U.S. patent application number 12/447342 was filed with the patent office on 2010-04-22 for hcv ns3 protease inhibitors.
Invention is credited to John W. Butcher, Maria Emilia Di Francesco, Marco Ferrara, Kevin F. Gilbert, Steven Harper, M. Katharine Holloway, Nigel J. Liverton, John A. McCauley, Charles A. McIntyre, Alessia Petrocchi, Marco Pompei, Joseph J. Romano, Michael T. Rudd, Vincenzo Summa.
Application Number | 20100099695 12/447342 |
Document ID | / |
Family ID | 39225095 |
Filed Date | 2010-04-22 |
United States Patent
Application |
20100099695 |
Kind Code |
A1 |
Liverton; Nigel J. ; et
al. |
April 22, 2010 |
HCV NS3 Protease Inhibitors
Abstract
The present invention relates to macrocyclic compounds of
formula (I) that are useful as inhibitors of the hepatitis C virus
(HCV) NS3 protease, their synthesis, and their use for treating or
preventing HCV infections. ##STR00001##
Inventors: |
Liverton; Nigel J.;
(Harleysville, PA) ; Summa; Vincenzo; (Rome,
IT) ; Di Francesco; Maria Emilia; (Rome, IT) ;
Ferrara; Marco; (Rome, IT) ; Gilbert; Kevin F.;
(Barto, PA) ; Harper; Steven; (Rome, IT) ;
McCauley; John A.; (Maple Glen, PA) ; McIntyre;
Charles A.; (Lansdale, PA) ; Petrocchi; Alessia;
(Rome, IT) ; Pompei; Marco; (Rome, IT) ;
Romano; Joseph J.; (Rome, IT) ; Rudd; Michael T.;
(Collegeville, PA) ; Butcher; John W.; (Telford,
PA) ; Holloway; M. Katharine; (Lansdale, PA) |
Correspondence
Address: |
MERCK AND CO., INC
P O BOX 2000
RAHWAY
NJ
07065-0907
US
|
Family ID: |
39225095 |
Appl. No.: |
12/447342 |
Filed: |
October 23, 2007 |
PCT Filed: |
October 23, 2007 |
PCT NO: |
PCT/US07/22460 |
371 Date: |
April 27, 2009 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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60854912 |
Oct 27, 2006 |
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60997434 |
Oct 3, 2007 |
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Current U.S.
Class: |
514/281 ;
514/286; 514/293; 514/411; 540/456 |
Current CPC
Class: |
A61P 31/14 20180101;
C07D 498/22 20130101; A61P 31/12 20180101; A61K 31/439 20130101;
C07K 5/0812 20130101; A61P 43/00 20180101; C07D 498/08 20130101;
C07D 498/18 20130101; A61K 31/437 20130101; A61K 38/00 20130101;
C07K 5/0804 20130101; A61K 45/06 20130101; A61K 31/407 20130101;
A61K 31/4192 20130101; C07K 5/0808 20130101; C07K 5/0806
20130101 |
Class at
Publication: |
514/281 ;
540/456; 514/293; 514/411; 514/286 |
International
Class: |
A61K 31/439 20060101
A61K031/439; C07D 513/18 20060101 C07D513/18; C07D 513/08 20060101
C07D513/08; A61K 31/407 20060101 A61K031/407; A61K 31/4748 20060101
A61K031/4748; A61P 31/12 20060101 A61P031/12 |
Claims
1. A compound of formula (I): ##STR00350## or a pharmaceutically
acceptable salt, hydrate or prodrug thereof, wherein: ##STR00351##
is one or more rings selected from the group consisting of: 1) aryl
rings, 2) C.sub.3-C.sub.8 cycloalkyl rings, and 3) heterocyclic
rings in which the heterocyclic ring system attaches to Z and X at
points that are two independently selected ring atoms that are
either two carbon ring atoms or one carbon ring atom and one
nitrogen ring atom, and the heterocyclic ring system is selected
from the group consisting of: a) 5- or 6-membered saturated or
unsaturated monocyclic rings with 1, 2, or 3 heteroatom ring atoms
independently selected from the group consisting of N, O or S, b)
8-, 9- or 10-membered saturated or unsaturated bicyclic rings with
1, 2, or 3 heteroatom ring atoms independently selected from the
group consisting of N, O or S, and c) 11- to 15-membered saturated
or unsaturated tricyclic rings with 1, 2, 3, or 4 heteroatom ring
atoms independently selected from the group consisting of N, O or
S, wherein ##STR00352## is substituted with 0 to 4 independently
selected substituents W, R.sup.5 or oxo; wherein for stable
heterocyclic rings containing S or N, the heterocyclic ring is
unsubstituted at the S or N atom or is substituted at the S or N
atom by oxo; wherein said W and R.sup.5 substitutions are located
on one or more ring atoms selected from C and N; and provided that
the 10-membered unsaturated bicyclic ring is not quinoline,
quinazoline or isoquinoline with the following modes of attachment
##STR00353## R.sup.1 is selected from the group consisting of
--CO.sub.2R.sup.10, --CONR.sup.10SO.sub.2R.sup.6,
--CONR.sup.10SO.sub.2NR.sup.8R.sup.9, tetrazolyl,
--CONHP(O)R.sup.11R.sup.12, and --P(O)R.sup.11R.sup.12; R.sup.2 is
selected from the group consisting of C.sub.1-C.sub.6 alkyl,
C.sub.2-C.sub.6 alkenyl, and C.sub.3-C.sub.8 cycloalkyl, wherein
said R.sup.2 are substituted with 0 to 3 independently selected
halogen atoms; R.sup.3 is selected from the group consisting of H,
C.sub.1-C.sub.8 alkyl, C.sub.3-C.sub.8 cycloalkyl, C.sub.3-C.sub.8
cycloalkyl(C.sub.1-C.sub.8)alkyl, phenyl(C.sub.1-C.sub.8)alkyl,
naphthyl(C.sub.1-C.sub.8)alkyl, and Het groups, wherein when
R.sup.3 is not H, said R.sup.3 is substituted with 0 to 3
substituents independently selected from the group consisting of
halogen atoms, --OR.sup.10, --SR.sup.10, --N(R.sup.10).sub.2,
--N(C.sub.1-C.sub.6 alkyl)O(C.sub.1-C.sub.6 alkyl), C.sub.1-C.sub.6
alkyl, C.sub.1-C.sub.6 haloalkyl, halo(C.sub.1-C.sub.6 alkoxy),
--NO.sub.2, --CN, --CF.sub.3, --SO.sub.2(C.sub.1-C.sub.6 alkyl),
--S(O)(C.sub.1-C.sub.6 alkyl), --NR.sup.10SO.sub.2R.sup.6,
SO.sub.2N(R.sup.6).sub.2, --NHCOOR.sup.6, --NHCOR.sup.6,
--NHCONHR.sup.6, --CO.sub.2R.sup.10, --C(O)R.sup.10, and
--CON(R.sup.10).sub.2; Het is selected from the group consisting of
substituted and unsubstituted 5- and 6-membered saturated
heterocyclic rings having 1 or 2 heteroatoms independently selected
from N, O and S, wherein said substituted rings are substituted
with 1 to 3 substituents independently selected from halogen atoms,
--OR.sup.10, --SR.sup.10, --N(R.sup.10).sub.2, --N(C.sub.1-C.sub.6
alkyl)O(C.sub.1-C.sub.6 alkyl), C.sub.1-C.sub.6 alkyl,
C.sub.1-C.sub.6 haloalkyl, halo(C.sub.1-C.sub.6 alkoxy),
--NO.sub.2, --CN, --CF.sub.3, --SO.sub.2(C.sub.1-C.sub.6 alkyl),
--S(O)(C.sub.1-C.sub.6 alkyl), --NR.sup.10SO.sub.2R.sup.6,
--SO.sub.2N(R.sup.6).sub.2, --NHCOOR.sup.6, --NHCOR.sup.6,
--NHCONHR.sup.6, --CO.sub.2R.sup.10, --C(O)R.sup.10, and
--CON(R.sup.10).sub.2; R.sup.5 is selected from the group
consisting of H, halogen atoms, --OH, C.sub.1-C.sub.6 alkoxy,
C.sub.1-C.sub.6 alkyl, --CN, --CF.sub.3, --OCF.sub.3, --C(O)OH,
--C(O)CH.sub.3, --SR.sup.10, --SO.sub.2(C.sub.1-C.sub.6 alkyl),
C.sub.3-C.sub.8 cycloalkyl, C.sub.3-C.sub.8 cycloalkoxy,
C.sub.1-C.sub.6 haloalkyl, --N(R.sup.7).sub.2, phenyl, naphthyl,
--O-phenyl, --O-naphthyl, heteroaryl and heterocyclyl groups;
wherein: said R.sup.5 heteroaryl is selected from the group
consisting of 5- and 6-membered aromatic rings having 1, 2 or 3
heteroatoms independently selected from N, O and S, and said
R.sup.5 heteroaryl is attached through a ring atom selected from C
or N, said R.sup.5 heterocyclyl is selected from the group
consisting of 5- to 7-membered saturated or unsaturated
non-aromatic rings having 1, 2, 3 or 4 heteroatoms independently
selected from N, O and S, and said R.sup.5 heterocyclyl is attached
through a ring atom selected from C or N, and said R.sup.5
heteroaryl, heterocyclyl, cycloalkyl, cycloalkoxy, alkyl and alkoxy
groups are substituted with 0 to 4 substituents independently
selected from the group consisting of halogen atoms, --OR.sup.10,
--SR.sup.10, --N(R.sup.10).sub.2, --N(C.sub.1-C.sub.6
alkyl)O(C.sub.1-C.sub.6 alkyl), C.sub.1-C.sub.6 alkyl,
C.sub.1-C.sub.6 haloalkyl, halo(C.sub.1-C.sub.6 alkoxy),
--NO.sub.2, --CN, --CF.sub.3, --SO.sub.2(C.sub.1-C.sub.6 alkyl),
--S(O)(C.sub.1-C.sub.6 alkyl), --NR.sup.10SO.sub.2R.sup.6,
SO.sub.2N(R.sup.6).sub.2, --NHCOOR.sup.6, --NHCOR.sup.6,
--NHCONHR.sup.6, --CO.sub.2R.sup.10, --C(O)R.sup.10, and
--CON(R.sup.10).sub.2, and 2 adjacent substituents of said R.sup.5
heteroaryl, heterocyclyl, cycloalkyl, cycloalkoxy, alkyl and alkoxy
groups may be taken together to form a 3-6-membered cyclic ring
containing 0 to 3 heteroatoms independently selected from N, O and
S; R.sup.6 is selected from the group consisting of C.sub.1-C.sub.6
alkyl, C.sub.3-C.sub.6 cycloalkyl, C.sub.3-C.sub.6
cycloalkyl(C.sub.1-C.sub.5)alkyl, phenyl, naphthyl,
phenyl(C.sub.1-C.sub.4)alkyl, naphthyl(C.sub.1-C.sub.4)alkyl,
heteroaryl, heteroaryl(C.sub.1-C.sub.4 alkyl), heterocyclyl, and
heterocyclyl(C.sub.1-C.sub.8 alkyl) groups, wherein said R.sup.6
are substituted with 0 to 2 independently selected W substituents,
each R.sup.6 heteroaryl is independently selected from the group
consisting of 5- and 6-membered aromatic rings having 1, 2 or 3
heteroatoms independently selected from N, O and S, and said
R.sup.6 heteroaryl is attached through a ring atom selected from C
or N, and each R.sup.6 heterocyclyl is independently selected from
the group consisting of 5- to 7-membered saturated or unsaturated
non-aromatic rings having 1, 2, 3 or 4 heteroatoms independently
selected from N, O and S, and said R.sup.6 heterocyclyl is attached
through a ring atom selected from C or N; Y is selected from the
group consisting of --C(O)--, --SO.sub.2--, --OC(O)--, --C(O)N(D)L-
and -LN(D)C(O)--. and -LN(D)C(O)--, where D is selected from the
group consisting of H, C.sub.1-C.sub.6 alkyl and C.sub.1-C.sub.6
alkenyl groups, L is selected from the group consisting of a direct
bond, -G-(C.sub.1-C.sub.6 alkylene)-, --(C.sub.1-C.sub.6
alkylene)-G-, -G-(C.sub.1-C.sub.6 alkenylene)-, and
--(C.sub.1-C.sub.6 alkenylene)-G-, groups, where said G is selected
from the group consisting of a direct bond, --O--, --N-- and --S--,
said alkylene and alkenylene groups are substituted with 0 to 4
substituents E independently selected from the group consisting of
C.sub.1-C.sub.6 alkyl and C.sub.1-C.sub.6 alkenyl groups, and said
D and E may be taken together to form a 3- to 6-membered ring
containing 0 to 3 heteroatoms selected from N, O and S; Z is
selected from the group consisting of --C(O)-- and a direct bond; M
is selected from the group consisting of C.sub.1-C.sub.12 alkylenes
and C.sub.2-C.sub.12 alkenylenes, wherein said M is substituted
with 0 to 2 substituents F independently selected from the group
consisting of C.sub.1-C.sub.8 alkyl, .dbd.CH.sub.2, C.sub.3-C.sub.8
cycloalkyl(C.sub.1-C.sub.8 alkyl), and aryl(C.sub.1-C.sub.8 alkyl),
and 2 adjacent substituents F may be taken together to form a 3- to
6-membered ring containing 0 to 3 heteroatoms selected from the
group consisting of N, O and S, and one or more adjacent
substituents F may be taken together and/or with an adjacent D or E
to form a 3- to 6-membered ring containing 0 to 3 heteroatoms
independently selected from the group consisting of N, O and S; X
is selected from the group consisting of --O--, --CH.sub.2O--,
--NHC(O)O--, --CH.sub.2NHC(O)O--, --C.ident.CH.sub.2O--, --C(O)O--,
--(CH.sub.2).sub.3O--, --OC(O)NH--, --(CH.sub.2).sub.2C(O)NH--,
--C(O)NH-- and a direct bond; each R.sup.7 is independently
selected from the group consisting of H, C.sub.1-C.sub.6 alkyl,
C.sub.3-C.sub.6 cycloalkyl, C.sub.3-C.sub.6
cycloalkyl(C.sub.1-C.sub.5)alkyl, phenyl, naphthyl,
phenyl(C.sub.1-C.sub.4)alkyl, naphthyl(C.sub.1-C.sub.4)alkyl,
heteroaryl, heteroaryl(C.sub.1-C.sub.4 alkyl), heterocyclyl, and
heterocyclyl(C.sub.1-C.sub.8 alkyl) groups, wherein when R.sup.7 is
not H, said R.sup.7 are substituted with 0 to 2 W substituents,
each R.sup.7 heteroaryl is independently selected from the group
consisting of 5- and 6-membered aromatic rings having 1, 2 or 3
heteroatoms independently selected from N, O and S, and said
R.sup.7 heteroaryl is attached through a ring atom selected from C
or N, and each R.sup.7 heterocyclyl is independently selected from
the group consisting of 5- to 7-membered saturated or unsaturated
non-aromatic rings having 1, 2, 3 or 4 heteroatoms independently
selected from N, O and S, and said R.sup.7 heterocyclyl is attached
through a ring atom selected from C or N, and said R.sup.7 may be
taken together with the atom to which it is attached and a second
R.sup.7 substituent to form a 4- to 7-membered heterocyclic ring;
each W is independently selected from the group consisting of
halogen atoms, --OR.sup.10, C.sub.1-C.sub.6 alkyl, --CN,
--CF.sub.3, --NO.sub.2, --SR.sup.10, --CO.sub.2R.sup.10,
--CON(R.sup.10).sub.2, --C(O)R.sup.10, --N(R.sup.10)C(O)R.sup.10,
--SO.sub.2(C.sub.1-C.sub.6 alkyl), --S(O)(C.sub.1-C.sub.6 alkyl),
C.sub.3-C.sub.8 cycloalkyl, C.sub.3-C.sub.8 cycloalkoxy,
C.sub.1-C.sub.6 haloalkyl, --N(R.sup.10).sub.2, --N(C.sub.1-C.sub.6
alkyl)O(C.sub.1-C.sub.6 alkyl), halo(C.sub.1-C.sub.6 alkoxy),
--NR.sup.10SO.sub.2R.sup.10, --SO.sub.2N(R.sup.10).sub.2,
--NHCOOR.sup.10, --NHCONHR.sup.10, phenyl, naphthyl, heteroaryl and
heterocyclyl groups; wherein said W heteroaryl is selected from the
group consisting of 5- and 6-membered aromatic rings having 1, 2 or
3 heteroatoms independently selected from N, O and S, and said W
heteroaryl is attached through a ring atom selected from C or N,
said W heterocyclyl is selected from the group consisting of 5- to
7-membered saturated or unsaturated non-aromatic rings having 1, 2,
3 or 4 heteroatoms independently selected from N, O and S, and said
W heterocyclyl is attached through a ring atom selected from C or
N; R.sup.8 is selected from the group consisting of C.sub.1-C.sub.8
alkyl, C.sub.3-C.sub.8 cycloalkyl, C.sub.3-C.sub.8
cycloalkyl(C.sub.1-C.sub.8 alkyl), phenyl, naphthyl,
phenyl(C.sub.1-C.sub.4)alkyl, naphthyl(C.sub.1-C.sub.4)alkyl,
heteroaryl, heterocyclic, heteroaryl(C.sub.1-C.sub.4 alkyl), and
heterocyclyl(C.sub.1-C.sub.8 alkyl) groups, wherein said R.sup.8
are substituted with 0 to 4 substituents selected from the group
consisting of phenyl, naphthyl, C.sub.3-C.sub.8 cycloalkyl,
heteroaryl, heterocyclyl, C.sub.1-C.sub.6 alkyl,
halo(C.sub.1-C.sub.6 alkoxy), halogen atoms, --OR.sup.10,
--SR.sup.10, --N(R.sup.10).sub.2, --N(C.sub.1-C.sub.6
alkyl)O(C.sub.1-C.sub.6 alkyl), C.sub.1-C.sub.6 alkyl,
--C(O)R.sup.10, C.sub.1-C.sub.6 haloalkyl, --NO.sub.2, --CN,
--CF.sub.3, --SO.sub.2(C.sub.1-C.sub.6 alkyl),
--S(O)(C.sub.1-C.sub.6 alkyl), --NR.sup.10SO.sub.2R.sup.6,
--SO.sub.2N(R.sup.6).sub.2, --NHCOOR.sup.6, --NHCOR.sup.6,
--NHCONHR.sup.6, --CO.sub.2R.sup.10, and --C(O)N(R.sup.10).sub.2,
each R.sup.8 heteroaryl is independently selected from the group
consisting of 5- and 6-membered aromatic rings having 1, 2 or 3
heteroatoms independently selected from N, O and S, and said
R.sup.8 heteroaryl is attached through a ring atom selected from C
or N, each R.sup.8 heterocyclyl is independently selected from the
group consisting of 5- to 7-membered saturated or unsaturated
non-aromatic rings having 1, 2, 3 or 4 heteroatoms independently
selected from N, O and S, and said R.sup.8 heterocyclyl is attached
through a ring atom selected from C or N, and 2 adjacent
substituents of said R.sup.8 may be taken together to form a 3- to
6-membered ring containing 0 to 3 heteroatoms independently
selected from the group consisting of N, O and S; R.sup.9 is
selected from the group consisting of C.sub.1-C.sub.8 alkyl,
C.sub.3-C.sub.8 cycloalkyl, C.sub.3-C.sub.8
cycloalkyl(C.sub.1-C.sub.8 alkyl), C.sub.1-C.sub.8 alkoxy,
C.sub.3-C.sub.8 cycloalkoxy, phenyl, naphthyl,
phenyl(C.sub.1-C.sub.4)alkyl, naphthyl(C.sub.1-C.sub.4)alkyl,
heteroaryl, heterocyclyl, heteroaryl(C.sub.1-C.sub.4 alkyl), or
heterocyclyl(C.sub.1-C.sub.8 alkyl) groups, wherein said R.sup.9
are substituted with 0 to 4 substituents selected from the group
consisting of phenyl, naphthyl, C.sub.3-C.sub.8 cycloalkyl,
heteroaryl, heterocyclyl, C.sub.1-C.sub.6 alkyl,
halo(C.sub.1-C.sub.6 alkoxy), halogen atoms, --OR.sup.10,
--SR.sup.10, --N(R.sup.10).sub.2, --N(C.sub.1-C.sub.6
alkyl)O(C.sub.1-C.sub.6 alkyl), C.sub.1-C.sub.6 alkyl,
--C(O)R.sup.10, C.sub.1-C.sub.6 haloalkyl, --NO.sub.2, --CN,
--CF.sub.3, --SO.sub.2(C.sub.1-C.sub.6 alkyl),
--S(O)(C.sub.1-C.sub.6 alkyl), --NR.sup.10SO.sub.2R.sup.6,
--SO.sub.2N(R.sup.6).sub.2, --NHCOOR.sup.6, --NHCOR.sup.6,
--NHCONHR.sup.6, --CO.sub.2R.sup.10, and --C(O)N(R.sup.10).sub.2,
each R.sup.9 heteroaryl is independently selected from the group
consisting of 5- and 6-membered aromatic rings having 1, 2 or 3
heteroatoms independently selected from N, O and S, and said
R.sup.9 heteroaryl is attached through a ring atom selected from C
or N, each R.sup.9 heterocyclyl is independently selected from the
group consisting of 5- to 7-membered saturated or unsaturated
non-aromatic rings having 1, 2, 3 or 4 heteroatoms independently
selected from N, O and S, and said R.sup.9 heterocyclyl is attached
through a ring atom selected from C or N, and 2 adjacent
substituents of said R.sup.9 may be taken together to form a 3- to
6-membered ring containing 0 to 3 heteroatoms independently
selected from the group consisting of N, O and S, and R.sup.8 and
R.sup.9 may be taken together, with the N to which they are
attached, to form a 4- to 8-membered monocyclic ring containing 0
to 2 additional heteroatoms independently selected from N, O and S;
each R.sup.10 is independently selected from the group consisting
of H and C.sub.1-C.sub.6 alkyl; each R.sup.11 is independently
selected from the group consisting of C.sub.1-C.sub.6 alkyl,
C.sub.1-C.sub.4 alkenyl, --OR.sup.13,
--N(R.sup.10)--V--CO.sub.2R.sup.10, --O--V--CO.sub.2R.sup.10,
--S--V--CO.sub.2R.sup.10, --N(R.sup.10)(R.sup.13), --R.sup.14, and
--N(R.sup.10SO.sub.2R.sup.6; each R.sup.12 is independently
selected from the group consisting of --OR.sup.13,
--N(R.sup.10)--V--CO.sub.2R.sup.10, --O--V--CO.sub.2R.sup.10,
--S--V--CO.sub.2R.sup.10, and --N(R.sup.10)(R.sup.13); R.sup.11 and
R.sup.12 may be taken together, with the phosphorus atom to which
they are attached, to form a 5- to 7-membered monocyclic ring;
each V is independently selected from the group consisting of
--CH(R.sup.15)-- and --(C.sub.1-C.sub.4 alkylene)-CH(R.sup.15)--;
each R.sup.13 is independently selected from the group consisting
of H, C.sub.1-C.sub.6 alkyl, C.sub.2-C.sub.6 alkenyl,
C.sub.3-C.sub.8 cycloalkyl, aryl, heteroaryl, and heterocyclyl
groups, wherein when R.sup.13 is not H, said R.sup.13 is
substituted with 0 to 2 substituents independently selected from
the group consisting of phenyl, naphthyl, phenyl(C.sub.1-C.sub.4
alkyl), naphthyl(C.sub.1-C.sub.4 alkyl), C.sub.3-C.sub.8
cycloalkyl, C.sub.3-C.sub.8 cycloalkyl(C.sub.1-C.sub.4 alkyl),
heteroaryl, heteroaryl(C.sub.1-C.sub.4 alkyl), heterocyclyl,
heterocyclyl(C.sub.1-C.sub.4 alkyl), C.sub.1-C.sub.6 alkyl, halogen
atoms, --OC(O)OR.sup.6, --OC(O)R.sup.6, --OR.sup.10, --SR.sup.10,
--N(R.sup.10).sub.2, --C(O)R.sup.10, --NO.sub.2, --CN, --CF.sub.3,
--SO.sub.2(C.sub.1-C.sub.6 alkyl), --S(O)(C.sub.1-C.sub.6 alkyl),
--NR.sup.10SO.sub.2R.sup.6, --SO.sub.2N(R.sup.6).sub.2,
--NHCOOR.sup.6, --NHCOR.sup.6, --NHCONHR.sup.6, --CO.sub.2R.sup.10,
and --C(O)N(R.sup.10).sub.2, each R.sup.13 heteroaryl is
independently selected from the group consisting of 5- and
6-membered aromatic rings having 1, 2 or 3 heteroatoms
independently selected from N, O and S, and said R.sup.13
heteroaryl is attached through a ring atom selected from C or N,
each R.sup.13 heterocyclyl is independently selected from the group
consisting of 5- to 7-membered saturated or unsaturated
non-aromatic rings having 1, 2, 3 or 4 heteroatoms independently
selected from N, O and S, and said R.sup.13 heterocyclyl is
attached through a ring atom selected from C or N, and 2 adjacent
substituents of said R.sup.13 may be taken together to form a 3- to
6-membered ring containing 0 to 3 heteroatoms independently
selected from the group consisting of N, O and S; R.sup.14 is
selected from the group consisting of C.sub.1-C.sub.6 alkyl,
C.sub.2-C.sub.6 alkenyl, phenyl, naphthyl and heteroaryl, wherein
each R.sup.14 heteroaryl is independently selected from the group
consisting of 5- and 6-membered aromatic rings having 1, 2 or 3
heteroatoms independently selected from N, O and S, and said
R.sup.14 heteroaryl is attached through a ring atom selected from C
or N, and said R.sup.14 phenyl, naphthyl or heteroaryl may be
substituted with 0 to 2 substituents independently selected from
the group consisting of C.sub.1-C.sub.6 alkyl, halogen atoms,
--OC(O)OR.sup.6, --OC(O)R.sup.6, --OR.sup.10, --SR.sup.10,
--N(R.sup.10).sub.2, --C(O)R.sup.10, --NO.sub.2, --CN, --CF.sub.3,
--SO.sub.2(C.sub.1-C.sub.6 alkyl), --S(O)(C.sub.1-C.sub.6 lkyl),
--NR.sup.10SO.sub.2R.sup.6, --SO.sub.2N(R.sup.6).sub.2,
--NHCOOR.sup.6, --NHCOR.sup.6, --NHCONHR.sup.6, --CO.sub.2R.sup.10,
and --C(O)N(R.sup.10).sub.2; and each R.sup.15 is independently
selected from the group consisting of C.sub.1-C.sub.6 alkyl,
C.sub.2-C.sub.6 alkenyl, C.sub.3-C.sub.8 cycloalkyl, phenyl,
naphthyl, heteroaryl, and heterocyclyl groups, wherein said
R.sup.15 are substituted with 0 to 2 substituents independently
selected from the group consisting of C.sub.1-C.sub.6 alkyl,
halogen atoms, --OC(O)OR.sup.6, --OC(O)R.sup.6, --OR.sup.10,
--SR.sup.10, --N(R.sup.10).sub.2, --C(O)R.sup.10, --NO.sub.2, --CN,
--CF.sub.3, --SO.sub.2(C.sub.1-C.sub.6 alkyl),
--S(O)(C.sub.1-C.sub.6 alkyl), --NR.sup.10SO.sub.2R.sup.6,
--SO.sub.2N(R.sup.6).sub.2, --NHCOOR.sup.6, --NHCOR.sup.6,
--NHCONHR.sup.6, --CO.sub.2R.sup.10, and --C(O)N(R.sup.10).sub.2,
each R.sup.15 heteroaryl is independently selected from the group
consisting of 5- and 6-membered aromatic rings having 1, 2 or 3
heteroatoms independently selected from N, O and S, and said
R.sup.15 heteroaryl is attached through a ring atom selected from C
or N, each R.sup.15 heterocyclyl is independently selected from the
group consisting of 5- to 7-membered saturated or unsaturated
non-aromatic rings having 1, 2, 3 or 4 heteroatoms independently
selected from N, O and S, and said R.sup.15 heterocyclyl is
attached through a ring atom selected from C or N, and 2 adjacent
substituents of said R.sup.15 are optionally taken together to form
a 3- to 6-membered ring containing 0 to 3 heteroatoms independently
selected from the group consisting of N, O and S.
2. The compound according to claim 1, wherein ##STR00354## is
selected from the group consisting of: 1) aryl rings, 2) cyclohexyl
rings, and 3) heterocyclic rings in which the heterocyclic ring
system attaches to Z and X at points that are two independently
selected ring atoms that are either two acarbon ring atoms or one
carbon ring atom and one nitrogen ring atom, and the heterocyclic
ring system is selected from the group consisting of: a) 5- or
6-membered saturated or unsaturated monocyclic rings containing 1,
2, or 3 nitrogen atoms, and b) 8-, 9- or 10-membered saturated or
unsaturated bicyclic rings containing 1 or 2 nitrogen atoms,
wherein said ##STR00355## is substituted with 0 to 4 independently
selected substituents W, R.sup.5 or oxo; wherein for stable
heterocyclic rings containing S or N, the heterocyclic ring is
unsubstituted at the S or N atom or is substituted at the S or N
atom by oxo; wherein said W and R.sup.5 substitutions are located
on one or more ring atoms selected from C and N; and provided that
the 10-membered unsaturated bicyclic ring is not quinoline,
quinazoline or isoquinoline.
3. The compound according to claim 2, wherein ##STR00356## is
unsubstituted or mono-substituted with a moiety selected from the
group consisting of --Br, --Cl, --CN, phenyl, --O-phenyl,
--OCF.sub.3, --OCH.sub.3, --C(O)OH, --CH.sub.3 and
--C(O)CH.sub.3.
4. The compound according to claim 1, wherein ##STR00357## is
selected from the group consisting of the group of rings consisting
of: ##STR00358## ##STR00359## ##STR00360##
5. The compound according to claim 4, wherein each R.sup.5 is
independently selected from the group consisting of H, --Br, --Cl,
--CN, phenyl, --O-phenyl, --OCF.sub.3, --OCH.sub.3, --OH,
C.sub.1-C.sub.6 alkoxy, C.sub.1-C.sub.6 alkyl, --CF.sub.3,
--C(O)OH, and --C(O)CH.sub.3.
6. The compound according to claim 1, wherein R.sup.1 is selected
from the group consisting of --CO.sub.2R.sup.10 and
--CONR.sup.10SO.sub.2R.sup.6.
7. The compound according to claim 6, wherein R.sup.1 is selected
from the group consisting of --C(O)OH and
--C(O)NHSO.sub.2cyclopropyl.
8. The compound according to claim 1, wherein R.sup.2 is selected
from the group consisting of C.sub.1-C.sub.6 alkyl and
C.sub.2-C.sub.6 alkenyl.
9. The compound according to claim 8, wherein R.sup.2 is selected
from the group consisting of --CH.dbd.CH.sub.2, --CH.sub.2CH.sub.3,
and --CH.sub.2CH.dbd.CH.sub.2.
10. The compound according to claim 1, wherein R.sup.3 is selected
from the group consisting of H, C.sub.1-C.sub.8 alkyl and
C.sub.3-C.sub.8 cycloalkyl.
11. The compound according to claim 10, wherein R.sup.3 is selected
from the group consisting of H, --C(CH.sub.3).sub.3,
--(CH.sub.2).sub.3CH.sub.3, cyclohexyl, and
--CH(CH.sub.3).sub.2.
12. The compound according to claim 1, wherein M is selected from
the group consisting of C.sub.1-C.sub.12 alkylene or
C.sub.2-C.sub.12 alkenylene, wherein M is substituted with 0 to 2
substituents F selected from the group consisting of
C.sub.1-C.sub.8 alkyl, and .dbd.CH.sub.2.
13. The compound according to claim 12, wherein M is selected from
the group consisting of --CH.dbd.CH(CH.sub.2).sub.5,
--(CH.sub.2).sub.7--, --CH.sub.2CH.dbd.CH(CH.sub.2).sub.4--,
--(CH.sub.2).sub.6--, --CH.dbd.CH(CH.sub.2).sub.4--,
--CH.dbd.CH(CH.sub.2).sub.3C(CH.sub.3).sub.2CH.sub.2--,
--CH.dbd.CH(CH.sub.2).sub.3--, --(CH.sub.2).sub.5--,
--CH.dbd.CH(CH.sub.2).sub.3--, --(CH.sub.2).sub.4--,
--(CH.sub.2).sub.3--,
--CH.dbd.H(CH.sub.2).sub.2C(CH.sub.3).sub.2CH.sub.2--,
--(CH.sub.2).sub.4C(CH.sub.3).sub.2CH.sub.2--,
--C(.dbd.CH.sub.2)(CH.sub.2).sub.5--,
--C(.dbd.CH.sub.2)(CH.sub.2).sub.3--, and
--CH.sub.2CH.dbd.CH(CH.sub.2).sub.3--.
14. The compound according to claim 13, wherein M is selected from
the group consisting of ##STR00361##
15. The compound according to claim 1, wherein Y is --C(O)N(D)L-
and -LN(D)C(O)--.
16. The compound according to claim 1, wherein one or more
substituents F are taken together and/or with one or more
substituents chosen from substituents D and E to form a 3- to
6-membered ring containing 0 to 3 heteroatoms selected from the
group consisting of N, O and S.
17. A compound selected from the group consisting of: ##STR00362##
##STR00363## ##STR00364## ##STR00365## ##STR00366## ##STR00367##
##STR00368## ##STR00369## ##STR00370## ##STR00371## ##STR00372##
##STR00373## ##STR00374## ##STR00375## ##STR00376## ##STR00377##
##STR00378## ##STR00379## ##STR00380## ##STR00381## ##STR00382##
##STR00383## ##STR00384## ##STR00385## ##STR00386## ##STR00387##
##STR00388## ##STR00389## ##STR00390## ##STR00391## ##STR00392##
##STR00393## ##STR00394## ##STR00395## ##STR00396##
18. A pharmaceutical composition comprising an effective amount of
the compound according to claim 1, and a pharmaceutically
acceptable carrier.
19. The pharmaceutical composition according to claim 16, further
comprising a second therapeutic agent selected from the group
consisting of HCV antiviral agents, immunomodulators, and
anti-infective agents.
20. The pharmaceutical composition according to claim 16, further
comprising a second therapeutic agent selected from the group
consisting of HCV protease inhibitors and HCV NS5B polymerase
inhibitors.
21. A method of preparing a medicament for inhibiting HCV NS3
protease activity in a subject in need thereof, said method
comprising providing a compound of formula (I): ##STR00397## or a
pharmaceutically acceptable salt, hydrate or prodrug thereof,
wherein: ##STR00398## is one or more rings selected from the group
consisting of: 1) aryl rings, 2) C.sub.3-C.sub.8 cycloalkyl rings,
and 3) heterocyclic rings in which the heterocyclic ring system
attaches to Z and X at points that are two independently selected
ring atoms that are either two acarbon carbon ring atoms or one
carbon ring atom and one nitrogen ring atom, and the heterocyclic
ring system is selected from the group consisting of: a) 5- or
6-membered saturated or unsaturated monocyclic rings with 1, 2, or
3 heteroatom ring atoms independently selected from the group
consisting of N, O or S, b) 8-, 9- or 10-membered saturated or
unsaturated bicyclic rings with 1, 2, or 3 heteroatom ring atoms
independently selected from the group consisting of N, O or S, and
c) 11- to 15-membered saturated or unsaturated tricyclic rings with
1, 2, 3, or 4 heteroatom ring atoms independently selected from the
group consisting of N, O or S, wherein ##STR00399## is substituted
with 0 to 4 independently selected substituents W, R.sup.5 or oxo;
wherein for stable heterocyclic rings containing S or N, the
heterocyclic ring is unsubstituted at the S or N atom or is
substituted at the S or N atom by oxo; wherein said W and R.sup.5
substitutions are located on one or more ring atoms selected from C
and N; and provided that the 10-membered unsaturated bicyclic ring
is not quinoline, quinazoline or isoquinoline with the following
modes of attachment ##STR00400## R.sup.1 is selected from the group
consisting of --CO.sub.2R.sup.10, --CONR.sup.10SO.sub.2R.sup.6,
--CONR.sup.10SO.sub.2NR.sup.8R.sup.9, tetrazolyl,
--CONHP(O)R.sup.11R.sup.12, and --P(O)R.sup.11R.sup.12; R.sup.2 is
selected from the group consisting of C.sub.1-C.sub.6 alkyl,
C.sub.2-C.sub.6 alkenyl, and C.sub.3-C.sub.8 cycloalkyl, wherein
said R.sup.2 are substituted with 0 to 3 independently selected
halogen atoms; R.sup.3 is selected from the group consisting of H,
C.sub.1-C.sub.8 alkyl, C.sub.3-C.sub.8 cycloalkyl, C.sub.3-C.sub.8
cycloalkyl(C.sub.1-C.sub.8)alkyl, phenyl(C.sub.1-C.sub.8)alkyl,
naphthyl(C.sub.1-C.sub.8)alkyl, and Het groups, wherein when
R.sup.3 is not H, said R.sup.3 is substituted with 0 to 3
substituents independently selected from the group consisting of
halogen atoms, --OR.sup.10, --SR.sup.10, --N(R.sup.10).sub.2,
--N(C.sub.1-C.sub.6 alkyl)O(C.sub.1-C.sub.6 alkyl), C.sub.1-C.sub.6
alkyl, C.sub.1-C.sub.6 haloalkyl, halo(C.sub.1-C.sub.6 alkoxy),
--NO.sub.2, --CN, --CF.sub.3, --SO.sub.2(C.sub.1-C.sub.6 alkyl),
--S(O)(C.sub.1-C.sub.6 alkyl), --NR.sup.10SO.sub.2R.sup.6,
SO.sub.2N(R.sup.6).sub.2, --NHCOOR.sup.6, --NHCOR.sup.6,
--NHCONHR.sup.6, --CO.sub.2R.sup.10, --C(O)R.sup.10, and
--CON(R.sup.10).sub.2; Het is selected from the group consisting of
substituted and unsubstituted 5- and 6-membered saturated
heterocyclic rings having 1 or 2 heteroatoms independently selected
from N, O and S, wherein said substituted rings are substituted
with 1 to 3 substituents independently selected from halogen atoms,
--OR.sup.10, --SR.sup.10, --N(R.sup.10).sub.2, --N(C.sub.1-C.sub.6
alkyl)O(C.sub.1-C.sub.6 alkyl), C.sub.1-C.sub.6 alkyl,
C.sub.1-C.sub.6 haloalkyl, halo(C.sub.1-C.sub.6 alkoxy),
--NO.sub.2, --CN, --CF.sub.3, --SO.sub.2(C.sub.1-C.sub.6 alkyl),
--S(O)(C.sub.1-C.sub.6 alkyl), --NR.sup.10SO.sub.2R.sup.6,
SO.sub.2N(R.sup.6).sub.2, --SO.sub.2N(R.sup.6).sub.2,
--NHCOOR.sup.6, --NHCOR.sup.6, --NHCONHR.sup.6, --CO.sub.2R.sup.10,
--C(O)R.sup.10, and --CON(R.sup.10).sub.2; R.sup.5 is selected from
the group consisting of H, halogen atoms, --OH, C.sub.1-C.sub.6
alkoxy, C.sub.1-C.sub.6 alkyl, --CN, --CF.sub.3--OCF.sub.3,
--C(O)OH, --C(O)CH.sub.3, --SR.sup.10, --SO.sub.2(C.sub.1-C.sub.6
alkyl), C.sub.3-C.sub.8 cycloalkyl, C.sub.3-C.sub.8 cycloalkoxy,
C.sub.1-C.sub.6 haloalkyl, --N(R.sup.7).sub.2, phenyl, naphthyl,
--O-phenyl, --O-naphthyl, heteroaryl and heterocyclyl groups;
wherein: said R.sup.5 heteroaryl is selected from the group
consisting of 5- and 6-membered aromatic rings having 1, 2 or 3
heteroatoms independently selected from N, O and S, and said
R.sup.5 heteroaryl is attached through a ring atom selected from C
or N, said R.sup.5 heterocyclyl is selected from the group
consisting of 5- to 7-membered saturated or unsaturated
non-aromatic rings having 1, 2, 3 or 4 heteroatoms independently
selected from N, O and S, and said R.sup.5 heterocyclyl is attached
through a ring atom selected from C or N, and said R.sup.5
heteroaryl, heterocyclyl, cycloalkyl, cycloalkoxy, alkyl and alkoxy
groups are substituted with 0 to 4 substituents independently
selected from the group consisting of halogen atoms, --OR.sup.10,
--SR.sup.10, --N(R.sup.10).sub.2, --N(C.sub.1-C.sub.6
alkyl)O(C.sub.1-C.sub.6 alkyl), C.sub.1-C.sub.6 alkyl,
C.sub.1-C.sub.6 haloalkyl, halo(C.sub.1-C.sub.6 alkoxy),
--NO.sub.2, --CN, --CF.sub.3, --SO.sub.2(C.sub.1-C.sub.6 alkyl),
--S(O)(C.sub.1-C.sub.6 alkyl), --NR.sup.10SO.sub.2R.sup.6,
SO.sub.2N(R.sup.6).sub.2, --SO.sub.2N(R.sup.6).sub.2,
--NHCOOR.sup.6, --NHCOR.sup.6, --NHCONHR.sup.6, --CO.sub.2R.sup.10,
--C(O)R.sup.10, and --CON(R.sup.10).sub.2, and 2 adjacent
substituents of said R.sup.5 heteroaryl, heterocyclyl, cycloalkyl,
cycloalkoxy, alkyl and alkoxy groups may be taken together to form
a 3-6-membered cyclic ring containing 0 to 3 heteroatoms
independently selected from N, O and S; R.sup.6 is selected from
the group consisting of C.sub.1-C.sub.6 alkyl, C.sub.3-C.sub.6
cycloalkyl, C.sub.3-C.sub.6 cycloalkyl(C.sub.1-C.sub.5)alkyl,
phenyl, naphthyl, phenyl(C.sub.1-C.sub.4)alkyl,
naphthyl(C.sub.1-C.sub.4)alkyl, heteroaryl,
heteroaryl(C.sub.1-C.sub.4 alkyl), heterocyclyl, and
heterocyclyl(C.sub.1-C.sub.8 alkyl) groups, wherein said R.sup.6
are substituted with 0 to 2 independently selected W substituents,
each R.sup.6 heteroaryl is independently selected from the group
consisting of 5- and 6-membered aromatic rings having 1, 2 or 3
heteroatoms independently selected from N, O and S, and said
R.sup.6 heteroaryl is attached through a ring atom selected from C
or N, and each R.sup.6 heterocyclyl is independently selected from
the group consisting of 5- to 7-membered saturated or unsaturated
non-aromatic rings having 1, 2, 3 or 4 heteroatoms independently
selected from N, O and S, and said R.sup.6 heterocyclyl is attached
through a ring atom selected from C or N; Y is selected from the
group consisting of --C(O)--, --SO.sub.2--, --OC(O)--, --C(O)N(D)L-
and -LN(D)C(O)--. and -LN(D)C(O)--, where D is selected from the
group consisting of H, C.sub.1-C.sub.6 alkyl and C.sub.1-C.sub.6
alkenyl groups, L is selected from the group consisting of a direct
bond, -G-(C.sub.1-C.sub.6 alkylene)-, --(C.sub.1-C.sub.6
alkylene)-G-, -G-(C.sub.1-C.sub.6 alkenylene)-, and
--(C.sub.1-C.sub.6 alkenylene)-G-, groups, where said G is selected
from the group consisting of a direct bond, --O--, --N-- and --S--,
said alkylene and alkenylene groups are substituted with 0 to 4
substituents E independently selected from the group consisting of
C.sub.1-C.sub.6 alkyl and C.sub.1-C.sub.6 alkenyl groups, and said
D and E may be taken together to form a 3- to 6-membered ring
containing 0 to 3 heteroatoms selected from N, O and S; Z is
selected from the group consisting of --C(O)-- and a direct bond; M
is selected from the group consisting of C.sub.1-C.sub.12 alkylenes
and C.sub.2-C.sub.12 alkenylenes, wherein said M is substituted
with 0 to 2 substituents F independently selected from the group
consisting of C.sub.1-C.sub.8 alkyl, .dbd.CH.sub.2, C.sub.3-C.sub.8
cycloalkyl(C.sub.1-C.sub.8 alkyl), and aryl(C.sub.1-C.sub.8 alkyl),
and 2 adjacent substituents F may be taken together to form a 3- to
6-membered ring containing 0 to 3 heteroatoms selected from the
group consisting of N, O and S, and one or more adjacent
substituents F may be taken together and/or with an adjacent D or E
to form a 3- to 6-membered ring containing 0 to 3 heteroatoms
independently selected from the group consisting of N, O and S; X
is selected from the group consisting of --O--, --CH.sub.2O--,
--NHC(O)O--, --CH.sub.2NHC(O)O--, --C.ident.CH.sub.2O--, --C(O)O--,
--(CH.sub.2).sub.3O--, --OC(O)NH--, --(CH.sub.2).sub.2C(O)NH--,
--C(O)NH-- and a direct bond; each R.sup.7 is independently
selected from the group consisting of H, C.sub.1-C.sub.6 alkyl,
C.sub.1-C.sub.6 cycloalkyl, C.sub.3-C.sub.6
cycloalkyl(C.sub.1-C.sub.5)alkyl, phenyl, naphthyl,
phenyl(C.sub.1-C.sub.4)alkyl, naphthyl(C.sub.1-C.sub.4)alkyl,
heteroaryl, heteroaryl(C.sub.1-C.sub.4 alkyl), heterocyclyl, and
heterocyclyl(C.sub.1-C.sub.8 alkyl) groups, wherein when R.sup.7 is
not H, said R.sup.7 are substituted with 0 to 2 W substituents,
each R.sup.7 heteroaryl is independently selected from the group
consisting of 5- and 6-membered aromatic rings having 1, 2 or 3
heteroatoms independently selected from N, O and S, and said
R.sup.7 heteroaryl is attached through a ring atom selected from C
or N, and each R.sup.7 heterocyclyl is independently selected from
the group consisting of 5- to 7-membered saturated or unsaturated
non-aromatic rings having 1, 2, 3 or 4 heteroatoms independently
selected from N, O and S, and said R.sup.7 heterocyclyl is attached
through a ring atom selected from C or N, and said R.sup.7 may be
taken together with the atom to which it is attached and a second
R.sup.7 substituent to form a 4- to 7-membered heterocyclic ring;
each W is independently selected from the group consisting of
halogen atoms, --OR.sup.10, C.sub.1-C.sub.6 alkyl, --CN,
--CF.sub.3, --NO.sub.2, --SR.sup.10, --CO.sub.2R.sup.10,
--CON(R.sup.10).sub.2, --C(O)R.sup.10, --N(R.sup.10)C(O)R.sup.10,
--SO.sub.2(C.sub.1-C.sub.6 alkyl), --S(O)(C.sub.1-C.sub.6 alkyl),
C.sub.3-C.sub.8 cycloalkyl, C.sub.3-C.sub.8 cycloalkoxy,
C.sub.1-C.sub.6 haloalkyl, --N(R.sup.10).sub.2, --N(C.sub.1-C.sub.6
alkyl)O(C.sub.1-C.sub.6 alkyl), halo(C.sub.1-C.sub.6 alkoxy),
--NR.sup.10SO.sub.2R.sup.10, --SO.sub.2N(R.sup.10).sub.2,
--NHCOOR.sup.10, --NHCONHR.sup.10, phenyl, naphthyl, heteroaryl and
heterocyclyl groups; wherein said W heteroaryl is selected from the
group consisting of 5- and 6-membered aromatic rings having 1, 2 or
3 heteroatoms independently selected from N, O and S, and said W
heteroaryl is attached through a ring atom selected from C or N,
said W heterocyclyl is selected from the group consisting of 5- to
7-membered saturated or unsaturated non-aromatic rings having 1, 2,
3 or 4 heteroatoms independently selected from N, O and S, and said
W heterocyclyl is attached through a ring atom selected from C or
N; R.sup.8 is selected from the group consisting of C.sub.1-C.sub.8
alkyl, C.sub.3-C.sub.8 cycloalkyl, C.sub.3-C.sub.8
cycloalkyl(C.sub.1-C.sub.8 alkyl), phenyl, naphthyl,
phenyl(C.sub.1-C.sub.4)alkyl, naphthyl(C.sub.1-C.sub.4)alkyl,
heteroaryl, heterocyclic, heteroaryl(C.sub.1-C.sub.4 alkyl), and
heterocyclyl(C.sub.1-C.sub.8 alkyl) groups, wherein said R.sup.8
are substituted with 0 to 4 substituents selected from the group
consisting of phenyl, naphthyl, C.sub.3-C.sub.8 cycloalkyl,
heteroaryl, heterocyclyl, C.sub.1-C.sub.6 alkyl,
halo(C.sub.1-C.sub.6 alkoxy), halogen atoms, --OR.sup.10,
--SR.sup.10, --N(R.sup.10).sub.2, --N(C.sub.1-C.sub.6
alkyl)O(C.sub.1-C.sub.6 alkyl), C.sub.1-C.sub.6 alkyl,
--C(O)R.sup.10, C.sub.1-C.sub.6 haloalkyl, --NO.sub.2, --CN,
CF.sub.3, --SO.sub.2(C.sub.1-C.sub.6 alkyl), --S(O)(C.sub.1-C.sub.6
alkyl), --NR.sup.10SO.sub.2R.sup.6, --SO.sub.2N(R.sup.6).sub.2,
--NHCOOR.sup.6, --NHCOR.sup.6, --NHCONHR.sup.6, --CO.sub.2R.sup.10,
and --C(O)N(R.sup.10).sub.2, each R.sup.8 heteroaryl is
independently selected from the group consisting of 5- and
6-membered aromatic rings having 1, 2 or 3 heteroatoms
independently selected from N, O and S, and said R.sup.8 heteroaryl
is attached through a ring atom selected from C or N, each R.sup.8
heterocyclyl is independently selected from the group consisting of
5- to 7-membered saturated or unsaturated non-aromatic rings having
1, 2, 3 or 4 heteroatoms independently selected from N, O and S,
and said R.sup.8 heterocyclyl is attached through a ring atom
selected from C or N, and 2 adjacent substituents of said R.sup.8
may be taken together to form a 3- to 6-membered ring containing 0
to 3 heteroatoms independently selected from the group consisting
of N, O and S; R.sup.9 is selected from the group consisting of
C.sub.1-C.sub.8 alkyl, C.sub.3-C.sub.8 cycloalkyl, C.sub.3-C.sub.8
cycloalkyl(C.sub.1-C.sub.8 alkyl), C.sub.1-C.sub.8 alkoxy,
C.sub.3-C.sub.8 cycloalkoxy, phenyl, naphthyl,
phenyl(C.sub.1-C.sub.4)alkyl, naphthyl(C.sub.1-C.sub.4)alkyl,
heteroaryl, heterocyclyl, heteroaryl(C.sub.1-C.sub.4 alkyl), or
heterocyclyl(C.sub.1-C.sub.8 alkyl) groups, wherein said R.sup.9
are substituted with 0 to 4 substituents selected from the group
consisting of phenyl, naphthyl, C.sub.3-C.sub.8 cycloalkyl,
heteroaryl, heterocyclyl, C.sub.1-C.sub.6 alkyl,
halo(C.sub.1-C.sub.6 alkoxy), halogen atoms, --OR.sup.10,
--SR.sup.10, --N(R.sup.10).sub.2, --N(C.sub.1-C.sub.6
alkyl)O(C.sub.1-C.sub.6 alkyl), C.sub.1-C.sub.6 alkyl,
--C(O)R.sup.10, C.sub.1-C.sub.6 haloalkyl, --NO.sub.2, --CN,
--CF.sub.3, --SO.sub.2(C.sub.1-C.sub.6 alkyl),
--S(O)(C.sub.1-C.sub.6 alkyl), --NR.sup.10SO.sub.2R.sup.6,
--SO.sub.2N(R.sup.6).sub.2, --NHCOOR.sup.6, --NHCOR.sup.6,
--NHCONHR.sup.6, --CO.sub.2R.sup.10, and --C(O)N(R.sup.10).sub.2,
each R.sup.9 heteroaryl is independently selected from the group
consisting of 5- and 6-membered aromatic rings having 1, 2 or 3
heteroatoms independently selected from N, O and S, and said
R.sup.9 heteroaryl is attached through a ring atom selected from C
or N, each R.sup.9 heterocyclyl is independently selected from the
group consisting of 5- to 7-membered saturated or unsaturated
non-aromatic rings having 1, 2, 3 or 4 heteroatoms independently
selected from N, O and S, and said R.sup.9 heterocyclyl is attached
through a ring atom selected from C or N, and 2 adjacent
substituents of said R.sup.9 may be taken together to form a 3- to
6-membered ring containing 0 to 3 heteroatoms independently
selected from the group consisting of N, O and S, and R.sup.8 and
R.sup.9 may be taken together, with the N to which they are
attached, to form a 4- to 8-membered monocyclic ring containing 0
to 2 additional heteroatoms independently selected from N, O and S;
each R.sup.10 is independently selected from the group consisting
of H and C.sub.1-C.sub.6 alkyl; each R.sup.11 is independently
selected from the group consisting of C.sub.1-C.sub.6 alkyl,
C.sub.1-C.sub.4 alkenyl, --OR.sup.13,
--N(R.sup.10)--V--CO.sub.2R.sup.10, --O--V--CO.sub.2R.sup.10,
--S--V--CO.sub.2R.sup.10, --N(R.sup.10)(R.sup.13), --R.sup.14, and
--N(R.sup.10SO.sub.2R.sup.6; each R.sup.12 is independently
selected from the group consisting of
--OR.sup.13, --N(R.sup.10)--V--CO.sub.2R.sup.10,
--O--V--CO.sub.2R.sup.10, --S--V--CO.sub.2R.sup.10, and
--N(R.sup.10)(R.sup.13); R.sup.11 and R.sup.12 may be taken
together, with the phosphorus atom to which they are attached, to
form a 5- to 7-membered monocyclic ring; each V is independently
selected from the group consisting of --CH(R.sup.15)-- and
--(C.sub.1-C.sub.4 alkylene)-CH(R.sup.15)--; each R.sup.13 is
independently selected from the group consisting of H,
C.sub.1-C.sub.6 alkyl, C.sub.2-C.sub.6 alkenyl, C.sub.3-C.sub.8
cycloalkyl, aryl, heteroaryl, and heterocyclyl groups, wherein when
R.sup.13 is not H, said R.sup.13 is substituted with 0 to 2
substituents independently selected from the group consisting of
phenyl, naphthyl, phenyl(C.sub.1-C.sub.4 alkyl),
naphthyl(C.sub.1-C.sub.4 alkyl), C.sub.3-C.sub.8 cycloalkyl,
C.sub.3-C.sub.8 cycloalkyl(C.sub.1-C.sub.4 alkyl), heteroaryl,
heteroaryl(C.sub.1-C.sub.4 alkyl), heterocyclyl,
heterocyclyl(C.sub.1-C.sub.4 alkyl), C.sub.1-C.sub.6 alkyl, halogen
atoms, --OC(O)OR.sup.6, --OC(O)R.sup.6, --OR.sup.10, --SR.sup.10,
--N(R.sup.10).sub.2, --C(O)R.sup.10, --NO.sub.2, --CN, --CF.sub.3,
--SO.sub.2(C.sub.1-C.sub.6 alkyl), --S(O)(C.sub.1-C.sub.6 alkyl),
--NR.sup.10SO.sub.2R.sup.6, --SO.sub.2N(R.sup.6).sub.2,
--NHCOOR.sup.6, --NHCOR.sup.6, --NHCONHR.sup.6, --CO.sub.2R.sup.10,
and --C(O)N(R.sup.10).sub.2, each R.sup.13 heteroaryl is
independently selected from the group consisting of 5- and
6-membered aromatic rings having 1, 2 or 3 heteroatoms
independently selected from N, O and S, and said R.sup.13
heteroaryl is attached through a ring atom selected from C or N,
each R.sup.13 heterocyclyl is independently selected from the group
consisting of 5- to 7-membered saturated or unsaturated
non-aromatic rings having 1, 2, 3 or 4 heteroatoms independently
selected from N, O and S, and said R.sup.13 heterocyclyl is
attached through a ring atom selected from C or N, and 2 adjacent
substituents of said R.sup.13 may be taken together to form a 3- to
6-membered ring containing 0 to 3 heteroatoms independently
selected from the group consisting of N, O and S; R.sup.14 is
selected from the group consisting of C.sub.1-C.sub.6 alkyl,
C.sub.2-C.sub.6 alkenyl, phenyl, naphthyl and heteroaryl, wherein
each R.sup.14 heteroaryl is independently selected from the group
consisting of 5- and 6-membered aromatic rings having 1, 2 or 3
heteroatoms independently selected from N, O and S, and said
R.sup.14 heteroaryl is attached through a ring atom selected from C
or N, and said R.sup.14 phenyl, naphthyl or heteroaryl may be
substituted with 0 to 2 substituents independently selected from
the group consisting of C.sub.1-C.sub.6 alkyl, halogen atoms,
--OC(O)OR.sup.6, --OC(O)R.sup.6, --OR.sup.10, --SR.sup.10,
--N(R.sup.10).sub.2, --C(O)R.sup.10, --NO.sub.2, --CN, --CF.sub.3,
--SO.sub.2(C.sub.1-C.sub.6 alkyl), --S(O)(C.sub.1-C.sub.6 alkyl),
--NR.sup.10SO.sub.2R.sup.6, --SO.sub.2N(R.sup.6).sub.2,
--NHCOOR.sup.6, --NHCOR.sup.6, --NHCONHR.sup.6, --CO.sub.2R.sup.10,
and --C(O)N(R.sup.10).sub.2; and each R.sup.15 is independently
selected from the group consisting of C.sub.1-C.sub.6 alkyl,
C.sub.2-C.sub.6 alkenyl, C.sub.3-C.sub.8 cycloalkyl, phenyl,
naphthyl, heteroaryl, and heterocyclyl groups, wherein said
R.sup.15 are substituted with 0 to 2 substituents independently
selected from the group consisting of C.sub.1-C.sub.6 alkyl,
halogen atoms, --OC(O)OR.sup.6, --OC(O)R.sup.6, --OR.sup.10,
--SR.sup.10, --N(R.sup.10).sub.2, --C(O)R.sup.10, --NO.sub.2, --CN,
--CF.sub.3, --SO.sub.2(C.sub.1-C.sub.6 alkyl),
--S(O)(C.sub.1-C.sub.6 alkyl), --NR.sup.10SO.sub.2R.sup.6,
--SO.sub.2N(R.sup.6).sub.2, --NHCOOR.sup.6, --NHCOR.sup.6,
--NHCONHR.sup.6, --CO.sub.2R.sup.10, and --C(O)N(R.sup.10).sub.2,
each R.sup.15 heteroaryl is independently selected from the group
consisting of 5- and 6-membered aromatic rings having 1, 2 or 3
heteroatoms independently selected from N, O and S, and said
R.sup.15 heteroaryl is attached through a ring atom selected from C
or N, each R.sup.15 heterocyclyl is independently selected from the
group consisting of 5- to 7-membered saturated or unsaturated
non-aromatic rings having 1, 2, 3 or 4 heteroatoms independently
selected from N, O and S, and said R.sup.15 heterocyclyl is
attached through a ring atom selected from C or N, and 2 adjacent
substituents of said R.sup.15 are optionally taken together to form
a 3- to 6-membered ring containing 0 to 3 heteroatoms independently
selected from the group consisting of N, O and S.
