U.S. patent application number 13/904109 was filed with the patent office on 2014-01-09 for inhibitors of serine proteases, particularly hcv ns3-ns4a protease.
This patent application is currently assigned to Vertex Pharmaceuticals Incorporated. The applicant listed for this patent is Vertex Pharmaceuticals Incorporated. Invention is credited to Luc J. Farmer, Robert B. Perni, Janos Pitlik, John H. van Drie, JR..
Application Number | 20140010784 13/904109 |
Document ID | / |
Family ID | 23348006 |
Filed Date | 2014-01-09 |
United States Patent
Application |
20140010784 |
Kind Code |
A1 |
Farmer; Luc J. ; et
al. |
January 9, 2014 |
INHIBITORS OF SERINE PROTEASES, PARTICULARLY HCV NS3-NS4A
PROTEASE
Abstract
The present invention relates to peptidomimetic 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.
Inventors: |
Farmer; Luc J.; (Montreal,
CA) ; Pitlik; Janos; (Westborough, MA) ;
Perni; Robert B.; (Marlborough, MA) ; van Drie, JR.;
John H.; (Andover, MA) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
Vertex Pharmaceuticals Incorporated |
Cambridge |
MA |
US |
|
|
Assignee: |
Vertex Pharmaceuticals
Incorporated
Cambridge
MA
|
Family ID: |
23348006 |
Appl. No.: |
13/904109 |
Filed: |
May 29, 2013 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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11805085 |
May 22, 2007 |
8486989 |
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13904109 |
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10280940 |
Oct 24, 2002 |
7241796 |
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11805085 |
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Current U.S.
Class: |
424/85.5 ;
424/85.6; 424/85.7; 435/184; 514/410; 514/43; 548/421 |
Current CPC
Class: |
C07K 7/02 20130101; C07K
5/101 20130101; A61P 37/02 20180101; A61P 43/00 20180101; A61K
38/00 20130101; C07K 7/06 20130101; C07K 5/1027 20130101; A61K
45/06 20130101; C07K 5/0827 20130101; A61P 31/12 20180101; C07K
5/06191 20130101; A61P 31/14 20180101; A61K 31/407 20130101; C07D
403/12 20130101; C07D 491/147 20130101 |
Class at
Publication: |
424/85.5 ;
548/421; 514/410; 424/85.7; 424/85.6; 514/43; 435/184 |
International
Class: |
C07D 491/147 20060101
C07D491/147; A61K 45/06 20060101 A61K045/06; A61K 31/407 20060101
A61K031/407 |
Claims
1. (canceled)
2. A compound of formula (II): ##STR00116## wherein: ring A is a
carbocyclic, heteroaryl or heterocyclic ring, wherein ring A is
optionally fused to an carbocyclic, heterocyclic or heteroaryl
ring; wherein ring A has up to 4 substituents selected
independently from J; ring C is a cycloalkyl or heterocyclic ring;
wherein ring C has up to 3 substituents selected independently from
J; J is halogen, --OR', --NO.sub.2, --CF.sub.3, --OCF.sub.3, --R',
oxo, --OR', --O-benzyl, --O-phenyl, 1,2-methylenedioxy,
1,2-ethylenedioxy, --N(R').sub.2, --SR', --SOR', --SO.sub.2R',
--C(O)R', --COOR' or --CON(R').sub.2, wherein R' is independently
selected from: hydrogen, (C1-C12)-aliphatic, (C3-C10)-cycloalkyl or
-cycloalkenyl, (C1-C12)-aliphatic-[(C3-C10)-cycloalkyl or
-cycloalkenyl], (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;
R.sub.1 and R.sub.3 are independently: (C1-C12)-aliphatic,
(C3-C10)-cycloalkyl or -cycloalkenyl,
(C1-C12)-aliphatic-[(C3-C10)-cycloalkyl or -cycloalkenyl],
(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 and R.sub.3 is independently and optionally
substituted with up to 3 substituents independently selected from
J; 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; R.sub.2 and R.sub.4
are independently hydrogen, (C1-C12)-aliphatic,
(C3-C10)-cycloalkyl-(C1-C12)-aliphatic, or
(C6-C10)aryl-(C1-C12)-aliphatic, 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 in a chemically
stable arrangement; Z is a carbon atom, --CHR--N--, --HN--CR-- or
--CHR--CHR--, --O--CHR, --S--CHR, --SO--CHR, --SO.sub.2--CHR, or
--N--; wherein R is aliphatic, aryl, aralkyl or cycloalkyl; R.sub.5
is --(C1-C12) aliphatic, wherein any hydrogen is optionally
substituted 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; W is selected from:
--C(O)OH; ##STR00117## wherein each R.sub.6 is independently:
hydrogen, (C1-C12)-aliphatic,
(C1-C12)-aliphatic-[(C3-C10)-cycloalkyl or -cycloalkenyl],
(C6-C10)-aryl, (C6-C10)-aryl-(C1-C12)aliphatic, (C3-C10)-cycloalkyl
or -cycloalkenyl, (C3-C10)-heterocyclyl,
(C3-C10)-heterocyclyl-(C1-C12)-aliphatic, (C5-C10)heteroaryl, or
(C5-C10)heteroaryl-(C1-C12)-aliphatic, or two R.sub.6 groups, which
are bound to the same nitrogen atom, form together with that
nitrogen atom, a (C3-C10)-heterocyclic ring; wherein R.sub.6 is
optionally substituted with up to 3 J substituents; each R.sub.7 is
hydroxy, alkoxy, or aryloxy; or each R.sub.7 is an oxygen atom
linked to an aliphatic group and, together with the boron to which
they are each bound, the two R.sub.7 groups form a 3-6 membered
ring; V is a bond, --CH(R.sub.8)--, --N(R.sub.8)--, --O--,
--O--CH(R.sub.8), --CH(R.sub.8)--O--, --S--, --S--CH(R.sub.8)--,
--CH(R.sub.8)--S--, --C(O)--, --C(O)--O--, --O--C(O)--,
--C(O)--S--, --C(O)--CHR.sub.8--, --CHR.sub.8--C(O)--
--N(R.sub.8)C(O)-- --C(O)N(R.sub.8)--, --S(O)--,
--S(O)--CH(R.sub.8), --CH(R.sub.8)--S(O)--, --S(O)N(R.sub.8)--,
--N(R.sub.8)S(O)--, --S(O)--N(R.sub.8)--CHR.sub.8,
--N(R.sub.8)--S(O)--CHR.sub.8--, --CHR.sub.8--S(O).sub.2,
--S(O).sub.2--CH(R.sub.8)--, --CH(R.sub.8)--S(O).sub.2--,
--S(O).sub.2N(R.sub.8)--, --N(R.sub.8)--S(O).sub.2--,
--S(O).sub.2--N(R.sub.8)--CHR.sub.8 or
--N(R.sub.8)--S(O).sub.2--CHR.sub.8; wherein R.sub.8 is hydrogen or
(C1-C12)-aliphatic; T is selected from: (C6-C10)-aryl,
(C6-C10)-aryl-(C1-C12)aliphatic, (C3-C10)-cycloalkyl or
-cycloalkenyl, (C1-C12)-aliphatic-[(C3-C10)-cycloalkyl or
-cycloalkenyl], (C3-C10)-heterocyclyl,
(C3-C10)-heterocyclyl-(C1-C12)-aliphatic, (C5-C10)heteroaryl, or
(C5-C10)heteroaryl-(C1-C12)-aliphatic; or T is selected from:
##STR00118## wherein: R.sub.10 is: hydrogen, (C1-C12)-aliphatic,
(C1-C12)-aliphatic-[(C3-C10)-cycloalkyl or -cycloalkenyl],
(C6-C10)-aryl, (C6-C10)-aryl-(C1-C12)aliphatic, (C3-C10)-cycloalkyl
or -cycloalkenyl, (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; 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 n is 1-3.
3. (canceled)
4. The compound according to claim 2, wherein: R.sub.5 is
--(C2-C7)alkyl optionally substituted with halogen; R.sub.2 and
R.sub.4 are independently (C1-C12)-aliphatic; R.sub.3 and R.sub.1
are independently --(C1-C10)alkyl, --(C3-C7)cycloalkyl, or
--((C1-C6)alkyl)-((C3-C7)cycloalkyl); V is a bond, --CH(R.sub.8)--,
--N(R.sub.8)--, --O--, --O--CH(R.sub.8), --S--, --S--CH(R.sub.8),
--C(O)--, --C(O)--O--, --C(O)--S--, --C(O)--CHR.sub.8--,
--C(O)N(R.sub.8)--, --S(O)--, --S(O)--CH(R.sub.8)--,
--S(O)N(R.sub.8)--, --S(O)--N(R.sub.8)--CHR.sub.8, --S(O).sub.2,
--S--(O).sub.2--CH(R.sub.8)--, --S(O).sub.2N(R.sub.8)--, or
--S(O).sub.2--N(R.sub.8)--CHR.sub.8; wherein R.sub.8 is hydrogen or
--(C1-C3)alkyl; T is --(C6-C10)aryl, --(C5-C10)heteroaryl,
--(C3-C6)cycloalkyl, --(C3-C10)heterocyclyl,
--(C1-C6)alkyl-(C6-C10)aryl, --(C1-C6)alkyl-(C5-C10)heteroaryl,
--(C1-C6)alkyl-(C3-C6)cycloalkyl,
--(C1-C6)alkyl-(C3-C10)heterocyclyl, --(C2-C6)alkenyl-(C6-C10)aryl,
--(C2-C6)alkenyl-(C5-C10)heteroaryl,
--(C2-C6)alkenyl-(C3-C6)cycloalkyl,
--(C2-C6)alkenyl-(C3-C10)heterocyclyl, ##STR00119## wherein:
R.sub.10 is --(C1-C4)alkyl; W is --C(O)OH, --C(O)--C(O)--R.sub.6,
or --C(O)--C(O)--NH(R.sub.6) wherein: R.sub.6 is --(C1-C6)alkyl,
--(C6-C10)aryl, --(C3-C6)cycloalkyl, --(C5-C10)heteroaryl,
--(C3-C10)heterocyclyl, --NH--((C1-C6)alkyl),
--NH--((C3-C6)cycloalkyl), --NH--CH(CH.sub.3)-aryl,
--NH--CH(CH.sub.3)--(C5-C10)heteroaryl or
--NH--CH(CH.sub.3)--(C3-C10)heterocyclyl, wherein said aryl,
heteroaryl, or heterocyclyl is optionally substituted with a
suitable electron withdrawing group.
5. The compound according to claim 4, wherein V is --NH--.
6. The compound according to claim 4, wherein V is --C(O)--.
7. The compound according to claim 4, wherein T is a
--(C5-C10)heteroaryl.
8. The compound according to claim 7, wherein T is:
##STR00120##
9. The compound according to claim 4, wherein T contains at least
one hydrogen bond donor moiety selected from --NH.sub.2, --NH--,
--OH, and --SH.
10. The compound according to claim 9, wherein T is: ##STR00121##
##STR00122## ##STR00123## wherein: T is optionally substituted with
up to 3 J substituents, wherein J is as defined in claim 1; Z is
independently O, S, NR.sub.10, or C(R.sub.10).sub.2; n is
independently 1 or 2; and is independently a single bond or a
double bond.
11. The compound according to claim 10, wherein T is:
##STR00124##
12. The compound according to claim 4, wherein T is:
##STR00125##
13. The compound according to claim 12, wherein T is:
##STR00126##
14. The compound according to claim 4, wherein R.sub.1 is:
##STR00127##
15. The compound according to claim 14, wherein R.sub.1 is
--CH.sub.2--C(CH.sub.3).sub.3, --C(CH.sub.3).sub.3,
--CH(CH.sub.3).sub.2, --CH(CH.sub.3)--CH.sub.2--CH.sub.3, or
cyclohexyl.
16. The compound according to claim 15, wherein R.sub.1 is
cyclohexyl.
17. The compound according to claim 4, wherein R.sub.3 is:
##STR00128##
18. The compound according to claim 17, wherein R.sub.3 is
--C(CH.sub.3).sub.2, --CH(CH.sub.3).sub.2,
--CH(CH.sub.3)--CH.sub.2--CH.sub.3, or cyclohexyl.
19. The compound according to claim 18, wherein R.sub.3 is
--C(CH.sub.3).sub.3 or --CH(CH.sub.3).sub.2.
20. The compound according to claim 4, wherein R.sub.5 is:
##STR00129##
21. The compound according to claim 20, wherein R.sub.5 is
--CH.sub.2CH.sub.2CH.sub.3, --CH.sub.2CH.sub.2CH.sub.2CH.sub.3,
--CH.sub.2CH.sub.2CH.sub.2F, --CH.sub.2CH.sub.2CHF.sub.2, or
--CH.sub.2CH.sub.2CF.sub.3.
22. The compound according to claim 21, wherein R.sub.5 is
--CH.sub.2CH.sub.2CH.sub.2CH.sub.3 or
--CH.sub.2CH.sub.2CHF.sub.2.
23. The compound according to claim 22, wherein R.sub.5 is
--CH.sub.2CH.sub.2CH.sub.2CH.sub.3.
24. The compound according to claim 4, wherein R.sub.2 and R.sub.4
are each independently H, methyl, ethyl, or propyl.
25. The compound according to claim 4, wherein W is
C(O)--C(O)--NH(R.sub.6).
26. The compound according to claim 25, wherein in the W, the
--NH(R.sub.6) is --NH--(C.sub.3-C.sub.6 cycloalkyl),
--NH--CH(CH.sub.3)-aryl, or --NH--CH(CH.sub.3)-heterocyclyl,
wherein said aryl or said heterocyclyl is optionally substituted
with halogen.
27. The compound according to claim 26, wherein in the W, the
NH(R.sub.6) is: ##STR00130##
28. A composition comprising a compound according to claim 1 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.
29. The composition according to claim 28, wherein said composition
is formulated for administration to a patient.
30. The composition according to claim 29, wherein said composition
comprises an additional agent selected from an immunomodulatory
agent; an antiviral agent; a second inhibitor of HCV protease; an
inhibitor of another target in the HCV life cycle; or combinations
thereof.
31. The composition according to claim 30, wherein said
immunomodulatory agent is .alpha.-, .beta.-, or .gamma.-interferon;
the antiviral agent is ribavirin or amantadine; or the inhibitor of
another target in the HCV life cycle is an inhibitor of HCV
helicase, polymerase, or metalloprotease.
32. A method of inhibiting the activity of a serine protease
comprising the step of contacting said serine protease with a
compound according to claim 1.
33. The method according to claim 32, wherein said protease is an
HCV NS3 protease.
34. A method of treating an HCV infection in a patient comprising
the step of administering to said patient a composition according
to claim 29.
35. The method according to claim 34, comprising the additional
step of administering to said patient an additional agent selected
from an immunomodulatory agent; an antiviral agent; a second
inhibitor of HCV protease; an inhibitor of another target in the
HCV life cycle; or combinations thereof; wherein said additional
agent is administered to said patient as part of said composition
according to claim 30 or as a separate dosage form.
36. The method according to claim 35, wherein said immunomodulatory
agent is .alpha.-, .beta.-, or .gamma.-interferon; said antiviral
agent is ribavarin or amantadine; or said inhibitor of another
target in the HCV life cycle is an inhibitor of HCV helicase,
polymerase, or metalloprotease.
37. 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 28.
38. The method according to claim 37, wherein said sample or
equipment is selected from blood, other body fluids, biological
tissue, a surgical instrument, a surgical garment, a laboratory
instrument, a laboratory garment, a blood or other body fluid
collection apparatus; a blood or other bodily fluid storage
material.
Description
RELATED APPLICATIONS
[0001] This application is a continuation application of U.S.
patent application Ser. No. 11/805,085, filed May 22, 2007, which
claims the benefit of U.S. patent application Ser. No. 10/280,940,
filed Oct. 24, 2002 and U.S. Provisional Patent Application
60/343,862 filed Oct. 24, 2001. The entire contents of each of the
above applications are incorporated herein by reference.
TECHNICAL FIELD OF THE INVENTION
[0002] The present invention relates to peptidomimetic 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 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)]. Unfortunately, there are no serine
protease inhibitors available currently as anti-HCV agents.
