U.S. patent application number 12/477581 was filed with the patent office on 2010-07-08 for inhibitors of serine proteases, particularly hcv ns3-ns4a protease.
Invention is credited to Kevin M. Cottrell, Lawrence F. Courtney, Luc J. Farmer, Mark A. Murcko, Robert B. Perni, Janos Pitlik, John H. van Drie.
Application Number | 20100173851 12/477581 |
Document ID | / |
Family ID | 29250748 |
Filed Date | 2010-07-08 |
United States Patent
Application |
20100173851 |
Kind Code |
A1 |
Pitlik; Janos ; et
al. |
July 8, 2010 |
INHIBITORS OF SERINE PROTEASES, PARTICULARLY HCV NS3-NS4A
PROTEASE
Abstract
The present invention relates to compounds that inhibit serine
protease activity, particularly the activity of hepatitis C virus
NS3-NS4A protease. As such, they act by interfering with the life
cycle of the hepatitis C virus and are also useful as antiviral
agents. The invention further relates to compositions comprising
these compounds either for ex vivo use or for administration to a
patient suffering from HCV infection. The invention also relates to
methods of treating an HCV infection in a patient by administering
a composition comprising a compound of this invention. The
invention further relates to processes for preparing these
compounds.
Inventors: |
Pitlik; Janos; (Westborough,
MA) ; Cottrell; Kevin M.; (Cambridge, MA) ;
Farmer; Luc J.; (Foxboro, MA) ; Perni; Robert B.;
(Marlborough, MA) ; Courtney; Lawrence F.;
(Medway, MA) ; van Drie; John H.; (Andover,
MA) ; Murcko; Mark A.; (Holliston, MA) |
Correspondence
Address: |
VERTEX PHARMACEUTICALS INC.
130 WAVERLY STREET
CAMBRIDGE
MA
02139-4242
US
|
Family ID: |
29250748 |
Appl. No.: |
12/477581 |
Filed: |
June 3, 2009 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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11880629 |
Jul 23, 2007 |
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12477581 |
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10412600 |
Apr 11, 2003 |
7273885 |
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11880629 |
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60371846 |
Apr 11, 2002 |
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Current U.S.
Class: |
514/1.1 ;
530/323 |
Current CPC
Class: |
C07D 403/14 20130101;
C07D 409/12 20130101; A61P 31/14 20180101; A61P 1/16 20180101; C07D
209/42 20130101; C07K 5/1024 20130101; C07D 401/14 20130101; C07D
403/12 20130101; A61P 37/02 20180101; C07D 417/12 20130101; C07D
209/12 20130101; C07D 401/12 20130101; C07K 5/1027 20130101; A61P
43/00 20180101; A61P 31/12 20180101; C07K 5/06008 20130101; C07D
405/12 20130101; C07K 5/0812 20130101; C07D 405/14 20130101; C07D
471/04 20130101 |
Class at
Publication: |
514/17 ;
530/323 |
International
Class: |
A61K 38/08 20060101
A61K038/08; C07K 5/02 20060101 C07K005/02; A61P 31/14 20060101
A61P031/14; A01N 43/38 20060101 A01N043/38; A01P 1/00 20060101
A01P001/00 |
Claims
1.-25. (canceled)
26. A compound of formula (II): ##STR00301## wherein: X.sub.1 is
--N(R.sub.20)--, --O--, --S--, or --C(R').sub.2--; X.sub.2 is
--C(O)--, --C(S)--, --S(O)--, or --S(O).sub.2--; W is: ##STR00302##
m is 0 or 1; each R.sub.17 is independently: hydrogen-,
(C1-C12)-aliphatic-, (C3-C10)-cycloalkyl- or cycloalkenyl-,
[(C3-C10)-cycloalkyl- or cycloalkenyl]-(C1-C12)-aliphatic-,
(C6-C10)-aryl-, (C6-C10)-aryl-(C1-C12)aliphatic-,
(C3-C10)-heterocyclyl-, (C3-C10)-heterocyclyl-(C1-C12)-aliphatic-,
(C5-C10)heteroaryl-, or (C5-C10)heteroaryl-(C1-C12)-aliphatic-, or
two R.sub.17 groups, which are bound to the same nitrogen atom,
form together with that nitrogen atom, a (C3-C10)-membered
heterocyclic ring having in addition to the nitrogen up to 2
additional heteroatoms selected from N, NH, O, S, SO, and SO.sub.2;
wherein R.sub.17 is optionally substituted with up to 3 J
substituents; each R.sub.18 is independently --OR'; or the OR'
groups together with the boron atom, is a (C5-C20)-membered
heterocyclic ring having in addition to the boron up to 3
additional heteroatoms selected from N, NH, O, S, SO, and SO.sub.2;
R.sub.5 and R.sub.5' are independently hydrogen or
(C1-C12)-aliphatic, wherein any hydrogen is optionally replaced
with halogen, and wherein any terminal carbon atom is optionally
substituted with sulfhydryl or hydroxy, and wherein up to two
aliphatic carbon atoms may be replaced by a heteroatom selected
from N, NH, O, S, SO, or SO.sub.2; or R.sub.5 and R.sub.5' together
with the atom to which they are bound is a 3- to 6-membered ring
having up to 2 heteroatoms selected from N, NH, O, S, SO, or
SO.sub.2; wherein the ring has up to 2 substituents selected
independently from J; R.sub.1, R.sub.1', R.sub.11, R.sub.11',
R.sub.13, and R.sub.13' are independently: hydrogen-,
(C1-C12)-aliphatic-, (C3-C10)-cycloalkyl or cycloalkenyl-,
[(C3-C10)-cycloalkyl or cycloalkenyl]-(C1-C12)-aliphatic-,
(C6-C10)-aryl-, (C6-C10)-aryl-(C1-C12)aliphatic-,
(C3-C10)-heterocyclyl-, (C6-C10)-heterocyclyl-(C1-C12)aliphatic,
(C5-C10)-heteroaryl-, or (C5-C10)-heteroaryl-(C1-C12)-aliphatic-,
wherein each of R.sub.1, R.sub.1', R.sub.11, R.sub.11', R.sub.13,
and R.sub.13' is independently and optionally substituted with up
to 3 substituents independently selected from J; wherein any ring
is optionally fused to a (C6-C10)aryl, (C5-C10)heteroaryl,
(C3-C10)cycloalkyl, or (C3-C10)heterocyclyl; wherein up to 3
aliphatic carbon atoms in each of R.sub.1, R.sub.1', R.sub.11,
R.sub.11', R.sub.13, and R.sub.13' may be replaced by a heteroatom
selected from O, N, NH, S, SO, or SO.sub.2 in a chemically stable
arrangement; or R.sub.1 and R.sub.1' together with the atom to
which they are bound is a 3- to 6-membered ring having up to 2
heteroatoms selected from N, NH, O, S, SO, or SO.sub.2; wherein the
ring has up to 2 substituents selected independently from J; or
R.sub.11 and R.sub.11' together with the atom to which they are
bound is a 3- to 6-membered ring having up to 2 heteroatoms
selected from N, NH, O, S, SO, or SO.sub.2; wherein the ring has up
to 2 substituents selected independently from J; or R.sub.13 and
R.sub.13' together with the atom to which they are bound is a 3- to
6-membered ring having up to 2 heteroatoms selected from N, NH, O,
S, SO, or SO.sub.2; wherein the ring has up to 2 substituents
selected independently from J; R.sub.2, R.sub.4, R.sub.12, and
R.sub.20 are independently hydrogen-, (C1-C12)-aliphatic-,
(C3-C10)-cycloalkyl or -cycloalkenyl-, [(C3-C10)-cycloalkyl or
-cycloalkenyl]-(C1-C12)-aliphatic-, (C6-C10)-aryl-,
(C6-C10)-aryl-(C1-C12)aliphatic-, (C3-C10)-heterocyclyl-,
(C6-C10)-heterocyclyl-(C1-C12)aliphatic, (C5-C10)-heteroaryl-, or
(C5-C10)-heteroaryl-(C1-C12)-aliphatic-, wherein each R.sub.2,
R.sub.4, R.sub.12, and R.sub.20 is independently and optionally
substituted with up to 3 substituents independently selected from
J; wherein up to two aliphatic carbon atoms in R.sub.2, R.sub.4,
R.sub.12, and R.sub.20 may be replaced by a heteroatom selected
from O, N, NH, S, SO, or SO.sub.2; or R.sub.11 and R.sub.12
together with the atoms to which they are bound form a 3- to a
20-membered mono-, a 4- to 20-membered bi-, or a 5- to 20-membered
tri-cyclic carbocyclic or heterocyclic ring system; wherein, in the
bi- and tri-cyclic ring system, each ring is linearly fused,
bridged, or spirocyclic; wherein each ring is either aromatic or
nonaromatic; wherein each heteroatom in the heterocyclic ring
system is selected from the group consisting of N, NH, O, S, SO,
and SO.sub.2; wherein each ring is optionally fused to a
(C6-C10)aryl, (C5-C10)heteroaryl, (C3-C10)cycloalkyl, or
(C3-C10)heterocyclyl; and wherein said ring has up to 3
substituents selected independently from J; or R.sub.12 and
R.sub.13 together with the atoms to which they are bound form a 4-
to a 20-membered mono-, a 5- to 20-membered bi-, or a 6- to
20-membered tri-cyclic carbocyclic or heterocyclic ring system;
wherein, in the bi- and tri-cyclic ring system, each ring is
linearly fused, bridged, or spirocyclic; wherein each ring is
either aromatic or nonaromatic; wherein each heteroatom in the
heterocyclic ring system is selected from the group consisting of
N, NH, O, S, SO, and SO.sub.2; wherein each ring is optionally
fused to a (C6-C10)aryl, (C5-C10)heteroaryl, (C3-C10)cycloalkyl, or
(C3-C10)heterocyclyl; and wherein said ring has up to 3
substituents selected independently from J; or R.sub.11 and
R.sub.13 together with the atoms to which they are bound form a 5-
to a 20-membered mono-, a 6- to 20-membered bi-, or a 7- to
20-membered tri-cyclic carbocyclic or heterocyclic ring system;
wherein, in the bi- and tri-cyclic ring system, each ring is
linearly fused, bridged, or spirocyclic; wherein each ring is
either aromatic or nonaromatic; wherein each heteroatom in the
heterocyclic ring system is selected from the group consisting of
N, NH, O, S, SO, and SO.sub.2; wherein each ring is optionally
fused to a (C6-C10)aryl, (C5-C10)heteroaryl, (C3-C10)cyclo alkyl,
or (C3-C10)heterocyclyl; and wherein said ring has up to 3
substituents selected independently from J; or R.sub.11, R.sub.12,
and R.sub.13 together with the atoms to which they are bound form a
5- to a 20-membered bi-, or a 6- to 20-membered tri-cyclic
carbocyclic or heterocyclic ring system; wherein, in the bi- and
tri-cyclic ring system, each ring is linearly fused, bridged, or
spirocyclic; wherein each ring is either aromatic or nonaromatic;
wherein each heteroatom in the heterocyclic ring system is selected
from the group consisting of N, NH, O, S, SO, and SO.sub.2; wherein
each ring is optionally fused to a (C6-C10)aryl,
(C5-C10)heteroaryl, (C3-C10)cyclo alkyl, or (C3-C10)heterocyclyl;
and wherein said ring has up to 3 substituents selected
independently from J; or R.sub.13' and R.sub.2 together with the
atoms to which they are bound form a 3- to a 20-membered mono-, a
4- to 20-membered bi-, or a 5- to 20-membered tri-cyclic
carbocyclic or heterocyclic ring system; wherein, in the bi- and
tri-cyclic ring system, each ring is linearly fused, bridged, or
spirocyclic; wherein each ring is either aromatic or nonaromatic;
wherein each heteroatom in the heterocyclic ring system is selected
from the group consisting of N, NH, O, S, SO, and SO.sub.2; wherein
each ring is optionally fused to a (C6-C10)aryl,
(C5-C10)heteroaryl, (C3-C10)cyclo alkyl, or (C3-C10)heterocyclyl;
and wherein said ring has up to 3 substituents selected
independently from J; or R.sub.5 and R.sub.13 together with the
atoms to which they are bound form a 18- to a 23-membered mono-, a
19- to 24-membered bi-, or a 20- to 25-membered tri-cyclic
carbocyclic or heterocyclic ring system; wherein, in the bi- and
tri-cyclic ring system, each ring is linearly fused, bridged, or
spirocyclic; wherein each ring is either aromatic or nonaromatic;
wherein each heteroatom in the heterocyclic ring system is selected
from the group consisting of N, NH, O, S, SO, and SO.sub.2; wherein
each ring is optionally fused to a (C6-C10)aryl,
(C5-C10)heteroaryl, (C3-C10)cycloalkyl, or (C3-C10)heterocyclyl;
and wherein said ring has up to 6 substituents selected
independently from J; or R.sub.1 and R.sub.12 together with the
atoms to which they are bound form a 18- to a 23-membered mono-, a
19- to 24-membered bi-, or a 20- to 25-membered tri-cyclic
carbocyclic or heterocyclic ring system; wherein, in the bi- and
tri-cyclic ring system, each ring is linearly fused, bridged, or
spirocyclic; wherein each ring is either aromatic or nonaromatic;
wherein each heteroatom in the heterocyclic ring system is selected
from the group consisting of N, NH, O, S, SO, and SO.sub.2; wherein
each ring is optionally fused to a (C6-C10)aryl,
(C5-C10)heteroaryl, (C3-C10)cycloalkyl, or (C3-C10)heterocyclyl;
and wherein said ring has up to 6 substituents selected
independently from J; or R.sub.14 is --H, --S(O)R', --S(O).sub.2R',
--C(O)R', --C(O)OR', --C(O)N(R').sub.2, --N(R')C(O)R',
--N(COR')COR', --SO.sub.2N(R').sub.2, --SO.sub.3R', --C(O)C(O)R',
--C(O)CH.sub.2C(O)R', --C(S)R', --C(S)N(R').sub.2,
--(CH.sub.2).sub.0-2NHC(O)R', --N(R')N(R')COR',
--N(R')N(R')C(O)OR', --N(R')N(R')CON(R').sub.2, --N(R')SO.sub.2R',
--N(R')SO.sub.2N(R').sub.2, --N(R')C(O)OR', --N(R')C(O)R',
--N(R')C(S)R', --N(R')C(O)N(R').sub.2, --N(R')C(S)N(R').sub.2,
--N(COR')COR', --N(OR')R', --C(.dbd.NH)N(R').sub.2, --C(O)N(OR')R',
--C(.dbd.NOR')R', --OP(O)(OR').sub.2, --P(O)(R').sub.2,
--P(O)(OR').sub.2, or --P(O)(H)(OR'); R.sub.15 and R.sub.16 are
independently halogen, --OR', --OC(O)N(R').sub.2, --NO.sub.2, --CN,
--CF.sub.3, OCF.sub.3, --R', oxo, 1,2-methylenedioxy,
1,2-ethylenedioxy, --N(R').sub.2, --SR', --SOR', --SO.sub.2R',
--SO.sub.2N(R').sub.2, --SO.sub.3R', --C(O)R', --C(O)C(O)R',
--C(O)CH.sub.2C(O)R', --C(S)R', --C(O)OR', --OC(O)R',
--C(O)N(R').sub.2, --OC(O)N(R').sub.2, --C(S)N(R').sub.2,
--(CH.sub.2).sub.0-2NHC(O)R', --N(R')N(R')COR',
--N(R')N(R')C(O)OR', --N(R')N(R')CON(R').sub.2, --N(R')SO.sub.2R',
--N(R')SO.sub.2N(R').sub.2, --N(R')C(O)OR', --N(R')C(O)R',
--N(R')C(S)R', --N(R')C(O)N(R').sub.2, --N(R')C(S)N(R').sub.2,
--N(COR')COR', --N(OR')R', --CN, --C(.dbd.NH)N(R').sub.2,
--C(O)N(OR')R', --C(.dbd.NOR')R', --OP(O)(OR').sub.2,
--P(O)(R').sub.2, --P(O)(OR').sub.2, or --P(O)(H)(OR'); Z.sub.2 is
.dbd.O, .dbd.NR', .dbd.NOR', or .dbd.C(R').sub.2; R.sub.19 is
--OR', --CF.sub.3, --OCF.sub.3, --R', --N(R').sub.2, --SR',
--C(O)R', --COOR'--CON(R').sub.2, --N(R')COR', or --N(COR')COR'; J
is halogen, --OR', --OC(O)N(R').sub.2, --NO.sub.2, --CN,
--CF.sub.3, --OCF.sub.3, --R', oxo, thioxo, 1,2-methylenedioxy,
1,2-ethylenedioxy, --N(R').sub.2, --SR', --SOR', --SO.sub.2R',
--SO.sub.2N(R').sub.2, --SO.sub.3R', --C(O)R', --C(O)C(O)R',
--C(O)CH.sub.2C(O)R', --C(S)R', --C(O)OR', --OC(O)R',
--C(O)N(R').sub.2, --OC(O)N(R').sub.2, --C(S)N(R').sub.2,
--(CH.sub.2).sub.0-2NHC(O)R', --N(R')N(R')COR',
--N(R')N(R')C(O)OR', --N(R')N(R')CON(R').sub.2, --N(R')SO.sub.2R',
--N(R')SO.sub.2N(R').sub.2, --N(R')C(O)OR', --N(R')C(O)R',
--N(R')C(S)R', --N(R')C(O)N(R').sub.2, --N(R')C(S)N(R').sub.2,
--N(COR')COR', --N(OR')R', --CN, --C(.dbd.NH)N(R').sub.2,
--C(O)N(OR')R', --C(.dbd.NOR')R', --OP(O)(OR').sub.2,
--P(O)(R').sub.2, --P(O)(OR').sub.2, or --P(O)(H)(OR'); wherein:
two R' groups together with the atoms to which they are bound form
a 3- to 10-membered aromatic or non-aromatic ring having up to 3
heteroatoms independently selected from N, NH, O, S, SO, or
SO.sub.2, wherein the ring is optionally fused to a (C6-C10)aryl,
(C5-C10)heteroaryl, (C3-C10)cycloalkyl, or a (C3-C10)heterocyclyl,
and wherein any ring has up to 3 substituents selected
independently from J.sub.2; or each R' is independently selected
from: hydrogen-, (C1-C12)-aliphatic-, (C3-C10)-cycloalkyl or
-cycloalkenyl-, [(C3-C10)-cycloalkyl or
-cycloalkenyl]-(C1-C12)-aliphatic-, (C6-C10)-aryl-,
(C6-C10)-aryl-(C1-C12)aliphatic-, (C3-C10)-heterocyclyl-,
(C6-C10)-heterocyclyl-(C1-C12)aliphatic-, (C5-C10)-heteroaryl-, or
(C5-C10)-heteroaryl-(C1-C12)-aliphatic-, wherein R' has up to 3
substituents selected independently from J.sub.2; and J.sub.2 is
halogen, --OR', --OC(O)N(R').sub.2, --NO.sub.2, --CN, --CF.sub.3,
--OCF.sub.3, --R', oxo, thioxo, 1,2-methylenedioxy, --N(R').sub.2,
--SR', --SOR', --SO.sub.2R', --SO.sub.2N(R').sub.2, --SO.sub.3R',
--C(O)R', --C(O)C(O)R', --C(O)CH.sub.2C(O)R', --C(S)R', --C(O)OR',
--OC(O)R', --C(O)N(R').sub.2, --OC(O)N(R').sub.2,
--C(S)N(R').sub.2, --(CH.sub.2).sub.0-2NHC(O)R', --N(R')N(R')COR',
--N(R')N(R')C(O)OR', --N(R')N(R')CON(R').sub.2, --N(R')SO.sub.2R',
--N(R')SO.sub.2N(R').sub.2, --N(R')C(O)OR', --N(R')C(O)R',
--N(R')C(S)R', --N(R')C(O)N(R').sub.2, --N(R')C(S)N(R').sub.2,
--N(COR')COR', --N(OR')R', --CN, --C(.dbd.NH)N(R').sub.2,
--C(O)N(OR')R', --C(.dbd.NOR')R', --OP(O)(OR').sub.2,
--P(O)(R').sub.2, --P(O)(OR').sub.2, or --P(O)(H)(OR').
27. The compound according to claim 26, wherein: R.sub.11 is H; and
R.sub.12 is (C1-C6)-alkyl, (C3-C10)-cycloalkyl,
[(C3-C10)-cycloalkyl]-(C1-C12)-alkyl, (C6-C10)-aryl,
(C6-C10)-aryl-(C1-C6)alkyl, (C3-C10)-heterocyclyl,
(C6-C10)-heterocyclyl-(C1-C6)alkyl, (C5-C10)-heteroaryl, or
(C5-C10)-heteroaryl-(C1-C6)-alkyl.
28. The compound according to claim 27, wherein R.sub.12 is
isobutyl, cyclohexyl, cyclohexylmethyl, benzyl, or phenylethyl.
29. The compound according to claim 26, wherein: R.sub.11 is:
(C1-C6)-alkyl, (C3-C10)-cycloalkyl,
[(C3-C10)-cycloalkyl]-(C1-C12)-alkyl, (C6-C10)-aryl,
(C6-C10)-aryl-(C1-C6)alkyl; (C3-C10)-heterocyclyl,
(C6-C10)-heterocyclyl-(C1-C6)alkyl, (C5-C10)-heteroaryl, or
(C5-C10)-heteroaryl-(C1-C6)-alkyl; and R.sub.12 is H.
30. The compound according to claim 26, wherein the ##STR00303##
radical is: ##STR00304##
31. The compound according to claim 30, wherein the ##STR00305##
radical is: ##STR00306## ##STR00307##
32. The compound according to claim 26, wherein the ##STR00308##
radical is: ##STR00309## wherein each B independently forms a 3- to
a 20-membered carbocyclic or heterocyclic ring system; wherein each
ring B is either aromatic or nonaromatic; wherein each heteroatom
in the heterocyclic ring system is N, NH, O, S, SO, or SO.sub.2;
wherein each ring is optionally fused to a (C6-C10)aryl,
(C5-C10)heteroaryl, (C3-C10)cyclo alkyl, or (C3-C10)heterocyclyl;
and wherein each ring has up to 3 substituents selected
independently from J.
