidin-3-yl)acetic
acid
##STR00537##
[2434] Step A.
N--((S)-2-((3S,5R,6S)-3-allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-met-
hyl-2-oxopiperidin-1-yl)butyl)-2-methylpropane-2-sulfonamide
##STR00538##
[2436] 202.6 mg (0.454 mmol)
(3S,5R,6S)-3-allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-hydroxy-
butan-2-yl)-3-methylpiperidin-2-one (Example 91, Step B) and
2-methylpropane-2-sulfonamide (130 mg, 0.948 mmol, Oakwood) were
dissolved in anhydrous toluene (4.5 mL).
Cyanomethylenetributylphosphorane, 421 mg, was transferred to the
reaction vessel via syringe. An additional ca. 30 mg of the
phosphorane reagent was added 2 minutes after the first addition.
The reaction mixture was stirred between 34-41.degree. C. in a
pre-heated oil bath. The reaction was monitored by LCMS. An
additional 133 mg of t-butyl sulfonamide was added after 2 h 15 min
the reaction mixture was heated at 35.degree. C. overnight.
[2437] On the following day, after 26 h, 15 min total reaction
time, additional 133 mg of t-butyl sulfonamide was added. 30
minutes later, an additional 421 mg of
cyanomethylenetributylphosphorane was added. Heating between 35 to
40.degree. C. was continued overnight.
[2438] On the third day, the reaction appeared complete by LCMS.
After 53 h total reaction time, the mixture was partitioned between
ethyl acetate and saturated ammonium chloride. The aqueous phase
was back extracted 2.times. with EtOAc, washed with sat. aq. NaCl
solution, dried over sodium sulfate, filtered, and the filtrate was
concentrated in vacuo to a residue that was chromatographed on a 24
g silica column, eluting with a gradient of 0 to 30% EtOAc in
hexanes. Fractions containing the desired product by were combined
and concentrated to give the title compound as an off-white solid
that was dried under high vacuum. MS (ESI) m/z=565 [M+H].sup.+.
Step B.
2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-(1,1--
dimethylethylsulfonamido)butan-2-yl)-3-methyl-2-oxopiperidin-3-yl)acetic
acid
[2439]
N--((S)-2-((3S,5R,6S)-3-allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-
-3-methyl-2-oxopiperidin-1-yl)butyl)-2-methylpropane-2-sulfonamide
(100 mg, 0.177 mmol; Example 181, Step A) was transferred to a
round bottom flask containing a stir bar, followed by carbon
tetrachloride (1.100 mL), acetonitrile (1.1 mL), and water (1.6
mL). The flask was then charged with sodium periodate (190 mg,
0.888 mmol) and ruthenium(III) chloride hydrate (6 mg, 0.023 mmol),
and the resulting reddish-brown suspension was stirred vigorously
at ambient temperature. After 18 h reaction time, an additional 200
mg of sodium periodate were added, along with another 2 mg of
ruthenium(III) chloride hydrate. Stirring at ambient temperature
was continued. After 4 h, the reaction was quenched by addition of
1.3 M aq. HCl and diluted with ethyl acetate. The resulting mixture
was filtered. Sat. aq. NaCl solution was added to the aqueous phase
to promote phase separation. Combined organics were washed with
sat. aq. NaCl solution, dried over sodium sulfate, filtered, and
the filtrate was concentrated in vacuo. The resulting residue was
chromatographed on a Sunfire.TM. reverse-phase prep HPLC column
(Waters, Milford, Mass.), eluting with a gradient of 50 to 95% MeCN
in water (0.1% TFA in both solvents) over the course of 35 minutes.
Fractions containing the desired product in high purity by HPLC
were combined, stripped of volatiles on the rotary evaporator, and
lyophilized to provide the title compound as an off-white
solid.
[2440] .sup.1H NMR (500 MHz, CD.sub.3OD) .delta. 0.46 (t, J=7.58
Hz, 3H), 1.30-1.42 (m, 9H), 1.45 (s, 3H), 1.52-1.66 (m, 1H),
1.75-1.89 (m, 1H), 1.96-2.10 (m, 1H), 2.33-2.49 (m, 1H), 2.64 (d,
J=13.45 Hz, 1H), 2.72-2.83 (m, 1H), 2.88-2.97 (m, 1H), 2.97-3.07
(m, 1H), 3.32-3.40 (m, 1H), 3.86-4.05 (m, 1H), 4.94-5.05 (m, 1H),
6.79-7.45 (m, 8H). MS (ESI) m/z=583 [M+H].sup.+.
Example 182
2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-(N,2-dimethyl-
propan-2-ylsulfonamido)butan-2-yl)-3-methyl-2-oxopiperidin-3-yl)acetic
acid
##STR00539##
[2441] Step A.
N--((S)-2-((3S,5R,6S)-3-allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-met-
hyl-2-oxopiperidin-1-yl)butyl)-N,2-dimethylpropane-2-sulfonamide
##STR00540##
[2443]
N--((S)-2-((3S,5R,6S)-3-allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-
-3-methyl-2-oxopiperidin-1-yl)butyl)-2-methylpropane-2-sulfonamide
(100 mg, 0.177 mmol; Example 181, Step A) was dissolved in DMF (2.5
mL), and sodium hydride (60% dispersion in mineral oil, 19 mg, 0.45
mmol) was added in a single portion. After 25 minutes, this mixture
was cooled to 0.degree. C. in an ice-water bath, and iodomethane
(0.04 mL, 0.643 mmol) was added dropwise by syringe. The mixture
was allowed to gradually warm to ambient temperature, gradually
becoming a pale yellow suspension. After 2 h water (2 mL) was added
very carefully. The resulting mixture was partitioned between ethyl
acetate and saturated aq. NH.sub.4Cl solution. The aqueous phase
was back-extracted (2.times.) and the combined organics were washed
with sat. aq. NaCl solution (2.times.), dried over sodium sulfate,
filtered, and the filtrate was concentrated in vacuo to an oily
residue that was chromatographed on a 12 g silica column, eluting
with a gradient of 0 to 35% EtOAc in hexanes. Fractions containing
the sulfonamide product were pooled and concentrated to give the
title compound. MS (ESI) m/z=579 [M+H].sup.+.
Step B.
2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-(N,2--
dimethylpropan-2-ylsulfonamido)butan-2-yl)-3-methyl-2-oxopiperidin-3-yl)ac-
etic acid
[2444] The compound was prepared from
N--((S)-2-((3S,5R,6S)-3-allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-met-
hyl-2-oxopiperidin-1-yl)butyl)-N,2-dimethylpropane-2-sulfonamide
(Example 182, Step A) by a procedure similar to the one described
in Example 181, Step B. The crude material obtained was taken up in
methanol, filtered, and purified by reversed phase HPLC on a
Sunfire.TM. reverse phase prep HPLC column (Waters, Milford,
Mass.), eluting with a gradient of 50 to 100% MeCN in water (0.1%
TFA in both solvents). Volatiles were removed and the suspension
was re-dissolved with minimal MeCN, frozen, and lyophilized to give
the title compound as an off-white solid.
[2445] .sup.1H NMR (500 MHz, CD.sub.3OD) .delta. 0.51 (t, J=7.21
Hz, 3H), 1.32-1.48 (m, 12H), 1.58-1.71 (m, 1H), 1.78-1.92 (m, 1H),
1.94-2.06 (m, 1H), 2.43 (t, J=13.69 Hz, 1H), 2.63 (d, J=13.20 Hz,
1H), 2.71-2.88 (m, 2H), 2.88-3.01 (m, 4H), 3.28 (d, J=2.93 Hz, O
H), 3.32-3.35 (m, 1H), 4.40 (br. s., 1H), 4.79 (d, J=10.76 Hz, 1H),
6.96-7.09 (m, 3H), 7.10-7.40 (m, 5H). MS (ESI) m/z=597
[M+H].sup.+.
Example 183
2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-1-((S)-1-(1-m-
ethylethylsulfonamido)butan-2-yl)-2-oxopiperidin-3-yl)acetic
acid
##STR00541##
[2446] Step A.
N--((S)-2-((3S,5R,6S)-3-allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-met-
hyl-2-oxopiperidin-1-yl)butyl)propane-2-sulfonamide
##STR00542##
[2448] The title compound was prepared from
(3S,5R,6S)-3-allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-hydroxy-
butan-2-yl)-3-methylpiperidin-2-one (Example 91, Step B) and
propane-2-sulfonamide as described in Example 181, Step A. MS (ESI)
m/z=551 [M+H].sup.+.
Step B.
2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-1-((S-
)-1-(1-methylethylsulfonamido)butan-2-yl)-2-oxopiperidin-3-yl)acetic
acid
[2449] The title compound was obtained from
N--((S)-2-((3S,5R,6S)-3-allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-met-
hyl-2-oxopiperidin-1-yl)butyl)propane-2-sulfonamide (Example 183,
Step A) by a procedure similar to the one described in Example 181,
Step B. The residue was purified by reversed phase HPLC on a
Sunfire.TM. reverse phase prep HPLC column (Waters, Milford,
Mass.), eluting with a gradient of 50 to 100% MeCN in water (0.1%
TFA in both solvents). Chromatography fractions were combined and
concentrated in vacuo. The resulting suspension was made
homogeneous by addition of minimal MeCN, frozen, and lyophilized to
give the title compound.
[2450] .sup.1H NMR (500 MHz, CD.sub.3OD) .delta. 0.45 (t, J=7.58
Hz, 3H), 1.35 (dd, J=8.56, 6.85 Hz, 6H), 1.41 (br. s., 3H),
1.51-1.64 (m, 1H), 1.83 (ddd, J=14.43, 8.56, 7.34 Hz, 1H), 2.05
(dd, J=13.69, 2.93 Hz, 1H), 2.39 (t, J=13.69 Hz, 1H), 2.64 (d,
J=13.45 Hz, 1H), 2.80 (t, J=9.29 Hz, 1H), 2.87-3.04 (m, 2H), 3.23
(dt, J=13.51, 6.82 Hz, 1H), 3.33-3.40 (m, 1H), 3.85 (dd, J=14.06,
10.15 Hz, 1H), 4.96 (d, J=11.00 Hz, 1H), 6.36-7.71 (m, 8H). MS
(ESI) m/z=569 [M+H].sup.+.
Example 184
2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-(N-ethylpropa-
n-2-ylsulfonamido)butan-2-yl)-3-methyl-2-oxopiperidin-3-yl)acetic
acid
##STR00543##
[2451] Step A.
N--((S)-2-((3S,5R,6S)-3-allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-met-
hyl-2-oxopiperidin-1-yl)butyl)-N-ethylpropane-2-sulfonamide
##STR00544##
[2453] The title compound was prepared from
N--((S)-2-((3S,5R,6S)-3-allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-met-
hyl-2-oxopiperidin-1-yl)butyl)propane-2-sulfonamide (Example 183,
Step A) by a procedure similar to the one described in Example 182,
Step A, replacing iodomethane with iodoethane. MS (ESI) m/z=579
[M+H].sup.+.
Step B.
2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-(N-et-
hylpropan-2-ylsulfonamido)butan-2-yl)-3-methyl-2-oxopiperidin-3-yl)acetic
acid
[2454] The title compound was prepared from
N--((S)-2-((3S,5R,6S)-3-allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-met-
hyl-2-oxopiperidin-1-yl)butyl)-N-ethylpropane-2-sulfonamide
(Example 184, Step A) by a procedure similar to the one described
in Example 71, Step F. The residue was chromatographed on a
Sunfire.TM. C18 reverse phase prep HPLC column (Waters, Milford,
Mass.), eluting with a gradient of 50 to 100% MeCN in water (0.1%
TFA in both solvents). Fractions containing the product in high
purity by HPLC were combined and stripped of volatiles on the
rotary evaporator. The suspension was re-dissolved in minimal MeCN,
frozen, and lyophilized overnight to give the title compound as a
white foam.
[2455] .sup.1H NMR (500 MHz, CD.sub.3OD) .delta. 0.52 (t, J=7.21
Hz, 3H), 1.09-1.20 (m, 3H), 1.30 (d, J=6.85 Hz, 3H), 1.38 (d,
J=6.85 Hz, 3H), 1.43 (s, 3H), 1.56-1.69 (m, 1H), 1.82-1.97 (m, 1H),
2.01 (dd, J=13.69, 2.93 Hz, 1H), 2.41 (t, J=13.69 Hz, 1H), 2.64 (d,
J=13.20 Hz, 1H), 2.82 (br. s., 1H), 2.88-3.02 (m, 2H), 3.15-3.25
(m, 1H), 3.28 (d, J=3.18 Hz, 1H), 3.33-3.36 (m, 1H), 3.40-3.55 (m,
1H), 4.29 (d, J=6.36 Hz, 1H), 4.84 (br. d, J=1.00 Hz, 1H),
6.81-7.55 (m, 8H). MS (ESI) m/z=597 [M+H].sup.+.
Example 185
2-((3R,5R,6S)-5-(3-Chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-hydroxybutan--
2-yl)-3-methyl-2-oxopiperidin-3-yl)acetic acid
##STR00545##
[2456] Step A. (S)-Methyl
2-((2S,3R)-3-(3-chlorophenyl)-2-(4-chlorophenyl)-6-oxopiperidin-1-yl)buta-
noate
##STR00546##
[2458] To a 50.degree. C. solution of 33.8 g (60% in mineral oil,
845 mmol) of sodium hydride in 2-methyltetrahydrofuran (550 mL) was
added a solution of 240 g (750 mmol) of
(5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)piperidin-2-one
(Example 1, Step E) in 2-methyltetrahydrofuran (550 mL) over a
period of 45 min. After an additional 1.25 h at 50.degree. C., 105
mL (912 mmol) of methyl 2-bromobutyrate was added over a 20 min
period. The resulting slurry was stirred at 50.degree. C. for 3.5
h, and then was cooled to room temperature and quenched with
saturated aq. NH.sub.4Cl solution. Water was added to dissolve the
precipitate and the resulting mixture was extracted with ethyl
acetate (4.times.). The combined organic layers were washed with
sat. aq. NaCl solution (1.times.), dried over Na.sub.2SO.sub.4,
filtered and the filtrate was concentrated. Purification of the
residue by chromatography on silica gel (Biotage.RTM. Snap.TM.
column (Biotage, LLC, Charlotte, N.C.), 0 to 35% EtOAc/DCM,
gradient elution) provided the title compound as a white oily
solid.
Step B.
(5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-hydroxybuta-
n-2-yl)piperidin-2-one
##STR00547##
[2460] To an ice-cooled solution of 48.5 g (115 mmol) of (S)-methyl
2-((2S,3R)-3-(3-chlorophenyl)-2-(4-chlorophenyl)-6-oxopiperidin-1-yl)buta-
noate (Example 185, Step A) in ethyl ether (850 mL) was added 5.96
g (90%, 246 mmol) of lithium borohydride. The resulting light
yellow solution was stirred at 0.degree. C. for 3 h, and then MeOH
(2.5 mL) and more ethyl ether (100 mL) were added. Gas evolution
was observed upon the addition of MeOH. After 40 min, the reaction
was quenched by cautious addition of 1 N HCl until bubbling
subsided. The mixture was extracted with EtOAc (2.times.), and the
combined organic layers were washed with saturated aqueous sodium
chloride (1.times.). The organic layer was dried over
Na.sub.2SO.sub.4, filtered and the filtrate was concentrated to
afford the title compound as a white foam. The crude product was
used directly in the next step without further purification.
Step C.
(5R,6S)-1-((S)-1-(tert-butyldiphenylsilyloxy)butan-2-yl)-5-(3-chlo-
rophenyl)-6-(4-chlorophenyl)piperidin-2-one
##STR00548##
[2462] To a solution of 44.7 g (114 mmol) of
(5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-hydroxybutan-2-yl)-
piperidin-2-one (Example 185, Step B) and 19.4 g (285 mmol) of
imidazole in DMF (350 mL) was added 39.4 mL (154 mmol) of
tert-butyldiphenylsilyl chloride. The colorless solution was
stirred at room temperature for 17 h. The reaction was partitioned
between water and ethyl ether (3.times.), and then the combined
organic layers were washed with saturated aqueous sodium chloride
(1.times.), dried over Na.sub.2SO.sub.4, filtered and the filtrate
was concentrated. Purification of the residue by chromatography on
silica gel (Biotage.RTM. Snap.TM. column (Biotage, LLC, Charlotte,
N.C.), 0 to 60% EtOAc/hexanes, gradient elution) provided the title
compound as a white foam.
Step D.
(5R,6S)-1-((S)-1-(tert-Butyldiphenylsilyloxy)butan-2-yl)-5-(3-chlo-
rophenyl)-6-(4-chlorophenyl)-3-methylpiperidin-2-one
##STR00549##
[2464] To a -78.degree. C. solution of 98.2 g (156 mmol) of
(5R,6S)-1-((S)-1-(tert-butyldiphenylsilyloxy)butan-2-yl)-5-(3-chloropheny-
l)-6-(4-chlorophenyl)piperidin-2-one (Example 185, Step C) and 10.0
mL (160 mmol) of methyl iodide in dry, degassed THF (400 mL) was
added 200 mL (200 mmol) of a degassed 1 M solution of lithium
bis(trimethylsilyl)amide in THF slowly over 20 min. The orange
solution was stirred at -78.degree. C. for 1.5 h and then warmed to
0.degree. C. and stirred for an additional 1.5 h. The reaction was
quenched with saturated aqueous ammonium chloride, and extracted
with EtOAc (3.times.). The combined organic layers were dried over
Na.sub.2SO.sub.4, filtered and the filtrate was concentrated.
Purification of the residue by chromatography on silica gel
(Biotage.RTM. Snap.TM. column; Biotage, LLC, Charlotte, N.C.),
5-55% EtOAc/hexanes, gradient elution) provided the title compound
as a light yellow foam.
Step E.
(3S,5R,6S)-3-allyl-1-((S)-1-(tert-butyldiphenylsilyloxy)butan-2-yl-
)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methylpiperidin-2-one
##STR00550##
[2466] To a -78.degree. C. solution of 37.3 mL (266 mmol) of
diisopropylamine in dry, degassed THF (150 mL) was added 100 mL
(250 mmol) of a degassed 2.5 M solution of n-butyllithium in
hexanes slowly via cannula. The light yellow solution was stirred
at -78.degree. C. for 15 min, then was warmed to 0.degree. C. and
stirred for an additional 5 min. To the ice-cooled LDA solution was
added a solution of 85.7 g (133 mmol) of
(5R,6S)-1-((S)-1-(tert-butyldiphenylsilyloxy)butan-2-yl)-5-(3-ch-
lorophenyl)-6-(4-chlorophenyl)-3-methylpiperidin-2-one (Example
185, Step D) in dry, degassed THF (210 mL) via cannula over a 15
min period. The dark orange solution was stirred at 0.degree. C.
for 30 min and then 34.5 mL (399 mmol) of allyl bromide was added
quickly via syringe. After 20 sec, the ice bath was removed and the
reaction was placed in a room temperature water bath and stirred
for an additional 15 min. The reaction was quenched with saturated
aq. ammonium chloride, and extracted with EtOAc (3.times.). The
combined organic layers were dried over Na.sub.2SO.sub.4, filtered
and the filtrate was concentrated. Purification of the residue by
chromatography on silica gel (Biotage.RTM. Snap.TM. column;
Biotage, LLC, Charlotte, N.C.), 6-14% EtOAc/hexanes, gradient
elution) provided the title compound as a white foam.
Step F.
2-((3R,5R,6S)-1-((S)-1-(tert-butyldiphenylsilyloxy)butan-2-yl)-5-(-
3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-2-oxopiperidin-3-yl)acetic
acid
##STR00551##
[2468] The title compound was prepared from
(3S,5R,6S)-3-allyl-1-((S)-1-(tert-butyldiphenylsilyloxy)butan-2-yl)-5-(3--
chlorophenyl)-6-(4-chlorophenyl)-3-methylpiperidin-2-one (Example
185, Step E) by a procedure similar to the one described in Example
71, Step F.
[2469] .sup.1H NMR (400 MHz, CHLOROFORM-d) .delta. ppm 0.30 (t,
J=7.53 Hz, 3H) 1.17 (s, 9H) 1.34-1.48 (m, 1H) 1.53 (s, 3H)
1.74-1.88 (m, 1H) 1.93-2.03 (m, 1H) 2.29 (t, J=13.69 Hz, 1H) 2.69
(d, J=15.85 Hz, 1H) 2.81-2.93 (m, 1H) 2.98-3.08 (m, 1H) 3.12 (d,
J=15.65 Hz, 1H) 3.52 (dd, J=10.66, 4.21 Hz, 1H) 4.32 (t, J=10.27
Hz, 1H) 4.71 (d, J=10.76 Hz, 1H) 6.56-6.66 (m, 1H) 6.91-6.97 (m,
1H) 7.02-7.09 (m, 1H) 7.12-7.18 (m, 1H) 7.20-7.30 (m, 4H) 7.33-7.51
(m, 6H) 7.64 (td, J=7.83, 1.57 Hz, 4H).
Step G.
2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-hydro-
xybutan-2-yl)-3-methyl-2-oxopiperidin-3-yl)acetic acid
[2470] To an ice-cooled solution of 370 g (0.53 mmol) of
2-((3R,5R,6S)-1-((S)-1-(tert-butyldiphenylsilyloxy)butan-2-yl)-5-(3-chlor-
ophenyl)-6-(4-chlorophenyl)-3-methyl-2-oxopiperidin-3-yl)acetic
acid (Example 185, Step F) in THF (15 mL) was added 2.60 mL (2.60
mmol) of a 1 M solution of TBAF in THF. The yellow solution was
warmed to rt and stirred for 5 h. At this time 2.60 mL (2.60 mmol)
of a 1 M solution of TBAF in THF was added and the reaction was
stirred for an additional 20 h. The reaction was partitioned
between 1 N HCl and EtOAc (4.times.). The combined organic layers
were dried over Na.sub.2SO.sub.4, filtered and the filtrate was
concentrated. The residue was purified by reverse phase prep. HPLC
(Sunfire.TM. Prep C.sub.18 OBD 10 .mu.m column (Waters, Milford,
Mass.), gradient elution of 40% MeCN in water to 80% MeCN in water
over a 30 min period, where both solvents contain 0.1% TFA)
provided the title compound as a white solid.
[2471] .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. ppm 7.23-7.28 (2H,
m), 7.15-7.20 (1H, m), 7.07-7.14 (1H, m), 6.98-7.06 (3H, m), 6.74
(1H, d, J=7.1 Hz), 4.55 (1H, dd J=9.8 Hz, 2.9 Hz), 3.71-3.79 (1H,
m), 3.58-3.66 (1H, m), 3.19-3.28 (1H, m), 3.07-3.16 (1H, m),
2.96-3.03 (1H, m), 2.75 (1H, dd, J=14.9 Hz, 2.9 Hz), 2.16-2.25 (1H,
m), 2.03-2.10 (1H, m), 1.87-1.98 (1H, m), 1.46 (3H, s), 1.41-1.54
(m, 1H), 0.63 (3H, dd, J=7.3 Hz, 3.3 Hz). Mass Spectrum (ESI)
m/z=464.1 (M+1).
Example 186
2-((3R,5R,6S)-5-(3-Chlorophenyl)-6-(4-chlorophenyl)-3-methyl-2-oxo-1-((S)--
1-(trifluoromethylsulfonamido)butan-2-yl)piperidin-3-yl)acetic
acid
##STR00552##
[2472] Step A. Methyl
2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-hydroxybutan-
-2-yl)-3-methyl-2-oxopiperidin-3-yl)acetate
##STR00553##
[2474] A solution of
2-((3R,5R,6S)-1-((S)-1-(tert-butyldiphenylsilyloxy)butan-2-yl)-5-(3-chlor-
ophenyl)-6-(4-chlorophenyl)-3-methyl-2-oxopiperidin-3-yl)acetic
acid (Example 185) in MeOH (2 mL) and benzene (8 mL) was stirred
with (trimethylsilyl)diazomethane, 2.0 M in diethyl ether (2.02 mL,
4.04 mmol) at rt for 0.5 h. After that time the mixture was
concentrated to give the crude methyl ester, which was treated with
TBAF in THF at rt for 30 h. The mixture was concentrated and
purified by chromatography on silica gel (0 to 100% EtOAc in
hexanes) to give the title compound. Mass Spectrum (ESI) m/z=478
(M+1).
Step B.
2-((3R,5R,6S)-5-(3-Chlorophenyl)-6-(4-chlorophenyl)-3-methyl-2-oxo-
-1-((S)-1-(trifluoromethylsulfonamido)butan-2-yl)piperidin-3-yl)acetic
acid
[2475] A reaction vial under argon was charged with methyl
2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-hydroxybutan-
-2-yl)-3-methyl-2-oxopiperidin-3-yl)acetate (0.048 g, 0.1 mmol;
Example 186, Step A), 2-(tributylphosphoranylidene)acetonitrile
(0.036 g, 0.15 mmol) and trifluoromethanesulfonamide (0.022 g, 0.15
mmol) in toluene (0.5 mL). The reaction mixture in the reaction
vial was sealed and stirred at 110.degree. C. for 1 h. Column
chromatography on silica gel gave a mixture of methyl
2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-2-oxo-1-((S)-
-1-(trifluoromethylsulfonamido)butan-2-yl)piperidin-3-yl)acetate
with an unknown impurity. This mixture was hydrolyzed with LiOH (1N
solution in water, 0.3 mL) in ethanol (0.5 mL) for 3 h at rt. HPLC
purification (C18 column, eluted with 10 to 95% CH.sub.3CN in
water, with 0.1% TFA) gave the title compound.
[2476] .sup.1H NMR (500 MHz, CHLOROFORM-d) .delta. ppm 7.26 (2H,
br. s.), 7.15-7.20 (1H, m), 7.12 (1H, t, J=7.8 Hz), 7.05 (1H, d,
J=9.3 Hz), 6.95 (1H, t, J=1.7 Hz), 6.75 (1H, d, J=7.6 Hz), 6.49
(1H, br. s.), 4.53 (1H, d, J=10.3 Hz), 3.13-3.27 (3H, m), 2.80-2.93
(3H, m), 2.24 (1H, t, J=13.8 Hz), 2.10 (1H, dd, J=14.1, 3.1 Hz),
1.83 (1H, br. s.), 1.55-1.66 (1H, m), 1.49 (3H, s), 0.71 (3H, br.
s.). Mass Spectrum (ESI) m/z=595 (M+1).
[2477] EXAMPLES 187-195 were, unless noted otherwise, prepared from
methyl
2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-hydroxybutan-
-2-yl)-3-methyl-2-oxopiperidin-3-yl)acetate (Example 186, Step A)
by procedures similar to the one described in Example 186, Step B,
replacing trifluoromethanesulfonamide with the appropriate
reagent.
TABLE-US-00008 ##STR00554## Example R Reagent used 187 ##STR00555##
4-Chlorobenzene- sulfonamide 188 ##STR00556## 4-Methylbenzene-
sulfonamide 189 ##STR00557## 2-Chlorobenzene- sulfonamide 190
##STR00558## 2-Methylbenzene- sulfonamide 191 ##STR00559##
4-Methoxybenzene- sulfonamide 192 ##STR00560## Benzenesulfonamide
193 ##STR00561## 1-Methylcyclopropane- 1-sulfonamide 194
##STR00562## 2,3-Dihydro-1,1-dioxo- 1,2-benzisothiazole 195
##STR00563## 2,3-Dihydro-3,3- dimethyl-1,2- benzisothiazole
1,1-dioxide
Example 187
2-((3R,5R,6S)-5-(3-Chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-(4-chlorophen-
ylsulfonamido)butan-2-yl)-3-methyl-2-oxopiperidin-3-yl)acetic
acid
[2478] .sup.1H NMR (500 MHz, CHLOROFORM-d) .delta. ppm 7.77 (2H, m,
J=8.6 Hz), 7.48-7.54 (2H, m), 7.23 (2H, d, J=8.1 Hz), 7.11-7.19
(2H, m), 7.05 (2H, d, J=5.9 Hz), 6.98 (1H, s), 6.86 (1H, d, J=7.3
Hz), 5.31 (2H, br. s.), 5.26 (3H, br. s.), 4.78 (1H, d, J=10.3 Hz),
3.43 (1H, br. s.), 3.17 (2H, ddd, J=13.5, 10.7, 2.9 Hz), 2.97 (1H,
d, J=14.4 Hz), 2.79 (1H, d, J=14.4 Hz), 2.74 (1H, d, J=13.7 Hz),
2.38 (1H, t, J=13.8 Hz), 2.05 (1H, dd, J=13.9, 2.9 Hz), 1.80 (1H,
dt, J=14.6, 7.5 Hz), 1.52 (3H, s), 1.43-1.50 (1H, m), 0.51 (3H, t,
J=7.1 Hz). Mass Spectrum (ESI) m/z=637 (M+1).
Example 188
2-((3R,5R,6S)-5-(3-Chlorophenyl)-6-(4-chlorophenyl)-3-methyl-1-((S)-1-(4-m-
ethylphenylsulfonamido)butan-2-yl)-2-oxopiperidin-3-yl)acetic
acid
[2479] .sup.1H NMR (500 MHz, CHLOROFORM-d) .delta. ppm 7.72 (2H, m,
J=8.3 Hz), 7.33 (2H, m, J=8.1 Hz), 7.23 (2H, d, J=8.1 Hz),
7.11-7.19 (2H, m), 7.05 (2H, d, J=6.6 Hz), 6.96-6.99 (1H, m),
6.85-6.91 (1H, m), 4.95 (1H, br. s.), 4.83 (1H, d, J=10.5 Hz), 3.49
(1H, br. s.), 3.14 (2H, ddd, J=13.4, 10.6, 2.8 Hz), 3.02 (1H, d,
J=14.9 Hz), 2.70-2.81 (2H, m), 2.45 (3H, s), 2.36-2.44 (1H, m),
2.01 (1H, dd, J=13.9, 2.9 Hz), 1.81 (1H, dd, J=15.3, 7.5 Hz), 1.53
(3H, s), 1.47 (1H, ddd, J=14.2, 7.6, 4.3 Hz), 0.47 (3H, t, J=7.5
Hz). Mass Spectrum (ESI) m/z=617 (M+1).
Example 189
2-((3R,5R,6S)-5-(3-Chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-(2-chlorophen-
ylsulfonamido)butan-2-yl)-3-methyl-2-oxopiperidin-3-yl)acetic
acid
[2480] .sup.1H NMR (500 MHz, CHLOROFORM-d) .delta. ppm 7.77 (2H, m,
J=8.6 Hz), 7.48-7.54 (2H, m), 7.23 (2H, d, J=8.1 Hz), 7.11-7.19
(2H, m), 7.05 (2H, d, J=5.9 Hz), 6.98 (1H, s), 6.86 (1H, d, J=7.3
Hz), 5.31 (2H, br. s.), 5.26 (3H, br. s.), 4.78 (1H, d, J=10.3 Hz),
3.43 (1H, br. s.), 3.17 (2H, ddd, J=13.5, 10.7, 2.9 Hz), 2.97 (1H,
d, J=14.4 Hz), 2.79 (1H, d, J=14.4 Hz), 2.74 (1H, d, J=13.7 Hz),
2.38 (1H, t, J=13.8 Hz), 2.05 (1H, dd, J=13.9, 2.9 Hz), 1.80 (1H,
dt, J=14.6, 7.5 Hz), 1.52 (3H, s), 1.43-1.50 (1H, m), 0.51 (3H, t,
J=7.1 Hz). Mass Spectrum (ESI) m/z=651 (M+1).
Example 190
2-((3R,5R,6S)-5-(3-Chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-(2-methylphen-
ylsulfonamido)butan-2-yl)-3-methyl-2-oxopiperidin-3-yl)acetic
acid
[2481] .sup.1H NMR (500 MHz, CHLOROFORM-d) .delta. ppm 7.89 (1H, d,
J=7.8 Hz), 7.46-7.52 (1H, m), 7.31-7.38 (2H, m), 7.23 (2H, d, J=7.8
Hz), 7.12-7.18 (2H, m), 7.06 (2H, br. s.), 6.99 (1H, s), 6.88 (1H,
d, J=7.1 Hz), 5.16 (1H, br. s.), 4.85 (1H, d, J=10.5 Hz), 4.46 (3H,
br. s.), 3.44 (1H, br. s.), 3.11-3.22 (2H, m), 2.99 (1H, d, J=14.9
Hz), 2.73-2.84 (2H, m), 2.67 (3H, s), 2.36-2.47 (1H, m), 2.04 (1H,
dd, J=13.9, 2.9 Hz), 1.80 (1H, dt, J=14.7, 7.7 Hz), 1.53 (3H, s),
1.45 (1H, ddd, J=14.1, 7.6, 4.4 Hz), 0.46 (3H, t, J=7.5 Hz). Mass
Spectrum (ESI) m/z=617 (M+1).
Example 191
2-((3R,5R,6S)-5-(3-Chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-(4-methoxyphe-
nylsulfonamido)butan-2-yl)-3-methyl-2-oxopiperidin-3-yl)acetic
acid
[2482] .sup.1H NMR (500 MHz, CHLOROFORM-d) .delta. ppm 7.76 (2H, d,
J=8.8 Hz), 7.24 (2H, d, J=7.8 Hz), 7.11-7.19 (2H, m), 7.04 (1H, br.
s.), 7.01 (1H, s), 6.98 (2H, d, J=4.4 Hz), 6.88 (1H, d, J=6.8 Hz),
4.92 (1H, br. s.), 4.83 (1H, d, J=10.5 Hz), 4.03 (3H, br. s.), 3.89
(3H, s), 3.49 (1H, br. s.), 3.14 (2H, t, J=10.8 Hz), 3.02 (1H, d,
J=14.9 Hz), 2.69-2.80 (2H, m), 2.42 (1H, t, J=13.8 Hz), 1.97-2.05
(1H, m), 1.82 (1H, dt, J=14.6, 7.5 Hz), 1.53 (3H, s), 1.41-1.50
(1H, m), 0.47 (3H, t, J=7.3 Hz). Mass Spectrum (ESI) m/z=633
(M+1).
Example 192
2-((3R,5R,6S)-5-(3-Chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-(phenylsulfon-
amido)butan-2-yl)-3-methyl-2-oxopiperidin-3-yl)acetic acid
[2483] .sup.1H NMR (500 MHz, CHLOROFORM-d) .delta. ppm 7.84 (2H, d,
J=7.3 Hz), 7.62 (1H, t, J=7.3 Hz), 7.55 (2H, t, J=7.7 Hz), 7.24
(2H, d, J=8.1 Hz), 7.12-7.19 (2H, m), 7.05 (2H, d, J=6.6 Hz), 6.98
(1H, s), 6.87 (1H, d, J=6.8 Hz), 5.03 (1H, br. s.), 4.82 (1H, d,
J=10.5 Hz), 4.01 (2H, br. s.), 3.49 (1H, br. s.), 3.09-3.21 (2H,
m), 3.02 (1H, d, J=14.9 Hz), 2.77 (2H, d, J=14.7 Hz), 2.41 (1H, t,
J=13.8 Hz), 2.02 (1H, dd, J=13.9, 2.7 Hz), 1.82 (1H, dt, J=14.9,
7.6 Hz), 1.53 (3H, s), 1.48 (1H, ddd, J=14.2, 7.7, 4.5 Hz), 0.49
(3H, t, J=7.5 Hz). Mass Spectrum (ESI) m/z=603 (M+1).
Example 193
2-((3R,5R,6S)-5-(3-Chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-(1-methylcycl-
opropanesulfonamido)butan-2-yl)-3-methyl-2-oxopiperidin-3-yl)acetic
acid
[2484] .sup.1H NMR (500 MHz, CHLOROFORM-d) .delta. ppm 7.24 (2H, d,
J=7.8 Hz), 7.10-7.17 (2H, m), 7.03 (1H, s), 7.06 (1H, s), 6.95-6.97
(1H, m), 6.84-6.89 (1H, m), 4.88 (2H, br. s.), 4.81 (2H, d, J=10.5
Hz), 4.71 (1H, br. s.), 3.71 (1H, br. s.), 3.03-3.18 (3H, m),
2.96-3.02 (1H, m), 2.76 (1H, d, J=14.7 Hz), 2.40 (1H, t, J=13.8
Hz), 1.98 (1H, dd, J=13.9, 2.9 Hz), 1.88 (1H, dt, J=15.0, 7.5 Hz),
1.52 (3H, s), 1.50 (3H, s), 1.45-1.49 (1H, m), 1.33-1.43 (2H, m),
0.77-0.86 (2H, m), 0.52 (3H, t, J=7.5 Hz). Mass Spectrum (ESI)
m/z=581 (M+1).
Example 194
2-((3R,5R,6S)-5-(3-Chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-(1,1-dioxidob-
enzo[d]isothiazol-2(3H)-yl)butan-2-yl)-3-methyl-2-oxopiperidin-3-yl)acetic
acid
[2485] .sup.1H NMR (500 MHz, CHLOROFORM-d) .delta. ppm 7.91 (1H, d,
J=7.6 Hz), 7.66-7.72 (1H, m), 7.60-7.65 (1H, m), 7.43 (1H, d, J=7.6
Hz), 7.25 (1H, br. s.), 7.06-7.11 (1H, m), 6.95-7.06 (3H, m), 6.87
(1H, s), 6.71 (1H, d, J=7.6 Hz), 4.86 (1H, d, J=10.3 Hz), 4.36-4.47
(2H, m), 4.20 (1H, dd, J=14.2, 10.5 Hz), 4.03 (5H, br. s.), 3.24
(1H, dd, J=14.7, 3.4 Hz), 3.01-3.15 (3H, m), 2.74 (1H, d, J=14.9
Hz), 2.32 (1H, t, J=13.8 Hz), 1.95-2.07 (1H, m), 1.90 (1H, dd,
J=13.8, 2.8 Hz), 1.53 (1H, ddd, J=10.7, 7.4, 3.9 Hz), 1.49 (3H, s),
0.53 (3H, t, J=7.5 Hz). Mass Spectrum (ESI) m/z=615 (M+1).
Example 195
2-((3R,5R,6S)-5-(3-Chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-(3,3-dimethyl-
-1,1-dioxidobenzo[d]isothiazol-2(3H)-yl)butan-2-yl)-3-methyl-2-oxopiperidi-
n-3-yl)acetic acid
[2486] .sup.1H NMR (500 MHz, CHLOROFORM-d) .delta. ppm 7.88 (1H, d,
J=7.6 Hz), 7.68-7.74 (1H, m), 7.58-7.64 (1H, m), 7.45 (1H, d, J=7.8
Hz), 7.25 (1H, br. s.), 7.02-7.12 (3H, m), 6.99 (1H, t, J=7.8 Hz),
6.94 (1H, s), 6.75 (1H, d, J=7.6 Hz), 5.02 (1H, d, J=10.0 Hz), 4.24
(1H, dd, J=14.8, 10.6 Hz), 3.15 (2H, d, J=13.0 Hz), 3.03-3.13 (3H,
m), 2.92 (8H, br. s.), 2.71 (1H, d, J=15.4 Hz), 2.36 (1H, t, J=13.6
Hz), 2.06-2.19 (1H, m), 1.90 (1H, dd, J=13.8, 3.1 Hz), 1.57 (3H,
s), 1.48-1.52 (4H, m), 1.47 (3H, s), 0.51 (3H, t, J=7.5 Hz). Mass
Spectrum (ESI) m/z=643 (M+1).
Example 196
2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-2-oxo-1-((S)--
1-(pyridine-3-sulfonamido)butan-2-yl)piperidin-3-yl)acetic acid, as
the 2,2,2-trifluoroacetic acid salt
##STR00564##
[2487] Step A. Methyl
2-((3R,5R,6S)-1-((S)-1-(bis(tert-butoxycarbonyl)amino)butan-2-yl)-5-(3-ch-
lorophenyl)-6-(4-chlorophenyl)-3-methyl-2-oxopiperidin-3-yl)acetate
##STR00565##
[2489] A solution of methyl
2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-hydroxybutan-
-2-yl)-3-methyl-2-oxopiperidin-3-yl)acetate (282 mg, 0.589 mmol;
Example 186, Step A), 2-(tributylphosphoranylidene)acetonitrile
(171 mg, 0.707 mmol) and di-tert-butyl iminodicarbonate (256 mg,
1.179 mmol) in toluene (3 mL) under argon was stirred at
110.degree. C. for 2 h. Flash column purification on silica gel (0
to 60% EtOAc in hexanes) gave the title compound. Mass Spectrum
(ESI) m/z=677 (M+1).
Step B. Methyl
2-((3R,5R,6S)-1-((S)-1-aminobutan-2-yl)-5-(3-chlorophenyl)-6-(4-chlorophe-
nyl)-3-methyl-2-oxopiperidin-3-yl)acetate
##STR00566##
[2491] A solution of methyl
2-((3R,5R,6S)-1-((S)-1-(bis(tert-butoxycarbonyl)amino)butan-2-yl)-5-(3-ch-
lorophenyl)-6-(4-chlorophenyl)-3-methyl-2-oxopiperidin-3-yl)acetate
(167 mg, 0.246 mmol) prepared in Step A above in dioxane was
stirred with HCl (4M, 0.6 mL) at rt for 2 h. Chromatography on
silica gel (0 to 20% MeOH/DCM) gave the title compound. Mass
Spectrum (ESI) m/z=477 (M+1).
Step C.
2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-2-oxo-
-1-((S)-1-(pyridine-3-sulfonamido)butan-2-yl)piperidin-3-yl)acetic
acid
[2492] A solution of methyl
2-((3R,5R,6S)-1-((S)-1-aminobutan-2-yl)-5-(3-chlorophenyl)-6-(4-chlorophe-
nyl)-3-methyl-2-oxopiperidin-3-yl)acetate (13 mg, 0.027 mmol;
Example 196, Step A) and pyridine-3-sulfonyl chloride (4.84 mg,
0.027 mmol) in pyridine (0.3 mL) was stirred at 110.degree. C. for
4 h. Chromatography on silica gel (0 to 60% EtOAc in hexanes) gave
methyl
2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-2-oxo-1-((S)-
-1-(pyridine-3-sulfonamido)butan-2-yl)piperidin-3-yl)acetate. This
was hydrolyzed with LiOH (1N solution in water, 0.3 mL) in ethanol
(0.5 mL) for 3 h at rt. HPLC purification (C18 column, eluted with
10 to 95% CH.sub.3CN in water, with 0.1% TFA) gave the title
compound as a 1:1 complex with 2,2,2-trifluoroacetic acid.
[2493] .sup.1H NMR (500 MHz, CHLOROFORM-d) .delta. ppm 9.29 (1H,
br. s.), 8.90 (1H, d, J=4.4 Hz), 8.32 (1H, d, J=8.1 Hz), 7.66-7.76
(1H, m), 7.15 (1H, d, J=8.1 Hz), 7.10 (1H, t, J=7.8 Hz), 7.02 (2H,
s), 7.06 (1H, s), 6.94 (1H, s), 6.74 (1H, d, J=7.3 Hz), 4.60 (1H,
d, J=9.0 Hz), 3.18 (1H, ddd, J=13.4, 10.4, 2.8 Hz), 2.86 (4H, br.
s.), 2.27-2.35 (3H, m), 2.03 (2H, dd, J=14.1, 3.1 Hz), 1.66 (1H,
br. s.), 1.54-1.64 (1H, m), 1.48 (3H, s), 0.72 (3H, br. s.). Mass
Spectrum (ESI) m/z=604 (M+1).
[2494] EXAMPLES 197-199 were also prepared from methyl
2-((3R,5R,6S)-1-((S)-1-aminobutan-2-yl)-5-(3-chlorophenyl)-6-(4-chlorophe-
nyl)-3-methyl-2-oxopiperidin-3-yl)acetate (Example 196, Step B) by
procedures similar to the one described in Example 196, Step C,
replacing pyridine-3-sulfonyl chloride with the appropriate
reagent.
TABLE-US-00009 ##STR00567## Example R Reagent used 197 ##STR00568##
4-Cyanobenzene-1- sulfonyl chloride 198 ##STR00569##
3-Cyanobenzene-1- sulfonyl chloride 199 ##STR00570## Pyridine-2-
sulfonyl chloride
Example 197
2-((3R,5R,6S)-5-(3-Chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-(4-cyanopheny-
lsulfonamido)butan-2-yl)-3-methyl-2-oxopiperidin-3-yl)acetic
acid
[2495] .sup.1H NMR (500 MHz, CHLOROFORM-d) .delta. ppm 7.95 (2H, m,
J=8.6 Hz), 7.81-7.87 (2H, m), 7.22 (2H, d, J=8.1 Hz), 7.16-7.20
(1H, m), 7.11-7.16 (1H, m), 7.06 (1H, s), 6.98 (1H, t, J=1.7 Hz),
6.80 (1H, d, J=7.6 Hz), 5.41 (1H, br. s.), 4.68 (1H, d, J=10.0 Hz),
3.38 (1H, br. s.), 3.17 (1H, ddd, J=13.5, 10.5, 2.7 Hz), 2.98 (1H,
d, J=14.7 Hz), 2.78 (1H, d, J=14.7 Hz), 2.69-2.76 (1H, m), 2.35
(1H, t, J=13.8 Hz), 2.00-2.08 (2H, m), 1.55 (1H, d, J=7.6 Hz), 1.52
(4H, s), 0.59 (3H, br. s.). Mass Spectrum (ESI) m/z=628 (M+1).
Example 198
2-((3R,5R,6S)-5-(3-Chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-(3-cyanopheny-
lsulfonamido)butan-2-yl)-3-methyl-2-oxopiperidin-3-yl)acetic
acid
[2496] .sup.1H NMR (500 MHz, CHLOROFORM-d) .delta. ppm 8.15 (1H, t,
J=1.5 Hz), 8.07 (1H, d, J=7.8 Hz), 7.89 (1H, dt, J=7.8, 1.2 Hz),
7.70 (1H, t, J=7.9 Hz), 7.20 (2H, d, J=7.8 Hz), 7.17 (1H, dt,
J=8.3, 1.5 Hz), 7.13 (1H, t, J=7.7 Hz), 7.06 (1H, s), 6.97 (1H, s),
6.80 (1H, d, J=7.3 Hz), 5.49 (1H, br. s.), 4.68 (1H, d, J=10.0 Hz),
3.40 (1H, br. s.), 3.27 (1H, br. s.), 3.17 (1H, ddd, J=13.4, 10.5,
2.9 Hz), 2.97 (1H, d, J=14.9 Hz), 2.80 (1H, d, J=14.7 Hz), 2.76
(1H, br. s.), 2.35 (1H, t, J=13.7 Hz), 2.04 (1H, dd, J=13.9, 2.9
Hz), 1.56 (1H, d, J=7.1 Hz), 1.52 (3H, s), 0.61 (3H, br. s.). Mass
Spectrum (ESI) m/z=628 (M+1).
Example 199
2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-2-oxo-1-((S)--
1-(pyridine-2-sulfonamido)butan-2-yl)piperidin-3-yl)acetic acid.
Compound obtained as 2,2,2-trifluoroacetic acid salt
[2497] .sup.1H NMR (500 MHz, CHLOROFORM-d) .delta. ppm 8.73 (1H, d,
J=4.2 Hz), 7.93-8.04 (2H, m), 7.53-7.60 (1H, m), 7.18-7.24 (2H, m),
7.11-7.18 (2H, m), 7.00-7.09 (2H, m), 6.98 (1H, s), 6.87 (1H, d,
J=6.8 Hz), 5.54 (1H, br. s.), 4.82 (1H, d, J=10.5 Hz), 3.51 (1H,
br. s.), 3.22 (1H, br. s.), 3.10-3.18 (1H, m), 3.03 (1H, d, J=14.9
Hz), 2.94 (1H, dt, J=14.0, 4.1 Hz), 2.75 (1H, d, J=14.9 Hz), 2.44
(1H, t, J=13.7 Hz), 1.99 (4H, dd, J=14.1, 2.8 Hz), 1.78-1.83 (3H,
m), 1.54 (3H, s), 1.43-1.53 (2H, m), 0.51 (3H, t, J=7.3 Hz). Mass
Spectrum (ESI) m/z=604 (M+1).
Example 200
2-((3R,5R,6S)-5-(3-Chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-(N,1-dimethyl-
cyclopropanesulfonamido)butan-2-yl)-3-methyl-2-oxopiperidin-3-yl)acetic
acid
##STR00571##
[2499] A solution of methyl
2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-1-((S)-1-(1--
methylcyclopropanesulfonamido)butan-2-yl)-2-oxopiperidin-3-yl)acetate
(21.7 mg, 0.036 mmol; Example 193),
2-(tributylphosphoranylidene)acetonitrile (8.8 mg, 0.036 mmol) and
one drop of MeOH in toluene (0.5 mL) was stirred at 110.degree. C.
for 1 h. Flash column purification on silica gel (0 to 60% EtOAc in
hexanes) gave methyl
2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-(N,1--
dimethylcyclopropanesulfonamido)butan-2-yl)-3-methyl-2-oxopiperidin-3-yl)a-
cetate. This was hydrolyzed with LiOH (1N solution in water, 0.3
mL) in ethanol (0.5 mL) for 3 h at rt. HPLC purification (C18
column, eluted with 10 to 95% CH.sub.3CN in water, with 0.1% TFA)
gave the title compound.
[2500] .sup.1H 1H NMR (500 MHz, CHLOROFORM-d) .delta. ppm 7.26 (2H,
br. s.), 7.13 (2H, d, J=3.7 Hz), 6.94 (2H, br. s.), 6.88 (1H, br.
s.), 4.80 (1H, d, J=9.5 Hz), 4.36 (1H, br. s.), 2.96-3.12 (3H, m),
2.86-2.93 (4H, m), 2.79 (3H, d, J=14.2 Hz), 2.69 (3H, d, J=15.4
Hz), 2.41-2.64 (15H, m), 1.96 (1H, dd, J=14.4, 7.3 Hz), 1.84 (1H,
d, J=13.7 Hz), 1.55-1.64 (2H, m), 1.53 (3H, br. s.), 1.38-1.48 (6H,
m), 0.81 (2H, br. s.), 0.51 (3H, t, J=6.2 Hz). Mass Spectrum (ESI)
m/z=595 (M+1).
Example 201
3-((3S,5R,6S)-5-(3-Chlorophenyl)-6-(4-chlorophenyl)-3-methyl-1-((S)-1-(N-m-
ethylcyclopropanesulfonamido)butan-2-yl)-2-oxopiperidin-3-yl)propanoic
acid or
3-((3R,5R,6S)-5-(3-Chlorophenyl)-6-(4-chlorophenyl)-3-methyl-1-((-
S)-1-(N-methylcyclopropanesulfonamido)butan-2-yl)-2-oxopiperidin-3-yl)prop-
anoic acid
##STR00572##
[2501] Step A.
(5R,6S)-5-(3-Chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-hydroxybutan-2-yl)-
piperidin-2-one
##STR00573##
[2503] To a mixture of
(5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-hydroxybutan-2-yl)-
piperidin-2-one (20.00 g, 51.0 mmol; Example 185, Step B) and
N-methylcyclopropanesulfonamide (10.34 g, 76 mmol) in 100 mL of
toluene at room temperature was added
cyanomethylenetributylphosphorane (20.51 mL, 76 mmol). The
resulting mixture was heated to 130.degree. C. for 12 h, then
cooled to room temperature and directly loaded onto a silica gel
column for purification, eluting with 0 to 10% MeOH in DCM to
provide the title compound. Mass Spectrum (ESI) m/z=509 (M+1).
Step B.
N-((2S)-2-((2S,3R)-3-(3-Chlorophenyl)-2-(4-chlorophenyl)-5-methyl--
6-oxopiperidin-1-yl)butyl)-N-methylcyclopropanesulfonamide
##STR00574##
[2505] The title compound was obtained as a mixture of
diastereomers from
N--((S)-2-((2S,3R)-3-(3-chlorophenyl)-2-(4-chlorophenyl)-6-oxopiperidin-1-
-yl)butyl)-N-methylcyclopropanesulfonamide (Example 201, Step A)
using a procedure similar to one described in Example 185, Step D.
Mass Spectrum (ESI) m/z=523 (M+1).
Step C.
N--((S)-2-((5R,6S)-3-(But-3-enyl)-5-(3-chlorophenyl)-6-(4-chloroph-
enyl)-3-methyl-2-oxopiperidin-1-yl)butyl)-N-methylcyclopropanesulfonamide
(Isomer 1)
##STR00575##
[2507] To a solution of
N-((2S)-2-((2S,3R)-3-(3-chlorophenyl)-2-(4-chlorophenyl)-5-methyl-6-oxopi-
peridin-1-yl)butyl)-N-methylcyclopropanesulfonamide (2618 mg, 5.0
mmol; Example 201, Step B) in degassed THF (10 mL) was added
lithium diisopropylamide (5.00 mL, 10.00 mmol) at -15.degree. C.
After stirring at -15.degree. C. for 30 min, the reaction mixture
was cooled to -74.degree. C.
[2508] 4-Bromobut-1-ene (1.066 mL, 10.50 mmol) was added slowly.
The reaction mixture was stirred at -74.degree. C. for 3 h before
warming up to rt and then stirred at rt for 66 h. Filtered and
purified by HPLC (C18 column, eluted with 10 to 95% CH.sub.3CN in
water, with 0.1% TFA) to give the title compound as the first
eluting isomer Its stereoisomer is obtained as the later eluting
isomer.
[2509] .sup.1H NMR (500 MHz, CHLOROFORM-d) .delta. ppm 7.22 (2H, d,
J=7.6 Hz), 7.10-7.17 (2H, m), 6.96 (2H, s), 6.90-6.95 (1H, m), 5.90
(1H, ddt, J=17.0, 10.3, 6.4, 6.4 Hz), 5.10 (1H, dd, J=17.1, 1.5
Hz), 5.03 (1H, dd, J=10.0, 1.5 Hz), 4.77 (1H, d, J=10.5 Hz), 4.24
(1H, br. s.), 3.07 (1H, ddd, J=13.7, 10.6, 3.1 Hz), 2.90 (3H, s),
2.74-2.87 (2H, m), 2.24-2.37 (2H, m), 2.11-2.21 (2H, m), 2.00 (1H,
ddd, J=13.6, 10.1, 6.6 Hz), 1.78-1.93 (3H, m), 1.60-1.70 (1H, m),
1.58 (2H, br. s.), 1.28-1.32 (3H, m), 1.22 (2H, d, J=3.2 Hz),
0.95-1.04 (2H, m), 0.53 (3H, t, J=7.5 Hz). Mass Spectrum (ESI)
m/z=577 (M+1).
Step D.
3-((3S,5R,6S)-5-(3-Chlorophenyl)-6-(4-chlorophenyl)-3-methyl-1-((S-
)-1-(N-methylcyclopropanesulfonamido)butan-2-yl)-2-oxopiperidin-3-yl)propa-
noic acid or
3-((3R,5R,6S)-5-(3-Chlorophenyl)-6-(4-chlorophenyl)-3-methyl-1-((S)-1-(N--
methylcyclopropanesulfonamido)butan-2-yl)-2-oxopiperidin-3-yl)propanoic
acid
[2510] The title compound was obtained from
N--((S)-2-((5R,6S)-3-(but-3-enyl)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-
-methyl-2-oxopiperidin-1-yl)butyl)-N-methylcyclopropanesulfonamide
(Isomer 1, 604 mg, 1.046 mmol; Example 201, Step C) by a procedure
similar to the one described in Example 71, Step F.
[2511] .sup.1H NMR (400 MHz, CHLOROFORM-d) .delta. ppm 7.23 (2H, d,
J=7.4 Hz), 7.11-7.17 (3H, m), 6.98 (2H, m), 6.89-6.94 (1H, m), 4.75
(1H, d, J=11.3 Hz), 4.24 (1H, br. s.), 3.17 (1H, ddd, J=13.8, 10.8,
3.1 Hz), 2.89 (3H, s), 2.63-2.82 (3H, m), 2.55 (1H, dd, J=8.5, 6.2
Hz), 2.39-2.52 (2H, m), 2.27-2.39 (2H, m), 1.82-1.94 (2H, m), 1.73
(1H, dd, J=13.7, 3.1 Hz), 1.48-1.65 (2H, m), 1.28-1.33 (4H, m),
1.17-1.25 (2H, m), 0.95-1.04 (2H, m), 0.46-0.55 (3H, m). Mass
Spectrum (ESI) m/z=595 (M+1).
Example 202
2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-ethyl-1-((S)-1-(N-me-
thylcyclopropanesulfonamido)butan-2-yl)-2-oxopiperidin-3-yl)acetic
acid
##STR00576##
[2512] Step A.
(5R,6S)-1-((S)-1-(tert-butyldiphenylsilyloxy)butan-2-yl)-5-(3-chloropheny-
l)-6-(4-chlorophenyl)-3-ethylpiperidin-2-one
##STR00577##
[2514] To a -78.degree. C. solution of
(5R,6S)-1-((S)---(tert-butyldiphenylsilyloxy)butan-2-yl)-5-(3-chloropheny-
l)-6-(4-chlorophenyl)piperidin-2-one (764 mg, 1.211 mmol; Example
185, Step C) in THF (6 mL) under argon was added 1.0M lithium
diisopropyl amide solution in THF (1.211 mL, 1.211 mmol). The
mixture was warmed to 0.degree. C. for 30 minutes. The mixture was
cooled to -78.degree. C. and iodoethane (0.117 mL, 1.454 mmol) was
added. The resulting solution stirred at 0.degree. C. for 1 hour.
The mixture was quenched with sat. aq. NH.sub.4Cl solution. The
mixture was extracted with ethyl acetate. The combined organic
layers were washed with sat. aq. NaCl solution, dried over
Na.sub.2SO.sub.4 and concentrated. The residue was purified by
flash chromatography on silica gel (eluent: 5 to 25% ethyl
acetate/hexanes) to afford the title compound as a mixture of
diastereomers.
Step B.
(5R,6S)-3-allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-ethyl-1-((-
S)-1-hydroxybutan-2-yl)piperidin-2-one
##STR00578##
[2516]
(5R,6S)-1-((S)-1-(Tert-butyldiphenylsilyloxy)butan-2-yl)-5-(3-chlor-
ophenyl)-6-(4-chlorophenyl)-3-ethylpiperidin-2-one (421 mg, 0.639
mmol; Example 202, Step A) was azeotroped with toluene (3.times.).
THF (1.6 mL) was added. The mixture was sparged with argon for 5
minutes and then cooled to 0.degree. C. 1.0 M lithium
diisopropylamide solution in THF (1.246 mL, 1.246 mmol) was added
dropwise. After 25 minutes, allyl bromide (0.166 mL, 1.917 mmol)
was added dropwise. After 20 minutes, the mixture was quenched with
sat. aq. NH.sub.4Cl solution. The mixture was extracted with ethyl
acetate. The organic layer was washed with sat. aq. NaCl solution,
dried over Na.sub.2SO.sub.4, and concentrated. The residue was
dissolved in THF (3 mL) and 1.0M tetrabutylammonium fluoride
solution in THF (2.335 mL, 2.335 mmol) was added. After stirring
overnight, the mixture was partitioned between 5% aq. HCl and ethyl
acetate. The organic layer was washed with sat. aq. NaCl solution,
dried over Na.sub.2SO.sub.4, and concentrated. The residue was
purified by flash chromatography on silica gel (eluent: 20 to 50%
ethyl acetate/hexanes) to afford the title compound as the more
polar major diastereomer.
Step C.
N-((2S)-2-((5R,6S)-3-allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-
-ethyl-2-oxopiperidin-1-yl)butyl)-N-methylcyclopropanesulfonamide
##STR00579##
[2518]
(5R,6S)-3-Allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-ethyl-1-((S-
)-1-hydroxybutan-2-yl)piperidin-2-one (147 mg, 0.319 mmol; Example
202, Step B) and N-methylcyclopropanesulfonamide (129 mg, 0.958
mmol) were dissolved in toluene (2 mL). The mixture was evacuated
and backfilled with argon (5.times.).
Cyanomethylenetributylphosphorane (0.251 mL, 0.958 mmol) was added.
The mixture was evacuated and backfilled with argon (5.times.). The
mixture was heated at 70.degree. C. for 2 hours. The mixture was
loaded onto silica gel and the product was eluted with 5 to 75%
ethyl acetate/hexanes to afford the title compound.
Step D.
2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-ethyl-1-((S)-
-1-(N-methylcyclopropanesulfonamido)butan-2-yl)-2-oxopiperidin-3-yl)acetic
acid
[2519] The title compound was obtained from
N-((2S)-2-((5R,6S)-3-allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-ethyl--
2-oxopiperidin-1-yl)butyl)-N-methylcyclopropanesulfonamide (Example
202, Step C) by a procedure similar to the one described in Example
71, Step F.
[2520] .sup.1H NMR (400 MHz, CHLOROFORM-d) .delta. ppm 0.54 (t,
J=7.53 Hz, 3H) 0.85-1.10 (m, 7H) 1.15-1.23 (m, 2H) 1.51-1.65 (m,
1H) 1.84-2.04 (m, 4H) 2.15-2.25 (m, 1H) 2.25-2.38 (m, 2H) 2.69-2.82
(m, 1H) 2.87 (s, 3H) 2.93-3.10 (m, 2H) 4.76 (d, J=10.37 Hz, 1H)
6.84 (d, J=6.65 Hz, 1H) 6.91-6.97 (m, 1H) 7.08-7.17 (m, 2H)
7.20-7.29 (m, 4H). Mass Spectrum (ESI) m/z=595.2 (M+1).
Example 203
2-((3S,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methoxy-1-((S)-1-(N--
methylcyclopropanesulfonamido)butan-2-yl)-2-oxopiperidin-3-yl)acetic
acid
##STR00580##
[2521] Step A.
(5R,6S)-1-((S)-1-(tert-butyldiphenylsilyloxy)butan-2-yl)-5-(3-chloropheny-
l)-6-(4-chlorophenyl)-3-hydroxypiperidin-2-one
##STR00581##
[2523]
(5R,6S)-1-((S)-1-(Tert-butyldiphenylsilyloxy)butan-2-yl)-5-(3-chlor-
ophenyl)-6-(4-chlorophenyl)piperidin-2-one (1.100 g, 1.744 mmol;
Example 185, Step C) was dissolved in THF (8.72 mL) and sparged
with argon for 5 minutes. The mixture was cooled to -78.degree. C.
and 1.0 M lithium bis(trimethylsilyl)amide solution in THF (2.093
mL, 2.093 mmol) was added dropwise. After 30 minutes,
peroxybis(trimethylsilane) (0.413 mL, 1.918 mmol) was added
dropwise. After 1 hour, the cooling bath was removed. After
stirring overnight, the mixture was quenched with sat. aq.
NH.sub.4Cl solution and extracted with ethyl acetate. The organic
layer was washed with sat. aq. NaCl solution, dried over
Na.sub.2SO.sub.4, and concentrated. The residue was dissolved in
EtOH (14 mL) and pyridine p-toluenesulfonate (131 mg, 0.523 mmol)
was added. After 1 hour, the mixture was basified with sat. aq.
NaHCO.sub.3 solution. The mixture was partitioned between ethyl
acetate and water. The organic layer was washed with sat. aq. NaCl
solution, dried over Na.sub.2SO.sub.4, and concentrated. The
residue was purified by flash chromatography on silica gel (40 g
column, eluent: 5 to 50% ethylacetate/hexanes) to afford the title
compound.
Step B.
(5R,6S)-1-((S)-1-(tert-butyldiphenylsilyloxy)butan-2-yl)-5-(3-chlo-
rophenyl)-6-(4-chlorophenyl)-3-methoxypiperidin-2-one
##STR00582##
[2525] To a 0.degree. C. solution of
(5R,6S)-1-((S)-1-(tert-butyldiphenylsilyloxy)butan-2-yl)-5-(3-chloropheny-
l)-6-(4-chlorophenyl)-3-hydroxypiperidin-2-one (476 mg, 0.736 mmol;
Example 203, Step A) in THF (7.360 mL) was added sodium hydride
(58.9 mg, 1.472 mmol). After 30 minutes, iodomethane (0.092 mL,
1.472 mmol) was added. After 5 minutes, the cooling bath was
removed. After 2 hours, the mixture was quenched with sat. aq.
NH.sub.4Cl solution. The mixture was partitioned between ethyl
acetate and water. The organic layer was washed with sat. aq. NaCl
solution, dried over Na.sub.2SO.sub.4, and concentrated to afford
the title compound.
Step C.
(3R,5R,6S)-3-allyl-1-((S)-1-((tert-butyldiphenylsilyl)oxy)butan-2--
yl)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methoxypiperidin-2-one
##STR00583##
[2527] A solution of
(5R,6S)-1-((S)-1-((tert-butyldiphenylsilyl)oxy)butan-2-yl)-5-(3-chlorophe-
nyl)-6-(4-chlorophenyl)-3-methoxypiperidin-2-one (495 mg, 0.749
mmol; Example 203, Step B) in THF (7.49 mL) was sparged with argon
for 5 minutes and cooled to 0.degree. C. 1.0 M
lithiumdiisopropylamide solution in THF (1.461 mL, 1.461 mmol) was
added dropwise. The internal temperature did not rise above
2.degree. C. After 30 minutes, allyl bromide (0.194 mL, 2.247 mmol)
was added. The cooling bath was replaced with a room temperature
water bath. After 70 minutes, the mixture was quenched with sat.
aq. NH.sub.4Cl solution and extracted with ethyl acetate. The
organic layer was washed with sat. aq. NaCl solution, dried over
Na.sub.2SO.sub.4 and concentrated. The residue was purified by
flash chromatography on silica gel (40 g column, eluent: 5 to 30%
ethyl acetate/hexanes) to afford the title compound as the more
polar diastereomer.
Step D.
(3R,5R,6S)-3-allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1--
hydroxybutan-2-yl)-3-methoxypiperidin-2-one
##STR00584##
[2529] To a solution of
(3R,5R,6S)-3-allyl-1-((S)-1-((tert-butyldiphenylsilyl)oxy)butan-2-yl)-5-(-
3-chlorophenyl)-6-(4-chlorophenyl)-3-methoxypiperidin-2-one (260
mg, 0.371 mmol; Example 203, Step C) in THF (1 mL) was added 1.0 M
tetrabutylammonium fluoride solution in THF (1.484 mL, 1.484 mmol).
After stirring overnight, the mixture was partitioned between water
and ethyl acetate. Sat. aq. NH.sub.4Cl solution was added to break
up the emulsion. The organic layer was washed with sat. aq. NaCl
solution, dried over Na.sub.2SO.sub.4, and concentrated. The
residue was purified by flash chromatography on silica gel (12 g
column, eluent: 35 to 100% ethyl acetate/hexanes) to afford the
title compound.
Step E.
N--((S)-2-((3R,5R,6S)-3-allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl-
)-3-methoxy-2-oxopiperidin-1-yl)butyl)-N-methylcyclopropanesulfonamide
##STR00585##
[2531] To a solution of
(3R,5R,6S)-3-allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-hydroxy-
butan-2-yl)-3-methoxypiperidin-2-one (124 mg, 0.268 mmol; Example
203, Step D) in toluene (1.3 mL) was added
N-methylcyclopropanesulfonamide (109 mg, 0.804 mmol). The mixture
was evacuated and backfilled with argon (5.times.).
Cyanomethylenetributylphosphorane (0.211 mL, 0.804 mmol) was added.
The mixture was evacuated and backfilled with argon (5.times.). The
mixture was heated in a 70.degree. C. oil bath for 12 hours then
cooled to room temperature and stirred for 2 days at room
temperature. The mixture was loaded onto silica gel and the product
was eluted with 20-60% ethyl acetate/hexanes. The residue was one
more time purified by flash chromatography on silica gel (12 g
column, eluent: 10 to 60% ethylacetate/hexanes) to afford the title
compound.
Step F.
2-((3S,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methoxy-1-((-
S)-1-(N-methylcyclopropanesulfonamido)butan-2-yl)-2-oxopiperidin-3-yl)acet-
ic acid
[2532] The title compound was obtained from
N--((S)-2-((3R,5R,6S)-3-allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-met-
hoxy-2-oxopiperidin-1-yl)butyl)-N-methylcyclopropanesulfonamide
(Example 203, Step E) by a procedure similar to the one described
in Example 71, Step F.
[2533] .sup.1H NMR (400 MHz, CHLOROFORM-d) .delta. ppm 0.59 (t,
J=7.53 Hz, 3H) 1.02-1.05 (m, 2H) 1.16-1.27 (m, 2H) 1.59-1.77 (m,
1H) 1.85-1.99 (m, 2H) 2.22-2.40 (m, 1H) 2.75 (d, J=13.30 Hz, 1H)
2.84-2.98 (m, 6H) 3.03-3.16 (m, 2H) 3.26 (d, J=15.65 Hz, 1H) 3.52
(s, 3H) 4.99 (d, J=10.76 Hz, 1H) 6.91-6.97 (m, 2H) 7.02 (s, 1H)
7.10-7.20 (m, 2H) 7.22-7.31 (m, 3H). Mass Spectrum (ESI) m/z=597.1
(M+1).
Example 204
2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-1-((S)-6-meth-
yl-4-oxoheptan-3-yl)-2-oxopiperidin-3-yl)acetic acid
##STR00586##
[2534] Step A.
(3S,5R,6S)-3-allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((3S)-4-hydrox-
y-6-methylheptan-3-yl)-3-methylpiperidin-2-one
##STR00587##
[2536] To a solution of
(S)-2-((3S,5R,6S)-3-allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl--
2-oxopiperidin-1-yl)butanal (1.755 mmol) (Example 91, Step C) in
THF (5 mL) at 0.degree. C. was added 2 M isobutylmagnesium bromide
(878 .mu.L, 1.742 mmol) under N.sub.2. The reaction was allowed to
warm to rt. After being stirred for 2 h at rt, the reaction was
quenched with saturated NH.sub.4Cl solution and extracted with
EtOAc. The combined organic layers were washed (sat. aq. NaCl
solution), dried over MgSO.sub.4, filtered and the filtrate was
concentrated under reduced pressure. The residue was purified by
the flash chromatography on silica gel (eluent: 15 to 35%
EtOAc/Hexane, gradient elution) to provide the title compound as a
mixture of two diastereomers.
Step B.
2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-1-((S-
)-6-methyl-4-oxoheptan-3-yl)-2-oxopiperidin-3-yl)acetic acid
[2537] To a rapidly stirring solution of 120 mg (0.239 mmol) of
(3S,5R,6S)-3-allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((3S)-4-hydrox-
y-6-methylheptan-3-yl)-3-methylpiperidin-2-one (Example 204, Step
A) in a mixture of 1.5 mL of water, 1.0 mL of acetonitrile and 1.0
mL of CCl.sub.4 was added sodium periodate (204 mg, 0.995 mmol),
followed by ruthenium(III) chloride hydrate (5.38 mg, 0.024 mmol).
After being stirred vigorously for 2 h, the reaction was acidified
(10% citric acid) and diluted with EtOAc. The reaction mixture was
filtered through Celite.RTM. (J. T. Baker, Phillipsberg, N.J.,
diatomaceous earth) and the filtrate was extracted with EtOAc. The
combined organic layers were washed with sat. NaCl solution, dried
over Na.sub.2SO.sub.4, filtered and the filtrate was concentrated
under reduced pressure. The residue was purified by the flash
chromatography on silica gel (eluent: 10 to 20% iPrOH/hexane,
gradient elution) to provide the title compound as a white
solid.
[2538] .sup.1H NMR (400 MHz, CHLOROFORM-d) .delta. ppm 0.64 (t,
J=8.0 Hz, 3H), 0.89 (d, J=8.0 Hz, 3H), 0.92 (d, J=8.0 Hz, 3H), 1.21
(m, 1H), 1.39 (s, 3H), 1.82 (m, 1H), 210-2.45 (m, 7H), 2.87 (dd,
J=16.0, 12 Hz, 2H), 3.09 (t, J=8.0 Hz, 1H), 3.26 (m, 1H), 4.44 (d,
J=8.0 Hz, 1H), 6.76 (d, J=8.0 Hz, 1H), 6.90-7.02 (m, 3H), 7.08 (t,
J=8.0 Hz, 1H), 7.12 (d, J=8.0 Hz, 1H), 7.23 (d, J=8.0 Hz, 2H); MS
(ESI) 531.1 [M+H].sup.+.
Example 205
2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-(ethylsulfony-
l)pentan-3-yl)-3-methyl-2-oxopiperidin-3-yl)acetic acid
##STR00588##
[2539] Step A. Diethyl ethylsulfonylmethylphosphonate
##STR00589##
[2541] To a stirred solution of diethyl ethylthiomethylphosphonate
(Aldrich, St. Louis, Mo.) (0.912 mL, 4.71 mmol) in dichloromethane
(47.1 mL) at 0.degree. C. was added meta-chloroperoxybenzoic acid
(2.63 g, 15.2 mmol). The reaction mixture was stirred at 25.degree.
C. for 24 hours. The reaction solvent was removed in vacuo, the
crude material was diluted with diethyl ether, and was then washed
with saturated sodium bicarbonate (3.times.). The organic layer was
dried over Na.sub.2SO.sub.4, filtered and the filtrate was
concentrated under reduced pressure to provide the title compound
as an off-white solid.
Step B.
(3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-((2,2-dimethyl--
1,3-dioxolan-4-yl)methyl)-1-((S,E)-1-(ethylsulfonyl)pent-1-en-3-yl)-3-meth-
ylpiperidin-2-one
##STR00590##
[2543] To a stirred solution of diethyl
ethylsulfonylmethylphosphonate (153 mg, 0.625 mmol; Example 202,
Step A) in THF (2.60 mL) at -78.degree. C. was added butyllithium
(177 .mu.L, 0.443 mmol). After 30 minutes, a solution of
(2S)-2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-((2,2-dimethyl-
-1,3-dioxolan-4-yl)methyl)-3-methyl-2-oxopiperidin-1-yl)butanal
(135 mg, 0.260 mmol; Example 150, Step D) in THF (0.50 mL) was
added. The reaction was stirred for 15 minutes at -78.degree. C.
and was then stirred at 25.degree. C. for 3 hours. The reaction was
partitioned between saturated ammonium chloride and EtOAc
(2.times.), and then the combined organic layers were dried over
Na.sub.2SO.sub.4, filtered and the filtrate was concentrated under
reduced pressure. Purification of the residue by flash
chromatography on silica gel (4 g column, eluent: 0 to 40%
EtOAc/hexanes) provided the title compound as an off-white
solid.
Step C.
(3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-((2,2-dimethyl--
1,3-dioxolan-4-yl)methyl)-1-((S)-1-(ethylsulfonyl)pentan-3-yl)-3-methylpip-
eridin-2-one
##STR00591##
[2545] To a solution of
(3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-((2,2-dimethyl-1,3-dio-
xolan-4-yl)methyl)-1-((S,E)-1-(ethylsulfonyl)pent-1-en-3-yl)-3-methylpiper-
idin-2-one (65.0 mg, 0.107 mmol; Example 205, Step B) in
1,2-dichloroethane (1.07 mL) at 25.degree. C. was added Crabtree's
catalyst (7.74 mg, 9.61 .mu.mol). The reaction system (a
hydrogenation bomb) was flushed with hydrogen gas 3.times.,
pressurized with hydrogen at 3447.38 kilopascal, and the reaction
was stirred at 25.degree. C. for 24 hours. The reaction mixture was
filtered through celite, washed with DCM, and concentrated under
reduced pressure to yield the title compound as an off-white
solid.
Step D.
2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-(ethy-
lsulfonyl)pentan-3-yl)-3-methyl-2-oxopiperidin-3-yl)acetic acid
[2546] To a stirred solution of
(3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-((2,2-dimethyl-1,3-dio-
xolan-4-yl)methyl)-1-((S)-1-(ethylsulfonyl)pentan-3-yl)-3-methylpiperidin--
2-one (70.0 mg, 0.115 mmol; Example 202, Step C) in THF (1.15 mL)
at 25.degree. C. was added a solution of Jones' Reagent (chromium
(VI) oxide) (138 .mu.L, 0.172 mmol) and the reaction mixture was
stirred for 1 hour. The reaction mixture was partitioned between
water and EtOAc (2.times.), and then the combined organic layers
were dried over Na.sub.2SO.sub.4, filtered and the filtrate was
concentrated under reduced pressure. Purification of the residue by
reverse phase high-pressure liquid chromatography (Eclipse column
(Agilient Technologies, Santa Clara, Calif.), eluent: 30-75%
acetonitrile/water) provided the title compound as an off-white
solid.
[2547] .sup.1H NMR (500 MHz, CDCl.sub.3) .delta. ppm 0.58 (t,
J=7.34 Hz, 3H), 1.43 (t, J=7.46 Hz, 3H), 1.49 (s, 3H), 1.51-1.57
(m, 1H), 1.86 (dt, J=14.55, 7.40 Hz, 1H), 1.98 (dd, J=12.84, 5.75
Hz, 1H), 2.04 (dd, J=13.94, 2.45 Hz, 1H), 2.16-2.23 (m, 2H), 2.76
(d, J=15.16 Hz, 1H), 2.97-3.04 (m, 5H), 3.11-3.20 (m, 1H),
3.24-3.38 (m, 1H), 4.58 (d, J=10.51 Hz, 1H), 6.75 (d, J=7.58 Hz,
1H), 6.95 (s, 1H), 7.05 (d, J=4.89 Hz, 2H), 7.09-7.14 (m, 1H),
7.14-7.18 (m, 1H), 7.23-7.27 (m, 2H); MS (ESI) 554.2
[M+H].sup.+.
Example 206
2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-(isopropylsul-
fonyl)pentan-3-yl)-3-methyl-2-oxopiperidin-3-yl)acetic acid
##STR00592##
[2548] Step A. S-(diisopropoxyphosphoryl)methyl ethanethioate
##STR00593##
[2550] To a stirred solution of diisopropyl bromomethylphosphonate
(5.00 g, 19.3 mmol) in N,N-dimethylformamide (15.4 mL) was added
potassium thioacetate (3.75 g, 32.8 mmol) followed by
tetrabutylammonium iodide (0.36 g, 0.97 mmol). The reaction mixture
was stirred at 85.degree. C. for 2.5 hours. The reaction mixture
was cooled and partitioned between water and EtOAc (3.times.) and
the layers were separated. The combined organic layers were dried
over Na.sub.2SO.sub.4, filtered and the filtrate was concentrated
under reduced pressure. Purification of the residue by flash
chromatography on silica gel (24 g column, eluent: 0 to 90%
EtOAc/hexanes) provided the title compound as an off-white
solid.
Step B. Diisopropyl isopropylthiomethylphosphonate
##STR00594##
[2552] To a stirred solution of S-(diisopropoxyphosphoryl)methyl
ethanethioate (1.00 g, 3.93 mmol; Example 206, Step A) in methanol
(39.3 mL) at 0.degree. C. was added sodium methoxide (7.87 mL, 3.93
mmol), followed by 2-bromopropane (0.44 mL, 4.72 mmol). The
reaction was stirred at 25.degree. C. for 16 hours. The reaction
solvent was removed in vacuo and the crude material was partitioned
between water and EtOAc (2.times.) and the layers were separated.
The aqueous layer was extracted with EtOAc and the combined organic
layers were dried over Na.sub.2SO.sub.4, filtered and the filtrate
was concentrated under reduced pressure. Purification of the
residue by flash chromatography on silica gel (40 g column, eluent:
0 to 75% DCM/hexanes) provided the title compound as an off-white
solid.
Step C. Diisopropyl isopropylsulfonylmethylphosphonate
##STR00595##
[2554] Diisopropyl isopropylthiomethylphosphonate was converted to
the title compound by the procedure described in Example 205, Step
A and was isolated as an off-white solid.
Step D.
(3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-((2,2-dimethyl--
1,3-dioxolan-4-yl)methyl)-1-((S,E)-1-(isopropylsulfonyl)pent-1-en-3-yl)-3--
methylpiperidin-2-one
##STR00596##
[2556]
(2S)-2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-((2,2-di-
methyl-1,3-dioxolan-4-yl)methyl)-3-methyl-2-oxopiperidin-1-yl)butanal
(Example 150, Step D) was converted to the title compound as
described in Example 205, Step B and was isolated as an off-white
solid.
Step E.
(3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-((2,2-dimethyl--
1,3-dioxolan-4-yl)methyl)-1-((S)-1-(isopropylsulfonyl)pentan-3-yl)-3-methy-
lpiperidin-2-one
##STR00597##
[2558]
(3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-((2,2-dimethyl-1-
,3-dioxolan-4-yl)methyl)-1-((S,E)-1-(isopropylsulfonyl)pent-1-en-3-yl)-3-m-
ethylpiperidin-2-one was converted to the title compound as
described in Example 205, Step C and was isolated as an off-white
solid.
Step F.
2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-(isop-
ropylsulfonyl)pentan-3-yl)-3-methyl-2-oxopiperidin-3-yl)acetic
acid
[2559]
(3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-((2,2-dimethyl-1-
,3-dioxolan-4-yl)methyl)-1-((S)-1-(isopropylsulfonyl)pentan-3-yl)-3-methyl-
piperidin-2-one was converted to the title compound as described in
Example 205, Step D and was isolated as an off-white solid.
[2560] .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. ppm 0.55 (t,
J=6.55 Hz, 3H), 1.43 (d, J=6.26 Hz, 6H), 1.49 (br. s., 3H),
1.81-1.96 (m, 1H), 1.98-2.10 (m, 2H), 2.14-2.25 (m, 1H), 2.27-2.41
(m, 1H), 2.77 (d, J=15.85 Hz, 2H), 2.95-3.07 (m, 3H), 3.09-3.19 (m,
2H), 3.19-3.31 (m, 1H), 4.65 (d, J=10.56 Hz, 1H), 6.75 (d, J=7.24
Hz, 1H), 6.96 (s, 1H), 7.01-7.10 (m, 2H), 7.12 (d, J=7.63 Hz, 1H),
7.14-7.19 (m, 1H), 7.23-7.27 (m, 2H); MS (ESI) 568.2
[M+H].sup.+.
Example 207
2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-(cyclopropylm-
ethylsulfonyl)pentan-3-yl)-3-methyl-2-oxopiperidin-3-yl)acetic
acid
##STR00598##
[2562]
(2S)-2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-((2,2-di-
methyl-1,3-dioxolan-4-yl)methyl)-3-methyl-2-oxopiperidin-1-yl)butanal
(Example 150, Step D) with
diisopropyl(cyclopropylmethylsulfonyl)methylphosphonate (prepared
as an off-white solid in analogy to the procedure of Example 206
steps A and B) were converted to the title compound by the sequence
as described in Example 205. The title compound is an off-white
solid.
[2563] .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. ppm 0.39-0.48 (m,
2H), 0.56 (t, J=7.10 Hz, 3H), 0.74-0.86 (m, 2H), 1.13-1.25 (m, 1H),
1.48 (br. s., 3H), 1.51-1.59 (m, 1H), 1.79-1.94 (m, 1H), 1.97-2.11
(m, 2H), 2.13-2.24 (m, 1H), 2.24-2.42 (m, 1H), 2.78 (d, J=14.87 Hz,
1H), 2.92 (d, J=5.28 Hz, 2H), 2.97-3.11 (m, 3H), 3.16 (t, J=11.54
Hz, 1H), 3.21-3.33 (m, 1H), 4.62 (d, J=10.37 Hz, 1H), 6.75 (d,
J=7.04 Hz, 1H), 6.96 (br. s., 1H), 7.01-7.20 (m, 4H), 7.21-7.27 (m,
2H); MS (ESI) 580.2 [M+H].sup.+.
Example 208
2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-2-oxo-1-((S)--
1-(2-oxopyrrolidin-1-yl)butan-2-yl)piperidin-3-yl)acetic acid
##STR00599##
[2564] Step A.
(3S,5R,6S)-3-allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-1-((S)--
1-(2-oxopyrrolidin-1-yl)butan-2-yl)piperidin-2-one
##STR00600##
[2566] To a solution of
(S)-2-((3S,5R,6S)-3-allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl--
2-oxopiperidin-1-yl)butanal (84 mg, 0.189 mmol; Example 91, Step
C), ethyl 4-aminobutyrate hydrochloride (127 mg, 0.756 mmol) and
acetic acid (3 drops) in DCE/MeOH (3/1, 4.0 mL) was added sodium
triacetoxyhydroborate (200 mg, 0.945 mmol) at 25.degree. C. After
being stirred at 25.degree. C. for 18 h, the reaction was quenched
by adding ice-cold saturated aqueous NaHCO.sub.3 solution and was
extracted with DCM. The combined organic layers were washed
(1.times.sat. aq. NaCl solution) and concentrated under reduced
pressure. The residue was purified by reverse phase preparatory
HPLC (acetonitrile in water with 0.1% TFA, gradient elution) to
give the title compound as a white solid.
Step B.
2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-2-oxo-
-1-((S)-1-(2-oxopyrrolidin-1-yl)butan-2-yl)piperidin-3-yl)acetic
acid
[2567] The title compound was obtained from
((3S,5R,6S)-3-allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-1-((S)-
-1-(2-oxopyrrolidin-1-yl)butan-2-yl)piperidin-2-one (Example 208,
Step A) by a procedure similar to the one described in Example 71,
Step F.
[2568] .sup.1H NMR (400 MHz, CHLOROFORM-d) .delta. ppm 0.55 (t,
J=8.0 Hz, 3H), 1.52 (s, 3H), 1.65 (m, 1H), 1.90-2.28 (m, 5H), 2.58
(m, 2H), 2.75 (d, J=12.0 Hz, 1H), 3.02 (d, J=12.0 Hz, 1H), 3.08 (m,
3H), 3.47 (m, 2H), 3.99 (m, 1H), 4.37 (d, J=12.0 Hz, 1H), 6.72 (d,
J=8.0 Hz, 1H), 6.89-7.00 (m, 3H), 71.0 (t, J=8.0 Hz, 1H), 7.16 (m,
1H), 7.26 (d, J=4.0 Hz, 2H); MS (ESI) 531.1 [M+H].sup.+.
Example 209
2-((3R,5R,6S)-1-((S)-1-((1R,4R)-2-oxa-5-azabicyclo[2.2.1]heptan-5-yl)butan-
-2-yl)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-2-oxopiperidin-3-yl)-
acetic acid--TFA salt
##STR00601##
[2569] Step A.
(3S,5R,6S)-1-((S)-1-((1R,4R)-2-oxa-5-azabicyclo[2.2.1]heptan-5-yl)butan-2-
-yl)-3-allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methylpiperidin-2-one
##STR00602##
[2571] To a solution of
(S)-2-((3S,5R,6S)-3-allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl--
2-oxopiperidin-1-yl)butanal (100 mg, 0.224 mmol; Example 91, Step
C) in DCE (2 mL) was added (1R,4R)-2-oxa-5-azabicyclo[2.2.1]heptane
(Butora, G.; Goble, S.; Pastemak, A.; Yang, L.; Zhou, C.; Moyes, C.
U.S. Patent Publication No. 2008/0081803 (50 mg, 0.504 mmol)
followed by sodium triacetoxyborohydride (95 mg, 0.448 mmol) and
acetic acid (1.2 .mu.L, 0.022 mmol). After stirring overnight, the
mixture was quenched with sat. aq. NaHCO.sub.3 solution. The
mixture was extracted with ethyl acetate (2.times.). The combined
organic layers were washed with sat. aq. NaCl solution, dried over
Na.sub.2SO.sub.4, and concentrated. The residue was purified by
flash chromatography on silica gel (eluent: 1 to 5%
methanol/dichloromethane) to afford the title compound.
Step B.
2-((3R,5R,6S)-1-((S)-1-((1R,4R)-2-oxa-5-azabicyclo[2.2.1]heptan-5--
yl)butan-2-yl)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-2-oxopiperid-
in-3-yl)acetic acid--TFA salt
[2572] To a solution of
(3S,5R,6S)-1-((S)-1-((1R,4R)-2-Oxa-5-azabicyclo[2.2.1]heptan-5-yl)butan-2-
-yl)-3-allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methylpiperidin-2-one
(87 mg, 0.17 mmol; Example 209, Step A) in THF (0.8 mL), water (0.4
mL), and t-butanol (0.4 mL) was added 4-methylmorpholine N-oxide
(29 mg, 0.25 mmol) and 5 drops of 4% aq. OsO.sub.4. After 18 hours,
Jones' Reagent (0.20 mL) was added. After 24 hours, 50 mL water was
added to the mixture and then the mixture was extracted with ethyl
acetate (3.times.). The combined organic layers were washed with
water, dried over Na.sub.2SO.sub.4 and concentrated. The residue
was purified by reverse phase preparatory HPLC (column: Gemini-NX
C.sub.18 5 um column; Phenomonex, Torrance, Calif.; eluent: 0 to
100% MeCN+0.1% TFA in water+0.1% TFA, over 20 minutes) to afford
the title compound.
[2573] .sup.1H NMR (400 MHz, CHLOROFORM-d) .delta. ppm 0.95-1.17
(m, 3H) 1.30-1.53 (m, 5H) 1.75-1.95 (m, 1H) 2.03-2.17 (m, 2H)
2.18-2.32 (m, 2H) 2.37-2.54 (m, 1H) 2.59-2.79 (m, 2H) 2.80-2.94 (m,
1H) 3.17-3.32 (m, 1H) 3.73-3.93 (m, 2H) 3.95-4.14 (m, 1H) 4.40-4.55
(m, 2H) 4.56-4.65 (m, 1H) 4.90-5.23 (m, 1H) 6.58-6.73 (m, 1H)
6.93-7.02 (m, 1H) 7.04-7.09 (m, 1H) 7.14 (d, J=7.43 Hz, 2H)
7.23-7.36 (m, 3H). Mass Spectrum (ESI) m/z=545.2 (M+1).
Example 210
2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-1-((S)-1-((S)-
-3-methylmorpholino)butan-2-yl)-2-oxopiperidin-3-yl)acetic acid or
2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-1-((S)-1-((R-
)-3-methylmorpholino)butan-2-yl)-2-oxopiperidin-3-yl)acetic
acid
##STR00603##
[2574] Step A.
2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-2-oxo-1-((2S-
)-1-oxobutan-2-yl)piperidin-3-yl)acetic acid
##STR00604##
[2576] To a -78.degree. C. solution of oxalyl chloride (0.166 mL,
0.332 mmol) in dichloromethane (2 mL) was added dimethylsulfoxide
(0.047 mL, 0.663 mmol) dropwise. After ten minutes,
2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-hydroxybutan-
-2-yl)-3-methyl-2-oxopiperidin-3-yl)acetic acid (140 mg, 0.301
mmol; Example 185) in dichloromethane (2 mL) was added dropwise.
After 15 minutes, triethylamine (0.210 mL, 1.507 mmol) was added
dropwise. The mixture was warmed to 0.degree. C. for 10 minutes and
then quenched with 10% aq. citric acid. The mixture was diluted
with water and extracted with dichloromethane (2.times.). The
combined organic layers were washed with sat. aq. NaCl solution,
dried over anhydrous Na.sub.2SO.sub.4, and concentrated to afford
the title compound.
Step B.
2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-1-((2-
S)-1-(3-methylmorpholino)butan-2-yl)-2-oxopiperidin-3-yl)acetic
acid
[2577] To a solution of
2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-2-oxo-1-((S)-
-1-oxobutan-2-yl)piperidin-3-yl)acetic acid (960 mg, 2.076 mmol;
Example 210, Step A) in 1,2-dichloroethane (15 mL) was added
3-methylmorpholine (Enamine Ltd, Kiev, Ukraine) (0.471 mL, 4.15
mmol) and sodium triacetoxyborohydride (880 mg, 4.15 mmol). After
stirring overnight, the mixture was quenched with sat. aq.
NH.sub.4Cl solution. The mixture was extracted with dichloromethane
(2.times.). The combined organic layers were washed with sat. aq.
NaCl solution, dried over anhydrous Na.sub.2SO.sub.4, and
concentrated. The residue was purified by flash chromatography on
silica gel (eluent: 1 to 10% methanol/dichloromethane) to afford
the title compound as the major diastereomer. Stereochemistry of
the 3-morpholine stereocenter is unknown.
[2578] .sup.1H NMR (400 MHz, CHLOROFORM-d) .delta. ppm 0.50 (t,
J=7.53 Hz, 3H) 1.02 (d, J=6.26 Hz, 3H) 1.46 (s, 3H) 1.54-1.68 (m,
1H) 1.85-1.98 (m, 2H) 2.01-2.06 (m, 1H) 2.15-2.28 (m, 2H) 2.58-2.89
(m, 4H) 2.97-3.13 (m, 2H) 3.26-3.37 (m, 1H) 3.55-3.71 (m, 2H)
3.77-3.85 (m, 1H) 3.90 (d, J=10.96 Hz, 1H) 4.78 (d, J=10.17 Hz, 1H)
6.77 (dt, J=7.48, 1.54 Hz, 1H) 6.82-6.96 (m, 2H) 6.97-7.02 (m, 1H)
7.08-7.30 (m, 4H). Mass Spectrum (ESI) m/z=547.2 (M+1).
Example 211
2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-(thiomorpholi-
no-1,1-dioxide)butan-2-yl)-3-methyl-2-oxopiperidin-3-yl)acetic
acid
##STR00605##
[2580] To a solution of
2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-2-oxo-1-((S)-
-1-oxobutan-2-yl)piperidin-3-yl)acetic acid (0.101 g, 0.219 mmol;
Example 210, Step A) in 1,2-dichloroethane (3 mL) was added
thiomorpholine 1,1-dioxide (0.128 g, 0.947 mmol), sodium
triacetoxyborohydride (0.093 g, 0.438 mmol), and 2 drops of acetic
acid. After stirring for 2 days, the mixture was quenched with
water. The mixture was extracted with ethyl acetate (2.times.). The
combined organic layers were washed with sat. aq. NaCl solution,
dried over anhydrous Na.sub.2SO.sub.4, and concentrated. The
colorless film was purified by reverse phase preparatory HPLC
(column: Gemini-NX C.sub.18 5 um column; Phenomonex, Torrance,
Calif.; eluent: 0 to 100% MeCN+0.1% TFA in water+0.1% TFA, over 20
minutes). Fractions containing the product were transferred to a
separatory funnel and sat. aq. NaHCO.sub.3 solution and
dichloromethane were added. The aqueous layer was back extracted
with dichloromethane. The combined organic layers were washed with
sat. aq. NaCl solution, dried over anhydrous Na.sub.2SO.sub.4, and
concentrated to afford the title compound.
[2581] .sup.1H NMR (400 MHz, CHLOROFORM-d) .delta. ppm 0.66 (t,
J=7.14 Hz, 3H) 1.46 (s, 4H) 1.53-1.64 (m, 1H) 1.78-1.91 (m, 1H)
1.99-2.26 (m, 5H) 2.77 (d, J=15.06 Hz, 1H) 2.91-3.17 (m, 9H) 4.41
(d, J=9.98 Hz, 1H) 6.73 (d, J=7.43 Hz, 1H) 6.90-6.91 (m 1H)
7.09-7.22 (m, 2H) 7.23-7.30 (m, 4H). Mass Spectrum (ESI) m/z=581.2
(M+1).
Example 212
2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-(3,3-difluoro-
azetidin-1-yl)butan-2-yl)-3-methyl-2-oxopiperidin-3-yl)acetic
acid
##STR00606##
[2583] To a solution of
2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-2-oxo-1-((S)-
-1-oxobutan-2-yl)piperidin-3-yl)acetic acid (99 mg, 0.215 mmol;
Example 210, Step A) in 1,2-dichloroethane (3 mL) was added
3,3-difluoroazetidine hydrochloride (55.7 mg, 0.430 mmol) followed
by sodium triacetoxyborohydride (91 mg, 0.430 mmol). After stirring
overnight, the mixture was quenched with water. The mixture was
extracted with ethyl acetate (2.times.). The combined organic
layers were washed with sat. aq. NaCl solution, dried over
anhydrous Na.sub.2SO.sub.4 and concentrated. The residue was
purified by reverse phase preparatory HPLC (column: Gemini-NX
C.sub.18 5 um column; Phenomonex, Torrance, Calif.; eluent: 0 to
100% MeCN+0.1% TFA in water+0.1% TFA, over 20 minutes). Fractions
containing the product were transferred to a separatory funnel and
sat. aq. NaHCO.sub.3 and dichloromethane were added. The aqueous
layer was back extracted with dichloromethane. The combined organic
layers were washed with sat. aq. NaCl solution, dried over
anhydrous Na.sub.2SO.sub.4, filtered and the filtrate was
concentrated to afford the title compound.