22. A method of preparing a medicament for preventing or treating
infection by HCV in a subject in need thereof, said method
comprising providing a compound of formula (I): ##STR00401## or a
pharmaceutically acceptable salt, hydrate or prodrug thereof,
wherein: ##STR00402## is one or more rings selected from the group
consisting of: 1) aryl rings, 2) C.sub.3-C.sub.8 cycloalkyl rings,
and 3) heterocyclic rings in which the heterocyclic ring system
attaches to Z and X at points that are two independently selected
ring atoms that are either two acarbon carbon ring atoms or one
carbon ring atom and one nitrogen ring atom, and the heterocyclic
ring system is selected from the group consisting of: a) 5- or
6-membered saturated or unsaturated monocyclic rings with 1, 2, or
3 heteroatom ring atoms independently selected from the group
consisting of N, O or S, b) 8-, 9- or 10-membered saturated or
unsaturated bicyclic rings with 1, 2, or 3 heteroatom ring atoms
independently selected from the group consisting of N, O or S, and
c) 11- to 15-membered saturated or unsaturated tricyclic rings with
1, 2, 3, or 4 heteroatom ring atoms independently selected from the
group consisting of N, O or S, wherein ##STR00403## is substituted
with 0 to 4 independently selected substituents W, R.sup.5 or oxo;
wherein for stable heterocyclic rings containing S or N, the
heterocyclic ring is unsubstituted at the S or N atom or is
substituted at the S or N atom by oxo; wherein said W and R.sup.5
substitutions are located on one or more ring atoms selected from C
and N; and provided that the 10-membered unsaturated bicyclic ring
is not quinoline, quinazoline or isoquinoline with the following
modes of attachment ##STR00404## R.sup.1 is selected from the group
consisting of --CO.sub.2R.sup.10, --CONR.sup.10SO.sub.2R.sup.6,
--CONR.sup.10SO.sub.2NR.sup.8R.sup.9, tetrazolyl,
--CONHP(O)R.sup.11R.sup.12, and --P(O)R.sup.11R.sup.12; R.sup.2 is
selected from the group consisting of C.sub.1-C.sub.6 alkyl,
C.sub.2-C.sub.6 alkenyl, and C.sub.3-C.sub.8 cycloalkyl, wherein
said R.sup.2 are substituted with 0 to 3 independently selected
halogen atoms; R.sup.3 is selected from the group consisting of H,
C.sub.1-C.sub.8 alkyl, C.sub.3-C.sub.8 cycloalkyl. C.sub.3-C.sub.8
cycloalkyl(C.sub.1-C.sub.8)alkyl, phenyl(C.sub.1-C.sub.8)alkyl,
naphthyl(C.sub.1-C.sub.8)alkyl, and Het groups, wherein when
R.sup.3 is not H, said R.sup.3 is substituted with 0 to 3
substituents independently selected from the group consisting of
halogen atoms, --OR.sup.10, --SR.sup.10, --N(R.sup.10).sub.2,
--N(C.sub.1-C.sub.6 alkyl)O(C.sub.1-C.sub.6 alkyl), C.sub.1-C.sub.6
alkyl, C.sub.1-C.sub.6 haloalkyl, halo(C.sub.1-C.sub.6 alkoxy),
--NO.sub.2, --CN, --CF.sub.3, --SO.sub.2(C.sub.1-C.sub.6 alkyl),
--S(O)(C.sub.1-C.sub.6 alkyl), --NR.sup.10SO.sub.2R.sup.6,
SO.sub.2N(R.sup.6).sub.2, --NHCOOR.sup.6, --NHCOR.sup.6,
--NHCONHR.sup.6, --CO.sub.2R.sup.10, --C(O)R.sup.10, and
--CON(R.sup.10).sub.2; Het is selected from the group consisting of
substituted and unsubstituted 5- and 6-membered saturated
heterocyclic rings having 1 or 2 heteroatoms independently selected
from N, O and S, wherein said substituted rings are substituted
with 1 to 3 substituents independently selected from halogen atoms,
--OR.sup.10, --SR.sup.10, --N(R.sup.10).sub.2, --N(C.sub.1-C.sub.6
alkyl)O(C.sub.1-C.sub.6 alkyl), C.sub.1-C.sub.6 alkyl,
C.sub.1-C.sub.6 haloalkyl, halo(C.sub.1-C.sub.6 alkoxy),
--NO.sub.2, --CN, --CF.sub.3, --SO.sub.2(C.sub.1-C.sub.6 alkyl),
--S(O)(C.sub.1-C.sub.6 alkyl), --NR.sup.10SO.sub.2R.sup.6,
SO.sub.2N(R.sup.6).sub.2, --SO.sub.2N(R.sup.6).sub.2,
--NHCOOR.sup.6, --NHCOR.sup.6, --NHCONHR.sup.6, --CO.sub.2R.sup.10,
--C(O)R.sup.10, and --CON(R.sup.10).sub.2; R.sup.5 is selected from
the group consisting of H, halogen atoms, --OH, C.sub.1-C.sub.6
alkoxy, C.sub.1-C.sub.6 alkyl, --CN, --CF.sub.3--OCF.sub.3,
--C(O)OH, --C(O)CH.sub.3, --SR.sup.10, --SO.sub.2(C.sub.1-C.sub.6
alkyl), C.sub.3-C.sub.8 cycloalkyl, C.sub.3-C.sub.8 cycloalkoxy,
C.sub.1-C.sub.6 haloalkyl, --N(R.sup.7).sub.2, phenyl, naphthyl,
--O-phenyl, --O-naphthyl, heteroaryl and heterocyclyl groups;
wherein: said R.sup.5 heteroaryl is selected from the group
consisting of 5- and 6-membered aromatic rings having 1, 2 or 3
heteroatoms independently selected from N, O and S, and said
R.sup.5 heteroaryl is attached through a ring atom selected from C
or N, said R.sup.5 heterocyclyl is selected from the group
consisting of 5- to 7-membered saturated or unsaturated
non-aromatic rings having 1, 2, 3 or 4 heteroatoms independently
selected from N, O and S, and said R.sup.5 heterocyclyl is attached
through a ring atom selected from C or N, and said R.sup.5
heteroaryl, heterocyclyl, cycloalkyl, cycloalkoxy, alkyl and alkoxy
groups are substituted with 0 to 4 substituents independently
selected from the group consisting of halogen atoms, --OR.sup.10,
--SR.sup.10, --N(R.sup.10).sub.2, --N(C.sub.1-C.sub.6
alkyl)O(C.sub.1-C.sub.6 alkyl), C.sub.1-C.sub.6 alkyl,
C.sub.1-C.sub.6 haloalkyl, halo(C.sub.1-C.sub.6 alkoxy),
--NO.sub.2, --CN, --CF.sub.3, --SO.sub.2(C.sub.1-C.sub.6 alkyl),
--S(O)(C.sub.1-C.sub.6 alkyl), --NR.sup.10SO.sub.2R.sup.6,
SO.sub.2N(R.sup.6).sub.2, --SO.sub.2N(R.sup.6).sub.2,
--NHCOOR.sup.6, --NHCOR.sup.6, --NHCONHR.sup.6, --CO.sub.2R.sup.10,
--C(O)R.sup.10, and --CON(R.sup.10).sub.2, and 2 adjacent
substituents of said R.sup.5 heteroaryl, heterocyclyl, cycloalkyl,
cycloalkoxy, alkyl and alkoxy groups may be taken together to form
a 3-6-membered cyclic ring containing 0 to 3 heteroatoms
independently selected from N, O and S; R.sup.6 is selected from
the group consisting of C.sub.1-C.sub.6 alkyl, C.sub.3-C.sub.6
cycloalkyl, C.sub.3-C.sub.6 cycloalkyl(C.sub.1-C.sub.5)alkyl,
phenyl, naphthyl, phenyl(C.sub.1-C.sub.4)alkyl,
naphthyl(C.sub.1-C.sub.4)alkyl, heteroaryl,
heteroaryl(C.sub.1-C.sub.4 alkyl), heterocyclyl, and
heterocyclyl(C.sub.1-C.sub.8 alkyl) groups, wherein said R.sup.6
are substituted with 0 to 2 independently selected W substituents,
each R.sup.6 heteroaryl is independently selected from the group
consisting of 5- and 6-membered aromatic rings having 1, 2 or 3
heteroatoms independently selected from N, O and S, and said
R.sup.6 heteroaryl is attached through a ring atom selected from C
or N, and each R.sup.6 heterocyclyl is independently selected from
the group consisting of 5- to 7-membered saturated or unsaturated
non-aromatic rings having 1, 2, 3 or 4 heteroatoms independently
selected from N, O and S, and said R.sup.6 heterocyclyl is attached
through a ring atom selected from C or N; Y is selected from the
group consisting of --C(O)--, --SO.sub.2--, --OC(O)--, --C(O)N(D)L-
and -LN(D)C(O)--. and -LN(D)C(O)--, where D is selected from the
group consisting of H, C.sub.1-C.sub.6 alkyl and C.sub.1-C.sub.6
alkenyl groups, L is selected from the group consisting of a direct
bond, -G-(C.sub.1-C.sub.6 alkylene)-, --(C.sub.1-C.sub.6
alkylene)-G-, -G-(C.sub.1-C.sub.6 alkenylene)-, and
--(C.sub.1-C.sub.6 alkenylene)-G-, groups, where said G is selected
from the group consisting of a direct bond, --O--, --N-- and --S--,
said alkylene and alkenylene groups are substituted with 0 to 4
substituents E independently selected from the group consisting of
C.sub.1-C.sub.6 alkyl and C.sub.1-C.sub.6 alkenyl groups, and said
D and E may be taken together to form a 3- to 6-membered ring
containing 0 to 3 heteroatoms selected from N, O and S; Z is
selected from the group consisting of --C(O)-- and a direct bond; M
is selected from the group consisting of C.sub.1-C.sub.12 alkylenes
and C.sub.1-C.sub.12 alkenylenes, wherein said M is substituted
with 0 to 2 substituents F independently selected from the group
consisting of C.sub.1-C.sub.8 alkyl, .dbd.CH.sub.2, C.sub.3-C.sub.8
cycloalkyl(C.sub.1-C.sub.8 alkyl), and aryl(C.sub.1-C.sub.8 alkyl),
and 2 adjacent substituents F may be taken together to form a 3- to
6-membered ring containing 0 to 3 heteroatoms selected from the
group consisting of N, O and S, and one or more adjacent
substituents F may be taken together and/or with an adjacent D or E
to form a 3- to 6-membered ring containing 0 to 3 heteroatoms
independently selected from the group consisting of N, O and S; X
is selected from the group consisting of --O--, --CH.sub.2O--,
--NHC(O)O--, --CH.sub.2NHC(O)O--, --C.ident.CH.sub.2O--, --C(O)O--,
--(CH.sub.2).sub.2O--, --OC(O)NH--, --(CH.sub.2).sub.2C(O)NH--,
--C(O)NH-- and a direct bond; each R.sup.7 is independently
selected from the group consisting of H, C.sub.1-C.sub.6 alkyl,
C.sub.3-C.sub.6 cycloalkyl, C.sub.3-C.sub.6
cycloalkyl(C.sub.1-C.sub.5)alkyl, phenyl, naphthyl,
phenyl(C.sub.1-C.sub.4)alkyl, naphthyl(C.sub.1-C.sub.4)alkyl,
heteroaryl, heteroaryl(C.sub.1-C.sub.4 alkyl), heterocyclyl, and
heterocyclyl(C.sub.1-C.sub.8 alkyl) groups, wherein when R.sup.7 is
not H, said R.sup.7 are substituted with 0 to 2 W substituents,
each R.sup.7 heteroaryl is independently selected from the group
consisting of 5- and 6-membered aromatic rings having 1, 2 or 3
heteroatoms independently selected from N, O and S, and said
R.sup.7 heteroaryl is attached through a ring atom selected from C
or N, and each R.sup.7 heterocyclyl is independently selected from
the group consisting of 5- to 7-membered saturated or unsaturated
non-aromatic rings having 1, 2, 3 or 4 heteroatoms independently
selected from N, O and S, and said R.sup.7 heterocyclyl is attached
through a ring atom selected from C or N, and said R.sup.7 may be
taken together with the atom to which it is attached and a second
R.sup.7 substituent to form a 4- to 7-membered heterocyclic ring;
each W is independently selected from the group consisting of
halogen atoms, --OR.sup.10, C.sub.1-C.sub.6 alkyl, --CN,
--CF.sub.3, --NO.sub.2, --SR.sup.10, --CO.sub.2R.sup.10,
--CON(R.sup.10).sub.2, --C(O)R.sup.10, --N(R.sup.10)C(O)R.sup.10,
--SO.sub.2(C.sub.1-C.sub.6 alkyl), --S(O)(C.sub.1-C.sub.6 alkyl),
C.sub.3-C.sub.8 cycloalkyl, C.sub.3-C.sub.8 cycloalkoxy,
C.sub.1-C.sub.6 haloalkyl, --N(R.sup.10).sub.2, --N(C.sub.1-C.sub.6
alkyl)O(C.sub.1-C.sub.6 alkyl), halo(C.sub.1-C.sub.6 alkoxy),
--NR.sup.10SO.sub.2R.sup.10, --SO.sub.2N(R.sup.10).sub.2,
--NHCOOR.sup.10, --NHCONHR.sup.10, phenyl, naphthyl, heteroaryl and
heterocyclyl groups; wherein said W heteroaryl is selected from the
group consisting of 5- and 6-membered aromatic rings having 1, 2 or
3 heteroatoms independently selected from N, O and S, and said W
heteroaryl is attached through a ring atom selected from C or N,
said W heterocyclyl is selected from the group consisting of 5- to
7-membered saturated or unsaturated non-aromatic rings having 1, 2,
3 or 4 heteroatoms independently selected from N, O and S, and said
W heterocyclyl is attached through a ring atom selected from C or
N; R.sup.8 is selected from the group consisting of C.sub.1-C.sub.8
alkyl, C.sub.3-C.sub.8 cycloalkyl, C.sub.3-C.sub.8
cycloalkyl(C.sub.1-C.sub.8 alkyl), phenyl, naphthyl,
phenyl(C.sub.1-C.sub.4)alkyl, naphthyl(C.sub.1-C.sub.4)alkyl,
heteroaryl, heterocyclic, heteroaryl(C.sub.1-C.sub.4 alkyl), and
heterocyclyl(C.sub.1-C.sub.8 alkyl) groups, wherein said R.sup.8
are substituted with 0 to 4 substituents selected from the group
consisting of phenyl, naphthyl, C.sub.3-C.sub.8 cycloalkyl,
heteroaryl, heterocyclyl, C.sub.1-C.sub.6 alkyl,
halo(C.sub.1-C.sub.6 alkoxy), halogen atoms, --OR.sup.10,
--SR.sup.10, --N(R.sup.10).sub.2, --N(C.sub.1-C.sub.6
alkyl)O(C.sub.1-C.sub.6 alkyl), C.sub.1-C.sub.6 alkyl,
--C(O)R.sup.10, C.sub.1-C.sub.6 haloalkyl, --NO.sub.2, --CN,
--CF.sub.3, --SO.sub.2(C.sub.1-C.sub.6 alkyl),
--S(O)(C.sub.1-C.sub.6 alkyl), --NR.sup.10SO.sub.2R.sup.6,
--SO.sub.2N(R.sup.6).sub.2, --NHCOOR.sup.6, --NHCOR.sup.6,
--NHCONHR.sup.6, --CO.sub.2R.sup.10, and --C(O)N(R.sup.10).sub.2,
each R.sup.8 heteroaryl is independently selected from the group
consisting of 5- and 6-membered aromatic rings having 1, 2 or 3
heteroatoms independently selected from N, O and S, and said
R.sup.8 heteroaryl is attached through a ring atom selected from C
or N, each R.sup.8 heterocyclyl is independently selected from the
group consisting of 5- to 7-membered saturated or unsaturated
non-aromatic rings having 1, 2, 3 or 4 heteroatoms independently
selected from N, O and S, and said R.sup.8 heterocyclyl is attached
through a ring atom selected from C or N, and 2 adjacent
substituents of said R.sup.8 may be taken together to form a 3- to
6-membered ring containing 0 to 3 heteroatoms independently
selected from the group consisting of N, O and S; R.sup.9 is
selected from the group consisting of C.sub.1-C.sub.8 alkyl,
C.sub.3-C.sub.8 cycloalkyl, C.sub.3-C.sub.8
cycloalkyl(C.sub.1-C.sub.8 alkyl), C.sub.1-C.sub.8 alkoxy,
C.sub.3-C.sub.8 cycloalkoxy, phenyl, naphthyl,
phenyl(C.sub.1-C.sub.4)alkyl, naphthyl(C.sub.1-C.sub.4)alkyl,
heteroaryl, heterocyclyl, heteroaryl(C.sub.1-C.sub.4 alkyl), or
heterocyclyl(C.sub.1-C.sub.8 alkyl) groups, wherein said R.sup.9
are substituted with 0 to 4 substituents selected from the group
consisting of phenyl, naphthyl, C.sub.3-C.sub.8 cycloalkyl,
heteroaryl, heterocyclyl, C.sub.1-C.sub.6 alkyl,
halo(C.sub.1-C.sub.6 alkoxy), halogen atoms, --OR.sup.10,
--SR.sup.10, --N(R.sup.10).sub.2, --N(C.sub.1-C.sub.6
alkyl)O(C.sub.1-C.sub.6 alkyl), C.sub.1-C.sub.6 alkyl,
--C(O)R.sup.10, C.sub.1-C.sub.6 haloalkyl, --NO.sub.2, --CN,
--CF.sub.3, --SO.sub.2(C.sub.1-C.sub.6 alkyl),
--S(O)(C.sub.1-C.sub.6 alkyl), --NR.sup.10SO.sub.2R.sup.6,
--SO.sub.2N(R.sup.6).sub.2, --NHCOOR.sup.6, --NHCOR.sup.6,
--NHCONHR.sup.6, --CO.sub.2R.sup.10, and --C(O)N(R.sup.10).sub.2,
each R.sup.9 heteroaryl is independently selected from the group
consisting of 5- and 6-membered aromatic rings having 1, 2 or 3
heteroatoms independently selected from N, O and S, and said
R.sup.9 heteroaryl is attached through a ring atom selected from C
or N, each R.sup.9 heterocyclyl is independently selected from the
group consisting of 5- to 7-membered saturated or unsaturated
non-aromatic rings having 1, 2, 3 or 4 heteroatoms independently
selected from N, O and S, and said R.sup.9 heterocyclyl is attached
through a ring atom selected from C or N, and 2 adjacent
substituents of said R.sup.9 may be taken together to form a 3- to
6-membered ring containing 0 to 3 heteroatoms independently
selected from the group consisting of N, O and S, and R.sup.8 and
R.sup.9 may be taken together, with the N to which they are
attached, to form a 4- to 8-membered monocyclic ring containing 0
to 2 additional heteroatoms independently selected from N, O and S;
each R.sup.10 is independently selected from the group consisting
of H and C.sub.1-C.sub.6 alkyl; each R.sup.11 is independently
selected from the group consisting of C.sub.1-C.sub.6 alkyl,
C.sub.1-C.sub.4 alkenyl, --OR.sup.13,
--N(R.sup.10)--V--CO.sub.2R.sup.10, --O--V--CO.sub.2R.sup.10,
--S--V--CO.sub.2R.sup.10, --N(R.sup.10)(R.sup.13), --R.sup.14, and
--N(R.sup.10SO.sub.2R.sup.6; each R.sup.12 is independently
selected from the group consisting of
--OR.sup.13, --N(R.sup.10)--V--CO.sub.2R.sup.10,
--O--V--CO.sub.2R.sup.10, --S--V--CO.sub.2R.sup.10, and
--N(R.sup.10)(R.sup.13); R.sup.11 and R.sup.12 may be taken
together, with the phosphorus atom to which they are attached, to
form a 5- to 7-membered monocyclic ring; each V is independently
selected from the group consisting of --CH(R.sup.15)-- and
--(C.sub.1-C.sub.4 alkylene)-CH(R.sup.15)--; each R.sup.13 is
independently selected from the group consisting of H,
C.sub.1-C.sub.6 alkyl, C.sub.2-C.sub.6 alkenyl, C.sub.3-C.sub.8
cycloalkyl, aryl, heteroaryl, and heterocyclyl groups, wherein when
R.sup.13 is not H, said R.sup.13 is substituted with 0 to 2
substituents independently selected from the group consisting of
phenyl, naphthyl, phenyl(C.sub.1-C.sub.4 alkyl),
naphthyl(C.sub.1-C.sub.4 alkyl), C.sub.3-C.sub.8 cycloalkyl,
C.sub.3-C.sub.8 cycloalkyl(C.sub.1-C.sub.4 alkyl), heteroaryl,
heteroaryl(C.sub.1-C.sub.4 alkyl), heterocyclyl,
heterocyclyl(C.sub.1-C.sub.4 alkyl), C.sub.1-C.sub.6 alkyl, halogen
atoms, --OC(O)OR.sup.6, --OC(O)R.sup.6, --OR.sup.10, --SR.sup.10,
--N(R.sup.10).sub.2, --C(O)R.sup.10, --NO.sub.2, --CN, --CF.sub.3,
--SO.sub.2(C.sub.1-C.sub.6 alkyl), --S(O)(C.sub.1-C.sub.6 alkyl),
--NR.sup.10SO.sub.2R.sup.6, --SO.sub.2N(R.sup.6).sub.2,
--NHCOOR.sup.6, --NHCOR.sup.6, --NHCONHR.sup.6, --CO.sub.2R.sup.10,
and --C(O)N(R.sup.10).sub.2, each R.sup.13 heteroaryl is
independently selected from the group consisting of 5- and
6-membered aromatic rings having 1, 2 or 3 heteroatoms
independently selected from N, O and S, and said R.sup.13
heteroaryl is attached through a ring atom selected from C or N,
each R.sup.13 heterocyclyl is independently selected from the group
consisting of 5- to 7-membered saturated or unsaturated
non-aromatic rings having 1, 2, 3 or 4 heteroatoms independently
selected from N, O and S, and said R.sup.13 heterocyclyl is
attached through a ring atom selected from C or N, and 2 adjacent
substituents of said R.sup.13 may be taken together to form a 3- to
6-membered ring containing 0 to 3 heteroatoms independently
selected from the group consisting of N, O and S; R.sup.14 is
selected from the group consisting of C.sub.1-C.sub.6 alkyl,
C.sub.2-C.sub.6 alkenyl, phenyl, naphthyl and heteroaryl, wherein
each R.sup.14 heteroaryl is independently selected from the group
consisting of 5- and 6-membered aromatic rings having 1, 2 or 3
heteroatoms independently selected from N, O and S, and said
R.sup.14 heteroaryl is attached through a ring atom selected from C
or N, and said R.sup.14 phenyl, naphthyl or heteroaryl may be
substituted with 0 to 2 substituents independently selected from
the group consisting of C.sub.1-C.sub.6 alkyl, halogen atoms,
--OC(O)OR.sup.6, --OC(O)R.sup.6, --OR.sup.10, --SR.sup.10,
--N(R.sup.10).sub.2, --C(O)R.sup.10, --NO.sub.2, --CN, CF.sub.3,
--SO.sub.2(C.sub.1-C.sub.6 alkyl), --S(O)(C.sub.1-C.sub.6 alkyl),
--NR.sup.10SO.sub.2R.sup.6, --SO.sub.2N(R.sup.6).sub.2,
--NHCOOR.sup.6, --NHCOR.sup.6, --NHCONHR.sup.6, --CO.sub.2R.sup.10,
and --C(O)N(R.sup.10).sub.2; and each R.sup.15 is independently
selected from the group consisting of C.sub.1-C.sub.6 alkyl,
C.sub.2-C.sub.6 alkenyl, C.sub.3-C.sub.8 cycloalkyl, phenyl,
naphthyl, heteroaryl, and heterocyclyl groups, wherein said
R.sup.15 are substituted with 0 to 2 substituents independently
selected from the group consisting of C.sub.1-C.sub.6 alkyl,
halogen atoms, --OC(O)OR.sup.6, --OC(O)R.sup.6, --OR.sup.10,
--SR.sup.10, --N(R.sup.10).sub.2, --C(O)R.sup.10, --NO.sub.2, --CN,
--CF.sub.3, --SO.sub.2(C.sub.1-C.sub.6 alkyl),
--S(O)(C.sub.1-C.sub.6 alkyl), --NR.sup.10SO.sub.2R.sup.6,
--SO.sub.2N(R.sup.6).sub.2, --NHCOOR.sup.6, --NHCOR.sup.6,
--NHCONHR.sup.6, --CO.sub.2R.sup.10, and --C(O)N(R.sup.10).sub.2,
each R.sup.15 heteroaryl is independently selected from the group
consisting of 5- and 6-membered aromatic rings having 1, 2 or 3
heteroatoms independently selected from N, O and S, and said
R.sup.15 heteroaryl is attached through a ring atom selected from C
or N, each R.sup.15 heterocyclyl is independently selected from the
group consisting of 5- to 7-membered saturated or unsaturated
non-aromatic rings having 1, 2, 3 or 4 heteroatoms independently
selected from N, O and S, and said R.sup.15 heterocyclyl is
attached through a ring atom selected from C or N, and 2 adjacent
substituents of said R.sup.15 are optionally taken together to form
a 3- to 6-membered ring containing 0 to 3 heteroatoms independently
selected from the group consisting of N, O and S.
23. A method of inhibiting HCV NS3 protease in a subject in need
thereof, said method comprising administering to the subject an
effective amount of a compound of formula (I): ##STR00405## or a
pharmaceutically acceptable salt, hydrate or prodrug thereof,
wherein: ##STR00406## is one or more rings selected from the group
consisting of: 1) aryl rings, 2) C.sub.3-C.sub.8 cycloalkyl rings,
and 3) heterocyclic rings in which the heterocyclic ring system
attaches to Z and X at points that are two independently selected
ring atoms that are either two carbon ring atoms or one carbon ring
atom and one nitrogen ring atom, and the heterocyclic ring system
is selected from the group consisting of: a) 5- or 6-membered
saturated or unsaturated monocyclic rings with 1, 2, or 3
heteroatom ring atoms independently selected from the group
consisting of N, O or S, b) 8-, 9- or 10-membered saturated or
unsaturated bicyclic rings with 1, 2, or 3 heteroatom ring atoms
independently selected from the group consisting of N, O or S, and
c) 11- to 15-membered saturated or unsaturated tricyclic rings with
1, 2, 3, or 4 heteroatom ring atoms independently selected from the
group consisting of N, O or S, wherein ##STR00407## is substituted
with 0 to 4 independently selected substituents W, R.sup.5 or oxo;
wherein for stable heterocyclic rings containing S or N, the
heterocyclic ring is unsubstituted at the S or N atom or is
substituted at the S or N atom by oxo; wherein said W and R.sup.5
substitutions are located on one or more ring atoms selected from C
and N; and provided that the 10-membered unsaturated bicyclic ring
is not quinoline, quinazoline or isoquinoline with the following
modes of attachment ##STR00408## R.sup.1 is selected from the group
consisting of --CO.sub.2R.sup.10, --CONR.sup.10SO.sub.2R.sup.6,
--CONR.sup.10SO.sub.2NR.sup.8R.sup.9, tetrazolyl,
--CONHP(O)R.sup.11R.sup.12, and --P(O)R.sup.11R.sup.12; R.sup.2 is
selected from the group consisting of C.sub.1-C.sub.6 alkyl,
C.sub.2-C.sub.6 alkenyl, and C.sub.3-C.sub.8 cycloalkyl, wherein
said R.sup.2 are substituted with 0 to 3 independently selected
halogen atoms; R.sup.3 is selected from the group consisting of H,
C.sub.1-C.sub.8 alkyl, C.sub.3-C.sub.8 cycloalkyl, C.sub.3-C.sub.8
cycloalkyl(C.sub.1-C.sub.8)alkyl, phenyl(C.sub.1-C.sub.8)alkyl,
naphthyl(C.sub.1-C.sub.8)alkyl, and Het groups, wherein when
R.sup.3 is not H, said R.sup.3 is substituted with 0 to 3
substituents independently selected from the group consisting of
halogen atoms, --OR.sup.10, --SR.sup.10, --N(R.sup.10).sub.2,
--N(C.sub.1-C.sub.6 alkyl)O(C.sub.1-C.sub.6 alkyl), C.sub.1-C.sub.6
alkyl, C.sub.1-C.sub.6 haloalkyl, halo(C.sub.1-C.sub.6 alkoxy),
--NO.sub.2, --CN, --CF.sub.3, --SO.sub.2(C.sub.1-C.sub.6 alkyl),
--S(O)(C.sub.1-C.sub.6 alkyl), --NR.sup.10SO.sub.2R.sup.6,
SO.sub.2N(R.sup.6).sub.2, --NHCOOR.sup.6, --NHCOR.sup.6,
--NHCONHR.sup.6, --CO.sub.2R.sup.10, --C(O)R.sup.10, and
--CON(R.sup.10).sub.2; Het is selected from the group consisting of
substituted and unsubstituted 5- and 6-membered saturated
heterocyclic rings having 1 or 2 heteroatoms independently selected
from N, O and S, wherein said substituted rings are substituted
with 1 to 3 substituents independently selected from halogen atoms,
--OR.sup.10, --SR.sup.10, --N(R.sup.10).sub.2, --N(C.sub.1-C.sub.6
alkyl)O(C.sub.1-C.sub.6 alkyl), C.sub.1-C.sub.6 alkyl,
C.sub.1-C.sub.6 haloalkyl, halo(C.sub.1-C.sub.6 alkoxy),
--NO.sub.2, --CN, --CF.sub.3, --SO.sub.2(C.sub.1-C.sub.6 alkyl),
--S(O)(C.sub.1-C.sub.6 alkyl), --NR.sup.10SO.sub.2R.sup.6,
--SO.sub.2N(R.sup.6).sub.2, --NHCOOR.sup.6, --NHCOR.sup.6,
--NHCONHR.sup.6, --CO.sub.2R.sup.10, --C(O)R.sup.10, and
--CON(R.sup.10).sub.2; R.sup.5 is selected from the group
consisting of H, halogen atoms, --OH, C.sub.1-C.sub.6 alkoxy,
C.sub.1-C.sub.6 alkyl, --CN, --CF.sub.3, --OCF.sub.3, --C(O)OH,
--C(O)CH.sub.3, --SR.sup.10, --SO.sub.2(C.sub.1-C.sub.6 alkyl),
C.sub.3-C.sub.8 cycloalkyl, C.sub.3-C.sub.8 cycloalkoxy,
C.sub.1-C.sub.6 haloalkyl, --N(R.sup.7).sub.2, phenyl, naphthyl,
--O-phenyl, --O-naphthyl, heteroaryl and heterocyclyl groups;
wherein: said R.sup.5 heteroaryl is selected from the group
consisting of 5- and 6-membered aromatic rings having 1, 2 or 3
heteroatoms independently selected from N, O and S, and said
R.sup.5 heteroaryl is attached through a ring atom selected from C
or N, said R.sup.5 heterocyclyl is selected from the group
consisting of 5- to 7-membered saturated or unsaturated
non-aromatic rings having 1, 2, 3 or 4 heteroatoms independently
selected from N, O and S, and said R.sup.5 heterocyclyl is attached
through a ring atom selected from C or N, and said R.sup.5
heteroaryl, heterocyclyl, cycloalkyl, cycloalkoxy, alkyl and alkoxy
groups are substituted with 0 to 4 substituents independently
selected from the group consisting of halogen atoms, --OR.sup.10,
--SR.sup.10, --N(R.sup.10).sub.2, --N(C.sub.1-C.sub.6
alkyl)O(C.sub.1-C.sub.6 alkyl), C.sub.1-C.sub.6 alkyl,
C.sub.1-C.sub.6 haloalkyl, halo(C.sub.1-C.sub.6 alkoxy),
--NO.sub.2, --CN, --CF.sub.3, --SO.sub.2(C.sub.1-C.sub.6 alkyl),
--S(O)(C.sub.1-C.sub.6 alkyl), --NR.sup.10SO.sub.2R.sup.6,
--SO.sub.2N(R.sup.6).sub.2, --NHCOOR.sup.6, --NHCOR.sup.6,
--NHCONHR.sup.6, --CO.sub.2R.sup.10, --C(O)R.sup.10, and
--CON(R.sup.10).sub.2, and 2 adjacent substituents of said R.sup.5
heteroaryl, heterocyclyl, cycloalkyl, cycloalkoxy, alkyl and alkoxy
groups may be taken together to form a 3-6-membered cyclic ring
containing 0 to 3 heteroatoms independently selected from N, O and
S; R.sup.6 is selected from the group consisting of C.sub.1-C.sub.6
alkyl, C.sub.3-C.sub.6 cycloalkyl, C.sub.3-C.sub.6
cycloalkyl(C.sub.1-C.sub.5)alkyl, phenyl, naphthyl,
phenyl(C.sub.1-C.sub.4)alkyl, naphthyl(C.sub.1-C.sub.4)alkyl,
heteroaryl, heteroaryl(C.sub.1-C.sub.4 alkyl), heterocyclyl, and
heterocyclyl(C.sub.1-C.sub.8 alkyl) groups, wherein said R.sup.6
are substituted with 0 to 2 independently selected W substituents,
each R.sup.6 heteroaryl is independently selected from the group
consisting of 5- and 6-membered aromatic rings having 1, 2 or 3
heteroatoms independently selected from N, O and S, and said
R.sup.6 heteroaryl is attached through a ring atom selected from C
or N, and each R.sup.6 heterocyclyl is independently selected from
the group consisting of 5- to 7-membered saturated or unsaturated
non-aromatic rings having 1, 2, 3 or 4 heteroatoms independently
selected from N, O and S, and said R.sup.6 heterocyclyl is attached
through a ring atom selected from C or N; Y is selected from the
group consisting of --C(O)--, --SO.sub.2--, --OC(O)--, --C(O)N(D)L-
and -LN(D)C(O)--. and -LN(D)C(O)--, where D is selected from the
group consisting of H, C.sub.1-C.sub.6 alkyl and C.sub.1-C.sub.6
alkenyl groups, L is selected from the group consisting of a direct
bond, -G-(C.sub.1-C.sub.6 alkylene)-, --(C.sub.1-C.sub.6
alkylene)-G-, -G-(C.sub.1-C.sub.6 alkenylene)-, and
--(C.sub.1-C.sub.6 alkenylene)-G-, groups, where said G is selected
from the group consisting of a direct bond, --O--, --N-- and --S--,
said alkylene and alkenylene groups are substituted with 0 to 4
substituents E independently selected from the group consisting of
C.sub.1-C.sub.6 alkyl and C.sub.1-C.sub.6 alkenyl groups, and said
D and E may be taken together to form a 3- to 6-membered ring
containing 0 to 3 heteroatoms selected from N, O and S; Z is
selected from the group consisting of --C(O)-- and a direct bond; M
is selected from the group consisting of C.sub.1-C.sub.12 alkylenes
and C.sub.2-C.sub.12 alkenylenes, wherein said M is substituted
with 0 to 2 substituents F independently selected from the group
consisting of C.sub.1-C.sub.8 alkyl, .dbd.CH.sub.2, C.sub.3-C.sub.8
cycloalkyl(C.sub.1-C.sub.8 alkyl), and aryl(C.sub.1-C.sub.8 alkyl),
and 2 adjacent substituents F may be taken together to form a 3- to
6-membered ring containing 0 to 3 heteroatoms selected from the
group consisting of N, O and S, and one or more adjacent
substituents F may be taken together and/or with an adjacent D or E
to form a 3- to 6-membered ring containing 0 to 3 heteroatoms
independently selected from the group consisting of N, O and S; X
is selected from the group consisting of --O--, --CH.sub.2O--,
--NHC(O)O--, --CH.sub.2NHC(O)O--, --C.ident.CH.sub.2O--, --C(O)O--,
--(CH.sub.2).sub.3O--, --OC(O)NH--, --(CH.sub.2).sub.2C(O)NH--,
--C(O)NH-- and a direct bond; each R.sup.7 is independently
selected from the group consisting of H, C.sub.1-C.sub.6 alkyl,
C.sub.3-C.sub.6 cycloalkyl, C.sub.3-C.sub.6
cycloalkyl(C.sub.1-C.sub.5)alkyl, phenyl, naphthyl,
phenyl(C.sub.1-C.sub.4)alkyl, naphthyl(C.sub.1-C.sub.4)alkyl,
heteroaryl, heteroaryl(C.sub.1-C.sub.4 alkyl), heterocyclyl, and
heterocyclyl(C.sub.1-C.sub.8 alkyl) groups, wherein when R.sup.7 is
not H, said R.sup.7 are substituted with 0 to 2 W substituents,
each R.sup.7 heteroaryl is independently selected from the group
consisting of 5- and 6-membered aromatic rings having 1, 2 or 3
heteroatoms independently selected from N, O and S, and said
R.sup.7 heteroaryl is attached through a ring atom selected from C
or N, and each R.sup.7 heterocyclyl is independently selected from
the group consisting of 5- to 7-membered saturated or unsaturated
non-aromatic rings having 1, 2, 3 or 4 heteroatoms independently
selected from N, O and S, and said R.sup.7 heterocyclyl is attached
through a ring atom selected from C or N, and said R.sup.7 may be
taken together with the atom to which it is attached and a second
R.sup.7 substituent to form a 4- to 7-membered heterocyclic ring;
each W is independently selected from the group consisting of
halogen atoms, --OR.sup.10, C.sub.1-C.sub.6 alkyl, --CN,
--CF.sub.3, --NO.sub.2, --SR.sup.10, --CO.sub.2R.sup.10,
--CON(R.sup.10).sub.2, --C(O)R.sup.10, --N(R.sup.10)C(O)R.sup.10,
--SO.sub.2(C.sub.1-C.sub.6 alkyl), --S(O)(C.sub.1-C.sub.6 alkyl),
C.sub.3-C.sub.8 cycloalkyl, C.sub.3-C.sub.8 cycloalkoxy,
C.sub.1-C.sub.6 haloalkyl, --N(R.sup.10).sub.2, --N(C.sub.1-C.sub.6
alkyl)O(C.sub.1-C.sub.6 alkyl), halo(C.sub.1-C.sub.6 alkoxy),
--NR.sup.10SO.sub.2R.sup.10, --SO.sub.2N(R.sup.10).sub.2,
--NHCOOR.sup.10, --NHCONHR.sup.10, phenyl, naphthyl, heteroaryl and
heterocyclyl groups; wherein said W heteroaryl is selected from the
group consisting of 5- and 6-membered aromatic rings having 1, 2 or
3 heteroatoms independently selected from N, O and S, and said W
heteroaryl is attached through a ring atom selected from C or N,
said W heterocyclyl is selected from the group consisting of 5- to
7-membered saturated or unsaturated non-aromatic rings having 1, 2,
3 or 4 heteroatoms independently selected from N, O and S, and said
W heterocyclyl is attached through a ring atom selected from C or
N; R.sup.8 is selected from the group consisting of C.sub.1-C.sub.8
alkyl, C.sub.3-C.sub.8 cycloalkyl, C.sub.3-C.sub.8
cycloalkyl(C.sub.1-C.sub.8 alkyl), phenyl, naphthyl,
phenyl(C.sub.1-C.sub.4)alkyl, naphthyl(C.sub.1-C.sub.4)alkyl,
heteroaryl, heterocyclic, heteroaryl(C.sub.1-C.sub.4 alkyl), and
heterocyclyl(C.sub.1-C.sub.8 alkyl) groups, wherein said R.sup.8
are substituted with 0 to 4 substituents selected from the group
consisting of phenyl, naphthyl, C.sub.3-C.sub.8 cycloalkyl,
heteroaryl, heterocyclyl, C.sub.1-C.sub.6 alkyl,
halo(C.sub.1-C.sub.6 alkoxy), halogen atoms, --OR.sup.10,
--SR.sup.10, --N(R.sup.10).sub.2, --N(C.sub.1-C.sub.6
alkyl)O(C.sub.1-C.sub.6 alkyl), C.sub.1-C.sub.6 alkyl,
--C(O)R.sup.10, C.sub.1-C.sub.6 haloalkyl, --NO.sub.2, --CN,
--CF.sub.3, --SO.sub.2(C.sub.1-C.sub.6 alkyl),
--S(O)(C.sub.1-C.sub.6 alkyl), --NR.sup.10SO.sub.2R.sup.6,
--SO.sub.2N(R.sup.6).sub.2, --NHCOOR.sup.6, --NHCOR.sup.6,
--NHCONHR.sup.6, --CO.sub.2R.sup.10, and --C(O)N(R.sup.10).sub.2,
each R.sup.8 heteroaryl is independently selected from the group
consisting of 5- and 6-membered aromatic rings having 1, 2 or 3
heteroatoms independently selected from N, O and S, and said
R.sup.8 heteroaryl is attached through a ring atom selected from C
or N, each R.sup.8 heterocyclyl is independently selected from the
group consisting of 5- to 7-membered saturated or unsaturated
non-aromatic rings having 1, 2, 3 or 4 heteroatoms independently
selected from N, O and S, and said R.sup.8 heterocyclyl is attached
through a ring atom selected from C or N, and 2 adjacent
substituents of said R.sup.8 may be taken together to form a 3- to
6-membered ring containing 0 to 3 heteroatoms independently
selected from the group consisting of N, O and S; R.sup.9 is
selected from the group consisting of C.sub.1-C.sub.8 alkyl,
C.sub.3-C.sub.8 cycloalkyl, C.sub.3-C.sub.8
cycloalkyl(C.sub.1-C.sub.8 alkyl), C.sub.1-C.sub.8 alkoxy,
C.sub.3-C.sub.8 cycloalkoxy, phenyl, naphthyl,
phenyl(C.sub.1-C.sub.4)alkyl, naphthyl(C.sub.1-C.sub.4)alkyl,
heteroaryl, heterocyclyl, heteroaryl(C.sub.1-C.sub.4 alkyl), or
heterocyclyl(C.sub.1-C.sub.8 alkyl) groups, wherein said R.sup.9
are substituted with 0 to 4 substituents selected from the group
consisting of phenyl, naphthyl, C.sub.3-C.sub.8 cycloalkyl,
heteroaryl, heterocyclyl, C.sub.1-C.sub.6 alkyl,
halo(C.sub.1-C.sub.6 alkoxy), halogen atoms, --OR.sup.10,
--SR.sup.10, --N(R.sup.10).sub.2, --N(C.sub.1-C.sub.6
alkyl)O(C.sub.1-C.sub.6 alkyl), C.sub.1-C.sub.6 alkyl,
--C(O)R.sup.10, C.sub.1-C.sub.6 haloalkyl, --NO.sub.2, --CN,
--CF.sub.3, --SO.sub.2(C.sub.1-C.sub.6 alkyl),
--S(O)(C.sub.1-C.sub.6 alkyl), --NR.sup.10SO.sub.2R.sup.6,
--SO.sub.2N(R.sup.6).sub.2, --NHCOOR.sup.6, --NHCOR.sup.6,
--NHCONHR.sup.6, --CO.sub.2R.sup.10, and --C(O)N(R.sup.10).sub.2,
each R.sup.9 heteroaryl is independently selected from the group
consisting of 5- and 6-membered aromatic rings having 1, 2 or 3
heteroatoms independently selected from N, O and S, and said
R.sup.9 heteroaryl is attached through a ring atom selected from C
or N, each R.sup.9 heterocyclyl is independently selected from the
group consisting of 5- to 7-membered saturated or unsaturated
non-aromatic rings having 1, 2, 3 or 4 heteroatoms independently
selected from N, O and S, and said R.sup.9 heterocyclyl is attached
through a ring atom selected from C or N, and 2 adjacent
substituents of said R.sup.9 may be taken together to form a 3- to
6-membered ring containing 0 to 3 heteroatoms independently
selected from the group consisting of N, O and S, and R.sup.8 and
R.sup.9 may be taken together, with the N to which they are
attached, to form a 4- to 8-membered monocyclic ring containing 0
to 2 additional heteroatoms independently selected from N, O and S;
each R.sup.10 is independently selected from the group consisting
of H and C.sub.1-C.sub.6 alkyl; each R.sup.11 is independently
selected from the group consisting of C.sub.1-C.sub.6 alkyl,
C.sub.1-C.sub.4 alkenyl, --OR.sup.13,
--N(R.sup.10)--V--CO.sub.2R.sup.10, --O--V--CO.sub.2R.sup.10,
--S--V--CO.sub.2R.sup.10, --N(R.sup.10)(R.sup.13), --R.sup.14, and
--N(R.sup.10SO.sub.2R.sup.6; each R.sup.12 is independently
selected from the group consisting of --OR.sup.13,
--N(R.sup.10)--V--CO.sub.2R.sup.10
, --O--V--CO.sub.2R.sup.10, --S--V--CO.sub.2R.sup.10, and
--N(R.sup.10)(R.sup.13); R.sup.11 and R.sup.12 may be taken
together, with the phosphorus atom to which they are attached, to
form a 5- to 7-membered monocyclic ring; each V is independently
selected from the group consisting of --CH(R.sup.15)-- and
--(C.sub.1-C.sub.4 alkylene)-CH(R.sup.15)--; each R.sup.13 is
independently selected from the group consisting of H,
C.sub.1-C.sub.6 alkyl, C.sub.2-C.sub.6 alkenyl, C.sub.3-C.sub.8
cycloalkyl, aryl, heteroaryl, and heterocyclyl groups, wherein when
R.sup.13 is not H, said R.sup.13 is substituted with 0 to 2
substituents independently selected from the group consisting of
phenyl, naphthyl, phenyl(C.sub.1-C.sub.4 alkyl),
naphthyl(C.sub.1-C.sub.4 alkyl), C.sub.3-C.sub.8 cycloalkyl,
C.sub.3-C.sub.8 cycloalkyl(C.sub.1-C.sub.4 alkyl), heteroaryl,
heteroaryl(C.sub.1-C.sub.4 alkyl), heterocyclyl,
heterocyclyl(C.sub.1-C.sub.4 alkyl), C.sub.1-C.sub.6 alkyl, halogen
atoms, --OC(O)OR.sup.6, --OC(O)R.sup.6, --OR.sup.10, --SR.sup.10,
--N(R.sup.10).sub.2, --C(O)R.sup.10, --NO.sub.2, --CN, --CF.sub.3,
--SO.sub.2(C.sub.1-C.sub.6 alkyl), --S(O)(C.sub.1-C.sub.6 alkyl),
--NR.sup.10SO.sub.2R.sup.6, --SO.sub.2N(R.sup.6).sub.2,
--NHCOOR.sup.6, --NHCOR.sup.6, --NHCONHR.sup.6, --CO.sub.2R.sup.10,
and --C(O)N(R.sup.10).sub.2, each R.sup.13 heteroaryl is
independently selected from the group consisting of 5- and
6-membered aromatic rings having 1, 2 or 3 heteroatoms
independently selected from N, O and S, and said R.sup.13
heteroaryl is attached through a ring atom selected from C or N,
each R.sup.13 heterocyclyl is independently selected from the group
consisting of 5- to 7-membered saturated or unsaturated
non-aromatic rings having 1, 2, 3 or 4 heteroatoms independently
selected from N, O and S, and said R.sup.13 heterocyclyl is
attached through a ring atom selected from C or N, and 2 adjacent
substituents of said R.sup.13 may be taken together to form a 3- to
6-membered ring containing 0 to 3 heteroatoms independently
selected from the group consisting of N, O and S; R.sup.14 is
selected from the group consisting of C.sub.1-C.sub.6 alkyl,
C.sub.2-C.sub.6 alkenyl, phenyl, naphthyl and heteroaryl, wherein
each R.sup.14 heteroaryl is independently selected from the group
consisting of 5- and 6-membered aromatic rings having 1, 2 or 3
heteroatoms independently selected from N, O and S, and said
R.sup.14 heteroaryl is attached through a ring atom selected from C
or N, and said R.sup.14 phenyl, naphthyl or heteroaryl may be
substituted with 0 to 2 substituents independently selected from
the group consisting of C.sub.1-C.sub.6 alkyl, halogen atoms,
--OC(O)OR.sup.6, --OC(O)R.sup.6, --OR.sup.10, --SR.sup.10,
--N(R.sup.10).sub.2, --C(O)R.sup.10, --NO.sub.2, --CN, --CF.sub.3,
--SO.sub.2(C.sub.1-C.sub.6 alkyl), --S(O)(C.sub.1-C.sub.6 alkyl),
--NR.sup.10SO.sub.2R.sup.6, --SO.sub.2N(R.sup.6).sub.2,
--NHCOOR.sup.6, --NHCOR.sup.6, --NHCONHR.sup.6, --CO.sub.2R.sup.10,
and --C(O)N(R.sup.10).sub.2; and each R.sup.15 is independently
selected from the group consisting of C.sub.1-C.sub.6 alkyl,
C.sub.2-C.sub.6 alkenyl, C.sub.3-C.sub.8 cycloalkyl, phenyl,
naphthyl, heteroaryl, and heterocyclyl groups, wherein said
R.sup.15 are substituted with 0 to 2 substituents independently
selected from the group consisting of C.sub.1-C.sub.6 alkyl,
halogen atoms, --OC(O)OR.sup.6, --OC(O)R.sup.6, --OR.sup.10,
--SR.sup.10, --N(R.sup.10).sub.2, --C(O)R.sup.10, --NO.sub.2, --CN,
--CF.sub.3, --SO.sub.2(C.sub.1-C.sub.6 alkyl),
--S(O)(C.sub.1-C.sub.6 alkyl), --NR.sup.10SO.sub.2R.sup.6,
--SO.sub.2N(R.sup.6).sub.2, --NHCOOR.sup.6, --NHCOR.sup.6,
--NHCONHR.sup.6, --CO.sub.2R.sup.10, and --C(O)N(R.sup.10).sub.2,
each R.sup.15 heteroaryl is independently selected from the group
consisting of 5- and 6-membered aromatic rings having 1, 2 or 3
heteroatoms independently selected from N, O and S, and said
R.sup.15 heteroaryl is attached through a ring atom selected from C
or N, each R.sup.15 heterocyclyl is independently selected from the
group consisting of 5- to 7-membered saturated or unsaturated
non-aromatic rings having 1, 2, 3 or 4 heteroatoms independently
selected from N, O and S, and said R.sup.15 heterocyclyl is
attached through a ring atom selected from C or N, and 2 adjacent
substituents of said R.sup.15 are optionally taken together to form
a 3- to 6-membered ring containing 0 to 3 heteroatoms independently
selected from the group consisting of N, O and S.