33. The compound according to claim 32, wherein the ##STR00310##
radical is: ##STR00311## ##STR00312##
34. The compound according to claim 32, wherein the ##STR00313##
radical is: ##STR00314## ##STR00315## ##STR00316##
35. The compound according to claim 32, wherein the ##STR00317##
radical is: ##STR00318## ##STR00319## ##STR00320##
36. The compound according to claim 32, wherein the ##STR00321##
radical is: ##STR00322## ##STR00323## ##STR00324##
37. The compound according to claim 32, wherein the ##STR00325##
radical is: ##STR00326##
38. The compound according to claim 26, wherein the ##STR00327##
radical is: ##STR00328## wherein each B independently forms a 3- to
a 20-membered carbocyclic or heterocyclic ring system; wherein each
ring B is either aromatic or nonaromatic; wherein each heteroatom
in the heterocyclic ring system is N, NH, O, S, SO, or SO.sub.2;
wherein each ring is optionally fused to a (C6-C10)aryl,
(C5-C10)heteroaryl, (C3-C10)cyclo alkyl, or (C3-C10)heterocyclyl;
and wherein each ring has up to 3 substituents selected
independently from J.
39. The compound according to claim 38, wherein the ##STR00329##
radical ##STR00330## ##STR00331## ##STR00332##
40. The compound according to claim 38, wherein the ##STR00333##
radical is: ##STR00334## ##STR00335## ##STR00336##
41. The compound according to claim 26, wherein the ##STR00337##
radical is: ##STR00338## ##STR00339##
42. The compound according to claim 26, wherein the ##STR00340##
radical is: ##STR00341## wherein B forms a 3- to a 20-membered
carbocyclic or heterocyclic ring system; wherein each ring B is
either aromatic or nonaromatic; wherein each heteroatom in the
heterocyclic ring system is N, NH, O, S, SO, or SO.sub.2; wherein
each ring is optionally fused to a (C6-C10)aryl,
(C5-C10)heteroaryl, (C3-C10)cycloalkyl, or (C3-C10)heterocyclyl;
and wherein each ring has up to 3 substituents selected
independently from J.
43. The compound according to claim 42, wherein the ##STR00342##
radical is: ##STR00343## ##STR00344##
44. The compound according to claim 26, wherein R.sub.11 and
R.sub.12 together with the atoms to which they are bound form a 6-
to 10-membered mono- or bicyclic carbocyclic or heterocyclic ring
system; wherein each heteroatom in the heterocyclic ring system is
selected from the group consisting of N, NH, O, S, SO, and
SO.sub.2; and wherein said ring has up to 3 substituents selected
independently from J.
45. The compound according to claim 26, wherein R.sub.5' is H and
R.sub.5 is (C1-C6)-alkyl, wherein the alkyl is optionally
substituted with fluoro or --SH.
46. The compound according to claim 45, wherein the (C1-C6)-alkyl
is substituted with 1 to 3 fluoro groups.
47. The compound according to claim 46, wherein R.sub.5 and
R.sub.5' are independently: ##STR00345##
48. The compound according to claim 26, wherein R.sub.13 is:
(C1-C6)-alkyl, (C3-C10)-cycloalkyl,
[(C3-C10)-cycloalkyl]-(C1-C12)-alkyl, (C6-C10)-aryl,
(C6-C10)-aryl-(C1-C6)alkyl, (C3-C10)-heterocyclyl,
(C6-C10)-heterocyclyl-(C1-C6)alkyl, (C5-C10)-heteroaryl, or
(C5-C10)-heteroaryl-(C1-C6)-alkyl; wherein R.sub.13 is optionally
substituted with up to 3 substituents independently selected from
J; and wherein up to 3 aliphatic carbon atoms in R.sub.13 may be
replaced by a heteroatom selected from O, NH, S, SO, or SO.sub.2 in
a chemically stable arrangement.
49. The compound according to claim 48, wherein R.sub.13 is:
##STR00346##
50. The compound according to claim 26, wherein R.sub.1 is
(C1-C6)-alkyl, (C3-C10)-cycloalkyl,
[(C3-C10)-cycloalkyl]-(C1-C12)-alkyl, (C6-C10)-aryl,
(C6-C10)-aryl-(C1-C6)alkyl, (C3-C10)-heterocyclyl,
(C6-C10)-heterocyclyl-(C1-C6)alkyl, (C5-C10)-heteroaryl, or
(C5-C10)-heteroaryl-(C1-C6)-alkyl; wherein R.sub.1 is optionally
substituted with up to 3 substituents independently selected from
J; and wherein up to 3 aliphatic carbon atoms in R.sub.1 may be
replaced by a heteroatom selected from O, NH, S, SO, or SO.sub.2 in
a chemically stable arrangement.
51. The compound according to claim 36, wherein R.sub.1 is:
##STR00347##
52. The compound according to claim 26, wherein W is:
##STR00348##
53. The compound according to claim 52, wherein W is: ##STR00349##
##STR00350## ##STR00351##
54. The compound according to claim 26, wherein R.sub.2, R.sub.4,
and R.sub.20 are each independently H or (C1-C3)-alkyl.
55. The compound according to claim 54, wherein R.sub.2, R.sub.4,
and R.sub.20 are each H.
56. The compound according to claim 26, wherein R.sub.14 is
hydrogen.
57. The compound according to claim 26, wherein each R.sub.15 and
R.sub.16 is independently (C1-C6)-alkyl-.
58. The compound according to claim 57, wherein each R.sub.15 and
R.sub.16 are each methyl.
59. The compound according to claim 26, wherein Z.sub.2 is O and
R.sub.19 is: (C1-C6)-alkyl- (C3-C10)-cycloalkyl-,
[(C3-C10)-cycloalkyl]-(C1-C12)-aliphatic-, (C6-C10)-aryl-,
(C6-C10)-aryl-(C1-C6)alkyl, (C3-C10)-heterocyclyl,
(C6-C10)-heterocyclyl-(C1-C6)alkyl, (C5-C10)-heteroaryl, or
(C5-C10)-heteroaryl-(C1-C6)-alkyl; wherein R.sub.19 has up to 3
substituents selected independently from J.sub.2; and wherein up to
3 aliphatic carbon atoms in R.sub.19 may be replaced by a
heteroatom selected from O, NH, S, SO, or SO.sub.2 in a chemically
stable arrangement.
60. The compound according to claim 59, wherein each R.sub.19 is
methyl.
61. The compound according to claim 26, wherein R.sub.14 is H;
Z.sub.2 is CH.sub.2; and R.sub.19 is: ##STR00352##
62. The compound according to claim 26, wherein each R.sub.19 is
methyl; Z.sub.2 is O; R.sub.14 is: ##STR00353##
63. The compound according to claim 26, wherein each R.sub.19 is
methyl; R.sub.14 is H; and Z.sub.2 is: ##STR00354##
64. The compound according to claim 63, wherein Z.sub.2 is:
##STR00355##
65. The compound according to claim 26, wherein the compound is
63-67 or 68.
66. A composition comprising a compound according to claim 26 or a
pharmaceutically acceptable salt, derivative or prodrug thereof in
an amount effective to inhibit a serine protease; and a acceptable
carrier, adjuvant or vehicle.
67. (canceled)
68. (canceled)
69. (canceled)
70. A method of inhibiting the activity of a serine protease
comprising the step of contacting said serine protease with a
compound according to claim 26.
71. The method according to claim 70, wherein said protease is an
HCV NS3 protease.
72. A method of treating an HCV infection in a patient comprising
the step of administering to said patient a composition according
to claim 67.
73. (canceled)
74. (canceled)
75. A method of eliminating or reducing HCV contamination of a
biological sample or medical or laboratory equipment, comprising
the step of contacting said biological sample or medical or
laboratory equipment with a composition according to claim 66.
76. (canceled)
Description
CROSS-REFERENCE TO RELATED APPLICATIONS
[0001] This application claims the benefit of U.S. Provisional
Application No. 60/371,846, filed Apr. 11, 2002, which is hereby
incorporated by reference.
TECHNICAL FIELD OF THE INVENTION
[0002] The present invention relates to compounds that inhibit
serine protease activity, particularly the activity of, hepatitis C
virus NS3-NS4A protease. As such, they act by interfering with the
life cycle of the hepatitis C virus and are also useful as
antiviral agents. The invention further relates to compositions
comprising these compounds either for ex vivo use or for
administration to a patient suffering from HCV infection. The
invention also relates to methods of treating an HCV infection in a
patient by administering a composition comprising a compound of
this invention.
BACKGROUND OF THE INVENTION
[0003] Infection by hepatitis C virus ("HCV") is a compelling human
medical problem. HCV is recognized as the causative agent for most
cases of non-A, non-B hepatitis, with an estimated human
sero-prevalence of 3% globally [A. Alberti et al., "Natural History
of Hepatitis C," J. Hepatology, 31., (Suppl. 1), pp. 17-24 (1999)].
Nearly four million individuals may be infected in the United
States alone [M. J. Alter et al., "The Epidemiology of Viral
Hepatitis in the United States," Gastroenterol. Clin. North Am.,
23, pp. 437-455 (1994); M. J. Alter "Hepatitis C Virus Infection in
the United States," J. Hepatology, 31., (Suppl. 1), pp. 88-91
(1999)].
[0004] Upon first exposure to HCV only about 20% of infected
individuals develop acute clinical hepatitis while others appear to
resolve the infection spontaneously. In almost 70% of instances,
however, the virus establishes a chronic infection that persists
for decades [S. Iwarson, "The Natural Course of Chronic Hepatitis,"
FEMS Microbiology Reviews, 14, pp. 201-204 (1994); D. Lavanchy,
"Global Surveillance and Control of Hepatitis C," J. Viral
Hepatitis, 6, pp. 35-47 (1999)]. This usually results in recurrent
and progressively worsening liver inflammation, which often leads
to more severe disease states such as cirrhosis and hepatocellular
carcinoma [M. C. Kew, "Hepatitis C and Hepatocellular Carcinoma",
FEMS Microbiology Reviews, 14, pp. 211-220 (1994); I. Saito et.
al., "Hepatitis C Virus Infection is Associated with the
Development of Hepatocellular Carcinoma," Proc. Natl. Acad. Sci.
USA, 87, pp. 6547-6549 (1990)]. Unfortunately, there are no broadly
effective treatments for the debilitating progression of chronic
HCV.
[0005] The HCV genome encodes a polyprotein of 3010-3033 amino
acids [Q. L. Choo, et. al., "Genetic Organization and Diversity of
the Hepatitis C Virus." Proc. Natl. Acad. Sci. USA, 88, pp.
2451-2455 (1991); N. Kato et al., "Molecular Cloning of the Human
Hepatitis C Virus Genome From Japanese Patients with Non-A, Non-B
Hepatitis," Proc. Natl. Acad. Sci. USA, 87, pp. 9524-9528 (1990);
A. Takamizawa et. al., "Structure and Organization of the Hepatitis
C Virus Genome Isolated From Human Carriers," J. Virol., 65, pp.
1105-1113 (1991)]. The HCV nonstructural (NS) proteins are presumed
to provide the essential catalytic machinery for viral replication.
The NS proteins are derived by proteolytic cleavage of the
polyprotein [R. Bartenschlager et. al., "Nonstructural Protein 3 of
the Hepatitis C Virus Encodes a Serine-Type Proteinase Required for
Cleavage at the NS3/4 and NS4/5 Junctions," J. Virol., 67, pp.
3835-3844 (1993); A. Grakoui et. al., "Characterization of the
Hepatitis C Virus-Encoded Serine Proteinase: Determination of
Proteinase-Dependent Polyprotein Cleavage Sites," J. Virol., 67,
pp. 2832-2843 (1993); A. Grakoui et. al., "Expression and
Identification of Hepatitis C Virus Polyprotein Cleavage Products,"
J. Virol., 67, pp. 1385-1395 (1993); L. Tomei et. al., "NS3 is a
serine protease required for processing of hepatitis C virus
polyprotein", J. Virol., 67, pp. 4017-4026 (1993)].
[0006] The HCV NS protein 3 (NS3) contains a serine protease
activity that helps process the majority of the viral enzymes, and
is thus considered essential for viral replication and infectivity.
It is known that mutations in the yellow fever virus NS3 protease
decreases viral infectivity [Chambers, T. J. et. al., "Evidence
that the N-terminal Domain of Nonstructural Protein NS3 From Yellow
Fever Virus is a Serine Protease Responsible for Site-Specific
Cleavages in the Viral Polyprotein", Proc. Natl. Acad. Sci. USA,
87, pp. 8898-8902 (1990)]. The first 181 amino acids of NS3
(residues 1027-1207 of the viral polyprotein) have been shown to
contain the serine protease domain of NS3 that processes all four
downstream sites of the HCV polyprotein [C. Lin et al., "Hepatitis
C Virus NS3 Serine Proteinase: Trans-Cleavage Requirements and
Processing Kinetics", J. Virol., 68, pp. 8147-8157 (1994)].
[0007] The HCV NS3 serine protease and its associated cofactor,
NS4A, helps process all of the viral enzymes, and is thus
considered essential for viral replication. This processing appears
to be analogous to that carried out by the human immunodeficiency
virus aspartyl protease, which is also involved in viral enzyme
processing HIV protease inhibitors, which inhibit viral protein
processing are potent antiviral agents in man, indicating that
interrupting this stage of the viral life cycle results in
therapeutically active agents. Consequently it is an attractive
target for drug discovery.
[0008] Several potential HCV protease inhibitors have been
described in the prior art [PCT publication Nos. WO 02/18369, WO
02/08244, WO 00/09558, WO 00/09543, WO 99/64442, WO 99/07733, WO
99/07734, WO 99/50230, WO 98/46630, WO 98/17679 and WO 97/43310,
U.S. Pat. No. 5,990,276, M. Llinas-Brunet et al., Bioorg. Med.
Chem. Lett., 8, pp. 1713-18 (1998); W. Han et al., Bioorg. Med.
Chem. Lett., 10, 711-13 (2000); R. Dunsdon et al., Bioorg. Med.
Chem. Lett., 10, pp. 1571-79 (2000); M. Llinas-Brunet et al.,
Bioorg. Med. Chem. Lett., 10, pp. 2267-70 (2000); and S. LaPlante
et al., Bioorg. Med. Chem. Lett., 10, pp. 2271-74 (2000)].
[0009] Furthermore, the current understanding of HCV has not led to
any other satisfactory anti-HCV agents or treatments. The only
established therapy for HCV disease is interferon treatment.
However, interferons have significant side effects [M. A. Wlaker et
al., "Hepatitis C Virus: An Overview of Current Approaches and
Progress," DDT, 4, pp. 518-29 (1999); D. Moradpour et al., "Current
and Evolving Therapies for Hepatitis C," Eur. J. Gastroenterol.
Hepatol., 11, pp. 1199-1202 (1999); H. L. A. Janssen et al.
"Suicide Associated with Alfa-Interferon Therapy for Chronic Viral
Hepatitis," J. Hepatol., 21, pp. 241-243 (1994); P. F. Renault et
al., "Side Effects of Alpha Interferon," Seminars in Liver Disease,
9, pp. 273-277. (1989)] and induce long term remission in only a
fraction (.about.25%) of cases [O. Weiland, "Interferon Therapy in
Chronic Hepatitis C Virus Infection", FEMS Microbiol. Rev., 14, pp.
279-288 (1994)]. Moreover, the prospects for effective anti-HCV
vaccines remain uncertain.
[0010] Thus, there is a need for more effective anti-HCV therapies.
Such inhibitors would have therapeutic potential as protease
inhibitors, particularly as serine protease inhibitors, and more
particularly as HCV NS3 protease inhibitors. Specifically, such
compounds may be useful as antiviral agents, particularly as
anti-HCV agents.
SUMMARY OF THE INVENTION
[0011] The present invention provides a compound of formulae
(IA):
##STR00001##
wherein:
[0012] A, together with X and Y, is: [0013] a 3- to 6-membered
aromatic or non-aromatic ring having up to 3 heteroatoms
independently selected from N, NH, O, SO, or SO.sub.2; [0014]
wherein said ring is optionally fused to a (C6-C10)aryl,
(C5-C10)heteroaryl, (C3-C10)cycloalkyl or (C3-C10)heterocyclyl;
[0015] wherein A has up to 3 substituents selected independently
from J; [0016] J is halogen, --OR', --NO.sub.2, --CF.sub.3,
--OCF.sub.3, --R', oxo, --OR', --O-benzyl, --O-phenyl,
1,2-methylenedioxy, --N(R').sub.2, --SR', --SOR', --SO.sub.2R',
--C(O)R', --COOR' or --CON(R').sub.2, wherein R' is independently
selected from: [0017] hydrogen, [0018] (C1-C12)-aliphatic, [0019]
(C3-C10)-cycloalkyl or -cycloalkenyl, [0020] [(C3-C10)-cycloalkyl
or -cycloalkenyl]-(C1-C12)-aliphatic, [0021] (C6-C10)-aryl, [0022]
(C6-C10)-aryl-(C1-C12)aliphatic, [0023] (C3-C10)-heterocyclyl,
[0024] (C6-C10)-heterocyclyl-(C1-C12)aliphatic, [0025]
(C5-C10)-heteroaryl, or [0026]
(C5-C10)-heteroaryl-(C1-C12)-aliphatic;
[0027] R.sub.1 and R.sub.3 are independently: [0028]
(C1-C12)-aliphatic, [0029] (C3-C10)-cycloalkyl or -cycloalkenyl,
[0030] [(C3-C10)-cycloalkyl or -cycloalkenyl]-(C1-C12)-aliphatic,
[0031] (C6-C10)-aryl, [0032] (C6-C10)-aryl-(C1-C12)aliphatic,
[0033] (C3-C10)-heterocyclyl, [0034]
(C6-C10)-heterocyclyl-(C1-C12)aliphatic, [0035]
(C5-C10)-heteroaryl, or [0036]
(C5-C10)-heteroaryl-(C1-C12)-aliphatic, [0037] wherein each of
R.sub.1 and R.sub.3 is independently and optionally substituted
with up to 3 substituents independently selected from J; [0038]
wherein up to 3 aliphatic carbon atoms in R.sub.1 and R.sub.3 may
be replaced by a heteroatom selected from O, NH, S, SO, or SO.sub.2
in a chemically stable arrangement;
[0039] R.sub.2 and R.sub.4 are independently [0040] hydrogen,
[0041] (C1-C12)-aliphatic, [0042]
(C3-C10)-cycloalkyl-(C1-C12)-aliphatic, or [0043]
(C6-C10)aryl-(C1-C12)-aliphatic, [0044] wherein each of R.sub.2 and
R.sub.4 is independently and optionally substituted with up to 3
substituents independently selected from J; wherein up to two
aliphatic carbon atoms in R.sub.2 and R.sub.4 may be replaced by a
heteroatom selected from O, NH, S, SO, or SO.sub.2;
[0045] R.sub.5 is (C1-C12)-aliphatic, wherein any hydrogen is
optionally replaced with halogen, and wherein any hydrogen or
halogen atom bound to any terminal carbon atom of R.sub.5 is
optionally substituted with sulfhydryl or hydroxy;
[0046] W is selected from:
##STR00002##
[0047] wherein each R.sub.6 is independently: [0048] hydrogen,
[0049] (C1-C12)-aliphatic, [0050] (C6-C10)-aryl, [0051]
(C6-C10)-aryl-(C1-C12)aliphatic, [0052] (C3-C10)-cycloalkyl or
-cycloalkenyl, [0053] [(C3-C10)-cycloalkyl or
-cycloalkenyl]-(C1-C12)-aliphatic, [0054] (C3-C10)-heterocyclyl,
[0055] (C3-C10)-heterocyclyl-(C1-C12)-aliphatic, [0056]
(C5-C10)heteroaryl, or [0057]
(C5-C10)heteroaryl-(C1-C12)-aliphatic, or
[0058] two R.sub.6 groups, which are bound to the same nitrogen
atom, form together with that nitrogen atom, a
(C3-C10)-heterocyclic ring;
[0059] wherein R.sub.6 is optionally substituted with up to 3 J
substituents;
[0060] V is --C(O)N(R.sub.8)--, --S(O)N(R.sub.8)--, or
--S(O).sub.2N(R.sub.8)--;
[0061] wherein R.sub.8 is hydrogen or (C1-C12)-aliphatic;
[0062] T is selected from: [0063] (C6-C10)-aryl, [0064]
(C6-C10)-aryl-(C1-C12)aliphatic, [0065] (C3-C10)-cycloalkyl or
-cycloalkenyl, [0066] [(C3-C10)-cycloalkyl or
-cycloalkenyl]-(C1-C12)-aliphatic, [0067] (C3-C10)-heterocyclyl,
[0068] (C3-C10)-heterocyclyl-(C1-C12)-aliphatic, [0069]
(C5-C10)heteroaryl, or [0070]
(C5-C10)heteroaryl-(C1-C12)-aliphatic; or
[0071] T is selected from:
##STR00003##
wherein:
[0072] R.sub.10 is: [0073] hydrogen, [0074] (C1-C12)-aliphatic,
[0075] (C6-C10)-aryl, [0076] (C6-C10)-aryl-(C1-C12)aliphatic,
[0077] (C3-C10)-cycloalkyl or -cycloalkenyl, [0078]
[(C3-C10)-cycloalkyl or -cycloalkenyl]-(C1-C12)-aliphatic, [0079]
(C3-C10)-heterocyclyl, [0080]
(C3-C10)-heterocyclyl-(C1-C12)-aliphatic, [0081]
(C5-C10)-heteroaryl, or [0082]
(C5-C10)-heteroaryl-(C1-C12)-aliphatic,
[0083] wherein each T is optionally substituted with up to 3 J
substituents;
[0084] K is a bond, (C1-C12)-aliphatic, --O--, --S--, --C(O)--, or
--C(O)--NR.sub.9--, wherein R.sub.9 is hydrogen or
(C1-C12)-aliphatic; and
[0085] n is 1-3.
[0086] The invention also provides compounds of formula (IB):
##STR00004##
and formula (II):
##STR00005##
wherein the variables are as defined herein.