[2584] .sup.1H NMR (400 MHz, ACETONITRILE-d.sub.3) .delta. ppm 0.48
(t, J=7.53 Hz, 3H) 1.32 (s, 3H) 1.46-1.62 (m, 1H) 1.68-1.82 (m, 1H)
1.90-1.98 (m, 2H) 2.01-2.05 (m 1H) 2.13-2.23 (m, 1H) 2.40 (dd,
J=12.42, 4.99 Hz, 1H) 2.67-2.78 (m, 1H) 2.82-2.92 (m, 1H) 3.16-3.29
(m, 1H) 3.43-3.70 (m, 4H) 4.55 (d, J=10.37 Hz, 1H) 6.96 (td,
J=4.35, 1.66 Hz, 1H) 7.03-7.10 (m, 1H) 7.12-7.21 (m, 4H) 7.23-7.31
(m, 2H). Mass Spectrum (ESI) m/z=539.0 (M+1).
Example 213
2-((3R,5R,6S)-1-((2S)-1-(8-oxa-3-azabicyclo[3.2.1]octan-3-yl)butan-2-yl)-5-
-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-2-oxopiperidin-3-yl)acetic
acid
##STR00607##
[2586] To a solution of
2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-2-oxo-1-((S)-
-1-oxobutan-2-yl)piperidin-3-yl)acetic acid (99 mg, 0.215 mmol;
Example 210, Step A) in DCE (3 mL) was added 48.7 mg (0.43 mmol) of
8-oxa-3-azabicyclo[3.2.1]octane (Connolly, T.; Considine, J.; Ding,
Z.; Forsatz, B.; Jennings, M.; MacEwan, M.; McCoy, K.; Place, D.;
Sharma, A.; Sutherland, K. Organic Process Research &
Development. 2010, 14 (2), 459-465. Note: reference is for the HCl
Salt). Sodium triacetoxyborohydride (91 mg, 0.430 mmol) was added
followed by acetic acid (1.2 .mu.L, 0.022 mmol). After stirring
overnight, the mixture was partitioned between 5% aq. HCl and ethyl
acetate. The organic layer was washed with sat. aq. NaCl solution,
dried over Na.sub.2SO.sub.4, and concentrated. The residue was
purified by reversed phase preparatory HPLC (eluent: 0-100%
MeCN+0.1% TFA in water+0.1% TFA, over 20 minutes). Fractions
containing the product were transferred to a separatory funnel and
sat. aq. NaHCO.sub.3 and dichloromethane were added. The aqueous
layer was back extracted with dichloromethane. The combined organic
layers were washed with sat. aq. NaCl solution, dried over
anhydrous Na.sub.2SO.sub.4, filtered and the filtrate was
concentrated to afford the title compound.
[2587] .sup.1H NMR (400 MHz, CHLOROFORM-d) .delta. ppm 0.37-0.53
(m, 3H) 1.48-1.58 (m, 4H) 1.83-2.15 (m, 7H) 2.18-2.31 (m, 2H) 2.50
(s, 2H) 2.60 (d, J=10.76 Hz, 1H) 2.70 (d, J=15.65 Hz, 1H) 2.96-3.17
(m, 4H) 4.29-4.42 (m, 2H) 4.55 (d, J=10.56 Hz, 1H) 6.65 (dt,
J=7.68, 1.44 Hz, 1H) 6.94-7.02 (m, 1H) 7.06-7.13 (m, 1H) 7.14-7.21
(m, 1H) 7.21-7.33 (m, 4H). Mass Spectrum (ESI) m/z=559.2 (M+1).
Example 214
2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-(3,3-dimethyl-
morpholino)butan-2-yl)-3-methyl-2-oxopiperidin-3-yl)acetic acid
##STR00608##
[2589] To a solution of
2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-2-oxo-1-((S)-
-1-oxobutan-2-yl)piperidin-3-yl)acetic acid (70 mg, 0.151 mmol;
Example 210, Step A) in DCE (3 mL) was added 45.9 mg (0.303 mmol)
of 3,3-dimethylmorpholine hydrochloride (Cottle, D.; Jeltsch, A.;
Stoudt, T.; Walters, D. Journal of Organic Chemistry. 1946, 11 (3),
286-91.; Note: reference is for the free base) and sodium
triacetoxyborohydride (64.2 mg, 0.303 mmol). After stirring
overnight, the mixture was diluted with sat. aq. NH.sub.4Cl
solution. The mixture was extracted with DCM (2.times.). The
combined organic layers were washed with sat. aq. NaCl solution,
dried over anhydrous Na.sub.2SO.sub.4, filtered and the filtrate
was concentrated. The residue was purified by preparative thin
layer chromatography on silica gel (eluent: 50% ethyl
acetate/hexanes). The product containing fractions were pooled,
concentrated and repurified by preparative thin layer
chromatography on silica gel (eluent: 10% MeOH/DCM) to afford the
title compound.
[2590] .sup.1H NMR (400 MHz, CHLOROFORM-d) .delta. ppm 0.47-0.51 (m
3H) 0.92-1.07 (m, 6H) 1.26 (s, 3H) 1.44-1.48 (m 6H) 1.83-1.98 (m,
2H) 1.99-2.08 (m, 1H) 2.14-2.52 (m, 3H) 3.34-3.37 (m 1H) 3.42-3.52
(m, 1H) 3.57-3.69 (m, 1H) 3.87 (d, J=10.96 Hz, 1H) 4.86 (d, J=11.15
Hz, 1H) 6.77 (d, J=7.43 Hz, 1H) 6.94-7.05 (m, 1H) 7.08-7.30 (m,
6H). Mass Spectrum (ESI) m/z=561.3 (M+1).
Example 215
2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-(3-hydroxy-3--
(trifluoromethyl)azetidin-1-yl)butan-2-yl)-3-methyl-2-oxopiperidin-3-yl)ac-
etic acid
##STR00609##
[2592] To a solution of
2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-2-oxo-1-((S)-
-1-oxobutan-2-yl)piperidin-3-yl)acetic acid (70 mg, 0.151 mmol;
Example 210, Step A) in DCE (3 mL) was added 53.8 mg (0.303 mmol)
of 3-(trifluoromethyl)azetidin-3-ol hydrochloride (U.S. patent
application publication no 2007/0275930) and sodium
triacetoxyborohydride (64.2 mg, 0.303 mmol). After stirring for 18
hours, the mixture was partitioned between water and DCM. The
aqueous layer was washed with DCM. The combined organic layers were
washed with sat. aq. NaCl solution, dried over anhydrous
Na.sub.2SO.sub.4, filtered and the filtrate was concentrated. The
residue was purified by preparative thin layer chromatography on
silica gel (eluent: 50% ethyl acetate/hexanes) to afford the title
compound.
[2593] .sup.1H NMR (400 MHz, MeOH) .delta. ppm 0.51 (t, J=7.43 Hz,
3H) 1.36 (s, 3H) 1.50-1.66 (m, 1H) 1.71-1.86 (m, 1H) 2.09-2.26 (m,
2H) 2.38 (dd, J=12.52, 3.91 Hz, 1H) 2.52-2.64 (m, 1H) 2.75 (br. s.,
1H) 2.93 (d, J=14.87 Hz, 1H) 3.11-3.27 (m, 2H) 3.28-3.43 (m, 3H)
3.66-3.79 (m, 2H) 4.62 (d, J=10.56 Hz, 1H) 6.86-6.98 (m, 1H) 7.03
(s, 1H) 7.09-7.22 (m, 4H) 7.27 (d, J=7.24 Hz, 2H). Mass Spectrum
(ESI) m/z=587.2 (M+1).
Example 216
2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-1-((S)-1-(met-
hyl(oxetan-3-yl)amino)butan-2-yl)-2-oxopiperidin-3-yl)acetic
acid
##STR00610##
[2594] Step A.
2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-1-((S)-1-(me-
thylamino)butan-2-yl)-2-oxopiperidin-3-yl)acetic acid-ammonium
salt
##STR00611##
[2596] To a solution of
2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-2-oxo-1-((S)-
-1-oxobutan-2-yl)piperidin-3-yl)acetic acid (201 mg, 0.434 mmol;
Example 210 Step A) in DCE (3 mL) was added methylamine
hydrochloride (117 mg, 1.736 mmol) followed by sodium
triacetoxyborohydride (184 mg, 0.868 mmol). After 4 hours, the
mixture was diluted with methanol and DCM, filtered, and
concentrated. The residue was purified by flash chromatography on
silica gel (eluent: 20-100% ethylacetate/hexanes followed by
6:1:0.1 DCM:MeOH:NH.sub.4OH) to afford the title compound.
Step B.
2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-1-((S-
)-1-(methyl(oxetan-3-yl)amino)butan-2-yl)-2-oxopiperidin-3-yl)acetic
acid
[2597] To a solution of oxetan-3-one (17.78 mg, 0.247 mmol) in DCE
(3 mL) was added
2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-1--
((S)-1-(methylamino)butan-2-yl)-2-oxopiperidin-3-yl)acetic acid
ammonium salt (61 mg, 0.123 mmol) obtained in Step A followed by
sodium triacetoxyborohydride (78 mg, 0.370 mmol) and 3 drops AcOH.
After 45 minutes, 3 ml MeOH and oxetan-3-one (12 mg, 0.17 mmol)
were added. After stirring overnight, oxetan-3-one (12 mg, 0.17
.mu.mol) and sodium triacetoxyborohydride (60 mg, 0.32 mmol) were
added. After 24 hours, the mixture was diluted with methanol and
evaporated onto silica gel. The solid was purified by flash
chromatography on silica gel (eluent: 0 to 100% [6:1:0.1
DCM/MeOH/NH.sub.4OH] in DCM). The product containing fractions were
pooled, concentrated and repurified by preparative thin layer
chromatography on silica gel (eluent: 10% MeOH/DCM) to afford the
title compound.
[2598] .sup.1H NMR (400 MHz, CHLOROFORM-d) .delta. ppm 0.51 (t,
J=7.53 Hz, 3H) 0.78-0.93 (m, 1H) 1.14-1.32 (m, 3H) 1.87-1.95 (m 1H)
2.04 (d, J=13.30 Hz, 1H) 2.12 (s, 3H) 2.19-2.38 (m, 2H) 2.71 (d,
J=15.65 Hz, 1H) 2.99-3.15 (m, 3H) 3.44-3.60 (m, 1H) 4.44-4.81 (m,
6H) 6.81 (d, J=7.24 Hz, 1H) 6.94-7.04 (m, 2H) 7.09-7.21 (m, 2H)
7.23-7.31 (m, 3H). Mass Spectrum (ESI) m/z=533.2 (M+1).
Example 217
2-((3R,5R,6S)-5-(3-Chlorophenyl)-6-(4-chlorophenyl)-3-methyl-2-oxo-1-((S)--
1-(2-oxooxazolidin-3-yl)butan-2-yl)piperidin-3-yl)acetic acid
##STR00612##
[2599] Step A.
(3S,5R,6S)-3-allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-((2-hyd-
roxyethyl)amino)butan-2-yl)-3-methylpiperidin-2-one and
(3S,5R,6S)-3-allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((R)-1-((2-hyd-
roxyethyl)amino)butan-2-yl)-3-methylpiperidin-2-one
##STR00613##
[2601]
(S)-2-((3S,5R,6S)-3-Allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-m-
ethyl-2-oxopiperidin-1-yl)butanal (180 mg, 0.405 mmol; Example 91,
Step C) in ClCH.sub.2CH.sub.2Cl (1 mL) was stirred with sodium
triacetoxyborohydride (172 mg, 0.81 mmol), ethanolamine (0.04 mL,
0.73 mmol) and acetic acid (0.06 mL, 1.013 mmol) at ambient
temperature for 18 h, by which time analysis by LC-MS indicated the
presence of the desired product. The mixture was partitioned
between saturated NaHCO.sub.3 and CH.sub.2Cl.sub.2. The organic
layer was concentrated, and the residue purified by chromatography
(silica gel, hexane/EtOAc, then EtOAc/MeOH, up to 15%) to afford
the title compounds as a 1:1 mixture of two diastereomers. MS (ESI)
m/z=489 (M+1).
Step B.
3-((S)-2-((3S,5R,6S)-3-Allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-
-3-methyl-2-oxopiperidin-1-yl)butyl)oxazolidin-2-one and
3-((R)-2-((3S,5R,6S)-3-Allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-meth-
yl-2-oxopiperidin-1-yl)butyl)oxazolidin-2-one
##STR00614##
[2603] A mixture of
(3S,5R,6S)-3-allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-((2-hyd-
roxyethyl)amino)butan-2-yl)-3-methylpiperidin-2-one and
(3S,5R,6S)-3-allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((R)-1-((2-hyd-
roxyethyl)amino)butan-2-yl)-3-methylpiperidin-2-one (60 mg, 0.123
mmol; Example 217, Step A) was mixed with 1,1'-carbonyldiimidazole
(99 mg, 0.61 mmol) and 1,8-diazabicyclo[5.4.0]undec-7-ene (37 mg,
0.245 mmol) in 1,4 dioxane (1 mL). The mixture was heated to
100.degree. C. in an oil bath for 18 h.
[2604] The mixture was allowed to cool to ambient temperature, was
diluted with EtOAc and washed with water three times. The crude
product was then filtered through a pad comprised of silica gel and
Na.sub.2SO.sub.4 to give the title compound, which was used without
further purification. MS (ESI) m/z=515 (M+1).
Step C.
2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-1-((2-
S)-1-(5-methyl-2-oxooxazolidin-3-yl)butan-2-yl)-2-oxopiperidin-3-yl)acetic
acid
[2605] The title compound was prepared from the mixture obtained in
Example 217, Step B by a procedure similar to the one described in
Example 71, Step F. A mixture of two diastereomers was isolated,
which was then further purified by chiral separation to afford the
title compound (250.times.30 mm Chiralpak.RTM. IC column (Chiral
Technologies, Inc., West Chester, Pa., USA) with 32 g/min MeOH (20
mM NH.sub.3)).
[2606] .sup.1H NMR (CDCl.sub.3, 500 MHz) .delta. ppm 0.57 (t, 3H),
1.50 (s, 3H), 1.70 (m, 1H), 1.90 (m, 1H), 2.00 (m, 1H), 2.25 (t,
1H), 2.78 (br, 1H), 2.98 (br, 1H), 3.13 (m, 3H), 3.62 (m, 2H), 3.85
(br, 1H), 4.40 (m, 3H), 6.67 (m, 1H), 6.93 (s, 1H), 6.99 (br, 2H),
7.14 (m, 2H), 7.24 (m, 2H). MS (ESI) m/z=533 (M+1).
Example 218
2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-2-oxo-1-((S)--
1-(2-oxopyridin-1(2H)-yl)butan-2-yl)piperidin-3-yl)acetic acid
##STR00615##
[2607] Step A.
(3S,5R,6S)-3-Allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-hydroxy-
butan-2-yl)-3-methylpiperidin-2-one
##STR00616##
[2609]
(3S,5R,6S)-3-Allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-h-
ydroxybutan-2-yl)-3-methylpiperidin-2-one (60 mg, 0.134 mmol;
Example 91, Step C) was mixed with triphenylphosphine (42 mg, 0.161
mmol), 2-hydroxypyridine (14.1 mg. 0.148 mmol) and diisopropyl
azodicarboxylate (0.029 mL, 0.148 mmol) in toluene in an oven-dried
3-neck roundbottom flask. The mixture was stirred at ambient
temperature for 18 h under nitrogen. Solvent was evaporated. The
residue was then purified by chromatography (silica gel,
hexane/EtOAc, 1:0 to 2:3) to afford the title compound as a
colorless oil.
Step B.
2-((3R,5R,6S)-5-(3-Chlorophenyl)-6-(4-chlorophenyl)-3-methyl-2-oxo-
-1-((S)-1-(2-oxopyridin-1(2H)-yl)butan-2-yl)piperidin-3-yl)acetic
acid
[2610] To a 25 mL roundbottom flask charged with
(3S,5R,6S)-3-allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-hydroxy-
butan-2-yl)-3-methylpiperidin-2-one (35 mg, 0.067 mmol; Example
218, Step A) was added THF, water (until the reaction became and
remained cloudy with gentle stirring), and tBuOH (until the cloudy
reaction became translucent). 4-Methylmorpholine 4-oxide
monohydrate (13.6 mg, 0.10 mmol) was added followed by osmium
tetroxide, 4 wt. %, in water (0.016 mL, 0.067 mmol). The reaction
was allowed to stir at ambient temperature for 16 h to complete the
formation of the diol. To the resulting mixture was added Jones
reagent (70 .mu.L) at ambient temperature and stirring was
continued for 18 h. The reaction was quenched with water, diluted
with EtOAc, and extracted with additional EtOAc (3.times.8 mL). The
combined organic layers were washed with water, dried over
MgSO.sub.4, filtered and the filtrate was concentrated. The light
greenish residue was purified by preparative HPLC to afford the
title compound.
[2611] .sup.1H NMR (CDCl.sub.3, 400 MHz) .delta. ppm 0.53 (t, 3H),
1.43 (s, 3H), 1.68 (m, 1H), 1.85 (t, 1H), 2.03 (m, 2H), 2.65 (m,
1H), 2.91 (m, 1H), 3.30 (m, 2H), 3.72 (m, 1H), 4.25 (m, 1H), 4.42
(m, 1H), 6.71 (m, 4H), 7.70 (m, 4H), 7.26 (m, 2H), 7.51 (m, 1H),
7.77 (m, 1H). Mass spectrum (ESI) m/z=541 (M+1).
Example 219
2-((3R,5R,6S)-5-(3-Chlorophenyl)-6-(4-chlorophenyl)-3-methyl-2-oxo-1-((S)--
1-(2-oxo-5-(trifluoromethyl)pyridin-1(2H)-yl)butan-2-yl)piperidin-3-yl)ace-
tic acid
##STR00617##
[2613]
2-((3R,5R,6S)-5-(3-Chlorophenyl)-6-(4-chlorophenyl)-3-methyl-2-oxo--
1-((S)-1-(2-oxo-5-(trifluoromethyl)pyridin-1(2H)-yl)butan-2-yl)piperidin-3-
-yl)acetic acid was prepared using the procedure described for
example 218 by using 2-hydroxy-5-(trifluoromethyl)pyridine, and
tri-n-butylphosphine, azodicarboxylic dipiperidine in Step A.
[2614] .sup.1H NMR (CDCl.sub.3, 500 MHz) .delta. ppm 0.54 (t, 3H),
1.42 (s, 3H), 1.60 (m, 1H), 1.78 (m, 1H), 2.01 (m, 2H), 2.77-2.93
(m, 2H), 3.13 (m, 1H), 3.42 (m, 1H), 3.81 (m, 1H), 4.32 (m, 2H),
6.50 (m, 1H), 6.71 (m, 1H), 6.77 (m, 1H), 6.91 (br, 2H), 7.03 (m,
1H), 7.11 (m, 1H), 7.23 (m, 2H), 7.69 (m, 2H). Mass spectrum (ESI)
m/z=609 (M+1).
Example 220
(3S,5R,6S)-3-allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-1-((S)-1-
-(pyridin-3-yloxy)butan-2-yl)piperidin-2-one
##STR00618##
[2616]
(3S,5R,6S)-3-Allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-1-
-((S)-1-(pyridin-2-yloxy)butan-2-yl)piperidin-2-one (10 mg) was
prepared as described for example 218 using 3-hydroypyridine in
place of 2 hydroxypyridine.
[2617] .sup.1H NMR (MeOH-d.sub.4, 500 MHz) .delta. ppm 0.62 (m,
3H), 1.27 (s, 3H), 1.70 (m, 1H), 1.97 (m, 1H), 2.18 (m, 2H), 2.59
(m, 1H), 2.96 (m, 1H), 3.44 (m, 2H), 4.11 (m, 1H), 4.58 (m, 1H),
4.70 (m, 1H), 6.97 (m, 1H), 7.06 (m, 1H), 7.15-7.28 (m, 6H), 7.81
(m, 1H), 7.98 (m, 1H), 8.37 (m, 1H), 8.56 (s, 1H). Mass spectrum
(ESI) m/z=541 (M+1).
Example 221
2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-2-oxo-1-((1S)-
-1-(tetrahydrofuran-2-yl)propyl)piperidin-3-yl)acetic acid (Isomer
1)
##STR00619##
[2618] Step A.
(3S,5R,6S)-3-allyl-1-((3S)-7-((tert-butyldimethylsilyl)oxy)-4-hydroxyhept-
an-3-yl)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methylpiperidin-2-one
##STR00620##
[2620] The Grignard reagent derived from of
(3-bromopropoxy)(tert-butyl)dimethylsilane was prepared on 1.8 mmol
scale according to Minguez, et al. Biorg. Med. Chem. 11, 3335, 2003
as a gray solution in THF (.about.3 mL). About 1.5 mL of the
Grignard regent was added slowly to a solution of
(S)-2-((3S,5R,6S)-3-allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl--
2-oxopiperidin-1-yl)butanal (100 mg, 0.22 mmol; Example 91, Step C)
in THF (1 mL) at ambient temperature. After 2 h, the reaction was
diluted in ethyl acetate and washed with saturated ammonium
chloride solution followed by sat. aq. NaCl solution. The organic
layer was dried over sodium sulfate and concentrated. Purification
by silica chromatography eluting with ethyl acetate/hexane provided
the title compound as a mixture of diastereomers.
[2621] .sup.1H NMR (400 MHz, CHLOROFORM-d) representative
signals:
[2622] major diastereomer .delta. ppm 1.17 (s, 3H), 4.25 (d J=10.6
Hz, 1H).
[2623] minor diastereomer .delta. ppm 1.21 (s, 3H), 4.37 (d, J=10.6
Hz, 1H).
[2624] Mass Spectrum (ESI) m/z=618.4 (M+1).
Step B.
(3S,5R,6S)-3-allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((3S)-4-
,7-dihydroxyheptan-3-yl)-3-methylpiperidin-2-one
##STR00621##
[2626] A solution of
(3S,5R,6S)-3-allyl-1-((3S)-7-(tert-butyldimethylsilyloxy)-4-hydroxyheptan-
-3-yl)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methylpiperidin-2-one
(127 mg, 0.21 mmol; Example 221, Step A) in THF (1.5 mL) was
treated with tetrabutylammonium fluoride (0.62 mL 1M in THF, 0.62
mmol) at ambient temperature for 1.5 hours. The solvent was removed
under vacuum. Purification by silica chromatography eluting with
ethyl acetate/hexane provided the title compound as a mixture of
diastereomers.
[2627] .sup.1H NMR (400 MHz, CHLOROFORM-d) representative
signals:
[2628] major diastereomer .delta. ppm 1.15 (s, 3H), 4.26 (d J=10.6
Hz, 1H),
[2629] minor diastereomer .delta. ppm 1.20 (s, 3H), 4.31 (d, J=10.6
Hz, 1H).
[2630] Mass Spectrum (ESI) m/z=504.3 (M+1).
Step C.
(3S,5R,6S)-3-allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl--
1-((S)-1-((S)-tetrahydrofuran-2-yl)propyl)piperidin-2-one and
(3S,5R,6S)-3-allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-1-((S)--
1-((R)-tetrahydrofuran-2-yl)propyl)piperidin-2-one
##STR00622##
[2632] A solution of
(3S,5R,6S)-3-allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((3S)-4,7-dihy-
droxyheptan-3-yl)-3-methylpiperidin-2-one (55 mg, 0.11 mmol;
Example 221, Step B) and triphenylphosphine (57.2 mg, 0.22 mmol) in
dichloromethane (2 mL) was treated with (E)-diethyl
diazene-1,2-dicarboxylate (0.033 ml, 0.22 mmol) at ambient
temperature for 2 hours. Purification by silica chromatography
eluting with ethyl acetate/hexane provided one of the title
compounds as the major diastereomer as the first eluting compound
followed by the minor diastereomer.
(3S,5R,6S)-3-allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-1-((1S)--
1-(tetrahydrofuran-2-yl)propyl)piperidin-2-one (major diastereomer;
first eluting compound)
[2633] .sup.1H NMR (400 MHz, CHLOROFORM-d) .delta. ppm 0.65 (t,
J=7.43 Hz, 3H) 1.20 (s, 3H) 1.51-1.58 (m, 3H), 1.71 (m, 3H),
1.83-1.97 (m, 4H), 2.54-2.57 (dd, J=7.53, 3.62 Hz, 2H), 3.08-3.14
(ddd, J=13.01, 10.47, 3.72 Hz, 1H), 3.53-3.58 (m, 2H), 3.73-3.77
(m, 1H), 4.30 (d, J=10.56 Hz, 1H), 5.08 (s, 1H), 5.11 (d, J=4 Hz,
1H), 5.74-5.84 (m, 1H), 6.62-6.64 (d, J=8 Hz, 1H), 6.86 (s, 3H),
7.02 (t, J=8 Hz, 1H), 7.04-7.09 (s, 1H), 7.15 (d, J=4 Hz, 2H). Mass
Spectrum (ESI) m/z=486.3 (M+1).
(3S,5R,6S)-3-allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-1-((1S)--
1-(tetrahydrofuran-2-yl)propyl)piperidin-2-one (minor diastereomer;
second eluting compound)
[2634] .sup.1H NMR (400 MHz, CHLOROFORM-d) .delta. ppm 0.47 (t,
J=7.53 Hz, 3H), 1.10-1.21 (m, 4H), 1.36-1.46 (m, 1H), 1.51 (s, 1H),
1.73-2.06 (m, 5H), 2.45-2.59 (m, 3H), 3.07-3.14 (ddd, J=13.60,
10.56, 3.23 Hz, 1H) 3.70-3.80 (m, 2H) 4.37 (d, J=0.59 Hz, 1H) 4.69
(d, J=10.76 Hz, 1H) 5.14-5.23 (m, 2H) 5.75-5.85 (m, J=17.17, 9.83,
7.43, 7.43 Hz, 1H) 6.68 (dt, J=7.38, 1.59 Hz, 1H) 6.90-6.94 (m, 3H)
7.04 (m, 2H), 7.12 (d, J=8 Hz, 2H). Mass Spectrum (ESI) m/z=486.3
(M+1)
Step D.
2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-2-oxo-
-1-((1S)-1-(tetrahydrofuran-2-yl)propyl)piperidin-3-yl)acetic acid
(Isomer 1)
[2635] The title compound was prepared from
(3S,5R,6S)-3-allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-1-((1S)-
-1-(tetrahydrofuran-2-yl)propyl)piperidin-2-one (major
diastereomer; first eluting compound; Example 121, Step C) by a
procedure similar to the one described in Example 71, Step F.
[2636] .sup.1H NMR (400 MHz, CHLOROFORM-d) .delta. ppm 0.61 (t,
J=7.63 Hz, 3H) 1.34 (s, 3H) 1.46-1.56 (m, 2H) 1.72 (s, br, 3H)
1.82-1.89 (m, 2H) 2.00-2.14 (m, 2H) 2.61 (d, J=13.89 Hz, 2H)
2.76-2.84 (m, 2H) 3.20 (dd, J=13.30, 7.24 Hz, 2H) 3.29 (br. s., 1H)
3.73 (td, J=7.87, 5.18 Hz, 1H) 4.34 (d, J=10.37 Hz, 1H) 6.68 (dd,
J=7.43, 1.56 Hz, 1H) 6.87 (s, 1H) 7.00-7.15 (m, 4H) 7.14 (dd,
J=8.12, 0.5 Hz, 2H). Mass Spectrum (ESI) m/z=504.3 (M+1)
Example 222
2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-2-oxo-1-((1S)-
-1-(tetrahydrofuran-2-yl)propyl)piperidin-3-yl)acetic acid (Isomer
2)
##STR00623##
[2638] The title compound was prepared from
(3S,5R,6S)-3-allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-1-((1S)-
-1-(tetrahydrofuran-2-yl)propyl)piperidin-2-one (minor
diastereomer; second eluting compound; Example 121, Step C) by a
procedure similar to the one described in Example 71, Step F.
[2639] .sup.1H NMR (400 MHz, CHLOROFORM-d) .delta. ppm 0.46 (t,
J=7.63 Hz, 3H) 1.15-1.26 (m, 3H) 1.36 (s, br. 3H), 1.46-1.50 (m,
1H), 1.79-1.85 (m, 4H), 2.05-2.09 (dd, J=12, 4 Hz, 1H), 2.17 (t,
J=12 Hz, 1H), 2.51 (s, br, 1H), 2.66 (d, J=12 Hz, 1H), 2.77 (d,
J=12 Hz, 1H), 3.76 (m, 2H), 4.68 (d, J=8 nHz, 1H), 6.76 (d, J=8 Hz,
1H), 6.92-7.03 (m, 3H), 7.06 (d, J=2.2 Hz, 2H), 7.16 (d, J=8.8 Hz,
2H). Mass Spectrum (ESI) m/z=504.3 (M+1)
Example 223
2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-2-oxo-1-((1S)-
-1-(5-oxotetrahydrofuran-2-yl)propyl)piperidin-3-yl)acetic acid
##STR00624##
[2641] The title compound was prepared using the oxidation
procedure of Example 221, but using a larger excess of sodium
periodate (7 eq) and reacting for a longer period of time (18
h).
[2642] .sup.1H NMR (400 MHz, CD.sub.3OD) .delta. ppm 0.7 (s, be,
3H), 1.42 (s, br, 3H), 1.68-1.75 (m, 1H), 1.96 (m, 1H), 2.21-2.24
(m, 3H), 2.33 (m, 1H), 2.49-2.67 (m, 3H), 2.97 (d, J=12 Hz, 1H),
3.37 (m, 2H), 3.51 (m, 1H), 4.60 (d, J=8 Hz, 1H), 6.96 (m, 1H),
7.10 (s, 1H) 7.13-7.19 (m, 2H), 7.31 (s, br, 4H). Mass Spectrum
(ESI) m/z=518.2 (M+1).
Example 224
2-((3R,5R,6S)-5-(3-Chlorophenyl)-6-(4-chlorophenyl)-3-methyl-2-oxo-1-((1S)-
-1-(tetrahydro-2H-pyran-2-yl)propyl)piperidin-3-yl)acetic acid
(Isomer 1)
##STR00625##
[2643] Step A.
(3S,5R,6S)-3-Allyl-1-((3S)-8-((tert-butyldimethylsilyl)oxy)-4-hydroxyocta-
n-3-yl)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methylpiperidin-2-one
##STR00626##
[2645] The title compound was prepared as a mixture of
diastereomers by a procedure similar to the one described in
Example 221, Step A, substituting
(4-chlorobutoxy)(tert-butyl)dimethylsilane for
(3-bromopropoxy)(tert-butyl)dimethylsilane during the preparation
of the Grignard reagent.
[2646] Mass Spectrum (ESI) m/z=632.2 (M+1).
Step B.
(3S,5R,6S)-3-Allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((3S)-4-
,8-dihydroxyoctan-3-yl)-3-methylpiperidin-2-one
##STR00627##
[2648] The title compound was obtained from
(3S,5R,6S)-3-allyl-1-((3S)-8-((tert-butyldimethylsilyl)oxy)-4-hydroxyocta-
n-3-yl)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methylpiperidin-2-one
(Example 224, Step B) by using a procedure similar to the one
described in Example 221, Step B. The diastereomer ratio was
observed by NMR to be about 2:1.
[2649] .sup.1H NMR (400 MHz, d.sub.4-methanol) representative
signals:
[2650] major diastereomer .delta. ppm 0.45 (t, J=7.6 Hz, 3H), 4.76
(d, J=12 Hz, 1H).
[2651] minor diastereomer: .delta. ppm 0.54 (t, J=7.6 Hz, 3H), 4.53
(d, J=12 Hz, 1H).
[2652] m/z=518.2 (M+1).
Step C.
(3S,5R,6S)-3-allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl--
1-((1S)-1-(tetrahydro-2H-pyran-2-yl)propyl)piperidin-2-one
##STR00628##
[2654] A solution of
(3S,5R,6S)-3-allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((3S)-4,8-dihy-
droxyoctan-3-yl)-3-methylpiperidin-2-one (31 mg, 0.060 mmol;
diastereomeric mixture; Example 224, Step B) and triphenylphosphine
(31.4 mg, 0.12 mmol) in dichloromethane (1.5 mL) was treated with
(E)-diethyl diazene-1,2-dicarboxylate (0.02 ml, 0.12 mmol) at
ambient temperature for 2 hours. Purification by silica
chromatography eluting with ethyl acetate/hexane provided the title
compound as a mixture of diastereomers.
[2655] .sup.1H NMR (400 MHz, d4-Methanol) representative
signals:
[2656] major diastereomer .delta. ppm 0.46 (t, J=8 Hz, 3H), 4.75
(d, J=12 Hz, 1H).
[2657] minor diastereomer .delta. ppm 0.55 (t, J=8 Hz, 3H), 4.53
(d, J=12 Hz, 1H).
[2658] Mass Spectrum (ESI) m/z=500.2 (M+1)
Step D.
(3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-(2,3-dihydroxyp-
ropyl)-3-methyl-1-((1S)-1-(tetrahydro-2H-pyran-2-yl)propyl)piperidin-2-one
##STR00629##
[2660] A solution of
(3S,5R,6S)-3-allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-1-((1S)-
-1-(tetrahydro-2H-pyran-2-yl)propyl)piperidin-2-one (3 mg, 5.99
.mu.mol; Example 224, Step C) in THF (37.5 .mu.L), H.sub.2O (25
.mu.L) and t-butanol (21 .mu.L) was treated with 4-methylmorpholine
N-oxide (2.45 mg, 0.021 mmol) and 2.5% osmium tetroxide in t-BuOH
(2 .mu.L, 0.15 .mu.mol) at ambient temperature for 18 h. The
mixture was diluted with ethyl acetate, washed with water then sat.
aq. NaCl solution and dried over sodium sulfate. After
concentration the diastereomeric mixture was used in the next step
without further purification.
[2661] Mass Spectrum (ESI) m/z=534.1 (M+1)
Step E.
2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-2-oxo-
-1-((1S)-1-(tetrahydro-2H-pyran-2-yl)propyl)piperidin-3-yl)acetaldehyde
##STR00630##
[2663] A solution of
(3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-(2,3-dihydroxypropyl)--
3-methyl-1-((1S)-1-(tetrahydro-2H-pyran-2-yl)propyl)piperidin-2-one
(3 mg, 5.61 .mu.mol; Example 224, Step D) in water (20.0 .mu.L) and
THF (40.0 .mu.L) was treated with sodium periodate (3.60 mg, 0.02
mmol). After a precipitate formed, methanol (40 .mu.L) was added to
form an emulsion which was stirred at ambient temperature for 1
hour. The reaction was diluted with sat. aq. NaCl solution and
extracted with ethyl acetate. The combined organic layers were
dried over sodium sulfate, filtered and the filtrate was
concentrated to provide a mixture of two diastereomers which was
used in the next step. Mass Spectrum (ESI) m/z=502.1 (M+1)
Step F.
2-((3R,5R,6S)-5-(3-Chlorophenyl)-6-(4-chlorophenyl)-3-methyl-2-oxo-
-1-((1S)-1-(tetrahydro-2H-pyran-2-yl)propyl)piperidin-3-yl)acetic
acid (Isomer 1)
[2664] A solution of
2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-2-oxo-1-((1S-
)-1-(tetrahydro-2H-pyran-2-yl)propyl)piperidin-3-yl)acetaldehyde (3
mg, 5.97 .mu.mol.; mixture of stereoisomers, Example 224, Step E)
in a solution of 1.25 M potassium phosphate monobasic in water
(0.050 mL), t-butanol (0.050 mL) and 2.0 M 2-methylbut-2-ene in THF
(0.15 mL, 0.30 mmol) was treated with sodium chlorite (2.16 mg,
0.024 mmol) at ambient temperature for 3 h. The reaction was
quenched with 1 M sodium thiosulphate solution (0.03 mL). After 10
min, the mixture was acidified with 1M potassium bisulphate
solution (0.03 mL) and extracted with ethyl acetate. The organic
layers were washed with sat. aq. NaCl solution and dried over
anhydrous sodium sulfate. Purification by reversed phase
preparatory HPLC (eluent: 0 to 100% MeCN+0.1% TFA in water+0.1%
TFA, over 20 minutes) gave the title compound as the first eluting
isomer.
[2665] .sup.1H NMR (400 MHz, MeOH-D4) .delta. ppm 0.51 (t, J=8 Hz,
3H), 1.03 (m, 1H), 1.32 (s, br, 1H), 1.39 (s, 3H), 1.50 (m, 2H),
1.67 (m, 1H), 1.85 (m, 1H), 1.96 (m, 3H), 2.19-2.22 (m, 2H), 2.60
(d, J=12 Hz, 1H), 2.99 (d, J=12 Hz, 1H), 3.16 (m, 1H), 3.44 (m,
1H), 3.51 (m. 1H), 3.85 (m, 1H), 4.57 (d, J=12 hZ, 1H), 6.97-6.99
(m, 1H), 7.06 (s, br, 1H), 7.15-7.21 (m, 3H), 7.29-7.31 (d, J=8 Hz,
2H). Mass Spectrum (ESI) m/z=518.2 (M+1).
[2666] Further elution provided Example 225 as the second eluting
isomer.
Example 225
2-((3R,5R,6S)-5-(3-Chlorophenyl)-6-(4-chlorophenyl)-3-methyl-2-oxo-1-((1S)-
-1-(tetrahydro-2H-pyran-2-yl)propyl)piperidin-3-yl)acetic acid
(Isomer 2)
##STR00631##
[2668] .sup.1H NMR (400 MHz, MeOH-d4) .delta. ppm 0.39 (t, J=8 Hz,
3H), 1.00-1.07 (m, 1H), 1.18-1.20 (m, 1H), 1.32 (s, br, 1H), 1.37
(s, br, 3H), 1.50-1.68 (m, 4H), 1.86 (m, 2H), 2.15-2.19 (m, 2H),
2.58 (d, J=16 Hz, 1H), 2.96 (d, J=16 Hz, 1H), 3.41 (m, 1H), 3.52
(m, 1H), 3.89-3.94 (m, 1H), 4.11 (m, 1H), 3.71 (d, J=8 HZ, 1H),
6.94 (m, 1H), 7.03 (s, br, 1H), 7.14-7.20 (m, 4H), 7.28-7.30 (d,
J=8 HZ, 2H). Mass Spectrum (ESI) m/z=518.2 (M+1)
Example 226
2-((3R,5R,6S)-1-((R)-1-(Benzo[d]thiazol-2-yl)propyl)-5-(3-chlorophenyl)-6--
(4-chlorophenyl)-3-methyl-2-oxopiperidin-3-yl)acetic acid or
2-((3R,5R,6S)-1-((S)-1-(Benzo[d]thiazol-2-yl)propyl)-5-(3-chlorophenyl)-6-
-(4-chlorophenyl)-3-methyl-2-oxopiperidin-3-yl)acetic acid (Isomer
1)
##STR00632##
[2669] Step A. 1-(Benzo[d]thiazol-2-yl)propan-1-ol
##STR00633##
[2671] To a solution of 1,3-benzothiazole-2-carbaldehyde (0.96 g,
5.88 mmol) in THF (15.0 mL) was added ethylmagnesium bromide (1.0 M
solution in THF, 12.0 mL, 12.0 mmol, 2 eq), slowly over 15 minutes
(an exotherm was observed). The resulting dark red solution was
stirred at room temperature for 55 minutes, then quenched with
saturated aqueous ammonium chloride solution (4 mL). The mixture
was then concentrated under reduced pressure. Purification by flash
chromatography on silica gel (0-70% EtOAc in hexanes gradient)
provided the title compound as a red oil.
Step B. 2-(1-Bromopropyl)benzo[d]thiazole
##STR00634##
[2673] To a 0.degree. C. solution of 891.4 mg (4.61 mmol) of
1-(benzo[d]thiazol-2-yl)propan-1-ol (Example 1, Step A) in THF
(12.0 mL) was added triphenylphosphine (1.8 g, 6.86 mmol, 1.5 eq),
followed by carbon tetrabromide (2.22 g, 6.69 mmol, 1.5 eq). The
resulting mixture was stirred at 0.degree. C. for 35 minutes, then
allowed to warm to room temperature overnight. The reaction mixture
was then concentrated under reduced pressure. Purification by flash
chromatography on silica gel (0-50% EtOAc in hexanes gradient)
provided the title compound as a dark oil.
Step C.
(3S,5R,6S)-3-Allyl-1-((R)-1-(Benzo[d]thiazol-2-yl)propyl)-5-(3-chl-
orophenyl)-6-(4-chlorophenyl)-3-methylpiperidin-2-one and
(3S,5R,6S)-3-Allyl-1-((S)-1-(benzo[d]thiazol-2-yl)propyl)-5-(3-chlorophen-
yl)-6-(4-chlorophenyl)-3-methylpiperidin-2-one
##STR00635##
[2675] To a suspension of sodium hydride (60% dispersion in oil,
100.0 mg, 2.500 mmol, 3.1 eq) in DMF (1 mL) at 0.degree. C. was
added a solution of 300 mg (0.801 mmol) of
(3S,5R,6S)-3-allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methylpiperidi-
n-2-one (Example 71, Step D) in DMF (1 mL) over 1 minute. After 5
minutes, a solution of 576.7 mg (2.25 mmol, 2.8 eq) of
2-(1-bromopropyl)benzo[d]thiazol (Example 226, Step B) in DMF (1
mL) was added dropwise. The resulting mixture was allowed to warm
to room temperature overnight. The reaction was quenched with
water, and then concentrated under reduced pressure. Purification
by reverse-phase preparative HPLC (Agilent Eclipse Plus C18 column
(Agilent Technologies, Santa Clara, Calif.), 0.1% TFA in
CH.sub.3CN/H.sub.2O, gradient 70% to 90% over 25 minutes) provided
a mixture of the title compounds as a white solid.
Step D.
2-((3R,5R,6S)-1-((R)-1-(Benzo[d]thiazol-2-yl)propyl)-5-(3-chloroph-
enyl)-6-(4-chlorophenyl)-3-methyl-2-oxopiperidin-3-yl)acetic acid
or
2-((3R,5R,6S)-1-((S)-1-(Benzo[d]thiazol-2-yl)propyl)-5-(3-chlorophenyl)-6-
-(4-chlorophenyl)-3-methyl-2-oxopiperidin-3-yl)acetic acid (Isomer
1)
[2676] To a solution of 97.5 mg (0.177 mmol) of
(3S,5R,6S)-3-allyl-1-((R)-1-(benzo[d]thiazol-2-yl)propyl)-5-(3-chlorophen-
yl)-6-(4-chlorophenyl)-3-methylpiperidin-2-one (Example 226, Step
C) in acetonitrile (1 mL), water (1.5 mL), and carbon tetrachloride
(1 mL) were added sodium periodate (154.2 mg, 0.721 mmol, 4.1 eq),
followed by ruthenium(III) chloride hydrate (11.0 mg, 0.049 mmol,
0.27 eq). The resulting mixture was stirred at room temperature for
2.75 hours, then passed through a 0.45 .mu.m filter to remove
residual solids, and then concentrated under reduced pressure.
Purification by reverse-phase preparative HPLC (Agilent Eclipse
Plus C18 column (Agilent Technologies, Santa Clara, Calif.), 0.1%
TFA in CH.sub.3CN/H.sub.2O, gradient 40% to 80% over 25 minutes)
provided one of the title compounds as the first eluting isomer as
a white solid.
[2677] .sup.1H NMR (500 MHz, CHLOROFORM-d) .delta. ppm 1.05 (t,
J=7.46 Hz, 3H) 1.55 (s, 3H) 2.10-2.32 (m, 3H) 2.41-2.54 (m, 1H)
2.87-2.98 (m, 2H) 3.16-3.25 (m, 1H) 4.62 (d, J=10.27 Hz, 1H) 4.81
(dd, J=8.56, 6.85 Hz, 1H) 6.71 (d, J=7.58 Hz, 1H) 6.80 (d, J=8.07
Hz, 2H) 6.88 (d, J=8.31 Hz, 2H) 6.96 (s, 1H) 7.03-7.10 (m, 1H) 7.16
(dd, J=7.95, 0.86 Hz, 1H) 7.42-7.47 (m, 1H) 7.48-7.54 (m, 1H) 7.85
(t, J=8.19 Hz, 2H). Mass Spectrum (ESI) m/z=567 (M+1).
Example 227
2-((3R,5R,6S)-1-((R)-1-(Benzo[d]thiazol-2-yl)propyl)-5-(3-chlorophenyl)-6--
(4-chlorophenyl)-3-methyl-2-oxopiperidin-3-yl)acetic acid or
2-((3R,5R,6S)-1-((S)-1-(Benzo[d]thiazol-2-yl)propyl)-5-(3-chlorophenyl)-6-
-(4-chlorophenyl)-3-methyl-2-oxopiperidin-3-yl)acetic acid (Isomer
2)
##STR00636##
[2679] One of the title compounds (Isomer 2) was prepared from
(3S,5R,6S)-3-allyl-1-((S)-1-(benzo[d]thiazol-2-yl)propyl)-5-(3-chlorophen-
yl)-6-(4-chlorophenyl)-3-methylpiperidin-2-one (Example 226, Step
C) as the second eluting isomer as described in Example 226, Step
D.
[2680] .sup.1H NMR (500 MHz, CHLOROFORM-d) .delta. ppm 0.77 (t,
J=7.34 Hz, 3H) 1.39 (s, 3H) 2.03-2.16 (m, 2H) 2.16-2.24 (m, 1H)
2.58 (dt, J=14.61, 7.49 Hz, 1H) 2.82-2.98 (m, 2H) 3.20-3.29 (m, 1H)
4.75-4.84 (m, 2H) 6.75 (d, J=7.58 Hz, 1H) 6.94 (s, 1H) 7.00 (d,
J=8.31 Hz, 2H) 7.05-7.11 (m, 3H) 7.13-7.17 (m, 1H) 7.44-7.49 (m,
1H) 7.53 (t, J=7.46 Hz, 1H) 7.87 (d, J=8.07 Hz, 1H) 8.01 (d, J=8.07
Hz, 1H). Mass Spectrum (ESI) m/z=567 (M+1).
[2681] Examples 228 to 240 were also prepared from
(3S,5R,6S)-3-allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methylpiperidi-
n-2-one (Example 71, Step D) as described in Example 226,
substituting 2-(1-bromopropyl)benzo[d]thiazole in Example 226, Step
C, with an equivalent amount of the appropriate alkylhalide. The
required alkylhalides (reagents) are prepared as described in the
individual examples.
TABLE-US-00010 ##STR00637## Example R Reagent used 228 ##STR00638##
5-(1-Bromopropyl)-3- methylisoxazole 229 ##STR00639##
2-(1-Bromopropyl)-6- chloropyridine 230 ##STR00640##
2-(1-Bromopropyl) pyridine 231 ##STR00641## 2-(1-Bromobutyl)
pyridine 232 ##STR00642## 2-(1-Bromo-2- cyclopropylethyl) pyridine
233 ##STR00643## 3-(1-Bromopropyl) pyridine 234 ##STR00644##
2-(1-Bromopropyl) pyrazine 235 ##STR00645## 2-(1-Bromopropyl)
pyrimidine 236 ##STR00646## 2-(1-Bromopropyl)-6- methylpyridine 237
##STR00647## 4-(1-Bromopropyl) pyridine 238 ##STR00648##
2-(1-Bromopropyl)-6- (trifluoromethyl)pyridine 239 ##STR00649##
2-(1-Bromopropyl)-6- bromopyridine 240 ##STR00650##
2-(1-Bromopropyl) thiazole
Example 228
2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-1-((S)-1-(3-m-
ethylisoxazol-5-yl)propyl)-2-oxopiperidin-3-yl)acetic acid or
2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-1-((R)-1-(3--
methylisoxazol-5-yl)propyl)-2-oxopiperidin-3-yl)acetic acid
[2682] .sup.1H NMR (400 MHz, CHLOROFORM-d) .delta. ppm 0.74 (t,
J=7.43 Hz, 3H) 1.33 (s, 3H) 1.90-2.11 (m, 2H) 2.14-2.29 (m, 5H)
2.90 (q, J=7.24 Hz, 2H) 3.37-3.47 (m, 1H) 4.47 (t, J=7.14 Hz, 1H)
4.60 (d, J=10.37 Hz, 1H) 5.70 (s, 1H) 6.80 (dt, J=7.48, 1.54 Hz,
1H) 6.90-7.02 (m, 3H) 7.04-7.19 (m, 4H). Mass Spectrum (ESI)
m/z=515 (M+1).
Synthesis of 5-(1-bromopropyl)-3-methylisoxazole
##STR00651##
[2683] Step A. 1-(3-methylisoxazol-5-yl)propan-1-ol
##STR00652##
[2685] To a solution of 3-methylisoxazole-5-carbaldehyde (0.801 g,
7.21 mmol) in 10 mL of THF at -78.degree. C. was added
ethylmagnesium bromide (3.60 mL, 10.81 mmol) slowly. The reaction
mixture was stirred at -78.degree. C. for 2 h, then quenched with
saturated aq. NH.sub.4Cl solution, and extracted with ether
(3.times.80 mL). The combined organic layers were dried over
Na.sub.2SO.sub.4 filtered and the filtrate was evaporated to
provide the crude product. The crude product was purified by
chromatography on silica gel, eluting with 10 to 60% EtOAc/hexane
to provide the title compound. Mass Spectrum (ESI) m/z=142.2
(M+1).
Step B. 5-(1-Bromopropyl)-3-methylisoxazole
[2686] To a solution of 1-(3-methylisoxazol-5-yl)propan-1-ol (0.589
g, 4.17 mmol) in 15 mL of THF was added CBr.sub.4 (1.730 g, 5.22
mmol) and triphenylphosphine (1.423 g, 5.42 mmol). The reaction
mixture was stirred at room temperature for 3 h. The solid was
filtered off, and washed with THF. The filtrate was concentrated
and residue was purified by chromatography on silica gel, eluting
with 5 to 30% EtOAc/hexane to provide the title compound. Mass
Spectrum (ESI) m/z=204.2 (M+1).
Example 229
2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-(6-chloropyri-
din-2-yl)propyl)-3-methyl-2-oxopiperidin-3-yl)acetic acid or
2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((R)-1-(6-chloropyr-
idin-2-yl)propyl)-3-methyl-2-oxopiperidin-3-yl)acetic acid
[2687] .sup.1H NMR (400 MHz, CHLOROFORM-d) .delta. ppm 0.77 (t,
J=7.43 Hz, 3H) 1.30 (s, 3H) 1.99-2.13 (m, 2H) 2.15-2.37 (m, 2H)
2.70-2.90 (m, 2H) 3.20 (ddd, J=12.96, 9.73, 3.33 Hz, 1H) 4.56 (t,
J=7.24 Hz, 1H) 4.84 (d, J=9.98 Hz, 1H) 6.82 (dt, J=7.43, 1.56 Hz,
1H) 6.88 (d, J=8.22 Hz, 2H) 6.99-7.24 (m, 7H) 7.47 (t, J=7.73 Hz,
1H). Mass Spectrum (ESI) m/z=545 (M+1).
Synthesis of 2-(1-bromopropyl)-6-chloropyridine
Step A. 1-(6-Chloropyridin-2-yl)propan-1-ol
##STR00653##
[2689] To a solution of 6-chloropicolinaldehyde (1.00 g, 7.06 mmol)
in 20 mL of THF at -78.degree. C. was added ethylmagnesium bromide,
3.0 M solution in diethyl ether (3.53 mL, 10.60 mmol) slowly. The
reaction mixture was stirred at -78.degree. C. for 2 h. The
reaction mixture was quenched with sat'd NH.sub.4Cl aqueous
solution, and extracted with ether (3.times.100 mL). The combined
organic layers were dried over Na.sub.2SO.sub.4 and evaporated to
provide the crude product. The crude product was purified by
chromatography on silica gel, eluting with 10 to 60% EtOAc/hexane
to provide the title compound. Mass Spectrum (ESI) m/z=172
(M+1).
Step B. 2-(1-bromopropyl)-6-chloropyridine
##STR00654##
[2691] A mixture of 1-(6-chloropyridin-2-yl)propan-1-ol (0.497 g,
2.90 mmol), CBr.sub.4 (1.2 g, 3.62 mmol) and triphenylphosphine
(0.987 g, 3.76 mmol) in 25 mL of THF was stirred at room
temperature for 2 h. The solid was filtered off and washed with
THF. The filtrate was concentrated and residue was purified by
chromatography on silica gel, eluting with 10 to 50% EtOAc/hexane
to provide the title compound. Mass Spectrum (ESI) m/z=236
(M+1).
Example 230
2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-2-oxo-1-((S)--
1-(pyridin-2-yl)propyl)piperidin-3-yl)acetic acid or
2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-2-oxo-1-((R)-
-1-(pyridin-2-yl)propyl)piperidin-3-yl)acetic acid
[2692] .sup.1H NMR (400 MHz, CHLOROFORM-d) .delta. ppm 0.75 (t,
J=7.43 Hz, 3H), 1.21-1.31 (m, 3H), 1.93-2.10 (m, 2H), 2.10-2.23 (m,
1H), 2.50 (dt, J=14.77, 7.48 Hz, 1H), 2.75 (d, J=13.89 Hz, 1H),
2.97 (d, J=14.28 Hz, 1H), 3.09-3.25 (m, 1H), 4.65 (dd, J=8.22, 6.06
Hz, 1H), 4.95 (d, J=9.00 Hz, 1H), 6.80 (d, J=7.63 Hz, 1H), 6.89 (d,
J=8.22 Hz, 2H), 7.02-7.21 (m, 6H), 7.34 (d, J=7.83 Hz, 1H), 7.54
(td, J=7.68, 1.66 Hz, 1H), 8.42 (d, J=4.30 Hz, 1H). Mass Spectrum
(ESI)
[2693] m/z=511.1 (M+1).
Synthesis of 2-(1-bromopropyl)pyridine
##STR00655##
[2695] To a mixture of 2-propylpyridine (2.5 g, 20.63 mmol,
purchased from Sigma-Aldrich, St. Louis, Mo.) and
(E)-2,2'-(diazene-1,2-diyl)bis(2-methylpropanenitrile) (1.253 g,
7.63 mmol, purchased from Sigma-Aldrich) in CCl.sub.4 (60 mL) at rt
was added n-bromosuccinimide (1.93 mL, 22.7 mmol, purchased from
Sigma-Aldrich). The mixture was stirred under fluorescent light at
rt for 12 hr. The precipitate was removed by filtration of the
mixture through a pad of Celite.RTM. (J. T. Baker, Phillipsberg,
N.J., diatomaceous earth), which was washed with CCl.sub.4 (10 mL).
The filtrate was concentrated under reduced pressure. Purification
of the residue by flash chromatography on silica gel (eluent: 20%
EtOAc/hexanes) provided the title compound as a yellow liquid. Mass
Spectrum (ESI) m/z=199.9 and 201.9 (M+1).
Example 231
2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-2-oxo-1-((S)--
1-(pyridin-2-yl)butyl)piperidin-3-yl)acetic acid or
2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-2-oxo-1-((R)-
-1-(pyridin-2-yl)butyl)piperidin-3-yl)acetic acid
[2696] .sup.1H NMR (400 MHz, CHLOROFORM-d) .delta. ppm 1.04 (m,
3H), 1.41-1.71 (m, 5H), 2.03 (br. s., 1H), 2.18 (d, J=13.69 Hz,
1H), 2.30 (t, J=13.69 Hz, 1H), 2.44-2.74 (m, 2H), 3.08 (d, J=15.26
Hz, 1H), 3.47 (t, J=10.56 Hz, 1H), 4.31 (br. s., 1H), 4.59 (d,
J=10.37 Hz, 1H), 6.77 (d, J=6.46 Hz, 1H), 6.89-7.20 (m, 8H), 7.79
(br. s., 1H), 8.17 (br. s., 1H), 8.72-9.01 (m, 1H), 11.51 (br. s.,
1H). Mass Spectrum (ESI) m/z=525.1 (M+1).
Synthesis of 2-(1-bromobutyl)-6-chloropyridine
Step A. 1-(Pyridin-2-yl)butan-1-ol
##STR00656##
[2698] To a solution of 2-bromopyridine (1.1 g, 6.96 mmol,
purchased from Sigma-Aldrich) in diethyl ether (8 mL) at
-78.degree. C. under N.sub.2 was added butyllithium (3.1
mL.times.2.5 M) over 10 min. The reaction solution was stirred at
-78.degree. C. for 1.0 hr. To the mixture was added butyraldehyde
(0.602 g, 8.35 mmol, purchased from Sigma-Aldrich) dropwise over 10
min.
[2699] After stirring at -78.degree. C. for 15 min, the mixture was
allowed to warm to rt and stirred at rt for 1.5 hr. The reaction
mixture was poured into saturated aqueous NH.sub.4Cl solution (10
mL), diluted with water (15 mL), and extracted with EtOAc (20
mL.times.3). The organic layers were combined, washed with water,
sat. aq. NaCl solution, and dried over MgSO.sub.4. After removal of
organic solvents under reduced pressure, purification of the
residue by flash chromatography on silica gel with 20-80%
EtOAc/Hexanes provided the title compound as a white solid. Mass
Spectrum (ESI) m/z=152.1 (M+1).
Step B. 2-(1-Bromobutyl)pyridine
##STR00657##
[2701] To a mixture of 1-(pyridin-2-yl)butan-1-ol (0.35 g, 2.3
mmol; Example 231, Step A) and triphenylphosphine (1.1 g, 4.2 mmol)
in THF (15 mL) at 0.degree. C. under N.sub.2 atmosphere was added
CBr.sub.4 (1.2 g, 3.5 mmol). The mixture was stirred at 0.degree.
C. for 2 min, and then was allowed to warm to rt and stirred for 25
min. The precipitate was filtered off through a pad of Celite.RTM.
(J.T. Baker, Phillipsberg, N.J., diatomaceous earth), the solid was
washed with cold THF (10 mL). The filtrate was concentrated under
reduced pressure. Purification of the residue by flash
chromatography on silica gel with 0-5-15% EtOAc/Hexanes provided
the title compound as colorless oil. Mass Spectrum (ESI) m/z=214.0
and 216.0 (M+1).
Example 232
2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((S)-2-cyclopropyl-1-
-(pyridin-2-yl)ethyl)-3-methyl-2-oxopiperidin-3-yl)acetic acid or
2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((R)-2-cyclopropyl--
1-(pyridin-2-yl)ethyl)-3-methyl-2-oxopiperidin-3-yl)acetic acid
[2702] .sup.1H NMR (400 MHz, CHLOROFORM-d) .delta. ppm -0.45--0.34
(m, 1H), -0.06 (dq, J=9.19, 4.63 Hz, 1H), 0.16-0.39 (m, 2H), 0.46
(dd, J=7.43, 5.28 Hz, 1H), 1.16-1.31 (m, 3H), 1.63 (dt, J=13.60,
6.90 Hz, 1H), 2.00-2.17 (m, 2H), 2.50-2.65 (m, 1H), 2.77 (br. s.,
1H), 2.88 (d, J=9.59 Hz, 1H), 3.19 (t, J=8.80 Hz, 1H), 4.84 (br.
s., 1H), 4.97 (d, J=9.19 Hz, 1H), 6.78 (d, J=7.43 Hz, 1H), 6.93 (d,
J=7.83 Hz, 2H), 7.00-7.17 (m, 7H), 7.34 (d, J=7.43 Hz, 1H),
7.48-7.57 (m, 1H), 8.34-8.56 (m, 1H). Mass Spectrum (ESI) m/z=537.2
(M+1).
Synthesis of 2-(1-bromo-2-cyclopropylethyl)pyridine
Step A. 2-Cyclopropyl-1-(pyridin-2-yl)ethanol
##STR00658##
[2704] To a solution of 2-cyclopropylacetaldehyde (1.00 g, 11.89
mmol, purchased from Beta Pharma, Inc., Branford, Conn.) in THF (15
mL) at 0.degree. C. under N.sub.2 was added 2-pyridylmagnesium
bromide (47.6 mL.times.0.25 M, purchased from Rieke Metals, Inc.,
Lincoln, Nebr.) dropwise over 15 min. The mixture was stirred at
0.degree. C. after 30 min, allowed to warm to rt and stirred at rt
for 3.5 hr. To the reaction mixture was added saturated aqueous
NH.sub.4Cl solution (5 mL) followed by water (15 mL). The mixture
was extracted with EtOAc (2.times.10 mL). The combined organic
layers were dried over Na.sub.2SO.sub.4. After removal of organic
solvents, purification of the residue by flash chromatography on
silica gel with 40-70% EtOAc/hexanes the title compound was
obtained as a white solid. Mass Spectrum (ESI) m/z=164.1 (M+1).
Step B. 2-(1-Bromo-2-cyclopropylethyl)pyridine
##STR00659##
[2706] The title compound was prepared from
2-cyclopropyl-1-(pyridin-2-yl)ethanol (Example 232, Step A) using a
procedure similar to the one described in Example 231, Step B. Mass
Spectrum (ESI) m/z=226.0 and 228.0 (M+1).
Example 233
2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-2-oxo-1-((S)--
1-(pyridin-3-yl)propyl)piperidin-3-yl)acetic acid or
2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-2-oxo-1-((R)-
-1-(pyridin-3-yl)propyl)piperidin-3-yl)acetic acid
[2707] .sup.1H NMR (400 MHz, CHLOROFORM-d) .delta. ppm 0.97-1.10
(d, J=8.6 Hz, 3H), 1.44 (s, 3H), 1.95-2.09 (m, 1H), 2.09-2.23 (m,
2H), 2.28 (s, 1H), 2.62 (d, J=13.89 Hz, 1H), 2.87 (d, J=13.89 Hz,
1H), 3.33 (ddd, J=13.40, 10.47, 3.13 Hz, 1H), 4.37 (d, J=10.37 Hz,
1H), 5.93 (t, J=7.92 Hz, 1H), 6.54-6.61 (m, 1H), 6.62-6.79 (m, 3H),
6.83-6.90 (m, 1H), 6.91-7.00 (m, 1H), 7.00-7.07 (m, 1H), 7.07-7.15
(m, 1H), 7.15-7.23 (m, 1H), 7.26 (dd, J=8.02, 5.67 Hz, 1H), 7.36
(d, J=8.02 Hz, 1H), 8.35 (d, J=5.48 Hz, 1H), 8.80 (s, 1H). Mass
Spectrum (ESI) m/z=511.1 (M+1).
Synthesis of 3-(1-bromopropyl)pyridine
Step A. 1-(Pyridin-3-yl)propan-1-ol
##STR00660##
[2709] To a solution of 1-(pyridin-3-yl)propan-1-one (2.46 g, 18.20
mmol, purchased from Lancaster Synthesis Ltd.) in MeOH (15 mL) at
rt under N.sub.2 atmosphere was added sodium borohydride powder
(0.690 g, 18.20 mmol). After stirring at rt for 1.5 hr, to the
reaction solution was added water (20 ml). The resulting mixture
was stirred for 4 min, extracted with EtOAc (20 mL.times.3). The
organic layers were combined, washed with water, sat. aq. NaCl
solution and dried over MgSO.sub.4. Removal of the solvents
provided the crude title compound as white solid. Mass Spectrum
(ESI) m/z=138.0 (M+1).
Step B. 3-(1-Bromopropyl)pyridine
##STR00661##
[2711] The title compound was prepared from
1-(pyridin-3-yl)propan-1-ol (Example 233, Step A) following the
procedure described in Example 231, Step B. Mass Spectrum (ESI)
m/z=199.9 and 201.9 (M+1).
Example 234
2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-2-oxo-1-((S)--
1-(pyrazin-2-yl)propyl)piperidin-3-yl)acetic acid or
2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-2-oxo-1-((R)-
-1-(pyrazin-2-yl)propyl)piperidin-3-yl)acetic acid
[2712] .sup.1H NMR (400 MHz, CHLOROFORM-d) .delta. ppm 0.95 (t,
J=7.14 Hz, 3H), 1.39 (s, 3H), 1.94-2.24 (m, 4H), 2.71 (s, 2H),
3.39-3.54 (m, 1H), 4.46 (d, J=9.98 Hz, 1H), 5.71 (t, J=7.43 Hz,
1H), 6.61 (d, J=7.82 Hz, 1H), 6.77 (br. s., 4H), 6.86-7.00 (m, 2H),
7.04 (d, J=8.80 Hz, 1H), 8.03-8.16 (m, 1H), 8.25 (br. s., 1H), 8.34
(s, 1H). Mass Spectrum (ESI) m/z=512.1 (M+1).
Synthesis of 2-(1-bromopropyl)pyrazine
##STR00662##
[2714] The title compound was prepared from 2-propylpyrazine
(purchased from Matrix Scientific) following a procedure similar to
the one described in Example 230. Mass Spectrum (ESI) m/z=200.8 and
202.9 (M+1).
Example 235
2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-2-oxo-1-((S)--
1-(pyrimidin-2-yl)propyl)piperidin-3-yl)acetic acid or
2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-2-oxo-1-((R)-
-1-(pyrimidin-2-yl)propyl)piperidin-3-yl)acetic
[2715] .sup.1H NMR (400 MHz, CHLOROFORM-d) .delta. ppm 0.78 (t,
J=7.43 Hz, 3H), 1.34 (s, 3H), 1.90-2.07 (m, 1H), 2.08-2.19 (m, 1H),
2.20-2.34 (m, 1H), 2.52 (dt, J=14.33, 7.21 Hz, 1H), 2.80 (br. s.,
1H), 2.93 (qd, J=7.27, 2.05 Hz, 1H), 3.29-3.49 (m, 1H), 4.50 (br.
s., 1H), 4.80 (d, J=10.17 Hz, 1H), 6.79 (d, J=7.63 Hz, 1H),
6.90-7.19 (m, 8H), 8.60 (d, J=4.69 Hz, 2H). Mass Spectrum (ESI)
m/z=512.2 (M+1).
Synthesis of 2-(1-bromopropyl)pyrimidine
Step A. 2-Propylpyrimidine
##STR00663##
[2717] To a 0.degree. C. solution of triphenylphosphine (2.290 g,
8.73 mmol), nickel(II) acetylacetonate (0.464 mL, 2.62 mmol) and
2-chloropyrimidine (5.00 g, 43.7 mmol, purchased from
Sigma-Aldrich) in THF (45 mL) under N.sub.2 atmosphere was added
propylmagnesium chloride (21.83 mL, 43.7 mmol) over 5 min. The
mixture was allowed to warm to rt and stirred at rt for 3 hr. To
the reaction mixture was added saturated aqueous NH.sub.4Cl
solution (5 mL) followed by water (12 mL). The mixture was
extracted with EtOAc (2.times.10 mL). The combined organic layers
were dried over Na.sub.2SO.sub.4.filtered and concentrated. The
residue was purified by flash chromatography on silica gel (eluent:
0 to 50% EtOAc/hexanes) to provide the title compound as a
colorless liquid.
Step B. 2-(1-Bromopropyl)pyrimidine
##STR00664##
[2719] The title compound was prepared from 2-propylpyrimidine
(Example 235, Step A) following a procedure similar to the one
described in Example 230. Mass Spectrum (ESI) m/z=201.0 and 203.0
(M+1).
Example 236
2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-1-((S)-1-(6-m-
ethylpyridin-2-yl)propyl)-2-oxopiperidin-3-yl)acetic acid or
2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-1-((R)-1-(6--
methylpyridin-2-yl)propyl)-2-oxopiperidin-3-yl)acetic acid
[2720] .sup.1H NMR (400 MHz, CHLOROFORM-d) .delta. ppm 0.99 (br.
s., 3H), 1.39 (s, 3H), 1.90-2.06 (m, 1H), 2.11 (d, J=12.72 Hz, 1H),
2.16-2.37 (m, 2H), 2.68 (d, J=15.06 Hz, 1H), 2.89 (s, 3H), 3.03 (d,
J=15.06 Hz, 1H), 3.34 (t, J=10.76 Hz, 1H), 4.78 (d, J=9.59 Hz, 1H),
5.61 (br. s., 1H), 6.76 (d, J=7.04 Hz, 1H), 6.96 (br. s., 6H),
6.99-7.20 (m, 2H), 7.50 (d, J=7.43 Hz, 1H), 7.90 (t, J=7.63 Hz,
1H), 8.60 (br. s., 1H). Mass Spectrum (ESI) m/z=525.1 (M+1).
Synthesis of 2-(1-bromopropyl)-6-methylpyridine
Step A. 1-(6-Methylpyridin-2-yl)propan-1-ol
##STR00665##
[2722] The title compound was prepared from
6-methyl-2-pyridinecarboxaldehyde (purchased from Tokyo Chemical
Industry Co. Ltd.) using a procedure similar to the one described
above for the synthesis of 2-cyclopropyl-1-(pyridin-2-yl)ethanol
(Example 232, Step A). Mass Spectrum (ESI) m/z=151.4 (M+1).
Step B. 2-(1-Bromopropyl)-6-methylpyridine
##STR00666##
[2724] The title compound was prepared from
1-(6-methylpyridin-2-yl)propan-1-ol (Example 236, Step A) following
a procedure similar to the one described in Example 231, Step B.
Mass Spectrum (ESI) m/z=214.0 and 216.0 (M+1).
Example 237
2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-2-oxo-1-((S)--
1-(pyridin-4-yl)propyl)piperidin-3-yl)acetic acid or
2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-2-oxo-1-((R)-
-1-(pyridin-4-yl)propyl)piperidin-3-yl)acetic acid
[2725] .sup.1H NMR (400 MHz, CHLOROFORM-d) .delta. ppm 1.14 (t,
J=7.14 Hz, 3H), 1.48-1.54 (m, 3H), 1.94-2.09 (m, 1H), 2.09-2.32 (m,
2H), 2.64 (d, J=16.24 Hz, 1H), 2.96-3.11 (m, 1H), 3.26 (d, J=16.24
Hz, 1H), 3.52-3.69 (m, 1H), 4.39 (d, J=10.37 Hz, 1H), 6.02 (br. s.,
1H), 6.61 (d, J=7.63 Hz, 3H), 6.77 (br. s., 2H), 6.89-7.09 (m, 5H),
7.13 (d, J=7.43 Hz, 1H), 8.33 (br. s., 1H). Mass Spectrum (ESI)
m/z=511.1 (M+1).
Synthesis of 4-(1-bromopropyl)pyridine
Step A. 1-(Pyridin-4-yl)propan-1-ol
##STR00667##
[2727] The title compound was prepared from
1-(pyridin-4-yl)propan-1-one (purchased from Waterstone Technology)
following a procedure similar to the one described for the
synthesis of 1-(pyridin-3-yl)propan-1-ol (Example 233, Step A).
Mass Spectrum (ESI) m/z=138.0 (M+1).
Step B. 4-(1-Bromopropyl)pyridine
##STR00668##
[2729] The title compound was prepared from
1-(pyridin-4-yl)propan-1-ol (Example 237, Step A) following a
procedure similar to the one described in Example 231, Step B. Mass
Spectrum (ESI) m/z=199.9 and 201.9 (M+1).
Example 238
2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-2-oxo-1-((S)--
1-(6-(trifluoromethyl)pyridin-2-yl)propyl)piperidin-3-yl)acetic
acid or
2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-2-oxo-1-((R)-
-1-(6-(trifluoromethyl)pyridin-2-yl)propyl)piperidin-3-yl)acetic
acid
[2730] .sup.1H NMR (400 MHz, CHLOROFORM-d) .delta. ppm 0.75 (t,
J=7.43 Hz, 3H), 1.21-1.30 (m, 3H), 1.98-2.19 (m, 2H), 2.29 (t,
J=13.50 Hz, 1H), 2.47 (dt, J=14.62, 7.46 Hz, 1H), 2.78 (d, J=14.87
Hz, 1H), 2.98 (d, J=14.87 Hz, 1H), 3.14-3.28 (m, 1H), 4.23-4.33 (m,
1H), 5.05 (d, J=9.98 Hz, 1H), 6.84 (d, J=7.24 Hz, 1H), 6.91-7.06
(m, 3H), 7.10-7.22 (m, 4H), 7.54 (d, J=7.63 Hz, 2H), 7.80 (t,
J=7.83 Hz, 1H). Mass Spectrum (ESI) m/z=579.0 (M+1).
Synthesis of 2-(1-bromopropyl)-6-(trifluoromethyl 1 pyridine
Step A. 1-(6-(Trifluoromethyl)pyridin-2-yl)propan-1-ol
##STR00669##
[2732] The title compound was prepared from
2-bromo-6-(trifluoromethyl)pyridine (purchased from Oakwood
Products Inc., West Columbia, S.C.) and propionaldehyde following
the procedure as described above for the synthesis of
1-(pyridin-2-yl)butan-1-ol (Example 231, Step A). Mass Spectrum
(ESI) m/z=206.1 (M+1).
Step B. 2-(1-Bromopropyl)-6-(trifluoromethyl)pyridine
##STR00670##
[2734] The title compound was prepared from
1-(6-(trifluoromethyl)pyridin-2-yl)propan-1-ol (Example 238, Step
A) following a procedure similar to the one described for the
synthesis of 2-(1-bromobutyl)pyridine (Example 231, Step B). Mass
Spectrum (ESI) m/z=268.0 (M+1) and 269.9 (M+1).
Example 239
2-((3R,5R,6S)-1-((S)-1-(6-bromopyridin-2-yl)propyl)-5-(3-chlorophenyl)-6-(-
4-chlorophenyl)-3-methyl-2-oxopiperidin-3-yl)acetic acid or
2-((3R,5R,6S)-1-((R)-1-(6-bromopyridin-2-yl)propyl)-5-(3-chlorophenyl)-6--
(4-chlorophenyl)-3-methyl-2-oxopiperidin-3-yl)acetic acid
[2735] .sup.1H NMR (400 MHz, CHLOROFORM-d) .delta. ppm 0.66 (t,
J=7.43 Hz, 3H), 1.23 (s, 3H), 1.90-2.10 (m, 2H), 2.15-2.34 (m, 2H),
2.69-2.88 (m, 2H), 3.05-3.22 (m, 1H), 4.29 (t, J=7.04 Hz, 1H), 4.84
(d, J=9.78 Hz, 1H), 6.77 (d, J=7.43 Hz, 1H), 6.85 (d, J=8.02 Hz,
2H), 6.97 (s, 1H), 6.99-7.14 (m, 4H), 7.16-7.27 (m, 2H), 7.29-7.40
(m, 1H), 8.16 (br. s., 1H). Mass Spectrum (ESI) m/z=589.0, 591.0,
593.0 (M+1).
Synthesis of 2-bromo-6-(1-bromopropyl)pyridine
Step A. 1-(6-Bromopyridin-2-yl)propan-1-ol
##STR00671##
[2737] The title compound was prepared from 2,6-dibromopyridine
(purchased from Sigma-Aldrich, St. Louis, Mo.) and propionaldehyde
following a procedure similar to the one described above for the
synthesis of 1-(pyridin-2-yl)butan-1-ol (Example 231, step A). Mass
Spectrum (ESI) m/z=219.9 and 217.9 (M+1).
Step B. 2-Bromo-6-(1-bromopropyl)pyridine
##STR00672##
[2739] The title compound was prepared from
1-(6-bromopyridin-2-yl)propan-1-ol (example 239, Step A) following
the procedure as described above for the synthesis of
2-(1-bromobutyl)pyridine (Example 231, Step B). Mass Spectrum (ESI)
m/z=277.7, 279.7 and 281.7 (M+1).
Example 240
2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-2-oxo-1-((S)--
1-(thiazol-2-yl)propyl)piperidin-3-yl)acetic acid or
2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-2-oxo-1-((R)-
-1-(thiazol-2-yl)propyl)piperidin-3-yl)acetic acid
[2740] .sup.1H NMR (400 MHz, CHLOROFORM-d) .delta. ppm 0.66 (t,
J=7.43 Hz, 3H), 1.19-1.41 (m, 3H), 1.90-2.06 (m, 1H), 2.06-2.25 (m,
2H), 2.54 (dt, J=15.11, 7.60 Hz, 1H), 2.77-2.98 (m, 2H), 3.14-3.37
(m, 1H), 4.57 (dd, J=8.41, 4.70 Hz, 1H), 4.85 (d, J=9.78 Hz, 1H),
6.79 (d, J=7.43 Hz, 1H), 6.95 (s, 1H), 6.99-7.24 (m, 6H), 7.40 (d,
J=3.33 Hz, 1H), 7.83 (d, J=3.13 Hz, 1H), 8.60 (br. s., 1H). Mass
Spectrum (ESI) m/z=517.0 (M+1).
Synthesis of 2-(1-bromopropyl)thiazole
##STR00673##
[2742] The title compound was prepared from 2-propylthiazole
(purchased from Waterstone Technologies, Inc., Carmel, Ind.)
following a procedure similar to the one described above for the
synthesis of 2-(1-bromopropyl)pyridine (Example 230). Mass Spectrum
(ESI) m/z=205.8 and 207.8 (M+1).
Example 241
2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-(6-(2-hydroxy-
propan-2-yl)pyridin-2-yl)propyl)-3-methyl-2-oxopiperidin-3-yl)acetic
acid or
2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((R)-1-(6-(2-hyd-
roxypropan-2-yl)pyridin-2-yl)propyl)-3-methyl-2-oxopiperidin-3-yl)acetic
acid
##STR00674##
[2743] Step A. Ethyl 6-propylpicolinate
##STR00675##
[2745] A solution of ethyl 6-bromopicolinate (8 g, 34.8 mmol,
purchased from AK Scientific, Inc., Union City, Calif.) in THF (200
mL) was sparged with N.sub.2 at 0.degree. C. for 20 min. To the
mixture under N.sub.2 atmosphere was added Pd(PPh.sub.3).sub.4
(3.21 g, 2.78 mmol) and a solution of propylzinc bromide (100 mL,
0.5 M in THF, 50.0 mmol) dropwise over 30 min. The mixture was
removed from the ice bath and heated to reflux for 18 h. After that
time the solution was cooled to rt, poured into saturated aqueous
NH.sub.4Cl solution (18 mL), diluted with water (30 mL), and
extracted with EtOAc (3.times.30 mL). The combined organic layers
were washed with water and sat. aq. NaCl solution and were dried
over Na.sub.2SO.sub.4. After removal of the organic solvents under
reduced pressure, purification of the residue by flash
chromatography on silica gel with 0 to 50% EtOAc/hexanes provided
the title compound. Mass Spectrum (ESI) m/z=194.0 (M+1).
Step B. Ethyl 6-(1-bromopropyl)picolinate
##STR00676##
[2747] The title compound was prepared from Example 241, Step A
following a procedure similar to the one described for the
synthesis of 2-(1-bromopropyl)pyridine (Example 230). Mass Spectrum
(ESI) m/z=272.0 and 274.0 (M+1).
Step C. Ethyl
6-((R)-1-((3S,5R,6S)-3-allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-meth-
yl-2-oxopiperidin-1-yl)propyl)picolinate and ethyl
6-((S)-1-((3S,5R,6S)-3-allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-meth-
yl-2-oxopiperidin-1-yl)propyl)picolinate
##STR00677##
[2749] The title compounds were prepared as a mixture from ethyl
6-(1-bromopropyl)picolinate (Example 241, Step B) following a
procedure similar to the one described in Example 226, Step C. Mass
Spectrum (ESI) m/z=566.2 (M+1).
Step D.
(3S,5R,6S)-3-allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((R)-1--
(6-(2-hydroxypropan-2-yl)pyridin-2-yl)propyl)-3-methylpiperidin-2-one
and
(3S,5R,6S)-3-allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-(6-(2-h-
ydroxypropan-2-yl)pyridin-2-yl)propyl)-3-methylpiperidin-2-one
##STR00678##
[2751] To a 0.degree. C. solution of ethyl
6-((R)-1-((3S,5R,6S)-3-allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-meth-
yl-2-oxopiperidin-1-yl)propyl)picolinate and ethyl
6-((S)-1-((3S,5R,6S)-3-allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-meth-
yl-2-oxopiperidin-1-yl)propyl)picolinate (160 mg, 0.283 mmol,
Example 241, Step C) in THF (3 mL) under N.sub.2 was added
CH.sub.3MgBr (3.0 M solution in diethyl ether, 0.377 mL, 1.132
mmol). The mixture was removed from the ice bath and stirred at rt
for 30 min. To the reaction mixture was added additional
CH.sub.3MgBr (3.0 M solution in diethyl ether, 0.24 mL, 0.78 mmol).
After stirring at rt for 2.0 hr, to the reaction mixture was added
saturated aqueous NH.sub.4Cl solution (3 mL) and water (4 mL). The
mixture was extracted with EtOAc (3.times.8 mL). The combined
organic layers were washed with water, sat. aq. NaCl solution, and
dried over Na.sub.2SO.sub.4. After removal of organic solvents
under reduced pressure, purification of the residue by flash
chromatography on silica gel with 20-80% EtOAc/hexanes provided the
title compounds as a mixture of stereoisomers. Mass Spectrum (ESI)
m/z=551.1 (M+1).
Step E.
2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-(6-(2-
-hydroxypropan-2-yl)pyridin-2-yl)propyl)-3-methyl-2-oxopiperidin-3-yl)acet-
ic acid or
2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((R)-1-(6-
-(2-hydroxypropan-2-yl)pyridin-2-yl)propyl)-3-methyl-2-oxopiperidin-3-yl)a-
cetic acid
[2752] The title compound was prepared from a mixture of
(3S,5R,6S)-3-allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((R)-1-(6-(2-h-
ydroxypropan-2-yl)pyridin-2-yl)propyl)-3-methylpiperidin-2-one and
(3S,5R,6S)-3-allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-(6-(2-h-
ydroxypropan-2-yl)pyridin-2-yl)propyl)-3-methylpiperidin-2-one
(Example 241, Step D) following a procedure similar to the one
described above in example 230, Step C. Purification of the crude
mixture as described provided one of the title compounds as a
single isomer as a white solid.
[2753] .sup.1H NMR (400 MHz, CHLOROFORM-d) .delta. ppm 1.08-1.17
(m, 3H), 1.32-1.50 (m, 9H), 1.87-1.97 (m, 1H), 1.97-2.08 (m, 1H),
2.08-2.18 (m, 1H), 2.27-2.48 (m, 1H), 2.70 (br. s., 2H), 3.23 (br.
s., 1H), 4.63-4.74 (m, 2H), 6.76 (m, 3H), 6.84 (br. s., 1H), 6.93
(d, J=5.87 Hz, 2H), 6.99-7.11 (m, 3H), 7.13-7.24 (m, 2H), 7.48 (br.
s., 1H). Mass Spectrum (ESI) m/z=569.1 (M+1).
Example 242
2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-(6-cyclopropy-
lpyridin-2-yl)propyl)-3-methyl-2-oxopiperidin-3-yl)acetic acid or
2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((R)-1-(6-cycloprop-
ylpyridin-2-yl)propyl)-3-methyl-2-oxopiperidin-3-yl)acetic acid
##STR00679##
[2754] Step A.
(3S,5R,6S)-3-Allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-(6-cycl-
opropylpyridin-2-yl)propyl)-3-methylpiperidin-2-one or
(3S,5R,6S)-3-Allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((R)-1-(6-cycl-
opropylpyridin-2-yl)propyl)-3-methylpiperidin-2-one
##STR00680##
[2756] To a rt solution of mixture of
((3S,5R,6S)-3-allyl-1-(1-(6-bromopyridin-2-yl)propyl)-5-(3-chlorophenyl)--
6-(4-chlorophenyl)-3-methylpiperidin-2-one (165 mg, 0.288 mmol;
Example 239 in DMF (3 mL) was added tricyclohexylphosphine (11.32
mg, 0.04 mmol), potassium phosphate (214 mg, 1.009 mmol),
cyclopropylboronic acid (49.5 mg, 0.577 mmol) and
diacetoxypalladium (4.53 mg, 0.020 mmol). The mixture was sparged
with N.sub.2 for 5 min and then heated to 80.degree. C. for 5 hr.
The resulting solution was cooled to rt, diluted with water (6 mL),
and extracted with EtOAc (8 mL.times.2). The organic layers were
combined, washed with water, sat. aq. NaCl solution, and dried over
MgSO.sub.4. After removal of organic solvents under reduced
pressure, purification of the residue by flash chromatography on
silica gel with 0 to 70% EtOAc/hexanes provided the title compound
as a colorless syrup.
Step B.
2-((3R,5R,6S)-5-(3-Chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-(6-cy-
clopropylpyridin-2-yl)propyl)-3-methyl-2-oxopiperidin-3-yl)acetic
acid
[2757] The title compound was prepared from
(3S,5R,6S)-3-allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-(1-(6-cyclopro-
pylpyridin-2-yl)propyl)-3-methylpiperidin-2-one (Example 242, Step
A) following a procedure similar to the one described in Example
71, Step F).
[2758] .sup.1H NMR (400 MHz, CHLOROFORM-d) .delta. ppm 0.95-1.08
(m, 3H), 1.08-1.23 (m, 2H), 1.36-1.44 (m, 3H), 1.44-1.54 (m, 1H),
1.54-1.66 (m, 1H), 1.99-2.29 (m, 4H), 2.49-2.60 (m, 1H), 2.72 (d,
J=15.26 Hz, 1H), 3.04 (d, J=15.26 Hz, 1H), 3.30-3.43 (m, 1H), 4.71
(d, J=10.17 Hz, 1H), 5.52 (br. s., 1H), 6.74 (d, J=7.63 Hz, 2H),
6.90-7.01 (m, 5H), 7.01-7.08 (m, 1H), 7.10 (d, J=8.02 Hz, 2H), 7.75
(t, J=8.02 Hz, 1H). Mass Spectrum (ESI) m/z=551.2 (M+1).
Example 243
2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-2-oxo-1-((S)--
3,3,3-trifluoro-1-(pyridin-2-yl)propyl)piperidin-3-yl)acetic acid,
2,2,2-trifluoroacetic acid salt (1:1) or
2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-2-oxo-1-((R)-
-3,3,3-trifluoro-1-(pyridin-2-yl)propyl)piperidin-3-yl)acetic acid,
2,2,2-trifluoroacetic acid salt (1:1)
##STR00681##
[2759] Step A.
(3S,5R,6S)-3-Allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-1-(pyri-
din-2-ylmethyl)piperidin-2-one
##STR00682##
[2761] To a solution of
(3S,5R,6S)-3-allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methylpiperidi-
n-2-one (2.246 g, 6 mmol; Example 71D) in DMF (25 mL) was added
sodium hydride, 60% dispersion in mineral oil (0.504 g, 12.60 mmol)
and the mixture was stirred at 0.degree. C. for 5 minutes. To this
was added 2-(bromomethyl)pyridine hydrobromide (1.593 g, 6.30 mmol)
at 0.degree. C. The resulting mixture was stirred at 0.degree. C.
for 10 min and quenched with saturated NH.sub.4Cl solution,
extracted with EtOAc, washed with sat. aq. NaCl solution, dried
over MgSO.sub.4, filtered and the filtrate was concentrated. The
residue was purified by flash chromatography on silica gel (eluent:
0 to 100% EtOAc in hexanes) to give the title compound.
[2762] Mass Spectrum (ESI) m/z=465 (M+1).
Step B.
(3S,5R,6S)-3-Allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl--
1-((S)-3,3,3-trifluoro-1-(pyridin-2-yl)propyl)piperidin-2-one or
(3S,5R,6S)-3-Allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-1-((R)--
3,3,3-trifluoro-1-(pyridin-2-yl)propyl)piperidin-2-one
##STR00683##
[2764] To a solution of
(3S,5R,6S)-3-allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-1-(pyri-
din-2-ylmethyl)piperidin-2-one (660 mg, 1.418 mmol; Example 243,
Step A) in inhibitor free THF (7 mL) under N.sub.2 at -78.degree.
C. was added lithium diisopropylamide (1.418 mL, 2.84 mmol) and the
mixture was stirred for 30 min. 1,1,1-Trifluoro-2-iodoethane (744
mg, 3.55 mmol; Sigma, St. Louis, Mo.) was added and the orange
reaction was stirred at -78.degree. C. for 1 h. The reaction was
then warmed to rt and stirred overnight. The mixture was quenched
with 0.2 mL of MeOH, filtered, concentrated and the residue was
purified by HPLC (C18 column, eluted with 10-95% CH.sub.3CN in
Water, with 0.1% TFA) to give the title compound as the slower
eluting diasteromer. Mass Spectrum (ESI) m/z=547 (M+1).
Step C.
2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-2-oxo-
-1-((S)-3,3,3-trifluoro-1-(pyridin-2-yl)propyl)piperidin-3-yl)acetic
acid/2,2,2-Trifluoroacetic acid (1:1)
##STR00684##
[2766] The title compound was obtained from
(3S,5R,6S)-3-allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-1-((S)--
3,3,3-trifluoro-1-(pyridin-2-yl)propyl)piperidin-2-one (61.2 mg,
0.112 mmol; Example 243, Step B) by a procedure similar to the one
described in Example 71, Step F.
[2767] .sup.1H NMR (400 MHz, CHLOROFORM-d) .delta. ppm 8.96 (1H, d,
J=4.7 Hz), 8.09 (1H, t, J=7.8 Hz), 7.86 (1H, d, J=8.2 Hz),
7.56-7.68 (1H, m), 7.22 (4H, s), 7.08-7.17 (3H, m), 6.94 (1H, s),
6.90 (1H, d, J=6.7 Hz), 5.27-5.38 (1H, m), 4.95 (1H, d, J=6.5 Hz),
3.63 (1H, dt, J=16.1, 9.8 Hz), 3.28-3.40 (1H, m), 2.88 (1H, d,
J=15.1 Hz), 2.74 (1H, d, J=15.1 Hz), 2.59-2.71 (1H, m), 2.12-2.25
(1H, m), 1.98-2.09 (1H, m), 1.15 (3H, s). Mass Spectrum (ESI)
m/z=565 (M+1).
Example 244
2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-2-oxo-1-((S)--
3,3,3-trifluoro-1-(pyridin-2-yl)propyl)piperidin-3-yl)acetic acid,
as the 2,2,2-trifluoroacetic acid (1:1) salt
##STR00685##
[2768] Step A.
(3S,5R,6S)-3-Allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((S)-3,3-diflu-
oro-1-(pyridin-2-yl)propyl)-3-methylpiperidin-2-one
##STR00686##
[2770] To a solution of
(3S,5R,6S)-3-allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-1-(pyri-
din-2-ylmethyl)piperidin-2-one (705 mg, 1.515 mmol; Example 71,
Step D) in inhibitor free THF (7 mL) under N.sub.2 at -78.degree.
C. was added lithium diisopropylamide (1.515 mL, 3.03 mmol) and the
mixture was stirred for 30 min. 1,1-Difluoro-2-iodoethane (727 mg,
3.79 mmol; Oakwood) was added and the orange reaction mixture was
stirred at -78.degree. C. for 1 h. The reaction was warmed to rt
overnight and quenched with 0.2 mL of MeOH, filtered and
concentrated. The residue was purified by HPLC (C18 column, eluted
with 10-95% CH.sub.3CN in water, with 0.1% TFA) to give
(3S,5R,6S)-3-allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((R)-3,3-diflu-
oro-1-(pyridin-2-yl)propyl)-3-methylpiperidin-2-one (HPLC retention
time 7.38 min, Agilent Eclipse Plus C18 column, 0.1% TFA in
CH.sub.3CN/H.sub.2O, gradient 70%-90% over 25 minutes) and
(3S,5R,6S)-3-allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((S)-3,3-diflu-
oro-1-(pyridin-2-yl)propyl)-3-methylpiperidin-2-one (HPLC retention
time 7.94 min, Agilent Eclipse Plus C18 column (Agilent
Technologies, Santa Clara, Calif.), 0.1% TFA in
CH.sub.3CN/H.sub.2O, gradient 70%-90% over 25 minutes). Mass
Spectrum (ESI) m/z=529 (M+1).
Step B.
2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-2-oxo-
-1-((S)-3,3,3-trifluoro-1-(pyridin-2-yl)propyl)piperidin-3-yl)acetic
acid/2,2,2-Trifluoroacetic acid (1:1)
##STR00687##
[2772] The title compound was obtained from
(3S,5R,6S)-3-allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((S)-3,3-diflu-
oro-1-(pyridin-2-yl)propyl)-3-methylpiperidin-2-one (50 mg, 0.095
mmol; Example 244, Step A;) by a procedure similar to the one
described in Example 71, Step F.
[2773] .sup.1H NMR (400 MHz, CHLOROFORM-d) .delta. ppm 9.03 (1H, d,
J=4.3 Hz), 8.17 (1H, t, J=7.8 Hz), 7.79 (1H, d, J=8.2 Hz), 7.72
(1H, t, J=6.3 Hz), 7.18-7.25 (4H, m), 7.08-7.16 (2H, m), 6.95 (1H,
s), 6.88-6.93 (1H, m), 5.44 (1H, br. s.), 5.31 (2H, d, J=10.4 Hz),
5.21 (6H, br. s.), 5.10 (2H, br. s.), 3.30-3.42 (1H, m), 3.18 (1H,
br. s.), 2.90 (1H, d, J=15.1 Hz), 2.72 (1H, d, J=15.1 Hz), 2.44
(1H, d, J=16.4 Hz), 2.27 (1H, t, J=13.8 Hz), 1.98-2.08 (1H, m),
1.21 (3H, s). Mass Spectrum (ESI) m/z=547 (M+1).
Example 245
2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-1-((S)-2-meth-
yl-1-(pyridin-2-yl)propyl)-2-oxopiperidin-3-yl)acetic acid or
2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-1-((R)-2-met-
hyl-1-(pyridin-2-yl)propyl)-2-oxopiperidin-3-yl)acetic acid
##STR00688##
[2774] Step A: 2-(1-Bromo-2-methylpropyl)pyridine
##STR00689##
[2776] The title compound was prepared from 2-isobutylpyridine
(5.17 g, 38.2 mmol; Alfa Aesar, Ward Hill, Mass.) following a
procedure similar to the one described in Example 230. The reaction
mixture was cooled to rt and filtered, washing the filtered cake
copiously with DCM. The filtrate was concentrated in vacuo and
purified by chromatography on silica gel, eluting with a 0 to 25%
gradient of EtOAc in hexanes. Fractions containing the desired
product were concentrated to give the title compound.
Step B.
(3S,5R,6S)-3-allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl--
1-((S)-2-methyl-1-(pyridin-2-yl)propyl)piperidin-2-one or
(3S,5R,6S)-3-allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-1-((S)--
2-methyl-1-(pyridin-2-yl)propyl)piperidin-2-one
##STR00690##
[2778] 2-(1-Bromo-2-methylpropyl)pyridine (Example 245, Step A) and
(3S,5R,6S)-3-allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methylpiperidi-
n-2-one (Example 71, Step D) were combined according to a procedure
similar to the one described in Example 226, Step C leading after
separation to the title compound as the less abundant diastereomer.
MS (ESI) 507 [M+H].sup.+.
Step C
2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-1-((S)-2-meth-
yl-1-(pyridin-2-yl)propyl)-2-oxopiperidin-3-yl)acetic acid or
2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-1-((R)-2-met-
hyl-1-(pyridin-2-yl)propyl)-2-oxopiperidin-3-yl)acetic acid
[2779] The title compound was obtained by treating the compound of
Example 245, Step B by the procedure as described in Example 71,
Step F.
[2780] .sup.1H NMR (500 MHz, DICHLOROMETHANE-d.sub.2) .delta. 0.87
(d, J=6.11 Hz, 3H), 1.18 (br. s., 3H), 1.33-1.47 (m, 3H), 1.96-2.10
(m, 1H), 2.10-2.27 (m, 1H), 2.70-2.88 (m, 3H), 3.19-3.30 (m, 1H),
4.66 (d, J=9.54 Hz, 1H), 6.73 (d, J=7.58 Hz, 1H), 6.84 (br. s.,
2H), 6.97 (br. s., 3H), 7.05-7.23 (m, 3H), 7.55 (t, J=6.60 Hz, 1H),
7.82 (t, J=8.31 Hz, 1H), 8.79 (d, J=4.89 Hz, 1H). MS (ESI) 525
[M+H].sup.+.
Example 246
(3R,5R,6S)-3-((1H-tetrazol-5-yl)methyl)-5-(3-chlorophenyl)-6-(4-chlorophen-
yl)-3-methyl-1-(pentan-3-yl)piperidin-2-one
##STR00691##
[2782] The title compound was prepared from
2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-2-oxo-1-(pen-
tan-3-yl)piperidin-3-yl)acetic acid (Example 71) as described in
Example 86.
[2783] .sup.1H NMR (400 MHz, CHLOROFORM-d) .delta. ppm 0.49 (t,
J=7.53 Hz, 3H) 0.97 (t, J=7.43 Hz, 3H) 1.33 (s, 3H) 1.37-1.58 (m,
2H) 1.84-2.05 (m, 2H) 2.17-2.35 (m, 2H) 2.77 (dt, J=9.00, 4.50 Hz,
1H) 3.05-3.21 (m, 1H) 3.42-3.64 (m, 2H) 4.36 (d, J=10.37 Hz, 1H)
6.71 (d, J=7.63 Hz, 1H) 6.82 (d, J=7.63 Hz, 2H) 6.98 (t, J=1.66 Hz,
1H) 7.06-7.25 (m, 4H). Mass spectrum (ESI) m/z 486.3
[M+H].sup.+.