[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 formula
(I):
##STR00001##
wherein:
[0012] ring A is a carbocyclic or heterocyclic ring, wherein ring A
is optionally fused to a carbocyclic, heterocyclic or heteroaryl
ring;
[0013] wherein ring A has up to 3 substituents selected
independently from J;
[0014] ring B is a carbocyclic or heterocyclic ring, wherein ring B
is optionally fused to a carbocyclic, heterocyclic or heteroaryl
ring;
[0015] wherein ring B 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, --O-benzyl, --O-phenyl, 1,2-methylenedioxy,
1,2-ethylenedioxy, --N(R').sub.2, --SR', --SOR', --SO.sub.2R',
--C(O)R', --COOR' or --CON(R').sub.2, --OC(O)R' wherein R' is
independently selected from: [0017] hydrogen, [0018]
(C1-C12)-aliphatic, [0019] (C3-C10)-cycloalkyl or -cycloalkenyl,
[0020] (C1-C12)-aliphatic-[(C3-C10)-cycloalkyl or -cycloalkenyl],
[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] (C1-C12)-aliphatic-[(C3-C10)-cycloalkyl or -cycloalkenyl],
[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, wherein each of R.sub.2 and
R.sub.4 is independently and optionally substituted with up to 3
substituents independently selected from J; [0044] 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 in a
chemically stable arrangement;
[0045] Z is a carbon atom, --CHR--N--, --HN--CR-- or --CHR--CHR--,
--O--CHR--, --S--CHR--, --SO--CHR--, --SO.sub.2--CHR--, or
--N--;
[0046] wherein R is aliphatic, aryl, aralkyl or cycloalkyl;
[0047] R.sub.5 is --(C1-C12) aliphatic, wherein any hydrogen is
optionally substituted 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;
[0048] W is selected from: --C(O)OH;
##STR00002##
wherein each R.sub.6 is independently: [0049] hydrogen, [0050]
(C1-C12)-aliphatic, [0051] (C1-C12)-aliphatic-[(C3-C10)-cycloalkyl
or -cycloalkenyl], [0052] (C6-C10)-aryl, [0053]
(C6-C10)-aryl-(C1-C12) aliphatic, [0054] (C3-C10)-cycloalkyl or
-cycloalkenyl, [0055] (C3-C10)-heterocyclyl, [0056]
(C3-C10)-heterocyclyl-(C1-C12)-aliphatic, [0057]
(C5-C10)heteroaryl, or [0058]
(C5-C10)heteroaryl-(C1-C12)-aliphatic, or
[0059] two R.sub.6 groups, which are bound to the same nitrogen
atom, form together with that nitrogen atom, a
(C3-C10)-heterocyclic ring;
[0060] wherein R.sub.6 is optionally substituted with up to 3 J
substituents;
[0061] each R.sub.7 is hydroxy, alkoxy, or aryloxy; or
[0062] each R.sub.7 is an oxygen atom linked to an aliphatic group
and, together with the boron to which they are each bound, the two
R.sub.7 groups form a 3-6 membered ring;
[0063] V is a bond, --CH(R.sub.8)--, --N(R.sub.8)--, --O--,
--O--CH(R.sub.8)--, --CH(R.sub.8)--O--, --S--, --S--CH(R.sub.8)--,
--CH(R.sub.8)--S--, --C(O)--, --C(O)--O--, --O--C(O)--,
--C(.+-.)--S--, --S--C(O)--, --C(O)--CHR.sub.8--,
--CHR.sub.8--C(O)--N(R.sub.8)C(O)--, --C(O)N(R.sub.8)--, --S(O)--,
--S(O)--CH(R.sub.8), --CH(R.sub.8)--S(O)--, --S(O)N(R.sub.8)--,
--N(R.sub.8) S(O)--, --S(O)--N(R.sub.8)--CH(R.sub.8)--,
--CH(R.sub.8)--N(R).sub.8--S(O)--,
--N(R.sub.8)--S(O)--CH(R.sub.8)--,
--CH(R.sub.8)--S(O)--N(R.sub.8)--, --CH(R.sub.8)--S(O).sub.2--,
--S(O).sub.2--CH(R.sub.8)--, --S(O).sub.2N(R.sub.8)--,
--N(R.sub.8)--S(O).sub.2--, --S(O).sub.2--N(R.sub.8)--CHR.sub.8--,
--CHR.sub.8--N(R.sub.8)--S(O).sub.2--,
--N(R.sub.8)--S(O).sub.2--CHR.sub.8 or
--CH(R.sub.8)--S(O).sub.2--N(R.sub.8)--;
[0064] wherein R.sub.8 is hydrogen or (C1-C12)-aliphatic;
[0065] T is selected from: [0066] (C6-C10)-aryl, [0067]
(C6-C10)-aryl-(C1-C12)aliphatic, [0068] (C3-C10)-cycloalkyl or
-cycloalkenyl, [0069] (C1-C12)-aliphatic-[(C3-C10)-cycloalkyl or
-cycloalkenyl], [0070] (C3-C10)-heterocyclyl, [0071]
(C3-C10)-heterocyclyl-(C1-C12)-aliphatic, [0072]
(C5-C10)heteroaryl, or [0073]
(C5-C10)heteroaryl-(C1-C12)-aliphatic; or
[0074] T is selected from:
##STR00003##
wherein:
[0075] R.sub.10 is: [0076] hydrogen, [0077] (C1-C12)-aliphatic,
[0078] (C1-C12)-aliphatic-[(C3-C10)-cycloalkyl or -cycloalkenyl],
[0079] (C6-C10)-aryl, [0080] (C6-C10)-aryl-(C1-C12)aliphatic,
[0081] (C3-C10)-cycloalkyl or -cycloalkenyl, [0082]
(C3-C10)-heterocyclyl, [0083]
(C3-C10)-heterocyclyl-(C1-C12)-aliphatic, [0084]
(C5-C10)-heteroaryl, or [0085]
(C5-C10)-heteroaryl-(C1-C12)-aliphatic,
[0086] wherein each T is optionally substituted with up to 3 J
substituents;
[0087] 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
[0088] n is 1-3.
[0089] The present invention also provides a compound of formula
(II):
##STR00004##
wherein:
[0090] T, V, R, R.sub.1, R.sub.2, R.sub.3, R.sub.4, R.sub.5, Z and
W are as defined above for compounds of formula (I);
[0091] ring A is a carbocyclic, heteroaryl or heterocyclic ring,
wherein ring A is optionally fused to an carbocyclic, heterocyclic
or heteroaryl ring;
[0092] wherein ring A has up to 4 substituents selected
independently from J;
[0093] ring C is a cycloalkyl or heterocyclic ring; and
[0094] wherein ring C has up to 3 substituents selected
independently from J; wherein J is as defined above for compounds
of formula (I).
[0095] The present invention also provides a compound of formula
(III):
##STR00005##
wherein:
[0096] T, V, R, R.sub.1, R.sub.2, R.sub.3, R.sub.4, R.sub.5, Z and
W are as defined above for compounds of formula (I);
[0097] ring B is a carbocyclic or heterocyclic ring,
[0098] wherein ring B is optionally fused to a carbocyclic,
heterocyclic or heteroaryl ring;
[0099] wherein ring B has up to 3 substituents selected
independently from J;
[0100] ring C is a cycloalkyl or heterocyclic ring; and
[0101] wherein ring C has up to 3 substituents selected
independently from J; wherein J is as defined above for compounds
of formula (I).
[0102] The present invention also provides a compound of formula
(IV):
##STR00006##
wherein:
[0103] T, V, R, R.sub.1, R.sub.2, R.sub.3, R.sub.4, R.sub.5, Z and
W are as defined above for compounds of formula (I);
[0104] ring B is a bridged bicyclic ring system containing 6-12
carbon atoms, wherein ring B is saturated or partially unsaturated;
or
[0105] the ring system comprising ring B, together with the ring
containing Z and the nitrogen atom, contains more than ten ring
atoms; and
[0106] wherein ring B has up to 3 substituents selected
independently from J; wherein J is as defined above for compounds
of formula (I).
[0107] The invention also relates to compositions that comprise the
above compounds and the use thereof. Such compositions may be
useful 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.
DETAILED DESCRIPTION OF THE INVENTION
[0108] In the description, the following abbreviations are
used:
TABLE-US-00001 Designation Reagent or Fragment Abu aminobutyric
acid Ac acetyl AcOH acetic acid Bn benzyl Boc tert-butyloxycarbonyl
Bz benzoyl Cbz carbobenzyloxy CDI carbonyldiimidazole DCE
1,2-dichloroethane DCM dichloromethane DIEA diisopropylethylamine
DMA dimethylacetamide DMAP dimethylaminopyridine DMF
dimethylformamide DPPA diphenylphosphorylazide DMSO
dimethylsulfoxide Et ethyl EtOAc ethyl acetate FMOC
9-fluorenylmethoxycarbonyl HbtU O-benzotriazolyl-N,N,N',N'-
tetramethyluronium hexafluorophosphate HOBt N-hydroxybenzotriazole
HPLC high performance liquid chromatography Me methyl MS mass
spectrometry NMP N-methyl pyrrolidinone ND not determined Pip
piperidine Prz piperazine PyBrop bromo-tris-pyrrolidinophosphonium
hexafluorophosphate Pyr pyridine THF tetrahydrofuran TFA
trifluoroacetic acid TFE trifluoroethanol Tol toluene
[0109] The present invention provides a compound of formula
(I):
##STR00007##
wherein:
[0110] ring A is a carbocyclic or heterocyclic ring, wherein ring A
is optionally fused to a carbocyclic, heterocyclic or heteroaryl
ring;
[0111] wherein ring A has up to 3 substituents selected
independently from J;
[0112] ring B is a carbocyclic or heterocyclic ring, wherein ring B
is optionally fused to a carbocyclic, heterocyclic or heteroaryl
ring;
[0113] wherein ring B has up to 3 substituents selected
independently from J;
[0114] J is halogen, --OR', --NO.sub.2, --CF.sub.3, --OCF.sub.3,
--R', oxo, --OR', --O-benzyl, --O-phenyl, 1,2-methylenedioxy,
1,2-ethylenedioxy, --N(R').sub.2, --SR', --SOR', --SO.sub.2R',
--C(O)R', --COOR' or --CON(R').sub.2, wherein R' is independently
selected from: [0115] hydrogen, [0116] (C1-C12)-aliphatic, [0117]
(C3-C10)-cycloalkyl or -cycloalkenyl, [0118]
(C1-C12)-aliphatic-[(C3-C10)-cycloalkyl or -cycloalkenyl], [0119]
(C6-C10)-aryl, [0120] (C6-C10)-aryl-(C1-C12)aliphatic, [0121]
(C3-C10)-heterocyclyl, [0122]
(C6-C10)-heterocyclyl-(C1-C12)aliphatic, [0123]
(C5-C10)-heteroaryl, or [0124]
(C5-C10)-heteroaryl-(C1-C12)-aliphatic;
[0125] R.sub.1 and R.sub.3 are independently: [0126]
(C1-C12)-aliphatic, [0127] (C3-C10)-cycloalkyl or -cycloalkenyl,
[0128] (C1-C12)-aliphatic-[(C3-C10)-cycloalkyl or -cycloalkenyl],
[0129] (C6-C10)-aryl, [0130] (C6-C10)-aryl-(C1-C12)aliphatic,
[0131] (C3-C10)-heterocyclyl, [0132]
(C6-C10)-heterocyclyl-(C1-C12)aliphatic, [0133]
(C5-C10)-heteroaryl, or [0134]
(C5-C10)-heteroaryl-(C1-C12)-aliphatic, [0135] wherein each of
R.sub.1 and R.sub.3 is independently and optionally substituted
with up to 3 substituents independently selected from J; [0136]
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;
[0137] R.sub.2 and R.sub.4 are independently [0138] hydrogen,
[0139] (C1-C12)-aliphatic, [0140]
(C3-C10)-cycloalkyl-(C1-C12)-aliphatic, or [0141]
(C6-C10)aryl-(C1-C12)-aliphatic, [0142] wherein each of R.sub.2 and
R.sub.4 is independently and optionally substituted with up to 3
substituents independently selected from J; [0143] 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 in a
chemically stable arrangement;
[0144] Z is a carbon atom, --CHR--N--, --HN--CR-- or --CHR--CHR--,
--O--CHR, --S--CHR, --SO--CHR, --SO.sub.2--CHR, or --N--;
[0145] wherein R is aliphatic, aryl, aralkyl or cycloalkyl;
[0146] R.sub.5 is --(C1-C12) aliphatic, wherein any hydrogen is
optionally substituted 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;
[0147] W is selected from: --C(O)OH;
##STR00008##
[0148] wherein each R.sub.6 is independently: [0149] hydrogen,
[0150] (C1-C12)-aliphatic, [0151]
(C1-C12)-aliphatic-[(C3-C10)-cycloalkyl or -cycloalkenyl], [0152]
(C6-C10)-aryl, [0153] (C6-C10)-aryl-(C1-C12)aliphatic, [0154]
(C3-C10)-cycloalkyl or -cycloalkenyl, [0155] (C3-C10)-heterocyclyl,
[0156] (C3-C10)-heterocyclyl-(C1-C12)-aliphatic, [0157]
(C5-C10)heteroaryl, or [0158]
(C5-C10)heteroaryl-(C1-C12)-aliphatic, or
[0159] two R.sub.6 groups, which are bound to the same nitrogen
atom, form together with that nitrogen atom, a
(C3-C10)-heterocyclic ring;
[0160] wherein R.sub.6 is optionally substituted with up to 3 J
substituents;
[0161] each R.sub.7 is hydroxy, alkoxy, or aryloxy; or
[0162] each R.sub.7 is an oxygen atom linked to an aliphatic group
and, together with the boron to which they are each bound, the two
R.sub.7 groups form a 3-6 membered ring;
[0163] V is a bond, --CH(R.sub.8)--, --N(R.sub.8)--, --O--,
--O--CH(R.sub.8), --CH(R.sub.8)--O--, --S--, --S--CH(R.sub.8)--,
--CH(R.sub.8)--S--, --C(O)--, --C(O)--O--, --O--C(O)--,
--C(O)--S--, --C(O)--CHR.sub.8--, --CHR.sub.8--C(O)--
--N(R.sub.8)C(O)--C(O)N(R.sub.8)--, --S(O)--, --S(O)--CH(R.sub.8),
--CH(R.sub.8)--S(O)--, --S(O)N(R.sub.8)--, --N(R.sub.8)S(O)--,
--S(O)--N(R.sub.8)--CHR.sub.8, --N(R.sub.8)--S(O)--CHR.sub.8--,
--CHR.sub.8--S(O).sub.2, --S(O).sub.2--CH(R.sub.8)--,
--CH(R.sub.8)--S(O).sub.2--, --S(O).sub.2N(R.sub.8)--,
--N(R.sub.8)--S(O).sub.2--, --S(O).sub.2--N(R.sub.8)--CHR.sub.8 or
--N(R.sub.8)--S(O).sub.2--CHR.sub.8;
[0164] wherein R.sub.8 is hydrogen or (C1-C12)-aliphatic;
[0165] T is selected from: [0166] (C6-C10)-aryl, [0167]
(C6-C10)-aryl-(C1-C12)aliphatic, [0168] (C3-C10)-cycloalkyl or
-cycloalkenyl, [0169] (C1-C12)-aliphatic-[(C3-C10)-cycloalkyl or
-cycloalkenyl], [0170] (C3-C10)-heterocyclyl, [0171]
(C3-C10)-heterocyclyl-(C1-C12)-aliphatic, [0172]
(C5-C10)heteroaryl, or [0173]
(C5-C10)heteroaryl-(C1-C12)-aliphatic; or
[0174] T is selected from:
##STR00009##
wherein:
[0175] R.sub.10 is: [0176] hydrogen, [0177] (C1-C12)-aliphatic,
[0178] (C1-C12)-aliphatic-[(C3-C10)-cycloalkyl or -cycloalkenyl],
[0179] (C6-C10)-aryl, [0180] (C6-C10)-aryl-(C1-C12)aliphatic,
[0181] (C3-C10)-cycloalkyl or -cycloalkenyl, [0182]
(C3-C10)-heterocyclyl, [0183]
(C3-C10)-heterocyclyl-(C1-C12)-aliphatic, [0184]
(C5-C10)-heteroaryl, or [0185]
(C5-C10)-heteroaryl-(C1-C12)-aliphatic,
[0186] wherein each T is optionally substituted with up to 3 J
substituents;
[0187] 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
[0188] n is 1-3.