[0087] The invention also relates to compositions that comprise the
above compounds and the use thereof. Such compositions may be used
to pre-treat invasive devices to be inserted into a patient, to
treat biological samples, such as blood, prior to administration to
a patient, and for direct administration to a patient. In each case
the composition will be used to inhibit HCV replication and to
lessen the risk of or the severity of HCV infection.
[0088] The invention also relates to processes for preparing the
compounds of formulae (IA), (IB), and (II).
DETAILED DESCRIPTION OF THE INVENTION
[0089] The present invention provides a compound of formula
(I):
##STR00006##
wherein:
[0090] A, together with X and Y, is: [0091] a 3- to 6-membered
aromatic or non-aromatic ring having up to 3 heteroatoms
independently selected from N, NH, O, SO, or SO.sub.2; [0092]
wherein said ring is optionally fused to a (C6-C10)aryl,
(C5-C10)heteroaryl, (C3-C10)cycloalkyl or (C3-C10)heterocyclyl;
[0093] wherein A has up to 3 substituents selected independently
from J; [0094] J is halogen, --OR', --NO.sub.2, --CF.sub.3,
--OCF.sub.3, --R', oxo, --OR', --O-benzyl, --O-phenyl,
1,2-methylenedioxy, --N(R').sub.2, --SR', --SOR', --SO.sub.2R',
--C(O)R', --COOR' or --CON(R').sub.2, wherein R' is independently
selected from: [0095] hydrogen, [0096] (C1-C12)-aliphatic, [0097]
(C3-C10)-cycloalkyl or -cycloalkenyl, [0098] [(C3-C10)-cycloalkyl
or -cycloalkenyl]-(C1-C12)-aliphatic, [0099] (C6-C10)-aryl, [0100]
(C6-C10)-aryl-(C1-C12)aliphatic, [0101] (C3-C10)-heterocyclyl,
[0102] (C6-C10)-heterocyclyl-(C1-C12)aliphatic, [0103]
(C5-C10)-heteroaryl, or [0104]
(C5-C10)-heteroaryl-(C1-C12)-aliphatic;
[0105] R.sub.1 and R.sub.3 are independently: [0106]
(C1-C12)-aliphatic, [0107] (C3-C10)-cycloalkyl or -cycloalkenyl,
[0108] [(C3-C10)-cycloalkyl or -cycloalkenyl]-(C1-C12)-aliphatic,
[0109] (C6-C10)-aryl, [0110] (C6-C10)-aryl-(C1-C12)aliphatic,
[0111] (C3-C10)-heterocyclyl, [0112]
(C6-C10)-heterocyclyl-(C1-C12)aliphatic, [0113]
(C5-C10)-heteroaryl, or [0114]
(C5-C10)-heteroaryl-(C1-C12)-aliphatic, [0115] wherein each of
R.sub.1 and R.sub.3 is independently and optionally substituted
with up to 3 substituents independently selected from J; [0116]
wherein up to 3 aliphatic carbon atoms in R.sub.1 and R.sub.3 may
be replaced by a heteroatom selected from O, NH, S, SO, or SO.sub.2
in a chemically stable arrangement;
[0117] R.sub.2 and R.sub.4 are independently [0118] hydrogen,
[0119] (C1-C12)-aliphatic, [0120]
(C3-C10)-cycloalkyl-(C1-C12)-aliphatic, or [0121]
(C6-C10)aryl-(C1-C12)-aliphatic, [0122] wherein each of R.sub.2 and
R.sub.4 is independently and optionally substituted with up to 3
substituents independently selected from J; [0123] wherein up to
two aliphatic carbon atoms in R.sub.2 and R.sub.4 may be replaced
by a heteroatom selected from O, NH, S, SO, or SO.sub.2;
[0124] R.sub.5 is (C1-C12)-aliphatic, wherein any hydrogen is
optionally replaced with halogen, and wherein any hydrogen or
halogen atom bound to any terminal carbon atom of R.sub.5 is
optionally substituted with sulfhydryl or hydroxy;
[0125] W is selected from:
##STR00007##
[0126] wherein each R.sub.6 is independently: [0127] hydrogen,
[0128] (C1-C12)-aliphatic, [0129] (C6-C10)-aryl, [0130]
(C6-C10)-aryl-(C1-C12)aliphatic, [0131] (C3-C10)-cycloalkyl or
-cycloalkenyl, [0132] [(C3-C10)-cycloalkyl or
-cycloalkenyl]-(C1-C12)-aliphatic, [0133] (C3-C10)-heterocyclyl,
[0134] (C3-C10)-heterocyclyl-(C1-C12)-aliphatic, [0135]
(C5-C10)heteroaryl, or [0136]
(C5-C10)heteroaryl-(C1-C12)-aliphatic, or
[0137] two R.sub.6 groups, which are bound to the same nitrogen
atom, form together with that nitrogen atom, a
(C3-C10)-heterocyclic ring;
[0138] wherein R.sub.6 is optionally substituted with up to 3 J
substituents;
[0139] V is --C(O)N(R.sub.8)--, --S(O)N(R.sub.8)--, or
--S(O).sub.2N(R.sub.8)--;
[0140] wherein R.sub.8 is hydrogen or (C1-C12)-aliphatic;
[0141] T is selected from: [0142] (C6-C10)-aryl, [0143]
(C6-C10)-aryl-(C1-C12)aliphatic, [0144] (C3-C10)-cycloalkyl or
-cycloalkenyl, [0145] [(C3-C10)-cycloalkyl or
-cycloalkenyl]-(C1-C12)-aliphatic, [0146] (C3-C10)-heterocyclyl,
[0147] (C3-C10)-heterocyclyl-(C1-C12)-aliphatic, [0148]
(C5-C10)heteroaryl, or [0149]
(C5-C10)heteroaryl-(C1-C12)-aliphatic; or
[0150] T is selected from:
##STR00008##
wherein:
[0151] R.sub.10 is: [0152] hydrogen, [0153] (C1-C12)-aliphatic,
[0154] (C6-C10)-aryl, [0155] (C6-C10)-aryl-(C1-C12)aliphatic,
[0156] (C3-C10)-cycloalkyl or -cycloalkenyl, [0157]
[(C3-C10)-cycloalkyl or -cycloalkenyl]-(C1-C12)-aliphatic, [0158]
(C3-C10)-heterocyclyl, [0159]
(C3-C10)-heterocyclyl-(C1-C12)-aliphatic, [0160]
(C5-C10)-heteroaryl, or [0161]
(C5-C10)-heteroaryl-(C1-C12)-aliphatic,
[0162] wherein each T is optionally substituted with up to 3 J
substituents;
[0163] K is a bond, (C1-C12)-aliphatic, --O--, --S--, --NR.sub.9--,
--C(O)--, or --C(O)--NR.sub.9--, wherein R.sub.9 is hydrogen or
(C1-C12)-aliphatic; and
[0164] n is 1-3.
[0165] In another embodiment, the invention provides a compound of
formula (IB):
##STR00009##
wherein:
[0166] A, together with X and Y, is: [0167] a 3- to 6-membered
aromatic or non-aromatic ring having up to 3 heteroatoms
independently selected from N, NH, O, S, SO, or SO.sub.2; [0168]
wherein said ring is optionally fused to a (C6-C10)aryl,
(C5-C10)heteroaryl, (C3-C10)cycloalkyl, or (C3-C10)heterocyclyl;
[0169] wherein A has up to 3 substituents selected independently
from J and wherein the 5-membered ring to which A is fused has up
to 4 substituents selected independently from J; and [0170] wherein
X and Y are independently C(H) or N;
[0171] J is halogen, --OR', --OC(O)N(R').sub.2, --NO.sub.2, --CN,
--CF.sub.3, --OCF.sub.3, --R', oxo, thioxo, 1,2-methylenedioxy,
1,2-ethylenedioxy, --N(R').sub.2, --SR', --SOR', --SO.sub.2R',
--SO.sub.2N(R').sub.2, --SO.sub.3R', --C(O)R', --C(O)C(O)R',
--C(O)CH.sub.2C(O)R', --C(S)R', --C(O)OR', --OC(O)R',
--C(O)N(R').sub.2, --OC(O)N(R').sub.2, --C(S)N(R').sub.2,
--(CH.sub.2).sub.0-2NHC(O)R', --N(R')N(R')COR',
--N(R')N(R')C(O)OR', --N(R')N(R')CON(R').sub.2, --N(R')SO.sub.2R',
--N(R')SO.sub.2N(R').sub.2, --N(R')C(O)OR', --N(R')C(O)R',
--N(R')C(S)R', --N(R')C(O)N(R').sub.2, --N(R')C(S)N(R').sub.2,
--N(COR')COR', --N(OR')R', --CN, --C(.dbd.NH)N(R').sub.2,
--C(O)N(OR')R', --C(.dbd.NOR')R', --OP(O)(OR').sub.2,
--P(O)(R').sub.2, --P(O)(OR').sub.2, or --P(O)(H)(OR');
wherein:
[0172] two R' groups together with the atoms to which they are
bound form a 3- to 10-membered aromatic or non-aromatic ring having
up to 3 heteroatoms independently selected from N, NH, O, S, SO, or
SO.sub.2, wherein the ring is optionally fused to a (C6-C10)aryl,
(C5-C10)heteroaryl, (C3-C10)cycloalkyl, or a (C3-C10)heterocyclyl,
and wherein any ring has up to 3 substituents selected
independently from J.sub.2; or
[0173] each R' is independently selected from: [0174] hydrogen-,
[0175] (C1-C12)-aliphatic-, [0176] (C3-C10)-cycloalkyl or
-cycloalkenyl-, [0177] [(C3-C10)-cycloalkyl or
-cycloalkenyl]-(C1-C12)-aliphatic-, [0178] (C6-C10)-aryl-, [0179]
(C6-C10)-aryl-(C1-C12)aliphatic-, [0180] (C3-C10)-heterocyclyl-,
[0181] (C6-C10)-heterocyclyl-(C1-C12)aliphatic-, [0182]
(C5-C10)-heteroaryl-, or [0183]
(C5-C10)-heteroaryl-(C1-C12)-aliphatic-; wherein R' has up to 3
substituents selected independently from J.sub.2; and
[0184] J.sub.2 is halogen, --OR', --OC(O)N(R').sub.2, --NO.sub.2,
--CN, --CF.sub.3, --OCF.sub.3, --R', oxo, thioxo,
1,2-methylenedioxy, 1,2-ethylenedioxy, --N(R').sub.2, --SR',
--SOR', --SO.sub.2R', --SO.sub.2N(R').sub.2, --SO.sub.3R',
--C(O)R', --C(O)C(O)R', --C(O)CH.sub.2C(O)R', --C(S)R', --C(O)OR',
--OC(O)R', --C(O)N(R').sub.2, --OC(O)N(R').sub.2,
--C(S)N(R').sub.2, --(CH.sub.2).sub.0-2NHC(O)R', --N(R')N(R')COR',
--N(R')N(R')C(O)OR', --N(R')N(R')CON(R').sub.2, --N(R')SO.sub.2R',
--N(R')SO.sub.2N(R').sub.2, --N(R')C(O)OR', --N(R')C(O)R',
--N(R')C(S)R', --N(R')C(O)N(R').sub.2, --N(R')C(S)N(R').sub.2,
--N(COR')COR', --N(OR')R', --CN, --C(.dbd.NH)N(R').sub.2,
--C(O)N(OR')R', --C(.dbd.NOR')R', --OP(O)(OR').sub.2,
--P(O)(R').sub.2, --P(O)(OR').sub.2, or --P(O)(H)(OR').
[0185] R.sub.1 and R.sub.3 are independently: [0186]
(C1-C12)-aliphatic-, [0187] (C3-C10)-cycloalkyl- or -cycloalkenyl-,
[0188] [(C3-C10)-cycloalkyl- or -cycloalkenyl]-(C1-C12)-aliphatic-,
[0189] (C6-C10)-aryl-, [0190] (C6-C10)-aryl-(C1-C12)aliphatic-,
[0191] (C3-C10)-heterocyclyl-, [0192]
(C6-C10)-heterocyclyl-(C1-C12)aliphatic-, [0193]
(C5-C10)-heteroaryl-, or [0194]
(C5-C10)-heteroaryl-(C1-C12)-aliphatic-, [0195] wherein each of
R.sub.1 and R.sub.3 is independently and optionally substituted
with up to 3 substituents independently selected from J; [0196]
wherein up to 3 aliphatic carbon atoms in R.sub.1 and R.sub.3 may
be replaced by a heteroatom selected from O, N, NH, S, SO, or
SO.sub.2 in a chemically stable arrangement;
[0197] R.sub.2 and R.sub.4 are independently: [0198] hydrogen-,
[0199] (C1-C12)-aliphatic-, [0200]
(C3-C10)-cycloalkyl-(C1-C12)-aliphatic-, or [0201]
(C6-C10)aryl-(C1-C12)-aliphatic-, [0202] wherein each of R.sub.2
and R.sub.4 is independently and optionally substituted with up to
3 substituents independently selected from J; [0203] wherein up to
two aliphatic carbon atoms in R.sub.2 and R.sub.4 may be replaced
by a heteroatom selected from O, N, NH, S, SO, or SO.sub.2; [0204]
R.sub.5 is (C1-C12)-aliphatic, wherein any hydrogen is optionally
replaced with halogen, and wherein any terminal carbon atom of
R.sub.5 is optionally substituted with sulfhydryl or hydroxy;
[0205] R.sub.5' is hydrogen or (C1-C12)-aliphatic, wherein any
hydrogen is optionally replaced with halogen, and wherein any
hydrogen or halogen atom bound to any terminal carbon atom of
R.sub.5 is optionally substituted with sulfhydryl or hydroxy;
[0206] W is:
##STR00010##
[0207] wherein each R.sub.6 is independently: [0208] hydrogen-,
[0209] (C1-C12)-aliphatic-, [0210] (C6-C10)-aryl-, [0211]
(C6-C10)-aryl-(C1-C12)aliphatic-, [0212] (C3-C10)-cycloalkyl or
-cycloalkenyl-, [0213] [(C3-C10)-cycloalkyl or
-cycloalkenyl]-(C1-C12)-aliphatic-, [0214] (C3-C10)-heterocyclyl-,
[0215] (C3-C10)-heterocyclyl-(C1-C12)-aliphatic-, [0216]
(C5-C10)heteroaryl-, or [0217]
(C5-C10)heteroaryl-(C1-C12)-aliphatic-, or
[0218] two R.sub.6 groups, which are bound to the same nitrogen
atom, form together with that nitrogen atom, a
(C3-C10)-heterocyclic ring;
[0219] wherein R.sub.6 is optionally substituted with up to 3 J
substituents;
[0220] each R.sub.18 is independently --OR'; or the R.sub.18 groups
together with the boron atom, is a (C3-C10)-membered heterocyclic
ring having in addition to the boron up to 3 additional heteroatoms
selected from N, NH, O, S, SO, and SO.sub.2;
[0221] V is --C(O)N(R.sub.8)--, --S(O)N(R.sub.8)--,
--S(O).sub.2N(R.sub.8)--, --OS(O)--, --OS(O).sub.2--, --OC(O)--, or
--O--;
[0222] wherein R.sub.8 is hydrogen or (C1-C12)-aliphatic;
[0223] T is: [0224] (C1-C12)-aliphatic-; [0225] (C6-C10)-aryl-,
[0226] (C6-C10)-aryl-(C1-C12)aliphatic-, [0227] (C3-C10)-cycloalkyl
or -cycloalkenyl-,
[0228] [(C3-C10)-cycloalkyl or -cycloalkenyl]-(C1-C12)-aliphatic-,
[0229] (C3-C10)-heterocyclyl-, [0230]
(C3-C10)-heterocyclyl-(C1-C12)-aliphatic-, [0231]
(C5-C10)heteroaryl-, or [0232]
(C5-C10)heteroaryl-(C1-C12)-aliphatic-; or
[0233] T is:
##STR00011## ##STR00012##
wherein:
[0234] R.sub.10 is: [0235] Hydrogen-, [0236] (C1-C12)-aliphatic-,
[0237] (C6-C10)-aryl-, [0238] (C6-C10)-aryl-(C1-C12)aliphatic-,
[0239] (C3-C10)-cycloalkyl or -cycloalkenyl-, [0240]
[(C3-C10)-cycloalkyl or -cycloalkenyl]-(C1-C12)-aliphatic-, [0241]
(C3-C10)-heterocyclyl-, [0242]
(C3-C10)-heterocyclyl-(C1-C12)-aliphatic-, [0243]
(C5-C10)-heteroaryl-, or [0244]
(C5-C10)-heteroaryl-(C1-C12)-aliphatic-,
[0245] wherein each T is optionally substituted with up to 3 J
substituents;
[0246] K is a bond, (C1-C12)-aliphatic, --O--, --S--, --NR.sub.9--,
--C(O)--, or --C(O)--NR.sub.9--, wherein R.sub.9 is hydrogen or
(C1-C12)-aliphatic; and
[0247] n is 1-3.