Example 247
(3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-((R)-2,3-dihydroxypropy-
l)-1-((2S,3S)-2-hydroxypentan-3-yl)-3-methylpiperidin-2-one and
(3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-((S)-2,3-dihydroxyprop-
yl)-1-((2S,3S)-2-hydroxypentan-3-yl)-3-methylpiperidin-2-one
##STR00692##
[2784] Step A.
(3S,5R,6S)-3-Allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((2S,3S)-2-hyd-
roxypentan-3-yl)-3-methylpiperidin-2-one
##STR00693##
[2786] To a stirred solution of
(3S,5R,6S)-3-allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-1-((S)--
2-oxopentan-3-yl)piperidin-2-one (185 mg, 0.40 mmol; Example 149,
Step B) in THF (4 mL) under a nitrogen atmosphere at -8.degree. C.
(internal temperature) was added L-Selectride.RTM. (Aldrich, St.
Louis, Mo.) (0.48 mL, 0.48 mmol, 1M solution in THF) dropwise over
2 minutes (internal temperature reached -5.degree. C.). After 10
minutes the reaction was quenched with MeOH (0.1 mL) and treated
with Oxone.RTM. (2 KHSO.sub.5.KHSO.sub.4.K.sub.2SO.sub.4, DuPont,
Wilmington, Del.) (992 mg, 1.61 mmol) in water (30 mL) and then it
was stirred at rt for 2 hours. After this time the reaction was
partitioned between EtOAc (50 mL) and Na.sub.2S.sub.2O.sub.3 (30
mL, saturated aqueous solution). The separated organic layer was
washed with brine (20 mL) and then it was dried over MgSO.sub.4,
filtered and evaporated in vacuo to give the title compound.
[2787] Mass Spectrum (ESI) m/z=460.0 (M+1).
Step B:
(3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-((R)-2,3-dihydr-
oxypropyl)-1-((2S,3S)-2-hydroxypentan-3-yl)-3-methylpiperidin-2-one
and
(3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-((S)-2,3-dihydroxyprop-
yl)-1-((2S,3S)-2-hydroxypentan-3-yl)-3-methylpiperidin-2-one
[2788] To a stirred solution of
(3S,5R,6S)-3-allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((2S,3S)-2-hyd-
roxypentan-3-yl)-3-methylpiperidin-2-one (75 mg, 0.163 mmol,
Example 247, Step A) in t-BuOH (2 mL) was added 4-methylmorpholine
4-oxide (76 mg, 0.652 mmol) and osmium tetroxide (2.1 mg, 8.14
.mu.mol) and the reaction was stirred at rt overnight. After this
time the reaction was partitioned between EtOAc (100 mL) and
Na.sub.2S.sub.2O.sub.3 (40 mL, saturated aqueous solution). The
separated organic layer was washed with NaHCO.sub.3 (40 mL,
saturated aqueous solution), dried over MgSO.sub.4, filtered and
evaporated in vacuo. The resulting residue was purified by reverse
phase HPLC (Sunfire.TM. Prep C.sub.18 OBD 10 .mu.m column (Waters,
Milford, Mass.), gradient of elution of 20% MeCN in water to 80%
MeCN in water over a 30 min period, where both solvents contain
0.1% TFA) to give the title compounds as a separable mixture of
diastereomers.
[2789] 1.sup.st eluted isomer: .sup.1H NMR (400 MHz, CHLOROFORM-d)
.delta. ppm 6.96-7.28 (8H, m), 6.73 (1H, dt, J=7.6, 1.6 Hz), 4.39
(1H, d, J=10.6 Hz), 3.96-4.06 (1H, m), 3.71 (1H, dd, J=11.0, 3.5
Hz), 3.56 (1H, dd, J=11.1, 7.3 Hz), 3.26-3.38 (1H, m), 1.78-2.15
(6H, m), 1.44 (3H, s), 1.19-1.39 (4H, m), 0.50-0.67 (3H, m). Mass
Spectrum (ESI) m/z=494.0 (M+1).
[2790] 2.sup.nd eluted isomer: .sup.1H NMR (400 MHz, CHLOROFORM-d)
.delta. ppm 6.96-7.28 (8H, m), 6.70 (1H, dd, J=6.2, 1.5 Hz), 4.38
(1H, d, J=10.4 Hz), 4.31 (1H, br.s.), 3.66-3.76 (1H, m), 3.53-3.63
(1H, m), 3.22-3.33 (1H, m), 1.80-2.32 (4H, m), 1.45 (3H, s),
1.16-1.45 (6H, m), 0.40-0.55 (3H, br.s.). Mass Spectrum (ESI)
m/z=494.0 (M+1).
Example 248
2-((3R,5R,6S)-5-(3-Chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-hydroxybutan--
2-yl)-3-methyl-2-oxopiperidin-3-yl)cyclopropanecarboxylic acid
##STR00694##
[2791] Step A. (3S,5R,6S)-Methyl
1-((S)-1-(tert-butyldiphenylsilyloxy)butan-2-yl)-5-(3-chlorophenyl)-6-(4--
chlorophenyl)-3-methyl-2-oxopiperidine-3-carboxylate
##STR00695##
[2793] A stirred solution of
(5R,6S)-1-((S)-1-(tert-butyldiphenylsilyloxy)butan-2-yl)-5-(3-chloropheny-
l)-6-(4-chlorophenyl)-3-methylpiperidin-2-one (1.3 g, 2.016 mmol;
Example 185, Step D) in inhibitor free THF (10 mL) was degassed for
30 minutes with argon. The reaction was transferred via cannula
over 5 minutes to a freshly prepared solution of LDA at -78.degree.
C. (the LDA solution was prepared by treating N,N-diisopropylamine
(0.72 mL, 5.04 mmol) in inhibitor free THF (2 mL) at -20.degree. C.
under an argon atmosphere with butyllithium (2.02 mL, 5.04 mmol,
2.5 M in hexanes) over 1 minute and stirring the mixture at
-15.degree. C. for 30 minutes). The resulting reaction mixture was
stirred while warming to 0.degree. C. over 30 minutes. The reaction
was cooled to -78.degree. C. and treated with methyl chloroformate
(0.47 mL, 6.05 mmol) dropwise over 2 minutes. The reaction was
stirred at -78.degree. C. for 2 hours and 30 minutes and then
quenched with 30 mL of a saturated aqueous NH.sub.4Cl solution and
allowed to warm to rt. The mixture was partitioned between ethyl
acetate (150 mL) and water (50 mL). The separated organic layer was
dried over MgSO.sub.4, filtered and evaporated in vacuo. Column
chromatography (SiO.sub.2, hexanes:EtOAc, 1:0 to 4:1) gave the
title compound. Mass Spectrum (ESI) m/z=702.1 (M+1).
Step B.
(3R,5R,6S)-1-((S)-1-(tert-Butyldiphenylsilyloxy)butan-2-yl)-5-(3-c-
hlorophenyl)-6-(4-chlorophenyl)-3-(hydroxymethyl)-3-methylpiperidin-2-one
##STR00696##
[2795] To a stirred solution of (3S,5R,6S)-methyl
1-((S)-1-(tert-butyldiphenylsilyloxy)butan-2-yl)-5-(3-chlorophenyl)-6-(4--
chlorophenyl)-3-methyl-2-oxopiperidine-3-carboxylate (450 mg, 0.640
mmol; Example 248, Step A) at 0.degree. C. in THF (4 mL) under a
nitrogen atmosphere was added dropwise lithium triethylborohydride
(1.60 mL, 1.60 mmol, 1M solution in THF). The reaction was stirred
at 0.degree. C. for 1 hour and then it was quenched with methanol
(0.2 mL) and treated with Oxone.RTM.
(2KHSO.sub.5.KHSO.sub.4.K.sub.2SO.sub.4, DuPont, Wilmington, Del.)
(1.18 g, 1.92 mmol) in water (50 mL). The mixture was stirred for 1
hour and then extracted with ethyl acetate (100 mL). The separated
organic layer was washed with Na.sub.2S.sub.2O.sub.3 (50 mL,
saturated aqueous solution) and then dried over MgSO.sub.4,
filtered and evaporated in vacuo. Column chromatography (SiO.sub.2,
hexanes:EtOAc, 1:0 to 7:3) gave the title compound. Mass Spectrum
(ESI) m/z=674.2 (M+1).
Step C.
(3R,5R,6S)-1-((S)-1-(tert-Butyldiphenylsilyloxy)butan-2-yl)-5-(3-c-
hlorophenyl)-6-(4-chlorophenyl)-3-methyl-2-oxopiperidine-3-carbaldehyde
##STR00697##
[2797] To a stirred solution of
(3R,5R,6S)-1-((S)-1-(tert-butyldiphenylsilyloxy)butan-2-yl)-5-(3-chloroph-
enyl)-6-(4-chlorophenyl)-3-(hydroxymethyl)-3-methylpiperidin-2-one
(210 mg, 0.311 mmol; Example 248, Step B) in CH.sub.2Cl.sub.2 (8
mL) at 0.degree. C. was added NaHCO.sub.3 (131 mg, 1.56 mmol) and
Dess Martin periodinane (158 mg, 0.373 mmol) in one portion. The
reaction was stirred at rt for 2 hours. The reaction was diluted
with CH.sub.2Cl.sub.2 (30 mL) and treated with
Na.sub.2S.sub.2O.sub.3 (15 mL, saturated aqueous solution) and
NaHCO.sub.3 (15 mL, saturated aqueous solution) at rt for 2 hours.
The separated aqueous layer was extracted with CH.sub.2Cl.sub.2
(2.times.50 mL) and the combined organic extracts were dried over
MgSO.sub.4, filtered and evaporated in vacuo to give the title
compound. Mass Spectrum (ESI) m/z=672.2 (M+1).
Step D. (E)-Methyl
3-((3R,5R,6S)-1-((S)-1-(tert-butyldiphenylsilyloxy)butan-2-yl)-5-(3-chlor-
ophenyl)-6-(4-chlorophenyl)-3-methyl-2-oxopiperidin-3-yl)acrylate
##STR00698##
[2799] To a stirred solution of THF (4 mL) and sodium hydride (16
mg, 0.40 mmol, 60% dispersion in oil) under a nitrogen atmosphere
at 0.degree. C. was added trimethyl phosphonoacetate (61 .mu.L,
0.43 mmol) dropwise over 30 seconds. The mixture was allowed to
warm to rt for 30 minutes. A solution of
(3R,5R,6S)-1-((S)-1-(tert-butyldiphenylsilyloxy)butan-2-yl)-5-(3-chloroph-
enyl)-6-(4-chlorophenyl)-3-methyl-2-oxopiperidine-3-carbaldehyde
(205 mg, 0.305 mmol; Example 248, Step C) in THF (3 mL) was added.
The resulting mixture was stirred at rt for 2 hours. The reaction
was partitioned between EtOAc (80 mL) and water (40 mL). The
separated organic layer was dried over MgSO.sub.4, filtered and
evaporated in vacuo. Column chromatography (SiO.sub.2,
hexanes:EtOAc, 1:0 to 8:2) gave the title compound. Mass Spectrum
(ESI) m/z=728.2 (M+1).
Step E. Methyl
2-((3R,5R,6S)-1-((S)-1-((tert-butyldiphenylsilyl)oxy)butan-2-yl)-5-(3-chl-
orophenyl)-6-(4-chlorophenyl)-3-methyl-2-oxopiperidin-3-yl)cyclopropanecar-
boxylate
##STR00699##
[2801] To a stirred solution of sodium hydride (12 mg, 0.30 mmol,
60% dispersion in oil) in THF (1.0 mL) under an argon atmosphere
was added trimethylsulfoxonium iodide (72 mg, 0.33 mmol)
portionwise over 1 minute. The reaction was stirred at rt for 1
hour. A solution of (E)-methyl
3-((3R,5R,6S)-1-((S)-1-(tert-butyldiphenylsilyloxy)butan-2-yl)-5-(3-chlor-
ophenyl)-6-(4-chlorophenyl)-3-methyl-2-oxopiperidin-3-yl)acrylate
(120 mg, 0.165 mmol; Example 248, Step D) in DMSO (1.0 mL) was
added dropwise over 1 minute. The reaction was stirred at rt
overnight. After this time more sulfur ylide was synthesized by
suspending trimethylsulfoxonium iodide (140 mg) in DMSO (0.5 mL)
under a nitrogen atmosphere and treating the mixture with NaH (24
mg, 60% dispersion in oil) and stirring for 30 minutes. The sulfur
ylide was then added to the reaction and the mixture was stirred at
rt for 16 hours After this time more sulfur ylide was synthesized
by suspending trimesulfoxonium iodide (140 mg) in DMSO (0.5 mL)
under a nitrogen atmosphere and treating the mixture with NaH (24
mg, 60% dispersion in oil) and stirring for 30 minutes. The sulfur
ylide was then added to the reaction and the mixture was stirred at
rt for 16 hours. The reaction was partitioned between ethyl acetate
(70 mL) and NH.sub.4Cl (30 mL, saturated aqueous solution). The
separated organic layer was dried over MgSO.sub.4, filtered and
evaporated in vacuo. Purification by reverse phase HPLC (Sunfire
Prep C.sub.18 OBD 10 .mu.m column, gradient elution of 40% MeCN in
water to 100% MeCN in water over a 40 min period, where both
solvents contain 0.1% TFA) gave the title compound as the first
eluting and major diastereomer. Stereochemistry at the cyclopropane
is a single but unassigned diastereomer. Mass Spectrum (ESI)
m/z=742.2 (M+1).
Step F.
2-((3R,5R,6S)-1-((S)-1-(tert-Butyldiphenylsilyloxy)butan-2-yl)-5-(-
3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-2-oxopiperidin-3-yl)cyclopropa-
necarboxylic acid
##STR00700##
[2803] To a stirred solution of the ester from Example 248, Step E
(10 mg, 0.013 mmol) in THF (1.0 mL) was added sodium hydroxide (404
.mu.L, 0.404 mmol, 1M aqueous solution). The reaction was stirred
at rt for 24 hours. After this time the reaction was partitioned
between EtOAc (30 mL) and 1.0 M HCl (5 mL). The separated organic
layer was dried over MgSO.sub.4, filtered and evaporated in vacuo
to give the title compound as a single diastereomer. Mass Spectrum
(ESI) m/z=728.2 (M+1).
Step G.
2-((3R,5R,6S)-5-(3-Chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-hydro-
xybutan-2-yl)-3-methyl-2-oxopiperidin-3-yl)cyclopropanecarboxylic
acid
[2804] To a stirred solution of the acid from Example 248, Step F
(10 mg, 0.014 mmol) in THF (0.2 mL) was added TBAF (0.1 mL, 1.0 M
solution in THF). After 30 minutes more TBAF (0.1 mL, 1.0 M
solution in THF) was added and the reaction was stirred at rt for 3
hours. After this time the reaction was partitioned between EtOAc
(30 mL) and 1M aqueous HCl (5 mL). The separated organic layer was
dried over MgSO.sub.4, filtered and evaporated in vacuo. The
resulting residue was purified by reverse phase HPLC (Sunfire Prep
C.sub.18 OBD 10 .mu.m column, gradient elution of 20% MeCN in water
to 80% MeCN in water over a 30 min period, where both solvents
contain 0.1% TFA) to give the title compound.
[2805] .sup.1H NMR (400 MHz, CD.sub.3OD) .delta. ppm 7.29-7.34 (2H,
m), 7.06-7.21 (5H, m), 6.87-6.98 (1H, m), 4.70 (1H, d, J=11.0 Hz),
4.06 (1H, dd, J=11.1, 9.3 Hz), 3.45-3.56 (2H, m), 2.89 (1H, dt,
J=8.9, 4.5 Hz), 2.48 (1H, t, J=13.5 Hz), 1.92-2.04 (1H, m),
1.78-1.88 (1H, m), 1.61-1.72 (1H, m), 1.43-1.53 (2H, m), 1.22-1.36
(6H, m), 0.41-0.52 (3H, m). Mass Spectrum (ESI) m/z=490.0
(M+1).
Example 249
2-((3R,5R,6S)-1-((S)-2-(tert-Butoxy)-1-cyclopropyl-2-oxoethyl)-5-(3-chloro-
phenyl)-6-(4-chlorophenyl)-2-oxopiperidin-3-yl)acetic acid
##STR00701##
[2806] Step A. Ethyl 2-bromo-2-cyclopropylacetate
##STR00702##
[2808] To a solution of 2-cyclopropylacetic acid (24.7 g, 247 mmol)
in anhydrous DCE (250 mL) was added thionyl chloride (22 mL, 302
mmol) dropwise for 5 minutes at 25.degree. C. After being refluxed
for 2 h, the reaction was cooled to room temperature,
N-bromosuccinimide (53.6 g, 301 mmol) and hydrogen bromide (48%
aqueous solution) (0.195 mL, 1.727 mmol) were added successively at
25.degree. C. The resulted mixture was heated to reflux for 96 h.
After the reaction mixture was cooled to room temperature, absolute
EtOH (200 mL) was added and the resulting dark brown solution was
stirred at room temperature for an hour. The reaction mixture was
concentrated under reduced pressure (35.degree. C., 4.0 kilopascal)
and the residue was suspended in carbon tetrachloride (300 mL) and
passed through a glass filter. The filtrate was concentrated under
reduced pressure (35.degree. C., 4.0 kilopascal). Purification of
the crude product by chromatography (silica gel, 330 g.times.2, 5%
ethyl acetate/hexane) and concentration of the desired combined
fractions under reduced pressure (35.degree. C., 4.0 kilopascal)
provided the title compound as a pale yellow liquid.
[2809] .sup.1H NMR (400 MHz, CHLOROFORM-d) .delta. ppm 4.20-4.32
(2H, m), 3.59 (1H, d, J=10.4 Hz), 1.53-1.66 (1H, m), 1.29-1.36 (3H,
m), 0.76-0.93 (2H, m), 0.51-0.61 (1H, m), 0.40-0.47 (1H, m).
Step B. (S)-Ethyl
2-((2S,3R)-3-(3-chlorophenyl)-2-(4-chlorophenyl)-6-oxopiperidin-1-yl)-2-c-
yclopropylacetate
##STR00703##
[2811] To a solution of
(3S,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-piperidin-2-one
(8.01 g, 25 mmol; Example 1, Step E) in DMF (60 mL) was added 60%
sodium hydride in mineral oil (2.0 g, 50 mmol) at 0.degree. C. and
the mixture thus obtained was stirred at same temperature for 30
min. To the mixture was added ethyl 2-bromo-2-cyclopropylacetate
(12.18 g, 50 mmol) in DMF (10 mL) dropwise and the mixture was
stirred at room temperature 2 h, then the reaction was quenched
with sat. ammonium chloride solution and diluted with ethyl
acetate. The organic layer was washed with 10% aq. citric acid, 5%
aq. NaHCO.sub.3 solution, water, sat. aq. NaCl solution, then dried
over MgSO.sub.4. The solvent was evaporated under reduced pressure
and the residue was purified by chromatography on silica gel
eluting with 20% to 50% ethyl acetate in hexane to give the title
compound as the first eluting diastereomer, a white solid.
[2812] .sup.1H NMR (400 MHz, CHLOROFORM-d) .delta. ppm -0.34 (m,
1H), 0.23 (m, 1H), 0.38 (m, 1H), 0.62 (m, 1H), 1.26 (t, J=8 Hz,
3H), 1.39 (m, 1H), 2.13 (m, 2H), 2.63 (m, 2H), 3.09 (m, 1H), 3.20
(d, J=12 Hz, 1H), 4.07 (m, 2H), 4.81 (d, J=8 Hz, 1H), 6.90 (dt,
J=7.1, 1.7 Hz, 1H), 7.11-7.19 (m, 5H), 7.28 (m, 2H). Mass Spectrum
(ESI) m/z=446.2 (M+1).
Step C. (S)-tert-Butyl
2-((2S,3R)-3-(3-chlorophenyl)-2-(4-chlorophenyl)-6-oxopiperidin-1-yl)-2-c-
yclopropylacetate
##STR00704##
[2814] To a solution of (S)-ethyl
2-((2S,3R)-3-(3-chlorophenyl)-2-(4-chlorophenyl)-6-oxopiperidin-1-yl)-2-c-
yclopropylacetate (500 mg, 1.12 mmol) (Example 249, Step B) in
THF/MeOH/H.sub.2O (5/5/5, 15 mL) was added lithium hydroxide (1.68
mL, 3.36 mmol) at rt, and then the reaction was heated to
60.degree. C. After being stirred at 60.degree. C. for 1.5 h, the
reaction was quenched with saturated aqueous NH.sub.4Cl solution
and extracted (2.times.DCM). The combined organic layers were
washed (1.times.sat. aq. NaCl solution), dried over
Na.sub.2SO.sub.4, filtered and the filtrate was concentrated and
concentrated under reduced pressure.
[2815] The crude acid (450 mg, 1.076 mmol) synthesized above was
dissolved in DCM (10 mL) and sulfuric acid (115 uL, 2.151 mmol) was
added, followed by 2-methylprop-1-ene (1.207 g, 21.51 mmol) at
-78.degree. C. The reaction vessel was sealed and the mixture was
slowly warmed to ambient temperature. After being vigorously
stirred for 4 days, the reaction was quenched with sat. aqueous
NH.sub.4Cl solution and extracted with ethyl acetate. The combined
organic layers were washed with sat. aq. NaCl solution and dried
over sodium sulfate, filtered and the filtrate was concentrated
under reduced pressure. Purification of the residue by flash
chromatography on silica gel (eluent: 40% EtOAc/hexanes) provided
the title compound.
Step D. (S)-tert-Butyl
2-((3S,5R,6S)-3-allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-2-oxopiperidi-
n-1-yl)-2-cyclopropylacetate
##STR00705##
[2817] A solution of lithium bis(trimethylsilyl)amide (1M in THF,
0.165 mL, 0.165 mmol) was added dropwise at -78.degree. C. to a
solution of (S)-tert-butyl
2-((2S,3R)-3-(3-chlorophenyl)-2-(4-chlorophenyl)-6-oxopiperidin-1-yl)-2-c-
yclopropylacetate (Example 249, Step C, 71 mg, 0.15 mmol) and allyl
bromide (15.54 uL, 0.165 mmol) in 0.5 mL of THF. The reaction was
allowed to warm to ambient temperature. After stirring for 2 h, the
reaction was quenched with sat. aqueous ammonium chloride solution
and extracted with ethyl acetate. The combined organic layers were
washed with sat. aq. NaCl solution and dried over sodium sulfate,
then filtered and the filtrate was concentrated under reduced
pressure. Purification by flash chromatography on silica gel
eluting with ethyl acetate/hexane provided the title compound.
Step E.
2-((3R,5R,6S)-5-(3-Chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-(N-cy-
clopropylacetamido)butan-2-yl)-3-methyl-2-oxopiperidin-3-yl)acetic
acid
[2818] The title compound was obtained from (S)-tert-butyl
2-((3S,5R,6S)-3-allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-2-oxopiperidi-
n-1-yl)-2-cyclopropylacetate (Example 249, Step D) by the procedure
of example 71, step F.
[2819] .sup.1H NMR (400 MHz, CHLOROFORM-d) .delta. ppm 0.08 (m,
1H), 0.49 (m, 1H), 0.58 (m, 1H), 0.66 (m, 1H), 1.02 (m, 1H), 1.44
(s, 9H), 1.99 (m, 1H), 2.19 (m, 1H), 2.58 (dd, J=16.0, 4.0 Hz, 1H),
2.66 (m, 1H), 2.93 (dd, J=12.0, 12.0 HZ, 1H), 3.20 (s, 1H), 3.34
(d, J=12 HZ, 1H), 5.37 (s, 1H), 7.14 (m, 1H), 7.25-7.33 (m, 3H),
7.37-7.45 (m, 4H). Mass Spectrum (ESI) m/z=532.2 (M+1).
Example 250
2-((3R,5R,6S)-5-(3-Chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-cyclopropyl-2-
-ethoxy-2-oxoethyl)-3-methyl-2-oxopiperidin-3-yl)acetic acid
##STR00706##
[2820] Step A. Ethyl
2-((3S,5R,6S)-3-allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-2-ox-
opiperidin-1-yl)-2-cyclopropylacetate
##STR00707##
[2822] Coupling of
(3S,5R,6S)-3-allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methylpiperidi-
n-2-one (Example 71, Step D) and ethyl 2-bromo-2-cyclopropylacetate
(Example 249, Step A) using the procedure as described in Example
9, step A afforded the title compound as a mixture of two
diastereomers.
Step B.
2-((3R,5R,6S)-5-(3-Chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-cyclo-
propyl-2-ethoxy-2-oxoethyl)-3-methyl-2-oxopiperidin-3-yl)acetic
acid
##STR00708##
[2824] The title compound was obtained from diastereomeric ethyl
2-((3S,5R,6S)-3-allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-2-ox-
opiperidin-1-yl)-2-cyclopropylacetate (Example 250, Step A) using
the oxidation procedure described in Example 71, Step F. Individual
stereoisomers were separated by chiral HPLC (150.times.30 mm
CHIRALPAK.RTM. IC column (CHIRAL TECHNOLOGIES, INC., West Chester,
Pa., USA) with 20% IPA (0.1% DEA)/CO.sub.2, 50 mL/min, on Thar 350
SFC (Thar Technologies, Inc., Pittsburg, Pa.)) to give the title
compound as the faster eluting stereoisomer.
[2825] .sup.1H NMR (400 MHz, CHLOROFORM-d) .delta. ppm -0.49--0.40
(m, 1H) 0.12-0.21 (m, 1H) 0.36-0.46 (m, 1H) 0.64 (m, 1H) 1.28 (t,
J=7.14 Hz, 3H) 1.37 (s, 3H) 1.40-1.56 (m, 1H) 2.14-2.27 (m, 2H)
2.83 (d, J=14.48 Hz, 1H) 2.95 (d, J=14.48 Hz, 1H) 3.02 (d, J=9.78
Hz, 1H) 3.22-3.36 (m, 1H) 4.06-4.22 (m, 2H) 4.75 (d, J=9.39 Hz, 1H)
6.81 (m, 1H) 7.00-7.21 (m, 5H) 7.21-7.35 (m, 2H). Mass Spectrum
(ESI) m/z=518.0 (M+1).
Example 251
2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-cyclopropyl-2-
-hydroxyethyl)-3-methyl-2-oxopiperidin-3-yl)acetic acid
##STR00709##
[2826] Step A.
(5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-cyclopropyl-2-hydr-
oxyethyl)piperidin-2-one
##STR00710##
[2828] A solution of lithium borohydride (2M in THF, 15.46 mL, 30.9
mmol) was added to a solution at 0.degree. C. of (S)-ethyl
2-((2S,3R)-3-(3-chlorophenyl)-2-(4-chlorophenyl)-6-oxopiperidin-1-yl)-2-c-
yclopropylacetate (Example 249, Step B, 2.3 g, 5.15 mmol) in ether
(40 mL). After stirring at ambient temperature for 20 hours, the
reaction was quenched with saturated aq. NH.sub.4Cl solution and
extracted into EtOAc. The organic layer was washed with sat. aq.
NaCl solution, dried over sodium sulfate and concentrated to give
the title compound as a solid, which was used without further
purification.
[2829] .sup.1H NMR (400 MHz, CHLOROFORM-d) .delta. ppm 0.00 (m,
1H), 0.23 (m, 1H), 0.48-0.57 (m, 2H), 0.85 (m, 1H), 1.99 (m, 1H),
2.07 (m, 1H), 2.61 (m, 2H), 2.64 (m, 1H), 3.22 (dd, J=11.2, 9.8 Hz,
1H), 3.42 (td, J=10.1, 4.3 Hz, 1H), 3.60 (m, 1H), 4.93 (d, J=6.5
Hz, 1H), 6.89 (m, 1H), 7.09 (m, 4H), 7.18 (m, 2H), 7.27 (m, 1H).
Mass Spectrum (ESI) m/z=404.0 (M+1).
Step B.
(5R,6S)-1-((S)-2-((tert-Butyldiphenylsilyl)oxy)-1-cyclopropylethyl-
)-5-(3-chlorophenyl)-6-(4-chlorophenyl)piperidin-2-one
##STR00711##
[2831] The product of example 251 step A was converted to the title
compound by a procedure similar to the one described in example 185
step C.
[2832] .sup.1H NMR (400 MHz, CHLOROFORM-d) .delta. ppm -0.70 (m,
1H), -0.40 (m, 1H), 0.02 (m, 1H), 0.13 (m, 1H), 0.91 (s, 9H), 1.09
(m, 1H), 1.92-1.91 (m, 2H), 2.47-2.50 (m, 2H), 2.78 (s, br, 1H),
2.80 (m, 1H), 3.31 (m, 1H), 3.98 (m, 1H), 4.62 (d, J=7.8 Hz, 1H),
6.60 (m, 1H), 6.82-6.91 (m, 4H), 6.91-7.03 (m, 3H), 7.18-7.26 (6H),
7.37-7.45 (m, 4H). Mass Spectrum (ESI) m/z=642.3 (M+1).
Step C.
(5R,6S)-1-((S)-2-((tert-Butyldiphenylsilyl)oxy)-1-cyclopropylethyl-
)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methylpiperidin-2-one
##STR00712##
[2834]
(5R,6S)-1-((S)-2-((tert-butyldiphenylsilyl)oxy)-1-cyclopropylethyl)-
-5-(3-chlorophenyl)-6-(4-chlorophenyl)piperidin-2-one (Example 251
Step B, 7.9 g, 12.29 mmol) was converted to the title compound,
mixture of diastereomers by the method of Example 185, Step D.
[2835] .sup.1H NMR (400 MHz, CHLOROFORM-d) .delta. ppm -0.15 (m,
1H), 0.00 (m, 1H), 0.41-0.52 (m, 2H), 1.26 (s, 9H), 1.41 (m, 1H),
1.62 (d, J=7.2 Hz, 3H), 2.09 (m, 1H), 2.30 (m, 1H), 2.87 (m, 1H),
3.28 (m, 2H), 3.68 (m, 1H), 4.23 (m, 1H), 5.11 (d, J=6.1 Hz, 1H),
7.16-7.34 (m, 4H), 7.37-7.46 (m, 4H), 7.51-7.65 (m, 6H), 7.74-7.78
(m, 4H).
Step D.
(5R,6S)-3-Allyl-1-((S)-2-((tert-butyldiphenylsilyl)oxy)-1-cyclopro-
pylethyl)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methylpiperidin-2-one
##STR00713##
[2837]
(5R,6S)-1-((S)-2-(tert-Butyldiphenylsilyloxy)-1-cyclopropylethyl)-5-
-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methylpiperidin-2-one (5.02
g, 7.64 mmol, Example 251, Step C) was converted into the title
compound by the procedure described for Example 185, Step E. After
workup, the unpurified product was used as obtained.
Step E.
2-((3R,5R,6S)-1-((S)-2-((tert-Butyldiphenylsilyl)oxy)-1-cyclopropy-
lethyl)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-2-oxopiperidin-3-yl-
)acetic acid
##STR00714##
[2839]
(5R,6S)-3-allyl-1-((S)-2-((tert-Butyldiphenylsilyl)oxy)-1-cycloprop-
ylethyl)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methylpiperidin-2-one
(Example 251, Step D, 106 mg, 0.15 mmol) was treated according to
the procedure of Example 185, Step F to provide
2-((3R,5R,6S)-1-((S)-2-((tert-butyldiphenylsilyl)oxy)-1-cyclopropylethyl)-
-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-2-oxopiperidin-3-yl)acetic
acid. Mass Spectrum (ESI) m/z=714.3 (M+1).
Step F.
2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-cyclo-
propyl-2-hydroxyethyl)-3-methyl-2-oxopiperidin-3-yl)acetic acid
[2840] A solution of tetrabutylammonium fluoride, (1.0 M in THF,
0.453 mL, 0.453 mmol) was added to a solution of
2-((3R,5R,6S)-1-((S)-2-(tert-butyldiphenylsilyloxy)-1-cyclopropylethyl)-5-
-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-2-oxopiperidin-3-yl)acetic
acid (Example 251, Step E, 108 mg, 0.151 mmol) in THF (4 ml) and
the reaction was stirred at ambient temperature for 20 hours.
Analysis by LC-MS showed incomplete reaction so an extra 0.225 ml
of tetrabutylammonium fluoride solution was added and the reaction
was stirred for another 26 hours. The mixture was diluted in ethyl
acetate then washed with water and sat. aq. NaCl solution. The
organic layer was dried over sodium sulfate and concentrated.
Purification by RP-HPLC (Sunfire Prep C.sub.18 OBD 10 .mu.m column,
gradient elution of 10% MeCN in water to 80% MeCN in water over a
30 min period, where both solvents contain 0.1% TFA) afforded the
title compound as a solid.
[2841] .sup.1H NMR (400 MHz, CHLOROFORM-d) .delta. ppm -0.30 (s, m,
1H), 0.00 (s, m, 1H), 0.37 (m, 2H), 0.79 (m, 1H), 1.22 (s, 3H),
2.00 (m, 2H), 2.52 (d, J=14.1 Hz, 1H), 2.70 (d, J=13.9 Hz, 1H),
3.00 (m, 2H), 3.20 (s, br, 3H), 3.29 (m, 1H), 4.65 (d, J=10.0 Hz,
1H), 6.61 (m, 1H), 6.84 (s, br, 2H), 6.97 (m, 3H), 7.04 (m, 2H).
Mass Spectrum (ESI) m/z=476.2 (M+1).
Example 252
2-((3R,5R,6S)-5-(3-Chlorophenyl)-6-(4-chlorophenyl)-1-((1S,2S)-1-cycloprop-
yl-2-hydroxybutyl)-3-methyl-2-oxopiperidin-3-yl)acetic acid or
2-((3R,5R,6S)-5-(3-Chlorophenyl)-6-(4-chlorophenyl)-1-((1S,2R)-1-cyclopro-
pyl-2-hydroxybutyl)-3-methyl-2-oxopiperidin-3-yl)acetic acid
##STR00715##
[2842] Step A.
(3S,5R,6S)-3-Allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-cyclopr-
opyl-2-hydroxyethyl)-3-methylpiperidin-2-one
##STR00716##
[2844] A solution of tetrabutylammonium fluoride in THF (1M, 2.10
mL, 2.10 mmol) was added to a solution of diastereomers
(5R,6S)-3-allyl-1-((S)-2-(tert-butyldiphenylsilyloxy)-1-cyclopropylethyl)-
-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methylpiperidin-2-one
(Example 251, Step D, 488 mg, 0.700 mmol) in THF (10 ml).The
reaction was stirred at ambient temperature for 2 hours. The
mixture was diluted in ethyl acetate and washed with water and sat.
aq. NaCl solution. The organic layer was dried over sodium sulfate.
Silica gel chromatography eluting with ethyl acetate/hexane gave
the title compound as a single diastereomer.
[2845] Mass Spectrum (ESI) m/z=458.0 (M+1)
Step B.
(S)-2-((3S,5R,6S)-3-Allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3--
methyl-2-oxopiperidin-1-yl)-2-cyclopropylacetaldehyde
##STR00717##
[2847]
(3S,5R,6S)-3-Allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-c-
yclopropyl-2-hydroxyethyl)-3-methylpiperidin-2-one (Example 252,
Step A, 80 mg, 0.17 mmol) was converted to the title compound as a
white foam by the procedure described in Example 91,
Step C. Mass Spectrum (ESI) m/z=456.1 (M+1)
Step C.
(3S,5R,6S)-3-Allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((1S,2S-
)-1-cyclopropyl-2-hydroxybutyl)-3-methylpiperidin-2-one or
(3S,5R,6S)-3-Allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((1S,2R)-1-cyc-
lopropyl-2-hydroxybutyl)-3-methylpiperidin-2-one
##STR00718##
[2849] By the procedure of Example 149, Step A, substituting ethyl
magnesium bromide for methyl magnesium bromide,
(S)-2-((3S,5R,6S)-3-allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl--
2-oxopiperidin-1-yl)-2-cyclopropylacetaldehyde (Example 252, Step
B, 90 mg, 0.20 mmol) was converted to the title compound which was
obtained as the second eluting diastereomer after
chromatography.
[2850] .sup.1H NMR (400 MHz, CHLOROFORM-d) .delta. ppm -0.43 (m,
1H), -0.16 (m, 1H), 0.32 (m, 1H), 0.51 (m, 1H), 0.78 (t, J=0.3 Hz,
3H), 1.18 (s, 3H), 1.21-1.35 (m, 1H), 2.54 (m, 2H), 1.57 (s, br,
1H), 1.87-2.0 (m, 2H), 2.21 (s, br, 1H), 2.50-2.62 (m, 2H), 3.22
(ddd, J=12.8, 10.2, 4.0 Hz, 1H), 3.68 (s, br, 1H), 4.34 (d, J=10.0
Hz, 1H), 5.12 (s, 1H), 5.14 (d, J=8 Hz, 1H), 5.79 (m, 1H), 6.65
(dt, J=7.6, 1.6 Hz, 1H), 6.87-6.91 (m, 3H), 7.01-7.07 (m, 2H),
7.16-7.18 (m, 2H).
[2851] Mass Spectrum (ESI) m/z=486.3 (M+1)
Step D.
2-((3R,5R,6S)-5-(3-Chlorophenyl)-6-(4-chlorophenyl)-1-((1S,2S)-1-c-
yclopropyl-2-hydroxybutyl)-3-methyl-2-oxopiperidin-3-yl)acetic acid
or
2-((3R,5R,6S)-5-(3-Chlorophenyl)-6-(4-chlorophenyl)-1-((1S,2R)-1-cyclopro-
pyl-2-hydroxybutyl)-3-methyl-2-oxopiperidin-3-yl)acetic acid
##STR00719##
[2853] The title compound was obtained by treating the compound of
Example 252, Step C by the method described in Example 71, Step
F.
[2854] .sup.1H NMR (400 MHz, Methanol-d4) .delta. ppm -0.16 (s, br,
1H), 0.26 (s, br, 1H), 0.55 (s, br, 1H), 0.67 (s, br, 1H), 0.86 (m,
3H), 1.32 (m, 4H), 1.41 (s, 3H), 1.68 (m, 1H), 1.92 (m, 2H), 2.64
(d, J=12 Hz, 1H), 2.99 (d, J=12 Hz, 1H), 3.51 (m, 1H), 4.97 (m,
1H), 6.97 (m, 1H), 7.06 (m, 1H), 7.17 (m, 4H), 7.28 (m, 2H). Mass
Spectrum (ESI) m/z=504.1 (M+1).
Example 253
2-((3R,5R,6S)-5-(3-Chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-cyclopropyl-2-
-(N-methylcyclopropanesulfonamido)ethyl)-3-ethyl-2-oxopiperidin-3-yl)aceti-
c acid
##STR00720##
[2855] Step A.
(5R,6S)-1-((S)-2-((tert-Butyldiphenylsilyl)oxy)-1-cyclopropylethyl)-5-(3--
chlorophenyl)-6-(4-chlorophenyl)-3-ethylpiperidin-2-one
##STR00721##
[2857] Using the procedure described for Example 185, Step D,
substituting ethyl iodide for methyl iodide,
(5R,6S)-1-((S)-2-(tert-butyldiphenylsilyloxy)-1-cyclopropylethyl)-5-(3-ch-
lorophenyl)-6-(4-chlorophenyl)piperidin-2-one (Example 251, Step B,
2.6 g, 4.05 mmol) was converted to the title compound as a
foam.
[2858] .sup.1H NMR (400 MHz, Methanol-d4) .delta. ppm -0.39 (m,
1H), -0.22 (m, 1H), 0.20-0.24 (m, 1H), 0.35-0.38 (m, 1H), 1.03-1.19
(m, 14), 1.26 (t, J=4 Hz, 1H), 1.78-1.84 (m, 1H), 1.94-1.99 (m,
1H), 2.13-2.19 (m, 2H), 2.46-2.51 (m, 1H), 3.24-3.26 (m, 1H),
3.52-3.53 (m, 1H), 5.0 (d, J=8 Hz, 1H), 7.06 (m, 1H), 7.17-7.24 (m,
5H), 7.30-7.32 (m, 2H), 7.37-7.50 (m, 6H), 7.58-7.62 (m, 4H). Mass
Spectrum (ESI) m/z=670.2 (M+1)
Step B.
(5R,6S)-3-Allyl-1-((S)-2-((tert-butyldiphenylsilyl)oxy)-1-cyclopro-
pylethyl)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-ethylpiperidin-2-one
##STR00722##
[2860] Using the procedure described for Example 185, Step E,
(5R,6S)-1-((S)-2-(tert-butyldiphenylsilyloxy)-1-cyclopropylethyl)-5-(3-ch-
lorophenyl)-6-(4-chlorophenyl)-3-methylpiperidin-2-one (Example
253, Step A, 1.6 g, 2.38 mmol) was converted to the title compound
which was used without further purification.
Step C.
(3S,5R,6S)-3-Allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1--
cyclopropyl-2-hydroxyethyl)-3-ethylpiperidin-2-one
##STR00723##
[2862] The title compound was prepared using a similar procedure as
Example 202, Step A. It was isolated as the second eluting
diastereomer after silica gel chromatography eluting with ethyl
acetate/hexanes.
[2863] .sup.1H NMR (400 MHz, Methanol-d4) .delta. ppm -0.48 (m,
1H), -0.01 (m, 1H), 0.40 (m, 1H), 0.48 (m, 1H), 0.97-1.01 (m, 3H),
1.37 (m, 1H), 1.49-1.58 (m, 1H), 1.75-1.78 (d, J=12 Hz, 1H), 1.97
(m, 1H), 2.38 (t, J=16 Hz, 1H), 2.65 (m, 2H), 2.76 (m, 1H), 3.94
(t, J=12 Hz, 1H), 4.79 (d, J=12 Hz, 1H), 5.20-5.28 (m, 2H),
5.94-6.03 (m, 1H), 6.96 (s, br, 1H), 7.09 (s, 2H), 3.01 (s, br,
3H), 7.29 (s, br, 2H). Mass Spectrum (ESI) m/z=472.1 (M+1).
Step D.
N--((S)-2-((3S,5R,6S)-3-Allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl-
)-3-ethyl-2-oxopiperidin-1-yl)-2-cyclopropylethyl)-N-methylcyclopropanesul-
fonamide
##STR00724##
[2865]
(3S,5R,6S)-3-Allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-c-
yclopropyl-2-hydroxyethyl)-3-ethylpiperidin-2-one (Example 253,
Step C, 125 mg, 0.265 mmol) was converted to the title compound by
the procedure described in Example 202, Step C.
[2866] .sup.1H NMR (400 MHz, Methanol-d4) .delta. ppm -0.46 (s, br,
1H), -0.24 (s, br, 1H), 0.48 (s, br, 2H), 0.96 (t, J=7.5 Hz, 3H),
0.99 (m, 6H), 1.71-1.79 (m, 2H), 1.88 (m, 1H), 2.35 (t, J=16 Hz,
1H), 2.51 (s, br, 1H), 2.69 (m, 2H), 3.43 (m, 2H), 4.89 (m, 1H),
5.17-5.28 (m, 2H), 5.94-6.05 (m, 1H), 7.0 (m, 1H), 7.05 (m, 1H),
7.17-7.19 (m, 4H), 7.30 (m, 2H). Mass Spectrum (ESI) m/z=589.2
(M+1).
Step E.
2-((3R,5R,6S)-5-(3-Chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-cyclo-
propyl-2-(N-methylcyclopropanesulfonamido)ethyl)-3-ethyl-2-oxopiperidin-3--
yl)acetic acid
[2867] The title compound was obtained from
N--((S)-2-((3S,5R,6S)-3-allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-eth-
yl-2-oxopiperidin-1-yl)-2-cyclopropylethyl)-N-methylcyclopropanesulfonamid-
e (Example 253, Step D) by the procedure described in Example 71,
Step F.
[2868] .sup.1H NMR (400 MHz, CHLOROFORM-d) .delta. ppm -0.71 (s,
br, 1H), -0.29 (s, br, 1H), 0.31-0.41 (d, br, 2H), 0.88 (m, 6H),
1.10 (s, br, 2H), 1.19 (m, 2H), 1.82-1.87 (m, 2H), 2.20-2.27 (m,
2H), 2.69-2.73 (d, J=16 Hz, 1H), 2.82 (s, br, 4H), 2.97-3.03 (m,
3H), 4.72 (d, J=12 Hz, 1H), 6.77 (m, 1H), 6.88 (s, br, 2H), 7.06
(m, 3H), 7.16 (s, br, 2H). Mass Spectrum (ESI) m/z=607.2 (M+1).
Example 254
2-((3R,5R,6S)-5-(3-Chlorophenyl)-6-(4-chlorophenyl)-1-((S)-2-(cyclopropane-
sulfonamido)-1-cyclopropylethyl)-3-ethyl-2-oxopiperidin-3-yl)acetic
acid
##STR00725##
[2869] Step A.
N--((S)-2-((3S,5R,6S)-3-Allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-eth-
yl-2-oxopiperidin-1-yl)-2-cyclopropylethyl)cyclopropanesulfonamide
##STR00726##
[2871]
(3S,5R,6S)-3-Allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-c-
yclopropyl-2-hydroxyethyl)-3-ethylpiperidin-2-one (Example 253,
Step C,) was coupled with cyclopropanesulfonamide by the procedure
described in example 202, step C to afford the title compound as a
white foam.
[2872] .sup.1H NMR (400 MHz, CHLOROFORM-d) .delta. ppm -0.28 (s,
br, 1H), 0.00 (s, br, 1H), 0.36 (d, br, 2H), 0.66 (m, 7H), 0.89 (m,
2H), 1.50 (m, 1H), 1.53 (dd, J=13.7, 3.1 Hz, 1H), 1.98 (t, J=13.7
Hz, 1H), 2.15 (m, 1H), 2.35 (m, 1H), 2.44 (m, 1H), 2.71 (s, br,
1H), 2.85 (m, 1H), 2.97 (ddd, J=13.6, 10.6, 3.0 Hz, 1H), 3.13 (s,
br, 1H), 4.54 (d, J=10.4 Hz, 1H), 4.91-4.96 (m, 2H), 5.63-5.73 (m,
1H), 6.49 (dt, J=7.5, 1.5 Hz, 1H), 6.72 (t, J=1.9 Hz, 2H),
6.85-6.91 (m, 3H), 6.94 (s, br, 2H). Mass Spectrum (ESI) m/z=575.2
(M+1).
Step B.
N-((2S)-2-((3R,5R,6S)-5-(3-Chlorophenyl)-6-(4-chlorophenyl)-3-(2,3-
-dihydroxypropyl)-3-ethyl-2-oxopiperidin-1-yl)-2-cyclopropylethyl)cyclopro-
panesulfonamide
##STR00727##
[2874] A solution of
N--((S)-2-((3S,5R,6S)-3-allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-eth-
yl-2-oxopiperidin-1-yl)-2-cyclopropylethyl)cyclopropanesulfonamide
(Example 254, Step A, 80 mg, 0.139 mmol) in THF (375 .mu.L), water
(250 .mu.L) and t-butanol (208 .mu.L) was treated with
4-methylmorpholine N-oxide (57.0 mg, 0.486 mmol) followed by 2.5%
osmium tetroxide in t-butanol (45.6 .mu.L, 3.47 .mu.mol). After
stirring at ambient temperature for 16 h, the mixture was diluted
with ethyl acetate and washed with water and sat. aq. NaCl
solution. The organic layer was dried over sodium sulfate and
concentrated to provide the title compound as a mixture of
diastereomers (85 mg) which was used directly in the next step.
Mass Spectrum (ESI) m/z=609.1 (M+1)
Step C.
N--((S)-2-((3R,5R,6S)-5-(3-Chlorophenyl)-6-(4-chlorophenyl)-3-ethy-
l-2-oxo-3-(2-oxoethyl)piperidin-1-yl)-2-cyclopropylethyl)cyclopropanesulfo-
namide
##STR00728##
[2876] Sodium periodate (89 mg, 0.418 mmol) was added to a clear
solution of
N-((2S)-2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-(2,3-dih-
ydroxypropyl)-3-ethyl-2-oxopiperidin-1-yl)-2-cyclopropylethyl)cyclopropane-
sulfonamide (Example 254, Step B, 85 mg, 0.14 mmol) in water (0.5
mL) and THF (1 mL). After several minutes, a solid formed. Methanol
(1 ml) was added and the resulting emulsion was stirred for 30 min.
The reaction was diluted with sat. aq. NaCl solution and extracted
twice with ethyl acetate. The combined organic layers were washed
with sat. aq. NaCl solution, dried over sodium sulfate and
concentrated under the reduced pressure to provide the title
compound (94 mg) which was used without purification in the next
step. Mass Spectrum (ESI) m/z=577.0 (M+1)
Step D.
2-((3R,5R,6S)-5-(3-Chlorophenyl)-6-(4-chlorophenyl)-1-((S)-2-(cycl-
opropanesulfonamido)-1-cyclopropylethyl)-3-ethyl-2-oxopiperidin-3-yl)aceti-
c acid
[2877] A solution of sodium chlorite (58.9 mg, 0.651 mmol) in
0.25.times.1.25 M potassium phosphate monobasic in water (1 mL) at
0.degree. C. was added to a clear solution of
N--((S)-2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-ethyl-2-oxo-
-3-(2-oxoethyl)piperidin-1-yl)-2-cyclopropylethyl)cyclopropanesulfonamide
(Example 254, Step C, 94 mg, 0.163 mmol) in 1.25 M potassium
phosphate monobasic in water (1 mL)+t-butanol (1 mL)+2 M
2-methylbut-2-ene in THF (4.07 mL, 8.14 mmol). After stirring at
ambient temperature for 4 hours, the reaction was quenched with 0.6
mL of 1 M sodium thiosulfate solution. After stirring for 10 min at
ambient temperature, the mixture was acidified with 1.2 mL of 1 M
potassium bisulphate solution. The mixture was extracted with ethyl
acetate. The organic layer was washed with water then sat. aq. NaCl
solution and dried over sodium sulfate. Purification by reverse
phase HPLC (Sunfire Prep C.sub.18 OBD 10 .mu.m column, gradient
elution of 20% MeCN in water to 80% MeCN in water over a 30 min
period, where both solvents contain 0.1% TFA) afforded the title
compound.
[2878] .sup.1H NMR (400 MHz, CHLOROFORM-d) .delta. ppm 0.00 (s, br,
1H), 0.30 (s, br, 1H), 0.64 (d, br, 2H), 0.96 (m, 7H), 1.12 (m,
3H), 1.75-1.82 (m, 1H), 1.92 (dd, J=13.8, 3.03 Hz, 1H), 2.02 (m,
1H), 2.34 (t, J=13.8 Hz, 1H), 2.47 (m, 1H), 2.84 (s, br, 3H), 3.05
(dd, J=13.0, 5.18 Hz, 1H), 3.24 (ddd, J=13.5, 10.3, 2.74 Hz, 1H),
3.53 (s, br, 1H), 4.84 (d, J=10.4 Hz, 1H), 6.78 (dt, J=7.63, 1.37
Hz, 1H) 7.02 (t, J=1.86 Hz, 2H) 7.10-7.20 (m, 5H). Mass Spectrum
(ESI) m/z=593.0 (M+1).
Example 255
2-((3R,5R,6S)-5-(3-Chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-cyclopropyl-2-
-(ethylsulfonamido)ethyl)-3-ethyl-2-oxopiperidin-3-yl)acetic
acid
##STR00729##
[2879] Step A.
N--((S)-2-((3S,5R,6S)-3-Allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-eth-
yl-2-oxopiperidin-1-yl)-2-cyclopropylethyl)ethanesulfonamide
##STR00730##
[2881] Coupling of
(3S,5R,6S)-3-allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-cyclopr-
opyl-2-hydroxyethyl)-3-ethylpiperidin-2-one (Example 253, Step C)
with ethylsulfonamide according to the procedure of Example 202,
Step D afforded the title compound.
[2882] .sup.1H NMR (400 MHz, CHLOROFORM-d) .delta. ppm -0.29 (s,
br, 1H), 0.00 (s, br, 1H), 0.37 (d, br, 2H), 0.69 (t, J=7.3 Hz,
3H), 1.14 (t, J=8 Hz, 3H), 1.30 (m, 1H), 1.56 (dd, J=13.7, 3.1 Hz,
1H), 1.69 (m, 1H), 2.01 (t, J=13.7 Hz, 1H), 2.38-2.40 (m, 1H),
2.44-2.48 (m, 1H), 2.77 (m, 4H), 2.99-3.12 (m, 2H), 4.58 (d, J=10.6
Hz, 1H), 4.96 (s, 1H), 4.98 (dd, J=7.0, 2.0 Hz, 1H), 5.43 (s, br,
1H), 5.67-5.76 (m, 1H), 6.54 (dt, J=7.4, 1.6 Hz, 1H), 6.75 (s, br,
2H), 63.87-6.93 (m, 3H), 6.94 (s, br, 2H). Mass Spectrum (ESI)
m/z=563.2 (M+1).
Step B.
N-((2S)-2-((3R,5R,6S)-5-(3-Chlorophenyl)-6-(4-chlorophenyl)-3-(2,3-
-dihydroxypropyl)-3-ethyl-2-oxopiperidin-1-yl)-2-cyclopropylethyl)ethanesu-
lfonamide
##STR00731##
[2884] The title compound was prepared as a mixture of
diastereomers using a procedure similar to the one described in
Example 254, Step B.
Step C.
N--((S)-2-((3R,5R,6S)-5-(3-Chlorophenyl)-6-(4-chlorophenyl)-3-ethy-
l-2-oxo-3-(2-oxoethyl)piperidin-1-yl)-2-cyclopropylethyl)ethanesulfonamide
##STR00732##
[2886] The title compound was prepared using a similar procedure as
described for Example 254, Step C. Mass Spectrum (ESI) m/z=565.2
(M+1).
Step D.
2-((3R,5R,6S)-5-(3-Chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-cyclo-
propyl-2-(ethylsulfonamido)ethyl)-3-ethyl-2-oxopiperidin-3-yl)acetic
acid
[2887] The title compound was obtained using a similar procedure as
described for Example 254, step D.
[2888] .sup.1H NMR (400 MHz, CHLOROFORM-d) .delta. ppm -0.51 (s,
br, 1H), 0.00 (s, br, 1H), 0.39 (s, br, 1H), 0.47 (s, br, 1H), 0.97
(t, J=7.4 Hz, 4H), 1.32 (t, J=7.4 Hz, 5H), 1.74-1.81 (m, 1H),
1.93-2.02 (m, 2H), 2.37 (t, J=12 Hz, 1H), 2.64 (d, J=13.7 Hz, 1H),
2.91 (d, J=13.5 Hz, 1H), 3.04 (m, 3H), 3.40 (m, 1H), 4.90 (d,
J=10.8 Hz, 1H), 6.99 (m, 1H), 7.05 (m, 2H), 7.14-7.19 (m, 5H). Mass
Spectrum (ESI) m/z=581.2 (M+1).
Example 256
2-((3R,5R,6S)-5-(3-Chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-cyclopropyl-2-
-(N-methylcyclopropanesulfonamido)ethyl)-3-methyl-2-oxopiperidin-3-yl)acet-
ic acid
##STR00733##
[2889] Step A.
N--((S)-2-((3S,5R,6S)-3-Allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-met-
hyl-2-oxopiperidin-1-yl)-2-cyclopropylethyl)-N-methylcyclopropanesulfonami-
de
##STR00734##
[2891] The title compound was prepared using a similar procedure as
described for Example 202, Step D.
[2892] .sup.1H NMR (400 MHz, CHLOROFORM-d) .delta. ppm -0.71 (s,
br, 1H), -0.31 (s, br, 1H), 0.31 (s, br, 1H), 0.40 (s, br, 1H),
1.01 (m, 2H), 1.25 (m, 3H), 1.29 (s, 3H), 1.59 (s, br, 1H),
1.85-1.89 (dd, J=13.6, 3.4 Hz, 2H), 2.22 (m, 1H), 2.35 (s, br, 1H),
2.67 (d, J=8 Hz, 2H), 2.94 (s, 3H), 3.11 (m, 1H), 3.19 (m, 1H),
4.78 (d, J=8 Hz, 1H), 5.19 (m, 2H), 5.25 (s, 1H), 5.85-5.95 (m,
1H), 6.93 (m, 2H), 7.06 (m, 2H), 7.14 (m, 2H), 7.23 (m, 2H). Mass
Spectrum (ESI) m/z=575.2 (M+1).
Step B.
N-((2S)-2-((3R,5R,6S)-5-(3-Chlorophenyl)-6-(4-chlorophenyl)-3-(2,3-
-dihydroxypropyl)-3-methyl-2-oxopiperidin-1-yl)-2-cyclopropylethyl)-N-meth-
ylcyclopropanesulfonamide
##STR00735##
[2894] The title compound was prepared as a mixture of
diastereomers using a similar procedure to the one described in
Example 254, Step B. Mass Spectrum (ESI) m/z=609.1 (M+1).
Step C.
N--((S)-2-((3R,5R,6S)-5-(3-Chlorophenyl)-6-(4-chlorophenyl)-3-meth-
yl-2-oxo-3-(2-oxoethyl)piperidin-1-yl)-2-cyclopropylethyl)-N-methylcyclopr-
opanesulfonamide
##STR00736##
[2896] The title compound was prepared using a similar procedure as
described for Example 254, Step C. Mass Spectrum (ESI) m/z=577.2
(M+1).
Step D.
2-((3R,5R,6S)-5-(3-Chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-cyclo-
propyl-2-(N-methylcyclopropanesulfonamido)ethyl)-3-methyl-2-oxopiperidin-3-
-yl)acetic acid
[2897] The title compound was prepared using a similar procedure as
described for Example 254, Step D.
[2898] .sup.1H NMR (400 MHz, Methanol-d4) .delta. ppm -0.71 (s, br,
1H), -0.28 (s, br, 1H), 0.29 (s, br, 1H), 0.40 (s, br, 1H), 1.06
(d, br, 4H), 1.44 (s, 3H), 1.73 (s, br, 1H), 2.08 (m, 1H), 2.20 (s,
br, 1H), 2.35 (t, J=8 Hz, 1H), 2.57 (s, br, 1H), 2.70 (d, J=12 Hz,
1H), 2.94 (s, 3H), 2.99 (d, J=12 Hz, 1H), 3.07 (m, 1H), 3.42 (m,
1H), 4.40 (s, br, 1H), 4.82 (d, J=8 Hz, 1H), 7.02-7.05 (m, 3H),
7.11 (m, 3H), 7.31 (s, br, 2H). Mass Spectrum (ESI) m/z=593.2
(M+1).
Example 257
2-((3R,5R,6S)-5-(3-Chlorophenyl)-6-(4-chlorophenyl)-1-((1S,2R)-1-cycloprop-
yl-2-hydroxypropyl)-3-methyl-2-oxopiperidin-3-yl)acetic acid
##STR00737##
[2899] Step A.
(3S,5R,6S)-3-Allyl-1-((S)-2-(tert-butyldiphenylsilyloxy)-1-cyclopropyleth-
yl)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methylpiperidin-2-one
##STR00738##
[2901] The mixture of diastereomers prepared from
(5R,6S)-1-((S)-2-(tert-butyldiphenylsilyloxy)-1-cyclopropylethyl)-5-(3-ch-
lorophenyl)-6-(4-chlorophenyl)-3-methylpiperidin-2-one (4.34 g,
6.61 mmol) by the method of Example 251, Step D was purified by
silica gel chromatography, eluting with ethyl acetate/hexanes.
Fractions containing the desired epimer were combined and
concentrated to give
(3S,5R,6S)-3-allyl-1-((S)-2-(tert-butyldiphenylsilyloxy)-1-cyclopropyleth-
yl)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methylpiperidin-2-one
as a white foam weighing 3.01 g (65% yield). MS (ESI) m/z=696
[M+H].sup.+.
Step B.
(3S,5R,6S)-3-Allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1--
cyclopropyl-2-hydroxyethyl)-3-methylpiperidin-2-one. (see also
Example 252 step A)
##STR00739##
[2903] Treating
(3S,5R,6S)-3-allyl-1-((S)-2-(tert-butyldiphenylsilyloxy)-1-cyclopropyleth-
yl)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methylpiperidin-2-one
(Example 257, Step A, 3.00 g, 4.31 mmol) according to the procedure
of Example 252, Step A gave
(3S,5R,6S)-3-allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-cyclopr-
opyl-2-hydroxyethyl)-3-methylpiperidin-2-one as a white foam (1.905
g, 97%).
[2904] .sup.1H NMR (500 MHz, CHLOROFORM-d) .delta. 0.00-0.15 (m,
1H), 0.18-0.35 (m, 1H), 0.44-0.69 (m, 2H), 0.75-0.87 (m, 1H), 1.28
(s, 3H), 1.87-2.03 (m, 2H), 2.48-2.72 (m, 2H), 3.01-3.22 (m, 2H),
3.41 (td, J=10.33, 4.52 Hz, 1H), 3.60 (dd, J=11.00, 4.40 Hz, 1H),
4.86 (d, J=10.03 Hz, 1H), 5.06-5.24 (m, 2H), 5.74-5.97 (m, 1H),
6.74 (d, J=7.58 Hz, 1H), 6.86-7.10 (m, 3H), 7.10-7.26 (m, 4H). MS
(ESI) m/z=458 [M+H].sup.+
Step C.
(S)-2-((3S,5R,6S)-3-Allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3--
methyl-2-oxopiperidin-1-yl)-2-cyclopropylacetaldehyde. (see also
Example 252 step B)
##STR00740##
[2906]
(3S,5R,6S)-3-Allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-c-
yclopropyl-2-hydroxyethyl)-3-methylpiperidin-2-one (Example 257,
Step B, 1.01 g, 2.2 mmol) was converted to the title compound as a
white foam (866 mg, 86%) by the procedure described in Example 91,
Step C. MS (ESI) m/z=456 [M+H].sup.+.
Step D.
(3S,5R,6S)-3-allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((1S,2R-
)-1-cyclopropyl-2-hydroxypropyl)-3-methylpiperidin-2-one and
(3S,5R,6S)-3-allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((1S,2S)-1-cyc-
lopropyl-2-hydroxypropyl)-3-methylpiperidin-2-one
##STR00741##
[2908] By the procedure of Example 149, Step A,
(S)-2-((3S,5R,6S)-3-allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl--
2-oxopiperidin-1-yl)-2-cyclopropylacetaldehyde (Example 257, Step
C, 866 mg, 1.897 mmol) was treated with methyl magnesium bromide to
give the diastereomeric alcohols
(3S,5R,6S)-3-allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((1S,2R)-1-cyc-
lopropyl-2-hydroxypropyl)-3-methylpiperidin-2-one and
(3S,5R,6S)-3-allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((1S,2S)-1-cyc-
lopropyl-2-hydroxypropyl)-3-methylpiperidin-2-one as a white foam.
MS (ESI) m/z=472 [M+H].sup.+.
Step E.
2-((3R,5R,6S)-5-(3-Chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-cyclo-
propyl-2-oxopropyl)-3-methyl-2-oxopiperidin-3-yl)acetic acid
##STR00742##
[2910]
(3S,5R,6S)-3-Allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-c-
yclopropyl-2-hydroxypropyl)-3-methylpiperidin-2-one (Example 257,
Step D, 809 mg, 1.71 mmol) was treated according to the procedure
described in Example 71, Step F, to afford, after SFC purification,
2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-cyclopropyl--
2-oxopropyl)-3-methyl-2-oxopiperidin-3-yl)acetic acid as a white
solid.
[2911] .sup.1H NMR (500 MHz, Methanol-D4) .delta.-0.70--0.47 (m,
1H), 0.10 (dq, J=9.78, 5.05 Hz, 1H), 0.31-0.48 (m, 1H), 0.63 (tt,
J=8.59, 5.35 Hz, 1H), 1.34 (s, 3H), 1.47-1.58 (m, 1H), 2.15-2.35
(m, 6H), 2.65 (d, J=13.69 Hz, 1H), 2.79 (d, J=10.03 Hz, 1H), 2.98
(d, J=13.69 Hz, 1H), 3.48-3.57 (m, 1H), 4.65 (d, J=10.51 Hz, 1H),
6.94-7.01 (m, 1H), 7.08 (s, 1H), 7.11-7.54 (m, 6H). MS (ESI)
m/z=488 [M+H].sup.+.
Step F.
2-((3R,5R,6S)-5-(3-Chlorophenyl)-6-(4-chlorophenyl)-1-((1S,2R)-1-c-
yclopropyl-2-hydroxypropyl)-3-methyl-2-oxopiperidin-3-yl)acetic
acid
##STR00743##
[2913] Reduction of
2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-cyclopropyl--
2-oxopropyl)-3-methyl-2-oxopiperidin-3-yl)acetic acid in methanol
at 0.degree. C. with sodium borohydride provided a mixture of the
diastereomeric alcohols in .about.2:1 ratio. The residue was
purified by silica gel chromatography eluting with a gradient of
isopropanol in hexanes. Fractions containing the major isomer were
concentrated and then lyophilized from acetonitrile/water to
provide the title compound as a fluffy white solid.
[2914] .sup.1H NMR (500 MHz, Methanol-d4) .delta. ppm -0.29 (br s,
1H), 0.20 (br s, 1H), 0.46 (br s, 1H), 0.60 (br s, 1H), 1.19 (br s,
3H), 1.24-1.35 (m, 1H), 1.39 (s, 3H), 2.10-2.29 (m, 2H), 2.63 (d,
J=13.69 Hz, 1H), 2.82 (br s, 1H), 2.98 (d, J=13.94 Hz, 1H),
3.40-3.50 (m, 1H), 3.57 (br s, 1H), 4.82 (d, J=11.00 Hz, 1H),
6.61-7.64 (m, 8H). MS (ESI) m/z=490 [M+H].sup.+.
Example 258
2-((3R,5R,6S)-5-(3-Chlorophenyl)-6-(4-chlorophenyl)-1-((1S,2S)-1-cycloprop-
yl-2-hydroxypropyl)-3-methyl-2-oxopiperidin-3-yl)acetic acid
##STR00744##
[2916] L-Selectride.RTM. (Aldrich, St. Louis, Mo.), (1M in THF, 5.0
ml, 5.00 mmol) was added dropwise over the course of 5 minutes to a
solution of
2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-cycloprop-
yl-2-oxopropyl)-3-methyl-2-oxopiperidin-3-yl)acetic acid (Example
257, Step E, 1.035 g, 2.12 mmol) in THF (35 ml) at -78.degree. C.
After 90 min, the mixture was allowed to warm to 0.degree. C. and
was carefully quenched by the addition of saturated ammonium
chloride. The aqueous phase was extracted three times with ethyl
acetate. The combined organic layer was washed with 1 M HCl, water,
sat. aq. NaCl solution and dried over sodium sulfate. After
concentration in vacuo, the residue was purified by silica
chromatography eluting with a gradient of isopropanol in hexanes.
Fractions containing the major isomer were concentrated and then
lyophilized from acetonitrile/water to provide the title compound
as a white powder. Stereochemistry assigned by analogy to Example
152.
[2917] .sup.1H NMR (500 MHz, DMSO-d.sub.6) .delta. -0.69 (br s,
1H), -0.35 (br s, 1H), 0.17 (br s, 1H), 0.36 (br s, 1H), 1.07 (br
s, 1H), 1.27 (s, 4H), 1.98-2.23 (m, 2H), 2.53-2.58 (m, 1H), 2.93
(d, J=13.94 Hz, 1H), 3.36-3.49 (m, 1H), 3.74-4.44 (m, 1H),
4.46-5.11 (m, 2H), 6.60-7.59 (m, 8H). MS (ESI) m/z=490
[M+H].sup.+.
Example 259
2-((3R,5R,6S)-5-(3-Chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-cyclopropyl-2-
-(1-methylethylsulfonamido)ethyl)-3-methyl-2-oxopiperidin-3-yl)acetic
acid
##STR00745##
[2918] Step A:
N--((S)-2-((3S,5R,6S)-3-Allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-met-
hyl-2-oxopiperidin-1-yl)-2-cyclopropylethyl)propane-2-sulfonamide
##STR00746##
[2920]
(3S,5R,6S)-3-Allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-c-
yclopropyl-2-hydroxyethyl)-3-methylpiperidin-2-one (Example 252,
Step A, 59.3 mg, 0.129 mmol;) and isopropyl sulfonamide (48.7 mg,
0.395 mmol) were coupled by the procedure as described in Example
202, Step C to form the title compound isolated after silica gel
chromatography as an off-white solid. MS (ESI) m/z=563
[M+H].sup.+.
Step B:
2-((3R,5R,6S)-5-(3-Chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-cyclo-
propyl-2-(1-methylethylsulfonamido)ethyl)-3-methyl-2-oxopiperidin-3-yl)ace-
tic acid
[2921] The title compound was obtained from
N--((S)-2-((3S,5R,6S)-3-allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-met-
hyl-2-oxopiperidin-1-yl)-2-cyclopropylethyl)propane-2-sulfonamide
(Example 259, Step A) by a procedure similar to the one described
in Example 71, Step F. The product was purified by reversed phase
HPLC, eluting with 60 to 95% MeCN in water (0.1% TFA in both
solvents). High purity fractions were combined, stripped of
volatiles, and the resulting solution was frozen and lyophilized to
provide the title compound as an off-white solid.
[2922] .sup.1H NMR (500 MHz, CD.sub.3OD) .delta. ppm -0.98--0.71
(m, 1H) -0.38--0.16 (m, 1H) 0.12-0.29 (m, 1H) 0.30-0.44 (m, 1H)
1.31-1.39 (m, 6H) 1.41 (s, 3H) 1.52-1.64 (m, 1H) 2.08 (dd, J=13.69,
3.18 Hz, 1H) 2.26 (br. s, 1H) 2.40 (t, J=13.69 Hz, 1H) 2.70 (d,
J=13.45 Hz, 1H) 3.00 (d, J=13.20 Hz, 1H) 3.09 (dd, J=13.69, 3.42
Hz, 1H) 3.25 (dt, J=13.51, 6.82 Hz, 1H) 3.33-3.34 (m, 1H) 3.41
(ddd, J=13.75, 10.82, 3.06 Hz, 1H) 3.96 (br s, 1H) 4.94 (d, J=11.00
Hz, 1H) 6.98-7.18 (m, 5H) 7.27 (br s, 3H). MS (ESI) m/z=581
[M+H].sup.+.
Example 260
2-((3R,5R,6S)-5-(3-Chlorophenyl)-6-(4-chlorophenyl)-1-((R)-1-cyclopropyl-2-
-(N-methylcyclopropanesulfonamido)ethyl)-3-methyl-2-oxopiperidin-3-yl)acet-
ic acid
##STR00747##
[2923] Step A:
(3S,5R,6S)-3-Allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((R)-1-cyclopr-
opyl-2-(methylamino)ethyl)-3-methylpiperidin-2-one
##STR00748##
[2925]
(S)-2-((3S,5R,6S)-3-Allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-m-
ethyl-2-oxopiperidin-1-yl)-2-cyclopropylacetaldehyde (Example 252,
Step B, 554 mg, 1.21 mmol) was taken up in 10 mL anhydrous toluene
and stripped to dryness in vacuo twice to effect azeotropic removal
of trace moisture. After removal of residual solvents under high
vacuum, the aldehyde was dissolved in dichloroethane (12 mL).
Methylamine (2.0 M in THF, 6.1 mL, 12.20 mmol) and acetic acid (2
mL, 35.0 mmol) were added to the solution which was stirred at
ambient temperature for about 30 minutes. Sodium
triacetoxyborohydride (1.12 g, 5.28 mmol) was added as a solid in a
single portion and the mixture was stirred at ambient temperature
overnight. HPLC analysis showed that epimerization had occurred to
give both diastereomers. The reaction was quenched with saturated
sodium bicarbonate solution. The amine diastereomers were extracted
into dichloromethane. The organic phase was washed with water, and
dried over sodium sulfate. After concentration the resulting
residue gave a slightly turbid solution on redissolution in ethyl
acetate, and was consequently redried over magnesium sulfate.
Concentration gave a mixture of diastereomers as a yellowish-white
foam (577 mg). The two epimeric products were separated by SFC
chromatography (250.times.30 mm Chiralpak.RTM. IC column (Chiral
Technologies, Inc., West Chester, Pa., USA) with 42 g/min IPA and
[20 mM NH.sub.3] and 78 g/min CO.sub.2. On concentration, the first
eluting, epimer
3S,5R,6S)-3-allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-cyclopro-
pyl-2-(methylamino)ethyl)-3-methylpiperidin-2-one was obtained.
Concentration of fractions containing the second eluting component
gave the title compound. MS (ESI) m/z=471 [M+H].sup.+.
Step B:
N--((R)-2-((3S,5R,6S)-3-Allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl-
)-3-methyl-2-oxopiperidin-1-yl)-2-cyclopropylethyl)-N-methylcyclopropanesu-
lfonamide
##STR00749##
[2927]
(3S,5R,6S)-3-allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((R)-1-c-
yclopropyl-2-(methylamino)ethyl)-3-methylpiperidin-2-one (Example
260, Step A, 168 mg, 0.356 mmol) was transferred as a solution in 3
mL anhydrous toluene to an oven-dried 10 mL round bottom flask and
the solution was stripped to dryness on a rotary evaporator. This
was repeated twice to effect azeotropic removal of trace moisture.
Cyclopropanesulfonyl chloride and pyridine were added to the flask.
The reaction was monitored for completion by LC-MS. Ultimately
5.times. (0.15 ml sulfonyl chloride and 0.15 mL pyridine) were
added over the course of 4 days. Dichloromethane was added when
solids began to appear. The reaction mixture was diluted with ethyl
acetate and citric acid solution (10%). The aqueous phase was
washed twice with ethyl acetate. The combined organic layer was
washed with sat. aq. NaCl solution and dried over sodium sulfate.
After concentration in vacuo, the yellow residual oil was purified
by chromatography on silica, eluting with a gradient of ethyl
acetate in hexanes. Fractions containing the title compound were
combined and concentrated to give the title compound as a white
foam. MS (ESI) m/z=575 [M+H].sup.+
Step C.
2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((R)-1-cyclo-
propyl-2-(N-methylcyclopropanesulfonamido)ethyl)-3-methyl-2-oxopiperidin-3-
-yl)acetic acid
[2928] The title compound was obtained from
N--((R)-2-((3S,5R,6S)-3-allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-met-
hyl-2-oxopiperidin-1-yl)-2-cyclopropylethyl)-N-methylcyclopropanesulfonami-
de (Example 260, Step B, 153 mg, 0.265 mmol) by a procedure similar
to the one described in Example 71, Step F. The compound was
purified by reverse phase HPLC on a Sunfire.TM. C18 column (Waters,
Milford, Mass.), eluting with a gradient of 50 to 100% MeCN in
water (0.1% TFA in both solvents), then further purified by SFC
chromatography (250.times.30 mm Lux2.RTM. column (Phenomenex,
Torrance, Calif. 90501, USA) with 32 g/min methanol [20 mM
NH.sub.3]+48 g/min CO.sub.2 on Thar 80 SFC (Thar Technologies,
Pittsburg, Pa.). Outlet pressure=100 bar; Temp.=23 C;
Wavelength=220 nm. Used 0.8 mL injections of 95 mg/15 mL [6.3 mg/mL
sample solution in methanol, i.e. 5.1 mg/injection]. Run time=6
min, Cycle time=3.5 min). Pooled fractions were concentrated to
give the title compound as a white solid.
[2929] .sup.1H NMR (500 MHz, CHLOROFORM-d) .delta. 0.14 (d, J=3.91
Hz, 2H), 0.51 (t, J=5.26 Hz, 2H), 0.93-1.11 (m, 2H), 1.14-1.23 (m,
1H), 1.25-1.28 (m, 1H), 1.46 (br s, 3H), 1.52-1.76 (m, 2H),
1.87-2.00 (m, 1H), 2.20-2.39 (m, 2H), 2.72 (d, J=15.41 Hz, 4H),
2.92-3.07 (m, 3H), 3.13 (d, J=15.41 Hz, 1H), 3.98 (dd, J=13.82,
11.13 Hz, 1H), 4.93 (br s, 1H), 6.90 (d, J=5.87 Hz, 1H), 7.00 (s,
1H), 7.05-7.26 (m, 6H). MS (ESI) m/z=593 [M+H].sup.+.
Example 261
2-((3R,5R,6S)-5-(3-Chlorophenyl)-6-(4-chlorophenyl)-1-((2S,3S)-2-hydroxy-4-
-methylpentan-3-yl)-3-methyl-2-oxopiperidin-3-yl)acetic acid
##STR00750##
[2930] Step A: Methyl
4-(3-chlorophenyl)-5-(4-chlorophenyl)-2-methyl-5-oxopentanoate
##STR00751##
[2932] Methyl methacrylate (82 mL, 773 mmol) was added to a
solution of 2-(3-chlorophenyl)-1-(4-chlorophenyl)ethanone (195.2 g,
736 mmol; Example 1, Step A) in anhydrous THF (1.5 L) under an
atmosphere of nitrogen. A suspension of potassium t-butoxide (8.26
g, 73.6 mmol) in anhydrous THF (340 mL) (sonicated to break up the
solids) was then prepared and cannulated into the solution
containing the 2-(3-chlorophenyl)-1-(4-chlorophenyl)ethanone. The
solution was cooled to .about.16.degree. C. and the orange colored
solution was left to stir at ambient temperature for 2.5 d. (After
2 d TLC shows the absence of the starting material). The mixture
was concentrated under vacuum. The residual reddish brown oil was
diluted with ethyl acetate (900 mL) and washed with water
(4.times.190 mL) and then sat. aq. NaCl solution. The organic layer
was dried over magnesium sulfate and concentrated under reduced
pressure to provide the title compound as a racemic mixture of
diastereomers.
[2933] .sup.1H-NMR (500 MHz, CDCl.sub.3) .delta. 7.88 (m, 4H), 7.39
(m, 2H), 7.27-7.12 (series of m, 4H), 4.62 (dd, J=9.0, 5.6 Hz,
0.5H), 4.59 (dd, J=9.3, 5.4 Hz, 0.5H), 3.69 (s, 1.5H), 3.60 (s,
1.5H), 2.46 (m, 1H), 2.33 (m, 1H), 2.08 (ddd, J=13.9, 9.3, 5.4 Hz,
0.5H), 1.97 (ddd, J=13.7, 9.0, 4.4 Hz, 0.5H), 1.23 (d, J=6.9 Hz,
1.5H), 1.16 (d, J=7.1 Hz, 1.5H) ppm.
Step B: Racemic mixture of (4R,5R)-methyl
4-(3-chlorophenyl)-5-(4-chlorophenyl)-5-hydroxy-2-methylpentanoate
(4S,5S)-methyl
4-(3-chlorophenyl)-5-(4-chlorophenyl)-5-hydroxy-2-methylpentanoate
##STR00752##
[2935] Anhydrous methanol (600 mL) was placed in a 3 L three-necked
round-bottomed flask equipped with a stir bar and temperature probe
under an atmosphere of N.sub.2 and cooled to about -20.degree. C.
Sodium borohydride (26.2 g, 693 mmol) was added in 5 g portions.
Via an addition funnel, a solution of methyl
4-(3-chlorophenyl)-5-(4-chlorophenyl)-2-methyl-5-oxopentanoate (253
g, 693 mmol; Example 261, Step A) in methanol (600 mL) was added
dropwise to the reaction, maintaining a temperature between
-27.degree. C. to -30.degree. C. The reddish solution was stirred
at -30.degree. C. for 30 minutes and then allowed to warm to
-15.degree. C. The reaction was monitored for completion by TLC.
The reaction was quenched by slowly adding water (68.6 mL, 3.8
.mu.mol) through the addition funnel. The mixture was allowed to
warm to ambient temperature. Solvents were removed under vacuum.
The residual yellowish oil was diluted in ethyl acetate (1.2 .mu.L)
and washed with water (400 mL). The organic layer was washed with
sat. aq. NaCl solution (2.times.300 mL), forming an emulsion. After
waiting for the most of the emulsion to separate, the organic layer
was dried over magnesium sulfate. The solution was filtered through
filter paper and concentrated under vacuum to provide a racemic
mixture of diastereomers.
[2936] .sup.1H-NMR (500 MHz, DMSO-d6) .delta. 7.33 (m, 2H),
7.27-7.17 (series of m, 5H), 7.04 (m, 1H), 5.43 (d, J=4.4 Hz,
0.5H), 5.37 (d, J=4.6 Hz, 0.5H), 4.77 (t, J=5.4 Hz, 0.5H), 4.71
(dd, J=6.6, 4.9 Hz, 0.5H), 5.33 (s, 1.5H), 3.46 (s, 1.5H), 2.87
(dt, J=10.2, 4.7 Hz, 0.5H), 2.75 (ddd, J=11.2, 6.6, 4.9 Hz, 0.5H),
2.04 (m, 1.5H), 1.71 (m, 1H), 1.46 (m, 0.5H), 0.97 (d, J=6.6 Hz,
1.5H), 0.94 (d, J=7.1 Hz, 1.5H) ppm. TLC (20% EtOAc/Hexane)
R.sub.f=0.34.
Step C.
(4R,5R)-4-(3-Chlorophenyl)-5-(4-chlorophenyl)-5-hydroxy-2-methylpe-
ntanoic acid and
(4S,5S)-4-(3-Chlorophenyl)-5-(4-chlorophenyl)-5-hydroxy-2-methylpentanoic
acid
##STR00753##
[2938] A solution of the racemic mixture of (4R,5R)-methyl
4-(3-chlorophenyl)-5-(4-chlorophenyl)-5-hydroxy-2-methylpentanoate
and (4S,5S)-methyl
4-(3-chlorophenyl)-5-(4-chlorophenyl)-5-hydroxy-2-methylpentanoate
(245.7 g, 669 mmol; Example 261, Step B) in THF (1.17 L) was
prepared by warming to 40.degree. C. The flask was cooled to
-14.degree. C., internal temperature. A solution of lithium
hydroxide hydrate (42.1 g, 1.0 mol) in water (585 mL) was
cautiously added to the THF solution. The mixture was left to stir
at ambient temperature and monitored by LC/MS for the absence of
starting material (.about.2.5 h). Upon completion, the solution was
again cooled to a temperature of .about.14.degree. C. 2N HCl (526
mL) was added slowly. The layers were partitioned and the aqueous
layer (pH.about.2) was washed with ethyl acetate (1.times.500 mL
then 1.times.250 mL). The combined organic layers were dried over
magnesium sulfate and concentrated to afford 264 g of a racemic
mixture of
(4R,5R)-4-(3-chlorophenyl)-5-(4-chlorophenyl)-5-hydroxy-2-methylpentanoic
acid and
(4S,5S)-4-(3-chlorophenyl)-5-(4-chlorophenyl)-5-hydroxy-2-methyl-
pentanoic acid was obtained. The crude material containing some
residual solvent was used as-is in the subsequent transformation.
The product (estimated after solvent correction 227 g) is a roughly
1:1 mixture of diastereomers at the 2-position.
[2939] .sup.1H-NMR (500 MHz, CDCl.sub.3) .delta. 7.31 (m, 2H), 7.25
(m, 3H), 7.17 (m, 2H), 7.05 (m, 1H) 4.74 (m, 1H), 2.99 (ddd,
J=11.2, 1.7, 3.7 Hz, 0.5H), 2.90 (ddd, J=11.5, 7.3, 4.6 Hz, 1H),
2.15 (m, 1.5H), 1.85 (m, 0.5H), 1.67 (ddd, J=14.3, 11.5, 3.4 Hz,
0.5H), 1.52 (m, 0.5H), 1.08 (d, J=7.1 Hz, 1.5H), 1.05 (d, J=6.9 Hz,
1.5H) ppm.
[2940] Alternatively,
(4R,5R)-4-(3-Chlorophenyl)-5-(4-chlorophenyl)-5-hydroxy-2-methylpentanoic
acid, as a mixture of methyl diastereomers, can be prepared from
racemic methyl
4-(3-chlorophenyl)-5-(4-chlorophenyl)-2-methyl-5-oxopentanoate.
[2941] In a three-neck flask, a solution of racemic methyl
4-(3-chlorophenyl)-5-(4-chlorophenyl)-2-methyl-5-oxopentanoate (500
g, 1.37 mol, 1 eq) in anhydrous 2-propanol (2.5 L) was charged with
KO.sup.tBu (46.1 g, 0.41 mol, 0.3 eq) and stirred for 30 min until
a clear yellow solution was formed. The solution was then treated
with a solution of dichloro
{(S)-(-)-2,2'-bis[di(3,5-xylyl)phosphino]-1,1'-binaphthyl}[(2S)-(+)-1,1-b-
is(4-methoxyphenyl)-3-methyl-1,2-butanediamine]ruthenium(II) (5 g,
4.1 mmol, 0.003 eq, Strem Chemicals inc., Newburyport, Mass.) in
anhydrous toluene (250 mL) and stirred at RT for 2 hours (Note:
Most of methyl ester was converted to isopropyl). The solution was
transferred to two Parr shakers, sealed and purged with hydrogen 3
times. The reaction was shaken at RT under 414 kilopascals hydrogen
pressure. After 18 hrs, the reaction was quenched with sat.
NH.sub.4Cl, concentrated and extracted with EtOAc (2 L.times.2).
The combined organics was washed with brine and concentrated as a
brown oil and used as such in the next step.
[2942] The crude intermediate (542 g, 1.37 mol) was dissolved in
THF (3 L) and MeOH (1 L) and charged with 2 M LiOH (1 L). The
solution was rotated at RT overnight, concentrated to remove most
of THF and MeOH, and quenched with 1 L of 2 M HCl. After phase
separation, the aqueous layer was extracted with EtOAc (1
L.times.2). The combined organics were washed with brine, dried
over anhydrous Na.sub.2SO.sub.4, filtered and concentrated in
vacuo. This product,
(4R,5R)-4-(3-Chlorophenyl)-5-(4-chlorophenyl)-5-hydroxy-2-methylpentanoic
acid, as a mixture of methyl diastereomers, was taken crude to the
next step.
Step D.
(5R,6R)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyltetrahydro-2-
H-pyran-2-one and
(5S,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyltetrahydro-2H-pyran-
-2-one
##STR00754##
[2944] The mixture of hydroxy acid diastereomers (227 g, 643 mmol;
Example 261, Step C) was lactonized under Dean-Stark conditions in
toluene (1.07 L) with pyridine 4-methylbenzenesulfonate (PPTS, 4.84
g, 19.28 mmol) under an atmosphere of nitrogen. After 2 h of
vigorous reflux the solution was cooled to ambient temperature and
transferred to a separatory funnel. The flask residue was rinsed in
with ethyl acetate. The combined organic phase was washed in
succession with water (1.times.250 mL), sat. sodium bicarbonate
solution (1.times.250 mL), and sat. aq. NaCl solution (1.times.250
mL). After drying with magnesium sulfate, concentration under
reduced pressure provides a mixture of diastereomeric lactones as a
light brown solid.
[2945] .sup.1H-NMR (500 MHz, CDCl.sub.3) .delta. 7.24-6.95 (series
of m, 6H), 6.91 (d, J=7.6 Hz, 0.5H), 6.82 (m, 1.5H), 6.73 (d, J=7.6
Hz, 0.5H), 5.77 (d, J=3.9 Hz, 0.5H), 5.69 (d, J=4.6 Hz, 0.5H), 3.67
(dt, J=7.6, 4.2 Hz, 0.5H), 3.55 (td, J=7.8, 4.6 Hz, 0.5H), 2.97 (m,
0.5H), 2.81 (doublet of quintets, J=14.4, 7.1 Hz, 0.5H), 2.56 (dt,
16.1, 8.0 Hz, 0.5H), 2.32 (dt, J=13.7, 6.9 Hz, 0.5H), 2.07 (ddd,
J=13.2, 8.6, 4.4 Hz, 0.5H), 1.85 (ddd, J=14.2, 12.7, 7.6 hz, 0.5H),
1.41 (d, J=7.1 Hz, 1.5H), 1.39 (d, J=6.9 Hz, 1.5H) ppm.
Step E:
(3S,5R,6R)-3-Allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methylt-
etrahydro-2H-pyran-2-one and
(3R,5S,6S)-3-Allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyltetrahyd-
ro-2H-pyran-2-one
##STR00755##
[2947] A solution of racemic lactone from the previous step
(Example 261, Step D, 190.28 g, 568 mmol) in THF (946 mL) was
prepared in a 1 neck round bottomed flask equipped with a Claisen
adapter, 500 mL dropping funnel, and internal temperature probe
under an atmosphere of nitrogen. The solution was cooled to a
temperature of -35.degree. C. Allyl bromide (120 mL, 1.42 mol) was
added via the addition funnel, maintaining the temperature below
-30.degree. C. during addition. A solution of LHMDS (1M in THF, 738
mL, 738 mmol) was added dropwise to the reaction, maintaining the
temperature below -30.degree. C. The reaction was allowed to slowly
warm to -5.degree. C. over a period of 1 h. The solution was
recooled to about -20.degree. C. and added via cannula into a
solution of ammonium chloride in water at about 5 C. After
separation of the layers, the aqueous layers were extracted twice
with ethyl acetate. The combined organic layers were washed with
sat. aq. NaCl solution and dried over sodium sulfate. Concentration
under vacuum provided 219 g of a light yellow solid. The solids
were slurried at ambient temperature for 2 h with hexane (2 L). The
solids were then collected by filtration, rinsed with hexane
(2.times.100 mL) and dried to provide the title compounds as a
racemic mixture.
[2948] .sup.1H-NMR (500 MHz, CDCl.sub.3) .delta. 7.24 (m, 1H),
7.20-7.15 (m, 3H), 6.91 (t, J=1.7 Hz, 1H), 6.77 (d, J=7.6 Hz, 1H),
6.59 (m, 2H), 5.84 (ddt, J=17.6, 10.3, 7.6 Hz, 1H), 5.71 (d, J=5.4
Hz, 1H), 5.21-5.13 (m, 2H), 3.81 (dt, J=12.0, 4.2 Hz, 1H), 2.62
(ABX J.sub.AB=14.0, J.sub.AX=7.8 Hz, 1H), 2.52 (ABX, J.sub.AB=13.9,
J.sub.AX=7.3 Hz, 1H), 1.98 (dd, J=14.0, 12.0 Hz, 1H), 1.91 (ddd,
J=14.0, 3.7, 1.2 Hz, 1H), 1.42 (s, 3H) ppm.
Step F: Separation of
(3S,5R,6R)-3-allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyltetrahyd-
ro-2H-pyran-2-one and
(3R,5S,6S)-3-allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyltetrahyd-
ro-2H-pyran-2-one
##STR00756##
[2950] A racemic mixture of
(3S,5R,6R)-3-allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyltetrahyd-
ro-2H-pyran-2-one and
(3R,5S,6S)-3-allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyltetrahyd-
ro-2H-pyran-2-one can be separated using chiral Supercritical Fluid
Chromatography (SFC) as follows: Using a 250.times.30 mm Lux2
column (Phenomenex, Torrance, Calif. 90501, USA) with 20 g/min
methanol (20 mM NH3)+60 g/min CO.sub.2 on a Thar 80 SFC. Outlet
pressure=100 bar; Temp.=23 C; Wavelength=220 nm. Used 0.3 mL
injections of 5.0 g/80 mL (62.5 mg/mL sample solution in
methanol/dichloromethane (75:5), i.e. 18.75 mg/injection. Run
time=8 min, Cycle time=3 min.
[2951] The first peak collected was assigned as
(3R,5S,6S)-3-allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyltetrahyd-
ro-2H-pyran-2-one. The second peak collected was determined to be
(3S,5R,6R)-3-allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyltetrahyd-
ro-2H-pyran-2-one by subsequent chemical derivatization with
(S)-2-amino-1-butanol and conversion to the same compound as
prepared in Example 91, Step B, by the procedures described for
Example 261, Steps G and H. The NMR of the separated enantiomers
was consistent with the spectrum of the racemate described
above.
[2952] Alternatively,
(3S,5R,6R)-3-allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyltetrahyd-
ro-2H-pyran-2-one can be prepared from racemic methyl
4-(3-chlorophenyl)-5-(4-chlorophenyl)-2-methyl-5-oxopentanoate.
[2953] In a three-neck flask, a solution of racemic methyl
4-(3-chlorophenyl)-5-(4-chlorophenyl)-2-methyl-5-oxopentanoate (500
g, 1.37 mol, 1 eq) in anhydrous 2-propanol (2.5 L) was charged with
KO.sup.tBu (46.1 g, 0.41 .mu.mol, 0.3 eq) and stirred for 30 mins
until a clear yellow solution was formed. The solution was then
treated with a solution of Dichloro
{(S)-(-)-2,2'-bis[di(3,5-xylyl)phosphino]-1,1'-binaphthyl}[(2S)-(+)-1,1-b-
is(4-methoxyphenyl)-3-methyl-1,2-butanediamine]ruthenium(II) (5 g,
4.1 mmol, 0.003 eq,/Strem Chemicals Inc., Newburyport, Mass.) in
anhydrous toluene (250 mL) and stirred at RT for 2 hours (Note:
Most of methyl ester was converted to isopropyl). The solution was
transferred to two Parr shakers, sealed and purged with hydrogen 3
times. The reaction was shaken at RT under 414 kilopascals hydrogen
pressure. After 18 hrs, the reaction was quenched with sat.
NH.sub.4Cl, concentrated and extracted with EtOAc (2 L.times.2).
The combined organics was washed with brine and concentrated as a
brown oil and used as such in the next step.
[2954] The crude intermediate (542 g, 1.37 mol) was dissolved in
THF (3 L) and MeOH (1 L) and charged with 2 M LiOH (1 L). The
solution was rotated at RT overnight, concentrated to remove most
of THF and MeOH, and quenched with 1 L of 2 M HCl. After phase
separation, the aqueous layer was extracted with EtOAc (1
L.times.2). The combined organics was washed with brine, dried over
anhydrous Na.sub.2SO.sub.4, filtered and concentrated in vacuo.
Step G:
(S)-2-((2R,3R)-2-(3-Chlorophenyl)-3-(4-chlorophenyl)-3-hydroxyprop-
yl)-N--((S)-1-hydroxy-3-methylbutan-2-yl)-2-methylpent-4-enamide
##STR00757##
[2956] A mixture of (S)-2-amino-3-methylbutan-1-ol (550 mg, 5.33
mmol) and
(3S,5R,6R)-3-allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyltetrahyd-
ro-2H-pyran-2-one (Example 261, Step H, 2.sup.nd compound, 500 mg,
1.332 mmol) was heated to 100.degree. C. for 24 h. After cooling to
room temperature, the residue was dissolved in ethyl acetate and
washed 3.times. with 1N HCl (5 mL) followed by sat. aq. NaCl
solution (5 mL). The organic phase was dried over MgSO.sub.4,
filtered, and the filtrate was concentrated to afford the title
compound.
[2957] .sup.1H-NMR (500 MHz, DMSO-d.sub.6) .delta. 7.21 (m, 2H),
7.10 (m, 2H), 7.06 (br s, 1H), 6.99 (m, 2H), 6.86 (br d, J=8.8 Hz,
1H), 6.84 (br d, J=7.1 Hz, 1H), 5.53 (dddd, J=16.9, 10.3, 8.1, 6.6
Hz, 1H), 5.46 (d, J=4.4 Hz, 1H), 4.90 (m, 2H), 4.78 (t, J=4.2 Hz,
1H), 4.56 (t, J=5.1 Hz, 1H), 3.56 (m, 1H), 3.37 (m, 2H), 2.87 (dt,
J=7.8, 4.2 Hz, 1H), 2.29 (dd, J=13.7, 6.4 Hz, 1H), 2.14 (dd,
J=14.4, 7.8 Hz, 1H), 1.97 (dd, J=14.4, 3.9 Hz, 1H), 1.88 (dd,
J=13.9, 8.1 Hz, 1H), 1.76 (octet, J=6.4 Hz, 1H), 0.97 (s, 3H), 0.81
(d, J=6.8 Hz, 3H), 0.75 (d, J=6.6 Hz, 3H) ppm.
Step H.
(3S,5R,6S)-3-Allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1--
hydroxy-3-methylbutan-2-yl)-3-methylpiperidin-2-one
##STR00758##
[2959]
(S)-2-((2R,3R)-2-(3-Chlorophenyl)-3-(4-chlorophenyl)-3-hydroxypropy-
l)-N--((S)-1-hydroxy-3-methylbutan-2-yl)-2-methylpent-4-enamide
(example 261, step G) was transferred as a solution in anhydrous
benzene to a pre-weighed, oven-dried 50 mL round bottom flask and
stripped to dryness. Azeotropic distillation of benzene/water was
performed twice more, and the residue was dried under high vacuum
for 2 h, after which it weighed 550 mg. An oven-dried stir bar was
added to the flask. The vessel was sealed and purged with nitrogen
and then anhydrous dichloromethane (23 mL) was added, followed by
triethylamine (1.3 mL, 9.33 mmol). The resulting stirred solution
was cooled to 0.degree. C. Methanesulfonyl chloride (0.270 mL, 3.49
mmol) was added dropwise by microsyringe. After 1 h, the reaction
was quenched by addition of HCl (1.2M, 12 mL) and diluted in ethyl
acetate. The organic layer was washed with 1.2 M HCl (30 mL),
saturated sodium bicarbonate (2.times.25 mL), and sat. aq. NaCl
solution. After drying over magnesium sulfate and concentration in
vacuo an intermediate was obtained as an off-white foam (0.64 g,).