24. A method of preventing or treating infection by HCV in a
subject in need thereof, said method comprising administering to
the subject an effective amount of a compound of formula (I):
##STR00409## or a pharmaceutically acceptable salt, hydrate or
prodrug thereof, wherein: ##STR00410## is one or more rings
selected from the group consisting of: 1) aryl rings, 2)
C.sub.3-C.sub.8 cycloalkyl rings, and 3) heterocyclic rings in
which the heterocyclic ring system attaches to Z and X at points
that are two independently selected ring atoms that are either two
carbon ring atoms or one carbon ring atom and one nitrogen ring
atom, and the heterocyclic ring system is selected from the group
consisting of: a) 5- or 6-membered saturated or unsaturated
monocyclic rings with 1, 2, or 3 heteroatom ring atoms
independently selected from the group consisting of N, O or S, b)
8-, 9- or 10-membered saturated or unsaturated bicyclic rings with
1, 2, or 3 heteroatom ring atoms independently selected from the
group consisting of N, O or S, and c) 11- to 15-membered saturated
or unsaturated tricyclic rings with 1, 2, 3, or 4 heteroatom ring
atoms independently selected from the group consisting of N, O or
S, wherein ##STR00411## is substituted with 0 to 4 independently
selected substituents W, R.sup.5 or oxo; wherein for stable
heterocyclic rings containing S or N, the heterocyclic ring is
unsubstituted at the S or N atom or is substituted at the S or N
atom by oxo; wherein said W and R.sup.5 substitutions are located
on one or more ring atoms selected from C and N; and provided that
the 10-membered unsaturated bicyclic ring is not quinoline,
quinazoline or isoquinoline with the following modes of attachment
##STR00412## R.sup.1 is selected from the group consisting of
--CO.sub.2R.sup.10, --CONR.sup.10SO.sub.2R.sup.6,
--CONR.sup.10SO.sub.2NR.sup.8R.sup.9, tetrazolyl,
--CONHP(O)R.sup.11R.sup.12, and --P(O)R.sup.11R.sup.12; R.sup.2 is
selected from the group consisting of C.sub.1-C.sub.6 alkyl,
C.sub.2-C.sub.6 alkenyl, and C.sub.3-C.sub.8 cycloalkyl, wherein
said R.sup.2 are substituted with 0 to 3 independently selected
halogen atoms; R.sup.3 is selected from the group consisting of H,
C.sub.1-C.sub.8 alkyl, C.sub.3-C.sub.8 cycloalkyl, C.sub.3-C.sub.8
cycloalkyl(C.sub.1-C.sub.8)alkyl, phenyl(C.sub.1-C.sub.8)alkyl,
naphthyl(C.sub.1-C.sub.8)alkyl, and Het groups, wherein when
R.sup.3 is not H, said R.sup.3 is substituted with 0 to 3
substituents independently selected from the group consisting of
halogen atoms, --OR.sup.10, --SR.sup.10, --N(R.sup.10).sub.2,
--N(C.sub.1-C.sub.6 alkyl)O(C.sub.1-C.sub.6 alkyl), C.sub.1-C.sub.6
alkyl, C.sub.1-C.sub.6 haloalkyl, halo(C.sub.1-C.sub.6 alkoxy),
--NO.sub.2, --CN, --CF.sub.3, --SO.sub.2(C.sub.1-C.sub.6 alkyl),
--S(O)(C.sub.1-C.sub.6 alkyl), --NR.sup.10SO.sub.2R.sup.6,
SO.sub.2N(R.sup.6).sub.2, --NHCOOR.sup.6, --NHCOR.sup.6,
--NHCONHR.sup.6, --CO.sub.2R.sup.10, --C(O)R.sup.10, and
--CON(R.sup.10).sub.2; Het is selected from the group consisting of
substituted and unsubstituted 5- and 6-membered saturated
heterocyclic rings having 1 or 2 heteroatoms independently selected
from N, O and S, wherein said substituted rings are substituted
with 1 to 3 substituents independently selected from halogen atoms,
--OR.sup.10, --SR.sup.10, --N(R.sup.10).sub.2, --N(C.sub.1-C.sub.6
alkyl)O(C.sub.1-C.sub.6 alkyl), C.sub.1-C.sub.6 alkyl,
C.sub.1-C.sub.6 haloalkyl, halo(C.sub.1-C.sub.6 alkoxy),
--NO.sub.2, --CN, --CF.sub.3, --SO.sub.2(C.sub.1-C.sub.6 alkyl),
--S(O)(C.sub.1-C.sub.6 alkyl), --NR.sup.10SO.sub.2R.sup.6,
--SO.sub.2N(R.sup.6).sub.2, --NHCOOR.sup.6, --NHCOR.sup.6,
--NHCONHR.sup.6, --CO.sub.2R.sup.10, --C(O)R.sup.10, and
--CON(R.sup.10).sub.2; R.sup.5 is selected from the group
consisting of H, halogen atoms, --OH, C.sub.1-C.sub.6 alkoxy,
C.sub.1-C.sub.6 alkyl, --CN, --CF.sub.3, --OCF.sub.3, --C(O)OH,
--C(O)CH.sub.3, --SR.sup.10, --SO.sub.2(C.sub.1-C.sub.6 alkyl),
C.sub.3-C.sub.8 cycloalkyl, C.sub.3-C.sub.8 cycloalkoxy,
C.sub.1-C.sub.6 haloalkyl, --N(R.sup.7).sub.2, phenyl, naphthyl,
--O-phenyl, --O-naphthyl, heteroaryl and heterocyclyl groups;
wherein: said R.sup.5 heteroaryl is selected from the group
consisting of 5- and 6-membered aromatic rings having 1, 2 or 3
heteroatoms independently selected from N, O and S, and said
R.sup.5 heteroaryl is attached through a ring atom selected from C
or N, said R.sup.5 heterocyclyl is selected from the group
consisting of 5- to 7-membered saturated or unsaturated
non-aromatic rings having 1, 2, 3 or 4 heteroatoms independently
selected from N, O and S, and said R.sup.5 heterocyclyl is attached
through a ring atom selected from C or N, and said R.sup.5
heteroaryl, heterocyclyl, cycloalkyl, cycloalkoxy, alkyl and alkoxy
groups are substituted with 0 to 4 substituents independently
selected from the group consisting of halogen atoms, --OR.sup.10,
--SR.sup.10, --N(R.sup.10).sub.2, --N(C.sub.1-C.sub.6
alkyl)O(C.sub.1-C.sub.6 alkyl), C.sub.1-C.sub.6 alkyl,
C.sub.1-C.sub.6 haloalkyl, halo(C.sub.1-C.sub.6 alkoxy),
--NO.sub.2, --CN, --CF.sub.3, --SO.sub.2(C.sub.1-C.sub.6 alkyl),
--S(O)(C.sub.1-C.sub.6 alkyl), --NR.sup.10SO.sub.2R.sup.6,
--SO.sub.2N(R.sup.6).sub.2, --NHCOOR.sup.6, --NHCOR.sup.6,
--NHCONHR.sup.6, --CO.sub.2R.sup.10, --C(O)R.sup.10, and
--CON(R.sup.10).sub.2, and 2 adjacent substituents of said R.sup.5
heteroaryl, heterocyclyl, cycloalkyl, cycloalkoxy, alkyl and alkoxy
groups may be taken together to form a 3-6-membered cyclic ring
containing 0 to 3 heteroatoms independently selected from N, O and
S; R.sup.6 is selected from the group consisting of C.sub.1-C.sub.6
alkyl, C.sub.3-C.sub.6 cycloalkyl, C.sub.3-C.sub.6
cycloalkyl(C.sub.1-C.sub.5)alkyl, phenyl, naphthyl,
phenyl(C.sub.1-C.sub.4)alkyl, naphthyl(C.sub.1-C.sub.4)alkyl,
heteroaryl, heteroaryl(C.sub.1-C.sub.4 alkyl), heterocyclyl, and
heterocyclyl(C.sub.1-C.sub.8 alkyl) groups, wherein said R.sup.6
are substituted with 0 to 2 independently selected W substituents,
each R.sup.6 heteroaryl is independently selected from the group
consisting of 5- and 6-membered aromatic rings having 1, 2 or 3
heteroatoms independently selected from N, O and S, and said
R.sup.6 heteroaryl is attached through a ring atom selected from C
or N, and each R.sup.6 heterocyclyl is independently selected from
the group consisting of 5- to 7-membered saturated or unsaturated
non-aromatic rings having 1, 2, 3 or 4 heteroatoms independently
selected from N, O and S, and said R.sup.6 heterocyclyl is attached
through a ring atom selected from C or N; Y is selected from the
group consisting of --C(O)--, --SO.sub.2--, --OC(O)--, --C(O)N(D)L-
and -LN(D)C(O)--. and -LN(D)C(O)--, where D is selected from the
group consisting of H, C.sub.1-C.sub.6 alkyl and C.sub.1-C.sub.6
alkenyl groups, L is selected from the group consisting of a direct
bond, -G-(C.sub.1-C.sub.6 alkylene)-, --(C.sub.1-C.sub.6
alkylene)-G-, -G-(C.sub.1-C.sub.6 alkenylene)-, and
--(C.sub.1-C.sub.6 alkenylene)-G-, groups, where said G is selected
from the group consisting of a direct bond, --O--, --N-- and --S--,
said alkylene and alkenylene groups are substituted with 0 to 4
substituents E independently selected from the group consisting of
C.sub.1-C.sub.6 alkyl and C.sub.1-C.sub.6 alkenyl groups, and said
D and E may be taken together to form a 3- to 6-membered ring
containing 0 to 3 heteroatoms selected from N, O and S; Z is
selected from the group consisting of --C(O)-- and a direct bond; M
is selected from the group consisting of C.sub.1-C.sub.12 alkylenes
and C.sub.2-C.sub.12 alkenylenes, wherein said M is substituted
with 0 to 2 substituents F independently selected from the group
consisting of C.sub.1-C.sub.8 alkyl, .dbd.CH.sub.2, C.sub.3-C.sub.8
cycloalkyl(C.sub.1-C.sub.8 alkyl), and aryl(C.sub.1-C.sub.8 alkyl),
and 2 adjacent substituents F may be taken together to form a 3- to
6-membered ring containing 0 to 3 heteroatoms selected from the
group consisting of N, O and S, and one or more adjacent
substituents F may be taken together and/or with an adjacent D or E
to form a 3- to 6-membered ring containing 0 to 3 heteroatoms
independently selected from the group consisting of N, O and S; X
is selected from the group consisting of --O--, --CH.sub.2O--,
--NHC(O)O--, --CH.sub.2NHC(O)O--, --C.ident.CH.sub.2O--, --C(O)O--,
--(CH.sub.2).sub.3O--, --OC(O)NH--, --(CH.sub.2).sub.2C(O)NH--,
--C(O)NH-- and a direct bond; each R.sup.7 is independently
selected from the group consisting of H, C.sub.1-C.sub.6 alkyl,
C.sub.3-C.sub.6 cycloalkyl, C.sub.3-C.sub.6
cycloalkyl(C.sub.1-C.sub.5)alkyl, phenyl, naphthyl,
phenyl(C.sub.1-C.sub.4)alkyl, naphthyl(C.sub.1-C.sub.4)alkyl,
heteroaryl, heteroaryl(C.sub.1-C.sub.4 alkyl), heterocyclyl, and
heterocyclyl(C.sub.1-C.sub.8 alkyl) groups, wherein when R.sup.7 is
not H, said R.sup.7 are substituted with 0 to 2 W substituents,
each R.sup.7 heteroaryl is independently selected from the group
consisting of 5- and 6-membered aromatic rings having 1, 2 or 3
heteroatoms independently selected from N, O and S, and said
R.sup.7 heteroaryl is attached through a ring atom selected from C
or N, and each R.sup.7 heterocyclyl is independently selected from
the group consisting of 5- to 7-membered saturated or unsaturated
non-aromatic rings having 1, 2, 3 or 4 heteroatoms independently
selected from N, O and S, and said R.sup.7 heterocyclyl is attached
through a ring atom selected from C or N, and said R.sup.7 may be
taken together with the atom to which it is attached and a second
R.sup.7 substituent to form a 4- to 7-membered heterocyclic ring;
each W is independently selected from the group consisting of
halogen atoms, --OR.sup.10, C.sub.1-C.sub.6 alkyl, --CN,
--CF.sub.3, --NO.sub.2, --SR.sup.10, --CO.sub.2R.sup.10,
--CON(R.sup.10).sub.2, --C(O)R.sup.10, --N(R.sup.10)C(O)R.sup.10,
--SO.sub.2(C.sub.1-C.sub.6 alkyl), --S(O)(C.sub.1-C.sub.6 alkyl),
C.sub.3-C.sub.8 cycloalkyl, C.sub.3-C.sub.8 cycloalkoxy,
C.sub.1-C.sub.6 haloalkyl, --N(R.sup.10).sub.2, --N(C.sub.1-C.sub.6
alkyl)O(C.sub.1-C.sub.6 alkyl), halo(C.sub.1-C.sub.6 alkoxy),
--NR.sup.10SO.sub.2R.sup.10, --SO.sub.2N(R.sup.10).sub.2,
--NHCOOR.sup.10, --NHCONHR.sup.10, phenyl, naphthyl, heteroaryl and
heterocyclyl groups; wherein said W heteroaryl is selected from the
group consisting of 5- and 6-membered aromatic rings having 1, 2 or
3 heteroatoms independently selected from N, O and S, and said W
heteroaryl is attached through a ring atom selected from C or N,
said W heterocyclyl is selected from the group consisting of 5- to
7-membered saturated or unsaturated non-aromatic rings having 1, 2,
3 or 4 heteroatoms independently selected from N, O and S, and said
W heterocyclyl is attached through a ring atom selected from C or
N; R.sup.8 is selected from the group consisting of C.sub.1-C.sub.8
alkyl, C.sub.3-C.sub.8 cycloalkyl, C.sub.3-C.sub.8
cycloalkyl(C.sub.1-C.sub.8 alkyl), phenyl, naphthyl,
phenyl(C.sub.1-C.sub.4)alkyl, naphthyl(C.sub.1-C.sub.4)alkyl,
heteroaryl, heterocyclic, heteroaryl(C.sub.1-C.sub.4 alkyl), and
heterocyclyl(C.sub.1-C.sub.8 alkyl) groups, wherein said R.sup.8
are substituted with 0 to 4 substituents selected from the group
consisting of phenyl, naphthyl, C.sub.3-C.sub.8 cycloalkyl,
heteroaryl, heterocyclyl, C.sub.1-C.sub.6 alkyl,
halo(C.sub.1-C.sub.6 alkoxy), halogen atoms, --OR.sup.10,
--SR.sup.10, --N(R.sup.10).sub.2, --N(C.sub.1-C.sub.6
alkyl)O(C.sub.1-C.sub.6 alkyl), C.sub.1-C.sub.6 alkyl,
--C(O)R.sup.10, C.sub.1-C.sub.6 haloalkyl, --NO.sub.2, --CN,
--CF.sub.3, --SO.sub.2(C.sub.1-C.sub.6 alkyl),
--S(O)(C.sub.1-C.sub.6 alkyl), --NR.sup.10SO.sub.2R.sup.6,
--SO.sub.2N(R.sup.6).sub.2, --NHCOOR.sup.6, --NHCOR.sup.6,
--NHCONHR.sup.6, --CO.sub.2R.sup.10, and --C(O)N(R.sup.10).sub.2,
each R.sup.8 heteroaryl is independently selected from the group
consisting of 5- and 6-membered aromatic rings having 1, 2 or 3
heteroatoms independently selected from N, O and S, and said
R.sup.8 heteroaryl is attached through a ring atom selected from C
or N, each R.sup.8 heterocyclyl is independently selected from the
group consisting of 5- to 7-membered saturated or unsaturated
non-aromatic rings having 1, 2, 3 or 4 heteroatoms independently
selected from N, O and S, and said R.sup.8 heterocyclyl is attached
through a ring atom selected from C or N, and 2 adjacent
substituents of said R.sup.8 may be taken together to form a 3- to
6-membered ring containing 0 to 3 heteroatoms independently
selected from the group consisting of N, O and S; R.sup.9 is
selected from the group consisting of C.sub.1-C.sub.8 alkyl,
C.sub.3-C.sub.8 cycloalkyl, C.sub.3-C.sub.8
cycloalkyl(C.sub.1-C.sub.8 alkyl), C.sub.1-C.sub.8 alkoxy,
C.sub.3-C.sub.8 cycloalkoxy, phenyl, naphthyl,
phenyl(C.sub.1-C.sub.4)alkyl, naphthyl(C.sub.1-C.sub.4)alkyl,
heteroaryl, heterocyclyl, heteroaryl(C.sub.1-C.sub.4 alkyl), or
heterocyclyl(C.sub.1-C.sub.8 alkyl) groups, wherein said R.sup.9
are substituted with 0 to 4 substituents selected from the group
consisting of phenyl, naphthyl, C.sub.3-C.sub.8 cycloalkyl,
heteroaryl, heterocyclyl, C.sub.1-C.sub.6 alkyl,
halo(C.sub.1-C.sub.6 alkoxy), halogen atoms, --OR.sup.10,
--SR.sup.10, --N(R.sup.10).sub.2, --N(C.sub.1-C.sub.6
alkyl)O(C.sub.1-C.sub.6 alkyl), C.sub.1-C.sub.6 alkyl,
--C(O)R.sup.10, C.sub.1-C.sub.6 haloalkyl, --NO.sub.2, --CN,
--CF.sub.3, --SO.sub.2(C.sub.1-C.sub.6 alkyl),
--S(O)(C.sub.1-C.sub.6 alkyl), --NR.sup.10SO.sub.2R.sup.6,
--SO.sub.2N(R.sup.6).sub.2, --NHCOOR.sup.6, --NHCOR.sup.6,
--NHCONHR.sup.6, --CO.sub.2R.sup.10, and --C(O)N(R.sup.10).sub.2,
each R.sup.9 heteroaryl is independently selected from the group
consisting of 5- and 6-membered aromatic rings having 1, 2 or 3
heteroatoms independently selected from N, O and S, and said
R.sup.9 heteroaryl is attached through a ring atom selected from C
or N, each R.sup.9 heterocyclyl is independently selected from the
group consisting of 5- to 7-membered saturated or unsaturated
non-aromatic rings having 1, 2, 3 or 4 heteroatoms independently
selected from N, O and S, and said R.sup.9 heterocyclyl is attached
through a ring atom selected from C or N, and 2 adjacent
substituents of said R.sup.9 may be taken together to form a 3- to
6-membered ring containing 0 to 3 heteroatoms independently
selected from the group consisting of N, O and S, and R.sup.8 and
R.sup.9 may be taken together, with the N to which they are
attached, to form a 4- to 8-membered monocyclic ring containing 0
to 2 additional heteroatoms independently selected from N, O and S;
each R.sup.10 is independently selected from the group consisting
of H and C.sub.1-C.sub.6 alkyl; each R.sup.11 is independently
selected from the group consisting of C.sub.1-C.sub.6 alkyl,
C.sub.1-C.sub.4 alkenyl, --OR.sup.13,
--N(R.sup.10)--V--CO.sub.2R.sup.10, --O--V--CO.sub.2R.sup.10,
--S--V--CO.sub.2R.sup.10, --N(R.sup.10)(R.sup.13), --R.sup.14, and
--N(R.sup.10SO.sub.2R.sup.6; each R.sup.12 is independently
selected from the group consisting of --OR.sup.13,
--N(R.sup.10)--V--CO.sub.2
R.sup.10, --O--V--CO.sub.2R.sup.10, --S--V--CO.sub.2R.sup.10, and
--N(R.sup.10)(R.sup.13); R.sup.11 and R.sup.12 may be taken
together, with the phosphorus atom to which they are attached, to
form a 5- to 7-membered monocyclic ring; each V is independently
selected from the group consisting of --CH(R.sup.15)-- and
--(C.sub.1-C.sub.4 alkylene)-CH(R.sup.15)--; each R.sup.13 is
independently selected from the group consisting of H,
C.sub.1-C.sub.6 alkyl, C.sub.2-C.sub.6 alkenyl, C.sub.3-C.sub.8
cycloalkyl, aryl, heteroaryl, and heterocyclyl groups, wherein when
R.sup.13 is not H, said R.sup.13 is substituted with 0 to 2
substituents independently selected from the group consisting of
phenyl, naphthyl, phenyl(C.sub.1-C.sub.4 alkyl),
naphthyl(C.sub.1-C.sub.4 alkyl), C.sub.3-C.sub.8 cycloalkyl,
C.sub.3-C.sub.8 cycloalkyl(C.sub.1-C.sub.4 alkyl), heteroaryl,
heteroaryl(C.sub.1-C.sub.4 alkyl), heterocyclyl,
heterocyclyl(C.sub.1-C.sub.4 alkyl), C.sub.1-C.sub.6 alkyl, halogen
atoms, --OC(O)OR.sup.6, --OC(O)R.sup.6, --OR.sup.10, --SR.sup.10,
--N(R.sup.10).sub.2, --C(O)R.sup.10, --NO.sub.2, --CN, --CF.sub.3,
--SO.sub.2(C.sub.1-C.sub.6 alkyl), --S(O)(C.sub.1-C.sub.6 alkyl),
--NR.sup.10SO.sub.2R.sup.6, --SO.sub.2N(R.sup.6).sub.2,
--NHCOOR.sup.6, --NHCOR.sup.6, --NHCONHR.sup.6, --CO.sub.2R.sup.10,
and --C(O)N(R.sup.10).sub.2, each R.sup.13 heteroaryl is
independently selected from the group consisting of 5- and
6-membered aromatic rings having 1, 2 or 3 heteroatoms
independently selected from N, O and S, and said R.sup.13
heteroaryl is attached through a ring atom selected from C or N,
each R.sup.13 heterocyclyl is independently selected from the group
consisting of 5- to 7-membered saturated or unsaturated
non-aromatic rings having 1, 2, 3 or 4 heteroatoms independently
selected from N, O and S, and said R.sup.13 heterocyclyl is
attached through a ring atom selected from C or N, and 2 adjacent
substituents of said R.sup.13 may be taken together to form a 3- to
6-membered ring containing 0 to 3 heteroatoms independently
selected from the group consisting of N, O and S; R.sup.14 is
selected from the group consisting of C.sub.1-C.sub.6 alkyl,
C.sub.2-C.sub.6 alkenyl, phenyl, naphthyl and heteroaryl, wherein
each R.sup.14 heteroaryl is independently selected from the group
consisting of 5- and 6-membered aromatic rings having 1, 2 or 3
heteroatoms independently selected from N, O and S, and said
R.sup.14 heteroaryl is attached through a ring atom selected from C
or N, and said R.sup.14 phenyl, naphthyl or heteroaryl may be
substituted with 0 to 2 substituents independently selected from
the group consisting of C.sub.1-C.sub.6 alkyl, halogen atoms,
--OC(O)OR.sup.6, --OC(O)R.sup.6, --OR.sup.10, --SR.sup.10,
--N(R.sup.10).sub.2, --C(O)R.sup.10, --NO.sub.2, --CN, --CF.sub.3,
--SO.sub.2(C.sub.1-C.sub.6 alkyl), --S(O)(C.sub.1-C.sub.6 alkyl),
--NR.sup.10SO.sub.2R.sup.6, --SO.sub.2N(R.sup.6).sub.2,
--NHCOOR.sup.6, --NHCOR.sup.6, --NHCONHR.sup.6, --CO.sub.2R.sup.10,
and --C(O)N(R.sup.10).sub.2; and each R.sup.15 is independently
selected from the group consisting of C.sub.1-C.sub.6 alkyl,
C.sub.2-C.sub.6 alkenyl, C.sub.3-C.sub.8 cycloalkyl, phenyl,
naphthyl, heteroaryl, and heterocyclyl groups, wherein said
R.sup.15 are substituted with 0 to 2 substituents independently
selected from the group consisting of C.sub.1-C.sub.6 alkyl,
halogen atoms, --OC(O)OR.sup.6, --OC(O)R.sup.6, --OR.sup.10,
--SR.sup.10, --N(R.sup.10).sub.2, --C(O)R.sup.10, --NO.sub.2, --CN,
--CF.sub.3, --SO.sub.2(C.sub.1-C.sub.6 alkyl),
--S(O)(C.sub.1-C.sub.6 alkyl), --NR.sup.10SO.sub.2R.sup.6,
--SO.sub.2N(R.sup.6).sub.2, --NHCOOR.sup.6, --NHCOR.sup.6,
--NHCONHR.sup.6, --CO.sub.2R.sup.10, and --C(O)N(R.sup.10).sub.2,
each R.sup.15 heteroaryl is independently selected from the group
consisting of 5- and 6-membered aromatic rings having 1, 2 or 3
heteroatoms independently selected from N, O and S, and said
R.sup.15 heteroaryl is attached through a ring atom selected from C
or N, each R.sup.15 heterocyclyl is independently selected from the
group consisting of 5- to 7-membered saturated or unsaturated
non-aromatic rings having 1, 2, 3 or 4 heteroatoms independently
selected from N, O and S, and said R.sup.15 heterocyclyl is
attached through a ring atom selected from C or N, and 2 adjacent
substituents of said R.sup.15 are optionally taken together to form
a 3- to 6-membered ring containing 0 to 3 heteroatoms independently
selected from the group consisting of N, O and S.
Description
FIELD OF THE INVENTION
[0001] The present invention relates to macrocyclic compounds that
are useful as inhibitors of the hepatitis C virus (HCV) NS3
protease, the synthesis of such compounds, and the use of such
compounds for treating HCV infection and/or reducing the likelihood
or severity of symptoms of HCV infection.
BACKGROUND OF THE INVENTION
[0002] Hepatitis C virus (HCV) infection is a major health problem
that leads to chronic liver disease, such as cirrhosis and
hepatocellular carcinoma, in a substantial number of infected
individuals, estimated to be 2-15% of the world's population. There
are an estimated 3.9 million infected people in the United States
alone, according to the U.S. Center for Disease Control, roughly
five times the number of people infected with the human
immunodeficiency virus (HIV). According to the World Health
Organization, there are more than 170 million infected individuals
worldwide, with at least 3 to 4 million people being infected each
year. Once infected, about 20% of people clear the virus, but about
80% of those infected harbor HCV the rest of their lives. Ten to
20% of chronically infected individuals eventually develop
liver-destroying cirrhosis or cancer. The viral disease is
transmitted parenterally by contaminated blood and blood products,
contaminated needles, or sexually and vertically from infected
mothers or carrier mothers to their off-spring.
[0003] Current treatments for HCV infection, which are restricted
to immunotherapy with recombinant interferon-.alpha. alone or in
combination with the nucleoside analog ribavirin, are of limited
clinical benefit. Moreover, there is no established vaccine for
HCV. Consequently, there is an urgent need for improved therapeutic
agents that effectively combat chronic HCV infection. The current
state of the art in the treatment of HCV infection has been
discussed in the following references: B. Dymock et al., "Novel
approaches to the treatment of hepatitis C virus infection," 11
Antiviral Chem. & Chemotherapy 79-96 (2000); H. Rosen et al.,
"Hepatitis C virus: current understanding and prospects for future
therapies," 5 Molec. Med. Today 393-399 (1999); D. Moradpour et
al., "Current and evolving therapies for hepatitis C," 11 Euro. J.
Gastroenterol. Hepatol. 1189-1202 (1999); R. Bartenschlager,
"Candidate Targets for Hepatitis C Virus-Specific Antiviral
Therapy," 40(5-6) Intervirology 378-393 (1997); G. M. Lauer &
B. D. Walker, "Hepatitis C Virus Infection," 345 N. Engl. J. Med.
41-52 (2001); B. W. Dymock, "Emerging therapies for hepatitis C
virus infection," 6 Emerging Drugs 13-42 (2001); and C. Crabb,
"Hard-Won Advances Spark Excitement about Hepatitis C," Science:
506-507 (2001).
[0004] Several virally-encoded enzymes are putative targets for
therapeutic intervention, including a metalloprotease (NS2-3), a
serine protease (NS3), a helicase (NS3), and an RNA-dependent RNA
polymerase (NS5B). The NS3 protease is located in the N-terminal
domain of the NS3 protein. Because it is responsible for an
intramolecular cleavage at the NS3/4A site and for downstream
intermolecular processing at the NS4A/4B, NS4B/5A and NS5A/5B
junctions, the NS3 protease is considered a prime drug target.
Previous research has identified classes of peptides, such as
hexapeptides as well as tripeptides discussed in U.S. Patent
Application Publications US2005/0020503, US2004/0229818, and
US2004/00229776, showing degrees of activity in inhibiting the NS3
protease. The aim of the present invention is to provide further
compounds which exhibit activity against the HCV NS3 protease.
SUMMARY OF THE INVENTION
[0005] The present invention relates to novel macrocyclic compounds
of formula (I) and/or pharmaceutically acceptable salts or hydrates
thereof. These compounds are useful in the inhibition of HCV
(hepatitis C virus) NS3 (non-structural 3) protease, the prevention
or treatment of one or more of the symptoms of HCV infection,
either as compounds or their pharmaceutically acceptable salts or
hydrates (when appropriate), or as pharmaceutical composition
ingredients. As pharmaceutical composition ingredients, these
compounds, salts and hydrates may be the primary active therapeutic
agent, and, when appropriate, may be combined with other
therapeutic agents including but not limited to other HCV
antivirals, anti-infectives, immunomodulators, antibiotics or
vaccines. More particularly, the present invention relates to a
compound of formula (I) and/or a pharmaceutically acceptable salt
or hydrate thereof:
##STR00002##
wherein:
##STR00003##
is one or more rings selected from the group consisting of:
[0006] 1) aryl rings,
[0007] 2) C.sub.3-C.sub.8 cycloalkyl rings, and
[0008] 3) heterocyclic rings in which the heterocyclic ring system
attaches to Z and X at points that are two independently selected
ring atoms that are either two acarbon ring atoms or one carbon
ring atom and one nitrogen ring atom, and the heterocyclic ring
system is selected from the group consisting of:
[0009] a) 5- or 6-membered saturated or unsaturated monocyclic
rings with 1, 2, or 3 heteroatom ring atoms independently selected
from the group consisting of N, O or S,
[0010] b) 8-, 9- or 10-membered saturated or unsaturated bicyclic
rings with 1, 2, or 3 heteroatom ring atoms independently selected
from the group consisting of N, O or S, and
[0011] c) 11- to 15-membered saturated or unsaturated tricyclic
rings with 1, 2, 3, or 4 heteroatom ring atoms independently
selected from the group consisting of N, O or S,
[0012] wherein
##STR00004##
is substituted with 0 to 4 independently selected substituents W,
R.sup.5 or oxo; wherein for stable heterocyclic rings containing S
or N, the heterocyclic ring is unsubstituted at the S or N atom or
is substituted at the S or N atom by oxo; wherein said W and
R.sup.5 substitutions are located on one or more ring atoms
selected from C and N; and provided that the 10-membered
unsaturated bicyclic ring is not quinoline, quinazoline or
isoquinoline with the following modes of attachment
##STR00005##
[0013] R.sup.1 is selected from the group consisting of
--CO.sub.2R.sup.10, --CONR.sup.10SO.sub.2R.sup.6,
--CONR.sup.10SO.sub.2NR.sup.8R.sup.9, tetrazolyl,
--CONHP(O)R.sup.11R.sup.12, and --P(O)R.sup.11R.sup.12;
[0014] R.sup.2 is selected from the group consisting of
C.sub.1-C.sub.6 alkyl, C.sub.2-C.sub.6 alkenyl, and C.sub.3-C.sub.8
cycloalkyl, wherein said R.sup.2 are substituted with 0 to 3
independently selected halogen atoms;
[0015] R.sup.3 is selected from the group consisting of H,
C.sub.1-C.sub.8 alkyl, C.sub.3-C.sub.8 cycloalkyl, C.sub.3-C.sub.8
cycloalkyl(C.sub.1-C.sub.8)alkyl, phenyl(C.sub.1-C.sub.8)alkyl,
naphthyl(C.sub.1-C.sub.8)alkyl, and Het groups, wherein when
R.sup.3 is not H, said R.sup.3 is substituted with 0 to 3
substituents independently selected from the group consisting of
halogen atoms, --OR.sup.10, --SR.sup.10, --N(R.sup.10).sub.2,
--N(C.sub.1-C.sub.6 alkyl)O(C.sub.1-C.sub.6 alkyl), C.sub.1-C.sub.6
alkyl, C.sub.1-C.sub.6 haloalkyl, halo(C.sub.1-C.sub.6 alkoxy),
--NO.sub.2, --CN, --CF.sub.3, --SO.sub.2(C.sub.1-C.sub.6 alkyl),
--S(O)(C.sub.1-C.sub.6 alkyl), --NR.sup.10SO.sub.2R.sup.6,
SO.sub.2N(R.sup.6).sub.2, --NHCOOR.sup.6, --NHCOR.sup.6,
--NHCONHR.sup.6, --CO.sub.2R.sup.10, --C(O)R.sup.10, and
--CON(R.sup.10).sub.2;
[0016] Het is selected from the group consisting of substituted and
unsubstituted 5- and 6-membered saturated heterocyclic rings having
1 or 2 heteroatoms independently selected from N, O and S, wherein
said substituted rings are substituted with 1 to 3 substituents
independently selected from halogen atoms, --OR.sup.10,
--SR.sup.10, --N(R.sup.10).sub.2, --N(C.sub.1-C.sub.6
alkyl)O(C.sub.1-C.sub.6 alkyl), C.sub.1-C.sub.6 alkyl,
C.sub.1-C.sub.6 haloalkyl, halo(C.sub.1-C.sub.6 alkoxy),
--NO.sub.2, --CN, --CF.sub.3, --SO.sub.2(C.sub.1-C.sub.6 alkyl),
--S(O)(C.sub.1-C.sub.6 alkyl), --NR.sup.10SO.sub.2R.sup.6,
SO.sub.2N(R.sup.6).sub.2, --NHCOOR.sup.6, --NHCOR.sup.6,
--NHCONHR.sup.6, --CO.sub.2R.sup.10, --C(O)R.sup.10, and
--CON(R.sup.10).sub.2;
[0017] R.sup.5 is selected from the group consisting of H, halogen
atoms, --OH, C.sub.1-C.sub.6 alkoxy, C.sub.1-C.sub.6 alkyl, --CN,
--CF.sub.3, --OCF.sub.3, --C(O)OH, --C(O)CH.sub.3, --SR.sup.10,
--SO.sub.2(C.sub.1-C.sub.6 alkyl), C.sub.3-C.sub.8 cycloalkyl,
C.sub.3-C.sub.8 cycloalkoxy, C.sub.1-C.sub.6 haloalkyl,
--N(R.sup.7).sub.2, phenyl, naphthyl, --O-phenyl, --O-naphthyl,
heteroaryl and heterocyclyl groups; wherein:
[0018] said R.sup.5 heteroaryl is selected from the group
consisting of 5- and 6-membered aromatic rings having 1, 2 or 3
heteroatoms independently selected from N, O and S, and said
R.sup.5 heteroaryl is attached through a ring atom selected from C
or N,
[0019] said R.sup.5 heterocyclyl is selected from the group
consisting of 5- to 7-membered saturated or unsaturated
non-aromatic rings having 1, 2, 3 or 4 heteroatoms independently
selected from N, O and S, and said R.sup.5 heterocyclyl is attached
through a ring atom selected from C or N, and
[0020] said R.sup.5 heteroaryl, heterocyclyl, cycloalkyl,
cycloalkoxy, alkyl and alkoxy groups are substituted with 0 to 4
substituents independently selected from the group consisting of
halogen atoms, --OR.sup.10, --SR.sup.10, --N(R.sup.10).sub.2,
--N(C.sub.1-C.sub.6 alkyl)O(C.sub.1-C.sub.6 alkyl), C.sub.1-C.sub.6
alkyl, C.sub.1-C.sub.6 haloalkyl, halo(C.sub.1-C.sub.6 alkoxy),
--NO.sub.2, --CN, --CF.sub.3, --SO.sub.2(C.sub.1-C.sub.6 alkyl),
--S(O)(C.sub.1-C.sub.6 alkyl), --NR.sup.10SO.sub.2R.sup.6,
SO.sub.2N(R.sup.6).sub.2, --NHCOOR.sup.6, --NHCOR.sup.6,
--NHCONHR.sup.6, --CO.sub.2R.sup.10, --C(O)R.sup.10, and
--CON(R.sup.10).sub.2, and 2 adjacent substituents of said R.sup.5
heteroaryl, heterocyclyl, cycloalkyl, cycloalkoxy, alkyl and alkoxy
groups may be taken together to form a 3-6-membered cyclic ring
containing 0 to 3 heteroatoms independently selected from N, O and
S;
[0021] R.sup.6 is selected from the group consisting of
C.sub.1-C.sub.6 alkyl, C.sub.3-C.sub.6 cycloalkyl, C.sub.3-C.sub.6
cycloalkyl(C.sub.1-C.sub.5)alkyl, phenyl, naphthyl,
phenyl(C.sub.1-C.sub.4)alkyl, naphthyl(C.sub.1-C.sub.4)alkyl,
heteroaryl, heteroaryl(C.sub.1-C.sub.4 alkyl), heterocyclyl, and
heterocyclyl(C.sub.1-C.sub.8 alkyl) groups, wherein
[0022] said R.sup.6 are substituted with 0 to 2 independently
selected W substituents,
[0023] each R.sup.6 heteroaryl is independently selected from the
group consisting of 5- and 6-membered aromatic rings having 1, 2 or
3 heteroatoms independently selected from N, O and S, and said
R.sup.6 heteroaryl is attached through a ring atom selected from C
or N, and
[0024] each R.sup.6 heterocyclyl is independently selected from the
group consisting of 5- to 7-membered saturated or unsaturated
non-aromatic rings having 1, 2, 3 or 4 heteroatoms independently
selected from N, O and S, and said R.sup.6 heterocyclyl is attached
through a ring atom selected from C or N;
[0025] Y is selected from the group consisting of --C(O)--,
--SO.sub.2--, --OC(O)--, --C(O)N(D)L- and -LN(D)C(O)--. and
-LN(D)C(O)--, where
[0026] D is selected from the group consisting of H,
C.sub.1-C.sub.6 alkyl and C.sub.1-C.sub.6 alkenyl groups,
[0027] L is selected from the group consisting of a direct bond,
-G-(C.sub.1-C.sub.6 alkylene)-, --(C.sub.1-C.sub.6 alkylene)-G-,
-G-(C.sub.1-C.sub.6 alkenylene)-, and --(C.sub.1-C.sub.6
alkenylene)-G-, groups, where said G is selected from the group
consisting of a direct bond, --O--, --N-- and --S--, said alkylene
and alkenylene groups are substituted with 0 to 4 substituents E
independently selected from the group consisting of C.sub.1-C.sub.6
alkyl and C.sub.1-C.sub.6 alkenyl groups, and
[0028] said D and E may be taken together to form a 3- to
6-membered ring containing 0 to 3 heteroatoms selected from N, O
and S;
[0029] Z is selected from the group consisting of --C(O)-- and a
direct bond;
[0030] M is selected from the group consisting of C.sub.1-C.sub.12
alkylenes and C.sub.2-C.sub.12 alkenylenes, wherein said M is
substituted with 0 to 2 substituents F independently selected from
the group consisting of C.sub.1-C.sub.8 alkyl, .dbd.CH.sub.2,
C.sub.3-C.sub.8 cycloalkyl(C.sub.1-C.sub.8 alkyl), and
aryl(C.sub.1-C.sub.8 alkyl), and 2 adjacent substituents F may be
taken together to form a 3- to 6-membered ring containing 0 to 3
heteroatoms selected from the group consisting of N, O and S, and
one or more adjacent substituents F may be taken together and/or
with an adjacent D or E to form a 3- to 6-membered ring containing
0 to 3 heteroatoms independently selected from the group consisting
of N, O and S;
[0031] X is selected from the group consisting of --O--,
--CH.sub.2O--, --NHC(O)O--, --CH.sub.2NHC(O)O--,
--C.ident.CCH.sub.2O--, --C(O)O--, --(CH.sub.2).sub.3O--,
--OC(O)NH--, --(CH.sub.2).sub.2C(O)NH--, --C(O)NH-- and a direct
bond;
[0032] each R.sup.7 is independently selected from the group
consisting of H, C.sub.1-C.sub.6 alkyl, C.sub.3-C.sub.6 cycloalkyl,
C.sub.3-C.sub.6 cycloalkyl(C.sub.1-C.sub.5)alkyl, phenyl, naphthyl,
phenyl(C.sub.1-C.sub.4)alkyl, naphthyl(C.sub.1-C.sub.4)alkyl,
heteroaryl, heteroaryl(C.sub.1-C.sub.4 alkyl), heterocyclyl, and
heterocyclyl(C.sub.1-C.sub.8 alkyl) groups, wherein
[0033] when R.sup.7 is not H, said R.sup.7 are substituted with 0
to 2 W substituents,
[0034] each R.sup.7 heteroaryl is independently selected from the
group consisting of 5- and 6-membered aromatic rings having 1, 2 or
3 heteroatoms independently selected from N, O and S, and said
R.sup.7 heteroaryl is attached through a ring atom selected from C
or N, and
[0035] each R.sup.7 heterocyclyl is independently selected from the
group consisting of 5- to 7-membered saturated or unsaturated
non-aromatic rings having 1, 2, 3 or 4 heteroatoms independently
selected from N, O and S, and said R.sup.7 heterocyclyl is attached
through a ring atom selected from C or N, and
[0036] said R.sup.7 may be taken together with the atom to which it
is attached and a second R.sup.7 substituent to form a 4- to
7-membered heterocyclic ring;
[0037] each W is independently selected from the group consisting
of halogen atoms, --OR.sup.10, C.sub.1-C.sub.6 alkyl, --CN,
--CF.sub.3, --NO.sub.2, --SR.sup.10, --CO.sub.2R.sup.10,
--CON(R.sup.10).sub.2, --C(O)R.sup.10, --N(R.sup.10)C(O)R.sup.10,
--SO.sub.2(C.sub.1-C.sub.6 alkyl), --S(O)(C.sub.1-C.sub.6 alkyl),
C.sub.3-C.sub.8 cycloalkyl, C.sub.3-C.sub.8 cycloalkoxy,
C.sub.1-C.sub.6 haloalkyl, --N(R.sup.10).sub.2, --N(C.sub.1-C.sub.6
alkyl)O(C.sub.1-C.sub.6 alkyl), halo(C.sub.1-C.sub.6 alkoxy),
--NR.sup.10SO.sub.2R.sup.10, --SO.sub.2N(R.sup.10).sub.2,
--NHCOOR.sup.10, --NHCONHR.sup.10, phenyl, naphthyl, heteroaryl and
heterocyclyl groups; wherein
[0038] said W heteroaryl is selected from the group consisting of
5- and 6-membered aromatic rings having 1, 2 or 3 heteroatoms
independently selected from N, O and S, and said W heteroaryl is
attached through a ring atom selected from C or N,
[0039] said W heterocyclyl is selected from the group consisting of
5- to 7-membered saturated or unsaturated non-aromatic rings having
1, 2, 3 or 4 heteroatoms independently selected from N, O and S,
and said W heterocyclyl is attached through a ring atom selected
from C or N;
[0040] R.sup.8 is selected from the group consisting of
C.sub.1-C.sub.8 alkyl, C.sub.3-C.sub.8 cycloalkyl, C.sub.3-C.sub.8
cycloalkyl(C.sub.1-C.sub.8 alkyl), phenyl, naphthyl,
phenyl(C.sub.1-C.sub.4)alkyl, naphthyl(C.sub.1-C.sub.4)alkyl,
heteroaryl, heterocyclic, heteroaryl(C.sub.1-C.sub.4 alkyl), and
heterocyclyl(C.sub.1-C.sub.8 alkyl) groups, wherein
[0041] said R.sup.8 are substituted with 0 to 4 substituents
selected from the group consisting of phenyl, naphthyl,
C.sub.3-C.sub.8 cycloalkyl, heteroaryl, heterocyclyl,
C.sub.1-C.sub.6 alkyl, halo(C.sub.1-C.sub.6 alkoxy), halogen atoms,
--OR.sup.10, --SR.sup.10, --N(R.sup.10).sub.2, --N(C.sub.1-C.sub.6
alkyl)O(C.sub.1-C.sub.6 alkyl), C.sub.1-C.sub.6 alkyl,
--C(O)R.sup.10, C.sub.1-C.sub.6 haloalkyl, --NO.sub.2, --CN,
--CF.sub.3, --SO.sub.2(C.sub.1-C.sub.6 alkyl),
--S(O)(C.sub.1-C.sub.6 alkyl), --NR.sup.10SO.sub.2R.sup.6,
--SO.sub.2N(R.sup.6).sub.2, --NHCOOR.sup.6, --NHCOR.sup.6,
--NHCONHR.sup.6, --CO.sub.2R.sup.10, and
--C(O)N(R.sup.10).sub.2,
[0042] each R.sup.8 heteroaryl is independently selected from the
group consisting of 5- and 6-membered aromatic rings having 1, 2 or
3 heteroatoms independently selected from N, O and S, and said
R.sup.8 heteroaryl is attached through a ring atom selected from C
or N,
[0043] each R.sup.8 heterocyclyl is independently selected from the
group consisting of 5- to 7-membered saturated or unsaturated
non-aromatic rings having 1, 2, 3 or 4 heteroatoms independently
selected from N, O and S, and said R.sup.8 heterocyclyl is attached
through a ring atom selected from C or N, and
[0044] 2 adjacent substituents of said R.sup.8 may be taken
together to form a 3- to 6-membered ring containing 0 to 3
heteroatoms independently selected from the group consisting of N,
O and S;
[0045] R.sup.9 is selected from the group consisting of
C.sub.1-C.sub.8 alkyl, C.sub.3-C.sub.8 cycloalkyl, C.sub.3-C.sub.8
cycloalkyl(C.sub.1-C.sub.8 alkyl), C.sub.1-C.sub.8 alkoxy,
C.sub.3-C.sub.8 cycloalkoxy, phenyl, naphthyl,
phenyl(C.sub.1-C.sub.4)alkyl, naphthyl(C.sub.1-C.sub.4)alkyl,
heteroaryl, heterocyclyl, heteroaryl(C.sub.1-C.sub.4 alkyl), or
heterocyclyl(C.sub.1-C.sub.8 alkyl) groups, wherein
[0046] said R.sup.9 are substituted with 0 to 4 substituents
selected from the group consisting of phenyl, naphthyl,
C.sub.3-C.sub.8 cycloalkyl, heteroaryl, heterocyclyl,
C.sub.1-C.sub.6 alkyl, halo(C.sub.1-C.sub.6 alkoxy), halogen atoms,
--OR.sup.10, --SR.sup.10, --N(R.sup.10).sub.2, --N(C.sub.1-C.sub.6
alkyl)O(C.sub.1-C.sub.6 alkyl), C.sub.1-C.sub.6 alkyl,
--C(O)R.sup.10, C.sub.1-C.sub.6 haloalkyl, --NO.sub.2, --CN,
--CF.sub.3, --SO.sub.2(C.sub.1-C.sub.6 alkyl),
--S(O)(C.sub.1-C.sub.6 alkyl), --NR.sup.10SO.sub.2R.sup.6,
--SO.sub.2N(R.sup.6).sub.2, --NHCOOR.sup.6, --NHCOR.sup.6,
--NHCONHR.sup.6, --CO.sub.2R.sup.10, and
--C(O)N(R.sup.10).sub.2,
[0047] each R.sup.9 heteroaryl is independently selected from the
group consisting of 5- and 6-membered aromatic rings having 1, 2 or
3 heteroatoms independently selected from N, O and S, and said
R.sup.9 heteroaryl is attached through a ring atom selected from C
or N,
[0048] each R.sup.9 heterocyclyl is independently selected from the
group consisting of 5- to 7-membered saturated or unsaturated
non-aromatic rings having 1, 2, 3 or 4 heteroatoms independently
selected from N, O and S, and said R.sup.9 heterocyclyl is attached
through a ring atom selected from C or N, and
[0049] 2 adjacent substituents of said R.sup.9 may be taken
together to form a 3- to 6-membered ring containing 0 to 3
heteroatoms independently selected from the group consisting of N,
O and S, and
[0050] R.sup.8 and R.sup.9 may be taken together, with the N to
which they are attached, to form a 4- to 8-membered monocyclic ring
containing 0 to 2 additional heteroatoms independently selected
from N, O and S;
[0051] each R.sup.10 is independently selected from the group
consisting of H and C.sub.1-C.sub.6 alkyl;
[0052] each R.sup.11 is independently selected from the group
consisting of C.sub.1-C.sub.6 alkyl, C.sub.1-C.sub.4 alkenyl,
--OR.sup.13, --N(R.sup.10)--V--CO.sub.2R.sup.10,
--O--V--CO.sub.2R.sup.10, --S--V--CO.sub.2R.sup.10,
--N(R.sup.10)(R.sup.13), --R.sup.14, and
--N(R.sup.10SO.sub.2R.sup.6;
[0053] each R.sup.12 is independently selected from the group
consisting of --OR.sup.13, --N(R.sup.10)--V--CO.sub.2R.sup.10,
--O--V--CO.sub.2R.sup.10, --S--V--CO.sub.2R.sup.10, and
--N(R.sup.10)(R.sup.13);
[0054] R.sup.11 and R.sup.12 may be taken together, with the
phosphorus atom to which they are attached, to form a 5- to
7-membered monocyclic ring;
[0055] each V is independently selected from the group consisting
of --CH(R.sup.15)-- and --(C.sub.1-C.sub.4
alkylene)-CH(R.sup.15)--;
[0056] each R.sup.13 is independently selected from the group
consisting of H, C.sub.1-C.sub.6 alkyl, C.sub.2-C.sub.6 alkenyl,
C.sub.3-C.sub.8 cycloalkyl, aryl, heteroaryl, and heterocyclyl
groups, wherein
[0057] when R.sup.13 is not H, said R.sup.13 is substituted with 0
to 2 substituents independently selected from the group consisting
of phenyl, naphthyl, phenyl(C.sub.1-C.sub.4 alkyl),
naphthyl(C.sub.1-C.sub.4 alkyl), C.sub.3-C.sub.8 cycloalkyl,
C.sub.3-C.sub.8 cycloalkyl(C.sub.1-C.sub.4 alkyl), heteroaryl,
heteroaryl(C.sub.1-C.sub.4 alkyl), heterocyclyl,
heterocyclyl(C.sub.1-C.sub.4 alkyl), C.sub.1-C.sub.6 alkyl, halogen
atoms, --OC(O)OR.sup.6, --OC(O)R.sup.6, --OR.sup.10, --SR.sup.10,
--N(R.sup.10).sub.2, --C(O)R.sup.10, --NO.sub.2, --CN, --CF.sub.3,
--SO.sub.2(C.sub.1-C.sub.6 alkyl), --S(O)(C.sub.1-C.sub.6 alkyl),
--NR.sup.10SO.sub.2R.sup.6, --SO.sub.2N(R.sup.6).sub.2,
--NHCOOR.sup.6, --NHCOR.sup.6, --NHCONHR.sup.6, --CO.sub.2R.sup.10,
and --C(O)N(R.sup.10).sub.2,
[0058] each R.sup.13 heteroaryl is independently selected from the
group consisting of 5- and 6-membered aromatic rings having 1, 2 or
3 heteroatoms independently selected from N, O and S, and said
R.sup.13 heteroaryl is attached through a ring atom selected from C
or N,
[0059] each R.sup.13 heterocyclyl is independently selected from
the group consisting of 5- to 7-membered saturated or unsaturated
non-aromatic rings having 1, 2, 3 or 4 heteroatoms independently
selected from N, O and S, and said R.sup.13 heterocyclyl is
attached through a ring atom selected from C or N, and
[0060] 2 adjacent substituents of said R.sup.13 may be taken
together to form a 3- to 6-membered ring containing 0 to 3
heteroatoms independently selected from the group consisting of N,
O and S;
[0061] R.sup.14 is selected from the group consisting of
C.sub.1-C.sub.6 alkyl, C.sub.2-C.sub.6 alkenyl, phenyl, naphthyl
and heteroaryl, wherein
[0062] each R.sup.14 heteroaryl is independently selected from the
group consisting of 5- and 6-membered aromatic rings having 1, 2 or
3 heteroatoms independently selected from N, O and S, and said
R.sup.14 heteroaryl is attached through a ring atom selected from C
or N, and
[0063] said R.sup.14 phenyl, naphthyl or heteroaryl may be
substituted with 0 to 2 substituents independently selected from
the group consisting of C.sub.1-C.sub.6 alkyl, halogen atoms,
--OC(O)OR.sup.6, --OC(O)R.sup.6, --OR.sup.10, --SR.sup.10,
--N(R.sup.10).sub.2, --C(O)R.sup.10, --NO.sub.2, --CN, --CF.sub.3,
--SO.sub.2(C.sub.1-C.sub.6 alkyl), --S(O)(C.sub.1-C.sub.6 alkyl),
--NR.sup.10SO.sub.2R.sup.6, --SO.sub.2N(R.sup.6).sub.2,
--NHCOOR.sup.6, --NHCOR.sup.6, --NHCONHR.sup.6, --CO.sub.2R.sup.10,
and --C(O)N(R.sup.10).sub.2; and
[0064] each R.sup.15 is independently selected from the group
consisting of C.sub.1-C.sub.6 alkyl, C.sub.2-C.sub.6 alkenyl,
C.sub.3-C.sub.8 cycloalkyl, phenyl, naphthyl, heteroaryl, and
heterocyclyl groups, wherein
[0065] said R.sup.15 are substituted with 0 to 2 substituents
independently selected from the group consisting of C.sub.1-C.sub.6
alkyl, halogen atoms, --OC(O)OR.sup.6, --OC(O)R.sup.6, --OR.sup.10,
--SR.sup.10, --N(R.sup.10).sub.2, --C(O)R.sup.10, --NO.sub.2, --CN,
--CF.sub.3, --SO.sub.2(C.sub.1-C.sub.6 alkyl),
--S(O)(C.sub.1-C.sub.6 alkyl), --NR.sup.10SO.sub.2R.sup.6,
--SO.sub.2N(R.sup.6).sub.2, --NHCOOR.sup.6, --NHCOR.sup.6,
--NHCONHR.sup.6, --CO.sub.2R.sup.10, and
--C(O)N(R.sup.10).sub.2,
[0066] each R.sup.15 heteroaryl is independently selected from the
group consisting of 5- and 6-membered aromatic rings having 1, 2 or
3 heteroatoms independently selected from N, O and S, and said
R.sup.15 heteroaryl is attached through a ring atom selected from C
or N,
[0067] each R.sup.15 heterocyclyl is independently selected from
the group consisting of 5- to 7-membered saturated or unsaturated
non-aromatic rings having 1, 2, 3 or 4 heteroatoms independently
selected from N, O and S, and said R.sup.15 heterocyclyl is
attached through a ring atom selected from C or N, and
[0068] 2 adjacent substituents of said R.sup.15 are optionally
taken together to form a 3- to 6-membered ring containing 0 to 3
heteroatoms independently selected from the group consisting of N,
O and S.
[0069] The present invention also includes pharmaceutical
compositions containing a compound of the present invention and
methods of preparing such pharmaceutical compositions. The present
invention further includes methods of treating or reducing the
likelihood or severity of one or more symptoms of HCV
infection.
[0070] Other embodiments, aspects and features of the present
invention are either further described in or will be apparent from
the ensuing description, examples and appended claims.
DETAILED DESCRIPTION OF THE INVENTION
[0071] The present invention includes compounds of formula (I)
above, and pharmaceutically acceptable salts and/or hydrates
thereof. These compounds and their pharmaceutically acceptable
salts and/or hydrates are HCV protease inhibitors (e.g., HCV NS3
protease inhibitors).
[0072] In one embodiment of the invention,
##STR00006##
is selected from the group consisting of
[0073] 1) aryl rings,
[0074] 2) cyclohexyl rings, and
[0075] 3) heterocyclic rings in which the heterocyclic ring system
attaches to Z and X at points that are two independently selected
ring atoms that are either two acarbon ring atoms or one carbon
ring atom and one nitrogen ring atom, and the heterocyclic ring
system is selected from the group consisting of:
[0076] a) 5- or 6-membered saturated or unsaturated monocyclic
rings containing 1, 2, or 3 nitrogen atoms, and
[0077] b) 8-, 9- or 10-membered saturated or unsaturated bicyclic
rings containing 1 or 2 nitrogen atoms,
[0078] wherein said
##STR00007##
is substituted with 0 to 4 independently selected substituents W,
R.sup.5 or oxo; wherein for stable heterocyclic rings containing S
or N, the heterocyclic ring is unsubstituted at the S or N atom or
is substituted at the S or N atom by oxo; wherein said W and
R.sup.5 substitutions are located on one or more ring atoms
selected from C and N; and provided that the 10-membered
unsaturated bicyclic ring is not quinoline, quinazoline or
isoquinoline.
##STR00008##
[0079] In a preferred group of this embodiment, is unsubstituted or
mono-substituted with a moiety selected from the group consisting
of --Br, --Cl, --CN, phenyl, --O-phenyl, --OCF.sub.3, --OCH.sub.3,
--C(O)OH, --CH.sub.3 and --C(O)CH.sub.3.
[0080] In another embodiment of the invention,
##STR00009##
is selected from the group of rings consisting of:
##STR00010## ##STR00011## ##STR00012##
which may be substituted as indicated above. In a preferred group
of this embodiment of the invention, R.sup.5 is independently
selected from the group consisting of H, --Br, --Cl, --CN, phenyl,
--O-phenyl, --OCF.sub.3, --OCH.sub.3, --OH, C.sub.1-C.sub.6 alkoxy,
C.sub.1-C.sub.6 alkyl, --CF.sub.3, --C(O)OH, and
--C(O)CH.sub.3.
[0081] In another embodiment of the invention, R.sup.1 is
--CO.sub.2R.sup.10 or --CONR.sup.10SO.sub.2R.sup.6. In a preferred
group of this embodiment, R.sup.1 is --C(O)OH or
--C(O)NHSO.sub.2cyclopropyl.
[0082] In another embodiment of the invention, R.sup.2 is
C.sub.1-C.sub.6 alkyl or C.sub.2-C.sub.6 alkenyl. In a preferred
group of this embodiment, R.sup.2 is --CH.dbd.CH.sub.2,
--CH.sub.2CH.sub.3, or --CH.sub.2CH.dbd.CH.sub.2.
[0083] In another embodiment of the invention, R.sup.3 is H,
C.sub.1-C.sub.8 alkyl or C.sub.3-C.sub.8 cycloalkyl.
[0084] In a preferred group of this embodiment, R.sup.3 is H,
--C(CH.sub.3).sub.3, --(CH.sub.2).sub.3CH.sub.3, cyclohexyl, or
--CH(CH.sub.3).sub.2.
[0085] In another embodiment of the invention, M is
C.sub.1-C.sub.12 alkylene or C.sub.2-C.sub.12 alkenylene, wherein
said M is substituted with 0 to 2 substituents F selected from the
group consisting of C.sub.1-C.sub.8 alkyl, and .dbd.CH.sub.2. In a
preferred group of this embodiment, M is selected from the group
consisting of --CH.dbd.CH(CH.sub.2).sub.5, --(CH.sub.2).sub.7--,
--CH.sub.2CH.dbd.CH(CH.sub.2).sub.4--, --(CH.sub.2).sub.6--,
--CH.dbd.CH(CH.sub.2).sub.4--,
--CH.dbd.CH(CH.sub.2).sub.3C(CH.sub.3).sub.2CH.sub.2--,
--CH.dbd.CH(CH.sub.2).sub.3--, --(CH.sub.2).sub.5--,
--CH.dbd.CH(CH.sub.2).sub.3--, --(CH.sub.2).sub.4--,
--(CH.sub.2).sub.3--,
--CH.dbd.CH(CH.sub.2).sub.2C(CH.sub.3).sub.2CH.sub.2--,
--(CH.sub.2).sub.4C(CH.sub.3).sub.2CH.sub.2--,
--C(.dbd.CH.sub.2)(CH.sub.2).sub.5--,
--C(.dbd.CH.sub.2)(CH.sub.2).sub.3--,
--CH.sub.2CH.dbd.CH(CH.sub.2).sub.3--. In some embodiments, M is
selected from the group consisting of
##STR00013##
[0086] In another embodiment of the invention, Y is selected from
--C(O)N(D)L- and -LN(D)C(O)--.
[0087] In still another embodiment, one or more substituents F are
taken together and/or with one or more substituents chosen from
substituents D and E to form a 3- to 6-membered ring containing 0
to 3 heteroatoms selected from the group consisting of N, O and S.
That is, two adjacent substituents F may be taken together to form
a 3- to 6-membered ring containing 0 to 3 heteroatoms independently
selected from the group consisting of N, O and S, or one
substituent F may be taken together with an adjacent D or E to form
a 3- to 6-membered ring containing 0 to 3 heteroatoms independently
selected from the group consisting of N, O and S.
[0088] In another embodiment of the invention, the compound of the
invention is selected from the exemplary species depicted in
Examples 1 through 109 shown below.
[0089] Other embodiments of the present invention include the
following:
[0090] (a) A pharmaceutical composition comprising an effective
amount of a compound of formula (I) and a pharmaceutically
acceptable carrier.
[0091] (b) The pharmaceutical composition of (a), further
comprising a second therapeutic agent selected from the group
consisting of HCV antiviral agents, immunomodulators, and
anti-infective agents.
[0092] (c) The pharmaceutical composition of (b), wherein the HCV
antiviral agent is an antiviral selected from the group consisting
of HCV protease inhibitors and HCV NS5B polymerase inhibitors.
[0093] (d) A pharmaceutical combination which is (i) a compound of
formula (I) and (ii) a second therapeutic agent selected from the
group consisting of HCV antiviral agents, immunomodulators, and
anti-infective agents; wherein the compound of formula (I) and the
second therapeutic agent are each employed in an amount that
renders the combination effective for inhibiting HCV NS3 protease,
or for treating HCV infection and/or reducing the likelihood or
severity of symptoms of HCV infection.
[0094] (e) The combination of (d), wherein the HCV antiviral agent
is an antiviral selected from the group consisting of HCV protease
inhibitors and HCV NS5B polymerase inhibitors.
[0095] (f) A method of inhibiting HCV NS3 protease in a subject in
need thereof which comprises administering to the subject an
effective amount of a compound of formula (I).
[0096] (g) A method of treating HCV infection and/or reducing the
likelihood or severity of symptoms of HCV infection in a subject in
need thereof which comprises administering to the subject an
effective amount of a compound of formula (I).
[0097] (h) The method of (g), wherein the compound of formula (I)
is administered in combination with an effective amount of at least
one second therapeutic agent selected from the group consisting of
HCV antiviral agents, immunomodulators, and anti-infective
agents.
[0098] The method of (h), wherein the HCV antiviral agent is an
antiviral selected from the group consisting of HCV protease
inhibitors and HCV NS5B polymerase inhibitors.
[0099] (j) A method of inhibiting HCV NS3 protease in a subject in
need thereof which comprises administering to the subject the
pharmaceutical composition of (a), (b), or (c) or the combination
of (d) or (e).
[0100] (k) A method of treating HCV infection and/or reducing the
likelihood or severity of symptoms of HCV infection in a subject in
need thereof which comprises administering to the subject the
pharmaceutical composition of (a), (b), or (c) or the combination
of (d) or (e).
[0101] In the embodiments of the compound provided above, it is to
be understood that each embodiment may be combined with one or more
other embodiments, to the extent that such a combination provides a
stable compound and is consistent with the description of the
embodiments. It is further to be understood that the embodiments of
compositions and methods provided as (a) through (k) above are
understood to include all embodiments of the compounds, including
such embodiments as result from combinations of embodiments.
[0102] The present invention also includes a compound of the
present invention for use (i) in, (ii) as a medicament for, or
(iii) in the preparation of a medicament for: (a) inhibiting HCV
NS3 protease, or (b) treating HCV infection and/or reducing the
likelihood or severity of symptoms of HCV infection. In these uses,
the compounds of the present invention can optionally be employed
in combination with one or more second therapeutic agents selected
from HCV antiviral agents, anti-infective agents, and
immunomodulators.
[0103] Additional embodiments of the invention include the
pharmaceutical compositions, combinations and methods set forth in
(a)-(k) above and the uses set forth in the preceding paragraph,
wherein the compound of the present invention employed therein is a
compound of one of the embodiments, aspects, classes, sub-classes,
or features of the compounds described above. In all of these
embodiments, the compound may optionally be used in the form of a
pharmaceutically acceptable salt or hydrate as appropriate.
[0104] As used herein, all ranges are inclusive, and all sub-ranges
are included within such ranges, although not necessarily
explicitly set forth. In addition, the term "or," as used herein,
denotes alternatives that may, where appropriate, be combined; that
is, the term "or" includes each listed alternative separately as
well as their combination.
[0105] As used herein, the term "alkyl" refers to any linear or
branched chain alkyl group having a number of carbon atoms in the
specified range. Thus, for example, "C.sub.1-6 alkyl" (or
"C.sub.1-C.sub.6 alkyl") refers to all of the hexyl alkyl and
pentyl alkyl isomers as well as n-, iso-, sec- and t-butyl, n- and
isopropyl, ethyl and methyl. As another example, "C.sub.1-4 alkyl"
refers to n-, iso-, sec- and t-butyl, n- and isopropyl, ethyl and
methyl. Alkyl groups may be substituted as indicated.
[0106] The term "halogenated" refers to a group or molecule in
which a hydrogen atom has been replaced by a halogen. Similarly,
the term "haloalkyl" refers to a halogenated alkyl group. The term
"halogen" (or "halo") refers to atoms of fluorine, chlorine,
bromine and iodine (alternatively referred to as fluoro, chloro,
bromo, and iodo).
[0107] The term "alkoxy" refers to an "alkyl-O--" group. Alkoxy
groups may be substituted as indicated.
[0108] The term "alkylene" refers to any linear or branched chain
alkylene group (or alternatively "alkanediyl") having a number of
carbon atoms in the specified range. Thus, for example,
"--C.sub.1-6 alkylene-" refers to any of the C.sub.1 to C.sub.6
linear or branched alkylenes. A class of alkylenes of particular
interest with respect to the invention is --(CH.sub.2).sub.1-6--,
and sub-classes of particular interest include
--(CH.sub.2).sub.1-4--, --(CH.sub.2).sub.1-3--,
--(CH.sub.2).sub.1-2--, and --CH.sub.2--. Also of interest is the
alkylene --CH(CH.sub.3)--. Alkylene groups may be substituted as
indicated.
[0109] The term "cycloalkyl" refers to any cyclic ring of an alkane
or alkene having a number of carbon atoms in the specified range.
Thus, for example, "C.sub.3-8 cycloalkyl" (or "C.sub.3-C.sub.8
cycloalkyl") refers to cyclopropyl, cyclobutyl, cyclopentyl,
cyclohexyl, cycloheptyl, and cyclooctyl. The term "cycloalkoxy"
refers to a "cycloalkyl-O--" group. Cycloalkyl groups may be
substituted as indicated.
[0110] The term "carbocycle" (and variations thereof such as
"carbocyclic" or "carbocyclyl") as used herein, unless otherwise
indicated, refers to (i) a C.sub.3 to C.sub.8 monocyclic, saturated
or unsaturated ring or (ii) a C.sub.7 to C.sub.12 bicyclic
saturated or unsaturated ring system. Each ring in (ii) is either
independent of, or fused to, the other ring, and each ring is
saturated or unsaturated. Carbocycle groups may be substituted as
indicated, for example with C.sub.1-6 alkyl, C.sub.1-6 alkenyl,
C.sub.1-6 alkynyl, aryl, halogen, --NH.sub.2 or --OH. The
carbocycle may be attached to the rest of the molecule at any
carbon atom which results in a stable compound. The fused bicyclic
carbocycles are a subset of the carbocycles; i.e., the term "fused
bicyclic carbocycle" generally refers to a C.sub.7 to C.sub.10
bicyclic ring system in which each ring is saturated or unsaturated
and two adjacent carbon atoms are shared by each of the rings in
the ring system. A fused bicyclic carbocycle in which both rings
are saturated is a saturated bicyclic ring system. Saturated
carbocyclic rings are also referred to as cycloalkyl rings, e.g.,
cyclopropyl, cyclobutyl, etc. A fused bicyclic carbocycle in which
one or both rings are unsaturated is an unsaturated bicyclic ring
system. A subset of the fused bicyclic unsaturated carbocycles are
those bicyclic carbocycles in which one ring is a benzene ring and
the other ring is saturated or unsaturated, with attachment via any
carbon atom that results in a stable compound. Representative
examples of this subset include
##STR00014##
[0111] Depicted ring systems include, where appropriate, an
indication of the variable to which a particular ring atom is
attached. For example, the indole structure
##STR00015##
shows ring atom 2 is directly attached to variable X and ring atom
4 is directly attached to variable Z. Variable R.sup.5 is shown as
a floating variable which can be attached to any ring atom,
provided that such attachment results in formation of a stable
ring.