[0248] In yet another embodiment, the invention provides a compound
of formula (II):
##STR00013##
wherein:
[0249] X.sub.1 is --N(R.sub.20)--, --O--, --S--, or
--C(R').sub.2--;
[0250] X.sub.2 is --C(O)--, --C(S)--, --S(O)--, or
--S(O).sub.2--;
[0251] W is:
##STR00014##
[0252] m is 0 or 1;
[0253] each R.sub.17 is independently: [0254] hydrogen-, [0255]
(C1-C12)-aliphatic-, [0256] (C3-C10)-cycloalkyl or
-cycloalkenyl-,
[0257] [(C3-C10)-cycloalkyl or -cycloalkenyl]-(C1-C12)-aliphatic-,
[0258] (C6-C10)-aryl-, [0259] (C6-C10)-aryl-(C1-C12)aliphatic-,
[0260] (C3-C10)-heterocyclyl-, [0261]
(C3-C10)-heterocyclyl-(C1-C12)-aliphatic-, [0262]
(C5-C10)heteroaryl-, or [0263]
(C5-C10)heteroaryl-(C1-C12)-aliphatic-, or
[0264] two R.sub.17 groups, which are bound to the same nitrogen
atom, form together with that nitrogen atom, a (C3-C10)-membered
heterocyclic ring having in addition to the nitrogen up to 2
additional heteroatoms selected from N, NH, O, S, SO, and
SO.sub.2;
[0265] wherein R.sub.17 is optionally substituted with up to 3 J
substituents;
[0266] each R.sub.18 is independently --OR'; or both OR' groups
together with the boron atom, is a (C5-C20)-membered heterocyclic
ring having in addition to the boron up to 3 additional heteroatoms
selected from N, NH, O, S, SO, and SO.sub.2;
[0267] R.sub.5 and R.sub.5' are independently hydrogen or
(C1-C12)-aliphatic, wherein any hydrogen is optionally replaced
with halogen, and wherein any terminal carbon atom is optionally
substituted with sulfhydryl or hydroxy, and wherein up to two
aliphatic carbon atoms may be replaced by a heteroatom selected
from N, NH, O, S, SO, or SO.sub.2; or
[0268] R.sub.5 and R.sub.5' together with the atom to which they
are bound is a 3- to 6-membered ring having up to 2 heteroatoms
selected from N, NH, O, S, SO, or SO.sub.2; wherein the ring has up
to 2 substituents selected independently from J;
[0269] R.sub.1, R.sub.1', R.sub.11, R.sub.11', R.sub.13, and
R.sub.13' are independently: [0270] hydrogen-, [0271]
(C1-C12)-aliphatic-, [0272] (C3-C10)-cycloalkyl or -cycloalkenyl-,
[0273] [(C3-C10)-cycloalkyl or -cycloalkenyl]-(C1-C12)-aliphatic-,
[0274] (C6-C10)-aryl-, [0275] (C6-C10)-aryl-(C1-C12)aliphatic-,
[0276] (C3-C10)-heterocyclyl-, [0277]
(C6-C10)-heterocyclyl-(C1-C12)aliphatic, [0278]
(C5-C10)-heteroaryl-, or [0279]
(C5-C10)-heteroaryl-(C1-C12)-aliphatic-; or
[0280] R.sub.1 and R.sub.1' together with the atom to which they
are bound is a 3- to 6-membered ring having up to 2 heteroatoms
selected from N, NH, O, S, SO, or SO.sub.2; wherein the ring has up
to 2 substituents selected independently from J; or
[0281] R.sub.11 and R.sub.11' together with the atom to which they
are bound is a 3- to 6-membered ring having up to 2 heteroatoms
selected from N, NH, O, S, SO, or SO.sub.2; wherein the ring has up
to 2 substituents selected independently from J; or
[0282] R.sub.13 and R.sub.13' together with the atom to which they
are bound is a 3- to 6-membered ring having up to 2 heteroatoms
selected from N, NH, O, S, SO, or SO.sub.2; wherein the ring has up
to 2 substituents selected independently from J; [0283] wherein
each of R.sub.1, R.sub.1', R.sub.11, R.sub.11', R.sub.13, and
R.sub.13' is independently and optionally substituted with up to 3
substituents independently selected from J; and wherein any ring is
optionally fused to a (C6-C10)aryl, (C5-C10)heteroaryl,
(C3-C10)cycloalkyl, or (C3-C10)heterocyclyl; and wherein up to 3
aliphatic carbon atoms in each of R.sub.1, R.sub.1', R.sub.11,
R.sub.11', R.sub.13, and R.sub.13' may be replaced by a heteroatom
selected from O, N, NH, S, SO, or SO.sub.2 in a chemically stable
arrangement;
[0284] R.sub.2, R.sub.4, R.sub.12, and R.sub.20 are independently
[0285] hydrogen-, [0286] (C1-C12)-aliphatic-, [0287]
(C3-C10)-cycloalkyl-, [0288]
(C3-C10)-cycloalkyl-(C1-C12)-aliphatic-, or [0289]
(C6-C10)aryl-(C1-C12)-aliphatic-, [0290] wherein each R.sub.2,
R.sub.4, R.sub.12, and R.sub.20 is independently and optionally
substituted with up to 3 substituents independently selected from
J; [0291] wherein up to two aliphatic carbon atoms in R.sub.2,
R.sub.4, R.sub.12, and R.sub.20 may be replaced by a heteroatom
selected from O, N, NH, S, SO, or SO.sub.2; or
[0292] R.sub.11 and R.sub.12 together with the atoms to which they
are bound form a 3- to a 20-membered mono-, a 4- to 20-membered
bi-, or a 5- to 20-membered tri-cyclic carbocyclic or heterocyclic
ring system; [0293] wherein, in the bi- and tri-cyclic ring system,
each ring is linearly fused, bridged, or spirocyclic; [0294]
wherein each ring is either aromatic or nonaromatic; [0295] wherein
each heteroatom in the heterocyclic ring system is selected from
the group consisting of N, NH, O, S, SO, and SO.sub.2; [0296]
wherein each ring is optionally fused to a (C6-C10)aryl,
(C5-C10)heteroaryl, (C3-C10)cycloalkyl, or (C3-C10)heterocyclyl;
and [0297] wherein said ring has up to 3 substituents selected
independently from J; or
[0298] R.sub.12 and R.sub.13 together with the atoms to which they
are bound form a 4- to a 20-membered mono-, a 5- to 20-membered
bi-, or a 6- to 20-membered tri-cyclic carbocyclic or heterocyclic
ring system; [0299] wherein, in the bi- and tri-cyclic ring system,
each ring is linearly fused, bridged, or spirocyclic; [0300]
wherein each ring is either aromatic or nonaromatic; [0301] wherein
each heteroatom in the heterocyclic ring system is selected from
the group consisting of N, NH, O, S, SO, and SO.sub.2; [0302]
wherein each ring is optionally fused to a (C6-C10)aryl,
(C5-C10)heteroaryl, (C3-C10)cycloalkyl, or (C3-C10)heterocyclyl;
and [0303] wherein said ring has up to 3 substituents selected
independently from J; or
[0304] R.sub.11 and R.sub.13 together with the atoms to which they
are bound form a 5- to a 20-membered mono-, a 6- to 20-membered
bi-, or a 7- to 20-membered tri-cyclic carbocyclic or heterocyclic
ring system; [0305] wherein, in the bi- and tri-cyclic ring system,
each ring is linearly fused, bridged, or spirocyclic; [0306]
wherein each ring is either aromatic or nonaromatic; [0307] wherein
each heteroatom in the heterocyclic ring system is selected from
the group consisting of N, NH, O, S, SO, and SO.sub.2; [0308]
wherein each ring is optionally fused to a (C6-C10)aryl,
(C5-C10)heteroaryl, (C3-C10)cycloalkyl, or (C3-C10)heterocyclyl;
and [0309] wherein said ring has up to 3 substituents selected
independently from J; or
[0310] R.sub.11, R.sub.12, and R.sub.13 together with the atoms to
which they are bound form a 5- to a 20-membered bi-, or a 6- to
20-membered tri-cyclic carbocyclic or heterocyclic ring system;
[0311] wherein, in the bi- and tri-cyclic ring system, each ring is
linearly fused, bridged, or spirocyclic; [0312] wherein each ring
is either aromatic or nonaromatic; [0313] wherein each heteroatom
in the heterocyclic ring system is selected from the group
consisting of N, NH, O, S, SO, and SO.sub.2; [0314] wherein each
ring is optionally fused to a (C6-C10)aryl, (C5-C10)heteroaryl,
(C3-C10)cycloalkyl, or (C3-C10)heterocyclyl; and [0315] wherein
said ring has up to 3 substituents selected independently from J;
or
[0316] R.sub.--' and R.sub.2 together with the atoms to which they
are bound form a 3- to a 20-membered mono-, a 4- to 20-membered
bi-, or a 5- to 20-membered tri-cyclic carbocyclic or heterocyclic
ring system; [0317] wherein, in the bi- and tri-cyclic ring system,
each ring is linearly fused, bridged, or spirocyclic; [0318]
wherein each ring is either aromatic or nonaromatic; [0319] wherein
each heteroatom in the heterocyclic ring system is selected from
the group consisting of N, NH, O, S, SO, and SO.sub.2; [0320]
wherein each ring is optionally fused to a (C6-C10)aryl,
(C5-C10)heteroaryl, (C3-C10)cycloalkyl, or (C3-C10)heterocyclyl;
and [0321] wherein said ring has up to 3 substituents selected
independently from J;
[0322] R.sub.5 and R.sub.13 together with the atoms to which they
are bound form a 18- to a 23-membered mono-, a 19- to 24-membered
bi-, or a 20- to 25-membered tri-cyclic carbocyclic or heterocyclic
ring system; [0323] wherein, in the bi- and tri-cyclic ring system,
each ring is linearly fused, bridged, or spirocyclic; [0324]
wherein each ring is either aromatic or nonaromatic; [0325] wherein
each heteroatom in the heterocyclic ring system is selected from
the group consisting of N, NH, O, S, SO, and SO.sub.2; [0326]
wherein each ring is optionally fused to a (C6-C10)aryl,
(C5-C10)heteroaryl, (C3-C10)cycloalkyl, or (C3-C10)heterocyclyl;
and [0327] wherein said ring has up to 6 substituents selected
independently from J; or
[0328] R.sub.1 and R.sub.12 together with the atoms to which they
are bound form a 18- to a 23-membered mono-, a 19- to 24-membered
bi-, or a 20- to 25-membered tri-cyclic carbocyclic or heterocyclic
ring system; [0329] wherein, in the bi- and tri-cyclic ring system,
each ring is linearly fused, bridged, or spirocyclic; [0330]
wherein each ring is either aromatic or nonaromatic; [0331] wherein
each heteroatom in the heterocyclic ring system is selected from
the group consisting of N, NH, O, S, SO, and SO.sub.2; [0332]
wherein each ring is optionally fused to a (C6-C10)aryl,
(C5-C10)heteroaryl, (C3-C10)cycloalkyl, or (C3-C10)heterocyclyl;
and wherein said ring has up to 6 substituents selected
independently from J; or
[0333] R.sub.14 is --H, --S(O)R', --S(O).sub.2R', --C(O)R',
--C(O)OR', --C(O)N(R').sub.2, --N(R')C(O)R', --N(COR')COR',
--SO.sub.2N(R').sub.2, --SO.sub.3R', --C(O)C(O)R',
--C(O)CH.sub.2C(O)R', --C(S)R', --C(S)N(R').sub.2,
--(CH.sub.2).sub.0-2NHC(O)R', --N(R')N(R')COR',
--N(R')N(R')C(O)OR', --N(R')N(R')CON(R').sub.2, --N(R')SO.sub.2R',
--N(R')SO.sub.2N(R').sub.2, --N(R')C(O)OR', --N(R')C(O)R',
--N(R')C(S)R', --N(R')C(O)N(R').sub.2, --N(R')C(S)N(R').sub.2,
--N(COR')COR', --N(OR')R', --C(.dbd.NH)N(R').sub.2, --C(O)N(OR')R',
--C(.dbd.NOR')R', --OP(O)(OR').sub.2, --P(O)(R').sub.2,
--P(O)(OR').sub.2, or --P(O)(H)(OR');
[0334] R.sub.15 and R.sub.16 are independently halogen, --OR',
--OC(O)N(R').sub.2, --NO.sub.2, --CN, --CF.sub.3, --OCF.sub.3,
--R', oxo, 1,2-methylenedioxy, 1,2-ethylenedioxy, --N(R').sub.2,
--SR', --SOR', --SO.sub.2R', --SO.sub.2N(R').sub.2, --SO.sub.3R',
--C(O)R', --C(O)C(O)R', --C(O)CH.sub.2C(O)R', --C(S)R', --C(O)OR',
--OC(O)R', --C(O)N(R').sub.2, --OC(O)N(R').sub.2,
--C(S)N(R').sub.2, --(CH.sub.2).sub.0-2NHC(O)R', --N(R')N(R')COR',
--N(R')N(R')C(O)OR', --N(R')N(R')CON(R').sub.2, --N(R')SO.sub.2R',
--N(R')SO.sub.2N(R').sub.2, --N(R')C(O)OR', --N(R')C(O)R',
--N(R')C(S)R', --N(R')C(O)N(R').sub.2, --N(R')C(S)N(R').sub.2,
--N(COR')COR', --N(OR')R', --CN, --C(.dbd.NH)N(R').sub.2,
--C(O)N(OR')R', --C(.dbd.NOR')R', --OP(O)(OR').sub.2,
--P(O)(R').sub.2, --P(O)(OR').sub.2, or --P(O)(H)(OR');
[0335] Z.sub.2 is .dbd.O, .dbd.NR', .dbd.NOR', or
.dbd.C(R').sub.2;
[0336] R.sub.19 is --OR', --CF.sub.3, --R', --N(R').sub.2, --SR',
--C(O)R', --COOR'--CON(R').sub.2, --N(R')COR', or
--N(COR')COR';
[0337] J is halogen, --OR', --OC(O)N(R').sub.2, --NO.sub.2, --CN,
--CF.sub.3, --OCF.sub.3, --R', oxo, thioxo, 1,2-methylenedioxy,
1,2-ethylenedioxy, --N(R').sub.2, --SR', --SOR', --SO.sub.2R',
--SO.sub.2N(R').sub.2, --SO.sub.3R', --C(O)R', --C(O)C(O)R',
--C(O)CH.sub.2C(O)R', --C(S)R', --C(O)OR', --OC(O)R',
--C(O)N(R').sub.2, --OC(O)N(R').sub.2, --C(S)N(R').sub.2,
--(CH.sub.2).sub.0-2NHC(O)R', --N(R')N(R')COR',
--N(R')N(R')C(O)OR', --N(R')N(R')CON(R').sub.2,
--N(R')SO.sub.2N(R').sub.2, --N(R')C(O)OR', --N(R')C(O)R',
--N(R')C(S)R', --N(R')C(O)N(R').sub.2, --N(R')C(S)N(R').sub.2,
--N(COR')COR', --N(OR')R', --CN, --C(.dbd.NH)N(R').sub.2,
--C(O)N(OR')R', --C(.dbd.NOR')R', --OP(O)(OR').sub.2, --P(O)
(R').sub.2, --P(O)(OR').sub.2, or --P(O)(H)(OR'); wherein:
[0338] two R' groups together with the atoms to which they are
bound form a 3- to 10-membered aromatic or non-aromatic ring having
up to 3 heteroatoms independently selected from N, NH, O, S, SO, or
SO.sub.2, wherein the ring is optionally fused to a (C6-C10)aryl,
(C5-C10)heteroaryl, (C3-C10)cycloalkyl, or a (C3-C10)heterocyclyl,
and wherein any ring has up to 3 substituents selected
independently from J.sub.2; or
[0339] each R' is independently selected from: [0340] hydrogen-,
[0341] (C1-C12)-aliphatic-, [0342] (C3-C10)-cycloalkyl or
-cycloalkenyl-, [0343] [(C3-C10)-cycloalkyl or
-cycloalkenyl]-(C1-C12)-aliphatic-, [0344] (C6-C10)-aryl-, [0345]
(C6-C10)-aryl-(C1-C12)aliphatic-, [0346] (C3-C10)-heterocyclyl-,
[0347] (C6-C10)-heterocyclyl-(C1-C12)aliphatic-, [0348]
(C5-C10)-heteroaryl-, or [0349]
(C5-C10)-heteroaryl-(C1-C12)-aliphatic-; wherein R' has up to 3
substituents selected independently from J.sub.2; and
[0350] J.sub.2 is halogen, --OR', --OC(O)N(R').sub.2, --NO.sub.2,
--CN, --CF.sub.3, --OCF.sub.3, --R', oxo, thioxo,
1,2-methylenedioxy, 1,2-ethylenedioxy, --N(R').sub.2, --SR',
--SOR', --SO.sub.2R', --SO.sub.2N(R').sub.2, --SO.sub.3R',
--C(O)R', --C(O)C(O)R', --C(O)CH.sub.2C(O)R', --C(S)R', --C(O)OR',
--OC(O)R', --C(O)N(R').sub.2, --OC(O)N(R').sub.2,
--C(S)N(R').sub.2, --(CH.sub.2).sub.0-2NHC(O)R', --N(R')N(R')COR',
--N(R')N(R')C(O)OR', --N(R')N(R')CON(R').sub.2, --N(R')SO.sub.2R',
--N(R')SO.sub.2N(R').sub.2, --N(R')C(O)OR', --N(R')C(O)R',
--N(R')C(S)R', --N(R')C(O)N(R').sub.2, --N(R')C(S)N(R').sub.2,
--N(COR')COR', --N(OR')R', --CN, --C(.dbd.NH)N(R').sub.2,
--C(O)N(OR')R', --C(.dbd.NOR')R', --OP(O)(OR').sub.2,
--P(O)(R').sub.2, --P(O)(OR').sub.2, or --P(O)(H)(OR').
DEFINITIONS
[0351] References herein to formula (I) are meant to include both
formula (IA) and formula (IB).
[0352] The term "aryl" as used herein means a monocyclic or
bicyclic carbocyclic aromatic ring system. Phenyl is an example of
a monocyclic aromatic ring system. Bicyclic aromatic ring systems
include systems wherein both rings are aromatic, e.g., naphthyl,
and systems wherein only one of the two rings is aromatic, e.g.,
tetralin.
[0353] The term "heterocyclyl" as used herein means a monocyclic or
bicyclic non-aromatic ring system having 1 to 3 heteroatom or
heteroatom groups in each ring selected from O, N, NH, S, SO, or
SO.sub.2 in a chemically stable arrangement. In a bicyclic
non-aromatic ring system embodiment of "heterocyclyl" one or both
rings may contain said heteroatom or heteroatom groups.
[0354] The term "heteroaryl" as used herein means a monocyclic or
bicyclic aromatic ring system having 1 to 3 heteroatom or
heteroatom groups in each ring selected from O, N, NH or S in a
chemically stable arrangement. In such a bicyclic aromatic ring
system embodiment of "heteroaryl": [0355] one or both rings may be
aromatic; and [0356] one or both rings may contain said heteroatom
or heteroatom groups.
[0357] The term "aliphatic" as used herein means a straight chained
or branched alkyl, alkenyl or alkynyl. It is understood that
alkenyl or alkynyl embodiments need at least two carbon atoms in
the aliphatic chain.
[0358] The term "cycloalkyl or cycloalkenyl" refers to a monocyclic
or fused or bridged bicyclic carbocyclic ring system that is not
aromatic. Cycloalkenyl rings have one or more units of
unsaturation. Preferred cycloalkyl groups include cyclopropyl,
cyclobutyl, cyclopentyl, cyclohexyl, cyclohexenyl, cycloheptyl,
cycloheptenyl, nornbornyl, adamantyl and decalin-yl.
[0359] The phrase "chemically stable arrangement" as used herein
refers to a compound structure that renders the compound
sufficiently stable to allow manufacture and administration to a
mammal by methods known in the art. Typically, such compounds are
stable at a temperature of 40.degree. C. or less, in the absence of
moisture or other chemically reactive condition, for at least a
week.
[0360] The compounds of formulae (IA) and (IB) of the present
invention represent a selection from the genus of WO 02/18369.
Applicants have invented a subgenus within the genus of WO 02/18369
that contain one or both of the following two distinct structural
elements:
[0361] 1. a fused azaheterocyclic ring system containing ring A,
wherein ring A in formula (I) is adjacent to the ring nitrogen atom
(i.e., atom X in formula (I) is adjacent to the ring nitrogen atom
of the backbone);
[0362] 2. a hydrogen bond donor in the P4 cap part of the compounds
of formula (I) [radical T in formula (I)].
[0363] Without wishing to be bound by theory, applicants believe
that the first structural element, namely, ring A, by being
adjacent to the ring nitrogen atom on the backbone of compounds of
formula (I), provides a facile orientation such that compounds of
the present invention have an enhanced interaction with the P2
region of the active site of the serine protease. Applicants
believe that the second structural element, a hydrogen bond donor
in radical T in formula (I), provides an additional point of
interaction between the compounds of the present invention and the
serine protease active site, thereby enhancing the binding
affinity.
[0364] In a preferred embodiment, the second structural element
comprises the following moiety:
##STR00015##
Without being bound by theory, applicants further believe that this
pyrrole moiety (as the second structural element) provides
particularly favorable hydrogen bond interactions with the serine
protease active site, thereby enhancing the binding affinity of
compounds having this moiety. This favorable interaction enhances
the binding affinity of compounds having the first structural
element (i.e., ring A) as well as those having other structural
elements.
[0365] As would be recognized by a skilled practitioner, the
hydrogen on the 1-position of the pyrrole could be substituted with
an appropriate group (e.g., R.sub.14 as defined herein) to enhance
biological properties. Therefore, one embodiment of this invention
provides a compound of formula (III), wherein P1, P2, P3, and P4
designate the residues of a serine protease inhibitor as known to
those skilled in the art and R.sub.14, R.sub.15, R.sub.16,
R.sub.19, and Z.sub.2 are as defined herein:
##STR00016##
[0366] All compounds, therefore, having: 1) structural elements of
a serine protease inhibitor; and 2) the pyrrole-moiety are
considered part of this invention. Compounds having the structural
elements of a serine protease inhibitor include, but are not
limited to, the compounds of the following publications: WO
97/43310, US20020016294, WO 01/81325, WO 02/08198, WO 01/77113, WO
02/08187, WO 02/08256, WO 02/08244, WO 03/006490, WO 01/74768, WO
99/50230, WO 98/17679, WO 02/48157 US20020177725, WO 02/060926,
US20030008828, WO 02/48116, WO 01/64678, WO 01/07407, WO 98/46630,
WO 00/59929, WO 99/07733, WO 00/09588, US20020016442, WO 00/09543,
WO 99/07734, U.S. Pat. No. 6,018,020, WO 98/22496, U.S. Pat. No.
5,866,684, WO 02/079234, WO 00/31129, WO 99/38888, WO 99/64442, and
WO 02/18369, which are incorporated herein by reference.
[0367] Thus, any compound of the above publications may be modified
to have this pyrrole moiety, or a derivative thereof. Any such
compound is part of this invention. For example, compound A in WO
02/18369 (p. 41):
##STR00017##
may be modified to provide the following compound of this
invention:
##STR00018##
wherein R.sub.14, R.sub.15, R.sub.16, R.sub.19, and Z.sub.2 are as
defined herein.
PREFERRED EMBODIMENTS
[0368] According to a preferred embodiment of formula (I), A
together with X and Y is a 3-6 membered carbocyclic non-aromatic or
aromatic ring. More preferably, A together with X and Y is
cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or phenyl. Even
more preferably, A together with X and Y is cyclohexyl or
cyclopentyl. Most preferably, A together with X and Y is
cyclohexyl.
[0369] According to another preferred embodiment, A together with X
and Y is a 3-6 membered heterocyclic ring. More preferably, A
together with X and Y is a 5-6 membered heterocyclic ring.
[0370] According to another preferred embodiment, A together with X
and Y is a 5-6 membered heteroaryl ring.
[0371] According to yet another preferred embodiment, A together
with X and Y is fused to a (C6-C10)aryl, (C5-C10)heteroaryl,
(C3-C10)cycloalkyl or (C3-C10)-heterocyclyl. Preferably, A together
with X and Y is fused to cyclohexyl, cyclopentyl, phenyl or
pyridyl.
[0372] According to another preferred embodiment, the ring
system
##STR00019##
in formula (I) is selected from Table 1 below:
TABLE-US-00001 TABLE 1 ##STR00020## ##STR00021## ##STR00022##
##STR00023## ##STR00024## ##STR00025## ##STR00026## ##STR00027##
##STR00028## ##STR00029## ##STR00030## ##STR00031## ##STR00032##
##STR00033## ##STR00034## ##STR00035## ##STR00036## ##STR00037##
##STR00038## ##STR00039## ##STR00040## ##STR00041## ##STR00042##
##STR00043## ##STR00044## ##STR00045## ##STR00046## ##STR00047##
##STR00048## ##STR00049## ##STR00050## ##STR00051## ##STR00052##
##STR00053## ##STR00054## ##STR00055## ##STR00056## ##STR00057##
##STR00058## ##STR00059## ##STR00060## ##STR00061## ##STR00062##
##STR00063## ##STR00064## ##STR00065## ##STR00066## ##STR00067##
##STR00068## ##STR00069## ##STR00070## ##STR00071## ##STR00072##
##STR00073## ##STR00074## ##STR00075## ##STR00076## ##STR00077##
##STR00078## ##STR00079##
[0373] According to a more preferred embodiment, the ring
system
##STR00080##
in formula (I) is selected from:
##STR00081##
[0374] According to another more preferred embodiment, A, together
with X, Y and the ring containing the nitrogen atom, is:
##STR00082##
[0375] More preferably, A, together with X, Y and the ring
containing the nitrogen atom, is:
##STR00083##
[0376] According to a preferred embodiment, T is selected from:
(C6-C10)-aryl, (C6-C10)-aryl-(C1-C12)aliphatic, (C3-C10)-cycloalkyl
or -cycloalkenyl, [(C3-C10)-cycloalkyl or
-cycloalkenyl]-(C1-C12)-aliphatic, (C3-C10)-heterocyclyl,
(C3-C10)-heterocyclyl-(C1-C12)-aliphatic, (C5-C10)heteroaryl, or
(C5-C10)heteroaryl-(C1-C12)-aliphatic, wherein each T is optionally
substituted with up to 3 J substituents.
[0377] According to another preferred embodiment, T is:
##STR00084##
wherein:
[0378] R.sub.10 is: [0379] hydrogen, [0380] (C1-C12)-aliphatic,
[0381] (C6-C10)-aryl, [0382] (C6-C10)-aryl-(C1-C12)aliphatic,
[0383] (C3-C10)-cycloalkyl or -cycloalkenyl, [0384]
[(C3-C10)-cycloalkyl or -cycloalkenyl]-(C1-C12)-aliphatic, [0385]
(C3-C10)-heterocyclyl, [0386]
(C3-C10)-heterocyclyl-(C1-C12)-aliphatic, [0387]
(C5-C10)heteroaryl, or [0388]
(C5-C10)heteroaryl-(C1-C12)-aliphatic,
[0389] wherein each T is optionally substituted with up to 3 J
substituents;
[0390] K is a bond, --R.sub.9, --O--, --S--, --NR.sub.9--,
--C(O)--, or --C(O)--NR.sub.9--, wherein R.sub.9 is hydrogen or
C1-C12 aliphatic; and
[0391] n is 1-3.