1,8-Bis(dimethylamino)naphthalene, 314 mg, 1.465 mmol) and water
(0.104 mL, 5.75 mmol) were added to the intermediate, followed by
dioxane (23 mL). The mixture was heated under nitrogen at
110.degree. C. overnight. After cooling, the mixture was dissolved
in ethyl acetate and washed with saturated ammonium chloride
solution. The aqueous phase was back-extracted with ethyl acetate.
The combined organic layers were washed with sat. aq. NaCl
solution, dried over sodium sulfate, filtered, and concentrated in
vacuo. The residue was purified by chromatography on silica,
eluting with ethyl acetate in hexanes. Chromatography fractions
containing predominantly the desired product were combined. The
product was re-purified by chromatography on a 40 g silica column,
eluting with a gradient of 0 to 50% ethyl acetate in hexanes to
give the title compound.
[2960] .sup.1H NMR (400 MHz, CHLOROFORM-d) .delta. 0.73 (d, J=6.46
Hz, 3H), 0.83 (d, J=6.65 Hz, 3H), 1.28 (s, 3H), 1.91-2.00 (m, 1H),
2.00-2.10 (m, 1H), 2.26-2.45 (m, 1H), 2.56-2.74 (m, 2H), 3.16 (br.
s., 1H), 3.26 (ddd, J=13.50, 10.47, 3.42 Hz, 1H), 3.43 (br. s.,
1H), 3.76 (dd, J=11.25, 3.42 Hz, 1H), 4.49 (d, J=10.56 Hz, 1H),
5.18 (s, 1H), 5.21 (d, J=6.46 Hz, 1H), 5.87 (ddt, J=16.95, 9.85,
7.53 Hz, 1H), 6.72 (apparent d, J=7.63 Hz, 1H), 6.95 (t, J=1.66 Hz,
1H), 6.97-7.17 (m, 4H), 7.23 (d, J=8.41 Hz, 2H). MS (ESI) m/z=460
[M+H].sup.+.
Step I.
(S)-2-((3S,5R,6S)-3-Allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3--
methyl-2-oxopiperidin-1-yl)-3-methylbutanal
##STR00759##
[2962] Dess-Martin periodinane (938 mg, 2.212 mmol) was added as a
solid to a solution of
(3S,5R,6S)-3-allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-hydroxy-
-3-methylbutan-2-yl)-3-methylpiperidin-2-one (Example 261, Step H,
365.4 mg, 0.794 mmol) in dichloromethane (8 mL) and water (0.04 mL,
2.220 mmol). The resulting suspension was vigorously stirred at
ambient temperature for 1.5 h. The reaction was quenched with
sodium thiosulfate solution (1M aq, 6 mL). Additional sodium
thiosulfate solution (1M aq, 6 mL) was added and stirred until the
chalky suspension became a slightly cloudy biphasic mixture. The
aqueous phase was separated and back extracted with
dichloromethane. The organic layer was washed with sodium
thiosulfate solution, saturated aqueous sodium bicarbonate and sat.
aq. NaCl solution. After drying over sodium sulfate and
concentration, the residue was purified on silica gel, eluting with
a gradient of 0 to 30% ethyl acetate in hexanes. Fractions
containing the desired product were pooled to give the title
compound as a white foam. MS (ESI) m/z=458 [M+H].sup.+.
Step J.
(3S,5R,6S)-3-Allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((S)-2--
hydroxy-4-methylpentan-3-yl)-3-methylpiperidin-2-one
##STR00760##
[2964] Methylmagnesium bromide (1.4 mL, 1.960 mmol, 1.4 M in 1:3
THF:toluene) was added by syringe to a solution under nitrogen of
pre-dried
(S)-2-((3S,5R,6S)-3-allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-
-3-methyl-2-oxopiperidin-1-yl)-3-methylbutanal (Example 261, Step
1,286 mg, 0.624 mmol) in THF (6.5 mL) at 0.degree. C. The ice bath
was removed. After 2 h, the solution was recooled to 0.degree. C.
and quenched by careful addition of saturated ammonium chloride
solution. The resulting mixture was extracted with ethyl acetate.
The organic layer was washed with sat. aq. NaCl solution, dried
over sodium sulfate, filtered, and concentrated. The residue was
purified by chromatography on silica, eluting with a gradient of 0
to 40% ethyl acetate in hexanes. Fractions containing the desired
product were combined and re-purified to give the title compound as
a mixture of diastereomeric alcohols) as a white foam.
[2965] MS (ESI) m/z=474 [M+H].sup.+.
Step K.
2-((3R,5R,6S)-5-(3-Chlorophenyl)-6-(4-chlorophenyl)-3-methyl-1-((S-
)-2-methyl-4-oxopentan-3-yl)-2-oxopiperidin-3-yl)acetic acid
##STR00761##
[2967]
(3S,5R,6S)-3-Allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((S)-2-h-
ydroxy-4-methylpentan-3-yl)-3-methylpiperidin-2-one (Example 261,
Step J, 244 mg, 0.51 mmol) was converted by a procedure similar to
the one described in Example 257, Step E to the title compound
obtained after silica gel chromatography eluting with ethyl acetate
in hexanes as a white solid. MS (ESI) 490 [M+H].sup.+.
Step L.
2-((3R,5R,6S)-5-(3-Chlorophenyl)-6-(4-chlorophenyl)-1-((2S,3S)-2-h-
ydroxy-4-methylpentan-3-yl)-3-methyl-2-oxopiperidin-3-yl)acetic
acid
[2968] The title compound was obtained from
2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-1-((S)-2-met-
hyl-4-oxopentan-3-yl)-2-oxopiperidin-3-yl)acetic acid (Example 261,
Step K, 79.9 mg, 0.16 mmol) by a procedure similar to the one
described in Example 258. After workup, the material was purified
by chromatography on a 24 g silica column, eluting with a gradient
of 10 to 20% isopropanol in hexanes. The purest fractions were
combined, concentrated, re-dissolved in 1:1 MeCN/water, passed
through a pall microfilter, frozen, and lyophilized to give the
title compound as a white solid. Stereochemistry assigned by
analogy to example 152.
[2969] .sup.1H NMR (400 MHz, Methanol-d4) .delta. 0.62 (d, J=7.04
Hz, 3H), 0.67 (d, J=6.65 Hz, 3H), 1.26 (d, J=6.46 Hz, 3H), 1.42 (s,
3H), 2.13-2.29 (m, 3H), 2.49 (t, J=7.14 Hz, 1H), 2.62 (d, J=13.69
Hz, 1H), 3.01 (d, J=13.69 Hz, 1H), 3.57 (td, J=10.81, 6.16 Hz, 1H),
4.23 (t, J=6.65 Hz, 1H), 4.70 (d, J=10.95 Hz, 1H), 6.65-7.51 (m,
8H). MS (ESI) m/z=492 [M+H].sup.+.
Example 262
2-((3R,5R,6S)-5-(3-Chlorophenyl)-6-(4-chlorophenyl)-1-((S)-cyclopropyl(pyr-
idin-2-yl)methyl)-3-methyl-2-oxopiperidin-3-yl)acetic acid or
2-((3R,5R,6S)-5-(3-Chlorophenyl)-6-(4-chlorophenyl)-1-((R)-cyclopropyl(py-
ridin-2-yl)methyl)-3-methyl-2-oxopiperidin-3-yl)acetic acid
##STR00762##
[2970] Step A.
(1S,2R)-4-Carboxy-2-(3-chlorophenyl)-1-(4-chlorophenyl)butan-1-aminium
chloride
##STR00763##
[2972] A suspension of
(5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)piperidin-2-one
(Example 1, Step E, 29 g, 91 mmol) in 5 M hydrochloric acid (91 mL,
453 mmol) was brought to reflux. After 2 h, TLC indicated complete
consumption of starting material to the ring opened product
(elution with 75% ethyl acetate in hexanes; R.sub.f starting
material=0.5, R.sub.f product=0.0). The reaction contents were
co-distilled with toluene (4.times.100 mL) then brought to dryness.
Solids were suspended in diethyl ether (100 mL), filtered, and
washed with ether (100 mL). The white crystalline solid was brought
to dryness under high vacuum to provide the title compound.
[2973] .sup.1H NMR (500 MHz, DMSO-d.sub.6) .delta. 7.31-7.39 (m,
2H), 7.24-7.30 (m, 2H), 7.10-7.23 (m, 3H), 6.90-7.01 (m, 1H), 4.65
(d, J=10.03 Hz, 1H), 3.27 (dt, J=3.67, 10.51 Hz, 1H), 2.25-2.36 (m,
1H), 1.95-2.10 (m, 1H), 1.77-1.94 (m, 2H).
Step B.
(4R,5S)-4-(3-Chlorophenyl)-5-(4-chlorophenyl)-5-(cyclopropyl(pyrid-
in-2-yl)methylamino)pentanoic acid
##STR00764##
[2975] Cyclopropyl(pyridin-2-yl)methanone (0.393 g, 2.67 mmol)
[Meijer, Louis H. P. et al., Tetrahedron, 40, 5185 (1984)] was
mixed with neat tetra-isopropoxy-titanium (0.782 mL, 2.67 mmol) and
stirred at room temperature for 20 min.
(1S,2R)-4-carboxy-2-(3-chlorophenyl)-1-(4-chlorophenyl)butan-1-aminium
chloride (0.500 g, 1.334 mmol; Example 262, Step A) was added as a
solid and stirred overnight. Methanol (13 mL) was added followed by
careful addition of sodium borohydride (0.151 g, 4.00 mmol). The
resulting solution was stirred at room temperature for 10 min. The
reaction was quenched with HCl (1 N aq.), extracted with
dichloromethane and washed with sat. aq. NaCl solution. The
combined organic layer was dried over sodium sulfate and
concentrated to provide a crude product used in the next step
without further purification.
Step C.
(5R,6S)-5-(3-Chlorophenyl)-6-(4-chlorophenyl)-1-((S)-cyclopropyl(p-
yridin-2-yl)methyl)piperidin-2-one or
(5R,6S)-5-(3-Chlorophenyl)-6-(4-chlorophenyl)-1-((R)-cyclopropyl(pyridin--
2-yl)methyl)piperidin-2-one
##STR00765##
[2977] The crude product from Example 162, Step B was dissolved in
dichloroethane (13 mL) in the presence of 4 .ANG. molecular sieves
(15 pieces) and heated at reflux overnight. The reaction was
filtered through Celite.RTM. (J. T. Baker, Phillipsberg, N.J.,
diatomaceous earth), rinsed with dichloromethane and concentrated
under reduced pressure. The residue was purified by reverse phase
HPLC (eluent: 10 to 90% acetonitrile, water, 0.1% TFA, gradient
elution) to give the title compound as the first eluting
diastereomer.
Step D.
(5R,6S)-5-(3-Chlorophenyl)-6-(4-chlorophenyl)-1-((S)-cyclopropyl(p-
yridin-2-yl)methyl)-3-methylpiperidin-2-one or
(5R,6S)-5-(3-Chlorophenyl)-6-(4-chlorophenyl)-1-((R)-cyclopropyl(pyridin--
2-yl)methyl)-3-methylpiperidin-2-one
##STR00766##
[2979] A solution of LHMDS (1M in THF, 0.585 mL, 0.585 mmol) was
added to a solution of the compound from Example 262, Step C (0.220
g, 0.487 mmol) and iodomethane (0.040 mL, 0.634 mmol) in THF (5.0
mL) at -78.degree. C. The reaction was allowed to warm to ambient
temperature, then was quenched (sat. aqueous NH.sub.4Cl solution),
extracted (2.times.EtOAc), and washed (sat. aq. NaCl solution). The
combined organic layers were dried over sodium sulfate and
concentrated under reduced pressure. The crude material was
absorbed onto a plug of silica gel and purified by chromatography
(SiO.sub.2, 40 g, eluting with 20% to 60% ethyl acetate in hexane)
to provide the title compound as a mixture of diastereomers.
Step E.
(5R,6S)-3-Allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((S)-cyclo-
propyl(pyridin-2-yl)methyl)-3-methylpiperidin-2-one or
(5R,6S)-3-Allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((R)-cyclopropyl(-
pyridin-2-yl)methyl)-3-methylpiperidin-2-one
##STR00767##
[2981] A solution of LHMDS (1.0M in THF, 0.838 mL, 0.838 mmol) was
added to a solution of the diastereomeric mixture from Example 262,
Step D (0.130 g, 0.279 mmol) and allyl bromide (0.095 mL, 1.117
mmol) in THF (2.80 mL). The reaction mixture was stirred at room
temperature for 5 min, then heated to 50.degree. C. for 3 h. The
solution was diluted with sat. NH.sub.4Cl solution, extracted
(2.times. ethyl acetate), and washed (sat. aq. NaCl solution). The
combined organic layers were dried over sodium sulfate and
concentrated under reduced pressure. The crude material was
absorbed onto a plug of silica gel and purified by chromatography
(SiO.sub.2, 40 g, eluted with a gradient of 0 to 35% EtOAc in
hexane) to provide the title compound as a mixture of diastereomers
as a white foam.
Step F.
2-((3R,5R,6S)-5-(3-Chlorophenyl)-6-(4-chlorophenyl)-1-((S)-cyclopr-
opyl(pyridin-2-yl)methyl)-3-methyl-2-oxopiperidin-3-yl)acetic acid
or
2-((3R,5R,6S)-5-(3-Chlorophenyl)-6-(4-chlorophenyl)-1-((R)-cyclopropyl(py-
ridin-2-yl)methyl)-3-methyl-2-oxopiperidin-3-yl)acetic acid
[2982] The compound of Example 262, Step E (90 mg, 0.178 mmol) was
treated by a procedure similar to the one described in Example 71,
Step F. Separation of the diastereomers by reverse phase
preparatory HPLC (eluent: 10 to 90% acetonitrile, water, 0.1% TFA,
gradient elution) gave the title compound as the first eluting
diastereomer.
[2983] .sup.1H NMR (400 MHz, CHLOROFORM-d) .delta. ppm 0.09 (br s,
1H) 0.28-0.34 (m, 1H) 0.77-0.95 (m, 2H) 1.37 (s, 3H) 1.51-1.66 (m,
1H) 2.13 (dd, J=14.09, 3.13 Hz, 1H) 2.28 (t, J=13.69 Hz, 1H) 2.79
(d, J=15.06 Hz, 1H) 2.98 (d, J=15.06 Hz, 1H) 3.29-3.41 (m, 1H) 4.83
(d, J=9.98 Hz, 1H) 5.08 (d, J=10.37 Hz, 1H) 6.80 (d, J=7.63 Hz, 1H)
6.96 (m, 5H) 7.04-7.17 (m, 2H) 7.63 (d, J=8.22 Hz, 1H) 7.72 (t,
J=6.65 Hz, 1H) 8.07 (t, J=7.24 Hz, 1H) 9.06 (d, J=4.89 Hz, 1H). MS
(ESI) m/z=523.2 (M+1).
Example 263
2-((3R,5R,6S)-5-(3-Chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-cyclopropyl-2-
-(thiophene-2-sulfonamido)ethyl)-3-methyl-2-oxopiperidin-3-yl)acetic
acid
##STR00768##
[2984] Step A.
2-((3R,5R,6S)-1-((S)-2-((tert-Butyldiphenylsilyl)oxy)-1-cyclopropylethyl)-
-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-2-oxopiperidin-3-yl)acetic
acid
##STR00769##
[2986] To a rapidly stirring solution of
(3S,5R,6S)-3-allyl-1-((S)-2-(tert-butyldiphenylsilyloxy)-1-cyclopropyleth-
yl)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methylpiperidin-2-one
(1450 mg, 2.08 mmol; Example 251, Step D) in a mixture of water (11
mL), acetonitrile (7.2 mL), and CCl.sub.4 (7.2 mL) was added sodium
periodate (1780 mg, 8.32 mmol), followed by ruthenium (III)
chloride hydrate (47 mg, 0.21 mmol). After being stirred vigorously
for 16 h, additional water (5.4 mL), acetonitrile (3.6 mL), and
CCl.sub.4 (3.6 mL) were added and to the resulting clear dark
solution as was added additional sodium periodate (890 mg, 4.16
mmol) and ruthenium (III) chloride hydrate (24 mg, 0.10 mmol).
After being stirred vigorously for additional 4 h, the reaction was
acidified (10% citric acid) and diluted (EtOAc). The reaction
mixture was filtered through pad of Celite.RTM. (J. T. Baker,
Phillipsberg, N.J., diatomaceous earth) and the filtrate was
extracted (2.times.EtOAc). The combined organic layers were washed
(brine), dried (Na.sub.2SO.sub.4), and concentrated under the
reduced pressure. Purification of the residue by chromatography on
silica gel (80 g SiO.sub.2, 30%, 40%, and 50% EtOAc/Hex) provided
the title compound as a pale yellow foam.
Step B. Methyl
2-((3R,5R,6S)-1-((S)-2-((tert-butyldiphenylsilyl)oxy)-1-cyclopropylethyl)-
-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-2-oxopiperidin-3-yl)acetat-
e
##STR00770##
[2988] To a solution of
2-((3R,5R,6S)-1-((S)-2-(tert-butyldiphenylsilyloxy)-1-cyclopropylethyl)-5-
-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-2-oxopiperidin-3-yl)acetic
acid (1400 mg, 1.96 mmol; Example 263, Step A) in a mixture of MeOH
(3.1 mL) and benzene (12.5 mL) was added 2.0 M
(trimethylsilyl)diazomethane in hexanes (1.96 mL, 3.92 mmol) at
0.degree. C. dropwise. After being stirred at 0.degree. C. for 1 h,
the reaction was concentrated under reduced pressure. Purification
of the residue by chromatography on silica gel (40 g SiO.sub.2,
10%, and 20% EtOAc/Hex) provided the title compound as a pale
yellow foam.
Step C. Methyl
2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-cyclopropyl--
2-hydroxyethyl)-3-methyl-2-oxopiperidin-3-yl)acetate
##STR00771##
[2990] To a solution of methyl
2-((3R,5R,6S)-1-((S)-2-(tert-butyldiphenylsilyloxy)-1-cyclopropylethyl)-5-
-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-2-oxopiperidin-3-yl)acetate
(578 mg, 0.793 mmol; Example 263, Step B) in THF (3.2 mL) was added
1 M TBAF in THF (2.38 mL, 2.38 mmol) at 0.degree. C. and the
reaction mixture was allowed to warm to rt. After being stirred at
rt for 6 h, the reaction was quenched (sat. NH.sub.4Cl), extracted
(2.times.EtOAc) and washed (brine). The combined organic layers
were dried (Na.sub.2SO.sub.4) and concentrated under the reduced
pressure. Purification of the residue by chromatography on silica
gel (40 g SiO.sub.2, 10% and 50% EtOAc/Hex) provided the title
compound as a colorless foam.
Step D. Methyl
2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-cyclopropyl--
2-(thiophene-2-sulfonamido)ethyl)-3-methyl-2-oxopiperidin-3-yl)acetate
##STR00772##
[2992] To a solution of methyl
2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-cyclopropyl--
2-hydroxyethyl)-3-methyl-2-oxopiperidin-3-yl)acetate (100 mg, 0.184
mmol; Example 263, Step C) and cyanomethylenetributylphosphorane
(177 .mu.L, 0.734 mmol) in toluene (0.92 mL) was added
thiophene-2-sulfonamide (90 mg, 0.55 mmol) and the resulting
solution was stirred at 35.degree. C. overnight. The reaction was
quenched (sat. NH.sub.4Cl), extracted (2.times.EtOAc), and washed
(brine). The combined organic layers were dried (Na.sub.2SO.sub.4)
and concentrated under the reduced pressure. Purification of the
residue by chromatography on silica gel (24 g SiO.sub.2, 35%
EtOAc/Hex) provided the title compound as a pale yellow foam.
Step E.
2-((3R,5R,6S)-5-(3-Chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-cyclo-
propyl-2-(thiophene-2-sulfonamido)ethyl)-3-methyl-2-oxopiperidin-3-yl)acet-
ic acid
[2993] To a solution of methyl
2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-cyclopropyl--
2-(thiophene-2-sulfonamido)ethyl)-3-methyl-2-oxopiperidin-3-yl)acetate
(30 mg, 0.048 mmol; Example 263, Step D) in a mixture of water
(0.16 mL), MeOH (0.16 mL), and THF (0.16 mL) was added 2 M aq. LiOH
(48 .mu.L, 0.095 mmol) at rt and the resulting solution was stirred
at rt for 5 h. The reaction was quenched (sat. NH.sub.4Cl),
extracted (2.times.EtOAc), and washed (brine). The combined organic
layers were dried (Na.sub.2SO.sub.4) and concentrated under the
reduced pressure. Purification of the residue by chromatography on
silica gel (12 g SiO.sub.2, gradient elution of 50% to 100% EtOAc
in Hex and 30% iPrOH/DCM) provided the title compound as a white
powder.
[2994] .sup.1H NMR (400 MHz, CHLOROFORM-d) .delta. ppm 7.50-7.66
(2H, m), 6.95-7.25 (8H, m), 6.81 (1H, d, J=7.4 Hz), 5.66 (1H, br,
s), 4.87 (1H, d, J=10.0 Hz), 3.05-3.26 (3H, m), 2.87-3.02 (2H, m),
2.78-2.84 (1H, m), 2.18-2.32 (1H, m), 2.04-2.15 (1H, m), 1.47 (3H,
s), 1.06-1.18 (1H, m), 0.41-0.57 (2H, m), -0.02-0.10 (1H, m),
-0.35--0.20 (1H, m); MS (ESI) 621.0 [M+H].sup.+.
Example 264
2-((3R,5R,6S)-5-(3-Chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-cyclopropyl-2-
-(N-methylthiophene-2-sulfonamido)ethyl)-3-methyl-2-oxopiperidin-3-yl)acet-
ic acid
##STR00773##
[2996] To a solution of methyl
2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-cyclopropyl--
2-(thiophene-2-sulfonamido)ethyl)-3-methyl-2-oxopiperidin-3-yl)acetate
(31 mg, 0.049 mmol; Example 263) in DMF (0.25 mL) was added sodium
hydride (60% dispersion in mineral oil; 6 mg, 0.15 mmol) at rt, and
the solution was stirred for 10 min. Then iodomethane (28 mg, 0.20
mmol) was added and the resulting solution was stirred at rt for 5
h. The reaction was quenched (sat. NH.sub.4Cl), extracted
(2.times.EtOAc), and washed (brine). The combined organic layers
were dried (Na.sub.2SO.sub.4) and concentrated under the reduced
pressure provided a mixture of the title compound and methyl
ester.
[2997] To a solution of this crude mixture in water (0.16 mL), MeOH
(0.16 mL), and THF (0.16 mL) was added lithium hydroxide (2.4 mg,
0.098 mmol) at rt and the resulting solution was stirred at RT
overnight. The reaction was quenched (sat. NH.sub.4Cl), extracted
(2.times.EtOAc) and washed (brine). The combined organic layers
were dried (Na.sub.2SO.sub.4) and concentrated under reduced
pressure. Purification of the residue by chromatography on silica
gel (4 g SiO.sub.2, 50% and 90% EtOAc/Hex) provided the title
compound as a white powder.
[2998] .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. ppm 7.50-7.68 (2H,
m), 7.23-7.27 (2H, m), 7.12-7.22 (4H, m), 6.88-7.02 (3H, m), 4.86
(1H, d, J=10.0 Hz), 2.98-3.24 (2H, m), 2.70-2.96 (3H, m), 2.80 (3H,
s), 2.35-2.50 (2H, m), 1.96-2.04 (1H, m), 1.54 (3H, br, s),
1.29-1.39 (1H, m), 0.15-0.50 (2H, m), -0.41--0.15 (1H, m),
-0.95--0.65 (1H, m); MS (ESI) 635.0 [M+H].sup.+.
Example 265
2-((3R,5R,6S)-5-(3-Chlorophenyl)-6-(4-chlorophenyl)-1-((S)-2-(5-chlorothio-
phene-2-sulfonamido)-1-cyclopropylethyl)-3-methyl-2-oxopiperidin-3-yl)acet-
ic acid
##STR00774##
[3000] The title compound was prepared from methyl
2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-cyclopropyl--
2-hydroxyethyl)-3-methyl-2-oxopiperidin-3-yl)acetate (Example 263,
Step C) by procedures similar to those described in Example 263,
Step D and E, substituting thiophene-2-sulfonamide in Step D with
the appropriate amount of 5-chlorothiophene-2-sulfonamide.
[3001] .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. ppm 7.35 (1H, d,
J=4.1 Hz), 6.97-7.25 (7H, m), 6.94 (1H, d, J=4.1 Hz), 6.78 (1H, d,
J=7.4 Hz), 5.82 (1H, br, s), 4.86 (1H, d, J=10.0 Hz), 2.87-3.20
(5H, m), 2.78-2.85 (1H, m), 2.19-2.27 (1H, m), 2.07-2.16 (1H, m),
1.46 (3H, s), 1.01-1.13 (1H, m), 0.50-0.60 (2H, m), 0.06-0.17 (1H,
m), -0.25--0.10 (1H, m);
[3002] MS (ESI) 655.0 [M+H].sup.+, 652.9 [M-H].sup.-.
Example 266
2-((3R,5R,6S)-1-((S)-2-(5-Chloro-N-methylthiophene-2-sulfonamido)-1-cyclop-
ropylethyl)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-2-oxopiperidin--
3-yl)acetic acid
##STR00775##
[3004] The title compound was prepared from the methyl ester
precursor of
2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((S)-2-(5-chlorothi-
ophene-2-sulfonamido)-1-cyclopropylethyl)-3-methyl-2-oxopiperidin-3-yl)ace-
tic acid (Example 265) by a procedure similar to the one described
in Example 264.
[3005] .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. ppm 7.28-7.40 (2H,
m), 6.83-7.18 (8H, m), 4.75-4.88 (1H, m), 3.00-3.21 (2H, m),
2.74-2.86 (2H, m), 2.81 (3H, s), 2.25-2.54 (2H, m), 1.95-2.05 (1H,
m), 1.57-1.84 (2H, m), 1.53 (3H, br, s), 0.18-0.55 (2H, m),
-0.46--0.15 (1H, m), -0.95--0.65 (1H, m); MS (ESI) m/z=669.0
[M+H].sup.+, 667.0 [M-H].sup.-.
Example 267
2-((3R,5R,6S)-5-(3-Chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-cyclopropyl-2-
-(N-(difluoromethyl)-2-methylpropan-2-ylsulfonamido)ethyl)-3-methyl-2-oxop-
iperidin-3-yl)acetic acid
##STR00776##
[3006] Step A.
N--((S)-2-((3S,5R,6S)-3-Allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-met-
hyl-2-oxopiperidin-1-yl)-2-cyclopropylethyl)-2-methylpropane-2-sulfonamide
##STR00777##
[3008] The title compound was obtained from
(3S,5R,6S)-3-allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-cyclopr-
opyl-2-hydroxyethyl)-3-methylpiperidin-2-one (300 mg, 0.654 mmol;
Example 252, Step A) and 2-methylpropane-2-sulfonamide (189 mg,
1.37 mmol) by a procedure similar to the one described in Example
127, Step F reacting for a total of 21 h. Purification of the
residue by chromatography on silica gel (40 g SiO.sub.2, 30% and
50% EtOAc/Hex) provided the title compound as a pale yellow
foam.
Step B.
N--((S)-2-((3S,5R,6S)-3-Allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl-
)-3-methyl-2-oxopiperidin-1-yl)-2-cyclopropylethyl)-N-(difluoromethyl)-2-m-
ethylpropane-2-sulfonamide
##STR00778##
[3010] To a solution of
N--((S)-2-((3S,5R,6S)-3-allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-met-
hyl-2-oxopiperidin-1-yl)-2-cyclopropylethyl)-2-methylpropane-2-sulfonamide
(88 mg, 0.152 mmol; Example 267, Step A) in DMF (1.0 mL) was added
60% sodium hydride in mineral oil (24 mg, 0.61 mmol) and the
resulting solution was stirred at rt for 10 min. Then
chlorodifluoromethane was bubbled into the reaction for 10 min
while the reaction was vigorously stirred and the resulting
reaction was stirred for 2 h. The reaction was quenched (sat.
NH.sub.4Cl), extracted (2.times.EtOAc) and washed (brine). The
combined organic layers were dried (Na.sub.2SO.sub.4) and
concentrated under the reduced pressure. Purification of the
residue by chromatography on silica gel (12 g SiO.sub.2, 20% and
30% EtOAc/Hex) provided the title compound as a colorless film.
Step C.
2-((3R,5R,6S)-5-(3-Chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-cyclo-
propyl-2-(N-(difluoromethyl)-2-methylpropan-2-ylsulfonamido)ethyl)-3-methy-
l-2-oxopiperidin-3-yl)acetic acid
[3011] The title compound was prepared from
N--((S)-2-((3S,5R,6S)-3-allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-met-
hyl-2-oxopiperidin-1-yl)-2-cyclopropylethyl)-N-(difluoromethyl)-2-methylpr-
opane-2-sulfonamide (57 mg, 0.091 mmol; Example 267, Step B) by a
procedure similar to the one described in Example 71, Step F.
Purification of the residue by reverse phase preparatory HPLC
(Gemini.TM. Prep C.sub.18 5 .mu.m column, Phenomenex, Torrance,
Calif.; gradient elution of 50% to 75% MeCN in water, where both
solvents contain 0.1% TFA) provided the title compound as a white
foam.
[3012] .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. ppm 7.08-7.27 (4H,
m), 6.93-7.00 (2H, m), 6.65-6.87 (2H, m), 5.50 (1H, br, s),
4.55-4.70 (2H, m), 3.55-3.68 (1H, m), 3.09-3.18 (2H, m), 2.79 (1H,
d, J=15.1 Hz), 2.35-2.69 (2H, m), 1.74-1.94 (2H, m), 1.53 (3H, s),
1.47 (9H, s.), 0.36-0.49 (1H, m), 0.23-0.35 (1H, m), -0.34--0.15
(1H, m), -0.87--0.71 (1H, m); MS (ESI) m/z=645.0 [M+H].sup.+, 643.0
[M-H].sup.-.
[3013] Examples 268 and 269 were also prepared from
(3S,5R,6S)-3-allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-cyclopr-
opyl-2-hydroxyethyl)-3-methylpiperidin-2-one (Example 252, Step A)
by procedures similar to the ones described in Example 267,
substituting 2-methylpropane-2-sulfonamide in step A with the
appropriate amount of reagent listed in the table.
TABLE-US-00011 ##STR00779## Example R Reagent used 268 ##STR00780##
ethanesulfonamide 269 ##STR00781## cyclopropanesulfonamide
Example 268
2-((3R,5R,6S)-5-(3-Chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-cyclopropyl-2-
-(N-(difluoromethyl)ethylsulfonamido)ethyl)-3-methyl-2-oxopiperidin-3-yl)a-
cetic acid
[3014] .sup.1H NMR (500 MHz, CHLOROFORM-d) .delta. ppm -0.78 (br.
s., 1H) -0.22 (br. s., 1H) 0.31 (br. s., 1H) 0.42 (br. s., 1H)
1.38-1.49 (m, 3H) 1.52 (s, 3H) 1.57-2.11 (br. s., 2H) 2.40-2.52
(m., 2H) 2.78 (d, J=15.41 Hz, 1H) 3.08-3.27 (m, 4H) 3.42-4.02 (br.
s., 2H) 4.57-4.74 (m, 2H) 6.80 (d, J=7.34 Hz, 1H) 6.95 (s, 1H)
7.08-7.18 (m, 2H) 7.27 (m., 4H); Mass Spectrum (ESI) m/z=617
(M+1).
Example 269
2-((3R,5R,6S)-5-(3-Chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-cyclopropyl-2-
-(N-(difluoromethyl)cyclopropanesulfonamido)ethyl)-3-methyl-2-oxopiperidin-
-3-yl)acetic acid
[3015] .sup.1H NMR (500 MHz, CHLOROFORM-d) .delta. ppm -0.79 (br.
s., 1H) -0.23 (br. s., 1H) 0.31 (br. s., 1H) 0.42 (br. s., 1H)
1.12-1.36 (m, 3H) 1.51 (s, 3H) 1.59-1.95 (m, 5H) 2.44 (br. s., 2H)
2.77 (d, J=15.41 Hz, 1H) 3.04-3.26 (m, 2H) 3.53 (m, 1H) 4.48-4.70
(m, 2H) 6.79 (d, J=7.34 Hz, 1H) 6.93 (s, 1H) 7.07-7.18 (m, 2H) 7.27
(m., 4H); Mass Spectrum (ESI) m/z=629 (M+1).
Example 270
1-((3R,5R,6S)-5-(3-Chlorophenyl)-6-(4-chlorophenyl)-1-((S)-2-(cyclopropane-
sulfonamido)-1-cyclopropylethyl)-3-methyl-2-oxopiperidin-3-yl)cyclopropane-
carboxylic acid
##STR00782##
[3016] Step A. (S)-Methyl
2-((3R,5R,6S)-1-((S)-2-((tert-butyldiphenylsilyl)oxy)-1-cyclopropylethyl)-
-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-2-oxopiperidin-3-yl)-3-hyd-
roxypropanoate
##STR00783##
[3018] To a solution of diisopropylamine (249 .mu.L, 1.75 mmol) in
THF (1.2 mL) was added 1.6 M n-BuLi in hexanes (984 .mu.L, 1.57
mmol) slowly at -15.degree. C. After 30 minutes, a solution of
methyl
2-((3R,5R,6S)-1-((S)-2-(tert-butyldiphenylsilyloxy)-1-cyclopropylethyl)-5-
-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-2-oxopiperidin-3-yl)acetate
(255 mg, 0.35 mmol; Example 263, Step B) in THF (1.2 mL) was added
dropwise to the LDA solution and the resulting solution was stirred
at -15.degree. C. for 30 min (the solution turned bright yellow).
Then, formaldehyde in N.sub.2 stream was carried over the reaction
surface for 5 min (formaldehyde was generated by cracking
para-formaldehyde (105 mg, 3.50 mmol) with heat gun) at -15.degree.
C. After being stirred at -15.degree. C. for 30 min, the reaction
was allowed to warm to rt and stirred for 4 h. The reaction was
quenched (ice cold sat. NH.sub.4Cl), extracted (2.times.EtOAc) and
washed (brine.times.3). The combined organic layers were dried
(Na.sub.2SO.sub.4) and concentrated under the reduced pressure.
Purification of the residue by chromatography on silica gel (24 g
SiO.sub.2, 20% and 50% EtOAc/Hex) provided the title compound as a
colorless film.
Step B. Methyl
2-((3R,5R,6S)-1-((S)-2-((tert-butyldiphenylsilyl)oxy)-1-cyclopropylethyl)-
-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-2-oxopiperidin-3-yl)acryla-
te
##STR00784##
[3020] To a solution of (S)-methyl
2-((3R,5R,6S)-1-((S)-2-(tert-butyldiphenylsilyloxy)-1-cyclopropylethyl)-5-
-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-2-oxopiperidin-3-yl)-3-hydro-
xypropanoate (132 mg, 0.173 mmol; Example 270, Step A) and
triethylamine (97 .mu.L, 0.69 mmol) in DCM (2.2 mL) was added a
solution of methanesulfonyl chloride (27 .mu.L, 0.35 mmol) in DCM
(2.2 mL) at 0.degree. C. Then the reaction was allowed to warm to
rt and stirred for 3 h. The reaction was quenched (water),
extracted (2.times.EtOAc) and washed (brine). The combined organic
layers were dried (Na.sub.2SO.sub.4) and concentrated under the
reduced pressure to provide a crude mesylated compound, (S)-methyl
2-((3R,5R,6S)-1-((S)-2-(tert-butyldiphenylsilyloxy)-1-cyclopropylethyl)-5-
-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-2-oxopiperidin-3-yl)-3-(meth-
ylsulfonyloxy)propanoate.
[3021] To a solution of the crude mesylated compound from above in
DCM (2.2 mL) was added DBU (78 .mu.L, 0.52 mmol) and the resulting
solution was stirred at rt for 1 h. The reaction was quenched (ice
cold sat. NH.sub.4Cl), extracted (2.times.EtOAc) and washed
(brine). The combined organic layers were dried (Na.sub.2SO.sub.4)
and concentrated under the reduced pressure. Purification of the
residue by chromatography on silica gel (12 g SiO.sub.2, 10% and
20% EtOAc/Hex) provided the title compound as a colorless film.
Step C. Methyl
1-((3R,5R,6S)-1-((S)-2-((tert-butyldiphenylsilyl)oxy)-1-cyclopropylethyl)-
-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-2-oxopiperidin-3-yl)cyclop-
ropanecarboxylate
##STR00785##
[3023] To a suspension of trimethylsulfoxonium iodide (39 mg, 0.18
mmol) in DMSO (0.71 mL) was added a suspension of 60% sodium
hydride in mineral oil (7.1 mg, 0.18 mmol). After being stirred 15
min, a solution of methyl
2-((3R,5R,6S)-1-((S)-2-(tert-butyldiphenylsilyloxy)-1-cyclopropylethyl)-5-
-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-2-oxopiperidin-3-yl)acrylate
(66 mg, 0.089 mmol; Example 270, Step B) in DMSO (0.71 mL) was
added and the mixture was stirred at rt for 3 h. The reaction was
quenched (ice cold sat. NH.sub.4Cl), extracted (2.times.EtOAc), and
washed (brine.times.3). The combined organic layers were dried
(Na.sub.2SO.sub.4) and concentrated under the reduced pressure.
Purification of the residue by chromatography on silica gel (4 g
SiO.sub.2, 10% and 20% EtOAc/Hex) provided the title compound as a
colorless film.
Step D. Methyl
1-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-cyclopropyl--
2-hydroxyethyl)-3-methyl-2-oxopiperidin-3-yl)cyclopropanecarboxylate
##STR00786##
[3025] To a solution of methyl
1-((3R,5R,6S)-1-((S)-2-(tert-butyldiphenylsilyloxy)-1-cyclopropylethyl)-5-
-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-2-oxopiperidin-3-yl)cyclopro-
panecarboxylate (53 mg, 0.070 mmol; Example 270, Step C) in THF
(0.70 mL) was added 1 M TBAF in THF (0.21 mL, 0.21 mmol) and the
reaction was stirred at rt overnight. The reaction was quenched
(sat. NH.sub.4Cl), extracted (2.times.EtOAc), and washed (brine).
The combined organic layers were dried (Na.sub.2SO.sub.4) and
concentrated under the reduced pressure. Purification of the
residue by chromatography on silica gel (4 g SiO.sub.2, 10%, 45%,
and 55% EtOAc/Hex) provided the title compound as a white foam
Step E. Methyl
1-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((S)-2-(cyclopropan-
esulfonamido)-1-cyclopropylethyl)-3-methyl-2-oxopiperidin-3-yl)cyclopropan-
ecarboxylate
##STR00787##
[3027] The tile compound was prepared from methyl
1-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-cyclopropyl--
2-hydroxyethyl)-3-methyl-2-oxopiperidin-3-yl)cyclopropanecarboxylate
(35 mg, 0.068 mmol; Example 270, Step D) and
cyclopropanesulfonamide (25 mg, 0.20 mmol) by a procedure similar
to the one described in Example 202, Step C. Purification of the
residue by chromatography on silica gel (4 g SiO.sub.2, 45% and 60%
EtOAc/Hex) provided the title compound as a pale yellow.
Step F.
1-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((S)-2-(cycl-
opropanesulfonamido)-1-cyclopropylethyl)-3-methyl-2-oxopiperidin-3-yl)cycl-
opropanecarboxylic acid
[3028] The title compound was prepared from methyl
1-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((S)-2-(cyclopropan-
esulfonamido)-1-cyclopropylethyl)-3-methyl-2-oxopiperidin-3-yl)cyclopropan-
ecarboxylate (27 mg, 0.043 mmol; Example 270, Step E) by a
procedure similar to the one described in Example 263, Step E.
Purification of the residue by reverse phase preparatory HPLC
(Gemini.TM. Prep C.sub.18 5 .mu.m column, Phenomenex, Torrance,
Calif.; gradient elution of 45% to 70% MeCN in water, where both
solvents contain 0.1% TFA) provided the title compound.
[3029] .sup.1H NMR (400 MHz, CHLOROFORM-d) .delta. ppm 7.03-7.26
(6H, m), 6.92-6.96 (1H, m), 6.79 (1H, d, J=7.0 Hz), 4.79 (1H, d,
J=10.6 Hz), 3.37-3.48 (1H, m), 3.12-3.20 (1H, m), 2.78 (1H, dd,
J=14.0, 2.2 Hz), 2.37-2.45 (1H, m), 2.15-2.25 (1H, m), 1.80-1.88
(1H, m), 1.38-1.50 (2H, m), 1.45 (3H, s), 1.10-1.31 (7H, m),
0.93-1.01 (2H, m), 0.35-0.54 (2H, m), -0.09-0.12 (1H, m),
-0.72--0.23 (1H, m); MS (ESI) m/z=605.0 [M+H].sup.+, 603.1
[M-H].sup.-.
Example 271
Intermediate
[3030] A: N-(2-fluorophenyl)ethanesulfonamide
[3031] To a solution of ethanesulfonyl chloride (0.368 ml, 3.89
mmol) in DCM (1 ml) and pyridine (1 ml) was added 2-fluoroaniline
(0.360 ml, 3.89 mmol) at rt and the reaction was stirred at
50.degree. C. for 5 hours. The reaction was then stirred at rt
overnight. The reaction was diluted with EtOAc and washed with
H.sub.2O and sat. NaCl solution. The organic layer was dried over
Na.sub.2SO.sub.4 and concentrated. Purification of the residue by
flash chromatography on silica gel (eluent: 0% to 35% EtOAc/hexane)
provided the title compound as a white solid.
[3032] .sup.1H NMR (400 MHz, CHLOROFORM-d) .delta. ppm 1.42 (t, J=8
Hz, 3H), 3.15 (q, J=8 Hz, 2H), 6.48 (s, br, 1H), 7.17 (m, 3H), 7.64
(m, 1H).
[3033] In a similar fashion the following were prepared:
[3034] B: N-(phenyl)ethanesulfonamide: .sup.1H NMR (400 MHz,
chloroform-d) .delta. ppm 1.38 (t, J=8 Hz, 3H), 3.14-3.20 (q, J=8
Hz, 2H), 7.15-7.17 (m, 1H), 7.29-7.36 (m, 4H).
[3035] C: N-(3-fluorophenyl)ethanesulfonamide: .sup.1H NMR (400
MHz, chloroform-d) .delta. ppm 1.42 (t, J=8 Hz, 3H), 3.17-3.23 (q,
J=8 Hz, 2H), 6.78 (s, br, 1H), 6.89 (m, 1H), 6.99 (m, 1H), 7.04 (m,
1H), 7.77 (m, 1H).
[3036] D: N-(pyridin-3-yl)methanesulfonamide: .sup.1H NMR (400 MHz,
methanol-d4) .delta. ppm 3.05 (s, 3H), 7.43-7.46 (dd, J=4, 8 Hz,
1H), 7.78-7.81 (dd, J=2, 4 Hz, 1H), 8.33 (d, J=4 Hz, 1H), 8.45 (s,
1H). Mass Spectrum (ESI) m/z=173.2 (M+1).
[3037] E: N-(phenyl)cyclopropanesulfonamide: .sup.1H NMR (400 MHz,
CHLOROFORM-d) .delta. ppm 0.96-1.00 (m, 2H), 1.18-1.22 (m, 2H),
2.48-2.55 (m, 1H), 7.20-7.22 (m, 1H), 7.28-7.30 (m, 2H), 7.37-7.39
(m, 2H).
[3038] F: propane-1-sulfonamide [CAS no. 24243-71-8]
[3039] A stream of anhydrous ammonia was bubbled into a solution of
propane-1-sulfonyl chloride (7.3 g, 51.2 mmol) in anhydrous THF
(100 ml) on ice bath. Bubbling was continued for 1 hour during
which a lot of white solid precipitated. The reaction was then
stirred at rt for 2 days. The reaction mixture was diluted with
EtOAc, washed with H.sub.2O and sat. NaCl, dried with
Na.sub.2SO.sub.4, and then concentrated. Purification of the crude
using flash chromatography on silica gel (eluted with 0% to 35%
EtOAc/hexane) gave the title compound as a white solid (3.0 g,
47.6%).
[3040] .sup.1H NMR (400 MHz, chloroform-d) .delta. ppm -1.10 (t,
J=8 Hz, 3H), 1.91 (m, 2H), 3.11 (m, 2H), 4.94 (s, 2H).
[3041] G: Cyclobutanesulfonamide [CAS no. 445305-91-9]
[3042] A stream of anhydrous ammonia was bubbled for 30 min through
a stirred solution of cyclobutanesulfonyl chloride (5 g, 32.3 mmol;
Hande Sciences) in dry THF (100 mL) at 0.degree. C., causing
formation of a white precipitate. The suspension was warmed to
ambient temperature and stirred overnight. The mixture was filtered
and the filter cake was copiously washed with ethyl acetate. The
filtrate was concentrated under reduced pressure, redissolved in
ca. 150 mL EtOAc, and washed 3.times. with brine. Organics were
dried over sodium sulfate, filtered, and concentrated in vacuo to
give a white, partially crystalline residue that was triturated
with hexanes and dried under high vacuum to give
cyclobutanesulfonamide as a fluffy white solid, 1.8 g (41%
yield).
[3043] .sup.1H NMR (400 MHz, CHLOROFORM-d) .delta. 1.96-2.10 (m,
2H), 2.30-2.43 (m, 2H), 2.43-2.59 (m, 2H), 3.72-4.01 (m, 1H), 4.70
(br. s., 2H).
Example 272
2-((3R,5R,6S)-5-(3-Chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-cyclopropyl-2-
-(N-(2-fluorophenyl)ethylsulfonamido)ethyl)-3-methyl-2-oxopiperidin-3-yl)a-
cetic acid
##STR00788##
[3044] Step A.
N--((S)-2-((3S,5R,6S)-3-allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-met-
hyl-2-oxopiperidin-1-yl)-2-cyclopropylethyl)-N-(2-fluorophenyl)ethanesulfo-
namide
##STR00789##
[3046] To a mixture of
(3S,5R,6S)-3-allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-cyclopr-
opyl-2-hydroxyethyl)-3-methylpiperidin-2-one (Example 252, Step A,
70 mg, 0.153 mmol) and N-(2-fluorophenyl)ethanesulfonamide (93 mg,
0.458 mmol) in toluene (1 ml) was added
cyanomethylenetri-n-butylphosphorane (0.111 ml, 0.458 mmol) at rt
and the mixture was flushed with N.sub.2 for about 20 minutes. The
reaction was sealed and heated to 70.degree. C. overnight. The
reaction mixture was purified by flash chromatography on silica gel
(eluent: 0% to 35% EtOAc/hexanes) to provide the title compound as
a solid.
[3047] .sup.1H NMR (400 MHz, methanol-d4) ppm -1.25 (s, br, 1H),
-0.64 (s, br, 1H), 0.00 (s, br, 1H), 0.16 (s, br, 1H), 0.73 (m,
1H), 0.92 (s, 3H), 1.19 (m, 4H), 1.48 (m, 1H), 1.66 (m, 1H), 2.00
(m, 2H), 2.24 (m, 1H), 2.52 (m, 1H), 2.97 (m, 2H), 3.71 (s, br,
1H), 4.56 (d, J=12 Hz, 1H), 5.01 (m, 1H), 5.05 (s, 1H), 5.73 (m,
1H), 6.83-6.91 (m, 3H), 7.03-7.16 (m, 7H), 7.28 (m, 1H), 7.45 (m,
1H).
[3048] Mass Spectrum (ESI) m/z=643.2 (M+1)
Step B:
2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-cyclo-
propyl-2-(N-(2-fluorophenyl)ethylsulfonamido)ethyl)-3-methyl-2-oxopiperidi-
n-3-yl)acetic acid
[3049] To a solution of
N--((S)-2-((3S,5R,6S)-3-allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-met-
hyl-2-oxopiperidin-1-yl)-2-cyclopropylethyl)-N-(2-fluorophenyl)ethanesulfo-
namide (Example 272, Step A, 72 mg, 0.112 mmol) in THF (0.600 ml),
water (0.396 ml) and BuOH (0.3 ml) was added 4-methylmorpholine
4-oxide (45.9 mg, 0.392 mmol) followed by osmium(VIII) oxide (0.037
ml, 2.80 .mu.mol). The reaction was stirred at rt overnight. Sodium
periodate (71.8 mg, 0.336 mmol) was added and the reaction was
stirred at rt for 2 hours. To this reaction was added 1.25M
KH.sub.2PO.sub.4 (0.80 ml), 1 M of 2-methylbut-2-ene solution in
THF (2.24 ml, 4.47 mmol) and sodium chlorite (50.6 mg, 0.56 mmol)
and the reaction was stirred at rt for 2 hours. Upon the end of the
reaction 0.8 ml of 1 M aq. NaS.sub.2O.sub.3aq. was added and the
reaction was stirred at rt for 10 minutes followed by adding 0.8 ml
of 1 M aq. KHSO.sub.4.
[3050] The reaction was then diluted with EtOAc and washed with
H.sub.2O and sat. NaCl.
[3051] The organic layer was dried with Na.sub.2SO.sub.4 and
concentrated. The product was purified by reversed phase
preparatory HPLC (eluents: 40-85% of acetonitile in water with 0.1%
of TFA gradient on Gemini.TM. Prep C.sub.18 5 um column,
Phenomenex, Torrance, Calif.) to give the title compound as a white
solid.
[3052] .sup.1H NMR (400 MHz, methanol-d.sub.4) ppm -1.28 (s, br,
1H), -0.63 (s, br, 1H), 0.00 (s, br, 1H), 0.17 (s, br, 1H), 1.07
(s, 3H), 1.20 (t, J=4 Hz, 3H), 1.51-1.55 (m, 1H), 1.91-1.95 (dd,
J=4 Hz, 16 Hz, 1H), 2.05 (s, br, 1H), 2.11 (t, J=12 Hz, 1H),
2.49-2.53 (d, J=16 Hz, 1H), 2.79-2.83 (d, J=16 Hz, 1H), 2.98 (s,
br, 2H), 3.27 (m, 1H), 3.71 (s, br, 1H), 4.62 (s, br, 2H), 6.87 (d,
J=8 Hz, 2H), 6.92 (s, 1H), 7.03-7.18 (m, 7H), 7.29 (m, 1H), 7.49
(s, br, 1H).
[3053] Mass Spectrum (ESI) m/z=661.2 (M+1)
[3054] Examples 273-289, were prepared in a similar fashion to
example 272. Using the corresponding sulfonamide and the alcohol of
Example 252, Step A, allyl sulfonamides were formed in Step A and
converted to the corresponding carboxylic acids in Step B.
TABLE-US-00012 Exam- ple Reagent used Source or CAS# 272
N-(2-fluorophenyl)ethanesulfonamide Example 271A 273
N-(2-fluorophenyl)methanesulfonamide [98611-90-6] 274
N-(phenyl)cyclopropanesulfonamide Example 271E 275
N-(phenyl)ethanesulfonamide Example 271B 276 ethanesulfonamide
[1520-70-3] 277 N-(3-fluorophenyl)ethanesulfonamide Example 271C
278 N-(2-cyanophenyl)methanesulfonamide [50790-29-9] 279
propane-1-sulfonamide Example 271F 280 N-(phenyl)methanesulfonamide
[1197-22-4] 281 N-(3-cyanophenyl)methanesulfonamide [50790-30-2]
282 N-(pyridin-3-yl)methanesulfonamide Example 271D 283
N-(thiophen-2- BBB-SCI ylmethyl)methanesulfonamide 3B3-026467,
Libertyville, IL 284 N-(3-MeOPhenylmethyl)- methanesulfonamide 285
alpha-toluenesulfonamide [4563-33-1] 286
pyridin-2-ylmethanesulfonamide Princeton PBMR006092, Monmouth
Junction NJ 287 pyridin-3-ylmethanesulfonamide Princeton
PBMR006093, Monmouth Junction NJ 288
N-(pyridin-2-yl)methanesulfonamide [74351-44-3] 289
methanesulfonamide [3144-09-0]
Example 273
2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-cyclopropyl-2-
-(N-(2-fluorophenyl)methylsulfonamido)ethyl)-3-methyl-2-oxopiperidin-3-yl)-
acetic acid
##STR00790##
[3055] Step A:
N--((S)-2-((3S,5R,6S)-3-allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-met-
hyl-2-oxopiperidin-1-yl)-2-cyclopropylethyl)-N-(2-fluorophenyl)methanesulf-
onamide
##STR00791##
[3057] .sup.1H NMR (400 MHz, methanol-d4) .delta. ppm -1.20 (s, br,
1H), -0.63 (s, br, 1H), 0.00 (s, br, 1H), 0.13 (s, br, 1H), 0.88
(s, 3H), 1.48 (m, 1H), 1.64 (d, J=12 Hz, 1H), 1.94-1.99 (s, 2H),
2.19 (d, J=8 Hz, 2H), 2.72 (s, 3H), 2.99 (m, 1H), 3.54 (s, br, 1H),
4.50 (d, J=8 Hz, 1H), 4.59 (s, br, 1H), 4.96-5.01 (m, 2H), 5.65 (m,
1H), 6.70 (s, br, 2H), 6.80 (s, br, 2H), 6.96-7.08 (m, 6H), 7.19
(m, 1H), 7.27 (m, 1H).
[3058] Mass Spectrum (ESI) m/z=629.2 (M+1).
Step B:
2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-cyclo-
propyl-2-(N-(2-fluorophenyl)methylsulfonamido)ethyl)-3-methyl-2-oxopiperid-
in-3-yl)acetic acid
[3059] .sup.1H NMR (400 MHz, methanol-d.sub.4) .delta. ppm -1.27
(s, br, 1H), -0.58 (s, br, 1H), 0.00 (s, br, 1H), 0.18 (s, br, 1H),
1.03 (s, 3H), 1.07-1.04 (m, 1H), 1.50 (m, 1H), 1.90-1.94 (dd, J=4,
12 Hz, 1H), 2.08 (t, J=16 Hz, 1H), 2.47 (d, J=16 Hz, 1H), 2.78 (d,
J=16 Hz, 1H), 2.81 (s, 3H), 3.26 (m, 1H), 3.67 (s, br, 1H), 4.57
(d, J=12 Hz, 1H), 6.84 (d, J=8 Hz, 2H), 6.90 (s, 1H), 7.03 (m, 4H),
7.16 (m, 2H), 7.29 (m, 1H), 7.31 (m, 1H).
[3060] Mass Spectrum (ESI) m/z=647.0 (M+1).
Example 274
2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-cyclopropyl-2-
-(N-phenylcyclopropanesulfonamido)ethyl)-3-methyl-2-oxopiperidin-3-yl)acet-
ic acid
##STR00792##
[3061] Step A:
N--((S)-2-((3S,5R,6S)-3-allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-met-
hyl-2-oxopiperidin-1-yl)-2-cyclopropylethyl)-N-phenylcyclopropanesulfonami-
de
##STR00793##
[3063] .sup.1H NMR (400 MHz, methanol-d.sub.4) .delta. ppm -1.24
(s, br, 1H), -0.56 (s, br, 1H), 0.00 (s, br, 1H) 0.20 (s, br, 1H),
0.69-0.78 (m, 4H), 0.92 (s, br, 3H), 1.55 (s, br, 1H), 1.62-1.66
(dd, J=4, 12 Hz, 1H), 1.93-2.00 (m, 2H), 2.36-2.45 (m, 2H),
2.51-2.57 (m, 1H), 3.12-3.19 (m, 1H), 3.81 (s, br, 1H), 4.42-4.45
(d, br, J=12 Hz, 1H), 4.76 (s, br, 1H), 5.00-5.05 (t, J=8 Hz, 1H),
5.09 (s, 1H), 5.70-5.79 (m, 1H), 6.79 (m, 2H), 6.92 (s, 1H), 7.04
(m, 4H), 7.18-7.30 (m, 2H), 7.72 (m, 2H), 7.44 (d, J=8 Hz).
[3064] Mass Spectrum (ESI) m/z=637.2 (M+1).
Step B:
2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-cyclo-
propyl-2-(N-phenylcyclopropanesulfonamido)ethyl)-3-methyl-2-oxopiperidin-3-
-yl)acetic acid
[3065] .sup.1H NMR (400 MHz, methanol-d.sub.4) .delta. ppm -1.28
(s, br, 1H), -0.54 (s, br, 1H), 0.00 (s, br, 1H), 0.20 (s, br, 1H),
0.70-0.78 (m, 5H), 1.06 (s, 3H), 1.53 (s, br, 1H), 1.91-2.07 (m,
3H), 2.37 (s, br, 1H), 2.48 (d, J=12 Hz, 1H), 2.78 (d, J=12 Hz,
1H), 3.24 (m, 1H), 3.80 (s, br, 1H), 4.43 (d, J=12 Hz, 1H), 6.82
(d, J=8 Hz, 2H), 6.92 (s, 1H), 7.05 (m, 4H), 7.22 (t, J=8 Hz, 2H),
7.33 (t, J=8 Hz, 2H), 7.44 (d, J=8 Hz, 2H).
[3066] Mass Spectrum (ESI) m/z=655.2 (M+1).
Example 275
2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-cyclopropyl-2-
-(N-phenylethylsulfonamido)ethyl)-3-methyl-2-oxopiperidin-3-yl)acetic
acid
##STR00794##
[3067] Step A:
N--((S)-2-((3S,5R,6S)-3-allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-met-
hyl-2-oxopiperidin-1-yl)-2-cyclopropylethyl)-N-phenylethanesulfonamide
##STR00795##
[3069] .sup.1H NMR (400 MHz, methanol-d.sub.4) .delta. ppm -1.23
(s, br, 1H), -0.56 (s, br, 1H), 0.00 (s, br, 1H), 0.19 (s, br, 1H),
0.92 (s, 3H), 1.13 (t, J=8 Hz, 3H), 1.55 (s, br, 2H), 1.63 (dd,
J=4, 8 Hz, 1H), 1.96 (m, 2H), 2.45 (m, 1H), 2.53 (m, 1H), 2.90 (m,
2H), 3.17 (m, 1H), 3.79 (s, br, 1H), 4.42 (d, J=12 Hz, 1H), 4.81
(s, br, 1H), 5.00 (m, 1H), 5.09 (s, 1H), 5.72 (m, 1H), 6.79 (m,
2H), 6.94 (s, 1H), 7.02 (m, 4H), 7.19 (m, 2H), 7.32 (t, J=8 Hz,
2H), 7.47 (d, J=8 Hz, 2H).
[3070] Mass Spectrum (ESI) m/z=625.2 (M+1).
Step B:
2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-cyclo-
propyl-2-(N-phenylethylsulfonamido)ethyl)-3-methyl-2-oxopiperidin-3-yl)ace-
tic acid
[3071] .sup.1H NMR (400 MHz, methanol-d4) .delta. ppm -1.26 (s, br,
1H), -0.55 (s, br, 1H), 0.19 (s, br, 1H), 1.06 (s, 3H), 1.13 (t,
J=8 Hz, 3H), 1.51 (s, br, 1H), 1.88 (dd, J=4, 8 Hz, 1H), 2.00 (s,
br, 1H), 2.03 (t, J=12 Hz, 1H), 2.48 (d, J=12 Hz, 1H), 2.78 (d,
J=12 Hz, 1H), 2.90 (m, 2H), 3.23 (m, 1H), 3.77 (d, J=12 Hz, 1H),
4.46 (d, J=8 Hz, 1H), 4.76 (s, br, 1H), Mass Spectrum (ESI)
m/z=643.2 (M+1).
Example 276
2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-cyclopropyl-2-
-(ethylsulfonamido)ethyl)-3-methyl-2-oxopiperidin-3-yl)acetic
acid
##STR00796##
[3072] Step A:
N--((S)-2-((3S,5R,6S)-3-allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-met-
hyl-2-oxopiperidin-1-yl)-2-cyclopropylethyl)ethanesulfonamide
##STR00797##
[3074] .sup.1H NMR (400 MHz, methanol-d.sub.4) .delta. ppm -1.06
(s, br, 1H), -0.98 (m, 1H), -0.02 (m, 1H), 0.14 (m, 1H), 1.08 (s,
3H), 1.14 (t, J=4 Hz, 3H), 1.39 (m, 1H), 1.59 (dd, J=4, 12 Hz, 1H),
2.05 (m, 1H), 2.10 (t, J=16 Hz, 1H), 2.42 (m, 1H), 2.50 (m, 1H),
2.89 (m, 3H), 3.12 (m, 1H), 3.74 (m, 1H), 4.68 (d, J=12 Hz, 1H),
4.96-5.06 (m, 2H), 5.71 (m, 1H), 6.79 (m, 2H), 6.87 (s, 1H), 6.93
(m, 3H), 7.06 (m, 2H).
[3075] Mass Spectrum (ESI) m/z=549.0 (M+1).
Step B:
2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-cyclo-
propyl-2-(ethylsulfonamido)ethyl)-3-methyl-2-oxopiperidin-3-yl)acetic
acid
[3076] .sup.1H NMR (400 MHz, methanol-d.sub.4) .delta. ppm -1.06
(s, br, 1H), -0.47 (m, 1H), -0.02 (m, 1H), 0.14 (m, 1H), 1.13 (t,
J=8 Hz, 3H), 1.22 (s, 3H), 1.06 (s, br, 1H), 1.89 (dd, J=4, 12 Hz,
1H), 2.08 (s, 1H), 2.15 (t, J=16 Hz, 1H), 2.46 (d, J=12 Hz, 1H),
2.80 (d, J=12 Hz, 1H), 3.07 (m, 3H), 3.19 (m, 1H), 3.65 (m, 1H),
4.69 (d, J=8 Hz, 1H), 6.81 (m, 2H), 6.92 (s, 1H), 6.87 (m, 3H),
7.05 (s, br, 2H).
[3077] Mass Spectrum (ESI) m/z=567.0 (M+1).
Example 277
2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-cyclopropyl-2-
-(N-(3-fluorophenyl)ethylsulfonamido)ethyl)-3-methyl-2-oxopiperidin-3-yl)a-
cetic acid
##STR00798##
[3078] Step A:
N--((S)-2-((3S,5R,6S)-3-allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-met-
hyl-2-oxopiperidin-1-yl)-2-cyclopropylethyl)-N-(3-fluorophenyl)ethanesulfo-
namide
##STR00799##
[3080] .sup.1H NMR (400 MHz, methanol-d.sub.4) .delta. ppm -1.20
(s, br, 1H), -0.56 (s, br, 1H), 0.00 (s, br, 1H), 0.19 (s, br, 1H),
0.89 (s, 3H), 1.08 (m, 3H), 1.53 (s, br, 1H), 1.62 (dd, J=4, 12 Hz,
1H), 1.90 (t, J=12 Hz, 1H), 1.95 (m, 1H), 2.38 (m, 1H), 2.52 (m,
1H), 2.86-2.96 (m, 2H), 3.11-3.17 (m, 1H), 3.76 (d, J=12 Hz, 1H),
4.77 (s, br, 1H), 5.00 (t, J=8 Hz, 1H), 5.06 (s, 1H), 5.72 (m, 1H),
6.77 (m, 2H), 6.89 (m, 3H), 7.00 (m, 4H), 7.28 (m, 3H).
[3081] Mass Spectrum (ESI) m/z=643.2 (M+1).
Step B:
2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-cyclo-
propyl-2-(N-(3-fluorophenyl)ethylsulfonamido)ethyl)-3-methyl-2-oxopiperidi-
n-3-yl)acetic acid
[3082] .sup.1H NMR (400 MHz, methanol-d4) .delta. ppm -1.06 (s, br,
1H), -0.39 (s, br, 1H), 0.16 (1H), 0.35 (s, br, 1H), 1.21 (s, br,
3H), 1.28 (t, J=4 Hz, 3H), 1.67 (s, br, 1H), 2.04-2.18 (m, 3H),
2.63 (d, J=12 Hz, 1H), 2.93 (d, J=12 Hz, 1H), 3.09 (s, br, 2H),
3.39 (m, 1H), 3.92 (m, 1H), 3.92 (s, br, 1H), 4.56 (s, br, 1H),
6.96 (m, 2H), 7.06 (m, 3H), 7.17 (m, 4H), 7.45 (m, 3H).
[3083] Mass Spectrum (ESI) m/z=661.2 (M+1)
Example 278
2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((S)-2-(N-(2-cyanoph-
enyl)methylsulfonamido)-1-cyclopropylethyl)-3-methyl-2-oxopiperidin-3-yl)a-
cetic acid
##STR00800##
[3084] Step A:
N--((S)-2-((3S,5R,6S)-3-allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-met-
hyl-2-oxopiperidin-1-yl)-2-cyclopropylethyl)-N-(2-cyanophenyl)methanesulfo-
namide
##STR00801##
[3086] .sup.1H NMR (400 MHz, methanol-d.sub.4) .delta. ppm -1.22
(s, br, 1H), -0.47 (s, br, 1H), 0.00 (s, br, 1H), 0.19 (s, br, 1H),
0.91 (s, br, 1H), 1.45 (m, 1H), 1.67 (d, J=12 Hz, 1H), 1.97 (m,
1H), 2.10 (s, br, 1H), 2.42 (m, 1H), 2.52 (m, 1H), 2.87 (s, 3H),
3.15-3.18 (m, 2H), 3.91 (s, br, 1H), 4.47 (s, br, 1H), 4.99 (m,
1H), 5.07 (s, 1H), 5.71 (m, 1H), 6.79 (s, br, 2H), 6.89 (s, 1H),
6.96 (s, br, 3H), 7.05 (s, br, 2H), 7.40 (m, 1H), 7.62 (m, 2H),
7.72 (s, br, 1H).
[3087] Mass Spectrum (ESI) m/z=636.2 (M+1).
Step B:
2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((S)-2-(N-(2-
-cyanophenyl)methylsulfonamido)-1-cyclopropylethyl)-3-methyl-2-oxopiperidi-
n-3-yl)acetic acid
[3088] .sup.1H NMR (400 MHz, methanol-d.sub.4) .delta. ppm -1.12
(s, br, 1H), -0.31 (s, br, 1H), 0.15 (s, br, 1H), 0.35 (s, br, 1H),
1.20 (s, 3H), 1.29 (m, 1H), 1.62 (s, br, 1H), 2.06 (d, 1H), 2.24
(t, J=12 Hz, 1H), 2.27 (s, br, 1H), 2.60 (d, J=12 Hz, 1H), 2.93 (d,
J=12 Hz, 1H), 3.02 (s, 3H), 3.41 (m, 1H), 4.01 (s, br, 1H), 4.68
(s, br, 1H), 6.98 (d, J=8 Hz, 2H), 7.06 (s, 1H), 7.12 (m, 3H), 7.21
(s, br, 2H), 7.57 (m, 1H), 7.79 (m, 2H), 7.88 (s, br, 1H).
[3089] Mass Spectrum (ESI) m/z=654.0 (M+1).
Example 279
2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-cyclopropyl-2-
-(propylsulfonamido)ethyl)-3-methyl-2-oxopiperidin-3-yl)acetic
acid
##STR00802##
[3090] Step A:
N--((S)-2-((3S,5R,6S)-3-allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-met-
hyl-2-oxopiperidin-1-yl)-2-cyclopropylethyl)propane-1-sulfonamide
##STR00803##
[3092] Crude product used directly in Step B.
[3093] Mass Spectrum (ESI) m/z=563.2 (M+1).
Step B:
2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-cyclo-
propyl-2-(propylsulfonamido)ethyl)-3-methyl-2-oxopiperidin-3-yl)acetic
acid
[3094] .sup.1H NMR (400 MHz, methanol-d.sub.4) .delta. ppm -0.85
(s, br, 1H), -0.25 (s, br, 1H), 0.22 (s, br, 1H), 0.35 (m, 1H),
1.08 (t, J=4 Hz, 3H), 1.43 (s, 3H), 1.55 (s, br, 1H), 1.84 (m, 2H),
2.10 (dd, J=4, 8 Hz, 1H), 2.30 (s, br, 1H), 2.36 (t, J=12 Hz, 1H),
2.67 (d, J=16 Hz, 1H), 2.98 (d, J=16 Hz, 1H), 3.05 (m, 3H), 3.41
(m, 1H), 3.88 (m, 1H), 4.92 (d, J=8 Hz, 1H), 7.02 (m, 2H), 7.08 (s,
1H), 7.14 (m, 3H), 7.26 (s, br, 2H).
[3095] Mass Spectrum (ESI) m/z=581.2 (M+1).
Example 280
2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-cyclopropyl-2-
-(N-phenylmethylsulfonamido)ethyl)-3-methyl-2-oxopiperidin-3-yl)acetic
acid
##STR00804##
[3096] Step A:
N--((S)-2-((3S,5R,6S)-3-allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-met-
hyl-2-oxopiperidin-1-yl)-2-cyclopropylethyl)-N-phenylmethanesulfonamide
##STR00805##
[3098] Mass Spectrum (ESI) m/z=611.2 (M+1).
Step B:
2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-cyclo-
propyl-2-(N-phenylmethylsulfonamido)ethyl)-3-methyl-2-oxopiperidin-3-yl)ac-
etic acid
[3099] .sup.1H NMR (400 MHz, methanol-d.sub.4) .delta. ppm -1.26
(s, br, 1H), -0.51 (s, br, 1H), 0.00 (s, br, 1H), 0.20 (s, br, 1H),
1.03 (s, 3H), 1.54 (s, br, 1H), 1.80-2.04 (m, 3H), 2.47 (d, J=16
Hz, 1H), 2.73 (s, 3H), 2.78 (d, J=16 Hz, 1H), 3.18 (m, 1H), 3.75
(s, br, 1H), 4.42 (s, J=12 Hz, 1H), 6.81 (m, 2H), 6.91 (s, 1H),
7.04 (m, 4H), 7.24 (m, 2H), 7.35 (m, 2H), 7.43 (m, 2H).
[3100] Mass Spectrum (ESI) m/z=629.0 (M+1).
Example 281
2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((S)-2-(N-(3-cyanoph-
enyl)methylsulfonamido)-1-cyclopropylethyl)-3-methyl-2-oxopiperidin-3-yl)a-
cetic acid
##STR00806##
[3101] Step A:
N--((S)-2-((3S,5R,6S)-3-allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-met-
hyl-2-oxopiperidin-1-yl)-2-cyclopropylethyl)-N-(3-cyanophenyl)methanesulfo-
namide
##STR00807##
[3103] .sup.1H NMR (400 MHz, chloroform-d.sub.1) .delta. ppm -1.17
(s, br, 1H), -0.59 (s, br, 1H), 0.00 (s, br, 1H), 0.12 (s, br, 1H),
0.74 (s, 3H), 1.36 (m, 1H), 1.44-1.60 (m, 2H), 1.68 (t, J=12 Hz,
1H), 2.36 (d, J=8 Hz, 2H), 2.60 (s, 3H), 2.95 (m, 1H), 4.33 (s, br,
1H), 4.70 (s, br, 1H), 4.92 (s, 1H), 4.95 (d, J=4 Hz, 1H), 5.58 (m,
1H), 6.62 (s, br, 2H), 6.69 (s, br, 2H), 6.95 (m, 4H), 7.33-7.40
(m, 2H), 7.50 (s, 1H), 7.54 (s, 1H).
[3104] Mass Spectrum (ESI) m/z=636.2 (M+1).
Step B:
2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((S)-2-(N-(3-
-cyanophenyl)methylsulfonamido)-1-cyclopropylethyl)-3-methyl-2-oxopiperidi-
n-3-yl)acetic acid
[3105] .sup.1H NMR (400 MHz, methanol-d.sub.4) .delta. ppm -1.21
(s, br, 1H), -0.55 (s, br, 1H), 0.00 (s, br, 1H), 0.18 (s, br, 1H),
0.95 (s, 3H), 1.45 (s, br, 1H), 1.89 (d, J=8 Hz, 2H), 1.99 (s, br,
1H), 2.42 (d, J=12 Hz, 1H), 2.72 (s, 3H), 2.75 (d, J=12 Hz, 1H),
3.19 (m, 1H), 3.73 (s, br, 1H), 4.37 (s, br, 1H), 6.80 (s, 3H),
6.96-7.05 (m, 5H), 7.45-7.49 (m, 1H), 7.52 (d, J=8 Hz, 1H), 7.70
(s, br, 1H), 7.77 (s, br, 1H).
[3106] Mass Spectrum (ESI) m/z=654.1 (M+1).
Example 282
2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-cyclopropyl-2-
-(N-(pyridin-3-yl)methylsulfonamido)ethyl)-3-methyl-2-oxopiperidin-3-yl)ac-
etic acid
##STR00808##
[3107] Step A:
N--((S)-2-((3S,5R,6S)-3-allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-met-
hyl-2-oxopiperidin-1-yl)-2-cyclopropylethyl)-N-(pyridin-3-yl)methanesulfon-
amide
##STR00809##
[3109] .sup.1H NMR (400 MHz, methanol-d.sub.4) .delta. ppm -1.18
(s, br, 1H), -0.57 (s, br, 1H), 0.00 (s, br, 1H), 0.17 (s, br, 1H),
0.78 (s, 3H), 1.45 (s, br, 1H), 1.60 (m, 1H), 1.86 (m, 1H), 2.00
(s, br, 1H), 2.38 (m, 1H), 2.47 (m, 1H), 2.74 (s, 3H), 3.14 (m,
2H), 3.76 (s, br, 1H), 4.41 (s, br, 1H), 4.95-5.00 (m, 2H), 5.67
(m, 1H), 6.78-6.82 (m, 3H), 6.97-7.04 (m, 5H), 7.36 (m, 1H), 7.84
(s, br, 1H), 8.31 (m, 11H), 8.60 (s, br, 1H).
[3110] Mass Spectrum (ESI) m/z=612.2 (M+1).
Step B:
2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-cyclo-
propyl-2-(N-(pyridin-3-yl)methylsulfonamido)ethyl)-3-methyl-2-oxopiperidin-
-3-yl)acetic acid
[3111] .sup.1H NMR (400 MHz, methanol-d.sub.4) .delta. ppm -1.19
(s, br, 1H), -0.55 (s, br, 1H), 0.00 (s, br, 1H), 0.16 (s, br, 1H),
0.95 (m, 4H), 1.34 (s, br, 1H), 1.90 (m, 2H), 2.42 (d, J=12 Hz,
1H), 2.72 (s, J=12 Hz, 1H), 2.75 (s, 3H), 3.20 (s, br, 1H), 3.38
(s, br, 1H), 4.43 (s, br, 2H), 6.83 (m, 3H), 6.98 (m, 5H), 7.52 (s,
br, 1H), 8.04 (s, br, 1H), 8.39 (s 1H), 0.68 (s, 1H).
[3112] Mass Spectrum (ESI) m/z=630.1 (M+1).
Example 283
2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-cyclopropyl-2-
-(N-(thiophen-2-ylmethyl)methylsulfonamido)ethyl)-3-methyl-2-oxopiperidin--
3-yl)acetic acid
##STR00810##
[3113] Step A:
N--((S)-2-((3S,5R,6S)-3-allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-met-
hyl-2-oxopiperidin-1-yl)-2-cyclopropylethyl)-N-(thiophen-2-ylmethyl)methan-
esulfonamide
##STR00811##
[3115] .sup.1H NMR (400 MHz, methanol-d.sub.4) .delta. ppm
(representative signals) 5.30-5.35 (m, 1H), 5.40 (s, 1H), 6.06 (m,
1H). Mass Spectrum (ESI) m/z=631.2 (M+1).
Step B:
2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-cyclo-
propyl-2-(N-(thiophen-2-ylmethyl)methylsulfonamido)ethyl)-3-methyl-2-oxopi-
peridin-3-yl)acetic acid
[3116] .sup.1H NMR (400 MHz, methanol-d.sub.4) .delta. ppm -1.12
(s, br, 1H), -0.59 (s, br, 1H), 0.00 (s, br, 1H), 0.14 (s, br, 1H),
1.21 (s, 3H), 1.49 (s, br, 1H), 1.80 (d, J=12 Hz, 1H), 1.94 (s, br,
1H), 2.19 (t, J=12 Hz, 1H), 2.47 (d, J=12 Hz, 1H), 2.58 (s, 3H),
2.73 (d, J=12 Hz, 1H), 3.01 (s, br, 1H), 3.14 (m, 1H), 2.47 (s, br,
1H), 4.53-4.47 (m, 3H), 6.76 (m, 3H), 6.85 (s, 2H), 6.95-7.02 (m,
5H), 7.11 (d, J=4 Hz, 1H).
[3117] Mass Spectrum (ESI) m/z=649.0 (M+1).
Example 284
2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-cyclopropyl-2-
-(N-(3-methoxybenzyl)methylsulfonamido)ethyl)-3-methyl-2-oxopiperidin-3-yl-
)acetic acid
##STR00812##
[3118] Step A:
N--((S)-2-((3S,5R,6S)-3-allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-met-
hyl-2-oxopiperidin-1-yl)-2-cyclopropylethyl)-N-(3-methoxybenzyl)methanesul-
fonamide
##STR00813##
[3120] .sup.1H NMR (400 MHz, methanol-d.sub.4) .delta. ppm -1.07
(s, br, 1H), -0.43 (s, br, 1H), 0.13 (s, br, 1H), 0.28 (s, br, 1H),
1.25 (s, 3H), 1.68 (s, br, 2H), 1.90 (s, br, 1H), 2.37 (s, br, 1H),
2.62 (m, 2H), 2.83 (s, 3H), 3.19 (m, 2H), 3.78 (s, 3H), 4.21 (s,
2H), 4.50 (s, br, 2H), 5.14-5.22 (m, 2H), 5.87 (m, 1H), 6.82-6.93
(m, 3H), 6.94 (m, 4H), 7.17-7.27 (m, 5H).
[3121] Mass Spectrum (ESI) m/z=655.2 (M+1).
Step B:
2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-cyclo-
propyl-2-(N-(3-methoxybenzyl)methylsulfonamido)ethyl)-3-methyl-2-oxopiperi-
din-3-yl)acetic acid
[3122] .sup.1H NMR (400 MHz, methanol-d.sub.4) .delta. ppm -1.23
(s, br, 1H), -0.55 (s, br, 1H), 0.00 (s, br, 1H), 0.16 (s, br, 1H),
1.28 (s, 3H), 1.81 (m, 2H), 2.31 (m, 1H), 2.54 (d, J=12 Hz, 1H),
2.77 (m, 4H), 3.10 (s, br, 1H), 3.16 (m, 1H), 3.59 (s, 5H), 3.98
(s, br, 1H), 4.45 (s, br, 2H), 6.73-6.78 (m, 3H), 6.85 (m, 2H),
6.94 (s, 1H), 7.06 (m, 5H).
[3123] Mass Spectrum (ESI) m/z=673.0 (M+1).
Example 285
2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-cyclopropyl-2-
-(phenylmethylsulfonamido)ethyl)-3-methyl-2-oxopiperidin-3-yl)acetic
acid
##STR00814##
[3124] Step A:
N--((S)-2-((3S,5R,6S)-3-allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-met-
hyl-2-oxopiperidin-1-yl)-2-cyclopropylethyl)-1-phenylmethanesulfonamide
##STR00815##
[3126] .sup.1H NMR (400 MHz, chloroform-d.sub.1) .delta. ppm -0.36
(s, br, 1H), 0.00 (s, br, 1H), 0.48 (s, br, 2H), 1.28 (s, br, 1H),
1.32 (s, 3H), 2.00 (m, 1H), 2.16 (m, 2H), 2.72 (m, 2H), 2.89 (s,
br, 2H), 3.23 (m, 1H), 3.26 (s, 1H), 4.84 (d, J=12 Hz, 1H), 5.11
(s, br, 1H), 5.26 (s, 1H), 5.29 (d, J=4 Hz, 1H), 5.93 (m, 1H), 6.89
(d, J=8 Hz, 1H), 7.05 (s, 1H), 7.10 (s, br, 1H), 7.22 (m, 2H), 7.29
(d, J=4 Hz, 2H), 7.48 (m, 5H).
[3127] Mass Spectrum (ESI) m/z=611.2 (M+1).
Step B:
2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-cyclo-
propyl-2-(phenylmethylsulfonamido)ethyl)-3-methyl-2-oxopiperidin-3-yl)acet-
ic acid
[3128] .sup.1H NMR (400 MHz, chloroform-d.sub.1) .delta. ppm -0.92
(s, br, 1H), -0.35 (s, br, 1H), 0.15 (s, br, 1H), 0.29 (m, 1H),
1.42 (s, 3H), 1.48 (s, 1H), 2.05 (dd, J=4, 12 Hz, 1H), 2.20 (s,
1H), 2.33 (t, J=16 Hz, 1H), 2.65 (d, J=12 Hz, 1H), 2.84 (dd, J=4,
12 Hz, 1H), 2.96 (d, J=12 Hz, 1H), 3.38 (m, 1H), 3.72 (m, 1H), 4.37
(s, 2H), 4.97 (m, 1H), 7.01 (d, J=4 Hz, 2H), 7.06 (s, 1H), 7.13 (m,
3H), 7.24 (s, br, 2H), 7.38-7.46 (m, 5H).
[3129] Mass Spectrum (ESI) m/z=629.2 (M+1).
Example 286
2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-cyclopropyl-2-
-(pyridin-2-ylmethylsulfonamido)ethyl)-3-methyl-2-oxopiperidin-3-yl)acetic
acid
##STR00816##
[3130] Step A:
N--((S)-2-((3S,5R,6S)-3-allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-met-
hyl-2-oxopiperidin-1-yl)-2-cyclopropylethyl)-1-(pyridin-2-yl)methanesulfon-
amide
##STR00817##
[3132] .sup.1H NMR (400 MHz, methanol-d.sub.4) .delta. ppm -1.08
(s, br, 1H), -0.49 (s, br, 1H), 0.02 (s, br, 1H), 0.12 (s, br, 1H),
1.09 (s, 3H), 1.36 (s, br, 1H), 1.63 (dd, J=4, 12 Hz, 1H), 1.93 (s,
br, 1H), 2.08 (t, J=12 Hz, 1H), 2.43 (m, 1H), 2.53 (m, 1H), 2.83
(m, 1H), 3.66 (m, 1H), 4.36 (s, 2H), 4.39 (s, br, 1H), 4.64 (m,
1H), 4.98-5.07 (m, 2H), 5.72 (m, 1H), 6.79 (m, 2H), 6.87 (s, 1H),
6.94 (m, 3H), 7.10 (s, br, 2H), 7.24 (m, 1H), 7.42 (d, J=8 Hz, 1H),
7.70 (m, 1H), 8.40 (m, 1H).
[3133] Mass Spectrum (ESI) m/z=612.2 (M+1).
Step B:
2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-cyclo-
propyl-2-(pyridin-2-ylmethylsulfonamido)ethyl)-3-methyl-2-oxopiperidin-3-y-
l)acetic acid
[3134] .sup.1H NMR (400 MHz, methanol-d.sub.4) .delta. ppm -1.07
(s, br, 1H), -0.47 (s, br, 1H), 0.00 (s, br, 1H), 0.16 (s, br, 1H),
1.20 (s, 3H), 1.35 (s, br, 1H), 1.87 (dd, J=4, 8 Hz, 1H), 2.10 (m,
2H), 2.45 (d, J=12 Hz, 1H), 2.75 (d, J=12 Hz, 1H), 2.84 (m, 1H),
3.59 (m, 1H), 4.43 (s, 2H), 4.61 (m, 1H), 6.76 (m, 2H), 6.84 (s,
1H), 6.91 (m, 3H), 7.05 (s, br, 2H), 7.45 (m, 1H), 7.57 (d, J=8 Hz,
1H), 7.92 (t, J=8 Hz, 1H), 8.47 (m, 1H).
[3135] Mass Spectrum (ESI) m/z=630.1 (M+1).
Example 287
2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-cyclopropyl-2-
-(pyridin-3-ylmethylsulfonamido)ethyl)-3-methyl-2-oxopiperidin-3-yl)acetic
acid
##STR00818##
[3136] Step A:
N--((S)-2-((3S,5R,6S)-3-allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-met-
hyl-2-oxopiperidin-1-yl)-2-cyclopropylethyl)-1-(pyridin-3-yl)methanesulfon-
amide
##STR00819##
[3138] .sup.1H NMR (400 MHz, methanol-d.sub.4) .delta. ppm -1.06
(s, br, 1H), -0.48 (s, br, 1H), 0.02 (s, br, 1H), 0.15 (s, br, 1H),
1.08 (s, 3H), 1.37 (s, br, 1H), 1.61 (dd, J=4, 8 Hz, 1H), 1.99 (s,
br, 1H), 2.08 (t, J=16 Hz, 1H), 2.43 (m, 1H), 2.50 (m, 1H), 2.78
(m, 1H), 3.14 (m, 1H), 3.69 (s, br, 1H), 4.26 (s, 2H), 4.63 (m,
1H), 4.97-5.05 (m, 2H), 5.71 (m, 1H), 6.78 (m, 2H), 6.86 (s, 1H),
6.93 (m, 3H), 7.10 (s, br, 2H), 7.28 (m, 1H), 7.75 (m, 1H), 8.36
(m, 1H), 8.41 (s, 1H).
[3139] Mass Spectrum (ESI) m/z=612.2 (M+1).
Step B:
2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-cyclo-
propyl-2-(pyridin-3-ylmethylsulfonamido)ethyl)-3-methyl-2-oxopiperidin-3-y-
l)acetic acid
[3140] .sup.1H NMR (400 MHz, methanol-d.sub.4) .delta. ppm -0.59
(s, br, 1H), 0.00 (s, br, 1H), 0.47 (s, br, 1H), 0.61 (s, br, 1H),
1.65 (s, 3H), 1.81 (s, br, 1H), 2.33 (m, 1H), 2.55 (m, 2H), 2.91
(d, J=12 Hz, 1H), 3.21 (d, J=12 Hz, 1H), 3.32 (m, 1H), 4.13 (s, br,
1H), 4.86 (s, 2H), 5.07 (m, 1H), 7.21 (m, 2H), 7.30 (s, 1H), 7.36
(m, 3H), 7.49 (s, 2H), 8.15 (m, 1H), 8.69 (m, 1H), 9.02 (m, 1H),
9.10 (s, 1H).
[3141] Mass Spectrum (ESI) m/z=630.1 (M+1).
Example 288
2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-cyclopropyl-2-
-(N-(pyridin-2-yl)methylsulfonamido)ethyl)-3-methyl-2-oxopiperidin-3-yl)ac-
etic acid
##STR00820##
[3142] Step A:
N--((S)-2-((3S,5R,6S)-3-allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-met-
hyl-2-oxopiperidin-1-yl)-2-cyclopropylethyl)-N-(pyridin-2-yl)methanesulfon-
amide
##STR00821##
[3144] .sup.1H NMR (400 MHz, methanol-d.sub.4) .delta. ppm -0.75
(s, br, 1H), 0.00 (s, br, 1H), 0.45 (s, br, 1H), 0.60 (s, br, 1H),
1.52 (s, 3H), 1.94-2.03 (m, 3H), 2.83-2.95 (m, 2H), 3.08 (s, 3H),
3.12 (s, br, 1H), 3.48 (m, 1H), 3.87 (s, br, 1H), 4.78 (s, br, 1H),
4.94 (s, br, 1H), 5.39-5.50 (m, 2H), 6.11 (m, 1H), 6.83 (s, br,
1H), 6.94 (s, br, 1H), 7.14 (m, 1H), 7.32 (m, 3H), 7.39 (s, br,
1H), 7.50 (s, br, 2H), 7.85 (m, 1H), 7.99 (m, 1H), 8.14 (s, br,
1H).
[3145] Mass Spectrum (ESI) m/z=612.2 (M+1).
Step B:
2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-cyclo-
propyl-2-(N-(pyridin-2-yl)methylsulfonamido)ethyl)-3-methyl-2-oxopiperidin-
-3-yl)acetic acid
[3146] .sup.1H NMR (400 MHz, methanol-d4) .delta. ppm -0.75 (s, br,
1H), 0.00 (s, br, 1H), 0.47 (s, br, 1H), 0.60 (s, br, 1H), 1.68 (s,
3H), 2.02 (s, br, 2H), 2.30 (m, 1H), 2.94 (d, J=12 Hz, 1H), 3.11
(s, 3H), 3.19 (d, J=12 Hz, 1H), 3.19 (s, br, 1H), 3.62 (m, 1H),
3.99 (s, br, 1H), 4.79 (s, br, 1H), 4.93 (s, br, 1H), 6.92 (s, br,
2H), 7.00 (s, br, 1H), 7.15 (s, br, 1H), 7.35 (m, 2H), 7.51 (s, br,
3H), 7.87 (s, br, 1H), 8.03 (d, J=4 Hz, 1H), 8.15 (s, br, 1H).
[3147] Mass Spectrum (ESI) m/z=630.1 (M+1).
Example 289
2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-cyclopropyl-2-
-(methylsulfonamido)ethyl)-3-methyl-2-oxopiperidin-3-yl)acetic
acid
##STR00822##
[3148] Step A:
N--((S)-2-((3S,5R,6S)-3-allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-met-
hyl-2-oxopiperidin-1-yl)-2-cyclopropylethyl)methanesulfonamide
##STR00823##
[3150] .sup.1H NMR (400 MHz, methanol-d.sub.4) .delta. ppm -0.87
(s, br, 1H), -0.24 (m, 1H), 0.22 (m, 1H), 0.38 (m, 1H), 0.90 (m,
1H), 1.28 (s, 3H), 1.58 (m, 2H), 1.84 (dd, J=4, 12 Hz, 1H), 2.13
(m, 1H), 2.27 (t, J=16 Hz, 1H), 2.63 (dd, J=8, 16 Hz, 1H), 2.70
(dd, J=8, 16 Hz, 1H), 2.97 (s, 3H), 3.13 (m, 1H), 3.90 (m, 1H),
2.42 (s, br, 1H), 5.17-5.27 (m, 2H), 5.92 (m, 1H), 6.98 (m, 2H),
7.06 (s, 1H), 7.14 (m, 3H), 7.27 (m, 2H).
[3151] Mass Spectrum (ESI) m/z=535.2 (M+1).
Step B:
2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-cyclo-
propyl-2-(methylsulfonamido)ethyl)-3-methyl-2-oxopiperidin-3-yl)acetic
acid
[3152] .sup.1H NMR (400 MHz, methanol-d.sub.4) .delta. ppm -1.07
(s, br, 1H), -0.45 (s, br, 1H), 0.01 (s, br, 1H), 0.13 (m, br, 1H),
1.21 (s, 3H), 1.33 (s, br, 1H), 1.89 (dd, J=4, 12 Hz, 1H), 2.11 (t,
J=12 Hz, 1H), 2.15 (s, br, 1H), 2.45 (d, J=16 Hz, 1H), 2.75 (s,
3H), 2.76 (d, J=16 Hz, 1H), 2.89 (m, 1H), 3.18 (m, 1H), 3.62 (m,
1H), 4.67 (d, 1H), 6.79 (m, 2H), 6.85 (s, 1H), 6.93 (m, 3H), 7.04
(s, br, 2H).
[3153] Mass Spectrum (ESI) m/z=553.2 (M+1).
Example 290
2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-cyclopropyl-2-
-(N-ethylmethylsulfonamido)ethyl)-3-methyl-2-oxopiperidin-3-yl)acetic
acid
##STR00824##
[3154] Step A:
N--((S)-2-((3S,5R,6S)-3-allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-met-
hyl-2-oxopiperidin-1-yl)-2-cyclopropylethyl)-N-ethylmethanesulfonamide
##STR00825##
[3156] To a solution of
N--((S)-2-((3S,5R,6S)-3-allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-met-
hyl-2-oxopiperidin-1-yl)-2-cyclopropylethyl)methanesulfonamide
(Example 289, Step A, 86 mg, 0.161 mmol) in DMF (1.5 ml) was added
sodium hydride (16.06 mg, 0.401 mmol) at rt and the reaction was
stirred at rt for 30 minutes. To this reaction was added iodoethane
(0.058 mL, 0.723 mmol) and the reaction was stirred at rt for 2
hours. The reaction was diluted with EtOAc, washed with water and
sat. NaCl, dried with Na.sub.2SO.sub.4 and then concentrated. The
crude was used on next reaction.
[3157] Mass Spectrum (ESI) m/z=563.2 (M+1).
Step B:
2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-cyclo-
propyl-2-(N-ethylmethylsulfonamido)ethyl)-3-methyl-2-oxopiperidin-3-yl)ace-
tic acid
[3158] The title compound was prepared using similar procedures as
described for Example 272, Step B.
[3159] .sup.1H NMR (400 MHz, methanol-d.sub.4) .delta. ppm -0.67
(s, br, 1H), -0.27 (s, br, 1H), 0.30 (s, br, 1H), 0.40 (s, br, 1H),
1.18 (t, J=8 Hz, 3H), 1.41 (s, 3H), 1.71 (s, br, 1H), 2.07 (dd,
J=4, 12 Hz, 1H), 2.24 (s, br, 1H), 2.36 (t, J=12 Hz, 1H), 2.68 (d,
J=16 Hz, 1H), 2.92 (s, 3H), 2.96 (d, J=16 Hz, 1H), 3.25 (s, br,
1H), 3.27 (m, 1H), 3.37 (m, 2H), 4.28 (s, br, 1H), 4.81 (s, br,
1H), 6.98 (m, 2H), 7.04 (s, 1H), 7.14 (m, 3H), 7.27 (s, br,
2H).
[3160] Mass Spectrum (ESI) m/z=581.2 (M+1).
Example 291
2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-cyclopropyl-2-
-(N-isopropylmethylsulfonamido)ethyl)-3-methyl-2-oxopiperidin-3-yl)acetic
acid
##STR00826##
[3161] Step A:
N--((S)-2-((3S,5R,6S)-3-allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-met-
hyl-2-oxopiperidin-1-yl)-2-cyclopropylethyl)-N-isopropylmethanesulfonamide
##STR00827##
[3163] This compound was prepared using similar procedures as
described for Example 290, Step A.
[3164] Mass Spectrum (ESI) m/z=577.2 (M+1).
Step B:
2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-cyclo-
propyl-2-(N-isopropylmethylsulfonamido)ethyl)-3-methyl-2-oxopiperidin-3-yl-
)acetic acid
[3165] This compound was prepared using similar procedures as
described for Example 272 Step B.
[3166] .sup.1H NMR (400 MHz, methanol-d.sub.4) .delta. ppm -0.43
(s, br, 1H), 0.00 (s, br, 1H), 0.51 (s, br, 1H), 0.62 (s, br, 1H),
1.36 (s, br, 3H), 1.45 (s, br, 3H), 1.62 (s, br, 3H), 1.97 (s, br,
1H), 2.24 (d, br, 1H), 2.54 (d, br, 2H), 2.90 (d, J=12 Hz, 1H),
3.12 (s, br, 3H), 3.16 (d, J=12 Hz, 1H), 3.42 (s, br, 1H), 3.59 (m,
1H), 4.17 (s, br, 1H), 4.42 (s, br, 1H), 7.19 (m, 2H), 7.24 (s,
1H), 7.38 (m, 3H), 7.47 (s, br, 2H).
[3167] Mass Spectrum (ESI) m/z=595.2 (M+1).
[3168] Examples 292-294 were prepared using similar procedures as
described for Example 272 starting with
(3S,5R,6S)-3-allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-cyclopr-
opyl-2-hydroxyethyl)-3-ethylpiperidin-2-one (Example 253, Step
C).
TABLE-US-00013 Example Reagent Used Source or CAS# 292
propane-2-sulfonamide [81363-76-0] 293 cyclobutanesulfonamide
Example 271G 294 cyclopentanesulfonamide [73945-39-8]
Example 292
2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-cyclopropyl-2-
-(1-methylethylsulfonamido)ethyl)-3-ethyl-2-oxopiperidin-3-yl)acetic
acid
##STR00828##
[3169] Step A:
N--((S)-2-((3S,5R,6S)-3-allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-eth-
yl-2-oxopiperidin-1-yl)-2-cyclopropylethyl)propane-2-sulfonamide
##STR00829##
[3171] .sup.1H NMR (400 MHz, methanol-d.sub.4) .delta. ppm -0.32
(s, br, 1H), 0.01 (s, br, 1H), 0.36 (d, br, 2H), 0.71 (t, J=8 Hz,
3H), 0.78 (m, 1H), 1.17 (m, 6H), 1.32 (m, 1H), 1.58 (dd, J=4, 12
Hz, 1H), 1.70-1.79 (m, 1H), 2.03 (t, J=12 Hz, 1H), 2.37 (dd, J=4,
12 Hz, 1H), 2.47 (dd, J=4, 12 Hz, 1H), 2.86 (s, br, 1H), 2.93 (m,
1H), 3.02 (m, 2H), 4.59 (d, J=12 Hz, 1H), 4.98 (s, 1H), 5.00 (d,
J=8 Hz, 1H), 5.27 (s, 1H), 5.72 (m, 1H), 6.56 (d, J=8 Hz, 2H), 6.77
(s, 1H), 6.89-6.97 (m, 3H), 6.98 (s, br, 2H).