DEFINITIONS
[0189] The term "aryl" as used herein means a monocyclic or
bicyclic carbocyclic aromatic ring system comprising 6 to 10 atoms.
Phenyl is an example of a monocyclic aromatic ring system. Bicyclic
carbocyclic 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.
[0190] The bond "---" refers to an optionally present bond.
[0191] The term "heterocyclyl" or "heterocyclic" as used herein
means a 3-10 membered monocyclic or bicyclic non-aromatic ring
system having up to 4 heteroatom or heteroatom groups in each ring
selected from O, N, NH, S, SO or SO.sub.2 in a chemically stable
arrangement. In such a bicyclic non-aromatic ring system embodiment
of "heterocyclyl":
[0192] both rings may contain said heteroatom or heteroatom groups;
or
[0193] one ring may contain said heteroatom or heteroatom groups
and the other ring may be a C3-C6 cycloalkyl or phenyl.
[0194] Heterocyclic rings include 3-1H-benzimidazol-2-one,
3-(1-alkyl)-benzimidazol-2-one, 2-tetrahydrofuranyl,
3-tetrahydrofuranyl, 2-tetrahydrothiophenyl,
3-tetrahydrothiophenyl, 2-morpholino, 3-morpholino, 4-morpholino,
2-thiomorpholino, 3-thiomorpholino, 4-thiomorpholino,
1-pyrrolidinyl, 2-pyrrolidinyl, 3-pyrrolidinyl,
1-tetrahydropiperazinyl, 2-tetrahydropiperazinyl,
3-tetrahydropiperazinyl, 1-piperidinyl, 2-piperidinyl,
3-piperidinyl, 1-pyrazolinyl, 3-pyrazolinyl, 4-pyrazolinyl,
5-pyrazolinyl, 1-piperidinyl, 2-piperidinyl, 3-piperidinyl,
4-piperidinyl, 2-thiazolidinyl, 3-thiazolidinyl, 4-thiazolidinyl,
1-imidazolidinyl, 2-imidazolidinyl, 4-imidazolidinyl,
5-imidazolidinyl, indolinyl, tetrahydroquinolinyl,
tetrahydroisoquinolinyl, benzothiolane, benzodithiane, and
1,3-dihydro-imidazol-2-one.
[0195] The term "heteroaryl" as used herein means a 5-10 membered
monocyclic or bicyclic aromatic ring system having up to 4
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":
[0196] one or both rings may be aromatic;
[0197] both rings may contain said heteroatom or heteroatom groups;
or
[0198] one ring may contain said heteroatom or heteroatom groups
and the other ring may be a C3-C6 cycloalkyl or phenyl.
[0199] Heteroaryl rings include 2-furanyl, 3-furanyl, N-imidazolyl,
2-imidazolyl, 4-imidazolyl, 5-imidazolyl, benzimidazolyl,
3-isoxazolyl, 4-isoxazolyl, 5-isoxazolyl, 2-oxazolyl, 4-oxazolyl,
5-oxazolyl, N-pyrrolyl, 2-pyrrolyl, 3-pyrrolyl, 2-pyridyl,
3-pyridyl, 4-pyridyl, 2-pyrimidinyl, 4-pyrimidinyl, 5-pyrimidinyl,
pyridazinyl (e.g., 3-pyridazinyl), 2-thiazolyl, 4-thiazolyl,
5-triazolyl, tetrazolyl (e.g., 5-tetrazolyl), triazolyl (e.g.,
2-triazolyl and 5-triazolyl), 2-thienyl, 3-thienyl, benzofuryl,
benzothiophenyl, indolyl (e.g., 2-indolyl), pyrazolyl (e.g.,
2-pyrazolyl), isothiazolyl, 1,2,3-oxadiazolyl, 1,2,5-oxadiazolyl,
1,2,4-oxadiazolyl, 1,2,3-triazolyl, 1,2,3-thiadiazolyl,
1,3,4-thiadiazolyl, 1,2,5-thiadiazolyl, purinyl, pyrazinyl,
1,3,5-triazinyl, quinolinyl (e.g., 2-quinolinyl, 3-quinolinyl,
4-quinolinyl), and isoquinolinyl (e.g., 1-isoquinolinyl,
3-isoquinolinyl, or 4-isoquinolinyl). Each of the above aryl,
heterocyclyl or heteroaryl above may contain up to 3 substituents
independently selected from halogen, --OR', --NO.sub.2, --CF.sub.3,
--OCF.sub.3, --R', oxo, --OR', --O-benzyl, --O-phenyl,
1,2-methylenedioxy, 1,2-ethylenedioxy, --N(R').sub.2, --C(O)R',
--COOR' or --CON(R').sub.2, wherein R' is independently selected
from H, (C1-C6)-alkyl, (C2-C6)-alkenyl or alkynyl.
[0200] 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.
[0201] In an alternate embodiment of formulae (I)-(IV), R.sup.1 is
--CH.sub.2--CH(CH.sub.3)--CH.sub.3, --C(CH.sub.3).sub.3,
--CH(CH.sub.3).sub.2, --CH(CH.sub.3)--CH.sub.2--CH.sub.3 or
cyclohexyl; V is --C(O)N(R.sub.8)--, --S(O)N(R.sub.8)--,
--S(O).sub.2N(R.sub.8)--, a bond, --CH(R.sub.8)--, --N(R.sub.8)--,
--O--, --O--CH(R.sub.8)--, --S--, --S--CH(R.sub.8), --C(O)--,
--C(O)--O--, --C(O)--S--, --C(O)--CHR.sub.8--, --S(O)--,
--S(O)--CH(R.sub.8), --S(O)--N(R.sub.8)--CHR.sub.8, --S(O).sub.2--,
--S--(O).sub.2--CH(R.sub.8)--, or
--S(O).sub.2--N(R.sub.8)--CHR.sub.8; or J is halogen, --OR',
--NO.sub.2, --CF.sub.3, --OCF.sub.3, --R', oxo, --OR', --O-benzyl,
--O-phenyl, 1,2-methylenedioxy, 1,2-ethylenedioxy, --N(R').sub.2,
--SR', --SOR', --SO.sub.2R', --C(O)R', --COOR' or --CON(R').sub.2,
wherein R' is independently selected from: [0202] hydrogen, [0203]
(C1-C12)-aliphatic, [0204] (C3-C10)-cycloalkyl or -cycloalkenyl,
[0205] (C1-C12)-aliphatic-[(C3-C10)-cycloalkyl or -cycloalkenyl],
[0206] (C6-C10)-aryl, [0207] (C6-C10)-aryl-(C1-C12)aliphatic,
[0208] (C3-C10)-heterocyclyl, [0209]
(C6-C10)-heterocyclyl-(C1-C12)aliphatic, [0210]
(C5-C10)-heteroaryl, or [0211]
(C5-C10)-heteroaryl-(C1-C12)-aliphatic;
[0212] and the other variables are as defined herein.
[0213] In compounds of formula (I), ring A is preferably selected
from:
##STR00010## ##STR00011##
wherein R is aliphatic, aryl, aralkyl or cycloalkyl.
[0214] More preferably, ring A is selected from:
##STR00012##
[0215] Ring B is preferably selected from:
##STR00013## ##STR00014## ##STR00015##
wherein R is aliphatic, aryl, aralkyl or cycloalkyl.
[0216] More preferably, ring B is selected from:
##STR00016##
[0217] According to another preferred embodiment of compounds of
formula (I), rings A, B, together with the ring connected thereto
include:
##STR00017##
[0218] According to another preferred embodiment, R.sub.1 is
selected from --(C1-C10)alkyl, --(C3-C7)cycloalkyl, or
--((C1-C6)alkyl)-((C3-C7)cycloalkyl). More preferably, R.sub.1 is
selected from:
##STR00018##
[0219] Even more preferably, R.sub.1 is selected from
--CH.sub.2--C(CH.sub.3).sub.3, --C(CH.sub.3).sub.3,
--CH(CH.sub.3).sub.2, --CH(CH.sub.3)--CH.sub.2--CH.sub.3, or
cyclohexyl. Most preferably R.sub.1 is cyclohexyl.
[0220] According to another preferred embodiment, R.sub.2 is
(C1-C12)-aliphatic. More preferably, R.sub.2 is selected from
hydrogen, methyl, ethyl or propyl. Even more preferably, R.sub.2 is
hydrogen or methyl. Most preferably, R.sub.2 is hydrogen.
[0221] According to another preferred embodiment, R.sub.3 is
selected from --(C1-C10)alkyl, --(C3-C7)cycloalkyl, or
--((C1-C6)alkyl)-((C3-C7)cycloalkyl).
[0222] More preferably, R.sub.3 is selected from:
##STR00019##
[0223] Even more preferably, R.sub.3 is selected from
--C(CH.sub.3).sub.2, --CH(CH.sub.3).sub.2,
--CH(CH.sub.3)--CH.sub.2--CH.sub.3, or cyclohexyl.
[0224] Most preferably, R.sub.3 is selected from
--C(CH.sub.3).sub.3 or --CH(CH.sub.3).sub.2.
[0225] According to another preferred embodiment, R.sub.4 is
(C1-C12)-aliphatic. More preferably, R.sub.4 is selected from
hydrogen, methyl, ethyl or propyl. Even more preferably, R.sub.4 is
selected from hydrogen.
[0226] According to another preferred embodiment, R.sub.5 is
--(C2-C7)alkyl optionally substituted with halogen.
[0227] Preferably, R.sub.5 is selected from:
##STR00020##
More preferably, R.sub.5 is selected from
--CH.sub.2CH.sub.2CH.sub.3, --CH.sub.2CH.sub.2CH.sub.2CH.sub.3,
--CH.sub.2CH.sub.2CH.sub.2F, --CH.sub.2CH.sub.2CHF.sub.2, or
--CH.sub.2CH.sub.2CF.sub.3. Even more preferably, R.sub.5 is
selected from --CH.sub.2CH.sub.2CH.sub.3,
--CH.sub.2CH.sub.2CH.sub.2CH.sub.3 or --CH.sub.2CH.sub.2CHF.sub.2.
Most preferably, R.sub.5 is --CH.sub.2CH.sub.2CH.sub.3 or
--CH.sub.2CH.sub.2CH.sub.2CH.sub.3.
[0228] According to another preferred embodiment W is selected
from: CHO, --C(O)--R.sub.6, --CO.sub.2H, --C(O)--C(O)--R.sub.6, or
--C(O)--C(O)--NH(R.sub.6), wherein R.sub.6 is selected from
hydrogen, aryl, heteroaryl, heterocyclyl, C3-C6 alkyl, C3-C6
cycloalkyl, hydroxy, --O--C1-C6 alkyl, wherein --NH(R.sub.6) is
selected from --NH--(C3-C6 cycloalkyl), NH-aralkyl,
--NH-alkylheteroaryl, --NH-alkylheterocyclyl, and wherein said
aryl, heterocyclyl or heteroaryl is optionally substituted with up
to 3 halogen atoms.
[0229] More preferably, R.sub.6 or --NH(R.sub.6) is selected
from:
##STR00021##
[0230] According to another preferred embodiment W is selected from
--C(O)OH or --C(O)--C(O)--R.sub.6. More preferably, W is
--C(O)--C(O)--R.sub.6. Preferably, R.sub.6 is isopropyl.
[0231] According to a preferred embodiment, W is
--C(O)--C(O)--R.sub.6. Preferably, R.sub.6 is isopropyl.
[0232] According to another preferred embodiment, W is
--C(O)--C(O)--OR.sub.6. Preferably, R.sub.6 is hydrogen,
(C1-C12)-aliphatic, (C6-C10)-aryl, (C3-C10)-cycloalkyl or
-cycloalkenyl, (C3-C10)-heterocyclyl or (C5-C10)heteroaryl. More
preferably, R.sub.6 is H or methyl.
[0233] According to yet another preferred embodiment, W is
--C(O)--C(O)--N(R.sub.6).sub.2. Preferably, R.sub.6 is hydrogen,
(C3-C10)-cycloalkyl or -cycloalkenyl, or (C3-C10)-heterocyclyl.
[0234] In another preferred embodiment of compounds of formula (I)
is where W is C(O)--C(O)--N(R.sub.6).sub.2, the NR.sub.6R.sub.6
portion of the W moiety is --NH--(C3-C6)cycloalkyl,
--NH--CH(CH.sub.3)--(C6-C10) aryl or
--NH--CH(CH.sub.3)--(C3-C10)heterocyclyl, or
--NH--CH(CH.sub.3)--(C5-C10)heteroaryl, wherein said aryl,
heterocyclyl, or heteroaryl is optionally substituted with
halogen.
[0235] Alternatively, the NR.sub.6R.sub.6 portion is
--NH--(C3-C6)cycloalkyl, --NH--CH(CH.sub.3)--(C6-C10) aryl, or
--NH--CH(CH.sub.3)--(C5-C10)heteroaryl, wherein said aryl or said
heterocyclyl is optionally substituted with halogen; or
NR.sub.6R.sub.6 is --NH-- (C3-C6)cycloalkyl,
--NH--CH(CH.sub.3)--(C6-C10) aryl, or
--NH--CH(CH.sub.3)--(C3-C10)heterocyclyl, wherein said aryl or said
heterocyclyl is optionally substituted with halogen.
[0236] In other preferred embodiment of formula I, NR.sub.6R.sub.6
in W is:
##STR00022##
[0237] More preferably, NR.sub.6R.sub.6 is:
##STR00023##
[0238] Even more preferably, NR.sub.6R.sub.6 is:
##STR00024##
[0239] Most preferably, NR.sub.6R.sub.6 is:
##STR00025##
[0240] According to another preferred embodiment, when W is
--B(R.sub.7).sub.2, each R.sub.7 is selected from hydroxy, alkoxy,
or aryloxy.
[0241] According to yet another preferred embodiment, when W is
--B(R.sub.7).sub.2, each R.sub.7 is selected from an oxygen atom
linked to an aliphatic group and, together with the boron to which
they are each bound, the two R.sub.7 groups form a 5-8 membered
ring.
[0242] According to another preferred embodiment, V is a bond,
--CH(R.sub.8)--, --N(R.sub.8)--, --O--, --O--CH(R.sub.8), --S--,
--S--CH(R.sub.8), --C(O)--, --C(O)--O--, --C(O)--S--,
--C(O)--CHR.sub.8--, --C(O)N(R.sub.8)--, --S(O)--,
--S(O)--CH(R.sub.8)--, --S(O)N(R.sub.8)--,
--S(O)--N(R.sub.8)--CHR.sub.8, --S(O).sub.2,
--S--(O).sub.2--CH(R.sub.8)--, --S(O).sub.2N(R.sub.8)--, or
--S(O).sub.2--N(R.sub.8)--CHR.sub.8; wherein R.sub.8 is hydrogen or
--(C1-C3)alkyl;
[0243] According to another preferred embodiment, V is --NH--.
[0244] According to yet another preferred embodiment, V is
--C(O)--.
[0245] According to yet another preferred embodiment, V is
--C(O)--NR.sub.8--. More preferably, V is --C(O)--NH--.
[0246] According to yet another preferred embodiment T is a
heterocyclyl or heteroaryl, optionally having up to 3 substituents
as defined above.
[0247] According to yet another preferred embodiment, T is a
--(C5-C10)heteroaryl.
[0248] According to yet another preferred embodiment, T is selected
from 3-1H-benzimidazol-2-one, 3-(1-alkyl)-benzimidazol-2-one,
2-tetrahydrofuranyl, 3-tetrahydrofuranyl, pyrazolinyl,
1,3-dihydro-imidazol-2-one, 2-imidazolyl, 4-imidazolyl,
5-imidazolyl, 2-oxazolyl, 4-oxazolyl, 5-oxazolyl, 2-pyrrolyl,
3-pyrrolyl, 2-pyrimidinyl, 4-pyrimidinyl, 5-pyrimidinyl,
5-tetrazolyl, pyrazolyl, pyrazinyl or 1,3,5-triazinyl.