[0392] In the above embodiment, T may also be:
##STR00085##
[0393] In a preferred embodiment, T is:
##STR00086##
[0394] According to a more preferred embodiment, T contains at
least one hydrogen bond donor moiety selected from --NH.sub.2,
--NH--, --OH or --SH.
[0395] According to another more preferred embodiment, T is
selected from:
##STR00087## ##STR00088##
wherein:
[0396] T is optionally substituted with up to 3 J substituents;
[0397] Z is independently O, S, NR.sub.10, C(R.sub.10)2;
[0398] n is independently 1 or 2; and
[0399] is independently a single bond or a double bond.
[0400] According to yet another preferred embodiment, T is selected
from:
##STR00089##
wherein Z is as defined above.
[0401] In a more preferred embodiment, T is:
##STR00090##
[0402] According to a preferred embodiment, W is
--C(O)--C(O)--R.sub.6 (or, in formula (II),
--C(O)--C(O)--R.sub.17).
Preferably, R.sub.6 (and/or R.sub.17) are: phenyl, pyridyl,
(C3-C6)-alkyl, (C3-C6)-cycloalkyl, --OH, --O--(C1-C6)-alkyl,
--N(H)--(C3-C6)-cycloalkyl, --N(H)--C(H)(CH.sub.3)--(C6-C10)aryl,
--N(H)--C(H)(CH.sub.3)--(C3-C10)-heterocyclyl, or
--N(H)--C(H)(CH.sub.3)--(C5-C10)-heteroaryl, wherein each aryl,
heterocyclyl, and heteroaryl is optionally substituted with
halogen. Preferred embodiments are selected from:
##STR00091##
More preferably, R.sub.6 (and/or R.sub.17) are isopropyl.
[0403] According to another preferred embodiment of formula (II), W
is --C(O)--H.
[0404] According to another preferred embodiment, W is
--C(O)--C(O)--OR.sub.6. More preferably, R.sub.6 is H or
methyl.
[0405] According to a more preferred embodiment, R.sub.6 is
selected from hydrogen, (C1-C12)-aliphatic, (C6-C10)-aryl,
(C3-C10)-cycloalkyl or -cycloalkenyl, (C3-C10)-heterocyclyl or
(C5-C10)heteroaryl.
[0406] According to another preferred embodiment, W is
--C(O)--C(O)--N(R.sub.6).sub.2. More preferably, R.sub.6 is
selected from hydrogen, (C3-C10)-cycloalkyl or -cycloalkenyl, or
(C3-C10)-heterocyclyl. Alternatively, one R.sub.6 is hydrogen and
the other R.sub.6 is: (C6-C10)-aryl-(C1-C3)alkyl-, wherein the
alkyl is optionally substituted with CO.sub.2H; (C3-C6)cycloalkyl-;
(C5)-heterocyclyl-(C1-C3)alkyl-; (C3-C6)alkenyl-; or each R.sub.6
is (C1-C6)-alkyl-. Alternatively, each R.sub.6 is
(C1-C3)-alkyl-.
[0407] Most preferably, --NHR.sub.6 in W is selected from:
##STR00092##
[0408] According to a preferred embodiment of formula (II),
W is:
##STR00093##
[0410] More preferred embodiments of W are as follows:
W is:
##STR00094##
[0411] wherein R.sub.17 is hydrogen or C5-heteroaryl, or
C9-heteroaryl, wherein R.sub.17 has up to 3 substituents selected
from J.
W is:
##STR00095##
[0412] wherein R.sub.17 is hydrogen, (C1-C6)-alkyl, (C6-C10)-aryl,
or C3-C6-cycloalkyl-(C1-C3)-alkyl, wherein the cycloalkyl is
preferably a cyclopropyl group. The aryl group is optionally
substituted with up to 3 J groups, wherein J is halogen, preferably
chloro or fluoro.
W is:
##STR00096##
[0413] wherein R.sub.17 is hydrogen or (C1-C6)-alkyl.
W is:
##STR00097##
[0414] wherein R.sub.17 is hydrogen, (C1-C6)-alkyl,
(C1-C6)-alkenyl, (C6-C10)-aryl-(C1-C6)-alkyl-, or
(C6-C10)-heteroaryl-(C1-C6)-alkyl-, wherein R.sub.17 is optionally
substituted with up to 3 J groups. Preferred J substituents on the
alkyl and aryl groups are halogen, carboxy, and heteroaryl. More
preferred substituents on the aryl groups are halogen (preferably
chloro or fluoro) and more preferred J substituents on the alkyl
groups are carboxy and heteroaryl.
[0415] According to yet other preferred embodiments of formula
(II), W is:
##STR00098## ##STR00099## ##STR00100##
[0416] According to a preferred embodiment, each R.sub.18 together
with the boron atom, is a (C5-C7)-membered heterocyclic ring having
no additional heteroatoms other than the boron and the two oxygen
atoms. Preferred groups are selected from:
##STR00101##
wherein R' is, preferably, (C1-C6)-alkyl) and is, most preferably,
methyl.
[0417] According to a preferred embodiment, R.sub.1 is selected
from:
##STR00102##
[0418] According to a preferred embodiment, R.sub.3 is selected
from:
##STR00103##
[0419] According to a preferred embodiment, R.sub.3 is:
##STR00104##
[0420] According to a preferred embodiment, R.sub.5 is:
##STR00105##
[0421] According to a preferred embodiment, R.sub.5 is selected
from:
##STR00106##
[0422] According to a preferred embodiment, R.sub.5' is hydrogen
and R.sub.5 is other than hydrogen.
[0423] According to a preferred embodiment, R.sub.2 and R.sub.4 are
each independently selected from H, methyl, ethyl or propyl.
[0424] According to a preferred embodiment, V is
--C(O)--NR.sub.8--. More preferably, V is --C(O)--NH--.
[0425] According to a preferred embodiment, J is halogen --OR',
--NO.sub.2, --CF.sub.3, --OCF.sub.3, --R', oxo, 1,2-methylenedioxy,
--N(R').sub.2, --SR', --SOR', --SO.sub.2R', --C(O)R',
--COOR'--CON(R').sub.2, --N(R')COR', --N(COR')COR', --CN, or
--SO.sub.2N(R').sub.2.
[0426] According to a preferred embodiment, J.sub.2 is halogen,
--OR', --NO.sub.2, --CF.sub.3, --OCF.sub.3, --R', oxo,
1,2-methylenedioxy, --N(R').sub.2, --SR', --SOR', --SO.sub.2R',
--C(O)R', --COOR'--CON(R').sub.2, --N(R')COR', --N(COR')COR', --CN,
or --SO.sub.2N(R').sub.2.
[0427] In J and J.sub.2 the halogen is preferably chloro or fluoro.
More preferably, the halogen is fluoro.
[0428] According to a preferred embodiment of formula (II), X.sub.1
is --N(R.sub.20)--, --O--, or --C(R').sub.2--. More preferably,
X.sub.1 is --N(R.sub.20)--.
[0429] According to a preferred embodiment of formula (II), X.sub.2
is --C(O)--.
[0430] According to a preferred embodiment of formula (II),
R.sub.2, R.sub.4, and R.sub.20, are each independently selected
from H or (C1-C3)-alkyl-. More preferably, each of R.sub.2,
R.sub.4, and R.sub.20, are H.
[0431] According to a preferred embodiment of formula (II),
R.sub.14 is --H, --S(O)R', --S(O).sub.2R', --C(O)R', --C(O)OR',
--C(O)N(R').sub.2, --N(R')C(O)R', --N(COR')COR', or
--SO.sub.2N(R').sub.2. More preferably, R.sub.14 is hydrogen.
[0432] According to a preferred embodiment of formula (II),
R.sub.15 and R.sub.16 are independently halogen, --OR', --NO.sub.2,
--CF.sub.3, --OCF.sub.3, --R', oxo, 1,2-methylenedioxy,
--N(R').sub.2, --SR', --SOR', --SO.sub.2R', --C(O)R',
--COOR'--CON(R').sub.2, --N(R')COR', --N(COR')COR', --CN, or
--SO.sub.2N(R').sub.2. More preferably, R.sub.15 and R.sub.16 are
independently (C1-C6)-alkyl-. Even more preferably, each R.sub.15
and R.sub.16 is methyl.
[0433] According to a preferred embodiment of formula (II), Z is O
and R.sub.19 is: (C1-C6)-alkyl-(C3-C10)-cycloalkyl-,
[(C3-C10)-cycloalkyl]-(C1-C12)-aliphatic-, (C6-C10)-aryl-,
(C6-C10)-aryl-(C1-C6)alkyl, (C3-C10)-heterocyclyl,
(C6-C10)-heterocyclyl-(C1-C6)alkyl, (C5-C10)-heteroaryl, or
(C5-C10)-heteroaryl-(C1-C6)-alkyl; wherein R.sub.19 has up to 3
substituents selected independently from J.sub.2; and wherein up to
3 aliphatic carbon atoms in R.sub.19 may be replaced by a
heteroatom selected from O, NH, S, SO, or SO.sub.2 in a chemically
stable arrangement. More preferably, R.sub.19 is (C1-C6)-alkyl-.
Most preferably, R.sub.19 is methyl.
[0434] According to a preferred embodiment of formula (II),
R.sub.14 is H; Z.sub.2 is CH.sub.2; or R.sub.19 is:
##STR00107##
[0435] More preferably, R.sub.14 is H; Z.sub.2 is CH.sub.2; and
R.sub.19 is as depicted immediately above.
[0436] According to another preferred embodiment of formula (II),
each R.sub.19 is methyl; Z.sub.2 is O; or R.sub.14 is:
##STR00108##
More preferably, each R.sub.19 is methyl; Z.sub.2 is O; and
R.sub.14 is as depicted immediately above. Even more preferably
R.sub.14 is:
##STR00109##
[0437] In this embodiment, R' is, preferably, (C1-C6)alkyl.
[0438] According to another preferred embodiment of formula (II),
Z.sub.2 is:
##STR00110##
[0439] More preferably, each R.sub.19 is methyl; R.sub.14 is H; and
Z.sub.2 is as depicted immediately above.
[0440] According to another preferred embodiment of formula (II),
Z.sub.2 is:
##STR00111##
[0441] According to a preferred embodiment of formula (II),
R.sub.1' is H.
[0442] According to a preferred embodiment of formula (II),
R.sub.13' is H.
[0443] According to a preferred embodiment of formula (II),
R.sub.11' is H.
[0444] According to a preferred embodiment of formula (II),
R.sub.12 is H.
[0445] According to a preferred embodiment of formula (II),
R.sub.12 is: (C1-C6)-alkyl-, (C3-C10)-cycloalkyl,
[(C3-C10)-cycloalkyl]-(C1-C12)-alkyl-, (C6-C10)-aryl-,
(C6-C10)-aryl-(C1-C6)alkyl-, (C3-C10)-heterocyclyl-,
(C6-C10)-heterocyclyl-(C1-C6)alkyl-, (C5-C10)-heteroaryl-, or
(C5-C10)-heteroaryl-(C1-C6)-alkyl-. More preferably, R.sub.12 is
isobutyl, cyclohexyl, cyclohexylmethyl, benzyl, or phenylethyl.
Even more preferably, R.sub.11 is H.
[0446] According to a preferred embodiment of formula (II),
R.sub.11 is (C1-C6)-alkyl-, (C3-C10)-cycloalkyl-,
[(C3-C10)-cycloalkyl]-(C1-C12)-alkyl-, (C6-C10)-aryl-,
(C6-C10)-aryl-(C1-C6)alkyl-; (C3-C10)-heterocyclyl-,
(C6-C10)-heterocyclyl-(C1-C6)alkyl-, (C5-C10)-heteroaryl-, or
(C5-C10)-heteroaryl-(C1-C6)-alkyl-. More preferably, R.sub.11 is
(C1-C6)-alkyl-, (C3-C10)-cycloalkyl-,
[(C3-C10)-cycloalkyl]-(C1-C12)-alkyl-, (C6-C10)-aryl-(C1-C6)alkyl-;
(C6-C10)-heterocyclyl-(C1-C6)alkyl-, or
(C5-C10)-heteroaryl-(C1-C6)-alkyl-. Even more preferably, R.sub.11'
and R.sub.12 are H.
[0447] According to a preferred embodiment of formula (II), the
##STR00112##
radical is:
##STR00113## [0448] More preferably, the radical is:
##STR00114##
[0449] According to a preferred embodiment of formula (II), the
##STR00115##
radical is:
##STR00116## ##STR00117##
[0450] Alternatively, this radical is:
##STR00118## ##STR00119##
[0451] According to a preferred embodiment of formula (II), the
##STR00120##
radical is:
##STR00121##
or the radical is:
##STR00122##
[0452] wherein each B independently forms a 3- to a 20-membered
carbocyclic or heterocyclic ring system;
[0453] wherein each ring B is either aromatic or nonaromatic;
[0454] wherein each heteroatom in the heterocyclic ring system is
N, NH, O, S, SO, or SO.sub.2;
[0455] wherein each ring is optionally fused to a (C6-C10)aryl,
(C5-C10)heteroaryl, (C3-C10)cycloalkyl, or (C3-C10)heterocyclyl;
and
[0456] wherein each ring has up to 3 substituents selected
independently from J.
[0457] In the embodiment immediately above, a preferred ring
systems is:
##STR00123##
[0458] wherein Z.sub.3 is a carbon atom, --CHR'--N--, --HN--CR'--
or --CHR'--CHR'--, --O--CHR'--, --S--CHR'--, --SO--CHR'--,
--SO.sub.2--CHR'--, or --N--. R' is, preferably,
(C1-C12)-aliphatic, (C6-C10)-aryl, (C6-C10)aryl-(C1-C12)-aliphatic,
or (C3-C10)-cycloalkyl. The aliphatic is, more preferably, a
(C1-C6)-alkyl and the cycloalkyl is more preferably, a
(C3-C7)-cycloalkyl. These ring systems are described more fully
below.
[0459] Preferred embodiments of ring systems 1, 2, 3, and 4, are
described below; ring systems 1, 2, 3, and 4, are respectively:
##STR00124##
[0460] In ring system 1, ring C is preferably selected from:
##STR00125## ##STR00126##
wherein R is aliphatic, aryl, aralkyl or cycloalkyl. [0461] More
preferably, ring C is selected from:
[0461] ##STR00127## [0462] Ring D is preferably selected from:
##STR00128## ##STR00129## ##STR00130##
[0462] wherein R is aliphatic, aryl, aralkyl or cycloalkyl. [0463]
More preferably, ring D is selected from:
##STR00131##
[0464] According to another preferred embodiment, ring system 1 is
selected from the group:
##STR00132## ##STR00133##
[0465] In ring system 2, ring F is preferably selected from:
##STR00134##
[0466] Ring system 2 is preferably selected from:
##STR00135##
[0467] In ring system 3, preferred embodiments of ring G are as
defined above for preferred embodiments of ring D. Preferred
embodiments of ring H are as defined above for preferred
embodiments of ring F.
##STR00136##
[0468] According to a preferred embodiment of ring system 3, ring I
is a bridged bicyclic ring system containing 6-12 carbon atoms,
wherein ring I is saturated or partially unsaturated, and ring I
has up to 3 substituents selected independently from J.
[0469] Preferred embodiments of ring I are selected from:
##STR00137## ##STR00138##
[0470] According to a preferred embodiment of formula (II), the
##STR00139##
radical is:
##STR00140##
[0471] According to a preferred embodiment of formula (II), the
##STR00141##
radical is:
##STR00142## ##STR00143## ##STR00144##
[0472] According to a preferred embodiment of formula (II), the
##STR00145##
radical is:
##STR00146## ##STR00147## ##STR00148##
[0473] According to a preferred embodiment of formula (II), the
##STR00149##
radical is:
##STR00150## ##STR00151## ##STR00152##
[0474] According to a preferred embodiment of formula (II), the
##STR00153##
radical is:
##STR00154##
[0475] According to a preferred embodiment of formula (II), the
##STR00155##
radical is:
##STR00156##
[0476] wherein each B independently forms a 3- to a 20-membered
carbocyclic or heterocyclic ring system;
[0477] wherein each ring B is either aromatic or nonaromatic;
[0478] wherein each heteroatom in the heterocyclic ring system is
N, NH, O, S, SO, or SO.sub.2;
[0479] wherein each ring is optionally fused to a (C6-C10)aryl,
(C5-C10)heteroaryl, (C3-C10)cycloalkyl, or (C3-C10)heterocyclyl;
and
wherein each ring has up to 3 substituents selected independently
from J.
[0480] According to a preferred embodiment of formula (II), the
##STR00157##
radical is:
##STR00158## ##STR00159## ##STR00160## ##STR00161##
##STR00162##
[0481] According to a preferred embodiment of formula (II), the
##STR00163##
radical is:
##STR00164## ##STR00165## ##STR00166## ##STR00167##
[0482] In the embodiment immediately above, the ring is also
selected from:
##STR00168##
[0483] According to a preferred embodiment of formula (II), the
##STR00169##
radical is:
##STR00170## ##STR00171##
[0484] According to a preferred embodiment of formula (II), the
##STR00172##
radical is:
##STR00173##
[0485] wherein B forms a 3- to a 20-membered carbocyclic or
heterocyclic ring system;
[0486] wherein each ring B is either aromatic or nonaromatic;
[0487] wherein each heteroatom in the heterocyclic ring system is
N, NH, O, S, SO, or SO.sub.2;
[0488] wherein each ring is optionally fused to a (C6-C10)aryl,
(C5-C10)heteroaryl, (C3-C10)cycloalkyl, or (C3-C10)heterocyclyl;
and
[0489] wherein each ring has up to 3 substituents selected
independently from J.
[0490] According to a preferred embodiment of formula (II), the
##STR00174##
radical is:
##STR00175## ##STR00176##
[0491] In the above radicals, it is understood that that R.sub.11'
variable is hydrogen.
[0492] According to a preferred embodiment of formula (II),
R.sub.11 and R.sub.12 together with the atoms to which they are
bound form a 6- to 10-membered mono- or bicyclic carbocyclic or
heterocyclic ring system; wherein each heteroatom in the
heterocyclic ring system is selected from the group consisting of
N, NH, O, S, SO, and SO.sub.2; and wherein said ring has up to 3
substituents selected independently from J.
[0493] According to a preferred embodiment, the ring formed from
R.sub.5 and R.sub.13, if present, is preferably an 18-membered
ring.
[0494] According to a preferred embodiment, the ring formed from
R.sub.1 and R.sub.12, if present, is preferably an 18-membered
ring.
[0495] Any of the ring systems may be substituted as set forth
herein. Preferably, the ring substituents are selected from oxo,
fluoro, difluoro (particularly vicinal difluoro), and hydroxy.
These substituents are the most preferred on the following ring
systems:
##STR00177##
wherein B is a 5-membered carbocyclic ring, optionally having one
unsaturated bond.
[0496] In preferred embodiments, heteroatoms are selected from the
group consisting of N, NH, O, SO, and SO.sub.2.
[0497] Preferred embodiments for any formula are also preferred
embodiments for any other formula (I). For example, the preferred
embodiments of R.sub.3 in formula (I) are also the preferred
embodiments of R.sub.13 in formula (II); the preferred embodiments
of R.sub.2 in formula (I) are also the preferred embodiments of
R.sub.20 in formula (II); and the preferred embodiments of R.sub.6
in formula (I) are also the preferred embodiments of R.sub.17 in
formula (II).
[0498] Any of the preferred embodiments recited above for T, V,
R.sub.1, R.sub.2, R.sub.3, A, X, Y, R.sub.4, R.sub.5 and W may be
combined to produce a preferred embodiment of a compound of formula
(IA).
[0499] Any of the preferred embodiments recited above for T, V,
R.sub.1, R.sub.2, R.sub.3, A, X, Y, R.sub.4, R.sub.5, and R.sub.5',
and W may be combined to produce a preferred embodiment of a
compound of formula (IB).
[0500] Any of the preferred embodiments recited above for R.sub.1,
R.sub.2, R.sub.4, R.sub.5, and R.sub.5', R.sub.11, R.sub.12,
R.sub.13, R.sub.13', R.sub.14, R.sub.15, R.sub.16, R.sub.19,
R.sub.20, Z.sub.2, W may be combined to produce a preferred
embodiment of a compound of formula (II).
[0501] According to another embodiment, the present invention
provides compounds of formula (I'):
##STR00178##
wherein:
[0502] R.sub.1 and R.sub.3 each is independently (C1-C6)aliphatic,
cyclopentyl or cyclohexyl;
[0503] R.sub.5 is ethyl, propyl or allyl;
[0504] R.sub.6 is cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl,
benzyl, (S)-methylbenzyl; and
[0505] T is (C3-C10)heterocyclyl or (C5-C10)heteroaryl ring wherein
said ring contains at least one hydrogen donor moiety selected from
--NH.sub.2, --NH--, --OH or --SH; or
[0506] T is selected from:
##STR00179##
[0507] wherein R.sub.10 and K are as defined above.
[0508] According to another embodiment, the present invention
provides compounds of formulae (II' and II''):
##STR00180##
wherein the variables are as defined herein.
[0509] According to a preferred embodiment, the stereochemistry of
a compound of this invention corresponds to that depicted in
compounds 1-62a and 63-68.
[0510] Another embodiment of this invention provides a process for
preparing a compound of this invention. These process are described
in the schemes and examples.
[0511] Examples of specific compounds of formula (I) are set forth
below in Table 2.
TABLE-US-00002 TABLE 2 ##STR00181## 1 ##STR00182## 2 ##STR00183## 3
##STR00184## 4 ##STR00185## 5 ##STR00186## 6 ##STR00187## 7
##STR00188## 8 ##STR00189## 9 ##STR00190## 10 ##STR00191## 11
##STR00192## 12 ##STR00193## 13 ##STR00194## 14 ##STR00195## 15
##STR00196## 16 ##STR00197## 17 ##STR00198## 18 ##STR00199## 19
##STR00200## 20 ##STR00201## 21 ##STR00202## 22 ##STR00203## 23
##STR00204## 24 ##STR00205## 25 ##STR00206## 26 ##STR00207## 27
##STR00208## 28 ##STR00209## 29 ##STR00210## 30 ##STR00211## 31
##STR00212## 32
[0512] Examples of specific compounds of formula (I) are set forth
below in Table 3.