[0112] The term "aryl" refers to aromatic mono- and
poly-carbocyclic ring systems, also referred to as "arenes,"
wherein the individual carbocyclic rings in the polyring systems
are fused or attached to each other via a single bond. Suitable
aryl groups include phenyl, naphthyl, and biphenylenyl. Aryl groups
may be substituted as indicated. Unless indicated otherwise, the
term "heterocycle" (and variations thereof such as "heterocyclic"
or "heterocyclyl") broadly refers to (i) a stable 4- to 8-membered,
saturated or unsaturated monocyclic ring, (ii) a stable 7- to
12-membered bicyclic ring system, or (iii) a stable 11- to
15-membered tricyclic ring system, wherein each ring in (ii) and
(iii) is independent of, or fused to, the other ring or rings and
each ring is saturated or unsaturated, and the monocyclic ring,
bicyclic ring system or tricyclic ring system contains one or more
heteroatoms (e.g., from 1 to 6 heteroatoms, or from 1 to 4
heteroatoms) independently selected from N, O and S and a balance
of carbon atoms (the monocyclic ring typically contains at least
one carbon atom and the bicyclic and tricyclic ring systems
typically contain at least two carbon atoms); and wherein any one
or more of the nitrogen and sulfur heteroatoms is optionally
oxidized, and any one or more of the nitrogen heteroatoms is
optionally quaternized. Unless otherwise specified, the
heterocyclic ring may be attached at any heteroatom or carbon atom,
provided that attachment results in the creation of a stable
structure. Heterocycle groups may be substituted as indicated, and
unless otherwise specified, the substituents may be attached to any
atom in the ring, whether a heteroatom or a carbon atom, provided
that a stable chemical structure results.
[0113] Saturated heterocyclics form a subset of the heterocycles.
Unless expressly stated to the contrary, the term "saturated
heterocyclic" generally refers to a heterocycle as defined above in
which the entire ring system (whether mono- or poly-cyclic) is
saturated. The term "saturated heterocyclic ring" refers to a 4- to
8-membered saturated monocyclic ring, a stable 7- to 12-membered
bicyclic ring system, or a stable 11- to 15-membered tricyclic ring
system, which consists of carbon atoms and one or more heteroatoms
independently selected from N, O and S. Representative examples
include piperidinyl, piperazinyl, azepanyl, pyrrolidinyl,
pyrazolidinyl, imidazolidinyl, oxazolidinyl, isoxazolidinyl,
morpholinyl, thiomorpholinyl, thiazolidinyl, isothiazolidinyl, and
tetrahydrofuryl (or tetrahydrofuranyl).
[0114] Unsaturated heterocyclics form another subset of the
heterocycles. Unless expressly stated to the contrary, the term
"unsaturated heterocyclic" generally refers to a heterocycle as
defined above in which the entire ring system (whether mono- or
poly-cyclic) is not saturated, i.e., such rings are either
unsaturated or partially unsaturated. Unless expressly stated to
the contrary, the term "heteroaromatic ring" refers a stable 5- or
6-membered monocyclic aromatic ring, a stable 7- to 12-membered
bicyclic ring system, or a stable 11- to 15-membered tricyclic ring
system, which consists of carbon atoms and one or more heteroatoms
selected from N, O and S. In the case of substituted heteroaromatic
rings containing at least one nitrogen atom (e.g., pyridine), such
substitutions can be those resulting in N-oxide formation.
Representative examples of heteroaromatic rings include pyridyl,
pyrrolyl, pyrazinyl, pyrimidinyl, pyridazinyl, thienyl (or
thiophenyl), thiazolyl, furanyl, imidazolyl, pyrazolyl, triazolyl,
tetrazolyl, oxazolyl, isooxazolyl, oxadiazolyl, thiazolyl,
isothiazolyl, and thiadiazolyl.
[0115] Representative examples of bicyclic heterocycles include
benzotriazolyl, indolyl, isoindolyl, indazolyl, indolinyl,
isoindolinyl, quinoxalinyl, quinazolinyl, cinnolinyl, chromanyl,
isochromanyl, tetrahydroquinolinyl, quinolinyl,
tetrahydroisoquinolinyl, isoquinolinyl, 2,3-dihydrobenzofuranyl,
2,3-dihydrobenzo-1,4-dioxinyl
##STR00016##
imidazo(2,1-b)(1,3)thiazole,
##STR00017##
and benzo-1,3-dioxolyl
##STR00018##
In certain contexts herein,
##STR00019##
is alternatively referred to as phenyl having as a substituent
methylenedioxy attached to two adjacent carbon atoms.
[0116] Unless otherwise specifically noted as only "unsubstituted"
or only "substituted", alkyl, cycloalkyl, aryl and heterocycle
groups are unsubstituted or substituted. Preferably, the
substituents are selected from the group which includes, but is not
limited to, halo, C.sub.1-C.sub.20 alkyl, --CF.sub.3, --NH.sub.2,
--N(C.sub.1-C.sub.6 alkyl).sub.2, --NO.sub.2, oxo, --CN, --N.sub.3,
--OH, --O(C.sub.1-C.sub.6 alkyl), C.sub.3-C.sub.10 cycloalkyl,
C.sub.2-C.sub.6 alkenyl, C.sub.2-C.sub.6 alkynyl, (C.sub.0-C.sub.6
alkyl) S(O).sub.0-2--, aryl-S(O).sub.0-2--, (C.sub.0-C.sub.6
alkyl)S(O).sub.0-2(C.sub.0-C.sub.6 alkyl)-, (C.sub.0-C.sub.6
alkyl)C(O)NH--, H.sub.2N--C(NH)--, --O(C.sub.1-C.sub.6
alkyl)CF.sub.3, (C.sub.0-C.sub.6 alkyl)C(O)--, (C.sub.0-C.sub.6
alkyl)OC(O)--, (C.sub.0-C.sub.6alkyl)O(C.sub.1-C.sub.6 alkyl)-,
(C.sub.0-C.sub.6 alkyl)C(O).sub.1-2(C.sub.0-C.sub.6 alkyl)-,
(C.sub.0-C.sub.6 alkyl)OC(O)NH--, aryl, aralkyl, heteroaryl,
heterocyclylalkyl, halo-aryl, halo-aralkyl, halo-heterocycle,
halo-heterocyclylalkyl, cyano-aryl, cyano-aralkyl,
cyano-heterocycle and cyano-heterocyclylalkyl.
[0117] Unless expressly stated to the contrary, all ranges cited
herein are inclusive. For example, a heteroaryl ring described as
containing from "1 to 3 heteroatoms" means the ring can contain 1,
2, or 3 heteroatoms. It is also to be understood that any range
cited herein includes within its scope all of the sub-ranges within
that range. The oxidized forms of the heteroatoms N and S are also
included within the scope of the present invention.
[0118] When any variable (e.g., R.sup.7 and R.sup.10) occurs more
than one time in any constituent or in formula (I) or in any other
formula depicting and describing compounds of the invention, its
definition on each occurrence is independent of its definition at
every other occurrence. Also, combinations of substituents and/or
variables are permissible only if such combinations result in
stable compounds.
[0119] Unless expressly stated to the contrary, substitution by a
named substituent is permitted on any atom in a ring (e.g., aryl, a
heteroaromatic ring, or a saturated heterocyclic ring) provided
such ring substitution is chemically allowed and results in a
stable compound. A "stable" compound is a compound which can be
prepared and isolated and whose structure and properties remain or
can be caused to remain essentially unchanged for a period of time
sufficient to allow use of the compound for the purposes described
herein (e.g., therapeutic or prophylactic administration to a
subject).
[0120] As a result of the selection of substituents and substituent
patterns, certain of the compounds of the present invention can
have asymmetric centers and can occur as mixtures of stereoisomers,
or as individual diastereomers, or enantiomers. All isomeric forms
of these compounds, whether isolated or in mixtures, are within the
scope of the present invention.
[0121] As would be recognized by one of ordinary skill in the art,
certain of the compounds of the present invention can exist as
tautomers. For the purposes of the present invention a reference to
a compound of formula (I) is a reference to the compound per se, or
to any one of its tautomers per se, or to mixtures of two or more
tautomers.
[0122] The compounds of the present inventions are useful in the
inhibition of HCV protease (e.g., HCV NS3 protease) and the
treatment of HCV infection and/or reduction of the likelihood or
severity of symptoms of HCV infection. For example, the compounds
of this invention are useful in treating infection by HCV after
suspected past exposure to HCV by such means as blood transfusion,
exchange of body fluids, bites, accidental needle stick, or
exposure to patient blood during surgery.
[0123] The compounds of this invention are useful in the
preparation and execution of screening assays for antiviral
compounds. For example, the compounds of this invention are useful
for isolating enzyme mutants, which are excellent screening tools
for more powerful antiviral compounds. Furthermore, the compounds
of this invention are useful in establishing or determining the
binding site of other antivirals to HCV protease, e.g., by
competitive inhibition. Thus, the compounds of this invention may
be commercial products to be sold for these purposes.
[0124] The compounds of the present invention may be administered
in the form of pharmaceutically acceptable salts. The term
"pharmaceutically acceptable salt" refers to a salt which possesses
the effectiveness of the parent compound and which is not
biologically or otherwise undesirable (e.g., is neither toxic nor
otherwise deleterious to the recipient thereof). Suitable salts
include acid addition salts which may, for example, be formed by
mixing a solution of the compound of the present invention with a
solution of a pharmaceutically acceptable acid such as hydrochloric
acid, sulfuric acid, acetic acid, trifluoroacetic acid, or benzoic
acid. Many of the compounds of the invention carry an acidic
moiety, in which case suitable pharmaceutically acceptable salts
thereof can include alkali metal salts (e.g., sodium or potassium
salts), alkaline earth metal salts (e.g., calcium or magnesium
salts), and salts formed with suitable organic ligands such as
quaternary ammonium salts. Also, in the case of an acid (--COOH) or
alcohol group being present, pharmaceutically acceptable esters can
be employed to modify the solubility or hydrolysis characteristics
of the compound.
[0125] The term "administration" and variants thereof (e.g.,
"administering" a compound) in reference to a compound of the
invention mean providing the compound or a prodrug of the compound
to the individual in need of treatment. When a compound of the
invention or a prodrug thereof is provided in combination with one
or more other active agents (e.g., antiviral agents useful for
treating HCV infection), "administration" and its variants are each
understood to include concurrent and sequential provision of the
compound or salt (or hydrate) and other agents.
[0126] As used herein, the term "prodrug" is intended to encompass
an inactive drug form or compound that is converted into an active
drug form or compound by the action of enzymes, chemicals or
metabolic processes in the body of an individual to whom it is
administered.
[0127] As used herein, the term "composition" is intended to
encompass a product comprising the specified ingredients, as well
as any product which results, directly or indirectly, from
combining the specified ingredients.
[0128] By "pharmaceutically acceptable" is meant that the
ingredients of the pharmaceutical composition must be compatible
with each other and not deleterious to the recipient thereof.
[0129] The term "subject" (alternatively referred to herein as
"patient") as used herein refers to an animal, preferably a mammal,
most preferably a human, who has been the object of treatment,
observation or experiment.
[0130] The term "effective amount" as used herein means that amount
of active compound or pharmaceutical agent that elicits the
biological or medicinal response in a tissue, system, animal or
human that is being sought by a researcher, veterinarian, medical
doctor or other clinician. In one embodiment, the effective amount
is a "therapeutically effective amount" for the alleviation of one
or more symptoms of the disease or condition being treated. In
another embodiment, the effective amount is a "prophylactically
effective amount" for reduction of the severity or likelihood of
one or more symptoms of the disease or condition. The term also
includes herein the amount of active compound sufficient to inhibit
HCV NS3 protease and thereby elicit the response being sought
(i.e., an "inhibition effective amount"). When the active compound
(i.e., active ingredient) is administered as the salt, references
to the amount of active ingredient are to the free acid or free
base form of the compound.
[0131] For the purpose of inhibiting HCV NS3 protease and treating
HCV infection and/or reducing the likelihood or severity of
symptoms of HCV infection, the compounds of the present invention,
optionally in the form of a salt or a hydrate, can be administered
by any means that produces contact of the active agent with the
agent's site of action. They can be administered by any
conventional means available for use in conjunction with
pharmaceuticals, either as individual therapeutic agents or in a
combination of therapeutic agents. They can be administered alone,
but typically are administered with a pharmaceutical carrier
selected on the basis of the chosen route of administration and
standard pharmaceutical practice. The compounds of the invention
can, for example, be administered orally, parenterally (including
subcutaneous injections, intravenous, intramuscular, intrasternal
injection or infusion techniques), by inhalation (such as in a
spray form), or rectally, in the form of a unit dosage of a
pharmaceutical composition containing an effective amount of the
compound and conventional non-toxic pharmaceutically-acceptable
carriers, adjuvants and vehicles. Liquid preparations suitable for
oral administration (e.g., suspensions, syrups, elixirs and the
like) can be prepared according to techniques known in the art and
can employ any of the usual media such as water, glycols, oils,
alcohols and the like. Solid preparations suitable for oral
administration (e.g., powders, pills, capsules and tablets) can be
prepared according to techniques known in the art and can employ
such solid excipients as starches, sugars, kaolin, lubricants,
binders, disintegrating agents and the like. Parenteral
compositions can be prepared according to techniques known in the
art and typically employ sterile water as a carrier and optionally
other ingredients, such as solubility aids. Injectable solutions
can be prepared according to methods known in the art wherein the
carrier comprises a saline solution, a glucose solution or a
solution containing a mixture of saline and glucose. Further
description of methods suitable for use in preparing pharmaceutical
compositions of the present invention and of ingredients suitable
for use in said compositions is provided in Remington's
Pharmaceutical Sciences, 18.sup.th edition (ed. A. R. Gennaro, Mack
Publishing Co., 1990).
[0132] The compounds of this invention can be administered orally
in a dosage range of 0.001 to 1000 mg/kg of mammal (e.g., human)
body weight per day in a single dose or in divided doses. One
dosage range is 0.01 to 500 mg/kg body weight per day orally in a
single dose or in divided doses. Another dosage range is 0.1 to 100
mg/kg body weight per day orally in single or divided doses. For
oral administration, the compositions can be provided in the form
of tablets or capsules containing 1.0 to 500 mg of the active
ingredient, particularly 1, 5, 10, 15, 20, 25, 50, 75, 100, 150,
200, 250, 300, 400, and 500 mg of the active ingredient for the
symptomatic adjustment of the dosage to the patient to be treated.
The specific dose level and frequency of dosage for any particular
patient may be varied and will depend upon a variety of factors
including the activity of the specific compound employed, the
metabolic stability and length of action of that compound, the age,
body weight, general health, sex, diet, mode and time of
administration, rate of excretion, drug combination, the severity
of the particular condition, and the host undergoing therapy.
[0133] As noted above, the present invention also relates to a
method of inhibiting HCV NS3 protease, inhibiting HCV replication,
treating HCV infection and/or reducing the likelihood or severity
of symptoms of HCV infection with a compound of the present
invention in combination with one or more therapeutic agents and a
pharmaceutical composition comprising a compound of the present
invention and one or more therapeutic agents selected from the
group consisting of a HCV antiviral agent, an immunomodulator, and
an anti-infective agent. Such therapeutic agents active against HCV
include, but are not limited to, ribavirin, levovirin, viramidine,
thymosin alpha-1, R7025 (an enhanced interferon (Roche)),
interferon-.beta., interferon-.alpha., pegylated interferon-.alpha.
(peginterferon-.alpha.), a combination of interferon-.alpha. and
ribavirin, a combination of peginterferon-.alpha. and ribavirin, a
combination of interferon-.alpha. and levovirin, and a combination
of peginterferon-.alpha. and levovirin. Interferon-.alpha.
includes, but is not limited to, recombinant interferon-.alpha.2a
(such as Roferon interferon available from Hoffmann-LaRoche,
Nutley, N.J.), pegylated interferon-.alpha.2a (Pegasys.TM.),
interferon-.alpha.2b (such as Intron-A interferon available from
Schering Corp., Kenilworth, N.J.), pegylated interferon-.alpha.2b
(PegIntron.TM.), a recombinant consensus interferon (such as
interferon alphacon-1), albuferon (interferon-.alpha. bound to
human serum albumin (Human Genome Sciences)), and a purified
interferon-.alpha. product. Amgen's recombinant consensus
interferon has the brand name Infergen.RTM.. Levovirin is the
L-enantiomer of ribavirin which has shown immunomodulatory activity
similar to ribavirin. Viramidine represents an analog of ribavirin
disclosed in International Patent Application Publication WO
01/60379. In accordance with the method of the present invention,
the individual components of the combination can be administered
separately at different times during the course of therapy or
concurrently in divided or single combination forms.
[0134] For the treatment of HCV infection, the compounds of the
present invention may also be administered in combination with an
agent that is an inhibitor of HCV NS3 serine protease. HCV NS3
serine protease is an essential viral enzyme and has been described
to be an excellent target for inhibition of HCV replication. Both
substrate and non-substrate based inhibitors of HCV NS3 protease
inhibitors are disclosed in International Patent Application
Publications WO 98/22496, WO 98/46630, WO 99/07733, WO 99/07734, WO
99/38888,
[0135] WO 99/50230, WO 99/64442, WO 00/09543, WO 00/59929, WO
02/48116 and WO 02/48172, British Patent No. GB 2 337 262, and U.S.
Pat. No. 6,323,180.
[0136] Ribavirin, levovirin, and viramidine may exert their
anti-HCV effects by modulating intracellular pools of guanine
nucleotides via inhibition of the intracellular enzyme inosine
monophosphate dehydrogenase (IMPDH). IMPDH is the rate-limiting
enzyme on the biosynthetic route in de novo guanine nucleotide
biosynthesis. Ribavirin is readily phosphorylated intracellularly
and the monophosphate derivative is an inhibitor of IMPDH. Thus,
inhibition of IMPDH represents another useful target for the
discovery of inhibitors of HCV replication. Therefore, the
compounds of the present invention may also be administered in
combination with an inhibitor of IMPDH, such as VX-497, which is
disclosed in International Patent Application Publications WO
97/41211 and WO 01/00622; another IMPDH inhibitor, such as that
disclosed in WO 00/25780; or mycophenolate mofetil. See A. C.
Allison and E. M. Eugui, 44 (Suppl.) Agents Action 165 (1993).
[0137] For the treatment of HCV infection, the compounds of the
present invention may also be administered in combination with the
antiviral agent amantadine (1-aminoadamantane). For a comprehensive
description of this agent, see J. Kirschbaum, 12 Anal. Profiles
Drug Subs. 1-36 (1983).
[0138] For the treatment of HCV infection, the compounds of the
present invention may also be administered in combination with the
antiviral agent polymerase inhibitor R7128 (Roche).
[0139] The compounds of the present invention may also be combined
for the treatment of HCV infection with antiviral 2'-C-branched
ribonucleosides disclosed in R. E. Harry-O'Kuru et al., 62 J. Org.
Chem. 1754-59 (1997); M. S. Wolfe et al., 36 Tet. Lett. 7611-14
(1995); U.S. Pat. No. 3,480,613; and International Patent
Application Publications WO 01/90121, WO 01/92282, WO 02/32920, WO
04/002999, WO 04/003000 and WO 04/002422; the contents of each of
which are incorporated by reference in their entirety. Such
2'-C-branched ribonucleosides include, but are not limited to,
2'-C-methyl-cytidine, 2'-C-methyl-uridine, 2'-C-methyl-adenosine,
2'-C-methyl-guanosine, and
9-(2-C-methyl-.beta.-D-ribofuranosyl)-2,6-diaminopurine, and the
corresponding amino acid ester of the ribose C-2', C-3', and C-5'
hydroxyls and the corresponding optionally substituted cyclic
1,3-propanediol esters of the 5'-phosphate derivatives.
[0140] The compounds of the present invention may also be combined
for the treatment of HCV infection with other nucleosides having
anti-HCV properties, such as those disclosed in International
Patent Application Publications WO 02/51425, assigned to Mitsubishi
Pharma Corp.; WO 01/79246, WO 02/32920, WO 02/48165 and
WO2005/003147 (including R1656,
(2'R)-2'-deoxy-2'-fluoro-2'-C-methylcytidine, shown as compounds
3-6 on page 77); WO 01/68663; WO 99/43691; WO 02/18404 and
WO2006/021341, and U.S. Patent Application Publication
US2005/0038240, including 4'-azido nucleosides such as R1626,
4'-azidocytidine; U.S. Patent Application Publications
US2002/0019363, US2003/0236216, US2004/0006007 and US2004/0063658;
and International Patent Application Publications WO 02/100415, WO
03/026589, WO 03/026675, WO 03/093290, WO 04/011478, WO 04/013300
and WO 04/028481; the content of each is incorporated herein by
reference in its entirety.
[0141] For the treatment of HCV infection, the compounds of the
present invention may also be administered in combination with an
agent that is an inhibitor of HCV NS5B polymerase. Such HCV NS5B
polymerase inhibitors that may be used as combination therapy
include, but are not limited to, those disclosed in International
Patent Application Publications WO 02/057287, WO 02/057425, WO
03/068244, WO 2004/000858, WO 04/003138 and WO 2004/007512; U.S.
Pat. No. 6,777,392 and U.S. Patent Application Publication
US2004/0067901; the content of each is incorporated herein by
reference in its entirety. Other such HCV polymerase inhibitors
include, but are not limited to, valopicitabine (NM-283; Idenix)
and 2'-F-2'-beta-methylcytidine (see also WO 2005/003147).
[0142] In one embodiment, nucleoside HCV NS5B polymerase inhibitors
that are used in combination with the present HCV NS3 protease
inhibitors are selected from the following compounds:
4-amino-7-(2-C-methyl-.beta.-D-arabinofuranosyl)-7H-pyrrolo[2,3-d]pyrimid-
ine;
4-amino-7-(2-C-methyl-.beta.-D-ribofuranosyl)-7H-pyrrolo[2,3-d]-pyrim-
idine;
4-methylamino-7-(2-C-methyl-.beta.-D-ribofuranosyl)-7H-pyrrolo[2,3--
d]-pyrimidine;
4-dimethylamino-7-(2-C-methyl-.beta.-D-ribofuranosyl)-7H-pyrrolo[2,3-d]-p-
yrimidine;
4-cyclopropylamino-7-(2-C-methyl-.beta.-D-ribofuranosyl)-7H-pyr-
rolo[2,3-d]pyrimidine;
4-amino-7-(2-C-vinyl-.beta.-D-ribofuranosyl)-7H-pyrrolo[2,3-d]-pyrimidine-
;
4-amino-7-(2-C-hydroxymethyl-.beta.-D-ribofuranosyl)-7H-pyrrolo[2,3-d]-p-
yrimidine;
4-amino-7-(2-C-fluoromethyl-.beta.-D-ribofuranosyl)-7H-pyrrolo[-
2,3-d]-pyrimidine;
4-amino-5-methyl-7-(2-C-methyl-.beta.-D-ribofuranosyl)-7H-pyrrolo[2,3-d]p-
yrimidine;
4-amino-7-(2-C-methyl-.beta.-D-ribofuranosyl)-7H-pyrrolo[2,3-d]-
-pyrimidine-5-carboxylic acid;
4-amino-5-bromo-7-(2-C-methyl-.beta.-D-ribofuranosyl)-7H-pyrrolo[2,3-d]-p-
yrimidine;
4-amino-5-chloro-7-(2-C-methyl-.beta.-D-ribofuranosyl)-7H-pyrro-
lo[2,3-d]-pyrimidine;
4-amino-5-fluoro-7-(2-C-methyl-.beta.-D-ribofuranosyl)-7H-pyrrolo[2,3-d]--
pyrimidine;
2,4-diamino-7-(2-C-methyl-.beta.-D-ribofuranosyl)-7H-pyrrolo[2,3-d]pyrimi-
dine;
2-amino-7-(2-C-methyl-.beta.-D-ribofuranosyl)-7H-pyrrolo[2,3-d]pyrim-
idine;
2-amino-4-cyclopropylamino-7-(2-C-methyl-.beta.-D-ribofuranosyl)-7H-
-pyrrolo[2,3-d]pyrimidine;
2-amino-7-(2-C-methyl-.beta.-D-ribofuranosyl)-7H-pyrrolo[2,3-d]-pyrimidin-
-4(3H)-one;
4-amino-7-(2-C-ethyl-.beta.-D-ribofuranosyl)-7H-pyrrolo[2,3-d]pyrimidine;
4-amino-7-(2-C,2-O-dimethyl-.beta.-D-ribofuranosyl)-7H-pyrrolo[2,3-d]pyri-
midine;
7-(2-C-methyl-.beta.-D-ribofuranosyl)-7H-pyrrolo[2,3-d]pyrimidin-4-
(3H)-one;
2-amino-5-methyl-7-(2-C,2-O-dimethyl-.beta.-D-ribofuranosyl)-7H--
pyrrolo[2,3-d]-pyrimidin-4(3M-one;
4-amino-7-(3-deoxy-2-C-methyl-.beta.-D-ribofuranosyl)-7H-pyrrolo[2,3-d]-p-
yrimidine;
4-amino-7-(3-deoxy-2-C-methyl-.beta.-D-arabinofuranosyl)-7H-pyr-
rolo[2,3-d]pyrimidine;
4-amino-2-fluoro-7-(2-C-methyl-.beta.-D-ribofuranosyl)-7H-pyrrolo[2,3-d]p-
yrimidine;
4-amino-7-(3-C-methy-.beta.-D-ribofuranosyl)-7H-pyrrolo[2,3-d]p-
yrimidine;
4-amino-7-(3-C-methyl-.beta.-D-xylofuranosyl)-7H-pyrrolo[2,3-d]-
pyrimidine;
4-amino-7-(2,4-di-C-methyl-.beta.-D-ribofuranosyl)-7H-pyrrolo[2,3-d]pyrim-
idine;
4-amino-7-(3-deoxy-3-fluoro-2-C-methyl-.beta.-D-ribofuranosyl)-7H-p-
yrrolo[2,3-d]pyrimidine; and the corresponding 5'-triphosphates; or
a pharmaceutically acceptable salt thereof.
[0143] The compounds of the present invention may also be combined
for the treatment of HCV infection with non-nucleoside inhibitors
of HCV polymerase such as those disclosed in International Patent
Application Publications WO 01/77091; WO 01/47883; WO 02/04425; WO
02/06246; WO 02/20497; WO 2005/016927 (in particular JTK003); the
content of each is incorporated herein by reference in its
entirety; and HCV-796 (Viropharma Inc.).
[0144] In one embodiment, non-nucleoside HCV NS5B polymerase
inhibitors that are used in combination with the present HCV NS3
protease inhibitors are selected from the following compounds:
14-cyclohexyl-6-[2-(dimethylamino)ethyl]-7-oxo-5,6,7,8-tetrahydroindolo[2-
,1-a][2,5]benzodiazocine-11-carboxylic acid;
14-cyclohexyl-6-(2-morpholin-4-ylethyl)-5,6,7,8-tetrahydroindolo[2,1-a][2-
,5]benzodiazocine-11-carboxylic acid;
14-cyclohexyl-6-[2-(dimethylamino)ethyl]-3-methoxy-5,6,7,8-tetrahydroindo-
lo[2,1-a][2,5]benzodiazocine-11-carboxylic acid;
14-cyclohexyl-3-methoxy-6-methyl-5,6,7,8-tetrahydroindolo[2,1-a][2,5]benz-
odiazocine-11-carboxylic acid; methyl
({[(14-cyclohexyl-3-methoxy-6-methyl-5,6,7,8-tetrahydroindolo[2,1-a][2,5]-
benzodiazocin-11-yl)carbonyl]amino}sulfonyl)acetate;
({[(14-cyclohexyl-3-methoxy-6-methyl-5,6,7,8-tetrahydroindolo[2,1-a][2,5]-
benzodiazocin-11-yl)carbonyl]amino}sulfonyl)acetic acid;
14-cyclohexyl-N-[(dimethylamino)sulfonyl]-3-methoxy-6-methyl-5,6,7,8-tetr-
ahydroindolo[2,1-a][2,5]benzodiazocine-11-carboxamide;
3-chloro-14-cyclohexyl-6-[2-(dimethylamino)ethyl]-7-oxo-5,6,7,8-tetrahydr-
oindolo[2,1-a][2,5]benzodiazocine 11-carboxylic acid;
N-(11-carboxy-14-cyclohexyl-7,8-dihydro-6H-indolo[1,2-e][1,5]benzoxazocin-
-7-yl)-N,N-dimethylethane-1,2-diaminium bis(trifluoroacetate);
14-cyclohexyl-7,8-dihydro-6H-indolo[1,2-e][1,5]benzoxazocine-11-carboxyli-
c acid;
14-cyclohexyl-6-methyl-7-oxo-5,6,7,8-tetrahydroindolo[2,1-a][2,5]b-
enzodiazocine-11-carboxylic acid;
14-cyclohexyl-3-methoxy-6-methyl-7-oxo-5,6,7,8-tetrahydroindolo[2,1-a][2,-
5]benzodiazocine-11-carboxylic acid;
14-cyclohexyl-6-[2-(dimethylamino)ethyl]-3-methoxy-7-oxo-5,6,7,8-tetrahyd-
roindolo[2,1-a][2,5]benzodiazocine-11-carboxylic acid;
14-cyclohexyl-6-[3-(dimethylamino)propyl]-7-oxo-5,6,7,8-tetrahydroindolo[-
2,1-a][2,5]benzodiazocine-11-carboxylic acid;
14-cyclohexyl-7-oxo-6-(2-piperidin-1-ylethyl)-5,6,7,8-tetrahydroindolo[2,-
1-a][2,5]benzodiazocine-11-carboxylic acid;
14-cyclohexyl-6-(2-morpholin-4-ylethyl)-7-oxo-5,6,7,8-tetrahydroindolo[2,-
1-a][2,5]benzodiazocine-11-carboxylic acid;
14-cyclohexyl-6-[2-(diethylamino)ethyl]-7-oxo-5,6,7,8-tetrahydroindolo[2,-
1-a][2,5]benzodiazocine-11-carboxylic acid;
14-cyclohexyl-6-(1-methylpiperidin-4-yl)-7-oxo-5,6,7,8-tetrahydroindolo[2-
,1-a][2,5]benzodiazocine-11-carboxylic acid;
14-cyclohexyl-N--[(dimethylamino)sulfonyl]-7-oxo-6-(2-piperidin-1-ylethyl-
)-5,6,7,8-tetrahydroindolo[2,1-a][2,5]benzodiazocine-11-carboxamide;
14-cyclohexyl-6-[2-(dimethylamino)ethyl]-N-[(dimethylamino)sulfonyl]-7-ox-
o-5,6,7,8-tetrahydroindolo[2,1-a][2,5]benzodiazocine-11-carboxamide;
14-cyclopentyl-6-[2-(dimethylamino)ethyl]-7-oxo-5,6,7,8-tetrahydroindolo[-
2,1-a][2,5]benzodiazocine-11-carboxylic acid;
14-cyclohexyl-5,6,7,8-tetrahydroindolo[2,1-a][2,5]benzodiazocine-11-carbo-
xylic acid;
6-allyl-14-cyclohexyl-3-methoxy-5,6,7,8-tetrahydroindolo[2,1-a][2,5]benzo-
diazocine-11-carboxylic acid;
14-cyclopentyl-6-[2-(dimethylamino)ethyl]-5,6,7,8-tetrahydroindolo[2,1-a]-
[2,5]benzodiazocine-11-carboxylic acid;
14-cyclohexyl-6-[2-(dimethylamino)ethyl]-5,6,7,8-tetrahydroindolo[2,1-a][-
2,5]benzodiazocine-11-carboxylic acid;
13-cyclohexyl-5-methyl-4,5,6,7-tetrahydrofuro[3',2':6,7][1,4]diazocino[1,-
8-a]indole-10-carboxylic acid;
15-cyclohexyl-6-[2-(dimethylamino)ethyl]-7-oxo-6,7,8,9-tetrahydro-5H-indo-
lo[2,1-a][2,6]benzodiazonine-12-carboxylic acid;
15-cyclohexyl-8-oxo-6,7,8,9-tetrahydro-5H-indolo[2,1-a][2,5]benzodiazonin-
e-12-carboxylic acid;
13-cyclohexyl-6-oxo-6,7-dihydro-5H-indolo[1,2-d][1,4]benzodiazepine-10-ca-
rboxylic acid; and pharmaceutically acceptable salts thereof.
[0145] The HCV NS3 protease inhibitory activity of the present
compounds may be tested using assays known in the art. One such
assay is HCV NS3 protease time-resolved fluorescence (TRF) assay as
described below and in International Patent Application Publication
WO2006/102087. Other examples of such assays are described in e.g.,
International Patent Application Publication WO2005/046712. HCV NS3
protease inhibitors, such as those described herein have a Ki less
than 50 .mu.M, such as less than 10 .mu.M, and less than 100 nM. Ki
is determined by an NS3 protease assay. The assay is performed in a
final volume of 100 .mu.l in assay buffer containing 50 mM HEPES,
pH 7.5, 150 mM NaCl, 15% glycerol, 0.15% Triton X-100, 10 mM DTT,
and 0.1% PEG 8000. NS3 protease is pre-incubated with various
concentrations of inhibitors in DMSO for 30 minutes. The reaction
is initiated by adding the TRF peptide substrate (final
concentration 100 nM). NS3 mediated hydrolysis of the substrate is
quenched after 1 hour at room temperature with 100 .mu.l of 500 mM
MES, pH 5.5. Product fluorescence is detected using either a VICTOR
V2 or FUSION fluorophotometer (Perkin Elmer Life and Analytical
Sciences) with excitation at 340 nm and emission at 615 nm with a
400 .mu.s delay. Testing concentrations of different enzyme forms
are selected to result in a signal to background ratio (SB) of
10-30. IC.sub.50 values are derived using a standard four-parameter
fit to the data. K, values are derived from IC.sub.50 values using
the following formula,
IC.sub.50=K.sub.i(1+[S]/K.sub.M), Eqn (1),
where [S] is the concentration of substrate peptide in the reaction
and K.sub.M is the Michaelis constant. See P. Gallinari et al., 38
BIOCHEM. 5620-32 (1999); P. Gallinari et al., 72 J. VIROL. 6758-69
(1998); M. Taliani et al., 240 ANAL. BIOCHEM. 60-67 (1996).
[0146] The present invention also includes processes for making
compounds of formula (I). The compounds of the present invention
can be readily prepared according to the following reaction schemes
and examples, or modifications thereof, using readily available
starting materials, reagents and conventional synthesis procedures.
In these reactions, it is also possible to make use of variants
which are themselves known to those of ordinary skill in this art,
but are not mentioned in greater detail. Furthermore, other methods
for preparing compounds of the invention will be readily apparent
to the person of ordinary skill in the art in light of the
following reaction schemes and examples. Unless otherwise
indicated, all variables are as defined above. The following
reaction schemes and examples serve only to illustrate the
invention and its practice.
[0147] Olefin metathesis catalysts include the following Ruthenium
based species: F. Miller et al., 118 J. AM. CHEM. SOC. 9606 (1996);
G. Kingsbury et al., 121 J. Am. Chem. Soc. 791 (1999); H. Scholl et
al., 1 ORG. LETT. 953 (1999); U.S. Patent Application Publication
US2002/0107138; K. Furstner et al., 64 J. ORG. CHEM. 8275 (1999).
The utility of these catalysts in ring closing metathesis is well
known in the literature (e.g. Trnka and Grubbs, 34 ACC. CHEM. RES.
18 (2001).
##STR00020## ##STR00021##
[0148] The following examples serve only to illustrate the
invention and its practice. The examples are not to be construed as
limitations on the scope or spirit of the invention.
List of Abbreviations
[0149] BOC (also Boc) t-Butyloxycarbonyl [0150] B(OMe).sub.3
Trimethyl borate [0151] BOP
Benzotriazole-1-yl-oxy-tris-(dimethylamino)-phosphonium
hexafluorophosphate [0152] Brosyl chloride 4-Bromophenyl
sulfonylchloride [0153] tBuOH t-Butanol [0154] BuLi Butyl lithium
[0155] CAN Ceric ammonium nitrate [0156] CDCl.sub.3
Deuterio-trichloromethane [0157] CDI N,N'-Carbonyl diimidazole
[0158] CH.sub.3CN Acetonitrile [0159] mCPBA m-Chloroperbenzoic acid
[0160] Cs.sub.2CO.sub.3 Cesium carbonate [0161] CuI Copper iodide
[0162] Cu(I) Br.SMe.sub.2 Copper (I) bromide dimethyl sulfide
complex [0163] DABCO 1,4-diazabicyclo[2.2.2]octane [0164] DBA (also
dba) Dibenzylidene acetone [0165] DBU
1,8-Diazabicyclo[5.4.0]undec-7-ene [0166] DCC
Dicyclohexylcarbodiimide [0167] DCE Dichloroethane [0168] DCM
Dichloromethane [0169] DEAD Diethyl azodicarboxylate [0170] DIAD
Diisopropyl azodicarboxylate [0171] DIEA Diethylamine [0172] DIPA
Diethylpropylamine [0173] DIPEA Diisopropylethylamine [0174] DMAP
4-Dimethylamino pyridine [0175] DMF Dimethylformamide [0176] DMSO
Dimethyl Sulfoxide [0177] DPPF (also dppf)
1,1'-bid(Diphenylphosphino)ferrocene [0178] EDC
N-(3-Dimethylaminopropyl)-N'-ethylcarbodiimide [0179] ESI
Electrospray ionization [0180] Et.sub.2O Diethyl ether [0181] EtOAc
Ethyl Acetate [0182] EtOH Ethanol [0183] H.sub.2 Hydrogen or
hydrogen atmosphere [0184] HATU
O-(7-Azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium
hexafluorophosphate [0185] HBr Hydrobromic acid [0186] HCl
Hydrochloric acid [0187] HMPA Hexamethylphosphoramide [0188] HOAc
Acetic acid [0189] HOAt 1-Hydroxy-7-azabenzotriazole [0190] HOBT
1-Hydroxy benzotriazole [0191] H.sub.2O Water [0192] H.sub.2O.sub.2
Hydrogen peroxide [0193] HPLC High performance liquid
chromatography [0194] I.sub.2 Iodine [0195] KHSO.sub.4 Potassium
bisulfate [0196] K.sub.2 SO.sub.4 Potassium sulfate [0197]
K.sub.2CO.sub.3 Potassium carbonate [0198] KOH Potassium hydroxide
[0199] LAH Lithium aluminium hydride [0200] LCMS High performance
liquid chromatography--mass spectrometry [0201] LiOH Lithium
hydroxide [0202] LiOH.H.sub.2O Lithium hydroxide monohydrate [0203]
LRMS Low resolution mass spectrometry [0204] Me.sub.3Al
Trimethylaluminium [0205] MeLi Methyllithium [0206] MeOH Methanol
[0207] MgSO.sub.4 Magnesium Sulfate [0208] MsCl Mesyl chloride
[0209] N.sub.2 Nitrogen or nitrogen atmosphere [0210] NH.sub.4Cl
Ammonium chloride [0211] NH.sub.4OH Ammonium hydroxide [0212] Nle
Norleucine [0213] NMP N-Methyl pyrrolidinone [0214] NaH Sodium
hydride [0215] NaHCO.sub.3 Sodium hydrogen carbonate (sodium
bicarbonate) [0216] NaHSO.sub.3Sodium bisulfite [0217] NaOH Sodium
hydroxide [0218] NaOMe Sodium methoxide [0219] Na.sub.2SO.sub.3
Sodium sulfite [0220] Na.sub.2S.sub.2O.sub.3Sodium thiosulfate
[0221] Na.sub.2SO.sub.4Sodium sulfate (anhydrous) [0222] PCy.sub.3
Tricyclohexyl phosphine [0223] POBr Phosphoryl bromide [0224]
POBr.sub.3 Phosphoryl tribromide [0225] P.sub.2O.sub.5 phosphorus
pentoxide (P.sub.4O.sub.10) [0226] Pd/C Palladium on carbon [0227]
PhMe Toluene [0228] PPh.sub.3 Triphenylphosphine [0229] RT Room
temperature, approximately 25 C [0230] Ru/C Ruthenium on carbon
[0231] SiO.sub.2 Silica or silica gel [0232] TBAF
Tetrabutylammonium fluoride [0233] TBTU
O-Benzotriazol-1-yl-N,N,N',N'-tetramethyluronium tetrafluoroborate
[0234] TEA Triethylamine [0235] TFA Trifluoroacetic acid [0236] THF
Tetrahydrofuran [0237] TIPSOTf Triisopropylsilyl triflate [0238]
TMSCl Chlorotrimethyl silane [0239] TsCl p-Toluenesulfonyl chloride
[0240] Zn(CN).sub.2 Zinc cyanide
Synthesis of Intermediates
Intermediates A
TABLE-US-00001 [0241] Literature Intermediate # Structure Name
Reference A1 ##STR00022## (1R,2S)-1-Amino-N-
(cyclopropylsulfonyl)-2- vinylcyclopropanecarboxamide hydrochloride
U.S. Pat. No. 6,995,174 A2 ##STR00023## Ethyl (1R,2S)-1-amino-2-
vinylcyclopropanecarboxylate hydrochloride U.S. Pat. No.
6,323,180
Intermediate A3:
(1R,2R)-1-Amino-N-(cyclopropylsulfonyl)-2-ethylcyclopropanecarboxamide
hydrochloride
##STR00024##
[0242] Step 1: t-Butyl
((1R,2R)-1-{[(cyclopropylsulfonyl)amino]carbonyl}-2-ethylcyclopropyl)carb-
amate
##STR00025##
[0244] A hydrogenation vessel was charged with a MeOH (1000 mL)
slurry of t-butyl
((1R,2S)-1-{[(cyclopropylsulfonyl)amino]carbonyl}-2-vinylcyclopro-
pyl)carbamate (164 g, 0.50 mol) (U.S. Pat. No. 6,995,174) and 5%
Ru/C (dry, 7.5 wt %, 12.4 g) and stirred. The vessel was placed
under N.sub.2 (20 psi) and vented to atmospheric pressure
(3.times.) to remove residual oxygen. The vessel was then placed
under H.sub.2 (50 psi). After 20 hours, the vessel was vented to
atmospheric pressure. The reaction slurry was then transferred out
of the reaction vessel and filtered through SOLKA FLOK (34 g,
wetted with 100 mL MeOH) to yield a clear, light brown solution.
The SOLKA FLOK was rinsed with MeOH (200 mL.times.2). The combined
MeOH solutions were concentrated under reduced pressure to yield
crude product as a white solid (153 g). The crude product was
slurried in EtOAc (800 mL), warmed to 40.degree. C. and aged 30
minutes. The solution was then seeded, aged 30 minutes, and heptane
(500 mL) was added via addition funnel over 30 minutes. The
partially crystallized solid was cooled to RT and aged overnight,
after which additional heptane (500 mL) was added. After 1 hour,
additional heptane (250 mL) was added via addition funnel, and the
white slurry aged for 1 hour. The solution was filtered, and the
solid was rinsed with heptane/EtOAc (500 mL, 4:1) and dried under
reduced pressure to give t-butyl
((1R,2R)-1-{[(cyclopropylsulfonyl)amino]carbonyl}-2-ethylcyclopropyl)carb-
amate (125.9 g).
Step 2:
(1R,2R)-1-Amino-N-(cyclopropylsulfonyl)-2-ethylcyclopropanecarboxa-
mide hydrochloride (Intermediate A3)
[0245] A solution of the product from Step 1 (92 g, 0.28 mol) in
DCM (1200 mL) was cooled to 0.degree. C., and HCl was bubbled
through the solution for 10 minutes. The cooling bath was then
removed, and the reaction mixture stirred for 2 hours. N.sub.2 was
bubbled through the reaction mixture for 5 minutes, and the
volatiles evaporated. The residue was azeotroped with DCM
(3.times.) to give an off-white powder (75 g). LRMS (M+H).sup.+
Calcd.=233; found 233.
Intermediate A4: Trans-4-pent-4-en-1-yltetrahydrofuran-3-ol
##STR00026##
[0247] To a mixture of CuI (1.66 g, 8.71 mmol) in THF (100 mL) at
-5.degree. C., a 0.5M solution of bromo(pent-4-en-1-yl)magnesium
(116 mL, 5.81 mmol) was added. The solution was stirred for 1 hour
and cooled to -20.degree. C. 3,6-Dioxabicyclo[3.1.0]hexane (5.0 g,
58.1 mmol) was added dropwise, and the reaction mixture was slowly
warmed to RT and stirred for 15 hours. The reaction mixture was
quenched with NH.sub.4Cl.sub.(aq.) and extracted with Et.sub.2O
(3.times.). The combined organics were washed with H.sub.2O and
brine, dried over Na.sub.2SO.sub.4, filtered and concentrated. The
crude product was purified on SO.sub.2 (gradient elution, 10-100%
EtOAc/hexanes). .sup.1H NMR (500 MHz, CDCl.sub.3) .delta. 5.83-5.75
(m, 1H); 5.04-4.95 (m, 2H); 4.14-4.07 (m, 3H); 3.85 (m, 1H); 3.70
(m, 1H); 3.44 (m, 1H); 2.07 (m, 3H); 1.45 (m, 3H) ppm.
Intermediate A5: Trans-2-pent-4-en-1ylcyclopentanol
##STR00027##
[0249] A solution of 5-bromopent-1-ene (11.81 mL, 100 mmol) in
Et.sub.2O (100 mL) was added to magnesium (2.43 g, 100 mmol) over
20 minutes. The resulting suspension was heated under reflux for 40
minutes, then cooled to 20.degree. C., taken up in a syringe, and
added dropwise at -5.degree. C. to a stirred suspension of CuI
(3.17 g, 16.6 mmol) in THF (160 mL). The resulting solution was
stirred for 30 minutes at -5.degree. C., then cooled to -20.degree.
C. Cyclopentene oxide (7.21 mL, 83 mmol) was added dropwise, and
the resulting mixture was warmed to 20.degree. C. over 2 hours,
then stirred for 48 hours. The reaction was quenched by addition of
NH.sub.4Cl.sub.(aq.); then the layers were separated, and the
aqueous layer was extracted with Et.sub.2O. The combined organic
phases were washed with H.sub.2O and brine, then dried over
Na.sub.2SO.sub.4. Filtration and removal of the volatiles gave a
residue that was purified by column chromatography on SiO.sub.2
(gradient elution, 1-100% EtOAc/petroleum ether) to afford the
title compound (7.92 g, 62%) as a liquid. .sup.1H NMR (400 MHz,
CDCl.sub.3) .delta. 5.88-5.76 (m, 1H), 5.01 (d, J=17.2 Hz, 1H),
4.95 (d, J=10.6 Hz, 1H), 3.83 (br s, 1H), 2.12-2.00 (m, 2H),
1.99-1.84 (m, 2H), 1.76-1.30 (m, 7H), 1.24-1.11 (m, 2H).
Intermediate A6: (1R,2R)-2-pent-4-en-1-ylcyclopentyl acetate
##STR00028##
[0251] AMANO LIPASE PS (7.0 g, 64.7 mmol) was added to a solution
of trans-2-pent-4-en-1-ylcyclopentanol (10.0 g, 64.7 mmol) and
vinyl acetate (19.5 g, 129.4 mmol) in Et.sub.2O (275 mL). The
mixture was stirred for 16 hours, then filtered through CELITE. The
filtrate was concentrated to afford a residue that was purified by
column chromatography on SiO.sub.2 (gradient elution, 0-100%
Et.sub.2O/petroleum ether) to afford in the first fractions the
title compound (5.43 g, 43%). NMR (300 MHz, CDCl.sub.3) .delta.
5.89-5.72 (m, 1H), 5.00 (d, J=18.1 Hz, 1H), 4.95 (d, J=11.0 Hz,
1H), 4.82-4.73 (m, 1H), 2.11-1.98 (m, 2H), 2.03 (s, 3H), 1.98-1.85
(m, 3H), 1.71-1.60 (m, 3H), 1.50-1.35 (m, 3H), 1.29-1.14 (m, 2H);
[.alpha.].sub.D=-36.1 (c=0.73 in CHCl.sub.3). The later fractions
contained enantio-enriched
(1S,2S)-2-pent-4-en-1-ylcyclopentanol.
Intermediate A7: (1R,2R)-2-pent-4-en-1-ylcyclopentanol
##STR00029##
[0253] A stirred solution of (1R,2R)-2-pent-4-en-1-ylcyclopentyl
acetate (3.79 g, 19.3 mmol) in MeOH (320 ml) was treated with
methanolic NaOMe (25%, 8.1 ml, 35.4 mmol) and stirred for 15 hours
at 20.degree. C. DOWEX 50WX8-100 ion-exchange resin (washed with
MeOH) was added portionwise until the pH was neutral, then the
mixture was filtered through CELITE. The filtrate was concentrated
in vacuo, and the residue was partitioned between EtOAc and
H.sub.2O. The organic layer was separated, washed with brine, and
dried over Na.sub.2SO.sub.4. Filtration and removal of the
volatiles afforded the title compound (2.61 g, 88%) as a liquid
that was used directly in the subsequent reactions. [.alpha.]D
-37.3 (c=0.65, CHCl.sub.3).
Intermediates B
Intermediate B1: N-[(Pent-4-en-1-yloxy)carbonyl]-L-norleucine
##STR00030##
[0255] To a solution of 1-penten-4-ol (0.95 g, 11.0 mmol) in DMF
(15 mL) at 0.degree. C., carbonyldiimidazole (1.79 g, 11.0 mmol)
was added. The reaction mixture was warmed to RT and stirred for 30
minutes. L-norleucine methyl ester hydrochloride (2.0 g, 11.0 mmol)
was then added, and the reaction mixture was heated to 50.degree.
C. and stirred for 15 minutes. Upon cooling, the reaction mixture
was diluted with Et.sub.2O and washed (2.times.) with H.sub.2O. The
organic layer was dried over Na.sub.2SO.sub.4, filtered and
concentrated. The crude product was purified by SiO.sub.2
chromatography (gradient elution, 10-90% EtOAc/hexanes) to afford
2.1 g (74%) methyl N--[(pent-4-en-1-yloxy)carbonyl]-L-norleucinate
as a clear oil.
[0256] To a stirred solution of methyl
N-[(pent-4-enyloxy)carbonyl]-L-norleucinate (8.50 g, 33.03 mmol) in
THF (20 mL) was added 1N NaOH (20 mL). This reaction solution was
stirred at RT for 3 hours, then acidified to pH 3 with 1N HCl and
extracted with (3.times.250 mL) EtOAc. The combined EtOAc layer was
washed with 50 mL H.sub.2O, 50 mL brine, dried over
Na.sub.2SO.sub.4, filtered and concentrated to give 7.09 g (88%) of
the title product as clear oil. LRMS (ESI) m/z 244 [(M+H).sup.+;
calcd for C.sub.12H.sub.22NO.sub.4: 244].
Intermediate B2:
(2S)-3,3-Dimethyl-2-{[(pent-4-en-1-yloxy)carbonyl]amino}butanoic
acid
##STR00031##
[0258] DIPEA (9.85 g, 76.2 mmol) was added dropwise to a 0.degree.
C. solution of 4-penten-1-ol (7.22 g, 83.9 mmol) and triphosgene
(11.3 g, 38.1 mmol) in 160 mL dioxane. The resulting white
suspension was stirred for 5 minutes at 0.degree. C., then allowed
to warm to 25.degree. C. over 1 hour. The suspension was cooled to
0.degree. C. with an ice bath, and 1N NaOH (76.2 mL) and
L-t-butylglycine (10.0 g, 76.2 mmol) were added. The reaction
mixture was warmed to 25.degree. C. and stirred for 18 hours. The
dioxane was removed in vacuo, and the reaction mixture was basified
to pH 12 with 1N NaOH. The aqueous layer was extracted with DCM
(3.times.150 mL), then acidified to pH-1 with 6N HCl. The aqueous
layer was extracted again with DCM (3.times.150 mL). The combined
organic layers were dried over MgSO.sub.4, and concentrated to give
the compound as a tan oil (13.7 g, 73.9% yield). LRMS (ESI) m/z 244
[(M+H).sup.+; calcd for C.sub.12H.sub.22NO.sub.4 244].
[0259] The following carbamate intermediates (B3-B19) were prepared
using the chemistry described for the preparation of Intermediate
B2, by utilizing the appropriate amino acid and alcohol.
TABLE-US-00002 LRMS Int. Amino Acid Alcohol Structure Name (M +
H).sup.+ B1 L-Norleucine 4-Penten-1-ol ##STR00032##
N-[(Pent-4-en-1- yloxy)carbonyl]-L- norleucine 244.3 B2 L-t-Butyl-
glycine 4-Penten-1-ol ##STR00033## (2S)-3,3-Dimethyl-2-
{[(pent-4-en-1- yloxy)carbonyl]amino} butanoic acid 244.2 B3
L-Norleucine 3-Buten-1-ol ##STR00034## N-[(but-3-en-1-
yloxy)carbonyl]-L- norleucine 230.3 B4 L-Norleucine 5-Hexen-1-ol
##STR00035## N-[(hex-5-en-1- yloxy)carbonyl]-L- norleucine 258.3 B5
L-Norleucine 6-Hepten-1-ol ##STR00036## N-[(hept-6-en-1-
yloxy)carbonyl]-L- norleucine 272.3 B6 L-Norleucine 7-Octen-1-ol
##STR00037## N-[(oct-7-en-1- yloxy)carbonyl]-L- norleucine 286.4 B7
L-Valine 4-Penten-1-ol ##STR00038## N-[(Pent-4-en-1-
ylocy)carbonyl]-L-valine 230.3 B8 L-Valine 4-Propen-1-ol
##STR00039## N-[(allyloxy)carbonyl]- L-valine 202.2 B9 L-Valine
4-Buten-1-ol ##STR00040## N-[(but-3-en-1- yloxy)carbonyl]-L- valine
216.3 B10 L-t-Butyl- glycine 5-Hexen-1-ol ##STR00041##
N-[(Hex-5-en-1- yloxy)carbonyl]-3- methyl-L-valine 258.3 B11
L-t-Butyl- glycine 6-Hepten-1-ol ##STR00042## N-[(Hept-6-en-1-
yloxy)carbonyl]-3- methyl-L-valine 272.3 B12 L-t-Butyl- glycine
3-Buten-1-ol ##STR00043## N-[(But-3-en-1- yloxy)carbonyl]-3-
methyl-L-valine 230.3 B13 L-t-Butyl- glycine 2,2-Dimethylhex-5-
en-1-ol Ref: 56 J. Org. Chem. 1623 (1991). ##STR00044##
N-{[(2,2-Dimethylhex-5- en-1-yl)oxy]carbonyl}-3- methyl-L-valine
286.3 B14 L-t-Butyl- glycine Allyl alcohol ##STR00045##
N-[(allyloxy)carbonyl]-3- methyl-L-valine 215.2 B15 L-t-Butyl-
glycine 7-Octen-1-ol ##STR00046## 3-Methyl-N-[(oct-7-en-1-
yloxy)carbonyl]-L-valine 286.3 B16 L-Cyclohexyl- glycine
6-Hepten-1-ol ##STR00047## (2S)-Cyclohexyl{[(hept- 6-en-1-
yloxy)carbonyl]amino} acetic acid 298.3 B17 L-Cyclohexyl- glycine
5-Hexen-1-ol ##STR00048## (2S)-Cyclohexyl{[(hex- 5-en-1-
yloxy)carbonyl]amino} acetic acid 284.4 B18 L-t-Butyl- glycine
6-Heptyn-1-ol ##STR00049## N-[(hept-6-yn-1- yloxy)carbonyl]-3-
methyl-L-valine 270.2 B19 L-Cyclohexyl- glycine 2,2-dimethylhept-
6-en-1-ol Ref: WO 2005/030796 ##STR00050## (2S)-cyclohexyl({[(2,2-
dimethylhept-6-en-1- yl)oxy]carbonyl}amino) acetic acid 326.5
Intermediate B20:
3-Methyl-N-{[methyl(pent-4-en-1-yl)amino]carbonyl}-L-valine
##STR00051##
[0260] Step 1: Methyl
3-methyl-N-{[methyl(pent-4-en-1-yl)amino]carbonyl}-L-valinate
##STR00052##
[0262] To a solution of N-methylpent-4-en-1-amine (ref: 2(20) Org.
Biomol. Chem. 3006-17 (2004)) (2.0 g, 21.2 mmol) in THF (20 mL),
methyl 3-methyl-N-(oxomethylene)-L-valinate (ref: EP 0 486 948 A2)
(3.5 g, 20.2 mmol) was added. After 2 hours, the solvent was
removed in vacuo, and the crude material was purified on SO.sub.2
(40% EtOAc/hexanes) to yield the title compound. LRMS (M+H).sup.+
271.3.
Step 2: N-{[(1,1-Dimethylpent-4-en-1-yl)amino]carbonyl}-L-valine
(Intermediate B20)
[0263] To a solution of the product from step 1, methyl
3-methyl-N-{[methyl(pent-4-en-1-yl)amino]carbonyl}-L-valinate, (3.0
g, 11.2 mmol) in THF (40 mL), 1M LiOH (56.0 mL, 1M solution 56.0
mmol) was added. The reaction mixture was stirred at 50.degree. C.
under N.sub.2 for 1 hour, cooled to RT, and THF was removed in
vacuo. KHSO.sub.4(aq.) was then added, and the mixture extracted
with DCM (3.times.). The combined organic extracts were dried over
anhydrous Na.sub.2SO.sub.4, and the solvent was removed in vacuo to
give the title compound as a colorless oil (2.95 g). LRMS
(M+H).sup.+=257.3.
Intermediate B21:
(2S)-Cyclopentyl[({[(1R,2R)-2-pent-4-en-1-ylcyclopentyl]oxy}carbonyl)amin-
o]acetic acid
##STR00053##
[0264] Step 1: Methyl (2S)-cyclopentyl(isocyanato)acetate
##STR00054##
[0266] A suspension of methyl (2S)-amino(cyclopentyl)acetate
hydrochloride (3.21 g, 16.57 mmol) in DCM (69 mL) and saturated
NaHCO.sub.3(aq.) (132 mL) was cooled to 0.degree. C. and treated
with triphosgene (2.21 g, 7.46 mmol). The mixture was stirred at
0.degree. C. for 3 hours, then warmed to 20.degree. C. and diluted
with DCM. The layers were separated, and the aqueous phase was
re-extracted with DCM. The combined organic phases were washed with
brine and dried over Na.sub.2SO.sub.4. Filtration and removal of
the volatiles afforded the title compound (2.95 g, 97%) as an oily
solid that was used directly in subsequent steps. NMR (400 MHz,
DMSO-d.sub.6). .delta. 4.36 (d, J=4.8 Hz, 1H), 3.73 (s, 1H),
2.35-2.24 (m, 1H), 1.76-1.24 (m, 8H).