[0249] Even more preferably, T is selected from
3-1H-benzimidazol-2-one, 3-(1-alkyl)-benzimidazol-2-one,
pyrazolinyl, 1,3-dihydro-imidazol-2-one, 2-imidazolyl, 2-pyrrolyl,
2-pyrimidinyl, 5-pyrimidinyl, 5-tetrazolyl or pyrazinyl.
[0250] Most preferred is when T or R.sup.7 is selected from:
##STR00026##
[0251] Preferred substituents on T in the above embodiments are
halogen, --CF.sub.3, --OCF.sub.3, oxo, --COOR', or --CON(R').sub.2,
wherein R' is as defined above.
[0252] According to another preferred embodiment of this invention,
T contains at least one hydrogen bond donor moiety selected from
--NH.sub.2, --NH--, --OH, and --SH.
[0253] In a preferred embodiment, T is:
##STR00027## ##STR00028##
wherein:
[0254] T is optionally substituted with up to 3 J substituents,
wherein J is as defined in claim 1;
[0255] Y is independently O, S, NR.sub.10, or
C(R.sub.10).sub.2;
[0256] n is independently 1 or 2; and
[0257] is independently a single bond or a double bond.
[0258] In another preferred embodiment, T is:
##STR00029##
wherein Y is as defined above.
[0259] More preferably T is
##STR00030##
[0260] According to yet another preferred embodiment, T is:
[0261] (C6-C10)-aryl,
[0262] (C6-C10)-aryl-(C1-C12)aliphatic,
[0263] (C3-C10)-cycloalkyl or -cycloalkenyl,
[0264] [(C3-C10)-cycloalkyl or
-cycloalkenyl]-(C1-C12)-aliphatic,
[0265] (C3-C10)-heterocyclyl,
[0266] (C3-C10)-heterocyclyl-(C1-C12)-aliphatic,
[0267] (C5-C10)heteroaryl, or
[0268] (C5-C10)heteroaryl-(C1-C12)-aliphatic,
[0269] wherein each T is optionally substituted with up to 3 J
substituents.
[0270] According to yet another preferred embodiment of this
invention, T:
##STR00031##
wherein:
[0271] R.sub.10 is: [0272] hydrogen, [0273] (C1-C12)-aliphatic,
[0274] (C6-C10)-aryl, [0275] (C6-C10)-aryl-(C1-C12)aliphatic,
[0276] (C3-C10)-cycloalkyl or -cycloalkenyl, [0277]
[(C3-C10)-cycloalkyl or -cycloalkenyl]-(C1-C12)-aliphatic, [0278]
(C3-C10)-heterocyclyl, [0279]
(C3-C10)-heterocyclyl-(C1-C12)-aliphatic, [0280]
(C5-C10)heteroaryl, or [0281]
(C5-C10)heteroaryl-(C1-C12)-aliphatic,
[0282] wherein each T is optionally substituted with up to 3 J
substituents;
[0283] K is a bond, --O--, --S--, --NR.sub.9--, --C(O)--, or
--C(O)--NR.sub.9--, wherein R.sub.9 is hydrogen or C1-C12
aliphatic; and [0284] n is 1-3.
[0285] More preferably, T is:
##STR00032##
[0286] According to another embodiment, the present invention
provides compounds of formula (II):
##STR00033##
wherein:
[0287] ring A is a carbocyclic, heteroaryl or heterocyclic ring,
wherein ring A is optionally fused to an carbocyclic, heterocyclic
or heteroaryl ring;
[0288] wherein ring A has up to 4 substituents selected
independently from J;
[0289] ring C is a cycloalkyl or heterocyclic ring;
[0290] wherein ring C has up to 3 substituents selected
independently from J;
[0291] J is halogen, --OR', --NO.sub.2, --CF.sub.3, --OCF.sub.3,
--R', oxo, --O-benzyl, --O-phenyl, 1,2-methylenedioxy,
1,2-ethylenedioxy, --N(R').sub.2, --SR', --SOR', --SO.sub.2R',
--C(O)R', --OC(O)R', --COOR' or --CON(R').sub.2, wherein R' is
independently selected from: [0292] hydrogen, [0293]
(C1-C12)-aliphatic, [0294] (C3-C10)-cycloalkyl or -cycloalkenyl,
[0295] (C1-C12)-aliphatic-[(C3-C10)-cycloalkyl or -cycloalkenyl],
[0296] (C6-C10)-aryl, [0297] (C6-C10)-aryl-(C1-C12)aliphatic,
[0298] (C3-C10)-heterocyclyl, [0299]
(C6-C10)-heterocyclyl-(C1-C12)aliphatic, [0300]
(C5-C10)-heteroaryl, or [0301]
(C5-C10)-heteroaryl-(C1-C12)-aliphatic;
[0302] R.sub.1 and R.sub.3 are independently: [0303]
(C1-C12)-aliphatic, [0304] (C3-C10)-cycloalkyl or -cycloalkenyl,
[0305] (C1-C12)-aliphatic-[(C3-C10)-cycloalkyl or -cycloalkenyl],
[0306] (C6-C10)-aryl, [0307] (C6-C10)-aryl-(C1-C12)aliphatic,
[0308] (C3-C10)-heterocyclyl, [0309]
(C6-C10)-heterocyclyl-(C1-C12)aliphatic, [0310]
(C5-C10)-heteroaryl, or [0311]
(C5-C10)-heteroaryl-(C1-C12)-aliphatic, [0312] wherein each of
R.sub.1 and R.sub.3 is independently and optionally substituted
with up to 3 substituents independently selected from J; [0313]
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;
[0314] R.sub.2 and R.sub.4 are independently [0315] hydrogen,
[0316] (C1-C12)-aliphatic, [0317]
(C3-C10)-cycloalkyl-(C1-C12)-aliphatic, or [0318]
(C6-C10)aryl-(C1-C12)-aliphatic, [0319] wherein each of R.sub.2 and
R.sub.4 is independently and optionally substituted with up to 3
substituents independently selected from J; [0320] 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 in a
chemically stable arrangement;
[0321] Z is a carbon atom, --CHR--N--, --HN--CR-- or --CHR--CHR--,
--O--CHR--, --S--CHR--, --SO--CHR--, --SO.sub.2--CHR--, or
--N--;
[0322] wherein R is aliphatic, aryl, aralkyl or cycloalkyl;
[0323] R.sub.5 is --(C1-C12) aliphatic, wherein any hydrogen is
optionally substituted 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;
[0324] W is selected from: --C(O)OH;
##STR00034##
wherein each R.sub.6 is independently: [0325] hydrogen, [0326]
(C1-C12)-aliphatic, [0327] (C1-C12)-aliphatic-[(C3-C10)-cycloalkyl
or -cycloalkenyl], [0328] (C6-C10)-aryl, [0329]
(C6-C10)-aryl-(C1-C12)aliphatic, [0330] (C3-C10)-cycloalkyl or
-cycloalkenyl, [0331] (C3-C10)-heterocyclyl, [0332]
(C3-C10)-heterocyclyl-(C1-C12)-aliphatic, [0333]
(C5-C10)heteroaryl, or [0334]
(C5-C10)heteroaryl-(C1-C12)-aliphatic, or
[0335] two R.sub.6 groups, which are bound to the same nitrogen
atom, form together with that nitrogen atom, a
(C3-C10)-heterocyclic ring; [0336] wherein R.sub.6 is optionally
substituted with up to 3 J substituents;
[0337] each R.sub.7 is hydroxy, alkoxy, or aryloxy; or
[0338] each R.sub.7 is an oxygen atom linked to an aliphatic group
and, together with the boron to which they are each bound, the two
R.sub.7 groups form a 3-6 membered ring;
[0339] V is a bond, --CH(R.sub.8)--, --N(R.sub.8)--, --O--,
--O--CH(R.sub.8), --CH(R.sub.8)--O--, --S--, --S--CH(R.sub.8)--,
--CH(R.sub.8)--S--, --C(O)--, --C(O)--O--, --O--C(O)--,
--C(O)--S--, --C(O)--CHR.sub.8--, --CHR.sub.8--C(O)--
--N(R.sub.8)C(O)--C(O)N(R.sub.8)--, --S(O)--, --S(O)--CH(R.sub.8),
--CH(R.sub.8)--S(O)--, --S(O)N(R.sub.8)--, --N(R.sub.8)S(O)--,
--S(O)--N(R.sub.8)--CHR.sub.8, --N(R.sub.8)--S(O)--CHR.sub.8--,
--CHR.sub.8--S(O).sub.2, --S(O).sub.2--CH(R.sub.8)--,
--CH(R.sub.8)--X(O).sub.2--, --S(O).sub.2N(R.sub.8)--,
--N(R.sub.8)--S(O).sub.2--, --S(O).sub.2--N(R.sub.8)--CHR.sub.8 or
--N(R.sub.8)--S(O).sub.2--CHR.sub.8;
[0340] wherein R.sub.8 is hydrogen or (C1-C12)-aliphatic;
[0341] T is selected from: [0342] (C6-C10)-aryl, [0343]
(C6-C10)-aryl-(C1-C12)aliphatic, [0344] (C3-C10)-cycloalkyl or
-cycloalkenyl, [0345] (C1-C12)-aliphatic-[(C3-C10)-cycloalkyl or
-cycloalkenyl], [0346] (C3-C10)-heterocyclyl, [0347]
(C3-C10)-heterocyclyl-(C1-C12)-aliphatic, [0348]
(C5-C10)heteroaryl, or [0349]
(C5-C10)heteroaryl-(C1-C12)-aliphatic; or
[0350] T is selected from:
##STR00035##
wherein:
[0351] R.sub.10 is: [0352] hydrogen, [0353] (C1-C12)-aliphatic,
[0354] (C1-C12)-aliphatic-[(C3-C10)-cycloalkyl or -cycloalkenyl],
[0355] (C6-C10)-aryl, [0356] (C6-C10)-aryl-(C1-C12)aliphatic,
[0357] (C3-C10)-cycloalkyl or -cycloalkenyl, [0358]
(C3-C10)-heterocyclyl, [0359]
(C3-C10)-heterocyclyl-(C1-C12)-aliphatic, [0360]
(C5-C10)-heteroaryl, or [0361]
(C5-C10)-heteroaryl-(C1-C12)-aliphatic,
[0362] wherein each T is optionally substituted with up to 3 J
substituents;
[0363] 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
[0364] n is 1-3.
[0365] In compounds of formula (II), ring C is preferably selected
from:
##STR00036##
[0366] In compounds of formula (II), rings A and C, together with
the ring that they are attached to, are preferably selected
from:
##STR00037##
[0367] According to another preferred embodiment, R.sub.1 is
selected from --(C1-C10)alkyl, --(C3-C7)cycloalkyl, or
--((C1-C6)alkyl)-((C3-C7)cycloalkyl). More preferably, R.sub.1 is
selected from:
##STR00038##
[0368] Even more preferably, R.sub.1 is selected from
--CH.sub.2--C(CH.sub.3).sub.3, --C(CH.sub.3).sub.3,
--CH(CH.sub.3).sub.2, --CH(CH.sub.3)--CH.sub.2--CH.sub.3, or
cyclohexyl. Most preferably R.sub.1 is cyclohexyl.
[0369] According to another preferred embodiment, R.sub.2 is
(C1-C12)-aliphatic. More preferably, R.sub.2 is selected from
hydrogen, methyl, ethyl or propyl. Even more preferably, R.sub.2 is
hydrogen or methyl. Most preferably, R.sub.2 is hydrogen.
[0370] According to another preferred embodiment, R.sub.3 is
selected from --(C1-C10)alkyl, --(C3-C7)cycloalkyl, or
--((C1-C6)alkyl)-((C3-C7)cycloalkyl).
[0371] More preferably, R.sub.3 is selected from:
##STR00039##
[0372] Even more preferably, R.sub.3 is selected from
--C(CH.sub.3).sub.2, --CH(CH.sub.3).sub.2,
--CH(CH.sub.3)--CH.sub.2--CH.sub.3, or cyclohexyl. Most preferably,
R.sub.3 is selected from --C(CH.sub.3).sub.3 or
--CH(CH.sub.3).sub.2.
[0373] According to another preferred embodiment, R.sub.4 is
(C1-C12)-aliphatic. More preferably, R.sub.4 is selected from
hydrogen, methyl, ethyl or propyl. Even more preferably, R.sub.4 is
selected from hydrogen.
[0374] According to another preferred embodiment, R.sub.5 is
--(C2-C7)alkyl optionally substituted with halogen.
[0375] Preferably, R.sub.5 is selected from:
##STR00040##
More preferably, R.sub.5 is selected from
--CH.sub.2CH.sub.2CH.sub.3, --CH.sub.2CH.sub.2CH.sub.2CH.sub.3,
--CH.sub.2CH.sub.2CH.sub.2F, --CH.sub.2CH.sub.2CHF.sub.2, or
--CH.sub.2CH.sub.2CF.sub.3. Even more preferably, R.sub.5 is
selected from --CH.sub.2CH.sub.2CH.sub.3,
--CH.sub.2CH.sub.2CH.sub.2CH.sub.3 or --CH.sub.2CH.sub.2CHF.sub.2.
Most preferably, R.sub.5 is --CH.sub.2CH.sub.2CH.sub.3 or
--CH.sub.2CH.sub.2CH.sub.2CH.sub.3.
[0376] According to another preferred embodiment W is selected
from: CHO, --C(O)--R.sub.6, --CO.sub.2H, --C(O)--C(O)--R.sub.6, or
--C(O)--C(O)--NH(R.sub.6), wherein R.sub.6 is selected from
hydrogen, aryl, heteroaryl, heterocyclyl, C3-C6 alkyl, C3-C6
cycloalkyl, hydroxy, --O--C1-C6 alkyl, wherein --NH(R.sub.6) is
selected from --NH--(C3-C6 cycloalkyl), NH-aralkyl,
--NH-alkylheteroaryl, --NH-alkylheterocyclyl, and wherein said
aryl, heterocyclyl or heteroaryl is optionally substituted with up
to 3 halogen atoms.
[0377] More preferably, R.sub.6 or --NH(R.sub.6) is selected
from:
##STR00041##
[0378] According to another preferred embodiment W is selected from
--C(O)OH or --C(O)--C(O)--R.sub.6. More preferably, W is
--C(O)--C(O)--R.sub.6. Preferably, R.sub.6 is isopropyl.
[0379] According to a preferred embodiment, W is
--C(O)--C(O)--R.sub.6. Preferably, R.sub.6 is isopropyl.
[0380] According to another preferred embodiment, W is
--C(O)--C(O)--OR.sub.6. Preferably, R.sub.6 is hydrogen,
(C1-C12)-aliphatic, (C6-C10)-aryl, (C3-C10)-cycloalkyl or
-cycloalkenyl, (C3-C10)-heterocyclyl or (C5-C10)heteroaryl. More
preferably, R.sub.6 is H or methyl.
[0381] According to yet another preferred embodiment, W is
--C(O)--C(O)--N(R.sub.6).sub.2. Preferably, R.sub.6 is hydrogen,
(C3-C10)-cycloalkyl or -cycloalkenyl, or (C3-C10)-heterocyclyl.
[0382] In another preferred embodiment of compounds of formula (II)
is where W is C(O)--C(O)--N(R.sub.6).sub.2, the NR.sub.6R.sub.6
portion of the W moiety is --NH--(C3-C6)cycloalkyl,
--NH--CH(CH.sub.3)--(C6-C10) aryl or
--NH--CH(CH.sub.3)--(C3-C10)heterocyclyl, or
--NH--CH(CH.sub.3)--(C5-C10)heteroaryl, wherein said aryl,
heterocyclyl, or heteroaryl is optionally substituted with
halogen.