[3172] Mass Spectrum (ESI) m/z=577.2 (M+1).
Step B:
2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-cyclo-
propyl-2-(1-methylethylsulfonamido)ethyl)-3-ethyl-2-oxopiperidin-3-yl)acet-
ic acid
[3173] .sup.1H NMR (400 MHz, chloroform-d.sub.1) .delta. ppm -0.47
(s, br, 1H), 0.00 (s, br, 1H), 0.41 (s, br, 1H), 0.48 (s, br, 1H),
0.97 (t, J=8 Hz, 3H), 1.32 (m, 7H), 1.80 (m, 1H), 1.94 (m, 2H),
2.38 (t, J=12 Hz, 3H), 2.64 (d, J=16 Hz, 1H), 2.70 (s, br, 1H),
2.91 (d, J=16 Hz, 1H), 3.01 (s, br, 1H), 3.19 (m, 1H), 3.40 (m,
1H), 3.53 (s, br, 1H), 4.94 (s, br, 1H), 7.00 (m, 2H), 7.06 (s,
1H), 7.17 (m, 3H), 7.25 (s, br, 2H). Mass Spectrum (ESI) m/z=595.2
(M+1).
Example 293
2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((S)-2-(cyclobutanes-
ulfonamido)-1-cyclopropylethyl)-3-ethyl-2-oxopiperidin-3-yl)acetic
acid
##STR00830##
[3174] Step A:
N--((S)-2-((3S,5R,6S)-3-allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-eth-
yl-2-oxopiperidin-1-yl)-2-cyclopropylethyl)cyclobutanesulfonamide
##STR00831##
[3176] Mass Spectrum (ESI) m/z=589.2 (M+1).
Step B:
2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((S)-2-(cycl-
obutanesulfonamido)-1-cyclopropylethyl)-3-ethyl-2-oxopiperidin-3-yl)acetic
acid
[3177] .sup.1H NMR (400 MHz, methanol-d.sub.4) .delta. ppm -0.48
(s, br, 1H), -0.01 (s, br, 1H), 0.40 (s, br, 1H), 0.48 (s, br, 1H),
0.97 (t, J=8 Hz, 3H), 1.33 (s, br, 1H), 1.81 (m, 1H), 1.94-2.05 (m,
4H), 2.34 (m, 2H), 2.37 (m, 3H), 2.64 (d, J=12 Hz, 1H), 2.72 (s,
br, 1H), 2.91 (d, J=12 Hz, 1H), 3.00 (s, br, 1H), 3.39 (m, 2H),
3.90 (m, 1H), 4.92 (s, br, 1H), 6.99 (m, 2H), 7.05 (s, br, 1H),
7.15 (m, 3H), 7.25 (s, br, 2H). Mass Spectrum (ESI) m/z=607.0
(M+1).
Example 294
2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((S)-2-(cyclopentane-
sulfonamido)-1-cyclopropylethyl)-3-ethyl-2-oxopiperidin-3-yl)acetic
acid
##STR00832##
[3178] Step A:
N--((S)-2-((3S,5R,6S)-3-allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-eth-
yl-2-oxopiperidin-1-yl)-2-cyclopropylethyl)cyclopentanesulfonamide
##STR00833##
[3180] .sup.1H NMR (400 MHz, methanol-d.sub.4) .delta. ppm -0.32
(s, br, 1H), 0.00 (s, br, 1H), 0.36 (s, br, 1H), 0.38 (s, br, 1H),
0.71 (t, J=8 Hz, 3H), 0.78 (m, 1H), 1.33 (m, 1H), 1.44 (m, 2H),
1.58 (m, 3H), 1.80 (m, 6H), 2.03 (t, J=12 Hz, 1H), 2.36 (dd, J=8
Hz, 16, 1H), 2.46 (dd, J=8, 16 Hz, 1H), 2.85 (s, br, 2H), 3.01 (m,
2H), 3.24 (m, 1H), 4.59 (d, J=12 Hz, 1H), 4.97 (s, 1H), 5.00 (d,
J=4 Hz, 1H), 5.32 (s, br, 1H), 5.72 (m, 1H), 6.56 (s, 1H), 6.58 (s,
1H), 6.77 (s, 1H), 6.91 (m, 3H), 6.98 (s, br, 2H). Mass Spectrum
(ESI) m/z=603.3 (M+1).
Step B:
2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((S)-2-(cycl-
opentanesulfonamido)-1-cyclopropylethyl)-3-ethyl-2-oxopiperidin-3-yl)aceti-
c acid
[3181] .sup.1H NMR (400 MHz, chloroform-d.sub.1) .delta. ppm -0.47
(s, br, 1H), 0.01 (s, br, 1H), 0.41 (s, br, 1H), 0.48 (s, br, 1H),
0.96 (t, J=12 Hz, 3H), 1.42 (s, br, 1H), 1.65 (m, 2H), 1.71 (m,
3H), 1.96 (m, 6H), 2.37 (t, J=12 Hz, 1H), 2.64 (d, J=16 Hz, 1H),
2.71 (s, br, 1H), 2.91 (d, J=16 Hz, 1H), 2.97 (s, br, 1H), 3.40 (m,
1H), 3.54 (m, 2H), 4.93 (s, br, 1H), 7.00 (s, 1H), 7.01 (s, 1H),
7.05 (s, 1H), 7.14 (m, 3H), 7.25 (s, br, 2H). Mass Spectrum (ESI)
m/z=621.1 (M+1).
Example 295
2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-1-((S)-3-meth-
yl-1-(N-methylcyclopropanesulfonamido)butan-2-yl)-2-oxopiperidin-3-yl)acet-
ic acid
##STR00834##
[3182] Step A:
N--((S)-2-((3S,5R,6S)-3-allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-met-
hyl-2-oxopiperidin-1-yl)-3-methylbutyl)-N-methylcyclopropanesulfonamide
##STR00835##
[3184] The title compound was prepared from
(3S,5R,6S)-3-allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-hydroxy-
-3-methylbutan-2-yl)-3-methylpiperidin-2-one (Example 261, Step H,
109 mg, 0.237 mmol) and N-methylcyclopropanesulfonamide
(WO2005/108358, 120 mg, 0.888 mmol) using the general procedure
described in Step A of Example 272 and was purified by silica
chromatography eluting with ethyl acetate in hexanes. The product
was obtained as a beige foam (113.5 mg, 83%). LCMS (ESI): m/z=577.2
(M+H).
Step B:
2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-1-((S-
)-3-methyl-1-(N-methylcyclopropanesulfonamido)butan-2-yl)-2-oxopiperidin-3-
-yl)acetic acid
[3185] A mixture of
N--((S)-2-((3S,5R,6S)-3-allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-met-
hyl-2-oxopiperidin-1-yl)-3-methylbutyl)-N-methylcyclopropanesulfonamide
(Example 295, Step A, 112.5 mg, 0.195 mmol), sodium periodate (170
mg, 0.795 mmol), and ruthenium(III) chloride hydrate (6 mg, 0.023
mmol) in acetonitrile (1.0 mL), carbon tetrachloride (1.0 mL), and
water (1.5 mL) was vigorously stirred at ambient temperature
overnight. The reaction mixture was acidified with aqueous citric
acid (10% by weight), diluted in ethyl acetate, and filtered
through a pad of Celite.RTM. (J. T. Baker, Phillipsberg, N.J.,
diatomaceous earth). The filtrate was partitioned between 2 M
aqueous HCl and ethyl acetate. Combined organics were washed with
brine, dried over sodium sulfate, filtered, and concentrated in
vacuo to a residue that was purified by preparative HPLC
(Sunfire.TM. Prep C.sub.18 OBD 10 .mu.m column, 30.times.150 mm,
Waters, Milford, Mass.) eluting with a gradient of 50 to 100%
acetonitrile in water (0.1% trifluoroacetic acid in both solvents).
Chromatography fractions containing the product were stripped of
volatiles, redissolved in minimal volumes of acetonitrile and
water, frozen, and lyophilized to give the product as a white
solid.
[3186] .sup.1H NMR (500 MHz, methanol-d.sub.4) .delta. ppm 0.63 (d,
J=6.60 Hz, 3H), 0.69 (s, 3H), 0.95-1.22 (m, 4H), 1.40 (s, 3H), 2.07
(dd, J=13.7, 3.2 Hz, 1H), 2.23 (dquin, J=9.5, 6.7 Hz, 1H), 2.38 (t,
J=13.7 Hz, 1H), 2.51-2.60 (m, 1H), 2.60-2.71 (m, 2H), 2.87-2.96 (m,
4H), 3.01 (d, J=13.5 Hz, 1H), 3.48 (ddd, J=13.8, 11.0, 3.1 Hz, 1H),
4.13-4.40 (m, 1H), 4.97 (d, J=11.0 Hz, 1H), 6.98-7.06 (m, 2H),
7.07-7.16 (m, 2H), 7.29 (br s, 4H). LCMS (ESI): m/z=595.2
(M+H).
Example 296
2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-(cyclopropane-
sulfonamido)-3-methylbutan-2-yl)-3-methyl-2-oxopiperidin-3-yl)acetic
acid
##STR00836##
[3187] Step A.
N--((S)-2-((3S,5R,6S)-3-allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-met-
hyl-2-oxopiperidin-1-yl)-3-methylbutyl)cyclopropanesulfonamide
##STR00837##
[3189] The title compound was prepared using
cyclopropanesulfonamide (101 mg, 0.834 mmol) according to the
procedure described in Step A of Example 272 and purified by silica
chromatography eluting with a gradient of ethyl acetate in hexanes.
The product was obtained as a solid. LCMS (ESI): m/z=563.2
(M+H).
Step B.
2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-(cycl-
opropanesulfonamido)-3-methylbutan-2-yl)-3-methyl-2-oxopiperidin-3-yl)acet-
ic acid
[3190] The title compound was prepared by the general procedure
described in step B of Example 295. The product was obtained as an
off-white powder.
[3191] .sup.1H NMR (500 MHz, methanol-d.sub.4) .delta. ppm 0.59 (d,
J=6.9 Hz, 3H), 0.63 (d, J=6.4 Hz, 3H), 0.95-1.10 (m, 3H), 1.10-1.18
(m, 1H), 1.42 (s, 3H), 2.09 (dd, J=13.7, 3.2 Hz, 1H), 2.14-2.24 (m,
1H), 2.38 (t, J=13.7 Hz, 1H), 2.52-2.61 (m, 1H), 2.62-2.80 (m, 2H),
3.01 (d, J=13.5 Hz, 1H), 3.21 (dd, J=14.1, 2.1 Hz, 1H), 3.51 (ddd,
J=13.6, 11.2, 3.1 Hz, 1H), 3.83 (br s, 1H), 5.07 (d, J=11.25 Hz,
1H), 7.04 (d, J=7.34 Hz, 1H), 7.07-7.63 (m, 7H). LCMS (ESI):
m/z=581.2 (M+H).
Example 297
2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-(ethylsulfona-
mido)-3-methylbutan-2-yl)-3-methyl-2-oxopiperidin-3-yl)acetic
acid
##STR00838##
[3192] Step A.
N--((S)-2-((3S,5R,6S)-3-allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-met-
hyl-2-oxopiperidin-1-yl)-3-methylbutyl)ethanesulfonamide
##STR00839##
[3194] The title compound was prepared from ethanesulfonamide (76
mg, 0.696 mmol; Allichem) by the general procedure described in
Step A of Example 295, and purified by silica gel chromatography
eluting with a gradient of ethyl acetate in hexanes. The product
was obtained in 89% yield. LCMS (ESI) m/z=551.2 (M+H).
Step B.
2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-(ethy-
lsulfonamido)-3-methylbutan-2-yl)-3-methyl-2-oxopiperidin-3-yl)acetic
acid
[3195] The title compound was prepared using the procedure
described in Step B of example 295 an obtained as a white solid
(56% yield).
[3196] .sup.1H NMR (500 MHz, methanol-d.sub.4) .delta. ppm 0.59 (d,
J=6.9 Hz, 3H), 0.62 (d, J=6.6 Hz, 3H), 1.36 (t, J=7.5 Hz, 3H), 1.42
(s, 3H), 2.09 (d, J=10.5 Hz, 1H), 2.14-2.23 (m, 1H), 2.34-2.47 (m,
1H), 2.64 (s, 0H), 2.70 (br. s., 1H), 3.02 (d, J=13.2 Hz, 1H),
3.06-3.20 (m, 3H), 3.53 (ddd, J=13.8, 11.1, 3.1 Hz, 1H), 3.79 (br.
s., 1H), 5.10 (d, J=11.0 Hz, 1H), 7.03-7.08 (m, 1H), 7.09-7.17 (m,
3H), 7.17-7.87 (m, 4H). LCMS (ESI): m/z=569.2 (M+H).
Example 298
2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-(cyclobutanes-
ulfonamido)butan-2-yl)-3-methyl-2-oxopiperidin-3-yl)acetic acid
##STR00840##
[3197] Step A.
N--((S)-2-((3S,5R,6S)-3-allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-met-
hyl-2-oxopiperidin-1-yl)butyl)cyclobutanesulfonamide
##STR00841##
[3199] The title compound was prepared from
(3S,5R,6S)-3-allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-hydroxy-
butan-2-yl)-3-methylpiperidin-2-one (Example 91, Step B, 250 mg,
0.560 mmol) and cyclobutanesulfonamide (Example 271G, 256 mg, 1.894
mmol) using the general procedure described in Step A of Example
272, albeit with an oil bath heated at 40.degree. C. The crude
product was purified by silica gel chromatography eluting with a
gradient of EtOAc in hexanes. The product was obtained as a white
powder (220 mg, 70%). LCMS (ESI): m/z=563.2 (M+H).
Step B.
2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-(cycl-
obutanesulfonamido)butan-2-yl)-3-methyl-2-oxopiperidin-3-yl)acetic
acid
[3200] The title compound was prepared from
N--((S)-2-((3S,5R,6S)-3-allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-met-
hyl-2-oxopiperidin-1-yl)butyl)cyclobutanesulfonamide (Example 298,
Step A, 50 mg, 0.089 mmol) by the general procedure described in
Step B of Example 295. The crude product was purified by
preparative HPLC chromatography (Sunfire.TM. Prep C.sub.18 OBD 10
.mu.m column, 30.times.150 mm, Waters, Milford, Mass.) eluting with
a 50 to 95% gradient of acetonitrile in water (0.1% trifluoroacetic
acid in both solvents) to afford a white powder.
[3201] .sup.1H NMR (500 MHz, methanol-d.sub.4) .delta. ppm 0.44 (t,
J=7.6 Hz, 3H), 1.42 (s, 3H), 1.50-1.63 (m, 1H), 1.73-1.88 (m, 1H),
1.94-2.14 (m, 3H), 2.20-2.53 (m, 5H), 2.62 (s, 1H), 2.80 (t, J=9.2
Hz, 1H), 2.87-3.01 (m, 2H), 3.32-3.39 (m, 1H), 3.80 (dd, J=13.9,
10.0 Hz, 1H), 3.92 (quin, J=8.25 Hz, 1H), 4.93 (d, J=11.00 Hz, 1H),
7.03 (d, J=7.3 Hz, 1H), 7.08 (s, 1H), 7.11-7.22 (m, 4H), 7.26 (d,
J=7.6 Hz, 2H). LCMS (ESI): m/z=581.2 (M+H).
Example 299
2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-(N-ethylcyclo-
butanesulfonamido)butan-2-yl)-3-methyl-2-oxopiperidin-3-yl)acetic
acid
##STR00842##
[3202] Step A.
N--((S)-2-((3S,5R,6S)-3-allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-met-
hyl-2-oxopiperidin-1-yl)butyl)-N-ethylcyclobutanesulfonamide
##STR00843##
[3204] By the method of Example 290, Step A,
N--((S)-2-((3S,5R,6S)-3-allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-met-
hyl-2-oxopiperidin-1-yl)butyl)cyclobutanesulfonamide (Example 298,
Step A) was treated with ethyl iodide to afford the title compound
as a white foam. LCMS (ESI) m/z=591.2 (M+H).
Step B.
2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-(N-et-
hylcyclobutanesulfonamido)butan-2-yl)-3-methyl-2-oxopiperidin-3-yl)acetic
acid
[3205] The title compound was prepared from
N--((S)-2-((3S,5R,6S)-3-allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-met-
hyl-2-oxopiperidin-1-yl)butyl)-N-ethylcyclobutanesulfonamide
(Example 299, Step A) by the general procedure described in Step B
of Example 295 and obtained as a fluffy white solid.
[3206] .sup.1H NMR (500 MHz, methanol-d.sub.4) .delta. ppm 0.50 (t,
J=7.21 Hz, 3H), 1.05-1.13 (m, 3H), 1.43 (s, 3H), 1.54-1.67 (m, 1H),
1.88 (dquin, J=15.2, 7.5 Hz, 1H), 1.93-2.12 (m, 3H), 2.22-2.36 (m,
2H), 2.37-2.59 (m, 3H), 2.64 (d, J=13.20 Hz, 1H), 2.70-2.99 (m,
3H), 3.17 (dq, J=14.6, 7.2 Hz, 1H), 3.33-3.43 (m, 1H), 3.96 (quin,
J=8.4 Hz, 1H), 4.06-4.33 (m, 1H), 4.83 (m, 1H), 7.02 (d, J=7.1 Hz,
1H), 7.05 (s, 1H), 7.08-7.21 (m, 3H), 7.27 (br. s., 3H). LCMS
(ESI): m/z=609.2 (M+H).
Example 300
2-((3R,5R,6S)-5-(3-Chlorophenyl)-6-(4-chlorophenyl)-3-methyl-2-oxo-1-((S)--
1-(phenylsulfonyl)butan-2-yl)piperidin-3-yl)acetic acid
##STR00844##
[3207] Step A.
(3S,5R,6S)-3-Allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-1-((S)--
1-(phenylthio)butan-2-yl)piperidin-2-one
##STR00845##
[3209] To a solution of
(3S,5R,6S)-3-allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-hydroxy-
butan-2-yl)-3-methylpiperidin-2-one (180 mg, 0.403 mmol; Example
91, Step B) in 2 mL of toluene was added
cyanomethylenetributylphosphorane (324 uL, 1.21 mmol) and
benzenethiol (121 .mu.L 1.21 mmol) at RT. The mixture was heated to
110.degree. C. for 2 h. The reaction was cooled down, quenched
(sat. aq. NH.sub.4Cl solution), extracted (2.times.EtOAc), and
washed with brine. The combined organic layers were dried over
Na.sub.2SO.sub.4, filtered and the filtrate was concentrated under
reduced pressure. Purification of the residue by chromatography on
silica gel (4 g SiO.sub.2, 10, 20, 40% EtOAc/hexane) provided the
title compound.
Step B.
2-((3R,5R,6S)-5-(3-Chlorophenyl)-6-(4-chlorophenyl)-3-methyl-2-oxo-
-1-((S)-1-(phenylsulfonyl)butan-2-yl)piperidin-3-yl)acetic acid
[3210] The title compound was prepared from
(3S,5R,6S)-3-allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-1-((S)--
1-(phenylthio)butan-2-yl)piperidin-2-one (Example 300, Step A) by a
procedure similar to the one described in Example 71, Step F. The
crude product was purified by reverse phase preparatory HPLC
(Gemini.TM. Prep C.sub.18 5 .mu.m column; Phenomenex, Torrance,
Calif.; MeCN in water with 0.1% TFA, gradient elution) to give a
white solid.
[3211] .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. ppm 0.37 (t, J=8
Hz, 3H), 1.46 (m, 1H), 1.58 (s, 3H), 1.94 (dd, J=12, 4 Hz, 1H),
2.08 (m, 1H), 2.50 (t, J=16 Hz, 1H), 2.79 (d, J=16 Hz, 1H), 2.88
(dd, J=16 Hz, 1H), 3.05 (d, J=16 Hz, 1H), 3.15 (m, 1H), 3.41 (m,
1H), 4.24 (dd, J=16, 12 Hz, 1H), 5.04 (d, J=8.0 Hz, 1H), 6.88 (d,
J=8.0 Hz, 1H), 6.99 (s, 1H), 7.14 (m, 4H), 7.27 (m, 2H), 7.61 (m,
2H), 7.71 (m, 1H), 7.93 (d, J=8 Hz, 2H); Mass Spectrum (ESI) 588.1
[M+H].sup.+.
Example 301
2-((3R,5R,6S)-5-(3-Chlorophenyl)-6-(4-chlorophenyl)-3-methyl-1-((S)-1-(met-
hylsulfonyl)butan-2-yl)-2-oxopiperidin-3-yl)acetic acid
##STR00846##
[3212] Step A.
(3S,5R,6S)-3-Allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-1-((S)--
1-(((trimethylsilyl)methyl)thio)butan-2-yl)piperidin-2-one
##STR00847##
[3214] The title compound was prepared from
(3S,5R,6S)-3-allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-hydroxy-
butan-2-yl)-3-methylpiperidin-2-one (Example 91, Step B) by a
procedure similar to the one described in Example 300, Step A,
replacing benzenethiol with the appropriate amount of
(trimethylsilyl)methanethiol.
Step B.
(3S,5R,6S)-3-Allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl--
1-((S)-1-(methylthio)butan-2-yl)piperidin-2-one
##STR00848##
[3216]
(3S,5R,6S)-3-allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-1-
-((S)-1-(((trimethylsilyl)methyl)thio)butan-2-yl)piperidin-2-one
(60 mg, 0.118 mmol, Example 301, Step A) was dissolved in a 1 M
solution of tetrabutylammonium fluoride in tetrahydrofuran (3.5 mL,
3.5 mmol) at room temperature. The resulting solution was stirred
at ambient temperature for 16 h. After that time volatiles were
removed under reduced pressure, and the residue was purified by
chromatography on silica gel (4 g SiO.sub.2, 10, 20, 40%
EtOAc/hexane) to provide the title compound.
Step C.
2-((3R,5R,6S)-5-(3-Chlorophenyl)-6-(4-chlorophenyl)-3-methyl-1-((S-
)-1-(methylsulfonyl)butan-2-yl)-2-oxopiperidin-3-yl)acetic acid
[3217] The title compound was prepared from
(3S,5R,6S)-3-allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-1-((S)--
1-(methylthio)butan-2-yl)piperidin-2-one (Example 301, Step B) to
by a procedure similar to the one described in Example 71, Step
F.
[3218] .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. ppm 0.42 (t, J=8.0
Hz, 3H), 1.45 (m, 1H), 1.48 (s, 3H), 1.90 (d, J=12 Hz, 1H), 2.14
(m, 1H), 2.37 (t, J=16.0 Hz, 1H), 2.76 (d, J=16 Hz, 1H), 2.90 (d,
J=12 Hz, 1H), 2.97 (m, 1H), 2.99 (s, 3H), 3.13 (m, 1H), 3.37 (m,
1H), 4.24 (m, 1H), 4.90 (d, J=8.0 Hz, 1H), 6.84 (d, J=8.0 Hz, 1H),
6.95 (s, 1H), 7.12 (m, 4H), 7.27 (m, 2H); Mass Spectrum (ESI) 526.0
[M+H].sup.+.
[3219] Examples 302 to 311 were also prepared from
(3S,5R,6S)-3-allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-hydroxy-
butan-2-yl)-3-methylpiperidin-2-one (Example 91, Step B) by
procedures similar to the one described in Example 300, replacing
benzenethiol with the appropriate amount of thiol. The requisite
thiols are either commercially available, prepared as described in
the table below or are prepared by the following general procedure
from the corresponding alcohols.
General Thiol Procedure
[3220] Methanesulfonyl chloride (1 eq.) was added dropwise to a 0.5
M solution of the corresponding alcohol and triethylamine (1 eq.)
in dichloromethane. The resulting mixture was stirred rt for 2 h.
The reaction was then partitioned with water, washed with brine,
dried over sodium sulfate, filtered and concentrated. This material
was dissolved in DMF to give a 0.5M solution of the mesylate. To
this sodium hydrosulfide (1.2 eq.) was added. The resulting mixture
was stirred overnight at 45.degree. C. The mixture was then
partitioned with ether/water, washed with brine, dried over sodium
sulfate, filtered the filtrate was concentrated under reduced
pressure. The crude thiol obtained was used in the next step
without further purification.
TABLE-US-00014 ##STR00849## Example R Reagent used 302 ##STR00850##
1-propanethiol 303 ##STR00851## 2-methyl-1- propanethiol 304
##STR00852## cyclopropyl- methanethiol; prepared from bromomethyl-
cyclopropane by the procedure described in U.S. Pat. No. 3,975,429.
305 ##STR00853## cyclobutyl- methanethiol; prepared from
bromomethyl- cyclobutane by a procedure similar to the one
described for the preparation of cyclopropyl- methanethiol in U.S.
Pat. No. 3,975,429. 306 ##STR00854## cyclopentanethiol; prepared
from bromocyclo- pentane by a procedure similar to the one
described for the preparalion of cyclopropyl- methanethiol in U.S.
Pat. No. 3,975,429. 307 ##STR00855## oxetan-3- ylmethanethiol 308
##STR00856## prepared by general procedure above 309 ##STR00857##
prepared by general procedure above 310 ##STR00858## prepared by
general procedure above 311 ##STR00859## butane-2-thiol 312
##STR00860## butane-2-thiol
Example 302
2-((3R,5R,6S)-5-(3-Chlorophenyl)-6-(4-chlorophenyl)-3-methyl-2-oxo-1-((S)--
1-(propylsulfonyl)butan-2-yl)piperidin-3-yl)acetic acid
[3221] .sup.1H NMR (400 MHz, CHLOROFORM-d) .delta. ppm 7.23-7.27
(2H, m), 7.01-7.21 (4H, m), 6.93-7.00 (1H, m), 6.84 (1H, dt, J=7.1,
1.6 Hz), 4.93 (1H, d, J=10.8 Hz), 4.05-4.20 (1H, m), 3.33 (1H, t,
J=10.1 Hz), 3.12 (1H, ddd, J=13.7, 10.9, 2.6 Hz), 2.95-3.04 (3H,
m), 2.71-2.85 (2H, m), 2.38 (1H, t, J=13.8 Hz), 2.14 (1H, ddd,
J=14.3, 9.9, 7.3 Hz), 1.86-1.98 (3H, m), 1.49 (3H, s), 1.39-1.48
(1H, m), 1.13 (3H, t, J=7.5 Hz), 0.41 (3H, t, J=7.5 Hz); Mass
Spectrum (ESI) 554.2 [M+H].sup.+.
Example 303
2-((3R,5R,6S)-5-(3-Chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-(isobutylsulf-
onyl)butan-2-yl)-3-methyl-2-oxopiperidin-3-yl)acetic acid
[3222] .sup.1H NMR (400 MHz, CHLOROFORM-d) .delta. ppm 7.27-7.24
(2H, m), 7.02-7.20 (4H, m), 6.93-7.00 (1H, m), 6.84 (1H, dt, J=7.2,
1.5 Hz), 4.93 (1H, d, J=10.6 Hz), 4.15 (1H, t, J=12.2 Hz), 3.33
(1H, t, J=9.5 Hz), 3.13 (1H, ddd, J=13.6, 10.9, 2.6 Hz), 2.84-3.03
(3H, m), 2.66-2.83 (2H, m), 2.33-2.47 (2H, m), 2.12 (1H, ddd,
J=14.3, 9.9, 7.3 Hz), 1.90 (1H, dd, J=13.7, 2.7 Hz), 1.48 (3H, s),
1.40-1.47 (1H, m), 1.17 (3H, d, J=6.8 Hz), 1.15 (3H, d, J=6.8 Hz)
0.41 (3H, t, J=7.5 Hz); Mass Spectrum (ESI) 568.2 [M+H].sup.+.
Example 304
2-((3R,5R,6S)-5-(3-Chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-((cyclopropyl-
methyl)sulfonyl)butan-2-yl)-3-methyl-2-oxopiperidin-3-yl)acetic
acid
[3223] .sup.1H NMR (400 MHz, CHLOROFORM-d) .delta. ppm 7.23-7.27
(2H, m), 7.00-7.22 (4H, m), 6.94-6.98 (1H, m), 6.85 (1H, dt, J=7.1,
1.5 Hz), 4.95 (1H, d, J=10.8 Hz), 4.17 (1H, t, J=12.1 Hz), 3.35
(1H, t, J=9.7 Hz), 3.13 (1H, ddd, J=13.6, 10.9, 2.7 Hz), 2.83-3.07
(4H, m), 2.77 (1H, d, J=14.9 Hz), 2.39 (1H, t, J=13.8 Hz),
2.07-2.22 (1H, m), 1.91 (1H, dd, J=13.9, 2.7 Hz), 1.48 (3H, s),
1.40-1.47 (1H, m), 1.12-1.25 (1H, m), 0.75-0.85 (2H, m), 0.37-0.48
(5H, m); Mass Spectrum (ESI) 566.2 [M+H].sup.+.
Example 305
2-((3R,5R,6S)-5-(3-Chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-((cyclobutylm-
ethyl)sulfonyl)butan-2-yl)-3-methyl-2-oxopiperidin-3-yl)acetic
acid
[3224] .sup.1H NMR (400 MHz, CHLOROFORM-d) .delta. ppm 7.22-7.27
(2H, m), 6.99-7.20 (4H, m), 6.93-6.98 (1H, m), 6.84 (1H, dt, J=7.2,
1.4 Hz), 4.91 (1H, d, J=10.8 Hz), 4.09 (1H, t, J=12.2 Hz), 3.31
(1H, t, J=10.1 Hz), 3.05-3.18 (3H, m), 2.84-3.02 (2H, m), 2.67-2.82
(2H, m), 2.36 (1H, t, J=13.8 Hz), 2.20-2.31 (2H, m), 2.01-2.18 (2H,
m), 1.82-1.97 (4H, m), 1.47 (3H, s), 1.38-1.46 (1H, m), 0.40 (3H,
t, J=7.5 Hz); Mass Spectrum (ESI) 580.2 [M+H].sup.+.
Example 306
2-((3R,5R,6S)-5-(3-Chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-(cyclopentyls-
ulfonyl)butan-2-yl)-3-methyl-2-oxopiperidin-3-yl)acetic acid
[3225] .sup.1H NMR (400 MHz, CHLOROFORM-d) .delta. ppm 0.40 (t,
J=8.0 Hz, 3H), 1.46 (m, 1H), 1.49 (s, 3H), 1.70 (m, 2H), 1.80-1.95
(m, 3H), 2.09 (m, 5H), 2.40 (t, J=12 Hz, 1H), 2.76 (d, J=16.0 Hz,
2H), 3.00 (d, J=16 Hz, 1H), 3.12 (m, 1H), 3.36 (m, 2H), 4.10 (t,
J=12 Hz, 1H), 4.97 (d, J=8.0 Hz, 1H), 6.85 (d, J=8.0 Hz, 1H), 6.96
(s, 1H), 7.12 (m, 4H), 7.25 (m, 2H); Mass Spectrum (ESI) 580.1
[M+H].sup.+.
Example 307
2-((3R,5R,6S)-5-(3-Chlorophenyl)-6-(4-chlorophenyl)-3-methyl-1-((S)-1-(oxe-
tan-3-ylsulfonyl)butan-2-yl)-2-oxopiperidin-3-yl)acetic acid
[3226] .sup.1H NMR (400 MHz, CD.sub.3OD) .delta. ppm 0.39 (t,
J=7.63 Hz, 3H) 1.34-1.43 (m, 3H) 1.46-1.63 (m, 1H) 2.02-2.10 (m,
2H) 2.29 (t, J=13.69 Hz, 1H) 2.61 (d, J=13.69 Hz, 1H) 2.95 (d,
J=13.69 Hz, 1H) 2.98-3.07 (m, 1H) 3.41 (ddd, J=13.60, 10.96, 2.84
Hz, 1H) 3.94-4.20 (m, 1H) 4.55-4.76 (m, 1H) 4.87-4.93 (m, 4H)
4.94-5.01 (m, 2H) 6.97 (dt, J=6.65, 1.76 Hz, 1H) 7.00-7.07 (m, 1H)
7.07-7.22 (m, 3H) 7.28 (br s, 3H); Mass Spectrum (ESI) m/z=568
(M+1).
Example 308
2-((3R,5R,6S)-5-(3-Chlorophenyl)-6-(4-chlorophenyl)-3-methyl-1-((S)-1-(((3-
-methyloxetan-3-yl)methyl)sulfonyl)butan-2-yl)-2-oxopiperidin-3-yl)acetic
acid
[3227] 1H NMR (500 MHz, CD.sub.3OD) .delta. ppm -1.06 (br s, 1H)
-0.21 (br s, 1H) 0.23 (br s, 1H) 0.37 (br s, 1H) 1.22-1.30 (m, 3H)
1.38-1.45 (m, 3H) 1.70-1.77 (m, 3H) 1.99-2.09 (m, 1H) 2.31 (t,
J=13.69 Hz, 1H) 2.65-2.73 (m, 1H) 2.95-3.03 (m, 1H) 3.39-3.49 (m,
1H) 3.59-3.66 (m, 1H) 3.66-3.73 (m, 1H) 4.07-4.16 (m, 2H) 4.40-4.45
(m, 2H) 4.80 (d, J=6.11 Hz, 2H) 4.91 (d, J=10.76 Hz, 2H) 6.94-7.00
(m, 1H) 7.06 (s, 1H) 7.08-7.22 (m, 3H) 7.32 (br s, 3H); Mass
Spectrum (ESI) m/z=608 (M+1).
Example 309
2-((3R,5R,6S)-5-(3-Chlorophenyl)-6-(4-chlorophenyl)-3-methyl-2-oxo-1-((S)--
1-((tetrahydro-2H-pyran-4-yl)sulfonyl)butan-2-yl)piperidin-3-yl)acetic
acid
[3228] .sup.1H NMR (400 MHz, CD.sub.3OD) .delta. ppm 0.41 (t,
J=7.53 Hz, 3H) 1.26 (t, J=7.14 Hz, 2H) 1.39 (s, 3H) 1.87 (dd,
J=12.52, 4.50 Hz, 2H) 2.04-2.16 (m, 4H) 2.28 (t, J=13.69 Hz, 1H)
2.61 (d, J=13.69 Hz, 1H) 2.96 (d, J=13.69 Hz, 1H) 3.34-3.58 (m, 4H)
3.98-4.26 (m, 4H) 4.98 (d, J=10.96 Hz, 1H) 6.97 (dt, J=6.55, 1.81
Hz, 1H) 7.04 (s, 1H) 7.09-7.22 (m, 3H) 7.30 (br s, 3H); Mass
Spectrum (ESI) m/z=596 (M+1).
Example 310
2-((3R,5R,6S)-5-(3-Chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-((2-hydroxy-2-
-methylpropyl)sulfonyl)butan-2-yl)-3-methyl-2-oxopiperidin-3-yl)acetic
acid
[3229] .sup.1H NMR (400 MHz, CD.sub.3OD) .delta. ppm 0.38 (t,
J=7.43 Hz, 3H) 1.17-1.27 (m, 2H) 1.38 (s, 3H) 1.44 (s, 6H)
1.46-1.56 (m, 1H) 2.01-2.12 (m, 2H) 2.26 (t, J=13.69 Hz, 1H)
2.50-2.66 (m, 1H) 2.94 (d, J=13.50 Hz, 1H) 3.33-3.46 (m, 3H) 4.19
(dd, J=13.99, 11.05 Hz, 1H) 4.97 (d, J=10.76 Hz, 1H) 6.85-6.99 (m,
1H) 7.03 (s, 1H) 7.08-7.18 (m, 3H) 7.26 (br s, 3H); Mass Spectrum
(ESI) m/z=584 (M+1).
Example 311
2-((3R,5R,6S)-1-((S)-1-((R)-sec-butylsulfonyl)butan-2-yl)-5-(3-chloropheny-
l)-6-(4-chlorophenyl)-3-methyl-2-oxopiperidin-3-yl)acetic acid or
2-((3R,5R,6S)-1-((S)-1-((S)-sec-butylsulfonyl)butan-2-yl)-5-(3-chlorophen-
yl)-6-(4-chlorophenyl)-3-methyl-2-oxopiperidin-3-yl)acetic acid
[3230] The crude product was purified by reversed phase preparatory
HPLC (Gemini.TM. Prep C.sub.18 5 mm column; Phenomenex, Torrance,
Calif.) (gradient elution of 50% to 85% MeCN in water, where both
solvents contain 0.1% TFA, 27 min method) to provide the title
compound as the faster eluting isomer (t.sub.R=9.43 min).
[3231] .sup.1H NMR (400 MHz, CHLOROFORM-d) .delta. ppm 7.24 (d,
J=7.43 Hz, 2H), 7.04-7.15 (m, 3H), 6.96 (s, 1H), 6.85 (td, J=1.83,
6.70 Hz, 1H), 4.96 (d, J=10.56 Hz, 1H), 4.15 (ddd, J=3.13, 10.81,
13.45 Hz, 1H), 3.29 (t, J=10.17 Hz, 1H), 3.14 (ddd, J=2.93, 10.86,
13.60 Hz, 1H), 2.77-2.93 (m, 2H), 2.62-2.74 (m, 2H), 2.38 (t,
J=13.79 Hz, 1H), 2.02-2.20 (m, 2H), 1.85 (dd, J=2.84, 13.79 Hz,
1H), 1.54-1.66 (m, 1H), 1.37-1.53 (m, 7H), 1.08 (dt, J=3.33, 7.43
Hz, 3H), 0.41 (t, J=7.53 Hz, 3H). Mass Spectrum (ESI) m/z=668.2
[M].sup.+.
Example 312
2-((3R,5R,6S)-1-((S)-1-((R)-sec-butylsulfonyl)butan-2-yl)-5-(3-chloropheny-
l)-6-(4-chlorophenyl)-3-methyl-2-oxopiperidin-3-yl)acetic acid or
2-((3R,5R,6S)-1-((S)-1-((S)-sec-butylsulfonyl)butan-2-yl)-5-(3-chlorophen-
yl)-6-(4-chlorophenyl)-3-methyl-2-oxopiperidin-3-yl)acetic acid
[3232] The crude product was purified by reversed phase preparatory
HPLC (Gemini.TM. Prep C18 5 mm column; Phenomenex, Torrance,
Calif.) (gradient elution of 50% to 85% MeCN in water, where both
solvents contain 0.1% TFA) to provide the title compound as the
slower eluting isomer (t.sub.R=10.2 min).
[3233] .sup.1H NMR (400 MHz, CHLOROFORM-d) .delta. ppm 9.97 (t,
J=2.74 Hz, 1H), 7.24 (d, J=7.43 Hz, 2H), 7.04-7.15 (m, 3H), 6.96
(s, 1H), 6.85 (td, J=1.83, 6.70 Hz, 1H), 4.96 (d, J=10.56 Hz, 1H),
4.15 (ddd, J=3.13, 10.81, 13.45 Hz, 1H), 3.29 (t, J=10.17 Hz, 1H),
3.14 (ddd, J=2.93, 10.86, 13.60 Hz, 1H), 2.77-2.93 (m, 2H),
2.62-2.74 (m, 2H), 2.38 (t, J=13.79 Hz, 1H), 2.02-2.20 (m, 2H),
1.85 (dd, J=2.84, 13.79 Hz, 1H), 1.54-1.66 (m, 1H), 1.37-1.53 (m,
7H), 1.08 (dt, J=3.33, 7.43 Hz, 3H), 0.41 (t, J=7.53 Hz, 3H);
[3234] Mass Spectrum (ESI) m/z=668.2 [M].sup.+.
[3235] Examples 313 to 323 were prepared from
(3S,5R,6S)-3-allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-cyclopr-
opyl-2-hydroxyethyl)-3-methylpiperidin-2-one (Example 252, Step A)
by procedures similar to the one described in Example 300,
replacing benzenethiol with the appropriate amount of thiol.
TABLE-US-00015 ##STR00861## Example R Reagent used 313 ##STR00862##
cyclopentanethiol; prepared from bromocyclopentane by a procedure
similar to the one described for the preparation of
cyclopropylmethanethiol in U.S. Pat. No. 3,975,429. 314
##STR00863## example 308 315 ##STR00864## benzenethiol 316
##STR00865## o-toluenethiol 317 ##STR00866## 2-chlorobenzenethiol
318 ##STR00867## 4-chlorobenzenethiol 319 ##STR00868##
4-fluorobenzenethiol 320 ##STR00869## 4-mercaptopyridine 321
##STR00870## 2-chloro-4-fluorobenzenethiol (Oakwood Products, West
Columbia, SC) 322 ##STR00871## cyclopropylmethanethiol; prepared
from bromomethylcyclopropane by a procedure similar to the one
described in U.S. Pat. No. 3,975,429. 323 ##STR00872##
2,2,2-trifluoroethanethiol
Example 313
2-((3R,5R,6S)-5-(3-Chlorophenyl)-6-(4-chlorophenyl)-1-((S)-2-(cyclopentyls-
ulfonyl)-1-cyclopropylethyl)-3-methyl-2-oxopiperidin-3-yl)acetic
acid
[3236] .sup.1H NMR (400 MHz, CHLOROFORM-d) .delta. ppm -1.08 (br.
s, 1H) -0.30 (br. s, 1H) 0.21-0.29 (m, 1H) 0.33-0.42 (m, 1H) 1.51
(s, 3H) 1.65-1.77 (m, 2H) 1.80-1.92 (m, 4H) 2.10 (m, 4H) 2.48 (t,
J=13.79 Hz, 1H) 2.75 (m, 2H) 2.89 (dd, J=13.60, 2.25 Hz, 1H)
3.09-3.18 (m, 2H) 3.38 (quin, J=8.02 Hz, 1H) 4.33 (m 1H) 4.92 (d,
J=10.56 Hz, 1H) 6.84-6.90 (m, 1H) 6.95 (s, 1H) 7.07-7.17 (m, 2H)
7.37 (m., 4H); Mass Spectrum (ESI) m/z=592 (M+1).
Example 314
2-((3R,5R,6S)-5-(3-Chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-cyclopropyl-2-
-(((3-methyloxetan-3-yl)methyl)sulfonyl)ethyl)-3-methyl-2-oxopiperidin-3-y-
l)acetic acid
[3237] .sup.1H NMR (500 MHz, CD.sub.3OD) .delta. ppm -1.06 (br s,
1H) -0.21 (br s, 1H) 0.23 (br s, 1H) 0.37 (br s, 1H) 1.22-1.30 (m,
3H) 1.38-1.45 (m, 3H) 1.70-1.77 (m, 3H) 1.99-2.09 (m, 1H) 2.31 (t,
J=13.69 Hz, 1H) 2.65-2.73 (m, 1H) 2.95-3.03 (m, 1H) 3.39-3.49 (m,
1H) 3.59-3.66 (m, 1H) 3.66-3.73 (m, 1H) 4.07-4.16 (m, 2H) 4.40-4.45
(m, 2H) 4.80 (d, J=6.11 Hz, 2H) 4.91 (d, J=10.76 Hz, 2H) 6.94-7.00
(m, 1H) 7.06 (s, 1H) 7.08-7.22 (m, 3H) 7.32 (br s, 3H); Mass
Spectrum (ESI) m/z=608 (M+1).
Example 315
2-((3R,5R,6S)-5-(3-Chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-cyclopropyl-2-
-(phenylsulfonyl)ethyl)-3-methyl-2-oxopiperidin-3-yl)acetic
acid
[3238] .sup.1H NMR (500 MHz, CHLOROFORM-d) .delta. ppm -1.12--1.02
(m, 1H) -0.33 (m, 1H) 0.19-0.27 (m, 1H) 0.29-0.35 (m, 1H) 1.60 (s,
3H) 1.77-1.89 (m, 1H) 1.92 (dd, J=13.69, 2.93 Hz, 1H) 2.57 (t,
J=13.94 Hz, 1H) 2.81 (d, J=15.16 Hz, 2H) 3.00 (dd, J=13.94, 2.45
Hz, 1H) 3.08-3.25 (m, 2H) 4.47 (t, J=12.35 Hz, 1H) 5.01 (d, J=10.51
Hz, 1H) 6.90 (dt, J=7.03, 1.62 Hz, 1H) 6.96-7.02 (m, 1H) 7.07-7.19
(m, 2H) 7.20-7.30 (m, 4H) 7.56-7.67 (m, 2H) 7.67-7.77 (m, 1H)
7.87-7.98 (m, 2H); Mass Spectrum (ESI) m/z=600 (M+1).
Example 316
2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-cyclopropyl-2-
-(o-tolylsulfonyl)ethyl)-3-methyl-2-oxopiperidin-3-yl)acetic
acid
[3239] .sup.1H NMR (400 MHz, CHLOROFORM-d) .delta. ppm 8.00 (1H,
dd, J=7.9, 1.1 Hz), 7.51-7.64 (1H, m), 7.34-7.48 (3H, m), 7.22-7.34
(2H, m), 7.06-7.18 (3H, m), 6.98-7.04 (1H, m), 6.86-6.96 (1H, m),
5.02 (1H, d, J=10.8 Hz), 4.60 (1H, t, J=12.4 Hz), 3.20 (1H, ddd,
J=13.7, 10.8, 2.7 Hz), 3.09 (1H, d, J=14.9 Hz), 2.99 (1H, dd,
J=14.0, 2.2 Hz), 2.77-2.87 (2H, m), 2.71 (3H, s), 2.53 (1H, t,
J=13.8 Hz), 1.94 (1H, dd, J=13.8, 2.8 Hz), 1.78-1.86 (1H, m), 1.56
(3H, s), 0.17-0.40 (2H, m), -0.40--0.30 (1H, m), -1.12--1.00 (1H,
m); Mass Spectrum (ESI) 614.2 [M+H].sup.+.
Example 317
2-((3R,5R,6S)-5-(3-Chlorophenyl)-6-(4-chlorophenyl)-1-((S)-2-((2-chlorophe-
nyl)sulfonyl)-1-cyclopropylethyl)-3-methyl-2-oxopiperidin-3-yl)acetic
acid
[3240] .sup.1H NMR (500 MHz, CHLOROFORM-d) .delta. ppm -1.08 (br s,
1H) -0.27 (m, 1H) 0.20-0.29 (m, 1H) 0.31-0.40 (m, 1H) 1.58 (s, 3H)
1.82-1.96 (m, 2H) 2.53 (t, J=13.82 Hz, 1H) 2.77-2.90 (m, 2H)
3.11-3.22 (m, 2H) 3.37 (dd, J=13.94, 2.45 Hz, 1H) 4.76 (t, J=12.23
Hz, 1H) 4.97 (d, J=10.51 Hz, 1H) 6.89 (d, J=7.09 Hz, 1H) 7.00 (s,
1H) 7.09-7.19 (m, 2H) 7.27-7.35 (m, 4H) 7.49-7.57 (m, 1H) 7.57-7.68
(m, 2H) 8.15 (dd, J=7.83, 1.47 Hz, 1H); Mass Spectrum (ESI) m/z=636
(M+1).
Example 318
2-((3R,5R,6S)-5-(3-Chlorophenyl)-6-(4-chlorophenyl)-1-((S)-2-((4-chlorophe-
nyl)sulfonyl)-1-cyclopropylethyl)-3-methyl-2-oxopiperidin-3-yl)acetic
acid
[3241] .sup.1H NMR (500 MHz, CHLOROFORM-d) .delta. ppm -0.38--0.22
(m, 1H) 0.26 (br s, 1H) 0.33 (dd, J=8.93, 4.52 Hz, 2H) 1.59 (s, 3H)
1.83 (br s, 1H) 1.96 (dd, J=13.82, 2.81 Hz, 1H) 2.55 (t, J=13.94
Hz, 1H) 2.84 (d, J=15.16 Hz, 2H) 2.98 (dd, J=13.94, 2.45 Hz, 1H)
3.11 (d, J=14.92 Hz, 1H) 3.22 (ddd, J=13.69, 10.76, 2.93 Hz, 1H)
4.99 (d, J=10.51 Hz, 1H) 6.88-6.96 (m, 1H) 6.98-7.03 (m, 1H)
7.09-7.21 (m, 2H) 7.29 (m, 4H) 7.56-7.66 (m, 2H) 7.83-7.94 (m, 2H);
Mass Spectrum (ESI) m/z=636 (M+1).
Example 319
2-((3R,5R,6S)-5-(3-Chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-cyclopropyl-2-
-((4-fluorophenyl)sulfonyl)ethyl)-3-methyl-2-oxopiperidin-3-yl)acetic
acid
[3242] .sup.1H NMR (500 MHz, CHLOROFORM-d) .delta. ppm -1.05 (br s,
1H) -0.33 (br s, 1H) 0.17-0.38 (m, 2H) 1.59 (s, 3H) 1.76-1.88 (m,
1H) 1.93 (dd, J=13.82, 2.81 Hz, 1H) 2.55 (t, J=13.82 Hz, 1H) 2.82
(m, 2H) 2.98 (dd, J=13.94, 2.45 Hz, 1H) 3.06-3.28 (m, 2H) 4.48 (t,
J=12.10 Hz, 1H) 4.99 (d, J=10.51 Hz, 1H) 6.89 (dt, J=7.09, 1.59 Hz,
1H) 6.95-7.04 (m, 1H) 7.06-7.21 (m, 2H) 7.21-7.40 (m, 6H) 7.86-8.01
(m, 2H); Mass Spectrum (ESI) m/z=618 (M+1).
Example 320
2-((3R,5R,6S)-5-(3-Chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-cyclopropyl-2-
-(pyridin-4-ylsulfonyl)ethyl)-3-methyl-2-oxopiperidin-3-yl)acetic
acid
[3243] .sup.1H NMR (500 MHz, CHLOROFORM-d) .delta. ppm -1.01 (br s,
1H) -0.30 (br s, 1H) 0.28 (br s, 1H) 0.30-0.46 (m, 1H) 1.58 (s, 3H)
1.83 (br s, 1H) 1.96 (dd, J=13.94, 2.93 Hz, 1H) 2.52 (t, J=13.94
Hz, 1H) 2.83 (m, 2H) 3.00 (dd, J=13.94, 2.45 Hz, 1H) 3.11 (d,
J=15.16 Hz, 1H) 3.21 (ddd, J=13.69, 10.64, 2.81 Hz, 1H) 4.55 (br s,
1H) 4.94 (d, J=10.51 Hz, 1H) 6.88 (d, J=7.09 Hz, 1H) 6.99 (s, 1H)
7.08-7.20 (m, 2H) 7.20-7.39 (m, 4H) 7.77-7.83 (m, 2H) 8.92-8.99 (m,
2H); Mass Spectrum (ESI) m/z=601 (M+1).
Example 321
2-((3R,5R,6S)-1-((S)-2-((2-Chloro-4-fluorophenyl)sulfonyl)-1-cyclopropylet-
hyl)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-2-oxopiperidin-3-yl)ac-
etic acid
[3244] .sup.1H NMR (400 MHz, CHLOROFORM-d) .delta. ppm -1.05 (br s,
1H), -0.29 (br s, 1H), 0.25 (br s, 1H), 0.29-0.44 (m, 1H), 1.56 (s,
3H), 1.84 (br s, 1H), 1.89-2.03 (m, 1H), 2.50 (t, J=13.89 Hz, 1H),
2.82 (d, J=14.87 Hz, 2H), 3.08 (d, J=14.67 Hz, 1H), 3.15-3.26 (m,
1H), 3.31 (d, J=13.69 Hz, 1H), 4.75 (br s, 1H), 4.96 (d, J=10.56
Hz, 1H), 6.89 (d, J=6.85 Hz, 1H), 7.00 (s, 1H), 7.08-7.18 (m, 3H),
7.18-7.25 (m, 2H), 7.26-7.31 (m, 1H), 7.33 (dd, J=7.92, 2.25 Hz,
2H), 8.17 (dd, J=8.80, 5.87 Hz, 1H); Mass Spectrum (ESI) m/z=652.0
and 653.9 (M+1).
Example 322
2-((3R,5R,6S)-5-(3-Chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-cyclopropyl-2-
-((cyclopropylmethyl)sulfonyl)ethyl)-3-methyl-2-oxopiperidin-3-yl)acetic
acid
[3245] .sup.1H NMR (400 MHz, CHLOROFORM-d) .delta. ppm -1.06 (m,
1H), -0.27 (m, 1H), 0.39 (m, 1H), 0.43 (m, 3H), 0.80 (m, 2H), 1.18
(m, 1H), 1.52 (s, 3H), 1.85 (d, J=12 Hz, 1H), 1.95 (m, 1H), 2.44
(t, J=12 Hz, 1H), 2.76 (d, J=16 Hz, 2H), 2.90 (m, 1H), 3.02 (m,
2H), 3.14 (m, 2H), 4.39 (m, 1H), 4.92 (d, J=12 Hz, 1H), 6.86 (d,
J=8.0 Hz, 1H), 6.96 (s, 1H), 7.13 (m, 3H), 7.27 (m, 3H); Mass
Spectrum (ESI) m/z=578.0 [M+H].sup.+.
Example 323
2-((3R,5R,6S)-5-(3-Chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-cyclopropyl-2-
-((2,2,2-trifluoroethyl)sulfonyl)ethyl)-3-methyl-2-oxopiperidin-3-yl)aceti-
c acid
[3246] .sup.1H NMR (500 MHz, CHLOROFORM-d) .delta. ppm 7.08-7.17
(2H, m), 6.95 (1H, s), 6.83 (1H, d, J=7.3 Hz), 4.79 (1H, d, J=10.5
Hz), 3.80-3.93 (2H, m), 3.11-3.23 (2H, m), 3.04 (1H, d, J=14.7 Hz),
2.82 (2H, d, J=14.7 Hz), 2.37 (1H, t, J=13.7 Hz), 1.94 (1H, d,
J=13.0 Hz), 1.49 (3H, s), 0.43 (1H, br. s.), 0.31 (1H, br. s.),
-0.24 (1H, br. s.), -1.03 (1H, br. s.); Mass Spectrum (ESI) m/z=606
(M+1).
Example 324
2-((3R,5R,6S)-5-(3-Chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-cyclopropyl-2-
-((trifluoromethyl)sulfonyl)ethyl)-3-methyl-2-oxopiperidin-3-yl)acetic
acid
##STR00873##
[3247] Step A.
(3S,5R,6S)-3-Allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-cyclopr-
opyl-2-((trifluoromethyl)thio)ethyl)-3-methylpiperidin-2-one
##STR00874##
[3249] A mixture of ((trifluoromethyl)thio)copper (41.3 mg, 0.251
mmol, TCI America, Portland, Oreg.),
2-(tributylphosphoranylidene)acetonitrile (194 mg, 0.803 mmol), and
(3S,5R,6S)-3-allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-cyclopr-
opyl-2-hydroxyethyl)-3-methylpiperidin-2-one (115 mg, 0.251 mmol,
Example 252, Step A) was stirred at 110.degree. C. for 3 h. A few
drops of 4N HCl in dioxane were added and the mixture stirred for
30 min. Toluene (0.15 ml) was added and stirring continued at
110.degree. C. for 20 h. HPLC purification (Gemini.TM. Prep
C.sub.18 5 .mu.m column; Phenomenex, Torrance, Calif.; gradient
elution of 10% to 95% MeCN in water with 0.1% TFA) gave the title
compound.
[3250] Mass Spectrum (ESI) m/z=542 (M+1).
Step B.
2-((3R,5R,6S)-5-(3-Chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-cyclo-
propyl-2-((trifluoromethyl)sulfonyl)ethyl)-3-methyl-2-oxopiperidin-3-yl)ac-
etic acid
[3251] The title compound was prepared from
(3S,5R,6S)-3-allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-cyclopr-
opyl-2-((trifluoromethyl)thio)ethyl)-3-methylpiperidin-2-one
(Example 324, step A) by a procedure similar to the one described
in Example 71, Step F. The crude product was purified by reverse
phase preparatory HPLC (Gemini.TM. Prep C.sub.18 5 .mu.m column;
Phenomenex, Torrance, Calif.; gradient elution of 10% to 95% MeCN
in water, where both solvents contain 0.1% TFA).
[3252] .sup.1H NMR (500 MHz, CDCl.sub.3) .delta. ppm 7.10-7.17 (3H,
m), 6.93 (1H, s), 6.82-6.86 (1H, m), 4.70 (1H, d, J=10.5 Hz),
3.17-3.26 (2H, m), 3.02 (1H, d, J=14.7 Hz), 2.85 (1H, d, J=14.9
Hz), 2.77 (1H, br. s.), 2.35 (1H, t, J=13.9 Hz), 1.99 (2H, dd,
J=13.9, 2.9 Hz), 1.51 (3H, s), 1.26 (1H, s), 0.41-0.50 (1H, m),
0.31 (1H, br. s.), -0.23 (1H, br. s.), -1.01 (1H, br. s.); Mass
Spectrum (ESI) m/z=592 (M+1).
[3253] Examples 325 to 335 were prepared from
(3S,5R,6S)-3-allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-cyclopr-
opyl-2-hydroxyethyl)-3-ethylpiperidin-2-one (Example 253, Step C)
by procedures similar to the one described in Example 300,
replacing benzenethiol with the appropriate amount of thiol.
TABLE-US-00016 ##STR00875## Example R Reagent used 325 ##STR00876##
benzenethiol 326 ##STR00877## 2-chlorobenzenethiol 327 ##STR00878##
2-fluorobenzenethiol 328 ##STR00879## 3-fluorobenzenethiol 329
##STR00880## 4-fluorobenzenethiol 330 ##STR00881## propanethiol 331
##STR00882## butanethiol 332 ##STR00883## 3-methylbutanethiol 333
##STR00884## cyclopentanethiol; prepared from bromocyclopentane by
a procedure similar to the one described for the preparation of
cyclopropylmethanethiol in U.S. Pat. No. 3,975,429. 334
##STR00885## cyclohexanethiol; prepared from bromocyclopentane by a
procedure similar to the one described for the preparation of
cyclopropylmethanethiol in U.S. Pat. No. 3,975,429. 335 Me--
trimethylsilylmethanethiol (as per Example 301)
Example 325
2-((3R,5R,6S)-5-(3-Chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-cyclopropyl-2-
-(phenylsulfonyl)ethyl)-3-ethyl-2-oxopiperidin-3-yl)acetic acid
[3254] .sup.1H NMR (500 MHz, CHLOROFORM-d) .delta. ppm -1.01 (br.
m., 1H) -0.32 (br. m., 1H) 0.19-0.37 (m, 2H) 1.06 (t, J=7.46 Hz,
3H) 1.87 (m, 2H) 2.02-2.17 (m, 2H) 2.54 (t, J=13.82 Hz, 1H) 2.83
(m, 2H) 3.03 (d, J=12.96 Hz, 1H) 3.07-3.23 (m, 2H) 4.38 (br s, 1H)
5.03 (d, J=10.51 Hz, 1H) 6.91 (d, J=7.09 Hz, 1H) 6.98-7.04 (m, 1H)
7.08-7.20 (m, 3H) 7.48 (m, 3H) 7.56-7.67 (m, 2H) 7.67-7.78 (m, 1H)
7.84-7.99 (m, 2H);
[3255] Mass Spectrum (ESI) m/z=614 (M+1).
Example 326
2-((3R,5R,6S)-5-(3-Chlorophenyl)-6-(4-chlorophenyl)-1-((S)-2-((2-chlorophe-
nyl)sulfonyl)-1-cyclopropylethyl)-3-ethyl-2-oxopiperidin-3-yl)acetic
acid
[3256] .sup.1H NMR (500 MHz, CHLOROFORM-d) .delta. ppm -1.01 (br.
m., 1H) -0.26 (br. m., 1H) 0.28 (br. m., 1H) 0.31-0.44 (m, 1H) 1.02
(t, J=7.46 Hz, 3H) 1.88 (m, 2H) 2.02-2.16 (m, 2H) 2.48 (t, J=13.82
Hz, 1H) 2.83 (d, J=15.65 Hz, 1H) 2.90 (br s, 1H) 3.07-3.23 (m, 2H)
3.42 (dd, J=14.06, 2.08 Hz, 1H) 4.64 (br s, 1H) 4.98 (d, J=10.51
Hz, 1H) 6.89 (d, J=7.09 Hz, 1H) 6.97-7.04 (m, 1H) 7.09-7.22 (m, 3H)
7.33-7.48 (m, 3H) 7.48-7.56 (m, 1H) 7.56-7.67 (m, 2H) 8.14 (dd,
J=7.95, 1.59 Hz, 1H); Mass Spectrum (ESI) m/z=648 (M+1).
Example 327
2-((3R,5R,6S)-5-(3-Chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-cyclopropyl-2-
-((2-fluorophenyl)sulfonyl)ethyl)-3-ethyl-2-oxopiperidin-3-yl)acetic
acid
[3257] .sup.1H NMR (400 MHz, CHLOROFORM-d) .delta. ppm -1.00 (br s,
1H), -0.26 (br s, 1H), 0.19-0.45 (m, 2H), 1.02 (t, J=7.43 Hz, 3H),
1.87 (dd, J=13.69, 2.93 Hz, 2H), 1.97-2.20 (m, 2H), 2.49 (t,
J=13.79 Hz, 1H), 2.83 (d, J=15.26 Hz, 2H), 3.08 (d, J=15.26 Hz,
1H), 3.19 (ddd, J=13.55, 10.71, 2.74 Hz, 1H), 3.30 (d, J=13.89 Hz,
1H), 4.57 (br s, 1H), 4.95 (d, J=10.76 Hz, 1H), 6.89 (d, J=6.85 Hz,
1H), 7.02 (s, 1H), 7.08-7.23 (m, 3H), 7.23-7.35 (m, 3H), 7.35-7.52
(m, 2H), 7.67-7.81 (m, 1H), 7.91-8.05 (m, 1H); Mass Spectrum (ESI)
m/z=632.0 (M+1).
Example 328
2-((3R,5R,6S)-5-(3-Chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-cyclopropyl-2-
-((3-fluorophenyl)sulfonyl)ethyl)-3-ethyl-2-oxopiperidin-3-yl)acetic
acid
[3258] .sup.1H NMR (400 MHz, CHLOROFORM-d) .delta. ppm -0.97 (br s,
1H), -0.31 (br s, 1H), 0.18-0.48 (m, 2H), 1.05 (t, J=7.43 Hz, 3H),
1.88 (dd, J=13.79, 2.84 Hz, 2H), 1.96-2.21 (m, 2H), 2.51 (t,
J=13.79 Hz, 1H), 2.84 (d, J=15.06 Hz, 2H), 2.95-3.13 (m, 2H),
3.13-3.31 (m, 1H), 4.41 (br s, 1H), 5.00 (d, J=10.56 Hz, 1H), 5.72
(br s, 2H), 6.91 (d, J=6.85 Hz, 1H), 7.01-7.04 (m, 2H), 7.09-7.18
(m, 3H), 7.36-7.45 (m, 2H), 7.57-7.66 (m, 3H), 7.70 (d, J=7.83 Hz,
1H); Mass Spectrum (ESI) m/z=632.0 (M+1).
Example 329
2-((3R,5R,6S)-5-(3-Chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-cyclopropyl-2-
-((4-fluorophenyl)sulfonyl)ethyl)-3-ethyl-2-oxopiperidin-3-yl)acetic
acid
[3259] .sup.1H NMR (400 MHz, CHLOROFORM-d) .delta. ppm -0.97 (br s,
1H), -0.31 (br s, 1H), 0.32 (d, J=4.89 Hz, 2H), 1.05 (t, J=7.53 Hz,
3H), 1.26 (s, 1H), 1.88 (dd, J=13.69, 2.93 Hz, 2H), 1.97-2.21 (m,
2H), 2.52 (t, J=13.79 Hz, 1H), 2.83 (d, J=15.26 Hz, 1H), 2.92-3.13
(m, 2H), 3.13-3.30 (m, 1H), 4.38 (br s, 2H), 5.01 (d, J=10.56 Hz,
1H), 6.91 (d, J=6.65 Hz, 2H), 7.01 (s, 2H), 7.07-7.22 (m, 3H),
7.28-7.37 (m, 3H), 7.83-8.03 (m, 2H); Mass Spectrum (ESI) m/e=632.0
(M+1).
Example 330
2-((3R,5R,6S)-5-(3-Chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-cyclopropyl-2-
-(propylsulfonyl)ethyl)-3-ethyl-2-oxopiperidin-3-yl)acetic acid
[3260] .sup.1H NMR (400 MHz, methanol-d4) .delta. ppm -0.71 (s, br,
1H), 0.00 (br s, 1H), 0.51 (br s, 1H), 0.60 (br s, 1H), 1.19 (t,
J=8 Hz, 3H), 1.32 (t, J=8 Hz, 3H), 1.93-2.14 (m, 5H), 2.24 (m, 1H),
2.61 (t, J=12 Hz, 1H), 2.87 (d, J=12 Hz, 1H), 2.97 (br s, 1H), 3.13
(d, J=12 Hz, 1H), 3.32 (m, 3H), 3.69 (m, 1H), 4.45 (s, br, 1H),
5.16 (d, J=12 Hz, 1H), 7.20-7.21 (d, J=4 Hz, 2H), 7.28 (s, 1H),
7.36 (m, 3H), 7.51 (br s, 2H); Mass Spectrum (ESI) m/z=580.2
(M+1).
Example 331
2-((3R,5R,6S)-1-((S)-2-(Butylsulfonyl)-1-cyclopropylethyl)-5-(3-chlorophen-
yl)-6-(4-chlorophenyl)-3-ethyl-2-oxopiperidin-3-yl)acetic acid
[3261] .sup.1H NMR (400 MHz, methanol-d4) .delta. ppm -0.73 (s, br,
1H), 0.00 (br s, 1H), 0.51 (br s, 1H), 0.60 (br s, 1H), 1.17-1.23
(m, 6H), 1.70-1.76 (m, 2H), 2.01 (m, 4H), 2.13 (d, J=8 Hz, 1H),
2.24 (m, 1H), 2.61 (t, J=12 Hz, 1H), 2.87 (d, J=16 Hz, 1H), 2.98
(br s, 1H), 4.14 (d, J=16 Hz, 1H), 3.31-3.42 (m, 3H), 3.69 (m, 1H),
4.48 (br s, 1H), 5.17 (d, J=16 Hz, 1H), 7.20 (m, 2H), 7.28 (s, 1H),
7.36 (m, 3H), 7.50 (br s, 2H); Mass Spectrum (ESI) m/z=594.2
(M+1).
Example 332
2-((3R,5R,6S)-5-(3-Chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-cyclopropyl-2-
-(isopentylsulfonyl)ethyl)-3-ethyl-2-oxopiperidin-3-yl)acetic
acid
[3262] .sup.1H NMR (400 MHz, methanol-d4) .delta. ppm -0.73 (br s,
1H), 0.00 (br s, 1H), 0.50 (br s, 1H), 0.60 (br s, 1H), 1.17-1.20
(m, 9H), 1.92 (m, 5H), 2.10 (dd, J=4, 12 Hz, 1H), 2.24 (m, 1H),
2.61 (t, J=12 Hz, 1H), 2.87 (d, J=12 Hz, 1H), 2.97 (br s, 1H), 3.13
(d, J=12 Hz, 1H), 3.37 (m, 3H), 3.69 (m, 1H), 4.46 (br s, 1H), 5.16
(d, J=12 Hz, 1H), 7.20 (m, 2H), 7.27 (s, 1H), 7.36 (m, 3H), 7.50
(br s, 2H); Mass Spectrum (ESI) m/z=608.2 (M+1).
Example 333
2-((3R,5R,6S)-5-(3-Chlorophenyl)-6-(4-chlorophenyl)-1-((S)-2-(cyclopentyls-
ulfonyl)-1-cyclopropylethyl)-3-ethyl-2-oxopiperidin-3-yl)acetic
acid
[3263] .sup.1H NMR (400 MHz, methanol-d4) .delta. ppm -0.94 (br s,
1H), -0.23 (br s, 1H), 0.30 (br s, 1H), 0.39 (br s, 1H), 0.99 (t,
J=4 Hz, 3H), 1.73-1.83 (m, 6H), 1.87 (m, 1H), 2.05 (m, 5H), 2.42
(t, J=12 Hz, 1H), 2.68 (d, J=12 Hz, 1H), 2.78 (br s, 1H), 2.94 (d,
J=12 Hz, 1H), 3.48 (br s, 1H), 3.50 (m, 1H), 3.61 (m, 1H), 4.27 (br
s, 1H), 4.98 (d, J=12 Hz, 1H), 7.02 (d, J=8 Hz, 2H), 7.08 (s, 1H),
7.17 (m, 3H), 7.31 (br s, 2H); Mass Spectrum (ESI) m/z=606.2
(M+1).
Example 334
2-((3R,5R,6S)-5-(3-Chlorophenyl)-6-(4-chlorophenyl)-1-((S)-2-(cyclohexylsu-
lfonyl)-1-cyclopropylethyl)-3-ethyl-2-oxopiperidin-3-yl)acetic
acid
[3264] .sup.1H NMR (400 MHz, methanol-d4) .delta. ppm -0.97 (s, br,
1H), -0.25 (br s, 1H), 0.29 (s, 1H), 0.39 (s, 1H), 0.99 (t, J=8 Hz,
3H), 1.24-1.52 (m, 6H), 1.75-1.78 (m, 2H), 1.91-1.96 (m, 3H), 2.05
(m, 1H), 2.18 (s, br, 2H), 2.39-2.46 (t, J=12 Hz, 1H), 2.68-2.71
(d, J=12 Hz, 1H), 2.78 (br s, 1H), 2.94-2.98 (d, J=12 Hz, 1H), 3.08
(m, 2H), 3.48-3.53 (m, 1H), 4.27 (s, br, 1H), 4.99 (d, J=12 Hz,
1H), 7.01 (d, J=8 Hz, 2H), 7.08 (s, 1H), 7.16-7.21 (m, 3H), 7.31
(s, br, 2H); Mass Spectrum (ESI) m/z=620.2 (M+1)
Example 335
2-((3R,5R,6S)-5-(3-Chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-cyclopropyl-2-
-(methylsulfonyl)ethyl)-3-ethyl-2-oxopiperidin-3-yl)acetic acid
[3265] .sup.1H NMR (400 MHz, methanol-d4) .delta. ppm -0.71 (s, br,
1H), 0.00 m (s, br, 1H), 0.47 (s, br, 1H), 0.55 (s, br, 1H), 1.14
(t, J=8 Hz, 3H), 1.92-1.94 (m, 2H), 2.08 (dd, J=4, 12 Hz, 1H), 2.18
(m, 1H), 2.55 (t, J=12 Hz, 1H), 2.86 (d, J=16 Hz, 1H), 3.03 (s, br,
1H), 3.12 (d, J=16 Hz, 1H), 3.43 (s, br, 1H), 3.48 (s, 3H), 3.63
(m, 1H), 4.41 (s, br, 1H), 5.09 (d, J=12 Hz, 1H), 7.14 (m, 2H),
7.30 (s, 1H), 7.32 (m, 3H), 7.46 (s, br, 2H); Mass Spectrum (ESI)
m/z=552.2 (M+1).
[3266] Examples 336 to 339 were prepared from
(3S,5R,6S)-3-allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-hydroxy-
-3-methylbutan-2-yl)-3-methylpiperidin-2-one (Example 261, Step H)
by procedures similar to the one described in Example 300,
replacing benzenethiol with the designated reagent.
TABLE-US-00017 ##STR00886## Example R Reagent used 336 ##STR00887##
2,2,2-trifluoroethanethiol 337 .sup.tBu-- 2-methylpropane-2-thiol
338 Me trimethylsilylmethanethiol (as per Example 301)
Example 336
2-((3R,5R,6S)-5-(3-Chlorophenyl)-6-(4-chlorophenyl)-3-methyl-1-((S)-3-meth-
yl-1-((2,2,2-trifluoroethyl)sulfonyl)butan-2-yl)-2-oxopiperidin-3-yl)aceti-
c acid
[3267] .sup.1H NMR (500 MHz, methanol-d.sub.4) .delta. ppm 0.52 (s,
3H), 0.67 (s, 3H), 1.35 (br s, 3H), 2.07 (dd, J=13.7, 2.9 Hz, 1H),
2.19 (dq, J=14.4, 7 Hz, 1H), 2.27 (t, J=13.7 Hz, 1H), 2.61 (d,
J=13.5 Hz, 1H), 2.99 (d, J=13.5 Hz, 1H), 3.26-3.30 (m, 1H), 3.41
(dd, J=13.8, 1.6 Hz, 1H), 3.58 (ddd, J=13.7, 11, 2.9 Hz, 1H), 4.24
(dd, J=13.9, 10.5 Hz, 1H), 4.36-4.60 (m, 2H), 4.99-5.07 (m, 1H),
6.95-7.01 (m, 1H), 7.01-7.05 (m, 1H), 7.08-7.16 (m, 3H), 7.17-8.26
(m, 3H); Mass Spectrum (ESI) m/z=608 (M+H)
Example 337
2-((3R,5R,6S)-1-((S)-1-(tert-Butylsulfonyl)-3-methylbutan-2-yl)-5-(3-chlor-
ophenyl)-6-(4-chlorophenyl)-3-methyl-2-oxopiperidin-3-yl)acetic
acid
[3268] .sup.1H NMR (500 MHz, methanol-d.sub.4) .delta. ppm 0.51 (d,
J=6.9 Hz, 3H), 0.65 (d, J=6.6 Hz, 3H), 1.37 (s, 3H), 1.45 (s, 9H),
2.01-2.10 (m, 1H), 2.11-2.25 (m, 1H), 2.30 (t, J=13.7 Hz, 1H), 2.61
(d, J=13.5 Hz, 1H), 2.99 (d, J=13.7 Hz, 1H), 3.10 (dd, J=13.7, 1.71
Hz, 1H), 3.25-3.29 (m, 1H), 3.57 (ddd, J=13.6, 11.1, 2.9 Hz, 1H),
3.96 (dd, J=13.8, 10.4 Hz, 1H), 5.15 (d, J=11.3 Hz, 1H), 6.98-7.03
(m, 1H), 7.04-7.17 (m, 3H), 7.18-8.01 (m, 3H); Mass Spectrum (ESI)
m/z=582.2 (M+H).
Example 338
2-((3R,5R,6S)-5-(3-Chlorophenyl)-6-(4-chlorophenyl)-3-methyl-1-((S)-3-meth-
yl-1-(methylsulfonyl)butan-2-yl)-2-oxopiperidin-3-yl)acetic
acid
[3269] .sup.1H NMR (500 MHz, methanol-d.sub.4) .delta. ppm 0.50 (d,
J=6.9 Hz, 3H), 0.67 (d, J=6.6 Hz, 3H), 1.37 (s, 3H), 2.05 (dd,
J=13.8, 3.1 Hz, 1H), 2.18 (dq, J=14.2, 6.9 Hz, 1H), 2.29 (t, J=13.6
Hz, 1H), 2.62 (d, J=13.5 Hz, 1H), 2.99 (d, J=13.5 Hz, 1H), 3.09 (br
s, 3H), 3.20-3.29 (m, 1H), 3.32-3.35 (m, 1H), 3.56 (ddd, J=13.8,
10.9, 2.9 Hz, 1H), 4.07 (dd, J=13.9, 10.5 Hz, 1H), 5.09 (d, J=11
Hz, 1H), 6.98 (dt, J=7.2, 1.4 Hz, 1H), 7.03-7.08 (m, 1H), 7.08-7.16
(m, 2H), 7.29 (br s, 4H); Mass Spectrum (ESI) m/z=540.2 (M+H).
Example 339
2-((3R,5R,6S)-5-(3-Chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-(ethylsulfony-
l)butan-2-yl)-3-methyl-2-oxopiperidin-3-yl)acetic acid
##STR00888##
[3270] Step A.
(3S,5S,6R,8S)-8-Allyl-6-(3-chlorophenyl)-5-(4-chlorophenyl)-3-ethyl-8-met-
hyl-2,3,5,6,7,8-hexahydrooxazolo[3,2-a]pyridin-4-ium
trifluoromethanesulfonate
##STR00889##
[3272] By the method of Example 361 Step A using (S)-2-aminobutanol
in place of L-valinol, the title compound was obtained as the first
eluting diastereomer.
[3273] .sup.1H NMR (500 MHz, DMSO-d.sub.6) .delta. ppm 7.95 (1H,
br. s), 7.34-7.60 (2H, m), 7.18-7.34 (4H, m), 7.13 (1H, dt, J=7.5,
1.3 Hz), 5.88 (1H, m), 5.37 (1H, dd, J=16.8, 1.6 Hz), 5.28 (1H, dd,
J=10.0, 2.0 Hz), 5.16 (1H, d, J=10.8 Hz), 5.06 (1H, t, J=9.8 Hz),
4.78 (1H, dd, J=9.5, 7.1 Hz), 4.45 (1H, m, J=2.7 Hz), 3.88-3.98
(1H, m), 2.66-2.85 (2H, m), 2.33 (1H, t, J=13.4 Hz), 1.99 (1H, dd,
J=13.7, 3.4 Hz), 1.32 (3H, s), 0.94 (1H, m), 0.59 (3H, t, J=7.2
Hz), 0.41-0.53 (1H, m); Mass Spectrum (ESI) m/z=428.2
(M.sup.+).
Step B.
(3S,5R,6S)-3-Allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1--
(ethylthio)butan-2-yl)-3-methylpiperidin-2-one
##STR00890##
[3275] To a solution of
(3S,5S,6R,8S)-8-allyl-6-(3-chlorophenyl)-5-(4-chlorophenyl)-3-ethyl-8-met-
hyl-2,3,5,6,7,8-hexahydrooxazolo[3,2-a]pyridin-4-ium
trifluoromethanesulfonate (86 mg, 0.15 mmol; Example 339, Step A)
in DMF (0.74 ml) was added sodium ethanethiolate (38 mg, 0.45
mmol). After being stirred at 25.degree. C. for 1.5 h, the reaction
was quenched (sat. aq. NH.sub.4Cl), extracted (2.times.EtOAc), and
washed (2.times. brine). The combined organic layers were dried
over Na.sub.2SO.sub.4, filtered and the filtrate was concentrated
under reduced pressure. Purification of the residue by
chromatography on silica gel (12 g SiO.sub.2, 10% and 20%
EtOAc/hex) provided the title compound as a colorless liquid.
Step C.
2-((3R,5R,6S)-5-(3-Chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-(ethy-
lsulfonyl)butan-2-yl)-3-methyl-2-oxopiperidin-3-yl)acetic acid
[3276] To a rapidly stirring solution of
(3S,5R,6S)-3-allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-(ethylt-
hio)butan-2-yl)-3-methylpiperidin-2-one (60 mg, 0.12 mmol; Example
339, Step B) in a mixture of water (0.66 mL), acetonitrile (0.44
mL), and CCl.sub.4 (0.44 mL) was added sodium periodate (157 mg,
0.734 mmol), followed by ruthenium(III) chloride hydrate (2.8 mg,
0.012 mmol). After being vigorously stirred for 5 h, the reaction
was acidified (10% citric acid) and diluted (EtOAc). The reaction
mixture was filtered through a pad of Celite.RTM. (J. T. Baker,
Phillipsberg, N.J., diatomaceous earth) and the filtrate was
extracted (2.times.EtOAc). The combined organic layers were washed
with brine, dried over Na.sub.2SO.sub.4 filtered and the filtrate
was concentrated under reduced pressure. Purification of the
residue by reverse phase preparatory HPLC (Gemini.TM. Prep C.sub.18
5 .mu.m column, Phenomenex, Torrance, Calif.; gradient elution of
40% to 60% MeCN in water, where both solvents contain 0.1% TFA)
provided the title compound as a white foam.
[3277] .sup.1H NMR (400 MHz, CHLOROFORM-d) .delta. ppm 7.24-7.26
(2H, m), 7.01-7.20 (4H, m), 6.93-6.98 (1H, m), 6.85 (1H, d, J=7.0
Hz), 4.94 (1H, d, J=10.6 Hz), 4.15 (1H, t, J=12.1 Hz), 3.24-3.37
(1H, m), 2.92-3.18 (4H, m), 2.71-2.82 (2H, m), 2.38 (1H, t, J=13.8
Hz), 2.06-2.21 (1H, m), 1.92 (1H, dd, J=13.7, 2.7 Hz), 1.48 (3H,
s), 1.42-1.46 (1H, m) 1.44 (3H, t, J=7.5 Hz), 0.41 (3H, t, J=7.5
Hz); Mass Spectrum (ESI) m/z=540.1 [M+H.
Example 340
2-((3R,5R,6S)-5-(3-Chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-(cyclopropyls-
ulfonyl)butan-2-yl)-3-methyl-2-oxopiperidin-3-yl)acetic acid
##STR00891##
[3278] Step A.
(3S,5R,6S)-3Allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-(cyclopr-
opylsulfonyl)butan-2-yl)-3-methylpiperidin-2-one
##STR00892##
[3280] To a solution of
(3S,5S,6R,8S)-8-allyl-6-(3-chlorophenyl)-5-(4-chlorophenyl)-3-ethyl-8-met-
hyl-2,3,5,6,7,8-hexahydrooxazolo[3,2-a]pyridin-4-ium
trifluoromethanesulfonate (75 mg, 0.130 mmol; Example 339, Step A)
in acetonitrile (1.3 mL) was added cyclopropanesulfinic acid sodium
salt (50 mg, 0.39 mmol) at 25.degree. C. After being stirred at
90.degree. C. for 1 day, the reaction was quenched with sat. aq.
NH.sub.4Cl solution, extracted (2.times.EtOAc) and the combined
organic layers were washed with brine (2.times.), dried over
Na.sub.2SO.sub.4, filtered and the filtrate was concentrated under
reduced pressure. Purification of the residue by chromatography on
silica gel (12 g SiO.sub.2, 35% and 45% EtOAc/hex) provided the
title compound as a colorless liquid.
Step B.
2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-(cycl-
opropylsulfonyl)butan-2-yl)-3-methyl-2-oxopiperidin-3-yl)acetic
acid
[3281] The title compound was prepared from
(3S,5R,6S)-3-allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-(cyclop-
ropylsulfonyl)butan-2-yl)-3-methylpiperidin-2-one (Example 340,
Step A) by a procedure similar to the one described in Example 339
Step C.
[3282] .sup.1H NMR (400 MHz, CHLOROFORM-d) .delta. ppm 7.22-7.26
(2H, m), 6.99-7.19 (4H, m), 6.91-6.97 (1H, m), 6.76-6.89 (1H, m),
4.91 (1H, d, J=10.8 Hz), 4.21 (1H, dd, J=13.5, 11.3 Hz), 3.31 (1H,
t, J=10.3 Hz), 3.12 (1H, ddd, J=13.6, 10.9, 2.6 Hz), 2.88-3.02 (2H,
m), 2.76 (1H, d, J=14.9 Hz), 2.31-2.49 (2H, m), 2.06-2.24 (1H, m),
1.90 (1H, dd, J=13.7, 2.7 Hz), 1.40-1.56 (1H, m), 1.47 (3H, s),
1.23-1.36 (2H, m), 1.01-1.16 (2H, m), 0.42 (3H, t, J=7.5 Hz); Mass
Spectrum (ESI) 552.2 [M+H].sup.+.
[3283] Examples 340 and 341 were prepared from
(3S,5S,6R,8S)-8-allyl-6-(3-chlorophenyl)-5-(4-chlorophenyl)-3-ethyl-8-met-
hyl-2,3,5,6,7,8-hexahydrooxazolo[3,2-a]pyridin-4-ium
trifluoromethanesulfonate (Example 339, Step A) by a procedure
similar to the one described in either Example 339 or Example 340,
using an equivalent amount of the appropriate reagent in step
B.
TABLE-US-00018 ##STR00893## Example R Method Reagent used 341
##STR00894## Example 339 propane-2-thiolate, prepared in situ from
cesium carbonate (206 mg, 0.63 mmol) and 2-propanethiol (59 .mu.l,
0.63 mmol) 342 ##STR00895## Example 339 2-methylpropanethiolate,
prepared in situ from 2-methylpropane- 2-thiol (113 .mu.l, 1.00
mmol) and sodium carbonate (106 mg, 1.00 mmol) 343 ##STR00896##
Example 340 cyclobutanesulfinic acid, sodium salt,
Example 341
2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-(isopropylsul-
fonyl)butan-2-yl)-3-methyl-2-oxopiperidin-3-yl)acetic acid
[3284] .sup.1H NMR (400 MHz, CHLOROFORM-d) .delta. ppm 7.22-7.26
(2H, br s), 7.02-7.21 (4H, m), 6.92-6.94 (1H, s), 6.85 (1H, d,
J=7.0 Hz), 4.97 (1H, d, J=10.8 Hz), 4.10 (1H, t, J=11.7 Hz),
3.27-3.42 (1H, m), 2.98-3.16 (3H, m), 2.70-2.78 (2H, m), 2.40 (1H,
t, J=13.9 Hz), 2.08-2.26 (1H, m), 1.86-1.93 (1H, s), 1.49 (3H, s),
1.43 (3H, d, J=6.8 Hz), 1.43 (3H, d, J=6.8 Hz), 1.40-1.50 (1H, m)
0.41 (3H, t, J=7.5 Hz); Mass Spectrum (ESI) m/z=554.2
[M+H].sup.+.
Example 342
2-((3R,5R,6S)-1-((S)-1-(tert-butylsulfonyl)butan-2-yl)-5-(3-chlorophenyl)--
6-(4-chlorophenyl)-3-methyl-2-oxopiperidin-3-yl)acetic acid
[3285] .sup.1H NMR (500 MHz, CHLOROFORM-d) .delta. ppm 7.21-7.26
(2H, m), 7.01-7.20 (4H, m), 6.92-6.94 (1H, m), 6.85 (1H, d, J=7.1
Hz), 4.99 (1H, d, J=10.8 Hz), 4.04 (1H, dd, J=13.2, 11.2 Hz), 3.33
(1H, t, J=10.4 Hz), 3.03-3.15 (2H, m), 2.80 (1H, dd, J=13.2, 2.0
Hz), 2.72 (1H, d, J=15.4 Hz), 2.43 (1H, t, J=13.8 Hz), 2.08-2.23
(1H, m), 1.86 (1H, dd, J=13.7, 2.4 Hz), 1.50 (3H, s), 1.46-1.49
(1H, m), 1.44 (9H, s), 0.41 (3H, t, J=7.6 Hz); Mass Spectrum (ESI)
568.2 [M+H].sup.+.
Example 343
2-((3R,5R,6S)-5-(3-Chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-(cyclobutylsu-
lfonyl)butan-2-yl)-3-methyl-2-oxopiperidin-3-yl)acetic acid
[3286] .sup.1H NMR (500 MHz, CHLOROFORM-d) .delta. ppm 7.21-7.27
(2H, m), 7.00-7.21 (4H, m), 6.93-6.97 (1H, s), 6.86 (1H, d, J=7.1
Hz), 4.97 (1H, d, J=10.8 Hz), 3.98 (1H, t, J=12.2 Hz), 3.76 (1H,
quin, J=8.3 Hz), 3.31 (1H, t, J=9.9 Hz), 3.12 (1H, ddd, J=13.6,
10.9, 2.7 Hz), 2.99 (1H, d, J=14.9 Hz), 2.75 (1H, d, J=14.9 Hz),
2.50-2.69 (3H, m), 2.27-2.46 (3H, m), 2.04-2.19 (3H, m), 1.91 (1H,
dd, J=13.7, 2.7 Hz), 1.48-1.52 (3H, m), 1.41-1.47 (1H, m), 0.40
(3H, t, J=7.6 Hz); Mass Spectrum (ESI) 566.2 [M+H].sup.+.
Synthesis of Cyclobutanesulfinic Acid, Sodium Salt
##STR00897##
[3288] The reagent was prepared by procedures similar to the ones
described in WO2007/14011 and WO2010/39982. To a suspension of
magnesium (306 mg, 12.6 mmol) in ether (7.4 mL) was added a
solution of bromocyclobutane (1.00 g, 7.41 mmol) in ether (7.4 mL)
in several small portions at 25.degree. C. After the initial
exotherm had ceased, the mixture was further heated to reflux for 1
h. Then the suspension was added in small portions to an ice cold
solution of sulfuryl dichloride (3.00 g, 22.2 mmol) in DCM (12 mL).
The suspension was warmed to room temperature and the volatiles
were removed under reduced pressure. The residue was dried under a
vacuum, then extracted with hexane (80 mL). The hexane suspension
was filtered and the filter cake was washed with hexanes. The
combined filtrates were dried (Na.sub.2SO.sub.4) and concentrated
under reduced pressure to give crude cyclobutanesulfonyl chloride.
The crude cyclobutanesulfonyl chloride (1.15 g, 7.44 mmol) was
added to a suspension of sodium sulfite (2.16 g, 17.1 mmol) in
water (9.7 ml) and sodium carbonate (1.42 g, 13.4 mmol). The
resulting solution was heated to reflux for 1 h. The reaction was
cooled and lyophilized to remove water. Ethanol (50 mL) was added
to the residue, and the resulting mixture was heated under reflux
for 2 h. The mixture was filtered. The filtrate was concentrated
under the reduced pressure to give the crude title compound which
was used as is in the next step.
Example 344
2-((3R,5R,6S)-5-(3-Chlorophenyl)-6-(4-chlorophenyl)-3-ethyl-1-((S)-1-(ethy-
lsulfonyl)butan-2-yl)-2-oxopiperidin-3-yl)acetic acid
##STR00898##
[3289] Step A.
(3S,5S,6R,8S)-8-Allyl-6-(3-chlorophenyl)-5-(4-chlorophenyl)-3,8-diethyl-2-
,3,5,6,7,8-hexahydrooxazolo[3,2-a]pyridin-4-ium
methanesulfonate
##STR00899##
[3291] To a solution of
(3S,5R,6S)-3-allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-ethyl-1-((S)-1-
-hydroxybutan-2-yl)piperidin-2-one (300 mg, 0.652 mmol) (Example
202, Step B) in DCM (6 mL) was added triethylamine (270 .mu.l,
1.955 mmol) and methanesulfonic anhydride (170 mg, 0.977 mmol)
successively at 0.degree. C. The reaction was allowed to warm to
rt. After being stirred at rt for 2 h, the reaction was quenched
with 10% aq. citric acid, extracted with DCM and the combined
extracts were washed with water, dried over Na.sub.2SO.sub.4,
filtered and the filtrate was and concentrated to give the title
compound.
Step B.
(3S,5R,6S)-3-Allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-ethyl-1-
-((S)-1-(ethylthio)butan-2-yl)piperidin-2-one
##STR00900##
[3293] The title compound was prepared from
(3S,5S,6R,8S)-8-allyl-6-(3-chlorophenyl)-5-(4-chlorophenyl)-3,8-diethyl-2-
,3,5,6,7,8-hexahydrooxazolo[3,2-a]pyridin-4-ium methanesulfonate
(Example 344, step A) by a procedure similar to the one described
in Example 339, step B.
Step C.
2-((3R,5R,6S)-5-(3-Chlorophenyl)-6-(4-chlorophenyl)-3-ethyl-1-((S)-
-1-(ethylsulfonyl)butan-2-yl)-2-oxopiperidin-3-yl)acetic acid
[3294] The title compound was prepared from
(3S,5R,6S)-3-allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-ethyl-1-((S)-1-
-(ethylthio)butan-2-yl)piperidin-2-one (Example 344, step B) by a
procedure similar to the one described in Example 339, step C.
[3295] .sup.1H NMR (400 MHz, CHLOROFORM-d) .delta. ppm 0.41 (t,
J=8.0 Hz, 3H), 0.97 (t, J=8.0 Hz, 3H), 1.44 (s, 3H), 1.50 (m, 1H),
1.86 (dd, J=12, 4 Hz, 1H), 1.97 (m, 2H), 2.15 (m, 1H), 2.36 (t,
J=12 Hz, 1H), 2.79 (m, 1H), 2.81 (d, J=16 Hz, 1H), 2.92 (d, J=16.0
Hz, 1H), 3.04 (m, 2H), 3.16 (m, 1H), 3.19 (m, 1H), 4.11 (m, 1H),
4.97 (d, J=12 Hz, 1H), 6.86 (d, J=8.0 Hz, 1H), 6.97 (s, 1H), 7.13
(m, 3H), 7.38 (m, 3H); Mass Spectrum (ESI) m/z=554.0
[M+H].sup.+.
[3296] Examples 345 to 347 were prepared from
(3S,5S,6R,8S)-8-allyl-6-(3-chlorophenyl)-5-(4-chlorophenyl)-3,8-diethyl-2-
,3,5,6,7,8-hexahydrooxazolo[3,2-a]pyridin-4-ium methanesulfonate
(Example 344, Step A) by a procedure similar to the one described
in either Example 339 or Example 340, using an equivalent amount of
the appropriate reagent in step B.
TABLE-US-00019 ##STR00901## Example R Method Reagent used 345
##STR00902## Example 339 propane-2-thiolate, prepared in situ from
cesium carbonate (206 mg, 0.63 mmol) and 2-propanethiol (59 .mu.l,
0.63 mmol) 346 ##STR00903## Example 339 2-methylpropanethiolate,
prepared in situ from 2- methylpropane-2-thiol (113 .mu.l, 1.00
mmol) and sodium carbonate (106 mg, 1.00 mmol) 347 ##STR00904##
Example 340 cyclobutanesulfinic acid sodium salt, prepared as
described in Example 343 348 ##STR00905## Example 340
cyclopropanesulfinic acid sodium salt, prepared by the method as
described in Example 343
Example 345
2-((3R,5R,6S)-5-(3-Chlorophenyl)-6-(4-chlorophenyl)-3-ethyl-1-((S)-1-(isop-
ropylsulfonyl)butan-2-yl)-2-oxopiperidin-3-yl)acetic acid
[3297] .sup.1H NMR (400 MHz, CHLOROFORM-d) .delta. ppm 0.40 (t,
J=8.0 Hz, 3H), 0.97 (t, J=8.0 Hz, 3H), 1.43 (d, J=4 Hz, 6H), 1.50
(m, 1H), 1.86 (dd, J=12, 4 Hz, 1H), 1.98 (m, 2H), 2.19 (m, 1H),
2.37 (t, J=12 Hz, 1H), 2.73 (d, J=12 Hz, 1H), 2.79 (d, J=12.0 Hz,
1H), 2.97 (d, J=12 Hz, 1H), 3.10 (m, 2H), 3.37 (m, 1H), 4.09 (m,
1H), 4.99 (d, J=12 Hz, 1H), 6.86 (d, J=8.0 Hz, 1H), 6.98 (s, 1H),
7.12 (m, 4H), 7.27 (m, 2H); Mass Spectrum (ESI) m/z=568.0
[M+H].sup.+.
Example 346
2-((3R,5R,6S)-1-((S)-1-(tert-butylsulfonyl)butan-2-yl)-5-(3-chlorophenyl)--
6-(4-chlorophenyl)-3-ethyl-2-oxopiperidin-3-yl)acetic acid
[3298] .sup.1H NMR (400 MHz, CHLOROFORM-d) .delta. ppm 0.39 (t,
J=8.0 Hz, 3H), 0.97 (t, J=8.0 Hz, 3H), 1.43 (s, 9H), 1.50 (m, 1H),
1.85 (dd, J=12, 4 Hz, 1H), 1.97 (m, 2H), 2.15 (m, 1H), 2.38 (t,
J=12 Hz, 1H), 2.80 (d, J=16 Hz, 1H), 2.96 (d, J=16.0 Hz, 1H), 3.14
(m, 2H), 3.35 (m, 1H), 4.01 (m, 1H), 5.02 (d, J=8 Hz, 1H), 6.87 (d,
J=8.0 Hz, 1H), 6.98 (s, 1H), 7.13 (m, 4H), 7.38 (m, 2H); Mass
Spectrum (ESI) m/z=582.1 [M+H].sup.+.
Example 347
2-((3R,5R,6S)-5-(3-Chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-(cyclobutylsu-
lfonyl)butan-2-yl)-3-ethyl-2-oxopiperidin-3-yl)acetic acid
[3299] .sup.1H NMR (400 MHz, CHLOROFORM-d) .delta. ppm 0.39 (t,
J=8.0 Hz, 3H), 0.98 (t, J=8.0 Hz, 3H), 1.50 (m, 1H), 1.84-2.45 (m,
6H), 2.38 (m, 3H), 2.62 (m, 3H), 2.80 (d, J=16 Hz, 1H), 2.94 (d,
J=16.0 Hz, 1H), 3.15 (d, J=12 Hz, 1H), 3.34 (m, 1H), 3.76 (m, 1H),
3.94 (m, 1H), 5.00 (d, J=12 Hz, 1H), 6.87 (d, J=8.0 Hz, 1H), 6.98
(s, 1H), 7.13 (m, 3H), 7.28 (m, 3H); Mass Spectrum (ESI) 580.0
[M+H].sup.+.