Step 2: Methyl
(2S)-cyclopentyl[({[(1R,2R)-2-pent-4-en-1-ylcyclopentyl]oxy}carbonyl)amin-
o]acetate
##STR00055##
[0268] A solution of methyl (2S)-cyclopentyl(isocyanato)acetate
(1.57 g, 8.56 mmol) and (1R,2R)-2-pent-4-en-1-ylcyclopentanol (1.20
g, 7.78 mmol) in PhMe (56 mL) was treated portionwise with DMAP
(0.95 g, 7.78 mmol). The resulting mixture was stirred for 5 hours
at 85.degree. C., then cooled to 20.degree. C., and diluted with
EtOAc and HCl.sub.(aq.) (1N). The organic layer was separated,
washed with brine, and dried over Na.sub.2SO.sub.4. Filtration and
removal of the volatiles gave a residue that was purified by column
chromatography (gradient elution, 4-40% Et.sub.2O/petroleum ether)
to afford the title compound (1.97 g, 76%) as an oil. LCMS (ES+)
m/z 338 (M+H).sup.+.
Step 3:
(2S)-Cyclopentyl[({[(1R,2R)-2-pent-4-en-1-ylcyclopentyl]oxy}carbon-
yl)amino]acetic acid
[0269] A mixture of methyl
(2S)-cyclopentyl[({[(1R,2R)-2-pent-4-en-1-ylcyclopentyl]oxy}carbonyl)amin-
o]acetate (1.97 g, 5.84 mmol) and LiOH.H.sub.2O (0.74 g, 17.51
mmol) in a 1:1 mixture of THF:H.sub.2O (60 mL) was heated to
40.degree. C. The solution was stirred for 4 hours, then cooled to
20.degree. C. The THF was removed under reduced pressure, and the
residual aqueous solution was extracted with EtOAc. The organic
phase was washed with H.sub.2O and brine, then dried over
Na.sub.2SO.sub.4. Filtration and removal of the volatiles afforded
the title compound (1.85 g, 98%) as an oil that was used directly
in subsequent steps. .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta.
12.25 (br s, 1H), 7.28 (d, J=8.1 Hz, 1H), 5.84-5.71 (m, 1H), 4.98
(d, J=17.4 Hz, 1H), 4.92 (d, J=10.1 Hz, 11-1), 4.60-4.52 (m, 1H),
3.78 (t, J=8.0 Hz, 1H), 2.18-2.05 (m, 1H), 2.04-1.94 (m, 3H),
1.91-1.74 (m, 3H), 1.70-1.06 (m, 15H).
Intermediates B21a-B24a
[0270] Intermediates B21a-B24a were prepared in a manner similar to
that utilized to prepare Intermediate B21.
TABLE-US-00003 LRMS Int. Amino Acid Alcohol Structure Name (M +
H).sup.+ B21a L-cyclopentyl- glycine trans-4-pent-4-en-1-
yltetrahydrofuran-3-ol ##STR00056## (2S)-cyclopentyl({[(trans-
4-pent-4-en-1- yltetrahydrofuran-3- yl)oxy]carbonyl}amino) acetic
acid B22 L-tBu-glycine trans-2-pent-4-en- 1-ylcyclopentanol
##STR00057## 3-methyl-N-{[(trans-2- pent-4-en-1- ylcyclopentyl)oxy]
carbonyl}-L-valine 312.4 B22a L-tBu-glycine (1R,2R)-2-pent-4- en-1-
ylcyclopentanol ##STR00058## 3-methyl-N-({[(1R,2R)- 2-pent-4-en-1-
ylcyclopentyl]oxy} carbonyl)-L-valine 312.4 B23 L-cyclopentyl-
glycine trans-2-pent-4-en- 1-ylcyclopentanol ##STR00059##
(2S)-cyclopentyl({[trans- (2-pent-4-en-1- ylcyclopentyl)oxy]
carbonyl}amino)acetic acid 324.2 B23a L-cyclopentyl- glycine
(1R,2R)-2-pent-4-en- 1-ylcyclopentanol ##STR00060##
(2S)-cyclopentyl[({[(1R,2R)- 2-pent-4-en-1- ylcyclopentyl]oxy}
carbonyl)amino]acetic acid 324.2 B23b L-cyclopentyl- glycine
(1S,2S)-2-pent-4-en- 1-ylcyclopentanol ##STR00061##
(2S)-cyclopentyl[({[(1S,2S)- 2-pent-4-en-1- ylcyclopentyl]oxy}
carbonyl)amino]acetic acid 324.2 B24 L-cyclohexyl- glycine
Trans-2-pent-4-en- 1-ylcyclopentanol ##STR00062##
(2S)-cyclohexyl({[(2-pent- 4-en-1-ylcyclopentyl)oxy]
carbonyl}amino)acetic acid 338.3 B24a L-cyclohexyl- glycine
(1R,2R)-2-pent-4-en- 1-ylcyclopentanol ##STR00063##
(2S)-cyclohexyl[({[(1R,2R)- 2-pent-4-en-1- ylcyclopentyl]oxy}
carbonyl)amino]acetic acid 360.3 (M + Na).sup.+
Intermediates B25a and B25b:
3-Methyl-N-({[(1R,2R)-2-pent-4-en-1-ylcyclopropyl]oxy}carbonyl)-L-valine
and
3-methyl-N-({[(1S,2S)-2-pent-4-en-1-ylcyclopropyl]oxy}carbonyl)-L-val-
ine
##STR00064##
[0271] Step 1: [(1E)-Hepta-1,6-dien-1-yloxy](trimethyl)silane
##STR00065##
[0273] A solution (0.5M) of butenyl magnesium bromide in THF (200
ml, 100 mmol) was added at -70.degree. C. to Cu(I) Br.SMe.sub.2
complex (734 mg, 3.57 mmol) and HMPA (29.8 ml, 171 mmol). After
stirring for 10 minutes, a solution of acrolein (4.00 g, 71.4 mmol)
and TMSCl (18.25 mL, 143 mmol) in THF (59.8 mL) was added over 30
minutes. After 2 hours, TEA (20 mL) was added, and the mixture was
diluted with anhydrous hexane. H.sub.2O (5 mL) was added, and the
mixture was filtered through CELITE. The filtrate was washed
(7.times.) with 16 mL portions of H.sub.2O, and then extracted with
hexane. The organic layer was washed with brine and dried over
Na.sub.2SO.sub.4, then concentrated to give a residue that was
distilled (bp c. 80.degree. C., 20 mbar) to furnish the title
compound (7.68 g, 58%) as a liquid that was used directly in the
subsequent reaction.
Step 2: Trimethyl
{[(1S,2S)-2-pent-4-en-1-ylcyclopropyl]oxy}silane
##STR00066##
[0275] A solution of diethyl zinc in toluene (15%, 3.29 mL, 3.62
mmol) was added to a solution of the product of Step 1 (303 mg,
1.64 mmol) in hexane (3.62 mL), and the resultant solution was
cooled with an ice bath before careful addition of diiodomethane
(292 .mu.L, 3.62 mmol). The reaction was stirred at 0.degree. C.
for 1 hour, and then warmed to 20.degree. C. The reaction was then
quenched with pyridine (0.80 mL) and stirred for 15 minutes before
pouring onto petrol. The reaction mixture was filtered through
CELITE and concentrated to afford the title compound as an oil that
was used directly in the subsequent step.
Step 3: 2-Pent-4-en-1-ylcyclopropanol
##STR00067##
[0277] A solution of
trimethyl{[(1S,2S)-2-pent-4-en-1-ylcyclopropyl]oxy}silane (5.81 g,
29.3 mmol) in THF (42 mL) was cooled to 0.degree. C. and treated
with a solution of TBAF in THF (1M, 35.2 mL, 35.2 mmol). The
mixture was stirred at 0.degree. C. for 10 minutes, and then warmed
to 15.degree. C. over 1 hour. The mixture was poured into H.sub.2O
(900 mL) and extracted (2.times.) with EtOAc. The combined organic
extracts were washed with brine, dried over Na.sub.2SO.sub.4 and
evaporated to afford a residue, which was purified by column
chromatography on SiO.sub.2, eluting with Et.sub.2O in petroleum
ether (0-66%) to give the title compound (2.63 g, 71%) as an oil
that was used directly in the subsequent reaction.
Step 4: Methyl
3-methyl-N-({[(1R,2R)-2-pent-4-en-1-ylcyclopropyl]oxy}carbonyl)-L-valinat-
e and methyl
3-methyl-N-({[(1S,2S)-2-pent-4-en-1-ylcyclopropyl]oxy}carbonyl)-L-valinat-
e
##STR00068##
[0279] The alcohol of Step 3 was treated, according to the
procedure above described for Intermediate B21 Step 2, with methyl
3-methyl-N-(oxomethylene)-L-valinate (1.221 g, 7.13 mmol) and DMAP
(0.871 g, 7.13 mmol) to afford a residue that was purified by flash
chromatography on SiO.sub.2 (gradient elution, 0-30%
Et.sub.2O/petroleum ether) to afford two fractions of the title
compound (815 mg and 598 mg, 38.4% and 28.2%) as oils. LCMS (ES+)
m/z 320.1 (M+Na).sup.+.
Step 5:
3-Methyl-N-({[(1R,2R)-2-pent-4-en-1-ylcyclopropyl]oxy}carbonyl)-L--
valine or
3-methyl-N-({[(1S,2S)-2-pent-4-en-1-ylcyclopropyl]oxy}carbonyl)--
L-valine
[0280] The esters of Step 4 were treated, according to the
procedure described for Intermediate B21 Step 3, with LiOH.H.sub.2O
afforded the title compounds as oils (95%). LCMS (ES+) m/z 282.2
(M-H).sup.-.
[0281] Intermediate B26:
(2S)-Cyclopentyl[({[(1R,2R)-1-methyl-2-pent-4-en-1-ylcyclopentyl]oxy}carb-
onyl)amino]acetic acid
##STR00069##
Step 1: (2R)-2-Pent-4-en-1-ylcyclopentanone
##STR00070##
[0283] Dess-Martin periodinane (6.27 g, 14.78 mmol) was added to a
stirred solution of Intermediate A7 (2.00 g, 12.97 mmol) in DCM
(120 ml). The mixture was stirred RT for 1 hour, and then diluted
with DCM and washed several times with a 1:1 mixture of saturated
NaHCO.sub.3(aq.) and Na.sub.2S.sub.2O.sub.3(aq.) (1 M). The mixture
was then with H.sub.2O and brine. The organics were dried over
Na.sub.2SO.sub.4 and concentrated to give a residue that was
dissolved in pentane, filtered, and concentrated. The resulting oil
was used directly in the subsequent reaction.
Step 2: (1R,2R)-1-methyl-2-pent-4-en-1-ylcyclopentanol
##STR00071##
[0285] A solution (2M) of Me.sub.3Al in toluene (9.85 ml, 19.71
mmol) was added dropwise to a stirred solution of
2,6-di-t-butyl-4-methylphenol (8.68 g, 39.4 mmol) in PhMe (66 mL).
After the evolution of gas had finished, the mixture was stirred at
RT for 1 hour and then cooled to -78.degree. C.
(2R)-2-pent-4-en-1-ylcyclopentanone (1.0 g, 6.57 mmol) was added
followed by a solution of MeLi (1.6 M) in Et.sub.2O (12.32 ml,
19.71 mmol). The resulting mixture was stirred at -78.degree. C.
for 2 hours and then treated with a further portion of MeLi
solution (12.32 mL, 19.71 mmol). The mixture was stirred for 1 hour
and then poured into HCl.sub.(aq.) (1N). The organic layer was
washed with brine dried over Na.sub.2SO.sub.4 and concentrated to
give a residue that was purified by column chromatography on
SiO.sub.2 (gradient elution, 0-20% EtOAc/petroleum ether) to give
the title compound (0.77 g, 70%) as a clear oil.
Step 3:
(2S)-cyclopentyl[({[(1R,2R)-1-methyl-2-pent-4-en-1-ylcyclopentyl]o-
xy}carbonyl)amino]acetic acid
[0286] The alcohol of Step 2 (0.77 g, 4.58 mmol) was treated,
according to the procedure described for Intermediate B21 Step 2,
with methyl (2S)-cyclopentyl(isocyanato)acetate (3 eq) and DMAP
(1.3 eq) afforded a residue that was purified by flash
chromatography (gradient elution, 5-40% Et.sub.2O/petroleum ether).
The resulting oil was hydrolysed as described for Intermediate B21,
Step 3 to furnish the title compound (0.53 g, 34%) as an oil. LCMS
(ES+) m/z 338.8 (M+H).sup.+.
Intermediate B27:
N-({[(1R,2S)-2-allylcyclopentyl]oxy}carbonyl)-3-methyl-L-valine
##STR00072##
[0288] Intermediate B27 was prepared in a manner similar to that
utilized to prepare
(2S)-cyclopentyl[({[(1R,2R)-1-methyl-2-pent-4-en-1-ylcyclopentyl]oxy}carb-
onyl)amino]acetic acid. LCMS (ES+) m/z 283.1.
Intermediate B28:
(2S)-[({[(1R,2S)-2-allylcyclopentyl]oxy}carbonyl)amino](cyclopentyl)aceti-
c acid
##STR00073##
[0290] Intermediate B28 was prepared in a manner similar to that
utilized to prepare
(23)-cyclopentyl[({[(1R,2R)-1-methyl-2-pent-4-en-1-ylcyclopentyl]oxy}carb-
onyl)amino]acetic acid. LCMS (ES+) m/z 283.1.
Intermediate B29:
(2S)-({[(3R)(3S)-3-(Allyloxy)piperidin-1-yl]carbonyl}amino)(cyclohexyl)ac-
etic acid
##STR00074##
[0291] Step 1: t-Butyl
(3R)(3S)-3-(allyloxy)piperidine-1-carboxylate
##STR00075##
[0293] An oven-dried, 3-neck, 1-L round-bottom flask under N.sub.2
was charged with N-Boc-(3R)(3S)-3-hydroxypiperidine (10.0 g, 49.7
mmol) and DMSO (100 mL). KOtBu (5.58 g, 49.7 mmol) was added in a
single portion. The reaction mixture was stirred at RT for 30
minutes, after which allyl bromide (4.30 mL, 49.7 mmol) in DMSO (50
mL) was added dropwise via an addition funnel. After 20 hours, the
contents of the reaction flask were poured into 5% KHSO.sub.4 and
extracted (3.times.) with Et.sub.2O. The combined organic portions
were washed with brine, dried with anhydrous MgSO.sub.4, filtered
and evaporated. The crude product was subjected to flash column
chromatography (90/10 hexanes/EtOAc). Evaporation of fractions
containing product gave the title compound as a colorless oil. LRMS
(M+H)=242.3.
Step 2: (3R)(3S)-3-(Allyloxy)piperidine
##STR00076##
[0295] A 500-mL round-bottom flask was charged with the product of
Step 1 (9.60 g, 39.8 mmol) and EtOAc (150 mL), and then cooled in
an ice bath under N.sub.2. The reaction solution was saturated with
HCl.sub.(g) and stirred for 1 hour with cooling then for 2 hours at
RT. Evaporation under reduced pressure gave a white solid, which
was triturated with Et.sub.2O and isolated. The solid was poured
into 10M NaOH.sub.(aq.) and extracted (3.times.) with DCM, dried
with anhydrous MgSO.sub.4, filtered and rotary evaporated to give
the title compound as a colorless oil.
Step 3: Methyl (2S)-cyclohexyl(isocyanato)acetate
##STR00077##
[0297] A 50-0 mL round-bottom flask was charged with saturated
NaHCO.sub.3 (80 mL) and DCM (80 mL) and cooled in an ice bath with
vigorous stirring. Methyl (2S)-amino(cyclohexyl)acetate
hydrochloride (4.0 g, 19.26 mmol) was added followed by triphosgene
(1.886 g, 6.36 mmol). The contents of the reaction flask were
stirred for 1 hour with cooling, and then the contents were poured
into a separatory funnel. The layers were separated, and the
aqueous layers were extracted with DCM (20 mL). The combined
organic portions were dried with anhydrous MgSO.sub.4, filtered and
evaporated to give the title compound as a colorless oil. .sup.1H
NMR (CDCl.sub.3): .delta. 3.90 (d, J 4, 1H), 3.81 (s, 3H),
1.88-1.83 (m, 1H), 1.79-1.76 (m, 2H), 1.69-1.62 (m, 2H), 1.54-1.48
(m, 1H), 1.29-1.11 (m, 5H) ppm.
Step 4:
Methyl(2S)-({[(3R)(3S)-3-(allyloxy)piperidin-1-yl]carbonyl}amino)(-
cyclohexyl)acetate
##STR00078##
[0299] A 500-mL round-bottom flask was charged with the product of
Step 3 (3.80 g, 19.27 mmol) and THF (50 mL). The product of Step 2
(3.80 g, 19.27 mmol) was added, and the resulting solution stirred
for 24 hours at RT. The solvent was removed by evaporation, and the
crude product was purified by flash column chromatography (60/40
hexanes/EtOAc), to yield the title compound as a colorless oil.
LRMS (M+H)=339.3.
Step 5:
(2)-({[(3R)(3S)-3-(Allyloxy)piperidin-1-yl]carbonyl}amino)(cyclohe-
xyl)acetic acid (Intermediate B29)
[0300] A 500-mL round-bottom flask was charged with the product of
Step 4 (7.00 g, 20.68 mmol), MeOH (20 mL), and THF (20 mL). LiOH
(1M, 62.0 mL, 62.0 mmol) was added, and the resulting solution was
stirred at RT for 18 hours. The organic solvents were removed under
reduced pressure, and the remaining aqueous was poured into 5%
K.sub.2SO.sub.4. The mixture was extracted (3.times.) with EtOAc,
the combined organic portions dried with anhydrous MgSO.sub.4,
filtered and rotary-evaporated to give the title compound as a
white foam/oil. LRMS (M+H)=325.3.
Step 6: (2S)-({[(3S) or
(3R)-3-(Allyloxy)piperidin-1-yl]carbonyl}amino)(cyclohexyl)acetic
acid (Intermediate B29a) (2S)-({[(3R) and
(3S)-3-(allyloxy)piperidin-1-yl]carbonyl}amino)(cyclohexyl)acetic
acid (Intermediate B29b)
##STR00079##
[0302] The mixture of diastereomers,
(2S)-({[(3R)(3S)-3-(Allyloxy)piperidin-1-yl]carbonyl}amino)(cyclohexyl)ac-
etic acid (4.00 g, 12.33 mmol), was resolved by preparative chiral
SFC using a CHIRALPAK AD (2.times.25 cm, 100 with a mobile phase of
80/20 CO.sub.2/MeOH, having a flow rate of 70 mL/minute, and a
detector of .lamda.=214 nm. Evaporation of like fractions gave the
title compounds as colorless oils. The first eluting diasteriomer
was (2S)-({[(3S) or
(3R)-3-(Allyloxy)piperidin-1-yl]carbonyl}amino)(cyclohexyl)acetic
acid (LRMS (M+H)=325.3), and the second eluting diastereomer was
(2S)-({[(3R) or
(3S)-3-(allyloxy)piperidin-1-yl]carbonyl}amino)(cyclohexyl)acetic
acid (LRMS (M+1)=325.3).
Intermediates B30-B34
[0303] Intermediates B30-B34 were prepared in a manner similar to
that utilized to prepare Intermediate B29.
TABLE-US-00004 LRMS Int. Amino Acid Alcohol Structure Name (M +
H).sup.+ B30 L-cyclopentyl- glycine N-Boc-(3S)- pyrrolidin-3-ol
##STR00080## (2S)-cyclopentyl({[(3S)-3-
(pent-4-en-1-yloxy)pyrrolidin- 1-yl]carbonyl}amino)acetic acid
325.4 B31 L-cyclopentyl- glycine N-Boc-(3R)- pyrrolidin-3-ol
##STR00081## (2S)-cyclopentyl({[(3R)-3-
(pent-4-en-1-yloxy)pyrrolidin- 1-yl]carbonyl}amino)acetic acid
325.4 B32 L-cyclohexyl- glycine N-Boc-piperidin-4-ol ##STR00082##
(2S)-cyclohexyl({[4-(pent-4- en-1-yloxy)piperidin-1-
yl]carbonyl}amino)acetic acid 353.3 B33 L-cyclohexyl- glycine
N-Boc-azetidin-3-ol ##STR00083## (2S)-cyclohexyl({[3-(pent-4-
en-1-yloxy)azetidin-1- yl]carbonyl}amino)acetic acid 325.3 B34
L-cyclohexyl- glycine N-Boc-(3S)- pyrrolidin-3-ol ##STR00084##
(2S)-cyclohexyl({[(3S)-3- (pent-4-en-1-yloxy)pyrrolidin-
1-yl]carbonyl}amino)acetic acid 339.4
Intermediates C
Intermediate C1: 4-Bromo-1-methyl-1H-indole-2-carboxylic acid
##STR00085##
[0305] To a solution of 4-bromo-1H-indole-2-carboxylic acid (514
mg, 2.14 mmol) in DMF (16 mL), dimethyl carbonate (4.5 mL, 53.4
mmol) and DABCO (25 mg, 0.214 mmol) was added, and the solution was
heated to 120.degree. C. for 7 hours. The reaction was diluted with
EtOAc, and the organics were washed with H.sub.2O (2.times.), 1N
HCl (1.times.), and brine (1.times.). The organics were dried over
Na.sub.2SO.sub.4, filtered, concentrated, and the resulting residue
was purified on SiO.sub.2 (gradient elution, 15-40% EtOAc/hexanes)
to yield the intermediate ester as a white solid. MeOH (3 mL),
H.sub.2O (1.5 mL) and LiOH monohydrate (3 eq.) were added to a
solution of the ester in THF (3 mL), and left to stir for 16 hours.
The reaction mixture was concentrated, and the residue was
partitioned between EtOAc and 1N HCl, and extracted with EtOAc
(2.times.). The organics were combined, washed with brine
(1.times.), dried over Na.sub.2SO.sub.4, filtered, and concentrated
to yield the title compound as a white solid. LRMS (M+H)+
Calcd.=254; found 254.
Intermediate C2: 4-Bromo-1H-indole-2-carboxylic acid
##STR00086##
[0307] The title compound is commercially available.
Intermediate C3: 8-Bromoimidazo[1,2-a]pyridine-2-carboxylic
acid
##STR00087##
[0309] To a solution of 2-amino-3-bromopyridine (7.4 g, 0.0428 mol)
in dimethoxyethane (70 mL) under N.sub.2, ethylbromopyruvate (9.28
g, 0.0428 mol) was added, and the mixture stirred at RT for 18
hours. The resulting solids were filtered and washed with
Et.sub.2O, then re-suspended in absolute EtOH (40 mL) and refluxed
for 2 hours. The reaction was concentrated to remove EtOH, diluted
with K.sub.2CO.sub.3(aq.) and extracted with DCM (2.times.100 mL).
The DCM extracts were dried over Na.sub.2SO.sub.4, filtered and
concentrated to give a foam (9.2 g). The foam was dissolved in THF
(230 mL) and treated with 1N NaOH (170 mL, 0.170 mol) at 40.degree.
C. for 2 hours. The reaction was cooled to RT, diluted with 1N HCl
(170 mL, 0.170 mol) and concentrated to remove the THF (pH of
mixture=3.0). The mixture was cooled to 0.degree. C., aged for 30
minutes and filtered. The cake was washed with H.sub.2O (40 mL) and
dried under vacuum to give 7.94 g. LRMS (M+H)+ 241.
Intermediate C4: 5-Bromoimidazo[1,2-a]pyridine-2-carboxylic
acid
##STR00088##
[0311] The title compound was prepared in a manner similar to that
utilized to prepare 8-bromoimidazo[1,2-a]pyridine-2-carboxylic acid
from ethyl 5-bromoimidazo[1,2-a]pyridine-2-carboxylate (ref: WO
91/08211). LRMS (M+H)+ 241.
Intermediate C5: 4-Bromoindane-2(R,S)-carboxylic acid
##STR00089##
[0313] Diethylmalonate (3.8 mL, 25 mmol) in THF (25 mL) was slowly
added to a solution of NaH (60% in mineral oil, 2.1 g, 87 mmol) in
THF (20 mL) at 0.degree. C. while under N.sub.2. The solution was
stirred for 30 minutes at 0.degree. C. and then for 30 minutes at
25.degree. C. The solution was cooled to 0.degree. C. and slowly
added to a solution of 1-bromo-2,3-bis(bromomethyl)benzene (8.5 g,
25 mmol) in THF (25 mL), and then warmed and stirred at 25.degree.
C. for 2 hours. The reaction mixture was quenched by pouring into
300 mL of 1N HCl and 200 mL of EtOAc/Et.sub.2O while stirring. The
mixture was extracted with EtOAc (2.times.), and the organics were
combined washed with brine, dried over Na.sub.2SO.sub.4, filtered,
and concentrated. The residue was purified on SiO.sub.2 (gradient
elution, 0-25% EtOAc/hexanes) to yield the di-ester as a clear oil.
To a solution of the di-ester (3.4 g, 9.97 mmol) in MeOH (25 mL),
3N NaOH (16.6 mL, 49.8 mmol) was added, and the mixture was warmed
to 50.degree. C. for 4 hours. The mixture was then cooled to
25.degree. C. and filtered to yield a white solid (1.54 g). This
solid was dissolved in 6M HCl, and the reaction mixture was heated
to reflux for 12 hours. The reaction mixture was extracted with
EtOAc (2.times.), combined organics, washed with brine, dried over
MgSO.sub.4, filtered and concentrated. The title compound was as a
tan solid after crystallizing from hot hexanes (548 mg, 9% yield).
.sup.1H NMR (500 Mhz) (CDCl.sub.3) .delta. 7.32 (d, 1H, J=7.8 Hz),
7.14 (d, 1H, J=7.6 Hz), 7.04 (t, 1H, J=7.6 Hz), 3.43-3.3 (m,
4H).
Intermediate C6: 4-Bromo-1-phenyl-1H-indole-2-carboxylic acid
##STR00090##
[0315] To a solution of 4-bromo-1H-indole-2-carboxylic acid (500
mg, 2.08 mmol) in DCM (75 mL), phenylboronic acid (508 mg, 4.17
mmol), copper (II) acetate (757 mg, 4.17 mmol), pyridine (0.337 mL,
4.17 mmol), 4A molecular sieves (3 g), and TEA (0.581 mL, 4.17
mmol) were added. After 15 hours, the mixture was diluted with DCM,
filtered through CELITE, and the filtrate was washed with 1N HCl
(2.times.) and brine (1.times.). The organic layers were dried over
Na.sub.2SO.sub.4, and the solvent was removed in vacuo. The crude
material was purified on SO.sub.2 (98/2/0.2/0.2 of
DCM/MeOH/HOAc/H.sub.2O) to yield the title compound. LRMS ESI.sup.+
(M+H).sup.+ 272.2.
Intermediate C7: 3-Bromo-5-(trifluoromethoxy)benzyl
methanesulfonate
##STR00091##
[0316] Step 1: [3-Bromo-5-(trifluoromethoxy)phenyl]methanol
##STR00092##
[0318] To a solution of LAH (100 mL, 1M in Et.sub.2O, 100 mmol)
that had been cooled to -70.degree. C., a solution of
3-bromo-5-(trifluoromethoxy)benzoic acid (12.0 g, 42.1 mmol) was
added slowly. The mixture was then slowly warmed to RT and stirred
overnight. After recooling to -70.degree. C., the reaction was
quenched with H.sub.2O (4 mL), 2N NaOH (4 mL), more H.sub.2O (8
mL), and then warmed to RT. The mixture was then filtered through
CELITE, MgSO.sub.4 was added, and the mixture was filtered again.
The solvent was removed in vacuo to yield the title compound as a
colorless oil. LRMS ESI.sup.+ (M+H).sup.+ 272.2.
Step 2: 3-Bromo-5-(trifluoromethoxy)benzyl methanesulfonate
[0319] To a solution of the product from Step 1 (11.4 g, 42.1 mmol)
in DCM (100 mL), DIEA (16.0 mL, 92.6 mmol) and MsCl (3.6 mL, 46.3
mmol) were added slowly at 0.degree. C. After 1 hour, the reaction
was poured into KHSO.sub.4(aq.) and extracted with DCM (3.times.).
The combined organic layers were extracted with brine, dried over
MgSO.sub.4, and the solvent was removed in vacuo. The crude
material was purified on SiO.sub.2 (gradient elution, 0-100%
EtOAc/hexanes) to yield the title compound as a colorless oil.
.sup.1H NMR (500 MHz) (CDCl.sub.3) .delta. 7.51 (s, 1H), 7.42 (s,
1H), 7.22 (s, 1H), 5.20 (s, 2H), 3.04 (s, 3H).
Intermediate C8: 3-Chloro-4-phenylpyridin-2-ol
##STR00093##
[0320] Step 1: 3-Chloro-4-iodopyridine
##STR00094##
[0322] The title compound was prepared according to the following
reference:
35 Heterocycles 151-69 (1993). To a solution of DIPA (3.77 mL, 26.4
mmol) in THF (20 mL) under N.sub.2 in a dry ice bath, n-BuLi (10.6
mL, 26.4 mmol) was added. The mixture was stirred in an ice bath
for 20 minutes, then treated dropwise over 10 minutes with a
solution of 3-chloropyridine (2.51 mL, 26.4 mmol) in 5 mL THF,
keeping the temperature less than -70.degree. C. The lithiopyridine
partially precipitated as a colorless solid in a light orange
solution. The mixture was stirred for 30 minutes in a dry ice bath,
and then I.sub.2 (6.71 g, 26.4 mmol) in 15 mL THF was added,
keeping the temperature less then -65.degree. C. The solution was
then allowed to warm to 0.degree. C. and was placed in an ice bath
for 2 hours, and then poured into 10% NaHSO.sub.3 and extracted
with ether (150 mL; 3.times.). The organics were washed with 50 mL
each of NaHSO.sub.3, NaHCO.sub.3, H.sub.2O, and brine. The residue
was purified on SiO.sub.2 (gradient elution, 2-20% EtOAc/hexanes)
to give the title compound (3.35 g, 85% pure). This was then
recrystallized from hot hexanes plus a few mL of EtOAc to dissolve
initially to give the title compound as a white powder (1.95 g).
LRMS ESI.sup.+ (M+H).sup.+ 240.0.
Step 2: 3-Chloro-4-phenylpyridine
##STR00095##
[0324] To a solution of the product from Step 1 (1.3 g, 5.43 mmol),
phenylboronic acid (827 mg, 6.79 mmol), PCy.sub.3 (228 mg, 0.814
mmol), and Cs.sub.2CO.sub.3 (4.25 g, 13.03 mmol) in dioxane (10
mL), Pd.sub.2(dba).sub.3 (497 mg, 0.543 mmol) was added under
N.sub.2. The mixture was then heated to 95.degree. C. for 18 hours,
filtered and extracted with H.sub.2O and EtOAc. The organic layer
was dried over MgSO.sub.4, and the solvent was removed in vacuo.
The residue was purified on SiO.sub.2 (gradient elution, 5-30%
EtOAc/hexanes) to give the title compound as a colorless oil (1.03
g). LRMS ESI.sup.+ (M+H).sup.+ 190.2.
Step 3: 3-Chloro-4-phenylpyridin-2-ol
[0325] To a solution of the product from Step 2 (348 mg, 1.83 mmol)
in DCM (10 mL), mCPBA (950 mg, 5.51 mmol) was added. After 2 hours,
the mixture was extracted with 10% NaHSO.sub.3(aq.) and then
NaHCO.sub.3 and brine. The organic layer was dried over MgSO.sub.4,
and the solvent was removed in vacuo to give crude
3-chloro-4-phenylpyridine 1-oxide as a white solid (230 mg). This
solid was then dissolved in acetic anhydride (1.05 mL, 11.18 mmol)
and heated to 150.degree. C. for 18 hours. The residue was purified
on SiO.sub.2 (gradient elution, 5-30% EtOAc/hexanes) to give 150 mg
of 3-chloro-4-phenylpyridin-2-yl acetate, which was dissolved in
MeOH (20 mL), combined with K.sub.2CO.sub.3 (419 mg, 3.03 mmol) and
heated to 65.degree. C. for 10 minutes. The mixture was then
filtered, and the solvent was removed in vacuo to yield the title
compound (125 mg). LRMS ESI.sup.+ (M+H).sup.+ 206.1.
Intermediate C9: 5-Bromo-2-chlorobenzyl methanesulfonate
##STR00096##
[0327] To a solution of (5-bromo-2-chlorophenyl)methanol (1.0 g,
4.52 mmol) in DCM (23 mL), TEA (0.88 mL, 6.32 mmol) and MsCl (0.49
mL, 6.32 mmol) in DCM (10 mL) were added at 0.degree. C. After 4
hours, the mixture was then extracted with H.sub.2O, the organic
layer was dried over MgSO.sub.4, and the solvent was removed in
vacuo. The crude material was purified on SiO.sub.2 (gradient
elution, 0-30% EtOAc/hexanes) to yield the title compound as a
white solid (1.03 g). .sup.1H NMR (500 MHz) (CDCl.sub.3) .delta.
7.62 (m, 1H), 7.43 (m, 1H), 7.28 (s, 1H), 5.27 (s, 2H), 3.08 (s,
3H) ppm.
Intermediate C10: 3-Bromo-5-methoxybenzyl methanesulfonate
##STR00097##
[0329] The title compound was prepared according to the procedure
given for Intermediate C9 using (3-bromo-5-methoxyphenyl)methanol
(ref: 43 J. Med. Chem. 599 (2000)). .sup.1H NMR (500 MHz)
(CDCl.sub.3) .delta. 7.13 (s, 1H), 7.05 (s, 1H), 6.87 (s, 1H), 5.14
(s, 2H), 3.80 (s, 3H), 2.98 (s, 3H) ppm.
Intermediate C11: Methyl
(4R)-4-[(7-methoxy-3-vinylquinolin-2-yl)oxy]-L-prolinate
hydrochloride
##STR00098##
[0330] Step 1: 3-Bromo-7-methoxyquinoline 1-oxide
##STR00099##
[0332] To a solution of 3-bromo-7-methoxyquinoline (2.0 g, 8.40
mmol) in DCM (42 mL) at RT, mCPBA (2.9 g, 16.8 mmol) was added, and
the reaction mixture was stirred at RT for 1 hour. A second portion
of mCPBA (2.9 g, 16.8 mmol) was then added, and the reaction
mixture was stirred at RT for 18 hours. The reaction mixture was
poured onto 10% Na.sub.2SO.sub.3(aq.) and DCM, and the layers were
separated. The organic layer was washed with NaHCO.sub.3, dried
over MgSO.sub.4, filtered and concentrated. The resulting product
was used with no further purification. LRMS (M+H).sup.+=254.2.
Step 2: 3-Bromo-7-methoxyquinolin-2(1H)-one
##STR00100##
[0334] To a solution of 3-bromo-7-methoxyquinoline 1-oxide (2.04 g,
8.03 mmol) in EtOAc (50 mL) and 15% K.sub.2CO.sub.3(aq.) (15 mL) at
RT, TsCl (1.68 g, 8.83 mmol) was added. The reaction mixture was
stirred vigorously at RT for 18 hours, at which time the product
was collected by filtration and washed with EtOAc. The solid was
dried in vacuo and used with no further purification. LRMS
(M+H).sup.+=254.1.
Step 3: 1-t-Butyl
2-methyl(2S,4R)-4-[(3-bromo-7-methoxyquinolin-2-yl)oxy]pyrrolidine-1,2-di-
carboxylate
##STR00101##
[0336] To a solution of 3-bromo-7-methoxyquinolin-2(1H)-one (1.31
g, 5.17 mmol) and 1-t-butyl
2-methyl(2S,4S)-4-{[(4-bromophenyl)sulfonyl]oxy}pyrrolidine-1,2-dicarboxy-
late (2.0 g, 4.31 mmol) in NMP (21.5 mL), Cs.sub.2CO.sub.3 (2.11 g,
6.46 mmol) was added, and the reaction mixture was stirred for 40
hours at 40.degree. C. An additional portion of 1-t-butyl
2-methyl(2S,4S)-4-{[(4-bromophenyl)sulfonyl]oxy}pyrrolidine-1,2-dicarboxy-
late (1.0 g, 2.16 mmol) was added, and the reaction mixture was
stirred at 40.degree. C. for 16 hours. The reaction mixture was
cooled and poured onto a mixture of EtOAc and H.sub.2O, and the
layers were separated. The organic layer was washed with H.sub.2O
(2.times.), NaHCO.sub.3 (2.times.) and brine, dried over
Mg.sub.2SO.sub.4, filtered and concentrated. The product was used
with no further purification. LRMS (M+H-Boc).sup.+=381.2.
Step 4: 1-t-Butyl
2-methyl(2S,4R)-4-[(7-methoxy-3-vinylquinolin-2-yl)oxy]pyrrolidine-1,2-di-
carboxylate
##STR00102##
[0338] To a solution of 1-t-butyl
2-methyl(2S,4R)-4-[(3-bromo-7-methoxyquinolin-2-yl)oxy]pyrrolidine-1,2-di-
carboxylate (2.0 g, 4.2 mmol) in EtOH (30 mL), TEA (0.87 mL, 6.23
mmol) was added. Potassium vinyltrifluoroborate (0.84 g, 6.23 mmol)
and dichloro[1,1'-bis(diphenylphosphino)ferrocene]palladium(II)
dichloromethane adduct (0.17 g, 0.21 mmol) were then added, and the
reaction mixture was stirred at 100.degree. C. for 2 hours. The
reaction mixture was worked up with EtOAc and H.sub.2O, and the
layers were separated. The organic layer was washed with brine,
dried over MgSO.sub.4, filtered and concentrated. The crude
material was purified on SiO.sub.2 (gradient elution, 0-40%
EtOAc/hexanes) to yield the title compound as an oil. LRMS
(M+H-tBu).sup.+=373.3.
Step 5: Methyl
(4R)-4-[(7-methoxy-3-vinylquinolin-2-yl)oxy]-L-prolinate
hydrochloride (Intermediate C11)
[0339] A solution of 1-t-butyl
2-methyl(2S,4R)-4-[(7-methoxy-3-vinylquinolin-2-yl)oxy]pyrrolidine-1,2-di-
carboxylate (0.85 g, 1.98 mmol) in 4M HCl in dioxane (10 mL) was
stirred at RT for 2 hours. The reaction mixture was concentrated,
and the product was used with no further purification. LRMS
(M+H-tBu).sup.+=329.3.
Intermediate C12: Methyl
(4R)-4-[(3-vinylquinolin-2-yl)oxy]-L-prolinate hydrochloride
##STR00103##
[0341] Intermediate C12 can be prepared according to the procedure
described for Intermediate C11 using 3-bromoquinoline instead of
3-bromo-7-methoxyquinoline in Step 1.
Intermediate C13: Methyl
(4R)-4-[(2-chloroquinolin-3-yl)oxy]-L-prolinate hydrochloride
##STR00104##
[0342] Step 1: 2-chloroquinolin-3-ol
##STR00105##
[0344] A suspension of 2-chloroquinoline-3-boronic acid (15 g, 72.3
mmol) and NH.sub.4Cl (7.16 g, 134 mmol) in Et.sub.2O:H.sub.2O (600
mL) was treated dropwise with H.sub.2O.sub.2(aq.) (30%, 62 mL, 709
mmol). The mixture was stirred for 16 hours, then the precipitate
was filtered, washed with H.sub.2O and Et.sub.2O, then dried at
60.degree. C. over P.sub.2O.sub.5 to afford the title compound
(11.5 g, 89%). LCMS (ES+) m/z 180 (M+H).sup.+.
Step 2: 1-t-Butyl
2-methyl(2S,4R)-4-[(2-chloroquinolin-3-yl)oxy]pyrrolidine-1,2-dicarboxyla-
te
##STR00106##
[0346] A solution of the 2-chloroquinolin-3-ol (4.00 g, 22.27
mmol), 1-t-butyl 2-methyl
(2S,4S)-4-hydroxypyrrolidine-1,2-dicarboxylate (5.74 g, 23.38 mmol)
and PPh.sub.3 (7.01 g, 26.7 mmol) in anhydrous THF (250 mL) was
cooled to 0.degree. C. and treated dropwise with DEAD (4.65 g, 26.7
mmol). The mixture was stirred for 3 hours at 20.degree. C., then
treated at 0.degree. C. with further PPh.sub.3 (1.75 g, 6.67 mmol)
and DEAD (1.16 g, 6.67 mmol). After stirring for 3 hours at
20.degree. C., the mixture was concentrated, and the residue was
purified on SiO.sub.2 (15% EtOAc/petroleum ether) to furnish the
title compound (5.08 g, 56%) as a white solid. LCMS (ES+) m/z 307
(M+H-Boc).sup.+.
Step 3: Methyl (4R)-4-[(2-chloroquinolin-3-yl)oxy]-L-prolinate
hydrochloride
[0347] A solution of 1-t-butyl
2-methyl(2S,4R)-4-[(2-chloroquinolin-3-yl)oxy]pyrrolidine-1,2-dicarboxyla-
te (8.9 g, 21.9 mmol) in HCl/dioxane (4 N, 80 mL) was prepared at
0.degree. C. The mixture was stirred for 1 hour at 0.degree. C.,
then at 20.degree. C. for 2 hours. Further HCl/dioxane (4N, 10 mL)
was added, and the mixture was stirred for 1 hour. Removal of the
volatiles and trituration of the residue with Et.sub.2O afforded
the title compound (7.19 g, 96%) as a solid that was used directly
in subsequent steps. LCMS (ES+) m/z 307 (M+H).sup.+.
Intermediate C14:
(2S,4R)-4-[(2-bromo-6-methoxyquinolin-3-yl)oxy]-2-(methoxycarbonyl)pyrrol-
idinium chloride
##STR00107##
[0348] Step 1: 2-Bromo-6-methoxyquinoline
##STR00108##
[0350] 6-Methoxyquinolin-2(1H)-one (6.81 g, 38.9 mmol) was
carefully added to POBr.sub.3 (18.9 g, 66.1 mmol) at 60.degree. C.
and the resulting solution was stirred at 140.degree. C. for 2.5
hours. The reaction mixture was cooled and poured onto crushed ice,
and the solid was collected by filtration. Purification of this
material on SiO.sub.2 (gradient elution, 5-12% EtOAc/petroleum
ether) afforded the title compound (4.57 g, 49.3%) as a solid. LCMS
(ES+) m/z 238, 240 (M+H).sup.+.
Step 2: (2-Bromo-6-methoxyquinolin-3-yl)boronic acid
##STR00109##
[0352] n-BuLi (1.6 N in hexanes, 14.4 mL, 23.0 mmol) was added at
-78.degree. C. to a solution of 2,2,6,6-tetramethylpiperidine (3.11
g, 22.05 mmol) in anhydrous THF (59 mL), and the mixture was then
warmed to 0.degree. C. for 30 minutes. The mixture was cooled back
to -78.degree. C. and treated with a solution of
2-bromo-6-methoxyquinoline (4.57 g, 19.17 mmol) in THF (14 mL).
After stirring for 1 hour, a solution of B(OMe).sub.3 (2.46 mL,
22.05 mmol) in THF (14 mL) was added, and the mixture was
maintained at -78.degree. C. for a further 2 hours. A mixture of
THF (14 mL) and H.sub.2O (3.5 mL) was added, then the solution was
warmed to -10.degree. C. and treated with H.sub.2O (70 mL) and
Et.sub.2O (70 mL). NaOH.sub.(aq.) (1N, 75 mL) was added, and the
aqueous layer was separated and acidified to pH 4 with
HCl.sub.(aq.) (3N). The aqueous phase was extracted with Et.sub.2O,
and the combined extracts were washed with brine and dried over
Na.sub.2SO.sub.4. Filtration and removal of the volatiles afforded
the title compound (4.64 g, 86% yield) as an oily solid that was
used directly in the subsequent step. LCMS (ES+) m/z 282, 284
(M+H).sup.+.
Step 3: 2-Bromo-6-methoxyquinolin-3-ol
##STR00110##
[0354] H.sub.2O.sub.2(aq.) (30%, 32.8 mL, 321 mmol) was added
dropwise to a stirred solution of
(2-bromo-6-methoxyquinolin-3-yl)boronic acid (4.64 g, 16.45 mmol)
and NH.sub.4Cl (3.29 g, 61.5 mmol) in Et.sub.2O (82 mL) and
H.sub.2O (82 mL). After 13 hours, NH.sub.4Cl (3.29 g, 61.5 mmol)
and H.sub.2O.sub.2(aq.) (30%, 32.8 mL, 321 mmol) were added, and
the mixture was stirred for 48 hours. The precipitate was collected
and washed with H.sub.2O, then dried at 50.degree. C. to afford the
title compound (4.18 g, 100%) as a solid that was used directly in
the subsequent step. LCMS (ES+) m/z 254, 256 (M+H).sup.+.
Step 4: 1-t-Butyl
2-methyl(2S,4R)-4-[(2-bromo-6-methoxyquinolin-3-yl)oxy]pyrrolidine-1,2-di-
carboxylate
##STR00111##
[0356] Cs.sub.2CO.sub.3 (10.7 g, 32.9 mmol) was added to a stirred
mixture of 1-t-butyl 2-methyl
(2S,4S)-4-{[(4-bromophenyl)sulfonyl]oxy}pyrrolidine-1,2-dicarboxylate
(8.78 g, 18.9 mmol) and 2-bromo-6-methoxyquinolin-3-ol (4.18 g,
16.45 mmol) in NMP (46 mL). The resulting mixture was stirred at
50.degree. C. for 3 hours, then cooled and diluted with EtOAc. The
organics were washed with saturated NaHCO.sub.3(aq.), H.sub.2O and
brine, then dried over Na.sub.2SO.sub.4. Filtration and removal of
the volatiles gave a residue that was purified by column
chromatography on SiO.sub.2 (gradient elution, 1-100%
EtOAc/petroleum ether) to give the title compound (5.56 g, 70.2%).
LCMS (ES+) m/z 481, 483 (M+H).sup.+.
Step 5:
(2S,4R)-4-[(2-bromo-6-methoxyquinolin-3-yl)oxy]-2-(methoxycarbonyl-
)pyrrolidinium chloride
[0357] A solution of 1-t-butyl
2-methyl(2S,4R)-4-[(2-bromo-6-methoxyquinolin-3-yl)oxy]pyrrolidine-1,2-di-
carboxylate (5.01 g, 10.40 mmol) in HCl/dioxane (4 N, 31 ml) was
prepared at 0.degree. C., and the mixture was stirred at 20.degree.
C. for 40 minutes. The volatiles were evaporated, and the residue
was triturated with Et.sub.2O to afford an approximately 1:1
mixture of the title compound and
(2S,4R)-4-[(2-chloro-6-methoxyquinolin-3-yl)oxy]-2-(methoxycarbonyl)pyrro-
lidinium chloride (4.34 g) as a solid that was used directly in
subsequent steps. LCMS (ES+) m/z 381, 383 (M+H).sup.+.
Intermediate C15:
(2S,4R)-4-[(3-chloroquinoxalin-2-yl)oxy]-2-(methoxycarbonyl)pyrrolidinium
chloride
##STR00112##
[0358] Step 1: 1-t-Butyl
2-methyl(2S,4R)-4-[(3-chloroquinoxalin-2-yl)oxy]pyrrolidine-1,2-dicarboxy-
late
##STR00113##
[0360] A solution of 3-chloroquinoxalin-2-ol (1.44 g, 7.97 mmol)
and 1-t-butyl 2-methyl
(2S,4S)-4-hydroxypyrrolidine-1,2-dicarboxylate (2.05 g, 8.37 mmol)
in THF (190 ml) was cooled to 0.degree. C., then treated with
PPh.sub.3 (2.51 g, 9.57 mmol). DIAD (1.86 ml, 9.57 mmol) was added
dropwise, and the mixture was stirred at 20.degree. C. for 1 hour.
After evaporation of the volatiles, the residue was purified on
SiO.sub.2 (gradient elution, 0-70% EtOAc/petroleum ether) to afford
the title compound (2.5 g, 77%). LCMS (ES+) m/z 408
(M+H).sup.+.
Step 2:
(2S,4R)-4-[(3-chloroquinoxalin-2-yl)oxy]-2-(methoxycarbonyl)pyrrol-
idinium chloride
[0361] A solution of 1-t-butyl
2-methyl(2S,4R)-4-[(3-chloroquinoxalin-2-yl)oxy]pyrrolidine-1,2-dicarboxy-
late (1.05 g, 2.57 mmol) in HCl/dioxane (4 N, 5 mL) was prepared at
0.degree. C., then stirred for 2 hours at 20.degree. C. The
reaction mixture was concentrated to afford a residue that was
triturated with Et.sub.2O to afford the title compound (0.88 g,
98%) as a white solid that was used directly in subsequent
reactions. LCMS (ES+) m/z 308 (M+H).sup.+.
Intermediate C16: Methyl
(4R)-4-[(2-bromo-6-chloroquinolin-3-yl)oxy]-L-prolinate
hydrochloride
##STR00114##
[0362] Step 1: 2-Bromo-6-chloroquinolin-3-yl)boronic acid
##STR00115##
[0364] A solution of 2,2,6,6-tetramethylpiperidine (1.34 g, 9.52
mmol) in THF (25 mL) was cooled to -78.degree. C. and treated with
BuLi (6.21 mL, 1.6N in hexanes, 9.93 mmol). The mixture was warmed
to 0.degree. C. for 30 minutes, then cooled back to -78.degree. C.
A solution of 2-bromo-6-chloroquinoline (2.01 g, 8.28 mmol) in THF
(6 mL) was added dropwise, and the mixture was stirred for 1 hour.
A solution of B(OMe).sub.3 (0.99 g, 9.52 mmol) in THF (6 ml) was
added dropwise, and the resulting mixture was maintained at
-78.degree. C. for 2 hours. The reaction was quenched by addition
of a 4:1 mixture of THF:H.sub.2O (7.5 mL), then the mixture was
warmed to -10.degree. C. and diluted with H.sub.2O and Et.sub.2O,
NaOH.sub.(aq.) (1N, 75 mL) was added, and then the aqueous layer
was separated and acidified to pH 4 by addition of HCl.sub.(aq.)
(3N). The mixture was extracted with Et.sub.2O, and the organic
phase was washed with brine and dried over Na.sub.2SO.sub.4.
Removal of volatiles afforded the title compound as an oil that was
used directly in the subsequent step (2.04 g, 86%). LCMS (ES+) ink
258.1, 260.1 (M+H).sup.+.
Step 2: 2-Bromo-6-chloroquinolin-3-ol
##STR00116##
[0366] A mixture of 2-bromo-6-chloroquinolin-3-yl)boronic acid
(2.04 g, 7.11 mmol) and NH.sub.4Cl (0.71 g, 13.30 mmol) in a 1:1
mixture of H.sub.2O:Et.sub.2O (55 mL) was treated dropwise with
H.sub.2O.sub.2(aq.) (30%, 7.10 mL). The mixture was stirred at
20.degree. C., and further portions of H.sub.2O.sub.2(aq.) (30%,
7.10 mL) were added after 3 hours and after 24 hours. The reaction
was judged complete after 48 hours, and the mixture was extracted
with EtOAc. The organic layer was washed with brine and dried over
Na.sub.2SO.sub.4. Filtration and removal of the volatiles afforded
the title compound (1.52 g, 83%) as a solid. .sup.1H NMR (300 MHz,
DMSO-d.sub.6) .delta. 11.41 (s, 1H), 8.04 (s, 1H), 7.88 (d, J=8.9
Hz, 1H), 7.62 (s, 1H), 7.56 (d, J=8.9 Hz, 1H).
Step 3: Methyl
(4R)-4-[(2-bromo-6-chloroquinolin-3-yl)oxy]-L-prolinate
[0367] Cs.sub.2CO.sub.3 (2.27 g, 6.96 mmol) was added to a stirred
solution of 1-t-butyl 2-methyl
(2S,4S)-4-{[(4-bromophenyl)sulfonyl]oxy}pyrrolidine-1,2-dicarboxylate
(1.62 g, 3.48 mmol) and 2-bromo-6-methoxyquinolin-3-ol (0.90 g,
3.48 mmol) in NMP (46 mL). The resulting mixture was stirred at
50.degree. C. for 3 hours, then cooled and diluted with EtOAc and
saturated NaHCO.sub.3(aq.). The organic phase was separated, washed
with H.sub.2O and brine, then dried over Na.sub.2SO.sub.4.
Filtration and removal of the volatiles gave a residue that was
taken up in DCM (22 mL) then treated with TFA (4.5 mL). The
resulting solution was stirred for 1 hour, then diluted with
saturated NaHCO.sub.3(aq.). The organic layer was separated, washed
with brine and dried over Na.sub.2SO.sub.4. Filtration and removal
of the volatiles afforded the title compound (0.67 g, 81%) as a
solid that was used directly in subsequent reactions. LCMS (ES+)
m/z 385.0, 387.0 (M+H).sup.+.
Intermediate C17: Methyl
(4R)-4-[(3-but-3-en-1-yl-7-methoxyquinoxalin-2-yl)oxy]-L-prolinate
hydrochloride
##STR00117##
[0368] Step 1: 1-t-Butyl
2-methyl(2S,4R)-4-[(3-but-3-en-1-yl-7-methoxyquinoxalin-2-yl)oxy]pyrrolid-
ine-1,2-dicarboxylate
##STR00118##
[0370] Ethyl 2-oxohex-5-enoate (1.130 g, 7.24 mmol) and
4-methoxybenzene-1,2-diamine (1 g, 7.24 mmol) were dissolved in
EtOH (24.1 mL), and the resulting mixture was heated to 50.degree.
C. for 1 hour. The mixture was cooled and concentrated under
reduced pressure to give a solid that was taken up in NMP (18 ml).
This solution was treated with 1-t-butyl 2-methyl
(2S,4S)-4-{[(4-bromophenyl)sulfonyl]oxy}pyrrolidine-1,2-dicarboxylate
(3.23 g, 6.95 mmol) and Cs.sub.2CO.sub.3 (3.40 g, 10.42 mmol). The
resulting mixture was stirred at 60.degree. C. for 12 hours and
then cooled and diluted with EtOAc and HCl.sub.(aq.) (1 N). The
organic phase was separated and washed with HCl.sub.(aq.) (1N),
saturated NaHCO.sub.3(aq.) and brine. The dried organics
(Na.sub.2SO.sub.4) were concentrated to give a residue containing a
mixture of isomers that was purified on SO.sub.2 (15%
EtOAc/petroleum ether) to give the title compound (0.57 g, 17%) as
a solid. LCMS (ES+) m/z 458.3 (M+H).sup.+.
Step 2: Methyl
(4R)-4-[(3-but-3-en-1-yl-7-methoxyquinoxalin-2-yl)oxy]-L-prolinate
hydrochloride
[0371] The product of Step 1 was treated as described for
Intermediate C15, Step 2, to afford the title compound (98%) as a
solid. LCMS (ES+) m/z 358.3 (M+H).sup.+.
Intermediate C18: Methyl
(4R)-4-[(2-bromo-6-methoxy-1,5-naphthyridin-3-yl)oxy]-L-prolinate
##STR00119##
[0373] 2-Bromo-6-methoxy-1,5-naphthyridine was treated according to
the procedures described for Intermediate C15, Steps 1-3, to afford
the title compound (11%) as a solid. LCMS (ES+) m/z 480.2
(M+H).sup.+.
Intermediate C19:
(2S,4R)-4-[(3-Bromo-2-naphthyl)oxy]-2-(methoxycarbonyl)pyrrolidinium
chloride
##STR00120##
[0375] Intermediate C19 can be prepared according to the procedure
described for Intermediate C14, Steps 4-5, using 3-bromo-2-naphthol
instead of 2-bromo-6-methoxyquinolin-3-ol. LCMS (ES) m/z 350.4
(M+H).sup.+.
Intermediate C20:
(2S,4R)-4-[(3-Bromo-1,8-naphthyridin-2-yl)oxy]-2-(methoxycarbonyl)pyrroli-
dinium chloride
##STR00121##
[0376] Step 1: Methyl 2-hydroxy-1,8-naphthyridine-3-carboxylate
##STR00122##
[0378] A solution of 30 wt % NaOMe in MeOH (27.9 g, 155 mmol) was
added to a solution of 2-aminonicotinaldehyde (5 g, 40.9 mmol) and
dimethyl malonate (8.11 g, 61.4 mmol) in MeOH (200 mL). The yellow
suspension was stirred for 3 days, and the yellow solids were
filtered, suspended in H.sub.2O, filtered and washed with MeOH. The
crude product (5.30 g) was taken crude onto the next step.
M+H=204.9.
Step 2: 2-Hydroxy-1,8-naphthyridine-3-carboxylic acid
##STR00123##
[0380] A mixture of the product of Step 1 (5.30 g, 26.0 mmol) and
LiOH (3.11 g, 130 mmol) were heated at 65.degree. C. and stirred in
THF/H.sub.2O (20 mL each) for 2 hours. The reaction was cooled, and
the white precipitate filtered and washed with H.sub.2O and THF.
The solids were dried in vacuo, giving the desired product (4.94
g). M+H=190.9.
Step 3: 3-Bromo-1,8-naphthyridin-2-ol
##STR00124##
[0382] A solution of bromine (3.78 g, 23.7 mmol) in pyridine (4 mL)
and DMF (8 mL) was added to the product of Step 2 (450 mg, 2.37
mmol) and heated at 105.degree. C. for 1 hour. The reaction was
cooled; H.sub.2O was added, and the mixture filtered. The filtrate
was extracted with EtOAc (2.times.). The organic layers washed with
brine and saturated NH.sub.4Cl.sub.(aq.) and dried over
Na.sub.2SO.sub.4. The solvent was concentrated in vacuo, and the
resulting gum was triturated with DCM, and filtered to give a brown
solid (156 mg) as desired product. M+H=224.9.
Step 4:
(2S,4R)-4-[(3-Bromo-1,8-naphthyridin-2-yl)oxy]-2-(methoxycarbonyl)-
pyrrolidinium chloride
[0383] Intermediate C20 can be prepared according to the procedure
described for Intermediate C14, Steps 4-5, using
3-bromo-1,8-naphthyridin-2-ol instead of
2-bromo-6-methoxyquinolin-3-ol. LCMS (ES) m/z 350.4
(M+H).sup.+.
Intermediate C21:
(2S,4R)-4-[(3-Bromo-1,6-naphthyridin-2-yl)oxy]-2-(methoxycarbonyl)pyrroli-
dinium chloride
##STR00125##
[0385] Intermediate C21 can be prepared according to the procedure
described for Intermediate C20, using 4-aminonicotinaldehyde
instead of 2-aminonicotinaldehyde. LCMS (ES) m/z 353.5
(M+H).sup.+.
Intermediate C22:
(2S,4R)-4-[(3-Bromo-1,5-naphthyridin-2-yl)oxy]-2-(methoxycarbonyl)pyrroli-
dinium chloride
##STR00126##
[0387] Intermediate C22 can be prepared according to the procedure
described for Intermediate C20, using 5-aminonicotinaldehyde
instead of 2-aminonicotinaldehyde. LCMS (ES) m/z 353.5
(M+H).sup.+.
Intermediate C23:
(2S,4R)-4-[(3-bromo-1,7-naphthyridin-2-yl)oxy]-2-(methoxycarbonyl)pyrroli-
dinium chloride
##STR00127##
[0389] Intermediate C22 can be prepared according to the procedure
described for Intermediate C20, using 3-aminonicotinaldehyde
instead of 2-aminonicotinaldehyde. LCMS (ES) m/z 353.5
(M+H).sup.+.