[0383] Alternatively, the NR.sub.6R.sub.6 portion is
--NH--(C3-C6)cycloalkyl, --NH--CH(CH.sub.3)--(C6-C10) aryl, or
--NH--CH(CH.sub.3)--(C5-C10)heteroaryl, wherein said aryl or said
heterocyclyl is optionally substituted with halogen; or
NR.sub.6R.sub.6 is --NH-- (C3-C6)cycloalkyl,
--NH--CH(CH.sub.3)--(C6-C10) aryl, or
--NH--CH(CH.sub.3)--(C3-C10)heterocyclyl, wherein said aryl or said
heterocyclyl is optionally substituted with halogen.
[0384] In other preferred embodiment of formula (II),
NR.sub.6R.sub.6 in W is:
##STR00042##
[0385] More preferably, NR.sub.6R.sub.6 is:
##STR00043##
[0386] Even more preferably, NR.sub.6R.sub.6 is:
##STR00044##
[0387] Most preferably, NR.sub.6R.sub.6 is:
##STR00045##
[0388] According to another preferred embodiment, when W is
--B(R.sub.7).sub.2, each R.sub.7 is selected from hydroxy, alkoxy,
or aryloxy.
[0389] According to yet another preferred embodiment, when W is
--B(R.sup.7).sub.2, each R.sub.7 is selected from an oxygen atom
linked to an aliphatic group and, together with the boron to which
they are each bound, the two R.sub.7 groups form a 5-8 membered
ring.
[0390] According to another preferred embodiment, V is a bond,
--CH(R.sub.8)--, --N(R.sub.8)--, --O--, --O--CH(R.sub.8), --S--,
--S--CH(R.sub.8), --C(O)--, --C(O)--O--, --C(O)--S--,
--C(O)--CHR.sub.8--, --C(O)N(R.sub.8)--, --S(O)--,
--S(O)--CH(R.sub.8)--, --S(O)N(R.sub.8)--,
--S(O)--N(R.sub.8)--CHR.sub.8, --S(O).sub.2,
--S--(O).sub.2--CH(R.sub.8)--, --S(O).sub.2N(R.sub.8)--, or
--S(O).sub.2--N(R.sub.8)--CHR.sub.8; wherein R.sub.8 is hydrogen or
--(C1-C3)alkyl;
[0391] According to another preferred embodiment, V is --NH--.
[0392] According to yet another preferred embodiment, V is
--C(O)--.
[0393] According to yet another preferred embodiment, V is
--C(O)--NR.sub.8--. More preferably, V is --C(O)--NH--.
[0394] According to yet another preferred embodiment T is a
heterocyclyl or heteroaryl, optionally having up to 3 substituents
as defined above.
[0395] According to yet another preferred embodiment, T is a
--(C5-C10)heteroaryl.
[0396] According to yet another preferred embodiment, T is selected
from 3-1H-benzimidazol-2-one, 3-(1-alkyl)-benzimidazol-2-one,
2-tetrahydrofuranyl, 3-tetrahydrofuranyl, pyrazolinyl,
1,3-dihydro-imidazol-2-one, 2-imidazolyl, 4-imidazolyl,
5-imidazolyl, 2-oxazolyl, 4-oxazolyl, 5-oxazolyl, 2-pyrrolyl,
3-pyrrolyl, 2-pyrimidinyl, 4-pyrimidinyl, 5-pyrimidinyl,
5-tetrazolyl, pyrazolyl, pyrazinyl or 1,3,5-triazinyl.
[0397] Even more preferably, T is selected from
3-1H-benzimidazol-2-one, 3-(1-alkyl)-benzimidazol-2-one,
pyrazolinyl, 1,3-dihydro-imidazol-2-one, 2-imidazolyl, 2-pyrrolyl,
2-pyrimidinyl, 5-pyrimidinyl, 5-tetrazolyl or pyrazinyl.
[0398] Most preferred is when T or R.sup.7 is selected from:
##STR00046##
[0399] Preferred substituents on T in the above embodiments are
halogen, --CF.sub.3, --OCF.sub.3, oxo, --COOR', or --CON(R').sub.2,
wherein R' is as defined above.
[0400] According to another preferred embodiment of this invention,
T contains at least one hydrogen bond donor moiety selected from
--NH.sub.2, --NH--, --OH, and --SH.
[0401] In a preferred embodiment, T is:
##STR00047## ##STR00048##
wherein:
[0402] T is optionally substituted with up to 3 J substituents,
wherein J is as defined in claim 1;
[0403] Y is independently O, S, NR.sub.10, or
C(R.sub.10).sub.2;
[0404] n is independently 1 or 2; and
[0405] is independently a single bond or a double bond.
[0406] In another preferred embodiment, T is:
##STR00049##
wherein Y is as defined above.
[0407] More preferably T is
##STR00050##
[0408] According to yet another preferred embodiment, T is:
[0409] (C6-C10)-aryl,
[0410] (C6-C10)-aryl-(C1-C12)aliphatic,
[0411] (C3-C10)-cycloalkyl or -cycloalkenyl,
[0412] [(C3-C10)-cycloalkyl or
-cycloalkenyl]-(C1-C12)-aliphatic,
[0413] (C3-C10)-heterocyclyl,
[0414] (C3-C10)-heterocyclyl-(C1-C12)-aliphatic,
[0415] (C5-C10)heteroaryl, or
[0416] (C5-C10)heteroaryl-(C1-C12)-aliphatic,
[0417] wherein each T is optionally substituted with up to 3 J
substituents.
[0418] According to yet another preferred embodiment of this
invention, T:
##STR00051##
wherein:
[0419] R.sub.10 is: [0420] hydrogen, [0421] (C1-C12)-aliphatic,
[0422] (C6-C10)-aryl, [0423] (C6-C10)-aryl-(C1-C12)aliphatic,
[0424] (C3-C10)-cycloalkyl or -cycloalkenyl, [0425]
[(C3-C10)-cycloalkyl or -cycloalkenyl]-(C1-C12)-aliphatic, [0426]
(C3-C10)-heterocyclyl, [0427]
(C3-C10)-heterocyclyl-(C1-C12)-aliphatic, [0428]
(C5-C10)heteroaryl, or [0429]
(C5-C10)heteroaryl-(C1-C12)-aliphatic,
[0430] wherein each T is optionally substituted with up to 3 J
substituents;
[0431] K is a bond, --O--, --S--, --NR.sub.9--, --C(O)--, or
--C(O)--NR.sub.9--, wherein R.sub.9 is hydrogen or C1-C12
aliphatic; and [0432] n is 1-3.
[0433] More preferably, T is:
##STR00052##
[0434] According to another embodiment, the present invention
provides compounds of formula (III):
##STR00053##
wherein:
[0435] ring B is a carbocyclic or heterocyclic ring, wherein ring B
is optionally fused to a carbocyclic, heterocyclic or heteroaryl
ring;
[0436] wherein ring B has up to 3 substituents selected
independently from J;
[0437] ring C is a cycloalkyl or heterocyclic ring;
[0438] wherein ring C has up to 3 substituents selected
independently from J;
[0439] Z is a carbon atom, --CHR--N--, --HN--CR-- or
--CHR--CHR--;
[0440] wherein, rings B and C are attached to the same carbon atom
in Z; or
[0441] rings B and C are attached vicinally to Z when Z is
--CHR--N--, --HN--CR-- or --CHR--CHR--;
[0442] wherein R is aliphatic, aryl, aralkyl or cycloalkyl;
[0443] J is halogen, --OR', --NO.sub.2, --CF.sub.3, --OCF.sub.3,
--R', oxo, --O-benzyl, --O-phenyl, 1,2-methylenedioxy,
1,2-ethylenedioxy, --N(R').sub.2, --SR', --SOR', --SO.sub.2R',
--C(O)R', --OC(O)R', --COOR' or --CON(R').sub.2, wherein R' is
independently selected from: [0444] hydrogen, [0445]
(C1-C12)-aliphatic, [0446] (C3-C10)-cycloalkyl or -cycloalkenyl,
[0447] (C1-C12)-aliphatic-[(C3-C10)-cycloalkyl or -cycloalkenyl],
[0448] (C6-C10)-aryl, [0449] (C6-C10)-aryl-(C1-C12)aliphatic,
[0450] (C3-C10)-heterocyclyl, [0451]
(C6-C10)-heterocyclyl-(C1-C12)aliphatic, [0452]
(C5-C10)-heteroaryl, or [0453]
(C5-C10)-heteroaryl-(C1-C12)-aliphatic;
[0454] R.sub.1 and R.sub.3 are independently: [0455]
(C1-C12)-aliphatic, [0456] (C3-C10)-cycloalkyl or -cycloalkenyl,
[0457] (C1-C12)-aliphatic-[(C3-C10)-cycloalkyl or -cycloalkenyl],
[0458] (C6-C10)-aryl, [0459] (C6-C10)-aryl-(C1-C12)aliphatic,
[0460] (C3-C10)-heterocyclyl, [0461]
(C6-C10)-heterocyclyl-(C1-C12)aliphatic, [0462]
(C5-C10)-heteroaryl, or [0463]
(C5-C10)-heteroaryl-(C1-C12)-aliphatic, [0464] wherein each of
R.sub.1 and R.sub.3 is independently and optionally substituted
with up to 3 substituents independently selected from J; [0465]
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;
[0466] R.sub.2 and R.sub.4 are independently [0467] hydrogen,
[0468] (C1-C12)-aliphatic, [0469]
(C3-C10)-cycloalkyl-(C1-C12)-aliphatic, or [0470]
(C6-C10)aryl-(C1-C12)-aliphatic, [0471] wherein each of R.sub.2 and
R.sub.4 is independently and optionally substituted with up to 3
substituents independently selected from J; [0472] 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 in a
chemically stable arrangement;
[0473] R.sub.5 is --(C1-C12) aliphatic, wherein any hydrogen is
optionally substituted 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;
[0474] W is selected from: --C(O)OH;
##STR00054##
[0475] wherein each R.sub.6 is independently: [0476] hydrogen,
[0477] (C1-C12)-aliphatic, [0478]
(C1-C12)-aliphatic-[(C3-C10)-cycloalkyl or -cycloalkenyl], [0479]
(C6-C10)-aryl, [0480] (C6-C10)-aryl-(C1-C12)aliphatic, [0481]
(C3-C10)-cycloalkyl or -cycloalkenyl, [0482] (C3-C10)-heterocyclyl,
[0483] (C3-C10)-heterocyclyl-(C1-C12)-aliphatic, [0484]
(C5-C10)heteroaryl, or [0485]
(C5-C10)heteroaryl-(C1-C12)-aliphatic, or
[0486] two R.sub.6 groups, which are bound to the same nitrogen
atom, form together with that nitrogen atom, a
(C3-C10)-heterocyclic ring;
[0487] wherein R.sub.6 is optionally substituted with up to 3 J
substituents;
[0488] each R.sub.7 is hydroxy, alkoxy, or aryloxy; or
[0489] each R.sub.7 is an oxygen atom linked to an aliphatic group
and, together with the boron to which they are each bound, the two
R.sub.7 groups form a 3-6 membered ring;
[0490] V is a bond, --CH(R.sub.8)--, --N(R.sub.8)--, --O--,
--O--CH(R.sub.8), --CH(R.sub.8)--O--, --S--, --S--CH(R.sub.8)--,
--CH(R.sub.8)--S--, --C(O)--, --C(O)--O--, --O--C(O)--,
--C(O)--S--, --C(O)--CHR.sub.8--, --CHR.sub.8--C(O)--
--N(R.sub.8)C(O)-- --C(O)N(R.sub.8)--, --S(O)--,
--S(O)--CH(R.sub.8), --CH(R.sub.8)--S(O)--, --S(O)N(R.sub.8)--,
--N(R.sub.8)S(O)--, --S(O)--N(R.sub.8)--CHR.sub.8,
--N(R.sub.8)--S(O)--CHR.sub.8--, --CHR.sub.8--S(O).sub.2,
--S(O).sub.2--CH(R.sub.8)--, --CH(R.sub.8)--S(O).sub.2--,
--S(O).sub.2N(R.sub.8)--, --N(R.sub.8)--S(O).sub.2--,
--S(O).sub.2--N(R.sub.8)--CHR.sub.8 or
--N(R.sub.8)--S(O).sub.2--CHR.sub.8;
[0491] wherein R.sub.8 is hydrogen or (C1-C12)-aliphatic;
[0492] T is selected from: [0493] (C6-C10)-aryl, [0494]
(C6-C10)-aryl-(C1-C12)aliphatic, [0495] (C3-C10)-cycloalkyl or
-cycloalkenyl, [0496] (C1-C12)-aliphatic-[(C3-C10)-cycloalkyl or
-cycloalkenyl], [0497] (C3-C10)-heterocyclyl, [0498]
(C3-C10)-heterocyclyl-(C1-C12)-aliphatic, [0499]
(C5-C10)heteroaryl, or [0500]
(C5-C10)heteroaryl-(C1-C12)-aliphatic; or
[0501] T is selected from:
##STR00055##
wherein:
[0502] R.sub.10 is: [0503] hydrogen, [0504] (C1-C12)-aliphatic,
[0505] (C1-C12)-aliphatic-[(C3-C10)-cycloalkyl or -cycloalkenyl],
[0506] (C6-C10)-aryl, [0507] (C6-C10)-aryl-(C1-C12)aliphatic,
[0508] (C3-C10)-cycloalkyl or -cycloalkenyl, [0509]
(C3-C10)-heterocyclyl, [0510]
(C3-C10)-heterocyclyl-(C1-C12)-aliphatic, [0511]
(C5-C10)-heteroaryl, or [0512]
(C5-C10)-heteroaryl-(C1-C12)-aliphatic,
[0513] wherein each T is optionally substituted with up to 3 J
substituents;
[0514] 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
[0515] n is 1-3.
[0516] According to a preferred embodiment, R.sub.1 is selected
from --(C1-C10)alkyl, --(C3-C7)cycloalkyl, or
--((C1-C6)alkyl)-((C3-C7)cycloalkyl). More preferably, R.sub.1 is
selected from:
##STR00056##
[0517] Even more preferably, R.sub.1 is selected from --CH.sub.2--C
C(CH.sub.3).sub.3, --C(CH.sub.3).sub.3, --CH(CH.sub.3).sub.2,
--CH(CH.sub.3)--CH.sub.2--CH.sub.3, or cyclohexyl. Most preferably
R.sub.1 is cyclohexyl.
[0518] According to another preferred embodiment, R.sub.2 is
(C1-C12)-aliphatic. More preferably, R.sub.2 is selected from
hydrogen, methyl, ethyl or propyl. Even more preferably, R.sub.2 is
hydrogen or methyl. Most preferably, R.sub.2 is hydrogen.
[0519] According to another preferred embodiment, R.sub.3 is
selected from --(C1-C10)alkyl, --(C3-C7)cycloalkyl, or
--((C1-C6)alkyl)-((C3-C7)cycloalkyl).
[0520] More preferably, R.sub.3 is selected from:
##STR00057##
[0521] Even more preferably, R.sub.3 is selected from
--C(CH.sub.3).sub.2, --CH(CH.sub.3).sub.2,
--CH(CH.sub.3)--CH.sub.2--CH.sub.3, or cyclohexyl. Most preferably,
R.sub.3 is selected from --C(CH.sub.3).sub.3 or
--CH(CH.sub.3).sub.2.
[0522] According to another preferred embodiment, R.sub.4 is
(C1-C12)-aliphatic. More preferably, R.sub.4 is selected from
hydrogen, methyl, ethyl or propyl. Even more preferably, R.sub.4 is
selected from hydrogen.
[0523] According to another preferred embodiment, R.sub.5 is
--(C2-C7)alkyl optionally substituted with halogen. Preferably,
R.sub.5 is selected from:
##STR00058##
More preferably, R.sub.5 is selected from
--CH.sub.2CH.sub.2CH.sub.3, --CH.sub.2CH.sub.2CH.sub.2CH.sub.3,
--CH.sub.2CH.sub.2CH.sub.2F, --CH.sub.2CH.sub.2CHF.sub.2, or
--CH.sub.2CH.sub.2CF.sub.3. Even more preferably, R.sub.5 is
selected from --CH.sub.2CH.sub.2CH.sub.3,
--CH.sub.2CH.sub.2CH.sub.2CH.sub.3 or --CH.sub.2CH.sub.2CHF.sub.2.