Example 348
2-((3R,5R,6S)-5-(3-Chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-(cyclopropyls-
ulfonyl)butan-2-yl)-3-ethyl-2-oxopiperidin-3-yl)acetic acid
[3300] .sup.1H NMR (400 MHz, CHLOROFORM-d) .delta. ppm 0.42 (t,
J=8.0 Hz, 3H), 0.97 (t, J=8.0 Hz, 3H), 1.10 (m, 2H), 1.26 (m, 2H),
1.52 (m, 1H), 1.83 (dd, J=16, 4 Hz, 1H), 1.96 (m, 2H), 2.14 (m,
1H), 2.34 (d, J=16.0 Hz, 1H), 2.42 (m, 1H), 2.79 (d, J=12 Hz, 1H),
2.95 (m, 1H), 2.98 (d, J=16 Hz, 1H), 3.12 (m, 1H), 3.34 (m, 1H),
4.15 (m, 1H), 5.00 (d, J=12 Hz, 1H), 6.84 (d, J=8.0 Hz, 1H), 6.96
(s, 1H), 7.12 (m, 4H), 7.27 (m, 2H);
[3301] Mass Spectrum (ESI) m/z=566.0 [M+H].sup.+.
Example 349
2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-cyclopropyl-2-
-(ethylsulfonyl)ethyl)-3-methyl-2-oxopiperidin-3-yl)acetic acid
##STR00906##
[3302] Step A.
(3S,5S,6R,8S)-8-Allyl-6-(3-chlorophenyl)-5-(4-chlorophenyl)-3-cyclopropyl-
-8-methyl-2,3,5,6,7,8-hexahydrooxazolo[3,2-a]pyridin-4-ium
methanesulfonate
##STR00907##
[3304] The title compound was prepared from
(3S,5R,6S)-3-allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-cyclopr-
opyl-2-hydroxyethyl)-3-methylpiperidin-2-one (Example 252, Step A)
by a procedure similar to the one described in Example 344, step
A.
Step B.
(3S,5R,6S)-3-Allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1--
cyclopropyl-2-(ethylthio)ethyl)-3-methylpiperidin-2-one
##STR00908##
[3306] The title compound was prepared from
(3S,5S,6R,8S)-8-allyl-6-(3-chlorophenyl)-5-(4-chlorophenyl)-3-cyclopropyl-
-8-methyl-2,3,5,6,7,8-hexahydrooxazolo[3,2-a]pyridin-4-ium
methanesulfonate (Example 349, Step A) and sodium ethanethiolate as
described in Example 339.
Step C.
2-((3R,5R,6S)-5-(3-Chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-cyclo-
propyl-2-(ethylsulfonyl)ethyl)-3-methyl-2-oxopiperidin-3-yl)acetic
acid
[3307] The title compound was prepared from
(3S,5R,6S)-3-allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-cyclopr-
opyl-2-(ethylthio)ethyl)-3-methylpiperidin-2-one (Example 349, step
B) by a procedure similar to the one described in Example 339, step
C.
[3308] .sup.1H NMR (400 MHz, CHLOROFORM-d) .delta. ppm 7.20-7.26
(3H, m), 7.07-7.17 (3H, m), 6.95-6.98 (1H, m), 6.82-6.88 (1H, m),
4.90 (1H, d, J=10.6 Hz), 4.25-4.46 (1H, m), 3.11-3.24 (1H, m),
2.99-3.09 (3H, m), 2.92 (1H, d, J=12.1 Hz), 2.80 (1H, d, J=14.7
Hz), 2.64-2.77 (1H, m), 2.42 (1H, t, J=13.8 Hz), 1.91 (1H, dd,
J=13.9, 2.5 Hz), 1.83 (1H, br. s.), 1.49 (3H, s), 1.44 (3H, t,
J=7.5 Hz), 0.32-0.42 (1H, m), 0.18-0.27 (1H, m), -0.35--0.24 (1H,
m), -1.15--0.95 (1H, m); Mass Spectrum (ESI) 552.2 [M+H].sup.+.
[3309] Examples 350 to 356 were prepared from
(3S,5S,6R,8S)-8-allyl-6-(3-chlorophenyl)-5-(4-chlorophenyl)-3-cyclopropyl-
-8-methyl-2,3,5,6,7,8-hexahydrooxazolo[3,2-a]pyridin-4-ium
methanesulfonate (Example 349, Step A) by a procedure similar to
the one described in either Example 339 or Example 340, using an
equivalent amount of the appropriate reagent in step B.
TABLE-US-00020 ##STR00909## Example R Method Reagent used 350
##STR00910## Example 339 propane-2-thiolate, prepared in situ from
2- propanethiol and sodium carbonate 351 ##STR00911## Example 339
2-methylpropanethiolate, prepared in situ from 2-
methylpropane-2-thiol and sodium carbonate 352 ##STR00912## Example
340 cyclobutanesulfinic acid sodium salt, prepared as described in
Example 343 353 ##STR00913## Example 340 cyclopropanesulfinic acid
sodium salt, prepared by the method as described in Example 343 354
Me Example 340 sodium methanesulfinate 355 ##STR00914## Example 339
2-methylbutane-2- thiolate, prepared in situ from 2-
methylbutane-2-thiol and NaH 356 ##STR00915## Example 339
2,4-di-fluorobenzene- thiolate prepared in situ from 2,4-di-
fluorobenzenethiol and NaH
Example 350
2-((3R,5R,6S)-5-(3-Chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-cyclopropyl-2-
-(isopropylsulfonyl)ethyl)-3-methyl-2-oxopiperidin-3-yl)acetic
acid
[3310] .sup.1H NMR (400 MHz, CHLOROFORM-d) .delta. ppm 7.23-7.26
(3H, m), 7.04-7.20 (3H, m), 6.93-6.97 (1H, m), 6.84-6.88 (1H, m),
4.93 (1H, d, J=10.8 Hz), 4.34 (1H, br. s.), 3.05-3.18 (3H, m), 2.86
(1H, d, J=13.3 Hz), 2.77 (2H, d, J=15.3 Hz), 2.46 (1H, t, J=13.8
Hz), 1.86 (2H, dd, J=13.5, 2.5 Hz), 1.51 (3H, s), 1.44 (6H, d,
J=6.8 Hz), 0.31-0.44 (1H, m), 0.18-2.80 (1H, m), -0.35--0.23 (1H,
m), -1.15--1.02 (1H, br. s.);
[3311] Mass Spectrum (ESI) 566.2 [M+H].sup.+.
Example 351
2-((3R,5R,6S)-1-((S)-2-(tert-Butylsulfonyl)-1-cyclopropylethyl)-5-(3-chlor-
ophenyl)-6-(4-chlorophenyl)-3-methyl-2-oxopiperidin-3-yl)acetic
acid
[3312] .sup.1H NMR (400 MHz, CHLOROFORM-d) .delta. ppm 7.20-7.26
(3H, m), 7.03-7.17 (3H, m), 6.93-6.97 (1H, m), 6.82-6.92 (1H, m),
4.95 (1H, d, J=10.6 Hz), 4.30 (1H, t, J=12.0 Hz), 3.14 (1H, ddd,
J=13.6, 10.8, 2.6 Hz), 3.07 (1H, d, J=15.1 Hz), 2.92 (1H, d, J=11.9
Hz), 2.79 (1H, d, J=15.1 Hz), 2.72 (1H, t, J=9.6 Hz), 2.45 (1H, t,
J=13.8 Hz), 1.88 (2H, dd, J=13.6, 2.4 Hz), 1.50 (3H, s), 1.44 (9H,
s), 0.30-0.44 (1H, m), 0.17-0.30 (1H, m), -0.37--0.26 (1H, m),
-1.15--1.05 (1H, m); Mass Spectrum (ESI) 580.2 [M+H].sup.+.
Example 352
2-((3R,5R,6S)-5-(3-Chlorophenyl)-6-(4-chlorophenyl)-1-((S)-2-(cyclobutylsu-
lfonyl)-1-cyclopropylethyl)-3-methyl-2-oxopiperidin-3-yl)acetic
acid
[3313] .sup.1H NMR (400 MHz, CHLOROFORM-d) .delta. ppm 7.20-7.27
(3H, m), 7.07-7.15 (3H, m), 6.94-6.98 (1H, m), 6.84-6.93 (1H, m),
4.93 (1H, d, J=10.6 Hz), 4.23 (1H, t, J=11.3 Hz), 3.77 (1H, quin,
J=8.3 Hz), 3.12-3.22 (1H, m), 3.08 (1H, d, J=15.1 Hz), 2.70-2.83
(3H, m), 2.53-2.69 (2H, m), 2.47 (1H, t, J=13.8 Hz), 2.27-2.40 (2H,
m), 2.04-2.19 (2H, m), 1.73-1.97 (2H, m), 1.51 (3H, s), 0.30-0.41
(1H, m), 0.20-0.30 (1H, m), -0.35--0.25 (1H, m), -1.12--0.95 (1H,
m); Mass Spectrum (ESI) 578.1 [M+H].sup.+.
Example 353
2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-cyclopropyl-2-
-(cyclopropylsulfonyl)ethyl)-3-methyl-2-oxopiperidin-3-yl)acetic
acid
[3314] .sup.1H NMR (400 MHz, CHLOROFORM-d) .delta. ppm 7.18-7.26
(3H, m), 7.06-7.15 (3H, m), 6.92-6.97 (1H, m), 6.82-6.88 (1H, m),
4.87 (1H, d, J=10.6 Hz), 4.44 (1H, br. s.), 3.11-3.23 (1H, m),
3.01-3.10 (2H, m), 2.78 (1H, d, J=15.1 Hz), 2.73 (1H, br. s.),
2.35-2.47 (2H, m), 1.88 (1H, dd, J=13.8, 2.6 Hz), 1.76-1.85 (1H,
m), 1.49 (3H, s), 1.24-1.35 (2H, m), 1.03-1.16 (2H, m), 0.32-0.44
(1H, m), 0.20-0.30 (1H, m), -0.33--0.21 (1H, m), -1.02--0.98 (1H,
br. s.); Mass Spectrum (ESI) 564.1 [M+H].sup.+.
Example 354
2-((3R,5R,6S)-5-(3-Chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-cyclopropyl-2-
-(methylsulfonyl)ethyl)-3-methyl-2-oxopiperidin-3-yl)acetic
acid
[3315] .sup.1H NMR (400 MHz, CHLOROFORM-d) .delta. ppm -1.03 (br s,
1H) -0.26 (br s, 1H) 0.27 (br s, 1H) 0.33-0.49 (m, 1H) 1.51 (s, 3H)
1.71-1.97 (m, 2H) 2.43 (t, J=13.79 Hz, 1H) 2.78 (m, 2H) 3.00 (s,
3H) 3.01-3.24 (m, 3H) 4.44 (br s, 1H) 4.87 (d, J=10.56 Hz, 1H)
6.81-6.92 (m, 1H) 6.96 (s, 1H) 7.07-7.20 (m, 2H) 7.27 (m, 4H); Mass
Spectrum (ESI) m/z=540 (M+1).
Example 355
2-((3R,5R,6S)-5-(3-Chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-cyclopropyl-2-
-(tert-pentylsulfonyl)ethyl)-3-methyl-2-oxopiperidin-3-yl)acetic
acid
[3316] .sup.1H NMR (400 MHz, CHLOROFORM-d) .delta. ppm -1.11 (br s,
1H), -0.31 (br s, 1H), 0.23 (br s, 1H), 0.36 (br s, 1H), 1.04 (t,
J=7.53 Hz, 3H), 1.28-1.44 (m, 6H), 1.50 (s, 3H), 1.73-1.95 (m, 4H),
2.48 (t, J=13.89 Hz, 1H), 2.76 (d, J=15.26 Hz, 2H), 2.91 (d,
J=13.11 Hz, 1H), 3.04-3.23 (m, 2H), 4.28 (t, J=11.15 Hz, 1H),
4.90-5.07 (m, 1H), 6.84-6.93 (m, 1H), 6.94-7.03 (m, 1H), 7.05-7.37
(br s, 6H); Mass Spectrum (ESI) m/z=594.0 (M+1).
Example 356
2-((3R,5R,6S)-5-(3-Chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-cyclopropyl-2-
-((2,4-difluorophenyl)sulfonyl)ethyl)-3-methyl-2-oxopiperidin-3-yl)acetic
acid
[3317] .sup.1H NMR (400 MHz, CHLOROFORM-d) .delta. ppm -1.06 (br s,
1H), -0.29 (br s, 1H), 0.15-0.28 (m, 1H), 0.28-0.44 (m, 1H), 1.37
(s, 1H), 1.54 (s, 3H), 1.77-1.95 (m, 2H), 2.48 (t, J=13.79 Hz, 1H),
2.67-2.85 (m, 1H), 3.07 (d, J=14.87 Hz, 1H), 3.13-3.32 (m, 2H),
4.65 (br s, 1H), 4.92 (d, J=10.56 Hz, 1H), 6.81-6.94 (m, 2H),
6.94-7.21 (m, 8H), 7.99 (td, J=8.31, 6.06 Hz, 1H); MS (ESI)
m/e=636.0 (M+1).
Example 357
2-((3R,5R,6S)-5-(3-Chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-cyclopropyl-2-
-(ethylsulfonyl)ethyl)-3-ethyl-2-oxopiperidin-3-yl)acetic acid
##STR00916##
[3318] Step A.
(3S,5S,6R,8S)-8-Allyl-6-(3-chlorophenyl)-5-(4-chlorophenyl)-3-cyclopropyl-
-8-ethyl-2,3,5,6,7,8-hexahydrooxazolo[3,2-a]pyridin-4-ium
methanesulfonate
##STR00917##
[3320] The title compound was prepared from
(3S,5R,6S)-3-allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-cyclopr-
opyl-2-hydroxyethyl)-3-ethylpiperidin-2-one (Example 253, Step C)
by a procedure similar to the one described in Example 344, step
A.
Step B.
(3S,5R,6S)-3-Allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1--
cyclopropyl-2-(ethylthio)ethyl)-3-ethylpiperidin-2-one
##STR00918##
[3322] The title compound was prepared from
(3S,5S,6R,8S)-8-Allyl-6-(3-chlorophenyl)-5-(4-chlorophenyl)-3-cyclopropyl-
-8-ethyl-2,3,5,6,7,8-hexahydrooxazolo[3,2-a]pyridin-4-ium
methanesulfonate (Example 357, Step A) and sodium ethanethiolate by
the method described in Example 339.
Step C.
2-((3R,5R,6S)-5-(3-Chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-cyclo-
propyl-2-(ethylsulfonyl)ethyl)-3-ethyl-2-oxopiperidin-3-yl)acetic
acid
[3323] The title compound was prepared from
(3S,5R,6S)-3-allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-cyclopr-
opyl-2-(ethylthio)ethyl)-3-ethylpiperidin-2-one (Example 357, step
B) by a procedure similar to the one described in Example 339, step
C.
[3324] .sup.1H NMR (500 MHz, CHLOROFORM-d) .delta. ppm -0.99 (br s,
1H) -0.25 (br s, 1H) 0.30 (br s, 1H) 0.40 (br s, 1H) 0.98 (t,
J=7.46 Hz, 3H) 1.44 (t, J=7.58 Hz, 3H) 1.83 (m, 2H) 1.92-2.09 (m,
2H) 2.41 (t, J=13.69 Hz, 1H) 2.71-2.88 (m, 2H) 2.94 (d, J=13.45 Hz,
1H) 3.00-3.20 (m, 4H) 4.30 (br. s, 1H) 4.92 (d, J=10.76 Hz, 1H)
6.81-6.87 (m, 1H) 6.97 (m, 1H) 7.08-7.26 (m, 3H); 7.30-7.50 (m,
4H); Mass Spectrum (ESI) m/z=566 (M+1).
[3325] Examples 358 to 360 were prepared from
(3S,5S,6R,8S)-8-allyl-6-(3-chlorophenyl)-5-(4-chlorophenyl)-3-cyclopropyl-
-8-ethyl-2,3,5,6,7,8-hexahydrooxazolo[3,2-a]pyridin-4-ium
methanesulfonate (Example 357, Step A) by a procedure similar to
the one described in either Example 339 or Example 340, using an
equivalent amount of the appropriate reagent in step B.
TABLE-US-00021 ##STR00919## Example R Method Reagent used 358
##STR00920## Example 339 propane-2-thiolate, prepared in situ from
2-propanethiol and NaH 359 ##STR00921## Example 339
2-methylpropanethiolate, prepared in situ from
2-methylpropane-2-thiol and NaH 360 ##STR00922## Example 340
cyclopropanesulfinate
Example 358
2-((3R,5R,6S)-5-(3-Chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-cyclopropyl-2-
-(isopropylsulfonyl)ethyl)-3-ethyl-2-oxopiperidin-3-yl)acetic
acid
[3326] .sup.1H NMR (400 MHz, CHLOROFORM-d) .delta. ppm -1.01 (br s,
1H), -0.27 (br s, 1H), 0.29 (br s, 1H), 0.39 (br s, 1H), 0.98 (t,
J=7.53 Hz, 3H), 1.33-1.52 (m, 6H), 1.71-1.94 (m, 2H), 2.01 (q,
J=7.43 Hz, 2H), 2.42 (t, J=13.79 Hz, 1H), 2.70-2.95 (m, 3H),
2.99-3.24 (m, 3H), 4.28 (br s, 1H), 4.95 (d, J=10.56 Hz, 1H),
6.83-6.94 (m, 2H), 6.94-7.05 (m, 2H), 7.05-7.21 (m, 4H); MS (ESI)
m/z=580.0 and 581.9 (M+1).
Example 359
2-((3R,5R,6S)-1-((S)-2-(tert-Butylsulfonyl)-1-cyclopropylethyl)-5-(3-chlor-
ophenyl)-6-(4-chlorophenyl)-3-ethyl-2-oxopiperidin-3-yl)acetic
acid
[3327] .sup.1H NMR (500 MHz, CHLOROFORM-d) .delta. ppm -1.05 (br s,
1H) -0.29 (br s, 1H) 0.27 (br s, 1H) 0.34-0.42 (m, 1H) 0.98 (t,
J=7.46 Hz, 3H) 1.44 (s, 9H) 1.81 (dd, J=13.69, 2.93 Hz, 1H)
1.87-2.11 (m, 3H) 2.43 (t, J=13.82 Hz, 1H) 2.79 (d, J=15.89 Hz, 2H)
2.95 (d, J=13.20 Hz, 1H) 3.04-3.19 (m, 2H) 4.21 (m, 1H) 4.97 (d,
J=10.76 Hz, 1H) 6.75-6.92 (m, 2H) 6.92-7.01 (m, 1H) 7.06-7.17 (m,
3H) 7.43 (m, 2H); Mass Spectrum (ESI) m/z=594 (M+1).
Example 360
2-((3R,5R,6S)-5-(3-Chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-cyclopropyl-2-
-(cyclopropylsulfonyl)ethyl)-3-ethyl-2-oxopiperidin-3-yl)acetic
acid
[3328] .sup.1H NMR (500 MHz, CHLOROFORM-d) .delta. ppm -0.99 (br s,
1H) -0.25 (br s, 1H) 0.29 (br s, 1H) 0.36-0.45 (m, 1H) 0.97 (t,
J=7.46 Hz, 3H) 1.07-1.16 (m, 2H) 1.21-1.34 (m, 2H) 1.82 (dd,
J=13.69, 2.93 Hz, 1H) 1.86-1.92 (m, 1H) 1.92-2.14 (m, 2H) 2.36-2.46
(m, 2H) 2.80 (d, J=15.65 Hz, 1H) 3.03-3.16 (m, 3H) 4.34 (m, 1H)
4.90 (d, J=10.51 Hz, 1H) 6.80-6.89 (m, 1H) 6.92-6.99 (m, 1H)
7.06-7.17 (m, 3H) 7.35-7.45 (m, 3H);
[3329] Mass Spectrum (ESI) m/z=578 (M+1).
Example 361
2-((3R,5R,6S)-5-(3-Chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-(ethylsulfony-
l)-3-methylbutan-2-yl)-3-methyl-2-oxopiperidin-3-yl)acetic acid
##STR00923##
[3330] Step A.
(3S,5S,6R,8S)-8-Allyl-6-(3-chlorophenyl)-5-(4-chlorophenyl)-3-isopropyl-8-
-methyl-2,3,5,6,7,8-hexahydrooxazolo[3,2-a]pyridin-4-ium
trifluoromethanesulfonate
##STR00924##
[3332] L-valinol (Sigma Aldrich, St. Louis, Mo.) (3.64 g), racemic
(3S/R,5R/S,6R/S)-3-allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methylte-
trahydro-2H-pyran-2-one (3.17 g; Example 261, step E) and lithium
t-butoxide (0.025 g) were heated as a melt for 17 hr using an oil
bath set at 135.degree. C. After cooling, the glassy solid was
dissolved in dichloromethane. The organic layer was washed with
sat. ammonium chloride solution followed by 1N sodium hydroxide
solution and then brine. The organic layer was dried over magnesium
sulfate and concentrated to give 3.88 g of a mixture of
diastereomers. A 2.61 g portion (67% of total) of the ca. 1:1
mixture obtained above was dissolved in toluene and evaporated to
dryness three times to remove residual moisture. Dichloromethane
(55 ml) and 2,6-dimethylpyridine (3.3 ml, 28.5 mmol) were added and
the resulting stirred solution was cooled to -50.degree. C. in a
dry ice/acetonitrile bath. Trifluoromethanesulfonic anhydride (2.4
ml, 14.27 mmol) was added over the course of 10 minutes such that
the internal temperature never exceeded -45.degree. C. After 40
min, the reaction was quenched by addition of 2 M HCl. The mixture
was warmed to room temperature, diluted in dichloromethane, washed
with 2 N HCl, water, and finally brine. The organics were dried
over magnesium sulfate, filtered, and concentrated to a yellow foam
that weighed ca. 2.6 g. A portion of this material (1.92 g, 74%)
was purified by medium-pressure liquid chromatography using a 120 g
column, eluting with a gradient of 20 to 100% acetone in hexanes.
Fractions containing the faster-eluting (less polar) diastereomer
were concentrated to give the title compound as a white foam.
[3333] .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. ppm 0.62 (d, J=2.4
Hz, 3H), 0.64-0.74 (m, 4H), 1.51 (s, 3H), 2.04 (dd, J=14.1, 3.5 Hz,
1H), 2.54-2.79 (m, 3H), 3.58 (ddd, J=13.7, 10.8, 3.5 Hz, 1H), 4.59
(dd, J=10.2, 4.7 Hz, 1H), 4.67 (dd, J=9.2, 4.9 Hz, 1H), 5.23-5.45
(m, 3H), 5.71 (d, J=11 Hz, 1H), 5.83 (ddt, J=17, 9.9, 7.4 Hz, 1H),
7.06 (t, J=1.8 Hz, 1H), 7.11-7.16 (m, 1H), 7.19 (t, J=7.7 Hz, 1H),
7.23-7.32 (m, 3H), 7.39 (br s, 2H);
[3334] Mass Spectrum (ESI) m/z=442.2 (M.sup.+).
Step B.
2-((3R,5R,6S)-5-(3-Chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-(ethy-
lsulfonyl)-3-methylbutan-2-yl)-3-methyl-2-oxopiperidin-3-yl)acetic
acid
[3335] The title compound was prepared from
(3S,5S,6R,8S)-8-allyl-6-(3-chlorophenyl)-5-(4-chlorophenyl)-3-isopropyl-8-
-methyl-2,3,5,6,7,8-hexahydrooxazolo[3,2-a]pyridin-4-ium
trifluoromethanesulfonate (Example 361, step A) by procedures
similar to the ones described in Example 339, using an equivalent
amount of ethanethiol in step B.
[3336] .sup.1H NMR (500 MHz, methanol-d.sub.4) .delta. ppm 0.51 (d,
J=7.1 Hz, 3H), 0.66 (d, J=6.6 Hz, 3H), 1.37 (s, 3H), 1.41 (t, J=7.5
Hz, 3H), 2.05 (dd, J=13.7, 2.9 Hz, 1H), 2.18 (dq, J=14.2, 6.9 Hz,
1H), 2.31 (t, J=13.7 Hz, 1H), 2.62 (d, J=13.7 Hz, 1H), 3.00 (d,
J=13.7 Hz, 1H), 3.14-3.24 (m, 3H), 3.25-3.30 (m, 1H), 3.57 (ddd,
J=13.8, 10.9, 2.9 Hz, 1H), 4.02 (dd, J=13.9, 10.5 Hz, 1H), 5.12 (d,
J=11 Hz, 1H), 7.00 (dt, J=7.3, 1.5 Hz, 1H), 7.04-8.17 (m, 7H); Mass
Spectrum (ESI) m/z=554.2 (M+1).
Example 362
2-((3R,5R,6S)-5-(3-Chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-(isopropylsul-
fonyl)-3-methylbutan-2-yl)-3-methyl-2-oxopiperidin-3-yl)acetic
acid
##STR00925##
[3338] The title compound was prepared from
(3S,5S,6R,8S)-8-allyl-6-(3-chlorophenyl)-5-(4-chlorophenyl)-3-isopropyl-8-
-methyl-2,3,5,6,7,8-hexahydrooxazolo[3,2-a]pyridin-4-ium
trifluoromethanesulfonate (Example 361, step A) by procedures
similar to the ones described in Example 339, using an equivalent
amount of propane-2-thiol in step B.
[3339] .sup.1H NMR (500 MHz, methanol-d.sub.4) .delta. ppm 0.50 (d,
J=6.9 Hz, 3H), 0.65 (d, J=6.6 Hz, 3H), 1.37 (s, 3H), 1.41 (d, J=6.9
Hz, 6H), 2.05 (dd, J=13.6, 2.8 Hz, 1H), 2.18 (dq, J=14, 6.9 Hz,
1H), 2.31 (t, J=13.7 Hz, 1H), 2.61 (d, J=13.5 Hz, 1H), 2.99 (d,
J=13.7 Hz, 1H), 3.11 (d, J=13.7 Hz, 1H), 3.25-3.29 (m, 1H),
3.32-3.37 (m, 1H), 3.49-3.65 (m, 1H), 4.01 (dd, J=13.7, 10.5 Hz,
1H), 5.13 (d, J=11 Hz, 1H), 6.93-7.03 (m, 1H), 7.03-8.23 (m, 7H);
Mass Spectrum (ESI) m/z=568.0 (M+1).
Example 363
2-((3R,5R,6S)-5-(3-Chlorophenyl)-6-(4-chlorophenyl)-1-((S)-3,3-dimethyl-1--
(methylsulfonyl)butan-2-yl)-3-methyl-2-oxopiperidin-3-yl)acetic
acid
##STR00926##
[3340] Step A.
(S)-2-((2R,3R)-2-(3-Chlorophenyl)-3-(4-chlorophenyl)-3-hydroxypropyl)-N-(-
(S)-1-hydroxy-3,3-dimethylbutan-2-yl)-2-methylpent-4-enamide
##STR00927##
[3342] (S)-tert-leucinol (0.937 g, 7.99 mmol) and
(3S,5R,6R)-3-allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyltetrahyd-
ro-2H-pyran-2-one (1 g, 2.66 mmol; Example 261, Step F) were
combined in a reaction flask and heated to 100.degree. C. After 2
d, the reaction mixture was cooled to RT and dissolved in ethyl
acetate. The organic phase was washed with 3.times.10 mL 1N HCl and
1.times.10 mL brine, dried over MgSO.sub.4, filtered and
concentrated to afford the title compound.
[3343] .sup.1H-NMR (500 MHz, CDCl.sub.3) .delta. 7.21-7.10 (series
of m, 5H), 7.07 (t, J=1.7 Hz, 1H), 6.97 (m, 2H), 6.87 (br d, J=7.6
Hz, 1H), 5.91 (br d, J=8.3 Hz, 1H), 5.65 (ddt, J=17.4, 10.3, 7.3
Hz, 1H), 5.05 (dd, J=10.5, 2.0 Hz, 1H), 4.77 (d, J=4.9 Hz, 1H),
3.77 (m, 2H), 3.42 (m, 1H), 3.02 (dt, J=7.6, 5.4 Hz, 1H), 2.42 (dd,
J=13.9, 7.1 Hz, 1H), 2.23 (dd, J=14.7, 5.6 Hz, 1H), 2.05 (dd
J=13.7, 7.6 Hz, 1H), 1.87 (dd, J=14.4, 7.6 Hz, 1H), 1.17 (s, 3H),
0.92 (s, 9H); Mass Spectrum (ESI) m/z=492.2 (M+1).
Step B.
(3S,5S,6R,8S)-8-Allyl-3-(tert-butyl)-6-(3-chlorophenyl)-5-(4-chlor-
ophenyl)-8-methyl-2,3,5,6,7,8-hexahydrooxazolo[3,2-a]pyridin-4-ium
triflate
##STR00928##
[3345] To a solution of
(S)-2-((2R,3R)-2-(3-chlorophenyl)-3-(4-chlorophenyl)-3-hydroxypropyl)-N---
((S)-1-hydroxy-3,3-dimethylbutan-2-yl)-2-methylpent-4-enamide
(Example 363, step A, 950 mg, 1.929 mmol) in DCM (19 mL) at
-50.degree. C. was added 2,6-lutidine (896 .mu.l, 7.72 mmol)
followed by trifluoromethanesulfonic anhydride solution (1M DCM,
4.34 mL, 4.34 mmol). The progress of the reaction was monitored by
LC/MS. An additional charge of 450 uL (2 eq) 2,6-lutidine followed
by 1.12 eq triflic anhydride (2.16 mmol, 2.16 mL of 1M solution in
dichloromethane). The reaction was allowed to warm to 0.degree. C.
and then poured into sat. aq. CuSO.sub.4 solution. To the mixture
was added 100 mL ethyl acetate. The layers were separated and the
organic phase was washed with sat. aq. CuSO.sub.4. The combined
organic layers were concentrated and purified by column
chromatography on silica gel (eluent: 20 to 50% acetone in hexanes)
to afford the title compound.
[3346] .sup.1H-NMR (500 MHz, DMSO-d.sub.6) .delta. ppm 7.80-7.42
(series of m, 3H), 7.38-7.28 (series of m, 4H), 7.14 (d, J=7.6 Hz,
1H), 5.85 (ddt, J=17.2, 10.0, 7.3 Hz, 1H), 5.61 (d, J=7.1 Hz, 1H),
5.37 (dd, J=16.9, 1.7 Hz, 1H), 5.22 (dd, J=10.0, 7.0 Hz, 1H), 5.17
(t, J=9.7 Hz, 1H), 4.61 (dd, J=9.3, 6.9 Hz, 1H), 3.92 (ddd, J=9.8,
7.6, 4.2 Hz, 1H), 2.71 (m, 2H), 2.23 (dd, J=14.2, 9.5 Hz, 1H), 2.10
(dd, J=14.2, 4.4 Hz, 1H), 1.08 (s, 3H), 0.62 (s, 9H);
[3347] Mass Spectrum (ESI) m/z=474.2 (M.sup.+).
Step C.
2-((3R,5R,6S)-5-(3-Chlorophenyl)-6-(4-chlorophenyl)-1-((S)-3,3-dim-
ethyl-1-(methylsulfonyl)butan-2-yl)-3-methyl-2-oxopiperidin-3-yl)acetic
acid
[3348] The title compound was prepared from
(3S,5S,6R,8S)-8-allyl-3-(tert-butyl)-6-(3-chlorophenyl)-5-(4-chlorophenyl-
)-8-methyl-2,3,5,6,7,8-hexahydrooxazolo[3,2-a]pyridin-4-ium
triflate (Example 363, Step B) by procedures similar to the ones
described in Example 340, using an equivalent amount of sodium
methanesulfinate in step B.
Example 364
2-((3R,5R,6S)-5-(3-Chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-(ethylsulfony-
l)-3,3-dimethylbutan-2-yl)-3-methyl-2-oxopiperidin-3-yl)acetic
acid
##STR00929##
[3350] The title compound was prepared from
(3S,5S,6R,8S)-8-allyl-3-(tert-butyl)-6-(3-chlorophenyl)-5-(4-chlorophenyl-
)-8-methyl-2,3,5,6,7,8-hexahydrooxazolo[3,2-a]pyridin-4-ium
triflate (Example 363, Step B) by procedures similar to the ones
described in Example 340, using an equivalent amount of sodium
ethanesulfinate in step B.
[3351] .sup.1H NMR (500 MHz, CHLOROFORM-d) .delta. ppm 7.13-7.60
(m, 4H), 7.04-7.12 (m, 2H), 6.94-7.00 (m, 2H), 5.90 (ddt, J=17.2,
9.8, 7.5 Hz, 1H), 5.17-5.29 (m, 2H), 5.12 (d, J=11.0 Hz, 1H), 4.27
(dd, J=13.2, 11.2 Hz, 1H), 3.56 (dd, J=11.0, 2.2 Hz, 1H), 3.45
(ddd, J=13.8, 10.9, 3.2 Hz, 1H), 3.03-3.14 (m, 2H), 2.78 (dd,
J=13.2, 2.2 Hz, 1H), 2.67 (ABX, J.sub.AB=13.7 Hz, J.sub.AX=8.1 Hz,
1H), 2.61 (ABX J.sub.AB=13.7 Hz, J.sub.BX=6.8 Hz, 1H) (m, 2H), 2.27
(t, J=13.7 Hz, 1H), 1.81 (dd, J=13.6, 3.3 Hz, 1H), 1.47 (t, J=7.5
Hz, 3H), 1.25 (s, 3H), 0.71 (s, 9H); Mass Spectrum (ESI) m/z=550.2
(M+1).
Example 365
2-((3R,5R,6S)-5-(3-Chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-(isopropylsul-
fonyl)-3,3-dimethylbutan-2-yl)-3-methyl-2-oxopiperidin-3-yl)acetic
acid
##STR00930##
[3352] Step A.
(3S,5R,6S)-3-Allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-hydroxy-
-3,3-dimethylbutan-2-yl)-3-methylpiperidin-2-one
##STR00931##
[3354] To a solution of
(3S,5S,6R,8S)-8-allyl-3-(tert-butyl)-6-(3-chlorophenyl)-5-(4-chlorophenyl-
)-8-methyl-2,3,5,6,7,8-hexahydrooxazolo[3,2-a]pyridin-4-ium
trifluoromethanesulfonate (290 mg, 0.478 mmol; Example 363, Step B)
in 1,2-dichloroethane (4.78 mL) was added 5 mL of sat. aq.
NaHCO.sub.3 solution. The reaction mixture was heated to 50.degree.
C. for 3 d. The reaction mixture was poured into a separatory
funnel and the aqueous layer was extracted with dichloromethane.
The combined organic layers were washed with sat. aq. NaHCO.sub.3
solution, dried over MgSO.sub.4, filtered and the filtrate was
concentrated. Purification by column chromatography using 25-35%
ethyl acetate in hexanes on a 4 g silica gel column afforded the
title compound.
[3355] .sup.1H-NMR (500 MHz, DMSO-d6) .delta. ppm 7.50-7.05 (series
of m, 7H), 6.97 (d, J=7.3 Hz, 1H), 5.87 (dddd, J=16.9, 10.0, 8.3,
6.6 Hz, 1H), 5.26 (br d, J=16.6 Hz, 1H), 5.14 (dd, J=10.0, 2.2 Hz,
1H), 4.76 (d, J=11.0 Hz, 1H), 3.97 (td, J=10.3, 6.8 Hz, 1H), 2.51
(m, 2H), 2.76 (dd, J=9.5, 4.4 Hz), 2.65 (dd, J=13.7, 8.3 Hz, 1H),
2.50 (m, obscured by solvent), 2.07 (t, J=13.5 Hz, 1H), 1.75 (dd,
J=13.2, 3.0 Hz, 1H), 1.12 (s, 3H), 0.63 (s, 9H); Mass Spectrum
(ESI) m/z=474.2 (M+1).
Step B.
2-((3R,5R,6S)-5-(3-Chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-(isop-
ropylsulfonyl)-3,3-dimethylbutan-2-yl)-3-methyl-2-oxopiperidin-3-yl)acetic
acid
[3356] The title compound was prepared from
(3S,5R,6S)-3-allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-hydroxy-
-3,3-dimethylbutan-2-yl)-3-methylpiperidin-2-one (Example 365, step
A) by a procedure similar to the one described in Example 300,
replacing benzenethiol with the appropriate amount of
propane-2-thiol.
[3357] .sup.1H-NMR (500 MHz, DMSO-d.sub.6) .delta. ppm 12.36 (s,
1H), 7.81 (br s, 1H), 7.48 (br s, 1H), 7.25 (br s, 1H), 7.22 (t,
J=7.8 Hz, 1H), 7.15 (ddd, J=7.8, 2.0, 0.7 Hz, 1H), 7.04 (t, J=1.7
Hz, 1H), 7.00 (br d, J=7.8 Hz, 1H), 5.05 (d, J=11.2 Hz, 1H), 3.90
(dd, J=13.7, 11.0, 2.6 Hz, 1H), 3.70 (ddd, J=13.7, 11.0, 2.6 Hz,
1H), 3.45 (m, 2H), 3.12 (dd, J=13.4, 2.0, 1H), 2.97 (d, J=13.9 Hz,
1H), 2.52 (m, obscured by solvent), 2.14 (t, J=13.2 Hz, 1H), 2.03
(dd, J=13.4 Hz, 1H), 1.32 (d, J=6.8 Hz, 3H), 1.31 (d, J=6.6 Hz,
3H), 1.23 (s, 3H), 0.62 (s, 9H); Mass Spectrum (ESI) m/z=582.2
(M+1).
Example 366
2-((3R,5R,6S)-5-(3-Chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-cyclopropyl-2-
-(pentan-3-ylsulfonyl)ethyl)-3-methyl-2-oxopiperidin-3-yl)acetic
acid
##STR00932##
[3358] Step A.
(3S,5R,6S)-3-allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-cyclopr-
opyl-2-mercaptoethyl)-3-methylpiperidin-2-one
##STR00933##
[3360] To a solution of
(3S,5S,6R,8S)-8-allyl-6-(3-chlorophenyl)-5-(4-chlorophenyl)-3-cyclopropyl-
-8-methyl-2,3,5,6,7,8-hexahydrooxazolo[3,2-a]pyridin-4-ium
methanesulfonate (370 mg; Example 349, Step A) in DMF (1.6 mL) was
added sodium hydrogensulfide (105 mg, 1.88 mmol). After being
stirred at rt overnight, the reaction was quenched (sat. aq.
NH.sub.4Cl solution), extracted (2.times.EtOAc) and the combined
organics were washed with brine (3.times.). The combined organic
layers were dried (Na.sub.2SO.sub.4) and concentrated under the
reduced pressure. Purification of the residue by chromatography on
silica gel (24 g SiO.sub.2, gradient elution of 10% to 40% EtOAc in
hex) provided the title compound.
Step B.
(3S,5R,6S)-3-allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1--
cyclopropyl-2-(pentan-3-ylthio)ethyl)-3-methylpiperidin-2-one
##STR00934##
[3362] To a solution of
(3S,5R,6S)-3-allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-cyclopr-
opyl-2-mercaptoethyl)-3-methylpiperidin-2-one (49 mg, 0.10 mmol;
Example 366, Step A) and 3-bromopentane (51 .mu.l, 0.41 mmol) in
DMF (0.52 mL) was added 60% sodium hydride in mineral oil (17 mg,
0.41 mmol) at 25.degree. C. The reaction was stirred at 25.degree.
C. for 1 h and then heated to 60.degree. C. After being stirred at
60.degree. C. overnight, the reaction was quenched (10% aq. citric
acid), extracted (2.times.EtOAc), and washed (3.times. brine). The
combined organic layers were dried (Na.sub.2SO.sub.4) and
concentrated under reduced pressure. Purification of the residue by
chromatography on silica gel (4 g SiO.sub.2, 9% and 18% EtOAc/hex)
provided the title compound.
Step C.
2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-cyclo-
propyl-2-(pentan-3-ylsulfonyl)ethyl)-3-methyl-2-oxopiperidin-3-yl)acetic
acid
[3363] The title compound was prepared from
(3S,5R,6S)-3-allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-cyclopr-
opyl-2-(pentan-3-ylthio)ethyl)-3-methylpiperidin-2-one (Example
366, Step B) by procedures similar to the one described in Example
71, Step F.
[3364] .sup.1H NMR (400 MHz, CHLOROFORM-d) .delta. ppm 7.20-7.34
(3H, m), 7.06-7.16 (3H, m), 6.93-6.98 (1H, s), 6.83-6.90 (1H, m),
4.93 (1H, d, J=10.6 Hz), 4.35 (1H, br, s), 3.05-3.20 (2H, m),
2.65-2.92 (4H, m), 2.46 (1H, t, J=13.8 Hz), 1.92-2.11 (2H, m),
1.75-1.91 (4H, m), 1.50 (3H, s), 1.06-1.19 (6H, m), 0.32-0.42 (1H,
m), 0.18-0.28 (1H, m), -0.35--0.25 (1H, m), -1.12--1.02 (1H, m);
Mass Spectrum (ESI) m/z=594.2 [M+H].sup.+.
Example 367
2-((3R,5R,6S)-5-(3-Chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-((S)-isopropy-
lsulfinyl)butan-2-yl)-3-methyl-2-oxopiperidin-3-yl)acetic acid or
2-((3R,5R,6S)-5-(3-Chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-((R)-isoprop-
ylsulfinyl)butan-2-yl)-3-methyl-2-oxopiperidin-3-yl)acetic acid;
more polar isomer
##STR00935##
[3365] Step A. Methyl
2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-(isopropylth-
io)butan-2-yl)-3-methyl-2-oxopiperidin-3-yl)acetate
##STR00936##
[3367] The above compound was obtained from methyl
2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-hydroxybutan-
-2-yl)-3-methyl-2-oxopiperidin-3-yl)acetate (Example 186, Step A,
187 mg, 0.391 mmol) and propane-2-thiol (119 mg, 1.56 mmol) by a
procedure similar to the one described in Example 300, Step A,
using the appropriate amount of propanethiol and reacting for a
total of 3 h. Purification of the residue by chromatography on
silica gel (12 g, SiO.sub.2, 5% to 20% EtOAc/Hex) provided the
title compound as a pale yellow oil.
[3368] .sup.1H NMR (400 MHz, CHLOROFORM-d) .delta. ppm 7.22 (d,
J=8.4 Hz, 2H), 7.05-7.18 (m, 2H), 7.02 (t, J=1.7 Hz, 2H), 6.79 (td,
J=1.4, 7.4 Hz, 1H), 4.66 (d, J=10.6 Hz, 1H), 3.70 (s, 3H), 3.41
(dd, J=11, 12.7 Hz, 1H), 3.16 (ddd, J=3.1, 10.6, 13.6 Hz, 1H),
2.82-2.94 (m, 2H), 2.67-2.79 (m, 2H), 2.57 (dd, J=4.1, 12.9 Hz,
1H), 2.16-2.27 (m, 1H), 1.97-2.12 (m, 2H), 1.57 (ddd, J=3.8, 7.8,
14. Hz, 1H), 1.41 (d, J=6.9 Hz, 3H), 1.29-1.34 (m, 5H), 0.49 (d,
J=15.3 Hz, 3H); Mass Spectrum (ESI) m/z=558.1 [M-H].sup.-, 560.1
[M+H].sup.+.
Step B. Methyl
2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-((S)-isoprop-
ylsulfinyl)butan-2-yl)-3-methyl-2-oxopiperidin-3-yl)acetate and
methyl
2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-((R)-isoprop-
ylsulfinyl)butan-2-yl)-3-methyl-2-oxopiperidin-3-yl)acetate
##STR00937##
[3370] 3-Chlorobenzoperoxoic acid (45.4 mg, 0.203 mmol) was added
to a solution of methyl
2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((S)---(isopropylth-
io)butan-2-yl)-3-methyl-2-oxopiperidin-3-yl)acetate (136 mg, 0.253
mmol; Example 367, Step A) in DCM (3 mL) at 0.degree. C. After 1 h
at 0.degree. C. the reaction was monitored by LCMS (MS (ESI) 552.2
[M+H].sup.+, 554.0 [M-H].sup.-) showing 60% conversion. At this
time an additional 0.2 eq. of 3-chorobenzoperoxoic acid was added.
The reaction was monitored again after 2 hours showing 85%
conversion and was quenched at this time with sat. aq. NaHCO.sub.3
solution. The solution was extracted with EtOAc and the combined
organic layers were washed with brine dried over MgSO.sub.4,
filtered and the filtrate was concentrated. The residue was
purified by chromatography on silica gel (12 g, SiO.sub.2, 10-60%
EtOAc/hexane, 50 min) to give the title compounds as a 2:1 mixture
of diatereomers, as a pale yellow oil.
[3371] .sup.1H NMR (400 MHz, CHLOROFORM-d) .delta. ppm 7.20-7.29
(m, 4H), 7.20-7.26 (m, 2H), 7.19-7.20 (m, 1H), 7.04-7.20 (m, 6H),
6.95-7.02 (m, 2H), 6.82-6.95 (m, 2H), 4.75-4.90 (m, 1H), 3.62-3.74
(m, 5H), 3.37-3.48 (m, 1H), 3.07-3.32 (m, 3H), 2.59-2.95 (m, 6H),
1.93-2.33 (m, 5H), 1.47-1.74 (m, 3H), 1.22-1.42 (m, 17H), 0.79-0.95
(m, 2H), 0.37-0.56 (m, 4H); Mass Spectrum (ESI)
m/z=552.2[M-H].sup.-, 554.0 [M+H].sup.+.
Step C.
2-((3R,5R,6S)-5-(3-Chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-((S)--
isopropylsulfinyl)butan-2-yl)-3-methyl-2-oxopiperidin-3-yl)acetic
acid or
2-((3R,5R,6S)-5-(3-Chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-((R)-isoprop-
ylsulfinyl)butan-2-yl)-3-methyl-2-oxopiperidin-3-yl)acetic acid;
more polar isomer
[3372] To a solution of methyl
2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-((S)-isoprop-
ylsulfinyl)butan-2-yl)-3-methyl-2-oxopiperidin-3-yl)acetate and
methyl
2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-((R)-isoprop-
ylsulfinyl)butan-2-yl)-3-methyl-2-oxopiperidin-3-yl)acetate (100
mg, 0.181 mmol, as a 2:1 mixture of isomers; Example 267, Step B)
in MeOH/THF/H.sub.2O (1 mL/2 mL/1 mL) was added lithium hydroxide
(43.3 mg, 1.810 mmol). The reaction mixture was allowed to stir for
18 h. After this period, the reaction mixture was acidified with 1N
HCl and extracted with EtOAc (3.times.10 mL). The organics were
pooled, washed with brine, dried (MgSO.sub.4), filtered and
concentrated in vacuo. The crude material was purified by
reverse-phase preparative HPLC (Gemini.TM. Prep C.sub.18 5 mm
column; Phenomenex, Torrance, Calif.; gradient elution of 25% to
55% MeCN in water, where both solvents contain 0.1% TFA, 30 min
method) to provide one of the title compounds as the more polar
isomer (t.sub.R=21.45 min)
[3373] .sup.1H NMR (400 MHz, CHLOROFORM-d) .delta. ppm 7.22 (d,
J=8.0 Hz, 2H), 7.00-7.17 (m, 4H), 6.80-6.98 (m, 2H), 4.80 (d,
J=10.8 Hz, 1H), 3.53-3.73 (m, 1H), 3.11-3.30 (m, 2H), 2.68-3.00 (m,
4H), 1.97-2.29 (m, 3H), 1.40-1.54 (m, 4H), 1.36 (d, J=6.9 Hz, 3H),
1.28 (d, J=6.9 Hz, 3H), 0.41 (t, J=7.5 Hz, 3H); Mass Spectrum (ESI)
538.2 [M-H].sup.-, 540.2 [M+H].sup.+.
[3374] Further elution from Example 367 provided the less polar
isomer:
Example 368
2-((3R,5R,6S)-5-(3-Chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-((S)-isopropy-
lsulfinyl)butan-2-yl)-3-methyl-2-oxopiperidin-3-yl)acetic acid or
2-((3R,5R,6S)-5-(3-Chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-((R)-isoprop-
ylsulfinyl)butan-2-yl)-3-methyl-2-oxopiperidin-3-yl)acetic acid
##STR00938##
[3376] Less polar isomer (t.sub.R=21.45 min).
[3377] .sup.1H NMR (400 MHz, CHLOROFORM-d) .delta. ppm 7.23-7.27
(m, 2H), 7.10 (td, J=7.9, 15.7 Hz, 4H), 6.96 (s, 1H), 6.81 (d,
J=7.4 Hz, 1H), 4.75 (s, 1H), 3.07-3.54 (m, 3H), 2.70-3.01 (m, 3H),
2.58 (d, J=10.4 Hz, 1H), 2.27-2.40 (m, 1H), 2.01-2.17 (m, 1H), 1.95
(dd, J=2.6, 13.8 Hz, 1H), 1.55-1.69 (m, 1H), 1.46 (s, 3H),
1.23-1.35 (m, 6H), 0.52 (d, J=14.3 Hz, 3H); Mass Spectrum (ESI)
m/z=538.2 [M-H].sup.-, 540.2 [M+H].sup.+.
Example 369
2-((3R,5R,6S)-5-(3-Chlorophenyl)-6-(4-chlorophenyl)-3-methyl-1-((2S,3S)-2--
(methylsulfonyl)pentan-3-yl)-2-oxopiperidin-3-yl)acetic acid or
2-((3R,5R,6S)-5-(3-Chlorophenyl)-6-(4-chlorophenyl)-3-methyl-1-((2R,3S)-2-
-(methylsulfonyl)pentan-3-yl)-2-oxopiperidin-3-yl)acetic acid
##STR00939##
[3378] Step A.
(3S,5S,6R,8S)-8-Allyl-6-(3-chlorophenyl)-5-(4-chlorophenyl)-3-ethyl-2,8-d-
imethyl-2,3,5,6,7,8-hexahydrooxazolo[3,2-a]pyridin-4-ium
4-methylbenzenesulfonate
##STR00940##
[3380] To a solution of
(3S,5R,6S)-3-allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((3S)-2-hydrox-
ypentan-3-yl)-3-methylpiperidin-2-one (2.25 g, 4.89 mmol; Example
151, Step C) in toluene (65 mL) was added p-toluenesulfonic acid
monohydrate (930 mg, 4.89 mmol). After being heated to reflux using
a Dean-Stark trap for 2.5 h, the reaction was concentrated under
reduced pressure to provide the title compound as a pale yellow
powder.
Step B.
(3S,5R,6S)-3-Allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl--
1-((2S,3S)-2-(methylsulfonyl)pentan-3-yl)piperidin-2-one and
(3S,5R,6S)-3-Allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-1-((2R,-
3S)-2-(methylsulfonyl)pentan-3-yl)piperidin-2-one
##STR00941##
[3382] The reaction was set in a high pressure reaction vessel. To
a solution of
(3S,5S,6R,8S)-8-allyl-6-(3-chlorophenyl)-5-(4-chlorophenyl)-3-ethyl-2,8-d-
imethyl-2,3,5,6,7,8-hexahydrooxazolo[3,2-a]pyridin-4-ium
4-methylbenzenesulfonate (0.200 g, 0.325 mmol; Example 370, step A)
in acetonitrile (2 ml) was added sodium methanesulfinate (0.166 g,
1.627 mmol) at 25.degree. C. Then the reaction was heated to
110.degree. C. for 24 h. The reaction was quenched with sat. aq.
NH.sub.4Cl solution, extracted (2.times.EtOAc) and washed (2.times.
brine). The combined organic layers were dried (Na.sub.2SO.sub.4)
and concentrated under reduced pressure. Purification by
chromatography on silica gel (40 g SiO.sub.2, gradient elution, 20%
to 40% EtOAc in hexanes) provided the title compounds as a mixture
of two stereoisomers.
Step C.
2-((3R,5R,6S)-5-(3-Chlorophenyl)-6-(4-chlorophenyl)-3-methyl-1-((2-
S,3S)-2-(methylsulfonyl)pentan-3-yl)-2-oxopiperidin-3-yl)acetic
acid or
2-((3R,5R,6S)-5-(3-Chlorophenyl)-6-(4-chlorophenyl)-3-methyl-1-((2R,3S)-2-
-(methylsulfonyl)pentan-3-yl)-2-oxopiperidin-3-yl)acetic acid
[3383] The title compound was obtained from a mixture of
3S,5R,6S)-3-allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-1-((2S,3-
S)-2-(methylsulfonyl)pentan-3-yl)piperidin-2-one and
(3S,5R,6S)-3-allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-1-((2R,-
3S)-2-(methylsulfonyl)pentan-3-yl)piperidin-2-one (Example 370,
Step B) by a procedure similar to the one described in Example 71,
Step F. The crude product was purified by reversed phase
preparatory HPLC (Gemini.TM. Prep C.sub.18 5 .mu.m column;
Phenomenex, Torrance, Calif.; eluent: 40 to 60% acetonitrile,
water, 0.1% TFA, gradient elution) to provide the title compound as
the first eluting isomer as a single stereoisomer.
[3384] .sup.1H NMR (400 MHz, CHLOROFORM-d) .delta. ppm 0.46 (t,
J=7.5 Hz, 3H) 1.55 (s, 3H) 1.60 (d, J=7.2 Hz, 3H) 1.78-1.81 (m, 1H)
1.84-1.93 (m, 1H) 2.29-2.43 (m, 2H) 2.72 (d, J=15.5 Hz, 1H) 2.93
(s, 3H) 2.97-3.09 (m, 2H) 3.14 (m, 1H) 3.53 (m, 1H) 5.00 (d, J=10.6
Hz, 1H) 6.82 (m, 1H) 6.92-6.97 (m, 1H) 7.07-7.18 (m, 2H), 7.27 (m,
4H);
[3385] Mass Spectrum (ESI) m/z=540 (M+1).
Example 370
2-((3R,5R,6S)-5-(3-Chlorophenyl)-6-(4-chlorophenyl)-1-((2S,3S)-2-(ethylsul-
fonyl)pentan-3-yl)-3-methyl-2-oxopiperidin-3-yl)acetic acid or
2-((3R,5R,6S)-5-(3-Chlorophenyl)-6-(4-chlorophenyl)-1-((2R,3S)-2-(ethylsu-
lfonyl)pentan-3-yl)-3-methyl-2-oxopiperidin-3-yl)acetic acid; first
eluting isomer
##STR00942##
[3387] The title compound was prepared from
(3S,5S,6R,8S)-8-allyl-6-(3-chlorophenyl)-5-(4-chlorophenyl)-3-ethyl-2,8-d-
imethyl-2,3,5,6,7,8-hexahydrooxazolo[3,2-a]pyridin-4-ium
4-methylbenzenesulfonate (Example 369, Step A) by a procedure
similar to the one described in Example 369, replacing replacing
sodium methanesulfinate in step B with sodium ethanesulfinate. The
crude product was purified by reversed phase preparatory HPLC
(Gemini.TM. Prep C.sub.18 5 mm column; Phenomenex, Torrance,
Calif.; eluent: 40 to 60% acetonitrile, water, 0.1% TFA, gradient
elution) to provide the title compound as the first eluting isomer
as a single stereoisomer.
[3388] .sup.1H NMR (400 MHz, CHLOROFORM-d) .delta. ppm 0.45 (t,
J=7.53 Hz, 3H) 1.41 (t, J=7.53 Hz, 3H) 1.48-1.62 (m, 6H) 1.69-1.92
(m, 2H) 2.29-2.43 (m, 2H) 2.70 (d, J=15.45 Hz, 1H) 2.92-3.19 (m,
5H) 3.49-3.56 (m, 1H) 5.02 (d, J=10.56 Hz, 1H) 6.84 (dt, J=6.99,
1.88 Hz, 1H) 6.95 (t, J=1.96 Hz, 1H) 7.08-7.19 (m, 3H) 7.25 (br s,
3H); Mass Spectrum (ESI) m/z=554 (M+1).
[3389] Further Elution Provided:
Example 371
2-((3R,5R,6S)-5-(3-Chlorophenyl)-6-(4-chlorophenyl)-1-((2R,3S)-2-(ethylsul-
fonyl)pentan-3-yl)-3-methyl-2-oxopiperidin-3-yl)acetic acid or
2-((3R,5R,6S)-5-(3-Chlorophenyl)-6-(4-chlorophenyl)-1-((2S,3S)-2-(ethylsu-
lfonyl)pentan-3-yl)-3-methyl-2-oxopiperidin-3-yl)acetic acid;
second eluting isomer
##STR00943##
[3391] The title compound was obtained in Example 370 as the second
eluting isomer.
[3392] .sup.1H NMR (400 MHz, CHLOROFORM-d) .delta. ppm 0.20 (t,
J=7.63 Hz, 3H) 1.12-1.30 (m, 3H) 1.30-1.45 (m, 6H) 1.45-1.60 (m,
1H) 1.71-1.80 (m, 1H) 1.85-1.98 (m, 1H) 2.40 (t, J=13.79 Hz, 1H)
2.63 (d, J=15.26 Hz, 1H) 2.86-3.09 (m, 5H) 4.05-4.19 (m, 1H) 4.93
(d, J=10.76 Hz, 1H) 6.78 (dt, J=6.90, 1.93 Hz, 1H) 6.89 (t, J=1.96
Hz, 1H) 6.95-7.11 (m, 4H) 7.11-7.25 (m, 2H); Mass Spectrum (ESI)
m/z=554 (M+1).
Example 372
2-((3R,5R,6S)-5-(3-Chlorophenyl)-6-(4-chlorophenyl)-3-methyl-1-((S)-1-(N-(-
oxetan-3-yl)sulfamoyl)butan-2-yl)-2-oxopiperidin-3-yl)acetic
acid
##STR00944##
[3393] Step A. Methyl
2-((3R,5R,6S)-1-((S)-1-(benzylthio)butan-2-yl)-5-(3-chlorophenyl)-6-(4-ch-
lorophenyl)-3-methyl-2-oxopiperidin-3-yl)acetate
##STR00945##
[3395] To a solution of methyl
2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-hydroxybutan-
-2-yl)-3-methyl-2-oxopiperidin-3-yl)acetate (214.4 mg, 0.448 mmol;
Example 186, Step A) in toluene (2.0 mL) was added benzyl mercaptan
(0.106 mL, 0.90 mmol), followed by
cyanomethylenetributylphosphorane (0.235 mL, 0.896 mmol; TCI). The
solution was heated at 100.degree. C. for 3.75 hours, then
concentrated in vacuo. Purification of the residue by
chromatography on silica gel (12 g SiO.sub.2, 0% to 50% EtOAc in
hexanes) provided the title compound as colorless oil.
Step B.
(S)-2-((3R,5R,6S)-5-(3-Chlorophenyl)-6-(4-chlorophenyl)-3-(2-metho-
xy-2-oxoethyl)-3-methyl-2-oxopiperidin-1-yl)butane-1-sulfonic
acid
##STR00946##
[3397] To a solution of methyl
2-((3R,5R,6S)-1-((S)-1-(benzylthio)butan-2-yl)-5-(3-chlorophenyl)-6-(4-ch-
lorophenyl)-3-methyl-2-oxopiperidin-3-yl)acetate (1.31 g, 2.24
mmol; Example 372, Step A) in acetic acid (9.5 ml) and water (1.0
ml) was added hydrogen peroxide (31.3% solution in water, 0.23 ml,
2.35 mmol). The resulting solution was stirred at room temperature
for 3 hours, then chlorine gas was bubbled into the reaction for
one minute. After stirring at room temperature for one hour, the
reaction was concentrated in vacuo, then a few mL of anhydrous
benzene were added and the solvent was removed under reduced
pressure on a rotary evaporator. This procedure was repeated
several times to provide the title compound as a yellow solid. This
crude material was used directly in the next step without
purification.
Step C. Methyl
2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-1-((S)-1-(N--
(oxetan-3-yl)sulfamoyl)butan-2-yl)-2-oxopiperidin-3-yl)acetate
##STR00947##
[3399] To a solution of
(S)-2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-(2-methoxy-2-ox-
oethyl)-3-methyl-2-oxopiperidin-1-yl)butane-1-sulfonic acid (189.8
mg, 0.35 mmol; Example 372, Step B) in dichloromethane (5.0 mL) was
added oxalyl chloride (0.061 mL, 0.70 mmol), followed by DMF (2
drops). The reaction was stirred at room temperature for 3.5 hours,
then concentrated in vacuo. The sulfonyl chloride intermediate was
dissolved in dichloromethane (5.0 mL), then treated with
3-oxetanamine (50.0 mg, 0.684 mmol; Pharmablock R & D Co. Ltd.,
Nanjing, China) and N,N-diisopropylethylamine (0.122 mL, 0.699
mmol). After stirring at room temperature for 16 hours, the
reaction was quenched with methanol (2.0 mL), then concentrated in
vacuo. Purification of the residue by chromatography on silica gel
(4 g SiO.sub.2, 0%-50% EtOAc in hexanes) provided the title
compound as a colorless oil.
Step D.
2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-1-((S-
)-1-(N-(oxetan-3-yl)sulfamoyl)butan-2-yl)-2-oxopiperidin-3-yl)acetic
acid
[3400] To a solution of methyl
2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-1-((S)-1-(N--
(oxetan-3-yl)sulfamoyl)butan-2-yl)-2-oxopiperidin-3-yl)acetate
(41.1 mg, 0.069 mmol; Example 372, Step C) in THF (2.0 ml) and MeOH
(1.0 ml) was added 1 N lithium hydroxide (3.0 ml, 3.0 mmol). The
suspension was stirred at room temperature for 15 hours, then
acidified to pH 4 using 1 N HCl, and then concentrated in vacuo.
Purification of the residue by chromatography on silica gel (4 g
SiO.sub.2, 5 to 25% gradient of a 1:6.5 MeOH/acetone mixture in
hexanes) provided the title compound. The material was purified
further by reversed phase preparatory HPLC (Eclipse Plus C.sub.18,
30.times.250 mm, 5 .mu.m column; Agilent, Santa Clara, Calif.)
(eluent: 0.1% TFA in acetonitrile/water, gradient 30% to 60% over
25 min) to provide the title compound, as a white solid.
[3401] .sup.1H NMR (500 MHz, methanol-d.sub.4) .delta. ppm 0.39 (t,
J=7.5 Hz, 3H) 1.38 (s, 3H) 1.45-1.56 (m, 1H) 1.91-2.01 (m, 1H)
2.02-2.08 (m, 1H) 2.26 (t, J=13.7 Hz, 1H) 2.59 (d, J=13.7 Hz, 1H)
2.88-2.99 (m, 2H) 3.07-3.19 (m, 1H) 3.34-3.41 (m, 2H) 3.91-4.01 (m,
1H) 4.55-4.66 (m, 3H) 6.91-6.97 (m, 1H) 7.02 (s, 1H) 7.10-7.19 (m,
3H) 7.28 (br s, 3H); Mass Spectrum (ESI) m/z=583.2 [M+H].sup.+.
[3402] Examples 373 and 374 were prepared from
(S)-2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-(2-methoxy-2-ox-
oethyl)-3-methyl-2-oxopiperidin-1-yl)butane-1-sulfonic acid
(Example 372, Step B) by procedures similar to the one described in
Example 372, replacing 3-oxetanamine in step B with the appropriate
reagent.
TABLE-US-00022 ##STR00948## Example R Reagent used 373 ##STR00949##
(3-methyloxetan-3-yl) methanamine (Pharmablock R & D Co. Ltd.,
Nanjing, China) 374 ##STR00950## oxetan-3-ylmethanamine
(Pharmablock R & D Co. Ltd., Nanjing, China)
Example 373
2-((3R,5R,6S)-5-(3-Chlorophenyl)-6-(4-chlorophenyl)-3-methyl-1-((S)-1-(N-(-
(3-methyloxetan-3-yl)methyl)sulfamoyl)butan-2-yl)-2-oxopiperidin-3-yl)acet-
ic acid
[3403] .sup.1H NMR (500 MHz, methanol-d.sub.4) .delta. ppm 0.42 (t,
J=7.58 Hz, 3H) 1.25 (s, 2H) 1.34 (s, 3H) 1.39 (s, 3H) 1.53 (ddd,
J=14.24, 7.76, 3.18 Hz, 1H) 1.97-2.08 (m, 2H) 2.16 (s, 1H) 2.18 (s,
1H) 2.29 (t, J=13.69 Hz, 1H) 2.57-2.64 (m, 1H) 2.95 (d, J=13.45 Hz,
1H) 3.00-3.06 (m, 1H) 3.19 (br s, 1H) 3.35-3.42 (m, 1H) 4.04 (t,
J=12.35 Hz, 1H) 4.37 (d, J=6.11 Hz, 1H) 4.54 (d, J=6.11 Hz, 1H)
4.91 (d, J=10.76 Hz, 1H) 6.96 (d, J=7.34 Hz, 1H) 7.03 (s, 1H)
7.11-7.20 (m, 3H) 7.28 (br s, 3H); Mass Spectrum (ESI) 611.2
[M+H].sup.+.
Example 374
2-((3R,5R,6S)-5-(3-Chlorophenyl)-6-(4-chlorophenyl)-3-methyl-1-((S)-1-(N-(-
oxetan-3-ylmethyl)sulfamoyl)butan-2-yl)-2-oxopiperidin-3-yl)acetic
acid
[3404] .sup.1H NMR (500 MHz, methanol-d.sub.4) .delta. ppm 0.41 (t,
J=7.58 Hz, 3H) 1.38 (s, 3H) 1.46-1.59 (m, 1H) 2.01-2.08 (m, 2H)
2.28 (t, J=13.69 Hz, 1H) 2.60 (d, J=13.69 Hz, 1H) 2.94 (d, J=13.69
Hz, 1H) 3.03 (d, J=12.47 Hz, 1H) 3.10-3.25 (m, 3H) 3.34-3.42 (m,
2H) 3.95-4.07 (m, 1H) 4.42-4.51 (m, 2H) 4.76-4.82 (m, 2H) 4.88-4.91
(m, 1H) 6.95 (dt, J=7.03, 1.62 Hz, 1H) 7.00-7.04 (m, 1H) 7.09-7.18
(m, 3H) 7.28 (br s, 3H);
[3405] Mass Spectrum (ESI) 597.1 [M+H].sup.+.
Example 375
2-((3R,5R,6S)-1-((S)-2-(N-(tert-Butyl)sulfamoyl)-1-cyclopropylethyl)-5-(3--
chlorophenyl)-6-(4-chlorophenyl)-3-methyl-2-oxopiperidin-3-yl)acetic
acid
##STR00951##
[3406] Step A.
(3S,5R,6S)-3-Allyl-1-((S)-2-(benzylthio)-1-cyclopropylethyl)-5-(3-chlorop-
henyl)-6-(4-chlorophenyl)-3-methylpiperidin-2-one
##STR00952##
[3408] A mixture of
(3S,5R,6S)-3-allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-cyclopr-
opyl-2-hydroxyethyl)-3-methylpiperidin-2-one (1.35 g, 2.94 mmol;
Example 252, Step A), benzyl mercaptan (0.691 ml, 5.89 mmol) and
2-(tributylphosphoranylidene) in acetonitrile (1.579 ml, 5.89 mmol)
was heated to 100.degree. C. for 2 h. The reaction mixture was
cooled to RT, and extracted with 80 mL of EtOAc. The combined
organics were washed with sat. aq. NH.sub.4Cl solution and brine,
dried over Na.sub.2SO.sub.4, filtered and the filtrate was
concentrated. The crude product was purified by chromatography on
silica gel eluting with 0 to 50% EtOAc/hexane to give the title
compound.
[3409] Mass Spectrum (ESI) m/z=564.1 (M+1).
Step B.
2-((3R,5R,6S)-1-((S)-2-(N-(tert-Butyl)sulfamoyl)-1-cyclopropylethy-
l)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-2-oxopiperidin-3-yl)acet-
ic acid
[3410] To a solution of
(3S,5R,6S)-3-allyl-1-((S)-2-(benzylthio)-1-cyclopropylethyl)-5-(3-chlorop-
henyl)-6-(4-chlorophenyl)-3-methylpiperidin-2-one (0.075 g, 0.133
mmol; Example 375, Step A) in 5 mL of a mixture of
MeCN/HOAc/H.sub.2O (40:1.5:1) at 0.degree. C. was added portionwise
1,3-dichloro-5,5-dimethylimidazolidine-2,4-dione (0.052 g, 0.266
mmol) (Alfa Aesar, Ward Hill, Mass.). The reaction mixture was
stirred at 0.degree. C.-5.degree. C. for 2 h. This solution was
added into a mixture of tert-butylamine (97 mg, 140 .mu.L, 5.0 eq.)
and DIEA (5.0 eq.) in 2 mL of DCM at 0.degree. C. The resulting
mixture was stirred at room temperature for 3 h. The solvents were
removed under reduced pressure and residue was purified by
chromatography on silica gel eluting with 30 to 80% EtOAc/hexane to
provide the corresponding sulfonamide. This sulfonamide was
converted into the title compound by a procedure similar to the one
described in Example 71, Step F. The crude product was purified by
reverse phase HPLC (40 to 90% acetonitrile in water, gradient with
0.1% TFA) to give the title compound.
[3411] .sup.1H NMR (400 MHz, CHLOROFORM-d) .delta. ppm -1.09 (br s,
1H), -0.26 (br s, 1H), 0.19-0.50 (m, 2H), 1.42 (s, 9H), 1.54 (s,
3H), 1.88 (d, J=13.30 Hz, 2H), 2.48 (d, J=12.32 Hz, 1H), 2.76 (d,
J=15.26 Hz, 1H), 2.97-3.26 (m, 3H), 4.14-4.52 (m, 2H), 4.82 (d,
J=10.76 Hz, 1H), 6.86 (d, J=5.87 Hz, 1H), 6.97 (s, 1H), 7.06-7.22
(m, 3H), 7.29 (br s, 3H). Mass Spectrum (ESI) m/z=595.2 (M+1).
[3412] Examples 376 to 382 were prepared from
(3S,5R,6S)-3-allyl-1-((S)-2-(benzylthio)-1-cyclopropylethyl)-5-(3-chlorop-
henyl)-6-(4-chlorophenyl)-3-methylpiperidin-2-one (Example 375,
Step A) by procedures similar to the one described in Example 375,
replacing tert-butylamine in step B with the appropriate
reagent.
TABLE-US-00023 ##STR00953## Example R Reagent used 376 ##STR00954##
methylamine 377 ##STR00955## dimethylamine 378 ##STR00956##
isopropylamine 379 ##STR00957## morpholine 380 ##STR00958##
piperidine 381 ##STR00959## pyrrolidine 382 ##STR00960##
azetidine
Example 376
2-((3R,5R,6S)-5-(3-Chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-cyclopropyl-2-
-(N-methylsulfamoyl)ethyl)-3-methyl-2-oxopiperidin-3-yl)acetic
acid
[3413] .sup.1H NMR (400 MHz, CHLOROFORM-d) .delta. ppm -1.13--0.88
(m, 1H), -0.23 (br s, 1H), 0.23-0.50 (m, 2H), 1.51 (s, 3H),
1.70-1.89 (m, 1H), 2.10-2.16 (m, 1H), 2.21-2.32 (m, 1H), 2.40-2.51
(m, 1H), 2.78 (d, J=15.26 Hz, 1H), 2.84 (d, J=3.52 Hz, 3H),
2.93-3.06 (m, 1H), 3.07-3.23 (m, 2H), 3.52-3.67 (m, 1H), 4.82 (d,
J=10.37 Hz, 1H), 6.83 (d, J=7.24 Hz, 1H), 6.96 (s, 1H), 7.12-7.15
(m, 3H), 7.19-7.27 (m, 3H).
[3414] Mass Spectrum (ESI) m/z=553.0. (M+1).
Example 377
2-((3R,5R,6S)-5-(3-Chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-cyclopropyl-2-
-(N,N-dimethylsulfamoyl)ethyl)-3-methyl-2-oxopiperidin-3-yl)acetic
acid
[3415] .sup.1H NMR (400 MHz, CHLOROFORM-d) .delta. ppm -1.07 (br s,
1H), -0.28 (br s, 1H), 0.18-0.44 (m, 2H), 1.53 (s, 3H), 1.87 (dd,
J=13.79, 2.84 Hz, 2H), 2.50 (t, J=13.79 Hz, 1H), 2.60 (br s, 1H),
2.73-2.84 (m, 2H), 2.90 (s, 6H), 3.07-3.19 (m, 2H), 4.19 (t,
J=12.42 Hz, 1H), 4.83 (d, J=10.56 Hz, 1H), 6.83-6.89 (m, 1H), 6.95
(s, 1H), 7.07-7.16 (m, 3H), 7.27 (br s, 3H). Mass Spectrum (ESI)
m/z=567.0 (M+1).
Example 378
2-((3R,5R,6S)-5-(3-Chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-cyclopropyl-2-
-(N-isopropylsulfamoyl)ethyl)-3-methyl-2-oxopiperidin-3-yl)acetic
acid
[3416] .sup.1H NMR (400 MHz, CHLOROFORM-d) .delta. ppm -1.08 (br s,
1H), -0.27 (br s, 1H), 0.19-0.49 (m, 2H), 1.22-1.33 (m, 6H), 1.50
(s, 3H), 1.67-1.99 (m, 2H), 2.44 (br s, 1H), 2.58 (br s, 1H), 2.77
(d, J=14.87 Hz, 1H), 2.98 (d, J=10.76 Hz, 1H), 3.02-3.25 (m, 2H),
3.64 (d, J=6.26 Hz, 1H), 4.10-4.46 (m, 1H), 4.81 (d, J=10.56 Hz,
1H), 6.84 (d, J=6.46 Hz, 1H), 6.95 (s, 1H), 7.06-7.16 (m, 3H), 7.27
(br s, 3H). Mass Spectrum (ESI) m/z=581.2 (M+1).
Example 379
2-((3R,5R,6S)-5-(3-Chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-cyclopropyl-2-
-(morpholinosulfonyl)ethyl)-3-methyl-2-oxopiperidin-3-yl)acetic
acid
[3417] .sup.1H NMR (400 MHz, CHLOROFORM-d) .delta. ppm -1.06 (br s,
1H), -0.29 (br s, 1H), 0.19-0.44 (m, 2H), 1.50 (s, 3H), 1.79-1.94
(m, 2H), 2.47 (t, J=13.89 Hz, 1H), 2.60 (br s, 1H), 2.79 (d,
J=15.06 Hz, 2H), 3.08 (d, J=15.06 Hz, 1H), 3.11-3.20 (m, 1H),
3.24-3.30 (m, 4H), 3.77-3.83 (m, 4H), 4.22 (t, J=12.52 Hz, 1H),
4.82 (d, J=10.76 Hz, 1H), 6.86 (d, J=7.04 Hz, 1H), 6.95 (s, 1H),
7.06-7.16 (m, 3H), 7.21-7.33 (m, 3H). Mass Spectrum (ESI) m/z=609.2
(M+1).
Example 380
2-((3R,5R,6S)-5-(3-Chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-cyclopropyl-2-
-(piperidin-1-ylsulfonyl)ethyl)-3-methyl-2-oxopiperidin-3-yl)acetic
acid
[3418] .sup.1H NMR (400 MHz, CHLOROFORM-d) .delta. ppm -1.09 (br s,
1H), -0.30 (br s, 1H), 0.20-0.43 (m, 2H), 1.53 (s, 3H), 1.56-1.62
(m, 2H), 1.63-1.96 (m, 5H), 2.00-2.13 (m, 1H), 2.52 (t, J=13.79 Hz,
1H), 2.60 (br s, 1H), 2.71-2.81 (m, 2H), 3.07-3.20 (m, 2H), 3.24
(t, J=5.28 Hz, 4H), 4.13 (d, J=13.11 Hz, 1H), 4.85 (d, J=10.76 Hz,
1H), 6.86 (d, J=7.04 Hz, 1H), 6.94 (s, 1H), 7.07-7.18 (m, 3H),
7.23-7.38 (m, 3H). Mass Spectrum (ESI) m/z=607.2 (M+1).
Example 381
2-((3R,5R,6S)-5-(3-Chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-cyclopropyl-2-
-(pyrrolidin-1-ylsulfonyl)ethyl)-3-methyl-2-oxopiperidin-3-yl)acetic
acid
[3419] .sup.1H NMR (400 MHz, CHLOROFORM-d) .delta. ppm -1.08 (br s,
1H), -0.28 (br s, 1H), 0.17-0.42 (m, 2H), 1.52 (s, 3H), 1.81 (br s,
1H), 1.88 (dd, J=13.79, 2.84 Hz, 1H), 1.94-2.01 (m, 4H), 2.50 (t,
J=13.79 Hz, 1H), 2.62 (br s, 1H), 2.78 (d, J=15.06 Hz, 1H), 2.86
(d, J=12.13 Hz, 1H), 3.05-3.20 (m, 2H), 3.28-3.45 (m, 4H), 4.24 (br
s, 1H), 4.84 (d, J=10.56 Hz, 1H), 6.89 (d, J=6.65 Hz, 1H), 6.98 (s,
1H), 7.07-7.19 (m, 3H), 7.21-7.37 (m, 3H). Mass Spectrum (ESI)
m/z=593.0 (M+1).
Example 382
2-((3R,5R,6S)-1-((S)-2-(Azetidin-1-ylsulfonyl)-1-cyclopropylethyl)-5-(3-ch-
lorophenyl)-6-(4-chlorophenyl)-3-methyl-2-oxopiperidin-3-yl)acetic
acid
[3420] .sup.1H NMR (400 MHz, CHLOROFORM-d) .delta. ppm -1.07 (br s,
1H), -0.28 (br s, 1H), 0.18-0.44 (m, 2H), 1.51 (s, 3H), 1.80 (br s,
1H), 1.90 (dd, J=13.79, 2.84 Hz, 1H), 2.31 (quin, J=7.68 Hz, 2H),
2.45 (t, J=13.79 Hz, 1H), 2.60 (br s, 1H), 2.74-2.82 (m, 1H), 2.94
(d, J=13.69 Hz, 1H), 3.07 (d, J=14.87 Hz, 1H), 3.16 (ddd, J=13.74,
10.71, 2.74 Hz, 1H), 3.94-4.06 (m, 4H), 4.27 (br s, 1H), 4.82 (d,
J=10.56 Hz, 1H), 6.81-6.88 (m, 1H), 6.97 (m, 1H), 7.07-7.17 (m,
3H), 7.24-7.28 (m, 3H). Mass Spectrum (ESI) m/z=579.0 (M+1).
Example 383
2-((3R,5R,6S)-5-(3-Chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-cyclopropyl-2-
-((N,N-dimethylsulfamoyl)amino)ethyl)-3-methyl-2-oxopiperidin-3-yl)acetic
acid
##STR00961##
[3421] Step A.
(3S,5R,6S)-5-(3-Chlorophenyl)-6-(4-chlorophenyl)-1-[(1S)-1-cyclopropyl-2--
[(dimethylsulfamoyl)amino]ethyl]-3-methyl-3-(prop-2-en-1-yl)piperidin-2-on-
e
##STR00962##
[3423] The title compound was prepared from
(3S,5R,6S)-3-allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-cyclopr-
opyl-2-hydroxyethyl)-3-methylpiperidin-2-one (Example 252, Step A)
and N,N-dimethylsulfamide (TCI America, Portland, Oreg.) following
a procedure similar to the one described in Example 202, Step
C.
[3424] Mass Spectrum (ESI) m/z=561.5 (M+1).
Step B.
2-((3R,5R,6S)-5-(3-Chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-cyclo-
propyl-2-((N,N-dimethylsulfamoyl)amino)ethyl)-3-methyl-2-oxopiperidin-3-yl-
)acetic acid
[3425] The title compound was prepared from
(3S,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-[(1S)-1-cyclopropyl-2--
[(dimethylsulfamoyl)amino]ethyl]-3-methyl-3-(prop-2-en-1-yl)piperidin-2-on-
e (Example 383, Step A) following a procedure similar to the one
described in Example 226, Step D.
[3426] .sup.1H NMR (400 MHz, CHLOROFORM-d) .delta. ppm -0.34 (br s,
1H), 0.02-0.19 (m, 1H), 0.42-0.60 (m, 2H), 1.14 (br s, 1H),
1.40-1.52 (m, 4H), 2.00-2.14 (m, 1H), 2.18-2.38 (m, 1H), 2.79 (s,
6H), 2.80-2.83 (m, 1H), 2.90-3.00 (m, 1H), 3.00-3.12 (m, 1H),
3.12-3.29 (m, 2H), 3.79 (br s, 1H), 4.89 (d, J=10.2 Hz, 1H), 6.82
(d, J=7.4 Hz, 1H), 6.94-7.02 (m, 1H), 7.03-7.21 (m, 4H), 7.24-7.28
(m, 2H); Mass Spectrum (ESI) m/z=582.0 (M+1).
Example 384
2-((3R,5R,6S)-5-(3-Chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-cyclopropyl-2-
-((N,N-dimethylsulfamoyl)(methyl)amino)ethyl)-3-methyl-2-oxopiperidin-3-yl-
)acetic acid
##STR00963##
[3427] Step A.
(3S,5R,6S)-5-(3-Chlorophenyl)-6-(4-chlorophenyl)-1-[(1S)-1-cyclopropyl-2--
[(dimethylsulfamoyl)(methyl)amino]ethyl]-3-methyl-3-(prop-2-en-1-yl)piperi-
din-2-one
##STR00964##
[3429] The title compound was prepared from
(3S,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-[(1S)-1-cyclopropyl-2--
[(dimethylsulfamoyl)amino]ethyl]-3-methyl-3-(prop-2-en-1-yl)piperidin-2-on-
e (Example 383, Step A) following a procedure similar to the one
described in Example 264.
Step B.
2-((3R,5R,6S)-5-(3-Chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-cyclo-
propyl-2-((N,N-dimethylsulfamoyl)(methyl)amino)ethyl)-3-methyl-2-oxopiperi-
din-3-yl)acetic acid
##STR00965##
[3431] The title compound was prepared from
(3S,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-[(1S)-1-cyclopropyl-2--
[(dimethylsulfamoyl)(methyl)amino]ethyl]-3-methyl-3-(prop-2-en-1-yl)piperi-
din-2-one (example 384, Step A) following a procedure similar to
the one described in Example 226, Step D.
[3432] .sup.1H NMR (400 MHz, CHLOROFORM-d) .delta. ppm -0.76 (br s,
1H), -0.34 (br s, 1H), 0.32 (br s, 1H), 0.42 (br s, 1H), 1.43-1.61
(m, 3H), 1.62-1.84 (m, 1H), 1.94 (d, J=13.3 Hz, 2H), 2.21 (d,
J=12.9 Hz, 1H), 2.44 (br s, 1H), 2.73-2.90 (m, 9H), 3.03-3.21 (m,
3H), 4.65 (br s, 6H), 4.81 (d, J=10.2 Hz, 2H), 6.83-6.96 (m, 2H),
7.00 (s, 2H), 7.08-7.18 (m, 3H), 7.25 (br s, 1H); Mass Spectrum
(ESI) m/z=596.0 (M+1).
[3433] Examples 385 to 389 were prepared from
(3S,5R,6S)-3-allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-cyclopr-
opyl-2-hydroxyethyl)-3-methylpiperidin-2-one (Example 252, step A)
following procedures similar to the one described in Example 202,
Step C and D, replacing N-methylcyclopropanesulfonamide in step B
with the appropriate reagent.
TABLE-US-00024 ##STR00966## Example R Reagent used 385 ##STR00967##
1-methylhydantoin (Sigma-Aldrich, St. Louis, MO) 386 ##STR00968##
1,5,5-trimethyl- imidazolidine-2,4-d (Sigma-Aldrich, St. Louis,
MO)) 387 ##STR00969## 5,5-dimethyl- imidazolidine-2,4-dione
(Sigma-Aldrich, St. Louis, MO) 388 ##STR00970## bentazon (Chan
Service, West Chester, PA) 389 ##STR00971## 1H-benzo[d]imidazol-
2(3H)-one (Sigma-Aldrich, St. Louis, MO)
Example 385
2-((3R,5R,6S)-5-(3-Chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-cyclopropyl-2-
-(3-methyl-2,5-dioxoimidazolidin-1-yl)ethyl)-3-methyl-2-oxopiperidin-3-yl)-
acetic acid
[3434] .sup.1H NMR (400 MHz, CHLOROFORM-d) .delta. ppm 0.24 (br s,
1H), 0.58 (br s, 2H), 1.12-1.36 (m, 1H), 1.36-1.55 (m, 3H),
1.99-2.11 (m, 1H), 2.11-2.26 (m, 1H), 2.71 (d, J=15.1 Hz, 1H),
3.01-3.08 (m, 4H), 3.08-3.23 (m, 2H), 3.53 (br s, 1H), 3.78-4.01
(m, 3H), 4.63 (br s, 1H), 5.58 (br s, 1H), 6.68 (d, J=7.6 Hz, 1H),
6.92-7.02 (m, 1H), 7.06-7.22 (m, 3H), (7.24-7.32 (m, 3H); Mass
Spectrum (ESI) m/z=572.0 (M+1).
Example 386
2-((3R,5R,6S)-5-(3-Chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-cyclopropyl-2-
-(3,4,4-trimethyl-2,5-dioxoimidazolidin-1-yl)ethyl)-3-methyl-2-oxopiperidi-
n-3-yl)acetic acid
[3435] .sup.1H NMR (400 MHz, CHLOROFORM-d) .delta. ppm 0.23 (br s,
1H), 0.56 (br s, 2H), 1.32-1.55 (m, 10H), 2.02 (dd, J=13.9, 2.7 Hz,
1H), 2.15-2.32 (m, 1H), 2.72 (d, J=15.1 Hz, 1H), 2.84-2.96 (m, 4H),
3.04-3.25 (m, 3H), 3.55 (br s, 1H), 3.87-4.10 (br s, 1H), 4.87 (br
s, 1H), 6.66 (d, J=7.0 Hz, 1H), 6.99 (s, 1H), 7.08 (t, J=7.8 Hz,
2H), 7.17 (d, J=8.6 Hz, 2H), 7.28 7.32 (m, 2H); Mass Spectrum (ESI)
m/z=600.0 (M+1).
Example 387
2-((3R,5R,6S)-5-(3-Chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-cyclopropyl-2-
-(4,4-dimethyl-2,5-dioxoimidazolidin-1-yl)ethyl)-3-methyl-2-oxopiperidin-3-
-yl)acetic acid
[3436] .sup.1H NMR (400 MHz, CHLOROFORM-d) .delta. ppm 0.18 (br s,
1H), 0.56 (br s, 2H), 1.37-1.52 (m, 11H), 2.05 (dd, J=13.89, 2.93
Hz, 1H), 2.20 (t, J=13.40 Hz, 1H), 2.74 (d, J=14.9 Hz, 1H), 3.05
(d, J=14.9 Hz, 1H), 3.18 (ddd, J=12.81, 9.9, 3.1 Hz, 1H), 3.53 (br
s, 1H), 3.99 (br s, 1H), 4.67 (br s, 1H), 5.31 (s, 1H), 5.44-5.73
(m, 5H), 6.27 (br s, 1H), 6.68 (d, J=7.4 Hz, 1H), 6.99 (s, 1H),
7.05-7.13 (m, 2H), 7.13-7.21 (m, 2H), 7.22 (br s, 1H);
[3437] Mass Spectrum (ESI) m/z=586.0 (M+1).
Example 388
2-((3R,5R,6S)-5-(3-Chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-cyclopropyl-2-
-(3-isopropyl-2,2-dioxido-4-oxo-3,4-dihydro-1H-benzo[c][1,2,6]thiadiazin-1-
-yl)ethyl)-3-methyl-2-oxopiperidin-3-yl)acetic acid
[3438] .sup.1H NMR (400 MHz, CHLOROFORM-d) .delta. ppm -0.11 (br s,
1H), 0.45 (br s, 2H), 1.22-1.34 (m, 1H), 1.43-1.66 (m, 9H),
1.95-2.14 (m, 1H), 2.21 (t, J=13.60 Hz, 1H), 2.83 (d, J=14.7 Hz,
1H), 3.07 (d, J=14.5 Hz, 1H), 3.14-3.28 (m, 1H), 3.51 (s, 3H), 3.69
(br s, 1H), 4.79 (br s, 1H), 4.95-5.12 (m, 1H), 6.78 (d, J=7.43 Hz,
1H), 6.93 (br s, 1H), 7.01 (br s, 1H), 7.04-7.20 (m, 3H), 7.28-7.31
(m, 3H), 7.39 (t, J=7.4 Hz, 1H), 7.59-7.70 (m, 1H), 8.19 (d, J=8.0
Hz, 1H); Mass Spectrum (ESI) m/z=698.0 (M+1).
Example 389
2-((3R,5R,6S)-5-(3-Chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-cyclopropyl-2-
-(2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)ethyl)-3-methyl-2-oxopiperidi-
n-3-yl)acetic acid
[3439] .sup.1H NMR (400 MHz, CHLOROFORM-d) .delta. ppm -0.29--0.06
(m, 1H), 0.41 (br s, 2H), 1.32-1.43 (m, 3H), 1.43-1.60 (m, 2H),
1.64-1.94 (m, 3H), 2.75 (d, J=14.1 Hz, 1H), 2.97 (d, J=14.1 Hz,
1H), 3.11 (br s, 1H), 3.51-3.72 (m, 1H), 3.74 (m, 1H), 4.34 (s,
1H), 6.45 (br s, 1H), 6.63 (br s, 1H), 6.75 (br s, 1H), 7.01 (d,
J=6.5 Hz, 2H), 7.11 (d, J=7.6 Hz, 2H), 7.15-7.27 (m, 4H), 9.55 (br
s, 1H); Mass Spectrum (ESI) m/z=592.0 (M+1).
Example 390
2-((3R,5R,6S)-5-(3-Chloro-4-fluorophenyl)-6-(4-chlorophenyl)-1-isopropyl-3-
-methyl-2-oxopiperidin-3-yl)acetic acid
##STR00972##
[3440] Step A.
(5R,6S)-5-(3-Chloro-4-fluorophenyl)-6-(4-chlorophenyl)piperidin-2-one
##STR00973##
[3442] The title compound was prepared using
2-(3-chloro-4-fluorophenyl)acetic acid according to the procedures
described in Example 1, Steps A-E. The individual enantiomers were
separated by chiral HPLC (flowrate: 400 mL/min on a Varian SD-2
prep HPLC system (Wakefield, R.I.) and a MODCOL spring load column
from Grace (Hesperia, Calif.) with an inner diameter of 10 cm and
packed to a length of approximately 35 cm with 2.0 kg of
Chiralcel.RTM. OD CSP (Chiral Technologies, Inc., West Chester,
Pa., USA) using 25% isopropyl alcohol/methanol as the eluent) to
give the title compound as an off-white solid.
[.alpha.].sub.D=+152.degree. (T=23.degree. C., c=1.0,
CHCl.sub.3).
Step B.
(4R,5S)-5-Amino-4-(3-chloro-4-fluorophenyl)-5-(4-chlorophenyl)pent-
anoic acid hydrochloride
##STR00974##
[3444] A suspension of
(5R,6S)-5-(3-chloro-4-fluorophenyl)-6-(4-chlorophenyl)piperidin-2-one
(5.00 g, 14.78 mmol; Example 390, step A) in 5 M HCl (15 mL) was
heated to reflux for seven hours. The reaction mixture was cooled
to rt and diluted with toluene. The solvent was removed in vacuo
and any remaining water was removed by azeotropic distillation with
toluene four times to provide a white solid (5.81 g).
Step C.
(5R,6S)-5-(3-Chloro-4-fluorophenyl)-6-(4-chlorophenyl)-1-isopropyl-
piperidin-2-one
##STR00975##
[3446] Sodium triacetoxyborohydride (1.796 g, 8.48 mmol) was added
to a solution of
(4R,5S)-5-amino-4-(3-chloro-4-fluorophenyl)-5-(4-chlorophenyl)pentanoic
acid hydrochloride (2.56 g, 6.52 mmol; Example 390, Step B) and
acetone (0.491 mL, 6.68 mmol) in anhydrous DMF (6.52 mL) at rt. The
reaction mixture was stirred at rt for 16 hours. Dichloroethane (25
mL) was added followed by 3 .ANG. molecular seives. The reaction
mixture was heated to 70.degree. C. for 22 hours, filtered and
concentrated in vacuo. Purification by flash chromatography on
silica gel using a 220 g column and eluting with 30 to 100%
EtOAc/hexanes provided the desired product as a white solid.
Step D.
(3S,5R,6S)-3-Allyl-5-(3-chloro-4-fluorophenyl)-6-(4-chlorophenyl)--
1-isopropyl-3-methylpiperidin-2-one
##STR00976##
[3448] A solution of
(5R,6S)-5-(3-chloro-4-fluorophenyl)-6-(4-chlorophenyl)-1-isopropylpiperid-
in-2-one (0.50 g, 1.32 mmol; Example 390, Step C) in anhydrous THF
(3 mL) was degassed by bubbling argon through the solution for 15
minutes. LHMDS (1 M in THF that was degassed by bubbling argon
through the solution for 15 minutes) (1.64 mL, 1.64 mmol) was added
to the lactam solution at -15.degree. C. dropwise while keeping the
temperature below -8.degree. C. After 15 minutes at -15.degree. C.
iodomethane (0.085 mL, 1.354 mmol) was added. Thirty five minutes
later freshly prepared LDA (3.29 mmol) in THF (1 mL) was added to
the reaction mixture. After 30 minutes the reaction mixture was
cooled to -78.degree. C. and allyl bromide (0.398 mL, 4.60 mmol)
was added slowly while keeping the temperature at or below
-68.degree. C. The reaction mixture was allowed to warm as the cold
bath warmed. After 16 hours the reaction mixture temperature was
18.degree. C. The reaction was quenched with MeOH (0.5 mL), washed
with 10 mL of 50% brine/water, brine, dried (Na.sub.2SO.sub.4),
decanted and concentrated in vacuo to provide a yellow oil.
Purification by flash chromatography on silica gel (eluent: 5-15%
EtOAc/hexanes, gradient elution) provided the title compound.
Step E.
2-((3R,5R,6S)-5-(3-Chloro-4-fluorophenyl)-6-(4-chlorophenyl)-1-iso-
propyl-3-methyl-2-oxopiperidin-3-yl)acetic acid
[3449] A solution of potassium permanganate (0.341 g, 2.155 mmol)
in water (2 mL) was added to a solution of
(3S,5R,6S)-3-allyl-5-(3-chloro-4-fluorophenyl)-6-(4-chlorophenyl)-1-isopr-
opyl-3-methylpiperidin-2-one (0.312 g, 0.718 mmol; Example 390,
step D) and tetrabutylammonium chloride hydrate (0.021 g, 0.072
mmol) in DCM (2 mL) at 0.degree. C. After 5 minutes the reaction
mixture was removed from the ice bath and stirred at rt. After 2
hours at rt the reaction mixture was diluted with aq. sodium
bisulfite. This solution was filtered and then extracted with DCM
three times. The combined organics were pooled, washed with 50 mL
of 10% sodium bisulfite, brine, dried (MgSO.sub.4), filtered and
concentrated in vacuo to provide a yellow oil. Purification by
flash chromatography on silica gel using a 24 g column and eluting
with 0 to 50% IPA/hexanes provided fractions containing the desired
product and an impurity. Upon standing over night the desired
product crystallized as colorless prisms and were collected by
vacuum filtration to provide the title compound.
[3450] .sup.1H NMR (500 MHz, CHLOROFORM-d) .delta. ppm 1.25 (d,
J=6.8 Hz, 3H), 1.26 (d, J=6.8 Hz, 3H), 1.40 (s, 3H), 2.00 (dd,
J=3.4 and 13.9 Hz, 1H), 2.09 (dd, J=11.9 and 13.7 Hz, 1H), 2.67 (d,
J=15.4 Hz, 1H), 3.02 (dt, J=3.2 and 9.3 Hz, 1H), 3.03 (d, J=15.4
Hz, 1H), 3.41 (m, 1H), 4.41 (d, J=9.0 Hz, 1H), 6.70-6.73 (m, 1H),
6.95-6.99 (m, 3H), 7.06 (dd, J=2.5 and 6.9 Hz, 1H), 7.28 (d, J=9.5
Hz, 2H); Mass Spectrum (ESI) m/z=452.2 [M+H].sup.+.
Example 391
2-((3R,5R,6S)-5-(3-Chloro-5-fluorophenyl)-6-(4-chlorophenyl)-1-isopropyl-3-
-methyl-2-oxopiperidin-3-yl)acetic acid
##STR00977##
[3451] Step A.