TABLE-US-00003 TABLE 3 ##STR00213## 1a ##STR00214## 2a ##STR00215##
3a ##STR00216## 4a ##STR00217## 5a ##STR00218## 6a ##STR00219## 7a
##STR00220## 8a ##STR00221## 9a ##STR00222## 10a ##STR00223## 11a
##STR00224## 12a ##STR00225## 13a ##STR00226## 14a ##STR00227## 15a
##STR00228## 16a ##STR00229## 17a ##STR00230## 18a ##STR00231## 19a
##STR00232## 20a ##STR00233## 21a ##STR00234## 22a ##STR00235## 23a
##STR00236## 24a ##STR00237## 25a ##STR00238## 26a ##STR00239## 27a
##STR00240## 28a ##STR00241## 29a ##STR00242## 30a ##STR00243## 31a
##STR00244## 32a ##STR00245## 33a ##STR00246## 34a ##STR00247## 35a
##STR00248## 36a ##STR00249## 37a ##STR00250## 38a ##STR00251## 39a
##STR00252## 40a ##STR00253## 41a ##STR00254## 42a ##STR00255## 43a
##STR00256## 44a ##STR00257## 45a ##STR00258## 46a ##STR00259## 47a
##STR00260## 48a ##STR00261## 49a ##STR00262## 50a ##STR00263## 51a
##STR00264## 52a ##STR00265## 53a ##STR00266## 54a ##STR00267## 55a
##STR00268## 56a ##STR00269## 57a ##STR00270## 58a ##STR00271## 59a
##STR00272## 60a ##STR00273## 61a ##STR00274## 62a
[0513] Examples of other specific compounds of formula (II) of the
present invention are set forth below in Table 4.
TABLE-US-00004 TABLE 4 ##STR00275## 63 ##STR00276## 64 ##STR00277##
65 ##STR00278## 66 ##STR00279## 67 ##STR00280## 68
[0514] The compounds of this invention may contain one or more
asymmetric carbon atoms and thus may occur as racemates and racemic
mixtures, single enantiomers, diastereomeric mixtures and
individual diastereomers. All such isomeric forms of these
compounds are expressly included in the present invention. Each
stereogenic carbon may be of the R or S configuration.
[0515] Preferably, the compounds of this invention have the
structure and stereochemistry depicted in compounds 1a-62a and
63-68.
[0516] Any of the preferred embodiments recited above, including
those embodiments in the above species, may be combined to produce
a preferred embodiment of this invention.
[0517] Abbreviations which are used in the schemes, preparations
and the examples that follow are: [0518] THF: tetrahydrofuran
[0519] DMF: N,N,-dimethylformamide [0520] EtOAc: ethyl acetate
[0521] AcOH: acetic acid [0522] HOBt: 1-hydroxybenzotriazole
hydrate [0523] EDC: 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide
hydrochloride [0524] NMM: N-methylmorpholine [0525] NMP:
N-methylpyrrolidinone [0526] EtOH: ethanol [0527] t-BuOH:
tert-butanol [0528] Et.sub.2O: diethyl ether [0529] BOC:
tert-butyloxycarbonyl [0530] BOC.sub.2O: di-tert-butyldicarbonate
[0531] Cbz: benzyloxycarbonyl [0532] Chg: cyclohexylglycine [0533]
tBG: tert-butylglycine [0534] Fmoc: 9-fluorenyl methyloxycarbonyl
[0535] DMSO: dimethyl sulfoxide [0536] TFA: trifluoroacetic acid
[0537] DCM: dichloromethane [0538] DCE: dichloroethane [0539] DIEA:
diisopropylethylamine [0540] MeCN: acetonitrile [0541] PyBrOP:
tris(pyrrolidino)bromophosphonium hexafluorophosphate [0542] TBTU
or HATU: 2-(1H-benzotriazole-1-yl)-1,1,3,3-tetramethyluronium
tetrafluoroborate [0543] DMAP: 4-dimethylaminopyridine [0544] PPTS:
pyridinium p-toluenesulfonate [0545] IBX: periodobenzoic acid
[0546] AIBN: 2,2'-azobisisobutyronitrile [0547] rt: room
temperature [0548] ON: overnight [0549] ND: not determined [0550]
MS: mass spectrometry [0551] LC: liquid chromatography
General Synthetic Methodology:
[0552] The compounds of this invention may be prepared in general
by methods known to those skilled in the art. Schemes 1-17 below
illustrate synthetic routes to the compounds of the present
invention. Other equivalent schemes, which will be readily apparent
to the ordinary skilled organic chemist, may alternatively be used
to synthesize various portions of the molecule as illustrated by
the general scheme below, and the preparative examples that
follow.
##STR00281##
[0553] Scheme 1 above provides a general route for the preparation
of compounds of formula I.
##STR00282##
[0554] Schemes 2 above provides another general route for the
preparation of compounds of formula I.
##STR00283##
[0555] Scheme 3 above depicts a general route for the preparation
of compounds of formula I, specifically compounds represented by
structure 62a.
##STR00284##
[0556] Scheme 4 above provides another method for the preparation
of compounds of formula I.
##STR00285##
[0557] Scheme 1 or 2 in combination with scheme 5 above provide
another general method for the preparation of compounds of formula
I.
##STR00286##
[0558] Scheme 1 or 2 in combination with scheme 6 above provide
another general method for the preparation of compounds of formula
I.
##STR00287##
[0559] Scheme 1 or 2 in combination with scheme 7 above provide
another general method for the preparation of certain compounds of
formula I.
##STR00288##
[0560] Scheme 1 or 2 in combination with scheme 8 above provide
another general route for the preparation of compounds of formula
I.
##STR00289##
[0561] Scheme 1 or 2 in combination with scheme 9 above provide
another general method for the preparation of certain compounds of
formula I.
##STR00290##
[0562] Scheme 1 or 2 in combination with scheme 10 above provide
yet another general method for the preparation of compounds of
formula I.
##STR00291##
[0563] Scheme 11 above shows a general route for the preparation of
compounds of formula I using a solid phase synthetic route based on
the procedure of Ellman, J. et al., J. Med. Chem. 1995, 38,
1427.
##STR00292##
[0564] Scheme 1 or 2 in combination with scheme 11 above provide a
general method for the preparation of compounds of formula I,
specifically compounds 39, 40, 39a, and 40a.
##STR00293##
[0565] Scheme 1 or 2 in combination with scheme 13 above provide a
general method for the preparation of compounds of formula I,
specifically compounds 25, 25a, 41a, 45a, 55a, 58a, 59a, and
61a.
##STR00294## ##STR00295##
[0566] Scheme 14 above provides a synthetic scheme for the
preparation of compound 25a.
##STR00296## ##STR00297##
[0567] Scheme 15 above provides a synthetic scheme for the
preparation of compound 39a.
##STR00298##
[0568] Scheme 16 above provides a synthetic scheme for the
preparation of compound 40a.
##STR00299## ##STR00300##
[0569] Scheme 17 above provides a general method for the
preparation of compounds of formula II.
[0570] Although certain exemplary embodiments are depicted and
described below, it will be appreciated that compounds of this
invention can be prepared according to the methods described
generally above using appropriate starting materials generally
available to one of ordinary skill in the art.
[0571] Another embodiment of this invention provides a composition
comprising a compound of formula I or a pharmaceutically acceptable
salt thereof. According to a preferred embodiment, the compound of
formula I is present in an amount effective to decrease the viral
load in a sample or in a patient, wherein said virus encodes a
serine protease necessary for the viral life cycle, and a
pharmaceutically acceptable carrier.
[0572] If pharmaceutically acceptable salts of the compounds of
this invention are utilized in these compositions, those salts are
preferably derived from inorganic or organic acids and bases.
Included among such acid salts are the following: acetate, adipate,
alginate, aspartate, benzoate, benzene sulfonate, bisulfate,
butyrate, citrate, camphorate, camphor sulfonate,
cyclopentane-propionate, digluconate, dodecylsulfate,
ethanesulfonate, fumarate, glucoheptanoate, glycerophosphate,
hemisulfate, heptanoate, hexanoate, hydrochloride, hydrobromide,
hydroiodide, 2-hydroxyethanesulfonate, lactate, maleate,
methanesulfonate, 2-naphthalenesulfonate, nicotinate, oxalate,
pamoate, pectinate, persulfate, 3-phenyl-propionate, picrate,
pivalate, propionate, succinate, tartrate, thiocyanate, tosylate
and undecanoate. Base salts include ammonium salts, alkali metal
salts, such as sodium and potassium salts, alkaline earth metal
salts, such as calcium and magnesium salts, salts with organic
bases, such as dicyclohexylamine salts, N-methyl-D-glucamine, and
salts with amino acids such as arginine, lysine, and so forth.
[0573] Also, the basic nitrogen-containing groups may be
quaternized with such agents as lower alkyl halides, such as
methyl, ethyl, propyl, and butyl chloride, bromides and iodides;
dialkyl sulfates, such as dimethyl, diethyl, dibutyl and diamyl
sulfates, long chain halides such as decyl, lauryl, myristyl and
stearyl chlorides, bromides and iodides, aralkyl halides, such as
benzyl and phenethyl bromides and others. Water or oil-soluble or
dispersible products are thereby obtained.
[0574] The compounds utilized in the compositions and methods of
this invention may also be modified by appending appropriate
functionalities to enhance selective biological properties. Such
modifications are known in the art and include those which increase
biological penetration into a given biological system (e.g., blood,
lymphatic system, central nervous system), increase oral
availability, increase solubility to allow administration by
injection, alter metabolism and alter rate of excretion.
[0575] Pharmaceutically acceptable carriers that may be used in
these compositions include, but are not limited to, ion exchangers,
alumina, aluminum stearate, lecithin, serum proteins, such as human
serum albumin, buffer substances such as phosphates, glycine,
sorbic acid, potassium sorbate, partial glyceride mixtures of
saturated vegetable fatty acids, water, salts or electrolytes, such
as protamine sulfate, disodium hydrogen phosphate, potassium
hydrogen phosphate, sodium chloride, zinc salts, colloidal silica,
magnesium trisilicate, polyvinyl pyrrolidone, cellulose-based
substances, polyethylene glycol, sodium carboxymethylcellulose,
polyacrylates, waxes, polyethylene-polyoxypropylene-block polymers,
polyethylene glycol and wool fat.
[0576] According to a preferred embodiment, the compositions of
this invention are formulated for pharmaceutical administration to
a mammal, preferably a human being.
[0577] Such pharmaceutical compositions of the present invention
may be administered orally, parenterally, by inhalation spray,
topically, rectally, nasally, buccally, vaginally or via an
implanted reservoir. The term "parenteral" as used herein includes
subcutaneous, intravenous, intramuscular, intra-articular,
intra-synovial, intrasternal, intrathecal, intrahepatic,
intralesional and intracranial injection or infusion techniques.
Preferably, the compositions are administered orally or
intravenously.
[0578] Sterile injectable forms of the compositions of this
invention may be aqueous or oleaginous suspension. These
suspensions may be formulated according to techniques known in the
art using suitable dispersing or wetting agents and suspending
agents. The sterile injectable preparation may also be a sterile
injectable solution or suspension in a non-toxic parenterally
acceptable diluent or solvent, for example as a solution in
1,3-butanediol. Among the acceptable vehicles and solvents that may
be employed are water, Ringer's solution and isotonic sodium
chloride solution. In addition, sterile, fixed oils are
conventionally employed as a solvent or suspending medium. For this
purpose, any bland fixed oil may be employed including synthetic
mono- or di-glycerides. Fatty acids, such as oleic acid and its
glyceride derivatives are useful in the preparation of injectables,
as are natural pharmaceutically-acceptable oils, such as olive oil
or castor oil, especially in their polyoxyethylated versions. These
oil solutions or suspensions may also contain a long-chain alcohol
diluent or dispersant, such as carboxymethyl cellulose or similar
dispersing agents which are commonly used in the formulation of
pharmaceutically acceptable dosage forms including emulsions and
suspensions. Other commonly used surfactants, such as Tweens, Spans
and other emulsifying agents or bioavailability enhancers which are
commonly used in the manufacture of pharmaceutically acceptable
solid, liquid, or other dosage forms may also be used for the
purposes of formulation.
[0579] Dosage levels of between about 0.01 and about 100 mg/kg body
weight per day, preferably between about 0.5 and about 75 mg/kg
body weight per day of the protease inhibitor compounds described
herein are useful in a monotherapy for the prevention and treatment
of antiviral, particularly anti-HCV mediated disease. Typically,
the pharmaceutical compositions of this invention will be
administered from about 1 to about 5 times per day or
alternatively, as a continuous infusion. Such administration can be
used as a chronic or acute therapy. The amount of active ingredient
that may be combined with the carrier materials to produce a single
dosage form will vary depending upon the host treated and the
particular mode of administration. A typical preparation will
contain from about 5% to about 95% active compound (w/w).
Preferably, such preparations contain from about 20% to about 80%
active compound.
[0580] When the compositions of this invention comprise a
combination of a compound of formula I, II, III or IV, and one or
more additional therapeutic or prophylactic agents, both the
compound and the additional agent should be present at dosage
levels of between about 10 to 100%, and more preferably between
about 10 to 80% of the dosage normally administered in a
monotherapy regimen.
[0581] The pharmaceutical compositions of this invention may be
orally administered in any orally acceptable dosage form including,
but not limited to, capsules, tablets, aqueous suspensions or
solutions. In the case of tablets for oral use, carriers that are
commonly used include lactose and corn starch. Lubricating agents,
such as magnesium stearate, are also typically added. For oral
administration in a capsule form, useful diluents include lactose
and dried cornstarch. When aqueous suspensions are required for
oral use, the active ingredient is combined with emulsifying and
suspending agents. If desired, certain sweetening, flavoring or
coloring agents may also be added.
[0582] Alternatively, the pharmaceutical compositions of this
invention may be administered in the form of suppositories for
rectal administration. These may be prepared by mixing the agent
with a suitable non-irritating excipient which is solid at room
temperature but liquid at rectal temperature and therefore will
melt in the rectum to release the drug. Such materials include
cocoa butter, beeswax and polyethylene glycols.
[0583] The pharmaceutical compositions of this invention may also
be administered topically, especially when the target of treatment
includes areas or organs readily accessible by topical application,
including diseases of the eye, the skin, or the lower intestinal
tract. Suitable topical formulations are readily prepared for each
of these areas or organs.
[0584] Topical application for the lower intestinal tract may be
effected in a rectal suppository formulation (see above) or in a
suitable enema formulation. Topically-transdermal patches may also
be used.
[0585] For topical applications, the pharmaceutical compositions
may be formulated in a suitable ointment containing the active
component suspended or dissolved in one or more carriers. Carriers
for topical administration of the compounds of this invention
include, but are not limited to, mineral oil, liquid petrolatum,
white petrolatum, propylene glycol, polyoxyethylene,
polyoxypropylene compound, emulsifying wax and water.
Alternatively, the pharmaceutical compositions may be formulated in
a suitable lotion or cream containing the active components
suspended or dissolved in one or more pharmaceutically acceptable
carriers. Suitable carriers include, but are not limited to,
mineral oil, sorbitan monostearate, polysorbate 60, cetyl esters
wax, cetearyl alcohol, 2-octyldodecanol, benzyl alcohol and
water.
[0586] For ophthalmic use, the pharmaceutical compositions may be
formulated as micronized suspensions in isotonic, pH adjusted
sterile saline, or, preferably, as solutions in isotonic, pH
adjusted sterile saline, either with our without a preservative
such as benzylalkonium chloride. Alternatively, for ophthalmic
uses, the pharmaceutical compositions may be formulated in an
ointment such as petrolatum.
[0587] The pharmaceutical compositions of this invention may also
be administered by nasal aerosol or inhalation. Such compositions
are prepared according to techniques well known in the art of
pharmaceutical formulation and may be prepared as solutions in
saline, employing benzyl alcohol or other suitable preservatives,
absorption promoters to enhance bioavailability, fluorocarbons,
and/or other conventional solubilizing or dispersing agents.
[0588] Most preferred are pharmaceutical compositions formulated
for oral administration.
[0589] In another embodiment, the compositions of this invention
additionally comprise another anti-viral agent, preferably an
anti-HCV agent. Such anti-viral agents include, but are not limited
to, immunomodulatory agents, such as .alpha.-, .beta.-, and
.gamma.-interferons, pegylated derivatized interferon-.alpha.
compounds, and thymosin; other anti-viral agents, such as
ribavirin, amantadine, and telbivudine; other inhibitors of
hepatitis C proteases (NS2-NS3 inhibitors and NS3-NS4A inhibitors);
inhibitors of other targets in the HCV life cycle, including
helicase and polymerase inhibitors; inhibitors of internal ribosome
entry; broad-spectrum viral inhibitors, such as IMPDH inhibitors
(e.g., VX-497 and other IMPDH inhibitors disclosed in U.S. Pat. No.
5,807,876, mycophenolic acid and derivatives thereof); or
combinations of any of the above.
[0590] Upon improvement of a patient's condition, a maintenance
dose of a compound, composition or combination of this invention
may be administered, if necessary. Subsequently, the dosage or
frequency of administration, or both, may be reduced, as a function
of the symptoms, to a level at which the improved condition is
retained when the symptoms have been alleviated to the desired
level, treatment should cease. Patients may, however, require
intermittent treatment on a long-term basis upon any recurrence of
disease symptoms.
[0591] It should also be understood that a specific dosage and
treatment regimen for any particular patient will depend upon a
variety of factors, including the activity of the specific compound
employed, the age, body weight, general health, sex, diet, time of
administration, rate of excretion, drug combination, and the
judgment of the treating physician and the severity of the
particular disease being treated. The amount of active ingredients
will also depend upon the particular described compound and the
presence or absence and the nature of the additional anti-viral
agent in the composition.
[0592] According to another embodiment, the invention provides a
method for treating a patient infected with a virus characterized
by a virally encoded serine protease that is necessary for the life
cycle of the virus by administering to said patient a
pharmaceutically acceptable composition of this invention.
Preferably, the methods of this invention are used to treat a
patient suffering from a HCV infection. Such treatment may
completely eradicate the viral infection or reduce the severity
thereof. More preferably, the patient is a human being.
[0593] In an alternate embodiment, the methods of this invention
additionally comprise the step of administering to said patient an
anti-viral agent preferably an anti-HCV agent. Such anti-viral
agents include, but are not limited to, immunomodulatory agents,
such as .alpha.-, .beta.-, and .gamma.-interferons, pegylated
derivatized interferon-.alpha. compounds, and thymosin; other
anti-viral agents, such as ribavirin and amantadine; other
inhibitors of hepatitis C proteases (NS2-NS3 inhibitors and
NS3-NS4A inhibitors); inhibitors of other targets in the HCV life
cycle, including helicase and polymerase inhibitors; inhibitors of
internal ribosome entry; broad-spectrum viral inhibitors, such as
IMPDH inhibitors (e.g., VX-497 and other IMPDH inhibitors disclosed
in U.S. Pat. No. 5,807,876, mycophenolic acid and derivatives
thereof); or combinations of any of the above.
[0594] Such additional agent may be administered to said patient as
part of a single dosage form comprising both a compound of this
invention and an additional anti-viral agent. Alternatively the
additional agent may be administered separately from the compound
of this invention, as part of a multiple dosage form, wherein said
additional agent is administered prior to, together with or
following a composition comprising a compound of this
invention.
[0595] In yet another embodiment the present invention provides a
method of pre-treating a biological substance intended for
administration to a patient comprising the step of contacting said
biological substance with a pharmaceutically acceptable composition
comprising a compound of this invention. Such biological substances
include, but are not limited to, blood and components thereof such
as plasma, platelets, subpopulations of blood cells and the like;
organs such as kidney, liver, heart, lung, etc; sperm and ova; bone
marrow and components thereof, and other fluids to be infused into
a patient such as saline, dextrose, etc.
[0596] According to another embodiment the invention provides
methods of treating materials that may potentially come into
contact with a virus characterized by a virally encoded serine
protease necessary for its life cycle. This method comprises the
step of contacting said material with a compound according to the
invention. Such materials include, but are not limited to, surgical
instruments and garments; laboratory instruments and garments;
blood collection apparatuses and materials; and invasive devices,
such as shunts, stents, etc.
[0597] In another embodiment, the compounds of this invention may
be used as laboratory tools to aid in the isolation of a virally
encoded serine protease. This method comprises the steps of
providing a compound of this invention attached to a solid support;
contacting said solid support with a sample containing a viral
serine protease under conditions that cause said protease to bind
to said solid support; and eluting said serine protease from said
solid support. Preferably, the viral serine protease isolated by
this method is HCV NS3-NS4A protease.
[0598] In order that this invention be more fully understood, the
following examples are set forth. These examples are for the
purpose of illustration only and are not to be construed as
limiting the scope of the invention in any way.
EXAMPLES
[0599] .sup.1H-NMR spectra were recorded at 500 MHz using a Bruker
AMX 500 instrument. Mass spec. samples were analyzed on a MicroMass
ZQ or Quattro II mass spectrometer operated in single MS mode with
electrospray ionization. Samples were introduced into the mass
spectrometer using flow injection (FIA) or chromatography. Mobile
phase for all mass spec. analysis consisted of acetonitrile-water
mixtures with 0.2% formic acid as a modifier.
[0600] As used herein, the term "R.sub.t(min)" refers to the HPLC
retention time, in minutes, associated with the compound. The HPLC
retention times listed were either obtained from the mass spec.
data or using the following method: [0601] Instrument: Hewlett
Packard HP-1050; [0602] Column: YMC C.sub.18 (Cat. No. 326289C46);
[0603] Gradient/Gradient Time: 10-90% CH.sub.3CN/H2O over 9
minutes, then 100% CH.sub.3CN for 2 minutes; [0604] Flow Rate: 0.8
ml/min; [0605] Detector Wavelength: 215 nM and 245 nM;
[0606] Chemical naming for selected compounds herein was
accomplished using the naming program provided by CambridgeSoft
Corporations ChemDraw Ultra.RTM., version 7.0.1.