Most preferably, R.sub.5 is --CH.sub.2CH.sub.2CH.sub.3 or
--CH.sub.2CH.sub.2CH.sub.2CH.sub.3.
[0524] According to another preferred embodiment W is selected
from: CHO, --C(O)--R.sub.6, --CO.sub.2H, --C(O)--C(O)--R.sub.6, or
--C(O)--C(O)--NH(R.sub.6), wherein R.sub.6 is selected from
hydrogen, aryl, heteroaryl, heterocyclyl, C3-C6 alkyl, C3-C6
cycloalkyl, hydroxy, --O--C1-C6 alkyl, wherein --NH(R.sub.6) is
selected from --NH--(C3-C6 cycloalkyl), NH-aralkyl,
--NH-alkylheteroaryl, --NH-alkylheterocyclyl, and wherein said
aryl, heterocyclyl or heteroaryl is optionally substituted with up
to 3 halogen atoms.
[0525] More preferably, R.sub.6 or --NH(R.sub.6) is selected
from:
##STR00059##
[0526] According to another preferred embodiment W is selected from
--C(O)OH or --C(O)--C(O)--R.sub.6. More preferably, W is
--C(O)--C(O)--R.sub.6. Preferably, R.sub.6 is isopropyl.
[0527] According to a preferred embodiment, W is
--C(O)--C(O)--R.sub.6. Preferably, R.sub.6 is isopropyl.
[0528] According to another preferred embodiment, W is
--C(O)--C(O)--OR.sub.6. Preferably, R.sub.6 is hydrogen,
(C1-C12)-aliphatic, (C6-C10)-aryl, (C3-C10)-cycloalkyl or
-cycloalkenyl, (C3-C10)-heterocyclyl or (C5-C10)heteroaryl. More
preferably, R.sub.6 is H or methyl.
[0529] According to yet another preferred embodiment, W is
--C(O)--C(O)--N(R.sub.6).sub.2. Preferably, R.sub.6 is hydrogen,
(C3-C10)-cycloalkyl or -cycloalkenyl, or (C3-C10)-heterocyclyl.
[0530] In another preferred embodiment of compounds of formula
(III) is where W is C(O)--C(O)--N(R.sub.6).sub.2, the
NR.sub.6R.sub.6 portion of the W moiety is --NH--(C3-C6)cycloalkyl,
--NH--CH(CH.sub.3)--(C6-C10)aryl or
--NH--CH(CH.sub.3)--(C3-C10)heterocyclyl, or
--NH--CH(CH.sub.3)--(C5-C10)heteroaryl, wherein said aryl,
heterocyclyl, or heteroaryl is optionally substituted with
halogen.
[0531] Alternatively, the NR.sub.6R.sub.6 portion is
--NH--(C3-C6)cycloalkyl, --NH--CH(CH.sub.3)--(C6-C10)aryl, or
--NH--CH(CH.sub.3)--(C5-C10)heteroaryl, wherein said aryl or said
heterocyclyl is optionally substituted with halogen; or
NR.sub.6R.sub.6 is --NH--(C3-C6)cycloalkyl,
--NH--CH(CH.sub.3)--(C6-C10)aryl, or
--NH--CH(CH.sub.3)--(C3-C10)heterocyclyl, wherein said aryl or said
heterocyclyl is optionally substituted with halogen.
[0532] In other preferred embodiment of formula (III),
NR.sub.6R.sub.6 in W is:
##STR00060##
[0533] More preferably, NR.sub.6R.sub.6 is:
##STR00061##
[0534] Even more preferably, NR.sub.6R.sub.6 is:
##STR00062##
[0535] Most preferably, NR.sub.6R.sub.6 is:
##STR00063##
[0536] According to another preferred embodiment, when W is
--B(R.sub.7).sub.2, each R.sub.7 is selected from hydroxy, alkoxy,
or aryloxy.
[0537] According to yet another preferred embodiment,
[0538] when W is --B(R.sup.7).sub.2, each R.sub.7 is selected from
an oxygen atom linked to an aliphatic group and, together with the
boron to which they are each bound, the two R.sub.7 groups form a
5-8 membered ring.
[0539] According to another preferred embodiment, V is a bond,
--CH(R.sub.8)--, --N(R.sub.8)--, --O--, --O--CH(R.sub.8), --S--,
--S--CH(R.sub.8), --C(O)--, --C(O)--O--, --C(O)--S--,
--C(O)--CHR.sub.8--, --C(O)N(R.sub.8)--, --S(O)--,
--S(O)--CH(R.sub.8)--, --S(O)N(R.sub.8)--,
--S(O)--N(R.sub.8)--CHR.sub.8, --S(O).sub.2,
--S--(O).sub.2--CH(R.sub.8)--, --S(O).sub.2N(R.sub.8)--, or
--S(O).sub.2--N(R.sub.8)--CHR.sub.8; wherein R.sub.8 is hydrogen or
--(C1-C3)alkyl;
[0540] According to another preferred embodiment, V is --NH--.
[0541] According to yet another preferred embodiment, V is
--C(O)--.
[0542] According to yet another preferred embodiment, V is
--C(O)--NR.sub.8--. More preferably, V is --C(O)--NH--.
[0543] According to yet another preferred embodiment T is a
heterocyclyl or heteroaryl, optionally having up to 3 substituents
as defined above.
[0544] According to yet another preferred embodiment, T is a
--(C5-C10)heteroaryl.
[0545] According to yet another preferred embodiment, T is selected
from 3-1H-benzimidazol-2-one, 3-(1-alkyl)-benzimidazol-2-one,
2-tetrahydrofuranyl, 3-tetrahydrofuranyl, pyrazolinyl,
1,3-dihydro-imidazol-2-one, 2-imidazolyl, 4-imidazolyl,
5-imidazolyl, 2-oxazolyl, 4-oxazolyl, 5-oxazolyl, 2-pyrrolyl,
3-pyrrolyl, 2-pyrimidinyl, 4-pyrimidinyl, 5-pyrimidinyl,
5-tetrazolyl, pyrazolyl, pyrazinyl or 1,3,5-triazinyl.
[0546] Even more preferably, T is selected from
3-1H-benzimidazol-2-one, 3-(1-alkyl)-benzimidazol-2-one,
pyrazolinyl, 1,3-dihydro-imidazol-2-one, 2-imidazolyl, 2-pyrrolyl,
2-pyrimidinyl, 5-pyrimidinyl, 5-tetrazolyl or pyrazinyl.
[0547] Most preferred is when T or R.sup.7 is selected from:
##STR00064##
[0548] Preferred substituents on T in the above embodiments are
halogen, --CF.sub.3, --OCF.sub.3, oxo, --COOR', or --CON(R').sub.z,
wherein R' is as defined above.
[0549] According to another preferred embodiment of this invention,
T contains at least one hydrogen bond donor moiety selected from
--NH.sub.2, --NH--, --OH, and --SH.
[0550] In a preferred embodiment, T is:
##STR00065## ##STR00066##
wherein:
[0551] T is optionally substituted with up to 3 J substituents,
wherein J is as defined in claim 1;
[0552] Y is independently O, S, NR.sub.10, or
C(R.sub.10).sub.2;
[0553] n is independently 1 or 2; and
[0554] is independently a single bond or a double bond.
[0555] In another preferred embodiment, T is:
##STR00067##
wherein Y is as defined above.
[0556] More preferably T is
##STR00068##
[0557] According to yet another preferred embodiment, T is:
[0558] (C6-C10)-aryl,
[0559] (C6-C10)-aryl-(C1-C12)aliphatic,
[0560] (C3-C10)-cycloalkyl or -cycloalkenyl,
[0561] [(C3-C10)-cycloalkyl or
-cycloalkenyl]-(C1-C12)-aliphatic,
[0562] (C3-C10)-heterocyclyl,
[0563] (C3-C10)-heterocyclyl-(C1-C12)-aliphatic,
[0564] (C5-C10)heteroaryl, or
[0565] (C5-C10)heteroaryl-(C1-C12)-aliphatic,
[0566] wherein each T is optionally substituted with up to 3 J
substituents.
[0567] According to yet another preferred embodiment of this
invention, T:
##STR00069##
wherein:
[0568] R.sub.10 is: [0569] hydrogen, [0570] (C1-C12)-aliphatic,
[0571] (C6-C10)-aryl, [0572] (C6-C10)-aryl-(C1-C12)aliphatic,
[0573] (C3-C10)-cycloalkyl or -cycloalkenyl, [0574]
[(C3-C10)-cycloalkyl or -cycloalkenyl]-(C1-C12)-aliphatic, [0575]
(C3-C10)-heterocyclyl, [0576]
(C3-C10)-heterocyclyl-(C1-C12)-aliphatic, [0577]
(C5-C10)heteroaryl, or [0578]
(C5-C10)heteroaryl-(C1-C12)-aliphatic,
[0579] wherein each T is optionally substituted with up to 3 J
substituents;
[0580] K is a bond, --O--, --S--, --NR.sub.9--, --C(O)--, or
--C(O)--NR.sub.9--,
[0581] wherein R.sub.9 is hydrogen or C1-C12 aliphatic; and [0582]
n is 1-3.
[0583] More preferably, T is:
##STR00070##
[0584] In compounds of formula (III), the preferred embodiments of
ring B are as defined for compounds of formula (I).
[0585] In compounds of formula (III), the preferred embodiments of
ring C are as defined for compounds of formula (II).
[0586] According to another embodiment, the present invention
provides compounds of formula (IV):
##STR00071##
wherein:
[0587] ring B is a bridged bicyclic ring system containing 6-12
carbon atoms, wherein ring B is saturated or partially unsaturated;
or
[0588] the ring system comprising ring B, together with the ring
containing Z and the nitrogen atom, contains more than ten ring
atoms;
[0589] wherein ring B has up to 3 substituents selected
independently from J;
[0590] J is halogen, --OR', --NO.sub.2, --CF.sub.3, --OCF.sub.3,
--R', oxo, --OR', --O-benzyl, --O-phenyl, 1,2-methylenedioxy,
1,2-ethylenedioxy, --N(R').sub.2, --SR', --SOR', --SO.sub.2R',
--C(O)R', --COOR' or --CON(R').sub.2, wherein R' is independently
selected from: [0591] hydrogen, [0592] (C1-C12)-aliphatic, [0593]
(C3-C10)-cycloalkyl or -cycloalkenyl, [0594]
(C1-C12)-aliphatic-[(C3-C10)-cycloalkyl or -cycloalkenyl], [0595]
(C6-C10)-aryl, [0596] (C6-C10)-aryl-(C1-C12)aliphatic, [0597]
(C3-C10)-heterocyclyl, [0598]
(C6-C10)-heterocyclyl-(C1-C12)aliphatic, [0599]
(C5-C10)-heteroaryl, or [0600]
(C5-C10)-heteroaryl-(C1-C12)-aliphatic;
[0601] R.sub.1 and R.sub.3 are independently: [0602]
(C1-C12)-aliphatic, [0603] (C3-C10)-cycloalkyl or -cycloalkenyl,
[0604] (C1-C12)-aliphatic-[(C3-C10)-cycloalkyl or -cycloalkenyl],
[0605] (C6-C10)-aryl, [0606] (C6-C10)-aryl-(C1-C12)aliphatic,
[0607] (C3-C10)-heterocyclyl, [0608]
(C6-C10)-heterocyclyl-(C1-C12)aliphatic, [0609]
(C5-C10)-heteroaryl, or [0610]
(C5-C10)-heteroaryl-(C1-C12)-aliphatic, [0611] wherein each of
R.sub.1 and R.sub.3 is independently and optionally substituted
with up to 3 substituents independently selected from J; [0612]
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;
[0613] R.sub.2 and R.sub.4 are independently [0614] hydrogen,
[0615] (C1-C12)-aliphatic, [0616]
(C3-C10)-cycloalkyl-(C1-C12)-aliphatic, or [0617]
(C6-C10)aryl-(C1-C12)-aliphatic, [0618] wherein each of R.sub.2 and
R.sub.4 is independently and optionally substituted with up to 3
substituents independently selected from J; [0619] 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 in a
chemically stable arrangement;
[0620] Z is a carbon atom, --CHR--N--, --HN--CR-- or --CHR--CHR--,
--O--CHR--, --S--CHR--, --SO--CHR--, --SO.sub.2--CHR--, or
--N--;
[0621] wherein R is aliphatic, aryl, aralkyl or cycloalkyl;
[0622] R.sub.5 is --(C1-C12) aliphatic, wherein any hydrogen is
optionally substituted 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;
[0623] W is selected from: --C(O)OH;
##STR00072##
wherein each R.sub.6 is independently: [0624] hydrogen, [0625]
(C1-C12)-aliphatic, [0626] (C1-C12)-aliphatic-[(C3-C10)-cycloalkyl
or -cycloalkenyl], [0627] (C6-C10)-aryl, [0628]
(C6-C10)-aryl-(C1-C12)aliphatic, [0629] (C3-C10)-cycloalkyl or
-cycloalkenyl, [0630] (C3-C10)-heterocyclyl, [0631]
(C3-C10)-heterocyclyl-(C1-C12)-aliphatic, [0632]
(C5-C10)heteroaryl, or [0633]
(C5-C10)heteroaryl-(C1-C12)-aliphatic, or
[0634] two R.sub.6 groups, which are bound to the same nitrogen
atom, form together with that nitrogen atom, a
(C3-C10)-heterocyclic ring;
[0635] wherein R.sub.6 is optionally substituted with up to 3 J
substituents;
[0636] each R.sub.7 is hydroxy, alkoxy, or aryloxy; or
[0637] each R.sub.7 is an oxygen atom linked to an aliphatic group
and, together with the boron to which they are each bound, the two
R.sub.7 groups form a 3-6 membered ring;
[0638] V is a bond, --CH(R.sub.8)--, --N(R.sub.8)--, --O--,
--O--CH(R.sub.8), --CH(R.sub.8)--O--, --S--, --S--CH(R.sub.8)--,
--CH(R.sub.8)--S--, --C(O)--, --C(O)--O--, --O--C(O)--,
--C(O)--S--, --C(O)--CHR.sub.8--, --CHR.sub.8--C(O)--
--N(R.sub.8)C(O)-- --C(O)N(R.sub.8)--, --S(O)--,
--S(O)--CH(R.sub.8), --CH(R.sub.8)--S(O)--, --S(O)N(R.sub.8)--,
--N(R.sub.8)S(O)--, --S(O)--N(R.sub.8)--CHR.sub.8,
--N(R.sub.8)--S(O)--CHR.sub.8--, --CHR.sub.8--S(O).sub.2,
--S(O).sub.2--CH(R.sub.8)--, --CH(R.sub.8)--S(O).sub.2--,
--S(O).sub.2N(R.sub.8)--, --N(R.sub.8)--S(O).sub.2--,
--S(O).sub.2--N(R.sub.8)--CHR.sub.8 or
--N(R.sub.8)--S(O).sub.2--CHR.sub.8;
[0639] wherein R.sub.8 is hydrogen or (C1-C12)-aliphatic;
[0640] T is selected from: [0641] (C6-C10)-aryl, [0642]
(C6-C10)-aryl-(C1-C12)aliphatic, [0643] (C3-C10)-cycloalkyl or
-cycloalkenyl, [0644] (C1-C12)-aliphatic-[(C3-C10)-cycloalkyl or
-cycloalkenyl], [0645] (C3-C10)-heterocyclyl, [0646]
(C3-C10)-heterocyclyl-(C1-C12)-aliphatic, [0647]
(C5-C10)heteroaryl, or [0648]
(C5-C10)heteroaryl-(C1-C12)-aliphatic; or
[0649] T is selected from:
##STR00073##
wherein:
[0650] R.sub.10 is: [0651] hydrogen, [0652] (C1-C12)-aliphatic,
[0653] (C1-C12)-aliphatic-[(C3-C10)-cycloalkyl or -cycloalkenyl],
[0654] (C6-C10)-aryl, [0655] (C6-C10)-aryl-(C1-C12)aliphatic,
[0656] (C3-C10)-cycloalkyl or -cycloalkenyl, [0657]
(C3-C10)-heterocyclyl, [0658]
(C3-C10)-heterocyclyl-(C1-C12)-aliphatic, [0659]
(C5-C10)-heteroaryl, or [0660]
(C5-C10)-heteroaryl-(C1-C12)-aliphatic,
[0661] wherein each T is optionally substituted with up to 3 J
substituents;
[0662] 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
[0663] n is 1-3.