Example 1
(2R,4S,7S,16E)-7-t-Butyl-N-((1R,2S)-1-{[(cyclopropylsulfonyl)amino]carbony-
l}-2-vinylcyclopropyl)-6,9-dioxo-3,4,6,7,8,9,12,13,14,15-decahydro-2H,11H--
2,5-methanopyrido[2,3-k][1,10,3,6]dioxadiazacyclononadecine-4-carboxamide
##STR00128##
[0390] Step 1: 1-t-Butyl
2-methyl(2S,4R)-4-[(3-bromopyridin-2-yl)oxy]pyrrolidine-1,2-dicarboxylate
##STR00129##
[0392] To a solution of 1-t-butyl
2-methyl(2S,4S)-4-{[(4-bromophenyl)sulfonyl]oxy}pyrrolidine-1,2-dicarboxy-
late (1.718 g, 3.70 mmol) and 3-bromopyridin-2-ol (0.773 g, 4.44
mmol) in NMP (18.50 mL) under N.sub.2, CS.sub.2CO.sub.3 (1.808 g,
5.55 mmol) was added. The mixture was then heated to 40.degree. C.
After 17 hours, the reaction was complete, and H.sub.2O and EtOAc
were added. The organic layer was then extracted with H.sub.2O
(3.times.), NaHCO.sub.3 (2.times.) and brine (2.times.). The
organic layer was dried over MgSO.sub.4, and the solvent was
removed in vacuo. The crude product was purified on SiO.sub.2
(gradient elution, 0-40% EtOAc/hexanes) to yield 1.04 g of the
title compound. LRMS ESI.sup.+ ((M-Boc)+H).sup.+ 301.2.
Step 2: 1-t-Butyl
2-methyl(2S,4R)-4-[(3-vinylpyridin-2-yl)oxy]pyrrolidine-1,2-dicarboxylate
##STR00130##
[0394] To a solution of a portion of the product from Step 1 (1.0
g, 2.49 mmol) in EtOH (25 mL), TEA (0.52 mL, 3.74 mmol), potassium
vinyltrifluoroborate (0.50 g, 3.74 mmol) and PdCl.sub.2(dppf)-DCM
complex (0.102 g, 0.125 mmol) were added. The mixture was then
heated to reflux for 17 hours. The EtOH was removed in vacuo, taken
up in EtOAc, and washed with H.sub.2O. The organic layer was then
dried over MgSO.sub.4, and the solvent was removed in vacuo. The
crude product was purified on SiO.sub.2 (gradient elution, 0-40%
EtOAc/hexanes) to yield 565 mg of the title compound. LRMS
ESI.sup.+ ((M-Boc)+H).sup.+ 249.2.
Step 3: Methyl (4R)-4-[(3-vinylpyridin-2-yl)oxy]-L-prolinate
hydrochloride
##STR00131##
[0396] A portion of the product from Step 2 (360 mg, 1.0 mmol) was
dissolved in 4M HCl in dioxane (12.9 mL, 51.6 mmol). After 1 hour,
the solvent was removed in vacuo, Et.sub.2O (50 mL) was added, and
the solvent was removed in vacuo again to yield 294 mg of the title
compound. LRMS ESI.sup.+ (M+H).sup.+ 249.3.
Step 4: Methyl
N-[(hept-6-en-1-yloxy)carbonyl]-3-methyl-L-valyl-(4R)-4-[(3-vinylpyridin--
2-yl)oxy]-L-prolinate
##STR00132##
[0398] To a solution of the product from Step 3 (294 mg, 1.0 mmol)
in DMF (10 mL) was added Intermediate B7 (336 mg, 1.24 mmol), DIEA
(0.72 mL, 4.13 mmol), and HATU (550 mg, 1.48 mmol). After 1 hour,
the mixture was extracted with H.sub.2O and EtOAc. The organic
layer was washed with H.sub.2O and brine, and then dried over
MgSO.sub.4. The solvent was removed in vacuo, and the crude product
was purified on SiO.sub.2 (gradient elution, 0-40% EtOAc/hexanes)
to yield 453 mg of the title compound. LRMS ESI.sup.+ (M+H).sup.+
502.4.
Step 5: Methyl
(2R,4S,7S,16E)-7-t-butyl-6,9-dioxo-3,4,6,7,8,9,12,13,14,15-decahydro-2H,1-
1H-2,5-methanopyrido[2,3-k][1,10,3,6]dioxadiazacyclononadecine-4-carboxyla-
te
##STR00133##
[0400] To a solution of a portion of the product from Step 4 (450
mg, 0.90 mmol) in DCM (179 mL), the Zhan 1b catalyst (79 mg, 0.11
mmol) was added. After 16 hours, the reaction was concentrated in
vacuo, and the crude product was purified on SiO.sub.2 (gradient
elution, 0-45% EtOAc/hexanes) to yield 396 mg of the title
compound. LRMS ESI.sup.+ (M+H).sup.+ 474.3.
Step 6:
(2R,4S,7S,16E)-7-t-Butyl-6,9-dioxo-3,4,6,7,8,9,12,13,14,15-decahyd-
ro-2H,11H-2,5-methanopyrido[2,3-k][1,10,3,6]dioxadiazacyclononadecine-4-ca-
rboxylic acid
##STR00134##
[0402] To a solution of a portion of the product from Step 5 (200
mg, 0.42 mmol) in THF (1.5 mL), MeOH (1.5 mL) and H.sub.2O (0.75
mL), LiOH.H.sub.2O (177 mg, 4.22 mmol) was added. After 1 hour, 1N
HCl and Et.sub.2O were added. The organic layer was separated, and
the aqueous layer was washed with EtOAc. The combined organic
layers were then dried over MgSO.sub.4, and the solvent was removed
in vacuo to yield 194 mg of the title compound. LRMS ESI.sup.+
(M+H).sup.+ 460.3.
Step 7:
(2R,4S,7S,16E)-7-t-Butyl-N-((1R,2S)-1-{[(cyclopropylsulfonyl)amino-
]carbonyl}-2-vinylcyclopropyl)-6,9-dioxo-3,4,6,7,8,9,12,13,14,15-decahydro-
-2H,11H-2,5-methanopyrido[2,3-k][1,10,3,6]dioxadiazacyclononadecine-4-carb-
oxamide
[0403] To a solution of a portion of the product from Step 6 (100
mg, 0.218 mmol) in DMF (2.2 mL), Intermediate A1 (70 mg, 0.26
mmol), DIEA (0.114 mL, 0.65 mmol), and HATU (108 mg, 0.283 mmol)
were added. After 15 minutes, the mixture was partitioned between
EtOAc and 1N HCl. The organic layer was separated, dried over
MgSO.sub.4, and the solvent was removed in vacuo. The crude product
was purified on SiO.sub.2 (gradient elution, 0-70% EtOAc/hexanes)
to yield 129 mg of the title compound. LRMS ESI.sup.+ (M+H).sup.+
672.4.
Example 2
(2R,4S,7S,16E)-7-t-Butyl-N-((1R,2R)-1-{[(cyclopropylsulfonyl)amino]carbony-
l}-2-ethylcyclopropyl)-6,9-dioxo-3,4,6,7,8,9,12,13,14,15-decahydro-2H,11H--
2,5-methanopyrido[2,3-k][1,10,3,6]dioxadiazacyclononadecine-4-carboxamide
##STR00135##
[0405] To a solution of a portion of the product from Example 1,
Step 6 (90 mg, 0.196 mmol) in DMF (2.2 mL), Intermediate A3 (63 mg,
0.235 mmol), DIEA (0.137 mL, 0.78 mmol), and HATU (97 mg, 0.255
mmol) was added. After 1 hour, the mixture was partitioned between
EtOAc and 1N HCl. The organic layer was separated, dried over
MgSO.sub.4, and the solvent was removed in vacuo. The crude product
was purified on SiO.sub.2 (gradient elution, 0-70% EtOAc/hexanes)
to yield 110 mg of the title compound. LRMS ESI.sup.+ (M+H).sup.+
674.4.
Example 3
[0406]
(2R,4S,7S)-7-t-Butyl-N-((1R,2S)-1-{[(cyclopropylsulfonyl)amino]carb-
onyl}-2-vinylcyclopropyl)-6,9-dioxo-3,4,6,7,8,9,12,13,14,15,16,17-dodecahy-
dro-2H,11H-2,5-methanopyrido[2,3-k][1,10,3,6]dioxadiazacyclononadecine-4-c-
arboxamide
##STR00136##
Step 1: Methyl
(2R,4S,7S)-7-t-butyl-6,9-dioxo-3,4,6,7,8,9,12,13,14,15,16,17-dodecahydro--
2H,11H-2,5-methanopyrido[2,3-k][1,10,3,6]dioxadiazacyclononadecine-4-carbo-
xylate
##STR00137##
[0408] To a solution of a portion of the product from Example 1,
Step 5 (200 mg, 0.422 mmol) in EtOAc (4.5 mL), 10% Pd/C (22.5 mg,
0.021 mmol) was added. The mixture was then place under H.sub.2,
stirred for 17 hours, and filtered through a pad of glass wool. The
solvent was then removed in vacuo to yield 195 mg of the title
compound. LRMS ESI.sup.+ (M+H).sup.+ 476.4.
Step 2:
(2R,4S,7S)-7-t-Butyl-6,9-dioxo-3,4,6,7,8,9,12,13,14,15,16,17-dodec-
ahydro-2H,11H-2,5-methanopyrido[2,3-k][1,10,3,6]dioxadiazacyclononadecine--
4-carboxylic acid
##STR00138##
[0410] To a solution of a portion of the product from Step 1 (190
mg, 0.40 mmol) in THF (1.5 mL), MeOH (1.5 mL) and H.sub.2O (0.75
mL) LiOH.H.sub.2O (168 mg, 4.0 mmol) was added. After 1 hour, 1N
HCl and Et.sub.2O were added. The organic layer was separated, and
the aqueous layer was washed with EtOAc. The combined organic
layers were then dried over MgSO.sub.4, and the solvent was removed
in vacuo to yield 184 mg of the title compound. LRMS ESI.sup.+
(M+H).sup.+ 462.3.
Step 3:
(2R,4S,7S)-7-t-Butyl-N-((1R,2S)-1-{[(cyclopropylsulfonyl)amino]car-
bonyl}-2-vinylcyclopropyl)-6,9-dioxo-3,4,6,7,8,9,12,13,14,15,16,17-dodecah-
ydro-2H,11H-2,5-methanopyrido[2,3-k][1,10,3,6]dioxadiazacyclononadecine-4--
carboxamide
[0411] To a solution of a portion of the product from Step 2 (93
mg, 0.201 mmol) in DMF (2.0 mL), Intermediate A1 (64.5 mg, 0.242
mmol), DIEA (0.141 mL, 0.81 mmol), and HATU (100 mg, 0.262 mmol)
were added. After 1 hour, the mixture was partitioned between EtOAc
and 1N HCl. The organic layer was separated, dried over MgSO.sub.4,
and the solvent was removed in vacuo. The crude product was
purified on SiO.sub.2 (gradient elution, 0-70% EtOAc/hexanes) to
yield 107 mg of the title compound. LRMS ESI.sup.+ (M+H).sup.+
674.4.
Example 4
[0412]
(2R,4S,7S)-7-t-Butyl-N-((1R,2R)-1-{[(cyclopropylsulfonyl)amino]carb-
onyl}-2-ethylcyclopropyl)-6,9-dioxo-3,4,6,7,8,9,12,13,14,15,16,17-dodecahy-
dro-2H,11H-2,5-methanopyrido[2,3-k][1,10,3,6]dioxadiazacyclononadecine-4-c-
arboxamide
##STR00139##
[0413] To a solution of a portion of the product from Example 3,
Step 2 (95 mg, 0.206 mmol) in DMF (2.2 mL), Intermediate A3 (66 mg,
0.247 mmol), DIEA (0.144 mL, 0.82 mmol), and HATU (102 mg, 0.268
mmol) were added. After 1 hour, the mixture was partitioned between
EtOAc and 1N HCl. The organic layer was separated, dried over
MgSO.sub.4, and the solvent was removed in vacuo. The crude product
was purified on SiO.sub.2 (gradient elution, 0-70% EtOAc/hexanes)
to yield 106 mg of the title compound. LRMS ESI.sup.+ (M+H).sup.+
676.4.
Example 5
[0414]
(1R,2S)-1-({[(2R,4S,7S)-7-Butyl-6,9-dioxo-3,4,6,7,8,9,12,13,14,15,1-
6,17-dodecahydro-2H,11H-2,5-methano-1,10,5,8-benzodioxadiazacyclononadecin-
-4-yl]carbonyl}amino)-2-vinylcyclopropanecarboxylic acid
##STR00140##
Step 1: 1-t-Butyl
2-methyl(2S,4R)-4-(2-allylphenoxy)pyrrolidine-1,2-dicarboxylate
##STR00141##
[0416] To a solution of 1-t-butyl
2-methyl(2S,4S)-4-hydroxypyrrolidine-1,2-dicarboxylate (0.2 g,
0.815 mmol), 2-allylphenol (0.117 mL, 0.897 mmol), and PPh.sub.3
(0.233 g, 0.889 mmol), DEAD (0.139 mL, 0.881 mmol) was added at
0.degree. C. The mixture was then warmed to RT. After 23 hours, the
reaction was complete, and the solvent was removed in vacuo. The
crude product was purified on SiO.sub.2 (gradient elution, 0-30%
EtOAc/hexanes) to yield 0.21 g of the title compound. LRMS
ESI.sup.+ ((M-Boc)+H).sup.+ 262.3.
Step 2: Methyl (4R)-4-(2-allylphenoxy)-L-prolinate
hydrochloride
##STR00142##
[0418] To a portion of the product from Step 1 (0.2 g, 0.553 mmol)
was added HCl in dioxane (4M, 9.6 mL, 38.7 mmol). After 1 hour, the
solvent was removed in vacuo to yield the title product. LRMS
ESI.sup.+ (M+H).sup.+ 262.3.
Step 3: Methyl
N-[(hex-5-en-1-yloxy)carbonyl]-L-norleucyl-(4R)-4-(2-allylphenoxy)-L-prol-
inate
##STR00143##
[0420] To a solution of the product from Step 2 (165 mg, 0.55 mmol)
in DMF (10 mL), Intermediate B4 (214 mg, 0.83 mmol), DMA (0.49 mL,
2.76 mmol), and TBTU (0.267 mg, 0.83 mmol) were added. After 1
hour, the mixture was extracted with 1N HCl and EtOAc. The organic
layer was washed with H.sub.2O and brine, and then dried over
MgSO.sub.4. The solvent was removed in vacuo, and the crude product
was purified on SiO.sub.2 (gradient elution, 5-40% EtOAc/hexanes)
to yield 270 mg of the title compound. LRMS ESI.sup.+ (M+H).sup.+
501.4.
Step 4: Methyl
(2R,4S,7S,15E/Z)-7-butyl-6,9-dioxo-3,4,6,7,8,9,12,13,14,17-decahydro-2H,1-
1H-2,5-methano-1,10,5,8-benzodioxadiazacyclononadecine-4-carboxylate
##STR00144##
[0422] To a solution of a portion of the product from Step 3 (196
mg, 0.39 mmol) in DCE (80 mL), the Zhan 1a catalyst (26 mg, 0.039
mmol) was added, and the mixture was heated to reflux under
N.sub.2. After 2 hours, the reaction was concentrated in vacuo, and
the crude product was purified on SiO.sub.2 (gradient elution,
10-60% EtOAc/hexanes) to yield 185 mg of the title compound as a
mixture of olefin isomers. LRMS ESI.sup.+ (M+H).sup.+ 473.3.
Step 5: Methyl
(2R,4S,7S)-7-butyl-6,9-dioxo-3,4,6,7,8,9,12,13,14,15,16,17-dodecahydro-2H-
,11H-2,5-methano-1,10,5,8-benzodioxadiazacyclononadecine-4-carboxylate
##STR00145##
[0424] To a solution of a portion of the product from Step 4 (185
mg, 0.39 mmol) in EtOAc (10 mL), 10% Pd/C (15 mg, 0.014 mmol) was
added. The mixture was then placed under H.sub.2, stirred for 5
hours, and filtered through a pad of glass wool. The solvent was
then removed in vacuo to yield 158 mg of the title compound. LRMS
ESI.sup.+ (M+H).sup.+ 475.4.
Step 6:
(2R,4S,7S)-7-Butyl-6,9-dioxo-3,4,6,7,8,9,12,13,14,15,16,17-dodecah-
ydro-2H,11H-2,5-methano-1,10,5,8-benzodioxadiazacyclononadecine-4-carboxyl-
ic acid
##STR00146##
[0426] To a solution of a portion of the product from Step 5 (158
mg, 0.33 mmol) in THF (10 mL), MeOH (5 mL) and H.sub.2O (2 mL),
LiOH.H.sub.2O (80 mg, 3.3 mmol) was added. After 1 hour, 1N HCl and
Et.sub.2O were added. The organic layer was separated, and the
aqueous layer was washed with EtOAc. The combined organic layers
were then dried over MgSO.sub.4, and the solvent was removed in
vacuo to yield 150 mg of the title compound. LRMS ESI.sup.+
(M+H).sup.+ 461.4.
Step 7:
(1R,2S)-1-({[(2R,4S,7S)-7-Butyl-6,9-dioxo-3,4,6,7,8,9,12,13,14,15,-
16,17-dodecahydro-2H,11H-2,5-methano-1,10,5,8-benzodioxadiazacyclononadeci-
n-4-yl]carbonyl}amino)-2-vinylcyclopropanecarboxylic acid
[0427] To a solution of a portion of the product from Step 6 (150
mg, 0.218 mmol) in DMF (15 mL), Intermediate A2 (128 mg, 0.66
mmol), DIEA (0.595 mL, 3.3 mmol), and TBTU (214 mg, 0.66 mmol) were
added. After 30 minutes, the mixture was partitioned between EtOAc
and 1N HCl. The organic layer was separated, dried over MgSO.sub.4,
and the solvent was removed in vacuo. The crude ester was taken up
in THF (10 mL), MeOH (5 mL) and H.sub.2O (2 mL) and LiOH.H.sub.2O
(80 mg, 3.3 mmol) was added. After 1 hour, 1N HCl and Et.sub.2O
were added. The organic layer was separated, and the aqueous layer
was washed with EtOAc. The combined organic layers were then dried
over MgSO.sub.4 and the solvent was removed in vacuo. The crude
product was purified by reverse-phase chromotography
(95/5H.sub.2O/ACN with 0.15% TFA to 5/95) to yield 100 mg of the
title compound. LRMS ESI.sup.+ (M+H).sup.+ 570.3.
Example 6
[0428]
(2R,4S,7S)-7-Butyl-N-((1R,2S)-1-{[(cyclopropylsulfonyl)amino]carbon-
yl}-2-vinylcyclopropyl)-6,9-dioxo-3,4,6,7,8,9,12,13,14,15,16,17-dodecahydr-
o-2H,11H-2,5-methano-1,10,5,8-benzodioxadiazacyclononadecine-4-carboxamide
##STR00147##
[0429] To a solution of the acid from Example 5, Step 7 (30 mg,
0.053 mmol) in DMF (0.34 mL), under N.sub.2, carbonyldiimidazole
(13 mg, 0.079 mmol) was added, and the mixture stirred at
40.degree. C. for 1 hour. Cyclopropylsulfonamide (10 mg, 0.079
mmol) and DBU (8 mg, 0.053 mmol) were added, and the reaction
stirred overnight (15 hours) at 40.degree. C. The reaction was
directly purified by reverse-phase chromatography, and the
resulting product was concentrated in vacuo to give the title
compound as a white solid (24 mg). LRMS ESI.sup.+ (M+H).sup.+
673.3.
Example 7
(2R,4S,7S,15E)-20-Bromo-7-t-butyl-N-((1R,2S)-1-{[(cyclopropylsulfonyl)amin-
o]carbonyl}-2-vinylcyclopropyl)-6,9-dioxo-3,4,6,7,8,9,12,13,14,17-decahydr-
o-2H,11H-2,5-methano-1,10,5,8-benzodioxadiazacyclononadecine-4-carboxamide
##STR00148##
[0431] Prepared according to Example 5, Steps 1-4 and 6-7 and
Example 6 starting from 2-allyl-5-bromophenol in place of
2-allylphenol in Example 5, Step 1. LRMS ESI.sup.+ (M+H).sup.+
751.3.
Example 8
(2R,4S,7S)-20-Bromo-74-butyl-N-((1R,2R)-1-{[(cyclopropylsulfonyl)amino]car-
bonyl}-2-ethylcyclopropyl)-6,9-dioxo-3,4,6,7,8,9,12,13,14,15,16,17-dodecah-
ydro-2H,11H-2,5-methano-1,10,5,8-benzodioxadiazacyclononadecine-4-carboxam-
ide
##STR00149##
[0433] To a solution of the product from Example 7 (280 mg, 0.373
mmol) in EtOAc (15 mL) was added Pd/C (30 mg). The mixture was then
placed under H.sub.2 and stirred for 4 hours. After filtering
through glass wool, the solvent was removed in vacuo to yield 280
mg of the title compound. LRMS ESI.sup.+ (M+H).sup.+ 755.3.
Example 9
(2R,4S,7S)-7-t-Butyl-20-cyano-N-((1R,2R)-1-{[(cyclopropylsulfonyl)amino]ca-
rbonyl}-2-ethylcyclopropyl)-6,9-dioxo-3,4,6,7,8,9,12,13,14,15,16,17-dodeca-
hydro-2H,11H-2,5-methano-1,10,5,8-benzodioxadiazacyclononadecine-4-carboxa-
mide
##STR00150##
[0435] To a solution of the product from Example 8 (25 mg, 0.033
mmol) in DMF (3 mL) and H.sub.2O (0.5 mL), Zn(CN).sub.2 (3.9 mg,
0.033 mmol), Pd.sub.2(dba).sub.3 (3 mg, 3.3 .mu.mol), and DPPF (1.8
mg, 3.3 .mu.mol) were added under N.sub.2. The mixture was then
heated to 120.degree. C. for 20 hours. The mixture was then
filtered and then purified by reverse-phase chromatography to yield
the title compound. LRMS ESI.sup.+ (M+H).sup.+ 700.3.
Example 10
(2R,4S,7S)-7-t-Butyl-N-((1R,2R)-1-{[(cyclopropylsulfonyl)amino]carbonyl}-2-
-ethylcyclopropyl)-6,9-dioxo-20-phenyl-3,4,6,7,8,9,12,13,14,15,16,17-dodec-
ahydro-2H,11H-2,5-methano-1,10,5,8-benzodioxadiazacyclononadecine-4-carbox-
amide
##STR00151##
[0437] To a solution of the product from Example 8 (20 mg, 0.027
mmol) in dioxane (1.75 mL), phenylboronic acid (9.7 mg, 0.08 mmol),
Cs.sub.2CO.sub.3 (21 mg, 0.064 mmol) Pd.sub.2(dba).sub.3 (2.4 mg,
2.6 .mu.mol), and PCy.sub.3 (1.1 mg, 3.9 .mu.mol) were added under
N.sub.2. The mixture was then heated to 95.degree. C. for 9 hours.
The mixture was then filtered and then purified by reverse-phase
chromatography to yield the title compound. LRMS ESI.sup.+
(M+H).sup.+ 751.4.
Example 11
(2R,4S,7S)-7-t-Butyl-N-((1R,2R)-1-{[(cyclopropylsulfonyl)amino]carbonyl}-2-
-ethylcyclopropyl)-6,9-dioxo-3,4,6,7,8,9,12,13,14,15,16,17-dodecahydro-2H,-
11H-2,5-methano-1,10,5,8-benzodioxadiazacyclononadecine-4-carboxamide
##STR00152##
[0439] To a solution of the product from Example 8 (21 mg, 0.028
mmol) in THF (5 mL) and 2N HOAc (5 mL), sodium acetate (34 mg, 0.42
mmol) and 10% Pd/C (2 mg) were added. The mixture was then
hydrogenated on a PARR apparatus for 18 hours. The mixture was then
filtered, basified with NaHCO.sub.3, and extracted with EtOAc.
After drying over MgSO.sub.4, the solvent was removed in vacuo. The
residue was purified by reverse-phase chromatography to yield the
title compound. LRMS ESI.sup.+ (M+H).sup.+ 675.3.
[0440] By using the appropriate procedures, the appropriate B
intermediates in place of Intermediate B4 or Intermediate B5, and
appropriate phenol or hydroxyl-heterocycle in place of
3-bromopyridin-2-ol or 2-allylphenol, the following compounds were
prepared, using the appropriate Intermediates according to the
procedures indicated. For each Example, Step 1 of the procedure
uses either phenol or hydroxyl heterocycle as indicated.
TABLE-US-00005 LRMS Ex. Structure Name (M + H).sup.+ Procedure Step
1 Int. 13 ##STR00153## (1R,2S)-1-({[(2R,4S,7S)-7-
butyl-6,9-dioxo-19-phenyl- 3,4,6,7,8,9,11,12,13,14,15,
16-dodecahydro-2H-2,5- methano-1,10,5,8- benzodioxadiaza
cyclooctadecin-4- yl]carbonyl}amino)-2- vinylcyclopropane
carboxylic acid 632.4 See Example 5 2-allyl-5- phenyl- phenol. Ref:
U.S. Pat. No. 2,548,704 B1 14 ##STR00154## (2R,4S,7S)-7-butyl-N-
((1R,2S)-1- {[(cyclopropylsulfonyl) amino]carbonyl}-2-
vinylcyclopropyl)-6,9- dioxo-19-phenyl- 3,4,6,7,8,9,11,12,13,14,15,
16-dodecahydro-2H-2,5- methano-1,10,5,8- benzodioxadiaza
cyclooctadecine-4- carboxamide 735.5 See Example 6 2-allyl-5-
phenyl- phenol. Ref: U.S. Pat. No. 2,548,704 B1 16 ##STR00155##
(8R,10S,13S,22E)-13-t- butyl-N-((1R,2S)-1- {[(cyclopropylsulfonyl)
amino]carbonyl}-2- vinylcyclopropyl)-12,15- dioxo-9,10,12,13,14,15,
18,19,20,21-decahydro- 8H,17H,8,11- methanonaphtho[2,1-k]
[1,10,3,6] dioxadiaza cyclononadecine-10- carboxamide 721.4 See
Example 1 1-bromo- 2- naphthol B11 17 ##STR00156##
(2R,4S,7S,16E)-7-t-butyl- N-((1R,2S)-1- {[(cyclopropylsulfonyl)
amino]carbonyl}-2- vinylcyclopropyl)-6,9- dioxo-3,4,6,7,8,9,12,
13,14,15-decahydro- 2H,11H-2,5- methano[1,10,3,6] dioxadiazacyclo
nonadecino[11,12-b] quinoline-4-carboxamide 722.5 See Example 1
3-bromo quinolin- 2-ol. Ref: 70 J. Org. Chem. 175 (2005). B11 18
##STR00157## (2R,4S,7S,16E)-7- cyclohexyl-N-((1R,2S)-1-
{[(cyclopropylsulfonyl) amino]carbonyl}-2- vinylcyclopropyl)-6,9-
dioxo-3,4,6,7,8,9,12,13, 14,15-decahydro-2H,11H-
2,5-methanol[1,10,3,6] dioxadiazacyclonona
decino[11,12-b]quinoline- 4-carboxamide 748.7 See Example 1 3-bromo
quinolin- 2-ol. Ref: 70 J. Org. Chem. 175 (2005). B16 19
##STR00158## (2R,4S,7S,15E)-7- cyclohexyl-N-((1R,2S)-1-
{[(cyclopropylsulfonyl) amino]carbonyl}-2- vinylcyclopropyl)-6,9-
dioxo-3,4,6,7,8,9,11, 12,13,14-decahydro-2H- 2,5-methano[1,10,3,6]
dioxadiazacyclooctadecino [11,12-b]quinoline-4- carboxamide 734.6
See Example 1 3-bromo quinolin- 2- ol. Ref: 70 J. Org. Chem. 175
(2005). B17 20 ##STR00159## (2R,4S,7S,16E)-7-
cyclohexyl-N-((1R,2S)-1- {[(cyclopropylsulfonyl) amino]carbonyl}-2-
vinylcyclopropyl)-12,12- dimethyl-6,9-dioxo-
3,4,6,7,8,9,12,13,14,15- decahydro-2H,11H-2,5- methano[1,10,3,6]
dioxadiazacyclo nonadecino[11,12- b]quinoline-4-carboxamide 776.8
See Example 1 3-bromo quinolin- 2-ol. Ref: 70 J. Org. Chem. 175
(2005). B19 21 ##STR00160## (2R,4S,7S,16E)-7- t-butyl-
N-((1R,2S)-1- {[(cyclopropylsulfonyl) amino]carbonyl}-2-
vinylcyclopropyl)-6,9- dioxo-3,4,6,7,8,9,12, 13,14,15-decahydro-
2H,11H-2,5- methanopyrido[3,2-k] [1,10,3,6]dioxadiaza
cyclononadecine-4- carboxamide 672.4 See Example 1 2-bromo pyridin-
3-ol B11 22 ##STR00161## (2R,4S,7S,16E)-7-t-butyl- 4-{[((1R,2S)-1-
{[(cyclopropylsulfonyl) amino]carbonyl}-2- vinylcyclopropyl)amino]
carbonyl}-6,9-dioxo- 3,4,6,7,8,9,12,13,14,15- decahydro-2H,11H-2,5-
metanopyrido[4,3-k] [1,10,3,6]dioxadiaza cyclononadecin-19-ium
trifluoroacetate 672.4 See Example 1 3-bromo pyridin- 4(1H)-one B11
23 ##STR00162## (2R,4S,7S,16E)-7-t-butyl- N-((1R,2S)-1-
{[(cyclopropylsulfonyl) amino]carbonyl}-2- vinylcyclopropyl)-6,9-
dioxo-18-phenyl- 3,4,6,7,8,9,12,13,14,15- decahydro-2H,11H-2,5-
methanopyrido[2,3- k][1,10,3,6]dioxadiaza cyclononadecine-4-
carboxamide See Example 1 3-chloro- 4- phenyl pyridin- 2-ol B11
Example 24
(1R,2S)-1-({[(4R,6S,9S,16E)-9-Butyl-8,11-dioxo-3,12-dioxa-7,10-diazatricyc-
lo[16.3.1.1.sup.4,7]-tricosa-1(22),16,18,20-tetraen-6-yl]carbonyl}amino)-2-
-vinylcyclopropanecarboxylic acid
##STR00163##
[0441] Step 1: 14-Butyl
2-methyl(2S,4R)-4-[(3-iodobenzyl)oxy]pyrrolidine-1,2-dicarboxylate
##STR00164##
[0443] To a solution of 1-t-butyl
2-methyl(2S,4R)-4-hydroxypyrrolidine-1,2-dicarboxylate (1.5 g, 6.12
mmol) and 1-(bromomethyl)-3-iodobenzene (2.18 g, 7.34 mmol) in DMF
(20 mL), Cs.sub.2CO.sub.3 (5.98 g, 18.4 mmol) was added at RT.
After 3 days, EtOAc was added, and the mixture was extracted with
1N HCl and then H.sub.2O. The organic layer was dried over
Na.sub.2SO.sub.4, and the solvent was removed in vacuo. The crude
product was purified on SiO.sub.2 (gradient elution, 5-70%
EtOAc/hexanes) to yield 1.5 g of the title compound. LRMS ESI.sup.+
((M-Boc)+H).sup.+ 362.2.
Step 2: 1-t-Butyl
2-methyl(2S,4R)-4-[(3-vinylbenzyl)oxy]pyrrolidine-1,2-dicarboxylate
##STR00165##
[0445] To a degassed solution of the product from Step 1 (1.4 g,
3.03 mmol) in PhMe (20 mL), vinyltributyltin (1.06 mL, 3.64 mmol)
and Pd(PPh.sub.3).sub.4 (70 mg, 0.06 mmol) were added. The mixture
was then heated to reflux for 1 hour. The solvent was removed in
vacuo, and the crude material was purified on SiO.sub.2 (gradient
elution, 5-50% EtOAc/hexanes) to yield 700 mg of the title
compound. LRMS ESI.sup.+ ((M-Boc)+H).sup.+ 262.3.
Step 3: Methyl (4R)-4-[(3-vinylbenzyl)oxy]-L-prolinate
hydrochloride
##STR00166##
[0447] To the product from Step 2 (700 mg, 1.94 mmol) was added
HCl/dioxane (20 mL, 4M, 60 mmol). After 1 hour, the solvent was
removed in vacuo to yield 575 mg of the title compound. LRMS
ESI.sup.+ (M+H).sup.+ 262.3
Step 4: Methyl
N-[(pent-4-en-1-yloxy)carbonyl]-L-norleucyl-(4R)-4-[(3-vinylbenzyl)oxy]-L-
-prolinate
##STR00167##
[0449] To a solution of the product from Step 3 (300 mg, 1.0 mmol)
in DMF (5 mL), Intermediate B1 (368 mg, 1.51 mmol), DIEA (0.702 mL,
4.03 mmol), EDC (386 mg, 2.01 mmol), and HOAt (274 mg, 2.01 mmol)
were added at RT. After 2 hours, the reaction diluted with
NaHCO.sub.3(aq.) and extracted with EtOAc (3.times.). The combined
organic layers were extracted with H.sub.2O and then brine, dried
over Na.sub.2SO.sub.4, and the solvent was removed in vacuo. The
residue was purified on SiO.sub.2 (gradient elution, 5-75%
EtOAc/hexanes) to yield the title compound. LRMS ESI.sup.+
(M+H).sup.+ 487.4.
Step 5: Methyl
(4R,6S,9S,16E)-9-butyl-8,11-dioxo-3,12-dioxa-7,10-diazatricyclo[16.3.1.1.-
sup.4,7]tricosa-1(22),16,18,20-tetraene-6-carboxylate
##STR00168##
[0451] The title compound was prepared according to Example 1, Step
5 using the product from Step 4. LRMS ESI.sup.+ (M+H).sup.+
459.4.
Step 6:
(4R,6S,9S,16E)-9-Butyl-8,11-dioxo-3,12-dioxa-7,10-diazatricyclo[16-
.3.1.1.sup.4,7]-tricosa-1(22),16,18,20-tetraene-6-carboxylic
acid
##STR00169##
[0453] To a solution of the product from Step 5 (160 mg, 0.35 mmol)
in THF (3 mL) and MeOH (0.5 mL), LiOH (3.49 mL, 1M solution, 3.49
mmol) was added. After 1 hour, the solution was acidified to pH 6
with 1N HCl and extracted with EtOAc (3.times.). The combined
organic layers were washed with H.sub.2O and then brine, dried over
Na.sub.2SO.sub.4, and the solvent was removed in vacuo to yield the
title compound. LRMS ESI.sup.+ (M+H).sup.+ 445.4.
Step 7:
(1R,2S)-1-({[(4R,6S,9S,16E)-9-Butyl-8,11-dioxo-3,12-dioxa-7,10-dia-
zatricyclo[16.3.1.1.sup.4,7]tricosa-1(22),16,18,20-tetraen-6-yl]carbonyl}a-
mino)-2-vinylcyclopropanecarboxylic acid
[0454] Using the product from Step 6, the title compound was
prepared according to Example 5, Step 7. LRMS ESI.sup.+ (M+H).sup.+
554.4.
Example 25
[0455]
(1R,2S)-1-({[(4R,6S,9S)-9-Butyl-8,11-dioxo-3,12-dioxa-7,10-diazatri-
cyclo[16.3.1.1.sup.4,7]tricosa-1(22),18,20-trien-6-yl]carbonyl}amino)-2-vi-
nylcyclopropanecarboxylic acid
##STR00170##
Step 1: 2-(Trimethylsilyl)ethyl
(4R)-4-[(3-vinylbenzyl)oxy]-L-prolinate hydrochloride
##STR00171##
[0457] Using 1-t-butyl
2-[2-(trimethylsilyl)ethyl](2S,4R)-4-hydroxypyrrolidine-1,2-dicarboxylate-
, the title compound was prepared according to Example 24, Steps
1-3. LRMS ESI.sup.+ (M+H).sup.+ 348.3.
Step 2: 2-(Trimethylsilyl)ethyl
N-[(pent-4-en-1-yloxy)carbonyl]-L-norleucyl-(4R)-4-[(3-vinylbenzyl)oxy]-L-
-prolinate
##STR00172##
[0459] Using the product from Step 1, the title compound was
prepared according to Example 24, step 4. LRMS ESI.sup.+
(M+H).sup.+ 573.4.
Step 3: 2-(Trimethylsilyl)ethyl
(4R,6S,9S,16E)-9-butyl-8,11-dioxo-3,12-dioxa-7,10-diazatricyclo[16.3.1.1.-
sup.4,7]tricosa-1(22),16,18,20-tetraene-6-carboxylate
##STR00173##
[0461] Using the product from Step 2, the title compound was
prepared according to Example 24, Step 5. LRMS ESI.sup.+
(M+H).sup.+ 545.4.
Step 4: 2-(Trimethylsilyl)ethyl
(4R,6S,9S)-9-butyl-8,11-dioxo-3,12-dioxa-7,10-diazatricyclo[16.3.1.1.sup.-
4,7]tricosa-1(22),18,20-triene-6-carboxylate
##STR00174##
[0463] Using the product from Step 3, the title compound was
prepared according to Example 3, Step 1. LRMS ESI.sup.+ (M+H).sup.+
547.4.
Step 5:
(4R,6S,9S)-9-Butyl-8,11-dioxo-3,12-dioxa-7,10-diazatricyclo[16.3.1-
.1.sup.4,7]tricosa-1(22),18,20-triene-6-carboxylic acid
##STR00175##
[0465] 2-(Trimethylsilyl)ethyl
(4R,6S,9S)-9-butyl-8,11-dioxo-3,12-dioxa-7,10-diazatricyclo[16.3.1.1.sup.-
4,7]tricosa-1(22),18,20-triene-6-carboxylate (60 mg, 0.11 mmol) in
THF (3 mL), TBAF (0.137 mL, 1M solution in THF, 0.137 mmol) were
added to a solution of the product from Step 4. After 2 hours, the
solvent was removed in vacuo to yield the title compound as an oil.
LRMS ESI.sup.+ (M+H).sup.+ 447.3.
Step 6:
(1R,2S)-1-({[(4R,6S,9S)-9-Butyl-8,11-dioxo-3,12-dioxa-7,10-diazatr-
icyclo[16.3.1.1.sup.4,7]tricosa-1(22),18,20-trien-6-yl]carbonyl}amino)-2-v-
inylcyclopropanecarboxylic acid
[0466] Using the product from Step 5, the title compound was
prepared according to Example 5, Step 7. LRMS ESI.sup.+ (M+H).sup.+
556.4.
Example 26
(4R,6S,9S,16E)-9-Butyl-N-((1R,2S)-1-{[(cyclopropylsulfonyl)amino]carbonyl}-
-2-vinylcyclopropyl)-8,11-dioxo-3,12-dioxa-7,10-diazatricyclo[16.3.1.1.sup-
.4,7]tricosa-1(22),16,18,20-tetraene-6-carboxamide
##STR00176##
[0468] To a solution of the product from Example 24, Step 6 (150
mg, 0.337 mmol) in DMF (5 mL), Intermediate A1 (108 mg, 0.41 mmol),
DIEA (0.147 mL, 0.844 mmol), and TBTU (163 mg, 0.51 mmol) were
added. After 2 hours, the mixture was diluted with NaHCO.sub.3(aq.)
and extracted with EtOAc. The organic layer was washed with brine,
dried over Na.sub.2SO.sub.4, and the solvent was removed in vacuo.
The crude material was purified by reverse-phase chromatography
(gradient elution, 5-95% acetonitrile/H.sub.2O (with 0.15% TFA)) to
yield the title compound. LRMS ESI.sup.+ (M+H).sup.+ 657.5.
Example 27
(4R,6S,9S)--N-((1R,2S)-1-{[(Cyclopropylsulfonyl)amino]carbonyl}-2-vinylcyc-
lopropyl)-9-isopropyl-8,11-dioxo-3,12-dioxa-7,10-diazatricyclo[16.3.1.1.su-
p.4,7]tricosa-1(22),18,20-triene-6-carboxamide
##STR00177##
[0469] Step 1: Methyl
(4R,6S,9S,16E)-9-isopropyl-8,11-dioxo-3,12-dioxa-7,10-diazatricyclo[16.3.-
1.1.sup.4,7]tricosa-1(22),16,18,20-tetraene-6-carboxylate
##STR00178##
[0471] Following the general procedure outlined in Example 24, the
title compound was prepared using Intermediate B7 in place of
Intermediate B1. LRMS ESI.sup.+ (M+H).sup.+ 445.3.
Step 2: Methyl
(4R,6S,9S)-9-isopropyl-8,11-dioxo-3,12-dioxa-7,10-diazatricyclo[16.3.1.1.-
sup.4,7]tricosa-1(22),18,20-triene-6-carboxylate
##STR00179##
[0473] Using the product from Step 1, the title compound was
prepared according to Example 3, Step 1. LRMS ESI.sup.+ (M+H).sup.+
447.4.
Step 3:
(4R,6S,9S)--N-((1R,2S)-1-{[(Cyclopropylsulfonyl)amino]carbonyl}-2--
vinylcyclopropyl)-9-isopropyl-8,11-dioxo-3,12-dioxa-7,10-diazatricyclo[16.-
3.1.1.sup.4,7]tricosa-1(22),18,20-triene-6-carboxamide
[0474] Using the product from Step 2, the title compound was
prepared according to Example 26. LRMS ESI.sup.+ (M+H).sup.+
645.4.
[0475] By using the appropriate procedures, the appropriate B
intermediates in place of Intermediate B1 or Intermediate B7, and
appropriate benzylating reagent in Step 1 in place of
1-bromo-3-(bromomethyl)benzene, the following compounds were
prepared.
TABLE-US-00006 LRMS Ex. Structure Name (M + H).sup.+ Procedure Step
1 Int. 29 ##STR00180## (1R,2S)-1-({[(4R,6S,9S)-
9-butyl-8,11-dioxo-3,12- dioxa-7,10-diazatricyclo
[17.3.1.1.sup.4,7]tetracosa- 1(23),19,21-trien-6-
yl]carbonyl}amino)-2- vinylcyclopropane carboxylic acid 570.4 See
Example 25 1-iodo-3- (bromo methyl) benzene B4 30 ##STR00181##
(1R,2S)-1-({[(4R,6S,9S)- 9-isopropyl-8,11-dioxo- 3,12-dioxa-7,10-
diazatricyclo [16.3.1.1.sup.4,7]tricosa- 1(22),18,20-trien-6-
yl]carbonyl}amino)-2- vinylcyclopropane carboxylic acid 542.4 See
Example 25 1-iodo- 3- (bromo methyl) benzene B7 31 ##STR00182##
(4R,6S,9S,16E)-9-t- butyl-N-((1R,2S)-1- {[(cyclopropyl
sulfonyl)amino] carbonyl}-2- vinylcyclopropyl)-8,11-
dioxo-3,12-dioxa-7,10- diazatricyclo [16.3.1.1.sup.4,7]tricosa-
1(22,16,18,20-tetraene- 6-carboxamide 657.3 See Example 26 1-iodo-
3- (bromo methyl) benzene B2 32 ##STR00183## (4R,6S,9S,16E)-9-t-
butyl-N-((1R,2S)-1- {[(cyclopropyl sulfonyl)amino] carbonyl}-2-
vinylcyclopropyl)-12- methyl-8,11-dioxo-3- oxa-7,10,12-
triazatricyclo [16.3.1.1.sup.4,7]tricosa- 1(22),16,18,20-tetraene-
6-carboxamide 670.4 See Example 26 1-iodo- 3- (bromo methyl)
benzene B20 33 ##STR00184## (4R,6S,9S)-N-((1R,2S)- 1-{[(cyclopropyl
sulfonyl)amino] carbonyl}-2-vinylcyclo propyl)-9-isopropyl-
8,11-dioxo-21-phenoxy- 3,12-dioxa-7,10- diazatricyclo
[16.3.1.1.sup.4,7]tricosa- 1(22),18,20-triene-6- carboxamide See
Example 26 B7 34 ##STR00185## (4R,6S,9S)-9-t-butyl-6- {[((1R,2S)-1-
{[(cyclopropyl sulfonyl)amino] carbonyl}-2-vinylcyclo propyl)amino]
carbonyl}-8,11-dioxo- 3,12-dioxa-7,10-diaza- 22-azoniatricyclo
[16.3.1.1.sup.4,7]tricosa- 1(22),18,20-triene trifluoroacetate
661.3 See Example 26 (6-bromo pyridin-2- yl)methyl methane
sulfonate. Ref: 61 Tetrahedron 12100 (2005). B2 35 ##STR00186##
(4R,6S,9S,16E)-9-butyl- 21-chloro-N-((1R,2S)-1- {[(cyclopropyl
sulfonyl)amino] carbonyl}-2-vinylcyclo propyl)-8,11-dioxo-3,12-
dioxa-7,10-diazatricyclo [16.3.1.1.sup.4,7]tricosa-
1(22),16,18,20-tetraene- 6-carboxamide 691.3 See Example 26
5-bromo- 2- chloro benzyl methane sulfonate (C9) B1 36 ##STR00187##
(4R,6S,9S,16E)-9-butyl- N-((1R,2S)-1- {[(cyclopropyl
sulfonyl)amino] carbonyl}-2-vinylcyclo propyl)-8,11-dioxo-20-
(trifluoromethoxy)-3,12- dioxa-7,10-diazatricyclo
[16.3.1.1.sup.4,7]tricosa- 1(22),16,18,20-tetraene- 6-carboxamide
741.3 See Example 26 3-bromo- 5- (trifluoro methoxy) benzyl methane
sulfonate (C7) B1 37 ##STR00188## (4R,6S,9S,16E)-20-
bromo-9-butyl-N- ((1R,2S)-1- {[(cyclopropyl sulfonyl)amino]
carbonyl}-2-vinylcyclo propyl)-8,11-dioxo-3,12-
dioxa-7,10-diazatricyclo [16.3.1.1.sup.4,7]tricosa-
1(22),16,18,20-tetraene- 6-carboxamide 736.3 See Example 26
1,3-dibromo- 5-(bromo methyl) benzene B1 38 ##STR00189##
(4R,6S,9S,16E)-9-butyl- N-((1R,2S)-1- {[(cyclopropyl
sulfonyl)amino] carbonyl}-2-vinylcyclo propyl)-20-methoxy-
8,11-dioxo-3,12-dioxa- 7,10-diazatricyclo [16.3.1.1.sup.4,7]ticosa-
1(22),16,18,20-tetraene- 6-carboxamide 687.6 See Example 26
3-bromo- 5- methoxy benzyl methane sulfonate (C10) B1
Example 40
(5R,7S,10S)-10-Butyl-N-((1R,2S)-1-{[(cyclopropylsulfonyl)amino]carbonyl}-2-
-vinylcyclopropyl)-3,9,12-trioxo-4,13-dioxa-2,8,11-triazatricyclo[17.3.1.1-
.sup.5,8]tetracosa-1(23),19,21-triene-7-carboxamide
##STR00190##
[0476] Step 1: 1-t-Butyl
2-methyl(2S,4R)-4-({[(3-bromophenyl)amino]carbonyl}oxy)pyrrolidine-1,2-di-
carboxylate
##STR00191##
[0478] To a solution of 1-t-butyl
2-methyl(2S,4R)-4-hydroxypyrrolidine-1,2-dicarboxylate (1.0 g, 4.08
mmol) in DCM (15 mL), 1-bromo-3-isocyanatobenzene (807 mg, 4.08
mmol), TEA (0.97 mL, 6.93 mmol), and DMAP (100 mg, 0.815 mmol) were
added. After 15 hours, the mixture was diluted with NaHCO.sub.3 and
extracted with EtOAc. The organic layer was washed with H.sub.2O
and then brine, dried over Na.sub.2SO.sub.4, and the solvent was
removed in vacuo. The crude material was purified on SiO.sub.2
(gradient elution, 5-75% EtOAc/hexanes) to yield the title
compound. LRMS ESI.sup.+ ((M-Boc)+H).sup.+ 343.1.
Step 2:
(5R,7S,10S)-10-Butyl-N-((1R,2S)-1-{[(cyclopropylsulfonyl)amino]car-
bonyl}-2-vinylcyclopropyl)-3,9,12-trioxo-4,13-dioxa-2,8,11-triazatricyclo[-
17.3.1.1.sup.5,8]tetracosa-1(23),19,21-triene-7-carboxamide
[0479] Using the product from Step 1, the title compound was
prepared according to Example 3. LRMS ESI.sup.+ (M+H).sup.+
688.4.
Example 41
(5R,7S,10S)-10-t-Butyl-N-((1R,2S)-1-{[(cyclopropylsulfonyl)amino]carbonyl}-
-2-vinyl
cyclopropyl)-22-methoxy-3,9,12-trioxo-4,13-dioxa-2,8,11-triazatri-
cyclo[19.3.1.1.sup.5,8]hexacosa-1(25),21,23-triene-7-carboxamide
##STR00192##
[0481] The title compound was prepared using the procedures of
Example 40, and replacing 3-bromoaniline with
3-bromo-4-methoxyaniline.
Example 42
(6R,8S,11S,18E)-N-((1R,2S)-1-{[(Cyclopropylsulfonyl)amino]carbonyl}-2-viny-
lcyclopropyl)-11-isopropyl-4,10,13-trioxo-5,14-dioxa-3,9,12-triazatricyclo-
[18.3.1.1.sup.6,9]pentacosa-1(24),18,20,22-tetraene-8-carboxamide
##STR00193##
[0482] Step 1: 1-t-Butyl
2-methyl(2S,4R)-4-({[(3-bromobenzyl)amino]carbonyl}oxy)pyrrolidine-1,2-di-
carboxylate
##STR00194##
[0484] To a solution of 1-t-butyl
2-methyl(2S,4R)-4-hydroxypyrrolidine-1,2-dicarboxylate (4.41 g,
17.97 mmol) in DMF (70 mL) cooled to 0.degree. C., CDI (2.91 g,
17.97 mmol) was added. After stirring at RT for 30 minutes,
1-(3-bromophenyl)methanamine hydrochloride (4.0 g, 17.97 mmol) was
added, and the mixture was heated to 50.degree. C. for 15 hours.
The reaction was then diluted with EtOAc, washed with H.sub.2O and
then brine, dried over Na.sub.2SO.sub.4, and the solvent was
removed in vacuo. The crude material was purified on SiO.sub.2
(gradient elution, 5-75% EtOAc/hexanes) to yield the title
compound. LRMS ESI.sup.+ ((M-Boc)+H).sup.+ 359.2.
Step 2:
(6R,8S,11S,18E)-N-((1R,2S)-1-{[(Cyclopropylsulfonyl)amino]carbonyl-
}-2-vinylcyclopropyl)-11-isopropyl-4,10,13-trioxo-5,14-dioxa-3,9,12-triaza-
tricyclo[18.3.1.1.sup.6,9]pentacosa-1(24),18,20,22-tetraene-8-carboxamide
[0485] Using the product from Step 1 and Intermediate B7, the title
compound was prepared according to Example 1. LRMS ESI.sup.+
(M+H).sup.+ 686.4.
[0486] By using the appropriate procedures, the appropriate B
intermediates in place of Intermediate B1 or Intermediate B7 or
N-[(Hept-6-en-1-yloxy)carbonyl]-3-methyl-L-valine, and appropriate
amino compound in Step 1, the following compounds were
prepared.
TABLE-US-00007 LRMS Ex. Structure Name (M + H).sup.+ Procedure Step
1 Int. 43 ##STR00195## (1R,2S)-1-({[(4R,6S,9S)-
9-butyl-2,8,11-trioxo- 1,2,5,6,8,9,10,11,13,14, 15,16,17,18-
tetradecahydro-4H-4,7- methano-3,12,1,7,10- benzodioxatriaza
cycloicosin-6- yl]carbonyl}amino)-2- vinylcyclopropane carboxylic
acid 599.3 See Example 39 2- bromophenyl isocyanate B4 44
##STR00196## (4R,6S,9S)-9-butyl-N- ((1R,2S)-1-
{[(cyclopropylsulfonyl) amino]carbonyl}-2- vinylcyclopropyl)-
2,8,11-trioxo- 1,2,5,6,8,9,10,11, 13,14,15,16,17,18-
tetradecahydro-4H-4,7- methano-3,12,1,7,10- benzodioxatriazacyclo
icosine-6-carboxamide 702.4 See Example 40 2- bromophenyl
isocyanate B4 46 ##STR00197## (5R,7S,10S)-10-butyl-N- ((1R,2S)-1-
{[(cyclopropyl sulfonyl)amino] carbonyl}-2- vinylcyclopropyl)-
3,9,12-trioxo-4,13-dioxa- 2,8,11-triazatricyclo
[16.3.1.1.sup.5,8]tricosa- 1(22),18,20-triene-7- carboxamide 674.4
See Example 40 3- bromophenyl isocyanate B3 47 ##STR00198##
(5R,7S,10S)-10-butyl-N- ((1R,2S)-1- {[(cyclopropyl sulfonyl)amino]
carbonyl}-2- vinylcyclopropyl)- 3,9,12-trioxo-4,13-dioxa-
2,8,11-triazatricyclo [18.3.1.1.sup.5,8]pentacosa-
1(24),20,22-triene-7- carboxamide 702.4 See Example 40 3-
bromophenyl isocyanate B4 48 ##STR00199## (5R,7S,10S,19E)-10-t-
butyl-N-((1R,2S)-1- {[(cyclopropyl sulfonyl)amino] carbonyl}-2-
vinylcyclopropyl)-22- methoxy-3,9,12-trioxo- 4,13-dioxa-2,8,11-
triazatricyclo [19.3.1.1.sup.5,8]hexacosa- 1(25),18,21,23-tetraene-
7-carboxamide See Example 40 2-bromo-4- isocyanato-1- methoxy-
benzene. Ref: 16 Biorg. Med. Chem. Lett. 404 (2006) B11 49
##STR00200## (5R,7S,10S)-10-t-butyl- 7-{[((1R,2S)-1- {[(cyclopropyl
sulfonyl)amino] carbonyl}-2- vinylcyclopropyl)
amino]carbonyl}-3,9,12- trioxo-4,13-dioxa-2,8,11- triazatricyclo
[19.3.1.1.sup.5,8]hexacosa- 1(25),21,23-triene-22- carboxylic acid
See Example 40 4-amino- 2-bromo benzoic acid B11 50 ##STR00201##
(6R,8S,11S)-N-((1R,2S)- 1-{[(cyclopropyl sulfonyl)amino]
carbonyl}-2- vinylcyclopropyl)-11- isopropyl-4,10,13-trioxo-
5,12-dioxa-3,9,12- triazatricyclo [16.3.1.1.sup.6,9]tricosa-
1(22),18,20-triene-8- carboxamide 660.4 See Example 41 1-(3-bromo
phenyl) methanamine B8 51 ##STR00202## (5R,7S,10S,17E)-N-
((1R,2S)-1- {[(cyclopropyl sulfonyl)amino] carbonyl]-2-
vinylcyclopropyl)-10- isopropyl-3,9,12-trioxo- 1,2,3,6,7,9,10,
11,12,14,15,16- dodecahydro-5H-5,8- methano-4,13,2,8,11-
benzodioxatriazacyclo icosine-7-carboxamide 686.4 See Example 42
1-(3-bromo phenyl) methanamine B7
Example 52
(5R,7S)--N-((1R,2S)-1-{[(Cyclopropylsulfonyl)amino]carbonyl}-2-vinylcyclop-
ropyl)-15,15,24-trimethyl-3,9,12-trioxo-6,7,9,10,11,12,14,15,16,17-decahyd-
ro-3H,5H-2,23-epimino-5,8-methano-4,13,8,11-benzodioxadiazacyclohenicosine-
-7-carboxamide
##STR00203##
[0487] Step 1: 1-t-Butyl
2-[2-(trimethylsilyl)ethyl](2S,4R)-4-hydroxypyrrolidine-1,2-dicarboxylate
##STR00204##
[0489] To a solution of N-Boc-L-4-hydroxyproline (14.5 g, 0.0591
mol) in toluene (175 mL),
O-2-trimethylsilyl-N,N'-diisopropylisourea (29.0 g, 0.118 mol) (T.
Eicher, SYNTHESIS 755-762 (1996)) was added, and the mixture heated
to reflux for 3 hours. The reaction mixture was cooled,
concentrated to an oil and redissolved in DCM (150 mL) and H.sub.2O
(1 mL). The mixture was stirred for 1 hour, filtered and the
filtrate concentrated to an oil. The oil was dissolved in 20%
EtOAc/hexanes (200 mL) and stirred, the solids were filtered, and
the filtrate was concentrated to an oil and purified on SiO.sub.2
(20-60% EtOAc/hexanes) to yield 9.4 g (48% yield) of the title
compound. LRMS (M+H).sup.+ Calcd.=332; found 332.
Step 2: 1-t-Butyl
2-[2-(trimethylsilyl)ethyl](2S,4R)-4-{[(4-bromo-1-methyl-1H-indol-2-yl)ca-
rbonyl]oxy}pyrrolidine-1,2-dicarboxylate
##STR00205##
[0491] To a solution of Intermediate C1 (360 mg, 1.4 mmol) in DMF
(10 mL), carbonyl diimidizole (230 mg, 1.4 mmol) was added, and
heated to 40.degree. C. for 2 hours while under N.sub.2. To the
reaction solution, the title compound from Step 1 (564 mg, 1.7
mmol) and DBU (0.318 mL, 2.12 mmol) were added. The reaction
mixture was heated to 40 C for an additional 2 hours. The reaction
mixture was diluted with EtOAc, and the organics were washed with
1N HCl (2.times.), brine, saturated NaHCO.sub.3 (2.times.), and
brine. The organics were then dried over Na.sub.2SO.sub.4,
filtered, and concentrated. The resulting residue was purified on
SiO.sub.2 (gradient elution, 10-40% EtOAc/hexanes) to yield the
product as a white foam (556 mg, 69% yield). LRMS (M+H).sup.+
Calcd.=567, 569; found 567, 569.
Step 3:
2-[2-(Trimethylsilyl)ethyl](2S,4R)-4-{[(4-bromo-1-methyl-1H-indol--
2-yl)carbonyl]oxy}pyrrolidine-2-carboxylate
##STR00206##
[0493] To a solution of the compound from Step 2 (554 mg, 0.98
mmol) in DCM (4 mL), TFA (1 mL) was added, and the mixture was
stirred for 1 hour. The reaction mixture was concentrated. The
resulting residue was partitioned between EtOAc and saturated
NaHCO.sub.3, and extracted with EtOAc (2.times.); the organics were
combined, washed with brine, dried over Na.sub.2SO.sub.4, filtered,
and concentrated to yield the title compound as a pale yellow oil
(340 mg). LRMS (M+H).sup.+ Calcd.=467, 469; found 467, 469.
Step 4: 2-(Trimethylsilyl)ethyl
N-{[(2,2-dimethylhex-5-en-1-yl)oxy]carbonyl}-3-methyl-L-valyl-(4R)-4-{[(4-
-bromo-1-methyl-1H-indol-2-yl)carbonyl]oxy}-L-prolinate
##STR00207##
[0495] To a solution of the compound from Step 3 (340 mg, 0.727
mmol) and Intermediate B13 (249 mg, 0.873 mmol) in DMF (5 mL), HATU
(332 mg, 0.873 mmol) and DIEA (0.36 mL, 2.2 mmol) were added, and
the mixture was stirred for 15 hours. The reaction mixture is
diluted with EtOAc; the organics were washed with 1N HCl
(2.times.), brine, saturated NaHCO.sub.3 (2.times.), brine. The
organics were then dried over Na.sub.2SO.sub.4, filtered, and
concentrated. The resulting residue was purified on SiO.sub.2
(gradient elution, 1.5% acetone/DCM) to yield the title compound as
a white foam (402 mg). LRMS (M+H).sup.+ Calcd.=734, 736; found 734,
736.