Example 1
3-Acetyl-1H-indole-2-carboxylic acid (4b) and
5-Acetyl-1H-indole-2-carboxylic acid (5b)
[0607] Aluminum chloride (7.75 g, 0.058 mol) was suspended in 200
ml of anhydrous dichloroethane at room temp. followed by a slow
addition of acetic anhydride (2.74 mL, 0.03 mol). The mixture was
stirred at room temp for 10 minutes after which,
1H-indole-2-carboxylic acid ethyl ester (1b, 5.0 g, 0.0264 mol) was
added as a solution in 15 mL of dichloroethane. The reaction
mixture was stirred under nitrogen at 40.degree. C. for 10 h. The
reaction was quenched with an ice-water mixture and the organic
layer was washed with water (3.times.). The organic phase was dried
over anh. Na.sub.2SO.sub.4, filtered and concentrated in vacuo.
Chromatography on SiO.sub.2 (4% Ethyl acetate/96% CH.sub.2Cl.sub.2)
provided 3.2 g of 3-acetyl-1H-indole-2-carboxylic acid ethyl ester
2b (52%) and 770 mg of 5-acetyl-1H-indole-2-carboxylic acid ethyl
ester 3b (13%).
[0608] 2b: .sup.1H NMR (CDCl.sub.3) d 9.1 (bs, 1H), 8.1 (d, 1H),
7.5 (m, 2H), 7.3 (s, 1H), 4.4 (q, 2H), 2.7 (s, 3H), 1.5 (t, 3H)
ppm.
[0609] 3b: .sup.1H NMR (CDCl.sub.3) d 9.3 (bs, 1H), 8.25 (s, 1H),
8.1 (d, 1H), 7.6 (d, 1H), 7.2 (s, 1H), 4.3 (q, 2H), 2.7 (s, 3H),
1.7 (t, 3H) ppm.
[0610] Saponification of 2b and 3b with 10% KOH in ethanol at
60.degree. C. for 1 h followed by acidification with 1M HCl
provided 3-acetyl-1H-indole-2-carboxylic acid 4b and
5-acetyl-1H-indole-2-carboxylic acid 5b in 95% and 93% yield
respectively. The crude acids were used directly without
purification in the next step.
Example 2
3-Acetyl-4,5-dimethyl-2-pyrrole carboxylic acid (10b)
[0611] A solution of sodium nitrite (36.9 g, 0.534 mol) in 70 mL of
water was added dropwise to a stirred solution of ethylacetoacetate
(70 g, 0.538 mol) in 1401 mL of glacial acetic acid at 0.degree. C.
After the addition was complete, the light yellow reaction mixture
was allowed to warm to room temperature. After 30 minutes, all the
starting material had been consumed, the reaction was quenched with
350 mL of water and extracted with ethyl acetate (2.times.125 mL).
The organic extracts were combined and washed with water
(2.times.125 mL) and saturated sodium hydrogen carbonate aqueous
solution (2.times.105 mL). The organic layer was dried with sodium
sulfate and concentrated in vacuo to give 84.2 g (98%) of
Ethyl-2-Hydroxyimino-3-oxobutanoate 6b as a pale yellow oil.
[0612] .sup.1H NMR (CDCl.sub.3) d 10.3 (s, 1H), 4.2 (q, 2H), 2.3
(s, 3H), 1.3 (t, 3H) ppm.
[0613] Crushed sodium (12.4 g, 0.540 mol) was added to a solution
of 2-butanone (48.2 mL, 0.538 mol) and ethyl formate (43.47 mL,
0.538 mol) in dry ether (540 mL) with vigorous mechanical stirring
over a period of 1 h, during which time the mixture was chilled in
an ice-salt bath. The mixture was then stirred at room temp. for 14
h. After cooling the reaction mixture to 4.degree. C. for a few
hours, the precipitated sodium salt was obtained by filtration and
washed thoroughly with cold, dry ether to afford 49.3 g (75%) of
the desired sodium salt of 2-Methyl-3-oxobutyraldehyde 7b.
[0614] .sup.1H NMR (DMSO-d.sub.6) d 9.1 (s, 1H), 1.9 (s, 3H), 1.3
(s, 3H) ppm.
[0615] Sodium salt 7b (49.3 g, 0.404 mol) and oxime 6b (64.23,
0.404 mol) were stirred in 300 mL of 70% acetic acid/30% water and
warmed to 50.degree. C. Zinc powder (42.21 g, 0.646 mol) was added
portion-wise over 30 minutes maintaining the temperature below
100.degree. C. When the addition was complete, the suspension was
refluxed for 15 minutes, then poured into 4 L of ice-water. After a
short time, the product precipitated out to give, after filtration,
30.1 g (45%) of the desired ethyl-4,5-dimethyl-2-pyrrole
carboxylate 8b. .sup.1H NMR (CDCl.sub.3) d 9.0 (bs, 1H), 6.7 (s,
1H), 4.3 (q, 2H), 2.3 (s, 3H), 2.0 (s, 3H), 1.3 (t, 3H) ppm.
[0616] To a solution of aluminum chloride (50.19 g, 0.376 mol) in
dry dichloroethane (580 mL) at 25.degree. C. was added slowly
acetic anhydride (17.75 mL, 0.188 mol). The resulting mixture was
stirred at room temp. for 10 minutes, then a solution of pyrrole 8b
(10.49 g, 0.0627 mol) in dichloroethane (30 mL) was added and the
reaction mixture was stirred at room temp. for 2 h. After an
additional 3 h at 80.degree. C., the mixture was poured into ice
water and extracted with dichloromethane. The organic layer was
dried with anhy. sodium sulfate and concentrated in vacuo to an
orange residue. Short plug filtration over silica gel (30% ethyl
acetate/70% hexanes) gave 7.5 g (60%) of
ethyl-3-acetyl-4,5-dimethyl-2-pyrrole carboxylate 9b.
[0617] .sup.1H NMR (CDCl.sub.3) d 9.0 (bs, 1H), 4.3 (q, 2H), 2.7
(s, 3H), 2.1 (s, 3H), 1.9 (s, 3H), 1.3 (t, 3H) ppm.
[0618] A mixture of pyrrole ester 9b (8.2 g, 0.0392 mol), in
ethanol and 100 mL of 10% potassium hydroxide were refluxed for 1
h. The mixture was cooled and concentrated in vacuo to an oil.
Water was added to the oil, the mixture acidified with dilute HCl
and extracted with ether. The organic phase was dried with anhy.
sodium sulfate and concentrated in vacuo to a solid residue. The
compound was recrystallized in 80 mL of ethanol to give 5.8 g of
pure 3-acetyl-4,5-dimethyl-2-pyrrole carboxylic acid 10b as a
solid.
[0619] .sup.1H NMR (DMSO-d.sub.6) d 2.5 (s, 3H), 2.2 (s, 3H), 2.0
(s, 3H) ppm.
Example 3
1-(2-{20[(3-Acetyl-4,5-dimethyl-1H-pyrrole-1H-2-carbonyl)-amino]-2-cyclohe-
xyl-acetylamino}-3,3-dimethyl-butyryl)-octahydro-indole-2-carboxylic
acid (1-cyclopropylaminooxalyl-butyl)-amide (25a)
[0620] Octahydro-indole-2-carboxylic acid 11b (5.0 g, 29.5 mmol,
purchased from Bachem) was suspended in 200 mL of CHCl.sub.3 then
cooled in a dry ice/acetone bath. H.sub.2SO.sub.4 (120 uL/mmol) was
added followed by bubbling in excess isobutylene. The mixture was
sealed and the ice bath removed. The mixture was stirred at RT for
12 hours. The reaction mixture was carefully unsealed after cooling
and concentrated. EtOAc was added and washed with saturated sodium
bicarbonate soln, brine, dried over sodium sulfate, then filtered
and concentrated to give octahydro-indole-2-carboxylic acid
tert-butyl ester 12b (6.65 g, 29.5 mmol, 100%).
[0621] .sup.1H-NMR (CDCl.sub.3) d 1.22 (2H, m), 1.38 (2H, m), 1.48
(9H, s), 1.50 (2H, m), 1.66 (2H, m), 1.71 (1H, m), 2.02, (1H m),
2.18 (1H, m), 2.85 (1H, bs), 3.10 (1H m), 3.70 (1H, dd) ppm.
[0622] L-CBz-tert-butyl glycine (5.0 g, 11.2 mmol) was stirred in
CH.sub.2Cl.sub.2 (40 mL). EDC (2.25 g, 11.7 mmol) and HOBt (1.58 g,
11.7 mmol) were added and the mixture stirred 15 minutes. This
solution was cannulated into a solution of 12b (2.4 g, 10.6 mmol)
in CH.sub.2Cl.sub.2 (20 mL) and stirred overnight. The reaction was
monitored by HPLC observing the consumption of the amine. The
mixture was concentrated, EtOAc added, followed by a 1.0N aqueous
glycine sodium salt solution and the mixture stirred until all
Cbz-tert-butyl glycine-OBt was consumed. The layers were separated
and the organic phase washed with 1N HCl (3.times.), brine, 10%
potassium carbonate (3.times.), and brine then dried over sodium
sulfate, filtered and concentrated in vacuo. Chromatography through
a silica gel plug (10% EA/Hex) gave
1-(2-benzyloxycarbonylamino-3,3-dimethyl-butyryl)-octahydro-indole-2-carb-
oxylic acid tert-butyl ester 13b (4.4 g, 9.3 mmol, 88%).
[0623] .sup.1H-NMR (CDCl.sub.3) d 1.05 (9H, s), 1.30 (2H, m), 1.46
(9H, s), 1.50-1.72 (5H, m), 1.94-2.10 (3H, m), 2.30 (1H m), 4.18
(1H, m), 4.22, (1H, d), 4.28 (1H, dd), 5.05-5.17 (2H, dd), 5.30
(1H, d), 7.33 (5H, m) ppm.
[0624] Ester 13b (4.0 g, 8.4 mmol) was stirred in EtOH (40 mL)
charged with 400 mg 10% Pd(OH).sub.2/C. H.sub.2 gas was bubbled
into the suspension until the reaction was complete. Catalyst was
removed by filtration and the filtrate concentrated in vacuo to
give 1-(2-amino-3,3-dimethyl-butyryl)-octahydro-indole-2-carboxylic
acid tert-butyl ester 14b (2.8 g, 8.4 mmol, 100%) which was used as
is in the next step without further purification.
[0625] .sup.1H-NMR (CDCl.sub.3) 3:2 ratio of rotamers, d 0.98 and
1.02 (9H, pair of singlets), 1.20-1.34 (2H, m), 1.47 and 1.50 (9H,
pair of singlets), 1.58-1.78 (6H, m), 1.99 (1H, m), 2.1 (1H, m),
2.3 (1H, m), 2.4 (1H, m), 3.86 and 4.13 (1H, m), 4.32 (1H, m)
ppm.
[0626] L-CBz-cyclohexyl glycine (3.0 g, 10.3 mmol) in
CH.sub.2Cl.sub.2 (30 mL) was treated with EDC (2.07 g, 10.8 mmol)
and HOBt (1.65 g, 10.8 mmol) and stirred for 15 minutes. The
resulting mixture was added to a solution of 14b (3.32 g, 9.8 mmol
in CH.sub.2Cl.sub.2 (20 mL) and stirred at RT, monitoring
consumption of amine by HPLC. 1.0N glycine sodium salt solution was
added until all L-CBz-cyclohexyl glycine-OBt was consumed (several
hours) with monitoring by HPLC. The reaction mixture was washed
with 1.0N HCl (3.times.), brine, 10% potassium carbonate
(3.times.), and brine, then dried over sodium sulfate, filtered and
concentrated in vacuo. The solid product obtained was
recrystallized from hot IPA/H.sub.2O (.about.3.3:1) by dissolving
the compound in hot IPA and adding water slowly until product
started to precipitate out. Cold filtration afforded 4.79 g (80%)
of
1-[2-(2-benzyloxycarbonylamino-2-cyclohexyl-acetylamino)-3,3-dimethyl-but-
yryl]-octahydroindole-2-carboxylic acid tert-butyl ester 15b as a
solid.
[0627] .sup.1H-NMR (CDCl.sub.3) d 0.98 (1H, m), 1.03 (9H, s),
1.12-1.32 (5H, m), 1.43 (9H, s), 1.59-1.79 (12H, m), 1.93-2.10 (3H,
m), 2.20 (1H, m), 3.98 (1H, m), 4.12 (1H, m), 4.22 (1H, m) 4.55
(1H, d), 5.10 (2H, m), 5.27 (1H, d), 6.25 (1H, d), 7.35 (5H, m)
ppm.
[0628] CBz ester 15b (3.0 g, 4.9 mmol) was stirred in EtOH (25 mL)
and charged with 300 mg 10% Pd(OH).sub.2/C. H.sub.2 gas was bubbled
into the suspension until the reaction was complete. Catalyst was
removed by filtration and the filtrate concentrated in vacuo to
give
1-[2-(2-amino-2-cyclohexyl-acetylamino)-3,3-dimethyl-butyryl]-octahydro-i-
ndole-2-carboxylic acid tert-butyl ester 16b (2.34 g, 4.9 mmol,
100%) which was used as is in the next step without further
purification.
[0629] .sup.1H-NMR (CDCl.sub.3) d 1.08 (9H, s), 1.10-1.25 (7H, m),
1.44 (9H, s), 1.50-1.78 (10H, m), 1.94 (2H, m), 2.07 (2H, m), 2.30
(1H, m), 3.21 (1H, m), 4.22 (1H, m), 4.34 (1H, m), 4.52 (1H, d),
8.04 (1H, d) ppm.
[0630] 3-acetyl-4,5-dimethyl-2-pyrrole carboxylic acid 10b (2.5 g,
13.7 mmol) in DMF (56 mL) was treated with EDC (2.75 g, 14.4 mmol)
and HOBt (2.20 g, 14.4 mmol) and stirred at RT for 15 minutes.
Amine 16b (6.23 g, 13.0 mmol) in DMF (10 mL) was added, the
reaction mixture stirred at RT and monitored by HPLC. The mixture
was concentrated in vacuo, then dissolved in EtOAc. 1.0N glycine
sodium salt aqueous solution was added until all excess amino ester
16b was consumed (several hours). The mixture was washed with 1N
HCl (3.times.), brine, bicarb (3.times.), and brine, then dried
over sodium sulfate, filtered, and concentrated in vacuo.
Purification through a short plug of silica gel (25% EA/Hex)
afforded 7.08 g, (85%) of
1-(2-{2-[(3-acetyl-4,5-dimethyl-1H-pyrrole-2-carbonyl)-amino]-2-cyclohexy-
l-acetylamino}-3,3-dimethyl-butyryl)-octahydro-indole-2-carboxylic
acid tert-butyl ester 17b.
[0631] .sup.1H-NMR (CDCl.sub.3) d 0.94 (9H, s), 0.99-1.33 (6H, m),
1.42 (9H, s), 1.45-2.22 (16H, m), 2.24 (3H, s), 2.28 (3H, s), 2.55
(3H, s), 4.30 (1H, m), 4.39 (1H, m), 4.73 (1H, d), 5.00 (1H, m),
11.30 (1H, d) ppm.
[0632] tert-Butyl ester 17b (3.0 g, 4.68 mmol) was stirred in
CH.sub.2Cl.sub.2 (20 mL) in an ice bath and TFA (20 mL) was added
slowly. The mixture was warmed to RT and stirred until ester was no
longer observed by HPLC. Added toluene and concentrated in vacuo
several times (3.times.). Most of the residual TFA was removed in
vacuo to give
1-(2-{2-[(3-acetyl-4,5-dimethyl-1H-pyrrole-2-carbonyl)-amino]-2-cyclohexy-
l-acetylamino}-3,3-dimethyl-butyryl)-octahydro-indole-2-carboxylic
acid tert-butyl ester 18b as a pink solid which was used in the
next step without further purification.
[0633] Crude acid 18b from above in CH.sub.2Cl.sub.2 (20 mL) was
treated with DIEA dropwise and stirred at RT until fuming ceased
(from quenching excess TFA). EDC (0.99 g, 5.1 mmol) and HOBt (0.78
g, 5.1 mmol) were added and the mixture stirred for 15 minutes.
3-Amino-2-hydroxy-hexanoic acid cyclopropylamine 19b (950 mg, 5.1
mmol, prepared according to the methods described by U. Schoellkopf
et al., Justus Liebigs Ann. Chem. GE, 1976, 183-202, and J. Stemple
et al., Organic Letters 2000, 2(18), 2769-2772) in CH.sub.2Cl.sub.2
(10 mL) was added and the mixture stirred at RT overnight. The
mixture was poured onto 1N HCl/EtOAc, the organic layer washed with
1N HCl (3.times.), brine, sat'd NaHCO.sub.3 (3.times.), and brine,
then dried over sodium sulfate, filtered, and concentrated in
vacuo. Purification through a plug of silica gel eluting with 100%
CH.sub.2Cl.sub.2-->>1% MeOH/CH.sub.2Cl.sub.2-->>>2%
MeOH/CH.sub.2Cl.sub.2 afforded 3.0 g (85% for two steps) of
1-(2-{(2-[(3-acetyl-4,5-dimethyl-1H-pyrrole-2-carbonyl)-amino]-2-cyclohex-
yl-acetylamino}-3,3-dimethyl-butyryl)-octahydro-indole-2-carboxylic
acid [1-(cyclopropylcarbamoyl-hydroxy-methyl)-butyl]-amide 20b.
[0634] NMR .sup.1H-NMR (CDCl.sub.3) d 0.50 (2H, m), 0.67 (1H, m),
0.75 (1H, m), 0.85 (4H, m), 0.93 (8H, m), 1.03 (3H, m), 1.22 (2H,
m), 1.30 (3H, m), 1.50-2.03 (18H, m), 2.25 (3H, s), 2.26 (3H, s),
2.60 (3H, s), 2.71 (1H, m), 3.89 and 3.91 (1H, bm), 4.10 and 4.21
(1H, pair of singlets), 4.38 (1H, m), 4.52 (1H, m), 4.67 and 4.71
(1H, pair of doublets), 4.80 (1H, m), 6.95 and 7.00 (1H, pair of
doublets) ppm.
[0635] To a solution of EDC (38.2 g. 199.2 mmol) in dry EtOAc (98
mL) was added keto-alcohol 20b (10.0 g, 13.3 mmol) in dry EtOAc (52
mL). Dry DMSO (75 mL) was added, the mixture cooled to 7.degree. C.
and dichloroacetic acid (10.97 mL, 133 mmol) in dry EtOAc (31 mL)
was added as quickly as possible allowing the temperature to go no
higher than 25.degree. C. The ice bath was removed and the mixture
stirred for 15 minutes. TLC showed complete disappearance of 20b.
The mixture was cooled to 15.degree. C. before adding 1.0N HCl (200
mL) to quench as quickly as possible without allowing the temp. to
go above 25.degree. C. The organic layer was washed with water
(3.times.), dried over sodium sulfate, filtered and concentrated in
vacuo. Purification through a silica gel plug (100%
CH.sub.2Cl.sub.2-->50% EtOAc/CH.sub.2Cl.sub.2) afforded a white
solid which was stirred in Et.sub.2O, filtered and dried in vacuo
to remove residual dimethyl sulfide and dichloroacetic acid.
Obtained 7.49 g (75%) of desired
1-(2-{2-[(3-acetyl-4,5-dimethyl-1H-pyrrole-2-carbonyl)-amino]-2-cyclohexy-
l-acetylamino}-3,3-dimethyl-butyryl)-octahydro-indole-2-carboxylic
acid (1-cyclopropylaminooxalyl-butyl)-butyl)-amide 25a.
[0636] .sup.1H-NMR (CDCl.sub.3) d 0.61 (2H, m), 0.82 (2H, d), 0.91
(3H, t), 0.97 (7H, s), 1.05 (3H, m), 1.20 (2H, m), 1.32 (4H, m),
1.50 (5H, m), 1.68 (5H, m), 1.79 (3H, m), 1.89 (3H, m), 2.01 (1H,
m), 2.18 (1H, m), 2.23 (3H, s), 2.24 (3H, s), 2.37 (1H, m), 2.59
(3H, s), 2.78 (1H, m), 4.41 (1H, m), 4.56 (1H, t), 4.85 (1H, d),
4.91 (1H, m), 5.31 (1H, m), 6.90 (1H, broad), 7.03 (1H, broad)
ppm.
Example 4
3-Acetyl-1H-indole-2-carboxylic acid
(cyclohexyl-{1-[2-(1-cyclopropylaminooxalyl-butylcarbamoyl)-octahydro-ind-
ole-1-carbonyl]-2,2-dimethyl-propylcarbamoyl}-methyl)-amide
(39a)
[0637] BOC-L-Octahydro-indole-2-carboxylic acid 21b (3.4 g, 12.6
mmol, purchased from Bachem), was suspended in 30 mL
CH.sub.2Cl.sub.2 and cooled in a water/ice bath. N-methylmorpholine
(3.0 eq., 4.2 mL, 38 mmol) was added followed by addition of solid
PyBOP (1.1 eq., 7.2 g, 13.8 mmole). The ice bath was removed and
the reaction stirred at RT for 1 hour under N.sub.2. In a separate
flask, 5.8 g of 3-amino-2-hydroxy-hexanoic acid cyclopropylamine
19b was dissolved in 30 mL of DMF and 10 mL of CH.sub.2Cl.sub.2. at
RT. The acid (21b)/PyBOP/NMM solution was cannulated into the
solution of amine 19b along with 20 mL of CH.sub.2Cl.sub.2. The
reaction was stirred at RT for 16 hours, then quenched with aqueous
sodium bicarbonate solution and concentrated in vacuo. The residue
was extracted twice with EtOAc. The combined organic layers were
washed with 10% citric acid solution, saturated sodium bicarbonate
solution, water (5.times.), then brine, dried over sodium sulfate,
filtered, and concentrated in vacuo. Flash chromatography on silica
gel eluting with 30% EtOAc/hexanes to 100% EtOAc gave 4.35 g of
2-[1-(Cyclopropylcarbamoyl-hydroxy-methyl)-butylcarbamoyl]-octahydro-indo-
le-1-carboxylic acid tert-butyl ester 22b. LC/MS M+H=438.2,
M-H=436.3.