[0664] According to a preferred embodiment of compounds of formula
(IV), ring B is a bridged bicyclic ring system containing 6-12
carbon atoms, wherein ring B is saturated or partially unsaturated,
and ring B has up to 3 substituents selected independently from
J.
[0665] Preferred embodiments of ring B in compound of formula (IV)
include:
##STR00074## ##STR00075##
[0666] According to a preferred embodiment, R.sub.1 is selected
from --(C1-C10)alkyl, --(C3-C7)cycloalkyl, or
--((C1-C6)alkyl)-((C3-C7)cycloalkyl). More preferably, R.sub.1 is
selected from:
##STR00076##
[0667] Even more preferably, R.sub.1 is selected from --CH.sub.2--C
C(CH.sub.3).sub.3, --C(CH.sub.3).sub.3, --CH(CH.sub.3).sub.2,
--CH(CH.sub.3)--CH.sub.2--CH.sub.3, or cyclohexyl. Most preferably
R.sub.1 is cyclohexyl.
[0668] According to another preferred embodiment, R.sub.2 is
(C1-C12)-aliphatic. More preferably, R.sub.2 is selected from
hydrogen, methyl, ethyl or propyl. Even more preferably, R.sub.2 is
hydrogen or methyl. Most preferably, R.sub.2 is hydrogen.
[0669] According to another preferred embodiment, R.sub.3 is
selected from --(C1-C10)alkyl, --(C3-C7)cycloalkyl, or
--((C1-C6)alkyl)-((C3-C7)cycloalkyl).
[0670] More preferably, R.sub.3 is selected from:
##STR00077##
[0671] Even more preferably, R.sub.3 is selected from
--C(CH.sub.3).sub.2, --CH(CH.sub.3).sub.2,
--CH(CH.sub.3)--CH.sub.2--CH.sub.3, or cyclohexyl.
[0672] Most preferably, R.sub.3 is selected from
--C(CH.sub.3).sub.3 or --CH(CH.sub.3).sub.2.
[0673] According to another preferred embodiment, R.sub.4 is
(C1-C12)-aliphatic. More preferably, R.sub.4 is selected from
hydrogen, methyl, ethyl or propyl. Even more preferably, R.sub.4 is
selected from hydrogen.
[0674] According to another preferred embodiment, R.sub.5 is
--(C2-C7)alkyl optionally substituted with halogen. Preferably,
R.sub.5 is selected from:
##STR00078##
More preferably, R.sub.5 is selected from
--CH.sub.2CH.sub.2CH.sub.3, --CH.sub.2CH.sub.2CH.sub.2CH.sub.3,
--CH.sub.2CH.sub.2CH.sub.2F, --CH.sub.2CH.sub.2CHF.sub.2, or
--CH.sub.2CH.sub.2CF.sub.3. Even more preferably, R.sub.5 is
selected from --CH.sub.2CH.sub.2CH.sub.3,
--CH.sub.2CH.sub.2CH.sub.2CH.sub.3 or --CH.sub.2CH.sub.2CHF.sub.2.
Most preferably, R.sub.5 is --CH.sub.2CH.sub.2CH.sub.3 or
--CH.sub.2CH.sub.2CH.sub.2CH.sub.3.
[0675] According to another preferred embodiment W is selected
from: CHO, --C(O)--R.sub.6, --CO.sub.2H, --C(O)--C(O)--R.sub.6, or
--C(O)--C(O)--NH(R.sub.6), wherein R.sub.6 is selected from
hydrogen, aryl, heteroaryl, heterocyclyl, C3-C6 alkyl, C3-C6
cycloalkyl, hydroxy, --O--C1-C6 alkyl, wherein --NH(R.sub.6) is
selected from --NH--(C3-C6 cycloalkyl), NH-aralkyl,
--NH-alkylheteroaryl, --NH-alkylheterocyclyl, and wherein said
aryl, heterocyclyl or heteroaryl is optionally substituted with up
to 3 halogen atoms.
[0676] More preferably, R.sub.6 or --NH(R.sub.6) is selected
from:
##STR00079##
[0677] According to another preferred embodiment W is selected from
--C(O)OH or --C(O)--C(O)--R.sub.6. More preferably, W is
--C(O)--C(O)--R.sub.6. Preferably, R.sub.6 is isopropyl.
[0678] According to a preferred embodiment, W is
--C(O)--C(O)--R.sub.6. Preferably, R.sub.6 is isopropyl.
[0679] According to another preferred embodiment, W is
--C(O)--C(O)--OR.sub.6. Preferably, R.sub.6 is hydrogen,
(C1-C12)-aliphatic, (C6-C10)-aryl, (C3-C10)-cycloalkyl or
-cycloalkenyl, (C3-C10)-heterocyclyl or (C5-C10)heteroaryl. More
preferably, R.sub.6 is H or methyl.
[0680] According to yet another preferred embodiment, W is
--C(O)--C(O)--N(R.sub.6).sub.2. Preferably, R.sub.6 is hydrogen,
(C3-C10)-cycloalkyl or -cycloalkenyl, or (C3-C10)-heterocyclyl.
[0681] In another preferred embodiment of compounds of formula (IV)
is where W is C(O)--C(O)--N(R.sub.6).sub.2, the NR.sub.6R.sub.6
portion of the W moiety is --NH--(C3-C6)cycloalkyl,
--NH--CH(CH.sub.3)--(C6-C10)aryl or
--NH--CH(CH.sub.3)--(C3-C10)heterocyclyl, or
--NH--CH(CH.sub.3)--(C5-C10)heteroaryl, wherein said aryl,
heterocyclyl, or heteroaryl is optionally substituted with
halogen.
[0682] Alternatively, the NR.sub.6R.sub.6 portion is
--NH--(C3-C6)cycloalkyl, --NH--CH(CH.sub.3)--(C6-C10)aryl, or
--NH--CH(CH.sub.3)--(C5-C10)heteroaryl, wherein said aryl or said
heterocyclyl is optionally substituted with halogen; or
NR.sub.6R.sub.6 is --NH--(C3-C6)cycloalkyl,
--NH--CH(CH.sub.3)--(C6-C10)aryl, or
--NH--CH(CH.sub.3)--(C3-C10)heterocyclyl, wherein said aryl or said
heterocyclyl is optionally substituted with halogen.
[0683] In other preferred embodiment of formula I, NR.sub.6R.sub.6
in W is:
##STR00080##
[0684] More preferably, NR.sub.6R.sub.6 is:
##STR00081##
[0685] Even more preferably, NR.sub.6R.sub.6 is:
##STR00082##
[0686] Most preferably, NR.sub.6R.sub.6 is:
##STR00083##
[0687] According to another preferred embodiment, when W is
--B(R.sup.7).sub.2, each R.sub.7 is selected from hydroxy, alkoxy,
or aryloxy.
[0688] According to yet another preferred embodiment, when W is
--B(R.sup.7).sub.2, each R.sub.7 is selected from an oxygen atom
linked to an aliphatic group and, together with the boron to which
they are each bound, the two R.sub.7 groups form a 5-8 membered
ring.
[0689] According to another preferred embodiment, V is a bond,
--CH(R.sub.8)--, --N(R.sub.8)--, --O--, --O--CH(R.sub.8), --S--,
--S--CH(R.sub.8), --C(O)--, --C(O)--O--, --C(O)--S--,
--C(O)--CHR.sub.8--, --C(O)N(R.sub.8)--, --S(O)--,
--S(O)--CH(R.sub.8)--, --S(O)N(R.sub.8)--, --S(O)--N(R.sub.8)--CHR,
--S(O).sub.2, --S--(O).sub.2--CH(R.sub.8)--,
--S(O).sub.2N(R.sub.8)--, or --S(O).sub.2--N(R.sub.8)--CHR.sub.8;
wherein R.sub.8 is hydrogen or --(C1-C3)alkyl;
[0690] According to another preferred embodiment, V is --NH--.
[0691] According to yet another preferred embodiment, V is
--C(O)--.
[0692] According to yet another preferred embodiment, V is
--C(O)--NR.sub.8--. More preferably, V is --C(O)--NH--.
[0693] According to yet another preferred embodiment T is a
heterocyclyl or heteroaryl, optionally having up to 3 substituents
as defined above.
[0694] According to yet another preferred embodiment, T is a
--(C5-C10)heteroaryl.
[0695] According to yet another preferred embodiment, T is selected
from 3-1H-benzimidazol-2-one, 3-(1-alkyl)-benzimidazol-2-one,
2-tetrahydrofuranyl, 3-tetrahydrofuranyl, pyrazolinyl,
1,3-dihydro-imidazol-2-one, 2-imidazolyl, 4-imidazolyl,
5-imidazolyl, 2-oxazolyl, 4-oxazolyl, 5-oxazolyl, 2-pyrrolyl,
3-pyrrolyl, 2-pyrimidinyl, 4-pyrimidinyl, 5-pyrimidinyl,
5-tetrazolyl, pyrazolyl, pyrazinyl or 1,3,5-triazinyl.
[0696] Even more preferably, T is selected from
3-1H-benzimidazol-2-one, 3-(1-alkyl)-benzimidazol-2-one,
pyrazolinyl, 1,3-dihydro-imidazol-2-one, 2-imidazolyl, 2-pyrrolyl,
2-pyrimidinyl, 5-pyrimidinyl, 5-tetrazolyl or pyrazinyl.
[0697] Most preferred is when T or R.sup.7 is selected from:
##STR00084##
[0698] Preferred substituents on T in the above embodiments are
halogen, --CF.sub.3, --OCF.sub.3, oxo, --COOR', or --CON(R').sub.2,
wherein R' is as defined above.
[0699] According to another preferred embodiment of this invention,
T contains at least one hydrogen bond donor moiety selected from
--NH.sub.2, --NH--, --OH, and --SH.
[0700] In a preferred embodiment, T is:
##STR00085## ##STR00086##
wherein:
[0701] T is optionally substituted with up to 3 J substituents,
wherein J is as defined in claim 1;
[0702] Y is independently O, S, NR.sub.10, or
C(R.sub.10).sub.2;
[0703] n is independently 1 or 2; and
[0704] is independently a single bond or a double bond.
[0705] In another preferred embodiment, T is:
##STR00087##
wherein Y is as defined above.
[0706] More preferably T is
##STR00088##
[0707] According to yet another preferred embodiment, T is:
[0708] (C6-C10)-aryl,
[0709] (C6-C10)-aryl-(C1-C12)aliphatic,
[0710] (C3-C10)-cycloalkyl or -cycloalkenyl,
[0711] [(C3-C10)-cycloalkyl or
-cycloalkenyl]-(C1-C12)-aliphatic,
[0712] (C3-C10)-heterocyclyl,
[0713] (C3-C10)-heterocyclyl-(C1-C12)-aliphatic,
[0714] (C5-C10)heteroaryl, or
[0715] (C5-C10)heteroaryl-(C1-C12)-aliphatic,
[0716] wherein each T is optionally substituted with up to 3 J
substituents.
[0717] According to yet another preferred embodiment of this
invention, T:
##STR00089##
wherein:
[0718] R.sub.10 is: [0719] hydrogen, [0720] (C1-C12)-aliphatic,
[0721] (C6-C10)-aryl, [0722] (C6-C10)-aryl-(C1-C12)aliphatic,
[0723] (C3-C10)-cycloalkyl or -cycloalkenyl, [0724]
[(C3-C10)-cycloalkyl or -cycloalkenyl]-(C1-C12)-aliphatic, [0725]
(C3-C10)-heterocyclyl, [0726]
(C3-C10)-heterocyclyl-(C1-C12)-aliphatic, [0727]
(C5-C10)heteroaryl, or [0728]
(C5-C10)heteroaryl-(C1-C12)-aliphatic,
[0729] wherein each T is optionally substituted with up to 3 J
substituents;
[0730] K is a bond, --O--, --S--, --NR.sub.9--, --C(O)--, or
--C(O)--NR.sub.9--,
[0731] wherein R.sub.9 is hydrogen or C1-C12 aliphatic; and [0732]
n is 1-3.
[0733] More preferably, T is:
##STR00090##
[0734] 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.
[0735] More preferably, the compounds of this invention have the
structure and stereochemistry depicted below in generalized formula
(V):
##STR00091##
wherein T, R, R.sub.3 and R.sub.6 represent the embodiments set
forth above and rings A, B, and C, if present, represent the
embodiments set forth for compounds of formulas (I), (II), (III),
and (IV).
[0736] Any of the preferred embodiments recited above may be
combined to produce a preferred embodiment of this invention.
[0737] The compounds of this invention may be synthesized by
standard chemical schemes well-known in the art. Schemes 1-22 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. A more specific
synthetic scheme for compound 1A within applicants' invention is
set forth in the examples.
Preparation of Compounds of Formula (I):
##STR00092##
[0738] Preparation of Compounds of Formula (I):
##STR00093##
##STR00094##
[0739] Preparation of Compounds of Formula (I):
##STR00095##
##STR00096##
[0740] Preparation of Compounds of Formula (I):
##STR00097##
##STR00098##
[0741] Preparation of Compounds of Formula (II):
##STR00099##
[0742] Preparation of Compounds of Formula (IV):
##STR00100##
[0743] Preparation of Compounds of Formula (IV):
##STR00101##
##STR00102##
[0744] Preparation of Compounds of Formula (IV):
##STR00103##
[0745] Preparation of Compounds of Formula (IV):
##STR00104##
[0746] Preparation of Compounds of Formula (IV):
##STR00105##
[0747] Preparation of Compounds of Formula (IV):
##STR00106## ##STR00107##
##STR00108##
##STR00109##
##STR00110##
[0748] Preparation of Compounds of Formula (IV):
##STR00111##
[0749] Preparation of Compounds of Formula (IV):
##STR00112##
[0750] Preparation of Compounds of Formula (III):
##STR00113##
##STR00114##
[0752] Compounds 1 to 26 and compound 1A in Schemes 1-15, 19-22
illustrate the multicyclic core of the peptidomimetic compounds of
the present invention. These cores are readily converted into the
compounds of the present invention by methods well known in the
art.
[0753] For example, compounds 1 to 8 in Schemes 1-7 illustrate the
core in compounds of formula (I). Compound 1, e.g., can be
converted into a compound of formula (I) using the methods of,
e.g., Schemes 16-18.
[0754] Compounds 9-12 in Scheme 8 illustrate the cores in compounds
of formula (II). Compounds 9 to 12 can be readily converted into
compounds of formula (II) using the methods of, e.g., Schemes
16-18.
[0755] Compounds 13 and 14 in Scheme 9 illustrate the cores in
compounds of formula (IV). Compounds 13 and 14 can be readily
converted into compounds of formula (IV) using the methods of,
e.g., Schemes 16-18.
[0756] Compound 26 in Scheme 21 illustrates the core in compounds
of formula (III). Compound 26 can be readily converted into a
compound of formula (III) using the methods of, e.g., Schemes
16-18.
[0757] One of skill in the art will readily appreciate that the
methods of Schemes 1-22 can be readily applied to any other ring or
ring system within the scope of the present invention. Thus,
Schemes 1-22 provide a facile synthetic route to the compounds of
the present invention.
[0758] As set forth above, the compounds of this invention are
capable of inhibiting the activity of HCV NS3-NS4A protease. In
order to quantitate the activity of the compounds of this
invention, cells containing HCV replicon were incubated with the
compounds of this invention, and a Taqman Real Time PCR assay was
conducted to determine the percentage inhibition of HCV RNA level
and the IC.sub.50 were calculated therefrom. The results are shown
below in Table 1:
TABLE-US-00002 TABLE 1 Cmpd. Ki IC.sub.50 No . Structure (nM) (nM)
1A ##STR00115## 39 202
[0759] Another embodiment of this invention provides a composition
comprising a compound of formula (I), formula (II), formula (III),
or formula (IV) or a pharmaceutically acceptable salt thereof 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.