Step 5: 2-(Trimethylsilyl)ethyl
N-{[(2,2-dimethylhex-5-en-1-yl)oxy]carbonyl}-3-methyl-L-valyl-(4R)-4-{[(1-
-methyl-4-vinyl-1H-indol-2-yl)carbonyl]oxy}-L-prolinate
##STR00208##
[0497] N.sub.2 was bubbled through a solution of the compound from
Step 4 (400 mg, 0.54 mmol) in PhMe (8 mL) for 30 minutes, and then
tributyl(vinyl)tin (0.19 mL, 0.65 mmol) and
tetrakistriphenylphosphine palladium (63 mg, 0.05 mmol) were added.
The reaction solution was heated to reflux for 2 hours,
concentrated, and purified the resulting residue on SiO.sub.2
(gradient elution, 0-1.5% acetone/DCM) to yield the title compound
as a yellow oil (320 mg). LRMS (M+H).sup.+ Calcd.=682; found
682.
Step 6:
2-(Trimethylsilyl)ethyl(5R,7S)-15,15,24-trimethyl-3,9,12-trioxo-6,-
7,9,10,11,12,14,15,16,17-decahydro-3H,5H-2,23-epimino-5,8-methano-4,13,8,1-
1-benzodioxadiazacyclohenicosine-7-carboxylate
##STR00209##
[0499] N.sub.2 was bubbled through a solution of the compound from
Step 5 (320 mg, 0.47 mmol) in DCM (80 mL) for 30 minutes, and then
Neolyst M1 catalyst (75 mg, 23 wt %) was added. The dark solution
was stirred for 6 hours, and N.sub.2 was bubbled through the
solution for 30 minutes, after which additional NEOLYST M1 catalyst
(75 mg, 23 wt %) was added, and the solution was stirred for 15
hours. Concentrated and purified the resulting residue on SiO.sub.2
(gradient elution, 10-40% EtOAc/hexanes) to yield the title
compound as a yellow oil (259 mg). LRMS (M+H).sup.+ Calcd.=654;
found 654.
Step 7:
(5R,7S)--N-((1R,2S)-1-{[(Cyclopropylsulfonyl)amino]carbonyl}-2-vin-
ylcyclopropyl)-15,15,24-trimethyl-3,9,12-trioxo-6,7,9,10,11,12,14,15,16,17-
-decahydro-3H,5H-2,23-epimino-5,8-methano-4,13,8,11-benzodioxadiazacyclohe-
nicosine-7-carboxamide
[0500] To a solution of the compound from Step 6 (86 mg, 0.13 mmol)
in THF (3 mL), TBAF (1M in THF, 0.66 mL, 0.66 mmol) was added, and
the mixture was stirred for 30 minutes. The reaction solution was
concentrated to dryness, and the resulting residue was dissolved in
DMF (4 mL). To this solution, Intermediate A1 (84 mg, 0.32 mmol),
HATU (120 mg, 0.32 mmol), and DIEA (0.22 mL, 0.66 mmol) were added,
and the mixture was stirred for 18 hours. The crude reaction
mixture was purified by reverse-phase HPLC to yield the title
compound as a white solid (40 mg). LRMS (M+H).sup.+ Calcd.=766;
found 766.
Example 53
(5R,7S)--N-((1R,2S)-1-{[(Cyclopropylsulfonyl)amino]carbonyl}-2-vinylcyclop-
ropyl)-15,15,24-trimethyl-3,9,12-trioxo-6,7,9,10,11,12,14,15,16,17,18,19-d-
odecahydro-3H,5H-2,23-epimino-5,8-methano-4,13,8,11-benzodioxadiazacyclohe-
nicosine-7-carboxamide
##STR00210##
[0501] Step 1: 2-(Trimethylsilyl)ethyl
(5R,7S)-15,15,24-trimethyl-3,9,12-trioxo-6,7,9,10,11,12,14,15,16,17,18,19-
-dodecahydro-3H,5H-2,23-epimino-5,8-methano-4,13,8,11-benzodioxadiazacyclo-
henicosine-7-carboxylate
##STR00211##
[0503] To a solution of the compound from Example 1 Step 6 (173 mg,
0.27 mmol) in EtOAc (6 mL), 10% Pd/C (42 mg) was added, and the
reaction mixture was placed under H.sub.2 for 15 hours. The
reaction mixture was filtered, and the filtrate is concentrated to
yield the title compound as a clear oil (170 mg). LRMS (M+H).sup.+
Calcd.=656; found 656.
Step 2:
(5R,7S)--N-((1R,2S)-1-{[(Cyclopropylsulfonyl)amino]carbonyl}-2-vin-
ylcyclopropyl)-15,15,24-trimethyl-3,9,12-trioxo-6,7,9,10,11,12,14,15,16,17-
,18,19-dodecahydro-3H,5H-2,23-epimino-5,8-methano-4,13,8,11-benzodioxadiaz-
acyclohenicosine-7-carboxamide
[0504] Hydrolysis of the trimethysilylethyl ester and coupling with
Intermediate A1 was carried out as described in Example 52 Step 7
to afford the title compound. LRMS (M+H).sup.+ Calcd.=768; found
768.
Example 54
(5R,7S)--N-((1R,2R)-1-{[(Cyclopropylsulfonyl)amino]carbonyl}-2-ethylcyclop-
ropyl)-15,15,24-trimethyl-3,9,12-trioxo-6,7,9,10,11,12,14,15,16,17,18,19-d-
odecahydro-3H,5H-2,23-epimino-5,8-methano-4,13,8,11-benzodioxadiazacyclohe-
nicosine-7-carboxamide
##STR00212##
[0506] Hydrolysis of the trimethylsilylethyl ester (Example 52 Step
1) and coupling to Intermediate A3 as described in Example 52 Step
7 afforded the title compound. LRMS (M+H).sup.+ Calcd.=770; found
770.
[0507] By using the appropriate A, B, and C intermediates in place
of Intermediates A1, B13, and C1 respectively, the following
compounds were prepared.
TABLE-US-00008 LRMS Ex. Structure Name (M + H).sup.+ Procedure Int.
55 ##STR00213## (5R,7S,10S)-10-t-butyl-N- ((1R,2R)-1-
{[(cyclopropylsulfonyl) amino]carbonyl}-2- ethylcyclopropyl)-15,15-
dimethyl-3,9,12-trioxo- 6,7,9,10,11,12,14,15,16,17,
18,19-dodecahydro-3H,5H- 2,23-epimino-5,8-methano- 4,13,8,11-
benzoioxadiazacyclo- henicosine-7-carboxamide 756 See Example 54 A3
B13, C2 56 ##STR00214## (5R,7S,10S)-10-t-butyl-N- ((1R,2S)-1-
{[(cyclopropylsulfonyl) amino]carbonyl}-2- vinylcyclopropyl)-15,15-
dimethyl-3,9,12-trioxo- 6,7,9,10,11,12,14,15,16,17-
decahydro-3H,5H-2,23- epimino-5,8-methano- 4,13,8,11-benzodioxa
diazacyclohenicosine-7- carboxamide 752 See Example 52 A1, B13, C2
57 ##STR00215## (5R,7S,10S)-10-t-butyl-N- ((1R,2R)-1-
{[(cyclopropylsulfonyl) amino]carbonyl}-2- ethylcyclopropyl)-15,15-
dimethyl-3,9,12-trioxo- 6,7,9,10,11,12,14,15,16,17-
decahydro-5H-5,8-methano- 23,2-methenopyrido[2,3- n][1,10,3,6,13]
dioxatriazacyclohenicosine-7- carboxamide 755 See Example 52 A3
B13, C3 58 ##STR00216## (5R,7S,10S)-10-t-butyl-N- ((1R,2R)-1-
{[(cyclopropylsulfonyl) amino]carbonyl}-2- ethylcyclopropyl)-15,15-
dimethyl-3,9,12-trioxo- 6,7,9,10,11,12,14,15,16,17-
decahydro-3H,5H-2,23- epiazeno-5,8- methanopyrido[1,2-
n][1,10,3,6,14]dioxatri azacyclohenicosine-7- carboxamide 755 See
Example 52 A3 B13, C4 59 ##STR00217## (5R,7S,10S)-10-t-butyl-N-
((1R,2S)-1- {[(cyclopropylsulfonyl) amino]carbonyl}-2-
vinylcyclopropyl)-3,9,12- trioxo-6,7,9,10,11,12,14,
15,16,17-decahydro-5H-5,8- methano-23,2- methenopyrido[2,3-
n][1,10,3,6,13]dioxa triazacyclohenicosine-7- carboxamide 725 See
Example 52 A1 B10, C3 60 ##STR00218## (2R or S,5R,7S,10S)-10-t-
butyl-N-((1R,2R)-1- {[(cyclopropylsulfonyl) amino]carbonyl}-2-
ethylcyclopropyl)-15,15- dimethyl-3,9,12-trioxo-
2,3,6,7,9,10,11,12,14,15,16, 17,18,19-tetradecahydro-
1H,5H-2,23:5,8-dimethano- 4,13,8,11-benzodioxadiaza
cyclohenicosine-7- carboxamide Earlier eluting diastereomer by
reverse phase chromatography 757 See Example 54 A3 B13, C5 61
##STR00219## (2S or R,5R,7S,10S)-10-t- butyl-N-((1R,2R)-1-
{[(cyclopropylsulfonyl) amino]carbonyl}-2- ethylcyclopropyl)-15,15-
dimethyl-3,9,2-trioxo- 2,3,6,7,9,10,11,12,14,15,16,
17,18,19-tetradecahydro- 1H,5H-2,23:5,8-dimethano-
4,13,8,11-benzodioxadiaza cyclohenicosine-7- carboxamide Later
eluting diastereomer by reverse phase chromatography 757 See
Example 54 A3 B13, C5 62 ##STR00220## (2R or S,5R,7S,10S)-10-t-
butyl-N-((1R,2S)-1- {[(cyclopropylsulfonyl) amino]carbonyl}-2-
vinylcyclopropyl)-15,15- dimethyl-3,9,12-trioxo-
2,3,6,7,9,10,11,12,14,15,16, 17-dodecahydro-1H,5H-
2,23:5,8-dimethano- 4,13,8,11-benzodioxadiaza cyclohenicosine-7-
carboxamide Earlier eluting diastereomer by reverse phase
chromatography 753 See Example 52 A1 B13, C5 63 ##STR00221## (2S or
R,5R,7S,10S)-10-t- butyl-N-((1R,2S)-1- {[(cyclopropylsulfonyl)
amino]carbonyl}-2- vinylcyclopropyl)-15,15- dimethyl-3,9,12-trioxo-
2,3,6,7,9,10,11,12,14,15,16, 17-dodecahydro-1H,5H-
2,23:5,8-dimethano- 4,13,8,11-benzodioxadiaza cyclohenicosine-7-
carboxamide Later eluting diastereomer by reverse phase
chromatrography 753 See Example 52 A1, B13, C5 64 ##STR00222##
(5R,7S,10S)-10-t-butyl-N- ((1R,2S)-1- {[(cyclopropylsulfonyl)
amino]carbonyl}-2- vinylcyclopropyl)-3,9,12-
trioxo-6,7,9,10,11,12,14, 15,16,17,18,19- dodecahydro-3H,5H-2,23-
epimino-5,8-methano- 4,13,8,11-benzodioxadiaza cyclohenicosine-7-
carboxamide 726 See Example 53 A1 B10, C2 65 ##STR00223##
(5R,7S,10S)-10-t-butyl-N- ((1R,2R)-1- {[(cyclopropylsulfonyl)
amino]carbonyl}-2- ethylcyclopropyl)-3,9,12-
trioxo-6,7,9,10,11,12,14, 15,16,17,18,19- dodecahydro-3H,5H-2,23-
epimino-5,8-methano- 4,13,8,11-benzodioxadiaza cyclohenicosine-7-
carboxamide 728 See Example 54 A3 B10, C2 66 ##STR00224##
(5R,7S,10S)-10-t-butyl-N- ((1R,2R)-1- {[(cyclopropylsulfonyl)
amino]carbonyl}-2- ethylcyclopropyl)-15,15- dimethyl-3,9,12-trioxo-
6,7,9,10,11,12,14,15,16,17, 18,19-dodecahydro-5H-5,8- methano-23,2-
(metheno)pyrido[2,3-n] [1,10,3,6,13]dioxatriaza cyclohenicosine-7-
carboxamide 757.5 See Example 54 A3, B13, C3 67 ##STR00225##
(5R,7S,10S,18E)-10-t-butyl- N-((1R,2S)-1- {[(cyclopropylsulfonyl)
amino]carbonyl}-2- vinylcyclopropyl)-15,15-
dimethyl-3,9,12-trioxo-24- phenyl-6,7,9,10,11,12,14,
15,16,17-decahydro-3H,5H- 2,23-epimino-5,8-methano-
4,13,8,11-benzodioxa diazacyclohenicosine-7- carboxamide 828.6 See
Example 52 A1, B13, C6 68 ##STR00226## (5R,7S,10S,18E)-10-t-butyl-
N-((1R,2R)-1- {[(cyclopropylsulfonyl) amino]carbonyl}-2-
ethylcyclopropyl)-15,15- dimethyl-3,9,12-trioxo-24-
phenyl-6,7,9,10,11,12,14, 15,16,17-decahydro-3H,5H-
2,23-epimino-5,8-methano- 4,13,8,11-benzodioxa
diazacyclohenicosine-7- carboxamide 830.6 See Example 52 A3 B13, C6
69 ##STR00227## (5R,7S,10S)-10-t-butyl-N- ((1R,2S)-1-
{[(cyclopropylsulfonyl) amino]carbonyl}-2- vinylcyclopropyl)-15,15-
dimethyl-3,9,12-trioxo-24- phenyl-6,7,9,10,11,12,14,
15,16,17,18,19- dodecahydro-3H,5H-2,23- epimino-5,8-methano-
4,13,8,11-benzodioxa diazacyclohenicosine-7- carboxamide 830.6 See
Example 53 A1, B13, C6 70 ##STR00228## (5R,7S,10S)-10-t-butyl-N-
((1R,2S)-1- {[(cyclopropylsulfonyl) amino]carbonyl}-2-
ethylcyclopropyl)-15,15- dimethyl-3,9,12-trioxo-24-
phenyl-6,7,9,10,11,12,14, 15,16,17,18,19- dodecahydro-3H,5H-2,23-
epimino-5,8-methano- 4,13,8,11-benzodioxa diazacyclohenicosine-7-
carboxamide 832.7 See Example 54 A3, B13, C6
Example 71
(10S,13S,15R)-10-Cyclohexyl-N--((1R,2S)-1-{[(cyclopropylsulfonyl)amino]car-
bonyl}-2-vinylcyclopropyl)-1-methylene-8,11-dioxo-1,2,3,4,5,6,8,9,10,11,14-
,15-dodecahydro-13H-12,15-methanonaphtho[2,1-k][1,10,3,6]dioxadiazacyclooc-
tadecine-13-carboxamide
##STR00229##
[0508] Step 1: 1-t-Butyl
2-methyl(2S,4R)-4-[(1-bromo-2-naphthyl)oxy]pyrrolidine-1,2-dicarboxylate
##STR00230##
[0510] To a solution of 1-t-butyl
2-methyl(2S,4S)-4-{[(4-bromophenyl)sulfonyl]oxy}pyrrolidine-1,2-dicarboxy-
late (0.5 g, 1.08 mmol) and 1-bromo-2-naphthol (0.29 g, 1.29 mmol)
in NMP (5.5 ml) under N.sub.2, Cs.sub.2CO.sub.3 (1.808 g, 5.55
mmol) was added. The mixture was then heated to 40.degree. C. After
17 hours, the reaction was complete, and H.sub.2O and EtOAc were
added. The organic layer was then extracted with H.sub.2O
(3.times.), NaHCO.sub.3 (2.times.) and brine (2.times.). The
organic layer was dried over MgSO.sub.4, and the solvent was
removed in vacuo. The crude product was purified on SiO.sub.2
(gradient elution, 10-60% EtOAc/hexanes) to yield 320 mg of the
title compound. LRMS ESI.sup.+. ((M-Boc)+H).sup.+ 350.1.
Step 2: Methyl (4R)-4-[(1-bromo-2-naphthyl)oxy]-L-prolinate
hydrochloride
##STR00231##
[0512] A portion of the product from Step 1 (320 mg, 0.77 mmol) was
dissolved in 4M HCl in dioxane (12.4 mL, 49.7 mmol). After 1 hour,
the solvent was removed in vacuo, Et.sub.2O (50 mL) was added, and
the solvent was removed in vacuo again to yield the title compound.
LRMS ESI.sup.+ (M+H).sup.+ 350.1.
Step 3: Methyl
(4R)-4-[(1-bromo-2-naphthyl)oxy]-1-((2S)-2-cyclohexyl-2-{[(hept-6-en-1-yl-
oxy)carbonyl]amino}acetyl)-L-prolinate
##STR00232##
[0514] To a solution of the product from Step 2 (297 mg, 0.77 mmol)
in DMF (7 mL), Intermediate B16 (254 mg, 0.85 mmol), DIEA (0.62 mL,
3.55 mmol), HOBT (131 mg, 0.85 mmol), and EDC (163 mg, 0.85 mmol)
were added. After stirring overnight, the mixture was extracted
with 1N HCl and EtOAc. The organic layer was washed with H.sub.2O
and brine, and then dried over MgSO.sub.4. The solvent was removed
in vacuo, and the crude product was purified on SiO.sub.2 (gradient
elution, 0-40% EtOAc/hexanes) to yield 111 mg of the title
compound. LRMS ESI.sup.+ (M+H).sup.+ 631.3.
Step 4: Methyl
(10S,13S,15R)-10-cyclohexyl-1-methylene-8,11-dioxo-1,2,3,4,5,6,8,9,10,11,-
14,15-dodecahydro-13H-12,15-methanonaphtho[2,1-k][1,10,3,6]dioxadiazacyclo-
octadecine-13-carboxylate
##STR00233##
[0516] To a solution of a portion of the product from Step 3 (111
mg, 0.176 mmol) in EtOH (3.5 mL) was added TEA (0.037 mL, 0.26
mmol), and PdCl.sub.2(dppf)-DCM complex (7.2 mg, 0.008 mmol). The
mixture was then heated to reflux for 48 hours. The EtOH was
removed in vacuo, taken up in EtOAc, and washed with H.sub.2O. The
organic layer was then dried over MgSO.sub.4, and the solvent was
removed in vacuo. The crude product was purified on SiO.sub.2
(gradient elution, 0-40% EtOAc/hexanes) to yield 51 mg of the title
compound. LRMS ESI.sup.+ ((M-Boc)+H).sup.+ 549.3.
Step 5:
(10S,13S,15R)-10-Cyclohexyl-1-methylene-8,11-dioxo-1,2,3,4,5,6,8,9-
,10,11,14,15-dodecahydro-13H-12,15-methanonaphtho[2,1-k][1,10,3,6]dioxadia-
zacyclooctadecine-13-carboxylic acid
##STR00234##
[0518] To a solution of a portion of the product from Step 4 (37
mg, 0.067 mmol) in THF (1.0 mL), EtOH (1.0 mL) and H.sub.2O (1.0
mL), LiOH.H.sub.2O (16 mg, 0.67 mmol) was added. After 1 hour, 1N
HCl and Et.sub.2O were added. The organic layer was separated, and
the aqueous layer was washed with EtOAc. The combined organic
layers were then dried over MgSO.sub.4, and the solvent was removed
in vacuo to yield 34 mg of the title compound. LRMS ESI.sup.+
(M+H).sup.+ 535.3.
Step 6:
(10S,13S,15R)-10-Cyclohexyl-N-((1R,2S)-1-{[(cyclopropylsulfonyl)am-
ino]carbonyl}-2-vinylcyclopropyl)-1-methylene-8,11-dioxo-1,2,3,4,5,6,8,9,1-
0,11,14,15-dodecahydro-13H-12,15-methanonaphtho[2,1-k][1,10,3,6]dioxadiaza-
cyclooctadecine-13-carboxamide
[0519] To a solution of a portion of the product from Step 5 (34
mg, 0.064 mmol) in DCM (6.4 mL), Intermediate A1 (19 mg, 0.070
mmol), DIEA (0.028 mL, 0.16 mmol), HATU (27 mg, 0.070 mmol), and
DMAP (2.3 mg, 0.019 mmol) were added. After overnight stirring, the
mixture was partitioned between EtOAc and 1N HCl. The organic layer
was separated, dried over MgSO.sub.4, and the solvent was removed
in vacuo. The crude product was purified by reverse-phase
chromatography to yield the title compound as a white powder. LRMS
ESI.sup.+ (M+H).sup.+ 747.3.
Example 72
(4R,6S,9S)-19-Bromo-9-butyl-N-((1R,2S)-1-{[(cyclopropylsulfonyl)amino]carb-
onyl}-2-vinylcyclopropyl)-16-methylene-8,11-dioxo-3,12-dioxa-7,10-diazatri-
cyclo[15.3.1.1.sup.4,7]docosa-1(21),17,19-triene-6-carboxamide
##STR00235##
[0520] Step 1: Methyl
N-[(pent-4-en-1-yloxy)carbonyl]-L-norleucyl-(4R)-4-[(3,5-dibromobenzyl)ox-
y]-L-prolinate
##STR00236##
[0522] The title compound was prepared according to the procedure
given in Example 24, Steps 1-3 using
1,3-dibromo-5-(bromomethyl)benzene in place of
1-bromo-3-(bromomethyl)benzene.
Step 2: Methyl
(4R,6S,9S)-19-bromo-9-butyl-16-methylene-8,11-dioxo-3,12-dioxa-7,10-diaza-
tricyclo[15.3.1.1.sup.4,7]docosa-1(21),17,19-triene-6-carboxylate.
##STR00237##
[0524] To a solution of a portion of the product from Step 1 (250
mg, 0.404 mmol) in EtOH (81 mL), TEA (0.085 mL, 0.61 mmol), and
PdCl.sub.2(dppf)-DCM complex (16.5 mg, 0.02 mmol) were added. The
mixture was then heated to reflux overnight. The EtOH was removed
in vacuo, taken up in EtOAc, and washed with H.sub.2O. The organic
layer was then dried over MgSO.sub.4, and the solvent was removed
in vacuo. The crude product was purified on SiO.sub.2 (gradient
elution, 0-50% EtOAc/hexanes) to yield the title compound. LRMS
ESI.sup.+ ((M-Boc)+H).sup.+ 549.3.
Step 3:
(4R,6S,9S)-19-Bromo-9-butyl-N-((1R,2S)-1-{[(cyclopropylsulfonyl)am-
ino]carbonyl}-2-vinylcyclopropyl)-16-methylene-8,11-dioxo-3,12-dioxa-7,10--
diazatricyclo[15.3.1.1.sup.4,7]docosa-1(21),17,19-triene-6-carboxamide
[0525] Using the product from Step 2, the title compound was
prepared according to Example 1 using Intermediate A1. LRMS
ESI.sup.+. ((M-Boc)+H).sup.+ 737.4.
Example 73
((5R,7S,10S,19E)-10-t-Butyl-N-((1R,2S)-1-{[(cyclopropylsulfonyl)amino]carb-
onyl}-2-vinylcyclopropyl)-9,12-dioxo-1,2-didehydro-3,6,7,9,10,11,12,14,15,-
16,17,18-dodecahydro-5H-5,8-methano-4,13,8,11-benzodioxadiazacyclodocosine-
-7-carboxamide
##STR00238##
[0526] Step 1: 1-t-Butyl
2-methyl(2S,4R)-4-(prop-2-yn-1-yloxy)pyrrolidine-1,2-dicarboxylate
##STR00239##
[0528] To a solution of 1-t-butyl
2-methyl(2S,4R)-4-hydroxypyrrolidine-1,2-dicarboxylate (1.0 g, 4.08
mmol) and propargyl bromide (2.262 ml, 20.39 mmol) in PhCH.sub.3
(40.8 mL) cooled to 0.degree. C., NaH (0.815 g, 20.39 mmol) was
added. After 3.5 hours, the reaction was warmed to RT. After 3
days, the reaction was complete and was worked up with H.sub.2O and
EtOAc, and then brine. The organic layer was dried over MgSO.sub.4,
and the solvent was removed in vacuo to give 1.33 g of crude
material. This was purified on SiO.sub.2 (gradient elution, 0-40%
EtOAc/hexanes) to yield 737 mg of the title compound. LRMS
ESI.sup.+ ((M-Boc)+H).sup.+ 184.2.
Step 2: 1-t-Butyl
2-methyl(2S,4R)-4-{[3-(2-bromophenyl)prop-2-yn-1-yl]oxy}pyrrolidine-1,2-d-
icarboxylate
##STR00240##
[0530] To a degassed solution of the product from Step 1 (735 mg,
2.59 mmol) and 1-bromo-2-iodobenzene (0.366 mL, 2.85 mmol) in TEA
(8.647 mL), PdCl.sub.2(PPh.sub.3).sub.2 (18.21 mg, 0.026 mmol) and
CuI (4.94 mg, 0.026 mmol) were added. The reaction was then heated
to 50.degree. C. After 2.5 hours, the reaction was worked up with
H.sub.2O and EtOAc. The organic layer was washed with H.sub.2O and
brine, dried over MgSO.sub.4, and the solvent was removed in vacuo
to yield 1.35 g of the title compound which was used directly in
further reactions. LRMS ESI.sup.+ ((M-Boc)+H).sup.+ 340.2.
Step 3: Methyl
(4R)-4-{[3-(2-bromophenyl)prop-2-yn-1-yl]oxy}-L-prolinate
hydrochloride
##STR00241##
[0532] To the product from Step 2 (1.14 g, 2.60 mmol), HCl/dioxane
(32.5 mL, 130 mmol) was added at RT. After 1 hour and 45 minutes,
the dioxane was removed in vacuo to yield 1.0 g of the title
compound as a dark oil. LRMS ESI.sup.+ (M+H).sup.+ 340.2.
Step 4: Methyl
N-[(hept-6-en-1-yloxy)carbonyl]-3-methyl-L-valyl-(4R)-4-{[3-(2-bromopheny-
l) prop-2-yn-1-yl]oxy}-L-prolinate
##STR00242##
[0534] Using the procedure from Example 1 Step 4, the title
compound was prepared starting with the product from Step 3 and
Intermediate B7. LRMS ESI.sup.+ (M+H).sup.+ 593.2.
Step 5: Methyl
N-[(hept-6-en-1-yloxy)carbonyl]-3-methyl-L-valyl-(4R)-4-{[3-(2-vinylpheny-
l) prop-2-yn-1-yl]oxy}-L-prolinate
##STR00243##
[0536] To degassed solution of the product from Step 4 (715 mg,
1.209 mmol) in PhMe (12.100 mL), vinyltributyltin (0.500 mL, 1.450
mmol) and Pd(PPh.sub.3).sub.4 (27.9 mg, 0.024 mmol) were added. The
reaction was then heated to reflux. After 24 hours, the solvent was
then removed in vacuo, and the crude material was purified on
SiO.sub.2 (gradient elution, 0-40% EtOAc/hexanes) to yield 292 mg
of the title compound. LRMS ESI.sup.+ (M+H).sup.+ 539.3.
Step 6: Methyl
N-[(hept-6-en-1-yloxy)carbonyl]-3-methyl-L-valyl-(4R)-4-{[3-(2-vinylpheny-
l) prop-2-yn-1-yl]oxy}-L-prolinate-dicobalt hexacarbonyl
complex
##STR00244##
[0538] To a solution of the product from Step 5 (95 mg, 0.176 mmol)
in DCM (8 mL), dicobaltoctacarbonyl (121 mg, 0.353 mmol) was added
under N.sub.2. This produces a dark red solution. After 30 minutes,
the solvent was concentrated in vacuo to approximately 1 mL and the
crude material was purified on SiO.sub.2 (gradient elution, 0-35%
EtOAc/hexanes) to yield 75 mg of the title compound as a red
oil.
Step 7: Methyl
(5R,7S,10S,19E)-10-t-butyl-9,12-dioxo-1,2-didehydro-3,6,7,9,10,11,12,14,1-
5,16,17,18-dodecahydro-5H-5,8-methano-4,13,8,11-benzodioxadiazacyclodocosi-
ne-7-carboxylate-dicobalt hexacarbonyl complex
##STR00245##
[0540] To a degassed solution of the product from Step 6 (75 mg,
0.090 mmol) in DCE (18.100 mL), the Zhan 1b catalyst (6.63 mg, 9.03
.mu.mol) was added. The mixture was then stirred at RT under
N.sub.2. After 19 hours, the mixture was then concentrated to
approximately 1 mL and purified on SiO.sub.2 (gradient elution,
0-30% EtOAc/hexanes) to yield 25 mg of the title compound as a red
oil along with 43 mg of recovered methyl
N-[(hept-6-en-1-yloxy)carbonyl]-3-methyl-L-valyl-(4R)-4-{[3-(2-vin-
ylphenyl)prop-2-yn-1-yl]oxy}-L-prolinate-dicobalt hexacarbonyl
complex.
Step 8: Methyl
(5R,7S,10S,19E)-10-t-butyl-9,12-dioxo-1,2-didehydro-3,6,7,9,10,11,12,14,1-
5,16,17,18-dodecahydro-5H-5,8-methano-4,13,8,11-benzodioxadiazacyclodocosi-
ne-7-carboxylate
##STR00246##
[0542] To a solution of the product from Step 7 (25 mg, 0.031 mmol)
in acetone (2 mL) cooled to -10.degree. C., CAN (102 mg, 0.187
mmol) was added in portions. After completion, the reaction was
quenched with DIEA (0.098 mL, 0.561 mmol), which caused a brown
precipitate to form. The mixture was then filtered through neutral
alumina with acetone as the eluent to yield 35 mg crude material.
This was purified on SiO.sub.2 (gradient elution, 0-35%
EtOAc/hexanes) to yield 12 mg of the title compound. LRMS ESI.sup.+
(M+H).sup.+ 511.5.
Step 9:
((5R,7S,10S,19E)-10-t-Butyl-N-((1R,2S)-1-{[(cyclopropylsulfonyl)am-
ino]carbonyl}-2-vinylcyclopropyl)-9,12-dioxo-1,2-didehydro-3,6,7,9,10,11,1-
2,14,15,16,17,18-dodecahydro-5H-5,8-methano-4,13,8,11-benzodioxadiazacyclo-
docosine-7-carboxamide
[0543] Using the product from Step 8, the title compound was
prepared according to the procedure in Example 1, Steps 6 and 7.
LRMS ESI.sup.+ (M+H).sup.+ 709.3
Example 74
[0544]
(5R,7S,10S)-10-t-Butyl-N-((1R,2S)-1-{[(cyclopropylsulfonyl)amino]ca-
rbonyl}-2-vinylcyclopropyl)-9,12-dioxo-1,2,3,6,7,9,10,11,12,14,15,16,17,18-
,19,20-hexadecahydro-5H-5,8-methano-4,13,8,11-benzodioxadiazacyclodocosine-
-7-carboxamide
##STR00247##
Step 1: Methyl
(5R,7S,10S)-10-t-butyl-9,12-dioxo-1,2,3,6,7,9,10,11,12,14,15,16,17,18,19,-
20-hexadecahydro-5H-5,8-methano-4,13,8,11-benzodioxadiazacyclodocosine-7-c-
arboxylate
##STR00248##
[0546] To a solution of the product from Example 73 Step 8 (24 mg,
0.047 mmol) in EtOAc (2 mL), 10% Pd/C (2.501 mg, 2.350 .mu.mol) was
added under H.sub.2. After 90 minutes, the mixture was then
filtered through a glass wool pad with EtOAc as the eluent. The
solvent was removed in vacuo to yield 22 mg of the title compound.
LRMS ESI.sup.+ (M+H).sup.+ 517.5.
Step 2:
(5R,7S,10S)-10-t-Butyl-N-((1R,2S)-1-{[(cyclopropylsulfonyl)amino]c-
arbonyl}-2-vinylcyclopropyl)-9,12-dioxo-1,2,3,6,7,9,10,11,12,14,15,16,17,1-
8,19,20-hexadecahydro-5H-5,8-methano-4,13,8,11-benzodioxadiazacyclodocosin-
e-7-carboxamide
[0547] The title compound was prepared according to the procedure
in Example 1 Steps 6 and 7, starting from the product from Step 1.
LRMS ESI.sup.+ (M+H).sup.+ 715.4.
Example 75
(9R,11S,14S)-14-t-Butyl-N-((1R,2S)-1-{[(cyclopropylsulfonyl)amino]carbonyl-
}-2-vinylcyclopropyl)-13,16-dioxo-6,7,10,11,13,14,15,16,18,19,20,21,22,23--
tetradecahydro-5H,9H-9,12-methanopyrido[3,2-n][1,10,3,6]dioxadiazacyclohen-
icosine-11-carboxamide
##STR00249##
[0549] The title compound was prepared according to the Example 73
Steps 1-9, using 2-chloro-3-iodopyridine in place of
1-bromo-2-iodobenzene in Step 2. LRMS ESI.sup.+ (M+H).sup.+
702.6.
Example 76
[0550]
(6R,8S,11S,20E)-11-t-Butyl-N-((1R,2S)-1-{[(cyclopropylsulfonyl)amin-
o]carbonyl}-2-vinylcyclopropyl)-10,13-dioxo-5,14-dioxa-9,12-diazatricyclo[-
20.3.1.1.sup.6,9]heptacosa-1(26),20,22,24-tetraen-2-yne-8-carboxamide
##STR00250##
[0551] The title compound was prepared according to the Example 73
Steps 1-9, using 1-bromo-3-iodobenzene in place of
1-bromo-2-iodobenzene in Step 2. LRMS ESI.sup.+ (M+H).sup.+
709.5.
Example 77
[0552]
(6R,8S,11S)-11-t-Butyl-N-((1R,2S)-1-{[(cyclopropylsulfonyl)amino]ca-
rbonyl}-2-vinylcyclopropyl)-10,13-dioxo-5,14-dioxa-9,12-diazatricyclo[20.3-
.1.1.sup.6,9]heptacosa-1(26),22,24-triene-8-carboxamide
##STR00251##
[0553] The title compound was prepared according to the procedures
in Examples 73 Steps 1-8 and Example 74 Steps, 1-2 using
1-bromo-3-iodobenzene in place of 1-bromo-2-iodobenzene in Example
73 Step 2. LRMS ESI.sup.+ (M+H).sup.+ 715.5.
Example 78
(1R,2S)-1-({[(1R,16S,19S)-16-Isopropyl-14,17-dioxo-2,13-dioxa-5,6,7,15,18--
pentaazatricyclo[16.2.1.1.sup.4,7]docosa-4(22),5-dien-19-yl]carbonyl}amino-
)-2-vinylcyclopropanecarboxylic acid
##STR00252##
[0554] Step 1: 1-t-Butyl
2-methyl(2S,4R)-4-({1-[5-(acetyloxy)pentyl]-1H-1,2,3-triazol-4-yl}methoxy-
)pyrrolidine-1,2-dicarboxylate
##STR00253##
[0556] To a solution of the product from Example 77 Step 1 (803 mg,
2.834 mmol) and 5-azidopentyl acetate (509 mg, 2.97 mmol) in t-BuOH
(6.67 mL) and H.sub.2O (6.67 mL), ascorbic acid (112 mg, 0.567
mmol) and copper (II) sulfate (23 mg, 0.142 mmol) were added. After
24 hours, the mixture was extracted with H.sub.2O and DCM. The
organic layer was dried over MgSO.sub.4, and the solvent was
removed in vacuo. The crude product was purified on SiO.sub.2
(gradient elution, 0-10% MeOH/DCM) to yield 1.2 g of the title
compound. LRMS ESI.sup.+ (M+H).sup.+ 455.5.
Step 2: 1-t-Butyl
2-methyl(2S,4R)-4-[(1-{5-[({[(1S)-1-(t-butoxycarbonyl)-2-methylpropyl]ami-
no}carbonyl)oxy]pentyl}-1H-1,2,3-triazol-4-yl)methoxy]pyrrolidine-1,2-dica-
rboxylate
##STR00254##
[0558] To a solution of the product from Step 1 (120 mg, 0.264
mmol) in MeOH (5 mL), K.sub.2CO.sub.3 (365 mg, 2.64 mmol) was
added. After 30 minutes, the solids were filtered, and the mixture
was extracted with EtOAc and 0.5N HCl. The organic layer was dried
over K.sub.2CO.sub.3, and the solvent was removed in vacuo to yield
1-t-butyl
2-methyl(2S,4R)-4-{([1-(5-hydroxypentyl)-1H-1,2,3-triazol-4-yl]methoxy}py-
rrolidine-1,2-dicarboxylate. To a solution of this material in PhMe
(5 mL), t-butyl N-(oxomethylene)-L-valinate (46 mg, 230 mmol) was
added, and the solution was heated to reflux for 3 days. The
solvent was then removed in vacuo, and the crude product was
purified on SiO.sub.2 (gradient elution, 0-10% MeOH/DCM) to yield
130 mg of the title compound. LRMS ESI.sup.+ (M+H).sup.+ 612.5.
Step 3: Methyl
(1R,16S,19S)-16-isopropyl-14,17-dioxo-2,13-dioxa-5,6,7,15,18-pentaazatric-
yclo[16.2.1.1.sup.4,7]docosa-4(22),5-diene-19-carboxylate
##STR00255##
[0560] To the product from Step 2 (60 mg, 0.098 mmol), 4N
HCl/dioxane (1.7 mL, 6.8 mmol) was added. After 12 hours, the
solvent was removed in vacuo, and the residue was taken up in DCM
(25 mL), and DIEA (0.088 mL, 0.49 mmol) and TBTU (47 mg, 0.147
mmol) were added. After 19 hours, the mixture was extracted with 1N
HCl. The organic layer was dried over MgSO.sub.4, and the solvent
was removed in vacuo. The crude product was purified by
reverse-phase chromatography to yield the title compound. LRMS
ESI.sup.+ (M+H).sup.+ 438.4.
Step 4:
(1R,2S)-1-({[(1R,16S,19S)-16-Isopropyl-14,17-dioxo-2,13-dioxa-5,6,-
7,15,18-pentaazatricyclo[16.2.1.1.sup.4,7]docosa-4(22),5-dien-19-yl]carbon-
yl}amino)-2-vinylcyclopropanecarboxylic acid
[0561] Starting from the product of Step 3, the title compound was
prepared according to the procedures in Example 5 Step 7. LRMS
ESI.sup.+ (M+H).sup.+ 533.3.
Example 79
(1R,16S,19S)--N-((1R,2S)-1-{[(Cyclopropylsulfonyl)amino]carbonyl}-2-vinylc-
yclopropyl)-16-isopropyl-14,17-dioxo-2,13-dioxa-5,6,7,15,18-pentaazatricyc-
lo[16.2.1.1.sup.4,7]docosa-4(22),5-diene-19-carboxamide
##STR00256##
[0563] The title compound was prepared starting from the product of
Example 78 Step 4 using the procedure outlined in Example 6. LRMS
ESI.sup.+ (M+H).sup.+ 636.4.
Example 80
(4R,6S,9S)-9-t-Butyl-6-{[((1R,2S)-1-{[(cyclopropylsulfonyl)amino]carbonyl}-
-2-vinylcyclopropyl)amino]carbonyl}-8,11-dioxo-3,12-dioxa-7,10-diaza-22-az-
oniatricyclo[16.3.1.1.sup.4,7]tricosane trifluoroacetate
##STR00257##
[0564] Step 1: Methyl
(4R,6S,9S,16E)-9-t-butyl-8,11-dioxo-3,12-dioxa-7,10,22-triazatricyclo[16.-
3.1.1.sup.4,7]tricosa-1(22),16,18,20-tetraene-6-carboxylate
##STR00258##
[0566] The title compound was prepared according to the procedure
in Example 26, using (6-bromopyridin-2-yl)methyl methanesulfonate
in place of 1-bromo-3-(bromomethyl)benzene in Step 1 and
Intermediate B2 in place of B1. LRMS ESI.sup.+ (M+H).sup.+
460.4.
Step 2: Methyl
(4R,6S,9S)-9-t-butyl-8,11-dioxo-3,12-dioxa-7,10,22-triazatricyclo[16.3.1.-
1.sup.4,7]tricosane-6-carboxylate
##STR00259##
[0568] To a solution of the product from Step 1 (210 mg, 0.457
mmol) in EtOH (5 mL), 10% Pd/C (20 mg) was added. The mixture was
then placed under H.sub.2. After 18 hours, the starting material
was consumed, and methyl
(4R,6S,9S)-9-t-butyl-8,11-dioxo-3,12-dioxa-7,10,22-triazatricyclo[-
16.3.1.1.sup.4,7]tricosa-1(22),18,20-triene-6-carboxylate was
formed along with the title compound in .about.1.5:1 ratio. LRMS
ESI.sup.+ (M+H).sup.+ 468.4.
Step 3:
(4R,6S,9S)-9-t-Butyl-6-{[((1R,2S)-1-{[(cyclopropylsulfonyl)amino]c-
arbonyl}-2-vinylcyclopropyl)amino]carbonyl}-8,11-dioxo-3,12-dioxa-7,10-dia-
za-22-azoniatricyclo[16.3.1.1.sup.4,7]tricosane
trifluoroacetate
[0569] Using the product from Step 2, the title compound was
prepared using the procedures outlined in Example 1 Steps 6 and 7.
LRMS ESI.sup.+ (M+H).sup.+ 666.4.
Example 82
(4R,6S,9S,19aS,23aS)-9-t-Butyl-N-((1R,2S)-1-{[(cyclopropylsulfonyl)amino]c-
arbonyl}-2-vinylcyclopropyl)-2,8,11-trioxoicosahydro-2H,13H-4,7-methano-1,-
12,3,7,10-benzodioxatriazacyclohenicosine-6-carboxamide
##STR00260##
[0570] Step 1: Methyl
(4R)-4-[({[2-allylcyclohexyl]oxy}carbonyl)amino]-L-prolinate
hydrochloride
##STR00261##
[0572] To a solution of racemic trans-2-allylcyclohexanol (200 mg,
1.42 mmol) in DMF (2 mL), CDI (0.23 g, 1.42 mmol) was added. After
1 hour, 1-t-butyl
2-methyl(2S,4R)-4-aminopyrrolidine-1,2-dicarboxylate (0.35 g, 1.42
mmol) was added, and the mixture was heated to 60.degree. C. After
complete conversion, the mixture was extracted with EtOAc and
NH.sub.4Cl.sub.(aq.). The organic layer was dried over
Na.sub.2SO.sub.4, and the solvent was removed in vacuo. The crude
material was purified on SiO.sub.2 (gradient elution, 5-45%
EtOAc/hexanes) to yield 170 mg of 1-t-butyl
2-methyl(2S,4R)-4-({[(2-allylcyclohexyl)oxy]carbonyl}amino)pyrr-
olidine-1,2-dicarboxylate. This material was dissolved in DCM/THF
(5 mL), and HCl gas was bubbled through the mixture until complete
removal of the Boc group. The solvent was then removed in vacuo to
yield the title compound as a mixture of trans-diastereomers. LRMS
ESI.sup.+ (M+H).sup.+ 311.4.
Step 2: Methyl
N-[(hex-5-en-1-yloxy)carbonyl]-3-methyl-L-valyl-(4R)-4-({[(2-allylcyclohe-
xyl)oxy]carbonyl}amino)-L-prolinate
##STR00262##
[0574] To a solution of the product of Step 1 (170 mg, 0.49 mmol)
in DCM (10 mL), Intermediate B10 (132 mg, 0.515 mmol), Et.sub.3N
(0.27 mL, 1.96 mmol), EDC (113 mg, 0.588 mmol), and HOBT (90 mg,
0.588 mmol) were added. After 24 hours, the mixture was extracted
with H.sub.2O and then KHSO.sub.4(aq.). The organic layer was dried
over MgSO.sub.4, and the solvent was removed in vacuo. The crude
material was purified on SiO.sub.2 (50% EtOAc/hexanes) to yield 222
mg of the title compound as a mixture of trans-diastereomers. LRMS
ESI.sup.+ (M+H).sup.+ 550.5.
Step 3: Methyl
(4R,6S,9S,17E/Z)-9-t-butyl-2,8,11-trioxo-3,4,5,6,8,9,10,11,14,15,16,19,19-
a,20,21,22,23,23a-octadecahydro-2H,13H-4,7-methano-1,12,3,7,10-benzodioxat-
riazacyclohenicosine-6-carboxylate
##STR00263##
[0576] To a solution of a portion of the product from Step 3 (222
mg, 0.40 mmol) in DCE (80 mL), the Zhan la catalyst (30 mg, 0.04
mmol) and the mixture was heated to reflux under N.sub.2. After 90
minutes, the mixture was concentrated in vacuo, and the crude
product was purified on SiO.sub.2 (gradient elution, 10-50%
EtOAc/hexanes) to yield 105 mg of the title compound as a mixture
of olefin isomers and trans-diastereomers. LRMS EsI.sup.+
(M+H).sup.+ 522.5.
Step 4: Methyl
(4R,6S,9S)-9-t-butyl-2,8,11-trioxoicosahydro-2H,13H-4,7-methano-1,12,3,7,-
10-benzodioxatriazacyclohenicosine-6-carboxylate
##STR00264##
[0578] To a solution of a portion of the product from Step 3 (105
mg, 0.20 mmol) in EtOAc (15 mL) was added 10% Pd/C (10 mg). The
mixture was then place under H.sub.2, stirred for 3 days, and
filtered through a pad of glass wool. The solvent was then removed
in vacuo to yield 105 mg of the title compound as a mixture of
trans-diastereomers. LRMS ESI.sup.+ (M+H).sup.+ 524.3.
Step 5:
(4R,6S,9S,19aS,23aS)-9-t-Butyl-N-((1R,2S)-1-{[(cyclopropylsulfonyl-
)amino]carbonyl}-2-vinylcyclopropyl)-2,8,11-trioxoicosahydro-2H,13H-4,7-me-
thano-1,12,3,7,10-benzodioxatriazacyclohenicosine-6-carboxamide
[0579] Using the product from Step 4, the title compound was
prepared by the procedure outlined in Example 1, Steps 6 and 7.
LRMS ESI.sup.+ (M+H).sup.+ 722.4.
Example 83
(1R,2S)-1-({[(2R,4S,7S)-7-Isopropyl-6,9,15-trioxo-3,4,6,7,8,9,12,13,14,15--
decahydro-2H,11H,17H-16,18-ethano-2,5-methano-1,10,5,8,16-benzodioxatriaza-
cyclononadecin-4-yl]carbonyl}amino)-2-vinylcyclopropanecarboxylic
acid
##STR00265##
[0580] Step 1:
8-[(Triisopropylsilyl)oxy]-1,2,3,4-tetrahydroisoquinoline
##STR00266##
[0582] 8-Methoxy-1,2,3,4-tetrahydroisoquinoline (3.5 g, 17.5 mmol)
was dissolved in 48% HBr.sub.(aq.) (50 mL), and the mixture was
stirred for 18 hours. The solids were then filtered, and the
filtrate was concentrated to yield 3.43 g of
1,2,3,4-tetrahydroisoquinolin-8-ol hydrobromide. To a solution of
1,2,3,4-tetrahydroisoquinolin-8-ol hydrobromide (2.85 g, 12.4 mmol)
in THF (75 mL), DIEA (7.57 mL, 43.3 mmol) and TIPSOTf (8.3 g, 27.2
mmol) were added. The mixture was then heated to reflux for 8
hours. The solvent was then removed in vacuo, and the residue
partitioned between EtOAc and H.sub.2O. The organic layer was
washed with brine, dried, and the solvent was removed in vacuo. The
crude product was purified on SiO.sub.2 (gradient elution, 50/50
EtOAc/hexanes -90/10/1 EtOAc/MeOH/NH.sub.4OH) to yield 4.2 g of the
title compound. LRMS ESI.sup.+ (M+H).sup.+ 306.4.
Step 2:
5-Oxo-5-[8-[(triisopropylsilyl)oxy]-3,4-dihydroisoquinolin-2(1H)-y-
l]pentan-1-ol
##STR00267##
[0584] To a solution of a portion of the product from Step 1 (900
mg, 2.94 mmol) in DMF (9 mL) and H.sub.2O (9 mL), TEA (0.74 mL, 5.3
mmol), sodium 5-hydroxypentanoate (1.24 g, 8.8 mol), EDC (621 mg,
3.24 mmol), and HOBT (495 mg, 3.24 mmol) were added. After 2 hours,
the mixture was extracted with EtOAc and H.sub.2O. The organic
layer was washed with NaHCO.sub.3(aq.) and brine, dried over
Na.sub.2SO.sub.4, and the solvent was removed in vacuo. The crude
product was purified on SiO.sub.2 (gradient elution, 40-100%
EtOAc/hexanes) to yield the title compound. LRMS ESI.sup.+
(M+H).sup.+ 406.3.
Step 3: t-Butyl
N-({[5-(8-hydroxy-3,4-dihydroisoquinolin-2(1H)-yl)-5-oxopentyl]oxy}carbon-
yl)-L-valinate
##STR00268##
[0586] To solution of a portion of the product from Step 2 (285 mg,
0.7 mmol) in toluene (1 mL), t-butyl N-(oxomethylene)-L-valinate
(0.28 g, 1.4 mmol) was added. The mixture was then heated to reflux
for 18 hours. The solvent was then removed in vacuo, and the crude
product was taken up in THF (5 mL), and TBAF (1.05 mL, 1M solution
in THF, 1.05 mmol) was added. After overnight, the solvent was
removed in vacuo, and the residue was taken up in EtOAc, extracted
with NaHCO.sub.3(aq.), and dried over Na.sub.2SO.sub.4. The solvent
was removed in vacuo. The crude material was purified on SiO.sub.2
(gradient elution, 25-80% EtOAc/hexanes) to yield the title
compound. LRMS ESI.sup.+ (M+H).sup.+ 449.5.
Step 4: Methyl
(4R)-4-[(2-{5-[({[(1S)-1-(t-butoxycarbonyl)-2-methylpropyl]amino}carbonyl-
)
oxy]pentanoyl}-1,2,3,4-tetrahydroisoquinolin-8-yl)oxy]-L-prolinate
hydrochloride
##STR00269##
[0588] To a solution of a portion of the product from Step 3 (0.24
g, 0.53 mmol) and 1-t-butyl
2-methyl(2S,4S)-4-{[(4-bromophenyl)sulfonyl]oxy}pyrrolidine-1,2-dicarboxy-
late (0.25 g, 0.53 mmol) in NMP (5 ml) under N.sub.2,
Cs.sub.2CO.sub.3 (0.259 g, 0.796 mmol) was added. The mixture was
then heated to 40.degree. C. After 24 hours, the reaction was
complete, and H.sub.2O and EtOAc were added. The organic layer was
then extracted with H.sub.2O (3.times.), NaHCO.sub.3 (2.times.) and
brine (2.times.). The organic layer was dried over MgSO.sub.4, and
the solvent was removed in vacuo. The crude product was purified on
SiO.sub.2 (gradient elution, 30-100% EtOAc/hexanes) to yield
1-t-butyl 2-methyl
(2S,4R)-4-[(2-{5-[({[(1S)-1-(t-butoxycarbonyl)-2-methylpropyl]amino}carbo-
nyl)
oxy]pentanoyl}-1,2,3,4-tetrahydroisoquinolin-8-yl)oxy]pyrrolidine-1,2-
-dicarboxylate. This material was then dissolved in 4N HCl/dioxane
(5 mL) and stirred at RT for 3 hours. The solvent was then removed
in vacuo to yield the title compound as a brown oil. LRMS ESI.sup.+
(M+H).sup.+ 520.4.
Step 5:
(2R,4S,7S)-7-Isopropyl-6,9,15-trioxo-3,4,6,7,8,9,12,13,14,15-decah-
ydro-2H,11H,17H-16,18-ethano-2,5-methano-1,10,5,8,16-benzodioxatriazacyclo-
nonadecine-4-carboxylic acid
##STR00270##
[0590] To a solution of the product from Step 4 (230 mg, 0.44 mmol)
in DCM (40 mL), TEA (0.128 mL, 1.3 mmol), EDC (93 mg, 0.49 mmol),
and HOBT (66 mg, 487 mmol) were added. After 18 hours, the mixture
was extracted with NaHCO.sub.3(aq.), dried over MgSO.sub.4, and
concentrated in vacuo. The crude product was purified on SiO.sub.2
(gradient elution, 50% EtOAc/hexanes -90/10/1
EtOAc/MeOH/NH.sub.4OH) to yield methyl
(2R,4S,7S)-7-isopropyl-6,9,15-trioxo-3,4,6,7,8,9,12,13,14,15-decahydro-2H-
,11H,17H-16,18-ethano-2,5-methano-1,10,5,8,16-benzodioxatriazacyclononadec-
ine-4-carboxylate. This material was then dissolved in MeOH (0.5
mL), THF (5 mL) and 1N LiOH (5 mL, 5 mmol), and solid LiOH (100 mg,
2.3 mmol) was added. After 1 hour, 10% citric acid was added to
adjust the pH to .about.3. EtOAc was then added, and following
extraction, the organic layer was dried over Na.sub.2SO.sub.4, and
the solvent was removed in vacuo to yield 100 mg of the title
compound. LRMS ESI.sup.+ (M+H).sup.+ 488.3.
Step 6:
(1R,2S)-1-({[(2R,4S,7S)-7-Isopropyl-6,9,15-trioxo-3,4,6,7,8,9,12,1-
3,14,15-decahydro-2H,11H,17H-16,18-ethano-2,5-methano-1,10,5,8,16-benzodio-
xatriazacyclononadecin-4-yl]carbonyl}amino)-2-vinylcyclopropanecarboxylic
acid
[0591] The title compound was prepared according to the procedure
outlined in Example 5, Step 7 using the product from Step 5. LRMS
ESI.sup.+ (M+H).sup.+ 597.3.
Example 84
(2R,4S,7S)-7-t-Butyl-N-((1R,2R)-1-{[(cyclopropylsulfonyl)amino]carbonyl}-2-
-ethylcyclopropyl)-6,9-dioxo-10-oxa-1,5,8,17,18-pentaazatricyclo[14.2.1.1.-
sup.2,5]icosa-16(19),17-diene-4-carboxamide
##STR00271##
[0592] Step 1:
N-{[(5-{1-[(3R,5S)-14-Butoxycarbonyl)-5-(methoxycarbonyl)pyrrolidin-3-yl]-
-1H-1,2,3-triazol-4-yl]pentyl)oxy}carbonyl}-3-methyl-L-valine
##STR00272##
[0594] To a solution of 1-t-butyl
2-methyl(2S,4R)-4-azidopyrrolidine-1,2-dicarboxylate (400 mg, 1.48
mmol) and Intermediate B18 (438 mg, 1.63 mmol) in t-BuOH (6 mL) and
H.sub.2O (6 mL), ascorbic acid (59 mg, 0.296 mmol) and copper(II)
sulfate (16.5 mg, 0.074 mmol) were added. After overnight stirring,
the mixture was extracted with H.sub.2O and EtOAc. The organic
layer was dried over MgSO.sub.4, and the solvent was removed in
vacuo to yield 799 mg of the title compound. LRMS ESI.sup.+
(M+H).sup.+ 540.4.
Step 2:
N-{[(5-{1-[(3R,5S)-5-(Methoxycarbonyl)pyrrolidin-3-yl]-1H-1,2,3-tr-
iazol-4-yl}pentyl)oxy]carbonyl}-3-methyl-L-valine hydrochloride
##STR00273##
[0596] To the product from Step 1 (799 mg, 1.48 mmol), 4N
HCl/dioxane (11.1 mL, 44.4 mmol) was added. After stirring
overnight, the solvent was removed in vacuo to yield 705 mg of the
title compound. LRMS ESI.sup.+ ((M-Boc)+H).sup.+ 440.4.
Step 3: Methyl
(2R,4S,7S)-7-t-butyl-6,9-dioxo-10-oxa-1,5,8,17,18-pentaazatricyclo[14.2.1-
.1.sup.2,5]icosa-16(19),17-diene-4-carboxylate
##STR00274##
[0598] To a solution of the product from Step 2 (705 mg, 1.604
mmol) in DCM (200 mL), DIEA (0.84 mL, 4.8 mmol), and HATU (640 mg,
1.68 mmol) were added. After overnight stirring, the solvent was
removed in vacuo, and the crude mixture was dissolved in EtOAc and
1.0N HCl. The EtOAc layer was washed with NaHCO.sub.3, dried over
MgSO.sub.4, and the solvent was removed in vacuo. The crude
material was purified on SiO.sub.2 (gradient elution, 0-100%
EtOAc/hexanes) to yield the title compound. LRMS ESI.sup.+
(M+H).sup.+ 422.4.
Step 4:
(2R,4S,7S)-7-t-Butyl-N-((1R,2R)-1-{[(cyclopropylsulfonyl)amino]car-
bonyl}-2-ethylcyclopropyl)-6,9-dioxo-10-oxa-1,5,8,17,18-pentaazatricyclo[1-
4.2.1.1.sup.2,5]icosa-16(19),17-diene-4-carboxamide
[0599] Using the product from Step 3, the title compound was
prepared according to the procedure described in Example 1 Steps 6
and 7, using Intermediate A1. LRMS ESI.sup.+ (M+H).sup.+ 622.4.
Example 85
(3R,5S,8S)--N-((1R,2S)-1-{[(Cyclopropylsulfonyl)amino]carbonyl}-2-vinylcyc-
lopropyl)-8-isopropyl-1,7,10-trioxo-4,5,7,8,9,10,12,13,14,17-decahydro-1H,-
3H-3,6-methano[1,10,3,6,13]dioxatriazacyclononadecino[13,12-a]indole-5-car-
boxamide
##STR00275##
[0600] Step 1: Ethyl 1-allyl-1H-indole-2-carboxylate
##STR00276##
[0602] To a suspension of NaH (254 mg, 60 wt %, 10.57 mmol) in THF
(5 mL), a solution of ethyl 1H-indole-2-carboxylate (1 g, 5.29
mmol) in DMF (10 mL) was added. After 1 hour, the mixture was
cooled to 0.degree. C. and allyl bromide (0.55 mL, 6.34 mmol) was
added. After stirring for 2 hours at 0.degree. C., the mixture was
slowly warmed to RT and stirred a further 15 hours. The reaction
was quenched with H.sub.2O and extracted with EtOAc. The organic
layer was dried over MgSO.sub.4, and the solvent was removed in
vacuo. The crude product was purified on SiO.sub.2 (gradient
elution, 15-40% EtOAc/hexanes) to yield the title compound as a
clear oil. LRMS EsI.sup.+ (M+H).sup.+ 230.2.
Step 2: 1-Allyl-1H-indole-2-carboxylic acid
##STR00277##
[0604] A solution of the product from Step 1 (560 mg, 2.44 mmol) in
1:1:1 2M KOH, dioxane, MeOH (10 mL) was refluxed for 2 hours and
stirred at RT overnight. The solvent was then removed in vacuo and
the residue was acidified with 1N HCl. The resulting solid was
filtered to yield the title compound as a white solid. LRMS
ESI.sup.+ (M+H).sup.+ 202.2.