(5R,6S)-5-(3-Chloro-5-fluorophenyl)-6-(4-chlorophenyl)piperidin-2-one
##STR00978##
[3453] The title compound was prepared using
2-(3-chloro-5-fluorophenyl)acetic acid according to the procedures
described in Example 1, Steps A-E. The individual enantiomers were
separated by chiral HPLC (150.times.50 mm Chiralpak.RTM. AD-H
column (Chiral Technologies, Inc., West Chester, Pa., USA) with 50
g/min methanol+(20 mM NH.sub.3)+130 g/min CO.sub.2 on Thar 350 SFC
(Thar Technologies, Inc., Pittsburg, Pa.)).
[.alpha.].sub.D=+114.degree. (T=23.degree. C., c=4.0,
CHCl.sub.3).
Step B.
(4R,5S)-5-Amino-4-(3-chloro-5-fluorophenyl)-5-(4-chlorophenyl)pent-
anoic acid hydrochloride
##STR00979##
[3455] The title compound was prepared from
(5R,6S)-5-(3-chloro-5-fluorophenyl)-6-(4-chlorophenyl)piperidin-2-one
(Example 391, Step A) using the procedure described in Example 390,
Step B.
Step C.
(5R,6S)-5-(3-Chloro-5-fluorophenyl)-6-(4-chlorophenyl)-1-isopropyl-
piperidin-2-one
##STR00980##
[3457] The title compound was prepared from
(4R,5S)-5-amino-4-(3-chloro-5-fluorophenyl)-5-(4-chlorophenyl)pentanoic
acid hydrochloride (Example 391, step B) using the procedure
described in Example 390, Step C.
Step D.
(3S,5R,6S)-5-(3-Chloro-5-fluorophenyl)-6-(4-chlorophenyl)-1-isopro-
pyl-3-methylpiperidin-2-one and
(3R,5R,6S)-5-(3-chloro-5-fluorophenyl)-6-(4-chlorophenyl)-1-isopropyl-3-m-
ethylpiperidin-2-one
##STR00981##
[3459] A solution of
(5R,6S)-5-(3-chloro-5-fluorophenyl)-6-(4-chlorophenyl)-1-isopropylpiperid-
in-2-one (0.400 g, 1.052 mmol; Example 391, Step C) was dissolved
in benzene and the solvent removed under a vacuum three times. The
resulting oil was dissolved in anhydrous 2-methylTHF (2 mL) and was
degassed by bubbling argon through the solution for 15 minutes
while cooling to -15.degree. C. LHMDS (1.0 M in THF) (1.315 ml,
1.315 mmol) was added and the solution turned yellow. After 10
minutes, iodomethane (0.069 ml, 1.104 mmol) was added dropwise
while keeping the temperature below -10.degree. C. Forty minutes
later the reaction mixture was quenched with sat. aq. NH.sub.4Cl
and warmed to rt. The layers were separated and the aqueous layer
was extracted with EtOAc twice. The organics were pooled, washed
with brine, dried (Na.sub.2SO.sub.4), decanted and concentrated in
vacuo to provide an orange oil. Purification by flash
chromatography on silica gel using a 24 g column and eluting with
10 to 30% EtOAc/hexanes provided a 96:4 mixture of
(3S,5R,6S)-5-(3-chloro-5-fluorophenyl)-6-(4-chlorophenyl)-1-isopropyl-3-m-
ethylpiperidin-2-one and
(3R,5R,6S)-5-(3-chloro-5-fluorophenyl)-6-(4-chlorophenyl)-1-isopropyl-3-m-
ethylpiperidin-2-one as a colorless syrup.
Step E.
(3S,5R,6S)-3-Allyl-5-(3-chloro-5-fluorophenyl)-6-(4-chlorophenyl)--
1-isopropyl-3-methylpiperidin-2-one and
(3R,5R,6S)-3-allyl-5-(3-chloro-5-fluorophenyl)-6-(4-chlorophenyl)-1-isopr-
opyl-3-methylpiperidin-2-one
##STR00982##
[3461] A solution of
(3S,5R,6S)-5-(3-chloro-5-fluorophenyl)-6-(4-chlorophenyl)-1-isopropyl-3-m-
ethylpiperidin-2-one and
(3R,5R,6S)-5-(3-chloro-5-fluorophenyl)-6-(4-chlorophenyl)-1-isopropyl-3-m-
ethylpiperidin-2-one (0.320 g, 0.812 mmol; Example 391, Step D) in
anhydrous 2-methylTHF (1.5 mL) was degassed by bubbling argon
through the solution for 15 minutes and then cooled to -15.degree.
C. Freshly prepared LDA (1.22 mmol) in 2-methyl-THF (1.5 mL) was
added slowly while keeping the temperature at or below -14.degree.
C. After 30 minutes at -15.degree. C. the reaction mixture was
cooled to -74.degree. C. and allyl bromide (0.176 ml, 2.029 mmol)
was added slowly while keeping the temperature below -70.degree. C.
After 2 hours additional allyl bromide (0.176 ml, 2.029 mmol) was
added and the reaction mixture was allowed to warm to rt. The
reaction was quenched with sat. aq. NH.sub.4Cl and the layers were
separated. The aqueous layer was extracted with EtOAc twice and the
organics were pooled, washed with brine, dried (Na.sub.2SO.sub.4),
decanted and concentrated under a vacuum to provide a pale yellow
oil. Purification by flash chromatography on silica gel using a 24
g column and eluting with 0 to 50% acetone/hexanes provided a
colorless oil as a 3.3:1 mixture of
(3S,5R,6S)-3-allyl-5-(3-chloro-5-fluorophenyl)-6-(4-chlorophenyl)-1-isopr-
opyl-3-methylpiperidin-2-one and
(3R,5R,6S)-3-allyl-5-(3-chloro-5-fluorophenyl)-6-(4-chlorophenyl)-1-isopr-
opyl-3-methylpiperidin-2-one.
Step F.
2-((3R,5R,6S)-5-(3-Chloro-5-fluorophenyl)-6-(4-chlorophenyl)-1-iso-
propyl-3-methyl-2-oxopiperidin-3-yl)acetic acid
[3462] Ruthenium(III) chloride hydrate (2.19 mg, 9.72 .mu.mol) was
added to a solution of
(3S,5R,6S)-3-allyl-5-(3-chloro-5-fluorophenyl)-6-(4-chlorophenyl)-1-isopr-
opyl-3-methylpiperidin-2-one and
(3R,5R,6S)-3-allyl-5-(3-chloro-5-fluorophenyl)-6-(4-chlorophenyl)-1-isopr-
opyl-3-methylpiperidin-2-one (0.192 g, 0.442 mmol; Example 391,
Step E) and NaIO.sub.4 (97 mg) in EtOAc (1 mL), ACN (1 mL) and
water (2 mL) at rt. After 3 minutes NaIO.sub.4 (97 mg) was added.
The remaining two portions of NaIO.sub.4 (97 mg each) were added
after three and six minutes respectively. After 30 minutes the
reaction mixture was filtered and the layers were separated. The
aqueous layer was extracted with EtOAc twice and the organics were
pooled, washed with 10% aq. NaHSO.sub.3, brine, dried
(Na.sub.2SO.sub.4), decanted and concentrated in vacuo to provide a
tan oil. Purification by flash chromatography on silica gel using a
24 g column and eluting with 5 to 30% (15% MeOH/acetone)/hexanes
provided a 3.3:1 mixture of
2-((3R,5R,6S)-5-(3-chloro-5-fluorophenyl)-6-(4-chlorophenyl)-1-isopropyl--
3-methyl-2-oxopiperidin-3-yl)acetic acid and
2-((3S,5R,6S)-5-(3-chloro-5-fluorophenyl)-6-(4-chlorophenyl)-1-isopropyl--
3-methyl-2-oxopiperidin-3-yl)acetic acid (170 mg, 85%). The
individual isomers were separated by chiral HPLC (2.times. (250
mm.times.30 mm) Chiralpak.RTM. AD-H column (Chiral Technologies,
Inc., West Chester, Pa., USA) with 20 g/min methanol+(20 mM
NH.sub.3)+80 g/min CO.sub.2 on Thar 350 SFC (Thar Technologies,
Inc., Pittsburg, Pa.)) to provide the title compound.
[3463] .sup.1H NMR (400 MHz, CHLOROFORM-d) .delta. ppm 1.26 (d,
J=6.9 Hz, 3H), 1.27 (d, J=6.7 Hz, 3H), 1.38 (s, 3H), 1.99-2.11 (m,
2H), 2.65 (d, J=15.7 Hz, 1H), 3.02 (d, J=15.7 Hz, 1H), 3.30 (dt,
J=2.2 and 8.8 Hz, 1H), 3.46 (m, 1H), 4.48 (d, J=8.8 Hz, 1H), 6.57
(dt, J=1.8 and 9.2 Hz, 1H), 6.79 (s, 1H), 6.97 (dt, J=2.2 and 8.4
Hz, 1H), 6.99 (d, J=8.4 Hz, 2H), 7.30 (d, J=8.6 Hz, 2H); Mass
Spectrum (ESI) m/z=452.2 [M+H].sup.+.
Example 392
2-((3S,5R,6S)-5-(3-Chloro-5-fluorophenyl)-6-(4-chlorophenyl)-1-isopropyl-3-
-methyl-2-oxopiperidin-3-yl)acetic acid
##STR00983##
[3465] Further elution from the HPLC column in Example 391, Step F
provided the title compound (14.8 mg). .sup.1H NMR (400 MHz,
CHLOROFORM-d) .delta. ppm 1.22 (d, J=6.9 Hz, 3H), 1.27 (d, J=7.0
Hz, 3H), 1.58 (s, 3H), 1.72 (dd, J=3.1 and 13.3 Hz, 1H), 2.32 (t,
J=13.5 Hz, 1H), 2.65-2.75 (m, 2H), 3.13 (dt, J=2.9 and 10.6 Hz,
1H), 3.26 (m, 1H), 4.33 (d, J=10.4 Hz, 1H), 6.53 (d, J=9.0 Hz, 1H),
6.74 (s, 1H), 6.91-6.97 (m, 3H), 7.27 (d, J=8.6 Hz, 2H); Mass
Spectrum (ESI) m/z=452.2 [M+H].sup.+.
Example 393
2-((3R,5R,6S)-5-(3-Chloro-5-fluorophenyl)-6-(4-chlorophenyl)-1-((S)-1-(eth-
ylsulfonamido)butan-2-yl)-3-methyl-2-oxopiperidin-3-yl)acetic
acid
##STR00984##
[3466] Step A.
(3S,5R,6S)-3-Allyl-1-((S)-1-((tert-butyldiphenylsilyl)oxy)butan-2-yl)-5-(-
3-chloro-5-fluorophenyl)-6-(4-chlorophenyl)-3-methylpiperidin-2-one
##STR00985##
[3468] The title compound was prepared as described in Example 185,
Step E replacing 2-(3-chlorophenyl aceytic acid with
2-(3-chloro-5-fluorophenyl)acetic acid in Example 1, Step A.
Step B.
(3S,5R,6S)-3-Allyl-5-(3-chloro-5-fluorophenyl)-6-(4-chlorophenyl)--
1-((S)-1-hydroxybutan-2-yl)-3-methylpiperidin-2-one
##STR00986##
[3470] To a solution of
(3S,5R,6S)-3-allyl-1-((S)-1-((tert-butyldiphenylsilyl)oxy)butan-2-yl)-5-(-
3-chloro-5-fluorophenyl)-6-(4-chlorophenyl)-3-methylpiperidin-2-one
(2.15 g, 3.06 mmol; Example 393, Step A) in THF (30.6 ml) at rt was
added TBAF (1.0 M in THF) (6.12 ml, 6.12 mmol). The light yellow
mixture was stirred at rt overnight. The mixture was diluted with
water and EtOAc. The organic layer was washed with brine, dried
over Na.sub.2SO.sub.4, filtered and the filtrate was concentrated.
The residue was purified by flash chromatography on silica gel (40
g column; eluent: 0 to 50% EtOAc in hexanes) to give the title
compound.
Step C.
N--((S)-2-((3S,5R,6S)-3-Allyl-5-(3-chloro-5-fluorophenyl)-6-(4-chl-
orophenyl)-3-methyl-2-oxopiperidin-1-yl)butyl)ethanesulfonamide
##STR00987##
[3472]
(3S,5R,6S)-3-allyl-5-(3-chloro-5-fluorophenyl)-6-(4-chlorophenyl)-1-
-((S)-1-hydroxybutan-2-yl)-3-methylpiperidin-2-one (100 mg, 0.215
mmol; Example 393, Step B) and ethanesulfonamide (70.5 mg, 0.646
mmol) were coupled by the procedure as described in Example 202,
Step C to form the title compound, isolated after silica gel
chromatography (4 g column; eluent 0 to 50% EtOAC/hexanes) as an
off-white solid.
Step D.
2-((3R,5R,6S)-5-(3-Chloro-5-fluorophenyl)-6-(4-chlorophenyl)-1-((S-
)-1-(ethylsulfonamido)butan-2-yl)-3-methyl-2-oxopiperidin-3-yl)acetic
acid
[3473] To a solution of
N--((S)-2-((3S,5R,6S)-3-allyl-5-(3-chloro-5-fluorophenyl)-6-(4-chlorophen-
yl)-3-methyl-2-oxopiperidin-1-yl)butyl)ethanesulfonamide (Example
393, Step C, 120 mg, 0.216 mmol) in EtOAc:MeCN:water (1.450 mL)
(2/2/3) at rt was added sodium periodate (185 mg, 0.864 mmol)
slowly. Then ruthenium chloride hydrate (1.071 mg, 4.75 .mu.mol)
was added. The mixture was stirred vigourously at rt for 2 h. Then
the mixture was filtered and the solid was washed with EtOAc. The
filtrate was extracted with EtOAc 2.times.. The combined organic
layers were dried over Na.sub.2SO.sub.4, filtered and the filtrate
was concentrated under reduced pressure. The residue was purified
by reverse phase preparatory HPLC (column: Gemini.TM. Prep C.sub.18
5 um column; Phenomenex, Torrance, Calif.; eluent: 0 to 100%
MeCN+0.1% TFA in water+0.1% TFA, over 20 minutes) to give the title
compound.
[3474] .sup.1H NMR (400 MHz, CHLOROFORM-d) .delta. ppm 0.53 (t,
J=7.6 Hz, 3H) 1.40 (t, J=7.3 Hz, 3H) 1.46-1.56 (m, 4H) 1.80-1.94
(m, 1H) 1.96-2.00 (m, 2H) 2.36 (t, J=13.9 Hz, 1H) 2.77 (d, J=14.9
Hz, 1H) 2.97 (d, J=14.9 Hz, 1H) 3.02-3.21 (m, 5H) 4.61 (br s, 1H)
4.81 (d, J=10.6 Hz, 1H) 6.62-6.69 (m, 1H) 6.79 (t, J=1.8 Hz, 1H)
6.90 (dt, J=8.3, 2.1 Hz, 1H) 7.07 (br s, 2H) 7.24-7.30 (m, 2H);
Mass Spectrum (ESI) m/z=573 (M+1).
Example 394
2-((3R,5R,6S)-5-(3-Chloro-5-fluorophenyl)-6-(4-chlorophhenyl)-3-methyl-1-(-
(S)-1-(N-methylethylsulfonamido)butan-2-yl)-2-oxopiperidin-3-yl)acetic
acid
##STR00988##
[3476] To a solution of
2-((3R,5R,6S)-5-(3-chloro-5-fluorophenyl)-6-(4-chlorophenyl)-1-((S)-1-(et-
hylsulfonamido)butan-2-yl)-3-methyl-2-oxopiperidin-3-yl)acetic acid
(Example 393, Step D, 26.6 mg, 0.046 mmol) in DMF (464 .mu.l) at rt
was added a dispersion of 60% sodium hydride in mineral oil (5.57
mg, 0.139 mmol). The grey slurry was stirred at rt for 30 min then
iodomethane (5.80 .mu.l, 0.093 mmol) was added. The mixture was
stirred at rt for 1 h. The mixture was quenched with 1 M HCl and
diluted with EtOAc. The aqueous layer was extracted with EtOAc
2.times.. The organic layer was dried over Na.sub.2SO.sub.4,
filtered and the filtrate was concentrated. The residue was
purified by reverse phase preparatory HPLC (column: Gemini.TM. Prep
C.sub.18 10 um column; Phenomenex, Torrance, Calif.; eluent: 0 to
100% MeCN+0.1% TFA in water+0.1% TFA, over 20 minutes) to give the
title compound.
[3477] .sup.1H NMR (400 MHz, CHLOROFORM-d) .delta. ppm 0.50 (t,
J=7.5 Hz, 3H) 1.38 (t, J=7.4 Hz, 3H) 1.52 (s, 3H) 1.57-1.63 (m, 1H)
1.85-2.00 (m, 2H) 2.46 (t, J=13.9 Hz, 1H) 2.66-2.89 (m, 6H)
2.94-3.16 (m, 4H) 4.31 (dd, J=13.7, 10.8 Hz, 1H) 4.81 (d, J=10.8
Hz, 1H) 6.59 (br s, 1H) 6.69 (dt, J=9.1, 2.1 Hz, 1H) 6.80 (t, J=1.8
Hz, 1H) 6.91 (dt, J=8.3, 2.0 Hz, 1H) 7.01 (br s, 1H) 7.29 (br s,
2H); Mass Spectrum (ESI) m/z=587 (M+1).
Example 395
2-((3R,5R,6S)-5-(3-Chloro-5-fluorophenyl)-6-(4-chlorophenyl)-3-methyl-1-((-
S)-1-(methylsulfonyl)butan-2-yl)-2-oxopiperidin-3-yl)acetic
acid
##STR00989##
[3478] Step A.
(3S,5S,6R,8S)-8-Allyl-6-(3-chloro-5-fluorophenyl)-5-(4-chlorophenyl)-3-et-
hyl-8-methyl-2,3,5,6,7,8-hexahydrooxazolo[3,2-a]pyridin-4-ium
methanesulfonate
##STR00990##
[3480] The title compound was prepared from
(3S,5R,6S)-3-allyl-5-(3-chloro-5-fluorophenyl)-6-(4-chlorophenyl)-1-((S)--
1-hydroxybutan-2-yl)-3-methylpiperidin-2-one (Example 393, Step B)
by a procedure similar to the one described in Example 344, Step
A.
Step B.
(3S,5R,6S)-3-Allyl-5-(3-chloro-5-fluorophenyl)-6-(4-chlorophenyl)--
3-methyl-1-((S)-1-(methylsulfonyl)butan-2-yl)piperidin-2-one
##STR00991##
[3482] To a solution of
(3S,5S,6R,8S)-8-allyl-6-(3-chloro-5-fluorophenyl)-5-(4-chlorophenyl)-3-et-
hyl-8-methyl-2,3,5,6,7,8-hexahydrooxazolo[3,2-a]pyridin-4-ium
methanesulfonate (Example 395, step A, 100 mg, 0.184 mmol) in MeCN
(1.8 mL) was added methanesulfinic acid, sodium salt (56.5 mg,
0.553 mmol). The mixture was heated to 114.degree. C. After heating
for 24 hours, the mixture was cooled to room temperature and
stirred for 2 days. The mixture was partitioned between EtOAc and
aq. NH.sub.4Cl. The organic layer was washed with brine, dried over
Na.sub.2SO.sub.4, filtered and the filtrate was concentrated. The
residue was purified by flash chromatography on silica gel (eluent:
20 to 60% EtOAc/hexanes, gradient elution) to afford the title
compound.
Step C.
2-((3R,5R,6S)-5-(3-Chloro-5-fluorophenyl)-6-(4-chlorophenyl)-3-met-
hyl-1-((S)-1-(methylsulfonyl)butan-2-yl)-2-oxopiperidin-3-yl)acetic
acid
[3483] To a solution of
(3S,5R,6S)-3-allyl-5-(3-chloro-5-fluorophenyl)-6-(4-chlorophenyl)-3-methy-
l-1-((S)-1-(methylsulfonyl)butan-2-yl)piperidin-2-one (Example 395,
Step B, 58 mg, 0.110 mmol) in acetonitrile (1.0 mL), EtOAc (1.0
mL), and water (1.5 mL) was added ruthenium(III) chloride hydrate
(0.55 mg, 2.42 .mu.mol) and sodium periodate (144 mg, 0.672 mmol).
After 2 hours, the mixture was partitioned between water and EtOAc.
The organic layer was washed with brine, dried over
Na.sub.2SO.sub.4, filtered and the filtrate was concentrated. The
residue was purified by preparative thin layer chromatography on
silica gel (eluent: 10% MeOH/DCM) to provide the title
compound.
[3484] .sup.1H NMR (400 MHz, CHLOROFORM-d) .delta. ppm 0.43 (t,
J=7.5 Hz, 3H) 1.48 (s, 3H) 1.64 (br s, 1H) 1.91 (dd, J=13.7, 2.4
Hz, 1H) 2.06-2.22 (m, 1H) 2.33 (t, J=13.8 Hz, 1H) 2.76 (d, J=15.1
Hz, 1H) 2.90 (d, J=12.1 Hz, 1H) 2.94-3.03 (m, 4H) 3.13 (t, J=11 Hz,
1H) 3.33 (t, J=9.7 Hz, 1H) 4.22 (t, J=12.3 Hz, 1H) 4.88 (d, J=10.8
Hz, 1H) 6.61 (d, J=9.2 Hz, 1H) 6.75 (s, 1H) 6.89 (dt, J=8.3, 1.9
Hz, 1H) 7.12 (br s, 2H) 7.21-7.35 (m, 2H). Mass Spectrum (ESI)
m/z=544.0 (M+1).
[3485] Examples 396 to 398 were prepared from
(3S,5S,6R,8S)-8-allyl-6-(3-chloro-5-fluorophenyl)-5-(4-chlorophenyl)-3-et-
hyl-8-methyl-2,3,5,6,7,8-hexahydrooxazolo[3,2-a]pyridin-4-ium
methanesulfonate (Example 395, Step A) by a procedure similar to
those described in either Example 339 or Example 395, using an
equivalent amount of the appropriate reagent in Step B. Example 399
was prepared from
(3S,5R,6S)-3-allyl-5-(3-chloro-5-fluorophenyl)-6-(4-chlorophenyl)-1--
((S)-1-hydroxybutan-2-yl)-3-methylpiperidin-2-one (Example 393,
step B) by a procedure similar to the one described in Example 300,
using an equivalent amount of the appropriate thiol in Step A.
TABLE-US-00025 ##STR00992## Example R Method Reagent used 396 Ethyl
Example 395 ethanesulfinic acid, sodium salt 397 ##STR00993##
Example 395 cyclopropanesulfinic acid, sodium salt 398 ##STR00994##
Example 339 2-methylpropanethiolate, prepared in situ from
2-methylpropane-2-thiol and sodium hydride 399 ##STR00995## Example
300 2-propanethiol
Example 396
2-((3R,5R,6S)-5-(3-Chloro-5-fluorophenyl)-6-(4-chlorophenyl)-1-((S)-1-(eth-
ylsulfonyl)butan-2-yl)-3-methyl-2-oxopiperidin-3-yl)acetic acid
[3486] .sup.1H NMR (400 MHz, CHLOROFORM-d) .delta. ppm 0.42 (t,
J=7.5 Hz, 3H) 1.45 (t, J=7.5 Hz, 3H) 1.49 (s, 3H) 1.65 (br s, 1H)
1.90 (dd, J=13.7, 2.4 Hz, 1H) 2.06-2.21 (m, 1H) 2.35 (t, J=13.8 Hz,
1H) 2.73-2.82 (m, 2H) 2.98 (d, J=15.1 Hz, 1H) 3.01-3.08 (m, 2H)
3.13 (t, J=11.0 Hz, 1H) 3.34 (t, J=10.2 Hz, 1H) 4.13 (t, J=12.1 Hz,
1H) 4.92 (d, J=10.8 Hz, 1H) 6.62 (d, J=9.2 Hz, 1H) 6.75 (s, 1H)
6.89 (dt, J=8.4, 2.0 Hz, 1H) 7.12 (br s, 2H) 7.21-7.34 (m, 2H).
Mass Spectrum (ESI) m/z=558.0 (M+1).
Example 397
2-((3R,5R,6S)-5-(3-Chloro-5-fluorophenyl)-6-(4-chlorophenyl)-1-((S)-1-(cyc-
lopropylsulfonyl)butan-2-yl)-3-methyl-2-oxopiperidin-3-yl)acetic
acid
[3487] .sup.1H NMR (400 MHz, CHLOROFORM-d) .delta. ppm 0.43 (t,
J=7.6 Hz, 3H) 1.05-1.15 (m, 2H) 1.25-1.33 (m, 2H) 1.38-1.54 (m, 4H)
1.90 (dd, J=13.8, 2.8 Hz, 1H) 2.07-2.21 (m, 1H) 2.34 (t, J=13.8 Hz,
1H) 2.42 (tt, J=8.0, 4.8 Hz, 1H) 2.76 (d, J=15.1 Hz, 1H) 2.88-3.01
(m, 2H) 3.13 (ddd, J=13.4, 10.8, 2.5 Hz, 1H) 3.31 (t, J=10.4 Hz,
1H) 4.20 (dd, J=13.5, 11.2 Hz, 1H) 4.90 (d, J=10.8 Hz, 1H) 6.61
(dt, J=9.0, 2.0 Hz, 1H) 6.74 (s, 1H) 6.88 (dt, J=8.4, 2.1 Hz, 1H)
7.11 (br s, 2H) 7.21-7.34 (m, 2H). Mass Spectrum (ESI) m/z=570.0
(M+1).
Example 398
2-((3R,5R,6S)-1-((S)-1-(tert-Butylsulfonyl)butan-2-yl)-5-(3-chloro-5-fluor-
ophenyl)-6-(4-chlorophenyl)-3-methyl-2-oxopiperidin-3-yl)acetic
acid
[3488] The crude product was purified by SFC 20 mL/min;
30.times.250 mm Chiralpak.RTM. IC column (Chiral Technologies,
Inc., West Chester, Pa., USA) using methanol (20 mM
NH.sub.3)/CO.sub.2 as the eluent on Thor SFC (Thor Technologies,
Inc. Pittsburg, Pa.) to provide the title compound.
[3489] .sup.1H NMR (400 MHz, CHLOROFORM-d) .delta. ppm 0.41 (t,
J=7.5 Hz, 3H) 1.38-1.68 (m, 13H) 1.88 (dd, J=13.7, 2.5 Hz, 1H)
2.06-2.26 (m, 1H) 2.38 (t, J=13.8 Hz, 1H) 2.73 (d, J=15.5 Hz, 1H)
2.80 (d, J=13.5 Hz, 1H) 3.01 (d, J=15.3 Hz, 1H) 3.11 (t, J=11.8 Hz,
1H) 3.33 (t, J=10.4 Hz, 1H) 4.03 (dd, J=13.0, 11.3 Hz, 1H) 4.97 (d,
J=10.8 Hz, 1H) 6.63 (d, J=9.2 Hz, 1H) 6.75 (s, 1H) 6.89 (d, J=8.4
Hz, 1H) 7.14 (br s, 2H) 7.25-7.36 (m, 2H). Mass Spectrum (ESI)
m/z=586.0 (M+1).
Example 399
2-((3R,5R,6S)-5-(3-Chloro-5-fluorophenyl)-6-(4-chlorophenyl)-1-((S)-1-(iso-
propylsulfonyl)butan-2-yl)-3-methyl-2-oxopiperidin-3-yl)acetic
acid
[3490] The crude product was purified by preparative thin layer
chromatography on silica gel (eluent: 10% MeOH/DCM) followed by
purification by reverse phase preparatory HPLC (column: Gemini.TM.
Prep C.sub.18 10 um column; Phenomenex, Torrance, Calif.; eluent: 0
to 100% MeCN+0.1% TFA in water+0.1% TFA, over 20 minutes) to give
the title compound.
[3491] .sup.1H NMR (400 MHz, CHLOROFORM-d) .delta. ppm 0.41 (t,
J=7.5 Hz, 3H) 1.34-1.55 (m, 10H) 1.88 (dd, J=13.8, 2.6 Hz, 1H)
2.07-2.24 (m, 1H) 2.38 (t, J=13.8 Hz, 1H) 2.68-2.81 (m, 2H) 3.01
(d, J=15.5 Hz, 1H) 3.06-3.18 (m, 2H) 3.35 (t, J=10.2 Hz, 1H) 4.08
(dd, J=13.1, 11.5 Hz, 1H) 4.95 (d, J=10.8 Hz, 1H) 6.63 (d, J=9.0
Hz, 1H) 6.75 (s, 1H) 6.89 (dt, J=8.2, 2.0 Hz, 1H) 7.14 (br s, 2H)
7.24-7.37 (m, 2H). Mass Spectrum (ESI) m/z=572.0 (M+1).
Example 400
2-((3R,5R,6S)-6-(4-Chlorophenyl)-5-(5-chloropyridin-3-yl)-1-((S)-1-(cyclop-
ropylsulfonyl)butan-2-yl)-3-methyl-2-oxopiperidin-3-yl)acetic
acid
##STR00996##
[3492] Step A.
1-(4-Chlorophenyl)-2-(5-chloropyridin-3-yl)ethanone
##STR00997##
[3494] 1-(4-chlorophenyl)ethanone (17.22 ml, 133 mmol) was added to
an ice cold solution of 3-bromo-5-chloropyridine (24.3 g, 126 mmol)
and sodium 2-methylpropan-2-olate (30.3 g, 316 mmol) in THF (158
ml) under an argon atmosphere.
(9,9-dimethyl-9H-xanthene-4,5-diyl)bis(diphenylphosphine) (0.731 g,
1.263 mmol) and diacetoxypalladium (0.283 g, 1.263 mmol) were then
added and the solution was heated to 70.degree. C. for 1.5 hours.
The solution was cooled to rt and diluted with ice, 2N HCl (95 mL)
followed by EtOAc (300 ml). The layers were partitioned and the
aqueous layer was washed with EtOAc (2.times.100 ml). The organics
were washed with brine, dried over Na.sub.2SO.sub.4, filtered, and
concentrated. The residue obtained was enriched on a silica gel
column. The fractions containing the product were combined and
concentrated. To the residue obtained was added 130 ml of Et.sub.2O
and the suspension was heated to a reflux in a water bath. The
suspension was then cooled in an ice bath. The solids were
collected by filtration to provide the title compound.
[3495] .sup.1H NMR (500 MHz, DMSO-d.sub.6) .delta. ppm 8.53 (1H, d,
J=2.4 Hz), 8.43 (1H, d, J=1.7 Hz), 8.05-8.11 (2H, m), 7.85 (1H, t,
J=2.1 Hz), 7.63-7.68 (2H, m), 4.55 (2H, s).
Step B. 1-Methyl
5-(4-chlorophenyl)-4-(5-chloropyridin-3-yl)-2-methyl-5-oxopentanoate
##STR00998##
[3497] The title compound was obtained from
1-(4-chlorophenyl)-2-(5-chloropyridin-3-yl)ethanone (Example 400,
Step A, 25.3 g, 95 mmol) by a procedure similar to the one
described in Example 261, Step A. Racemic product is a 1:1 mixture
of diastereomers.
[3498] .sup.1H NMR (500 MHz, DMSO-d.sub.6) .delta. ppm 8.57 (1H, d,
J=2.0 Hz), 8.54 (1H, d, J=1.7 Hz), 8.50 (2H, dd, J=4.4, 2.4 Hz),
8.05-8.09 (4H, m), 7.90 (2H, t, J=2.1 Hz), 7.57-7.64 (4H, m),
4.93-5.04 (2H, m), 3.54 (3H, s), 3.45 (3H, s), 2.34-2.42 (1H, m),
2.24-2.33 (2H, m), 2.19 (1H, dt, J=13.7, 6.8 Hz), 2.05-2.13 (1H,
m), 1.88-1.96 (1H, m), 1.13 (3H, d, J=7.1 Hz), 1.08 (3H, d, J=7.1
Hz); Mass Spectrum (ESI) m/z=366.1 [M+H].sup.+.
Step C. Racemic mixture of (4R,5R)-methyl
5-(4-chlorophenyl)-4-(5-chloropyridin-3-yl)-5-hydroxy-2-methylpentanoate
and (4S,5S)-methyl
5-(4-chlorophenyl)-4-(5-chloropyridin-3-yl)-5-hydroxy-2-methylpentanoate
##STR00999##
[3500] 1-Methyl
5-(4-chlorophenyl)-4-(5-chloropyridin-3-yl)-2-methyl-5-oxopentanoate
(Example 400, Step B, 31 g, 85 mmol) was converted to the title
compounds by a procedure similar to the one described in Example
261, Step B. Product is a 1:1 mixture of diastereomers at the 2
position.
[3501] .sup.1H NMR (500 MHz, CHLOROFORM-d) .delta. ppm 8.43 (2H,
s), 8.13 (2H, d, J=11.7 Hz), 7.59 (2H, dt, J=6.8, 2.0 Hz),
7.24-7.30 (4H, m), 7.03-7.10 (4H, m), 4.88 (1H, d, J=5.6 Hz), 4.84
(1H, d, J=5.6 Hz), 3.64 (3H, s), 3.56 (3H, s), 2.91 (2H, tt,
J=10.7, 5.3 Hz), 2.22-2.29 (1H, m), 2.13-2.22 (4H, m), 2.00-2.10
(1H, m), 1.72-1.87 (2H, m), 1.11 (3H, d, J=7.1 Hz), 1.09 (3H, d,
J=6.8 Hz); Mass Spectrum (ESI) m/z=368.0 [M+H].sup.+.
Step D.
(4R,5R)-5-(4-Chlorophenyl)-4-(5-chloropyridin-3-yl)-5-hydroxy-2-me-
thylpentanoic acid and
(4S,5S)-5-(4-chlorophenyl)-4-(5-chloropyridin-3-yl)-5-hydroxy-2-methylpen-
tanoic acid
##STR01000##
[3503] The racemic mixture of (4R,5R)-methyl
5-(4-chlorophenyl)-4-(5-chloropyridin-3-yl)-5-hydroxy-2-methylpentanoate
and (4S,5S)-methyl
5-(4-chlorophenyl)-4-(5-chloropyridin-3-yl)-5-hydroxy-2-methylpentanoate
(Example 400, Step C, 16.5 g, 43.4 mmol) was converted to the title
compounds by the procedure described in Example 261, Step C. Mass
Spectrum (ESI) m/z=354.1 [M+H].sup.+.
Step E.
(5R,6R)-6-(4-Chlorophenyl)-5-(5-chloropyridin-3-yl)-3-methyltetrah-
ydro-2H-pyran-2-one and
(5S,6S)-6-(4-chlorophenyl)-5-(5-chloropyridin-3-yl)-3-methyltetrahydro-2H-
-pyran-2-one
##STR01001##
[3505] The diastereomeric mixture of
(4R,5R)-5-(4-chlorophenyl)-4-(5-chloropyridin-3-yl)-5-hydroxy-2-methylpen-
tanoic acid and
(4S,5S)-5-(4-chlorophenyl)-4-(5-chloropyridin-3-yl)-5-hydroxy-2-methylpen-
tanoic acid (Example 400, Step D, 15.39 g, 43.4 mmol) was converted
to the title compounds by the procedure described in Example 261,
Step D. The product is a 3:2 mixture of diastereomers at the 2
position.
[3506] .sup.1H NMR (500 MHz, CHLOROFORM-d) .delta. ppm 8.42 (0.6H,
d, J=2.4 Hz), 8.37 (1H, d, J=2.2 Hz), 8.22 (0.6H, d, J=2.0 Hz),
7.91 (1H, d, J=2.0 Hz), 7.35 (0.6H, t, J=2.1 Hz), 7.23-7.27 (1.3H,
m), 7.16-7.23 (3H, m), 7.08 (1.3H, d, J=8.6 Hz), 6.90 (2H, d, J=8.6
Hz), 5.80 (0.6H, d, J=3.9 Hz), 5.74 (1H, d, J=4.4 Hz), 3.67-3.73
(0.6H, m), 3.60 (1H, ddd, J=9.3, 6.4, 4.6 Hz), 2.96-3.10 (1H, m),
2.74-2.84 (0.6H, m), 2.69 (1H, ddd, J=14.4, 9.0, 8.1 Hz), 2.30-2.39
(0.6H, m), 2.18 (0.6H, ddd, J=13.8, 9.2, 4.4 Hz), 1.76-1.86 (1H,
m), 1.44 (1.8H, d, J=7.1 Hz), 1.42 (3H, d, J=6.6 Hz).
Step F.
(3S,5R,6R)-3-Allyl-6-(4-chlorophenyl)-5-(5-chloropyridin-3-yl)-3-m-
ethyltetrahydro-2H-pyran-2-one and
(3R,5S,6S)-3-allyl-6-(4-chlorophenyl)-5-(5-chloropyridin-3-yl)-3-methylte-
trahydro-2H-pyran-2-one
##STR01002##
[3508] The mixture of diastereomers of
(5R,6R)-6-(4-chlorophenyl)-5-(5-chloropyridin-3-yl)-3-methyltetrahydro-2H-
-pyran-2-one and
(5S,6S)-6-(4-chlorophenyl)-5-(5-chloropyridin-3-yl)-3-methyltetrahydro-2H-
-pyran-2-one (Example 400, Step E, 12.2 g, 36.28 mmol) was
converted to the title compounds by the procedure described in
Example 261, Step E.
[3509] .sup.1H NMR (500 MHz, CHLOROFORM-d) .delta. ppm 8.44 (1H, d,
J=2.2 Hz), 8.11 (1H, d, J=2.0 Hz), 7.18-7.24 (2H, m), 7.07 (1H, t,
J=2.1 Hz), 6.62-6.67 (2H, m), 5.82 (1H, ddt, J=17.1, 9.9, 7.4 Hz),
5.71 (1H, d, J=5.1 Hz), 5.13-5.23 (2H, m), 3.85 (1H, dt, J=11.7,
4.7 Hz), 2.48-2.66 (2H, m), 1.93-2.07 (2H, m), 1.42 (3H, s).
Step G.
(S)-2-((2R,3R)-3-(4-Chlorophenyl)-2-(5-chloropyridin-3-yl)-3-hydro-
xypropyl)-N--((S)-1-hydroxybutan-2-yl)-2-methylpent-4-enamide and
(R)-2-((2S,3S)-3-(4-chlorophenyl)-2-(5-chloropyridin-3-yl)-3-hydroxypropy-
l)-N--((S)-1-hydroxybutan-2-yl)-2-methylpent-4-enamide
##STR01003##
[3511] The racemic mixture of
(3S,5R,6R)-3-allyl-6-(4-chlorophenyl)-5-(5-chloropyridin-3-yl)-3-methylte-
trahydro-2H-pyran-2-one and
(3R,5S,6S)-3-allyl-6-(4-chlorophenyl)-5-(5-chloropyridin-3-yl)-3-methylte-
trahydro-2H-pyran-2-one (Example 400, Step F, 12.4 g, 33.0 mmol)
was converted to the title compounds by the procedure described in
Example 261, Step G.
[3512] Mass Spectrum (ESI) m/z=465.2 [M+H].sup.+.
Step H.
(3S,5R,6S)-3-Allyl-6-(4-chlorophenyl)-5-(5-chloropyridin-3-yl)-1-(-
(S)-1-hydroxybutan-2-yl)-3-methylpiperidin-2-one
##STR01004##
[3514] The mixture of diastereomers of
(S)-2-((2R,3R)-3-(4-chlorophenyl)-2-(5-chloropyridin-3-yl)-3-hydroxypropy-
l)-N--((S)-1-hydroxybutan-2-yl)-2-methylpent-4-enamide and
(R)-2-((2S,3S)-3-(4-chlorophenyl)-2-(5-chloropyridin-3-yl)-3-hydroxypropy-
l)-N--((S)-1-hydroxybutan-2-yl)-2-methylpent-4-enamide (Example
400, Step G, 6.34 g) was combined in DCM (68 ml) and triethylamine
(13.3 ml, 95 mmol). After cooling in an ice bath, trimethylamine
hydrochloride (1.953 g, 20.43 mmol) was added.
4-Methylbenzenesulfonic anhydride (17.78 g, 54.5 mmol) was added
slowly as a solid, keeping the temperature below 10.degree. C. The
brownish colored solution was allowed to slowly warm to room
temperature, and then stirred over night. The next day more
trimethyl amine hydrochloride (0.271 mg, 2.91 mmol) was added and
the solution was stirred for another day. The reaction was quenched
with ice water. The layers were partitioned and the aqueous layer
was washed with DCM. The combined organics were dried over
MgSO.sub.4, filtered, and concentrated to provide a brown oil. The
oil was dissolved in MeCN (100 ml) and then heated to 60.degree. C.
for 4 hours. The solution was concentrated and the residue
dissolved in 100 ml of DCM. To this was added 100 ml of sat.
NaHCO.sub.3 and the biphasic solution was stirred at rt. for 5
days. The solution was partitioned and the aqueous layer was washed
with DCM. The organics were dried over MgSO.sub.4, filtered and
concentrated. The product was purified by silica gel chromatography
to give
(3S,5R,6S)-3-allyl-6-(4-chlorophenyl)-5-(5-chloropyridin-3-yl)-1-((S-
)-1-hydroxybutan-2-yl)-3-methylpiperidin-2-one as the second
eluting diastereomer.
[3515] .sup.1H NMR (500 MHz, CHLOROFORM-d) .delta. ppm 8.40 (1H, d,
J=2.0 Hz), 7.91 (1H, d, J=1.5 Hz), 7.35 (1H, t, J=1.8 Hz), 7.26
(1H, br s), 7.00 (2H, br d, J=6.8 Hz), 5.78-5.94 (1H, m), 5.15-5.24
(2H, m), 4.45 (1H, d, J=10.3 Hz), 3.59-3.73 (2H, m), 3.13-3.27 (3H,
m), 2.62 (2H, d, J=7.6 Hz), 2.02-2.11 (1H, m), 1.85-2.00 (2H, m),
1.40-1.52 (1H, m), 1.30 (3H, s), 0.66 (3H, t, J=7.5 Hz). Mass
Spectrum (ESI) m/z=447.2 [M+H].sup.+.
Step I.
(3S,5S,6R,8S)-8-allyl-5-(4-chlorophenyl)-6-(5-chloropyridin-3-yl)--
3-ethyl-8-methyl-2,3,5,6,7,8-hexahydrooxazolo[3,2-a]pyridin-4-ium
methanesulfonate
##STR01005##
[3517] The title compound was prepared from
(3S,5R,6S)-3-allyl-6-(4-chlorophenyl)-5-(5-chloropyridin-3-yl)-1-((S)-1-h-
ydroxybutan-2-yl)-3-methylpiperidin-2-one (Example 400, Step H) by
a procedure similar to the one described in Example 344, Step
A.
[3518] Mass Spectrum (ESI) m/z=429.2 [M].sup.+.
Step J.
(3S,5R,6S)-3-Allyl-6-(4-chlorophenyl)-5-(5-chloropyridin-3-yl)-1-(-
(S)-1-(cyclopropylsulfonyl)butan-2-yl)-3-methylpiperidin-2-one
##STR01006##
[3520]
(3S,5S,6R,8S)-8-allyl-5-(4-chlorophenyl)-6-(5-chloropyridin-3-yl)-3-
-ethyl-8-methyl-2,3,5,6,7,8-hexahydrooxazolo[3,2-a]pyridin-4-ium
methanesulfonate (Example 400, Step 1, 0.188 g, 0.358 mmol) was
converted to the title compound by a procedure similar to the one
described in Example 340 using cyclopropane sulfinic acid, sodium
salt (Oakwood Products, West Columbia, S.C.).
[3521] MS (ESI) m/z=535.1 [M+H].sup.+.
Step K.
2-((3R,5R,6S)-6-(4-Chlorophenyl)-5-(5-chloropyridin-3-yl)-1-((S)-1-
-(cyclopropylsulfonyl)butan-2-yl)-3-methyl-2-oxopiperidin-3-yl)acetic
acid
[3522] To a solution of
(3S,5R,6S)-3-allyl-6-(4-chlorophenyl)-5-(5-chloropyridin-3-yl)-1-((S)-1-(-
cyclopropylsulfonyl)butan-2-yl)-3-methylpiperidin-2-one (Example
400, Step J, 0.06 g, 0.112 mmol) in DCM (2.241 ml) was added acetic
acid (0.160 ml, 2.80 mmol) and tetrabutylammonium chloride hydrate
(3.32 mg, 0.011 mmol). The solution was cooled in an ice bath. A
solution of potassium permanganate (0.053 g, 0.336 mmol) in 1 ml of
water was prepared and added dropwise to the above solution (rinsed
with 1 ml of water). The purple solution was stirred in the ice
bath for 30 minutes and then allowed to warm to room temperature
and left overnight. The next day a solution of sodium bisulfite
(10% in water) was added. The pH of the aq. layer was adjusted to 2
with 30% H.sub.2SO.sub.4 in water. The layers were partitioned and
then the aqueous was washed with DCM followed by 10% iPrOH/DCM. The
combined organics were concentrated under vacuum. The product was
purified by silica gel chromatography to provide the title compound
as a white solid.
[3523] .sup.1H NMR (500 MHz, CHLOROFORM-d) .delta. ppm 8.38 (1H, d,
J=2.2 Hz), 8.00 (1H, d, J=1.7 Hz), 7.67 (1H, t, J=2.0 Hz), 7.26
(2H, br s, overlaps with solvent), 7.17 (2H, br s), 4.99 (1H, d,
J=11.0 Hz), 4.28 (1H, dd, J=13.4, 11.2 Hz), 3.51 (1H, ddd, J=13.6,
11.1, 2.4 Hz), 3.30 (1H, t, J=10.0 Hz), 2.89-2.97 (2H, m), 2.78
(1H, d, J=13.7 Hz), 2.38-2.46 (1H, m), 2.19-2.26 (1H, m), 2.03-2.14
(1H, m), 1.85-1.93 (1H, m), 1.46-1.53 (1H, m), 1.44 (3H, s), 1.27
(2H, m, J=5.6 Hz), 1.07-1.11 (2H, m), 0.43 (3H, t, J=7.6 Hz) Mass
Spectrum (ESI) m/z=553.0 [M+H].sup.+.
Example 401
2-((3R,5R,6S)-1-((S)-1-(tert-Butylsulfonyl)butan-2-yl)-6-(4-chlorophenyl)--
5-(5-chloropyridin-3-yl)-3-methyl-2-oxopiperidin-3-yl)acetic
acid
##STR01007##
[3524] Step A.
2-(3S,5R,6S)-3-Allyl-1-((S)-1-(tert-butylthio)butan-2-yl)-6-(4-chlorophen-
yl)-5-(5-chloropyridin-3-yl)-3-methylpiperidin-2-one
##STR01008##
[3526]
(3S,5R,6S)-3-Allyl-6-(4-chlorophenyl)-5-(5-chloropyridin-3-yl)-1-((-
S)-1-hydroxybutan-2-yl)-3-methylpiperidin-2-one (Example 400, Step
H, 0.2 g, 0.447 mmol) was converted to the title compounds as a
clear film (0.145 g, 62%) by the procedure described in Example
339, Step B using an equivalent of 2-methylpropanethiol.
[3527] .sup.1H NMR (500 MHz, CHLOROFORM-d) .delta. ppm 8.40 (1H, d,
J=2.2 Hz), 7.98 (1H, d, J=1.7 Hz), 7.41 (1H, t, J=2.1 Hz), 7.24
(2H, br d, J=8.3 Hz), 6.99 (2H, br d, J=6.6 Hz), 5.87 (1H, m),
5.13-5.23 (2H, m), 4.65 (1H, d, J=10.8 Hz), 3.51 (1H, t, J=11.4
Hz), 3.19 (1H, ddd, J=13.7, 10.8, 2.9 Hz), 2.63-2.74 (1H, m),
2.53-2.62 (3H, m), 2.16 (1H, t, J=13.6 Hz), 2.08 (1H, m, J=14.2,
8.8, 7.3 Hz), 1.88 (1H, dd, J=13.4, 3.2 Hz), 1.51-1.60 (1H, m),
1.36 (9H, br s), 1.31 (3H, br s), 0.49 (3H, t, J=7.6 Hz). Mass
Spectrum (ESI) m/z=519.2 [M+H].sup.+.
Step B.
2-((3R,5R,6S)-1-((S)-1-(tert-Butylsulfonyl)butan-2-yl)-6-(4-chloro-
phenyl)-5-(5-chloropyridin-3-yl)-3-methyl-2-oxopiperidin-3-yl)acetic
acid
[3528] A solution of
(3S,5R,6S)-3-allyl-1-((S)-1-(tert-butylthio)butan-2-yl)-6-(4-chlorophenyl-
)-5-(5-chloropyridin-3-yl)-3-methylpiperidin-2-one (Example 401,
Step A, 0.147 g, 0.283 mmol) with acetic acid (0.972 mL, 16.98
mmol) and tetrabutylammonium chloride hydrate (8.37 mg, 0.028 mmol)
in 4 ml of DCM was cooled in an ice bath. A solution of potassium
permanganate (0.268 g, 1.698 mmol) in 3 mL of water was added. The
purple solution was stirred while cooling with an ice bath and
allowed to warm to room temperature over 2 hours. Aq.
NaS.sub.2O.sub.3 solution was added along with additional DCM.
After filtering the solution through filter paper the filtrate was
partitioned and then the aq. layer was washed with DCM. The
combined organics were dried over Na.sub.2SO.sub.4 and
concentrated. The product was purified by silica gel chromatography
followed by preparatory HPLC (Agilent column, EXTEND C.sub.18
PrepHT, 5 .mu.M, 30.times.250 mm) eluting with a gradient of 20%
MeCN/H.sub.2O/0.1% TFA to 80% MeCN/H.sub.2O/0.1% TFA over 25
minutes. The fractions containing the product were combined, frozen
in a acetone/dry ice bath and the solvents were removed on a
lyophilizer to provide the title compound as an off-white
solid.
[3529] .sup.1H NMR (500 MHz, DMSO-d.sub.6) .delta. ppm 12.38 (1H,
br s), 8.42 (1H, d, J=2.2 Hz), 8.02 (1H, d, J=1.7 Hz), 7.57 (1H, t,
J=2.0 Hz), 7.11-7.47 (4H, m), 4.83 (1H, d, J=11.0 Hz), 3.84 (1H,
dd, J=13.0, 10.5 Hz), 3.47-3.57 (1H, m), 3.13 (1H, br s), 3.05 (1H,
d, J=12.5 Hz), 2.91 (1H, d, J=13.9 Hz), 2.13-2.23 (1H, m),
2.03-2.13 (2H, m), 1.81-1.97 (1H, m), 1.43-1.53 (1H, m), 1.33 (9H,
s), 1.26 (3H, s), 0.33 (3H, t, J=7.6 Hz).
[3530] Mass Spectrum (ESI) m/z=569.2 [M+H].sup.+.
Example 402
2-((3R,5R,6S)-6-(4-Chlorophenyl)-5-(5-chloropyridin-3-yl)-1-((S)-1-(cyclop-
ropanesulfonamido)butan-2-yl)-3-methyl-2-oxopiperidin-3-yl)acetic
acid
##STR01009##
[3531] Step A.
N--((S)-2-((3S,5R,6S)-3-Allyl-6-(4-chlorophenyl)-5-(5-chloropyridin-3-yl)-
-3-methyl-2-oxopiperidin-1-yl)butyl)cyclopropanesulfonamide
##STR01010##
[3533]
(3S,5R,6S)-3-allyl-6-(4-chlorophenyl)-5-(5-chloropyridin-3-yl)-1-((-
S)-1-hydroxybutan-2-yl)-3-methylpiperidin-2-one (Example 400, Step
H, 0.076 g, 0.170 mmol) was converted to the title compound by a
procedure similar to the one described in Example 272, Step A,
using cyclopropanesulfonamide.
[3534] MS (ESI) m/z=550.2 [M+H].sup.+.
Step B.
2-((3R,5R,6S)-6-(4-Chlorophenyl)-5-(5-chloropyridin-3-yl)-1-((S)-1-
-(cyclopropanesulfonamido)butan-2-yl)-3-methyl-2-oxopiperidin-3-yl)acetic
acid
[3535]
N--((S)-2-((3S,5R,6S)-3-allyl-6-(4-chlorophenyl)-5-(5-chloropyridin-
-3-yl)-3-methyl-2-oxopiperidin-1-yl)butyl)cyclopropanesulfonamide
(Example 402, Step A, 0.073 g, 0.133 mmol) was converted to the
title compound by a procedure similar to the one described in
Example 400, Step K.
[3536] .sup.1H NMR (500 MHz, CHLOROFORM-d) .delta. ppm 8.46 (1H, d,
J=1.7 Hz), 8.17 (1H, br s), 7.75 (1H, s), 7.25 (2H, br s, overlaps
with solvent), 7.02-7.18 (2H, m), 5.08 (1H, br s), 4.92 (1H, d,
J=11.0 Hz), 3.78 (1H, br s), 3.46-3.56 (1H, m), 3.14 (1H, dt,
J=14.2, 4.5 Hz), 3.02 (1H, br s), 2.77-2.95 (2H, m), 2.43-2.50 (1H,
m), 2.36 (1H, t, J=13.8 Hz), 2.00 (1H, dd, J=13.7, 2.7 Hz),
1.79-1.89 (1H, m), 1.50-1.59 (1H, m), 1.48 (3H, s), 1.15-1.20 (2H,
m), 0.98-1.05 (2H, m), 0.51 (3H, t, J=7.6 Hz). Mass Spectrum (ESI)
m/z=568.2 [M+H].sup.+.
Example 403
2-((3R,5R,6S)-6-(4-Chlorophenyl)-5-(5-chloropyridin-3-yl)-3-methyl-1-((S)--
1-(N-methylcyclopropanesulfonamido)butan-2-yl)-2-oxopiperidin-3-yl)acetic
acid
##STR01011##
[3537] Step A:
N--((S)-2-((3S,5R,6S)-3-Allyl-6-(4-chlorophenyl)-5-(5-chloropyridin-3-yl)-
-3-methyl-2-oxopiperidin-1-yl)butyl)-N-methylcyclopropanesulfonamide
##STR01012##
[3539]
(3S,5R,6S)-3-Allyl-6-(4-chlorophenyl)-5-(5-chloropyridin-3-yl)-1-((-
S)-1-hydroxybutan-2-yl)-3-methylpiperidin-2-one (Example 400, Step
H, 0.1 g, 0.224 mmol) was converted to the title compound by a
procedure similar to the one described in Example 272, Step A using
N-methylcyclopropanesulfonamide.
[3540] MS (ESI) m/z=564.2 [M+H].sup.+.
Step B.
2-((3R,5R,6S)-6-(4-Chlorophenyl)-5-(5-chloropyridin-3-yl)-3-methyl-
-1-((S)-1-(N-methylcyclopropanesulfonamido)butan-2-yl)-2-oxopiperidin-3-yl-
)acetic acid
[3541]
N--((S)-2-((3S,5R,6S)-3-allyl-6-(4-chlorophenyl)-5-(5-chloropyridin-
-3-yl)-3-methyl-2-oxopiperidin-1-yl)butyl)-N-methylcyclopropanesulfonamide
(Example 403, Step A, 0.090 g, 0.159 mmol) was converted to the
title compound by a procedure similar to the one described in
Example 400, Step K.
[3542] .sup.1H NMR (500 MHz, Acetone-d.sub.6) .delta. ppm 8.38 (1H,
d, J=1.7 Hz), 8.11 (1H, s), 7.68 (1H, t, J=2.0 Hz), 7.21-7.43 (4H,
m), 4.92 (1H, d, J=10.8 Hz), 4.02-4.21 (1H, m), 3.57 (1H, ddd,
J=13.8, 10.9, 2.9 Hz), 2.99 (1H, d, J=14.2 Hz), 2.91-2.96 (5H, m),
2.76 (1H, d, J=14.2 Hz), 2.53-2.62 (1H, m), 2.39 (1H, t, J=13.7
Hz), 2.19 (1H, dd, J=13.4, 2.9 Hz), 1.75-1.86 (1H, m), 1.66-1.74
(1H, m), 1.42 (3H, s), 0.96-1.12 (4H, m), 0.52 (3H, t, J=7.6 Hz).
Mass Spectrum (ESI) m/z=582.0 [M+H].sup.+.
Example 404
2-((3R,5R,6S)-5-(3-Chlorophenyl)-6-(5-chloropyridin-2-yl)-1-((S)-1-(ethyls-
ulfonyl)butan-2-yl)-3-methyl-2-oxopiperidin-3-yl)acetic acid
##STR01013##
[3543] Step A.
(3S,5R,6S)-3-Allyl-5-(3-chlorophenyl)-6-(5-chloropyridin-2-yl)-1-((S)-1-(-
ethylthio)butan-2-yl)-3-methylpiperidin-2-one
##STR01014##
[3545]
(3S,5R,6S)-3-allyl-5-(3-chlorophenyl)-6-(5-chloropyridin-2-yl)-1-((-
S)-1-hydroxybutan-2-yl)-3-methylpiperidin-2-one (Example 121, Step
L, 100 mg, 0.224 mmol) was azeotroped three times in benzene on a
rotary evaporator. The residue was dissolved in toluene and
transferred to a reaction vessel. The vessel was flushed with
argon. Ethanethiol (33.1 .mu.l, 0.447 mmol) was added followed by
cyanomethylenetributylphosphorane (216 .mu.l, 0.894 mmol). The
vessel was sealed and the solution was heated to 100.degree. C. for
4 h. The reaction mixture was diluted with DCM (10 ml) and
Si-maleimide (Silicycle, 2.1 g; 0.66 mmol/g; 40-63 microns) was
added to scavenge excess thiol. After stirring for about 1 h, the
mixture was filtered and the silica gel was rinsed with DCM. The
filtrate was concentrated on a rotary evaporator. The residue was
dissolved in DCM and loaded directly onto a dry 12 g gold-capped
Redisep.RTM. column (Teledyne Isco, Lincoln, Nebr.). The column was
eluted with a gradient of 0 to 5% MeOH:DCM. The fractions
containing the desired product were combined and concentrated to
afford the title compound as a colorless film.
Step B.
2-((3R,5R,6S)-5-(3-Chlorophenyl)-6-(5-chloropyridin-2-yl)-1-((S)-1-
-(ethylsulfonyl)butan-2-yl)-3-methyl-2-oxopiperidin-3-yl)acetic
acid
[3546]
(3S,5R,6S)-3-Allyl-5-(3-chlorophenyl)-6-(5-chloropyridin-2-yl)-1-((-
S)-1-(ethylthio)butan-2-yl)-3-methylpiperidin-2-one (Example 404,
step A) was converted to the title compound by a procedure similar
to the one described in Example 395, Step C.
[3547] .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. ppm 8.65 (d, J=2.3
Hz, 1H), 7.48 (dd, J=2.4, 8.1 Hz, 1H), 7.16-7.07 (m, 2H), 6.98 (s,
1H), 6.92-6.86 (m, 2H), 5.00 (d, J=10.2 Hz, 1H), 4.25-4.16 (m, 1H),
3.57-3.46 (m, 1H), 3.26 (br s, 1H), 3.15 (d, J=15.3 Hz, 1H),
3.10-3.01 (m, 2H), 2.91 (d, J=15.5 Hz, 1H), 2.80 (d, J=11.7 Hz,
1H), 2.36 (t, J=13.9 Hz, 1H), 2.04-1.90 (m, 2H), 1.50-1.40 (m, 7H),
0.38 (t, J=7.0 Hz, 3H); Mass Spectrum (ESI) m/z=541.2
[M+H].sup.+.
Example 405
2-((3R,5R,6S)-5-(3-Chlorophenyl)-6-(4-chlorophenyl)-3-methyl-1-((S)-1-((S)-
-morpholin-2-yl)propyl)-2-oxopiperidin-3-yl)acetic acid, TFA salt
or
2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-1-((S)-1-((R-
)-morpholin-2-yl)propyl)-2-oxopiperidin-3-yl)acetic acid, TFA
salt
##STR01015##
[3548] Step A. (S)-tert-Butyl
2-((S)-1-hydroxypropyl)morpholine-4-carboxylate and (R)-tert-Butyl
2-((S)---hydroxypropyl)morpholine-4-carboxylate and (S)-tert-Butyl
2-((R)-1-hydroxypropyl)morpholine-4-carboxylate and (R)-tert-Butyl
2-((R)-1-hydroxypropyl)morpholine-4-carboxylate
##STR01016##
[3550] To a solution of (rac)-tert-butyl
2-formylmorpholine-4-carboxylate (0.996 g, 4.63 mmol) (Tyger
Scientific Inc., Ewing, N.J., USA) in THF (25 mL) at RT was added a
solution of 3.0 M ethylmagnesium bromide in diethyl ether (1.851
mL, 5.55 mmol) dropwise. After 4 h, the mixture was quenched with
sat. aq. NH.sub.4Cl solution. The mixture was extracted with EtOAc.
The organic layers were washed with brine, dried over
Na.sub.2SO.sub.4, filtered and the filtrate was concentrated to
afford a mixture of the title compounds.
Step B. (S)-tert-butyl
2-((S)-1-(((4-bromophenyl)sulfonyl)oxy)propyl)morpholine-4-carboxylate
and (R)-tert-butyl
2-((S)-1-(((4-bromophenyl)sulfonyl)oxy)propyl)morpholine-4-carboxylate
and (S)-tert-butyl
2-((R)-1-(((4-bromophenyl)sulfonyl)oxy)propyl)morpholine-4-carboxylate
and (R)-tert-butyl
2-((R)-1-(((4-bromophenyl)sulfonyl)oxy)propyl)morpholine-4-carboxylate
##STR01017##
[3552] To a solution of the mixture of diastereomers from Example
405, step A (509 mg, 2.075 mmol) in DCM (6.9 mL) was added DMAP
(558 mg, 4.56 mmol) and 4-bromobenzenesulfonyl chloride (795 mg,
3.11 mmol). After stirring for 18 h, the mixture was partitioned
between EtOAc and water. The organic layer was washed with brine,
dried over Na.sub.2SO.sub.4, filtered and the filtrate was
concentrated. The residue was purified by flash chromatography on
silica gel (40 g column, eluent: 5 to 30% EtOAc/hexanes) to afford
a mixture of the title compounds.
Step C. (S)-tert-butyl
2-((S)-1-((3S,5R,6S)-3-allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-meth-
yl-2-oxopiperidin-1-yl)propyl)morpholine-4-carboxylate and
(R)-tert-butyl
2-((S)-1-((3S,5R,6S)-3-a-allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-me-
thyl-2-oxopiperidin-1-yl)propyl)morpholine-4-carboxylate and
(S)-tert-butyl
2-((R)-1-((3S,5R,6S)-3-allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-meth-
yl-2-oxopiperidin-1-yl)propyl)morpholine-4-carboxylate and
(R)-tert-butyl
2-((R)-1-((3S,5R,6S)-3-allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-meth-
yl-2-oxopiperidin-1-yl)propyl)morpholine-4-carboxylate
##STR01018##
[3554] The diastereomeric brosylates (Example 404, Step B, 124 mg,
0.267 mmol) were dissolved in toluene and concentrated in vacuo
twice. Dioxane (1 mL) was added followed by sodium tert-butoxide
(25.7 mg, 0.267 mmol). The mixture was heated at 85.degree. C. for
2 days. The mixture was partitioned between EtOAc and dilute aq.
NH.sub.4Cl solution. The organic layer was washed with brine, dried
over Na.sub.2SO.sub.4, filtered and the filtrate was concentrated.
The residue was purified by flash chromatography on silica gel (4 g
column, eluent: 5 to 35% EtOAc/hexanes) to afford a mixture of the
title compounds.
Step D.
2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-1-((S-
)-1-((S)-morpholin-2-yl)propyl)-2-oxopiperidin-3-yl)acetic acid,
TFA salt or
2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-1-((S)-1--
((R)-morpholin-2-yl)propyl)-2-oxopiperidin-3-yl)acetic acid, TFA
salt
[3555] The mixture of diastereomers obtained in Example 404, Step C
(100 mg, 0.166 mmol) was dissolved in THF (1 mL). Water (about 0.5
mL) was added until the solution became cloudy. t-BuOH was added
until the solution became clear. NMO (29.2 mg, 0.249 mmol) was
added followed by 4% aq. osmium tetroxide solution (5.28 .mu.l,
0.831 .mu.mol). After stirring for 18 h, another 3 drops of 4% aq.
OsO.sub.4 solution was added. After stirring for 4 h, 0.20 mL of
Jones Reagent was added. After 2 days, the mixture was partitioned
between aq. NaHCO.sub.3 and DCM. The aqueous layer was extracted
with DCM and EtOAc. The combined organic layers were washed with
brine, dried over Na.sub.2SO.sub.4, filtered and the filtrate was
concentrated. The mixture was stirred in DCM (3 mL) and TFA (1 mL,
12.98 mmol) for 25 minutes and was concentrated. The residue was
purified by reversed phase preparative HPLC (column: Gemini-NX
C.sub.18 5 um column; Phenomonex, Torrance, Calif.; eluent: 30 to
50% MeCN+0.1% TFA in water+0.1% TFA over 20 minutes) to provide
three of the four possible diasteromers of the title compound. The
first eluting of these diastereomers is Example 405:
[3556] .sup.1H NMR (400 MHz, CHLOROFORM-d) .delta. ppm 0.33 (t,
J=7.5 Hz, 3H) 1.30-1.42 (m, 1H) 1.47 (s, 3H) 1.68-1.82 (m, 1H)
1.82-1.91 (m, 1H) 2.19-2.26 (m, 2H) 2.56-2.64 (m, 3H) 2.68-2.87 (m,
1H) 3.03 (d, J=12.3 Hz, 1H) 3.07-3.33 (m, 2H) 3.54-3.76 (m, 1H)
3.76-3.99 (m, 1H) 4.25-4.36 (m, 1H) 4.51 (d, J=10.6 Hz, 1H)
4.57-4.71 (m, 1H) 6.70 (d, J=7.8 Hz, 1H) 7.00 (t, J=1.9 Hz, 1H)
7.14 (t J=7.6 Hz, 1H) 7.21 (d, J=8.0 Hz, 1H) 7.28-7.32 (m, 4H) 8.13
(br s, 1H) 11.54 (br s, 1H). Mass Spectrum (ESI) m/z=519.1
(M+1).
Example 406
2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-1-((R)-1-((S)-
-morpholin-2-yl)propyl)-2-oxopiperidin-3-yl)acetic acid, TFA salt
or
2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-1-((R)-1-((R-
)-morpholin-2-yl)propyl)-2-oxopiperidin-3-yl)acetic acid, TFA
salt
##STR01019##
[3558] Further elution of the HPLC column in Example 405, Step D
provided one of the title compounds as the second eluting
isomer.
[3559] .sup.1H NMR (400 MHz, CHLOROFORM-d) .delta. ppm 0.93-1.11
(m, 3H) 1.39-1.58 (m, 3H) 1.62-1.78 (m, 1H) 1.79-1.92 (m, 1H)
1.93-2.02 (m, 1H) 2.16-2.29 (m, 1H) 2.55-2.70 (m, 2H) 2.73-3.00 (m,
2H) 3.03-3.24 (m, 2H) 3.26-3.44 (m, 2H) 3.45-3.54 (m, 1H) 3.60-3.67
(m, 1H) 3.75-3.97 (m, 1H) 4.30-4.47 (m, 2H) 6.73 (d, J=7.4 Hz, 1H)
6.98 (br s, 1H) 7.11 (t, J=8.0 Hz, 1H) 7.17 (d, J=8.0 Hz, 1H)
7.23-7.33 (m, 4H) 8.99 (br s, 1H) 9.96 (br s, 1H).
[3560] Mass Spectrum (ESI) m/z=519.1 (M+1).
Example 407
2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-1-((R)-1-((R)-
-morpholin-2-yl)propyl)-2-oxopiperidin-3-yl)acetic acid, TFA salt
or
2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-1-((R)-1-((S-
)-morpholin-2-yl)propyl)-2-oxopiperidin-3-yl)acetic acid, TFA
salt
##STR01020##
[3562] Further elution from the HPLC column in Example 405 provided
the other (relative to Example 406) of the title compounds as the
third eluting isomer.
[3563] .sup.1H NMR (400 MHz, CHLOROFORM-d) .delta. ppm 1.10 (t,
J=7.5 Hz, 3H) 1.47 (s, 3H) 1.83-1.93 (m, 1H) 1.98-2.09 (m, 2H)
2.15-2.32 (m, 2H) 2.59-2.64 (m, 1H) 2.66-2.72 (m, 2H) 2.73-2.85 (m,
2H) 3.23 (d, J=13.3 Hz, 1H) 3.43 (t, J=12.2 Hz, 1H) 3.66 (t, J=11.7
Hz, 1H) 3.77-3.92 (m, 2H) 4.34 (t, J=8.1 Hz 1H) 4.41 (d, J=10.6 Hz,
1H) 6.73 (d, J=7.6 Hz 1H) 6.96 (br s, 1H) 7.08 (t, J=8.0 Hz, 1H)
7.13 (d, J=8.0 Hz, 1H) 7.25-7.42 (m, 4H) 9.16 (br s, 1H) 9.43 (br
s, 1H). Mass Spectrum (ESI) m/z=519.1 (M+1).
Example 408
2-((3S,5R,6S)-5-(3-Chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-(N-methylcycl-
opropanesulfonamido)butan-2-yl)-3-(2-morpholinoethyl)-2-oxopiperidin-3-yl)-
acetic acid
##STR01021##
[3564] Step A.
(3R,5R,6S)-3-Allyl-1-((S)-1-((tert-butyldiphenylsilyl)oxy)butan-2-yl)-5-(-
3-chlorophenyl)-6-(4-chlorophenyl)-3-(2-((4-methoxybenzyl)oxy)ethyl)piperi-
din-2-one and
(3S,5R,6S)-3-Allyl-1-((S)-1-((tert-butyldiphenylsilyl)oxy)butan-2-yl)-5-(-
3-chlorophenyl)-6-(4-chlorophenyl)-3-(2-((4-methoxybenzyl)oxy)ethyl)piperi-
din-2-one
##STR01022##
[3566] The title compound was obtained from
(3R,5R,6S)-1-((S)-1-((tert-butyldiphenylsilyl)oxy)butan-2-yl)-5-(3-chloro-
phenyl)-6-(4-chlorophenyl)piperidin-2-one (Example 127, Step A) and
1-((2-iodoethoxy)methyl)-4-methoxybenzene [J. Am. Chem. Soc., 124,
8206-8219, (2002)] by a procedure similar to the one described in
Example 69, Step A. Purification of the residue by flash
chromatography on silica gel (eluent: 0 to 20% EtOAc/hexane,
gradient elution over 30 min) provided the desired products as a
mixture of C3 epimers.
[3567] Mass Spectrum (ESI) m/z=834.4 (M+1) and 856.4 (M+Na).
Step B.
(3R,5R,6S)-3-Allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1--
hydroxybutan-2-yl)-3-(2-((4-methoxybenzyl)oxy)ethyl)piperidin-2-one
##STR01023##
[3569] To a solution of a mixture of
(3R,5R,6S)-3-allyl-1-((S)-1-((tert-butyldiphenylsilyl)oxy)butan-2-yl)-5-(-
3-chlorophenyl)-6-(4-chlorophenyl)-3-(2-((4-methoxybenzyl)oxy)ethyl)piperi-
din-2-one and
(3S,5R,6S)-3-allyl-1-((S)-1-((tert-butyldiphenylsilyl)oxy)butan-2-yl)-5-(-
3-chlorophenyl)-6-(4-chlorophenyl)-3-(2-((4-methoxybenzyl)oxy)ethyl)piperi-
din-2-one (19.23 g, 23.03 mmol; Example 408, Step A) in THF (92 ml)
at rt was slowly added a solution of TBAF (1.0M in THF, 34.5 ml,
34.5 mmol). The reaction was monitored by LCMS, and when judged
complete was concentrated under reduced pressure (no heat), then
diluted in 400 mL of EtOAc. HCl (1N, 150 ml) was added. The layers
were separated and the aqueous layer was extracted with EtOAc. The
combined organics were washed several times with water, dried over
MgSO.sub.4, filtered, and the filtrate was concentrated.
Purification by chromatography on silica gel (eluent: 10 to 20%
EtOAc/hexane, gradient elution over 30 min) provided the title
compound along with its C3 epimer as a clear, colorless foam.
Individual steroisomers were separated by chiral HPLC (flowrate:
120 ml/min, 1 g per injection, on a Chiralcel.RTM. OD-H 5 cm
I.D..times.50 cm, 20 .mu.m column; Daicel Chemical Industries LTD,
using 6% isopropyl alcohol/hexane as the eluent) to give the title
compound as the first eluting isomer (t.sub.R=11-23 min) as a
clear, viscous oil.
[3570] .sup.1H NMR (500 MHz, CHLOROFORM-d) .delta. ppm 0.61 (t,
J=7.5 Hz, 3H) 1.33 (ddd, J=13.9, 7.8, 5.8 Hz, 1H) 1.79 (dd, J=13.7,
2.9 Hz, 1H) 1.94 (dt, J=14.8, 7.5 Hz, 1H) 2.02 (s, 1H) 2.11-2.21
(m, 3H) 2.26 (t, J=13.6 Hz, 1H) 2.77 (dd, J=13.3, 6 Hz, 1H) 3.12
(br s, 1H) 3.22 (ddd, J=13.5, 10.6, 2.8 Hz, 1H) 3.58 (d, J=3.7 Hz,
2H) 3.70 (t, J=6.4 Hz, 2H) 3.81 (s, 3H) 4.35 (d, J=10.5 Hz, 1H)
4.37-4.50 (m, 2H) 5.12-5.22 (m, 2H) 5.75-5.86 (m, 1H) 6.64 (d,
J=7.8 Hz, 1H) 6.85 (m, 2H) 6.92 (s, 2H) 7.06 (t, J=7.8 Hz, 1H)
7.10-7.19 (m, 3H) 7.21 (m, J=8.6 Hz, 2H). Mass Spectrum (ESI)
m/z=596.2 (M+H) and 618.2 (M+Na).
Step C.
N--((S)-2-((3R,5R,6S)-3-Allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl-
)-3-(2-(4-methoxybenzyloxy)ethyl)-2-oxopiperidin-1-yl)butyl)-N-methylcyclo-
propanesulfonamide
##STR01024##
[3572] The title compound was prepared from
(3R,5R,6S)-3-allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-hydroxy-
butan-2-yl)-3-(2-(4-methoxybenzyloxy)ethyl)piperidin-2-one (Example
408, Step B) and N-methylcyclopropanesulfonamide by a procedure
similar to the one described in Example 201, Step A.
[3573] .sup.1H NMR (500 MHz, CHLOROFORM-d) .delta. ppm 0.55 (br s,
3H) 0.87-0.99 (m, 2H) 1.19 (td, J=5.4, 1.6 Hz, 1H) 1.48-1.65 (m,
4H) 1.75 (dd, J=13.7, 3.2 Hz, 1H) 1.85 (dquin, J=14.7, 7.5 Hz, 1H)
2.02 (s, 1H) 2.06-2.11 (m, 1H) 2.16-2.30 (m, 3H) 2.52 (br s, 2H)
2.87 (s, 1H) 2.89 (s, 3H) 3.20 (ddd, J=13.6, 10.7, 3.1 Hz, 1H) 3.71
(t, J=7 Hz, 2H) 3.81 (s, 3H) 4.41-4.50 (m, 2H) 4.66 (br s, 1H)
5.04-5.12 (m, 2H) 5.76-5.88 (m, 1H) 6.83 (d, J=6.9 Hz, 1H)
6.85-6.90 (m, 2H) 6.91 (s, 1H) 7.08-7.20 (m, 4H) 7.25 (s, 1H). Mass
Spectrum (ESI) m/z=713.2 (M+1) and 735.2 (M+Na).
Step D.
N--((S)-2-((3R,5R,6S)-3-Allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl-
)-3-(2-hydroxyethyl)-2-oxopiperidin-1-yl)butyl)-N-methylcyclopropanesulfon-
amide
##STR01025##
[3575] To a solution of 3.09 g (4.33 mmol)
N--((S)-2-((3R,5R,6S)-3-allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-(2--
(4-methoxybenzyloxy)ethyl)-2-oxopiperidin-1-yl)butyl)-N-methylcyclopropane-
sulfonamide (Example 408, step C) in a mixture of DCM (82 mL) and
water (4.56 mL) [18:1] was added 2,6-di-tert-butylpyridine (2.93
mL, 12.99 mmol) followed by DDQ (3.93 g, 17.32 mmol). The reaction
mixture was stirred vigorously at ambient temperature for 15 min.
The reaction mixture was diluted with 150 mL sat. NaHCO.sub.3/brine
solution and extracted into 600 mL of ethyl acetate, then 200 mL of
EtOAc.times.2 (precipitate was removed by filtration). The combined
organic layers were dried over MgSO.sub.4, filtered and the
filtrate was evaporated. Purification by chromatography on silica
gel (eluent: 50-100%% EtOAc/hexane, gradient elution) provided the
desired product as a foam.
[3576] .sup.1H NMR (500 MHz, CHLOROFORM-d) .delta. ppm 0.54 (br s,
3H) 0.92-1.06 (m, 2H) 1.20 (dd, J=4.8, 2.1 Hz, 2H) 1.27 (t, J=7.2
Hz, 1H) 1.53-1.66 (m, 1H) 1.66-1.76 (m, 2H) 1.95 (dt, J=14.9, 7.6
Hz, 1H) 2.23-2.39 (m, 3H) 2.59 (br s, 1H) 2.87 (s, 1H) 2.90 (s, 3H)
3.17 (ddd, J=13.8, 10.6, 3.1 Hz, 1H) 3.77 (dt, J=12.0, 4.6 Hz, 1H)
4.10-4.20 (m, 1H) 4.71 (br s, 1H) 5.07-5.21 (m, 2H) 5.65-5.80 (m,
1H) 6.90 (br s, 1H) 6.96 (s, 1H) 7.11-7.16 (m, 2H) 7.22 (br s, 1H)
7.26 (br s, 2H). Mass Spectrum (ESI) m/z=593.2 (M+1) and 615.2
(M+Na).
Step E.
N--((S)-2-((3R,5R,6S)-3-Allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl-
)-2-oxo-3-(2-((triisopropylsilyl)oxy)ethyl)piperidin-1-yl)butyl)-N-methylc-
yclopropanesulfonamide
##STR01026##
[3578] To a solution of 2.52 g (4.25 mmol)
N--((S)-2-((3R,5R,6S)-3-allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-(2--
hydroxyethyl)-2-oxopiperidin-1-yl)butyl)-N-methylcyclopropanesulfonamide
(Example 408, Step D), DMAP (0.026 g, 0.212 mmol), and imidazole
(0.723 g, 10.61 mmol) in DCM (16.98 mL) at 0.degree. C. was added
slowly by syringe TIPS-Cl (1.17 mL, 5.52 mmol). The reaction was
stirred at ambient temperature, with addition of reagents until
reaction was judged complete by LCMS and TLC. The reaction mixture
was quenched by addition of 6 mL of MeOH, then extracted with DCM
(70 mls.times.2). The combined organics were washed with water (30
mL), satd. aq.NH.sub.4Cl solution (20 mL), dried over
Na.sub.2SO.sub.4, filtered and the filtrate was concentrated.
Purification by chromatography on silica gel (eluent: 0 to 40%
EtOAc/DCM, gradient elution) provided the title compound as a
clear, colorless oil.
[3579] Mass Spectrum (ESI) m/z=749.4 (M+1).
Step F.
N--((S)-2-((3R,5R,6S)-5-(3-Chlorophenyl)-6-(4-chlorophenyl)-2-oxo--
3-(2-oxoethyl)-3-(2-(triisopropylsilyloxy)ethyl)piperidin-1-yl)butyl)-N-me-
thylcyclopropanesulfonamide
##STR01027##
[3581]
N--((S)-2-((3R,5R,6S)-3-allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-
-2-oxo-3-(2-(triisopropylsilyloxy)ethyl)piperidin-1-yl)butyl)-N-methylcycl-
opropanesulfonamide (Example 408, Step E) was treated by a
procedure similar to the one described in Example 91, Step E.
Purification by chromatography on silica gel (12 g SiO.sub.2,
eluent: 0 to 30% EtOAc/hexane, gradient elution) provided the title
compound as a clear oil.
[3582] Mass Spectrum (ESI) m/z=751.2 (M+1)
Step G.
N--((S)-2-((3S,5R,6S)-5-(3-Chlorophenyl)-6-(4-chlorophenyl)-3-(2-m-
orpholinoethyl)-2-oxo-3-(2-(triisopropylsilyloxy)ethyl)piperidin-1-yl)buty-
l)-N-methylcyclopropanesulfonamide
##STR01028##
[3584]
N--((S)-2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-2-oxo-3-
-(2-oxoethyl)-3-(2-((triisopropylsilyl)oxy)ethyl)piperidin-1-yl)butyl)-N-m-
ethylcyclopropanesulfonamide (Example 408, Step F) and morpholine
were combined according to a procedure similar to the one described
in Example 91, Step F. Purification by chromatography on silica gel
(eluent: 50 to 100% EtOAc/DCM, gradient elution over 15 min)
provided the title compound as a clear, colorless glass.
[3585] Mass Spectrum (ESI) m/z=822.4 (M+1)
Step H.
N--((S)-2-((3S,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-(2-h-
ydroxyethyl)-3-(2-morpholinoethyl)-2-oxopiperidin-1-yl)butyl)-N-methylcycl-
opropanesulfonamide
##STR01029##
[3587]
N--((S)-2-((3S,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-(2-mo-
rpholinoethyl)-2-oxo-3-(2-(triisopropylsilyloxy)ethyl)piperidin-1-yl)butyl-
)-N-methylcyclopropanesulfonamide (Example 408, Step G) was treated
according to a procedure similar to the one described in Example
69, step D to afford the title compound.
[3588] .sup.1H NMR (500 MHz, CHLOROFORM-d) .delta. ppm 0.53 (t,
J=7.6 Hz, 3H) 1.02-1.06 (m, 1H) 1.06-1.14 (m, 1H) 1.14-1.22 (m, 1H)
1.22-1.31 (m, 1H) 1.49 (d, J=7.1 Hz, 1H) 1.64 (ddd, J=14.2, 7.8,
3.7 Hz, 3H) 1.77-1.98 (m, 4H) 1.98-2.02 (m, 1H) 2.02-2.06 (m, 3H)
2.25-2.43 (m, 4H) 2.44-2.50 (m, 1H) 2.61 (dd, J=13.8, 1.8 Hz, 1H)
2.79-2.89 (m, 3H) 2.89-3.06 (m, 2H) 3.12-3.26 (m, 1H) 3.39-3.50 (m,
2H) 3.50-3.56 (m, 1H) 3.61 (d, J=12.7 Hz, 1H) 3.75-3.90 (m, 1H)
3.92-4.09 (m, 3H) 4.14-4.38 (m, 2H) 4.48 (br s, 1H) 4.68 (d, J=10.5
Hz, 1H) 6.82-6.93 (m, 1H) 6.98 (s, 2H) 7.08-7.21 (m, 2H) 12.31 (br
s, 1H).
[3589] Mass Spectrum (ESI) m/z=666.2 (M+1)
Step I.
2-((3S,5R,6S)-5-(3-Chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-(N-me-
thylcyclopropanesulfonamido)butan-2-yl)-3-(2-morpholinoethyl)-2-oxopiperid-
in-3-yl)acetic acid
[3590]
N--((S)-2-((3S,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-(2-hy-
droxyethyl)-3-(2-morpholinoethyl)-2-oxopiperidin-1-yl)butyl)-N-methylcyclo-
propanesulfonamide (Example 408, Step H) was treated according to a
procedure similar to the one described in Example 69, step E. The
reaction (using 4 eq. of Jones Reagent) went to completion in less
than 2 minutes at 0.degree. C., after which it was quenched with
MeOH (10 eq) and diluted in EtOAc. The solution was decanted from
insoluble material, washed with aq. NaHCO.sub.3 solution, dried
over MgSO.sub.4, filtered and concentrated under reduced pressure.
Purification by reversed phase prep. HPLC (Sunfire Prep C.sub.18
OBD 10 .mu.m column (Waters, Milford, Mass.), gradient elution of
40% MeCN in water to 75% MeCN in water over a 30 min period, where
both solvents contain 0.1% TFA) provided the title compound as the
TFA salt.
[3591] .sup.1H NMR (500 MHz, CHLOROFORM-d) .delta. ppm 0.49 (t,
J=7.5 Hz, 3H) 0.96-1.16 (m, 3H) 1.17-1.28 (m, 1H) 1.56-1.67 (m, 1H)
1.85 (dt, J=15.2, 7.7 Hz, 1H) 2.00 (dd, J=13.6, 3.1 Hz, 1H)
2.06-2.16 (m, 1H) 2.22-2.41 (m, 3H) 2.57-2.66 (m, 1H) 2.71 (br s,
1H) 2.85 (s, 3H) 2.87-2.96 (m, 3H) 2.99 (br s, 1H) 3.03 (br s, 1H)
3.16-3.27 (m, 1H) 3.34 (br s, 1H) 3.52-3.66 (m, 2H) 3.70 (d, J=12
Hz, 1H) 3.79-3.96 (m, 2H) 4.03 (d, J=1 Hz, 2H) 4.38 (br s, 1H) 4.68
(d, J=10.5 Hz, 1H) 6.84-6.94 (m, 2H) 6.98 (s, 2H) 7.10-7.17 (m, 2H)
7.22-7.27 (m, 1H) 8.42 (br s, 3H) 11.01 (br s, 1H). Mass Spectrum
(ESI) m/z=680.2 (M+1).
[3592] Examples 409-411 were prepared from
N--((S)-2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-2-oxo-3-(2-ox-
oethyl)-3-(2-(triisopropylsilyloxy)ethyl)piperidin-1-yl)butyl)-N-methylcyc-
lopropanesulfonamide (Example 408, Step F) by procedures similar to
those described in Example 408, substituting morpholine in step G
with the appropriate amine.
TABLE-US-00026 ##STR01030## Example R = 409 ##STR01031## 410
##STR01032## 411 ##STR01033##
Example 409
2-((3S,5R,6S)-5-(3-Chlorophenyl)-6-(4-chlorophenyl)-3-(2-(1,1-dioxidothiom-
orpholino)ethyl)-1-((S)-1-(N-methylcyclopropanesulfonamido)butan-2-yl)-2-o-
xopiperidin-3-yl)acetic acid, TFA salt
[3593] .sup.1H NMR (500 MHz, CD.sub.3OD) .delta. ppm 0.51 (t, J=7.5
Hz, 3H) 1.00-1.07 (m, 1H) 1.07-1.19 (m, 2H) 1.21-1.30 (m, 2H)
1.54-1.68 (m, 1H) 1.79-1.91 (m, 1H) 1.95 (dd, J=13.7, 2.7 Hz, 1H)
2.26 (t, J=13.5 Hz, 2H) 2.29-2.39 (m, 2H) 2.61 (d, J=13 Hz, 1H)
2.73 (br s, 1H) 2.79 (d, J=13.7 Hz, 1H) 2.84 (s, 3H) 2.88-2.96 (m,
1H) 3.20 (ddd, J=13.4, 10.7, 3.1 Hz, 1H) 3.52 (br s, 3H) 3.57 (d,
J=8.3 Hz, 3H) 3.86 (br s, 4H) 4.43 (t, J=12.1 Hz, 1H) 4.70 (d,
J=10.8 Hz, 1H) 6.87 (d, J=7.1 Hz, 1H) 6.99 (s, 3H) 7.12-7.21 (m,
2H) 7.27 (br s, 1H). Mass Spectrum (ESI) m/z=728.2 (M+1).
Example 410
2-((3S,5R,6S)-5-(3-Chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-(N-methylcycl-
opropanesulfonamido)butan-2-yl)-2-oxo-3-(2-(pyrrolidin-1-yl)ethyl)piperidi-
n-3-yl)acetic acid, HCl salt
[3594] .sup.1H NMR (500 MHz, CD.sub.3OD) .delta. ppm 0.52 (t, J=7.6
Hz, 3H) 0.98-1.21 (m, 4H) 1.69 (ddd, J=14.2, 7.6, 4.9 Hz, 1H)
1.77-1.92 (m, 1H) 1.92-2.10 (m, 3H) 2.10-2.24 (m, 3H) 2.27-2.42 (m,
2H) 2.54-2.62 (m, 1H) 2.76 (dd, J=14.2, 2 Hz, 1H) 2.79-2.87 (m, 1H)
2.88 (s, 3H) 2.91-3.03 (m, 1H) 3.12 (dtd, J=11.3, 8.0, 3.2 Hz, 2H)
3.33-3.46 (m, 2H) 3.63 (ddd, J=12.9, 8.9, 7.1 Hz, 1H) 3.66-3.77 (m,
2H) 4.39 (t, J=10.9 Hz, 1H) 4.81 (d, J=11 Hz, 1H) 6.94-7.02 (m, 1H)
7.08 (s, 1H) 7.12-7.24 (m, 3H) 7.32 (d, J=7.8 Hz, 2H). Mass
Spectrum (ESI) m/z=728.2 (M+1).
Example 411
2-((3S,5R,6S)-5-(3-Chlorophenyl)-6-(4-chlorophenyl)-3-(2-(dimethylamino)et-
hyl)-1-((S)-1-(N-methylcyclopropanesulfonamido)butan-2-yl)-2-oxopiperidin--
3-yl)acetic acid, HCl salt
[3595] .sup.1H NMR (500 MHz, CD.sub.3OD) .delta. ppm 0.52 (t, J=7.6
Hz, 3H) 0.98-1.21 (m, 4H) 1.69 (ddd, J=14.3, 7.7, 4.2 Hz, 1H)
1.76-1.93 (m, 1H) 1.98 (dd, J=13.7, 3.2 Hz, 1H) 2.12 (ddd, J=14.5,
7.6, 5 Hz, 1H) 2.29-2.44 (m, 2H) 2.55-2.66 (m, 1H) 2.76 (dd,
J=14.2, 2 Hz, 1H) 2.80-2.88 (m, 1H) 2.88-3.06 (m, 11H) 3.24-3.37
(m, 2H) 3.42 (ddd, J=13.6, 10.8, 3.1 Hz, 1H) 3.61 (dt, J=13.3, 7.8
Hz, 1H) 4.42 (t, J=11.3 Hz, 1H) 4.81 (d, J=11 Hz, 1H) 6.93-7.04 (m,
1H) 7.09 (s, 1H) 7.12-7.26 (m, 3H) 7.32 (d, J=7.6 Hz, 2H). Mass
Spectrum (ESI) m/z=638.2 (M+1).
Example 412
2-((3S,5R,6S)-5-(3-Chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-(N-methylcycl-
opropanesulfonamido)butan-2-yl)-3-(2-morpholinoethyl)-2-oxopiperidin-3-yl)-
acetamide, HCl salt
##STR01034##
[3597] HATU (119 mg, 0.313 mmol) was added to a solution of 83 mg
(0.522 mmol)of the TFA salt of
2-((3S,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-(N-methylcyc-
lopropanesulfonamido)butan-2-yl)-3-(2-morpholinoethyl)-2-oxopiperidin-3-yl-
)acetic acid (Example 408, step I) and TEA (72.8 .mu.L, 0.522 mmol)
in DMF (2.09 mL). The mixture was stirred for 3 min at ambient
temperature, then a solution of NH.sub.3 (7M in MeOH, 0.45 mL, 3.13
mmol) was added. The starting material was consumed within minutes.
The mixture was concentrated under reduced pressure and purified by
reversed phase prep. HPLC (Sunfire Prep C.sub.18 OBD 10 .mu.m
column (Waters, Milford, Mass.), gradient elution of 40% MeCN in
water to 75% MeCN in water over a 30 min period, where both
solvents contain 0.1% TFA). A few drops of HCl were added prior to
lyophilization, so that the title compound was generated as the HCl
salt.
[3598] .sup.1H NMR (500 MHz, CHLOROFORM-d) .delta. ppm 0.55 (t,
J=7.6 Hz, 3H) 0.98-1.09 (m, 2H) 1.09-1.24 (m, 2H) 1.61-1.78 (m, 1H)
1.83-1.99 (m, 1H) 2.08-2.17 (m, 1H) 2.33 (t, J=13.7 Hz, 1H) 2.46
(ddd, J=15, 8.1, 7.2 Hz, 1H) 2.56-2.64 (m, 1H) 2.73-2.83 (m, 2H)
2.83-2.93 (m, 4H) 2.99 (d, J=14.4 Hz, 1H) 3.11 (td, J=12.1, 3.4 Hz,
1H) 3.16-3.27 (m, 1H) 3.36-3.51 (m, 2H) 3.51-3.67 (m, 2H) 3.67-3.73
(m, 1H) 3.74-3.88 (m, 2H) 4.13 (t, J=9.8 Hz, 2H) 4.39 (t, J=12.4
Hz, 1H) 4.81 (d, J=111 Hz, 1H) 6.89-7.05 (m, 1H) 7.08 (s, 1H)
7.11-7.27 (m, 3H) 7.34 (d, J=7.1 Hz, 2H). Mass Spectrum (ESI)
m/z=679.2 (M+1).
Example 413
2-((3S,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-(N-methylcycl-
opropanesulfonamido)butan-2-yl)-3-(2-morpholinoethyl)-2-oxopiperidin-3-yl)-
acetamide, HCl salt
##STR01035##
[3600]
2-((3S,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-(2-(1,1-dioxi-
dothiomorpholino)ethyl)-1-((S)-1-(N-methylcyclopropanesulfonamido)butan-2--
yl)-2-oxopiperidin-3-yl)acetic acid (Example 409) was treated
according to a procedure similar to the one described in Example
412 to afford the title compound.
[3601] .sup.1H NMR (500 MHz, CD.sub.3OD) .delta. ppm 0.53 (t, J=7.6
Hz, 3H) 0.98-1.07 (m, 2H) 1.07-1.16 (m, 1H) 1.20 (td, J=8.6, 4.4
Hz, 1H) 1.70 (ddd, J=14.2, 7.8, 3.9 Hz, 1H) 1.91 (dt, J=15, 7.6 Hz,
1H) 2.01 (dd, J=13.5, 2.9 Hz, 1H) 2.12 (dt, J=14.8, 5.3 Hz, 1H)
2.32 (t, J=13.7 Hz, 1H) 2.39-2.51 (m, 1H) 2.59 (dt, J=12.6, 6.4 Hz,
1H) 2.75-2.87 (m, 3H) 2.89 (s, 3H) 2.98 (d, J=14.7 Hz, 1H)
3.37-3.49 (m, 1H) 3.50-3.65 (m, 5H) 3.65-3.75 (m, 1H) 3.95 (br s,
4H) 4.38 (t, J=12 Hz, 1H) 4.79 (d, J=10.8 Hz, 1H) 7.01 (dd, J=6.5,
2.1 Hz, 1H) 7.07 (s, 1H) 7.10-7.26 (m, 3H) 7.32 (d, J=7.1 Hz, 2H).
Mass Spectrum (ESI) m/z=727.2 (M+1).
Example 414
(1R,3S,6S,7R)-7-(3-Chlorophenyl)-6-(4-chlorophenyl)-5-((S)-1-(N-methylcycl-
opropanesulfonamido)butan-2-yl)-4-oxo-5-azaspiro[2.5]octane-1-carboxylic
acid and
(3S,6S,7R)-7-(3-Chlorophenyl)-6-(4-chlorophenyl)-5-((S)-1-(N-met-
hylcyclopropanesulfonamido)butan-2-yl)-4-oxo-5-azaspiro[2.5]octane-1-carbo-
xylic acid
##STR01036##
[3602] Step A.
(3R,5R,6S)-3-Allyl-1-((S)-1-(tert-butyldiphenylsilyloxy)butan-2-yl)-5-(3--
chlorophenyl)-6-(4-chlorophenyl)-3-((2-(trimethylsilyl)ethoxy)methyl)piper-
idin-2-one
##STR01037##
[3604] Lithium bis(trimethylsilyl)amide, (1M solution in toluene,
4.76 mL, 4.76 mmol) was added to a solution of
(5R,6S)-1-((S)-1-(tert-butyldiphenylsilyloxy)butan-2-yl)-5-(3-chloropheny-
l)-6-(4-chlorophenyl)piperidin-2-one (Example 185, Step C, 2.0 g,
3.17 mmol) and 3-bromopropene (0.274 mL, 3.17 mmol) in THF at
-78.degree. C. The reaction was warmed to 0.degree. C. and stirred
for 2 hours. After recooling to -78.degree. C., a solution of LDA
(7.93 mmol in THF) followed by
2-(chloromethoxy)ethyltrimethylsilane (0.842 mL, 4.76 mmol) was
added. The reaction was warmed to 50.degree. C. and stirred for 1.5
hours. The reaction mixture was diluted with EtOAc and washed with
HCl (1N). The organic extract was washed with satd NaCl and dried
over Na.sub.2SO.sub.4. The solution was filtered and concentrated
in vacuo. The crude material was purified by chromatography on
silica gel, eluting with a gradient of 0% to 20% EtOAc in hexane,
to provide
(3S,5R,6S)-3-allyl-1-((S)-1-(tert-butyldiphenylsilyloxy)butan-2-yl)-5-(3--
chlorophenyl)-6-(4-chlorophenyl)-3-((2-(trimethylsilyl)ethoxy)methyl)piper-
idin-2-one as the first eluting diastereomer and the title compound
as the second diastereomer as an oil.