[0760] 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.
[0761] 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.
[0762] 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.
[0763] 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.
[0764] According to a preferred embodiment, the compositions of
this invention are formulated for pharmaceutical administration to
a mammal, preferably a human being.
[0765] 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.
[0766] 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.
[0767] 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.
[0768] 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.
[0769] 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.
[0770] 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.
[0771] 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.
[0772] 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.
[0773] 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.
[0774] 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.
[0775] 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.
[0776] Most preferred are pharmaceutical compositions formulated
for oral administration.
[0777] In a related 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 and pegylated derivatized interferon-.alpha.
compounds; 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.
[0778] 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.
[0779] 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.
[0780] 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.
[0781] 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 and pegylated
derivatized interferon-.alpha. compounds; 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.
[0782] 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.
[0783] 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.
[0784] 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.
[0785] 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.
[0786] 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.
Example 1
3-(tert-Butyl-dimethyl-silanyloxymethyl)-5-oxo-4-aza-tricyclo[5.2.1.0.sup.-
2,6]dec-8-ene-4-carboxylic acid tert-butyl ester (28)
[0787]
2-(tert-Butyl-dimethyl-silanyloxymethyl)-5-oxo-2,5-dihydro-pyrrole--
1-carboxylic acid tert-butyl ester (27) (4 g; 12.2 mmol) and
freshly distilled cyclopentadiene (8 mL; 12 eq.) were heated in a
sealed tube in toluene for 6 h at 110.degree. C. Concentration and
purification by flash chromatography (10% EtOAc/90% hexanes)
afforded 3.23 g (67%) of the desired product 28. .sup.1H NMR
(CDCl.sub.3) 6.1 (bs, 1H), 6.0 (bs, 1H), 3.8 (dd, 1H), 3.6 (d, 1H),
3.5 (s, 1H), 3.3 (s, 1H), 3.1 (dd, 1H), 2.9 (s, 1H), 2.6 (bs, 1H),
1.6 (d, 2H), 1.5 (s, 9H), 1.3 (d, 1H), 0.9 (s, 9H), 0.15 (s, 3H),
0.1 (s, 3H) ppm.
Example 2
3-Hydroxymethyl-5-oxo-4-aza-tricyclo[5.2.1.0.sup.2,6]dec-8-ene-4-carboxyli-
c acid tert-butyl ester (29)
[0788] A solution of 28 (3.2 g; 8.1 mmol) in 60 mL of THF and
acetic acid (1.16 mL; 20.3 mmol) was treated with TBAF 1M in THF.
The reaction mixture was stirred for 16 h then was diluted with
CH.sub.2Cl.sub.2 (120 mL) and washed with water (75 mL). The
organic layer was dried with sodium sulfate and concentrated in
vacuo to a yellow oil. Flash chromatography (60% EtOAc/40% hexanes)
afforded 1.81 g (81%) of the desired product 29. .sup.1H NMR
(CDCl.sub.3) .delta. 6.2 (bs, 1H), 6.1 (bs, 1H), 3.8 (d, 1H), 3.6
(m, 2H), 3.3 (s, 1H), 3.15 (dd, 1H), 3.1 (s, 1H), 2.5 (dd, 1H), 1.5
(app. t, 3H), 1.35 (s, 9H) ppm.
Example 3
3-Hydroxymethyl-4-aza-tricycloc-4-carboxylic acid benzyl ester
(32)
[0789] To a solution of 29 (1.81 g, 6.5 mmol) in 50 mL of dry ethyl
acetate at 0.degree. C. was bubbled dry HCl gas for 5 minutes.
Stirring was continued while warming up to room temperature over a
period of 10 minutes. Concentration to dryness afforded a solid
residue that was subjected to lithium aluminium hydride reduction
(2.5 equivalents) in refluxing THF for 2 h. Fieser work up afforded
1.07 g of the reduced product 31 that was used directly for the
next step. A solution of 31 (1.07 g, 6.5 mmol) in 10 mL of dry THF
was added to a vigorously stirred solution of potassium carbonate
in 4 mL of water at -2.degree. C. to 0.degree. C. Cbz-Cl was added
dropwise maintaining the temperature around 0.degree. C. After the
addition was completed (10 minutes), the reaction was further
stirred for an additional 15 minutes at 0.degree. C. and poured
onto crushed ice and water (14 mL). Sodium chloride was added to
saturate the aqueous phase. The organic phase was separated and the
aqueous further extracted (3.times.50 mL) with ethyl acetate. The
combined organic phase was washed with 5% aqueous HCl, water and
brine, dried (Na.sub.2SO.sub.4) and concentrated in vacuo to give,
after flash chromatography (50% EtOAc/50% hexanes) 960 mg (50%) of
desired product 32. .sup.1H NMR (CDCl.sub.3) .delta. 7.3 (m, 5H),
6.2 (M, 2H), 5.1 (m, 2H), 3.8 (m, 2H), 3.4 (m, 2H), 3.0 (m, 3H),
2.5 (m, 2H), 1.3 (m, 2H) ppm.
Example 4
4-Aza-tricyclo[5.2.1.0.sup.2,6]dec-8-ene-3,4-dicarboxylic acid
4-benzyl ester 3-tert-butyl ester (34)
[0790] Compound 32 (410 mg, 1.37 mmol) was dissolved in 5 mL of
acetone and added dropwise to a stirred solution of Jones reagent
(1.1 mL) in 1 mL of acetone at 0.degree. C. The reaction mixture
was stirred at 5.degree. C. for 3 h and was concentrated in vacuo
to a dark residue. Residue was re-dissolved in ethyl acetate (50
mL) and washed (5.times.10 mL). The organic phase dried
(Na.sub.2SO.sub.4) and concentrated in vacuo to give 400 mg (93%)
of compound 33 that was used directly for the next step. To a
solution of 33 (400 mg, 1.28 mmol) in 10 mL of CH.sub.2Cl.sub.2
containing a catalytic amount of concentrated sulfuric acid at
-20.degree. C. was condensed 2 mL of isobutylene. The tube was
sealed and stirred at room temperature for 60 h. The excess
isobutylene was released and the CH.sub.2Cl.sub.2 removed in vacuo
to a residue that was subjected to after flash chromatography (20%
EtOAc/80% hexanes) which gave 378 mg (80%) of the desired ester 34.
.sup.1H NMR (CDCl.sub.3) .delta. 7.3 (m, 5H), 6.2 (m, 2H), 5.0 (m,
2H), 3.8 (m, 1H), 3.5 (m, 1H), 3.2 (m, 1H), 3.1 (m, 1H), 2.8 (m,
3H), 1.5 (m, 2H), 1.2 (m, 9H) ppm.
Example 5
4-(2-{2-Cyclohexyl-2-[(pyrazine-2-carbonyl)-amino]-acetylamino}-3,3-dimeth-
yl-butyryl)-4-aza-tricyclo[5.2.1.0.sup.2,6]dec-8-ene-3-carboxylic
acid tert-butyl ester (35)
[0791] Removal of the Cbz group of 34 (378 mg, 1.02 mmol) with
hydrogenation under 1 atm of hydrogen using Pd--C10% in ethanol
gave, after 5 h, the desired aminoester intermediate in
quantitative yield.
[0792] The crude compound was coupled to tert-butylglycine shown in
the next step. To a solution of Cbz-tert-butyl glycine (271 mg,
1.02 mmol) in 2 mL of CH.sub.2Cl.sub.2 at 0.degree. C. was added
EDC (235 mg, 1.23 mmol), HOBt (203 mg, 1.33 mmol) and DIEA (0.534
mL, 3.07 mmol). The resulting mixture was stirred at 0.degree. C.
for 15 min. after which, the above amino ester was slowly added in
2 mL of CH.sub.2Cl.sub.2. The resulting reaction mixture was
stirred at room temp. for 16 h. Concentration gave a residue that
was re-dissolved in EtOAc. Successive washes with 0.5N HCL,
saturated aqueous NaHCO.sub.3 and brine gave after drying
(Na.sub.2SO.sub.4) and concentration in vacuo the desired product.
Flash chromatography (20% EtOAc/80% hexanes) provided 480 mg (100%)
of pure dipeptide. The Cbz group of the dipeptide was removed as
described above and the resulting aminoester dipeptide was coupled
to Cbz-cyclohexyl glycine shown in the next step.
[0793] To a solution of Cbz-cyclohexyl glycine (289 mg, 1 mmol) in
2 mL of CH.sub.2Cl.sub.2 at 0.degree. C. was added EDC (228 mg,
1.19 mmol), HOBt (190 mg, 1.29 mmol) and DIEA (0.517 mL, 2.97
mmol). The resulting mixture was stirred at 0.degree. C. for 15
min. after which, the above amino ester was slowly added in 2 mL of
CH.sub.2Cl.sub.2. The resulting reaction mixture was stirred at
room temp. for 16 h. Concentration gave a residue that was
re-dissolved in EtOAc. Successive washes with 0.5N HCL, satd'
aqueous NaHCO.sub.3 and brine gave after drying (Na.sub.2SO.sub.4)
and concentration in vacuo the desired product which was subjected
to flash chromatography (20% EtOAc/80% hexanes) to provide 556 mg
(90%) of pure tripeptide. The Cbz group of the tripeptide was
removed as described above and the resulting aminoester tripeptide
was coupled to 1,4-pyrazine carboxylic acid shown in the next
step.
[0794] To a solution of 1,4-pyrazine carboxylic acid (110 mg, 0.891
mmol) in 2 mL of CH.sub.2Cl.sub.2 was added PyBrOP (457 mg, 0.98
mmol and DIEA (0.465 mL, 2.67 mmol). The resulting mixture was
stirred at room temp. for 15 min. after which, the above amino
ester was slowly added in 2 mL of CH.sub.2Cl.sub.2. The resulting
reaction mixture was stirred at room temp. for 16 h. Concentration
gave a residue that was re-dissolved in EtOAc. Successive washes
with 0.5N HCL, satd' aqueous NaHCO.sub.3 and brine gave after
drying (Na.sub.2SO.sub.4) and concentration in vacuo the desired
product which was subjected to flash chromatography (50% EtOAc/50%
hexanes) to provide 410 mg (79%) of pure capped tripeptide 35.
.sup.1H NMR (CDCl.sub.3) .delta. 9.3 (s, 1H), 8.8 (s, 1H), 8.5 (s,
1H), 8.3 (d, 1H), 6.7 (d, 1H), 4.9 (d, 1H), 4.7 (s, 1H), 4.5 (tr,
1H), 3.95 (d, 1H), 3.6 (app. dd, 1H), 2.6 (m, 2H), 2.3 (d, 2H),
1.75 (m, 5H), 1.5 to 0.9 (m, 12H), 1.4 (s, 9H), 1.0 (s, 9H)
ppm.
Example 6
4-(2-{2-Cyclohexyl-2-[(pyrazine-2-carbonyl)-amino]-acetylamino}-3,3-dimeth-
yl-butyryl)-4-aza-tricyclo[5.2.1.0.sup.2,6]dec-8-ene-3-carboxylic
acid (1-cycloproylaminooxalyl-butyl)-amide (1A)
[0795] The t-butyl ester group of the capped tripeptide 35 (410 mg,
0.688 mmol) was cleaved with a 1:1 mixture of TFA-CH.sub.2Cl.sub.2
at room temp. for 45 minutes and concentrated in vacuo. The
resulting aminoester dipeptide was coupled to hydroxyamide 36 shown
in the next step.
[0796] To a stirring solution of the capped tripeptide acid in 6 mL
of dry DMF at 0.degree. C. was added, PyBOP (376 mg, 0.722 mmol)
followed by NMM (0.226 mL, 2.06 mmol). The reaction mixture was
stirred for 1 h at room temp. after which a solution of 36 (168 mg,
0.758 mmol) and 0.226 mL of NMM was slowly added. The coupling
reaction was stirred for 16 hours, diluted with ethyl acetate and
was successively washed with; water (3.times.), citric acid 10%,
water and brine. The organic layer was dried (Na.sub.2SO.sub.4) and
concentrated in vacuo. Flash chromatography (2.5% MeOH/97.5% ethyl
acetate) provided 362 mg of hydroxy amide tetrapeptide that was
oxidized with Dess-Martin periodinane reagent (650 mg, 1.53 mmol)
and t-butanol (0.65 mL) in 5 mL of CH.sub.2Cl.sub.2 at room temp.
for 3 hours. The reaction mixture was quenched with sodium
thiosulfate 1M solution (2 mL) and stirred until the two phases
were clearly separated. The organic layer was diluted with 5 more
mL of CH.sub.2Cl.sub.2 and washed (3.times.) with 10% potassium
carbonate aqueous solution (5 mL), dried (Na.sub.2SO.sub.4) and
concentrated in vacuo. Flash chromatography (2.5% MeOH/97.5% ethyl
acetate) provided 270 mg of ketoamide tetrapeptide LA. LCMS
M+H=706.42, M-H=704.42. Retention Time (10-90% MeCN--H.sub.2O with
0.1% TFA over 6 minutes)=3.94 min.
Example 7
[0797] 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).
[0798] On day 1, replicon cell monolayer was treated with a
trypsin:EDTA mixture, removed, and then dilutedh media A into a
final concentration of 100,000 cells per ml wit. 10,000 cells in
100 ul are plated into each well of a 96-well tissue culture plate,
and culture overnight in a tissue culture incubator at 37.degree.
C.
[0799] 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.
[0800] The 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.
[0801] Cells were incubated with compound or 0.5% DMSO in media B
for 48 hours in a tissue culture incubator at 37.degree. C.
[0802] 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.
[0803] 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.
[0804] 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 were 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 that is 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.
[0805] The IC50 values inhibitory activity of some of the compounds
of the present invention is shown in Table 1 above.
Example 8
[0806] The Ki determinations were performed as follows. The Ki
values for some compounds of the present invention are recited
above in Table 1.
HPLC Microbore Method for Separation of 5AB Substrate and Products
Substrate
[0807] NH.sub.2-Glu-Asp-Val-Val-(alpha)Abu-Cys-Ser-Met-Ser-Tyr-COOH
Stock solution of 20 mM 5AB was made in DMSO w/0.2M DTT. This was
stored in aliquots at -20 C.
Buffer: 50 mM HEPES, pH 7.8; 20% glycerol; 100 mM NaCl Total assay
volume was 200 .mu.L
TABLE-US-00003 X1 Conc. in (.mu.L) assay Buffer 155 see above 5 mM
KK4A 1 25 .mu.M 1 M DTT 1 5 mM DMSO or inhibitor 3 1.5% v/v 0.25
.mu.M tNS3 20 25 nM 200 .mu.M 5AB 20 20 .mu.M (initiate)
[0808] The buffer was combined with KK4A, DTT, and tNS3; 177 .mu.L
of this solution was distributed each into wells of 96 well plate
and incubated at 30.degree. C. for .about.5-10 min. 3 .mu.L of
appropriate concentration of test compound dissolved in DMSO (DMSO
only for control) was added to each well and incubate at 30.degree.
C. for 15 min.
[0809] Reaction was initiated by addition of 20 .mu.L of 200 .mu.M
5AB substrate (20 .mu.M concentration is equivalent or slightly
lower than the Km for 5AB) and incubated for 20 min at 30.degree.
C. The reaction was terminated by addition of 50 .mu.L of 10% TFA
200 .mu.L aliquots were transferred to HPLC vials The SMSY product
was isolated from substrate and KK4A by the method which
follows.
Microbore Separation Method
Instrumentation:
Hewlett Packard 1100
Degasser G1322A
[0810] Binary pump G1312A
Autosampler G1313A
[0811] Column themostated chamber G1316A Diode array detector
G1315A Column: Phenomenex Jupiter; 5 micron C18; 300 angstroms;
150.times.2 mm; P/O 00F-4053-B0 Column thermostat: 40.degree. C.
Injection volume: 100 .mu.L Solvent A=HPLC grade water+0.1% TFA
Solvent B=HPLC grade acetonitrile+0.1% TFA
TABLE-US-00004 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
* * * * *