[0638] .sup.1H-NMR (CDCl.sub.3) d 0.50 (2H, m), 0.70 (2H, m), 0.91
(3H, t), 1.14 (1H, m), 1.2-1.37 (4H, m), 1.42 (9H, s), 1.59-1.71
(5H, m), 1.93 (2H, m), 2.10 (1H, bs), 2.22 (1H, m), 2.7 (1H, m),
3.8 (1H, bs), 3.98 (1H, bs) 4.02-4.2 (3H, m), 5.80 (1H, s), 7.1
(2H, bs) ppm.
[0639] BOC ester 22b (4.35 g, 7.43 mmol) was dissolved in 25 ml of
CH.sub.2Cl.sub.2 and cooled in an ice water bath. 25 mL of TFA was
added dropwise, the bath was removed and the reaction was allowed
to warm to RT. TLC showed the BOC group removed after 30 minutes.
After 1 hour, 25 mL of toluene was added and the reaction was
concentrated to dryness and used as is in the next step.
[0640] L-CBz-tert-butyl glycine (3.16 g, 11.9 mmol) in
CH.sub.2Cl.sub.2 (25 mL) was treated with solid PyBOP (6.7 g, 12.9
mmol) and DIEA (1.7 mL, 9.8 mmol) in 5 mL of CH.sub.2Cl.sub.2. The
bath was removed and the reaction was allowed to warm to RT and
stirred for 50 minutes. The crude free amine was dissolved in
CH.sub.2Cl.sub.2 (25 mL), treated with DIEA (3.5 mL, 20 mmol) and
then the mixture was cannulated into the Cbz-L-Tbg-OH/PyBOP
solution with additional CH.sub.2Cl.sub.2 (40 mL) added and the
mixture stirred overnight. After 21 hours, the reaction was
quenched with saturated sodium bicarbonate solution and
concentrated. The residue was partitioned between EtOAc and water
and extracted twice with EtOAc, the combined organic layers were
washed with 0.5N HCl, saturated sodium bicarbonate, water, and
brine then dried over sodium sulfate, filtered, and concentrated in
vacuo. Flash chromatography on silica gel eluting with 2%
MeOH/EtOAc to 5% MeOH/EtOAc gave 4.2 g (72%) of
(1-{2-[1-(Cyclopropylcarbamoyl-hydroxy-methyl)-butylcarbamoyl]-octahydro--
indole-1-carbonyl}-2,2-dimethyl-propyl)-carbamic acid benzyl ester
23b. LC/MS M+H=585.4, M-H=583.3.
[0641] .sup.1H-NMR (CDCl.sub.3) d 0.55 (2H, m), 0.75 (2H, m), 0.88
(3H, t), 0.98 (9H, s), 1.22-1.41 (5H, m), 1.71 (5H, m), 1.96 (2H,
m), 2.21-2.44 (2H, m), 2.72 (1H, m), 3.98 (1H, m), 4.07 (1H, s)
4.2-4.29 (2H, m), 4.39-4.49 (1H, m), 5.02-5.15 (2H, m), 5.4 (1H,
m), 6.75 (1H, m) 6.85 (1H, m), 7.33 (5H, m) ppm.
[0642] Cbz ester 23b (4.2 g, 7.2 mmol) was stirred in EtOH (50 mL)
and flushed with N.sub.2. 800 mg of 10% Pd/C was added with EtOH
(100 mL). The reaction was flushed with H.sub.2 and left under an
H.sub.2 atmosphere overnight. After 18 hours, the reaction was
filtered and concentrated, azeotroped first with CH.sub.3CN then
with CH.sub.2Cl.sub.2 and concentrated in vacuo to provide
intermediate free amine (3.26 g 7.2 mmol, 100%) which was used as
is in the next step.
[0643] 2-(1H-benzotriazole-1-yl)-1,1,3,3-tetramethyluronium
tetrafluoroborate (TBTU, 2.45 g, 7.6 mmol) was combined with DMF
(20 mL) and CH.sub.2Cl.sub.2 (10 mL) and warmed slightly
(45.degree. C.) to dissolve all solids, then cooled in an ice water
bath. A solution of L-CBz-cyclohexyl glycine (2.2 g, 7.6 mmol) in
CH.sub.2Cl.sub.2 (30 mL) was added and the ice bath was removed.
The reaction was warmed to 35.degree. C. for 5 minutes.
N-methylmorpholine (1.5 eq., 1.05 mL, 9.5 mmol) was added and the
reaction stirred at RT for 30 minutes. A solution of the crude
amine (2.85 g 6.32 mmol) obtained above in CH.sub.2Cl.sub.2 (20 mL)
was cannulated into the reaction with additional CH.sub.2Cl.sub.2
(20 mL) and the reaction was stirred at RT overnight. After 19
hours, the reaction was quenched with saturated sodium bicarbonate
solution and concentrated. The residue was partitioned between
EtOAc and water and extracted twice with EtOAc. The combined
organic layers were washed with 0.5N HCl, saturated sodium
bicarbonate, water (4.times.). The water washes were back extracted
with EtOAc and the combined organics were washed with brine, dried
over sodium sulfate, filtered, and concentrated. Flash
chromatography on silica gel eluting with 1% MeOH/CH.sub.2Cl.sub.2
to 4% MeOH/CH.sub.2Cl.sub.2 gave 2.8 g (61%) of
[Cyclohexyl-(1-{2-[1-(cyclopropylcarbamoyl-hydroxy-methyl)-butylcarbamoyl-
]-octahydro-indole-1-carbonyl}-2,2-dimethyl-propylcarbamoyl)-methyl]-carba-
mic acid benzyl ester 24b. LC/MS M+H=724.2, M-H=722.3.
[0644] .sup.1H-NMR (CDCl.sub.3) d 0.55 (2H, m), 0.74 (2H, m), 0.88
(3H, t), 1.02 (9H, s), 1.1-1.65 (22H, mm), 1.94 (2H, m), 2.12 (2H,
m), 2.68-2.79 (1H, m), 3.98-4.27 (4H, m), 4.46-4.6 (1H, m), 4.68
(1H, d) 4.55 (1H, d), 5.10 (2H, s), 5.40 (1H, s), 5.62 (1H, m),
6.96-7.1 (2H, m), 7.3 (5H, m) ppm.
[0645] Cbz amine 24b (2.8 g, 3.9 mmol) was stirred in EtOH (60 mL)
and treated with 520 mg of 10% Pd/C in EtOH (100 mL). The reaction
was flushed with H.sub.2 and left under H.sub.2 atmosphere
overnight. After 19 hours, the reaction was filtered and
concentrated, azeotroped with CH.sub.2Cl.sub.2 and concentrated to
obtain the intermediate free amine (2.33 g 3.9 mmol, 100%) which
was used as is.
[0646] 3-Acetyl-1H-indole-2-carboxylic acid 25b (67 mg, 0.33 mmol)
in CH.sub.2Cl.sub.2 (2 mL) and DMF (2 mL) was treated with EDC (69
mg, 0.36 mmol) and HOAT (123 mg, 0.39 mmol) dissolved in
CH.sub.2Cl.sub.2 (1 mL) and DIEA (160 ul, 0.9 mmol) and stirred at
RT for 5 minutes. Crude amine obtained above (175 mg, 0.30 mmol) in
CH.sub.2Cl.sub.2 (5 mL) was added via cannula and the mixture
stirred at RT. After 46 hours, the reaction was quenched with 0.5N
HCl and concentrated. The residue was partitioned between EtOAc and
water, extracted twice with EtOAc, the combined organic layers
washed with 0.5N HCl, water (4.times.), brine then dried over
sodium sulfate, filtered, and concentrated. Flash chromatography on
silica gel eluting with EtOAc to 5% MeOH/EtOAc gave 166 mg (71%) of
3-acetyl-1H-indole-2-carboxylic acid
[cyclohexyl-(1-{2-[1-(cyclopropylcarbamoyl-hydroxy-methyl)-butylcarbamoyl-
]-octahydro-indole-1-carbonyl}-2,2-dimethyl-propylcarbamoyl)-methyl]-amide
26b. FIA MS M+H=775.4, M-H=773.4, HPLC RT 8.75+8.85 (2
diastereomers). .sup.1H-NMR was consistent for the desired
product.
[0647] Keto alcohol 26b (166 mg, 0.21 mmol) was dissolved in dry
EtOAc (6 mL), treated with EDC (605 mg, 3.15 mmol), dry DMSO (3 mL)
was added and the reaction was cooled to 7.degree. C. A solution of
dichloroacetic acid (175 uL, 2.1 mmol) in dry EtOAc (1 mL) was
added over 1 minute with a slight exotherm. Additional EtOAc (2 mL)
was added and the ice bath was removed. After 1 hour, the reaction
was cooled to 10.degree. C., quenched with 1.0N HCl (2 mL), then
extracted twice with EtOAc. The combined organics were washed with
water (4.times.) and brine, then dried over sodium sulfate,
filtered, and concentrated. Flash chromatography on silica gel
eluting with 25% EtOAc/CH.sub.2Cl.sub.2 to 100% EtOAc followed by
dissolving in CH.sub.3CN/water and lyophilizing gave 139 mg (86%)
of 3-acetyl-1H-indole-2-carboxylic acid
(cyclohexyl-{1-[2-(1-cyclopropylaminooxalyl-butylcarbamoyl)-octahydro-ind-
ole-1-carbonyl]-2,2-dimethyl-propylcarbamoyl}-methyl)-amide 39a.
LC/MS M+H=773.41, M-H=771.49, LC/MS RT=5.01 min, HPLC RT=9.53
min.
[0648] .sup.1H-NMR (CDCl.sub.3) d 0.50 (2H, m), 0.72 (5H, m), 0.92
(9H, s), 1.0-1.32 (10H, m), 1.47-1.75 (10H, m), 1.79-1.93 (3H, m),
2.03 (1H, m), 2.16 (1H, m), 2.32 (1H, dd), 2.68 (1H, m), 2.83 (3H,
s), 4.4 (1H, m) 4.6 (1H, t), 4.8 (1H, d), 5.05 (1H, m), 5.3 (1H,
m), 6.77 (1H, d), 7.02 (1H, m), 7.27 (2H, m), 7.61 (1H, d), 7.9
(1H, d) 8.86 (1H, bs) ppm.
Example 5
5-Acetyl-1H-indole-2-carboxylic acid
(cyclohexyl-{1-[2-(1-cyclopropylaminooxalyl-butylcarbamoyl)-octahydro-ind-
ole-1-carbonyl]-2,2-dimethyl-propylcarbamoyl}-methyl)-amide
(40a)
[0649] 5-Acetyl-1H-indole-2-carboxylic acid 27b (67 mg, 0.33 mmol)
stirred in CH.sub.2Cl.sub.2 (2 mL) and DMF (2 mL) was treated with
EDC (69 mg, 0.36 mmol) and HOAT (123 mg, 0.39 mmol) dissolved in
CH.sub.2Cl.sub.2 (1 mL) and DIEA (160 ul, 0.9 mmol) and the mixture
stirred at RT for 5 minutes. Added crude intermediate amine (175
mg, 0.30 mmol, identically prepared above in example 4) in
CH.sub.2Cl.sub.2 (5 mL) via cannula and stirred at RT. After 45
hours, the reaction was quenched with 0.5N HCl solution and
concentrated. The residue was partitioned between EtOAc and water,
extracted twice with EtOAc, the combined organic layers washed with
0.5N HCl, water (4.times.), and brine, then dried over sodium
sulfate, filtered, and concentrated in vacuo. Flash chromatography
on silica gel eluting with neat EtOAc to 5% MeOH/EtOAc gave 142 mg
(61%) of 5-acetyl-1H-indole-2-carboxylic acid
[cyclohexyl-(1-{2-[1-(cyclopropylcarbamoyl-hydroxy-methyl)-butylcarbamoyl-
]-octahydro-indole-1-carbonyl}-2,2-dimethyl-propylcarbamoyl)-methyl]-amide
28b. LC/MS M+H=775.44, M-H=773.52, LC/MS RT=3.78 min., HPLC RT=7.70
min. .sup.1H-NMR was consistent for the desired product.
[0650] Keto-alcohol 28b (142 mg, 0.18 mmol) was dissolved in dry
EtOAC (10 mL) treated with EDC (520 mg, 2.7 mmol) and dry DMSO (5
mL) and then cooled to 7.degree. C. A solution of dichloroacetic
acid (150 uL, 1.8 mmol) in dry EtOAc (1 mL) was added over 1 minute
giving a slight exotherm. EtOAc (1 mL) was added and the ice bath
was removed. After 1 hour, the reaction was cooled to 10.degree.
C., quenched with 1.0N HCl (2 mL) and extracted twice with EtOAc.
The combined organics were washed with water (4.times.) and brine,
then dried over sodium sulfate, filtered and concentrated in vacuo.
Flash chromatography on silica gel eluting with 10%
EtOAc/CH.sub.2Cl.sub.2 to 75% EtOAc/CH.sub.2Cl.sub.2 followed by
dissolving in CH.sub.3CN/water and lyophilizing afforded 129 mg
(93%) of 5-acetyl-1H-indole-2-carboxylic acid
(cyclohexyl-{1-[2-(1-cyclopropylaminooxalyl-butylcarbamoyl)-octahydro-ind-
ole-1-carbonyl]-2,2-dimethyl-propylcarbamoyl}-methyl)-amide 40a.
LC/MS M+H=773.44, M-H=771.48, LC/MS RT=4.99 min, HPLC RT=9.30
[0651] .sup.1H-NMR (CDCl.sub.3) d 0.56 (2H, m), 0.8 (5H, m), 0.98
(9H, s), 1.0-2.2 (25H, m), 2.45 (1H, m), 2.68 (3H, s), 2.86 (1H,
m), 4.27 (1H, m) 4.72 (1H, t), 4.8 (1H, d), 5.18 (1H, m), 5.42 (1H,
m), 6.92 (1H, d), 7.09 (2H, m), 7.21 (1H, m), 7.6 (1H, d), 7.91
(1H, d), 8.36 (1H, s), 9.1 (1H, bs), 11.32 (1H, bs) ppm.
Example 6
HCV Replicon Cell Assay Protocol
[0652] Cells containing hepatitis C virus (HCV) replicon were
maintained in DMEM containing 10% fetal bovine serum (FBS), 0.25 mg
per ml of G418, with appropriate supplements (media A).
[0653] On day 1, replicon cell monolayer was treated with a
trypsin:EDTA mixture, removed, and then media A was diluted into a
final concentration of 100,000 cells per ml with 10,000 cells in
100 ul were plated into each well of a 96-well tissue culture
plate, and cultured overnight in a tissue culture incubator at
37.degree. C.
[0654] On day 2, compounds (in 100% DMSO) were serially diluted
into DMEM containing 2% FBS, 0.5% DMSO, with appropriate
supplements (media B). The final concentration of DMSO was
maintained at 0.5% throughout the dilution series.
[0655] Media on the replicon cell monolayer was removed, and then
media B containing various concentrations of compounds was added.
Media B without any compound was added to other wells as no
compound controls.
[0656] Cells were incubated with compound or 0.5% DMSO in media B
for 48 hours in a tissue culture incubator at 37.degree. C. At the
end of the 48-hour incubation, the media was removed, and the
replicon cell monolayer was washed once with PBS and stored at
-80.degree. C. prior to RNA extraction.
[0657] Culture plates with treated replicon cell monolayers were
thawed, and a fixed amount of another RNA virus, such as Bovine
Viral Diarrhea Virus (BVDV) was added to cells in each well. RNA
extraction reagents (such as reagents from RNeasy kits) were added
to the cells immediately to avoid degradation of RNA. Total RNA was
extracted according the instruction of manufacturer with
modification to improve extraction efficiency and consistency.
Finally, total cellular RNA, including HCV replicon RNA, was eluted
and stored at -80.degree. C. until further processing.
[0658] A Taqman real-time RT-PCR quantification assay was set up
with two sets of specific primers and probe. One was for HCV and
the other was for BVDV. Total RNA extractants from treated HCV
replicon cells was added to the PCR reactions for quantification of
both HCV and BVDV RNA in the same PCR well. Experimental failure
was flagged and rejected based on the level of BVDV RNA in each
well. The level of HCV RNA in each well was calculated according to
a standard curve run in the same PCR plate. The percentage of
inhibition or decrease of HCV RNA level due to compound treatment
was calculated using the DMSO or no compound control as 0% of
inhibition. The IC50 (concentration at which 50% inhibition of HCV
RNA level is observed) was calculated from the titration curve of
any given compound.
Example 7
HCV Ki Assay Protocol
HPLC Microbore Method for Separation of 5AB Substrate and
Products
Substrate:
NH.sub.2-Glu-Asp-Val-Val-(alpha)Abu-Cys-Ser-Met-Ser-Tyr-COOH
[0659] A stock solution of 20 mM 5AB (or concentration of your
choice) was made in DMSO w/0.2M DTT. This was stored in aliquots at
-20 C.
[0660] Buffer: 50 mM HEPES, pH 7.8; 20% glycerol; 100 mM NaCl
[0661] Total assay volume was 100 .mu.L
TABLE-US-00005 X1 conc. in (.mu.L) assay Buffer 86.5 see above 5 mM
KK4A 0.5 25 .mu.M 1 M DTT 0.5 5 mM DMSO or inhibitor 2.5 2.5% v/v
50 .mu.M tNS3 0.05 25 nM 250 .mu.M 5AB (initiate) 20 25 .mu.M
[0662] The buffer, KK4A, DTT, and tNS3 were combined; distributed
78 .mu.L each into wells of 96 well plate. This was incubated at 30
C for .about.5-10 min.
[0663] 2.5 .mu.L of appropriate concentration of test compound was
dissolved in DMSO (DMSO only for control) and added to each well.
This was incubated at room temperature for 15 min.
[0664] Initiated reaction by addition of 20 .mu.L of 250 .mu.M 5AB
substrate (25 .mu.M concentration is equivalent or slightly lower
than the Km for 5AB).
[0665] Incubated for 20 min at 30 C.
[0666] Terminated reaction by addition of 25 .mu.L of 10% TFA
[0667] Transferred 120 .mu.L aliquots to HPLC vials
[0668] Separated SMSY product from substrate and KK4A by the
following method:
Microbore Separation Method:
Instrumentation: Agilent 1100
Degasser G1322A
[0669] Binary pump G1312A
Autosampler G1313A
[0670] Column thermostated chamber G1316A Diode array detector
G1315A
Column:
[0671] Phenomenex Jupiter; 5 micron C18; 300 angstroms; 150.times.2
mm; P/O 00F-4053-B0
Column thermostat: 40 C Injection volume: 100 .mu.L Solvent A=HPLC
grade water+0.1% TFA Solvent B=HPLC grade acetonitrile+0.1% TFA
TABLE-US-00006 Time Flow Max (min) % B (ml/min) press. 0 5 0.2 400
12 60 0.2 400 13 100 0.2 400 16 100 0.2 400 17 5 0.2 400
Stop time: 17 min Post-run time: 10 min.
[0672] Table 5 below depicts Mass Spec., HPLC, Ki and IC.sub.50
data for certain compounds of the invention.
[0673] Compounds with Ki's ranging from 1 .mu.M to 5 .mu.M are
designated A. Compounds with Ki's ranging from 1 .mu.M to 0.5 .mu.M
are designated B. Compounds with Ki's below 0.5 .mu.M are
designated C. Compounds with IC50's ranging from 1 .mu.M to 5 .mu.M
are designated A. Compounds with IC50's ranging from 1 .mu.M to 0.5
.mu.M are designated B. Compounds with IC50's below 0.5 .mu.M are
designated C.
TABLE-US-00007 HPLC, Compound MS+ R.sub.t (min) Ki IC.sub.50 1a 749
9.50 C ND 2a 640 3.51 B ND 3a 681 3.49 C A 4a 694 3.71 C B 5a 731
3.81 C ND 6a 745 4.02 C ND 7a 758 4.69 C ND 8a 782 4.23 C ND 9a 855
4.29 C C 10a 694 3.69 C B 11a 681 3.98 C C 12a 726 4.09 C C 13a 727
3.97 C B 14a 727 3.97 C A 15a 682 3.45 C C 16a 738 3.88 C A 17a 696
3.31 A ND 18a 749 4.16 C C 19a 736 4.84 C B 20a 736 4.80 C B 21a
735 4.60 C C 22a 700 3.77 B A 23a 688 3.97 C A 24a 686 4.55 C A 25a
751 4.61 C C 26a 682 3.96 C A 27a 682 4.01 C A 28a 737 3.35 C ND
29a 751 3.94 C B 30a 693 4.35 B A 31a 693 3.56 C A 32a 694 3.48 C A
33a 751 4.76 C C 34a 825 9.69 C A 35a 744 4.35 C A 36a 744 5.04 C A
37a 737 4.18 C C 38a 717 4.03 B ND 39a 773 5.02 C C 40a 773 4.37 C
C 41a 751 4.70 A C 42a 751 4.30 C C 43a 750 4.59 C C 44a 737 4.25 C
C 45a 805 8.41 C C 46a 733 4.41 C A 47a 725 3.58 B A 48a 738 3.99 C
A 49a 738 3.99 A ND 50a 682 3.78 A ND 51a 694 4.05 C B 52a 762 4.05
C C 53a 814 4.70 C C 54a 739 3.57 A ND 55a 612 4.06 A ND 56a 761
4.99 C ND 57a 718 4.83 C ND 58a 711 4.50 C ND 59a 725 4.90 C ND 60a
694 4.10 A A 61a 773 4.20 C C 62a 738 5.29 B ND 63 780 5.40 C B 64
739 4.82 C C 65 723 4.56 C C 66 842 4.15 C C 67 825 4.77 C C 68 737
9.75 C C
* * * * *