[3605] .sup.1H NMR (400 MHz, CHLOROFORM-d) .delta. ppm -0.07-0.05
(m, 9H) 0.37 (t, J=7.6 Hz, 3H) 0.91-1.05 (m, 3H) 1.28-1.46 (m, 2H)
1.79 (dd, J=13.6, 2.8 Hz, 1H) 1.86 (ddd, J=14.1, 9.3, 7.2 Hz, 1H)
2.35 (dd, J=13.8, 7.9 Hz, 1H) 2.49-2.65 (m, 2H) 2.68-2.83 (m, 1H)
3.02-3.17 (m, 2H) 3.39-3.53 (m, 2H) 3.59 (td, J=10, 7.0 Hz, 2H)
3.84 (d, J=7.8 Hz, 1H) 4.08 (t, J=10 Hz, 1H) 4.42 (d, J=10.6 Hz,
1H) 5.03-5.19 (m, 2H) 5.76-5.95 (m, 1H) 6.66 (d, J=7.6 Hz, 1H) 6.92
(t, J=1.8 Hz, 2H) 6.97-7.10 (m, 3H) 7.15 (d, J=7.4 Hz, 2H).
Step B.
(3S,5R,6S)-3-Allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1--
hydroxybutan-2-yl)-3-((2-(trimethylsilyl)ethoxy)methyl)piperidin-2-one
##STR01038##
[3607] A 1M solution of TBAF in THF (2.15 mL, 2.15 mmol) was added
to a solution of
(3S,5R,6S)-3-allyl-1-((S)-1-(tert-butyldiphenylsilyloxy)butan-2-yl)-5-(3--
chlorophenyl)-6-(4-chlorophenyl)-3-((2-(trimethylsilyl)ethoxy)methyl)piper-
idin-2-one (Example 414, Step A; 860 mg, 1.074 mmol) in THF. The
reaction was heated to reflux for 3 hours. After cooling, it was
diluted with EtOAc and washed with HCl (1N in water). The organic
extract was washed with satd NaCl and dried over Na.sub.2SO.sub.4.
The solution was filtered and concentrated to give the crude
material as a glass which was purified by chromatography on silica
eluting with 20% EtOAc in hexane, to provide the title compound as
a solid.
Step C.
N--((S)-2-((3S,5R,6S)-3-Allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl-
)-2-oxo-3-((2-(trimethylsilyl)ethoxy)methyl)piperidin-1-yl)butyl)cycloprop-
anesulfonamide
##STR01039##
[3609] The title compound was prepared from
(3S,5R,6S)-3-allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-hydroxy-
butan-2-yl)-3-((2-(trimethylsilyl)ethoxy)methyl)piperidin-2-one
(Example 414, Step B) and N-methylcyclopropanesulfonamide by a
procedure similar to the one described in Example 201, Step A. The
product was purified by chromatography through a RediSep.RTM.
pre-packed silica gel column (Teledyne Isco, Lincoln, Nebr.) (12
g), eluting with a gradient of 0% to 80% EtOAc in hexane, to
provide the title compound as an oil.
[3610] Mass Spectrum (ESI) m/z=665.2 (M+1).
Step D.
N--((S)-2-((3S,5R,6S)-3-Allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl-
)-2-oxo-3-((2-(trimethylsilyl)ethoxy)methyl)piperidin-1-yl)butyl)-N-methyl-
cyclopropanesulfonamide
##STR01040##
[3612] A solution of
N--((S)-2-((3S,5R,6S)-3-allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-2-oxo-
-3-((2-(trimethylsilyl)ethoxy)methyl)piperidin-1-yl)butyl)cyclopropanesulf-
onamide (Example 414, Step C, 1.5 g, 2.253 mmol) in THF was treated
with sodium hydride (60% dispersion in mineral oil, 6.76 mmol) and
iodomethane (0.280 ml, 4.51 mmol) at room temperature for 3 hours.
The reaction mixture was quenched with HCl (1N) and diluted with
DCM. The organic extract was washed with satd NaCl and dried over
Na.sub.2SO.sub.4. The solution was filtered and concentrated in
vacuo to give the crude material as an oil. The product was
purified by chromatography through a RediSep.RTM. pre-packed silica
gel column (Teledyne Isco, Lincoln, Nebr.) (4 g), eluting with a
gradient of 0% to 80% EtOAc in hexane, to provide the title
compound as an oil.
[3613] .sup.1H NMR (400 MHz, CHLOROFORM-d) .delta. ppm -0.06-0.03
(m, 9H) 0.54 (t, J=6.9 Hz, 3H) 0.80-1.03 (m, 5H) 1.13 (d, J=8.8 Hz,
1H) 1.14-1.23 (m, 2H) 1.56-1.65 (m, 2H) 1.75-1.93 (m, 2H) 2.28 (t,
J=4.5 Hz, 1H) 2.51 (t, J=13.8 Hz, 1H) 2.60 (d, J=7.4 Hz, 2H) 3.01
(s, 3H) 3.20 (ddd, J=13.9, 10.8, 3.1 Hz, 1H) 3.31-3.40 (m, 1H)
3.40-3.49 (m, 1H) 3.49-3.60 (m, 1H) 3.79 (d, J=8.6 Hz, 1H) 4.71 (d,
J=10.8 Hz, 1H) 5.11-5.24 (m, 2H) 5.83-6.00 (m, 1H) 6.84-6.91 (m,
1H) 6.94 (s, 1H) 7.01 (d, J=7.8 Hz, 2H) 7.07-7.16 (m, 2H) 7.21 (d,
J=8.2 Hz, 2H).
Step E.
((3S,5R,6S)-3-Allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-
-(N-methylcyclopropanesulfonamido)butan-2-yl)-2-oxopiperidin-3-yl)methyl
methanesulfonate
##STR01041##
[3615] A solution of
N--((S)-2-((3S,5R,6S)-3-allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-2-oxo-
-3-((2-(trimethylsilyl)ethoxy)methyl)piperidin-1-yl)butyl)-N-methylcyclopr-
opanesulfonamide (Example 414, Step D, 1.85 g, 2.72 mmol) in DCM
was treated with boron trifluoride (diethyl etherate, purified,
redistilled, 0.672 ml, 5.44 mmol) for 2 hours. The reaction mixture
was diluted with DCM and washed with satd NaCl. The organic extract
was dried over Na.sub.2SO.sub.4, filtered and concentrated in vacuo
to give the crude material as an oil. The product was purified by
chromatography on a RediSep.RTM. pre-packed silica gel column
(Teledyne Isco, Lincoln, Nebr.) (12 g), eluting with a gradient of
0% to 80% EtOAc in hexane, to provide the intermediate
N--((S)-2-((3S,5R,6S)-3-allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-(hy-
droxymethyl)-2-oxopiperidin-1-yl)butyl)-N-methylcyclopropanesulfonamide
(1.55 g, 2.67 mmol, 98% yield) as an oil which was used directly in
the next reaction.
[3616] Methanesulfonyl chloride (0.200 ml, 2.59 mmol) was added to
a solution of
N--((S)-2-((3S,5R,6S)-3-allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-(hy-
droxymethyl)-2-oxopiperidin-1-yl)butyl)-N-methylcyclopropanesulfonamide
(1.0 g, 1.725 mmol) and triethylamine (0.480 ml, 3.45 mmol) in DCM.
The reaction was stirred for 2 hours. The reaction mixture was
diluted with DCM and washed with HCl (1N) and satd NaCl and dried
over Na.sub.2SO.sub.4. The solution was filtered and concentrated
in vacuo to give the crude material as an oil. The product was
purified by chromatography through a RediSep.RTM. pre-packed silica
gel column (Teledyne Isco, Lincoln, Nebr.) (12 g), eluting with a
gradient of 0% to 80% EtOAc in hexane, to provide the title
compound as an oil. Mass Spectrum (ESI) m/z=657.2 (M+1).
Step F.
((3R,5R,6S)-5-(3-Chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-(N-meth-
ylcyclopropanesulfonamido)butan-2-yl)-2-oxo-3-(2-oxoethyl)piperidin-3-yl)m-
ethyl methanesulfonate
##STR01042##
[3618] Ozone was bubbled through a solution of
((3S,5R,6S)-3-allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-(N-met-
hylcyclopropanesulfonamido)butan-2-yl)-2-oxopiperidin-3-yl)methyl
methanesulfonate (Example 414, Step E, 1.12 g, 1.703 mmol) in 10%
MeOH-DCM at -78.degree. C. until a blue color developed. The
reaction was purged with nitrogen gas followed by addition of
dimethyl sulfide (1.251 ml, 17.03 mmol). The reaction was warmed to
room temperature. The crude material was purified by chromatography
on a RediSep.RTM. pre-packed silica gel column (Teledyne Isco,
Lincoln, Nebr.) (12 g), eluting with a gradient of 0% to 80% EtOAc
in hexane, to provide the title compound as an oil.
[3619] .sup.1H NMR (400 MHz, CHLOROFORM-d) .delta. ppm 0.35-0.59
(m, 3H) 0.95 (dt, J=5.0, 2.5 Hz, 2H) 1.05-1.17 (m, 2H) 1.43-1.69
(m, 1H) 1.69-1.90 (m, 2H) 2.04-2.18 (m, 1H) 2.17-2.32 (m, 2H)
2.32-2.53 (m, 1H) 2.58-2.94 (m, 5H) 2.94-3.11 (m, 4H) 3.49 (s, 1H)
3.53-3.72 (m, 2H) 4.34-4.82 (m, 3H) 5.02-5.52 (m, 1H) 7.01-7.15 (m,
2H) 7.15-7.23 (m, 2H), 9.89 (s, 1H).
Step G: Methyl
2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-(N-methylcyc-
lopropanesulfonamido)butan-2-yl)-3-(((methylsulfonyl)oxy)methyl)-2-oxopipe-
ridin-3-yl)acetate
##STR01043##
[3621] A solution of
((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-(N-methylcyclo-
propanesulfonamido)butan-2-yl)-2-oxo-3-(2-oxoethyl)piperidin-3-yl)methyl
methanesulfonate (Example 414, Step F, 1.0 g, 1.516 mmol) in MeOH
was treated with Oxone (0.932 g, 1.516 mmol) over a weekend. The
reaction mixture was diluted with DCM and water. The organic
extract was washed with satd NaCl and dried over Na.sub.2SO.sub.4.
The solution was filtered and concentrated in vacuo to give the
crude material as a white solid. The product was purified by
chromatography through a RediSep.RTM. pre-packed silica gel column
(Teledyne Isco, Lincoln, Nebr.) (12 g), eluting with a gradient of
0% to 80% EtOAc in hexane, to provide the title compound as an
oil.
[3622] .sup.1H NMR (400 MHz, CHLOROFORM-d) .delta. ppm 0.46-0.63
(m, 5H) 1.01 (dd, J=7.7, 2.3 Hz, 4H) 1.15-1.26 (m, 4H) 1.79-1.98
(m, 2H) 2.05 (dd, J=13.9, 3.1 Hz, 1H) 2.19 (dd, J=13.5, 5.1 Hz, 1H)
2.28-2.40 (m, 2H) 2.47-2.61 (m, 1H) 2.76-2.91 (m, 5H) 2.91-3.02 (m,
6H) 3.03-3.12 (m, 5H) 3.12-3.26 (m, 2H) 3.42 (d, J=0.8 Hz, 2H) 3.75
(s, 3H) 4.05-4.28 (m, 1H) 4.50-4.62 (m, 2H) 4.64-4.75 (m, 2H) 4.81
(d, J=10.6 Hz, 1H) 6.87-7.01 (m, 3H) 7.01-7.12 (m, 2H) 7.13-7.21
(m, 3H) 7.27 (d, J=7.6 Hz, 2H).
Step H. (1S,3S,6S,7R)-Methyl
7-(3-chlorophenyl)-6-(4-chlorophenyl)-5-((S)-1-(N-methylcyclopropanesulfo-
namido)butan-2-yl)-4-oxo-5-azaspiro[2.5]octane-1-carboxylate and
(1R,3S,6S,7R)-methyl
7-(3-chlorophenyl)-6-(4-chlorophenyl)-5-((S)-1-(N-methylcyclopropanesulfo-
namido)butan-2-yl)-4-oxo-5-azaspiro[2.5]octane-1-carboxylate
##STR01044##
[3624] A solution of lithium bis(trimethylsilyl)amide, (1.0M in
toluene, 290 .mu.l, 0.290 mmol) was added to a solution of methyl
2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-(N-methylcyc-
lopropanesulfonamido)butan-2-yl)-3-(((methylsulfonyl)oxy)methyl)-2-oxopipe-
ridin-3-yl)acetate (Example 414, Step G, 200 mg, 0.290 mmol) in THF
at 0.degree. C. over 10 mins. The reaction mixture was quenched
with 1N HCl and extracted with DCM. The organic extract was washed
with sat. aq. Na.sub.2CO.sub.3 solution and dried over
Na.sub.2SO.sub.4. The solution was filtered and concentrated in
vacuo to give the crude material as a white glass. The product was
purified by chromatography on a Redi-Sep pre-packed silica gel
column (4 g), eluting with a gradient of 0% to 80% EtOAc in hexane,
to provide the title compounds as a mixture of diastereomers.
[3625] .sup.1H NMR (400 MHz, CHLOROFORM-d) .delta. ppm 0.40 (t,
J=7.5 Hz, 3H) 0.69-0.86 (m, 3H) 0.86-0.95 (m, 2H) 1.01-1.14 (m, 3H)
1.14-1.23 (m, 2H) 1.25 (dd, J=6.5, 4.3 Hz, 2H) 1.43 (br. s., 3H)
1.77 (dt, J=14.7, 7.4 Hz, 1H) 1.89-2.02 (m, 2H) 2.14-2.26 (m, 2H)
2.51 (t, J=11.7 Hz, 1H) 2.70-2.82 (m, 2H) 2.84 (s, 3H) 3.57-3.73
(m, 3H) 4.67 (d, J=9.6 Hz, 1H) 6.74-6.88 (m, 2H) 6.98 (d, J=8.0 Hz,
2H) 7.06 (d, J=5.1 Hz, 2H) 7.17 (s, 2H). Mass Spectrum (ESI)
m/z=593.2 (M+H.sup.+).
Step I:
(1R,3S,6S,7R)-7-(3-Chlorophenyl)-6-(4-chlorophenyl)-5-((S)-1-(N-me-
thylcyclopropanesulfonamido)butan-2-yl)-4-oxo-5-azaspiro[2.5]octane-1-carb-
oxylic acid and
(1S,3S,6S,7R)-7-(3-Chlorophenyl)-6-(4-chlorophenyl)-5-((S)-1-(N-methylcyc-
lopropanesulfonamido)butan-2-yl)-4-oxo-5-azaspiro[2.5]octane-1-carboxylic
acid
[3626] The mixture of diastereomeric esters from Example 414, Step
H was treated with NaOH (3N in MeOH) overnight at room temperature.
The reaction mixture was acidified with 1N HCl (1N) and extracted
into DCM. The organic extract was washed with satd NaCl and dried
over Na2SO4. The product was purified by chromatography on silica,
eluting with a gradient of 40% EtOAc in hexane, to provide the
title compounds as a mixture of diastereomers as a white glass.
[3627] .sup.1H NMR (400 MHz, CHLOROFORM-d) .delta. ppm 0.39 (t,
J=7.5 Hz, 3H) 0.81 (s, 1H) 0.89-1.02 (m, 2H) 1.16-1.21 (m, 2H)
1.21-1.30 (m, 1H) 1.37 (dd, J=9.2, 5.7 Hz, 1H) 1.47 (ddd, J=14.5,
7.6, 4.1 Hz, 1H) 1.84 (ddd, J=14.5, 8.7, 7.3 Hz, 1H) 1.95-2.05 (m,
1H) 2.18 (dd, J=7.0, 5.7 Hz, 1H) 2.22-2.32 (m, 1H) 2.66-2.85 (m,
3H) 2.87 (s, 3H) 3.11 (ddd, J=13.1, 10.4, 2.9 Hz, 1H) 3.42 (s, 1H)
4.05 (d, J=7.0 Hz, 1H) 4.71 (d, J=10.4 Hz, 1H) 6.74 (dt, J=6.9, 1.6
Hz, 1H) 6.82-6.95 (m, 3H) 6.98-7.11 (m, 2H) 7.18 (d, J=8.4 Hz, 2H);
Mass Spectrum (ESI) m/z=579.1 (M+H.sup.+).
Example 415
2-((3R,5R,6S)-5-(3-Chlorophenyl)-6-(4-chlorophenyl)-1-((2S,3S)-1,2-dihydro-
xypentan-3-yl)-3-methyl-2-oxopiperidin-3-yl)acetic acid or
2-((3R,5R,6S)-5-(3-Chlorophenyl)-6-(4-chlorophenyl)-1-((2R,3S)-1,2-dihydr-
oxypentan-3-yl)-3-methyl-2-oxopiperidin-3-yl)acetic acid
##STR01045##
[3628] Step A. Methyl
2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-2-oxo-1-((S)-
-1-oxobutan-2-yl)piperidin-3-yl)acetate
##STR01046##
[3630] To a stirred solution of methyl
2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-hydroxybutan-
-2-yl)-3-methyl-2-oxopiperidin-3-yl)acetate (Example 186, Step A,
360 mg, 0.752 mmol) in DCM (3.76 mL) was added Dess-Martin
periodinane (383 mg, 0.903 mmol) and the reaction was stirred at rt
for 20 minutes. After this time the reaction was treated with
Na.sub.2S.sub.2O.sub.3 (30 mL, saturated aqueous solution) and DCM
(40 mL) and stirred at rt for 10 minutes. The organic layer was
separated and washed with Na.sub.2S.sub.2O.sub.3 (20 mL, saturated
aqueous solution) and NaHCO.sub.3 (20 mL, saturated aqueous
solution), dried over MgSO.sub.4, filtered and concentrated to give
the title compound. MS (ESI) m/z=476.0 (M+1).
Step B. Methyl
2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-2-oxo-1-((S)-
-pent-1-en-3-yl)piperidin-3-yl)acetate
##STR01047##
[3632] Tebbe reagent
(Bis(cyclopentadienyl)-t-chloro(dimethylaluminum)-t-methylenetitanium,
0.5 M solution in toluene, 1.7 mL, 0.85 mmol) was added dropwise
over 5 minutes to a stirred solution of methyl
2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-2-oxo-1-((S)-
-1-oxobutan-2-yl)piperidin-3-yl)acetate (Example 415, Step A, 360
mg, 0.756 mmol) in toluene (4.7 mL) at 0.degree. C. The reaction
was stirred at 0.degree. C. for 20 minutes and at rt for 30
minutes. The reaction was recooled to 0.degree. C. and an
additional portion of Tebbe reagent (0.5 M solution in toluene, 1
mL, 0.5 mmol) was added. The reaction was allowed to warm to rt for
20 minutes. The reaction was recooled to 0.degree. C. and treated
with sat. aq. NaHCO.sub.3 solution (40 mL) and EtOAc (100 mL). The
separated aqueous layer was extracted with EtOAc (2.times.60 mL)
and the combined organic extracts were washed with brine (80 ml),
dried over MgSO.sub.4, filtered and the filtrate was concentrated
under reduced pressure. Column chromatography on silca gel (24 g,
SiO.sub.2, eluent: hexanes:EtOAc, 1:0 to 3:1, gradient elution)
gave the title compound.
[3633] MS (ESI) m/z=474.0 (M+1).
Step C. Methyl
2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((3S)-1,2-dihydroxy-
pentan-3-yl)-3-methyl-2-oxopiperidin-3-yl)acetate
##STR01048##
[3635] To a stirred solution of methyl
2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-2-oxo-1-((S)-
-pent-1-en-3-yl)piperidin-3-yl)acetate (Example 415, Step B, 85 mg,
0.18 mmol) in THF (1 mL), t-butanol (1 mL) and water (1.5 mL) was
added 4-methylmorpholine 4-oxide (63.0 mg, 0.54 mmol) and OsO.sub.4
(1.1 mg, 4.5 .mu.mol). The reaction was stirred at rt overnight.
The reaction was diluted with EtOAc (40 mL) and
Na.sub.2S.sub.2O.sub.3 (20 mL, saturated aqueous solution). The
separated aqueous layer was extracted with EtOAc (20 mL) and the
combined organic extracts were washed with brine (20 mL), dried
over MgSO.sub.4, filtered and evaporated in vacuo to give the title
compound as a 5:1 mixture of diastereomers.
[3636] Mass Spectrum (ESI) m/e=508.0 (M+1).
Step D.
2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((2S,3S)-1,2-
-dihydroxypentan-3-yl)-3-methyl-2-oxopiperidin-3-yl)acetic acid or
2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((2R,3S)-1,2-dihydr-
oxypentan-3-yl)-3-methyl-2-oxopiperidin-3-yl)acetic acid
[3637] A solution of LiOH in water (1M, 502 .mu.l, 0.502 mmol) was
added to a stirred solution of methyl
2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((3S)-1,2-dihydroxy-
pentan-3-yl)-3-methyl-2-oxopiperidin-3-yl)acetate (Example 415,
Step C; 85 mg, 0.167 mmol) in EtOH (1.67 mL). The reaction was
stirred at rt for 4 hours. After this time the reaction was
quenched with sat. aq. NH.sub.4Cl solution (20 mL) and treated with
EtOAc (40 mL). The separated aqueous layer was extracted with EtOAc
(2.times.20 mL) and the combined organic extracts were dried over
MgSO.sub.4, filtered and the filtrate was concentrated under
reduced pressure. The product was purified by reverse phase
preparatory HPLC (Gemini.TM. Prep C.sub.18 10 .mu.m column;
Phenomenex, Torrance, Calif., using 25 to 75% acetonitrile in water
with 0.1% TFA as eluent) to give one of the title compounds as the
minor diastereomer, as the first eluting component.
[3638] .sup.1H NMR (400 MHz, methanol-d.sub.4) .delta. ppm 7.26
(4H, br s), 7.11-7.17 (2H, m), 7.07 (1H, s), 6.93-6.98 (1H, m),
4.75 (1H, d, J=10.8 Hz), 3.78 (1H, br s), 3.56-3.66 (2H, m), 3.43
(1H, td, J=11.3, 4.8 Hz), 2.92-3.01 (2H, m), 2.60 (1H, d, J=13.7
Hz), 2.14-2.22 (2H, m), 1.94-2.05 (1H, m), 1.72 (1H, ddd, J=14.6,
7.6, 5.2 Hz), 1.38 (3H, s), 0.51 (3H, t, J=7.5 Hz); Mass Spectrum
(ESI) m/z=494.0 (M+1).
Example 416
2-((3R,5R,6S)-5-(3-Chlorophenyl)-6-(4-chlorophenyl)-1-((2R,3S)-1,2-dihydro-
xypentan-3-yl)-3-methyl-2-oxopiperidin-3-yl)acetic acid or
2-((3R,5R,6S)-5-(3-Chlorophenyl)-6-(4-chlorophenyl)-1-((2S,3S)-1,2-dihydr-
oxypentan-3-yl)-3-methyl-2-oxopiperidin-3-yl)acetic acid
##STR01049##
[3640] In the purification described in Example 415, Step D, the
other of the title compounds was isolated as the major
diastereomer, as the second eluting component.
[3641] .sup.1H NMR (500 MHz, methanol-d.sub.4) .delta. ppm
7.18-7.25 (3H, br s), 7.05-7.17 (4H, m), 6.88-6.98 (1H, m), 4.83
(1H, d, J=10.8 Hz), 3.96 (1H, br s), 3.59 (1H, dd, J=11.2, 5.4 Hz),
3.51 (1H, dd, J=11.2, 5.1 Hz), 3.39-3.46 (1H, m), 2.81-2.99 (2H,
m), 2.61 (1H, d, J=13.7 Hz), 2.12-2.27 (2H, m), 1.84-1.96 (1H, m),
1.60 (1H, ddd, J=14.2, 7.8, 4.6 Hz), 1.41 (3H, m), 0.43 (3H, t,
J=7.3 Hz); Mass Spectrum (ESI) m/z=494.0 (M+1).
Example 417
2-((3R,5R,6S)-5-(3-Chlorophenyl)-6-(4-chlorophenyl)-1-((1S,2S)-1-cycloprop-
yl-1-hydroxybutan-2-yl)-3-methyl-2-oxopiperidin-3-yl)acetic acid or
2-((3R,5R,6S)-5-(3-Chlorophenyl)-6-(4-chlorophenyl)-1-((1R,2S)-1-cyclopro-
pyl-1-hydroxybutan-2-yl)-3-methyl-2-oxopiperidin-3-yl)acetic
acid
##STR01050##
[3642] Step A.
(3S,5R,6S)-3-Allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((2S)-1-cyclop-
ropyl-1-hydroxybutan-2-yl)-3-methylpiperidin-2-one
##STR01051##
[3644] Cyclopropylmagnesium bromide (0.5 M solution in THF, 2.0 mL,
1.013 mmol) was added dropwise via syringe over a period of 1 min
to a stirred solution of
(S)-2-((3S,5R,6S)-3-allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl--
2-oxopiperidin-1-yl)butanal (Example 91, Step C, 150 mg, 0.338
mmol) in THF (1.7 mL) at rt. The reaction mixture was stirred at rt
for 20 minutes and then quenched with NH.sub.4Cl (30 mL, saturated
aqueous solution) and diluted with EtOAc (50 mL). The organic layer
was dried over MgSO.sub.4, filtered and evaporated in vacuo.
Purification by column chromatography (24 g SiO.sub.2,
Hexanes:EtOAc, 1:0 to 4:1) gave the title compound as a mixture of
diastereomers.
[3645] MS (ESI) m/z=486.2 (M+1).
Step B.
2-((3R,5R,6S)-5-(3-Chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-cyclo-
propyl-1-oxobutan-2-yl)-3-methyl-2-oxopiperidin-3-yl)acetic
acid
##STR01052##
[3647] To a stirred solution of
(3S,5R,6S)-3-allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((2S)-1-cyclop-
ropyl-1-hydroxybutan-2-yl)-3-methylpiperidin-2-one (Example 417,
Step A; 60 mg, 0.123 mmol) in EtOAc (1 mL), acetonitrile (1 mL) and
water (1.5 mL) was added ruthenium chloride hydrate (2.8 mg, 0.012
mmol) and sodium meta-periodate (6.83 .mu.l, 0.123 mmol)
(portionwise over 5 minutes). The reaction was stirred at rt for 20
minutes and then partitioned between EtOAc (60 mL) and water (20
mL). The separated aqueous layer was extracted with EtOAc
(2.times.20 mL) and the combined organic extracts were dried over
MgSO.sub.4, filtered and evaporated in vacuo. Purification by
column chromatography (12 g, SiO.sub.2, hexanes/IPA, 1:0 to 9:1)
gave the title compound.
[3648] MS (ESI) m/z=502.1 (M+1).
Step C.
2-((3R,5R,6S)-5-(3-Chlorophenyl)-6-(4-chlorophenyl)-1-((1S,2S)-1-c-
yclopropyl-1-hydroxybutan-2-yl)-3-methyl-2-oxopiperidin-3-yl)acetic
acid or
2-((3R,5R,6S)-5-(3-Chlorophenyl)-6-(4-chlorophenyl)-1-((1R,2S)-1-cyclo-
propyl-1-hydroxybutan-2-yl)-3-methyl-2-oxopiperidin-3-yl)acetic
acid
[3649] To a stirred solution of
2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-cyclopropyl--
1-oxobutan-2-yl)-3-methyl-2-oxopiperidin-3-yl)acetic acid (Example
417, Step B, 33 mg, 0.066 mmol) in THF (657 .mu.l) at -78.degree.
C. was added dropwise a solution of L-select ride (144 .mu.l, 0.144
mmol). The reaction mixture was stirred at -78.degree. C. for 20
minutes and then it was allowed to warm to rt for 30 minutes. After
this time the reaction was quenched with a solution of oxone (121
mg, 0.197 mmol) in water (3 mL). The reaction was diluted with
EtOAc (30 mL) and the separated aqueous layer was extracted with
EtOAc (2.times.10 mL), dried over MgSO.sub.4, filtered and
evaporated in vacuo. Column chromatography (4 g, SiO.sub.2,
hexanes:IPA, 1:0 to 4:1) gave the title compound as a single
stereoisomer.
[3650] .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. ppm 6.95-7.27 (7H,
m), 6.72 (1H, dt, J=7.6, 1.6 Hz), 4.58-4.70 (1H, m), 3.07-3.34 (1H,
m), 2.80-2.93 (2H, m), 2.09-2.25 (4H, m), 1.47 (3H, s), 0.28-1.47
(10H, m); Mass Spectrum (ESI) m/z=504.0 (M+1).
Example 418
2-((3S,5R,6S)-5-(3-Chlorophenyl)-6-(4-chlorophenyl)-1-isopropyl-6-methyl-2-
-oxopiperidin-3-yl)acetic acid
##STR01053##
[3651] Step A.
(S)-2-(3-Chlorophenyl)-1-(4-chlorophenyl)pent-4-en-1-one and
(R)-2-(3-chlorophenyl)-1-(4-chlorophenyl)pent-4-en-1-one
##STR01054##
[3653] To a solution of KOH (57.1 g, 1.02 mol) in water (113 mL)
was added N-benzyl-N,N-diethylethanaminium chloride (1.289 g, 5.66
mmol). A solution of 2-(3-chlorophenyl)-1-(4-chlorophenyl)ethanone
(Example 1, Step A) (30 g, 113 mmol) in toluene (113 mL) was added
followed by 3-bromoprop-1-ene (10.77 mL, 124 mmol). The resulting
biphase was vigorously stirred at ambient temperature for
twenty-one hours, then separated. The organic layer was washed with
aqueous citric acid solution followed by brine then dried over
anhydrous MgSO.sub.4 and concentrated to afford the title compounds
as a pale yellow oil.
[3654] .sup.1H NMR (400 MHz, CHLOROFORM-d) .delta. ppm 2.49-2.67
(m, 1H) 2.86-3.04 (m, 1H) 4.57 (t, J=7.3 Hz, 1H) 4.95-5.15 (m, 2H)
5.75 (ddt, J=17.1, 10.2, 6.9 Hz, 1H) 7.14-7.35 (m, 4H) 7.36-7.47
(m, 2H) 7.83-7.98 (m, 2H).
Step B.
(R)--N--((R)-2-(3-Chlorophenyl)-1-(4-chlorophenyl)pent-4-en-1-ylid-
ene)-2-methylpropane-2-sulfinamide
##STR01055##
[3656] 2-(3-Chlorophenyl)-1-(4-chlorophenyl)pent-4-en-1-one
(Example 418, Step A, 48 g, 157 mmol), titanium(IV) ethoxide,
technical grade (65.9 mL, 315 mmol) and
(R)-(+)-2-methyl-2-propanesulfinamide (Combi-Blocks, San Diego,
Calif., 33.1 g, 267 mmol) were dissolved in 400 mL of THF. The
mixture was heated with stirring under reflux for eighteen hours.
The reaction was cooled and poured into brine. The resulting white
solid was removed by filtration, rinsing with ethyl acetate. Ethyl
acetate was added to the biphasic filtrate and the layers
separated. The organic layer was washed with brine, then dried with
anhydrous magnesium sulfate and concentrated. The crude product was
purified by three chromatographies (330 g RediSep.RTM. pre-packed
silica gel column (Teledyne Isco, Lincoln, Nebr.), eluting with
hexane:ethyl acetate, 95:5 to 85:5) to afford the title compound
eluting second on silica gel TLC in hexane/ethyl acetate, the
diastereomer
(R)--N--((S)-2-(3-chlorophenyl)-1-(4-chlorophenyl)pent-4-en-1-ylidene)-2--
methylpropane-2-sulfinamide eluting third on silica gel TLC in
hexane/ethyl acetate, and some starting ketone eluting first on
silica gel TLC in hexane/ethyl acetate.
[3657] .sup.1H NMR (400 MHz, CHLOROFORM-d) .delta. ppm 1.28 (s, 9H)
2.58-2.75 (m, 1H) 2.85-3.02 (m, 1H) 3.80-4.12 (m, 1H) 5.01-5.16 (m,
2H) 5.76 (ddt, J=17.0, 10.2, 6.8 Hz, 1H) 6.94-7.11 (m, 2H)
7.11-7.20 (m, 1H) 7.20-7.38 (m, 5H).
Step C.
(R)--N-((2S,3R)-3-(3-Chlorophenyl)-2-(4-chlorophenyl)hex-5-en-2-yl-
)-2-methylpropane-2-sulfinamide
##STR01056##
[3659] A solution of
(R)--N--((R)-2-(3-chlorophenyl)-1-(4-chlorophenyl)pent-4-enylidene)-2-met-
hylpropane-2-sulfinamide (Example 418, Step B, 9.97 g, 24.41 mmol)
in THF (98 ml) was cooled to -78.degree. C. Methyllithium (1.6M in
ether, 16.78 ml, 26.9 mmol) was added over a period of six min. The
reaction was removed from the cold bath and diluted with 500 mL
ether and quenched with 150 mL of saturated aqueous ammonium
chloride solution. The organic layer was separated and washed with
brine, then dried with anhydrous magnesium sulfate and concentrated
to afford a colorless oil. The crude material was adsorbed onto a
plug of silica gel and purified by chromatography through
(3.times.80 g) RediSep.RTM. pre-packed silica gel column (Teledyne
Isco, Lincoln, Nebr.), eluting with 30% ethyl acetate in hexane.
Fractions containing the desired product, eluting as the bottom
spot on silica gel TLC in hexane/ethyl acetate, were combined and
concentrated under reduced pressure to provide the title compound
as a glass.
[3660] .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. ppm 1.06 (s, 9H)
1.80 (s, 3H) 2.23 (td, J=13.3, 7.5 Hz, 1H) 2.62-2.76 (m, 1H) 3.30
(d, J=3.3 Hz, 1H) 4.81 (d, J=10.4 Hz, 1H) 4.85-4.97 (m, 1H) 5.10
(s, 1H) 5.31-5.52 (m, 1H) 6.79 (d, J=7.2 Hz, 1H) 6.97 (s, 1H)
7.05-7.23 (m, 4H) 7.28 (d, J=8.8 Hz, 2H).
Step D.
(2S,3R)-3-(3-Chlorophenyl)-2-(4-chlorophenyl)hex-5-en-2-amine
##STR01057##
[3662] A solution of
(R)--N-((2S,3R)-3-(3-chlorophenyl)-2-(4-chlorophenyl)hex-5-en-2-yl)-2-met-
hylpropane-2-sulfinamide (Example 418, Step C, 5.96 g, 14.04 mmol)
in THF (56.2 ml) was treated with. hydrochloric acid in water
(36-38% wt, 6.40 ml, 211 mmol) for three hours. The reaction was
diluted with 300 mL ether and the acidic aqueous layer made
alkaline with sat. aq. NaHCO.sub.3 solution. The organic layer was
washed with sat. aq. NaHCO.sub.3 solution, dried over MgSO.sub.4
and concentrated to provide the title compound as a colorless
glass.
[3663] .sup.1H NMR (400 MHz, CHLOROFORM-d) .delta. ppm 1.29 (s, 3H)
1.46 (br s, 2H) 2.09-2.25 (m, 1H) 2.41 (ddd, J=13.6, 12.7, 6.9 Hz,
1H) 2.99 (dd, J=11.9, 3.3 Hz, 1H) 4.71-4.88 (m, 2H) 5.39 (ddt,
J=17.0, 10.2, 6.8 Hz, 1H) 6.99-7.13 (m, 1H) 7.17-7.31 (m, 3H)
7.31-7.38 (m, 2H) 7.38-7.48 (m, 2H).
Step E.
(2S,3R)-3-(3-Chlorophenyl)-2-(4-chlorophenyl)-N-isopropylhex-5-en--
2-amine
##STR01058##
[3665] A mixture of
(2S,3R)-3-(3-chlorophenyl)-2-(4-chlorophenyl)hex-5-en-2-amine
(Example 418, Step D) (270 mg, 0.843 mmol), acetic acid (0.243 mL,
4.22 mmol), acetone (3.10 mL, 42.2 mmol) and sodium
cyanoborohydride (0.442 mL, 8.43 mmol) in methanol (4 mL) was
heated to 65.degree. C. overnight. After sixteen hours, an
additional ten equivalents of sodium cyanoborohydride were added
and heating continued for another five hours then equilibrated to
room temperature and concentrated under reduced pressure. The
concentrate was partitioned between aqueous sodium hydroxide
solution and ethyl acetate. The aqueous layer was extracted again
with ethyl acetate. The combined organic layers were washed with
brine, dried over MgSO.sub.4 and concentrated to afford a yellow
oil. The crude product was adsorbed onto silica and purified by
chromatography (24 g RediSep.RTM. pre-packed silica gel column
(Teledyne Isco, Lincoln, Nebr.)) eluting with 30 to 100% ethyl
acetate gradient in hexane. Fractions containing product were
combined and concentrated to afford the title compound as a
colorless glass.
[3666] .sup.1H NMR (400 MHz, CHLOROFORM-d) .delta. ppm 0.95 (d,
J=6.1 Hz, 3H) 1.09 (d, J=6.1 Hz, 3H) 1.38 (br s, 1H) 1.51 (s, 3H)
2.32-2.50 (m, 1H) 2.59-2.81 (m, 3H) 4.78-4.86 (m, 1H) 4.86-4.98 (m,
1H) 5.46 (ddt, J=17, 10.2, 6.7 Hz, 1H) 6.78 (d, J=7.6 Hz, 1H) 6.96
(t, J=1.8 Hz, 1H) 7.03-7.11 (m, 1H) 7.11-7.21 (m, 3H) 7.21-7.29 (m,
2H).
Step F.
(4R,5S)-4-(3-Chlorophenyl)-5-(4-chlorophenyl)-5-(isopropylamino)he-
xan-1-ol
##STR01059##
[3668] To a solution of
(2S,3R)-3-(3-chlorophenyl)-2-(4-chlorophenyl)-N-isopropylhex-5-en-2-amine
(Example 418, Step E, 160 mg, 0.442 mmol) in THF (4 mL) cooled by
an ice-water bath was added borane-tetrahydrofuran complex, (1.0M
in THF, 2.21 mL, 2.21 mmol). After 90 minutes, an additional 5
equivalents of borane-THF were added and the cold bath removed.
After 30 minutes the reaction was cooled in an ice-water bath and
quenched by addition of 0.5 mL water followed by 4N aqueous sodium
hydroxide (1.1 mL, 4.42 mmol) and aqueous hydrogen peroxide
solution, (30% (w/w), 0.45 mL, 4.42 mmol). The biphasic mixture was
stirred rapidly at 0-5.degree. C. for 15 minutes then partitioned
between water and ethyl acetate. The aqueous layer was extracted
again with ethyl acetate. The combined organic layers were washed
with brine then dried with anhydrous magnesium sulfate and
concentrated to afford a colorless oil. The product was isolated by
chromatography on silica (24 g RediSep.RTM. pre-packed silica gel
column (Teledyne Isco, Lincoln, Nebr.)) eluting with 50 to 100%
ethyl acetate gradient in hexane to afford the title compound as a
colorless oil.
[3669] .sup.1H NMR (400 MHz, CHLOROFORM-d) .delta. ppm 0.91 (d,
J=6.3 Hz, 3H) 1.06 (d, J=6.3 Hz, 3H) 1.13-1.37 (m, 2H) 1.48 (s, 3H)
1.56-1.86 (m, 3H) 1.89-2.04 (m, 1H) 2.50-2.75 (m, 2H) 3.52 (t,
J=6.4 Hz, 2H) 6.76 (d, J=7.6 Hz, 1H) 6.89-6.98 (m, 1H) 7.01-7.08
(m, 1H) 7.08-7.17 (m, 3H) 7.17-7.26 (m, 2H).
Step G.
(4R,5S)-4-(3-Chlorophenyl)-5-(4-chlorophenyl)-5-(isopropylamino)he-
xanoic acid
##STR01060##
[3671] To a solution of
(4R,5S)-4-(3-chlorophenyl)-5-(4-chlorophenyl)-5-(isopropylamino)hexan-1-o-
l (Example 418, Step F, 185 mg, 0.486 mmol) in wet acetonitrile
(0.75% water v/v) (3 mL) at ambient temperature was added over
three minutes a solution of periodic acid (0.44M in acetonitrile
(0.75% water v/v), 2.76 mL, 1.216 mmol) with chromium trioxide
(2.43 mg, 0.024 mmol). The reaction was stirred for fifteen
minutes. To the reaction was added a solution of 0.6 g disodium
hydrogen phosphate in 10 mL water. The aqueous mixture was
extracted with toluene. The organic layer was washed with
water/brine then with a solution of 0.2 g sodium hydrogen sulfite
in 5 mL water. The organic layer was then dried with anhydrous
magnesium sulfate and concentrated to afford a peach-colored foamy
solid. The product was isolated by chromatography on silica (24 g
RediSep.RTM. pre-packed silica gel column (Teledyne Isco, Lincoln,
Nebr.)) eluting with 50-100% ethyl acetate gradient in hexane to
afford the title compound as a colorless foam.
[3672] .sup.1H NMR (400 MHz, CHLOROFORM-d) .delta. ppm 1.16 (d,
J=6.7 Hz, 4H) 1.32 (d, J=6.7 Hz, 4H) 1.43 (s, 3H) 1.76-1.88 (m, 1H)
2.22-2.38 (m, 1H) 2.55-2.67 (m, 2H) 2.79 (quin, J=6.65 Hz, 1H) 3.11
(dd, J=13.1, 2.4 Hz, 1H) 6.21 (d, J=7.8 Hz, 1H) 6.49 (s, 1H) 6.91
(dd, J=7.9, 7.9 Hz, 1H) 6.96-7.17 (m, 3H) 7.23 (d, J=8.2 Hz,
2H).
Step H.
(5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-isopropyl-6-methyl-
piperidin-2-one
##STR01061##
[3674] Oxalyl chloride (.about.0.38 M in benzene, 0.617 mL, 0.234
mmol) was added to a room temperature solution of
(4R,5S)-4-(3-chlorophenyl)-5-(4-chlorophenyl)-5-(isopropylamino)hexanoic
acid (Example 418, Step G, 84 mg, 0.213 mmol) in benzene (3 mL)
followed by a drop of DMF. The reaction solution was stirred at
room temperature for 25 minutes then heated to 80.degree. C. After
3.5 hours the reaction was removed from heat and saturated aqueous
sodium bicarbonate solution was added. The organic phase was
diluted with ethyl acetate. The aqueous layer was extracted again
with ethyl acetate. The combined organic layers were washed with
brine, then dried with anhydrous magnesium sulfate and concentrated
to afford a red-orange oil. The product was isolated by
chromatography on silica (12 g RediSep Rf cartridge) eluting with
20-40% ethyl acetate gradient in hexane to afford the title
compound as a pale yellow film. [.alpha.].sub.D=+89.33.degree.
(T=24.0.degree. C.; c=1, CHCl.sub.3)
[3675] .sup.1H NMR (400 MHz, CHLOROFORM-d) .delta. ppm 1.25 (d,
J=6.7 Hz, 3H) 1.41 (d, J=6.7 Hz, 3H) 1.52 (s, 3H) 1.84-1.98 (m, 1H)
2.30-2.50 (m, 1H) 2.64-2.75 (m, 2H) 2.88 (quin, J=6.7 Hz, 1H) 3.20
(dd, J=13.2, 2.5 Hz, 1H) 6.31 (d, J=7.6 Hz, 1H) 6.58 (dd, J=1.8,
1.8 Hz, 1H) 7.00 (dd, J=7.9, 7.9 Hz, 1H) 7.05-7.27 (m, 3H)
7.27-7.42 (m, 2H); Mass Spectrum (ESI) m/z=376.1 [M+H].sup.+.
Step I.
(3R,5R,6S)-3-Allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-isoprop-
yl-6-methylpiperidin-2-one and
(3S,5R,6S)-3-Allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-isopropyl-6-me-
thylpiperidin-2-one
##STR01062##
[3677] sec-Butyllithium (0.8N in cyclohexane, 0.274 mL, 0.219 mmol)
was added over a period of one minute to a degassed (Argon bubbled
through solution for 10 minutes at RT) solution of
(5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-isopropyl-6-methylpiperid-
in-2-one (Example 418, Step H, 75 mg, 0.199 mmol) in THF (6 mL)
cooled by an acetone-dry ice bath. The cold bath was removed and
the reaction equilibrated to room temperature over fifteen minutes.
The reaction was stirred at room temperature for 30 minutes. Allyl
bromide (1M in THF, 0.219 mL, 0.219 mmol) was added over one minute
at room temperature. After two hours the reaction was quenched by
addition of saturated aqueous ammonium chloride solution. The
organic layer was diluted with ethyl acetate and separated. The
aqueous layer was extracted again with ethyl acetate. The combined
organic layers were then dried with anhydrous magnesium sulfate and
concentrated to afford a faintly orange glass. The diastereomeric
products were isolated by chromatography on silica gel (12 g
RediSep.RTM. pre-packed silica gel column (Teledyne Isco, Lincoln,
Nebr.)) eluting with 20 to 80% ethyl acetate gradient in hexane to
afford 25 mg of
(3R,5R,6S)-3-allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-isopr-
opyl-6-methylpiperidin-2-one as the product eluting first on silica
gel TLC plate (R.sub.f=0.52 in 3:1 hexane:ethyl acetate eluent) and
25 mg of
(3S,5R,6S)-3-allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-isopropyl-6-me-
thylpiperidin-2-one as the product eluting second on silica gel TLC
plate (R.sub.f=0.28 in 3:1 hexane:ethyl acetate eluent).
Diastereomer 1:
(3R,5R,6S)-3-allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-isopropyl-6-me-
thylpiperidin-2-one
[3678] .sup.1H NMR (400 MHz, CHLOROFORM-d) .delta. ppm 1.17 (d,
J=6.7 Hz, 3H) 1.31 (d, J=6.7 Hz, 3H) 1.41 (s, 3H) 1.84 (ddd,
J=13.3, 5.8, 2.5 Hz, 1H) 2.03-2.21 (m, 1H) 2.41-2.54 (m, 1H)
2.54-2.69 (m, 2H) 2.78 (quin, J=6.7 Hz, 1H) 3.18 (dd, J=13.4, 2.3
Hz, 1H) 4.92-5.18 (m, 2H) 5.56-5.84 (m, 1H) 6.20 (d, J=7.8 Hz, 1H)
6.50 (s, 1H) 6.90 (dd, J=7.8, 7.8 Hz, 1H) 7.00-7.08 (m, 1H)
7.08-7.37 (m, 4H); MS (ESI) 416.2 [M+H].sup.+
[3679] Diastereomer 2:
(3S,5R,6S)-3-allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-isopropyl-6-me-
thylpiperidin-2-one
[3680] .sup.1H NMR (400 MHz, CHLOROFORM-d) .delta. ppm 1.16 (d,
J=6.7 Hz, 3H) 1.35 (d, J=6.7 Hz, 3H) 1.43 (s, 3H) 1.75-1.80 (m, 1H)
2.25-2.48 (m, 2H) 2.56-2.68 (m, 1H) 2.69-2.89 (m, 2H) 3.23 (dd,
J=13.6, 2.6 Hz, 1H) 4.91-5.06 (m, 2H) 5.76 (dddd, J=17.6, 9.5, 8.3,
5.9 Hz, 1H) 6.25 (d, J=7.8 Hz, 1H) 6.51 (dd, J=1.8, 1.8 Hz, 1H)
6.87-6.97 (m, 1H) 6.97-7.12 (m, 3H) 7.19-7.32 (m, 2H); MS (ESI)
416.2 [M+H].sup.+
Step J.
2-((3S,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-isopropyl-6--
methyl-2-oxopiperidin-3-yl)acetic acid
[3681] The title compound was prepared from
(3R,5R,6S)-3-allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-isopropyl-6-me-
thylpiperidin-2-one (Example 418, Step I, diastereomer 1) by a
procedure similar to the one described in Example 1, Step H.
[3682] .sup.1H NMR (400 MHz, CHLOROFORM-d) .delta. ppm 1.16 (d,
J=6.7 Hz, 3H) 1.33 (d, J=6.7 Hz, 3H) 1.46 (s, 3H) 1.87-2.01 (m, 1H)
2.27 (q, J=13 Hz, 1H) 2.62 (dd, J=15.8, 3.2 Hz, 1H) 2.76-3.06 (m,
3H) 3.24 (dd, J=13.3, 2.2 Hz, 1H) 6.19 (d, J=7.8 Hz, 1H) 6.40-6.52
(m, 1H) 6.92 (dd, J=7.9, 7.9 Hz, 1H) 7.07 (ddd, J=8.0, 2, 0.98 Hz,
1H) 7.10-7.40 (m, 4H); MS (ESI) 432.0 [M-H].sup.-.
Example 419
2-((3R,5R,6S)-5-(3-Chlorophenyl)-6-(4-chlorophenyl)-1-isopropyl-6-methyl-2-
-oxopiperidin-3-yl)acetic acid
##STR01063##
[3684] The title compound was prepared from
(3S,5R,6S)-3-allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-isopropyl-6-me-
thylpiperidin-2-one (Example 418, Step I, diastereomer 2) by a
procedure similar to the one described in Example 1, Step H.
[3685] .sup.1H NMR (400 MHz, CHLOROFORM-d) .delta. ppm 1.18 (d,
J=6.7 Hz, 3H) 1.34 (d, J=6.7 Hz, 3H) 1.47 (s, 3H) 1.75 (d, J=13.9
Hz, 1H) 2.46-2.65 (m, 2H) 2.92 (quin, J=6.7 Hz, 1H) 2.99-3.22 (m,
3H) 6.26 (d, J=7.8 Hz, 1H) 6.51 (s, 1H) 6.94 (dd, J=7.9, 7.9 Hz,
1H) 6.98-7.12 (m, 3H) 7.28 (d, J=8.6 Hz, 2H); Mass Spectrum (ESI)
m/z=432.0 [M-H].sup.-.
Example 420
(3S,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-(1,1-dioxidoisot-
hiazolidin-2-yl)butan-2-yl)-3-((6-methoxypyridin-2-yl)methyl)piperidin-2-o-
ne
##STR01064##
[3686] Step A:
(5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-(1,1-dioxidoisothi-
azolidin-2-yl)butan-2-yl)piperidin-2-one
##STR01065##
[3688] This compound was made according to the procedure of Example
174, Step A, utilizing propanesulfatam (J. Org. Chem., 1963, 28
3537, 4.63 g, 38.2 mmol) and
(5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-hydroxybutan-2-yl)-
piperidin-2-one (Example 185, Step B, 6.0 g, 15.29 mmol). The title
compound was crystallized from ethyl acetate and hexanes.
[3689] .sup.1H NMR (500 MHz, CHLOROFORM-d) .delta. ppm 7.24 (d,
J=8.1 Hz, 2H), 7.10-7.20 (m, 2H), 6.99-7.09 (m, 3H), 6.86 (d, J=7.1
Hz, 1H), 4.74 (d, J=9.3 Hz, 1H), 3.36-3.46 (m, 1H), 2.96-3.33 (m,
5H), 2.93 (ddd, J=3.2, 9.3, 12 Hz, 1H), 2.63-2.71 (m, 2H),
2.32-2.50 (m, 2H), 2.12-2.26 (m, 1H), 1.97-2.04 (m, 1H), 1.91
(quind, J=7.5, 14.8 Hz, 1H), 1.44-1.61 (m, 1H), 0.53 (t, J=7.5 Hz,
3H). Mass Spectrum (ESI) m/z=495.1 (M+1).
Step B. 2-(iodomethyl)-6-methoxypyridine
##STR01066##
[3691] To a 0.degree. C. solution of iodine (1.094 g, 4.31 mmol)
and imidazole (0.294 g, 4.31 mmol) in dichloromethane (10.27 ml)
was added portionwise triphenylphosphine (1.131 g, 4.31 mmol).
After 20 min of stirring, (6-methoxypyridin-2-yl)methanol (Adesis,
New Castle, Del., 0.5 g, 3.59 mmol) was added to the solution. The
reaction was allowed to stir for 1 h at 0.degree. C., quenched with
water (50 mL) and extracted with Et.sub.2O. The combined organics
were dried over MgSO.sub.4, and concentrated in vacuo. Silica gel
chromatography (gradient elution 1 to 5% Et.sub.2O in pentane)
afforded 2-(iodomethyl)-6-methoxypyridine. .sup.1H NMR (500 MHz,
CHLOROFORM-d) .delta. ppm 7.49 (dd, J=7.3, 8.3 Hz, 1H), 6.96 (d,
J=7.1 Hz, 1H), 6.61 (d, J=8.1 Hz, 1H), 4.44 (s, 2H), 3.94 (s, 3H).
Mass Spectrum (ESI) m/z=249.9 (M+1).
Step C.
(3S,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-(1,1-dio-
xidoisothiazolidin-2-yl)butan-2-yl)-3-((6-methoxypyridin-2-yl)methyl)piper-
idin-2-one
[3692] To a solution of
(5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-(1,1-dioxidoisothi-
azolidin-2-yl)butan-2-yl)piperidin-2-one (Example 420, Step A, 0.7
g, 1.413 mmol) in THF (5.65 ml) at -78.degree. C. was added
dropwise sec-butyllithium, (1.4 M in cyclohexane, 1.06 ml, 1.483
mmol). The reaction was warmed to -10.degree. C. After about 5
minutes, the reaction was returned to a -78.degree. C. bath. A
solution of 2-(iodomethyl)-6-methoxypyridine (Example 420, Step B,
0.387 g, 1.554 mmol) in THF (1 mL) was added dropwise to the cooled
reaction mixture. The reaction was allowed to warm to room
temperature and stirred for 1 h. The reaction contents were poured
into saturated sodium bicarbonate and the aqueous layer was
extracted with dichloromethane (3.times.50 mL). The combined
organics were dried with sodium sulfate and concentrated in vacuo.
Silica gel chromatography (step gradient elution 5 to 50% diethyl
ether in dichloromethane) afforded the title compound as the more
polar diastereomer.
[3693] .sup.1H NMR (500 MHz, CHLOROFORM-d) .delta. ppm 7.50 (t,
J=7.8 Hz, 1H), 7.25 (d, J=8.6 Hz, 2H), 7.09-7.18 (m, 3H), 7.03 (d,
J=8.3 Hz, 2H), 6.92-6.99 (m, 1H), 6.82 (d, J=7.3 Hz, 1H), 6.58 (d,
J=8.1 Hz, 1H), 4.87 (d, J=7.6 Hz, 1H), 3.80 (s, 3H), 3.36-3.46 (m,
2H), 2.99-3.32 (m, 7H), 2.26-2.50 (m, 2H), 2.03-2.15 (m, 1H),
1.90-2.03 (m, 2H), 1.43-1.73 (m, 2H), 0.56 (t, J=7.6 Hz, 3H). Mass
Spectrum (ESI) m/z=616.1 (M+1).
Example 421
(3R,5R,6S)-5-(3-Chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-(1,1-dioxidoisot-
hiazolidin-2-yl)butan-2-yl)-3-((6-methoxypyridin-2-yl)methyl)piperidin-2-o-
ne
##STR01067##
[3695] From the purification described in Example 420, Step C,
(3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-(1,1-dioxidoiso-
thiazolidin-2-yl)butan-2-yl)-3-((6-methoxypyridin-2-yl)methyl)piperidin-2--
one was isolated as the less polar diastereomer.
[3696] .sup.1H NMR (500 MHz, CHLOROFORM-d) .delta. ppm 7.46 (t,
J=7.8 Hz, 1H), 7.22 (d, J=8.31 Hz, 2H), 7.10-7.17 (m, 1H),
7.05-7.10 (m, 1H), 6.98-7.03 (m, 3H), 6.79 (d, J=7.1 Hz, 1H), 6.75
(d, J=7.3 Hz, 1H), 6.54 (d, J=8.3 Hz, 1H), 4.68 (d, J=10.3 Hz, 1H),
3.91 (s, 3H), 3.72 (dd, J=3.8, 14.1 Hz, 1H), 3.30 (t, J=6.7 Hz,
2H), 3.09-3.26 (m, 4H), 3.00-3.08 (m, J=14.4 Hz, 1H), 2.95 (ddd,
J=3.2, 10.2, 13.0 Hz, 2H), 2.68 (dd, J=10.0, 14.2 Hz, 1H),
2.30-2.53 (m, 2H), 2.10 (q, J=12.9 Hz, 1H), 1.85-2.01 (m, 2H),
1.57-1.63 (m, J=2.2, 7.1 Hz, 1H), 0.53 (t, J=7.6 Hz, 3H). Mass
Spectrum (ESI) m/z=616.1 (M+1).
Example 422
(3S,5R,6S)-5-(3-Chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-(1,1-dioxidoisot-
hiazolidin-2-yl)butan-2-yl)-3-((6-hydroxypyridin-2-yl)methyl)piperidin-2-o-
ne
##STR01068##
[3698] To the product of Example 420, Step C (0.05 g, 0.081 mmol)
in chloroform (1.622 ml) was added iodotrimethylsilane (0.046 ml,
0.324 mmol). The reaction was warmed to 50.degree. C. After 4
hours, the reaction was quenched with saturated bicarbonate (10 mL)
and extracted with dichloromethane (2.times.15 mL) and 5% MeOH in
CH.sub.2Cl.sub.2 (1.times.15 mL). The combined organics were dried
with sodium sulfate and concentrated in vacuo. Silica gel
chromatography (0.5 to 7.5% MeOH in dichloromethane) afforded the
title compound.
[3699] .sup.1H NMR (500 MHz, CHLOROFORM-d) .delta. 7.36 (dd, J=6.7,
9.2 Hz, 2H), 7.28 (br s, 1H), 7.26 (s, 1H), 7.12-7.20 (m, J=7.1 Hz,
3H), 7.05 (d, J=7.1 Hz, 1H), 7.00 (d, J=8.3 Hz, 2H), 6.46 (d, J=9.1
Hz, 1H), 6.03 (d, J=6.6 Hz, 1H), 5.01 (d, J=4.9 Hz, 1H), 3.64-4.03
(m, 1H), 3.40-3.57 (m, 1H), 2.85-3.34 (m, 8H), 2.74 (quin, J=6.4
Hz, 1H), 2.25-2.50 (m, 2H), 1.91-2.17 (m, J=6.8 Hz, 3H), 1.39-1.55
(m, 1H), 0.61 (t, J=7.5 Hz, 3H). Mass Spectrum (ESI) m/z=602.2
(M+1).
Example 423
(3R,5R,6S)-5-(3-Chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-(1,1-dioxidoisot-
hiazolidin-2-yl)butan-2-yl)-3-((6-hydroxypyridin-2-yl)methyl)piperidin-2-o-
ne
##STR01069##
[3701] Following the procedure of Example 422 using the product of
Example 421,
(3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-(1,1-dioxi-
doisothiazolidin-2-yl)butan-2-yl)-3-((6-hydroxypyridin-2-yl)methyl)piperid-
in-2-one was obtained.
[3702] .sup.1H NMR (500 MHz, CHLOROFORM-d) .delta. ppm 7.22 (dd,
J=6.6, 9.3 Hz, 1H), 7.16 (d, J=8.3 Hz, 2H), 7.07-7.11 (m, 1H),
7.00-7.06 (m, 1H), 6.95 (s, 1H), 6.90 (d, J=8.07 Hz, 2H), 6.70 (d,
J=7.6 Hz, 1H), 6.36 (d, J=9.1 Hz, 1H), 5.87 (d, J=6.6 Hz, 1H), 4.65
(d, J=10.5 Hz, 1H), 3.29 (td, J=6.7, 9.60 Hz, 1H), 3.18 (td, J=6.7,
9.6 Hz, 1H), 3.11 (t, J=7.5 Hz, 2H), 2.87-3.04 (m, 3H), 2.76-2.86
(m, 1H), 2.71 (dd, J=2.7, 14.4 Hz, 1H), 2.32 (quin, J=7.0 Hz, 2H),
2.17 (q, J=13 Hz, 1H), 1.84-1.99 (m, 2H), 1.37-1.58 (m, 2H), 0.43
(t, J=7.6 Hz, 3H).
Example 424
(3S,5R,6S)-5-(3-Chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-(1,1-dioxidoisot-
hiazolidin-2-yl)butan-2-yl)-3-((6-methoxypyridin-2-yl)methyl)-3-methylpipe-
ridin-2-one
##STR01070##
[3704] sec-Butyllithium (1.4 M in cyclohexane, 0.59 ml, 0.824 mmol)
was added to a solution of
(3S,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-(1,1-dioxidoiso-
thiazolidin-2-yl)butan-2-yl)-3-((6-methoxypyridin-2-yl)methyl)piperidin-2--
one (Example 420, Step C, 0.484 g, 0.785 mmol) in THF (3.92 ml) at
-78.degree. C. After 15 minutes iodomethane (0.098 ml, 1.57 mmol)
was added and the reaction was allowed to warm to room temperature.
The reaction contents were poured into saturated sodium bicarbonate
(20 mL) and extracted with dichloromethane (3.times.30 mL). The
combined organics were dried with sodium sulfate and concentrated
in vacuo. Silica gel chromatography (10% step gradient elution 30
to 90% EtOAc in hexanes) afforded the title compound as the first
eluting diastereomer.
[3705] .sup.1H NMR (500 MHz, CHLOROFORM-d) .delta. 7.48 (t, J=7.6
Hz, 1H), 7.21 (d, J=8.1 Hz, 2H), 6.92-7.15 (m, 5H), 6.88 (d, J=7.1
Hz, 1H), 6.74 (d, J=7.6 Hz, 1H), 6.57 (d, J=8.3 Hz, 1H), 4.64 (d,
J=10.5 Hz, 1H), 3.04-3.25 (m, 7H), 2.98 (d, J=14.7 Hz, 2H), 2.69
(t, J=13.8 Hz, 1H), 2.21-2.44 (m, 2H), 1.89 (td, J=7.4, 14.6 Hz,
1H), 1.75 (dd, J=2.8, 13.6 Hz, 1H), 0.50 (t, J=7.6 Hz, 3H). Mass
Spectrum (ESI) m/z=630.2 (M+1).
Example 425
(3R,5R,6S)-5-(3-Chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-(1,1-dioxidoisot-
hiazolidin-2-yl)butan-2-yl)-3-((6-methoxypyridin-2-yl)methyl)-3-methylpipe-
ridin-2-one
##STR01071##
[3707] The title compound is the second eluting diastereomer from
the purification described in Example 424.
[3708] .sup.1H NMR (500 MHz, CHLOROFORM-d) .delta. ppm 7.53 (t,
J=7.7 Hz, 1H), 7.19 (d, J=8.1 Hz, 2H), 7.03-7.13 (m, 2H), 6.87-7.03
(m, 3H), 6.84 (d, J=7.3 Hz, 1H), 6.76 (d, J=7.3 Hz, 1H), 6.62 (d,
J=8.3 Hz, 1H), 4.72 (d, J=10.8 Hz, 1H), 3.86-4.00 (m, 1H), 3.69 (s,
3H), 3.43 (d, J=12.7 Hz, 1H), 3.26-3.39 (m, 2H), 3.14-3.26 (m, 3H),
2.96-3.05 (m, 2H), 2.91 (br. s., 1H), 2.31-2.51 (m, 2H), 2.14-2.23
(m, 1H), 2.02-2.12 (m, 1H), 1.95 (quind, J=7.6, 14.8 Hz, 1H),
1.39-1.64 (m, 2H), 1.29 (s, 3H), 0.51 (t, J=7.6 Hz, 3H). Mass
Spectrum (ESI) m/z=630.2 (M+1).
Example 426
(3S,5R,6S)-5-(3-Chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-(1,1-dioxidoisot-
hiazolidin-2-yl)butan-2-yl)-3-((6-hydroxypyridin-2-yl)methyl)-3-methylpipe-
ridin-2-one
##STR01072##
[3710] Following the procedure of Example 422 using the product of
Example 424,
(3S,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-(1,1-dioxi-
doisothiazolidin-2-yl)butan-2-yl)-3-((6-hydroxypyridin-2-yl)methyl)-3-meth-
ylpiperidin-2-one was obtained.
[3711] .sup.1H NMR (500 MHz, CHLOROFORM-d) .delta. ppm 7.33 (dd,
J=6.7, 9.2 Hz, 1H), 7.23 (d, J=8.1 Hz, 2H), 7.08-7.19 (m, 2H),
6.87-7.05 (m, 4H), 6.81 (d, J=7.6 Hz, 1H), 6.49 (d, J=9.1 Hz, 1H),
5.95 (d, J=6.6 Hz, 1H), 4.74 (d, J=10.3 Hz, 1H), 3.75-4.14 (m, 1H),
3.30-3.42 (m, 1H), 3.10-3.28 (m, 4H), 2.68-3.09 (m, J=4.2 Hz, 4H),
2.26-2.50 (m, 3H), 1.89-2.06 (m, 1H), 1.53-1.70 (m, J=3.2, 13.2 Hz,
2H), 1.49 (s, 3H), 0.52 (t, J=7.5 Hz, 3H). Mass Spectrum (ESI)
m/z=616.1 (M+1).
Example 427
(3R,5R,6S)-5-(3-Chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-(1,1-dioxidoisot-
hiazolidin-2-yl)butan-2-yl)-3-((6-hydroxypyridin-2-yl)methyl)-3-methylpipe-
ridin-2-one
##STR01073##
[3713] Following the procedure of Example 422 using the product of
Example 425,
(3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-(1,1-dioxi-
doisothiazolidin-2-yl)butan-2-yl)-3-((6-hydroxypyridin-2-yl)methyl)-3-meth-
ylpiperidin-2-one was obtained.
[3714] .sup.1H NMR (500 MHz, CHLOROFORM-d) .delta. ppm 7.36-7.44
(m, 1H), 7.10-7.23 (m, 2H), 6.77-7.07 (m, 5H), 6.66 (d, J=7.8 Hz,
1H), 6.48 (d, J=9.1 Hz, 1H), 6.11 (d, J=6.6 Hz, 1H), 4.74 (d,
J=10.5 Hz, 1H), 3.93 (dd, J=9.8, 13.9 Hz, 1H), 3.29 (t, J=6.6 Hz,
2H), 3.20 (dt, J=0.9, 7.5 Hz, 2H), 3.15 (d, J=13.9 Hz, 1H),
2.75-2.99 (m, 4H), 2.32-2.48 (m, 1H), 2.24 (t, J=13.8 Hz, 1H),
1.98-2.10 (m, 1H), 1.88-1.96 (m, J=2.9 Hz, 1H), 1.44-1.59 (m, 1H),
1.39 (s, 3H), 0.48 (t, J=7.6 Hz, 3H). Mass Spectrum (ESI) m/z=616.1
(M+1).
Example 428
(3R,5R,6S)-5-(3-Chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-cyclopropyl-2-(e-
thylsulfonyl)ethyl)-3-(3-hydroxy-2-oxopropyl)-3-methylpiperidin-2-one
##STR01074##
[3716] Oxalyl chloride (0.063 ml, 0.715 mmol) was added to a
solution of
2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-cyclopropyl--
2-(ethylsulfonyl)ethyl)-3-methyl-2-oxopiperidin-3-yl)acetic acid
(Example 349, 0.316 g, 0.572 mmol) in dichloromethane (1.9 ml). The
reaction was stirred for 3 h at room temperature. The solvents were
removed in vacuo. To the solids was added
tris(trimethylsiloxy)ethylene (0.42 ml, 1.26 mmol) and the reaction
was stirred at 90.degree. C. After 2 h, the reaction was cooled,
charged with THF (1 mL) and HCl (1.4 M, 0.982 ml, 1.375 mmol), and
brought to reflux for 30 min. After cooling, the reaction was
poured into water (20 mL) and extracted with dichloromethane
(3.times.20 mL). The combined organics were dried over sodium
sulfate and concentrated in vacuo. Silica gel chromatography (step
gradient elution 1 to 5% 2 M ammonia in MeOH in dichloromethane)
afforded the title compound.
[3717] .sup.1H NMR (500 MHz, CHLOROFORM-d) .delta. 7.11-7.30 (m,
3H), 6.96-7.10 (m, 3H), 6.89 (s, 1H), 6.70-6.85 (m, 1H), 4.82 (d,
J=10.8 Hz, 1H), 4.13-4.45 (m, J=1.7 Hz, 3H), 3.15 (ddd, J=2.9,
10.6, 13.6 Hz, 1H), 2.74-3.10 (m, 6H), 2.60 (br s, 1H), 2.28 (t,
J=13.8 Hz, 1H), 1.96 (dd, J=3.1, 13.8 Hz, 1H), 1.77 (br s, 1H),
1.27-1.42 (m, 6H), 0.10-0.41 (m, 2H), -0.33 (br s, 1H), -1.01 (br
s, 1H). Mass Spectrum (ESI) m/z=566.2 (M+1).
Example 429
2-((3R,5R,6S)-5-(3-Chlorophenyl)-6-(4-chlorophenyl)-1-(diethylamino)-3-met-
hyl-2-oxopiperidin-3-yl)acetic acid
##STR01075##
[3718] Step A. Methyl
2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-2-oxopiperid-
in-3-yl)acetate
##STR01076##
[3720] Sodium periodate (21.03 g, 98 mmol) was added slowly to a
solution containing ruthenium(III) chloride hydrate (0.277 g, 1.229
mmol) and
(3S,5R,6S)-3-allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methylpiperidi-
n-2-one (4.6 g, 12.29 mmol; Example 71, step D) in acetonitrile
(35.1 mL), ethyl acetate (35.1 mL) and water (52.7 mL) while
maintaining a temperature below 20.degree. C. The resulting mixture
was then stirred for 2 h at room temperature. Next, the reaction
was filtered and concentrated, and the resulting residue was
further processed by dissolving in ethyl acetate. The organics were
washed with water and brine, dried over MgSO.sub.4, filtered and
concentrated. Next, the residue was dissolved in a small amount of
a mixture of ether and methanol (1:1) and a 2M solution of
(trimethylsilyl)diazomethane in diethyl ether (12.29 ml, 24.58
mmol) was added. This solution was then allowed to stir at ambient
temperature overnight. The solution was concentrated and the
resulting residue was purified on silica gel (eluent: hexane/ethyl
acetate 0 to 100%, gradient elution) to give the title
compound.
[3721] Mass Spectrum (ESI) m/z=406 (M+1).
Step B. Methyl
2-((3R,5R,6S)-1-amino-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-2-ox-
opiperidin-3-yl)acetate
##STR01077##
[3723] A suspension of 60% sodium hydride in mineral oil (0.953 g,
23.82 mmol) was added to solution of methyl
2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-2-oxopiperid-
in-3-yl)acetate (Example 429, step A, 4.84 g, 11.9 mmol) in DMF (25
mL). The resulting mixture was stirred for 15 min at 23.degree. C.
O-(2,4-dinitrophenyl)hydroxylamine (4.74 g, 23.82 mmol) was added
at room temperature. The solution was stirred for 1 h at room
temperature then quenched with MeOH (1 mL). Excess solvent was
removed under reduced pressure and the residue was purified by
chromatography on silica (eluent: 0 to 5% MeOH in DCM; stepwise
gradient) to give the title compound.
[3724] Mass Spectrum (ESI) m/z=421 (M+1), 443 (M+23).
Step C. Methyl
2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-(diethylamino)-3-me-
thyl-2-oxopiperidin-3-yl)acetate
##STR01078##
[3726] Ethyl iodide (67.1 .mu.L, 0.831 mmol) was added to a
solution of methyl
2-((3R,5R,6S)-1-amino-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-meth-
yl-2-oxopiperidin-3-yl)acetate (Example 429, step B, 35 mg, 0.083
mmol) and DIEA (145 .mu.L, 0.831 mmol) in DMF. The resulting
mixture was stirred at 80.degree. C. for 12 h. The mixture was
concentrated and purified by reversed phase HPLC (Sunfire.TM. Prep
C.sub.18 OBD 10 .mu.m column; Waters, Milford, Mass.; 40-90%
water/acetonitrile gradient with 0.1% TFA). Desired fractions were
pooled and concentrated to give the title compound.
[3727] Mass Spectrum (ESI) m/z=477 (M+1).
Step D.
2-((3R,5R,6S)-5-(3-Chlorophenyl)-6-(4-chlorophenyl)-1-(diethylamin-
o)-3-methyl-2-oxopiperidin-3-yl)acetic acid
[3728] A solution of methyl
2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-(diethylamino)-3-me-
thyl-2-oxopiperidin-3-yl)acetate (Example 429, step C) in
water/methanol (1:1) was treated with lithium hydroxide (1N, 5 eq)
at room temperature for 15 h. The mixture was concentrated and
purified by reversed phase HPLC (Sunfire.TM. Prep C.sub.18 OBD 10
.mu.m column; Waters, Milford, Mass.; 40-90% water/acetonitrile
gradient with 0.1% TFA). Desired fractions were then pooled and
concentrated to give the title compound.
[3729] .sup.1H NMR (500 MHz, Methanol-d.sub.4) .delta. ppm 0.222
(t, J=7 Hz, 3H) 1.179 (t, J=7 Hz, 3H) 1.389 (s, 3H) 2.143 (dd,
J=14, 3.5 Hz, 1H) 2.200 (t, J=13.5 Hz, 1H) 2.570 (d, J=13.5 Hz, 1H)
2.713 (m, 1H) 2.967 (d, J=13.5 Hz, 1H) 3.116 (m, 1H) 3.251 (m, 1H)
3.519 (ddd, J=13, 11, 3.5 Hz, 1H) 4.598 (d, J=11 Hz, 1H) 6.972 (d,
J=7 Hz, 1H) 7.070 (m, 1H) 7.099-7.16 (m, 2H) 7.229 (m, 4H); Mass
Spectrum (ESI) m/z=463 (M+1), 485 (M+23).
Example 430
2-((3R,5R,6S)-5-(3-Chlorophenyl)-6-(4-chlorophenyl)-1-(dimethylamino)-3-me-
thyl-2-oxopiperidin-3-yl)acetic acid
##STR01079##
[3731] Methyl
2-((3R,5R,6S)-1-amino-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-2-ox-
opiperidin-3-yl)acetate (Example 429 step C) was treated by a
procedure similar to the one described in Example 429, using methyl
iodide instead of ethyl iodide in Step C.
[3732] .sup.1H NMR (500 MHz, Methanol-d.sub.4) .delta. ppm 1.356
(s, 3H) 2.088 (dd, J=14, 3.5 Hz, 1H) 2.166 (t, J=13.5 Hz, 1H) 2.599
(br s, 6H) 2.601 (d, J=13.5, 1H) (m, 7H) 2.933 (d, J=13.5 Hz, 1H)
3.429 (ddd, J=13, 10.5, 3.5 Hz, 1H) 4.672 (d, J=10.5 Hz, 1H) 6.965
(m, 1H) 7.10-7.16 (m, 5H) 7.206 (d, J=8.5 Hz, 2H); Mass Spectrum
(ESI) m/z=435 (M+1).
Example 431
(2S,3S,5S,6R,7aR,100aS)-6-(3-Chlorophenyl)-5-(4-chlorophenyl)-3-ethyl-2,7a-
-dimethylhexahydrofuro[2,3-b]oxazolo[3,2-a]pyridin-9(5H)-one
##STR01080##
[3733] Step A:
(3S,5R,6S)-3-Allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((2S,3S)-2-hyd-
roxypentan-3-yl)-3-methylpiperidin-2-one
##STR01081##
[3735] L-Selectride.TM. (1M in THF, 5.24 ml, 5.24 mmol) was added
to a solution at -10.degree. C. of
(3S,5R,6S)-3-allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-1-((S)--
2-oxopentan-3-yl)piperidin-2-one (Example 149, step A, 2 g, 4.36
mmol) in THF (29.1 ml) being careful to maintain the temperature
below -7.degree. C. The reaction was stirred for 40 min then
quenched into an aqueous solution of Oxone.TM. (10.73 g, 17.45
mmol) in 60 mL water. It was noted that the temperature spiked up
to 40.degree. C. during the addition. The reaction was cooled to RT
using a water/ice bath and stirred at RT for 1 h, then diluted with
ethyl acetate. The layers were separated and the aq layer was
extracted with ethyl acetate. The combined organics were washed
with brine and dried over MgSO.sub.4, filtered and concentrated.
The crude material was dried under high vacuum overnight.
Purification by column chromatography using 10-20% acetone in
hexanes afforded the title compound.
[3736] .sup.1H NMR (400 MHz, CHLOROFORM-d) .delta. ppm 7.21-7.27
(m, 2H), 7.16 (ddd, J=8, 2, 1.2 Hz, 1H), 7.10 (t, J=7.7 Hz, 1H),
6.95-7.07 (m, 2H), 6.93 (t, J=1.8 Hz, 1H), 6.70 (dt, J=7.5, 1.2 Hz,
1H), 5.80-5.92 (m, 1H), 5.13-5.25 (m, 2H), 4.66 (br s, 1H), 4.37
(d, J=10.6 Hz, 1H), 3.52-4.11 (m, 1H), 3.20 (ddd, J=13.4, 10.5, 3.2
Hz, 1H), 2.61 (d, J=7.4 Hz, 3H), 2.11-2.30 (m, 1H), 2.06 (t, J=13.7
Hz, 1H), 1.95 (dd, J=13.7, 3.3 Hz, 1H), 1.32-1.42 (m, 1H), 1.22 (d,
J=6.3 Hz, 3H), 0.59 (br s, 3H). LC/MS (M+H) m/z=460.2.
Step B:
(2S,3S,5S,6R,8S)-8-Allyl-6-(3-chlorophenyl)-5-(4-chlorophenyl)-3-e-
thyl-2,8-dimethyl-2,3,5,6,7,8-hexahydrooxazolo[3,2-a]pyridin-4-ium
4-methylbenzenesulfonate
##STR01082##
[3738] A solution of
(3S,5R,6S)-3-allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((2S,3S)-2-hyd-
roxypentan-3-yl)-3-methylpiperidin-2-one (Example 431, Step A, 600
mg, 1.303 mmol) in toluene (43 mL) with pyridinium
p-toluenesulfonate (PPTS, 327 mg, 1.30 mmol) was treated for 1 h
under Dean-Stark conditions. When monitoring by NMR indicated about
95 to 97% completion, the reaction was treated with an additional
3% (10 mg) PPTS and returned to reflux for 30 min. The reaction
mixture was concentrated under high vacuum and used as is for
subsequent reactions.
[3739] .sup.1H NMR (500 MHz, DMSO-d.sub.6) .delta. ppm 8.15-7.10
(series of m, 12H), 5.89 (ddt, J=17.4, 10.3, 7.3, Hz, 1H), 5.38 (d,
J=11.0 Hz, 1H), 5.36 (dd, J=16.9, 1.7 Hz, 1H), 5.27 (dd, J=10.1,
2.1 Hz, 1H), 5.17 (quin, J=6.3 Hz, 1H), 4.12 (td, J=6.5, 2.6 Hz,
1H), 3.97 (ddd, J=13.7, 11.0, 3.4 Hz, 1H), 2.81 (ABX, J.sub.AB=13.7
Hz, J.sub.AX=7.1 Hz, 1H), 2.72 (ABX, J.sub.AB=13.7 Hz, J.sub.BX=7.8
Hz, 1H), 2.43 (t, J=13.2 Hz, 1H), 2.29 (s, 3H), 1.99 (dd, J=13.3,
3.3 Hz, 1H), 1.57 (d, J=6.1 Hz, 3H), 1.32 (s, 3H), 0.95 (dqd,
J=14.7, 7.3, 3.4 Hz, 1H), 0.58 (t, J=7.2 Hz, 3H), 0.45 (dquin,
J=14.7, 7.2, Hz, 1H). LC/MS m/z=442.2 (M+).
Step C:
(2S,3S,5S,6R,7aR,100aS)-6-(3-Chlorophenyl)-5-(4-chlorophenyl)-3-et-
hyl-2,7a-dimethylhexahydrofuro[2,3-b]oxazolo[3,2-a]pyridin-9(5H)-one
[3740] A solution of
(2S,3S,5S,6R,8S)-8-allyl-6-(3-chlorophenyl)-5-(4-chlorophenyl)-3-ethyl-2,-
8-dimethyl-2,3,5,6,7,8-hexahydrooxazolo[3,2-a]pyridin-4-ium
4-methylbenzenesulfonate (Example 431, Step B, 775 mg, 1.261 mmol)
in dichloromethane (12 mL) at 0.degree. C. with acetic acid (2.89
mL, 50.4 mmol) and tetra-n-butylammonium chloride (35.0 mg, 0.126
mmol) was treated by adding KMnO.sub.4 (797 mg, 5.04 mmol) as a
solution in water (12 mL), followed by a water rinse (12 mL).
[3741] After 20 min at 0.degree. C., the reaction was quenched by
addition of 15 mL sat. Na.sub.2S.sub.2O.sub.3. The reaction was
diluted with 150 mL of ethyl acetate and the layers were separated.
The organic phase was washed with water and brine., dried over
MgSO.sub.4, filtered through Celite.RTM. (J. T. Baker,
Phillipsberg, N.J., diatomaceous earth), and concentrated. The
sample was placed under high vacuum overnight to afford product
with entrained acetic acid (about 4 eq). An aliquot was purified
using 60-80% ethyl acetate in hexanes to afford the title
compound.
[3742] .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. ppm 7.18-7.26
(m, 5H), 7.07-7.16 (m, 2H), 7.05 (dt, J=7.0, 1.7 Hz, 1H), 3.92
(quin, J=6.1 Hz, 1H), 3.84 (d, J=10.8 Hz, 1H), 3.48 (d, J=17.4 Hz,
1H), 3.34-3.42 (m, 1H), 2.52-2.56 (m, 1H), 2.34 (d, J=17.6 Hz, 1H),
1.92 (ABX, J.sub.AB=13.9 Hz, J.sub.AX=13.2 Hz, 1H), 1.82 (ABX,
J.sub.AB=13.9 Hz, J.sub.BX=2.9 Hz, 1H), 1.43 (d, J=6.3 Hz, 3H),
1.22 (s, 5H), 0.41 (t, J=7.5 Hz, 3H). LC/MS (M+H) m/z=460.2.
[3743] Compounds of the present invention display inhibition of the
interaction between HDM2 and p53 in the following assays.
Homogenous Time-Resolved Fluorescence Assay (HTRF1 Assay)
[3744] The standard assay conditions for the in vitro HTRF assay
consisted of a 50 ul total reaction volume in black 384-well Costar
polypropylene plates in 1.times.PBS buffer pH 7.4, 1 mM DTT, 0.1%
BSA, 2.5 nM GST-hMDM2 (aa 1-188), 5 nM biotinylated-p53 (aa 1-83),
1.8 nM SA-XLent (Cisbio; Bedford, Mass.), 0.6 nM anti-GST cryptate
monoclonal antibody (Cisbio; Bedford, Mass.) and 200 mM KF. Amino
acid residues 1-188 of human MDM2 were expressed as an
amino-terminal glutathione-5-transferase (GST) fusion protein
(GST-hMDM2) in Escherichia coli. Residues 1-83 of human p53 were
expressed as an amino-terminal AviTag.TM.-TrxA-6.times.His fusion
protein (biotinylated p53) in E. coli. Each protein was purified
from cell paste by affinity chromatography.
[3745] Specifically, 10 uL of GST-hMDM2 was incubated with 10 ul of
diluted compound (various concentrations, serially diluted) in 10%
DMSO for 20 minutes at room temperature. 20 uL of biotinylated-p53
was added to the GST-hMDM2+compound mixture, and then incubated at
room temperature for 60 min. 10 uL of detection buffer consisting
of SA-XLent, anti-GST cryptate antibody and KF was added to
GST-hMDM2, biotinylated-p53 and compound reaction and left at room
temperature to reach equilibrium for >4 hrs. The final
concentration of DMSO in the reaction was 2%. Time-resolved
fluorescence readings were measured on a microplate multilabel
reader. Percentage of inhibition was calculated relative to
nutlin-3.
[3746] As the potencies of the HDM2 inhibitors increased, an
improved HTRF assay (HTRF2 assay) was developed. All assay
conditions remained the same as described above, with the exception
of the following changes in reagent concentrations: 0.2 nM
GST-hMDM2 (1-188), 0.5 nM biotinylated-p53 (1-83), 0.18 nM
SA-XLent, and 100 mM KF.
[3747] Results are provided in the table below.
TABLE-US-00027 TABLE 1 Example HTRF1 IC.sub.50 (.mu.M) HTRF2
IC.sub.50 (.mu.M) 1 0.04 0.004 2 0.20 3 0.06 0.01 4 0.19 5 0.27 6
0.04 7 0.05 8 0.04 9 0.03 10 0.07 11 0.09 12 0.04 13 0.11 14 0.29
15 0.24 16 0.07 17 0.24 18 0.11 19 0.01 20 0.07 21 0.07 22 0.49 23
0.17 24 0.57 25 0.14 26 0.13 27 0.10 28 0.18 29 0.03 30 0.03 0.004
31 0.05 32 0.09 33 0.41 34 0.71 35 0.15 0.03 36 4.3 37 0.06 38 0.19
39 0.30 40 0.17 41 0.32 42 0.41 43 1.97 44 0.45 45 0.55 46 0.27 47
3.63 48 1.37 49 2.38 50 0.83 51 3.06 52 1.70 53 0.13 54 2.09 55
0.09 56 1.89 57 1.60 58 0.70 59 0.87 60 0.16 61 0.31 62 0.09 63
0.43 64 0.22 65 0.02 0.003 66 0.31 67 0.02 0.002 68 0.03 0.002 69
0.06 70 0.13 71 0.02 0.003 72 0.06 73 0.03 0.006 74 0.07 75 0.03
0.005 76 0.22 77 0.26 78 0.53 79 0.58 80 0.08 81 0.49 82 0.02 83
0.03 84 1.76 85 1.98 86 0.01 87 0.02 88 0.84 89 0.08 90 0.04 91
0.01 0.004 92 0.04 93 0.01 0.003 94 0.01 95 0.03 0.009 96 0.02
0.008 97 0.01 0.002 98 0.01 0.004 99 0.01 0.002 100 0.02 101 0.02
0.006 102 0.05 103 0.28 104 0.04 105 1.09 106 0.19 107 0.21 108
0.11 109 0.30 110 0.34 111 0.61 112 0.23 113 0.03 114 0.03 115
<0.01 0.001 116 0.39 117 0.71 118 0.65 119 0.12 120 0.56 121
0.05 122 0.05 0.011 123 0.92 124 0.02 125 0.02 0.005
TABLE-US-00028 TABLE 2 Example HTRF1 IC.sub.50 (.mu.M) HTRF2
IC.sub.50 (.mu.M) 126 {grave over ( )} 0.012 127 0.02 128 0.01
0.001 129 0.01 0.001 130 0.01 0.003 131 0.07 132 0.12 0.070 133
0.01 0.002 134 0.01 0.002 135 0.01 136 0.01 0.001 137 0.01 0.002
138 0.01 0.002 139 <0.01 0.001 140 0.01 0.004 141 <0.01 0.001
142 0.01 0.001 143 0.03 0.019 144 0.04 0.014 145 0.01 0.004 146
0.01 0.004 147 0.01 0.002 148 <0.01 0.001 149 0.04 0.006 150
0.01 0.002 151 0.02 0.006 152 0.01 0.001 153 0.002 154 0.01 0.002
155 0.011 156 157 0.01 0.002 158 0.01 159 0.01 0.002 160 0.01 161
0.10 162 0.006 163 0.053 164 0.049 165 0.026 166 0.044 167 0.064
168 0.058 169 0.002 170 0.106 171 0.028 172 0.001 173 0.015 174
0.002 175 0.001 176 0.003 177 0.053 178 0.02 0.006 179 0.04 180
0.03 0.008 181 0.002 182 0.004 183 0.003 184 0.013 185 0.02 0.002
186 0.007 187 0.003 188 0.001 189 0.003 190 0.005 191 0.001 192
0.001 193 0.001 194 0.005 195 0.002 196 <0.001 197 <0.001 198
<0.001 199 0.001 200 0.001 201 0.044 202 0.002 203 0.001 204
0.002 205 0.01 0.001 206 0.01 0.003 207 0.04 0.009 208 0.02 0.007
209 0.07 0.009 210 0.01 0.002 211 0.02 0.004 212 0.03 0.005 213
0.03 214 0.02 0.003 215 0.04 0.006 216 0.03 0.003 217 0.03 0.005
218 0.08 0.019 219 0.03 0.012 220 0.03 221 0.02 0.003 222 0.01
0.001 223 0.02 0.004 224 0.001 225 0.002 226 0.09 227 0.07 228 0.04
229 0.001 230 0.03 0.010 231 0.08 232 0.08 233 0.08 234 0.05 0.011
235 0.06 236 0.01 237 0.04 0.009 238 0.001 239 240 0.05 241 0.02
0.003 242 0.03 243 0.03 244 0.04 245 0.03 0.009 246 0.02 0.003
247-A 0.100 247-B 0.371 248 0.100 249 0.03 0.006 250 0.01 0.001 251
0.01 0.001 252 0.06 253 0.001 254 <0.001 255 <0.001 256
<0.01 <0.001 257 0.001 258 0.08 0.002 259 0.002 260 0.007 261
0.001 262 0.02 0.003
TABLE-US-00029 TABLE 3 Example HTRF1 IC.sub.50 (.mu.M) HTRF2
IC.sub.50 (.mu.M) 263 0.0002 264 0.0003 265 0.0005 266 0.0005 267
0.0003 268 0.0001 269 0.0001 270 0.0055 272 0.0001 273 0.0002 274
0.0002 275 0.0003 276 0.0005 277 0.0002 278 0.0002 279 0.0005 280
0.0006 281 0.0003 282 0.0002 283 0.0007 284 0.0015 285 0.0008 286
0.0006 287 0.0003 288 0.0135 289 0.0003 290 291 292 0.0009 293
0.0008 294 0.0007 295 0.0018 296 0.0044 297 0.0161 298 0.0013 299
0.0100 300 301 0.0003 302 0.0004 303 0.0005 304 0.0003 305 0.0005
306 0.0003 307 0.0003 308 0.0001 309 0.0002 310 0.0002 311 0.0001
312 0.0112 313 0.0002 314 0.0001 315 0.0014 316 0.0029 317 0.0012
318 0.0029 319 0.0024 320 0.0005 321 0.0013 322 0.0001 323 0.0002
324 0.0003 325 0.0016 326 0.0004 327 0.0004 328 0.0014 329 0.0016
330 0.0002 331 0.0002 332 0.0003 333 0.0002 334 0.0001 335 0.0003
336 0.0018 337 0.0006 338 0.0003 339 0.0003 340 0.0002 341 0.0002
342 0.0001 343 0.0002 344 0.0004 345 0.0002 346 0.0001 347 0.0003
348 0.0003 349 0.0001 350 0.0001 351 0.0001 352 0.0002 353 0.0001
354 0.0001 355 0.0006 356 0.0009 357 0.0002 358 0.0001 359 0.0002
360 0.0003 361 0.0005 362 0.0010 363 0.0002 364 0.0003 365 0.0008
366 0.0001 367 0.0026 368 0.0019 369 0.0006 370 0.0004 371 0.0001
372 0.0002 373 0.0002 374 0.0002 375 0.0001 376 0.0010 377 0.0002
378 0.0001 379 0.0001 380 0.0006 381 0.0001 382 0.0002 383 0.0005
384 0.0005 385 386 0.0018 387 0.0070 388 389 0.0014 390 391 0.0050
392 0.1230 393 0.0007 394 0.0004 395 0.0005 396 0.0002 397 0.0002
398 0.0001 399 0.0001 400 0.0038 401 0.0015 402 0.0046 403 0.0040
404 0.0009 405 406 407 408 0.0035 409 410 0.0026 411 412 413 0.0010
414 0.0238 415 0.0010 416 0.0027 417 0.0013 418 0.0183 419 0.0034
420 0.1230 421 0.1940 422 0.1040 423 0.0231 424 0.1300 425 0.2750
426 0.0526 427 0.1190 428 0.0041 429 0.01 0.0024 430 0.02 431
0.0018
[3748] Compounds in the present invention display activation of
cyclin-dependent kinase inhibitor p21.sup.WAF1/CPI1.
p21 TaqMan.degree. Assay
[3749] Inhibition of the interaction between hMDM2 and p53 results
in activation of the p53 pathway via stabilization and accumulation
of p53. p53 activates the transcription of many genes, one of which
is p21.sup.WAF1/CIP1. In order to assess the potency of hMDM2
inhibitors, quantitative reverse transcription polymerase chain
reaction (qRT-PCR or TaqMan) was used to measure the levels of p21
transcript in compound-treated cells relative to dimethyl sulfoxide
(DMSO)-treated control cells.
[3750] On Day 1, SJSA-1 cells were plated at a density of
3.times.10.sup.4 cells/well in 96-well cell culture plates in 100
ul of growth medium (RPMI 1640; 10 mM HEPES; 1 mM sodium pyruvate;
1.times. Penicillin-Streptomycin-Glutamine (PSQ); and 10% fetal
bovine serum (all reagents from Invitrogen; Carlsbad, Calif.)). The
cells were cultured overnight at 37.degree. C. and 5% CO.sub.2.
[3751] On Day 2, hMDM2 inhibitors were serially diluted in DMSO
(Sigma-Aldrich; St. Louis, Mo.). 5 ul of each compound dilution was
added to 245 ul of filtered assay medium (RPMI 1640, 10 mM HEPES, 1
mM sodium pyruvate, and 1.times.PSQ), containing 10% FBS.
Alternatively, the assay was also run in the presence of 10% human
serum or 10% mouse serum, or in the absence of any serum. The
growth medium was removed from the plated SJSA-1 cells and replaced
with 100 ul/well of assay medium. Then 100 ul of medium containing
diluted inhibitor was added to each well, to a final volume of 200
ul. The compound dose titration yielded final concentrations
ranging from 0.049 uM-50 uM, plus a DMSO control. The cells were
incubated in the presence of inhibitor at 37.degree. C. and 5%
CO.sub.2 for 7 hours. At the end of the incubation period, the
medium was removed from the cells, and the plates were stored at
-80.degree. C.
[3752] On Day 3, total RNA was purified from the inhibitor- and
DMSO-treated SJSA-1 cells using the Qiagen BioRobot Universal
workstation following the RNeasy 96 BioRobot 8000 kit protocol from
the manufacturer (Qiagen; Valencia, Calif.), with the following
exceptions: the protocol began with RLT lysis buffer addition,
omitted DNase treatment, omitted addition of Top Elute fluid, and
changed the final elution volume to 120 ul. After the BioRobot
Universal finished the RNA extraction procedure, the collection
plate containing total RNA from each well was briefly centrifuged
to collect the eluate at the bottom of the tubes.
[3753] To measure the levels of p21 transcript present, qRT-PCR was
used. The levels of both p21 and the housekeeping gene,
glyceraldehyde 3-phosphate dehydrogenase (GAPDH) were assayed from
total RNA from each inhibitor- or DMSO-treated well in technical
duplicates. Each qRT-PCR assay well contained the following
components from the TaqMan.RTM. One-Step RT-PCR Master Mix Reagents
Kit (Invitrogen): 10 ul of 2.times.TaqMan.RTM. Universal PCR Master
Mix, 0.5 ul of 40.times.Multiscribe.TM. Reverse Transcriptase/RNase
Inhibitor Mix, 1 ul of either p21 20.times.TaqMan.RTM. Gene
Expression Assay (Invitrogen) or 1 ul of GAPDH 20.times.TaqMan.RTM.
Gene Expression Assay (Invitrogen), plus 5 ul of total RNA and 3.5
ul of DEPC-H.sub.2O (EMD Chemicals; Gibbstown, N.J.). The qRT-PCR
reactions were assayed on the Applied Biosystems Prism 7900HT
instrument, using the relative quantification (delta delta Ct)
method with the following cycling conditions: 30 minutes at
48.degree. C., followed by 10 minutes at 95.degree. C., then 40
cycles of 15 seconds at 95.degree. C. and 1 minute at 60.degree. C.
The data were analyzed with Applied Biosystems SDS2.2 software,
using GAPDH as the endogenous control and DMSO-treated samples as
the calibrator. The SDS2.2 software calculated relative
quantification (RQ) or fold increase of p21 levels relative to DMSO
control for each treated sample. Maximum (100%) p21 fold induction
was defined by the maximum of a fitted curve of a reference
compound. The p21 fold induction at each inhibitor dose tested was
converted to a value representing percentage of maximum.
Dose-response curves were generated using XLFit software (ID
Business Solutions, Alameda, Calif.) to calculate IC.sub.50 transit
values for each inhibitor tested.
* * * * *