Step 3: 1-t-Butyl
2-[2-(trimethylsilyl)ethyl](2S,4R)-4-{[(1-allyl-1H-indol-2-yl)carbonyl]ox-
y}pyrrolidine-1,2-dicarboxylate
##STR00278##
[0606] To a solution of the product from Step 2 (250 mg, 1.24 mmol)
in DMF (5 mL), CDI (201 mg, 1.24 mmol) was added, and the resulting
mixture was heated to 40.degree. C. for 1 hour. At this time,
1-t-butyl
2-[2-(trimethylsilyl)ethyl](2S,4R)-4-hydroxypyrrolidine-1,2-dicarboxylate
(494 mg, 1.49 mmol) and DBU (0.279 mL, 1.86 mmol) were added, and
stirring was continued for 2 hours. The mixture was the diluted
with Et.sub.2O, washed with 1N HCl, brine, saturated NaHCO.sub.3,
brine, dried over Na.sub.2SO.sub.4, and the solvent was removed in
vacuo. The crude product was purified on SiO.sub.2 (gradient
elution, 0-40% EtOAc/hexanes) to yield the title product as a clear
oil. LRMS ESI.sup.+ (M+H).sup.+ 515.4.
Step 4: 2-(Trimethylsilyl)ethyl
N-[(pent-4-en-1-yloxy)carbonyl]-L-valyl-(4R)-4-{[(1-allyl-1H-indol-2-yl)c-
arbonyl]oxy}-L-prolinate
##STR00279##
[0608] To a solution of the product from Step 3 (550 mg, 1.07 mmol)
in DCM (3 mL), TFA (1.5 mL) was added. After 30 minutes, the
mixture was concentrated in vacuo, taken up in PhMe (2.times.) and
concentrated, and finally taken up in Et.sub.2O (2.times.) and
concentrated. The residue was then partitioned between EtOAc and
NaHCO.sub.3 and extracted with EtOAc (2.times.). The combined
organic layers were then washed with brine, dried over
Na.sub.2SO.sub.4, and the solvent was removed in vacuo to yield
(3R,5S)-5-{[2-(trimethylsilyl)ethoxy]carbonyl}pyrrolidin-3-yl
1-allyl-1H-indole-2-carboxylate. To this crude material (328 mg,
0.791 mmol) in DMF (5 mL), Intermediate B7 (200 mg, 0.870 mmol),
TBTU (279 mg, 0.87 mmol), and DIEA (0.262 mL, 1.58 mmol) were
added. After 4 hours, EtOAc was added, and the mixture was
extracted with 1N HCl, NaHCO.sub.3, and brine. The organic layer
was then dried over Na.sub.2SO.sub.4, and the solvent was removed
in vacuo. The crude material was purified on SiO.sub.2 (gradient
elution, 10-50% EtOAc/hexanes) to yield the title compound. LRMS
ESI.sup.+ (M+H).sup.+ 626.3.
Step 5: 2-(Trimethylsilyl)ethyl
(3R,5S,8S,15E)-8-isopropyl-1,7,10-trioxo-4,5,7,8,9,10,12,13,14,17-decahyd-
ro-1H,3H-3,6-methano[1,10,3,6,13]dioxatriazacyclononadecino[13,12-a]indole-
-5-carboxylate
##STR00280##
[0610] To a degassed solution of the product from Step 4 (480 mg,
0.767 mmol) in DCE (160 mL), the Zhan 1B catalyst (51 mg, 0.077
mmol) was added, and the mixture was heated to reflux for 2 hours.
The solvent was then removed in vacuo, and the mixture was purified
on SiO.sub.2 (gradient elution, 10-50% EtOAc/hexanes) to yield the
title compound as a tan foam. LRMS ESI.sup.+ (M+H).sup.+ 598.4.
Step 6:
(3R,5S,8S)--N-((1R,2S)-1-{[(Cyclopropylsulfonyl)amino]carbonyl}-2--
vinylcyclopropyl)-8-isopropyl-1,7,10-trioxo-4,5,7,8,9,10,12,13,14,17-decah-
ydro-1H,3H-3,6-methano[1,10,3,6,13]dioxatriazacyclononadecino[13,12-a]indo-
le-5-carboxamide
[0611] To a solution of the product from Step 5 (50 mg, 0.084 mmol)
in THF (2 mL), TBAF (0.42 mL, 1M solution in THF, 0.42 mmol) was
added. After 30 minutes, the solvent was removed in vacuo, and the
residue was dissolved in DMF (2 mL). Intermediate A1 (50 mg, 0.187
mmol), TBTU (60 mg, 0.187 mmol), and DIEA (0.086 mL, 0.52 mmol)
were then added. After 15 hours, the reaction mixture was directly
purified by reverse-phase chromatography (0-100%
CH.sub.3CN/H.sub.2O (with 0.15% TFA) to yield the title compound as
a white powder. LRMS ESI.sup.+ (M+H).sup.+ 710.4.
Example 86
(3R,5S,8S)--N-((1R,2S)-1-{[(Cyclopropylsulfonyl)amino]carbonyl}-2-vinylcyc-
lopropyl)-8-isopropyl-1,7,10-trioxo-4,5,7,8,9,10,12,13,14,15,16,17-dodecah-
ydro-1H,3H-3,6-methano[1,10,3,6,13]dioxatriazacyclononadecino[13,12-a]indo-
le-5-carboxamide
##STR00281##
[0612] Step 1: 2-(Trimethylsilyl)ethyl
(3R,5S,8S)-8-isopropyl-1,7,10-trioxo-4,5,7,8,9,10,12,13,14,15,16,17-dodec-
ahydro-1H,3H-3,6-methano[1,10,3,6,13]dioxatriazacyclononadecino[13,12-a]in-
dole-5-carboxylate
##STR00282##
[0614] To a solution of the product from Example 85, Step 5 (141
mg, 0.236 mmol) in EtOAc (3 mL), 10% Pd/C (14 mg) was added. The
mixture was then placed under H.sub.2 for 1 hour and then filtered
through CELITE. The solvent was removed in vacuo to yield the title
compound as a tan foam. LRMS ESI.sup.+ (M+H).sup.+ 600.4.
Step 2:
(3R,5S,8S)--N-((1R,2S)-1-{[(Cyclopropylsulfonyl)amino]carbonyl}-2--
vinylcyclopropyl)-8-isopropyl-1,7,10-trioxo-4,5,7,8,9,10,12,13,14,15,16,17-
-dodecahydro-1H,3H-3,6-methano[1,10,3,6,13]dioxatriazacyclononadecino[13,1-
2-a]indole-5-carboxamide
[0615] Using the product from Step 1, the title compound was
prepared according to Example 85 Step 6. LRMS ESI.sup.+ (M+H).sup.+
712.4.
Example 87
[0616]
(5R,7S,10S,19E)-10-t-Butyl-N-((1R,2S)-1-{[(cyclopropylsulfonyl)amin-
o]carbonyl}-2-vinylcyclopropyl)-3,9,12-trioxo-1,2,3,4,5,6,7,9,10,11,12,14,-
15,16,17,18-hexadecahydro-5,8-methano-13,4,8,11-benzoxatriazacyclodocosine-
-7-carboxamide
##STR00283##
Step 1: 1-t-Butyl
2-methyl(2S,4R)-4-{[3-(2-bromophenyl)propanoyl]amino}pyrrolidine-1,2-dica-
rboxylate
##STR00284##
[0618] To a solution of 1-t-butyl
2-methyl(2S,4R)-4-aminopyrrolidine-1,2-dicarboxylate hydrochloride
(1 g, 3.56 mmol), 3-(2-bromophenyl)propanoic acid (0.898 g, 3.92
mmol) DMF (10 mL), EDC (0.751 g, 3.92 mmol), HOBT (0.600 g, 3.92
mmol), and DIEA (2.177 mL, 12.47 mmol) were added, and the mixture
was left to stir for 2 days. The reaction was then diluted with
EtOAc, washed with 1N HCl (2.times.) and brine (1.times.), and the
organic layer was dried over Na.sub.2SO.sub.4, and the solvent was
removed in vacuo. The resulting oil was purified by column
chromatography on SiO.sub.2 (gradient elution, 20%-60%
EtOAc/hexanes) to yield the title compound as a clear oil which
slowly solidified. LRMS ESI.sup.+ (M+H).sup.+ 455.2, 457.2.
Step 2:
(5R,7S,10S,19E)-10-t-Butyl-N-((1R,2S)-1-{[(cyclopropylsulfonyl)ami-
no]carbonyl}-2-vinylcyclopropyl)-3,9,12-trioxo-1,2,3,4,5,6,7,9,10,11,12,14-
,15,16,17,18-hexadecahydro-5,8-methano-13,4,8,11-benzoxatriazacyclodocosin-
e-7-carboxamide
[0619] Using the product from Step 1, the title compound was
prepared according to the procedures in Example 1, Steps 2-7. LRMS
ESI.sup.+ (M+H).sup.+ 726.5.
Example 88
[0620]
(5R,7S,10S,19E)-10-t-Butyl-N-((1R,2R)-1-{[(cyclopropylsulfonyl)amin-
o]carbonyl}-2-ethylcyclopropyl)-3,9,12-trioxo-1,2,3,4,5,6,7,9,10,11,12,14,-
15,16,17,18-hexadecahydro-5,8-methano-13,4,8,11-benzoxatriazacyclodocosine-
-7-carboxamide
##STR00285##
[0621] Using the product from Example 87, the title compound was
prepared according to the procedures in Example 1 Steps 2-7, using
Intermediate A3 in place of Intermediate A1 in Step 7. LRMS
ESI.sup.+ (M+H).sup.+ 728.5.
Example 89
(5R,7S,10S)-10-t-Butyl-N-((1R,2S)-1-{[(cyclopropylsulfonyl)amino]carbonyl}-
-2-vinylcyclopropyl)-3,9,12-trioxo-1,2,3,4,5,6,7,9,10,11,12,14,15,16,17,18-
,19,20-octadecahydro-5,8-methano-13,4,8,11-benzoxatriazacyclodocosine-7-ca-
rboxamide
##STR00286##
[0623] Using the product from Example 87, the title compound was
prepared according to the procedures in Example 3. LRMS ESI.sup.+
(M+H).sup.+ 728.6.
Example 90
(5R,7S,10S)-10-t-Butyl-N-((1R,2R)-1-{[(cyclopropylsulfonyl)amino]carbonyl}-
-2-ethylcyclopropyl)-3,9,12-trioxo-1,2,3,4,5,6,7,9,10,11,12,14,15,16,17,18-
,19,20-octadecahydro-5,8-methano-13,4,8,11-benzoxatriazacyclodocosine-7-ca-
rboxamide
##STR00287##
[0625] Using the product from Example 87, the title compound was
prepared according to the procedures in Example 4. LRMS ESI.sup.+
(M+H).sup.+ 730.6.
Example 91
(5R,7S,10S,18E)-10t-Butyl-N-((1R,2R)-1-{[(cyclopropylsulfonyl)amino]carbon-
yl}-2-ethylcyclopropyl)-15,15,24-trimethyl-3,9,12-trioxo-4,5,6,7,9,10,11,1-
2,14,15,16,17-dodecahydro-3H-2,23-epimino-5,8-methano-13,4,8,11-benzoxatri-
azacyclohenicosine-7-carboxamide
##STR00288##
[0626] Step 1: 1-t-Butyl
2-methyl(2S,4R)-4-{[(4-bromo-1H-indol-2-yl)carbonyl]amino}pyrrolidine-1,2-
-dicarboxylate
##STR00289##
[0628] To a solution of 1-t-butyl
2-methyl(2S,4R)-4-aminopyrrolidine-1,2-dicarboxylate hydrochloride
(350 mg, 1.247 mmol), Intermediate C2 (299 mg, 1.247 mmol), and
HATU (569 mg, 1.496 mmol) in DMF (8 mL), DIEA (0.871 mL, 4.99 mmol)
was added, and left to stir overnight. The reaction mixture was
then diluted with EtOAc, washed with HCl (1M), brine, saturated
NaHCO.sub.3 and brine, dried over Na.sub.2SO.sub.4 and filtered,
and the solvent was evaporated. The residue was purified by column
chromatography on SiO.sub.2 (gradient elution, 20-60%
EtOAc/hexanes) to give the title compound as a white foam. LRMS
ESI.sup.+ (M+H).sup.+ 468.1.
Step 2: 1-t-Butyl
2-methyl(2S,4R)-4-{[(4-bromo-1-methyl-1H-indol-2-yl)carbonyl]amino}pyrrol-
idine-1,2-dicarboxylate
##STR00290##
[0630] To a mixture of the product from Step 1 (471 mg, 1.010 mmol)
and K.sub.2CO.sub.3 (154 mg, 1.111 mmol) in DMF (8 ml), iodomethane
(0.069 mL, 1.111 mmol) was added, and the mixture was left to stir
overnight. The reaction mixture was then diluted with Et.sub.2O and
H.sub.2O and the layers were separated the layers. The organics
were then washed with saturated NaHCO.sub.3 and brine. The organic
layer was then dried over Na.sub.2SO.sub.4, filtered, concentrated,
and re-concentrated from Et.sub.2O to yield the title compound as a
white foam. LRMS ESI.sup.+ (M+H).sup.+ 480.1/482.1.
Step 3: Methyl
(4R)-4-{[(4-bromo-1-methyl-1H-indol-2-yl)carbonyl]amino}-L-prolinate
trifluoro acetate
##STR00291##
[0632] To a solution of the product from Step 2 (440 mg, 0.916
mmol) in DCM (4 ml), TFA (1 mL) was added, and left to stir for 1
hour. The reaction mixture was then concentrated, reconcentrated
from PhMe (1.times.) and DCM (2.times.) to yield the title compound
as a yellow oil. LRMS ESI.sup.+ (M+H).sup.+ 380.0/382.0.
Step 4: Methyl
N-{[(2,2-dimethylhex-5-en-1-yl)oxy]carbonyl}-3-methyl-L-valyl-(4R)-4-{[(4-
-bromo-1-methyl-1H-indol-2-yl)carbonyl]amino}-L-prolinate
##STR00292##
[0634] Using the product from Step 3, the title compound was
prepared using the procedure from Example 1 Step 4, using
Intermediate B13 in place of Intermediate B7. LRMS ESI.sup.+
(M+H).sup.+ 647.3/649.3.
Step 5: Methyl
N-{[(2,2-dimethylhex-5-en-1-yl)oxy]carbonyl}-3-methyl-L-valyl-(4R)-4-{[(1-
-methyl-4-vinyl-1H-indol-2-yl)carbonyl]amino}-L-prolinate
##STR00293##
[0636] To a degassed (bubbled N.sub.2 for 30 minutes) solution of
the product from Step 4 (532 mg, 0.821 mmol) in PhMe (10 mL),
tributylvinyltin (0.288 ml, 0.986 mmol) and Pd(PPh.sub.3).sub.4 (95
mg, 0.082 mmol) were added, and the mixture was heated to reflux
for 90 minutes. The reaction mixture was then concentrated, and the
resulting residue was purified by column chromatography on
SiO.sub.2 (gradient elution, 20%-45% EtOAc/hexanes) to yield the
title compound as a clear oil. LRMS ESI.sup.+ (M+H).sup.+
595.5.
Step 6:
(5R,7S,10S,18E)-10-t-Butyl-N-((1R,2R)-1-{[(cyclopropylsulfonyl)ami-
no]carbonyl}-2-ethylcyclopropyl)-15,15,24-trimethyl-3,9,12-trioxo-4,5,6,7,-
9,10,11,12,14,15,16,17-dodecahydro-3H-2,23-epimino-5,8-methano-13,4,8,11-b-
enzoxatriazacyclohenicosine-7-carboxamide
[0637] Using the product from Step 5, the title compound was
prepared using the procedures in Example 1, Steps 5-7 with
Intermediate A3 used in place of Intermediate A1 in Step 7. LRMS
ESI.sup.+ (M+H).sup.+ 767.6.
Example 92
(5R,7S,10S,18E)-10-t-Butyl-N-((1R,2S)-1-{[(cyclopropylsulfonyl)amino]carbo-
nyl}-2-vinylcyclopropyl)-15,15,24-trimethyl-3,9,12-trioxo-4,5,6,7,9,10,11,-
12,14,15,16,17-dodecahydro-3H-2,23-epimino-5,8-methano-13,4,8,11-benzoxatr-
iazacyclohenicosine-7-carboxamide
##STR00294##
[0639] The title compound was prepared according to the procedures
in Example 91, using Intermediate A1 in place of Intermediate A3.
LRMS ESI.sup.+ (M+H).sup.+ 765.6.
Example 93
(5R,7S,10S)-10-t-Butyl-N-((1R,2S)-1-{[(cyclopropylsulfonyl)amino]carbonyl}-
-2-vinylcyclopropyl)-15,15-dimethyl-9,12-dioxo-6,7,9,10,11,12,14,15,16,17,-
18,19-dodecahydro-5H-5,8-methano-23,2-(metheno)pyrido[2,3-n][1,10,3,6,13]d-
ioxatriazacyclohenicosine-7-carboxamide
##STR00295##
[0640] Step 1: 8-Bromo-2-(chloromethyl)imidazo[1,2-a]pyridine
hydrochloride
##STR00296##
[0642] To a solution of 3-bromo-2-aminopyridine (10 g, 57.8 mmol)
in EtOAc (200 mL), a solution of 1,3-dichloroacetone (7.34 g, 57.8
mmol) in EtOAc (50 mL) was added dropwise. The mixture was stirred
at RT for 5 days. The solids were then filtered; the mother liquors
separated; and the solids washed with Et.sub.2O, dried in vacuo to
give a white solid. The solids were then slurried in 15 mL HOAc and
heated to 90.degree. C. for 15 minutes to give a clear solution.
The mixture was then cooled to RT and concentrated to remove most
of the HOAc. The residue was treated with 30 mL Et.sub.2O and let
stir overnight to give the title compound as a white solid (3.0 g).
LRMS ESI.sup.+ (M+H).sup.+ 245.0/247.0.
Step 2:
(4R)-4-[(8-Bromoimidazo[1,2-a]pyridin-2-yl)methoxy]-1-(t-butoxycar-
bonyl)-L-proline
##STR00297##
[0644] To a solution of
(4R)-1-(t-butoxycarbonyl)-4-hydroxy-L-proline (1.0 g, 4.32 mmol) in
DMF (20 mL), NaH (692 mg, 60%, 17.3 mmol) was added at RT. After 20
minutes, the product from the step 1 (1.22 g, 4.32 mmol) was added,
and the mixture was stirred for 30 minutes at RT and at 45.degree.
C. for 1 hour. The reaction was then diluted with KHSO.sub.4 and
EtOAc. The pH was then adjusted to 5.5 with 2N NaOH. The organic
layer was separated, and the aqueous layer was washed with
additional EtOAc. The combined organic layers were dried over
Na.sub.2SO.sub.4, and the solvent was removed in vacuo. The crude
material was purified on SiO.sub.2 (90/10/1 DCM/MeOH/HOAc) to give
the title compound as a foam (1.7 g). LRMS ESI.sup.+ (M+H).sup.+
440.0/442.0.
Step 3: Ethyl
(4R)-4-[(8-bromoimidazo[1,2-a]pyridin-2-yl)methoxy]-L-prolinate
hydrochloride
##STR00298##
[0646] To a solution of the product from Step 2 (1.7 g, 3.86 mmol)
in EtOH (200 mL) was bubbled HCl (g) for 30 minutes. The mixture
was then stirred an additional 2 hours. The solvent was then
removed in vacuo and the following titration, the title compound
was isolated as a solid (1.5 g). LRMS ESI.sup.+ (M+H).sup.+
340.0/342.0.
Step 4: Ethyl
N-{[(2,2-dimethylhex-5-en-1-yl)oxy]carbonyl}-3-methyl-L-valyl-(4R)-4-[(8--
bromoimidazo[1,2-a]pyridin-2-yl)methoxy]-L-prolinate
##STR00299##
[0648] To a solution of the product from Step 3 (900 mg, 2.22 mmol)
in DMF (12 mL), Intermediate B13 (698 mg, 2.45 mmol), DIEA (1.16
mL, 6.67 mmol), and HATU (1.26 g, 3.34 mmol) were added. After 1
hour, the mixture was extracted with KHSO.sub.4 and EtOAc. The
organic layer was washed with H.sub.2O and brine, and then dried
over Na.sub.2SO.sub.4. The solvent was removed in vacuo, and the
crude product was purified on SiO.sub.2 (20% EtOAc/hexanes) to
yield 1.4 g of the title compound. LRMS ESI.sup.+ (M+H).sup.+
635.3/637.3.
Step 5: Ethyl
N-{[(2,2-dimethylhex-5-en-1-yl)oxy]carbonyl}-3-methyl-L-valyl-(4R)-4-[(8--
vinylimidazo[1,2-a]pyridin-2-yl)methoxy]-L-prolinate
##STR00300##
[0650] Using the product from Step 4, the title compound was
prepared according to the procedure in Example 1 Step 2. LRMS
ESI.sup.+ (M+H).sup.+ 583.5.
Step 6:
5R,7S,10S)-10-t-Butyl-N-((1R,2S)-1-{[(cyclopropylsulfonyl)amino]ca-
rbonyl}-2-vinylcyclopropyl)-15,15-dimethyl-9,12-dioxo-6,7,9,10,11,12,14,15-
,16,17,18,19-dodecahydro-5H-5,8-methano-23,2-(metheno)pyrido[2,3-n][1,10,3-
,6,13]dioxatriazacyclohenicosine-7-carboxamide
[0651] Using the product from Step 5, the title compound was
prepared according to the procedures in Example 2 Steps 1-3. LRMS
ESI.sup.+ (M+H).sup.+ 741.6.
Example 94
(1R,18R,22R,26S,29S)-26-cyclopentyl-N-((1R,2S)-1-{[(cyclopropylsulfonyl)am-
ino]carbonyl}-2-vinylcyclopropyl)-24,27-dioxo-2,23-dioxa-11,25,28-triazape-
ntacyclo[26.2.1.0.sup.3,12.0.sup.5,10.0.sup.18,22]hentriaconta-3(12),4,5,7-
,9,10-hexaene-29-carboxamide
##STR00301##
[0652] Step 1: Methyl
(4R)-4-[(2-chloroquinolin-3-yl)oxy]-1-{(2S)-2-cyclopentyl-2-[({[(1R,2R)-2-
-pent-4-en-1-ylcyclopentyl]oxy}carbonyl)amino]acetyl}-L-prolinate
##STR00302##
[0654] A solution of Intermediate C13 (0.50 g, 1.46 mmol) and
Intermediate B23 in DMF (10 mL) was treated with DIPEA (1.53 mL,
8.74 mmol) and HATU (0.83 g, 2.19 mmol). The mixture was stirred
for 1 hour, then partitioned between HCl.sub.(aq.) (1N) and EtOAc.
The organic layer was separated, washed with saturated
NaHCO.sub.3(aq.) and brine, and then dried over Na.sub.2SO.sub.4.
Filtration and removal of the volatiles gave a residue that was
purified by flash chromatography on SiO.sub.2 (gradient elution,
1-100% EtOAc/petroleum ether) to afford the title compound (671 mg,
75%) as a solid. LCMS (ES+) m/z 612 (M+H).sup.+.
Step 2: Methyl
(4R)-1-{(2S)-2-cyclopentyl-2-[({[(trans)-2-pent-4-en-1-ylcyclopentyl]oxy}-
carbonyl)amino]acetyl}-4-[(2-vinylquinolin-3-yl)oxy]-L-prolinate
##STR00303##
[0656] A solution of the product of Step 1 (669 mg, 1.09 mmol) in
absolute EtOH (10.9 mL) was treated with potassium
vinyltrifluoroborate (234 mg, 1.75 mmol) and TEA (244 .mu.L, 1.75
mmol). Pd(dppf).DCM (178 mg, 0.22 mmol) was added, and the mixture
was heated under reflux for 15 minutes. The mixture was cooled and
diluted with H.sub.2O and EtOAc. The organic layer was separated,
washed with brine and dried over Na.sub.2SO.sub.4. The filtered
solution was concentrated to afford a residue that was purified by
column chromatography on SiO.sub.2 (gradient elution, 1-100%
EtOAc/petroleum ether) to give the title compound (485 mg, 74%) as
a solid. LCMS (ES+) m/z 604 (M+H).sup.+.
Step 3: Methyl
(3aR,7S,10S,12R,20E,24aR)-7-cyclopentyl-5,8-dioxo-1,2,3,3a,5,6,7,8,11,12,-
22,23,24,24a-tetradecahydro-10H-9,12-methanocyclopenta[18,19][1,10,3,6]dio-
xadiazacyclononadecino[12,11-b]quinoline-10-carboxylate and methyl
(3aS,7S,10S,12R,20E,24aS)-7-cyclopentyl-5,8-dioxo-1,2,3,3a,5,6,7,8,11,12,-
22,23,24,24a-tetradecahydro-10H-9,12-methano
cyclopenta[18,19][1,10,3,6]dioxadiazacyclononadecino[12,11-b]quinoline-10-
-carboxylate
##STR00304##
[0658] A solution of the product of Step 2 (483 mg, 0.800 mmol) in
DCE (80 mL) was treated with Zhan catalyst (79 mg, 0.120 mmol),
then heated at 90.degree. C. for 90 minutes. The mixture was cooled
and then concentrated in vacuo. The residue was purified by flash
chromatography on SiO.sub.2 (gradient elution, 15-65%
EtOAc/petroleum ether) to give in the first fractions methyl
(3aR,7S,10S,12R,20E,24aR)-7-cyclopentyl-5,8-dioxo-1,2,3,3a,5,6,7,8,11,12,-
22,23,24,24a-tetradecahydro-10H-9,12-methanocyclopenta[18,19][1,10,3,6]dio-
xadiazacyclononadecino[12,11-b]quinoline-10-carboxylate (194 mg,
42%). LCMS (ES+) m/z 576 (M+H).sup.+. The later fractions contained
methyl
(3aS,7S,10S,12R,20E,24aS)-7-cyclopentyl-5,8-dioxo-1,2,3,3a,5,6,7,8,11,12,-
22,23,24,24a-tetradecahydro-10H-9,12-methanocyclopenta[18,19][1,10,3,6]dio-
xadiazacyclononadecino[12,11-b]quinoline-10-carboxylate (148 mg,
32%). LCMS (ES+) m/z 576 (M+H).sup.+.
Step 4: Methyl
(3aR,7S,10S,12R,24aR)-7-cyclopentyl-5,8-dioxo-1,2,3,3a,5,6,7,8,11,12,20,2-
1,22,23,24,24a-hexadecahydro-10H-9,12-methanocyclopenta[18,19][1,10,3,6]di-
oxadiazacyclononadecino[12,11-b]quinoline-10-carboxylate
##STR00305##
[0660] Pd/C (10%, 29 mg) was added to a solution of
(3aR,7S,10S,12R,20E,24aR)-7-cyclopentyl-5,8-dioxo-1,2,3,3a,5,6,7,8,11,12,-
22,23,24,24a-tetradecahydro-10H-9,12-methanocyclopenta[18,19][1,10,3,6]dio-
xadiazacyclononadecino[12,11-b]quinoline-10-carboxylate (115 mg,
0.20 mmol) in MeOH (20 mL), and the mixture was stirred under
H.sub.2 for 1 hour. The solution was filtered through CELITE, and
the filtrate was concentrated to afford the title compound (95 mg,
83%) as a solid that was used directly in the next step. LCMS (ES+)
m/z 578 (M+H).sup.+.
Step 5:
(3aR,7S,10S,12R,24aR)-7-cyclopentyl-5,8-dioxo-1,2,3,3a,5,6,7,8,11,-
12,20,21,22,23,24,24a-hexadecahydro-10H-9,12-methanocyclopenta[18,19][1,10-
,3,6]dioxadiazacyclononadecino[12,11-b]quinoline-10-carboxylic
acid
##STR00306##
[0662] LiOH.H.sub.2O (34.6 mg, 0.825 mmol) was added to a stirred
solution of the product of Step 4 (95.3 mg, 0.165 mmol) in a 1:1
mixture of H.sub.2O:THF (5.4 mL). The solution was heated at
40.degree. C. for 1 hour, then the THF was evaporated in vacuo, and
the remaining aqueous solution was acidified to pH 4 by addition of
HCl.sub.(aq.) (1N). EtOAc was added, and the organic layer was
separated, washed with brine, then dried over Na.sub.2SO.sub.4. The
mixture was filtered, and the volatiles were removed to afford the
title compound (61.4 mg, 66%) as a solid that was used directly in
the next step. LCMS (ES+) m/z 564 (M+H).sup.+.
Step 6:
(1R,18R,22R,26S,29S)-26-cyclopentyl-N-((1R,2S)-1-{[(cyclopropylsul-
fonyl)amino]carbonyl}-2-vinylcyclopropyl)-24,27-dioxo-2,23-dioxa-11,25,28--
triazapentacyclo[26.2.1.0.sup.3,12.0.sup.5,10.0.sup.18,22]hentriaconta-3(1-
2),4,5,7,9,10-hexaene-29-carboxamide
##STR00307##
[0664] DIPEA (124 .mu.l, 0.708 mmol), DMAP (6.65 mg, 0.054 mmol)
and TBTU (45.5 mg, 0.142 mmol) were added to a stirred solution of
the product of Step 5 (61.4 mg, 0.109 mmol) and Intermediate A1
(43.6 mg, 0.163 mmol) in DCM (5.7 mL). After 15 hours, the
volatiles were evaporated, and the residue was purified by
automated mass-triggered HPLC (FractionLynx) to afford after
lyophilisation the title compound (51.9 mg, 61%) as a white powder.
LCMS (ES+) m/z 776.3 (M+H).sup.+.
Example 95
(1R,13E,18R,22R,26S,29S)-26-cyclopentyl-N-((1R,2S)-1-{[(cyclopropylsulfony-
l)amino]carbonyl}-2-vinylcyclopropyl)-24,27-dioxo-2,23-dioxa-11,25,28-tria-
zapentacyclo[26.2.1.0.sup.3,12.0.sup.5,10.0.sup.18,22]hentriaconta-3(12),4-
,5,7,9,10,13-heptaene-29-carboxamide
##STR00308##
[0666] Treatment of methyl
(3aS,7S,10S,12R,20E,24aS)-7-cyclopentyl-5,8-dioxo-1,2,3,3a,5,6,7,8,11,12,-
22,23,24,24a-tetradecahydro-10H-9,12-methanocyclopenta[18,19][1,10,3,6]dio-
xadiazacyclononadecino[12,11-b]quinoline-10-carboxylate (87 mg,
0.151 mmol) as described in Example 94 Steps 4-6 afforded the title
compound (72.8 mg, 62%) as a white powder. LCMS (ES+) m/z 776.3
(M+H).sup.+.
[0667] By using the appropriate A, B, and C intermediates, the
following compounds were prepared according to the procedures of
Example 1.
TABLE-US-00009 Intermediates LRMS according to Ex. Structure Name
(M + H).sup.+ Procedure Int. 96 ##STR00309##
(1R,13E,18R,22R,26S,29S)- 26-cyclopentyl-N-((1R,2S)-
1-{[(cyclopropylsulfonyl) amino]carbonyl}-2-
vinylcyclopropyl)-24,27- dioxo-2,23-dioxa-11,25,28-
triazapentacyclo [26.2.1.0.sup.3,12.0.sup.5,10.0.sup.18,22]
hentriaconta- 3(12),4,5,7,9,10,13- heptaene-29-carboxamide 774.3
See Example 94, omit Step 4, separate isomers A1, B23, C13 97
##STR00310## (1R,18R,22R,26S,29S)-26- cyclopentyl-N-((1R,2S)-1-
{[(cyclopropylsulfonyl) amino]carbonyl}-2- vinylcyclopropyl)-24,27-
dioxo-2,23-dioxa- 4,11,25,28- tetraazapentacyclo
[26.2.1.0.sup.3,12.0.sup.5,10.0.sup.18,22] hentriaconta-
3(12),4,5,7,9,10-hexaene- 29-carboxamide 777.2 See Example 94,
separate isomers A1, B23, C15 98 ##STR00311##
(1R,18S,22S,26S,29S)-26- cyclopentyl-N-((1R,2S)-1-
{[(cyclopropylsulfonyl) amino]carbonyl}-2- vinylcyclopropyl)-24,27-
dioxo-2,23-dioxa- 4,11,25,28- tetraazapentacyclo
[26.2.1.0.sup.3,12.0.sup.5,10.0.sup.18,22] hentriaconta-
3(12),4,5,7,9,10-hexaene- 29-carboxamide 777.2 See Example 94,
separate isomers A1, B23, C15 99 ##STR00312##
(1R,13E,18R,22R,26S,29S)- 26-cyclopentyl-N-((1R,2S)-
1-{[(cyclopropylsulfonyl) amino]carbonyl}-2- vinylcyclopropyl)-7-
methoxy-24,27-dioxo-2,23- dioxa-4,25,28- triazapentacyclo
[26.2.1.0.sup.3,12.0.sup.5,10.0.sup.18,22] hentriaconta-
3(12),4,5,7,9,10,13- heptaene-29-carboxamide 804.5 See Example 1,
Steps 4-7, separate isomers A1, B23, C11 100 ##STR00313##
(1R,13E,18S,22S,26S,29S)- 26-cyclopentyl-N-((1R,2S)-
1-{[(cyclopropylsulfonyl) amino]carbonyl}-2- vinylcyclopropyl)-7-
methoxy-24,27-dioxo-2,23- dioxa-4,25,28- triazapentacyclo
[26.2.1.0.sup.3,12.0.sup.5,10.0.sup.18,22] hentriaconta-
3(12),4,5,7,9,10,13- heptaene-29-carboxamide 804.5 See Example 1,
Steps 4-7, separate isomers A1, B23, C11 101 ##STR00314##
(1R,13E,18R,22S,26S,29S)- 26-cyclopentyl-N-((1R,2S)-
1-{[(cyclopropylsulfonyl) amino]carbonyl}-2- vinylcyclopropyl)-7-
methoxy-24,27-dioxo- 2,20,23-trioxa-4,25,28- triazapentacyclo
[26.2.1.0.sup.3,12.0.sup.5,10.0.sup.18,22] hentriaconta-
3(12),4,5,7,9,10,13- heptaene-29-carboxamide 806.5 See Example 1,
steps 4-7, separate isomers A1, B21a, C11 102 ##STR00315##
(1R,13E,18S,22R,26S,29S)- 26-cyclopentyl-N-((1R,2S)-
1-{[(cyclopropylsulfonyl) amino]carbonyl}-2- vinylcyclopropyl)-7-
methoxy-24,27-dioxo- 2,20,23-trioxa-4,25,28- triazapentacyclo
[26.2.1.0.sup.3,12.0.sup.5,10.0.sup.18,22] hentriaconta-
3(12),4,5,7,9,10,13- heptaene-29-carboxamide 806.4 See Example 1,
Steps 4-7, separate isomers A1, B21a, C11 103 ##STR00316##
(1R,18R,22R,26S,29S)-26- cyclopentyl-N-((1R,2S)-1-
{[(cyclopropylsulfonyl) amino]carbonyl}-2- vinylcyclopropyl)-7-
methoxy-24,27-dioxo-2,23- dioxa-11,25,28- triazapentacyclo
[26.2.1.0.sup.3,12.0.sup.5,10.0.sup.18,22] hentriaconta-
3(12),4,5,7,9,10-hexaene- 29-carboxamide 806.3 See Example 94 A1,
B23a, C14 104 ##STR00317## (1R,18R,22R,26S,29S)-26-
cyclopentyl-N-((1R,2R)-1- {[(cyclopropylsulfonyl)
amino]carbonyl}-2- ethylcyclopropyl)-7- methoxy-24,27-dioxo-2,23-
dioxa-11,25,28- triazapentacyclo
[26.2.1.0.sup.3,12.0.sup.5,10.0.sup.18,22] hentriaconta-
3(12),4,5,7,9,10-hexaene- 29-carboxamide 808.3 See Example 94 A3,
B23a, C14 105 ##STR00318## (1R,18R,22R,26S,29S)-26-
cyclohexyl-N-((1R,2S)-1- {[(cyclopropylsulfonyl) amino]carbonyl}-2-
vinylcyclopropyl)-7- methoxy-24,27-dioxo-2,23- dioxa-11,25,28-
triazapentacyclo [26.2.1.0.sup.3,12.0.sup.5,10.0.sup.18,22]
hentriaconta- 3(12),4,5,7,9,10-hexaene- 29-carboxamide 820.3 See
Example 94 A1, B24a, C14 106 ##STR00319## (1R,18R,22R,26S,29S)-7-
chloro-26-cyclopentyl-N- ((1R,2S)-1- {[(cyclopropylsulfonyl)
amino]carbonyl}-2- vinylcyclopropyl)-24,27-
dioxo-2,23-dioxa-11,25,28- triazapentacyclo
[26.2.1.0.sup.3,12.0.sup.5,10.0.sup.8,22] hentriaconta-
3(12),4,5,7,9,10-hexaene- 29-carboxamide 810.6 See Example 94,
separate isomers A1, B23, C16 107 ##STR00320##
(1R,18S,22S,26S,29S)-7- chloro-26-cyclopentyl-N- ((1R,2S)-1-
{[(cyclopropylsulfonyl) amino]carbonyl}-2- vinylcyclopropyl)-24,27-
dioxo-2,23-dioxa-11,25,28- triazapentacyclo
[26.2.1.0.sup.3,12.0.sup.5,10.0.sup.18,22] hentriaconta-
3(12),4,5,7,9,10-hexaene- 29-carboxamide 810.6 See Example 94,
separate isomers A1, B23, C16 108 ##STR00321##
(1R,18R,22R,26S,29S)-26-t- butyl-N-((1R,2S)-1-
{[(cyclopropylsulfonyl) amino]carbonyl}-2- vinylcyclopropyl)-24,27-
dioxo-2,23-dioxa- 4,11,25,28- tetraazapentacyclo
[26.2.1.0.sup.3,12.0.sup.5,10.0.sup.18,22] hentriaconta-
3(12),4,5,7,9,10-hexaene- 29-carboxamide 765.2 See Example 94 A1,
B22a, C15
Example 109
(1R,18R,22R,26S,29S)-26-t-butyl-N-((1R,2S)-1-{[(cyclopropylsulfonyl)amino]-
carbonyl}-2-vinylcyclopropyl)-7-methoxy-24,27-dioxo-2,23-dioxa-11,25,28-tr-
iazapentacyclo[26.2.1.0.sup.3,12.0.sup.5,10.0.sup.18,22]hentriaconta-3(12)-
,4,5,7,9,10-hexaene-29-carboxamide
##STR00322##
[0668] Step 1: Methyl
3-methyl-N-({[(1R,2R)-2-pent-4-en-1-ylcyclopentyl]oxy}carbonyl)-L-valyl-(-
4R)-4-[(6-methoxy-2-vinylquinolin-3-yl)oxy]-L-prolinate
##STR00323##
[0670] A solution of Intermediate C14 (0.50 g, 1.46 mmol) and
Intermediate B23 was treated as described for Example 94 Step 1, to
produce a residue that was then taken up in in absolute EtOH. The
resulting solution (0.2 M) was treated with potassium
vinyltrifluoroborate (1.6 eq) and TEA (1.6 eq).
Pd(dppf).CH.sub.2Cl.sub.2(0.2 eq) was added, and the mixture was
heated under reflux for 1 hour. The mixture was cooled and diluted
with H.sub.2O and EtOAc. The organic layer was separated, washed
with brine and dried over Na.sub.2SO.sub.4. The filtered solution
was concentrated to afford a residue that was purified by column
chromatography on SiO.sub.2 (gradient elution, 1-100%
EtOAc/petroleum ether) to give the title compound (30%) as a solid.
LCMS (ES+) m/z 622 (M+H).sup.+.
Step 2: Methyl
(3aR,7S,10S,12R,20E,24aR)-7-t-butyl-16-methoxy-5,8-dioxo-1,2,3,3a,5,6,7,8-
,11,12,22,23,24,24a-tetradecahydro-10H-9,12-methanocyclopenta[18,19][1,10,-
3,6]dioxadiazacyclononadecino[12,11-b]quinoline-10-carboxylate
##STR00324##
[0672] A solution of the product of Step 1 (300 mg, 0.48 mmol) in
DCE (30 mL) was treated with Zhan catalyst (48 mg, 0.07 mmol), then
heated at 90.degree. C. for 2 hours. The mixture was cooled and
concentrated in vacuo to furnish a residue that was purified by
flash chromatography on SiO.sub.2 (gradient elution, 10-80%
EtOAc/petroleum ether) to give the title compound (228 mg, 84%).
LCMS (ES+) m/z 594 (M+H).sup.+.
Step 3:
(3aR,7S,10S,12R,24aR)-7-t-Butyl-16-methoxy-5,8-dioxo-1,2,3,3a,5,6,-
7,8,11,12,20,21,22,23,24,24a-hexadecahydro-10H-9,12-methanocyclopenta[18,1-
9][1,10,3,6]dioxadiazacyclononadecino[12,11-b]quinoline-10-carboxylic
acid
##STR00325##
[0674] The product of Step 2 (125 mg, 0.21 mmol) was dissolved in a
1:2 mixture of H.sub.2O:MeOH (30 mL) and treated with LiOH.H.sub.2O
(35 mg, 0.84 mmol). The solution was heated at 50.degree. C. for 3
hours. The MeOH was evaporated in vacuo, and the aqueous solution
was diluted with EtOAc and acidified to pH 4 with HCl.sub.(aq.)
(1N). The organic layer was separated, then washed with brine and
dried over Na.sub.2SO.sub.4. After filtration and removal of the
volatiles, the residue was dissolved in MeOH (55 mL) and treated
with Pd/C (10%, 10 mg). The solution was stirred under H.sub.2 for
2 hours, then filtered through CELITE. The filtrate was
concentrated to afford the title compound (120 mg, 98%) as a solid
that was used directly in the next step. LCMS (ES+) ink 582
(M+H).sup.+.
Step 4:
(3aR,7S,10S,12R,24aR)-7-t-Butyl-N-((1R,2S)-1-{[(cyclopropylsulfony-
l)amino]carbonyl}-2-vinylcyclopropyl)-16-methoxy-5,8-dioxo-1,2,3,3a,5,6,7,-
8,11,12,20,21,22,23,24,24a-hexadecahydro-10H-9,12-methanocyclopenta[18,19]-
[1,10,3,6]dioxadiazacyclononadecino[12,11-b]quinoline-10-carboxamide
##STR00326##
[0676] The product of Step 3 was treated as described in Example 94
Step 6 to afford a residue that was purified by automated
mass-triggered HPLC (FractionLynx) to furnish, after freeze drying,
the title compound (112 mg, 68%) as a white solid. LCMS (ES+) m/z
794 (M+H).sup.+.
[0677] By using the appropriate A, B, and C intermediates, the
following compounds were prepared according to the procedures of
Example 94.
TABLE-US-00010 LRMS Ex. Structure Name (M + H).sup.+ Int. 110
##STR00327## (1aR,5S,8S,10R,22aR)-5-t-butyl-N-((1R,2S)-1-
{[(cyclopropylsulfonyl)amino]carbonyl}-2-
vinylcyclopropyl-14-methoxy-3,6-dioxo-
1,1a,3,4,5,6,9,10,18,19,20,21,22,22a-
tetradecahydro-8H-7,10-methanocyclopropa
[18,19][1,10,3,6]dioxadiaza cyclononadecino[12,11-b]quinoline-8-
carboxamide 766.6 A1, B25a, C14 111 ##STR00328##
(1aS,5S,8S,10R,22aS)-5-t-butyl-N-((1R,2S)-1-
{[(cyclopropylsulfonyl)amino]carbonyl}-2-
vinylcyclopropyl)-14-methoxy-3,6-dioxo-
1,1a,3,4,5,6,9,10,18,19,20,21,22,22a-
tetradecahydro-8H-7,10-methanocyclopropa
[18,19][1,10,3,6]dioxadiaza cyclononadecino[12,11-b]quinoline-8-
carboxamide 766.5 A1, B25a, C14 112 ##STR00329##
(1aR,5S,8S,10R,22aR)-5-t-butyl-N-((1R,2R)-1-
{[(cyclopropylsulfonyl)amino]carbonyl}-2-
ethylcyclopropyl)-14-methoxy-3,6-dioxo-
1,1a,3,4,5,6,9,10,18,19,20,21,22,22a-
tetradecahydro-8H-7,10-methanocyclopropa
[18,19][1,10,3,6]dioxadiaza cyclononadecino[12,11-b]quinoline-8-
carboxamide 768.5 A3, B25a, C14 113 ##STR00330##
(1aS,5S,8S,10R,22aS)-5-t-butyl-N-((1R,2R)-1-
{[(cyclopropylsulfonyl)amino]carbonyl}-2-
ethylcyclopropyl)-14-methoxy-3,6-dioxo-
1,1a,3,4,5,6,9,10,18,19,20,21,22,22a-
tetradecahydro-8H-7,10-methanocyclopropa
[18,19][1,10,3,6]dioxadiaza cyclononadecino[12,11-b]quinoline-8-
carboxamide 768.5 A3, B25a, C14 114 ##STR00331##
(3aR,7S,10S,12R,24aR)-7-cyclopentyl-N-
((1R,2S)-1-{[(cyclopropylsulfonyl)amino]
carbonyl}-2-vinylcyclopropyl)-16-methoxy-5,8-
dioxo-1,2,3,3a,5,6,7,8,11,12,20,21,22,
23,24,24a-hexadecahydro-10H-9,12-
methanocyclopenta[18,19][1,10,3,6]dioxadiaza
cyclononadecino[12,11-b]-1,5-naphthyridine- 10-carboxamide 807.9
A1, B23a, C18 115 ##STR00332##
(3aS,7S,10S,12R,24aS)-7-cyclopentyl-N-
((1R,2R)-1-{[(cyclopropylsulfonyl)amino]
carbonyl}-2-ethylcyclopropyl)-16-methoxy-5,8-
dioxo-1,2,3,3a,5,6,7,8,11,12,20,21,22,
23,24,24a-hexadecahydro-10H-9,12-
methanocyclopenta[18,19][1,10,3,6]dioxadiaza
cyclononadecino[12,11-b]quinoline-10- carboxamide 19-oxide 824.6
A3, B23a, C14 116 ##STR00333##
(3aS,7S,10S,12R,24aS)-7-cyclopentyl-N-
((1R,2S)-1-{[(cyclopropylsulfonyl)amino]
carbonyl}-2-ethylcyclopropyl)-16-methoxy-5,8-
dioxo-1,2,3,3a,5,6,7,8,11,12,20,21,22,
23,24,24a-hexadecahydro-10H-9,12-
methanocyclopenta[18,19][1,10,3,6]dioxadiaza
cyclononadecino[12,11-b]quinoline-10- carboxamide 19-oxide 820.6
A1, B26, C14 117 ##STR00334##
(3aR,7S,10S,12R,24aR)-7-cyclopentyl-N-
((1R,2S)-1-{[(cyclopropylsulfonyl)amino]
carbonyl}-2-vinylcyclopropyl)-16-methoxy-3a-
methyl-5,8-dioxo-1,2,3,3a,5,6,7,8,11,12,
20,21,22,23,24,24a-hexadecahydro-10H-9,12-
methanocyclopenta[18,19][1, 10,3,6]dioxadiazacyclo
nonadecino[12,11- b]quinoline-10-carboxamide 822.7 A3, B26, C14 118
##STR00335## (3aR,7S,10S,12R,24aR)-7-cyclopentyl-N-
((1R,2R)-1-{[(cyclopropylsulfonyl)amino]
carbonyl}-2-ethylcyclopropyl)-16-methoxy-3a-
methyl-5,8-dioxo-1,2,3,3a,5,6,7,8,11,
12,20,21,22,23,24,24a-hexadecahydro-10H-
9,12-methanocyclopenta[18,19][1, 10,3,6]dioxadiazacyclo
nonadecino[12,11- b]quinoline-10-carboxamide 795.8 A1, B27, C17
Example 119
(3aR,7S,10S,12R,24aR)-7-t-butyl-N-((1R,2S)-1-{[(cyclopropylsulfonyl)amino]-
carbonyl}-2-vinylcyclopropyl)-16-methoxy-5,8-dioxo-1,2,3,3a,5,6,7,8,11,12,-
20,21,22,23,24,24a-hexadecahydro-10H-9,12-methanocyclopenta[18,19][1,10,3,-
6]dioxadiazacyclononadecino[11,12-b]quinoxaline-10-carboxamide
##STR00336##
[0678] Step 1: Methyl
(3aS,7S,10S,12R,24aS)-7-cyclopentyl-5,8-dioxo-1,2,3,3a,5,6,7,8,11,12,20,2-
1,22,23,24,24a-hexadecahydro-10H-9,12-methanocyclopenta[18,19][1,10,3,6]di-
oxadiazacyclononadecino[12,11-b]quinoline-10-carboxylate
##STR00337##
[0680] Following the procedure described for example 94 Steps 1-4,
a combination of Intermediates B23b and C14 furnished the title
compound as a solid.
Step 2: Methyl
(3aS,7S,10S,12R,24aS)-7-cyclopentyl-16-methoxy-5,8-dioxo-1,2,3,3a,5,6,7,8-
,11,12,20,21,22,23,24,24a-hexadecahydro-10H-9,12-methanocyclopenta[18,19][-
1,10,3,6]dioxadiazacyclononadecino[12,11-b]quinoline-10-carboxylate
19-oxide
##STR00338##
[0682] m-CPBA (46.6 mg, 0.27 mmol) was added to a stirred solution
of the product of Step 1 (130 mg, 0.225 mmol) in DCM (1.13 ml) at
0.degree. C. Additional mCPBA was added after 1 hour (66.0 mg,
0.383 mmol) and after 4 hours (38.8 mg, 0.225 mmol). The mixture
was diluted with DCM (1 mL) and stirred for 1 hour. The reaction
was diluted with DCM, and the organic layer was washed with 10%
Na.sub.2S.sub.2O.sub.3(aq.) and 10% NaHCO.sub.3(aq.). The organics
were washed with brine and dried over Na.sub.2SO.sub.4 and
concentrated to give the title compound as a solid that was used
directly in the subsequent step. LCMS (ES+) m/z 363.8
(M+H).sup.+.
Step 3:
(3aS,7S,10S,12R,24aS)-7-Cyclopentyl-N-((1R,2R)-1-{[(cyclopropylsul-
fonyl)amino]carbonyl}-2-ethylcyclopropyl)-16-methoxy-5,8-dioxo-1,2,3,3a,5,-
6,7,8,11,12,20,21,22,23,24,24a-hexadecahydro-10H-9,12-methanocyclopenta[18-
,19111,10,3,6]dioxadiazacyclononadecino[12,11-b]quinoline-10-carboxamide
19-oxide
[0683] Treatment of the product of Step 2, by the procedures
described in Example 94 Steps 5-6, furnished the title compound
(12% over 3 steps) as a solid. LCMS (ES+) m/z 824.6
(M+H).sup.+.
[0684] By using the appropriate A, B, and C intermediates, the
following compounds were prepared according to the procedures of
Example 94.
TABLE-US-00011 LRMS Ex. Structure Name (M + H).sup.+ Example Int.
120 ##STR00339## ((1R,13E,19S,25S,28S)-25-
cyclopentyl-N-((1R,2S)-1- {[(cyclopropylsulfonyl)amino]
carbonyl}-2-vinylcyclopropyl)-7- methoxy-23,26-dioxo-2,18-dioxa-
4,22,24,27-tetraazapentacyclo
[25.2.1.1.sup.18,22.0.sup.3,12.0.sup.5,10]hentriaconta-
3(12),4,5,7,9,10,13-heptaene-28- carboxamide 805.5 See Example 1,
Steps 1-7 A1, B30, C11 121 ##STR00340##
(1R,19S,25S,28S)-25-cyclopentyl-N- ((1R,2S)-1-
{[(cyclopropylsulfonyl)amino] carbonyl}-2-vinylcyclopropyl)-7-
methoxy-23,26-dioxo-2,18-dioxa- 4,22,24,27-tetraazapentacyclo
[25.2.1.1.sup.19,22.0.sup.3,12.0.sup.5,10]hentriaconta-
3(12),4,5,7,9,10-hexaene-28- carboxamide 807.4 See Example 3, Steps
1 & 3, using product of Example 120, Step 6 A1, B30, C11 122
##STR00341## (1R,13E,19S,25S,28S)-25- cyclopentyl-N-((1R,2R)-1-
{[(cyclopropylsulfonyl)amino] carbonyl}-2-ethylcyclopropyl-7-
methoxy-23,26-dioxo-2,18-dioxa- 4,22,24,27-tetraazapentacyclo
[25.2.1.1.sup.19,22.0.sup.3,12.0.sup.5,10]hentriaconta-
3(12),4,5,7,9,10,13-heptaene-28- carboxamide 807.5 See Example 2
A3, B30, C11 123 ##STR00342## (1R,19S,25S,28S)-25-
cyclopentyl-N-((1R,2R)-1- {[(cyclopropylsulfonyl)amino]
carbonyl}-2-ethylcyclopropyl)-7- methoxy-23,26-dioxo-2,18-dioxa-
4,22,24,27-tetraazapentacyclo
[25.2.1.1.sup.19,22.0.sup.3,12.0.sup.5,10]hentriaconta-
3(12),4,5,7,9,10-hexaene-28- carboxamide 809.4 See Example 3, Steps
1 & 3, and Example 2, using product of Example 120, Step 6 A3,
B30, C11 124 ##STR00343## (1R,13E,19R,25S,28S)-25-
cyclopentyl-N-((1R,2S)-1- {[(cyclopropylsulfonyl)amino]
carbonyl}-2-vinylcyclopropyl)-7- methoxy-23,26-dioxo-2,18-dioxa-
4,22,24,27-tetraazapentacyclo
[25.2.1.1.sup.19,22.0.sup.3,12.0.sup.5,10]hentriaconta-
3(12),4,5,7,9,10,13-heptaene-28- carboxamide 805.4 See Example 1,
Steps 1-7 A1, B31, C11 125 ##STR00344##
(4S,7S,9R,21E)-4-cyclohexyl-N- ((1R,2S)-1-
{[(cyclopropylsulfonyl)amino] carbonyl}-2-vinylcyclopropyl)-15-
methoxy-2,5-dioxo-10,26-dioxa- 1,3,6,12-tetraazapentacyclo
[25.2.2.1.sup.6,9.0.sup.11,20.0.sup.13,18]dotriaconta-
11(20),12,13,15,17,18,21-heptaene-7- carboxamide 834.1 See Example
1, Steps 1-7 A1, B32, C11
Example 137
[0685]
(1R,20S,26S,29S)-26-cyclopentyl-N-((1R,2S)-1-{[(cyclopropylsulfonyl-
)amino]carbonyl}-2-vinylcyclopropyl)-7-methoxy-24,27-dioxo-2,19-dioxa-4,23-
,25,28-tetraazahexacyclo[26.2.1.1.sup.20,23.0.sup.3,12.0.sup.13,15]dotriac-
onta-3(12),4,5,7,9,10-hexaene-29-carboxamide
##STR00345##
Step 1 Methyl
(1R,13E,19S,25S,28S)-25-cyclopentyl-7-methoxy-23,26-dioxo-2,18-dioxa-4,22-
,24,27-tetraazapentacyclo[25.2.1.1.sup.19,22.0.sup.3,12.0.sup.5,10]hentria-
conta-3(12),4,5,7,9,10,13-heptaene-28-carboxylate
##STR00346##
[0687] Methyl
(1R,13E,19S,25S,28S)-25-cyclopentyl-7-methoxy-23,26-dioxo-2,18-dioxa-4,22-
,24,27-tetraazapentacyclo[25.2.1.1.sup.19,22.0.sup.3,12.0.sup.5,10]hentria-
conta-3(12),4,5,7,9,10,13-heptaene-28-carboxylate was prepared
using the procedures of Example 1 Steps 1-5, employing
Intermediates B30 and C11. LCMS (ES) m/z 607.1 (M+H).sup.+.
Step 2: Methyl
(1R,20S,26S,29S)-26-cyclopentyl-7-methoxy-24,27-dioxo-2,19-dioxa-4,23,25,-
28-tetraazahexacyclo[26.2.1.1.sup.20,23.0.sup.3,12.0.sup.5,10.0.sup.13,15]-
dotriaconta-3(12),4,5,7,9,10-hexaene-29-carboxylate
##STR00347##
[0689] Pd(OAc).sub.2 (6.7 mg, 0.03 mmol) was added to a solution of
the product of Step 1 (90 mg, 0.15 mmol) in Et.sub.2O (6 mL). A
freshly prepared solution of diazomethane in Et.sub.2O was then
added dropwise to this solution. Repeated additions of diazomethane
solution gave .about.60% conversion to product. N.sub.2 was bubbled
through the reaction mixture. The reaction mixture was concentrated
and purified by reverse-phase HPLC to give the title product. LCMS
(ES) m/z 621.1 (M+H).sup.+.
Step 3:
(1R,20S,26S,29S)-26-cyclopentyl-N-((1R,2S)-1-{[(cyclopropylsulfony-
l)amino]carbonyl}-2-vinylcyclopropyl)-7-methoxy-24,27-dioxo-2,19-dioxa-4,2-
3,25,28-tetraazahexacyclo[26.2.1.1.sup.20,23.0.sup.3,12.0.sup.5,10.0.sup.1-
3,15]dotriaconta-3 (12),4,5,7,9,10-hexaene-29-carboxamide
[0690] The title compound was prepared from the product of Step 2,
using the procedures of Example 1 Steps 6 and 7. LCMS (ES) m/z
819.9 (M+H).sup.+.
Example 138
(1R,18R,22R,26S,29S)-26-Cyclopentyl-N-((1R,2S)-1-{[(cyclopropylsulfonyl)am-
ino]carbonyl}-2-vinylcyclopropyl)-11,24,27-trioxo-2,23-dioxa-12,25,28-tria-
zapentacyclo[26.2.1.0.sup.3,12.0.sup.5,10.0.sup.18,22]hentriaconta-3,5,7,9-
-tetraene-29-carboxamide
##STR00348##
[0691] Step 1: 2-But-3-en-1-ylisoquinoline-1,3(2H,4H)-dione
##STR00349##
[0693] A solution of homophthalic anhydride (250 mg, 1.54 mmol) and
3-buten-1-amine (132 mg, 1.85 mmol) in PhMe (5 mL) was heated to
reflux and stirred for 18 hours. The reaction mixture was
concentrated and purified by SO.sub.2 chromatography (gradient
elution, 10-40% EtOAc/hexanes) to give the title compound. LCMS
(ES) m/z 353.5 (M+H).sup.+ 216.0.
Step 2:
(1R,18R,22R,26S,29S)-26-Cyclopentyl-N-((1R,2S)-1-{[(cyclopropylsul-
fonyl)amino]carbonyl}-2-vinylcyclopropyl)-11,24,27-trioxo-2,23-dioxa-12,25-
,28-triazapentacyclo[26.2.1.0.sup.3,12.0.sup.5,10.0.sup.18,22]hentriaconta-
-3,5,7,9-tetraene-29-carboxamide
[0694] The title compound was prepared from the product of Step 1,
using the following sequence of procedures: Example 1 Steps 1, 3, 4
(using Intermediate B24) and 5; and Example 3 Steps 1-3. LCMS (ES)
m/z 792.2 (M+H).sup.+.
[0695] It will be appreciated that various of the above-discussed
and other features and functions, or alternatives thereof, may be
desirably combined into many other different systems or
applications. Also that various presently unforeseen or
unanticipated alternatives, modifications, variations or
improvements therein may be subsequently made by those skilled in
the art which are also intended to be encompassed by the following
claims.
* * * * *